Alternative approach to the synthesis of optically active β-keto sulfoxides by furylhydroperoxides enantioselective oxidations

Article abstract of DOI:10.1016/S0957-4166(98)00264-X

Enantiomerically enriched β-keto sulfoxides are obtainable by an alternative method to the classical reaction of the enantiomerically pure α- sulfinyl anion with esters or by Anderson's synthesis, through Sharpless modified kinetic resolution of racemic β-keto sulfoxides. High e.e.s are achieved by combining asymmetric oxidation and kinetic resolution using furylhydroperoxides as oxidants.

Full text of DOI:10.1016/S0957-4166(98)00264-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2619–2625
Alternative approach to the synthesis of optically active β-keto
sulfoxides by furylhydroperoxides enantioselective oxidations
Alessandra Lattanzi,a,∗ Francesco Bonadies,b Annamaria Schiavo a and Arrigo Scettri a
aDipartimento di Chimica, Università degli Studi di Salerno, 84081 Baronissi (Salerno), Italy
bCentro di Studio CNR per la Chimica delle Sostanze Organiche Naturali, Dipartimento di Chimica, Università ‘La Sapienza’,
P. le A. Moro 5, 00185 Roma, Italy†
Received 19 May 1998; accepted 6 July 1998
Abstract
Enantiomerically enriched β-keto sulfoxides are obtainable by an alternative method to the classical reaction
of the enantiomerically pure α-sulfinyl anion with esters or by Andersen’s synthesis, through Sharpless modified
kinetic resolution of racemic β-keto sulfoxides. High e.e.s are achieved by combining asymmetric oxidation and
kinetic resolution using furylhydroperoxides as oxidants. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiomerically pure sulfoxides represent a convenient class of enantiocontrol elements for realizing
useful transformations.1 In particular, the employment of β-keto sulfoxides in the asymmetric synthesis
of several natural compounds1c has been frequently reported in a large number of publications. For
example, the highly diastereocontrolled reduction2 of the carbonyl functionality after elimination of the
sulfinyl group yields enantiomerically pure carbinols.
Chiral acyclic β-keto sulfoxides are generally available by the condensation of (−)-(R)-p-tolyl methyl
sulfinyl anion and an ester.3a Enantiomerically pure sulfinyl cycloalkanones are synthesized by an
Andersen-type reaction of an enolate4 or azaenolate5 species with a chiral sulfinate ester.
The access to β-keto sulfoxides with a chiral methylsulfinyl group is limited by the fact that O-
menthyl methanesulfinates cannot be obtained in an enantiomerically pure form;6 only recently was their
preparation reported, making use of the DAG (diacetone D-glucose) methodology.7
In recent years we8 and others9 have addressed the reactivity of furylhydroperoxides in Sharpless mod-
ified asymmetric epoxidations and sulfoxidations and they have proved successful alternative oxidants to
∗
†
Corresponding author. E-mail: lattanzi@ponza.dia.unisa.it
Associated to the National Institute of Biological Systems — CNR.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00264-X

2620
A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
t-butyl hydroperoxide (TBHP) and cumyl hydroperoxide (CHP). Moreover, under the same conditions,
they can perform kinetic resolution of racemic aryl methyl sulfoxides.10 In fact we were able to recover,
with good yields and high e.e.s, unreacted starting sulfoxides (e.e.>90%). Intrigued by the possibility of
extending the study of kinetic resolution to other types of sulfur compounds we decided to examine if
the process was feasible for racemic β-keto sulfoxides (Scheme 1).
Scheme 1.
2. Results and discussion
Racemic β-keto sulfoxides 1 were prepared according to known procedures3b and were oxidized with
different alkyl hydroperoxides adopting the same conditions as those reported in Table 1.
Two important features appear in Table 1:
(i) With the employment of the commercial hydroperoxides (TBHP and CHP) very low enantio-
discrimination was achieved, consequently only in some examples did an extremely poor kinetic
resolution of racemic β-keto sulfoxides occur (entries 1, 2, 6, 9). Next we studied the reactivity
of furylhydroperoxide 2a as oxidant under the same conditions and we found a substantial general
improvement in the kinetic resolution of the starting racemic compounds. As can be seen from the
data, analogously to aryl methyl sulfoxides, the S-enantiomer was transformed faster to sulfone in
the course of the oxidation.
(ii) Both the steric and electronic character of R1 influenced the efficiency of the process. Increasing
bulkiness of R1 group brought a decrease in enantioselectivity (compare entries 7, 11 and 13), while
in the case of R1=Ph (entry 3) the combination of the steric and electronic character of the phenyl
substituent exerted a beneficial effect.
Kinetic resolution of starting compounds also took place when R1CO was an ester (last entries).
Furthermore, the process seems to be slightly influenced by temperature. Very similar stereoselectivity
factors were evaluated in reactions conducted at −25°C and 0°C (entries 3, 4, 7 and 8). The lower
enantiocontrol that emerged in the kinetic resolution of β-keto sulfoxides compared with the simple aryl
methyl sulfoxides10 is believed to arise from the presence of the co-ordinating carbonyl function (R1CO).
In fact, it could offer a further site of chelation to the titanium chiral complex, forming a structure with a
smaller enantiodifferentiation at the oxidation level.
So far the paucity of results reported on the asymmetric oxidation of β-keto sulfides adopting Sharpless
modified conditions12 and the possibility of exploiting kinetic resolution to improve the e.e. of β-keto
sulfoxides prompted us to investigate (Scheme 2; Table 2).
We initially chose to investigate the asymmetric oxidation of the model β-keto sulfide 5a (entries 1, 2
and 3) using Modena’s molar ratios14 (2/5/Ti(Oi-Pr)4/L-DET 1/1/1/4). Optimum conditions for yield and
enantioselectivity were observed with oxidant 2a and, as expected, (R)-3a was recovered preferentially.
On the basis of these results and those reported in Table 1 (entries 1, 2, 3) we could have exploited most

A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
2621
Table 1
Kinetic resolution of racemic β-keto sulfoxides 1 with alkyl hydroperoxides
Scheme 2.
successfully both enantioconvergent oxidations only with the use of furyl hydroperoxide 2a so we ran
the experiment increasing the amount of 2a. The following kinetic resolution of β-keto sulfoxide during
the oxidation to sulfone led to the isolation of 3a in fair yield and with excellent e.e. (entry 4). In order
to assess the generality and the scope of the asymmetric oxidation and kinetic resolution one-pot process
as an improved Sharpless type procedure, we extended the reactions to several β-keto sulfides.
Acting together, the two oxidations employing furylhydroperoxide 2a accounted for the high e.e.
detected for compounds 3 susceptible to further enhancement, increasing the extent of conversion to
sulfone. A control experiment was carried out with CHP on compound 5h (entry 7) and as expected the

2622
A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
Table 2
Asymmetric oxidation and kinetic resolution as combined routes to chiral β-keto sulfoxides
corresponding β-keto sulfoxide was recovered with a modest e.e. compared to that obtained with oxidant
2a (entry 6). Although moderate e.e.s were checked with the furyl hydroperoxide, when R1 is a sterically
demanding group (entries 9 and 10), the previous optical purity data concerning asymmetric oxidation of
compound 5i under Sharpless modified conditions with TBHP was very low (9% e.e.).12b
To the best of our knowledge those are the highest e.e.s ever reported in asymmetric oxidation of
β-keto sulfides using the Ti(Oi-Pr)4/tartrate system.
3. Conclusions
Kinetic resolution under Sharpless modified conditions of racemic sulfoxides using furylhydroperox-
ides as oxidants has proved to have a wider application, to include functionalized β-keto sulfoxides.
Moreover, the combined enantioconvergent oxidations open up an additional approach to the synthesis
of optically active β-keto sulfoxides.
4. Experimental
4.1. General
1H-NMR and 13C-NMR spectra were recorded with Bruker DRX 400 MHz and Bruker AM 250 MHz
spectrometers. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), hept
(heptuplet), m (multiplet), dd (double doublet), ss (sharp singlet). Chemical shifts are reported in (δ) ppm
relative to internal CDCl3 δ (7.26) for 1H-NMR and CDCl3 δ (77.0) for 13C-NMR. Optical rotations were
measured with a JASCO Dip-1000 digital polarimeter at λ=589 nm. Silica gel (230–400 mesh Merck)
was used for flash chromatography. Analytical thin layer chromatography was carried out on Merck
1
Kieselgel F254 plates. Enantiomeric excesses of compounds 3 were measured by H-NMR analysis on
the AB system of CH2SO* in CDCl3:CCl4 (3:1) solutions with the presence of a stoichiometric amount

A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
2623
of R-(−)-(3,5-dinitrobenzoyl)-α-methylbenzyl amine. Dichloromethane was stored over activated 4 Å
molecular sieves.
Compounds 5a, 5b, 5d and 5i were synthesized according to procedures reported in the literature.15
Other chemicals (Aldrich, Fluka or Lancaster) were used as supplied.
4.2. Typical experimental procedure of kinetic resolution
To a solution of CH2Cl2 (10 ml), at room temperature and under an argon atmosphere were added
Ti(Oi-Pr)4 (1 mmol), L-DET (4 mmol) and 1 (2 mmol). The resulting pale yellow solution was stirred at
−20°C for 20 min. Then 2 (1.6 mmol) dissolved in 10 ml of CH2Cl2 was added to the mixture and the
reaction was monitored by TLC. Water was added (4 ml) to the solution at −20°C and vigorous stirring
was maintained for 1 h at room temperature. The white gel was filtered through Celite and thoroughly
washed with CH2Cl2. The organic phase was dried over Na2SO4 and then removed in vacuo. Flash
chromatography of the crude mixture (petroleum ether/AcOEt) furnished the desired β-keto sulfoxides.
4.3. 5-(1-Hydroperoxyethyl)-3-ethoxycarbonyl-2-isopropylfuran 2a
The procedure for the synthesis and the spectroscopic data of compound 2a are reported in the
literature.16
4.4. Typical experimental procedure of combined asymmetric oxidation and kinetic resolution
To a solution of CH2Cl2 (7 ml), at room temperature and under an argon atmosphere were added
Ti(Oi-Pr)4 (1 mmol), L-DET (4 mmol) and 5 (1 mmol). The stirred mixture was cooled to −20°C for 20
min. Then 2 (2 mmol) dissolved in 7 ml of CH2Cl2, was added and the reaction was monitored by TLC.
The procedure is then the same as that reported above. Spectroscopic data of compounds 3a, 3b, 3c, 3d,
3e, 3f, 3g and 3i are consistent with the published data.1a,2a,b,c,3a,12b
4.5. (R)-(p-Tolylsulfinyl)methyl phenyl ketone 3a
24
1
[α]D +174.1 (c 1.1, CHCl3); H-NMR (CDCl3): 2.37 (s, 3H), 4.39 (AB system, 2H, J=14.1 Hz),
7.24–7.30 (m, 2H), 7.38–7.61 (m, 5H), 7.82–7.88 (m, 2H); 13C-NMR (CDCl3): 21.1, 65.9, 124.2, 128.8.
130.0, 134.1, 136.0, 140.1, 142.2, 191.6. Anal. calcd for C15H14SO2: C, 69.74; H, 5.46%. Found: C
69.61; H, 5.38%.
4.6. (R)-(p-Tolylsulfinyl)methyl n-octyl ketone 3b
[α]D24 +118.7 (c 1.3, CHCl3); 1H-NMR (CDCl3): 0.86 (t, 3H J=6.8 Hz), 1.10–1.42 (m, 8H), 1.43–1.60
(m, 2H), 2.30–2.60 (m, 5H), 3.80 (AB system, 2H, J=13.4 Hz), 7.30–7.36 (m, 2H), 7.49–7.58 (m, 2H);
13C-NMR (CDCl3): 14.0, 21.4, 22.5, 23.0, 29.0, 29.2, 29.6, 31.7, 45.0, 68.0, 124.0, 130.0, 139.7, 142.1,
201.8. Anal. calcd for C17H26SO2: C, 69.34; H, 8.90%. Found: C, 69.50; H, 8.84%.
4.7. (R)-(p-Tolylsulfinyl)methyl n-pentyl ketone 3c
[α]D +85.8 (c 1.1, CHCl3); 1H-NMR (CDCl3): 0.86 (t, 3H, 7.0 Hz), 1.14–1.38 (m, 4H), 1.42–1.58
24
(m, 2H), 2.35–2.62 (m, 5H), 3.80 (AB system, 2H, J=13.4 Hz), 7.23–7.36 (m, 2H), 7.49–7.58 (m, 2H);

2624
A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
13C-NMR (CDCl3): 13.7, 21.4, 22.3, 22.7, 44.9, 68.2, 124.1, 130.1, 140.5, 142.1, 201.7. Anal. calcd for
C14H20SO2: C, 66.63; H, 7.99%. Found: C, 66.81; H, 8.11%.
4.8. (R)-(p-Tolylsulfinyl)methyl isopropyl ketone 3d
[α]D24 +95.9 (c 1.0, CHCl3); 1H-NMR (CDCl3): 1.00 (d, 3H, J=6.8 Hz), 1.08 (d, 3H, J=6.8 Hz), 2.41
(s, 3H), 2.58 (hept, 1H, J=6.8 Hz), 3.92 (AB system, 2H, J=14.0 Hz), 7.26–7.38 (m, 2H), 7.51–7.60 (m,
2H); 13C-NMR (CDCl3): 17.2, 17.3, 21.4, 42.2, 66.8, 124.1, 130.0, 140.0, 142.1, 205.5. Anal. calcd for
C12H16SO2: C, 64.25; H, 7.19%. Found: C, 64.42; H, 7.07%.
4.9. (R)-(p-Tolylsulfinyl)methyl trans-β-methylvinyl ketone 3e
[α]D +142.8 (c 1.0, CHCl3); 1H-NMR (CDCl3): 1.83 (dd, 3H, J1=6.9 Hz, J2=1.3 Hz), 2.37 (s, 3H),
24
3.93 (AB system, 2H, J=13.5 Hz), 6.09 (dd, 1H, J1=15.8 Hz, J2=1.3 Hz), 6.63 (dq, 1H, J1=15.8 Hz,
J2=6.9 Hz), 7.26–7.32 (m, 2H), 7.47–7.54 (m, 2H); 13C-NMR (CDCl3): 18.4, 21.3, 66.2, 124.0, 129.8,
131.7, 139.7, 141.9, 146.9, 190.5. Anal. calcd for C12H14SO2: C, 64.84; H, 6.35%. Found: C, 64.75; H,
6.27%.
4.10. (R)-Methyl phenylsulfinyl acetate 3f
[α]D24 +78.8 (c 1.3, acetone); 1H-NMR (CDCl3): 3.68 (s, 3H), 3.74 (AB system, 2H, J=13.6 Hz), 7.51
(m, 3H), 7.65 (m, 2H); 13C-NMR (CDCl3): 52.6, 61.4, 123.9, 129.3, 131.7, 142.9, 165.1. Anal. calcd for
C9H10SO3: C, 54.53; H, 5.08%. Found: C, 54.67; H, 5.00%.
4.11. (R)-Ethyl methylsulfinyl acetate 3g
18
1
[α]D −43.0 (c 0.9, acetone); H-NMR (CDCl3): 1.30 (t, 3H, J=7.0 Hz), 2.70 (s, 3H), 3.69 (AB
system, 2H, J=13.6 Hz), 4.24 (q, 2H, J=7.0 Hz); 13C-NMR (CDCl3): 14.1, 39.4, 57.9, 62.1, 164.9. Anal.
calcd for C5H10SO3: C, 39.99; H, 6.71%. Found: C, 40.10; H, 6.62%.
4.12. (R)-(p-Tolylsulfinyl)methyl acetone 3h
24
1
[α]D +165.0 (c 0.9, CHCl3); H-NMR (CDCl3): 2.24 (s, 3H), 2.43 (s, 3H), 3.78 (AB system, 2H,
J=13.4 Hz), 7.31–7.36 (m, 2H), 7.51–7.55 (m, 2H); 13C-NMR (CDCl3): 21.3, 31.9, 68.5, 123.9, 130.0,
139.4, 142.1, 199.4. Anal. calcd for C10H12SO2: C, 61.20; H, 6.16%. Found: C, 61.09; H, 6.22%.
4.13. (R)-t-Butyl (p-tolylsulfinyl) acetate 3i
20
1
[α]D +61.4 (c 1.5, ethanol); H-NMR (CDCl3): 1.35 (s, 9H), 2,37 (s, 3H), 3.64 (AB system, 2H,
J=13.6 Hz), 7.27–7.31 (m, 2H), 7.52–7.57 (m, 2H); 13C-NMR (CDCl3): 21.2, 27.7, 62.6, 83.1, 124.5,
130.0, 140.1, 142.4, 164.0. Anal. calcd for C13H18SO3: C, 61.39; H, 7.13%. Found: C, 61.51; H, 7.05%.
Acknowledgements
The authors thank Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) and
C.N.R. for financial support.

A. Lattanzi et al. / Tetrahedron: Asymmetry 9 (1998) 2619–2625
2625
References
1. (a) Solladié, G. Synthesis 1982, 185. (b) Andersen, K. K. In The Chemistry of Sulfones and Sulfoxides, Patai, S., Rappoport,
Z., Stirling, C. J. M., Eds; John Wiley & Sons: Chichester, England, 1988; Chapter 16, pp. 823–849. (c) Carreño, M. C.
Chem. Rev. 1995, 95, 1717. (d) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961.
2. (a) Annunziata, R.; Cinquini, M.; Cozzi, F. J. Chem. Soc., Perkin Trans. 1 1979, 1687. (b) Solladié, G.; Greek, C.; Demailly,
G.; Solladié-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047. (c) Solladié, G.; Greek, C.; Demailly, G. Tetrahedron Lett. 1985,
26, 435. (d) Solladié, G.; Demailly, G.; Greck, C. J. Org. Chem. 1985, 50, 1552. (e) Solladié, G.; Fréchou, C.; Demailly, G.;
Greck, C. J. Org. Chem. 1986, 51, 1912. (f) Carreño, M. C.; García Ruano, J. L.; Martín, A. M.; Pedegral, C.; Rodríguez,
J. H.; Rubio, A.; Sánchez, J.; Solladié, G. J. Org. Chem. 1990, 55, 2120.
3. (a) Kunieda, N.; Nokami, J.; Kinoshita, M. Chem. Lett. 1974, 369. (b) Corey, E. J.; Chaykowski, M. J. Am. Chem. Soc.
1962, 84, 866; ibid. 1965, 87, 1345.
4. Carreño, M. C.; García Ruano, J. L.; Rubio, A. Tetrahedron Lett. 1987, 28, 4861.
5. Carreño, M. C.; García Ruano, J. L.; Pedegral, C.; Rubio, A. J. Chem. Soc., Perkin Trans. 1 1989, 1335.
6. Andersen, K. K. J. Org. Chem. 1964, 29, 1953.
7. Ouazzani, H. El; Khiar, N.; Fernandez, I.; Alcudia, F. J. Org. Chem. 1997, 62, 287.
8. Lattanzi, A.; Bonadies, F.; Scettri, A. Tetrahedron: Asymmetry 1997, 8, 2141.
9. Adam, W.; Korb, M. N. Tetrahedron: Asymmetry 1997, 8, 1131.
10. Lattanzi, A.; Bonadies, F.; Senatore, A.; Soriente, A.; Scettri, A. Tetrahedron: Asymmetry 1997, 8, 2473.
11. (a) Deshmukh, M.; Duñach, E.; Juge, S.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 3467. (b) Diter, P.; Taudien, S.; Samuel,
O.; Kagan, H. B. J. Org. Chem. 1994, 59, 370.
12. (a) Kagan, H. B.; Dunach, E.; Nemecek, C.; Pitchen, P.; Samuel, O.; Zhao, S. Pure & Appl. Chem. 1985, 12, 1911. (b)
Duñach, E.; Kagan, H. B. Nouv. J. Chim. 1985, 9, 1.
13. (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b) Capellos, C.; Bielski, B. J. H. Kinetic System:
Mathematical Descriptions of Chemical Kinetics in Solution; Wiley: New York, 1972.
14. Di Furia, F.; Modena, G.; Seraglia, G. Synthesis 1984, 325.
15. Trost, B. M.; Salzmann, Y. S.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887.
16. Scettri, A.; Bonadies, F.; Lattanzi, A.; Palombi, L.; Pesci, S. Tetrahedron 1997, 53, 17139.