Enantioselective synthesis of ent-stellettamide A via a novel dipolar cycloaddition reaction of (trimethylsilyl)diazomethane

Full text of DOI:10.1021/jo971571l

7916
J . Org. Chem. 1997, 62, 7916-7917
En a n tioselective Syn th esis of
en t-Stelletta m id e A via a Novel Dip ola r
Cycloa d d ition Rea ction of
(Tr im eth ylsilyl)d ia zom eth a n e
Gavin A. Whitlock and Erick M. Carreira*
Arnold and Mabel Beckman Laboratory for Chemical
Synthesis, California Institute of Technology,
Pasadena, California 91125
Received August 25, 1997
F igu r e 1. Retrosynthetic strategy for stellettamide A.
Stellettamide A (1), the first indolizidine metabolite
from a marine sponge, was isolated recently using a
bioassay-guided strategy (Figure 1).1 It possesses anti-
fungal activity and displays cytotoxicity against K562
epithelium cell lines. The initial structural studies did
not lead to assignment of the stereogenic center present
in the trienoic acid side chain or of the absolute stereo-
chemistry of the natural product. We became interested
in stellettamide A as a target for synthesis since, upon
retrosynthetic analysis, it presented an opportunity for
the construction of the indolizidine core via a novel
strategy involving an intermediate chiral pyrazoline 2
(Figure 1).2 In this paper, we report an enantioselective
synthesis of ent-stellettamide A that establishes its
absolute stereochemistry. Moreover, the synthetic route
employs an asymmetric diazoalkane dipolar cycloaddition
and the use of the pyrazoline adducts of such reactions
as useful starting materials for asymmetric synthesis.3,4
We have been interested in the development of practi-
cal [3 + 2]-cycloaddition reactions between chiral dipo-
larophiles and (trimethylsilyl)diazomethane.5 This 1,3-
dipole is a safe, stable diazoalkane that is commercially
available as a solution in hexane and ready for use.
Previous use of diazoalkane/olefin cycloadducts in syn-
thesis has been limited to the preparation of cyclopro-
panes or pyrazoles obtained upon N2 extrusion or oxida-
tive aromatization, respectively. However, optically active
pyrazolines such as 4 are potentially useful precursors
to functionalized chiral acyclic synthons 7 (Scheme 1).
The implementation of such a strategy would require two
key points to be resolved. First, prior reports on cycload-
ditions of diazoalkanes with esters had highlighted the
propensity of adducts 4 to undergo tautomerization to
the conjugated ∆2-pyrazoline 5.6 In this regard, we
speculated that the electrofugal Me3Si moiety in the Me3-
SiCHN2 cycloadduct would dictate its subsequent mode
of isomerization (Scheme 1, 4 f 2 vs 4 f 5). Second,
Sch em e 1
the successful strategy would require the development
of reaction methodology for N-N and CdN bond reduc-
tions of functionalized, chiral ∆2-pyrazolines (Scheme 1,
2 f 7).
When a solution of dipolarophile 8 in hexane/CH2Cl2
was treated with a commercial solution of Me3SiCHN2
(2.2 equiv), the pyrazoline cycloadducts were isolated in
quantitative yield upon evaporation of the solvent (eq 1).
(1)
Analysis by 1H NMR spectroscopy revealed that the
adducts had been formed as a 93:7 mixture of C(2)/C(3)
diastereomers. Treatment of the unpurified diastereo-
meric cycloadduct mixture with EtO2CCl and AgOTf led
to formation of the desired desilylated pyrazolines, which
could be readily separated by chromatography on silica
gel to give 10 in 71% isolated yield and 11 in 6% yield
(92:8 diastereoselectivity).7 This two-step sequence of
reactions has been reproducibly carried out on a large
scale to deliver substantial quantities of the protected
isomerically pure pyrazoline 10.
Having established two key stereocenters in the cy-
cloaddition reaction, we proceeded to assemble the pip-
eridine ring (Scheme 2). Aldehyde 12 was prepared by
reduction of 10 to the corresponding primary alcohol
(LiAlH4, 91%) followed by Swern oxidation (93%). Treat-
ment of 12 with the acetylide derived from Me2-
tBuSiOCH2CtCH gave a secondary propargyl alcohol,
(1) (a) Hirota, H.; Matsunaga, S.; Fusetani N. Tetrahedron Lett.
1990, 31, 4163. (b) Shin, J .; Seo, Y.; Cho, K. W.; Rho, J . R.; Sim, C. J .
J . Nat. Prod. 1997, 60, 611.
(2) For a review indolizidine syntheses, see: Michael, J . P. Nat.
Prod. Rep. 1995, 12, 535. For recent advances in methodology aimed
at the preparation of indolizidines, see: (a) Li, Y. W.; Marks, T. J . J .
Am. Chem. Soc. 1996, 118, 707. (b) Ciufolini, M. A.; Roschangar, F. J .
Am. Chem. Soc. 1996, 118, 12082. (c) Comins, D. L.; Zhang, Y. J . Am.
Chem. Soc. 1996, 118, 12248.
(3) For general references, see: (a) Carruthers, W. Cycloaddition
Reactions in Organic Sythesis; Pergammon: Oxford, 1990; p 269. (b)
Padwa, A. In Comprehensive Organic Synthesis; Trost, B., Ed.; Wiley:
New York, 1991; Vol. 4, p 1069. (c) Wade, P. A. In Comprehensive
Organic Synthesis; Trost, B., Ed.; Wiley: New York, 1991; Vol. 4, p
1111. (d) Little, R. D. In Comprehensive Organic Synthesis; Trost, B.,
Ed.; Wiley: New York, 1991; Vol. 5, p 239.
(4) For a comprehensive review of asymmetric dipolar cycloadditions,
see: Cinquini, M., Cozzi, F. Formation of C-C Bonds by [3+2]
Cycloadditions. In Stereoselective Synthesis; Helmchen, G., Hoffman,
R., Mulzer, J ., Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 5,
p 2953.
(6) (a) Galley, G.; Pa¨tzel, M.; J ones, P. G. Tetrahedron 1995, 51,
1631. (b) Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. J .
Organomet. Chem. 1972, 44, 279.
(7) We have obtained X-ray crystal structures of the adducts formed
from the addition of crotyl and methacryloyl camphor sultam and Me3-
SiCHN2. The stereochemistry of the adducts is consistent with the
models that have been previously proposed; see: Kim, B. H.; Curran,
D. P. Tetrahedron 1993, 49, 293.
(5) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J . Am. Chem. Soc.
1997, 119, 8379.
S0022-3263(97)01571-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 23, 1997 7917
Sch em e 2
benzyl ether followed by treatment of the resulting
primary alcohol with CBr4 and Ph3P resulted in ring
closure.9 Subsequent alkaline hydrolysis of the trifluo-
roacetamide delivered the indolizidine core of stelletta-
mide 18.
Since the relative configuration of the side chain was
not determined in the isolation studies, both (R)- and (S)-
trienoic acids 19 and ent-19 were synthesized.10 Each of
the two carboxylic acids was coupled with 18 to produce
diastereomeric indolizidines that were separately meth-
ylated (MeI, DMF) to give stellettamide A and its C(4′)
epimer (eq 2). Upon spectroscopic analysis of each,
diastereomer 20 was shown to be identical (1H NMR, 13
C
NMR and in chromatographic behavior HPLC, 72%
20mM KH2PO4, 28% iPrOH, Sephadex C18) with natural
stellettamide A,11 except for its optical rotation, which
differed only in sign.12
a
Key: (a) TBSOCH2CtCMgBr, THF, 0 °C; (b) MsCl, Et3N,
CH2Cl2, 0 °C, 68% two steps; (c) Bu3P, Pd2dba3, (NH4)HCO2, PhH,
76%; (d) 5% Pd/BaSO4, H2, quinoline, MeOH, 95%; (e) Ba(OH)2,
aqueous dioxane, 100 °C; (f) Boc2O, aqueous NaOH, THF, 23 °C,
80% two steps; (g) 10% H2SO4 dioxane; 2 N NaOH, 83%; (h) Ra-
Ni, H2, EtOH; (i) CF3CO2Et, THF, 0 °C, 85% two steps; (j) Pd(OH)2/
C, (NH4)HCO2, MeOH, reflux, 85%; (k) CBr4, PPh3, Et3N, MeCN,
0 °C, 75%; (l) 5% K2CO3, aqueous MeOH.
(2)
which without purification underwent mesylation to
afford 13 (68% two steps). Conversion of 13 to cis-alkene
14 was effected by hydrogenolysis of the propargyl
mesylate (76%) followed by semihydrogenation of the
alkyne (95%).8 Treatment of 14 with aqueous Ba(OH)2
effected hydrolysis of the ethyl carbamate and the silyl
ether to afford a pyrazoline that was selectively protected
as the corresponding N-Boc-carbamate (80%, two steps)
and treated with MsCl to afford 15. An in situ procedure
was developed for cleavage of the Boc-amide with con-
comitant pyrazolidine ring formation: dissolution of 15
in 10% concentrated H2SO4/dioxane resulted in hydroly-
sis of the carbamate; this was followed by addition of the
reaction mixture to a 2 M NaOH solution from which 16
was isolated (83%, two steps). Treatment of 16 with Ra-
Ni/H2 effected CdC and CdN reduction along with N-N
bond cleavage to give a diamine, which was subsequently
selectively protected as the corresponding N-trifluoro-
acetamide (17) (85%, two steps). Hydrogenolysis of the
We have described an enantioselective synthesis of the
unusual marine metabolite ent-stellettamide A. The
salient features of the route include the following: (1)
unambiguous assignment of the absolute stereochemistry
of stellettamide A and (2) synthesis of the indolizidine
core from an optically active substituted pyrazoline that
is prepared using a novel dipolar cycloaddition reaction.
The development of asymmetric [3 + 2]-cycloaddition
reactions utilizing Me3SiCHN2 as a safe, commercially
available diazoalkane dipole provides rapid access to
optically active pyrazolines that may be elaborated, as
the synthesis described demonstrates, to give useful
chiral diamine starting materials. Further applications
of these dipolar cycloaddition reactions are currently
being studied and will be the subject of future reports.
Ack n ow led gm en t. This research has been sup-
ported by generous grants from the National Science
Foundation, the National Institutes of Health, the David
and Lucille Packard Foundation, Sloan Foundation,
Merck, Pfizer, Lilly, Zeneca, and Upjohn.
(8) Mandai, T.; Matsumoto, T.; Tsujiguchi, Y.; Matsuoka, S.; Tsuji,
J . J . Organomet. Chem. 1994, 473, 343.
(9) Stoilova, V.; Trifonov, L. S.; Orahovats, A. S. Synthesis 1979,
105.
(10) The synthesis of 19 and ent-19 commences with alkylation of
N-propionylpseudoephedrineamide with the known homogeranyl iodide
following the general procedure recently described by Myers, giving
alkylated product in 92% yield as a single diastereomer by 1H NMR
spectroscopy (Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J . L. J .
Am. Chem. Soc. 1994, 116, 9361). Reduction of the alkylation product
to the corresponding aldehyde followed by condensation with (carbe-
thoxy-methylene)triphenylphosphorane gave the ethyl esters of 19 and
ent-19, which were subsequently saponified (LiOH, THF) to furnish
19 and ent-19.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures including synthesis and characterization of new
compounds reported herein (15 pages).
J O971571L
(11) We are grateful to Prof. Fusetani for generously furnishing us
with authentic natural stellettamide A.
(12) The iodide salt of 20 was dissolved in 25% MeOH/KH2PO4 and
extracted with CH2Cl2 to give the monobasic phosphate salt, which
was shown to be identical with stellettamide A by spectroscopic
methods.