Stereoselective Preparation of Vitamin D Precursors Using the Intramolecular Coupling of Alkynes and Cyclopropylcarbene-Chromium Complexes: A Formal Total Synthesis of (±)-Vitamin D3

Article abstract of DOI:10.1021/jo972186z

The intramolecular coupling of alkynes and cyclopropylcarbene-chromium complexes has been examined. Complexes that feature a stereogenic center at the propargylic position of the alkyne- carbene tether are the focus of this paper. The reaction produces a cyclopentadienone intermediate fused to an oxygen heterocycle, which is reduced to the corresponding cyclopentenone under the reaction conditions (100 °C in 1% aqueous toluene). The preexisting stereogenic center has a powerful influence on the reduction of the cyclopentadienone ring, and predominantly a single diastereomer is produced in the reaction. Reductive cleavage of the heterocyclic ring with retention of stereochemistry affords compounds featuring a stereocenter on the five-membered ring and on a side chain. Use of the above reaction processes for the synthesis of the vitamin D precursor de-ABC-cholestan-14-one is also discussed.

Full text of DOI:10.1021/jo972186z

J . Org. Chem. 1998, 63, 2325-2331
2325
Ster eoselective P r ep a r a tion of Vita m in D P r ecu r sor s Usin g th e
In tr a m olecu la r Cou p lin g of Alk yn es a n d
Cyclop r op ylca r ben e-Ch r om iu m Com p lexes: A F or m a l Tota l
Syn th esis of (()-Vita m in D3
J ingbo Yan1a and J ames W. Herndon*,1b
Department of Chemistry & Biochemistry, New Mexico State University, Box 30001, Department 3C,
Las Cruces, New Mexico 88003-8001, and Department of Chemistry & Biochemistry,
University of Maryland, College Park, Maryland 20742-2021
Received December 2, 1997
The intramolecular coupling of alkynes and cyclopropylcarbene-chromium complexes has been
examined. Complexes that feature a stereogenic center at the propargylic position of the alkyne-
carbene tether are the focus of this paper. The reaction produces a cyclopentadienone intermediate
fused to an oxygen heterocycle, which is reduced to the corresponding cyclopentenone under the
reaction conditions (100 °C in 1% aqueous toluene). The preexisting stereogenic center has a
powerful influence on the reduction of the cyclopentadienone ring, and predominantly a single
diastereomer is produced in the reaction. Reductive cleavage of the heterocyclic ring with retention
of stereochemistry affords compounds featuring a stereocenter on the five-membered ring and on
a side chain. Use of the above reaction processes for the synthesis of the vitamin D precursor
de-ABC-cholestan-14-one is also discussed.
Sch em e 1
In tr od u ction
The intramolecular coupling of alkynes and cyclopro-
pylcarbene complexes affords cyclopentenones fused to
oxygen heterocycles (e.g., 3, Scheme 1) in good-excellent
yield2 by way of an unstable cyclopentadienone interme-
diate (e.g. 2).3 As noted in some cases,2 if a stereogenic
center is present in the tethering chain, the heterocyclic
ring can be constructed in a stereoselective fashion since
the preexisting stereocenter can control the cyclopenta-
dienone reduction event. Acyclic stereocenters adjacent
to cyclopentane rings (featured in compound 4) are a
(1) (a) University of Maryland. (b) New Mexico State University.
(2) (a) Herndon, J . W.; Matasi, J . J . J . Org. Chem. 1990, 55, 786-
788. (b) Herndon, J . W.; Matasi, J . J . Tetrahedron Lett. 1992, 33, 5725-
5728.
(3) (a) Herndon, J . W.; Patel, P. P. Tetrahedron Lett. 1997, 38, 59-
62. (b) Herndon, J . W.; Tumer, S. U. Tetrahedron Lett. 1989, 34, 295-
296.
(4) Watt, D. S.; McKenna, M. J .; Spencer, T. A. J . Org. Chem. 1967,
32, 2674-2678.
(5) Construction via ring opening of norbornane derivatives: (a)
Trost, B. M.; Bernstein, P. R.; Funfschilling, P. C. J . Am. Chem. Soc.
1979, 101, 4378-4380. (b) Grieco, P. A.; Takigawa, T.; Moore, D. R. J .
Am. Chem. Soc. 1979, 101, 4380-4381. (c) Stevens, R. V.; Lawrence,
D. S. Tetrahedron 1985, 41, 93-100. (d) Shimizu, I.; Matsuda, N.;
Noguchi, Y.; Zako, Y.; Nagasawa, K. Tetrahedron Lett. 1990, 31, 4899-
4902. Construction via stereoselective enolate alkylation: (e) Clase, J .
A.; Money, T. Can. J . Chem. 1992, 70, 1537-1544. (f) Daniewski, A.
R.; Warchol, T. Liebigs Ann. Chem. 1992, 965-973. Construction via
stereoselective addition to exo-alkylidenecyclopentane derivatives: (g)
Batchco, A. D.; Berger, D. E.; Davoust, S. G.; Wovkulich, P. M.;
Uskokovic´, M. R. Helv. Chim. Acta 1981, 64, 1682-1687. (h) Hatekeya-
ma, S.; Numata, H.; Takano, S. Tetrahedron Lett. 1984, 25, 3617-
3620. (i) Takahashi, T.; Yamada, H.; Tsuji, J . J . Am. Chem. Soc. 1981,
103, 5259-5261. Construction via stereoselective Michael addition: (j)
Haynes, R. K.; Stokes, J . V.; Hambley, T. W. J . Chem. Soc., Chem.
Commun. 1991, 58-60. (k) Grzymacz, P.; Marczak, S.; Wicha, J . J .
Org. Chem. 1997, 62, 5293-5298. (l) Pen, L.-R.; Tokoroyama, T.
Tetrahedron Lett. 1992, 33, 1469-1472. Construction via stereoselec-
tive hydrolysis-ring opening of an enamine-cyclobutene derivative:
(m) Desmaele, D.; Ficini, J .; Guingant, A.; Touzin, A. M. Tetrahedron
Lett. 1983, 24, 3083-3087. Construction via stereoselective Claisen
rearrangement: (n) Chapleo, C. B.; Hallett, P.; Lythgoe, B.; Water-
house, I.; Wright, P. W. J . Chem. Soc., Perkin Trans. 1 1977, 1211-
1218.
common structural feature for a variety of biologically
important natural products (most notably steroids and
steroid derivatives), and this class of compounds could
result from reductive ring opening of vinylogous ester
derivative 3.2b,4 Unique in this approach for stereose-
lective steroid side-chain construction5 is that the ste-
reogenic center in the carbene complex ultimately con-
trols all of the other stereocenters in the five-membered
ring. This stereogenic center corresponds to the acyclic
stereogenic center for steroid derivatives.
In this paper, examination of thermolysis reactions for
alkyne-carbene complexes containing propargylic ste-
reocenters, further discussion of the cyclopentadienone
reduction event, and development of a procedure for
reductive opening of the heterocyclic ring in vinylogous
S0022-3263(97)02186-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/19/1998

2326 J . Org. Chem., Vol. 63, No. 7, 1998
Yan and Herndon
Sch em e 2a
Sch em e 4
Ta ble 1. Ster eoselectivity in th e Th er m olysis of
Alk yn e-Ca r ben e Com p lexes 1A-C
a
Key: (i) TBDMSCl; (ii) BH3-THF, then NaOH/H2O2; (iii)
second
stereoselectivity
for the
(ClCO)2/DMSO; (iv) CBr4/PPh3; (v) 2 equiv of n-BuLi, (vi) BF3‚OEt2;
(vii) PhI/Pd catalyst; (viii) n-BuLi, then CH3I.
yield
major
most abundant
Ra
of 3b ratioc isomer of 3d isomer of 3d heterocyclic ring
H (1A)
Ph (1B)
57 94:6
72 84:9:7 trans-trans
trans
cis
94:6
91:9
95:5
Sch em e 3
cis-trans
CH3 (1C) 70 90:5:5 trans-trans
N/Ae
a
The suffixes A, B, and C define the R groups for compounds
1-3 and 10. Combined yield of all stereoisomers. c The ratio was
b
determined by integration of the alkene protons in the region δ
d
5.2-5.4 of the crude reaction mixture. The first stereochemical
label refers to heterocycle stereochemistry and the second refers
to carbocycle stereochemistry. e The minor isomers are equally
abundant.
ester 3 will be discussed. Application of these reactions
for the synthesis of (()-de-ABC-cholestan-14-one (5),6 a
synthetic precursor to vitamin D3 derivatives,7,8 will be
discussed. Vitamin D3 and various synthetic derivatives
display a diverse range of biologically activity, including
regulation of calcium, treatment of psoriasis, treatment
of breast cancer, and regulation of hormonal responses.9
synthesis, and this may account for the low yield in this
case. In the other cases, the purified alkynol was
employed.
Th er m olysis of Alk yn e-Ca r ben e Com p lexes. Car-
bene complexes 1A-C were heated in refluxing 99/1
toluene/water to effect the cycloaddition/cyclization reac-
tion. In all cases, the expected â-alkoxycyclopentenone
derivatives were produced in good yield (combined yield
of all stereoisomers) and with a high degree of stereose-
lectivity (Scheme 4 and Table 1). Contrary to intramo-
lecular terminal alkyne-carbene couplings conducted in
dioxane or THF,2a,10 thermolysis of carbene complex 1A
proceeds in respectable yield. Only three out of the four
possible stereoisomers were obtained during thermolysis
of the internal alkynes 1B and 1C. The major isomer in
all cases was assigned as the compound having the trans
arrangement of substituents on the heterocyclic ring. For
cyclopentenones derived from internal alkynes (3B and
C), the major isomer also features the trans arrangement
of substituents in the carbocyclic ring.
Assign m en t of Ster eoch em istr y. The stereochem-
istry in the heterocyclic ring for all of the major isomers
in Table 1 was assigned as trans on the basis of the large
value for the coupling constant between the allylic
hydrogen and the hydrogen next to the methyl group
(11.4, 11.0, and 11.1 Hz in 3A-trans, 3B-trans-trans,11
and 3C-trans-trans, respectively). A minor isomer as-
signed as a cis heterocycle features a considerably smaller
value for this coupling (7.8 Hz in 3B-cis-trans). The
larger coupling observed for the trans heterocycles is
more consistent with the diaxial coupling anticipated for
this isomer. The stereochemistry in the carbocyclic rings
for the major isomers of 3B and 3C was assigned as trans
on the basis of the smaller coupling between the allylic
Resu lts a n d Discu ssion
P r epar ation of Alkyn ol Star tin g Mater ials. Alkynol
10A was prepared from commercially available 3-methyl-
3-buten-2-ol according to the synthetic route in Scheme
2. The protected terminal alkyne 9 was transformed to
the phenylacetylene derivative via palladium-catalyzed
coupling with iodobenzene or to the methylacetylene
derivative by deprotonation and alkylation with methyl
iodide. Conversion of alkynols to the corresponding
cyclopropylcarbene complexes was accomplished through
the acetoxycarbene route (Scheme 3)10 and proceeded in
about 70% yield. Due to volatility problems, an ether
solution containing crude alkynol 10A (from silyl ether
cleavage) was used directly for the carbene complex
(6) For the latest synthesis, see: Pen, L.-R.; Tokoroyama, T.
Tetrahedron Lett. 1992, 33, 1473-1474. See also ref 5f,h,m.
(7) For a review of synthetic aspects of vitamin D, see: Zhu, G.-D.;
Okamura, W. H. Chem. Rev. 1995, 95, 1877-1952.
(8) For transformation of 5 into vitamin D3, see ref 5m, followed
by: (a) Kocienski, P. J .; Lythgoe, B.; Roberts, D. A. J . Chem. Soc.,
Perkin Trans. 1, 1980, 897-901. (b) Littlewood, P. S.; Lythgoe, B.;
Saksena, A. K. J . Chem. Soc. C 1971, 2955-2959. (c) Dawson, T. M.;
Dixon, J .; Littlewood, P. S.; Lythgoe, B.; Saksena, A. K. J . Chem. Soc.
C 1971, 2960-2966. (d) Kocienski, P. J .; Lythgoe, B. J . Chem. Soc.,
Perkin Trans. 1, 1980, 1400-1404. (e) Kocienski, P. J .; Lythgoe, B. J .
Chem. Soc., Perkin Trans. 1 1980, 1405-1406.
(9) For a review of the biological activity of vitamin D and its
synthetic analogues, see: Bouillon, R.; Okamura, W. H.; Norman, A.
W. Endocrine Rev. 1995, 16, 200-257.
(10) (a) Wulff, W. D.; McCallum, J . S.; Kunng, F.-A. J . Am. Chem.
Soc. 1988, 110, 7419-7434. (b) Semmelhack, M. F.; Bozell, J . J .; Keller,
L.; Sato, T.; Speiss, E. J .; Wulff, W. D.; Zask, A. Tetrahedron 1985,
41, 5803-5812.
(11) The first stereochemical label refers to the stereochemistry of
heterocyclic ring substituents, and the second label refers to the
stereochemistry of carbocyclic ring substituents.

Synthesis of Intermediates for Vitamin D Synthesis
J . Org. Chem., Vol. 63, No. 7, 1998 2327
Sch em e 5
and R-carbonyl hydrogens (3.2 and 3.4 Hz in 3B-trans-
trans and 3C-trans-trans, respectively) compared with a
larger value for the same couplings in isomers assigned
as cis carbocycles (7.0 and 6.6 Hz in 3B-trans-cis and 3C-
trans-cis, respectively); a similar correlation has been
noted in similar systems.2a,12 The stereochemistry of the
remaining isomers was assigned on the basis of the
observation that the diastereotopic hydrogens of the
methylene group next to oxygen are separated by about
0.2 ppm in the trans heterocycles, while these same
hydrogens appear as one signal in the cis heterocycles.
Ra tion a le for th e Ster eoselectivity. As noted in
previous studies, the substituents on the carbocyclic ring
undergo isomerization under the conditions of carbene-
alkyne coupling, and the trans carbocycle is usually the
major product of the reaction;2a,12 this equilibration occurs
predominantly at the R-carbonyl position on the basis of
deuterium-exchange studies.12 The major heterocyclic
ring stereoisomer from the intramolecular alkyne-car-
bene coupling reaction also corresponds to the thermo-
dynamically more stable isomer. The stereochemistry,
which arises during the cyclopentadienone reduction
step, can be rationalized on the basis of the series of
events depicted in Scheme 5. First, the cyclopentadi-
enone oxygen complexes to chromium (12),13 and negative
charge is delocalized into the five-membered ring through
back-bonding (13).14 The anionic cyclopentadiene ring
is then protonated once to afford cyclopentadiene deriva-
tive 14, which then undergoes a series of 1,5-hydrogen
shifts,15 ultimately equilibrating cyclopentadienide ste-
reoisomers 14 and 19. Protonation of stereoisomers 14
or 19 a second time affords the observed major isomer,
3- trans or 3-cis. This sequence of events is supported by
several previous observations:12 The high degree of
anionic character of the five-membered ring is supported
by the appearance of â-elimination products when pro-
pargyl ethers couple with cyclopropylcarbene complexes.
The hydride shifts are supported by the scrambling of
the deuterium label when D2O is used as the proton
source. That cyclopentadiene regioisomers 14 and 19 are
the major species at equilibrium is supported by the
exclusive formation of vinylogous ester regioisomers and
not 4-alkoxy-2-cyclopentenone derivatives (e.g., 20) or
unconjugated cyclopentenones, and previous studies have
shown that vinylogous ester isomers (e.g., 3) and cyclo-
pentenones analogous to 20 do not interconvert under
the conditions required for the alkyne-cyclopropylcar-
bene coupling, although isomerization to vinylogous ester
derivatives can be effected by treatment with base.
An alternative but more direct explanation for the
stereochemistry would involve preferential protonation
of intermediate 13 from the pseudoaxial direction16 giving
(12) Tumer, S. U.; Herndon, J . W.; McMullen, L. A. J . Am. Chem.
Soc. 1992, 114, 8394-8404.
(14) Cyclopentadienones are excellent electron acceptors. (a) O¨ strich,
S.; Broser, W.; Kurreck, H. Z. Naturforsch. B 1977, 32B, 686-692. (b)
Burk, M. J .; Calabrese, J . C.; Davidson, F.; Harlow, R. L.; Roe, D. C.
J . Am. Chem. Soc. 1991, 113, 2209-2222.
(15) This process is anticipated to be very rapid at the reaction
temperature. For a recent example, see: Himeda, Y.; Yamataka, H.;
Ueda, I.; Hatanaka, M. J . Org. Chem. 1997, 62, 6529-6538.
(16) (a) Caine, D. Org. React. 1976, 23, 1-258. (b) House, H. O.;
Giese, R. W.; Kronberger, K.; Kaplan, J . P.; Simeone, J . F. J . Am.
Chem. Soc. 1970, 92, 2800-2810.
(13) Both oxygen and η4-diene complexes have been proposed in the
reaction of cyclopentadienones with group VI metal carbonyls. These
results are more consistent with
a
simple reduction-protonation
sequence, which employs an oxygen-bound complex. (a) Brown, D. A.;
Hargaden, J . P.; McMullin, C. M.; Gogan, N.; Sloan, H. J . Chem. Soc.
1963, 4914-4918. (b) Adams, H.; Bailey, N. A.; Hempstead, P. D.;
Morris, M. J .; Riley, S.; Beddoes, R. L.; Cook, E. S. J . Chem. Soc.,
Dalton Trans. 1993, 91-100.

2328 J . Org. Chem., Vol. 63, No. 7, 1998
Yan and Herndon
Sch em e 6
Sch em e 7
cyclopentadiene 14, followed by a second protonation to
afford cyclopentenone 3 trans. This scenario is, however,
not consistent with previous studies of reactions con-
ducted in the presence of D2O, where the deuterium
incorporation at the 2-, 4-, and 5-positions (cyclopenten-
one numbering) was noted.12
Cyclop en ten on e 3C-tr a n s-tr a n s a s a n In ter m ed i-
a te for Vita m in D Syn th esis. As noted in Table 1, the
intramolecular alkyne-cyclopropylcarbene coupling reac-
tion offers a very effective method to control the relative
configuration between the asterisked carbons in the
major isomer of 3C (Scheme 6).5 This stereochemistry
matches that present in numerous steroid derivatives
such as vitamin D3. The retrosynthetic analysis for a
formal total synthesis of vitamin D3 is depicted in Scheme
6. The objective in this manuscript is to transform
cyclopentenone 3C-trans-trans into de-ABC-cholestan-14-
one (5), which has previously been converted to vitamin
D3.8 The synthesis requires the reductive ring opening
of the vinylogous ester functionality in 3C-trans-trans,
followed by a chain extension of the resulting alcohol 4C.
Sch em e 8
The synthesis of de-ABC-cholestan-14-one in this paper
employs the purified major isomer, 3C-trans-trans. Since
the enolate of de-ABC-cholestan-14-one was employed for
further transformation to vitamin D3,5m,7 either 3C-trans-
trans or 3C-trans-cis could in theory be employed for the
synthesis of vitamin D3. Thus, the stereoselectivity of
the alkyne-carbene thermolysis reaction can be regarded
as 95:5 since 3C-trans-trans (90% of the mixture) and
the trans-cis isomer (5% of the mixture) both have the
correct relative stereochemistry at the asterisked car-
bons, while the other minor isomer, 3C cis-trans (5% of
the mixture), has the wrong relative stereochemistry.
the position of the CdO and OH groups are reversed. On
the basis of previous observations,2b the conversion of 3C
trans-trans to 4C-trans is postulated to occur via pal-
ladium-catalyzed ether exchange, affording ethoxycyclo-
pentenone 26, followed by hydrogenation and â-elimina-
tion. Compounds similar to 26 have previously been
noted in the catalytic hydrogenation of vinylogous esters
in ethanol solvent, while simple hydrogenation products
(e.g., 25) are the major products from hydrogenation in
THF. The origin of the â-hydroxycarbonyl compound is
unclear.
Eventual transformation of keto alcohol 4C-trans into
de-ABC-cholestan-14-one is relatively straightforward
and is depicted in Scheme 9. Protection of the ketone,
followed by oxidation of the alcohol to an aldehyde,
followed by chain extension and deprotection affords de-
ABC-cholestan-14-one. The overall process occurs with-
out epimerization of any of the stereogenic centers. The
overall conversion of 4C-trans to de-[ABC]-cholestan-14-
one occurs in 88% yield.
Red u ctive Rin g Op en in g of Vin ylogou s Ester s. A
transformation similar to the desired reductive ring
opening has been reported for 3-ethoxycyclohexenone
using a dissolving metal reduction at -33 °C, followed
by protonation.4 Exposure of cyclopentenone 3C-trans-
trans to these conditions afforded only the net hydroge-
nation product 25 in 84% yield (Scheme 7). Apparently,
the critical â-elimination step (22 f 23) does not occur
at -33 °C. Dissolving metal reduction at 25 °C in
ethylenediamine afforded a mixture of the desired reduc-
tive ring opening product 4C-trans (46%) and hydrogena-
tion product 25 (40%). The desired transformation was
most successfully accomplished by catalytic hydrogena-
tion in ethanol (Scheme 8). In this reaction, the desired
reductive ring opening product was the major product
(65%), accompanied by a side product tentatively identi-
fied as â-hydroxy ketone derivative 29 (17%); the spectral
data for 29 are also consistent with the compound where
Con clu sion
The intramolecular coupling of alkyne-cyclopropyl-
carbene chromium complexes featuring a propargylic
stereocenter proceeds with a high degree of stereoselec-
tivity and leads to cyclopentenones fused to tetrahydro-

Synthesis of Intermediates for Vitamin D Synthesis
J . Org. Chem., Vol. 63, No. 7, 1998 2329
Sch em e 9
Gen er a l P r oced u r e II: Th er m olysis of Alk yn e-
Ca r ben e Com p lexes. To a three-neck round-bottom
flask equipped with a reflux condenser and rubber
septum, under nitrogen, were added toluene (100 mL)
and water (1 mL), and the solution was heated to reflux.
To this refluxing solution was added a solution of carbene
complex in toluene (30 mL) via syringe pump over a
period of 4 h. After the addition was complete, the
mixture was heated at reflux for an additional 20 h and
then cooled to room temperature. The resulting green
mixture was filtered through Celite, and the solvent was
removed on a rotary evaporator. Final purification was
achieved by flash chromatography on silica gel.
Th er m olysis of Alk yn e-Ca r ben e Com p lex 1C.
General procedure II was followed using carbene complex
1C (465 mg, 1.31 mmol). Purification by flash chroma-
tography on silica gel using hexane/ethyl acetate (3:2) as
the eluent provided two fractions.
pyran rings. The reaction produces preferentially the
trans heterocycle, and this selectivity has been attributed
to thermodynamic control during the reduction of a
cyclopentadienone intermediate. The major diastereomer
produced in this coupling reaction matches the stereo-
chemical features found in steroid derivatives, and this
reaction has been used as the cornerstone for a stereo-
selective formal total synthesis of vitamin D3 through the
cyclopentanone derivative de-ABC-cholestan-14-one (5).
Subsequent reductive ring opening of the major isomer
using catalytic hydrogenation followed by a chain exten-
sion provides (()-de-ABC-cholestan-14-one in stereochem-
ically pure form. Further evaluation of the scope and
limitation of the stereoselective five-membered ring-
forming reaction is presently underway in our laboratory.
The first fraction was identified as compound 3C-trans-
trans (137 mg, 63%): 1H NMR (CDCl3) δ 5.20 (d, 1 H, J
) 1.6 Hz), 4.30 (ddd, 1 H, J ) 11.1, 5.8, 4.6 Hz), 4.05
(ddd, 1 H, J ) 11.1, 8.3, 4.5 Hz), 2.09 (qd, 1 H, J ) 7.3
(q), 3.4 (d) Hz), 1.99 (ddd, 1 H, J ) 11.1, 3.4, 1.6 Hz),
1.91 (dddd, 1 H, J ) 14.0, 5.8, 5.8, 4.5 Hz), 1.59 (m, 2 H),
1.15 (d, 3 H, J ) 7.3 Hz) 1.06 (d, 3 H, J ) 6.5 Hz); 13C
NMR (CDCl3) δ 206.3, 189.1, 106.2, 68.7, 51.1, 46.4, 32.3,
31.7, 20.6, 15.7; IR (neat) 1694 (s), 1614 (s) cm-1; MS (EI)
m/e 166 (M, 91), 151 (73) 111 (100); HRMS calcd for
C10H14O2 166.0994, found 166.0994.
The second fraction was a mixture of two compounds,
believed to a mixture of compounds 3C-trans-cis and 3C-
cis-trans (15.2 mg, 7%). Further purification using
preparative thin-layer chromatography afforded a small
sample of pure 3C-trans-cis: 1H NMR (CDCl3) δ 5.27 (d,
1 H, J ) 1.9 Hz), 4.39 (dt, 1 H, J ) 11.2 (d), 4.5 (t) Hz),
4.06 (td, 1 H, J ) 11.2 (t), 3.6 (d) Hz), 2.61 (qd, 1 H, J )
7.2 (q), 6.6 (d) Hz), 2.53 (ddd, 1 H, J ) 11.2, 6.6, 1.9 Hz),
1.94 (m, 1 H), 1.80 (m, 1 H), 1.60 (m, 1 H), 1.15 (d, 3 H,
J ) 6.9 Hz), 1.07 (d, 3 H, J ) 7.2 Hz); 13C NMR (CDCl3)
δ 208.5, 189.1, 105.8, 68.9, 46.8, 43.2, 32.0, 26.5, 21.2,
14.0; IR (neat) 1682 (s, 1595 (s) cm-1; MS (EI) m/e 166
(100), 151 (87), 111 (96); HRMS calcd for C10H14O2
166.0994, found 166.0992. The following resonances
appear in the mixture but not in purified 3C-trans-cis
and have been attributed to 3C-cis-trans: 1H NMR
(CDCl3) δ 5.28 (d, 1 H, J ) 1.4 Hz), 4.28 (t, 2 H, J ) 6.3
Hz), 1.13 (d, 3 H, J ) 6.5 Hz), 0.93 (d, 3 H, J ) 7.0 Hz).
Exp er im en ta l Section
General methods have been described previously.12
Gen er a l P r oced u r e I: Con ver sion of Alk yn ols to
Ca r ben e Com p lexes. To the solution of acylate salt
1117 (400 mg, 1.20 mmol) in 20 mL of dichloromethane
at 0 °C under nitrogen was added acetyl chloride (0.08
mL, 1.20 mmol) via syringe, followed by immediate
addition of the alkynol (1.20 mmol). The reaction mix-
ture was stirred at 0 °C for about 1 h and then warmed
to 25 °C and stirred for 20 min. The solvent was removed
on a rotary evaporator. Flash chromatography (hexane
eluent) of the residue gave the pure carbene complex after
solvent removal.
P r ep a r a tion of Alk yn e-Ca r ben e Com p lex 1C.
General procedure I was followed using a solution of
3-methyl-4-hexyn-1-ol18 (350 mg, 3.13 mmol) in dichlo-
romethane (20 mL), acylate salt 1117 (1050 mg, 3.13
mmol), and acetyl chloride (0.22 mL, 1.7 mmol) in
dichloromethane (20 mL). After chromatographic puri-
fication, a yellow oil (790 mg, 71%) identified as carbene
complex 1C was obtained: 1H NMR (CDC13) δ 5.03 (t, 2
H, J ) 5.6 Hz), 3.45 (m, 1 H), 2.29 (m, 1 H), 1.94 (m, 2
H), 1.75 (d, 3 H, J ) 2.3 Hz), 1.24 (m, 7 H); 13C NMR
(CDCl3) δ 351.6, 223.7, 216.8, 81.2, 78.9, 77.7, 41.3, 36.4,
The ratio of 90:5:5 was determined by NMR integration
on the alkene protons at around 5.2 ppm prior to
attempted isomer separation.
Red u ctive Rin g Op en in g of Vin ylogou s Ester
Der iva tive 3C-tr a n s-tr a n s Usin g Ca ta lytic Hyd r o-
gen a tion . To a 250 mL round-bottom flask equipped
with a three-way adapter and a stir bar was added a
solution of vinylogous ester 3C-trans-trans (205 mg, 1.24
mmol) in ethanol (200 mL) followed 10% palladium on
carbon (10 mg). The reaction system was evacuated and
refilled with nitrogen (three times) followed by hydrogen
(three times); an aspirator was used as the vacuum
source. The hydrogen pressure was adjusted to about 1
atm using a balloon. The reaction mixture was allowed
to stir at room temperature under a hydrogen atmo-
sphere for a 12 h period. The catalyst was removed by
filtration through Celite, and the solvent was removed
on a rotary evaporator. Purification of the residue by
23.2, 21.5, 17.6, 3.3; IR (CCl4) 2060 (s), 1921 (vs) cm-1
;
MS (CI) m/e 356 (M, 3), 164 (100); HRMS calcd for C16H16-
CrO6 356.0352, found 356.0339
(17) Herndon, J . W.; Tumer, S. U.; McMullen, L. A.; Matasi, J . J .;
Schnatter, W. F. K. In Advances in Metal-Organic Chemistry; Liebe-
skind, L. S., Ed.; J AI Press: Greenwich, CT, 1994; Vol. III, pp 51-95.
(18) See the Supporting Information.

2330 J . Org. Chem., Vol. 63, No. 7, 1998
Yan and Herndon
preparative TLC using hexane/ethyl acetate (3:2) as the
eluent led to two major fractions.
18.7, 14.0; IR (neat) 1726 cm-1; MS (EI) m/e 212 (M, 1),
141 (39), 99 (100); HRMS calcd for C12H18O3 212.1413,
found 212.1422.
The compound in the first fraction was assigned as
reductive ring opening product 4C-trans (135 mg, 65%):
1H NMR (CDCl3) δ 3.75 (ddd, 1 H, J ) 10.4, 7.8, 5.0 Hz),
3.64 (ddd, 1 H, J ) 10.4, 7.3, 7.3 Hz), 2.32 (ddt, 1 H, J )
18.2, 8.7, 1.2(t) Hz), 2.09 (ddd, 1 H, J ) 18.2, 11.6, 9.0
Hz), 1.98 (m, 1 H), 1.88 (m, 1 H), 1.69 (m, 3 H), 1.48 (ddd,
1 H, J ) 23.2, 11.4, 8.2 Hz), 1.34 (m, 1 H), 1.07 (d, 3 H,
J ) 6.9 Hz), 0.99 (d, 3 H, J ) 6.8 Hz); 13C NMR (CDCl3)
δ 221.4, 61.2, 50.3, 46.9, 37.2, 35.3, 31.2, 23.3, 17.7, 14.0;
IR (neat) 3408 (s), 1732 (s) cm-1; MS (EI) m/e 170 (M, 1),
97 (100); HRMS calcd for C10H18O2 170.1307, found
170.1293.
Syn th esis of De-ABC-ch olesta n -14-on e Keta l. To
a solution of (isobutyl)triphenylphosphonium bromide (72
mg, 0.18 mmol) in diethyl ether (20 mL) was added
n-butyllithium (0.11 mL of a 1.6 M hexane solution, 0.18
mmol) at -78 °C. The reaction was stirred at -78 °C
for 0.5 h. The reaction mixture was allowed to warm to
room temperature and stirred for an additional 1 h. The
reaction mixture was cooled to 0 °C, and then a solution
of ketal aldehyde 21-trans (38 mg, 0.18 mmol) in diethyl
ether (10 mL) was added at -78 °C. The mixture was
allowed to warm to room temperature and stirred for 3
h. The reaction was quenched with water (30 mL) and
extracted with diethyl ether (3 × 50 mL). The organic
phases were dried over anhydrous magnesium sulfate,
and the solvent was removed on a rotary evaporator. The
residue was dissolved in dry hexane (50 mL), the solid
portion was removed by filtration, and the solvent was
removed on a rotary evaporator to give a light yellow
color oil. The compound was not further purified but
immediately subjected to hydrogenation. To a 250 mL
round-bottom flask equipped with a three-way adapter
and a stir bar was added a solution of the light yellow
compound and 10% palladium-carbon (10 mg) in ethanol
(50 mL) at room temperature. The reaction system was
evacuated and refilled with nitrogen (three times) fol-
lowed by hydrogen (three times); an aspirator was used
as the vacuum source. The hydrogen pressure was
adjusted to about 1 atm using a balloon. The reaction
mixture was stirred at room temperature for 12 h. The
catalyst was removed by filtration through Celite, and
the solvent was removed on a rotary evaporator. Puri-
fication of the residue by preparative TLC using hexane/
ethyl acetate (3:2) as the eluent led to de-ABC-cholestan-
14-one ketal (40.5 mg, 90%): 1H NMR (CDCl3) δ 3.87 (m,
4 H), 1.78 (m, 1 H), 1.70 (m, 3 H), 1.46 (m, 3 H), 1.31 (m,
3 H), 1.12 (m, 3 H), 0.98 (m, 1 H), 0.88 (d, 3 H, J ) 7.0
Hz), 0.86 (d, 3 H, J ) 6.4 Hz), 0.831 (d, 3 H, J ) 6.6 Hz),
0.828 (d, 3 H, J ) 6.4 Hz); 13C NMR (CDCl3) δ 118.4,
64.6, 64.4, 50.0, 43.1, 39.3, 35.5, 34.8, 32.7, 27.9, 25.2,
24.4, 22.7, 22.5, 17.9, 14.0; MS (EI) m/e 254 (M, 0.2), 99
(100); HRMS calcd for C16H30O2 254.2246, found 254.2240.
The compound in the second fraction was assigned as
keto diol 29 (39.3 mg, 17%; appears to be a 9:1 mixture
of stereoisomers): 1H NMR (CDCl3) δ 4.19 (ddd, 1 H, J
) 5.5, 4.0, 1.5 Hz), 3.67 (m, 2 H), 2.39 (m, 1 H), 2.30 (br
s, 1 H), 2.27 (d, 1 H, J ) 4.0 Hz) 2.05 (m, 1 H), 1.95 (m,
1 H), 1.20 (m, 1 H), 1.19 (d, 3 H, J ) 7.4 Hz), 1.04 (d, 3
H, J ) 7.0 Hz); 13C NMR (CDCl3) δ 219.0, 70.6, 62.1, 49.7,
45.6, 43.4, 26.2, 25.3, 18.8, 12.8; IR (neat) 3400 (s), 1735
(s) cm-1; MS (EI) m/e 186 (M, 1), 125 (100); HRMS calcd
for C10H18O3 186.1256, found 186.1238.
Con ver sion of Keto Alcoh ol 4C-tr a n s to th e Cor -
r esp on d in g Ket a l. To a 100 mL round-bottom flask
equipped with a Dean-Stark trap and a condenser was
added a solution of keto alcohol 4C-trans (75.6 mg, 0.45
mmol) in ethylene glycol (559 mg, 9.00 mmol) and
p-toluenesulfonic acid monohydrate (30 mg 0.16 mmol)
in dry benzene (50 mL) at room temperature. The
reaction mixture was refluxed for 8 h and then was cooled
to room temperature. Saturated aqueous sodium bicar-
bonate solution (30 mL) was added, and the mixture was
poured into water (50 mL) and extracted with diethyl
ether (3 × 50 mL). The combined organic phases were
washed with water (50 mL) and dried over anhydrous
magnesium sulfate. The solvent was removed on a rotary
evaporator. Purification of the residue by preparative
TLC using hexane/ethyl acetate (3:2) as the eluent
afforded the ketal (85.6 mg, 95%): 1H NMR (CDCl3) δ
3.88 (m, 4 H), 3.73 (m, 1 H), 3.62 (ddd, 1 H, J ) 10.2,
7.4, 7.4 Hz), 1.80-1.60 (m, 4 H), 1.50 (m, 1 H), 1.30 (m,
3 H), 0.91 (d, 3 H, J ) 6.6 Hz), 0.89 (d, 3 H, J ) 6.2 Hz);
13C NMR (CDCl3) δ 118.3, 64.7, 64.4, 61.6, 49.9, 43.2,
Syn th esis of De-ABC-ch olesta n -14-on e (5). To a
solution of de-ABC-cholestan-14-one ketal (39.6 mg, 0.16
mmol) in acetone (20 mL) was added 10% hydrochloric
acid (20 mL) at room temperature. The reaction mixture
was stirred at room temperature for 12 h. The reaction
was quenched with water (30 mL) and extracted with
diethyl ether (3 × 50 mL). The combined organic phases
were dried over anhydrous magnesium sulfate, and the
solvent was removed on a rotary evaporator. Purification
of the residue by preparative TLC using hexane/ethyl
acetate (3:2) as the eluent led to de-ABC-cholestan-14-
one (5) (31.9 mg, 95%): 1H NMR (CDCl3) δ 2.23 (m, 1
H), 2.06 (m, 1 H), 1.91 (m, 2 H), 1.59 (m, 2 H), 1.44 (m,
2 H), 1.33 (m, 2 H), 1.15 (m, 4 H), 1.06 (d, 3 H, J ) 6.9
Hz), 0.95 (d, 3 H, J ) 6.7 Hz), 0.85 (d, 3 H, J ) 6.6 Hz),
0.84 (d, 3 H, J ) 6.6 Hz); 13C NMR (CDCl3) δ 221.8, 50.3,
46.9, 39.2, 37.3, 34.7, 32.6, 27.9, 25.2, 23.3, 22.7, 22.5,
17.8, 14.1; IR (neat) 1744 (s) cm-1; MS (El) m/e 210 (m,
8), 140 (3), 126 (5), 125 (10), 99 (2), 98 (11), 97 (100), 84
35.7, 34.7, 32.0, 24.2, 18.0, 13.9; IR (neat) 3418 (s) cm-1
;
MS (EI) m/e 214 (M, 1), 99 (100); HRMS calcd for
C12H20O3 214.1569, found 214.1576.
Syn th esis of Keta l Ald eh yd e 21-tr a n s. To a solu-
tion of the ketal alcohol from the previous experiment
(89.5 mg, 0.42 mmol) in dichloromethane (20 mL) was
added pyridinium chlorochromate (108 mg, 0.5 mmol) at
room temperature. The reaction mixture was stirred at
room temperature for a 2 h period. The reaction mixture
was quenched with water (30 mL) and extracted with
diethyl ether (3 × 50 mL). The combined organic phases
were dried over magnesium sulfate, and the solvent was
removed on a rotary evaporator. Purification of the
residue by preparative TLC using hexane/ethyl acetate
(3:2) as the eluent yielded aldehyde 21-trans (85.6 mg,
95%) as a colorless oil: 1H NMR (CDCl3) δ 9.75 (dd, 1 H,
J ) 2.6, 1.4), 3.88 (m, 4 H), 2.45 (m, 1 H), 2.15 (m, 2 H),
1.58 (m, 5 H), 1.27 (m, 2 H), 0.96 (d, 3 H, J ) 6.3 Hz),
0.92 (d, 3 H, J ) 6.9 Hz); 13C NMR (CDCl3) δ 202.9, 118.0,
64.7, 64.4, 49.5, 49.3, 47.3, 43.5, 34.6, 32.5, 30.4, 24.3,
(16), 83 (13), 71 (14), 69 (30); HRMS calcd for C14H26
210.1984, found 210.1986.
O

Synthesis of Intermediates for Vitamin D Synthesis
J . Org. Chem., Vol. 63, No. 7, 1998 2331
Literature-reported 13C NMR data of compound 5:
Ficini’s results:19 13C NMR (CDCl3) δ 221.4, 50.3, 46.9,
39.3, 37.3, 34.8, 32.7, 27.9, 25.3, 23.4, 22.7, 22.5, 17.7,
14.1.
Tokoroyama’s results:6 13C NMR (CDCl3) δ 221.71,
50.34, 46.95, 39.29, 37.35, 34.81, 32.68, 27.98, 25.26,
23.41, 22.77, 22.50, 17.80, 14.14.
Takano’s results:5h 13C NMR (CDCl3) δ 221.4, 50.3,
46.9, 39.3, 37.3, 34.8, 32.6, 28.0, 25.2, 23.4, 22.8, 22.5,
17.8, 14.1.
Ack n ow led gm en t. We thank the Petroleum Re-
search Fund, administered by the American Chemical
Society, for financial support of this research.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures for synthesis of alkynols, synthesis and thermolysis of
complexes 1A and 1B, and dissolving metal reductions.
Photocopies of 1H and 13C NMR spectra for compounds
produced in these studies have also been included (42 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
(19) Desmaele, D.; Ficini, J .; Guingant, A.; Kahn, P. Tetrahedron
Lett. 1983, 24, 3079-3082.
J O972186Z