Assembling Polycyclic Bisguanidine Motifs Resembling Batzelladine Alkaloids by Double Tethered Biginelli Condensations

Article abstract of DOI:10.1021/ol0357999

(Equation presented) Double tethered Biginelli condensations furnish linked polycyclic bisguanidines or bisureas. Alteration of the bis-β-ketoester component allows bispolycyclic guanidine motifs to be constructed that resemble natural batzelladine alkalo

Full text of DOI:10.1021/ol0357999

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4485-4488
Assembling Polycyclic Bisguanidine
Motifs Resembling Batzelladine
Alkaloids by Double Tethered Biginelli
Condensations
Frederick Cohen,† Shawn K. Collins,‡ and Larry E. Overman*
Department of Chemistry, 516 Rowland Hall, UniVersity of California-IrVine,
IrVine, California, 92697-2025
leoVerma@uci.edu
Received September 17, 2003
ABSTRACT
Double tethered Biginelli condensations furnish linked polycyclic bisguanidines or bisureas. Alteration of the bis-â-ketoester component
allows bispolycyclic guanidine motifs to be constructed that resemble natural batzelladine alkaloids or have novel linkages.
Members of the batzelladine family of sponge-derived
alkaloids are rare examples of small natural products that
regulate protein-protein interactions.1,2 Batzelledines A and
B (1) were the first low-molecular weight natural products
reported to inhibit the binding of HIV gp-120 to human CD4,
a critical step in the life cycle of the AIDS virus,1 whereas
batzelladines F (2)-I induce dissociation of the protein
tyrosine kinase p56 from its complex with CD4.2a Various
batzelladine alkaloids and analogues also inhibit HIV
envelope-mediated cell fusion.3 The most complex batzel-
ladine alkaloids, exemplified by batzelladines B (1) and F
(2), contain two polycyclic guanidine units, whereas batzel-
ladines C, D (3), and E display a single tricyclic guanidine
moiety (Figure 1). The decahydro- or octahydro-5,6,8b-
triazaacenaphthalene unit that is the common structural
feature of the batzelladine alkaloids occurs with both the cis
and trans stereorelationships of the angular hydrogens that
flank the pyrrolidine nitrogen.
The batzelladine family of polycyclic guanidine alkaloids
has stimulated many synthetic endeavors.4-7 Some of these
studies established the relative configuration5c,f-h,6c and
constitution6c of various batzelladine alkaloids, whereas
others defined their absolute configuration.5i,6j Total syntheses
of (-)-batzelladine D (3),6b (()-batzelladine D (3),5k (()-
batzelladine E,5f and (-)-batzelladine F (2)6c have been
accomplished.
† Current address: Department of Medicinal Chemistry, Genentech, Inc.,
1 DNA Way, South San Francisco, CA 94080.
Although significant advances in synthesis and structural
verification of the batzelladine alkaloids have been achieved,
identification of the essential features required to impart
biological activity to these marine natural products remains
a long-standing goal. Investigations of structure-activity
‡ Current address: Universite´ de Montre´al, De´partemente de Chimie,
C.P. 6128, Succursale Centre-ville, Montre´al, QC., Canada, H3C 3J7.
E-mail: s.collins@umontreal.ca.
(1) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A.
J.; Debrosse, C.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.; Breen, A.
L.; Hertzberg, R. P.; Johnson, R. K.; Westley, J. W.; Potts, B. C. M. J.
Org. Chem. 1995, 60, 1182-1188.
(2) (a) Patil, A. D.; Freyer, A. J.; Taylor, P. B.; Carte´, B.; Zuber, G.;
Johnson, R. K.; Faulkner, D. J. J. Org. Chem. 1997, 62, 1814-1819. (b)
Braekman, J. C.; Daloze, D.; Tavares, R.; Hajdu, E.; Vas Soest, R. W. M.
J. Nat. Prod. 2000, 63, 193-196.
(3) Bewley, C. A.; Cohen, F.; Collins, S. K.; Overman, L. E. Manuscript
in preparation.
(4) For reviews of early studies, see: Berlinck, R. G. S. Nat. Prod. Rep.
1999, 339-365.
10.1021/ol0357999 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/15/2003

right-hand fragment 7 of batzelladine B (1) in 94% yield
with 10:1 stereoselectivity for forming the isomer having a
cis relationship of the angular hydrogens (Scheme 1).6a If
the nucleophilic component in such a reaction were a bis-
â-ketoester, Biginelli condensation with a tethered guanidine
aldehyde should rapidly assemble hexacyclic bisguanidine
analogues of complex batzelladines such as 9. Our initial
investigation of this proposal is the subject of this com-
munication.
Scheme 1. Single and Double Tethered Biginelli Reactions
Figure 1. Representative batzelladine alkaloids.
relationships would be greatly facilitated by a streamlined
synthesis of batzelladine-like bisguanidines. Herein we report
our initial investigations into the use of double tethered
Biginelli cyclizations7,8 to synthesize molecular architectures
that resemble naturally occurring batzelladine alkaloids.
The tethered Biginelli reaction has played a central role
in our laboratory’s total syntheses of crambescidin and
batzelladine alkaloids.6,7 For example, morpholinium acetate-
promoted condensation of guanidine aldehyde 4 with methyl
acetoacetate in trifluoroethanol (TFE) at 90 °C provided the
To study double tethered Biginelli cyclizations for ac-
cessing molecular architectures resembling naturally occur-
ring batzelladines, the series of bis-â-ketoesters summarized
in Figure 2 was prepared. These syntheses were ac-
complished using standard methods that exploited transfor-
mations developed by Taber9 and Wieler;10 experimental
details can be found in Supporting Information.
Exploratory investigations of double tethered Biginelli
condensations were carried out at 60 °C using the procedure
employed to form 7.6a Under these conditions, the reaction
of guanidine aldehyde 5 with bis-â-ketoester 6 produced the
double Biginelli product 9 in low yield, the major product
being the mono Biginelli adduct 8 (Scheme 1). However,
the yield of 9 was improved to 41% when 3.5-4 equiv of 5
were employed. Methanol, which appears to better dissolve
the Biginelli monoadduct, could also be used as the solvent.
Results of double tethered Biginelli condensations of two
representative tethered guanidine aldehydes and the series
of bis-â-ketoesters shown in Figure 2 are summarized in
Table 1. The reaction reported in entry 2 is typical, providing
two stereoisomeric bisguanidine products that could be
separated by HPLC. The major product 16, showing only
(5) For studies from other laboratories, see: (a) Murphy, P. J.; Williams,
H. L.; Hursthouse, M. B.; Abdul Malik, K. M. J. Chem Soc., Chem.
Commun. 1994, 119-121. (b) Rao, A. V. R.; Gurjar, M. K.; Vasudevan,
Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron Lett. 1996, 37, 6977-
6980. (c) Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron
Lett. 1996, 37, 6977-6980. (d) Black, G. P.; Murphy, P. J.; Walshe, N. D.
A.; Hibbs, D. E.; Hursthouse, M. B.; Abdul Malik, K. M. A. Tetrahedron
Lett. 1996, 37, 6043-6946. (e) Louwrier, S.; Ostendorf, M.; Tuynman, A.;
Hiemstra, H. Tetrahedron Lett. 1996, 37, 905-908. (f) Snider, B. B.; Chen,
J. Tetrahedron Lett. 1998, 39, 5697-5700. (g) Black, G. P.; Murphy, P. J.;
Walshe, N. D. A. Tetrahedron 1998, 54, 9481-9488. (h) Black, G. P.;
Murphy, P. J.; Thornhill, A. J.; Walshe, N. D. A.; Zanetti, C. Tetrahedron
1999, 55, 6547-6554. (i) Duron, S. G.; Gin, D. Y. Org. Lett. 2001, 3,
1551-1554. (j) Nagasawa, K.; Koshino, H.; Nakata, T. Org. Lett. 2001, 3,
4155-4158. (k) Ishiwata, T.; Hino, T.; Koshino, H.; Hasimoto, Y.; Nakata,
T.; Nagasawa, K. Org. Lett. 2002, 4, 2921-2924.
(6) For our studies in this area, see: (a) Franklin, A. S.; Ly, S. K.; Mackin,
G. H.; Overman, L. E.; Shaka, A. J. J. Org. Chem. 1999, 64, 1512-1519.
(b) Cohen, F.; Overman, L. E.; Sakata, S. K. L. Org. Lett, 1999, 1, 2169-
2172. (c) Cohen, F.; Overman, L. E. J. Am. Chem. Soc. 2001, 123, 10782-
10783.
(7) For the use of tethered Biginelli condensations for stereocontrolled
assembly of decahydro- and octahydro-5,6,8b-triazaacenaphthalenes, see:
ref 6 and: (a) Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58,
3235-3237. (b) Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J.
Am. Chem. Soc. 1995, 117, 2657-2658. (c) McDonald, A.; Overman, L.
E. J. Org. Chem. 1999, 64, 1520-1528. (d) Coffey, D. S.; McDonald, A.
I.; Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc.
2000, 122, 4893-4903. (e) Coffey, D. S.; Overman, L. E.; Stappenbeck,
F. J. Am. Chem. Soc. 2000, 122, 4904-4914.
(9) Taber, D. F.; Amedio, J. C.; Patel, Y. K. J. Org. Chem. 1985, 50,
3618-3619.
(10) Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702-6704.
(8) For a recent review of the classical Biginelli reaction, see: Kappe,
O. C. Acc. Chem. Res. 2000, 33, 879-888.
4486
Org. Lett., Vol. 5, No. 23, 2003

in which case double Biginelli condensations with these bis-
â-keto esters proceeded in useful yields (entries 6 and 7).
Gratifyingly, employing unsymmetrical bis-â-ketoester 15
made it also possible to obtain bisguanidine products having
linkage patterns similar to those found in batzelladines F-I
(entry 3). In all cases reported in Table 1, the corresponding
mono Biginelli product (analogous to 7) was observed as a
major byproduct in 5-20% yield.
Not surprisingly, the C2- and C1-symmetric products of
the double tethered Biginelli reactions reported in Table 1
showed nearly identical physical properties. Nonetheless,
these stereoisomers could be resolved by HPLC, although
baseline separation was rarely achieved. In all cases, the
major C2-symmetric isomer eluted with a shorter retention
time, allowing it to be isolated easily in pure form by
preparative HPLC. The later-eluting C1-symmetric product
was typically contaminated with small amounts of the
corresponding C2-symmetric stereoisomer.
Tethered urea aldehydes were found to be superior
substrates for double tethered Biginelli reactions (Scheme
2). For example, condensation of 4 equiv of 247a,c with bis-
Figure 2. Bis-â-ketoester substrates.
21 signals in its 13C NMR spectrum, was C2-symmetric. That
this product was the expected stereoisomer having a cis
relationship of the angular hydrogens6a was established by
the NOE enhancement (3%) observed between these hydro-
gens (δ 4.53 dd, J ) 9.7, 6.1 Hz; δ 3.78-3.83, m). The
minor stereoisomer showed more than 30 resolved signals
in the 13C NMR spectra, supporting its assignment as C1-
symmetric isomer 22.
Scheme 2. Double Tethered Biginelli Reaction to Form
Bisureas
A variety of bisguanidine motifs can be assembled in this
manner. Varying the nature of the symmetrical bis-â-
ketoester component allowed the tricyclic guanidine subunits
to be linked at their carboxyl carbons (entries 1, 4-7) or be
connected by a methylene chain (entry 2). In the former case,
the diol linkage could be a simple methylene chain or a chain
containing an aromatic spacer. Surprisingly, when bis-â-
ketoesters 11 and 13 were employed, double Biginelli
condensations with 4 or 5 carried out in methanol provided
only the tricyclic guanidine methyl ester 23. Apparently, the
â-ketoester 12 proceeded in 92% yield to deliver bis-1-
oxohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester 25
and its C1-symmetric epimer in 92% yield. Likewise, 27 and
its epimer were produced in 81% yield from condensation
of 24 and bis-â-ketoester 26.
In summary, the scope of the tethered Biginelli condensa-
tion has been expanded to include the formation of linked
bisguanidines and bisureas. Judicious choice of the bis-â-
ketoester component allows the octahydro-5,6,6a-tri-
azaacenaphthalene moieties of the bisguanidines to be
juxtaposition of the nonyl and ester side chains makes the
double Biginelli product susceptible to transesterification.11
Fortunately, the increased solubility provided by the C9 alkyl
chain allowed trifluoroethanol to be employed as the solvent,
Org. Lett., Vol. 5, No. 23, 2003
4487

Table 1. Bisguanidine Products of Double Tethered Biginelli Condensationsa
a Reaction conditions: Bis-â-ketoester (1 equiv), guanidine-aldehyde (4 equiv), morpholine (10 equiv), AcOH (10 equiv), and Na2SO4 (10 equiv) in
MeOH (0.1 M) at 60 °C for 48-96 h. b Combined yields of the C2- and C1-symmetric stereoisomers. c Minor stereoisomer was not isolated. d Trifluoroethanol
was the solvent. e The major double Biginelli product in this case is not C2-symmetric; the minor products (37%) were a mixture of two isomers, assumed
to each possess one cis and one trans tricyclic guanidine unit.
connected at either their carboxylate carbons, vinylic C4
carbons, or a combination thereof.12 As myriad variations
in the electrophilic and bis-â-ketoester components are
possible, the formation of novel linked heterocyclic structures
in a large library format should be readily achieved. Results
of biological evaluation of the bisguanidines and bisureas
prepared during this initial survey will be reported elsewhere.
Division Graduate Fellowship sponsored by Pharmacia &
Upjohn and S.K.C. by a National Sciences and Engineering
Research Council of Canada (NSERC) Postdoctoral Fellow-
ship. NMR and mass spectra were determined at UCI using
instruments acquired with the assistance of NSF and NIH
shared instrumentation grants.
Supporting Information Available: Experimental pro-
cedures and characterization data for bis-â-ketoesters 6, 10-
15 and double Biginelli products 9, 16-21, 25, and 27;
Acknowledgment. We thank NIH (HL-25854) for fi-
nancial support. F.C. was supported by an ACS Organic
1
copies of H and 13C spectra for these new compounds,
(11) Control experiments showed that bis-â-ketoesters 11 and 13 are
stable to the Biginelli reaction conditions in methanol over a period of 7
days, strongly suggesting that methanolysis is occurring after Biginelli
condensation.
(12) Such variation should be possible also in the formation of bisureas,
although this feature was not demonstrated in the present study.
selected minor double Biginelli products, and 23 (R )
n-C7H15). This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0357999
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Org. Lett., Vol. 5, No. 23, 2003