Enantioselective strategy to the spirocyclic core of Palau'amine and related bisguanidine marine alkaloids.

Article abstract of DOI:10.1021/ol015864j

[structure: see text] An enantioselective strategy to the spirocyclic core found in the oroidin-derived family of bisguanidine marine alkaloids has been devised, premised on a biosynthetic proposal. Herein, we describe the successful implementation of thi

Full text of DOI:10.1021/ol015864j

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1535-1538
Enantioselective Strategy to the
Spirocyclic Core of Palau’amine and
Related Bisguanidine Marine Alkaloids
Anja S. Dilley and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77843-3012
romo@mail.chem.tamu.edu
Received March 19, 2001
ABSTRACT
An enantioselective strategy to the spirocyclic core found in the oroidin-derived family of bisguanidine marine alkaloids has been devised,
premised on a biosynthetic proposal. Herein, we describe the successful implementation of this strategy, which entails a Diels−Alder reaction
and a chlorination/ring contraction sequence that delivers the fully functionalized spirocyclic core. In this initial report, an intermolecular
chlorination delivers a cyclopentane that is epimeric at C17 relative to the palau’amines and epimeric at C11 relative to the axinellamines.
The remarkable structural diversity of guanidine-containing
marine natural products makes them attractive synthetic
targets.1 In addition, many of these compounds possess potent
biological activity that renders them potentially useful as
biochemical probes. In this regard, the class of bioactive
marine natural products that includes the palau’amines (1),2
the styloguanidines (2),3 and the axinellamines (3)4 possess
a common, highly complex cyclopentane that is stereogenic
at every carbon including one quaternary spiro center (Figure
1).5 These alkaloids also include two cyclic guanidines within
their structure. Biosynthetically, these metabolites are thought
to be derived from a common precursor, oroidin. Our interest
in these natural products stems from their challenging
structure coupled with the potent immunosuppressive activity
of palau’amine.6 Two approaches to these metabolites that
have been described are a concise route to an abbreviated
tetracyclic core structure by Overman7a and a desymmetri-
zation strategy to the axinellamine cyclopentane described
by Carreira.7b Herein, we describe our synthetic approach
to this class of bisguanidine alkaloids that is premised on
the biosynthetic proposal of Kinnel and Scheuer.2a,8 This
(1) (a) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365. (b)
Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7-55.
(2) (a) Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376-3377. (b) Kinnel, R. B.; Gehrken, H.-P.; Swali, R.;
Skoropowski, G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281-3286.
(3) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A.; Endo, M.
Tetrahedron Lett. 1995, 36, 2133-2136.
(4) (a) Urban, S.; Leone, P. D. A.; Carroll, A. R.; Fechner, G. A.; Smith,
J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731-735. (b) It
should be noted that the same name was previously given to related, simpler
pyrrole alkaloids; see: Bascombe, K. C.; Peter, S. R.; Tinto, W. F.; Bissada,
S. M.; McLean, S.; Reynolds, W. F. Heterocycles 1998, 48, 1461-1464.
(5) The absolute configuration of these natural products has not been
determined unambiguously; however, the absolute stereochemistry of
palau’amine (as shown in Figure 1) has been tenatively assigned on the
basis of similarities of its CD spectrum with monobromophakellin hydro-
choride (see ref 2a).
(6) Palau’amine has an IC50 of 42.8 nM in the mixed lymphocyte reaction
(ref 2a).
(7) (a) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J.
Am. Chem. Soc. 1997, 119, 7159-7160. (b) Starr, J. T.; Koch, G.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 8793-8794.
10.1021/ol015864j CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

contraction to deliver the spirocycle found in the palau’amines
and styloguanidines after capture of the resulting iminium
ion by water.
Initially, to validate this approach, we envisioned a 1,2-
alkyl shift induced by a nondirected, intermolecular chlo-
rination of cyclohexene 8 followed by trapping of the
resulting iminium ion with water (Scheme 2). This would
Scheme 2. Retrosynthetic Analysis of the Palau’amine
Spirocyclic Core 7
deliver spirocyclic lactam 7a, which is epimeric at C5 (C17,
palau’amine numbering) relative to the cyclopentane of
palau’amine. Ultimately, to access the stereochemistry found
in palau’amine, we anticipated the use of the pendant group
at C4 to perform a directed or intramolecular chlorination.
A Diels-Alder reaction involving the pyroglutamic acid
derived lactam 912 and vinyl imidazolone 10 would furnish
the tricyclic scaffold 8.13 Notably, all relative and absolute
stereochemistry in palau’amine would be derived from the
single stereogenic center of pyroglutamic acid. We expected
high facial and endo selectivity on the basis of Diels-Alder
reactions with related dienophiles;14 however, the extent of
regiocontrol was less secure. Support for the proposed
chlorination-induced 1,2-shift was garnered from recently
described, related ring contractions in synthetic studies of
the paraherquamides and the spirotryprostatins.15
Figure 1. Structure of oroidin and oroidin-derived sponge alkaloids.
strategy provides a rapid entry into the complex spirocycle
of these compounds and includes a Diels-Alder reaction of
a vinyl imidazolone and a chlorination-induced 1,2-alkyl
migration as key steps.9
The biosynthetic proposal of Kinnel and Scheuer invokes
a Diels-Alder reaction between dehydrophakellin 5, an
unknown metabolite related to the known mono- and
dibromophakellins,10 and the known metabolite 2-amino-1-
(2-aminoimidazolyl)prop-1-ene (4, AAPE) (Scheme 1).11
A
The synthesis of diene 10 was initiated by perbenzylation
of the known imidazolone 11 (Scheme 3).16 Reduction of
Scheme 1. Proposed Biosynthesis of Palau’amine
Scheme 3. Synthesis of the Dienea
a (a) DMF, 80 °C (41%); (b) CH2Cl2, -78 °C (84%); (c) CH2Cl2,
25 °C (98%); (d) NaH, THF, 0 f 25 °C; (e) CH2Cl2, -78 °C (78%,
two steps).
subsequent chlorination, presumably involving a chloroper-
oxidase, is proposed to initiate a pinacol-like 1,2-shift/ring
(8) (a) This biosynthetic proposal was suggested by a reviewer of the
publication by Kinnel and Scheuer (see footnote 23, ref 2b). (b) For a
recently described unifying biosynthetic proposal of oroidin-derived
metabolites, see: Mourabit, A. A.; Potier, P. Eur. J. Org. Chem. 2001,
237-243.
(9) For related Diels-Alder reactions of vinyl imidazoles, see: Lovely,
C.; Du, H.; Rasika Dias, H. V. Org. Lett. 2001, 3, 1319-1322.
(10) Sharma, G.; Magdoff-Fairchild, B. J. Org. Chem. 1977, 42, 4118-
4124.
the benzyl ester 12 with DIBAl-H to the alcohol followed
by oxidation with MnO2 gave the corresponding aldehyde.
(11) Wright, A. E.; Chiles, S. A.; Cross, S. S. J. Nat. Prod. 1991, 54,
1694-1686.
1536
Org. Lett., Vol. 3, No. 10, 2001

A subsequent olefination gave ester 13, which was reduced
to furnish alcohol 10. Because of the pronounced acid
sensitivity of this alcohol it was used without purification,
and subsequent Diels-Alder reactions could only be per-
formed under thermal conditions with added base.
Scheme 5. Oxidation Chemistry of Imidazolone 16 and X-ray
Structure of Overoxidation Product 19; POVchem Rendering;
Nitrogen and Oxygen Protecting Groups Are Omitted for Clarity
Upon heating dienophile 9 and diene 10 in benzene in a
sealed tube at 95 °C for 4 days, we were pleased to find that
the desired cycloadduct 14 could be isolated as the major
adduct (64%) along with the expected regioisomer 15 (15%)
(Scheme 4). However, the double bond migrates to regenerate
Scheme 4. Diels-Alder Reaction
the imidazolone ring under the conditions of the Diels-Alder
reaction. Stereochemical proof of the major cycloadduct was
based upon NMR studies including a critical GOESY
experiment17 that showed an NOE correlation between a
benzylic proton and Hc, which would only be possible in
regioisomer 14 (Scheme 4). Mosher ester analysis of Diels-
Alder adduct 14 indicated an enantiomeric excess of >95%.18
Structural confirmation of the minor Diels-Alder regioiso-
mer was secured by X-ray analysis.
Despite isomerization of the double bond in the Diels-
Alder reaction, we proceeded to study the viability of the
1,2-shift/ring-contraction sequence. We reasoned that ep-
oxidation of imidazolone 14 would furnish a rearranged
deschloro spirohydantoin analogous to 7. However, after silyl
protection of alcohol 14, treatment of imidazolone 16 with
m-CPBA rapidly (<5 min) led to what we initially believed
to be allylic alcohol 17 (Scheme 5). This structure was
quickly excluded since mass spectral analysis indicated the
incorporation of three oxygen atoms.
ylsilylbromide.19 This suggested the structure of the over-
oxidation product to be hemiacetal 18 (Scheme 5).
Our current mechanistic proposal for this overoxidation
involves an initial epoxidation of alkene 16 with m-CPBA,
followed by epoxide ring opening via presumed iminium ion
formation and deprotonation to give carbinol 17. A second
epoxidation/ring opening sequence was followed by a
proposed Baeyer-Villiger-type oxidation of the resulting
iminium intermediate.20 Furthermore, subsequent rearrange-
ment to the spirocyclic hydantoin 18 spontaneously ensued.
The stereochemistry of the quaternary center of 18 suggests
that epimerization of the proposed intermediate 17 occurs
under the acidic conditions of the epoxidation. We deter-
mined that epimerization at C4 occurs under the basic
conditions of the TBAF deprotection of lactol 18. While not
useful for our synthesis, the formation of this rearrangement
product did suggest the viability of the proposed 1,2-shift
leading to a spirocyclic hydantoin.
At this stage, we recognized the potential of alcohol 17
as an ideal substrate for the projected chlorination/rearrange-
ment sequence since it possesses an alkene in the desired
position and also provides the driving force of CdO bond
formation during the rearrangement. Ultimately, we were able
to generate alcohol 17 in a highly diastereoselective manner
and in high yield by careful treatment of imidazolone 16
with dimethyldioxirane (DMDO) at -45 °C. The structure
and stereochemical proof of carbinolurea 17 was provided
Although extensive spectral analysis was performed on
the overoxidation product, complete structure elucidation was
only possible following X-ray analysis of a derivative
obtained after deprotection and silylation with trityldimeth-
(12) Dienophile 9 was synthesized from (S)-pyroglutamic acid (five steps)
in analogy to reported procedures for related dienophiles; see: (a) Ohfune,
Y.; Tomita, M. J. Am. Chem. Soc. 1982, 104, 3511-3513. (b) Ackermann,
J.; Matthes, M.; Tamm, C. HelV. Chim. Acta 1990, 73, 122-132.
(13) Current efforts are directed toward the presumed enantiomeric
tricyclic core structure in order to utilize the less expensive (S)-pyroglutamic
acid.
(14) Sauter, R.; Thomas, E. J.; Watts, J. P. J. Chem. Soc., Perkin Trans.
1 1989, 519-523. See also ref 12b.
(15) (a) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am.
Chem. Soc. 1996, 118, 557-579. (b) Edmondson, S.; Danishefsky, S. J.;
Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147-2155.
(c) Ganesan, A.; Wang, H. J. Org. Chem. 2000, 65, 4685-4693.
(16) Baxter, R. L.; Camp, D. J.; Coutts, A.; Shaw, N. J. Chem. Soc.,
Perkin Trans. 1 1992, 255-258.
(17) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem.
Soc. 1994, 116, 6037-6038.
(18) See Supporting Information for details.
(19) Ager, D. J.; Fleming, I. J. Chem. Res. 1977, 6-7.
Org. Lett., Vol. 3, No. 10, 2001
1537

by detailed spectral analysis including COSY and HMQC
spectra. Key data included the presence of a carbinolurea
carbon in the 13C spectra (δ 86.5, d6-acetone)21 and a
GOESY22 experiment that showed a NOE between the
carbinol hydroxyl proton and the C4 proton (Scheme 5). This
hydroxyl proton appears as a sharp singlet at δ 5.57 and is
exchangeable with D2O. In support of the mechanism
proposed above, treatment of alcohol 17 with m-CPBA also
led to acetal 18.
In summary, we have developed a concise, enantioselective
approach to the spirocyclic core of the bisguanidine family
of marine natural products. Spirocycle 20 possesses the
full complement of cyclopentane functionality found in
palau’amine but is epimeric at the chlorine-bearing atom C5
(C17 in palau’amine, see Figure 1). Epimerization at C3
would also provide the cyclopentane stereochemistry of the
axinellamines. Studies toward a substrate-directed or in-
tramolecular chlorination by the pendant C4 substituent to
access the cyclopentane stereochemistry of palau’amine are
in progress.
With a suitable substrate in hand, we studied a nondirected,
intermolecular chlorination. Pleasingly, treatment of carbinol-
urea 17 with N-chlorosuccinimide (NCS) in the presence of
cyclohexene23 delivered the chlorinated spirocyclic hydantoin
20 in 75% yield (Scheme 6). The stereochemistry of the
Acknowledgment. We thank the NIH (GM 52964-06),
the Welch Foundation (A-1280), and Zeneca Pharmaceuticals
for support of these investigations. A.S.D. was a NIH CBI
Training Grantee (1998-2000, T32 GM-08523). D.R. is an
Alfred P. Sloan Fellow and a Camille-Henry Dreyfus
Teacher-Scholar. We thank Jay Hartwell for technical
assistance and Dr. Joe Reibenspies for X-ray structure
determination using instruments obtained with funds from
the NSF (CHE-9807975).
Scheme 6. Chlorination/Ring Contraction Sequence Leading
to Spirocyclic Hydantoin 20; Observed NOE’s Indicated with
Arrows
Supporting Information Available: Selected experi-
1
mental procedures and characterization data (including H,
GOESY, and 13C NMR spectra) for compounds 9, 12-14,
17, and 20. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL015864J
(21) This chemical shift correlates well with related carbinolurea carbons
found in: (a) agelastatin A (δ 93.3, CD3OD): D’Ambrosio, M.; Guerriero,
A.; Debitus, C.; Ribes, O.; Pusset, J.; Leroy, S.; Pietra, F. J. Chem. Soc.,
Chem. Commun. 1993, 1305-1306. (b) slagenin A (δ 93.3, d6-DMSO):
Tsuda, M.; Uemota, H.; Kobayashi, J. Tetrahedron Lett. 1999, 40, 5709-
5712.
(22) GOESY experiments shown were performed on spirocycle 20 and
a deprotected derivative. See Supporting Information for details.
(23) Substantial quantities of aromatized byproducts were produced unless
cyclohexene was added as an “alkene buffer”. An example of this concept
(unpublished results of J. J. Hans) was described to us recently by Professor
T. R. Hoye.
spirohydantoin was determined by GOESY experiments
(Scheme 6) and is consistent with mechanistic considerations
involving initial intermolecular chlorination from the convex
face of alcohol 17 followed by a suprafacial 1,2-alkyl shift.
(20) For a Baeyer-Villiger oxidation of an oxocarbenium ion, see: Hunt,
K. W.; Grieco, P. A. Org. Lett. 2000, 2, 1717-1719. We thank Dr. Eric
Moher (Eli Lilly) for bringing this related work to our attention.
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Org. Lett., Vol. 3, No. 10, 2001