A Concise Enantioselective Synthesis of a Key A-Ring Synthon for 1α-Hydroxyvitamin D3 Compounds

Article abstract of DOI:10.1021/ol006982u

(Matrix Presented) This report describes a concise enantioselective synthesis of the A-ring synthon for the synthesis of 1α-hydroxyvitamin D₃ compounds. The synthesis involves two notable transformations: (i) stereoselective construction of the

Full text of DOI:10.1021/ol006982u

ORGANIC
LETTERS
2001
Vol. 3, No. 3
473-475
A Concise Enantioselective Synthesis of
a Key A-Ring Synthon for
1r-Hydroxyvitamin D Compounds
3
Hiroko Hiyamizu, Hidenori Ooi, Yoko Inomoto, Tomoyuki Esumi,
Yoshiharu Iwabuchi, and Susumi Hatakeyama*
Faculty of Pharmaceutical Sciences, Nagasaki UniVersity, Nagasaki 852, Japan
susumi@net.nagasaki-u.ac.jp
Received December 8, 2000
ABSTRACT
This report describes a concise enantioselective synthesis of the A-ring synthon for the synthesis of 1r-hydroxyvitamin D compounds. The
3
synthesis involves two notable transformations: (i) stereoselective construction of the enol triflate from the vinyl ketone by Michael addition
of Ph2P(O)Li followed by in situ triflation of the resulting enolate and (ii) palladium-catalyzed Heck type cyclization of the enol triflate.
1R,25-Dihydroxyvitamin D3 (1), the hormonally active form
of vitamin D3, plays an important role in the modulation of
cell proliferation and cell differentiation as well as in the
maintenance of calcium homeostasis via regulation of gene
transcription. In view of its intriguing biological function
and growing potential therapeutic applications, current
research has focused on the synthesis of analogues having
separated and specific biological activities for developing
drugs for osteoporosis, cancer, psoriasis, and so on.1 For the
synthesis of analogues bearing a modified C/D-ring part, one
A-ring synthon 2 based on a new strategy, which centers
around an unprecedented palladium-catalyzed intramolecular
Heck reaction5,6 of triflate 7.
We envisaged that Michael addition of metalated diphen-
ylphosphine oxide 5 to vinyl ketone 4, followed by triflation,
would allow stereoselective formation of enol triflate 7 via
chelated intermediate 6. It was anticipated that palladium-
of the most useful approaches is the Hoffmann La Roche
route2 via coupling of A-ring synthon 2 and the correspond-
ing C/D-ring ketone 3, based on Lythgoe’s methodology.3
We now wish to report a short and efficient synthesis4 of
(1) (a) Vitamin D; Feldman, D., Glorieux, F. H., Pike, J. W., Eds.;
Academic Press: New York, 1997. (b) Bouillon, R.; Okamura, W. H.;
Norman, A. W. Endocr. ReV. 1995, 16, 200.
(2) Baggiolini, E. G.; Iacobelli, J. A.; Hennessy, B. M.; Uskokovic, M.
R. J. Am. Chem. Soc. 1982, 104, 2945.
(3) For a review, see: Zhu, G. D.; Okamura, W. H. Chem. ReV. 1995,
95, 1877.
(4) For recent reports, see: (a) Koiwa, M.; Hareau, G. P. J.; Sato, F.
Tetrahedron Lett. 2000, 41, 2389. (b) Hareau, G. P. J.; Koiwa, M.; Sato, F.
Tetrahedron Lett. 2000, 41, 2385. (c) Anne´, S.; Yong, W.; Vandewalle,
M. Synlett 1999, 1435. (d) Mourin˜o, A.; Torneiro, M.; Vitale, C.; Fernandez,
S.; Pe`rez-Sestlo, J.; Anne´, S.; Gregorio, C. Tetrahedron, Lett. 1997, 38,
4713. (e) Yokoyama, H.; Miyamoto, K.; Hirai, Y.; Takahashi, T. Synlett
1997, 187. (f) Achmatowicz, B.; Jankowski, P.; Wicha, J. Tetrahedron Lett.
1996, 37, 5589. (g) Vrielyneck, S.; Vandewalle, M.; Garcia, A. Mascaren˜as,
J.; Mourin˜o, A. Tetrahedron Lett. 1995, 36, 9023.
(5) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic:
New York, 1985.
10.1021/ol006982u CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/12/2001

catalyzed Heck type cyclization of 7 would produce A-ring
synthon 2 stereoselectively (Scheme 1).
The Michael addition-triflation process was surveyed
using Ph2P(O)Li,11 Ph2P(O)Na, and Ph2P(O)K as a metalated
diphenylphosphine oxide and 2-[N,N-bis(trifluoromethylsul-
fonyl)amino]-5-chloropyridine12 as a triflating agent. The
results are summarized in Table 1. To our delight, we found
Scheme 1
Table 1. Preparation of Enol Triflate 7 from Vinyl Ketone 4a
isolated yield (%)
entry
phosphorus reagentb
7 (E:Z)c
13
1
2
3
4
5
Ph2P(O)Li
89 (0:100)
71 (0:100)
7 (0:100)
3 (8:92)
7
12
13
13
28
Ph2P(O)Li (HMPA)d
Ph2P(O)Na
Ph2P(O)K
The required vinyl ketone 4 was prepared from known
S-dioxinone 9 (97% ee), easily available4c,7 from 2,2,6-
trimethyl-4H-1,3-dioxi-4-one (8), as depicted in Scheme 2.
Ph2PLi
64 (0:100)
aAfter reaction of 4 and Ph2P(O)M or Ph2PLi (1.2 equiv) in THF at
-78 °C for 30 min, the reaction mixture was treated with the triflating
reagent (1.6 equiv) and stirred at -78 °C for 20 h. b Prepared from
Ph2P(O)H or Ph2PH (1.2 equiv) using n-BuLi, NaH, or KH (1.2 equiv) as
a base in THF at 0 °C for 1 h. c Determined by 1H NMR analysis. d HMPA
(1.2 equiv) was added with the triflating reagent.
Scheme 2
that this process was realized very effectively using Ph2P-
(O)Li under the conditions listed in entry 1. Thus, upon
successive treatment with Ph2P(O)Li and the triflating agent
in THF at -78 °C, vinyl ketone 4 underwent stereoselective
Michael addition-triflation reaction to give enol triflate 7
in 89% yield together with untriflated ketone 13 (7% yield).
The corresponding E-isomer of 7 was not produced in this
case. This result strongly suggests the participation of
chelated intermediate 6 (M ) Li) in this process as we
expected. Addition of HMPA appeared to interfere with
triflation of the resulting lithium enolate to decrease the yield
of 7 although the combined yield of 7 and 13 was almost
same as that of entry 1 (entry 2). Both Ph2P(O)Na and Ph2P-
(O)K are ineffective in this transformation, producing 7 and
13 in poor combined yield in each case (entries 3 and 4).
Furthermore, it was also found that Michel addition of Ph2-
PLi13 to 4, followed by in situ triflation of the resulting
enolate, gave 7 in 64% yield along with 13 (28% yield) after
oxidative workup with aqueous H2O2 (entry 5). This process
again proceeded with complete Z-selectivity, suggesting
participation of enolate 14 stabilized by chelation. It is
important to note that ketone 13 could be converted to 7 in
60% yield by deprotonation with n-BuLi, followed by
triflation at -78 °C in THF. The perfect regio- and
stereoselectivity of this process can be explained by assuming
preferential deprotonation of Ha rather than Hb via chelation
Reaction of 9 with Cl2Al[N(OMe)Me],8,9 followed by reduc-
tion of the resulting 10 with Me4NB(OAc)3,10 gave anti-diol
11 in 94:6 diasteroselectivity. Diol 11 was then subjected to
silylation and Grignard reaction8 using vinylmagnesium
bromide to afford vinyl ketone 4 in 75% overall yield.
(6) For relevant intramolecular Heck reactions, see: refs 4d-g and (a)
Codesido, E. M.; Cid, M. M.; Castedo, L.; Mourin˜o, Granja, J. R.
Tetrahedron Lett. 2000, 41, 5861. (b) Higashi, T.; Miura, K.; Kikuchi, R.;
Shimada, K.; Hiyamizu, H.; Ooi, H.; Iwabuchi, Y.; Hatakeyama, S.;
Kubodera, N. Steroids 2000, 65, 281. (c) Hatakeyama, S.; Ikeda, T.;
Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Kawase, A.; Kubodera, N.
Bioorg. Med. Chem. Lett. 1997, 7, 2871. (d) Yokoyama, H.; Takahashi, T.
Tetrahedron Lett. 1997, 38, 595. (e) Hatakeyama, S.; Irie, H.; Shintani, T.;
Noguchi, Y. Yamada, H. Nishizawa, M. Tetrahedron 1994, 50, 13369. (f)
Takahashi, T.; Nakazawa, M. Synlett 1993, 37. (g) Mascaren˜as, J. L.; Garc´ıa,
A. M.; Castedo, L.; Mourin˜o, A. Tetrahedron Lett. 1992, 33, 4365.
(7) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
(8) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1991, 22, 3815.
(9) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685.
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988. 110, 3560.
(11) Edwards, M. L.; Stemerick, D. M.; Jarvi, E. T. Tetrahedron Lett.
1990, 31, 5571.
(12) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(13) Vedejs, E.; Fuch, P. L. J. Am. Chem. Soc. 1973, 95. 822.
474
Org. Lett., Vol. 3, No. 3, 2001

generating 6 (M ) Li) as depicted in 15. Interestingly, LDA
was not an effective base in this particular case.
yield. Finally, we also found that photochemical isomeriza-
tion15 of the cyclization product in the presence of 9-fluo-
renone using a medium-pressure mercury arc lamp resulted
in exclusive formation of the Z-isomer to furnish A-ring
synthon 2 in 95% yield (Scheme 3).
Scheme 3
With enol triflate 7 in hand, we then examined palladium-
catalyzed cyclization of 7 under various conditions (Table
2). As a result, Pd(OAc)2-Ph3P was eventually found to be
the catalyst of choice although some Z/E-isomerization
always occurred.14 Thus, upon treatment of 7 with a catalytic
amount of Pd(OAc)2-Ph3P (10 mol %) and Et3N in THF at
room temperature, cyclization took place very cleanly to give
an inseparable 86:14 mixture of 2 and its E-isomer in 94%
In conclusion, A-ring fragment 2 for the synthesis of 1R-
hydroxyvitamin D3 analogues was successfully synthesized
in nine steps from commercially available 8 in 23% overall
yield. The present work illustrates a new methodology of
potential value for the stereoselective preparation of various
functionalized allylphosphine oxides.
Table 2. Palladium Catalyzed Cyclization of Enol Triflate 7a
entry catalyst (10 mol %) solvent time (h) yield (%)b (E:Z)c
1
2
3
4
5
6
7
Pd(OAc)2-Ph3P
Pd(OAc)2-Ph3P
Pd(OAc)2-Ph3P
(Ph3P)4Pd
Pd2(dba)2‚CHCl3
PdCl2(CN)2
THF
20
16
21
13
8
94 (14:86)
79 (17:83)
20 (43:57)
34 (29:71)
55 (13:87)
0c
Supporting Information Available: Experimental
procedures and spectral data for all new compounds.
This material is available free of charge via Internet at
http://pubs.acs.org.
MeCN
DMSO
THF
THF
THF
17
20
OL006982U
PdCl2(PhCN)2
THF
0d
a Reactions were carried out using Et3N (1.2 equiv) as a base at room
(14) Compound 2 did not isomerize to the E-isomer at all under the
cyclization conditions.
(15) Wovkulich, P. M.; Barcelos, F. Batco, A. D.; Sereno, J. F.;
Baggiolini, E. G.; Hennessy, B. M.; Uskokovic, M. R. Tetrahedron 1984,
40, 2283.
temperature. b 7 could not be recovered unless otherwise noted. c Determined
1
by H NMR analysis. d 7 was recovered in 83% yield. e 7 was recovered
in 87% yield.
Org. Lett., Vol. 3, No. 3, 2001
475