Asymmetric total synthesis of vindorosine, vindoline, and key vinblastine analogues

Article abstract of DOI:10.1021/ja106284s

Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced 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 products in a single step. Implementation of the approach for the synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring suitably functionalized for introduction of the Δ^6,7-double bond found in the core structure of the natural products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of these studies, several analogues of vindoline were prepared containing deep-seated structural changes presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define the potential role of the vinblastine Δ^6,7-double bond.

Full text of DOI:10.1021/ja106284s

Published on Web 09/01/2010
Asymmetric Total Synthesis of Vindorosine, Vindoline, and
Key Vinblastine Analogues
Yoshikazu Sasaki,† Daisuke Kato,† 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 July 15, 2010; E-mail: boger@scripps.edu
Abstract: Concise asymmetric total syntheses of vindoline (1) and vindorosine (2) are detailed based on
a unique intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles inspired by the natural
product structures. A chiral substituent on the tether linking the dienophile and oxadiazole was used to
control the facial selectivity of the initiating Diels-Alder reaction and set the absolute stereochemistry of
the remaining six stereocenters in the cascade cycloadduct. This key reaction introduced 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 products in a single step. Implementation of the approach for the
synthesis of 1 and 2 required the development of a ring expansion reaction to provide a 6-membered ring
suitably functionalized for introduction of the ∆6,7-double bond found in the core structure of the natural
products. Two unique approaches were developed that defined our use of a protected hydroxymethyl group
as the substituent that controls the stereochemical course of the cycloaddition cascade. In the course of
these studies, several analogues of vindoline were prepared containing deep-seated structural changes
presently accessible only by total synthesis. These analogues, bearing key modifications at C6-C8, were
incorporated into vinblastine analogues and used to probe the unusual importance (100-fold) and define
the potential role of the vinblastine ∆6,7-double bond.
Introduction
Vindoline (1),1,2 a major alkaloid of Cantharanthus roseus,
constitutes the more complex lower half of vinblastine (4)2–5
and serves as both a biosynthetic3,4 and synthetic6,7 precursor
to this important natural product (Figure 1). Vinblastine (4) and
vincristine (5) represent the most widely recognized members
of the Vinca alkaloids as a result of their clinical use as antitumor
drugs. Originally isolated in trace quantities from Cantharanthus
roseus (L.) G. Don,3 their biological properties were among
† These authors contributed equally to the work.
(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.
For related, naturally occurring Vinca alkaloids, see the following.
Leurosidine: (d) Svoboda, G. H. Lloydia 1961, 24, 173. Deoxyvin-
blastine: (e) De Bruyn, A.; Sleechecker, J.; De Jonghe, J. P.; Hannart,
J. Bull. Soc. Chim. Belg. 1983, 92, 485. Neuss, N.; Gorman, M.; Cone,
N. J.; Huckstep, L. L. Tetrahedron Lett. 1968, 783. N-Desmethylvin-
blastine: (f) Simonds, R.; De Bruyn, A.; De Taeye, L.; Verzele, M.;
De Pauw, C. Planta Med. 1984, 50, 274. Desacetoxyvinblastine: (g)
Neuss, N.; Barnes, A. J.; Huckstep, L. L. Experientia 1975, 31, 18.
Desacetylvinblastine: (h) Svoboda, G. H.; Barnes, A. J. J. Pharm. Sci.
1964, 53, 1227. Anhydrovinblastine: (i) Goodbody, A. E.; Watson,
C. D.; Chapple, C. C. S.; Vukovic, J.; Misawa, M. Phytochemistry
1988, 27, 1713.
Figure 1. Natural product structures.
the first to be shown to arise from inhibition of microtubule
formation and mitosis that today is still regarded as one of the
more successful drug targets for the treatment of cancer.3–5 We
previously reported the development of a concise total synthesis
of (-)- and ent-(+)-vindoline8-10 enlisting a powerful intramo-
lecular tandem [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-
oxadiazoles with resolution of a key intermediate,11 its extension
to the preparation of a series of related natural products including
vindorosine (2),10,12 and the subsequent development of a
biomimetic Fe(III)-promoted coupling with catharanthine (3)
for their single step incorporation into total syntheses of
vinblastine, vincristine, and related natural products.6f
(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.
9
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A R T I C L E S
Sasaki et al.
Diels-Alder reaction could be conducted under milder conditions11
than previously observed. More significantly, this change permitted
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
pentacyclic ring system that was not observed with a longer
dienophile tether.10 The approach required that the activating acyl
chain carbonyl now reside in the dipolarophile tether and that the
initiating Diels-Alder reaction of the cycloaddition cascade afford
a fused 5-membered ring. A subsequent ring expansion to provide
the unsaturated 6-membered ring found in the core structure of
the natural products was anticipated to be accomplished by using
a hydroxymethyl side chain substituent that, upon alcohol activation
for displacement, would undergo aziridinium ion formation and
subsequent nucleophilic attack to provide a more stable 6- versus
5-membered ring suitably functionalized for introduction of the
∆6,7-double bond. As detailed herein, this rearrangement is subject
to stereoelectronic control for both the aziridinium ion formation
as well as its subsequent cleavage by nucleophilic attack, the latter
of which also proved to be subject to kinetic and thermodynamic
control of the regioselectivity. Investigations into these issues
provided a unique and remarkably concise approach to the total
synthesis of the natural products, clarified an important stereo-
chemical requirement for the final regioselective elimination, and
ultimately led to the development of an additional second unan-
ticipated approach to the key ring expansion.
Results and Discussion
Cycloaddition Substrate Preparation and Examination of
the Cycloaddition Cascade. The most important question ad-
dressed in initial studies was the stereochemical fate of the key
(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. (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.
Figure 2. Key elements of the initial synthetic strategy.
Herein, we report full details13 of the development of
asymmetric total syntheses of vindoline (1) and the related
natural product vindorosine (2) based on an additional imple-
mentation 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 absolute stereo-
chemistry of the remaining six stereocenters in the cascade
cycloadducts (Figure 2).
(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.
Relative to our early work,10 the dienophile linking tether was
reduced in length by one carbon ensuring that the initiating
(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.
(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. (d) Campbell, E. L.; Zuhl, A. M.; Liu,
C. M.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3009. (e) Va, P.;
Campbell, E. L.; Robertson, W. M.; Boger, D. L. J. Am. Chem. Soc.
2010, 132, 8489.
(7) Review: Kuehne, M. E.; Marko, I. In The Alkaloids; Brossi, A.,
Suffness, M., Eds.; Academic: San Diego, 1990; Vol. 37, p 77.
(13) Kato, D.; Sasaki, Y.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 3685.
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Vindorosine and Vindoline Asymmetric Total Synthesis
A R T I C L E S
considerably less effective (67% vs quant.).17 Wittig olefination
with Ph3PdCHOBn18 provided a 1:1 mixture of the separable
(E)- and (Z)-enol ethers 12, which were independently carried
through the subsequent 3-4 steps for oxadiazole formation and
the preparation of (E)- and (Z)-15. Thus, their Teoc deprotection
(Bu4NF) and treatment of the crude amines with carbonyldi-
imidazole afforded (Z)- and (E)-13 (86-100%) that were
converted to the oxadiazole precursors 14 by treatment with
methyl oxalylhydrazide19 in the presence of HOAc. Cyclization
to form the corresponding oxadiazoles 15 was mediated by TsCl
and Et3N (CH2Cl2, 94-97%). Coupling of (Z)-15 and (E)-15
with 2-(1-methylindol-3-yl)acetic acid (16) provided the sub-
strates (Z)-17 and (E)-17, respectively, with which the initial
examination of the cycloaddition cascade was conducted.
Although they lack the aryl methoxy substituent required for
the total synthesis of vindoline, they are substrates that lead to
vindorosine and were judged to be ideal surrogates for detailed
examination of the key cycloaddition reaction.
Scheme 1
As detailed in early studies, trisubstitution on the dienophile
typically precludes [4 + 2] cycloaddition initiation of the
reaction cascade.11 The exception to this generalization is the
use of trisubstituted olefins bearing an electron-donating sub-
stituent to activate the tethered dienophile for participation in
an inverse electron demand Diels-Alder reaction with the
electron-deficient 1,3,4-oxadiazole. The additional shortening
of the dienophile tether length from four to three atoms was
expected to further enhance this reactivity leading to a cycload-
dition cascade that would proceed under milder conditions than
previously observed. Thus, the electron-rich dienophiles of (Z)-
17 and (E)-17 were judged to be well suited for initiation of
the cycloaddition cascade enhancing the intrinsic reactivity of
the dienophile, reinforcing the [4 + 2] cycloaddition regiose-
lectivity dictated by the dienophile tether, and introducing the
C4 alkoxy substituent. The distinction in the two substrates is
that (Z)-17 permits the direct introduction of the naturally
occurring C4 stereochemistry, whereas (E)-17 provides the C4
isomer requiring a subsequent inversion of configuration at this
center. Cyclization of (E)-17 proceeded cleanly and effectively
providing essentially or predominantly a single diastereomer
20 in superb conversions (72%, xylene, 145-150 °C, 10 h),
and only small amounts (0-13%) of a second diastereomer were
occasionally isolated (Scheme 2). Notably, the temperature
needed 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 In fact, (E)-17 possessed sufficient
reactivity that cycloaddition was observed even in refluxing
toluene (110 °C), albeit requiring longer reaction times (e.g.,
50% 20 at 66 h). Diastereoselective reductive cleavage of the
oxido bridge in 20 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
subsequently reduced by hydride addition to the less hindered
convex face, and provided 21 whose structure and stereochem-
istry were confirmed in a single crystal X-ray structure deter-
cycloaddition cascade. In prior studies, we observed significant
differences in the rate and facility of the reaction that were
dependent on the stereochemistry of the initiating dienophile.
Although both (Z)- and (E)-enol ethers proved successful at
initiating the cycloaddition cascade, the reaction rate for the
(Z)-isomer, providing directly the correct C4 stereochemistry,
was considerably slower than that of the corresponding (E)-
isomer, the latter of which required an inversion of the
cycloadduct C4 sterochemistry for use in the targeted synthe-
sis.10 Accordingly, substrates bearing both the (Z)-enol ether
illustrated in Figure 2 and the corresponding (E)-enol ether were
prepared and examined (Scheme 1). The side chain chirality
was set using aspartic acid as the starting material (both
enantiomers prepared, natural enantiomer series shown). Teoc
protection of D-H2N-Asp(OBn)-OH (6, quant.) followed by
mixed anhydride formation (i-BuOCOCl, NMM, DME, -15
°C, 15 min) and its reduction (NaBH4, H2O, -20 °C) provided
the primary alcohol 8 (91%), which was protected as its MOM
ether 9 (MOMCl, i-Pr2NEt, CH2Cl2, 25 °C, 2 h, 84%).14 Benzyl
ester hydrogenolysis (H2, 10% Pd/C, THF, 25 °C, 0.5 h),
coupling of the crude carboxylic acid with N,O-dimethylhy-
droxylamine (1.2 equiv of EDCI, DMAP, i-Pr2NEt, CH2Cl2,
0-25 °C, 16 h, 94% from 9), and reaction of the Weinreb amide
1015,16 with EtMgBr (3 equiv, 3 equiv of CeCl3, THF, 0 °C,
1 h, quant.) cleanly provided the ethyl ketone 11. Notably, the
reaction of the Grignard reagent with a substrate closely related
to 10 (-OTBS vs -OMOM) in the absence of CeCl3 was
(14) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J.
Tetrahedron Lett. 1991, 32, 923.
(15) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(16) Compound 10 was also prepared in a single operation (47%) from
L-TeocHN-Ser(OMOM)-OH by treatment with (1) i-BuOCOCl, Et3N,
THF; (2) CH2N2, THF; (3) PhCO2Ag, MeNH(OMe), Et3N, THF. This
avoids the use of an unnatural amino acid precursor for the natural
enantiomer series.
(17) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya,
Y. J. Am. Chem. Soc. 1989, 111, 4392.
(18) Tam, T. F.; Fraser-Reid, B. J. Chem. Soc., Chem. Commun. 1980,
556.
(19) Christl, M.; Lanzendoerfer, U.; Groetsch, M. M.; Ditterich, E.;
Hegmann, J. Chem. Ber. 1990, 123, 2031.
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A R T I C L E S
Sasaki et al.
Scheme 2
the electron-deficient oxadiazole in an inverse electron demand
Diels-Alder reaction (Figure 2). Loss of N2 from the initial
cycloadduct provides a carbonyl ylide, which undergoes a
subsequent 1,3-dipolar cycloaddition with the tethered indole.21
The diene and dienophile substituents complement and reinforce
the [4 + 2] cycloaddition regioselectivity dictated by the linking
tether, the intermediate 1,3-dipole is stabilized by the comple-
mentary substitution at the dipole termini, and the intrinsic
regioselectivity of the attached dipolarophile (indole) reinforces
the [3 + 2] cycloaddition regioselectivity that is set by its linking
chain. The chiral substituent on the dienophile tether effectively
controls the facial selectivity of the initiating [4 + 2] cycload-
dition reaction preferring that the protected hydroxylmethyl
group at C7 and the C5 ethyl group reside trans to one another
on the newly formed 5-membered ring avoiding a cis pseudodi-
axial-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] cycload-
dition sterically directed to the face opposite the newly formed
5-membered ring.10–12 The minor diastereomer derived from
the cycloaddition of (E)-17 that was occasionally observed and
isolated (>7-15:1) is derived from exo indole [3 + 2]
cycloaddition on the face of the 1,3-dipole opposite the newly
formed 5-membered ring (C2/C11 diastereomer), indicating that
the facial selectivity for the initiating Diels-Alder reaction is
>20:1 (detection limits), whereas the minor diastereomer isolated
from the cycloaddition of (Z)-17 (6-10:1) is derived from the
alternative [4 + 2] cycloaddition facial selectivity and has the
C7 protected hydroxymethyl group and C5 ethyl cis to one
another. The latter minor diastereomer and 18 both are recovered
unchanged when independently resubjected to thermal reaction
conditions as pure samples (175 °C, 8 h), whereas the former
pure minor diastereomer isolated from the reaction of (E)-17
slowly converts to 20 (80-98%, whereas pure 20 is recovered
unchanged) indicating that, in selected instances, the 1,3-dipolar
cycloaddition may be thermally reversible, partitioning to the
thermodynamically more stable reaction product (∆E ) >4.9
kcal/mol for 20, MM2). Significantly, this latter observation
accounts for the fact that this minor diastereomer was not always
observed, having been funneled on to the thermodynamically
more stable product because of the reaction conditions em-
ployed. With recognition of this unique ability to funnel this
minor diastereomer into the desired diastereomer 20 under
thermal conditions, the reaction conditions employed for (E)-
17 were adjusted to first promote the cycloaddition cascade
(125-140 °C, 8 h, xylene), then warmed at a higher temperature
of 175 °C (8 h) to promote the further in situ conversion of the
minor diastereomer to 20 (74% overall following oxido bridge
cleavage).
mination.20 Following initial studies in which 20 was charac-
terized and as we scaled up the reaction sequence, it proved
most convenient to run the cycloaddition reaction and subse-
quent reductive oxido bridge cleavage without the intermediate
purification of 20, providing 21 directly in good overall
conversions (70% for the two steps). By contrast and consistent
with expectations,10 the tandem cycloaddition of (Z)-17 proved
more challenging to implement. After considerable exploration,
(Z)-17 was found to provide the desired cycloadduct 18 as the
major diastereomer (6-10:1 dr) when warmed in o-Cl2C6H4
(140 °C, 20 h, 51-57%). Like substrate (E)-17, the reaction is
initiated at the lower reaction temperatures (140 °C), but
satisfactory conversions required more dilute reaction concentra-
tions (0.1 mM vs 1-5 mM) to avoid competitive intermolecular
reactions in the slower 1,3-dipolar cycloaddition. Because the
immediate cycloadduct 18 proved somewhat unstable to the
conditions of chromatographic purification, the crude product
was typically subjected to reductive oxido bridge cleavage
(NaCNBH3, HCl, THF/i-PrOH, 0 °C, 1 min, 99%) providing
19 directly in yields up to 61% for the two step conversion. In
this case, the corresponding C18 methoxy N,O-ketal was isolated
if the reaction was conducted in MeOH (vs i-PrOH) resulting
from oxido bridge cleavage and solvent trap of the iminium
ion without reduction and more extended reaction times or
higher reaction temperatures can lead to increasing amounts of
MOM ether deprotection (0-10%) under the mildly acidic
conditions employed.
Although the stereochemical assignments were firmly estab-
lished by X-ray analysis of various intermediates described
herein including 21,20 detailed spectroscopic analysis of the
cycloaddition products 18 and 20, as well as their minor
diastereomers, confirmed the assignments distinguishing the two
series (Figure 3). The cycloadduct 18 exhibited diagnostic NOEs
of C5-Et with C4-H, C6-HR, C7-H and C13-H and of C4-H
with N1-Me placing them all on the R-face of the structure, as
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
(20) The structure and stereochemistry of 21 were established by X-ray
(CCDC 758511) and conducted on the unnatural enantiomer series.
(21) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556. 1995, 60, 6258.
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Vindorosine and Vindoline Asymmetric Total Synthesis
A R T I C L E S
Scheme 3
Figure 3. Structure of minor diastereomers and diagnostic NOEs.
well as between C2-H/C10-Hꢀ, C6-HR/C7-H and C6-Hꢀ/C19-
H2. Its minor diastereomer, enantiomeric in structure with 18
except for the C7 stereochemistry, exhibited diagnostic NOEs
of C5-Et with C4-H, C6-HR, C19-H2 and C13-H and of C4-H
with N1-Me placing them all on the R-face of the structure, as
well as between C2-H/C10-Hꢀ, C6-Hꢀ/C7-H, and C6-HR/C19-
H2. The cycloadduct 20 exhibited diagnostic NOEs of C5-Et
with C4-OBn, C6-HR, C7-H, and C13-H and failed to show a
C4-H/N1-Me NOE. Instead, C4-H exhibited an NOE with C6-
Hꢀ and the expected NOEs of C6-Hꢀ/C19-H2 and C6-HR/C7-H
were observed. Its minor diastereomer, epimeric only at C2 and
C11, displayed diagnostic NOEs of C5-Et with C2-H and C10-
HR and no longer displayed an NOE with C13-H. Otherwise,
the diagnostic NOEs of 20 characterizing the C3-C7 stereo-
chemistry were also observed with this minor diastereomer (C5-
Et with C4-OBn, C6-HR, and C7-H, C4-H/C6-Hꢀ, C6Hꢀ/C19-
H2, and C6-HR/C7-H).
Asymmetric Total Synthesis of Vindorosine. With 19 and 20
in hand, their conversion to vindorosine was explored as a
prelude to efforts on vindoline itself. Vindorosine (2)22 is among
the most highly functionalized and stereochemically rich natural
products within the family of alkaloids isolated from the
Madagascan periwinkle (Catharanthus roseus (L.) G. Don). It
is identical in structure to vindoline with the exception that it
lacks the C16 methoxy substituent. As a consequence, it has
been the subject of a series of beautiful and historically important
total syntheses.10,23
alcohol acetylation (Ac2O, DMAP, pyridine, 25 °C, 1 h, 98%)
provided 25. Consequently, the routes to vindorosine from either
19 or 21 converged requiring only the additional two steps of
oxidation and reduction for the inversion of the C4 stereochem-
istry for utilization of 21.
Several approaches for the conversion of 25 to vindorosine
were examined, and the first of the most concise routes that
emerged from the efforts is summarized in Scheme 3.24
Reductive removal of the lactam carbonyl was most directly
accomplished by O-methylation (MeOTf, 2,6-di-t-butylpyridine,
CH2Cl2, 25 °C, 2 h) followed by NaBH4 reduction of the
intermediate methoxyiminium ion (MeOH, 25 °C, 5 min, 89%)
to provide 26, although alternative approaches involving thi-
(23) (a) Buchi, G.; Matsumoto, K. E.; Nishimura, H. J. Am. Chem. Soc.
1971, 93, 3299. (b) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.;
Bornmann, W. G. J. Org. Chem. 1987, 52, 347. (c) Elliott, G. I.;
Velcicky, J.; Ishikawa, H.; Li, Y.; Boger, D. L. Angew. Chem., Int.
Ed. 2006, 45, 620. (d) Formal syntheses: Takano, S.; Shishido, K.;
Sato, M.; Ogasawara, K. Heterocycles 1977, 6, 1699. (e) Veenstra,
S. J.; Speckamp, W. N. J. Am. Chem. Soc. 1981, 103, 1645. (f)
Natsume, M.; Utsunomiya, I. Chem. Pharm. Bull. 1984, 32, 2477. (g)
Andriamialisoa, R. Z.; Langlois, N.; Langlois, Y. J. Org. Chem. 1985,
50, 961. (h) Winkler, J. D.; Scott, R. D.; Williard, P. G. J. Am. Chem.
Soc. 1990, 112, 8971. (i) Heurenx, N.; Wouters, J.; Marko, I. E. Org.
Lett. 2005, 7, 5245.
The two cycloadducts 19 and 21 were converted to the same
key intermediate 24 by hydrogenolysis of benzyl ether 19 to
liberate the free alcohol or benzyl ether hydrogenolysis (86%),
oxidation of the free alcohol 22 to the ketone 23 (IBX, DMSO,
25 °C, 3.5 h, 78%) and diastereoselective ketone reduction
(LiAl(OtBu)3H, THF, 0 °C, 12 h, 90%, 10:1 dr) from the less
hindered convex face for 21 (Scheme 3).24,25 Subsequent C4
(24) Oftentimes the work was conducted with only the natural or unnatural
enantiomer series (see Supporting Information), but this is represented
herein depicting only the natural enantiomer series for the sake of
clarity.
(22) Mosa, B. K.; Trojanek, J. Collect. Czech. Chem. Commun. 1963, 28,
(25) Reduction of 23 with NaBH4 predominately provided the epimeric
C4 alcohol 22.
1427.
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A R T I C L E S
Sasaki et al.
olactam formation and reduction also proved effective. Having
liberated the basic amine and following MOM ether deprotection
of 26 (HCl, MeOH, 25 °C, 4 h, 92%) to liberate the primary
alcohol 27, the ring expansion by way of alcohol activation and
aziridinium ion formation was examined. Disappointingly albeit
not surprising, all efforts to effect the ring expansion upon
activation of the alcohol 27 by way of conversion to the tosylate
32 (TsCl, DMAP, Et3N, CH2Cl2, 25 °C, 16 h, 91%), chloride
33 (Ph3P-CCl4, Et3N, MeCN, 80 °C, 30 min, 90%), or bromide
34 (Ph3P-CBr4, Et3N, MeCN, 25 °C, 30 min, 96%) failed to
lead to aziridinium ion formation (eq 1). Instead and only upon
exposure to forcing conditions, such derivatives simply led to
elimination and subsequent N,O-ketal formation to provide 35,
whose structure and stereochemistry were confirmed by X-ray
analysis26 (eq 1). Protection of the C3 tertiary alcohol prevented
the N,O-ketal formation, but still led to elimination and not
aziridinium ion formation. Clearly, the geometrical constraints
imposed by the fused 6,5,5-ring system, which place the nitrogen
lone pair on the convex face of the molecule opposite the
hydroxymethyl substituent, are sufficient to preclude its par-
ticipation in the requisite stereoelectronically controlled dis-
placement reaction for aziridinium ion formation.27
of tosylate 29 with mild base in the presence of water
(HOCO2NH4, EtOH-H2O, 50 °C, 24 h)28 led to clean ring
expansion to provide the 6-membered ketone 30 (76%, Scheme
2). Originally examined using NaOAc28 (THF-H2O, reflux,
36 h, 65%), the conversion of 29 to 30 improved using
ammonium hydrogen carbonate (ammonium bicarbonate) and
the two significant byproducts (eq 3) were no longer observed.
Although several mechanistic possibilities can be envisioned
for this transformation, some of which proceed through an
aziridinium ion,27,28 it is most simply and formally represented
as hydrolysis of the N,O-ketal to release a reactive R-tosyl-
oxymethyl ketone followed by its intramolecular N-alkylation
to provide the 6-membered ketone 30 (eq 3). This acyclic
intermediate was not detected in the reaction mixture and could
not be trapped with the inclusion of Boc2O, but its intermediacy
would nicely account for the generation of the first of the two
byproducts by base-catalyzed oxidative elimination of p-
toluenesulfenic acid to produce the corresponding aldehyde.
Final conversion of 30 to vindorosine required diastereoselective
reduction (L-Selectride, THF, -78 °C, 0.5 h, 93%)12c from the
less hindered, convex face of the ketone to provide alcohol 31,
which we have previously converted to the natural product
(74%)10,12 enlisting a regioselective elimination reaction that
occurs upon Mitsunobu activation of the secondary alcohol in
the absence of added nucleophiles (Scheme 3). The approach,
which was explored further with the total synthesis of vindoline,
provided vindorosine in 11 or 13 steps starting from the
cycloaddition precursors (Z)- or (E)-17, respectively.
Although such an elimination reaction might be used to effect
the required ring expansion and its potential was briefly
examined (e.g., NBS, H2O-THF), a more attractive approach
emerged as we began examining methods for the inversion of
stereochemistry at C7 in order to place the hydroxymethyl
substituent on the same face of the molecule as the nitrogen
lone pair. Since this entails isomerization of the C7 substituent
from the congested concave face of the molecule to its less
hindered convex face, oxidation of the alcohol 27 to the
corresponding aldehyde and its epimerization were examined.
Swern oxidation (CH2Cl2, 1 h, 80%) provided an unstable
R-aminoaldehyde that not only rapidly epimerized but also was
especially prone to hydrate and enol formation. Moreover, we
found that simply exposing the crude aldehyde to silica gel in
the presence of Et3N (EtOAc) led to clean conversion to the
stable N,O-ketal 28 (80%), eq 2.
Activation of the primary alcohol for displacement (TsCl,
DMAP, Et3N, CH2Cl2, 25 °C, 16 h, 87%) followed by treatment
(26) The structure and stereochemistry of 35 (CCDC 780504) were
confirmed by X-ray analysis conducted in the unnatural enantiomer
series.
(27) Cossey, J.; Pardo, D. G. Chemtracts: Org. Chem. 2002, 15, 579.
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13538 J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010

Vindorosine and Vindoline Asymmetric Total Synthesis
A R T I C L E S
Scheme 4
Unlike 27, activation of the primary alcohol of 42 for
displacement led to aziridinium ion formation that could be
kinetically trapped with nucleophiles to provide products
resulting from attack on the least hindered center without ring
expansion or thermodynamically trapped to provide the more
stable, ring expanded products derived from attack on the more
substituted center (eq 4). The latter reaction leading to ring
expansion requires a nucleophile capable of reversible aziri-
dinium ion formation and was effectively observed in reactions
leading to the chlorides 43 or 44. Thus, treatment of 42 with
Ph3P-CCl4 (Et3N, MeCN, 25 °C, 30 min) at room temperature
provided the primary chloride 43 (72%) that on warming
(MeCN, 70 °C, 2 h) smoothly converted to the ring expanded
secondary chloride 44 (91%) whose structure and stereochem-
istry were confirmed by X-ray analysis.30 Alternatively, the
addition of NaI (5 equiv) to a solution containing the primary
chloride 43 generated in situ at room temperature and warming
the mixture at 70 °C (MeCN, 1 h) cleanly provided the ring
expanded secondary iodide 45 (72-80%), whose structure and
stereochemistry were also confirmed by X-ray analysis (Scheme
4).31 Kuehne32 and, earlier, Hammer33 both describe a similar
kinetic versus thermodynamic preference for aziridinium ring-
opening reactions, although Kuehne has also observed a reversal
of this intrinsic preference32a and the propensity for even kinetic
ring expansion has been generalized with simpler systems.27
Interestingly and although not investigated in detail, a single
effort to prepare either the corresponding primary bromide
(Ph3P-CBr4) or iodide (Ph3P, I2, imidazole) from 42 provided
the desired products by TLC and LCMS, but both reverted back
to 42 upon aqueous workup, suggesting they possess a reactivity
for aziridinium ion formation that might preclude their simple
isolation. Thus, the chloride addition to such an intermediate
aziridinium ion is reversible, and yet sufficiently stable that it
can provide two regioisomeric products whose generation is
condition and temperature dependent.
As the work progressed, we continued to pursue the use of a
well-precedented ring expansion reaction proceeding via an
intermediate aziridinium ion.27 With the recognition that this
requires inversion of the C7 stereochemistry and that a C7
aldehyde epimerization from the congested concave to convex
face of the molecule is facile, we examined its potential with
intermediates in which the R-amino group is still a part of the
adjacent amide anticipating that this would permit the generation
of an intrinsically less electrophilic aldehyde (Scheme 4). Acid-
catalyzed MOM deprotection of 25 (HCl, H2O-MeOH, 25 °C,
7 h, 93%) and oxidation of the primary alcohol 3629 (IBX,
DMSO, 40 °C, 3.5 h) provided the aldehyde 37 that underwent
smooth and complete (>99%) epimerization to the isomeric
aldehyde 38 upon exposure to silica gel (EtOAc) in the presence
of Et3N (Scheme 4). Subsequent reduction of the aldehyde 38
with NaBH4 (MeOH-THF, 0 °C, 0.5 h) provided the alcohol
39 (90% from 36, 3 steps) that was reprotected as its MOM
ether 40 (MOMCl, i-Pr2NEt, CH2Cl2, 25 °C, 4 h, 95%).
Although a bit lengthy, the first 3 steps of this sequence as well
as the epimerization could be conducted without the purification
or storage of intermediates providing 39 in ca. 80% yield overall
from 25 (Scheme 4). Reductive removal of the lactam carbonyl
by O-methylation (MeOTf, CH2Cl2, 25 °C, 2 h) and NaBH4
treatment of the resulting methoxyiminium ion (HCl, MeOH,
25 °C, 1 h, 70%) and subsequent MOM ether deprotection of
41 (HCl, H2O-MeOH, 25 °C, 1 h, 97%) provided the primary
alcohol 42, isomeric at C7 with the primary alcohol 27.
The final stages of the conversion of 44 or 45 to vindorosine
also provided a series of important observations. To date, neither
the chloride 44 nor the more reactive iodide 45 could be
eliminated directly upon base treatment to provide vindorosine,
although this was not extensively examined. Rather, and
representative of the reactions observed upon use of the more
(28) (a) Frehel, D.; Badorc, A.; Pereillo, J.-M.; Maffrand, J.-M. J. Het-
erocycl. Chem. 1985, 22, 1011. (b) Kavadias, G.; Velkof, S.; Belleau,
B. Can. J. Chem. 1979, 57, 1861 and 1866. (c) Takeda, M.; Inoue,
H.; Konda, M.; Saito, S.; Kugita, H. J. Org. Chem. 1972, 37, 2677.
(d) Hoffman, R. V.; Jankowski, B. C.; Carr, C. S.; Duesler, E. N. J.
Org. Chem. 1986, 51, 130.
(29) The structure and stereochemistry of 36 (CCDC 759386) were
confirmed by X-ray analysis conducted in the unnatural enantiomer
series.
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A R T I C L E S
Sasaki et al.
forcing conditions, treatment of iodide 45 with DBU (toluene,
120 °C, 3 h) provided 3526 (>90%, eq 5) in a reaction that
apparently first undergoes ring contraction to the corresponding
primary iodide, base-catalyzed elimination of HI, and subsequent
N,O-ketal formation (see eq 1). Similarly, efforts to displace
the iodide with typical oxygen nucleophiles resulted in ring
contraction in reactions that also proceed through aziridinium
ion formation and subsequent irreversible kinetic nucleophilic
addition to its least substituted center (eq 5). An especially
attractive approach combining both the ring expansion reaction
and a subsequent in situ oxidation34 was also initially explored
at this stage and entailed the exposure of 43 or 45 to a modified
Kornblum oxidation35 with DMSO as the oxygen nucleophile,
providing products capable of in situ oxidation to the corre-
sponding carbonyl compound. Although treatment of 43 with
AgBF4/DMSO was not productive, treatment of 45 (10 equiv
of AgBF4, DMSO, 25 °C, 9 h) provided 28 (49%) derived from
the ring contracted aldehyde and the corresponding primary
alcohol 42 (19%) indicative of kinetic DMSO addition to the
less hindered carbon of the intermediate aziridinium ion
followed by eliminative oxidation or solvolysis (eq 5). As
highlighted and developed below, the successful implementation
of this approach would require a DMSO equivalent capable of
reversible aziridinium ion formation and slower in situ oxidation
(elimination). Unsure whether this might be practical to imple-
ment and avoiding the complicating reactions derived from an
intermediate aziridinium ion for the time being, treatment of
iodide 45 with Bu3SnH in the presence of TEMPO provided
the TEMPO adducts 46 (93%, 2:1 R:ꢀ) as a mixture of
diastereomers (Scheme 4). Reductive cleavage of the ꢀ-dias-
tereomer of the TEMPO adduct 46 (Zn, HOAc/THF/H2O 3:1:
1, 60 °C, 3 h, 77%) provided the key alcohol 31 that we
previously converted to vindorosine. Additionally, the isomeric
C7 R-alcohol derived from the R-diastereomer of the TEMPO
adduct or the diastereomeric mixture of alcohols was oxidized
to the ketone 30 (IBX, DMSO) and converted to vindorosine
in two steps by diastereoselective reduction and regioselective
elimination of the resulting alcohol 31 (L-Selectride;
Ph3P-DEAD) as detailed in Scheme 3. Significant in these
studies, the additional key observation was made that efforts to
eliminate a C7 leaving group bearing the R-stereochemistry
preferentially and nonproductively form the aziridinium ion,
whereas those bearing the ꢀ-stereochemistry (e.g., 31) are
stereoelectronically precluded from forming an analogous
aziridinium ion and productively participate in a regioselective
elimination reaction to provide vindorosine.
ethyl side chain stereochemistry, and the final conversions to
the key secondary alcohol 31 were still disappointing. Thus,
after establishing the viability of the approach and following
its implementation in a synthesis of vindoline, we reexamined
the two limiting features of the approach. First, conditions were
developed that avoid the MOM ether reprotection/deprotection
of the epimerized alcohol and streamlined the preparation of
the secondary iodide 45. Thus, direct conversion of the primary
alcohol 39 to the corresponding primary chloride 47 (polymer-
bound Ph3P, CCl4, 25 °C, 12 h, 98%) followed by reductive
removal of the lactam carbonyl (MeOTf; NaBH4) provided the
sensitive primary chloride 43 avoiding the intermediate primary
alcohol MOM ether protection/deprotection (Scheme 5). Direct
treatment of 43, without purification, with NaI (MeCN, 70 °C,
30 min) provided the ring expanded secondary iodide 45 in good
overall conversions (59%, for 3 steps from 47). Next, we
examined modifications on the Kornblum oxidation that would
permit O-nucleophile displacement of the iodide, albeit with
the potential for reversible aziridinium ion formation with a
reagent that would necessarily undergo a slower eliminative
oxidation reaction to generate the ketone 30 directly. Meeting
these requirements, treatment of 45 with 4-(dimethylamino)py-
ridine N-oxide (DMAPO)36 under conditions that first entail
aziridinium ion formation and kinetic DMAPO addition to the
less substituted carbon (50 °C, 2 h, EtCN; LCMS detection of
intermediate) and its subsequent partitioning to the thermody-
namically more stable ring-expanded 6-membered ring addition
product (120 °C, 2 h, EtCN; LCMS detection of rearrangement
product), followed by treatment of the reaction mixture with
base (1.5 equiv of BEMP,37 25 °C, 3 h) to promote the oxidative
elimination of DMAP, provided the ketone 30 in a single step
and in excellent conversions (78%) given the complexity of the
reaction. The use of DBU36 in place of BEMP was effective,
but required higher reaction temperatures (80 vs 25 °C), and
little or no desired product was observed without exposure of
the mixture to the higher reaction temperatures (50 vs 120 °C)
despite the disappearance of 45. Efforts to convert the primary
chloride 43 directly to 30 under these conditions were not as
effective. However, if the conversion was conducted with KI
As informative as these latter studies were, this second
approach to vindorosine still suffered in length, requiring a
cumbersome deprotection/reprotection/deprotection of the MOM
ether in the sequence required for inversion of the hydroxym-
(30) The structure and stereochemistry of 44 (CCDC 759385) were
confirmed by X-ray analysis conducted in the unnatural enantiomer
series.
(31) The structure and stereochemistry of 45 (CCDC 759387) were
confirmed by X-ray analysis conducted in the natural enantiomer series.
(32) (a) Kuehne, M. E.; Okuniewicz, F. J.; Kirkemo, C. L.; Bohnert, J. C.
J. Org. Chem. 1982, 47, 1335. (b) Kuehne, M. E.; Podhorez, D. E. J.
Org. Chem. 1985, 50, 924.
(33) Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetraherdon Lett. 1972,
28, 239.
(34) D’hooghe, M.; Baele, J.; Contreras, J.; Boelens, M.; De Kimpe, N.
Tetrahedron Lett. 2008, 49, 6039.
(35) Kornblum, N.; Jones, W. J.; Anderson, G. J. J. Am. Chem. Soc. 1959,
81, 4113. Ganem, B.; Boeckman, R. K., Jr. Tetrahedron Lett. 1974,
15, 917. Lemal, D. M.; Fry, A. J. J. Org. Chem. 1964, 29, 1673. Dave,
P.; Byun, H. S.; Engel, R. Synth. Commun. 1986, 16, 1343.
(36) Mukaiyama, S.; Inanaga, J.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1981, 54, 2221.
(37) Schwesinger, R. Chimia 1985, 39, 269.
9
13540 J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010

Vindorosine and Vindoline Asymmetric Total Synthesis
A R T I C L E S
Scheme 5
Scheme 6
(1.5 equiv) as an additive (3 equiv of DMAPO, 40 °C, 2 h; 120
°C, 1 h, EtCN) followed by treatment with base (3 equiv of
BEMP, 25 C, 3 h), the direct conversion of 43 to 30 was
achieved in comparable overall yields (48%). Interestingly, the
use of the more common and soluble NaI in place of KI simply
led to unproductive and preferential consumption of DMAPO.
With these modifications and following diastereoselective ketone
reduction (L-Selectride) and alcohol elimination (Ph3P-DEAD)
to provide vindorosine, this second route employing a ring
expansion reaction proceeding through an aziridinium ion
required 12 or 14 steps from the cycloaddition substrates (Z)-
and (E)-17, respectively.
Asymmetric Total Synthesis of Vindoline. Coupling of both
(Z)-15 and (E)-15 with 2-(6-methoxy-1-methylindol-3-yl)acetic
acid (48)38 provided the cycloaddition substrates (Z)-49 and (E)-
49 for extension of the studies to the total synthesis of vindoline.
Both substrates participated in the cycloaddition cascade (140
to 150 °C, 10-16 h) in a fashion analogous to 17 with the (E)-
isomer again providing higher yields and a better diastereose-
lectivity than the (Z)-isomer (Scheme 6). In both instances, the
initial cascade cycloadducts 50 and 52 were isolated and
characterized, but most conveniently subjected to reductive
oxido bridge cleavage prior to purification providing 51 and 53
directly, and X-ray analysis39 of the primary alcohols derived
from both 51 and 53 confirmed the structural and stereochemical
assignments. Unlike the studies with 19 and 21, a significant
competitive indole-initiated [4 + 2] cycloaddition was also now
observed, especially with (Z)-49, lowering the effective two-
step conversions to 51 (41% vs 61% for 19) or 53 (55% vs
70-74% for 21).
most other aspects of the two approaches developed for the
synthesis of vindorosine translated nicely to the synthesis of
vindoline. Occasionally and with the benefit of further studies,
the conversions for some steps were improved considerably.
The two cycloadducts 51 and 53 were converted to the same
key intermediate 56 by hydrogenolysis of benzyl ether 51 to
liberate the free alcohol or benzyl ether hydrogenolysis (91%),
oxidation of the free alcohol 54 to the ketone 55 (DMP,
pyridine-CH2Cl2 1:4, 0 °C, 3 h, 76%) and diastereoselective
ketone reduction (LiAl(OtBu)3H, THF, 0 °C, 10 h, 87%) from
the less hindered convex face for 53 (Scheme 7). In the
conversion of 54 to 55, IBX (vs DMP) proved less effective,
and the optimized reduction of ketone 55 (87%) was established
to be highly diastereoselective (30:1 dr). Subsequent C4 alcohol
acetylation (Ac2O, DMAP, pyridine, 95%) provided 57. Thus,
the routes to vindoline using either 51 or 53 converged requiring
only the additional two steps of oxidation (76%) and reduction
(87%) for the inversion of the C4 stereochemistry for use of
53, the product of the more effective of the cascade cycload-
dition reactions.
O-Methylation and reductive removal of the lactam carbonyl
(MeOTf, 2,6-di-t-butylpyridine, CH2Cl2, 25 °C, 2 h; NaBH4,
MeOH, 25 °C, 5 min, 96%) followed by MOM ether depro-
tection (HCl, MeOH, 25 °C, 16 h) liberated the primary alcohol
59 (85% for two steps from 57, Scheme 7). Oxidation of 59 (3
equiv of SO3-pyr, 3 equiv of Et3N, CH2Cl2-DMSO 5:1, 25
°C, 0.5 h) followed by exposure of the crude aldehyde to silica
gel in the presence of Et3N (EtOAc) cleanly afforded the N,O-
ketal 60 (85%). Formation of the primary tosylate 61 (TsCl,
DMAP, Et3N, CH2Cl2, 25 °C, 16 h, 93%) and it subjection to
the ring expansion reaction conditions developed herein
(HOCO2NH4, EtOH-H2O, 50 °C, 24 h) provided the key
With notable exceptions to accommodate the more nucleo-
philic aryl system derived from the added C16 methoxy group,
(38) Feldman, P. L.; Rapoport, H. Synthesis 1986, 735. Drost, K. J.; Jones,
R. J.; Cava, M. P. J. Org. Chem. 1989, 54, 5985.
(39) The structure and stereochemistry of 53 were confirmed by X-ray
analysis conducted on the free alcohol derived by MOM ether
deprotection (HCl, MeOH, 0-25 °C, 1.5 h, 66%) in the natural
enantiomer series (CCDC 758510). Similarly, the structure and
stereochemistry of 51 were confirmed by X-ray analysis conducted
on the free alcohol derived by MOM ether deprotection (HCl, MeOH,
25 °C, 16 h, quant.) in the natural enantiomer series (CCDC 780505).
9
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A R T I C L E S
Sasaki et al.
Scheme 7
Scheme 8
25 °C, 2 h, 78-99%) provided the penultimate secondary
alcohol 63, as well as the C7 epimeric alcohol 71, the former
of which was previously converted to vindoline (Ph3P-DEAD,
THF, 25 °C, 75%). As detailed below, both 71 and 73 (eq 6)
available only through implementation of this approach, as well
63, were incorporated into vinblastine analogues.
6-membered ring ketone 62 (78%) in conversions that represent
an improvement over that originally reported (NaOAc,
dioxane-H2O, 70 °C, 61%).13 Diastereoselective reduction of
62 (L-Selectride, THF, -78 °C, 0.5 h, 91%)12c provided the
penultimate secondary alcohol 63 (91%), which underwent
regioselective elimination10 to provide vindoline (1) upon
Mitsunobu activation in the absence of added nucleophiles.
In an analogous fashion and in a second route to vindoline
utilizing the aziridinium ion-based ring expansion reaction
(Scheme 8), MOM ether deprotection of 57 (HCl, MeOH, 25
°C, 2 h, 84%) followed by oxidation of the primary alcohol 64
to the corresponding aldehyde (1.2 equiv of DMP,
pyridine-CH2Cl2 1:4, 0 °C, 1 h), its clean and complete
epimerization to the C7 epimeric aldehyde (SiO2, 2%
Et3N-EtOAc, 25 °C), and subsequent reduction (NaBH4,
MeOH-THF, 0 °C, 0.5 h) provided the C7 epimeric primary
alcohol 65 (82% from 64). MOM ether protection of 65 (98%),
reductive removal of the lactam carbonyl (MeOTf, CH2Cl2, 25
°C, 2 h; NaBH4, HCl-MeOH, 0 °C, 0.5 h, 71%), and MOM
ether deprotection (HCl, 85%) provided the primary alcohol 68
poised for the key ring expansion reaction. Treatment of 68
with Ph3P-CCl4 for in situ generation of the primary chloride
followed by addition of NaI (10 equiv) and warming of the
solution at 70 °C (0.5 h) provided 69 (76%) resulting from
reversible aziridinium ion formation partitioning to the ther-
modynamically more stable secondary iodide. Finally, treatment
of 69 with Bu3SnH in the presence of TEMPO followed by
reduction of the TEMPO adducts 70 (Zn, HOAc, THF/H2O 2:1,
The final improvement on this approach is detailed in Scheme
9 and follows advancements first developed with vindorosine
altering the order of the steps to avoid the primary alcohol
deprotection/reprotection and implementing the unique ring
expansion-Kornblum oxidation. Thus, following inversion of
the C7 stereochemistry, conversion of the primary alcohol 65
to the primary chloride 74 (91%) and reductive removal of the
lactam carbonyl provided the chloride 72, which was im-
mediately subjected to ring expansion treatment with NaI to
provide 69 (69% from 74). Modified Kornblum oxidation of
69 under conditions that lead to aziridinium ion formation and
that thermally partition the initially formed aminooxonium
addition product on to the thermodynamically more stable
6-membered ring adduct provided the ketone 62 (66%) that was
previously converted to vindoline.
Key Vinblastine Analogues. One of the most surprising
observations made in studies with an initial series of key
analogues of vinblastine6f was the impact of removing the 6,7-
double bond in the vindoline subunit. The compound ∆6,7-
dihydrovinblastine was found to be ca. 100-fold less active
(cytotoxic) than vinblastine, indicating that this region of the
9
13542 J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010

Vindorosine and Vindoline Asymmetric Total Synthesis
A R T I C L E S
Scheme 9
Scheme 10
natural product has a pronounced impact on its properties. An
examination of the recent X-ray crystal structure of vinblastine
bound to tubulin40 does not reveal an obvious pronounced
stabilizing interaction with the olefin that might account for the
difference. As a result, this impact potentially could be derived
from either steric or conformational features resulting from the
presence of the double bond, or arises from an effect that the
olefin might have on the pKa of the allylic amine in 1. Several
key vindoline analogues prepared herein contain subtle (63, 71,
and 73) or more deep-seated changes (59 and 68) in this C6-C8
region of vindoline with which we could now probe the origin
of this effect. Each contains a heteroatom ꢀ to the basic amine
modulating its pKa in a manner potentially analogous to the 6,7-
double bond, and 59 and 68 incorporate the additional deep-
seated change of replacing the olefin-containing 6-membered
ring with a saturated 5-membered ring bearing either an R or ꢀ
oriented C7 hydroxymethyl substituent. These five compounds
were coupled with catharanthine (3) using the single-step
biomimetic Fe(III)-promoted coupling and subsequent free
radical oxidation6f to afford the corresponding vinblastine
analogues without optimization (Scheme 10). In addition to
providing the vinblastine analogues shown, the corresponding
epimeric C20′ leurosidine analogues (76, 79, 82, and 85) were
generated in the now characteristic ca. 2:1 ꢀ:R diastereoselec-
tivity for the introduction of the C20′ alcohol and the intermedi-
ate anhydrovinblastines (77, 80, 83, 86, and 89) were also
isolated in yields ranging from 17 to 22%. Interestingly and
for presently unknown reasons, the couplings and in situ
oxidation of the analogues 59 and 68 containing the ring
contracted 5-membered rings did not proceed nearly as well as
typical substrates.
cell line (HCT116/VM46).41 Key elements of the results of these
studies are summarized in Figure 4.
As observed in prior studies, the vinblastine analogues proved
more active than the corresponding anhydrovinblastine ana-
logues (ca. 10-fold), which in turn were more active than the
corresponding leurosidine derivatives (not shown, see Support-
ing Information). Although the vinblastine analogues containing
the vindoline saturated and C7 substituted 6-membered rings
(75, 78, and 81) were found to approach the activity of ∆6,7-
dihydrovinblastine (90),42 they remained at least 100-fold less
potent than vinblastine. Thus, the C7 substitutions in 75 and
81 did not significantly affect the activity adversely relative to
The vinblastine analogues bearing the key changes in the
structure of 1 were used to further assess the importance and
potential role of the 6,7-double bond in the cellular activity of
the natural product (cytotoxic activity against L1210 murine
leukemia and HCT116 colon cancer cell lines). Additionally,
the analogues were examined for their susceptibility to multidrug
resistance (MDR), resulting from overexpression and drug efflux
by Pgp, using a well-established companion vinblastine resistant
(41) (a) Dumontet, C.; Sikic, B. I. J. Clin. Oncol. 1999, 17, 1061. (b)
Kavallaris, M.; Verrills, N. M.; Hill, B. T. Drug Res. Updates 2001,
4, 392.
(42) For an earlier characterization of 90, see: (a) Neuss, N.; Barnes, A. J.;
Huckstep, L. L. Experientia 1975, 31, 18. (b) Barnett, C. J.; Cullinan,
G. J.; Gerzon, K.; Hoying, R. C.; Jones, W. E.; Nevlon, W. M.; Poore,
G. A.; Robison, R. L.; Sweeney, M. J.; Todd, G. C.; Dyke, R. W.;
Nelson, R. L. J. Med. Chem. 1978, 21, 88.
(40) Gigant, B.; Wang, C.; Ravelli, R. B. G.; Roussi, F.; Steinmetz, M. O.;
Curmi, P. A.; Sobel, A.; Knossow, M. Nature 2005, 435, 519.
9
J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010 13543

A R T I C L E S
Sasaki et al.
enlisting an intramolecular [4 + 2]/[3 + 2] cycloaddition
cascade of 1,3,4-oxadiazoles in which a chiral substituent on
the tether linking the dienophile and oxadiazole was used to
control the facial selectivity of the initiating Diels-Alder
reaction and set the absolute stereochemistry of the remaining
six stereocenters in the cascade cycloadduct. Implementation
of the approach for the synthesis of 1 and 2 required that the
initiating Diels-Alder reaction of the cycloaddition cascade
afford a fused 5-membered ring and the development of a
subsequent ring expansion reaction to provide a 6-membered
ring suitably functionalized for introduction of the 6,7-double
bond found in the core structure of the natural products. Two
unique approaches were developed for the key ring expansion
that defined our use of a protected hydroxymethyl group as the
substituent used to control the stereochemical course of the
cycloaddition cascade. In the course of these studies, several
analogues of vindoline were prepared containing deep-seated
structural changes presently accessible only by total synthesis.
These analogues, bearing key modifications at C6-C8, were
incorporated into vinblastine analogues and used to probe the
importance (100-fold) and further define the potential role of
the vinblastine 6,7-double bond.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA042056 and
CA115526) and the Skaggs Institute for Chemical Biology. We
wish to thank Dr. Raj Chadha for the X-ray structures disclosed
herein and William M. Robertson for the cytotoxic assays, and we
are especially grateful to Dr. Paul Hellier of Pierre Fabre for the
generous gift of catharanthine. D.K. is a Skaggs Fellow. Dedicated
to Professor Raymond Funk in honor of his 60th birthday.
Figure 4. Cytotoxic activity.
90, but they also did not make up for the loss in activity
observed with removal of the 6,7-double bond, whereas 78
experienced a further 10-fold loss in activity. Notably, analogue
81 possesses the opportunity to generate an aziridinium ion
capable of reacting with tubulin, yet its cellular activity did not
reflect an enhancement in activity that would be expected to
accompany such an alkylation. Finally, the vinblastine analogues
84 and 87 incorporating the vindoline subunits containing the
5-membered rings bearing a hydroxymethyl substituent were
even 10-fold less potent and ca. 1000-fold less active than
vinblastine. Clearly, the C6-C8 region of vinblastine including
its 6,7-double bond has a surprisingly large impact on the
properties of 1, and plays a previously unappreciated major role
in establishing its functional activity. Additional studies further
probing this effect are in progress and will be disclosed in due
time.43
Supporting Information Available: Full experimental details
and compound characterizations. This material is available free
of charge via the Internet at http://pubs.acs.org.
JA106284S
(43) Abbreviations: Ac, acetyl; BEMP, 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine; Boc, tert-butyloxycar-
bonyl; Bn, benzyl; CDI, 1,1′-carbonyldiimidazole; DBU, 1,8-
diazabicyclo[5.4.0]undec-7-ene; DEAD, diethyl azodicarboxylate;
DMAP, 4-(dimethylamino)pyridine; DMAPO, 4-(dimethylamino)py-
ridine N-oxide; DME, dimethoxyethane; DMF, N,N-dimethylforma-
mide; DMP, Dess-Martin periodinane; DMSO, dimethylsulfoxide;
EDCI, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochlo-
ride; Fe2(ox)3, iron(III) oxalate; IBX, 2-iodoxybenzoic acid; KHMDS,
potassium bis(trimethylsilyl)amide; MOM, methoxymethyl; NBS,
N-bromosuccinimide; Pyr, pyridine; NMM, N-methylmorpholine;
TEMPO, 2,2,6,6-tetramethylpiperidine-1-oxyl; Teoc, 2-(trimethylsi-
lyl)ethoxycarbonyl; Teoc-OSu, 1-[2-(trimethylsilyl)ethoxycarbonyl-
oxy]pyrrolidine-2,5-dione; THF, tetrahydrofuran; Tf, trifluoromethane-
sulfonyl; Ts, p-toluenesulfonyl.
Conclusions
Full details of the development of two concise asymmetric
total syntheses of vindorosine and vindoline are disclosed
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13544 J. AM. CHEM. SOC. VOL. 132, NO. 38, 2010