Total synthesis of cis-solamin.

Article abstract of DOI:10.1021/ol0102803

[structure: see text] A convergent total synthesis of cis-solamin and its diastereomer was accomplished using VO(acac)2-catalyzed diastereoselective epoxidation followed by cyclization of bis-homoallylic alcohol as the key step. By comparison of the optic

Full text of DOI:10.1021/ol0102803

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1083-1085
Total Synthesis of cis-Solamin
Hidefumi Makabe,* Yasunao Hattori, Akira Tanaka,† and Takayuki Oritani‡
Graduate School of Agriculture, Sciences of Functional Foods, Integrated Department,
Shinshu UniVersity, 8304 Mimamiminowa Kamiina, Nagano 399-4598, Japan
makabeh@gipmc.shinshu-u.ac.jp
Received December 3, 2001 (Revised Manuscript Received February 18, 2002)
ABSTRACT
A convergent total synthesis of cis-solamin and its diastereomer was accomplished using VO(acac)2-catalyzed diastereoselective epoxidation
followed by cyclization of bis-homoallylic alcohol as the key step. By comparison of the optical rotation of two possible diastereomers, it is
suggested that the absolute configuration of natural cis-solamin is 1a.
The Annonaceous acetogenins, which are isolated from a
number of plants of Annonaceae, have attracted much
attention in recent years due to a wide variety of biological
activities, i.e., cytotoxic, antitumoral, antimalarial, immu-
nosuppressive, pesticidal, and antifeedant. So far, over 350
compounds have been isolated.1 Their unique structures are
characterized by one or more tetrahydrofuran rings, together
with a terminal γ-lactone moiety on a C-35 or C-37 carbon
chain.1 cis-Solamin (1, Figure 1) is a mono-tetrahydrofuran
acetogenin,2 isolated from Annona muricata in 1998.3 A
similar compound corresponding to the well-known solamin
(2)4 was synthesized by Keinan5a and Trost5b and by us.5c
The absolute configuration of natural 1 has not been reported.
However, because the cis-threo-cis stereochemistry of the
tetrahydrofuran ring of 1 has been determined by A. Laurens
et al.,3 and the (S) configuration of the secondary methyl
group of the γ-lactone moiety is well-known, it follows that
the absolute stereochemistry of 1 is (15R,16R,19S,20S) or
(15S,16S,19R,20R). Two possible structures, 1a and 1b,
would be difficult to differentiate by 1H NMR or 13C NMR
spectroscopic data, since two stereogenic regions, that is, the
THF ring core part and the γ-lactone moiety are separated
† College of Technology, Toyama Prefectural University, 5180 Kuroka-
wa, Kosugimachi, Toyama 939-0398, Japan.
‡ Department of Applied Bioorganic Chemistry, Division of Life Science,
Graduate School of Agricultural Science, Tohoku University, 1-1 Tsutsu-
midori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan.
(1) For recent reviews for annonaceous acetogenins, see: (a) Alali, F.
Q.; Liu, X. -X,; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (b)
Zafra-Polo, M. C.; Figade`re, B.; Gallardo, T.; Tormo, J. R.; Cortes, D.
Phytochemistry 1998, 48, 1087-1117. (c) Cave´, A.; Figade`re, B.; Laurens,
A.; Cortes, D. In Progress in the Chemistry of Organic Natural Products:
Acetogenins from Annonaceae; Herz, W., Eds; Springer-Verlag: New York,
1997; Vol. 70, pp 81-288.
(2) For recent total synthesis of mono-THF acetogenins, see: (a) Hu,
T.-S.; Yu, Q.; Wu, Y.-L.; Wu, Y. J. Org. Chem. 2001, 66, 853-861. (b)
Maezaki, N.; Kojima, N.; Sakamoto, A.; Iwata, C.; Tanaka, T. Org. Lett.
2001, 3, 429-432. (c) Ba¨urle, S,; Peters, U.; Friedrich, T.; Koert, U. Eur.
J. Org. Chem. 2000, 2207-2217. (d) Dixon, D.; Ley, S. V.; Reynolds, D.
J. Angew. Chem., Int. Ed. 2000, 39, 3622-3626. (e) Hu, T.-S.; Wu, Y.-L.;
Wu, Y. Org. Lett. 2000, 2, 887-889. (f) Yu, Q.; Yao, Z.-J.; Chen, X. G.;
Wu, Y. L.; J. Org. Chem. 1999, 64, 2440-2445. (g) Hu, T. S.; Yu, Q.;
Lin, Q.; Wu, Y.-L.; Wu, Y. Org. Lett. 1999, 1, 399-401. (h) Yu, Q, Wu,
Y.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin Trans. 1 1999, 1183-1188.
(i) Kuriyama, W, Ishigami, K.; Kitahara, T. Heterocycles 1999, 50, 981-
988. (j) Wang, Z.-M.; Tian, S.-K, Shi, M. Tetrahedron: Asymmetry 1999,
10, 667-670.
Figure 1.
(3) Gleye, C.; Duret, P.; Laurens, A.; Hocquemiller, R.; Cave´, A. J. Nat.
Prod. 1998, 61, 576-579.
10.1021/ol0102803 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

effective catalyst system in the diastereoselective epoxidation.
On the other hand, Ti and Mo catalysts were ineffective.
Halogenic solvents, especially 1,2-dichloroethane, gave a
good stereoselectivity and yield. Determination of the relative
stereochemistry of 4a and 4b was performed J. M. Cassady’s
method as we have previously reported (Figure 2).5c,7
Scheme 1
by a long carbon chain. X-ray analysis is also very difficult
due to the waxy nature of this compound. To establish the
absolute configuration of cis-solamin, we planned to syn-
thesize the two candidates 1a and 1b, employing a TBHP-
VO(acac)2 diastereoselective epoxidation6 followed by a
cyclization strategy.
Scheme 1 outlines our synthetic strategy. One of the key
steps is TBHP-VO(acac)2 diastereoselective epoxidation6
followed by cyclization in the presence of 4A molecular
sieves. The starting material is bis-homoallylic alcohol 3,
whose enantiomer had been reported earlier by us.5c
The results of diastereoselective epoxidation of 3 and
spontaneous cyclization are summarized in Table 1. The
Figure 2.
Diastereoisomers 4a and 4b were separated by column
chlomatography (benzene-AcOEt ) 20:1) after the hydroxy
group of 4a and 4b had been protected as a benzoate ester
(5a and 5b). Hydrolysis of the benzoate ester gave 6 and
protection of the hydroxyl group as MOM ether afforded
tetrahydrofuran moiety 7 (Scheme 2).
Scheme 2a
Table 1. Epoxidation and Subsequent Cyclization of
Bis-homoallyl Alcohol 3a
a Reagent and conditions: (a) BzCl, pyridine (94%); (b) separa-
tion (81%); (c) NaOH, MeOH (92%); (d) MOMCl, i-Pr2NEt (94%).
a The reactions were carried out at room temperature.
results shown in Table 1 indicate the following. VO(acac)2
in the presence of 4A molecular sieves can serve as the most
As shown in Figure 3, the γ-lactone moiety 9 was
constructed as we had reported earlier starting from γ-lactone
8.5c,8
Both segments were coupled by the Sonogashira cross
coupling9 reaction mediated by Cl2Pd(PPh3)2/CuI in the THF
(4) Mynt, S. H.; Cortes, D.; Laurens, A.: Hocquemiller, R.; Leboeuf,
M.; Cave´, A, Cotte, J.; Quero, A.-M. Phytochemistry 1991, 30, 3335-
3338.
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Org. Lett., Vol. 4, No. 7, 2002

Table 2. 1H NMR Chemical Shifts of the Bis (R)- and
(S)-MTPA Esters of 1a and 1ba
MTPA ester
15-H
16-H
19-H
20-H
(R)-MTPA-1a
(S)-MTPA-1a
δ (S)-(R)-1a
abs confign
5.06
5.06
3.87
3.86
0.01
S
4.08
4.09
-0.01
R
4.92
4.93
-0.01
R
Figure 3.
S
(R)-MTPA-1b
(S)-MTPA-1b
δ (S)-(R)-1b
abs confign
5.06
5.06
3.86
3.87
-0.01
R
4.09
4.08
0.01
S
4.93
4.92
0.01
S
solvent system to give compound 10 (Scheme 3). Catalytic
hydrogenation of 10 using Wilkinson’s catalyst afforded
saturated product 11. Oxidation of the sulfur with mCPBA
followed by thermal elimination and deprotection of MOM
ethers with BF3‚Et2O in DMS10 afforded the candidate 1a.
On the other hand, the other candidate 1b was synthesized
from the enantiomer of compound 2 using the same
procedure as that employed for 1a.
R
a Proton chemical shifts are referenced to CHCl3 (δ 7.25).
contrast. While the specific rotation of synthetic 1a ([R]21
D
) +26, c 0.45, MeOH) is similar to the reported value of
the naturally occurring cis-solamin ([R]D ) +22, c 0.55,
MeOH), that of 1b ([R]21 ) +42, c 0.50, MeOH) showed
D
a much higher value.11,12 As shown in Table 2, the 1H NMR
spectra of the carbinol centers of the corresponding bis (R)-
and (S)-MTPA esters of synthetic 1a and 1b showed a slight
chemical shift difference. According to the sign of ∆δH [)
(δS - δR)] values of each carbinol center, the absolute
configuration of 1a is assigned as C-15S, C-16S, C-19R, and
C-20R. Similarly, the absolute configuration of 1b is assigned
as C-15R, C-16R, C-19S, and C-20S. This indicates that if
natural 1 is available, we can determine the absolute
stereochemistry of cis-solamin by applying advanced Mosher
methodology.13
Scheme 3a
In conclusion, the first total synthesis of cis-solamin (1a)
and its diastereomer 1b was accomplished using VO(acac)2-
catalyzed diastereoselective epoxidation followed by spon-
taneous cyclization. On the basis of the present data, it is
strongly suggested that the natural cis-solamin is 1a.
Acknowledgment. This work was supported in part by
a Grant-in-aid from the Japan Society for the Promotion of
Science (13760085). We thank Prof. Dr. Mitsuru Hirota of
the Faculty of Agriculture, Shinshu University, and Mrs.
Teiko Yamada, Graduate School of Agricultural Science,
Tohoku University, for obtaining Mass spectra. We also
thank Mrs. Keiko Hashimoto of the Faculty of Agriculture,
Shinshu University, for the 500 MHz NMR measurements.
a Reagent and conditions: (a) 5% Cl2Pd(PPh3)2, 10% CuI, Et3N
(74%); (b) H2/ClRh(PPh3)3 (68%); (c) (i) mCPBA, toulene reflux;
(ii) BF3‚Et2O/dimethyl sulfide (60%).
The two synthetic samples (1a, 1b) could not be dif-
ferentiated by the spectral data (1H NMR, 13C NMR). On
the other hand, their specific rotations showed a sharp
Supporting Information Available: 1H and 13C NMR
spectra for compounds 4a, 5, 6, 8, 1a, and 1b and 1H NMR
spectra for compounds 9 and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
(5) (a) Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E. J. Am. Chem. Soc.
1993, 115, 4891-4893. (b) Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1994,
114, 7459-7460. (c) Makabe, H.; Tanaka, A.; Oritani, T.; J. Chem. Soc.,
Perkin Trans. 1 1994, 1975-1981.
(6) (a) Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J.
Org. Chem. 1991, 56, 2299-2311. (b) Avedissian, H.; Sinha, S. C.; Yazbak,
A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65,
6035-6051.
(7) (a) Yu, J.-G.; Ho, D. K.; Cassady, J. M. J. Org. Chem. 1992, 57,
6198-6202. (b) Gale, J. B.; Yu, J.-G.; Khare, A.; Hu, X. E.; Ho, D. K.;
Cassady, J. M. Tetrahedron Lett. 1993, 34, 5851-5854.
(8) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991-4998.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. (b) Hoye, T. R.; Hanson, P. R.; Kovelesky, A. C.; Ocain, T.
D.; Zhuang, Z. J. Am. Chem. Soc. 1991, 113, 9369-9371.
(10) Naito, H.; Kawahara, K.; Maruta, E.; Maeda, M.; Sasaki, S. J. Org.
Chem. 1995, 60, 4419-4427.
OL0102803
(11) Physical and spectroscopic data for 1a: mp 66-68 °C, [R]21D +26
(c 0.45, MeOH). 1H and 13C NMR spectra were identical with those reported
in ref 3. HREIMS: calcd for C35H64O5 564.4753, found 564.4720.
(12) Physical and spectroscopic data for 1b: mp 61-63 °C, [R]21D +42
(c 0.50, MeOH). 1H and 13C NMR spectra were identical with those reported
in ref 3. HRFABMS (M + Na): calcd for C35H64O5Na 587.4651, found
587.4650.
(13) (a) Ohtani, I.; Kusumi, T.; Kashuwan, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092-4096. (b) Rieser, J. M.; Hui, Y.-H.; Rupprecht,
J. K.; Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.;
Zhuang, Z.; Hoye, T. R, J. Am. Chem. Soc. 1992, 114, 10203-10213.
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