Asymmetric total synthesis of vindoline

Article abstract of DOI:10.1021/ja910695e

"Chemical equation presented" A concise asymmetric total synthesis of (-)-vindoline (1) is detailed based on a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which the tether linking the initiating dienophile and oxadiazole bears a chiral substituent that controls the facial selectivity of the initiating Diels-Alder reaction and sets absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduces three rings and four C-C bonds central to the pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. Implementation of the approach also required the development of a unique ring expansion reaction to provide a six-membered ring suitably functionalized for introduction of the .(6, 7)-double bond found in the core structure of vindoline and defined our use of a protected hydroxymetyl group as the substituent used to control the stereochemical course of the cycloaddition cascade.

Full text of DOI:10.1021/ja910695e

Published on Web 02/26/2010
Asymmetric Total Synthesis of Vindoline
Daisuke Kato, Yoshikazu Sasaki, and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La Jolla, California 92037
Received December 18, 2009; E-mail: boger@scripps.edu
Vindoline (1),1,2 a major alkaloid of Cantharanthus roseus,
constitutes the more complex lower half of vinblastine (2)2-5 and
serves as both a biosynthetic3,4 and synthetic6,7 precursor to this
important natural product (Figure 1). We recently reported the
developmentofaconcisetotalsynthesisof(-)-andent-(+)-vindoline8-10
enlisting an intramolecular tandem [4+2]/[3+2] cycloaddition cascade
of 1,3,4-oxadiazoles11 with resolution of a key intermediate, its
extension to the preparation of a series of related natural products
including vindorosine,10,12 and the subsequent development of a
biomimetic Fe(III)-promoted coupling with catharanthine for their
single step incorporation into total syntheses of vinblastine and related
natural products.6f Herein, we report the development of an asymmetric
total synthesis of (-)-vindoline based on an additional implementation
of the tandem [4+2]/[3+2] cycloaddition reaction in which the tether
linking the initiating dienophile and oxadiazole bears a chiral substituent
that sets the absolute stereochemistry of the remaining six stereocenters
in the cascade cycloadduct. Relative to our earlier work,10 the
dienophile linking tether was reduced in length by one carbon
permitting the effective control of the facial selectivity of the initiating
Diels-Alder reaction and subsequent transmission of the attached
substituent stereochemistry throughout the newly constructed penta-
cyclic ring system that was not observed in our studies with a four
atom tether to the initiating dienophile.10 Moreover, this ensured that
the initiating Diels-Alder reaction could be conducted under milder
conditions than previously observed.11 The approach required that the
activating acyl chain carbonyl now reside in the dipolarophile tether
and that the [4+2] cycloaddition afford a fused five-membered versus
six-membered ring. A subsequent, unique ring expansion reaction was
developed to provide a six-membered ring suitably functionalized for
introduction of the ∆6,7-double bond found in the core structure of
vindoline and defined our use of a protected hydroxymethyl group as
the substituent used to control the stereochemical course of the
cycloaddition cascade.
Scheme 1
The most important question addressed in initial studies was the
stereochemical fate of the key cycloaddition cascade. Accordingly,
substrate 13 was prepared and examined in detail. Although 13 lacks
the aryl methoxy substituent required for the synthesis of vindoline, it
was judged to be an ideal surrogate for examination of the key
cycloaddition reaction. The side chain chirality was set using aspartic
acid as the starting material (Scheme 1, both enantiomers prepared,
natural enantiomer series shown). Teoc protection of D-H2N-Asp(OBn)-
Figure 1. Natural product and key cycloaddition cascade.
9
10.1021/ja910695e  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 3685–3687 3685

C O M M U N I C A T I O N S
Scheme 2
OH (TeocOSu, quant.) followed by mixed anhydride formation (i-
BuOCOCl, NMM, DME, -15 °C) and reduction (NaBH4, H2O)
provided the alcohol 5 (91%), which was protected as its MOM ether
6 (MOMCl, i-Pr2NEt, CH2Cl2, 84%). Benzyl ester hydrogenolysis (H2,
10% Pd/C, THF), coupling of the crude carboxylic acid with N,O-
dimethylhydroxylamine (EDCI, DMAP, i-Pr2NEt, CH2Cl2, 94% from
6), and reaction of the Weinreb amide 7 with EtMgBr (3 equiv, 3
equiv of CeCl3, THF, 0 °C, 1 h, quant.)13 cleanly provided the ethyl
ketone 8.
Wittig olefination of 8 with Ph3PdCHOBn provided a 1:1 mixture
of the separable (E) and (Z) enol ethers 9. Teoc deprotection (Bu4NF)
and treatment of the liberated amine with carbonyldiimidazole (CDI)
afforded 10 (86%, two steps) that was converted to the oxadiazole
precursor 12 by treatment with methyl oxalylhydrazide14 in the
presence of HOAc (78%) and cyclization of 11 to form the corre-
sponding oxadiazole (TsCl, Et3N, CH2Cl2, 94%). Coupling of 12 with
(1-methylindol-3-yl)-2-acetic acid provided the substrate 13 with which
the initial examination of the cycloaddition cascade was conducted.
Cyclization of 13 proceeded effectively providing essentially or
predominantly a single cascade cyloaddition diastereomer 14 in
superb conversions (72%, xylene, 145-150 °C, 10 h), and only
small amounts (0-13%) of a second diastereomer were detected,
Scheme 2. The temperature required to initiate the cycloaddition
cascade is lower (145 vs 180 °C), and the reaction time required
for complete reaction is shorter (10 vs 24 h) than those observed
with substrates bearing a longer dienophile tether.10
Diastereoselective reductive cleavage of the oxido bridge was
effected by treatment with NaCNBH3 (2 equiv, 20% HOAc/i-PrOH,
0-25 °C, 40 min, 94%) in a reaction that proceeds by acid-catalyzed
generation of an acyliminium ion flanked by two quaternary centers
that is reduced by hydride addition to the less hindered convex face
and provided 15 whose structure and stereochemistry were confirmed
in a single crystal X-ray structure determination.15 Following initial
studies characterizing the cascade cycloaddition reaction of 13, it
proved most convenient to run the cycloaddition and subsequent
reductive oxido bridge cleavage without the intermediate purification
of 14, which proved sensitive to silica gel exposure, providing 15
directly in good overall conversions (57-70% for two steps).
The reaction cascade is initiated by [4+2] cycloaddition of the
1,3,4-oxadiazole with the tethered electron-rich enol ether whose
reactivity and regioselectivity are matched to react with the electron-
deficient oxadiazole in an inverse electron demand Diels-Alder
reaction (Figure 1). Loss of N2 from the initial cycloadduct provides
a carbonyl ylide, which undergoes a subsequent 1,3-dipolar
cycloaddition with the tethered indole.16 The diene and dienophile
substituents reinforce the [4+2] cycloaddition regioselectivity
dictated by the linking tether, the intermediate 1,3-dipole is
stabilized by the complementary substitution at the dipole termini,
and the intrinsic regioselectivity of the attached dipolarophile
(indole) complements the [3+2] cycloaddition regioselectivity that
is set by its linking chain. The dienophile tether substituent
effectively controls the facial selectivity of the initiating [4+2]
cycloaddition reaction dictating that the protected hydroxylmethyl
group at C7 and the C5 ethyl group reside trans to one another on
the newly formed five-membered ring avoiding a cis pseudodiaxial-
1,3-interaction on the sterically more congested concave face of
the transition state leading to the initial [4+2] cycloadduct. This
establishes the absolute stereochemistry at C5, which in turn is
transmitted throughout the cascade cycloadduct where the remaining
relative stereochemistry is controlled by a combination of the
dienophile geometry (C4 and C5 stereochemistry) and an endo
indole [3+2] cycloaddition that is sterically directed to the face of
the 1,3-dipole opposite the newly formed five-membered ring.10-12
The minor diastereomer occasionally observed in the cycloaddition
of 13 appears to be derived from endo indole [3+2] cycloaddition
on the same face of the 1,3-dipole as the newly formed 5-membered
ring (C2/C11 diastereomer) suggesting the facial selectivity for the
initiating Diels-Alder reaction is >20:1 (detection limits).17
The substrate 16, required for the synthesis of vindoline and
bearing the indole methoxy group, participated in the cycloaddition
cascade (130 °C, 8 h and 175 °C, 8 h, xylene) in an analogous
fashion, and although the initial cascade cycloadduct 17 was isolated
and characterized, it was most conveniently subjected to reductive
oxido bridge cleavage (NaCNBH3, 10% HOAc/i-PrOH) prior to
purification providing 18 directly (55% for two steps, Scheme 2).
The product 18 was converted to the key intermediate 22 by benzyl
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C O M M U N I C A T I O N S
ether hydrogenolysis (91%), oxidation of the free alcohol 19 (DMP,
pyridine-CH2Cl2, 0 °C, 3 h, 76%), and diastereoselective ketone
reduction (LiAlH(OtBu)3, THF, 0 °C, 10 h, 87%, 30:1 dr) from
the less hindered convex face of 20, followed by C4 alcohol 21
acetylation (Ac2O, DMAP, pyridine, 95%) to provide 22 (Scheme
2). O-Methylation and reductive removal of the lactam carbonyl
(MeOTf, 2,6-di-tert-butylpyridine, CH2Cl2, 25 °C, 2 h; NaBH4,
MeOH, 25 °C, 5 min) followed by MOM ether deprotection (HCl,
MeOH, 25 °C, 16 h) liberated the primary alcohol 24 (85% for
two steps from 22). Oxidation (3 equiv of SO3-Py, 3 equiv of
Et3N, CH2Cl2/DMSO, 25 °C, 1-2 h) of 24 provided an unstable
R-aminoaldehyde that not only rapidly epimerized but also was found
to be prone to hydrate and enol formation. Moreover, we found that
simply exposing the crude aldehyde to silica gel in the presence of
Et3N (1% Et3N/EtOAc) in the course of conventional purification led
to clean conversion to the stable N,O-ketal 25 (85%), eq 1.
Supporting Information Available: Full experimental details are
provided. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Gorman, M.; Neuss, N.; Biemann, K. J. Am. Chem. Soc. 1962, 84, 1058.
(2) Moncrief, J. W.; Lipscomb, W. N. J. Am. Chem. Soc. 1965, 84, 4963.
(3) (a) Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N.Y. Acad. Sci. 1958, 76,
882. (b) Noble, R. L. Lloydia 1964, 27, 280. (c) Svoboda, G. H.; Nuess,
N.; Gorman, M. J. Am. Pharm. Assoc. Sci. Ed. 1959, 48, 659.
(4) Review: Neuss, N.; Neuss, M. N. In The Alkaloids; Brossi, A., Suffness,
M., Eds.; Academic: San Diego, 1990; Vol. 37, p 229.
(5) Reviews: (a) Pearce, H. L. In The Alkaloids; Brossi, A., Suffness, M., Eds.;
Academic: San Diego, 1990; Vol. 37, p 145. (b) Borman, L. S.; Kuehne,
M. E. In The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic: San
Diego, 1990; Vol. 37, p 133.
(6) (a) Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y.; Potier,
P. J. Am. Chem. Soc. 1979, 101, 2243. (b) Kutney, J. P.; Choi, L. S. L.;
Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A. Heterocycles 1988,
27, 1845. (c) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org.
Chem. 1991, 56, 513. Bornmann, W. G.; Kuehne, M. E. J. Org. Chem.
1992, 57, 1752. Kuehne, M. E.; Zebovitz, T. C.; Bornmann, W. G.; Marko,
I. J. Org. Chem. 1987, 52, 4340. (d) Magnus, P.; Mendoza, J. S.; Stamford,
A.; Ladlow, M.; Willis, P. J. Am. Chem. Soc. 1992, 114, 10232. (e)
Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11966. (f) Ishikawa, H.; Colby, D. A.; Boger,
D. L. J. Am. Chem. Soc. 2008, 130, 420. Ishikawa, H.; Colby, D. A.; Seto,
S.; Va, P.; Tam, A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am.
Chem. Soc. 2009, 131, 4904.
(7) Review: Kuehne, M. E.; Marko, I. In The Alkaloids; Brossi, A., Suffness,
M., Eds.; Academic: San Diego, 1990; Vol. 37, p 77.
(8) Racemic total syntheses: (a) Ando, M.; Bu¨chi, G.; Ohnuma, T. J. Am. Chem.
Soc. 1975, 97, 6880. (b) Kutney, J. P.; Bunzli-Trepp, U.; Chan, K. K.; De
Souza, J. P.; Fujise, Y.; Honda, T.; Katsube, J.; Klein, F. K.; Leutwiler,
A.; Morehead, S.; Rohr, M.; Worth, B. R. J. Am. Chem. Soc. 1978, 100,
4220. (c) Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. J. Org. Chem.
1985, 50, 961. Formal total syntheses: (d) Ban, Y.; Sekine, Y.; Oishi, T.
Tetrahedron Lett. 1978, 2, 151. (e) Takano, S.; Shishido, K.; Sato, M.;
Yuta, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun. 1978, 943. Takano,
S.; Shishido, K.; Matsuzaka, J.; Sato, M.; Ogasawara, K. Heterocycles 1979,
13, 307. (f) Danieli, B.; Lesma, G.; Palmisano, G.; Riva, R. J. Chem. Soc.,
Chem. Commun. 1984, 909. Danieli, B.; Lesma, G.; Palmisano, G.; Riva,
R. J. Chem. Soc., Perkin Trans. 1 1987, 155. (g) Zhou, S.; Bommeziijn,
S.; Murphy, J. A. Org. Lett. 2002, 4, 443.
(9) Enantioselective total syntheses: (a) Feldman, P. L.; Rapoport, H. J. Am.
Chem. Soc. 1987, 109, 1603. (b) Kuehne, M. E.; Podhorez, D. E.; Mulamba,
T.; Bornmann, W. G. J. Org. Chem. 1987, 52, 347. (c) Cardwell, K.; Hewitt,
B.; Ladlow, M.; Magnus, P. J. Am. Chem. Soc. 1988, 110, 2242. (d)
Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883.
(10) (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am.
Chem. Soc. 2006, 128, 10596. (b) Choi, Y.; Ishikawa, H.; Velcicky, J.;
Elliott, G. I.; Miller, M. M.; Boger, D. L. Org. Lett. 2005, 7, 4539.
(11) (a) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.; Soenen,
D. B.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc. 2002,
124, 11292. (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.;
Tao, H.; Yuan, Z.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589. For
reviews of heterocyclic azadiene cycloaddition reactions, see: (c) Boger,
D. L. Tetrahedron 1983, 39, 2869. (d) Boger, D. L. Chem. ReV. 1986, 86,
781. (e) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in
Organic Synthesis; Academic: San Diego, 1987.
Formation of the primary tosylate 26 (TsCl, DMAP, Et3N, CH2Cl2,
25 °C, 16 h, 93%) and its subjection to conditions developed for ring
expansion18 (NaOAc, dioxane-H2O, 70 °C) provided the key six-
membered ring ketone 17 (61%). Although several mechanistic
possibilities can be envisioned for this transformation, some of which
proceed through an aziridinium ion, it is most simply and formally
represented as hydrolysis of the N,O-ketal to release a reactive
R-tosyloxymethyl ketone followed by its intramolecular N-alkylation
to provide the six-membered ketone 17 (eq 2).
(12) (a) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y.; Boger, D. L. Angew. Chem.,
Int. Ed. 2006, 45, 620. (b) Yuan, Z.; Ishikawa, H.; Boger, D. L. Org. Lett.
2005, 7, 741. (c) Ishikawa, H.; Boger, D. L. Heterocycles 2007, 72, 95.
(13) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. J. Am.
Chem. Soc. 1989, 111, 4392.
(14) Christl, M.; Lanzendoerfer, U.; Groetsch, M. M.; Ditterich, E.; Hegmann,
J. Chem. Ber. 1990, 123, 2031.
(15) The structure and stereochemistry of 15 (CCDC 758511) and the MOM-
deprotected primary alcohol of 18 (CCDC 758510) were established by
X-ray and conducted on the unnatural and natural enantiomer series,
respectively.
(16) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. and 1995, 60, 6258.
(17) The substrate 13 bearing the (Z)-enol ether also participates in the
cycloaddition cascade but not as effectively as the (E)-enol ether (51-
57% vs 72%) and requires more dilute reaction conditions (0.1 vs 1-5
mM).
(18) (a) Frehel, D.; Badorc, A.; Pereillo, J.-M.; Maffrand, J.-M. J. Heterocyclic
Chem. 1985, 22, 1011. (b) Kavadias, G.; Velkof, S.; Belleau, B. Can.
J. Chem. 1979, 57, 1861.
(19) Abbreviations: EDCI ) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride; DMP ) Dess-Martin periodinane; MOM ) methoxymethyl;
DMAP ) 4-dimethylaminopyridine; DMSO ) dimethylsulfoxide; NMM
) N-methylmorpholine; Teoc ) 2-(trimethylsilyl)ethoxycarbonyl.
Diastereoselective reduction of 27 (L-selectride, THF, -78 °C, 0.5 h)
provided the penultimate secondary alcohol 28 (91%, >30:1 dr),12c
which in turn underwent regioselective elimination as previously
described10 to provide vindoline (1) upon Mitsunobu activation in the
absence of added nucleophiles, Scheme 2.19
Exploration of additional means to effect the key ring expansion
reaction, extensions to the preparation of additional Aspidosperma
alkaloids and key vindoline analogues, and their incorporation (e.g.,
24 and 28) into vinblastine analogues are in progress and will be
reported in due course.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA115526 and CA042056)
and the Skaggs Institute for Chemical Biology. We wish to thank Dr.
Raj Chadha for the X-ray crystal structures and the Uehara Memorial
Foundation for fellowship support (Y.S.). D.K. is a Skaggs Fellow.
JA910695E
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