Total synthesis of natural (-)- and ent-(+)-4-desacetoxy-6,7- dihydrovindorosine and natural and ent-minovine: Oxadiazole tandem intramolecular diels-alder/1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1021/ol050017s

(Chemical Equation Presented) Efficient and unusually concise total syntheses of both enantiomers of the Aspidosperma alkaloids 4-desacetoxy-6,7- dihydrovindorosine (12) and minovine (1) are detailed. A tandem intramolecular Diels-Alder/1,3-dipolar cycloaddition reaction of the 1,3,4-oxadiazole 8, in which three new rings, four new C-C bonds, and five stereocenters are formed, is a key step in the sequence. The availability of optically active material permitted an assessment of the enantiomeric integrity of minovine and the source of its reported unusual optical rotation.

Full text of DOI:10.1021/ol050017s

ORGANIC
LETTERS
2005
Vol. 7, No. 4
741-744
Total Synthesis of Natural (
−)- and
ent-( )-4-Desacetoxy-6,7-dihydrovindorosine
+
and Natural and ent-Minovine:
Oxadiazole Tandem Intramolecular
Diels−Alder/1,3-Dipolar Cycloaddition
Reaction
Zhong Qing Yuan, Hayato Ishikawa, 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
boger@scripps.edu
Received January 5, 2005
ABSTRACT
Efficient and unusually concise total syntheses of both enantiomers of the Aspidosperma alkaloids 4-desacetoxy-6,7-dihydrovindorosine (12)
and minovine (1) are detailed. A tandem intramolecular Diels Alder/1,3-dipolar cycloaddition reaction of the 1,3,4-oxadiazole 8, in which three
new rings, four new C C bonds, and five stereocenters are formed, is a key step in the sequence. The availability of optically active material
permitted an assessment of the enantiomeric integrity of minovine and the source of its reported unusual optical rotation.
−
−
Minovine (1),1 a naturally occurring Aspidosperma alkaloid
isolated from Vinca minor L., bears the pentacyclic vincadif-
formine skeleton. Due to its inherent structural complexity
and pentacyclic skeleton characteristic of the Aspidosperma
alkaloids, minovine has attracted considerable synthetic
interest throughout the years.2 We describe herein a concise
total synthesis of minovine and 4-desacetoxy-6,7-dihydrovin-
dorosine enlisting a novel tandem intramolecular Diels-
Alder/1,3-dipolar cycloaddition cascade of a suitably sub-
stituted 2-amino-1,3,4-oxadiazole.
they typically employ symmetrical oxadiazoles bearing strong
electron-withdrawing substituents (CF3, SO2Et, CO2Me) in
intermolecular reactions.3 Reactions with olefinic dienophiles
have been shown to proceed through an initial [4 + 2]
cycloadduct that subsequently loses N2 to generate a carbonyl
ylide, which reacts further with the olefin in a 1,3-dipolar
cycloaddition. In recent efforts, we have extended the scope
of this reaction beyond that which provides symmetrical 2:1
cycloadducts by implementing the reaction cascade in an
(2) Kutney, J. P.; Chan, K. K.; Failli, A.; Fromson, J. M.; Gletsos, C.;
Leutwiler, A.; Nelson, V. R. J. Am. Chem. Soc. 1968, 90, 3891-3893.
Ziegler, F. E.; Spitzner, E. B. J. Am. Chem. Soc. 1973, 95, 7146-7149.
Kutney, J. P.; Chan, K. K.; Failli, A.; Fromson, J. M.; Gletsos, C.; Leutwiler,
A.; Nelson, V. R.; de Souza, J. P. HelV. Chim. Acta 1975, 58, 1648-1671.
Kuehne, M. E.; Huebner, J. A.; Matsko, T. H. J. Org. Chem. 1979, 44,
2477-2480. Kalaus, G.; Kiss, M.; Kajtar-Peredy, M.; Brlik, J.; Szabo, L.;
Szantay, C. Heterocycles 1985, 23, 2783-2787.
Only a limited number of reports have described the
cycloaddition of electron-deficient 1,3,4-oxadiazoles, and
(1) Mokry, J.; Dubravkova, L.; Sefcovic, P. Experientia 1962, 18, 564-
565. Mokry, J.; Kompis, I.; Dubravkova, L.; Sefcovic, P. Experientia 1963,
19, 311. Zachystalova, D.; Strouf, O.; Trojanek, J. Chem. Ind. 1963, 13,
610-611.
10.1021/ol050017s CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/25/2005

intramolecular fashion.4 In the cases examined, olefinic
dienophiles tethered to a 2-amino-1,3,4-oxadiazole react to
form the initial [4 + 2] cycloadduct that loses N2 to generate
a carbonyl ylide that was trapped by a tethered indole (Figure
1). The relative stereochemistry is set by a combination of
Scheme 1. Preparation of 1,3,4-Oxadiazole 6
Coupling of 6 with 4-ethyl-4-pentenoic acid (7)6 was
effected by EDCI (1-[3-(dimethylamino)propyl]-3-ethylcar-
bodiimidide hydrochloride) and DMAP to provide the
substrate 8 (87%) for the key [4 + 2]/[3 + 2] cycloaddition
cascade (Scheme 2). The tandem intramolecular cycloaddi-
Figure 1. Tandem intramolecular [4 + 2]/[3 + 2] cycloaddition
reactions of a 1,3,4-oxadiazole.
Scheme 2. Synthesis of 4-Desacetoxy-6,7-dihydrovindorosine
the dienophile geometry and the exclusive indole endo [3 +
2] cycloaddition sterically directed to the face opposite the
fused lactam. Impressively, the tandem cycloadditions con-
struct three new rings with formation of four new C-C bonds
and set all six stereocenters about the central six-membered
ring in a single step without a trace of a second diastereomer.
Herein, we describe the application of this cycloaddition
cascade to the total synthesis of minovine and 4-desacetoxy-
6,7-dihydrovindorosine.
and Minovine
The starting 2-amino-1,3,4-oxadiazole 6 was prepared from
N-methyl tryptamine (2, Scheme 1). Treatment of 2 with
carbonyldiimidazole afforded 3 (86%), which was converted
to the oxadiazole precursor 5 (93%) by treatment with methyl
oxalylhydrazide (4)5 in the presence of HOAc. Cyclization
of 5 to form the corresponding oxadiazole 6 was mediated
by TsCl and Et3N (83%).
(3) Vasiliev, N. V.; Lyashenko, Y. E.; Kolomiets, A. F.; Sokolskii, G.
A. Khim. Geterotsikl. Soedin. 1987, 562. Vasiliev, N. V.; Lyashenko, Y.
E.; Galakhov, M. V.; Kolomiets, A. F.; Gontar, A. F.; Sokolskii, G. A.
Khim. Geterotsikl. Soedin. 1990, 95-100. Vasiliev, N. V.; Lyashenko, Y.
E.; Patalakha, A. E.; Sokolskii, G. A. J. Fluorine Chem. 1993, 65, 227-
231. Thalhammer, F.; Wallfahrer, U.; Sauer, J. Tetrahedron Lett. 1988, 29,
3231-3234. Seitz, G.; Gerninghaus, C. H. Pharmazie 1994, 49, 102-106.
Seitz, G.; Wassmuth, H. Chem.-Ztg. 1988, 112, 80-81. Review: Warrener,
R. N. Eur. J. Org. Chem. 2000, 3363-3380. Warrener, R. N.; Margetic,
D.; Foley, P. J.; Butler, D. N.; Winling, A.; Beales, K. A.; Russell, R. A.
Tetrahedron 2001, 57, 571-582. Warrener, R. N.; Wang, S.; Maksimovic,
L.; Tepperman, P. M.; Butler, D. N. Tetrahedron Lett. 1995, 36, 6141-
6144. Warrener, R. N.; Elsey, G. M.; Russell, R. A.; Tiekink, E. R. T.
Tetrahedron Lett. 1995, 36, 5275-5278. Warrener, R. N.; Maksimovic,
L.; Butler, D. N. J. Chem. Soc., Chem. Commun. 1994, 1831-1888.
Warrener, R. N.; Butler, D. N.; Liao, W. Y.; Pitt, I. G.; Butler, D. N.; Russell,
R. A. Tetrahedron Lett. 1991, 32, 1885-1888. Warrener, R. N.; Margetic,
D.; Tiekink, E. R. T.; Russell, R. A. Synlett 1997, 196-198.
(4) Wilkie, G. D.; Elliott, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc.
2002, 124, 11292-11294. Wolkenberg, S. E.; Boger, D. L. J. Org. Chem.
2002, 67, 7361-7364.
(5) Christl, M.; Lanzendoerfer, U.; Groetsch, M. M.; Ditterich, E.;
Hegmann, J. Chem. Ber. 1990, 123, 2031-2037.
742
Org. Lett., Vol. 7, No. 4, 2005

tion reaction proceeded in excellent yield (74%) upon
warming a solution of 8 at 180 °C in o-diclorobenzene for
24 h to provide 9 as a single detectable diastereomer
possessing the Aspidosperma alkaloid pentacyclic skeleton
(natural enantiomer depicted). Treatment of cycloadduct 9
with Lawesson’s reagent7 furnished thiolactam 10 in 85%
yield. Desulfurization and opening of the oxido bridge was
initially effected by reduction of 10 with Raney-Ni to provide
11 (90%) followed by reductive oxido bridge cleavage by
PtO2-catalyzed hydrogenation8 providing 4-desacetoxy-6,7-
dihydrovindorosine (12, 73%).9 Alternatively, S-methylation
of the thiolactam 10 with Me3OBF4 followed by NaBH4
reduction10 in MeOH directly provided 4-desacetoxy-6,7-
dihydrovindorosine (12) in superb yield (92%) as a single
operation sequence (Scheme 3). The relative stereochemistry
Figure 2. X-ray ORTEP of 12.
Scheme 3. Desulfurization and Reductive Oxido-Bridge
Naturally occurring minovine (1) has been reported only
with an [R]D ) 0 in alcoholic solvents.1 This raised the
question of whether the rotation of 1 was simply 0 or whether
natural minovine might suffer from a facile racemization.
This latter racemization could be envisioned to occur simply
by retro [4 + 2] cycloaddition of 1, providing an achiral
intermediate lacking any stereocenters, followed by a dia-
stereoselective but not enantioselective [4 + 2] cycloaddition,
eq 1. Consequently, the synthesis of 1 and 14 was repeated
Opening
with optically active material obtained by chromatographic
resolution of 9. Thus, separation of the enantiomers of 9 (R
) 1.19, 20 mg/injection) was carried out on a semipreparative
Daicel Chiralcel OD column (2 cm × 25 cm, 10% i-PrOH/
hexane, 10 mL/min flow rate) providing natural-(+)-9 (tR
) 31.7 min) and ent-(-)-9 (tR ) 26.7 min) which were
converted to natural-(-)-14 ([R] 23D -145 (c 0.33, CHCl3),
[R] 23D -122 (c 0.67, MeOH)) and ent-(+)-14 ([R] 23D +143
(c 0.90, CHCl3), [R] 23D +126 (c 0.83, MeOH)) and natural
and ent-1. The natural enantiomer series was assigned on
the basis of comparison with 129, which has been indepen-
dently prepared in optically active form in prior studies.
Minovine exhibited a remarkable solvent-dependent but
concentration-independent range of optical rotations: natural
1 [R] 23D -17 (c 0.35, CHCl3), +16 (c 0.40, MeOH), and 0
(3 (c 0.28, EtOH). Moreover, the enantiomeric integrity of
1 was maintained not only upon storage but also upon
deliberate attempts to promote racemization via the poten-
tially reversible Diels-Alder reaction illustrated in eq 1.
Thus, warming 1 in MeOH (80 °C, 24-48 h), toluene (120
in 12 was first established by observation of diagnostic 1H-
1H ROSEY NOEs between the C5 ethyl and C19 protons
and was confirmed with a single-crystal X-ray structure of
12 (Figure 2).11 Treatment of 12 with the Burgess reagent12
in CH3CN first provided the sulfamate 13 (91%) which upon
isolation and heating in toluene at 100 °C in the presence of
NaH furnished minovine (1) and its isomer 14. Although
not investigated in detail, attempts to promote a direct single
pot dehydration of 12 to provide 1 with the Burgess reagent
were not successful, analogous initial efforts to utilize
Martin’s sulfurane13 were not successful, and no effort was
made to alter or optimize the isomeric ratio of 1 and 14.14
(6) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137-2139.
Reinheckel, H.; Sonnek, G.; Gensike, R. J. Prakt. Chem. 1975, 317, 273-
283. McCaffery, E. L.; Shalaby, S. W. J. Organomet. Chem. 1967, 8, 17-
27.
(7) Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S. O.
Tetrahedron 1984, 40, 2047-2052.
(8) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556-565.
(9) Enantiomerically pure 12 has been reported: Calabi, L.; Danieli, B.;
Lesma, G.; Palmisano, G. J. Chem. Soc., Perkin Trans. I 1982, 1371-
1379. Hugel, G.; Levy, J. Tetrahedron 1984, 40, 1067-1073.
(10) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4061-4064.
(11) Atomic coordinates for 12 have been deposited with Cambridge
Crystallographic Data Center under the deposition number CCDC 231165.
(12) Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem.
1973, 38, 26-31. Lamberth, C. J. Prakt. Chem. 2000, 342, 518-522.
(13) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003-
5010. Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329.
Box, J. M.; Harwood, L. M.; Humphreys, J. L.; Morris, G. A.; Redon, P.
M.; Whitehead, R. C. Synlett 2002, 358-360.
(14) This reaction proceeds in part by aziridinium formation via
intramolecular sulfamate displacement favoring formation of 14.
Org. Lett., Vol. 7, No. 4, 2005
743

°C, 21 h), or DMF (80, 120, or 160 °C, 20 h) led to no
evidence of racemization, albeit with variable amounts of
decomposition. The potential racemization was easily moni-
tored by chiral phase HPLC where the two enantiomers of
1 were readily separable (tR ) 10.0 min (natural 1) and 8.29
min (ent-1), Chiralcel OD 0.46 cm × 25 cm column, 0.5%
i-PrOH/hexane, 1 mL/min flow rate, R ) 1.21). Thus,
naturally occurring minovine exhibits an unusual optical
rotation, whose sign is dependent on the choice of solvent.
In EtOH, its value is 0 (EtOH) as reported,1 but this is not
because it is racemic.
optically active material permitted an assessment of the
enantiomeric integrity of minovine and the source of its
reported unusual optical rotation. Further studies of the scope
of such reactions and their applications are in progress and
will be reported in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the National Institutes of Health (CA42056)
and thank Dr. R. Chadha for the X-ray structure determi-
nation of 12.
Thus, an unusually concise and convergent total synthesis
of both enantiomers of 4-desacetoxy-6,7-dihydrovindorosine
and minovine was developed enlisting a tandem intra-
molecular Diels-Alder/1,3-dipolar cycloaddition cascade of
a suitably substituted 1,3,4-oxadiazole. The availability of
Supporting Information Available: Full experimental
details and compound characterizations. This material is
available free of charge via the Internet at http://pubs.acs.org.
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