DMAP-promoted racemization-free deacylation of carboxthioimide adducts: Carboxthioimide as a versatile carboxy protecting group

Article abstract of DOI:10.1039/a900577c

The DMAP-promoted deacylation of carboxthioimide adducts can be directed to form either acid or various ester protecting groups with no detectable levels of epimerization.

Full text of DOI:10.1039/a900577c

DMAP-promoted racemization-free deacylation of carboxthioimide† adducts:
carboxthioimide as a versatile carboxy protecting group
Dah-Wei Su, Ying-Chuan Wang and Tu-Hsin Yan*
Department of Chemistry, National Chung-Hsing University, Taichung, Taiwan 400, Republic of China.
E-mail: thyan@mail.nchu.edu.tw
Received (in Cambridge, UK) 21st January 1999, Accepted 9th February 1999
The DMAP-promoted deacylation of carboxthioimide ad-
ducts can be directed to form either acid or various ester
protecting groups with no detectable levels of epimeriza-
tion.
ification of 2 to afford phenyl ester 3b in 91% yield. Similarly,
DMAP (1.1 equiv.) promoted hydrolysis of 2 with H2O as the
nucleophile afforded the acid 3c. The broad scope of the
transesterification is illustrated by the tolerance of b-sub-
stituents on ethanol. Thus deacylation of 2 with 2,2,2-tri-
chloroethanol under the same conditions gave the correspond-
ing b-substituted ethyl ester protecting group. A labile alcohol,
2-bromoethanol, also proved to be a satisfactory nucleophile
under our standard conditions in the presence of the DMAP
catalyst. Trimethylsilylethanol gave similar results, albeit in a
somewhat slower reaction. After 24 h, an 89% yield of
2-(trimethylsilyl)ethyl ester 3f was obtained.‡ The utility of
allyl and benzyl esters as useful carboxy-protecting groups led
to our examination of allyl and benzyl alcohols, which
participated equally well, giving the corresponding esters 3g
and 3h in excellent yield (!95%).11 Steric hindrance plays a
role; in contrast to the above, tert-butyl alcohol failed to react
with thioimide adduct 2 under the above conditions.
The suitability of these mild conditions for oxazolidinethione
deacylation is illustrated by the additional examples provided
below. Camphor-based N-acyloxazolidinethiones such as
Diels–Alder cycloadduct 4 and aldol adduct 65 were utilized to
test the feasibility of DMAP-promoted nucleophilic cleavage.
The DMAP-promoted transesterification of cycloadduct 4,
which was prepared from the TiCl4-mediated Diels–Alder
reaction of camphor-based crotonyloxazolidinethione with
cyclopentadiene, with benzyl alcohol proceeded more slowly
The development of protecting groups of carboxy functionality
which are stable under the usual reaction conditions and which
can be activated by a specific reagent for nucleophilic
deacylation under very mild conditions has been a challenging
undertaking. Oxazolidinone-derived carboximides1–4 as well as
oxazolidinethione- and thiazolidinethione-based carboxthio-
imides5,6 have proven to be valuable carboxy-protecting groups
for the construction of enantiomerically pure substances. While,
traditionally, the use of basic reagents (LiOCH2Ph, BrMgOMe,
LiOH, LiOOH, K2CO3/MeOH)6,7 for the nucleophilic cleavage
of imide the thioimide adducts has been the method of choice
for removing the auxiliary from substances, progress in
nucleophilic catalyst-promoted imide and thioimide deacylation
with oxygen nucleophiles like H2O, alcohols and phenol
remains far less developed. Effecting such nucleophilic acyl
substitution may have the advantage of (i) controlling the
nucleophilic cleavage without causing racemization of the
newly created stereocenters, (ii) promoting further useful
transformations of the initial adducts without influencing the
pendent functional groups, and (iii) enhancing synthetic
efficiency by direct conversion of the initial adducts to various
ester protecting groups. The tremendous impact of DMAP8 in
catalyzing the acylation of alcohols suggested the feasibility of
DMAP as a catalyst to effect transesterification or hydrolysis of
imides and thioimides. Here we report protocols whereby the
thioimide transesterification promoted by DMAP can be
directed to form either acid or various ester protecting groups
with no detectable levels of epimerization.
The reactions of crotonyloxazolidinone-derived Diels–Alder
adduct 1 with MeOH and H2O were chosen to test the feasibility
of the DMAP-promoted oxazolidinone deacylation (Scheme 1).
In view of the well-documented excellent shelf lives of N-
acyloxazolidinones,9 we were not surprised to observe no
detectable methanolysis and hydrolysis at the exocyclic car-
bonyl center. Believing a more polarizable auxiliary might
facilitate nucleophilic attack, we turned to the deacylation of
carboxthioimide derived adducts. Initial work centered on the
deacylation of the Diels–Alder adduct 2 derived from the
unsaturated N-acylthiazolidine-2-thione (cf. Scheme 1) which
has been shown to exhibit enhanced dienophilic reactivity in a
copper(ii)-catalyzed asymmetric cycloaddition.10 The requisite
thioimide adduct 2 was available by treating crotonyl-
thiazolidienethione with excess cyclopentadiene (5–10 equiv.)
and 1.2 equiv. of ZnCl2 in CH2Cl2 at 0 °C. Treatment of
thioimide 2 with 1.5 equiv. of MeOH in MeCN with 20 mol%
DMAP at room temperature gave the methyl ester 3a in 96%
yield along with a 93% recovery of the auxiliary (Scheme 1).
The DMAP-promoted thiazolidinethione deacylation exhibited
good generality. Thus, switching the nucleophile from MeOH to
PhOH had little effect. The same conditions effected transester-
Scheme 1 Reagents and conditions: i, ZnCl2, cyclopentadiene, CH2Cl2
0 °C; ii, ROH or H2O, DMAP (0.2–1.1 equiv.), MeCN, room temp., 4–24
h.
† General IUPAC name: 3-acyl-1,3-thiazolidine-2-thione.
Chem. Commun., 1999, 545–546
545

oxazolidinone bromohydrins, in which benzyl a,b-epoxy esters
are formed.3
In conclusion, we have demonstrated that carboxthioimides
are very versatile and useful carboxy-protecting groups.
Significantly, the thioimide transesterification via DMAP
catalysis provides the acids or various ester protecting groups
without danger of racemization. The successful control of
oxazolidinethione deacylation vs. cyclization of nucleophiles
with bromohydrin aldol adducts illustrates the power of our
newly developed DMAP-promoted nucleophilic cleavage.
Further details in this area will be forthcoming.
We thank the National Science Council of the Republic of
China for support of this work (NSC 88-2213-M-005-006).
Notes and references
‡ Selected data for 3f: dH(400 MHz, CDCl3) 6.22 (dd, J 5.6, 3.2, 1H,
CHNCH), 5.96 (dd, J 5.6, 2.8, 1H, CHNCH), 4.07 (m, 2H, OCH2CH2), 3.06
(m, 1H, HCCNC), 2.43 (m, 1H, CNCCH), 2.31 (dd, J 4.0, 4.0, 1H, HCCNO),
1.79 (m, 1H, HCCH3), 1.37–1.52 (m, 2H, H2CCH), 1.14 (d, J 7.2, 3H,
CHCH3), 0.92 [m, 2H, CH2CH2Si(CH3)3], 0.01 [s, 9H, Si(CH3)3]; dC(100
MHz, CDCl3) 174.97, 138.59, 133.21, 62.31, 52.60, 48.79, 45.96, 45.90,
37.71, 20.96, 17.30, 21.50 (HRMS: calc. for C14H24O2Si, 252.1546. Found
252.1545. Calc. for C14H24O2Si: C, 66.62; H, 9.58. Found: C, 66.40; H,
9.69%). For 8: dH(400 MHz, CDCl3) 7.35 (br s, 5H, C6H5), 5.20 (2d, J 12.0,
2H, C6H5CH2), 4.47 (d, J 3.6, 1H, CHCHBr), 3.53 (dd, J 7.2, 3.6, 1 H,
Scheme 2
but still in excellent yield (Scheme 2). After 72 h, the
transesterification product 5, [a]2D5 +129.3 (c 0.9, CH2Cl2),9 was
obtained in 95% with no detectable levels of epimerization.
Using the above standard conditions, both hydrolysis and
methanolysis of aldol adduct 6 were easily effected without
racemization of either center (Scheme 3). The acid 6a, [a]D25
+13.6 (c 1.1, CH2Cl2), and ester 6b, [a]2D5 +22.5 (c 1.4,
CH2Cl2),2 were obtained in 87 and 92% yield, respectively.
CHCHCHBr), 1.87 (br s, 1H, OH), 1.78 (app. octet,
J 7.2, 1H,
(CH3)2CHCH), 1.00 (d, J 6.8, 3H, CH3CHCH3), 0.91 (d, J 6.8, 3H,
CH3CHCH3); dC(100 MHz, CDCl3) 169.18, 134.67, 128.60, 128.48,
128.25, 75.91, 67.94, 51.07, 31.61, 18.90, 17.60; [a]2D5 +15.5 (c 0.9,
CH2Cl2) (HRMS: calc. for C13H17O3Br, 300.0361. Found, 300.0355. Calc.
for C13H17O3Br: C, 51.82; H, 5.69. Found: C, 51.80; H, 5.65%).
1 Selected reviews: D. A. Evans, J. V. Nelson and T. R. Taber, Top.
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Scheme 3
In conjunction with a program directed toward the asym-
metric synthesis of b-hydroxy-a-amino acids, a key inter-
mediate toward biologically active peptides and b- and g-lactam
antibiotics,12 we were particularly interested in bromohydrin
substrates.13 To demonstrate the utility of this protocol, we
examined the transesterification of bromohydrin aldol 7,14
which by virtue of the ease of bromide displacement demands
very mild methods. In the DMAP (0.2 equiv.) catalyzed
transesterification (PhCH2OH) of bromohydrin 7 at 0 °C,
epoxide formation was completely suppressed and benzyl b-
hydroxy-a-amino ester 8 was isolated in 96% yield with no
apparent loss of stereochemistry (Scheme 4).‡ This result is in
directed contrast to the BnOLi deacylation conditions for
10 D. A. Evans, S. J. Miller and T. Lectka, J. Am. Chem. Soc., 1993, 115,
6460.
11 New compounds have been satisfactorily characterized spectroscop-
ically, and elemental composition has been established by high-
resolution mass spectroscopy and/or combustion analysis.
12 Amino Acids, Peptides and Proteins, Specialist Periodical Reports, vol.
1–16, ed. G. T. Young and R. C. Sheppard, Chemistry Society, London,
1968–1983; T. Sunazuka, T. Nagamitsu, K. Matsuzaki, H. Tanaka, S.
Omura and A. B. Smith, III, J. Am. Chem. Soc., 1993, 115, 5302.
13 D. A. Evans, E. B. Sjogren, A. E. Weber and R. E. Conn, Tetrahedron
Lett., 1987, 28, 39; E. J. Corey, D.-H. Lee and S. Choi, Tetrahedron
Lett., 1992, 33, 6735.
14 Prepared from the TiCl4-mediated aldolization of camphor-based
3-bromoacetyl-1,3-oxazolidine-2-thione with isobutyraldehyde.
Scheme 4
Communication 9/00577C
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Chem. Commun., 1999, 545–546