6944
J. Am. Chem. Soc. 1999, 121, 6944-6945
Enantioselective Total Synthesis of
13,14,15-Isocrambescidin 800
D. Scott Coffey, Andrew I. McDonald,
Larry E. Overman,* and Frank Stappenbeck1
Department of Chemistry, 516 Rowland Hall
UniVersity of California, IrVine, California 92697-2025
ReceiVed March 29, 1999
Crambe crambe, a bright red encrusting sponge commonly
found at shallow depths along the rocky coast of the Mediter-
ranean, is a rich source of structurally novel, bioactive alkaloids.2
Rinehart and co-workers3 and later Braekman and his group,4
described a series of complex guanidinium alkaloids, including
13,14,15-isocrambescidin 800 (1), crambescidin 800 (2), and
crambescidin 816 (3), from C. crambe. The related alkaloid,
ptilomycalin A (4), was reported earlier by Kashman, Kakisawa,
and co-workers from sponges collected in the Caribbean and Red
Sea.5 Ptilomycalin A5,6 and several of the crambescidins3,4 show
substantial antitumor, antiviral, and antifungal activities. As a
result of its low abundance, 13,14,15-isocrambescidin 800 has
not been extensively screened, although it is reported to be less
cytotoxic to L-1210 cells than other crambescidins.3b The defining
structural feature of the crambescidin alkaloids is a pentacyclic
guanidine linked by a straight chain ω-hydroxycarboxylic acid
spacer to a spermidine or hydroxyspermidine unit. Extensive NMR
studies demonstrated that the relative stereochemistry of the
pentacyclic cores of 2-4 is identical,3,4 while 13,14,15-isocram-
bescidin 800 (1) is epimeric at C13, C14, and C15.3b,4b The
absolute configuration of the guanidine moieties of 1 and 3 was
established by oxidative degradation of the oxepene rings of these
alkaloids to yield (S)-2-hydroxybutanoic acid,3b while the absolute
configuration of the hydroxyspermidine unit of 3 was assigned
using Mosher’s method.4b,7 Since 1H NMR and 13C NMR chemical
shifts in the hydroxyspermidine fragments of 1 are nearly identical
to those of 2 and 3, it has been assumed that the stereochemistry
member of the crambescidin family available for detailed
pharmacological screening. The defining reaction of the synthesis
is a tethered-Biginelli condensation10,11 of guanidino aminal 14
with â-ketoester 15; this reaction unites all of the atoms of the
guanidine core of 1 and sets the pivotal C10-C13 stereorelation-
ship.10b
Diene 13, the precursor of the C1-C13 guanidino aminal,
was prepared from 3-butyne-1-ol (5) as summarized in Scheme
1. The C3 stereocenter was introduced by the method of Weber
and Seebach12 through condensation of ynal 6 with Et2Zn in the
presence of (-)-TADDOL (20 mol %) and Ti(Oi-Pr)4 to give
(S)-7 in 94% yield and >98% ee. Standard manipulations yielded
iodide 8 which was converted to the corresponding lithium reagent
and coupled with 913-15 to generate dienone 10 in 60-70% yield.
Ketalization of 10 with ortho ester 1116 and 1,3-propanediol in
the presence of Amberlyst-15 provided 12 in 80% yield. Mit-
sunobu displacement of the secondary alcohol with azide,
reduction to the primary amine, and condensation with 1H-
pyrazole-1-carboxamidine hydrochloride17 furnished guanidine 13
in ∼30% overall yield from 6.
Selective dihydroxylation of the trisubstituted double bond of
13,18 followed by cleavage of the vicinal diol with Pb(OAc)4 in
toluene containing several equiv of morpholinium acetate, yielded
14 (Scheme 2).19 Biginelli condensation of 14 with â-ketoester
1510b under Knoevenagel conditions took place with modest
(3:1) diastereoselectivity in ethanol. Fortunately, diastereoselection
was improved to 7:1 in 2,2,2-trifluoroethanol, and, after chro-
matographic separation of the minor C13 epimer, the major isomer
16 was isolated in 49% yield for the 3 steps.
4b
at C43 is the same for all crambescidins.
In 1995 we reported an enantioselective total synthesis of (-)-
ptilomycalin A (4), which was the first (and to date only) total
synthesis of a member of the crambescidin alkaloid family.8,9
Herein, we disclose an enantioselective total synthesis of 13,14,15-
isocrambescidin 800 (1) which for the first time makes this rare
The silyl-protecting groups of 16 were next discharged with
TBAF to provide the corresponding guanidine diol. After
considerable experimentation, we found that exposure of this
intermediate to 3 equiv of anhydrous HCl in ethyl acetate at 23
°C gave a single pentacyclic product 17, which was isolated in
62% yield from 16. Since the spirohydropyran evolves from trans-
addition of the C19 alcohol to the C14-C15 double bond
(1) Current Address: Elan Pharmaceuticals, 800 Gateway Boulevard, South
San Francisco, CA 94080.
(2) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113-158 and earlier reviews
in this series.
(3) (a) Jares-Erijman, E. A.; Sakai, R.; Rinehart, K. L. J. Org. Chem. 1991,
56, 5712-5715. (b) Jares-Erijman, E. A.; Ingrum, A. L.; Carney, J. R.;
Rinehart, K. L.; Sakai, R. J. Org. Chem. 1993, 58, 4805-4808.
(4) (a) Tavares, R.; Daloze, D.; Braekman, J. C.; Hajdu, E.; Muricy, G.;
Van Soest, R. W. M. Biochem. Syst. Ecol. 1994, 22, 645-646. (b) Berlinck,
R. G. S.; Braekman, J. C.; Daloze, D.; Bruno, I.; Riccio, R.; Ferri, S.;
Spampinato, S.; Speroni, E. J. Nat. Prod. 1993, 56, 1007-1015.
(5) (a) Kashman, Y.; Hirsh, S.; McConnell, O. J.; Ohtani, I.; Kusumi, T.;
Kakisawa, H. J. Am. Chem. Soc. 1989, 111, 8925-8926. (b) Ohtani, I.;
Kusumi, T.; Kakisawa, H.; Kashman, Y.; Hirsh, S. J. Am. Chem. Soc. 1992,
114, 8472-8479. (c) Ohtani, I.; Kusumi, T.; Kakisawa, H. Tetrahedron Lett.
1992, 33, 2525-2528.
(10) (a) Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1993, 58, 3235-
3237. (b) McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64, 1520-
1528.
(11) For a recent review of the Biginelli reaction, see: Kappe, C. O.
Tetrahedron 1993, 49, 6937-6963.
(12) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 7473-7484.
(13) Prepared by treating the known â-hydroxyester14 with Me(MeO)NH‚
HCl and Me3Al,15 followed by TES-Cl and i-PrNEt2.
(14) (a) Taber, D. F.; Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227-
4230. (b) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345-350.
(15) Garipati, R. S.; Tschaen, D. M.; Weinreb, S. M. J. Am. Chem. Soc.
1985, 107, 7790-7792.
(16) (a) Roush, W. R.; Gillis, H. R. J. Org. Chem. 1980, 45, 4283-4287.
(b) Baganz, H.; Domaschke, L. Chem. Ber. 1958, 91, 650-653.
(17) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J. Org. Chem. 1992,
57, 2497-2502.
(18) Sharpless, K. B.; Williams, D. R. Tetrahedron Lett. 1975, 3045-3046.
(19) This intermediate is a mixture of several components as judged by
1H and 13C NMR data.
(6) Synthetic ptilomycalin A (NSC 700559) exhibits mid-nanomolar activity
against many tumors in the NCI in vitro panel, with particular selectivity
realized against non-small cell lung cancer (HOP-62) and melanoma (M14).
(7) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.
(8) Overman, L. E.; Rabinowitz, M. H.; Renhowe P. A. J. Am. Chem. Soc.
1995, 117, 2657-2658.
(9) For other synthetic investigations not cited in ref 8, see: (a) Grillot,
A.-L.; Hart, D. J. Tetrahedron 1995, 51, 11377-11392. (b) Murphy, P. J.;
Williams, H. L.; Hibbs, D. E.; Hursthouse, M. B.; Malik, K. M. A. Tetrahedron
1996, 52, 8315-8332. (c) Anderson, G. T.; Alexander, M. D.; Taylor, S. D.;
Smithrud, D. B.; Benkovic, S. J.; Weinreb, S. M. J. Org. Chem. 1996, 61,
125-132.
10.1021/ja990992c CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/07/1999