Stereoselective chloroacetate aldol reactions: Syntheses of acetate aldol equivalents and darzens glycidic esters

Article abstract of DOI:10.1021/ol0490835

Aldol reaction of the Ti-enolate derived from cis-1-tosylamido-2-indanyl chloroacetate with representative aldehydes proceeded in excellent yield and high diastereoselectivities. Removal of chlorine provided alternative access to highly diastereoselective acetate aldol equivalents or the corresponding glycidic ester condensation products.

Full text of DOI:10.1021/ol0490835

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2725-2728
Stereoselective Chloroacetate Aldol
Reactions: Syntheses of Acetate Aldol
Equivalents and Darzens Glycidic Esters
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received May 18, 2004
ABSTRACT
Aldol reaction of the Ti-enolate derived from cis-1-tosylamido-2-indanyl chloroacetate with representative aldehydes proceeded in excellent
yield and high diastereoselectivities. Removal of chlorine provided alternative access to highly diastereoselective acetate aldol equivalents or
the corresponding glycidic ester condensation products.
Enantioselective synthesis of anti- or syn-R-halo-â-hydroxy
carbonyl units is of considerable interest since this structural
feature can provide access to a variety of useful intermedi-
ates. Asymmetric aldol reaction of chloroacetate derivatives
appeared to be the most direct route to these intermediates;
however, reports of R-halo acetate aldol reactions are rather
limited.1 Furthermore, most reported methodologies are based
upon syn-aldol reactions of haloacetate derivatives.1,2 The
corresponding anti-selective R-halo acetate aldol reaction has
thus far been very rare. Numerous halo-aldolates have already
been utilized in syntheses, including their transformation into
R-amino-â-hydroxy derivatives,2 as well as in the synthesis
of acetate aldol equivalents.3 In addition, R-chloro-â-hydroxy
aldolates are precursors to Darzens condensation products
leading to R,â-epoxycarbonyl derivatives, which are impor-
tant subunits of taxol and taxostere.4 In continuing our studies
aimed at developing practical methodologies utilizing ester-
derived Ti-enolate aldol reactions, we have investigated
asymmetric syn- and anti-aldol reactions of chloroacetate
derivatives. Herein we report that reactions of chiral sul-
fonamido chloroacetate-derived titanium enolates with a
variety of monodentate and bidentate aldehydes provided
highly diastereoselective anti- and syn-R-chloro-â-hydroxy
carbonyl derivatives, respectively. Additive effects on anti
diastereoselectivity with monodentate aldehydes are note-
worthy. Various aldolates were obtained in excellent dia-
stereoselectivities (up to 99% dr) and isolated yields.
Aldolates so formed were converted to optically active
acetate aldol derivatives and R,â-epoxy esters, the corre-
sponding Darzens condensation product under mild reaction
conditions.
(1) (a) Wang, Y.-C.; Su, D.-W.; Lin, C.-M.; Tseng, H.-L.; Li, C.-L.;
Yan, T.-H. Tetrahedron Lett. 1999, 40, 3577. (b) Kiyooka, S.-I.; Shahid,
K. A. Tetrahedron: Asymmetry 2000, 11, 1357. (c) Corey, E. J.; Choi, S.
Tetrahedron Lett. 1991, 32, 2857. (d) Pridgen, L. N.; Abdel-Magid, A.;
Lantos, I.; Shilcrat, S.; Eggleston, D. S. J. Org. Chem. 1993, 58, 5107.
(2) Palomo, C.; Oiarbide, M.; Sharma, A. K.; Gonzalez-Rego, M. C.;
Lindea, A.; Garcia, J. M.; Gonzalez, A. J. Org. Chem. 2000, 65, 9007.
(3) (a) Guz, N, R.; Phillips, A. J. Org. Lett. 2002, 4, 2253. (b) Zhang,
Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004, 6, 23. (c) Palomo, C.;
Gonzalez, A.; Garcia, J. M.; Landa, C.; Oiarbide, M.; Rodr´ıguez, S.; Linden,
A. Angew. Chem., Int. Ed. 1998, 37, 180.
We recently reported cis-1-tosylamido-2-indanyl propi-
onate-derived titanium enolate aldol reactions of monodentate
and bidentate aldehydes providing highly diastereoselective
(4) (a) Geneˆt, J. P.; Cano de Andrade, M. C.; Ratovelomanana-Vidal,
V. Tetrahedron Lett. 1995, 36, 2063. (b) Righi, G.; Rumboldt, G. J. Org.
Chem. 1996, 61, 3557. (c) Yamaguchi, T.; Harada, N. Ozaki, K.; Hayashi,
M.; Arakawa, H.; Hashiyama, T. Tetrahedron 1999, 55, 1005. (d) Toda,
F.; Takumi, H.; Tanaka, K. Tetrahedron: Asymmetry 1995, 6, 1059.
10.1021/ol0490835 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004

Scheme 1. Ti-Enolate Aldol Reactions with Aldehydes
Figure 1. Ester-derived Ti-enolate aldol reaction.
anti- and syn-aldol products, respectively (Figure 1).5
Subsequently, we speculated that the corresponding R-chloro
acetate-derived enolate would provide a similar degree of
diastereoselectivity under similar reaction conditions. Thus,
(1R,2S)-1-tosylamido-2-indanol 45 was treated with chloro-
acetyl chloride and pyridine in CH2Cl2 at 0 °C for 2 h to
furnish R-chloro acetate 5 in 96% yield (Scheme 1). In a
preliminary experiment, 5-derived Ti-enolate (generated from
1.1 equiv of TiCl4 and 2.5 equiv of Hunig’s base at 0 °C)
was reacted with isobutyraldehyde precomplexed with TiCl4
(2.2 equiv) at -78 °C for 2 h. This provided a mixture of
aldol products in 82% yield with the anti isomer as the major
product (anti:syn ratio 75:25). Out of four possible diaster-
eomers, only formation of anti diastereomer 6a (R ) iPr)
and syn diastereomer 7a (R ) iPr) was observed by 1H NMR
and 13C NMR analysis. The anti diastereoselectivity is
significantly lower than the corresponding propionate
derivative.5a To further improve anti diastereoselectivity, we
investigated the effects of additives on anti diastereoselec-
tivity with a range of additives, and the results are shown in
shown Table 1. As can be seen, acetonitrile and N-methyl
pyrrolidinone (NMP) showed significant effects on anti
diastereoselectivities and yields (entries 2 and 3). Optimum
results were observed with 2.2 equiv of additive. Reaction
of isobutyraldehyde in the presence of 1 equiv of CH3CN
provided significantly lower anti diastereoselectivity (entry
4) compared to 2.2 equiv of CH3CN (entry 2). We have
recently observed similar additive effects leading to improved
anti-aldol reaction of the Ti-enolate derived from cis-2-
arylsulfonamido-1-acenaphthenyl propionate.6 Additive ef-
fects with PPh3, NMP, and THF in titanium-mediated aldol
at 0 °C for 5 min followed by further treatment with N,N-
diisopropylethylamine (2.5 equiv) at 0 °C for 1 h. The
resulting titanium enolate was added to a precomplexed
mixture of isobutyraldehyde (2 equiv), TiCl4 (2.2 equiv), and
CH3CN (2.2 equiv) at -78 °C. The resulting mixture was
stirred at that temperature for 2 h prior to quenching with
aqueous NH4Cl. This reaction protocol was equally effective
when the reaction was carried out on a multigram scale.
Aldol reactions with other additives in Table 1 were carried
out using an analogous procedure. While additive effects of
Ph3P, HMPA, and THF (entries 5, 8, and 9) resulted in
Table 1. Additive Effect on Aldol Reaction with iPrCHO
entry
additives
equiv
yielda
anti:synb
1
2
3
4
5
6
7
8
9
none
CH3CN
NMP
CH3CN
Ph3P
NC(CH2)2CN
(CH3)3CCN
HMPA
THF
0
82
66
71
60
22
64
44
17
15
75:25
98:2
94:6
88:12
99:1
93:7
91:9
99:1
99:1
2.2
2.2
1.0
2.2
1.1
2.2
2.2
2.2
reactions have been investigated by others as well.7
A
representative reaction (entry 2) in Table 1 with CH3CN as
an additive was carried out as follows: Ti-enolate of R-chloro
acetate was formed by reaction of 5 with TiCl4 (1.1 equiv)
(5) (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.
(b) Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahedron
Lett. 1997, 38, 7171.
1
a Isolated yield of diastereomeric mixtures. b Ratio determinded by H
NMR before chromatography.
(6) Ghosh, A. K.; Kim, J.-H. Org. Lett. 2003, 5, 1063.
2726
Org. Lett., Vol. 6, No. 16, 2004

Scheme 2. Acetate Aldol and Epoxide Synthesis
Table 2. Aldol Reactions with Representative Aldehydes
major
entry
aldehyde
iBuCHO
iBuCHO
BuCHO
BuCHO
PrCHO
PrCHO
PhCHO
product yielda anti (6):syn (7)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
6b
6b
6c
6c
6d
6d
6e
6e
7e
7f
88c
90d
68c
70d
79c
60d
62c
47d
64
99:1
99:1
96:4
96:4
96:4
97:3
96:4
96:4
10:90
1:99
4:96
26:74
1:99
99:1
5:95
PhCHO
PhCHO
BnOCH2CHO
BnO(CH2)2CHO
BnO(CH2)3CHO
(R)-BnOCH-(Me)CHO
(S)-BnOCH-(Me)CHO
(()-BnOCH-(Me)CHO
86
7g
7h
7i
79
82e
94
6j
7i
82
95e
a Isolated yield of pure diastereomer. b Ratio determined by 1H NMR
before chromatography. c CH3CN (2.2 equiv) was used as an additive.
d NMP (2.2 equiv) was used as an additive. e Isolated yield of diastereomeric
mixtures.
excellent anti diastereoselectivities, reaction yields are far
from satisfactory. Also, systematic attempts to improve
reaction yields have been unsuccessful thus far.
The scope and utility of chloroacetate aldol reactions in
the presence of CH3CN or NMP as additive were then
investigated with a range of representative monodentate and
bidentate aldehydes. The results are shown in Table 2. As it
turned out, the chloroacetate aldol reactions with monodenate
aliphatic aldehydes proceeded with excellent anti selectivities
and good to excellent yields (entries 1-6). Interestingly,
reaction with benzaldehyde, in the presence of either CH3-
CN or NMP as an additive showed good anti diastereo-
selectivity (entries 7 and 8). However, the corresponding
reaction in the absence of additive displayed syn diastereo-
facial selectivity (entry 9). Consistent with our previous
observation with propionate aldol reactions, bidentate oxy-
aldehydes such as benzyloxy acetaldehyde and benzyloxy-
propionaldehyde exhibited excellent syn diastereoselectivities
and yields (entries 10 and 11) without any additive. Reaction
of benzyloxyacetaldehyde in the presence of 2 equiv of CH3-
CN as an additive provided no change in syn diastereo-
selectivity, but the aldol product was obtained in only 37%
yield.
14). On the basis of these results, we performed kinetic
resolution experiments with racemic 2-benzyloxypropion-
aldehyde. The aldol reaction was carried out with 2 equiv
of racemic aldehyde for 30 min to provide a 95:5 syn
diastereomeric ratio in 95% yield (entry 15). Formation of
major syn diastereomer 7i resulted from preferential reaction
with matched 2(R)-benzyloxypropionaldehyde. Recovered
2(S)-benzyloxypropionaldehyde showed 98.7% enantiomeric
excess and 40% recovered yield.8
The relative stereochemistry of aldol products was assigned
on the basis of comparison of observed vicinal coupling
constants of the major aldol products (J2,3 ) 6-10 Hz for
anti-aldols and J2,3 ) 3-4 Hz for syn-aldols) with the
corresponding propionate aldol products.10 Further confirma-
tion of the relative stereochemistry of anti-aldols 6b-j and
syn-aldols 7e-i was established by their conversion to the
corresponding isopropylidene derivatives (9 and 11) and
comparison of coupling constants with the literature values
as described by us previously.6 For synthesis of isopropyli-
dene derivatives, aldolates were treated with LiBH4 in a
mixture of THF and methanol at 23 °C to provide chloro-
hydrins 8 and 10. Exposure of chlorohydrins 8 and 10 to
Furthermore, we have investigated double asymmetric
induction employing 2(R)- and 2(S)-benzyloxypropionalde-
hyde. In the matched case, aldol reaction with 2(R)-
benyloxypropionaldehyde provided only a single syn dia-
stereomer 7i in excellent yield (entry 13). However, for the
mismatched case, aldol reaction with 2(S)-benzyloxypropion-
aldehyde exclusively afforded an anti-aldol adduct 6j (entry
(8) Enantiomeric excess was calculated from comparison of the observed
optical rotation value with the reported value ([R]D20 -51.5 (c 0.89, CHCl3);
20
(7) For previous investigations with PPh3, NMP, and THF as additives,
see: (a) Gennari, C.; Colombo, L.; Bertolini, G.; Schimperna G. J. Org.
Chem. 1987, 52, 2754. (b) Palazzi, C.; Colombo, L.; Gennari, C.
Tetrahedron Lett. 1986, 27, 1735. (c) Crimmins, M. T.; King, B. W.; Tabet,
E. A.; Chaudhary, K. J. Org. Chem. 2001, 66, 894. (d) Shirokar, S.; Nerz-
Stormes, M.; Thorntorn, E. R. Tetrahedron Lett. 1990, 31, 4699.
lit.9 [R]D -52.2 (c 6.5, CHCl3)).
(9) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50, 3247.
(10) (a) Yan, T.-H.; Tan, C.-W.; Lee, H.-C.; Lo, H.-C.; Huang, T.-Y. J.
Am. Chem. Soc. 1993, 115, 2613. (b) Heathcock, C. H.; Buse, C. T.;
Kleschick, W. A.; Pirrung, M. C.; John, J. E.; Lampe, J. J. Org. Chem.
1980, 45, 1066.
Org. Lett., Vol. 6, No. 16, 2004
2727

dimethoxypropane in CH2Cl2 in the presence of a catalytic
amount of PPTS furnished isopropylidene derivatives 9 and
11, respectively.
7f,i afforded the corresponding acetate aldol equivalents in
excellent yields. The stereochemical outcome of chloroacetate
aldol reactions to provide anti diastereoselectivities with
monodentate aldehydes and syn selectivities with bidentate
aldehydes is consistent with our previous stereochemical
models.5 Presumably, the additive provides more steric bias
on the titanium metal center, inducing improved anti
selectivity with monodentate aldehydes.
The absolute configuration of the aldolates was established
after their conversion to the corresponding R,â-epoxy acid
and 1,3-diols and comparison of optical rotation with the
literature. Treatment of aldolate 6a with K2CO3 in methanol
at 23 °C effected removal of the chiral auxiliary and
concominant formation of R,â-epoxy acid 15a in 70% yield.
Catalytic hydrogenation of 6a over Pd-C in the presence
of ammonium formate afforded dechlorination product 12a.
Reduction of 12a with LiBH4 furnished alcohol 13a. Optical
rotations and spectroscopic data of alcohols 13a, 17f, and
acid 15a were compared with literature values.11 When the
aldolates were treated with K2CO3 in aqueous DMF at 23
°C, the corresponding R,â-epoxy esters were formed.15
Furthermore, catalytic dechlorination of aldolates 6a,b and
In summary, we have developed highly diastereoselective
titanium enolate-based anti- and syn-aldol reactions with
chiral R-chloro acetate derivatives. Pronounced additive
effects resulted in improved anti selectivity with monodentate
aldehydes. The ready availability of the chiral auxiliary and
the use of Ti-reagent renders this methodology very useful.
Acknowledgment. Financial support by the National
Institutes of Health is gratefully acknowledged.
(11) 15a: [R]23 11.4 (c 0.71, 95% EtOH); lit.12 ent-15a [R]23 -15.2
D
D
(c 0.52, 95% EtOH). 13a: [R]23 -18 (c 0.5, CHCl3); lit.13 [R]D -11.3 (c
Supporting Information Available: Experimental pro-
D
2, CHCl3). 17f: [R]23D 8.98 (c 0.88, MeOH); lit.14 [R]D 7.66 (c 1.75, MeOH).
(12) Caldwell, C. G.; Bondy, S. S. Synthesis 1990, 34.
(13) Harada, T.; Kurokawa, H.; Kagamihara, Y.; Tanaka, S.; Inoue, A.;
Oku, A. J. Org. Chem. 1992, 57, 1412.
(14) Takano, S.; Kasahara, C.; Ogasawara, K. Chem. Lett. 1983, 175.
(15) Yields for 14a, 14b, and 18g were 58, 65, and 49%, respectively.
1
cedures, spectral data for compounds 5-18, and H NMR
and 13C NMR spectra for compounds 5-18. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0490835
2728
Org. Lett., Vol. 6, No. 16, 2004