Total synthesis of (-)-aspidospermine via diastereoselective ring-closing olefin metathesis

Article abstract of DOI:10.1021/ol034020s

(Matrix presented) An enantiocontrolled total synthesis of (-)-aspidospermine has been achieved. The key element of the strategy is the diastereoselective construction of the quaternary stereogenic center employing 1,4-asymmetric induction during the ring-closing olefin metathesis.

Full text of DOI:10.1021/ol034020s

ORGANIC
LETTERS
2003
Vol. 5, No. 5
749-751
Total Synthesis of (−)-Aspidospermine
via Diastereoselective Ring-Closing
Olefin Metathesis
Yu-ichi Fukuda, Mitsuru Shindo, and Kozo Shishido*
Institute for Medicinal Resources, UniVersity of Tokushima,
1-78 Sho-machi, Tokushima 770-8505, Japan
shishido@ph2.tokushima-u.ac.jp
Received January 7, 2003
ABSTRACT
An enantiocontrolled total synthesis of (−)-aspidospermine has been achieved. The key element of the strategy is the diastereoselective
construction of the quaternary stereogenic center employing 1,4-asymmetric induction during the ring-closing olefin metathesis.
Aspidospermine (1), an alkaloid that belongs to a family of
aspidosperma indole alkaloids,1 has generated considerable
interest because of its characteristic pentacyclic structural
feature and its biological profile. Consequently, for almost
40 years, intense activity has been directed toward the total
synthesis of this intriguing alkaloid (Figure 1).
reaction, we developed a novel methodology based on the
ring-closing metathesis (RCM) reaction4 as shown in Scheme
1.5
When the trienes 2 with a tertiary stereogenic center and
a prochiral quaternary carbon center were treated with
(2) Synthesis of (()-aspidospermine: (a) Stork, G.; Dolfini, J. E. J. Am.
Chem. Soc. 1963, 85, 2872-2873. (b) Ban, Y.; Sato, Y.; Inoue, I.; Nagai,
M.; Oishi, T.; Terashima, M.; Yonemitsu, O.; Kanaoka, Y. Tetrahedron
Lett. 1965, 2261-2268. (c) Kuehne, M. E.; Bayha, C. Tetrahedron Lett.
1966, 1311-1315. (d) Stevens, R. V.; Fitzpatrick, J. M.; Kaplan, M.;
Zimmerman, R. L. J. Chem. Soc., Chem. Commun. 1971, 857-858. (e)
Martin, S. F.; Desai, S. R.; Phillips, G. W.; Miller, A. C. J. Am. Chem.
Soc. 1980, 102, 3294-3296. (f) Pearson, A. J.; Rees, D. C. J. Chem. Soc.,
Perkin Trans. 1 1982, 2467-2476. (g) Wu, P.; Chu, M.; Fowler, F. W. J.
Org. Chem. 1988, 53, 963-972. For the synthesis of (()-aspidospermi-
dine: (h) Patro, B.; Murphy, J. A. Org. Lett. 2000, 2, 3599-3601. (i)
Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642. (j)
Callaghan, O.; Lampard, C.; Kennedy, A. R.; Murphy, J. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 995-1001. (k) Urrutia, A.; Rodriguez, J. G.
Tetrahedron 1999, 55, 11095-11108. (l) Quinn, J. F.; Bos, M. E.; Wulff,
W. D. Org. Lett. 1999, 1, 161-164. (m) Kozmin, S. A.; Rawal, V. H. J.
Am. Chem. Soc. 1998, 110, 966-968.
(3) Formal synthesis of (+)-aspidospermine: (a) Meyers, A. I.; Berney,
D. J. Org. Chem. 1989, 54, 4673-4676. Asymmetric synthesis of
aspidospermidine: (b) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios, A. J.
Am. Chem. Soc. 2002, 124, 13398-13399. (c) Kozmin, S. A.; Iwama, T.;
Huang, Y.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628-4641. (d)
Iyengar, R.; Schildknegt, K.; Aube´, J. Org. Lett. 2000, 2, 1625-1627. (e)
Schultz, A. G.; Pettus, L. J. Org. Chem. 1997, 62, 6855-6861. (f) Desmae¨le,
D.; d’Angelo, J. J. Org. Chem. 1994, 59, 2292-2303. (g) Node, M.;
Nagasawa, H.; Fuji, K. J. Org. Chem. 1990, 55, 517-521.
Figure 1.
There have been many reports on the total synthesis of
this family of alkaloids in both racemic2 and optically active
forms.3 During the course of our studies on the diastereo-
selective construction of a quaternary stereogenic center
employing 1,4-asymmetric induction in the cyclization
(1) Saxton, J. E. In The Alkaloids; Cordell, G. A., Ed.; Academic Press:
New York, 1998; Vol. 51, Chapter 1.
10.1021/ol034020s CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003

provide the alcohol 12 in good overall yield. Dehydration10
followed by selective deprotection of the TBS ether afforded
the hydroxy diene 8, which was converted into the hydroxy
triene 13 via sequential Wittig olefination and DIBAL-H
reduction. Katsuki-Sharpless asymmetric epoxidation,11
iodination of the resulting epoxy alcohol 14, and treatment
with zinc/AcOH produced the optically pure hydroxy triene
7 (R ) H) (>99% ee by the MTPA ester). The absolute
stereochemistry of the tertiary stereogenic center was con-
firmed to be S according to the modified Mosher method12
(Scheme 3).
Scheme 1. Diastereoselective Ring-Closing Metathesis
Grubbs’ ruthenium carbene complex 4, the cyclohexenes 3
with a quaternary stereogenic center were obtained via 1,4-
asymmetric induction in good chemical yield with up to 86%
de (in the case of R1 ) iPr, R2 ) TMS). In this communica-
tion, the application of our RCM methodology in an
enantiocontrolled total synthesis of (-)-aspidospermine (1)
is described.
Scheme 3a
(-)-Aspidospermine (1) can be obtained from optically
active lactam 5, which could be prepared from 6, according
to the procedure developed by Stork.2a We envisaged that a
pivotal construction of the quaternary carbon in 6 might be
realized diastereoselectively by RCM reaction of the triene
7, which in turn would be derived from the dienyl alcohol
8, as shown in Scheme 2.
Scheme 2. Retrosynthetic Analysis
a Reagents and conditions: (a) (i) TBSO(CH2)3Br, tBuLi, THF,
-78 °C f rt; (ii) (EtO)2P(O)CH2CO2Et, NaH, DME, reflux. (b)
(i) DIBAL-H, THF, 0 °C; (ii) EtOCHdCH2, Hg(OAc)2, reflux. (c)
iBu3Al, CH2Cl2, rt. (d) (i) o-Nitrophenyl selenocyanate, nBu3P, THF,
rt; (ii) H2O2, THF, rt; (iii) 1% HCl, EtOH, rt. (e) (i) (COCl)2,
DMSO, Et3N, CH2Cl2, rt; (ii) Ph3PdCHCO2Et, benzene, reflux;
(iii) DIBAL-H, THF, 0 °C. (f) L-(+)-DIPT, Ti(OiPr)4, TBHP, 4 Å
MS, CH2Cl2, 25 °C. (g) (i) I2, Ph3P, imidazole, benzene, rt; (ii) Zn,
AcOH, 50 °C.
The triene 7 (R ) H) was converted by conventional
means into the corresponding MOM, benzyl, and TMS ethers
and the benzoate ester. These compounds were treated with
10 mol % ruthenium carbene complex 4 in CH2Cl2 solution
(0.02 M) at room temperature for 48 h. The results are shown
in Table 1. The best result was obtained in the case of R )
TMS to afford the cyclohexenol 6 (R ) H) quantitatively
with 74% de (entry 5) after acidic hydrolysis. Fortunately,
since the two diastereomers could be easily separated by
chromatography, the optically pure 6 was obtained in 74%
yield (Table 1). Although the absolute configuration of the
newly generated quaternary stereogenic center could not be
determined at this stage, it was proposed to be R according
to our previous study. This was confirmed by its conversion
into the known lactam 5.
Preparation of the triene 7 (R ) H), the substrate of dia-
stereoselective RCM reaction, began with the reaction of the
amide 9, prepared from γ-butyrolactone,7 with 3-(tert-butyl-
dimethylsilyloxy)propyllithium8 followed by the Horner-
Emmons reaction to give the unsaturated ester 10. Reduction
with DIBAL-H followed by vinylation afforded the vinyl
ether 11, which was treated with triisobutylaluminum9 to
(4) For recent reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997,
36, 2036-2056. (d) Armstrong, S. K. J. J. Chem. Soc., Perkin Trans. 1
1998, 371-388. (e) Grubbs, R. H., Chang, S. Tetrahedron 1998, 54, 4413-
4450.
(5) Fukuda, Y.; Sasaki, H.; Shindo, M.; Shishido, K. Tetrahedon Lett.
2002, 43, 2047-2049.
(6) Schweb, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(10) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
(7) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38, 2685-
1485-1486.
2688.
(11) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-
5976.
(8) Wilson, S. R.; Zucker, P. A. J. Org. Chem. 1988, 53, 4682-4693.
(9) Takai, K.; Mori, I.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1984, 57, 446-451.
(12) Ohtani, I.; Kusumi, T.; Kashmann, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092-4096.
750
Org. Lett., Vol. 5, No. 5, 2003

Scheme 4a
Table 1. RCM Reaction of Triene 7 Leading to 6
yield [%] of 6
diastereomeric
entry
R
(recovered 7 [%])
ratio
1
2
3
4
5
H
Bz
MOM
Bn
TMS
7 (81)
95 (5)
92 (5)
94 (6)
59:41
72:28b
85:15
88:12
87:13b
quantitativea (0)
a Isolated as alcohol 6 (R ) H) after hydrolysis. b Diastereomers can be
separated by chromatography.
a Reagents and conditions: (a) (i) TBAF, THF, rt; (ii) Jones
oxidation, acetone, rt. (b) (i) (COCl)2, CH2Cl2, rt; (ii) NH3, THF,
rt. (c) (i) p-TsOH‚H2O, benzene, reflux, then HO(CH2)2OH, reflux;
(ii) H2, PtO2, EtOH, rt. (d) (i) LiAlH4, THF, reflux; (ii) ClCOCH2Cl,
Et3N, CH2Cl2, rt. (e) (i) 1 N HCl, THF, reflux; (ii) KOtBu, benzene,
reflux. (f) (i) HO(CH2)2OH, p-TsOH‚H2O, benzene, reflux; (ii)
BH3‚THF,reflux;(iii)1NHCl,THF,reflux.(g)(i)o-Methoxyphenyl-
hydrazine‚HCl, Na2CO3, EtOH, reflux; (ii) AcOH, 95 °C. (h) (i)
LiAlH4, THF, rt; (ii) Ac2O, pyridine, rt.
The optically pure 6 (R ) H) thus prepared was desilylated
and oxidized to give the keto acid 15, which was converted
into the amide 16 via the acid chloride. Treatment of the
amide 16 with p-TsOH in refluxing benzene afforded the
corresponding keto lactam, which was ketalized and whose
double bond was reduced to give the keto lactam 5. The
enantiomer of compound 5 is identical to an intermediate
synthesized by Meyers.3a With the key intermediate in hand,
we converted 5 into 1 using a slightly modified procedure
of Stork.2a Reduction of the lactam carbonyl followed by
acylation with chloroacetyl chloride afforded 17. After
hydrolysis of the ketal moiety, treatment with base produced
the tricyclic keto lactam 18. For the selective reduction of
the lactam carbonyl, the ketone was reprotected as a ketal,
reduced with borane, and hydrolyzed to give 19. It was then
converted into the o-methoxyphenylhydrazone, which was
heated in acetic acid to afford the pentacyclic compound 20.
Finally, sequential treatment with LiAlH4 and acetic anhydride/
pyridine produced (-)-aspidospermine (1), whose spectral
properties and optical rotations are identical to those
reported13 (Scheme 4).
In summary, we have completed an enantiocontrolled total
synthesis of (-)-aspidospermine using a methodology for
assembling the quaternary stereogenic center via a diastereo-
selective RCM reaction developed in our laboratory. The
optically active cyclohexenol derivative 6 produced by the
RCM reaction is suitably functionalized and could be a
versatile chiral building block not only for aspidosperma
indole alkaloids but also for other biologically important
natural products.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Campbell, W. E.; Jackson, G. E.; Ravenscroft, N. Spectrosc. Lett.
1993, 26, 707-719.
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