Diastereoselective alkylation and aldol reactions mediated by the D-mannitol-derived oxazolidin-2-one as a chiral auxiliary

Article abstract of DOI:10.1081/SCC-120015404

Chiral N-acylated oxazolidin-2-ones readily available from D-mannitol have been demonstrated to undergo highly diastereoselective alkylation reactions via their lithium imide Z-enolates to afford α-branched products. Evans syn and non-Evans syn aldol products were also selectively obtained using this new auxiliary in high diastereomeric purity by simply changing the stoichiometry of TiCl₄ and the nature of the amine base.

Full text of DOI:10.1081/SCC-120015404

This article was downloaded by: [Flinders University of South Australia]
On: 05 October 2014, At: 00:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
DIASTEREOSELECTIVE ALKYLATION AND ALDOL
REACTIONS MEDIATED BY THE d-MANNITOL-DERIVED
OXAZOLIDIN-2-ONE AS A CHIRAL AUXILIARY
Si-Min Kim a & Jong-Gab Jun b
a Department of Chemistry , Hallym University , Chunchon, 200-702, Republic of Korea
b Department of Chemistry , Hallym University , Chunchon, 200-702, Republic of Korea
Published online: 23 Aug 2006.
To cite this article: Si-Min Kim & Jong-Gab Jun (2002) DIASTEREOSELECTIVE ALKYLATION AND ALDOL REACTIONS MEDIATED BY
THE d-MANNITOL-DERIVED OXAZOLIDIN-2-ONE AS A CHIRAL AUXILIARY, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:24, 3851-3863, DOI: 10.1081/SCC-120015404
To link to this article: http://dx.doi.org/10.1081/SCC-120015404
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONS
Vol. 32, No. 24, pp. 3851–3863, 2002
DIASTEREOSELECTIVE ALKYLATION
AND ALDOL REACTIONS MEDIATED BY
THE D-MANNITOL-DERIVED
OXAZOLIDIN-2-ONE AS A
CHIRAL AUXILIARY
*
Si-Min Kim and Jong-GabJun
Department of Chemistry, Hallym University,
Chunchon 200-702, Republic of Korea
ABSTRACT
Chiral N-acylated oxazolidin-2-ones readily available from
D-mannitol have been demonstrated to undergo highly dia-
stereoselective alkylation reactions via their lithium imide
Z-enolates to afford a-branched products. Evans syn and
non-Evans syn aldol products were also selectively obtained
using this new auxiliary in high diastereomeric purity by
simply changing the stoichiometry of TiCl4 and the nature of
the amine base.
Key Words: Oxazolidin-2-one; D-mannitol; Alkylation;
Aldol reaction
*Corresponding author. E-mail: jgjun@hallym.ac.kr
3851
DOI: 10.1081/SCC-120015404
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3852
KIM AND JUN
The chiral enolate alkylation and aldol reactions employing chiral
oxazolidin-2-one have been widely used and well documented in fundamen-
tal carbon–carbon bond forming reactions since pioneered by Evans.[1]
Many sources for oxazolidin-2-one structure were known, however, the
preparative access to chiral auxiliary is quite difficult because enantio-
merically pure amino alcohols are required.[2] We report herein the diaste-
reoselective alkylation reactions using a new chiral oxazolidin-2-one derived
from a cheap D-mannitol.
3-Amino-3-deoxy-1,2 : 5,6-di-O-isopropylidene-D-altritol (1)[3] obtained
from D-mannitol served as a chiral amino alcohol for the synthesis of
(4S,5R)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-2-one(2).DMAP-
catalyzed reaction[4] of amino alcohol 1 with di-tert-butyl dicarbonate,
(Boc)2O, for the oxazolidinone synthesis gave only 41.2% yield. The reac-
tion yield was improved to 91% by using diethyl carbonate with sodium
methoxide.[5] The N-acylated derivatives 3a–c were easily prepared in high
yield by reaction of auxiliary 2 with acyl chlorides a–c using butyllithium
in THF at ꢀ60ꢁC (Sch. 1). The crystalline N-acylated substrates were
recrystallized from hexane.
The lithium enolate of the N-acyl derivative 3a was formed in THF
by addition at ꢀ60ꢁC of lithium diisopropylamide, LDA, (1.5 equiv. solu-
tion in THF). After benzyl bromide was added, the mixture was stirred for
2 h at ꢀ40ꢁC. The reaction was quenched by addition of water at ꢀ0ꢁC
and the crude product 4A was extracted with ethyl acetate. The non
crystalline product 4A was purified by flash column chromatography on
silica gel and obtained in 95.5% yield with a diastereoisomeric excess of
1
94.0% which was determined by 400 MHz H NMR spectroscopic analysis
with the relative configurations being assigned after removal of the
auxiliary, as described below (Sch. 2). The enolization of imide 3 with
LDA is known to generate a Z-enolate exclusively,[6] because the corres-
ponding E-enolate would receive a severe nonbonded repulsion between R
Scheme 1.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3853
Rxn Yield1
De2
(% )
Entry
R
R0X
(h)
(%)
[ꢁ]D
A
B
C
D
E
F
CH3
PhCH2 Mel
PhCH2Br
2
4
2
4
20
20
95.5
79.5
89.5
86.9
63.9
70.1
94.0 þ24.3 (c ¼ 1.7, CHCl3)
92.6 þ72.8 (c ¼ 1.4, CHCl3)
91.6 þ17.1 (c ¼ 0.9, CHCl3)
92.9 þ75.8 (c ¼ 0.4, CHCl3)
91.6 þ89.5 (c ¼ 1.8, CHCl3)
96.7 þ35.6 (c ¼ 1.4, CHCl3)
CH3
Allyl
Allyl bromide
Mel
PhCH2 Allyl bromide
Allyl PhCH2Br
2
1
1Isolated yield; Determined by 400 MHz H NMR.
Scheme 2.
Figure 1.
and the dioxolane moiety. The lithium enolate of 3 comprises two distinct
ꢀ-faces (re and si face) because the lithium ion coordinates to both the
N-acyl and the oxazolidinone carbonyl oxygens. The si-face is difficult to
access for electrophiles because of the steric hindrance of the dioxolane
substituent as shown in Fig. 1. The result is well matched with this
argument.
The reaction product of the lithium enolate of 3a with benzyl bromide
1
(Entry A) showed the H NMR chemical shift at 4.63 (1H, m, a-proton),
1.10 (3H, d, J ¼ 6.7 Hz, a-methyl), 2.56 (1H, dd, J ¼ 8.7 and 13.2 Hz, benzyl
proton), and 3.28 (1H, dd, J ¼ 5.8 and 13.2 Hz, benzyl proton). To ensure

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3854
KIM AND JUN
Scheme 3.
the diastereoselectivity of D-mannitol-based oxazolidinone, the methylation
of the lithium enolate 3b (Entry B) was examined and showed the 1H NMR
chemical shift at 4.52 (1H, m, a-proton), 1.28 (3H, d, J ¼ 6.7 Hz, a-methyl),
2.93 (1H, dd, J ¼ 8.3 and 13.2 Hz, benzyl proton), and 2.73 (1H, dd, J ¼ 7.0
and 13.3 Hz, benzyl proton). The diasteromeric ratio was easily identified by
the integration of benzyl proton in 1H NMR chemical shift. The integration
of the product 4A containing the trace amount of peaks at 2.93 and 2.73,
which was compared with the peaks at 2.56 and 3.28, showed the diastereo-
meric excess of 94%. The absolute configuration of the stereogenic centers
in 4A was assigned after removal of the chiral auxiliary. Reduction of 4A
using LiAlH4 in THF at r.t. generated 2-benzyl-1-propanol (5A) in 60.8%
yield after column chromatography (Sch. 3). Comparison of the specific
25
rotation ½ꢁŠ ¼ +1 4 :1 ðc ¼ 1:05, C6H6Þ of the alcohol 5A thus obtained,
D
25
D
with the literature value[7] for ½ꢁŠ ¼ +1 1 :1 ðc ¼ 1:25, C6H6Þ established its
absolute configuration as (R). The chiral auxiliary 2 was recovered nearly
quantitatively in this reduction (99.8%). The enantiomer 5B was also
obtained in same manner from 4B and showed the absolute configuration
25
24
D
as (S ) ½ꢁŠ ¼ ꢀ12:1 ðc ¼ 1:05, C6H6Þ lit.[8] ½ꢁŠ ¼ ꢀ11:1 ðc ¼ 4:6, C6H6Þ.
D
The other examples (Entries C–F), also, easily figured the diastereomeric
1
excess in same manner by using integration of H NMR of structure 4 even
without the reduction to 5. These results indicate that the new chiral
oxazolidin-2-one derived from D-mannitol showed to be a very effective
chiral auxiliary in asymmetric alkylation reactions through Z-enolate and
re-face selectivity.
In order to explore the utility of the new chiral oxazolidin-2-one
derived from D-mannitol, we applied the chiral auxiliary 3a in asymmetric
aldol reaction using chlorotitanium enolate.[9] The use of titanium(IV)
enolates of N-acyloxazolidinethions has been reported for the preparation
of either the ‘‘Evans’’ or ‘‘non-Evans’’ syn aldol products in high diaster-
eomeric purity by simply changing the stoichiometry of the Lewis acid and
the nature of the amine base.[10] We first examined the titanium enolate of
the Evans acyloxazolidinone by using TiCl4 (1 equiv), TMEDA (2.5 equiv.)
and benzaldehyde (2 equiv.), and found the Evans syn aldol product 6

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3855
Scheme 4.
Figure 2.
via non-chelated Z-enolate 6A in 91% yield (Sch. 4). Selectivity was >99 : 1
Evans syn 6 : non-Evans syn 7. The absolute configuration of 6 and the
selectivity of syn : anti ratio were determined after hydrolytic cleavage of
6–8 by using LiOOH.[11] The hydrolysis gave 76.8% yield of (2S, 3S)-acid
25
D
22
D
8 ½ꢁŠ ¼ ꢀ24:4 ðc ¼ 0:9, CH2Cl2Þ lit.[12] ½ꢁŠ ¼ ꢀ 26:4 ðc ¼ 1:04, CH2Cl2Þ
with quantitative recovery (>99%) of auxiliary 2. The 1H NMR of the prod-
uct 8 indicated the selectivity >99 : 1 for syn 8 : anti 8A ratio (Fig. 2). The
correlation between the vicinal coupling constant of the a and b protons at
the syn/anti chiral centers of the aldol adducts, where adducts, having
3
relatively small a and b substituents, give small values of Jab (3–5 Hz)
for syn diastereomers and larger values (7–10 Hz) for anti, is well estab-
lished.[13] The Jab values are 4.0 Hz at 5.18 pm and 8.8 Hz at 4.75 ppm
for the diastereomers assigned as syn 8 (2S, 3S) and anti 8A (2R, 3S),
3
respectively.[14]

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3856
KIM AND JUN
Scheme 5.
Experiment employing 2 equiv of TiCl4 and 1.5 equiv of Et3N gave
also excellent selectivity for the non-Evans syn aldol product 7 via chelated
Z-enolate 7A. Selectivity is >96 : 4 for syn 9 : anti 9A and >99 : 1 for non-
Evans syn : Evans syn. No products from endocyclic cleavage in hydrolysis
reaction were observed.[11] Crimmins[10] used oxazolidinethione auxiliary for
the titanium enolate of asymmetric aldol reaction because the titanium
prefers to coordinate to sulfur rather than oxygen.[15] Comparable high
stereoselectivity was obtained in asymmetric aldol additions for non-
Evans syn product using our new oxazolidinone auxiliary instead of oxazo-
lidinethione. Non-Evans syn product was produced via chelated transition
state 7A resulting from abstraction of chloride ion by the second equivalent
addition of TiCl4 (Sch. 5).[16]
In conclusion, the results presented in this communication show the
chiral auxiliary (4S,5R)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-
2-one (2) derived from D-mannitol to be a very effective chiral auxiliary
in asymmetric alkylations and aldol reactions. In particular the reactions
to remove the chiral auxiliary from the elaborated substrate occur very
efficiently allowing effective recovery of the chiral auxiliary.
EXPERIMENTAL
All chemicals used were purchased from commercial sources and used
as received unless otherwise stated. NMR spectra were recorded at Varian
Gemini-400 MHz FT-NMR for 1H and 100 MHz for 13C, with the chemical
shifts (ꢂ) reported in parts per million (ppm) relative to TMS and the
coupling constants (J) quoted in Hz. CDCl3 was used as a solvent and an
internal standard. Infrared spectra were recorded on a Shimadzu IR-435

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3857
spectrometer. GC-MS analyses were performed using a HP-5890/JMS-AM
150, JEOL. Flash chromatography was carried out using silica gel Merck 60
(230–400 mesh). Thin-layer chromatography (TLC) was performed on DC-
Plastikfolien 60, F254 (Merck, layer thickness 0.2 mm) plastic-backed silica
gel plates with visualization by UV light (254 nm) or by treatment with
p-anisaldehyde. Melting points were measured on a MEL-TEMP II
apparatus and were uncorrected.
(4S,5R)-4,5-bis-(2,2-Dimethyl-1,3-dioxolan-4-yl)-oxazolidin-2-one (2):
To a solution of 3-amino-3-deoxy-1,2 : 5,6-di-O-isopropylidene-D-altritol
(1) (1.00 g, 3.83 mmol) in diethyl carbonate (15 mL) under nitrogen atmos-
phere was added sodium methoxide (0.21 mL of 25% solution in MeOH,
0.96 mmol) and heated for 3 h at 70–80ꢁC. Diethyl carbonate was removed
by evaporation and the residual solid was washed with hexane, recrystallized
by MeOH to give the white solid
2
(1.00 g, 91%). Rf 0.45
20
D
(MeOH : CHCl3 ¼ 1 : 9); m.p. 195–197ꢁC; ½ꢁŠ ꢀ24:2 ðc1:0, CHCl3Þ; ꢃmax
(film)/cmꢀ1 3297, 2993, 1759, 1744; 1H NMR (400 MHz, CDCl3) ꢂ 1.35
(6H, s, 2CH3), 1.41 (3H, s, CH3), 1.45 (3H, s, CH3), 3.78 (1H, dd, J 9.1,
4.7 Hz), 3.87 (1H, br t, J 6.1 Hz), 4.02 (1H, dd, J 8.8, 3.5 Hz), 4.15 (1H, dd,
J 9.1, 5.5 Hz), 4.18 (1H, m), 4.41–4.34 (2H, m), 4.44 (1H, dd, J 11.2, 6.1 Hz),
5.67 (1H, br s, NH); 13C NMR (100 MHz, CDCl3) ꢂ 158.70 (C¼O), 110.63
(CMe2), 110.46 (CMe2), 78.15, 74.32, 72.54, 68.07, 67.41, 58.14, 27.31
(CH3), 26.89 (CH3), 25.53 (CH3), 25.28 (CH3); MS (EI), m/e 288 (Mþ),
272, 244, 230, 214, 172, 101 (base), 83, 73, 59, 43.
Typical Procedure for the Preparation of
N-Acyloxazolidin-2-ones, 3a–c
To a solution of oxazolidinone 2 (1.50 g, 5.22 mmol) in THF (130 mL)
under nitrogen atmosphere was added n-BuLi (4.90 mL of 1.6 M solution in
Hexane, 7.83 mmol) at ꢀ60ꢁC and stirred for 30 min. Propionyl chloride
(0.91 mL, 10.44 mmol) was added to this reaction mixture at ꢀ40ꢁC and
stirred for 30 min. The reaction was quenched by the addition of water at
0ꢁC. The organic product was extracted with ethyl acetate, washed with
brine, dried and concentrated to give the solid. The solid was washed with
hexane to give the white solid 3a (1.53 g, 85.3%).
(4S,5R)-3-(1-Oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxa-
20
zolidin-2-one (3a): Rf 0.32 (EtOAc : Hex ¼ 1 : 4); m.p. 105–108ꢁC; ½ꢁŠ
D
+4 4 :37 ðc 0:8, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.18 (3H, t, J
7.3 Hz), 1.34 (3H, s, CH3), 1.36 (3H, s, CH3), 1.37 (3H, s, CH3), 1.42 (3H,
s, CH3), 3.00–2.85 (2H, m), 4.08–3.99 (3H, m), 4.18 (1H, dd, J 9.3, 5.9 Hz),
4.30 (1H, dd, J 9.9, 7.0 Hz), 4.64–4.58 (2H, m), 4.73 (1H, d, J 7.0 Hz);

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3858
KIM AND JUN
13C NMR (100 MHz, CDCl3) ꢂ 174.28 (C¼O), 153.33 (C¼O), 110.27
(CMe2), 109.72 (CMe2), 77.15, 74.28, 72.62, 67.35, 66.15, 56.10, 28.86,
27.18, 25.78, 25.11, 25.09, 8.52.
(4S,5R)-3-(3-Phenyl-1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-
yl)-oxazolidin-2-one (3b): 85.3%; Rf 0.52 (EtOAc : Hex ¼ 1 : 2); m.p.
98–100ꢁC; ½ꢁŠD20+5 4 :9 ðc1:1,CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.33
(6H, s), 1.36 (3H, s), 1.41 (3H, s), 3.05–2.95 (2H, m), 3.29–3.21 (2H, m),
4.10–4.00 (3H, m), 4.28–4.14 (2H, m), 4.65–4.55 (2H, m), 4.71 (1H, d, J
7.0 Hz), 7.29–7.19 (5H, m); 13C NMR (100 MHz, CDCl3) ꢂ 171.53 (C¼O),
152.22 (C¼O), 139.34, 127.49 (ꢂ2), 127.44 (ꢂ2), 125.24, 109.25, 108.69,
76.11, 73.20, 71.55, 66.30, 65.09, 55.07, 35.70, 29.70, 26.14, 24.75, 24.09
(ꢂ2).
(4S,5R)-3-(1-Oxo-4-pentenyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-
oxazolidin-2-one (3c): 77.3%; Rf 0.58 (EtOAc : Hex ¼ 1 : 2); m.p. 55–57ꢁC;
½ꢁŠ2D0+5 3 :2 ðc 0:9, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.34 (3H, s, CH3),
1.36 (3H, s, CH3), 1.37 (3H, s, CH3), 1.42 (3H, s, CH3), 2.49–2.39 (2H, m),
3.11–2.93 (2H, m), 4.07–3.98 (3H, m), 4.18 (1H, dd, J 9.2, 6.0 Hz), 4.29 (1H,
dd, J 9.8, 7.0 Hz), 4.63–4.58 (2H, m), 4.73 (1H, d, J 7.0 Hz), 5.02 (1H, dd,
J 10.1, 1.3 Hz, ¼CH trans), 5.10 (1H, dd, J 17.2, 1.3 Hz, ¼CH cis), 5.87 (1H,
m, ¼CH internal); 13C NMR (100 MHz, CDCl3) ꢂ 172.72 (C¼O), 153.30
(C¼O), 136.65, 115.75, 110.31, 109.75, 77.18, 74.26, 72.62, 67.37, 66.16,
56.13, 34.47, 28.23, 27.20, 25.83, 25.13, 25.11.
Typical Procedure for the Preparation of Alkylated Products, 4A–4F
To a solution of diisopropyl amine (0.06 mL, 0.44 mmol) in THF
(3 mL) at ꢀ20ꢁC under nitrogen atmosphere was added n-BuLi (0.27 mL
of 1.6 M solution in Hexane, 0.44 mmol) and stirred for 30 min. N-Propionyl
oxazolidinone 3a (0.10 g, 0.29 mmol) in THF (2 mL) was added to this
reaction mixture at ꢀ60ꢁC and stirred for 30 min. Benzyl bromide
(0.14 mL, 1.16 mmol) was added to this reaction mixture at ꢀ40ꢁC and
stirred for 2 h. The reaction was quenched by the addition of water at
0ꢁC. The organic product was extracted with ethyl acetate, washed with
brine, dried, concentrated, and chromatographed (EtOAc : Hex ¼ 1 : 4) to
give the liquid 4A (0.12 g, 95.5%).
(4S,5R,20R)-3-(2-Methyl-3-phenyl-1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-
20
D
dioxolan-4-yl)-oxazolidin-2-one (4A): Rf 0.48 (EtOAc : Hex ¼ 1 : 3); ½ꢁŠ
1
+2 4 :3 ðc 1:7, CHCl3Þ; H NMR (400MHz, CDCl3) ꢂ 1.10 (3H, d, J 6.7 Hz,
a-methyl), 1.19 (3H, s, CH3), 1.32 (3H, s, CH3), 1.36 (3H, s, CH3), 1.42 (3H, s,
CH3), 2.56 (1H, dd, J 13.2, 8.7 Hz, benzyl proton), 3.28 (1H, dd, J 13.2,

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3859
5.8Hz, benzyl proton), 3.68 (1H, dd, J 9.1, 6.6 Hz), 3.95 (1H, dd, J 9.1,
6.6 Hz), 4.00 (1H, dd, J 6.4, 2.1 Hz), 4.05 (1H, dd, J 9.2, 3.4 Hz), 4.18 (1H,
dd, J 9.2, 5.9 Hz), 4.31 (1H, dd, J 9.7, 6.9 Hz), 4.54 (1H, t, J 6.6 Hz), 4.63 (1H,
m, a-proton), 4.75 (1H, d, J 6.4 Hz), 7.20 (1H, m), 7.28–7.25 (4H, m);
13C NMR (100MHz, CDCl3) ꢂ 177.0 (C¼O), 153.3 (C¼O), 139.6, 129.7
(ꢂ2), 128.7 (ꢂ2), 126.7, 110.6 (CMe2), 109.8 (CMe2), 77.4, 74.5, 72.9, 67.7,
66.2, 55.9, 40.0, 39.9, 27.5, 26.1, 25.7, 25.5, 16.6.
(4S,5R,20S )-3-(2-Methyl-3-phenyl-1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-
dioxolan-4-yl)-oxazolidin-2-one (4B): 79.5%; Rf 0.62 (EtOAc : Hex ¼ 1 : 2);
½ꢁŠ2D0+7 2 :8 ðc 1:4, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.28 (3H, d,
J 6.7 Hz, a-methyl), 1.33 (6H, s, 2CH3), 1.34 (3H, s, CH3), 1.40 (3H, s,
CH3), 2.73 (1H, dd, J 13.3, 7.0 Hz, benzyl proton), 2.93 (1H, dd, J 13.2,
8.3 Hz, benzyl proton), 3.85 (1H, dd, J 9.8, 6.7 Hz) 4.01–3.92 (3H, m),
4.15–4.09 (2H, m), 4.52 (1H, m, a-proton), 4.55 (2H, m), 7.22–7.17 (3H, m),
7.28–7.24 (2H, m); 13C NMR (100MHz, CDCl3) ꢂ 176.8 (C¼O), 152.9 (C¼O),
139.1, 129.1 (ꢂ2), 128.4 (ꢂ2), 126.4, 110.2 (CMe2), 109.5 (CMe2), 76.9, 74.2,
72.5, 67.3, 66.0, 55.9, 40.1, 39.0, 27.1, 25.7, 25.2, 25.1, 17.6.
(4S,5R,20R)-3-(2-Methyl-1-oxo-4-pentenyl)-4,5-bis-(2,2-dimethyl-1,3-
dioxolan-4-yl)-oxazolidin-2-one (4C): 89.5%; Rf 0.60 (EtOAc : Hex ¼ 1 : 2);
½ꢁŠ2D0+1 7 :1 ðc 0:9, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.14 (3H, d,
J 6.9 Hz, a-methyl), 1.34 (3H, s, CH3), 1.35 (3H, s, CH3), 1.37 (3H, s,
CH3), 1.42 (3H, s, CH3), 2.19 (1H, m), 2.59 (1H, m), 3.78 (1H, sextet,
J 6.7 Hz), 3.91 (1H, dd, J 9.0, 6.1 Hz), 4.00 (1H, dd, J 9.1, 6.8 Hz), 4.06
(1H, dd, J 9.2, 3.5 Hz), 4.12 (1H, q, J 7.3 Hz), 4.19 (1H, dd, J 9 2, 6.0 Hz),
4.31 (1H, dd, J 9.8, 6.9 Hz), 4.63–4.58 (2H, m), 4.75 (1H, dd, J 6.8, 1.0 Hz),
5.06 (1H, dd, J 10.1, 1.5 Hz, ¼CH trans), 5.11 (1H, dd, J 17.1, 1.5 Hz, ¼CH
cis), 5.80 (1H, m, ¼CH internal); 13C NMR (100 MHz, CDCl3) ꢂ 177.0
(C¼O), 153.3 (C ¼ O), 135.6, 117.7, 110.6 (CMe2), 109.9 (CMe2), 77.4,
74.5, 73.0, 67.7, 66.3, 56.2, 38.2, 37.5, 27.6, 26.2, 25.6, 25.5, 16.7.
(4S,5R,20S )-3-(2-Methyl-1-oxo-4-pentenyl)-4,5-bis-(2,2-dimethyl-1,3-
dioxolan-4-yl)-oxazolidin-2-one (4D): 86.9%; Rf 0.38 (EtOAc:Hex ¼ 1 : 4);
½ꢁŠ2D0+7 5 :8 ðc 0:4, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.26 (3H, d,
J 6.9 Hz, a-methyl), 1.31 (3H, s, CH3), 1.36 (3H, s, CH3), 1.37 (3H, s,
CH3), 1.42 (3H, s, CH3), 2.18 (1H,quintet, J 7.0 Hz), 2.42 (1H, quintet,
J 7.0 Hz), 3.81 (1H, sextet, J 7.1 Hz), 3.94 (1H, dd, J 9.1, 6.0 Hz), 4.01
(1H, dd, J 9.1, 6.8 Hz), 4.05 (1H, dd, J 9.2, 3.5 Hz), 4.18 (1H, dd, J 7.2,
6.0 Hz), 4.26 (1H, dd, J 9 1, 6.0 Hz), 4.64–4.56 (2H, m), 4.74 (1H, dd, J 7.0,
0.8 Hz), 5.03 (1H, dd, J 9.9, 1.5 Hz, ¼CH trans), 5.05 (1H, dd, J 16.0,
1.5 Hz, ¼CH cis), 5.77 (1H, m, ¼CH internal); 13C NMR (100 MHz,
CDCl3) ꢂ 176.8 (C¼O), 152.9 (C¼O), 135.5, 117.1 110.3 (CMe2), 109.6
(CMe2), 77.2, 74.2, 72.6, 67.4, 66.0, 55.8, 37.6, 37.2, 27.2, 27.8, 25.2,
25.1, 17.6.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3860
KIM AND JUN
(4S,5R,20S )-3-(2-Benzyl-1-oxo-4-pentenyl)-4,5-bis-(2,2-dimethyl-1,3-
dioxolan-4-yl)-oxazolidin-2-one (4E): 63.9%; Rf 0.70 (EtOAc:Hex ¼ 1 : 2);
½ꢁŠ2D0+8 9 :5 ðc 1:8, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.28 (3H, s,
CH3), 1.31 (3H, s, CH3), 1.33 (3H, s, CH3), 1.38 (3H, s, CH3), 2.36 (1H,
m), 2.59 (1H, quintet, J 7.1 Hz), 2.78 (1H, dd, J 13.0, 10.0 Hz), 2.88 (1H, dd,
J 13.0, 6.1 Hz), 3.46 (1H, dd, J 9.9, 6.8 Hz), 3.83 (1H, dd, J 9.0, 7.0 Hz), 3.88
(1H, dd, J 9.3, 3.4 Hz), 3.97 (1H, dd, J 8.9, 6.5 Hz), 4.90 (1H, dd, J 9.1,
5.9 Hz), 4.31 (1H, m), 4.33 (1H, dd, J 6.6, 0.9 Hz), 4.49–4.41 (2H, m), 5.05
(1H, br d, J 10.9 Hz, ¼CH trans), 5.15 (1H, dd, J 17.1, 1.5 Hz, ¼CH cis),
5.85 (1H, m, ¼CH internal), 7.20–7.15 (2H, m), 7.28–7.21 (3H, m);
13C NMR (100 MHz, CDCl3) ꢂ 176.0 (C¼O), 153.3 (C¼O), 139.1, 135.4
129.5 (ꢂ2), 128.8 (ꢂ2), 127.0, 117.9, 110.5 (CMe2), 109.9 (CMe2), 77.2,
74.4, 72.8, 67.7, 66.4, 56.2, 44.1, 39.7, 36.9, 27.6, 26.1, 25.9, 25.5.
(4S,5R,20R)-3-(2-Benzyl-1-oxo-4-pentenyl)-4,5-bis-(2,2-dimethyl-1,3-
dioxolan-4-yl)-oxazolidin-2-one (4F): 70.1%; Rf 0.70 (EtOAc : Hex ¼ 1 : 2);
½ꢁŠ2D0+3 5 :6 ðc 1:4, CHCl3Þ; 1H NMR (400 MHz, CDCl3) ꢂ 1.07 (3H, s,
CH3), 1.30 (3H, s, CH3), 1.35 (3H, s, CH3), 1.42 (3H, s, CH3), 2.23 (1H,
m), 2.35 (1H, m), 2.71 (1H, dd, J 13.5, 7.6 Hz), 3.19 (1H, dd, J 13.5, 7.2 Hz),
3.57 (1H, dd, J 9.0, 7.1 Hz), 3.92 (1H, dd, J 9.2, 6.9 Hz), 4.03 (1H, dd,
J 9.2, 3.5 Hz), 4.26–4.15 (3H, m), 4.49 (1H, br t, J 6.9 Hz), 4.59 (1H, m),
4.69 (1H, dd, J 6.9, 0.7 Hz), 5.02 (1H, br d, J 10.1 Hz, ¼CH trans), 5.06 (1H,
br d, J 16.9 Hz, ¼CH cis), 5.75 (1H, m, ¼CH internal), 7.10 (1H, m),
7.27–7.21 (4H, m); 13C NMR (100 MHz, CDCl3) ꢂ 175.2 (C¼O), 153.1
(C¼O), 139.0, 135.3, 129.3 (ꢂ2), 128.5 (ꢂ2), 126.5, 117.3, 110.3 (CMe2),
109.4 (CMe2), 77.1, 74.1, 72.6, 67.4, 65.8, 55.6, 44.3, 37.9, 36.2, 27.2, 25.5
(ꢂ2), 25.1.
(R)-2-Benzyl-1-propanol (5A): To a solution of LiAlH4 (35 mg,
0.92 mmol) in THF (2 mL) under nitrogen atmosphere in ice bath was
added (4S,5R,20R)-3-(2-methyl-3-phenyl-1-oxopropyl)-4,5-bis-(2,2-dimethyl-
1,3-dioxolan-4-yl)-oxazolidin-2-one (4A) (0.10 g, 0.23 mmol) and stirred
for 20 min at r.t. The reaction was quenched by the addition of 1 N
NaOH aqueous solution (4 mL) and filtered. The filtrate was evaporated,
diluted with EtOAc, dried, concentrated and chromatographed
(EtOAc:Hex ¼ 1 : 2) to give the alcohol 5A (21 mg, 60.8%) and the auxiliary
2 (60 mg, 99.8%). Rf 0.40 (EtOAc:Hex ¼ 1 : 2); ½ꢁŠ2D5+1 4 :1 ðc 1:05,C6H6Þ;
25
D
1
½lit:7½ꢁŠ ¼ +1 1 :1, ðc 1:25, C6H6ފ; H NMR (400 MHz, CDCl3) ꢂ 0.91 (3H,
d, J 6.7 Hz, 2-methyl), 1.59 (1H, br s, OH), 1.94 (1H, m, CHMe),
2.41 (1H, dd, J 13.4, 7.9 Hz, benzyl H), 2.75 (1H, dd, J 13.4, 6.4 Hz,
benzyl H), 3.50 (2H, m, CH2OH), 7.20 (5H, m, aromatic). The data were
consistent with those reported in the literature.[2e,6]
(S )-2-Benzyl-1-propanol (5B): Prepared from 4B (0.04 g, 0.09 mmol) as
same as above procedure and gave the alcohol 5B (11 mg, 79.3%) and the

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3861
25
auxiliary 2 (23 mg, 99.8%). Rf 0.40 (EtOAc : Hex ¼ 1 : 2); ½ꢁŠ ꢀ12:1
D
½8Š
25
D
ðc 1:05,C6H6Þ; ½lit: ½ꢁŠ ¼ ꢀ11:1, ðc 4:6, C6H6ފ.
(4S,5R,20S,30S)-3-(3-Hydroxy-2-methyl-3-phenyl-1-oxopropyl)-4,5-bis-
(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-2-one (6): To a solution of
(4S,5R)-3-(1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-
2-one (3a) (42 mg, 0.12 mmol) in CH2Cl2 (2 mL) under nitrogen atmosphere
was added TiCl4 (0.14 mL in 1.0 M solution in CH2Cl2, 0.14 mmol) at
ꢀ60ꢁC and stirred for 5 min. TMEDA (46 mg, 0.31 mmol) was added to
this reaction mixture at ꢀ60ꢁC and stirred for 30 min. Benzaldehyde
(0.03 mL, 0.24 mmol) was added to this reaction mixture at ꢀ60ꢁC and
stirred for 2 h. The reaction was quenched by the addition of 50% aqueous
NH4Cl at 0ꢁC. The organic product was extracted with ethyl acetate,
washed with brine, dried and concentrated to give the product 6 (50 mg,
91%). Rf 0.30 (EtOAc : Hex ¼ 1 : 2); 1H NMR (400 MHz, CDCl3) ꢂ 1.28 (3H,
d, J 6.9 Hz, a-methyl), 1.33 (6H, s, 2CH3), 1.36 (3H, s, CH3), 1.41 (3H, s,
CH3), 3.11 (1H, br s), 4.03–3.93 (4H, m), 4.08 (1H, m), 4.15 (1H, dd, J 9.2,
6.0 Hz), 4.57 (3H, m), 4.98 (1H, br d, J 3.4 Hz), 7.26 (2H, m), 7.40–7.30
(3H, m).
(4S,5R,20R,30R)-3-(3-Hydroxy-2-methyl-3-phenyl-l-oxopropyl)-4,5-bis-
(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-2-one (7): To a solution of
(4S,5R)-3-(1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-
2-one (3a) (0.10 g, 0.29 mmol) in CH2Cl2 (5 mL) under nitrogen atmosphere
was added TiCl4 (0.58 mL in 1.0 M solution in CH2Cl2, 0.58 mmol) at
ꢀ60ꢁC and stirred for 5 min. Et3N (0.06 mL, 0.44 mmol) was added to
this reaction mixture at ꢀ60ꢁC and stirred for 30 min. Benzaldehyde
(0.06 mL, 0.58 mmol) was added to this reaction mixture at ꢀ60ꢁC and
stirred for 2 h. The reaction was quenched by the addition of water at
0ꢁC. The organic product was extracted with ethyl acetate, washed with
brine, dried and concentrated to give the product 7 (60 mg, 46%). Rf 0.35
1
(EtOAc : Hex ¼ 1 : 2); H NMR (400 MHz, CDCl3) ꢂ 0.97 (3H, d, J 6.8 Hz,
a-methyl), 1.33 (3H, s, CH3), 1.38 (3H, s, CH3), 1.43 (3H, s, CH3), 1.44 (3H,
s, CH3), 3.37 (1H, d, J 4.5 Hz), 4.04–3.95 (3H, m), 4.08 (1H, m), 4.20 (2H,
m), 4.34 (1H, dd, J 9.8, 7.1 Hz), 4.66 (2H, m), 4.89 (1H, dd, J 7.0, 0.9 Hz),
7.42–7.32 (3H, m), 7.49 (2H, d, J 7.5 Hz).
syn (2S,3S )- and anti (2R,3S )-3-Hydroxy-2-methyl-3-phenylpropanoic
acid (8 and 8A): To a solution of (4S,5R,20S,30S)-3-(3-hydroxy-2-methyl-3-
phenyl-1-oxopropyl)-4,5-bis-(2,2-dimethyl-1,3-dioxolan-4-yl)-oxazolidin-2-
one (6) (60 mg, 0.13 mmol) in THF (2 mL) and H2O (0.65 mL) was added
30% H2O2 (0.76 g, 0.67 mmol) and LiOHH2O (11 mg, 0.27 mmol) at 0ꢁC
and stirred for 30 min. Solid sodium sulfite and saturated NaHCO3 solution
were added to this reaction mixture until pH 10. THF in the reaction mix-
ture was evaporated. The mixture was diluted with water (2 mL), extracted

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3862
KIM AND JUN
with CH2Cl2, washed with brine, dried and concentrated to give the
auxiliary 2 (34 mg, 100%). The water layer was acidified with the addition
of 3N HCl solution until pH 2, and extracted with EtOAc, washed with
brine, dried, concentrated and chromatographed to give the acids 8 and 8A
25
(18 mg, 76.8%). Rf 0.19 (EtOAc : Hex ¼ 1 : 2); ½ꢁŠ ꢀ24:4 ðc 0:9,CH2Cl2Þ;
D
½12Š
22
D
½lit: ½ꢁŠ ꢀ26:4 ðc 1:04,CH2Cl2ފ; 1H NMR (400 MHz, CDCl3) ꢂ 1.14
(3H, d, J 9.0 Hz, a-methyl), 2.83 (1H, m, a-H), 4.75 (0.01H, d, J 8.8 Hz,
anti CHOH), 5.18 (0.99H, d, J 4.0 Hz, syn CHOH), 5.42 (2H, br s, OH
and CO2H), 7.35 (5H, s, aromatic). 1H NMR integration afforded a
ratio 8 : 8A ¼ 99 : 1. The data were consistent with those reported in the
literature.[12,14]
syn (2R,3R)- and anti (2S,3R)-3-Hydroxy-2-methyl-3-phenylpropanoic
acid (9 and 9A): Prepared from 7 (24 mg, 0.05 mmol) as same as above
procedure and gave the acids 9 and 9A (8 mg, 83.7%) and the auxiliary 2
(15 mg, 100%). Rf 0.19 (EtOAc : Hex ¼ 1 : 2); ½ꢁŠ2D5+2 6 :5 ðc 0:35, CH2Cl2Þ;
½12Š
22
D
½lit: ½ꢁŠ ꢀ26:4 ðc 1:04, CH2Cl2ފ for the enantiomer 8; 1H NMR
(400 MHz, CDCl3) ꢂ 4.75 (0.04H, d, J 8.8 Hz, anti CHOH), 5.18 (0.96H,
d, J 4.0 Hz, syn CHOH). 1H NMR integration afforded a ratio 9 : 9A ¼ 96 : 4.
ACKNOWLEDGMENT
This research was supported by the Hallym Academy of Sciences at
Hallym University, Korea, 2001.
REFERENCES
1. (a) Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc. 1981, 103,
2127; (b) Evans, D.A.; Takacs, J.M.; McGee, L.R.; Ennis, M.D.;
Mathre, D.J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109; (c) Evans,
D.A. Aldrichim. Acta 1982, 15, 23; (d) Evans, D.A.; Nelson, J.V.;
Taber, T.R. Top. Stereochem. 1982, 13, 1.
2. (a) Koll, P.; Lutzen, A. Tetrahedron: Asymmetry 1995, 6, 43; (b) Kunz,
H. Pure Appl. Chem. 1995, 67, 1627; (c) Banks, M.R.; Cadogen, J.I.G.;
Gosney, I.; Gaur, S.; Hodgson, P.K.G. Tetrahedron: Asymmetry 1994,
5, 2447; (d) Banks, M.R.; Blake, A.J.; Dawson, I.M.; Gosney, I.; Grant,
K.J.; Gaur, S.; Knight, K.S.; Smith, G.W.; Hodgson, P.K.G.; Cadogen,
J.I.G.; Stevenson, D.E. Tetrahedron 1992, 48, 7979; (e) Parrodi, C.A.;
Clara-Sosa, A.; Perez, L.; Quintero, L.; Marason, V.; Toscano, R.A.;
Avina, J.A.; Rojas-Lima, S.; Juaristi, E. Tetrahedron: Asymmetry 2001,
12, 69.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
N-ACYLATED OXAZOLIDIN-2-ONES
3863
3. Kim, B.M.; Sharpless, K.B. Tetrahedron Lett. 1989, 30, 655.
4. (a) Knolker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1998, 39, 9407; (b)
Hofle, G.; Steglich, W. Vorbruggen, H. Angew. Chem. 1978, 90, 602.
5. (a) Homeyer, A.H.U.S. Patent 2,399,118, C.A. 1946, 40, 4084; (b)
Newman, M.S.; Kutner, A.J. J. Am. Chem. Soc. 1951, 73, 4199.
6. Evans, D.A.; Ennis, M.D.; Mathre, D.J. J. Am. Chem. Soc. 1982, 104,
1737.
7. Palomo, C.; Oiarbide, M.; Gonzalez, A.; Garcia, J.M.; Berree, F.
Tetrahedron Lett. 1996, 37, 4565.
8. Terashima, S.; Yamada, S.-I. Chem. Pharm. Bull. 1968, 16, 1953.
9. (a) Siegel, C.; Thornton, E.R. J. Am. Chem. Soc. 1989, 111, 5722;
(b) Evans, D.A.; Rieger, D.L.; Bilodeau, M.T.; Urpi, F. J. Am.
Chem. Soc. 1991, 113, 1047.
10. Crimmins, M.T.; King, B.W.; Tabet, E.A. J. Am. Chem. Soc. 1997,
119, 7883.
11. Evans, D.A.; Britton, T.C.; Ellman, J.A. Tetrahedron Lett. 1987, 28,
6141.
12. Gage, J.R.; Evans, D.A. Org. Syn. 1990, 68, 83.
13. (a) Heathcock, C.H. Asymmetric Synthesis; Morrison, J.D., Ed.;
Academic Press: Orlando, FL, 1984; Vol. 3, pp. 111–212; (b) Nerz-
Stormes, M.; Thornton, E.R. J. Org. Chem. 1991, 56, 2489.
14. Evans, D.A.; Nelson, J.V.; Vogel, E.; Taber, T.R. J. Am. Chem. Soc.
1981, 103, 3099.
15. Fowles, G.W.A.; Rice, D.A.; Wilkins, J.D. J. Chem. Soc. A 1971, 1920.
16. (a) Evans, D.A.; Chapman, K.T.; Bisaha, J. J. Am. Chem. Soc. 1988,
110, 1238; (b) Castellino, S.; Dwight, W.J. J. Am. Chem. Soc. 1993,
115, 2986.
Received in Japan October 22, 2001

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.