Furan approach to the synthesis of the A-ring of Vitamin D analogues

Article abstract of DOI:10.1016/S0040-4039(02)02824-1

The efficient transformation of 2,3-disubstituted furan (3) into (Z)-dienol (2) illustrates a useful strategy for the synthesis of the A-ring of Vitamin D analogues.

Full text of DOI:10.1016/S0040-4039(02)02824-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1161–1163
Furan approach to the synthesis of the A-ring of Vitamin D
analogues
William H. Miles* and Katelyn B. Connell
Department of Chemistry, Lafayette College, Easton, PA 18042, USA
Received 27 November 2002; revised 13 December 2002; accepted 13 December 2002
Dedicated to Professor Charles P. Casey on the occasion of his 60th birthday
Abstract—The efficient transformation of 2,3-disubstituted furan (3) into (Z)-dienol (2) illustrates a useful strategy for the
synthesis of the A-ring of Vitamin D analogues. © 2003 Elsevier Science Ltd. All rights reserved.
Calcitriol (1a), the active metabolite of Vitamin D3 (1b),
has an extraordinary range of biological activity,
including inhibition of tumor cell proliferation.1 The
clinical utility of 1a, however, is restricted due to dose-
limiting hypercalcemia. In an effort to reduce cal-
cemetic effects and improve desired therapeutic activity,
hundreds of analogues of Vitamin D3 have been pre-
pared.2,3 One of the most successful synthetic strategies
for the synthesis of Vitamin D3 analogues, initially
developed by Lythgoe,4 has been based on the coupling
of A-ring phosphine oxides with C, D-ring ketones
(Fig. 1). The Hoffmann–La Roche chemists used this
strategy for the synthesis of 1a.5 The continued interest
in the synthesis of analogues and labeled com-
pounds for biological studies has stimulated efforts
to develop new synthetic methods and strategies in
this field.6–8 This paper describes a new synthetic
approach to the A-ring of Vitamin D3 based on furan
chemistry.
The diverse chemistry of the furan ring is the focal
point of many syntheses.9 The oxidation of the furan
ring, for example, has been exploited in the synthesis of
macrolides10 and carbohydrates.11 Previous work by
Jennings12 has demonstrated the facile peracid oxida-
tion of a 2,3-disubstituted annulated furan to the corre-
sponding unsaturated 1,4-dicarbonyl compound. We
reasoned that the selective reduction of the aldehyde
and the methylenation of the ketone would provide the
desired (Z)-dienol moiety of the A-ring of Vitamin D3
compounds. Since most Vitamin D3 analogues have a
stereogenic center at C-1, typically a hydroxyl group,
we chose as our first synthetic target (Z)-dienol 2 (Fig.
2).13,14 The furan precursor 3 required for this synthetic
Figure 1.
* Corresponding author. Tel.: 610-330-5221; fax: 610-330-5714; e-mail: milesw@lafayette.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02824-1

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W. H. Miles, K. B. Connell / Tetrahedron Letters 44 (2003) 1161–1163
acrolein gave furanyl aldehyde 4 (80% yield), which
cyclized with TBSOTf in a Friedel–Crafts alkyation
reaction to give rac-3 in 71% yield (Scheme 1). There is
some precedent for Friedel–Crafts cyclization reactions
of aldehydes to give a-hydroxy/alkoxy products,17,18
but usually there are further Friedel–Crafts reactions of
the initial product.19 The ready access to racemic mate-
rial facilitated our initial oxidation studies, but the
synthesis of non-racemic 3 was necessary for testing the
durability of the C-1 chiral center during our synthetic
protocol. Furanyl ketone 5,20 available from either the
condensation of 1,2-cyclohexadione with chloro-
acetaldehyde15 or in three steps from 3-methylene-2,3-
dihydrofuran and ethyl acrylate,16 was reduced using
Figure 2.
Noyori’s
ruthenium(II)
asymmetric
transfer
hydrogenation21 to give alcohol 6 in 91% yield and 96%
ee. The assignment of the stereochemistry as S was
1
determined by H NMR studies of the corresponding
Mosher ester of 6 and is consistent with the previous
sense of stereochemistry found in the reduction of other
aromatic ketones.21 Conversion of alcohol 6 into the
corresponding silyl ether 3 using standard procedures
proceeded in 81% yield.
Scheme 1. Reagents and conditions: (a) CH2Cl2, 40°C, 20 h;
(b) TBSOTf, 2,6-lutidine, 0°C, 1 h; (c) (R)-RuCl[(1S,2S)-p-
TsNCH(C6H5)CH(C6H5)NH2](h6-p-cymene) (0.5 mol%),
HCO2H/NEt3, 6 days; (d) TBSCl, imidazole, 16 h.
The oxidation of 3 with MCPBA gave the desired acid-
and base-sensitive unsaturated 1,4-dicarbonyl com-
pound 7 in moderate yields along with several other
products (Scheme 2). When the reaction was buffered
with NaOAc, the product distribution changed dramat-
ically, giving g-hydroxybutenolide 8 as the sole product.
The separation of 8 and m-chlorobenzoic acid was
difficult, so the preferred oxidation conditions employ
peracetic acid buffered with NaOAc (87% yield). The
clean oxidation of 3 to 8 was not unwelcome; Sato has
recently demonstrated that the ethyl ester of a similar
g-hydroxybutenolide could be converted into the
desired (Z)-dienol moiety.8 The methylenation of 8 or
its ethyl ester with Tebbe’s reagent, however, gave low
yields of the desired alkene, so we developed an alterna-
target has been previously prepared in racemic form,15
and we envisioned a simple modification of the litera-
ture procedure for the asymmetric synthesis of 3. This
paper describes our preliminary results for the conver-
sion of non-racemic furan 3 into 2.
The synthesis of racemic TBS-protected 3 in three steps
from 1,2-cyclohexadione has been previously reported
in the literature.15 We developed an alternative two-step
procedure starting with 3-methylene-2,3-dihydrofuran,
an exceptionally reactive ene in the ene reaction.16 The
ene reaction of 3-methylene-2,3-dihydrofuran with
Scheme 2. Reagents and conditions: (a) m-ClC6H5CO3H, 2 h; (b) CH3CO3H (2.1 equiv.), NaOAc, CH2Cl2, 6.5 h; (c) CeCl3 (3
equiv.), LiCH2SiMe3 (2.4 equiv.), −78°C (1 h) to −42°C (1 h); (d) DIBAL, −78 to −42°C, 1 h; CH3OH, NaBH4, 16 h; (e) aq. HF,
CH3CN, 12 min.

W. H. Miles, K. B. Connell / Tetrahedron Letters 44 (2003) 1161–1163
1163
tive strategy based on the Peterson olefination.22,23 The
reaction of LiCH2SiMe3/CeCl3 with 8 gave lactone 9
6. Daniewski, A. R.; Garofalo, L. M.; Hutchings, S. D.;
Kabat, M. M.; Liu, W.; Okabe, M.; Radinov, R.; Yian-
nikouros, G. P. J. Org. Chem. 2002, 67, 1580–1587.
7. Hiyamizu, H.; Ooi, H.; Inomoto, Y.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2001, 3, 473–
475.
8. Koiwa, M.; Hareau, G. P. J.; Sato, F. Tetrahedron Lett.
2000, 41, 2389–2390.
9. Lipshutz, B. H. Chem. Rev. 1986, 86, 795–819.
10. Martin, S. F.; Lee, W.; Pacofsky, G. J.; Gist, R. P.;
Mulhern, T. A. J. Am. Chem. Soc. 1994, 116, 4674–4688.
11. Martin, S. F.; Zinke, P. W. J. Org. Chem. 1991, 56,
6600–6606.
24
as a single diastereomer (76% yield), with the carboxylic
acid/alcohol precursor as an observable intermediate.
Lactone 9 was reduced to diol 10 in two steps (89%
yield). When LiAlH4 was used for the reduction of 9,
there was significant cleavage of the TBS ether. Brief
treatment of diol 10 with aqueous HF in acetonitrile
gave the desired (Z)-dienol 2 in 68% yield and 96% ee.
The conversion of furan 3 into (Z)-dienol 2 in 40%
overall yield without racemization of the stereogenic
center demonstrates the viability of the furan approach
for the synthesis of the A-ring of Vitamin D3 com-
pounds. The (Z)-stereochemistry is inherent in the
furan precursor, so no photochemical isomerization
step is necessary, unlike many other syntheses of A-ring
precursors. We are exploring the applicability of this
approach for the synthesis of the A-ring precursors of
both 1a and 1b using the asymmetric carbonyl-ene
reaction of 3-methylene-2,3-dihydrofuran for the for-
mation of the C-3 stereogenic center.25 These results
will be reported in due course.
12. Manfredi, K. P.; Jennings, P. W. J. Org. Chem. 1989, 54,
5186–5188.
13. For a previous synthesis of 2, see: Uskokovic´, M. R.;
Baggiolini, E.; Shiuey, S.; Iacobelli, J.; Hennessy, B. In
Vitamin D: Gene Regulation, Structure Function Analysis
and Clinical Application; Norman, A. W.; Bouillon, R.;
Thomasset, M., Eds.; Walter de Gruyter and Co: Berlin,
1991; p. 139.
14. For a previous synthesis of rac-2, see: Mascaren˜as, J. L.;
Garc´ıa, A. M.; Castedo, L.; Mourin˜o, A. Tetrahedron
Lett. 1992, 33, 4365–4368.
15. Seki, M.; Sakamoto, T.; Suemune, H.; Kanematsu, K. J.
Chem. Soc., Perkin Trans. 1 1997, 1707–1714.
16. Miles, W. H.; Berreth, C. L.; Smiley, P. M. Tetrahedron
Lett. 1993, 34, 5221–5222.
Acknowledgements
17. The Friedel–Crafts alkylation of phenols with aldehydes
and the reaction of electron-rich aromatic compounds
with electron-deficient aldehydes are the most notable
exceptions. See (a) Casiraghi, G.; Cornia, M.; Rassu, G.
J. Org. Chem. 1988, 53, 4919–4922; (b) Ishii, A.;
Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65,
1597–1599.
We would like to thank the Lafayette Committee on
Academic Research for support of K.B.C. in the form
of a summer stipend. We gratefully acknowledge a
grant from the Kresge Foundation for the purchase of
a JEOL Eclipse+400 NMR spectrometer.
18. Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120,
9074–9075.
19. Roberts, R. M.; El-Khawaga, A. M.; Sweeney, K. M.;
El-Zohry, M. F. J. Org. Chem. 1987, 52, 1591–1599.
20. Walsh, E. J., Jr.; Stone, G. B. Tetrahedron Lett. 1986, 27,
1127–1130.
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