Highly diastereoselective Michael additions onto dienyl bis-sulfoxides

Article abstract of DOI:10.1055/s-2005-872089

An optimized procedure for the preparation of (S_S,S _S)-bis(p-tolylsulfinyl)methane (4) is reported. Condensation of the lithium salt of 4 onto cinnamaldehyde furnished bis-sulfoxide dienyl derivative 5, a remarkable 1,4-Michael accep

Full text of DOI:10.1055/s-2005-872089

PRACTICAL SYNTHETIC PROCEDURES
2449
Highly Diastereoselective Michael Additions onto Dienyl Bis-Sulfoxides
D
iastereoselec
r
tive Mic
a
hael
A
dditi
n
ons ck Brebion, Jean Philippe Goddard, Louis Fensterbank,* Max Malacria*
Université Pierre et Marie Curie, UMR CNRS 7611, Institut de chimie moleculaire, FR 2769,
case 229, 4 place Jussieu, 75252 Paris cedex 05, France
E-mail: louis.fensterbank@upmc.fr; E-mail: max.malacria@upmc.fr
PSP
Received 14 March 2005; revised 27 May 2005
Dedicated to Professor Iwao Ojima for his outstanding achievement in asymmetric synthesis
and on the occasion of his 60th birthday.
No55
Abstract: An optimized procedure for the preparation of (SS,SS)-bis(p-tolylsulfinyl)methane (4) is reported. Condensation of the lithium
salt of 4 onto cinnamaldehyde furnished bis-sulfoxide dienyl derivative 5, a remarkable 1,4-Michael acceptor that can lead in a highly dia-
stereoselective manner to vinylcyclopropyl adducts. In a chelating mode of reactivity using a methylcopper reagent, a complete reversal of
stereoselectivity is observed giving an enantiopure b,g-unsaturated methyl ester intermediate that is used in the synthesis of cryptophycin.
Key words: bis-sulfoxide, Michael addition, vinylcyclopropane, cryptophycin
O
S
O
S
O
S
p-Tol
source of enantiopure
monooxidized sulfur:
p-Tol
p-Tol
OMent
(Ss)-2
1
R
O
S
O
S
O
S
O
p-Tol
O
S
1) BuLi, THF,
–40 °C
1) LDA, THF
0 °C to r.t.
p-Tol
p-Tol
p-Tol
S
p-Tol
Me
(Ss,Ss)-4, 88%
2) Cinnamaldehyde
–78 °C to –15 °C
2) 2, 0 °C to r.t.
3) Precipitation
(Ss,Ss)-5, 76%
(Rs)-3
Ph
Scheme 1
tions should be possible leaving an untouched double
bond, and a masked carbonyl group (Scheme 2).
Introduction
Alkylidene bis-p-tolylsulfoxides1 of type 12 (Scheme 1)
are highly versatile partners for asymmetric synthesis that
we have used in the context of radical chemistry3 and po- Scope and Limitations
lar Michael additions.4 In comparison, dienyl derivatives
like 5 which have been first reported by Solladié et al. To probe this point, we focused on dienyl bis-sulfoxide 5
have not been exploited.5 While cycloaddition reactions that was easily obtained from the condensation of cinna-
are likely an interesting field of applications for these sub- maldehyde on the lithium anion of (SS,SS)-bis(p-tolylsul-
strates,6 we have initially examined Michael additions to foxide)methane (4),2,5 itself originating from the addition
these compounds because of the interesting array of func- of the lithium anion of (RS)-37 on (SS)-2. We herein report
tionalities of the putative adducts. Both 1,4- or 1,6-addi- an optimized procedure for the isolation of 4 compared to
Kunieda’s original procedure.8 This allows a net yield im-
O
S
O
S
O
S
O
S
O
S
O
S
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
1. Nu
2. H
and/or
Nu
R
R
R
Nu
1,4
1,6
Scheme 2
SYNTHESIS 2005, No. 14, pp 2449–2452
x
x.
x
x
.
2
0
0
5
Advanced online publication: 20.07.2005
DOI: 10.1055/s-2005-872089; Art ID: Z05905SS
© Georg Thieme Verlag Stuttgart · New York

2450
F. Brebion et al.
PRACTICAL SYNTHETIC PROCEDURES
provement (88% vs 35%8) as well as a large scale prepa- No 1,6-product was detected.9 This adduct was then en-
ration (>10 g, see experimental).
gaged in a Pummerer saponification-esterification se-
quence leading to enantio-enriched (ee >96% ee, [a]D
20
Based on our precedent findings, we decided to examine
an efficient nucleophile4 and investigated the addition of
the sodium anion of dimethyl bromomalonate. Interest-
ingly, this reaction gave the 1,4-addition product 6 and the
1,6- plus 1,4-one 7 whose distribution was dependent on
the temperature (see Scheme 3). Conducting the reaction
at low temperature (entry 3) resulted in a poor conversion
and gave only 6 as a single diastereoisomer. Stereochem-
–52.1 (c = 1.60, CHCl3) {Lit.10 [a]D20 –52.5 (c = 5.2)})
a-methylated ester (R)-9 in 21% overall yield. Thus, the
determination of the absolute configuration of 9 con-
firmed the reversal of stereoselectivity we anticipated.
The b,g-unsaturated methyl ester (R)-9 is an interesting
building block that can be used in the synthesis of crypto-
phycin.10
istry of 6 was deduced by analogy with previous work on In conclusion, we have shown that the previously unex-
the formation of cyclopropyl derivatives.4 Raising the ploited dienyl bis-sulfoxide precursor 5 is an outstanding
temperature improved the conversion and resulted in the Michael acceptor which allows the formation of cyclopro-
generation of 7 as a minor product. At room temperature pyl derivatives in a highly diastereoselective manner. A
(entry 1), a severe competition between the formation of methyl copper reagent addition gives an access to an
6 and 7 was observed. It should be noted that 7 was enantiopure precursor of cryptophycin.
formed as a very major diastereomer.
Presumably, monocyclopropyl adduct 6 results from a
(SS,SS)-Bis(p-tolylsulfinyl)methane (4)
1,4-addition followed by a nucleophilic substitution at the
malonate center, while the dicyclopropyl one would orig-
inate from a tandem version of this process starting initial-
ly by a 1,6-addition. This is consistent with the fact that 6
does not react in the presence of an excess of the sodium
anion of dimethyl bromomalonate, thereby suggesting
that an activated Michael type acceptor is required.
In a four-necked flask, a solution of DIPA (14.72 mL, 105 mmol,
2.1 equiv) in THF (100 mL) was cooled to 0 °C and a 2.5 M solution
of n-BuLi in hexanes (42 mL, 2.1 equiv) was added dropwise. After
15 min, a solution of (RS)-S-methyl-S-p-tolylsulfoxide (3; 15.4 g, 2
equiv) in THF (100 mL) was added by a canula over a period of 30
min. The reaction mixture was warmed to r.t. and stirred during 45
min. The mixture was cooled to 0 °C, and a solution of (SS)-(–)-
menthyl-p-toluenesulfinate (2; 14.72 g, 50 mmol, 1 equiv) in THF
(100 mL) was added by a canula over a period of 25 min. The solu-
tion was stirred for 1 h, warmed to r.t. and stirred for an additional
45 min. Then the solution was quenched at 0 °C with an aq sat. so-
lution of NH4Cl (100 mL) and extracted with Et2O (1 × 300 mL and
2 × 200 mL). The combined organic layers were washed with H2O
(150 mL) and the aqueous layer was extracted with Et2O (2 × 100
mL). The combined organic layers were washed with brine (150
It was also important to check if the chelate mode of reac-
tivity we have previously encountered4 could also apply to
dienyl substrate 5. So, we investigated the conjugate addi-
tion of a methyl copper reagent on such systems. In that
case, a very clean reaction took place giving only the 1,4-
adduct 8 in high yield and complete diastereoselectivity.
MeO2C
2 equiv
CO2Me
O
S
O
S
O
S
O
S
p-Tol
Ph
p-Tol
Br
p-Tol
p-Tol
5
CO2Me
CO2Me
NaH, THF
MeO2C
MeO2C
CO2Me
CO2Me
Ph
6, 1 diastereomer
7
Entry
Temp. (°C)
6 (%)
7 (%)
r.t.
1
2
57
85
42
9
–50
3
–65
34
0a
a 66% of 5 was recovered.
Scheme 3
O
S
O
S
p-Tol
1) (CF3CO)2O, Pyr
CH2Cl2, –20 °C
Me
CuI, MeLi
p-Tol
5
Ph
CO2Me
(R)-9, 21%
THF
–40 °C to r.t.
2) H2O2, NaOH,
THF, H2O, r.t.
3) MeOH, H2SO4
Me
Ph
8, quantitative
1 diastereomer
Scheme 4
Synthesis 2005, No. 14, 2449–2452 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Diastereoselective Michael Additions
2451
mL), dried (MgSO4), filtered and concentrated by rotary evapora-
tion under reduced pressure. The ratio of (–)-menthol/4/3 (1:1:0.75)
was determined by 1H NMR spectroscopy of the crude. A 1:1 mix-
ture of hexane–Et2O (200 mL) was added to the crude and refluxed
for 15 min. The suspension was slowly cooled to r.t. and filtered to
afford a mixture of 4/3 (1:0.1). A 1:1 mixture of hexane–Et2O (100
mL) was added to the mixture, heated to reflux, cooled to r.t. and the
suspension was filtered to afford 4 (12.9 g, 88%) as a white solid;
mp 129–131 °C; [a]D20 +315 (c = 1.0, acetone) {Lit.8 [a]D20 +318 (c
= 0.19, acetone)].
CO2CH3), 3.81 (s, 3 H, CO2CH3), 6.13 (dd, J = 15.8, 10.2 Hz, 1 H,
CH=CHCH), 6.50 (d, J = 15.8 Hz, 1 H, CH=CHCH), 6.56 (d,
J = 8.1 Hz, 2 Harom), 7.07 (d, J = 8.6 Hz, 2 Harom), 7.19–7.29 (m, 7
Harom), 7.61 (d, J = 8.1 Hz, 2 Harom).
13C NMR (100 MHz, CDCl3): d = 21.4, 21.5, 36.7, 45.7, 53.5, 53.7,
71.3, 119.3, 125.9, 126.4, 127.6, 128.4, 128.8, 129.5, 129.9, 137.0,
135.8, 136.6, 136.7, 142.3, 143.5, 164.3, 164.5.
HRMS: m/z calcd for C29H29O6S2 [M + H]+: 537.1405; found:
537.1411.
1H NMR (400 MHz, CDCl3): d = 2.40 (s, 6 H, ArCH3), 3.97 [s, 2 H,
CH2(SOTol-p)2], 7.32 (d, J = 8.2 Hz, 4 Harom), 7.54 (d, J = 8.2 Hz,
4 Harom).
13C NMR (100 MHz, CDCl3): d = 21.9, 85.1, 124.4, 130.8, 139.9,
143.0.
3,3-Bis(p-tolylsulfinyl)-3¢-phenylbicyclopropyl-2,2,2¢,2¢-tetra-
carboxylic Acid Tetramethyl Ester (7)
Compound 7 was formed as a mixture of two diastereomers
7M:7m, from which 7M was the major product (>90:10) based on
1H NMR spectra.
7M
(SS,SS,3E)-1,1-Bis(p-tolylsulfinyl)-4-phenylbuta-1,3-diene (5)
To a solution of anhyd (heated under vacuum at 70 °C) (SS,SS)-
bis(p-tolylsulfinyl)methane (4; 2.045 g, 7 mmol, 1 equiv) in anhyd
THF (40 mL) cooled to –40 °C, was added a 2.2 M solution of n-
BuLi in hexanes (3.5 mL, 7.7 mmol, 1.1 equiv). The solution was
stirred at –40 °C during 1 h and cooled to –78 °C during 30 min.
Cinnamaldehyde (2.77 g, 21 mmol, 3 equiv) was then added. The
mixture was stirred at –78 °C for 30 min and warmed to –15 °C in
2 h. The mixture was hydrolyzed by addition of aq sat. NH4Cl solu-
tion and concentrated by rotary evaporation under reduced pressure.
The residue was diluted with CH2Cl2 (60 mL) and successively
washed with H2O (2 × 30 mL) and brine (30 mL). The organic
phase was dried (MgSO4) and the solvent was removed by rotary
evaporation under reduced pressure. Purification by silica gel chro-
matography [petroleum ether (bp 40–65 °C)–EtOAc, 80:20] afford-
ed 5 (2.17 g, 76%) as a pale yellow solid; mp 178–180 °C; Rf 0.45
[EtOAc–petroleum ether (bp 40–65 °C), 1:1]; [a]D20 –157 (c = 1.3,
CHCl3).
White solid; mp 105 °C (dec.); [a]D20 –60 (c = 1, CHCl3).
IR (neat): 2995, 1735, 1725, 1430, 1295, 1215, 1080 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.33 (s, 3 H, ArCH3), 2.48 (s, 3 H,
ArCH3), 2.58 (d, J = 10.2 Hz, 1 H, CH of cyclopropane), 3.00 (dd,
J = 10.2, 8.1 Hz, 1 H, CH of cyclopropane), 3.29 (d, J = 8.1 Hz, 1
H, CH of cyclopropane), 3.38 (s, 3 H, CO2CH3), 3.41 (s, 3 H,
CO2CH3), 3.51 (s, 3 H, CO2CH3), 3.82 (s, 3 H, CO2CH3), 6.45 (d,
J = 8.1 Hz, 2 Harom), 7.08 (d, J = 8.2 Hz, 2 Harom), 7.12 (d, J = 7.1
Hz, 2 Harom), 7.20–7.29 (m, 3 Harom), 7.37 (d, J = 8.2 Hz, 2 Harom),
7.95 (d, J = 8.1 Hz, 2 Harom).
13C NMR (100 MHz, CDCl3): d = 21.5, 21.7, 26.3, 32.2, 36.6, 44.3,
45.0, 52.8, 52.9, 53.5, 53.8, 73.2, 126.0, 127.7, 127.9, 128.5, 129.7,
130.2, 133.4, 136.8, 137.0, 141.9, 143.2, 164.9, 165.0, 166.4, 166.5.
HRMS: m/z calcd for C34H34O10S2 [M + H]+: 667.1672; found:
667.1669.
7m
IR (neat): 3052, 3030, 2922, 1613, 1577, 1491, 1448, 1080, 1041,
968, 802, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H, ArCH3), 2.34 (s, 3 H,
ArCH3), 6.99 (d, J = 8.0 Hz, 2 Harom), 7.03 (d, J = 8.0 Hz, 2 Harom),
7.10–7.13 (m, 3 Harom, PhCH=CH), 7.27 (d, J = 9.1 Hz, 2 Harom),
Characteristic signals:
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H, ArCH3), 2.41 (s, 3 H,
ArCH3), 2.68 (d, J = 10.1 Hz, 1 H, CH of cyclopropane), 3.41 (s, 3
H, CO2CH3), 3.81 (s, 9 H, 3 CO2CH3), 6.87 (d, J = 8.3 Hz, 2 Harom),
7.75 (d, J = 8.4 Hz, 2 Harom).
7.40–7.42 (m, 3Harom, PhCH=CH), 7.55–7.65 (m, 4 Harom
PhCH=CHCH=).
,
13C NMR (100 MHz, CDCl3): d = 21.7, 21.8, 25.7, 28.0, 37.1, 42.9,
43.7, 52.6, 53.4, 53.7, 53.9 (4 CO2CH3), 68.2, 126.6, 128.3, 128.7,
129.1, 129.8, 133.9, 136.3, 143.5, 144.0, 164.6, 164.8, 166.3, 167.5.
13C NMR (100 MHz, CDCl3): d = 21.4, 21.6, 120.4, 124.2, 126.3,
127.9, 129.1, 129.7, 130.1, 135.5, 138.2, 138.8, 139.7, 141.1, 142.5,
144.0, 146.7.
(SS,SS,2R,3E)-1,1-Bis(p-tolylsulfinyl)-2-methyl-4-phenylbut-3-
ene (8)
(SS,SS,3R)-2,2-Bis(p-tolylsulfinyl)-3-styrylcyclopropane-1,1-di-
carboxylic Acid Dimethyl Ester (6)
To a suspension of anhyd CuI (1.324 g, 6.96 mmol, 4 equiv) in an-
hyd THF (25 mL) was added a 1.6 M solution of MeLi in Et2O (4.35
mL, 6.96 mL, 4 equiv) at 0 °C. The suspension was stirred at this
temperature for 30 min and became yellow. To this suspension
(cooled to –40 °C) was added a solution of 5 (707 mg, 1.74 mmol,
1 equiv) in anhyd THF (20 mL) by a canula. The resulting suspen-
sion was stirred for 1 h at –40 °C and warmed to r.t. over 1 h. Then
the solution was quenched by the addition of sat. aq NH4Cl solution
(1 mL) and diluted with EtOAc (100 mL). The organic phase was
washed successively with a 2:1 mixture of NH4OH (10%)/NH4Cl
(10%) (3 × 50 mL) and brine (50 mL). The organic phase was dried
(MgSO4) and solvent was removed by rotary evaporation. Precipi-
tation with Et2O and petroleum ether (bp 40–65 °C) afforded 8 (731
mg, quant) as a white solid; mp 77 °C (dec.); Rf 0.4 [Et2O–petro-
leum ether (bp 40–65 °C), 8:2]; [a]D20 +40.1 (c = 1.12, CHCl3).
To a solution of alkylidene bis-sulfoxide 5 (100 mg, 0.25 mmol, 1
equiv) and dimethyl bromomalonate (2 equiv) in THF (10 mL/
mmol of 4) was added NaH (60% suspension in mineral oil, 2
equiv) at –50 °C. The reaction mixture was stirred 2 d. Then, it was
diluted with CH2Cl2, quenched with aq sat. solution of NH4Cl, con-
centrated by rotary evaporation under reduced pressure to remove
THF, and extracted with CH2Cl2. The CH2Cl2 extract was washed
with H2O, brine, dried (MgSO4), filtered and concentrated by rotary
evaporation under reduced pressure. The residue was purified by
silica gel chromatography (pentane–EtOAc, from 70:30 to 50:50) to
give a mixture of 6 (85%) and 7 (9%). Compound 6 and 7 can be
isolated as pure compounds by a second chromatography;
6
IR (neat): 2924, 1596, 1492, 1448, 1082, 1044 cm–1.
White solid; mp 65 °C (dec.); [a]D20 –375 (c = 1.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.19 (d, 3 H, J = 6.6 Hz, CHCH3),
2.35 (s, 3 H, ArCH3), 2.45 (s, 3 H, ArCH3), 3.54 [d, 1 H, J = 7.1 Hz,
CH(SOTol-p)2], 3.61 (ddq, 1 H, J = 7.8, 7.1, 6.6 Hz, CHCH3), 6.43
IR (neat): 2952, 1733, 1491, 1434, 1233, 1085, 1048, 806, 749 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.29 (s, 3 H, ArCH3), 2.33 (s, 3 H,
ArCH3), 3.19 (d, J = 10.2 Hz, 1 H, CH=CHCH), 3.77 (s, 3 H,
Synthesis 2005, No. 14, 2449–2452 © Thieme Stuttgart · New York

2452
F. Brebion et al.
PRACTICAL SYNTHETIC PROCEDURES
(dd, J = 15.9, 7.8 Hz, 1 H, PhCH=CH), 6.67 (d, J = 15.9 Hz, 1 H,
PhCH=CH), 6.97 (d, J = 8.8 Hz, 2 Harom), 7.17 (d, J = 8.8 Hz, 2
13C NMR (100 MHz, CDCl3): d = 17.4, 43.2, 52.0, 126.3 127.5,
128.5, 128.7, 131.2, 136.8, 175.0.
Harom), 7.24–7.35 (m, 5 Harom), 7.44–7.49 (m, 4 Harom).
13C NMR (100 MHz, CDCl3): d = 19.8, 21.3, 21.5, 33.7, 92.0,
124.1, 125.0, 126.6, 127.7, 128.6, 129.6, 129.9, 130.0, 132.5, 136.8,
138.6, 140.8, 141.2, 142.0.
Acknowledgment
The authors thank the Ministère de l’Education Nationale for a
Ph.D. grant to F.B. M.M. is a member of Institut Universitaire de
France and we thank IUF for financial support.
(2R)-Methyl 2-Methyl-2-(trans-styryl)acetate (9)
To a solution of 8 (200 mg, 0.47 mmol, 1 equiv) in anhyd CH2Cl2
(5 mL) at –20 °C was added trifluoroacetic anhydride (268 mL, 1.89
mmol, 4 equiv) and anhyd pyridine (306 mL, 3.79 mmol, 8 equiv).
The reaction was stopped after 2 h by addition of sat. aq NH4Cl so-
lution (2 mL) and extracted with CH2Cl2 (2 × 20 mL). The organic
phase was washed successively with 10% aq NaHCO3 solution
(2 × 10 mL), brine (10 mL) and dried (MgSO4). The solvent was re-
moved by rotary evaporation under reduced pressure to give a yel-
low oil. The crude product was directly used in the next step without
further purification. To a stirred solution of crude thioester in 10%
aq THF (2 mL) was added 30% aq H2O2 (1 mL), followed by 0.1 M
aq NaOH solution (2 mL). The resulting mixture was stirred at 0 °C
for 1 h. The mixture was treated with 20% aq Na2S2O3 solution (10
mL) and 10% aq HCl (2 mL), and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried (MgSO4) and the sol-
vent was removed by rotary evaporation under reduced pressure.
Treatment with MeOH (2 mL) in acidic conditions (2 drops of conc.
H2SO4) followed by filtration on silica gel afforded 9 (18.5 mg,
References
(1) For a review on bis-sulfoxides, see: Delouvrié, B.;
Fensterbank, L.; Nájera, F.; Malacria, M. Eur. J. Org. Chem.
2002, 3507.
(2) For an article dealing with the preparation of substrates 1,
see: Delouvrié, B.; Nájera, F.; Fensterbank, L.; Malacria, M.
J. Organomet. Chem. 2002, 643-644, 130.
(3) Brebion, F.; Vitale, M.; Fensterbank, L.; Malacria, M.
Tetrahedron: Asymmetry 2003, 14, 2889.
(4) Brebion, F.; Delouvrié, B.; Nájera, F.; Fensterbank, L.;
Malacria, M.; Vaissermann, J. Angew. Chem. Int. Ed. 2003,
42, 5342.
(5) Solladié, G.; Colobert, F.; Ruiz, P.; Hamdouchi, C.; Carreño,
M. C.; Garcia Ruano, J. L. Tetrahedron Lett. 1991, 32, 3695.
(6) Evans, D. A.; Bryan, C. A.; Sims, C. L. J. Am. Chem. Soc.
1972, 94, 2891.
(7) Solladié, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(8) Kunieda, N.; Nokami, J.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1976, 49, 256.
(9) Krause, N.; Hoffmann-Röder, A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002,
145–166.
(10) Salamonczyk, G. M.; Han, K.; Guo, Z.-W.; Sih, C. J. J. Org.
Chem. 1996, 61, 6893.
20
21%) as a colorless oil; [a]D20 –52.1 (c = 1.60, CHCl3) {Lit.10 [a]D
–52.5 (c = 5.2, CHCl3)}.
IR (neat): 3026, 2952, 2926, 2854, 1737, 1494, 1450, 1194, 965,
746, 694 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.38 (d, J = 7.1 Hz, 3 H, CHCH3),
3.33 (m, 1 H, CHCH3), 3.72 (s, 3 H, CO2CH3), 6.29 (dd, 1 H,
J = 15.9, 7.8 Hz, PhCH=CH), 6.49 (d, 1 H, J = 15.9 Hz,
PhCH=CH), 7.20–7.41 (m, 5 Harom).
Synthesis 2005, No. 14, 2449–2452 © Thieme Stuttgart · New York