Stereocontrolled synthesis of the tetracyclic core of the bisguanidine alkaloids palau'amine and styloguanidine [4]

Full text of DOI:10.1021/ja9712985

J. Am. Chem. Soc. 1997, 119, 7159-7160
7159
Scheme 1
Stereocontrolled Synthesis of the Tetracyclic Core
of the Bisguanidine Alkaloids Palau’amine and
Styloguanidine
Larry E. Overman,* Bruce N. Rogers, John E. Tellew,1 and
William C. Trenkle
Department of Chemistry, 516 Physical Sciences 1
UniVersity of California, IrVine
IrVine, California 92697-2025
ReceiVed April 23, 1997
A diversity of structurally novel secondary metabolites is
found in sponges.2 Among the most remarkable is palau'amine
(1), which was isolated by Kinnel, Gehrken, and Scheuer from
a sponge (Stylotella agminata) collected in the Western Caroline
Islands.3 The unprecedented hexacyclic bisguanidine structure
of palau’amine was proposed following extensive mass spectral
and NMR investigations.4 Two years later, the isomeric alkaloid
styloguanidine (2), two brominated analogs, and palau’amine
were reported from a sponge (Stylotella aurantinium) collected
in the Yap sea.5 Palau’amine is reasonably nontoxic, exhibits
Scheme 2a
cytotoxic, antibiotic, antifungal activities and shows particularly
striking immunomodulatory activity;3 styloguanidine is a power-
ful chitinase inhibitor.5 Palau'amine is stable in acid; however,
it decomposes rapidly above pH 6.5.3 This instability, and the
complex hexacyclic constitution of palau'amine and styloguani-
dine, renders these marine alkaloids daunting total synthesis
targets.6 Much of their structural complexity resides in the
central 3-azabicyclo[3.3.0]octane ring system, particularly the
cyclopentane ring which is substituted on the R face at each
carbon. This density of functionality and the stereochemical
relationship of the two spirocyclic guanidine subunits present
a formidable challenge to synthesis. In this paper, we report a
concise strategy for assembling the central cis-3-azabicyclo-
[3.3.0]octane core of palau’amine and styloguanidine in which
the critical stereochemical relationship between the ring fusion
stereocenters C-11 and C-12 and the two spiro guanidine units
(C-10 and C-16) is established by an intramolecular azomethine
imine cycloaddition.7,8
a Key: (a) H2NCH2CO2Na, EtOH, reflux; (b) H2SO4, EtOH, reflux;
(c) CbzCl, Et3N; (d) tBuOK, THF, -78 °C; (e) NaBH4, EtOH; (f) MsCl,
Et3N, DMAP, C6H6, 0 °C; (g) O3, CH2Cl2; Ph3P; (h) LiCl, DBU, MeCN,
(MeO)2POCH(OTBDMS)CO2Me; (i) CsF, AcOH, MeCN.
ment of the oxidation state of carbons 6 and 20 afford 3, a
pentacyclic intermediate that could serve as a common precursor
of 1 and 2 (Scheme 1). A formidable challenge in constructing
3 is relating the orientation of the two spiro guanidine units
and the cis-3-azabicyclo[3.3.0]octane unit. Our approach to
palau'amine and styloguanidine is driven by the perception that
this stereorelationship could be established through intramo-
lecular cycloaddition of azomethine imine 5 to form triaza-
hexahydrotriquinacene 4.9 In order to facilitate initial investi-
gations of this pivotal intramolecular cycloaddition step, we
chose to investigate the sequence depicted in Scheme 1 in a
model series that lacks functionality (X and/or Y) which would
eventually be required for introduction of the aminomethyl and
chloride substituents.
In our initial survey, R-keto ester cycloaddition substrate 10
was assembled by the sequence summarized in Scheme 2.
Conjugate addition of the sodium salt of glycine to ethyl (2-
allyl)acrylate (6),10 followed by Fisher esterification and protec-
tion of nitrogen with a benzyloxycarbonyl group, delivered 7.
Dieckmann cyclization11 of 7 and subsequent reduction12 of the
â-keto ester product provided pyrrolidine 8 in good yield.
Reaction of 8 with methanesulfonyl chloride, followed by direct
Disconnection of the linkage between C-6 and the 2-acylpyr-
role unit of palau'amine (1) and styloguanidine (2) and adjust-
(1) Current address: Bristol-Myers Squibb Pharmaceutical Research
Institute, Department of Medicinal Chemistry, P.O. Box 4000, Princeton,
NJ 08543-4000.
(2) Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75 and earlier reviews in
this series.
(3) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993,
115, 3376.
(4) Palau'amine isolated from S. agminata is levorotatory; however, the
absolute stereochemistry is unknown.
(5) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, M.
Tetrahedron Lett. 1995, 36, 2133.
(8) For the seminal use of intramolecular azomethine imine cycloadditions
for the synthesis of guanidine alkaloids, see: (a) Jacobi, P. A.; Martinelli,
M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5595. (b) Jacobi, P. A.;
Brownstein, A.; Martinelli, M.; Grozinger, K. J. Am. Chem. Soc. 1981,
103, 239. (c) Martinelli, M. J.; Brownstein, A. D.; Jacobi, P. A.; Polanc, S.
Croat. Chem. Acta 1986, 59, 267.
(6) The tetracyclic skeleton defined by carbons 1-15 of 1 and 2 is found
in the marine alkaloid dibromophakellin. For a pioneering synthesis of this
simpler marine metabolite, see: Foley, L. H.; Bu¨chi, G. J. Am. Chem. Soc.
1982, 104, 1776.
(7) (a) Oppolzer, W. Tetrahedron Lett. 1970, 35, 3091. (b) For a brief
review of intramolecular azomethine ylide cycloadditions, see: Wade, P.
A. Intramolecular 1,3-Dipolar Cycloadditions. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: London, 1991; Vol.
4, pp 1144-49.
(9) For the construction of diazahexahydrotriquinacenes by intramolecular
azomethine ylide cycloadditions, see: Overman, L. E.; Tellew, J. E. J. Org.
Chem. 1996, 61, 8338.
(10) Helquist, P.; Yu, L. C. J. Org. Chem. 1981, 46, 4536.
S0002-7863(97)01298-5 CCC: $14.00 © 1997 American Chemical Society

7160 J. Am. Chem. Soc., Vol. 119, No. 30, 1997
Communications to the Editor
Scheme 3
Scheme 4
reaction of 14 with phosphoryl isothiocyanate fashioned the
second thiohydantoin ring but it also accomplished reductive
cleavage of the N-N bond.19,20 Finally, the two spiro thiohy-
dantoins were efficiently converted into the desired bis-
(acylguanidine) units of 17 by sequential reaction of 15 with
MeI and benzylamine.21
In conclusion, a concise approach to the total synthesis of
the complex hexacyclic bisguanidine alkaloids palau'amine (1)
and styloguanidine (2) has been defined in a model series. The
central step is an intramolecular azomethine imine cycloaddition,
10 f 11, which fashions the cis-3-azabicyclo[3.3.0]octane and
two pendant spiro guanidine units with complete stereocontrol.
Current efforts focus on elaborating this strategy to realize a
comprehensive solution to the total synthesis challenge posed
by 1 and 2.
ozonolysis of the somewhat unstable crude mesylate derivative,
yielded the corresponding aldehyde, which was directly con-
densed with methyl 2-(tert-butyldimethylsiloxy)-2-(dimeth-
ylphosphono)acetate13 in the presence of excess 1,8-diazobicyclo-
[5.4.0]undec-7-ene (DBU) and LiCl.14 This three-step sequence
provided dihydropyrrole 9 in 50% overall yield. Desilylation
of 9 with CsF provided racemic R-keto ester 10 in high yield.
When an acetic acid solution of 10 and thiosemicarbazide (3
equiv) was heated at 70 °C, intramolecular cycloaddition and
subsequent acylation took place smoothly to deliver tetracycle
11 in excellent yield (Scheme 3). In this pivotal step, the single
stereogenic center of 10 directs formation of the three additional
stereocenters in 11. Treatment of 11 at room temperature with
HBr in AcOH provided the crystalline hydrobromide salt 12,
whose structure was confirmed by single-crystal X-ray diffrac-
tion analysis.15 Cleavage of the N-N bond of 11 proceeded
smoothly in the presence of 2 equiv of SmI2 in THF-MeOH
(9:1) to yield tricyclic R-amino ester 13, whose constitution was
also established by single-crystal X-ray diffraction analysis.15,16
Initial attempts to fashion a second spiro thiohydantoin from
the R-amino ester functionality of 11 by reaction with an
isothiocyanate followed by base-promoted cyclization proved
unproductive.17 However, hydrolysis of ester 11 and subsequent
treatment of carboxylic acid 14 with 2.5 equiv of phosphoryl
isothiocyanate18 in refluxing THF provided bis(thiohydantoin)
15 in 72% overall yield from 11 (Scheme 4). Not only had
Acknowledgment. This paper is dedicated to the memory of
Professor Wolfgang Oppolzer. Grant support from the National Heart,
Lung, and Blood Institute (HL-25854), NIH NRSA postdoctoral
fellowships to B.N.R. (CA-73122) and J.E.T. (GM-16617), and graduate
fellowships (W.C.T.) from the Department of Education and Abbott
Laboratories are 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. John
Greaves for assistance with mass spectral analyses and Dr. Joe Ziller
for the X-ray analyses of 12 and 13.
Supporting Information Available: Characterization data and
preliminary experimental procedures for preparing compounds 7-12,
15, and 17 (5 pages). See any current masthead page for ordering and
Internet access instructions.
(11) (a) Blake, J.; Willson, C. D.; Rapaport, H. J. Am. Chem. Soc. 1964,
86, 5293. (b) Miyamoto, M.; Morimoto, H.; Sugawa, T.; Uchibayashi, M.;
Sanno, Y.; Tanaka, K. Yakugaku Zassi 1957, 77, 571; Chem. Abstr. 1957,
51, 16422.
(12) Rozing, G. P.; de Koning, H.; Huisman, H. O. Recl. TraV. Chim.
Pays-Bas 1981, 100, 359.
JA9712985
(19) To our knowledge, this is the first use of phosphoryl isothiocyanate
to form thiohydantoins from R-amino acids; however, this reagent has
previously been used to prepare acyl isothiocyanates from simple carboxylic
acids.18
(20) At this point only speculation can be advanced regarding the
mechanism of this unexpected reduction. We would note that the N-N
bond of 14, or potential pentacyclic intermediate 18, would be significantly
weakened by ring strain. Whether the reductant is thiocyanate or a trivalent
phosphorous species is under investigation.
(13) (a) Nakamura, E. Tetrahedron Lett. 1981, 22, 663. (b) Horne, D.;
Gaudino, J.; Thompson, W. Tetrahedron Lett. 1984, 25, 3529.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Escenteld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(15) Crystallographic data for this compound has been deposited with
the Cambridge Crystallographic Data Centre. The coordinates can be
obtained on request from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K.
(16) Freshly prepared SmI2 was required to obtain reproducible yields
for this reaction.
(17) (a) Rasmussen, C. R.; Villani, F. J., Jr.; Weaner, L. E.; Reynolds,
B. E.; Hood, A. R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo,
M. J.; Powell, E. T.; Molinari, A. J. Synthesis 1988, 456. (b) Elmore, D.
T.; Ogle, J. R.; Toseland, P. A. J. Chem. Soc. 1956, 192.
(18) Kniezo, L.; Berna´t, J. Synth. Commun. 1990, 20, 509.
(21) Gadwood, R. C.; Kamdar, B. V.; Cipkus Dubray, L. A.; Wolfe, M.
A.; Smith, M. P.; Watt, W.; Miszak, S. A.; Groppi, V. E. J. Med. Chem.
1993, 36, 1480.