Enantioselective [1,2]-Stevens rearrangement using sugar-derived alkoxides as chiral promoters

Article abstract of DOI:10.1055/s-2008-1032107

The first example of enantioselective base-induced [1,2]-Stevens rearrangement was achieved by using the newly developed D-glucose-derived lithium alkoxide as a chiral promoter. This rearrangement provides an α-amino ketone having a pseudoquaternary chira

Full text of DOI:10.1055/s-2008-1032107

LETTER
683
Enantioselective [1,2]-Stevens Rearrangement Using Sugar-Derived Alkoxides
as Chiral Promoters
E
nantioselective [1
a
,2]-Steven
t
Rearr
s
angementuhiko Tomooka,*a,b Junichiro Sakamaki,b Manabu Harada,b Ryoji Wadab
a
Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-shi, Fukuoka 816-8580, Japan
Fax +81(92)5837810; E-mail: ktomooka@cm.kyushu-u.ac.jp
b
Department of Applied Chemistry, Tokyo Institute of Technology, Meguro-ku, Tokyo 152-8552, Japan
Received 21 December 2007
Dedicated to the memory of the late Professor Yoshihiko Ito who passed away on 23 Dec. 2006
R2
Abstract: The first example of enantioselective base-induced [1,2]-
Stevens rearrangement was achieved by using the newly developed
D-glucose-derived lithium alkoxide as a chiral promoter. This rear-
rangement provides an a-amino ketone having a pseudoquaternary
chiral center in an enantioenriched form.
O
R2
OLi
O
O
R1
O
R'
R
R'
O
H
O
Key words: asymmetric synthesis, amines, carbohydrates, radical
reactions, rearrangements
R1
R
Y
Y
N
R"2N
R"2
X–
O
racemic
enantioenriched
[1,2]-Stevens rearrangement, which involves an 1,2-alkyl
shift from nitrogen to carbon in a quaternary ammonium
ylide system, is one of the most classical anionic rear-
Scheme 2
rangements.1,2 This class of rearrangements has been pro- the exploration of appropriate chiral alkoxides in the reac-
posed to proceed via a radical dissociation–recombination tion involving the classical Stevens’ substrate 1a (R = H)
mechanism, but not in a concerted fashion (Scheme 1).
as a model (Scheme 3).1,7 The reactions were carried out
in a THF solution of 1a in the presence of excess of easily
available chiral alkoxides at 0 °C to room temperature.8,9
However, all the chiral alkoxides 3–6 derived from (S)-a-
phenethyl alcohol,10 (S)-(–)-1,1¢-bi-2-naphthol [(S)-
BINOL],11 (–)-borneol,12 and (–)-norephedrine-derived a-
amino alcohol13 yielded only a racemic 2a (R = H) in poor
yields (Figure 1).14 At this stage, we suspected the possi-
bility of the racemization of 2a, and changed the substrate
from 1a to 1b (R = Me, racemic), which provided 2b with
a pseudoquaternary chiral center.15,16 Not surprisingly, the
reaction of 1b with excess of 6 in THF at 0 °C afforded 2b
in an optically active form, albeit with low enantiopurity
[20% yield, 13% ee (S)].17
R'
R'
R'
R
base
R
R
Y
Y
Y
N
N
R"2N
X–
R"2
R"2
O
O
O
R
R'
Y
R"2N
O
Scheme 1
Despite its long history and significant synthetic potential
as a straightforward approach to chiral amines and a-ami-
no ketones, the development of an enantioselective ver-
sion of the [1,2]-Stevens rearrangement is severely
limited, mainly due to its radical mechanism.2–6
R
Ph
R
Br–
chiral alkoxide
0 °C to r.t.
+
Ph
Ph
Ph
N
N
O
O
1a: R = H
1b: R = Me
2a: R = H
2b: R = Me
We now disclose an efficient enantioselective approach
for the [1,2]-Stevens rearrangement, which has been
achieved by the newly developed D-glucose-derived
alkoxide protocol (Scheme 2).
Scheme 3
OLi
One of the characteristic features of the Stevens rear-
rangement is that the reaction can be promoted by a mild
base such as aqueous alkali. Therefore, we have envisaged
that a chiral alkoxide would be a suitable chiral promoter
for this rearrangement. Our initial efforts were directed to
OLi
Ph
OX
OY
Ph
N
OLi
3
4a: X = Li, Y = H
4b: X,Y = Li
5
6
SYNLETT 2008, No. 5, pp 0683–0686
Advanced online publication: 26.02.2008
x
x.
x
x.
2
0
0
8
Figure 1
DOI: 10.1055/s-2008-1032107; Art ID: U12707ST
© Georg Thieme Verlag Stuttgart · New York

684
K. Tomooka et al.
LETTER
After several attempts using 6, no significant improve-
ment was observed, except for a slightly better result ob-
tained by changing the solvent from THF to toluene [43%
yield, 16% ee (S)]. The absolute stereochemistry of the re-
arrangement product 2b was determined as S by compar-
ing the specific rotation of its alcohol derivative 7 with
that of an authentic sample of (S)-7, which was prepared
from L-alanine-derived oxazolidinone via the Seebach
and Mutter procedure, as shown in Scheme 4.18–20
O
O
OLi
O
O
OLi
O
O
O
O
O
O
8
9
O
O
OLi
O
OLi
O
O
O
O
O
O
O
O
O
3 steps
ref. 19
10
11
a
b
O
O
L-alanine
Ph
Ph
N
O
N
O
Ph
Ph
Ph
Figure 2
i
ii
Ph
ref. 20
OH
Ph
ClH3N
Table 1 [1,2]-Stevens Rearrangement of 1b using Sugar-Derived
Lithium Alkoxide 8–14ba
c, d
e
OMe
N
O
O
Entry
Alkoxide
Yield of 2b (%)b ee (%)c
iii
iv
1
2
3
4
5
6
7
8
57
60
77
46
49
50
91
24 (S)
19 (S)
38 (S)
30 (S)
45 (S)
4 (R)
Ph
N
e
9
Ph
OH Ph
(–)-2b (38% ee)
10
7
11
[α]D28 +94.7 (c 1.1, CHCl3) from L-alanine
[α]D25 +28.3 (c 1.4, CHCl3) from (–)-2b (38% ee)
12b
13b
14b
Scheme 4 Reagents and conditions: (a) LHMDS then BnBr, THF–
DMPU; (b) concd HCl; (c) SOCl2, MeOH; (d) MeI, K2CO3, acetone;
(e) PhLi, THF.
61 (S)
a All the reactions were conducted in toluene solution with alkoxide
(10 equiv) at 0 °C, followed by warming to r.t.
b Isolated yields.
As the abovementioned results indicated the possibility of
a suitable chiral promoter yielding high enantioselectivity
in the reaction providing amino ketones with a stereogenic
pseudoquaternary center, we focused our attention on sug-
ar-derived alkoxides for the construction of an appropriate
chiral environment in this reaction due to their availability
and structural diversity.21 Accordingly, we first examined
a similar reaction of 1b using the easily available D-glu-
cose-derived lithium alkoxide 8 as a chiral promoter
(Figure 2).22 As we expected, the reaction afforded 24%
ee of (S)-2b in moderate yield (Table 1, entry 1).23,24 En-
couraged by this promising result, we next examined the
reaction using a variety of D-glucose-derived lithium
alkoxides 9–11 having two identical bulky acetal moieties
at the 1,2- and 5,6-positions.25 Among them, the alkoxide
10 with cyclohexylidene acetals greatly improved the re-
sult in terms of the reactivity and enantioselectivity (entry
3). The steric congestion due to the acetal moiety in the
chiral promoters possibly has an impact on the efficiency
of the reaction.
c Determined by chiral HPLC analysis using a chiral stationary col-
umn (see ref. 14).
Among the differently protected D-glucose-derived lithi-
um alkoxides examined, 14b with 1,2-cyclohexylidene
and 5,6-diisopropylmethyl groups gave the best results
(91% yield, 61% ee: entry 7).26 It is noteworthy that the
chiral promoters were easily recoverable from the reac-
tion mixture almost quantitatively (>95%) and reusable.
The exact mechanism of the asymmetric induction in the
rearrangement step is unclear at present; a more detailed
study is required.
In summary, we have described the effectiveness of sug-
ar-derived alkoxides as chiral promoters for the enantiose-
lective [1,2]-Stevens rearrangement. This reaction
provides enantioenriched amines having a pseudoquater-
nary chiral center, which are otherwise difficult to obtain.
Thus, this work opens a new chapter in the classical
Stevens chemistry and demonstrates a novel facet of an
ordinary sugar-derived acetal as an efficient chiral pro-
moter. Further work is in progress to strengthen the syn-
thetic potential of asymmetric Stevens rearrangement as
well as the synthetic utility of sugar-derived alkoxides.
Next, we carried out further optimization of the alkoxide
structure by fixing the cyclohexylidene acetal moiety at
the 1,2-position. New alkoxides 12b–14b were prepared
from D-glucose in four steps, as shown in Scheme 5.
Synlett 2008, No. 5, 683–686 © Thieme Stuttgart · New York

LETTER
Enantioselective [1,2]-Stevens Rearrangement
685
OH
OH
OH
O
a
b
c, d
D-glucose
O
ref. 25a
O
Ph
Ph
O
O
O
O
Ph
Ph
OX
O
OX
O
OX
O
O
O
O
O
O
O
O
O
12a: X = H
12b: X = Li
13a: X = H
13b: X = Li
14a: X = H
14b: X = Li
Scheme 5 Reagents and conditions: (a) cyclohexanone, cat. H2SO4, r.t., 29%; (b) AcOH–H2O (2:1), r.t., 65%; (c) corresponding ketone, tri-
methyl formate, cat. TsOH, r.t. to 60 °C, 12a: 65%, 13a: 68%, 14a: 81%; (d) n-BuLi, toluene, 0 °C.
using copper(I) complex, see: Nozaki, H.; Takaya, H.;
Acknowledgment
Moriuti, S.; Noyori, R. Tetrahedron 1968, 24, 3655. For
This research was supported in part by a Grant-in-Aid for Scientific
representative studies using dirhodium(II) complex, see:
Research on Priority Areas (A) ‘Creation of Biologically Functional
(b) Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Tedrow, J. S.
Molecules’ and Basic Area (B) (No. 14350473) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
Tetrahedron Lett. 1997, 38, 4367. (c) Kitagaki, S.;
Yanamto, Y.; Tsutsui, H.; Anada, M.; Nakajima, M.;
Hashimoto, S. Tetrahedron Lett. 2001, 42, 6361.
(7) All the ammonium salts were prepared from the
References and Notes
corresponding a-amino ketones and alkyl bromides and
purified by recrystallization.
(1) Stevens, T. S.; Creighton, E. M.; Gordon, A. B.; MacNicol,
M. J. Chem. Soc. 1928, 3193.
(8) Alkoxides were prepared from the corresponding alcohols
using n-BuLi (1 equiv) at 0 °C.
(9) For a review of asymmetric synthesis using chiral alkoxide,
see: Plaquevent, J.-C.; Perrard, T.; Cahard, D. Chem. Eur. J.
2002, 8, 3300.
(10) Alkoxide 3 has been utilized as a chiral ligand for
asymmetric Michael reaction. See: Kumamoto, T.; Aoki, S.;
Nakajima, M.; Koga, K. Tetrahedron: Asymmetry 1994, 5,
1431.
(11) Alkoxide 4 has been utilized as a chiral promoter for
asymmetric hydrocyanation reaction. See: (a) Holmes, I. P.;
Kagan, H. B. Tetrahedron Lett. 2000, 41, 7453.
(b) Holmes, I. P.; Kagan, H. B. Tetrahedron Lett. 2000, 41,
7457. (c) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K.
J. Am. Chem. Soc. 2005, 127, 10776.
(2) For reviews, see: (a) Schöllkopf, U. Angew. Chem. 1970, 82,
795. (b) Markó, I. E. In Comprehensive Organic Synthesis,
Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
1991, 913–974. (c) Vanecko, J. A.; Wan, H.; West, F. G.
Tetrahedron 2006, 62, 1043.
(3) For mechanistic studies of [1,2]-Stevens rearrangement,
see: (a) Millard, B. J.; Stevens, T. S. J. Chem. Soc. 1963,
3397. (b) Schöllkopf, U.; Ludwig, U.; Ostermann, G.;
Patsch, M. Tetrahedron Lett. 1969, 10, 3415. For
theoretical studies of [1,2]-Stevens rearrangement, see:
(c) Heard, G. L.; Frankcombe, K. E.; Yates, B. F. Aust. J.
Chem. 1993, 46, 1375. (d) Heard, G. L.; Yates, B. F. Aust. J.
Chem. 1994, 47, 1685.
(4) (a) Recently, Somfai and co-workers reported the first
example of enantioselective [2,3]-Stevens rearrangement of
allylic ammonium ylide using chiral Lewis acid promoter:
Blid, J.; Panknin, O.; Somfai, P. J. Am. Chem. Soc. 2005,
127, 9352. (b) Also, the concomitantly occurred
(12) Alkoxide 5 has been utilized as a chiral initiator for
asymmetric polymerization. See: Okamoto, Y.; Matsuda,
M.; Nakano, T.; Yashima, E. J. Polym. Sci., Part A: Polym.
Chem. 1994, 32, 309.
(13) Alkoxide 6 has been utilized as a chiral base for asymmetric
elimination and chiral ligand for asymmetric alkynylation.
See: (a) Soai, K.; Yokoyama, S.; Hayasaka, T. J. Org. Chem.
1991, 56, 4264. (b) Thompson, A. S.; Corley, E. G.;
Huntington, M. F.; Grabowski, E. J. J. Tetrahedron Lett.
1995, 36, 8937.
(14) HPLC analysis was carried out on a Chiralcel OD-H column
(0.46 × 25 cm) using hexane–i-PrOH (150:1; 0.5 mL/min) as
the mobile phase.
enantioselective [1,2]-Stevens rearrangement has been
reported therein.
(5) Asymmetric [1,2]-Stevens rearrangement using
enantioenriched ammonium ylide has been reported. For the
rearrangement with chiral migrating group, see:
(a) Campbell, A.; Houston, A. H. J.; Kenyon, J. J. Chem.
Soc. 1947, 93. (b) Brewster, J. H.; Kline, M. W. J. Am.
Chem. Soc. 1952, 74, 5179. (c) Joshua, H.; Gans, R.;
Mislow, K. J. Am. Chem. Soc. 1968, 90, 4884.
(15) A rapid racemization of a similar chiral a-amino ketone
under weakly basic conditions had been observed; see ref.
5e.
(d) Brewster, J. H. J. Org. Chem. 1969, 354. (e) Harada,
M.; Nakai, T.; Tomooka, K. Synlett 2004, 365. For the
rearrangement with nitrogen chiral center, see: (f) Glaeske,
K. W.; West, F. G. Org. Lett. 1999, 1, 31. (g) Tayama, E.;
Nanbara, S.; Nakai, T. Chem. Lett. 2006, 35, 478.
(6) Enantioselective [1,2]-Stevens rearrangement of oxonium
ylide generated from a diazo compound using a chiral metal
complex has been developed: (a) For a representative study
(16) All the compounds were characterized by 1H and 13C NMR
analyses. Data for selected products are as follows. 1b: 1H
NMR (300 MHz, CDCl3): = 8.48 (d, J = 7.5 Hz, 2 H), 7.50–
7.70 (m, 8 H), 6.88 (q, J = 7.2 Hz, 1 H), 5.29 (d, J = 12.0 Hz,
1 H), 5.06 (d, J = 12.0 Hz, 1 H), 3.42 (s, 3 H), 3.34 (s, 3 H),
Synlett 2008, No. 5, 683–686 © Thieme Stuttgart · New York

686
K. Tomooka et al.
LETTER
(22) Synthesis and structural study of alkoxide 8 has been
1.79 (d, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): =
196.8, 135.4, 134.0, 133.6, 131.0, 129.9, 129.5, 129.3,
126.7, 69.4, 66.5, 48.1, 47.0, 14.1. 2b: 1H NMR (300 MHz,
CDCl3): = 8.46 (d, J = 6.9 Hz, 2 H), 6.90–7.50 (m, 8 H), 3.46
(d, J = 12.3 Hz, 1 H), 2.96 (d, J = 12.3 Hz, 1 H), 2.36 (s, 6
H), 1.18 (s, 3 H). 13C NMR (75 MHz, CDCl3): d = 203.1,
137.7, 137.6, 132.5, 130.9, 130.5, 128.3, 128.1, 126.5, 72.2,
41.2, 39.0, 14.5. 14: 1H NMR (300 MHz, acetone-d6): = 5.83
(d, J = 3.6 Hz, 1 H), 4.48 (d, J = 3.6 Hz, 1 H), 4.38 (ddd, J =
6.6, 6.6, 8.4 Hz, 1 H), 4.16 (d, J = 2.7 Hz, 1 H), 4.12 (dd, J =
2.7, 6.6 Hz, 1 H), 4.10 (dd, J = 6.6, 8.1 Hz, 1 H), 3.80 (dd,
J = 8.1, 8.4 Hz, 1 H), 2.82 (s, 1 H), 1.90–2.10 (m, 2 H), 1.40–
1.60 (m, 10 H), 0.90 (s, 3 H), 0.90 (s, 3 H), 0.88 (s, 3 H), 0.87
(s, 3 H). 13C NMR (75 MHz, CDCl3): = 117.2, 112.7, 105.2,
84.6, 82.1, 75.6, 75.0, 71.2, 36.4, 35.6, 34.4, 33.7, 24.8, 23.8,
23.4, 17.4, 17.2.
reported. See: (a) Piarulli, U.; Williams, D. N.; Floriani, C.;
Gervasio, G.; Viterbo, D. J. Chem. Soc., Chem. Commun.
1994, 1409. (b) Piarulli, U.; Williams, D. N.; Floriani, C.;
Gervasio, G.; Viterbo, D. J. Chem. Soc., Chem. Commun.
1995, 3329.
(23) Significant countercation-effect for enantioselectivity was
observed, i.e., the reaction using the corresponding K or Na
alkoxide of 8 afforded only the racemic 2b in moderate
yields.
(24) The enantioselectivity significantly decreased (18% ee),
when one equivalent of 8 was used.
(25) The corresponding alcohols of 10, 11, and 13 have been
reported: (a) For 10, see: Einhorn, C.; Luche, J. Carbohydr.
Res. 1986, 155, 258. (b) For 11, see: Luboradzki, R.;
Pakulski, Z.; Sartowska, B. Tetrahedron 2005, 61, 10122.
(c) For 13, see: Mereyala, H. B.; Kodyry, S. R.;
Cheemalapati, V. N. Tetrahedron: Asymmetry 2006, 17,
259.
(26) Typical Experimental Procedure: To a solution of 1,2-O-
cyclohexylidene-5,6-O-(diisopropyl)methylidene-a-D-
glucofuranose (14a; 104 mg, 0.29 mmol) in anhyd toluene (2
mL), was added a solution of n-BuLi (0.21 mL of 1.37 M
solution in hexane, 0.29 mmol) at 0 °C. After stirring for 30
min at that temperature, benzyldimethyl(a-methylphen-
acyl)ammonium bromide (1b; 10.0 mg, 0.029 mmol) was
added. Then, the temperature of the resulting solution was
allowed to rise to r.t. and the mixture was stirred for 8 h. The
reaction was quenched with pH 7 phosphate buffer, and the
product was extracted with EtOAc. The combined organic
layers were washed with brine, dried over MgSO4, filtered,
and the solvent was removed in vacuo. The residue was
purified by silica gel chromatography to afford the a-amino
ketone (S)-2b (7.0 mg, 91%, 61% ee) and recovered 14a
(103 mg, 99%).
(17) Similar reactions using alkoxides 3–5 afforded racemic 2b in
16–29% yields.
(18) (a) Seebach, D.; Naef, R. Helv. Chim. Acta 1981, 64, 2704.
(b) Beck, A. K.; Seebach, D. Chimia 1988, 42, 142.
(19) Nebel, K.; Mutter, M. Tetrahedron 1988, 44, 4793.
(20) Absolute stereochemistry of iii was confirmed by the
comparison of the specific rotation of its free amine with the
reported value. See: Karady, S.; Amato, J. S.; Weinstock, L.
M. Tetrahedron Lett. 1984, 25, 4337.
(21) For representative studies on asymmetric synthesis using
sugar derivatives as chiral auxiliary, see: (a) Kunz, H.;
Mohy, J. J. Chem. Soc., Chem. Commun. 1988, 1315.
(b) Kakinuma, K.; Li, H.-Y. Tetrahedron Lett. 1989, 31,
4157. (c) Tomooka, K.; Nakamura, Y.; Nakai, T. Synlett
1995, 321. (d) Kishida, M.; Eguchi, T.; Kakinuma, K.
Tetrahedron Lett. 1996, 37, 2061. (e) For a representative
study on asymmetric synthesis using sugar derivatives as
chiral ligand, see: Riediker, M.; Duthaler, R. O. Angew.
Chem., Int. Ed. Engl. 1989, 28, 494.
Synlett 2008, No. 5, 683–686 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.