Asymmetric construction of the diazatricyclic core of the marine alkaloids sarains A-C

Full text of DOI:10.1021/jo9817117

8096
J . Org. Chem. 1998, 63, 8096-8097
Sch em e 1a
Asym m etr ic Con str u ction of th e
Dia za tr icyclic Cor e of th e Ma r in e Alk a loid s
Sa r a in s A-C
Robert Downham,1 Fay W. Ng, and Larry E. Overman*
Department of Chemistry, University of California,
Irvine, California 92697-2025
Received August 24, 1998
A breathtaking variety of structurally novel alkaloids are
found in sponges.2 Arguably the most remarkable are
sarains A-C (1-3), which were isolated by Cimino and co-
workers from the sponge Reniera sarai collected in the Bay
of Naples.3,4 The diazatricycloundecane core with its “prox-
imity” interaction between the aldehyde substituent at C2
and N15 and the 14-membered ring containing a vicinal diol
and three (two cis and one trans) double bonds is unprec-
edented, defining this class of marine alkaloids.6 A prelimi-
nary survey of biological activity identified antibacterial,
insecticidal, and antitumor activities with sarains A-C.7 The
fascinating structures of these alkaloids have stimulated
several synthetic investigations in this area. Sisko and
Weinreb reported the first assembly of the basic diazatri-
cycloundecane core,8 while notable progress toward sarain
A has also been registered by the Heathcock group.9 Herein,
we report the first asymmetric construction of the diazatri-
cycloundecane core of sarains A-C (1-3) by a strategy that
deals effectively with the critical, fully substituted, C3′
center and relates this stereocenter to that of the proximal
diol unit of the 14-membered ring.
a
Reagents: (a) BH3‚DMS, THF, cat. NaBH4, 54%; (b) TBDPSCl,
imid., THF, 82%; (c) H2, Pd/C, EtOAc; (d) methyl benzimidate
hydrochloride, CH2Cl2, 73% over two steps; (e) LHMDS, THF,
DME, -78 °C, 71%; (f) DMSO, 180 °C, 69%; (g) Me3Al, PhMe, 91%;
(h) LHMDS, THF, DMPU, 3-bromo-2-methylpropene, -78 °C, 79%;
(i) THF, 2 N HCl 75%. DMPU ) N,N-dimethylpropylene urea.
Our analysis of the synthetic challenge presented by
sarains A-C (1-3)
tion of the 14-membered dihydroxy-skipped triene ring. Our
strategy was to fashion early on the C4′-C3′-C7′ stereotriad
as well as assemble most of the carbon framework of 4 with
an intermolecular Michael reaction (Scheme 1). Since
diethyl tartarate was to be the starting enantiopure building
block, our initial investigations employed the less expensive
L enantiomer and targeted ent-1-3.10 The carbonyl group
of the R-hydroxy ester unit of diester 511 was selectively
reduced with borane in the presence of catalytic NaBH4 to
provide the corresponding diol in 54% yield.12 Protection of
the primary alcohol as a tert-butyldiphenylsilyl (TBDPS)
ether generated ester 6 in 82% yield.13 After hydrogenation
of the azide group of 6, the resulting vicinal amino alcohol
was converted to oxazoline 7 in 73% overall yield.14 This
intermediate was deprotonated with lithium hexamethyl-
disilazane (LHMDS) at -78 °C, and the resulting lithium
enolate was condensed with (Z)-enoate 815-17 under carefully
optimized conditions (-78 °C in a 2:1 mixture of DME-THF)
to provide Michael adduct 10 as a single stereoisomer in 71%
yield.18 The stereochemical outcome of this key Michael
reaction is in accord with transition-state assembly 9.19,20
identified diazatricycle 4 as a particularly attractive subgoal,
since this intermediate contains all the key elements of the
diazatricycloundecane core of sarains A-C and sufficient
functionality in the side chain for potential future elabora-
(1) Current address: Cambridge Combinatorial Limited, Rosemary Lane,
Cambridge CB1 3LQ, England.
(2) For reviews, see: (a) Kobayashi, J .; Ishibashi, M. In The Alkaloids;
Brossi, A., Ed.; Academic: New York, 1992; Vol. 41, Chapter 2. (b) Faulkner,
D. J . Natl. Prod. Rep. 1998, 15, 113 and previous reviews in this series.
(3) Both the names sarain and saraine have been employed to describe
these alkaloids.4,6
(4) Cimino, G.; De Stefano, S.; Scognamiglio, G.; Trivellone, E. Bull. Soc.
Chim. Belg. 1986, 95, 783.
(5) Leonard, N. J .; Oki, M.; Chiavarelli, S.J . Am. Chem. Soc. 1955, 77,
6234 and references cited therin.
(10) Since D-diethyl tartrate is also commercially available, our strategy
can just as well be directed at the natural alkaloids.
(11) Saito, S.; Komada, K.; Moriwake, T. Organic Syntheses; Wiley: New
York, 1998; Collect. Vol. IX, p 220.
(12) Sauret-Cladiere, S.; J eminet, G. Tetrahedron: Asymmetry 1997, 8,
417.
(13) Hanessian, S.; Lavalle´e, P. Can. J . Chem. 1975, 53, 2975.
(14) For a comprehensive review of the chemistry of oxazolines, see:
Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(15) Prepared in three standard steps and 55% overall yield from 3-butyn-
1-ol: (a) (Boc)NHTs, Ph3P, DEAD, THF;16 (b) n-BuLi, MeOCOCl, Et2O; (c)
H2, Pd/CaCO3/Pb, MePh.17
(16) Henry, J . R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D., J r.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.
(17) Taschner, M. J .; Rosen, T.; Heathcock, C. H. Org. Synth. 1986, 64,
108.
(6) (a) Cimino, G.; Mattia, C. A.; Mazzarella, L.; Pulti, R.; Scognamiglio,
G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45, 3863. (b) Cimino, G.;
Puliti, R.; Scognamiglio, G.; Spinella, A.; Trivellone, E. Pure Appl. Chem.
1989, 61, 535. (c) Cimino, G.; Scognamiglio, G.; Spinella, A.; Trivellone, E.
J . Nat. Prod. 1990, 53, 1519. (d) Guo, Y.-W.; Madaio, A.; Scognamiglio, G.;
Trivellone, E.; Cimino, G. Tetrahedron 1996, 52, 8341.
(7) Caprioli, V.; Cimino, G.; DeGuilio, A.; Madaio, A.; Scognamiglio, G.;
Trivellone, E. Comp. Biochem. Physiol. 1992, 103B, 293.
(8) Sisko, J .; Henry, J .; Weinreb, S. M. J . Org. Chem. 1993, 58, 4945.
(9) (a) Heathcock, C. H.; Clasby, M.; Griffith, D. A.; Henke, B. R.; Sharp,
M. J . Synlett 1995, 467. (b) Denhart, D. J .; Griffith, D. A.; Heathcock, C. H.
Abstracts of Papers, 216th National Meeting of the American Chemical
Society, Boston, MA; American Chemical Society: Washington, DC, 1998;
ORGN 526.
10.1021/jo9817117 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

Communications
J . Org. Chem., Vol. 63, No. 23, 1998 8097
Sch em e 2a
pyrrolidine 15 in 67% overall yield. The silyl ether of 15
was next discharged with TBAF. The liberated primary
alcohol was allowed to react with K2CO3 in MeOH, which
cleaved the benzoate and sulfonamide Boc protecting groups
and promoted lactonization to provide 16 in 79% yield. This
spirolactone was then treated with 4 equiv of DIBALH at
-78 °C, followed by quenching with aqueous HCl to generate
tricyclic aminal 17 in 78% yield. At this point, the stereo-
chemistry of the methallyl group was readily confirmed by
1H NMR NOESY studies. Exposure of 17 to sodium hexa-
methyldisilazane (NaHMDS) promoted cyclization to gener-
ate oxazolidinone 18 (90%), which was hydroborated and
oxidized to yield a 1:1 mixture of primary alcohols. Oxida-
tion of this mixture with Dess-Martin periodinane26 and
reaction of the resulting aldehyde epimers with triisopro-
pylsilyl triflate provided an inseparable 1.5:1.0 mixture of
enoxysilane stereoisomers 19 in 53% overall yield from 18.27
With the synthesis of 19 in hand, we turned to the crucial
N-tosyliminium ion-enoxysilane cyclization, which derives
some precedent from Sisko and Weinreb’s earlier assembly
of a simpler sarain A core using an N-tosyliminium ion-allyl-
silane cyclization.8,28 Attempts to promote Mannich cycli-
zation of 19 with SnCl4, BF3‚OEt2, or Me3Al proved unsuc-
cessful and typically returned the aldehyde precursors of 19.
However, the desired cyclization was successfully realized
when 19 was exposed to 3.5 equiv of BBr3 in CH2Cl2 at -78
°C to room temperature, which produced the diazatricyclo-
undecanes 20 and 21 in a 3:1 ratio and 81% combined yield.29
The structure of the major isomer 20 (mp 214-216 °C) was
confirmed by single-crystal X-ray diffraction analysis.30
In summary, an enantioselective total synthesis of the core
of sarains A-C (1-3) has been developed. Our strategy
integrates generation of the diazatricycloundecane core of
these alkaloids with formation of a side chain containing the
C7′ alcohol stereocenter, the latter of which provides a con-
venient handle for further elaboration of the 14-membered
dihydroxy-skipped triene ring.31 A stereoselective bimolecu-
lar Michael reaction of a tartrate-derived oxazoline and a
(Z)-enoate to set the C4′-C3′-C7′ stereocenters and the first
example of an intramolecular N-tosyliminium ion-enoxysi-
lane condensation are the central strategic steps of this
sequence.
a
Reagent: (a) (Boc)2O, CH3CN, cat. DMAP, 98%; (b) DIBALH,
CH2Cl2, -78 °C; (c) NaCNBH3, HOAc, 67% over two steps; (d) TBAF,
THF; (e) K2CO3, MeOH, 79% over two steps; (f) DIBALH, CH2Cl2, -78
°C; 2 N HCl, 78%; (g) NaHMDS, THF, -78 to 0 °C, 90%; (h) BH3‚THF,
THF, 0 °C; EtOH, 4 N NaOH, 30% H2O2; (i) Dess-Martin periodinane,
CH2Cl2, 0 °C, 69% over two steps; (j) TIPSOTf, Et3N, CH2Cl2, 0 °C,
77%.
The remaining carbons of the diazatricyclic core were
incorporated using lactam derivative 11, since attempts to
alkylate 10, or directly trap the lithium enolate produced
from the Michael reaction, were unsuccessful. Lactam 11
was accessed in 63% yield by thermal cleavage of the tert-
butoxycarbonyl (Boc) group of 10,16 followed by cyclization
of the resulting amino ester with Me3Al.21 Deprotonation
of 11 with LHMDS and alkylation with 3.5 equiv of 3-bromo-
2-methylpropene at -78 °C resulted in the formation of 12
as a single stereoisomer in 79% yield. The stereochemical
assignment for 12 was made initially on the expectation that
allylation would proceed preferentially from the enolate face
opposite the oxazoline side chain. Finally, exposure of 12
to dilute HCl cleaved the oxazoline ring22 and promoted
translactamization to provide pyrrolidinone 13 in 75% yield.
Elaboration of 13 to arrive at Mannich cyclization precur-
sor 19 was initiated by protection of both nitrogens with Boc
groups23 to yield 14 (Scheme 2). Selective reduction of the
pyrrolidinone carbonyl group of this intermediate with
DIBALH at -78 °C provided a 3:2 mixture of hemiaminals,24
which was immediately reduced with NaCNBH325 to furnish
Ack n ow led gm en t. This research was supported by
NIH grant HL-25854 and an NIH postdoctoral fellowship
(CA76739) to F.W.N. NMR and mass spectra were deter-
mined at UCI using instrumentation acquired with the
assistance of NSF and NIH Shared Instrumentation pro-
grams. We are grateful to Dr. J ohn Greaves and Mr. J ohn
Mudd for their assistance with mass spectrometric analyses
and Dr. J oseph Ziller for X-ray crystallographic analysis.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic and analytical data for compounds 5-21
and NOESY data for 17 (13 pages).
J O9817117
(26) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(18) For seminal contributions to the use of enantiopure oxazolidines in
asymmetric synthesis, see: (a) Seebach, D.; Aebi, J . D. Tetrahedron Lett.
1983, 24, 3311. (b) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68,
1592.
(19) Optimization of this condensation and definition of its stereochem-
istry was initially accomplished with a related threonine-derived oxazoli-
dine.20
(20) J aroch, S.; Matsuoka, R.; Overman, L. E. Manuscript in preparation.
(21) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171.
(22) Meyers, A. I.; Roth, G. P.; Hoyer, D.; Barner, B. A.; Laucher, D. J .
Am. Chem. Soc. 1988, 110, 4611.
(27) Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Gotz, A.; Hergott, H.
H.; Hofmann, K.; Kober, W.; Krageloh, K.; Oesterle, T.; Steppan, W.; West,
W.; Simchen, G. Synthesis 1982, 1.
(28) For
a recent review of N-sulfonyliminium ion chemistry, see:
Weinreb, S. M. Topics in Current Chemistry; Springer-Verlag: Berlin, 1997;
Vol. 190, p 131.
(29) When the reaction was conducted at lower temperature (-78 °C f
-40 °C), product formation was sluggish (40% conversion after 48 h at -40
°C) and the ratio of 20 to 21 was unchanged.
(30) The authors have deposited coordinates for compound 20 with the
Cambridge Crystallographic Data Centre.
(23) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1985, 24,
510.
(24) Hubert, J . C.; Wijnberg, J . B. P. A.; Speckamp, W. N. Tetrahedron
1975, 31, 1437.
(31) The formation of the undesired stereochemistry at C3 as the major
product from cyclization of 19 is anticipated to be of little significance in
extending this chemistry toward the natural products themselves if the
saturated macrocyclic ring of sarain A (or the corresponding unsaturated
rings of sarain B or C) is present prior to Mannich cyclization.
(25) Lenz, G. R. J . Chem. Soc., Perkin Trans. 1 1990, 33.