Asymmetric synthesis of 1 α,25-dihydroxyvitamin D3 A-ring precursor starting with 5-tert-butyldimethylsiloxy-2-cyclohexenone

Article abstract of DOI:10.1016/S0040-4039(00)00169-6

The A-ring precursor of 1 α,25-dihydroxyvitamin D₃ [(E)-4] has been prepared starting from the (5S)-tert-butyldimethylsiloxy-2-cyclohexenone [(S)-1] via eight steps in 19% overall yield, where a catalytic osmium dihydroxylation which sets the stereochemistry of the hydroxyl group at C₁ and a regioselective protection of the hydroxy group as a TBS-ether are the key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00169-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2385–2388
Asymmetric synthesis of 1α,25-dihydroxyvitamin D3
A-ring precursor starting with
5-tert-butyldimethylsiloxy-2-cyclohexenone
Georges P. J. Hareau, Masakazu Koiwa and Fumie Sato ∗
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received 13 December 1999; revised 17 January 2000; accepted 21 January 2000
Abstract
The A-ring precursor of 1α,25-dihydroxyvitamin D3 [(E)-4] has been prepared starting from the (5S)-tert-
butyldimethylsiloxy-2-cyclohexenone [(S)-1] via eight steps in 19% overall yield, where a catalytic osmium
dihydroxylation which sets the stereochemistry of the hydroxyl group at C1 and a regioselective protection of
the hydroxy group as a TBS-ether are the key steps. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; hydroxylation; selective protection; vitamins.
The optically active 5-tert-butyldimethylsiloxy-2-cyclohexenone [(R)- and (S)-1], prepared in our
laboratory, has proved to be an efficient chiral building block in the synthesis of natural products.1
We have recently reported an enantioselective synthesis of palitantin where an impressive, highly
diastereoselective cat. OsO4–NMO dihydroxylation of 1 was the key step.1d With these results in hand,
we became interested in the A-ring precursor of 1α,25-dihydroxyvitamin D3 which appeared to be
an attractive target for the further utilization of 1, together with its diastereoselective dihydroxylation
reaction.
1α,25-Dihydroxyvitamin D3 [1,25-(OH)2-VD3], which plays an important role in human physiology,
has attracted substantial interest in its pharmacology and therapeutic potential. The chemical synthesis
of 1,25-(OH)2-VD3 and its analogues, therefore, has been the subject of much research over a period
of 15 years because organic synthesis is the only means to supply sufficient quantities and to create
more effective compounds.2 One of the most useful methods for producing 1,25-(OH)2-VD3 and its
various analogues employs a Horner–Wittig olefination between the (Z)-allylic phosphine oxide 2 (A-ring
portion) and the bicyclic ketone 3 (C,D-ring portion) as shown in Scheme 1. The Hoffmann–La Roche
group prepared 2 starting from carvone via α,β-unsaturated ester (E)-4 which, in turn, was converted
∗
Corresponding author. Tel: +81 45 924 5787; fax: +81 45 924 5826; e-mail: fsato@bio.titech.ac.jp (F. Sato)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00169-6
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into (Z)-4 by photoisomerization and then to the allylic chloride 5.3 This synthetic method remains one
of the most efficient syntheses of 2, and further effort has been devoted to the synthesis of 4.4
Scheme 1. The Hoffmann–La Roche protocol for synthesis of 1,25-(OH)2-VD3 from carvone
Here we report the synthesis of (E)-4 from (S)-1 according to the retrosynthetic approach illustrated in
Scheme 2. We anticipated that a 1,2-addition of the enolate of acetate on 6, prepared by a stereoselective
dihydroxylation of 1, and the following regioselective monoprotection of the less embedded hydroxy
group and oxidation of the remaining secondary alcohol might afford the ketone 9. The conversion of 9
to (E)-4 was expected to be carried out by a Wittig-type methylenation and the following β-elimination
of the protected tertiary alcohol.
Scheme 2. Retrosynthetic analysis of (E)-4 from (S)-1
As previously reported, the dihydroxylation of (S)-1 with catalytic osmium tetroxide–NMO gave 6
exclusively in 80% yield1d (Scheme 3). The compound 6 was subjected to the Reformatsky reaction
(Zn/BrCH2CO2tert-Bu) to give the 1,2-addition product 7 very efficiently when trimethyl borate–THF
was used as the solvent.5 Under these conditions, 7 was obtained in 91% yield in which one diastereomer
was produced highly predominantly. The treatment of 7 with TBSCl/imidazole at rt yielded, to our
satisfaction, the exclusive monoprotected bis-TBS-ether 8 quantitatively. Regiospecific oxidation of the
secondary alcohol under the Swern conditions using 1.1 equiv. of oxalylchloride gave the ketone 9
in 94% yield.6 The methylenation reaction of 9, according to the Nozaki protocol7 using the ‘aged’
Zn–CH2Br2–TiCl4 reagent,7b afforded the expected product 10 in 37% yield (checked by NMR) which
contained an unseparable by-product in 7% yield, which, presumably, was produced by the conversion
of the tertiary OH group of 9 to H. Other methylenation conditions (olefination using Cp2TiCH2, or
PPh3CH2, or Peterson methylenation) did not afford good results.8

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Scheme 3. Reagents and conditions: (a) OsO4 (5 mol%)–NMO (2.5 equiv.), acetone–water, rt, 24 h; (b) Zn (5 equiv.),
BrCH2CO2t-Bu (4 equiv.), (MeO)3B–THF, rt→reflux→rt; (c) TBSCl (1.2 equiv.), imidazole, DMF, rt, 12 h; (d) Swern oxidation
[oxalylchloride (1.1 equiv.)]; (e) ‘aged’ Zn–CH2Br–TiCl4 (4 equiv.), THF, rt, 4 h; (f) Ac2O, Sc(OTf)3 (10 mol%); (g) Pd(PPh)4
(20 mol%), Et2NH (10 equiv.), THF, rt, 15 h; (h) (1) TMSOTf (30 equiv.), 2,6-lutidine (40 equiv.), THF, reflux, 2 h; (2) EtI (3
equiv.), K2CO3 (4 equiv.), DMF, rt, 1 h
Protection of the tertiary alcohol moiety of 10 as acetate (in neat acetic anhydride for 12 h at rt in
the presence of 10 mol% amounts of Sc(OTf)3)9 and the separation of the aforementioned by-product
by column chromatography afforded pure 11 in 90% yield (based on 10, and thus, 33% yield from
9). The β-elimination of 11 yielding 12 was found to be troublesome and, unexpectedly, that became
the major problem to be resolved for the completion of the synthesis. Standard procedures (DBU, p-
TSA) met with utter failure, presumably due to conformational reasons; under these conditions, the
target compound could not be detected despite variations of the solvent, temperature and/or reaction
time which resulted in the clean recovery of the starting material or in its decomposition when conditions
that were too harsh were used. After numerous unfruitful attempts, such as the β-elimination of 11 under
basic conditions using MeONa, DMAP, LDA, KHMDS/toluene (the last yielded the corresponding spiro-
Robinson annelation product cleanly), or under acidic conditions using PPTS, CSA or Lewis acids (all
recovered the starting material), we finally found that the conversion of 11 to (E)-12 was effectively
achieved by treatment with Et2NH in the presence of a catalytic amount of Pd(PPh3)4 in THF (rt, 15 h)
which yielded, after hydrolysis, the desired α,β-unsaturated ester (E)-12 in 90% isolated yield.10 Finally,
in order to reach the known (E)-4, we saponified (E)-12 by treatment with TMS–triflate11 and reacted
the corresponding carboxylic acid with ethyl iodide; thus, the target (E)-4 was obtained in 95% yield and
showed identical physical and spectroscopic data to those previously reported.4
Acknowledgements
G.H. thanks the Japan Society for the Promotion of Science for financial support.
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ester series, but in the methylenation step, the corresponding 10 further reacted with the Lombardo reagent at the ethyl ester
functionality, thus producing the methyl ketone 10 (Σ=COMe) in a somehow uncontrollable yield; we then switched to the
tert-butyl ester series where the formation of the methyl ketone has not been observed.
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