Diastereoselective [4+2] annulation of vinyl carbodiimides with N-alkyl imines. Asymmetric synthetic access to the batzelladine alkaloids

Article abstract of DOI:10.1021/ja0519029

A diastereoselective [4+2] annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich tricyclic core of the batzelladine alkaloids. Its application to the asymmetric synthesis of batzelladine D perm

Full text of DOI:10.1021/ja0519029

Published on Web 04/22/2005
Diastereoselective [4+2] Annulation of Vinyl Carbodiimides with N-Alkyl
Imines. Asymmetric Synthetic Access to the Batzelladine Alkaloids
Michael A. Arnold, Sergio G. Duro´n, and David Y. Gin*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received March 24, 2005; E-mail: gin@scs.uiuc.edu
Scheme 1 a
The stereoselective construction of complex polycyclic guanidine
structures is of paramount importance given the abundance of
biologically active complex guanidine natural products. This is
exemplified by members of the batzelladine family of polycyclic
guanidine marine alkaloids (Chart 1),1 several of which exhibit
notable biological activity, including inhibition of binding of HIV
gp120 to human CD4, as well as the induction of protein tyrosine
kinase p56lck dissociation from CD4. Consequently, this family of
alkaloids has been the focus of extensive synthetic studies in which
stereoselective construction of the tricyclic guanidine core 1 presents
the principal challenge. Elegant synthetic strategies directed toward
this goal have included multiple N-acylation,2 N-acyliminium
cyclization,3 aza-Diels-Alder reaction,4 stereoselective acyl radical
cyclization,5 condensation of isoureas and guanidines with bis-
(enones),6 tethered Biginelli condensation,7 and nitrone 1,3-dipolar
cycloaddition,8 with the latter three approaches culminating in
racemic6b,8b and asymmetric7b,c,8c total syntheses. We report herein
a new strategy to the batzelladine alkaloids employing a diastereo-
selective [4+2] annulation reaction of chiral N-alkyl imines and
vinyl carbodiimides, illustrated in a concise asymmetric synthesis
of batzelladine D (2).
a Reagentsandconditions: (a)PPh3,CH2Cl2,71%;(b)p-MeOC6H4CH2NCO,
PhMe, 85 °C, 71%; (c) (ClCH2)2, 23 °C, 98%.
Scheme 2
Chart 1
dihydro-2H-pyrrole (8)11 resulted in efficient [4+2] annulation to
provide exclusively the S,S-diastereomer of the bicyclic dihydro-
pyrimidine 9 (98%), a substructure that maps onto the batzelladine
skeleton 1 with the requisite anti relationship of its C8 and C11
hydrogens.12
Despite the diverse mechanistic pathways through which the
annulation process can proceed (Scheme 2), the stereochemical
preference can be rationalized based on steric influences arising
from the lone stereocenter of the chiral imine. Reasonable pathways
include: (1) a hetero-Diels-Alder (HDA) cycloaddition in a
sterically minimized endo (10endo f 11) or exo (10exo f 12) mode;
(2) generation of the transient 2,4-diaza-1,3,5-hexatriene 13, fol-
lowed by sterically governed torquo-selective disrotatory 6π-
electrocyclic ring closure (13 f 11); or (3) generation of iminium
14 followed by intramolecular Mannich cyclization (i.e., 14 f 12)
onto the less hindered face of the electrophile. Irrespective of the
possible annulation pathways, the formation of either of the
guanidine diastereomers 11 or 12 would ultimately result in
convergence to the vinylogous carbamate 9 upon tautomerization.
This stereoselective approach to the bicyclic guanidine 9 also
provides a superb opportunity for establishing the C7 and C15
stereochemistry (Scheme 3)12 present in the alkaloids, a formidable
challenge highlighted in previous synthetic efforts. Thus, the
TBDPS ether within 9 was removed, and the vinylogous carbamate
Although vinyl carbodiimides have been employed in N-
heterocycle syntheses,9 their annulation reactions with imines have
been limited to the use of only PhCHdNPh in a modest-yielding
nonstereoselective process.9b Nevertheless, the prospect of develop-
ing an efficient [4+2] annulation of chiral N-alkyl imines with vinyl
carbodiimides seemed to be ideally suited for the preparation of
the tricyclic batzelladine skeleton 1, both in terms of convergent
strategic bond construction as well as providing an attractive means
for stereocontrol.
Assessing the feasibility of the process in a model investigation
commenced with the preparation of the electron-deficient vinyl
carbodiimide 7 (Scheme 1). Thus, (E)-3-azidobut-2-enoic acid
methyl ester (5)10 was readily converted to its iminophosphorane
6 with PPh3 (71%) followed by aza-Wittig condensation with
p-methoxybenzyl isocyanate to form 7 (71%). Exposure of the vinyl
carbodiimide 7 to readily available (S)-2-O-TBDPS-methyl-3,4-
9
6924
J. AM. CHEM. SOC. 2005, 127, 6924-6925
10.1021/ja0519029 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
carbamate (80%) with complete stereocontrol, even with the further-
removed homologated hydroxyl directing group in 23 (cf. 15).
Subsequent IBX oxidation afforded the tricyclic guanidine hemi-
aminal 24 (98%), which underwent sequential benzyl ester hydro-
genolysis (99%) and cis-selective Wittig olefination17 with the ylide
derived from nonyltriphenylphosphonium bromide to form 25
(72%). Introduction of the guanidine-containing side chain of
batzelladine D (2) was then effected by carboxylate O-alkylation
with (BocHN)2CdN(CH2)4OSO2Me18 to form 26 in 93% yield.
Closure of the remaining ring was accomplished via intramolecular
regio- and stereoselective iodoamination (70%) of the alkene in
26, relying on minimization of A1,3-like strain between C11 and
C18 of the reacting cis-alkene hydrocarbon chain to establish the
desired C13 configuration.12 Subsequent reductive deiodination19
provided 27 (89%), whose protective groups were removed with
TFA to provide (-)-2 (82%) as its bis(trifluoroacetate) salt.
A diastereoselective [4+2] annulation of vinyl carbodiimides
with chiral N-alkyl imines has been developed to access the
stereochemically rich tricyclic core of the batzelladine alkaloids.
Its application to the asymmetric synthesis of batzelladine D (2)
permitted the use of long-range, directed hydrogenation and
stereoselective intramolecular iodoamination as additional key steps
to establish the remaining stereocenters within 2 with excellent
stereocontrol. Efforts are underway to apply this novel approach
to other members of the batzelladine alkaloids.
a Reagents and conditions: (a) TBAF, THF, 97%; (b) [Ir(cod)pyr(PCy3)]-
PF6, H2 (400 psi), CH2Cl2, 81%.
Scheme 4 a
Acknowledgment. This research was supported by the NIH
(GM67659), Merck, and Pfizer, Inc.
Supporting Information Available: Complete ref 1a, and experi-
mental procedures. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) (a) Patil, A. D. et al. 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) Rao, A. V. R.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem.
Commun. 1995, 1369-1370.
(3) Louwrier, S.; Ostendorf, M.; Tuynman, A.; Hiemstra, H. Tetrahedron Lett.
1996, 37, 905-908.
(4) Elliott, M. C.; Long, M. S. Org. Biomol. Chem. 2004, 2, 2003-2011.
(5) Evans, P. A.; Manangan, T. Tetrahedron Lett. 2001, 42, 6637-6640.
(6) (a) Snider, B. B.; Chen, J. Tetrahedron Lett. 1996, 37, 6977-6980. (b)
Snider, B. B.; Chen, J. Tetrahedron Lett. 1998, 39, 5697-5700. (c) Black,
G. P.; Murphy, P. J.; Walshe, N. D. A. Tetrahedron 1998, 54, 9481-
9488.
a Reagents and conditions: (a) (MeHN)2CNMe2N3, CHCl3, 84% (2:1
E:Z); (b) PPh3, CH2Cl2, 75% (E), 58% (Z); (c) p-MeOC6H4CH2NCO, PhMe,
85 °C, 73% (E), 67% (Z); (d) Cp2ZrHCl, THF, -20 °C, 66%; (e) (ClCH2)2,
23 °C, 86% from (E)-19, 88% from (Z)-19; (f) TBAF, THF, 99%; (g)
[Ir(cod)pyr(PCy3)]PF6, H2 (400 psi), CH2Cl2, 80%; (h) IBX, DMSO,
CH3CN, 98%; (i) 10% Pd(OH)2/C, AcOH, H2 (1 atm), MeOH, 99%; (j)
Me(CH2)8PPh3, THF, 50 °C, 72%; (k) (BocHN)2CdN(CH2)4OMs, Cs2CO3,
DMF, 40 °C, 93%; (l) I2, K2CO3, DME, 70%; (m) 10% Pd/C, Et3N, H2 (1
atm), EtOAc, 89%; (n) TFA, 82%.
(7) (a) Franklin, A. S.; Ly, S. K.; Mackin, G. H.; Overman, L. E.; Shaka, A.
J. J. Org. Chem. 1999, 64, 1512-1519. (b) Cohen, F.; Overman, L. E.;
Sakata, S. K. L. Org. Lett. 1999, 1, 2169-2172. (c) Cohen, F.; Overman,
L. E. J. Am. Chem. Soc. 2001, 123, 10782-10783.
(8) (a) Nagasawa, K.; Koshino, H.; Nakata, T. Tetrahedron Lett. 2001, 42,
4155-4158. (b) Ishiwata, T.; Hino, T.; Koshino, H.; Hashimoto, Y.;
Nakata, T.; Nagasawa, K. Org. Lett. 2002, 4, 2921-2924. (c) Shimokawa,
J.; Shirai, K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem.,
Int. Ed. 2004, 43, 1559-1562.
(9) (a) Wamhoff, H.; Richardt, G.; Sto¨lben, S. AdV. Heterocycl. Chem. 1995,
64, 159-249. (b) Wamhoff, H.; Schmidt, A. Heterocycles 1993, 35,
1055-1066. (c) Saito, T.; Ohkubo, T.; Kuboki, H.; Maeda, M.; Tsuda,
K.; Karakasa, T.; Satsumabayashi, S. J. Chem. Soc., Perkin Trans. 1 1998,
3065-3080.
(10) Palacios, F.; Peres de Heredia, I.; Rubiales, G. J. Org. Chem. 1995, 60,
2384-2390.
15 was subjected to long-range, hydroxy-directed hydrogenation
with Crabtree’s catalyst13,14 to provide the â-guanidino ester 16 as
a single stereoisomer (81%), whose structure was verified through
X-ray analysis.
Having secured the feasibility and favorable stereochemical
consequences of the heteroannulation, the strategy was validated
in a short asymmetric synthesis of batzelladine D (2, Scheme 4).
1,4-But-2-ynoic acid benzyl ester (17) was treated with tetrameth-
ylguanidinium azide to afford the â-azido acrylate 18 (84%; 2:1
E:Z). Both the E and Z isomers of 18 separately underwent
Staudinger-aza-Witting condensation with p-methoxybenzyl iso-
cyanate to form the vinyl carbodiimides (E)-19 and (Z)-19 with
comparable efficiency. Treatment of either (E)- or (Z)-19 with 2-(2-
O-TBDPS-ethyl)-3,4-dihydro-2H-pyrrole (21), derived from
Cp2ZrHCl-mediated reduction15 of its lactam precursor 20,16
provided the bicyclic dihydropyrimidine 22 with complete diaste-
reoselectivity (86 and 88%, respectively). Removal of the TBDPS
ether in 22 allowed for directed hydrogenation of its vinylogous
(11) Woo, K.; Jones, K. Tetrahedron Lett. 1991, 32, 6949-6952.
(12) Carbon numbering assignments conform to that of batzelladine D.
(13) (a) Crabtree, R. H.; Davis, M. W. Organometallics 1983, 2, 681-682.
(b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072-1073.
(14) Hydrogenation of 9 (Rh/Al2O3) led to 2:1 dr favoring the undesired C7/
C15 configurations, in addition to concomitant reduction of the PMB
group.
(15) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem. 1996, 61, 4115-
4119.
(16) Browning, R. G.; Badarinarayana, V.; Mahmud, H.; Lovely, C. J.
Tetrahedron 2004, 60, 359-365.
(17) Wang, Q.; Wei, H.; Schlosser, M. Eur. J. Org. Chem. 1999, 3263-3268.
(18) Neubert, B. J.; Snider, B. B. Org. Lett. 2003, 5, 765-768.
(19) Li, N. S.; Piccirilli, J. A. J. Org. Chem. 2004, 69, 4751-4759.
JA0519029
9
J. AM. CHEM. SOC. VOL. 127, NO. 19, 2005 6925