Reformatsky-type reaction of chiral nonracemic α-bromo-α′ -sulfinyl ketones with aldehydes. Synthesis of enantiomerically pure 2-methyl-1,3-diol moieties

Article abstract of DOI:10.1021/ol027223+

Figure presented Chiral nonracemic α-bromo-α′-sulfinyl ketones were shown to react with aldehydes in the presence of Sml₂ in a Reformatsky-type reaction to give the corresponding adduct with excellent syn diastereoselectivity. Further reduction

Full text of DOI:10.1021/ol027223+

ORGANIC
LETTERS
2003
Vol. 5, No. 5
629-632
Reformatsky-Type Reaction of Chiral
Nonracemic r-Bromo-r′-sulfinyl
Ketones with Aldehydes. Synthesis of
Enantiomerically Pure 2-Methyl-1,3-diol
Moieties
Michel Obringer, Franc¸oise Colobert,* Benjamin Neugnot, and Guy Solladie´
Laboratoire de Ste´re´ochimie Associe´ au CNRS, UniVersite´ Louis Pasteur, E.C.P.M,
25 rue Becquerel, 67087 Strasbourg Cedex 2, France
fcolober@chimie.u-strasbg.fr
Received November 4, 2002 (Revised Manuscript Received January 27, 2003)
ABSTRACT
Chiral nonracemic r-bromo-r′-sulfinyl ketones were shown to react with aldehydes in the presence of SmI2 in a Reformatsky-type reaction
to give the corresponding adduct with excellent syn diastereoselectivity. Further reduction of the Reformatsky adducts furnished anti- and
syn-2-methyl-1,3-diol moieties in excellent yields and diastereoselectivities.
The Reformatsky reaction employing zinc metal is a
convenient and useful protocol for carbon-carbon bond
formation using R-halo carbonyl compounds.1 However, the
yield and diastereoselectivity of this type of reaction are not
always satisfactory.
To overcome these problems, most efforts have been
focused on the activation of zinc such as Rieke-Zn, Zn-Cu
couple, Zn/Hg amalgam, or the use of a variety of other
metals and low-valent metal reagents.2
synthetic chemist. To date, very few asymmetric Reformatsky
reactions are known.3
In this field, samarium(II)iodide is known to be a poly-
valent reducing agent that has been applied to a multitude
of important synthetic reactions with generally high chemo-
selectivity and high levels of stereochemical control.4
Its use in an intramolecular sense in an asymmetric
Reformatsky reaction has already been reported.5 In addition,
Fukuzawa recently described the SmI2-mediated Refor-
matsky-type reaction of chiral 3-bromoacetyl-2-oxazolidi-
nones with various aldehydes.3b
Highly stereocontrolled asymmetric Reformatsky reactions
are of current interest, and an efficient asymmetric version
of the Reformatsky reaction would be very useful for the
(2) (a) Shibata, I.; Suwa, T.; Sakakibara, H.; Baba, A. Org. Lett. 2002,
4, 301. (b) Kagoshima, H.; Hashimoto, Y.; Saigo, K. Tetrahedron Lett.
1998, 39, 8465. (c) Shimizu, M.; Kobayashi, F.; Hayakawa, R. Tetrahedron
2001 57, 9591. (d) Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Kutsuna,
T.; Saigo, K. Tetrahedron Lett. 1998, 39, 1203. (e) Kanai, K.; Wakabayashi,
H.; Honda, T. Org. Lett. 2000, 2, 2549. (f) Wessjohann, L.; Gabriel, T. J.
Org. Chem. 1997, 62, 3772.
(1) For recent reviews of the Reformatsky reaction, see: (a) Fu¨rstner,
A. Synthesis 1989, 571. (b) Rathke, M. W.; Weipert, P. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds; New York, 1991; Vol.
2, p 277. (c) Fu¨rstner, A. In Organozinc Reagents; Knochel, P., Jones, P.,
Eds; Oxford University Press: New York, 1999, 287.
10.1021/ol027223+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/07/2003

In this communication, we report a highly stereoselective
Reformatsky addition of chiral nonracemic R-bromo-R′-
sulfinyl ketones with various aldehydes promoted by sa-
marium(II)diiodide. Further stereoselective reduction of the
Reformatsky adduct led to anti- and syn-2-methyl-1,3-diols,
very useful moieties in total synthesis of biologically active
compounds (Scheme 1).
Initially, we performed the reaction of R-halo-R′-p-tolyl-
sulfinyl ketones 4a with benzaldehyde using various sources
of metals (GeI2/K3a; ZnEt2/RhCl(PPh3)32e; CrCl2/LiI2f; CrCl2;
SmI23b), and the results are summarized in Table 1.
Table 1. Diastereoselective Reformatsky Reaction of 4a-b
with Benzaldehyde
Scheme 1
entry
4
metal
T (°C)
syn/antia 6/7a % yieldb
1
2
4a GeI2/K
4a ZnEt2/
25
0
65/35
60/40
45/55
55/45
15
57
The chiral nonracemic R-halo-R′-sulfinyl ketones were
prepared according to the Bravo procedure (Scheme 2).6
RhCl(PPh3)3
3
4
5
6
7
8
9
4a CrCl2/LiI
4a CrCl2
4a CrCl2/LiI
4a SmI2
4a SmI2
4b SmI2
25
40/60
45/55
70/30
70/30
70/30
75/25
75/25
40/60
70/30
45/55
80/20
85/15
90/10
96/4
60
55
45
47
47
45
51
-78 f -10
-78 f -20
-78
-100
-78
Scheme 2
4b SmI2
-100
a Determined by 1H NMR analysis of the product. b Isolated yield of
the mixture of diastereomers. Reaction conditions: 4a (1 equiv), PhCHO
(1.1 equiv), SmI2 (2 equiv), THF, 30 min.
The best syn diastereoselectivity was obtained using SmI2
in THF at -100 °C. The diastereofacial selectivity is higher
at -100 °C than at -78 °C (entries 6 and 7).
Using activated germanium, diethylzinc with rhodium
catalyst, and chromiumdichloride did not improve the
diastereoselectivity (entries 1-5).
Condensation of the lithiated anion of (+)-(R)-methyl-p-
tolylsulfoxide7 1 or (-)-(R)-methyl-tert-butylsulfoxide8 2 on
the methyl-2-bromopropionate 3 afforded the R-bromo-R′-
sulfinyl ketones 4a and 4b in 92 and 95% yields, respec-
tively.
Then we thought that the selectivity could be improved
by using a more hindered substituent on the sulfur. We
choose the optimum conditions established before to perform
the Reformatsky reaction between the R-bromo-R′-tert-
butylsulfinyl ketone 4b (with tert-butyl instead of p-tolyl on
the sulfoxide) and benzaldehyde (entries 8 and 9). We
observed a higher diastereofacial selectivity leading to a syn
ratio of 96/4 instead of 85/15 with p-tolyl sulfinyl derivatives
(entries 7 and 9).
(3) (a) Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo, K. J. Org.
Chem. 1998, 63, 691. (b) Fukuzawa, S.-I.; Matsuzawa, H.; Yoshimitsu,
S.-I. J. Org. Chem. 2000, 65, 1702. (c) Basavaiah, D.; Bharathi, T. K.
Tetrahedron Lett. 1991, 32, 3417. (d) Ito, Y.; Terashima, S. Tetrahedron
1991, 47, 2821. (e) Soai, K.; Kawase, Y. Tetrahedron Asymmetry 1991, 2,
781. (f) Soai, K.; Oshio, A.; Saito, T. Chem. Commun.. 1993, 811.
(4) For recent reviews of samarium(II)iodide in organic synthesis, see:
(a) Krief, A.; Laval, A.-M. Chem. ReV. 1999, 99, 745. (b) Molandar, G.
A.; Harris, C. H. Chem. ReV. 1996, 96, 307.
(5) (a) Molandar, G. A.; Etter, J. B.; Harring, L. S.; Thorel, P.-J. J. Am.
Chem. Soc. 1991, 113, 8036.
(6) Bravo, P.; Resnati, G. Tetrahedron Lett. 1985, 26, 5601.
(7) (+)-(R)-Methyl-p-tolylsulfoxide was prepared from the (-)-(S)-
menthyl-p-tolylsulfinate: Solladie´ G.; Hutt, J.; Girardin, A. Synthesis 1987,
173.
Then the SmI2-promoted asymmetric Reformatsky reaction
with 4b was applied to various aldehydes at -100 °C (Table
2).
As shown in Table 2, excellent diastereoselectivities and
moderate to good yields were obtained with linear aliphatic
aldehydes (entries 4-7). The yields were slightly improved
when an excess amount of 4b (2 equiv instead of 1equiv)
was employed.
(8) (-)-(R)-Methyl-tert-butylsulfoxide was prepared by addition of tert-
butylmagnesiumchloride followed by methylmagnesiumbromide on chiral
sulfites: Rebiere, F.; Samuel, O.; Ricard, L.; Kagan, H. B. J. Org. Chem.
1991, 56, 5991.
630
Org. Lett., Vol. 5, No. 5, 2003

On the other hand, we performed the Reformatsky reaction
starting from R-bromo-R′-tert-butylsulfinyl ketone 4c with
the opposite configuration on the sulfoxide (S(S)). Condensa-
tion of 4c with n-hexanal followed by sulfoxide reductive
elimination afforded the known methyl ketone 11, whose
absolute configuration (by comparison with literature9) was
confirmed to be 3(S)-4-(R) (Scheme 4).
Table 2. Diastereoselective Reformatsky Reaction of 4b with
Various Aldehydes
Scheme 4
entry
R′CHO
PhCHO
syn/antia
6b/7ba
% yieldb
1
2
3
4
5
6
7
8
9
75/25
55/45
90/10
98/2
98/2
98/2
98/2
75/25
45/55
96/4
61%
55%
55%
85%
85%
75%
77%
65%
87%
tBuCHO
isovaleraldehyde
n-C2H5CHO
n-C3H7CHO
n-C5H11CHO
n-C7H15CHO
acroleine
90/10
95/5
95/5
92/8
95/5
92/8
80/20
With these Reformatsky adducts 6b in hand, we performed
the well-known diastereoselective reduction of â-ketosul-
foxides10 either with DIBAL-H only or with DIBAL-H in
the presence of Yb(OTf)3. Starting from adduct 9 (obtained
by Reformatsky condensation with n-propanal) the 2-methyl-
1,3 syn or anti diols 12 and 13, respectively, were obtained
in good yields and diastereoselectivities11 (Scheme 5).
n-trans-2-hexenal
a Determined by 1H NMR analysis of the product. b Isolated yield of
the mixture of diastereomers. Reaction conditions: 4b (2 equiv), R′CHO
(1 equiv), SmI2 (2 equiv), THF, -100 °C, 30 min.
Isovaleraldehyde, which is more hindered, gave good
diastereoselectivity but a lower yield (entry 3). With piv-
alaldehyde, no selectivity was observed (entry 2).
Surprisingly, condensation with acroleine and n-trans-2-
hexenal did not give a high diastereoselectivity (entries 8
and 9).
Scheme 5
To confirm the strong effect of the tert-butyl group on
sulfur on the diastereofacial selectivity, we carried out the
condensation of R-halo-R′-p-tolyl-sulfinyl ketone 4a with
n-hexanal and we found as expected a lower diastereo-
selectivity (syn/anti ) 85/15; 6a/7a ) 85/15).
The absolute configuration of 9 (R ) C2H5) was deter-
mined after sulfoxide reductive cleavage with aluminum
amalgam, giving the known methyl ketone 10 (Scheme 3).
In this paper, the sulfoxide auxiliary was shown to be
efficient for the asymmetric samarium Reformatsky reaction
by providing high stereoselectivities and chemical yields with
linear aliphatic aldehydes. The particular advantage of this
reaction stems from the fact that the site of reaction is strictly
determined by the halogen moiety. Regioselective enolate
formation can occur in contrast with base-induced proton
abstraction.
Scheme 3
(10) (a) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett. 1985,
26, 435. (b) Solladie´, G.; Demailly, Greck, C. J. Org. Chem. 1985, 50,
1552. (c) Solladie´, G.; Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem.
1986, 51, 1912. (d) Solladie´-Cavallo, A.; Suffert, J.; Adib, A.; Solladie´, G.
Tetrahedron Lett. 1990, 31, 6649. (e) Solladie´, G.; Rubio, A.; Carren˜o, M.
C.; Garcia-Ruano, J. L. Tetrahedron: Asymmetry 1990, 1, 187. (f) Carren˜o,
M. C.; Garcia Ruano, J. L.; Martin, A.; Pedregal, C.; Rodriguez, J. H.;
Rubio, A.; Sanchez, J.; Solladie´, G. J. Org. Chem. 1990, 55, 2120.
By comparison with the literature,9 the configuration 3(R)-
4-(S) was assigned to 10.
(9) (a) Ukata, M.; Onoue, S.; Takeda, A. Chem. Lett. 1987, 971 (b)
Vicario, J. L.; Badia, D.; Dominguez, E.; Rodriguez, M.; Carrillo, L. J.
Org. Chem. 2000, 65, 3754.
Org. Lett., Vol. 5, No. 5, 2003
631

Further diastereoselective reduction of the â-ketosulfoxide
was performed as expected with high diastereoselectivities
leading to anti- and syn-2-methyl-1,3-diol moieties. These
asymmetric syntheses are promising because methods to
remove or transform the chiral sulfoxide are well-known.12
Extension of this methodology is now under investigation
in our laboratory.
Acknowledgment. This work was supported by the
CNRS and Ministe`re de la Recherche. M.O. thanks the
Ministe`re de la Recherche for a fellowship.
(11) (S)-Configuration of the new hydroxylic carbon in compound 12
and the (R)-configuration in compound 13 were expected from the reaction
mechanism already proposed10d and also from our 1H NMR characterization
of the product. From the numerous examples of reduction of â-ketosul-
foxides already reported,11a-d we noticed that the nonequivalence of the
methylene hydrogens R to the sulfoxide group is quite different in the two
diastereomers: in the [(R),S(R)]-configuration the ∆ν value between these
two hydrogens is around 40 Hz (in 13, ∆ν ) 50 Hz) and around 80 Hz in
the [(S),S(R)]-epimers (in 12 ∆ν ) 79 Hz). (a) Colobert, F.; Des Mazery,
R.; Solladie´, G.; Carreno, M. C. Org. Lett. 2002, 4, 1723. (b) Solladie´, G.;
Gressot, L.; Colobert, F. Eur. J. Org. Chem. 2000, 357. (c) Solladie´, G.;
Adamy, M.; Colobert, F. J. Org. Chem. 1996, 61, 4369. (d) Solladie´, G.;
Colobert, F.; Denni, D. Tetrahedron: Asymmetry 1998, 9, 3081.
Supporting Information Available: Experimental pro-
cedures for 4b, 9, 12, and 13, spectral and analytical data,
1
reductive elimination of 9 and 4c with H and 13C NMR
data, and correlation of configuration. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL027223+
(12) (a) De Lucchi, O.; Mioti, U.; Modena, G. Org. React. 1991, 40,
157 (b) Zasshi, Y. J. Pharm. Soc. Jpn. 1997, 117, 282.
632
Org. Lett., Vol. 5, No. 5, 2003