Toward the development of a general chiral α-substituted acetate enolate synthon for aldolization. DMAP- and NET3-promoted oxazolidinethione 'deacylation'

Full text of DOI:10.1021/jo990444h

J . Org. Chem. 1999, 64, 6495-6498
6495
Sch em e 1
Tow a r d th e Develop m en t of a Gen er a l
Ch ir a l r-Su bstitu ted Aceta te En ola te
Syn th on for Ald oliza tion . DMAP - a n d
NEt3-P r om oted Oxa zolid in eth ion e
“Dea cyla tion ”
Ying-Chuan Wang, Dah-Wei Su, Chen-Men Lin,
Hsi-Liang Tseng, Chi-Lung Li, and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing
University, Taichung, Taiwan 400, Republic of China
Received March 11, 1999
In tr od u ction
R,â-Difunctional carboxylates such as R,â-epoxy esters,
R-azido-â-hydroxy esters, and R-amino-â-hydroxy acids
are versatile synthons for the synthesis of biologically
active peptides,1 aziridines,2 and â- and γ-lactam anti-
biotics.3 The vast importance of chiral difunctional car-
boxylates has stimulated the development of new meth-
odology for their construction. Several examples of highly
diastereoselective and enantioselective aldolizations em-
ploying chiral boron bromoacetate enolates4,5 and stan-
nous isothiocyanoacetate enolates6 have been reported.
Despite the significant utility that these metal-mediated
aldolizations would enjoy in the construction of syn-4 and
anti-bromohydrin aldols,5 issues associated with the
conversion efficiency, synthetic flexibility of the initial
aldol transformation, stereoisomers separation, reaction
generality, and chemistry efficiency continue to pose an
important challenge in the area of reaction design. In
light of recent reports, wherein the boron-mediated
bromoacetate enolate aldolizations consistently proceeded
to no more than 80% conversion4a and 52% yield,4b we
report that acetate titanium enolate derived from thio-
imide efficiently effects one-step bromination-aldoliza-
tion with excellent yields and exceptionally high levels
of asymmetric induction in aldol additions (Scheme 1).
Synthetic efficiency will be enhanced if the initial thio-
imide aldols can be transformed into a different product.
However, control of the transformation profile (Scheme
2, deacylation vs substitution) is difficult for basic
reagents, e.g. LiOBn- and LiOH-mediated deacylation of
the oxazolidinone bromohydrin.4 We envisioned the fea-
sibility of complete control of the reaction profile, which
Sch em e 2
requires a very mild condition for removing the chiral
auxiliary from bromohydrin aldols.
Resu lts a n d Discu ssion
Since earlier work in our laboratories established the
fesasibility of TiCl4 as a Lewis acid to effect rapid and
highly stereoselective aldolization of camphor-based N-
acyloxazolidinethione with aldehydes,7 we aimed at using
previously reported camphor-based chiral N-acetyloxazo-
lidinethione 2 as starting material and explored one-step
enolate bromination-aldolization reactions (Scheme 1).
The titanium enolate,8,9 generated by the sequential
addition of TiCl4 (1.6 equiv) and diisopropylethylamine
(1.2 equiv) to a cold (0 °C) solution of the thioimide 2 (0.25
M in CH2Cl2), was treated with bromine (1 equiv) at -78
°C to give an intermediate adduct, which was isolated
1
and characterized by H NMR spectroscopy [(400 MHz,
(1) (a) Kurokawa, N.; Ohfune, Y. J . Am. Chem. Soc. 1986, 108, 6041.
(b) Amino Acids, Peptides and proteins. Specialist Periodical Reports;
Young, G. T., Sheppard, R. C., Ed.; Royal Society of Chemistry:
London, 1968-1983; Vol. 1-16.
(2) Legters, J .; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1989,
30, 4881.
(3) (a) Holden, K. G. In Cephalosporins and Penicillins: Chemistry
and Biology; Flynn, E. H., Ed.; Academic Press: New York, 1972; Vol.
2, p 133. (b) Floyd, D. M. A.; Fritz, W.; Pluscec, J .; Weaver, E. R.;
Cimarusti, C. M. J . Org. Chem. 1982, 47, 5160. (c) Labia, R.; Morin,
C. J . Antibiot. 1984, 37, 1103. (d) Miller, M. J . Acc. Chem. Res. 1986,
19, 49. (e) Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.;
Omura, S.; Smith, A. B., III. J . Am. Chem. Soc. 1993, 115, 5302.
(4) (a) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39-42. (b) Abdel-Magid, A.; Pridgen, L.
N.; Drake, S. E.; Ivan, L. J . Am. Chem. Soc. 1986, 108, 4595-4602.
(5) (a) Corey, E. J .; Lee, D.-H.; Choi, S. Tetrahedron Lett. 1992, 33,
6735-6738. (b) Corey, E. J .; Choi, S. Tetrahedron Lett. 1991, 32, 2857-
2860.
CDCl3) δ 5.03 (d, J ) 12 Hz, 1 H), 4.83 (d, J ) 12 Hz, 1
(7) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J .
Am. Chem. Soc. 1993, 115, 2613. (b) Yan, T.-H.; Hung, A.-W.; Lee,
H.-C.; Chang, C.-S. J . Org, Chem. 1994, 59, 8187. (c) Yan, T.-H.; Hung,
A.-W.; Lee, H.-C.; Chang, C.-S.; Liu, W.-H. J . Org, Chem. 1995, 60,
3301. (d) Wang, Y.-C.; Hung, A.-W.; Chang, C.-S.; Yan, T.-H. J . Org,
Chem. 1996, 61, 2038.
(8) For leading references to TiCl4-NR3 enolization, see: (a) Leh-
nert, W. Tetrahedron Lett. 1970, 11, 4723. (b) Harrison, C. R.
Tetrahedron Lett. 1987, 28, 4135. (c) Brocchini, S. J .; Eberle, M.;
Lawton, R. G. J . Am. Chem. Soc. 1988, 110, 5211.
(9) For representative titanium-mediated aldol-type reactions, see:
(a) Siegel, C.; Thornton, E. R. J . Am. Chem. Soc. 1989, 111, 5722. (b)
Evans, D. A.; Clark, J . S.; Metternich, R.; Novack, V. J .; Sheppard, G.
S. J . Am. Chem. Soc. 1990, 112, 866. (c) Evans, D. A.; Urpi, F.; Somers,
T. C.; Clark, J . S.; Bilodeau, M. T. J . Am. Chem. Soc. 1990, 112, 8215.
(c) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am. Chem.
Soc. 1991, 113, 1047.
(6) Evans, D. A.; Weber, A. E. J . Am. Chem. Soc. 1986, 108, 6757-
6761.
10.1021/jo990444h CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999

6496 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
Ta ble 1. Tita n iu m -Med ia ted Br om in a tion -Ald oliza tion
Sch em e 3
Rea ction s of Aceta te Th ioim id e 2 (Sch em e 1)
entry
electrophile
n-PrCHO
(E)-MeCHdCHCHO
PhCHO
ratioa
yieldb (%)
adduct
1
2
3
4
c
c
c
c
91
90
94
91
3a
3b
3c
3d
Me2CHCHO
a
b
Ratio determined by 400-MHz 1H NMR spectroscopy. Iso-
lated yield. c The syn aldol 3 was the only detected product by 1H
NMR analysis.
H), 4.52 (dd, J ) 8.4, 4.0 Hz, 1 H), 2.91-1.21 (m, 7 H),
1.16 and 1.04 (2s, 6 H)] as the bromoacetate carboxthio-
imide.10 Treatment of this intermediate, generated in
situ, with an additional 1.2 equiv of diisopropylethy-
lamine at -78 °C and subsequent aldolization of the
resulting titanium bromoacetate enolate with n-butyral-
dehyde (1.3 equiv) at -78 °C led within 1.5 h to the
bromohydrin 3a in 94% yield (Scheme 1, Table 1, entry
1). We believe the enhanced electrophilicity of aldehyde
carbonyl group, promoted by TiCl4, is crucial to this high-
yield asymmetric aldolization reaction. The crude aldol
Sch em e 4
1
adduct showed a single set of peaks in the 400-MHz H
NMR spectrum suggestive of complete asymmetric in-
duction. Assignment of the erythro configuration is based
on the 1H NMR vicinal coupling using the well-estab-
lished fact that J threo (7-9 Hz) > J erythro (3-6 Hz).7a,11 The
sense of asymmetric induction in this reaction is fully
consistent with the observed stereochemical course of the
previously reported titanium propionate thioimide eno-
late.7 Having established the feasibility of the use of
titanium acetate thioimide enolate to effect bromination-
aldolization with excellent stereoselection, we established
its generality with respect to the nature of the aldehyde.
From the data in Table 1, it is clear that the reaction
exhibits generality as well as extraordinary reactivity and
asymmetric induction. Either the presence of conjugation
(Table 1, entries 2 and 3) or R-methyl substitution (entry
4) in the aldehyde molecule does not appear to exert any
influence on either the yield or the selectivity of the
reaction. The absolute stereochemical assignment of the
syn bromohydrin 3d was made via nondestructive re-
moval of the chiral auxiliary and correlation of the
resultant benzyl epoxy ester (vide infra).4b
To promote further useful transformations of the initial
aldol adducts without influencing the pendent functional
groups, we sought to establish a very mild method for
chiral auxiliary removal from thioimide 3. Believing a
nucleophilic catalysis route might be a useful method for
the deacylation of thioimide, we initially explored DMAP-
promoted transesterification of aldol 3a . Exposing 3a to
1.2 equiv of PhCH2OH in the presence of 25 mol % DMAP
in CH2Cl2 at 0 °C for 8 h did indeed produce exclusively
benzyl R-bromo-â-hydroxy ester 4a in 98% yield with no
apparent loss of stereochemistry (Scheme 3). Thioimide
aldol 3b, which by virtue of the acidity of its â-hydrogen
is particularly prone to elimination, was also cleanly
converted to the bromohydrin ester 4b. Under our
standard conditions, aldol adduct 3c bearing a benzylic
hydrogen led to exclusive deacylation to give R-bromo-
â-hydroxy ester 4c with no detectable elimination prod-
uct. Transesterification of the hindered imide enolate/
isobutyraldehyde aldol adduct 3d can also lead to the
corresponding ester 4d in almost quantitative yield.
The efficiency of the method of general base and
nucleophilic catalyst promoted thioimide deacylation for
construction of useful R,â-difunctional compounds is
illustrated by the additional examples provided below.
Hindered thioimide aldol 3d serves as our test substrate.
Exposure of 3d to LiOH/H2O2 produced bromohydrin acid
5 but also a second product readily identified as epoxy
acid by its spectroscopic properties. Since more basic
reagent LiOH enhances epoxide formation, replacing
LiOH by a base like triethylamine may serve as a general
base catalyst for promoting deacylation but inhibiting
internal SN2 displacement of bromide. Indeed, in the
reaction of 3d with H2O (6 equiv) in the presence of NEt3
(3 equiv) in CH2Cl2 at 0 °C, epoxide formation was
completely suppressed and 5 was isolated in 93% yield
(Scheme 4, path a). Bromohydrin 3d can also be directed
to form R-azido-â-hydroxy carboxylate via a deacylation-
substitution protocol without any need to isolate the
deacylation product and to protect the â-hydroxy group.5a
Thus, exposing 3d to PhCH2OH (1.2 equiv) in the
presence of DMAP (0.25 equiv) in CH2Cl2 at 0 °C for 6 h,
and subsequently adding NaN3 (2.0 equiv) and n-Bu4N+-
-
HSO4 (50 mol %) and warming to room temperature,
(10) This R-bromo thioimide intermediate is unstable at 0 °C.
Attempts to obtain pure N-(R-bromoacetyl)oxazolidinethione from
bromoacetyl chloride and oxazolidinethione 1 were not successful.
(11) (a) House, H. O.; Crumrine, D. S.; Olmstead, H. D. J . Am. Chem
Soc. 1973, 95, 3310. (b) Kleschick, W. A.; Buse, C. T.; Heathcock, C.
H. J . Am. Chem. Soc. 1977, 99, 247. (c) Heathcock, C. H.; Buse, C. T.;
Kleschick, W. A. J . Org, Chem. 1980, 45, 1066.
(12) For previous asymmetric synthesis of hydroxyleucine, see: (a)
J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1989, 30, 6637-6640. (b)
Caldwell, C. G.; Bondy, S. S. Synthesis 1990, 34-36. (c) Blaser, D.;
Seebach, D. Liebigs Ann. Chem. 1991, 1067-1078.
led within 20 h to smooth SN2 displacement of the
bromide to give a 91% yield of azide 6 (Scheme 4, path
b), a precursor of nonracemic 3-hydroxyleucine.10 The
NMR spectrum of the crude product showed it to be a
single compound, free of the epoxide or the diastereomer
at C-2. Switching the external nucleophile N3- to a base
like F- led to an internal SN2 displacement of the bromide
to give epoxide. Thus, exposure of the acyl-transfer

Notes
J . Org. Chem., Vol. 64, No. 17, 1999 6497
ca n e (3a ). As described above, 2.39 g (10 mmol) of 2 was
converted to its chlorotitanium enolate. Condensation with
n-butyraldehyde (14 mmol) provided a crude reaction mixture.
Diastereomer analysis (400 MHz 1H NMR) of the unpurified
mixture revealed the presence of essentially a single syn
bromohydrin aldol. Purification by flash chromatography (15%
ethyl acetate/hexane, silica gel, 0-5 °C) afforded 3.54 g (91%)
of 3a : IR (neat) 3508, 1696 cm-1; 1H NMR (400 MHz, CDCl3) δ
6.61 (d, J ) 2.0 Hz, 1 H), 4.54 (dd, J ) 8.0, 4.0 Hz, 1 H), 4.01
(m, 1 H), 2.76-1.20 (m, 12 H), 1.08 (s, 3 H), 0.99 (s, 3 H), 0.90
(m, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 187.52, 172.77, 90.64,
69.52, 51.16, 49.19, 42.52, 36.34, 34.63, 31.53, 25.78, 23.90, 21.33,
product 4d , generated in situ, to KF (5 equiv) and LiF (5
equiv) in the presence of n-Bu4N+HSO4 (50 mol %) in
-
CH2Cl2 at 25 °C for 36 h led to smooth epoxide formation
to afford an 89% yield of the cis-benzyl R,â-epoxy ester
7, [R]25D -35.5° (c 0.5, CHCl3), with e1% of trans-epoxide
being detected (Scheme 4, path c). The literature value
for the rotation of the enantiomer of 7 ([R]25 +35.7°)
D
confirms the stereochemical assignment.4b Finally, the
utility of this nucleophilic catalyst promoted oxazolidi-
nethione deacylation was examined in the transesterifi-
cation of aldol 3d with 2-(trimethylsilyl)ethanol (Scheme
4, path d), which participated equally well albeit in a
somewhat slower reaction, giving the â-substituted ethyl
ester 8 in 82% isolated yield.
19.31, 18.56, 18.71, 13.92; [R]25 +48.0° (c 5.1, CH2Cl2); high-
D
resolution MS m/e calcd for C16H24NO3SBr: 389.0660, found:
389.0661. Anal. Calcd for C16H24NO3SBr: C, 49.22; H, 6.20; N,
3.59. Found: C, 49.31; H, 6.16; N, 3.62.
N-[(2R,3S)-2-Br om o-3-h ydr oxy-(E)-4-h exen oyl]-(1S,5R,7R)-
10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]d e-
ca n e (3b). As described above, 2.39 g (10 mmol) of 2 was
converted to its chlorotitanium enolate. Condensation with
crotonaldehyde (14 mmol) provided a crude reaction mixture.
Diastereomer analysis (400 MHz 1H NMR) of the unpurified
mixture revealed the presence of essentially a single syn
bromohydrin aldol. Purification by flash chromatography (15%
ethyl acetate/hexane, silica gel, 0-5 °C) afforded 3.49 g (90%)
of 3b: IR (neat) 3488, 1698 cm-1; 1H NMR (400 MHz, CDCl3) δ
6.64 (d, J ) 4.4 Hz, 1 H), 5.87 (dq, J ) 15.6, 6.8 Hz, 1 H), 5.56
(dd, J ) 15.6, 6.8 Hz, 1 H), 4.60 (dd, J ) 6.8, 4.4 Hz, 1 H), 4.54
(dd, J ) 8.0, 4.0 Hz, 1 H), 2.73-1.18 (m, 11 H), 1.07 (s, 3 H),
0.98 (s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 187.40, 171.77,
130.81, 128.37, 90.43, 71.50, 50.63, 49.14, 42.41, 34.51, 31.43,
We have demonstrated, to our knowledge, the first
example of employing titanium-mediated bromination-
aldolization of N-acetyloxazolidinethione to develop a
general chiral R-substituted acetate enolate synthon.
Synthetically, the remarkable facility of nucleophilic
catalyst and general base promoted oxazolidinethione
deacylation not only expands the scope of asymmetric
aldol addition method by providing direct access to a
variety of optically active R,â-difunctional acids and
esters but also opens the question of the importance of
the nature of the chiral auxiliary on further useful
transformations of the initial chiral adducts. In addition,
the preceding studies highlight the unexpected reactivity
and stereoselection of bromoacetate titanium enolate
aldolizations, which offer a practical alternative to the
use of other expensive metalloids such as boron to achieve
excellent yield as well as exceptional stereocontrol.
Further studies will determine whether this DMAP-
promoted deacylation will be generally useful for other
adducts derived from chiral carboximides. At present we
know that the DMAP-promoted transesterification of
standard thioimide aldol adducts is also easily effected
without recemization of either center.
25.85, 24.17, 21.31, 19.24, 17.87; [R]25 +60.4° (c 4.8, CH2Cl2);
D
high-resolution MS m/e calcd for C16H22NO3SBr: 387.0503,
found: 387.0506. Anal. Calcd for C16H22NO3SBr: C, 49.48; H,
5.71; N, 3.61. Found: C, 49.50; H, 5.73; N, 3.56.
N -[(2R ,3S )-2-Br om o-3-h yd r oxy-3-p h e n ylp r op ion yl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3c). As described above, 2.39 g (10 mmol)
of 2 was converted to its chlorotitanium enolate. Condensation
with benzaldehyde (14 mmol) provided a crude reaction mixture.
Diastereomer analysis (400 MHz 1H NMR) of the unpurified
mixture revealed the presence of essentially a single syn
bromohydrin aldol. Purification by flash chromatography (15%
ethyl acetate/hexane, silica gel, 5 °C) afforded 3.98 g (94%) of
3c as a white solid: mp 113-114 °C; IR (neat) 3524, 1694 cm-1
;
Exp er im en ta l Section
1H NMR (400 MHz, CDCl3) δ 7.49-7.24 (m, 5 H), 7.00 (d, J )
4.4 Hz, 1 H), 5.28 (d, J ) 4.4 Hz, 1 H), 4.52 (dd, J ) 8.0, 4.0 Hz,
1 H), 2.73-1.20 (m, 8 H), 1.02 (s, 3 H), 0.90 (s, 3 H); 13C NMR
(75.5 MHz, CDCl3) δ 187.19, 171.99, 138.65, 128.30, 126.74,
125.50, 90.40, 72.24, 51.32, 49.08, 42.44, 34.50, 31.53, 25.69,
24.08, 21.03, 18.93; [R]25D +74.5° (c 5.1, CH2Cl2); high-resolution
MS m/e calcd for C19H22NO3SBr: 423.0503, found: 423.0501.
Anal. Calcd for C19H22NO3SBr: C, 53.76; H, 5.23; N, 3.30.
Found: C, 53.79; H, 5.22; N, 3.36.
Gen er a l. Diisopropylamine and dichloromethane were dried
by distillation under N2 from calcium hydride. TiCl4 (1 M in CH2-
Cl2) was used as received. All aldehydes were freshly distilled
prior to use. Unless otherwise noted, all nonaqueous reactions
were carried out under a dry nitrogen atmosphere with oven-
dried glassware. Flash chromatography was done on E. Merck
silica gel 60 (230-400 mesh). Melting points (Pyrex capillary)
are uncorrected. Concentrations for rotation data are given as
g/100 mL of solvent. Diastereomeric excesses (de) were deter-
mined by 400-MHz 1H NMR.
Gen er a l P r oced u r e for th e TiCl4-Med ia ted Br om in a -
tion -Ald oliza tion of Th ioim id e 2. To a solution of 2 (10
mmol) in 40 mL of CH2Cl2 cooled to 0 °C was added 16 mL (1 M
in CH2Cl2, 16 mmol, 1.6 equiv) of TiCl4. After stirring at 0 °C
for 3 min, slow addition of diisopropylethylamine (1 M in CH2-
Cl2, 12 mL, 12 mmol) and further stirring for 10 min at 0 °C,
the reaction mixture was cooled to -78 °C. To the above reaction
mixture was slowly added a solution of Br2 (10 mmol) in 10 mL
of CH2Cl2. After stirring at -78 °C for 10 min, a second
equivalent of diisopropylethylamine (1 M in CH2Cl2, 12 mL, 12
mmol) was added and stirred for 10 min at -78 °C. To the above
enolate solution was slowly added a solution of freshly distilled
aldehyde (13 mmol) in 13 mL of CH2Cl2. The reaction mixture
was stirred at -78 °C for 1.5 h and quenched with 40 mL of
aqueous phosphate buffer (pH ) 7). The aqueous layer was
extracted with 60 mL of CH2Cl2. The combined organic extracts
were washed with brine (20 mL), dried (MgSO4), and concen-
trated in vacuo. Purification by flash chromatography (ethyl
acetate/hexane, silica gel, 0-5 °C) afforded pure aldol adduct 3.
N-[(2R,3S)-2-Br om o-3-h yd r oxyh exa n oyl]-(1S,5R,7R)-10,-
10-d im e t h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]d e -
N -[(2R ,3S )-2-Br om o-3-h yd r oxy-4-m e t h ylp e n t a n oyl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3d ). As described above, 2.39 g (10 mmol)
of 2 was converted to its chlorotitanium enolate. Condensation
with isobutyraldehyde (14 mmol) provided a crude reaction
mixture. Diastereomer analysis (400 MHz 1H NMR) of the
unpurified mixture revealed the presence of essentially a single
syn bromohydrin aldol. Purification by flash chromatography
(15% ethyl acetate/hexane, silica gel, 0-5 °C) afforded 3.54 g
(91%) of 3d as a white solid: mp 98-99 °C; IR (KBr) 3636, 1694
cm-1 1H NMR (400 MHz, CDCl3) δ 6.82 (d, J ) 2.0 Hz, 1 H),
;
4.54 (dd, J ) 8.2, 4.0 Hz, 1 H), 3.68 (dd, J ) 8.2, 2.0 Hz, 1 H),
2.68-1.20 (m, 9 H), 1.13 (s, 3 H), 1.09 (d, J ) 6.8 Hz, 3 H), 1.05
(s, 3 H), 0.93 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3)
δ 187.51, 173.15, 90.56, 74.85, 49.25, 42.51, 34.59, 31.77, 31.50,
25.75, 23.83, 21.21, 21.04, 19.28, 18.71, 19.52; [R]25 +46.5° (c
D
2.4, CH2Cl2); high-resolution MS m/e calcd for C16H24NO3SBr:
389.0660, found: 389.0663. Anal. Calcd for C16H24NO3SBr: C,
49.22; H, 6.20; N, 3.59. Found: C, 49.31; H, 6.16; N, 3.62.
Gen er a l P r oced u r e for th e Dea cyla tion Rea ction P r o-
m oted by DMAP . To a solution of aldol adduct 3 (1 mmol) and
PhCH2OH (1.2 mmol) in CH2Cl2 (0.5 mL) at 0 °C was added a
solution of DMAP (0.2 mmol) in 0.5 mL of CH2Cl2. After stirring

6498 J . Org. Chem., Vol. 64, No. 17, 1999
Notes
at that temperature for 8-12 h, the reaction mixture was
quenched with HCl (1 N, 2 mL) and diluted with CH2Cl2 (10
mL). The organic layer was washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The pale yellow oil
was purified by chromatography on silica gel (using eluent
gradient 15% ethyl acetate/hexane to 50% ethyl acetate/hexane)
to afford bromohydrin ester and recovered oxazolidinethione
auxiliary.
MHz, CDCl3) δ 4.49 (d, J ) 3.6 Hz, 1 H), 3.54 (dd, J ) 6.8, 3.6
Hz, 1 H), 3.45 (bs, 2 H), 1.85 (octet, J ) 6.8 Hz, 1 H), 1.04 (d, J
) 6.8 Hz, 3 H), 0.92 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 172.80, 76.17, 51.06, 31.87, 18.71, 17.73; [R]25 +22.2°
D
(c 1.2, CH2Cl2); high-resolution MS m/e calcd for C6H12O3Br
(FAB, MH+): 210.9970, found: 210.9977. Anal. Calcd for
C6H11O3Br: C, 34.13; H, 5.25. Found: C, 34.07; H, 5.24.
P h en ylm eth yl (2S,3S)-2-Azid o-3-h yd r oxy-4-m eth ylp en -
ta n oa te (6). To a solution of aldol adduct 3d (390 mg, 1 mmol)
and PhCH2OH (1.2 mmol) in CH2Cl2 (2 mL) at 0 °C was added
a solution of DMAP (0.2 mmol) in 0.2 mL of CH2Cl2. After
P h en ylm eth yl (2R,3S)-2-Br om o-3-h ydr oxyh exan oate (4a).
Bromohydrin aldol 3a (390 mg, 1 mmol) was converted to its
corresponding benzyl ester 4a (295 mg, 98%) as described in the
1
general protocol. Diastereomer analysis (400 MHz H NMR) of
stirring for 8-10 h at 0 °C, NaN3 (2.0 mmol) and n-Bu4N+HSO4
-
the unpurified mixture revealed the presence of essentially a
single syn bromohydrin 4a : IR (neat) 3479, 1730 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.35 (bs, 5 H), 5.20 (2d, J ) 12.0 Hz, 2 H),
4.30 (d, J ) 3.6 Hz, 1 H), 3.91 (dt, J ) 4.2, 4.0 Hz, 1 H), 2.71
(bs, 1 H). 1.58-1.30 (m, 4 H), 0.89 (t, J ) 7.2 Hz, 3 H); 13C NMR
(75.5 MHz, CDCl3) δ 168.61, 134.55, 128.41, 128.25, 128.07,
70.69, 67.79, 52.41, 36.18, 18.72, 13.85; [R]25D +67.2° (c 4.3, CH2-
Cl2); high-resolution MS m/e calcd for C13H17O3Br: 300.0361,
found: 300.0355. Anal. Calcd for C13H17O3Br: C, 51.82; H, 5.69.
Found: C, 51.86; H, 5.67.
(25 mol %) were added and stirring was continued for 20 h at
room temperature. The product was extracted with 20 mL of
CH2Cl2 and washed with H2O (5 mL x 6) and brine (5 mL). The
organic layer was dried (MgSO4), filtered, and concentrateed in
vacuo. The pale yellow oil was purified by chromatography on
silica gel (using eluent gradient 20% ethyl acetate/hexane to 50%
ethyl acetate/hexane) to afford recovered auxiliary and azido
ester 6 (239 mg, 91%): IR (neat) 3481, 1740 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.36 (bs, 5 H), 5.25 and 5.23 (2d, J ) 12.0 Hz, 2
H), 3.92 (d, J ) 6.0 Hz, 1 H), 3.65 (t, J ) 6.0 Hz, 1 H), 1.88
(octet, J ) 6.0 Hz, 1 H), 0.95 (d, J ) 6.4 Hz, 3 H), 0.93 (d, J )
6.4 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 169.18, 134.65,
128.54, 128.51, 128.27, 76.38, 67.70, 63.89, 30.26, 19.42, 16.59;
P h en ylm et h yl (2R,3S)-2-Br om o-3-h yd r oxy-(E)-4-h ex-
en oa te (4b). Bromohydrin aldol 3b (390 mg, 1 mmol) was
converted to its corresponding benzyl ester 4b (283 mg, 95%) as
described in the general protocol. Diastereomer analysis (400
1
[R]25 -18.7° (c 1.7, CH2Cl2); high-resolution MS m/e Calcd for
MHz H NMR) of the unpurified mixture revealed the presence
D
of essentially a single syn bromohydrin 4b: IR (neat) 3481, 1731
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.34 (bs, 5 H), 5.69 (dq, J )
15.6, 6.8 Hz, 1 H), 5.34 (dd, J ) 15.6, 6.4 Hz, 1 H), 5.09 (2d, J
) 12.0 Hz, 2 H), 4.35 (t, J ) 6.4 Hz, 1 H), 4.17 (d, J ) 6.4 Hz,
1 H), 2.75 (bs, 1 H). 1.54 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5
MHz, CDCl3) δ 167.77, 134.57, 130.98, 128.33, 128.28, 128.06,
C
C
13H17O3N3: 263.1269. Found: 263.1275. Anal. Calcd for
13H17O3N3: C, 59.28; H, 6.51. Found: C, 59.34; H, 6.49.
P h en ylm eth yl (2S,3S)-2,3-Epoxy-4-m eth ylpen tan oate (7).
To a solution of aldol adduct 3d (390 mg, 1 mmol) and PhCH2-
OH (1.2 mmol) in CH2Cl2 (1 mL) at 0 °C was added a solution of
DMAP (0.2 mmol) in 1 mL of CH2Cl2. The resulting mixture was
stirred for 8-10 h at 0 °C. A solution of LiF (5 mmol), KF (5
127.56, 72.45, 67.60, 51.64, 17.74; [R]25 +5.6° (c 3.5, CH2Cl2);
D
high-resolution MS m/e calcd for C13H15O3Br: 298.0204, found:
mmol), and n-Bu4N+HSO4 (25 mol %) in 2 mL of CH2Cl2 was
-
298.0208. Anal. Calcd for
Found: C, 52.36; H, 5.11.
C13H15O3Br: C, 52.17; H, 5.06.
added in one portion. After stirring for 36 h at room temperature,
the reaction mixture was partitioned between CH2Cl2 (10 mL)
and HCl (1 N, 5 mL). The aqueous phase was washed with CH2-
Cl2 (5 mL × 2). The organic layer was combined, washed with
water and brine, dried over MgSO4, filtered, and concentrated
in vacuo to afford crude epoxy ester 7. Diastereomer analysis
P h en ylm eth yl (2R,3S)-2-Br om o-3-h yd r oxy-3-p h en ylp r o-
p a n oa te (4c). Bromohydrin aldol 3c (390 mg, 1 mmol) was
converted to its corresponding benzyl ester 4c (320 mg, 96%) as
described in the general protocol. Diastereomer analysis (400
1
MHz H NMR) of the unpurified mixture revealed the presence
1
of essentially a single syn bromohydrin 4c: IR (neat) 3477, 1732
(400 MHz H NMR) of the unpurified mixture revealed a >98:2
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.29-7.09 (ms, 10 H), 5.02
ratio of cis and trans epoxides. The pale yellow oil was purified
by chromatography on silica gel (using eluent gradient 6% ethyl
acetate/hexane to 50% ethyl acetate/hexane) to afford recovered
oxazolidinethione auxiliary and epoxy ester 7 (196 mg, 89%):
(d, J ) 6.8 Hz, 1 H), 5.01 (s, 2 H), 4.42 (d, J ) 6.8 Hz, 1 H), 1.56
(bs, 1 H); 13C NMR (75.5 MHz, CDCl3) δ 167.78, 137.91, 134.32,
128.48, 128.30, 128.22, 128.04, 127.93, 126.51, 73.80, 67.61,
52.69; [R]25D +33.9° (c 0.8, CH2Cl2); high-resolution MS m/e calcd
for C16H15O3Br: 334.0204, found: 334.0209. Anal. Calcd for
IR (neat) 1733 cm-1 1H NMR (400 MHz, CDCl3) δ 7.32 (bs, 5
;
H), 5.21 and 5.19 (2d, J ) 12.0 Hz, 2 H), 3.54 (d, J ) 4.8 Hz, 1
H), 2.82 (dd, J ) 9.2, 4.8 Hz, 1 H), 1.71-1.50 (m, 1 H), 1.08 (d,
J ) 6.8 Hz, 3 H), 0.78 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 167.94, 135.03, 128.46, 128.44, 128.43, 67.09, 63.24,
C
16H15O3Br: C, 57.31; H, 4.51. Found: C, 57.54; H, 4.55.
P h en ylm eth yl (2R,3S)-2-Br om o-3-h yd r oxy-4-m eth ylp en -
ta n oa te (4d ). Bromohydrin aldol 3d (390 mg, 1 mmol) was
converted to its corresponding benzyl ester 4d (288 mg, 96%)
as described in the general protocol. Diastereomer analysis (400
53.25, 27.12, 20.21, 18.34; [R]25 -35.5° (c 0.5, CHCl3); high-
D
resolution MS m/e calcd for C13H16O3: 220.1099, found: 220.1095.
1
MHz H NMR) of the unpurified mixture revealed the presence
2-(Tr im et h ylsilyl)et h yl (2R,3S)-2-Br om o-3-h yd r oxy-4-
m eth ylp en ta n oa te (8). Bromohydrin aldol 3d (390 mg, 1
mmol) was converted to its corresponding â-(trimethylsilyl)ethyl
ester 8 (254 mg, 82%) as described in the general protocol.
Diastereomer analysis (400 MHz 1H NMR) of the unpurified
mixture revealed the presence of essentially a single syn
bromohydrin 8: IR (neat) 3490, 1736 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.39 (d, J ) 4.0 Hz, 1 H), 4.25 (m, 2 H), 3.50 (dd, J )
4.8, 4.0 Hz, 1 H), 1.94 (bs, 1 H), 1.81 (m, 1 H), 1.02 (m, 2 H),
1.01 (d, J ) 6.8 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 3H), 0.03 (s, 9 H);
13C NMR (75.5 MHz, CDCl3) δ 169.46, 75.83, 64.83, 51.24, 31.53,
of essentially a single syn bromohydrin 4d : IR (neat) 3481, 1730
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35 (bs, 5 H), 5.20 (2d, J )
12.0 Hz, 2 H), 4.47 (d, J ) 3.6 Hz, 1 H), 3.53 (dd, J ) 7.2, 3.6
Hz, 1 H), 1.87 (bs, 1 H), 1.78 (octet, J ) 7.2 Hz, 1 H), 1.00 (d, J
) 6.8 Hz, 3 H), 0.91 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 169.18, 134.67, 128.60, 128.48, 128.25, 75.91, 67.94,
51.07, 31.61, 18.90, 17.60; [R]25 +15.5° (c 0.9, CH2Cl2); high-
D
resolution MS m/e Calcd for C13H17O3Br: 300.0361, found:
300.0355. Anal. calcd for C13H17O3Br: C, 51.82; H, 5.69. Found:
C, 51.80; H, 5.65.
(2R,3S)-2-Br om o-3-h yd r oxy-4-m eth ylp en ta n oic Acid (5).
To a solution of aldol adduct 3d (390 mg, 1 mmol) and H2O (6
mmol) in CH3CN (1.5 mL) at 0 °C was added a solution of NEt3
(3 mmol) in 0.5 mL of CH3CN. After stirring at that temperature
for 8 h, the reaction was quenched with HCl (1 N, 3 mL) and
diluted with CH2Cl2 (10 mL). The organic layer was washed with
1 N aqueous NaHCO3 (5 mL × 2). The aqueous phases were
combined, cooled to 0 °C, neutralized with HCl, and extracted
with three portions of CH2Cl2. The combined organic phases were
washed with brine, dried over MgSO4, filtered, and concentrated
in vacuo to afford pure bromohydrin acid 5 (196 mg, 93%): IR
18.94, 17.57, 17.06, -1.60; [R]25 +21.5° (c 1.0, CH2Cl2); high-
D
resolution MS m/e calcd for C11H23O3BrSi: 310.0599, found:
310.0595. Anal. Calcd for C11H23O3BrSi: C, 42.44; H, 7.44.
Found: C, 42.12; H, 7.33.
Ack n ow led gm en t. National Science Council of the
Republic of China provides generous support of this
program (NSC 88-2113-M-005-006).
(neat) 3509, 3400-2411 (br COOH), 1703 cm-1
;
1H NMR (400
J O990444H