Novel stereoselective construction of a quaternary carbon: Application to synthesis of the cyclopentenedione moiety of madindolines

Article abstract of DOI:10.1016/S0040-4039(00)00937-0

Enantioselective synthesis of the cyclopentenedione moiety of madindolines was achieved. Stereoselective construction of a quaternary carbon was realized by alkylation of an enolate possessing chiral auxiliary. Cyclopentenedione was derived from a triketone precursor by intramolecular condensation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00937-0

Tetrahedron Letters 41 (2000) 6429±6433
Novel stereoselective construction of a quaternary carbon:
application to synthesis of the cyclopentenedione moiety of
madindolines
Seijiro Hosokawa, Kazuhiko Sekiguchi, Manabu Enemoto and Susumu Kobayashi*
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku,
Tokyo 162-0826, Japan
Received 15 May 2000; accepted 26 May 2000
Abstract
Enantioselective synthesis of the cyclopentenedione moiety of madindolines was achieved. Stereoselective
construction of a quaternary carbon was realized by alkylation of an enolate possessing chiral auxiliary.
Cyclopentenedione was derived from a triketone precursor by intramolecular condensation. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: madindoline; cyclopentenedione; alkylation; quaternary carbon.
Madindoline A (1) and B (2) were isolated from the culture of Streptomyces nitrosporeus K93-
-
0711 by Omura in 1996 as a selective inhibitor of IL-6 activity.1 The structural feature of
madindolines is characterized by the furoindolidine skeleton and the cyclopentenedione moiety
having a chiral quaternary carbon. The ®rst total synthesis of madindolines was recently achieved
-
by Omura's group, and their absolute stereochemistries were determined as shown in Fig. 1.2
Interested in their structures as well as biological activities, we have also been investigating the
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00937-0

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total synthesis of madindolines. Our basic strategy for madindolines is to couple the furoindoline
4 and cyclopentenedione 3 or its precursor. The present paper focuses on the enantioselective
synthesis of 3 by developing a novel method to construct a quaternary carbon,3 and the
accompanying paper describes the total synthesis of madindoline A.
Our synthetic strategy for cyclopentenedione 3 is shown in Scheme 1. The cyclopentenedione
skeleton might be constructed by regioselective intramolecular condensation of triketone 5.
Triketone 5, in turn, could be derived from ole®nic 6 which might be derived from 7. For the
synthesis of 7, we expected the quaternary carbon to be generated by regio- and stereoselective
alkylation of a,b-unsaturated carbonyl derivative 8 possessing chiral auxiliary.4,5
Scheme 1.
Prior to the synthesis of 3, we ®rst examined stereoselective construction of a quaternary
carbon using a tiglic acid derivative as a model substrate. Among several chiral substrates exam-
ined, Evans oxazolidone derivative 10 showed high stereoselectivity by the reaction with benzyl-
oxymethyl chloride or methoxymethyl chloride (Table 1). In these reactions, the regioselectivity
of alkylation was excellent, a€ording an a-alkylation product exclusively. In a separate experi-
ment, the intermediate dienolate anion was trapped as TBDMS ether 12 which was isolated as a
single isomer in 90% yield (Scheme 2). The stereochemistry was unambiguously determined to be
E by NOE experiment. NOEs were observed between the vinyl and isopropyl methyl protons as
well as between the methyl and TBDMS protons. From these results, we speculate that the
Table 1
a-Alkylation of a,b-unsaturated imide 10

6431
electrophile might approach from the opposite side of the i-Pr group in dienolate anion 13,6 and
we tentatively assigned the absolute con®guration of 11 as shown below.
Scheme 2.
Having obtained these promising results, we started on the synthesis of cyclopentenedione
moiety 3 (Scheme 3). Hexanal was converted into acid chloride 14, which was reacted with lithio-
oxazolidone to give a,b-unsaturated oxazolidone 15. Alkylation of 15 proceeded with 8.4:1
diastereoselectivity to a€ord 16 in 61% yield. The ole®nic part of 16 was exclusively E (J3,4=16.1
Hz),5,7 and the stereochemistry of the quaternary carbon was tentatively assigned as S as
above.7,8 The chiral auxiliary of 16 was reductively removed, and the resulting primary alcohol 17
was transformed to ethyl ketone 18 by a 3-step sequence including PCC oxidation, ethylation,
and another PCC oxidation. After protection of the ketone as ethylene acetal9, the C C double
bond of 19 was oxidized to a-diketone by dihydroxylation with osmium tetroxide followed by
Swern oxidation10 to provide diketone 20. Deprotection of ethylene acetal11 of 20 gave triketone
5 (13C-NMR: ꢀ 208.1, 199.9, 197.5) in 85% yield. When the triketone 5 was treated with DBU in
1
benzene at room temperature, cyclopentenedione 3 (13C-NMR: ꢀ 205.9, 205.6; H-NMR: ꢀ 2.04
(3H, s, vinyl-Me))12 was isolated in 91% yield as a single product. Removal of the benzyl group
followed by oxidation gave cyclopentenedione aldehyde 21 (1H-NMR: ꢀ 9.36 (1H, s, CHO))
which was very unstable and rapidly decomposed at room temperature.
Regioselectivity of the intramolecular condensation might be explained by Fig. 2. Comparing
the stability of intermediates 22 and 23, 22 might su€er from steric repulsion between side chains
of the quaternary carbon and the tertiary alkoxide carbon; additionally, it has an electronically
unstable a-diketone form. On the other hand, intermediate 23 has neither of these shortcomings.
Thus, the equilibrium between 22 and 23 tended to 23 which led to the desired diketone 3
exclusively.
In conclusion, we were able to synthesize the cyclopentenedione moiety of madindolines. The
characteristic features of the present study are: (1) a novel method for the stereoselective con-
struction of a quaternary carbon; and (2) regioselective intramolecular cyclization of triketone.
In the following paper, we describe an application of this method to the total synthesis of
madindoline A.

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Scheme 3. Reagents and conditions: (a) i) Ph3PˆCMeCOOMe, benzene, re¯ux, 2 h, 92%, ii) NaOH aq, MeOH, 99%,
iii) SOCl2, benzene, re¯ux, 3 h, 93%. (b) oxazolidone, n-BuLi, THF, ^78ꢀC; acylchloride, 96%. (c) NaHMDS, THF,
^78ꢀC; BnOCH2Cl, 61%. (d) LiAlH4, THF, 0ꢀC, 70 min, 85%. (e) i) DMSO, (COCl)2, CH2Cl2, ^78ꢀC; Et3N, ii) EtBr,
ꢀ
.
Mg, THF, ^45 C, 35 min, 86%, iii) PCC, MS-4A, AcONa, CH2Cl2, rt, 30 min, 90%. (f) (TMSOCH2)2, BF3 OEt2,
CHꢀ2Cl2, 0ꢀC, 2 h, 86%. (g) i) OsO4 (0.05 equiv.), NMO, acetone, t-BuOH, H2O, 5 days, ii) TFAA, DMSO, CH2Cl2,
ꢀ
.
^78 C, 35 min; Et3N, 15 min, 76% (2 steps). (h) TsOH H2O, acetone, 60 C, 1 day, 85%. (i) DBU, benzene, rt, 12 h,
91%, (j) i) BCl3, CH2Cl2, ^78ꢀC, 1 h, 80%, ii) PCC, MS-4A, CH2Cl2, rt, 30 min
Figure 2.

6433
Acknowledgements
We thank Prof. T. Sunazuka (Kitasato University) for helpful discussions. This work was
supported in part by the Fujisawa Foundation (S.H.), Grant-in-Aid for Scienti®c Research from
the Ministry of Education, Science, Sports, and Culture, Japan, and Shin-Etsu Chemical Co.,
Ltd.
References
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3. For excellent reviews which cover most of the methods for construction of asymmetric quaternary carbon centers,
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7. Oxazolidone 10; ‰ꢁŠ2D5=+43.7ꢀ (c=1.03, CHCl3); 1H-NMR (400 MHz, CDCl3): ꢀ 0.86 (3H, t, J=7.1 Hz), 0.87 (3H,
d, J=7.1 Hz), 1.24±1.34 (4H, m), 1.49 (3H, s), 1.99 (2H, q, J=6.8 Hz), 2.32 (1H, m), 3.46 (1H, d, J=8.8 Hz), 4.15
(1H, dd, J=2.9, 9.0 Hz), 4.21 (1H, t, J=9.0 Hz), 4.29 (1H, d, J=8.8 Hz), 4.47 (1H, d, J=12.2 Hz), 4.50 (1H, dd,
J=2.9, 3.7 Hz), 4.58 (1H, d, J=12.2 Hz), 5.37 (1H, td, J=1.8, 16.1 Hz), 5.75 (1H, td, J=1.5, 16.1 Hz), 7.23±7.34
(5H, m); 13C-NMR (100 MHz, CDCl3): ꢀ 13.9, 14.6, 14.7, 18.0, 22.1, 23.0, 28.3, 31.3, 32.3, 51.3, 60.0, 63.1, 73.2,
75.5, 127.3, 127.4, 128.2, 130.3, 130.6, 130.7, 138.4, 152.4, 174.3.
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25
12. Cyclopentenedione 3; ‰ꢁŠD =+3.7ꢀ (c=1.05, CHCl3); H-NMR (400 MHz, CDCl3): ꢀ 0.87 (3H, t, J=7.3 Hz), 1.00
(3H, s), 1.31 (2H, m, J=7.3, 7.6 Hz), 1.47 (2H, m), 2.04 (3H, s), 2.50 (2H, m), 3.61 (2H, s), 4.35 (2H, s), 7.21±7.35
(5H, m).; 13C-NMR (100 MHz, CDCl3): ꢀ 9.3, 13.8, 15.1, 22.6, 23.8, 29.8, 50.2, 72.2, 73.2, 127.1, 127.5, 128.3,
137.6, 154.7, 159.1, 205.6, 205.9.
1