Stereocontrolled total synthesis of (+)-vinblastine

Article abstract of DOI:10.1021/ja0177049

A stereocontrolled total synthesis of (+)-vinblastine was accomplished, featuring preparations of the two indole units by means of a novel indole synthesis via radical cyclization of thioanilide, and a stereoselective coupling of these units. Copyright

Full text of DOI:10.1021/ja0177049

Published on Web 02/16/2002
Stereocontrolled Total Synthesis of (+)-Vinblastine
Satoshi Yokoshima, Toshihiro Ueda, Satoshi Kobayashi, Ayato Sato, Takeshi Kuboyama,
Hidetoshi Tokuyama, and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received December 7, 2001
Vinblastine (1), isolated from Catharanthus roseus,1 has been
Scheme 1
widely known as a prominent agent in cancer chemotherapy. Since
chemical modifications of the natural product have been the major
means for exploration of the more potent analogues, a limited
number of its derivatives have so far been accessible.2a Total
synthesis of vinblastine, on the other hand, has been the subject of
intensive investigations in the area of alkaloid synthesis.2b Despite
the endeavors spanning over the past three decades, only four
syntheses have been reported to date.3 In all cases, however, the
supply of the lower half of vinblastine (i.e., vindoline) relied upon
the natural sources. The major challenges in the total synthesis of
1 include controlling the stereochemistry of C18′ as well as
establishment of efficient routes to the two halves of the indole
units.
Our synthetic plan is shown in Scheme 1. Model studies by Schill
as well as our molecular modeling study strongly suggested that a
Scheme 2a
stereocontrolled coupling with vindoline (2) could be performed
when one employs an eleven-membered intermediate such as 3 as
a partner.4 Synthesis of the lower half, vindoline (2), would require
substantial improvement over our biomimetic total synthesis to
supply a sizable amount of the mateiral.5 On the other hand, we
planned to synthesize the upper half by means of our indole
synthesis via radical cyclization of o-alkenylthioanilide.6
An improved preparation of the requisite amine unit 8 for the
a Reagents and conditions: (a) NaCN, AcOH, room temperature; (b)
synthesis of vindoline is outlined in Scheme 2. 3-Ethyl-5-phenyl-
4-pentenal (4), readily derived from 2-pentenal,7 was transformed
into cyanohydrin acetate 5 in 2 steps. Enzymatic hydrolysis of the
acetate 5 afforded a diastereomeric mixture of (S)-cyanohydrins.
Ozonolysis and subsequent dehydration of the resulting hemiacetal
gave dihydrofuran 7. Reduction of the cyano group with LiAlH4
furnished a volatile amine, which was immediately converted to
the corresponding 2,4-dinitrobenzensulfonamide (DNs-NHR) 8.8
The key indole unit 13 was prepared by means of the protocol
developed recently in our laboratories for facile conversion of
quinolines to indoles (Scheme 3). Thus, 7-mesyloxyquinoline (9)9
was converted to isothiocyanate 10 by treatment with thiophosgene
followed by reduction with NaBH4.10 After protection of the
hydroxyl group as its THP ether, nucleophilic addition of the anion
of benzyl methyl malonate to the isothiocyanate afforded thioanilide
11. The radical cyclization of 11 proceeded smoothly to furnish
indole 12. For conversion to indole acrylate 13, benzyl ester of
Boc-protected 12 was first subjected to hydrogenolysis, and the
subsequent decarboxylative Mannich reaction proceeded without
incident to give, after deprotection of the THP group, the desired
indole unit 13.
Ac2O, pyridine, room temperature, 95% (2 steps); (c) Lipase PS, THF-
H2O, 50 °C, 44%, 97% ee; (d) O3, MeOH, CH2Cl2, -78 °C; Me2S, 91%;
(e) MsCl, Et3N, toluene, 0 to 80 °C, 71%; (f) LiAlH4, THF, -10 °C to
room temperature; H2O, NaOH; DNsCl, CH2Cl2, 75%.
were performed according to the synthetic pathway reported earlier5
to provide (-)-vindoline (2) in several hundred-milligram quantities
(Scheme 3).11
With synthetic (-)-vindoline in hand, we next focused on the
synthesis of the upper half (3) of vinblastine. The synthesis of the
requisite ester 23 commenced with introduction of (R)-4-benzyl-
2-oxazolidinone to 4-ethylpent-4-enoic acid (16)12 via its mixed
anhydride (Scheme 4).13 According to Evans’ method,14 diastereo-
selective cyanoethylation of the resulting imide 17 afforded adduct
18 as a sole isomer. Reduction of 1815 followed by protection of
the resulting alcohol as its TBDPS ether furnished 19. Reduction
of the nitrile 19 with DIBAL followed by treatment of the resulting
aldehyde with hydroxylamine gave the oxime, which, upon
exposure to sodium hypochlorite, underwent facile intramolecular
1,3-dipolar cycloaddition via the nitrile oxide to afford isoxazoline
20 as a single diastereomer. Subsequent reductive cleavage of the
N-O bond gave hydroxyketone 21. Baeyer-Villiger oxidation of
21 was best effected by treatment with mCPBA in acetic acid,
leading to lactone 22. Finally, methanolysis of the lactone and
protection of the resultant diol furnished the desired ester 23.
Having established much more efficient processes for the
preparation of both the indole unit 13 and the amine unit 8, the
coupling reaction of the two units and subsequent transformations
9
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J. AM. CHEM. SOC. VOL. 124, NO. 10, 2002 2137

C O M M U N I C A T I O N S
Scheme 3a
a Reagents and conditions: (a) thiophosgene, Na2CO3, THF-H2O, 0 °C; NaBH4, MeOH, 0 °C; (b) DHP, CSA, CH2Cl2, room temperture, 65% (2 steps);
(c) benzyl methyl malonate, NaH, THF, 0 °C; (d) AIBN, Bu3SnH, toluene, 110 °C; (e) Boc2O, Et3N, DMAP, CH2Cl2, room temperature, 60%
(3 steps); (f) H2, Pd/C, EtOH, room temperature; Me2NH‚HCl, HCHO, AcONa, AcOH-EtOH, room temperature, 72% (2 steps); (g) CSA, MeOH, room
temperature, 99%; (h) 8, DEAD, Ph3P, benzene, 79%; (i) TFA, Me2S, CH2Cl2, room temperature; (j) pyrrolidine, MeOH-CH3CN, 0 °C to 50 °C, 73%
(2 steps).
Scheme 4a
Scheme 5a
a Reagents and conditions: (a) PivCl, Et3N, Et2O, 0 °C; n-BuLi, (R)-4-
benzyl-2-oxazolidinone, THF, -78 °C, 89%; (b) (i-PrO)TiCl3, i-Pr2NEt,
acrylonitrile, CH2Cl2, 0 °C, 82%; (c) NaBH4, THF-H2O, room temperature,
92%; (d) TBDPSCl, imidazole, DMF, room temperature, 92%; (e) DIBAL,
CH2Cl2, -78 °C; (f) H2NOH‚HCl, NaOAc, EtOH, room temperature; (g)
NaClO aqueous, CH2Cl2, room temperature, 59% (3 steps); (h) Zn, AcOH,
66%; (i) mCPBA, AcOH, room temperature; (j) K2CO3, MeOH, room
temperature, 80% (2 steps); (k) TESCl, imidazole, DMF, room temperature;
TMSCl, room temperature, 92%.
a Reagents and conditions: (a) LDA, THF, -78 °C; 24, -78 to 0 °C,
76%; (b) Bu3SnH, Et3B, THF, room temperature, 67%; (c) Boc2O, Et3N,
DMAP, CH2Cl2, room temperature, 87%; (d) AcOH-H2O (95:5), 80 °C,
71%; (e) TsCl, Bu2SnO, Et3N, CH2Cl2, room temperature, 84%; (f)
NaHCO3, DMF, 80 °C, 90%; (g) NsNH2, DEAD, Ph3P, toluene, room
temperature, 88%; (h) K2CO3, DMF, 90 °C, 82%; (i) TFA, CH2Cl2, room
temperature, 85%; (j) TsCl, Me2N(CH2)3NMe2, CH3CN-toluene, room
temperature, 88%; (k) TFAA, pyridine, CH2Cl2, room temperature, 90%.
Construction of the key intermediate 3 features an indole
formation of the fully functionalized thioanilide 25 and a macro-
cyclization using 2-nitrobenzenesulfonamide (Ns amide) (Scheme
5).16 First, addition of the enolate of 23 to isothiocyanate 24 afforded
an inconsequential mixture of thioamides 25, which was subjected
to the radical conditions to furnish indole 26. At this stage, it became
necessary to differentiate the three hydroxyl groups. Protection of
the indole NH and acid-catalyzed deprotection of the hydroxyl
groups gave triol 27. Upon treatment of the triol 27 with TsCl and
triethylamine in the presence of dibutyltin oxide, tosylation occurred
selectively at the primary alcohol of the1,2-diol.17 After conversion
of the resulting tosylate into epoxide, the remaining primary alcohol
was treated with NsNH2 under Mitsunobu conditions18 to give 28.
Upon heating with potassium carbonate in DMF, 28 underwent a
critical macrocyclization to yield the eleven-membered-ring product
29. Acid-catalyzed deprotection of the Boc group and the TBDPS
ether, tosylation19 of the resulting primary alcohol, and subsequent
protection of the tertiary alcohol as its trifluoroacetate afforded the
key intermediate 3.20
The final stages of the total synthesis of (+)-vinblastine are
illustrated in Scheme 6. Chlorination of the indole nucleus of 3
with tert-butyl hypochlorite furnished chloroindolenine 30. To our
great satisfaction, upon treatment of the mixture of 30 and vindoline
(2) with trifluoroacetic acid, the coupling reaction proceeded
smoothly to furnish the desired product 32 as a sole isomer in 97%
yield. After deprotection of the tertiary alcohol, the Ns group was
removed under mild conditions to liberate the secondary amine,
which formed the piperidine ring to give (+)-vinblastine (1). The
synthetic product was identical in all respects to natural (+)-
vinblastine.
In conclusion, an efficient total synthesis of (+)-vinblastine has
been accomplished through the use of the radical cyclization of
o-alkenylthioanilides as well as the chemistry of 2-nitro- and 2,4-
9
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C O M M U N I C A T I O N S
Scheme 6a
a Reagents and conditions: (a) t-BuOCl, CH2Cl2, 0 °C; (b) (-)-vindoline (2), TFA, CH2Cl2, 0 °C to room temperature, 97%; (c) Et3N, MeOH, room
temperature, quantitative; (d) HSCH2CH2OH, DBU, CH3CN, room temperature, 76%; (e) NaHCO3, i-PrOH-H2O, room temperature, 66%.
reported that the coupling of (-)-vindoline with a racemic 11-membered-
ring compound proceeded with desired stereochemistry, leading to a
vinblastine analogue lacking both the ethyl group and the hydroxyl group
of the upper part. Schill, G.; Priester, C. U.; Windho¨vel, U. F.; Fritz, H.
Tetrahedron 1987, 43, 3765.
dinitrobenzenesulfonamides that have been developed in our
laboratories for the synthesis of indole alkaloids. We believe that
the present synthetic pathway could be applied to the synthesis of
a wide variety of vinblastine analogues.
(5) Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883.
(6) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama,
T. J. Am. Chem. Soc. 1999, 121, 3791.
Acknowledgment. We thank Drs. Michael J. Martinelli and
Kevin Lydon (Eli Lilly & Co.) for providing samples of natural
vindoline and vinblastine, Dr. Yoshihiko Hirose (Amano Pharma-
ceutical) for providing lipase PS, and Dr. Yoichi Nakao (University
of Tokyo) for mass spectrometric analysis. This work was
financially supported by CREST, JST, the Mitsubishi Foundation,
the Naito Foundation, and JSPS (pre-doctoral fellowship for S.Y.).
(7) PhMgBr, THF; n-butyl vinyl ether (5 equiv), Hg(OAc)2 (0.1 equiv),
NaOAc (0.1 equiv), reflux, 8 h, 79% (2 steps), see: Tokuyama, H.;
Makido, T.; Ueda, T.; Fukuyama, T. Syn. Commun. 2002, 32, 869.
(8) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373. (b) Fukuyama, T.; Cheung, M.; Jow, C.-K.; Hidai, Y.; Kan, T.
Tetrahedron Lett. 1997, 38, 5831. (c) For a review on nitrobenzene-
sulfonamide chemistry, see: Kan, T.; Fukuyama, T. J. Synth. Org. Chem.,
Jpn. 2001, 59, 779.
(9) Since the classical Skraup quinoline synthesis proved surprisingly inef-
fective, we established a practical protocol for the preparation of
quinolines, by which the desired quinoline was readily prepared on a 50-g
scale from 3-hydroxyaniline in 4 steps, see: Tokuyama, H.; Sato, M.;
Ueda, T.; Fukuyama, T. Heterocycles 2001, 54, 105.
Supporting Information Available: Experimental details and
spectral data for new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(10) (a) Hull, R. J. Chem. Soc. C 1968, 1777. (b) Farrand, R.; Hull, R. Org.
Synth. Collect. Vol. VII 1990, 302.
(11) (-)-Vindoline was synthesized from 7-hydroxyquinoline in a 17-step
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