Asymmetric total synthesis of batzelladine D.

Article abstract of DOI:10.1021/ol991269u

[formula: see text] The first enantioselective total synthesis of a batzelladine alkaloid is described. The central reaction in the synthesis of (-)-batzelladine D (2) is a tethered Biginelli condensation of a guanidine aldehyde and an acetoacetic ester t

Full text of DOI:10.1021/ol991269u

ORGANIC
LETTERS
1999
Vol. 1, No. 13
2169-2172
Asymmetric Total Synthesis of
Batzelladine D
Frederick Cohen, Larry E. Overman,* and Sylvie K. Ly Sakata
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
IrVine, California 92697-2025
leoVerma@uci.edu
Received November 22, 1999
ABSTRACT
The first enantioselective total synthesis of a batzelladine alkaloid is described. The central reaction in the synthesis of (−)-batzelladine D (2)
is a tethered Biginelli condensation of a guanidine aldehyde and an acetoacetic ester to generate a 7-substituted-1-iminohexahydropyrrolo-
[1,2-c]pyrimidine intermediate having the anti stereochemistry of the methine hydrogens flanking the pyrrolidine nitrogen.
The batzelladines are a novel class of polyguanidine alkaloids
isolated from the red Caribbean sponge Batzella sp.1 Nine
members of this group have now been identified by Smith-
Kline Beecham scientists from a program searching for
modulators of protein-protein interactions. The most com-
plex batzelladine alkaloids, exemplified by batzelladine A
(1), have two polycyclic guanidine units, while batzelladines
C, D (2), and E (3) display a single tricyclic guanidine
moiety. A decahydro- or octahydro-5,6,8b-triazaacenaph-
thalene is the common structural feature of the batzelladines,
with these tricyclic units occurring with both the syn and
anti stereorelationships of the angular hydrogens that flank
the pyrrolidine nitrogen.1,2 Batzelladines A (1) and B are
micromolar inhibitors of binding of the HIV envelope protein
gp-120 to the human CD4 receptor, while at similar
concentrations batzelladines F-I induce dissociation of the
protein kinase called p56lck from CD4.1
Stimulated by their novel structures and the potential
therapeutic significance of ligands that regulate protein
association, the batzelladines have been subject to several
synthetic investigations.3 In the earliest work in this area,
Rao and co-workers prepared an enantioenriched alcohol
analogue of the syn tricyclic guanidine core of batzelladine
B from an azetidine precursor,4 and Snider and Chen, using
a presumed biomimetic strategy, constructed tricyclic deg-
radation products of several batzelladine alkaloids.5 Signifi-
cantly, this latter study showed that the angular hydrogens
(1) (a) 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. (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.
(2) Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron Lett.
1996, 37, 6977-6980.
(3) For a brief review, see: Berlinck, R. G. S. Nat. Prod. Rep. 1999,
339-365.
(4) Rao, A. V. R.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem.
Commun. 1995, 1369-1370.
(5) Snider, B. B.; Chen, J. Tetrahedron Lett. 1996, 37, 6977-6980.
10.1021/ol991269u CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/10/1999

of the tricyclic guanidine portions of batzelladines A and D
have the anti stereochemistry as depicted in 1 and 2.5 More
recently, the Snider group reported the total synthesis of (()-
batzelladine E (3), which like batzelladine B has the syn
stereochemistry.6,7 Our laboratory disclosed earlier this year
that enantiopure syn octahydro-5,6,8b-triazaacenaphthalenes
could be synthesized in high yield using a tethered Biginelli
condensation8 as the central strategic step.9 This chemistry
was employed to prepare the tricyclic portion of batzelladine
B and to establish the absolute configuration of this alkaloid.9
We also described the first asymmetric synthesis of anti
octahydro-5,6,8b-triazaacenaphthalenes and their decahydro
analogues; however, low stereoselectivity in the tethered
Biginelli condensation compromised this route to batzella-
dines having the anti stereochemistry.9
Scheme 2
We disclose herein a modification of our tethered Biginelli
strategy that allows enantiopure anti octahydro-5,6,8b-
triazaacenaphthalenes to be prepared efficiently and the use
of this chemistry to prepare (-)-batzelladine D (2). We
recently showed that 4a,7 anti iminohexahydropyrrolo[1,2-
c]pyrimidines similar to 5 were produced with high stereo-
selectivity in tethered Biginelli condensations of guanidine
aldehydes and â-ketoesters.8c Thus, we envisaged construct-
ing batzelladine D (2) from iminopyrrolopyrimidine 5, which
in turn would derive from Biginelli condensation of acetoac-
etate 6 and guanidine aldehyde 7 (Scheme 1).
Hoveyda, provided monoprotected anti 1,3-diol 9 in nearly
quantitative yield.12 Mitsunobu reaction of 9 with hydrazoic
acid13 and cleavage of the ester gave syn azido alcohol 11
in 95% yield from 8. Since the third ring of the triaz-
aacenaphthalene core of 2 would arise from an SN2 reaction
(Scheme 1), the alcohol group of 11 was inverted by
Mitsunobu reaction with p-nitrobenzoic acid,14 and the
resulting azido ester 12 was hydrolyzed and the product was
reduced with H2 over Pd/C to furnish anti amino alcohol
13. Reaction of this intermediate with 1H-pyrazole-1-
carboxamidine hydrochloride (14) proceeded without incident
to generate guanidine 15.15
Scheme 1
The dimethyl acetal of 15 was cleaved by exposure to
aqueous acetic acid, and the resulting crude product was
immediately condensed at 70 °C in trifluoroethanol with
N-benzyloxycarbonyl-4-aminobutyl acetoacetate (16, 2
equiv),16,17 morpholinium acetate (2 equiv), and Na2SO4 (2
equiv) to provide guanidinium acetate 17 in 55% overall yield
from 12 (Scheme 3). This critical step generated 17 and its
4a,7 syn stereoisomer in a ratio of 6.1:1.18 The octahydro-
5,6,8b-triazaacenaphthalene unit of 2 was then generated by
Our synthesis of (-)-batzelladine D (2) begins with (R)-
â-hydroxy ketone 8 (96% ee),10 which is available in four
steps and 50% overall yield from 2-undecanone (Scheme
2).11 Tischenko reduction of 8, as described by Evans and
(6) Snider, B. B.; Chen, J. Tetrahedron Lett. 1998, 39, 5697-5700.
(7) (a) The biomimetic approach has also been extensively developed
by the Murphy group.3 For their recent synthesis of the left-hand unit of
batzelladine F in racemic form, see: Black, G. P.; Murphy, P. J.; Thornhill,
A. J.; Walshe, N. D. A.; Zanetti, C. Tetrahedron 1999, 55, 6547-6554.
(b) For an alternate approach, see: Louwrier, S.; Ostendorf, M.; Tuynman,
A.; Hiemstra, H. Tetrahedron Lett. 1996, 37, 905-908.
(12) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-
6449.
(13) (a) Hassner, A.; Dehaen, W. J. Org. Chem. 1990, 55, 2243-2244.
(b) Mitsunobu, O. Synthesis 1981, 1-32.
(8) (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.
(14) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-3020.
(15) (a) Bernatowicz, M. Z.; Wu, Y.; Matsueda, G. R. J. Org. Chem.
1992, 57, 2497-2502. (b) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R.
Tetrahedron Lett. 1993, 34, 3389-3392.
(9) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shaka,
A. J. J. Org. Chem. 1999, 64, 1512-1519.
(16) Prepared in 91% yield from methyl acetoacetate and N-benzyloxy-
carbonyl-4-aminobutanol.17
(17) Taber, D. F.; Amedio, J. J. C.; Pate, Y. K. J. Org. Chem. 1985, 50,
3618-3619.
(18) Stereoselection in the identical condensation in ethanol was 4.6:1.
(10) Dale, J. A.; Dull, D. L.; Mosher, H. S.J. Org. Chem. 1969, 34,
2543-2549.
(11) Details for the synthesis of the enantiomer of 8 have been described.9
2170
Org. Lett., Vol. 1, No. 13, 1999

and the intermediate quenched with malononitrile at 0 °C, a
1:1 mixture of 19 and 21 was produced.19,20 However, many
side products were generated and the yield of 21 was
consequently low. Reasoning that one problem might be the
large number of acidic hydrogens present in the starting
material, 19 was treated with an excess of benzyl bromide
in the presence of Na2CO3 to give largely one dibenzylated
product which we provisionally assign as 20. Reaction of
20 with 4 equiv of LHMDS at -78 °C in THF and quenching
the resulting enolate with various proton donors again
delivered 22 in low yield only.21
Scheme 3
We therefore turned to catalytic hydrogenation. Similar
to earlier investigations of a methyl ester analogue of 18,9
we were unsuccessful in finding hydrogenation conditions
that delivered hydrogen from the â face to selectively give
tetrahydro-5,6,8b-triazaacenaphthalene 23 (Scheme 5).22 The
Scheme 5
converting the secondary alcohol of 17 to its mesylate
derivative, which cyclized in refluxing CHCl3 in the presence
of excess triethylamine to deliver 18 in 60% yield.
To complete the synthesis of batzelladine D (2), we needed
to reduce the double bond of 18 from the â face to set the
C3 and C4 stereochemistry. Using a modification of condi-
tions reported by Snider,5 18 cleanly gave decahydro-5,6,-
8b-triazaacenaphthalene 19 upon reduction with NaCNBH3
at 90 °C in methanol containing 10 equiv of acetic acid
(Scheme 4). When 19 was deprotonated with 2-5 equiv of
LiCPh3, or 2,4,6-trimethylphenyllithium, at -78 °C in THF
Scheme 4
yield of 23 was optimal when 18 was hydrogenated over
Rh/Al2O3 at 50 psi in MeOH-H2O (1:3) at room tempera-
ture. Preparative HPLC separation of the resulting product
(19) (a) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549-557. (b)
Zimmerman, H. E. Acc. Chem. Res. 1987, 20, 263-268. (c) Vedejs, E.;
Kruger, A. W. J. Org. Chem. 1998, 63, 2792 and references therein.
(20) Structural assignments followed unambiguously from NOE studies.9
(21) Enolization was achieved under these conditions since quenching
with CD3CO2D provided a ∼1:1 mixture of 20 and 22, with the former
having 70% deuterium incorporation at C2. Exposure of 20, or a 1:1 mixture
of 20 and 22, to excess (i-Pr)2NEt in toluene at 70 °C provided 20 and 22
in a time-invariant ratio of 13:1, confirming the expectation that that 20
would be favored at equilibrium.
Org. Lett., Vol. 1, No. 13, 1999
2171

mixture gave 23 (contaminated with 10% of the 2a,3-dehydro
analogue 25) in ∼30% yield and stereoisomer 24 in 38%
yield. Guanylation of this sample of 23 with 1H-pyrazole-
1-carboxamidine hydrochloride, followed by preparative
HPLC purification (C18 silica gel, H2O-MeCN-CF3CO2H),
provided batzelladine D (2), as its bistrifluoroacetate salt, in
75% yield. Synthetic 2, a colorless oil that solidified at 0
°C, showed 1H and 13C NMR, IR, and mass spectra consistent
with those described for the natural isolate. Specific rotations
lective route to related syn tricyclic guanidines we reported
earlier9 provide the tools required to pursue the enantiose-
lective total synthesis of any member of the batzelladine
alkaloid family.
Acknowledgment. This research was supported by a
grant from NIH NHLBIS (HL-25854). Merck, Pfizer, Roche
Biosciences, and SmithKline Beecham provided additional
support. S.K.L.S. received partial support from a University
of California Presidents’ Fellowship and a Patricia Roberts
Harris Fellowship, while F.C. was supported by an American
Chemical Society Organic Division Graduate Fellowship
sponsored by Pharmacia & Upjohn. We particularly thank
Drs. Ashok Patil and James Chan for providing samples of
natural batzelladine D. NMR and mass spectra were deter-
mined at UCI using instruments acquired with the assistance
of NSF and NIH shared instrumentation grants.
of synthetic 2 ditrifluoroacetate were [R]25D -4.6 and [R]25
546
-18.0 (c ) 0.6, MeOH), while [R]25D -1.2 (c ) 0.9, MeOH)
is reported for the natural product.1a
In conclusion, the first enantioselective total synthesis of
a natural batzelladine alkaloid has been accomplished. The
central strategic step in the total synthesis of (-)-batzelladine
D (2) is tethered Biginelli condensation of a guanidine acetal
and a â-ketoester to form a 7-substituted-1-iminohexahy-
dropyrrolo[1,2-c]pyrimidine having the anti stereochemistry
of the critical methine hydrogens that flank the pyrrolidine
nitrogen. This synthesis, though currently not without
significant weaknesses, and the complementary enantiose-
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds
reported in Schemes 2, 3, and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
(22) A variety of reduction conditions, employing both heterogeneous
and homogeneous catalysts, were surveyed. Details have been reported:
Ly, S. K. Ph.D. Dissertation, University of California, Irvine, 1998.
OL991269U
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Org. Lett., Vol. 1, No. 13, 1999