Total synthesis of (+)-batzelladine A and (-)-batzelladine D via [4 + 2]-annulation of vinyl carbodiimides with N-alkyl imines

Article abstract of DOI:10.1021/ja063860+

A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol.

Full text of DOI:10.1021/ja063860+

Published on Web 09/15/2006
Total Synthesis of (+)-Batzelladine A and (-)-Batzelladine D
via [4 + 2]-Annulation of Vinyl Carbodiimides with N-Alkyl
Imines
Michael A. Arnold,† Kenneth A. Day,† Sergio G. Duro´n,† and David Y. Gin*,‡
Contribution from the Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801,
and Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer
Center, 1275 York AVenue, New York, New York 10021
Received June 1, 2006; E-mail: gind@mskcc.org
Abstract: A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been
developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids.
Application of this strategy, together with additional key steps such as long-range directed hydrogenation
and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-
batzelladine D and (+)-batzelladine A with excellent stereocontrol.
Chart 1
Introduction
Polycyclic guanidine natural products comprise an intriguing
class of structurally diverse marine alkaloids possessing varied
and potent biological activities. In the mid to late 1990s, nine
novel tricyclic guanidine marine alkaloids were isolated as
metabolites of the Crambe genus.1 This family of batzelladine
alkaloids (1-9, Chart 1) is characterized by at least one
stereochemically rich fused tricyclic guanidine core to which
are appended additional guanidine fragments (R1-R6) of varying
complexity. Members of the batzelladine alkaloids have exhib-
ited biological activities that include potential antiviral activity
in the inhibition of the binding of HIV gp120 to human CD4
(batzelladines A and B), as well as potential immunosuppressive
activity in the induction of dissociation of protein tyrosine kinase
p56lck from CD4 (batzelladines F-I).
Over the past decade, considerable effort has been devoted
to the synthesis of this class of alkaloids. The first total synthesis
of any member of the batzelladine alkaloids was reported by
Snider and Chen,2 involving a biomimetic strategy consisting
of the condensation of isourea derivatives with multifunctional
bis(enones) in the preparation of (()-batzelladine E (5). A
nonracemic synthesis of (-)-batzelladine D (2) by Overman
and co-workers soon followed employing a versatile tethered
Biginelli condensation approach that later served in their
† University of Illinois at Urbana-Champaign.
‡ Memorial Sloan-Kettering Cancer Center.
(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. (c) Snider, B. B.;
Busuyek, M. V. J. Nat. Prod. 1999, 62, 1707-1711. (d) Braekman, J. C.;
Daloze, D.; Tavares, R.; Hajdu, E.; Van Soest, R. W. M. J. Nat. Prod.
2000, 63, 193-196 (e) Structure verification of batzelladines G-I via total
synthesis has yet to be accomplished.
(2) (a) Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A. J. Tetrahedron Lett.
1996, 37, 6977-6980. (b) Snider, B. B.; Chen, J. Tetrahedron Lett. 1998,
39, 5697-5700.
9
10.1021/ja063860+ CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 13255-13260
13255

A R T I C L E S
Scheme 1
Arnold et al.
Scheme 2 a
enantioselective synthesis and structure revision of (+)-batzel-
ladine F (7).3 A completely distinct strategy involving a nitrone
1,3-dipolar cycloaddition was showcased by Nagasawa and
co-workers first in their synthesis of (()-batzelladine D (2) and
later in the only report to date of the synthesis of (+)-
batzelladine A (1) employing the same strategy.4 Other
creative approaches to complex fragments of the batzelladines
have included N-acylation,5 N-acyliminium cyclizations,6
biomimetic guanidine-bis(enone) condensations,7 formal aza-
Diels-Alder reactions,8 and stereoselective radical cycliza-
tions.9
a Reagents and conditions: (a) (MeHN)2CNMe2N3, CHCl3, 44% (E);
(b) PPh3, CH2Cl2, 81%; (c) p-MeOC6H4NCO, PhMe, 72%; (d) p-MeOC6H4-
CH2NCO, PhMe, 85 °C, 74%; (e) TBDPSCl, imidazole, DMF, 83%; (f)
Cp2ZrHCl, THF, -20 °C, 68%; (g) (ClCH2)2, 62% (R ) PMP), 98% (R )
PMB).
imines and its application to the nonracemic total syntheses of
batzelladines D11 and A.
Within a considerable number of the batzelladine alkaloids,
namely batzelladines A, D, F, and G, there exists a common
tricyclic tetrahydropyrimidine core (10, Scheme 1) incorporating
multiple stereogenic centers along its periphery. Consideration
of this tetrahydropyrimidine core suggests a potentially expedi-
ent route toward its construction, in which simple retrosynthetic
oxidation state adjustment of 10 would provide the tricyclic
dihydropyrimidine intermediate 11. A direct [4 + 2]-discon-
nection along the highlighted C-C and C-N bonds in 11 would
yield simple precursors in the form of a vinyl carbodiimide 12
and a chiral imine 13. Ideally, the lone chiral center in 13 would
dictate the entire stereochemical course of the synthesis. Reports
on annulations of vinyl carbodiimides with imines in N-
heterocycle syntheses are rare,10 in which only achiral PhCHd
NPh was used as a coupling partner with generally modest
yields. We report herein our establishment of a diastereoselective
[4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl
Results and Discussion
To assess the feasibility and stereochemical outcome of the
diastereoselective [4 + 2]-annulation of vinyl carbodiimides and
imines, model investigations commenced with the preparation
of electron-deficient vinyl carbodiimides 16 and 17 (Scheme
2). 2-Butynoic acid methyl ester (14) was subjected to 1,4-
conjugate addition with tetramethylguanidinium azide (TMGA)
to afford the â-azido acrylate 15 as a mixture of geometrical
isomers. The E-isomer 15 could be isolated in high purity (44%)
and was thus employed in the initial model experiments for
carbodiimide formation. Treatment of E-1512 with PPh3 led to
conversion to its iminophosphorane derivative (81%), which
allowed for its condensation by aza-Wittig reaction with either
p-methoxyphenyl isocyanate or p-methoxybenzyl isocyanate to
form the carbodiimides 16 (72%) and 17 (74%), respectively.
Notably, both of these vinyl carbodiimides could be purified
by silica gel chromatography. The model chiral imine coupling
partner was derived from (S)-5-(hydroxymethyl)-2-pyrrolidinone
(18), which, after TBDPS protection of the hydroxyl group
(83%), could be directly reduced to the imine 19 with Schwartz’s
reagent (68%).13,14
Exposure of the vinyl carbodiimide 16 or 17 to the imine 19
resulted in successful [4 + 2]-annulation in both cases to provide
exclusively the (S,S)-diastereomer of the bicyclic dihydropyri-
midines 20 and 21 (62% and 98%, respectively). Detailed NMR
analysis of the dihydropyrimidine products confirmed the anti-
stereochemical configuration of the pyrrolidine substructure
within both 20 and 21. The high efficiency and degree of
diastereoselectivity in this annulation process highlight the
potential for its application to the synthesis of batzelladines D
and A, both of which share a common anti-fused tricyclic
guanidine core.
(3) (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. (d) Cohen, F.; Overman,
L. E. J. Am. Chem. Soc. 2006, 128, 2594-2603. (e) Cohen, F.; Overman,
L. E. J. Am. Chem. Soc. 2006, 128, 2604-2608.
(4) (a) Ishiwata, T.; Hino, T.; Koshino, H.; Hashimoto, Y.; Nakata, T.;
Nagasawa, K. Org. Lett. 2002, 4, 2921-2924. (b) Shimokawa, J.; Shirai,
K.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Angew. Chem., Int. Ed.
2004, 43, 1559-1562. (c) Shimokawa, J.; Ishiwata, T.; Shirai, K.; Koshino,
H.; Tanatani, A.; Nakata, T.; Hashimoto, Y.; Nagasawa, K. Chem.-Eur.
J. 2005, 11, 6878-6888.
(5) Rao, A. V. R.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem. Commun.
1995, 1369-1370.
(6) Louwrier, S.; Ostendorf, M.; Tuynman, A.; Hiemstra, H. Tetrahedron Lett.
1996, 37, 905-908.
(7) (a) Black, G. P.; Murphy, P. J.; Walshe, N. D. A.; Hibbs, D. E.; Hursthouse,
M. B.; Malik, K. M. A. Tetrahedron Lett. 1996, 37, 6943-6946. (b) Black,
G. P.; Murphy, P. J.; Walshe, N. D. A. Tetrahedron 1998, 54, 9481-
9488. (c) Black, G. P.; Murphy, P. J.; Thornhill, A. J.; Walshe, N. D. A.;
Zanetti, C. Tetrahedron 1999, 55, 6547-6554.
(8) (a) Elliott, M. C.; Long, M. S. Tetrahedron Lett. 2002, 43, 9191-9194.
(b) Elliott, M. C.; Long, M. S. Org. Biomol. Chem. 2004, 2, 2003-2011.
(9) (a) Evans, P. A.; Manangan, T. Tetrahedron Lett. 2001, 42, 6637-6640.
(b) Evans, P. A.; Manangan, T. Tetrahedron Lett. 2005, 46, 8811.
(10) (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.
(11) For a preliminary report on the use of this strategy for the synthesis of
batzelladine D, see: Arnold, M. A.; Duro´n, S. G.; Gin, D. Y. J. Am. Chem.
Soc. 2005, 127, 6924-6925.
(12) Palacios, F.; Perez de Heredia, I.; Rubiales, G. J. Org. Chem. 1995, 60,
2384-2390.
(13) Schedler, D. J. A.; Li, J.; Ganem, B. J. Org. Chem. 1996, 61, 4115-4119.
(14) Woo, K.; Jones, K. Tetrahedron Lett. 1991, 32, 6949-6952.
9
13256 J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006

Synthesis of Batzelladines A and D
A R T I C L E S
Scheme 3
Chart 2
Scheme 5 a
a Reagents and conditions: (a) TsCl, TEA, DMAP, CH2Cl2, 85%; (b)
KCN, CH3CN, 85 °C, 91%; (c) HCl(g), EtOH, 65 °C, 89%; (d) LiBH4,
MeOH, THF, 0 °C, 91%; (e) TBDPSCl, imidazole, DMF, 88%; (f)
Cp2ZrHCl, THF, -20 °C, 66%.
Scheme 4 a
difficulties.3 However, the presence of the Lewis basic oxygen
functionality in the C11 side chain of 21 offered unique
opportunities to explore a long-range directed hydrogenation
process to secure these two C-stereocenters. Thus, the TBDPS
ether within 21 was removed (TBAF, 97%), and the vinylogous
carbamate 27 was subjected to hydrogenation with Crabtree’s
catalyst16 under 400 psi H2. The â-guanidino dihydropyrimidine
product 28 was formed as a single stereoisomer (81%), whose
structure was verified through X-ray analysis. The free hydroxyl
functionality in 27 was found to be critical in this stereoselective
reduction, as attempts at Crabtree hydrogenation of the silyl
ether 21 under otherwise identical conditions led to no reaction,
and Rh/Al2O3-catalyzed hydrogenation of 27 led to 2:1 dr,
favoring the undesired C7/C15 configurations in addition to
reduction of the PMB group.
Synthesis of (-)-Batzelladine D. The promising results of
these initial annulation investigations prompted efforts to apply
this approach to the total synthesis of the simplest of the
batzelladine alkaloids, namely batzelladine D (2, Chart 2).
Although the stereoselective production of tetrahydropyrimidine
28 (Scheme 4) suggested the direct use of this intermediate in
the total synthesis efforts, advancement of 28 to the tricyclic
core of batzelladine D was not possible owing to functional
group incompatibilities during its late-stage elaboration to close
the third ring. As a result, a new imine coupling partner was
prepared to overcome these difficulties (Scheme 5). In this
sequence, the chiral imine was again derived from (S)-5-
(hydroxymethyl)-2-pyrrolidinone (18), in which the primary
hydroxyl was activated (TsCl, Et3N, 85%) and displaced with
cyanide to form nitrile 29 (91%). Ethanolysis of the nitrile (89%)
and reduction to the primary alcohol (LiBH4, 91%) allowed for
its subsequent conversion to the TBDPS ether 30 (88%), which
then underwent amide reduction with Cp2ZrHCl13 to afford the
chiral imine 31 (66%), an intermediate corresponding to the
single carbon homologation derivative of the original imine 19.
Preparation of an appropriately protected vinyl carbodiimide
employed 1,4-but-2-ynoic acid benzyl ester (32, Scheme 6),
which was subjected to 1,4-conjugate addition with TMGA to
a Reagents and conditions: (a) TBAF, THF, 97%; (b) [Ir(cod)pyr-
(PCy3)]PF6, H2 (400 psi), CH2Cl2, 81%.
The mechanism by which the formation of the bicyclic
dihydropyrimidines 20 and 21 occurs is unclear. Be it a
concerted or stepwise process, the anti-stereochemical outcome
could be rationalized primarily on the basis of steric factors.
For example, in the case of an asynchronous concerted
[4 + 2]-cycloaddition (Scheme 3), the inverse electron-demand
hetero-Diels-Alder (IED-HDA) may proceed through an endo
(22) or exo (23) transition state. In either case, approach of the
diene should preferentially occur on the imine dienophile face
opposite to that of the alkyl ether side chain, thereby committing
to the anti-cycloadduct 24 following tautomerization. Alterna-
tively, a stepwise process could entail initial nucleophilic
addition of the imine to form the guanidine zwitterion 25,
followed by an intramolecular Mannich closure in which the
π-nucleophile approaches from the less sterically encumbered
face of the iminium group. An additional stepwise process
invokes the zwitterionic resonance structure of the initial adduct
25 in the form of 26, which incorporates a conjugated 1,3,5-
triene substructure, thereby setting the stage for a 6π-electro-
cyclic rearrangement. If such a process were thermally induced,
disrotatory closure would likely be torquo-selective wherein the
sterically demanding alkyl ether substituent adopts an “out-
orientation” to again secure formation of the anti-cycloadduct
24 after tautomerization.
Despite the different mechanistic pathways by which the
annulation process can proceed, the outcome nonetheless
appeared ideally suited for a stereoselective synthesis of the
batzelladine core 10, especially with the presence of the
â-oriented alkyl ether side chain within 21 (Scheme 4). Previous
approaches at employing hydrogenation protocols to establish
the C7 and C15 stereochemistry15 within the tetrahydropyrimi-
dine core of the batzelladine alkaloids were met with significant
(16) (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. (c)
Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655-2661.
(15) Carbon numbering assignments conform to that of batzelladine D.
9
J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006 13257

A R T I C L E S
Scheme 6 a
Arnold et al.
Scheme 7 a
a Reagents and conditions: (a) I2, K2CO3, DME, 70%; (b) 10% Pd/C,
Et3N, H2 (1 atm), EtOAc, 89%; (c) TFA, 82%.
Chart 3
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) 31, (ClCH2)2, 23 °C, 86% from E-34, 88%
from Z-34; (e) TBAF, THF, 99%; (f) [Ir(cod)pyr(PCy3)]PF6, H2 (400 psi),
CH2Cl2, 80%; (g) IBX, DMSO, CH3CN, 98%; (h) Me(CH2)7CHdPPh3,
THF; (i) 10% Pd(OH)2/C, AcOH, H2 (1 atm), MeOH, 99%; (j) Me(CH2)7-
CHdPPh3, THF, 50 °C, 72%; (k) (BocHN)2CdN(CH2)4OMs, Cs2CO3,
DMF, 40 °C, 93%.
of the vinylogous carbamate functionality. Even with the further
extended hydroxyl group in 36, the Ir+-catalyzed reduction16
proceeded with complete stereocontrol to provide the corre-
sponding tetrahydropyrimidine (80%), which efficiently under-
went IBX oxidation to provide the tricyclic guanidine hemi-
aminal 37 (98%). At this juncture, advancement of 37 through
the direct attachment of the C7-C2515 fragment via selective
Wittig fragment coupling proved troublesome. For example,
treatment of hemiaminal 37 with the ylide derived from
nonyltriphenylphosphonium bromide led to stereoselective
formation of the cis-alkene 38, although with unavoidable C7
epimerization of the pseudo-axial ester substituent. To remedy
this situation, the benzyl ester in 37 was first subjected to
hydrogenolysis (99%), allowing for cis-selective Wittig olefi-
nation17 with excess ylide (thereby generating the carboxylate
anion in situ) to afford the alkene acid 39 after acidification
(72%). Attachment of the guanidine-containing side chain of
batzelladine D (2) was then accomplished by carboxylate
O-alkylation with (BocHN)2CdN(CH2)4OSO2Me18 to form 41
in 93% yield.
Closure of the remaining ring in (-)-batzelladine D was
effected by intramolecular iodo-amination of the alkene in 41
(Scheme 7), employing I2 in the presence of K2CO3. Preferential
6-exo-cyclization (70%) proceeded with complete regio- and
stereocontrol to establish the desired C13-(R)-configuration15
in 42 after reductive deiodination19 (89%). The high stereose-
lectivity of this final ring closure can be rationalized by the
preferential formation and reaction of the iodonium diastereomer
43 (Chart 3), directly derived from oxidation of the cis-alkene.
Cyclization in this manifold would place the alkyl group in a
pseudo-equatorial orientation. Conversely, cyclization to form
afford the â-azido acrylate 33 as a mixture of geometrical
isomers (84%; 2:1 E:Z). In the earlier model investigations into
the key [4 + 2]-annulation reaction (Scheme 2), only the
E-isomers of the vinyl carbodiimides 16/17 were employed in
the successful study. Since the formation of the alkenyl azide
33 was nearly nonstereoselective, it was prudent to determine
the suitability of both isomers in the key annulation for the
efficient synthesis of batzelladine D (2). Thus, both the E- and
Z-isomers of 33 (Scheme 6) were separated by silica gel
chromatography and subjected to Staudinger-aza-Wittig con-
densation with p-methoxybenzyl isocyanate to form the vinyl
carbodiimides E-34 and Z-34 with comparable efficiency (73%
and 67%, respectively). Treatment of either E-34 or Z-34 with
2-(2-O-TBDPS-ethyl)-3,4-dihydro-2H-pyrrole (31) led to the
formation of a single diastereomer of the dihydropyrimidine 35
(86% from E-34 and 88% from Z-34), incorporating the
expected anti-stereochemistry. It is worth noting that the
formation of 35 may arise from either (1) both E- and Z-isomers
of 34 undergoing the annulation or (2) in situ interconversion
of the E/Z isomers of 34 wherein one preferentially undergoes
dihydropyrimidine formation. Nevertheless, this sequence does
illustrate that the low stereoselectivity in the conversion of 32
f 33 is not a liability given that both isomers comparably
converge to the bicylic guanidine 35.
The synthesis of (-)-batzelladine D (2) continued with
removal of the TBDPS ether in 35 to expose the primary
hydroxyl group (TBAF, 99%) in 36 for directed hydrogenation
(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.
9
13258 J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006

Synthesis of Batzelladines A and D
A R T I C L E S
Scheme 8
Scheme 9 a
the undesired C13-(S)-diastereomer would arise from formation
and reaction of the iodonium diastereomer 44, which places the
alkyl group in a pseudo-axial orientation to experience pro-
nounced A1,3-like strain. It is worth noting that the current data
does not discount the possibility of iodine-induced alkene E/Z
isomerization prior to cyclization. Unfortunately, further elu-
cidation of the stereocontrol elements in the cyclization was
hampered by difficulties both in the determination of the
configuration of the newly formed iodine-bearing stereocenter
in the immediate iodo-amination product and in the independent
synthesis of the trans-alkene isomer of 41 to probe its oxidative
cyclization. Nevertheless, the favorable outcome of this final
cyclization event permitted the global deprotection of 42
(Scheme 7) with aqueous TFA to conclude the synthesis of (-)-
batzelladine D (2, 82%).
Synthesis of (+)-Batzelladine A. The successful application
of the carbodiimide annulation strategy in the synthesis of the
simplest member of batzelladine alkaloids (2) prompted inves-
tigation of this approach to more complex members of the
family, namely the small-molecule binder to CD4,20 batzelladine
A (1, Scheme 8). Unfortunately, the highlighted [4 + 2]-annu-
lation approach does not immediately map onto the bicylic
guanidine substructure 45 within 1. However, retrosynthetic
rupture of the pyrrolidine at C11-N21 in 45 would generate a
dihydropyrimidine intermediate 46, which should be amenable
to the key [4 + 2]-disconnection wherein the absolute config-
uration of the lone C13-chiral center21 would be established.22
The preparation of a suitable vinyl carbodiimide substrate
for the synthesis of the bicyclic guanidine substructure 45 within
(+)-1 commenced (Scheme 9) with sequential O-benzylation
(NaH, BnBr, 80%) and C-acylation (MeOC(O)Cl, 85%) of pent-
4-yn-1-ol to afford the propargyllic ester 48. Treatment of alkyne
48 with TMGA led to conjugate 1,4-addition of azide to afford
a 2:1 (E:Z) mixture of vinyl azides 49, which was then converted
to vinyl carbodiimide 50 via Staudinger-aza-Wittig condensation
with p-methoxybenzyl isocyanate (63%). The mixture of both
geometrical isomers of 50 was exposed to chiral imine (R)-19,
prepared similarly to that of its S-enantiomer (see Scheme 2).
The annulation process proceeded at 23 °C to provide the
dihydropyrimidine 51 (89%) as a single diastereomer. While it
remains unclear whether the cyclization proceeded via a
concerted or stepwise mechanism, the anti-stereochemistry of
a Reagents and conditions: (a) BnCl, NaH, TBAI, THF, 70 °C, 80%;
(b) nBuLi, methyl chloroformate, THF, -78 °C, 85%; (c) TMGA, CHCl3,
23 °C, 78% (2:1 E/Z); (d) PPh3, CH2Cl2, 23 °C; PMBNCO, PhMe, 80 °C,
63%; (e) (ClCH2)2, 23 °C, 89%; (f) NaH, Boc2O, DMAP, THF, 23 °C,
86%; (g) TBAF, AcOH, THF, 23 °C, 91%; (h) I2, PPh3, imidazole, PhMe,
23 °C, 97%; (i) t-BuLi, THF, -78 °C, 93%; (j) 54, Grubbs-G2, CH2Cl2,
45 °C, 73%; (k) 10% Pd(OH)2, AcOH, H2 (1 atm), MeOH, CH2Cl2, 23 °C,
90%; (l) DIAD, PPh3, PhMe, 23 °C, 93%; (m) NaH, Boc2O, DMAP, THF,
23 °C, 85%; (n) EtSLi, HMPA, 23 °C; (o) 57, BOPCl, TEA, CH2Cl2, 23
°C, 55% (two steps); (p) TBAF, THF, 23 °C, 92%; (q) MsCl, TEA, CH2Cl2,
0 °C, 91%.
the product emerged as expected based on our previous
experience with this reaction. Thus, annulation of chiral imine
R-19 with vinyl carbodiimide 50 secured the required C13-R-
configuration in 51 via relay of stereochemical information from
the sacrificial stereogenic center originally obtained from chiral
pyrrolidinone (R)-18.
Construction of the bicyclic guanidine skeleton in batzelladine
A continued as the guanidine group in 51 was fully protected
by acylation with Boc2O (86%), allowing for conversion of the
primary alkyl silyl ether to its iodo-counterpart 52 via sequential
treatment with TBAF and I2/PPh3 (88%, two steps). Low-
temperature lithium-halogen exchange of 52 occurred rapidly
with concomitant â-elimination of the acylated guanidine
(20) Shimokawa, J.; Ishiwata, T.; Shirai, K.; Koshino, H.; Tanatani, A.; Nakata,
T.; Hashimoto, Y.; Nagasawa, K. Chem.-Eur. J. 2005, 11, 6878-6888.
(21) Carbon numbering assignments conform to that of batzelladine A.
(22) For the determination of the absolute configuration of C13 in 1, see: Duro´n,
S. G.; Gin, D. Y. Org. Lett. 2001, 3, 1551-1554.
9
J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006 13259

A R T I C L E S
Scheme 10 a
Arnold et al.
steps for elaboration of the bicyclic guanidine fragment of
batzelladine A involved thiolate-induced removal of the viny-
logous methyl carbamate followed by BOPCl-mediated esteri-
fication25 of (BocHN)2CdN(CH2)4OH (57) to provide the
vinylogous carbamate 58 (55%, two steps). Subsequent conver-
sion of the silyl ether in 58 to its methanesulfonate ester
derivative (TBAF; MsCl, 84%, two steps) provided 59, an
appropriately derivatized bicyclic guanidine core of batzelladine
A.
The convergent final sequence in the assembly of both
polycyclic guanidine fragments employed the advanced bicyclic
guanidine construct 39, originally prepared (Scheme 6) for the
synthesis of batzelladine D. The cesium carboxylate of 39
(Scheme 10) was generated to undergo O-alkylation with the
alkyl methanesulfonate 59 to provide the C23 ester 60 (68%).
The third ring within the tricyclic core of batzelladine A was
then closed by way of a stereoselective intramolecular iodo-
amination (I2, Cs2CO3, 72%) to establish the desired C30-R-
stereocenter, followed by reductive de-iodination (Et3N, H2, Pd/
C, 71%) to afford 61, a fully protected form of batzelladine A.
Global deprotection of 61 (TFA) completed the total synthesis
of batzelladine A (75%), whose analytical data were found to
be identical in all respects to that reported for the natural product.
Conclusions
Through the use of a unified strategy involving the diaste-
reoselective [4 + 2]-annulation of chiral imines with vinyl
carbodiimides, the total syntheses of (+)-batzelladine A (1) and
(-)-batzelladine D (2) were accomplished in highly convergent
and stereoselective sequences. The successful application of this
approach to dihydropyrimidine construction in the synthesis of
1 and 2 illustrates its potential for the synthesis of other related
alkaloids such as the crambescidin family of natural products,
as well as for the construction of complex non-natural N-
heterocycles of potential biological utility.
a Reagents and conditions: (a) Cs2CO3, DMF, 50 °C, 68%; (b) I2,
Cs2CO3, DME, 23 °C, 72%; (c) 10% Pd/C, TEA, H2 (1 atm), EtOAc, 71%;
(d) TFA, 0 °C, 75%.
functionality to cleave the pyrrolidine ring (93%). The resultant
R-olefin in 53 served as a convenient handle with which to attach
the C17-C2221 oligomethylene linker present in batzelladine
A; thus, alkene 53 was exposed to the TBDPS ether of hept-
6-en-1-ol (54) in the presence of Grubbs-G2 ruthenium catalyst23
to effect olefin cross-metathesis to provide a mixture of E- and
Z-disubstituted alkene isomers (73%). Subsequent treatment with
H2 and Pd(OH)2 led to benzyl ether hydrogenolysis, p-
methoxybenzyl removal from the guanidine, and alkene hydro-
genation in a single pot procedure to yield the primary alcohol
55 (90%). Closure of the pyrrolidine ring was accomplished
by intramolecular aza-Mitsunobu (DIAD, PPh3, 93%),24 fol-
lowed by acylation of the guanidine core with Boc2O to provide
the bicyclic vinylogous carbamate 56 (85%). The remaining
Acknowledgment. This research was supported by the NIH
(GM67659), Abbott, Eli Lilly, Johnson & Johnson, Merck, and
Pfizer. A Bristol-Myers Squibb predoctoral fellowship to M.A.A.
is acknowledged.
Supporting Information Available: Complete ref 1a; experi-
mental details for the preparation and analytical characterization
of synthetic intermediates. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA063860+
(23) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
(25) Diago-Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.; Zugaza-
(24) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127-164.
Bilbao, A. Synthesis 1980, 547-551.
9
13260 J. AM. CHEM. SOC. VOL. 128, NO. 40, 2006