Chelation-controlled ester-derived titanium enolate aldol reaction: Diastereoselective syn-aldols with mono- and bidentate aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)01113-9

A chelation-controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of (S)-valinol-derived ester with a variety of aldehydes proceeded with high syn-diastereoselectivities (up to 99:1) and isolated yields (94%).

Full text of DOI:10.1016/S0040-4039(02)01113-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5621–5624
Chelation-controlled ester-derived titanium enolate aldol reaction:
diastereoselective syn-aldols with mono- and bidentate aldehydes
Arun K. Ghosh* and Jae-Hun Kim
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 5 May 2002; revised 7 June 2002; accepted 10 June 2002
Abstract—A chelation-controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of (S)-valinol-
derived ester with a variety of aldehydes proceeded with high syn-diastereoselectivities (up to 99:1) and isolated yields (94%).
© 2002 Elsevier Science Ltd. All rights reserved.
Optically active syn- and anti-2-alkyl-3-hydroxycar-
bonyl units are inherent to numerous biologically active
natural products.1 As a consequence, a number of
stereoselective methodologies have been developed for
their syntheses.2,3 In our recent work on ester-derived
titanium enolate aldol reactions4 we have demonstrated
that the aldol reactions of phenylalaninol-derived sul-
fonamido esters with a number of bidentate oxyalde-
hydes provided syn-aldols diastereoselectively. The
corresponding reactions with monodentate aldehydes,
however, have shown little syn-selectivities. The chiral-
ity transfer presumably proceeds through chelation by
the b-sulfonamide functionality. In our continuing
effort to further develop these ester-derived titanium
enolate aldol reactions, we have subsequently investi-
gated the effect of a b-chiral substituent on aldol stere-
ochemistry by replacing the phenylmethyl substituent of
phenylalaninol with other alkyl groups. Herein, we
report that the aldol reaction of an (S)-valinol-derived
sulfonamido ester with a variety of mono- and biden-
tate aldehydes proceeded with good to excellent syn-
diastereoselectivities and isolated yields. Removal of the
chiral auxiliary by mild saponification provided opti-
cally active syn-a-alkyl-b-hydroxy acids and full recov-
ery of the chiral auxiliary. The ready availability of
valinol and use of inexpensive TiCl4 make this method-
ology practical and provide rapid access to syn-aldols
in optically active form.
ethylamine in the presence of DMAP at 0°C for 2 h
(89% yield). As shown in Scheme 1, reaction of sulfon-
amide 1 with propionylchloride and triethylamine
afforded propionyl ester 2 in 85% yield after silica gel
chromatography (mp 78°C, [h]2D3=−19.1 (c 0.92,
CHCl3)). The corresponding titanium enolate of 2 was
prepared by treatment with TiCl4 (1.1 equiv., 1 M
solution in CH2Cl2) in CH2Cl2 at 0°C followed by
addition of N,N%-diisopropylethylamine (3 equiv.) after
10 min and stirring of the resulting mixture at 0°C for
1 h. The enolate so formed was reacted with a variety
of aldehydes precomplexed with TiCl4 (3 equiv.) at
O
H
N
H
N
p-Tol
p-Tol
a
S
O
S
OH
O
O
H
O
O
H
H
1
2
b
OH
O
OH
O
H
N
H
N
p-Tol
p-Tol
S
O
R
S
O
R
O
O
O
O
H
+
Me
Me
4
3
c
e
OH
OH
O
HO
R
5 R1 = H
6 R1 = Me
R1O
R
d
7
Me
Me
Optically active N-p-tosyl-(2S)-valinol 1 was prepared
in multigram quantities by reduction of L-valine with
Scheme 1. Reagents and conditions: (a) CH3CH2COCl, Et3N,
CH2Cl2, 0°C, 2 h; (b) TiCl4, iPr2NEt, 0°C, 1 h, then RCHO
and TiCl4, CH2Cl2, −78°C, 2 h; (c) LiOH, THF–H2O, 23°C,
2–3 h; (d) CH2N2, Et2O, 23°C, 30 min; (e) LiBH4, THF–
MeOH, 23°C, 2 h.
LiAlH4 and followed by sulfonylation of the amine
functionality with p-toluenesulfonyl chloride and tri-
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01113-9

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A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 43 (2002) 5621–5624
−78°C for 1.5–2 h. Interestingly, aldol reaction of 2
with various aldehydes proceeded with excellent
diastereoselectivity and isolated yields; the results are
summarized in Table 1. Out of four possible
diastereomers, formation of syn-diastereomer 3 (major)
1
and anti-diastereomer 4 were observed by H and 13C
NMR as well as HPLC analysis before and after chro-
matography. Reaction of 2 with monodentate alde-
hydes exhibited high syn-diastereoselectivity (entries
1–5)8 except with phenylpropargyl aldehyde which
afforded the anti-isomer as the major product (entry 6).
Furthermore, reaction with bidentate aldehydes such as
benzyloxyacetaldehyde and benzyloxypropionaldehyde
provided a single syn-aldolate in high yield (entries 7
and 8). We have also carried out double stereodifferen-
tiating experiments in which an oxyaldehyde bearing an
a-chiral center was reacted with the chiral enolate
derived from propionate ester 2. Aldol reaction of 2
and 2(S)-benzyloxypropionaldehyde (stereochemically
matched case) under identical conditions afforded virtu-
Scheme 3.
2(R)-benzyloxypropionaldehyde, a mismatched case,
afforded a 34:64 mixture of syn and anti isomers in 82%
isolated yield (entry 10). Because of the marked stereo-
chemical preference (matched isomer), we then
attempted reaction of 2 (1 equiv.) with racemic benzyl-
oxypropionaldehyde (2 equiv.) at −78°C for 0.5 h
(Scheme 2).
1
ally a single (by HPLC and 400 MHz H NMR analy-
sis) aldol product 3h (entry 9) in 77% yield after silica
gel chromatography. However, the reaction of 2 and
Interestingly, 2-derived Ti-enolate reacted exclusively
with the 2(S)-benzyloxypropionaldehyde (1 equiv.)
under these reaction conditions providing only
diastereomer 3i (matched case) in 82% isolated yield
after silica gel chromatography. Separation and purifi-
cation of the corresponding unreacted enantioenriched
2(R)-benzyloxypropionaldehyde was difficult due to
overlapping by-product. Subsequently, the crude alde-
hyde was reduced with NaBH4 in ethanol at 23°C to
afford 2(R)-(benzyloxy)propanol with an enantiomeric
excess of 81% ee (41% recovered, [h]2D3=−36.2 (c 1.9,
CHCl3); lit.:9 [h]D20=−45 (c 1.0, CHCl3).
Table 1. Aldol reaction of ester 2 with representative alde-
hydes
Entry Aldehyde
Compda Yield (%)b syn:anti (3/4)c
1
2
3
Me2CHCHO
3a
3b
3c
89
93
89
90:10
95:5
96:4
Me2CHCH2CHO
trans-PhCHꢀ
CHCHO
4
5
6
7
8
9
PhCHO
3d
3e
3f
3g
3h
3i
94
96
86
74
81
77
88:12
82:18
36:64d
99:1
99:1
99:1
The relative and absolute stereochemistry of various
Me(CH2)6CHO
Ph-CꢁC-CHO
BnOCH2CHO
BnOCH2CH2CHO
syn-aldolates (3) were established based upon compari-
1
son of optical rotation as well as H and 13C NMR
spectra of the resulting acids, esters or diols with litera-
ture values.5 Thus, saponification of the above aldolates
with aqueous lithium hydroxide in THF at 23°C for 2 h
furnished the corresponding b-hydroxy acids (5). Treat-
ment of these acids with CH2N2 afforded the corre-
sponding methyl esters (6). Various aldolates were
converted to diols 7 by treatment with LiBH4 at 23°C
for 2–4 h. In either case, the chiral auxiliary was fully
recovered without loss of optical activity.
BnO
CHO
Me
Me
10
3j
82
34:66d
BnO
CHO
a Major isolated product.
We subsequently investigated substituent effects on the
chiral auxiliary as well as the influence of various
achiral and chiral bases on diastereoselectivity. As
shown in Scheme 3, we have examined ester enolate
aldol reactions of N-p-tosyl-(S)-tert-leucinol and N-p-
b Isolated yield after chromatography.
c Ratios determined by 1H MR and HPLC analysis before and after
chromatography. Reaction time=1.5–2 h.
d Ratio after removal of chiral auxiliary.
OH
O
H
N
p-Tol
OBn
TiCl4, iPr2NEt,
2
+
BnO
CHO
S
O
O
O
H
CH2Cl2, -78°C
Me
Me
(±)
Me
(82% yield, 99:1 dr)
3i
Scheme 2.

A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 43 (2002) 5621–5624
Table 2. Aldol reaction of various esters with representative aldehydes
5623
Entry
Ester
Aldehyde
Base (equiv.)
Yield (%)a
syn:anti (9/10)b
1
2
3
4
5
6
7
8
9
R1=tBu, R2=Me
R1=iBu, R2=Me
R1=Bn, R2=Me
R1=iBu, R2=Me
R1=iBu, R2=Me
R1=iBu, R2=Me
R1=iBu, R2=Me
R1=iBu, R2=Me
R1=iPr, R2=iBu
Me2CHCHO
Me2CHCHO
Me2CHCHO
Me2CHCHO
Me2CHCHO
PhCHO
Ph-CꢁC-CHO
BnOCH2CHO
Me2(CH2)2CHO
DIPEA (3)
DIPEA (2.5)
DIPEA (2.5)
(−)-Spartein (2.2)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
DIPEA (3)
DIPEA (3)
35
73
86
63
83
77
83
80
97
90:10
85:15
86:14
88:12
88:12
85:15
14:86
99:1
87:13
a Isolated yield after chromatography.
b Ratios determined by 1H NMR before and after chromatography.
tosyl-(S)-leucinol-derived esters and a number of alde-
hydes. The results of these various aldol reactions are
illustrated in Table 2. As can be seen, the sterically
demanding tert-leucinol-derived chiral auxiliary exhib-
ited lower yield over leucinol-derived auxiliary; how-
ever, stereoselectivities were comparable (entries 1 and
2). The phenylalaninol-derived chiral auxiliary has also
shown comparable syn-diastereoselectivity under the
reaction conditions described above (entry 3). Interest-
ingly however, the same aldol reaction with fewer
equivalents of TiCl4 precomplexed to isovaleraldehyde
displayed anti-diastereoselectivity.10 Such reversal in
diastereoselectivity is not totally unexpected as the
Lewis acid to aldehyde ratio is known to effect aldol
stereoselectivity.11 The choice of base is quite important
for reaction yield but does not seem to effect observed
stereoselectivity (entries 3–5). The chirality on the base
has little influence on diastereoselectivities. Bidentate
oxyaldehydes are in general very good substrates for
ester enolate aldol reactions, providing syn-aldolates in
excellent yields and diastereoselectivities (entry 8). The
valinol-derived chiral auxiliary has also shown very
good syn-diastereoselectivity and reaction yield with
isocaproate ester (entry 9).
Wu, B. Org. Lett. 2000, 2, 1439; (c) Roush, W. R.;
Pfeifer, L. A. Org. Lett. 2000, 2, 859; (d) Evans, D. A.;
Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.;
Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55,
8671; (e) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2,
2405; (f) Ghosh, A. K.; Bischoff, A. Org. Lett. 2000, 2,
1537; (g) Kobayashi, S.; Hamada, T.; Nagayama, S.;
Manabe, K. Org. Lett. 2001, 3, 165; (h) Andrus, M. B.;
Meredith, E. L.; Soma Sekhar, B. B. V. Org. Lett. 2001,
3, 259.
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. Angew. Chem., Int. Ed. Engl.
1985, 24, 1; (e) Jackson, R. F. W.; Sutter, M. A.; See-
bach, 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. J. Am. Chem.
Soc. 1990, 112, 2767; (i) Evans, D. A.; Rieger, D. L.;
Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 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)
Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775
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;
(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,
In summary, we devised a chelation-controlled ester-
derived titanium enolate-based highly diastereoselective
syn-aldol reaction with various aldehydes. The current
methodology is quite practical due to the ready
availability of optically pure chiral auxiliary and use of
inexpensive TiCl4 as the key reagent. Further mechanis-
tic investigations, effects of various sulfonamido func-
tionalities and synthetic applications are underway in
our laboratories.
Acknowledgements
Financial support for this work was provided by the
National Institutes of Health (GM 53386).
References
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5624
A. K. Ghosh, J.-H. Kim / Tetrahedron Letters 43 (2002) 5621–5624
30, 1318; (m) Gennari, C.; Moresca, D.; Vieth, S.;
cannula over 30 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 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 aldol product (363 mg, 93%) as a viscous oil. Com-
pound 3b: [h]2D3=−19.6 (c 1.58, CHCl3); 1H NMR (400
MHz, CDCl3): l 0.81 (d, 6H, J=6.9 Hz), 0.84 (d, 6H,
J=6.9 Hz), 1.10 (d, 3H, 7.1 Hz), 1.43 (m, 1H), 1.77 (m,
2H), 2.38 (m, 2H), 2.41 (s, 3H), 2.48 (br, 1H), 3.34 (m,
1H), 3.95 (dd, 1H, J=11.6, 4.5 Hz), 4.01 (m, 1H), 4.06
(dd, 1H, J=11.6, 5.9 Hz), 5.17 (d, 1H, J=9.0 Hz), 7.28
(d, 2H, J=8.3 Hz), 7.75 (d, 2H, J=8.3 Hz); 13C NMR
(100 MHz, CDCl3): l 10.1, 18.3, 18.9, 21.5, 21.9, 23.4,
24.6, 30.0, 42.9, 44.7, 57.9, 64.0, 69.6, 127.0, 129.6, 138.2,
143.3, 175.8; IR (neat): 3521, 3286, 1730, 1327, 1161
Vulpetti, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1618;
(n) Paterson, I.; Wren, S. P. J. Chem. Soc., Chem. Com-
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5. Optical rotation of corresponding carboxylic acids, diols
and methylesters (CHCl3 solvent for all, unless otherwise
noted), 5g: [h]D23=+13.6 (c 1.1), lit.:4c [h]2D3=+12.97 (c
3.7); 7a: [h]2D3=−10.29 (c 0.68), lit.:6 [h]2D5=−10.3 (c 0.2);
7c: [h]2D3=+12.2 (c 0.83, MeOH), lit.:7 [h]2D5=+15.1 (c
0.55, MeOH); 6b: [h]2D3=+16 (c 0.48), sample prepared
from Evans aldol: [h]2D3=+12 (c 0.13).
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cm−1
.
8. All new compounds gave satisfactory spectroscopic and
analytical results. Preparation of syn-aldol 3b: To a
stirred solution of propionate ester 2 (313 mg, 1 mmol) in
CH2Cl2 (10 mL) at 0°C was added a 1 M solution of
TiCl4 (1.1 mL, 1.1 mmol) dropwise under a N2 atmo-
sphere. The resulting solution was stirred for 10 min. To
this solution was added N,N-diisopropylethylamine (0.52
mL, 3 mmol) in a dropwise manner. The mixture was
stirred for 1 h at 0°C and then warmed to 23°C. In a
separate flask, to a stirred solution of isovaleraldehyde
(172 mg, 2 mmol) in CH2Cl2 (20 mL) at −78°C under N2
atmosphere, was added a 1 M solution of TiCl4 (3 mL,
3 mmol). After stirring for 10 min, the above enolate
solution was added to this aldehyde solution dropwise via
9. (a) Takai, K.; Heathcock, C. H. J. Org. Chem. 1985, 50,
3247; (b) Fuganti, C.; Grasselli, P.; Servi, S.; Spreafico,
F.; Zirotti, C. J. Chem. Res. 1984, 976.
10. Reaction of titanium enolate of 8 (R1=Bn, R2=Me)
with isovaleraldehyde (2 equiv.) precomplexed with 1.05
equiv. of TiCl4 at −78°C afforded a mixture of anti and
syn diastereomers (70% yield). Removal of chiral auxil-
iary provided anti/syn ratio of 68:32. We have previously
reported a 70:30 anti/syn ratio and 70% yield for this
reaction. See: Ref. 4a.
11. (a) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991,
56, 5747; (b) Oppolzer, W.; Lienard, P. Tetrahedron Lett.
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