Enantioselective syntheses of key a-ring precursors of 1α, 25- dihydroxyvitamin D3 and analogues

Article abstract of DOI:10.1055/s-1999-2842

A practical synthesis of (3S, 5R) oct-1-en-7-yne-3,5-diol derivatives 7 involving a catalytic enantioselective aldol reaction is described. Also a new synthesis of (3S, 5R) non-1-en-7-yne-3,5,9-triol derivatives 3, starting from (2S, 4S)-1,2:4,5-diepoxy-p

Full text of DOI:10.1055/s-1999-2842

LETTER
1435
Enantioselective Syntheses of Key A-ring Precursors of 1a, 25-
Dihydroxyvitamin D3 and Analogues
Sofia Anné, Wu Yong, Maurits Vandewalle*
University of Gent, Department of Organic Chemistry, Laboratory for Organic Synthesis, Krijgslaan, 281 (S.4), B-9000 GENT (Belgium)
Received 11 June 1999
Abstract: A practical synthesis of (3S, 5R) oct-1-en-7-yne-3,5-diol
derivatives 7 involving a catalytic enantioselective aldol reaction is
described. Also a new synthesis of (3S, 5R) non-1-en-7-yne-3,5,9-
triol derivatives 3, starting from (2S, 4S)-1,2:4,5-diepoxy-pentane 2
is reported.
Key words: 1a,25-dihydroxyvitamin D3, catalytic enantioselective
aldol, 1,3-anti-diol, Pummerer reaction, Tebbe reaction.
It is presently well established that the hormonally active
form of vitamin D3, 1a,25-dihydroxyvitamin D3 (1;
1a,25(OH)2D3) may generate biological responses via
regulation of gene transcription.1 The discovery of the
presence of specific vitamin D receptors in more than 30
tissues initiated consideration of possible functions of
1a,25(OH)2D3 (1) outside its classical role in calcium-
bone homeostasis. The hormone was found to be capable
of regulating cell proliferation and differentiation of a va-
riety of immunological and malignant cells. In view of
this extraordinary flexibility, current research is aimed at
the synthesis of analogues with superagonistic potency
and especially with dissociation of effect on cell differen-
tiation compared with their calcemic effects.1,2
A convergent modular synthesis of analogues, modified in
the C/D ring or side chain (S) fragments, involves cou-
pling of an A-ring precursor with a suitable C/D S moiety
(Scheme 1).3 An effective method is based on Lythgoe’s
classical synthesis4 of vitamin D consisting of reaction of
4 with Windaus-Grundman ketone derivatives 8.
Since Uskokovic’s5 synthesis, a number of other ap-
proaches of phosphine oxide 4a have emerged.6 Most of
the novel syntheses of 4 are of the convergent type and in-
volve ring closure of an acyclic precursor possessing the
a R=R’=TBS; b R=TBS, R’=TBDPS; c R=R’=MEM; d R=R’=TBD-
PS; S=side chain
1,3-anti-diol unit.
A conceptually new construction of the vitamin D skele-
Scheme 1
ton has been developed by Trost et al.7 employing Pd-cat-
alyzed enyne cyclization of 7a and vinylic bromide 9. A-
ring precursor 7a was constructed in 8 steps (96% ee, 78%
de) and involved asymmetric hydrogenation of ethyl 4-
We presently want to report a synthesis of 7c via a catalyt-
chloroacetoacetate.8 Moriarty et al 9. described a diastere-
ic asymmetric aldol reaction together with an alternative
oselective synthesis of 7c from D-xylose in 13 steps. We
reported a 7 step synthesis of 7b via lipase-catalyzed ki-
synthesis of 3d starting from bis-epoxide 2.10
netic resolution of t-butyl 3-hydroxy-4-pentenoate (99% The catalytic enantioselective aldol reaction of O-TMS
ee, 30% de) and also its subsequent transformation into 4b dienolate 511 with acrolein using Carreira’s Ti(IV) cata-
via 3b.6d
lyst 1012 afforded the adduct 6 with 97.5 % ee13,14
(Scheme 2). Cleavage of the dioxolin ring in 6 upon trans-
esterification with n-BuOH led to ester 12. The proof of
the absolute configuration of 12 will be provided by the
Synlett 1999, No. 9, 1435–1437 ISSN 0936-5214 © Thieme Stuttgart · New York

1436
S. Anné et al.
LETTER
eventual synthesis of the known 7c with reported [a]D val- Pummerer19 rearrangement. Classical conditions
ue.9 Reduction of 12 using the Evans conditions15 provid- (K2CO3,MeOH) gave epimerisation of the resulting a-si-
ed the anti-diol 13 in 8:1 diastereoselectivity; the anti and lyloxy aldehyde, on the other hand Dibal-H reduction20 at
syn isomers could by separated by preparative HPLC. –78 °C led cleanly to the expected product 22. As Wittig
Protection of the hydroxy groups as MEM-ethers and sub- reaction on 22 failed, methylenation was performed with
sequent DIBAL-H reduction of 14 provided aldehyde 15. the Tebbe21 reagent. Finally deprotection of the primary
Finally
Seyferth’s
method16
using
dimethyl hydroxy function in 23 led to intermediate 3d which can
diazomethylphosphonate17 smoothly converted 15 into 7c be transformed into phosphine oxide 4d5 as described by
with [a]D = -66.0 ( c 1.02, CHCl3); lit9 = -60.0 (c 0.57, us6d (for 4b) and others6h (for 4a). The yields given in
CHCl3).
20
Scheme 3 have not been optimized.
a: n-BuLi, BF3.OEt2, THF, -78 °C, 1.5h; b: PhSH, NaOH (1N), dioxa-
ne, D, 3h; c: TBDPSCl, imidazole, CH2Cl2, Et2O, DMAP, 0 °C to rt.,
overnight; d: mCPBA, CH2Cl2, rt., 7h; e: NaOAc, Ac2O, reflux, 11h;
f: DIBAL-H, toluene, -78 °C, 1h; g: Tebbe reagent, THF, 0 °C, 30
min.; h: DDQ, CH2Cl2/H2O (18:1), rt., 3h
Scheme 3
Evaluating both approaches, the first one (Scheme 2) is
largely preferred due to the efficiency of the initiating cat-
alytic step. The only drawback is the low yield of 5. From
5 the 6-steps give an overall yield of 35% with 97.5% ee
and 78% de. Obviously, in the future the more classical
protection as TBS ethers ( compare 14) will be peferred.
a: LDA, THF, Me3SiCl, -78 °C, 4h.; b: (i) 10 (2 mmol), CH2=CH-
CHO, Et2O, 0 °C, 5.5h (ii) 10% TFA in THF, 24h; c: n-BuOH, 96 °C,
7h; d: Me4NHB(OAc)3, AcOH-MeCN, 1:1, 0 °C, 2h; e: MEMCl, (i-
Pr)2EtN, 24 h; f: DIBAL-H, CH2Cl2, -78 °C, 1.5 h; g:
(MeO)2P(O)CHN2, t-BuOK, THF, -78 °C to -30 °C, 3h.
Scheme 2
For the alternative synthesis of 3d6d (vide supra) and
hence 4d, (2S,4S)-1,2,4,5,-diepoxyenpentane 2, devel-
oped by Rychnovsky et al.10, was chosen as the chiral
Acknowledgement
We thank the “FWO” the “ Ministerie voor Wetenschapsbeleid”
and Théramex S.A. for financial support to the laboratory and Prof.
template. We have already used 2 for the construction of Carreira for providing us with a sample of catalyst 10 and details for
a novel 19-nor A-ring precursors18.
its synthesis. We also thank Dr. Carl T. Wigal for sending us details
for the preparation of compound 5.
Reaction of diepoxide 2 with the lithiated alkyne 16 al-
lowed stepwise manipulation of both epoxy functions
References and Notes
(Scheme 3). Subsequent to mono-alkynylation, the epoxy
group in 17 was opened by the phenylthiolate anion. Pro-
tection of the hydroxy functions in 18 and subsequent ox-
idation afforded sulfoxide 20, which was submitted, to a
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Synlett 1999, No. 9, 1435–1437 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Key A-ring Precursors of 1a, 25-Dihydroxyvitamin D3
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Synlett 1999, No. 9, 1435–1437 ISSN 0936-5214 © Thieme Stuttgart · New York