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6<7!*49>7!7Q*5AB7@N!59@6!<*>7!
*!;<%?*B!;7'67?!
*6!6<7
!!!;*?49'S!
,6!%@!R7BB!
V'9R'!6<*6!6<7!;9'C%(3?*6%9'!9C!
6<7!!!;*?49'!
<*@!*!4%(!%'CB37';7!9'
!6<7!4%9B9(%;*B!*;6%>%6#!
9C!!M*5%'9!A<9@A<9'%;!*;%8@!*'8!6<7%?!87?%>*6%>7@S!W9?!7Q*5AB7N!T
2XMA<9@A<9B73;%'7!
<X!oJgMJ`p%@!*!59?7!A967'6!%'<%4%69?
!9C!6<7!576*BB97'L#57!B73;%'7!*5%'9A7A6%8*@7!C?95!A9?;%'7!
V%8'7#
!;95A*?78!R%6<!%6@!T
,X!%@957?
N!*'8!T
,3(2
XM*B*A<9@A<*B%'!
<<oJiMJKp!<*@!<%(<7?!
*'6%4*;67?%*B!*;6%>%6#!6<*'!6<7!96<7?!6<?77!8%*@67?9%@957?@!TW%(3?7!JSgXS
!4EFC@G'<=N'!IE@HW'!-HSE>A'LIAJLIA>ED'HDEBJ'!+@!*!?7@3B6!9C
!6<7!>*?%76#!9C!4%9B9(%;*B!
*;6%>%6%7@
!*'8!;<75%;*B!*AAB%;*6%9'@!9C!;<%?*B!
!M*5%'9!A<9@A<9'%;!*;%8@!*'8!6<7%?!87?%>*6%>7@N!5*'#!*@#5576?%;!576<989B9(%7@
!C9?!
6<7%?!@#'6<7@%@
!<*>7!477'!87>7B9A78S!
0<7!<%@69?#!9C!;
*6*B#6%;!*@#5576?%;!
<#8?9
A<9@A<9'#B*6%9'!4#!;<%?*B!;*6*B#@6@N!7@A7;%*BB#!8%?7;6!h
M;95A9
'7'6!U*4*;<'%V
MW%7B8@!?7*;6%9'!R%BB!
47!87@;?%
478!%'!6<%@!;<*A67?S
!!PHNSNH3CFOOEt
OEt
7, Dufulin
ONPO3Ph2NH2H2N8, inhibitor of DPP 8
DPP: dipeptidyl peptidases
HNPOOOO2NONHONH2HOOC9, antibodies for coupling of amino acids
P(OH)
2H2NOMeMe10, (R)-Phospholeucine
H2NMeNP(OH)
2MeOHO11, (
S, R
)-Alaphosphalin
!g!<=M'!H?HWY?ED'"JYSSG?@ED'3YB@ALIAJLIA>YWH?EA>'AK'ESE>G'
'0<7!C%?@6!@#'6<7@%@!9C!9A6%;*B!A3?7!
!M*5%'9!A<9@A<9'%;!*;%8@
!C?95!%5%'7
@!TG389>%V!
?7*;6%9'X
!R*@!?7A9?678!4#!]%B59?7!*'8!:;"?%87!%'!JYiH
oJYpS!,'!6<7%?!
576<98N!8%76<#B!
A<9@A<%67!R*@!*8878!69!47'L#B!%5%'7!
<P!R<%;<
!R*@!87?%
>78!C?95!
6<7!7'*'6%957?%;*BB#!
A3?7!
!M576<#B47'L#B*5%'7!
<MS!-34@7D37'6!7@67?<#8?9B#@%@!R%6<
!<#8?9;<B9?%
;!*;%8!*'8!
6<7'!<#8?9(7'B9#@%@!A?9>%878
!6<7!A?983;6!
<Q!%'!3'@A7;%C%78!;<75%;*B!*'8!9A6%;*B!#%7B8@!
T-;<757!JSJXS
!(DIGSG'
<=<'4E@J?'HJYSSG?@ED'JY>?IGJEJ'AK'
!-HSE>A'LIAJLIA>ED'HDEBJZ<V['!-<%4*@*V%!*'8!<%@!(?93A!?7A9?678!6<7!C%?@6!7Q*5AB7!9C!*!;*6*B#6%;!*
@#5576?%;!
<#8?9A<9@
A<9'#B*6%9'!9C!*'
!%5%'7
!%'!JYYc
!4#!3@%'(
!*!B*'6<*'9%8MA96*@@%35
M",21P!
<767?94%576*BB%;!;95AB7Q!TPG"N!
MXXoHIpN!R<%;<!(%>7@!9A6%;*BB#!*;6%>7!
!M*5%'9!
A<9@A<9'*67@!%'!5987?*67!69!<%(<!7'*'6%957?%;!7Q;7@@S!+C67?!;B7*>*(7!9C!6<7!
8%*'%@#B576<#B!(?93A!9'!6<7!'%6?9(7'!*'8!<#8?9B#@%@!9C!6<7!8%576<#B!A<9@A<9'*67N!6<7!
7'*'6%957?%;*BB#!7'?%;<78!
!M*5%'9!A<9@A<9'%;!*;%8
!<V!;*'!47!
946*%'78!%'!YIZ!#%7B8
!T-;<757!JSHXS
!!!NH2PhPhCHO
NPhPhP(OEt)
2OH140¡CHNPhPO3Et2PhHClH2OHNPhPO3H2PhH2, Pd(OH)
2/CH2NPO3H2Ph1213141516!c!'(DIGSG
'<=M'4E@J?'DH?HWY?ED'HJYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'\E?I'ESE>GJ
ZMX['!1'7!#7*?!B*67?
N!6<7!-<%4*@*V%!(?93A
!A34B%@<78!*'96<7?!7Q*5AB7!9C!*@#5576?%;!
<#8?9A<9@A<9'#B*6%9'!9C!;#;B%;!%5%'7@!
R%6<!;<%?*B!
$667?4%35
!;*6*B#@6!T
MPXoHJpN!R<%;<!
87B%>7?78!6<7!g
M6<%*L9B%8%'#BA<9@A<9'*67@!
%'!3A!69
!YKZ!!!!T-;<757!JShXS!
0<7@7
!6R9!7Q;7A6%9'*B!A*A7?@!9A7'78!6<7!(*67!9C!;<%?*B!;*6*B#@6!;9'6?9BB78!7'*'6%9@7B7;6%>7!
<#8?9A<9@A<9'#B*6%9'!9C!%5%'7
@!C9?!6<7!A?7A*?*6%9'!9C!*!>*?%76#!9C!
!M*5%'9!A<9@A<9'*67@S!
!(DIGSG
'<=P'"JYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'AK'DYDWED'ESE>GJ
ZM<['!,'!HIIgN!\*;94@7'!*'8!<%@!(?93A!87>7B9A78!*!3'%D37!;<%?*B!6<%93?7*!;*6*B#@6!
TMTXoHHpN!R<%;<!;*'!;*6*B#L7!<#8?9A<9@A<9'#B*6%9'!9C!496<!*?95*6%;!*'8!*B%A<*6%;!%5%'7@!
R%6<!8%MTHM'%6?947'L#B
X!A<9@A<%67!%'!7Q;7BB7'6!#%7B8!*'8!
!!S!0<7!47'L#B!(?93A!9'!'%6?9(7'!
*'8!6<7!'%6?947'L#B!A<9@A<%67!;*'!47!7*@%B#!
?783;6%>7B#!;B7*>78
!3'87?!G8[b
H!69!(%>7
!6<7!7'*'6%957?%;!7'?%;<78!
!M*5%'9!A<9@A<9'%;!*;%8@!T-;<757!JSgXS
!HNDAMP(OMe)
2OH(R)-LPB, r.t
toluene/THF
HNP(OMe)
2ODAM1870%, 96% ee2. HCl, reflux
NH2P(OH)
2O171990%1. Pd(OH)
2, MeOH
LaOOOOOOKK20, (R)-LPB
OO=OOOMe
MeO
DAMNSMeMeMeMe(R)-YbPB (20 mol%)
toluene/THF, r.t
P(OMe)
2OHNHSMeMeMeMe(H3CO)2PHO2286%, 98%eeYbOOOOOOKK23, (R)-YbPB
OO=OO21!`!'(DIGSG
'<=N'"JYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'\E?I'H'DIE@HW'?IEAC@GH'DH?HWYJ?
ZMM['!+'96<7?!
;B*@@!9C!
'9>7B!;*6*B#
6%;!@#@675
@!87>7B9A78
!C9?!6<%@!?7*;6%9'!75AB9#
@!;<%?*B!
"?m'@678!*;%8@N!@3;<!*@!",21PN!-G,21P!*'8!96<7?!A<9@A<9'%;!*;%8@
oHhMHcpS!0<
7@7!
A<9@A<9'%;!*;%8@!
;*'
!(7'7?*BB#!@7?>7!*@!4%C3';6%9'*B!;*6*B#@6
@N!4#!*;6%>
*6%'(!6<7!%5%'7!
*'8!6<7!A<9@A<%67!4#!6<7%?!
"?m'@678!*;%8%;!*'8!P7R%@!4*@%;!@%67
@SoH`p!-;<757!JSc!@<9R@!
9'7!7Q*5AB7!4#!W3;<%47!*'8!<%@!(?93A
oHhpS!!(DIGSG'
<=O'"JYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'\E?I'H'DIE@HW'2@
]>J?GB'HDEB
ZMM[^'!P*67?!
%'!HIJJN!+'6%BB*!*'8!<%@!;9R9?V7?@!87>7B9A78!*!<%(<B#!7'*'6%9@7B7;6%>7!
*88%6%9'!9C!8%A<7'#BA<9@A<%'7!9Q%87!69!
-M@34@6%63678!%5%'7@!;*6*B#L78!4#!*!
;<%?*B!",21P!
5*('7@%35!A<9@A<*67!T
P<XoHipS!0<%@!R9?V!C3?6<7?!
@3AA9?6@!6<7!%87*
!6<*6!A<9@A<9'%;!*;%8!
;*'!*;6%>
*67!496<
!6<7!%5%'7!*'8!
*B@9!C*;%B%6*67!6<7
!'3;B79A<%B%;!*88%6%9'!9C!6<7!A<9@A<%'7
!T-;<757!JS`XS
!PhNHBnP(OR)
2OH10 mol% catalyst 27
Et2OPhNHBnP(OR)
2O2587%, 98%eeH2, Pd/C
MeOH
2687%PhNH2P(OH)
2ONHNOOtBuHOtBuNHSNOMeMetBu2724R= 2-nitrobenzyl
RNOMe
+POOiPrOiPrH10 mol% Chiral Br¿nsted acid 31
m-Xylene
RHNOMe
PO52-90% ee
R= aryl
OOPOOHCF3CF3CF3CF32928!i!(DIGSG
'<=Q'"JYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'\E?I'H'DIE@HW')HF>GJECS'
DH?HWYJ?
ZMT['!,'!HIIi!*'8!HIIKN!U*6@3V%
_@!*'8!$*5*5969_@!(?93A
@!@34@7D37'6B#!A34B%@<78!6R9!
8%CC7?7'6!576<98@
!*4936!3@%'(!;<%?*B!*B35%'35!;*6*B#@6@!
PMoHKp!*'8!PPoHYp!C9?!6<7!
<#8?9A<9@A<9'#B*6%9'!9C!*B8%5%'7@!%'!(998!#%7B8!*'8!
!!N!?7@A7;6%>7B#!T
-;<757
JSiXS!,'!6<7!
57;<*'%@6%;
!%'>7@6%(*6%9'!
%'!U*6@3V%_@!A*A7?
oHKpN!%6!
%@!?7>7*B78!6<*6
!6<7!'%6?9(7'!9C!6<7!%5%'7!
%@!493'8!69!6<7!
*B35%'35
!*'8!6<7!
-M576<#B!(?93A!9'!6<7!?7@3B6%'(!;<%?*B!'%6?9(7'!*695!%@!
)*&
!69!6<7!;<B9?9!B%(*'8
!T+B!;95AB7Q!
PPXN!R<%;<!A?9>%87@!*!3'%D37!*@#5576?%;!?7*;6%9'!@%67S!
,6!@<93B8!47!'9678
!6<*6!U*6@3V%_@!?7*;6%9'!;*'!47!;*??%78!936!%'!
*!9'7!A96!>7?@%9'S!^%6<!6<7!
*88%6%9'!9C!*5%'7@!*'8!*B87<#87@!R%6<!59B7;3B*?!@%7>7@!%'!0bW!C9?!@6%??%'(!h
Mg!<93?@N!
8%576<#B!A<9@A<%67!*'8!6<7!;*6*B#@6!
PM!R*@!*8878!69!6<7!?7*;6%9'S!0<7!5%Q63?7!R*@!
?7*;6
78!*6!MJcqE!C9?!Hg!<93?@!69!C3?'%@<!6<7!87@%?78!
!M*5%'9!A<9@A<9'*67@S
!'''RNRÕ+Ph2PH10 mol% Mg catalyst 35
RHNRÕPPh2OR= aryl, alkyl
RÕ=PhPhorOOPOOMgRÕÕ
RÕÕ
31RÕÕ= 9-anthryl
Mg catalyst
nCH3CN, r.t
48-99% ee
30O!K!(DIGSG
'<=T'3YB@ALIAJLIA>YWH?EA>'AK'HWBESE>GJ'_Y'DIE@HW'HWCSE>CS'DH?HWYJ?J
ZMU^'MV['!0<7!B*@6!7Q*5AB7
!%@!6<7!;*6*B#6%;!*@#5576?%;!;9'@6?3;6%9'!9C!*!676?*@34@6%63678!
@67?79
(7'%;!;7'67?!%'!
*'!!M*5%'9!A<9@A<9'*67@!@#'6<7@%@!?7A9?678!4#!-<%4*@*V%!*'8!<%@!
(?93A
ohIpS!,'!HIJhN!6<7#!75AB9#78
!-M6<%9A<9@A<%
'9#B!V76%5%'7@!
PN!*@!@3%6*4B7!@9C6!P7R%@!
4*@%;!7B7;6?9A<%B7!*'8!@7;9'8*?#!A<9@A<%67@!*@!'3;B79A<%B7N!
A?9>%8%'(!
676?*@34@6%63678!r
M*5%'9!A<9@A<9'*67@
!PQ!*@!A?983;6@
S!0<%@!A?9;7@@!%'>9B>7@!6<7!*;6%9'!9C!*!
@9C6!P7R%@!
*;%8[<*?8!"?m'@678!4*@7!;99A7?*6%>7!;*6*B#
@6!;9'@%@6%'(!9C!;9AA7?!*'8!6?%76<#B*5%'7
S!0<7!@34@7D37'6
!?759>*B!9C!
6<7!6<%9A<9@A<%'9#B!(?93A!;*'!47!7*@%B#!;*??%78!
936!R%6<!A7?;<B9?%;!
*;%8!T-;<757!JS
KXS!NOAlONCltButBuAl complex 32RNHPOPhPh+HP(OCH
2CF3)2OAl complex 32 (1 mol%)
hexanes, 1hRNHPPOPhPhO(OCH
2CF3)2up to 98%, 96% 
eeR = aryl
NNOOAlCltButButButBuAl complex 33RNHAr+HPOOMe
OMe
Al complex 33 (10 mol%)
THF, -15¡C, 24h
R*NHPOOMe
OMe
Ar=OMe
orPhPhR = aryl or alkyl
up to 99%, 95% 
eeAr!Y!(DIGSG
'<=U'"JYSSG?@ED'IYB@ALIAJLIA>YWH?EA>'\E?I'`G?ESE>GJ
ZPX['!<=P'5E@GD?'#I@GG
-!ASLA>G>?'!H?HWY?ED'"JYSSG?@ED'3YB@ALIAJLIA>YWH?EA>'
a1H_HDI>E`
-4EGWBJ'+GHD?EA>b
'0<7!U*4*;<'%V
MW%7B8@!
?7*;6%9'!R*@!8%@;9>7?78!%'!JYcH!4#!U*4*;<'%V!*'8!W%7B8@
ohJpS!,6!%@!*!6<?77
M;95A9'7'6!?7*;6%9'!
(7'7?*6%'(
!!M*5%'9!A<9@A<9'*67@!C?95!*!*5%'7N!*'!
*B87<#87!*'8!*!A<9@A<9'*67S!
b9R7>7?N!%6!R*@'_6!3'6%B!HIIY
!6<*6!P%@6!*'8!<%@!;9R9?V7?@!
?7A9?678!%6@!C%?@6!*@#5576?%;!>7?@%9'
ohHp!S!"#!75AB9#%'(!?*;75%;!
!M4?*';<78!*B87<#87@N!
%M*'%@%8%'7
!*'8!8%*BV#B!A<9@A<9'*67@!%'!6<7!A?7@7';7!9C!*!'7R!;<%?*B!A<9@A<9?%;!*;%8!
;*6*B#@6!TEG+N!
NPXN!6<7!?7*;6%9'!A?983;7@!
&M4?*';<78!
!M*5%'9!A<9@A<9'*67@!R%6<!<%(<!
8%*@67?79@7B7;6%>%6#!*'8!7'*'6%9@7B7;6%>%6#!4#!*!8#'*5%;!V%'76%;!?7@9B36%9'S!/759>*B!9C!6<7!
G:G!(?
93A!R%6<!E+2!C9BB9R78!4#!<#8?9B#@%@!9C!!
6<7!7@67?!69!
6<7!*;%8!4#!0:-"?N!A?983;78!
6<7!;9??7@A9'8%'(!
!M*5%'9!A<9@A<9'%;!*;%8!R%6<!6<7!?76
7'6%9'!9C!7'*'6%9@7B7;6%>%6#
S!b9R7>7?N!6<%@!?7*;6%9'!R*@!B%5%678!69!
!M@34@6%63678!A<7'#B!*;76*B87<#87@
!T-;<757JS
YXS!PhNPPh2S+P(OEt)
2OH0.5 mol% [Cu(CH
3CN)4]PF610.5 mol% (R, R)-Ph-BPE
25 mol% Et
3NTHF, r.t,72h
PhHNPPh2SP(OEt)
2O3690%, 96%ee60% HClO4 aq.EtOH, 80¡C
PhNH2P(OH)
2O3782%PPPhPhPhPh(R, R)-Ph-BPE
3435!JI!(DIGSG
'<=V'4E@J?'HJYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>
ZPM['!,'!HIIYN!W7'(!*'8!<%@!(?93A!87>7B9A78!
*!@7;9'8
!'9>7B!;*6*B#@6!T
NQXohhpN!R<%;<!%@!*!
;<%?*B!@;*'8%35T,,,X
M!-N!-_M8%9Q%87!;95AB7QS!
^%6<!*
!JI!59BZ!B9*8%'(!9C!@;*'8%35!;95AB7Q!
NQN!6<7
!6<?77
M;95A9'7'6!?7*;6%9'
!?7*;6%9'
!R%6<!*?95*6%;!*B87<#87@N!H
M*5%'9
A<7'9B!*'8!
8%A<7'#B!A<9@A<%67!
(%>7@!6<7
!87@%?78!
!M*5'%9!A<9@A<9'*67!A?983;6!%'!(998!#%7B8!*'8!
<%(<!7'*'6%9@7B7;6%>%6#!T3A!69!KiZ!
!!X!T-;<757!JSJI
XS!
)3?%'(!
6<7!9A6%5%L
*6%9'!A?9;7@@N!
5*'#
!B*'6<*'%87@!R7?7!*
B@9
!*6675A678!%'!6<7!?7*;6%9'!;9'8%6%9'!
R<%;<!<*>7!
@%5%B*?
!P7R%@!
*;%8%6#N!53B6%C3';6%9'*B%6#!*'8!;99?8%'*6%9'!
;*A*4%B%6#
!*@!@;*'8%35N!<9R7>7?N!'9'7!
(*>7!
47667?!?7@3B6
@S!"*@78!9'!6<7!
!A?9;783?7!%'!6<7%?!@3AA9?6%'(!%'C9?5*6%9'N!%6!%@!
'96!*!53B6%
M;95A9'7'6!
!?7*;6%9'!
@%';7!6<7!*B87<#87N!*5%'7!*'8!;*6*B#@6!*?7!@6%??78
!C9?!*'!<93?!%'!0bW!
*6!?995!675A7?*63?7!C9BB9R78!4#!6<7!*88%6%9'!9C!
6<7!8%A<7'#B!A<9@A<%67@!!*6!
MHIqES!PhHO+MeO
NH2POOOMeMeMeMeNHPMB
PhPOHOOMeMeMeMeOOPOOHiPriPr9-Anth
iPriPr9-Anth
10 mol% CPA 47
cyclohexane, 50 ¡C4186%, 16:1 dr, 92% ee
+1. CAN, CH3CN/H2O2. TMSBr, CH
2Cl2POOHOHNH2Ph4254%38394043!JJ!(DIGSG
'<=<X'"JYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>'\E?I'H'JDH>BECS'DH?HWYJ?
ZPP['!+'96<7?!?7B*678!7Q*5AB7!%@!C?95!:*!*'8!<%@!;9R9?V7?@
ohgpS!,'!HIJIN!6<7#!87@;?%478!
*!8%?7;6!9?(*'9;*6*B#6%;!6<?77
M;95A9
'7'6!<#8?9A<@9A<9'#B*6%9'!R%6<!
;<%?*B!A<9@A<9'%;!
*;%8!
OP!*@!6<7!;*6*B#@6S!0<7!7'*'6%9@7B7;6%>%6#!9C!6<%@!?7*;6%9'!%@!5987?*67!69!(998!ThH
MKiZ!!!X!*'8!6<7!?7*;6%9'!6%57!%@!J`K!<93?@!
9'!*>7?*(7S!+BB!6<7!*B87<#87!@34@6?*67@!R7?7!
B%5%678!69!*?95*6%;!
*B87<#87@S!,6!%@!R9?6<!57'6%9'%'(!6<*6!6<7#!7Q67'878
!6<7!?7*;6%9'
!69!6<7!T
2X!*'8!T
,XMJNJ_M4%'*A<6<#B
MhMC9?5*B87<#87@!T
NT!*'8!NUX!69!%BB3@6?*67!*AAB%;*6%9'!9C!
6<%@!576<989B9(#S!0<7!?7@3B6!@<9R@!6<*6!6<7!T
2XM4%'*A<6<#B!*B87<#87!
NT!(*>7!<%(<7?!
@67?79@7B7;6%>%6#!T8?k!Yg[`X
!6<*'!6<7!T,XM7'*'6%957?!T8?k!KI[HIX!
T-;<757!JSJJ
XS!(DIGSG
'<=<<'"JYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>'\E?I'_E>HLI?IYW'HWBGIYBGJ
ZPN['!RHO+OHNH2+POHOPh
OPh
10 mol% N, NÕ-Dioxide-Sc(III)
THF, -20¡C, <1h
HNHORP(OPh)
2OR= aryl
84-87% ee
NNNOHNHOOOArArAr= 2,6-
iPr2C6H3N, NÕ-Dioxide-Sc(III) complex 46
4445CHOOMe
OMe
47, (Rax)48, (Sax)+NH2MeO
+POOiPrOiPrH10 mol% 534† MS, toluene, 40¡C
OMe
OMe
PNHOOiPrOiPrMeO
51, (Rax, S): 94/6 dr, 91% 
52, (Sax, S): 80/20 dr, 85%
CF3CF3CF3CF3OOPOOH534950!JH!:9?7!?7;7'6B#N!-<%4*6*!*'8!<%@!(?93A!8%@;9>7?78!6<7!
;954%'*6%9'
!9C!;*6*B#6%;!
*593'6@!9C!d'T20C
HXH!*'8!JNhM4%@T%5%8*L9B%'
MHMB#X!A#?%8%'7!TA#4%5X!T
OOX!*@!*!
45M@#5576?%;!
B%(*'8ohcpN!A?983;78!*!@A7;%7@!6<*6!
;*'!;*6*B#L7!8%?7;6!U*4*;<'%V
MW%7B8@!?7*;6%9'!R%6<!
*B87<#87@N!
%M*'%@%8%'7@!
ON!*'8!8%*?#B!A<9@A<%67@!%'!(998!#%7B8@!*'8!7'*'6%9@7B7;6%>%6#!
T-;<757!JSJ
HXS!
,6!%@!69!47!'9678!6<*6
!6R9!*B%A<*6%;!*B87<#87@!T;#;B9<7Q#B!*'8!%@9436#B!
;*?49Q#B%;!*B87<#87X!R7?7!*B@9!7Q*5%'78!3'87?!6<7!@6*'8*?8!;9'8%6%9'
@S!+B6<93(<!6<7!
7'*'6%9@7B7;6%>%6#!%@!9'
B#!`JZ!*'8!hJZ!
!!N!?7@A7;6%>7B#N!
%6!%@!6<7!C%?@6!6%57!6<*6!*B%A<*6%;!
*B87<#87!@34@6?*67@!R7?7!*AAB%78!%'!
6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!69!A?9>%87!
@%5AB7!
!M*5%'9!A<9@A<9'*67@S
!(DIGSG
'<=<M'"JYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>'\E?I'H'LY_ES'WEFH>B
ZPO['!<=N'(CSSH@Y
','!6<%@!;<*A67?N!
*'!9>7?>%7R!9C!6<7!6R9!;95A9'7'6!;*6*B#6%;!*@#5576?%;!@#'6<7@%@!
9C!!M*5%'9!A<9@A<9'%;!*;%8@!C?95!%5%'7@!*'8!
A<9@A<%67@!TG389>%V!?7*;6%9'X!*'8!6<7!
6<?77
M;95A9'7'6!@#'6<7@%@!C?95!*5%'7@N!*B87<#87@!*'8!A<9@A<%67@!TU*4*;<'%V
MW%7B8@!
?7*;6%9'X!R7?7!87@;?%478S!
E95A*?78!R%6<!6<7!6R9
M;95A9'7'6!?7*;6%9'N!6<7!@6?*67(#!9C!
6<7!53B6%;95A9'7'6!@#'6<7@%@!%@!59?7!*66?*;6%>7S!
0<7#!<*>7!<%(<7?
!B7>7B@!9C!*695!7CC%;%7';#!
*'8!6<7!@%5AB%;%6#!9C!6<7!?7*;6%9'!A?9;783?7!9C!6<7
!R9?V
M3A!5*V7!6<7!?7*;6%9'!
7'>%?9'57'6*BB#!C?%7'8B#!*'8!59?7!7;9'95%;
*BS!b9R7>7?N!
69!6<7!47@6!9C!93?!V'9RB78(7N!
6<7?7!*?7
!9'B#!6<?77!?7A9?6@!9'!6<7!8%?7;6!6<?77
M;95A
9'7'6!7'*'6%9@7B7;6%>7!?7*;6%9'!
*'8!RHO+10 mol% Zn(NTf
2)210 mol% Ligand 55CH2Cl2, - 50 ¡C
31-93% ee
OMe
NH2POHOArOAr+POOArOArNHPMB
RNNNNNOMeMeOMeMePhPhPhPhLigand 55R= aryl, alkyl
Ar= 
o-CH
3OC6H454!Jh!6<7@7!R7?7!87@;?%478!*49>7
S!,'!*88%6%9'N!
6<7%?!@34@6?*67!@;9A7!%@!>7?#!B
%5%678
S!P%@6_@!R9?V!
C9;3@7@
!9'!!M4?*';<78!
*?#B*;76
*B87<#87
@!*'8!6<7!?7*;6%9'!%6@7BC!%@!*!8#'*5%;!V%'76%;!
?7@9B36%9'S!0<7!96<7?!6R9!
576<98@
!6*?(76
!59@6B#!*?95*6%;!*B87<#87@!*'8!6<7!<%(<7@6!
7'*'6%9@7B7;6%>%6#!
?7A9?678!
6<7!*B%A<*6%;!*B87<#87!%@!9'B#!`JZ!
!!S!:9?79>7?
N!6<7!?7*;6%9'!
675A7?*63?7!C9?!-<%4*6*_@!?7*;6%9'!%@!
McIqES!0<7?7C9?7N!7QA
*'8%'(!6<7!?7*;6%9'!@34@6?*67!
@;9A7N!7@A7;%*BB#!C9?!6<7!*B%A<*6%
;!*B87<#87@!*'8!@77V%'(!53;<!5%B87?!;9'8%6%9'@!
C9?!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!%@!<%(<B#!87@%?*4B7!*'8!'7;7@@*?#S
!!!!!!!'''''           !Jg!!3"/#*+'#:.
''!"#"$%#&!'"(%))*#+&!'1"2"!30&1
-4&*$5('+*"!#&.0':&#3'
"+.)"#&!'"$5*3%5*(
'M=<'&>?@ABCD?EA>
'+@!936B%'78!%'!6<7!B*@6!;<*A67?!6<7?7!
*?7
!9'B#!C93?!A*A7?@!TP%@6_@N!:*N!W7'(!*'8!
-<%4*6*_@!(?93AX
ohHN!
hgMhcp!!<*>7!*AA7*?78!%'!6<7!A*@6!87;*87!87@;?%4%'(!*!;*6*B#6%;!
*@#5576?%;!>7?@%9'!9C!6<7!U*4*;<'%V
MW%7B8@!?7*;6%9'S!,'!*88%6%9'N!%'!W7'(
_@!R9?V
ohhpN!%6!%@!
?7D3%?78!6<*6!6<7!%5%'7@!47!A
?7MC9?578!C?95!*B87<#87@!*'8!*5%'7@N!C9BB9R78!4#!*88%6%9'!
9C!8%A<7'#B!A<9@A<%67@S!:9?79>7?N!59@6!9C!6<7@7!@638%7@!*?7!C9;3@78!9'!*?95*6%;!
*B87<#87@!9?!96<7?!B%5%678!@34@6?*67@N!@3;<!*@!
!M4?*';<78!*?#B*;76*B87<#87@N!*'8!
?7*;6%9'@!@9576%57@!?7D3%?7!<*?@<!?7*
;6%9'!;9'8%6%9'@S!,'!P%@6_@!576<98N!6<7!?7*;6%9'!6%57!
%@!J`K!<93?@S!0<7?7C9?7N!@77V%'(!*'96<7?!59?7!7CC7;6%>7!576<98!C9?!6<7!8%?7;6!*@#5576?%;!
;*6*B#6%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!
R<%;<
!<*@!R%87!?*'(7!9C!*?95*6%;!*'8!*B%A<*6%;!
*B87<#87@!%@!<%(<B#!87@%?*4B7S
!!,'!HIIJN!*!A?7>%93@!!57547?!e37!-9'(!9C!93?!(?93A!A34B%@<78!*!:3V*%#*5*!6#A7!
;9'87'@*6%9'!9C!V767'7!*;76*B@!R%6<!%5%'7@!4#!75AB9#%'(!*!O+G1P
ML%?;9'%35!;*6*B#@6!
TOUX!R%6<!<%(<!*@#5576?%;!%'83;6%9'!T-;<757!HSJX
oh`pS!!(DIGSG
'M=<'&SE>A'HWBAW'@GHD?EA>'_Y'6"/.$
-cE@DA>ECS'DH?HWYJ?
'!OHNPh+OTMS
OMe
20 mol% Zr-(
S)-VAPOL catalyst 58
24% mol NMI, toluene
25¡COMe
PhNHOOH59100%, 98%ee5657PhPhOHOH(S)-VAPOL
!Jc!W9BB9R%'(!U94*#*@<%_@
ohip!",21P
ML%?;9'%35!;95AB7Q!(7'7?*6%9'!A?969;9BN!e37_@!
;*6*B#
@6!%@!*@@754B78!4#!*88%'(!O+G1PN!L%?;9'%35!676?**BV9Q%87!*'8!
-M576<#B!%5%8*L9B7!
%'!HkJkJSH!?*6%9!%'!69B37'7!@6%??%'(!C9?!J!<93?!*6!?995!675A7?*63?7S!,6!%@!6<93(<6!6<*6!6<%@!
?7*;6%9'!%'>9B>7@!*!;*6*B#@6!@34@6?*67!;95AB7Q!
QX!47*?%'(!6R9!O+G1P!B%(*'8@!*'8!*!
"M<#8?9Q#A<7'#B%5%'7!*@!*'96<7?!4%87'6*67!B%(*'8!9'!6<7!L%?;9'%35!TW%(3?7!HSJXS!0<%@!V7#!
%'67?578%*67!6<7'!%@!6<93(<6!69!?7*;6!R%6<!V767'7!*;76*B@!69!87B%>7?!6<7!C%'*B!
&M*5%'9!7@67?@!
*@!A?983;6@S
(4EFC@G'M=<'7E@DA>ECS'DH?HWYJ?'\E?I'?\A'6"/.$'H>B'H'
"-IYB@AdYLIG>YWESE>G'!0<%?677'!#7*?@!B*67?N!%'!HIJgN!*'96<7?!'9>7B!L%?;9'%35!;*6*B#@6!AB*6C9?5!R*@!
87>7B9A78!4#!*'96<7?!(?93A!57547?!e%'!
d<*'(ohKpS0<7!;*6*B#@6!%@!A?7A*?78!C?95!JSI
!7D3%>*B7'6!9C!L%?;9'%35!676?*%@9A?9A9Q%87N!H
SI!7D3%>*B7'6@!9C!T
,XMO+21P!%'!6<7!A?7@7';7!
9C!J
SI!7D3%>*B7'6!9C!
-M576<#B!%5%8
*L9B7!*@!4*@7!*6!`IqE!C9?
!J!<93?S!0
<%@!;*6*B#@6!R*@!
C93'8!69!47!<%(<B#!7CC7;6%>7!69R*?8@!
!M%5%'9B!?7*??*'(757'6S!^%6<!HSc!59BZ!;*6*B#@6!
B9*8%'(N!6<7!@6*?6%'(!
!M<#8?9Q#B!%5%'7@!C3?'%@<78!6<7!;9??7@A9'8%'(!
!M*5%'9!V769'7!R%6<!
D3*'6%6*6%>7!
#%7B8@!*'8!9>7?!YY
Z!!!!T-;<757!HSHXS!!W?95!6<7!;?#@6*B
!@6?3;63?7!9C!6<7!
;*6*B#@6N!%6!%@!?7>7*B78!6<*6!6<7!L%?;9'%35!7Q%@6@!*@!*!@%Q
M;99?8%'*67!<959B7A6%;!;95AB7Q!
R%6<!6<?77!O+21P!B%(*'8@!*'8!%@!;<*?(7!4*B*';78!R%6<!6R9!A?969'*678!
-M576<#B!
ZrNMI
ONPhOOOO60!J`!%5%8*L9B7@!TW%(3?7!HSHXS!:*'#!?*?7!7*?6<!576*B@!<*>7!477'!?7A9?678!69!4
7!49'878!R%6<!
6<?77!",21P!B%(*'8@!%'!6<7!A*@6
ohYMgJpN!436!'96!R%6<!L%?;9'%35S!,6!%@!6<7!C%?@6!6%57!6<*6!
L%?;9'%35!<*@!477'!C93'8!69!7Q%@6!*@!*!<959B7A6%;!;95AB7Q!R%6<!6<?77!4%@
MA<7'9B!B%(*'8@S!
!(DIGSG
'M=M'!-&SE>AW'@GH@@H>FGSG>?'\E?I'>G\'DIE@HW'cE@DA>ECS'DH?HWYJ?
''4EFC@G'M=M'!@YJ?HW'J?@CD?C@G'AK'?IG'cE@DA>ECS'DASLWGd
' ''!!!!!!!!!-%';7!*49>7!O+G1P!*'8!O+21P!87?%>78!L%?;9'%35!;95AB7Q7@!496<!*?7!>7?#!
7CC7;6%>7!69R*?8@!*@#5576?%;!;*6*B#6%;!?7*;6%9'@!9C!%5%'7@N!%6!R*@!;9'@%87?78!6<*6!A7?<*A@!
NHOHRR2.5 mol% Zr complex with (
R)-VANOL 61
Toluene, 60 ¡C, 1h
NHRORR = Aryl and Alkyl
up to 100% yield, 99% ee
(R)-VANOL
OHOHPhPhPhPhPhPhPhPhZrOOOOOOOHHNNMeHNHOHHNMe61!Ji!6<7#!;93B8!47!*AAB%78!69!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!69!(7'7?*67!
!M*5%'9!
A<9@A<9'*67@!R%6<!<%(<!7'*'6%9@7B7;6%>%6#S!0<79?76%;*BB#N!4*@78!9'!6<7!57;<*'%@5!9C!6<7!
U*4*;<'%V
MW%7B8@!?7*;6%9'!R%6<!*'%B%'7
ogHpN!%5%'7!C9?5*6%9'!;93B8!47!C9BB9R78!4#!6R9!
8%CC7?7'6!A*6<R*#@!%'!?7*;6%9'!R%6<!A<9@A<%67S!,'!;9'@%87?%'(!6<7!6R9!6*36957?@!9C!
A<9@A<%67@N!6<7!?7*;6%9'!;93B8!7%6<7?!(9!6<
?93(<!*!C93?!9?!C%>7
M57547?78!?%'(!6?*'@%6%9'!
@6*67!
T-;<757!HSh
XS!+@!6<7!;<%?*B!49?9Q!*'8!L%?;9'%35!;95AB7Q7@!R7?7!A?9>78!69!47!>7?#!
7CC7;6%>7!69R*?8!?7*;6%9'@!6<*6!%'>9B>%'(!%5%'7!%'67?578%*67@N!%6!5%(<6!*!(998!9AA9?63'%6#!
69!7Q*5!6<7@7!;*6*B#6%;!@#@675@!
%'!U*4*;<'%V
MW%7B8@!?7*;6%9'!%'!%6@!*@#5576?%;!>7?@%9'!9C!
496<!*?95*6%;!*'8!*B%A<*6%;!@34@6?*67@S
!(DIGSG
'M=P'#\A'LAJJE_WG'@GHD?EA>'LH?I\HYJ
'!M=M'&>E?EHW'@GJCW?J
'M=M=<'4E@J?'KAC@'?@EHWJ
'0<7!C%?@6!6?%*B!R*@!89'7!4#!3@%'(!JSI!7D3%>*B7'6!9C!47'L*B87<#87!
QPHN!JSI!
7D3%>*B7'6!9C!
"M<#8?9Q#B!*'%B%'7!
QNH!*'8!JSI!7D3%>*B7'6!9C!8%76<#B!A<9@A<%67!
QOH!*@!6<7!
6<?77!@6*?6%'(!5*67?%*B@!R%6<!c!59BZ!9C!6<7!L%?;9'%35!;95AB7QS!0<7!L%?;9'%35!;95AB7Q!
R*@!A?7A*
?78!C9BB9R%'(!e%'_@!A?969;9B!R%6<!JSI!7D3%>*B7'6!9C!6<7!L%?;9'%35!
676?*%@9A?9A#B9Q%87N!HSI!7D3%>*B7'6@!9C!6<7!T
,XMO+21P!*'8!JI!7D3%>*B7'6@!9C!6<7!
-M576<#B!
%5%8*L9B7!T2:,XN!R<%;<!R7?7!@6%??78!*6!?995!675A7?*63?7!C9?!J!<93?!%'!69B37'7S!+C67?!6<7!
OR2R1NR2R1R3-H2OOPHOR4OR4OHPOR4OR4NPHR1R3R2OR4OR4ONHR3PR1R2OOR4OR4NR1R2R3R4OPOHOR4!-aminophosphonate
imineR3NH2!JK!?7*;6%9'!
@6%
??78!9>7?
'%(<6!*6!?995!675A7?*63?7N!6<7!87@%?78!
!M*5%'9!A<9@A<9'*67!
QQH!R*@!946*%'78!%'!JYSiZ!#%7B8!*'8!hcZ!
!!S!,'!*!@7;9'8!?3'!*6!cIqEN!6<7!#%7B8!8?9AA78!69!
JJScZ!T-;<757!HS
gXS!
,'%6%*BB#!6<7
!*4@9B367!;9'C%(3?*6%9'!9C!6<7!A?983;6!
T,XMQQH!R*@!
*@@%('78!4#!;95A*?%'(!6<7!bGPE!?767'6%9'!6%57!9C!6<7!
!M*5%'9
M8%*@9A?9A#B!A<9@A<9'*67@N!
R<%;<!%@!;B9@7B#!?7B*678
oHhpS0<%@!*@@%('57'6!R*@!3B6%5*67B#!;9'C%?578!4#!;<75%;*B!
;9??7B*6%9'!R%6<!*!V'9R'!;95A93'8!T@77!;<*A67?!h
SiXS!+BB!?7B*678!@6?3;63?7@!C?95
!*?95*6%;!
*'8!*B%A<*6%;!*B87<#87!R7?7!*@@357!69!47!<959!;<%?*BS
!(DIGSG
'M=N'&>E?EHW'?\A'?@EHWJ'A>'?IG'HJYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>
' !W9?!6<7!;9'6?9B!7QA7?%57'6N!6<7!%5%'7!T
QTHeX!R*@!(7'7?*678!C?95!6<7!47'L*B87<#87!
*'8!"M<#8?9Q#B!*'%B%'7!*'8!R*@!@345%6678!69!6<7!?7*;6%9'!R%6<!6<7!8%76<#B!A<9@A<%67S!='87?!
6<7!@*57!?7*;6%9'!;9'8%6%9'@!*@!*49>7N!6<7!#%7B8!9C!
!M*5%'9!A<9@A<9'*67!T
QQHX!&35A78!
69!iiZ!*'8!ihZ!*6!?995!675A7?*63?7!*'8!`IqEN!?7@A7;6%>7B#!T-;<757!HS
cXS!HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
23 ¡C, toluene, 
16h(S)-66a
19.7%, 35%ee11.5% (50¡C)
(S)-VANOL
OHOHPhPh1.0 equiv.
63a1.0 equiv.
64a1.0 equiv.
65a!JY!(DIGSG
'M=O'!A>?@AW'GdLG@ESG>?'\E?I'M
-DASLA>G>?'IYB@ALIAJLIA>YWH?EA>'a/CBA@E`'
@GHD?EA>b
' 'M=M=M'&>E?EHW'J?CBY'A>'cE@DA>ECS'DH?HWYJ?J
'#H_WG'M=<'7E@DA>ECS'DASLWGdGJ'AK'6"0.$'H>B'6"/.$'H?'BEKKG@G>?'?GSLG@H?C@GJ
H''!075A7?*63?7!TqEX
!P%(*'8
!Z!$%7B8
4!Z!!!;(J!Mgc!T,XMO+G1P
!I!M!H!MHI!T,XMO+G1P
!I!M!h!MJI!T,XMO+G1P
!gI!Hc!g!I!T,XMO+G1P
!gg!Y!c!Hh!T,XMO+G1P
!Yg!HJSc
!`!Mgc!T,XMO+21P
!M!M!i!MHI!T,XMO+21P
!I!M!K!MJI!T,XMO+21P
!iJ!JY!Y8!I!T,XMO+21P
!KY!Mi!JI8!Hh!T,XMO+21P
!ig!M`!*d%?;9'%35!;*6*B#@
6@!R7?7!A?7A*?78!4#!@6%??%'(!*
!5%Q63?7!9C!JSI!
7D3%>*B7'6!9C!d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!
T2:,X!*'8!HSI!7D3%>*B7'6@!9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!
?995!675A7?*63?7!3'87?!6<7!*%?a!JII!R6Z!gj!59B7;3B*?!@%7>7@!R7?7!
*8878!?7B*6%>7!69!6<7!5*@@!9C!
QNHa!4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!
4#!bGPEa
!8T2XM%@957?!R*@!94@7?>78S
!0<7!;9'6?9B!7QA7?%57'6!?7>7*B78!6<*6!6<7!#%7B8!9C!6<7!?7*;6%9'!4#!75AB9#%'(!%5%'7@
'NHHO+POHOEt
OEt
P(OEt)
2HNO23¡C, toluene, 
16hHO(S)-66a
77.1% (isolated)
72.5% (60 ¡C, NMR yield)
1.0 equiv.
67aÕ1.0 equiv.
65a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
HO++POHOEt
OEt
P(OEt)
2HNONH2OHHOTemp (¡C), 4† M.S (100 wt%), 
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64a1.0 equiv.
65a(S)-66a
PhPhOHOHVAPOL and VANOL
5 mol% [Zr(O
iPr)
4 / NMI / Ligand]
(1:10:2)
!HI!%@!53;<!<%(<7?!6<*'!C9?!6<7!8%?7;6!6<?77
M;95A9'7'6!?7*;6%9'S!0<7?7C9?7N!%'!6<7!C9BB9R%'(!
9A6%5%L*6%9'N!59B7;3B*?!@%7>7@!R7?7!*8878!69!A?95967!6<7!%5%'7!C9?5*6%9'!
*%(&*"6
!%'!6<7!
?7*;6%9'S!!O+G1P!*'8!O+21P!L%?;9'%35!;95AB7Q7@!R7?7!7Q*5%'78!*6!8%CC7?7'6!?7*;6%9'!
675A7?*63?7@!T0*4B7!HSJXS!
!0<7!47@6!?7@3B6!R*@!*;<%7>78!4#!3@%'(!O+G1P!*@!B%(*'8!*6!?995!675A7?*63?7N!
R<%;<!(*>7!6<7!;9??7@A9'8%'(!A?983;6!
QQH!%'!YgZ!#%7B8!*'8!HJScZ
!!!(T7'6?#!cXS!0<7!
7'*'6%9@7B7;6%>%6#!R*@!'96!%5A*;678!4#!87;?7*@%'(!9C!6<7!675A7?*63?7N!436!6<7!?7*;6%9'!
R*@!53;<!@B9R7?!T7'6?#!hN!gXS!^<7'!6<7!675A7?*63?7!R*@!
MHIqEN!'9!A?983;6!R*@!8767;678S!
E95A*?78!69!O+G1PN!O+21P!(*>7!496<!@B%(<6B#!B9R7?!#%7B8@!*'8!
!!!%'!6<7!?7*;6%9'S!
!M=M=P'(?CBEGJ'\E?I'?IG'A?IG@'DH?HWYJ?J
'0<7!"h!;*6*B#@6!<*@!477'!R7BB!87>7B9A78!4#!93?!(?93A!C9?!*!'3547?!9C!8%CC7?7'6!
*@#5576?%;!?7*;6%9'@!9C!%5%'7@
oghMgipS!"#!@R%6;<%'(!6<7!A?967;6%'(!(?93A!9'!6<7!%5%'7@N!<%(<!
7'*'6%9@7B7;6%>%6#!;*'!47!946*%'78!%'!
"#$%&
'*L%?%8%'*6%9'@N!
)*&
M*L%?%8%'*6%9'@!*'8
!*@#5576?%;!6<?77
M;95A9'7'6!=(%!?7*;6%9'
ogKMgYpS!0<7?7C9?7N!%'!*88%6%9'!69!L%?;9'%35!
;*6*B#@6@N!49?9Q!;*6*B#@6@!R7?7
!*B@9!7Q*5%'78!%'!6<7!?7*;6%9'!9'!47'L*B87<#87!
QPHN!:.)+:!*5%'7!
QNe!*'8!8%76<#B!A<9@A<%67!
QOH!%'!6<7!U*4*;<'%V
MW%7B8@!?7*;6%9'
!T0*4B7!
HSHXS
!!HJ!#H_WG'M=M'(D@GG>'E>'?IG'2P'DH?HWYJ?'E>'?IG'1H_HDI>E`
-4EGWBJ'@GHD?EA>
H'!!gj!:S-!Te!R6ZX
!Z!$%7B8
4!Z!!!;!J!I!I!M!H!H!cI!HY!*c!59BZ!9C!T
,XMO+21PN!Jc!59BZ!9C!6?%A<7'#B49?*'7!*'8!JII!59BZ!9C!
QNe!R7?7!
*8878!69!8?#!69B37'7!*'8!6<7!5%Q63?7!R*@!@6%??78!hI!5%'367@!*6!KIqEN!C9BB9R78!4#!
6<7!*88%6%9'!9C!
QPHN!QOH!*'8!gj!:S-!T5*@@!7D3%>*B7'6@!9C!
QNeXS!0<7!?7*;6%9'!R*@!
@6%??78!*6!HhqE!9>7?'%(<6a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPES
!0<7!?7*;6%9'!R%6<!6<7!"h!;*6*B#@6!*CC9?878!6<7!A?983;6!
QQS!%'!cIZ!#%7B8!*'8!HY
Z!!!!R<7'!59B7;3B*?!@%7>7@!R7?7!*8878S!,'!6<7!*4@7';7!9C!59B7;3B*?!@%7>7@N!'9!A?983;6!
R*@!C9?578S!"36!;95A*?78!69!6<7!L%?;9'%35!;95AB7QN!"h!;*6*B#@6@!(*>7!6<7!B9R7?!
7'*'6%9@7B7;6%>%6#!THYZ!O@!hcZN!@;<757!HShX!*'8!#%7B8!TcIZ!O@!KYZN!6*4B7!HSJX!9C!6<7!
A?983;6S!0
<7?7C9?7N!L%?;9'%35!;95AB7Q7@!R7?7!@7B7;678!69!;95AB767!C3?6<7?!9A6%5%L*6%9'S!
!M=M=N'(?CBY'A>'LIAJLIE?GJ
'O*?%93@!A<9@A<%67@!
QO_-G!*'8!8%A<7'#B!A<9@A<%'7!
QOK!9Q%87!R7?7!67@678!%'!6<7!
?7*;6%9'!T0*4B7!HShXS!^%6<!%';?7*@%'(!6<7!@%L7!9C!76<#B!(?93A!9'!6<7!A<9@A
<%67!69!
*&+
A?9A#BN!
"!#"
436#B!*'8!A<7'#BN!#%7B8@!8?9AA78!*;;9?8%'(B#!C?95!igZ!69!I!R%6<!O+21P!L
%?;9'%35!
;*6*B#@6N!436!R%6<936!%';?7*@7@
!%'!7'*'6%9@7B7;6%>%6#S!29!A?983;6!R*@!(7'7?*678!R<7'!
8%A<7'#B!A<9@A<%'7!9Q%87!R*@!3@78!%'@67*8!9C!*!A<9@A<%67S!)%
M*&+
'A?9
A#B!A<9@A<%67!R*@!
HO+MEDAM-NH
2+POHOEt
OEt
P(OEt)
2HNOMEDAM
5 mol%B3 Catalyst with (
S)-VANOL
additive, 23¡C, toluene
1.0 equiv.
63a1.0 equiv.
65a(S)-66m
NH2OMe
MeO
MEDAM amine 64Õ
OBOBOBOOB3 catalyst with (S)-VANOL
OOPhPh1.0 equiv.
64Õ!HH!*B@9!7Q*5%'78!R%6<!6<7!O+G1P!L%?;9'%35N!;*6*B#@6!(%>%'(!KIZ!#%7B8N!436!6<7?7!R*@!'9!
%';?7*@7!%'!6<7!*@#5576?%;!%'83;6%9'S
!#H_WG'M=P'/IAJLIE?GJ'JD@GG>
H''!/!Z!$%7B8
4!Z!!!;!J8!1.6!T
QO_X!ig!M`!H!1*G?!T
QODX!gg!JJ!h!1""3!T
QOGX!I!M!g!1G<!T
QOKX!I!M!c!G<!T
QOFX!I!M!`8N7
!1*G?!T
QODX!KI!MJI!*d%?;9'%35!;*6*B
#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*
!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!T
,XMO+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!JII!
R6Z!gj!59B7;3B*?!@%7>7@!R7?7!*8878!?7B*6%>7!69!6<7!5*@@!9C!
QNHa!4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa!
8T/X
M%@957?!R*@!94@7>7?78a!
7P%(*'8!%@!T
,XMO+G1PS
!'M=M=O'(AWRG>?'
J?CBEGJ
'-9B>7'6@!@3;<!*@!8%;<B9?9576<*'7N!47'L7'7N!*;769'%6?%B7!*'8!0bW!R7?7!7Q*5%'78!
C9?!6<7!?7*;6%9'N!436!'9'7!(*>7!*!@%('%C%;*'6!%5A?9>757'6!%'!6<7!7'*'6%9@7B7;6%>%6#S!0<7!
47@6!@9B>7'6!R*@!*;769'%6?%B7!R<%;<!87B%>7?78!6<7!A?983;6!%'!KJZ!#%7B8!*'8!HJZ!
!!S!b9R7>7?N!69B37'7!R*@!@6%BB!@7B7;678!69!47!6<7!@9B>7'6!C9?!6<7!9A6%5%L*6%9'!*@!6<7!A?9;783?7!
C9?!A?7A*?%'(!L%?;9'%35!;*6*B#@6!%@!7*@%7?!%'!69B37'7!T0*4B7!HSgXS
!#H_WG'M=N'(AWRG>?'JD@GG>
H''HO++POHRRP(R)
2HNONH2OHHO4† M.S (100 wt%),  23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64a1.0 equiv.
65b-g 
(no 65d)
5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
(S)-66a, 66pc-pg
HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (
100 wt%
),  23¡C
solvent, 16h
1.0 equiv.
63a1.0 equiv.
64a1.0 equiv.
65a(S)-66a
5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
!Hh!#H_WG'M=N'aDA>?E>CGBb
'!-9B>7'6
!Z!$%7B8
4!Z!!!;!J!09B37'7
!ig!M`!H!)E:!Yc!Mc!h!"7'L7'7
!KK!M`!g!+;769'%6?%B7
!KJ!MHJ!c!0bW
!`g!Mi!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!T
,XMO+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!JII!
R6Z!gj!59B7;3B*?!@%7>7@!R7?7!*8878!?7B*6%>7!69!6<7!5*@@!9C!
QNHa!4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPES
!!M=M=Q'#IG'KE@J?'_@GH`?I@ACFI'\E?I'
!2C-6"0.$'H>B'BESG?IYW'IYB@AdYW
H>EWE>G'b*>%'(!89'7!@;?77'@!9C!A<9@A<%67@N!@9B>7'6@N!*'8!675A7?*63?7@!R%6<!L%?;9'%35!
;*6*B#@6@!C?95!O+21P!*'8!O+G1PN!*667'6%9'!R*@!63?'78!69!9A6%5%L*6%9'!9C!6<7!?7*;6%9'!
69!96<7?!B%(*'8@!*'8!96<7?!<#8?9Q#B!*'%B%'7@S!,6!R*@!*!87B%(<6!69!94@7?>7!6<*6!6<7!
7'*'6%9@7B7;6%>%6#!9C!6<7!87@%?78!A?983;6!
QQH!R*@!%';?7*@78!69!hiZ!
!!!R<7'!T
,XM""3MO+21P!R*@!75AB9#78!*@!6<7!B%(*'8!T.
D3*6%9'!HSJX!;95A*?78!69!`Z!
!!!R%6<!6<7!T
,XMO+21P!B%(*'8!3'87?!6<7!@*57!;9'8%6%9'@!T
0*4B7!HSJXS
!*fCH?EA>
'M=<'#IG'KE@J?'_@GH`?I@ACFI?'_Y'
GSLWAYE>F'!2C-6"0.$
''W3?6<7?59?7N!*C67?!?7AB*;%'(!6<7!3'@34@6%63678!H
M<#8?9Q#*'%B%'7!
QNH!R%6<!H
M<#8?9Q#
MhNcM8%576<#B*'%B%'7!
QN_N!6<7!#%7B8!*'8!6<7!7'*'6%9@7B7;6%>%6#!%';?7*@78!69!KcZ!
*'8!ciZ!
!!N!?7@A7;6%>7B#!R%6<!T
,XMO+21P!
;*6*B#@6!T.
D3*6%9'!HSHXS!0<9@7!6R9!7QA7?%57'6@!
%'8%;*678!6<7!@67?%;!7CC7;6!9C!@34@6%637'6@!9'!6<7!*'%B%'7!*'8!%'!6<7!iNi_!A9@%6%9'@!9C!6<7!
O+21P!<*>7!*!(?7*6!%5A*;6!9'!6<7!*@#5576?%;!%'83;6%9'S
!HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (100 wt%),  23¡C
toluene, 16h
(S)-66a
82%, 37%ee(S)-tBu-VANOL
OHOHPhPhtButBu5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
1.0 equiv.
63a1.0 equiv.
64a1.0 equiv.
65a!Hg!*fCH?EA>
'M=M'#IG'KE@J?'_@GH`?I
@ACFI'_Y'GSLAWYE>F'M-IYB@AdY-P^O-BESG?IYWH>EWE>G
'''M=P'4C@?IG@'AL?ESEcH?EA>J'AK'?IG'1H_HDI>E`
-4EGWBJ'@GHD?EA>
'M=P=<'$EFH>B'JD@GG>'\E?I'P^O
-BESG?IYW
-M-IYB@AdYWH>EWE>G'+!@76!9C!7B7>7'!8%CC7?7'6!iNi_
M@34@6%63678!O+21P!87?%>*6%>7!T
$<-$<MX!R7?7!
7Q*5%'78!%'!6<7!5987B!?7*;6%9'!R%6<!47'L*B87<#87!
QPHN!hNc
M8%576<#B
MHM<#8?9Q#B*'%B%'7!
QN_!*'8!8%76<#B!A<9@A<%67!
QOH!T-;<757!HS`
XS!=A9'!;<*'(%'(!6<7!@34@6%637'6@!9'!6<7!iNi_!
A9@%6%9'@!9'!6<7!O+21P!B%(*'8N!%6!R*@!C93'8!6<*6!43BV#!*BV#B!@34@6%63678!O+21
P!(*>7!
47667?!?7@3B6!6<*'!96<7?!C3';6%9'*B!(?93A@N!@3;<!*@!<*B9(7'N!*?#B!9?!<767?9;#;B%;!(?93A@S!
+59'(!*BB!9C!6<7!*BV#B!@34@6%63678!O+21P@N!
%"3!*'8!;#;B9<7Q#B
MO+21P!T
$N!*'8!$<MX!(*>7!*?93'8!`KZ!
M!ihZ!!!!*'8!KIZ!#%7B8@S!-B%(<6B#!B9R7?!#%7B8@!*'8!
!!!TccZN!
M`iZ!!!X!R*@!946*%'78!R%6<!
""3MO+21P!T
$OXS!,'!67?5@!9C!6<7!A?7>%93@!@9B>7'6!@;?77'N!*;769'%6?%B7!
@<9R78!(998!?7@3B6@!69!@95
7!7Q67'6!%'!6<7!5987B!?7*;6%9'!
*'8!R*@!67@678!R%6<!T
,XM""3MO+21P!T
$OXN!436!496<!#%7B8!*'8!7'*'6%9@7B7;6%>%6#!R*@!'96!47667?!
;95A*?78!69
!69B37'7S!0<7!@%B#B!@34@6%63678!O+21P!T
$PX!*B@9!(*>7!iJ
Z!!!!C9?!6<7!A?983;6N!<9R7>7?!6<7!#%7B8!
R*@!9'B#!giZS!
!HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (100 wt%),  23¡C
toluene, 16h
66b85%, 57%ee5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
1.0 equiv.
63a1.0 equiv.
64b1.0 equiv.
65a!Hc!(DIGSG
'M=Q'$EFH>B'JD@GG>'\E?I'P^O
-BESG?IYW
-M-IYB@AdYWH>EWE>G''''''HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (100 wt%),  23¡C
toluene, 16h
66b85%, 57%ee5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:10:2)
1.0 equiv.
63a1.0 equiv.
64b1.0 equiv.
65aPhPhOHOH(S)-L1
85%, 57%eePhPhOHOH(S)-L2
62%, 7%eeFFPhPhOHOHSiSiPhtButButBuPhtBuPhPhOHOHnBunBu(S)-L3
47%, 71%ee(R)-L4
82%, -68%ee
aPhPhOHOHMeMePhPhOHOHOMe
OMe
tButButButBuPhPhOHOHMeMeMeMe(S)-L6
58%, 15%ee(S)-L7
10%, 6%ee(S)-L8
77%, 50%eePhPhOHOHtButBu(S)-L5
55%, 67%ee45%, 48% (in acetonitrile)
b!H`!(DIGSG'M=Q'aDA>?E>CGBb
''*T2XM%@957?!9C!6<7!A?983;6!R*@!946*%'78a!
46<7!@9B>7'6!%@!*;769'%6?%B7a!
;HII!R6Z!9C!:S-!R*@!3@78S
'M=P=M'&SLHD?'AK'?IG'HSAC>?'AK'Ng'SAWGDCWH@'JEGRGJ
':9B7;3B*?!@%7>7@!;*'!A?95967!6<7!
*%'&*"6
!(7'7?*6%9'!9C!%5%'7!%'!6<7!6<?77
M;95A9'7'6!U*4*;<'%V
MW%7B8@!?7*;6%9'!T6*4B7!HSHXS!W?95!6<7!B%(*'8!@;?77'N!%6!R*@!C93'8!
6<*6!6<7!*88%6%9'!9C!HSI!7D3%>*B7'6@!9C!gj!59B7;3B*?!@%7>7@!T5*@@!7D3%>*B7'6!69!H
M<#8?9Q#B*'%B%'7X!R%6<!E#
HO+21P!T
$<MX!(*>7!*!<%(<7?!#%7
B8!*'8!7'*'6%9@7B7;6%>%6#!6<*'!JSI!
7D3%>*B7'6S!0<7?7C9?7N!8%CC7?7'6!*593'6@!9C!gj!59B7;3B*?!@%7>7@!R7?7!7Q*5%'78!%'!6<7!
9A6%5%L*6%9'!A?9;7@@!T0*4B7!HScXS
!#H_WG'M=O'(D@GG>'AK'GfCERHWG>?'AK'Ng'SAWGDCWH@'JEGRGJ
H'''PhPhOHOHSSPhPhOHOHOOPhPhOHOH(R)-L10
43%, -56%ee
a(R)-L11
38%, -59%ee
a(R)-L12
81%, -73%ee
a(200 wt% M.S)
cPhPhOHOHCF3CF3CF3CF3(S)-L9
70%, 7%eeP(OEt)
2HNOHO4†  M.S (X wt%) 
23¡C, toluene, 16h
(S)-66b5 mol% [Zr(O
ipr)4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
HO++POHOEt
OEt
NH2OH1.0 equiv.
63a1.0 equiv.
64b1.0 equiv.
65a!Hi!#H_WG'M=O'aDA>?E>CGBb
'!e!R6Z!T5*@@!7D3%>S!69!
QN_X!Z!$%7B8
4!Z!!!;!J!J!cc!`i!H!H!Ki!KH!h!g!KK!iY!g!`!ig!gi!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(
!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!d?T1
*G?X
gsb1
*G?N!
JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!
7D3%>*B7'6@!9C!T
,XM""3MO+21P!%'!8?#!
69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!
4#!bGPES
!!W9?5!6<7@7!7QA7?%
57'6@N!%6!R*@!C93'8!6<*6!R<7'!HI
I!R6Z!9C!gj!59B7;3B*?!@%7>7@!
R*@!%'83;78!%'69!6<7!?7*;6%9'N!6<7!#%
7B8!9C!6<7!A?983;6!?7*;<78!KiZ!*'8!6<7!
!!!R*@!KHZS!
+B6<93(<!gII!R6Z!9C!gj!59B7;3B*?!@%7>7@!(*>7!@%5%B*?!?7@3B6@N!6<7!?7*;6%9'!47;*57!>7?#!
@6%;V#!*'8!%6!R*@!<*?8!69!@6%?S!hj!*'8!cj!59B7;3B*?!@%7>7@!T'96!@<9R
'!<7?7X!R7?7!*B@9!
7Q*5%'78!%'!A?7>%93@!@638%7@!R%6
<!47'L*B87<#87!T
QPHXN!H
M<#8?9Q#*'%B%'7!T
QNHX!*'8!8%76<#B!
A<9@A<%67@!T
QOHXN!6<7#!8%8!'96
!5*V7!53;<!8%CC7?7';7!9'!6<7!?7*;6%9'!936;957S
!M=P=P'(D@GG>'AK'BEHW`YW
-M-IYB@AdYH>EWE>GJ'+@!%@!87@;?%478!*49>7!%'!93?!C%?@6!4?7*V6<?93(<!;*57!R<7'!%6!R*@!C93'8!496<!6<7!
@6?3;63?7!9C!6<7!B%(*'8@!*'8!9C!6<7!*'%B%'7@!<*>7!6<7!@6?9'(!%5A*;6!9'!#%7B8@!*'8!
7'*'6%9@7B7;6%>%6#!9'!6<7!?7*;6%9'!T
.D3*6%9'!HSJ!*'8!HSHXN!6<3@N!*88%6%9'*B!8%*BV#B
MHM<#8?9Q#*'%B%'7@!R7?7!@#'6<7@%L78!*'8!7Q*5%'78!%'!6<7%?!?7*;6%9'@!R%6<!6<7!47'L*B87<#87!
TQPHX!T0*4B7!HS`XS!,6!R*@!87B%(<6C3B!69!@77!6<*6!*C67?!@R%6;<%'(!C?95!*!576<#B!69!
*&+
'A?9A#B!
(?93A!9'!6<7!*'%B%'7N!6<7!7'*'6%9@7B7;6%>%6#!%';?7*@78!69!YIZ!
!!!R%6<!i`Z!#%7B8!T
0*4B7!HS`N!
7'6?#!HXS!0<7!?7*;6%9'!R%6<!
%"36#B!<#8?9Q#*'B%'7!T
QNBX!(*>7!*!@B%(<6!87;
?7*@7!%'!6<7!#%7B8!
*'8!!!(TihZ!*'8!KHZ!77XS!"3BV%7?!
"!#"
M436#B!(?93AN!499@678!6<7!7'*'6%9@7B7;6%>%6#!69!YHZ!
!!!*6!6<7!?995!675A7?*63?7!436!R%6<!9'B#!JHZ!#%7B8!T7'6?#!gXS!,';?7*@%'(!6<7!675A7?*63?7!
69!gIqE!*'8!`IqE!8%8!<7BA!69!%5A?9>7!6<7!#%7B8N!436!
!!!8?9A
A78!4*;V!69!KYZ!T7'6?#!c!*'8!
!HK!`XS!0<7?7C9?7!hNc
M8%%@9A?9A#B
MHM<#8?9Q#B*'%B%'7!T
QNDX!R*@!@7B7;678!*@!6<7!@6*'8*?8!*'%B%'7!
%'@67*8!9C!hNc
M8%576<#B
MHM<#8?9Q#B*'%B%'7!T
QN_XS!#H_WG'M=Q'(D@GG>'AK'BEKKG@G>?'BEHW`YW
-JC_J?E?C?GB'
IYB@AdYWH>WE>GJH''!/!075A7?*63?7TqEX
!Z!$%7B8
4!Z!!!;!J!:7!T
QN_X!Hh!Ki!KH!H!*G?!T
QNDX!Hh!i`!YI!h8!%"3!T
QNBX!Hh!ih!MKH!g!""3!T
QNGX!Hh!JH!Yc!c!""3!T
QNGX!gI!gJ!YH!`8!""3!T
QNGX!`I!cH!MKY!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!d?T1
*G?X
gsb1
*G?N!JISI!
7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!9C!T
,XM""3MO+21P!%'!8?#!69B37'7!C9?!hI!
5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!6<7!
*'%B%'
7!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa!
8T2XM""3MO+21P!R*@!3@78!%'!6<7!
?7*;6%9'S
!!M=P=N'(D@GG>'AK'BEHW`YW'LIAJLIE?GJ
'W?95!6<7!A?7>%93@!@;?77'!9C!8%*BV#B!A<9@A<%67@N!8%76<#B!A<9@A<%67@!T
QOHX!(*>7!6<7!
47@6!?7@3B6!C9?!87B%>7?%'(!6<7!
87@%?78!A?983;6!R%6<!H
M<#8?9Q#*'%B%'7!T
0*4B7!HShXS!b9R7>7?N!
*C67?!hNc
M8%%@9A?9A#B
MHM<#8?9Q#B*'%B'7!T
QNDX!R*@!%87'6%C%78!*@!6<7!@3A7?%9?!@34@6?*67N!%6!
R*@!87;%878!69!7Q*5%'7!8%CC7?7'6!8%*BV#B!A<9@A<%67@!*(*%'!3'87?!6<7!@6*'8*?8!;9'8%6%9'!
69!@77!%C!*!47667?!
;954%'*6%9'!9C!?7*(7'6@!;93B8!47!C93'8!69!%5A?9>7!6<7!#%7B8!*'8!
7'*'6%9@7B7;6%>%6#!T0*4B7!HSiXS
!HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (200 wt%), 23¡C
toluene, 16h
RRRR1.0 equiv.
63a1.0 equiv.
64b-e
1.0 equiv.
65a(S)-66b, 67a, 66d, 66e5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
!HY!#H_WG'M=T'(D@GG>'AK'BEHW`YW'LIAJLIE?GJ'\E?I'P^O
-BE"#$L@ALYW-M-IYB@AdYH>EWE>GH''!/!Z!$%7B8
4!Z!!!;!J!.6!T
QOHX!i`!YI!H!:7!
TQO_X!iJ!iY!h!*G?!
TQODX!gc!MYJ!g8!%"3!
TQOBX!`c!MYI!c8!""3!
TQOGX!I!M!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!T
,XM""3MO+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!
HII!R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!!
4,@9B*678!
#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa!
8T2XM""3MO+21P!R*@!3@78!%'!6<7!?7*;6%9'S
!!^%6<!%';?7*@%'(!6<7!@%L7!9C!6<7!*BV#B!(?93A!9C!6<7!A<9@A<%67@!C?95!576<#B!69!
"!#"
M436#B!(?93AN!6<7!#%7B8!8?9AA78!C?95!iJZ!69!IS!b9R7>7?N!7Q;7A6!C9?!8%576<#B!A<9@A<%67!
TQO_XN!6<7!7'*'6%9@7B7;6%>%6#!?75*%'78!*?93'8!YIZ!
!!!C9?!8%76<#BN!8%
*&+
A?9A#B!*'8!8%
%436#B!A<9@A<%67@S!29!A?983;6!;93B8!47!8767;678!R<7'!8%
"!#"
M436#B!A<9@A<%67!R*@!75AB9#78!%'!
6<7!?7*;6%9'S!0<%@!;93B8!47!6<7!?7@3B6!9C!6<7!@67?%;!7CC7;6!9C!6<7!
"!#"
M436#B!(?93AS
!M=P=O'2G>cAED'HDEB'HJ'HBBE?ERG
'+'!
3'3@3*B!94@7?>*6%9'!R*@!5*87!R<7'!C?7@<B#!
8%@6%BB78!47'L*B87<#87!R*@!
75AB9#78!%'!6<7!?7*;6%9'S!0<7!#%7B8!9C!6<7!?7*;6%9'!87;?7*@78!69!`IZ!C?95!i`ZS!
E9'@%87?%'(!6<*6!47'L*B87<#87!%@!>7?#!7*@%B#!9Q%8%L78!69!47'L9%;!*;%8!8
3?%'(
!@69?*(7N!
7Q6?*!*593'6@!9C!47'L9%;!*;%8!R7?7!*8878!69!6<7!?7*;6%9'!69!@77!
%C!6<7#!<7BA!69!%';?7*@7!
6<7!#%7B8!T0*4B7!HSKXS
!HO++POHORORP(OR)
2HNONH2OHHO4† M.S (200 wt%), 23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65a-e
5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
(S)-67pa-pe
!hI!#H_WG'M=U'5EKKG@G>?'HSAC>?J'AK'_G>cAED'HDEB'E>'?IG'@GHD?EA>
H''!e!59BZ
!Z!$%7B8
4!Z!!!;!J!I!`I!KY!H!c!K`!YH!h!JI!Kh!Ti`X
8!Yg!TYgX
!g!JII!KH!ii!c!7!c!cY!KK!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!T
,XM""3MO+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!
HII!R6Z!gj!59B7
;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!
#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa!
80<7!#%7B8!%'!A*?7'6<7@7@!R*@!6<7!@7;9'8!6%57!
9C!?3''%'(!6<7!@*57!?7*;6%9'a!
7JII!R6Z!9C!gj!59B7;3B*?!?7B*6%>7!69!6<7!5*@@!9C!
QND!R*@!*8878!69!6<7!?7*;6%9'S
!!W?95!6*4B7!HSKN!%6!;*'!47!'96%;78!6<*6!6<7!*88%6%9'!9C!c!9?!JI!59BZ!9C!47'L9%;!*;%8!
A?959678!6<7!#%7B8!9C!6<7!5987B!?7*;6%9'!69!*?93'8!KIZ!*'8!(*>7!*!@B%(<6!%';?7*@7!%'!6<7!
!!!69!MYgZ!R<7'!JI!59BZ!9C!47'L9%;!*;%8!R*@!3@78!T7'6?#!hXS!W3?6<7?!?*%@%'(!6<7!*59
3'6!9C!47'L9%;!*;%8!69!JII!59BZ!?7@3B678!%'!*!8?9A!%'!496<!#%7B8!*'8!
!!!69!KHZ!*'8!KKZN!
?7@A7;6%>7B#S!0<7!B*@6!7QA7?%57'6!R*@!;*??%78!936!R%6<!JSI!7D3%>*B7'6!9C!59B7;3B*?!@%7>7@!
*'8!c!59BZ!9C!47'L9%;!*;%8!69!@77!%C!6<7!*593'6!9C!59B7;3B*?!@%7>7@!;93B8!47!?
783;78S!
b9R7>7?N!6<7!?7@3B6!%'8%;*678!6<*6!HII!R6Z!9C!gj!59B7;3B*?!@%7>7!?7B*6%>7!69!*'%B%'7!R*@!
@6%BB!'7;7@@*?#S!
!09!C3?6<7?!;9'C%?5!6<7!7CC7;6!9C!47'L9%;!*;%8N!6<?77!8%*BV#B
MHM<#8?9Q#!T
QN_-GX!*'%B%'7@!R7?7!67@678!%'!6<7!A?7@7';7!9C!47'L9%;!*;%8!T0*4B7!HS
YXS!0<7!#%7B8@!C9?!*BB!6<?77!
9C!6<7!8%*BV#B
MHM<#8?9Q#B*'%B%'7!@B%(<6B#!%';?7*@78N!436!6<7!
!!!@6*#78!*B59@6!6<7!@*57S!0<%@!
HO++POHOEt
OEt
P(OEt)
2HNONH2OHHOx mol% benzoic acid
4A M.S (
200 wt%
), 23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65a(S)-67a
5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
!hJ!%'8%;*67@!6<*6!6<7!7CC7;6!9C!47'L9%;!*;%8!%@!5*%'B#!9'!6<7!#%7B8!9C!6<7!?7*;6%9'N!'96!
7'*'6%9@7B7;6%>%6#S
!#H_WG'M=V'#I@GG'BEHW`YW'IYB@AdYWH>WE>GJ'\E?I'<X'SAWh'AK'_G>cAED'HDEB
H''!/!Z!$%7B8
4N;
!Z!!!;N8
!J!:7!
aQN_b
!KiTKiX
!KITKHX
!H!*G?!
aQNDb
!KhTi`X
!YgTYIX
!h!""3!
aQNGb
!JiTJHX
!YcTYcX
!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JISI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!T
,XM""3MO+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!
HII!R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!6<7!*'%B%'7!R7?7!*8878a!
4,@9B*678!#%7B8a!
;0<7!#%7B8!*'8!
!!!%'!A*?7'6<7@7@!R7?7!C?95!*!?7*;6%9'!R%6<936!JI!
59BZ!9C!47'L9%;!*;%8a!
8!!!R*@!8767?5%'78!4#!bGPES
!!0<7!47'L9%;!*;%8!7CC7;6!R*@!7Q67'878!69!g
M'%6?947'L9%;!*;%8!*'8!g
M576<9Q#B47'L9%;!*;%8N!R<%;<!R7?7!*B@9!67@678!%'!6<7!?7*;6%9'!69!8%@;9>7?!6<7!%5A*;6!9C!6<7!
7B7;6?9'%;!@6*63@!9C!6<7!47'L9%;!*;%8!T0*4B7!HSJIXS!0<7!7'*'6%9@7B7;6%>
%6#!9C!6<7!?7*;6%9'@!
R%6<!*BB!9C!6<7!47'L9%;!*;%8!87?%>*6%>7@!*?7!@%5%B*?!TYgZ!
!!XN!<9R7>7?N!6<7!#%7B8!%';?7*@78!
C?95!iHZ!R%6<!6<7!7B7;6?9'
M?%;<!g
M576<9Q#B47'L9%;!*;%8!69!JIIZ!R%6<!6<7!7B7;6?9'
MA99?!
gM'%6?947'L9%;!*;%8S!0<%@!8%@;9>7?#!;93B8!47!9C!>*B37!%'!
9A6%5%L*6%9'!9C!*B%A<*6%;!*B87<#87@!
%'!U*4*;<'%V
MW%7B8@!?7*;6%9'!*'8!R%BB!47!8%@;3@@78!%'!6<7!;<*A67?!hS
!HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO10 mol% benzoic acid
4† M.S (
200 wt%
), 23¡C 
toluene, 16h
RRRR1.0 equiv.
63a1.0 equiv.
64b, c, e1.0 equiv.
65a(S)-66b, 67a, 66e5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
!hH!#H_WG'M=<X'(D@GG>'AK'_G>cAED'HDEBJ
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4!Z!!!)!J!b!Kh!Yg!H!1:7
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d?T1
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9C!T
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;9';7'6?*6%9'!69!J:N!6<7!?7*;6%9'!(*>7!6<7!@%5%B*?!?7@3B6@!TKhZN!YgZ!
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*'8!J`ZN!?7@A7;6%>7B#N!436!
6<7!7'*'6%9@7B7;6%>%6#!8?9AA78!9'B#!@B%(<6B#!69!KcZ!
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H''''HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO4† M.S (
200 wt%
), 23¡C, toluene, 16h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65a(S)-67a
10 mol%OOHR5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO10 mol% benzoic acid 
4† M.S (200 wt%), 23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65a(S)-67a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:10:2)
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P(OEt)
2HNONH2OHHO10 mol% benzoic acid 
4† M.S (
200 wt%
), 23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65b(S)-67a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(x:y:z)
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H'''''HO++POHOEt
OEt
P(OEt)
2HNONH2OHHO10 mol% benzoic acid 
4† M.S (
200 wt%
), 23¡C
toluene, h
1.0 equiv.
63a1.0 equiv.
64c1.0 equiv.
65b(S)-67a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
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OEt
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2HNONH2HO4A M.S (
200 wt%
), 23 ¡C
10 mol% benzoic acid 
toluene, 16h
1 equiv.
1 equiv.
1 equiv.
OH5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
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2HNONH2HO5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
4† M.S (
200 wt%
), 23 ¡C
10 mol% benzoic acid 
toluene, 16h
1 equiv1 equiv1 equivOH63a-m
64c65b67a-m
bOEt
OEt
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'M=<X'(Y>?IGJEJ'AK'P^O
-BE%_C?YW
-M-IYB@AdYH>EWE>G'!!!!OHCOOHquinoline, reflux, 4h
OHOHNO2HNO3 (90%)
687051.3%HOAc, 0¡C6998.4%OHNH2graphite, EtOH
100¡C64c60%NH2NH2áH2OOOnBuLi (3 equiv)
THF, -78¡C to r.t, 6h
OHnBunBu7235%HNO3 (90%)
73100%HOAc, 0¡COHnBunBuNO271!hY!(DIGSG'M=<X'aDA>?E>CGBb
''M=O=P'(Y>?IGJEJ'AK'P^O
-BE!_C?YW
-M-IYB@AdYH>EWE>G'aQNGb'
'0<7!@#'6<7@%@!9C!
QNG!@6*?6@!R%6<!6<7!'%6?*6%9'!9C!HNg
M8%"436#BA<7'9B!T
TPXN!R<%;<!(*>7!
6<7!HNg
M8%"436#B
M`M'%6?9A<7'9B!T
TNX!%'!c`Z!#%7B8
ocJpS!-34@7D37'6!<#8?*L%'7!?783;6%9'
ocJp!;95AB7678!6<7!@#'6<7@%@!9C!6<7!87@%?78!A?983;6!
QNG!%'!YgZ!#%7B8!T-;<757!HSJ
JXS!(DIGSG'
M=<<'(Y>?IGJEJ'AK'P^O
-BE!_C?YW
-M-IYB@AdYH>EWE>G' 'M=Q'!A>DWCJEA>','!6<%@!;<*A67?N!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!R%6<!*?95*6%;!*B87<#87@!
;*6*B#L78!4#!*!
""3MO+21P!L%?;9'%35!;95AB7Q!<*@!477'!87@;?%478!%'!876*%BN!%';B38%'(!%6@!
%'%6%*B!87>7B9A57'6N!9A6%5%L*6%9'N!@34@6?*67!@;9A7!*'8!6<7!@#'6<7@%@!9C!'7;7@@*?#!@6*?6%'(!
5*67?
%*B@S
!,'!6<7!C%'8%'(!9C!
9A6%5%L*6%9'!A?9;7@@N!6R9!V7#!7CC7;6@!
R7?7!94@7?>78!
6<*6!(?7*6B#!%5A*;6
78!6<7!7'*'6%9@7B7;6%>%6#S!0<7!C%?@6!%@!6<7!@34@6%637'6
@!9'!6<7
!i!*'8!i_MA9@%6%9'@!9C!
O+21P
!B%(*'8S!-R%6;<%'(!6<7!@34@6%637'6!C?95!b!69!
"436#BN!
%436#B!*'8!
;#;B9<
7Q#B!(?93A@N!6<7!7'*'6%9@7B7;6%>%6#!%';?7*@78!8?*5*6%;*BB#S!0<7!@7;9'8!<*@!69!89!
R%6<!6<7!8%CC7?7'6!@%L7@!9C!6<7!@34@6%637'6@!9'!6<7!H
M<#8?9Q#*'%B%'7@S!^%6<!%';?7*@%'(!6<7!
graphite, EtOH
100¡C64d49%OHnBunBuNH2NH2NH2áH2OOHOHNO2HNO3 (90%)
73HOAc, 0¡C7456%OHNH2graphite, EtOH
100¡C64e94%NH2NH2áH2O!gI!@%L7!9C!*BV#B!(?93A@!%'!6<7!h
M!*'8!c
M!A9@%6%9'@!9C!6<7!H
M<#8?9Q#*'%B%'7@!C?95!b!69!
"436#B!
(?93AN!6<7!
!!!R*@!499@678!C?95!hiZ!69!YcZS!0<7@7!6R9!V7#!7CC7;6@!
R%BB!*B@9!47!9C!A?%57!
%5A9?6*';7!%'!8%?7;6%'(!6<7!9A6%5%L*6%9'!9'!*B%A<*6%;!*B87<#87@!%'!6<7!*@#5576?%;!
U*4*;<'%V
MW%7B8@!?7*;6%9'N!R<%;<!%@!59?7!;<*BB7'(%'(!47;*3@7!%6!%@!59@6!3'87>7B9A
78!*@A7;6!9C!6<7!?7*;6%9'S!
!!!!''''''''''''''''''''''''''!gJ!!3"/#*+'#3+**
''!"#"$%#&!'"(%))*#+&!'1"2"!30&1
-4&*$5('+*"!#&.0':&#3'
"$&/3"#&!'"$5*3%5*(
'P=<'&>?@ABCD?EA>
','!6<%@!;<*A67?N!6<7!8%@;3@@%9'!R%BB!47!C9;3@78!9'!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!
?7*;6%9'!R%6<
!*B%A<*6%;!*B87<#87@S!+@!57'6%9'78!%'!!;<*A67?!9'7N!6<7?7!R*@!9'B#!9'7!A*A7?!
6<*6!?7A9?678!9'!6<7!*@#5576?%;!6<?77
M;95A9'7'6!U*4*;<'%V
MW%7B8@!?7*;6%9'!R%6<!@%5AB7!
*B%A<*6%;!*B87<#87@!T9'B#!6R9!7Q*5AB7@X!*'8!6<7!7'*'6%9@7B7;6%>%6#!R*@!A99?!69!5987?*67!
T-;<7
57!hSJXS
ohcp!(DIGSG
'P=<'/@GREACJ'GdHSLWGJ'AK'HJYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>'\E?I'
HWELIH?ED'HWBGIYBGJ
''0<7?7C9?7N!*;<%7>%'(!<%(<7?!7'*'6%9@7B7;6%>%6#!*'8!87>7B9A%'(!*!4?9*87?!?7*;6%9'!
@;9A7!R%6<!5%B87?!?7*;6%9'!;9'8%6%9'!C9?!*B%A<*6%;!*B87<#87@!R93B8!47!;95A7BB%'(!*'8!
%5A9?6*'6S!"*@78!9'!6<7!7QA7?%7';7!9C!9A6%5%L*6%9'!R%6<!*?95*6%;!*B87<#87@N!*6!6<7!
47(%''%'(!@638#!9C!6<7!*B%A<*6%;!@34@6?*67@N!6<7!9A6%5*B!?7*;6%9'!;9'8%6%9'!9C!*?95*6%;!
*B87<#87@!%'!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!R*@!*AAB%78!69!%6S!
!RHO+10 mol% Zn(NTf
2)210 mol% Ligand 55CH2Cl2, - 50 ¡C
OMe
NH2POHOArOAr+POOArOArNHPMB
RNNNNNOMeMeOMeMePhPhPhPhLigand 55R= cyclohexyl, 98%, 61%ee
R= (CH
3)2CHCH2, 99%, 31%eeAr= 
o-CH
3OC6H454!gH!P=M'&>E?EHW'@GJCW?J
'P=M=<'$EFH>B'JD@GG>'\E?I'<j<jM'cE@DA>ECS'DH?HWYJ?'
']%>7'!6<7!@3;;7@@!R%6<!6<7!9A6
%5%L78!;9'8%6%9'!9C!*?95*6%;!*B87<#87@!T
E<*A67?!HN!
0*4B7!HSJHXN!6<7!C%?@6!7QA7?%57'6!9'!*'!*B%A<*6%;!*B87<#87!R*@!;*??%78!936!R%6<!
;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!T
TQHXN!H
M<#8?9Q#
MhScM8%*&+
A?9A#B*'%B%'7!T
QNDX!*'8!8%76<#B!
A<9@A<%67!T
QOHX!3'87?!;*6*B#@%@!4#!6<7!
""3MO+21P!L%?;9'%35!;95AB7QN!R<%;<!R*@!
A?7A*?78!R%6<!JSI!7D3%>*B7'6!9C!
d%?;9'%35T,OX!%@9A?9A9Q%87!%@9A?9A*'9BN!JSI!7D3%>*B7'6!9C!
-M576<#B!%5%8*L9B7!*'8!HSI!7D3%>*B7'6@!9C!
""3MO+21PS!,'!*88%6%9'N
!c!59BZ!9C!47'L9%;!
*;%8!*'8!HII!R6Z!
9C!gj!59B7;3B*?!@%7>7@!T5*@@!7D3%>*B7'6@!69!*'%B%'7!
QNDX!!R7?7!*B@9!
*8878!*@!*88%6%>7@!%'69!6<7!?7*;6%9'N!*C67?!@6%??%'(!J`!<93?@N!*!gcZ!#%7B8!*'8!JJZ!
!!!!!9C!!6<7!!87@%?78!
 !M*5%'9!A<9@A<9'*67@!
TTH!R7?7!946*%'78!T0*4B7!hSJN!7'6?#!JXS!
!#H_WG'P=<'$EFH>B'JD@GG>'\E?I'<j<jM'cE@DA>ECS'DASLWGd
H''!P%(*'8
!Z!$%7B8
4!Z!!!;!J!T,XM""36#B
MO+21P
!gc!JJ!H!T,XMO+G1P
!`c!`!h!T,XMKNK_
MG<HMO+21P
!hY!I!g!T2XM"=)+:
MO+G1P
(Jc!I!c!T,XMO+21P
(`h!HK!`8!T,XMO+21P!TJkHkhX
(`h!ch!*d%?;9'%35!
;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JSI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!HSI!7D3%>*B7'6@!
9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!
gj!59B7;3B*?!@%7>7@!?7B*6
%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa!
8E*6*B#@6!
;95A9'7'6!
?*6%9!%@!JkHkhS
!!!HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO5 mol% [Zr(O
iPr)
4 / NMI / Ligand
(1:1:2)
1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76a(S)-77a
10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
!gh!#H_WG'P=<'aDA>?E>CGBb
'!0<7!47@6!936;957!R*@!94@7?>78!R%6<!*!;*6*B#@6!87?%>78!C?95!O+21P!T6*4B7!hSJN!7'6?#!c!
*'8!`XS
!E95A*?%'(!R%6<!7'6?#
!c!R%6<!7'6?#!`N
!6<7!9'B#!8%CC7?7';7!%@!6<7!?*6%9!9C!6<7
!;95A9'7'6@!%'!6<7!;*6*B#@6S!^%6<!hSI!7D3%>*B7'6@!9C!O+21PN!53;<!<%(<!7'*'6%9@7B7;6%>%6#!
;*'!47!*;<%7>78!6<*'!R%6<!HSI!7D3%>*B7'6@!TchZ!
!!!>@S!HKZ!
!!XS!0<%@!R*@!'96!7QA7;678N!
@%';7!C9?!6<7!*?95*6%;!*B
87<#87@!6<7!?*6%9!9C!6<7!;95A9'7'6@!%'!6<7!;*6*B#@6!897@'_6!%5A*;6!
6<7!7'*'6%9@7B7;6%>%6#!*'8!6<7!#%7B8!9C!6<7!?7*;6%9'S!W9?!96<7?!B%(*'8@N!@3;<!*@!O+G1P!*'8!
%6@!87?%>*6%>7@N!*'8!KNK_
M8%A<7'#B!O+21PN!496<!6<7!#%7B8!*'8!
!!!R7?7!B9RS!
!P=M=M'/IAJLIE?G'JD@GG>
'#H_WG'P=M'/IAJLIE?G'JD@GG>
H''!G<9@A<%67
!Z!$%7B8
4!Z!!!;!J!.6!!T
QOHX(`h!ch!H!*A?!
aQODb
!hc!I!h!G<!
aQOKb
!I!I!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!HSI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!
9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!
gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPES
!'(S)-8,8Õ-Ph-VANOL
OHOHPhPhPhPhOHOHArArAr=OMe
(R)-BUDAM-VAPOL
HO++P(OR)
2OHP(OR)
2HNONH2OHHO1.0 equiv.
64c1.0 equiv.
65c, 65f1.0 equiv.
76a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:2:3)
10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
(S)-77a
!gg!)%*&+
A?9A#B!*'8!8%A<7'#B!A<9@A<%67@!T
QOD^'QOK
X!R7?7!7Q*5%'78!*C67?!%6!R*@!C93'8!
6<*6!6<7!O+21P
ML%?;9'%35!;95AB7Q!R%6<!JkHkh!?*6%9!R9?V@!7CC%;%7'6B#!R%6<!6<7!
;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!T0*4B7!hSHXS!"#!3@%'(!8%
*&+
A?9A#B!A<9@A<%67N!9'B#!*!hcZ!
9C!6<7!A?983;6!
TTH!R*@!94@7?>78!R%6<!'9!7'*'6%957?%;!7Q;7@@S!W9?!8%A<7'#B!A<9@A<%67@N!
'9!A?983;6!R*@!8767;678!*C67?!*!?7*;6%9'!9C!J`!<93?@S
!P=M=P'(D@GG>'AK'_G>cAED'HDEBJ
'G?7>%93@B#!%6!R*@!8%@;9>7?78!6<*6!g
M'%6?947'L9%;!*;%8!;*'
!%5A?9>7!6<7!#%7B8!9C!6<7!
5987B!?7*;6%9'!R%6<!47'L*B87<#87!T
E<*A67?!HN!
0*4B7!HSJIXS!+
!@7?%7@!9C!47'L9%;!*;%8@!
47*?%'(!8%CC7?7'6!C3';6%9'*B!(?93A@!R7?7!7Q*5%'78!<7?7!69!@77!%C!6<7#!;93B8!*B@9!<*>7!
@957!%5A*;6!9'!6<7!?7*;6%9'!R%6<!6<7!*B%A<*6%;!@34@6?*67!
TQH!T0*4B7!hShXS!W9?!*BB!9C!6<7!g
M@34@6%63678!47'L9%;!*;%8@N!@%5%B*?!7'*'6%9@7B7;6%>%6%7@!R7?7!94@7?>78N!R<%;<!R7?7!*?93'8!
ccZ!!!S!"7'L9%;!*;%8!T7'6?#!JX!*'8!g
M'%6?947'L9%;!T7'6?#!gX!*;%8@
!(*>7!`hZ
!*'8!`gZ!!#H_WG'P=P'(D@GG>'AK'_G>
cAED'HDEBJ
H'!!/!Z!$%7B8
4!Z!!!;!J!b!`hTK`X
8!chTciX
8!H!1:7
!cc!cc!h!EWh!gI!ch!g!21H!`g!cc!c!W!hK!gY!`!HNgN`
M6?%576<#B
!gI!c`!i!G<7'#B!*;76%;!*;%8
!i`!hh!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!HSI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!
9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!
gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa
8JI!59BZ!;*6*B#@6!B9*8%'(!R*@!3@78S
!!HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO4† M.S (
(200 wt%
), 23¡C
toluene, 16
1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-VANOL]
(1:2:3)
COOHR10 mol%(S)-77a!gc!#%7B8@!9C!87@%?78!A?983;6@
!?7@A7;6%>7B#
S!.B7;6?9'
M87C%;%7'6!g
M'%6?947'L9%;!*;%8!8%8'_6!@<9R!
@%('%C%;*'6!*8>*'6*(7
@!;95A*?78!R%6<!@%5AB7!47'L9%;!*;%8S!0<7!7B7;6?9'%;!@6*63@!9C!6<7!
47'L9%;!*;%8@!8%8'_6!<*>7!*!5*&9?!7CC7;6!6<*6!;*'!%5A*;6!9'!6<7!#%7B8!9C!6<7!?7*;6%9'S!W9?!
7Q*5AB7N!g
M576<9Q#47'L9%;!*;%8!T7'6?#!HX!87B%>7?78!6<7!A?983;6!%'!ccZ!#%7B8N!R<%;<!R*@!
<%(<7?!6<*'!g
M6?%CB9?9576<#B47'L9%;!*;%8!TgIZN!7'6?#!hXS!0<7!<%(<7@6!#%7B8!Ti`ZN!7'6?#!iX!
R*@!*;<%7>78!4#!75AB9#%'(!A<7'#B!*;76%;!*;%8N!436!6<7!7'*'6%9@7B7;6%>%6#!R*@!9'B#!hhZS!
!P=M=N'(D@GG>'AK'DH?HWYJ?'DASLA>G>?'@H?EA
'#H_WG'P=N'(D@GG>'AK'D
H?HWYJ?'DASLA>G>?'@H?EA'\E?I'6"0.$^'
!2C-6"0.$'H>B'6"/.$
H'!!P%(*'8
!Qk#kL
4!Z!$%7B8
;!Z!!!8!J!O+21P
'!JkJkH
!`h!HK!H!O+21P
!JkHkh
!`h!ch!h!""36#B
MO+21P
!JkJkH
!gc!JJ!g!""36#B
MO+21P
!JkHkh
!`H!cc!c!O+G1P
!JkJkH
!`c!`!`!O+G1P
!JkHkh
!hJ!I!*d%?;9'%35!;*6*B#@6@!R7?7!
A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!Q!7D3%>*B7'6@!
9C!d?T1
*G?X
gsb1
*G?N!#!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!L!
7D3%>*B7'6@!9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!
3'87?!6<7!*%?a!HII!R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4Q!%@!L%?;9'%35T,OX!
*&+
A?9A9Q%87!
*&+
A?9A*'9Ba!#!%@!
-M576<#B!
%5%8*L9B7!*'8!L!%@!B%(*'8a!
;,@9B*678!#%7B8a!
8!!!R*@!8767?5%'78!4#!bGPES
!!,'!6<7!A?7>%93@!9A6%5%L*6%9'!A?9;7@@!R%6<!*?95*6%;!*B87<#87@N!7QA7?%57'6@!R%6<!
>*?%*6%9'!%'!6<7!?*6%9!9C!;95A9'7'6!%'!6<7!;*6*B#@6!R7?7!;9'83;678!*'8!6<7!?7@3B6!@<9R78!
6<*6!%'!;95A*?%'(!6<7!?*6%9!9C!JkJkH!69!JkJkh!TL%?;9'%35!
*&+
A?9A9Q%87k!2:,k!T
,XM"43MO+21
PN!E<*A67?!HN!
0*4B7!HSJHXN!6<7!@*57!7'*'6%9@7B7;6%>%6%7@!TYhZ!
!!X!R7?7!946*%'78N!436!6<7!
HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76a5 mol% [Zr(O
iPr)
4 / NMI / (
S)-Ligand]
(x:y:z)
(S)-77a10 mol% benzoic acid
4† M.S (
200 wt%
), 23¡C
toluene, 16h
!g`!B*667?!9'B#!(*>7!*!iZ!%5A?9>757'6!%'!6<7!#%7B8S!b9R7>7?N!;9'@%87?%'(!6<*6!*B%A<*6%;!
@34@6?*67@!5*#!<*>7!8%CC7?7'6!?7*;6%>%6%7@N!59?7!876*%B78!@;?77'!9C!6<7!;*6*B#@6!;9
5A9'7'6!
?*6%9!R%6<!6<7!B%(*'8@!R7?7!7Q*5%'78!T0*4B7!hS
gXS','!6<7!%'%6%*B!9A6%5%L*6%9'!9C!6<7!*B%A<*6%;!
*B87<#87!
TQHN!L%?;9'%35
MO+21P!;95AB7Q!R%6<!*!;*6*B#@6!;95A9'7'6!?*6%9!9C!JkHkh!
TL%?;9'%35!
*&+
A?9A9Q%87k!2:,k!O+21PX!(*>7!6<7!47@6!?7@3B6N!R<%;<!%@!`hZ!#%
7B8!*'8!chZ!
!!!T7'6?#!HXS!"36!R<7'!
""3MO+21P!R*@!75AB9#78!%'!6<7!?7*;6%9'N!6<7!7'*'6%9@7B7;6%>%6#!
%';?7*@78!@%(<6B#!69!ccZ!
!!!T7'6?#!gXS!0<7?7!R*@!*B59@6!'9!7'*'6%9@7B7;6%>7!%'83;6%9'!C9?!
6<7!O+G1P!B%(*'8!R%6<!496<!?*6%9@!9C!JkJkH!*'8!JkHkh!T7'6?#!c!*'8!`X
S!'#H_WG'P=O'(D@GG>'AK'DH?HWYJ?'DASLA>G>?'@H?EA'\E?I'
!_C-6"0.$
H'!!E*6*B#@6!
;95A9'7'6!
?*6%9
4!Z!$%7B8
;!Z!!!8!J!JkJkH
!gc!JJ!H!JkHkh
!`H!cc!h!JkJkh
!KI!KH!g!Jkckh
!``!KJ!c!JkJIkh
!iK!KI!`!JkJckh
!gi!iY!i!JkHIkh
!`I!KH!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!
*!5%Q63?7!9C!Q!7D3%>*B7'6@!9C!
d?T1
*G?X
gsb1
*G?N!#!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!L!7D3%>*B7'6@!9C!
T,XM!O+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!
R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4Q!%@!L%?;9'%35T,OX!
*&+
A?9A9Q%87!
*&+
A?9A*'9Ba!#!%@!
-M576<#B!%5%8*L9B7!*'8!L!%@!T
,XM""3MO+21Pa!
;,@9B*678!#%7B8a!
8!!!R*@!8767?5%'78!4#!bGPEa!
!!-%';7!
""3MO+21P!%@!*B@9!6<7!9A6%5*B!B%(*'8!%'!6<7!@6*'8*?8!A?969;9B!C9?!*?95*6%;!
*B87<#87@N!%6!R*@!@7B7;678!69!47!67@678!R%6<!*88%6%9'*B!>*?%*6%9'!%'!6<7!;*6*B#@6!;95A9'7'6!
?*6%9!T0*4B7!hScXS!^<7'!6<7!;*6*B#@6!R*@!A?7A*?78!C?95!
JSI!7D3%>*B7'6!9C!L%?;9'%35!
*&+
A?9A9Q%87N!JSI!7D3%>*B7'6!9C!
-M576<#B!%5%8*L9B7!*'8!hSI!7D3%>*B7'6@!9C!T
,XM""3MO+21PN!
HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76a5 mol% [Zr(O
iPr)
4 / NMI /(
S)-tBu-VANOL]
(x:y:z)
(S)-77a10 mol% benzoic acid
4† M.S (
200 wt%
), 23¡C
toluene, 16h
!gi!6<7!#%7B8!9C!
TTH!R*@!KIZ!
R%6<!KHZ!77!T7'6?#!hXS!,6!R*@!D3%67!@3?A?%@%'(!69!
C%'8!;<*'(%'(!
6<7!;*6*B#@6!;95A9@%6%9'!?*6%9!C?95!JkHkh!69!JkJkh
!;*3@78!6<7!7'*'6%9@7B7;6%>%6#!69!%';?7*@7!
ccZ!!!!69!KHZ!
!!S!T0*4B7!hSgN!7'6?#!g!>@!0*4B7!hScN!7'6?#!hXS!!b9R7>7?N!;9'6%'393@B#!
%';?7*@%'(!6<7!7D3%>*B7'6@!9C!
-M576<#B!%5%8*L9B7!C?95!c!69!HI!T7'6?#!g
MiX!8%8!'96!?7@3B6!%'!
%';?7*@78!#%7B8@!*'8!6<7!7'*'6%9@7B7
;6%>%6#!R*@!3';<*'(78!*?93'8!KIZ!
!!S!0<%@!%@!
;9'@%@67'6!R%6<!6<7!?7@3B6@!C?95!6<7!9A6%5%L*6%9'!9C!*?95*6%;!*B87<#87@!R<7?7!%6!R*@!C93'8!
6<*6!7Q6?*!*593'6@!9C!6<7!4*@7!T2:,X!
8%8!'96!V%BB!6<7!?7*;6%9'!T
E<*A67?!HN!
0*4B7!HSJHXS
!0<7(%'436*'*B!R*@!*B@9!7Q*5%'78!R%6<!6R9!;*6*B#@6@!R%6<!8%CC7?7'6!?*6%9@!9C!;*6*B#@6!
;95A9'7'6@!69!;9'C%?5!6<7!%5A*;6!9C!6<7!;*6*B#@6!;95A9'7'6!?*6%9!T0*4B7!hS`XS!W?95!6<7!
?7@3B6@N!
""3MO+21P!%@!@3A7?%9?!69!O+21P!R%6<!*!;*6*B#@6!;95A9'7'6!?*6%9!9C!JkHkhS!W9?!*!
;*6*B#@6!;95A9'7'6!?*6%9!9C!JkJkhN!*!c`Z!#%7B8!*'8!KcZ!
!!!R*@!946*%'78!C9?!T
,XMTT_N!R<%;<!%@!@B%(<6B#!<%(<7?!6<*'!*!?*6%9!9C!JkHkhS!
!#H_WG'P=Q'(D@GG>'AK'DH?HWYJ?'DASLA>G>?'@H?EA'\E?I'
%-_C?H>HW
H''!P%(*'8
!E*6*B#@6!
;95A9'7'6!
?*6%9!
TQk#kLX
4!Z!$%7B8
;!Z!!!8!J!O+21P
!JkHkh
!cH!hY!H!""36#B
MO+21P
!JkHkh
!cJ!KJ!h!""36#B
MO+21P
!JkJkh
!c`!Kc!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!Q!7D3%>*B7'6@!9C!
d?T1
*G?X
gsb1
*G?N!#!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!L!7D3%>*B7'6@!
9C!T
,XM!O+21P!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!gj!
59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4Q!%@!L%?;9'%35T,OX!
*&+
A?9A9Q%87!
*&+
A?9A*'9Ba!#!%@!
-M576<#B!%5%8*L9B7!*'8!L!%@!T
,XM""3MO+21Pa!
;,@9B*678!#%7B8a!
8!!!R*@!
8767?5%'78!4#!bGPES
!'HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO5 mol% [Zr(O
iPr)
4 / NMI / (
S)-ligand]
(x:y:z)
(S)-77b1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76b10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
!gK!P=M=O'.?IG@'SG?HW'DH?HWYJ?J
','!*88%6%9'!69!L%?;9'%35!;95AB7Q7@N!6%6*'%35!*'8!#66?%35!;95AB7Q7@N!A?7A*?78!C?95!
T,XM""3MO+21P!*'8!
-M576<#B!%5%8*L9B7N!R7?7!*B@9!67@678!%'!?7*;6%9'@!R%6<!
;#;B9<7Q*'7;*?49Q#B%;!
*B87<#87!*'8!47'L*B87<#87!T0*4B7!hSiXS!0<7!6%6*'%35!;*6*B#@6!
R%6<!*!;*6*B#@6!;95A9'7'6!?*6%9!9C!JkHkh!*'8!JkJkH!*CC9?878!6<7!A?983;6!R%6<!hIZ!*'8!JIZ!
#%7B8!*'8!'9!*@#5576
?%;!%'83;6%9'!R*@!8767;678S!+
AAB#%'(!6<7!#66?%35!;95AB7Q!R%6<!*!
;*6*B#@6!;95A9'7'6!?*6
%9!9C!JkJkh!%'!6<7!?7*;6%9'N!R%6<!;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!
(*>7!ihZ!#%7B8!*'8!hIZ!
!!S!/7*;6%9'!R%6<!47'L*B87<#87!(*>7!HcZ!#%7B8!*'8!ghZ!
!!!R%6<!*!;*6*B#@6!;95A9'7'6!?*6%9!9C!JkJIkhS!,'!67?5@!9C!6<7!?7@3B6@N!496<!6%6*'%35!*'8!#66?%35!
;*6*B#@6@!*?7!'96
!*@!(998!*@!L%?;9'%35!;95AB7QS!W9?!;#;B9<7Q*'7;*?49Q#B%;!*B87<#87N!
6<7!#66?%35!;95AB7Q!@<9R78!<%(<7?!#%7B8!*'8!7'*'6%9@7B7;6%>%6#!;95A*?78!69!6<7!6%6*'%35!
;*6*B#@6S!,'!6<7!C363?7N!C3?6<7?!@638%7@!;93B8!47!89'7!9'!#66?%35!;95AB7Q7@N!R<%;<!5*#!
A9@@%4B#!
47!3@7C3B!%'!6<7!87>7B9A57'6!9C!96<7?!'7R!?7*;6%9'@S
!#H_WG'P=T'(D@GG>'AK'A?IG@'SG?HW'DH?HWYJ?J
H''!/!576*B
!Qk#kL
4!Z!$%7B8
;!Z!!!8!J!E#;B9<7Q#B!
TQH!0%6*'%35
!JkHkh
!hI!I!H!E#;B9<7Q#B!
TQH!0%6*'%35
!JkJkH
!JI!M!h!E#;B9<7Q#B!
TQH!$66?%35
!JkJkh
!ih!hI!g!G<7'#B!
QPH!$66?%35
!JkJIkh
!Hc!Mh!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!Q!
7D3%>*B7'6@!9C!0%T1
*G?X
g!9?!$T1
*G?X
hN!#!7D3%>*B7'6@!9C!2
M576<#B!
%5%8*L9B7!T2:,X!*'8!L!7D3%>*B7'6@!9C!T
,XM!O+21P!%'!8?#!69B37'7!C9?!hI!
5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!gj!59B7;3B*?!
@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4Q!%@
!0%T1
*G?X
g!9?!
$T1
*G?X
hN!#!%@!
-M576<#B!%5%8*L9B7!*'8!L!%@!T
,XM""3MO+21Pa!
;,@9B*678!
#%7B8a!
8!!!R*@!8767?5%'78!4#!bGPES
!'RHO++P(OR)
2OHRP(OEt)
2HNONH2OHHO1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
5 mol%[Metal / 
NMI / (
S)-tBu-VANOL]
(x:y:z)
(S)-63a, 77a10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
!gY!P=P'4C@?IG@'J?CBEGJ'A>'AL?ESEcH?EA>
'P=P=<'$EFH>B'JD@GG>'W?95!6<7!%'%6%*B!9A6%5%L*6%9'N!R%6<!;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!
TQHN!6<7!
L%?;9'%35!;*6*B#@6!R%6<!*!;*6*B#@6!;95A9'7'6!JkJkh!?*6%9!TJSI!7D3%>*B7'6!9C!L%?;9'%35!
*&+
A?9A#B!9Q%87N!JSI!7D3%>*B7'6!9C!
-M576<#B!%5%8*L9B7!*'8!hSI!7D3%>*B7'6@!9C!
""3MO+21PX!
*'8!JI!59BZ!47'L9%;!*;%8!R*@!C93'8!69!47!6<7!9A6%5*B!;9'8%6%9'@S!+6!6<%@!A9%'6N!6<7!
<%(<7@6!7'*'6%9@7B7;6%>%6#!*;<%7>78!R*@!KHZ!R%6<!
""3MO+21PS!b9R7>7?N!%'!93?!(9*BN!C9?!
6<7!5987B!?7*;6%9'!R%6<!;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!
TQH!%@!69!*;<%7>7!*'!
7'*'6%9@7B7;6%>%6#!;*'!?7*;<!9>7?!YIZ!
!!S!0<7?7C9?7N!*!'7R!@7?%7@!9C!O+21P[O+G1P!
87?%>*6%>7@!R7?7!7Q*5%'78!69!6<7!?7*;6%9'!T-;<757!hSHXS
!(DIGSG'
P=M'(D@
GG>'AK'SA@G'WEFH>BJ
'!!!HO++P(OEt)
2OHP(OEt)
2HNONH2OHHO10 mol% benzoic acid
4† M.S (
(200 wt%
),  23¡C
toluene, 16h
1.0 equiv.
64c1.0 equiv.
65a1.0 equiv.
76a5 mol% [Zr(O
iPr)
4 / NMI / ligand]
(1:1:3)
(S)-77aOHOHPhPhClClOHOHPhPhMeO
MeO
(R)-L13
63%, -60%ee
a(R)-L14
51.5%, -53%ee
aOHOHPhPhBrBr(R)-L15
75%, -54%ee
aOHOHPhPhtButBu(S)-tBu-VANOL (L5)
80%, 82%ee!cI!(DIGSG'P=M'aDA>?E>CGBb
'!*T2XM%@957?!9C!6<7!A?983;6!R*@!946*%'78
a!4JI!59BZ!9C!;*6*B#@6!R*@!3@78S
!=A9'!7Q*5%'%'(!C93?!cNc
M@34@6%63678!O+21P!87?%>*6%>7@!T
$<P-$<QXN!%6!R*@!C93'8!
6<*6!6<7!7'*'6%9@7B7;6%>%6%7@!9C!6<7!5987B!?7*;6%9'!R7?7
!*BB!*?93'8!`IZS!0<7!<%(<7@6!#%7B8!
R*@!946*%'78!4#!3@%'(!cNc_
M8%6?%CB39?9576<#B!O+21P!T
$<QXN!R<%;<!(*>7!KIZ!#%7B8!*'8!%@!
;B9@7!6<*6!C9?!6<7!
""3MO+21PS!+88%6%9'*BB#N!,@9
MO+G1P!T
$<UX!(*>7!iKZ!#%7B8!*'8!`Y
Z!!!S!1;6*<#8?9
MO+21P!T
$<TX!*CC9?878!6<7!A?983;6!R%6<!%'!B7@@!6<*'!cZ!#%7B8S!+!'7R!iNi_
M8%@34@6%63678!O+21P!87?%>*6%>7!
$<V'R*@!*B@9!67@678!*'8!(*>7!`IZ!#%7B8!*'8!c`Z!
!!S!='C9?63'*67B#N!'9'7!9C!6<7!*49>7!B%(*'8@!R9?V@!47667?!6<*'!
""3MO+21PS
!P=P=M'(D@GG>'AK'M
-IYB@AdYH>EWE>GJ'+C67?!@;
?77'%'(!9C!B%(*'8@!%'!-;<757!hSHN!'9!%5A?9>757'6!9'!6<7!7'*'6%9@7B7;6%>%6#!
R*@!C93'8!C9?!*'#!9C!6<7!B%(*'8@S!+
667'6%9'!R*@!'7Q6!C9;3@78!9'!6<7!@34@6%636%9'!A*667?'!
%'!6<7!H
M<#8?9Q#*'%B'7S!,'!6<7!9A6%5%L*6%9'!A?9;7@@!C9?!*?95*6%;!@34@6?*67@N!4%(!%';?7*@
7@!
%'!6<7!7'*'6%9@7B7;6%>%6#!R7?7
!*;<%7>78!R<7'!H
M<#8?9Q#
MhScM8%%&+A?9A#B*'%B%'7!T
QNDX!R*@!
3@78!%'!6<7!?7*;6%9'!T
E<*A67?!HN!
0*4B7!HS`XS!0<7?7C9?7N!;9'@%87?%'(!6<*6!4#!67@6%'(!@957!
96<7?!*'%B%'7@!R%6<!@34@6%637'6@!%'!8%CC7?7'6!A9@%6%9'@!9C!6<7!A<7'#B!?%'(N!*!?7
B*6%9'@<%A!5*#!
OHOHPhPhF3CF3C(R)-L16
80%, -58%ee
aOHOHPhPh(R)-L17
<5%
OHOHPhPh(R)-L18
78%, -69%ee
aOHOHPhPhb(R)-L19
60%, -56%ee
a!cJ!47!?7>7*B78!476R77'!@67?%;!7CC7;6!9C!*'%B%'7@!*'8!6<7!7'*'6%9@7B7;6%>%6#!9C!6<7!?7*;6%9'S!+!
@76!9C!H
M<#8?9Q#*'%B%'7@!R%6<!576<#B!(?93A@!%'!*BB!C93?!A9@@%4B7!A9@%6%9'@!T
QNK-EX!9'!6<7!
A<7'#B!?%'(!R7?7!C%?@6!7Q*5%'78!%'!6<7!?7*;6%9'!T-;<757!hSh
XS!(DIGSG'
P=P'(D@GG>'AK'SG?IYW
-M-IYB@AdYH>EWE>G'\E?I'DYDWAIGdH>GDH@_AdYWED'
HWBGIYBG''0<7!47@6!?7@3B6!R*@!*;<%7>78!R%6<!h
M576<#B
MHM<#8?9Q#*'%B%'7!T
QNKXN!R<%;<!(*>7!6<7!
A?983;6!%'!`KZ!#%7B8!*'8!c`Z!
!!S!0<7!@7;9'8!47@6!R*@!C93'8
!69!47!c
M576<#B
MHM<#8?9Q#*'%B%'7!T
QNIX!*'8!6<7!;9??7@A9'8%'(!A?983;6!R*@!946*%'78!%'!hIZ!#%7B8!*'8!hhZ!
!!S!W9?!*!576<#B!(?93A!9'!6<7!g!9?!`!A9@%6%9'@!T
QNF^'QNE
XN!<%(<7?!#%7B8@!R7?7!94@7?>78N!
436!R%6<!B9R7?!*@#5576?%;!%'83;6%9'@S!G?7>%93@B#N!%'!6<7!?7*;6%9'
!R%6<!*?95*6%;!@34@6?*67@N!
HM<#8?9Q#
MhNcM8%*&+
A?9A#B*'%B%'7!T
QNDX!R*@!C93'8!69!47!6<7!47@6!9'7N!R<%;<!;*'!(7'7?*67!
6<7!A?983;6@!R%6<!
!!!3A!69!YgZ!T
E<*A*67?!HN!
0*4B7!HSYXS!0<%@!%@!;9'@%@67'6!R%6<!6<7!?7@3B6@!
*49>7!6<*6!*!576<#B!9'!6<7!h!9?!c!A9@%6%9'!;*'!;?
3;%*BB#!7CC7;6!6<7!*@#5576?%;!%'83;6%9'S!
0<%@!A?9>%878!*!B7*8!C9?!C3?6<7?!7CC9?6@!69!*;<%7>7!<%(<7?!7'*'6%9@7B7;6%>%6#!R%6<!*B%A<*6%;!
*B87<#87@!%'!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'S
!++P(OEt)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
), 23 ¡C
toluene, 16h
OH5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
HOMeMe1.0 equiv.
76a1.0 equiv.
64f-i
1.0 equiv.
65a64g72%, 17%eeNH2OHMeNH2OHMeNH2OHNH2OHMe64h30%, 33%ee64i84%, 0%ee64f68%, 56%eeMe!cH!!W93?!'7R!h!9?!c
M@34@6%63678
MHM<#8?9Q#*'%B'7!R7?7!@#'6<7@%L78!C9BB9
R%'(!*!@%5%B*?!
A?969;9B!C9?!6<7!@#'6<7@%@!9C!hNc
M8%*&+
A?9#B
MHM<#8?9Q#*'%B%'7!87@;?%478!%'!6<7!;<*A67?!6R9S!
2*57B#N!
%6!%';B387@
!hMA?9A#B
'HM<#8?9Q#*'%B%'7!T
QNiXN!h
M*&+
A?9A#B
MHM<#8?9Q#*'%B%'7!T
QN`XN!h
M"436#B
MHM<#8?9Q#*'%B'7!T
QNSX!*'8!c
M"436#B
M<#8?9Q#*'%B%'7!T
QNWX!T-;<757!hS
gXS!(DIGSG'
P=N'(D@GG>'AK'M
-IYB@AdYH>EW>GJ'\E?I'DYDWAIGdH>GDH@_AdYWED'HWBGIYBG
''^%6<!6<7!%';?7*@%'(!
%'!@%L7!9C!6<7!*BV#B!(?93A!T
*&+
A?9A#BN!
%436#BN!
"436#BX!9'!6<7!h
MA9@%6%9'!9C!6<7!A<7'#B!?%'(N!6<7!
7'*'6%9@7B7;6%>%6#!9C!6<7!A?983;6!?9@7!C?95!ccZ!69!YIZS!
0<7!hNc
M8%6436#B
MHM<#8?9Q#*'%B%'7!T
QNGX!R*@!*B@9!67@678N!436!*CC9?878!9'B#!*!JhZ!#%7B8!9C!
6<7!87@%?78!A?983;6!A?94*4B#!47;*3@7!9C!6<7!@67?%;!43BV#!9C!6R9!
"436#B!(?93A@S!0<7!
A?7>%93@!9A6%5*B!*'%B%'7!C9
?!6<%@!?7*;6%9'!R*@!6<7!H
M<#8?9Q#
MhNcM8%%@9A?9A#B*'%B%'7!
QND!++P(OEt)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
), 23 ¡C
toluene, 16h
OH5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
HORR1.0 equiv.
76a1.0 equiv.
64c, 64e, 64j-m
1.0 equiv.
65a64j61%, -67%ee
NH2OH64k70%, -55%ee
NH2OHNH2OH64c80%, -82ee%
NH2OH64l58%, -26%ee
NH2OH64m43%, -90%ee
NH2OH64e13%!ch!T0*4B7!hScN!7'6?#!
hXS!b9R7>7?N!6<7!A?7@7'6!@;?77'!%'!-;<757!hS
g!?7>7*B78!6<*6!6<7!h
M""3#B
MHM<#8?9Q#*'%B%'7!
QNS!(%>7@!6<7!A?983;6!%'!YIZ!
!!!*'8!ghZ!#%7B8S!
!-%5%B*?!6<?7*8@!C9?!6<7!@34@6%636%9'!
A*667?'!%'!6<7!H
M<#8?9Q#*'%B%'7@!R7?7!*B@9!
94@7?>78!C9?!6<7!?7*;6%9'!R%6<!47'L*B87<#87!T-;<757hScXS!0<7!H
M*'8!c
M576<#B
MHM<#8?9Q#*'%B%'7@!T
QNK^'QNI
X!(*>7!<%(<7?!7'*'6%9@7B7;6%>%6#!TicZ!
!!!*'8!i`Z!
!!X!6<*'!g!
*'8!`
MA9@%6%9'78!576<#B!87?%>*6%>7@!T
QNF^'QNE
X!Tgh
Z!!!!*'8!hhZ!
!!XS!W9?!59'9
M@34@6%63678
MHM<#8?9Q#*'%B%'7@N!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNSX!(*>7!Yh
Z!!!N!R<%;<!R*@!
6<7!@*57!*@!hNc
M8%*&+
A?9A#B
MHM<#8?9Q#*'%B'7!T
QNDXS!0<7!h
MA?9A#B
MHM<#8?9Q#*'%B%'7!T
QNiXN!
!(DIGSG'
P=O'(D@GG>'AK'M
-IYB@AdYH>EWE>GJ'\E?I'_G>cHWBGIYBG
''*'8!6<7!h
M*&+
A?9A#B
MHM<#8?9Q#*'%B%'7!T
QN`X!A?9>%878!@B%(<6B#!B9R7?!
!!!TKcZ!
!!!*'8!K`Z!
!!XN!436!<%(<7?!#%7B8@!TKhZ!*'8!KJZX!6<*'!
QNSS!,'67?7@6%'(B#N!R%6<!6<7!c
M6436#B
MHM<#8?9Q#*'%B%'7!T
QNWXN!6<7!A?983;6!;*'!47!946*%'78!%'!
YYZ!#%7B8N!436!R%6<!9'B#!hg
Z!!!S!++P(OEt)
2OHPhP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
OHPhHO5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
RR1.0 equiv.
63a1.0 equiv.
64f-i
1.0 equiv.
65b64g85%, 3%eeNH2OHMeNH2OHNH2OHMeMeNH2OHMe64h97%, 76%ee64i53%, -33%ee
64f100%, 75%eeNH2OH64l99%, 34%ee64j83%, 85%eeNH2OH64k81%, 86%eeNH2OHNH2OH64c92%, 93%eeNH2OH64m62%, 93%ee!cg!0<7@7!?7@3B6@!%'8%;*67!6<*6!6<7!@34@6%637'6!9'!6<7!h
MA9@%6%9'!9C!6<7!A<7'#B!?%'(!<*@!6<7!
B*?(7@6!7CC7;6!9C!6<7!*@#5576?%;!%'83;6%9'S!b9R7>7?N!R%6<!%';?7*@%'(!6<7!@%L7!9C!6<7!(?93A!
9'!6<*6!A9@%6%9'N!6<7!#%7B8!R%BB!87;?7*@7!*
;;9?8%'(B#S!0<3@!H
M<#8?9Q#
MhScM8%*&+
A?9A#B*'%B%'7!T
QNDX!@6%BB!?75*%'@!*@!6<7!9A6%5*B!@6*?6%'(!5*67?%*B!%'!6<7!?7*;6%9'@!9C!
*?95*6%;!*B87<#87!837!69!%6@!<%(<7?!#%7B8!6<*'!
QNS=!P=P=P'#GSLG@H?C@G'JD@GG>
'0<7!7'*'6%9@7B7;6%>%6#!9C!6<7!?7*;6%9'!R%6<!;#;B9<7Q*'7;
*?49Q#B%;!*B87<#87!
?7*;<78!YIZ!
!!!C%?@6!6%57!R%6<!H
M<#8?9Q#
MhM"43#B*'%B%'7!T-;<757!hSgXS!b9R7>7?N!6<7!#%7B8!
R*@!9'B#!gIZ!*'8!6<7?7C9?7N!59?7!7CC9?6@!*?7!'77878!69!%5A?9>7!6<7!?7*;6%9'!#%7B8S!0<7!
C%?@6!@3;<!7CC9?6!%'>9B>78!7Q*5%'%'(!6<7!?7*;6%9'!675A7?*63?7
!T0*4B7!hSKXS!^<7'!6<7!
675A7?*63?7!R*@!87;?7*@78!69!IqEN!6<7!#%7B8!8%5%'%@<78!69!HhZN!R%6<!*!@B%(<6!%';?7*@7!9C!
!#H_WG'P=U'#GSLG@H?C@G'JD@GG>
H''!075A7?*63?7
!Z!$%7B8
4!Z!!!;!J!I!Hh!YH!H!Hh!gI!KY!h8!gI!gK!KY!g!iI!hH!KJ!c8!Hh!ch!YI!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JSI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!
9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!
gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPEa
8JI!59BZ!9C!6<7!;*6*B#@6!B9*8%'(S
!!6<7!7'*'6%9@7B7;6%>%6#!69!YHZS!^<7'!6<7!675A7?*63?7!R*@!?*%@78!69!iIqEN!496<!6<7!#%7B8!
*'8!7'*'6%9@7B7;6%>%6#!8?9AA78!ThHZN!KJZ!
!!N!7'6?#!gXS!296*4B#N!%6!R*@!C93'8!6<*6!*'!
++P(OEt)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
),  ¡C
toluene, 16h
OH5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
HO1.0 equiv.
76a1.0 equiv.
64m1.0 equiv.
65a(S)-78a!cc!%';?7*@7!%'!6<7!B9*8%'(!9C!6<7!59?7!L%?;9'%35!
;*6*B#@6!69!JI!59BZ!%'!6<7!?995!675A7?*63?7N!
499@678!6<7!#%7B8!69!chZ!R%6<936!*'#!;<*'(7!%'!6<7!7'*'6%9@7B7;6%>%6#!T7'6?#!cXS
!P=P=N'/IAJLIE?G'JD@GG>
!E9'@%87?%'(!6<*6!6<7!53;<!43BV%7?!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNSX!R*@!'9R!3@78!
%'!6<7!?7*;6%9'!%'@67*8!9C!H
M<#8?9Q#
MhScM8%*&+
A?9A#B*'%B%'7!T
QNDXN!8%CC7?7'6!*BV#B!(?93A@!9'!
A<9@A<%67!R7?7!67@678!69!@77!%C!6<7!#%7B8!;93B8!47!%5A?9>78
!T0*4B7!hSY
XS!=A9'!;<*'(%'(!
8%76<#B!A<9@A<%67!
QO_!69!8%576<#B!A<9@A<%67!
QOHN!6<7!#%7B8!@B%(<6B#!%';?7*@78!69!gcZN!436!
6<7!!!!8?9AA78!69!iYZ!R%6<!c!59BZ!;*6*B#@6!B9*8%'(S!W9?!6<7!8%%@9A?9A#B!A<9@A<%67!T
QODXN!
B7@@!6<*'!JIZ!9C!6<7!A?983;6!R*@!94@7?>78S!0<3@N!8%76<#B!A<9@A<%67!%@!@6%BB!6<7!9A6%5*B!
9'7!%'!6<7!?7*;6%9'!R%6<!*B%A<*6%;!*B87<#87@S
!#H_WG'P=V'(D@GG>'AK'?IG'@GHD?EA>'\E?I'H>EWE>G'QNS'\E?I'LIAJLIE?GJ
H''!/!Z!$%7B8
!Z!!!!J!.6!
aQOHb
!cI!YI!H!:7!
aQO_b
!gc!iY!h!7&+
A?9A#B!
aQODb
!tJI!M!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JSI!7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!
9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!
gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!8767?5%'78!4#!bGPES
!'P=P=N'4C@?IG@'H??GSL?J'H?'AL?ESEcH?EA>'\E?I'HBBE?EA>HW'6"0.$'WEFH>BJ'
'W%'*BB#N!*'96<7?!6<?77!iNi
M@34@6%63678!O+21P!B%(*'8@!R7?7!7Q*5%'78!3'87?!6<7!
'7R!;9'8%6%9'@!R%6<!H
M<#8?9Q#
MhM"436#B*'%B%'7!
T0*4B7!hSJI
XS!"96<!6<7!
T,XMiNi_M;#;B9<7Q#B!
++P(OR)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
,  Temp (¡C)
toluene, 16h
OH5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
HO1.0 equiv.
76a1.0 equiv.
64m1.0 equiv.
(S)-78a!c`!O+21P!T
$<MX!*'8!
6<7!T
,XMiNi_M*&+
A7'6#B!O+21P!T
$MXX!87B%>7?78!6<7!A?983;6!
TUH!R%6<!@%5%B*?!#%7B8@!*'8!
!!8&
!*@!6<7!T
,XM""3MO+21PS!W9?!6<7!iNi_
M*8*5*'6#B!O+21P!T
$M<XN!'9!
A?983;6!R*@!C9?578N!A?94*4B#!837!69!%6@!53;<!43BV%7?!@%L7S!0<7?7!*AA7*?@!69!47!*!
?7B*6%9'@<%A!476R77'!6<7
!7CC7;6%>7'7@@!9C!6<7!?7*;6%9'!R%6<!6<7!@%L7!9C!6<7!@34@6%637'6!%'!
6<7!iNi_
MA9@%6%9'@!9'!6<7!O+21P!B%(*'8S!G?7@7'6!(?93A!57547?@!*?7!'9R!5*V%'(!96<7?!
iNi_M*BV#B!@34@6%63678!O+21P!87?%>*6%>7@N!%';B38%'(!576<#BN!76<#BN!
*&+
A?9A#B!76;S!,'!C363?7!
@638%7@N!6<7@7
!B%(*'8@!;93B8!47!67@678!%'!6<7!?7*;6%9'!69!C%'8!%C!6<7?7!%@!*!;9??7B*6%9'!R%6<!
6<7!@67?%;!@%L7!9C!6<7!@34@6%637'6S!
!#H_WG'P=<X'.?IG@'?\A'WEFH>BJ'JD@GG>
H'!!/!Z!$%7B8
4!Z!!!;!J!T,XM""3MO+21P!
a$<Mb
!cI!YI!H!T,XMiNi_
M;#;B9<7Q#B!O+21P!
a$<Mb
!cH!KY!h!T,XMiNi_
M*&+
A7'6#B!O+21P!
a$MXb
!gg!Ki!g!T,XMiNi_
M*8*5*'6#B!O+21P!
a$M<b
!M!M!*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!7D3%>*B7'6!9C!
d?T1
*G?X
gsb1
*G?N!JSI!7D3%>*B7'6!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!9C!
B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!gj!
59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QNS!R7?7!*8878a!
4,@9B*678!#%7B8a!
;!!!R*@!
8767?5%'78!4#!bGPES
!'P=P=O'#IG'AL?ESHW'DA>BE?EA>'KA@'HWELIH?ED'HWBGIYBGJ
'+C67?!*BB!7CC9?6@!<*>%'(!477'!5*87!C9?!6<7!9A6%5%L*6%9'!9C!*B%A<*6%;!*B87<#87@N!6<7!
9A6%5*B!?7*;6%9'!;9'8%6%9'@!C9?!*B%A<*6%;!*B87<#87@!%'!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!
?7*;6%9'!%@!@<9R'!%'!
-;<757!hS`
S!0<7!A?969;9B!%'>9B>7@!JI!59BZ!9C!6<7!L%?;9'%35!;*6*B#@6!
A?7A*?78!C?95!JSI!7D3%>*B7'6!9C!L%?;9'%35T,OX!
*&+
A?9A9Q%87!
*&+
A?9A*'9BN!JSI!7D3%>*B7'6!9C!
++P(OEt)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
OHHO(S)-78a10 mol% [Zr(O
iPr)
4 / NMI /
 (S)-7,7Õ-R-VANOL
(1:1:3)
(S)-7,7Õ-R-VANOL
OHOHPhPhRRR= cyclohexyl (L12)
R= isopentyl (L20)
R= admentyl (L21)
1.0 equiv.
76a1.0 equiv.
64m1.0 equiv.
65a!ci!-M576<#B!%5%8*L9B7!*'8!hSI!7D3%>*B7'6@!9C!T
,XM""3MO+21P!%'!69B37'7S!09!6<7!;*6*B#@6!R*@!
*8878!JI!59BZ!47'L9%
;!*;%8!*'8!HSI!5*@@!7D3%>*B7'6@!9C!gj!59B7;3B*?!@%7>7@!*B9'(!R%6<!
JSI!7D3%>*B7'6!7*;<!6<7!9C!*B%A<*6%;!*B87<#87N!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNSX!*'8!8%76<#B!
A<9@A<%67!T
QOHXS!0<7!5%Q63?7!@6%??78!C9?!J`
MgK!<93?@!*6!?995!675A7?*63?7!*'8!A?983;78!
6<7!87@%?78!
 *B%A<*6%;!
!M*5%'9!A<9@A<9'*67@S!
!(DIGSG'
P=Q'.L?ESHW'@GHD?EA>'DA>BE?EA>
''P=N'(C_J?@H?G'JDALG'AK'HWELIH?ED'HWBGIYBGJ
'+!@76!9C!JY!*B%A<*6%;!*B87<#87@!47*?%'(!>*?%93@!C3';6%9'*B!(?93A@!<*>7!477'!
7Q*5%'78!3'87?!6<7!@6*'8*?8!
?7*;6%9'!;9'8%6%9'@!87@;?%478!%'!-;<757!hS
`!*'8!6<7!?7@3B6@!
*?7!(%>7'!
-;<757!hSi
S!,'!;9'6?*@6!R%6<!;#;B9<7Q*'7;*?49Q#B%;!*B87<#87N!
;#;B9A7'6*'7;*?49Q#B%;!*B87<#87!T
TQKX!(*>7!496<!B9R7?!#%7B8!*'8!7'*'6%9@7B7;6%>%6#!TgIZN!
iJZ!!!XS!W9?!4?*';<78!*B%A<*6%;!*B87<#87@N!6<7!43BV%7@6!
"436#B!*B87<#87!T
TQGX!*CC9?878!
6<7!A?983;6!R%6<!<%(<7@6!7'*'6%9@7B7;6%>%6#!*'8!B9R7@6!#%7B8N!R<%;<!%@!YiZ!
!!!*'8!HKZ!
#%7B8S!0<7!96<7?!@%5AB7!B%'7*?!*B87<#87@!R%6<!8%CC7?7'6!;*?49'!'3547?@N!@3;<!*@!
436#?*B87
<#87!T
TQ_X!*'8!A7'6*'*B!T
TQFX!(*>7!KIZ!*'8!iIZ!#%7B8!*'8!KYZ!
!!!*'8!YIZ!
!!N!?7@A7;6%>7B#S!W9?!'9'*'*B!
TQI!R%6<!*!B9'(7?!;*?49'!;<*%'N!5987?*67!#%7B8!TiKZ!#%7B8X!
*'8!7'*'6%9@7B7;6%>%6#!TKJZ!
!!X!R*@!946*%'78S!:*'#!C3';6%9'78!*B%A<*6%;!@34@6?*67@!R7?7!
*B@9!67
@678!%'!6<7!?7*;6%9'S!,6!R*@!87B%(<6C3B!69!@77!6<*6!@%B#B!76<7?!T
TQE^'i
XN!576<#B!7@67?!
++P(OEt)
2OHP(OEt)
2HNONH2HO10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
OHHO(S)-78a10 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
1.0 equiv.
76a1.0 equiv.
64m1.0 equiv.
65a!cK!TTQ`XN!A?967;678!*5%'7@!T
TQW^'L
XN!4?959!*B87<#87!T
TQSX!*'8!*L%89!*B87<#87@!T
TQfX!;*'!
*BB!A*?6%;%A*67!%'!6<7!?7*;6%9'!69!(%>7!6<7!87@%?78!A?983;6@!R%6<!5987?*67!69!(998!#
%7B8@!
*'8!*?93'8!YIZ!
!!S!0<?93(<!B*67?!@6*(7!598%C%;*6%9'@N!6<9@7!
!M*5%'9!A<9@A<9'*67@!
;93B8!A967'6%*BB#!47!6?*'@C9?578!%'69!>*B3*4B7!596%C@!%'!A<*?5*;736%;*B!*'8!%'83@6?%*B!
C%7B8@S!+!<%(<7?!#%7B8!R*@!94@7?>78!THgZ!>@S!chZX!C9?!6<7!?7*;6%9'!R%6<!A<6<*B%5%8
7!@34@6?*67!T
TQLXN!R<7'!%';?7*@%'(!6<7!?7*;6%9'!6%57!C?95!J`!<93?@!69!iH!<93?@S!!
b7A6M`M#'*B!T
TQAX!*'8!<7Q
McM7'*B!T
TQ@X!R7?7!*B@9!7Q*5%'78!%'!6<7!?7*;6%9'S!0<7!C9?57?!(*>7!cIZ!
#%7B8!*'8!YIZ!
!!!*'8!6<7!B*67?!(*>7!HIZ!*'8!KKZ!
!!S!b9R7>7?N!C9?!6<7!;#;B%;!*BV7
'7!@34@6?*67!T
TQJXN!6<7!;9??7@A9'8%'(!A?983;6!R*@!*B59@6!?*;75%;!%'!HcZ!#%7B8S
!(DIGSG'
P=T'(DALG'AK'HWELIH?ED'HWBGIYBGJ
H'''!!RHO+P(OEt)
2OHRP(OEt)
2HNONH2HO10 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
4† M.S (
(200 wt%
), 23 ¡C
10 mol% benzoic acid 
toluene, 16-72h
1.0 equiv.
64m1.0 equiv.
65aOH+1.0 equiv.
76a-s
b(S)-78a-s
HOHOHOOHHOHOHO476a52%, 91% ee76f40%, 71% ee48%, -71% ee (R)
76c83%, 91% ee84%, -91%ee (R)
76d48%, 80% ee40%, -83% ee (R)
76b80%, 89% ee76e28%, 97% ee16%, -97% ee (R)
76h78%, 81% ee70%, -81% ee (R)
HO76g70%, 90%ee71%,  -90%ee (R)
!cY!(DIGSG'P=T'aDA>?E>CGBb
'''*d%?;9'%35!;*6*B#@6@!R7?7!A?7A*?78!4#!@6%??%'(!*!5%Q63?7!9C!JSI!
7D3%>*B7'6!9C!d?T1
*G?X
gsb1
*G?N!JSI!
7D3%>*B7'6@!9C!2
M576<#B!%5%8*L9B7!T2:,X!*'8!hSI!7D3%>*B7'6@!9C!B%(*'8!%'!8?#!69B37'7!C9?!hI!5%'367@!*6!?995!
675A7?*63?7!3'87?!6<7!*%?a!HII!R6Z!gj!59B7;3B*?!@%7>7@!?7B*6%>7!69!6<7!5*@@!9C!
QND!R7?7!*8878a!
4+BB!#%7B8@!
*?7!%@9B*678!#%7B8@!*'8!
!!!R*@!8767?5%'78!4#!bGPEa!
;T2XM%@957?!9C!6<7!A?983;6!R*@!946*%'78!R<7'!T
2XM""3MO+21P!R*@!3@78!%'!6<7!?7*;6%9'!*'8!
!!!R*@!@<9R'!%'!5%'3@S
!P=O'(Y>?IGJEJ'AK'SA>A
-JC_J?E?C?GB
-M-IYB@AdYH>EWE>GJ''0<7!@#'6<7@%@!9C!6<7!
59'9
M@34@6%63678
MHM<#8?9Q#*'%B%'7@!*BB!@6*?678!C?95!6<7%?!
;9??7@A9'8%'(!A<7'9B@!4#!'%6?*6%9'!*'8!6<7%?!?783;6%9'!69!(7'7?*67!A?9A7?!H
M<#8?9Q#*'%B%'7@S!T
0*4B7!hSJJXS!HOTBSO
76i44%, 85% ee (48h)
40%, -85% ee (48h,R)
HTBSO
O76j53%, 85% ee (24h)
51%, -81% ee (24h,R)
MeOOC
OH76k33%, 93%ee41%, -93%ee (R)
BocHNHO76l64%, 95% ee 63%, -95% ee (R)
HO76m60%, 87%ee66%, -86%ee (R)
HO76n63%, 91%ee 50%, -89%ee (R)
HONHOOO76p53%, 91%ee (72h)
24%, 91%ee (16h, R)
N3HO76q52%, 90%ee (48h)
66%, -90%ee (48h, R)
HO76r20%, 88%ee14%, -88%ee, (R)
HO76s25%, 3%ee76o50%, 91%ee 45%, -89%ee (R)
BrN3!`I!#H_WG'P=<<'(Y>?IG?ED'@AC?G'KA@'SA>A
-P-JC_J?E?C?GB
-M-IYB@AdYH>EWE>GJ' '!/!Z!$%7B8!T'%6?*6%9'X
!Z!$%7B8!T?783;6%9'X
!J*!:7!
aQNKb
!HIochp!iI!H!%G?9A#B!
aQNib
!Jiocgp!iI!h!*&+
G?9A#B!
aQN`b
!Hcoccp!ic!g!""36#B!
aQNSb
!ccoc`p!iI!*0<7!'%6?*6%9'!R*@!;*??%78!%'!6<7!*;76%;!*;%8!R%6<!'%6?%;!*;%8!*6!
MJcqES
!P9R!#%7B8@!R7?7!6#A%;*BB#!
*;<%7>78!%'!6<7!C%?@6!'%6?*6%9'!@67AS!W9?!6<7!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNSXN!?7*;6%9'!6%57!R*@!h!8*#@N!R<%;<!(*>7!6<7!87@%?78!A?983;6!%'!ccZ!
#%7B8S!0<7!@34@7D37'6!?783;6%9'!R%6<!<#8?*L%'7!3@3*BB#!(%>7@!*?93'8!iIZ!#%7B8!C9?!59@6!
9C!6<7!*'%B%'7@S!/7;?#@6*B
B%L*6%9'!'778@!69!47!;*??%78
!936!*C67?!A3?%C%;*6%9'!4#!CB*@<!;9B35'!
;<?95*69(?*A<#S
!P=Q'/@GWESE>H@Y'SGDIH>EJS'E>RGJ?EFH?EA>
'-7>7?*B!@76@!9C!7QA7?%57'6@!R7?7!;9'83;678!69!%'>7@6%(*67!6<7!57;<*'%@5!9C!6<7!
?7*;6%9'S!W%?@6B#N!6<7!H
M576<9Q#
MhNcM8%*&+
A?9A#B*'%B%'7!T
QNDeX!R*@!@#'6<7@%L78!*'8!67@678!
3'87?!6<7!@6*'8*?8!;9'8%6%9'@!C9?!*?95*6%;!*B87<#87@!T.D3*6%9'!hSJXS!1'B#!*!YZ!#%7B8!9C!
?*;75%;!A?983;6!R*@!94@7?>78!*C67?!6<7!?7*;6%9'S!0<%@!%5AB%7@!6<*6!6<7!<#8?9Q#B!(?93A!9'!
6<7!*'%B%'7!%@!V7#!69!496<!6<7!
#%7B8!*'8!*@#5576?%;!%'83;6%9'S!+@!87@;?%478!%'!;<*A67?!6R9!
TW%(3?7!HSJXN!%'!A?7>%93@!@638%7@!9'!6<7!:*''%;<!?7*;6%9'
oh`pN!*!
L%?;9'%35!;95AB7Q!
%'67?578%*67!R*@!A?9A9@78!R%6<!*!;9>*B7'6!49'8!476R77'!6<7!9Q#(7'!9'!6<7!*'%B%'7!*'8!
6<7!L%?;9'%35!576*BS!,'!6<7!A?7@7'6!?7*;6%9'N!6<7!A<7'9B!<#8?9Q#B!%@!;7?6*%'B#!%5A9?6*'6!
*'8!5*#!47!%'>9B>78!%'!b
M49'8%'(!R%6<
!6<7!;*6*B#@6!9?!<*>7!*!;9>
*B7'6!49'8
!R%6<!6<7!
;*6*B#@6S!
!HNO3OHOHNO2hydrazine
OHNH2RRRH2O/Et
2O, r.t
graphite, EtOH
reflux
64f, 64j, 64k, 64m
!`J!*fCH?EA>'
P=<'#IG'J?H>BH@B'@GHD?EA>'\E?I'M
-SG?IAdY
-P^O-BE"#$L@ALYWH>WE>G'!',6!%@!V'9R'!6<*6!>*?%93@!;*6*B#@6@!C*;%B%6*67!6<7!?7*;6%9'!9C!A<9@A<%67@!R%6<!
*B87<#87@!69!(%>7!
!M<#8?9Q#B!
A<9@A<9'*67@S
ocip!0<3@!*!!;9
'6?9B!7QA7?%57'6!R*@!;*??%78!
936!%'!6<7!8
KM69B37'7!69!8767;6!6<7!7Q%@67';7!9C!*'#!4*;V(?93'8!?7*;6%9'@!T.D3*6%9'!hSH
MhScXS!E#;B9<7Q*'7;*?49Q#B%;!*B87<#87!T
TQHX!*'8!8%76<#B!A<9@A<%67!T
QOHX!R7?7!@6%??78!
3'87?!6<7!@6*'8*?8!?7*;6%9'!;9'8%6%9'@!C9?!J`!<93?@S!+C
67?!;95A*?%'(!R%6<!6<7!b
J2:/!
@A7;6?35!9C!A3?7!8%76<#B!A<9@A<%67!*'8!T-X
M"43MO+21PN!%6!R*@!;9';B3878!6<*6!'9!
!M<#8?9Q#B!A<9@A<9'*67!
R*@!
C9?578!*'8!9'B#!@6*?6%'(!5*67?%*B@!R7?7!94@7?>78S
!*fCH?EA>'
P=M'#IG'@GHD?EA>'AK'DYDWAIGdYW'DH@_AdYWED'HWBGIYBG'
H>B'BEG?IYW'LIAJLIE?G
''0<7'!%6!R*@!87;%878!69!;<7;V!*'8!@77!%C!*'#!?7*;6%9'!476R77'!8%76<#B!A<9@A<%67!
TQOHX!*'8!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNDX!*;?9@@!3'87?!6<7!@6*'8*?8!?7*;6%9'!;9'8%6%9'@!
436!9'B#!@6*?6%'(
!5*67?%*B@!R7?7!8767;678!*C67?!J`!<93?@!R<7'!6<7!?7*;6%9'!R*@!C9BB9R78!
%'!8KM69B37'7!T.D3*6%9'!hShXS
!++P(OEt)
2OHP(OEt)
2HNONH2MeO
5 mol% [Zr(O
iPr)
4 / NMI / (
S)-tBu-VANOL]
(1:1:3)
OMe
OH(S)-799% yield, 0 ee10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
toluene, 16h
1.0 equiv.
63a1.0 equiv.
64cÕ1.0 equiv.
65a10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
d8-toluene, 16h
P(OEt)
2OH10 mol%[Zr(O
ipr)4 / NMI / (
R)-tBu-VANOL]
(1:1:3)
+HOP(OEt)
2OHO1.0 equiv.
76a1.0 equiv.
65anot detected
!`H!*fCH?EA>'
P=P'#IG'@GHD?EA>'AK'M
-IYB@AdY-P-!_C?YWH>EWE>G
'H>B'BEG?IYWLIAJLIE?G
'','!*'!*88%6%9'
*B!7QA7?%57'6N!H
M<#8?9Q#
MhM"436#B*'%B%'7!T
QNSX!*'8!
;#;B9<7Q*'7;*?49Q#B%;!*B87<#87!T
TQHX!R7?7!?7*;678!3'87?!6<7!@6*'8*?8!?7*;6%9'!
;9'8%6%9'@!%'!8
KM69B37'7!T.D3*6%9'!hSgXS!"96<!@6*?6%'(!5*67?%*B@!R7?7!;9'@3578!*'8!*!
'3547?
!9C!A?983;6@!R7?7!94@7?>78!4#!0PE!*'8!
Jb!2:/S!0<3@N!6<7!%5%'7!
5*#!<*>7!
C9?578N!436!?7*;678!69!(%>7!96<7?!;95A93'8@S!P*67?!*6675A6@!69!@#'6<7@%L7!6<%@!@*57!
%5%'7!4#!6?*8%6%9'*B!%5%'7!(7'7?*6%9'!576<98@
!C*%B78SocKp!!]%>7'!6<*6!6<7!53B6%
M;95A9'7'6!
U*4*;<'%V
MW%7B8@!?7*;6%9'@!897@!R9?VN!%6!%@!6<93(<6
!B%V7B#!9';7!6<7!%5%'7!%@!C9?578!%'!6<7!
A?7@7';7!9C!6<7!;*6*B#@6N!%6!%5578%*67B#!?7*;6@!R%6<!6<7!A<9@A<%67S!
!*fCH?EA>'
P=N'#IG'@GHD?EA>'AK'DYDWAIGdYW'DH@_AdYWED'HWBGIYBG'H>B'M
-IYB@AdY-P-!_C?YWH>EWE>G
''P=T'5GL@A?GD?EA>'AK'
!-HSE>A'LIAJLIA>H?GJ
'29R!6<*6!!6<7!A?967;678!
!M*5%'9!A<9@A<9'*67@!*?7!%'!<*'8N!*!A?9A7?!576<98!R*@!
'77878!69!?759>7!6<7!hNc
M8%*&+
A9?A#B
MHM<#8?9Q#
MA<7'#B!9?!h
M"436#B
MHM<#8?9Q#
MA<7'#B!
10 mol% benzoic acid
4† M.S (
200 wt%
),  23¡C
d8-toluene, 16h
P(OEt)
2OHNH210 mol%[Zr(O
iPr)
4 / NMI / (
R)-tBu-VANOL]
(1:1:3)
OH+1.0 equiv.
64m1.0 equiv.
65ano reaction
NH2OH10 mol% benzoic acid
4† M.S (
200 wt%
), 23¡C
d8-toluene, 16h
10 mol%[Zr(O
iPr)
4 / NMI / (
R)-tBu-VANOL]
(1:1:3)
+HONHOH1.0 equiv.
76a1.0 equiv.
64mnot detected
!`h!A?967;6%'(!(?93A!9'!6<7!'%6?9(7'!69!*;;7@@!6<7!3'A?967;678!C9?5@!9C!
!M*5%'9
!A<9@A<9'*67@S!
!P=T=<'5GL@A?GD?EA>'AK'?IG'H@ASH?ED'
!-HSE>A'LIAJLIA>H?GJ'_Y'!"0'H>B'A?IG@'
AdEBH>?J
'0<7!59@6!;9559'!R*#!69!?759>7!6<7!G:G!TA*?*
M576<9Q#BA<7'#BX!(?93A!9'!!
'%6?9(7'!%@!4#!3@%'(!E+2!T;7?%;!*559'%35!'%6?*67X!%'!*!;9
M@9B>7'6!9C!R*67?!*'8!
*;769'%6?%B7S
ohHN!h`
p!-%';7!6<7!A?967;6%'(!(?93A@!%'!
!M*5%'9!
A<9@A<9'*67@!A?983;78!%'!6<%@!
R9?V!*?7!?7B*678!69!6<7!G:G!(?93AN!6R9!8%CC7?7'6!;9'8%6%9'
@!R%6<!E+2!R7?7!C%?@6!7Q*5%'78!
T0*4B7!hSJ
HXS!#H_WG'P=<M'5GL@A?GD?EA>'AK'QPH'_Y'!"0
''!e!T7D3%>SX
!*88%6%>7
!Z!$%7B8
!J!g!J!2!b21
h!2)!H!c!'9'7!2)!!!!!!!!!!!!!!!!!!!!!!!!!!2)u!'96!8767;678S
!0<7?7!R*@!'9!87@%?78!87A?967;678!A?983;6!(7'7?*678!%'!7%6<7?!9C!6<7!6R9!?7*;6%9'@S!
,'@67*8N!*!@%87!A?983;6!
U<!9C!hhZ!#%7B8!R*@!94@7?>78S!0<7!A?9A9@78!57;<*'%@5!C9?!6<7!
C9?5*6%9'!9C!6<%@!@%87!A?983;6!%@!87@;?%478!%'!@;<757!hS
KS!P(OEt)
2HNOHOP(OEt)
2NH2OCAN (X equiv.)
additive
MeCN/H
2O (1:!)
0-25¡C, 3.5h
67a80!`g!(DIGSG'
P=U'/@ALAJGB'SGDIH>EJS'KA@'?IG'KA@SH?EA>'AK'U<
'','@67*8!9C!9Q%8%L%'(!6<7!A<7'#B!?%'(!9'!6<7!'%6?9(7'
N!*@!R93B8!47!7QA7;678!%'!6<7!
'9?5*B!G:G!87A?967;6%9'!A*6<R*#N!6<7!'%6?9(7'!%6@7BC!%'!
QTH!R*@!9Q%8%L78!4#!E+2!69!
(7'7?*67!*!?*8%;*B!;*6%9'!
UMS!0<%@!%@!C9BB9R78!4#!;B7*>*(7!9C!6<7!E
MG!49'8!*'8!6<7'!*66*;V!
4#!9Q#(7'!9'69!6<7!E
M2!8934B7!49'8!9C!6<7!%55%'%35!;
*6%9'!UP'69!(*>7!6<7!?%'(
M;B9@78!
%'67?578%*67!
UN='+C67?!6<7!@7;9'8!9Q%8*6%9'!9C!6<7!'%6?9(7'!4#!E+2!*'8!*4@6?*;6%9'!9C!
<#8?9(7'!4#!6<7!A?7>%93@B#!?7B7*@78!A<9@A<9'*67!?*8%;*B!C?95!6<7!%'67?578%*67!
UO^'6<7!C%'*B!A?983;6!
U<!R*@!946*%'78S!0<%@!A?9A9@78!57;<*'%@5!%'8%;*67@!6<*6!6<7!E+2!9Q%8*6%9'!
A?7C7?@!69!6*V7!AB*;7!9'!'%6?9(7'!?*6<7?!6<*'!9'!6<7!A<7'#B!?%'(!%'!
QTH'*'8!6<7!@34@7D37'6!
;B7*>*(7!9C!6<7!E
MG!49'8!5*V7@!6<%@!@67A!'9'
M?7>7?@%4B7S!0<7?7C9?7N!69!*>9%8!6<7!
9Q%8*6%9'!9C
!6<7!'%6?9(7'N!%6!R*@!6<93(<6!69!*88!*'!7B7;6?9'!R%6<8?*R%'(!(?93AN!@3;<!*@!
P(OEt)
2HNOHONOPhP(OEt)
2HNOHOCANPOOEt
EtOHNHOHNOPhHCANHNOPhHPOOEt
EtO-H+PHOOEt
EtO-H+67a8281838485!`c!"9;N!9'!6<7!'%6?9(7'N!R<%;<!;93B8!A9@@%4B#!%';?7*@7!6<7!8%CC%;3B6#!9C!6<7!9Q%8*6%9'!9C!6<7!
'%6?9(7'S!+B67?'*6%>7B#N!6<7!A<7'9B!;93B8!47!576<#B*678!*'8!6<%@!5*#!;*3@7!*!;<*'(7!%'!
6<7!9Q%8*6%9'S!
!+C67?!6?7*6%'(!
QTH!R%6<!576<#B!%98%87!*'8!A96*@@%35!;*?49'*67!%'!):WN!
TV'R*@!
A?983;78!%'!icZ!#%7B8S!0<7'!%6!R*@!
6?7*678
!R%6<!g!7D3%>*B7'6@!9C!E+2S!+!5%Q63?7!9C!@7>7?*B!
3'V'9R'!;95A93'8@!R7?7!A?983;78N!'9!87@%?78!A?983;6!
UX!436!6<7!@*57!@%87!A
?983;6!
U<'R*@!8767;678!THIZ!#%7B8X!T.D
3*6%9'ShScXS
!*fCH?EA>'
P=O'5GL@A?GD?EA>'AK'?IG'SG?IYWH?GB'L@ABCD?'TV'_Y'!"0
'!0<7!"9;
M*5%87!
QT_N!R<%;<!@#'6<7@%L78!4#!"9;!*'<#8?%87!*'8!):+G!%'!igZ!#%7B8S!
,6!?7*;678!R%6<!cSI!7D3%>*B7'6@!
9C!E+2!*@!%'8%;*678!%'!.D3*6%9'!hS`S!+C67?!JH!<93?@!9C!
@6%??%'(N!*BB!@6*?6%'(!5*67?%*B!R*@!;9'@3578!436!'9'7!9C!6<7!87@%?78!A?983;6!
2AD-UX!R*@!
C9?578!T.D
3*6%9'ShS`XS
!*fCH?EA>'
P=Q'5GL@A?GD?EA>'AK'?IG'_AD'L@A?GD?GB'QT_'_Y'!"0'
''P(OEt)
2HNOMeO
P(OEt)
2NH2OCAN (4 equiv.)
MeCN/H
2O (1:1)
0-25¡C, 3.5h
7975%80not detected
P(OEt)
2HNOHOMeI (1.25 equiv.)
K2CO3 (2.0 equiv.) 
DMF
67aP(OEt)
2BocNOHOMeO
P(OEt)
2NHBocOMeO
HNO3 (1.0 equiv.)
CH3CN/H2O (1:1)
0¡C-r.t, overnight
CAN (5.0 equiv. )
Boc-67b
Boc-80
not detected
Boc2O (1.2 equiv.)
DMAP (1.2 equiv.)
DCM, 0¡C-r.t
P(OEt)
2HNOHOMeO
67b!``!-%';7!;B7*>*(7!9C!2
MA?967;6%'(!(?93A!R%6<!!E+2!8%8'_6!R9?V!9'!7%6<7?!"9;!A?967;678!
9?!576<9Q#B*678!U*4*;<'%V
MW%7B8@!*883;6@N!96<7?!9Q%8*'6@!
ocYp!R7?7!67@678!%'!6<7!?7*;6%9'S!
0?%;<B9?9%@9;#*'3?%;!*;%8!T0EE+XN!A#?%8%'%35!4?95%87
MA7?4?95%87!TG""XN!
T)%*;769Q#%989X47'L7'7N!)7@@
M:*?6%'!?7*(7'6!*'8!A7?%98%;!*;%8!R7?7!7Q*5%'78!R%6<!6<7!
@*57!
87A?967;6%9'!;9'8%6%9'!9C!E+2!T0*4B7!hSJ
hX!*'8!C9?!6<7!)7@@
M:*?6%'!?7*(7'6!*'8!
A7?%98%;!*;%8N!6<7#!<*8!477'!*B@9!67@678!R%6<!"9;!A?967;678!
QT_'*@!6<7
!@6*?6%'(!5*67?%*B!
T'96!B%@678XS!b
9R7>7?
N!C?95!*BB!6<7@7!?7*;6%9'@N!'9!87@%?78!*5%'7!A?983;6!R*@!94@7?>78!
*'8!?7*;6%9'!3@3*BB#!(*>7!6<7!'%6?9(7'!9Q%8%L78!A?983;6@
'R%6<!*!5%Q63?7!9C!96<7?!3'V'9R'!
;95A93'8@S!
!#H_WG'P=<P'5GL@A?GD?EA>'AK'QPH'_Y'
A?IG@'AdEBH>?J
''!9Q%8*'6
!Z!$%7B8
!J!0EE+
!2)!H!G""!2)!h!G<,T1+;X
H!2)!g!)7@@
M:*?6%'!?7*(7'6
!2)!c!bc,1`!2)!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!2)u!'96!8767;678
!P=T=M'5GL@A?GD?EA>'AK'?IG'H@ASH?ED'
!-HSE>A'LIAJLIA>H?GJ'_Y'0
-IHWAJCDDE>ESEBG','!6<7!R9?V!9C!-<%4*6*!*'8!;9
MR9?V7?@N!2
M4?959@3;;%'%5%87!T2"-X
'R*@!3@78!69!
;B7*>7!6<7!G:G!(?93A!9'!
6<7%?!U*4*;<
'%VMW%7B8@!A?983;6@!T-;<757!hSY
XSohcp!+;;9?8%'(!69!
6<7%?!A?969;9BN!JSI!7D3%>*B7'6!9C!2"-!%'!*!;9
M@9B>7'6!9C!R*67?!*'8!*;769'%6?%B7!R*@!*8878!
69!T
,XMUQ!*'8!6<7!5%Q6
3?7!
R*@!
R*?578!C?95!!I!qE!69!?995!675A7?*63?7S!0<7!87A?967;678!
P(OEt)
2HNOHOP(OEt)
2NH2Ooxidant (4 equiv)
MeCN/H
2O (1:!)
0-25¡C, 3.5h
67a80!`i!!M*5%'9!A<9@A<9'*67@!T
,XMUT!R*@!946*%'78!%'!ccZ!#%7B8!R%6<!'9!B9@@!%'!6<7!9A6%;*B!A3?%6#S!
0<7@7!@*57!;9'8%6%9'@!R7?7!*AAB%78!69!
QTHS!+!5%Q63?7!9C!6<7!@6*?6%'(!5*67?%*B!*'8!96<7?!
3'V'9R'!
;95A93'8@!R*@!946*%'78N!436!'9!87@%?78!A?983;6!T
UX_X!R*@!C93'8!T0*4B7!hSJ
hN!7'6?#!JXS
!(DIGSG'
P=V'(IE_H?HeJ'BGL@A?GD?EA>'L@A?ADAW'\E?I'02(
' '#H_WG'P=<N'5GL@A?GD?EA>'_Y'02(
''!+88%6%>7
!Z!$%7B8
!J!29'7
!2)!H!J:!b
H-1g!TJSI!7D3%>SX
!2)!h!J:!b
H-1g!TJISI!7D3%>SX
!2)!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!2)u!'96!8767;678S
!+'96<7?!A?9;783?7!6<*6!R*@!?7A9?678!4#!/36&7@
ocYp!%';B3878!6<7!*88%6%9'!9C!JSI!
7D3%>*B7'6!9C!J:!
@3BC3?%;!*;%8
!*B9'(!R%6<!6<7!2"-S!0<%@!A?9;783?7!R*@!*B@9!67@678!R%6<!
JSI!7D3%>*B7'6
!*'8!JI
SI!7D3%>*B7'6@
!9C!b
H-1g!T0*4B7!hSJJN!7'6?#!H!*'8!hXN!<9R7>7?!'9!
87@%?78!A?983;6!R*@!8767;678!*'8!6<7!
Jb!2:/!R*@!57@@#S!
!HNPPMPOOArOAr(S)-86, 90% 
eeAr= 
o-CH
3OC6H4NBS (1.0 equiv.)
H2O/CH3CN (1:1)
0¡C to r.t., 1h
NH2POOArOAr(S)-87, 55%
90% eeP(OEt)
2HNOHOP(OEt)
2NH2ONBS (1.0 equiv.)
additive
H2O/CH3CN (1:1)
r.t, overnight
MeO
MeO
67ka80b!`K!0<7!"9;!A?967;678!
QT_'R*@!?7
*;678
!R%6<!2"-N!2E-!T2
M;<B9?9@3;;%'%5%87X!*'8!
2,-!T2
M%989@3;;%'%5%87X!*'8!6<7?7!R*@!*!5*&9?!@%87!A?983;6!Tv!hIZ!#%7B8X!C9?578!*C67?!
6<7!?7*;6%9'@!TW%(3?7!hSJXS
!4EFC@G'P=<'<3'0)+'JLGD?@CS'AK'H'SHiA@'JEBG'L@ABCD?'AK'BGL@A?GD?EA>'_Y'08('\E?I'
QT_'!!!+6!C%?@6N!6<7!5%Q63?7!R*@!6<93(<6!69!47!*!;954%'*6%9'!9C!6<7!87@%?78!A?983;6!
UX'*'8!*'96<7?!%5A3?%6#S!,C!6<7!@%'(B76!*6!`Sh!AA5!T%'!4B37!;%?;B7X!*'8!6<7!6R9!8934B76@!*6!JSIY!AA5!
*'8!ISKc!AA5!T%'!4B37!;%?;B7X!R7?7!7Q;B3878N!6<7!96<7?!A7*V@!@775!69!5*6;<!R7BB!R%6<!6<7!
P(OEt)
2NHBocOMeO
no desired 80 was observedP(OEt)
2BocNOHOMeO
1M H
2SO4 (1.0 equiv.)
CH3CN/H2O (1:1)
overnightNXS(1.0 equiv.)
67b?X= Cl, Br, I
!`Y!87@%?78!A?983;6!
UXS!0<3@N!6<%@!@*5AB7!R*@!@34&7;678!<%(<!?7@9B36%9'!5
*@@!*'*B#@%@!
Tb/:-XN!436!'9!7Q*;6!5*@@!9C!6<7!87@%?78!
UX!R*@!C93'8S
!-%';7!87A?967;6%9'!9C!6<7!"9;!A?967;678!
QT_'R7?7!C*%B78!3'87?!8%CC7?7'6!
87A?967;6%9'!;9'8%6%9'@!T.DS!hS`XN!6<7!87A?967;6%9'!9C!
QTH!R*@!6<7'!*6675A678!%'!6<7!C9?5!
9C!%6@!576<#B!76<7?!
TV!TW%(3?7!hSHXS
!4EFC@G'P=M'<3'0)+'JLGD?@CS'AK'?IG'BGL@A?GD?EA>'AK'TV'\E?I'02('H>B'JCWKC@ED'HDEB'
'!!P(OEt)
2HNOMeO
P(OEt)
2NH2O1M H
2SO4 (1.0 equiv.)
CH3CN/H2O (1:1)
r.t, 6h
NBS (1
 equiv.)
8079P(OEt)
2HNOMeO
79!iI!0<7!?7*;6%9'!5%Q63?7!C
9?!TV!*'8!2"-!9'!*!@%B%;*!(7B!;9B35'!69!(%>7!
6R9!5*&9?!
A9?6%9'@!R<%;<!R7?7!;9BB7;678!*'8!7Q*5%'78!4#!
Jb!2:/S!"#!;95A*?%@9'!R%6<!6<7!
Jb!2:/!
@A7;6?35!9C!6<7!@6*?6%'(!5*67?%*B!
TV'T*6!6<7!496695N!W%(3?7!hSHXN!6<7!69A!@A7;6?35!R*@!9C!
*!5%Q63?7!9C!@6*?6%'(!5*67?%*B!
TV!*'8!*'!3'V'9R'!@%87!A?983;6N!R<%;<!
R*@!*!@%5%B*?!@%87!
A?983;6!@77'!%'!W%(3?7!hSJN!*'8!6<7!@7;9'
8!@A7;6?35!R*@!6<*6!9C!6<7!A3?7!@%87!A?983;6S!
0<7!@*57!?7*;6%9'!R*@!?7A7*678!R%6<936!@3BC3?%;!*;%8!*'8!6<7!
Jb!2:/!@A7;6?35!%@!@<9R'!
%'!W%(3?7!hShS
!4EFC@G'P=P'<3'0)+'JLGD?@CS'AK'?IG'BGL@A?GD?EA>'@GHD?EA>'AK'TV'\E?I'02(
'''!P(OEt)
2HNOMeO
P(OEt)
2NH2OCH3CN/H2O (1:1)
r.t 6h
NBS (1.0 equiv.)
8079P(OEt)
2HNOMeO
79!iJ!)7@A%67!6<7!A?7@7';7!9C!6<7!@*57!@%87!A?983;6N!6<7?7!R*@!'9!@6*?6%'(!5*67?%*B!
TV'B7C6!*'8!*!8934B76!@<9R78!3A!*?93'8!KSH!AA5N!R<%;<!R93B8!47!7QA7;678!C9?!*!A?969'!9'!
*'!%5%'7!;*?49'S!W?95!6<9@7!6R9!?7*;6%9'@N!%6!%@!%'8%;*678!6<*6!%'!9'7!*@A7;6N!@3BC3?%;!*;
%8!%@!;9'@%87?78!69!47!59?7!B%V7B#!69!A?7>7'6!6<7!C9?5*6%9'!9C!%5%'7!4#A?983;6@S!
1'!6<7!96<7?
!<*'8N!6<7!A9@@%4B7!@6?3;63?7
!9C!6<*6!3'V'9R'!@%87!A?983;6!'778@!69!47!A?9A9@78S!
!,'!6<7!
Jb!2:/!@A7;6?35!9C!@6*?6%'(!5*67?%*B!
TVN!6<7?7!*?7!6R9!@%'(B76!A7*V@!%'!6<7!
?*'(7!9C!`SI
M`Sc!AA5!TW%(3?7!hSHN!6<7!496695!@A7;6?35X!*'8!6<9@7!*?7!6<7!6R9!A?969'@!9'!
6<7!A<7'#B!?%'(!9'!6<7!'%6?9(7'S!!b9R7>7?N!%'!6<7!
Jb!2:/!@A7;6?35!9C!6<7!3'V'9R'N!9'B#!
9'7!@%'(B76!*AA7*?@!*6!`SH!AA5!TW%(3?7!hSHN!
6<7!5%88B7!@A7;6?35XS!,'!93?!<#A96<7@%@N!9'7!
9C!6<7!A?969'!%'!6<7!*?95*6%;!?*'(7!%@!@3AA9@78!69!47!?7AB*;78!4#!4?95%'7S!0R9!A9@@%4B7!
@6?3;63?7@!R7?7!B%@678!%'!6<7!W%(3?7!hSgS
!4EFC@G'P=N'#\A'LAJJE_WG'J?@CD?C@GJ'AK'?IG'C>`>A\>'J
EBG'L@ABCD?'UU'H>B'UV
''0<7!7Q*;6!5*@@!TAB3@!2*
wX!9C
!6<7!3'V'9R'!;95A93'8
!%@!chgSJhKcN!R<%;<!%@!
%87'6%;*B
!69!6<7!;*B;3B*678!5*@@!9C!7%6<7?!
UU!9?!
UVS!29R!%6!%@!V'9R'!6<*6
!2"-
!?7*;6
78!R%6<!TV!6<?93(<!6<7!7B7;6?9A<%
B%;!*?95*6%;!@34@6%636%9'N!436!6<7!
@34@7D37'6B#!6<7!87A?967;6%9'!
8%8!'96!9;;3?S!,C!59?7!7D3%>*B7'6@!2"-!R*@!*8878!69!6<7!?7*;6%9'N!9'B#!6<7!<#8?9B#@%@!
A?983;6!9C!6<7!
UU!9?!
UV!R%BB!47!946*%'78S!!,'!6<7!;
9'6?*@6!69
!2"-N!2,-!<*@!8%CC7?7'6!7B7;6?9'%;!*'8!@67?%;!@6*63@!*'8!%6!%@!53;<!
<*?87?!C9?!
*88%'(!6<7!%98%'7!69!6<7!A<7'#B!?%'(!6<*'!4?95%'7N!R<%;<!A9@@%4B#!;93B8!A?7>7'6!
P(OEt)
2HNOMeO
BrP(OEt)
2HNOMeO
Br8889!iH!6<7!C9?5*6%9'!9C!6<7!@%87!A?983;6!*'8!A?95967!6<7!87A?967;6%9'S!"#!75AB9#%'(!HSI!
7D3%>*B7'6@!9C!6<7!2,-!*'8!JSI!7D3%>*B7'6!9C!J:!@3BC3?%;!*;%8N!icZ!#%7B8!9C!6<7!87A?967;678!
A?9
83;6!
UX!R*@!C%'*BB#!*;<%7>78!T.D
3*6%9'ShSiXS
!*fCH?EA>'
P=T'5GL@A?GD?EA>'AK'?IG'H@ASH?ED'L@ABCD?'TV'_Y'0&(
''2,-!9Q%8*6%9'!R*@!*B@9!67@678!8%?7;6B#!9'!6<7!U*4*;<%V
MW%7B8@!A?983;6!
QTHN!436!6<7!
?7*;6%9'!*CC9?878!6<7!87@%?78!87A?967;678!
!M*5%'9!A<9@A<9'*67!
UX'%'!9'B#!JIZ!#%7B8S!
0<3@N!%6!%@!;B7*?!6<*6!6<7!87A?967;6%9'!9C!
QTH!R%BB!?7D3%?7!6R9!@67A@S!-A7;%C%;*BB#!6<7!
@6*'8*?8!A?969;9B!C9?!87A?967;6%9'!9C!*?95*6%;!
!M*5%'9!A<9@A<9'*67@!%'>9B>
7@!C%?@6!
576<#B*6%9'!R%6<!576<#B!%98%87!*'8!6<7'!9Q%8*6%9'!R%6<!2,-!69!(
%>7
!UX!%'!9>7?*BB!`cZ!#%7B8S!
T-;<757!hSJ
IXS!0<7!*4@9B367!;9'C%(3?*6%9'!9C!
UX!R*@!;9'C%?578!4#!;95A*?%'(!6<7!
6<7!@%('!9C!%6@!9A6%;*B!?96*6%9'!R%6<!6<*6!?7A9?678!%'!6<7!B%67?*63?7
o`Ip!*'8!.EE)!*B@9!(*>7!6<7!
%87'6%;*B!?7@3B6!4*@78
!9'!6<7!576<98!87>7B9A78!4#!
"*4*V!
"9<*'_@!(?93A!T@77!876*%B@!%'!
;<*A67?!`XS
o`Jp!'''P(OEt)
2HNOMeO
NIS (2.0 equiv.)
CH3CN/H2O (1:1)
H2SO4 (1.0 equiv.)
r.t, 3h
P(OEt)
2NH2O8075%79!ih!(DIGSG'
P=<X'(?H>BH@B'L@ADGBC@G'KA@'
BGL@A?GD?EA>'AK'H@ASH?ED'
!-HSE>A'LIAJLIA>H?GJ
''P=T=P'5GL@A?GD?EA>'AK'?IG'HWELIH?ED'
!-HSE>A'LIAJLIA>H?GJ'_Y'0
-EABAJCDDE>ESEBG'W9BB9R%'(!6<7!@6*'8*?8!A?969;9B!9C!87A?967;6%9'!9C!*?95*6%;!
!M*5%'9!
A<9@A<9'*67@N!%6!R*@!C93'8!6<*6!6<7!576<9Q#B*6%9'!9C!6<7!*B%A<*6%;!
!M*5%'9!A<9@A<9'*67@!
A?983;78!@957!3'V'9R'!@%87!A?983;6@!*'8!6<7!#%7B8!9C!6<7!87@%?78!576<9Q#B*678!A?983;6!
R*@!B9R!Tvh
IZXS!0<3@!6<7!87A?967;6%9'!R*@!7Q*5%'78!8%?7;6B#!R%6<936!576<9Q#
B*6%9'S!TQD'R*@!@7B7;678!69!A7?C9?5!6<7!87A?967;6%9'N!*@!%6@!
!M*5%'9!A<9@A<9'%;!*;%8N!!T
2XMA<9@A<9B73;%'7
oJgMJ`pN!%@!*!
A967'6!%'<%4%69?!9C!6<7!576*BB97'L#57!B7
3;%'7!*5%'9A7A6%8*@7
!%'!4%9;<75%@6?#!T0*4B7!hSJ
gXS!#H_WG'P=<O'5GL@A?GD?EA>'AK'TQD'\E?I'0&(
' !P(OEt)
2HNOHOCH3I (1.25 equiv.)
K2CO3 (2.0 equiv.)
r.t, DMF
NIS (2.0 equiv.)
H2SO4 (1.0 equiv.)
CH3CN/H2O (1:1)
r.t, 3h
P(OEt)
2NH2O8065% (two steps)
(R)-67a
90% ee[a]
D20 = +17.2 (c= 1.0)
[7]
[a]
D20 = +10.2 (c= 0.8)
[a]
D20 = -20.6 (c= 1.0)
[12]
[a]
D20 = -36.7 (c= 0.72)
P(OEt)
2HNOHO NIS (x equiv.)
H2SO4 (1.0 equiv.)
CH3CN/H2O (1:1)
r.t, 3h
P(OEt)
2NH2O9076c!ig!#H_WG'P=<O'aDA>?E>CGBb
'!2,-!TQ!7D3%>SX
!Z!$%7B8
!J!JSI
!Hi!H!hSI
!`I!h!cSI
!cI!!^%6<!*88%'(
!9C!JSI!7D3%>*B7'6!9C!2,-N!6<7!?7*;6%9'!9'B#!*CC9?878!6<7!87A?967;678!
A?983;6!
VX'%'!HiZ!#%7B8S!,';?7*@%'(!6<7!7D3%>*B7'6@!9C!2,-!69!hSIN!6<7!#%7B8!
?7*;<78
!69!`IZS!b9R7>7?N!R<7'!cSI!7D3%>*B7'6@!9C!2,-!R*@!*8878!69!6<7!?7*;6%9'N!6<7!#%7B8!8?9AA78!
69!cIZ!*B9'(!R
%6<!@957!3'V'9R'!@9B%8!@%87!A?983;6@S!2"-!*'8!E+2!R7?7!*B@9!7Q*5%'78!
%'!6<7!87A?967;6%9'!9C!
TQDN!'7%6<7?!9C!6<75!(*>7!6<7!87@%?78!A?983;6!
VXS!0<7!*4@9B367!
;9'C%(3?*6%9'!9C!6<7!
VX!R*@!;9'C%?578!4#!;95A*?%'(!6<7!
6<7!@%('!9C!%6@!9A6%;*B!?96*6%9'!R%6<!
6<*6!?7A
9?678!%'!6<7!B%67?*63?7
o`Hp!*'8!.EE)!576<98
o`JpS!!P=U'!A>DWCJEA>'','!6<%@!;<*A67?N!*!'7R!576<98!C
9?!6<7!*@#5576?%;!U*4*;<'%V
MW%7B8@!?7*;6%9'!R%6<!
*B%A<*6%;!*B87<#87@!R*@!87>7B9A78S!"#!36%B%L%'(!H
M<#8?9Q#
MhM"436#B*'%B%'7!*@!6<7!*5%'7!
@93?;7N!6<7!*@#5576?%;!%'83;6%9'!9C!8%?7;6!6<?77
M;95A9'7'6!
<#8?9A<9@A<9'#B*6%9'
!?7*;6%9'!9C!*B%A<*6%;!*B87<#87@!?7*;<7@!9>7?!YIZ!
!!!C9?!6<7!C%?@6!6%57S!0<7!A?967;6%'(!
(?93A!9'!6<7!A?9
83;6!;93B8!47!;B7*>78!4#!*!'7R
!2,-!87A?967;6
%9'!A?969;9BS!:3B6%
MC3';6%9'*B!*B%A<*6%;!*B87<#87@!R7?7!69B7?*678!3'87?!6<7!5%B8!?7*;6%9'!;9'8%6%9'@!*'8!*CC
9?8!
87@%?78!A?983;6@!R%6<!(998!#%7B8@!*'8!7'*'6%9@7B7;6%>%6%7@S!W?95!57;<*'%@5!
%'>7@6%(*6%9'@N!%6!R*@!C93'8!6<*6!6<7!<#8?9Q#B!(?93A!9'!6<7!*'%B%'7!AB*#@!*'!%5A9?6*'6!?9B7!
%'!*@#5576?%;!%'83;6%9'S!"*@78!9'!96<7?!;9'6?9B!7QA7?%57'6@N!%6!R*@!C93'8!6<7?7!R*@!'
9!4*;V(?93'8!?7*;6%9'!476R77'!6<7!*B87<#87!*'8!6<7!A<9@A<%67S!,'!6<7!C363?7!@638%7@N!59?7!
7QA7?%57'6@!R%BB!47!C9;3@78!9'!(766%'(!*!;?#@6*B!@6?3;63?7!9C!6<7!L%?;9'%35!;*6*B#@6!*'8!69!
*AAB#%'(!6<%@!;*6*B#@6!69!96<7?!*@#5576?%;!?7*;6%9'@!%'>9B>%'(!*'!%5%'7S
!!ic!!3"/#*+'4.,+
''#.#"$'(%0#3*(&('.4'(/3&09.&5'2"(*(
'N=<'&>?@ABCD?EA>
'-A<%'(9B%A%8@!*?7!*'!%5A9?6*'6!;B*@@!9C!B%A%8@!;9'6*%'%'(!6<7!4*;V49'7!9C!@A<%'(9%8!
4*@7@S!0<7#!;*'!47!C93'8!%'!496<!AB*'6@!*'8!*'%5*B@N!*'8!AB*#!>*?%93@!@6?3;63?*B!*'8!
?7(3B*69?#!?9B7@!%'@%87
!6<7!498#S
o`hM`cp!-957!<%(<B#!598%C%78!@A<%'(9B%A%8@N!@3;<!*@!6<7!
@A<%'(9C3'(%'@!*'8!@A<%'(9@%'7!TW%(3?7!gSJX
N!R<%;<!7Q%@6!%'!B9R7?!%'>7?674?*67@!*'8!
5%;?947@!;*'!C3';6%9'!*@!%'<%4%69?@!%'!6<7!A*6<R*#!9C!5*55*B%*'!@A<%'(9B%A%8!
4%9@#'6<7@%@
o``pS!4EFC@G'N=<'(?@CD?C@GJ'AK'JLIE>FAKC>FE>J'H>B'JLIE>FAJE>GJ
' !,'!;9'6?*@6!69!59@6!*BB!@A<%'(%9'9%8!59B7;3B*?N!6R9
M<7*878!@A<%'(9B%A%8@!C?95!
5*?%'7!@A9'(7@!<*>7!*'!3'%D37!6*%B
M69M6*%B!8%57?%;!T4%A9B*?X!@6?3;63?7@!;95A*?78!69!
'9?5*B!@A<%'(9@%'7N!R<%;<!!*?7!;95A9@78!9C!*!
!N'M4%@M*5%'9*BV*'9B!9?!*5%'9*BV*'78%9B@!
596%CS!W
9?!7Q*5AB7N!?<%L9;<*B%'!T
<XXXN!R<%;<!R*@!C%?@6!8%@;9>7?78!'7*?!6<7!'9?6<
MR7@6!
@<9?7!9C!:*8*(*@;*?!%@B*'8!T
MJc5X!%'!JYKY!4#!-69'%V!(?93A!TW%(3?7!gSHX
o`ipN!;9'6*%'@!*!
OHOHNH29sphingosineOHOHNH29OHphytosphingosine
OHOROHOHNHRÕOOHsphingofungin A (R = H; RÕ = C(NH)NH
2)sphingofungin B (R = H; RÕ = H)
sphingofungin C(R = Ac; RÕ = H)
sphingofungin D (R = H; RÕ = Ac)
!i`!EHK!B%A%8!;<*%'!R%6<!496<!7'8@!67?5%'*678!4#!*!>%;%'*B!!*5%'9!*B;9<9B!T9'7!9C!6<75!%@!6<7!
(B#;9@%8%;!*5%'9!*B;9<9BXS!P7
3;766*59B@!+!T
<X<X!*'8!"!T
<XMXN!%@9B*678!%'!JYYH!4#!W*3BV'7?!
*'8!<%@!;9R9?V7?@N!*B@9!<*>7!*!@%5%B*?!@6?3;63?7!TW%(3?7!gSHX
o`KpS!0<9@7!6R9
M<7*878!@A<%'(9B%A%8@!7Q<%4%6!>*?%78!A967'6!4%9B9(%;*B!7CC7;6@!%';B38%'(!*'6%C3'(*B!*;6%>%6#!*(*%'@6!
6<7!A*6<9(7'%;!WB3;9'*L9B7?7@%@6*'6!#7*@6!
4$%9*9$(0:$;#$"$
o`YMiIpN!*'6%4*;67?%*B!*;6%>%6#!
*(*%'@6!
,"$.<=:+)+))6&($6#!6&
o`ipN!*'6%;*?;%'9(7'%;!A?9A7?6%7@
oiJpN!%'83;6%9'!9C!*A9A69@%@!
%'!;3B63?78!B73V75%;!;7BB@
oiHpN!@7B7;6%>7!)2+!8*5*(%'(!*;6%>%6#
oihpN!%'<%4%6%9'!9C!A?967%'!
V%'*@7!E
oigp!*'8!=";Jh
M=7>J+!%'67?*;6%9'
oicpS!4EFC@G'N=M'(?@CD?C@GJ'AK'@IEcADIHWE>'a<XXb'H>B'WGCDG??HSAWJ'a<X<^'<XMb
''b9R7>7?N!3A!69!'9R!6<7?7!%@!9'B#!9'7!?7A9?6!87@;?%478!696*B!@#'6<7@%@!9C!
?<%L9;<*B%'%'!E!T
<XVX!%'!4#!:9B%'@V%_@!(?93A!%'!HIJh
oi`pS!"#!75AB9#%'(!*'!3'A?967;6
78!)
M(B3;9@*5%'7!T
<XPXN!6<7#!8%@;B9@78!*'!9A6%5%L78!A?9;783?7!4*@78!9'!*'!,'
M578%*678!
*BB#B*6%9'!C9?!?*A%8!8%*@67?79@7B7;6%>7!*;;7@@!69!A?967;678!P
M6<?79
M@A<%'(9%8!4*@7!
@#'6<9'@!T
<XNHX!*'8!T
<XN_X!%'!*!C%>7
M@67AN!9'7
MA96!;9'>7?@%9'S!0<%@!A?969;9B!R*@!;<9@7'!
MeNHR2OR1OMeNHR2OR2100Rhizochalin, R
1= !-D-galactopyransyl, R
2= H
MeOHNH2NH2OHMeOHNH2NH2OHOHá2HClá2HCl101leucettamols A
102leucettamols B
!ii!*@!*'!*B67?'*6%>7!69!75AB9#%'(!7QA7'@%>7!)
M*5%'9!*;%8@S!-34@7D37'6!;<*%'!7B9'(*6%9'!9C!
496<!<7*8@!*'8!C%'*B!b9?'7?
M.559'@
M^*8@R9?6<!;93AB%'(!?7*;6%9'!C9BB9R78!4#!
87A?967;6%9'!A?9>%878!6<7!C?77!
4*@7!?<%L9;<*B%'%'!E!T
<XVX!*@!*!@%'(B7!@67?79%@957?!
T-;<757!gSJXS!0<%@!@#'6<7@%@!%@!'9'
M*@#5576?%;!@%';7!%6!@6*?6@!R%6<!)
M(B3;9@*5%'7!C?95!
6<7!;<%?*B!A99BS
!(DIGSG'
N=<'#A?HW'JY>?IGJEJ'AK'@IEcADIHWE>E>'!'a<XVb'K@AS'5
-FWCDAJHSE>G'','!6<7!6R9!A*@6!87;*87@N!6<7!;*6*B#6%;!*@#5576?%;!@#'6<7@%@!9C!
)*&
M!*'8!"#$%&
M!*L%?%8%'*6%9'!<*@!477'!87>7B9A78!%'!93?!(?93AS
oghN!gcN!giN!ii
MKIp!"96<!576<989B9(%7@!R7?7!
*AAB%78!!69!6<7!@#'6<7@%@!9C!*BB!C93?!8%*@67?9%@957?@!9C!@A<%'(*'%'7@!T
<XON!<XQN!<XTN!<XUN!-;<757!gSHXS
oKJMKHp!0<7!C%?@6!*AA?9*;<!%'>9B>78!6<7!@67?79
M;9'6?9BB78!9A7'%'(!9C!7*;<!
7'*'6%957?!9C!;%@
M*L%?%8%'7!*!R%6<!*'!9Q#(7'!'3;B79A<%B7!R%6<!7%6<7?!?767'6%9'!9?!%'>7?@%9'!
9C!;9'C%(3?*6%9'!69!*;<%7>7!*BB!C93?!8%*@67?9%@957?@S
oKJp!!,'!*!@7;9'8!*AA?9*;<N!*!A?7>%
93@!
(?93A!57547?!$34*%!d<93!A34B%@<78!*'96<7?!576<98!*CC9?8%'(!*BB!C93?!8%*@67?7957?@!
8%?7;6B#!>%*!7%6<7?!*!
)*&
'!9?!!
"#$%&
M*L%?%8%'*6%9'!T-;<757!gSHXS
oKHp!!''OHOHNHCbzOHOHNHCbz+threo-
104aerythro
-104b
OOHH2NHOHOOHa. In0,     1,4-dioxane:H
2O (3:1)
    100 ¡CBrb. Cbz-Cl, NaHCO
3, aq.c. NaIO4, H2Od. NaBH4, MeOH
OOHNH25OHOHNH211103D-glucosamine
109 rhizochalinin C
96% 7.5: 1
!iK!(DIGSG'
N=M'(Y>?IGJEJ'AK'HWW'KAC@'BEHJ?G@AEJA
SG@J'AK'JLIE>FH>E>G'_Y'DH?HWY?ED'
HJYSSG?@ED'HcE@EBE>H?EA>
''"*@78!9'!6<7@7!A?95%@%'(!?7@3B6@N!*667'6%9'!R*@!63?'78!69!6<7!@#'6<7@%@!9C!6<7!
59?7!;95AB%;*678!6R9
M<7*878!@A<%'(9%8!4*@7@N!?<%L9;<*B%'%'!E!T
<XVX!*'8!)!T
<<<XoKhMKgpN!;*B#Q%'%'!T
<<XXoihp!*'8!9;7*'%'!T
<<MXo`YMiIN!Kc
p!TW%(3?7!gShXS!0<7#!*BB!<*>7!7%6<7?!*!EHK!9?!
EHY!;<*%'!436!R%6<!8%CC7?7'6!;<%?*B%6#!%'!6<7!*5%'9*BV*'9B!9?!(B#;9@%8%;!*5%'9*BV*'9B!596%C@!
*6!496<!67?5%'%S!,6!R*@!6<93(<6!6<*6!6<7@7!;95A93'8@!;93B8!47!*;<%7>78!>%*!*!;*6*B#6%;!
OHNH2OH12105D-threo
-sphinganine
OHNH2OH12106L-threo
-sphinganine
OHNH2OH12107D-erythro
-sphinganine
OHNH2OH12108L-erythro
-sphinganine
NPGCO2Et12NPGCO2Et12O nucleophileinversionO nucleophileretention
O nucleophileinversionO nucleophileretention
HO12(R)-Borox
catalyst
(S)-Borox
catalyst
NPGCO2Et12NPGCO2Et12NPGCONHR12NPGCONHR12HO12NH2CNHRON2HCOEt
O+PG-NH
2+PG-NH
2(R)-Borox
catalyst
(S)-Borox
catalyst
O nucleophileinversionO nucleophileinversionO nucleophileinversionO nucleophileinversion!iY!*@#5576?%;!*L%?%8%'*6%9'!%'!<%(<!8%*@67?79@7B7;6%>%6#!R%6<936!?7B#%'(!9'!6<7!;<%?*B!A99BS!0<%@!
;<*A67?!R%BB!5*%'B#!C9;3@!9'!6<7!@#'6<7@%@!9C!?<%L9;<*B%'%'!E!T
<XVX!*'8!)!T
<<<XS!4EFC@G'N=P'(?@CD?C@GJ'AK'?IG'?\A
-IGHBGB'JLIE>FAEB'
_HJGJ'@IEcADIHWE>E>'!'a<XVb'H>B'
5'a<<<b^'DHWYdE>E>'a<<Xb'H>B'ADGH>E>'a<<M
b'!N=M'9G>G@HW'JY>?IG?ED'@AC?G'?A'?IG'KAC@'?\A
-IGHBGB'JLIE>FAEB'_HJGJ'<XV-<<M'0<7!(7'7?*B!@#'6<76%;!87@%('!%@!936B%'78!%'!-;<757!gShS!,6!R*@!7'>%@%9'78!6<*6!6<7!
@#'6<7@%@!9C!6<7!C93?
!6R9M<7*878!@A<%'(9%8!4*@7@!;93B8!47!*;;95AB%@<78!4#!*!;93AB%'(!
?7*;6%9'!9C!B7C6!<7*8!*'8!?%(<6!<7*8!C?*(57'6@N!R<%;<!%'!63?'!;93B8!47!946*%'78!C?95!7%6<7?!
6<7!;*6*B#6%;!*@#5576?%;!;%@
M!9?!6?*'@
M*L%?%8%'*6%9'!C9BB9R78!4#!6<7!?%'(
M9A7'%'(!?7*;6%9'S!
!!!!!!!!!ONH213OHNH2OH5O13OHNH2OH5NH2OHO13OHNH2NH2OH5ONH213OHNH2OH6OHOH109 rhizochalinin C
111 
rhizochalinin D
110
 calyxinin112 
oceaninOH!KI!(DIGSG'
N=P'9G>G@HW'JY>?IG?ED'BGJEF>'AK'KAC@'?\A
-IGHBGB'JLIE>FAEB'_HJGJ' !N=M=<'+G?@A
-JY>?IG?ED'H>HWYJEJ'AK'@IEcADIHWE>E>'!'a<XVb'H>B'5'a<<<b
'/<%L9;<*B%'%'!E!T
<XVX!*'8!)!T
<<<X!<*>7!6<7!%87'6%;*B!;9'C%(3?*6%9'!9C!6<7!C93?!
@67?79!;7'67?@!%'!6<7!@6?3;63?7N!6<7!9'B#!8%CC7?7';7!47%'(!6<*6!6<7!;*?49'!;<*%'!%'!
?<%L9;<*B%'%'!)!T
<<<X!%@!9'7!;*?49'!B9'(7?!6<*'!E!T
<XVXS!"96<!59B7;3B7@!@<93B8!47!
*;<%7>*4B7
!>%*!*!'3;B79A<%B%;!*88%6%9'!69!6<7!?%(<6!<7*8!*5%87
'<<N!R%6<!7%6<7?!6<7!B7C6!<7
*8!*;76#B7'7!
<<P!9?!
<<QS!0<7!;9'@6?3;6%9'!9C!?%(<6!<7*8!
<<N!%@!7'>%@%9'78!C?95!6<7!
)*&
M*L%?%8%'7!
<MNN!R<%;<!%@!69!47!@#'6<7@%L78!6<?93(<!
)*&
M*L%?%8%'*6%9'!9C!6<7!*B87<#87!
<MON!NOOOTBSNCO2EtMEDAM
H11OBn114   (right head)
116  (left head)
NOOOTBSNCO2EtBUDAMH11115   (right head)
ent-
113  (left head)
OBn113  (left head)
NMEDAM
NMEDAM
ONH213OHNH2OH5O13OHNH2OH5NH2calyxinin(ent-113+115)
OHO13OHNH2NH2OH5ONH213OHNH2OH6OHOHrhizochalinin C
(113+114)
oceanin(113+115)
rhizochalinin D
(116+114)
OBnNMEDAM
NEtO2CRMEDAM
NCONHRBUDAMR+MeO
RRRROMe
NEtO2CRMEDAM
MEDAM, R= Me
BUDAM, R= 
t-Bu!KJ!R%6<!76<#B!8%*L9*7;6*67!T.)+X!*'8!:.)+:!*5%'7!
QNe!;*6*B#L78!4#!*!;<%?*B!49?9Q!;9
5AB7Q!
C9BB9R78!4#!?%'(
M9A7'%'(!?7*;6%9'S!:9?79>7?N!6<7!B7C6!<7*8@!
<<P!*'8!<<Q!*?7!69!47!
*;;7@@78!4#!*L%?%8%'7!C9?5*6%9'!C?95!
<<T!*'8!<<UN!R<9@7!;<%?*B!*5%'9!*B;9<9B!@;*CC9B8@!
;*'!47!%'@6*BB78!C?95!6<7!
)*&
M*L%?%8%'*6%9'!C?95!*B87<#87!
<M<!*'8!<MM!47*?%'(!*!67?5%'*B!
*;76#B7'7!*'8!6<7!@34@7D37'6!?%'(
M9A7'%'(!?7*;6%9'!T-;<757!gSgXS
!(DIGSG'
N=N'+G?@AJY>?IG?ED'@AC?G'AK'@IEcADIHWE>E>'!
'''OBnNMEDAM
ONH213OHNH2OHnn= 3, left head 113
n= 4, leff head 116
109 rhizochalinin C, n= 5
111 rhizochalinin D, n= 6
NEtO2CMEDAM
MEDAM
NCO2EtNOO11MEDAM
NH2HOOEt
ON2ONCO2EtOOTBSNHMEDAM
11right head 114
NHOO13On++117, n= 3
118, n=4
124EtO2COHNHMEDAM
ONCO2EtOOHNHMEDAM
11123119, n= 3
120, n=4
OOBOBOBOOONRHMEDAM
(R)-VAPOL
BOROXcatalyst
*121, n= 5
122, n=6
12564Õnnn+Reduction of ester
Aziridine formation
Protection of 2¡ alcohol
Protection of
     2¡ alcoholRing openingreaction
Ring openingreaction
OHEDA
!KH!N=P'(Y>?IGJEJ'AK'@EFI?'IGHB'<<N
'0<7!@#'6<7@%@!?9367!C9?!6<7!?%(<6!<7*8!
<<N!R*@!87>7B9A7
8!4#!93?!C9?57?!(?93A!
'57547?!e%'!d<*'(
ocJpN!R<%;<!;9557';78!R%6<!;9557?;%*BB#!*>*%B*4B7!J`
M<7Q*87;*'9B%87!
<MQ!T-;<757!gScXS!/%'(
M9A7'%'(!9C!
<MQ!R%6<!^7%'?74_@!*5%'7!*'8!6<7'!
-R7?'!9Q%8*6%9'!A?983;78!6<7!;9??7@A9'8%'(!*B87<#87!
<MO!%'!`YZ!#%7B8!9>7?!6R9!@67A@S!
0<7!@34@7D37'6!
)*&
'*L%?%8%'*6%9'!;*6*B#
L78!4#!T
2XMO+G1P
M49?9Q!;95AB7Q!R%6<!76<#B!
8%*L9*7;6*67!*'8!:.)+:!*5%'7!T
QNeX!*6!
MJIqE!(*>7!6<7!
)*&
'*L%?%8%'7!
<MN!%'!iHZ!#%7B8!
*'8!Yc
Z!!!S!/%'(
M9A7'%'(!R%6<!0W+!C9BB9R78!4#!<#8?9B#@%@!87B%>7?78!6<7!;95A93'8!T
<MPX!%'!9>7?*BB!KgZ!#%7B8!%'!JIkJ!?*6%9!9C!?7(%9%
@957?@N!R<%;<!R7?7!@7A*?*678S!0<7!C%'*B!Hq!
<#8?9Q#B!(?93A!A?967;6%9'!R%6<!0"-10C!*CC9?878!6<7!?%(<6!<7*8!T
<<NX!%'!KJZ!#%7B8S
!(DIGSG'
N=O'(Y>?IGJEJ'AK'@EFI?'IGHB'<<N
'''N=N'(Y>?IGJEJ'AK'WGK?'IGHB'<<P'
'0<7!@#'6<7@%@!9C!B7C6!<7*8!
<<P!R*@!;*??%78!936!*;;9?8%'(!69!6<7!A?9;783?7!
87>7B9A78!*!C9?57?!(?93A!57547?!^7'&3'!d<*9
!T-;<757!gS`X
SoK`p!E9557?;%*BB#!
*>*%B*4B7!
9;6
MhM#'MJM9B!T<MTX!R*@!6?*'@C7??78!69!%6@!;9??7@A9'8%'(!*B87<#87!
<M<!*'8!6<7'!
@34&7;678!69!T
2XMO+G1P
M49?9Q!;95AB7Q!;*6*B#L78!
)*&
M*L%?%8%'*6%9'!R%6<!76<#B!
8%*L9*7;6*67!*'8!:.)+:!*5%'7!T
QNeX!*6!
MJIqEN!R<%;<!
(7'7?*678!6<7!*L%?%8%'7!T
<<VX!%'!
OOHNOMe3Al2) (COCl)
2  DMSO
ONHO11O69%over two steps
OEt
ON25 mol %(R)-VAPOL/B(OPh)
3MEDAM-NH
2 (64Õ)
toluene, - 10 ¡C, 16 h
MEDAM
NCO2EtNOO111) CF
3CO2H    1 equiv2) NaOH
    1 equiv    H2O/EtOH
ONCO2EtOOHNHMEDAM
11TBSOTf
Et3NONCO2EtOOTBSNHMEDAM
1172%, 95% ee1261)12512412384%right head 114
81%PhPhOHOH(R)-VAPOL
!Kh!YHZ!#%7B8!*'8!YcZ!
!!>!0<%@!A?9;783?7!%'>9B>7@!(7'7?*6%9'!9C!6<7!"1/1e!;*6*B#@6!R%6<!
%M576<9Q#A<7'9BS!0<7!"1/1e!;*6*B#@6!%';9?A9?*6%'(!A<7'9B!%@!7D3*BB#!7CC7;6%>7!436!
@7A*?*6%9'!9C!6<7!A?983;6!C?95!A<7'9B!%@!8%CC%;3B6S!0<7!@
34@7D37'6!?%'(
M9A7'%'(!?7*;6%9'!
R%6<!0W+!*'8!<#8?9B#@%@!4#!*D3793@!2*1b!*6!?995!675A7?*63?7!*CC9?878!6<7!87@%?78!
A?983;6!
<<T!%'!`JZ!#%7B8!R%6<!*!?7(%9@7B7;6%>%6#!9C!J`SikJN!*'8!496<!9C!%@957?@!;*'!47!
@7A*?*678!C?95!;9B35'!;<?95*69(?*A<#S!0<7!Hq!<#8?9Q#B!(?
93A!%'!
<<T!R*@!A?967;678!R%6<!
"'"?N!C9BB9R78!4#!6<7!?783;6%9'!9C!6<7!7@67?!69!6<7!A?%5*?#!*B;9<9B!
<MV'%'!9>7?*BB!gIZ!
#%7B8S!W%'*BB#N!6<7!B7C6!<7*8!
<<P!R*@!*;;95AB%@<78!%'!icZ!#%7B8!4#!*;6%>*6%9'!9C!6<7!A?%5*?#!
*B;9<9B!R%6<!0@EB!%'!8%;<B9?9576<*'7!*'8!6<7!C
9?5*6%9'!9C!*L%?%8%'7S
!(DIGSG'
N=Q'(Y>?IGJEJ'AK'WGK?'IGHB'<<P
'!!!(5 mol %)
BH3áSMe
2 (15 mol %)
H2O (15 mol %)
p-methoxyphenol (10 mol %)
100 ¡Ctoluene, 1h
MEDAM-NH
2 (64Õ)
(100 mol %)
rt, 0.5 h
(R)-BOROX catalyst
5 mol % (R)-BOROX cat
2.0 equiv EDA 
1.0 equiv MEDAM-NH
2 (64)Õ
toluene, Ð10¡C, 4† MS
1. TFA (1.0 equiv)
    DCM,  T ¡C
2. NaOH, H2O/EtOH
   rt, 0.5 h
117
61%, 16.7:1 (117:117Õ)
EtO2COHNHMEDAM
OHNHEtO2CMEDAM
117Õ
NaH, BnBrDMF, nBu
4NI0 ¡C Ñrt
EtO2COBnNHMEDAM
12840%LiAlH4, THF0 ¡C - rt, 1.5 h
OBnNHMEDAM
HOTsCl, DCM
Et3N, 0 ¡C 2 h, rt, 46 h
OBnNMEDAM
right head 113
75%129100%HOMEDAM
EtO2CN12169%119
91%, 95%ee2. oxalyl chlorideDMSO
Et3N, DCM, -78¡C
12725.7 mmol (C8)
OH1. ethylene diamine
NaH!Kg!'N=O'(Y>?IGJEJ'AK'WGK?'IGHB'<<Q
'P7C6!<7*8!
<<Q!9C!?<%L9;<*B%'%'!E!%@!9'B#!9'7!59?7!;*?49'!B9'(7?!6<*'!B7C6!<7*8!
<<PN!R<9@7!@#'6<7@%@!%@!@<9R'!%'!-;<757!gS
iS!0<7!@#'6<76%;!?9367!69!
<<Q!%@!*B59@6!%87'6%;*B!
69!6<*6!C9?!
<<PN!*'8!9'B#!5%'9?!598%C%;*6%9'@!R7?7!5*87!69!@7>7?*B!;7?6*%'!@67A@S!0<7!
@#'6<7@%@!@6*?6@!R%6<!%@957?%L*6%9'!9C!
'9'MhM#'MJM9B!<PX!69!67?5%'*B!*;76#B7'7!
<P<N!*'8!
6<7!C9BB9R%'(!-R7?'!9Q%8*6%9'!A?9>%878!6<7!;9??7@A9'8%'(!*B87<#87!
<MM!%'!KhZ!#%7B8S!
+L%?%8%'7!
<MX!R*@!*;<%7>78!4#!*AAB#%'(!6<7!53B6%
M;95A9'7'6!
)*&
'!*L%?%8%'*6%9'!R%6<!76<#B!
8%*L9*7;6*67!T.)+X!*'8!:.)+:!*5%'7!T
QNeX!;*6*B#L78!4#!T
2XMO+G1P
M49?9Q!;95AB7Q
!*6!?995!675A7?*63?7!%'!D3*'6%6*67!#%7B8!*'8!YcZ!
!!S!(DIGSG'
N=T'(Y>?IGJEJ'AK'HcE@EBE>G'<MX
''0<7!?7(%9@7B7;6%>%6#!%'!?%'(
M9A7'%'(!9C!
<<V!%'!-;<757!gS`!%@!J`SikJS!+AAB#%'(!6<7!
@*57!?%'(
M9A7'%'(!;9'8%6%9'@!69!*L%?%8%'7!
<MXN!%6!R*@!@3?A?%@%'(B#!C93'8!6<*6!496<!6<7!#%7B8!
*'8!?7(%9@7B7;6%>%6#!
R7?7
!B9R7?!87@A%67!6<7!C*;6!6<*6!;95A93'8!
<MX!9'B#!<*@!*!;*?49'!
;<*%'!6<*6!%@!9'7!;*?49'!B9'(7?!6<*'!
<<VS!0<7?7C9?7N!8%CC7?7'6!?7*;6%9'!;9';7'6?*6%9'@!*'8!
120 mol% oxalyl chloride260 mol% DMSO
260 mol% Et
3N, DCM, -78¡C
NMEDAM
EtO2CHO12283%120100%, 95% eeethylene-1,2-diamine
NaH, 60¡C, 1hHO13180%HO20 mmol (C9)
130(5 mol %)
BH3áSMe
2 (15 mol %)
H2O (15 mol %)
p-methoxyphenol (10 mol %)
100 ¡Ctoluene, 1h
MEDAM-NH
2 (64Õ)
(100 mol %)
rt, 0.5 h
(R)-BOROX catalyst
5 mol % (R)-BOROX cat
2.0 equiv EDA , 
1.0 equiv MEDAM-NH
2 (64)Õ
toluene, Ð10¡C, 4† MS
!Kc!?7*;6%9'!6%57@!R7?7!7Q*5%'78!T0*
4B7!gSJXS!0<7!;9'>7?@%9'!?7*;<78!JIIZ!R%6<!%';?7*@%'(!
6<7!?7*;6%9'!6%57N!*'8!'9!@6*?6%'(!5*67?%*B!R*@!94@7?>78!*C67?!gH!<93?@S!/783;%'(!6<7!
?7*;6%9'!;9';7'6?*6%9'!C?95!ISJ!:!69!ISIc!:!?7@3B678!%'!*!@B%(<6!%';?7*@7!%'!496<!9C!6<7!
#%7B8!*'8!?7(%9@7B7;6%>%6#!
69!`KZ!#%7B8!*'8!JJkJ!?*6%9!9C!
<<U!69!<<U_!T7'6?#!hXS!+!P*?(7!
@;*B7!?7*;6%9'!R*@!*B@9!;*??%78!936!6R%;7!*6!6<7!B9R7?!;9';7'6?*6%9'!9C!ISIc!:!69!(%>7!*!
icZ!#%7B8!*'8!*!YkJ!?7(%9@7B7;6%>%6#!*C67?!gK!<93?@!T7'6?#!gX!*'8!496<!9C!%@957?@!;*'!47!
@7A*?*678!9'!;9B
35'!;<?95*69(?*A<#S!
!#H_WG'N=<'+E>F-ALG>E>F'@GHD?EA>'AK'HcE@EBE>G'<MX
'!!/7*;6%9'!@;*B7
!E9';S!T:X
!075A!TqEX
!0%57!T<X
!<<U[<<Ue!$%7B8!TZX!9C!
<<Uo*p
!J!IShg
!ISJI
!?S6
!HH!JI[J
!cKo4p
!H!ISHc
!ISJI
!?S6
!gH!JI[J
!`h!h!ISH`
!ISIc
!?S6
!gc!JJ[J
!`K!g!iSYH
(ISIc
!?S6
!gK!Y[J
!ico;p
!*p!,@9B*678!#%7B8S!o4p!JKZ!9C!@6*?6%'(!5*67?%*B@!R*@!?7;9>7?78!*C67?!6<7!?7*;6%9'S!o;p
!+>7?*(7!?7@3B6!
9C!6R9!?3'@
S!!W3?6<7?59?7N!C9BB9R%'(!Hq!*B;9<9B!A?967;6%9'!R%6<!"'"?!*'8!6<7'!?783;6%9'!9C!6<7!
7@67?!69!*!A?%5*?#!
*B;9<9B!4#!P%+Bb
gN!;95A93'8!
<PP!R*@!946*%'78!%'!KiZ!#%7B8!9>7?!6R9!
@67A@S!W%'*BB#N!*L%?%8%'7!C9?5*6%9'!R%6<!0@EB!*'8!6?%76<#B*5%'7!*CC9?878!6<7!B7C6!<7*8!T
<<QX!%'!KKZ!#%7B8!T-;<757!gSKXS
!(DIGSG'
N=U'(Y>?IGJEJ'AK'WGK?'IGHB'<<Q
''NMEDAM
EtO2CEtO2CNHMADEM
OH1.TFA (1.0 equiv.), DCM
2. NaOH, EtOH/H
2OEtO2COHHNMEDAM
+118
118Õ
120EtO2CNHMADEM
OH12 mmol118
BnBr, NaH, Bu
4NIDMF, 0¡C-r.t
EtO2CNHMADEM
OBn13287%!K`!(DIGSG'N=U'aDA>?E>CGBb
'!N=Q'!ACLWE>F'@GHD?EA>'\E?I'@EFI?'IGHB'<<N'H>B'WGK?'IGHB'<<Q
'1';7!6<7!?%(<6!<7*8!
<<N!*'8!6<7!B7C6!<7*8!
<<Q!R7?7!%'!<*'8N!6<7!'7Q6!@67A!%@!69!
;93AB7!6<75!4#!*!'3;B79A<%B%;!*88%6%9'!9C!6<7!*BV#'7!R%6<!6<7!^7%'?74!*5%87S!"*@78!9'!
^7'&3'_@!576<98
opK`N!.6:("?!R*@!C%?@6!*8878!69!*!0bW!@9B36%9'!9C!B7C6!<7*8!
<<P!*@!*!4*@7!
*6!IqE!C9BB9R78!4#!6<7!*88%6%9'!9C!?%(<6!*5%87!<7*8!
<<Q!*'8!6<7'!%';?7*@%'(!?7*;6%9'!
675A7?*63?7!69!`cqES!+C67?!6<7!5%Q63?7!R*@!@6%??78!
C9?!`!<93?@N!6<7!87@%?78!A?983;6!
<PO!;*'!47!*;<%7>78!%'!KHZ!#%7B8!T-;<757!gSYXS
!(DIGSG'
N=V'!ACLWE>F'AK'@EFI?'IGHB'<<N'H>B'WGK?'IGHB'<<P'_Y':G>iC>eJ'L@A?ADAW
''b9R7>7?N!R<7'!B7C6!<7*8!
<<Q!R*@!75AB9#78!69!?7*;6!R%6<!?%(<6!<7*8!
<<NN!3'87?!
6<7!@*57!;9'8%6%9'@N!9'B#!@6*?6%'(!5*67?%*B!R*@!?7;9>7?78S!^%6<!6<7!;9';7?'%'(!6<7!
;9';7'6?*6%9'!9C!6<7!.6:("?!THSc!:!%'!76<7?!@9B36%9'XN!8%CC7?7'6!7D3%>*B7'6@!9C!.6:("?!R*@!
67@678!%'!6<7!;93AB%'(!?7*;6%9'!T0*4B7!gSHXS
!LAH, THFNHMADEM
OBnHOTsCl, Et
3N, DCMTHF, 0¡C-r.t
0¡C, 2h, r.t, 46h
OBnNMADEM
133100%left head 116
88%EtMgBr
ONO11OTBSCO2EtNHMEDAM
THF, ¡C
left head 113
right head 114
135 (C28)
82%OBnNMEDAM
OBnNMEDAM
O13OTBSNCO2EtHMEDAM
!Ki!#H_WG'N=M'!ACLWE>F'AK'@EFI?'IGHB'<<N'H>B'WGK?'IGHB'<<Q=
'!!/7*;6%9'!@;*B7
!.D3%>*B7'6!9C!.6:("?
!$%7B8!TZX!9C!
<PNo*p
!Jo4p
!ISJ
!JSI
!Io8p
!Ho4p
!ISJ
!JSc
!Io8p
!ho4p
!ISJ
!HSI
!Hgo7p
!go4p
!ISJ
(hSI
!hIoCp!co4p
!ISJ
!hSc
!gJoCp!`o4p
!ISJ
!cSI
!`H!io;p
!ISc
!JSI
!Io(p
!Ko;p
!ISg
!HSI
!Hc!Yo;p
!ISg
!hSI
!gI!JIo<p
!ISg
!hSI
!hco%p!o*p
!,@9B*678!#%7B8S!o4p!+'!9B8!4966B7!9C!.6:("?!THSc!:!%'!76<7?X!R*@!3@78!
%'!6<7!?7*;6%9'S!o;p!.6:("?!R*@!6%6?*678S!o8p!+BB!@6*?6%'(!5*67?%*B!
<<N!R*@!
?7;9>7?78S!o7p
!-957!3'V'9R'!A?983;6!R*@!94@7?>78S!
oCp!2:/!#%7B8S!o(p!
+BB!3'V'9R'!A?983;6@S!o<p!27R!4966B7!9C!.6:("?!C?95!-%(5*
M+B8?%;<!
;95A*'#S!o%p!+>7?*(7!#%7B8@!4*@78!9'!c!?3'@!9C!?7*;6%9'S
!+B6<93(<!*!`HZ!#%7B8!9C!
<PN!R*@!946*%'78!R<7'!cSI!7D3%>*B7'6@!9C!.6:("?!T9B8!
4966B7!R%6<936!6%6?*6%9'X!R
7?7
!*8878!69!6<7!?7*;6%9'N!6<%@!?7@3B6!R*@!'96!?7A?983;%4B7!T7'6?#!
`XS!P*67?N!*C67?!6<7!.6:("?!@9B36%9'!R*@!6%6?*678!*'8!hSI!7D3%>*B7'6@!R*@!3@78!%'!6<7!
?7*;6%9'!TR<%;<!R*@!7D3%>*B7'6!69!6<7!cSI!7D3%>*B7'6@!%'!6<7!9B8!4966B7XN!436!6<7!?7*;6%9'!
9'B#!*CC9?878!*!gIZ!#
%7B8!T7'6?#!YXS!+!'7R!4966B7!9C!.6:("?!THSc!:!%'!76<7?X!R*@!A3?;<*@78!
C?95!-%(5*
M+B8?%;<N!*'8!6<%@!?7*(7'6!(*>7!*'!*>7?*(7!hcZ!#%7B8!%'!c!?3'@!T7'6?#!JIXS!
16<7?!4*@7@!@3;<!*@!
%"3P%!*'8!2*b!R7?7!*B@9!7Q*5%'78!%'!6<7!?7*;6%9'N!436!'9!87@%?78!
A?983;6!R*@!8767
;678S!^<7'!6<7!?7*;6%9'!9C!?%(<6!<7*8!
<<N!*'8!B7C6!<7*8!
<<P!R*@!
;*??%78
!936!R%6<!6<7!'7R!4966B7!9C!.6:("?!C9BB9R%'(!6<7!A?9;783?7!?7A9?678!4#!^7'&3'!d<*9N!9'B#!
hIZ!#%7B8!9C!6<7!A?983;6!
<PO'R*@!946*%'78!T@*57!?7*;6%9'!*@!@<9R'!%'!-;<757!gSYXS
!OBnNMEDAM
EtMgBr
ONO11OTBSCO2EtNHMEDAM
THF, ¡C
OBnNMEDAM
O11CO2EtOTBSNMEDAM
Hleft head 116
right head 114
134(C29)
!KK!N=T'$H?G@'J?HF
G'JGWGD?ERG'AdEBH?EA>
','!^7'&3'_@!@#'6<76%;!?9367
oK`pN!*C67?!*BB!A?967;6%'(!(?93A@!R7?
7!?759>78N!6<7!C%'*B!
@67A!R*@!69!47!*!@7B7;6%>7!?783;6%9'!9C!!6<7!*;%8!%'!6<7!A?7@7';7!9C!V769'7!9'!6<7!;*?49'
!JJS!-7>7?*B!*6675A6@!<*8!477'!5*87N!436!'9'7!R7?7!@3;;7@@C3B!T-;<757!gSJIXS
!(DIGSG'
N=<X':G>iC>eJ'WH?G@'J?HFG'JGWGD?
ERG'@GBCD?EA>'
'!0<7?7C9?7N!%'!;9'@%87?*6%9'!9C!6<7!8%CC%;3B6%7@!%'!@7B7;6%>7!?783;6%9'!9C!6<7!*;%8!9>7?!
6<7!V769'7N!*!@6?*67(#!R*@!*6675A678!%'!R<%;<!496<!7@67?!*'8!V769'7!R7?7!?783;78!69!
(%>7!6<7!8%9B!
<PTS!0<%@!%@!69!47!C9BB9R78!4#!@7B7;6%>7!9Q%8%L*6%9'!
9C!6<7!Hq!<#8?9Q#B!(?93A!
TA?9A*?(#B%;!*B;9<9BX!4*;V!69!6<7!V769'7!69!C3?'%@<!6<7!6*?(76!59B7;3B7!
<PU'T-;<757!gSJJ
XS!(DIGSG'
N=<<'(Y>?IG?ED'@AC?G'E>RAWRE>F'H'WH?G@'J?HFG'JGWGD?ERG'AdEBH?EA>
''!!ONH2CH2OH13OHNH2OH5 rhizochalinin C (109)
ONHBocCO2H13OHOHNH5BocONHBoc13OHOHNH5BocOH[H]
136135(C28)
selective
reduction
deprotection
C11
OBnNMEDAM
O11CO2EtOTBSNMEDAM
H134(C29)
LAH (6 equiv)
THF, 0¡C to r.t
OBnNMEDAM
OHNMEDAM
HOHOH1113763%oxidation
OBnNMEDAM
OHNMEDAM
HOHO11138Pd(OH)
2/CH2, MeOH, Boc
2Or.t
!KY!(DIGSG'N=<<'aDA>?E>CGBb
''/783;6%9'!9C!496<!6<7!V769'7!*'8!;*?49Q#B%;!7@67?!4#!P%+Bb
g!A?9>%878!6<7!;95A93'8!
<PT!%'!`hZ!#%7B8!%'!R<%;<!6<7!0"-!(?93A!R*@!*B@9!?759>78S!0<7!@34@7D37'6!@7B7;6%>7!
9Q%8*6%9'!9C!6<7!!A?9A*?(#B!*B;9<9B!!%'!6<7!6<7!A?7@7';7!9C!!*!A?%5*?#!*B;9<9B!R*@!*6675A678!
3'87?!:'1
H!*'8!O9T*;*;X
hoKip%'!@7>7?*B!8%CC7?7'6!;9'8%6%9'@N!<9R7>7?!'9!87@%?78!A?983;6!
R*@!@3;;7@@C3BB#!94@7?>78S!:9?79>7?N!*@!6<7!#%7B8!9C!A?7>
%93@!;93AB%'(!?7*;6%9'!R*@!B9RN!
*!'7R!@#'6<76%;!?9367!R*@!87@%('78!C9?!6<7!*AA?9*;<!69!?<%L9;<*B%'%'!E!T
<XVX!*'8!)!T
<<<XS!N=U'0G\'BGJEF>'AK'@EFI?'IGHB'<NX
'+'!*B67?'*6%>7!R*#!69!*>9%8!6<7!B*67!@6*(7!@7B7;6%>7!9Q%8*6%9'!9?!?783;6%9'!%@!69!
75AB9#!*!?783;78!C?
95!9C!6<7!;*?49Q#B%;!7@67?!%'!6<7!?%(<6!<7*8!
<<N!A?%9?!69!;93AB%'(!R%6<!
6<7!B7C6!<7*8!
<<QS!W3?6<7?59?7N!%'!6<%@!'7R!@6?*67(#N!6<7!*5%87!%@!69!47!?7AB*;78!R%6<!6<7!
59?7!?7*;6%>7!*B87<#87!%'!6<7!?%(<6!<7*8!*'8!6<%@!@<93B8!A?95967!*!59?7!7CC%;%7'6!;93AB%'(!
?7*;6%9'!69!*;<%7>7!%'!%'6*;6!;*?49'!@V7B769'S!0<7?7C9?7N!6<7!C%'*B!59B7;3B7@!;93B8!47!
*;;95AB%@<78!4#!9Q%8*6%9'!9C!Hq!*B;9<9B!*'8!6<7!@34@7D37'6!87A?967;6%9'!T-;<757!gSJ
HXS!(DIGSG'
N=<M'0G\'BGJEF>'AK'@EFI?'IGHB'<NX'?A\H@BJ'?IG'JY>?IGJEJ'AK'@IEcADIHWE>E>'
!'a<XVb'H>B'5'a<<<b
' '!!!OH11OHNHOHOBocNHBoc139HClOH11OHNH2OHONH2rhizochalinin D (111)
ONO11OTBSCO2EtNHMEDAM
right head 114
11OTBSNHMEDAM
HOBnOnew right head 140
!YI!(DIGSG'N=<M'aDA>?E>CGBb
''''N=V'(Y>?IGJEJ'AK'>G\'@EFI?'IGHB'<NX
'0<7!@#'6<76%;!?9367!C9?!6<7!'7R!?%(<6!<7*8!
<NX!%@!87@;?%478!%'!6<7!-;<757!gSJ
hS!,6!
;9557';7@!R%6<!6<7!?783;6%9'!9C!6<7!;9557?;%*BB#!*>*%B*4B7!J`
M<7Q*87;*'9B%87!
<MQ!69!6<7!8%9B!
<NO!R%6<!P%+Bb
g!%'!YhZ!#%7B8S!:9'9
MA?967;678!8%9B!
<NQ!R*@!A?983;78!4#!?7*;6%9'!
R%6<!A%>*B9#B!;<B9?%87!*'8!'"3P%!%'!cIZ!#%7B8!ThcZ!9C!6<7!@6*?6%'(!8%9B!R*@!?7;
9>7?78XS!
-34@7D37'6!-R7?'!9Q%8*6%9'!*'8!
)*&
M*L%?%8%'*6%9'!R%6<!T
2XMO+G1P
M49?9Q!;*6*B#@6!
*CC9?878!6<7!*L%?%8%'7!
<NU!%'!JIIZ!#%7B8!*'8!YcZ!
!!!9>7?!6R9!@67A@S!/%'(
M9A7'%'(!9
'!6<7!6<7!*L%?%8%'7!
<NU!R%6<!0W+!*'8!@34@7D37'6!<#8?9B#@%@!(*>7!6<7!*B;9<9B!
<NV!cIZ!#%
7B8!*'8!R%6<!*!JIkJ!?7(%9@7B7;6%>%6#!T%@957?@!R7?7!'96!@7A*?*678XS!0<7!7@67?!?783;6%9'!9C!6<7!
76<#B!7@67?!%'!6<7!A?7@7';7!9C!6<7!A%>*B9#B!7@67?!4#!P%+Bb
g!A?9>%878!6<7!8%9B!
<OX!%'!hiZ!
#%7B8S!0<7!C9BB9R%'(!A?967;6%9'!9C!6<7!A?%5*?#!<#8?9Q#B!(?93A!%'!6<7!A?7@
7';7!9C!6<7!Hq!
*B;9<9B!*CC9?878!*'!3'V'9R'!4#A?983;6!*B9'(!R%6<!6<7!87@%?78!A?983;6!
<O<!%'!B9R!#%7B8N!
R<%;<!R7?7!'96!@7A*?*678S!+6!6<%@!A9%'6N!6<?77!*88%6%9'*B!@67A@!R%BB!47!87>7B9A78!%'!6<7!
C363?7!69!*;;7@@!6<7!'7R!?%(<6!<7*8!
<NXS!OBnNMEDAM
right head 113 or 116
OBnNMEDAM
OH12OTBSNHMEDAM
OBnOTBSNHMEDAM
HOBnOn= 3 or 4
n141, n=3
142, n=4
n= 3 or 4
Oxidation
1). Pd(OH)
2/C, H2MeOH, Boc
2O, r.t, 62h
2). TBAF
rhizochalinin C (109) or D (111)
143, n= 3
144, n=4
OBnNMEDAM
O12OTBSNHMEDAM
OBnn= 3 or 4
!YJ!(DIGSG'
N=<P'(Y>?IGJEJ'AK'>G\'@EFI?'IGHB'<NX
'''!!!100 mol% PivCl
200 mol% nBuLiOHOOLAH, THFHO14593%12611OOPiv
11H5 mol% (R)-VAPOL/ B(OPh)
3100 mol% MEDAM-NH
2 (64Õ), 
4† M.S, toluene, r.t, 24h
200 mol% EDA
N11CO2EtMEDAM
PivO
1). 100 mol% TFA
DCM, 45 ¡C, 16h
2).100 mol% NaOH
H2O/EtOH, rt. 0.5h
11OHCO2EtNHMEDAM
PivO
125 mol% oxalyl chloride260 mol% DMSO
150 mol% LAH11OHNHMEDAM
PivO
OH100 mol% BnBr100 mol% NaH11OHNHMEDAM
PivO
OBn260 mol% Et
3NDCM, -78¡C-r.t, overnight
147100%148100%14950%, 10:1
THF, 45¡C
15037%OPiv
11HODMF/THF, 0¡C-r.t
151pdt and unknown
14648% (35% SM)
TBSCl, imidazole
MeLi
11OTBSNHMEDAM
HOOBn11OTBSNHMEDAM
PivO
OBnswern oxidation
11OTBSNHMEDAM
HOBnO152153new left head B (140)
!YH!N=<X'!A>DWCJEA>'','!6<%@!;<*A67?N!6R9!@#'6<76%;!?9367@!69!?<%L9;<*B%'%'@!E!T
<XVX!*'8!)!T
<<<X!R7?7!
7QAB9?78S!,'!6<7!C%?@6!*AA?9*;<N!?%(<6!<7*8!
<<N!*'8!B7C6!<7*8!
<<PN!<<Q!R7?7!*;;95AB%@<78!
*'8!%'!6<7!B*67?!@6*(7!6?*'@C9?5*6%9'
!69!6<7!6*?(76!?<%LL9;<*B%'%'@!)!T
<<<XN!3'@3;;7@@C3B!
*6675A6@!R7?7!5*87!69!@7B7;6%>7B#!9Q%8%L7!6<7!Hq!*B;9<9B!%'!6<7!A?7@7';7!9C!A?%5*?#!
*B;9<9B
S!+'96<7?!*B67?'*6%>7!*AA?9*;<!R*@!6<7'!7QAB9?78!69!*>9%8!%'!*'!7CC9?6!7%6<7?!*!
@7B7;6%>7!9Q%8*6%9'!9?!?783;6%9'!%'!*!B*67!@6*(7!%'67?578%*67S!,'!6<%@!'7R!*AA?9*;<N!?%(<6!
<7*8!<NX!R*@!87@%('78!*'8!;9'@%87?*4B7!A?9(?7@@!R*@!5*87!%'!%6@!@#'6<7@%@S!W363?7!
R9?V!
R%BB!47!C9;3@78!9'!C%'%@<%'(!6<7!@#'6<7@%@!9C!6<7!'7R!?%(<6!<7*8!
<NX!*'8!%'!*88%6%9'*BN!
%6!R93B8!47!%5A9?6*'6!69!9A6%5%L7!@7>7?*B!9C!6<7!@67A@!R%6<!B9R!#%7B8@S!
!!!!!!!!!!!!''!Yh!!3"/#*+'4&6*
''!"#"$%(#
-!.0#+.$$*5'),$#&!.)/.0*0#'"7&+&5&0"#&.0'.4'
!3&+"$'"$5*3%5*(
'O=<'&>?@ABCD?EA>
'+@#5576?%;!;*6*B#@%@!<*@!477'!R7BB!87>7B9A78!
9>7?!*!?*'(7!9C!8%>7?@7
!?7*;6%9'@!
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6<7!A<*?5*;736%;*B!*'8!%'83@6?%*B!
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C9?!6<7!;9'@6?3;6%9'!9C
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B!59B7;3B7@!%'!*!59?7!
7'>%?9'57'6*B!*'8!7;9'95%;!R*#
oKKpS!b9R7>7?N!576<989B9(%7@!%'>9B>%'(
!9C!?7*B!;*6*B#@6!
;9'6?9B!%'!@766%'(
!6<7!@67?79;<75%@6?#!9C!'7R!;<%?*B!;7'67?@!%'!6<7!A?7@7';7!9C!*'96<7?!
;<%?*B!;7'67?
!6<*6!*B?7*8#!7Q%@6@!%'!*!59B7;3B7
!%@!'96!;9559'S
oKYp!,'!6<7!;*@7!9C!;*6*B#@6!
;9'6?9BB%'(!?7*;6%9'@N!C%'8%'(!5*6;<78!*'8!5%@
M5*6;<78!A*%?@!476R77'!6<7!;*6*B#@6
!*'8!6<7!9A6%;*B!@34@6?*67@!R<%;<!
@7B7;6%>7B#!(7'7?*67@!9'7!9C!6<7!A9@@%4B7!8%*@67?7957?@!%@!
6<7!V7#
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oghN!gcN!
giN!ii
MKHpN!6<7!C%?@6!7Q*5AB7!9C!
*!;*6*B#@6
M;9'6?9BB78!53B6%;95A9'7'6!*@#5576?%;!*L%?%8%'*6%9'!
9C!;<%?*B!*B8
7<#87!R*@!%87'6%C%78
!T-;<757!cSJX
oYJpS!0<7!*4@9B367!@67?79;<75%@6?#!
9C!6<7!'7RB#!C9?578!*L%?%8%'7!%@!
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A?7@7'6!*6!7%6<7?!6<7!
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!(DIGSG'
O=<'!H?HWYJ?
-DA>?@AWWGB'SCW?EDASLA>G>?'HcE@EBE>H?EA>
''*FG*R1R2HO*FG*R1R2NPGOOEt
*FG*R1R2NPGOOEt
(S)-catalyst
(R)-catalyst
!Yg!-%';7!93?!A?7>%93@!(?93A!57547?!:3'53'
!:3V<7?&77
oYHp!C%'%@<78!6<7!A?%5*?#!
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!d<93oYhp8%8!53;<!9C
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!6R9!96<7?!;<%?*B!*B87<#87!@34@6?*67@!
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lhM<959
M)M*BB9@%@9B73;%'7!*'8!l
hMPM%@9B73;%'7
!R%BB!47!87@;?%478
S!!O=M'#\A'DIE@HW'HWBGIYBG'JC_J?@H?GJ'AK'?IG'DH?HWYJ?
-DA>?@AWWGB'HcE@EBE>H?EA>
'0<7!9A6%5%L78!?7*;6%9'!;9'8%6%9'
@!R7?7!9'B#
!87>7B9A78!
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<*8!477'!5*87!4#!:3'53'!*'8!$34*%!T
0*4B7!cSJXS!W9?!6<7!5987B!?7*;6%9'N!6<7!T
2XM!M@%B#B9Q#A<7'#B*;76*B87<#87!T
<ONHXN!:.)+:!*5%'7!T
QNeX!*'8!76<#B!8%*L9*;76*67!
*;;95AB%@<78!*!YKkH!@7B7;6%>%6#!C9?!6<7!
$%"*M*L%?%8%'7!T
<OOHX!9>7?!6<7!
&=%M*L%?%8%'7!T
<OOHeX!R%6<!6<7!;*6*B#@6!87?%>78!C?95!T
,XMO+G1PS!0<7!
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M;<%?*B!*B87<#87@!
;*6*B#L78!4#!T
,XMB%(*'8!;*6*B#@6!(*>7!*88%6%9'!69!6<7!
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6<7!;9??7@A9'8%'(!*L%?%8%'7!R%6<!*!TH
2XM;9'C%(3?*6%9'
oggMgcpS!^<7'!6<7!T
2XMO+G1P!;*6*B#@6!
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&=%M%@957?!T
<OOHeX!R*@!
946*%'78S!W?95!6<9@7!?7@3B6
@N!*!>7?#!<%(<!B7>7B!9C!;*6*B#@6!;9'6?9B!;*'!47!;9'C%?578!
%'!6<7!?7*;6%9'
!4#!$34*%!*'8!:3'53'
S!!#H_WG'O=<'.L?ESEcGB'@GHD?EA>'DA>BE?EA>'KA@'?IG'SABGW'@GHD?EA>
'''''HOTBSO
(R)-154a
10 mol% catalyst
MEDAM-NH
2 (64Õ)
EDA
4† MS, toluene
-10¡C, 24h
NMEDAM
OOEt
OTBSNMEDAM
OOEt
OTBS(2R, 4R)-155a
(2S, 4R)-155aÕ
+!Yc!#H_WG'O=<'aDA>?E>CGBb
'.'6?#
!P%(*'8
!Z!096*B!#%7B8
o*p
!TH2X[TH
,X!J'T,XMO+G1P
!YI!YKkH
!H!T2XMO+G1P
!YI!JkYY
!='B7@@!96<7?R%@7!@A7;%C%78N!*BB!?7*;6%9'@!R7?7!A7?C9?578!R%6<!*5%'7!
QNe!TISH!559BN!JSI!
7D3%>SXN!R%6<!.)+!TJSH!7D3%>SXN!*'8!*B87<#87!T
2XM<ONH!TJSIc!7D3%>SX!*6!ISg!:!%'!69B37'7!C9?!Hg!
<!*6!
MJIqE!%'!6<7!A?7@7';7!9C!A9R87?78!gj!59B7;3B*?!@%7>7@N!*'8!?7*;<78!JIIZ!;95AB76%9'S!
0<7!"1/1e!;*6*B#@6!R*@!*@@754B78!4#!<7*6%'(!*!@9B36%9'!9C!
QNe!TJII!59BZXN!B%(*'8!TJI!
59BZXN!*'8!"T1G<X
h!ThI!59BZX!%'!69B37'7!
*6!KIqE!C9?!ISc!<S!+C67?!;99B%'(!69!
MJIqEN!T
2XM<ONH!*'8!gj!59B7;3B*?!@%7>7@!R7?7!*8878N!C9BB9R78!8%?7;6B#!4#!.)+S!
o*p
$%7B8!9C!TH
2Ng2XM<OOH!*!*'8!TH
,Ng2XM<OOHe!%@9B*678!69(76<7?!*C67?!@%B%;*!(7B!;<?95*69(?*A<#S
!!+@!A*?6!9C!6<%@!6<7@%@!R9?V!6<7!*L%?%8%'*6%9
'!9C!6<7!*B87<#87!T
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@%L7!(?93A@!*6!6<7!H
M;<%?*B!;7'67?!R*@!7Q*5%'78S!
+!'3547?!9C!;<%?*B!*B87<#87@!
?7*;6!R%6<!
<%(<!;*6*B#@6!;9'6?9B!
3'87?!6<7!@6*'8*?8!;9'8%6%9'N!436!C9?!6<7!
!M4?*';<78!*B%A<*6%;!
*B87<#87!
<ON_N!6<7!?7*;6%9'!8%8'_6!(%>7!*!<%(<7?!87(?77!9C!;*6*B#@6!;9'6?9B!R%6<!
6<7!O+G1P!
;*6*B#@6
!TickHc!*'8!hhk`iXS!P*67?!
%6!R*@
!8%@;9>7?78!6<*6!3@%'(!
""3MO+21P!%'@67*8!9C!
O+G1P!*'8!87;?7*@%'(!6<7!?7*;6%9'!675A7?*63?7!69!
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;*6*B#@6!;9'6?9B!
;93B8!
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-DA>?@AWWGB'SCW?EDASLA>G>?'HcE@EBE>H?EA>'\E?I'HWBGIYBG'a<ON_b
' '''''HO(S)-154b
10 mol% catalyst
MEDAM-NH
2 (64Õ)
EDA
4† MS, toluene
T ¡C, 24hNMEDAM
OOEt
NMEDAM
OOEt
(2R, 4S)-155b
(2S, 4S)-155bÕ
+!Y`!#H_WG'O=M'aDA>?E>CGBb
'.'6?#
!E*6S!T59BZX
!P%(*'8
!0!TqEX
!!Z!096*B!#%7B8
o*p
!!TH2X[TH
,X!Jo4p
'c!T,XMO+G1P
!MJI!`I!ickHc
!Ho4p
!c!T2XMO+G1P
!MJI!cI!hhk`i
!ho4p'c!T,XM""3MO+21P
!MJI!xYY!YHkK
!go4p!c!T2XM""3MO+21P
!MJI!KI!JikKh
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PhHO154c, 99% eeMEDAM-NH
2 (64Õ)
EDA
5 mol%(S)-VAPOL 
borox catalyst
5 mol%(R)-VAPOL 
borox catalyst
NMEDAM
PhNCO2EtMEDAM
NMEDAM
PhNCO2EtMEDAM
NMEDAM
PhCO2Et43%156155c, syn/anti = 95:5
155cÕ, syn/anti = 4:96
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(S)-tBu-VANOL
borox catalyst
(10 mol%)
(R)-tBu-VANOL
BOROX catalyst
(10 mol%)
95%, 155b/155bÕ = 96:4
90%, 155b/155bÕ = 4:96
FmocHNOEt
OMe1) HOTf
2) FmocCl
3) SmI
21) HOTf
2) FmocCl
3) SmI
2FmocHNOEt
OMe158 (59%, 3 steps)
N-Fmoc-
!3-homo-L-isoleucine
ethyl ester
157 (58%, 3 steps)
N-Fmoc-
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ethyl ester
(S)-154b
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HNgM8%*&+
A?9A#B
M`M'%6?9A<7'9B!
TX!THSgi!(N!JJSJ!559BN!JSII!7D3%>SXN!(?*A<%67!TJScK!(XN!<#8?*L%'7!59'9<#8?*67!
TJShc!5PN!HiSi!559BN!HSc!7D3%>SX!*'8!76<*'9B!ThJSi!5PXS!0<7!CB*@V!R*@!7D3%AA78!R%6<!*!
;9'87'@7?!*'8!6<7
!69A!R*@!@7*B78!4#!*!@7A635!R%6<!*!'778B7!*66*;<78!69!%6S!0<7!CB*@V!
R*@!<7*678!%'!*!JII!qE!C9?!hSc!<!T*'96<7?!cSII!7D3%>S!9C!<#8?*L%'7!59'9<#8?*67!R*@!
*8878!%'!6R9!7D3*B!A9?6%9'@!7>7?#!96<7?!<93?XS!0<7!@9B36%9'!R*@!*BB9R78!69!;99B!69!?995!
675A7?*63?7N!*'8!
C%B67?78!6<?93(<!;7B%67!A*8N!6<7!C%B67?!;*V7!R*@!R*@<78!4#!
8%;<B9?9576<*'7!TcISI!5PXS!0<7!C%B6?*67!R*@!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'!*'8!
CB*@<!;<?95*69(?*A<#!TgI!55!Q!J`I!55N!b7Q*'7[.61+;!KkHX!*CC9?8!6<7!;?387!A?983;6!*@!
*!4?9R'!@9B%8S!0<7!C3?6<7?!
?7;?#@6*BB%L*6%9'!R%6<!b7Q*'7[.61+;!TYkJX!(*>7!6<7!A3?7!A?983;6!
QND!*@!*!R<%67!@9B%8!TJShI!(N!`S`g!559BN!`IZ!#%7B8N!5Ak!JI`SK
MJIKSH!qEXS!
/Cu!ISg!Tikh!
<7Q*'7[.61+;XS!-A7;6?*B!8*6*!C9?!
TXk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!`ScI!T@N!JbXN!
`Sg`!T@N!JbXN!
hS`iMhS`g!T4?N!2b
HXN!hSHJ!T<7A6N!
A!u!`SY!bLN!JbXN!HSih!T<7A6N!
A!u!`SY!bLN!JbXN!
JSJK!T88N!
A!u!JIScN!`SK!bLN!JhbXS
!JhE!2:/!TJH`!:bLN!E<B9?9C9?5
M9X!y!JgJS`KN!JhYS`HN!
Jh`ScKN!JhcSKhN!JJgSchN!JJHSJIN!hhSiJN!HiSHIN!HgSH`!THEXN!HHSYg!THEXS!
,/!T6<%'!C%B5X!
hhYI@N!OHNO2OHNH27051.3%graphite, EtOH
100¡C64c60%NH2NH2áH2O!JIg!hhJi@N!HYc`>@N!JigI>@N!JcYH>@N!JgK`@NJgh`@N!JHJc>@N!KcY>@!;5
MJS!b/:-!T.-,
M01WX!
1DC
!C93'8!JYgSJccg!To:wbp
wXa!;*B;8S!JYgSJcgc!C9?!E
JHbHI21S!?#!.$#$"*+%(+@($%*:*%!(
&'+)!HNgM8%%"36#BA<7'9B!
,-k!09!*!@9B36%9'!9C!A
M47'L9D3%'9'7!
T<!TJSII!(N!YSHc!559BN!JSII!
7D3%>SX!%'!0bW!THcSI!5BX!R*@!*8878!6<7!;9??7@A9'8%'(!
%436#BB%6<%35!?7*(7'6!TJJSJ!5PN!HSc!
:!%'!<7Q*'7N!hSII!7D3%>SX!*6!
MiKqES!0<7!?7@3B6%'(!@9B36%9'!R*@!@6%??78!C9?!`!<93?@!*BB9R%'(!
6<7!675A7?*63?7!69!?%@7!69!HIqES!0<7!?7@3B6%'(!5%
Q63?7!R*@!6<7'!<#8?9B#L78!R%6<!R*67?!THI!
5BXN!*;%8%C%78!R%6<!H!2!@3BC3?%;!*;%8N!*'8!7Q6?*;678!R%6<!76<7?!Th!Q!HISI!5BXS!0<7!9?(*'%;!
B*#7?!R*@!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!69!(%>7!6<7!;?387!A?983;6@!
TM'TIS`i(N!hSHh!
559BN!hcZ!#%7B8X!*@!*!#7BB9R!9%BN!R<%;<!R7?7!A3?%C%78!4#!CB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!
gI!55!Q!J`I!55N!<7Q*'7[.61+;!YkJXS!
/Cu!ISK!Tikh!<7Q*'7[.61+;XS!-A7;6?*B!8*6*!C9?!
TMk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!iSIi!T8N!
A!u!HSh!bLN!JbXN!`SYY!T88
N!A!u!KSJN!HSh!bLN!
JbXN!`SiY!T8N!
A!u!KSI!bLN!JbXN!cScc!T@N!JbN!1bXN!HSi`!
F!HS`Y!T5N!HbXN!HS`Y!
F!HS`H!T5N!HbXN!
JSiK!F!JS`c!T5N!gbXN!JSc`!
F!JShc!T5N!cbXN!JSIi!T6N!
A!u!iSh!bLN!`bXS!
JhE!2:/!TJH`!:bLN!
E<B9?9C9?5
M8X!y!JcJSgHN!JhcSJHN!JhISHcN!JHKS`KN!JH`SiJN!JJcS
HgN!hcSIIN!hgSJcN!hHSHcN!
HHSKIN!HHScIN!JgSJI!THEXS
!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!
;95A93'8
ocHpS!OOnBuLi (3 equiv)
THF, -78¡C to r.t, 6h
OHnBunBu7235%71!JIc!!HNgM8%%"36#B
M`M'%6?9A<7'9B!
,.k!+;;9?8%'
(!69!6<7!
0!%!#$:(.#+)!96#!(+@(%*"#$"*+%
N!HNg
M8%%"36#BA<7'9B!
TM'TIS`i!(N!hSH`!559BXN!'%6?%;!*;%8!TISHc!5PX!*'8!*;76%;!*;%8!TgSIc!5P!w!
JShc!5PX!R7?7!*8878!69!6<7!?7*;6%9'S!+C67?!A3?%C%;*6%9'!4#!CB*@<!;<?95*69(?*A<#!T@%B%;*!
(7BN!HI!55!Q!J`I!55N!<7Q*'7[.61+;!
YckcXN!6<7!?7*;6%9'!*CC9?878!hNc
M8%%436#B
M`M'%6?9A<7'9B!
TP'TISYh!(N!hSH`!559BN!JIIZ!#%7B8X!*@!*'!9?*'(7!9%BS
!/Cu!ISY!Tikh!
<7Q*'7[.61+;XS
!-A7;6?*B!8*6*!C9?!
TPk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!JISKI!T8N!JbN!
1bXN!iSiH!T8N!
A!u!HSh!bLN!JbXN!iSH`!T8N!
A!u!HSH!bL
N!JbXN!HSiH!
F!HS`c!T5N!HbXN!HScK!
F!HScJ!T5N!HbXN!JS`h!
F!JScH!T5N!gbXN!JSgh!
F!JSHY!T5N!gbXN!ISYh!T6N!
A!u!iSg!bLN!`bXS!
JhE!2:/!TJH`!
:bLN!E<B9?9C9?5
M9X!y!JcJS`YN!JhKSJIN!JhgSIgN!JhhScgN!JhhSJhN!JHJSHHN!hgSgcN!hhShIN!
hJScHN!HYScHN!HHScHN!HHSJKN!JhSK`N!JhSKJS!!!HMb#8?9Q#
MhNcM8%%436#B*'%B%'7!
&'+k!+;;9?8%'(!69!6<7!
0!%!#$:(.#+)!96#!(+@(<=9#$C*%!(
#!96)"*+%
N!HNgM8%%436#B
M`M'%6?9A<7'9B!
TP!TISKH!(N!hSH`!559BN!JSII!7D3%>SX
N!<#8?*L%'7!TISgI!
5P!
Q!hN!HSc!7D3%>S
X!*'8!(?*A<%67!TISgi!(X!R7?7!*8878!69!6<7!76<*'9B!TYShH!5PXS!+
C67?!
A3?%C%;*6%9'!4#!CB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!
HI!55!Q!J`I!55N!<7Q*'7[.61+;!KkH
X!*'8!?7;?#@6*BB%L*6%9'!R%6<!<7Q*'7[.61+;!TYkJXN!6<7!?7*;6%9'!*CC9?878!6<7!A?983;6!
QNB!TIShc!
(N!JScY!559BN!gYZ!#%7B8X!*@!*!#7BB9R!9%BS
!/Cu!ISg!Tikh!<7Q*'7[.61+;XS
!-A7;6?*B!8*6*!C9?!
OHnBunBu7235%HNO3 (90%)
73100%HOAc, 0¡COHnBunBuNO273100%graphite, EtOH
100¡C64d49%OHnBunBuNO2OHnBunBuNH2NH2NH2áH2O!JI`!QNBk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!`ScI!T8N!
A!u!HSJ!bLN!JbXN!`Sgg!T8N!
A!u!HSJ!bLN!
JbXN!hScH!T@N!HbN!2b
HXN!HScK!
F!HScJ!T5N!HbXN!HSgY!
F!HSgH!T5N!HbXN!JS`g!
F!JSgY!T5N!gbXN!
JSg`!F!JShH!T5N!gbXN!ISYg!T6N!
A!u!iSh!bLN!`bXS
!JhE!2:/!TJH`!:bLN!E
<B9?9C9?5
M9X!y!JgIS`gN!
JhcSgIN!JHKSJgN!JHISKHN!JJcScYN!hcSIKN!hhSYgN!hHSIKN!HYSKgN!HHS`YN!HHSgJN!JgSII!THEXS
!,/!T6<%'!C%B5X!
hhYc@N!hhJh@N!HYHc>@N!J`IH>@N!JgK`>@N!JHIh>@N!KgKN!iHg@!;5
MJS!b/:-!T.-,
M01WX!
1DC
!C93'8!HHHSJK``!To:wbp
wXa!;*B;8S!HHHSJKcK!C9?!E
JgbHg21S!?#!.$#$"*+%(+@($%*:*%!(
&'/)!HNgM8%"!#"
'"36#B
M`M'%6?9A<7'9B!
,0k!+;;9?8%'(!69!6<7!
0!%!#$:(.#+)!96#!(+@(%*"#$"*+%
N!HNg
M8%"436#BA<7'9B!
TN!TgSYi!(N!HgSJ!559BN!JSII!7D3%>SXN!'%6?%;!*;%8!TJSYI!5PX!*'8!*;76%;!*;%8!
ThISI!5P!w!JISI!5PX!R7?7!*8878!69!6<7!?7*;6%9'S!+C67?!A3?%C%;*6%9'!4#!CB*@<!
;<?95*69(?*A<#!T@%B%;*!(7BN!gI!55!Q!J`I!55N!<7Q*'7[.61+;!YckcXN!6<7!?7*;6%9'!*CC9?878!
HNgM8%"436#B
M`M'%6?9A
<7'9B!TO'ThShK!(N!JhSc!559BN!c`Z!#%7B8X!*@!*!#7BB9R!9%BS!
/Cu!ISY!Tikh!
<7Q*'7[.61+;XS!-A7;6?*B!8*6*!C9?!
TOk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!JJSgi!T8N!
A!u!IS`!bLN!JbXN!iSYi!T8N!
A!u!HSc!bLN!JbXN!iS``!T8N!
A!u!HS`!bLN!JbXN!JSg`!T@N!
YbXN!JShh!T@N!
YbXS
!JhE!2:/!
TJH`!:bLN!E<B9?9C9?5
M9X!y!JchSIJN!JgJSYhN!
JhYSKHN!JhhS`HN!JhHScYN!JJKSK
gN!hcSiHN!hgScJN!hJSJI!ThEXN!HYSh`!ThEX
S!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!
8*6*!C9?!6<%@!;95A93'8S
oJIip!!OHOHNO2HNO3 (90%)
74HOAc, 0¡C7556%!JIi!S!HMb#8?9Q#
MhNcM8%"436#B*'%B%'7!
&'/k!+;;9?8%'(!69!6<7!
0!%!#$:(.#+)!96#!(+@(
<=9#$C*%!(
#!96)"*+%
N!HNgM8%"436#B
M`M'%6?9A<7'9B!
TO!ThShK!(N!JhSc!559BN!JSII!7D3%>SX
N!<#8?*L%'7!TJS`g!
5P!
Q!hN!HSc!7D3%>S
X!*'8!(?*A<%67!TJSYH!(X!R7?7!*8878!69!6<7!76<*'9B!ThKSc!5PXS!+C67?!
A3?%C%;*6%9'!4#!CB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!
gI!55!Q!J`I!55N!<7Q*
'7[.61+;!KkH
X!*'8!?7;?#@6*BB%L*6%9'!R%6<!<7Q*'7[.61+;!TYkJXN!6<7!?7*;6%9'!*CC9?878!6<7!A?983;6!
QNG!*@!*!
B%(<6!A3?AB7!@9B%8!TJSKI!(N!KSJg!559BN!`JZ!#%7B8N!5Ak!J`h
MJ`K!qEXS!/
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<7Q*'7[.61+;XS
!-A7;6?*B!8*6*!C9?!
QNGk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!`SYJ!T8N!
A!u!HSh!bLN!JbXN!`SKJ!T8N!
A!u!HSh!bLN!JbXN!hSHH!T4?N!HbN!2bHXN!JSgH!T@N!YbXN!JSHK!T@N!YbXS!
JhE!2:/!TJH`!:bLN!E<B9?9C9?5
M9X!y!JghSYJN!JgHSgKN!JhcSKIN!JhHS`HN!JJ`SKKN!JJcScYN!hgS`YN!
hgSH`N!hJS`JT`EXN!HYSKg!T`EXS!
,/!T6<%'!C%B5X!
hh`c@N!hHKY@N!HYgh
>@N!Hh`c@N!JcYH@N!JgK`>@N!
JgJK>@N!JhhJ>@N!JHhi@N!Yg`>@N!igJ>@!;5
MJS!b/:-!T.-,
M01WX!
1DC
!C93'8!HHHSJK`I!
To:wbp
wXa!;*B;8S!HHHSJKcK!C9?!E
JgbHg21S!Q=M=M'/@GLH@H?EA>'KA@'?IG'HWBGIYBG'QPE
'?#!.$#$"*+%(+@($:9!<=9!(
&.")!""36#B!H
MC9?5#B
MJEMA#??9B7
MJM;*?49Q#B*67!
QPEk!09!*'!9>7'
M8?%78!cI!5P!?93'8!49669578!
CB*@V!R7?7!*8878!J
EMA#??9B7
MHM;*?4*B87<#87!
QPEe!TIScI!(N!cShI!559BN!JSII!7D3%>SXN!"9;!
OHNO27556%OHNH2graphite, EtOH
100¡C64e94%NH2NH2áH2OHNOHBoc
2O (1.1 equiv.)
DMAP (0.01 equiv)
CH3CNBoc
NOH63i63iÕ!JIK!*'<#8?%87!TJShI!(N!cSKh!559BN!JSJI!7D3%>SXN!g
M)%576<#B*5%'9A#?%8%'7!T):+GN!`SgI!5(N!
ISIJ!7D3%>SX!*'8!*;769'%6?%B7!TJISI!5PX!3'87?!'
%6?9(7'S!!+C67?!hI!5%'367@!@6%??%'(N!6<7!
?7*;6%9'!R*@!;9';7'6?*678!3'87?!
?96*?#!7>*A9?*6%9'S!0<7!?7@3B6%'(!;?387!A?983;6!R*@!
A3?%C%78!R%6<!CB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!HI!55!
Q!J`I!55N!<7Q*'7[.61+;!YkJ
X!*'8!
*CC9?878!6<7!A?983;6!
QPE'TJSIh!(N!cShI!559BN!
JIIZ!#%7B8X
'*@!6<7!;9B9?B7@@!9%BS
!/Cu!ISK!Tikh!
<7Q*'7[.61+;XS
!-A7;6?*B!8*6*!C9?!
QPEk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!JIShJ!T8N!
A!u!ISi!bLN!JbXN!iSgH!T88N!
A!u!hSJN!JSi!bLN!JbXN!iSJ`!T88N!
A!u!hSKN!JSK!bLN!JbXN!`SH`!T888N!
A!u!hSKN!hSJN!ISi!bLN!JbXN!JS`H!T@N!
YbXS!
JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!JKHShYN!JgKShKN!
JhgSigN!JHiSh`N!JHJSHhN!JJJSiHN!KcSKJN!HiSY`S!,/!T6<%'!C%B5X!JigK!@N!J``i!5N!JhYI!@N!gHi!
>@!;5
MJS!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
oJIKp!Q=M=P'/@GLH@H?EA>'KA@'"JYSSG?@ED'1H_HDI>E`
-4EGWBJ'@GHD?EA>'
L@ABCD?J'QTH
-S'F!%!#$:(.#+)!96#!(G(@+#($&&!1;:*%0("<!("H6"=:
'C*#)+%*61()$"$:=&"I
(!d?T1
*G?XgTb1
*G?X!L%?;9'%35T,OX!%@9A?9A9Q%87!%@9A?9A*'9B!;95AB7Q!ThKSK!5(N!ISJ!
559BN!JSII!7D3%>SXN!T
,XM""36#B!O+21P!TJ`c!5(N!IShI!559BN!hSI!I7D3%>SXN!*'8!g!5P!69B37'7!
R7?7!5%
Q78!3'87?!*%?!*6!?995!675A7?*63?7!%'!*'!9>7'
M8?%78!HI
M5P!>%*BS!+C67?!*BB!@9B%8@!
R7?7!8%@@9B>%'(!%'!6<7!69B37'7N!6<7!2
M576<#B%5%8*L9B7!TKSII!zPN!ISJ!559BN!JSII!7D3%>SX!
R*@!*8878!>%*!*!5%;?9!@#?%'(7S!0<7!?7@3B6%'(!5%Q63?7!R*@!@6%??78!*6!?995!675A7?*63?7!
3'87?!*%?!C9?!hI!5%'!47C9?7!47%'(!75AB9#78!%'69!6<7!*@#5576?%;!;*6*B#6%;!U*4*;<'%V
MW%7B8@!?7*;6%9'S!+'8!6<7!?7@6!9C!6<7!;*6*B#@6!;*'!47!@69?78!%'!69B37'7!*6!
MHIqE!C9?!C3?6<7?!
3@7@S
!Zr(O-iPr)
4.HO-iPr
+NNMe+(S)-tBu-VANOL
toluene
0.5 h, 23 ¡CZirconium complex catalyst
1.0 equiv.
1.0 equiv.
3.0 equiv.
!JIY!!F!%!#$:(.#+)!96#!(H(@+#($&=11!"#*)(J$;$)<%*K
'L*!:9&(#!$)"*+%(+@($#+1$"*)(
$:9!<=9!&I
!09!*!JI
M5P!CB*57
M8?%78!<957
M5*87!-;<B7'V!CB*@VN!A?7A*?78
!C?95!*!@%'(B7!
'7;V78!Hc!5P!A7*?
M@<*A78!CB*@V!6<*6!<*8!%6@!Jg[HI!(B*@@!&9%'6!?7AB*;78!R%6<!*!<%(<!
>*;335!6<?7*878!07CB9'!>*B>7N!CB3@<78!R%6<!'%6?9(7'!R*@!
*8878!H
M<#8?9Q#
MhNcM8%*&+
A?9A#B*'%B
%'7!QND'TJYSh!5(N!ISJI!559BN!JSII!7D3%>SXN!g!j!59B7;3B*?!@%7>7@!ThKS`!5(X!
*'8!47'L9%;!*;%8!TJSHI!5(N!ISIJ!559BN!ISJI!7D3%>SX!
='87?!*!'%6?9(7'!CB9RN!L%?;9'%35!
;*6*B#@6!%'!69B37'7!TISHI!5PN!
c!59BZN!ISHc!:N!A?7A*?78!C?95!(7'7?*B!A?9;783?7!+
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/Cu!IS`!Tckc!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
<QUk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!
hS`I!T86N!
A!u!KSHN!`S`!bLN!gbXN!JS`H!
F!JSgg!T5N!gbXN!JSgh!
F!JShJ!T5N!HbXN!ISK`!T8N!
A!u!JSH!
bLN!YbXN!ISIc!
F!MISIg!T5N!`bXS
!0<7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!
6<%@!;95A93'8S
oJIYp!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@($:)+<+:
N!6<7!?7*;6%9'!9C!
<QU!T`SI!
(N!HJSI!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!THShJ!5PN!HcSH!559BNJSH!7D3%>SXN!):-1!ThSi`!
5PN!cgS`!559BN!HS`I!7D3%>SX!*'8!6?%76<#B*5%'7!TiScI!5PN!cgS`!559BN!HS`I!7D3%>SX!%'!
8%;<B9?9576<*'7!TcHSI!5P!Q!HX!*CC9?8!6<7!A?983;6!
TQE'ThSKc!(N!JiSY!559BN!KcZX
'*@!*!
;9B9?B7@@!9%BS!
/Cu!ISK!Tikh!<7Q*'7[.61+;XS
!-A7;6?*B!8*6*!C9?!
TQEk'!Jb!2:/!TcII!:bLN!
E<B9?9C9?5
M9X!y!YSi`!T@N!JbXN!hS`J!T68N!
A!u!`ShN!JSJ!bLN!HbXN!HSgc!T68N!
A!u!iSgN!JSK!bLN!HbXN!
JSig!F!JS`g!T5N!HbXN!JScY!
F!JSgK!T5N!HbXN!ISKK!T@N!YbXN!ISIh!T@N!`bXS
!0<7@7!@A7;6?*B!8*6*!
5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
oJIYp!!JHK!!hMTT"!#"
M"36#B8%576<#B@%B#BX9Q#XA?9A*'*B!
TQik!09!6<7!0bW!TJHSc!5PX!@9B36%9'!9C!
A?9A*'7
MJNhM8%9B!<QV'TJSK
!5PN!Hc!559BN!JSII!7D3%>SX!R*@!*8878!0bW!THc!5PX!@9B36%9'!9C!2*b!TJ!
(N!Hc!559BN!JSII!7D3%>SX!8?9AR%@7B#!*6!IqES!0<7!5%Q63?7!R*@!@6%??%'(!gc!5%'367@!*6!?995!
675A7?*63?7!*'8!R*@!*8878!0"-EB!ThSic!(N!HcSI!559BN!JSII!7D3%>SX!@9B36%9'!%'!0bW!TJHSc!
5PXS!0<7!?7*;
6%9'!@6%??78!J!<93?!*'8!D37';<78!R%6<!@*6S!2*bE1
h!*6!IqES!+C67?!6R9!B*#7?@!
R*@!@7A*?*678N!6<7!*D3793@!B*#7?!R*@!7Q6?*;678!R%6<!8%76<#B!76<7?!TJcSI!5P!
Q!h
XS!0<7!
;954%'78!9?(*'%;!B*#7?!R*@!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!3'87?!?96*?#!
7>*A9?*6%9'S!!
WB*@<!;<
?95*69(?*A<#!T@%B%;*!(7BN!HI!55!Q!J`I!55N!<7Q*'7[.61+;!ickHcX!
*CC9?878!6<7!A3?7!59'9
MA?967;678!8%9B!
<TX'TgS`I!(N!HgSI!559BN!Y`ZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISH!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
<TXk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!
hSKi!F!hSi`!T5N!gbXN!JSii!TAN!
A!u!cS`!bLN!HbXN!ISKY!T@N!YbXN!ISJI!
F!ISIc!T5N!`bXS
!0<7@7!
@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
ogip!W9BB9R%'(!6<7!
F!%!#$:(
.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@($:)+<+:
N!6<7!?7*;6%9'!9C!
<TX!TgS`I!
(N!HgSI!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!THS`I!5PN!HKSK!559BNJSHI!7D3%>SXN!):-1!TgSh!
5PN!`HSg!559BN!HS`!7D3%>SX!*'8!6?%76<#B*5%'7!TKScI!5PN!`HSg!559BN!HS`!7D3%>SX!%'!
8%;<B9?9576<*'7!TcYSI!5P!Q!HX!*CC9?8!6<7!A?983;6!
TQi'ThS`I!(N!JYSH!559BN!KIZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISK!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQik'Jb!2:/!TcII!:bLN!
E<B9?9C9?5
M9X!y!YSKI!T@N!JbXN!hSYK!T6N!
A!u!`SI!bLN!HbXN!HScY!T68N!
A!u!`SJN!HSI!bLN!HbXN!ISKK!
T@N!YbXN!ISI`!T@N!`bXS
!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*
!C9?!6<%@!
;95A93'8S
ogip!oxalyl chloride (1.2 equiv.)
DMSO (2.6 equiv.)
Et3N (2.6 equiv.)
DCM, -78¡C-r.t, 0.5 h
TBSO
HOOHTBSO
HOOHTBSCl (1.0 equiv.)
NaH (1.0 equiv.)
THF, 2h, 0¡C-r.t
76i85%16917096%!JHY!!:76<#B!g
M9Q9436*'9*67!
TQ`k!09!6<7!@9B36%9'!9C!576<*'9B!TcI!5PX!9C!
8%<#8?9C3?*'
MHTh
EXM9'7!<T<'TISi`!5PN!JI!559BN!JSII!7D3%>SX!R*@!*8878!6?%76<#B*5%'7!TKSgI!5PN!`ISI!559BN!
`SI!7D3%>SXS!0<7!?7*;6%9'!R*@!6<7'!<7*678!3A!69!`IqE!*'8!@6%??%'(!C9?!Jc!<93?@S!+C67?!6<7!
5%Q63?7!R*@!;99B!89R'!69!6<7!?995!675A7?*63?7N!%6!R*@!8%B3678!R%6<!<7Q*'7!TcI!5PX!*'8!
;9'
;7'6?*678!3'87?!6<7!?96*?#!7>*A9?*6%9'S!0<7!;?387!A?983;6!
<TM!TISYI!(N!iSKI!559BN!
iKZX!;*'!47!8%?7;6B#!3@78!%'69!6<7!C3?6<7?!?7*;6%9'!R%6<936!A3?%C%;*6%9'S
!/Cu!ISH!Tckc!
<7Q*'7[.61+;XS!
!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@($:)+<+:
N!6<7!?7*
;6%9'!9C!
<TM!TISYH!
(N!iSKI!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!TIS`K!5PN!YSgI!559BNJSHI!7D3%>SXN!):-1!TJSJI!
5PN!HISh!559BN!HS`I!7D3%>SX!*'8!6?%76<#B*5%'7!TcSg!5PN!HISh!559BN!HS`I!7D3%>SX!%'!
8%;<B9?9576<*'7!TJJSi!5P!Q!HX!*CC9?8!6<7!A?983;6!
TQ`'TISJK!(N!JS`!
559BN!HIZX
'*@!*!
;9B9?B7@@!9%BS!0<7!B9R!#%7B8!R*@!837!69!6<7!B9@@!9C!6<7!A?983;6!83?%'(!6<7!?96*?#!7>*A9?*6%9'!
*@!6<7!B9R!49%B%'(!A9%'6!9C!6<7!A?983;6S!
/Cu!ISi!Tckc!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQ`k!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSKH!T@N!JbXN!hSiI!T@N!hbXN!HSKJ!T6N!
A!u!`S`!bLN!HbXN!
HS`g!T6N!
A!u!`S`!bLN!HbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!JYYSYcN!JiHSiIN!cJSYcN!hKScHN!
H`ShIS!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
ogip!!MeOOC
OHoxalyl chloride (1.2 equiv.)
DMSO (2.6 equiv.)
Et3N (2.6 equiv.)
DCM, -78¡C-r.t, 0.5 h
76k20%17278%MeOOC
OHOO171Et3N (6.0 equiv.)
MeOH, 60¡C, 15h
BocHNHOoxalyl chloride (1.0 equiv.)
DMSO (2.0  equiv.)
Et3N (1.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
76l90%173BocHNOH!JhI!"!#"
M"36#B!Th
M9Q9A?9A#BX;*?4*5*67!
TQWk!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(
+N*9$"*+%(+@($:)+<+:
N!6<7!?7*;6%9'!9C!
<TP!ThScI!(N!HISJ!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!
TJScI!5PN!HgSJ!559BNJSHI!7D3%>SXN!):-1!T
hS`I!5PN!cJSI!559BN!HSII!7D3%>SX!*'8!
6?%76<#B*5%'7!TcSgI!5PN!HISh!559BN!JSII!7D3%>SX!%'!8%;<B9?9576<*'7!THISI!5P!Q!HX!*CC9?8!
6<7!A?983;6!
TQW'ThSJ!(N!JKSJ!559BN!YIZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISc!Tckc!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQWk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSii!T@N!JbXN!hShK!T6N!
A!u!cSY!bLN!
HbXN!HS`i!T6N!
A!u!`SJ!bLN!HbXN!JShY!T@N!YbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!HIJSgcN!
ggShHN!hhSYKN!HKSgJ!T9'7!@A
H!*'8!9'7!@A
h!;*?49'!*?7!'96!B9;*678XS!
0<7@7!@A7;6?*B!8*6*!
5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
ogip!!`M"?959<7Q*'*B!
TQSk!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(
+@($:)+<+:
N!6<7!?7*;6%9'!9C!
`M4?959<7Q*'
MJM9B!<TN!TJShI!5P!(N!JISI!559BN!JSII!7D3%>SXN!9Q*B#B!
;<B9?%87!TISKi!5PN!JISI!559BNJSII!7D3%>SXN!):-1!TJS
gI!5PN!HISI!559BN!HSII!7D3%>SX!*'8!
6?%76<#B*5%'7!T`SYI!5PN!cISI!559BN!cSI!7D3%>SX!%'!8%;<B9?9576<*'7!THISI!5P!Q!HX!*CC9?8!
6<7!A?983;6!
TQS'TJSHg!(N!iSII!559BN!iIZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISc!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQSk!Jb!2:/!TcII!:bLN!E<B9?9
C9?5
M9X!y!YSi`!T@N!JbXN!hShY!T6N!
A!u!`Si!
bLN!HbXN!HScI!
F!HSgI!T5N!HbXN!JSYH!
F!JSKH!T5N!HbXN!JSih!
F!JScY!T5N!HbXN!JScc!
F!JSgI!T5N!
HbXS
!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
oJJIp!!Et3N (5.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
76m70%174HOOHBrBroxalyl chloride (1.0 equiv.)
DMSO (2.0 equiv.)
HON3HOBr76m76n70%NaN3 (2.0 equiv.)
DMF, 36h, r.t
!JhJ!`M*L%89<7Q*'*B!
TQ>k!09!*'!9>7'
M8?%78!cI!5P!?93'8!49669578!CB*@V!R7?7!*8878!`
M"?959<7Q*'*B!
TQS'TIShc!(N!HSII!559BN!JSII!7D3%>SXN!@98%35!*L%87!TISH`!(N!gSII!559BN!
HSII!7D3%>SX!*'8!):W!TKSI!5PXS!0<7!?7*;6%9'!R*@!@6%??%'(!*6!?995!675A7?*63?7!C9?!J`!
<93?@!*'8!R*@<78!R%6<!R*67?[8%76<#B!76<7?!TJISI!5P!
Q!hN!JkJ
XS!0<7!;954%'78!9?(*'%;!B*#7?!
R*@!8?%78!9>7?!2
*-1
g!*'8!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'S!
WB*@<!;<?95*69(?*A<#!
T@%B%;*!(7BN!HI!55!Q!J`I!55N!<7Q*'7[.61+;!hkiX!*CC9?878!6<7!A3?7!
TQ>'TISHI!(N!JSgI!
559BN!iIZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISH!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQ>k!Jb!2:/!
TcII!:bLN!
E<B9?9C9?5
M9X!y!YSiK!T@N!JbXN!hSHK!T6N!
A!u!`SK!bLN!HbXN!HScI!
F!HSgh!T5N!HbXN!JSiJ!
F!JScY!T5N!gbXN!JSgi!
F!JSh`!T5N!hbXS!0<7
!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!
C9?!6<%@!;95A93'8S
oJJJp!S!b7A6M`M#'*B!
TQAk!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(
+N*9$"*+%(+@($:)+<+:
N!6<7!
?7*;6%9'!
9C!<7A6M`M#'MJM9B!<TO!TJSII!(N!KSYI!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!TJSch!5PN!
JiSK!559BN
!HSI!7D3%>SXN!):-1!TJSYI!5PN!H
`Si!559BN!hSI!7D3%>SX!*'8!6?%76<#B*5%'7!T`SHI!
5PN!cISI!559BN!cSII!7D3%>SX!%'!8%;<B9?9576<*'7!ThcSI!5P!Q!HX!*CC9?8!6<7!A?983;6!
TQA'TISKh!(N!iS`I!559BN!KcZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISc!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!
C9?!
TQAk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSiK!T6N!
A!u!JSi!bLN!JbXN!HSgi!T68N!
A!u!iShN!JSi!
bLN!HbXN!HSHh!T68N!
A!u!iSIN!HSi!bLN!HbXN!JSY`!T6N!
A!u!HSi!bLN!JbXN!JSKH!
F!JSiJ!T5N!HbXN!JS`g!
F!JSg`!T5N!HbXS!
0<7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!
;95A93'8S
oJJHp!!oxalyl chloride (2.0 equiv.)
DMSO (3.0 equiv.)
Et3N (5.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
76o85%175HOOH!JhH!!gMTJNh
M)%9Q9%@9%'89B%'
MHM#BX436*'*B!
TQLk!09!*'!9>7'
M8?%78!cI!5P
!?93'8!49669578!CB*@V!
R7?7!*8878!
%@947'L9C3?*'
MJNhM8%9'7!<TO'TISig!(N!cSII!559BN!JSII!7D3%>SXN!
gM*5%'9436*'
MJM9B!<TQ!TISgc!(N!cSII!559BN!JSII!7D3%>SX!*'8!69B37'7!THISI!5PXS!0<7!?7*;6%9'!R*@!
?7CB3Q78!C9?!h!<93?@!*'8!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'S!
WB*@<!;<?95*69(?*A<#!
T@%B%;*!(7BN!HI!55!Q!J`I!55N!A3?7!.61+;X!*CC9?878!6<7!A3?7!
<TT'TISiJ!(N!hShI!559BN!`cZX
'*@!*!R<%67!@9B%8S!
/Cu!ISJ!TA3?7!.61+;XS
!-A7;6?*B!8*6*!C9?!
<TTk!Jb!2:/!TcII!:bLN!
E<B9?9C9?5
M9X!y!iSKi!
F!iSKI!T5N!HbXN!iSic!
F!iS`i!T5N!HbXN!hSig!T6N!
A!u!iSH!bLN!HbXN!hS`Y!T6N!
A!u!`Sg!bLN!HbXN!JSiK!TAN!
A!u!iSh!bLN!HbXN!JS`H!TAN!
A!u!iSh!bLN!HbXS
!0<7!@A7;6?*B!8*6*!5*6;<!
6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
oJJhp!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@($:)+<+:
N!6<7!?7*;6%9'!
9C!HMTgM<#8?9Q#436#BX%@9%'89B%'7
MJNhM8%9'7!<TT!TISiH!(N!hShI!559BN!JSII!7D3%>SXN!9Q*B#B!;<B9?%87!
TISci!5PN!`S`I!559BN!HSI!7D3%>SXN!):-1!TISYh!5PN!JhSH!559BN!gSI!7D3%>SX!*'8!
6?%76<#B*5%'7!THSig!5PN!JYSK!559BN!`SI!7D3%>SX!%'!8%;<B9?9576<*'7!TJcSI!5P!Q!HX!*CC9?8!
6<7!A?983;6!
TQL'TIShi!(N!JSiI!
559BN!cJZX
'*@!*!;9B9?B7@@!9%BS!
/Cu!ISK!TA3?7!.61+;XS!
-A7;6?*B!8*6*!C9?!
TQLk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSii!T@N!JbXN!iSYg!
F!iSiY!T5N!
HbXN!iSic!
F!iS`Y!T5N!HbXN!hSig!T6N!
A!u!`SK!bLN!HbXN!HScg!T6N!
A!u!iSH!bLN!HbXN!HSIH!TAN!
A!u!iSI!
bLN!HbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!HIISK`N!J`KShiN!JhgSIhN!JhJSYiN!JHhSHYN!
gJSIYN!hiSJJN!HJSJ`S
!0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!C9?!6<%@!
;95A93'8S
oJJhp!!oxalyl chloride (2.0 equiv.)
DMSO (4.0 equiv.)
Et3N (6.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
76p51%17765%NHOOONOHOOOOO+H2NOHtoluene
reflux, 3h
175176!Jhh!!gM+L%89436*'*B!
TQfk!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@($:)+<+:
N!6<7!
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6?%76<#B*5%'7!T`SY!5PN!cISI!559BN!cSI!7D3%>SX!%'!8%;<B9?9576<*'7!TJc!5P!Q!HX!*CC9?8!6<7!
A?983;6!
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-A7;6?*B!8*6*!C9?!
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M9X!y!YSKH!T@N!JbXN!hSg`!T6N!
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0<7!?7*;6%9'!R*@!@6%??%'(!*6!?995!675A7?*63?
7!C9?!J`!<93?@!*'8!R*@<78!R%6<!R*67?[8%76<#B!
76<7?!THISI!5P!
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g!*'8!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'S!
WB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!HI!55!Q!J`I!
55N!<7Q*'7[.61+;!hkiX!*CC9?878!6<7!A3?7!
TQf'TIShH!(N!HSKI!559BN!iIZX
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9%BS!/Cu!ISH!Tikh!<7Q*'7[.61+;XS!
-A7;6?*B!8*6*!C9?!
TQfk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSKI!T@N!JbXN!hShc!T8N!
A!u!`Si!bLN!HbXN!HScK!T6N!
A!u!iSJ!bLN!HbXN!JSYH!TAN!
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0<7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93
@B#!?7A9?678!8*6*!C9?!6<%@!;95A93'8S
oJJcp!!Et3N (5.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
17840%177HBrOOHBroxalyl chloride (1.0 equiv.)
DMSO (2.0 equiv.)
76q70%HN3ONaN3 (2.0 equiv.)
DMF, 36h, r.t
Et3N (6.0 equiv.)
DCM, -78¡C-r.t, 0.5 h
179oxalyl chloride (1.2 equiv.)
DMSO (2.4 equiv.)
76r60%HOOH!Jhg!b7QMcM7'*B!TQ@k!W9BB9R%'(!6<7!
F!%!#$:(
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5PN!`ISI!559BN!`SII!7D3%>SX!%'!8%
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A!u!iShN!JSi!bLN!HbXN!HSJH!
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oJJ`p!Q=P=P'/@GLH@H?EA>'KA@'"JYSSG?@ED'1H_
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07CB9'!>*B>7N!CB3@<78!R%6<!'%6?9(7'!R*@!
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JI!59BZN!ISHc!:N!A?7A*?78!C?95!(7'7?*B!A?9;783?7!+
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RHO++POHRP(OEt)
2HNONH2HO10 mol%Zr complex with (
S)-tBu-VANOL
(1:1:3)
4† M.S (2 equiv), 23 ¡C
10 mol% benzoic acid 
toluene, 16-72h
1 equiv1 equiv1 equivOH76a-s
64m65b78a-s
OEt
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A96*@@%35!;*?49'*67!TISHK!(N!HSII!559BN!HSII!7D3%>SX!*'8!8?%78!):W!TcSII!5PXS!0<7!
5%Q63?7!R*@!@6%??%'(!C9?!c!5%'367@!C9BB9R78!4#!6<7!*88%6%9'!9C!576<#B!%98%'7!TYHSh
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P(OEt)
2HNOHOCH3I (1.25 equiv.)
K2CO3 (2.0 equiv.) 
DMF
NIS (2.0 equiv.)
CH3CN/H2O100 mol% H2SO4P(OEt)
2NH2O67aP(OEt)
2HNOMeO
8080%7980%!JcJ!D37';<78!R%6<!R*67?!TcSI!5PXS!0<7!9?(*'%;!B*#7?!R*@!R*@<78!4#!R*67?!Th!
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6<7!*D3793@!B*#7?!R*@!7Q6?*;678!R%6<!8%76<#B!76<7?!Th!
Q!cSII!5PXS!0<7!;954%'78
!9?(*'%;!
B*#7?!R*@!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'
S!WB*@<!
;<?95*69(?*A<#!T@%B%;*!(7BN!JI!55!
Q!JII!55N!<7Q*'7[.61+;N!ikhX!*CC9?878!6<7!
TV'TIShc!
(N!ISKI!559BN!KIZX!*@!*!B%(<6!#7BB9R!9%BS!
/C!u!IShI!T<7Q*'7[.61+;!ikhXa!
-A7;%C%;!
/96*6%9'k!!"#$%&u!wcS`!T;!JSIN!EbEB
hXa!
-A7;6?*B!8*6*!C9?!
TVk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!iScg!
F!iSgi!T5N!HbXN!iShK!
F!iSHY!T5N!HbXN!iSHY!
F!iSHJ!T5N!JbXN!`Sgg!T8N!
A!u!HSI!bLN!JbXN!`SJi!
T8N!
A!u!HSJ!bLN!JbXN!gSic!T8N!
A!u!HhSi!bLN!JbXN!gSJK!
F!hSYh!T5N!hbXN
!hSiY!T@N!hbXN!hSiK!
F!hSig!T5N!JbXN!hSHK!T<7A6N!
A!u!`SY!bLN!JbXN!HS``!T<7A6N!
A!u!`SY!bLN!JbXN!JSHi!T6N!
A!u!iSJ!bLN!
hbXN!JSHg!
F!JSJi!T5N!`bXN!JSJc!T6N!
A!u!iSJ!bLN!hbXN!JSIY!T8N!
A!u!`SY!bLN!hbXN!JSIg!T8N!
A!u!`SY!bLN!hbXS!
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M9X!y!JggSKKN!JgHS`JN!JgIS`cN!JhYSJgN!JhYSIhN!
Jh`SHiN!JHKScHN!JHiSYgN!JHiSYIN!JHiSKhN!JJhShgN!JIKSIIN!`hSJH!T6N!
A!u!iS`!bLXN!`IScIN!
c`S`gN!ccSggN!hhSYKN!H`ShYN!HgSJJN!HhSYhN!HhSKgN!HhSKHN!`Sg`!T8N!
A!u!cSK!bLXN!J`SHc!T8N!
A!u!cSY!bLXS
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HYc`@N!Jig
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@N!JH`h>@N!ihh>@!
;5MJa!b/:-!
T.-,M01WX!
1DC
!C93'8!ghgSHg`I!To:wbp
wXa!;*B;8S!ghgSHg`I!C9?!E
Hgbhi21gGS!)%76<#B!T*5%'9TA<7'#BX576<#BXA<9@A<9'*67@!
UXk'09!*'!9>7'
M8?%78!c!5P!?93'8!496695!
CB*@V!R7?7!*8878!
TV'THHSI!5(N!ISIc!559BN!JSII!7D3%>SXN!2,-!TKSiI!5(N!ISJI!559BN!HSI!
7D3%>SXN!@3BC3?%;!*;%8!TJ!:N!ISIc!5PN!ISIc!559BN!JSII!7D3%>SX!*'8!*;769'%6?%B7[R*67?!TJSII!
5PN!JkJXS!0<7!?7*;6%9'!R*@!@6%??%'(!C9?!h!<93?@!*6!?995!675A7?*63?7!*'8!D37';<78!R%6<!
@98%35!4%;*?49'
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Q!HSII!5PXS!0<7!;954%'78!9?(*'%;!B*#7?!R*@!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!3'87?!
?96*?#!7>*A9?*6%9'
S!WB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!JI!55!
Q!JII!55N!EbEB
h[:71bN!
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UX'TYS`!5(N!ISIK!559BN!KIZX!*@!*!B%(<6!#7BB9R!9%BS!
/C!u!IS
J!T.61+;Xa!
!JcH!-A7;%C%;!/96*6%9'k
!!"#$%&!uwJISJ
!T;!ISYN!EbEB
hXa!
-A7;6?*B!8*6*!C9?!
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E<B9?9C9?5
M9X!y!iSgi!
F!iSgh!T5N!HbXN!iShK!
F!iShh!T5N!HbXN!iShH!
F!iSHi!T5N!JbXN!gSH`!T8N!
A!u!JiSJ!bLN!JbXN!gSIY!
F!hSY`!T5N!hbXN!hSYJ!
F!hSKh!T5N!JbXNHSgY
MHSJY!T4?N!JbN!2b
HXN!JSHK!T6N!
A!u!iSJN!ISc!bLN!hbXN!JSJK!T6N!
A!u!iSJN!IS`!bLN!hbXS!
JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!
JHKSg`N!JHKSggN!JHiSKiN!JHiSKgN!JHiSiHN!JHiS`iN!`HSii!T88N!
A!u!JKSKN!iSH!bLXN!cgS`cN!chSgiN!
J`Sgg!T8N!
A!u!cSi!bLXN!J`ShH!T8N!
A!u!cSi!bLXS!
,/!T6<%'!C%B5X!
hgII4?N!HY
Hc>@N!H
hcY>@N!J`cI@N!
JHcK@N!JIH`>@N!iYK@!
;5MJa!b/:-!T.-,
M01WX!
1DC
!C93'8!H``SIYHg!oT:w2*X
wa!;*B;8S!
H``SIYHH!C9?!E
JJbJK21hG2*S!0<7!*4@9B367!;9'C%(3?*6%9'!R
*@!8767?5%'78!69!47!T
2X!4#!
;95A*?%'(!6<7!9A6%;*B!?96*6%9'!R%6<!B%67?*63?7!?7A9?678!@*57!;95A93'8
o`Ip!*'8!.EE)!
@A7;6?35S!
!!cNiM)%*&+
A?9A#B
MHMA<7'#B47'L9o
9p9Q*L9B7!
U<k!09!*'!9>7'
M8?%78!c!5P!?93'8!496695!CB*@V!
R7?7!*8878!
QTH'TgHSK!5(N!ISJI!559BN!JSII!7D3%>SXN!E+2!TISHH!(N!ISgI!559BN!gSI!7D3%>SXN!
*'8!*;769'%6?%B7[R*67?!TISKI!5PN!JkJXS!0<7!?7*;6%9'!R*@!@6%??%'(!C9?!`!<93?@!*6!?995!
675A7?*63?7!*'8!D37';<78!R%6<!@98%35!4%;*?49'*67!TJSI!5PXS!0<7!*D3793@!B*#7?!R*@!
7Q6?*;678!R%6<!8%7
6<#B!76<7?!Th!
Q!HSII!5PXS!0<7!;954%'78!9?(*'%;!B*#7?!R*@!8?%78!9>7?!
2*-1
g!*'8!;9';7'6?*678!3'87?!?96*?#!7>*A9?*6%9'
S!WB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!JI!
55!Q!JII!55N!.61+;[b7Q*'7N!HkKX!*CC9?878!6<7!
U<'TYSg5(N!ISIhg!559BN!hgZX!*@!*!B%(<6!
#7BB9R!9%BS!
/C!u!IS
i!T<7Q*'7[.61+;!ikhXa!
-A7;6?*B!8*6*!C9?!
U<k!Jb!2:/!TcII!:bLN!
NO8134% (major side product)
P(OEt)
2HNOHO67aCAN (4.0 equiv.)
CH3CN/H2O (1:1)
0¡C-r.t
!Jch!E<B9?9C9?5
M9X!y!KShI!
F!KSHc!T5N!HbXN!iSc`!
F!iScJ!T5N!hbXN!iSgK!T8N!
A!u!JS`!bLN!JbXN!iSIK!
F!iSIc!T5N!JbXN!hShK!T<7A6N!
A!u!iSI!bLN!JbXN!hSIh!T<7A6N!
A!u!`SY!bLN!JbXN!JSgc!T8N!
A!u!iSI!
bLN!`bXN!JShH!T8N!
A!u!`SY!bLN!`bXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!J`HSiJN!JgiSHJN!
JgcSK`N!JgHSJIN!JhJScIN!JhJSHcN!JHKSK`N!JHiSgiN!JHJS``N!JJgSghN!hgShcN!hISIKN!HgScIN!
HHS`H!T9'7!@AH!;*?49'!%@!'96!B9;*678XS!
!,/!T6<%'!C%B5X!
HY`I>@
N!HYHc>@N!Jccc@N!J
gcI@N!
JIcK@N!JIH`>
@N!iYK@!
;5MJa!b/:-!T.-,
M01WX!
1DC
!C93'8!HKISJiIc!oT:wbX
wa!;*B;8S!
HKISJiIJ!C9?!E
JYbHH21S!'')%76<#B!TJ
M*5%'9
MhM576<#B436#BXA<9@A<9'*67@!
VXk!09!*'!9>7'
M8?%78!c!5P!?93'8!496695!
CB*@V!R7?7!*8878!
TQD'THISK!5(N!ISI
`559BN!JSII!7D3%>SXN!2,-!T
hiSK!5(N!ISJK!559BN!
hSI!7D3%>SXN!@3BC3?%;!*;%8!TJ!:N!ISI
`!5PN!ISI
`!559BN!JSII!7D3%>SX!*'8!*;769'%6?%B7[R*67?!TJS
JH!5PN!JkJXS!0<7!?7*;6%9'!R*@!@6%??%'(!C9?!h!<93?@!*6!?995!675A7?*63?7!*'8!D37';<78!R%6<!
@98%35!4%;*?49'*67!TJSI!5PXS!0<7!*D3793@!B*#7?!R*@!7Q6?*;67
8!R%6<!8%76<#B!76<7?!ThSI!5P!
Q!HXS!0<7!;954%'78!9?(*'%;!B*#7?!R*@!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!3'87?!?96*?#!
7>*A9?*6%9'
S!WB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!JI!55!
Q!JII!55N!EbEB
h[:71bN!YkJX!
*CC9?878!6<7!
VX'TiSH!5(N!ISIhH!559BN!`IZX!*@!*!B%(<6!#7BB9R!9%BS!
!!"#$%&u!Mh`Si!T;!ISiHN!EbEBhXa!/
C!u!ISJ!T.61+;XS!
-A7;6?*B!8*6*!C9?!
VXk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!gSJi!
T@N!gbXN!hSJI!T@N!JbXN!JSYh!T@N!JbXN!JScg!T@N!HbXN!JShc!T6N!
A!u!`Sc!bLN!`bXN!ISYK!T8N!
A!u!`Sc!
bLN!hbXN!ISYH!T8N!
A!u!`Sg!bLN!hbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!`hShhN!g`SIIN!
P(OEt)
2HNOHONIS (3.0 equiv.)
CH3CN/H2O100 mol% H2SO43hP(OEt)
2NH2O9060%76c!Jcg!hYSIKN!HgShiN!HhSHgN!HJShiN!J`S`IS
!,/!T6<%'!C%B5X!
hhY`4?N!HYHJ
>@N!J`ch@N!JHHh
@N!JIHh>@
a!b/:-!T.-,
M01WX!
1DC
!C93'8!Hg`SJHhK!To:w2*p
wXa!;*B;8S!Hg`SJHhc!C9?!E
YbHH21hG2*a!
0<7!*4@9B367!;9'C%(3?*6%9'!R*@!8767?5%'78!69!47!T
2X!4#!;95A*?%'(!6<7!9A6%;*B!?96*6%9'!R%6<!
B%67?*63?7!?7A9?678!@*57!;95A93'8
o`Hp!*'8!.EE)!@A7;6?35S!
!4EFC@G'PO=<'!5'JLGD?@CS'AK'
!-HSE>A'LIAJLIA>H?G'UX
''!Jcc!!4EFC@G'PO=M'!5'JLGD?@CS'AK'
!-HSE>A'LIAJLIA>H?G'VX
'!OOOOZnZnNPOOEt
EtO
SLP-1P-23NNNNNNNNArArArArArArZnZnOOOOAr = C
6F580PhNH2POEtOOEt
!Jc`!'Q=N'*dLG@ESG>?HW'LH@?'KA@'DIHL?G@'KAC@
'Q=N=<'(Y>?IGJEJ'AK'@EFI?'IGHB'<<N
'''OOOOZnZnNPOOEt
EtO
SLP-1P-23NNNNNNNNArArArArArArZnZnOOOOAr = C
6F5NH2POEtOOEt
90ONHO11O90%OEt
ON25 mol %(R)-VAPOL/B(OPh)
3MEDAM-NH
2 (64Õ)
toluene, - 10 ¡C, 16 h
MEDAM
NCO2EtNOO111) CF
3CO2H    1 equiv2) NaOH
    1 equiv    H2O/EtOH
ONCO2EtOOHNHMEDAM
11TBSOTf
Et3NONCO2EtOOTBSNHMEDAM
1172%, 95% ee12512412384%right head 114
81%oxalyl chlorideDMSO
Et3N, DCM-78¡C-r.t
ONOHO11180MEDAM =
OMe
MeO
!Jci!'-M576<9Q#
M-M576<#B
MJ`M9Q9<7Q*87;*'*5%87
(2-0k!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(
,M!#%(+N*9$"*+%(+@($:)+<+:(
T`ShSHXN!6<7!?7*;6%9'!9C!
<UXocJp!ThSJc!(N!
JISI!559BN!JSII!7D3%>SXN!
9Q*B#B!;<B9?%87!TJSJI!5PN!JHSc!559BNJSHc!7D3%>SXN!):-1!TJSKc!5PN!H`SI!559BN!HS`!7D3%>SX!
*'8!6?%76<#B*5%'7!ThS`I!5PN!H`SI!559BN!HS`!7D3%>SX!%'!8%;<B9?9576<*'7!TH`SI!5P!Q!HX!
*CC9?8!6<7!A?983;6!
<MO'THSKI!(N!YSII!559BN!YIZX
'*@!*!R<%67!
@9B%8S!
/Cu!ISH!Tikh!
<7Q*'7[.61+;XS!
5S!AS!u!hg
Mh`qES!-A7;6?*B!8*6*!C9?!
<MOk!!
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M9X!y!YS`g!T@N!JbXN!hSc`!T@N!hbXN!hSIc!T@N!hbXN!HSh`!
F!HSJY!T5N!gbXN!JSc`!
F!JSgJ!T5N!gbXN!JSJg!
T8N!
A!u!YS`!bLN!HIbXS!
JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!
HIHSYiN!`JSJ`N!ghSKYN!HYScYN!
HYSchN!HYSciN!HYSgiN!HYSghN!HYSgIN!HYShKN!HYShJN!HYSJhN!HcSiIN!HgS`hN!HHSIcN!T9'7!@A
H!*'8!6R9!@A
h!;*?49'@
(*?7
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0<7@7!@A7;6?*B!8*6*!5*6;<!6<7!A?7>%93@B#!?7A9?678!8*6*!
C9?!6<%@!;95A93'8S
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MhMTJc
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MJcM9Q9A7'6*87;#BX*L%?%8%'7
MHM;*?49Q#B*67
(<MNk!09!*!CB*57
M8?%78!cI5P!-;<B7'V!CB*@V!
7D3%AA78!R%6<!*!5*('76%;!@6%?!4*?!*'8!C%BB78!R%6<!'%6?9(7'!(*@!R*@!*8878!T
2XMO+G1P!TISJK!
(N!IShg!559B
N!c!59BZXN!"T1G<X
h!TISHY!(N!JSI!559BN!Jc!59BZX!*'8!:.)+:
M2bH!QNe!THSIJ!
(N!`Sih!559BN!JSII!7D3%>SX!*'8!JhSg`!5P!69B37'7S!0<7!CB*@V!R*@!@7*B78!*'8!6<7!?7@3B6%'(!
ONOHO125ONO124NOEt
OOMe
MeO
!JcK!5%Q63?7!R*@!<7*678!*6!KIqE!C9?!J!<93?S!0<7'!%6!R*@!;99B78!69!?995!675A7?*63?7!*'8!
C9BB9R78!4#!;99
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MJIqE!R%6<!*'!%557?@%9'!;99B7?S!+!'%6?9(7'!CB9R!R*@!%'6?983;78!69!
6<7!'7;V!9C!6<7!CB*@V!69!*>9%8!*4@9?A6%9'!9C!59%@63?7S!0<7!CB*@V!R*@!9A7'78N!*'8!gj!
59B7;3B*?!THSI!(X!@%7>7N!*B87<#87!
<MO!THShH!(N!iSgJ!559BN!JSJ!7D3%>SX!*'8!76<#B!
8%*L9*;76*67!ThSIi
!5PN!H`SY!559BN!gSI!7D3%>SX!R*@!@3;;7@@%>7B#!*8878!*6!
MJIqES!0<7!
CB*@V!R*@!@7*B78!*(*%'S!0<7!?7@3B6%'(!?7*;6%9'!5%Q63?7!R*@!@6%??78!*6!
MJIqE!C9?!J`!<93?@S!
0<7'!%6!R*@!R*?578!3A!69!?995!675A7?*63?7!*'8!8%B3678!R%6<!Jc!5P!<7Q*'7N!C%B67?78!
6<?93(<!;7B%67!A*8!
%'!@%'67?78!(B*@@!C3''7BS!0<7!C%B6?*67!R*@!;9';7'6?*678!3'87?!?783;78!
A?7@@3?7!*'8!C9BB9R78!4#!7QA9@3?7!69!<%(<!>*;335!C9?!J!<93?S!0<7!;?387!9%B!R*@!A3?%C%78!
4#!@%B%;*!(7B!;9B35'!;<?95*69(?*A<#N!KkH!<7Q*'7[.61+;!*@!7B37'6!T/
C!u!ISh!%'!ikh!
<7Q*'7[.61+;XN!*C
C9?8%'(!6<7!A?983;6!TgSih!(N!`SgI!559BN!YcZX!*@!*!#7BB9R!9%BS!,6!R*@!
8767?5%'78!69!47!YcZ!
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Mb!;9B35'N!Yikh!
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6!u!KSHK!5%'!*@!6<7!
5*&9?!7'*'6%957?!*'8!!/
6!u!`ScH5%'!*@!6<7!5%'9?!7'*'6%957?S!-A7;6?*B!8*6*!C9?!
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M9X!y!iSJI!T@N!HbXN!iSIJ!T@N!HbXN!gSHc!
F!gSJH!T5N!HbXN!hSiY!
F!hS`J!Th@N!YbXN!hSgJ!T@N!JbXN!hSJK!T@N!hbXN!HSgH!T6N!
A!u!iS`!bLN!HbXN!HSHg!T@N!JHbXN!HSHJ!T8N!
A!u!`Si!bLN!JbXN
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A!u!iS`!bLN!HbXN!JScc!
F!JSgH!T5N!HbXN!JShY!
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M9X!y!J`YSccN!Jc`SIcN!JccS`YN!JhKSJIN!
JhiS`KN!JhIShHN!JhISHiN!JHiSYYN!JHiSHYN!iiSHHN!`JSIgN!`ISgYN!cYSgHN!g`SKKN!ghSggN!hJSKJN!
HYSchN!HYS
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6<7'!76<*'9B
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cgS`KN!hHSJJN!hJSYIN!hJSIJN
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946*%'78!*@!;9B9?B7@@!9%BS!-A7;%C%;!/96*6%9'k!
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A!u!cShN!HSc!bLN!JbXN!hSig!
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A!u!HSg!bLN!JbXN!
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F!JSYI!T5N!HbXN!JSiH!
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F!ISYY!T5N!HbXN!ISKg!T@N!YbXN!ISIJ!T@NhXN!
MISIK!T@N!hbXS!
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M9X!y!JigSJKN!JccSYIN!JccSihN!JgIShKN!JhKSHIN!JhISciN!JhISghN!JHKSJ`N!
JHiSghN!igScHN!`gSIJN!`JSKJN!`JSHIN!`ISg`N!c
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HYSiJN!HYS`iN!HYS`hN!HYSc`N!HYSgYN!HYSgiN!HcSK`N!HcSiKN!HgS`KN!JiSYKN!J`SHhN!J`SHJN!JgShhN!
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'IGHB'<<P''5 mol % (R)-BOROX cat
2.0 equiv EDA 
1.0 equiv MEDAM-NH
2 (64)Õ
toluene, Ð10¡C, 4† MS
117
61%, 16.7:1 (117:117Õ)
EtO2COHNHMEDAM
NaH, BnBrDMF, nBu
4NI0 ¡C Ñrt
EtO2COBnNHMEDAM
12840%LiAlH4, THF0 ¡C - rt, 1.5 h
OBnNHMEDAM
HOTsCl, DCM
Et3N, 0 ¡C 2 h, rt, 46 h
OBnNMEDAM
right head 113
75%129100%HOMEDAM
EtO2CN121119
91%, 95%ee1. TFA (1.0 equiv)
    Additive (x equiv)
    DCM,  T ¡C
2. NaOH, H2O/EtOH
   rt, 0.5 h
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R*@!6<7'!C%B67?78!6<?93(<!*!E7B%67!A*8!69!*!HcI
M5P!?93'8!496695!CB*@VS!0<7!?7*;6%9'!CB*@V!
R*@!?%'@78!R%6<!.61+;!TJISI!5P!{!hX!*'8!6<7!?%'@7!R*@!C%B67?78!6<?93(<!6<7!@*57!E7B%67!
A*8S!0<7!?7@3B6%'(!@9B3
6%9'!R*@!6<7'!;9';7'6?*678!%'!>*;35!C9BB9R78!4#!7QA9@3?7!69!<%(<!
>*;335!TISIc!55!b(X!C9?!J!<!69!*CC9?8!6<7!;?387!*L%?%8%'7!
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EtO2CNOMe
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119
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;95A93'8!
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6!u!cSiI!5%'!T5%'9?!7'*'6%957?N!
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MJSHK!T5N!cbXN!JSHY
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A!u!`S`!bLXN!HSIg!
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A!u!`SK!bLXN!HSHJc!T@N!`bXN!HSHHI!T@N!`bXN!hShK!
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JhISgiN!JHKSJIN!JHiShHN!KgSgYN!iiShhN!`KSJHN!`ISiHN!cYS`HN!cYScYN!g`SiiN!ghSc`N!HKShKN!
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4*?!*'8!C%BB78!R%6<!'%6?9(7'!(*@!R*@!*8878!6<7!*L%?%8%'7!
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EtO2COHNHMeO
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117
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7Q6?*;678!R%6<!76<
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A!u!iSJ!bLN!HbXN!hSiI!T@N!hbXN!hS`K!T@N!hbXN!hS`h!TDN!
A!u!`SI!bLN!JbXN!hSIc!T8N!
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<MMk!120 mol% oxalyl chloride260 mol% DMSO
260 mol% Et
3N, DCM, -78¡C
NMEDAM
EtO2CHO12283%120100%, 95% eeethylene-1,2-diamine
NaH, 60¡C, 1hHO131[28]
80%HO20 mmol (C9)
1305 mol % (R)-BOROX cat
2.0 equiv EDA , 
1.0 equiv MEDAM-NH
2 (64)Õ
toluene, Ð10¡C, 4† MS
EtO2CNHMADEM
OH118
75% (9:1 regioselectivity)
BnBr, NaH, Bu
4NIDMF, 0¡C-r.t
EtO2CNHMADEM
OBn13287%LAH, THFNHMADEM
OBnHOTsCl, Et
3N, DCMTHF, 0¡C-r.t
0¡C, 2h, r.t, 46h
OBnNMADEM
13395%left head 116
88%1. TFA, DCM
2. NaOH, EtOH/H
2OMEDAM =
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A!u!iSYN!cSHN!HSg!bLN!JbXN!hSiJ!T@N!hbXN!hS`Y!T@N!hbXN!hS`K!
T@N!hbXN!hSc`!T@N!hb
XN!hSHY!T@N!JbXN!hSJJ!T@N!JbXN!hSI`!T68N!
A!u!KSIN!hSg!bLN!JbXN!HSHK!T@N!`bXN!
HSHc!T@N!JHbXN!HSHI!T@N!`bXN!HSJK
MHSJ`!T5N!JbX!HSI`!T@N!JbXN!HSIg!
F!JSYg!T5N!HbXN!JSKH!T68N!
A!u!iSIN!hS`!bLN!JbXN!JSiH!
F!JS`J!T5N!gbXN!JScY!
F!JScJ!T5N!HbXN!JSgY!
F!JSgI!T5N!`bXN!JS
hh!F!JSHc!T5N!HibXN!ISKg!T@N!YbXN!
MISIH!T@N!hbXN!
MISIi!T@N!hbXS!
JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!JigSHIN!Jc`SHIN!JccSKYN!JccSihN!JccS`KN!JgISgIN!JhYSHhN!JhKS``N!JhKScKN!JhKSccN!
JhKSHHN!JhIScKN!JhISg`N!JhISggN!JHKSciN!JHKScgN!JHKSJiN!JHKSIgN!JHiSghN!JHiSIY
N!JH`SYKN!
KcShgN!KJScIN!KISiiN!iKSHYN!igScgN!iISYgN!iISYJN!`cSh`N!`gSIJN!`HSiIN!`JSKhN!`ISgiN!cYS`hN!
cYScYN!cYSg`N!ggSicN!hKSH`N!hgSJHN!hhSh`N!hIS`JN!HYSYHN!HYSigN!HYS`cN!HYS`HN!HYShcN!HKSYcN!
HKSKKN!HKS`YN!HKS`hN!HKSc`N!HKSchN!HcSKKN!HcSiYN!HcSggN!HcSHYN!J
KS`HN!JiSYYN!J`SHiN!J`SHcN!
!Jii!J`SHHN!JgShgN!
MgSHgN!McSIh!T9'7!@A
H!*'8!9'7!@A
h!;*?49'!*?7!'96!B9;*678XS!b/:-!T.-,
M01WX!
1DC
!C93'8!JhIcSKKIJ!To:wbp
wXa!;*B;8S!JhIcSKKgJ!C9?!
EKHbJHJ2H1YS!!!!TH,Nh,NHi2XMHiMT47'L#B9Q#X
MHMTT4%@Tg
M576<9Q#
MhNcM8%576<#BA<7'#BX576<#BX*5%'9X
MHiMTT2XMJMT4%@Tg
M576<9Q#
MhNcM8%576<#BA<7'#BX576<#BX*L%?%8%'
MHM#BX
MhMTT"!#"
M436#B8%576<#B@%B#BX9Q#X<7A6*;9@
MJYM#'7
MJNJKM8%9B!<PTk!09!*'!9>7'
M8?%78!cI!5P!?93'8!
496695!CB*@V!C%BB78!R%6<!'%6?9
(7'!R7?7!*8878!
<PN!TISJh!(N!ISJI!559BN!JSII!7D3%>SX!*'8!0bW!
TJSII!5PXS!+C67?!6<7!@9B36%9'!R*@!;99B!89R'!69!IqEN!P%+Bb
g!THHSK!5(N!IS`I!559BN!`SI!7D3%>SX!
R*@!@B9RB#!*8878S!0<7!?7*;6%9'!5%Q63?7!R*@!@6%??78!*6!I!qE!C9?!hI!5%'!*'8!6<7'!?995!
675A7?*63?7!C9?!J!<9
3?S!,6!R*@!D37';<78!4#!*88%6%9'!9C!b
H1!TIScI!5PXN!C9BB9R78!4#!
*88%6%9'!9C!*DS!2*1b!TJcZN!ISJI!5PX!*'8!6<7'!*'96<7?!6R9!A9?6%9'@!9C!b
H1!TIScI!5P!Q!
OBnNOHOHNH13763%OMe
MeO
OMe
MeO
OBnNMEDAM
O11CO2EtOTBSNMEDAM
H134LAH (6.0 equiv)
THF, 0¡C to r.t
OHMEDAM =
OMe
MeO
!JiK!HXS!+C67?!6<7!5%Q63?7!R*@!>%(9?93@B#!@6%??78!*6!?995!675A7?*63?7!C9?!hI!5%'N!%6!47;*57!*!
R<%67!753B@%9'N!R<%;<
!R*@!C%B67?78!6<?93(<!*!;7B%67!A*8S!0<7!;7B%67!A*8!R*@!R*@<78!R%6<!
76<#B!*;76*67!@7>7?*B!6%57@!3'6%B!0PE!%'8%;*678!6<7?7!R*@!'9!A?983;6!%'!6<7!?%'@7S!0<7!
;954%'78!9?(*'%;!@9B36%9'!R*@!;9';7'6?*678!69!(%>7
!6<7!;?387!A?983;6!
<PT'TiHSI!5(N!ISI`!
559BN!`hZX!
*@!
*'!9A*D37!9%BN!R<%;<!;93B8!47!8%?7;6B#!3@78!%'69!6<7!'7Q6!@67A!R%6<936!
C3?6<7?!A3?%C%;*6%9'
XS!/
C!u!ISJI!T<7Q*'7[.61+;!ikhXS
!-A7;6?*B!8*6*!C9?!
<PTk!Jb!2:/!TcII!
:bLN!E<B9?9C9?5
M9X!y!iShK!
F!iSHY!T5N!HbXN!iSHc!
F!iSJ`!T5N!hbXN!iSIK!T@N!HbXN!iSIc!
F!iSII!T5N!`bXN
!gSii!T@N!JbXN!gSic!T@N!JbXN!gShg!
F!gSHY!T5N!JbXN!gSJH!
F!gSIK!T5N!HbXN!hSi`!T88N!
A!u!JJSHN!gSI!bLN!JbXN!hSiI!T@N!hbXN!hS`K!T@N!`bXN!hSci!T88N!
A!u!JJSHN!HSY!bLN!JbXN!hScg!T@N!
hbXN!hSHi!T@N!JbXN!hSIg!T8DN!
A!u!KSJN!gSc!bLN!JbXN!HSgY!
F!HSgg!T5N!HbXN!HSH`!T@N!`
bXN!HSHc!
T@N!JHbXN!HSJK!T@N!`bXN!HSIg!T@N!JbXN!JSYK!TDN!
A!u!iShN!`SY!bLN!JbXN!JSKJ!T68N!
A!u!iSIN!hS`!bLN!
JbXN!JSiJ!
F!JS`I!T5N!hbXN!JSci!
F!JSgY!T5N!hbXN!JSgY!
F!JShK!T5N!`bXN!JShh!
F!JSJK!T5N!HcbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!Jc`SJKN!JccSYcN!JccS``N!
JhYSghN!JhYSJYN!JhKS`HN!
JhKShKN!JhHSI`N!JhISKHN!JhISi`N!JhISciN!JhISgcN!JHYSiHN!JHKS`IN!JHKScHN!JHKSIhN!JHiS`KN!
JHiSgJN!JHiSIKN!KISKhN!KISihN!iKSH`N!ihSgcN!ihSHJN!iISYJN!`gShIN!`hSYJN!`HS`KN!`HSJgN!
cYS`HN!cYSgcN!cKS`KN!ggSigN!hKSHHN!hiShcN!hgShYN!hhShgN!hH
SJcN!hIScYN!HYS`cN!HYShIN!HKSYgN!
HKScgN!HcSKiN!HcScgN!HcSgJN!HcSHcN!JKS`JN!J`SHKN!J`SHcN!J`SHIN!JgSHI!T9'7!@A
H!*'8!@7>7'!
@Ah!;*?49'@!*?7!'96!B9;*678XS
!''''!JiY!Q=N=O'(Y>?IGJEJ'AK'>G\'@EFI?'IGHB'<NX
'!!!!J`Mb#8?9Q#<7Q*87;#B!A%>*B*67!
<NQk!%"3P%!THSc!:N!JSJ!5PN!HS`i!559BN!HSI!7D3%>SX!R*@!
@B9RB#!*8878!69!6<7!@9B36%9'!9C!
<NOoJHIp'TIScH!(N!HSII!559BN!JSII!7D3%>SX!%'!0bW!THISI!5PX!
*6!IqE!3'87?!'%6?9(7'S!+C67?!6<7!?7*;6%9'!R*@!@6%??%'(!C9?!hI!5%'367@N!%6!R*@!*8878!6<7!
@9B36%9'!9C
!G%>EB!TISJ`!5PN!HSI!559BN!JSII!7D3%>SX!%'!0bW!TKSII!5PXS!0<7!5%Q63?7!R*@!
6<7'!*BB9R78!69!R*?5!69!6<7!?995!675A7?*63?7!*'8!R*@!?7CB3Q%'(!C9?!K!<93?@S!
0<7!?7*;6%9'!
OOPiv
11H5 mol% (R)-VAPOL/ B(OPh)
3100 mol% MEDAM-NH
2 (64Õ), 
4† M.S, toluene, r.t, 24h
200 mol% EDA
N11CO2EtMEDAM
PivO
1). 100 mol% TFA
DCM, 45 ¡C, 16h
2).100 mol% NaOH
H2O/EtOH, rt. 0.5h
11OHCO2EtNHMEDAM
PivO
125 mol% oxalyl chloride260 mol% DMSO
150 mol% LAH11OHNHMEDAM
PivO
OH260 mol% Et
3NDCM, -78¡C-r.t, overnight
147100%148100%14950%THF, 45¡C
15037%OPiv
11HO100 mol% PivCl
200 mol% nBuLiOH11OOLAH, THFHO145[30]
93%14648% (35% SM)
126MEDAM =
OMe
MeO
HO146OPiv
!JKI!R*@!D37';<78!4#!R*67?!TcSI!5PX
!*'8!7Q6?*;678!4#!8%;<B9?9576<*'7!TJISI!5P!Q!HXS!0<7!
;954%'78!9?(*'%;!B*#7?!R*@!R*@<78!R%6<!4?%'7N!8?%78!9>7?!2*-1
g!*'8!;9';7'6?*678!3'87?!
?96*?#!7>*A9?*6%9'S!
WB*@<!;<?95*69(?*A<#!T@%B%;*!(7BN!HI!55!Q!J`I!55N!<7Q*'7[.61+;!
gkJX!*CC9?878!6<7!
<NQ'TISHH!(N!ISY
`!559BN!gKZX
'*@!*!;9B9?B7@@!9%B!ThcZ!9C!@6*?6%'(!
<NO!R*@!?7;9>7?78!*C67?!6<7!;9B35'XS!
/Cu!ISg!Tikh!<7Q*'7[.61+;XS!
-A7;%C%;!/96*6%9'k!
!"#$%&u!MhcSKq!T
)!HSIN!EbEB
hXS!-A7;6?*B!8*6*!C9?!
<NQk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!gSIJ!T6N!
A!u!`S`!bLN!HbXN!hScY!T6N!
A!u!`Si!bLN!HbXN!JS`J!
F!JScc!T86N!
A!u!KSHN!`Sc!bLN!HbXN!JScH!T86N!
A!u!KSHN!`Sc!bLN!HbXN!JSHh!T8N!
A!u!JJSH!bLN!HHbXN!JSJ`!T@N!YbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!JiKS`YN!`gSg`N!`HSYiN!hKSiIN!hHSiiN!HYS`gN!HYS`IN!HYScKN!HYSchN!HYSgYN!HYSghN!HYSHIN!
HKSciN!H
iSJiN!HcSKKN!HcSig!TC93?!@A
h!;*?49'@!*?7!'96!B9;*678Xa!
,/!T6<%'!C%B5X!
hhII4?N!HYJY>@N!HKgY>@N!JiHg>@N!Jgih@N!
JHK`@N!JJiJ@N!JIi`
@!;5
MJab/:-!T.-,
M01WX!
1DC
!C93'8!hghShHJh!To:wbp
wXa!;*B;8S!hgHShHJH!C9?!
EHJbgh21hS!!J`M1Q9<7Q*87;#B!A%>*B*67!
<NTk!W9BB9R%'(!6<7!
F!%!#$:(.#+)!96#!(@+#(,M!#%(+N*9$"*+%(+@(
$:)+<+:(
T`ShSHXN!6<7!?7*;6%9'!9C!
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5PN!JSH!559BNJSHc!7D3%>SXN!):-1!TISJi!5PN!HScI!559BN!HS`I!7D3%>SX!*'8!6?%76<#B*5%'7!
TIShg!5PN!HSc!559BN!HS`I!7D3%>SX!%'!8%;
<B9?9576<*'7!THSgI!5P!Q!HX!*CC9?8!6<7!A?983;6!
<NT'TIShh!(N!ISY`!559BN!JIIZX
'*@!*!B%(<6!#7BB9R!9%BS!
/Cu!IS`!Tikh!<7Q*'7[.61+;X
S!-A7;6?*B!8*6*!
C9?!
<NTk!Jb!2:/!TcII!:bLN!E<B9?9C9?5
M9X!y!YSi`!T8N!
A!u!HSI!bLN!JbXN!gSIg!T6N!
A!u!`S`!bLN!
HbXN!HSgH!T68N!
A!u!iSgN!JSY!bLN!HbXN!JS``!
F!JSci!T5N!gbXN!JShg!
F!JSHH!T5N!HHbXN!JSJY!T@N!YbXS
!JhE!2:/!T
JH`!:bLN!E<B9?9C9?5
M9X!y!HIhSIJN!JiKS`iN!`gSg`N!ghSYHN!hKSiHN!HYS`HN!HYSc`N!
HYScJN!HYSgHN!HYShcN!HYSHHN!HYSJ`N!HKS`IN!HiSHIN!HcSYIN!HHSIi!T6<?77!@A
h!;*?49'@!*?7!'96!
H147OPiv
O!JKJ!B9;*678Xa!
,/!T6<%'!C%B5X!
hghc4?N!HYHH>@N!HKcH@N!JiHK>@N!JgKI@N!JhYi@N!JHKg>@N!
JJcK>@N!
JIhg@!;5MJa!b/:-!T.-,
M01WX!
1DC
!C93'8!hgJShIcH!oT:wbX
wa!;*B;8S!hgJShIc`!C9?!
EHJbgJ1hS!!JcMTTH,Nh,XMJMT"%@Tg
M576<9Q#
MhNcM8%576<#BA<7'#BX576<#BX
MhMTHM76<9Q#
MHM9Q9*;76#BX*L%?%8%'
MHM#BXA7'6*87;#B!A%>*B*67!
<NUk!09!*!CB*57
M8?%78!cI5P!-;<B7'V!CB*@V!
7D3%AA78!R%6<!*!5*('76%;!@6%?!4*?!*'8!C%BB78!R%6<!'%6?9(7'!(*@!R*@!*8878!T
2XMO+G1P!TYiSc!
5(N!ISJK!559BN!JI!59BZ
XN!"T1G<X
h!TISJ`!(N!IScg!559BN!hI!59BZX!*'8!:.)+:
M2bH!QNe!TIScg!(N!JSK!559BN!JSII!7D3%>SX!*'8!hS`!5P!69B37'7S!0<7!CB*@V!R*@!@7*B78S!0<7!?7@3B6%'(!
5%Q63?7!R*@!<7*678!*6!KIqE!C9?!J<S!0<7'!%6!R*@!;99B78!69!?995!675A7?*63?7S!+!'%6?9(7'!
CB9R!R*@!%'6?983;78!69!6
<7!'7;V!9C!6<7!CB*@V!69!*>9%8!*4@9?A6%9'!9C!59%@63?7S!0<7!CB*@V!R*@!
9A7'78N!*'8!gj!TIScg!(X!59B7;3B*?!@%7>7N!*B87<#87!
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*'8!76<#B!8%*L9*;76*67!TISi`!5PN!iSHI!559BN!gSI!7D3%>SX!R*@!@3;;7@@%>7B#!*8878!*6!?995!
675A7?*63?7S!0
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MJIqE!C9?!J`!<93?@S!0<7'!%6!R*@!R*?578!3A!69!?995!675A7?*63?7!*'8!8%B3678!R%6<!c!5P!
<7Q*'7N!C%B67?78!6<?93(<!;7B%67!A*8!%'!@%'67?78!(B*@@!C3''7BS!0<7!C%B6?*67!R*@!;9';7'6?*678!
3'87?!?
783;78!A?7@@3?7!*'8!C9BB9R78!4#!7QA9@3?7!69!<%(<!>*;335!C9?!J<S!0<7!;?387!9%B!
R*@!A3?%C%78!4#!@%B%;*!(7B!;9B35'!;<?95*69(?*A<#N!KkH!<7Q*'7[.61+;!*@!7B37'6!T/
C!u!ISg!
%'!ikh!<7Q*'7[.61+;XN!*CC9?8%'(!6<7!A?983;6!TJShI!(N!JSKI!559BN!YcZX!*@!*!#7BB9R!9%BS!
-A7;%
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<NUk!Jb!2:/!TcII!:bLN!
NPivO
OEt
OOMe
MeO
148!JKH!E<B9?9C9?5
M9X!y!iSJJ!T@N!HbXN!iSIH!T@N!HbXN!gSHi!
F!gSJh!T5N!HbXN!gSIc!T6N!
A!u!`S`!bLN!HbXN!
hS`K!T8N!
A!u!`Sg!bLN!`bXN!hSgJ!T@N!JbXN!HSHg!T@N!JHbXN!HSHH!T8N!
A!u!`SK!bLN!JbXN!JSYi!T68N!
A!u!iSIN!cSY!bLN!JbXN!JS`c!
F!JScY!T5N!hbXN!JShi!
F!JSHJ!T5N!HhbXN!JSHI!T@N!YbXN!JSJc!
F!JSIc!T5N!
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!JhE!2:/!T
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M9X!y!JiKS`KN!J`YSiJN!Jc`SJHN!JccSiKN!JhKSJiN!JhiSi`N!
JhIScIN!JhISggN!JHKSJIN!JHiShYN!`gSgKN!`IS`YN!cY
ScYN!chSggN!giSIHN!ghSciN!hKSihN!HYS`KN!
HYS`gN!HYScKN!HYSchN!HYSHcN!HYSJYN!HKS`JN!HiSYcN!HiSH`N!HiSHJN!HcSYHN!J`SJYN!J`SJgN!JgSh`!
T6<?77!@A
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;5MJa!b/:-!T.-,
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6!u!gSH!5%'!*@!5%'9?!7'*'6%957?p!*'8!/
6!u!cSh!5%'!*@!5*&9?!7'*'6%957?S
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MhM<#8?9Q#
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M8?%78!cII!5P!?93'8!496695!CB*@V!7D3%AA78!
R%6<!*!5*('76%;!@6%?!4*?!*'8!C%BB78!R%6<!'%6?9(7'!(*@!R*@!*8878!6<7!*L%?%8%'7!
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EbHEBH!THSII!5PN!ISJ!:X!*'8!
EWhE11b!TJcSg!
 µPN!ISHI!559BN!
JSII!7D3%>SXS!0<7!CB*@V!R*@!7D
3%AA78!R%6<!*!;9'87'@7?N!@7*B78!R%6<!*!@7A635!69!R<%;<!*!
'%6?9(7'!4*BB99'!R*@!*66*;<78!>%*!*!'778B7N!*'8!@6%??78!9>7?'%(<6!*6!?995!675A7?*63?7S!
0<7'!6<7!>9B*6%B7!R*@!?759>78!3'87?!?783;78!A?7@@3?7S!IS`K!5P!JckH!.61b[b
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120 mol% NaHCO3DCM (0.5M), 0¡C to r.t
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OOMe
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155b1. HOTf (5 equiv.)
Anisole, 0¡C-r.t, overnight
2. FmocCl (1 equiv.)
NaHCO3 (1.2 equiv.)
Acetone/H2O (3:1), 50¡C, 48h
NOEt
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J`JSYHN!J`iSgIa!orp
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R*@!@6%??78!C9?!Hg!<93?@N!gSc!5P!9C!0bW!R*@!*8878N!C9BB9R78!4#!ISJg!(!TIScc!559BX!9C!
%98%'7!8%@@9B>78!%'!J5P!9C!0bW!3'87?!'%6?9(7'S!0<7!?7*;6%9'!CB*@V!R*@!@7*B78!*'8!<7*678!
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M4B37!@B3??#S!0<7!@B3??#!R*@!6<7'!A?7;99B78!69!I
!qE!%'!
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2 (6 equiv.)
DMEA,THF, 0¡C, 2h
FmocHNOEt
OMe157NOEt
OFmoc187N-Fmoc-
!3-homo-D-alloisoleucine 
ethyl ester
!JYY!*'!%;7!4*6<S!-34@7D37'6B#N!69!*!CB*57
M8?%78!c!5P!?93'8
M49669578!CB*@V!C%BB78!R%6<!'%6?9(7'!
R7?7!*8878!
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2N2M8%576<#B76<*'9B*5%'7!TISgI!5PN!ISKg!559BN!JHSI!7D3%>XS!0<7!@9B36
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;9'6*%'%'(!6<7!-5,
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5*%'6*%'78!83?%'(!6<7!*88%6%9'!9C!6<7!*L%?%8%'7!69!6<7!-5,
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CB*@V!;9'6*%'%'(!-5,
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D37';<78!4#!6<7!*88%6%9'!9C!@*6!*D!2*bE1
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OOMe
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155bÕ1. HOTf (5 equiv.)
Anisole, 0¡C-r.t, overnight
2. FmocCl (1 equiv.)
NaHCO3 (1.2 equiv.)
Acetone/H2O (3:1), 50¡C, 48h
NOEt
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MJShY!T5N!HbXN!JScK
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N!`JScJN!`KSJJN!JJYSYgN!JJYSYKN!
JHgSKKN!JHgSYKN!JHiSI`N!JHiSJgN!JHiSKJN!JHiSKHN!JgJShcN!JgJSgiN!JghShcN!JghSg`N!J`JSiiN!
J`iShga!orp
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JHic!T@XN!JH`I!T>@XN!icI!T>@X!;5
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MYM#BX576<9Q#X;*?49'#BX*5%'9X
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M8?%78!c!5P!?93'8
M49669578!CB*@V!C%BB78!R%6<!'%6?9(7'!
SmI
2 (6 equiv.)
DMEA,THF, 0¡C, 2h
FmocHNOEt
OMe158N-Fmoc-
!3-homo-L-isoleucine 
ethyl ester
NOEt
OFmoc188!HIH!R7?7!*887
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