Convergent synthesis of vitamin D3 metabolites. Control of the stereoselectivity in samarium-induced cyclopropanations of cyclopentenes

Article abstract of DOI:10.1021/jo951229d

The 25-hydroxy and 1α,25-dihydroxy vitamin D₃ metabolites are obtained by solvolytic rearrangements of the 1-desoxy and 1α-hydroxy cyclopropyl vinylogous alcohols 31 and 29, respectively, with simultaneous formation of the vitamin D structural triene and the 3-hydroxy function. Two complementary methods have been employed to direct the stereoselectivity of the samarium induced olefin cyclopropanations which ultimately lead to key chiral ring A precursors. One protocol uses the two stereogenic centers of the (R,R)-2,3-butanediol ketal moiety of 8, while the other method uses the allylic hydroxyl group of (R)-16.

Full text of DOI:10.1021/jo951229d

118
J . Org. Chem. 1996, 61, 118-124
Con ver gen t Syn th esis of Vita m in D3 Meta bolites. Con tr ol of th e
Ster eoselectivity in Sa m a r iu m -In d u ced Cyclop r op a n a tion s of
Cyclop en ten es
M. M. Kabat, J . Kiegiel, N. Cohen, K. Toth, P. M. Wovkulich, and M. R. Uskokovic´*
Roche Research Center, Hoffmann-La Roche Inc., Nutley, New J ersey 07110
Received J uly 7, 1995X
The 25-hydroxy and 1R,25-dihydroxy vitamin D3 metabolites are obtained by solvolytic rearrange-
ments of the 1-desoxy and 1R-hydroxy cyclopropyl vinylogous alcohols 31 and 29, respectively, with
simultaneous formation of the vitamin D structural triene and the 3-hydroxy function. Two
complementary methods have been employed to direct the stereoselectivity of the samarium induced
olefin cyclopropanations which ultimately lead to key chiral ring A precursors. One protocol uses
the two stereogenic centers of the (R,R)-2,3-butanediol ketal moiety of 8, while the other method
uses the allylic hydroxyl group of (R)-16.
The hormonally active metabolite of vitamin D3, 1,25-
would have improved biological profiles. The original
partial synthesis approach from steroidal precursors
employing a photolytic opening of ring B13 has been
supplanted in time by totally synthetic procedures. Most
of these are convergent approaches which involve the
coupling of preformed C,D-side chain units with ring A
units or precursors.14 One of the synthetic approaches
to 1 pursued in our laboratories was inspired by the early
work of Mazur15 and Wilson.16 As illustrated in a
retrosynthetic sense in Scheme 1, we have examined the
solvolytic behavior of the vinylogous cyclopropyl alcohol
2. It was anticipated that, under the solvolytic condi-
tions, rearrangement of 2 would lead to intermediate
cyclopropyl π-allyl cation 3, which, on capture of water,
would generate the 1R-hydroxy triene system in 1.17 In
this report we describe, in detail, the results of this
investigation which involves two asymmetric prepara-
tions of the acetylenic ring A precursors 4a -c from
2-cyclopentenone (5) and which culminates in an efficient
overall synthesis of 1.
dihydroxycholecalciferol (1,25-(OH)2D3, 1), plays a major
role in the maintenance of calcium and phosphorous
homeostasis in the blood, and mineralization and calcium
mobilization in the bones.1 The widespread tissue dis-
tribution of specific nuclear receptors for 1,25-(OH)2D3
(VDR) and the participation of these receptors in the
regulation of transcriptional processes in various cells
significantly expands the scope of the hormonal activity
of 1.2 These transcriptional activities of 1,25-(OH)2D3
have been implicated in the control of cellular prolifera-
tion and differentiation and may well form the basis of
many of its physiological activities; however, more re-
cently, a number of 1,25-(OH)2D3 activities have been
recognized that do not involve binding to VDR. Instead,
they appear to be initiated at the cellular membrane level
by mechanisms which are not yet fully elucidated.3 1,25-
(OH)2D3 was developed as a therapeutic agent for the
treatment of diseases associated with renal failure,
secondary hyperparathyroidism4,5 and osteodystrophy,6
post menopausal osteoporosis,7-9 psoriasis,10,11 and scle-
roderma.12 Ongoing investigations with 1 and its numer-
ous analogs have now focused on cancer and autoimmune
diseases.
In contrast to our previous work on convergent ap-
proaches to vitamin D systems where the synthesis and
This compelling and robust progress in the pharmacol-
ogy and medicine of 1,25-(OH)2D3 has stimulated efforts
aimed at the development of efficient synthetic methodol-
ogy that could be applied not only to the preparation of
1 but also to the synthesis of analogs, which, ideally,
(13) Semmler, E. J .; Holick, M. F.; Schnoes, H. K.; DeLuca, H. F.
Tetrahedron Lett. 1972, 13, 4147.
(14) (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. D.; Sereno, J . F.; Uskokovic´, M. R. J . Org. Chem.
1986, 51, 3098. (d) Mascarenas, J . L.; Sarandeses, L. A.; Castedo, L.:
Mourino, A. Tetrahedron 1991, 47, 3485. (e) Trost, B. M.; Dumas, J .
J . Am. Chem. Soc. 1992, 114, 1924.
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Walters, M. R. Endocrine Rev. 1992, 13, 719.
(2) Studzinski, G. P.; McLane, J . A.; Uskokovic´, M. R. Crit. Rev.
Eukaryotic Gene Expression 1993, 3, 279.
(15) Sheves, M.; Mazur, Y. Tetrahedron Lett. 1976, 17, 2987.
(16) Wilson, S. R.; Venkatesan, A. M.; Augelli-Szafran, C. E.
(3) Norman, A. W.; Okamura, W. H.; Farach-Carson, M. C.; Alle-
waer, K; Branisteanu, D.; Nemere, I.; Muralidharan, K. R.; Bouillon,
R. J . Biol. Chem. 1993, 268, 13811. Nemere, I.; Dormanen, M. C.;
Hammond, M. W.; Okamura, W.; Norman. A. W. J . Biol. Chem. 1994,
269, 23750.
(4) Llach, F.; Massry, S. G. J . Clin. Endocrinol. Metab. 1985, 61,
601.
Proceedings of the Seventh Workshop on Vitamin D: Vitamin D
Molecular, Cellular and Clinical Endocrinology; de Gruyter: Berlin,
1988; p 43. Wilson, S. R.; Venkatesan, A. M.; Augelli-Szafran, C. E.;
Yasmin, A. Tetrahedron Lett. 1991, 32, 2339.
(17) Preliminary communication: Kabat, M.; Kiegiel, J .; Cohen, N.;
Toth, K.; Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett. 1991,
32, 2343.
(5) Massry, S. G. Metabolism 1990, 39, 13.
(6) Healy, M.; Malluche, H. H.; Goldstein, D. S. Arch. Intern. Med.
1980, 140, 1030.
(7) Caniggia, A.; Nuti, R.; Lore, F.; Martini, G.; Turchetti, V.; Righi,
G. Metabolism 1990, 39, 43.
(8) Gallagher, J . C.; Riggs, B. L. Metabolism 1990, 39, 30.
(9) Tilyard, M. W.; Spears, G. F. S.; Thomson, J .; Dovey, S. New
Eng. J . Med. 1992, 326, 357.
(10) Smith, E. L.; Pincus, S. H.; Donovan, L.; Holick, M. F. J . Am.
Acad. Derm. 1988, 19, 516.
(11) Langer, A.; Verjans, H.; Stapor, V.; Mol, M.; Fraczykowska, M.
Br. J . Derm. 1993, 128, 566.
(12) Humbert, P.; Delaporte, E.; Dupond, J . L.; Rochefort, A.;
Laurent, R.; Drobacheff, C.; DeWazieres, B.; Bergoend, H.; Agache, P.
Eur. J . Derm. 1994, 4, 21.
(18) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B. M.; Uskokovic´,
M. R. J . Am. Chem. Soc. 1982, 104, 2945. Wovkulich, P. M.; Baggiolini,
E. G.; Hennessy, B. M.; Uskokovic´, M. R.; Mayer, E.; Norman, A. W.
J . Org. Chem. 1983, 48, 4433. Wovkulich, P. M.; Barcelos, F.; Batcho,
A. D.; Sereno, J . F.; Baggiolini, E. G.; Hennessy, B. M.; Uskokovic´, M.
R. Tetrahedron 1984, 40, 2283. Baggiolini, E. G.; Iacobelli, J . A.;
Hennessy, B. M.; Batcho, A. D.; Sereno, J . F.; Uskokovic´, M. R. J . Org.
Chem. 1986, 51, 3098. Baggiolini, E. G.; Hennessy, B. M.; Iacobelli, J .
A.; Uskokovic´, M. R. Tetrahedron Lett. 1987, 28, 2095. Shiuey, S.;
Kulesha, I.; Baggiolini, E. G.; Uskokovic´, M. R. J . Org. Chem. 1990,
55, 243. Kiegiel, J .; Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron
Lett. 1991, 32, 6057. Kabat, M. M.; Lange, M.; Wovkulich, P. M.;
Uskokovic´, M. R. Tetrahedron Lett. 1992, 33, 7701. Wovkulich, P. M.;
Baggiolini, E. G.; Hennessy, B. M.; Uskokovic´, M. R. Heterocycles 1993,
35, 791. See also: Dai, H.; Posner, G. H. Synthesis 1994, 1383.
0022-3263/96/1961-0118$12.00/0 © 1996 American Chemical Society

Convergent Synthesis of Vitamin D3 Metabolites
J . Org. Chem., Vol. 61, No. 1, 1996 119
Sch em e 1
Sch em e 2
use of preformed ring A units as six-membered rings was
explored,18 the present study addressed the use of ring
A units in a latent form, as embodied in a suitably
functionalized bicyclo[3.1.0]hexane. Since the solvolytic
addition of water to the cyclopropyl system was expected
to be stereospecific, it was essential to secure a facile
preparation of the chiral bicyclo[3.1.0]hexane fragment
possessing high enantiomeric and diastereomeric puri-
ties. We investigated two approaches, each of which
involved the cyclopropanation of a substituted cyclopen-
tene but differed by the elements utilized to influence
the asymmetric cyclopropanation. Conveniently, both
routes emanated from a common starting material,
2-cyclopentenone (5).
In the first approach, facial discrimination at the
cyclopropanation step was envisioned as being directed
by the two stereogenic centers present in an (R,R)-2,3-
butanediol-derived ketal, following the precedent of
Mash.19 For this sequence, ketone 7, obtained from
2-cyclopentenone (5) and formaldehyde,20 was converted
to the corresponding ketal 8 under acidic conditions with
(R,R)-2,3-butanediol (Scheme 2). The diastereoselective
cyclopropanation of ketal 8 using Zn(Cu)- or Et2Zn-based
methods was relatively inefficient, unlike the earlier
examples of this reaction which were not complicated by
the presence of free hydroxyl groups. However, applica-
tion of the samarium-mediated cyclopropanation condi-
tions described by Molander [ICH2Cl, Sm(Hg)]21 provided
a very clean reaction, generating the desired bicyclo[3.1.0]-
hexane 9 in good yield and with greater than 20:1
diastereoselectivity.22 At this stage, the absolute config-
uration of 9 was assigned on the basis of an X-ray
analysis of the corresponding ketone 9a obtained by
p-bromobenzoylation of 9 followed by ketal hydrolysis.23
The acetylenic portion of this ring A precursor was
introduced by the reaction of aldehyde 10, obtained
uneventfully from 9 by Swern24 oxidation, with diethyl-
diazomethyl phosphonate25 to form acetylene 11. Acidic
hydrolysis of the ketal (11 f 12) and Wittig olefination
completed the first construction of the ring A synthon
13.
In the second approach to the ring A synthon, the
cyclopropanation would also be directed by a temporarily
situated stereogenic center, only this time it would exist
in the form of a secondary allylic alcohol. For this
sequence, cyclopentenone (5) was iodinated under our
newly developed conditions to form 2-iodo-2-cyclopenten-
one (14).26 Asymmetric reduction of 14 using the cataly-
tic system described by Corey27 and co-workers produced
alcohol 15 in 82% yield and 92% ee (Scheme 3). Further
improvement of the enantiomeric purity to 96% ee was
achieved by recrystallization.28 The acetylenic side chain
(19) (a) Mash, E. A.; Nelson, K. A. Tetrahedron 1987, 43, 679. (b)
Nelson, K. A.; Mash, E. A. J . Org. Chem. 1986, 51, 2721.
(20) Wovkulich, P. M.; Kiegiel, J .; Uskokovic´, M. R. Manuscript in
preparation. For an alternative preparation see: Smith, A. B.; Branca,
S. J .; Guaciaro, M. A.; Wovkulich, P. M.; Korn, A. Org. Syn. 1983, 61,
65.
(24) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(25) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1979, 44, 4997.
Regitz, M.; Liedhegener, A.; Eckstein, U.; Martin, M.; Anschutz, W.
Ann. 1971, 748, 207. Seyferth, D.; Marmor, R. S.; Hilbert, P. J . Org.
Chem. 1971, 36, 1379.
(26) J ohnson, C. R.; Adams, J . P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett. 1992, 33,
917.
(21) Molander, G. A.; Etter, J . F. J . Org. Chem. 1987, 52, 3942.
Molander, G. A.; Harring, L. S. J . Org. Chem. 1989, 54, 3525.
(22) The diastereoselectivity was 97:3 by capillary GC (50 M OV-
17 column, 80-250 °C), which was also observed to be >95:5 by NMR.
(23) The keto p-bromobenzoate derivative 9a has the [1(S)-cis]
(27) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
configuration, as shown: mp 65-66 °C, [R]25 ) -20° (c 0.5, hexane).
D

120 J . Org. Chem., Vol. 61, No. 1, 1996
Kabat et al.
Sch em e 3
Sch em e 4
Sch em e 5
was then introduced by (Ph3P)2PdCl2-CuI29 -catalyzed
coupling of the allylic (1R)-2-iodocyclopenten-1-ol (15)
with (trimethylsilyl)acetylene.30 As before, the cyclopro-
panation was best carried out under the Sm-mediated
conditions, which proceeded in this case to give 17 in 67%
yield. Wittig olefination of the corresponding ketone 18
gave the ring A precursor 19, and further desilylation
gave 13, identical with the material prepared above.
In terms of biological activity, a critical structural
feature of 1,25-(OH)2D3 is the presence of the 1R-hydroxy
group. To introduce this functionality into our bicyclo-
[3.1.0]hexane precursor units, we first investigated the
allylic hydroxylation of compounds 13 and 19. Treatment
of 13 with an excess of t-BuOOH in the presence of a
catalytic amount of SeO2 afforded a mixture of allylic
alcohols 20 and 21 in an 8:1 ratio in 54% yield (Scheme
4). The stereochemistry of 20 was established by an
X-ray crystallographic analysis of the corresponding tert-
butyldiphenylsilyl derivative 22. An improvement on
this hydroxylation scheme was realized in the oxidation
of the C-silylated acetylene 19, which could be smoothly
oxidized all the way to the corresponding ketone. With-
out isolation, the intermediate ketone was then reduced
with lithium triethylborohydride to give allylic alcohols
23 and 24 as a 19:1 mixture in 75% overall yield.
With the preparation of the ring A units in hand, we
next turned our attention to the attachment of these
synthons to the CD fragments, focusing our efforts first
on the coupling reactions with 22. The acetylide anion
of 22, formed in THF with an equimolar amount of
n-butyllithium, reacted with 25-trimethylsilyloxy
Windaus-Grundman ketone 631 to produce the propar-
(28) The ee was measured by NMR of the corresponding MTPA
esters. The methoxy group was diagnostic for this measurement at
3.67 ppm for the RR ester and at 3.57 ppm for the RS ester.
(29) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(30) In contrast, when the order of events was reversed, i.e.,
acetylenic coupling with iodo enone 14 first, followed by the asymmetric
reduction, the enantiomeric purity of the product alcohol 16 was lower
(70% ee).
gylic alcohol 25 as a single diastereomer in 89% yield
(Scheme 5).17 We next investigated an alternative prepa-
ration of this key intermediate using the nonhydroxylated
ring A precursor 19. In addition to the preparation of
25, this second approach also provides access to the

Convergent Synthesis of Vitamin D3 Metabolites
J . Org. Chem., Vol. 61, No. 1, 1996 121
(2.2 mmol) of pyridinium p-toluenesulfonate, and 1.5 L of CCl4
was heated at reflux for 8 h with azeotropic removal of water.
The mixture was cooled to rt, 2 mL of pyridine was added,
and the solution was filtered through silica gel (400 g). The
filtrate was concentrated in vacuo. Chromatography of the
crude product on silica gel, eluting with hexane-EtOAc (85:
synthesis of 25-hydroxy vitamin D3 (32), another me-
tabolite of vitamin D3. It is noteworthy that in this
instance the C-Si bond cleavage may be carried out in
situ by the treatment of the silylated acetylene 19 with
an equimolar amount of n-butyllithium, to give the
corresponding acetylide anion which on reaction with 6
formed the corresponding nonhydroxylated propargylic
alcohol 26 in 78% yield. Application of the same hy-
droxylating conditions used for the 19 to 23 conversion
(excess t-BuOOH, catalytic SeO2, followed by LiEt3BH
reduction) produced the 1R-hydroxy epimer 27 as a single
isomer. Selective protection of the secondary hydroxyl
group with t-BuPh2SiCl gave 25 (88% yield), which was
identical by analytical and spectral comparisons with the
material derived from 22.
The final phase of this synthetic strategy comprised a
solvolytic opening of the bicyclo[3.1.0]hexane system,
which would generate the triene system with concomit-
tant introduction of the required 3â hydroxyl group of
vitamin D. For this operation the propargylic alcohol
portion of 25 was reduced stereoselectively to trans-allylic
alcohol 28 (88% yield) using LiAlH4 in the presence of
sodium methoxide. The silyl groups of 28 were then
removed (Bu4NF) to form the free hydroxy derivative 29.
The solvolysis of 29 was carried out with p-toluene-
sulfonic acid in dioxane-water at 75 °C to produce, in
75% yield, a 7:3 mixture of 1,25-(OH)2D3 (1) and its 5,6-
trans diastereomer. The undesired trans compound was
isomerized by photolysis of the mixture in the presence
of 9-acetoxyanthracene using a 450 W mercury lamp
equipped with a uranium filter. In this manner the
desired isomer 1 was obtained in 95% yield, which was
analytically and spectroscopically identical to authentic
material.14c
15), gave 22.3 g (68%) of ketal 8 as a colorless oil: [R]25
)
D
1
-3.2° (c 1, EtOH); IR (CHCl3) 3533 cm-1; H NMR δ 1.27 (d,
J ) 6 Hz, 3H), 1.30 (d, J ) 6 Hz, 3H), 2.13 (m, 2H), 2.37 (m,
2H), 3.68 (m, 2H), 4.25 (d, J ) 3.8 Hz, 2H), 6.03 (s, 1H); MS
(m/ z) 184 (M+, 25), 169 (M - Me, 20), 167 (M - OH, 18), 155
(36), 140 (8), 129 (16), 111 (100), 95 (36), 83 (35), 67 (45), 55
(53); HRMS for C10H16O3 calcd 184.1099, found 184.1105.
Anal. Calcd for C10H16O3: C, 65.19; H, 8.75. Found: C, 64.99;
H, 8.72.
[4′R,5′R-(1S-cis)]-(+)-4′,5′-Dim eth ylsp ir o[bicyclo[3.1.0]-
h exa n e-2,2′-[1,3]d ioxola n e]-1-m eth a n ol (9). The procedure
of Molander21 was employed. A 500 mL, three-necked flask
fitted with a magnetic stirrer, reflux condenser, rubber septum,
and thermometer was charged with 15.0 g (0.1 g-atom of 35
mesh, Rhone-Poulenc) of samarium powder. The metal and
apparatus were cautiously flame dried after thorough evacu-
ation of air and introduction of argon. The metal was stirred
during deaeration and drying steps to insure the elimination
of air pockets. After being cooled to rt, the metal was covered
with 500 mL of anhydrous THF and a solution of 2.6 g (9.57
mmol) of HgCl2 in 30 mL of dry THF was added with stirring,
followed by the addition of a solution of 4.15 g (22.5 mmol) of
hydroxy ketal 8 in 25 mL of dry THF. The mixture was stirred
and cooled to -73 °C (dry ice-acetone bath), and 16.8 g (92.35
mmol) of ICH2Cl was added dropwise via syringe. After being
stirred at -73 °C for 20 min, the reaction mixture was allowed
to warm spontaneously by removal of the cooling bath, but
the internal temperature was kept below 40 °C by occasional
immersion in an ice bath. When the temperature fell to 24
°C, the reaction mixture was warmed in a hot water bath to
40 °C for 30 min. The total reaction time at 24-37 °C was 2
h. A saturated aqueous K2CO3 solution was then added, and
workup was carried out by extraction with ether. The crude
product (5.0 g) was chromatographed on silica gel, eluting with
hexane-EtOAc (2:1), to give 4.05 g (90%) of cyclopropane
alcohol 9 as a colorless liquid: [R]25D ) +32.6° (c 1, EtOH); 1H
NMR δ 0.58 (dd, J ) 5.2, 7.8 Hz, 1H), 0.77 (t, J ) 0.9 Hz, 1H),
1.24 (d, J ) 6.0 Hz, 3H), 1.34 (d, J ) 6.0 Hz, 3H), 1.45-1.65
(m, 3H), 1.72 (dd, J ) 8.6, 12.7 Hz, 1H), 1.85-1.98 (m, 1H),
2.77 (dd, J ) 0.8, 9.6 Hz, 1H), 3.34 (dd, J ) 9.6, 12 Hz, 1H),
3.60 (m, 1H), 3.77 (m, 1H), 4.07 (d, J ) 12.0 Hz, 2H); MS (m/
z) 198 (M+, 25), 181 (M - OH, 46), 169 (39), 155 (64), 143 (17),
127 (52), 114 (100), 95 (30), 85 (64), 55 (98); HRMS for C11H18O3
calcd 198.1256, found 198.1244. Anal. Calcd for C11H18O3: C,
66.64; H, 9.15. Found: C, 66.46; H, 9.18.
In a similar fashion, intermediate 31, the compound
lacking the 1R-hydroxyl group, was correspondingly
transformed to 25-OH vitamin D3 (32). As in the previ-
ous case, reduction of the propargylic alcohol in 26 to the
trans allylic alcohol was conducted with LiAlH4-NaOMe
to give 30 in 78% yield. After removal of the silyl ether,
the resulting diol 31 underwent solvolytic rearrangement
(pyridinium p-toluenesulfonate, CH3CN-H2O, 50 °C) to
a mixture of 25-(OH)-D3 (32) and its 5,6 trans isomer.
Subsequent photoisomerization of the mixture gave 32
in 65% overall yield.
[4′R-[2′r(1S*,5R*),4′r,5â]]-4′,5′-Dim eth ylsp ir o[bicyclo-
[3.1.0]h exa n e-2,2′-[1,3]d ioxola n e]-1-ca r boxa ld eh yd e (10).
A solution of 17.6 mL (240 mmol) of DMSO in 30 mL of CH2-
Cl2 was added slowly to a cold solution (-60 °C) of 10.84 mL
(120 mmol) of oxalyl chloride in 200 mL of CH2Cl2. The
resulting mixture was stirred at -60 °C for 15 min, and then
8.2 g (40 mmol) of alcohol 9 in 20 mL of CH2Cl2 was added
dropwise. The reaction mixture was allowed to warm to -20
°C over 30 min, cooled again to -60 °C and then treated with
35.6 mL (240 mmol) of triethylamine. The cooling bath was
then removed, and stirring was continued at rt for 1 h. The
solution was washed with water and dried. The crude product
was chromatographed on a silica gel, eluting with hexane-
ether (9:1), to give 6.59 g (81%) of aldehyde 10, as a slightly
In summary, we have demonstrated the utility of the
solvolysis of vinylogous cyclopropyl alcohols for the
sterespecific introduction of the C3 hydroxyl group along
with the simultaneous generation of the vitamin D triene
system, a bond reorganization process reminiscent of the
classical i-steroid rearrangement. Two practical routes
to the key chiral bicyclo[3.1.0]hexane intermediates 19
and 22 were devised, each involving different cyclopro-
panations of substituted cyclopentenes and both starting
from 2-cyclopentenone.
Exp er im en ta l Section
Gen er a l. Ma ter ia ls a n d Meth od s. Melting points were
measured in open capillary tubes and are uncorrected. 1H
NMR spectra were obtained in CDCl3 at 400 MHz. Unless
otherwise noted, reactions were conducted under an atmo-
sphere of dry argon. Organic extracts mixtures were dried
over anhydrous Na2SO4 or MgSO4, and filtered, and the solvent
was then removed under reduced pressure. Chromatography
was performed on 230-400 mesh EM silica gel 60.
yellow oil: [R]25 ) -46.8° (c 0.95, EtOH); IR (CHCl3) 1752,
D
1
1700 cm-1; H NMR δ 1.26 (d, J ) 6.0 Hz, 3H), 1.36 (d, J )
6.0 Hz, 3H), 1.5-1.85 (m, 4H), 1.85-2.05 (m, 1H), 2.05-2.15
(m, 1H), 3.65-3.75 (m, 1H), 3.75-3.85 (m, 1H), 10.00 (s, 1H);
MS (m/ z) 196 (M+, 19), 179 (M - OH, 10), 167 (95), 114 (80),
96 (61), 83 (100); HRMS for C11H16O3 calcd 196.1099, found
196.1087.
[4′R,5′R-(1S-cis)]-1-Eth yn yl-4′,5′-d im eth ylspir o[bicyclo-
[3.1.0]h exen e-2,2′-[1,3]d ioxola n e (11). A suspension of 6.03
g (5.4 mmol) of t-BuOK in 200 mL of THF at -70 °C was
treated with a solution of 8.98 g (5.0 mmol) of (EtO)2P(O)-
CHN225 in 20 mL of THF. The mixture was stirred for 15 min,
and then a solution of 6.59 g (3.3 mmol) of aldehyde 10 in 30
mL of THF was added dropwise. Stirring was continued
(2R,3R)-(-)-2,3-Dim eth yl-1,4-d ioxa sp ir o[4.4]n on -6-en e-
6-m eth a n ol (8). A solution of 20.0 g (0.18 mol) of hydroxy
ketone 7,20 32.1 g (0.36 mol) of (2R,3R)-(-)-butanediol, 0.55 g
(31) Kiegiel, J .; Wovkulich, P. M.; Uskokovic´, M. R. Tetrahedron Lett.
1991, 32, 6057. See also ref 14b,c.

122 J . Org. Chem., Vol. 61, No. 1, 1996
Kabat et al.
for 30 min, and then the temperature was allowed to rise to
rt. Then 500 mL of H2O was added, and the solution was
extracted with ether. The extracts were combined and washed
three times with water and dried. The crude product was
chromatographed on silica gel, eluting with hexane-ether (97:
mL of brine. The washes were back extracted and the
combined organic layers were dried. The residue was distilled
bulb to bulb (oven 85-105 °C, 2 mm Hg) to afford 17.74 g (96%)
of 16 as colorless, low melting crystals. An analytical sample
was obtained by chromatography on silica gel eluting with
3), to give 6.35 g (98%) of acetylene 11 as a colorless oil: [R]25
hexane-EtOAc (4:1): [R]25 ) -7.2° (c 0.9, EtOH); IR (CHCl3)
D
D
) -49.6° (c 1.19, EtOH); IR (CHCl3) 3310, 2115 cm-1; 1H NMR
δ 1.03 (m, 2H), 1.23 (d, J ) 3.9 Hz, 3H), 1.38 (d, J ) 4.0 Hz,
3H), 1.5-1.7 (m, 2H), 1.82 (m, 1H), 2.01 (s, 1H), 3.55-3.62
(m, 1H), 3.97-4.05 (m, 1H); MS (m/ z) 192 (M+, 23), 177 (M -
15, 2), 120 (71), 144 (100), 91 (69); HRMS for C21H16O2 calcd
192.1152, found 192.1150. Anal. Calcd for C12H16O2: C, 74.97;
H, 8.39. Found: C, 74.76; H, 8.55.
3590, 2145 cm-1; H NMR δ 0.21 (s, 9H), 1.73-1.80 (m, 1H),
1
2.25-2.41 (m, 2H), 2.50-2.61 (m, 1H), 4.79 (brs, 1H), 6.27 (t,
J ) 2.7 Hz, 1H); MS (m/ z) 180 (M+, 18), 165 (23), 99 (100).
Anal. Calcd for C10H16OSi: C, 66.61; H, 8.94. Found: C,
66.80; H, 8.84.
[S-(1r,2â,5r)-1-[(Tr im eth ylsilyl)eth yn yl]bicyclo[3.1.0]-
h exa n -2-ol (17). A 500 mL, three-necked, round bottom flask
was charged with 58.37 g (388 mmol) of samarium metal
powder (obtained from Rhone-Poulenc Inc.). The metal and
apparatus were cautiously flame dried after thorough evacu-
ation of air and introduction of argon. The metal was stirred
during deaeration and drying steps to insure the elimination
of air pockets. After cooling to rt, 250 mL of THF was added
followed by 2.635 g (9.7 mmol) of HgCl2 in 10 mL of THF and
7.0 g (38.8 mmol) of alcohol 16 in 20 mL of THF. This mixture
was cooled to -60 °C, and 2.55 mL (35 mmol) of ICH2Cl was
added. The mixture was then heated to 17 °C whereupon an
exothermic reaction started. The further addition of 23.0 mL
(314 mmol) of ICH2Cl was continued at such a rate so as to
maintain the temperature in the range 31-40 °C (cooled if
neccessary with an acetone-dry ice bath). When the addition
was complete and the exothermic reaction concluded, the
mixture was cooled to 0 °C and then 75 mL of saturated
aqueous K2CO3 was added portionwise (exothermic). Then 250
mL of H2O was added, and the mixture was extracted with
ether. The crude product was purified by silica gel chroma-
tography, eluting with hexane-EtOAc (4:1), to give 5.054 g
(67%) of 17 as colorless, low-melting crystals: [R]25D ) -131.1°
(1S-cis)-1-Eth yn ylbicyclo[3.1.0]h exa n -2-on e (12). A so-
lution of 6.90 g (3.6 mmol) of ketal 11, 0.07 g of p-TsOH, 50
mL of acetone, and 10 mL of H2O was refluxed for 2 d. The
acetone was evaporated in vacuo, and the residue was ex-
tracted with ether. The organic phase was washed succes-
sively with water and an aqueous NaHCO3 solution and dried.
The crude product was purified by chromatography on silica
gel, eluting with hexane-ether (85:15), to give 3.45 g (80%) of
ketone 12 as a colorless oil: [R]25 ) -78.3° (c 1.1, EtOH); IR
D
(CHCl3) 3315, 2125, 1695 cm-1; 1H NMR δ 1.44 (t, J ) 5.1 Hz,
1H), 1.64 (m, 1H), 1.95-2.05 (m, 1H), 2.15-2.30 (m, 3H), 2.18
(s, 1H), 2.45-2.55 (m, 1H); MS (m/ z) 120 (M+, 8), 105 (M -
15, 5), 91 (70), 79 (34), 63 (45, 51 (100), 39 (78); HRMS for
C8H8O calcd 120.0575, found 120.0573. Anal. Calcd for
C8H8O: C, 79.97; H, 6.71. Found: C, 79.60; H, 6.71.
(1S-cis)-1-Eth yn yl-2-m eth ylen ebicyclo[3.1.0]h exan e (13).
A suspension of 14.22 g (39.8 mmol) of methyltriphenylphos-
phonium bromide and 4.46 g (39.8 mmol) of t-BuOK in 100
mL of THF was stirred under argon, at rt for 30 min. To the
above mixture, a solution of 2.39 g (19.9 mmol) of ketone 12
in 10 mL of THF was added. After stirring for 1 h, 200 mL of
H2O was added and the solution was extracted with pentane.
The pentane layer was washed with 8 × 100 mL of H2O and
then dried. The solution was passed through a short pad of
silica gel (300 g) eluting with pentane-ether (9:1). Fractional
distillation at atmospheric pressure of the combined fractions
containing the product afforded 1.66 g (71%) of olefin 13, bp
1
(c 1, EtOH); IR (CHCl3) 3605, 2155 cm-1; H NMR δ 0.15 (s,
9H), 0.87-0.90 (m, 1H), 1.11-1.18 (m, 2H), 1.67-1.72 (m, 2H),
1.84-1.95 (m, 3H), 4.56 (brt, J ) 8.2 Hz, 1H); MS (m/ z) 194
(M+, 2), 161 (21), 99 (35), 75 (100). Anal. Calcd for C11H18
OSi: C, 67.98; H, 9.34. Found: C, 67.39; H, 9.57.
-
(1S-cis)-1-[(Tr im eth ylsilyl)eth yn yl]bicyclo[3.1.0]h exan -
2-on e (18). Pyridinium chlorochromate (10.43 g, 484 mmol)
of was added to a solution of 4.70 g (24.2 mmol) of 17 in 250
mL of CH2Cl2. The slurry was stirred at rt for 3 h. The brown
solution was decanted from the gummy dark solid, washed
successively with 200 mL of saturated NaHCO3 and 200 mL
H2O, and then dried. The crude product was purified by silica
gel chromatography, eluting with hexane-EtOAc (10:1), to give
153-155 °C: [R]25 ) -46.2° (c 1.1, EtOH); IR (CHCl3) 3305,
D
2115, 1657 cm-1; 1H NMR δ 1.03 (t, J ) 4.8 Hz, 1H), 1.23 (dd,
J ) 4.4, 7.7 Hz, 1H), 1.60-1.70 (1H, m), 1.90-2.05 (m, 2H),
2.14 (s, 1H), 2.20-2.30 (m, 1H), 4.90 (s, 1H), 5.17 (d, J ) 0.9
Hz, 1H); MS (m/ z) 118 (M+, 32), 117 (M - 1, 100), 115 (M -
2H, 50), 103 (M - Me, 61). HRMS for C9H10 118.0783 calcd,
found 118.0781. Anal. Calcd for C9H10: C, 91.47; H, 8.53.
Found: C, 91.06; H, 8.59.
3.81 g (82%) of 18 as colorless crystals, mp 47-48.5 ° [R]25
)
D
-70.6° (c 1.2, EtOH); IR (CHCl3) 2165, 1728 cm-1; 1H NMR δ
0.16 (s, 9H), 1.41 (t, J ) 5.0 Hz, 1H), 1.63-1.66 (m, 1H), 1.94-
2.00 (m, 1H), 2.12-2.27 (m, 3H), 2.45-2.51 (m, 1H); MS (m/
z) 192 (M+, 3), 177 (100). Anal. Calcd for C11H16OSi: C, 68.69;
H, 8.39. Found: C, 68.45; H, 8.37.
(R)-2-Iod o-2-cyclop en ten -1-ol (15). To a solution of 3.639
g (13.13 mmol) of (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-
pyrrolo[1,2-c]oxazaborole27 in 260 mL of THF at 0 °C were
added simultaneously over 0.5 h solutions of 27.30 g (131
mmol) of 2-iodo-2-cyclopentenone 1426 in 80 mL of THF and
78.8 mL (78.8 mmol) of 1.0 M BH3‚THF in THF. The reaction
mixture was stirred at 5 °C for 30 min, after which 60 mL of
aqueous buffer (pH ) 7) was added, followed by 20 mL of 30%
H2O2. After being stirred for 20 min, 400 mL of EtOAc was
added and the solution was washed successively with 200 mL
of 1 N HCl, 200 mL of H2O, 200 mL of saturated NaHCO3,
and 200 mL of brine and then dried. The product was
crystallized from ether-pentane to give 23.16 g (84%) of 15
as colorless crystals, mp 61.3-61.7 °C; The 1H NMR of the
Mosher ester of 15 ((R)-acid) showed 92% ee for crude product
(1R-cis)-Tr im et h yl[(2-m et h ylen eb icyclo[3.1.0]h exyl)-
eth yn yl]sila n e (19). To a slurry of 78.09 g (219 mmol) of
methyltriphenylphosphonium bromide in 1.2 L of THF at rt
was added 26.77 g (219 mmol) of t-BuOK. The resulting
mixture was stirred for 2 h, and then a solution of 21.02 g
(109 mmol) of ketone 18 in 100 mL of THF was added over 15
min. After the mixture was stirred for an additional 30 min,
1 L of H2O was added and the mixture was extracted with
hexane. The organic layers were combined, dried, and con-
centrated under reduced pressure. The residue was dissolved
in hexane, and the solution was filtered through silica gel (2
cm layer) eluting with hexane. The hexane was evaporated
under reduced pressure. The residue was distilled (bp 71-76
°C at 2 mmHg) to afford 18.1 g (87%) of 19 as a colorless oil:
and 96% ee after crystallization: [R]25 ) +16° (c 1.1, EtOH);
D
IR (CHCl3) 3590, 1600 cm-1
;
1H NMR δ 1.81-1.90 (m, 1H),
2.26-2.38 (m, 2H), 2.45-2.54 (m, 1H), 4.69 (brs, 1H), 6.29 (t,
J ) 2.4 Hz, 1H); MS (m/ z) 210 (M+, 25), 83 (100). Anal. Calcd
for C5H7IO: C, 28.60; H, 3.36. Found: C, 28.94; H, 3.38.
(R)-2-[(Tr im eth ylsilyl)eth yn yl]-2-cyclop en ten -1-ol (16).
To a solution of 21.50 g (102.4 mmol) of 15 in 250 mL of dry
benzene was added 28.52 mL (204.6 mmol) Et3N at rt and the
reaction flask was flushed with argon. Then 32.5 g (330.9
mmol) of trimethylsilylacetylene was added followed by 0.359
g (0.515 mmol) of (Ph3P)2PdCl2 and 0.294 g (1.545 mmol) of
CuI. An exothermic reaction occurred and the temperature
rose to ca 40 °C. After stirring for 20 min, the reaction mixture
was diluted with 300 mL of EtOAc and the organic solution
was washed successively with 200 mL of 0.5 N H2SO4, 200
mL of H2O, 200 mL of saturated aqueous NaHCO3, and 100
[R]25 ) -70.2° (c 0.9, EtOH); IR (CHCl3) 3305, 2115, 1650
D
1
cm-1; H NMR δ 0.17 (s, 9H), 1.04 (t, J ) 4.7 Hz, 1H), 1.23-
1.28 (m, 1H), 1.69-1.76 (m, 1H), 1.90-2.07 (m, 3H), 2.19-
2.27 (m, 1H), 4.90 (s, 1H), 5.16 (s, 1H); MS (m/ z) 190 (M+,
22), 175 (100). Anal. Calcd for C12H18Si: C, 75.71; H, 9.53.
Found: C, 75.05; H, 9.38.
(1S-cis)-1-Eth yn yl-2-m eth ylen ebicyclo[3.1.0]h exan e (13).
A mixture of 0.7 g (3.68 mmol) of compound 19, 0.39 g (3.68
mmol) of Na2CO3 and 20 mL of MeOH was stirred at rt for
3.5 h. Then 10 mL of H2O was added, and the mixture was
extracted (3 × 10 mL) with pentane. The extracts were
combined and dried. Solvents were removed under atmo-

Convergent Synthesis of Vitamin D3 Metabolites
J . Org. Chem., Vol. 61, No. 1, 1996 123
18, 14), 173 (100), 145 (21), 73 (80). Anal. Calcd for C12H18
spheric pressure by distillation using a 10 cm Vigreux column.
The residue was distilled to afford 0.404 g (93%) of 13, bp 153
°C. The analytical and spectral properties of the material
prepared in this way were in full accord with those of
compound 13 obtained via Scheme 2.
-
OSi: C, 69.84; H, 8.79. Found: C, 70.06; H, 8.77.] and 0.024
g (4%) of [1R-(1r,3â,5r)]-2-m eth ylen e-1-[(tr im eth ylsilyl)
eth yn yl] bicyclo[3.1.0] h exa n -3-ol (24), as a low melting
solid [R]25 ) -158.1° (c 1.0, EtOH); IR (CHCl3) 3605, 2160,
D
1650 cm-1
.
1H NMR δ 0.17 (s, 9H), 1.36-1.39 (m, 1H), 1.53-
SeO2 Oxid a tion of 13. A suspension of 0.468 g (4.22 mmol)
of SeO2, 14.07 mL of a 3 M solution of t-BuOOH in 2,2,4-
trimethylpentane (42.21 mmol), and 40 mL of CH2Cl2 was
stirred at rt for 30 min and then cooled to 0 °C. 13 (1.66 g,
14.07 mmol) in 5 mL of CH2Cl2 was added slowly. The reaction
mixture was stirred at 0 °C for 2 h and then at rt for 4 h before
being washed with water and dried. The crude product was
chromatographed on silica gel, eluting with hexane-ether (92:
8), to give 0.110 g (6%) of [1S-(1R,3â,5R)]-1-ethynyl-2-meth-
ylenebicyclo[3.1.0]hexan-3-ol (21) as a solid, mp 32-34 °C:
1.56 (m, 1H), 1.79 (d, J ) 14.1 Hz, 1H), 2.07-2.12 (m, 1H),
2.20-2.27 (m, 1H), 4.51 (d, J ) 6.8 Hz, 1H), 5.22 (s, 1H), 5.37
(s, 1H); MS (m/ z) 206 (M+, 1), 173 (100), 145 (20), 73 (75).
Anal. Calcd for C12H18OSi: C, 69.84; H, 8.79. Found: C,
69.54; H, 8.88.
[1R-[1r(R*),3a â,4r(1S*,3S*,5S*),7a r]]-4-[[3-[[(1,1-Di-
m eth yleth yl)diph en ylsilyl]oxy]-2-m eth ylen ebicyclo[3.1.0]-
h exa n -1-yl]eth yn yl]octa h yd r o-7a -m eth yl-1-[1,5,5-tr im e-
th yl-5-[(tr im eth ylsilyl)oxy)p en tyl]-1H-in d en -4-ol (25). A
solution of 1.104 g (2.97 mmol) of acetylene 22 in 40 mL of
THF at -30 °C was treated with 1.86 mL of an n-BuLi solution
(1.6 M in hexane, 2.97 mmol) and then stirred at room
temperature for 20 min. A solution of 0.950 g (2.70 mmol) of
Grundmann ketone 6 in 5 mL of THF was added via syringe,
and the resulting mixture was stirred at rt for 30 min. The
reaction was quenched by the addition of 40 mL of H2O, and
the mixture was then extracted with ether. The extracts were
combined, washed with water, and dried. The crude product
was chromatographed on a silica gel, eluting with hexane-
ether (99:1), to give 0.132 g of unreacted 6. Further elution
with hexane-ether (98:2) gave 1.742 g (89%) of 25 as a
[R]25 ) -162.7° (c 1.05, EtOH); IR (CHCl3) 3605, 3305, 2115,
D
1660, 1650 cm-1; 1H NMR δ 1.38 (m, 1H), 1.54 (t, J ) 4.7 Hz,
1H), 1.81 (d, J ) 14.2 Hz, 1H), 2.09 (m, 1H), 2.15 (s, 1H), 2.25
(m, 1H), 4.53 (d, J ) 6.2 Hz, 1H), 5.23 (s, 1H), 5.39 (s, 1H);
MS (m/ z) 133 (M - H, 12), 115 (100), 105 (32), 91 (82), 77
(59); HRMS for C9H9O (M - H) calcd 133.0653, found
133.0654.
Further elution with hexane-ether (9:1) gave 0.905 g (48%)
of the desired [1S-(1R,3R,5R)]-1-ethynyl-2-methylenebicyclo-
[3.1.0]hexan-3-ol (20), also as a low melting solid, mp 38-39
°C: [R]25 ) +18.8° (c 0.96, EtOH); IR (CHCl3) 3620, 3585,
D
3305, 2115, 1645 cm-1
;
1H NMR δ 0.93 (t, J ) 5.1 Hz, 1H),
colorless oil: [R]25 ) -49.6° (c 1.1, EtOH); UV λmax (EtOH)
1.24 (dd, J ) 5.1, 8.5 Hz, 1H), 1.6-1.7 (m, 1H), 1.96 (m, 1H),
2.19 (s, 1H), 2.34 (dd, J ) 7.6, 12.6 Hz, 1H), 4.17 (brs, 1H),
5.20 (d, J ) 2.1 Hz, 1H), 5.37 (d, J ) 2.5 Hz, 1H); MS (m/ z)
133 (M - H, 10%), 115 (M-18, 100), 105 (25), 91 (60), 77 (42),
63 (40), 51 (31), 39 (55). HRMS for C9H9O (M-H) calcd
133.0653, found 133.0642. Anal. Calcd for C9H10O: C, 80.56;
H, 7.51. Found: C, 80.29; H, 7.59.
D
215 nm (ꢀ ) 18 580), 247 (260), 253 (380), 259 (520), 264 (580),
1
270 (430); IR (CHCl3) 3590, 2230, 1660, 838 cm-1; H NMR δ
0.11 (s, 9H), 0.72 (t, J ) 5 Hz, 1H), 0.90 (s, 3H), 0.91 (d, J )
6.5 Hz, 3H), 1.07 (s, 6H), 1.20 (s, 9H), 4.20 (brt, 1H), 5.30 (s,
1H), 5.32 (s, 1H), 7.3-7.45 (m, 6H), 7.65-7,70 (m, 4H); MS
(m/ z) 724 (M+, 1), 667 (M - C4H9, 1), 315 (30), 237 (15), 199
(40), 131 (100); HRMS for C46H68O3Si2 calcd 724.4707, found
724.4722. Anal. Calcd for C46H68O3Si2: C, 76.19; H, 9.45.
Found: C, 75.99; H, 9.37.
[1S -(1r,3r,5r)]-(1,1-D im e t h y le t h y l)[(1-e t h y n y l-2-
m et h ylen eb icyclo[3.1.0]h exa n -3-yl)oxy]d ip h en ylsila n e
(22). A solution of 0.710 g (5.30 mmol) of alcohol 20, 1.21 mL
(6.89 mmol) of t-BuPh2SiCl, 0.469 g (6.89 mmol) of imidazole,
and 10 mL of DMF was stirred at rt for 4 h. Water was then
added, and the mixture was extracted with hexane. The
extracts were combined, washed with water, and dried. The
crude product was purified by silica gel chromatography,
eluting with hexane-ether (97:3), to give 1.85 g (94%) of silyl
ether 22, mp 62-64 °C (MeOH). [R]25D ) -71.8° (c 1.1, EtOH);
UV λmax (EtOH) 218 (ꢀ ) 19 500), 253 (430), 259 (635), 264
[1R-[1r(R*),3a â,4r(1S*,3S*,5S*), 7a r]]-1-[1,5-Dim eth yl-
5-[(t r im e t h y ls ily l)o x y ]h e x y l]-4-[(3-h y d r o x y -2-m e t h -
ylen ebicyclo[3.1.0]h exan -1-yl)eth yn yl]octah ydr o-7a-m eth -
yl-1H-in d en -4-ol (27) via Hyd r oxyla tion of 26. To a
suspension of 0.0707 g (0.64 mmol) of SeO2 in 30 mL of dry
CH2Cl2 was added 2.124 mL of a t-BuOOH solution (3.0 M in
2,2,4-trimethylpentane, 6.37 mmol), and the resulting mixture
was stirred at rt for 1 h, and cooled to 0 °C and then 1.0 g
(2.12 mmol) of olefin 26 in in 5 mL of CH2Cl2 was added. The
reaction mixture was kept at 4 °C for 20 h whereupon 30 mL
of 20% aqueous Na2S2O3 was added. The mixture was stirred
vigorously at rt for 0.5 h. The phases were separated, and
the aqueous solution was extracted with ether. The organic
extracts were combined, dried, and concentrated in vacuo. The
residue was dried under high vacuum for 2 h, then dissolved
in 40 mL of dry THF, and cooled to -50 °C. A lithium
triethylborohydride solution (3.19 mL, 1 M in THF) was added
dropwise over 5 min. The solution was then allowed to warm
up to 0 °C and quenched by the addition of 30 mL of H2O. The
mixture was extracted with ether. The crude product was
purified by silica gel chromatography, eluting with hexane-
EtOAc (10:1), to give 0.827 g (80%) of 27.
[1R-[1r(R*),3a â,4r(1S*,3S*,5S*),7a r]]-4-[[3-[[(1,1-Di-
m eth yleth yl)diph en ylsilyl]oxy]-2-m eth ylen ebicyclo[3.1.0]-
h exa n -1-yl]eth yn yl]octa h yd r o-7a -m eth yl-1-[1,5,5-tr im e-
t h yl-5-[(t r im et h ylsilyl)oxy]p en t h yl]-1H -in d en -4-ol (25)
fr om 27. A solution of 0.146 g (0.3 mmol) of alcohol 27, 0.041
g (0.6 mmol) of imidazole, 0.124 g (0.45 mmol) of t-BuPh2SiCl,
and 8 mL of CH2Cl2 was stirred at rt for 1 h. Then 20 mL of
H2O was added, and the mixture was extracted with hexane.
The crude product was purified by silica gel chromatography,
eluting with hexane-EtOAc (20:1), to give 0.190 g (88%) of
25 as a colorless oil.
(695), 270 (530); IR (CHCl3) 3305, 2115, 1660, 821, 702 cm-1
;
1H NMR δ 0.75 (t, J ) 4.8 Hz, 1H), 1.54 (s, 10 H), 1.7-1.9 (m,
3H), 2.15 (s, 1H), 4.21 (t, J ) 4.8 Hz, 1H), 5.36 (s, 2H), 7.3-
7.45 (m, 6H), 7.6-7.7 (m, 4H); MS (m/ z) 372 (M+, 1), 357 (M
- 15, 1), 315 (M - C4H9, 65), 237 (50), 199 (100); HRMS for
C25H28OSi calcd 372.1909, found 372.1901. Anal. Calcd for
C25H28OSi: C, 80.59; H, 7.58. Found: C, 80.77; H, 7.76.
H yd r oxyla t ion of Olefin 19: P r ep a r a t ion of [1R-
(1r,3â,5r)]-2-Meth ylen e-1-[(tr im eth ylsilyl)eth yn yl]bicyclo-
[3.1.0]h exa n -3-ol (24). A total of 2.625 mL of a 3.0 M
t-BuOOH in 2,2,4-trimethylpentane (7.88 mmol) solution was
added to a stirred slurry of 0.0875 g (0.788 mmol) SeO2 in 15
mL of dry CH2Cl2, and the resulting mixture stirred at rt for
2 h. The reaction mixture was then cooled to 0 °C and treated
with a solution of 0.5 g (2.627 mmol) of 19 in 5 mL of CH2Cl2.
The reaction mixture was kept at 4 °C for 22 h whereupon 20
mL of 20% aqueous Na2S2O3 was added and the mixture
stirred for 30 min. The phases were separated, and the
aqueous solution was extracted with ether. The organic
solutions were combined, dried, and concentrated in vacuo. The
residue was dissolved in 25 mL of dry THF and cooled to -50
°C, and 3.15 mL (3.15 mmol) of lithium triethylborohydride
(1.0 M in THF) was added. The reaction mixture was allowed
to warm to rt. Then 20 mL of H2O was added, and the mixture
was extracted with ether (2 × 20 mL). The extracts were
combined, dried, and concentrated. The residue was chro-
matographed on silica gel, eluting with hexane-EtOAc (4:1),
to give 0.408 g (75%) of [1R-(1r,3r,5r)]-2-m eth ylen e-1-
[(tr im eth ylsilyl)eth yn yl]bicyclo[3.1.0]h exa n -3-ol (23), mp
Analytical and spectral data of 25 obtained in this manner
were identical with those recorded for the material obtained
by the coupling of 6 with 22 as described above.
[1R-[1r(R*),3a â,4r[(E)-(1S*,3S*,5S*)],7a r]]-1-[1,5-Di-
m eth yl-5-[(tr im eth ylsilyl)oxy]h exyl]-4-[2-[3-[[(1,1-d im e-
th yleth yl)d ip h en ylsilyl]oxy]-2-m eth ylen ebicyclo[3.1.0]-
h exa n -1-yl]et h en yl]oct a h yd r o-7a -m et h yl-1H-in d en -4-ol
(28). A solution of 0.730 g (1.01 mmol) of acetylene 25 , 0.16
mL of a MeONa solution (25% in MeOH), 4 mL of a LiAlH4
74-79 °C (ether-hexane) [R]25 ) -10.4° (c 1.0, EtOH); IR
D
(CHCl3) 3585, 2160, 1655 cm-1; H NMR δ 0.17 (s, 9H), 0.92
1
(t, J ) 4.9 Hz, 1H), 1.22-1.26 (m, 1H), 1.72-1.78 (m, 1H),
1.93-1.99 (m, 1H), 2.30-2.35 (m, 1H), 4.16 (m, 1H), 5.18 (d,
J ) 2.0 Hz, 1H), 5.34 (d, J ) 2.5 Hz, 1H); MS (m/ z) 188 (M -

124 J . Org. Chem., Vol. 61, No. 1, 1996
Kabat et al.
solution (1 M in THF), and 20 mL of THF was refluxed for 1h.
The mixture was cooled and then quenched by the addition of
50 mL of saturated aqueous NH4Cl. The mixture was ex-
tracted with ether, and the organic extract was washed with
brine and then dried. The crude product was purified by
chromatography on silica gel, eluting with hexane-ether (98:
2), to give 0.648 g (88%) of 28 as a colorless oil: [R]25D ) -5.0°
oil: [R]25 ) -9.2° (c 1.0, EtOH); IR (CHCl3) 3595, 2225, 1650
D
cm-1; 1H NMR δ 0.13 (s, 9H), 0.89 (d, J ) 4.3 Hz, 3H), 0.90 (s,
3H), 1.01 (t, J ) 4.5 Hz, 1H), 1.20 (s, 6H), 4.87 (s, 1H), 5.11 (s,
1H); MS (m/ z) 131 (100), 73 (40), 28 (63). Anal. Calcd for
C30H50O2Si: C, 76.53; H, 10.70. Found: C, 76.56; H, 10.86.
[1R-[1r(R*),3a â,4r[(E)-(1S*,5R*)],7a r]]-1-[1,5-Dim eth yl-
5-[(t r im et h ylsilyl)oxy)h exyl]oct a h yd r o-7a -m et h yl-4-[2-
[2-m eth ylen ebicyclo-[3.1.0]h exan -1-yl)eth en yl]-1H-in den -
4-ol (30). A 1 M LiAlH4 in THF solution (24.3 mL) was added
to 45 mL of THF followed by 2.75 mL of MeONa (4.37 M in
MeOH, 12.0 mmol). The mixture was stirred at rt for 10 min
and cooled to 0 °C, and then 3.82 g (8.12 mmol) of 26 in 8 mL
of THF was added over 10 min. The reaction mixture was
stirred at rt for 15 min and then quenched by the careful
addition of 50 mL of H2O. The mixture was extracted with 2
× 30 mL of ether, and the combined extracts were dried. The
crude product was purified by silica gel chromatography,
eluting with hexane-EtOAc (10:1), to afford 2.99 g (78%) of
(c 0.98, EtOH); UV λ
(EtOH) 220 (ꢀ ) 25 000), 247 (390),
max
253 (480), 259 (645), 264 (690), 271 (515); IR (CHCl3) 3600,
1652, 840 cm-1; 1H NMR δ 0.10 (s, 9H), 0.53 (brt, 1H), 0.88 (d,
J ) 6.4 Hz, 3H), 0.94 (s, 3H), 1.08 (s, 9H), 1.20 (s, 6H), 4.30 (t,
J ) 7.5 Hz, 1H), 4.95 (s, 1H), 5.24 (s, 1H), 5.37 (d, J ) 15.5
Hz. 1H), 6.00 (d, J ) 15.5 Hz, 1H), 7.3-7.5 (m, 6H), 7.6-7.7
(m, 4H); MS (m/ z) 726 (M+, 1), 711 (M - Me, 1), 669 (4), 199
(100), 131 (81); HRMS for C46H70O3Si2 calcd 726.4864, found
726.4857. Anal. Calcd for C46H70O3Si2: C, 75.97; H, 9.70.
Found: C, 76.26; H, 9.97.
[1R-[1r(R*),3a â,4r[(E)-(1S*,3S*,5S*)],7a r]]-Octa h yd r o-
4-h yd r oxy-4-[2-[(3-h yd r oxy-2-m et h ylen eb icyclo[3.1.0]-
h exa n -1-yl)eth en yl]-r,r,E,7a -tetr a m eth yl-1H-in d en e-p en -
ta n ol (29). A solution of 0.541 g (0.75 mmol) of 28, 2.26 mL
of tetrabutylammonium fluoride solution (1 M in THF, 2.26
mmol), and 8 mL of THF was stirred at rt for 16 h. The
mixture was diluted with 50 mL of EtOAc and then washed 3
× 20 mL with water. The crude product was purified by
chromatography on silica gel, eluting with CH2Cl2-ether (98:
30: [R]25 ) +50.9° (c 0.9, EtOH); ) IR (CHCl3) 3595, 1642
D
cm-1; 1H NMR δ 0.00 (s, 9H), 0.71 (t, J ) 4.5 Hz, 1H), 0.81 (d,
J ) 6.5 Hz, 3H), 0.85 (s, 3H), 1.01 (s, 6H), 4.64 (s, 1H), 4.70 (s,
1H), 5.31 (d, J ) 15.6 Hz, 1H), 5.85 (d, J ) 15.6 Hz, 1H); MS
(m/ z) 131 (100); HRMS for C30H52O2Si calcd 472.3737, found
472.3744. Anal. Calcd for C30H52O2Si: C, 76.21; H, 11.09.
Found: C, 76.11; H, 11.26.
[1R-[1r(R*),3a â,4r[(E)-(1S*,5R*)],7a r]]-Oct a h yd r o-4-
h yd r oxy-r,r,E,7a -tetr a m eth yl-4-[2-(2-m eth ylen ebicyclo-
2), to give 0.307 g (99%) of 30 as a foam; [R]25 ) +70.2° (c
D
1
0.88, EtOH); IR (CHCl3) 3605, 1652 cm-1; H NMR δ 0.71 (t,
[3.1.0]h exa n -1-yl)eth en yl]-1H-in d en e-p en ta n ol (31).
A
J ) 5.7 Hz, 1H), 0.92 (d, J ) 6.5 Hz, 3H), 0.95 (s, 3H), 4.25 (q,
J ) 8.1 Hz, 1H, -CH-O-), 4.96 (d, J ) 2.1 Hz, 1H), 5.08 (d,
J ) 2.0 Hz, 1H), 5.43 (d, J ) 15.6 Hz, 1H), 5.97 (d, J ) 15.6
Hz, 1H). MS (m/ z) 416 (M+, 1), 398 (M - 18, 3), 380 (M-32,
3), 355 (5), 139 (40), 55 (78), 28 (100); HRMS for C27H44O3 calcd
416.3290, found 416.3313. Anal. Calcd for C27H44O3: C, 77.84;
H, 10.64. Found: C, 77.77; H, 10.64.
solution of 1.95 g (4.13 mmol) of 30, 8.24 mL of an n-Bu4NF
solution (1 M in THF) and 20 mL of THF was stirred at rt for
3 h. Then 20 mL of H2O was added, and the mixture was
extracted with 2 × 20 mL of ether. The extracts were
combined and dried. The crude product was purified by silica
gel chromatography, eluting with hexane-EtOAc (4:1), to give
1.62 g (98%) of 31 as a colorless oil: IR (CHCl3) 3606, 1645
cm-1; 1H NMR δ 0.81 (t, J ) 4.5 Hz, 1H), 0.92 (d, J ) 6.2 Hz,
3H), 0.95 (s, 3H), 1.21 (s, 6H), 4.75 (s, 1H), 4.80 (s, 1H), 5.41
(d, J ) 15.6 Hz, 1H), 5.96 (d, J ) 15.6 Hz, 1H); MS (m/ z) 41
(100). HRMS for C27H44O2 calcd 400.3341, found 400.3344.
Anal. Calcd for C27H44O2: C, 80.94; H, 11.09. Found: C,
80.87; H, 11.36.
1,25-Dih yd r oxych oleca lcifer ol (1). A solution of 0.140
g (0.34 mmol) of 29, 0.010 g of p-TsOH, and 25 mL of dioxane-
H2O (3:1) was stirred at 75 °C for 4 h. The cooled solution
was extracted with EtOAc. The organic extracts were com-
bined, washed successively with water and aqueous NaHCO3,
and then dried. The crude product was purified by silica gel
chromatography, eluting with CH2Cl2-MeOH (96:4), to afford
0.105 g (75%) of a 5,6-cis/ trans mixture of 1,25-(OH)2D3 which
was subsequently irradiated for 1 h using a 450 W mercury
lamp (uranium filter) in 70 mL of tert-butyl methyl ether
containing 0.010 g of 9-acetoxyanthracene. The solvent was
then evaporated in vacuo, and the residue was purified by
chromatography on silica gel, eluting with CH2Cl2-MeOH (96:
4), to give 0.100 g (71%) of 1,25-(OH)2D3 (1), mp 118-119 °C
(methyl formate); [R]25D ) +48° (c 0.5, EtOH); UV λ max (EtOH)
25-Hyd r oxych oleca lcifer ol (32). A solution of 1.23 g (3.07
mmol) of 31, 0.231 g (0.92 mmol) of pyridinium p-toluene-
sulfonate, 24 mL of acetonitrile, and 12 mL of H2O was stirred
vigorously at 50 °C for 2.5 h. Then 20 mL of saturated aqueous
NaHCO3 was added and the mixture extracted with ether. The
extracts were combined and dried and solvents were removed
under reduced pressure at 30 °C. The residue was dissolved
in a mixture of hexane-EtOAc (2:1) and filtered through a 1
cm pad of silica gel, eluting with the same solvent mixture.
The filtrates were evaporated at 30 °C under reduced pressure,
and the residue was subsequently dissolved in 20 mL of
t-BuOMe. The solution was irradiated under argon with a 450
W mercury lamp, through a uranium filter, in the presence of
0.181 g (0.77 mmol) of 9-acetoxyanthracene for 2 h. The
solvent was then evaporated under reduced pressure at 30 °C,
and the residue was purified by silica gel chromatography,
eluting with hexane-EtOAc (2:1), to give 0.8 g (65%) of 25-
hydroxycholecalciferol (32) as a white solid. The analytical
sample was prepared by crystallization from methyl formate,
210 nm (ꢀ ) 15 980), 263 (16 780); IR (CHCl3) 1645, 1628 cm-1
;
1H NMR (CDCl3 + DMSO) δ 0.54 (s, 3H), 0.93 (d, J ) 6.4 Hz,
3H), 1.20 (s, 6H), 4.19 (brs, 1H), 4.42 (brs, 1H), 4.97 (s, 1H),
5.33 (s, 1H), 6.04 (d, J ) 11.0 Hz, 1H), 6.35 (d, J ) 11.0 Hz,
1H); MS (m/ z) 416 (M+, 1), 398 (M - 18, 51), 380 ((M - 2 ×
18, 76), 362 (M - 3 × 18, 22), 347 (10), 269 (14), 251 (28), 105
(59), 55 (72), 41 (100); HRMS for C27 H44O3 calcd 416.3296,
found 416.3286. Anal. Calcd for C27H44O3: C, 77.84; H, 10.65.
Found: C, 77.64; H, 10.67.
[1R-[1r(R*),3a â,4r(1R*,5R*),7a r]]-1-[1,5-Dim et h yl-5-
[(t r im et h ylsilyl)oxy]h exyl]oct a h yd r o-7a -m et h yl-4-[(2-
m eth ylen ebicyclo[3.1.0]h exa n -1-yl)eth yn yl]-1H-in d en -4-
ol (26). A total of 9.30 mL (14.9 mmol) of an n-BuLi solution
(1.6 M in hexane) was added at 0 °C to a solution of 2.36 g
(12.4 mmol) of 19 in 70 mL of THF. The solution was then
stirred at 50 °C for 15 min before being cooled to -30 °C,
whereupon a solution of 3.97 g (11.3 mmol) of 6 in 10 mL of
THF was added. The reaction mixture was stirred at -15 °C
for 20 min and at 0 °C for 30 min and then quenched by the
addition of 100 mL of H2O. The mixture was extracted with
ether, and the extracts were combined and dried. The crude
product was purified by silica gel chromatography, eluting with
hexane-EtOAc (10:1), to give 4.14 g (78%) of 26 as a colorless
mp 96-106 °C (lit.32 mp 95-100 °C, acetone), [R]25 ) +88.1°
D
(c 0.5, EtOH).
Ack n ow led gm en t. We express our gratitude to the
members of the Physical Chemistry Department of
Hoffmann-La Roche, Inc., for the determination of
spectral and analytical data and to Dr. L. J . Todaro and
Ms. A.-M. Chiu for X-ray crystallographic analysis.
J O951229D
(32) Halkes, S. J .; van Vliet, N. P. Rec. 1969, 88, 1080.