effects stereospecific dinitrogenation.7 Initial attempts to
prepare the labile azidoformate group, which involved
carbamoylation with 1,1′-carbonyldiimidazole and subse-
quent azidation with NaN3, were not fruitful owing to an
inefficient azide-imidazole exchange as well as more pro-
nounced SN2 substitution at the allylic position. Nevertheless,
we eventually found that azidoformate 5 could be efficiently
produced by treating the imidazolide intermediate with
TMSN3 in the presence of water. The addition of water in
this case was indispensable for successful transformation; it
presumably in situ produced hydrazic acid (HN3) that
efficiently effects the azidation reaction with carbonyl
imidazolide and also prevented resultant azidoformate 5 from
undergoing reversible imidazolation since highly protic water
could reduce the nucleophilicity of imidazole that is respon-
sible for the undesired side reaction.8
nucleus by aziridination of the π-bond. The aziridination of
5 was carried out at 160 °C in CH2Cl2 in a high-pressure
stainless steel tube to furnish aziridine 4 in 92% yield.9,10
Aziridine 4 was then subjected to ring-opening reaction at
room temperature with NaN3 in DMF, giving azide 3 as the
sole product (Scheme 4).11 As expected, cleavage of the weak
outer bond of the tricyclic system with an azide anion took
place selectively, leading to the regioselective azidation at
the 3-position of the cyclopentane ring. It should be noted
that basic nitrogen nucleophiles, such as aqueous ammonia
and benzylamine, exclusively underwent addition to the
oxazolidinone moiety to produce urea derivatives rather than
aziridine-cleaving products.
Lactamization with 3 was, however, difficult despite
extensive trials: the initial attempt to transform intermediate
3 into lactam 14 via amidine 18, which was readily obtained
by hydrogenolysis of 3 under Pearlman conditions, was
unsuccessful due to the significant tolerance of the amidine
group to hydrolysis (Scheme 5). Therefore, we first converted
Scheme 4. Total Synthesis of (-)-Agelastatin A (1)
Scheme 5. Attempted Hydrolysis of Amidine 18
azide 3 into amide 13 by hydrolysis of the nitrile group with
alkaline-hydrogen peroxide, followed by reduction of azide,
(9) Thermolysis and related reactions of azidoformates leading to
aziridination: (a) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1999,
64, 2852. (b) Bergmeier, S. C.; Stanchina, D. M. J. Org. Chem. 1997, 62,
4449. (c) Bergmeier, S. C.; Stanchina, D. M. Tetrahedron Lett. 1995, 36,
4533. (d) Bach, T.; Schlummer, B.; Harms, K. Chem. Commun. 2000, 287.
(e) Minakata, S.; Kano, D.; Oderaotoshi, Y.; Komatsu, M. Angew. Chem.,
Int. Ed. 2004, 43, 79. (f) Zhou, Y.; Murphy, P. V. Org. Lett. 2008, 10,
3777. (g) Ruppel, J. V.; Jones, J. E.; Huff, C. A.; Kamble, R. M.; Chen,
Y.; Zhang, X. P. Org. Lett. 2008, 10, 1995
.
(10) This aziridination under photolytic conditions, however, furnished
only a low yield (ca. 10%) of aziridine 4. For the photolysis of azidofor-
mates, see: (a) Mendlik, M. T.; Tao, P.; Hadad, C. M.; Coleman, R. S.;
Lowary, T. L. J. Org. Chem. 2006, 71, 8059. (b) Kan, C.; Long, C. M.;
Paul, M.; Ring, C. M.; Tully, S. E.; Rojas, C. M. Org. Lett. 2001, 3, 381
.
(11) For recent examples of aziridine opening with azides, see: (a)
Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am.
Chem. Soc. 2007, 129, 12084. (b) Das, B.; Reddy, V. S.; Krishnaiah, M.;
Rao, Y. K. J. Mol. Catal. A 2007, 270, 89. (c) Savoia, D.; Alvaro, G.; Di
Fabio, R.; Gualandi, A. J. Org. Chem. 2007, 72, 3859. (d) Fukuta, Y.; Mita,
T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006, 128,
6312. (e) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron Lett. 2006, 47,
4813. (f) Wu, J.; Sun, X.; Xia, H.-G. Eur. J. Org. Chem. 2005, 4769. (g)
D’hooghe, M.; Rottiers, M.; Kerkaert, I.; De Kimpe, N. Tetrahedron 2005,
61, 8746. (h) Minakata, S.; Okada, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2005, 7, 3509. (i) Kim, Y.; Ha, H.-J.; Han, K.; Ko, S. W.; Yun, H.;
Yoon, H. J.; Kim, M. S.; Lee, W. K. Tetrahedron Lett. 2005, 46, 4407. (j)
Kumar, G. D. K.; Maskaran, S. Synlett 2004, 10, 1719. (k) Yadav, J. S.;
Reddy, B. V. S.; Premalatha, K. AdV. Synth. Catal. 2003, 345, 948. (l)
Bisai, A.; Pandey, G.; Pandey, M. K.; Singh, V. K. Tetrahedron Lett. 2003,
44, 5839. (m) Sabitha, G.; Babu, R. S.; Rajkumar, M.; Yadav, J. S. Org.
Lett. 2002, 4, 343. (n) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2000,
65, 1344. (o) Li, Z.; Ferna´ndez, M.; Jacobsen, E. N. Org. Lett. 1999, 1,
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With this pivotal compound in hand, we sought to
construct vicinal dinitrogen functionalities of the agelastatin
(7) For recent reviews on catalytic aziridination chemistry using azides,
see: (a) Katsuki, T. Chem. Lett. 2005, 34, 1304. (b) Mu¨ller, P.; Fruit, C.
Chem. ReV. 2003, 103, 2905.
(8) It is also likely that water hydrolyzes TMS-imidazole that is possibly
generated by the reaction of carbonyl imidazolide with TMSN3 and readily
undergoes addition to azidoformate 5.
Org. Lett., Vol. 10, No. 23, 2008
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