Synthesis of (23R)- and (23S)-23H-isocalysterols, marine sterols with a cyclopropene moiety in the side chain

Article abstract of DOI:10.1002/(sici)1099-0690(200003)2000:6<1027::aid-ejoc1027>3.0.co;2-e

A synthesis of (23R)- and (23S)-23H-calysterols 2a and 2b from pregnanoic ester 10 is reported. Alkylation of 10 with dibromide 19b, followed by reduction of the carboethyloxy group to a methyl group, afforded (Z)-vinylic bromide 22. Dibromocyclopropanati

Full text of DOI:10.1002/(sici)1099-0690(200003)2000:6<1027::aid-ejoc1027>3.0.co;2-e

FULL PAPER
Synthesis of (23R)- and (23S)-23H-Isocalysterols, Marine Sterols with a
Cyclopropene Moiety in the Side Chain
Alicja Kurek-Tyrlik,[a] Kazimierz Minksztym,[a] and Jerzy Wicha*[a]
Keywords: Sterols / Cyclopropene / Vinylic bromides / Vinylsilanes / Dibromocyclopropanation
A synthesis of (23R)- and (23S)-23H-calysterols 2a and 2b
bromocyclopropane derivatives 15c and 15d. The corres-
from pregnanoic ester 10 is reported. Alkylation of 10 with ponding 3-hydroxy-5-ene 17c was transformed into 2a via 25
dibromide 19b, followed by reduction of the carboethyloxy
group to a methyl group, afforded (Z)-vinylic bromide 22. Di-
bromocyclopropanation of 22 yielded the diastereomeric tri-
and a cyclopropenyllithium intermediate. An alternative syn-
thetic route involving vinylsilane 13 and (E)-vinylic bromide
14 has also been examined.
Introduction
For a study of calysterol synthesis, we have chosen 23H-
isocalysterols 2 since both epimers of this compound dif-
Many marine natural products[1,2] show structural fea- fering in the configuration at the stereogenic center in the
tures rarely occurring in those of terrain origin, posing new cyclopropane ring (C-23) are known. Difficulties encoun-
questions regarding their biosynthesis, structure–biological tered in the unsuccessful attempts to synthesize calysterols
activity relationships, and synthesis. Calysterols are unusual have stemmed mainly from the high reactivity of the cyclo-
sterols in that they have cyclopropene moieties incorporated propene system.[17–19] For this reason, we planned to intro-
in their structures. The first compound of this group, calys- duce the double bond into a preformed cyclopropane inter-
terol 1 [(28R), Figure 1 ], isolated from the Mediterranean mediate in the final stages of the synthesis. Our retrosyn-
sponge Calyx niceaensis, was reported[3] in 1975. It has thetic analysis is illustrated in Scheme 1. It was envisaged
since been shown that certain other sponges contain calys- that calysterols could be generated by methylation of the
terol along with isomers differing in the position of the lithiocyclopropenyl derivative i, which, in turn, could be ob-
double bond in the cyclopropene ring (2 and 3) as well as tained from the gem-dihalo intermediate iii, where X ϭ hal-
the respective 5,6-dihydro derivatives.[4–6] Two diastereom- ogen and Y ϭ trimethylsilyl group or halogen. The latter
eric 23H-isocalysterols have been identified, 2a (23R) isol- represent the products of dihalocyclopropanation of olefin
ated from Calyx niceaensis[6] and 2b (23S)[7] obtained from iv, where Y ϭ trimethylsilyl group or halogen. It was an-
the Caribbean sponge Calyx podatypa. Cyclopropene deriv- ticipated that iv could be prepared stereoselectively by al-
atives are scarce in Nature; as far as we are aware, the only kylation of the easily accessible pregnanoic ester v using
reported examples are calysterols, sterculic acid and few an allylic bromide bearing an appropriate substituent Y vi.
other fatty acids,[8,9] the antibiotic penitricin,[10] and two Alternatively, a precursor with the methyl group at the
sesquiterpenes.[11]
cyclopropane ring ii, where X ϭ halogen or other leaving
Figure 1. Structures of isomeric calysterols isolated from sponges Calyx niceaensis and Calyx podatypa
Studies by Djerassi and co-workers on marine sterols group and Y ϭ halogen or trimethylsilyl group, was consid-
have led to the elucidation of the biosynthetic pathways ered. It was assumed that the intermediate ii could be ob-
leading to calysterols[12,13] and have contributed a great deal tained from iii by methylation. Some model experiments
to the understanding of their chemical and spectroscopic verified important points of this plan and also indicated
properties.[14] An account of the efforts made towards con- that an i-steroid system (6β-methoxy-3α,5-cyclo-) could be
structing a cyclopropene-containing sterol side-chain has used for temporary protection of the latent C-3 hydroxy
been published,[15] but none of the calysterols have hitherto group and the C-5,C-6 double bond in isocalysterol.[20]
been synthesized.[16]
In a first series of experiments, we set out to synthesize
a dibromo-trimethylsilyl intermediate corresponding to iii,
where Y ϭ SiMe3 and X ϭ Br (Scheme 1). Its methyl-
[a]
Institute of Organic Chemistry, Polish Academy of Sciences,
ul. Kasprzaka 44, PL-01-224 Warsaw, Poland
Eur. J. Org. Chem. 2000, 1027Ϫ1036
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0306Ϫ1027 $ 17.50ϩ.50/0
1027

A. Kurek-Tyrlik, K. Minksztym, J. Wicha
FULL PAPER
Scheme 1. Retrosynthetic analysis of compounds 2
Scheme 2. Synthesis of the side chain building block 9
ation[21–23] was to be followed by halodesilylation, which cholestane carbon skeleton, which was transformed into
appeared to be the most promising method for generating the corresponding C-21 methyl derivative 13 in the stand-
the double bond.[24,25] Accordingly, 4-methylpent-2-yn-1-ol ard manner via alcohol 12a and tosylate 12b. Vinylsilane
4[26,27] (Scheme 2) was treated with Red-Al and then with 13 was envisaged as the key intermediate for the cyclopro-
iodine[28] to yield vinylic iodide 5a. After protecting the hy- panation reaction. However, all our attempts to carry
droxy group as a trityl derivative to give 5b, this was treated out its reaction with bromoform under the phase-transfer
with two molar equivalents of tert-butyllithium in order to conditions[33,34] were unsuccessful. Similarly, 13 resisted
effect iodine–lithium exchange, and then with an excess of reaction with phenyl(tribromomethyl)mercury.[35] The syn-
trimethylsilyl chloride. No silylation product could be de- thesis of steroids with cyclopropane-bearing side-chains by
tected. However, when the alcohol 5a was first transformed dichloro-[36,37] or dibromocarbene[12,38] addition to olefins
into the trimethylsilyl ether 6 and the latter was treated with under phase-transfer conditions has been widely studied.
tert-butyllithium (2.1 molar equivalents), a 1,4-shift of the It has been shown that trisubstituted alkenes afford the
silyl group proceeded smoothly[29] providing vinylsilane 7 in corresponding dihalocyclopropanes in good yields. On the
59% yield along with ca. 5% of the‘‘retro-Brook’’ product other hand, 4-methyl-1-trimethylsilylcyclohex-1-ene has
8[30] and some desilylated product [(E)-4-methylpent-2-en- been found to react readily with dichlorocarbene[39] and
1-ol]. Alcohol 7 was transformed into bromide 9 using our own model experiments concerning the addition of
phosphorus tribromide.
dibromocarbene to some vinylsilanes were encouraging.[20]
Alkylation of ester 10[31,32] (Scheme 3) with bromide The lack of reactivity of compound 13 suggests that the
9 afforded virtually stereoselectively product 11 with a combined steric effect of the trimethylsilyl and isopropyl
Scheme 3. Attempted synthesis of calysterols via the vinylsilane derivative 13
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Eur. J. Org. Chem. 2000, 1027Ϫ1036

Synthesis of (23R)- and (23S)-23H-Isocalysterols
FULL PAPER
Scheme 4. Synthesis of calysterols via the vinyl bromide derivative 14
groups prevents the reagent from gaining access to the
double bond.
From some side products formed in the dibromocyclo-
propanation reaction, a fraction consisting mainly of one
compound was isolated by column chromatography (ca.
10% yield). On the basis of its MS data (5 bromine atoms)
and its 1H-NMR spectrum (which lacked a 6-H signal), this
compound was assigned the structure 16, resulting from a
carbene insertion into the C(6)–H bond.
The above experiments prompted a revision of our initial
choice of the Y group in the key intermediates iii and iv
(Scheme 1). We turned our attention to the intermediates
where Y ϭ Br, in the expectation that the less hindered
vinylic bromide iv, Y ϭ Br, would be better suited for the
cyclopropanation reaction. In an initial examination of the
Transformation of the tribromocyclopropanes 15 into the
modified scheme, (Z)-vinylsilane 13 was treated with brom- corresponding methylcyclopropene derivative was carried
ine in carbon tetrachloride solution and then the crude di- out using the method developed by Baird and co-
bromo derivative was reacted with tetrabutylammonium workers.[47,48] Thus, 15a and 15b were treated with an excess
fluoride. (E)-Vinylic bromide 14 was obtained stereospecif- of methyllithium in diethyl ether at –70 °C. The reaction
ically in 80% yield (inversion of configuration). The (23E)- mixture was allowed to warm to room temperature so as to
configuration was assigned to this product by direct com- generate
the
intermediate
cyclopropenyl
anion
parison with the (Z)-isomer (22) obtained by a stereochem- (corresponding to i, Scheme 1), which was then quenched
ically unambiguous route (vide infra). The stereoselectivity with methyl iodide. Two diastereomeric calysterol derivat-
of the bromodesilylation reaction of the sterically congested ives 18a and 18b were obtained in 44% overall yield. The
vinylsilane 13 is noteworthy. It has been reported that silyl- structures of these products were confirmed by their high-
1
styrenes[40,41] and some sterically hindered β,β-disubstituted resolution MS data and their H-NMR spectra, in particu-
vinylsilanes[42,43] afford the corresponding vinylic halides lar by the presence in the latter of two doublets at δ ϭ 1.99
with retention of the double-bond configuration. Only un- and 2.01, J ϭ 1.6 Hz. These chemical shifts and coupling
hindered vinylsilanes tend to react with inversion of config- constant are in good agreement with the signals of cyclo-
uration.[44]
propene methyl group protons reported for calysterols.
Having completed the construction of the cyclopropene-
in bearing side-chain, we attempted to hydrolyse the i-steroid
Vinylic bromide 14 was subjected to dibromocyclopro-
panation by the method of Ma¸kosza and Fedorynski
[33]
´
a small scale reaction in which magnetic stirring was sup- grouping in 18a–b. Compounds 18a–b were heated at 93–
plemented by sonication[45] (ultrasonic cleaning tank, 95 °C in aqueous dioxane containing some TsOH. It was
140 W). The reaction proceeded relatively rapidly (ca. 2 h) gratifying to find that the product consisted of a mixture
to afford an inseparable mixture of two dibromocyclopro- of calysterols, which could be separated by HPLC using a
panes in a ratio of ca. 1:1, to which structures 15a and 15b reversed-phase analytical column. Pure compounds 2a and
1
[(23R,24R) and (23S,24S), respectively] (Scheme 4) were as- 2b were identified by their H- and 13C-NMR spectra as
signed. The respective alcohols 17a and 17b, obtained after well as by MS data and were shown to be identical to the
hydrolysis of the protecting grouping (TsOH/aqueous diox- natural products (Table 1 and 2; see Experimental Section).
ane[46]), were separated (HPLC) and fully identified. Ulti-
The cyclopropene derivatives were found to decompose
mately, all four diastereomeric tribromides corresponding upon storage in a refrigerator for a few days. Decomposi-
to the structure 17 were characterized in the course of this tion products of 18 could be detected by HPLC and by MS
work (vide infra).
analysis; the mass spectrum of an aged sample of 18 fea-
Eur. J. Org. Chem. 2000, 1027Ϫ1036
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A. Kurek-Tyrlik, K. Minksztym, J. Wicha
FULL PAPER
1
Table 1. H-NMR data (500 MHz) of synthetic 23H-isocalysterols 2a and 2b, and reported[7] data (400 MHz) for the natural products
H
2a (23R)
2b (23S)
recorded
reported
∆δ
recorded
reported
∆δ
18
21
19
27
26
29
25
3
0.694 (s)
0.689 (s)
0.005
0.005
0.005
0.004
0.004
0.003
0.006
0.687 (s)
0.681 (s)
0.006
0.007
0.006
0.006
0.005
0.004
0.006
1.009 (d, 6.2)
1.012 (s)
1.004 (d, 6.5)
1.007 (s)
1.012 (d, 6.5)
1.012 (s)
1.005 (d, 6.5)
1.006 (s)
1.102 (d, 7.0)
1.117 (d, 6.9)
1.993 (d, 1.5)
2.660 (sept, q, 6.8, 1.5)
3.470–3.560 (m)
5.320–5.370 (m)
1.098 (d, 6.8)
1.113 (d, 6.7)
1.990 (d, 1.6)
2.654 (sept, q, 6.9, 1.6)
3.521 (m)
1.094 (d, 6.9)
1.119 (d, 6.9)
2.013 (d, 1.5)
2.632 (sept, q, 6.8, 1.5)
3.470–3.570 (m)
5.330–5.370 (m)
1.088 (d, 6.9)
1.114 (d, 6.9)
2.009 (d, 1.6)
2.626 (sept, q, 6.8, 1.6)
3.520 (m)
6
5.349 (m)
5.349 (m)
Scheme 5. Improved synthesis of calysterols 2a and 2b
tured an ion corresponding to [Mϩ ϩ O] as well as ions of sired dibromocyclopropane derivatives 15. The bulk of the
higher mass. Oxidation[49] and dimerization[50,51] are well- latter product was eluted as a mixture of diastereomers
known reactions of cyclopropene derivatives.
(42%). Small amounts of pure 15c (more mobile, 5%) and
Having synthesized isocalysterols from the steroidal 15d (3%) were also collected. Diastereomers 15c and 15d
building block 10 via the vinylsilane 13 and the vinylic could be completely separated by preparative HPLC. An
bromide 14, we then attempted to synthesize these natural (R) configuration at C-23 was subsequently established for
products by a shorter and more efficient synthetic route. the isomer 15d through its transformation to (23S)-23H-
(Z)-Dibromide[52] 19b was prepared from propargyl alcohol isocalysterol 2b. This allowed configurational assignments
4 via bromo alcohol 19a (Scheme 5) in a manner analogous for 15c and 15d of (23S,24R) and (23R,24S), respectively.
to that used for the preparation of iodide 5a. The (Z)-con-
Diastereomer 15d was subjected to the Baird elimina-
figuration of the double bond in 19b follows from the estab- tion–methylation procedure to give i-methyl ether 18b
lished mechanism of hydroalumination–bromination reac- (Scheme 6) in 53% yield. Acid hydrolysis of the protective
tions.[28,53,54] Alkylation of ester 10 with dibromide 19b gave group provided crude (23S)-23H-isocalysterol 2b in 31%
20 in 80% yield. For transforming 20 into 22, DIBAH was yield and purification of this product by HPLC yielded a
used to reduce the ester group, while L-Selectride was used sample identical to that already prepared. In order to min-
for the tosylane reduction. With these reagents, the vinylic imize material losses during i-steroid hydrolysis in cyclopro-
bromide (Z)-22 was obtained (82% overall yield), isomeric pene ring-containing intermediates, it is best carried out at
to the previously prepared compound (E)-14.
the stage of tribromocyclopropane derivatives. Two iso-
Bromoolefin 22 was subjected to dibromocyclopropan- meric 3-hydroxy-tribromocyclopropanes, 17a and 17b, had
ation using Cetrimid (Aldrich) as a phase-transfer catalyst. already been prepared by hydrolysis of the respective i-ster-
Chromatography of the crude product on a silica gel col- oids 15 followed by HPLC separation. Since it was tempting
umn afforded, in order of elution, 3β,24-dibromide 23 (12% to synthesize all four diastereomers of 17, which would con-
yield), the carbene insertion product 24 (13%), and the de- firm the diastereoselectivity of the cyclopropanation reac-
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Eur. J. Org. Chem. 2000, 1027Ϫ1036

Synthesis of (23R)- and (23S)-23H-Isocalysterols
FULL PAPER
an SPD-6A variable-wavelength detector. – Column chromato-
graphy was performed on Merck silica gel 60, 230–400 mesh, deac-
tivated with 0.1% Et3N in hexane. – TLC was performed on alumi-
num-backed sheets, Merck silica 5554. – Anhydrous solvents were
obtained by distillation from benzophenone ketyl (diethyl ether,
THF) or calcium hydride (CH2Cl2, pyridine, toluene). – Air-sensit-
ive reactions were performed in oven- or flame-dried glassware un-
der argon. – Organic extracts were dried with anhydrous Na2SO4
and solvents were evaporated in a rotary evaporator. – Microana-
lyses were performed at our analytical laboratory.
(Z)-3-Iodo-4-methylpent-2-en-1-ol (5a): To a stirred mixture of Red-
Al (29 mL, 98.7 mmol, 3.4  in toluene) and diethyl ether
(40 mL), a solution of alcohol 4[26] (5.7 g, 58.1 mmol) in diethyl
ether (40 mL) was added over a period of 40 min. at –5 °C. The
mixture was set aside at room temp. until the starting material had
been consumed (TLC, hexane/AcOEt, 3:1; ca. 4 h) and was then
cooled to –78 °C, whereupon iodine (36.6 g, 114 mmol) was added.
After 30 min., the mixture was partitioned between diethyl ether
and satd. aq. potassium sodium tartrate solution. The aqueous
layer was extracted with diethyl ether and the combined organic
extracts were washed with satd. aq. Na2S2O7 solution. The solvent
Scheme 6
tion, pure tribromide 15d was treated with TsOH in aque-
ous dioxane to give free alcohol 17d in 96% yield. In an
analogous manner, 15c was transformed into 17c. Compar-
ison of the four isomeric tribromides 17 by HPLC con-
firmed their isomeric purities.
Alcohol 17c was treated with 2-methoxypropene to pro-
vide a temporary protection of the hydroxy group. The de-
was then evaporated and the residue (12.5 g) was distilled (48–50
1
rivative 25 (Scheme 6), without isolation, was treated with °C/0.05–0.1 Torr) to give iodide 5a (7.6 g, 58%). – H NMR: δ ϭ
1.06 (d, J ϭ 6.6 Hz, 6 H, iPr), 1.70 (br. s, 1 H, OH), 2.30 (sept,
J ϭ 6.6 Hz, 1 H, iPr), 4.22 (d, J ϭ 5.7 Hz, 2 H, CH2), 5.9 (t d, J ϭ
5.7, 0.9 Hz, 1 H, CϭCH). – 13C NMR: δ ϭ 23.05 (iPr), 41.37 (iPr),
67.25 (CH2), 121.40 (CI), 131.06.
methyllithium and then with methyl iodide. The crude reac-
tion product was hydrolyzed with methanol in the presence
of pyridine-deactivated[55] Amberlyst-15 to give (23R)-23H-
isocalysterol 2a in 73% yield. A sample purified by prepar-
20
ative HPLC showed [α] ϭ –44.4, in accord with the re-
(Z)-3-Iodo-4-methyl-O-tritylpent-2-en-1-ol (5b): To a solution of
value [α] ϭ –47.3. The melting point of 109– TrCl (3.29 g, 11.8 mmol) in CH2Cl2 (10 mL) containing pyridine
589
[38]
22
ported
589
(1 mL), alcohol 5a (2.68 g, 11.8 mmol) was added at 0 °C. The
resulting mixture was set aside at room temp. for 18 h and then
partitioned between diethyl ether and 0.25  aq. HCl. The organic
phase was washed with satd. aq. sodium hydrogen carbonate solu-
tion and then the solvent was evaporated. The residue was filtered
through SiO2 (50 g; hexane) to give the ether 5b (5.08 g, 92%); m.p.
111 °C determined for the synthetic material (the quantity
was insufficient for recrystallization) was somewhat lower
than that reported for the natural product (115–116 °C).
In the modified synthetic cycle, the diastereoisomeric tri-
bromides 15c and 15d were obtained in 66% yield from pre-
gnanoic ester 10, and calysterol 2a was obtained from 15c
in 68% yield. The overall synthetic sequence from 10 to 2a
involves 9 steps.
1
75–78 °C (hexane). – H NMR: δ ϭ 1.01 (d, J ϭ 6.6 Hz, 6 H) and
2.22 (sept, J ϭ 6.6 Hz, 1 H, iPr), 3.76 (br. d, J ϭ 5.0 Hz, 2 H,
CH2), 5.89 (td, J ϭ 5.0, 0.8 Hz, 1 H, CϭCH), 7.1–7.6 (m, 15 H,
Tr). – 13C NMR: δ ϭ 23.07 and 41.22 (iPr), 69.32 (CH2), 86.97
In conclusion, a simple synthesis of representative calys-
terols 2a and 2b from the readily available steroidal interme- (PhC), 119.09 (CI), 126.99 (Cp), 127.83 (Cm), 128.69 (Co), 129.96
(CϭCH), 143.96 (Cipso). – C25H25OI (468.38): calcd. C 64.11, H
5.38, I 27.10; found C 64.11, H 5.41, I 27.11.
diate 10 has been developed. Some methods for the genera-
tion of the cyclopropane moiety have been evaluated and
adapted to multi-step transformations.
(Z)-4-Methyl-3-trimethylsilylpent-2-en-1-ol (7): To a solution of al-
cohol 5a (4.1 g, 18.1 mmol) in CH2Cl2 (5 mL), HMDS (6.1 mL,
29.6 mmol) was added at 5 °C. The resulting mixture was stirred
for 1 h at room temp., the solvent was then evaporated, and the
residue was distilled. The fraction distilling at 74–75 °C/1.8 Torr
was collected to give trimethylsilyl ether 6 (4.7 g, 87%). After pre-
paring further batches, 6 (5.6 g, 18.9 mmol) was dissolved in THF
(74 mL), the solution was cooled to –78 °C, and then tert-BuLi
(30.5 mL, 1.3  in pentane, 39.7 mmol) was added. The resulting
mixture was stirred for 30 min. at –78 °C, then allowed to warm to
Experimental Section
General: Melting points were determined on a hot-stage apparatus
and are uncorrected. – Optical rotations were measured on a Per-
kin–Elmer model 141 polarimeter using 1 mL capacity cells (5 cm
path length). – NMR spectra were recorded in CDCl3 solutions, 1H
at 200 MHz and 13C at 50 MHz on a Varian Gemini instrument, or
1H at 500 MHz and 13C at 125 MHz on a Bruker AMX. Chemical room temp. and poured into a satd. aq. NH4Cl/ice mixture. The
shifts are reported in δ units. TMS was used as an internal stand-
ard, except with compounds bearing a trimethylsilyl group and
with isocalysterols 2a and 2b, where chloroform was used (CHCl3,
product was extracted with diethyl ether. The combined extracts
were washed with brine and the solvent was evaporated. The res-
idue was chromatographed on SiO2 (80 g; hexane/diethyl ether, 50:1
1H-NMR δ ϭ 7.26; CDCl3, 13C-NMR δ ϭ 77.00). In the 13C-NMR and then 25:1). The major fraction (TLC, hexane/AcOEt, Rf ϭ
spectra, multiplicities of signals were assigned using the DEPT
technique. – IR spectra were recorded on Perkin–Elmer 1640 FT
spectrophotometer. – MS (electron impact, 70 eV) were recorded
0.36) was distilled (94–100 °C/13 Torr) to give alcohol 7 (1.93 g,
59%). – 1H NMR (200 MHz): δ ϭ 0.16 (s, 9 H, Me3Si), 1.00 (d,
J ϭ 6.9 Hz, 6 H, iPr), 1.40 (br. s, 1 H, OH), 2.43 (sept, J ϭ 6.8 Hz,
on an AMD 604 (AMD Intectra GmbH). – HPLC analyses were 1 H, iPr), 4.21 (d, J ϭ 6.9 Hz, 2 H, CH2), 6.14 (td, J ϭ 6.9, 0.9 Hz,
performed using a Shimadzu LC-8A chromatograph equipped with
1 H, CϭCH). – 13C NMR (50 MHz): δ ϭ 0.61 (Me3Si), 23.07 (Me),
Eur. J. Org. Chem. 2000, 1027Ϫ1036
1031

A. Kurek-Tyrlik, K. Minksztym, J. Wicha
32.59 (iPr), 62.33 (CH2), 136.34 (CH), 150.56. – MS: m/z (%) ϭ H), 2.08–2.49 (m, 3 H, 22- and 25-H), 2.77 (t, J ϭ 2.5 Hz, 1 H, 6-
FULL PAPER
173 [MHϩ] (0.1), 157 [Mϩ – Me] (6), 154 [Mϩ – H2O] (8), 139
H), 3.32 (s, 3 H, OCH3), 3.59–3.80 (m, 2 H, 21-H), 6.07 (t, J ϭ
[Mϩ – Me – H2O] (5), 129 [Mϩ – iPr] (6), 82 [MHϩ – H2O – Me3Si] 6.8 Hz, 1 H, 23-H). – C31H54O2Si (486.80): calcd. C 76.48, H 11.18;
(26), 75 [Me2SiOHϩ] (100), 72 [Me3Siϩ] (55), 67 (39). – HRMS: found C 76.23, H 11.23.
C9H20OSi [Mϩ]: calcd 172.12834; found 172.12829.
(23Z)-6β-Methoxy-24-(trimethylsilyl)-3α,5-cyclo-5α-cholest-23-ene
(13): To a solution of 12a (405 mg, 0.833 mmol) in CH2Cl2
(10 mL), Et3N (1.6 mL), TsCl (534 mg, 2.8 mmol), and DMAP
(5 mg) were added. The resulting mixture was set aside for 48 h
and then partitioned between hexane (20 mL) and water (10 mL).
The aqueous layer was extracted with hexane (20 mL) and the com-
bined organic extracts were washed with saturated aq. NaHCO3
solution and water. The solvent was then evaporated to leave the
tosylate 12b (552 mg). – 1H NMR (200 MHz): δ ϭ 0.10 (s, 9 H,
SiCH3), 0.43 (dd, J ϭ 7.9, 4.9 Hz, 1 H, 4α-H), 0.66 (s, 3 H, 18-H),
0.83 and 0.85 (2 d, J ϭ 6.7 Hz, 6 H, 26- and 27-H), 1.00 (s, 3 H,
19-H), 2.43 (s, 3 H, Ts), 2.76 (t, J ϭ 2.6 Hz, 1 H, 6-H), 3.31 (s, 3
H, OCH3), 4.05 (d, J ϭ 3.7 Hz, 2 H, 21-H), 5.71 (t, J ϭ 6.7 Hz, 1
H, 23-H), 7.32 (d, J ϭ 8.5 Hz, 2 H, Ts), 7.78 (d, J ϭ 8.4 Hz, 2 H,
Ts). Crude 12b (528 mg) was dissolved in THF (5 mL) and this
solution was added to a suspension of LiAlH4 (203 mg) in THF
(5 mL). The resulting mixture was heated under reflux for 20 min.,
then cooled, and the excess reagent was decomposed by adding
satd. aq. Na2SO4 solution. The mixture was diluted with hexane
and successively washed with 1  NaOH solution and water. The
solvent was then evaporated and the residue (380 mg) was chroma-
tographed on SiO2 (2 g; hexane) to give the cholestane derivative
(E)-4-Methyl-1-trimethylsilylpent-2-en-1-ol (8): This was obtained
from the less polar fractions (TLC, Rf ϭ 0.47). – 1H NMR
(200 MHz): δ ϭ 0.02 (s, 9 H, Me3Si), 0.98 (d, J ϭ 6.8 Hz, 6 H) and
2.15–2.45 (m, 1 H, iPr), 3.87–3.93 (m, 1 H, CHOH), 5.35–5.62 (m,
2 H, CϭCH). – 13C NMR (50 MHz): δ ϭ –4.22 (Me3Si), 22.75
(iPr), 30.99 (iPr), 68.32 (CHOH), 128.19, 134.77.
(Z)-1-Bromo-4-methyl-3-trimethylsilylbut-2-ene (9): To a stirred
mixture of alcohol 7 (1.06 g, 6.16 mmol), diethyl ether (6 mL), and
pyridine (195 µL), a mixture of PBr3 (250 µL, 2.58 mmol) and di-
ethyl ether (2 mL) was added dropwise at –40 °C. Stirring was con-
tinued at –40 to –30 °C for 45 min. and then a few drops of meth-
anol were added. The mixture was partitioned between diethyl
ether and satd. aq. ammonium sulfate solution. The organic layer
was collected, washed with water, and concentrated. The residue
(1.4 g) was redissolved in pentane and filtered through SiO2 (14 g;
pentane). The crude product (0.82 g) was distilled and the fraction
distilling at 118–126 °C/29 Torr was collected to afford bromide 9
(0.77 g, 53%). – 1H NMR (200 MHz): δ ϭ 0.19 (s, 9 H, SiCH3),
0.98 (d, J ϭ 6.7 Hz, 6 H, iPr), 2.43 (sept d, J ϭ 6.7, 0.9 Hz, 2 H,
iPr), 4.08 (d, J ϭ 8.5 Hz, 2 H, CH2Br), 6.18 (td, J ϭ 8.5, 1.1 Hz,
1 H, CϭCH).
1
13 (308 mg, 82%). – IR (film): ν˜ ϭ 1610 cm–1 (CϭC). – H NMR:
δ ϭ 0.13 (s, 9 H, SiCH3), 0.74 (s, 3 H, 18-H) 0.89 (d, J ϭ 6.4 Hz,
3 H, 21-H), 0.98 (d, J ϭ 6.7 Hz, 6 H, 26- and 27-H), 1.03 (s, 3 H,
19-H), 2.77 (t, J ϭ 2.6 Hz, 1 H, 6-H), 3.32 (s, 3 H, OCH3), 5.93
(ddd, J ϭ 8.3, 6.2, 0.5 Hz, 1 H, 23-H). – MS: m/z (%) ϭ 470 (10),
455 (12), 438 (10), 415 (25), 283 (58), 253 (100), 73 (28). –
C31H54OSi: calcd. 470.39439; found 470.39442 (MS).
Ethyl (23Z)-6β-Methoxy-24-(trimethylsilyl)-3α,5-cyclo-5α-cholest-
23-en-21-oate (11): To a stirred solution of LDA [prepared from
diisopropylamine (300 µL, 2.14 mmol) and n-BuLi (1.8  in hex-
ane, 2.01 mmol) in THF (2.5 mL)], a solution of ester 10[31]
(657 mg, 1.76 mmol) in THF (4 mL) was added over a period of
10 min. at –72 °C. The resulting mixture was stirred for 1 h at –72
°C and then the temp. was gradually allowed to rise to –35 °C,
whereupon bromide 9 (358 mg, 1.52 mmol) was added. The mix-
ture was stirred for 2 h and was then allowed to warm to 0 °C over
ca. 30 min. The reaction was then quenched by the addition of
satd. aq. ammonium sulfate solution and the mixture was parti-
tioned between hexane and water. The organic layer was washed
with satd. aq. ammonium sulfate solution and water, and then the
solvent was evaporated. The residue (915 mg) was chromato-
graphed on SiO2 (20 g; hexane/AcOEt, 99.5:0.5) to give compound
11 (600 mg, 75%) and unchanged 10 (70 mg). 11: IR (film): ν˜ ϭ
(23E)-24-Bromo-6β-methoxy-3α,5-cyclo-5α-cholest-23-ene (14): To
a stirred solution of silane 13 (305 mg, 0.648 mmol) in CCl4
(15 mL) containing powdered K2CO3 (224 mg, 1.623 mmol), brom-
ine (105 mg) in CCl4 (1.8 mL) was added portionwise over a period
of 3 h at –10 °C. The mixture was subsequently partitioned between
hexane and water. The organic layer was washed with aq. Na2S2O4
solution and water and then the solvent was evaporated. The crude
dibromide (429 mg) was redissolved in THF (10 mL) and tetrabu-
tylammonium fluoride (370 mg, 1.117 mmol) was added. The re-
sulting mixture was set aside for 24 h and then partitioned between
hexane and water. The organic phase was washed with water and
the solvent was evaporated. The residue (300 mg) was chromato-
graphed on SiO2 (10 g; hexane) to give the bromide 14 (248 mg,
1
1732 (CϭO), 1613 (CϭC) cm–1. – H NMR (200 MHz): δ ϭ 0.14
(s, 9 H, SiCH3), 0.42 (dd, J ϭ 7.9, 5.0 Hz, 1 H, 4α-H), 0.64 (t, J ϭ
4.5 Hz, 1 H, 4β-H), 0.75 (s, 3 H, 18-H), 0.92 and 0.95 (2 d, J ϭ
5.7 Hz, 6 H, 26- and 27-H), 1.00 (s, 3 H, 19-H), 1.25 (t, J ϭ 7.1 Hz,
3 H, OEt), 2.20–2.42 (m, 3 H, 22- and 25-H), 2.76 (t, J ϭ 2.8 Hz,
1 H, 6-H), 3.32 (s, 3 H, OCH3), 4.07 (m, 2 H, OEt), 5.85 (t, J ϭ
6.5 Hz, 1 H, 23-H). – MS: m/z (%) ϭ 528 (28), 513 (100), 473 (18),
446 (35), 241 (56), 199 (44), 123 (12), 73 (27). – C33H56O3Si
(528.83): calcd. C 74.94, H 10.67; found C 75.01, H 10.73.
1
80%). – IR (film): ν˜ ϭ 1636 cm–1 (CϭC). – H NMR: δ ϭ 0.71 (s,
3 H, 18-H), 0.93 (d, J ϭ 6.5 Hz, 3 H, 21-H), 1.02 (s, 3 H, 19-H)
overlapping 1.03 (d, J ϭ 6.5 Hz, 6 H, 26- and 27-H), 2.77 (t, J ϭ
2.7 Hz, 1 H, 6-H) overlapping 2.83 (sept., J ϭ 6.5 Hz, 1 H, 25-H),
3.32 (s, 3 H, OCH3), 5.75 (dd, J ϭ 8.7, 6.8 Hz, 1 H, 23-H). –
C28H45OBr: calcd. 476.26537; found 476.26611 (MS).
(23Z)-6β-Methoxy-24-(trimethylsilyl)-3α,5-cyclo-5α-cholest-23-en-
21-ol (12a): To a solution of ester 11 (500 mg, 0.95 mmol) in diethyl
ether (25 mL), LiAlH4 (130 mg, 3.4 mmol) was added portionwise
over a period of 4 h. The excess reagent was then decomposed by
adding wet diethyl ether. The solution was washed with 0.1 
NaOH and water. The solvent was evaporated to give alcohol 12a
Reaction of 14 with Dibromocarbene Generated in a Phase-Transfer
System: (23R,24R)- and (23S,24S)-24-Bromo-23,24-(dibromomethy-
lene)-6β-methoxy-3α,5-cyclo-5α-cholestane (15a and 15b): A mixture
of (E)-bromide 14 (132 mg, 0.27 mmol), CHBr3 (2.5 mL), 50% aq.
NaOH solution (1.25 mL), TEBACl (1 mg), and EtOH (96%, 2
drops) was stirred and sonicated using a 140 W ultrasonic cleaning
(427 mg, 93%). – IR (film): ν˜ ϭ 3467 (OH), 1608 (CϭC) cm–1. – bath for 2 h at 25–35 °C and then partitioned between hexane and
1H NMR (200 MHz): δ ϭ 0.16 (s, 9 H, SiCH3), 0.43 (dd, J ϭ 8.0, water. The organic phase was washed with water and then the solv-
5.0 Hz, 1 H, 4α-H), 0.65 (t, J ϭ 4.7 Hz, 1 H, 4β-H), 0.76 (s, 3 H,
18-H), 0.98 (d, J ϭ 6.8 Hz, 6 H, 26- and 27-H), 1.02 (s, 3 H, 19-
ent was evaporated. The residue (orange liquid, ca. 2 mL) was chro-
matographed on SiO2 (3 g; hexane) to give first a mixture of prod-
1032
Eur. J. Org. Chem. 2000, 1027Ϫ1036

Synthesis of (23R)- and (23S)-23H-Isocalysterols
FULL PAPER
ucts incorporating 5 Br atoms (by MS) (19 mg, 12%), to which
the structure 16 was tentatively assigned, and then the tribromo
derivatives 15a and 15b (93 mg, 52%). – MS: m/z (%) ϭ 652, 650,
648, 646 [Mϩ] (50), 637, 635, 633, 631 [Mϩ – Me] (52), 620, 618,
ated by HPLC (Merck LiChrospher 100 RP-18, 5 µm, 250 ϫ 4 mm
column, 1% H2O in methanol, flow rate 0.6 mL/min, UV detection,
λ ϭ 220 nm) to give 2a and 2b; retention times tR ϭ 19.58 and
18.37 min, respectively. The relative retention times are in agree-
616, 614 [Mϩ – MeOH] (67), 597, 595, 593, 591 [Mϩ – 55] (100), ment with literature data.[14] Chemical shifts and coupling con-
539, 537, 535 [Mϩ – MeOH – Br] (37), 515, 513, 511 [Mϩ – 55 – stants in the 1H-NMR spectra of synthetic isocalysterols 2a and 2b
Br] (18), 253 (85). – C29H45O79Br281Br: calcd. 648.1000; found (500 MHz) were in agreement with those reported for the respective
648.0999 (MS).
natural products; see Table 1. Chemical shifts in the 13C-NMR
spectrum of 2a (125 MHz) were also in agreement with those re-
ported; see Table 2.
(23R,24R)- and (23S,24S)-24-Bromo-23,24-(dibromomethylene)-
cholest-5-ene-3β-ols (17a and 17b): A solution of i-steroids 15a and
15b (8 mg) in a mixture of dioxane and water (8:1, 2.5 mL) con-
taining TsOH (1 mg) was kept at 93–95 °C for 3.5 h. The product
was then extracted with CHCl3 to afford a solid material (6 mg),
which was chromatographed on SiO2 (320 mg; hexane/AcOEt,
Table 2. 13C-NMR data (125 MHz) of 2a and recorded data
(100 MHz) for the natural product[7]
recorded reported ∆δ
recorded reported ∆δ
1
95:5) to give crystalline alcohols 17a and 17b (4 mg). – H NMR
(200 MHz): δ ϭ 0.71 and 0.74 (2 s, 3 H, 18-H), 1.02 (s, 3 H, 19-
H), 3.4–3.7 (m, 1 H, 3-H), 5.3–5.4 (m, 1 H, 6-H). – MS: m/z (%) ϭ
638, 636, 634, 632 [Mϩ] (65). – C28H43Br3O: calcd. 632.0864; found
632.0863 (MS). The mixture was separated by HPLC (Merck Lich-
rospher 100 RP-18, 5 µm, 250 ϫ 4 mm, methanol, 10 mL/min, UV
C-1 37.27
37.26
31.67
71.82
42.31
140.75
121.74
31.91
31.91
50.15
0.01 C-16 28.46
28.46
56.56
11.87
19.40
0
C-2 31.69
C-3 71.83
C-4 42.32
C-5 140.77
C-6 121.74
C-7 31.92
C-8 31.92
C-9 50.17
0.02 C-17 56.57
0.01 C-18 11.87
0.01 C-19 19.40
0.01
0
0
detection, λ ϭ 220 nm) to give a pure diastereomer with tR
ϭ
0.02 C-20 36.51[a] 36.48
0.03
0
1
22.16 min: H NMR (500 MHz): δ ϭ 0.74 (s, 3 H, 18-H), 1.02 (s,
3 H, 19-H), 1.07 (d, J ϭ 6.5 Hz, 6 H, 26- and 27-H), 1.12 (d, J ϭ
6.4 Hz, 3 H, 21-H), 3.48–3.57 (m, 1 H, 3-H), 5.33–5.37 (m, 1 H,
6-H). Another diastereomer with tR ϭ 25.6 min was found to be
contaminated with ca. 12% of the more mobile component; notable
signals in 1H NMR (500 MHz): δ ϭ 0.71, 1.02, 1.10, and 1.11 (2 d,
J ϭ 6.5 Hz, 3 H each, 26- and 27-H), 1.12 (d, J ϭ 6.6 Hz, 3 H, 21-
H), 3.48–3.56 (m, 1 H), 5.33–5.37 (m, 1 H, 6-H).
0
C-21 19.23
19.23
43.53
18.99
122.67
26.40
21.08
21.24
112.23
10.67
0.01 C-22 43.53
0.01 C-23 19.00
0.02 C-24 122.70
–0.01 C-25 26.40
0
0.1
0.03
0
C-10 36.47[a] 36.48
C-11 21.11
C-12 39.82
C-13 42.34
C-14 56.85
C-15 24.31
[a]
21.11
39.81
42.34
56.83
24.31
0
C-26 21.07
0.02 C-27 21.24
C-28 112.24
–0.01
0
(23R)- and (23S)- 6β-Methoxy-3α,5:23,28-dicyclo-5α-stigmasta-
24(28)-ene (18a and 18b): To a stirred solution of tribromides 15a
and 15b (69 mg, 0.11 mmol) in diethyl ether (1.7 mL), methylli-
thium (1.5  in pentane, 600 µL, 0.90 mmol) was added at –70 °C.
The resulting mixture was allowed to warm to room temp. (over
ca. 2.5 h), then cooled to –60 °C, whereupon methyl iodide (200
µL, 0.32 mmol) was added. The mixture was stirred at –60 °C for
30 min., then allowed to warm to room temp., and subsequently
partitioned between hexane and water. The organic phase was
washed with water and the solvent was evaporated. The residue
(45 mg) was chromatographed on SiO2 (1.5 g; hexane) to give a
0
0.01
0.01
0.02 C-29 10.65
0
Alternative assignments.
MS and HR-MS of 2a: m/z ϭ 410 [Mϩ] (3), 395 [Mϩ – CH3] (3),
377 [Mϩ – CH3 – H2O] (1), 367 [Mϩ – CH(CH3)2] (2), 353 (1), 349
mixture of cyclopropenes 18a and 18b (20 mg, 44%). – 1H NMR (1), 339 (1), 314 [Mϩ – C7H11] (4), 300 [Mϩ – C7H11 – CH3] (8),
(200 MHz): δ ϭ 0.42 (dd, J ϭ 7.9 Hz, 1 H, 4α-H), 0.65 (t, J ϭ
283 (16), 271 [Mϩ – side chain – 2 H] (93), 253 [Mϩ – side chain –
5 Hz, 1 H, 4β-H), 0.72 and 0.73 (2 br. s, 3 H, 18-H), 1.00 (d, J ϭ H2O – 2 H] (19), 241 (8), 215 (14), 199 (7), 187 (8), 173 (12), 159
7.1 Hz, 3 H, 21-H), 1.02 (br. s, 3 H, 19-H), 1.07, 1.08, 1.10, 1.11, (28), 145 (20), 133 (31), 121 (17), 109 (48), 96 [C7H12] (53), 95
1.12, 1.13 (6 H, 26-, and 27-H), 1.99 and 2.01 (2 d, J ϭ 1.6 Hz, 3
[C7H11] (100), 81 (27), 67 (26), 55 (22), 41 (11). – C29H46O [Mϩ]:
H, 29-H), 2.5–2.7 (sept. t, J ϭ 6.9, 1.4 Hz, 1 H, 25-H), 2.76 (t, J ϭ calcd. 410.3549; found 410.3545; C28H41 [Mϩ – CH3 – H2O]: calcd.
2.8 Hz, 1 H, 6-H), 3.32 (s, 3 H, OCH3). – MS: m/z (%) ϭ 424 [Mϩ] 377.3208; found 377.3203; C26H39O [Mϩ – CH(CH3)2]: calcd.
(8), 409 [Mϩ – Me] (25), 392 [Mϩ – MeOH] (18), 377 (17), 369 367.3001; found 367.2999; C14H27O [Mϩ – side chain – 2 H]: calcd.
(30), 253 [Mϩ – side chain – 2H – MeOH] (100), 95 [C7H11] (37). –
271.2062; found 271.2066. These data are in agreement with the
C30H48O [Mϩ]: calcd. 424.3705; found 424.3700; C26H41O [Mϩ
–
reported values.[38]
C4H7]: calcd. 369.3157; found 369.3159; C7H11 [CH2–Cϭ
MS and HR-MS of 2b: 410 [Mϩ] (3), 395 [Mϩ – CH3] (3), 377
[Mϩ – CH3 – H2O] (1), 367 [Mϩ – iPr] (2), 353 [Mϩ – iPr] (1), 349
[Mϩ – iPr – H2O] (1), 339 (1), 300 [Mϩ – C6H11] (7), 283 (16), 271
[Mϩ – side chain – 2 H] (85), 253 [Mϩ – side chain – H2O – 2 H]
C(CHϩ)iPr]: calcd. 95.0861; found 95.0860 (MS).
(23R)-23H-Isocalysterol [(23R)-23,28-Cyclostigmasta-5,24(28)-dien-
3β-ol] (2a) and (23S)-23H-Isocalysterol [(23S)-23,28-Cyclostig-
masta-5,24(28)-dien-3β-ol] (2b): A solution of i-steroids 18a and 18b (17), 241 (7), 215 (14), 199 (7), 187 (9), 173 (11), 159 (26), 145 (20),
(17 mg, 0.04 mmol) in a mixture of dioxane (8 mL) and water
(2 mL) containing TsOH (2 mg) was kept at 93–95 °C for 5 h and
then partitioned between chloroform and water. The chloroform
phase was then washed with water and the solvent was evaporated.
The solid residue (12 mg) was subsequently chromatographed on
SiO2 (600 mg; hexane/acetone, 98:2) to give a mixture of calysterols
2a and 2b in a ratio of ca. 1:1 (7 mg, 44%). This mixture was separ-
133 (29), 121 (16), 109 (47), 96 (53), 95 (100), 81 (27), 67 (26), 55
(21), 41 (10). – C29H46O [Mϩ]: calcd. 410.3549; found 410.3545;
C28H41 [Mϩ – CH3 – H2O]: calcd. 377.3208; found 377.3207;
C26H39O [Mϩ – CH(CH3)2]: calcd. 367.3001; found 367.3000;
C14H27O [Mϩ – side chain – 2 H]: calcd. 271.2062; found 271.2062.
These data are in agreement with the reported values.[7][14] For m.p.
and optical rotation of 2a, vide infra.
Eur. J. Org. Chem. 2000, 1027Ϫ1036
1033

A. Kurek-Tyrlik, K. Minksztym, J. Wicha
FULL PAPER
(Z)-3-Bromo-4-methylpent-2-en-1-ol (19a): To a stirred mixture of
(35 mL), DIBAH (0.75  in hexane, 8.4 mL, 6.3 mmol) was added
Red-Al (1.7  in toluene, 34.4 mL, 117 mmol) and diethyl ether at –30 to –20 °C. After 30 min., the mixture was diluted with diethyl
(49 mL), a solution of propargylic alcohol 4 (6.76 g, 68.8 mmol) in
diethyl ether (49 mL) was added dropwise over a period of 20 min.
at 0 °C. The resulting mixture was set aside at room temp. for 4 h,
then cooled to 0 °C once more, whereupon pyridine (16.6 mL, 0.21
mol) was added. The mixture was cooled to –78 °C and then brom-
ine (6.9 mL, 133.6 mmol) in CH2Cl2 (84 mL) was added dropwise,
ether and satd. aq. sodium potassium tartrate solution was added.
The aqueous layer was separated and extracted with diethyl ether.
The combined organic extracts were concentrated to dryness and
the residue was chromatographed on SiO2 (22 g; hexane/acetone,
100:1) to give alcohol 21a (0.977 g, 95%). – IR (film): ν˜ ϭ 3451
1
cm–1 (OH). – H NMR: δ ϭ 0.44 (dd, J ϭ 7.9, 5.2 Hz, 1 H, 4α-
with the temp. being maintained below –60 °C. Stirring at –78 °C H), 0.65 (t, J ϭ 4.9 Hz, 1 H, 4β-H), 0.75 (s, 3 H, 18-H), 1.02 (s, 3
was continued for 20 min. and then the mixture was poured into 1
 NaOH solution and ice. The product was extracted with diethyl
ether. The combined extracts were washed with 6  HCl (50 mL)
and satd. aq. NaHCO3 solution. The solvent was then evaporated
and the residue was chromatographed on SiO2 (100 g; hexane/
CH2Cl2, 2:1 and then 1:1). The crude product was distilled at 70–
H, 19-H), 1.11 (d, J ϭ 6.6 Hz, 6 H, 26- and 27-H), 2.15–2.45 (m,
3 H, 20- and 22-H), 2.52 (sept, J ϭ 6.6 Hz, 1 H, 25-H), 2.73–2.81
(m, 1 H, 6-H), 3.33 (s, 3 H, CH3O), 3.50–3.80 (m, 2 H, CH2OH),
5.62 (t, J ϭ 6.5 Hz, 1 H, 23-H). –MS: m/z (%) ϭ 494, 492 [Mϩ]
(37), 479, 477 [Mϩ – CH3] (56), 462, 460 [Mϩ – CH3OH] (41), 439,
437 [Mϩ – C4H7] (100), 436, 434 (15), 381 (27), 299 (10), 285 (34),
86 °C/1.5–2 Torr to give alcohol 19a (9.36 g, 77%). – IR (film): ν˜ ϭ 281 (10), 253 (52), 227 (14), 213 (21), 201, 199 (12). – C28H45O2Br:
1
3332 cm–1 (OH). – H NMR: δ ϭ 1.13 (d, J ϭ 6.6 Hz, 6 H, iPr), calcd. 492.2603; found 492.2604 (MS).
2.00 (br. s, 1 H, OH), 2.58 (sept, J ϭ 6.7 Hz, 1 H, iPr), 4.27 (d,
(23Z)-24-Bromo-6β-methoxy-21-tosyloxy-3α,5-cyclo-5α-cholest-23-
J ϭ 5.9 Hz, 2 H, CH2), 5.96 (dt, J ϭ 5.9, 0.8 Hz, 1 H, CϭCH). –
ene (21b): To a solution of alcohol 21a (1.81 g, 3.68 mmol) in
13C NMR: δ ϭ 21.68 (CH3), 38.92 (CH), 62.32 (CH2), 125.26 (Cϭ
CH2Cl2 (24 mL) containing pyridine (1.78 mL, 22 mmol), TsCl
CH), 137.79 (CBr). – C6H11OBr (179.06): calcd. C 40.24, H 6.19,
(1.56 g, 8.22 mmol) was added. The mixture was set aside for 24 h
Br 44.63; found C 39.95, H 6.19, Br 44.75.
and then partitioned between diethyl ether and water. The aqueous
(Z)-1,3-Dibromo-4-methylpent-2-ene (19b): To a solution of alcohol
19a (517 mg, 2.90 mmol) in diethyl ether (2.5 mL) containing pyr-
layer was extracted with diethyl ether and the combined organic
extracts were washed with satd. aq. NH4Cl solution. The solvent
idine (8 µL), a solution of PBr3 (360 µL, 1.26 mmol) in diethyl was then evaporated and the residue was chromatographed on SiO2
ether (1 mL) was added at 4 °C. The resulting mixture was stirred
for 20 min. and then the reaction was quenched by adding meth-
anol (0.5 mL) and ice. The aqueous layer was separated and ex-
tracted with pentane. The combined extracts were washed with
satd. aq. NaHCO3 solution. The pentane was then evaporated and
(50 g; hexane/CH2Cl2, 1:1) to give tosylate 21b (2.264 g, 95%). – 1H
NMR: δ ϭ 0.43 (dd, J ϭ 8.2, 5.1 Hz, 1 H, 4α-H), 0.67 (s, 3 H, 18-
H), 1.01 (s, 3 H, 19-H), 1.01 (d, J ϭ 6.7 Hz, 6 H, 26- and 27-H),
1.98–2.50 (m, 3 H, 22- and 25-H), 2.44 (s, 3 H, MePh), 2.72–2.81
(m, 1 H, 6-H), 3.32 (s, 3 H, CH3O), 3.95–4.10 (m, 2 H, 21-H), 5.43
the residue was distilled in a kugelrohr apparatus (100 °C/5 Torr) (t, J ϭ 6.7 Hz, 1 H, 23-H), 7.31 (d, J ϭ 8.0 Hz, 2 H, Ts), 7.80 (d,
to yield dibromide 19b (598 mg, 85%). – 1H NMR: δ ϭ 1.13 (d,
J ϭ 6.7 Hz, 6 H) and 2.61 (sept, 1 H, J ϭ 6.7 Hz, iPr) 4.08 (d, J ϭ
7.9 Hz, 2 H, CH2), 6.02 (dt, J ϭ 7.9, 0.8 Hz, 1 H, CϭCH). – 13C
J ϭ 8.2 Hz, 2 H, Ts). –MS: m/z (%) ϭ 648, 646 [Mϩ] (4), 633, 631
[Mϩ – CH3] (8), 616, 614 [Mϩ – CH3OH] (7), 593, 591 [Mϩ – C4H7]
(14), 444, 442 [Mϩ – TsOH – CH3OH] (22), 363 [Mϩ – TsOH –
NMR: δ ϭ 21.64 (CH3), 30.34 (CH2Br), 39.16 (CH), 122.17 (Cϭ CH3OH – Br] (10), 285 (28), 253 [Mϩ – side chain – CH3OH – 2
CH), 142.25 (CBr). – C6H10Br2 (241.95): calcd. C 29.78, H 4.17; H] (100), 227 (12), 213 (14). – C35H51O4BrS: calcd. 646.2691; found
found C 29.82, H 4.24.
646.2687 (MS).
Ethyl (23Z)-24-Bromo-6β-methoxy-3α,5-cyclo-5α-cholest-23-en-21-
oate (20): To a stirred solution of LDA [prepared from diisopropyl-
(23Z)-24-Bromo-6β-methoxy-3α,5-cyclo-5α-cholest-23-ene (22): To
a stirred solution of tosylate 21b (1.24 g, 1.92 mmol) in THF
amine (1.22 mL, 8.72 mmol) in THF (8.3 mL) and n-BuLi (1.9  (30 mL), LiEt3BH (1  in THF, 11.5 mL, 11.52 mmol) was added
in hexane, 4.6 mL, 8.74 mmol)], a solution of ester 10[31] (2.96 g, dropwise at 0 °C. The resulting mixture was stirred for 5 h and then
7.92 mmol) in THF (24 mL) was added dropwise at –78 °C. The
mixture was stirred at –78 °C for 1 h and then bromide 19b (1.99 g,
8.21 mmol) was added. Stirring at –78 °C was continued for 3.5 h,
then the mixture was allowed to warm to room temp. and parti-
tioned between diethyl ether and water. The aqueous layer was ex-
tracted with diethyl ether. The combined organic extracts were
washed with satd. aq. ammonium chloride solution and the solvent
was evaporated. The residue was chromatographed on SiO2 (200 g;
partitioned between diethyl ether and water. The aqueous layer was
extracted with diethyl ether and the combined organic extracts were
washed with satd. aq. NH4Cl solution. The solvent was then evap-
orated and the residue was chromatographed on SiO2 (17 g; hex-
ane/toluene, 6:1) to yield the cholestene derivative 22 (0.84 g, 91%).
An analytical sample was crystallized from methanol; m.p. 60–63
°C. – 1H NMR: δ ϭ 0.43 (dd, J ϭ 7.7, 5.0 Hz, 1 H, 4α-H), 0.65 (t,
J ϭ 4.4 Hz, 1 H, 4β-H), 0.73 (s, 3 H, 18-H), 0.93 (d, J ϭ 6.5 Hz,
hexane/CH2Cl2, 2.5:1 2:1) to give ester 20 (3.38 g, 80%). – IR 3 H, 21-H), 1.02 (s, 3 H, 19-H), 1.11 (d, J ϭ 6.6 Hz, 6 H, 26- and
1
(film): ν˜ ϭ 1732 cm–1 (CϭO). – H NMR: δ ϭ 0.43 (dd, J ϭ 7.9,
4.9 Hz, 1 H, 4α-H), 0.65 (t, J ϭ 4.5 Hz, 1 H, 4β-H), 0.76 (s, 3 H, H), 3.33 (s, 3 H, CH3O), 5.67 (t, J ϭ 6.7 Hz, 1 H, 23-H). –MS: m/
18-H), 1.01 (s, 3 H, 19-H), 1.07 (d, J ϭ 6.7 Hz, 6 H, 26- and 27-
z (%) ϭ 478, 476 [Mϩ] (41), 463, 461 [Mϩ – CH3] (50), 446, 444
H), 1.26 (t, J ϭ 7.1 Hz, 3 H, CH3CH2O), 2.28–2.43 (m, 3 H, 20- [Mϩ – CH3OH] (39), 423, 421 [Mϩ – C4H7] (100), 315 [Mϩ
27-H), 2.55 (sept, J ϭ 6.6 Hz, 1 H, 25-H), 2.73–2.81 (m, 1 H, 6-
–
and 22-H), 2.52 (sept, J ϭ 6.6 Hz, 1 H, 25-H), 2.73–2.81 (m, 1 H,
6-H), 3.32 (s, 3 H, CH3O), 4.09 (q, J ϭ 7.1 Hz, 2 H, CH2O), 5.62
(t, J ϭ 6.5 Hz, 1 H, 23-H). MS: m/z (%) ϭ 536, 534 [Mϩ] (4), 521,
C6H10Br] (14), 257 (11), 253 (34). – C28H45OBr (477.57): calcd. C
70.31, H 9.75, Br 16.87; found C 70.42, H 9.50, Br 16.73.
Reaction of 22 with Dibromocarbene Generated in a Phase-Transfer
System: A mixture of vinylic bromide 22 (332 mg, 0.70 mmol),
CH2Cl2 (1.5 mL), bromoform (487 µL, 5.58 mmol), Cetrimid
(4 mg), ethanol (10 µL), and 50% aq. NaOH solution (1.174 mL,
22.306 mmol) was stirred for 50 h and then partitioned between
519 [Mϩ – Me] (11), 504, 502 [Mϩ – CH3OH] (6), 479, 481 [Mϩ
–
C4H7] (20), 455 [Mϩ – Br] (100), 397 (12), 253 (14). – C30H47O3Br:
calcd. 534.27085; found 534.27014 (MS).
(23Z)-24-Bromo-6β-methoxy-3α,5-cyclo-5α-cholest-23-en-21-ol
(21a): To a stirred solution of ester 20 (1.12 g, 2.1 mmol) in CH2Cl2 diethyl ether and water. The layers were separated and the aqueous
1034 Eur. J. Org. Chem. 2000, 1027Ϫ1036

Synthesis of (23R)- and (23S)-23H-Isocalysterols
FULL PAPER
layer was extracted with further diethyl ether. The combined or-
ganic extracts were washed with satd. aq. NH4Cl solution, the solv-
ent was evaporated, and the residue was chromatographed on SiO2
(10–40 µm, Merck 7736, 24 g). Fractions were collected as follows:
(5 mL). The aqueous layer was extracted with further diethyl ether
and the combined organic extracts were washed with satd. aq.
NaHCO3 solution. The solvent was then evaporated and the res-
idue was chromatographed on SiO2 (0.5 g, hexane/diethyl ether,
elution with hexane gave 23 (58 mg, 12%); elution with hexane/ 100:1) to give the calysterol derivative 18b (12 mg, 53%). – 1H
CH2Cl2, 8:1, gave 24 (76 mg, 13%), followed by (23S,24R)-15c
NMR: δ ϭ 0.43 (dd, J ϭ 8.0, 5.0 Hz, 1 H, 4α-H), 0.65 (t, J ϭ
(22 mg), a mixture of 15c and 15d (190 mg), and (23R,24S)-15d 4.4 Hz, 1 H, 4β-H), 0.72 (s, 3 H, 18-H), 0.98–1.14 (d, J ϭ 7.0 Hz,
(15 mg). The chromatography was monitored by TLC (hexane/
CH2Cl2, 2:1, developed 3 times). The combined yield of 15c and
15d amounted to 50%. The mixture of products was also separated
by preparative HPLC on a Macherey–Nagel Duren Nucleosil
100–10 C18 column eluting with hexane/CH2Cl2, 3:1, flow rate
8 mL/min., UV detection at λ ϭ 235 nm.
3 H, 21-H coincident with s, 3 H, 19-H), 1.10 (d, J ϭ 6.9 Hz, 3 H,
26-H), 1.12 (d, J ϭ 6.9 Hz, 3 H, 27-H), 2.02 (d, J ϭ 1.6 Hz, 3 H,
29-H), 2.63 (sept q, J ϭ 6.8, 1.6 Hz, 1 H, 25-H), 2.74–2.81 (m, 1
H, 6-H), 3.32 (s, 3 H, CH3O). – MS: m/z (%) ϭ 424 [Mϩ] (2), 409
[Mϩ – Me] (3), 392 [Mϩ – CH3OH] (3), 381 [Mϩ – CH(CH3)2] (7),
377 [Mϩ – CH3 – CH3OH] (2), 369 [Mϩ – C4H7] (5), 349 [Mϩ
–
CH(CH3)2 – CH3OH] (2), 283 (10), 253 [Mϩ – side chain –
CH3OH – 2 H] (100), 227 (8), 213 (9), 199 (8), 187 (8), 173 (10),
159 (18), 155 (12), 143 (12), 121 (17), 109 (17), 95 (35), 91 (12), 77
(12), 65 (10), 51 (5). – C30H48O: calcd. 424.3705; found 424.3707
(MS).
(23R*,24S*)-3β,24-Dibromo-23,24-(dibromomethylene)cholest-5-ene
(23) (Mixture of Diastereoisomers): 1H NMR: δ ϭ 0.70 and 0.73
(s, 3 H, 18-H), 1.04 (s, 3 H, 19-H), 1.09 (d, J ϭ 6.5 Hz, 27- and 21-
H), 1.10 (d, J ϭ 6.6 Hz, 26- and 21-H), 1.17 (d, J ϭ 6.4 Hz, 3 H,
27-H), 3.80–4.05 (m, 1 H, CHBr), 5.30–5.42 (m, 1 H, CϭCH). –
MS: m/z (%) ϭ 702, 700, 698, 696, 694 [Mϩ] (6), 687, 685, 683,
681, 679 [Mϩ – CH3] (8), 621, 619, 617, 615 [Mϩ – Br] (100), 365,
363 [Mϩ – C7H10Br3] (57), 335, 333 (77), 295, 293 (25), 241, 239,
237 (27), 229, 227, 225, 223 (25), 215, 213 (42).
(23S)-23H-Isocalysterol [(23S)-23,28-Cyclostigmasta-5,24(28)-dien-
3β-ol] (2b): A mixture of i-steroid 18b (12 mg, 0.028 mmol), dioxane
(1 mL), water (250 µL), and TsOH (1 mg) was stirred at 80 °C for
1 h, cooled to room temp., and then partitioned between diethyl
ether (3 mL) and satd. aq. NaHCO3 solution (2 mL). The aqueous
layer was extracted with further diethyl ether and the combined
organic extracts were washed with brine. The solvent was then
evaporated and the residue was chromatographed on a column
packed with silica gel for TLC (10–40 µm, Merck 7736) eluting
with hexane/diethyl ether, 15:1, to give isocalysterol 2b (3.6 mg,
31%) and 2b contaminated with a UV light-absorbing substance
(23R*,24S*)-24-Bromo-6α-dibromomethyl-23,24-dibromomethylene-
1
6β-methoxy-3α,5-cyclo-5α-cholestane (24): – H NMR: δ ϭ 0.78 (s,
3 H, 18-H), 1.06–1.12 (s, 3 H, 19-H coincident with d, 3 H, 21-H),
1.10 (d, J ϭ 6.3 Hz, 3 H, 26-H), 1.18 (d, 3 H, J ϭ 6.0 Hz, 27-H),
3.31 (s, 3 H, CH3O), 5.75 (s, 1 H, CHBr2). – MS: m/z (%) ϭ 824,
822, 820, 818, 816, 814 [Mϩ] (3), 712, 710, 708, 706, 704 [Mϩ
–
Br – CH3OH] (97), 651, 649, 647, 645 [Mϩ – CHBr2] (100), 628
[Mϩ – Br2 – CH3OH] (88), 617, 615, 613, 611, 609 [C22H29Br4]
(44), 549, 547, 545 [Mϩ – Br3 – CH3OH] (20). – LSIMS (with
NaOAc): m/z (%) ϭ 849, 847, 845, 843, 841, 839 [M ϩ Na]ϩ (37),
651, 649, 647, 645 [Mϩ – CHBr2] (100).
(2.8 mg). An analytical sample was obtained by HPLC (tR
18.25 min). Its H-NMR and mass spectra were identical to those
of a sample obtained as described above.
ϭ
1
(23R,24S)-24-Bromo-23,24-(dibromomethylene)cholest-5-en-3β-ol
(17d): A mixture of i-steroid 15d (40 mg, 0.062 mmol), dioxane
(1.6 mL), water (250 µL), and TsOH (1 mg) was stirred at 81–84
°C for 30 min., allowed to cool to room temp., and then partitioned
between diethyl ether and satd. aq. NaHCO3 solution. The aqueous
layer was extracted with further diethyl ether and the combined
organic extracts were concentrated to dryness. The residue was
chromatographed on SiO2 (1 g; hexane/diethyl ether, 6:1) to yield
alcohol 17d (37.7 mg, 96%). An analytical sample was obtained by
crystallization from hexane; m.p. 132–135 °C and 149–152 °C. –
1H NMR: δ ϭ 0.73 (s, 3 H, 18-H), 1.01 (s, 3 H, 19-H), 1.09 (d,
J ϭ 6.6 Hz, 3 H, 21-H or 26-H), 1.10 (d, J ϭ 6.6 Hz, 3 H, 21-H
or 26-H), 1.18 (d, J ϭ 6.4 Hz, 3 H, 27-H), 3.40–3.65 (m, 1 H, 3-
H), 5.30–5.40 (m, 1 H, 6-H). – C28H43OBr3 (635.35): calcd. C 52.93,
H 6.82; found C 53.00, H 6.94.
(23S,24R)-24-Bromo-23,24-dibromomethylene-6β-methoxy-3α,5-
cyclo-5α-cholestane (15c): Rf ϭ 0.44, tR ϭ 39.18 min. – H NMR:
1
δ ϭ 0.43 (dd, J ϭ 7.9, 5.1 Hz, 1 H, 4α-H), 0.65 (t, J ϭ 4.9 Hz, 1
H, 4β-H), 0.74 (s, 3 H, 18-H), 1.03 (s, 3 H, 19-H), 1.09 (d, 3 H,
J ϭ 5.6 Hz, 21-H), 1.09 (d, 3 H, J ϭ 6.6 Hz, 26-H), 1.18 (d, J ϭ
6.4 Hz, 3 H, 27-H), 2.74–2.81 (m, 1 H, 6-H), 3.32 (s, 3 H, CH3O). –
MS: m/z (%) ϭ 652, 650, 648, 646 [Mϩ] (51), 637, 635, 633, 631
[Mϩ – Me] (54), 620, 618, 616, 614 [Mϩ – CH3OH] (69), 597, 595,
593, 591 [Mϩ – C4H7] (100), 553 (11). – C29H45OBr3: calcd.
646.102048; found 646.101578 (MS).
(23R,24S)-24-Bromo-23,24-dibromomethylene-6β-methoxy-3α,5-
1
cyclo-5α-cholestane (15d): Rf ϭ 0.41, tR ϭ 43.24 min. – H NMR:
δ ϭ 0.43 (dd, J ϭ 7.9, 5.4 Hz, 1 H, 4α-H), 0.65 (t, J ϭ 4.4 Hz, 1
H, 4β-H), 0.79 (s, 3 H, 18-H), 1.03 (s, 3 H, 19-H), 1.09 (d, 3 H,
J ϭ 6.6 Hz, 21-H), 1.10 (d, J ϭ 6.6 Hz, 3 H, 26-H), 1.18 (d, J ϭ
6.5 Hz, 3 H, 27-H), 2.73–2.80 (m, 1 H, 6-H), 3.33 (s, 3 H, CH3O). –
MS: m/z (%) ϭ 652, 650, 648, 646 [Mϩ] (50), 637, 635, 633, 631
[Mϩ – Me] (56), 620, 618, 616, 614 [Mϩ – CH3OH] (67), 597, 595,
593, 591 [Mϩ – C4H7] (100), 553 (9). – C29H45Br3O: calcd.
646.10205; found 646.10222 (MS).
(23S,24R)-24-Bromo-23,24-(dibromomethylene)cholest-5-en-3β-ol
(17c): A mixture of i-steroid 15c (33 mg, 0.051 mmol), dioxane
(1 mL), water (250 µL), and TsOH (1 mg) was stirred at 85 °C for
2 h, then allowed to cool, and worked-up as described above to
1
give alcohol 17c (31 mg, 95%). – H NMR: δ ϭ 0.71 (s, 3 H, 18-
H), 1.01 (s, 3 H, 19-H), 1.09 (d, J ϭ 6.5 Hz, 6 H, 26- and 27-H or
26- and 21-H), 1.17 (d, J ϭ 6.5 Hz, 3 H, 21-H or 27-H), 3.40–3.65
(m, 1 H, 3-H), 5.30–5.40 (m, 1 H, 6-H). – MS: m/z (%) ϭ 638, 636,
634, 632 [Mϩ] (8), 539, 537, 535 [Mϩ – Br – H2O] (15), 283 (21),
271, 253, 213 (27), 199 (15). – C28H43OBr3: calcd. 632.0864; found
632.0863 (MS).
(23S)-6β-Methoxy-3α,5:23,28-dicyclo-5α-stigmasta-24(28)-ene
(18b): To a stirred solution of (23R,24S)-tribromide 15d (34 mg,
0.053 mmol) in diethyl ether (0.5 mL), MeLi (1.45  in diethyl
ether, 146 µL, 0.212 mmol) was added at –78 °C. The resulting
mixture was allowed to warm to room temp., then cooled to –65
°C, whereupon MeI (100 µL, 1.6 mmol) was added. The cooling
bath was then removed and, after 2.5 h, the mixture was parti-
(23R)-23H-Isocalysterol [(23R)-23,28-Cyclostigmasta-5,24(28)-dien-
3β-ol] (2a): To a solution of 17c (24.5 mg, 0.04 mmol) in CH2Cl2
tioned between diethyl ether (5 mL) and satd. aq. NH4Cl solution (1 mL), 2-methoxypropene (16 µL, 0.16 mmol) and Amberlyst-15H
Eur. J. Org. Chem. 2000, 1027Ϫ1036 1035

A. Kurek-Tyrlik, K. Minksztym, J. Wicha
FULL PAPER
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thus obtained was redissolved in diethyl ether (0.9 mL). This solu-
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70 °C once more, whereupon MeI (100 µL, 1.6 mmol) was added.
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