Alkenylzinc-Mediated Approach to the Vitamin D Skeleton. Application to the Synthesis of 6-Methyl Analogs of Vitamin and Previtamin D

Article abstract of DOI:10.1021/jo970605m

Palladium-catalyzed cross-coupling of alkenylzinc reagents, bearing the C,D-ring/side chain portion, and (Z)-1-iodo-1,3-bis-exocyclic dienes (as A-ring precursors), provides a mild, convergent entry to the vitamin D skeleton, that is suitable for the synt

Full text of DOI:10.1021/jo970605m

J . Org. Chem. 1997, 62, 6353-6358
6353
Alk en ylzin c-Med ia ted Ap p r oa ch to th e Vita m in D Sk eleton .
Ap p lica tion to th e Syn th esis of 6-Meth yl An a logs of Vita m in a n d
P r evita m in D
Ana M. Garc´ıa, J ose´ L. Mascaren˜as, Luis Castedo, and Antonio Mourin˜o*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Universidad de Santiago de
Compostela, 15706 Santiago de Compostela, Spain
Received April 2, 1997X
Palladium-catalyzed cross-coupling of alkenylzinc reagents, bearing the C,D-ring/side chain portion,
and (Z)-1-iodo-1,3-bis-exocyclic dienes (as A-ring precursors), provides a mild, convergent entry to
the vitamin D skeleton, that is suitable for the synthesis of thermally labile derivatives such as
those bearing substituents on the triene system.
Sch em e 1
In tr od u ction
An increasing body of evidences suggests that the
hormone 1R,25-dihydroxyvitamin D3 [1, 1R,25-(OH)2-D3;
Scheme 1], in addition to its well known functions in
calcium and phosphate metabolism,1 plays a critical role
in regulation of the proliferation and differentiation of a
large variety of malignant cells.2 It has also been
reported to have a complex role in the immune system2d
and possibly to be of use in the treatment of multiple
sclerosis.3 These findings have considerably stimulated
research aimed at the development of nontoxic vitamin
D derivatives suitable for use as drugs for the treatment
of hyperproliferative diseases such as psoriasis and
cancer and of immunological conditions such as autoim-
mune diseases and graft rejection.4
by convergent strategies in which the C/D-side chain and
A-ring fragments are elaborated separately. The classi-
cal Lythgoe approach, relying on the coupling between
A-ring phosphine oxides and upper-part ketones (route
a, Scheme 1), provides an excellent stereoselective entry
to the natural triene system.6 Unfortunately, prepara-
tion of the required A-ring fragment usually entails
numerous, scarcely flexible steps.7
This problem was to some extent overcome by the
introduction of a particularly elegant convergent strategy
based on a Pd-catalyzed tandem carbometalation-cy-
clization (route b, Scheme 1).8 In this approach, the
vitamin D triene system is assembled in a single opera-
tion, from relatively simple and readily accessible acyclic
A-ring precursors, considerably speeding up the synthetic
process and providing a means for the synthesis of
diverse analogs modified at the A-ring. A drawback to
this approach is that heating is required for achieving
the palladium-catalyzed coupling, which restricts its
application to the synthesis of thermally stable deriva-
tives.9
Although a variety of strategies for the synthesis of
the natural hormone 1 and its analogs have been
reported, there remains a need for more practical and
versatile approaches.5 The greatest flexibility is offered
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) (a) DeLuca, H. F. FASEB J . 1988, 2, 224. (b) Minghetti, P. P.;
Norman A. W. FASEB J . 1988, 2, 3043. (c) Reichel, H; Koeffler, H.
P.; Norman, A. W. New. Eng. J . Med. 1989, 320, 980. (d) DeLuca, H.
F.; Burmester, J .; Darwish, H.; Krisinger, J . Comprehensive Medicinal
Chemistry; Pergamon Press: New York, 1990; Vol. 3, p 1129.
(2) (a) Bikle, D. D. Endocr. Rev. 1992, 13, 765. (b) Ross, T.; Darwish,
H.; DeLuca, H. F. Molecular Biology of Vitamin D Action. In Vitamins
and Hormones, Litwack, E., Ed.; Academic Press: San Diego, 1993.
(c) Vitamin D, A Pluripotent Steroid Hormone: Structural Studies,
Molecular Endocrinology and Clinical Applications; Norman, A. W.,
Bouillon, R., Thomasset, M., Eds.; Walter de Gruyter and Co.: Berlin,
New York, 1994. (d) Bouillon, R; Okamura, W. H.; Norman, A. W.
Endocr. Rev. 1995, 16, 200.
(3) Cantorna, M. T.; Hayes, C. E.; DeLuca, H. F. Proc. Nat. Acad.
Sci. 1996, 93, 7861.
(4) In recent years, a wide range of analogs of 1 with weak calcemic
effects have been prepared, some of which have been shown to be
promising drugs for the treatment of psoriasis and certain cancers:
(a) Ikekawa, N. Med. Chem. Rev. 1987, 7, 333. (b) Abe, J .; Morikawa,
M.; Miyamoto, K.; Kaiho, S.; Fukushima, M.; Miyaura, C.; Abe, E.;
Suda, T.; Nishii, Y. FEBS Lett. 1987, 226, 58. (c) Ostrem, V. K.; Lau,
W. F.; Lee, S. H.; Perlman, K.; Prahl, J .; Schnoes, H. K.; DeLuca, H.
F. J . Biol. Chem. 1987, 262, 14164. (d) Shiuey, S. J .; Partridge, J . J .;
Uskokovic, M. R. J . Org. Chem. 1988, 53, 1040. (e) Zhou, J .; Norman,
A. W.; Lubbert, M.; Collins, E. D.; Uskokovic, M. R.; Koeffler, H. P.
Blood 1989, 74, 82. (f) Perlman, R. R.; Sicinski, H. K.; Schnoes, H.
K.; DeLuca, H. F. Tetrahedron Lett. 1990, 31, 1823. (g) Figadere, B.;
Norman, A. W.; Henry, H. L.; Koeffler, H. P.; Zhou, J .-Y.; Okamura,
W. H. J . Med. Chem. 1991, 34, 2452. (h) Kissmeyer, A.-M.; Binderup.
L. Biochem. Pharmacol. 1991, 41, 1601. (i) Zhou, J .-Y; Norman, A.
W.; Akashi, M.; Chen, D.-L.; Uskokovic, M. R.; Aurrecoechea, J . M.;
Dauben, W. H.; Okamura, W. H.; Koeffler, H. P. Blood 1991, 78, 75.
(j) Binderup, L. Biorg. Med. Chem. Lett. 1993, 3, 1891.
(6) (a) Lythgoe, B. Chem. Soc. Rev. 1981, 449. (b) Baggiolini, E. G.;
Iacobelli, J . A.; Hennessy, B. M.; Uskokovic, M. R. J . Am. Chem. Soc.
1982, 104, 2945. (c) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B.
M.; Batcho, A.; Sereno, J . F.; Uskokovic, M. R. J . Org. Chem. 1986,
51, 3098.
(7) For more recent approaches, see: (a) Vryelink, S.; Vandewalle,
M.; Garc´ıa, A. M.; Mascaren˜as, J . L.; Mourin˜o, A. Tetrahedron Lett.
1995, 36, 9023. (b) Acmatowicz, B.; J ankowski, P.; Wicha, J . Tetra-
hedron Lett. 1996, 37, 5589.
(8) (a) Trost, B. M.; Dumas, J . J . Am. Chem. Soc. 1992, 114, 1925.
(b) Trost, B. M.; Dumas, J .; Villa, M. J . Am. Chem. Soc. 1992, 114,
9836.
(9) Most vitamin D derivatives equilibrate with their previtamin
isomers under the coupling conditions. It has recently been reported
that the Trost methodology was of limited utility for the synthesis of
oxa-A-ring analogs : Daniel, D.; Middleton, R.; Henry, H. L.; Okamura,
W. H. J . Org. Chem. 1996, 61, 5617.
(5) For recent reviews, see: (a) Dai, H.; Posner, G. H. Synthesis 1994,
1383. (b) Schmalz, H.-G. Nachr. Chem. Tech. Lab. 1994, 42, 397. (c)
Zhu, G. D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
S0022-3263(97)00605-1 CCC: $14.00 © 1997 American Chemical Society

6354 J . Org. Chem., Vol. 62, No. 18, 1997
Garc´ıa et al.
Sch em e 2
F igu r e 1.
Sch em e 3
We have recently discovered that the conjugated triene
system of vitamin D can be efficiently assembled under
mild conditions by coupling alkenyl-organometallic re-
agents bearing the C,D-ring/side chain portion (2) with
A-ring iododiene units (3) derived from acyclic precursors
(Scheme 2).10
Herein we describe the full details of this approach and
its application to the synthesis of 3-deoxy-1R- and 1â-
hydroxyvitamin D3. We also demonstrate its potential
for the synthesis of thermally labile derivatives such as
those in which the triene system bears substituents.
These types of analogs are difficult to make by other
approaches and might prove useful for evaluation of the
role of the triene system in biological activity,11 and also
for studying the chemistry of vitamin-previtamin isomer-
ization.12
THF], the desired diiodo derivative 5a was obtained in
yields ranging from 30 to 50%. Systematic modification
of different reaction parameters revealed that more
reproducible and slightly better yields (57%) can be
obtained if the intermediate zirconacycle is slowly added
to a cooled (-50 °C) solution of N-iodosuccinimide (NIS)
in CH2Cl2. Using NBS instead of NIS provides the
expected dibromo compound 5b, albeit in a lower 23%
yield. Changing the metal from Zr to Ti or using other
iodinating agents did not provide better results. The
stereochemistry of 5a was assigned on the basis of
previously reported data for the related compound 5c.13c,d
1
In the H NMR spectrum of 5a , in contrast to that of 5c
Resu lts a n d Discu ssion
there was no observable coupling between H-1 and H-2,
indicating that both these lay equatorial (Figure 1).15
The exocyclic double bond was efficiently introduced
by treatment of 5a with DBU in CH2Cl2 at room tem-
perature for 12 h (90% yield), and the trimethylsilyl
group was smoothly removed by reaction of 6a with
Cs2CO3 in DMF (84% yield). Compound 6b can also be
obtained by inverting the procedure, treating 5a firstly
with Cs2CO3 in DMF (or alternatively stirring it with KF
in CH3CN) to remove the trimethylsilyl group and then
with DBU in CH2Cl2 (81% yield for both steps). Most
interestingly, treatment of compound 5a with excess of
DBU (3 equiv) for five days at room temperature gave
the desired vinyl iodide 6b in a one-pot reaction in 97%
yield. The (Z)-stereochemistry of compound 6b was
confirmed by 1H NMR spectroscopy and NOE experi-
ments (Figure 1). In summary, the desired A-ring
precursor 6b was obtained from the acyclic enyne 4b in
three steps and 53% overall yield.
Cou p lin g of 6b w ith a Mod el P a r tn er . To rapidly
establish whether these vinyl iodides could be used as
A-ring precursors of a typical vitamin D skeleton, the
cross-coupling reaction of 6b with the vinyltributyltin
derivative 7 was attempted under typical Stille condi-
tions.16 Stirring a solution of 6b and 717 in DMF in the
presence of (CH3CN)2PdCl2 for two days at room tem-
perature, followed by desilylation, provided the expected
triene 8 in a 50% yield. The structure of this compound
Zir con ocen e-Med ia ted Ap p r oa ch to th e A-Rin g
Iod od ien e Un it 6b. The key step in the synthesis of
the (Z)-1-iodovinyl bis-exocyclic A-ring precursors was a
zirconium-promoted cyclization-iodonolysis of acyclic 1,7-
enynes.13 The required silylated enyne 4c13c,d was readily
prepared by treatment of 4b14 with methyllithium and
trapping the resulting acetylide with TMSCl. Using the
classical conditions developed by Negishi for the cycliza-
tion-iodonolysis reaction [(a) Cp2ZrCl2, n-BuLi; (b) I2,
(10) (a) Mascaren˜as, J . L.; Garc´ıa, A. M.; Castedo, L; Mourin˜o, A.
Tetrahedron Lett. 1992, 33, 7589. (b) Garc´ıa, A. M.; Mascaren˜as, J .
L.; Castedo, L; Mourin˜o, A. Tetrahedron Lett. 1995, 36, 5413.
(11) Although the conjugated triene system of natural vitamin D is
believed to be necessary for biological activity, there has been little
research into the biological effect of modifying this triene system.
However, several substituted derivatives have been synthesized and
shown to have interesting activities: (a) Wilhelm, F.; Dauben, W. G.;
Kohler, B.; Roesle, A.; Norman, A. W. Arch. Biochem. Biophys. 1984,
233, 127. (b) Gray, T. K.; Millington, D. S.; Maltby, D. A.; Williams,
M. E.; Cohen, M. S.; Dodd, R. C. Proc. Nat. Acad. Sci. U.S.A. 1985, 82,
8218. (c) Shiina, Y. Y.; Miyaura, C.; Tanaka, H.; Abe, E.; Yamada, S.;
Yamamoto, K.; Ino, E.; Takayama, H.; Matsunaga, I.; Nishii, Y.; Suda,
T. J . Med. Chem. 1985, 28, 1153. (d) Steinmeyer, A.; Neef, G.
Tetrahedron Lett. 1992, 33, 4879.
(12) (a) Enas, J . D.; Palenzuela J . A.; Okamura, W. H. J . Am. Chem.
Soc. 1991, 113, 1355. (b) Enas, J . D.; Shen, G.-Y.; Okamura, W. H. J .
Am. Chem. Soc. 1991, 113, 3873. (c) Okamura, W. H.; Elnagar, H. Y.;
Ruther, M.; Dobreff, S. J . Org. Chem. 1993, 58, 600. (d) Okabe, M.;
Garofalo, L. M. Tetrahedron Lett. 1995, 36, 5853. (e) Igarashi, J .;
Ikeda, M.; Sunagawa, M. Tetrahedron Lett. 1996, 37, 1431.
(13) (a) Negishi, E.-I.; Holmes, S. J .; Tour, J . M.; Miller, J . A. J .
Am. Chem. Soc. 1985, 107, 2568. (b) Negishi, E.-I.; Holmes, S. J .; Tour,
J . M.; Miller, J . A.; Cederbaun, F. I.; Swanson, D. R.; Takahashi, F. I.
J . Am. Chem. Soc. 1989, 111, 3336. (c) Lunds, E. C.; Livinghouse, T.
J . Org. Chem. 1989, 54, 4487. (d) Pagenkopf, B. L.; Lunds, E. C.;
Livinghouse, T. Tetrahedron 1995, 51, 4421. (e) Negishi, E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I. A., Eds.;
Pergamon: New York, 1991; Vol 5, p 1163. (f) Negishi, E.; Takahashi,
T. Acc. Chem. Res. 1994, 27, 124.
(15) The greater stability of this conformation is consistent with
molecular mechanics calculations (MMX).
(16) (a) Stille, J . K. Angew. Chem., Int. Ed. Eng. 1986, 25, 508. (b)
Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813. (c) Mitchel,
T. N. Synthesis 1992, 803. (d) Farina, V. Pure Appl. Chem. 1996, 68,
73.
(17) Compound 7 was prepared by a known procedure: Nemoto, H.;
Wu, X.-M.; Kurobe, H.; Minemura, K.; Ihara, M.; Fukumoto, K. J .
Chem. Soc., Perkin Trans. 1 1985, 1185.
(14) Compound 4b was prepared by addition of vinylmagnesium
bromide to 5-hexynal, followed by protection of the resulting alcohol
with TBSCl, see: Ihle, N. C.; Heathcock, C. H. J . Org. Chem. 1993,
58, 560.

Alkenylzinc-Mediated Approach to the Vitamin D Skeleton
J . Org. Chem., Vol. 62, No. 18, 1997 6355
Ta ble 1. P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin g of 10 a n d 6ba
M
catalystb
solvent
DMF
temp (°C)
timec
11 (% yield)
n-Bu3Sn
n-Bu3Sn
n-Bu3Sn
n-Bu3Sn
Me3Sn
Me3Sn
Me3Sn
Me3Sn
BrZn
(CH3CN)2PdCl2
(CH3CN)2PdCl2
25
60
60
25
25
25
60
25
25
3 days
1.5 day
1 day
3 days
4 days
2 days
2 days
4 days
2 h
-
-
DMF
(PPh3)2PdCl2/CuI (1:2)
Pd2dba3/TFP (1:2)
(CH3CN)2PdCl2
Pd2dba3/TFP (1:2)
Pd2dba3/TFP (1:2)
Pd2dba3/TFP/CuI (1:4:4)
Pd(PPh3)4
THF
-
NMPd
DMF
-
20
23
-
NMP
NMP
DMF
THF-Et2O
33
95
a
b
d
1.5 equiv of 6b were used. 5 mol %. c Until 6b disappeared (TLC and NMR monitoring). N-Methylpyrrolidinone.
Sch em e 4
Sch em e 5
was confirmed by comparison of its spectroscopic data
with those previously reported.18 Although a triene such
as 8 is known to rapidly equilibrate with their previtamin
isomers, the mild thermal conditions used in the coupling
reaction allowed isolation of the vitamin type triene (a
small amount of the previtamin form was detected in the
1H NMR spectrum), which is not possible using coupling
procedures that require thermal activation.8
mixture of protected 1R- and 1â-hydroxy-3-deoxyvitamin
D3 derivatives 11 smoothly and in excellent yield (95%).
These diastereoisomers were easily separated by flash
chromatography and then deprotected by treatment with
TBAF in THF. The structures of 11a and 11b were
corroborated by comparison of the 1H NMR spectra of
their respective deprotected derivatives 12a and 12b with
those of authentic samples.21
Syn th esis of 3-Deoxy-1r- a n d 1â-Hyd r oxyvita m in
D3. Following the success of the above experiment we
investigated the coupling of vinyl iodide 6b with stannane
10a , which bears the C,D ring-side chain of the naturally
occurring vitamin D skeleton. Compound 10a was
prepared by treatment of vinyl bromide 98 with t-BuLi
and trapping the resulting anion with tributyltin chlo-
ride. Unfortunately, initial attempts at cross-coupling
10a and vinyl iodide 6b using (CH3CN)2PdCl2 as catalyst
failed, even at temperatures higher than room temper-
ature (Table 1). We then proceeded to study the effects
of other catalysts, ligands, and additives. The results are
summarized in Table 1. Note that no coupling was
observed using additives such as CuI or ligands such as
tris(2-furyl)phosphine (TFP), which have recently been
reported to accelerate the Stille coupling reaction.19
However, by using the less sterically demanding trim-
ethyltin derivative 10b as organometallic partner, we
were able to isolate a mixture of protected diastereoiso-
meric vitamins 11a and 11b, albeit in low yield (20-
33%).
Syn th esis of An a logs w ith a Tr ien e-Su bstitu ted
System . Having developed a mild, efficient approach to
the natural vitamin D skeleton, we next examined the
feasibility of using the same approach to prepare vitamin
D analogs with a substituted triene system, compounds
that are difficult to make by classical routes. Little is
known about how substituents that can perturb the steric
and electronic characteristics of the triene system affect
the biological activity.11,12 Since the presence of a methyl
group at position 6 of vitamin D is known to considerably
decrease the energetic barrier to its isomerization to the
previtamin form,22 we firstly attempted the synthesis of
this type of derivatives, on the assumption that success
would give a good indication of the suitability of this
approach to the synthesis of thermally sensitive analogs.
In order to facilitate spectroscopic identification of the
coupling products, the A-ring iododiene precursor was
prepared in an optically active form. Sharpless kinetic
resolution of the racemic allylic alcohol 4a (Scheme 3),
by reaction with titanium tetraisopropoxide, dicyclohexyl
D-(-)-tartrate and tert-butyl hydroperoxide in CH2Cl2 at
-20 °C,23 gave the desired (S)-(-)-eninol 13a almost
quantitatively (45%, Scheme 6). The optical purity
(>97% ee) was established by conversion of the alcohol
13a to the corresponding (S)-(+)-O-methylmandelic ester
Since the coupling reaction appeared to be mainly
affected by the nature of the organometallic fragment, it
was envisaged that use of an even less sterically de-
manding and more reactive derivative, such as an orga-
nozinc halide,20 might give better results. To our delight,
room temperature reaction (2 h) of iodide 6b with 10c in
the presence of 5 mol % Pd(PPh3)4 gave the expected
(18) Condran, P.; Okamura, W. H. J . Org. Chem. 1980, 45, 4011.
(19) (a) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(b) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L. S.
J . Org. Chem. 1994, 59, 5905.
(20) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J . Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (c)
Gilchrist, T. L.; Summersell, R. J . Tetrahedron Lett. 1987, 28, 1469.
(d) Duffault, J .-M.; Einhorn, J .; Alexakis, A. Tetrahedron Lett. 1991,
32, 3701. (e) Erdik, E. Tetrahedron 1992, 48, 9577. (f) Rottlander,
M.; Palmer, N.; Knochel, P. Synlett 1996, 573.
(21) (a) Condran, P.; Hammond, M. L.; Mourin˜o, A.; Okamura, W.
H J . Am. Chem. Soc. 1980, 102, 6259. (b) Condran, P. Ph.D. Thesis,
University of California, Riverside, 1980.
(22) Sheves, M.; Mazur, Y. J . Chem. Soc., Chem. Commun. 1977,
21.
(23) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. K.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.

6356 J . Org. Chem., Vol. 62, No. 18, 1997
Garc´ıa et al.
followed and quantified by integration of the 1H NMR
signal due to the 18-CH3, which appears at 0.51 ppm for
the vitamin D form and at 0.66 ppm for the previtamin
D form. The origin of the increased rate of isomerization
with respect to that for unsubstituted vitamin D most
probably lies in the predisposition of the methyl-
substituted vitamin to adopt the 6,7-cis conformation
required for the [1,7]-sigmatropic hydrogen shift. The
deprotected previtamin derivative 18b was easily ob-
tained by treatment of 18a with TBAF in THF (65%).
Sch em e 6
Sch em e 7
Con clu sion
Palladium-catalyzed coupling of acyclic iododienes (as
A-ring precursors) with alkenylzinc reagents bearing the
C/D ring-side chain of vitamin D3 provides a new, efficient
entry to the vitamin D skeleton. In contrast to other
convergent approaches that require high temperatures
to assemble the triene system,8 this coupling reaction
proceeds under mild conditions, thus allowing prepara-
tion of thermally sensitive vitamin D analogs such as
those bearing substituents on the triene system. By way
of example, we prepared 3-deoxy-1R-[(tert-butyldimeth-
ylsilyl)oxy]-6-methylvitamin D3, a compound that is
extremely prone to undergo equilibration to the corre-
sponding previtamin isomer under gentle thermal activa-
tion.
1
and comparison of its H NMR spectrum with that of the
mixture obtained by esterification of racemic 4a .24
After silylation, treatment of 13b with n-butyllithium
and trapping of the resulting acetylide with MeI gave the
enyne 14 in 94% yield. Cyclization-iodonolysis of 14
using Cp2ZrCl2 as organometallic promoter and NIS as
iodine source gave the expected diiodide 15 in low yield
(24%). In this case we found that Cp2TiCl2 provides
slightly better results. Thus treatment of 14 with the
titanocene complex obtained by reaction of Cp2TiCl2 with
n-BuLi, followed by slow addition of the resulting mixture
to a cooled solution of NIS in CH2Cl2, gave the diiodide
15 in 41% yield.
Diodide 15 was easily transformed into the iododiene
16 by treatment with DBU at room temperature (70%
yield). The stereochemistry of the double bond was
confirmed by the observation of NOE between the methyl
group and the pseudoequatorial H-4.
Exp er im en ta l Section
Gen er a l P r oced u r es. See preceding paper.25
3-[(t-Bu tyld im eth ylsilyl)oxy]-1-octen -7-yn e (4b). Vi-
nylmagnesium bromide (76 mL, 76 mmol, 1 M in THF) was
added to a solution of 5-hexynal (5 g, 51 mmol) in THF (60
mL) at -78 °C.14 The reaction mixture was allowed to reach
rt and stirred for 12 h. The reaction was quenched with
aqueous NH4Cl (20 mL) and extracted with Et2O (3 × 15 mL).
The combined organic phases were washed with aqueous HCl
(5%), dried, and concentrated in vacuo. The residue was
filtered through a short pad of silica gel eluting with 10%
EtOAc/hexane to give the allylic alcohol 4a (3.3 g, 52% yield,
viscous oil). t-Butyldimethylsilyl chloride (5.2 g, 34.6 mmol)
and imidazole (5.8 g, 85.1 mmol) were added to a solution of
this compound in DMF (30 mL) . The mixture was stirred at
rt for 12 h, poured into H2O (10 mL), and extracted with
CH2Cl2. The combined organic layers were washed with brine
(15 mL), dried, filtered, and concentrated. Flash chromatog-
raphy of the residue (4% EtOAc/hexanes) gave 5.7 g of the
enyne 4b [46% yield from hexynal, Rf ) 0.7 (10% EtOAc/
hexanes), colorless oil]. 1H NMR δ: 5.8 (1 H, ddd, J ) 17.2,
10.4 and 6.0), 5.15 (1 H, ddd, J ) 17.0, 1.6 and 1.5), 5.04 (1 H,
ddd, J ) 10.0, 1.8 and 1.5), 4.14 (1 H, m), 2.19 (2 H, m), 1.95
(1H, t, J ) 2.6), 1.56-1.60 (4 H, m), 0.06, 0.04 (6 H, 2 s); 13C
NMR δ: 141.6 (CH), 113.8 (CH2), 84.4 (C), 73.3 (CH), 68.2
(CH), 37 (CH2), 25.8 (CH3), 24 (CH2), 18.4 (CH2), 18.3 (C), -4.9,
-4.5 (CH3).
3-[(t-Bu tyldim eth ylsilyl)oxy]-8-(tr im eth ylsilyl)-1-octen -
7-yn e (4c). A solution of 4b (500 mg, 2.09 mmol) in Et2O (5
mL) was slowly added to MeLi‚LiBr (3 mL, 4.5 mmol, 1.5 M
in Et2O) at -20 °C. Freshly distilled TMSCl (0.8 mL, 6.3
mmol) was added, and the mixture stirred at rt for 7 h. The
reaction was quenched with aqueous HCl (5 mL, 5%), poured
into brine, and extracted with Et2O. The combined organic
layers were dried, filtered, and concentrated. Flash chroma-
tography (hexanes) gave 4c [572 mg, 88%, Rf ) 0.6 (3% EtOAc/
hexanes), colorless oil]. 1H NMR δ: 5.79 (1 H, ddd, J ) 17.2,
10.4, and 6.0), 5.15 (1 H, ddd, J ) 17.1, 1.8, and 1.5), 5.03 (1
H, ddd, J ) 10.4, 1.8 and 1.3), 4.12 (1 H, m), 2.23 (2 H, br t,
J ) 6.5), 1.6 (4 H, m), 0.9 (9 H, s), 0.14 (9 H, s), 0.06, 0.04 (6
Finally, a solution of iododiene 16 and zincate 10c
(Scheme 7) in THF containing 5 mol % of (PPh3)4Pd was
stirred at room temperature for 2 h to give the desired
vitamin derivative 17 in an excellent 94% yield. The
structure of this compound was confirmed by spectro-
1
scopic analysis. The H NMR spectrum shows, as more
relevant, the peaks of the three alkenyl hydrogens of the
triene portion, and the singlet at 0.51 ppm due to the
C18-CH3, characteristic of a vitamin D type structure. As
previously described by Mazur for 6-methylvitamin D3,22
the UV spectrum of the 6-substituted vitamin 17 differs
from that of the natural vitamins, in that their absorption
maxima appears at considerably shorter wavelength (λ
) 242 nm for the methyl derivative 17 as against λ )
264 nm for an unsubstituted vitamin). This shift has
been attributed to deviations in the planarity of the
conjugated system due to steric interactions between the
methyl group and H-9.22
As expected, the 6-methylvitamin D analog 17 showed
a great propensity to isomerize to the corresponding
previtamin D form 18a . Thus, we found that the isomer-
ization equilibrium lies completely in favor of the previ-
tamin isomer, and were able to calculate a half life of
15.3 h in CD2Cl2 at 37 °C. The isomerization was easily
(25) Torneiro, M.; Fall, Y.; Castedo, L. Mourin˜o, A. J . Org. Chem.
1997, 62, 6344.
(24) Only one enantiomer could be detected by 1H NMR.

Alkenylzinc-Mediated Approach to the Vitamin D Skeleton
J . Org. Chem., Vol. 62, No. 18, 1997 6357
H, 2 s); 13C NMR δ: 141.5 (CH), 113.7 (CH2), 107.4 (C), 84.5
(C), 73.3 (CH), 37.0 (CH2), 26.0 (CH3), 24.0 (CH2), 19.7 (CH2),
18.0 (C), 1.0 (CH3), -4.5, -5 (CH3); LRMS [m/z (%)]: 310.2
(M+, 1), 283 (7), 253.2 (M+ - t-Bu, 9), 179.05 (M+ - OTBS, 3),
147 (100); HRMS calcd for C17H34OSi2: 310.2148; found:
310.2142.
P r oced u r e for th e P r ep a r a tion of Sta n n a n es 10a a n d
10b. Exemplified for the preparation of 10b: tert-butyllithium
(0.32 mL, 0.63 mmol, 1.95 M in pentane) was added to a
solution of bromide 98 (100 mg, 0.29 mmol) in THF (2 mL) at
-78 °C. The mixture was stirred for 1 h, and n-Bu3SnCl (75.5
mg, 0.37 mmol) was added. The reaction mixture was stirred
for 12 h at rt and quenched with H2O (10 mL). The resulting
mixture was extracted with hexanes, and the combined organic
phases were dried, filtered, and concentrated. The oily residue
(112 mg, ≈91%) was proved to be primarily the desired
stannane 10b by 1H NMR. This crude was subjected to the
coupling reaction without any further purification. 1H NMR
δ: 5.26 (1 H, s), 2.2 (1 H, m), 0.92 (3 H, d, J ) 5.8), 0.87 (6 H,
d, J ) 6.1), 0.54 (3 H, s), 0.14 (9 H, s); 13C NMR δ: 158.7 (C),
117.3 (CH), 57.9, 56.6, 45.5, 40.36, 39.5, 37.8, 37.4, 36.1, 29.7,
27.9, 27.5, 24.4, 23.9, 22.8, 22.5, 22.4, 22.2, 18.8, 11.9, -8.6;
(1S*, 2S*, 3Z)-1-[(t-Bu t yld im et h ylsilyl)oxy]-3-[(t r i-
m e t h y ls i ly l)i o d o m e t h y le n e ]-2-(i o d o m e t h y l)c y c lo -
h exa n e (5a ). n-BuLi (0.8 mL, 1.96 mmol, 2.46 M in hexanes)
was added dropwise to a solution of Cp2ZrCl2 (290 mg, 0.98
mmol) in THF (6 mL) at -80 °C. The mixture was allowed to
warm to -55 °C in 1 h, and a solution of enyne 4b (200 mg,
0.64 mmol) in THF (4 mL) was added dropwise via cannula.
The reaction mixture was allowed to warm to rt and stirred
for 7 h. The resulting solution was slowly added to a solution
of NIS (436 mg, 1.96 mmol) in CH2Cl2 at -80 °C. The mixture
was stirred for 1 h at -50 °C and 1 h at rt and poured into
saturated aqueous NH4Cl (10 mL). The resulting suspension
was filtered through a pad of Celite and extracted with
hexanes. The combined organic phases were dried, filtered,
and concentrated in vacuo. Flash chromatography (hexanes)
yielded the diiodide 5a [207 mg, 57%, Rf ) 0.8 (2% EtOAc/
hexanes), glassy solid]. 1H NMR δ: 4.27 (1 H, m), 3.40 (1 H,
m), 3.15 (2 H, m), 2.75 (1 H, br d, J ) 14.0), 1.90 (1 H, m),
1.80-1.20 (4 H, m), 0.87 (9 H, s), 0.28 (9 H, s), 0.14, 0.06 (6 H,
2 s); 13C NMR δ: 156.3 (C), 109.5 (C), 71.3 (CH), 59.0 (CH),
31.0 (CH2), 28.0 (CH2), 26.0 (CH3), 21.0 (CH2), 18.0 (C), 4.4
(CH2), 2.2 (CH3), -4.9 (CH3), -4.7 (CH3); LRMS [m/z (%)]: 549
(M+- Me, 0.3), 506.9 (M+ - t-Bu, 20), 307 (27), 184.9 (32), 73
(100); HRMS calcd for C17H34OI2Si2 - C4H9: 506.9533, found:
506.9533.
LRMS [m/z (%)]: 411.2 (M+ + H+ - Me, 100), 410.2 (M+
-
Me, 41), 409.2 (73), 408.2 (31), 407.2 (41). 10a : 1H NMR δ:
5.20 (1 H, s), 2.17 (1 H, m), 0.52 (3 H, s).
Cou p lin g of Iod id e 6b w ith Tr im eth ylsta n n a n e 10b.
A mixture of iodide 6b (31 mg, 0.085 mmol), stannanne 10b
(32 mg, 0.074 mmol), and (CH3CN)2PdCl2 (approximately 2 mg)
in DMF (2 mL) was stirred at rt for 4 days. The reaction was
poured into H2O (5 mL) and extracted with hexanes. The
combined organic layers were dried, filtered, and concentrated
in vacuo. Flash chromatography (hexanes) afforded the
mixture of protected vitamins 11 [8 mg, 20%, Rf ) 0.45
(hexanes)].
Cou p lin g of Iod id e 6b w ith Zin ca te 10c. Syn th esis of
3-Deoxy-1r-[(t-bu tyld im eth ylsilyl)oxy]vita m in D3 (11a )
a n d 3-Deoxy-1â-[(t-b u t yld im et h ylsilyl)oxy]vit a m in D3
(11b). tert-Butyllithium (0.5 mL, 0.61 mmol, 1.3 M in pentane)
was slowly added to a solution of bromide 9 (100 mg, 0.29
mmol) in Et2O (2.5 mL) at -78 °C. The mixture was stirred
for 15 min, and a solution of ZnBr2 (71.8 mg, 0.32 mmol, freshly
dried under vacuum) in Et2O (2 mL) was added. After stirring
at -10 °C for 1 h, the reaction mixture was cooled to -78 °C,
and a solution of iodide 6b (70 mg, 0.19 mmol) and Pd(Ph3P)4
(9 mg, 0.07 mmol) in THF (1 mL) was added. The resulting
solution was allowed to reach rt and stirred for 2 h. The
reaction was quenched with H2O (3 mL), and the resulting
mixture was extracted with hexanes. The combined organic
layers were dried, filtered, and concentrated in vacuo. Flash
chromatography (hexanes) afforded 11a (45 mg) and 11b (47
mg) [96% overall yield]. 11a : 1H NMR δ: 6.2 and 6.0 (2 H,
AB, J ) 11 Hz), 5.23 (1 H, br t, J ) 1.8 Hz), 4.8 (1 H, br t, J
) 1.8), 4.05 (1 H, m), 2.79 (1 H, br s), 0.93-0.82 (18 H, m),
0.52 (3 H, s), 0.06, 0.05 (6 H, 2 s); 13C NMR δ: 150.1(C), 141.4
(C), 139.5 (C), 121 (CH), 118 (CH), 109.9 (CH2), 74.3 (CH), 56.7,
56.4, 46.0, 41.0, 39.9, 37.8, 37.5, 36.5, 30.0, 29.3, 28.4, 28.1,
26.2, 24.4 24.2, 24.1, 22.9, 22.7, 22.6, 19.0, 18.0, 12.1, -4.7,
-4.9. 11b: 1H NMR δ: 6.2 and 5.97 (2 H, AB, J ) 11), 5.22
(1 H, br t, J ) 1.8), 4.78 (1 H, br t, J ) 1.5) 4.07 (1 H, m), 2.79
(1 H, m), 0.91-0.82 (18 H, m), 0.51 (3 H, s), 0.06 (6 H, 2 s);
13C NMR δ: 150.1 (C), 141.4 (C), 139.5 (C), 121.1 (CH), 118
(CH), 109.9 (CH2), 74.3 (CH), 57 (C), 56.7, 46, 40.1, 39.9, 37.8,
37.5, 36.5, 30.1, 29.3, 28.4, 28.1, 26.2, 24.3, 24.2, 23.9, 22.9,
22.7, 19.0, 12.0, -4.7, -4.9.
3-Deoxy-1r-h yd r oxyvita m in D3 (12a ) a n d 3-Deoxy-1â-
h yd r oxyvita m in D3 (12b). Exemplified for the deprotection
of 11a : tetrabutylammonium fluoride (0.03 mL, 0.03 mmol, 1
M in THF) was added to a solution of 11a (14 mg, 0.028 mmol)
in THF (1 mL). The reaction mixture was stirred at rt for 12
h and poured into H2O (6 mL). The aqueous layer was
extracted with Et2O, and the combined organic layers were
dried, filtered, and concentrated in vacuo. Flash chromatog-
raphy gave the alcohol 12a [8 mg, 80%, Rf ) 0.25 (30% EtOAc/
hexanes)]. 12a : 1H NMR δ: 6.27 and 5.98 (2 H, AB, J ) 11.3),
5.24 (1 H, br t, J ) 1.8), 4.88 (1 H, br t, J ) 1.8), 4.04 (1 H, m),
2.81 (1 H, br d, J ) 11), 2.13 (2 H, m), 0.91 (3 H, d, J ) 6),
0.85 (6 H, br d, J ) 6), 0.53 (3 H, s). 12b: 1H NMR δ: 6.28
and 5.98 (2 H, AB, J ) 11.3), 5.23 (1 H, br t, J ) 1.7), 4.86 (1
H, br t, J ) 1.7), 4.09 (1 H, m), 2.8 (1 H, br d, J ) 11), 2.23 (2
H, m), 0.90 (3 H, d, J ) 6), 0.85 (6 H, br d, J ) 6), 0.52 (3 H,
s).
(1S*, 2S*, 3Z)-1-[(t-Bu t yld im et h ylsilyl)oxy]-3-[(t r i-
m eth ylsilyl)br om om eth ylen e]-2-(br om om eth yl)cycloh ex-
a n e (5b). This compound was obtained following a similar
procedure to the above described for 5a [23% yield, oil]. 1H
NMR δ: 4.31 (1 H, m), 3.65 (1 H, m), 3.4 (2 H, m), 2.6 (1 H, br
d, J ) 13.6), 1.96-1.47 (5 H, m), 0.86 (9 H, s), 0.26 (9 H, s),
0.10, 0.06 (6 H, 2 s); 13C NMR δ: 150.2 (C), 126.7 (C), 69.3
(CH), 52.2 (CH), 31.9 (CH2), 30.3 (CH2), 28.1 (CH2), 25.6 (CH3),
20.7 (CH2), 17.8 (C), 1.05 (CH3), -4.9 (CH3), -4.7 (CH3); LRMS
[m/z (%)]: 412.9 (M+ - t-Bu, 12), 340.9 (0.3), 331 (5), 259 (70),
73 (100); HRMS calcd for C17H34OBr2Si2 - C4H9: 412.9790,
found: 412.9793.
(3Z)-1-[(t -B u t y ld im e t h y ls ily l)o x y ]-2-m e t h y le n e -3-
(iod om eth ylen e)cycloh exa n e (6b). DBU (0.8 mL, 5.31
mmol) was added to a solution of 5a (200 mg, 0.35 mmol) in
CH2Cl2 (4 mL) at 0 °C . The reaction mixture was stirred at
rt for 5 days. The solvent was removed under reduced
pressure and the residue diluted with hexanes and washed
with H2O (15 mL). The organic layer was dried, filtered, and
concentrated. Flash chromatography (hexanes) gave 6b [125
mg, 97%, Rf ) 0.5 (5% EtOAc/hexanes), colorless oil]. 1H NMR
δ: 6.06 (1 H, br s), 5.33 (1 H, t, J ) 1.8), 5.05 (1 H, t, J ) 1.7),
4.06 (1 H, m), 2.50 (1 H, m), 2.3 (1 H, m), 2.00-1.80 (2 H, m),
1.70-1.40 (2 H, m), 0.90 (9 H, s), 0.40, 0.30 (6 H, 2 s); 13C
NMR δ: 150.5 (C), 150.1 (C), 110.9 (CH), 73.1 (CH2), 72.1 (CH),
38.1 (CH2), 36.7 (CH2), 25.8 (CH3), 23.4 (CH2), 18.2 (C), -5.1,
-4.8 (CH3); LRMS [m/z (%)]: 364 (M+, 0.04), 349 (M+ - Me,
1), 307 (M+ - t-Bu, 100), 233 (M+ - OTBS, 8); HRMS calcd
for C14H25OISi - C4H9: 307.0015; found: 307.0011.
Cou p lin g of 6b a n d 7. A mixture of iododiene 6b (60 mg,
0.16 mmol), stannane 717 (40 mg, 0.10 mmol), and
(CH3CN)2PdCl2 (approximately 4 mg) in DMF (5 mL) was
stirred for 48 h at rt. The reaction was quenched with aqueous
NH4OH, poured into brine (10 mL), and extracted with CH2Cl2.
The combined organic phases were dried and concentrated in
vacuo. The residue was dissolved in THF (6 mL) and treated
with TBAF (0.15 mL, 0.15 mmol, 1.0 M in THF). After stirring
in the dark for 2 h at rt, the mixture was poured into brine
(10 mL), extracted with Et2O, dried, filtered, and concentrated
in vacuo. Flash chromatography (5% EtOAc/hexanes) afforded
compound 8 [15 mg, 50%].18 1H NMR δ: 6.23 and 6.10 (2 H,
AB, J ) 11.4), 5.28 (1 H, s), 4.93 (1 H, s), 4.16 (1 H, m), 2.38-
2.11 (4 H, m), 2.07-1.8 (2 H, m), 1.6 (4 H, m), 1.23 (4H, m),
0.95 (2 H, m).

6358 J . Org. Chem., Vol. 62, No. 18, 1997
Garc´ıa et al.
Kin etic Resolu tion of (()-1-Octen -7-yn -3-ol (4a). Freshly
distilled titanium tetraisopropoxide (1.5 mL, 5 mmol) was
added to a stirred suspension of freshly activated powdered
molecular sieves (600 mg), racemic 4a (0.625 g, 5.09 mmol),
and (2S,3S)-(-)-dicyclohexyl tartrate (1.9 g, 6 mmol) in CH2Cl2
(20 mL) at -20 °C. After stirring for 30 min, t-BuOOH (1.1
mL, 3.3 mmol, 3 M in isooctane) was added to the mixture
cooled at -40 °C. The reaction flask was placed in the freezer
(-20 °C) for 18 days and then poured into an ice-cooled
suspension of FeSO4‚7H2O (3.3 g) and tartaric acid (1 g) in
H2O (10 mL). The mixture was extracted with Et2O (3 × 15
mL), and the combined organic layers were washed with brine
(15 mL), dried, filtered, and concentrated in vacuo. Flash
chromatography (15% EtOAc/hexanes) afforded 13a (280 mg,
45%, >97% ee by 1H NMR analysis of the (S)-(+)-O-methyl-
mandelic ester derivative and compared with that of the
rt for 48 h and poured into H2O (15 mL). The aqueous layer
was extracted with hexanes, and the combined organic phases
were dried, filtered, and concentrated in vacuo. Flash chro-
matography (hexanes) gave the iodide 16 [45 mg, 70%, Rf )
0.7 (1% EtOAc/hexanes)]. 1H NMR δ: 5.26 (1 H, t, J ) 1.9),
4.92 (1 H, t, J ) 1.8), 4.06-4.01 (1 H, m), 2.7 (1 H, m), 2.58 (3
H, s), 2.09-1.88 (2 H, m), 1.82-1.65 (1 H, m), 1.57-1.2 (2 H,
m), 0.94 (9 H, s), 0.14, 0.11 (6 H, 2 s); 13C NMR δ: 155 (C),
144.9 (C), 110.6 (CH), 92 (CH2), 73.1 (CH), 37.6 (CH2), 31 (CH2),
30.3 (CH3), 25.9 (CH3), 23.6 (CH2), 18.3 (C), -5.1 (CH3), -4.7
(CH3); LRMS [m/z (%)]: 378.3 (M+, 1.6), 363.25 (M+ - Me, 2),
320.9 (M+ - t-Bu, 40), 263.20 (M+ - TBS, 10); HRMS calcd
for C15H27OISi: 378.0876; found: 378.0882.
3-Deoxy-1r-[(t-b u t yld im et h ylsilyl)oxy]-6-m et h ylvit a -
m in D3 (17). t-Butyllithium (0.22 mL, 0.28 mmol, 1.3 M in
pentane) was slowly added to a solution of bromide 9 (45 mg,
0.13 mmol) in Et2O (1 mL) at -78 °C. The mixture was stirred
for 15 min, and a solution of ZnBr2 (32.4 mg, 0.14 mmol) in
Et2O (1 mL) was added. After stirring at -10 °C for 1 h, the
reaction mixture was cooled at -78 °C, and a solution of iodide
16 (33 mg, 0.09 mmol) and Pd(Ph3P)4 (approximately 4 mg) in
THF (1 mL) was added. The resulting solution was allowed
to reach rt and stirred for 2 h. The reaction was quenched
with H2O (3 mL). The mixture was extracted with hexanes.
The combined organic layers were dried, filtered, and concen-
trated in vacuo. Flash chromaography (hexanes) gave 17 [38
mg, 94%, Rf ) 0.5 (hexanes), colorless oil]. 1H NMR [CD2Cl2,
500 MHz] δ: 5.61 (1 H, s), 5.12 (1 H, br s), 4.69 (1 H, br s),
3.96 (1 H, m), 2.53 (1H, br d, J ) 5.4), 2.48 (1H, br d, J ) 3.2),
1.96 (1 H, m), 1.79 (3 H, s), 0.88-0.82 (18 H, m), 0.51 (3H, s),
0.06, 0.05 (6 H, 2 s); 13C NMR [CD2Cl2, 500 MHz] δ: 151.9
(C), 139.0 (C), 137.0 (C), 127.0 (C), 124.4 (CH), 110.2 (CH2),
74.1, 56.9, 56.5, 46.0, 40.9, 39.9, 37.8, 36.5, 30.9, 30.2, 28.5,
28.0, 26.1, 24.3, 24.2, 23.9, 23.1, 22.8, 19.9, 19.0, 18.8, 12.1,
-4.7, -4.9; LRMS [m/z (%)]: 512 (M+, 5), 455.2 (M+ - t-Bu,
15), 366.25 (12), 326.2 (18); HRMS calcd for C34H60OSi:
512.4416; found: 512.4419; UV (Et2O, nm): λmin 220; λmax 242.
3-Deoxy-1r-[(t-bu tyld im eth ylsilyl)oxy]-6-m eth ylp r evi-
ta m in D3 (18a ). A solution of 17 in CH2Cl2 was heated at
reflux for two days in the dark. After removal of the solvent
racemic mixture). [R]20 ) -10.7 (c 1.2, CHCl3).
D
(3S)-3-[(t-Bu tyld im eth ylsilyl)oxy]-1-octen -7-yn e (13b).
Imidazole (178 mg, 2.5 mmol) and TBSCl (0.15 g, 1 mmol) were
added to a solution of 13a (100 mg, 0.8 mmol) in DMF (5 mL).
The reaction mixture was stirred for 12 h and poured into H2O
(15 mL). The resulting mixture was extracted with hexanes,
and the combined organic phases were dried, filtered, and
concentrated in vacuo. The residue was filtered through a
short pad of silica gel (hexanes) to give 13b (185 mg, 98%).
(3S)-3-[(t-Bu tyld im eth ylsilyl)oxy]-1-n on en -7-yn e (14).
A solution of 13b (260 mg, 1.09 mmol) in THF (8 mL) was
added to n-BuLi (0.6 mL, 1.3 mmol, 2.35 M in hexanes) cooled
at -78 °C. After stirring for 1 h, MeI (0.2 mL, 3.27 mmol)
was added, and the reaction mixture was allowed to warm to
rt and stirred for 7 h. The reaction was quenched with H2O
(10 mL), and the aqueous layer was extracted with Et2O. The
combined organic layers were dried, filtered, and concentrated
in vacuo. Flash chromatography (1% EtOAc/hexanes) gave 14
1
[261 mg, 94%, Rf ) 0.5 (3% EtOAc/hexanes), colorless oil]. H
NMR δ: 5.79 (1 H, ddd, J ) 17.2, 10.4, and 6), 5.14 (1 H, ddd,
J ) 17.1, 1.7, and 1.4), 5.03 (1H, ddd, J ) 10.4, 1.5, and 1.3),
4.11 (1 H, q, J ) 5.8), 2.12 (2 H, m), 1.77 (3 H, t, J ) 2.6), 1.54
(4 H, m), 0.9 (9 H, s), 0.04, 0.06 (6 H, 2 s); 13C NMR δ: 141.6
(CH), 113.7 (CH2), 79 (C), 79 (C), 75 (C), 73.4 (CH), 37.1 (CH2),
25.8 (CH3), 24.6 (CH2), 18.7 (CH2), 18 (C), 3.3 (CH3), -5 (CH3),
-4.5 (CH3); LRMS [m/z (%)]: 237.1 (M+ - Me, 5), 207 (6), 195.1
(M+ - t-Bu, 30), 171 (37); HRMS calcd for C15H28OSi - CH3:
237.1674; found: 237.1671.
1
under reduced pressure, H NMR analysis showed the previ-
tamin 18a to be the major component. 1H NMR [CD2Cl2, 500
MHz] δ: 5.48 (2 H, br s), 3.97 (1 H, br s), 1.73 (3 H, s), 1.24 (3
H, s), 0.91-0.81 (18 H, m), 0.66 (3 H, s), 0.09, 008 (6 H, 2 s);
13C NMR δ: [CD2Cl2, 125.76 MHz] δ: 139.2, 136.1, 125.0, 124.6,
70.9, 55.0, 51.4, 42.5, 39.9, 36.7, 36.6, 33.4, 30.1, 29.2, 28.7,
28.4, 26.0, 25.3, 24.2, 24.1, 23.1, 22.9, 22.7, 19.0, 18.3, 11.3,
11.2, -4.1, -4.6; UV (Et2O, nm): λmin 224; λmax 248.
(1S, 2S, 3E)-1-[(t-Bu tyld im eth ylsilyl)oxy]-3-(iod oeth -
ylid en e)-2-(iod om eth yl)cycloh exa n e (15). n-Butyllithium
(0.96 mL, 2.37 mmol, 2.46 M in hexanes) was added dropwise
by syringe to a solution of Cp2TiCl2 (300 mg, 1.19 mmol) in
THF (6 mL) cooled at -80 °C. The mixture was stirred for 1
h while allowing to warm to -55 °C, and a solution of enyne
14 (200 mg, 0.79 mmol) in THF (4 mL) was added dropwise
via cannula. The reaction mixture was allowed to warm to rt
and stirred for 7 h. The resulting solution was added slowly
(2 h) by syringe to a solution of NIS (535.2 mg, 2.37 mmol) in
CH2Cl2 (4 mL) cooled at -78 °C. Stirring was continued for 1
h at -50 °C and 1 h at rt. The reaction was quenched with
saturated aqueous NH4Cl (10 mL). The resulting suspension
was filtered through a pad of Celite and extracted with
hexanes. Drying and concentration in vacuo afforded a residue
that was purified by flash chromatography (hexanes) to give
the diiodide 15 [164 mg, 41%, Rf ) 0.7 (2% EtOAc/hexanes),
white glassy solid]. [R]d ) +7.2 (c 1.1, CHCl3). 1H NMR δ:
4.25 (1 H, m), 3.19-3.06 (3 H, m), 2.75 (1 H, m), 2.56 (3 H, s),
1.76-1.4 (5 H, m), 0.87 (9 H, s), 0.14, 0.07 (6 H, 2 s); 13C NMR
δ: 140.9 (C), 98 (C), 70.8 (CH), 57.2 (CH), 30.1 (CH3), 28.4
(CH2), 25.8 (CH3), 25.4 (CH2), 20.2 (CH2), 17.9 (C) , 5.39 (CH2),
-5, -4.8 (CH3); LRMS [m/z (%)]: 448.9 (M+ - t-Bu, 100),
379.05 (M+ - I, 18), 321.9 (22), 246.9 (33), 214.9 (20); HRMS
calcd for C15H28OI2Si - C4H9: 448.92947; found: 448.92981.
(1S,3E)-1-t[(t-Bu t yld im et h ylsilyl)oxy]-2-m et h ylen e-3-
(iod oeth ylid en e)cycloh exa n e (16). DBU (0.22 mL, 1.4
mmol) was added to a solution of 15 (86 mg, 0.17 mmol) in
CH2Cl2 (1.5 mL) at 0 °C. The reaction mixture was stirred at
3-Deoxy-1r-h ydr oxy-6-m eth ylpr evitam in D3 (18b). Tet-
rabutylammonium fluoride (0.06 mL, 0.06 mmol, 1 M in THF)
was added to a solution of 19a (10 mg, 0.019 mmol) in THF (1
mL). The mixture was stirred for 12 h at rt, diluted with H2O
(6 mL), and extracted with Et2O. The combined organic phases
were dried, filtered, and concentrated in vacuo. Flash chro-
matography gave 19b [5 mg, 65%, Rf 0.5 (20% EtOAc/
hexanes)]. 1H NMR δ: 5.57 (1 H, br s), 5.41 (1 H, br s), 3.87
(1H, m), 2.11 (2H, m), 1.80 (3 H, s), 1.75 (3 H, s), 0.93 (3 H, d,
J ) 6.1), 0.86 (6 H, d, J ) 6.0), 0.66 (3 H, s).
Ack n ow led gm en t. We thank the DGICYT (Spain,
projects SAF 92-0572 and 95-0878) and Solvay-Duphar
B. V. (Weesp, The Netherlands) for financial support.
A.M.G. also thanks the Xunta de Galicia for a fellow-
ship.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
13C NMR spectra (18 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O970605M