around a SmI2-mediated intramolecular radical cyclization
of oxime ethers.6 This methodology afforded the azepine core
as a 6.6:1 mixture of diastereomers; however, the major
isomer required a lipase resolution at a later stage in the
synthesis. A racemic total synthesis of balanol was achieved
by Adams and co-workers in 1995 utilizing a ring expansion
of 3-bromopiperidin-4-ones to access the azepine core.7 The
Tanner group utilized a regio- and stereoselective opening
of a chiral epoxide to control the C3-C4 stereogenic centers
of the heterocycle.8 An asymmetric synthesis of balanol was
reported by Nicolaou and co-workers using D-serine and an
asymmetric allylation with [Ipc]2B-allyl to install the vicinal
amino alcohol functionality as a 12:1 mixture of diastereo-
mers.9 Hughes and Lampe utilized (2S,3R)-hydroxylysine as
a key synthon in their total synthesis of balanol.10 However,
the preparation of the hydroxylysine synthon required eight
steps, which resulted in a somewhat lengthy synthesis.
Additionally, a number of formal syntheses of the hexahy-
droazepine core 2 have been reported.11 It was our intention
to develop a streamlined approach to enantiomerically pure
2 which would make use of a modified aminohydroxylation
methodology to construct the (2R,3S)-hydroxylysine needed
for the rapid assembly of the azepine core.
of 3 to the ꢀ-caprolactam and reduction of the amide would
afford the hexahydroazepine core.
We have previously demonstrated that the asymmetric
aminohydroxylation of p-bromo-substituted aryl esters of
various â-substituted acrylate systems provides access to
unnatural amino acid derivatives including the desired
hydroxylysine derivative for use in the synthesis of the
hexahydroazepine core of (-)-balanol (Scheme 2).12a
Scheme 2
The preparation of substrate 4 and its conversion to the
hydroxylysine synthon starting from commercially available
4-chloro-1-butanol are shown in Scheme 3. Swern oxidation
Our synthetic plans for the construction of the azepine core
of (-)-balanol centered around the use of the modified
asymmetric aminohydroxylation (AA) methodology devel-
oped in our laboratories and recently applied in our synthesis
of (+)-lactacystin.12 This AA methodology is capable of
installing the C3-C4 stereocenters in an efficient one-step
procedure provided the proper regiochemical outcome could
be achieved in the AA process. Our retrosynthetic analysis
is illustrated in Scheme 1. Disconnection of the ester linkage
Scheme 3
Scheme 1
of 4-chloro-1-butanol provided 4-chlorobutanal which was
subjected to a Horner-Emmons olefination with diethyl (p-
bromophenyl)phosphonate 5 to give the requisite olefin 4 in
(6) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito,
T. J. Org. Chem. 1998, 63, 4397-4407.
(7) Adams, C. P.; Fairway, S. M.; Hardy, C. J.; Hibbs, D. E.; Hursthouse,
M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.; Warner, I. J. Chem Soc.,
Perkin Trans. 1 1995, 2335-2362.
(8) Tanner, D.; Almario, A. Ho¨gberg, T. Tetrahedron 1995, 51, 6061-
6070.
(9) Nicolaou, K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994,
116, 8402-8403.
(10) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H.
J. Org. Chem. 1996, 61, 4572-4581.
(11) (a) Fu¨rstner, A.; Thiel, O. R. J. Org. Chem. 2000, 65, 1738-1742.
(b) Cook, G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615-
617. (c) Morie, T.; Kato, S. Heterocycles 1998, 48, 427-431. (d) Wu, M.
H.; Jacobsen, E. N. Tetrahedron Lett. 1997, 38, 1693-1696. (e) Albertini,
E.; Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V.
Tetrahedron 1997, 53, 17177-17182. (f) Tuch, A.; Saniere, M.; Le Merrer,
Y.; Depezay, J.-C. Tetrahedron: Asymmetry 1996, 7, 2901-2905. (g) Mu¨ler,
A.; Takyar, D. K.; Witt, S.; Ko¨nig, W. A. Liebigs Ann. Chem. 1993, 651-
655.
of (-)-balanol affords the azepine and aromatic fragments.
The hexahydroazepine core of (-)-balanol (2) can be further
disconnected to the hydroxylysine synthon (3). Cyclization
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Org. Lett., Vol. 2, No. 17, 2000