1178
A. Yoshida et al.
LETTER
OP'
sepn.
OH
H
H
O
OMOM
LiN(TMS)2
H
by HPLC
H
H
+
2β-3a–c
+
6
TBSO
OTBS
H
R
ArO2S
5
2
PO
OP
HO
OH
6a–c
4
R
R
2α-3a–c
a: R = CH2CH=CH2
17a–c: P = TBS, P' = MOM
3a–c: P = P' = H
CSA
CH2CH2CH3
CH2CH2CH2OH (3c), CH2CH2CH2OTBS (6c)
b:
c:
(2 steps, ~51%)
Scheme 4 Synthesis of 2-alkylated 19-norvitamin D3 analogues through Julia-type coupling
the b-orientation (aR-configuration) directed to equatori- Acknowledgment
al, which is thermodynamically more stable for the A-ring
We thank Ms. Junko Shimode and Ms. Maroka Kitsukawa (Teikyo
University) for spectroscopic measurements. This study was sup-
ported by a Grant-in-Aid from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
than the occupation of axial position of the C2-allyl group.
Observations of NOE between H4b–H6 and the small cou-
pling constants between H2a–H3a (6.3 Hz) and H3a–H4b
(3.0 Hz) support the above stereochemistry and conforma-
tional analysis. For the other isomer, its NOE between
H4a–H6 and coupling constants of H3a–H4b (9.6 Hz) and
H1b–H10a (4.1 Hz) as shown in Figure 4 for 2a-3a prove
that it has the 2a-allyl group (aS-configuration) at the
equatorial position in the chair-like a-form.
References
(1) New address: A. Yoshida, The Noguchi Institute and Japan
Chemical Innovation Institute (JCII), Itabashi-ku, Tokyo
173-0003, Japan. Y. Suhara, Kobe Pharmaceutical
University, Higashinada-ku, Kobe 658-8558, Japan
(2) Vitamin D; Feldman, D.; Glorieux, F. H.; Pike, J. W., Eds.;
Academic Press: New York, 1997.
(3) (a) Umesono, K.; Murakami, K. K.; Thompson, C. C.;
Evans, R. M. Cell 1991, 65, 1255. (b) Evans, R. M. Science
1988, 240, 889.
In summary, we have established the short-step synthesis
of several 2a- and 2b-alkylated 1a,25-dihydroxy-19-nor-
vitamin D3 in overall 17% yield. Efficacy of this route is
very high if compared with the reported overall yield
(0.3%) for synthesis of similar analogues.6d,13 This con-
vergent coupling strategy should be much more effective
than the classical standard route. Testing of biological ac-
tivities of these novel six analogues is now under way.
(4) (a) For 2-methyl series: Konno, K.; Fujishima, T.; Maki, S.;
Liu, Z.-P.; Miura, D.; Chokki, M.; Ishizuka, S.; Yamaguchi,
K.; Kan, Y.; Kurihara, M.; Miyata, N.; Smith, C.; DeLuca,
F. H.; Takayama, H. J. Med. Chem. 2000, 43, 4247. (b) For
2a-alkyl and 2a-(w-hydroxyalkyl) series: Suhara, Y.; Nihei,
K.; Kurihara, M.; Kittaka, A.; Yamaguchi, K.; Fujishima, T.;
Konno, K.; Miyata, N.; Takayama, H. J. Org. Chem. 2001,
66, 8760. (c) For 2a-(w-hydroxyalkoxy) series: Kittaka, A.;
Suhara, Y.; Takayanagi, H.; Fujishima, T.; Kurihara, M.;
Takayama, H. Org. Lett. 2000, 2, 2619.
(5) For our account: Takayama, H.; Kittaka, A.; Fujishima, T.;
Suhara, Y. J. Synth. Org. Chem., Jpn. 2002, 60, 370.
(6) (a) Perlman, K. L.; Swenson, R. E.; Paaren, H. E.; Schnoes,
H. K.; DeLuca, H. F. Tetrahedron Lett. 1991, 32, 7663.
(b) Sicinski, R. R.; Perlman, K. L.; DeLuca, H. F. J. Med.
Chem. 1994, 37, 3730. (c) Sicinski, R. R.; Prahl, J. M.;
Smith, C. M.; DeLuca, H. F. J. Med. Chem. 1998, 41, 4662.
(d) Sicinski, R. R.; Rotkiewicz, P.; Kolinski, A.; Sicinska,
W.; Prahl, J. M.; Smith, C. M.; DeLuca, H. F. J. Med. Chem.
2002, 45, 3366. (e) Huang, P.-q.; Sabbe, K.; Pottie, M.;
Vandewalle, M. Tetrahedron Lett. 1995, 36, 8299.
(f) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681.
(g) Hanazawa, T.; Inamori, H.; Masuda, T.; Okamoto, S.;
Sato, F. Org. Lett. 2001, 3, 2205. (h) Wu, Y.; Zhao, Y.;
Tian, H.; De Clercq, P.; Vandewalle, M.; Berthier, M.;
Pellegrino, G.; Maillos, P.; Pascal, J.-C. Eur. J. Org. Chem.
2001, 3779. (i) Okano, T.; Nakagawa, K.; Kubodera, N.;
Ozono, K.; Isaka, A.; Osawa, A.; Terada, M.; Mikami, K.
NOE
5.3%
OH
NOE
1.7%
H
H
6
H
4
H
H
10
J = 3.0 Hz
H
H
10.3 Hz (axial-axial coupling)
1
H
OH
2
3
HO
H
J = 10.3 Hz (axial-axial coupling)
J = 6.3 Hz
(aR)-2β-3a
NOE
7.1%
NOE
4.6%
H
J = 9.6 Hz
H
6
(axial-axial coupling)
H
H
3
OH
OH
HO
4
1
H
2
H 10
H
H
H
J = 4.1 Hz
(aS)-2α-3a
Figure 4 Stereochemical assignment of axial chirality in 3a
Synlett 2003, No. 8, 1175–1179 ISSN 1234-567-89 © Thieme Stuttgart · New York