Enantioselective total synthesis of hispidospermidin [13]

Full text of DOI:10.1021/ja974361z

J. Am. Chem. Soc. 1998, 120, 4039-4040
4039
Scheme 1
Enantioselective Total Synthesis of Hispidospermidin
Larry E. Overman* and Adam L. Tomasi
Department of Chemistry, 516 Physical Sciences 1
UniVersity of California, IrVine, IrVine, California 92697-2025
ReceiVed December 29, 1997
Signal-transduction therapy is drawing increasing attention for
its potential to combat ailments resulting from deviations in
normal cell signaling pathways.1-4 Studies conducted in the early
1980s showed that phosphoinositol is metabolized in response to
extracellular peptide growth factors with phospholipase C (PLC)
being a key enzyme.5,6 PLC catalyzes the hydrolysis of phos-
phatidylinositol diphosphate to produce diacylglyceride (DAG)
and myoinositol triphosphate (IP3). DAG in turn activates protein
kinase C (PKC) which initiates phosphorylation of proteins, while
IP3 stimulates the release of intracellular Ca2+ effecting many
cellular processes.7 Because of its key role in the cell growth
signaling pathway, inhibition of PLC could provide a novel means
to manage certain proliferative diseases.8 In this paper, we report
the first enantioselective total synthesis of (-)-hispidospermidin
(1), a recently discovered inhibitor of PLC.
The tetracyclic spermidine alkaloid (-)-hispidospermidin (1)
was isolated in 1994 from a fungal culture broth by Nippon Roche
scientists.9 While 1 is a micromolar inhibitor of PLC,10 amine 2
shows little activity, suggesting that both the hydrophobic tetra-
cyclic core and polyamine side chain are required for inhibitory
activity.10,11 Stimulated by the unique skeleton of 1 and the oppor-
tunity to further probe structure-activity relationships for this
novel PLC inhibitor, we initiated efforts to access (-)-hispido-
spermidin (1) by total synthesis. During the course of our inves-
tigations, the Danishefsky group recorded the first total synthesis
in this area, an incisive construction of (()-hispidospermidin.12
Tricyclic ketone 3 was targeted as an attractive platform for
assembling 2, since the rigid geometry of this intermediate should
regulate stereochemistry in subsequent elaboration of the het-
eroatom substituents at C2 and C11 (Scheme 1). We envisaged
3 as arising from an intramolecular Friedel-Crafts acylation, 5
f 3. Although direct cyclization to 3 was ultimately subverted
by an unexpectedly facile hydride shift (vide infra), construction
of 3 was realized as suggested in Scheme 1 by engaging an
external nucleophile in the pivotal cyclization step.13 The acid
precursor of 5 was seen as arising from hydrindenone 6 and
ultimately enantiopure â-ketoester 7, the latter being readily
available from (R)-pulegone.14
Scheme 2
The construction of hydrindene acid 12 is summarized in
Scheme 2. Base-catalyzed condensation of 7 with ethyl vinyl
ketone (1.5 equiv, 60 °C, 28 h), followed by cyclization of the
resulting Michael adduct in refluxing toluene in the presence of
p-TsOH (0.5 equiv) provided hydrindenone 6 in 78% yield.
Hydrogenation of 6 under carefully optimized conditions (20%
Pd(OH)2/C, 0.2 equiv of DBU, 32:1 MeOH-H2O, rt) afforded a
single hydrindanone 8 (91%),15-17 whose trans ring fusion
stereochemistry was confirmed by single-crystal X-ray analysis
of thiosemicarbazide derivative 9.18 The presence of DBU during
hydrogenation was critical and served to epimerize the initially
formed axial methyl group and suppress competing reduction of
(1) Levitzki, A.; Gazit, A. Science 1995, 267, 1782.
(2) Langdon, S. P.; Smyth, J. F. Cancer Treatment ReV. 1995, 21, 65.
(3) Powis, G. Pharmac. Ther. 1994, 62, 57.
(4) Levitzki, A. Eur. J. Biochem. 1994, 226, 1.
(13) For earlier disclosures from our laboratories of the decisive role that
external nucleophiles can play in cationic cyclizations initiated by iminium
ion or N-acyliminium ion electrophiles, see, inter alia: (a) Overman, L. E.;
Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612. (b) Lin, N.-H.; Overman, L.
E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am.
Chem. Soc. 1996, 118, 9062. (c) Caderas, C.; Lett, R.; Overman, L. E.;
Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem.
Soc. 1996, 118, 9073. (d) Brosius, A. D.; Overman, L. E. J. Org. Chem. 1997,
62, 440.
(14) Hudlicky, T.; Short, R. P. J. Org. Chem. 1982, 47, 1522.
(15) Exclusive formation of 8 is noteworthy, since hydrogenation of a
related hydrindenone lacking the R-methyl substituent yielded only the cis-
fused hydrindanone.16 That the R-methyl group would enhance trans stereo-
selection has precedent.17.
(16) Coates, R. M.; Vettel, P. R. J. Org. Chem. 1980, 45, 5430.
(17) McKenzie, T. C. J. Org. Chem. 1974, 39, 629.
(5) Majerus, P. W.; Connolly, T. M.; Deckmyn, H.; Ross, T. S.; Bross, T.
E.; Ishii, H.; Bansal, V. S.; Wilson, D. B. Science 1986, 234, 1519.
(6) Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315.
(7) Abel-Latif, A. A. Pharmacol. ReV. 1986, 38, 227.
(8) Aoki, M.; Itezono, Y.; Shirai, H.; Nakayama, N.; Sakai, A.; Tanaka,
Y.; Yamaguchi, A.; Shimma, N.; Yokose, K.; Seto, H. Tetrahedron Lett. 1991,
32, 4737.
(9) Yanagisawa, M.; Sakai, A.; Adachi, K.; Sano, T.; Watanabe, K.; Tanaka,
Y.; Okuda, T. J. Antibiot. 1994, 47, 1.
(10) Ohtsuka, T.; Itezono, Y.; Nakayama, N.; Sakai, A.; Shimma, N.;
Yokose, K. J. Antibiot. 1994, 47, 6.
(11) The polyamine side chain alone was 20 times less active than 1 against
PLC.
(12) Frontier, A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc.
1997, 119, 6686.
S0002-7863(97)04361-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

4040 J. Am. Chem. Soc., Vol. 120, No. 16, 1998
Communications to the Editor
Scheme 3
transformation, since 3 is recovered unchanged after 24 h at room
temperature when exposed to (N-(p-tolysulfonyl)imino)phenylio-
dinane in the absence of Cu(OTf)2.24,25 Addition of methyllithium
to 16 then provided 17 in near quantitative yield. Despite some
precedent,26 attempts to close the final tetrahydrofuran ring by
reaction of 17 with protic acids, Hg(OAc)2, or Hg(OCOCF3)2 were
uniformly unsuccessful. However, the desired cyclization was
eventually realized by treating a 1,2-dichloroethane solution of
17 with 1.1 equiv of m-CPBA (rt, 1 h), adding camphorsulfonic
acid (CSA) (1.6 equiv), and then heating the resulting solution at
100 °C for 7 h; this sequence delivered tetracyclic ether 18 in
73% yield. The â-epoxide and tertiary alcohol that are intermedi-
ates in this conversion could be isolated by quenching the reaction
at intermediate stages.
To complete the synthesis 1, the double bond and tosyl
protecting group must be removed and the spermidine side chain
appended. The order in which the first two operations is carried
out proved critical. Hydrogenation of 18 using several catalysts
(Pd, Pt, and Rh) resulted in predominant hydrogen delivery from
the face opposite the axial sulfonamide substituent to generate
the undesired cis hydrindane unit. However, hydrogenation of
the corresponding primary amine over 5% Rh/Al2O3 at 1300 psi
provided 2 as the only detectable stereoisomer in 84% yield. This
dramatic change in stereoselectivity could result from a decrease
in steric hindrance of the exo face upon removal of the tosyl group
or from a directing effect of the primary amine.27 The synthesis
of (-)-hispidospermidin (1) was then completed by acylation of
2 with amido acid 1928 followed by reduction of the resulting
diamide with LiAlH4. Synthetic (-)-hispidospermidin (1) was
identical in all respects, including optical rotation [R]23D -55.6°,9
with an authentic sample.
In conclusion, the first enantioselective total synthesis of natural
(-)-hispidospermidin was completed in 20 steps. This synthesis
defines a new strategy for assembling the tetracyclic core of
hispidospermidin and highlights the propitious role that external
nucleophiles can play in Friedel-Crafts cyclizations.
Acknowledgment. Financial support provided by grants from the
National Institutes of Health (NS 12389) and Roche Biosciences is
gratefully acknowledged. NMR and mass spectra were determined using
instruments acquired with the assistance of NSF and NIH shared
instrumentation grants. We particularly thank Dr. Masahiro Aoki, Nippon
Roche Research Center, for a sample of natural (-)-hispidospermidin
and Dr. Joe Ziller, UCI X-ray Crystallography Laboratory, for the X-ray
analysis of 9.
Supporting Information Available: Characterization data and
preliminary experimental procedures for new compounds described in
Schemes 2 and 3 and 13C NMR spectra of synthetic and natural (-)-
hispidospermidin (21 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
the ketone.19 To create the nucleophilic partner for the Friedel-
Crafts cyclization, the ketone carbonyl of 8 was converted to an
alkene. This was accomplished in two steps,20 and after reduction
of the hindered ester with LiAlH4, alcohol 10 was obtained in
75% overall yield. Oxidation of 10 to the corresponding aldehyde
and Horner-Wadsworth-Emmons olefination produced enoate
11 (86% yield). Saturation of the double bond of this intermediate
was not straightforward, since the substantial steric hindrance at
the â-carbon resulted in partial (or exclusive) 1,2-reduction when
11 was treated with many standard reducing agents.21 This
problem was solved by hydrolysis of 11 to the carboxylate, which
22
reduced cleanly with potassium in t-BuOH-NH3 to give
cyclization precursor 12 in 92% yield.
JA974361Z
Attempts to cyclize the acid chloride derivative of 12 with
various Lewis acids did not yield 3, but rather a mixture of 15
and tricyclic chloride 13 (Scheme 3). Apparently the initially
formed secondary tricyclic carbenium ion does not suffer direct
proton loss to form 3, but rather is partitioned between 1,2 hydride
shift to form a tertiary carbenium ion (and ultimately 15) and
halide capture to form 13. Fortunately, increasing the nucleo-
philicity of the halide counterion partially suppressed this deleteri-
ous hydride migration. Thus, exposure of the acyl bromide
derivative of 12 to 1.0 equiv of TiBr4 in CH2Cl2 at -78 °C
provided tricyclic bromide 14 in yields as high as 73%.
With the carbocyclic framework established, there remained
the challenge of introducing the trans diaxial nitrogen and oxygen
functionality. To accomplish this elaboration, bromide 12 was
first dehydrobrominated under forcing conditions to form 3 (77%).
We were delighted to discover that reaction of 3 with (N-(p-
tolysulfonyl)imino)phenyliodinane and 5 mol % of Cu(OTf)2 at
-20 °C f rt for 2 h in MeCN, conditions generally used to
aziridinate alkenes,23 produced allyl sulfonamide 16 as the
predominant product. The Cu(II) salt plays a critical role in this
(18) The authors have deposited atomic coordinates for this compound with
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,
CB2 1EZ, U.K.
(19) When this hydrogenation was carried out in the absence of DBU, the
epimer of 8 having an axial methyl group was isolated.
(20) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821.
(21) Larock, R. C. ComprehensiVe Organic Transformations; VCH: New
York, 1989; pp 915-19.
(22) Arth, G. E.; Poos, G. I.; Lukes, R. M.; Robinson, F. M.; Johns, W.
F.; Feurer, M.; Sarett, L. H. J. Am. Chem. Soc. 1954, 76, 1715.
(23) Evans, D. A.; Faul, M. M.; Bilodeau, M. T. J. Am. Chem. Soc. 1994,
116, 2742.
(24) To the best of our knowledge, this formal ene process has not been
previously recognized in Cu(II)-catalyzed reactions of sulfonyliminoiodoarenes
with alkenes. Rearranged allylic sulfonamides have been reported as minor
products from manganese-porphyrin-catalyzed reactions of (N-(p-tolysulfo-
nyl)imino)phenyliodinane with alkenes.25
(25) Mahy, J. P.; Bedi, G.; Battioni, P.; Mansuy, D. Tetrahedron Lett. 1988,
29, 1927.
(26) Baker, R.; Evans, D. A.; McDowell, P. G. J. Chem. Soc., Chem.
Commun. 1977, 111.
(27) Thompson, H. W.; Wong, J. K. J. Org. Chem. 1985, 50, 4270.
(28) Amido acid 19 was prepared by reaction of succinic anhydride with
N,N-dimethyl-3-(methylamino)propylamine. An excess of the crude product
from this reaction was employed in the coupling reaction.