Stereoselective 2-hydroxy-1,2,2-triphenylethyl propionate-based aldol additions to ketones

Article abstract of DOI:10.1055/s-1999-2885

The TiCl₄-mediated reaction of enone 3 with the silyl ketene acetal 2 derived from (R)-propionate 1 occurs in a stereoselective manner. The major aldol adduct 4, whose configuration was proven by an X-ray structure analysis of 6, affords the enantiomerically pure carboxylic acid 5 upon hydrolysis.

Full text of DOI:10.1055/s-1999-2885

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LETTER
Stereoselective 2-Hydroxy-1,2,2-triphenylethyl Propionate-Based Aldol
Additions to Ketones
Manfred Braun*, Brigitte Mai, Daniel M. Ridder
Institut für Organische und Makromolekulare Chemie, Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany
Fax Int. + 211 81 13085; E-mail: braunm@uni-duesseldorf.de
Received 22 June 1999
nantly among the aldol adducts so that the ratio of major
Abstract: The TiCl4-mediated reaction of enone 3 with the silyl
stereoisomer 4 to the sum of all others was 91 : 9. Careful
ketene acetal 2 derived from (R)-propionate 1 occurs in a stereose-
column chromatography delivered not only the main
product as a single isomer but also the three minor diaste-
reomers which differ, as expected, in their NMR spectra.
lective manner. The major aldol adduct 4, whose configuration was
proven by an X-ray structure analysis of 6, affords the enantiomer-
ically pure carboxylic acid 5 upon hydrolysis.
Key words: asymmetric synthesis, aldol reaction, ketones, titani-
um, tertiary alcohols
Impressive progress has been made in the development of
stereoselective aldol additions during the last two de-
cades, so that a large variety of b-hydroxy carbonyl com-
pounds have become available.1 Whereas in the beginning
of this evolution, covalently bound chiral auxiliary re-
agents were used in order to bring about diastereofacial
selectivity,2 enantioselective variants were developed
more recently, most of which rely on chiral catalysts.3 In
almost all cases aldehydes were chosen as electrophiles.
However, stereoselective aldol additions to prochiral ke-
tones are extremely rare,4 undoubtedly due to their low re-
activity and the fact that they are more difficult substrates
for enantiofacial and diastereofacial differentiation. In-
deed, the very few examples described rely widely on ac-
tivated ketones, in particular a-ketoesters and a-
diketones.5 In this communication, we report on a novel
Mukaiyama-type aldol addition6 to non-activated ketones,
a protocol which provides both simple diastereoselection
and diastereofacial selectivity.7 It is based on 2-hydroxy-
1,2,2-triphenylethyl propionate 18 and makes enantiomer-
ically pure tertiary alcohol derivatives easily accessible.
Reagents and conditions: a) 1) LDA, THF, -78 °C, 2) ClSiMe3, -78
°C, 94-98%; b) 1) TiCl4, CH2Cl2, -78 °C, 3 h, 77%, 2) H2O; c)
LiOH∑H2O, CH3OH, H2O, rt, 3 d, 65%; d) n-Bu4NF∑3 H2O, THF, 12
h, rt, 74%
Scheme 1
For this purpose, (R)-propionate 1, readily available from
(R)-1,1,2-triphenyl-1,2-ethanediol,9 was deprotonated
with 2 equivalents of lithium diisopropylamide and the di-
anion formed thereby was treated with chlorotrimethylsi-
lane to give the ketene acetal 2 which formed under
simultaneous protection of the tertiary hydroxyl group.8 It
turned out that the (E)-isomer of the ketene acetal 2 was
formed predominantly, with an E : Z ratio of 87 : 13. The
enone 3, considered to be a representative non-activated
ketone, was submitted to a titanium tetrachloride-mediat-
ed reaction with ketene acetal 2. It should be noted that, in
this reaction, four diastereomeric aldol-type products
could arise beside four diastereomeric 1,4-adducts.
Amazingly, the crude product formed in 91% yield con-
tained a single isomer to a large extent. NMR analysis re-
vealed that the ratio of 1,2- to 1,4-adducts exceeded 95 :
5. Furthermore, one diastereomer had formed predomi-
A smooth alkaline hydrolysis of ester 4, isolated in 77%
yield, afforded the enantiomerically and diastereomerical-
ly pure carboxylic acid 5 aside from recovered triphenyl-
ethanediol. Obviously, any epimerization was avoided
during the saponification. A minor amount of propionic
acid formed by retro aldol reaction was removed from the
crude product by evaporation. Since neither the relative
nor the absolute configuration of acid 5 was known, the
question of stereochemistry was solved by an X-ray struc-
ture analysis of the aldol adduct. The desilylated ester 6
turned out to form suitable crystals in contrast to the O-
protected compound 4. The result of the X-ray structure
analysis,10 clearly reveals the (2S, 3S) configuration of the
carboxylic acid moiety in the ester 6. An intramolecular
hydrogen bridge between the tertiary hydroxy group at the
Synlett 1999, No. 10, 1600–1602 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Propionate Aldol Additions to Ketones
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stereogenic center and the carbonyl oxygen atom forces
the C1-C2 and the C3-C4 bonds to occupy a gauche rather
than an antiperiplanar conformation.
Acknowledgement
This work was supported by the Fonds der Chemischen Industrie
and BAYER AG. We would like to thank Mrs. S. Houben, who car-
ried out several experiments.
Both the relative and the absolute configuration of the car-
boxylic acid 5 could be deduced from that of the ester 6.
Thus, the stereochemical outcome of this novel Mukaiya-
ma-type aldol reaction can be summarized as follows: The
enone 3 was attacked by (R)-ketene acetal 2 predominant-
ly from the Re face and the ketene acetal itself, assumed
to have the E configuration, reacts preferentially on its Re
face as well. The cyclic transition state model11 proposed
in Figure 1 might be suitable to explain that R, Re, Re top-
icity. The very bulky diphenylsiloxy moiety could force
the ketone 3 to approach from the front side to the ketene
acetal 2 in such a way that the sterically more demanding
substituent R ( = CH=CHCH3) occupies the antiperipla-
nar position of the acetal’s double bond. It seems that,
here again,12 the diphenylhydroxymethyl group, in this
case protected as silyl ether, is crucial for the stereoselec-
tivity.
References and Notes
(1) Braun, M. In Houben-Weyl, 4th ed., Vol. E 21b; Helmchen,
G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.;
Thieme: Stuttgart, 1995; p 1603, 1713, 1723, 1730.
(2) For reviews, see: a) Evans, D. A.; Takacs, J. M.; McGee, L.
R.; Ennis, M. D.; Mathre, D. J. Top. Stereochem. 1982, 13, 1.
b) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem. 1985, 97, 1; Angew. Chem. Int. Ed. Engl. 1985, 24, 1.
c) Braun, M. Angew. Chem. 1987, 99, 24; Angew. Chem. Int.
Ed. Engl. 1987, 26, 24. d) Heathcock, C. H. In Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M.; Fleming, I.;
Heathcock, C. H., Pergamon: Oxford, 1991; Chapter 1.6.
e) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis Vol. 2; Trost, B. M.;
Fleming, I.; Heathcock, C. H., Eds.; Pergamon: Oxford, 1991;
Chapter 1.7. f) Paterson, I. In Comprehensive Organic
Synthesis, Vol. 2; Trost, B. M.; Fleming, I.; Heathcock, C. H.,
Eds; Pergamon: Oxford, 1991; Chapter 1.9. g) Braun, M.;
Sacha, H. J. Prakt. Chem. 1993, 335, 653. h) McCallum, J. S.;
Liebeskind, L. S. In Houben-Weyl, 4th ed., Vol. E 21b;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995; p 1667.
(3) For rewies, see: Sawamura, M.; Ito, Y. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; VCH: Weinheim, 1993;
Chapter 7.2. Gröger, H.; Vogl, E.; Shibasaki, M. Chem. Eur.
J. 1998, 4, 1137. Nelson, S. G. Tetrahedron: Asymmetry 1998,
9, 357.
(4) Acetate enolate equivalents have been added to ketones with
moderate stereoselectivity in most cases: Guetté, M.;
Capillon, J.; Guetté, J.-P. Tetrahedron 1973, 29, 3659.
Dongala, E. B.; Dull, D. L.; Mioskowski, C.; Solladié, G.
Tetrahedron Lett. 1973, 4983. Mioskowski, C.; Solladié, G.
Tetrahedron 1980, 36, 227.
(5) Kobayashi, S.; Fujishita, Y.; Mukaiyama, T. Chem. Lett.
1989, 2069. Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.;
MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893.
Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am.
Chem. Soc. 1997, 119, 10859.
(6) Mukaiyama, T. Org. React. N. Y. 1982, 28, 203.
(7) See ref. 2c,g for an elucidation of these terms.
(8) Sacha, H.; Waldmüller, D.; Braun, M. Chem. Ber. 1994, 127,
1959.
Cyclic transition state model of the TiCI4-mediated addition of silyl
ketene acetal (R)-2 to enone 3 (R = MeCH=CH)
Figure 1
Having in hand a protocol for a stereoselective aldol reac-
tion of the ester 1, the extension to other ketones was
briefly investigated. It turned out that acetophenone gave
a slightly lower selectivity, but again one stereoisomer
was formed predominantly (85 : 15). Remarkably higher
selectivity (94 : 6) was reached when trifluoroacetone was
submitted to the protocol outlined above. The assignment
7 and 8, is based on analogy with that of the ester 4.
(9) Braun, M.; Gräf, S.; Herzog, S. Org. Synth. 1993, 72, 32.
(10) Crystallographic data (excluding structrue factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-122182. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: Int. code +(44)1223-
336033; e-mail: deposit@ccdc.cam.ac.uk).
(11) Cf. Shambayati, S.; Schreiber, S. L. In Comprehensive
Organic Synthesis, Vol. 1; Trost, B. M.; Fleming, I.;
Heathcock, C. H., Eds.; Pergamon: Oxford 1991; Chapter
1.10.
Figure 2
We are aware that, according to this transition state model, the
diastereoselectivity of the aldol addition should reflect the E :
Z ratio of the silyl ketene acetal. Since, however, the mixture
(87 :13) of E- and Z- silyl ketene acetal is used in excess (1,3
mol%), one might assume the E- isomer to react
Thus, the protocol disclosed offers for the first time a rath-
er general opportunity to provide both simple diastereose-
lection and diastereofacial selectivity in aldol additions to
non-activated ketones.13,14
predominantly. On the other hand, open transition state
Synlett 1999, No. 10, 1600–1602 ISSN 0936-5214 © Thieme Stuttgart · New York

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M. Braun et al.
LETTER
models could also be taken into account; Cf. Oppolzer, W.;
Marco-Contelles, J. Helv.Chim.Acta 1986, 69, 1699.
(12) Braun, M. Angew. Chem. 1996, 108, 565; Angew. Chem. Int.
Ed. Engl. 1996, 35, 519.
Ph2COH), 3.19 [s, C(OH)CH3], 5.31 (dq, Jd = 14 Hz, Jq = 1.3
Hz, =CH), 5.40 [dq, Jd = 14 Hz, Jq = 6.1 Hz, =CH(CH3)], 6.66
(s, CHPh), 7.01-7.57 (m, aromatic H); 13C NMR (75 MHz;
CDCl3): d = 11.7 [CH(CH3), 17.4 [=CH(CH3)], 24.7
C(OH)CH3], 48.0 [CHCCH3], 72.6 [C(OH)CH3], 78.7
(CHPh), 80.3 (CPh2), 123.8 [=CH(CH3)], 136.5 (=CH), 175.4
(CO).
(13) Typical procedure: To a solution of 3 (0.1 ml, 1 mmol) in dry
CH2Cl2, stirred under N2 was added TiCl4 (0.11 ml, 1 mmol)
at -78°C and stirring was continued for 15 min at -78°C. Crude
2 (638 mg, 1.3 mmol) prepared according to ref.8 was
dissolved in CH2Cl2 (1 ml) and added dropwise to the solution
of 3. Stirring was continued for 3 h at -78°C, and then H2O
(0.5 ml) was added. The mixture was diluted with ethyl acetate
(60 ml) and washed with H2O (20 ml). The organic layer was
dried over Na2SO4 and the solvent was evaporated. The pure
aldol adduct 4 (387 mg; 77%) was isolated by column
chromatography on silica gel; Rf = 0,5 (n-hexane/ethyl acetate
5 : 1).
The minor diastereomers of 6 differ in: d = 0.91 (d, J = 6.9
Hz), 0.93 (d, J = 6.8 Hz), 0.94 (d, J = 6.9 Hz)
5: colorless oil: [a]D20 = +25.5 (c = 1, CHCl3); 1H NMR (300
MHz, CDCl3) d = 1.22 [d, J = 7.1 Hz, CH(CH3)], 1.26 [s,
C(OH)CH3], 1.69 [d, J = 6.3 Hz, =CH(CH3)], 2.57 [q, J = 7.1
Hz, -CH(CH3)], 5.55 (dq, Jd = 15 Hz, Jq = 1.3 Hz, =CH); 5,71
[dq, Jd = 15 Hz, Jq = 6.1 Hz, =CH(CH3)]; 13C (75 MHz;
CDCl3): d = 12.2 [-CH(CH3)], 17.7 [=CH(CH3)], 24.0
[C(OH)CH3], 48.2 [CH(CH3)], 73.3 [C(OH)CH3], 124.4
[=CH(CH3)], 136.2 (=CH), 180.6 (CO).
(14) Correct elemental analyses were obtained for the new
compounds. Selected data:
6: white solid, m.p.: 182.5°C; [a]D20 = +66.8 (c = 0.6, CHCl3);
1H NMR (300 MHz, CDCl3) d = 0.97 [d, J = 7.1 Hz,
CH(CH3)], 1.09 [s, C(OH)CH3], 1.35 [d, J = 6.1 Hz,
=CH(CH3)], 2.48 [q, J = 7.1 Hz, CH(CH3)], 2.85 (s,
Article Identifier:
1437-2096,E;1999,0,10,1600,1602,ftx,en;G16499ST.pdf
Synlett 1999, No. 10, 1600–1602 ISSN 0936-5214 © Thieme Stuttgart · New York