J.-W. Jung et al. / Tetrahedron Letters 46 (2005) 573–575
575
deprotection of both the PMB and Cbz groups in the
presence of Boc2O provided the b-aminoester 12, which
Acknowledgements
is identical in all aspects to the reported b-aminoester.12
This research work was supported by the grant from
Center for Bioactive Molecular Hybrids, Yonsei
University.
CO2Me
1) OsO4, oxone, DMF
2) CH2N2,ether, 0 o
3) Pd-C, H2,
(Boc)2O, MeOH
C
Boc
PMB
N
H
N
References and notes
Cbz
2
12
53%
1. For excellent reviews on the chemistry of N-acyliminium
ions and the related intermediates, see: (a) Speckamp, W.
N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817–3856;
(b) Hiemstra, H.; Speckamp, W. N. In Comprehensive
Organic Synthesis; Trost, B., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 2, pp 1047–1082.
2. For selected recent reports, see: (a) Kamatani, A.; Over-
man, L. E. Org. Lett. 2001, 3, 129; (b) Overman, L. E.;
Wolfe, J. P. J. Org. Chem. 2001, 66, 3167; (c) Heredia, M.
L.; Cuesta, E. de la; Avendano, C. Tetrahedron: Asym-
metry 2001, 12, 2883; (d) Chao, W.; Waldman, J. H.;
Weinreb, A. M. Org. Lett. 2003, 5, 2915.
3. (a) Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N.
Tetrahedron Lett. 1985, 26, 3155; (b) Mooiweer, H. F.;
Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetra-
hedron Lett. 1987, 28, 3285.
4. (a) Suh, Y.-G.; Shin, D.-Y.; Jung, J.-K.; Kim, S.-H. Chem.
Commum. 2002, 1064; (b) Suh, Y.-G.; Kim, S.-H.; Jung,
J.-K.; Shin, D.-Y. Tetrahedron Lett. 2002, 43, 3165; (c)
Shin, D.-Y.; Jung, J.-K.; Seo, S.-Y.; Lee, Y.-S.; Paek,
S.-M.; Chung, Y. K.; Shin, D. M.; Suh, Y.-G. Org. Lett.
2003, 5, 3635.
Scheme 3. Synthesis of trans-ACPC derivative 12.
Encouraged by the successful cyclizations of various
amidoalkylation substrates, we attempted to investigate
the extension of this methodology to the asymmetric
variants4c for the optically enriched cycloalkylamines.
Thus, the N,O-acetal TMS ether 14, prepared from the
N-acyl-oxazolidinone 13, was subjected to the standard
intramolecular amidoalkylation condition. SnCl4 treat-
ment of 14 provided more than 20:1 diastereoselectivity
in favor of the trans-isomer with 60% de.13 The excellent
diastereoselectivity was compatible with that of the achi-
ral case, while the observed facial selectivity was lower
than expected. However, this preliminary work on the
asymmetric variant envisions its synthetic potential for
the optically active cycloalkylamines, although the
enantioselectivity is not satisfactory yet (Scheme 4).
5. For reviews on cyclic b-amino acids, see: (a) Park, K.-H.;
Kurth, M. J. Tetrahedron 2002, 58, 8629; (b) Liu, M.; Sibi,
M. P. Tetrahedron 2002, 58, 7991.
6. Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
4976.
7. (a) Gademann, K.; Hintermann, T.; Schreiber, J. V. Curr.
Med. Chem. 1999, 6, 905; (b) Porter, E. A.; Wang, X.; Lee,
H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404,
565; (c) Wang, X.; Espinosa, J. F.; Gellman, S. H. J. Am.
Chem. Soc. 2000, 122, 4821, and the related references
cited therein.
OTMS
( )3
O
O
O
DIBAL
( )3
O
N
TMS
O
N
TMS
TMSOTf
pyridine
87%
Ph
Ph
14
13
SnCl4
CH2Cl2
78%
+
Ph
O
Ph
N
O
N
O
O
8. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900.
16
15
9. Santelli, M.; Pons, J.-M. Lewis Acids and Selectivity in
Organic Synthesis; CRC, 1996; pp 91–177.
Scheme 4. Asymmetric variant of intramolecular amidoalkylation.
10. Wasserman, H. H.; Rotello, V. M.; Krause, G. B.
Tetrahedron Lett. 1992, 33, 5419. The initial introduction
of allylic moiety was conducted by reaction of a-bromo-N-
p-methoxybenzyl acetamide with allyl mercaptan/NaH,
allyl alcohol/NaH and allyl amine, respectively.
11. The enamide formation by b-elimination of the acylimium
ion rather than allylsilane addition was consistently
observed.
12. For the trans-ACPC derivative, see: Yokota, Y.; Cortez,
G. S.; Romo, D. Tetrahedron 2002, 58, 7075. See also Ref.
6.
13. The isomer 15 is considered as the major product on the
basis of our previous work. Refer to Ref. 4c.
In conclusion, we have developed a novel and versatile
intramolecular amidoalkylation of acyclic N-acylimin-
ium ion precursors for a variety of cycloalkylamines.
This procedure appears to be quite useful for synthetic
and medicinal chemists, in terms of synthetic efficiency
and functional diversity. Currently, the studies on asym-
metric variants of intramolecular amidoalkylation,
based on our preliminary work, are in good progress.
A report on the successful results as well as the advances
in synthetic applications is forthcoming.