Highly enantioselective oxidations of ketene dithioacetals leading to trans bis-sulfoxides

Article abstract of DOI:10.1021/jo034032r

Ketene dithioacetals undergo a Sharpless-type asymmetric oxidation using (+)-DET, Ti(OZPr)4, and cumene hydroperoxide to give the trans bis-sulfoxides 4a-f with essentially complete control of enantioselectivity and dia-stereoselectivity. The high enantio

Full text of DOI:10.1021/jo034032r

SCHEME 1. Possible Routes to Ketene
Dithioacetal Bis-sulfoxides
Highly Enantioselective Oxidations of
Ketene Dithioacetals Leading to Trans
Bis-sulfoxides
Varinder K. Aggarwal,*,† Rebecca M. Steele,† Ritmaleni,†
Juliet K. Barrell,† and Ian Grayson‡
School of Chemistry, University of Bristol, Cantock’s Close,
Bristol BS8 1TS, U.K., and Degussa Fine Chemicals,
Seal Sands, Middlesbrough TS2 1UB, U.K.
SCHEME 2. Route to Ketene Dithioacetal
Bis-sulfoxidesa
v.aggarwal@bristol.ac.uk
Received January 9, 2003
Abstract: Ketene dithioacetals undergo a Sharpless-type
asymmetric oxidation using (+)-DET, Ti(OiPr)4, and cumene
hydroperoxide to give the trans bis-sulfoxides 4a-f with
essentially complete control of enantioselectivity and dia-
stereoselectivity. The high enantioselectivity is a conse-
quence of carrying out two asymmetric processes on the
same substrate. However, this should lead to the formation
of a small amount of the meso isomer but none was isolated.
From monitoring the enantioselectivity of the monoxide over
time, it was concluded that small amounts of the meso
isomer must be formed. The inability to isolate this com-
pound could be because it acted as a ligand on titanium and
remained tightly bound even upon workup.
a Reagents and conditions: (i) n-BuLi, THF, -78 °C to rt; (ii)
Ti(OiPr)4 (0.5 equiv), (+)-DET (2 equiv), PhC(Me)2OOH (4 equiv),
CH2Cl2, -40 to -20 °C.
above cases, the ketene dithioacetal bis-sulfoxides were
prepared by either a Wittig-Horner reaction with phos-
phonate 1 or an aldol-type reaction with bis-sulfoxide 2
(Scheme 1).
Ketene dithioacetals are useful intermediates in or-
ganic synthesis as they are able to participate in a variety
of [3 + 2] and [4 + 2] cycloaddition reactions.1 The
corresponding mono- or bis-sulfoxides are potentially
capable of performing such reactions with good to excel-
lent diastereocontrol,2 thus leading to products with high
enantiomeric excess after deprotection. Indeed, we have
shown that chiral ketene dithioacetal bis-sulfoxides
undergo inter-3 and intramolecular4 [3 + 2] nitrone
cycloadditions and [4 + 2] Diels-Alder5 reactions with
essentially complete diastereocontrol. In addition, the
ketene dithioacetal bis-sulfoxides also undergo highly
diastereoselective nucleophilic epoxidation reactions, and
the intermediate epoxides react stereospecifically with
amines to generate enantiopure R-aminoamides.6 In the
Although we have developed efficient and highly enan-
tioselective routes to 1 and 2, we questioned whether the
ketene dithioacetal bis-sulfoxides could be prepared more
directly and in higher yield by oxidation of ketene
dithioacetals 3 (Scheme 2). A further motivation for this
strategy came from the sensitivity of dithiane dioxides 1
and the precursor of 2 to acid/Lewis acid (present in the
oxidation process), which resulted in a facile Pummerer
reaction leading to partial decomposition and thus re-
duced yields. Such processes were clearly not possible
with ketene dithioacetals 3. Although there were numer-
ous examples of asymmetric oxidation of 1,3-dithianes
with substituents in the 2-position, to give mono-sulfox-
ides with good ee7 and bis-sulfoxides with essentially
complete selectivity,5b,c,6,8 there were no examples of the
asymmetric oxidation of ketene dithioacetals. We there-
fore embarked on this study.
† Degussa Fine Chemicals.
‡ University of Bristol.
(1) For reviews, see: (a) Aggarwal, V. K.; Ali, A.; Coogan, M. P.
Tetrahedron 1999, 55, 293-312. (b) Junjappa, H.; Ila, H.; Asokan, C.
V. Tetrahedron 1990, 46, 5423-5506. (c) Kolb, M. Synthesis 1990, 171-
190.
(2) (a) Ruano, J. L. G.; de la Plata, B. C. Top. Curr. Chem. 1999,
204, 1-126. (b) Ruano, J. L. G.; Carretero, J. C.; Carreno, M. C.;
Cabrejas, L. M. M.; Urbano, A. Pure Appl. Chem. 1996, 68, 925-930.
(c) Carreno, M. C. Chem. Rev. 1995, 95, 1717-1760. (d) Lopez, R.;
Carretero, J. C. Tetrahedron: Asymmetry 1991, 2, 91-92.
(3) Aggarwal, V. K.; Grainger, R. S.; Adams, H.; Spargo, P. L. J.
Org. Chem. 1998, 63, 3481-3485.
A range of ketene dithioacetals was prepared by
Peterson olefination of dithiane 59 with aldehydes and
ketones. These substrates were then subjected to our
previously developed conditions for oxidation of 1,3-
(4) Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.; Alexander, R.
Org. Lett. 2002, 4, 1227-1229.
(7) (a) Page, P. C. B.; McKenzie, M. J.; Buckle, D. R. Tetrahedron
1998, 54, 14581-14596. (b) Samuel, O.; Ronan, B.; Kagan, H. B. J.
Organomet. Chem. 1989, 370, 43-50.
(8) (a) Aggarwal, V. K.; Esquivel-Zamora, B. N.; Evans, G. R.; Jones,
E. J. Org. Chem. 1998, 63, 7306-7310. (b) Aggarwal, V. K.; Evans,
G.; Moya, E.; Dowden, J. J. Org. Chem. 1992, 57, 6390-6391.
(9) (a) Seebach, D.; Kolb, M.; Gro¨bel, B.-T. Chem. Ber. 1973, 106,
2277-2290. (b) Seebach, D.; Kolb, M.; Gro¨bel, B.-T. Tetrahedron Lett.
1974, 36, 3171-3174.
(5) (a) Aggarwal, V. K.; Lightowler, M.; Lindell, S. D. Synlett 1992,
730-731. (b) Aggarwal, V. K.; Drabowicz, J.; Grainger, R. S.; Gu¨ltekin,
Z.; Lightowler, M.; Spargo, P. L. J. Org. Chem. 1995, 60, 4962-4963.
(c) Aggarwal, V. K.; Gu¨ltekin, Z.; Grainger, R. S.; Adams, H.; Spargo,
P. L. J. Chem. Soc., Perkin Trans. 1 1998, 2771-2781.
(6) Aggarwal, V. K.; Barrell, J. K.; Worrall, J. M.; Alexander, R. J.
Org. Chem. 1998, 63, 7128-7129.
10.1021/jo034032r CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/16/2003
J. Org. Chem. 2003, 68, 4087-4090
4087

TABLE 1. Oxidation of Ketene Dithioacetals 3a-f
substrate
time (h)
yielda (%)
eeb,c (%)
3a
3b
3c
3d
3e
3f
5.5
6
20
24
21
18
65
62
75
73
71
60
98d
>99
>99e
>99
>99
>98f
FIGURE 1. Meso bis-sulfoxide binding to titanium.
a Isolated yield. b Enantiomeric excess determined by chiral
HPLC (see the Supporting Information for details). c Absolute
configurations of 4b and 4d were determined by comparison of
[R]D with the literature6 and assigned (R,R). All others assigned
by analogy. d Enantiomeric excess of monoxide 6a was found to
be 82% by chiral HPLC for the major geometric isomer. e Enan-
tiomeric excess of monoxide 6c was found to be 85% by chiral
HPLC. f Enantiomeric excess was determined by NMR using the
Pirkle chiral shift reagent. This represents the limits of detection
of the other enantiomer by this method.
SCHEME 3. Proposed Synthesis of Meso
Bis-sulfoxide 7c
as both the meso and C2-symmetric bis-sulfoxides were
expected to be equally stable, as there is no C-2 proton,
and therefore, the bis-sulfoxides cannot decompose through
an acid-catalyzed Pummerer reaction.
There are three possible explanations for the current
observation: (1) the meso bis-sulfoxide is not formed to
any appreciable extent because the stereochemistry of
the initial sulfoxide does influence the second oxidation;
i.e. the second oxidation is subject to both substrate and
reagent control; (2) the meso bis-sulfoxide is oxidized to
the sulfoxide-sulfone more rapidly than the C2 isomer;
or (3) the meso bis-sulfoxide acts as a bidentate ligand
to titanium (Figure 1) and remains tightly bound even
on workup.
Of the three possibilities, the first explanation seemed
the more reasonable as the meso bis-sulfoxide had never
been observed and only by leaving the reaction for
extended periods of time was any of the sulfone-sulfoxide
ever obtained. To determine which of the explanations
was most likely, we attempted to prepare the meso bis-
sulfoxide 7c. However, treatment of 3c with m-CPBA
only gave the dl isomer 4c, indicating that there was a
substantial degree of substrate control in favor of the
trans isomer. To prepare the meso compound, we there-
fore needed to control the second oxidation through
reagent control. The Sharpless-type reagent employing
(+)-DET showed a high degree of reagent control in the
oxidation of dithiane 3c to the (R)-mono-sulfoxide 6c
(ratio of R/S was 93:7). We reasoned that the meso isomer
7c should therefore be favored by employing the opposite
enantiomer of DET in the second oxidation, if reagent
control was able to overcome substrate control (Scheme
3).
dithiane derivatives, and the results are presented in
Table 1. We were delighted to find that good yields and
essentially complete enantioselectivity were obtained
with all substrates without exception. While we had
previously employed chiral shift reagents to determine
the enantiomeric excess, we discovered that excellent
separation of the two enantiomers of the polar bis-
sulfoxides could be achieved by chiral HPLC.
The reactions have to be carefully monitored to ensure
maximum conversion of the mono-sulfoxide to the bis-
sulfoxide with minimum over-oxidation to the sulfoxide-
sulfone.
The oxidation of 3c10 was studied in more detail. At
the end of the reaction, in addition to the bis-sulfoxide
4c, the mono-sulfoxide 6c was isolated in 7% yield and
85% enantiomeric excess. Based on our belief that the
second oxidation would also occur with substantial
reagent control and with minimal influence from the
existing sulfoxide, we expected to find substantial quan-
tities of the meso bis-sulfoxide. From the Horeau prin-
ciple, we would expect to obtain 14% of the meso bis-
sulfoxide if the second oxidation occurred with the same
level of reagent control.11 However, we were unable to
isolate this material. A similar situation arose in the
oxidation of 1,3-dithianes bearing ester and phosphonate
moieties in the 2-position: the trans bis-sulfoxides were
obtained with high enantiomeric excess but none of the
meso isomers were isolated.6,8 The bis-sulfoxides of these
substrates are sensitive to acid-catalyzed decomposition
via a Pummerer reaction, and in these cases, we assumed
that the meso isomer decomposed more readily than the
C2 isomer as it is substantially more acidic.12 However,
this could not be a viable explanation in the current study
In the event, treatment of the (R)-mono-sulfoxide of
86% enantiomeric excess (obtained from (+)-DET) with
the Sharpless-type reagent employing (-)-DET led to the
trans bis-sulfoxide, but again without isolation of any of
the meso isomer (Scheme 4). This indicates that substrate
control dominates over reagent control in the second
oxidation. However, we could not achieve complete mass
balance and so the possibility remained that the meso
isomer was formed but not isolated.
To test whether the second oxidation is subject to both
substrate control and reagent control (Scheme 5), we
decided to monitor the enantiomeric excess of the mono-
sulfoxide 6c over time. If no meso isomer is formed and
(10) This substrate was chosen to simplify the analysis, as no double-
bond isomers of the mono-sulfoxide are possible.
(11) According to the x2, y2 rule (Horeau principle), the ratio of the
enantiomers of the bis-sulfoxide should be close to the square of the
enantiomers of the mono-sulfoxide in the asymmetric oxidation of bis-
sulfides. The enantioselectivity of the mono-sulfoxide 6c is 85%, so if
this principle is followed then the expected enantioselectivity for the
bis-sulfoxide would be 99.2%. This rule would also predict that there
should be approximately 14% (2xy) of the meso bis-sulfoxide, assuming
complete reagent control. For an explanation of the Horeau principle,
see ref 8a and: Rautenstrauch, V. Bull. Chim. Soc. Fr. 1994, 131, 515-
524.
(12) The C-2 proton of cis-1,3-dithiane 1,3-dioxide has a pKa of 22.0,
whereas trans-1,3-dithiane 1,3-dioxide has a pKa of 24.9. See: Aggar-
wal, V. K.; Davies, I. W.; Franklin, R.; Maddock, J.; Mahon, M. F.;
Molloy, K. C. J. Chem. Soc., Perkin Trans. 1 1994, 2363-2368.
4088 J. Org. Chem., Vol. 68, No. 10, 2003

SCHEME 4. Oxidation of Mono-sulfoxide 6c with
60 g of (R) and 5 g of (S) mono-sulfoxide 6c were present,
and after 24 h, 30 g of (R) and 3 g of (S) remained. While
we know that the (R)-enantiomer was converted to the
(R,R)-bis-sulfoxide, the loss of the (S)-enantiomer was a
mystery.
(-)-DETa
The only explanation we can offer to account for this
situation is that some meso bis-sulfoxide (R,S) is formed,
but it forms a tightly bound complex with titanium
(Figure 1) and so is never isolated. Our inability to
achieve good mass balance (despite testing different
workups, including using citric acid13) and the constancy
of the enantiomeric excess of the monoxide over time
support this view.
In conclusion, we have demonstrated that ketene
dithioacetals can be selectively oxidized to the trans bis-
sulfoxides in good yield with essentially complete control
over enantioselectivity. We believe that the high diaste-
reoselectivity observed is a consequence of tight binding
with titanium of the small amount of the meso diaste-
reomer formed, which effectively removes this isomer.
This explanation could also account for the high enantio-
and diastereoselectivities observed in the bis-sulfoxida-
tions of other dithiane derivatives.
a Reagents and conditions: (i) Ti(OiPr)4 (0.5 equiv), (+)-DET (2
equiv), PhC(Me)2OOH (4 equiv), CH2Cl2, -40 to -20 °C; (ii)
Ti(OiPr)4 (0.5 equiv), (-)-DET (2 equiv), PhC(Me)2OOH (4 equiv),
CH2Cl2, -40 to -20 °C.
SCHEME 5. Proposed Route for Diastereo- and
Enantioselective Oxidation of 3c to Trans
Bis-sulfoxide 4c
Experimental Section
General Procedures for the Synthesis of Ketene Dithio-
acetals 3a-e. 2-Cyclohexylidene-1,3-dithiane 3c. 2-Tri-
methylsilyl-1,3-dithiane (3.00 g, 15.63 mmol) was dissolved in
THF (30 mL) under nitrogen with stirring. The solution was
cooled to -78 °C, and n-BuLi (1.6 M solution in hexanes: 11.70
mL, 18.73 mmol) was added. The solution was allowed to warm
to 0 °C over 5 h. The solution was re-cooled to -78 °C, and
cyclohexanone (2.06 mL, 19.88 mmol) was added. The solution
was allowed to warm to room temperature over 47 h. The
reaction solution was poured onto H2O (50 mL), extracted with
CH2Cl2 (5 × 50 mL), and dried (MgSO4), and the solvent was
removed under reduced pressure. Purification by column chro-
matography, on SiO2 (hexane/Et2O, 1:0-0.9:0.1), afforded 3c as
a colorless solid (1.922 g, 61%): mp (EtOH) 94-94.5 °C (lit.14
91.5-93.5 °C); 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 6H), 2.13
(dtd, J ) 6.0 Hz, J ) 4.0 Hz, J ) 2.0 Hz, 2H), 2.46 (m, 4H), 2.86
(ddd, J ) 6.0, 4.0, 2.0 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ
25.4, 26.8, 27.6, 30.5, 32.2, 114.0, 145.3; MS (EI) m/z 200 (M+),
125, 84.
TABLE 2. Monitoring the Oxidation of 3c over Time
(Conditions as in Table 1)
mono-sulfoxide 6c
bis-sulfoxide 4c
time (h)
yielda (%), (ee, %)b
yielda (%), (ee, %)b
0.5
1
65 (84)
65 (88)
65 (83)
49 (86)
36 (84)
33 (80)
4 (>99)
10 (>99)
12 (>99)
30 (>99)
50 (>99)
53 (>99)
4
6
14
24
General Procedures for the Synthesis of Ketene Dithio-
acetal Dioxides 4. (1R,3R)-2-Cyclohexylidene-1λ4,3λ4-di-
thiane 1,3-Dioxide 4c. (+)-Diethyl tartrate (0.34 mL, 2.01
mmol) and titanium(IV) isopropoxide (0.15 mL, 0.50 mmol) were
dissolved in CH2Cl2 (5 mL) at room temperature under nitrogen
and stirred for 20 min. 2-Cyclohexylidene-1,3-dithiane was
dissolved in CH2Cl2 (1.0 mL) and added to the reaction mixture,
which was then cooled to -40 °C and stirred for 1 h. Cumene
hydroperoxide (80%; 0.76 mL, 4.01 mmol) was added, and the
mixture was stirred at -40 °C for 10 min and then allowed to
stand at -20 °C for 22 h. Distilled water (0.36 mL) was added
and the reaction mixture allowed to warm to room temperature
with stirring for 1 h. The reaction mixture was filtered through
a pad of Celite and washed well with CH2Cl2, and the solvent
removed under reduced pressure. Purification by column chro-
matography on SiO2 (hexane/Et2O/EtOH, 1:1:0-0:1:0-0:1:1)
afforded 4c as a colorless solid (173 mg, 75%): mp (EtOH/
a NMR yield. b Enantiomeric excesses were determined by chiral
HPLC.
if the trans bis-sulfoxide 4c is formed with very high
enantiomeric excess, then in the second oxidation only
the (R)-enantiomer of the mono-sulfoxide reacts with
chiral oxidant to give the (R,R)-bis-sulfoxide 4c. Thus,
as the major (R)-enantiomer of the mono-sulfoxide 6c is
converted to the trans bis-sulfoxide 4c, the enantiomeric
excess of the remaining mono-sulfoxide 6c should gradu-
ally decrease over time and eventually the mono-sulfoxide
should be enriched in the (S)-isomer.
This experiment was therefore conducted (Table 2) but
instead of a gradual decrease in enantioselectivity of the
mono-sulfoxide 6c over time, the enantioselectivity re-
mained approximately constant! After 0.5 h, a 65% yield
of mono-sulfoxide 6c was obtained with 84% enantio-
meric excess, and after 24 h, a 33% yield of mono-
sulfoxide 6c remained with 80% enantiomeric excess. If
the reaction was conducted on a 100 g scale, after 0.5 h,
hexane) 159.5-161 °C; [R]22 -21.5 (c 1.0, CHCl3); IR (neat)
D
2919, 1042 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.69 (m, 2H),
1.75-1.88 (m, 4H), 2.53 (tt, J ) 9.0 Hz, J ) 5.0 Hz, 2H), 2.84
(13) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S.
Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(14) Hwu, J. R.; Taekyo, L.; Gilbert, B. A. J. Chem. Soc., Perkin
Trans. 1 1992, 3219-3223.
J. Org. Chem, Vol. 68, No. 10, 2003 4089

(m, 4H), 3.39 (dt, J ) 14.5 Hz, J ) 5.0 Hz, 2H), 3.53 (dt, J )
14.5 Hz, J ) 9.0 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 7.5, 25.9,
28.2, 32.7, 40.3, 135.5, 168.9; MS (EI) m/z 232 (M+), 215, 184;
HRMS (EI) found m/z 232.0594 (M+), C10H16S2O2 requires
232.0591.
sity, Yogyakarta, Indonesia, for a studentship to R., and
Bristol University.
Supporting Information Available: Experimental de-
tails and spectroscopic data for the preparation of all com-
pounds. Chiral HPLC data for appropriate compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Degussa Fine Chemi-
cals for a studentship to R.M.S., Gadjah Mada Univer-
JO034032R
4090 J. Org. Chem., Vol. 68, No. 10, 2003