Synthesis and Determination of Absolute Configuration of the Bicyclic Guanidine Core of Batzelladine A

Article abstract of DOI:10.1021/ol015848m

matrix presented The synthesis of a selectively protected form of the bicyclic guanidine fragment of batzelladine A from L-aspartic acid is reported, thereby establishing the absolute configuration of the bicyclic guanidine ring system within the natural

Full text of DOI:10.1021/ol015848m

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1551-1554
Synthesis and Determination of
Absolute Configuration of the Bicyclic
Guanidine Core of Batzelladine A
Sergio G. Duron and David Y. Gin*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
gin@scs.uiuc.edu
Received March 15, 2001
ABSTRACT
The synthesis of a selectively protected form of the bicyclic guanidine fragment of batzelladine A from L-aspartic acid is reported, thereby
establishing the absolute configuration of the bicyclic guanidine ring system within the natural product.
The batzelladine alkaloids, exemplified by batzelladine A
(1), make up a family of polyguanidine marine natural
products isolated from the Caribbean sponge Batzella sp.
Structurally, all of the members of this class of alkaloids
(batzelladines A-I)1 contain at least one fused tricyclic
guanidine moiety, with certain members of this family
incorporating either an additional bicyclic guanidine sub-
structure (batzelladines A and B) or a second tricyclic
guanidine fragment (batzelladines F-I). The biological
activities of these complex alkaloids are of particular interest
in that the batzelladines A and B were found to inhibit the
binding of human CD4 and HIV gp120, while the batzella-
dines F-I induced dissociation of protein kinase p56lck from
CD4. In the past several years, considerable synthetic efforts
have been devoted to the synthesis of this family of alkaloids,
with the bulk of the work focusing on the construction of
the fused tricyclic fragment of the batzelladine alkaloids.2
However, efforts directed toward the asymmetric synthesis
of the bicyclic crambescin-like fragment3 of batzelladines
A and B, the two members of this class that exhibit gp120-
CD4 binding inhibitory activity, have not been addressed.4
In the original structural determination of 1, chemical
degradation studies necessitated the base hydrolysis of the
ester functionalities within the natural product prior to
(2) (a) Rao, A. V. R.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem.
Commun. 1995, 1369-1370. (b) Louwrier, S.; Ostendorf, M.; Tuynman,
A.; Hiemstra, H. Tetrahedron Lett. 1996, 37, 905-908. (c) Black, G. P.;
Murphy, P. J.; Walshe, N. D. A.; Hibbs, D. E.; Hursthouse, M. B.; Malik,
K. M. A. Tetrahedron Lett. 1996, 37, 6943-6946. (d) Snider, B. B.; Chen,
J. Tetrahedron Lett. 1996, 37, 6977-6980. (e) Snider, B. B.; Chen, J.
Tetrahedron Lett. 1998, 39, 5697-5700. (f) Black. G. P.; Murphy, P. J.;
Walshe, N. D. A. Tetrahedron 1998, 54, 9481-9488. (g) Franklin, A. S.;
Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shaka, A. J. J. Org. Chem.
1999, 64, 1512-1519. (h) McDonald, A. I.; Overman, L. E. J. Org. Chem.
1999, 64, 1520-1528. (i) Cohen, F.; Overman, L. E.; Sakata, S. K. L. Org.
Lett. 1999, 1, 2169-2172. (j) Snider, B. B.; Busuyek, M. V. J. Nat. Prod.
1999, 62, 1707-1711. (k) Black, G. P.; Murphy, P. J.; Thornhill, A. J.;
Walshe, N. D. A.; Zanetti, C. Tetrahedron 1999, 55, 6547-6554.
(1) (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer,
A. J.; De Brosse, 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. (b) 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.
10.1021/ol015848m CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/24/2001

extensive spectroscopic analysis, thus separating the sole
stereogenic center at C135 within the bicyclic guanidine
fragment from the remainder of the natural product. As a
result, the determination of the absolute configuration at C13
has remained in question. Moreover, the stereochemical
assignment of this chiral center is further hampered by the
relatively long hydrocarbon linker that separates the two
guanidine ring systems; consequently, correlation of relative
stereochemical relationship between the polycyclic guanidine
fragments has not been possible. We report herein the
establishment of the absolute configuration of the bicyclic
guanidine fragment of batzelladine A via the nonracemic
synthesis of a selectively protected form of the bicyclic
guanidine fragment 2, which is amenable to coupling with
the tricyclic guanidine ring system of 1.
Scheme 2a
It was envisioned that a protected form of the bicyclic
guanidine ring system (2, Scheme 1) could be derived from
Scheme 1
a (a) Refs 6 and 7; (b) pyrrolidine-2-thione (4), 90 °C, neat; (c)
PPh3, Et3N, CHCl3, reflux, 51% (from 7), (1:4, E:Z); (d) NaH, (p-
NO2-C6H4-O)2CO, THF, 71%; (e) H2, 10% Pd/C, EtOAc, >99%;
(f) NaOMe, MeOH, 85%; (g) Ac2O, Et3N, DMAP, CH2Cl2, 98%;
(h) MeOTf, CH2Cl2, 90%; (i) NaOMe, MeOH, 99%.
the convergent assembly of aspartic acid (3), pyrrolidine-2-
thione (4), and the two extended oligomethylene fragments
5 and 6, which constitute the central hydrocarbon linker and
the peripheral acyclic guanidine functionality, respectively,
in the natural product. In this strategy, L-aspartic acid (3) is
employed as the starting material to define the absolute
configuration of C13 within 1.
the R-bromolactone 7 with pyrrolidine-2-thione (4) via an
Eschenmoser sulfide contraction.8 In the event, a neat mixture
of pyrrolidine-2-thione (4) and lactone 7 was heated at 90
°C to induce condensation of the coupling partners. The
resulting mixture was then diluted with chloroform and
heated to reflux in the presence of Et3N and Ph3P to induce
the formation of the transient episulfide 8, which was
subsequently reduced with Ph3P to form the vinylogous
carbamate 9 as a 1:4 mixture of E:Z isomers (51% from 7).
Although a mixture of E/Z isomers of 9 is formed,
treatment of this mixture of isomers with NaH followed by
addition of bis(p-nitrophenyl)carbonate led to the formation
of the tricyclic urea 10 in 71% yield.9 It is worth noting that
The synthesis begins with a derivatization sequence of
L-aspartic acid (3) that entails (Scheme 2) (1) N-protection
of L-aspartic acid; (2) intramolecular anhydride formation;
(3) regioselective carbonyl reduction; and (4) R-bromination
to provide the R,â-substituted γ-lactone 7.6,7 The first con-
vergent step in the synthesis involves the condensation of
(3) (a) Berlinck, R. G. S.; Braekman, J. C.; Daloze, D.; Hallenga, K.;
Ottinger, R.; Bruno, I.; Riccio, R. Tetrahedron Lett. 1990, 31, 6531-6534.
(b) Berlinck, R. G. S.; Braekman, J. C.; Daloze, D.; Bruno, I.; Riccio, R.;
Rogeau, D.; Amade, P. J. Nat. Prod. 1992, 55, 528-532. (c) Jares-Erijman,
E. A.; Ingrum, A. A.; Sun, F.; Rinehart, K. L. J. Nat. Prod. 1993, 56, 2186-
2188.
(4) The bicyclic guanidine portion of 1 is virtually identical to crambescin/
crambine A, which has an 11-carbon saturated alkyl side chain. For a
biomimetic synthesis of racemic crambescins/crambines, see: (a) Snider,
B. B.; Shi, Z. J. Org. Chem. 1992, 57, 2526-2528. (b) Snider, B. B.; Shi,
Z. J. Org. Chem. 1993, 58, 3828-3839.
(7) R-Bromination to form 7 proceeded via a modification of the reported
procedure (Hanessian, S.; Vanasse, B.; Yang, H.; Alpegiani, M. Can. J.
Chem. 1993, 71, 1407-1411) in order to minimize unwanted R-dibromi-
nation (see Supporting Information).
(8) (a) Roth, M.; Dubs, P.; Gotschi, E.; Eschenmoser, A. HelV. Chim.
Acta 1971, 54, 710-734. (b) Marchand, P.; Bellassoued, M.-C.; Lhommet,
G. Synth. Commun. 1994, 24, 2577-2584.
(9) It is likely that treatment of 9E/Z with 2.2 equiv of NaH led to
formation of the E-dianion, which underwent efficient cyclic urea formation.
(5) Carbon number labeling is in accordance with the original isolation
paper (ref 1a).
(6) McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh,
T. J. Am. Chem. Soc. 1986, 108, 4943-4952.
1552
Org. Lett., Vol. 3, No. 10, 2001

the use of no more that 2.2 equiv of base is essential in the
urea formation reaction as the use of a large excess of the
strong base led to partial racemization of the stereogenic
center in 10.10 Hydrogenolysis of the benzyl carbamate group
in 10 affords the unprotected tricyclic urea 11. Attempts at
the direct O-methylation of the urea functionality in 11 were
unsuccessful. However, O-methylation in the bicyclic urea
could be achieved in high yield following ring opening of
the lactone functionality; thus, treatment of 11 with anhy-
drous NaOMe in MeOH afforded the primary alcohol 12
(85%), which was subsequently acetylated (13, 98%).
Treatment of the urea 13 with excess MeOTf in the absence
of an acid scavenger11 led to selective O-methylation to form
the corresponding methyl isourea 14 (90%), incorporating
the required guanidine precursor functionality. Selective
methanolysis of the acetate ester revealed the primary alcohol
functionality in 15, which serves as a key intermediate for
its coupling to the central oligomethylene linker (i.e., 5) in
the natural product.
Scheme 4a
Preparation of the hydrophobic side chain 5 was straight-
forward (Scheme 3), beginning with commercially available
a (a) (COCl)2, DMSO, Et3N, THF, -35 to 23 °C; 18, KHMDS,
-78 to -45 °C, 81% (1:9, E:Z); (b) H2, 10% Pd/C, EtOH, 99%;
(c) TBAF, THF, 98%; (d) NH3, NH4OAc, MeOH, 58 °C; HCO2H,
58%.
Scheme 3a
of the O-methyl isourea group in 21 to the bicyclic guanidine
product 22 via condensation with excess ammonia. The
guanidinium formate salt 22 derived from L-aspartic acid was
found to be identical in all respects, including optical rotation,
to that reported for the chemical degradation of natural 1,
thereby establishing the absolute configuration of C13
stereocenter in 1 to be R.
a (a) TIPSCl, imidazole, DMAP, CH2Cl2, 94%; (b) PPh3, CH3CN,
reflux, 59%.
8-bromo-1-octanol (16). Protection of the hydroxyl func-
tionality as the triisopropyl silyl ether (94%) followed by
heating of the bromide in the presence of Ph3P generated
the corresponding phosphonium salt 18.
Scheme 5a
Coupling of the phosphonium salt 18 to 15 proceeded via
the Ireland protocol involving a one-pot sequential Swern
oxidation/Wittig condensation (Scheme 4).12 This procedure
resulted in the efficient formation of the alkene 19 (81%) as
a 1:9 mixture of E:Z isomers, which subsequently underwent
hydrogenation to afford the fully saturated oligomethylene
side chain within 20 (99%). With synthetic access to
nonracemic 20, determination of the absolute configuration
of the bicyclic guanidine fragment of 1 was possible by its
conversion to the guanidinium formate 22, a common
intermediate also derived from the reported methanolysis of
natural 1.1 The synthetic sequence included (1) removal of
the silyl ether protective group (21, 98%); and (2) conversion
a (a) Saturated NaOH/MeOH, 65 °C, 81%; (b) 23, BOP-Cl, Et3N,
CH2Cl2, 75%; (c) 49% HF, H2O, CH3CN, 97%.
(10) The use of 5 equiv of NaH for urea formation led to an increase in
the isolated yield of the urea 10, although partial racemization led to the
formation of a 3:1 mixture of enantiomers as evidenced by Mosher ester
analysis of intermediate of 15. The use of 2.2 equiv of NaH minimized the
extent of racemization to form 10 (er, 95:05).
(11) The use of 2,4,6-tri(tert-butyl)pyridine as an acid scavenger led to
N-methylation.
The isourea intermediate 20 not only serves as a key
intermediate in the determination of the absolute configura-
tion at C13 in 1, but it is also a versatile intermediate for
the introduction of the acyclic guanidine fragment that
comprises the C1-C5 portion of 1. This was readily
accomplished by the base hydrolysis of the methyl ester in
(12) Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198-
2200.
Org. Lett., Vol. 3, No. 10, 2001
1553

20 (81%) followed by esterification of the carboxylic acid
with the N-protected 4-guanidinyl-1-butanol 23, a compound
previously prepared by Snider and co-workers.4b The result-
ant ester adduct 25 (75%) was then subjected to silyl ether
removal (97%) to afford 26, a convenient precursor to the
bicyclic guanidine core of 1. This advanced intermediate
should serve as a suitably functionalized intermediate for
attachment to the tricylic guanidine fragment of 1.
for synthetic access not only to members of the batzelladine
natural products but also to the related family of crambescin
alkaloids.
Acknowledgment. This research was supported by the
National Institutes of Health (GM-57143) and the Research
Corporation. S.G.D. acknowledges support from the Uni-
versity of Illinois for an IMGIP fellowship.
In summary, the first synthesis of the bicyclic guanidine
core within batzelladines A and B is reported. By employing
L-aspartic acid as the starting material, the absolute config-
uration of the sole stereocenter in the bicyclic guanidine
moiety of 1 was determined to be R. Moreover, the
preparation of the advanced intermediate 26 should allow
Supporting Information Available: Experimental details
and spectral/analytical data for synthetic intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL015848M
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Org. Lett., Vol. 3, No. 10, 2001