Total synthesis of (+)-benzastatin E via diastereoselective Grignard addition to 2-acylindoline.

Article abstract of DOI:10.1021/ol027215t

[reaction: see text] A stereoselective total synthesis of (+)-benzastatin E (1) is described. The synthesis involves a diastereoselective Grignard addition to 2-acylindoline 2, which is derived from commercially available (S)-2-indolinecarboxylic acid (3). The unknown absolute configuration of (+)-1 is determined as (9S,10R).

Full text of DOI:10.1021/ol027215t

ORGANIC
LETTERS
2003
Vol. 5, No. 3
269-271
Total Synthesis of (+)-Benzastatin E via
Diastereoselective Grignard Addition to
2-Acylindoline
Narihiro Toda, Mayuko Ori, Kazuko Takami, Keiko Tago, and Hiroshi Kogen*
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi,
Shinagawa-ku, Tokyo 140-8710, Japan
hkogen@shina.sankyo.co.jp
Received November 1, 2002
ABSTRACT
A stereoselective total synthesis of (+)-benzastatin E (1) is described. The synthesis involves a diastereoselective Grignard addition to
2-acylindoline 2, which is derived from commercially available (S)-2-indolinecarboxylic acid (3). The unknown absolute configuration of (+)-1
is determined as (9S,10R).
Benzastatin E (1) and its congeners, a family of indoline
alkaloids that were isolated from Streptomyces nitrosporeus
30643 in 1997,1 show neuronal cell protecting activity that
can be used to prevent brain ischemia injury.2 Benzastatin
E (1) is the most potent inhibitor of glutamate toxicity using
neuronal hybridoma N18-RE-105 among the benzastatin
family.1 The relative stereochemistry of benzastatin E (1)
was elucidated by extensive NMR spectroscopic analysis.1
However, the absolute stereochemistry of 1 was undeter-
mined. Herein, we wish to report the first total synthesis of
(+)-benzastatin E (1) and its absolute configuration.
The key step is a diastereoselective Grignard addition to
2-acylindoline 2, which is readily prepared from com-
mercially available (S)-(-)-indoline-2-carboxylic acid (3) as
shown in Scheme 1.
Bromination of 4 with NBS (1 equiv) in DMF afforded
bromide 5 in 93% yield. The bromide was converted to
Weinreb amide3 6 by treatment with N,O-dimethylhydroxy-
lamine hydrochloride and isopropylmagnesium chloride4 in
83% yield. Coupling of methoxymethyllithium,5 derived from
Sn-Li exchange of methyl tributylstannylmethyl ether, with
6 afforded ketone 7 in 61% yield.
Scheme 1
Key intermediate 2-acylindoline 7 was prepared as shown
in Scheme 2. Carboxylic acid 3 was treated with sulfuric
acid in methanol, followed by nitrogen protection with di-
tert-butyl dicarbonate to provide methyl ester 4 in 92% yield.
(1) Kim, W. G.; Kim, J.-P.; Koshino, H.; Shin-Ya, K.; Seto, H.; Yoo,
I.-D. Tetrahedron 1997, 53, 4309.
(2) Kim, W. G.; Kim, J. P.; Lim, C. J.; Lee, K. H.; Yoo, I. D. J. Antibiot.
1996, 49, 20. Kim, W. G.; Kim, J. P.; Yoo, I. D. J. Antibiot. 1996, 49, 26.
10.1021/ol027215t CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003

were derived from major-8 and minor-8 in a two-step
sequence, respectively, as shown in Scheme 3. Thus, the
absolute configuration of major-8 was assigned as (9S,10R).
Scheme 2a
This diastereoselective Grignard addition was successfully
extended to a variety of substrates and Grignard reagent
combinations.7 The results are summarized in Table 1.
Inspection of the data in Table 1 demonstrates that the
additions are quite diastereoselective. Moreover, as shown
in runs 1 and 2, either diastereomer can be easily obtained
by exchanging the order of the metal reagent addition to
Weinreb amide. The enantiomer of 8 can also be readily
prepared by using (R)-(+)-indoline-2-carboxylic acid8 as a
starting material (run 3). The chiral HPLC analysis9 of 8a
shows that no racemization occurs during these manipulations
(from 4 to 8). The stereochemical outcome of these facially
selective additions can be rationalized in terms of a Felkin-
Anh model10 as depicted in Figure 1.
a Key: (a) (i) MeOH, H2SO4, 80 °C, (ii) Boc2O, CH2Cl2, rt, 92%
(two steps); (b) NBS, DMF, 0 °C, 93%; (c) i-PrMgCl, Me(MeO)-
NH‚HCl, THF, -20 to -10 °C, 83%; (d) MeOCH2Sn(n-Bu)3,
n-BuLi, THF, -78 °C, 61%.
Construction of the tert-alcohol moiety was efficiently
achieved by diastereoselective Grignard addition to 7.
Reaction of ketone 7 with 3,4-dimethyl-3-pentenylmagne-
sium bromide6 in THF at -78 °C gave tert-alcohols in a
25:1 ratio of separable isomers major-8 and minor-8 as
determined by HPLC analysis of the product mixture
(Scheme 3). Configurations of the newly created stereo-
Scheme 3
Figure 1.
Finally, total synthesis of (+)-1 was accomplished in three
steps from major-9 as shown in Scheme 4. Conversion of
Scheme 4a
centers in major-8 and minor-8 were determined with NOE
experiments of the acetonides major-9 and minor-9, which
a Key: (a) t-BuLi, CO2, Et2O, -78 to 0 °C, 53%; (b) CDI, 28%
aq NH3, THF, rt, 74%; (c) PPTS, MeOH, rt, 64%.
(3) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(4) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(5) Kaufman, T. S. Synlett 1997, 1377.
(6) De Silva, A. N.; Francis, C. L.; Ward, D. Aust. J. Chem. 1993, 46,
1657.
(7) Ding et al. reported the diastereoselective addition of lithium ethyl
propiolate to an 2-acetylpyrrolidine derivative. Ni, Y.; Zhao, G.; Ding, Y.
J. Chem. Soc., Perkin Trans. 1 2000, 3264.
major-9 to the corresponding aryllithium species followed
by carboxylation with CO2 provided 10. Amidation of 10
with aqueous ammonia and 1,1′-carbonyldiimidazole (CDI)
(8) Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62, 7679.
(9) DAICEL CHIRALCEL OD (0.46 cm L × 25 cm), n-hexane-i-PrOH
(95:5), 1 mL/min.
(10) Anh, N. T. Top. Curr. Chem. 1980, 88, 145.
Org. Lett., Vol. 5, No. 3, 2003
270

Table 1. Diastereoselective Grignard Addition to 2-Acylindolines
a Readily prepared from the corresponding Weinreb amide and either Grignard reagent or alkyllithium by the same method for preparation of 7 except
for 7c. Substrate 7c was prepared from (R)-(+)-indoline-2-carboxylic acid. b Absolute configuration of the major isomer was determined by NOE experiments
of the corresponding acetonide derivative. c Isolated yield of a mixture of diastereoisomers. d Diastereomeric ratios determined by HPLC analysis of crude
product mixtures.
gave amide 11. Removal of the acetonide protecting group
was effected by treatment of 11 with PPTS in MeOH to
furnish (+)-benzastatin E (1) [[R]24D +21.3 (c 0.10, MeOH)
(lit.1 [R]18D +17 (c 0.1, MeOH))] in 64% yield. Spectral data
(IR, 1H NMR, and 13C NMR) for synthetic (+)-1 are identical
to that reported for the natural product.
selective Grignard addition to 7. The unknown absolute
stereochemistry of (+)-1 was determined as (9S,10R).
Supporting Information Available: Representative ex-
perimental procedures, characterization data, and 1H and 13
C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
In summary, the first total synthesis of (+)-benzastatin E
(1) has been accomplished in 11 steps from 3 via diastereo-
OL027215T
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