New Convergent Synthesis of 1α,25-Dihydroxyvitamin D3 and Its Analogues by Suzuki-Miyaura Coupling between A-Ring and C,D-Ring Parts

Article abstract of DOI:10.1021/jo0353435

A new convergent method for the synthesis of 1α,25 -dihydroxyvitamin D3 and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromom-ethylene-3,5-bis(tert-butyldimethylsilyloxy) -2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-l-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)₄/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo-(trimethylsilyl)methylene] -5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which la was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs₂CO₃. The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl₂(dppf) catalyst to furnish 1α,25 -dihydroxyvitamin D₃ in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1α,25-dihydroxyvitamin D₃ were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1α,25-dihydroxyvitamin D₃ analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.

Full text of DOI:10.1021/jo0353435

New Con ver gen t Syn th esis of 1r,25-Dih yd r oxyvita m in D3 a n d Its
An a logu es by Su zu k i-Miya u r a Cou p lin g betw een A-Rin g a n d
C,D-Rin g P a r ts
Takeshi Hanazawa, Akiko Koyama, Kunio Nakata, Sentaro Okamoto, and Fumie Sato*
Graduate school of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama, Kanagawa 226-8501, J apan
fsato@bio.titech.ac.jp
Received September 11, 2003
A new convergent method for the synthesis of 1R,25-dihydroxyvitamin D3 and its analogues has
been developed that involves efficient preparation of the A-ring part 1a , (Z)-(3S,5R)-1-bromom-
ethylene-3,5-bis(tert-butyldimethylsilyloxy)-2-methylenecyclohexane, starting from epichlorohydrin
(4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted
to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-1-en-7-yn-3-ol (3a ) through a ten-step
reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-
Pr)4/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo-
(trimethylsilyl)methylene]-5-(tert-butyldimethylsilyloxy)cyclohexanol (10a ) in 51% yield, from which
1a was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs2CO3.
The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a
PdCl2(dppf) catalyst to furnish 1R,25-dihydroxyvitamin D3 in 82% yield after protodesilylation.
Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared,
from which 1-epi-, 3-epi-, and 1,3-di-epi-1R,25-dihydroxyvitamin D3 were synthesized by coupling
with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1R,25-dihydroxyvitamin
D3 analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.
SCHEME 1
In tr od u ction
Metabolic activation of vitamin D3 involves hydroxy-
lation in the liver to form 25-hydroxyvitamin D3 and the
following further hydroxylation in the kidney to produce
1R,25-dihydroxyvitamin D3 [1,25-(OH)2-VD3]. The latter
metabolite serves as a regulator of calcium homeostasis.
In addition to its role, 1,25-(OH)2-VD3 has recently been
shown to promote normal cell differentiation and prolif-
eration as well as to generate a variety of biological
responses through nongenomic mechanisms. Because of
its important role in human physiology, it has attracted
substantial interest in its pharmacology and therapeutic
potential.1 The chemical synthesis of 1,25-(OH)2-VD3 and
its analogues, therefore, has been the subject of extensive
research because organic synthesis is the only means of
supplying sufficient quantities and creating more effec-
tive compounds.2 Hitherto, two efficient convergent syn-
theses have been developed and have been used for the
preparation of 1,25-(OH)2-VD3 and its derivatives. As
shown in Scheme 1, one is the Lythgoe-Roche method,
which uses a connection of the A-ring and C,D-ring parts
by the Horner-Wittig reaction,3 and the other is the
Trost method, which involves a Pd-catalyzed carbometa-
lation-cyclization reaction of the acyclic precursor of the
A-ring and C,D-ring parts.4 The coupling approach
between the A-ring part 1a and the C,D-ring part 2
shown in Scheme 1 is anticipated to furnish another
efficient convergent synthesis. And, actually, the prepar-
* Address correspondence to this author. Phone: +81-45-924-5788.
Fax: +81-45-924-5826.
(3) Baggiolini, E. G.; Iacobelli, J . A.; Hennessy, B. M.; Batcho, A.
D.; Sereno, J . F.; Uskokovic, M. R. J . Org. Chem. 1986, 51, 3098 and
references therein.
(4) (a) Trost, B. M.; Dumas, J .; Villa, M. J . Am. Chem. Soc. 1992,
114, 9836. (b) Trost, B. M.; Hanson, P. R. Tetrahedron Lett. 1994, 35,
8119.
(1) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J . W., Eds.;
Academic Press: New York, 1997. Bouillon, R.; Okamura, W. H.;
Norman, A. W. Endocr. Rev. 1995, 16, 200.
(2) Zhu G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
10.1021/jo0353435 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/19/2003
J . Org. Chem. 2003, 68, 9767-9772
9767

Hanazawa et al.
SCHEME 2
SCHEME 3a
ation of 3-deoxy-1-hydroxyvitamine D3 by coupling of the
corresponding A-ring part with 2 (M ) SnR3 or ZnX),
using the Stille coupling or Negishi coupling reaction, was
reported by Mourin˜o and co-workers.5 We also synthe-
sized 19-nor-1,25-(OH)2-VD3 by Suzuki-Miyaura cou-
pling6 between the corresponding A-ring part and 2 (M
) B(OR)2).7 However, the preparation of 1a had not been
achieved until our communication reference, and thus the
preparation of 1,25-(OH)2-VD3 through such a coupling
pathway has not been reported. Herein we report an
efficient method for synthesizing 1a and its coupling with
the C,D-ring part 2 (M ) B(OR)2) providing 1,25-(OH)2-
VD3 by Suzuki-Miyaura coupling. We also report the
synthesis of three other possible stereoisomers of 1a , thus
consequently, the preparation of all of the A-ring dia-
stereomers of 1,25-(OH)2-VD3, the unique biological activ-
ity of which has been reported.8,9
Resu lts a n d Discu ssion
We envisaged that the synthesis of 1a and its stere-
oisomers could be achieved by Ti(II)-mediated cycliza-
tion10 of the corresponding 1,7-enyne 3 as shown in
Scheme 2 by a retrosynthetic method. The synthesis of
optically active 3 has been previously reported by
Ogasawara and co-workers by starting with optically
active epichlorohydrin (4).11 According to this method and
with several modifications, we synthesized all four pos-
sible stereoisomers 3a -d as shown in Scheme 3. Thus,
(R)-4 was converted to epoxide (R)-5,12 which in turn was
a
Reaction conditions: (i) Ti(O-i-Pr)4, L-(+)-DIPT, t-BuOOH,
CH2Cl2. (ii) Ti(O-i-Pr)4, D-(-)-DIPT, t-BuOOH, CH2Cl2. (iii)
MeSO2Cl, Et3N, CH2Cl2. (iv) NaI, NaHCO3, acetone. (v) Zn, AcOH,
MeOH.
(5) Garc´ıa, A. M.; Mascaren˜as J . L.; Castedo, L.; Mourin˜o, A. J . Org.
Chem. 1997, 62, 6353. Garc´ıa, A.; Mascaren˜as, J . L.; Castedo, L.;
Mourin˜o, A. Tetrahedron Lett. 1995, 36, 5413.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(7) Hanazawa, T.; Wada, T.; Masuda, T.; Okamoto, S.; Sato, F. Org.
Lett. 2001, 3, 3975.
reacted with alkynyllithium 6 in the presence of boron
trifluoride etherate13 to provide, after hydrolysis, diol
(S)-7 in 82% yield. Selective acylation of the primary
hydroxyl group of (S)-7 to (S)-8 was attained by treatment
with vinyl acetate in the presence of porcine pancreatic
lipase (PPL) in 96% yield.14 Protection of the secondary
hydroxy group of (S)-8 as tert-butyldimethylsilyl (TBS)
ether, and the following treatment with sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) afforded (S)-9
in 97% yield. From (S)-9, compounds 3a and 3b were
prepared in excellent overall yield by the conventional
reaction sequence,11,15 which involves Sharpless catalytic
asymmetric epoxidation with L-(+)- or D-(-)-diisopropyl
tartrate (DIPT) as a chiral ligand, respectively, conver-
sion of the hydroxy group to iodide, and reductive opening
(8) For the synthesis of A-ring diastereomers of 1,25-(OH)2-VD3,
see: (a) Konno, K.; Maki, S.; Fujishima, T.; Liu, Z.; Miura, D.; Chokki,
M.; Takayama, H. Bioorg. Med. Chem. Lett. 1998, 8, 151. (b) Mu-
ralidharan, K. R.; de Lera, A. R.; Isaeff, S. D.; Norman, A. W.;
Okamura, W. H. J . Org. Chem. 1993, 58, 1895. For their biological
activity, see in addition to refs 8a and 8b: (c) Norman, A. W.; Bouillon,
R.; Farach-Carson, M. C.; Bishop, J . E.; Zhou, L.-X.; Nemere, I.; Zhao,
J .; Muralidharan, K. R.; Okamura, W. H. J . Biol. Chem. 1993, 268,
20022. (d) Bischof, M. G.; Siu-Caldera, M.-L.; Weiskopf, A.; Vouros,
P.; Cross, H. S.; Peterlik, M.; Reddy, G. S. Exp. Cell. Res. 1998, 241,
194.
(9) The preparation of [1,25-(OH)2-VD3] by the present method was
reported as a preliminary result. Hanazawa, T.; Koyama, A.; Wada,
T.; Morishige, E.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 523. See
also: Org. Lett. 2003, 5, 3167 (Additions and Corrections).
(10) Urabe, H.; Sato, F. Tetrahedron Lett. 1998, 39, 7329.
(11) Tazumi, K.; Ogasawara, K. J . Chem. Soc., Chem. Commun.
1994, 1903.
(13) Yamaguchi, M.; Hirano, I. Tetrahedron Lett. 1983, 24, 391.
(14) Ramaswamy, S.; Morgan, B.; Oehlschlager, A. C. Tetrahedron
Lett. 1990, 31, 3405.
(15) Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.; Yamada,
H.; Nishizawa, M. Tetrahedoron 1994, 50, 13369.
(12) Subburaj, K.; Okamoto, S.; Sato, F. J . Org. Chem. 2002, 67,
1024. Hanazawa, T.; Sasaki, K.; Takayama, Y.; Sato, F. J . Org. Chem.
2003, 68, 4980.
9768 J . Org. Chem., Vol. 68, No. 25, 2003

New Convergent Synthesis of 1R,25-Dihydroxyvitamin D3
SCHEME 4a
SCHEME 5
in 10 thus produced could not be assigned by the 1H NMR
analysis, it was tentatively assigned as depicted in
Scheme 4 on the basis of our previous results of the
cyclization of similar compounds.10 After protection of the
hydroxyl group of 10 as TBS ether, the resulting 11 was
treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in
toluene or CH2Cl2 and then with Cs2CO3 in DMF to
provide 1.5 In these reaction sequences the following
results should be noted: The yield of 10 from 3 is
somewhat dependent on the stereochemistry of 3 and it
was 49-51% for 3a (3d ) and 81-88% for 3b (3c). While
dehydrobromination of 11b (11c) with DBU proceeded
readily at room temperature in CH2Cl2, that of 11a (11d )
did not proceed under these reaction conditions and
required heating at 70 °C in toluene. The overall yield of
1 from 3 and the [R]D value of 1a -d thus prepared are
shown in Scheme 4.
With the A-ring unit 1 in hand, we carried out the
synthesis of 1,25-(OH)2-VD3 and its A-ring diastereomers
using the Suzuki-Miyaura coupling reaction. Thus, the
reaction of 1a with 127 in the presence of KOH and PdCl2-
(dppf) [8 mol %, dppf ) 1,1′-bis(diphenylphosphino)-
ferrocene] in aqueous THF furnished, after desilylation,
1,25-(OH)2-VD3 in 82% yield as shown in Scheme 5.
Similarly, three other possible A-ring diastereomers of
1,25-(OH)2-VD3 shown in Figure 1, i.e., 1-epi-, 3-epi-, and
1,3-di-epi-1,25-(OH)2-VD3, were prepared from the cor-
responding 1 and 12 in excellent yield.
Among the analogues of 1,25-(OH)2-VD3, those which
lack the C,D-ring structure have recently attracted much
interest as potentially therapeutic compounds.17 The
present method for synthesizing 1,25-(OH)2-VD3 with use
of 1 is also very efficient for synthesizing other com-
pounds as exemplified by the synthesis of retiferol 13.17a
Thus, as shown in Scheme 6, the coupling of 1a with 147
prepared from the corresponding alkyne by hydroboration
reaction afforded retiferol 13 in 78% overall yield after
desilylation.18 Similarly, 3-epi-13 was prepared in excel-
lent yield by starting from 1c and 14.
a
Reaction conditions: (i) i-PrMgCl then Ti(O-i-Pr)4/2 i-PrMgCl,
ether. (ii) NBS. (iii) TBSCl, imidazole, DMF. (iv) DBU, toluene,
70 °C. (v) Cs2CO3, DMF. (vi) DBU, CH2Cl2, room temperature.
of the epoxy iodide moiety. Meanwhile, starting with (S)-4
instead of (R)-4 in the reactions mentioned above, two
other stereoisomers 3c and 3d were prepared similarly
via (R)-9, which is also shown in Scheme 3. The diaster-
eomeric purity of crude 3 thus obtained was found to be
more than 97% for 3a and 3d , 95% for 3b, and 96% for
3c, and in all cases, the corresponding pure 3 was isolated
by column chromatography. The isolated yield of pure 3
from 4 was respectively 49, 46, 40, and 43% for 3a , 3b,
3c, and 3d .
With all four possible stereoisomers of 3 with excellent
purity in hand, we proceeded to convert them to the
corresponding 1. As shown in Scheme 4, the titanacy-
clization of 3, mediated by a divalent titanium reagent
Ti(O-i-Pr)4/2 i-PrMgCl,16 and the following reaction with
N-bromosuccinimide (NBS) afforded the corresponding
dibromo compound 10 in good to excellent yield and in
all cases as a single diastereomer in relation to the newly
generated stereogenic center. Although the stereochem-
istry of the carbon center bearing a bromomethyl moiety
In summary, we have now succeeded in developing a
new efficient method for synthesizing 1,25-(OH)2-VD3 and
its derivatives. The synthetic method involves practical
preparation of the A-ring part of 1,25-(OH)2-VD3 and its
(17) (a) Kutner, A.; Zhao, H.; Fitak, H.; Wilson, S. R. Bioorg. Chem.
1995, 23, 22. (b) Wirz, B.; Iding, H.; Hilpert, H. Tetrahedron: Asym-
metry 2000, 11, 4171. (c) Hilpart, H.; Wirz, B. Tetrahedron 2001, 57,
681. (d) U.S. Patent 5,969,190, 1998. (e) U.S. Patent 6,184,422, 1999.
(18) For the synthesis of des-C,D-VD3-analogues by the Lythgoe-
Roche method, see ref 17. Synthesis of des-C,D-VD3-analogues by the
Trost method was not reported.
(16) Reviews for synthetic reactions mediated by a Ti(O-i-Pr)4/2 i-
PrMgCl reagent: Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000,
100, 2835. Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343, 759.
Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319-354.
J . Org. Chem, Vol. 68, No. 25, 2003 9769

Hanazawa et al.
F IGURE 1. A-ring diastereomers of 1,25-(OH)2-VD3.
Et2O (3 × 100 mL). The combined organic layers were washed
with saturated aqueous NaHCO3 (100 mL), dried over MgSO4,
concentrated, and chromatographed on silica gel (hexanes-
EtOAc) to give (S)-7 (8.61 g, 82%). 1H NMR (CDCl3) δ 4.26 (br
s, 2H), 3.86-3.96 (m, 1H), 3.31 (br s, 2H), 2.45-2.60 (m, 4H),
0.15 (s, 9H); 13C NMR (CDCl3) δ 102.4, 87.6, 81.9, 80.9, 68.5,
50.9, 27.6, 26.3, 0.1; IR (neat) 3350, 2959, 2177, 1424, 1249,
SCHEME 6
1137, 1027, 840, 760 cm-1. [R]28 -14.0 (c 2.69, CHCl3). Anal.
D
Calcd for C11H18O2Si: C,62.81; H, 8.63. Found: C, 62.56; H,
8.93.
Acetic Acid (S)-5-Hyd r oxy-8-(tr im eth ylsilyl)octa -2,7-
d iyn yl Ester ((S)-8). To a solution of (S)-7 (16.5 g, 78.4 mmol)
in vinyl acetate (78 mL) was added porcine pancreatic lipase
(PPL, 42 units/mg, Sigma-Aldrich, 16.5 g). After being stirred
for 3 days at room temperature, the mixture was filtered
through a pad of Celite with Et2O (200 mL). The filtrate was
concentrated and chromatographed on silica gel (hexanes-
1
Et2O) to give (S)-8 (19.0 g, 96%). H NMR (CDCl3) δ 4.68 (t, J
) 2.1 Hz, 2H), 3.87-3.97 (m, 1H), 2.52-2.58 (m, 4H), 2.36 (s,
1H), 2.10 (s, 3H), 0.17 (s, 9H); 13C NMR (CDCl3) δ 170.2, 102.0,
88.0, 83.1, 76.7, 68.3, 52.6, 27.7, 26.4, 20.9, 0.1; IR (neat) 3462,
2958, 2176, 1748, 1379, 1250, 1028, 845, 761 cm-1. [R]27D -0.76
(c 2.22, CHCl3). Anal. Calcd for C13H20O3Si: C, 61.87; H, 7.99.
Found: C, 62.24; H, 7.60.
(S,E)-5-(ter t-Bu tyld im eth ysilyloxy)-8-(tr im eth ylsilyl)-
oct-2-en -7-yn -1-ol ((S)-9). To a mixture of (S)-8 (22.0 g, 87.2
mmol) and imidazole (13.0 g, 191 mmol) in DMF (180 mL) was
added TBSCl (14.4 g, 95.6 mmol) at 0 °C. After the mixture
was stirred for 12 h at room temperature, saturated aqueous
NaHCO3 (100 mL) at 0 °C was added. The mixture was
extracted with hexane (3 × 100 mL). The combined organic
layers were dried over MgSO4 and concentrated. The resulting
pale yellow residue was directly used for the next reaction
without purification. To a solution of the residue thus obtained
in Et2O (200 mL) was slowly added Red-Al (63.3 mL, 3.42 M
in toluene, 216 mmol) at 0 °C. After the solution was stirred
for 1 h at the same temperature, saturated aqueous 1 N HCl
(200 mL) was added carefully. The mixture was extracted with
Et2O (3 × 100 mL). The combined organic layers were dried
over MgSO4, concentrated, and chromatographed on silica gel
high yield coupling with the C,D-ring portion by the
Suzuki-Miyaura protocol. Thus, in addition to the Trost
and Lythgoe-Roche methods, another practical entry to
1,25-(OH)2-VD3 and its derivatives has now been opened
up.
1
(hexane-Et2O) to give (S)-9 (27.8 g, 97%). H NMR (CDCl3) δ
5.68-5.71 (m, 2H), 4.10 (m, 2H), 3.80-3.89 (m, 1H), 2.21-
2.40 (m, 2H), 2.33 (d, J ) 6.0 Hz, 2H), 1.38 (s, 1H), 0.88 (s,
9H), 0.14 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3)
δ 131.8, 128.5, 104.4, 86.3, 70.8, 63.7, 39.8, 28.4, 25.9, 18.2,
0.2, -4.3, -4.5; IR (neat) 3326, 2956, 2857, 2178, 1472, 1362,
Exp er im en ta l Section
(S)-8-(Tr im eth ylsilyl)octa -2,7-d iyn e-1,5-d iol ((S)-7). To
a stirred solution of 3-triethylsilyloxy-1-propyne (18.7 g, 110
mmol) in THF (100 mL) was slowly added n-BuLi (63.7 mL,
1.57 M in hexane, 100 mmol) at -78 °C. After the mixture
was stirred for 1 h at the same temperature, a solution of
epoxide (R)-5 (7.71 g, 50.0 mmol) in THF (70 mL) and then
boron trifluoride etherate (12.6 mL, 100 mmol) were added.
The mixture was stirred for 1 h at -78 °C and warmed to room
temperature over 30 min. After addition of saturated aqueous
NH4Cl (100 mL), the mixture was extracted with Et2O (3 ×
100 mL). The combined organic layers were dried over MgSO4
and concentrated. To a stirred solution of the crude residue
in THF (150 mL) was slowly added aqueous 3 N HCl (50 mL)
at 0 °C. After being stirred for 1 h at room temperature, the
mixture was diluted with H2O (100 mL) and extracted with
1250, 1101, 1031, 973, 841, 776 cm-1. [R]28 3.39 (c 2.82,
D
MeOH) [lit.11 [R]28 3.9 (c 0.92, MeOH)].
D
(3S,5R)-5-(ter t-Bu tyld im eth ylsilyloxy)-8-(tr im eth ylsi-
lyl)oct-1-en -7-yn -3-ol (3a ). To a mixture of Ti(O-i-Pr)4 (5.00
mL, 17.0 mmol) and 4Å molecular sieves (5.56 g) in CH2Cl2
(50 mL) was added diisopropyl L-(+)-tartarate (L-(+)-DIPT)
(4.28 mL, 20.4 mmol) at -15 °C and the mixture was stirred
for 30 min. To this was slowly added a solution of (S)-9 (27.8
g, 85.1 mmol) in CH2Cl2 (30 mL). After being stirred for 40
min at -15 °C, the mixture was cooled to -30 °C and t-BuOOH
(49.7 mL, 3.41 M in CH2Cl2, 169 mmol) was added. The
resulting mixture was allowed to warm to -20 °C and stirred
9770 J . Org. Chem., Vol. 68, No. 25, 2003

New Convergent Synthesis of 1R,25-Dihydroxyvitamin D3
for 24 h. After addition of methyl sulfide (9.34 mL, 127 mmol)
and stirring for 1 h at -20 °C, 10% tartaric acid (30 mL) was
added to the mixture. The mixture was then warmed to room
temperature over 1 h and diluted with Et2O (500 mL). After
addition of NaF (55.6 g) and Celite (55.6 g), the mixture was
stirred for 1 h and filtered through a pad of Celite. The
resulting filtrate was evaporated to remove solvents. The
residue was diluted with Et2O (300 mL) and aqueous 3 N
NaOH (85 mL) and was vigorously stirred for 1.5 h at room
temperature. After addition of H2O (300 mL), the mixture was
extracted with Et2O (3 × 150 mL) and the combined organic
layers were dried over MgSO4 and concentrated in vacuo to
give the epoxy alcohol as a pale yellow oil, which was subjected
to the next reaction without purification. To a mixture of the
epoxide thus obtained and NEt3 (21.1 mL, 187 mmol) in CH2-
Cl2 (130 mL) was slowly added MsCl (7.88 mL, 102 mmol) at
0 °C. After being stirred for 1 h, the mixture was quenched by
addition of saturated aqueous NaHCO3 (100 mL) and extracted
with CH2Cl2 (3 × 90 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure
to give a colorless residue, which was subjected to the next
reaction without purification. To a mixture of the crude
mesylate and NaHCO3 (2.13 g, 25.4 mmol) in dry acetone (200
mL) was added NaI (38.2 g, 255 mmol) at room temperature.
After being stirred for 20 h, the mixture was concentrated by
rotary evaporation and then diluted with saturated aqueous
Na2S2O3 (200 mL). After extraction with Et2O (3 × 100 mL),
the combined organic layers were dried over MgSO4 and
concentrated in vacuo to give the corresponding iodide, which
was directly used for the next reaction without purification.
To a mixture of zinc powder (16.6 g, 254 mmol, activated by
washing with diluted HCl and drying in vacuo) in MeOH (20
mL) was added acetic acid (0.273 mL, 4.80 mmol). To this
mixture was added a solution of the crude iodide, prepared
above, in MeOH (40 mL) under sonication. After 1 h of
sonication, acetic acid (4.83 mL, 84.9 mmol) was added. The
mixture was filtered with NH4Cl (200 mL) and CH2Cl2 (200
mL) and extracted with CH2Cl2 (2 × 200 mL). The combined
organic layers were dried over MgSO4, concentrated, and
chromatographed on silica gel (hexanes-Et2O) to give 3a (21.7
g, 78% overall yield from (S)-9). 1H NMR (CDCl3) δ 5.87 (ddd,
J ) 5.4, 10.5, 17.1 Hz, 1H), 5.26 (dt, J ) 1.5, 17.1 Hz, 1H),
5.09 (dt, J ) 1.5, 10.5 Hz, 1H), 4.38-4.46 (m, 1H), 4.10-4.18
(m, 1H), 2.92 (s, 1H), 2.48 (d, J ) 6.6 Hz, 2H), 1.83 (ddd, J )
3.3, 5.7, 14.4 Hz, 1H), 1.75 (ddd, J ) 3.6, 9.3, 14.4 Hz, 1H),
0.89 (s, 9H), 0.13 (s, 9H), 0.12 (s, 6H); 13C NMR (CDCl3) δ
140.9, 113.9, 103.4, 87.0, 69.5, 69.4, 42.0, 28.2, 25.9, 18.0, 0.1,
-4.4, -4.7; IR (neat) 3447, 2957, 2858, 2178, 1647, 1472, 1362,
1.65 (br s, 1H), 1.63 (ddd, J ) 2.7, 10.5, 13.8 Hz, 1H), 0.88 (s,
9H), 0.30 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3) δ 147.2, 129.7,
69.2, 66.6, 51.7, 39.9, 37.5, 31.3, 25.8, 18.1, 1.3, -4.4; IR (neat)
3447, 2954, 2857, 1472, 1361, 1251, 1096, 876, 839, 776 cm-1
;
[R]27D 0.50 (c 2.96, CHCl3). Anal. Calcd for C17H34Br2O2Si2: C,
41.98; H, 7.05. Found: C, 42.31; H, 6.85.
(Z)-(2S,3S,5R)-2-Br om om eth yl-1-[br om o(tr im eth ylsilyl)-
m eth ylen e]-3,5-bis(ter t-bu tyld im eth ylsilyloxy)cycloh ex-
a n e (11a ). To a mixture of 10a (1.70 g, 3.49 mmol), imidazole
(0.47 g, 6.90 mmol), and DMF (5 mL) was added TBSCl (0.573
g, 3.80 mmol) at 0 °C. After the mixture was stirred for 12 h
at room temperature, saturated aqueous NaHCO3 (20 mL) was
added. The mixture was extracted with hexane (3 × 20 mL)
and the combined organic layers were dried over MgSO4,
concentrated, and chromatographed on silica gel (hexanes-
Et2O) to give 11a (2.02 g, 96%) as a colorless oil. 1H NMR
(CDCl3) δ 4.34-4.38 (m, 1H), 3.97-4.08 (m, 1H), 3.57-3.63
(m, 1H), 3.27-3.45 (m, 2H), 2.79 (dd, J ) 4.5, 13.8 Hz, 1H),
1.92 (dd, J ) 10.8, 13.8 Hz, 1H), 1.82-1.90 (m, 1H), 1.58 (ddd,
J ) 2.4, 10.5, 12.9 Hz, 1H), 0.89 (s, 9H), 0.86 (s, 9H), 0.29 (s,
9H), 0.10 (s, 3H), 0.07 (s, 3H), 0.06 (s, 6H); 13C NMR (CDCl3)
δ 148.0, 128.5, 69.3, 66.9, 51.6, 40.1, 38.1, 31.6, 25.9, 25.7, 18.2,
17.9, 1.3, -4.5, -4.6, -4.9; IR (neat) 2953, 2857, 1471, 1361,
1252, 1100, 1018, 837, 775 cm-1; [R]27 14.2 (c 2.85, CHCl3).
D
Anal. Calcd for C23H48Br2O2Si3: C, 45.99; H, 8.05. Found: C,
46.11; H, 7.86.
(Z)-(3S,5R)-1-Br om om eth ylen e-3,5-bis(ter t-bu tyldim eth -
ylsilyloxy)-2-m eth ylen ecycloh exa n e (1a ). To a solution of
11a (1.70 g, 2.83 mmol) in toluene (5.6 mL) was added DBU
(1.68 mL, 11.2 mmol) at 0 °C. The reaction mixture was stirred
at 70 °C for 20 h. After addition of saturated aqueous NaHCO3
(15 mL), the mixture was extracted with hexane (3 × 10 mL)
and the combined organic layers were dried over MgSO4 and
concentrated to give the crude diene product as a yellow oily
residue. To a mixture of the crude residue thus obtained and
DMF (6 mL) was added Cs2CO3 (3.69 g, 11.3 mmol). The
reaction mixture was stirred at room temperature for 12 h.
After addition of saturated aqueous NaHCO3 (30 mL), the
mixture was extracted with hexane (3 × 15 mL) and the
combined organic layers were dried over MgSO4, concentrated,
and chromatographed on silica gel (hexane-Et2O) to give 1a
1
(1.16 g, 91%) as a colorless oil. H NMR (CDCl3) δ 6.03 (t, J )
1.5 Hz, 1H), 5.34 (br s, 1H), 5.16 (br s, 1H), 4.39-4.44 (m, 1H),
4.14-4.21 (m, 1H), 2.41 (ddd, J ) 1.5, 3.6, 13.5 Hz, 1H), 2.23
(dd, J ) 6.3, 13.5 Hz, 1H), 1.73-1.87 (m, 2H), 0.91 (s, 9H),
0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H); 13C NMR
(CDCl3) δ 146.3, 140.4, 112.1, 100.8, 70.7, 66.8, 44.7, 44.5, 25.9,
25.8, 18.4, 18.2, -4.6, -4.66, -4.71, -5.0; IR (neat) 2950, 1621,
1251, 1099, 924, 839, 777 cm-1. [R]27 -26.3 (c 4.77, CHCl3)
1472, 1361, 1253, 1082, 1006, 776 cm-1; [R]27 -9.1 (c 3.69,
D
D
[lit.11 [R]28 -26.0 (c 1.06, CHCl3)].
D
CHCl3). Anal. Calcd for C20H39BrO2Si2: C, 53.67; H, 8.78.
Found: C, 53.39; H, 8.80.
(Z)-(1S,2S,5R)-2-Br om om eth yl-3-[br om o(tr im eth ylsilyl)-
m eth ylen e]-5-(ter t-bu tyld im eth ylsilyloxy)cycloh exa n ol
(10a ). To a solution of 3a (1.63 g, 4.99 mmol) in Et2O (50 mL)
was added dropwise i-PrMgCl (2.51 mL, 1.99 M in Et2O, 4.99
mmol) at 0 °C. After the solution was stirred for 10 min at the
same temperature, Ti(O-i-Pr)4 (2.95 mL, 10.0 mmol) was
added. The resulting mixture was cooled to -78 °C and
i-PrMgCl (10.1 mL, 1.99 M in Et2O, 20.1 mmol) was added
slowly. After the solution was stirred for 30 min at -78 °C,
the resulting yellow mixture was warmed to -50 °C over 30
min and stirred for 3 h at this temperature. After the mixture
was cooled to -78 °C, a solution of NBS (4.90 g, 27.5 mmol) in
THF (30 mL) was slowly added and the mixture was allowed
to warm to room temperature. After the solution was stirred
for 1 h at room temperature, saturated aqueous NH4Cl (60
mL) was added. The mixture was extracted with Et2O (3 × 50
mL), washed with saturated aqueous NaHCO3 (80 mL) and
H2O (60 mL), dried over MgSO4, concentrated, and chromato-
graphed on silica gel (hexane-Et2O) to give 10a (1.26 g, 51%).
1H NMR (CDCl3) δ 4.36-4.40 (m, 1H), 3.92-4.04 (m, 1H),
3.65-3.71 (m, 1H), 3.32-3.48 (m, 2H), 2.82 (dd, J ) 4.8, 14.1
Hz, 1H), 1.94-2.50 (m, 1H), 1.97 (dd, J ) 11.1, 14.1 Hz, 1H),
(Z)-(3S,5R)-1-Br om om eth ylen e-3,5-bis(ter t-bu tyldim eth -
ylsilyloxy)-2-m eth ylen ecycloh exa n e (1b). To a solution of
11b (2.00 g, 3.33 mmol) in CH2Cl2 (4 mL) was added DBU
(1.60 mL, 10.7 mmol) at 0 °C. The reaction mixture was stirred
at room temperature for 18 h. After addition of saturated
aqueous NaHCO3 (20 mL), the mixture was extracted with
CH2Cl2 (3 × 20 mL) and the combined organic layers were
dried over MgSO4 and concentrated to give the crude diene
product as a yellow oily residue. To a mixture of the crude
residue thus obtained and DMF (4 mL) was added Cs2CO3
(4.30 g, 13.2 mmol). The reaction mixture was stirred at room
temperature for 20 h. After addition of saturated aqueous
NaHCO3 (40 mL), the mixture was extracted with hexane (3
× 30 mL) and the combined organic layers were dried over
MgSO4, concentrated ,and chromatographed on silica gel
1
(hexane-Et2O) to give 1b (1.32 g, 89%) as a colorless oil. H
NMR (CDCl3) δ 6.11 (d, J ) 2.1 Hz, 1H), 5.48 (t, J ) 2.1 Hz,
1H), 5.18 (t, J ) 2.1 Hz, 1H), 3.93-4.01 (m, 1H), 3.64-3.74
(m, 1H), 2.53 (ddd, J ) 2.1, 4.5, 12.9 Hz, 1H), 2.07-2.21 (m,
2H), 1.55 (q, J ) 11.4 Hz, 1H), 0.94 (s, 9H), 0.89 (s, 9H), 0.12
(s, 3H), 0.10 (s, 3H), 0.07 (s, 6H); 13C NMR (CDCl3) δ 145.8,
J . Org. Chem, Vol. 68, No. 25, 2003 9771

Hanazawa et al.
140.0, 111.4, 101.5, 69.3, 67.8, 46.2, 45.7, 25.94, 25.89, 18.4,
44.4, 42.9, 40.5, 36.4, 36.1, 29.4, 29.3, 29.1, 27.7, 23.7, 22.3,
18.2, -4.5, -4.6, -4.8, -5.0; IR (neat) 2951, 2862, 1619, 1471,
20.9, 18.9, 12.1; [R]30 47.2 (c 1.29, EtOH) [lit.3 [R]24 47.9 (c
D
D
1361, 1258, 1080, 911, 835, 675 cm-1; [R]28 +57.4 (c 7.05,
0.50, EtOH)].
D
CHCl3). Anal. Calcd for C20H39BrO2Si2: C, 53.67; H, 8.78.
Found: C, 54.05; H, 8.52.
Retifer ol 13 fr om 1a a n d 14. 13 (55.1 mg) was obtained
in 78% yield starting from 1a (94.0 mg, 0.210 mmol) and 147
(130 mg, 0.306 mmol) under similar reaction conditions as
described for the synthesis of 1R,25-dihydroxyvitamin D3 from
1a and 12. The 1H NMR spectroscopic spectra were in full
agreement with those reported.17a 13C NMR (CDCl3) δ 147.3,
135.4, 133.4, 129.4, 126.6, 112.0, 71.13, 71.09, 66.7, 45.1, 44.2,
42.9, 37.5, 36.4, 33.1, 32.6, 29.8, 29.3, 26.8, 21.8, 19.8; IR (neat)
1R,25-Dih yd r oxyvita m in D3 fr om 1a a n d 12. To a
mixture of boronate 127 (160 mg, 0.336 mmol), aqueous 3 N
KOH (0.11 mL), and THF (0.3 mL) was added dropwise a
mixture of bromide 1a (89.5 mg, 0.200 mmol), PdCl2(dppf) (12.3
mg, 0.0167 mmol), and THF (0.3 mL) at room temperature.
The resulting mixture was stirred for 24 h at 60 °C. After
addition of Et2O (20 mL), the mixture was washed with
aqueous 1 N HCl (10 mL) and brine (10 mL), dried over
MgSO4, concentrated, and purified by passing through a short
silica gel column with 1% ether in hexane to provide the
corresponding coupling product. To a solution of the coupling
product thus obtained in THF (5 mL) was added TBAF (1 mL,
1 M in THF, 1.0 mmol). After the mixture was stirred for 24
h at room temperature, the solvents were removed under
reduced pressure. The residue was diluted with H3O (10 mL)
and then extracted with EtOAc (5 × 10 mL). The combined
organic layers were dried over MgSO4, concentrated, and
chromatographed on silica gel (hexane-ethyl acetate) to give
1R,25-Dihydroxyvitaminn D3 (68.3 mg) in 82% yield, the
spectral data (1H NMR, IR) and [R]D value of which were
identical with those reported.3 13C NMR (CDCl3) δ 147.5, 143.0,
132.8, 124.8, 116.9, 111.7, 71.1, 70.8, 66.8, 56.5, 56.4, 45.9, 45.3,
3373, 2925, 1653, 1458, 1375, 1052, 908, 842, 759 cm-1; [R]27
+14.7 (c 0.65, CHCl3).
D
Ack n ow led gm en t. We thank the Ministry of Edu-
cation, Science, Sports and Culture (J apan) for financial
support. T.H. thanks the J apan Society for the Promo-
tion of Science for financial support. We also appreciate
Mr. Takeshi Wada and Miss Eiko Morishige for their
assistance in an early stage of this work.
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
compounds 1c, 1d , 3b-d , (R)-9, 10b-d , 11b-d , and 3-epi-
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0353435
9772 J . Org. Chem., Vol. 68, No. 25, 2003