Highly stereocontrolled formal synthesis of brassinolide via chiral sulfoxide-directed SN2′ reactions

Article abstract of DOI:10.1021/jo951264k

An efficient stereocontrolled methodology for the preparation of the four contiguous chiral centers of the brassinosteroid side chain is described. Allylic mesyloxy sulfinyl steroids have been found to undergo highly stereoselective S_N2′ displacements when treated with cyanocuprates that provide the required acyclic stereocontrol in the key C-24 position of the steroidal side chain. Preparation of a direct precursor of brassinolide 1, as well as a precursor of naturally occurring (24R)-epibrassinolide, (+)-18, is carried out in two additional steps utilizing asymmetric dihydroxylations of (22E)-olefins (+)-2 and (+)-17. In this manner, a formal synthesis of this plant growth promoter has been completed, and the extension of the scope of this methodology has been explored providing a straightforward route to this family of steroids. Alternative routes to the key olefin (+)-2 are also outlined. Improved selectivity in the addition to aldehyde 7 for the preparation of the Cram (22R)-allylic hydroxy sulfoxides is achieved by controlling the chirality at sulfur or by a condensation-symmetric oxidation sequence employing the analogous vinyl sulfide reagent 22.

Full text of DOI:10.1021/jo951264k

J . Org. Chem. 1996, 61, 109-117
109
High ly Ster eocon tr olled F or m a l Syn th esis of Br a ssin olid e via
Ch ir a l Su lfoxid e-Dir ected SN2′ Rea ction s
J oseph P. Marino,* Alfonso de Dios, Laura J . Anna, and Roberto Ferna´ndez de la Pradilla1
Department of Chemistry, The University of Michigan, Ann Arbor, Michigan 48109-1055
Received J uly 14, 1995X
An efficient stereocontrolled methodology for the preparation of the four contiguous chiral centers
of the brassinosteroid side chain is described. Allylic mesyloxy sulfinyl steroids have been found
to undergo highly stereoselective SN2′ displacements when treated with cyanocuprates that provide
the required acyclic stereocontrol in the key C-24 position of the steroidal side chain. Preparation
of a direct precursor of brassinolide 1, as well as a precursor of naturally occurring (24R)-
epibrassinolide, (+)-18, is carried out in two additional steps utilizing asymmetric dihydroxylations
of (22E)-olefins (+)-2 and (+)-17. In this manner, a formal synthesis of this plant growth promoter
has been completed, and the extension of the scope of this methodology has been explored providing
a straightforward route to this family of steroids. Alternative routes to the key olefin (+)-2 are
also outlined. Improved selectivity in the addition to aldehyde 7 for the preparation of the Cram
(22R)-allylic hydroxy sulfoxides is achieved by controlling the chirality at sulfur or by a
condensation-symmetric oxidation sequence employing the analogous vinyl sulfide reagent 22.
In tr od u ction
side chain remains a challenging synthetic objective. In
this context, a direct access to brassinosteroids via
The discovery and structural determination of the
plant growth regulator brassinolide (1), isolated from bee-
collected pollen of Brassica Napus L., was reported by
USDA scientists in 19792 and was a breakthrough in the
fields of phytochemistry, plant physiology, and agronomy.3
A large number of analogs of this benign steroidal, highly
oxygenated lactone have also been obtained from a wide
variety of plants,3a many of them holding promising
applications in agriculture.3b The extremely low abun-
dance in natural sources3d and challenging structure of
brassinolide have produced an increasing interest and
intense activity in the synthesis of these brassinosteroids
during the last 15 years.3e,4 The unique biological activity
of this family of plant hormones relies on the specific
stereochemistry of its side chain consisting of four
contiguous chiral centers. Several routes for the syn-
thesis of brassinolide (1) (Scheme 1) and other brass-
inosteroids have been reported, such as: (a) epoxidation-
ring opening of ∆23(24) olefins,5 (b) stereocontrolled addi-
tion of R-oxygen-substituted organometallic species to
steroidal aldehydes,6 and (c) ring-opening reactions of
oxygen-containing cyclic derivatives of the side chain,7
etc. Despite the numerous reports on this topic, the
required acyclic stereocontrol for the construction of the
osmylations of (22E)-∆22(23)-(24R)-methyl or (22E)-∆22(23)
(24S)-ethyl olefins8 derived from ergosterol/brassicasterol
or stigmasterol, respectively, has been the subject of
limited study since no versatile procedure to generate the
key C-24 chiral center has been available. The lack of a
general and highly stereoselective methodology that
would facilitate the preparation of a variety of brass-
inosteroidal side chains motivated the research described
herein.
In a previous communication, we have shown that the
cuprate-mediated reactions of simple, acyclic allylic me-
sylates activated with a chiral sulfoxide group efficiently
proceed with complete SN2′ regioselectivity, high Z/E
-
(5) For some leading examples, see: (a) Ishiguro, M.; Takatsuto, S.;
Morisaki, M.; Ikekawa, N. J . Chem. Soc., Chem. Commun. 1980, 962-
964. (b) Fung, S.; Siddall, J . B. J . Am. Chem. Soc. 1980, 102, 6580-
6581. (c) Hayami, H.; Sato, M.; Kanemoto, S.; Morizawa, Y.; Oshima,
K.; Nozaki, H. J . Am. Chem. Soc. 1983, 105, 4491-4492. (d) Sakak-
ibara, M.; Mori, K. Agric. Biol. Chem. 1983, 47, 663-664. (e) Mori, K.;
Sakakibara, M.; Okada, K. Tetrahedron 1984, 40, 1767-1781. (f)
Takahashi, T.; Ootake, A.; Yamada, H.; Tsuji, J . Tetrahedron Lett.
1985, 26, 69-72. (g) Aburatani, M.; Takeuchi, T.; Mori, K. Agric. Biol.
Chem. 1986, 50, 3043-3047. (h) Shen, Z.-W.; Zhou, W.-S. J . Chem.
Soc., Perkin Trans. 1 1990, 1765-1767. (i) Back, T. G.; Krishna, M.
V. J . Org. Chem. 1991, 56, 454-457. (j) Zhou, W.-S.; J iang, B.; Pan,
X.-F. Tetrahedron 1992, 48, 1837-1852. (k) Back, T. G.; Blazecka, P.
G.; Krishna, M. V. Can. J . Chem. 1993, 71, 156-163. (l) Hazra, B. G.;
J oshi, P. L.; Bahule, B. B.; Argade, N. P.; Pore, V. S.; Chordia, M. D.
Tetrahedron 1994, 50, 2523-2532. See also ref 31.
(6) (a) Donaubauer, J . R.; Greaves, A. M.; McMorris, T. C. J . Org.
Chem. 1984, 49, 2833-2834. (b) Kametani, T.; Katoh, T.; Tsubuki, M.;
Honda, T. J . Am. Chem. Soc. 1986, 108, 7055-7060. (c) Koreeda, M.;
Tanaka, Y. Tetrahedron Lett. 1987, 28, 143-146. (d) Kametani, T.;
Kigawa, M.; Tsubuki, M.; Honda, T. J . Chem. Soc., Perkin Trans. 1
1988, 1503-1507. (e) Kametani, T.; Katoh, T.; Fujio, J .; Nogiwa, I.;
Tsubuki, M.; Honda, T. J . Org. Chem. 1988, 53, 1982-1991. (f)
Khripach, V. A.; Zhabinskii, V. N.; Zhernosek, E. V. Tetrahedron Lett.
1995, 36, 607-608. See also: (g) Nakamura, T.; Tanino, K.; Kuwajima,
I. Tetrahedron Lett. 1993, 34, 477-480.
(7) (a) Anastasia, M.; Allevi, P.; Ciuffreda, P.; Fiecchi, A.; Scala, A.
J . Org. Chem. 1984, 49, 4297-4300. (b) Zhou, W.-S.; Tian, W.-S.
Tetrahedron 1987, 43, 3705-3712. (c) Zhou, W.-S.; J iang, B.; Pan, X.
J . Chem. Soc., Chem. Commun. 1989, 612-614. (d) Honda, T.; Keino,
K.; Tsubuki, M. J . Chem. Soc., Chem. Commun. 1990, 650-652. (e)
Zhou, W.-S.; J iang, B.; Pan, X. Tetrahedron 1990, 46, 3173-3188.
(8) (a) Mori, K.; Sakakibara, M.; Ichikawa, Y.; Ueda, H.; Okada, K.;
Umemura, T.; Yabuta, G.; Kuwahara, S.; Kondo, M. Tetrahedron 1982,
38, 2099-2109. (b) Anastasia, M.; Ciuffreda, P.; Fiecci, A. J . Chem.
Soc., Perkin Trans 1 1983, 379-382. (c) Takatsuto, S.; Ikekawa, N.
Chem. Pharm. Bull. 1985, 32, 2001-2004.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Instituto de Qu´ımica Orga´nica, C.S.I.C., J uan de la Cierva, 3,
28006 Madrid, Spain.
(2) Grove, M. D.; Spencer, G. F.; Rohwedder, W. K.; Mandava, N.;
Worley, J . F.; Warthen, J . D.; Steffens, G. L.; Flippen-Anderson, J . L.;
Cook, J . C., J r. Nature 1979, 281, 216-217.
(3) Brassinosteroids, Chemistry, Bioactivity and Applications; Cutler,
H. G., Yokota, T., Adam, G., Eds.; ACS Symposium Series 474;
American Chemical Society: Washington DC, 1991: (a) Natural
occurrences: Kim, S.-K., Chapter 3. (b) Improvements in elongation,
yields and resistance of various crops, inter alia: Schilling, G.; Schiller,
C.; Otto, S., Chapter 18; He, R.; Wang, G.; Wang, X., Chapter 19; Sasse,
J . M., Chapter 22. (c) Antitumoral activity: Bach, T. J .; Roth, P. S.;
Thompson, M. J ., Chapter 15. (d) Isolation: Steffens, G. L., Chapter
1. (e) Synthesis: McMorris, T. C.; Donaubauer, J . R.; Silveira, M. H.;
Molinski, T. F., Chapter 4. (f) Biological activity of naturally occurring
24-epibrassinolide: Ikekawa, N.; Zhao, Y.-J ., Chapter 24.
(4) For accounts on this topic, see: (a) Zhou, W.-S. Pure Appl. Chem.
1989, 61, 431-434. (b) Khripach, V. A. Pure Appl. Chem. 1990, 62,
1319-1324.
0022-3263/96/1961-0109$12.00/0 © 1996 American Chemical Society

110 J . Org. Chem., Vol. 61, No. 1, 1996
Marino et al.
Sch em e 1
Sch em e 3a
Sch em e 2a
a
Key: (a) LDA, THF, -78 °C, 7, 86% overall. (b) Ms2O, pyr, 0
°C, 84%. (c) MeCuCNLi or MeCuCNMgBr, THF, -23 to 0 °C, 76%.
(d) EtCuCNMgBr, THF, -23 °C to rt, 70%. (e) 1. t-BuLi, THF,
-78 °C. 2. MeOH, 98%. (f) 10 mol % K2OsO2(OH)4, 40 mol %
(DHQD)2-PHAL, K3Fe(CN)6, K2CO3, MeSO2NH2, t-BuOH/H2O, 1:1,
rt, 30 h, 70% for (+)-2; 5 days, 75% overall for (+)-11.
a
straightforward and stereoselective manner from
(+)-2 employing ADH reactions.
Resu lts a n d Discu ssion
a
R ) Me, t-Bu, Ph; R1 ) Et, Ph(CH2)2-; R2 ) Ph, n-Bu, Me.
At the initial stage of our investigation, we explored
the lithiation of the (Rs)-vinyl sulfoxide (+)-6 and its
condensation with the C-22 steroidal aldehyde 713 (Scheme
3) to produce a disappointing 60:40 mixture of readily
separable (22R)- and (22S)-allylic alcohols (+)-8a and
(+)-8b, respectively, in excellent overall yield. The
stereochemistry was unambiguously established from the
1H NMR data (J 20-22 ) 0 Hz for the (22R)- and 6.4 Hz
for the (22S)-alcohol),14 the major product being the one
arising from the Cram attack through the less hindered
carbonyl face. Thorough studies of the reaction of lithi-
ated vinyl sulfoxides and nonchiral aldehydes by Posner15a
stereoselectivity (15:1), and high asymmetric induction
to produce homochiral trisubstituted vinyl sulfoxides
(Scheme 2).9 When type A substrates were employed and
regardless of the size of the R ligand introduced, highly
selective formation of the (Z)-vinyl sulfoxide 4a was
observed. For type B diastereomers, either of the two
possible substitution products, 5a ,b was obtained. Over-
all, the results could be rationalized in terms of SN2′
oxidative addition of the cuprate anti to the mesylate and
anti to the p-tolyl group.10 For the latter diastereomer,
the observed ratio 5a /5b seems to depend on the reaction
conditions and the steric requirements of the substrate.
As a result, the new carbon stereocenter is allylic to the
synthetically useful vinyl sulfoxide group. Therefore, we
envisioned that the absolute configuration at the chiral
C-24 position of the brassinosteroidal side chains could
be selectively controlled by means of this methodology if
C-23 sulfinyl derivatives 3 were employed and led to the
steroidal ∆22(23) olefin (+)-2 (Scheme 1). Since several
disclosures in asymmetric dihydroxylation (ADH) of
steroidal olefins11 and continuous developments of new
alkaloidal ligands for ADH have recently appeared,12
direct precursors of brassinolide should be accessible in
(11) (a) Huang, L.-F.; Zhou, W.-S.; Sun, L.-Q.; Pan, X.-F. J . Chem.
Soc., Perkin Trans. 1 1993, 1683-1686. (b) McMorris, T. C.; Patil, P.
A. J . Org. Chem. 1993, 58, 2338-2339. (c) Brosa, C.; Peracaula, R.;
Puig, R.; Ventura, M. Tetrahedron Lett. 1992, 33, 7057-7060. (d) Zhou,
W.-S.; Huang, L.-F.; Sun, L.-Q.; Pan, X.-F. Tetrahedron Lett. 1991, 32,
6745-6748.
(12) (a) Lohray, B. B. Tetrahedron: Asymmetry 1992, 3, 1317-1349.
(b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771.
(13) Easily available from stigmasterol; see: (a) Anderson, G. D.;
Thomas, J . P.; Djerassi, C.; Fayos, J .; Clardy, J . J . Am. Chem. Soc.
1975, 97, 388-394. (b) Salmond, W. G.; Sobala, M. C. Tetrahedron
Lett. 1977, 20, 1695-1698.
(14) For analogous structural assignments in similar products, see
refs 5b, c, e, and k and ref 31.
(15) (a) Posner, G. H.; Mallamo, J . P.; Miura, K.; Hulce, M. Pure
Appl. Chem. 1981, 53, 2307-2314 and references cited therein. (b)
Cheng, H.-C.; Yan, T.-H. Tetrahedron Lett. 1990, 31, 673-676. (c)
Solladie, G.; Moine, G. J . Am. Chem. Soc. 1984, 106, 6097-6098. (d)
Fawcett, J .; House, S.; J enkins, P. R.; Lawrence, N. J .; Russell, D. R.
J . Chem. Soc., Perkin Trans 1 1993, 67-72.
(9) Marino, J . P.; Viso, A.; Ferna´ndez de la Pradilla, R.; Ferna´ndez,
P. J . Org. Chem. 1991, 56, 1349-1351.
(10) For the proposed predominate conformations in solution of A
and B diastereomeric mesylates showing the most favored approach
of the cuprate, see ref 9.

Stereocontrolled Synthesis of Brassinolide
J . Org. Chem., Vol. 61, No. 1, 1996 111
and others15b failed to result in high levels of diastereo-
selectivity, although complete selectivity was encountered
in one isolated example.15c Recent insight in this process15d
showed that an increase in the steric size of the aldehyde
with respect to unbiased substrates should favor (up to
70% diastereomeric excess the formation of type B
diastereomers (Scheme 2, (S)-allylic alcohols when (Rs)-
vinyl sulfoxides are employed). We anticipated that
useful selectivities in the addition of chiral vinyl sulfox-
ides to R-substituted chiral aldehydes, an outcome that
had not been previously reported, could be eventually
obtained.
On the basis of the rationale we previously proposed,9
the highly diastereoselective anti SN2′ displacements16
on steroidal allylic mesylates appeared feasible. How-
ever, steric factors inherent in the steroid nucleus should
affect the stereochemical outcome of the cuprate addi-
tions. The functionalization of these allylic steroidal
alcohols with the appropriate leaving group proved not
to be straightforward. After considerable experimenta-
tion, only reactions with methanesulfonic anhydride
(Ms2O) in pyridine provided good to excellent yields of
the desired mesylate derivatives.17 When the reaction
of the mesylate derived from (+)-8a (a type A diastereo-
mer) with lower order methyl cyanocuprate was carried
out, no reaction was observed between -78 and -30 °C;18
however, the addition of 3 equiv of MeCuCNLi or
MeCuCNMgBr in THF from -23 to 0 °C cleanly afforded
a good yield of the desired (22Z,24S)-vinyl sulfoxide (-)-9
as a sole product (Scheme 3). No traces of the diastereo-
meric (22E,24R)-vinyl sulfoxide 19 (vide infra) could be
detected within the detection limit of 360 MHz 1H NMR.19
Reductive desulfurization of (-)-9 using Okamura’s
procedure20 smoothly proceeded in almost quantitative
yield. As expected, upon addition of a slight excess21 of
t-BuLi, a rapidly formed intermediate20b was stereo-
specifically protonated to yield the (E)-alkene (+)-2,
which upon osmylation led to (+)-12â.
data for (+)-11 matched those previously described for
this product,22 confirming the stereochemical assign-
ments for the SN2′ products.
It is also known that the observed ratio of diols in the
osmium-catalyzed cis-dihydroxylations of ∆22(23) steroidal
side chains strongly depends on the specific substitution
at the C-24 position. In particular, osmylation of (24S)-
ethyl substituents leads almost exclusively to the un-
desired (22S,23S)-diol (attack from the R face). On the
other hand, ca. equimolecular mixtures of â/R diols have
been obtained in different examples using (24R)-methyl
derivatives.8,23 When ADH procedures are utilized with
the bis(chinchona) alkaloidal ligands, â diols are obtained
selectively.11b Thus, we explored the AD-mix-â
osmylation12b,24 of (+)-11 as a model to afford (+)-13â,11c
which exhibited the side chain of 24-homobrassinolide,
along with (+)-13R in an 80:20 ratio. On the other hand,
we were pleased to discover that under the same condi-
tions, ADH reaction of olefin (+)-2 gave rise to the
(22R,23R,24S)-diol (+)-12â ([R]D ) +37.6°, c ) 1.65,
CHCl3, mp 76-78 °C),
a
known precursor of
brassinolide,5b,c,g with total stereoselectivity.25
Encouraged by these selectivities and in order to
extend the scope of our methodology, we addressed the
introduction of the opposite C-24 stereochemistry. In the
condensation of the 1-(E)-propenyl sulfoxide (+)-14 with
7 (Scheme 4), a 60:40 separable mixture of diastereomers
(+)-15a and (+)-15b was observed. The naturally oc-
curring side chain of (24R)-epibrassinolide3f could be
synthesized following a similar protocol from the (R)-
alcohol (+)-15a to the vinyl sulfoxide (-)-16 and then to
the (+)-18â diol. Once again, complete stereoselectivity
was encountered for SN2′ displacement using i-PrCu-
CNMgCl and ADH osmylation of desulfurized olefin (+)-
17.7a We also envisioned from our models9 that brass-
inolide side chain stereochemistry could be alternatively
obtained from (+)-15b (type B diastereomer) and iso-
propyl cyanocuprate addition if a (Z)-vinyl sulfoxide of
type 5a (Scheme 2) becomes the main product of the
reaction. In this case, an inseparable mixture of (-)-9
(5.64 ppm, d, H-22) and 19 (6.20 ppm, d, H-22) was
produced, probably due to the fact that the sterically
unbiased methyl group is not bulky enough to favor one
of the two possible reaction pathways.
In order to secure more evidence on the absolute
configuration of the acyclic stereocenter, a reaction of the
aforementioned mesylate with ethyl cyanocuprate was
performed to give (-)-10, followed by t-BuLi-mediated
removal of the sulfinyl group. In this manner, stigmas-
terol isomethyl ether, (+)-11, was obtained, again with
complete stereoselectivity. The spectral and analytical
In an effort to improve the initial diastereoselectivity
of the vinyl sulfoxide (+)-6 addition (Scheme 3),26 we
examined the condensation of the (Ss)-vinyl sulfoxide
(-)-6 with 7 (Scheme 5). If double diastereoselection27
were achieved, an improved ratio of alcohols (+)-20a and
(16) For conjugate addition of organometallic reagents to R-sulfinyl
enones, see: Posner, G. H. Acc. Chem. Res. 1987, 20, 72-78 and
references cited therein. For a key reference in asymmetric carbon-
carbon bond formation by SN2′ displacements on allylic mesylates,
see: Ibuka, T.; Habashita, H.; Funakoshi, S.; Fujii, N.; Oguchi, Y.;
Uyehara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1990, 29,
801-803.
(17) In all cases, any other conditions employing MsCl and/or
different solvents and bases led to much slower transformations
resulting in extensive decomposition of the reaction mixtures.
(18) It should be pointed out that the use of Gilman cuprates
resulted in formation of allenic products derived from 1,2-elimination
of sulfoxide and mesyloxy groups. Recently we reported the preparation
of allenes, of high enantiomeric purity, from unusually stabilized
Cu(III) intermediates in this reaction; see: Ferna´ndez de la Pradilla,
R.; Rubio, M. B.; Marino, J . P.; Viso, A. Tetrahedron Lett. 1992, 33,
4985-4988.
(19) The stereochemistry of the double bond in all the adducts can
be deduced from the chemical shift of the vinylic proton and by
comparison with the model substrates, whose absolute configuration
was unambiguously established by X-ray analyses (see ref 9).
(20) (a) Park, G.; Okamura, W. H. Synth. Commun. 1991, 21, 1047-
1054. (b) Theobald, P. G.; Okamura, W. H. J . Org. Chem. 1990, 55,
741-750.
(21) In the original procedure (ref 20), 4.0 equiv of organolithium
reagent was used. For our substrates, we found much better yields
and smooth, instantaneous transformations when only 1.25 equiv of
t-BuLi is added in THF at -78 °C.
(22) Steele, J . A.; Mosettig, E. J . Am. Chem. Soc. 1963, 85, 571-
572.
(23) Takatsuto, S.; Ikekawa, N. Chem. Pharm. Bull. 1982, 30, 4181-
4185.
(24) In our hands, larger amounts of osmium catalyst and (DHQD)2-
PHAL were required for this transformation (see Experimental Sec-
tion). The use of the commercially available AD-mix-â reagent resulted
in extremely slow olefin conversion.
(25) In contrast with these results, Zhou (ref 10a) has reported
identical selectivities (8:1) for ADH of stigmasterol and (24S)-ergosterol
derivatives using monochinchona ligands, DHQD-PHN and DHQD-
p-chlorobenzoate, respectively. The spectral and physical data of (+)-
12â, identical to those reported in the literature, confirms the
stereochemistry of all the intermediates (see Experimental Section).
(26) All attempts to interconvert the allylic alcohols 8a and b failed.
A large number of conditions for the Mitsunobu protocol or the
inversion of the mesylate derivative of (+)-8b were unsuccessful. For
similar puzzling observations where inversion of propargylic C-22
steroidal alcohols afforded very low yields, see ref 5e.
(27) For an elegant approach to brassinosteroids taking advantage
of this concept, see: Furuta, T.; Yamamoto, Y. J . Org. Chem. 1992,
57, 2981-2982.

112 J . Org. Chem., Vol. 61, No. 1, 1996
Marino et al.
Sch em e 4a
F igu r e 1.
other hand, for (Ss)-sulfoxides, one of the two possible
Cram transition states, II, would present an axial
orientation for the aldehyde substituent but no over-
whelming steric interactions should occur. As a result,
the reaction of (-)-6 and 7 could be the matched
combination in this process consistent with the 4:1
selectivity observed.29
Since (+)-20a is also a type B diastereomer with
regard to the relative stereochemistry between hydroxyl
and p-tolyl groups, the stereoselectivity in the nucleo-
philic displacement on this substrate was not predictable.
Then, we were pleased to discover that formation of the
mesylate derivative of (+)-20a and reaction with MeCu-
CNMgBr afforded the (Z)-vinyl sulfoxide (+)-21 (5.76
ppm, d, H-22) as the major product (85:15 d.e.). As
expected, (+)-21 also exhibits the required absolute
configuration at the key C-24 postition. In this case, the
predominate conformation in solution requires that the
bulkier isopropyl substituent is displayed away from the
steroid nucleus, and then the anti attack of the cuprate
affords the (Z)-olefin with good stereoselectivity. Sub-
sequent addition of t-BuLi produced the olefin (+)-2 in
nearly quantitative yield (Scheme 5).
a
Key: (a) LDA, THF, -78 °C, 7, 73% overall. (b) Ms2O, pyr, 0
°C, 82%. (c) i-PrCuCNMgCl, THF, -23 °C to rt, 73%. (d) 1. t-BuLi,
THF, -78 °C. 2. MeOH, 95%. (e) AD-mix-â osmylation (see Scheme
3f), 48 h, 67%. (f) 1. (b) Ms2O, pyr, 0 °C. 2. i-PrCuCNMgCl, THF,
-78 °C to rt, 65% overall.
Sch em e 5a
An additional improvement in the stereoselectivity was
achieved in the condensation of 7 with the lithio deriva-
tive of the R-iodovinyl sulfide 2230 (Scheme 6) that
smoothly provided the Cram/anti-Cram products in a
ratio of 92:8 and excellent overall yield.31 Thus, it seems
that the nonchelated transition state clearly favors a
higher Cram/anti-Cram ratio of adducts than the che-
lated model. At this point and in an effort to secure an
alternative highly stereoselective sequence to obtain (+)-
8a , the most convenient substrate for the cuprate dis-
placement, we explored different conditions for the
oxidation of the vinyl sulfide (+)-23a . The results are
a
Key: (a) LDA, THF, -78 °C, 5, 75% overall. (b) Ms2O, pyr,
93%. (c) MeCuCNMgBr, THF, 0 °C to rt, 71%. (d) 1. t-BuLi, THF,
-78 °C. 2. MeOH, 95%.
20b would result. An 80:20 mixture of diastereomers
was obtained favoring the Cram product. We propose a
chairlike chelation-controlled transition state15c,d where
the aldehyde adopts a Felkin-Anh rotational conforma-
tion.28 Then, the aldehyde substituent can be either axial
or equatorial (Figure 1). For the (Rs)-sulfoxides, Cram
transition state I would display p-tolyl and aldehyde
groups in the most favorable equatorial positions, but
strong steric interaction between isopropyl and methyl
substituents could explain the low ratio of products
encountered. In order to relieve this steric hindrance,
both p-tolyl and the steroid nucleus could adopt axial
dispositions with strong 1,3-diaxial interactions. On the
(29) At this point,
a more important influence of the steroid
framework cannot be ruled out. More detailed studies to determine if
the chirality at sulfur can control the Cram selectivity in additions to
different R-branched chiral aldehydes are underway.
(30) Prepared from p-tolyl thioacetylene (Magriotis, P. A.; Brown,
J . T. Org. Synth. 1993, 72, 252-264) in one step via addition of 0.5
equiv of i-Pr2CuMgBr in Et2O at -35 °C followed by addition of iodine
(2.0 equiv) 84%; see: (a) Alexakis, A.; Cahiez, G.; Normant, J . F.;
Villieras, J . Bull. Soc. Chim. Fr. 1977, 693-698. (b) Vermeer, P.; de
Graaf, C.; Meijer, J . Recl. Trav. Chim. Pays-Bas 1974, 93, 24-25.
(31) For similar results using an analogous 1-iodovinyl silane, see:
Khripach, V. A.; Zhabinskiy, V. N.; Olkhovick, V. K. Tetrahedron Lett.
1990, 31, 4937-4940.
(28) See: Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987,
109, 3353-3361 and references cited therein.

Stereocontrolled Synthesis of Brassinolide
J . Org. Chem., Vol. 61, No. 1, 1996 113
Sch em e 6a
control experiment (entry 4) which also afforded (+)-20a ,
although with low chemical yield. Finally, the asym-
metric oxidation using the most effective Davis reagent,
(-)-N-(phenylsulfonyl)(3,3-dichlorocamphoryl)oxaziri-
dine,34 in CCl4 (entry 5) also favored the same product
with high diastereomeric excess. Thus, we can conclude
that the stereochemistry at the C-22 hydroxyl group is
the determinant for the stereochemical outcome of the
oxidation and that only the S configuration at sulfur can
be selectively obtained from vinyl sulfide (+)-23a .
Concurrent model studies from our group employing
different oxidation states at sulfur for the SN2′ reaction35
have indicated that similar stereoselectivities for the
cuprate additions could be eventually achieved using the
analogous sulfides. Consequently, we also explored the
reactivity of the unstable mesylate derived from (+)-23a
(Scheme 6) with a methyl cyanocuprate and found that
the (22Z,24S)-vinyl sulfide (+)-24 was produced in a
highly stereoselective manner. Subsequent oxidation of
(+)-24 with 1.0 equiv of m-CPBA and t-BuLi-mediated
desulfurization of the crude mixture of sulfoxides led
again to the desired olefin (+)-2. In this manner, the
aforementioned routes of Schemes 5 and 6 also provide
a stereoselective alternative for the formal synthesis of
1 outlined in Scheme 1.
a
Key: (a) t-BuLi, THF, -78 °C, 5, 84% overall. (b) Modified
Sharpless oxidation; see Table 1. (c) Ms2O, Et3N, cat. DMAP, THF,
0 °C. (d) MeCuCNLi, -78 °C to rt, 55% (2 steps). (e) m-CPBA,
CH2Cl2, 0 °C. (f) t-BuLi, THF, -78 °C, 80% (2 steps).
Sch em e 7
In summary, the results described herein conclusively
establish a new stereoselective and practical route to
brassinolide (1), taking advantage of the nucleophilic
displacement of allylic mesyloxy vinyl sulfoxides and
sulfides. The extension of the scope of this methodology
to another episteroidal side chain synthesis has also been
successfully developed. The diastereoselective nature of
these procedures indicates that our proposed model for
acyclic stereocontrol using chiral sulfoxides will provide
promising applications in natural product synthesis
involving asymmetric carbon-carbon bond formation.
Ta ble 1. Oxid a tion Rea ction s of Ster oid a l Vin yl Su lfid e
(+)-23a
entry
conditionsa
ratio RS/SS yieldb
1
2
3
4
5
m-CPBA, 0 °C
13:87
0:100
0:100
0:100
15:85
80
90
82
45c
64
CHP, Ti(Oi-Pr)4, (+)-DET, -20 °C
CHP, Ti(Oi-Pr)4, (-)-DET, -20 °C
tBuOOH, Ti(Oi-Pr)4, -78 °C
Davis reagent,d rt
Exp er im en ta l Section
Gen er a l Meth od s. All reactions except bis hydroxylations
were carried out under a positive pressure of dry nitrogen
using freshly distilled solvents under anhydrous conditions.
Reagents and solvents were handled by using standard syringe
techniques. Diethyl ether and tetrahydrofuran were distilled
from sodium and benzophenone, dichloromethane, N,N-diiso-
propylamine, and triethylamine from calcium hydride, and
pyridine from sodium hydroxide. Commercial methyllithium
(low halide solution in ether), n-butyllithium (solution in
hexanes), and tert-butyllithium (solution in pentanes) were
purchased from Aldrich and titrated prior to use.36 Methyl-
magnesium bromide, ethylmagnesium bromide, and isopro-
pylmagnesium chloride (solutions in diethyl ether) were
purchased from Aldrich. Copper cyanide was dried at 50-60
°C/0.2 mmHg for 16 h prior to use. All other reagents were
used without further purification. 1,4-Bis(dihydroquinidine)-
phthalazine, (DHQD)2-PHAL, was prepared using the proce-
dure reported by Sharpless et al.12b Flash chromatography
was performed using Baker 40 µm silica gel. Analytical TLC
was carried out on 250 micro Analtech silica gel plates with
detection by UV light, iodine, or acidic vanillin solution.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded at 300 or 360 MHz using CDCl3 as the solvent. The
following abbreviations were used to describe peak patterns
a
All reactions were carried out in CH2Cl2 except for entry 5
b
where CCl4 was employed. Unoptimized yields of pure product
after chromatography. c Significant amounts (ca. 20%) of starting
d
material and corresponding sulfone were removed. (3′S,2R)-
(-)-N-(Phenylsulfonyl)(3,3-dichlorocamphoryl)oxaziridine; see ref
34.
summarized in Scheme 7 and Table 1. Remarkably, the
asymmetric oxidation employing the modified Sharpless
reagent32 with cumene hydroperoxide (CHP) and L-(+)-
diethyl tartrate at low temperature (entry 2) led to the
(Ss)-sulfoxide (+)-20a as the only product. It is likely
that the proximal hydroxyl group, to which the oxidant
can bind, enhanced the diastereoselectivity because the
simple oxidation employing m-CPBA afforded an 87:13
mixture of (Ss)-sulfoxide/(Rs)-sulfoxide, respectively (entry
1).33 Surprisingly, when the same conditions were uti-
lized in the presence of the D-(-)-diethyl tartrate (entry
3) the same stereochemistry at sulfur was obtained.
Once again, any traces of the known Rs diastereomer
could not be detected. The assumption that the chiral
auxiliary might not be really enhancing the diastereo-
selection in the oxidation process was confirmed with the
(34) Davis, F. A.; Thimma Reddy, R.; Han, W.; Carroll, P. J . J . Am.
Chem. Soc. 1992, 114, 1428-1437. For an account, see: Davis, F. A.;
Thimma Reddy, R.; Han, W.; Reddy, R. E. Pure Appl. Chem. 1993, 65,
633-640.
(35) Marino, J . P.; Ferna´ndez de la Pradilla, R.; et al. Manuscript
in preparation.
(32) (a) Pitchen, P.; Dun˜ach, E.; Deshmunkh, M. N.; Kagan, H. B.
J . Am. Chem. Soc. 1984, 106, 8188-8193. (b) Di Furia, F.; Modena,
G.; Seraglia, R. Synthesis 1984, 325-326.
(33) The directing effect of a hydroxyl group in m-CPBA diastereo-
selective oxidation of 10-sulfinyl isoborneols is known; see: Arai, Y.;
Matsui, M.; Koizumi, T. Synthesis 1990, 320-323.
(36) Watson, S. C.; Eastham, J . J . Organomet. Chem. 1967, 9, 165-
168.

114 J . Org. Chem., Vol. 61, No. 1, 1996
Marino et al.
when appropriate: br ) broad, s ) singlet, d ) doublet, t )
triplet, q ) quartet, m ) multiplet. Optical rotations were
measured at 20 °C using a sodium lamp and in CHCl3 solution.
Gen er a l P r oced u r e for th e Con d en sa tion of Vin yl
Su lfoxid es a n d Ster oid Ald eh yd e 7. To a cold (-78 °C)
0.1 M solution of 1.5 equiv of LDA, previously formed at 0 °C
over 30 min, was slowly added 1 equiv of (E)-3-methyl-1-p-
tolylsulfinyl-1-butene, 6,37 or (E)-1-(p-tolylsulfinyl)-1-propene,
1438 (0.05 M solution in THF), via syringe. After the mixture
was stirred for 10 min, 1.2 equiv of (20S)-6â-methoxy-3R,5-
cyclo-5R-pregnane-20-carboxaldehyde, 713 (1.0 M solution), was
added dropwise. The reaction mixture was quenched after 1.5
h of stirring at -78 °C with a saturated NH4Cl solution. The
aqueous layer was extracted with EtOAc (40 mL/mmol of
starting material), and the combined organic layers were
washed with water and a saturated NaCl solution, dried over
MgSO4, and filtered. Concentration under reduced pressure
gave a crude product, which was purified by column chroma-
tography on silica gel, using the appropriate mixture of
hexanes and EtOAc.
of starting alcohol). The aqueous phase was extracted with
CH2Cl2 (two times, 20 mL/mmol), and the combined organic
layers were washed sequentially with 10% aqueous HCl (four
times, 20 mL/mmol), water (two times, 15 mL/mmol), and brine
(20 mL/mmol). Drying over anhydrous MgSO4, filtration, and
evaporation of the solvent in vacuo afforded a crude product
which was purified by column chromatography on deactivated
silica gel (washed with a MeOH/5% aqueous solution of
NaHCO3, 95:5) to give the corresponding mesylate derivatives
which were used shortly thereafter for the cuprate displace-
ment without further purification. Formation of the mesylates
1
was checked by H NMR.
Gen er a l P r oced u r e for th e SN2′ Ad d ition of Meth yl
Cya n ocu p r a te Rea gen ts to Ster oid Mesyla tes. To a cold
(-23 or -78 °C) solution of the organocuprate reagent (formed
from CuCN and organolithium or Grignard reagents, amounts
shown in each case) in THF (20 mL/mmol of mesylate) was
added dropwise the mesylate in THF (2 mL/mmol) with
vigorous stirring, and the resulting mixture was stirred and
slowly warmed (conditions shown in each case). After comple-
tion (TLC) the solution was quenched with a saturated NH4Cl
solution and diluted with ethyl ether. The layers were
separated, the aqueous layer was extracted with Et2O (two
times, 20 mL/mmol), the combined organic extracts were
washed with a saturated solution of Na2S2O3 (two times, 10
mL/mmol) and brine and dried over MgSO4. Removal of the
drying agent by filtration and evaporation of the solvent in
vacuo afforded a crude product which was purified by column
chromatography on silica gel with the appropriate eluent.
(-)-(22Z,24S ,R s )-6â-Me t h oxy-24-m e t h yl-23-(p -t olyl-
su lfin yl)-3r,5-cyclo-5r-er gost-22-en e, (-)-9. From (+)-8a
(300 mg, 0.54 mmol) and Ms2O (280 mg, 1.63 mmol, 3.0 equiv),
the mesylate derivative (287 mg, 84%) was obtained. 1H NMR
data: δ 0.68 (s, 3 H), 1.01 (s, 3 H), 1.05 (d, 3 H, J ) 6.7 Hz),
1.08 (d, 3 H, J ) 6.5 Hz), 1.14 (d, 3 H, J ) 6.4 Hz), 2.41 (s, 3
H), 2.47 (s, 3 H), 2.76 (br s, 1 H), 3.02 (m, 1 H), 3.33 (s, 3 H),
5.29 (br s, 1 H), 6.41 (d, 1 H, J ) 11.2 Hz), 7.33 (d, 2 H, J )
8.0 Hz), 7.53 (d, 2 H, J ) 8.1 Hz). From this compound (400
mg, 0.63 mmol) and 3.0 equiv of MeCuCNLi or MeCuCNMgBr,
in THF from -23 to 0 °C over 2 h, (-)-9 was isolated (265 mg,
76%) as a single isomer (360 MHz 1H NMR), after silica gel
chromatography (hexanes/EtOAc, 5:1). Data of (-)-9: white
solid; Rf ) 0.18 (hexanes/EtOAc, 4:1); mp 206-207 °C (EtOH);
[R]D ) -81.8° (0.82); 1H NMR δ 0.15 (d, 3 H, J ) 6.6 Hz), 0.44
(dd, 1 H, J ) 7.9, 5.1 Hz), 0.66 (apparent t, 1 H, J ) 4.6 Hz),
0.72 (d, 3 H, J ) 6.5 Hz), 0.85 (s, 3 H), 0.88-0.99 (m, 3 H),
1.04 (s, 3 H), 1.10 (d, 3 H, J ) 6.8 Hz), 1.14 (d, 3 H, J ) 6.5
Hz), 1.07-1.30 (m, 7 H), 1.42-1.57 (m, 5 H), 1.59-1.67 (m, 1
H), 1.71-1.83 (m, 3 H), 1.91 (dt, 1 H, J ) 13.3, 2.8 Hz), 2.02
(dt, 1 H, J ) 12.8, 2.1 Hz), 2.21 (apparent q, 1 H, J ) 7.1 Hz),
2.39 (s, 3 H), 2.78 (t, 1 H, J ) 1.2 Hz), 3.33 (s, 3 H), 5.64 (d, 1
H, J ) 10.8 Hz), 7.26 (d, 2 H, J ) 8.1 Hz), 7.41 (d, 2 H, J ) 8.1
Hz); 13C NMR δ 13.0, 13.2, 19.1, 19.4, 20.1, 20.7, 21.1, 21.3,
21.7, 22.9, 24.3, 25.1, 28.2, 30.6, 32.0, 33.5, 35.1, 35.2, 35.5,
35.9, 40.5, 43.2, 43.5, 48.3, 56.5, 56.6, 56.7, 82.4, 124.4, 129.4,
139.9, 140.3, 141.8, 146.3; IR (CCl4) 2957, 2868, 1456, 1372,
1261, 1099, 1082, 1045, 1015 cm-1; MS (CI/NH3) m/ e 551 [M
+ H]+ (100), 519, 503, 247; HRMS calcd for C36H54SO2H [M +
H]+: 551.3923, found 551.3936. Anal. Calcd for C36H54SO2:
C, 78.49; H, 9.88. Found: C, 78.37; H, 9.84.
(+)-(22R,23E,Rs)-22-H yd r oxy-6â-m et h oxy-23-(p -t olyl-
su lfin yl)-3r,5-cyclo-5r-ch olest-23-en e, (+)-8a , a n d (+)-
(22S,23E,Rs)-22-h yd r oxy-6â-m eth oxy-23-(p-tolylsu lfin yl)-
3r,5-cyclo-5r-ch olest-23-en e, (+)-8b. From (+)-6 ([R]D
)
+66.0° (c ) 1.00), 900 mg, 4.32 mmol) and 7 (1.78 g, 5.18
mmol), (+)-8a and (+)-8b were obtained as a 60:40 mixture
(360 MHz 1H NMR) and were separated by chromatography
on silica gel (hexanes/EtOAc, 4:1) to afford (+)-8a (1.23 g) and
(+)-8b (825 mg), overall yield 86%. Data of (+)-8a : white
solid; Rf ) 0.39 (hexanes/EtOAc, 2:1); mp: 193-194 °C (Et2O/
1
hexanes); [R]D) +100.1° (1.03); H NMR δ 0.44 (d, 1 H, J )
7.9, 5.1 Hz), 0.65 (m, 1 H), 0.67 (s, 3 H), 0.84-0.89 (m, 2 H),
1.00-1.15 (m, 3 H), 1.02 (s, 3 H), 1.03 (d, 3 H, J ) 6.8 Hz),
1.08 (d, 3 H, J ) 6.5 Hz), 1.10 (d, 3 H, J ) 6.4 Hz), 1.21-1.32
(m, 4 H), 1.35-1.65 (m, 6 H), 1.71-1.78 (m, 3 H), 1.83-1.97
(m, 2 H), 2.07 (br s, 1 H), 2.34 (s, 3 H), 2.73 (m, 2 H), 3.28 (s,
3 H), 4.58 (br s, 1 H), 6.26 (d, 1 H, J ) 10.8 Hz), 7.20 (d, 2 H,
J ) 8.1 Hz), 7.49 (d, 2 H, J ) 8.1 Hz); 13C NMR δ 12.0, 12.2,
13.0, 14.1, 19.2, 21.3, 21.3, 22.3, 22.5, 22.7, 24.0, 24.9, 27.4,
28.2, 30.5, 33.3, 35.0, 40.1, 42.6, 42.6, 43.3, 47.9, 52.1, 56.3,
56.5, 72.1, 82.3, 125.8, 129.7, 139.6, 141.3, 142.4, 143.5; IR
(KBr) 3613, 3673, 2960, 2869, 1596, 1457, 1382, 1247, 1080,
1039, 1015, 928 cm-1; MS (CI/NH3) m/ e 553 [M + H]+ (100),
521, 505, 381, 237, 109, 91; HRMS calcd for C35H52SO3H [M
+ H]+: 553.3715, found 553.3693. Anal. Calcd for C35H52
-
SO3: C, 76.03; H, 9.48. Found: C, 76.25; H, 9.38. Data of
(+)-8b: white solid; Rf ) 0.29 (hexanes/EtOAc, 2:1); mp 143-
1
144 °C (Et2O/hexanes); [R]D) +76.9° (1.00); H NMR δ 0.43
(dd, 1 H, J ) 7.9, 5.1 Hz), 0.65 (apparent t, 1 H, J ) 4.8 Hz),
0.72 (s, 3 H), 0.78-0.90 (m, 3 H), 0.88 (d, 3 H, J ) 6.8 Hz),
0.98-1.84 (m, 5 H), 1.01 (s, 3 H), 1.05 (d, 3 H, J ) 6.5), 1.07
(d, 3 H, J ) 6.2 Hz), 1.27 (m, 2 H), 1.33-1.56 (m, 4 H), 1.61-
1.77 (m, 3 H), 1.80-1.95 (m, 3 H), 2.14 (br d, 1 H, J ) 5.1 Hz),
2.40 (s, 3 H), 2.77 (br s, 1 H), 3.00 (m, 1 H), 3.32 (s, 3 H), 4.10
(dd, 1 H, J ) 6.4, 5.3 Hz), 6.14 (d, 1 H, J ) 10.8 Hz), 7.28 (d,
2 H, J ) 8.3 Hz), 7.55 (d, 2 H, J ) 8.1 Hz); 13C NMR δ 12.3,
13.0, 15.8, 19.2, 21.4, 22.1, 22.6, 22.7, 24.6, 24.9, 28.5, 28.9,
30.4, 33.3, 35.0, 35.2, 40.1, 42.7, 43.3, 43.6, 47.9, 54.1, 56.0,
56.5, 74.7, 82.3, 126.0, 129.9, 140.6, 141.8, 142.0, 142.2; IR
(CCl4) 3358, 2937, 2867, 1459, 1264, 1177, 1097, 1013 cm-1
;
MS (CI/NH3) m/ e 553 [M + H]+, 363, 253, 237 (100), 140, 109;
HRMS calcd for C35H52SO3H [M + H]+: 553.3715, found
553.3716. Anal. Calcd for C35H52SO3: C, 76.03; H, 9.48.
Found: C, 75.78; H, 9.55.
(-)-(Rs)-23-(p -Tolylsu lfin yl)st igm a st er yl Isom et h yl
Eth er , (-)-10. From the mesylate derivative of (+)-8a (260
mg, 0.42 mmol) and 3.0 equiv of EtCuCNMgBr, in THF from
-23 °C to rt over 4 h, (-)-10 was isolated (170 mg, 73%) as a
single isomer after silica gel chromatography (hexanes/EtOAc,
5:1). Data of (-)-10: white solid; Rf ) 0.27 (hexanes/EtOAc,
Gen er a l P r oced u r e for th e Mesyla tion of Ster oid a l
Allylic Alcoh ols. To a vigorously stirred cold (0 °C) solution
of 22-hydroxyl derivative (ca. 0.5 mmol) in pyridine (6 mL)
was added methanesulfonic anhydride (amounts shown in each
case). The reaction mixture was stirred and warmed to rt over
3 h, after which time it was poured into an ice-cold saturated
solution of NaHCO3 and diluted with CH2Cl2 (100 mL/mmol
1
4:1); mp 203-204 °C (EtOH); [R]D) -63.7° (1.10); H NMR δ
0.27 (d, 3 H, J ) 4.7 Hz), 0.45 (dd, 1 H, J ) 7.9, 5.2 Hz), 0.64
(d, 3 H, J ) 6.6 Hz), 0.65 (apparent t, 1 H, J ) 4.8 Hz), 0.83-
0.92 (m, 2 H), 0.85 (t, 3 H, J ) 6.6 Hz), 0.86 (s, 3 H), 1.04 (s,
3 H), 1.15 (d, 3 H, J ) 6.5 Hz), 1.02-1.29 (m, 5 H), 1.42-1.63
(m, 10 H), 1.73-1.78 (m, 4 H), 1.91 (dt, 1 H, J ) 13.0, 2.7 Hz),
2.02 (br d, 1 H, J ) 12.8 Hz), 2.21 (m, 1 H), 2.39 (s, 3 H), 2.78
(br s, 1 H), 3.34 (s, 3 H), 5.63 (d, 1 H, J ) 10.7 Hz), 7.26 (d, 2
H, J ) 8.2 Hz), 7.43 (d, 2 H, J ) 8.2 Hz); 13C NMR δ 10.6,
12.7, 13.0, 18.3, 19.3, 20.1, 20.7, 21.3, 21.4, 22.7, 23.8, 24.3,
(37) Prepared by the Horner-Wittig procedure; see: Mikolajczyk,
M.; Midura, W.; Grzejszczak, S.; Zatorski, A.; Chefczynska, A. J . Org.
Chem. 1978, 43, 473-478.
(38) Prepared from commercially available 1-bromo-1-propene.

Stereocontrolled Synthesis of Brassinolide
J . Org. Chem., Vol. 61, No. 1, 1996 115
24.9, 28.5, 30.2, 30.4, 33.3, 35.0, 35.2, 35.5, 40.3, 41.0, 43.0,
43.3, 48.0, 56.2, 56.5, 56.5, 82.3, 124.3, 129.4, 140.0, 140.4,
142.7, 143.6; IR (CCl4) 2958, 2869, 1549, 1455, 1253, 1082,
1048, 1016 cm-1; MS (EI/70 eV) m/ e 564 [M]+, 547, 393, 261
(100), 253, 109, 83, 69; HRMS calcd for C37H56SO2: 564.4001,
found 564.4006. Anal. Calcd for C37H56SO2: C, 78.67; H, 9.99.
Found: C, 79.09; H, 9.61.
Gen er a l P r oced u r e for th e Red u ctive Desu lfu r iza tion
of Vin yl Su lfoxid es. To a ca. 0.02 M solution of starting vinyl
sulfoxide in THF at -78 °C was added MeLi (1.4 M, 0.25
equiv). After the mixture was stirred for 3 min, t-BuLi (1.7
M, 1.25 equiv) was added dropwise, and the reaction was
stirred for an additional 3 min period. The solution was
quenched with methanol (>20 equiv) at -78 °C and diluted
with water (15 mL/mmol) and diethyl ether (35 mL/mmol). The
aqueous phase was extracted with Et2O (two times, 10 mL/
mmol), and the combined organic layers were washed with
brine (15 mL/mmol) and dried over MgSO4. Removal of the
drying agent and evaporation gave a crude product which was
purified by silica gel chromatography with the appropriate
eluent.
1.54 (m, 4 H), 1.60-1.67 (m, 2 H), 1.71-1.76 (m, 2 H), 1.88
(dt, 1 H, J ) 13.4, 2.9 Hz), 1.95 (dt, 1 H, J ) 12.5, 3.2 Hz),
2.01 (br s, 1 H), 2.05 (br s, 1 H), 2.77 (t, 1 H, J ) 2.7 Hz), 3.32
(s, 3 H), 3.55 (br d, 1 H, J ) 8.5 Hz), 3.70 (br d, 1 H, J ) 8.5
Hz); 13C NMR δ 10.1, 11.9, 12.1, 13.1, 19.3, 20.7, 20.9, 21.4,
22.8, 24.0, 24.9, 27.9, 30.6, 30.8, 33.3, 35.1, 35.2, 36.8, 40.0,
40.3, 42.6, 43.3, 47.9, 52.5, 56.4, 56.6, 73.5, 74.9, 82.4; IR (CCl4)
3406, 2943, 2868, 1549, 1458, 1381, 1098, 978 cm-1; MS (EI/
70 eV) m/ e 446 [M]+, 391, 346, 313 (100), 295, 121, 43; HRMS
calcd for C29H50O3: 446.3760, found 446.3751. Anal. Calcd
for C29H50O3: C, 78.02; H, 11.29. Found: C, 77.78; H, 11.55.
(+)-(22R,23R,24S)-22,23-Dih ydr oxy-24-eth yl-6â-m eth oxy-
3r,5-cyclo-5r-ch olesta n e, (+)-13â, a n d (+)-(22S,23S,24S)-
22,23-Dih ydr oxy-24-eth yl-6â-m eth oxy-3r,5-cyclo-5r-ch oles-
ta n e, (+)-13r. From (+)-11 (990 mg, 2.33 mmol), (DHQD)2-
PHAL (725 mg, 0.93 mmol), K2OsO2(OH)4 (86 mg, 0.23 mmol),
K3Fe(CN)6 (4.60 g, 14 mmol), K2CO3 (1.93 mg, 14 mmol), and
methanesulfonamide (442 mg, 4.66 mmol) in a mixture of
t-BuOH/H2O, 1:1 (50 mL) stirred over 5 days, (+)-13â (600
mg) and (+)-13R (150 mg) were obtained after separation by
silica gel chromatography, overall yield 70%. The NMR data
for these compounds matched those previously described.11c
Data of (+)-13â: Rf ) 0.40 (hexanes/EtOAc, 2:1); [R]D ) +69.1°
(1.38); MS (EI/70 eV) m/ e 460 [M]+, 445, 428, 405, 346, 313
(100), 295, 255, 213, 145, 121, 85, 43; HRMS calcd for
C30H52O3: 460.3916, found 460.3918. Data of (+)-13R: Rf )
0.49 (hexanes/EtOAc, 2:1); [R]D ) +32.7° (0.75); MS (EI/70 eV)
m/ e 460 [M]+, 445, 428, 405, 346, 313 (100), 295, 255, 213,
145, 121, 81, 43; HRMS calcd for C30H52O3: 460.3916, found
460.3902.
(+)-(22E,24S)-6â-Met h oxy-3r,5-cyclo-5r-er gost a n -22-
en e, (+)-2. From (-)-9 (252 mg, 0.60 mmol), MeLi (1.4 M,
0.10 mL), and t-BuLi (1.7 M, 0.44 mL), (+)-2 (236 mg, 98%)
was obtained. No traces of the (22Z)-olefin could be detected
1
by 360 MHz H NMR. Data of (+)-2: white solid; Rf ) 0.37
(hexanes/EtOAc, 19:1); mp 73-74 °C (acetone/H2O, 50:1, v/v);
[R]D ) +50.9° (1.18); 1H NMR δ 0.43 (dd, 1 H, J ) 7.9, 5.0
Hz), 0.65 (dd, 1 H, J ) 4.9, 4.1 Hz), 0.73 (s, 3 H), 0.82 (d, 3 H,
J ) 6.6 Hz), 0.83 (d, 3 H, J ) 6.5 Hz), 0.89 (m, 2 H), 0.93 (d,
3 H, J ) 7.2 Hz), 1.00 (d, 3 H, J ) 6.6 Hz), 1.02 (s, 3 H), 1.04-
1.25 (m, 6 H), 1.37-2.02 (m, 14 H), 2.77 (t, 1 H, J ) 2.7 Hz),
3.32 (m, 3 H), 5.16 (m, 2 H); 13C NMR δ 12.4, 13.1, 18.0, 19.3,
19.6, 20.1, 21.0, 21.5, 22.7, 24.2, 25.0, 28.9, 30.5, 33.2, 33.3,
35.1, 35.3, 40.2, 40.3, 42.7, 43.1, 43.4, 48.1, 56.1, 56.5, 56.6,
82.4, 131.8, 136.1; IR (CCl4) 2957, 2868, 1551, 1456, 1372,
1260, 1098, 1016 cm-1; MS (EI/70 eV) m/ e 412 [M]+, 397, 380,
357 (100), 255, 69; HRMS calcd for C29H48O: 412.3705, found
412.3696. Anal. Calcd for C29H48O: C, 84.40; H, 11.72.
Found: C, 84.60; H, 11.75.
(+)-(22R,23E,Rs)-22-H yd r oxy-6â-m et h oxy-23-(p -t olyl-
su lfin yl)-3r,5-cyclo-5r-26,27-d in or ch olest-23-en e, (+)-15a ,
a n d (+)-(22S,23E,Rs)-22-h yd r oxy-6â-m eth oxy-23-(p-tolyl-
su lfin yl)-3r,5-cyclo-5r-26,27-d in or ch olest -23-en e, (+)-
15b. From (+)-14 (900 mg, 5.0 mmol) and 7 (2.07 g, 6.0 mmol),
(+)-15a and (+)-15b were obtained as a 60:40 mixture (360
MHz 1H NMR) and were separated by chromatography on
silica gel (hexanes/EtOAc, 4:1) to afford (+)-15a (1.06 g) and
(+)-15b (850 mg), overall yield, 73%. Data of (+)-15a : white
solid; Rf ) 0.22 (hexanes/EtOAc, 2:1); mp 191-192 °C (Et2O/
1
Gen er a l P r oced u r e for th e AD-Mix-â Cis-Dih yd r oxyl-
a tion of Ster oid a l Olefin s. To a vigorously stirred cold
solution of (DHQD)2-PHAL (40 mol %), K2OsO2(OH)4 (10 mol
%), K3Fe(CN)6 (6.0 equiv), and K2CO3 (6.0 equiv) in a mixture
of t-BuOH/H2O, 1:1 (20 mL/mmol) at 0 °C, methanesulfon-
amide (2.0 equiv) was added, and the resulting sluggish
solution was stirred for 10 min, after which time the olefin
(1.0 equiv) was added. Stirring was continued, and the
reaction was monitored by TLC until total disappearance of
the starting material. Then, Na2SO3 (500 mg/mmol) was
added, and the mixture was stirred overnight. After dilution
with EtOAc (80 mL/mmol) and water (25 mL/mmol), the
aqueous phase was extracted with EtOAc (three times, 25 mL/
mmol), and the combined organic layers were washed with 2
N KOH (10 mL/mmol) and brine (20 mL/mmol), dried over
MgSO4, and filtered off to give, after evaporation of the
solvents, a crude oil that was purified by silica gel chroma-
tography (hexanes/EtOAc, 4:1).
hexanes); [R]D ) +59.7° (1.24); H NMR δ 0.42 (dd, 1 H, J )
7.9, 5.1 Hz), 0.63 (m, 1 H), 0.64 (s, 3 H), 0.72-0.91 (m, 4 H),
0.95-1.19 (m, 4 H), 1.00 (s, 3 H), 1.01 (d, 3 H, J ) 6.5 Hz),
1.24-1.61 (m, 7 H), 1.69-1.75 (m, 3 H), 1.85 (dt, 1 H, J )
13.4, 2.9 Hz), 1.92 (m, 1 H), 1.92 (d, 3 H, J ) 7.3 Hz), 2.36 (s,
3 H), 2.40 (d, 1 H, J ) 3.8 Hz), 2.75 (t, 1 H, J ) 2.6 Hz), 3.30
(s, 3 H), 4.63 (brs, 1 H), 6.56 (qd, 1 H, J ) 7.3 Hz, 1.0 Hz),
7.23 (d, 2 H, J ) 8.1 Hz), 7.53 (d, 2 H, J ) 8.1 Hz);
13C NMR
δ 12.1, 12.5, 13.1, 14.7, 19.2, 21.3, 21.5, 22.8, 24.1, 25.0, 27.5,
30.6, 33.4, 35.2, 35.3, 40.3, 41.8, 42.8, 43.4, 48.1, 52.3, 56.5,
56.5, 72.4, 82.4, 125.8, 129.0, 129.7, 141.2, 142.4, 147.2. IR
(CCl4
) 3356, 2937, 2868, 1492, 1455, 1378, 1098, 1082, 1013
cm-1; MS (CI/NH3) m/ e 525 [M+H]+, 507, 330, 313, 295, 181
(100); HRMS calcd for C33H48SO3H [M+H]+: 525.3402, found
525.3405. Anal. Calcd for C33H48SO3: C, 75.54; H, 9.22.
Found: C, 75.28; H, 9.34. Data of (+)-15b: white solid; Rf )
0.15 (hexanes/EtOAc, 2:1); mp 156-157 °C (Et2O/hexanes);
[R]D
) +68.0° (0.95); 1H NMR δ 0.42 (dd, 1 H, J ) 7.9, 5.1
Hz), 0.64 (apparent t, 1 H, J ) 4.5 Hz), 0.71 (s, 3 H), 0.74-
0.90 (m, 3 H), 0.86 (d, 3 H, J ) 6.9 Hz), 0.94-1.18 (m, 4 H),
1.01 (s, 3 H), 1.21-1.77 (m, 8 H), 1.85-2.04 (m, 5 H), 1.98 (d,
3 H, J ) 7.3 Hz), 2.31 (br d, 1 H, J ) 4.6 Hz), 2.39 (s, 3 H),
2.77 (t, 1 H, J ) 2.6 Hz), 3.32 (s, 3 H), 4.18 (br dd, 1 H, J )
5.9, 3.8 Hz), 6.42 (q, 1 H, J ) 7.2 Hz), 7.28 (d, 2 H, J ) 8.1
Hz), 7.54 (d, 2 H, J ) 8.1 Hz); 13C NMR δ 12.4, 13.1, 15.1,
15.8, 19.2, 21.4, 21.6, 22.8, 24.7, 25.0, 28.8, 30.6, 33.5, 35.1,
35.4, 40.3, 42.9, 43.4, 43.8, 48.2, 54.3, 56.2, 56.5, 74.6, 82.5,
126.0, 129.9, 130.5, 140.8, 141.9, 146.3; IR (CCl4) 3380, 2934,
2868, 1455, 1374, 1324, 1214, 1098, 1015 cm-1; MS (CI/NH3)
m/ e 525 [M + H]+, 507, 313, 295, 181 (100); HRMS calcd for
C33H48SO3H [M + H]+: 525.3402, found 525.3400. Anal.
Calcd for C33H48SO3: C, 75.54; H, 9.22. Found: C, 75.20; H,
9.41.
(+)-(22R,23R,24S)-22,23-Dih yd r oxy-6â-m et h oxy-3r,5-
cyclo-5r-er gosta n e (+)-12â. From (+)-2 (120 mg, 0.29
mmol), (DHQD)2-PHAL (90 mg, 0.12 mmol), K2OsO2(OH)4
(10.8 mg, 0.029 mmol), K3Fe(CN)6 (575 mg, 1.75 mmol), K2CO3
(240 mg, 1.75 mmol), and methanesulfonamide (56 mg, 0.58
mmol) in a mixture of t-BuOH/H2O, 1:1 (4 mL) stirred over 30
h, (+)-12â (91 mg, 70%) was isolated as a colorless syrup which
was recrystallized from a mixture of CHCl3/hexanes. No other
1
products could be detected by 360 MHz H NMR of the crude
materials. The physical and analytical data for (+)-12â
matched those previously described in the literature. Data of
(+)-12â: white solid; Rf ) 0.38 (hexanes/EtOAc, 2:1); mp 76-
78 °C (CHCl3/hexanes) (lit. mp 70-73 °C,5b 84-90 °C,5g 76-
1
79 °C);5k [R]D ) +37.6° (1.65); H NMR δ 0.43 (dd, 1 H, J )
8.0, 5.1 Hz), 0.64 (apparent t, 1 H, J ) 4.7 Hz), 0.72 (s, 3 H),
0.80-0.91 (m, 4 H), 0.84 (d, 3 H, J ) 6.9 Hz), 0.89 (d, 3 H, J
) 6.2 Hz), 0.94 (d, 3 H, J ) 6.8 Hz), 0.96 (d, 3 H, J ) 6.8 Hz),
1.01 (s, 3 H), 1.02-1.27 (m, 6 H), 1.36-1.43 (m, 2 H), 1.47-
(-)-(22Z,24R ,R s )-6â-Me t h oxy-24-m e t h yl-23-(p -t olyl-
su lfin yl)-3r,5-cyclo-5r-er gost-22-en e, (-)-16. From (+)-
15a (350 mg, 0.67 mmol) and Ms2O (345 mg, 2.0 mmol, 3.0

116 J . Org. Chem., Vol. 61, No. 1, 1996
Marino et al.
equiv), the mesylate derivative (330 mg, 82%) was obtained.
1H NMR data: δ 0.60 (s, 3 H), 0.98 (d, 3 H, J ) 6.6 Hz), 0.99
(s, 3 H), 2.06 (d, 3 H, J ) 7.4 Hz), 2.39 (s, 3 H), 2.49 (s, 3 H),
2.75 (br s, 1 H), 3.31 (s, 3 H), 5.21 (br s, 1 H), 6.75 (q, 1 H, J
) 7.4 Hz), 7.31 (d, 2 H, J ) 8.2 Hz), 7.52 (d, 2 H, J ) 8.2 Hz).
From this compound (240 mg, 1.26 mmol) and 3.0 equiv of
i-PrCuCNMgCl, in THF from -23 °C to rt over 4 h, (-)-16
was isolated (160 mg, 73%) as a single isomer (360 MHz 1H
NMR), after silica gel chromatography (hexanes/EtOAc, 5:1).
Data of (-)-16: white solid; Rf ) 0.18 (hexanes/EtOAc, 4:1);
mp 210-211 °C (EtOH); [R]D ) -87.6° (0.91); 1H NMR δ 0.15
(d, 3 H, J ) 6.6 Hz), 0.45 (dd, 1 H, J ) 7.9, 5.4 Hz), 0.66
(apparent t, 1 H, J ) 4.4 Hz), 0.72 (d, 3 H, J ) 6.6 Hz), 0.85
(s, 3 H), 0.87-1.01 (m, 3 H), 1.04 (s, 3 H), 1.07-1.39 (m, 7 H),
1.11 (d, 3 H, J ) 6.9 Hz), 1.14 (d, 3 H, J ) 6.5 Hz), 1.42-1.60
(m, 6 H), 1.72-1.78 (m, 3 H), 1.88 (dt, 1 H, J ) 13.0, 2.1 Hz),
2.03 (dt, 1 H, J ) 12.9, 2.0 Hz), 2.22 (m, 1 H), 2.39 (s, 3 H),
2.78 (t, 1 H, J ) 1.0 Hz), 3.33 (s, 3 H), 5.64 (d, 1 H, J ) 10.8
Hz), 7.27 (d, 2 H, J ) 7.9 Hz), 7.41 (d, 2 H, J ) 8.2 Hz); 13C
NMR δ 12.8, 13.1, 19.2, 19.3, 20.6, 21.3, 21.3, 21.5, 21.7, 22.8,
24.2, 25.0, 28.2, 30.5, 31.9, 33.4, 35.0, 35.2, 35.8, 40.3, 43.0,
43.4, 48.1, 56.3, 56.6, 82.3, 124.3, 129.5, 139.7, 140.4, 141.8,
146.1; IR (CCl4) 2957, 2869, 1082, 1046 cm-1; MS (CI/NH3)
mg), overall yield, 75%. Data of (+)-20a : white solid; Rf )
0.31 (hexanes/EtOAc, 2:1); mp 196-197 °C (Et2O/hexanes);
1
[R]D) +24.7° (1.50); H NMR δ 0.42 (m, 1 H), 0.42 (s, 3 H),
0.64 (apparent t, 1 H, J ) 4.3 Hz), 0.76-0.90 (m, 4 H), 0.84
(d, 3 H, J ) 6.2 Hz), 1.00-1.18 (m, 3 H), 1.00 (s, 3 H), 1.06 (d,
3 H, J ) 6.5 Hz), 1.09 (d, 3 H, J ) 6.5 Hz), 1.23-1.58 (m, 7
H), 1.66-1.79 (m, 2 H), 1.83-1.87 (m, 4 H), 2.38 (s, 3 H), 2.76
(br s, 1 H), 3.03 (m, 1 H), 3.24 (br s, 1 H), 3.32 (s, 3 H), 4.69
(br s, 1 H), 6.17 (d, 1 H, J ) 10.8 Hz), 7.27 (d, 2 H, J ) 8.2
Hz), 7.44 (d, 2 H, J ) 8.1 Hz); 13C NMR δ 11.9, 12.4, 13.1,
19.2, 21.3, 21.5, 22.4, 22.4, 22.8, 24.1, 25.0, 27.6, 28.6, 30.6,
33.4, 35.1, 35.3, 40.1, 41.6, 42.6, 43.4, 48.0, 52.0, 56.3, 56.5,
72.0, 82.4, 124.5, 129.6, 140.4, 140.7, 143.7, 145.1; IR (CCl4)
3392, 2962, 2869, 1422, 1264, 1080, 1042, 908, 896 cm-1; MS
(CI/NH3) m/ e 553 [M + H]+, 519, 487, 323, 305, 251, 237, 209
(100), 165, 117; HRMS calcd for C35H52SO3H [M + H]+:
553.3715, found 553.3694. Anal. Calcd for C35H52SO3H: C,
76.03; H, 9.48. Found: C, 75.80; H, 9.57.
(-)-(22Z,24S,Ss)-6â-Met h oxy-23-(p -t olylsu lfin yl)-3r,5-
cyclo-5r-er gost-22-en e, (+)-21. From (+)-20a (150 mg, 0.27
mmol) and Ms2O (115 mg, 0.67 mmol, 2.5 equiv), the mesylate
derivative was obtained (158 mg, 93%). 1H NMR data: δ 0.29
(s, 3 H), 0.85 (d, 3 H, J ) 6.5 Hz), 0.99 (s, 3 H), 1.00 (d, 3 H,
J ) 6.8 Hz), 1.13 (d, 3 H, J ) 6.2 Hz), 2.39 (s, 3 H), 2.76 (br s,
1H), 2.89 (s, 3 H), 3.07 (m, 1 H), 3.32 (s, 3 H), 5.25 (d, 1 H, J
) 1.0 Hz), 6.40 (d, 1 H, J ) 11.3 Hz), 7.31 (d, 2 H, J ) 8.0 Hz),
7.45 (d, 2 H, J ) 8.2 Hz). From this compound (150 mg, 0.24
mmol) and 3.0 equiv of MeCuCNMgBr in THF from -23 °C
to rt over 4 h, a 85:15 mixture of SN2′ products was obtained.
m/ e 551 [M + H]+ (100), 519, 503, 247; HRMS calcd for C36H54
-
SO2H [M + H]+: 551.3923, found 551.3915. Anal. Calcd for
C36H54SO2: C, 78.49; H, 9.88. Found: C, 78.78; H, 9.77.
(+)-(22E,24R)-6â-Met h oxy-3r,5-cyclo-5r-er gost a n -22-
en e, (+)-17. From (-)-16 (200 mg, 0.36 mmol), MeLi (1.4 M,
0.09 mL), and t-BuLi (1.7 M, 0.25 mL), (+)-17 (140 mg, 95%)
was obtained. No traces of the (22Z)-olefin could be detected
1
360 MHz H NMR of the crude materials showed doublets at
1
by 360 MHz H NMR. The analytical data for this compound
5.75 ppm (J ) 10.2 Hz) and 6.17 ppm (J ) 10.9 Hz) for
(22Z,24S) and (22E,24R) isomers, respectively. Major isomer
(+)-21 was isolated (94 mg, 71%) after silica gel chromatog-
raphy (hexanes/EtOAc, 5:1). Data of (+)-21: white solid; Rf
matched those described in the literature.7a Data of (+)-17:
white solid; Rf ) 0.37 (hexanes/EtOAc, 19:1); mp 74-75 °C
(acetone/H2O, 50:1, v/v) (lit.7a mp 72-74 °C); [R]D ) +17.6°
(0.72); 1H NMR δ 0.43 (dd, 1 H, J ) 8.0, 5.1 Hz), 0.65 (dd, 1 H,
J ) 4.6, 4.2 Hz), 0.72 (s, 3 H), 0.82 (d, 3 H, J ) 6.6 Hz), 0.84
(d, 3 H, J ) 5.8 Hz), 0.88 (m, 2 H), 0.91 (d, 3 H, J ) 6.8 Hz),
1.01 (d, 3 H, J ) 6.7 Hz), 1.02 (s, 3 H), 1.05-1.27 (m, 6 H),
1.40-2.07 (m, 14 H), 2.77 (t, 1 H, J ) 2.6 Hz), 3.32 (s, 3 H),
5.18 (m, 2 H); 13C NMR δ 12.4, 13.1, 17.6, 19.3, 19.6, 20.0,
20.9, 21.5, 22.8, 24.2, 25.0, 28.6, 30.5, 31.4, 33.1, 33.4, 35.1,
40.2, 40.2, 42.7, 42.8, 43.4, 48.1, 56.2, 56.5, 56.6, 82.4, 131.7,
136.0; IR (CCl4) 2957, 2869, 1550, 1456, 1372, 1324, 1295,
1200, 1098, 1016, 970 cm-1; MS (EI/70 eV) m/ e 412 [M]+, 397,
380, 357 (100), 255, 69; HRMS calcd for C29H48O: 412.3705,
found 412.3695. Anal. Calcd for C29H48O: C, 84.40; H, 11.72.
Found: C, 84.81; H, 11.72.
) 0.26 (hexanes/EtOAc, 5:1); mp 195-196 °C (EtOH); [R]D
)
+115.9° (0.95); 1H NMR δ 0.44 (dd, 1 H, J ) 8.0, 5.2 Hz), 0.58
(d, 3 H, J ) 7.0 Hz), 0.66 (apparent t, 1 H, J ) 4.5 Hz), 0.82
(s, 3 H), 0.86 (d, 3 H, J ) 6.7 Hz), 0.87 (d, 3 H, J ) 6.6 Hz),
1.04 (s, 3 H), 1.06-1.14 (m, 2 H), 1.17-1.37 (m, 3 H), 1.18 (d,
3 H, J ) 6.6 Hz), 1.41-1.59 (m, 6 H), 1.64 (m, 6 H), 1.74 (m,
2 H), 1.88 (m, 1 H), 2.02 (m, 1 H), 2.14 (quintet, 1 H, J ) 7.4
Hz), 2.39 (s, 3 H), 2.78 (t, 1 H, J ) 2.6 Hz), 3.33 (s, 3 H), 5.76
(d, 1 H, J ) 10.2 Hz), 7.27 (d, 2 H, J ) 8.2 Hz), 7.50 (d, 2 H,
J ) 8.2 Hz); 13C NMR δ 12.8, 13.1, 19.1, 19.2, 19.2, 19.3, 21.0,
21.3, 21.4, 22.7, 24.2, 24.9, 28.5, 30.5, 33.3, 33.7, 35.1, 35.2,
35.4, 36.4, 40.1, 43.1, 43.4, 48.0, 56.4, 56.4, 56.6, 82.2, 124.6,
129.5, 140.0, 140.5, 143.9, 145.6; IR (CCl4) 2961, 2869, 1473,
1081, 1030, 928 cm-1; MS (CI/CH4) m/ e 551 [M + H]+, 519,
(+)-(22R,23R,24R)-22,23-Dih yd r oxy-6â-m et h oxy-3r,5-
cyclo-5r-er gosta n e, (+)-18â. From (+)-17 (120 mg, 0.29
mmol), (DHQD)2-PHAL (90 mg, 0.12 mmol), K2OsO2(OH)4
(10.8 mg, 0.029 mmol), K3Fe(CN)6 (575 mg, 1.75 mmol), K2CO3
(240 mg, 1.75 mmol), and methanesulfonamide (56 mg, 0.58
mmol) in a mixture of t-BuOH/H2O, 1:1 (4 mL) stirred over 48
h, (+)-18â (87 mg, 67%) was isolated as a colorless syrup. No
503, 381, 321 (100), 305, 247, 209, 97; HRMS calcd for C36H54
-
SO2H [M + H]+: 551.3923, found 551.3914. Anal. Calcd for
C36H54SO2: C, 78.49; H, 9.88. Found: C, 78.71; H, 9.76.
(+)-(22R ,23E )-22-H y d r o x y -6â-m e t h o x y -23-(p -t o ly l-
su lfen yl)-3r,5-cyclo-5r-ch olest-23-en e, (+)-23a . To a cold
(-78 °C) stirred solution of 1-iodo-3-methyl-1-p-tolylsulfenyl-
1-butene, 2230 (1.52 g, 4.80 mmol, 1.2 equiv), in THF (50 mL),
t-BuLi (1.7 M, 5.6 mL, 2.4 equiv) was added dropwise. The
resulting mixture was stirred for 10 min, after which time 7
(1 M solution in THF, 1.37 g, 1.0 equiv) was added. The
reaction was quenched after 15 min by addition of methanol
(1 mL) at -78 °C and diluted with Et2O (150 mL) and water
(50 mL), and the layers were separated. The aqueous phase
was extracted with Et2O (two times, 30 mL), and the combined
organic layers were washed with brine (two times, 30 mL).
Drying over MgSO4, removal of the drying agent by filtration,
and evaporation in vacuo gave a crude product (92:8 mixture
of (22R)- and (22S)-alcohols by 360 MHz 1H NMR), which was
purified by silica gel chromatography (hexanes/EtOAc, 19:1)
to yield pure (+)-23a (1.65 g) and 23b (150 mg) as colorless
syrups, overall yield, 84%. Data of (+)-23a : Rf ) 0.25
1
other products could be detected by 360 MHz H NMR. Data
of (+)-18â: Rf ) 0.37 (hexanes/EtOAc, 2:1); [R]D ) +18.3°
(0.47); 1H NMR δ 0.43 (dd, 1 H, J ) 8.0, 4.8 Hz), 0.65 (apparent
t, 1 H, J ) 4.6 Hz), 0.74 (s, 3 H), 0.79-0.93 (m, 4 H), 0.86 (d,
3 H, J ) 6.6 Hz), 0.88 (d, 3 H, J ) 6.3 Hz), 0.94 (d, 3 H, J )
6.8 Hz), 0.96 (d, 3 H, J ) 6.8 Hz), 1.02 (s, 3 H), 1.06-1.43 (m,
8 H), 1.49-1.67 (m, 6 H), 1.71-1.78 (m, 2 H), 1.86-2.12 (m, 4
H), 2.77 (t, 1 H, J ) 2.5 Hz), 3.33 (s, 3 H), 3.41 (br dd, 1 H, J
) 5.1, 3.9 Hz), 3.70 (br d, 1 H, J ) 3.9 Hz); 13C NMR δ 11.0,
12.2, 12.6, 13.2, 17.5, 19.3, 21.6, 22.2, 22.9, 24.2, 25.1, 27.2,
28.1, 30.7, 33.5, 35.2, 35.4, 40.4, 40.4, 41.7, 42.8, 43.5, 48.1,
53.1, 56.5, 56.9, 72.9, 76.5, 82.5; IR (CCl4) 3420, 2958, 2865,
1549, 1466, 1383, 1098, 1015 cm-1; MS (EI/70 eV) m/ e 446
[M]+, 391, 346, 313 (100), 295, 282, 227, 159, 121; HRMS calcd
for C29H50O3: 446.3760, found 446.3764.
1
(+)-(22R,23E,Ss)-22-H yd r oxy-6â-m et h oxy-23-(p -t olyl-
su lfin yl)-3r,5-cyclo-5r-ch olest-23-en e, (+)-20a. From (-)-6
([R]D ) -66.5° (c ) 1.00), 500 mg, 2.40 mmol) and 7 (1.07 g,
3.12 mmol), (+)-20a and 20b were obtained as an 80:20
(hexanes/EtOAc, 19:1); [R]D ) +65.2° (1.00); H NMR δ 0.43
(dd, 1 H, J ) 7.9, 4.9 Hz), 0.65 (apparent t, 1 H, J ) 4.2 Hz),
0.71 (s, 3 H), 0.80-0.92 (m, 4 H), 0.97 (d, 3 H, J ) 6.6 Hz),
0.98 (d, 3 H, J ) 6.4 Hz), 1.00 (d, 3 H, J ) 6.7 Hz), 1.02 (s, 3
H), 1.04-1.21 (m, 4 H), 1.36-1.42 (m, 2 H), 1.47-1.55 (m, 4
H), 1.60 (m, 2 H), 1.75 (m, 2 H), 1.86-1.97 (m, 2 H), 2.14 (d,
1 H, J ) 7.9 Hz), 2.30 (s, 3 H), 2.77 (m, 2 H), 3.33 (s, 3 H),
1
mixture (360 MHz H NMR) and were partially separated by
chromatography on silica gel (hexanes/EtOAc, 4:1) to afford
pure (+)-20a (690 mg) and an enriched sample of 20b (305

Stereocontrolled Synthesis of Brassinolide
J . Org. Chem., Vol. 61, No. 1, 1996 117
4.65 (br d, 1 H, J ) 7.9 Hz), 5.71 (d, 1 H, J ) 10.6 Hz), 7.08 (d,
2 H, J ) 8.1 Hz), 7.23 (d, 2 H, J ) 8.1 Hz); 13C NMR δ 12.1,
12.5, 13.1, 19.2, 21.0, 21.4, 22.6, 22.8, 24.1, 24.5, 24.9, 27.1,
27.8, 28.5, 30.6, 33.3, 35.0, 35.2, 40.1, 42.6, 42.7, 47.9, 49.5,
52.5, 56.3, 56.5, 72.9, 82.4, 129.2, 129.7, 133.6, 134.8, 146.9;
IR (CCl4) 3480, 2938, 2868, 1491, 1457, 1380, 1324, 1270, 1183,
1098, 1016, 1002, 944 cm-1; MS (EI/70 eV) m/ e 536 [M]+, 283,
a catalytic amount of DMAP (10 mol %), and Ms2O (122 mg,
0.70 mmol, 2.0 equiv), sequentially. After 10 min at 0 °C the
reaction mixture was added via cannula to a cold (-78 °C)
solution of MeCuCNLi (5.0 equiv) in THF. The reaction was
stirred and warmed to room temperature over 5 h and
quenched with a saturated solution of NH4Cl. Standard
workup and evaporation of the solvents afforded a crude
product (diastereomeric excess of (+)-24 at least 95:5 by 360
MHz 1H NMR), which was purified by silica gel chromatog-
raphy (hexanes/EtOAc, 49:1 to 19:1) to give pure (+)-24 (100
mg, 55% overall). Data of (+)-24: Rf ) 0.44 (hexanes/EtOAc,
269, 222 (100), 213, 159, 133, 121, 91; HRMS calcd for C35H52
SO2: 536.3688, found 551.3679.
-
Asym m etr ic Oxid a tion of (+)-23a . Ti(OiPr)4 (0.05 mL,
0.26 mmol, 1.0 equiv) was added at room temperature to a
solution of (L)-(+)-diethyl tartrate (0.09 mL, 0.52 mmol, 2.0
equiv) in CH2Cl2 (3 mL), and the mixture was stirred for 10
min. To this solution, cooled at -20 °C, were added cumene
hydroperoxide (0.3 mL of solution at 80% of peroxide) and
sulfide (+)-23a (140 mg, 0.26 mmol, 1.0 equiv) dissolved in 1
mL of CH2Cl2, sequentially. The reaction mixture was kept
at -20 °C, and aliquots of cumene hydroperoxide were added
every 12 h until the starting sulfide was completely consumed
(TLC, 60 h). The reaction was quenched at -20 °C with 1 mL
of H2O, diluted with CH2Cl2, and warmed to room temperature.
After 1 h, the layers were separated, and the organic phase
was washed with water, stirred with 5% NaOH (5 mL) and
brine (5 mL) for 3 h, washed with saturated aqueous NH4Cl,
dried (MgSO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexanes/EtOAc,
19:1 to 4:1) to afford pure (Ss)-sulfoxide (+)-20a (130 mg, 90%)
as a colorless oil. No traces of the (Rs)-sulfoxide (+)-8a could
be detected by 360 MHz 1H NMR analysis of the crude product.
(+)-(22Z,24S )-6â-Me t h oxy-23-(p -t olylsu lfe n yl)-3r,5-
cyclo-5r-er gost-22-en e, (+)-24. To a vigorously stirred
solution of (+)-23a (190 mg, 0.35 mmol, 1.0 equiv) in THF (3
mL) at 0 °C were added Et3N (0.15 mL, 1.06 mmol, 3.0 equiv),
1
19:1); [R]D ) +63.8° (0.73); H NMR δ 0.42 (dd, 1 H, J ) 8.0,
5.1 Hz), 0.64 (br t, 1 H, J ) 4.5 Hz), 0.72 (s, 3 H), 0.74-0.93
(m, 4 H), 0.77 (d, 3 H, J ) 6.6 Hz), 0.83 (d, 3 H, J ) 6.7 Hz),
0.97-1.29 (m, 3 H), 0.98 (d, 3 H, J ) 6.8 Hz), 0.99 (d, 3 H, J
) 6.6 Hz), 1.01 (s, 3 H), 1.37-1.57 (m, 6 H), 1.67-1.78 (m, 4
H), 1.85-2.01 (m, 4 H), 2.31 (s, 3 H), 2.76 (br t, 1 H, J ) 2.5
Hz), 2.92 (m, 1 H), 3.31 (s, 3 H), 5.60 (d, 1 H, J ) 9.5 Hz), 7.06
(d, 2 H, J ) 8.0 Hz), 7.16 (d, 2 H, J ) 8.2 Hz); 13C NMR δ
12.6, 13.0, 15.6, 18.0, 19.3, 20.4, 21.0, 21.6, 22.8, 24.3, 25.0,
28.2, 29.7, 30.3, 30.5, 30.9, 33.3, 35.0, 35.3, 37.0, 40.2, 42.9,
43.4, 46.3, 48.1, 56.4, 56.6, 82.4, 125.5, 128.6, 129.2, 134.2,
136.9, 142.9; IR (CCl4) 2957, 2868, 1549, 1491, 1456, 1381,
1211, 1098, 1016, 972 cm-1; MS (EI/70 eV) m/ e 534 [M]+, 283,
256, 247 (100), 245, 160, 128, 121, 81; HRMS calcd for C36H54
SO: 534.3895, found 534.3888.
-
Ack n ow led gm en t. We are pleased to acknowledge
support of this research by NIH (CA 22237). We are
also grateful to Upjohn for generous gifts of Stigmasterol.
J O951264K