Epimerization of diastereomeric α-amino nitriles to single stereoisomers in the solid state

Article abstract of DOI:10.1021/ol049256q

A diastereomeric mixture of the α-amino nitrile prepared by the Strecker reaction of benzaldehyde, (1S,2R)-1-aminoindan-2-ol, and cyanotrimethylsilane thermally epimerizes in the solid state to give a single diastereomer with an (S)-configuration at the α

Full text of DOI:10.1021/ol049256q

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2241-2244
Epimerization of Diastereomeric
r-Amino Nitriles to Single
Stereoisomers in the Solid State
Rumiko Sakurai,† Shuji Suzuki,‡ Junichi Hashimoto,‡ Manabu Baba,‡
,†
Osamu Itoh,§ Akira Uchida,§ Tetsutaro Hattori,* Sotaro Miyano,† and
,‡
Masanori Yamaura*
Department of EnVironmental Studies, Graduate School of EnVironmental Studies,
Tohoku UniVersity, Aramaki-Aoba 07, Aoba-ku, Sendai 980-8579, Japan,
Department of EnVironmental Science, Faculty of Science and Engineering,
Iwaki Meisei UniVersity, Iwaki 970-8551, Japan, and Department of Biomolecular
Science, Faculty of Science, Toho UniVersity, Funabashi 274-8510, Japan
hattori@orgsynth.che.tohoku.ac.jp; yamaura@iwakimu.ac.jp
Received April 22, 2004
ABSTRACT
A diastereomeric mixture of the r-amino nitrile prepared by the Strecker reaction of benzaldehyde, (1S,2R)-1-aminoindan-2-ol, and
cyanotrimethylsilane thermally epimerizes in the solid state to give a single diastereomer with an (S)-configuration at the r position to the
nitrile moiety. This shows a sharp contrast to the reaction conducted in DMSO at room temperature, which gives a 1:1 mixture of (S)- and
(R)-isomers. Several other r-amino nitriles also epimerize in the solid-state toward single diastereomers.
Synthesis of optical isomers in crystals, taking advantage of
the well-ordered arrangement of organic molecules as well
as their defined conformation, has recently been the subject
of much interest. Studies on the asymmetric synthesis in
inclusion crystals by using chiral hosts,1 as well as the
absolute asymmetric synthesis in crystals of achiral molecules
that adopt chiral conformation or arrangement,2 have been
burgeoning. However, most of them are limited to intramo-
lecular or intraspecific photochemical reactions, which is
presumably due to the difficulty of reagent molecules to react
in the substrate crystals without decomposition of the crystal
lattice.3 Another type of reaction, which is feasible in a
crystal lattice but has had only limited success to date, is
enantiomeric or diastereomeric enrichment, that is, derace-
mization or epimerization to a single isomer. Wilson and
Pincock reported that metastable racemic-compound crystals
of 1,1′-binaphthalene were transformed into a nonracemic
mixture of stable enantiomeric crystals in an appropriate
temperature range.4 Solid-state epimerization of atropodia-
stereomeric teraryls has also been reported.5 A single crystal
of a racemic or diastereomeric (1-cyanoethyl)cobaloxime
complex, where a racemic or diastereomeric pair of com-
plexes are in a unit cell but occupy crystallographically
distinct positions from each other, has been reported to show
enantiomeric or diastereomeric enrichment on exposure to
† Tohoku University.
‡ Iwaki Meisei University.
§ Toho University.
(1) Reviews: (a) Toda, F. Synlett 1993, 303. (b) Toda, F. Acc. Chem.
Res. 1995, 28, 480. (c) Gamlin, J. N.; Jones, R.; Leibovitch, M.; Patrick,
B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203. (d) Toda, F.
Aust. J. Chem. 2001, 54, 573.
(2) Reviews: (a) Green, B. S.; Lahav, M.; Rabinovich, D. Acc. Chem.
Res. 1979, 12, 191. (b) Sakamoto, M. Chem. Eur. J. 1997, 3, 684.
(3) Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino,
T.; Fujita, T. J. Org. Chem. 2003, 68, 942.
(4) Wilson, K. R.; Pincock, R. E. J. Am. Chem. Soc. 1975, 97, 1474.
(5) Einhorn, C.; Durif, A.; Averbuch, M.-T.; Einhorn, J. Angew. Chem.,
Int. Ed. 2001, 40, 1926.
10.1021/ol049256q CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/03/2004

X-rays or UV light.6 In the course of our studies on the
optical resolution of cis-1-aminoindan-2-ol for application
to asymmetric synthesis,7,8 we have found that a diastereo-
meric mixture of R-amino nitriles, which was prepared by
the diastereoselective Strecker reaction using the amino
alcohol as a chiral auxiliary,9,10 thermally epimerizes to a
single stereoisomer in the solid state.11 To the best of our
knowledge, such a diastereomeric enrichment phenomenon
of organic molecules in crystals caused by inversion of
C-centrochirality has yet to be disclosed with the exception
of the recent report by Rao and co-workers dealing with the
dynamic kinetic resolution of epoxides by means of ami-
nolysis in the inclusion complex with â-cyclodextrin.12
The diastereoselective Strecker reaction of benzaldehyde
was performed by modifying the literature procedure and
using cyanotrimethylsilane (TMSCN) as a cyanide source
and ytterbium tris(trifluoromethanesulfonate) [Yb(OTf)3] as
a Lewis acid catalyst.10b Thus, the aldehyde was allowed to
react with 1.0 mol equiv of (1S,2R)-1-aminoindan-2-ol in
DMF at room temperature for 2 h with the aid of 5.0 mol %
Yb(OTf)3, and the resulting imine was cyanated in a one-
pot manner by addition of 1.5 mol equiv of TMSCN with
induction of desilylation of the O-silylated intermediate by
simultaneous addition of 4.0 mol equiv of methanol and
continuous stirring for 3 h. The reaction gave a diastereo-
meric mixture of R-amino nitrile 1a in an almost quantitative
yield after column chromatography on silica gel. The
diastereomeric excess of the sample determined by 1H NMR
analysis varied from 53 to 66% de with every experiment
repeated, the reason for which was suspected to be incidental
epimerization. To our surprise, the de value of the crystalline
sample stored at room-temperature had increased from 66
to 90% de after one month, which prompted us to examine
the epimerization of 1a in the solid state (Scheme 1). The
absolute stereochemistry of the major diastereomer was
determined to be 1S,2R,(S), which is denoted hereafter as
(S), by X-ray crystallographic analysis (vide infra).
The differential scanning calorimetric (DSC) analysis of
(S)-1a of 66% de showed a broad exothermic peak between
65 and 90 °C with a maximum at 72 °C, followed by a sharp
endothermic peak at 124 °C, which may be attributed to the
epimerization and melting (decomposition), respectively.
Therefore, the de change of the same sample was followed
at 65 °C, revealing that it epimerized thermally to a single
stereoisomer within 24 h. During the experiment, macro-
scopic change, particularly melting or even partial melting,
was not observed. Interestingly, diastereomerically pure (S)-
1a thus obtained, on standing at room temperature for one
week as a DMSO solution, epimerized to a 1:1 mixture of
(S)- and (R)-1a.11 In chloroform, however, the sample of 66%
de showed no change in the diastereomeric composition after
one week at room temperature but decomposed on heating
at reflux, giving an unidentifiable complex mixture; dissocia-
tion of the cyanide anion from the amino nitrile9b and sub-
sequent reaction of the resulting iminium species, e.g., intra-
molecular cyclization to an oxazolidine, may be responsible.
The Strecker reaction of several other aldehydes gave the
corresponding R-amino nitriles 1b-f with moderate to low
diastereoselectivity, except in the case of 1b, where 100%
de was achieved. Heating the crystalline solids of 1c-f to
below their melting temperatures also led to epimerization
toward single diastereomers (Table 1, entries 2-5). It is of
Table 1. Thermal Epimerization of Diastereomeric R-Amino
Nitriles in the Solid State
entry
compound
temp (°C)
time (h)
24
48
48
de (%) change
1
2
3
4
5
6
7
8
9
1a
1c
1d
1e
1f
2a
3a
4
65
60
60
40
60
65
80
65
70
66f100
24f100
44f100
8f61
3 weeks
50
48
36
56
48
3f63
29f100
12f100
46f100
17f100
5
Scheme 1
a Racemate.
interest to note that complete diastereomeric enrichment
could be achieved for R-amino nitriles similarly prepared
(6) (a) Osano, Y. T.; Uchida, A.; Ohashi, Y. Nature, 1991, 352, 510.
(b) Hashizume, D.; Ohashi, Y. J. Phys. Org. Chem. 2000, 13, 415.
(7) For utilization of cis-1-aminoindan-2-ol in asymmetric synthesis,
see: Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998, 937.
(8) Sakurai, R.; Sakai, K. Tetrahedron: Asymmetry 2003, 14, 411.
(9) Recent reviews on the asymmetric Strecker reactions: (a) Gro¨ger,
H. Chem. ReV. 2003, 103, 2795. (b) Enders, D.; Shilvock, J. P. Chem. Soc.
ReV. 2000, 29, 359. (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539.
(10) For utilization of amino alcohols as chiral auxiliaries for the Strecker
reaction, see: (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V.
Tetrahedron 1995, 51, 9179. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. Synlett
1997, 115. (c) Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120. (d)
Dave, R. H.; Hosangadi, B. D. Tetrahedron 1999, 55, 11295.
(11) A crystallization-induced asymmetric transformation in the Strecker
reaction has been reported: Boesten, W. H. J.; Seerden, J.-P. G.; de Lange,
B.; Dielemans, H. J. A.; Elsenberg, H. L. M.; Kaptein, B.; Moody, H. M.;
Kellogg, R. M.; Broxterman, Q. B. Org. Lett. 2001, 3, 1121.
(12) Reddy, L. R.; Bhanumathi, N.; Rao, K. R. Chem. Commun. 2000,
2321.
2242
Org. Lett., Vol. 6, No. 13, 2004

Figure 2. X-ray powder diffraction patterns of (R)-1a (a) and (S)-
1a (b) simulated from each single-crystal X-ray data by using
PLATON.14 Experimental X-ray powder diffraction pattern of a
diastereomeric mixture of 1a (c) and that of the same sample
measured after heating (d).
mixture consisted of the (S)- and (R)-crystals having the same
structures as those of the single crystals and that the (R)-crys-
tal was converted into the (S)-counterpart by heating. A
drastic rearrangement of molecules during the epimerization
is perceived from the large difference in the crystal structures
between the two (Figure 1a,b).13 Although the precise mech-
anism is not clear at present, hydrogen bonds seem to play
an important role. Thus, the thermally unstable (R)-isomer
had an intramolecular N-H‚‚‚O bond (2.353 Å) (c), whereas
an O-H‚‚‚N bond (2.121 Å) existed in the (S)-isomer (d).
In addition, a 21 helical structure is created along the b-axis
by intermolecular CN‚‚‚HO bonds (2.136 Å) in the (R)-crys-
tals, while no intermolecular hydrogen bond could be found
in the (S)-crystals (a as compared with b). The intramolec-
ular hydrogen bond in the (R)-isomer should increase the
electron density on the amino nitrogen, which will mediate
dissociation of the cyanide anion with the assistance of the
intermolecular hydrogen bond. On the other hand, the intra-
Figure 1. Crystal and molecular structures of (R)-1a (a,c) and (S)-
1a (b,d). Dotted lines indicate intermolecular (a) and intramolecular
hydrogen bonds (c,d).
by using racemic trans-1-aminoindan-2-ol (2), cis-2-ami-
noindan-1-ol (3), and even other optically pure â-amino
alcohols bearing no indan skeleton (4, 510b) as the amine
component (entries 6-9).
To gain insight into the origin of the thermal epimerization,
X-ray crystallographic analysis was carried out. The requisite
diastereomerically pure (S)- and (R)-1a could be isolated
from the mixture by flash chromatography on silica gel after
conversion into O-tert-butyldimethylsilyl ethers. Deprotection
of the hydroxy group, followed by crystallization from
toluene or 2-propanol, gave single crystals of each diaste-
reomer, which were subjected to single-crystal X-ray analysis
(Figure 1).13 The X-ray data nicely simulated the experi-
mental X-ray powder diffraction pattern of a diastereomeric
mixture of 1a, as well as that of (S)-1a obtained by the
epimerization (Figure 2), indicating that the diastereomeric
(13) (R)-1a: monoclinic, space group P21, a ) 10.9347(14), b ) 5.099-
(3), c ) 13.547(2) Å, â ) 109.070(12)°, V ) 713.8(4) Å3, Z ) 2. (S)-1a:
triclinic, space group P1, a ) 5.7296(12), b ) 11.8879(19), c ) 5.0674(8)
Å, R ) 100.472(13), â ) 92.263(16), γ ) 83.228(15)°, V ) 336.98(10)
Å3, Z ) 1.
(14) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.
Org. Lett., Vol. 6, No. 13, 2004
2243

molecular hydrogen bond in the (S)-isomer forms a quater-
nary ammonium salt, the positive charge of which retards
the dissociation of the cyanide anion. As a result, the (R)-
isomer selectively epimerizes to the (S)-counterpart via an
iminium or imine intermediate. Therefore, it may be con-
cluded that the relative stability between the two diastereo-
mers in crystals is strongly affected by the hydrogen bonds,
leading to the enrichment of the more stable diastereomer.
Supporting Information Available: DSC thermogram
of 1a, figure showing de % change of 1a in the solid state,
experimental details and results of the Strecker reaction,
spectral and physical data of compounds 1-5, and CIF data
for (R)- and (S)-1a. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL049256Q
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Org. Lett., Vol. 6, No. 13, 2004