New and highly enantioselective catalysts for the rearrangement of meso- epoxides into chiral allylic alcohols [1]

Full text of DOI:10.1021/ja982381a

10760
J. Am. Chem. Soc. 1998, 120, 10760-10761
Communications to the Editor
Scheme 1
New and Highly Enantioselective Catalysts for the
Rearrangement of meso-Epoxides into Chiral Allylic
Alcohols
Mikael J. So¨dergren and Pher G. Andersson*
Department of Organic Chemistry
Institute of Chemistry, Uppsala UniVersity
Box 531, S-751 21, Uppsala, Sweden
Scheme 2a
ReceiVed July 7, 1998
The asymmetric base-mediated rearrangement of meso-epoxides
into optically active allylic alcohols is a reaction of great interest
since allylic alcohols are useful intermediates for organic syn-
thesis.1 As a consequence, this transformation has been employed
as the key step in the syntheses of numerous commercially and
biologically important substances, for example, carbovir,2 lasiol,3
faranal,4 leukotrienes,5 and prostaglandin precursors.6 The reac-
tion is, however, sowewhat limited since it generally requires
1.5-2 equiv of a chiral base. Although it has been found that
adequate enantioselectivity could be retained using 1 or 2 in less
than stoichiometric amounts, (Scheme 1),7 a versatile catalyst,
highly enantioselective for a variety of substrates and readily
accessible in both enantiomeric forms, remains to be found.
We herein report our initial studies of the preparation of the
3-aminomethyl-2-azabicyclo[2.2.1]heptanes 4a-b (Scheme 2),8
and the use of their Li-amides as catalysts for the title reaction.
We reasoned that a Li-amide having a more rigid backbone than
2 would adopt a more well-ordered TS in the deprotonation
reaction and give rise to higher asymmetric induction as the result
of a more strict discrimination between the enantiotopic protons
in the substrate. For this purpose, we have developed a
straightforward and high-yielding route to diamines 4 in either
enantiomeric form (Scheme 2). Enantiopure amino alcohol 58d
is simply oxidized to aldehyde 6, which gives the catalyst
a Reagents and conditions: (i) Swern ox. (98%). (ii) a: pyrrolidine;
b: piperidine; MS 3A, methanol, then NaBH3CN (a: 83; b: 91%). (iii)
H2 (1 atm), Pd(OH)2/C; methanol/AcOH (a: 89; b: 93%).
Table 1.
mol
%
%
absolute
entry
epoxide
catalyst
yielda eeb configc product
1
2
3
4
5
6
7
8
9
n ) 0
n ) 0
n ) 1
n ) 1
n ) 1
n ) 1
n ) 2
n ) 2
n ) 3
4a 120 78d 95
4a
15 67d 49
4a 120 87
Re
R
8
8
3
3
3
3
9
9
10
10
11
11
97
96
95
93
98
96
81
78
67h
66h
Re
R
4a
ent-4af
4b
5
5
5
91
90
85
S
R
4a 120 93
4a 89
4a 120 84
4a 81
4a 120 88
4a 82
Rg
R
5
Re
R
10 n ) 3
11 (Z)-4-octene-oxide
12 (Z)-4-octene-oxide
5
Re
R
5
a Isolated. Conversions >90% (determined by GLC using n-dodecane
as internal standard. b Determined by GLC (Chrompack Chirasil Dex-
CB). c Assignment based on the sign of optical rotation. d After
benzoylation (ref 7b). Reaction was run at rt. e See ref 6b. f Enantiomer
of 7a. g See ref 14. h Determined by analysis of the (R)-MTPA ester
(1H NMR, 400 MHz).
(1) Reviews: (a) O’Brien, P. J. Chem. Soc., Perkin Trans. 1 1998, 1439.
(b) Asami, M. J. Synth. Org. Chem., Jpn. 1996, 54, 188. (c) Hodgson, D. M.;
Gibbs, A. R.; Lee, G. P. Tetrahedron 1996, 52, 14361. (d) Cox, P. J.; Simpkins,
N. S. Tetrahedron: Asymmetry 1991, 2, 1. (e) Crandall, J. K.; Apparu, M.
Org. React. 1983, 29, 345.
(2) (a) Hodgson, D. M.; Whiterington, J.; Moloney, B. A. J. Chem. Soc.,
Perkin Trans. 1 1994, 3373. (b) Hodgson, D. M.; Gibbs, A. R. Synlett 1997,
657. (c) Asami, M.; Takahashi, J.; Inoue, S. Tetrahedron: Asymmetry 1994,
5, 1649. (d) Saravanan, P.; Singh, V. K. Tetrahedron Lett. 1998, 39, 167.
(3) Kasai, T.; Watanabe, H,; Mori, K. Bioorg. Med. Chem. 1993, 1, 67.
(4) Mori, K.; Murata, N. Liebigs Ann. Chem. 1995, 2089.
(5) (a) Sabol, J. S.; Cregge, R. J. Tetrahedron Lett. 1989, 30, 3377. (b)
Hayes, R.; Wallace, T. W. Tetrahedron Lett. 1990, 31, 3355.
(6) (a) Asami, M. Chem. Lett. 1985, 5803. (b) Asami, M. Bull. Chem. Soc.
Jpn. 1990, 63, 721. (c) Asami, M.; Inoue. S. Tetrahedron 1995, 51, 11725.
(d) Bhuniya, D.; DattaGupta, A.; Singh, V. K. J. Org. Chem. 1996, 61, 6108.
(e) See ref 2d.
(7) (a) Asami, M.; Ishizaki, T.; Inoue. S. Tetrahedron: Asymmetry 1994,
5, 793. (b) Asami, M.; Suga, T.; Honda, K.; Inoue. S. Tetrahedron Lett. 1997,
38, 6425. (c) Tierney, J. P.; Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1997, 8, 1019.
(8) Optically pure exo-2-azabicyclo[2.2.1]heptane-3-carboxylic acid deriva-
tives have previously been used for the preparation of chiral catalysts: (a)
Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530. (b)
Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.; Andersson, P. G. J. Org.
Chem. 1998, 63, 2749. (c) So¨dergren, M. J.; Andersson, P. G. Tetrahedron
Lett. 1996, 37, 7577. (d) Both enantiomers of amino alcohol 5 are available
in three steps from cheap starting materials and on a multigram scale; Nakano,
H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, H. Tetrahedron:
Asymmetry 1997, 8, 1700. (e) Stella, L.; Abraham, H.; Feneau-Dupont, J,:
Tinant, B.; Declercq, J. P. Tetrahedron Lett. 1990, 31, 2603. (f) Waldmann,
H.; Braun, M. Liebigs Ann. Chem. 1991, 1045. (g) Trost, B. M.; Organ, M.
G.; O’Doherty, G. A. J. Am. Chem. Soc. 1995, 117, 9662.
precursors 4 after a one-pot reductive amination and subsequent
N-debenzylation. Considering its high overall yields and enan-
tiodivergence, this approach should offer a practical and flexible
alternative to the existing methods for preparing this kind of
diamine derivatives.9
The catalytic ability of these new bases was evaluated using
the conditions developed by Asami,7 that is, the reactions were
carried out by adding a solution of the meso-epoxide to a catalyst
mixture containing LDA as the stoichiometric base and DBU as
cosolvent in THF.10 Our preliminary results are presented in
Table 1. The levels of asymmetric induction for the cyclic
epoxides are, to our knowledge, the highest reported so far for
(9) The amide-coupling step in the preparation of diamine derivatives related
to 1 (as described in ref 6b) has been reported to be troublesome, and
alternative strategies have been described: (i) Optimization of reagents and
conditions to minimize racemization in the coupling of phenylglycine
derivatives, see ref 6d. (ii) Construction of the tertiary amine moiety via
nucleophilic substitution: (a) Hendrie, S. K.; Leonard, J. Tetrahedron 1987,
14, 3289. (b) Alker, D.; Doyle, K. J.; Harwood: L. M.; McGregor, A.
Tetrahedron: Asymmetry 1990, 1, 877. (c) de Sousa, S. E.; O’Brien, P.;
Poumellec, P. Tetrahedron: Asymmetry 1997, 8, 2613. (d) See ref 2d.
10.1021/ja982381a CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/02/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 41, 1998 10761
enantioselectivity in base-mediated epoxide rearrangements. It
has been suggested that such additives inhibit the formation of
reactive but unselective aggregates of the chiral Li-amides.1c,2c,6a-b
To test this hypothesis, a series of experiments was carried out
where cyclohexene oxide was reacted in the presence of a catalyst
generated from partly racemic diamine 4a and varying amounts
of DBU. The results are shown in Figure 1 where the ee of the
obtained (R)-2-cyclohexenol 3 is plotted versus the enantiomeric
purity of 4a. At high DBU concentrations, the relationship
between the ee’s of the catalyst and the product is strictly linear,
whereas a pronounced negative nonlinear relationship is observed
at intermediate catalyst enantiopurity with lower DBU loadings.
The fact that the presence of DBU increases the enantioselectivity
of the enantiopure catalyst supports the idea that DBU inhibits
the formation of kinetically competent but less enantioselective
aggregates of type (Li+4a-)n. The linear relationship between
the catalyst and the product ee indicates that the active catalyst
is mainly monomeric (or a Li+4a-•DBU heterodimer) in the
presence of DBU of sufficient concentration. The nonlinear effect
could be explained by the action of heterochiral, meso-type
aggregates (Li+4a-•Li+ent-4a-)n, for which DBU-assisted dis-
sociation occurs more easily than for the corresponding homo-
chiral dimers.12 This would thus give a monomeric catalyst of
lower enantiomeric purity than that of the original 4a. Another
explanation which would account for the observed nonlinear effect
would be the formation of meso-type aggregates having a superior
catalytic activity for the formation of racemic product.
In conclusion, we have developed an efficient route to both
enantiomers of diamines 4 and, in a preliminary study, have found
their Li-amides to be highly efficient catalysts for the asymmetric
base-mediated rearrangement of epoxides. Cyclic meso-epoxides
gave the corresponding chiral 2-cycloalken-1-ol derivatives of
excellent ee, even at very low catalyst loading. Furthermore, a
study of the relationship between asymmetric induction in the
reaction and enantiomeric purity of the catalyst efficiently
illustrates how DBU can improve the catalytic performance by
preventing the formation of less selective Li-amide aggregates.
Extended studies of diamine catalysts of this family are underway,
including the development of catalysts with altered steric proper-
ties,13 additional chelation sites and/or stereocentra as well as their
application in total synthesis, and ab initio calculations, aiming
to find a rationale for the origin of the asymmetric induction.
Figure 1. Asymmetric induction versus enantiomeric purity of catalyst
4a. Influence of DBU as cosolvent.
the asymmetric epoxide deprotonation (entries 1-10, Table 1).
It is also the first example of a catalytic system for this reaction
which, except for cyclopentene oxide (entries 1-2, Table 1),11
gives very high enantioselectivity regardless of whether a full
equivalent or 5 mol % of the chiral base is used (cf. entries 3-4,
7-8, 9-10, and 11-12, respectively, Table 1).
The presence of a chelating cosolvent like HMPA or DBU has
often been observed to have a beneficial influence on the
(10) The reaction of cycloheptene oxide (entry 8, Table 1) was carried out
using a representative procedure. To a solution of 4a (50 µmol), DIPA (2.0
mmol) and DBU (5.0 mmol; 0.75 mL) in dry THF (4 mL) under Ar at 0 °C
was added n-BuLi (2.0 mmol, 1.6 M in hexanes) dropwise during 5 min. The
resulting yellowish solution was stirred at 0 °C for another 30 min, and
cycloheptene oxide (1 mmol) in THF (3.5 mL) was then added dropwise during
5 min. The reaction mixture was kept for 24 h at 0 °C before it was partitioned
between saturated aqueous NH4Cl (5 mL) and Et2O (15 mL). The phases were
separated and the ether layer washed with 2 M HCl (2 × 5 mL), water (5
mL), brine (5 mL), and dried (MgSO4). Enantiomeric excess was determined
using a sample from this mixture to be 96% ee by using GLC with a chiral
stationary phase (Chirasil Dex-CB). The crude alcohol was coated on silica
gel by evaporation of the solvent and directly purified by column chroma-
tography to give (R)-9 (89%) as a colorless oil.
(11) Cyclopentene oxide needs higher reaction temperatures than higher
homologues (see ref 6b), and there is no report describing its catalytic
rearrangement. The highest reported enantioselectivity (41% ee) was obtained
using 1.5 equiv of Li-amide 1 (Scheme 1).
(12) About nonlinear effects in asymmetric catalysis, see, e.g.: (a) Puchot,
C.; Samuel, O.; Dunach, E.; Zhao, S.; Agami, C.; Kagan, H. B. J. Am. Chem.
Soc. 1986, 108, 2353. (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori, R. J.
Am. Chem. Soc. 1989, 111, 4028.
Acknowledgment. We are grateful for the financial support provided
by the Swedish Natural Science Research Council (NFR) and The Swedish
Foundation for Strategic Research (SSF).
(13) Diamine derivatives bearing substituents in R-position to the tertiary
amine would be of particular interest since such catalysts could be expected
to give severe steric repulsions with the substrate in the TS of the disfavored
pathway of the reaction. For related mechanistic studies, see: Kahn, A. Z.-
Q.; deGroot, R. W.; Arvidsson, P. I.; Davidsson, O¨ . Tetrahedron: Asymmetry
1998, 9, 1223.
Supporting Information Available: Experimental procedures, meth-
ods for determination of enantiomeric mixtures, characterization data for
new compounds (6 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
(14) Trost, B. M.; Organ, M. G.; O’Doherty, G. A. J. Am. Chem. Soc.
1995, 117, 9662.
JA982381A