Total synthesis of (+)-aspidospermidine: A new strategy for the enantiospecific synthesis of aspidosperma alkaloids

Article abstract of DOI:10.1021/ja026357f

A new strategy was developed for the enantiospecific synthesis of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide to efficiently set up the quaternary carbon center, and a tandem Michael addi

Full text of DOI:10.1021/ja026357f

Published on Web 10/22/2002
Total Synthesis of (+)-Aspidospermidine: A New Strategy for the
Enantiospecific Synthesis of Aspidosperma Alkaloids
Joseph P. Marino,*,† Maria B. Rubio, Ganfeng Cao, and Alfonso de Dios
Department of Chemistry, The UniVersity of Michigan, Ann Arbor, Michigan 48109
Received March 28, 2002
Over the last three decades, aspidosperma alkaloids1 have caught
Scheme 1
the attention of synthetic chemists due to the unique structural
features of many of their members, and because of their important
biological properties. Aspidospermidine (1), the parent structure,
has been the primary target for most of the efforts toward
aspidosperma alkaloids syntheses and has served as the ideal test
case for newly developed synthetic strategies.2,3 Among those
strategies, Stork’s Fischer-indole approach, Harley-Mason’s in-
doloquinolizidine rearrangement approach, Bu¨chi and Wenkert’s
Diels-Alder approach, and Overman’s aza-Cope rearrangement
approach have been at the forefront and have considerably enriched
the chemistry of aspidosperma alkaloids. Most strategies were
originally designed for their racemic syntheses; as such, many of
these approaches cannot be readily developed into a feasible
asymmetric total synthesis. Only a few asymmetric syntheses
reported were derived from their racemic versions,4 some involving
the lengthy construction of intermediates. More than a decade ago,
our group developed a powerful ketene lactonization reaction which
can transfer the chirality of sulfur to as many as three contiguous
carbon centers through a novel [3,3]-sigmatropic rearrangement of
chiral vinyl sulfoxide with ketenes.5 The reaction was later applied
by our group and others to the total syntheses of natural products
and had been demonstrated as a powerful tool for the construction
of quaternary carbon atoms.6 In this communication, through the
total synthesis of (+)-aspidospermidine employing the ketene
lactonization reaction, we reveal a unique approach to the enan-
tiospecific synthesis of aspidosperma alkaloids.
Scheme 2 a
a (a) HOCH2CH2OH, benzene, cat. p-TsOH, reflux, 90%; (b) THF,
n-BuLi, -78 °C, then MgBr2, 0 °C, then A (4R, 5S)-4-methyl-5-phenyl-
3-[(R)-p-tolysulfinyl]-2-isoxazolidinone, -78 °C, 83%.
Scheme 1 elucidates the key synthetic events. First, the critical
ketene lactonization reaction of chiral vinyl sulfoxide 6 enantiospe-
cifically sets the quaternary carbon in lactone 8. Compound 8 was
transformed into an enone-amide structure 10 by lactone-opening,
intramolecular aldol condensation, and then by amide formation
reaction. From 10, a structure with all of the necessary carbons,
(+)-aspidospermidine 1 was obtained by a tandem conjugate
addition-alkylation reaction followed by further elaboration.
The synthesis started with the protection of alkynyl ketone 27 to
provide alkynyl ketal 3 (93%). Treatment of 3 with n-BuLi and
then MgBr2 formed an alkynyl Grignard reagent, which was added
to Evans’ chiral N-sulfinyloxazolidinone A8 to give chiral alkynyl
sulfoxide 4 (83%)9 (Scheme 2). HPLC analysis10 of compound 4
showed the presence of only one enantiomer.
Compound 4 was then added to the cuprate reagent formed from
transmetalation of the ortholithiated Boc-protected aniline (formed
from compound 5 and 2 equivalents of t-BuLi) with CuBr‚Me2S;11
after introduction of a second Boc group, the stereodefined chiral
vinylic sulfoxide 6 was obtained. With compound 6 in hand, we
proceeded to perform the ketene lactonization reaction. Dichlo-
roketene was generated in situ by the reaction of excess trichlo-
roacetyl chloride with freshly prepared zinc-copper couple.12 For
the best results, compound 6 was added first to the zinc-copper
couple/THF solution; then trichloroacetyl chloride was slowly added
at -45 °C to afford the dichlorolactone 7 as a single diastereomer
(78%). The quaternary carbon was formed in this step. After
dechlorination with Et3B/n-Bu3SnH in refluxing benzene (94%) and
deprotection of the ketal in acetone with a catalytic amount of
p-TsOH, lactone 8 was generated (96%) (Scheme 3). To our delight,
we were able to obtain crystals of compound 8, and an X-ray
crystallographical analysis was carried out.13 The relative stereo-
chemistry shown was consistent with the proposed [3,3]-sigmatropic
rearrangement mechanism for the ketene lactonization reaction.
Opening of lactone 8 with pyrrolidine afforded aldehyde 9 (86%).
Subsequent intramolecular aldol condensation under conditions of
pyrrolidine and 33% aqueous acetic acid in 2-propanol gave a
carboxylic acid. This acid was directly converted to amide 10 using
the mixed anhydride protocol (64% over two steps). Interestingly,
amide 10 can be formed from lactone 8 in a one-pot reaction by
simply mixing 8 with 3-chloropropylamine hydrochloride and
triethylamine in THF. However, the reaction usually took 5-8 days,
and the yield varied significantly from 10 to 40%. Through a chiral
* To whom correspondence should be addressed. E-mail: jpmarino@nd.edu.
† Current address: Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, IN 46556.
9
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J. AM. CHEM. SOC. 2002, 124, 13398-13399
10.1021/ja026357f CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
strategy, other members of the family of aspidosperma alkaloids
could be synthesized by starting with appropriately substituted
anilines and alkynyl sulfoxides and by derivatization of advanced
intermediates (e.g., from compound 1416). In addition, with both
enantiomers of Evans’ chiral N-sulfinyloxazolidinone easily ac-
cessible, either enantiomer of aspidosperma alkaloids can be
constructed. We are currently applying this new strategy in the total
syntheses of aspidophytine4f and related structures; the results will
be reported in due course.
Acknowledgment. The work was originally supported by NIH
(CA22237). We thank Dr. Jeff Kampf for the X-ray crystallography
on compound 8.
a (a) Two equivalents of t-BuLi, 1 equivalent of CuBr‚Me2S, then 4,
THF, -78 °C, 82%; (b) MeLi, Boc2O, THF, -78 °C, 81%; (c) Zn(Cu),
Cl3CCOCl, THF, -45 °C, 78%; (d) n-Bu3SnH, cat. Et3B, benzene, reflux,
92%; (e) acetone, cat. p-TsOH, room temperature, 96%.
Supporting Information Available: Experimental procedures and
1
spectroscopic data (IR, H NMR, 13C NMR, HRMS) (PDF). Crystal
data for compound 8 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 4 a
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a (a) Pyrrolidine, benzene, room temperature, 86%; (b) pyrrolidine,
2-propanol, 33% aqueous AcOH; (c) i-BuOCOCl, Et3N, 3-chloropropy-
lamine hydrochloride, THF, 0 °C, 64% (two steps); (d) NaH, DMF, 0 °C,
86%; (e) KHMDS, TMSCl, THF, -78 °C, then Pd(OAc)2/O2, DMSO, 60
°C, 80%; (f) 3 M HCl/2-propanol, reflux, 0.5 h, 90%; (g) H2NNH2‚H2O/
Na/HOCH2CH2OH, 160 °C, 1 h, then 210 °C, 3 h, 75%; (h) LiAlH4, THF
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HPLC analysis, amide 10 was determined to be a single enantiomer
by comparison with the result of its racemic form, indicating that
the above ketene lactonization reaction was a highly enantiospecific
process.14 Treatment of amide 10 with NaH initiated a tandem
conjugate addition/intramolecular alkylation reaction sequence and
furnished the tricyclic core structure 11 (86%). Compound 11 was
oxidized to enone 12 (80%) through a modified Saegusa reaction.15
A sequential deprotection-conjugate addition process under acidic
condition completed the indoline ring giving 5,17-dioxo-aspidosper-
midine 13 (90%). Ketone 13 was then reduced by a Wolff-Kishner
reduction16 yielding 5-oxo-aspidospermidine 14 (75%). Finally, (+)-
aspidospermidine 1 was obtained by the reduction of 14 with
LiAlH4 (90%) (Scheme 4). The spectroscopic data and optical
rotation of 1 were fully consistent with reported values.17
1552.
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(see the Supporting Information).
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(13) See the Supporting Information.
(14) Attempts to directly establish the enantiomeric purity of compounds 7
through 9 failed. Because any obvious enantio-enriching process (e.g.,
recrystallization) was carefully avoided during the transformations from
compound 7 to 10, the optical purity of compound 7 should be as
represented by that of compound 10.
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In summary, we have developed a new, efficient strategy for
the enantiospecific synthesis of aspidosperma alkaloids exemplified
by the synthesis of (+)-aspidospermidine 1. By employing this new
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