Diastereofacial selectivity in aldol-type condensation induced by optically pure α-sulfinyl acetate with α-substituted aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.02.033

Highly diastereoselective aldol-type condensations induced by the chiral magnesium enolate of tert-butyl p-tolyl sulfinyl acetate were performed with optically pure alkyl or hydroxy α-substituted aldehydes. The addition of chiral α-sulfinyl acetate to var

Full text of DOI:10.1016/j.tetlet.2008.02.033

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Tetrahedron Letters 49 (2008) 2243–2246
Diastereofacial selectivity in aldol-type condensation induced
by optically pure a-sulfinyl acetate with a-substituted aldehydes
Claude Bauder
Institut de Chimie, UMR 7177 associe´ au CNRS—Universite´ Louis Pasteur, 1 rue Blaise Pascal, 67000 Strasbourg, France
Received 4 January 2008; revised 6 February 2008; accepted 6 February 2008
Available online 10 February 2008
This Letter is dedicated with respect to the late Dr. Charles Mioskowski
Abstract
Highly diastereoselective aldol-type condensations induced by the chiral magnesium enolate of tert-butyl p-tolyl sulfinyl acetate were
performed with optically pure alkyl or hydroxy a-substituted aldehydes. The addition of chiral a-sulfinyl acetate to various aldehydes,
a-substituted or not, results mainly with a syn stereochemistry of the two newly created stereocenters. Applications were investigated for
the synthesis of syn and trans 1,2-diol models and polysubstituted precursor for natural products.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Asymmetric aldolization; Chiral sulfinyl acetate; 1,2-Diol; b-Hydroxyester analogs
The control of the stereochemistry in the synthesis of
complex natural products and their analogs requires vari-
ous methodologies. In particular, much efforts have been
devoted to the prevalent chiral enolate chemistry for the
stereoselective construction of asymmetric centers in aldol
condensation.1 To this end, the use of chiral auxiliaries in
asymmetric acetate aldol addition remains one of the most
common and convenient strategy in organic synthesis. This
procedure is widely developed in the literature to obtain
with high diastereoselectivity, b-hydroxy acid derivatives
which are chiral building blocks for the elaboration of bio-
active compounds.2
tBuMgCl
O
OH
O
O
R2(H)
pTol
pTol
*
S
S
*
R*
*
OtBu
*
R*CHO
or R*COR2
t
(H)R1
CO2 Bu
R1(H)
Fig. 1. General diastereoselective aldol-type reaction directed by optically
pure a-sulfinyl ester.
O
S
O
S
O
pTol
Omenthyl
OtBu
pTol
78 % (ee > 99 %)
(+)-R-2
[α] = + 128
(c 1.08, CHCl3)
(-)-S-1
CH3CO2tBu
LDA
For our part, we have been using for the last few years
the chiral a-sulfinyl acetate in asymmetric aldol-type con-
densations3 as shown in Figure 1.
O
S
O
S
O
96 % (ee > 99 %)
pTol
Omenthyl
OtBu
pTol
The well known optically active sulfoxide derivatives4
were first studied by Gilman, and then successively devel-
(+)-R-1
(-)-S-2
[α] = - 125
(c 1.19, CHCl3)
´
oped by Andersen and Solladie. They are prepared from
diastereomerically pure (À)-(S) or (+)-(R) menthyl p-tolyl
Scheme 1. Synthesis of the enantiomers of tert-butyl p-tolyl sulfinyl
acetate 2.
sulfinate 1 by treatment with a Grignard or other organo-
metallic reagents.5 In this way, the two enantiomers of t-
butyl p-tolyl sulfinyl acetate 2 (Scheme 1) were obtained
E-mail address: cbauder@chimie.u-strasbg.fr
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.033

2244
C. Bauder / Tetrahedron Letters 49 (2008) 2243–2246
in high yield from the appropriate menthyl sulfinate ester
(À)-S 1 or (+)-R 1 and the lithium anion of tert-butyl
acetate.
Subsequently, as shown in Figure 1, an aldehyde can be
added now to the magnesium enolate of the a-sulfinyl
acetate 2, generating two new centers at C1 and C2 whose
stereochemistry is governed by the chirality of the a-sulfi-
nyl ester 2. Such concept of asymmetric aldolization
aldehydes in aldol condensation with optically pure sulfinyl
ester were described so far. We first achieved in good yield
(65%) the condensation of (À)-R 2 and 3-benzyloxyprop-
anal to isolate by simple crystallization product 4 (mp =
108 °C; [a]D +195 (c 1, CHCl3)), which is the enantiomer
of 3. The structure as well as the syn stereochemistry of 4
1
were assigned by H NMR analysis (J = 5.48 Hz between
H-1 and H-2). That means a real transfer of chirality from
the optically pure sulfinyl acetate to the prochiral a-unsub-
stituted aldehyde with high p-diastereofacial selectivity as
shown in Figure 3.
Interested in the synthesis of natural products, we have
selected compound 10 as a suitable fragment (Scheme 2).
We envisaged our application in aldol condensation of
the chiral sulfinylester (À)-S 2 with the readily available
aldehyde 9 having an a-methyl group.
induced by optically pure sulfinyl ester was pioneered 30
5f,6
´
years ago by Solladie and Mioskowski
and then has
been used successfully in many applications in which an
enantiomerically pure b-hydroxyester was needed.7 Since
then, a number of examples have been reported involving
the use of chiral a-sulfinyl acetamides,8 dihydrooxazoles,9
hydrazones10 or cyclic sulfinamides.11 But in all these cases,
the sulfoxide products were directly subjected to desulfur-
ization resulting in b-hydroxycarbonyl derivatives (or
b-aminoacid, when the sulfinyl ester 2 was added to an
imine function12) with no consideration for the absolute
configuration assignment at C1.
Recently, we have clearly assigned by X-ray analysis the
absolute stereochemistry of the b-hydroxyester 3 (Fig. 2)
which was obtained by direct aldol condensation from
the magnesium enolate of the sulfinylester (À)-S 2 and
achiral 3-benzyloxypropanal.3
Thus, these earlier results revealed a syn aldol relation-
ship between the two newly created centers C1 and C2 as
shown in molecule 3 (mp = 108 °C; [a]D À199 (c 0.85,
CHCl3)) with a coupling constant of 5.5 Hz between H-1
and H-2.13 We have also noticed an unexpected substituent
effect when a,b-unsaturated aldehyde was used which nec-
essarily involves a different transition state as previously
postulated5e (Fig. 3). On this basis we needed to explore
the effect of a-substituted chiral aldehyde in the view to
observe if in this case, the aldolization is matching either
with achiral or a,b-unsaturated aldehyde situation.
In this Letter, we will examine a new series of condensa-
tions using various a-substituted (alkyl or hydroxyl) alde-
hydes. To our knowledge, no examples of a-substituted
Aldehyde 9 was obtained by baker’s yeast microbial
reduction of ethyl acetylacetate to produce the (S)-ethyl
b-hydroxy butanoate 5 in high enantiomerical purity.14
Then a-alkylation with LDA/MeI, according to the
Frater–Seebach protocol15 led to the anti compound 6 in
63% yield. A sequential silylation–reduction of the ethyl
(+)-(2S,3S) 3-hydroxy-2-methylbutyrate 6 followed by a
Swern oxidation16 furnished the desired aldehyde 9 (69%
yield for three steps). Subjection to an aldol condensation
with the chiral sulfinylester (À)-S 2 provided the expected
1
sulfoxide 10 as the sole isomer according to the H NMR
analysis of the crude material. Sulfoxide 10 was isolated
by column chromatography from the unreacted sulfinyl
ester, as an oily compound (68% yield, [a]D À130 (c 0.82,
CHCl3)). Its absolute stereochemistry was elucidated by
NMR analysis. A coupling constant of 3 Hz is consistent
with a syn stereochemistry between H-1 and H-2 in com-
parison with the value of 5.48 Hz for the known syn correl-
ation in 3 and 4. Moreover, an anti stereochemistry was
clearly established (NOESY) between H-2 and H-3. Conse-
quently, on the basis of 1H NMR spectral data we assigned
the configuration (SS,1R,2S,3R,4S) to sulfoxide 10.
Then, we extended this aldol-type condensation to a-
hydroxy substituted aldehydes leading to the synthesis
O
S
OH
O
S
OH
pTol
1
1
2
2
OBn
OBn
pTol
1) baker's yeast; 5
O
O
TBSO
O
2) LDA / MeI (63%); 6
tBuO2C
tBuO2C
(SS,1S,2S)-3
(RS,1R,2R)-4
OEt
OEt
3) TBSCl (89%)
7
[α] = - 199 (c 0.85, CHCl3)
[α] = + 195 (c 1.00, CHCl3)
mp = 108-109 °C
mp = 108-110 °C
4) DiBAL 78 %; 8
5) Swern 99 %; 9
Fig. 2. Configuration of 3 and 4 obtained by aldolization reaction.
OTBS
OH
O
S
TBSO
1
Br
(-)-S-2
2
Mg
O
pTol
O
S
OH
tBuMgCl
68%
tBuO2C
O
R
O
S
pTol
O
R
pTol
(SS,1R,2S,3R,4S)-10
[α] = - 130 (c 0.82, CHCl3)
9
OtBu
tBuO2C
H
Fig. 3. Illustration of a plausible chelated intermediate.
Scheme 2. Synthesis of sulfoxide 10.

C. Bauder / Tetrahedron Letters 49 (2008) 2243–2246
2245
O
O
O
O
S
S
R
R
H
H
H
H
OBn
OBn
OBn
OBn
(-)-S-2 76%
(-)-S-2 54%
(+)-R-2 60%
(+)-R-2 81%
O
S
OH
O
S
OH
O
S
OH
O
S
OH
pTol
1
1
pTol
1
1
2
2
2
2
pTol
pTol
tBuO2C
OBn
tBuO2C
OBn
tBuO2C
OBn
tBuO2C
OBn
(SS,1R,2S,3S)-13
(SS,1R,2S,3R)-14
(RS,1S,2R,3S)-11
(RS,1S,2R,3R)-12
[α] = - 173 (c 1, CHCl3)
[α] = - 133 (c 1, CHCl3)
[α] = + 138 (c 1, CHCl3)
[α] = + 175 (c 1, CHCl3)
mp = 92-95 °C
mp = 92-95 °C
Scheme 3. Aldol-condensation of sulfinyl ester (+)-R-2 and (À)-S-2 with (R) and (S) 2-benzyloxypropionaldehyde.
of highly functionalized syn and anti 1,2-diol models
(Scheme 3).
pling constant of 5.9 Hz between H-1 and H-2, which is
consistent with a syn stereochemistry. Finally, in the aldol
condensation of the appropriated sulfinate 2 with the (R)
or (S) 2-benzyloxy propionaldehyde leading to the pure
enantiomers 12 ([a]D +175 (c 1, CHCl3)) and 13 ([a]D
À173 (c 1, CHCl3)), we observed obviously in both cases
a syn stereochemistry in agreement with their coupling con-
stant of 2.9 Hz between H-1 and H-2. That implies the
(RS,1S,2R,3R) and (SS,1R,2S,3S) configurations for sulf-
oxides 12 and 13, respectively. The specific rotation [a]D
Thus, the treatment of magnesium enolate of sulfinyl
ester (+)-R 2 with (S) and (R) 2-benzyloxy propionalde-
hyde gave, respectively, the aldol products 11 and 12 in
good yields. On the other hand, we have obtained the aldol
products 13 and 14 using the sulfinyl ester (À)-S 2. Enanti-
omers 11 and 14 were isolated by simple crystallization,
whereas the oily enantiomers 12 and 13 had to be purified
by column chromatography. In the case of 11, the absolute
configuration was determined through derivative 16
(Scheme 4). Indeed, after desulfurization of 11, the result-
ing b-hydroxyester 15 (84% yield; [a]D +9.5 (c 0.83,
CHCl3))17 was silylated with tert-butyldimethylsilyl chlo-
ride to afford the known17b silylether 16 (96% yield) as it
1
and H coupling constant values of the different adducts18
are summarized in Table 1.
In this Letter, we have shown a straightforward use of
the readily available chiral a-sulfinyl acetate (R) and (S)-
2 in controlled asymmetric aldol reactions with a-substi-
tuted aldehydes. We have observed a high syn diastereo-
selective induction, independently of the chirality of the
aldehydes. The desired products can be obtained in good
yield and in multigramme amounts either by simple crystal-
lization or by column chromatography of the main isomer.
The absolute configuration at C1 of the sulfoxide aldol
product was also determined to generate further controlled
reactions like an asymmetric epoxidation or anything else.
In conclusion, this method constitutes a powerful route
to optically pure a-alkylated b-hydroxyesters analogs as
well as highly functionalized syn and trans a-diols which
are potent intermediates for the synthesis of a variety of
natural products and bioactive macromolecules.
1
can be seen from the H and 13C NMR data.
The optical rotation of 16 [a]D À20.6 (c 0.52, CHCl3) is
identical to that reported in the literature17b ([a]D À19.2 (c
2, CHCl3)). Consequently, we can assign the (R) absolute
configuration at C-2 of the aldol product 11. Besides, the
coupling constant between H-1 and H-2 in the compound
11 has a value of 5.6 Hz, which indicates a syn stereochem-
istry—that is the (RS,1S,2R,3S) configuration for this sulf-
oxide 11 (mp = 92–95 °C; [a]D +138 (c 1, CHCl3)).
In the same manner, its expected enantiomer 14
(mp = 90–93 °C; [a]D À133 (c 1, CHCl3)) obtained from
(À)-S 2 and (R) 2-benzyloxy propionaldehyde shows a cou-
O
OH
Al / Hg
83.6%
tBuO
(RS,1S,2R,3S)-11
Table 1
15
OBn
Characteristic details for the different cited sulfoxides
[α] = + 9.5 (c 0.83, CHCl3)
Sulfoxides
(configuration)
Yield (%)
[a]
Mp (°C)
dH1/J1À2
(ppm)/(Hz)
O
OTBS
3 (SS,1S,2S)
4 (RS,1R,2R)
60
65
68
60
81
76
54
À199
+195
À130
+138
+175
À173
À133
108–109
108–110
Oil
92–95
Oil
3.49/5.5
3.49/5.5
3.63/2.9
3.58/5.6
3.87/2.9
3.87/2.9
3.58/5.9
TBSCl / Im
96.2%
tBuO
10 (SS,1S,2S,3R,4S)
11 (RS,1S,2R,3S)
12 (RS,1S,2R,3R)
13 (SS,1R,2S,3S)
14 (SS,1R,2S,3S)
16 OBn
[α] = - 20.6 (c 0.52, CHCl3)
lit16b: [α] = - 19.2 (c 2, CHCl3)
Oil
90–93
Scheme 4. Conversion of sulfoxide 11 to the known protected a-diol 16.

2246
C. Bauder / Tetrahedron Letters 49 (2008) 2243–2246
´
Moghadam, F. J. Org. Chem. 1982, 47, 91–94; (c) Solladie, G.;
Hamdouchi, C. Synthesis 1991, 979–982; (d) Masquelin, T.; Hengart-
ner, U.; Streith, J. Helvetica 1997, 80, 43–58; (e) Beecher, J.;
Brackenridge, I.; Roberts, M. R.; Tang, J.; Willets, A. J. J. Chem.
Soc., Perkin Trans. 1 1995, 1641–1643; (f) Tang, J.; Brackenridge, I.;
Roberts, S. M.; Beecher, J.; Willetts, A. J. Tetrahedron 1995, 51,
13217–13238.
Supplementary data
Experimental procedures and spectroscopic data for the
compounds and copies of 1H NMR and 13C NMR spectra.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.033.
8. Annunziata, R.; Cinquini, M.; Cozzi, F.; Montanari, F.; Restelli, J. J.
Chem. Soc., Chem. Commun. 1983, 1138–1139; (b) Annunziata, R.;
Cinquini, M.; Cozzi, F.; Montanari, F.; Restelli, J. J. Chem. Soc.,
Chem. Commun. 1984, 3815–3822.
References and notes
9. Annunziata, R.; Cinquini, M.; Gilardi, A. Synthesis 1983, 1016–1017;
(b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Restelli, J. J. Chem. Soc.,
Chem. Commun. 1984, 1253–1255.
10. Colombo, L.; Gennari, C.; Poli, G.; Scolastico, C.; Annunziata, R.;
Cinquini, M.; Cozzi, F. J. Chem. Soc., Chem. Commun. 1983, 403–404.
11. Wills, M.; Butlin, R. J.; Linney, I. D. Tetrahedron Lett. 1992, 33,
5427–5430.
1. For selected reviews, see: (a) Nelson, S. G. Tetrahedron: Asymmetry
1998, 9, 357–389; (b) Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120;
(c) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432–
440; (d) Denmark, S. E.; Heemstra, J. R.; Beutner, G. L., Jr. Angew.
Chem., Int. Ed. 2005, 44, 4682–4698; (e) Wu, G.; Huang, M. Chem.
Rev. 2006, 106, 2596–2616.
12. Sivakumar, A. V.; Babu, G. S.; Bhat, S. V. Tetrahedron: Asymmetry
2001, 12, 1095–1099.
13. We have isolated the anti isomer of 3 which has a coupling constant of
2. For reviews on the asymmetric acetate aldol addition, see: (a)
Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem.,
Int. Ed. 1985, 24, 1–30; (b) Braun, M. Angew. Chem., Int. Ed. 1987,
26, 24–37; (c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–947; (d)
Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev.
2006, 106, 2734–2793.
´
8.0 Hz. Arce-Dubois, M. E.; Ph.D. Dissertation; Universite Louis
Pasteur: Strasbourg, France, 1998.
14. Wipf, B.; Kupfer, E.; Bertazzi, R.; Leuenberger, H. G. W. Helv. Chim.
Acta 1983, 66, 485–488; (b) Seebach, D.; Sutter, M. A.; Weber, R. H.;
´
3. Solladie, G.; Bauder, C.; Arce-Dubois, E.; Pasturel-Jacope, Y.
Zuger, M. F. Org. Synth. 1985, 63, 1–9.
¨
Tetrahedron Lett. 2001, 42, 2923–2925.
15. Seuring, B.; Seebach, D. Helv. Chim. Acta 1977, 60, 1175–1181; (b)
Frater, G. Helv. Chim. Acta 1979, 62, 2825–2828; (c) Frater, G. Helv.
4. Carreno, M. C. Chem. Rev. 1995, 1717–1760; (b) Hanquet, G.;
˜
´
Colobert, F.; Lanners, S.; Solladie, G. Arkivoc 2003, vii, 328–401; (c)
Chim. Acta 1979, 62, 2829–2832; (d) Hungerbuhler, E.; Seebach, D.;
¨
´
Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651–3705; (d)
Wasmuth, D. Helv. Chim. Acta 1981, 64, 1467–1487; (e) Frater, G.;
Pellissier, H. Tetrahedron 2006, 62, 5559–5601.
Muller, U.; Gunther, W. Tetrahedron 1984, 40, 1269–1277; (f)
¨
¨
5. (a) Gilman, H.; Robinson, J.; Beaber, N. J. J. Am. Chem. Soc. 1926,
48, 2715–2718; (b) Andersen, K. K. Tetrahedron Lett. 1962, 37, 93–95;
(c) Andersen, K. K. J. Org. Chem. 1964, 29, 1953–1956; (d) Andersen,
K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I.
Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63, 197–200; (g)
Arigoni, D.; Wasmuth, D.; Seebach, D. Helv. Chim. Acta 1982, 65,
344.
16. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660; (b)
Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482; (c) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
17. (a) Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A. J.
Org. Chem. 1986, 51, 3027–3037; Uenishi, J.; Tomozane, H.; Yamato,
M. J. Chem. Soc., Chem. Commun. 1985, 717–719. The optical
rotation for molecule 15 was not mentioned; (b) Uenishi, J.;
Tomozane, H.; Yamato, M. Tetrahedron Lett. 1985, 3467–3470.
18. All new compounds exhibited satisfactory spectroscopic (1H and 13C
NMR) and combustion analysis data.
´
J. Am. Chem. Soc. 1964, 86, 5637–5646; (e) Mioskowski, C.; Solladie,
´
G. Tetrahedron 1980, 36, 227–236; (f) Solladie, G. Synthesis 1981,
185–196; (g) Hulce, M.; Mallamo, J. P.; Frye, L. L.; Kogan, T. P.;
Posner, G. H. Org. Synth. 1986, 64, 196–206; (i) Solladie, G.; Hutt, J.;
´
Girardin, A. Synthesis 1987, 173–174.
´
´
6. Mioskowski, C.; Solladie, G. Tetrahedron Lett. 1975, 3341–3342; (b)
Mioskowski, C.; Solladie, G. J. Chem. Soc., Chem. Commun. 1977,
162–163.
7. Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua, D. H.
J. Am. Chem. Soc. 1980, 102, 6613–6615; (b) Solladie´, G.; Matloubi-