1.355..“- .. u a r .....,..,v.r .. i)! .K .p‘..&1_ . (:3. . 1 . .
. o ‘ ‘ o W. . L ‘ . . .A
.. l ‘ . ‘ . . 1 . L. 4.
‘ \ . w y . i x. ‘ ¢ ‘ ‘ . x
v . v v ‘ » . . . . . . . . .
‘ . . y . I y .4 . o
. . , . . . . “A
. . . ‘ w .v | .. . 1...
. . . . . . . . . y . . . N
. . . ‘ . ‘ . ‘ . .
v , v V ‘ . . . ‘ ‘ .
v ‘ . , . . . ..
V . . w ‘ . . 1‘
\ . ‘ l v
V , t u A l ‘ ‘
v v p ‘ . . . , ‘
. ‘ ‘ . u . y . , . _ . . .
1 ‘ ‘ . . ‘
V . . ‘ . ‘ .. ‘ .
H‘ » m . .
A ‘ W V . . ‘7 .
‘ ‘ .9 C. | ‘. . . > . n u ‘ v .-
.. y . . . H . n.
. ‘ A . w ‘ I
1 . I .
. u ‘ ‘... I. I u , .. y. . . .
. ‘ H. n:.... .ynhn..........,. . 1 . ‘ .. ‘ . . . .. . .u
. . 2b.... ...... ‘ . . . .. , ‘ . .. ,.w x y A I
‘ ~. .X.l‘~os.1un‘uv..w , .. . .. ‘ ‘n . ‘ v . . . n‘ I
y . . ‘ .. .vh..uvvu. CHM...‘ 1:31 . . _ x .
v . ~ , u. y .!|1 “y» IVvI. .nV Qv ‘
up . .v x ‘ ‘ ‘ ‘ . .

 

 

 

 

‘\.y
I i
I gigs-cm n T“? ”'1' I
(fs;._,.«',- .w i

4
a I0 :' u , l
1 rm - u
4“qu arr. ' . '«r— 1
I
.. I
TY‘Yfl I I
4 L , .
I ~"’ b_J A _ l 3” E
\ :3!

 

This is to certify that the
dissertation ent‘tled
mu I
A NOVEL ANNULATION BASED ON SEQUENTIAL
PERICYCLIC REACTIONS

PART II
APPROACHES TO THE SYNTHESIS OF LANOSTEROL

presented by

WILLIAM DANIEL MUNSLOW

has been accepted towards fulfillment
of the requirements for

Ph . D . degree in ChaTliStIy

, - Major professor

Date December 11, 1981

 

MS U is an Affirmative Action/Equal Opportunity Institution 0- 12771

 

 

 

RETURNING MATERIALS:
bV1531_] Place in book drop to
LIBRARJES remove this checkout from

gagggggggnL your record. FINES will
be charged if book is

 

 

returned after the date
stamped below.

 

 

 

 

 

 

PART I

A NOVEL ANNULATION BASED ON SEQUENTIAL
PERICYCLIC REACTIONS

PART II
APPROACHES TO THE SYNTHESIS OF LANOSTEROL

By

William Daniel Munslow

A DISSERTATION

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1981

ABSTRACT

PART I

A NOVEL ANNULATION BASED ON SEQUENTIAL

PERICYCLIC REACTIONS

PART II

APPROACHES TO THE SYNTHESIS OF LANOSTEROL

By

William Daniel Munslow

"Tandem rearrangement" describes a molecular rear-
rangement of two or more well-known rearrangements occurring
in a sequential fashion. For such a transformation to occur,
the molecular structure must be favorable for an initial
rearrangement, the product from which is susceptible to a
subsequent rearrangement. Part I of this dissertation des-
cribes the synthesis of compound éé and its thermolysis
to @Q via

 

William Daniel Munslow

o O O
U / A O6 .‘
/ if
59
N

sequential pericyclic reactions. Part I also describes the
reduction of dienone QQ to its corresponding conjugated
enolate, and alkylation of this enolate to the angularly
methylated product §2°

Part II of this dissertation describes efforts directed

toward converting compound 1,

   

17
“J

a Diels-Alder adduct, into the lanastone skeleton, compound

li-

For those who care most.

11

ACKNOWLEDGMENTS

I wish to extend my appreciation and gratitude to
Professor William H. Reusch who prOposed and oversaw this
investigation. I would also like to acknowledge the sound
technical advice offered by Dr. J. Tou, J. Gibson, J.
Dickenson, J. Christensen, B. Chenera, and L. Kolaczkowski.

A special thanks to Mr. Ernst Oliver for his assistance

in obtaining mass spectra and an ample supply of Creamora.

iii

TABLE OF CONTENTS

Chapter

LIST OF TABLES. . . . . . .
PART I

INTRODUCTION.

RESULTS AND DISCUSSION. . . . . .
EXPERIMENTAL. . . . .
General . . . . .
Preparation of Enol Ether Qé°
Preparation of Triene 5%.
Preparation of Dienone $8

Pyrolysis of Triene “6 at 290°
to 305°C. . . .

Preparation of Silyl Enol Ether 2Q

Direct Methylation of Enolate
Anion m2. . . . .

Catalytic Reduction of Compound $2.
REFERENCES.
PART II
INTRODUCTION.
RESULTS AND DISCUSSION.
EXPERIMENTAL.
General

Preparation of £9

iv

Page

vi

16
33
33
3A
35
37

37
38

39
A0
Al

60
67
85
85
86

 

Chapter

Preparation
Preparation
Preparation
Preparation
Preparation
Preparation
Preparation
Preparation
Preparation
Preparation

REFERENCES.

of
of
of
of
of
of
of
of
of
of

Page

86
87
88
88
89
89
90
90
91
91
93

 

Table

LIST OF TABLES

Pyrolysis of 36

Attempted Methylations.

vi

Page

20
8A

PART I

INTRODUCTION

Many terpenoid natural products incorporate fused
six-membered rings bearing a gem-dimethyl grouping adjacent
to the ring fusion. These include sesquiterpenes of the
bicyclofarnesol class (for example, drimenol (I)), many
diterpenes (for example, ferrunginol (g) of the abietane
class; mannol (é) of the labdane class; and hibaene (A)
of the beyerane class), and virtually all the triterpenes
having two or more carbocyclic rings (for example, lano-
sterol (é). See Scheme I.

Other features common to these structures are a trans—
fused ring geometry and an angular methyl group at the
bridgehead carbon remote to the gem-dimethyl moiety.

Synthesis of this structural unit has frequently been
accomplished by the alkylation of an appropriate cyclic
enone, as shown by the retrograde analysis in Equation
1. Since alkylation of extended metal enolates normally
occurs a to the carbonyl, treatment of a species such as
I with a strong base, followed by reaction with methyl
iodide will generally introduce the gem-dimethyl moiety.

1 in Equation 2 for the

This procedure is exemplified
octalin IQ. This method of introducing methyl groups is

also quite common in the construction of the A ring of

 

SCheme I

 

 

¢\\

 

 

 

 

tetracyclic triterpenes and will be discussed in more

detail in Part II of this thesis.

 

Q. t o.
0

By appropriate modification in the synthesis of enones

such as 1 it has been possible to prepare precursors of Q

with one of the methyl groups of the gem-dimethyl moiety

already in place.2

With a structure such as IT in hand,
it becomes possible to introduce the second methyl group

concurrently with the trans ring fusion by the reductive

 

Q. :— ‘0
0 k

C)
1"

2i?)

alkylation procedure developed by Stork3 (Equation 3).

The cyclic enones used in these alkylations are most
commonly prepared by an annulation sequence. A great
variety of annulations exist,“ however the Robinson annula-
tion and a modification of it termed the Enol-lactone
annulation have found the greatest application in this
area. Indeed the Robinson annulation is used to prepare
the important bicyclic intermediate known as the Wieland
Miescher ketone (lg) (Equation A).5 This versatile inter-
mediate and its methyl analog II have been used exten-
sively in the field of natural products synthesis. Com-
pound (t8) has been converted to I5 in five steps.6

A second annulation procedure frequently employed for

the construction of thesecyclic enones may be considered

a modification of the Robinson Annulation. This Enol-

lactone-Grignard method (Scheme II) was developed by

. INC
0 \

 

 

 

 

7 to introduce a labeled carbon at the

Turner and FuJimoto
A-position of steroid enones. This method involves the
addition of a Grignard reagent (lg) to a six-membered
enol lactone (lg) which rearranges to the ketol salt I8.
The Grignard reaction stops at this stage, since the
normally reactive carbonyl function is now so sterically
hindered that the Grignard reagent no longer can add to
it. The ketal obtained upon hydrolysis then undergoes a
base catalyzed reverse aldol condensation to the 1,5-

diketone l2, which is the same intermediate product found

in the Robinson annulation, and it then cyclizes to the

enone fig.

The cyclic enones I needed for alkylation have also
been prepared by reduction of an apprOpriate aromatic
precursor. Phenol is only one equivalent of hydrogen
away from cyclohexenone hence the dissolving metal reduc-
tion developed by Birch8 provides the means by which this
latent functionality can be realized. In practice, a

phenolic ether QT (Equation 6) is used as the substrate

for reduction and the immediate product of that reduction

 

 

 

 

is the enol ether gg. Mild hydrolysis of fig affords the
unconjugated enone, while treatment under more strenuous
conditions gives the conjugated isomer. This procedure
has found extensive use in the syntheses of steroids and

tri-cyclic terpenes; however, it is not particularly

well-suited to the construction of the AB ring moiety in.
many of these compounds because of an angular methyl group
at the AB ring Junction. An example in which this scheme
has been used to construct the A ring of a naturally oc-
curring tri-cyclic terpene is the synthesis of rimnene (gé),
which has no angular methyl at the AB ring Juncture. Re-
duction of gg led to £3 and Birch reduction then gave the

enone 36 which was converted to rimnene (3%).9

 

 

 

Since this procedure provides ring fusions in which

angular methyl substituents are necessarily missing, work

has been directed towards correcting this deficiency.

For example, addition of methanol to the enol ether ob—
tained from Birch reduction of estrone-l7 ketal gave the
mixed ketal g1. This readily added dibromocarbene to

afford the cyclopropane £8. The ketones were then re-
ketalized and the halogens removed by treatment with lithium
in liquid ammonia. The ketone obtained upon hydrolysis

£2: underwent ring-opening with B-elimination upon treat-

ment with acid to give androstenedione (éQ).lO

 

 

 

10

A completely different approach directed towards the
synthesis of trans-fused six-membered rings bearing both
a gem-dimethyl grouping adjacent to the ring Juncture and
an angular methyl group is found in polyene cyclizations.ll
Polyene cyclizations have been of interest to workers in
the field of natural products because it is known that the
biogenesis of triterpenes and steroids proceeds by a
cyclization of the open chain polyolefin, squalene.12
In studies directed toward a better understanding of the
chemical and enzymatic processes involved in polyene

1“ have used

cyclizations, both Eschemmoser,13 and Stork
this technique to prepare decalins similar in structure to

compounds prepared in this Thesis (Equation 7).

 

€0,043
\\-—’ a
q

\ , EQ. 7

com cozn.

flfi U
§§Mfl
\

 

 

ll

Polyene cyclizations of appropriate substrates have also
been used to prepare a wide variety of tetracyclic struc-
tures.

Part I of this thesis will describe a novel synthetic
sequence for the preparation of decalins having the sub-
stitution pattern described above. The key reaction in
this scheme may be described as a tandem, pericyclic
thermal rearrangement.

"Tandem rearrangement" describes a molecular rearrange-
ment of two or more well-known rearrangements occurring
in a sequential fashion. For such a transformation to
occur the molecular structure must be favorable for an
initial rearrangement, the product from which is suscep-
tible to a subsequent rearrangement. This requirement
limits the generality of the reaction, since rather
specific structural conditions must be met; hence examples
of these transformation are rare. However, when an ap-
propriate substrate can be designed, tandem rearrangements
are often useful because a great deal of structural re-
organization takes place in one reaction. This technique
therefore provides an efficient synthetic tool.

Of the examples of tandem rearrangements in the litera-
ture perhaps the most extensively studied is the tandem
Claisen-Cope rearrangement, discovered by Alan F. Thomas
and applied by him to the synthesis of long chain alde-

hydes. The utility of this sequence is demonstrated by

12

the synthesis of the natural product B-Sinensal (éé),15
as shown in Scheme III.

In this synthesis compound éé is prepared by ether ex-
change of §l with 33 in the presence of Hg+2. This product
first reacts by a Claisen rearrangement to yield éfi, which
then rearranges by a Cope process to yield B-Sinensal (éé).
It is interesting to note that the overall transformation
from %l + éé takes place in one pot and the net result has
been the introduction of a functionalized isoprene unit
to the starting allyl alcohol gl. Furthermore since it
is possible to reduce the a,B-unsaturated aldehyde that
results from the tandem Claisen-Cope to an a,B-unsaturated
alcohol it is possible to repeat the sequence, which there-
fore provides a means to link iSOprene units.

The utility of these procedures was further demon—
strated by Thomas in the synthesis of a series of furan
ring—containing natural products, as shown in Scheme IV.l6
These transformations illustrate two interesting points:
the additions of more than one isoprene unit as discussed
above, and the use of an allylic alcohol, the 0-0 double
bond of which is part of an aromatic ring. Thiophene and
vinyl ether %3 were also found to undergo the tandem
Claisen-Cope sequence in good yield.16

In Part I of this dissertation I will describe a novel

method for the synthesis of fused six-membered rings bear-

ing a gem-dimethyl grouping adjacent to the ring. The

l3

 

 

CHO

28

Scheme III

1A

 

OH ‘ \ CHO
+ MOE? 4-: \

32
N

 

W _. W“

 

 

perillene
" l43i111C&
CHO
\ \ \ \
4f
neo-torreyal torreyal

Scheme IV

 

15

key reaction in this scheme is a tandem rearrangement of

the triene 36, which upon pyrolysis yields dienone $8.

 

 

Presumably the pyrolysis of %6 first gives 31 via a 1,5
sigmatropic shift of hydrogen, and this is followed by an

electrocyclic ring closure of 31 to 38. I will also discuss

 

the reductive alkylation of ES to the angularly methylated

tran-decalin 32.

RESULTS AND DISCUSSION

The key transformation in this synthetic sequence is
the conversion of triene $6 to the cyclic dienone 38.

(Equation 8).

o 0 °
- / / /
—' o as
/ \

is L 2.7 ’ R95

 

 

It was prOposed that upon pyrolysis, structure §6 would
first undergo a 1,5 sigmatrOpic shift of hydrogen to give
gz, which would then react further by an electrocyclic
ring closure to yield the desired intermediate $8. In-
deed, if triene 36 could be induced to react in this man-
ner then this would constitute the first known example of
a tandem rearrangement involving a 1,5 sigmatropic hydro-
gen shift followed by an electrocyclic ring closure.

In order to investigate the pyrolysis of 36 it was
first necessary to prepare it, and this synthesis is

described in Scheme V. Reaction of dihydrorescorcinol

l6

17

O

‘+ War—KL“
H30
0 0
.3. N

 

 

+0 v4l
(\J EtOH, pTSH .
L. OH
'1 Et 0
e
‘ B O I
-géf QSQD
42
(\1

 

Scheme V

 

18

and allylbromide according to a previously described pro-
cedure17 yielded the allylated diketone 5% in good yield.
It was then necessary to mask one of the carbonyl groups
of the dione and this was accomplished by conversion to
the enol ether 5g. Although this reaction went in high
yield in small scale preparations, conversions were not
as high in large scale reactions and unreacted starting
material was usually recovered. In the conversion of a
ketone to its enol ether an equilibrium is established
between the ketone and alcohol reactants and the enol
ether and water products. In order to favor the products
in reactions in which water is produced, a common pro-
cedure is to use a Dean-Stark trap to remove the water as
it is produced and thereby shift the equilibrium to the
product side. However, this procedure did not work well
in this case because it was necessary to conduct the
reaction in a large excess of ethanol. The water pro-
duced in the conversion of Al + 3% was missable in the
reaction media and the Dean-Stark trap alone was not ef-
fective, In small scale reactions the Dean-Stark trap
was filled with molecular sieve to remove the water as it
was produced. For large scale runs it was more con-
venient to extract the unreacted starting material with
base prior to isolation of the desired enol ether.

The next step in this synthesis was the addition of

iSOpropenyl lithium to the enol ether 3%. Isopropenyl

 

l9

lithium was prepared from the corresponding bromide and
an alloy containing 97% Li and 3% Na. It is interesting
to note that neither alkyl nor alkenyl halides will react
with lithium metal unless a small amount (l-5%) sodium is
present.18 The tertiary alcohol 5% obtained from this
addition usually was not isolated; instead it was shaken
(as an ether solution) with 5% aqueous HCl, which hydrolyzed
the enol ether and dehydrated the alcohol, yielding the
desired triene 36 in excellent yield.

With triene 36 in hand, its pyrolysis was studied,
and the results are summarized in Table 1. Initial ef-
forts involved heating solutions of 36 in solvents of dif-
ferent boiling points. Benzene, toluene, and xylene were
tried and, as indicated in Table 1, complex mixtures re-
sulted. Next sealed tube reactions were investigated.
Both temperature and reaction time were varied but again
only complicated reaction mixtures were obtained. Although
these results were discouraging, there was one redeeming

1H NMR

feature in most of these experiments. In the
spectra of the complex product mixtures frequently there
was a strong singlet at 61.0 ppm. Since this signal was
in the range expected for the gem-dimethyl substituent
or the desired product @8, we continued to search for
appropriate pyrolysis conditions for this transforma-

tion.

As indicated in Table l, the pyrolysis of $6 in a flow

Table 1. Pyrolysis of 36.

2O

 

 

Pyrolysis Conditions

Products

 

Triene in solution
Benzene (8A°C)
Toluene (110°C)
Xylene (138°)

Complex Product Mixtures

 

Sealed tube reactions
180°C
200°C
250°C

Complex product mixtures

 

Flow tube apparatus
Contact time <1 min.
Temperature <265°

Starting material (36)

 

Flow tube apparatus
Contact time <1 min.
Temperature 270<T<280°

 

 

 

Flow tube apparatus
Temperature 320°<T<3A0°

O /
4Q? ++dr

 

 

 

21

apparatus with a short contact time and a temperature
carefully maintained at 270-280°C gave a reasonable yield
(65%)of 88 along with a minor component 88 isolated in 8%
yield. No reaction was observed below 265°C and unchanged
starting material was recovered. If the temperature was
raised above 320°C 88 was not obtained; instead, aromatic
structures 88 and 88 were isolated, along with larger
amounts of decomposition products. The structure assign—
ment for compounds 88, 88, 88, 88, rests on their NMR,
IR, and mass spectra. (See Experimental.) Additionally,
compounds 88, and 88, were identified by matching their
mass spectra to that contained in the computer library
and compound 88 was compared to an authentic sample (A1-
drich). At this point in our work we were pleased with
the 65% yield of dienone 88. We were also intrigued by
the minor product 88 since at first it appears to result
from a 1,3 methyl shift. The Woodward-Hoffman rules19
require that a 1,3 methyl shift must occur in an antara-
facial fashion if it is concerted. In practice this has
proved to be a rare event. The products resulting from
the pyrolysis at 320-380°C also raise interesting mechanism
questions. They are known compounds, but this is not the
best way to make them.

In order to determine the origin of structures 88, 88
and 88’ one can consider the various rearrangement pathways
available to both the starting triene 88 (see Scheme VI) and

the dienone product 88 (see Scheme VII). As stated previously,

23

 

 

 

 

 

 

 

 

 

Scheme VII

28

it was expected that 88 would first react by a 1,5 sigma-
tropic shift of hydrogen to yield 88. (Scheme VI) It

is also possible for a 1,5 shift to yield 88, which differs
from 88 in the geometry about the newly formed double bond.
Since 1,5 hydrogen shifts are equilibrium reactions, we ex-
pected that 88 could rearrange back to 88, and eventually all
the material might end up as 88. We also considered the
possibility that 88 would react further to give 88 by an-
other 1,5 shift of hydrogen, but felt that this would not
present serious problems because both 88 and 88 were ex-
pected to give the same enolate anion upon Li/NH3 reduction
(see below). Other possible reaction paths are also

shown in Scheme VI. A 1,5 vinyl migration in 88 may lead

to the observed minor product 88 via the steps indicated,

and it is also possible to account for the over pyrolysis
products observed by a series of rearrangements start-

ing with 88 and terminating with an elimination of H2
or CH”.

Scheme VII shows some rearrangement pathways that might
be followed by the product of the desired tandem rearrange-
ment (88). Note that it is possible to account for both the
minor product 88, and the over pyrolysis products 88 and 88
by these pathways. In order to gain some insight regarding
the origin of products 88, 88 and 88, two simple experiments
were performed: First the purified dienone 88 was pyrolyzed
at 275°C. It failed to react and thus it is apparent that

compound 88 does not come from further reaction of 88 at

25

275°C, as suggested in Scheme VII. Next, the purified di-
enone 88 was pyrolysed at 320°C. Under these conditions
the aromatic compounds 88, and 88 were obtained, and hence the
pathway to these structures shown in Scheme VII is at least
feasible.

A summary of what is believed to occur upon pyrolysis of
88 at 275°C is given in Scheme VIII. There are two compet-
ing 1,5 sigmatropic rearrangements. A 1,5 shift of hydrogen
followed by electrocyclic ring closure yields the desired
structure 88 while a less favored 1,5 vinyl migration fol-
lowed by a 1,5 shift of hydrogen and then electrocyclic ring
closure gives the minor product 88. The existence of this
minor product is interesting, since sigmatropic vinyl migra-
tions have been known for a relatively short period of time.
Work which supports the suggestion that 1,5-hydrogen shifts
proceed with greater facility than corresponding vinyl shifts
was published by Jones, g£_al. in 1978.20 He was able to
measure the migratory aptitude for a series of substituents
(X) in the reaction shown in Equation 9. The ranking of
migratory aptitudes was CHO>COR>H>CH=CH2>CONH >CO2Ph>CO2CH3

2
>CN>CECH>Alkyl.

26

 

Scheme VIII

28

 

 

 

 

 

L'
'/~H.., 06
/ 4’3
. (093 Si (‘2
(00,55 0 $
‘1) Me Li
w ‘6
50
m

Scheme IX

29

trimethylsilyl chloride, and a good yield of QR was ob-
tained.

With this knowledge in hand the trapping of enolate
£2 with methyl iodide was reinvestigated. Using glyme
as a co—solvent, with careful removal of ammonia after
the reduction, trapping of £2 with methyl iodide yielded
$2 plus two other products. Analysis of the product mix-
ture by GC/MS indicated that the two by-products were
formed by over alkylation of 52. To account for this
the mechanism of dissolving metal reductions must be

21

considered. The first step is an electron transfer from

the metal to

W0 1286 0 Li
/ 2)H@ N

the enone and this is followed by a proton abstraction from
the solvent. In a glyme-ammonia mixture the most acidic
component is the ammonia, hence proton extraction from
ammonia leads to the formation of one equivalent of lithium
amide. Since lithium amide is a sufficiently strong base

to abstract a proton from ketone 32, and since excess
methyl iodide is present, over-alkylation of $2 can occur.
To prevent this from happening, one equivalent of a proton
donor was added to the system. Water was chosen as the

proton donor because the conjugate base, LiOH is not strong

3O

enough to abstract protons alpha to carbonyl groups. When
the reduction-alkylation was repeated, using glyme as the
co-solvent and with one equivalent of water added as a
proton donor, we were able to obtain a good yield (65%)
of 32 as the sole product.

As part of the structure proof of $2 it was necessary
to demonstrate the trans nature of the ring geometry.
This was accomplished in two ways. First, catalytic re-

1

duction of $3 gave l5 (Scheme IX) and the H NMR line-

width of the angular methyl group minus the linewidth of

TMS was determined to be 0.8 Hz. Williamson and Spencer22

1H NMR linewidths of the angular methyl groups

measured the
of a large number of gig and Eggng decalins, and found
that the linewidth relative to TMS for the angular methyl
groups for all the gig compounds was 0.25:0.11 Hz. The
corresponding values for the EEEEE compounds was 0.80:0.2
Hz. Since there is no overlap between the gis values and
the igang values this provides an unambiguous method for
distinguishing gig from EEEEE even when one can only
measure one of the isomers. A second method for assign—
ing the Egans ring geometry of §g is available because i3
is a known compound23 and its 2,“ DNP has been reported
to melt at168-17o°. the 2,u DNP of $3 melts at167-17o°
The stereoselective alkylation of enolate anion 52
giving only the trans ring fusion of ég, is one of the

more interesting aspects of this work. To understand

the preference for this product it is necessary to consider

31

the conformational analysis of enolate 32. From the
principle of axial attack one would expect the EEEQE
product to be formed by alkylation of conformer Q; while
the gi§_ product could result from either 23 or Q}. In-
spection of Q3 leads to the conclusion that it is un-
favorable due to the large t-butyl like substituent oc-
cupying an axial orientation. To accommodate this large
group in an equitorial position, Qg can ring flip to
give SQ. In S; however p-orbital overlap is not main-
tained over the entire conjugated system, and hence éé
is also unfavorable relative to éi. Since conformation
éi maintains good p-orbital overlap and also orients the
large t-butyl like substituent in an equitorial position

it is the most favored conformation for alkylation.

 

 

 

32

 

EXPERIMENTAL

General

Except as indicated, all reactions were conducted under
dry nitrogen or argon, using solvent purified by distilla-
tion from suitable drying agents. Magnetic stirrers were
used for small scale reactions; larger reactions were agi-
tated by paddle stirrers. Organic extracts were always
dried over anhydrous sodium sulfate or anhydrous magnesium
sulfate. The progress of most reactions was followed by
thin layer chromatography and/or gas liquid chromatography.
Visualization of the thin layer chromatograms was effected
by 30% sulfuric acid with subsequent heating.

Analysis by GLPC was conducted with a Varian 1200 gas
chromatograph. Melting points were determined on a Hoover-
Thomas apparatus and are uncorrected. Infrared spectra
were recorded on a Perkin-Elmer 237B grating spectro-
photometer. Proton magnetic resonance spectra were taken
in deuterochloroform solutions with either a Varian T-6O
or a Bruker 250 MHz spectrometer and are calibrated in
parts per million downfield from tetramethylsilane as an
internal standard. Mass spectra were obtained with a Fin-

nigan “000 GC/MS spectrometer.

33

3“

Preparation of Enol Ether fig

 

For small scale preparations the following procedure
was used: 0.5 g (0.003 m) 2-allyldihydroresorcinal was
dissolved in a mixture of 3 mL ethanol and 20 mL benzene
containing about 21 mg p-toluenesulfonic acid. The re-
action flask was fitted with a Dean-Stark trap that had
been filled with molecular sieves. The mixture was then
heated to reflux under nitrogen for 2“ hours, allowed to
cool to room temperature and washed twice with 10% NaOH
saturated in NaCl. The organic layer was then washed with
H20 to neutral pH, then washed with brine and dried (MgSOu).
Removal of the solvent followed by Kugelrohr distillation
of the resulting yellowish liquid gave 0.5 g (85%) of
product.

For large scale preparations the following procedure
was used: 2.“ g (0.013 m) p-toluenesulfonic acid was
dissolved in 1 liter benzene and this mixture was heated
to reflux with removal of water by a Dean-Stark trap.

To this solution was added “0 g (0.26) 2—allyl dihydro-
resorcinol and 360 mL ethanol. The Dean-Stark trap was

replaced with a soxhlet extractor filled with molecular

35

sieves and the whole heated to reflux for 12 hours. The

- mixture was allowed to cool to room temperature and washed
twice with 125 mL 10% NaOH saturated on NaCl. Acidifica-
tion of the combined base washes gave 11 g starting
material. The organic layer was washed with H2O to neutral
pH, brine and dried (MgSOu). Removal of solvent left a
yellowish liquid which was distilled through a six inch
vigreux column. A small for run was collected 120-147/7
mm, and the product 1u0-1u20/7 mm. Yield 17.4 g (37%),

6M% based on recovered starting material.

 

Preparation of Trienefié

For small scale preparations the following procedure
was used: A solution of isopropenyl lithium was prepared
by slowly adding a solution of 2.0 g (0.017 m) isopropenyl
bromide in 30 mL ether to about 0.5 g of a Li/3Z Na alloy
suspended in 30 mL ether and maintained at 0°C under Argon.
The resulting mixture was allowed to come to room tempera-
ture, and was then heated to gentle reflux for a few min—
utes. During this time LiBr precipitated and was allowed
to settle to the bottom of the flask while the unreacted
Li alloy floated on top. The ethereal solution of iso-
propenyl lithium was added dropwise to l g (0.005) of the
enol ether dissolved in #0 mL ether and maintained at -78°C
under argon. The resulting solution was stirred at -78°C

for 1 hour then warmed to room temperature and stirred

36

for about 2 hours. After quenching by addition of
saturated NHuCl, the layers were separated and the or-
ganic portion washed twice with 5% HCl, brine and dried
over MgSOu. Removal of the solvent left a yellowish liquid
which was distilled on the Kugelrohr to yield 0.82 g

(85%).

For large scale preparations the following procedure
was used: A solution of isopropenyl lithium was prepared
by slowly adding a solution of 13.5 g (0.11 m) isopropenyl
bromide in 125 mL dry ether to a suspension of about 2.5 g
Li/3% Na alloy in 200 mL dry ether; maintained at 0°C
under Argon. The resulting mixture was allowed to warm
to room temperature and then heated to gentle reflux for
a few minutes. During this time LiBr precipitated and
settled to the bottom while the unreacted Li/Na alloy
floated on top. The ethereal solution of isoprOpenyl
lithium was transferred to an addition funnel under Argon
and was added dropwise to 13 g (0.072 m) of the enol ether
in 200 mL maintained at -78°. The resulting mixture was
allowed to warm to room temperature, stirred for 2-3
hours, then cooled to 0° and quenched by slow addition of
150 mL saturated NHuCl. The layers were separated and
the ether layer was washed twice with 150 mL 5% H01,

5% NaHCOB, water, brine, and dried over MgSOu. Removal
of solvent gave 12.8 g yellowish liquid which was distilled
through an 8 inch virreux column to yield 9.5 g (75%) of

the trienone product, bp 96-98°/2.75 mm.

 

 

37

Preparation of Dienone3§

 

The trienone “6 (5.9 g, 0.033 m) in 75 mL benzene was
pyrolyzed in a flow tube maintained between 270° and 280°C.
The product (5.7 g) was collected and chromatographed on
“0 g silica gel. Elution with 20% ethylacetate in hexanes
gave two products: compounds 5“, (0.“? g, 8%) and 38 (“.8
g, 65%).

Pyroiysis of Triene “6 at 290° to 305°C

 

 

The trienone 8.7 g (0.0“9 m) in 100 mL benzene was
pyrolysed in a flow tube maintained between 290-305°C.
The product (8.1 g) was collected and passed through a
silica column, eluting with ethyl acetate. About 0.2 g
of tar was removed and 7.1 g of the collected material was
then chromatographed on a High Pressure Liquid Chromato-
graphy apparatus. A silica gel column was used and
upon elution with 8% ethyl acetate in hexanes, “.6 g (65%)
of the material was found in one fraction with 1.0 g (13%)
of the product appearing in three earlier fractions - all
complex mixtures. The remaining product proved to be
polar tarry material. PMR and GC analysis of the main
fraction showed this to be a fairly complex mixture, having
1H NMR peaks corresponding to the cyclized diene together
with significant peaks in the aromatic region. Since

aromatic products could result from further pyrolytic

reactions of the desired cyclic dienone, this premise

38

was tested by heating 3.0 g of the mixture obtained by
HPLC separation in a flow tube at 335°C. The product of
this pyrolysis no longer contained any of the cyclic
dienone (absence of olefinic protons and gem-dimethyl
protons in the NMR). The product of this pyrolysis re-
quired extensive purification. It was first subjected to
a gravity column (silica gel; 20% ethylacetate in hex-
anes) from which three fractions were collected. All
three fractions were mixtures but the third and major
fraction was mainly two compounds. A small portion of
this fraction was purified by preparatory gas chroma-
tography and the two major components identified as “5
and “6 from their spectra, comparison with authentic

samples and computer search and matching.

Preparation of Silyl Enol Ether 50

 

To a solution of Li metal (0.02“ g, 3.“ x 10‘3 mol)

in 50 mL ammonia containing 5 mL dry glyme and maintained
at reflux was added over 15 minutes the dienone (0.20 g,
1.1“ x 10-3 mol) in 10 mL glyme. The resulting mixture
was stirred for 10 minutes then the ammonia was allowed
to evaporate through a bubbler and the mixture pumped on
at 0.2 torr until it was taken to dryness. The enolate
was redissolved in 15 mL fresh glyme, cooled to 0°, and a
quenching solution of trimethylsilylchloride added rapidly.

The quenching solution was prepared as follows: To a

 

39

solution of trimethylsilyl chloride (0.21 g, 1.9 x 10’3
mol) in 5 mL glyme was added triethylamine (0.08 mL,

5.7 x lO'Ll

mol) and the mixture allowed to stand at room
temperature for about 15 minutes until precipitation was
complete. The precipitate was filtered and the fil-
trate used as the quenching solution. After quenching
at 0°, the reaction mixture was allowed to come to room
temperature and poured into a mixture of 50 mL pentane
and 20 mL 5% NaHC03. The organic layer was washed with
brine, dried (MgSOu) and evaporated to give 0.2 g

product.

Direct Methylation of Enolate Anionfig

 

A solution of H20 in glyme was prepared by dissolving

0.10 mL H O in 50.0 mL dry glyme. The cyclic dienone 0.20

2
g (1.1“ x 10-3) was then dissolved in 10 mL of the above
solution and added dropwise to a refluxing solution of
0.02“ g (3.“ x 10'3) Li metal in 50 mL ammonia. Stirring
was continued for a few minutes after the addition was
complete, the ammonia allowed to distill out through a
bubbler, and the mixture pumped on at about 0.2 torr until
it was taken to dryness. The remaining residue was dis-
solved in “0 mL glyme, cooled to 0°C and to it was added

2 mL CH3I in 5 mL glyme. The mixture was allowed to come

to room temperature and stirred for about 1 hour, 3 mL

H20 was added, and the mixture taken almost to dryness on

“O

the evaporator. The remaining residue was dissolved in
CH2C12, washed with H20 brine, dried over MgSOu, and

evaporated to dryness to yield 0.1“ g (6“%) product.

Catalytic Reduction of Compound_39

To 0.050 (2.6 x 10-“

m) of the trimethyl decalone in
200 mL ethanol was added a catalytic amount of 10% Pd/C
and this mixture shaken under “0 psi H2 for seven hours.
The catalyst was filtered and the solvent removed to give

0.0“5 g of product.

REFERENCES

10.

ll.
12.
13.

l“.

150

REFERENCES

W. G. Dauben and A. C. Ashcroft, J. Am. Chem. Soc.,
£2. 3673. (1963).

J. S. Dutcher, J. G. Macmillan, C. H. Heathcock, J.
Org. Chem., “i, 2663 (1976).

G. Stork, P. Rosen, N. Goldman, R. V. Coombs, and J.
Tsuji, J. Am. Chem. Soc., 81, 275 (1965).

M. E. Tung, Tetrahedron, 32, 3 (1976).

S. Ramachandrian and M. S. Newman, Org. Syn., “i,
38 (1961).

D. L. Snitman, Mei-Yuan, D. S. Watt C. L. Edwards,
and P. L. Stotter, J. Org. Chem., 3“, 2838 (1979).

R. B. Turner, J. Am. Chem. Soc., 72, 579 (1950).
G. Fujumoto, Ibid, 73, 1856 (195177 For a review of

enol-lactone-GrignaFd see J. Weill-Raynal, Synthesis

A. J. Birch, J. Chem. Soc., “30 (19““).

R. E. Ireland and L. N. Mander, J. Org. Chem., 32,
689 (1967).

A. J. Birch, J. M. Brown, and G. S. R. Subba Rao,
J. Chem. Soc., 3309 (196“).

W. S. Johnson, Accounts of Chem. Res., i, 1 (1968).
R. B. Clayton, Quart. Rev., i9, 168 (1965).
P. A. Stadler, A. Nechvated, A. J. Frey and A. Eschen-

moser, Helv. Chim. Acta., “9, 1373 (1957). P. A.
Stadler, A. Eschenmoser, H. Schinz and G. Stork, Ibid,

2191 (1957).

G. Stork and A. W. Burgstahler, J. Am. Chem. Soc.,
11. 5068 (1955).

A. F. Thomas, Chem. Comm. 9“7 (1967). A. F. Thomas,
J. Am. Chem. Soc., 9i, 3261 (1969).

“l

l6.

17.

18.

190

20.

21.

22.

23.

“2

A. F. Thomas, Chem. Comm. 1657 (1968). A. F. Thomas,
J. Am. Chem. Soc., 2i, 3281 (1969).

R. Verke, N. Schamp, L. Debuyck n. Dekimpe and m.
Sandoner, Bull. Soc. Chem., 8“ (7), 7“7 (1975).

J. A. Beel, W. G. Koch, G. E. Tomasi, D. E. Hermansen
and P. Fleetwood, J. Org. Chem., 2“, 2036 (1959).

R. B. Woodward and R. Hoffman, The Conservation of
Orbital Symmetry, Verlag Chemie, GmbH, Weinheim/
Bergster, 1971.

D. J. Field, D. W. Jones, C. Kneen, J. Chem. Soc.,;
Perkin I, 1050 (1978).

D. Caine, Organic Reactions, Vol. 23, John Wiley &
Sons, Inc., New York, New York, 1976, p. l.

 

K. L. Williamson T. Howell, and T. A. Spencer, J.
Am. Chem. Soc., _8 (2), 325-““ (1966).

See Reference 6 and F. Sondheimer and D. Elad, J.
Am. Chem. Soc., 12, 55“2 (1057). J. D. Cocker and T.
G. Halsall, J. Chem. Soc., 3“11 (1957).

 

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800

1000

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quI.

1400
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Infrared spectrum of H2

1000

1600

 

IUUU

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

5' ~55 “C1911! 0919: 35 .229 BHSE IVE: 105
“A” 13:03:” 0 783 CH.“ C“. .3 RIC: 17288.
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Infrared spectrum ofI5§.

 

 

 

TRANSMITTANCE 1%)

 

 

 

 

 

2.5 A 3.0 3.5 4.0 "M'CRONS 5.0 5.0 - so
. I 1 1 1 l I | L l l 1 l 1 l l l 1 I l l l 1 l 1 n 4 J n . ,, . 1
100 100
80 so
60 60
40 40
20 20
2000 3500 3000 2500 2000 1500 "
moumcv 104"]
NMR spectrum of 55
5.0 4 5.0 7.0 8.0 M'CRONS 10.0 11.0 12.0 16.0

TRANSMITTANCE(%)

 

1800 1600 1400 1200 1000 800

FREQUENCY (CM '1

Mass Spectrum of 53

53

V

fl

v

V

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. _ , " 1‘ ~' ,, ' , ' ’ _,.
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at .1 y _ .91: ha; :3 no 159

; Mass spectrum of 4R6

1m-

56

1

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r I 1 7 i V j i r 1' 1 1 v v w 1 f v v T I v T 1 v I fi‘v Vlfi J W V v—v‘v I v ifi
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PART II

59

INTRODUCTION

The tetracyclic triterpenes are a group of thirty-

carbon natural products having a common perhydrocyclo-
1,2

60
+00 "

l
N

pentanthrene skeleton l.

Because of their structural resemblance to steroids, the
tetracyclic triterpenes are also called methyl steroids
or lH-alpha analogs of steroids. A number of tetracyclic
triterpenes such as the curcurbitacins have been shown to
have anti-tumor activity and some of their derivatives
are also found to be as physiologically active as
steroids.3
It is known that the tetracyclic triterpenes are
formed in nature by an enzymatic cyclization of squalene
2,3-oxide g.“ In these biosynthesis, enzymes play an
important role in folding the squalene oxide in two dif-

ferent modes: one leads to the lanosterol system via a

chair-boat-chair-boat folding and one to the euphol system

60

'I'l

61

via the corresponding chair-chair-chair-boat conformation.
Steroids are formed by enzymatic demethylation of lanostane

intermediates.

 

Lanosterol Euphol

Other examples of lanostanes and euphanes which

occur in nature are the following:

62

   

Agnostero] Butyrospermo]

“w

HO

Parkeol

The tetracarbocyclic skeleton and stereochemical com-
plexities of these triterpenes poses a considerable
synthetic challange to the organic chemist. In fact, at
the present time, only two distinct approaches have been
successful in achieving the total synthesis of a tetra-
cyclic triterpene. The first, developed by Woodward 23
al., used cholesterol as the starting material for a lano-
sterol synthesis. The other entirely different approach,
pioneered by van Tamelen, uses a biogenetically patterned
polyene cyclization.

5

In Woodward's approach, a key step involved the

introduction of a lh-alpha methyl group onto a lS-keto

63

cholestane derivative é as shown in Equation 1. The en-

tire sequence of reactions for the lanosterol synthesis

required over 25 steps.

 

ml
/
2

III!

 

I flf‘u“ :‘.".c '— ”a. ‘1’.
c

The van Tamelen strategy involved acid catalyzed
cyclization of a suitable polyene monoepoxide. For ex-

ample, acid treatment of a mono-carbocyclic derivative of

squalene oxide h and its 3-epimer led to the total syn-
6

0"”

thesis of Parkeol and Isotirucallol, respectively.

 

 

 

C-3 epimer of Q

 

6U

Similarly, when bicyclic epoxide Q is used, cycliza-
7

tion to a dihydrolanosterol precursor took place.

 

 

Recently, work in our laboratory has been directed
toward the total synthesis of several classes of triter-
penes. Impetus for this goal came from the discovery of
an efficient way to make the bicyclic diketone, trans-
l,6-dimethyl-bicyclo(fl.3.0)nonan-2,7 dione (é).8

 

This diketone incorporates a common skeletal feature found

in all the previously described triterpenes. Thus compound

65

6 could be used as a CD synthon in the synthesis of these
natural products. In order to achieve such a total syn-
thesis two maJor transformations must be accomplished.
The alkyl side chain must be attached to the five membered
ring and rings A and B of the tetracyclic triterpene must
be attached to the six membered ring of 6 in a stereo-
selective manner.
There are three important advantages to using compound
6 as a starting material in tetracyclic triterpene syn-
thesis. First, because of the presence of the lH-alpha
methyl group, some of the tedious methylation steps in
Woodward's synthesis5 will be eliminated. Secondly, stereo-
chemical control during the introduction of the methyl
group at C-lO would allow synthesis of both important fami-
lies of triterpenes. If the alpha configuration is gen-
erated at C-lO, the euphane class results; if the beta
configuration is obtained, then the lanostane ring struc-
ture results. A third advantage of compound 6 is that it
can be prepared enantiomerically pure in either configura-
tion. Synthesis of 6 begins with Wieland-Miescher ketone,
a versatile bicyclic intermediate, which can be prepared
optically active in either enantiomeric form by using
(+) or (-) proline as a condensation catalyst.9
Jacob Tou of this laboratory was able to attach rings
A and B onto 6 by way of an acid-catalyzed Diels-Alder

reaction as shown in Equation 2.10

66

 

 

Although structure Z is tetracyclic, with all the ring-

carbons and angular methyl groups in place, a number of
transformations remain to convert 1 into a lanostane natural
product. For example, the stereochemistry at C-5 and C-9

needs to be changed, the A7’8

double bond should be moved,
the functionality of ring A needs to be altered drastically
and a gem-dimethyl group must be introduced at C-u. Part
II of this thesis describes efforts directed toward these

goals.

RESULTS AND DISCUSSION

Our initial strategy for the conversion of 7 into the
lanostane skeleton is outlined in Scheme I. The first
step is the isomerization of the A7’8 double bond to the
A8’9 position, where it would be tetra-substituted and
presumably thermodynamically favored. If this reaction
were successful the double bond would be in the correct
position for lanosterol and obviously would remove the
unnatural configuration at C-9. Next our plan called for
epimerization at C-5 to yield compound 2 which has the
desired trans AB ring Junction. With these isomerizations
accomplished the functionality of ring A must be manipulated
to convert it to the substitution pattern observed in the
triterpenes. In order to achieve this functional group
manipulation, we anticipated following a scheme developed
by Woodward and applied by him to a decalin system (Scheme
II) which contained an enedione substitution pattern

11 In this manner com-

similar to that of intermediate 2.
pound 2 would be converted to II, which on treatment with
t-butoxide and methyl iodede should give the gem-dimethylat-
ed derivative lg. Lithium/ammonia reduction, followed by
an oxidation would then yield a dione suitable for subse-

quent conversion to lanosterol.

67

 

 

oAc

 

2) CH5I

   

Scheme I

 

69

OH

 

O
m LiAl H4-
045 CH-

 

 

O OH
H300
C. A“ O 3‘
O FY 0
OAc 0”
ZN [A

 

Scheme 11

 

70

Our efforts to convert Diels-Alder adduct 1 into the
lanostane ring system began with attempts to epimerize C-S
and/or move the A7’8 double bond to the tetrasubstituted

A8’9 position. This double bond migration has been ob-

served in both the lanostane and euphane series (Equation
12

3) under the influence of dry HCl gas. We had expected

 

 

 

 

:4 IS
OJ nu

epimerization of Z to proceed easily, because trans-fused
six-membered rings are usually more stable than the cor-
responding cis fused system. Since C-S is alpha to a
carbonyl group in 1, treatment with acid or base should

allow equilibration to the thermodynamically favored epimer.

"I

71

Surprisingly, adduct 1 was found to be resistant to either
C-S epimerization or double bond migration under both acidic

and basic conditions. Jacob Toul3

reported that 1 was
recovered unchanged from treatment with p-TSA/benzene, Dowex
50-8/methanol, sodium bicarbonate/methanol or sodium hy-
droxide/methanol. He showed however that the enolate at

C-5 was formed by isolating enol acetate $6 in good yield.

 

E\l

 

o-Ac

‘6
ru

Additional efforts to isomerize 1 have also proven un-
successful. For example, the work of Irving SE.§l- showed
that dry HCl has effected the isomerization of Is to lg in

12 However, under these conditions

chloroform solution.
Z was recovered unchanged, except for some tarry material
which did not move on a tlc plate. Possibly the HCl re-
acted preferentially with the enedione portion of ring A,
causing slow decomposition rather than double bond iso-
merization. We therefore attempted to protect the ene-

dione functionality through complexation with titanium

tetrachloride prior to treatment with HCl gas. In this

72

experiment no decomposition was observed, hence it appears
that complexation does protect the ring A functions; how-
ever, no isomerization was observed and starting material
was recovered unchanged. Since rhodium trichloride is

l“ the pos-

known to catalyze double bond isomerization
sibility of isomerizing 1 to Q with this reagent was also
studied. Unfortunately, no reaction of any kind could be
effected.

The resistance of Z to epimerization under a variety
of conditions, including some that are known to effect
enolization, can only be interpreted to mean that this
A/B gig compound is more stable than its trans isomer.
This contrasts strikingly with the facile epimerization of
lg to lg accomplished by Jacob Toul3 (Figure 1).

An examination of Drieding molecular models of 1, Q
and lQ and their trans isomers l1, 3 and A2, is helpful in
explaining the difficulty encountered here (Figure 1).

In all cases having a 9-beta hydrogen configuration, the C
ring is forced to assume a twist boat conformation. The

cis-syn configuration of 1 allows a chair-like B ring;

however, the trans-syn configuration of ii would require a

 

half-boat conformation of B, with H-9 and C-19 eclipsed.
Therefore, l1 should be less stable than 1, and the failure
of Z to epimerize is understandable. Both compound lQ and
its C-lO epimer l2 have chair-like conformations of the B

ring; however, the A ring is fused in a diequatorial

73

 

 

 

 

 

EQO
2000

Figure 1

74

fashion in IQ instead of the less stable equatorial-axial
fashion found in lg. This accounts for the successful iso—
merization of lg to lg. A similar conformational analysis
also suggests structure 2 would be more stable than Q.
Therefore, a shift of the A7 double bond to A8 should
facilitate epimerization at C-5 to give compound 2. Since
the A7 double bond proved to be stable under all the condi- E‘
tions studied, this attractive solution to the epimeriza-
tion problem has not yet been realized.

An alternative way to introduce the A8 double bond is

 

by dissolving metal reduction of the corresponding

1']

A7’9(ll) diene. Brewis15 studied the reduction of the
A7’9(11) diene system in several tetracyclic triterpenes
and found both 1,2 and 1,“ addition of hydrogen, leading
to A7 and A8 double bonds in the products. In several
instances only the A8 unsaturated product was formed, and
we hoped this would be the case in our system. Another
reason for introducing a A9<ll> double bond is that this
would remove the 9-beta configuration, which is apparently
responsible for earlier difficulty in the epimerization of

C-5. Hence, we began to look for an efficient way to

introduce the A9(11) double bond (Equation H).

 

E‘J

 

75

Transformations similar to this have been accomplished
in other systems by the action of 8e02, N-Bromosuccinimide
or Hg(OAc)2.l6 We found that reaction of 1 with SeO2
and N-Bromosuccinimide gave intractable mixtures; however,
Hg(OAc)2 gave a mixture of two major components, which
were separable by chromatography. The first fraction to
elute gave a 20% yield of the desired diene £8 and the
second a 50% yield of what appeared to be a mixture
of acetates 3%. Since gl could be treated with p-TSA
and converted to diene 3Q, conditions were worked out where-
by the reaction mixture from the Hg(OAc)2 oxidation was
treated with p-TSA without isolation of 3;. However, the

overall yield of gg from Z was only 30-H0% (Equation 5).

 

 

E‘Q

EQ. 5

 

 

 

 

76

An understanding of how acetate is incorporated into
the substrate was an important first step to improving the
synthesis of 30. In Scheme III diene g0 is formed by loss
of the C-11 proton from the allylic cation fig. However,
intermediate g; or cation 3% may react with acetate anion
to give gl. If this is true, it argues that oxidation
with a mercury II salt having a less nucleophilic counter- r
ion should lead to a higher proportion of diene product.

Indeed when Hg(CF3C02)2 was used as the oxidizing agent,

 

diene g0 was obtained as the sole product in 90% yield. ~
Surprisingly diene 30 also failed to epimerize at i

C-5. That the enol does form was again shown by conversion

of £0 to its enol acetate. Hydrolysis of the enol acetate

back to the starting ketone indicates that here too the AB

 

Na 0A5
Acao , 43ka' Q
20
(L)

 

 

gig Juncture is favored relative to the trans.

In the course of studying the formation of enolacetate
g5 an interesting rearrangement was discovered. When diene
39 was refluxed in acetic anhydride containing excess sodium

acetate (no co-solvent) the aromatic compound gé was

77

 

 

 

 

 

 

Scheme III

 

78

obtained. Apparently the enol acetate is formed first and

this is followed by acylation of the ester like carbonyl.

 

 

Subsequent methyl migration and aromatization then yields
gé. It is not possible to unambiguously determine the
position of the methoxy substituent in ring A from spec-
troscopic or analytical data.

Because of the difficulties encountered in epimeriza-
tion of C-5, we decided to investigate some transformations
of ring A functionality and return to the question of C-5
stereochemistry at a later stage. Therefore the Diels-
Alder adduct 1 and its dehydro derivative g0 were carried
through the sequence of reactions shown in Scheme IV.
Reduction of all the carbonyl groups with diisobutylaluminum
hydride followed by acid catalyzed hydrolysis and dehydra-
tion led to a mixture of epimeric diols gfi or ex. Di-
acetylation followed by reductive removal of acetate gave
a mixture of epimeric acetates gg or £2. At each stage

of this sequence a mixture of at least two components is

 

79

 

 

 

Scheme IV

 

79

 

 

 

 

Scheme IV

80

present because of the hydroxyl epimers in the five mem-i
bered ring. Since this function will eventually be re-
oxidized to a ketone prior to introduction of the side chain,
both epimers are useful in this synthesis and are there-

fore carried along. Although the presence of these epi-
mers shouldn't matter chemically, it makes crystallization
of the product unlikely and at times complicates the spec- F
tral data. In the sequence in Scheme IV for both sub- *
strates, purification was not attempted until after the
zinc reduction. HPLC purification at this stage yields the

indicated products in about 40% overall yield.

 

i
Ii

Having obtained gQ, we felt we had another handle to
control the stereochemistry of C-5. Although DDQ failed
to react with gé, it was possible to introduce a A“ double
bond in 70% yield by oxidation with selenium dioxide. Our
plan at this stage was to introduce the gem-dimethyl moiety
at C-4, and to then isomerize to the transoid diene 3g.
Unfortunately g0 proved unreactive when treated with t-
butoxide and methyl iodide. To confirm this surprising
inertness some work with model compounds was conducted.

In this study steroidal enone g; was gem-dimethylated in
good yield by the classical procedure developed by Wood-
ward.17 The cross-conjugated dienone 35, however, proved
completely unreactive to equivalent reaction conditions.

1,14

The reluctance of a A -3-ketosteroid to methylate has

also been reported in the literature for compound §§.18

81

 

 

o
a? so

nJ f

. T

0 (CH3)5 C OGK@

CH 1'

. §i§
1

I

 

 

OAc

 

 

The reason for this surprising behavior is unknown.

Since the A1 double bond seems to interfere with the

methylation of 39, the A1 double bond of 3p was selec-

tively reduced over Wilkenson's catalyst17

to give

éé. Methylation of gé was then investigated using 35
butoxide/CH3I in Egbutanol and LDA in THF but again no
satisfactory method was found for the introduction of

the gem-dimethyl moiety. A summary of these methylation

82

 

 

zvo Rxn

 

 

No Rxn

 

55
m

attempts is presented in Table 2.

83

 

 

407%an 3 :07?

50
m

 

 

 

8U

Table 2. Attempted Methylations.

 

 

 

Compound Condition Results

 

t-butoxide, CH3I/

t-butanol No RXN

t-butoxide, CH
O :50 DMSO
(u

t-butoxide, CHBI/ Complicated
.. t-butanol mixtures

LDA CH

I/ NO RXN

 

3

3I/THAF

t-butoxide CH I/ No RXN

3
t-butanol

t-butoxide CH I/DMSO Complicated

3

 

mixture
t-butoxide CH3I/THF complicated
mixture
LDA CH I/THF No RXN

3

 

 

 

 

EXPERIMENTAL

General

Except as indicated, all reactions were conducted under
dry nitrogen or argon, using solvent purified by distilla-
tion from suitable drying agents. Magnetic stirrers were
used for small scale reactions; larger reactions were agi-
tated by paddle stirrers. Organic extracts were always
dried over anhydrous sodium sulfate or anhydrous magnesium
sulfate. The progress of most reactions was followed by
thin layer chromatography and/or gas liquid chromatography.
Visualization of the thin layer chromatograms was effected
by 30% sulfuric acid with subsequent heating.

Analysis by GLPC was conducted with a Varian 1200 gas
chromatograph. Melting points were determined on a Hoover-
Thomas apparatus and are uncorrected. Infrared spectra
were recorded on a Perkin-Elmer 237B grating spectrophotom-
eter. Proton magnetic resonance spectra were taken in
deuterochloroform solutions with either a Varian T-60 or
a Bruker 250 MHz spectrometer and are calibrated in parts
per million downfield from tetramethylsilane as an internal
standard. Mass spectra were obtained with a Finnigan U000

GC/MS spectrometer.

85

 

86

 

Preparation of 20

A solution of the tetracyclic adduct(Z) (1.5 g, “.38

-2

x 10 mol) in 250 ml dry THF was stirred at room tempera-

ture under a blanket of nitrogen until the solid completely
dissolved. Mercury trifluoroacetate (u.8 g, 1.1 x 10"2
mol) was then added in one portion and the mixture was
stirred for eleven hours while the progress of the reaction I
was monitored by tlc (silica gel, 50/50 Hexanes/Ethyl-

acetate). The reaction mixture was then evaporated to dry-

ness and chromatographed on a silica column (30% Ethyl-

 

acetate on Hexanes) to remove the mercury salts. The frac-
tions containing the desired product were combined, evap-
orated to dryness and the solid product was crystallized

from ethanol to give 1.3 g (87%) gg mp 191-192.

Preparation of 21

 

The dehydro adduct gg (1 g, 2.9 x 10‘3 mol) was dis-
solved in 100 m1 CH2Cl2 and cooled to 0° under a blanket
of nitrogen. To this was added slowly, via a syringe, 11
m1 of a 1 molar solution of diisobutylaluminum hydride in
hexane. The resulting mixture was stirred at 0° for two
hours, then quenched by slow addition of a saturated sodium
sulfate solution until the evolution of gas ceased. The
cooling bath was removed, and methanol added slowly until

the solution became less viscous. 0n standing this solution

87

deposited a precipitate. The solid was filtered and washed
twice with boiling methanol; and the combined filtrate and_
washings were refiltered, evaporated almost to dryness, re-
dissolved in a mixture of 50 m1 dioxane plus 50 ml 10%
H280“ and held at room temperature for 6-12 hours. The
volume of this mixture was reduced to half by evaporation
and the resulting solution was extracted twice with CH2012.
The combined organic layers were washed with brine, dried
(MgSOu) and evaporated to dryness to give 0.9 g 21 as an
oil. Thin layer chromatography of this product showed the
absence of starting material and two new spots with Rf
lower than that for starting material. (Silica, 50/50

Hexanes/Ethylacetate.)

Preparation of 38

 

D101 21 (0.6, 1.95 x 10.3 mol) was dissolved in 50 ml
pyridine and then treated with 20 ml acetic anhydride. The
resulting mixture was kept at room temperature for 18
hrs. and then evaporated almost to dryness. The residue

was dissolved in CH 012, washed with 10% H280“, sat. NaHCO

2
and brine and then dried (MgSOu). Evaporation gave 0.7 g

3

(90%) 38 as an oil.

 

 

88

Preparation of 29

 

To a solution of the diacetate gg (0.60 g, 1.51 x 10’3

mol) in 25 ml glacial acetic acid was added 0.60 g of

washed Zn dust and two drops of concentrated HCl. This
mixture was heated to reflux for 1.25 hours, allowed to

cool to room temperature, filtered by gravity and evaporated
to dryness. The residue was then chromatographed by HPLC .
(silica, 35% ethylacetate in Hexanes). The main fraction
contained the desired product 29, 0.21 g. The ultraviolet

spectrum of B (Amax = 235, 2N0 nm e = 12,690) is consistent

 

with the enone and diene chromophores designated in the

formula.

Preparation of 25

The dehydro adduct 20 (0.10 g, 2.9 x 10-“ mol) was
dissolved in 10 ml benzene containing 5 ml acetic anhydride
and 0.05 g sodium acetate. This mixture was heated to
reflux for 2“ hours, cooled and then evaporated to dryness.
A solution of the residue in CH2C12 was washed with sat.
NaHCO3, H20 and brine, dried (MgSOu) and evaporated. The
resulting oil solidified upon standing, and crystallization

from acetone/water gave 23, mp 205-207°.

89

 

Preparation of 25

A solution of dehydro adduct 20 (0.10 g, 2.9 x 10-“

mol) in 10 ml acetic anhydride containing sodium acetate

u mol) was heated to reflux for four

(0.05 g, 6.1 x 10-
hours. Most of the acetic anhydride was removed by evapora-
tion at reduced pressure and the residue was dissolved in
CH2C12, filtered and evaporated to dryness. The result-

ing dark oil solidified and was crystallized from acetone/

water, to give 0.05 g of an off—white solid, mp 215-217.

Preparation of g@

 

A solution of the Diels-Alder adduct 1 (5.0 g, l.u6

x 10"2

mol) in 500 m1 CH2C12 was cooled to 0°, and main-
tained under nitrogen as 66 m1 of a 1 molar solution of di-
isobutylaluminum hydride in hexane was added dropwise.
During this addition a precipitate formed, which redis-
solved as the addition was completed. The resulting mix-
ture was stirred at 0° for two hours, then quenched by slow
addition of saturated Na2SOu, until the evolution of gas
ceased. The cooling bath was removed and methanol was
added dropwise slowly until the solution became less vis-
cous. On standing at room temperature a precipitate
formed. This solid was filtered and washed twice with
boiling methanol. The filtrate and washings were combined,

refiltered and evaporated almost to dryness. The residue

 

90

was dissolved in a mixture of 250 ml dioxane plus 250 ml
10% H280“ and stirred at room temperature for 6-2“ hours.
The volume of this mixture was reduced to half by evapora-
tion at reduced pressure then extracted twice with CH2Cl2.
The combined organic layers were washed with brine, dried

over MgSOu and evaporated to give “.6 g (100%) of an oil.

Preparation of 37

 

 

Diol 26 (“.7 g, 0.0149 mol) was dissolved in 100 mL dry
pyridine and treated with 75 mL acetic anhydride. The
resulting mixture was kept at room temperature for six
hours, during which time the solution darkened. This mix-
ture was evaporated and the residue was dissolved in CH2Cl2,
washed with 10% H280“ sat. NaHCO3, H20, brine and dried over
MgSOu. Thin layer chromatography (silica, ethylacetate/
hexanes l/l) showed the starting material had been con-
sumed and displayed two new spots of higher Rf. Evaporation

to dryness gave 5.6 g of an oil (95%).

Preparation of2§

 

2 mol) was dissolved in

Diacetate 37, (5 g, 1.25 x 10-
225 mL glacial acetic acid. To this was added 5 g freshly
washed Zn dust, and this mixture was heated to reflux for
one hour, allowed to cool to room temperature, filtered and

evaporated to dryness. The residue was dissolved in a

91

mixture of 50/50 Hexanes/Ethylacetate, and on standing at
room temperature for about one hour deposited a gummy solid.
This solid was filtered and the filtrate evaporated to give
“.1 g of a dark yellow oil, which was chromatographed on
silica (20% ethylacetate in hexanes). Two small fractions
0.17 g and 0.33 g were first collected followed by one

major fraction, 1.5 g, which contained the desired product.

 

Preparation of 30

Enone 28 (1.2 g, 3.5 x 10"3 mol) was dissolved in 50 mL 7

 

dry t-butanol containing 2 drops pyridine and 1.0 g Se02.
This mixture was heated to reflux under N2 for one hour,
cooled to room temperature, diluted with CH2C12 and fil-
tered. The filtrate was evaporated to dryness, dissolved

in 3D% ethylacetate in hexanes and chromatographed on 60 g
silica. The product eluted in an 80 mL portion of the first

300 mL of eluent, to give 0.9 g of the desired product (75%).

Preparation of 36

A 100 mL flask was evacuated and filled with hydrogen
three times and then charged with 0.38 g (1.1 x 10'3 mol)
of the trienone 30, in 50 mL absolute ethanol. To this
solution was added 0.35 g of freshly prepared Wilenson's
catalyst, and the mixture was stirred at room temperature,

under a positive pressure of hydrogen for four hours. The

92

reaction mixture was evaporated to dryness, dissolved in 50/
50 hexane/ethylacetate, and filtered through a short column
of silica, using 50/50 hexanes/ethylacetate as the eluent
solvent. The product was eluted along with some colored
impurities but is reasonably pure. Evaporation of the
solvent gave 0.28 g (74%).

 

'g.‘!.""..‘ . .

REFERENCES

8a.

REFERENCES

A. A. Newman, "Chemistry of Terpenes and Terpenoids",
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G. Ourisson, P. Crabbe, and O. R. Rodig, "Tetracyclic
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N. Applezwig, "Steroid Drugs", Vol. I, McGraw-Hill,
New York, 1962, N. Applezwig, "Steroid Drugs", Vol.
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T. A. Geissman, D. H. G. Crout, "Organic Chemistry of
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19 9.

R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A.

 

1]

Ives, R. B. Kelley, J. Am. Chem. Soc., 16, 2852 (195“).

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9

10.

11.

l2.

l3.
1“.

15.

16.

17.

18.

19.

9“

J. S. Tou and W. H. Reusch, J. Org. Chem., 99, 5012
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R. B. Woodward, F. Sondheimer, D. Taub, K. Heusler and
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(1968) .

S. Brewis, T. G. Halsall, and G. C. Sayer, J. Chem.
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L. J. Bellamy and C. Doree, J. Chem. Soc., 176 (19“1).
J. F. Cavalla and J. F. McGhie, J. Chem. Soc., 7““,

83“ (1951).

C. Doree, J. F. McGlie and F. Kurzer, J. Chem. Soc.,
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W. V. Ruyle, T. A. Jacob, J. M. Chemerda, E. M. Cham-
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R. B. Woodward, A. A. Patchett, D. H. R. Barton, D.
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W. J. Adams, K. D. Patel, V. Petrow, I. A. Stuart-
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Carl Djerassi and J. Gutzwiller, J. Am. Chem. Soc.,

 

 

 

 

95

 

 

 

 

 

1 :
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