Enolate conjugate addition to alkylidene bis-sulfoxides: Sphaeric acid synthesis and absolute configuration determination

Article abstract of DOI:10.1055/s-2006-933122

The first stereoselective synthesis of sphaeric acid is described. The key step of this synthesis is an efficient ester enolate conjugate addition onto alkylidene bis-sulfoxides with good to high diastereoselectivity. Formation of sphaeric acid allowed th

Full text of DOI:10.1055/s-2006-933122

LETTER
713
Enolate Conjugate Addition to Alkylidene Bis-Sulfoxides: Sphaeric Acid
Synthesis and Absolute Configuration Determination
Enolate
C
onju
r
gate Add
a
ition to A
l
n
cSulfoxidesk Brebion, Jean-Philippe Goddard, Catherine Gomez, Louis Fensterbank,* Max Malacria*
Université Pierre et Marie Curie, UMR CNRS 7611, Institut de chimie moléculaire FR 2769, case 229, 4 place Jussieu,
75252 Paris Cedex 05, France
E-mail: louis.fensterbank@upmc.fr; E-mail: max.malacria@upmc.fr
Received 16 December 2005
Conjugate addition of ester enolates has been extensively
investigated by Heathcock,7 who has shown the im-
portance of the ester substituents and the enolate configu-
ration on the stereochemical outcome. Esters partners
with bulky alcohol substituents (e.g. tert-butyl and 2,6-
dimethylphenyl) were chosen to avoid Claisen side reac-
tions generating ketoesters and alkoxides. E-Enolates
were obtained by deprotonation of esters 4–6 with LDA in
THF at low temperature, while the Z-enolates were ob-
tained under the same conditions in the presence of eight
equivalents of HMPA.7d Enolate addition to the chiral
Michael acceptors 1–3 proceeded in good to quantitative
yield (Scheme 2) affording substituted esters 7–12. The
results of conjugate additions are summarized in Table 1.
Abstract: The first stereoselective synthesis of sphaeric acid is de-
scribed. The key step of this synthesis is an efficient ester enolate
conjugate addition onto alkylidene bis-sulfoxides with good to high
diastereoselectivity. Formation of sphaeric acid allowed the deter-
mination of its absolute configuration as 2R,3R.
Key words: alkylidene bis-sulfoxides, sphaeric acid, enolate addi-
tion, succinic acid, E/Z-enolate
In the field of asymmetric synthesis, alkylidene bis-sul-
foxides have been reported as molecules of diverse de-
signs.1 Their cyclic variants (cyclic dithioacetal dioxides)
have been mainly investigated by Aggarwal in cycloaddi-
tion reactions or epoxidations.2 The acyclic variant (bis-p-
tolylsulfoxides), essentially developed by our group, has
shown very attractive features toward asymmetric trans-
formations and more particularly for asymmetric conju-
gate additions. The use of different nucleophiles, such as
amines,3 alkoxides,3 organocopper reagents,3,4 malonate
anions,3,4 and ester enolates, providing enantiopure
succinic acid derivatives,3 has been reported. Recently,
the addition of ketone enolates to cyclic alkylidene bis-
sulfoxides was reported by Podlech.5
O
S
O
S
O
S
O
S
p-Tol
p-Tol
4, 5 or 6 (2 equiv)
p-Tol
p-Tol
LDA (2 equiv)
THF, –78 °C,
additives
R1
R
R
1: R = n-Oct
2: R = i-Pr
O
OR2
3: R = Styryl
n7: R = n-Oct, R1 = H
2 = t-Bu
8: R = i-Pr, R1 = H
2 = t-Bu
9: R = Styryl, R1 = H
2 = t-Bu
10: R = n-Oct, R1 = Me
2 = t-Bu
11: R = n-Oct, R1 = Me
2 = (2,6-Me)C6H3
12: R = i-Pr, R1 = Me
2 = (2,6-Me)C6H3
R
O
O
Herein, we report new developments in the addition of
ester enolates to chiral alkylidene bis-sulfoxide substrates.
This transformation will be applied to the total synthesis
of succinic acid derivatives, in particular sphaeric acid.
The alkylidene (SS,SS)-bis(p-tolylsulfoxide) derivatives
were prepared in good yields according to a previously
reported procedure by condensation of the lithium anion
of (SS,SS)-bis(p-tolylsulfoxide)methane with the corre-
sponding aldehyde followed by dehydration of the result-
ing alcohol (Scheme 1).6
R
Ot-Bu
Ot-Bu
4
5
R
O
R
O
R
6
R
Scheme 2
The addition of deprotonated tert-butyl acetate 4 (R1 = H)
to alkylidene 1 (Table 1, entry 1) afforded the ester 7 in
81% yield with an excellent diasteromeric excess.8 Only
one stereogenic center has been created during this reac-
tion. Thus, like in the case of malonate anion addition,3 the
conjugate addition of an unsubstituted enolate proceeds
with complete diastereoselectivity and in high yield. By
correlation with previous results3 we propose absolute R
configuration for the newly created center.
O
S
O
S
O
S
O
S
p-Tol
p-Tol
a) condensation
b) dehydration
p-Tol
p-Tol
O
R
R
H
Scheme 1
The same enolate reacted at 0 °C with isopropylidene 2
(Table 1, entry 2) to give 8 quantitatively but the diaste-
reomeric ratio decreased to 88:12. It seems that there is no
problem with competitive reactions at higher temperature,
SYNLETT 2006, No. 5, pp 0713–0716
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933122; Art ID: G40005ST
© Georg Thieme Verlag Stuttgart · New York
1
7.
0
3.
2
0
0
6

714
F. Brebion et al.
LETTER
A favored
(E-enolate)
B favored
(Z-enolate)
Table 1 Conjugate Addition of the tert-Butyl Acetate Enolate of 4
Entry
Substrate
Products
7M/7m
8M/8m
9M/9m
Yield (%)
81
dr (M/m)a
>95:5
1
2
3
1
2
3
88:12b
88:12
O
S
O
S
quant.
88
O
O
p-Tol
S
S
S
S
p-Tol
O
O
Me
Me
H
H
a M: major, m: minor.
b Reaction carried out at 0 °C.
n-Oct
n-Oct
n-Oct
CO2t-Bu
Major, 10M
t-BuO
OLi
LiO
Ot-Bu
but a lower temperature is required to ensure high dia-
stereoselectivity. With dienyl bis-sulfoxide 3 (Table 1,
entry 3), only 1,4-addition product 9 was detected. The
stereochemistry of the carbon b to the ester group was not
completely controlled during the addition at –78 °C.
O
S
O
S
O
O
S
p-Tol
S
S
S
O
O
p-Tol
H
H
Me
n-Oct
Me
n-Oct
n-Oct
Table 2 Conjugate Addition of the Propionate-Derived Enolate
CO2t-Bu
minor, 10m
t-BuO
OLi
LiO
Ot-Bu
Entry
Substrate Ester Products
Yield (%) dr (M/m)a
C unfavored
(E-enolate)
D unfavored
(Z-enolate)
1
1
1
1
1
2
5
6
5
5
6
10M/10m
11M/11m
10M/10m
10M/10m
12M/12m
80
75
70
81
80
76:24
>95:5
55:45
53:47
>95:5
Figure 1
2
3b
4b,c
5
The alkylidene bis-sulfoxide adopts a conformation
where the lone pair of one sulfinyl group is quasi-eclips-
ing the syn R1 group on the alkene, the second sulfinyl
group is in an s-cis position, and the two tolyl groups are
face-to-face stabilized by a p-stacking interaction.3 The
attack on the re face of the alkylidene is blocked by the
two aromatic rings while the nucleophile approaches the
si face, maintaining the Bürgi–Dunitz angle.10 Two tran-
sition states are proposed for the E-enolate (A and C) and
two for the Z-enolate (B and D). For each enolate config-
uration, the favored transition state (A or B) avoids the
steric interaction between the methyl and the alkyl chain.
A synergic effect from the steric interaction from the R2
group would take place and a high diastereoselectivity is
obtained with a 2,6-dimethylphenyl group. In this case,
destabilization of the transition state originating from C is
increased and the amount of the minor diastereomer
formed is reduced. The lack of diastereoselectivity with
the Z-enolate could be explained by the dissociative effect
of HMPA on the lithium enolate aggregates. The OLi unit
becomes less sterically demanding and the differentiation
between OLi and OR2 is weaker than without HMPA.
Thus, transition states B and D would be energetically
close and the proportion of minor diastereomer increases.
a M: major, m: minor.
b HMPA (8 equiv).
c Reaction carried out at –20 °C.
Under the same conditions, the enolate of tert-butyl pro-
pionate 5 reacted with octylidene 1 (Table 2, entry 1) to
afford the desired product in good chemical yield. Only
two (10M and 10m) of the four possible diastereomers
were formed. Consistent with the results reported above,
the presence of two diastereomers would originate from
poor control of the stereogenic center a to the ester.
When the tert-butyl group was replaced with the bulkier
2,6-dimethylphenyl group (Table 2, entry 2),9 the addition
of the corresponding enolate (from 6) to 1 became highly
diastereoselective while maintaining a high yield. A sin-
gle diastereomer 12 was obtained from isopropylidene 2
(Table 2, entry 5). Eight equivalents of HMPA as an addi-
tive presumably changed the configuration of the enolate
from E to Z7d without modifying the efficiency of the re-
action but decreased the diastereoselectivity dramatically
(Table 2, entries 3 and 4). This diastereoselectivity was
also affected by a higher temperature (Table 2, entry 4).
Importantly, the same two diastereomers 10M and 10m
were obtained with and without HMPA.
We targeted succinic acid derivatives and more specifi-
cally sphaeric and epi-sphaeric acid. Sphaeric acid was
isolated in 1999 by Strobel from the fermentation broth of
Sphaeropsis sp.11 This succinic acid derivative has ex-
hibited two interesting biological activities. The first is a
selective antibiotic activity against Staphylococcus aurus
and Bacillus subtilis. This compound also exhibits inter-
action with interleukin-1 that plays an important role in
the immune system. Six years after its first isolation, only
the relative configuration of sphaeric acid is known.
We propose a diastereoselectivity model in order to ratio-
nalize the different results reported above. This model
(Figure 1) involves steric interactions between alkylidene
and enolates according to their conformation and config-
uration.
Synlett 2006, No. 5, 713–716 © Thieme Stuttgart · New York

LETTER
Enolate Conjugate Addition to Alkylidene Bis-Sulfoxides
715
O
S
O
S
p-Tol
O
OH
O
Sp-Tol
p-Tol
TFAA, pyridine
LiOH·H2O, H2O2
( )7
CH2Cl2, r.t.
0.5 M
( )7
( )7
n-Bu4NBr, THF–H2O
79%
O
OH
O
OAr
O
OAr
69%
epi-Sphaeric acid
11M
13
14
1) LiOH·H2O, H2O2
n-Bu4NBr (cat.)
O
S
O
S
p-Tol
O
OH
O
Sp-Tol
TFAA, pyridine
THF–H2O, r.t., 10 h
p-Tol
CH2Cl2, 0 °C, 3 h
2) TMSCl (4 equiv)
NaI (4 equiv)
MeCN, 45 °C, 3 h
28%
( )7
( )7
( )7
54%
O
OH
O
Ot-Bu
O
Ot-Bu
Sphaeric acid
16
10m
15
Scheme 3
Sphaeric and epi-sphaeric acids were synthesized enantio-
merically pure (Scheme 3). Compound 11M (Table 2,
entry 2) underwent a Pummerer reaction with trifluoacetic
anhydride in the presence of pyridine; thioester 13 was
isolated in 69% yield. Saponification of the two esters
groups by lithium hydroxide/hydrogen peroxide in THF–
water with a phase transfer catalyst allows the formation
of epi-sphaeric acid 14 in 79% yield.12 The absolute con-
figuration of 14 was determined by correlation with the
NMR data of roccellic acid, with which it showed very
high spectral similarity.3
Acknowledgment
The authors thank the Ministère de l’Education Nationale for a PhD
grant to F.B. M.M. is a member of Institut Universitaire de France
and we thank IUF for financial support. We thank Gary Strobel for
providing the NMR spectra of the original sample of sphaeric acid.
References and Notes
(1) (a) The more accurate name is ‘alkenylidene bis-sulfoxides’
but ‘alkylidene bis-sulfoxides’ is conveniently used in
analogy with the corresponding malonate derivatives.
(b) For a review on bis-sulfoxides, see: Delouvrié, B.;
Fensterbank, L.; Nájera, F.; Malacria, M. Eur. J. Org. Chem.
2002, 3507.
(2) (a) Aggarwal, V. K.; Roseblade, S. J.; Barrell, J. K.;
Alexander, R. Org. Lett. 2002, 4, 1227. (b) Aggarwal, V.
K.; Steele, R. M.; Barrell, J. K.; Grayson, I. J. Org. Chem.
2003, 68, 4087. (c) Aggarwal, V. K.; Barrell, J. K.; Worrall,
J. M.; Alexander, R. J. Org. Chem. 1998, 63, 7128.
(3) Brebion, F.; Delouvrié, B.; Nájera, F.; Fensterbank, L.;
Malacria, M.; Vaissermann, J. Angew. Chem. Int. Ed. 2003,
42, 5342.
(4) Brebion, F.; Goddard, J.-P.; Fensterbank, L.; Malacria, M.
Synthesis 2005, 2449.
(5) Wedel, T.; Podlech, J. Org. Lett. 2005, 7, 4013.
(6) Delouvrié, B.; Nàjera, F.; Fensterbank, L.; Malacria, M. J.
Organomet. Chem. 2002, 643-644, 130.
(7) (a) Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pirrung, M.
C.; White, C. T.; VanDerveer, D. J. Org. Chem. 1980, 45,
3846. (b) Heathcock, C. H.; Pirrung, M. C.; Young, S. D.;
Hagen, J. P.; Jarvi, E. T.; Badertscher, U.; Märki, H.-P.;
Montgomery, S. H. J. Am. Chem. Soc. 1984, 106, 8161.
(c) Heathcock, C. H.; Oare, D. A. J. Org. Chem. 1985, 50,
3022. (d) Heathcock, C. H.; Oare, D. A. J. Org. Chem. 1990,
55, 157.
The diastereomer 10m (Table 2, entry 4) was treated with
trifluoroacetic anhydride and pyridine in dichloromethane
at 0 °C to yield the thioester 15 in 54% yield as a single
diastereomer. In this case, two different saponification re-
actions were necessary to obtain sphaeric acid 16. Lithium
hydroxide/hydrogen peroxide allowed the cleavage of the
thioester group generating the first carboxylic acid while
the tert-butyl ester is not hydrolyzed. Chlorotrimethyl-
silane and sodium iodide are used to saponify this unreac-
tive ester.13 Sphaeric acid 16 was isolated in 28% yield for
the last two steps.14 All the spectroscopic and analytical
data are similar to the reported characterization of
20
sphaeric acid 16 {[a]D20 +8.1 (c 0.78, MeOH), Lit. [a]D
+7.0 (c 0.90, MeOH)}.11 Thus, we determined the
absolute configuration of sphaeric acid as 2R,3R and we
confirmed the relative stereochemistry proposed by
Strobel.
In conclusion, we reported an efficient and diasteroselec-
tive conjugate addition of E- and Z-enolates to different
acyclic alkylidene bis-sulfoxides. Complete diastereose-
lectivity is observed with the 2,6-dimethylphenyl group
on the ester residue. The first asymmetric total synthesis
of biologically active sphaeric acid has been developed by
this methodology and the absolute configuration of this
succinic acid derivative has been determined.
(8) Enolate Conjugate Addition
General Procedure A (E-Enolate): To a solution of LDA
(2 equiv) in THF (2.4 mL/mmol) at –78 °C, a solution of
ester (2 equiv) in THF (1.4 mL/mmol) was added. After
45 min at –78 °C, a solution of alkylidene bis-sulfoxide (1
equiv) in THF (4.8 mL) was added via cannula. The reaction
mixture was stirred at –78 °C for 15 min, quenched with an
aq sat. solution of NH4Cl, and diluted with CH2Cl2. The
organic layer was washed with water, brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by silica gel chromatography.
Synlett 2006, No. 5, 713–716 © Thieme Stuttgart · New York

716
F. Brebion et al.
LETTER
Procedure B (Z-Enolate): To a solution of LDA (2 equiv)
in THF (2.4 mL/mmol) at –78 °C, freshly distilled HMPA (8
equiv) and a solution of ester (2 equiv) in THF (1.4 mL/
mmol) was added. After 45 min at –78 °C, a solution of
alkylidene bis-sulfoxide (1 equiv) in THF (4.8 mL) was
added via cannula. The reaction mixture was stirred at
–78 °C for 15 min, quenched with an aq sat. solution of
NH4Cl and diluted with CH2Cl2.The organic layer was
washed with water, brine, dried over MgSO4, and
ArCH), 171.8 (CO). HRMS: m/z calcd for C30H44O4NaS2 [M
+ Na]+: 555.2579; found: 555.2584.
(9) Heathcock, C. H.; Pirrung, M. C.; Montgomery, J.; Lampe,
J. Tetrahedron 1981, 37, 4087.
(10) Bürgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.
(11) Wilkinson, R. A.; Strobel, G.; Stierle, A. J. Nat. Prod. 1999,
62, 358.
(12) epi-Sphaeric Acid (14): White solid; mp 121–125 °C (dec.);
[a]D20 +18.9 (c 1.1, CH3OH). IR (neat): 3100, 2918, 2852,
2615, 1689, 1462, 1419, 1275, 1198, 945 cm–1. 1H NMR
(400 MHz, CD3OD): d = 0.93 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.19 (d, J = 6.6 Hz, 3 H, CH3CH), 1.32 (br s, 12 H, 6 × CH2),
1.51 (m, 1 H, CH2), 1.63 (m, 1 H, CH2), 2.54–2.62 (m, 2 H,
2 × CHCOOH). 13C NMR (100 MHz, CD3OD): d = 15.3
(CH3), 16.9 (CH3CH), 24.6, 29.3, 31.2, 31.3 (2 C), 32.9, 33.9
(7 × CH2), 44.4, 51.0 (2 × CHCOOH), 178.9, 179.5 (2 ×
COOH). HRMS: m/z calcd for C13H24NaO4 [M + Na]+:
267.1572; found: 267.1602.
concentrated in vacuo. The residue was purified by silica gel
chromatography.
(SS,SS,3R)-3-[Bis(p-tolylsulfinyl)methyl]undecanoic Acid
tert-Butyl Ester (7): Prepared by general procedure A from
1 (50 mg, 0.12 mmol). Column chromatography (pentane–
EtOAc, 90:10 to 80:20) afforded 52 mg (81%) of 6 as a
colorless oil; [a]D20 +79.0 (c 0.4, CHCl3). IR (neat): 2926,
2855, 1728, 1492, 1367, 1152, 1086, 1058, 811, 755 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.85 (t, J = 7.0 Hz, 3 H,
CH2CH3), 0.90–1.27 (m, 14 H, 7 × CH2), 1.42 [s, 9 H,
C(CH3)3], 2.31 (s, 3 H, p-Tol), 2.44 (s, 3 H, p-Tol), 2.69 [dd,
J = 16.6, 8.6 Hz, 1 H, CHHCO2C(CH3)3], 2.82 [m, 1 H,
CHCH(SOp-Tol)2], 3.18 [dd, J = 16.6, 3.3 Hz, 1 H,
CHHCO2C(CH3)3], 3.60 [d, J = 4.4 Hz, 1 H, CH(SOp-
Tol)2], 6.88 (d, J = 8.2 Hz, 2 H, Ar), 7.12 (d, J = 8.0 Hz, 2 H,
Ar), 7.37 (d, J = 8.0 Hz, 2 H, Ar), 7.54 (d, J = 8.2 Hz, 2 H,
Ar). 13C NMR (100 MHz, CDCl3): d = 14.4 (CH2CH3), 21.5
(p-Tol), 21.8 (p-Tol), 22.9, 26.7, 29.2, 29.3, 29.6, 32.1, 32.6
(7 × CH2), 28.4 [C(CH3)3], 31.5 [CHCH(SOp-Tol)2], 37.3
[CH2CO2C(CH3)3], 80.8 [CO2C(CH3)3], 89.2 [CH(SOp-
Tol)2], 124.0 (2 C, ArCH), 125.0 (2 C, ArCH), 130.1 (2 C,
ArCH), 130.4 (2 C, ArCH), 139.2, 140.9, 141.2, 142.3 (4 C,
(13) Zhang, Q.; Remsen, E. E.; Wooley, K. L. J. Am. Chem. Soc.
2000, 122, 3642.
(14) Sphaeric Acid (16): Colorless oil; [a]D20 +8.1 (c 0.78,
MeOH). IR (neat): 3027, 3018, 2924, 2855, 2680, 1705,
1464, 1416, 1282, 1240, 932 cm–1. 1H NMR (400 MHz,
CDCl3): d = 0.90 (t, J = 6.6 Hz, 3 H, CH2CH3), 1.27–1.36
(m, 15 H, 6 × CH2, CH2CH3), 1.56–1.63 (m, 2 H, CH2), 2.57
(dt, 1 H, J = 9.6, 4.3 Hz, CH), 2.72 (dq, J = 9.8, 4.2 Hz, 1 H,
CH), 11.04 (br s, 2 H, CO2H). 13C NMR (100 MHz, CDCl3):
d = 14.1 (CH3), 15.2 (CH3), 22.7, 26.5, 29.2 (2 C), 29.3, 29.5,
31.8 (7 × CH2), 40.9, 47.9 (2 CHCOOH), 181.9, 182.5 (2 ×
COOH).
Synlett 2006, No. 5, 713–716 © Thieme Stuttgart · New York