Formation and reaction of 2-metalated N-Boc-4,4-dimethyl-1,3- oxazolidines in the presence of (-)-sparteine: New chiral formyl anion equivalents

Article abstract of DOI:10.1016/S0957-4166(98)00319-X

Lithiation of N-Boc-4,4-dimethyl-1,3-oxazolidine with s-BuLi and the following reaction with benzaldehyde was carried out in the presence of (-)- sparteine. The reaction was not diastereoselective (syn:anti=46:54), but each isomer of the adducts was obtai

Full text of DOI:10.1016/S0957-4166(98)00319-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3125–3128
Formation and reaction of 2-metalated N-Boc-4,4-dimethyl-1,3-
oxazolidines in the presence of (−)-sparteine: new chiral formyl
anion equivalents
Naoki Kise,∗,† Tadashi Urai and Jun-ichi Yoshida ∗
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Yoshida,
Sakyo, Kyoto 606-01, Japan
Received 23 July 1998; accepted 5 August 1998
Abstract
Lithiation of N-Boc-4,4-dimethyl-1,3-oxazolidine with s-BuLi and the following reaction with benzaldehyde
was carried out in the presence of (−)-sparteine. The reaction was not diastereoselective (syn:anti=46:54), but
each isomer of the adducts was obtained enantioselectively (syn: 90% ee, anti: 88% ee). Addition of MgBr2 to
the reaction mixture increased the diastereoselectivity to syn:anti=90:10. © 1998 Elsevier Science Ltd. All rights
reserved.
Chiral formyl anion equivalents are useful reagents for asymmetric homologation of aldehydes.
Although a variety of chiral formyl anion equivalents have been developed so far, these are based on chiral
pool and chiral auxiliary methods employing chiral derivatives of dithioacetals,1,2 hemithioacetals,3 1,3-
dioxolanes,4 and 1,3-oxazolidines.5 On the other hand, chiral ligand methods with (−)-sparteine have
recently been reported for formation of chiral anions adjacent to oxygen6,7 and nitrogen atoms.8–10
We report herein 2-metalation of N-Boc-4,4-dimethyl-1,3-oxazolidine 1 and subsequent reaction with
benzaldehyde in the presence of (−)-sparteine (Scheme 1). To our knowledge, this is the first example of
chiral formyl anion equivalents based on chiral external ligand methodology.
Scheme 1.
∗
†
Corresponding authors. E-mail: kise@bio.tottori-u.ac.jp
Present address: Naoki Kise, Department of Biotechnology, Faculty of Engineering, Tottori University, Tottori 680, Japan.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00319-X
tetasy 2468 Article

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N. Kise et al. / Tetrahedron: Asymmetry 9 (1998) 3125–3128
Table 1
Diastereoselective addition of 2 to benzaldehyde
First, we examined formation of 2-lithiated N-Boc-4,4-dimethyl-1,3-oxazolidine 2 (M=Li) and its
reaction with benzaldehyde (Table 1, entry 1). Treatment of 1‡ with 1.2 equiv. of s-BuLi at −78°C in
THF for 3 h followed by addition of benzaldehyde (1.2 equiv.) gave the adduct 3 with a 47:53 (syn:anti)
dr (diastereomeric ratio) in 78% yield. Use of Et2O as a solvent and addition of TMEDA (1.2 equiv.)
did not improve the dr of 3 (entries 2 and 3). Addition of MgBr2 (1.2 equiv.) to the reaction mixture,
however, increased the dr (syn:anti) to 90:10 (entry 4).
The stereochemistry of each diastereomer of 3 was determined by 1H NMR spectrum analysis of cyclic
carbamate 4, prepared from 3 by refluxing with NaH in THF for 30 min (Scheme 2). The isomer showing
the larger coupling constant and NOE between Ha and Hb is assigned to be cis-4.11
Scheme 2.
Next, we carried out lithiation of 1 and the following reaction of 2 (M=Li) with benzaldehyde in the
presence of (−)-sparteine in Et2O (Table 2, entry 1). The adduct 3 was obtained with a 46:54 (syn:anti) dr
in 71% yield. The ee values were determined to be 90 and 88% for syn- and anti-3, respectively, by chiral
HPLC analysis. The absolute configurations of each isomer of 3 were confirmed to be 1’S,2R for syn and
1’R,2R for anti by their conversion to known alcohols 6: lit.12 [α]25 −53.9 (c 1.5, CHCl3) for (R)-6
D
1
(Scheme 3). The ee values of 6 were measured by H NMR analysis with Eu(hfc)3 and demonstrated
‡
N-Boc-4,4-dimethyl-1,3-oxazolidine (1) was prepared from the reaction of 2-amino-2-methyl-1-propanol with formaldehyde
and subsequent treatment with di-tert-butyldicarbonate and DMAP in 48% yield (two steps).

N. Kise et al. / Tetrahedron: Asymmetry 9 (1998) 3125–3128
3127
Table 2
Enantioselective addition of 2 to benzaldehyde
that only marginal racemization occurred during hydrolysis and reduction steps. Addition of MgBr2
to the reaction mixture remarkably increased the dr (syn:anti=90:10) in a similar manner to the above
results, but slightly decreased the ee of each isomer (entry 2). The experimental procedure is as follows.
To a solution of (−)-sparteine (0.56 g, 2.4 mmol) in Et2O (5 mL) at −78°C was added a solution of
1.0 M s-BuLi in cyclohexane (2.4 mL, 2.4 mmol). After stirring for 10 min, a solution of 1 (403 mg,
2.0 mmol) in Et2O (2 mL) was added at −78°C and the reaction mixture was stirred for 3 h. To the
mixture were added THF (5 mL) and a solution of freshly prepared MgBr213 (2.4 mmol) in Et2O (3 mL)
successively at −78°C. The mixture was allowed to warm to 0°C, stirred for 30 min at this temperature,
and then recooled to −78°C. Benzaldehyde (0.24 mL, 2.4 mmol) was added dropwise to the mixture.
After stirring for an additional 3 h at −78°C, the mixture was allowed to reach 25°C. The mixture was
quenched with H2O (20 mL) and extracted with Et2O (3×10 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on
silica gel (hexane:EtOAc=10:1) to give syn-3 (371 mg) and anti-3 (41 mg) as colorless oils (67% yield).
Each isomer gave satisfactory spectroscopic data and elemental analysis: syn-3 (86% ee): [α]20 +87.1
D
(c=1.16, CHCl3); anti-3 (83% ee): [α]20D +73.2 (c=1.05, CHCl3).
Scheme 3.

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N. Kise et al. / Tetrahedron: Asymmetry 9 (1998) 3125–3128
The reaction of 2 with benzaldehyde proceeds with high stereoselectivity to give the 2R configuration
of adducts 3. According to previous studies,6–10 it is likely that asymmetric deprotonation of 1 with s-
BuLi/(−)-sparteine forms (R)-2 and the following addition to benzaldehyde takes place with retention
of stereoconfiguration at the C-2 position selectively. The high diastereoselectivity in the reaction of
magnesium salts cannot be explained clearly. Their reaction mechanisms seem to be different from that
of lithium salts as mentioned by Gawley.14
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