Asymmetric total synthesis of (-)-azaspirene, a novel angiogenesis inhibitor

Article abstract of DOI:10.1021/ja0276826

The asymmetric total synthesis of (-)-azaspirene, an angiogenesis inhibitor, has been accomplished, establishing its absolute stereochemistry. The key steps are a MgBr₂·OEt₂-mediated, diastereoselective Mukaiyama aldol reaction, a NaH-promoted, intramolecular cyclization of an alkynylamide, and the aldol reaction of a ketone containing functionalized γ-lactam moiety without protection of tert-alcohol and amide functionalities. Copyright

Full text of DOI:10.1021/ja0276826

Published on Web 09/18/2002
Asymmetric Total Synthesis of (-)-Azaspirene, a Novel Angiogenesis
Inhibitor
Yujiro Hayashi,*,† Mitsuru Shoji,† Junichiro Yamaguchi,† Kenji Sato,† Shinpei Yamaguchi,†
Takasuke Mukaiyama,† Ken Sakai,§ Yukihiro Asami,| Hideaki Kakeya,| and Hiroyuki Osada|
Department of Industrial Chemistry, Faculty of Engineering, and Department of Applied Chemistry,
Faculty of Science, Tokyo UniVersity of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and
Antibiotics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received July 12, 2002
Table 1. Effect of Lewis Acid in Mukaiyama Aldol Reaction of 5
and 7a
The inhibition of angiogenesis is a promising method of treating
angiogenesis-related diseases such as cancer and rheumatoid
arthritis.1 We have recently completed an asymmetric total synthesis
of epoxyquinols A and B,2 which we have isolated and identified
as novel, unique angiogenesis inhibitors.3 Our continuing search
for new angiogenesis inhibitors from natural sources led us to
azaspirene (1), isolated from the fungus Neosartorya sp.4 Structur-
ally, azaspirene (1) contains a highly oxygenated 1-oxa-7-azaspiro-
[4.4]non-2-ene-4,6-dione skeleton with benzyl and hexadiene
substituents, and a core structure also found in the pseurotins5 and
synerazol.6 Although several synthetic studies on the pseurotins have
been reported,5e-h their total synthesis has not yet been ac-
complished. Because of its interesting biological properties and rare
structure, we have investigated the total synthesis of azaspirene
(1), aiming to determine its absolute stereochemistry.
c
isomer ratio /%
b
Lewis acid
SnCl2
BF3‚OEt2
ZnBr2
Ti(O-i-Pr)Cl3
MgBr2‚OEt2
yield/%
6a
6b
other isomers
67
41
62
49
72
61
63
68
91
94
33
34
31
9
6
3
1
0
0
6
a Reaction conditions; 7:5:Lewis acid ) 1:1.5:2.5, CH2Cl2, -78 °C.
b Isolated yield based on ester 4. c Isomer ratio was determined by 400 MHz
1H NMR analysis.
with the results summarized in Table 1. Although the desired syn-
aldol 6a was obtained as the major isomer using SnCl2, BF3‚OEt2,
and ZnBr2, the diastereoselectivity was insufficient. Ti(O-i-Pr)Cl3
11
afforded the desired isomer 6a with high selectivity but in poor
yield. MgBr2‚OEt2,12 on the other hand, was found to be a suitable
promoter, affording 6a with both high diastereoselectivity and in
good yield, without loss of enantioselectivity as checked by chiral-
HPLC analysis.8 The stereochemistry of 6a was established
unambiguously by X-ray crystallographic analysis of a crystalline
amide,13 synthesized by the following sequence: protection of the
hydroxy group of 6a as its benzyl ether, ester hydrolysis, and amide
formation. The stereochemistry of 6b was determined by oxidation
of 6a, followed by reduction, affording 6a and 6b.
Protection of 6a with TIPSOTf and 2,6-lutidine, afforded silyl
ether 8 in 98% yield, which was hydrolyzed to provide carboxylic
acid 9. This was next treated with oxalyl chloride and NEt3,
providing the acid chloride, which was reacted with NH3 to give
amide 10 in 45% yield over two steps, along with recovered
carboxylic acid 9 in 34% yield. Amide 10 was crystalline, and a
single recrystallization gave optically pure compound.8 When this
amide 10 was reacted with NaH in DMF at room temperature for
1 h, the Z-benzylidene γ-lactam 1114 and its E-isomer14 were
obtained in 92 and 7% yield, respectively.15 Treatment of 11 with
CF3CO2H in the presence of MeOH cleaved the acetal, affording
diol 12 in 92% yield without affecting the benzylidene moiety.
Oxidation of 12 with the Dess-Martin periodinane (DMP)16 in the
presence of water according to Schreiber’s modified conditions17
gave R-hydroxy ketone 13 in 82% yield. Aldol condensation of
the lithium enolate of 13 and heptadienal in the presence of HMPA
afforded a mixture of diastereomeric aldols 14 in 50% yield. Ketone
13 was recovered in 47% yield, and thus a high conversion yield
(94%) had been achieved. It should be noted that it is not necessary
to protect the tert-alcohol or amide functionality during this aldol
reaction. Oxidation of 14 with DMP gave 1,3-diketone 15,18 which
was partially converted to the azaspiro[4.4]nonenedione bicycle 16
when purified on thin-layer chromatography (15 + 16, 94%, 15:
Our synthesis (see Scheme 1) started with the Sharpless
asymmetric dihydroxylation of methyl 2-pentenoate (2) using
(DHQ)2PHAL as the chiral ligand.7 This gave (2R,3S)-diol 3 in
88% yield. This was treated with dimethoxypropane in the presence
of a catalytic amount of TsOH‚H2O, to afford acetal 4 in 95% ee8
and 79% yield. The next step, an aldol condensation of 4 with
phenylpropargyl aldehyde (5),9 proved troublesome. Although the
lithium enolate of 4 reacted with 5 smoothly at -78 °C, all four
possible aldol products 6 were obtained with very poor diastereo-
selectivity (57:20:13:8), albeit in good yield (total 98%). The desired
syn-aldol 6a was obtained in only a small amount (13%), while
the major isomer was anti-aldol 6b (57%). As screening of solvent,
base, and additives did not significantly improve this result, we
examined the alternative, Mukaiyama aldol reaction.
After conversion of ester 4 to its ketene silyl acetal 7,10 the aldol
reaction of this was investigated in the presence of various Lewis
acids (eq 1),
* To whom correspondence should be addressed. E-mail: hayashi@
ci.kagu.tus.ac.jp.
† Department of Industrial Chemistry, Faculty of Engineering, Tokyo University
of Science.
§ Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science.
| Antibiotics Laboratory, RIKEN.
9
12078
J. AM. CHEM. SOC. 2002, 124, 12078-12079
10.1021/ja0276826 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Total Synthesis of (-)-azaspirene (1)
(2) Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y. Angew.
Chem., Int. Ed. 2002, 41, 3192.
(3) Kakeya, H.; Onose, R.; Koshino, H.; Yoshida, A.; Kobayashi, K.;
Kageyama, S.-I.; Osada, H. J. Am. Chem. Soc. 2002, 124, 3496.
(4) Asami, Y.; Kakeya, H.; Onose, R.; Yoshida, A.; Matsuzaki, H.; Osada,
H. Org. Lett. 2002, 4, 2845.
(5) (a) Bloch, P.; Tamm, C.; Bollinger, P.; Petcher, T. J.; Weber, H. P. HelV.
Chim. Acta 1976, 59, 133. (b) Bloch, P.; Tamm, C. HelV. Chim. Acta
1981, 64, 304. (c) Breitenstein, W.; Chexal, K. K.; Mohr, P.; Tamm, C.
HelV. Chim. Acta 1981, 64, 379. (d) Mohr, P.; Tamm, C. Tetrahedron
1981, 37, 201. (e) Dolder, M.; Shao, X.; Tamm, C. HelV. Chim. Acta
1990, 73, 63. (f) Shao, X.; Dolder, M.; Tamm, C. HelV. Chim. Acta 1990,
73, 483. (g) Su, Z.; Tamm, C. HelV. Chim. Acta 1995, 78, 1278. (h) Su,
Z.; Tamm, C. Tetrahedron 1995, 51, 11177. (i) Komagata, D.; Fujita, S.;
Yamashita, N.; Saito, S.; Morino, T. J. Antibiot. 1996, 49, 958.
(6) Ando, O.; Satake, H.; Nakajima, M.; Sato, A.; Nakamura, T.; Kinoshita,
T.; Furuya, K.; Haneishi, T. J. Antibiot. 1991, 44, 382.
16 ) 1:1). When a mixture of 15 and 16 was treated with a catalytic
amount of TsOH‚H2O for 2.8 h, complete formation of the azaspiro-
[4.4]nonenedione bicycle and hydration of the benzylidene group
occurred concurrently to afford 17 as a single isomer19 in 91% yield.
Deprotection of the TIPS group with NH4F in MeOH afforded
azaspirene (1) in 35% yield. The order of the last two reactions is
very important: When the benzylidene derivative 1620 was first
deprotected with NH4F, and then hydrated with TsOH‚H2O, racemic
azaspirene was formed, probably because of a retro-aldol reaction.
During the sequence of hydration and deprotection, the presence
of an hydroxy group at C8 of the azaspiro[4.4]nonenedione seems
to prevent the recemization. Synthetic azaspirene exhibited proper-
ties identical to those of the natural product (1H NMR, 13C NMR,
IR, mp, Rf value, and chiral HPLC analysis). Comparison of the
optical rotation (synthetic 1; [R]27D -207 (c ) 0.13, MeOH), natural
(7) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung,
J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.;
Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(8) For the determination of ee, see the Supporting Information.
(9) Allen, C. F. H.; Endens, C. O., Jr. Organic Syntheses; Wiley & Sons:
New York, 1973; Collect. Vol. 3, p 731.
1[4]; [R]25 -204.4 (c ) 0.158, MeOH), established the absolute
D
stereochemistry of the natural product to be (5S,8R,9R).
In summary, the first asymmetric total synthesis of (-)-
azaspirene (1) has been achieved, and its absolute stereochemistry
has been determined. There are several noteworthy features to this
total synthesis: The MgBr2‚OEt2-mediated, diastereoselective Mu-
kaiyama aldol reaction of 5 and 7, the NaH-promoted intramolecular
cyclization of the alkynylamide 10 to form selectively the Z-
benzylidene γ-lactam 11, the aldol reaction of 13 containing
functionalized γ-lactam moiety without protection of tert-alcohol
and amide functionalities, and the importance of the order of the
last two reactions.
(10) Ketene silyl acetal 7 was obtained as a single isomer, the geometry of
which has not been determined.
(11) In the elegant total syntheses of zaragozic acid and cinatrins by Evans et
al., Ti(O-i-Pr)Cl3 is an effective Lewis acid in Mukaiyama aldol reaction
of a silylketene acetal derived from di-tert-butyl-(2S,3S)-1,4-dioxaspiro-
[4.4]nonane-2,3-dicarboxylate. Evans, D. A.; Barrow, J. C.; Leighton, J.
L.; Robichaud, A. J.; Sefkow, M. J. Am. Chem. Soc. 1994, 116, 12111;
Evans, D. A.; Trotter, B. W.; Barrow, J. C. Tetrahedron 1997, 53, 8779.
(12) For recent elegant use of MgBr2‚OEt2 as an effective Lewis acid, see:
(a) Fujisawa, H.; Sasaki, Y.; Mukaiyama, T. Chem. Lett. 2001, 190. (b)
Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392. (c) Sibi, M. P.; Sausker, J. B. J. Am. Chem. Soc.
2002, 124, 984.
(13) Crystal data: monoclinic, space group P21, a ) 11.404(3) Å, b ) 7.941-
(2) Å, c ) 12.843(3) Å, â ) 105.643(5)°, V ) 1120.0(5) Å3, Z ) 2, R1
) 0.0698 for I > 2.0σ(I), wR2 ) 0.1713 for all data (5002 reflections).
The details are supplied as Supporting Information (Figure S1).
(14) The geometry of the olefins was determined by NOESY experiment.
(15) (a) Koseki, Y.; Kusano, S.; Ichi, D.; Yoshida, K.; Nagasaka, T. Tetrahedron
2000, 56, 8855. (b) Cid, M. M.; Dominguez, D. D.; Castedo, L.; Vazquez-
Lopez, E. M. Tetrahedron 1999, 55, 5599.
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Dess, D.
B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. (c) Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899.
(17) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549.
(18) 1H and 13C NMR analyses show that 15 exists in the 1,3-diketo form
rather than the keto-enol form.
(19) The stereochemistry at C8 was confirmed by NOESY and difference NOE
experiments, see Supporting Information.
Acknowledgment. This work was partially supported by the
Sumitomo Foundation.
Supporting Information Available: Detailed experimental pro-
1
cedures, full characterization, copies of H, 13C NMR, and IR spectra
of all new compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(20) 16 was obtained in 94% yield from 15 by repeated treatment with thin-
(1) (a) Folkman, J. J. Natl. Cancer Inst. 1990, 82, 4. (b) Risau, W. Nature
1997, 386, 671. (c) Klagsbrum, M.; Moses, M. A. Chem. Biol. 1999, 6,
R217. (d) Gasparini, G. Drugs 1998, 58, 17.
layer chromatography (TLC).
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