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. LIBRARY
100} Michigan State
’ University

 

 

 

This is to certify that the
thesis entitled

NEW METHODOLOGY FOR CONSTRUCTION OF
OXYGEN -CONT AINING HETEROCYCLES

presented by

ZHIHUA SHANG

has been accepted towards fulfillment
of the requirements for the

MS. degree in Chemistry

 

 

z? m

‘~ g /~—.\<:/

 

Major Professor’s Signature

35/101051

Date

MSU is an Affirmative Action/Equal Opportunity Institution

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DATE DUE

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(A

 

 

 

 

 

 

 

 

 

 

 

 

 

2/05 p:/ClRC/DateDue.indd-p.1

 

NEW METHODOLOGY FOR CONSTRUCTION OF
OXYGEN -CONTAININ G HETEROCYCLES

By

Zhihua Shang

A THESIS

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

MASTER OF SCIENCE
Department of Chemistry
2006

ABSTRACT

NEW METHODOLOGY FOR CONSTRUCTION OF
OXYGEN-CONTAINING HETEROCYCLES

By
Zhihua Shang

In this thesis we report a new methodology that utilizes ring-closing metathesis
(RCM) to make oxygen-containing heterocycles. The motif is approached by a novel
stereoselective nucleophilic attack on cyclic orthoesters to generate a bis-alkene
intermediate. RCM of the bis-alkene would lead to a bicyclic ketal and selective
reduction of the ketal would yield the oxygen-containing heterocycle. Heterocycles of
various ring sizes could be constructed if this strategy is applicable. The stereocontrol in
the methodology could be accessed via Sharpless asymmetric dihydroxylation and
translated to the final product via substrate control.

My results to date have been promising in seteroselective nucleophilic attack on
cyclic orthoesters. However, the diastereomer of the bis-alkene obtained from anti attack
would only lead to the strained inside-out bicyclic ketals, which was either difficult to be
constructed by RCM or too unstable to be isolated once formed. Approaches to achieve
opposite diastereoselectivity have been tried without success. Mechanism of a previously

reported transformation of cyclic orthoesters was also elucidated in this thesis.

To my parents

To those who fight minor depression

iii

ACKNOWLEDGEMENTS

This thesis would be incomplete without the mention of all those who contributed
to my three-year graduate study. Professor Babak Borhan has been an enthusiastic
advisor who continues to be supportive of my decisions and has always encouraged me to
be independent and explore my own ideas. I would also like to thank Profs. Wulff,
Maleczka and Pinnavaia for serving on my committee along with the advice they have
provided.

I am grateful to the love and support of my parents. They motivate me throughout
my school years and give me courage to face challenges in life.

The friends I have in graduate school have been a great source of support. I
would especially like to thank Jennifer Schomaker, who is the most passionate, devoted
and brilliant scientist I have ever met, for giving me so much help and advice in both
study and life. I have enjoyed the wonderful time spent in East Lansing with Xin, Chang,
Xiaoyu, Meng and Bingwei, who help me fight through minor depression. I also want to
thank Jun, Tao, Chryssoula, Courtney, Montse, Marina, Stewart, Dan, Sing, Xiaofei,
Xiaoyong and all Borhan group members.

Finally, I would like to quote a word from my genius friend Chen, who said ‘if
God makes me ordinary all my life, I will take it and thank him until death; yet if there is

a tiny bit of uncertainty about it, I will fight for that uncertainty until death.’

iv

TABLE OF CONTENTS

LIST OF TABLES ................................................................................... vii
LIST OF FIGURES ................................................................................ viii
LIST OF SCHEMES ................................................................................. ix
LIST OF ABBREVIATIONS ...................................................................... xii

Chapter 1. Background: A Brief Review of Oxygen-Containing Hetereocycle
Synthesis ............................................................................................... l
1.1. Introduction .................................................................................. l
1.2. Strategies to Construct Oxygen-Containing Heterocycles ............................ 2
1.2.1. Intramolecular C-O Bond Formation ............................................... 2

1.2.2. Intramolecular C-C Bond Formation: Ring-Closing Metathesis (RCM).. . .6

1.3. Proposed Strategy to Construct Oxygen-Containing Heterocycles............. . ....13

Chapter 2. Results and Discussion ................................................................. 22
2.1. Study of RCM on Model Substrates ..................................................... 22
2.2. Stereoselective Nucleophilic Sttack at C-1 ............................................. 24

2.2.1. Optimization of Conditions .......................................................... 24
2.2.2. Attempts to Make the Other C-l Epimer .......................................... 31

2.3. Attempts of Intramolecular Prins-Type Cyclization on Cyclic Orthoesters. ......35

2.4. Correction of Mechanism of Lewis Acid-Mediated Cyclization of Cyclic

Orthoesters Derived from 1,2,n-triols .......................................................... 37
2.5. Study of Ring-Closing Metathesis of Model Substrates .............................. 40
2.6. Conclusions ................................................................................. 42

Chapter 3. Experimental ............................................................................ 43
3.1. General Information ...................................................................... 43
3.1.1. Orgins of Starting Materials ....................................................... 43

3.1.2. List of Compounds that were Compared to Literature Reports .............. 44

3.2. Data for Chapter 2.1 ....................................................................... 44
3.3. Data for Chapter 2.2.1 ..................................................................... 49
3.4. Data for Chapter 2.2.2 ..................................................................... 60
3.5. Data for Chapter 2.3 ....................................................................... 62
3.6. Data for Chapter 2.4 ........................................................ ‘ ............... 67
3.7. Data for Chapter 2.5 ....................................................................... 69
REFERENCES ....................................................................................... 73

vi

LIST OF TABLES

Table 11-1. Optimization of conditions for stereoselective nucleophilic attack of

cyclic orthoesters ..................................................................................... 29
Table II-2. Allylation of different substrates under optimized conditions .................. 30
Table 11-3. Conditions for vinylation ............................................................. 31
Table 11-4. Attempts to make cis diastereomers using orthocarbonates ..................... 32
Table 11-5. RCM for model substrates ............................................................ 41

vii

LIST OF FIGURES

Figure I-l. Examples of natural products containing a THF ring ............................. 2
Figure I-2. Grubbs and Schrock catalyst ........................................................... 7
Figure I-3. Examples of natural products with larger oxygen-containing heterocycles...l6
Figure 11-1. Model substrates ...................................................................... 22

Figure H-2. Other substrates tried for Prins cyclization ....................................... 37

viii

LIST OF SCHEMES

Scheme I-1. General scheme of nucleophile-electrophile cyclization ......................... 3
Scheme I-2. Intramolecular Williamson ether synthesis ....................................... 4
Scheme I-3. Borhan’s synthesis of substituted THFs using cyclic orthoesters .............. 4
Scheme I-4. Rychnovsky’s cascade cyclization of cyclic sulfates ............................. 4

Scheme I-5. Sharpless asymmetric dihydroxylation mnemonic for predicting absolute

Stereochemistry ........................................................................................ 5
Scheme I-6. First synthesis of oxygen-containing heterocycles using RCM ................. 8
Scheme I-7. Cyclization of vinyl ethers using Grubbs catalyst A ............................. 9
Scheme I—8. RCM approach to generate substituted THF rings ............................... 10
Scheme I—9. RCM application in Mioskowski’s total synthesis of solamin ................ 10

Scheme I-lO. Construction of THF ring using asymmetric aldol and RCM reaction in
Crimmins’s total synthesis of (+)-gigantecin ..................................................... 11

Scheme LI 1. Rhodium-catalyzed allylic etherification with the copper(I) alkenyl

alkoxide ............................................................................................... 12
Scheme I-12. Construction of cyclic ethers using RCM in Evan’s total synthesis of

gaur acid ............................................................................................... 12
Scheme I-13. Our group’s previous research on orthoesters .............................. 13, 38
Scheme I-14. Origin of proposed strategy ........................................................ 14
Scheme I-15. Proposed strategy to make substituted THF .................................... 14
Scheme I-l6. Regioselective reduction of cyclic acetals ....................................... 15
Scheme I-17. Alternative strategy for generation of THF and TI-IP rings ................... 15
Scheme I-l8. Extension of our strategy to make larger oxygen-containing

Heterocycles .......................................................................................... 16
Scheme I-19. Retrosythetic analysis of brasilenyne using proposed strategy .............. 17

ix

Scheme 1-20. Inside-in and inside-out bicyclic ketal systems ................................ 17
Scheme I-21. Grubbs’ synthesis of (-)—frontalin using RCM ................................. 18
Scheme I-22. Burke’s methodology to synthesize bridged bicyclic ethers using RCM...19

Scheme I-23. Burke’s methodology to synthesize bridged bicyclic ethers using RCM...19

Scheme I-24. Burke’s synthesis of sialic acid KDN ............................................ 20
Scheme I-25. Using RCM to make medium-sized oxabicyclic systems .................... 20
Scheme I-26. Synthesis of Ingenol via RCM .................................................... 21
Scheme I-27. Reductive ring opening of bicyclic ketals ...................................... 21
Scheme II-l. Synthesis of model substrates using traditional ketalization.... . . . . . . .........23
Scheme H-2. Early study of RCM on model substrates ....................................... 23

Scheme 11-3. Woerpel’s model of stereoselective nucleophilic attack of five-membered
oxo-carbenium cations .............................................................................. 25

Scheme H-4. Stereoselectivity of nucleophilic attack on 3-substituted five-membered

cyclic acetals .......................................................................................... 26
Scheme II-S. Model for stereoselective nucleophilic attack of cyclic orthoesters... . . . . .27
Scheme 11-6. Two routes to approach the model substrate .................................... 27
Scheme 11-7. Typical procedures to make diol precursors of model substrates ............ 28
Scheme II-8. Proposed strategy to achieve opposite stereoselectivity ...................... 31
Scheme 11-9. Possible mechanism for formation of cyclic carbonates ...................... 32
Scheme II-lO. Alternative strategy to use orthocarbonates .................................... 33
Scheme 11-1 1. Use of an intramolecular delivery strategy .................................... 33

Scheme II-12. Proposed intramolecular delivery strategy using a silyl ether linkage... . .34
Scheme 11-13. One-pot approach to make the silyl ether linkage ............................ 34

Scheme II-14. Stepwise approach to make the silyl ether linkage ........................... 35

Scheme 11-15. Prins cyclizations of a-acetoxy homoallylic ethers .......................... 36
Scheme 11-16. Prins cyclizations to make oxygen-bridged carbocycles ..................... 36
Scheme 11-17. Proposed Prins cyclization of cyclic orthoesters .............................. 36
Scheme 11-18. Attempts for Prins cyclization of cyclic orthoesters ......................... 37
Scheme 11-19. Our groups’ previous study on cyclic orthoesters ............................. 38
Scheme 11-20. Correction of mechanism ......................................................... 38
Scheme H-21. Further confirmation of corrected mechanism ................................ 39
Scheme 11-22. Mechanism for transformation of byciclic orthoester to

substituted THF ...................................................................................... 39
Scheme 11-23. Extended chemistry to orthocarbonates ........................................ 39
Scheme 11-24. Final steps to make model substrates for RCM ................................ 40
Scheme 11-25. Substrate that has trouble for the oxidation to aldehyde ..................... 40
Scheme 11-26. Hydrogenation of the double bond after RCM ................................ 42

xi

Ac
SAD
Ar

aq

Bn
CHzClz
CSA
DCM
DIBAL
DMAP
DMF
DMP
DMSO
d.r.

ee
equiv

GC

L.A.

min

LIST OF ABBREVIATIONS
acetyl
Sharpless asymmetric dihydroxylation
Aryl
aqueous
benzyl
dichloromethane
camphorsulfonic acid
dichloromethane
diisobutylaluminum hydride
4-(dimethylamino)pyridine
N, N -dimethylformamide
Dess-Martin periodinane
dimethyl sulfoxide
diastereomeric ratio
enantiomeric excess
equivalent
gas chromatography
hour
Homers-Wadsworth-Emmons reaction
Lewis acid
minute

milliliter

xii

mmol

MS

NaHMDS

NMO

NOE

PDC

PG

Ph

PMP

PPTS

RT

TBS

Th

THF

THP

TMS

TsOH

millimole

mass spectrometry

sodium bis(trimethylsilyl)amide
n-methylmorpholine-n-oxide
nuclear magnetic resonance
nuclear Overhauser effect
pyridimium dichromate
protecting group

phenyl

p-methoxyphenyl

pyridinium p-toluenesulfonate
room temperature
t-butyldimethylsilyl
triethylamine

2-thiazolyl

tetrahydrofuran
tetrahydropyran

trimethylsilyl

p-toluenesulfonic acid

xiii

Chapter 1

Background: A Brief Review of
Oxygen-Containing Hetereocycle Synthesis

1.1. Introduction

Oxygen-containing heterocycles are an important class of organic compounds due
to their immense biological and industrial importance. Many pharmaceuticals and
biologically active agrochemicals contain oxygen heterocycles, as do countless additives
and modifiers used in industries as varied as cosmetics, reprography, information storage,
and plastics. One of the simplest oxygen-containing heterocycles, tetrahydrofuran
(THF), is a five-membered cyclic ether. This motif represents the core structure in a
variety of biologically important natural products such as polyether antibiotics and
annonaceous acetogenins. For example, molvizarin, a member of the annonaceous
acetogenin family, contains two THFs in the structure and has selectivity for targeting
ovarian cancer cell replication over a million times greater than its activity towards other

I“ The inostamycin family of polyether antibiotics, which contain two

cell lines.
trisubstituted THF rings, elicit a wide range of pharmacological effects including
significant anti-HIV and anticancer activities.lb Several members of the schlerophytin
diterpene family also have a THF embedded in the polycyclic structure. These
compounds show significant cytotoxic activity (Figure 1-1).1c

Organic chemistry has its origins in the study of natural products and this is
reflected in the ongoing interest in natural product synthesis. Natural products are often
isolated in only small quantities from natural sources which can make it difficult to obtain

sufficient material for complete biological evaluation. Organic chemists can provide a

solution to this problem by devising creative laboratory syntheses. Efficient construction

of the core structures in the natural products is often the key step in a proposed synthetic
scheme. Thus, stereoselective, reliable and convenient syntheses of oxygen-containing
heterocycles has always been an important goal for organic chemists. Because of the
varying substituents present in these heterocycles, the synthesis of oxygen-containing
heterocycles, especially stereoselective synthesis, has also been a challenge for organic
chemists. Over the past century, organic chemists have invested much effort in the
development of methodologies to construct oxygen-containing heterocycles. The goal of
developing these methodologies is obviously to prepare these compounds in a milder,

higher yielding, asymmetric or ‘greener’ way.

 
  

        
 

€120 ; Et - 0'9 EtOH
R1: COQH, EI 3’
R2: Et, Me, H OCCCaH’
the inostamycin natural products a schlerophytin diterpene

Figure [-1. Examples of natural products containing a THF ring

1.2. Strategies to Construct Oxygen-Containing Heterocycles
1.2.1. Intramolecular C-O Bond Formation

Construction of an oxygen-containing n'ng can be approached in two major ways.
The ring can be formed by final construction of either a C-C or a C-O bond. The ring-
forming reaction can be divided into two broad groups. Reactions in which a ‘single’

ring bond is formed in the ring-closure process are stepwise reactions termed cyclization

reactions, whereas those in which two ring bonds are formed with no elimination of small

molecules are concerted reactions called cycloaddition reactions.2

Cycloaddition
reactions, especially 1,3-dipolar cycloadditions3 and hetero-Diels-Alder reactions4
provide useful synthetic routes to five- and six-membered oxygen-containing
heterocycles. However, the work described herein falls into the former class of
cyclization reactions.

Cyclization reactions involve many intramolecular versions of common 0- or n-
bond-forming processes. By far the most common are those in which a nucleophilic
atom interacts with an electrophile. The predominant reaction types are nucleophilic

displacement at a saturated carbon atom, nucleophilic addition to unsaturated carbon, and

nucleophilic addition-elimination (Scheme I-l).

cc"—» c: Cd‘— cf“

Nu displacement Nu addition

H
Hr» (RH

Y
/

XL Ct - Ci
<2 2 2
Nu addition-elemination
X: Electrophilic carbon, 2: Nucleophilic atom

Scheme [-1. General scheme of nucleophile-electrophile cyclization
A cyclization process usually involves prior transformation to set the functionality
and stereochemistry in an acyclic intermediate. The subsequent cyclization closes up the
intermediate to form the ring in an intramolecular fashion. In the ‘traditional’ method of
making an oxygen-containing heterocycle, the carbon skeleton is usually established in
pre-cyclization steps, followed by the final C-O bond formation by intramolecular

nucleophilic attack of the hydroxyl group on a carbon electrophile. Common carbon

electrophiles that have been used include alkyl halides, epoxides and aldehydes, etc. The
well-known Williamson ether synthesis was one of the earliest methods used to form

cyclic ethers in this fashion (Scheme 1-2).5
3’ KOH Br
B‘I’VKAOH —" .-_-_. (j
V EtZO, 77% o
H l-2
Scheme I-2. Intramolecular Williamson ether synthesis
Even today, intramolecular nucleophilic substitution and addition are popular
tools to cyclize oxygen-containing rings. Organic chemists are continually searching for
new and better carbon electrophiles that can be installed in an acyclic intermediate. For
example, Borhan et. al.6 have converted a series of 1,2,n-trisubstituted triols (I-3) into a
substituted THF (I-5) by using cyclic orthoesters (L4) as in situ electrophiles (Scheme 1-

3). Rychnovsky et. al.7 have reported cascade cyclizations of cyclic sulfates (L7) to

generate polysubstituted TI-IFs (Scheme I-4).

 

OMe
OH cat. PPTS H OH 0°C, 69-99% RWH Rm
R=alkyl, aryl
I-3 l-4 I-5

Scheme I-3. Borhan’s synthesis of substituted TI-[Fs using cyclic orthoesters

WX 1)SOlm2,THF_
06H13 OH 0 2) RuCla, NalO4

 

  

 

l-6
P P P
[:0 [:0 ’so >4 CHacN, H20 HO
C6H13 O reflux, 12h, 937: C6H13 W0 W0 "’0
l-7 I-8

Scheme I-4. Rychnovsky’s cascade cyclization of cyclic sulfates

In both Borhan’s and Rychnovsky’s work, the stereochemistry of the final
products is translated from the starting vicinal diols. This chirality is initially set using
Sharpless asymmetric dihydroxylation.

The Sharpless aymmetric dihydroxylation (SAD), developed by Sharpless et. al.8
in early 1990s, converts an olefin to a vicinal diol with great stereoselectivity induced by
the chelation of the osmium catalyst with an enantiomerically pure chiral ligand. All of
the necessary ingredients in the SAD (catalyst system, oxidant, and ligand) are solids and
preformulated and commercialized as two “cake mixes”, one for each enantiomer. “AD-
mix 0t” contains K20304' H20 and K3Fe(CN)6 as the cooxidants, (DHQ)2PHAL
(dihydroquinine phthalazine) as the chiral ligand and K2CO3 as a base additive while
“AD-mix [3” uses (DHQD)2PHAL (dihydroquinidine . phthalazine) instead of
(DHQ)2PHAL. Depending on the substitution pattern of the double bond and the types of
cake mixes used, one can easily predict, for a simple olefin, which enantiomer diol will

be obtained using the mnemonic depicted in Scheme I-5.

 

 

 

 

B
> RSI I I ."RM
Rs, .‘BM t-BuOH/HZO (1:1) RL H
/=\
“L H Ao-mixa Rt H
4 RSIIIHI lRM
or HO OH

Scheme I-5. Sharpless asymmetric dihydroxylation mnemonic for predicting absolute
stereochemistry

Although there are a variety of well-established “reagent-control” methodologies,
including the Sharpless asymmetric epoxidation9 and the Jacobsen-Katsukilo and Shi

l

epoxidations,l the structural requirements of the parent olefin can limit synthetic

strategy. Compared to asymmetric epoxidations, the well-defined Sharpless asymmetric

dihydroxylation is less limited in substrate scope. Since its inception, substantial
progress has been attained in the development of ligands for the SAD that generate high
levels of enantioselectivity from unfunctionalized olefins of various substitution patterns.
8“ This flexibility has made the SAD a popular a tool for organic chemists to set the
chirality of a vicinal diol from an easily obtained olefin and transfer this chirality into the
synthesis of oxygen-containing heterocycles.
1.2.2. Intramolecular C-C bond Formation: Ring-Closing Metathesis (RCM)
Intramolecular C—C bond formation has not been used as a traditional method in
the synthesis of heterocycles before mid-19905 because of the harsh conditions and

l12 and carbene reactionsl3 used to

intolerance of many functional groups to the radica
form the C-C bonds. The low efficiency and selectivity in forming a non-polar bond also
presents difficulties to synthetic chemists. However, the development of ring-closing
metathesis has radically changed the way chemists view C-C bond formation as an
method for the syntheses of heterocycles.

Ring-closing metathesis, catalyzed by transition metal carbenes, converts acyclic
dienes to cycloolefins via the loss of ethylene or its equivalent. The olefin metathesis
reaction has been known since the 19605, but it was not until the early 1990s that this
transformation became an important tool in synthetic organic chemistry. In 1992, Grubbs
and Fu published two seminal papers describing the application of ring-closing
metathesis to the synthesis of simple five-, six-, and seven-membered monocyclic
systems containing oxygen and nitrogen atoms using a molybdenum catalyst first

prepared by Schrock.14 After this exciting report, many organic chemists became

interested in using RCM to form the functionalized rings present in natural products and

other biologically active compounds, and a number of elegant applications of RCM in
total synthesis have been reported, many of which will be discussed in this chapter.

There are two main types of catalysts in use for RCM today. The first group
consists of ruthenium-complexes such as A and B, whereas the second group is
comprised of molybdenum complexes such as C (Figure 1-2). The catalysts A and B are
most commonly used for the RCM reactions, namely first and second generation Grubbs
catalyst. The functional group tolerance of the ruthenium and the molybdenum catalysts
can vary somewhat, but the Mo-based complexes suffer the disadvantage of being very
air and moisture sensitive. The high selectivity and reactivity of A, B and C for the
formation of carbon-carbon fl-bonds minimizes protecting group manipulations while
enabling the use of RCM as an excellent alternative to other ring-forming reactions for

the efficient construction of complex cyclic targets having a variety of ring sizes.

PCy Mes-NmN-Mes MD" ”3'
Cl"Fiu=/3Ph CI": 1‘.‘ j:
C" I o .UR (F C)2M60C'MO\ Me

A B C

1st Generation 2nd Generation Schrock catalyst

Grubbs catalyst Grubbs catalyst
Figure 1-2. Grubbs and Schrock catalyst
The considerable potential of RCM as a useful reaction in synthesis of oxygen-
containing heterocycles was clearly revealed in 1992 when Grubbs and co-workers
reported that allylic ethers having a variety of substitution patterns (1-9) could be cyclized
in the presence of Schrock’s molybdenum catalyst C to give dihydrofurans (I-10) and

dihydropyrans in excellent yields (Schemes I-6).l4 It was noteworthy that even tetra-

substituted double bonds could be formed in high yields, although it was necessary to run

the reaction for longer periods.

 

9

Ph ”1
WW9 c(5 mol°/o) Ode
O M

/ R» CGHS, RT 7

R. 89-93% R'
R, R', R": H or CH3
l-9 I-10

Scheme [-6. First synthesis of oxygen-containing heterocycles using RCM

The Schrock catalyst C is highly active, but its general suitability for RCM
reactions is somewhat limited, since it is not compatible with a wide range of
functionalities such as any protic functional groups like thiols, alcohols and carboxylic
acids.15 It is also very moisture and air sensitive, so special precautions must be
employed. It was thus significant that Grubbs reported in 1993 that the ruthenium
alkylidene A was an active metathesis catalyst that could be employed to form cyclic
ethers in excellent yields.14b Although A could not be used to form tri- or tetrasubstituted
double bonds, this new catalyst tolerated a wide range of functional groups, and it could
be used in reagent grade solvents without an inert atmosphere. These seminal reports
were the spark that ignited a wide range of studies that expanded the scope of RCM
reactions in organic synthesis. There have subsequently been many reports of
applications of RCM using A and the more reactive catalyst B to the syntheses of a
diverse array of mono- and poly- heterocyclic compounds, some in enantiomerically pure
form.16

Schrock’s catalyst C was used to prepare the first 3,4-dihydropyrans by RCM.l7

Early reports suggested that enol ethers were poor substrates for Grubbs’ catalyst A,

because the carbene resulting from the initial metathesis of the vinyl ether and A seemed

to be inert to further reaction.18 However, Sturino was able to use A to catalyze the
cyclizations of a variety of vinyl ethers, including the highly efficient conversion of I-11

to 1-12 (Scheme I-7).19

 

thfif A(10mol%) Ph 0|
CSHG, heat : W0
l-11 \ 95% H2
Scheme I-7. Cyclization of vinyl ethers using Grubbs catalyst A

The great efficiency of RCM in carbon-carbon bond formation and compatibility
with various functional groups have stimulated strategic reconsiderations of
stereoselective synthetic approaches to oxgen-containing heterocycles. The focus has
changed to the synthesis of the acyclic intermediate for RCM, an intermediate with two
olefin moieties tethered by an oxygen atom, a bis-alkene (Scheme [-8) Efforts have
been made to synthesize this type of intermediate and most of them involve an
intermolecular nucleophilic attack on a carbon electrophile. The following discussion
will survey strategies applied in the synthesis of natural products containing THF rings
using RCM reactions. The key in these strategies is how to generate the bis-alkene
intermediate in an efficient and stereocontrolled manner.

One of the most popular methods to make a bis-alkene is the reaction of a
complex alcohol (2° or 3°) with a vinyl epoxide under acidic conditions (Scheme I-8).
However, the relatively poor nucleophilicity of secondary or tertiary alcohols and the
high basicity of the corresponding alkali-metal alkoxides are often problematic. The
importance of finding a proper Lewis acid to activate the epoxide cannot be overstated.
Extensive work has been performed in optimizing conditions, especially screening Lewis

21
9

acids, yet with limited success.20 In Mioskowski’s total synthesis of solamin the

central THF core was obtained by means of a RCM reaction. The RCM substrate MS
was prepared from a vinyl-substituted epoxide 1-14 by reaction with a 2° allylic alcohol
1-13, both synthesized from propargylic alcohol using Sharpless asymmetric epoxidation.
Despite efforts to modulate the basicity of the alkoxide by forming a copper alkoxide, the
yield was low. The major by-product arises from a 1,2-hydride shift that converts the
epoxide into a ketone under the Lewis acidic conditions (Scheme 1-9).

1 / RCM — n'
Fl 0“ R' R 0“

OH

 

bls-alkene

Lewis acld \ /
/R' + R‘
R OH 0

Scheme [-8. RCM approach to generate substituted THF rings

\ resort
\1 8 Cu(OTf)2 \lo <5 2,6-Iutidine
C12HZS .-. OH+ \v" =(3121425 H3012Hg40 n

_ ’012H24OBDCH2012,35°/ .
OBn CHZCIZ, 95 A.
I-13 '45

catalystB —
012H25\l0\<’C1I2H:4OBn refluxed CH 0'2 =C12H25\/£;¢\\;’C12H2408n
OBnO (N33 80% 2 can Ores

l-16 l-17

 

 

 

 

0 Lewis Acid 0 R
l E = R + R1 2
R. R2 1,2-hydride shift Rik 2 dd,

Scheme 1-9. RCM application in Mioskowski’s total synthesis of solamin

Asymmetric aldol reactions can also be used to generate bis-alkenes with good
stereocontrol. In the synthesis of (+)-gigantecin, Crimmins er. al.22 exploited a modified
asymmetric aldol protocol using chlorotitanium enolates of oxazolidinone glycolates I-18
to make the bis-alkene intermediate 1-20 (Scheme I-10). The limitation of this

methodology is that asymmetric aldol reactions may only be applied to certain substrates

10

 

as the harsh conditions may be intolerant to many functional groups and stereoselectivity
achieved with the help of a chiral auxiliary may not always be good depending on

whether it is a matched or mismatched case.

H8” TiCl4, i-PerEt

 

 

 

 

steps £OBn N-methyl-2-pyrrolidinone
33.:- ~ =
BnO \g‘n/VH TIPS : CHO
93%
0MB
HQH HOB nsteps MOMQH MOMQH HC')Bn

' g o M \ ncatalyst B ‘ z O .«

a /F °L m
TIPS Xc O \ TIPS CHZCIZ, 99% TIPS
l-19 I-20 I-21

Scheme 1-10. Construction of THF ring using asymmetric aldol and RCM reaction in
Crimmins’s total synthesis of (+)-gigantecin

The transition-metal-catalyzed intermolecular allylic etherification is a
fundamentally important cross-coupling strategy for the construction of enantiomerically

23 The problem in the application of this strategy is the poor

enriched allylic ethers.
nucleophicility of a complex alcohol and activation of the allylic carbon. In response to
these underlying problems, Evans et. al. has done inspiring work by developing a
regioselective and enantiospecific rhodium-catalyzed allylic etherification with copper(1)
alkoxides as nucleophiles (Scheme I-ll).24 The transmetalation of an alkali-metal

alkoxide served to diminish its basicity, thereby promoting the etherification of a soft
metal - allyl electrophile.25 The stereospecific etherification of the acyclic
enantiomerically enriched allylic carbonate (I-22) with secondary alkenyl alcohols (I-23)
followed by RCM affords the cis- and trans-disubstituted cyclic ethers. The method was
successfully applied in the total synthesis of gaur acid. Treatment of the allylic carbonate

[-26 with the trimethylphosphite-modified Wilkinson catalyst and the copper(1) alkoxide

11

derived from the allylic alcohol [-27, afforded the diene 1-28 in 69% yield with excellent
regioselectivity and enantiospecificity (Scheme I-12). The inherent advantage of this
approach is the ability to vary both ring size and relative configuration as a direct
function of the alkenyl alcohol nucleophile employed in the cross-coupling reaction.
However, there are also limitations. The enantiomerically pure allylic carbonate is
required for the reaction and it is prepared by an initial kinetic resolution of the allylic
alcohol followed by acylation. The cost of the Rhodium catalyst should also be taken

into consideration.

PMPo\/Q\H/\
900213U l'23 V6 fan \r/ «(I HOB”
BnON LiHMDS, additive, PMPO "I +PMPO PMPO

then catatlyst OBn
I-24a - -
THF, 0 °C- RT '24” '25

 

l-22
Catalyst RhCI(PPh3)3/P(0Me)3 Additive Cul/P(OMe)3 24/25 49:1 d.r. 24aI24b >99:1 Yield 72%

Scheme [-1]. Rhodium-catalyzed allylic etherification with the copper(l) alkenyl

 

alkoxide
LiHMDS,THF,Cul \ /
OCOztBu QB" P(OMe)3.0 ”‘94) M
/ I
Tesow W [RhC|(pph3)3] ”We: TBSO
0” THF, o°c- RT 69% 03“
catalyst B
CHZCIZ, 40°C
OBn
I-29

Scheme 1-12. Construction of cyclic ethers using RCM in Evan’s total synthesis of
gaur acid

From the strategies discussed above, we see success as well as limitations in

applying RCM to construct oxygen-containing heterocycles. So are there other ways to

12

generate the bis-alkene intermediate, milder, higher yielding and stereoselective ways?

My research was initiated to search answers to this question.

1.3. Proposed Strategy to Construct Oxygen-Containing Heterocycles

Orthoesters represent a class of masked acid derivatives that greatly modify the
reactivity pattern of the parent carboxylates and permit entry into a much broader range
of nucleophilic and electrophilic transformations.2° As electrophiles, orthoesters are
more reactive than epoxides, allylic esters, etc. They can easily transform into
oxocarbenium cations under acidic conditions without side reactions. Our group has
been interested in developing new methodologies using orthoester chemistry. We have
reported a general and practical cyclization to construct TIE: and THP structures from
1,2,n-triols based on the Lewis acid-mediated cyclization of cyclic orthoesters.° As
depicted in Scheme 1-13, ionization of the cyclic orthoester 1-30 with a Lewis acid leads
to a reactive acetoxonium species I-31, which displacement at C-3 with the pendant

hydroxyl yields the cyclized ether 1-32.

1OMe 1
(fir BFaEtZO 53° 3 >200
H
F: 3 0” O°C,69-99% R U M
R
R=alkyl, aryl
I-30 I-31 I-32

 

 

Scheme I-l3. Our group’s previous research on orthoesters
As a continuation of this work, intramolecular nucleophilic attack by carbon
nucleophiles was tried on similar substrate to form carbocycles yet without any success.
However, we found that, similar to nucleophilic attack on cyclic acetals,27 nucleophiles

such as Grignards and allyl trimethylsilane could introduce vinyl and allyl functional

13

groups intermolecularly to C-1, but the conditions were not optimized (Scheme 1-14).
Stereoselectivity of the nucleophilic attack at C-1 are expected with different
stereochemistry established at C-3 and C-4, which will be further discussed in Chapter

2.2.1.

*OMe
Lewis Acid AGO

0 \/ L
8a.. ,. «so
“v

Q =carbonucleophile

0&OM6N

8—832 Lewis AcidR

 

 

Scheme 1-14. Origin of proposed strategy
If one of the olefin moieties is already established in the ortho ester substrate [-33,
introduction of another alkene by intermolecular nucleophilic displacement would
generate the bis-alkene I-34. Success of the ring closing metathesis and control of the
correct C-O bond cleavage in reductive ring opening of 1-3528 would lead to the desired

THF core [-36 (Scheme I-15).

Fi' OMe _ R: r1:—
fi —\MgBr O
R _

l-33 R-I 34

WM

 

OH OH

 

Lewis Acid 0 n'
__ _ Hydride source /
R
I-36 I-35

Scheme 1-15. Proposed strategy to make substituted THF
The major advantage of this strategy is that the stereochemistry in the bis-alkene

could be accessed via Sharpless asymmetric dihydroxylation and translated to the final

14

product via substrate control. Also, the cleavage of the temporary oxy-bridge in the last
step would be facile and selective due to the strain release and judicious choice of
reducing agents.28c

Alternatively, if RCM proves to be unfeasible for generating the bicyclic system,
we may have to control the reductive ring opening before RCM. Regioselective
reduction of cyclic ketals can be achieved using proper Lewis acid and hydride
source.2°°‘° In the example shown in Scheme [-16, the regioselective cleavage of C-0
bond is presumed to occur via intramolecular delivery of hydride. This approach could

also offer the possibility of preparing disubstituted tetrahydropyrans with stereocontrol

(Scheme I-17).
0 03 OH
>—Ph DIBALH n
0 ———> EOH EOBn
OB OBn OBn
” 4 - 1
a)
H... gig)“

 

19
’H
"A\
BnO Fli R

 

 

i—-

Scheme I-16. Regioselective reduction of cyclic acetals

Fi‘ OMe Fl“ R' / \L<R'
k vinyl MgBr 0% Lewis Acid XIJ

OH and/or HO
Hi Hydride source R
R — Fl _

RCM

 

 

RCM

 

 

. OH
RIOJR W”
/ R
HO -

Scheme I-17. Alternative strategy for generation of THF and THP rings

15

Larger oxygen-containing heterocycles could also be made using this strategy if
longer side chains are installed in the substrate. Depending on which carbon-oxygen

bond is cleaved (a or b), different products could be obtained (Scheme I-18).

 

 

R ) Lewis Acid a

CH ,
reductive ring opening a o R' R O
: or HO'”
n/ /
n
a b

Scheme I-18. Extension of our strategy to make larger oxygen-containing heterocycles

 

These structures are not new in the nature either. Listed in Figure 1-3 are a
couple of examples of natural products with substructures containing larger oxygen-

containing heterocycles.29

I nor
.Ho Hem

 

brasilenyne pachyclavulariaenone D
Figure [-3. Examples of natural products with larger oxygen-containing heterocycles
A brief retrosynthetic analysis of brasilenyne from a vicinal diol using proposed

strategy is shown in Scheme 1-19.

16

Selective

—- - reduction of _g_
I no] 1 "OH cyclic acetal 1
=> fie O .....
. I,’/’.\\ ' lu/OPG ' c“ I: OPG
HOH \ HOH o '/

brasilenyne fl Fl CM
Steroselective

WOMQ Nu attack on cyclic
“U“ 0 0 ‘ orthoesters X‘=\___

GPO-‘ ’-OPG GPO-‘5 a_// GPO—‘5 'aJ/

 

 

 

 

Scheme 1-19. Retrosythetic analysis of brasilenyne using proposed strategy

Presumably, different epimers at C-1 (1-36, 1-39) obtained would lead to different
bicyclic ketal systems (1-37, 1-40). Theoretically, the smallest inside-in bicyclic system
that can be formed is [2,2,1] (I-37) while the smallest inside-out system would be [4,2,1]
(1-40). Examples of both systems (1-38, 1-41) can be found in the literature (Scheme 1-
20).3° However, no study has been reported on inside-out byciclic ketals. It is obvious
from sterics that the inside-out system is more strained, which would be potentially

difficult for the RCM yet an advantage for the reductive ring opening.

Examples

I
’1

Theoretically

O O o O smallest inside-in g
R — R Th
I I-38

bicyclic system [2, 2, 1]

I-36 -37

R. \“V R. “0“
OX : 0X0 I smallest inside-out
)_i—// bicyclic system [4, 2, 1]
Fl R

I-39 l-40

 

Ingenol, "-41

Scheme I-20. Inside-in and inside-out bicyclic ketal systems
Applications of RCM to the syntheses of bridged bicyclic oxygen heterocycles are

relatively rare, despite the fact that such structures are commonly found in natural

17

32 Grubbs first reported a

products31 and are useful templates in organic synthesis.
synthesis of the bicyclic ether (-)-frontalin, employing an approach that featured a RCM
reaction.33 The metathesis substrate was prepared as a mixture of C-1 epimers 1-42, in
which the absolute stereochemistry at C-3 was set by an asymmetric Mukaiyama
allylation. When this mixture was treated with first generation Grubbs catalyst, the
cyclized product 1-43 was obtained. The uncyclized ‘trans’ epimer 1-44 was equilibrated

under acidic conditions to provide a mixture of both epimers that was resubjected to the

RCM conditions (Scheme 1-21).

">2:

’ O .‘\\=
O 03 A (5 mol%) X
.. 4- +
"’ 0.01 M in CH20l2 #3 ”
RT, 10min /
i-43 l

 

if

90%
-44

I Amberlyst 15

 

Scheme 1-21. Grubbs’ synthesis of (-)-frontalin using RCM
Burke et. al. have also developed a concise strategy for the stereoselective
synthesis of bridged bicyclic ethers that has been applied to the preparation of a number
of targets.34 For example, an enantiomerically pure diol I-45 was transformed in two
steps into the ketal I-46 wherein the two vinyl groups are diastereotopic (Scheme 1-
22).34° The RCM reaction of 1-46 in the presence of first generation Grubbs catalyst
furnished the bridged bicyclic ketal 1-47 with complete diastereoselectivity. Catalytic

hydrogenation of 1-47 then gave the natural product (+)-ex0-brevicomin 11-48.

18

H \ H

”or: __. O ,\ 3 A (2 mol%) 0\ H H2, Pd/C O H
- / ——’ l l o >

H0 : O _;_ :/ E CHZCIZ, 86 /o O ‘. ___ CHCI3, RT 0 ‘. _—
H H """ ~. H 82% H

MS ME “~‘ 1-47 (+)-exo-brevicomin
diastereotopic l-48

 

 

Scheme I-22. Burke’s methodology to synthesize bridged bicyclic ethers using RCM
When the corresponding achiral (meso-) diol 1-49 was used as the starting
material, the derived ketal 1-50, in which the two vinyl groups are enantiotopic,
underwent RCM to give the bicyclic ketal I-51, reduction of which then provided endo-

brevicomin I-52 (Scheme I-23).

Hrm': .
1101:: kip \: A(2moI/o)‘ O\H H2,Pd/C @H
HO:I:: ' CHzClz. 87% 0H; ,_ MeOH, 87% 0 ‘-

 

$_—
_—-—

I-49 l-50 ...... “x i-51 endo-brevicomin
enatiotopic l-52
Scheme I-23. Burke’s methodology to synthesize bridged bicyclic ethers using RCM
Hydrogenation of the carbon-carbon double bond formed by the RCM reaction of
a diene might be regarded as an undesirable waste of functionality. It is thus noteworthy
that Burke has exemplified a more expedient use of such a double bond in developing a
synthesis of sialic acids, 8 family of biologically important compounds related to
neuraminic acid.34b Bis-hydroxylation of the double bond in I-54 under Sharpless

conditions after RCM gave the tetraol I-55 which was converted into the acetate and then

transformed into the sialic acid KDN (Scheme I-24).34c

l9

 

 

 

 

o / A 2 l°/ Me
( m0 0) : / O 0M9 AD'miX 0t :
”O CHzc'z, 930/0 k (BUOH, H20
0\ 94%
M90 OMe
|-53 l-54
OH OH OH
HOwAr HOW
—* HO_ COzH
*01/\0H HOHO
L55 0H sialic acid KDN

Scheme 1-24. Burke’s synthesis of sialic acid KDN
A RCM approach toward medium-sized oxabicyclic systems in enantiomerically
pure form is depicted in Scheme I-25. The dienes (I-56) were easily synthesized in a
stereospecific fashion from inexpensive, commercially available carbohydrates using
straightforward procedures. Upon treatment with first generation Grubbs catalyst in

refluxing benzene, they underwent metathesis to afford the bicyclic products (1-57) in

\ O )/ A l )n
n C6H6! heat H“. ”'H

TBSO "ores 43;??? TBSO "oTBs

I-56 l-57

good yields.35

Scheme I-25. Using RCM to make medium-sized oxabicyclic systems
Both Grubbs and Burke prepared the cyclic ketal intermediate in a traditional
way: ketalization of a vicinal diol with a ketone, which will lead to a mixture of C-1
epimers. In Grubbs’ synthesis of (-)-frontalin, he re-equilibrated unreacted epimer back
to the mixture of both epimers in order to make full use of the starting ketal while Burke
took advantage of the C2 symmetry of the starting diol, which made RCM with either of

the diastereotopic vinyl groups lead to the same product. The proposed strategy herein

20

would yield one major C-l epimer of the cyclic ketal, which would offer more synthetic
flexibility, if successful.

The work of Grubbs and Burke does not describe the construction of inside-out
bicyclic systems. In fact, formation of the strained inside-out bicyclic system via RCM
has also been proved possible in the successful synthesis of Ingenol (Scheme I-26).36
Second generation Grubbs catalyst was used to transform the trans-diene substrate I-58

into an inside-out [4, 4,1] bicyclic system I-59 in fairly good yield.

Toluene, refluxv
87%

 

   

l-58 l-59
Scheme I-26. Synthesis of Ingenol via RCM
A detailed discussion on the reductive ring opening of bicyclic acetals is not
presented here since my research work has not proceeded that far. However, considering
the strain present in the bicyclic system, the reduction process would be expected to be
facile and selective. The following example illustrates this type of reduction can be

performed in a regio- and stereoselective fashion by internal or external delivering of the

 

hydride (Scheme 1.27).37
condition a,“ o .,,CH20H o (\CHZOH
/ + U
o 0‘
condition Yield cis trans
DIBALH 82 3 97
Et3$iH, TiCl4 82 99 1

Scheme I-27. Reductive ring opening of bicyclic ketals

21

Chapter 2
Results and Discussion

2.1. Study of RCM on Model Substrates

My study started by investigating the feasibility to construct larger bicyclic ketals
and the possibility to make inside-out bicyclic systems using RCM reactions. By
repeating the work of Grubbs’ and Burke’s, the reaction of a vicinal diol with a ketone
was used to generate the ketals as a mixture of C-1 epimers and then each of the epimers
was subjected to RCM conditions. The basic structure of model substrates is shown in
Figure II-l. The side chain of the substrate was installed with enough carbons (for

example, m=1, n=1) so that the inside-out system could possibly form.

R' /
m m: 0, 1
0 0 n= 0, 1, 2, 3
/ R, R': alkyl, phenyl
R n

Figure II-l. Model substrates

Commercially available cis-4-decen-l-ol (II-l) was chosen as the starting
substrate, which was protected as acetate (II-2) or silyl ether. The Upjohn procedure38
gave the cis diol II-3 in good yield. In a first attempt, vinyl ketal was made by refluxing
diol with methylvinylketone and catalytic TsOH in benzene under Dean-Stark conditions.
However, the product was mostly transesterified diol-ester instead of the ketal. The
problem was solved utilizing TMSOTf as catalyst for ketalization.39 Two diastereomers
II-Sa and II-Sb (d.r. 1:1) were obtained and separated. The following deprotection,
oxidation, and Wittig olefination led to the model substrate II-7a and II-7b (Scheme II-

1).

22

0504“). 20/0)
NMO HO OH

 

 

_ AcCI, TEA _ A
RWOH *‘ 9W0 cAcetone-water RHJ—OAC
DMAP, CHZCIZ 870/
H=C5HH 90% °
"-1 "-2 "-3
TMSCI, Et3N PTSA, MVK
_>=o DCM, o °C-FlT PhH, 4120

>5 TMSO OTMS
O TMSOTf (1 % mol)
OAc HO OAc
OAC 1 W
h DCM. -78 °C H RWOH

 

 

 

dr=1:1 (separated) 21% "’4
ll-5a 8. 5b
K2003 88% and 82%
MeOH, H20 for two diastereomers respectively
\ \
OH -78 00, then TEE ' a —
R 27°/ and 207 for trirvBoULI FR—U—
"'68 8‘ 6" diastereomers in two "'73 3' 7"
steps

Scheme “-1. Synthesis of model substrates using traditional ketalization

Similar to Grubbs’ result,33 RCM worked well for one of the C-1 epimers II-7b to
form the [4,2,1] bicyclic system using first generation Grubbs catalyst A. The cyclized
product II-8 was obtained in about 30% yield yet could not be purified. However,
evidence from NMR and GC-MS suggested the existence of II-8. There was no reaction
for the corresponding trans isomer II-7a even when second generation Grubbs catalyst B
was used and refluxed overnight. Concentration of the substrate can be crucial for
success of the reaction. 0.01M solution of “-78 in dichloromethane yield only

polymerized products upon cross metathesis reactions (Scheme II-2).

\ .~Ҥ
0X1: A g of "’o > + m

"-71: & 7b "-8 "-78

 

Scheme II-2. Early study of RCM on model substrates

23

The results confirmed the feasibility of the proposed strategy to construct larger
bicyclic acetals though it failed to yield inside-out systems. The low yields and poor
stereoselctivity using traditional methods to make cyclic ketals could be overcome by
applying stereoselective nucleophilic attack on cyclic orthoesters. Research on
generation of inside-out bicyclic systems would be continued by screening various

conditions.

2.2. Stereoselective Nucleophilic Attack at C-1
2.2.1. Optimization of Conditions

As discussed in Chapter 1, the stereoselective nucleophilic attack at the
orthoester carbon C-l is unique compared to ketalization to form a mixture of
diastereomeric acetals. Therefore, it is essential to study and discuss the stereoselective
nucleophilic attack in advance.

Woerpel et. al.40 have extensively studied on the stereoselective addition of
carbon nucleophiles to five-membered oxo-carbenium ions, which is structurally similar
to the intermediate derived from our orthoester substrates. The diastereoselectivity was
suggested to arise from the nucleophile attacking five-membered ring oxocarbenium ion
in the envelope conformation, attacking preferentially from the inside face of the
envelope. Attack from the outside face is disfavored, because of eclipsing interactions

between the substituents at C-1 and C-2 in the product (Scheme II-3).

24

 

 

 

 

- Nu - H
41 "inside" attack 3 Nu 4
‘20 ’ WC ZD—O
I \
_ 2 1H j favored 1 H
staggered product
"outside" attack
EEC? disfavored figs:
211. H 2 3 NuH
Nu eclipsed product

Scheme II-3. Woerpel’s model of stereoselective nucleophilic attack of five-membered
oxo-carbenium cations

In addition, his study indicated that the impetus to minimize eclipsing interactions
is not the only factor that governs selectivity, but that the overall three-dimensional
structure of the ring must be favorable as well. In other words, substituents on the ring
also play an important role on the stereoselectivity.

The “inside-attack” model provides an explanation for the stereoselectivity of
nucleophilic substitution of five-membered cyclic acetals (Scheme 1140.4031 For example,
the cation derived from 3-methyl-substituted acetal could exist as two conformers II-4a
and II-4b. Attack from “inside” the cation II-4a would lead to the 1,3-trans product 11-
4c as first-formed conformer. Alternatively, “inside attack” on the diaxial conformer II-
4b would be disfavored because of developing, destabilizing 1,3-diaxial interactions
between the nucleophile and the alkyl group in the product II-4d. Therefore, the 1,3-

trans product II-4c would be expected to predominate.

25

 

TM
BnO 0 OAc =/_ S BnOYJ..o\/
«SJ SnBr4, 95% V e

 

 

 

Me dr: 93:7 M
TM
BnO/WOAC =/_ S WOW
3. SnBr4, 95% ' Mes
M8 dr: 95:5
OBn
Bno * TMS I
M 41 =/_ g 3 _é
e’Ecy 7 Me
/ 1 O
1 H
1,3-trans
"-48 ll-4c
BnO TMS
4 0+ * '—_/_ 3 4 OBn
\1 * 1 . O
3 T \ 9
Me .
1,3-CIS
ll-4b ll-4d

Scheme “-4. Stereoselectivity of nucleophilic attack of 3-substituted five-membered
cyclic acetals

Analogy could be made from Woerpel’s model to our substrate. However,
because of the involvement of two oxygen atoms in the formation of the oxocarbenium
cation, the hybridization of both oxygens and C-1 become spz' Therefore, the five-
membered-ring oxocarbenium cation has become planar rather than envelope-like and the
stereoselectivity of nucelophilic attack would totally depend on the relative
stereochemistry of substituents on C-3 and C-4 (R, and R2, respectively). If R; and R2 are
syn to each other, anti-attack would be expected in order to avoid steric hindrance. If R;
and R2 are anti to each other, the situation would become more complicated and may
depend heavily on the identity of the substituents at C-3 and C-4. That is why cis-1,2-
diols are chosen as initial target substrates, which can be easily obtained by using the

Upjohn method 38 on a Z-alkene (Scheme II-S).

26

 

OMe R1 .~NU
0x0 Lewis Acid kaz 0'95?— 35}
H l
R, R2 Nu F11 R
Scheme II-5. Model for stereoselective nucleophilic attack of cyclic orthoesters
There are two possible routes to make the desired substrates using the orthoester
chemistry, based on which double bond is formed first (Scheme II-6). Both approaches

have been studied and typical transformations to make the diol precursors are listed in

Scheme II-7.

I / I
13W RXOMG H H

O :> = OPG

a Mom OPG n n
/ H n R n n
m \ ”3.50M" HO OH Y

R / n a ,,

n

n=0, 1, 2, 3
Scheme II-6. Two routes to approach the model substrate

l

R, R'=alkyl, phenyl

27

H AcCl, TEA _ OAc 0304, NMO HO OH
/—\_/— ————» RWOAC

 

_ o t
H/_\—/— DMAP, CHZCIZ R acetone-water
R=05H1 1 900/0 940/0
".1 “-2 "-3
AcCl

_ BnBr, NaH __ TEA, DMAP _/=\_

HO OH THF/ DMSO BnO OHW BnO OAc
“-19 96% “-20 94% "'21

91% Os04, NMO
acetone-water

MeggMe
jsOH (10 mol%) HO OH

BnO OH MGOH/ H20. BnO OAc DMF. 88% BnO OAc
"-24 93% "-23 "-22
1. (00002. DMSO

2. (Ph)3PCHaBr, nBuLi
60% for two steps

Y THF/HCI HO OH

H
83%
BnO _ BnO
"-26

"-25
Scheme II-7. Typical procedures to make diol precursors of model substrates

 

Once the desired precursors were prepared, different nucleophiles, Lewis acids
and reaction conditions were tried for the nucleophilic attack of the orthoesters. Some of

the results are listed in Table II-l. As expected, nucleophiles attack opposite R1 and R2,

All the products obtained were single diastereomers.

28

Table II-l. Optimization of conditions for stereoselective nucleophilic attack of
cyclic orthoesters

 

 

 

R' OMe xNu
HO OH ope R'CH(OMe)3 o 0 Nu o
= OPG ‘—-——-’ OPG
Rm PPTS(1%moI) Rm LeW'S AC'd R n
94-99%
Substrate Nu“l L.A. Condition Product Yieldb
XOMG : N/A 5:20, RT mixture N/A
0 O MgBr
OAc O
05H, R—L =\ N/A THF, RT ”<0 57%
MgBr
CSH11
=\ N/A toluene reflux mixture N/A
MgBr .
_ AcO OH
—\—TMS BFa'Et20 THF, RT R)—K_,0Ac
(10 mol%) + quantitative
HO OAc
FLOAC
R
\J
—\_TM S SnBrfi CHQCIQ, OX0 300/00
(1equ) -78 oC- RT OAc
C5H11

 

a. 3 equiv vinylmagnesiumbromide and 2 equiv allyltrimethylsilane were used. b. All are
isolated yields for single diastereomers unless specified. c. Yield of two steps (intermediate orthoester not
isolated).

It was found that allylation works with stoichiometric SnBr4 Lewis acid in
dichloromethane. Catalytic conditions for allylation were optimized using 4 equivalents
of allyltrimethylsilane and 25 mol% of San. Different substrates derived from different
diols and orthoesters were examined and most of them led to good yields under these
condition (Table II-2). The relative stereochemistry for the product was confirmed by

nOe experiments.

29

Table II-2. Allylation of different substrates under optimized conditions

 

 

Substrate L.A. Condition Product Yield
XOMG ‘\j
0 :LTMS 258:??? CH2Cl2, '78 0C ' RT X 910/
B—L/OAC ( ° °) won °
05H” C5H11
"-27 "-33
H OMe H j
0X0 =\__TMS zsnBrit/ CH2CI2, -78 °C - RT 0x0 91%
OAc ( 5mo °) OAc
CSH11 C5H11
II-28 "'34
PhXOMe
— SnBr - d
o ‘3, CH Cl , -78 °C - RT meture N/A
ROM xms (25 mom.) 2 2
C5H11
ll-29
WAC =\—TMS (zssrr‘rtiadii’x) CHZC'Z’JB QC- RT 0 ‘0 OAc 80%
05H” 05“"
"-30 "-35
XOMe
o o ores =\—ms (nggg/o) CH2C|2.-78°C-RT mixturee N/A
C5H11
"-31
H OMe H ,J
71%

X — SHBQ o X
R —\—TMS (25 mol%) CH2C'2' ‘78 C ' RT 0 0
BnO OAc

ll-32

BHOAOAC

"-36

 

d. The orthobenzoate is unstable and the major product isolated is methyl benzoate.
e. TBS group fell off.

Vinylization was also achieved when TBS was chosen as protecting group for the

30

A single diastereomer was obtained in moderate yield (Table II-3).

hydroxyl group and excessive vinylmagnesiumbromide was used in toluene and refluxed.

Table II-3. Conditions for vinylization

 

Substrate Nu L.A. Condition Product Yield

 

OMe THF RT
=\ — , mixture N/A
0 o ores MgBr

CSH11 X
=\MgBr _ toluene, reflux O O OTBS 45%
C5H11

II-37

 

 

 

2.2.2. Attempts to Make the Other C-l Epimer

Since the product ketal derived from anti-attack on the intermediate orthoester can
only lead to the strained inside-out system after RCM (Scheme I-20), methods to achieve
the opposite diastereoselectivity are highly desired. Based on the orthoester chemistry
and the oxocarbenium cation intermediate discussed above, orthocarbonates was tried to
substitute for orthoesters to obtain the cis diastereomer.

Assuming that the methoxy group in a cyclic orthocarbonate is similar, in terms of
sterics, to the methyl group at C-1 in a cyclic orthoacetate, similar nucleophilic attack
would be expected at C-1 of orthocarbonates. After introduction of first nucleophile (Nul)
to C-1, the orthocarbonate would become an orthoester, which is then subjected to second
nucleophilic attack (Nuz) under similar conditions. Twice anti-attack would eventually
direct Nul to the position relative syn to R1 and R2 (Scheme II-8). Thus, the cis

diastereomer would be obtained when N u1 contains alkene functionality.

 

 

MeO OMe Nu} OMe Nu‘ Nu2
X Nu1 " Nu2 “
O O 0K0 (3X0
R1 R2 R1 R2 R1 R2

Scheme II-8. Proposed strategy to achieve opposite stereoselectivity

31

Different orthocarbonates, nucleophiles, Lewis acids and conditions were
examined but none met with success. The major problem occurs when the first
nucleophile is being introduced under acidic conditions. The orthocarbonate (II-38)
readily transforms into the cyclic carbonate (II-39), which prevents the second
nucleophilic attack (Table II-4).

Table II-4. Attempts to make cis diastereomers using orthocarbonates

 

 

Substrate Nu L.A. Condition Product Yield
MeO OMe o
X =\_ $an CHZCIZ, A ,,
K TMS (25 mol%) ~78 °C - RT 0 60 /o
BnO — Bnoj \=
"-38 C C o
— TMSOTf H2 '2. )k ,,
_\—TMS (10 mol%) -78 00 - RT X 52 4’
BnO
C C "-39
_ BFaEtzo H2 '2, .
_\—TMS (10 mol%) -78 °C - RT "“Xture N/A

:MgBr N/A toluene, reflux mixture N/A

 

A possible reason for this transformation is that when the oxo-carbenium cation
intermediate is formed, the nucleophile is more likely to attack the remaining methoxy

carbon rather than C-l (Scheme II-9).

 

(\
MerOMe L . “(1 EM \ fl
eWIs aCI ' -
(3 O O’é‘O Nu ___. 0
R1 R2 R1 R2 R1 R2

Scheme II-9. Possible mechanism for formation of cyclic carbonates
A potential solution to this problem is to make the intermediate oxocarbonium

less susceptible to nucleophilic attack, for example, to replace methoxy with a phenoxy

32

group. However, several attempts to make tetraphenyl orthocarbonate failed following

Samuelson’s procedure (Scheme II-10).41

HO) (OH PhO OPh . . Q’P“ R Nu OPh
R R X LeWIs aCld KANu‘ X
1 2 4:: 0 O ............. - 0’50 ........ - (3 O
+ R R R R
C(oph), 1' 2 8i '82 1 2
OH NaH, CuCl C(OPh)
+CS """""" *
O 2 NaOH (10%) 4
CH3CN

Scheme II-10. Alternative strategy to use orthocarbonates
An intramolecular delivery strategy was also tried to achieve the opposite
diastereoselectivity. The strategy was first introduced by Stork 42 and Hindsgaul,43 both
of whom exploited an axial alcohol in a sugar derivative to temporarily attach the
acceptor to a suitable donor. Activation of the donor then results in intramolecular
transfer of the acceptor to the anomeric center (Scheme II-ll).

op 1) activation 0P
w intramolecular allylation 05'
PO 0 / .. : PO
p0 II) cleave tether p0 /
X

H

 

X=leaving group
P=protecting group

Scheme II-ll. Use of an intramolecular delivery strategy
I was interested in investigating the possibility of using a similar strategy to
achieve syn nucleophilic attack by delivering an ally] nucleophile that has been tethered
through a silyl ether linkage to the substrate (Scheme II-12). The intramolecular delivery,

if applicable, would lead to a syn attack to avoid steric hindrance.

33

OMe I ,,
X0 ; g H‘) workup fl

LewisAcid '2‘
R .1 ' —~ 22
R 09: n 8 OH

'Me

 

Scheme II-12. Proposed intramolecular delivery strategy using a silyl ether linkage
Initial attempts focused on generating the allyldimethylsilyl ether in situ after
formation of the orthoester from the trio]. However, only the bicyclic orthoester II-53
was isolated after workup (Scheme II-l3). The mechanism of this transformation will be

discussed in Chapter 2.4.

CH C OMe
HO OH 3 ( )3

l.
Won PPTS(1°/om0|) =/‘SI"C'
05H" n Cchlz EtaN,THF CSH11
n=1, 2 quantitative "-53

1,". O
/<O
)n

 

 

Scheme “-13. One-pot approach to make the silyl ether linkage
Stepwise attempt was also investigated. The primary alcohol was first protected
as an acetate and de-protected after the cyclic orthoester II-40 was made. The
intermediate was then treated with allylchlorodimethylsilane. The silyl ether II-41 was
finally obtained, although in poor yield, and subjected to SnBr4 in dichloromethane.
However, no desired products were obtained and the products were identified as a

mixture of hydrolyzed derivatives of orthoesters II-42 (Scheme II-14).

34

CH3C(OM6)3 XOMQ K CO XOMG
2 3

W PPTS (1 mol%) R R
Bno OAc CH2C'2, 9770 BnO OAC MGOH Bno OH

 

 

 

Il-40
Et3N I
DMAP, CH2C|2 =/-El‘:i-C|
22% for
two steps
‘><OMe
Aw + We SnBr4(1 equiv) O O
BnO OH BnO OH CH2C'2' BnO 043/:
"-42 -78 OC-RT ".41

Scheme II-l4. Stepwise approach to make the silyl ether linkage

2.3. Attempts of Intramolecular Prins-Type Cyclization on Cyclic Orthoesters

The electrophilic cyclization of homoallylic ethers with aldehydes under strongly
acidic conditions was initially explored by Hanschke 4" and later by Stapp,45 and came to
be known as the Prins cyclization. A typical Prins cyclization is a concerted process
which usually involves the attack of an olefinic electron pair onto an electrophilic carbon
followed by trapping of the carbon cation by another nucleophile. The reaction leads to
formation of tetrahydropyrans (THP) with stereocontrol achieved presumably through a
six-member transition state.46 For example, Rychnovsky et. al.47 reported a
stereoselective synthesis of 2,4,6-trisubstituted THP rings using Prins cyclization of or-
acetoxy homoallylic ethers II-l5a. The electrophilic intermediate is an oxocarbenium
cation II-le formed under acidic conditions and different stereoselectivity can be

achieved when different Lewis acids are used (Scheme II-lS).

35

 

Ph R 5
Lewis Acid
VY: : 65m ——> Na + /\/(‘j\
IUtldlne, CH20|2 Ph 0 Ph 0

OAc o to 23 °C

 

 

 

"-1 Se lI-15b
Lewis Acid / Yield "-1 5c ll-15d
San 9% 79%
TMSBr 98% O

 

Scheme II-15. Prins cyclizations of a-acetoxy homoallylic ethers
The Prins cyclization has also been used to construct oxygen-bridged medium-

sized carbocycles (Scheme II-16).48

 

OMe
SnCl4 ” C'
/ CHZCIQ, '78 0C /
TMS 82%, d..r.=82 TMS
"-166 II-16b

Scheme II-16. Prins cyclizations to make oxygen—bridged carbocycles
Since an orthoester is easily transformed into an oxocarbenium cation under
acidic conditions and a double bond can be installed in our substrate, theoretically Prins
reaction could be applied to our system to construct a bicyclic acetal system. Depending
on the size of the ring to be formed and the stability of the carbocation intermediate, both

endo- and exo-attacks are expected (Scheme II-l7).

—

 

 

 

 

M
>10 8 Lewis Acid R1 60
R or CA
R1 n/ 2 2 / R2
n=1, 2 _ n: -
——~ mega; (31
n- 1 1 R2

endoX exo

Scheme “-17. Proposed Prins cyclization of cyclic orthoesters

36

Many substrates and conditions were investigated for the Prins cyclization.

Unfortunately none of them worked. The major products after workup were the

hydrolyzed derivatives of orthoesters (Scheme II-18).

Substrates with electron rich

double bonds (II-49, II-50, II-Sl), which can form more stable carbon cation

intermediates, were also tried yet without success (Figure II-2).

OMe
3’58
CsH11 /
"-43

TsOH or CSA

 

SnBr4, lutidine

 

V

CHchz, -78 °C - RT

 

TMSBr

A

CHZClz, 0 °C - RT

11

”$8;
05H /

+

H0 OAc
/
C5H11

Scheme II-18. Attempts for Prins cyclization of cyclic orthoesters

OMe
>(O

1
"-49

05H13V

XoMe
m
CSH1 1 —

ll-50

xOMe

W's"
CSH11

"-51

Figure II-2. Other substrates tried for Prins cyclization

2.4. Correction of Mechanism of Lewis Acid-Mediated Cyclization of Cyclic
Orthoesters Derived from 1,2,n-triols

Our group’s previous research has revealed a one-pot method to access cyclic
ethers directly from 1,2,n-t1iols via the intermediacy of a cyclic orthoester.6 We have
proposed a mechanism that ionization of the intermediate orthoester with a Lewis acid
leads to a reactive acetoxonium species, which upon intramolecular displacement with
the pendant hydroxyl yields the cyclized ether (Scheme II-l9). However, as it is a one-
pot method, the intermediate orthoester with a free hydroxyl group II-19a was not

isolated.

37

 

CH30(OM9)3 XOMB
HO OH OH PPTS (1 mol%) 0 o BFa'Et20(10°/;) Q; Z or A°3_<Oj
CSHW CH2012 C H W0?! CHZCIZ 05H" OAC CSHH
”=1 ’ 2 5 11 n n—1 ":2
"-198 —

Scheme II-19. Our groups’ previous study on cyclic orthoesters
In my study of orthoesters, I have isolated, more than once, bicyclic orthoesters
II-53. Further studies have revealed that this type of compounds are the real
intermediates for the transformations discussed in Scheme II-19. When the assumed
intermediate was obtained under reported acidic condition and then treated with
allylchlorodimethylsilane, no silyl ether was formed; only the bicylic orthesters II-53 was

isolated quantatively (Scheme II-13).

 

CH30(OMe)3 l_ 0

HO OH OH PPTS (1 mol%) —_—/‘S.' 0' /<o
CSH“ CH20'2 Et3N,THF 05H11

quantitative "-53

Scheme II-13. Unexpected discovery of bicyclic ortho esters
The only reasonable explanation for this would be that the II-53 was already
formed after treating the triol with trimethyl orthoacetate under slightly acidic conditions
(PPTS). A more detailed mechanism involves the free hydroxyl attacking C-1 of the

oxocarbenium cation II-20a formed under acidic conditions (Scheme II-20).

 

 

CH3C(OM6)3 d I” O
Fig—€110H PPTS (1 mol%) 0%0 @
H CH20|2 7 RHJOH R

"-208 "-53
Scheme II-20. Correction of mechanism
The proposed mechanism was further confirmed when bicyclic orthoester II-53,

obtained from orthoester II-52 treated with vinylmagnesiumbromide, transformed rapidly

38

into substituted tetrahydrofuran II-56 with addition of BF3' Et2O, as reported (Scheme 11-

21). ‘8
OMG I,“
x =\MgBr ‘ @ BF3‘E120 Q: 2 O
CSHRJOAC THF’ 57% C5H11 CHZCIZI 71% C5H11 OJK
"-52 "_53 “-56

 

Scheme II-21. Further confirmation of corrected mechanism
The transformation from II-53 to II-56 can be explained by the equilibrium
between the bicyclic orthoester II-22a, which is coordinated to Lewis acid, and a five-
membered dioxonium cation II-22b under Lewis acidic conditions. The formation of the
stable THF ring II-56 is the thermodynamic trap, which drives the transformation

forward (Scheme II-22).49

R

R'
Rafi/LA: fig? __> (31 0
U VOH A .
lI-22a "-221: "-56
Scheme II-22. Mechanism for transformation of byciclic orthoester to substituted THF
The study was also extended to cyclic orthocarbonates and similar results were

obtained (Scheme II-23).

iii

 

 

C(OMe)4 M90 ' 670/0
HO OH OH PPTS (1 %mol) Oy’b ) BF3'Et20 C5H11n=10w53M°
CSH11)—S\'in_/ CH2C|2 C5H11 n CHzclz

n=1,2

Me
((33:30 94%
C5H1 (LG

n=2, "-58

Scheme II-23. Extended chemistry to orthocarbonates

39

2.5. Study of Ring-Closing Metathesis of Model Substrates

The model substrates were made following the routes discussed in Chapter 2.2
(Scheme II-6). Some of the transformations are listed below (Scheme II-24). It took
some time to screen the conditions for oxidation of the primary alcohol to the aldehyde.
Pyridimium dichromate (PDC) was found to be the best. However, it still does not work
very well for one of the substrates derived from cis-3-nonen-l-ol due to potential aldol
condensation induced by enolate formation (Scheme II-25). Both the electron rich and
poor olefins have been made because both of them have been reported to be used in

olefin metathesis.50

J J .J
X K2003 X poc X

OAc 9 2 CH Cl
05H” 94-99% 05H" n 2 2 Can n/

 

 

 

 

n=1, 2
X‘J
n=1, 35% (Ph)3PCHaBr
n=2, 71% O =
in two steps CSHW NaHMDS
n
/
n=1, 69% XJ PhaPCHCOOEt
n=2, 71% O O O t

in two steps W THF, reflux
C5H11 n OEt

Scheme II-24. Final steps to make model substrates for RCM

>4 slightly basic >4
0 0 conditions 0 Q'Hb aldol condensation

/0 am ------------------ 9
05H" 05H“

 

Scheme Il-25. Substrate that has trouble for the oxidation to aldehyde
Various conditions were utilized in the RCM to construct the inside-out bicyclic
acetal (Table II-5). Unfortunately, either inseparable mixtures were obtained or starting
material was recovered except when 20% of second generation Grubbs catalyst were used

in toluene and refluxed. Evidence from both l3C NMR and GC-MS suggested the

40

existence of cyclized product II-65. Compared to starting diene II-61, new peaks in 13C

NMR between 130—125 ppm suggested the formation of new double bond. In GC-MS,

the parent peak m/z 210 matched the molecular weight of II-65. However, probably due

to strain of the system, it was too unstable to be isolated even after reduction of the

double bond by catalytic hydrogenation (Scheme II-26).

Table II-S. RCM of model substrates

 

 

\_//
OX0 conditions m
/ R
CSHW C5H11 n
R=H, COOEt; n=1, 2
Substrate Conditions Products ldenificatlon
yJ 1St generation Grubbs Inseparable mixture N /A
OX0 catalyst (80 mol%) \
W 2nd generation Grubbs OX0 \ ‘H, 13c NMR(not pure)
C5H11 catalyst (20 mol%) GC-MS
".51 Toluene (0.004M), Reflux 05H“
"-65, Unstable
/ .
XJ tst generation GrUbPS Recovered S.M. 1H, 13C NMR
0 O O catalyst(80 mol /o)
2nd eneration Grubbs .
(35H1 1 / OEt gcatalyst(20 m ol% ) Inseparable mixture N IA
"-63 Toluene (0.004M), Reflux
_/
X 1st generation Grubbs
W catalyst (80 mol%) Inseparable mixture N / A
05H“ Toluene (0.004M), Reflux
Il-62
/
X'J Et 1st generation Grubbs
O O O catalyst(80 mol%) Recovered S.M. 1H. ‘30 NMR
— Toluene (0.004M), Reflux
05”“
"-64

 

41

X2» "jaguar- 3X23}
EtOAc/CHCIa

Can CsH11

"-65, Mixtures "-66

Scheme II-26. Hydrogenation of the double bond after RCM

2.6. Conclusions

In conclusion, my results to date have been promising in seteroselective
nucleophilic attack on cyclic orthoesters. However, the C—1 epimer obtained from anti
attack would only lead to the strained inside-out bicyclic ketals after RCM. It was proved
that the inside-out system was not only difficult to be constructed by RCM but too
unstable to be isolated once formed. Possible solutions to these problems are: using more
active Schrock catalyst for RCM; trapping the inside-out intermediate by in situ
hydrolysis or reduction of the ketal. The opposite diastereoselectivity was not obtained
by using either orthocarbonate chemistry or intramolecular delivery strategy. However,
the strategy of twice nucleophilic attack on cyclic orthocarbonates could still be applied if
better ways could be found to make the tetraphenyl orthocarbonate derivatives. The Prins
cyclization reaction was found not applicable on the five-membered oxocarbenium
intermediate.

The unexpected discovery of the bicyclic orthoester intermediates helped
elucidate the mechanism of previously reported reactions.

Further improvement needs to be done to make the methodology applicable.

42

Chapter3
Experimental

3.1. General Information

All commercially available starting materials were used without further
purification. Commercially available starting materials were obtained from Aldrich,
Acros Strem Chemicals and Alfa Aesar. Some compounds were prepared as previously
reported. All of the spectral data for known compounds either matched those reported by
Aldrich or by comparison to literature reports. lH, l3C NMR and nOe spectra were
recorded on either a 300 MHz NMR spectrometer (VARIAN INOVA) or on a 500 MHz
NMR spectrometer (VARIAN VXR). Column chromatography was performed using
Silicycle (40-60 pm) silica gel. Analytical TLC was done using pre-coated silica gel 60
F254 plates. GC-MS analyses were carried out with HP589O GC and HP4286 MS.
3.1.1. Orgins of Starting Materials

Materials obtained from Aldrich: allyltrimethylsilane,
benzyltriphenylphosphonium chloride, BF3'Et20, cis—4-decen-1-ol, methylvinylketone,
methyltriphenylphosphonium bromide, cis-3-nonen-l-ol, NaHMDS (1.0 M in THF),
PDC, isopropyltriphenylphosphonium iodide, tetramethylorthocarbonate, tin(IV)
tetrabromide, trimethylorthoacetate, trimethylorthobenzoate, trimehtylorthoformate,
vinylmagnesiumbromide (1.0 M in THF).

Materials obtained from Acros: allylchlorodimethylsilane.

Materials obtained from Strem Chemicals: first and second generation Grubbs
catalyst.

Materials obtained from Alfa Aesar: cis-2-buten-1,4—diol.

43

The triphenylphosphine ylide for HWE reaction was made previously by other
group members.
3.1.2. List of Compounds that were Compared to Literature Reports

11.21,“ 11.53,49 II-56, 57, 58.6

3.2. Data for Chapter 2.1

__ OH AcCl, TEA _ 0 Ac
CSHW DMAP, CHZCI; CSHW

"-1 "-2

 

Preparation of compound II-l: cis-4-Decen-1-ol II-l (3.125 g, 20 mmol) was
dissolved in dichloromethane (100 mL) and TEA (2.5 mL, 33 mmol), and DMAP (0.12 g,
5 mol%) were added. AcCl (0.22 mL, 30 mmol) was added afterwards. The reaction
was stirred at ambient temperature for 30 min. The resulting solution was washed with
water (2 x), brine (2 x) and then dried with Na2804, Purification by Flash
Chromatography (5% AcOEt/hexane) afforded 3.567 g acetal ester II-2 (90%). 1H NMR
(CDCl3, 300 MHz) 5 5.35 (2H, m), 4.03 (2H, t, J = 6.6 Hz), 2.06 (4H, m), 2.02 (3H, s),

1.65 (2H, p, J = 7.5 Hz), 1.27 (6H, m), 0.87 (3H, t, J = 7.2 Hz).

0304 (0.2%)
NMO HO OH OAc

— OAc :
(:us acetone-water C5H“" 3 2

 

Preparation of compound II-3: To a mixture of N-methylmorphline-N-oxide
(NMO, 2.29 g, 18 mmol), acetone/HZO (18 mL/2 mL) and 0804 (0.1 mL, 0.02M, 0.2
mol%) was added II-2 (2.400 g, 12.1 mmol). The reaction was stirred overnight at
ambient temperature. Na28204 (0.115 g) and water (10 mL) were added to the resulting

solution, which was saturated with NaCl subsequently and extracted with EtOAc (3 x).

The combined organic layers were dried with Na2SO4 and evaporated. Flash
chromatography (75% EtOAc / hexane, 1% MeOH) afforded 2.450 g diol II-3 (87%). 1H
NMR (CDCl3, 300 MHz) 5 4.07 (2H, t, J = 6.3 Hz), 3.58 (2H, br), 2.02 (3H, s), 1.85 (2H,

m), 1.66 (2H, m), 1.44 (4H, m), 1.27 (4H, br), 0.86 (3H, t, J = 6.3 Hz).

 

HO OH TMSO OTMS
HHOAC TMSC', EtaNfiA WOAC
CSH" ( 2 CHQClg, 0 OC'RT CSHH 2
"'3 "-4

Preparation of compound II-4: To a solution of diol II-3 (0.800 g, 3.44 mmol)
in dichloromethane (25 mL) was added TEA (2.5 mL) and cooled to 0 °C. TMSC] (2.2
mL, 17.2 mmol) was added subsequently and the solution was warmed up to ambient
temperature after addition. The reaction was complete in 2 h. The solution was washed
with saturate NaHCO3 very quickly, dried with Na2S04, concentrated and subjected to
the next step without purification.
=>=° w

TMSO OTMS o O
0 Ac TMSOTf (1 mol/o)>

°an CHZCIZ, -78 °C-RT <3an
"-4 lI-5a & b

OAc

 

Preparation of compound II-Sa & 5b: A stirred solution of II-4 (1.505 g, 5.3
mmol) and TMSOTf (0.05 mL, 1 mol%) in dichloromethane (20 mL) was cooled to —78
oC and added methylvinylketone (2.2 mL, 26 mmol) subsequently. The reaction was
stirred at —78 °C under N2 overnight. The reaction was complete in 20 h (monitored by
TLC) and quenched by addition of dry pyridine (0.05 mL) at the same temperature,
poured into a saturate NaHCO3 solution (10 mL) and extracted with ether (3 x). The
combined extracts were dried over a 1:1 mixture of Na2C03 and Na2804, and the solvent

was removed under reduced pressure. Flash chromatography (10% EtOAc/hexane)

45

afforded two mixtures of diastereomers (II-5a & 5b), 0.134 g and 0.140 g respectively
(21% in total) and each with a d. r. 5/1. Parallel reactions were run for both of the
diastereomers in the following transformations. 1H NMR II-Sa (CDCl3, 300 MHz)
8 5.76 (1H, q, J = 10.5 Hz), 5.30 (1H, dd, J = 17.1, 1.8 Hz), 5.06 (1H, dd, J = 10.5, 1.5
Hz), 4.06 (2H, m), 3.94 (2H, m), 2.02 (3H, s), 1.82 (2H, m), 1.66 (2H, m), 1.46 (4H, m),
1.42 (3H, s), 1.27 (4H, br), 0.86 (3H, t, J = 6.6 Hz); 13C NMR II-5a (CDCl3, 75 MHz)
8 171.2, 139.3, 114.1, 106.1, 77.8, 77.1, 64.3, 31.5, 29.2, 26.3, 26.1, 25.7, 25.1, 22.2, 20.6,
13.7. 1H NMR II-Sb (CDC13, 300 MHz) 5 5.81 (1H, q, J = 10.5 Hz), 5.38 (1H, dd, J =
17.1, 1.8 Hz), 5.06 (1H, dd, J = 10.5, 1.5 Hz), 4.06 (4H, m), 2.02 (3H, s), 1. 82 (2H, m),
1.66 (2H, m), 1.46 (4H, m), 1.37 (3H, s), 1.27 (4H, br), 0.86 (3H, t, J = 6.6 Hz); 13C
NMR II-Sb (CDCl3, 75 MHz) 5 171.1, 140.9, 114.1, 106.5, 78.4, 78.0, 64.3, 31.8, 29.2,

25.9, 25.5, 25.4, 24.7, 22.5, 20.9, 14.1.

 

\ \
0A0 MeOH H 0' 0”
C5H11 ' 2 Can
II-5a & b ll-6a & b

Preparation of compound II-6a & 6b: Each of the two diastereomers in II-Sa &
b (0.134 g, 0.47 mmol) was dissolved in MeOH/Hzo (10 mL/2 mL) and K2CO3 (0.154 g,
0.94 mmol) was added. The reaction was stirred at ambient temperature overnight.
Water (5 mL) was added and the organic layer was separated from the aqueous layer,
which was extracted by ether (3 x) and dried over Na2S04, Flash chromatography (67%
EtOAc/hexane, 1% MeOH) afforded 0.101 g product II-6a (82%) and its C-l epimer 11-
6b 0.126 g (88%). lH NMR II-6a (CDC13, 300 MHz) 8 5.91 (1H, q, J = 10.5 Hz), 5.43
(1H, dd, J = 17.4, 1.5 Hz), 5.07 (1H, dd, J = 10.5, 1.5 Hz), 4.07 (2H, m), 3.64 (2H, t, J =

6.0 Hz), 1.80 (1H, br), 1. 82 (2H, m), 1.68 (2H, m), 1.46 (4H, m), 1.38 (3H, s), 1.34 (4H, ‘

46

br), 0.85 (3H, t, J = 6.6 Hz): l3CNMR II-6a (CDCl3, 75 MHz) 8 140.8, 114.2, 106.5, 78.7,
78.5, 62.7, 31.8, 29.8, 29.3, 26.2, 25.9, 24.6, 22.5, 14.0.‘H NMR II-6b (CDCl3, 300 MHz)
6 5.76 (1H, q, J = 10.5 Hz), 5.30 (1H, dd , J = 17.4, 1.5 Hz), 5.07 (1H, dd, J = 10.5, 1.5
Hz), 3.94 (2H, m), 3.65 (2H, 1, J = 6.0 Hz), 2.01 (1H, br), 1.82 (2H, m), 1.68 (2H, m),
1.46 (4H, m), 1.43 (3H, s), 1.34 (4H, br), 0.86 (3H, t, J = 6.5 Hz); l3CNMR II-6b (CDC13,
75 MHz) 5 139.3, 114.2, 106.1, 78.0, 77.9, 62.7, 31.8, 29.8, 29.7, 26.8, 26.6, 26.0, 22.5,

14.0.

\ \
W (00002, DMSQ (Ph)3PCH3B; >5:

OH -78 °C, then TEA nBuLi -—
05”" Cerr

"-68 81 b "-78 81 b

 

Preparation of compound II-7a & 7b: To a solution of oxalyl chloride (0.12
mL, 1.35 mmol) in dichloromethane (5 mL) was slowly added DMSO (0.22 mL, 3.12
mmol) in dichloromethane (1 mL) at -78 oC, and successively alcohol II-6a (0.126 g,
0.52 mmol) or II-6b (0.101 g, 0.50 mmol) in dichloromethane (2 mL) was added
dropwise. After the mixture was stirred at —78 0C for 15 min, TEA (0.56 mL, 4.05 mmol)
was added to the reaction mixture and allowed to warm up to 0 0C. After addition of
saturate NH4C1 (10 mL) and extraction with dichloromethane, the organic phase was

washed with brine and dried over MgSO4. Evaporation of solvent afforded crude

aldehyde, which was subjected to the following Wittig reaction without separation.

THF (5 mL) was added to methyltriphenylphosphonium bromide (203 mg, 0.57
mol) at 0 °C, and then a hexane solution of 2.5 M n-butyllithum (0.22 mL, 0.55 mmol)
was added at 0 °C for 30 min and the temperature was raised to ambient for 1 h. After
addition of saturate NH4C1 (10 ml), the reaction was extracted with ether (3 x). The

organic layer was washed with brine (1 x) and dried over MgSO4. Flash chromatography

47

(5% EtOAc/hex) afforded desired product H-7a 0.033 g (27%) and its diastereomer II-7b
0.017 g (20%). 1H NMR II-7a (CDC13, 300 MHz) 5 5.92 (1H, q, J = 10.8 Hz), 5.77 (1H,
m), 5.43 (1H, dd, J = 17.1, 1.5 Hz), 5.06 (1H, dd, J = 10.5, 1.5 Hz), 4.96 (1H, m), 4.07
(2H, m), 2.24 (1H, m), 2.07 (1H, m) 1.80 (1H, br), 1.57 (2H, m), 1.46 (2H, m), 1.38 (3H,
s), 1.27 (6H, br), 0.86 (3H, m); 13C NMR II-7a (CDCl3, 75 MHz) 5 141.3, 138.1, 114.9,
114.1, 106.2, 78.5, 77.8, 31.6, 30.3, 29.3, 28.7, 25.9, 24.7, 22.6, 14.1. 1H NMR II-7b
(CDC13, 300 MHz) 5 5.80 (1H, m), 5.77 (1H, q, J = 10.8 Hz), 5.34 (1H, dq, J = 17.1, 1.5
Hz), 5.06 (1H, dq, J = 10.5, 1.5 Hz), 4.95 (1H, m), 3.94 (2H, m), 2.24 (1H, m), 2.07(1H,
m), 1.57 (2H, m), 1.46 (2H, m), 1.43 (3H, s), 1.27 (6H, br), 0.86 (3H, m); 13C NMR II-7b
(CDC13, 75 MHz) 5 139.4, 138.2, 114.8, 114.0, 106.0, 77.8, 77.3, 31.9, 30.4, 29.7, 29.2,

26.7, 26.0, 22.6, 14.0.

6". .“\\
W A (10 mol%) 0 X \

34° 7 — 333 * Hf
_ 0.005 M in CHzclz C5H11 C5H11 —

Cer 1
ll-7a & b "-8 "-73

 

Preparation of compound II-8: II-7a (0.033 g, 0.1 mmol) was dissolved in
dichloromethane (21 mL) and lst generation Grubbs catalyst (A, 1.2 mg, 10 mol%) in
dichloromethane (7 mL) was added dropwise at ambient temperature. The reaction was
stirred at ambient temperature overnight. II-7a was not consumed at all (monitored by
TLC). More catalyst (A, 1 mg) was added and the reaction refluxed overnight. II-7a
was still not consumed. Second generation Grubbs catalyst (B, 1 mg) was added and the
solution was refluxed for another 12h. II-7a was recovered.

Run parallel reaction for II-7b (0.017 g) in dichloromethane (10 mL). First
generation Grubbs catalyst (A, 1 mg, 10 mol%) in dichloromethane (5 mL) was added

dropwise at ambient temperature. After the reaction was stirred for 12 h, a major product

48

was formed (monitored by TLC). Pipet chromatography afforded 5 mg Il-8 (not pure, <
30%). Yet no good ‘3CNMR could be obtained. Characteristic 1H NMR II-8 (CDCl3,
500 MHz) 5 5.85-5.75 (2H, m), 4.05 (2H, m), 1.48 (3H, s); GC-MS m/z 210 M“, 139 [M-

C5H111+-

3.3. Data for Chapter 2.2.1

TBSCI
_ OH imidazole _ OTBS
C5H11/—\—/_ DMF C5H11/V
“-9 "-10

Preparation of compound Il-10: tert-butyldimethyl-silyl chloride (5.426 g,
36.00 mmol) was added to a solution of cis-3-decen-l-ol II-9 (4.688 g, 30.0 mmol) and
imidazole (5.100 g, 75.0 mmol,) in N, N-dimethylformamide (DMP, 2 ml/g of alkenol,
10 mL) at ambient temperature and stirred for 10 h. Water was added and ethylacetate (1
x) was used to extract the solution. The extract was then concentrated and flash
chromatography (5% EtOAc/hexane, 1% TEA) afforded silyl ether II-10 1.826 g (99%).
1H NMR (CDC13, 300 MHz) 5 5.37 (2H, m), 3.57 (2H, t, J = 7.2 Hz), 2.28 (2H, q, J = 6.9
Hz), 2.01 (2H, q, J = 6.9 Hz), 1.26 (8H, m), 0.87 (9H, s), 0.85 (3H, m), 0.03(6H, s).

0304 (0.2%)
NMO HO OH

Cwm acetone-water CSHH 9

Preparation of compound “-11 & II-12: For general procedure of

 

dihydroxylation, please refer to II-3.

HO OH

C5H11
"-11

OAc

49

11-11 was prepared in 85% yield. 1H NMR (CDC13, 300 MHz) 5 4.07 (2H, t, J =
6.3 Hz), 3.58 (2H, br), 2.02 (3H, s), 1.85 (2H, m), 1.66 (2H, m), 1.44 (4H, m), 1.27 (4H,

br), 0.86 (3H, t, J = 6.3 H2).

HO OH

C5H11
"-12

OTBS

11.12 was prepared in 95% yield. 'H NMR (CDCl3, 300 MHz) 5 3.59 (4H, m),
1.65 (2H, m), 1.40 (2H, m), 1.37 (2H, m), 1.26 (6H, m, br), 0.86 (9H, s), 0.84 (3H, m),
0.02 (6H, s); 13C NMR (CDC13, 75 MHz) 5 74.4, 74.3, 63.6, 31.9, 31.6, 29.4, 28.5, 25.8,

22.6, 22.5, 18.3, 14.1, -5.5.

 

MeO OMe
HO OH 0
FLOAC TsOH(1O mol 4: M40“
CsHii DMF C51"11
"-13 "-14

Preparation of compound II-l4: 2,2-dimethoxypropane (0.74 mL, 6.0 mmol)
was added to a mixture of diol “-13 (0.872 g, 4.0 mmol) and TsOH (26 mg, 10% mol) in
N, N-dimethylformide (20 mL). The mixture was stirred for 2 h and TLC showed that
the reaction was complete. Water (40 mL) was added and ethylacetate was used to
extract the solution. The extract was then concentrated and flash chromatography (10%
EtOAc/hexane) afforded product “-14 1.021 g (99%). 1H NMR (CDC13, 300 MHz)
5 4.23 (2H, m), 4.07 (2H, m), 2.01(3H, s), 1.70 (2H, m), 1.48 (2H, m), 1.39 (3H, s), 1.29
(3H, s), 1.27 (6H, m, br), 0.85 (3H, t, J = 6.6 Hz); 13C NMR (CDC13, 75 MHz) 5 171.0,

107.7, 77.8, 74.5, 61.7, 31.8, 29.4, 29.1, 28.5, 26.0, 22.5, 210,140.

Cffi/ K2003 0 0

OAc ————-> OH

CsH1 1 MeOH/Hzo CSHW
"-14 "-1 5

50

Preparation of compound “-15: For general procedure of hydrolysis of acetates,
please refer to II-6.

11-15 was prepared in quantitive yield. 1H NMR (CDClg, 300 MHz) 5 4.20 (1H,
m), 4.05 (1H, m), 3.79 (2H, m), 2.47 (1H, q, J = 3.9 Hz), 1.71 (2H, m), 1.55 (2H, m),
1.42 (3H, s), 1.30 (3H, s), 1.27 (6H, m, br), 0.85 (3H, m); 13C NMR (CDC13, 75 MHz)

5 107.5, 79.2, 78.0, 62.0, 28.3, 25.9, 25.6, 22.1, 18.2. 11.1.

 

OXO (COCI) , DMSO X
)—K_/OH 2 t /O
C5H11 ~78 °C-RT, then TEA C5H11
"-15 “-16

Preparation of compound “-16: To a solution of oxalyl chloride (0.21 mL, 2.4
mmol) in dichloromethane (24 mL) was slowly added anhydrous DMSO (0.34 mL, 4.8

mmol, 2.4eq) at —78 0C, and successively alcohol II-15 (0.433 g, 2.0 mmol) in

dichloromethane (20 mL) was dropwise added. After the mixture was stirred at -78°C
for 15 min, triethylamine (1.5 mL) was added to the reaction mixture and allowed to
warm up to 0 °C. After addition of saturate N114Cl and extraction with

dicholoromethane, the organic phase was washed with brine and dried over MgSO4. The

crude mixture was concentrated under reduced pressure and purification by flash
chromatography (20% EtOAc/hexane) afforded 0.213 g product II-16 (49%). 1H NMR
(CDCl3, 300 MHz) 5 9.78 (1H, t, J = 3.6 Hz), 4.54 (1H, m), 4.13 (1H, m), 2.48 (2H, m),

1.45 (2H, m), 1.40 (3H, s), 1.31 (3H, s), 1.26 (6H, m, br), 0.85 (3H, t, J = 6.6 Hz).

 

OX0 (Ph)3PCHaBr ><0
wo ' 4' 3V
CSH11 n-BuLl, THF 05H11
“-16 "-1 7

51

Preparation of compound II-17: T HF (17 mL) was added to
methyltriphenylphosphonium bromide (0.68 g, 1.9 mol) at 0 °C, and then a hexane
solution of 1.6 M n-butyllithum (1.2 mL, 1.9 mmol) was added at 0 °C. After 30min,
aldehyde “-16 (0.263 g, 1.24 mmol) in THF (6 mL) was dropwise added to the reaction
mixture and stirring was continued for 30min and then at ambient temperature for 1 h.
After addition of saturate NH4Cl, the reaction was extracted with ether. The combined
organic layer was washed with brine and dried over MgSO4. The crude mixture was
concentrated under reduced pressure and purification by flash chromatography (5%
EtOAc/hexane) afforded 0.113 g alkene II-17 (43%). 1H NMR (CDC13, 300 MHz)
5 5.82 (1H, m), 5.07 (2H, m), 4.05 (2H, m), 2.23 (2H, m), 1.48 (2H, m), 1.28 (6H, m, br),
1.42 (3H, s), 1.31 (3H, s), 0.85 (3H, m); 13C NMR (CDCl3, 75 MHz) 5134.9, 117.0,

107.5, 78.0, 77.4, 34.6, 31.9, 29.5, 28.5, 25.94, 25.92, 22.5, 14.0.

 

oyo THF/HCI (1 M) H OH
: /
CSH11 / CSH11
"-17 "-18

Preparation of compound II-l8: Acetonide II-17 (0.237g, 1.1 mmol) was
dissolved in THF/HCl (1N) and the reaction was stirred overnight. The mixture was
extracted with ether (3 x) and the combined organic phase was washed with brine (1 x)
and dried with Na2804. The crude mixture was concentrated under reduced pressure and
purification by flash chromatography (75% EtOAc/hexane) afforded 0.132g diol II-18 in
69% yield. 1H NMR (CDCl3, 300 MHz) 5 5.80 (1H, m), 5.10 (2H, dt, J = 9.3, 1.2 Hz),
3.59 (2H, m), 2.64 (2H, 8, br), 2.20 (2H, m), 1.40 (2H, m), 1.25 (6H, m, br), 0.84 (3H, J =
6.6 Hz); ”C NMR (CDC13, 75 MHz) 5 135.0, 117.9, 74.0, 73.4, 35.8, 31.8, 31.5, 25.6,

22.5, 13.9.

52

 

— BnBr, NaH —
Hoflott Bno—/—\-0H

ll-19 THF/ DMSO "_20

 

Preparation of Compound II-20: A solution of cis-2-buten-1,4-diol (II-19, 2.20
g, 25.0 mmol) in THF (63 mL) was added dropwise to a suspension of NaH (1.1 g of a
60% dispersion in mineral oil, 27.5 mmol) in a 4:1 mixture of dry THF/DMSO (125 mL).
The mixture was stirred at ambient temperature for 30 min, then a solution of benzyl
bromide (4.70 g, 27.5 mmol) in THF (63 mL) was added dropwise. The mixture was
heated to 60 °C overnight. After cooling, an equal volume of water was added and the
mixture extracted with diethyl ether(3 x). The combined organics were washed with
brine, dried over sodium sulfate, and the solvent was removed under reduced pressure.
The residue was column chromatographed (33% EtOAc/hexane) to give 2.58 g II-20 in
58% yield. Dibenzyl ether (1.00 g) was obtained as by product. 1H NMR (CDCl3, 300

MHz) 5 7.35 (5H, m), 5.8 (2H, m), 4.5 (2H, s), 4.15 (2H, br), 4.1 (2H, d, J = 6.3 Hz).

AcCl

— TEA, DMAP —
BnOflOH W BnOflOAC
2 2

Preparation of compound II-21: For general procedure of acylation, please refer
to lI-2.
II-21 was made in 94% yield. 1H NMR (CDC13, 300 MHz) 5 7.35 (5H, m), 5.75

(2H, m), 4.60 (2H, d, J = 6.3 Hz), 4.50 (2H, s), 4.10 (2H. d, J = 6.6 Hz), 2.02 (3H, s).

0304 (0.2%) HO OH
— NMO
BnO-/—\—OAC BnO—HOAC

 

Preparation of compound II-22: for general procedure of dihydroxylation,

please refer to II-3.

53

II-22 was made in 91% yield. 1H NMR (CDC13, 300 MHZ) 5 7.31 (5H, m), 4.53
(2H, s), 4.23 (2H, q, J = 6.0 Hz), 3.84 (1H, m), 3.73(1H, m), 2.80 (2H, t, J = 5.4 Hz),
2.06 (s, 3H); 13C NMR (CDC13, 75 MHZ) 5 171.6, 137.4, 128.5, 127.9, 127.8, 73.6, 71.2,

71.1, 70.1, 65.8, 20.8.

 

 

MeO OMe y
M TsOH(10 mol%) R
BnO OAc DMF ’BnO ON;
"-22 "-23

Preparation of compound “-23: for procedure of making acetonide: please refer
to II-14.

II-23 was made in 88% yield. 1H NMR (CDC13, 300 MHz) 5 7.31 (5H, m), 4.52
(2H, q, J = 12.0 Hz), 4.35 (3H, m), 4.05 (1H, m), 3.50 (2H, d, J = 9.6 Hz), 2.03 (3H, s),
1.44 (3H, s), 1.34 (3H, 8).

Y K2C03 Y

o
BnOROAC MeOH/HZO BnOJ—QOH

11-23 11-24

 

Preparation of Compound II-24: For general procedure of hydrolysis of
acetates, please refer to II-6.

11.24 was made in 93% yield. 'H NMR(CDC13, 300 MHz) 6 7.35 (5H, m), 4.54
(2H, q, J = 12.0 Hz), 4.30 (2H, m), 3.60 (4H, d, J = 9.6 Hz), 2.60 (1H, t), 1.44 (s, 3H),
1.38 (s, 3H). 13C NMR(CDC13, 75 MHz) 5 137.1, 128.5, 128.1, 127.9, 108.5, 75.3, 7711,
73.8, 68.2, 60.8, 27.7, 25.1.

R (cocoaomsq (Ph)3PCHaBL 3 0:
8110 OH -78 °C, then TEA nBuLi BnO —

11-24 11-25

 

54

 

Preparation of Compound II-25: For procedure of oxidation and olefination:
please refer to II-7.

II-25 was made in 77% yield. 1H NMR (CDCl3, 300 MHZ) 5 7.31 (5H, m), 5.78
(1H, m), 5.34 (2H, m), 4.59 (2H, s), 4.20 (1H, t, J = 7.8 Hz), 3.90 (1H, m), 3.57 (2H, m),
1.43 (6H, s). ”C NMR (CDCl3, 75 MHz) 5 137.9, 135.2, 128.3, 127.7, 127.6, 118.6,

109.4, 79.9, 79.4, 73.5, 69.3, 26.9.

3 0: THF/HCI H OH
BnO _ BnO —

11-25 11-26

 

Preparation of Compound II-26: For procedure, please refer to II-18.

II-26 was made in 83% yield. 1H NMR (CDCl3, 300 MHZ) 5 7.35 (5H, m), 5.80
(1H, m), 5.31 (2H, dd, J = 16.5, 1.5 Hz), 4.56 (2H, m), 4.10 (1H, m), 3.62 (1H, m), 3.54
(2H, m), 2.90 (2H, br). l3C NMR (CDC13, 75 MHz) 5 137.9, 136.9, 136.4, 128.4, 127.8,

117.1, 74.1, 73.5, 72.8, 71.4.

 

RXOMG
HO} O! H R'C(OMe)3 ‘ 3—8
R1 R2 PPTS (1 (Vernon R1 R2

General procedure to make cyclic orthoesters II-27 to II-32, II-42: Orthoester
(1.2 equiv) was added to a mixture of diol and PPT S (1 mol%) in dichloromethane
(0.1M). The mixture was stirred for 15 min. The crude mixture was concentrated under
reduced pressure and purified by flash chromatography (10% EtOAc/hexane, 5% TEA).
All the cyclic orthoesters were obtained as a mixture of C-1 epimers. The 1H and13C

NMR data shown are for the major isomer peaks.

55

 

xOMe
O 0
OAc
C5H1 1
"-27

II-27 was made in 99% yield. IH NMR (CDCl3, 300 MHZ) 5 4.12 (2H, m), 4.24
(2H, m), 3.22 (3H, s), 2.01 (3H, s), 1.71 (2H, m), 1.51 (3H, s), 1.48 (2H, m), 1.27 (6H, m,
br), 0.85 (3H, t, J = 6.6 HZ); 13C NMR (CDCl3, 75 MHZ) 5 171.0, 120.2, 78.1, 75.0, 61.6,

50.3, 31.7, 29.4, 29.0, 25.9, 22.5, 22.4, 20.9, 14.0.

H OMe

0x0

CsH1 1
"-28

OAc

II-28 was made in 99% yield. 1H NMR (CDCl3, 300 MHZ) 55.65 (1H, s),
4.14(2H, m), 4.26 (2H, m), 3.28 (3H, s), 2.02 (3H, s), 1.70 (2H, q, J = 6.6 Hz), 1.47 (2H,
m), 1.28 (6H, m, br), 0.85 (3H, m); 13C NMR (CDCl:,, 75 MHz) 5 171.0, 114.7, 77.2,

74.4, 61.4, 51.9, 31.7, 29.0, 28.6, 25.9, 22.5, 20.9, 13.9.

Ph OMe

OX0

CsH1 1
"-29

OAc

II-29 was obtained as a mixture of cyclic orthobenzoate and a majority of methyl

benzoate.
XoMe
0
OAc
C5H1 1
"-30

II-30 was made in 88% yield. 1H NMR (CDCl3, 300 MHZ) 5 4.20 (2H, m), 4.07

(2H, m), 3.24 (3H, s), 2.01 (3H, s), 1.84 (1H, m), 1.64 (1H, m), 1.52 (3H, s), 1.48 (4H, m),

56

1.27 (6H, m, br), 0.85 (3H, m); 13C NMR (CDCl3, 75 MHZ) 5 171.1, 120.2, 78.0, 75.0,
61.6, 50.3, 31.7, 29.4, 29.0, 25.9, 22.5, 22.4, 21.3, 20.9, 14.0.
OMe
OX0

CsH11
"-31

OTBS

II-31 was made in 93% yield. 1H NMR (CDCl3, 300 MHZ) 5 4.21 (2H, m), 3.64
(2H, m), 3.25 (3H, s), 1.52 (3H, s), 1.50 (4H, m), 1.29 (6H, m, br), 0.80 (9H, s), 0.02 (6H,
s); 13C NMR (CDC13, 75 MHZ) 5 120.0, 78.6, 78.5, 62.7, 50.2, 31.8, 31.6, 29.4, 25.9, 22.8,

22.5, 18.4, 14.0, -5.3.

H OMe

OX0

BnOAOAc
"-32
“-32 was made in 90% yield. 1H NMR (CDCl3, 300 MHZ) 5 7.31 (5H, m), 5.78
(1H, s), 4.52 (2H, s), 4.50 (2H, m), 4.38 (1H, m), 4.12 (1H, m), 3.54 (1H, d, J = 5.1 HZ),
3.31(3H, s), 2.03 (3H, s); 13C NMR (CDCl3, 75 MHZ) 5 170.6, 137.3, 128.4, 127.8,

115.5, 74.9, 74.6, 73.6, 71.2, 67.5, 62.4, 51.9, 20.8.

 

/
R' OMe _ R' J
H - o -

R1 R2 SnBr4,CHZC|2, 78 CRT R1 R2

General procedure for allylation of cyclic orthoesters: SnBr4 (0.25 equiv) in

CH2C12 (0.1 M) was added dropwise to a solution of cyclic orthoester and
allyltrimethylsilane (2.0 equiv) in dichloromethane (0.1 M) at -780C and the mixture was

stirred at -78°C for 30min and another 2.0 equiv allyltrimethylsilane was added and the

mixture was warmed up to room temperature and stirred overnight. The reaction was

57

quenched with saturate NaHCOg, extracted with ether and dried with Na2804_ The crude
mixture was concentrated under reduced pressure and purification by flash
chromatography (5% EtOAc/hexane, 1% TEA) afforded allylation product as a single

diastereomer.

/

.~\/
X

00

CsH1 1
"-33

OAc

“-33 was made in 91% yield. 1H NMR (CDC13, 300 MHZ) 5 5.75 (1H, m), 5.02
(2H, dd, J = 13.8, 3.3 Hz), 4.23 (2H, m), 4.06 (2H, m), 2.32 (2H, d, J = 6.6 Hz), 2.01 (3H,
s), 1.68 (2H, m), 1.46 (2H, m), 1.31 (3H, s), 1.25 (6H, m, br), 0.84 (3H, t, J = 6.6 Hz);
13C NMR (CDCI3, 75 MHz) 6 170.9, 133.7, 117.8, 108.6, 78.0, 74.7, 61.7, 44.0, 31.8,
29.5, 29.2, 26.3, 25.9, 22.5, 20.9, 13.9. GC-MS m/z 243 [M—C3H5]+. NOElD data proved

the relative anti stereochemistry between the allyl group and substituents at C-3 and C-4.

0 O
CsH11
"-34

OAc

11-34 was made in 91% yield. 1H NMR (CDC13, 300 MHZ) 5 5.76 (1H, m), 5.07
(3H, m), 4.09 (4H, m), 2.30 (2H, t, J = 5.7 Hz), 1.99 (3H, s), 1.69 (2H, m), 1.46 (2H, m),
1.25 (6H, m, br), 0.84 (3H, m); 13C NMR (CDC13, 75 MHZ) 5 170.9, 132.4, 118.0, 101.8,
78.1, 75.0, 61.6, 39.8, 31.7, 28.5, 27.6, 25.9, 22.5, 20.9, 13.9. NOElD data proved the

relative anti stereochemistry between the allyl group and substituents at C-3 and C-4.

.J
X

00

58

 

II-35 was made in 80% yield. 1H NMR (CDCl3, 300 MHZ) 5 5.80 (1H, m), 5.04
(2H, dd, J = 13.8, 3.9 Hz), 4.04 (4H, m), 2.32 (2H, d, J = 7.2 Hz), 2.01 (3H, s), 1.84 (1H,
m), 1.62 (1H, m), 1.46 (4H, m), 1.32 (3H, s), 1.27 (6H, m, br), 0.84 (3H, m); 13C NMR
(CDCl3, 75 MHZ) 5 170.9, 133.9, 117.8, 108.4, 78.2, 77.7, 64.3, 44.1, 31.8, 29.6, 26.4,

26.3, 25.9, 25.4, 22.5, 20.9, 13.9.

H 36¢
OX0

BnO-{g‘S-OAC
II-36 was made in 71% yield. 1H NMR (CDC13, 300 MHZ) 5 7.30 (5H, m), 5.80
(1H, s), 5.26 (1H, t, J = 4.5 Hz), 5.16 (2H, m), 4.52 (2H, d, J = 2.1 HZ), 4.37 (2H, m),
4.20 (2H, m), 3.54 (2H, m), 2.37 (2H, t, J = 5.7 Hz), 2.04 (3H, s); 13C NMR (CDCl3, 75

MHZ) 5170.7, 137.4, 131.9, 128.4, 127.9, 127.8, 118.4, 103.7, 75.7, 75.4, 73.6, 67.7,

 

62.3, 39.4, 20.8.
0M9 “\=
0x0 :Mger Q/
TB T OTBS
CsHfi—VO S Toluene, reflux C5H11
"-31 "-37

Preparation of compound II-37: Vinylmagnesium bromide ( 1.0 M in THF, 1.5
mL) was added to a solution of II-31 (0.180 g, 0.5 mmol) in dry toluene (5 mL). After
being refluxed overnight, the mixture was poured into aqueous NH4Cl and extracted with
ether. The combined organic layers were dried over NaZSO4 and concentrated in vacuo.
Purification by flash chromatography (10% EtOAc/hexane, 1% TEA) afforded 0.080 g
product (not pure, <45%). Characteristic 1H NMR (CDCl3, 300 MHZ) 5 5.76 (1H, q, J =

10.5 HZ), 5.30 (1H, dd, J = 15.6, 1.8 HZ), 5.06 (1H, dd, J = 8.7, 1.8 Hz), 3.95 (2H, m),

59

3.60 (2H, m), 4.06 (4H, m), 1.42 (3H, s); 13C NMR (CDC13, 75 MHZ) 5 139.5, 113.9,

106.0, 78.0, 77.8, 62.9, 31.9, 29.7, 29.5, 26.7, 26.2, 25.9, 22.6, 18.3, 14.0, -5.3.

3.4. Data for Chapter 2.2.2

MeOXOMe
HO OH C(QMQ)4 A M

 

H, F12 PPTS (1 %moT) R
CH2C|2 ‘ R2

General procedure to make cyclic ortho carbonates: Tetramethyl
orthocarbonate (1.2 equiv) was added to a mixture of vicinal diol and PPTS (1 mol%) in
dichloromethane (0.1 M). The crude mixture was concentrated under reduced pressure

and purification by flash chromatography.

MeO OMe
X

R
BnO —

"-38
II-38 was made in 63% yield. 1H NMR (CDCl3, 300 MHz) 5 7.35 (5H, m), 5.85
(1H, m), 5.30 (2H, m), 4.58 (2H, s), 4.50 (1H, m), 4.10 (1H, m), 3.62 (2H, d, J = 9.6),
3.41 (6H, m); 13C NMR (CDC13, 75 MHZ) 5 137.8, 134.3, 131.8, 128.4, 127.7, 127.6,

119.2, 80.2, 79.6, 73.4, 69.0, 51.5.

 

Me OMe _ 0
5'1: MS ‘ fl
BnO LeWIs a093,: 5:202, BnO _
"-38 ‘73 ‘ "-39

Attempts of nucleophilic attack on cyclic orthocarbonates: Lewis acid (San,
25 mol% or TMSOTf 10 mol%) in CH2C12 was added dropwise to a solution of cyclic
orthocarbonate “-38 and allyltrimethylsilane (1.0 equiv) in CHzClz (0.1M) at -78 °C and

the mixture was stirred at -—78 0C for 30 min and warmed up to ambient temperature

60

overnight. The reaction was quenched with saturate NaHC03, extracted with ether and
dried with NaZSOa The crude mixture was concentrated under reduced pressure and
purification by flash chromatography (10% EtOAc/hexane, 5% TBA) afforded cyclic
carbonate II-39 (60% for San, 52% for TMSOTf). 1H NMR (CDCl3, 300 MHZ) 5 7.30
(5H, m), 5.86 (1H, m), 5.39 (2H, t, J = 15.0 Hz), 4.95 (1H, t, J = 6.6 HZ), 4.58 (2H, q, J =
9.0 Hz), 4.40 (1H, p, J = 3.6 Hz), 3.66 (2H, dq, J = 11.4, 3.6 Hz); 13C NMR (CDCl3, 75

MHZ) 5 186.3, 137.0, 132.3, 128.6, 128.1, 127.7, 120.8, 80.1, 78.8, 73.7, 67.8.

 

 

OMe OMe |._ OMe
fi-‘t fit J1 "' 9‘"
= I —
BnO OAc M90” 8110 OH 33”! DMAP BnOflOSiJ—
11.40 CH20'2 11-41 '

Preparation of compound II-41: Cyclic orthoester II-40 (0.303 g, 0.98 mmol)
was was dissolved in methanol (10 mL) and KZCO3 (0.204 g, 1.46 mmol) was added.
The reaction was stirred at ambient temperature for 2 h. The suspension was filtered and
the solvent was removed under reduced pressure. The oil-like intermediate was dissolved
in dichloromethane (10 mL) and TEA (0.34 mL, 2.44 mmol) and DMAP (1 mg, 5 mol%)
were added. Allylchlorodimethylsilane (0.15 mL, 0.98 mmol) was added afterwards.
The reaction was stirred at ambient temperature for 1 h. The resulting solution was
washed with water (2 x), brine (2 x) and then dried with Na2804, Removal of the solvent
afforded crude product II-41 0.077 g in 22% yield. 1H NMR (CDC13, 300 MHZ) 5 7.31
(5H, m), 5.72 (1H, m), 4.83 (2H, m), 4.54 (2H, q, J = 12.0 Hz), 4.49 (1H, m), 4.35 (1H,
m), 4.67 (4H, m), 3.27 (3H, s), 1.56 (3H, s), 1.54 (2H, d, J = 19.2 Hz), 0.07 (6H, 8); ‘3C
NMR (CDCl3, 75 MHZ) 5 138.0, 133.7, 128.4, 127.7, 113.8, 77.9, 77.2, 73.4, 68.3, 61.3,

50.4, 24.2, 21.7, -2.6.

61

OMe
OX0

A +
Bnoh OH BnO OH

| _ v
osif CH2CI2, -78°C-RT 800
"-41 11-42

 

Attempts for intramolecular nucleophilic delivery of II-41: SnBr4 (0.093 g,
0.22 mmol) in dichloromethane (0.5 mL) was added dropwise to a solution of II-41
(0.524 g, 2.0 mmol) in dichloromethane (60 mL) at —78 °C and the mixture was stirred at
—78 °C for 30 min and the mixture was warmed up to room temperature overnight. The
reaction was quenched with saturated NaHC03, extracted with ether and dried with
N aZSO4_ The crude mixture was concentrated under reduced pressure and purification by
flash chromatography afforded a mixture of hydrolyzed derivatives of the cyclic
orthoesters “-42 in quantitive yield. 1H NMR (CDC13, 500 MHZ) 5 7.32 (5H, m), 5.35
(2H, m), 4.53 (2H, q, J = 12.0 HZ), 3.56 (4H, m), 2.10 (3H, ds); 13C NMR (CDCl3, 125

MHZ) 5 170.0, 169.9, 137.4, 128.4, 127.9, 127.8, 77.2, 73.4, 71.2, 70.8, 29.9, 20.8, 20.7.

3.5. Data for Chapter 2.3

OMe
OX0

C5H1W

1
"-43

Preparation of Compound II-43: for procedure, please refer to II-27.
11.43 was made in quantitive yield. 'H NMR (CDC13, 300 MHz) 6 5.81 (1H, m),
5.09 (2H, m), 4.25 (2H, m), 3.25 (3H, s), 2.24 (2H, m), 1.53 (3H, s), 1.48 (2H, m), 1.25

(6H, m, br), 0.84 (3H, m).

62

 

O 0 M60 OMe y
H H TsOH (10 mol%) 0 O
OH = MOH
05H“ DMF (35H11
"-44

Preparation of Compound II-44: for procedure, please refer to II-14.
II-44 was made in 88% yield. 1H NMR (CDCl3, 300 MHZ) 5 4.01 (2H, m), 3.63

(2H, t, J = 6.0 HZ), 2.22 (1H, br), 1.65 (2H, m), 1.55 (2H, m), 1.47 (2H, m), 1.40 (3H, s),

 

1.30 (3H, S), 1.26 (6H, m, br), 0.85 (3H, m).
°><° €53]
OH —’ —
Cus CHZCIZ 05H1 1 O
"-44 "-45

Oxidation of alcohol using PDC: Alcohol Il-44 (3.455 g, 15 mmol) was
dissolved in dichloromethane (40 mL) and PDC (8.46 g, 1.5 equiv. ) was added. The
reaction was stirred at ambient temperature for 24 h. The resulting suspension was
filtered and evaporated and purification by column chromatography (20%
EtOAc/hexane) afforded aldehyde II-45 2.21g (65%). 1H NMR (CDC13, 300 MHZ)
5 9.78 (1H, t, J = 1.8 HZ), 4.03 (2H, m), 2.56 (2H, m), 1.49 (4H, m), 1.38 (3H, s), 1.28

(3H, s), 1.27 (6H, m, br), 0.85 (3H, m).

 

_o ' _
C5H11 NaHMDS,THF 05H”
"-45 "-46

Preparation of Compound II-46: please refer to II-17.

II-46 was made in 65% yield. 1H NMR (CDCl3, 300 MHZ) 5 5.81 (1H, m), 4.98
(2H, m), 4.01 (2H, m), 2.22 (1H, m), 2.05 (1H, m), 1.48 (4H, m), 1.40 (3H, s), 1.30 (3H,
s), 1.28 (6H, m, br), 0.85 (3H, m); 13c NMR (CDC13, 75 MHz) 6 138.2, 114.8, 107.3,

78.0, 77.3, 31.9, 30.3, 29.6, 29.0, 28.6, 26.0, 25.9, 22.5, 14.0.

63

 

0X0 (Ph)3PCH(CH3)2l m
05H£_&/:O THF,NaHMDS CSH11
11.45 "-47

Preparation of Compound II-47: THF (15 mL) was added to
isopropyltriphenylphosphonium iodide (1.82 g, 3.5 mol) at 0 °C, and then a THF
solution of 1.0 M NaHMDS (4.3 mL, 4.3 mmol) was added at 0 0C. After 30min,
aldehyde II-45 (0.800 g, 3.5 mmol) in THF (15mL) was dropwise added to the reaction
mixture and stirring was continued at 0 0C for 30min and then at ambient temperature for

1 h. After addition of saturate N114Cl (10 mL), the reaction was extracted with ether (3 x)

 

and washed with brine (1 x) and dried over NaZSO4, Flash Chromatography (10%
EtOAc/hexane) afforded desired product II-47 0.446 g (51%). 1H NMR (CDC13, 300
MHZ) 5 5.09 (1H, m), 3.98 (2H, m), 2.00 (1H, m), 2.12 (1H, m), 1.65 (3H, s), 1.58 (3H,
s), 1.47 (4H, m), 1.39 (3H, s), 1.28 (3H, s), 1.27 (6H, m), 0.85 (3H, m); 13C NMR (CDC13,

75 MHZ) 5 132.0, 123.9, 107.2, 78.1, 77.5, 31.9, 29.9, 29.6, 28.6, 26.0, 25.7, 24.6, 22.5,

 

17.6, 14.0.
0X0 (Ph)3PCH2PhCI mph
CanWO NaHMDS, THF'CsH11
"-45 "-48

Preparation of Compound II-48: THF (30 mL) was added to
benzyltriphenylphosphonium chloride (1.64 g, 3.5 mol) at 0 °C, and then a THF
solution of 1.0 M NaHNflDS (4.3 mL, 4.3 mmol) was added at 0 °C. After 30 min,
aldehyde II-45 (0.800 g, 3.5 mmol) in THF (15 mL) was dropwise added to the reaction
mixture and stirring was continued at 0 °C for 30min and then at ambient temperature for

1h. After quenched with saturate N114Cl ( 10 mL), the reaction was extracted with ether

64

(3 x) and washed with brine (1 x) and dried over NaZSO4, Flash chromatography (10%
EtOAc/hexane) afforded desired product II-48 1.06 g (68%). 1H NMR (CDC13, 300
MHZ) 5 7.29 (5H, m), 6.24 (1H, m), 5.66 (1H, m), 4.03 (2H, m), 2.38 (1H, m), 2.24 (1H,
m), 1.65 (2H, m), 1.49 (2H, m), 1.43 (3H, s), 1.32 (3H, s), 1.28 (6H, m, br), 0.86 (3H, m);
13C NMR (CDC13, 75 MHZ) 5 130.3, 130.0, 128.4, 128.1, 126.9, 125.9, 107.4, 78.0, 77.3,

31.9, 30.2, 29.6, 29.6, 28.6, 26.0, 25.9, 22.5, 14.0.

><0 THF/HCI _ HO OH
oath/2 05mm—

"-46 "-49

 

Preparation of Compound II-49: For procedure, please refer to II-18.

11.49 was made in 71 % yield. 'H NMR(CDC13, 300 MHz) 6 5.80 (1H, m), 5.10
(2H, dt, J = 10.8, 1.5 Hz), 3.59 (2H, m), 2.50 (2H, 8, br), 2.20 (2H, m), 1.48 (4H, m), 1.25
(6H, m, br), 0.84 (3H, J = 6.6 Hz); 13C NMR (CDC13, 75 MHZ) 5 135.0, 117.9, 74.0, 73.4,

34.9, 31.8, 31.5, 25.6, 24.1, 22.5, 13.9.

 

gm TFA HW
(351-111 — THF/ H20 05H" _
“-47 "-50

Preparation of Compound 11-50: II-47 (0.446 g, 1.1 mmol) was dissolved in 4:1
THF/1120 (10 mL) and trifloroacetic acid (0.34 mL) was added. The reaction was stirred
overnight. The mixture was extracted with ether (3 x) and the combined organic phase
was washed with brine (1 x) and dried with MgSO4. The crude mixture was concentrated
under reduced pressure and purification by flash chromatography (75% EtOAc/hexane,
1% MeOH) afforded 0.131 g product II-50 (35%) and recovered starting material II-47

0.240 g. 1H NMR (CDC13, 300 MHZ) 5 5.11 (1H, m), 3.57 (2H, m), 2.10 (2H, m), 1.67

65

 

(3H, s), 1.61 (3H, s), 1.44 (4H, m), 1.28 (6H, m), 0.86 (3H, m). 13C NMR (CDC13, 75

MHZ) 5 134.0, 125.8, 74.1, 73.5, 31.9, 31.6, 28.6, 26.0, 25.3, 24.6, 22.5, 19.3, 14.0.

 

OX0 Ph TsOH HO OH __Ph
(:us CHCl3/MeOH CsHtt
11-48 "-51

Preparation of Compound II-Sl: II-48 (0.338 g, 1.2mmol) and TsOH (10
mol%) was dissolved in 1:1 CH3Cl/MeOH (10 mL) and one drop of water was added.
The reaction was stirred overnight. The mixture was concentrated under reduced
pressure, dissolved in ether, washed with brine (1 x) and dried with Na2SO4. The crude
mixture was concentrated under reduced pressure and purification by flash
chromatography (75% EtOAc/hexane, 1% MeOH) afforded 0.229 g product II-Sl (78%).
1H NMR (CDCl:,, 300 MHZ) 5 7.29 (5H, m), 6.24 (1H, m), 5.66 (1H, m), 3.60 (2H, m),
2.40 (1H, m), 2.28 (1H, m), 1.49 (4H, m), 1.28 (6H, m, br), 0.86 (3H, m); 13C NMR

(CDC13, 75 MHZ) 5 130.5, 130.1, 128.5, 126.9, 125.9, 74.7, 74.0, 31.8, 31.3, 30.7, 29.5,

 

 

 

25.6, 22.6, 14.0.
TsOH or CSA_
AcO OH
XoMe C H / R
SnBr4,lutidine 5 11 n
O O 3 +
/ R - o -
CSHW CHZCIz, 78 C RT HO 0 Ac
"=12 TMSBr 0an n/ R

 

R: H, (CH3)2, Ph 3
CHZCIZ, 0 °C-F1T

General procedure for Prins cyclization of cyclic orthoesters: Cyclic
orthoester prepared from diol (II-49, II-50 and 11-51) was dissolved in dichloromethane

(0.005 M) under certain temperatures and protic acid (10 mol%) or Lewis acid (1.0 equiv)

66

 

was added. The reaction was stirred overnight. The major products obtained are

mixtures of hydrolyzed derivatives of orthoesters.

3.6. Data for Chapter 2.4

 

OMe O
OX0 =\MgB, _ 029
OAc '
05H“ THF 05H”
"-52 "-53

Preparation of Compound II-53: Vinylmagnesium bromide (1.0 M in THF, 2.2
mL) was added to a solution of cyclic orthoester II-52 (0.274 g, 1.0 mmol) in dry THF
(20 mL). After being stirred overnight, the mixture was poured into aqueous NH.,C1 and
extracted twice with ether. The combined organic layers were dried over NaZSO4 and
concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexane)
afforded 0.113 g bicyclic orthoester II-53 in 57% yield. 1H NMR (CDC13, 300 MHZ)
5 4.22 (1H, br), 4.04 (2H, m), 3.71 (1H, dd, J = 7.5 Hz), 2.15 (1H, m), 1.78 (1H, m), 1.50
(3H, s), 1.48 (2H, m), 1.26 (6H, m), 0.85 (3H, m); 13C NMR (CDC13, 75 MHz) 5 118.6,

79.8,. 74.8, 58.7, 31.8, 31.5, 27.7, 26.2, 23.6, 22.6, 13.9.

 

CH3C(OM9)3 I . ’ko
”0 OH OH PPTS (1 %mol) =/_S." 0'
05“" CH20|2 Et3N, THF 05H11
".54 quantitative "-55

Preparation of Compound II-SS: Triol II-54 (0.095 g, 0.5 mmol), obtained from
dihydroxylation of cis-4-decen-1-ol, was dissolved in dichloromethane (5 mL) and PPTS
(1 mg, 1 mol%) and trimethyl orthoacetate (0.09 mL, 0.75 mmol) was added. The
reaction was stirred for 10 min and the solution was concentrated under reduced pressure.

The crude intermediate was dissolved in THF (5 mL). Triethylamine (0.11 mL, 0.8

67

 

mmol) and allylchlorodimethylsilane (0.101 g, 0.75 mmol) were added consequently.
The reaction was stirred at ambient temperature for 1 h and quenched with water. The
organic layer was washed with brine (2 x) and then dried with Na2SO4. Removal of the

solvent afforded 0.100 g crude product bicyclic orthoester II-SS (100%).

I

3’ng BF3-Et20 9:2 51:
CH Cl
CsH11 2 2 05H" O
"-53 "-56
Preparation of Compound II-56: Bicyclic orthoester II-53 (0.037 g, 0.18 mmol)
was dissolved in dichloromethane (2 mL) and BF3'EtzO (2.4 11L, 0.01 mmol) was added
at 0 oC. The crude mixture was concentrated under reduced pressure and purification by
flash chromatography (15% EtOAc/hexane) afforded 0.037 g product II-56 in 100%
yield. 1H NMR (CDC13, 300 MHZ) 5 5.22 (1H, m), 3.98 (1H, q, J = 7.8 Hz), 3.71 (2H,

m), 2.25 (1H, m), 2.04 (3H, s), 1.97 (1H, m), 1.51 (2H, m), 1.30 (6H, m, br), 0.85 (3H,

m); 13C NMR (CDC13, 75 MHZ) 5 170.6, 81.7, 74.6, 65.7, 33.4, 31.9, 28.8, 26.0, 22.5,

 

21.0, 14.0.
31 it
“0 OH OH PP$(SO(Ti/3.1nol): M60 8 )n BF3°Et20 05H11n=18w53M°
CsHttfgéfir/ 0142012 0511,, CH2C|2

Me
(i=3,
(351'111)—\j

n=2, "-58
Preparation of Compound II-57 & II-58: For procedure, please refer to II-38 &

II-56.

“-57 was made in 94% yield. 1H NMR (CDC13, 300 MHZ) 5 5.12 (1H, m), 3.98

(1H, q, J = 7.8 HZ), 3.74 (3H, s), 3.72 (2H, m), 2.27 (1H, m), 2.00 (1H, m), 1.57 (2H, m),

68

 

 

1.26 (6H, m, br), 0.85 (3H, m); 13c NMR (cook, 75 MHz) 6155.5, 81.6, 78.5, 65.6,
54.7, 33.4, 31.8, 28.6, 26.1, 22.5, 13.9.

11-58 was made in 67% yield. ‘H NMR (coca, 300 MHz) 6 4.63 (1H, m), 3.88
(1H, m), 3.74 (3H, s), 3.73 (2H, m), 1.87 (2H, m), 1.71 (2H, m), 1.56 (2H, m), 1.26 (6H,
m, br), 0.85 (3H, m); 13c NMR(CDC13, 75 MHz) 5158.2, 79.9, 79.5, 68.2, 54.6, 31.6,

30.8, 27.8, 25.9, 24.8, 22.4, 13.9.

3.7. Data for Chapter 2.5

X0 K2003 0X0

0

W40“ MeOH/HZO CH
Can n Can n

Preparation of compound II-59 & II-60: For procedure, please refer to 11-6.

XJ
o ‘ o
C5H1 1

"-59

OH

II-59 was made in 94% yield. 1H NMR (CDCl3, 300 MHZ) 5 5.78 (1H, m), 5.04
(2H, dd, J = 12.6, 4.2 Hz), 4.22 (1H, m), 4.07 (1H, m), 3.78 (2H, m), 2.38 (1H, br), 2.32
(2H, d, J = 6.9 Hz), 1.73 (2H, m), 1.50 (2H, m), 1.35 (3H, s), 1.26 (6H, m, br), 0.84 (3H,
m); 13C NMR (CDCl3, 75 MHz) 5 133.6, 118.0, 108.7, 78.2, 77.5, 61.2, 43.9, 32.0, 31.8.

31.6, 29.6, 26.2, 25.9, 22.6, 14.0.

69

II-60 was made in 99% yield. 1H NMR (CDC13, 300 MHz) 6 5.77 (1H, m), 5.04
(2H, dd, J = 11.4, 4.2 Hz), 4.04 (2H, m), 3.64 (2H, q, J = 6.0 Hz), 2.32 (2H, d, J = 7.2
Hz), 2.15 (1H, br), 1.68 (2H, m), 1.50 (4H, m), 1.34 (3H, s), 1.27 (6H, m, br), 0.85 (3H,
m); 13c NMR (CDCl,, 75 MHz) 6 133.9, 117.9, 108.4, 78.4, 78.3, 62.7, 44.0, 31.8, 29.9,
29.8, 26.8, 26.4, 25.9, 22.5, 14.0.

(J ,_// J
X poo >9 (PhisPCHsB; 05;“

OO O

O
OH CH c. We NaHMDS W
CSHH 2 2 C5H11 n/ 05““ n/

Preparation of compound II-61 & “-62: For procedure of oxidation of alcohol

 

 

using PDC and Witti g olefination, please refer to 11-44 and 11-17.

J

C5"111
"-51

/

II-61 was made in 35% yield for two steps. 1H NMR (CDC13, 300 MHZ) 5 5.83
(2H, m), 5.06 (4H, m), 4.22 (1H, m), 4.08 (1H, m), 2.33 (2H, d, J = 7.2 Hz), 2.19 (2H, m),
1.48 (2H, m), 1.35 (3H, s), 1.26 (6H, m, br), 0.84 (3H, m); 13C NMR (CDCl3, 75 MHZ)
5134.8, 133.8, 117.8, 116.9, 108.4, 78.2, 77.6, 44.0, 34.6, 31.8, 29.6, 26.4, 25.9, 22.5,

14.0.

_//

OO

C5H)—‘K_/=

11
"-62

II-62 was made in 71% yield for two steps. 1H NMR (CDCl3, 300 MHZ) 5 5.77
(2H, m), 5.00 (4H, dd, m), 4.02 (2H, m), 2.32 (2H, d, J = 7.2 Hz), 2.22 (1H, m), 2.05 (1H,

m), 1.47 (4H, m), 1.34 (3H, s), 1.28 (6H, m, br), 0.84 (3H, m); 13C NMR (CDC13, 75

7O

MHZ) 5 138.2, 134.0, 117.7, 114.8, 108.3, 78.3, 77.6, 44.1, 31.9, 30.3, 29.8, 29.2, 26.4,

25.9, 22.5, 14.0.

J J J

o PhaPCHCOOEt X 0
OH 0 THF, refl , W
CsHfi—Sifi/ CHZC'Z CsHm ux C5H11 n OEt

Preparation of compound II-63 & II-64: For procedure of oxidation of alcohol

 

 

using PDC, please refer to II-44.

General procedure of HWE reaction: The crude aldehyde was dissolved in THF
(0.1 M) and triphenylphosphine ylide (1.5 equiv) was added. The suspension was then
heated to reflux for 3 h. After quenched with saturate NHaCl (10 ml), the reaction was
extracted with ether (3 x) and washed with brine (1 x) and dried over Na2804_ Flash
chromatography (5 % EtOAc/hex, 5% TBA) afforded desired product.

J

3M

"-63

II-63 was made in 65% yield for two steps. 1H NMR (CDCl3, 300 MHZ)
5 6.95 (1H, dt, J = 15.6, 6.9 Hz), 5.87 (1H, d, J = 15.6 Hz), 5.77 (1H, m), 5.05 (2H, dd, J
= 13.8, 1.5 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.11 (2H, m), 2.33 (2H, d, J = 7.5 Hz), 2.30 (2H,
m), 1.49 (2H, m), 1.35(3H, s), 1.30 (6H, m, br), 1.26 (3H, t, J = 7.2 Hz), 0.87 (3H, m);
13C NMR (CDC13, 75 MHZ) 5 166.3, 145.1, 133.7, 123.4, 118.0, 108.8, 78.2, 74.6, 60.2,

43.9, 33.4, 31.8, 29.6, 26.3, 26.0, 22.5, 14.2, 14.0.

xJ
Wcooa
CsH1 1
"-64

71

II-64 was made in 71% yield for two steps. 1H NMR (CDC13, 300 MHZ)
5 6.95 (1H, p, J = 7.8 Hz), 5.81 (1H, d, J = 15.6 HZ), 5.76 (1H, m), 5.05 (2H, dd, J =
13.2, 4.8 HZ), 4.15 (2H, q, J = 7.2 Hz), 4.01 (2H, m), 2.33 (2H, d, J = 6.9 HZ), 2.30 (1H,
m), 1.61 (1H, m), 1.46 (4H, m), 1.32 (3H, s), 1.27 (9H, m, br), 0.87 (3H, m); 13C NMR
(CDCl3, 75 MHz) 5 166.5, 148.3, 133.8, 121.7, 117.8, 108.4, 78.2, 77.3, 60.1, 44.0, 31.8,

29.6, 28.8, 28.5, 26.4, 26.0, 22.5, 14.2, 14.0.

General procedure for RCM on model substrates: Bis-alkene (II-61, II-62, II-
63 & II-64) was dissolved in toluene (0.004 M) and four portions of A (80 mol% in total)
or B (20 mol% in total) was added every 45 min and the mixture was refluxed. The
reaction was monitored by TLC. The reaction mixture was filtered through a thin silica

pad and the solvent was evaporated to afford crude product.

X‘\

0

C5"'11
"-55

II-65 was obtained as a mixture of more than two compounds which can not be
purified even after hydrogenation of the double bond. Both 13C NMR and GC-MS
suggested the existence of cyclized product. Characteristic '3 C NMR (CDCl3, 125 MHZ)

5 128.7, 128.4, 126.5, 126.1, 110.1, 81.3, 79.6; GC-MS m/z 210 M, 139 [M-C5H11]+.

72

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