The asymmetric total synthesis of (+)- and (-)-spirotryprostatin B [16]

Full text of DOI:10.1021/ja001133n

5666
J. Am. Chem. Soc. 2000, 122, 5666-5667
Scheme 1
The Asymmetric Total Synthesis of (+)- and
(-)-Spirotryprostatin B
Paul R. Sebahar and Robert M. Williams*
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado 80523
ReceiVed March 29, 2000
The spirotryprostatins,1 tryprostatins,2 and cyclotryprostatins3
represent a promising class of antimitotic arrest agents. Isolated
from the fermentation broth of Aspergillus fumigatus, spiro-
tryprostatin B has been shown to completely inhibit the G2/M
progression of mammalian tsFT210 cells at concentrations over
12.5 µg/mL. While the cyclotryprostatins and tryprostatins have
been shown to act by affecting microtubule assembly,4 much less
is known about the spirotryprostatins due to the limited availability
of these compounds. Fermentation of 400 L of culture medium
yielded 1 mg of spirotryprostatin A and 11 mg of spirotryprostatin
B (1), respectively.
Scheme 2
Although numerous naturally occurring prenylated alkaloids
derived from proline and tryptophan are known,5 the unique
spirooxindole ring system distinguishes the spirotryprostatins. This
unique structural array along with the limited quantities and the
interesting biological activity render the spirotryprostatins attrac-
tive synthetic targets. Recently, the total synthesis of spirotrypros-
tatin A was completed using the classical halohydrin to oxindole
spiro-ring-forming contraction sequence.6 We have directed our
research interests toward the total synthesis of the more biologi-
cally active congener, spirotryprostatin B, using an entirely new
strategy to access this type of amino acid substructure.
In contemplating the synthesis of spirotryprostatin B, it was
envisioned that the core pyrrolidine ring could be formed through
an asymmetric [1,3]-dipolar cycloaddition reaction, (Scheme 1).7
Reaction of a chiral azomethine ylide of the type 3 with an
oxindolylideneacetate 2 could set four contiguous stereogenic
centers. Of these, the quaternary spirooxindolyl center at C3 and
the adjacent C18 center would have to be controlled in a relative
and absolute sense culminating in amino acid 4. Standard peptide
coupling protocol with protected proline 5 followed by cyclization
would generate the diketopiperazine 6. Completion of the
synthesis mandates unmasking of the prenyl side-chain followed
by oxidative decarboxylation. We record here the successful
execution of this strategy.
We have previously reported that the addition of an aldehyde
to 5,6-diphenylmorpholin-2-one (7) generates a mixture of the
corresponding E- and Z-azomethine ylides with a preference for
the E-ylide in the cases of sterically demanding aldehydes.8
Dipolar cycloadditions of ylides generated from this system
proceed with a high degree of endo selectivity to give substituted
pyrrolidines. On the basis of this premise that a bulky isoprene
aldehyde progenitor would favor the E-ylide geometry, the relative
stereochemistry at the isoprene-bearing carbon (C18) of spiro-
tryprostatin seemed attainable. However, it was more difficult to
predict the regio- and stereochemical course at the C3 and
consequently the C8 positions. Previous reports with azomethine
ylides and oxindolylideneacetate dipolarophiles related to 2 sug-
gested that the undesired regiochemistry may result from this type
of cycloaddition.9 The reaction of oxazinone8 7 with aldehyde
810 and oxindole 911 in toluene at room temperature in the presence
of 3 Å mol sieves, however, afforded cycloadduct 11 in 82%
yield.
(1) (a) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832-835.
(b) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 51, 12651-12666.
(2) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron. 1997, 53, 59-72.
(3) (a) Cui, C. B.; Kakeya, H.; Okada, G.; Ubukata, M.; Takahashi, I.;
Isono, K.; Osada, H. J. Antibiot. 1995, 48, 1382-1384. (b) Cui, C. B.; Kakeya,
H.; Okada, G.; Onose, R.; Osada, H. J. Antibiot. 1996, 49, 527-533. (c) Cui,
C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 534-540.
(4) (a) Usui, T.; Kondoh, M.; Cui, C. B.; Mayumi, T.; Osada, H. Biochem.
J. 1998, 333, 543. (b) Kondoh, M.; Usui, T.; Cui, C. B.; Mayumi, T.; Osada,
H. J. Antibiot. 1998, 51, 801-804.
(5) For a review, see: Williams, R. M.; Sanz-Cervera, J. F.; Stocking, E.
In Topics in Current Chemistry, Volume on Biosynthesis-Terpenes and
Alkaloids; Leeper, F., Vederas, J. C., Eds.; Springer-Verlag: Duesseldorf,
Germany, 2000; Vol. 209, pp 97-173.
(6) (a) Edmonson, S. D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998,
37, 1138-1140. (b) Edmonson, S. D.; Danishefsky, S. J. J. Am. Chem. Soc.
1999, 121, 2147-2155. For an entirely different approach to spirotryprostatin
B, see: (c) Overman, L. E.; Rosen, M. D.; Osada, H.; Shaka, A. J.; Taylor,
N. D. Abstracts of the ACS National Meeting, San Francisco, March 26-30,
2000; American Chemical Society: Washington, DC;Abstract No. 843.
(7) For a recent review, see: Gothelf, K. V.; Jorgensen, K. A. Chem. ReV.
1998, 98, 863-909.
(8) Williams, R. M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. J. Org. Chem.
1992, 57, 6527-6532.
10.1021/ja001133n CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/23/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 23, 2000 5667
Scheme 3
The relative and absolute stereochemistry of this substance was
firmly secured through single-crystal X-ray analysis (see Sup-
porting Information). The dipolar cycloaddition reaction of
azomethine ylide 10 therefore must proceed via the E-â-exo
transition state (shown in Scheme 2).12 This reaction, which sets
four contiguous stereogenic centers, constructs the entire pren-
ylated tryptophyl moiety of spirotryprostatin B in a single, simple
operation.
With this key intermediate in hand, the synthesis of spiro-
tryprostatin B required coupling of the spriooxindole amino acid
with proline, and installation of the two olefinic units (Scheme
3). Thus, reductive cleavage of bibenzyl from oxazinone 11
proceeded in essentially quantitative yield affording the amino
acid 12. Coupling with D-proline benzyl ester (BOP reagent,
MeCN, triethylamine, 74%) furnished the requisite dipeptide.13
It is interesting to note that the steric bulk of the environment
around the amino group of 12 obviated the need for a protecting
group during the peptide coupling procedure and the free amino
acid 12 was directly and effectively used in the reaction.
Deprotection of the benzyl ester under standard conditions
followed by BOP-mediated cyclization generated the diketopip-
erazine 13 in 94% yield over 2 steps.
(LiOH in THF/MeOH/H2O) failed to give any of the desired
product. We found that the use of LiI in refluxing pyridine
produced the desired carboxylic acid in 74% yield.14 The final
oxidative decarboxylation proved problematic under a range of
Kochi-type conditions (Pb(OAc)415 or iodosobenzene diacetate16).
After extensive experimentation, we found that a modified
Hunsdiecker reaction using conditions developed by Barton et
al.17 gave 12-epi-spirotryprostatin B in 34-43% yield. This
substance was then epimerized with NaOMe in MeOH to give a
2:1 ratio of 1 to 12-epi-spirotryprostatin B that were easily
separable by silica gel chromatography. The synthetic (-)-
spirotryprostatin B (1) spectra were identical with the 1H NMR,13C
NMR, IR, and HR-EI-MS spectra of the natural product kindly
provided by Dr. Hiroyuki Osada.1 With use of the antipode of 7,
(+)-ent-spirotryprostatin B was prepared in like manner (see data
in Supporting Information).
In summary, the application of a stereochemically distinct
asymmetric 1,3 dipolar cycloaddition provides access to both
antipodes of spirotryprostatin B in an efficient nine-step sequence.
This approach appears well-suited to preparing the simpler
congener spirotryprostatin A, and several analogues that may
prove useful in defining the antimitotic properties of this class of
unique spirooxindole alkaloids and studies toward those objectives
are in progress in these laboratories.18
Several strategies were examined for the installation of the two
olefinic units that had to be judiciously sequenced with the
planned oxidative decarboxylation. Ultimately, it was found that
installation of the isoprenyl unsaturation could be accomplished
by subjecting 13 to dehydrating conditions in the presence of
TsOH in refluxing toluene yielding 14 in 82-89% yield without
the production of double bond isomers. It should be noted that
hydrolysis of the ethyl ester of 14 under standard conditions
Acknowledgment. Financial support is gratefully acknowledged from
the National Science Foundation (CHE9731947). Dr. Hiroyuki Osada of
the Riken Institute, Japan, is acknowledged for providing detailed spectra
of natural spirotryprostatin B.
Supporting Information Available: Complete spectroscopic data for
all new compounds including details of the X-ray structure determination
for compound 11 (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) (a) Grigg, R.; Basanagoudar, L. D.; Kennedy, D. A.; Malone, J. F.;
Thianpatanagul, S. Tetrahedron Lett. 1982, 23, 2803-2806. (b) Grigg, R.;
Aly, M. F.; Seidharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun.
1984, 182-183. (c) Wenkert, E.; Liu, S. Synthesis 1992, 323-327. (d)
Casaschi, A.; Faita, G.; Gamba Invernizzi, A.; Grunanger, P. Gazz. Chim.
Ital. 1993, 123, 137-143. (d) Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti,
M. Tetrahedron Asymm. 1996, 7, 1-4. (e) Nyerges, M.; Gajdics, L.; Szollosy,
A.; Toke, L. Synth. Lett. 1999, 111-113. (f) Grigg, R.; Landsell, M. I.;
Thorton-Pett, M. Tetrahedron, 1999, 55, 2025-2044. (g) Fejes, I.; Toke, L.;
Nyerges, M.; Pak, C. S. Tetrahedron 2000, 56, 639-644.
(10) Aldehyde 8 is obtained from inexpensive, commercially available
3-methoxy-3-methyl-1-butanol (Aldrich Chemical Co.) by Swern oxidation
in 89% yield.
(11) The unsaturated oxindole 10 is readily prepared from isatin (Aldrich
Chemical Co.) by condensation with (Ph)3PCHCO2Et in refluxing diglyme
in 84% yield.
(12) “â” refers to the approach of the dipolarophile from the top face as
drawn in Scheme 2.
JA001133N
(14) (a) Elsinger, F.; Schreiber, J.; Eschenmoser, A. HelV. Chim. Acta 1960,
43, 113-117. (b) Borch, R. F.; Grudzinskas, C. V.; Peterson, D. A.; Weber,
L. D. J. Org. Chem. 1972, 37, 1141-1145.
(15) For examples of Pb(OAc)4 used in the total synthesis of natural
products see: (a) Patel, D. V.; VanMiddlesworth, F.; Donubauer, J.; Gannett,
P.; Sih, C. J. J. Am. Chem. Soc. 1986, 108, 4603-4614. (b) Sternbach, D. D.;
Hughes, J. W.; Burdi, D. F.; Banks, B. A. J. Am. Chem. Soc. 1985, 107,
2149-2153.
(16) Concepcion, J. I.: Francisco, C. G.; Friere, R.; Hernandez, R.; Slazar,
J. A.; Suarez, E. J. J. Org. Chem. 1986, 51, 402.
(17) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
(18) Since submission of our paper, we have learned that Profs. Overman
and Danishefsky have also independently achieved the synthesis of spirot-
ryprostatin B; we thank both Profs. Danishefsky and Overman for making us
aware of their work prior to publication.
(13) The yield for the conversion of 12 to the L-proline isomer correspond-
ing to 13 was 52% and this diminished yield appears to reflect the
thermodynamic instability of forming the corresponding trans-diketopiperazine.