Asymmetric [1,2] Stevens rearrangement of (S)-N-benzylic proline-derived ammonium salts under biphasic conditions

Article abstract of DOI:10.1246/cl.2006.478

The Stevens rearrangement of (S)-N-benzylic proline-derived ammonium salt with cesium hydroxide in 1,2-dichloroethane is shown to proceed with a high degree of the N-to-C chirality transmission to afford the α-substituted proline derivatives in high enantio-purities. Copyright

Full text of DOI:10.1246/cl.2006.478

478
Chemistry Letters Vol.35, No.5 (2006)
Asymmetric [1,2] Stevens Rearrangement of (S)-N-Benzylic Proline-derived Ammonium Salts
under Biphasic Conditions
Eiji Tayama,ꢀ Shintaro Nanbara, and Takeshi Nakai
Graduate School of Science and Technology, Niigata University, Niigata 950-2181
(Received January 25, 2006; CL-060110; E-mail: tayama@gs.niigata-u.ac.jp)
The Stevens rearrangement of (S)-N-benzylic proline-de-
rived ammonium salt with cesium hydroxide in 1,2-dichloro-
ethane is shown to proceed with a high degree of the N-to-C chi-
rality transmission to afford the ꢀ-substituted proline derivatives
in high enantio-purities.
CO2But
Ph
t-BuOK
(1.5 eq)
LiAlH4
THF
0 °C to rt
OH
Ph
(R)-6a
CO2But
Ph
N
N
N
THF
rt, 1.5 h
I
3 h, >70%
(1S)-4a
(R)-5a
80%, 72% ee
Scheme 2. Asymmetric [1,2] Stevens rearrangement using t-
BuOK.
The [1,2] Stevens rearrangement of ammonium ylides is a
useful transformation for organic synthesis since it converts a
readily accessible C–N bond into a new C–C bond and hence
has found applications for synthesis of ꢀ-amino acids and ke-
tones.1 However, its asymmetric versions remains largely unex-
plained probably because the rearrangement proceeds via the
radical cleavage–recombination mechanism, thus leading to
low stereoselectivities.2 We became particularly interested in
the asymmetric version which involves the transmission of a ni-
trogen-centered chirality to the newly-formed carbon-centered
chirality. Recently, West et al. have reported that the Stevens re-
arrangement of the (1S,2S)-N-benzylproline methyl ester–de-
rived ammonium salt [(1S)-1] proceeds with a moderate level
(54%) of the N-to-C chirality transmission (Eq 1).3 Herein, we
wish to report that this type of the [1,2] Stevens rearrangement,
when performed under a proper biphasic condition, exhibits a re-
markably enhanced level of the chirality transmission to afford
the ꢀ-substituted proline derivatives in high enantio-purities.4
was obtained in 80% yield and its enantio-purity was determined
to be 72% ee by chiral HPLC analysis of the amino alcohol 6a
prepared by reduction of 5a with LiAlH4 (Scheme 2).7 The
(R)-configuration of the major product isomer was determined
by comparison of the HPLC retention time of 6a with the authen-
tic sample prepared by reduction of the known methyl ester (R)-2
with LiAlH4.3 The observed degree of chirality transmission,
albeit significantly higher than that reported for the methyl ester
(1S)-1, is still unsatisfactory. In order to further improve the
stereoselectivity, we next attempted the application of biphasic
conditions to the present rearrangement. Thus, we carried out
the rearrangement of 4a under the liquid–liquid biphasic condi-
tion using a 50% aqueous KOH solution and dichloromethane
(3:1 vol %) (Table 1, Entry 1). While the selectivity was slightly
improved to 86% ee, the yield was lowered (45%). Significantly,
however, application of the solid–liquid biphasic condition using
KOH (powder, 5 equiv.) and dichloromethane was found to pro-
vide a notably enhanced selectivity (94% ee), although the yield
was still moderate (Entry 2). Interestingly, use of CsOH (solid, 5
equiv.) in the place of KOH provided an increased yield (88%),
together with a slightly lower % ee (Entry 3). The best result was
obtained by using CsOH as a base and 1,2-dichloroethane as a
solvent to afford 73% yield and 92% ee (Entry 4).8
CO2Me
t-BuOK
THF
rt, 1.5 h
(73%)
CO2Me
Ph
(1S)-1 (100% de)
(1)
N
N
Ph
I
(R)-2 (54% ee)
For this study, we employed (S)-N-benzyl-N-methylproline
t-butyl ester–derived ammonium salt [(1S)-4a] as the ylide pre-
cursor to avoid hydrolysis during the rearrangement under aque-
ous conditions. The requisite precursor (1S)-4a was prepared in
diastereomerically pure form from (S)-N-benzylproline ester 3a5
via quaternarization with methyl iodide followed by recrystalli-
zation (Scheme 1).6 The (1S)-configuration was assigned by the
similarity of the NMR spectrum to that of (1S)-1.3
With the optimized biphasic procedure in hand, we carried
out the rearrangements of several other N-(arylmethyl)proline
Table 1. Asymmetric [1,2] Stevens rearrangement under bipha-
sic conditions
CO2But
base
solvent
−10 °C, 24 h
CO2But
First, we examined the rearrangement of (1S)-4a using
West’s conditions (t-BuOK, THF, rt). The Stevens product 5a
N
N
Ph
(R)-5a
Ph
I
(1S)-4a
Yielda
/%
eeb
/%
MeI
CO2But
CO2But
Ph
Entry
Base
Solvent
N
N
CH3CN
reflux
92%
I
1
2
3
4
50% aq. KOH
KOH powderc
CsOH solidc
CsOH solidc
CH2Cl2
CH2Cl2
CH2Cl2
45
52
88
73
86
94
84
92
Ph
3a
4a: (1S)/(1R) = 87:13
recrystallization
CO2But
N
hexane−CH2Cl2
ClCH2CH2Cl
78%
Ph
(1S)-4a
I
aDetermined by 1H NMR assay using mesitylene as an inter-
nal standard. bDetermined by chiral HPLC analysis of 6a. c5
equiv. was used.
Scheme 1. Preparation of ammonium salt (1S)-4a.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.5 (2006)
479
Table 2. CsOH-induced asymmetric [1,2] Stevens rearrange-
ment
References and Notes
1
For reviews see: a) J. A. Vanecko, H. Wan, F. G. West,
´
Tetrahedron 2006, 62, 1043. b) I. E. Marko, in Comprehen-
sive Organic Synthesis, ed. by B. M. Trost, I. Fleming, Perga-
mon, Oxford, 1991, Vol. 3, Chap. 3.10.
CO2But
CsOH (5 equiv.)
CO2But
N
N
1,2-dichloroethane
Ar
(R)-5
Ar
I
−10 °C, 24 h
2
a) R. K. Hill, T. H. Chan, J. Am. Chem. Soc. 1966, 88, 866.
b) W. D. Ollis, M. Rey, I. O. Sutherland, J. Chem. Soc., Per-
kin Trans. 1 1983, 1009.
(1S)-4
Entry
Ar
Product
Yield/%a
ee/%b
3
4
K. W. Glaeske, F. G. West, Org. Lett. 1999, 1, 31.
For preparations of ꢀ-substituted proline derivatives, see:
a) T. Kawabata, S. Kawakami, S. Majumdar, J. Am. Chem.
Soc. 2003, 125, 13012. b) V. Ferey, P. Vedrenne, L. Toupet,
T. L. Gall, C. Mioskowski, J. Org. Chem. 1996, 61, 7244, and
references therein.
1
2
3
4c
4-Me-Ph
4-MeO-Ph
4-F-Ph
b
c
d
77
56
69
42d
84
86
90
>99
4-tBuOCOPh
e
aDetermined by 1H NMR assay using mesitylene or diphenyl-
methane as an internal standard. bDetermined by chiral
HPLC analysis after reduction of 5 with LiAlH4. cPerformed
at 0 ꢁC. dt-Butyl p-toluate was isolated in 55% yield.
5
6
Prepared from Cbz-L-proline in three steps: (i) isobutene, cat.
H2SO4, CH2Cl2, rt. (ii) H2 (1 atm), 10% Pd–C, EtOAc, rt. (iii)
PhCH2Cl, NaHCO3, CH3CN, reflux. Other substrates (3b–
3e) were prepared by the same procedure using the corre-
sponding benzylic chloride or bromide in step (iii).
Spectroscopic data; (1S, 2S)-N-benzyl-N-methylproline am-
Me
CO2But
CO2But
N
25
monium salt (1S)-4a; mp 155–156 ꢁC; ½ꢀꢂD ¼ ꢃ20:2ꢁ
(R)-5
N
Me
on (R)-face
(c ¼ 1:00, MeOH); 1H NMR (270 MHz, CDCl3) ꢁ 7.69–
7.65 (m, 2H, Ph), 7.53–7.42 (m, 3H, Ph), 5.41 (d, 1H,
J ¼ 12:7 Hz, CH2Ph), 5.22 (dd, 1H, J ¼ 10:5, 9.2 Hz,
CHCO2But), 5.12 (d, 1H, J ¼ 12:7 Hz, CH2Ph), 4.76 (ddd,
1H, J ¼ 10:5, 10.5, 10.5 Hz, 5-H), 3.46 (ddd, 1H, J ¼ 10:5,
8.4, 1.9 Hz, 5-H), 3.08 (s, 3H, CH3), 2.81–2.68 (m, 1H, 3-
or 4-H), 2.39–2.19 (m, 2H, 3- or 4-H), 2.09–1.95 (m, 1H,
.
CH2Ar
"solvent cage"
Ar
[outside the solvent cage]
(S)+(R)-5
Scheme 3. Pathways of the chirality transmission.
ammonium salts 4b–4e which were prepared in stereo-pure form
in the same way as described for 4a.9 As shown in Table 2, these
rearrangements afforded the corresponding ꢀ-(arylmethyl)-
proline t-butyl esters (5b–5d) with 84–90% ee in reasonable
yields except for the case of 4e where 5e was obtained as an
almost single enantiomer in only 42% yield, together with a
considerable amount of t-butyl p-toluate (Entry 4).
The question arises as to why the solid–liquid biphasic
condition provides such a remarkably enhanced % ee. While
the exact reason cannot be advanced at present, it is safe to
say that under the biphasic conditions, the recombination of
the radical pair initially formed from the N-ylide occurs more
rapidly in a solvent cage and hence more preferentially in the
retentive fashion (on the bottom side) to give an enhanced %
ee (Scheme 3). In other words, the recombination outside the
solvent cage leading to a decrease in % ee would be suppressed
under the biphasic conditions. The stability of the benzylic radi-
cal involved might be another factor in dictating the % ee. The
more unstable benzylic radical involved is, the more rapidly
the recombination would occur inside the solvent cage,
thus leading to a higher % ee as actually observed in Entry 4
(Table 2), although the p-(t-butoxycarbonyl)benzyl radical is
so reactive (unstable) and hence abstracts a hydrogen leading
to the formation of t-butyl p-toluate as a by-product.
t
3- or 4-H), 1.54 (s, 9H, Bu); 13C NMR (68 MHz, CDCl3) ꢁ
164.8, 132.5, 130.7, 129.2, 127.5, 85.7, 71.9, 65.9, 63.8,
44.0, 28.0, 24.6, 18.4; IR (KBr) 1744, 1148 cmꢃ1; Anal. calcd
for C17H26INO2: C, 50.63; H, 6.50; N, 3.47%. Found: C,
50.79; H, 6.61; N, 3.51%.
7
8
Similar rearrangements at 0 and ꢃ10 ꢁC gave 5a with 80% ee
(71% yield) and 84% ee (91% yield), respectively.
Reaction procedure: To a solution of (1S)-4a (180 mg,
0.447 mmol) in 1,2-dichloroethane (5 mL) was added CsOH
(0.37 g, 2.5 mmol) in one portion at ꢃ10 ꢁC under a nitrogen
atmosphere. After stirring for 24 h at the same temperature,
the resulting mixture was diluted with H2O and extracted
with Et2O. The combined extracts were washed with brine,
dried over Na2SO4 and concentrated. The yield of (R)-5a
was determined by 1H NMR spectroscopy of the crude
product using mesitylene as an internal standard (73% yield).
The pure (R)-5a was obtained after chromatography on silica
gel (Hex/EtOAc = 20:1 as eluent) as a colorless oil (84.1
22
mg, 68% yield). ½ꢀꢂ ¼ 8:4ꢁ (c ¼ 1:00, EtOH); 1H NMR
(270 MHz, CDCl3) ꢁD7.27–7.15 (m, 5H, Ph), 3.27 (d, 1H,
J ¼ 13:2 Hz, CH2Ph), 3.06–2.99 (m, 1H, 5-H), 2.65 (d, 1H,
J ¼ 13:2 Hz, CH2Ph), 2.70–2.58 (m, 1H, 5-H), 2.46 (s, 3H,
CH3), 2.06–1.93 (m, 1H, 3- or 4-H), 1.81–1.53 (m, 3H, 3-
t
and 4-H), 1.45 (s, 9H, Bu); 13C NMR (68 MHz, CDCl3) ꢁ
171.9, 138.0, 130.3, 127.6, 126.0, 80.9, 71.4, 54.4, 40.5,
35.5, 33.8, 28.4, 21.6; IR (film) 1714, 1160 cmꢃ1; Anal. calcd
for C17H25NO2: C, 74.14; H, 9.15; N, 5.09%. Found: C,
74.23; H, 9.39; N, 5.11%. The ee was determined to be
92% ee by chiral HPLC analysis of the amino alcohol 6a
which prepared by reduction of (R)-5a with LiAlH4 in THF
[Daicel CHIRALPAK AD-H, Hex/EtOH = 85:15, 0.50
mL/min, tR ¼ 15:7 min for the (S)-isomer and 18.4 min for
the (R)-isomer].
In summary, we demonstrated that the [1,2] Stevens rear-
rangement of the (S)-N-benzylic proline-derived ammonium
salts, when carried out under the solid–liquid biphasic condi-
tions, exhibits a remarkably high level of the N-to-C chirality
transmission to afford the corresponding ꢀ-arylmethyl-substitut-
ed proline derivatives in high enantio-purities. Further works on
other asymmetric Stevens rearrangements are underway.
This work was financially supported by the Uchida Energy
Science Promotion Foundation.
9
Recrystallization solvents: Hex/CH2Cl2 for 4b and 4d,
Hex/THF for 4c, and Hex/CH2Cl2/PhH for 4e.
Published on the web (Advance View) April 1, 2006; DOI: 10.1246/cl.2006.478