Asymmetric synthesis of 4,5,6- and 3,4,5,6-substituted azepanes by a highly diastereoselective and enantioselective lithiation-conjugate addition sequence

Article abstract of DOI:10.1021/ja057592b

Asymmetric syntheses of 4,5,6- and 3,4,5,6-substituted azepanes have been achieved by highly diastereoselective and enantioselective (-)-sparteine-mediated asymmetric lithiation-conjugate additions of N-Boc-N-(p-methoxyphenyl)-2,3-substituted allylamines to a β-aryl α,β-unsaturated ester followed by hydrolysis, cyclization, and reduction. Access to the enantiomeric adduct is provided by an invertive lithiation-stannylation-lithiation sequence. Copyright

Full text of DOI:10.1021/ja057592b

Published on Web 02/01/2006
Asymmetric Synthesis of 4,5,6- and 3,4,5,6-Substituted Azepanes by a Highly
Diastereoselective and Enantioselective Lithiation-Conjugate Addition
Sequence
Suk Joong Lee and Peter Beak*
Department of Chemistry, UniVersity of Illinois at UrbanasChampaign, Urbana, Illinois 61801
Received November 7, 2005; E-mail: beak@scs.uiuc.edu
Azepane rings are present in a number of biologically interesting
molecules and are homologues of the five- and six-membered
nitrogen heterocycles which have been extensively developed as
core pharmacophores. Methodology for the asymmetric synthesis
of polysubstituted azepanes has not been developed. Syntheses of
enantioenriched azepane rings have been reported coincident to the
preparations of specific compounds of biological interest, but
general approaches, particularly for substitutions nonadjacent to the
nitrogen atom, have not been available.1-3
Conversion of ester 3 to the amides 6 and 96a followed by acid
hydrolysis of the enamide to the aldehyde and subsequent cycliza-
tion provided the corresponding N-alkyl lactams 7 and 10, as
shown in Scheme 2.7 Reductive conversions of 7 and 10 to 8 and
11 were accompanied by debrominations of the aromatic ring.6b
Scheme 2
We now wish to report lithiation-addition methodology for the
asymmetric synthesis of both enantiomers of 4,5,6 and 3,4,5,6
carbon-substituted azepanes. The key step in our approach is a
highly diastereoselective and enantioselective conjugate addition
of a lithiated N-Boc-2,3-substituted allylamine to a â-aryl R,â-
unsaturated ester, which is shown as the first step in the retrosyn-
thetic analysis of Scheme 1.
Efficient syntheses of 4,5,6-substituted azepanes are shown in
Scheme 3. Enantioenriched 1, 2, and 3 were converted to the
corresponding 4,5,6-substituted N-Boc azepanes 16, 21, and 26 in
high yields via aminolysis, hydrolysis, reduction, debenzylation,
and addition of the Boc group. The stereochemistry at the C-6
positions of 14, 19, and 24 generated by hydrogenation was
identified as trans geometry by X-ray crystallography as well as
Scheme 1
1
by H NMR analysis.7,8
(-)-Sparteine-mediated asymmetric lithiation of N-Boc-N-(p-
methoxyphenyl)-2,3-substituted allylamines with n-BuLi at -78 °C
followed by conjugate additions to ethyl trans-p-bromocinnamate
provides the highly diastereo- and enantioenriched enecarbamates
1-3 in the yields shown in Table 1. The absolute configuration of
3, determined by X-ray crystallography, indicates that the stereo-
chemical course of the conjugate addition is inversion of config-
uration.4
Scheme 3
Table 1. (-)-Sparteine-Mediated Asymmetric
Lithiation-Substitution Sequences
R1
R2
product
yield (%)
dra
er
CH3
Ph
(CH2)2-
CH3
CH3
(CH2)2-
(Z,S,R)-1
(Z,S,R)-2
(Z,S,R)-3
92
86
75
95:5
93:7
96:4
>95:5b
>97:3b
99:1c
a Diastereomeric ratios (dr) were determined by 1H NMR analysis.
b Enantiomeric ratios (er) were assessed to be >95:5 and >97:3 after
aminolysis of 1 and 2 with (S)-(-)-R-methylbenzylamine, respectively.5
c The enantiomeric ratio of 3 was determined by CSP-HPLC analysis.
Enolization and substitution of the lactam 29 provides a route
to 3,4,5,6-substituted azepanes, as shown in Scheme 4.9 Aminolysis
of 1 with p-anisidine to 27 followed by hydrolysis and hydrogena-
9
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J. AM. CHEM. SOC. 2006, 128, 2178-2179
10.1021/ja057592b CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Asymmetric Synthesis of 3,4,5,6-Substituted
Azepanes
and/or further substitutions at positions adjacent to nitrogen in the
intact ring are available for further development.
Acknowledgment. We are grateful to the National Institutes
of Health (GM-18874) and to funds provided by the James R.
Eiszner Chair for the support of this work.
Supporting Information Available: All experimental procedures
and spectroscopic data for new compounds, and crystallographic data
of 7, 24, 36, and (R,S,S)-4 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews which include azepane ring syntheses, see: (a) Yet,
L. Chem. Rew. 2000, 100, 2963-3007. (b) Kantorowski, E. J.; Kurth, M.
J. Tetrahedron 2000, 56, 4317-4353. (c) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073-2077.
(2) For recent syntheses of compounds of biological interest containing
azepane rings, see: (a) Jacobi, P. A.; Lee, K. A. J. Am. Chem. Soc. 2000,
122, 4295-4303. (b) Boeckman, R. K.; Clark, T. J.; Shook, B. C. Org.
Lett. 2002, 4, 2109-2112. (c) Smith, A. B., III; Cho, Y. S.; Pettit, G. R.;
Hirschmann, R. Tetrahedron 2003, 59, 6991-7009. (d) Painter, G. F.;
Eldridge, P. J.; Falshaw, A. Bioorg. Med. Chem. 2004, 12, 225-232. (e)
Li, H.; Bleriot, Y.; Mallet, J. M.; Rodriguez-Garcia, E.; Vogel, P.; Zhang,
Y.; Sinay, P. Tetrahedron: Asymmetry 2005, 16, 313-319. (f) Wipf, P.;
Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225-235.
(3) For asymmetric azepane syntheses with one or two carbons and, in some
cases, an oxygen or nitrogen as substituents, see: (a) Lautens, M.; Fillion,
E.; Sampat, M. J. Org. Chem. 1997, 62, 7080-7081. (b) Masse, C. E.;
Morgan, A. J.; Panek, J. S. Org. Lett. 2000, 2, 2571-2573. (c) Meyers,
A. I.; Downing, S. V.; Weiser, M. J. J. Org. Chem. 2001, 66, 1413-
1419. (d) Cutri, S.; Bonin, M.; Micouin, L.; Husson, H. P. J. Org. Chem.
2003, 68, 2645-2651. (e) Sahasrabudhe, K.; Gracias, V.; Furness, K.;
Smith, B. T.; Katz, C. E.; Reddy, D. S.; Aube, J. J. Am. Chem. Soc. 2003,
125, 7914-7922. (f) Alibes, R.; Blanco, P.; Casas, E.; Closa, M.; March,
P. D.; Figueredo, M.; Font, J.; Sanfeliu, E.; Alvarez-Larena, A. J. Org.
Chem. 2005, 70, 3157-3167.
tion provided 29.8 Substitutions of 29 by selected electrophiles using
LDA as the base provided (R,S,R,S)-30-33 and (S,S,R,S)-34 in good
yields with high diastereoselectivities (Table 2). In all cases, the
C-3 and C-4 stereochemistry is assigned as trans by 1H NMR
analysis.8 Dearylation of 31 by CAN6c proceeds smoothly to give
(R,S,R,S)-35 in good yield with diastereomeric and enantiomeric
purities greater than 98:2.
Table 2. Substitutions of 29
(4) (a) Kim, D. D.; Lee, S. J.; Beak, P. J. Org. Chem. 2005, 70, 5376-5386
and references therein. For more complete reference to related heteroatom
allyllithiums, see also: (b) Whisler, M. C.; Beak, P. J. Org. Chem. 2003,
68, 1207-1215. (c) Ozlugedik, M.; Kristensen, J.; Wibbeling, B.; Fro¨lich,
R.; Hoppe, D. Eur. J. Org. Chem. 2002, 414-427.
(5) The diastereomeric ratios of (S,R,S)-4 and (S,R,S)-5 were determined to
be 96:4 and 98:2 by 1H NMR analysis, respectively.
electrophile
product
yield (%)
dr
CH3I
(R,S,R,S)-30
(R,S,R,S)-31
(R,S,R,S)-32
(R,S,R,S)-33
(S,S,R,S)-34
96
94
73
71
82
98:2
98:2
99:1
99:1
95:5
p-BrPhCH2Br
CH2dCHCH2Br
PhOC(dO)Cl
p-BrPhC(dO)Cl
To provide a route to the enantiomeric azepanes, we have taken
advantage of the lithiation-stannylation-lithiation sequence, which
provides the epimeric N-Boc-substituted allyllithium intermediate.4
The sequence leading to (R,S)-1 is shown in Scheme 5.10 The
enantiomeric ratio of (R,S)-1 was assessed to be 99:1 by determi-
nation of the diastereomeric ratio of (R,S,S)-4 after aminolysis of
(R,S)-1 with (S)-(-)-R-methylbenzylamine.7,11 Use of the sequences
in Schemes 3 and 4 with (R,S)-1 would provide the enantiomeric
azepanes.
(6) (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
4171-4174. (b) Wanner, M. J.; Koomen, G. J. Tetrahedron Lett. 1989,
30, 2301-2304. (c) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org.
Chem. 1982, 47, 2765-2768.
(7) The absolute configurations of 7, 24, 36, and (R,S,S)-4 were established
by X-ray crystallography structures. Crystallographic data for structures
7, 24, 36, and (R,S,S)-4 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary CCDC numbers 286543,
286544, 286545, and 286546, respectively. These data can be obtained
free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(8) Coupling constants between H5 on C-5 and H6 on C-6 for 14, 19, 24, and
29, and between H3 on C-3 and H4 on C-4 for 30-34 are the typical
trans-coupling constants (JH-JH ) 10.4 Hz). See Supporting Information.
(9) Attempted enolization-substitution of 24 resulted in substitution at
benzylic carbon due to benzylic metalation. See: Meyers, A. I.; Kunnen,
K. B.; Still, W. C. J. Am. Chem. Soc. 1987, 109, 4405-4407.
(10) The enantiomeric ratio (er ) >99:1) of (R)-36 was directly determined
by CSP-HPLC, after crystallization.
Scheme 5. Enantioselective Synthesis of Enantiomer (R,S)-1
(11) The diastereomeric ratio of (R,S,S)-4 was determined to be 99:1 by 1H
NMR analysis.
In summary, enantioselective synthesis of both enantiomers 4,5,6-
and 3,4,5,6-substituted azepanes can be achieved from the highly
diastereoenriched and enantioenriched enecarbamates 1-3 gener-
ated by (-)-sparteine-mediated asymmetric deprotonative lithia-
tions-conjugate additions of N-Boc-N-(p-methoxyphenyl)-2,3-
substituted allylamines. Opening the ring of the lactam intermediates
JA057592B
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