Ester derived titanium enolate aldol reaction: Chelation controlled diastereoselective synthesis of syn-aldols

Article abstract of DOI:10.1016/S0040-4039(00)02227-9

A chelation controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of commercially available L-phenylalaninol derived esters with a variety of bidentate oxyaldehydes proceeded with excellent syn-diastereoselectivities and isolated yields.

Full text of DOI:10.1016/S0040-4039(00)02227-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1227–1231
Ester derived titanium enolate aldol reaction: chelation controlled
diastereoselective synthesis of syn-aldols
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 1 November 2000; revised 4 December 2000; accepted 5 December 2000
Abstract—A chelation controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of commercially
available
L-phenylalaninol derived esters with a variety of bidentate oxyaldehydes proceeded with excellent syn-diastereoselectiv-
ities and isolated yields. © 2001 Elsevier Science Ltd. All rights reserved.
The asymmetric aldol reaction is one of the most
powerful carbonꢀcarbon bond forming reactions in
organic synthesis.1 Both syn- and anti-aldols are often
inherent to numerous biologically active natural prod-
ucts and a number of stereoselective methodologies
have been developed for their effective synthesis.2,3 We
presence of an a-chiral center may not be critical to
high observed syn-diastereoselectivities with the biden-
tate oxyaldehydes. To further understand the origin of
syn-selectivities, we have now investigated aldol reac-
tions of phenylalaninol derived sulfonamido esters with
a view to generating syn-aldols diastereoselectively by a
chelation through the b-sulfonamide functionality. To
extend the utility of these aldol processes, we herein
report that the reaction of sulfonamido ester derived
titanium enolates with a number of bidentate oxyalde-
hydes provided syn-aldol products with excellent
diastereoselectivities (up to 99% de) and isolated yields.
Mild saponification resulted in various optically active
recently reported
a cis-1-arylsulfonamido-2-indanyl
ester derived titanium enolate based novel stereoselec-
tive anti-aldol reaction.4a Subsequently, utilizing the
same chiral auxiliary, we developed an efficient syn-
aldol reaction with bidentate oxyaldehydes.4b Based
upon our proposed chelated transition-state assembly,
we speculated that the presence of an indane ring or the
R
HC
O
O
O
H
N
H
N
HA
HB
p-Tol
p-Tol
a
b
N
Ti
S
O
S
OH
O
O
H
O
O
H
S
R
p-Tol
O
H
O
1
2a R = Me
2b R = Bn
2c R = iBu
3
R1CHO
(Bidentate)
OH
OH
X
O
OH
O
H
N
H
N
p-Tol
p-Tol
c or d
HO
R1
S
O
R1
S
O
R1
O
O
H
O
O
H
R
R
R
6 X = O
7 X = H2
5
4
+
Scheme 1. (a) CH3CH2COCl, Et3N, CH2Cl2, 0°C, 1 h for 2a; RCO2H, DCC, DMAP, CH2Cl2, 23°C, 18–24 h for 2b and 2c; (b)
TiCl4, iPr2NEt, 0°C, 1 h then R1CHO and TiCl4, CH2Cl2, −78°C, 2 h; (c) LiOH, THF–H2O, 23°C, 2–3 h; (d) LiBH4, THF, 23°C.
* Corresponding author. E-mail: arunghos@uic.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02227-9

1228
A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 42 (2001) 1227–1231
syn-a-alkyl-b-hydroxy acids and full recovery of the
chiral auxiliary without loss of optical purity. The
ready availability of both enantiomers of phenyl-
alaninol, as well as the use of inexpensive titanium
tetrachloride reagent make the present syn-aldol pro-
cess particularly useful.
ing mixture was stirred at 0°C for 1 h. Complete
enolization under these conditions was established by
1H NMR (500 MHz) studies of the titanium enolate
generated in a mixture of CDCl3 and CH2Cl2. We
speculated that the enolization proceeds through for-
mation of a NꢀTi bond followed by intramolecular
Lewis acid activation of the ester carbonyl. The enolate
is a seven-membered metallocycle 3, presumably with a
Z-enolate geometry.5 The enolate so formed was
reacted with various oxyaldehydes precomplexed with
TiCl4 (2.1 equiv.) at −78°C for 2 h to provide the
respective aldol products in good to excellent isolated
yields. As can be seen in Table 1, reaction of propi-
onate ester 2a with bidentate benzyloxyacetaldehyde
proceeded with near complete syn-diastereoselectivity
As depicted in Scheme 1, commercially available and
optically active (2S)-phenylalaninol was reacted with
p-toluenesulfonylchloride and triethylamine in CH2Cl2
in the presence of a catalytic amount of DMAP to
provide optically pure (2S)-sulfonamide 1 in 95% iso-
lated yield ([h]2D3=−29.4, c 2.5, CHCl3). Reaction of
sulfonamide 1 with propionyl chloride and triethyl-
amine in CH2Cl2 at 0°C for 1 h afforded the propionate
ester 2a in 93% yield after silica gel chromatography.
Acylation of 1 with hydrocinnamic acid and 4-methyl-
valeric acid with DCC and DMAP afforded the respec-
tive esters 2b and 2c in 86 and 87% yield. The
corresponding titanium enolates of these esters were
generated by slightly modified conditions. For example,
propionyl ester 2a was reacted with 1 M TiCl4 (1.05
equiv.) in CH2Cl2 at 0°C and after 15 min, N,N-diiso-
propylethylamine (3 equiv.) was added and the result-
1
(98:2 ratio by HPLC; 400 MHz H NMR revealed only
one diastereomer, entry 1) with 80% isolated yield after
silica gel chromatography.6 Similarly, reaction with
benzyloxypropionaldehyde (entry 2) also afforded aldol
product with excellent syn-diastereoselectivity and iso-
lated yields. In comparison, reaction with benzyloxybu-
tyraldehyde (entry 3) furnished the syn-aldol product 5c
with slightly lower selectivity and yield. The reaction of
hydrocinnamate derivative 2b and 4-methylvalerate
Table 1. Aldol reaction of various esters 2a–c with representative aldehydes
Compda
5a
% Yieldb
Syn:Anti (5/4)c
98 : 2
r
Aldehyde
80
81
58
BnOCH2CHO
BnO(CH2)2CHO
BnO(CH2)3CHO
BnOCH2CHO
5b
97 : 3
5c
91 : 9
97 : 3
96 : 4
5d
5e
63
60
BnOCH2CHO
99 : 1
5f
BnO
BnO
CHO
CHO
84
59
Me
30 : 70d
4g

A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 42 (2001) 1227–1231
1229
OH
OH
O
O
H
N
H
N
p-Tol
O
Ph
p-Tol
O
Ph
S
O
S
O
O
O
H
O
O
H
Me
Me
Me
Me
5f
4g (mixture)
OH
OH
O
O
H
N
H
N
p-Tol
p-Tol
S
O
O
Ph
S
O
O
Ph
O
O
H
O
O
H
Me
Me
Me
Me
5h
5i
Figure 1.
derivative 2c with benzyloxyacetaldehyde also pro-
ceeded with excellent syn-diastereoselectivities (entries 4
and 5).
Saponification of the aldolates with aqueous lithium
hydroxide in THF at 23°C for 2–3 h furnished the
corresponding b-hydroxyacids (85–92% yield). Various
aldolates were also converted to their corresponding
alcohols 7 by lithium borohydride reduction in THF at
23°C for 2–4 h. In either case, the chiral auxiliary was
fully recovered without loss of optical purity. The rela-
tive and absolute stereochemistry of various syn aldo-
lates 5 were assigned by comparison of optical rotation,
We have also carried out double stereodifferentiating
experiments in which an oxyaldehyde bearing an a-chi-
ral center was reacted with the chiral enolate derived
from propionate ester 2a (Fig. 1). Aldol reaction of the
propionate ester 2a and 2(S)-benzyloxypropionalde-
hyde (stereochemically matched case) under identical
conditions afforded virtually a single (by HPLC and
1
as well as H and 13C NMR spectra of the resulting
acids or diols with literature values.8 The transfer of
chirality and observed diastereoselectivity can be ratio-
nalized by a Zimmerman–Traxler type transition state
model A as postulated previously.4,9 As shown in Fig.
2, the metallocycle adopts a chair-like conformation
and chirality transfer proceeds through the sulfonamide
bearing chiral center through effective metal chelation
with the bidentate aldehydes.10 Higher syn-selectivity
for benzyloxyacetaldehyde or benzyloxypropionalde-
hyde as opposed to benzyloxybutyraldehyde is due to
rigid five- or six-membered rather than flexible seven-
membered metal chelation. Furthermore, the observed
diastereoselectivities resulting from the double stereo-
differentiating experiments are consistent with this
model. As is evident in the model, the lack of syn-selec-
tivity for the 2(S)-benzyloxypropionaldehyde is due to
destabilizing non-bonded interaction between the
methyl (R1=Me) group and the benzyl side chain of
1
400 MHz H NMR analysis) aldol product 5f (entry 6)
in 84% yield after silica gel chromatography. In a
mismatched case, the reaction of 2a and 2(R)-benzyl-
oxypropionaldehyde, however, afforded a 30:70 mix-
ture of (syn:anti ) isomers in 59% isolated yield (entry
7). Matched stereochemical effects are also evident in
the aldol reaction of 2a with 2(R)-methyl benzyl-
oxypropionaldehyde (single diastereomer, entry 8). The
corresponding reaction with 2(S)-methylbenzyloxy-
propionaldehyde (mismatched pair) also proceeded in
good selectivity (83:17 mixture, entry 9).7 In contrast,
reaction of 2a with monodentate aldehydes such as
isovaleraldehyde and phenylpropargyl aldehyde pro-
vided the corresponding anti-isomer as the major
product. However, anti-diastereoselectivity is signifi-
cantly diminished compared to constrained 1-amino-2-
indanol derived chiral auxiliary.4a
O
R
OH
O
‡
O
H
N
O
p-Tol
Ti
N
O
S
O
R1
Ti
H
O
O
H
O
R1
R
S
p-Tol
H
Bn
O
5
A
Figure 2.

1230
A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 42 (2001) 1227–1231
the chiral template in the transition state. The choice of
benzyl side chain in the chiral auxiliary is not critical
since L-valinol derived propionyl ester enolate also pro-
vided comparable syn-diastereoselectivity (syn:anti ratio
>99:1; 74% isolated yield) with benyloxyacetaldehyde
under similar reaction conditions.
(f) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 173; (g) Corey, E. J.; Kim, S. S. J. Am.
Chem. Soc. 1990, 112, 4976; (h) Corey, E. J.; Kim, S. S.
Tetrahedron Lett. 1990, 31, 3715; (i) Meyers, A. G.;
Widdowson, K. L. J. Am. Chem. Soc. 1990, 112, 9672; (j)
Duthaler, R. O.; Herold, P.; Helfer, S.-W.; Riediker, M.
Helv. Chim. Acta 1990, 73, 659; (k) Walker, M. A.;
Heathcock, C. H. J. Org. Chem. 1991, 56, 5747; (l)
Braun, M.; Sacha, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 1318; (m) Gennari, C.; Moresca, D.; Vieth, S.;
Vulpetti, A. ibid 1993, 32, 1618; (n) Paterson, I.; Wren, S.
P. J. Chem. Soc., Chem. Commun. 1993, 1790; (o) Abiko,
A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586 and references cited therein.
In conclusion, we devised a chelation controlled ester
derived Ti-enolate based highly diastereoselective (82–
98% de) syn-aldol reaction with bidentate oxyalde-
hydes. The methodology is convenient since inexpensive
reagents and readily available optically active chiral
auxiliaries were utilized. The scope of the reaction can
also be extended to other bidentate aldehydes. Further
studies including synthetic applications are in progress.
4. (a) Ghosh, A. K.; Onishi, M. J. Am. Chem. Soc. 1996,
118, 2527; (b) Ghosh, A. K.; Fidanze, S.; Hussain, K. A.
Tetrahedron Lett. 1997, 38, 7171.
Acknowledgements
5. Our tentative assignment of the Z-enolate geometry is
1
based upon a H NOESY (CD2Cl2) experiment in which
a weak NOE was observed between the vinyl proton (HC)
and the methylene protons (HA and HB). The absence of
NOE between the vinyl methyl and the same methylene
Financial support for this work was provided by the
National Institutes of Health (GM 55600).
1
protons further supported this assignment. H NMR (3,
R=Me, CDCl3): l 1.57 (d, 1H, J=7 Hz), 2.38 (s, 3H),
2.76 (dd, 1H, J=9.4, 13.6 Hz), 3.10 (dd, 1H, J=5.5, 13.6
Hz), 3.16 (dd, 1H, J=6.5, 8.5 Hz), 3.68 (dd, 1H, J=2.1,
8.5 Hz), 4.73 (q, 1H, J=7 Hz), 7.17–7.30 (m, 7H), 7.65
(d, 2H, J=8.2 Hz).
References
1. (a) Arya, P.; Quin, H. Tetrahedron 2000, 56, 917; (b)
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994,
317; (c) Kim, B.-M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter
1.7, p. 239; (d) Heathcock, C. H. In Asymmetric Synthe-
sis; Morrision, J. D., Ed.; Academic Press: New York,
1984; Vol. 3, p. 111 and references cited therein.
6. All new compounds gave satisfactory spectroscopic and
analytical results. Preparation of syn-aldol 5a: To a
stirred solution of propionate ester 2a (550 mg, 1.52
mmol) in CH2Cl2 (15 ml) at 0°C was added a 1 M
solution of TiCl4 (1.6 ml, 1.6 mmol) dropwise under a N2
atmosphere. The resulting solution was stirred for an
additional 15 min. To this solution was added N,N-diiso-
propylethylamine (0.8 ml, 4.6 mmol) in a dropwise man-
ner. The mixture was stirred for 1 h at 0°C and then was
warmed to 23°C. In a separate flask, to a stirred solution
of benzyloxyacetaldehyde (457 mg, 3.04 mmol) in CH2Cl2
(20 ml) at −78°C under a N2 atmosphere, was added a 1
M solution of TiCl4 (3.2 ml, 3.2 mmol). After stirring for
10 min, the above enolate solution was added to this
aldehyde solution dropwise via syringe over 8 min. The
mixture was stirred at −78°C for 1.5 h before quenching
by aqueous NH4Cl. The resulting mixture was warmed to
23°C and the layers were separated. The aqueous layer
was extracted twice with CH2Cl2. The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to
afford the aldol products. Silica gel chromatography of
the crude product yielded the syn aldol product 5a (620
mg, 80%) as a viscous oil. [h]2D3 −4.9 c 1.2, CHCl3; 1H
NMR (500 MHz, CDCl3): l, 1.19 (d, 3H, J=7.1 Hz),
2.41 (s, 3H), 2.68 (m, 1H), 2.76 (d, 2H, J=7.2 Hz), 3.17
(d, 1H, J=4.0 Hz), 3.53 (d, 2H, J=5.8 Hz), 3.72 (m, 1H),
3.97–4.05 (m, 2H), 4.20 (m, 1H), 4.57 (dd, 2H, J=11.8,
20.5 Hz), 5.58 (d, 1H, J=8.1 Hz), 7.03–7.05 (m, 2H),
7.20–7.25 (m, 5H), 7.31–7.39 (m, 5H), 7.68 (d, 2H, J=
8.3); 13C NMR (125 MHz, CDCl3) l, 11.5, 21.9, 38.9,
42.6, 54.5, 65.4, 71.1, 72.1, 73.8, 127.2, 127.4, 128.3,
128.9, 129.1, 129.7, 130.1, 136.9, 138.0, 138.3, 143.7,
2. For syn-aldol reactions, see: (a) Masamune, S.; Bates, G.
S.; Corcoran, J. W. Angew. Chem., Int. Ed. Engl. 1977,
16, 585; (b) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am.
Chem. Soc. 1981, 103, 2127; (c) Roder, H.; Helmchen, G.;
Peters, E.-M.; von Schmering, H.-G. Angew. Chem., Int.
Ed. Engl. 1984, 23, 898; (d) Masamune, S.; Choy, W.;
Peterson, J. S.; Sita, L. R. ibid 1985, 24, 1; (e) Jackson, R.
F. W.; Sutter, M. A.; Seebach, D. Liebigs Ann. Chem.
1985, 2313; (f) Paterson, I.; Lister, M. A.; McClure, C. K.
Tetrahedron Lett. 1986, 27, 4787; (g) Corey, E. J.;
Imwinkelreid, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem.
Soc. 1989, 111, 5493; (h) Oppolzer, W.; Blagg, J.;
Rodriguez, I.; Walther, E. J. ibid 1990, 112, 2767; (i)
Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F.
ibid 1991, 113, 1047; (j) Ghosh, A. K.; Duong, T. T.;
McKee, S. P. J. Chem. Soc., Chem. Commun. 1992, 1673;
(k) Abiko, A.; Liu, J.-F.; Masamune, S. J. Org. Chem.
1996, 61, 2590; (l) Sulikowski, G. A.; Lee, W.-M.; Jin, B.;
Wu, B. Org. Lett. 2000, 2, 1439; (m) Roush, W. R.;
Pfeifer, L. A. Org. Lett. 2000, 2, 859 and references cited
therein.
3. For anti-aldol reactions, see: (a) Meyers, A. I.;
Yamamoto, Y. Tetrahedron 1984, 40, 2309; (b) Helm-
chen, G.; Leikauf, U.; Taufer-Knopfel, I. Angew. Chem.,
Int. Ed. Engl. 1985, 24, 874; (c) Gennari, C.; Bernardi, A.;
Colombo, L.; Scolastico, C. J. Am. Chem. Soc. 1985, 107,
5812; (d) Oppolzer, W.; Marco-Contelles, J. Helv. Chim.
Acta 1986, 69, 1699; (e) Masamune, S.; Sato, T.; Kim, B.
M.; Wollman, T. A. J. Am. Chem. Soc. 1986, 108, 8279;
175.1; IR (neat): 3508, 3282, 1731, 1328, 1159 cm−1
.

A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 42 (2001) 1227–1231
1231
7. Mukaiyama aldol reactions of N-methylephidrine derived
silyl ketene acetal and 2(R)- and 2(S)-methylbenzyl-
oxypropionaldehyde have also exhibited similar syn-selec-
tivities, see: Gennari, C.; Colombo, L.; Bertolini, G.;
Schimperna, G. J. Org. Chem. 1987, 52, 2754.
8. Optical rotation of corresponding carboxylic acids
(CHCl3 solvent for all), 6a: [h]2D3 +11.93 (c 2.43), lit4b:
[h]D +12.97 (c 3.7); 6b: [h]2D3 +13.6 (c 2.2), lit4b: [h]D
+9.44 (c 1.8); 6c: [h]2D3 +28.6 (c 1.0), from Evans aldol:
[h]2D3 +32 (c 0.53); 6f: [h]2D3 +50 (c 0.5), from Evans aldol:
[h]D23 +50 (c 0.3); 7h: [h]D23 −43.5 (c 1.5), lit7: [h]D −38.5
(c 1.0).
9. Zimmmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc.
1957, 79, 1920.
10. The evidence of titanium chelation with the benzylether
oxygen of oxyaldehydes is supported by the fact that
BF3·OEt2 instead of TiCl4 for complexation of aldehydes
resulted in very little syn-selectivity (syn:anti=52:48). We
are currently investigating the importance of sulfonamide
functionality and its role in the transition state assembly.
.