Diastereo- and enantioselective synthesis of α,β-disubstituted γ-nisalkoxycarbonyl sulfonates

Article abstract of DOI:10.1055/s-0029-1218017

The asymmetric synthesis of ,-disubstituted -bisalkoxycarbonyl sulfonates is reported. The synthesis is based on the Michael addition of a lithiated enantiopure sulfonate bearing a cheap chiral sugar auxiliary to Knoevenagel acceptors. The reaction procee

Full text of DOI:10.1055/s-0029-1218017

2872
LETTER
Diastereo- and Enantioselective Synthesis of a,b-Disubstituted
g-Bisalkoxycarbonyl Sulfonates
S
a
ynthesis of
a
,
b
-D
i
isubsti
e
g
-
Bisa
t
lkoxyc
e
arbonyl Su
r
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
b
Department of Chemistry, Sharif University of Technology, Tehran, Iran
Received 16 July 2009
The variation of the substituents of the Michael acceptors
indicated a strong influence on the diastereoselectivity of
the reaction. Michael acceptors containing heterocycles
(2e,f) afforded the Michael products in good yields (62%
Abstract: The asymmetric synthesis of a,b-disubstituted g-bis-
alkoxycarbonyl sulfonates is reported. The synthesis is based on the
Michael addition of a lithiated enantiopure sulfonate bearing a
cheap chiral sugar auxiliary to Knoevenagel acceptors. The reaction
proceeds with high asymmetric inductions (ds = 69–96%) and good and 69%, respectively) and excellent diastereoselectivi-
yields (62–79%). The absolute configuration was determined by X-
ray crystal-structure analysis.
ties (82% and 96%, respectively). The more sterically
hindered alkene 2g reacted with sulfonate 1 in high dia-
stereoselectivity (87%), whereas the aliphatic Michael
acceptor 2h gave only a moderate diastereoselectivity
(69%). The effect of the electron-withdrawing groups of
the Michael acceptor was also investigated. The replace-
Key words: sulfonate, asymmetric synthesis, Michael addition,
sugar auxiliary, Knoevenagel acceptor
Sulfonic acid derivatives constitute an important class of ment of an ester group with a cyanide function did not lead
organic compounds, which exist in a large number of nat- to any significant changes in yield and diastereoselectivity
ural products. They are also present in synthetic com- (entry 9). A significant difference was observed, however,
pounds with important biological or pharmacological when two tert-butyl ester groups instead of the two methyl
activities, such as antiulcer, antibacterial, antipseudomon- ester were used (entry 10). This result may be explained
al, and squalene synthase inhibition activities.1 On the by the steric hindrance caused by the two tert-butyl
other hand, sulfonates are of interest as bioactive isosteres groups.
of carboxylates, phosphates, and sulfates such as phos-
In all of these cases, only three out of four possible dia-
pholipids, sulfated steroid conjugates, and oligonucleo-
stereomers could be detected. The major diastereomers
tides.2
could be isolated by preparative HPLC as was demon-
However, only a few asymmetric syntheses of this impor- strated with 3b (de ≥ 98%).
tant class of compounds are described in the literature.3 In
EWG1
continuation of our research on the asymmetric synthesis
of sulfonic acid derivatives,4 we now wish to report a con-
venient diastereo- and enantioselective approach for the
synthesis of a,b-disubstituted g-bisalkoxycarbonyl sul-
fonates.
R2
EWG2
OR1
O
1. n-BuLi, THF
–90 to 95 °C, 1 h
SO3R1
S
EWG1
2.
O
1
EWG2
3a–j
10, 62–79%
ds = 69–96%
The asymmetric synthesis of the title compounds is based
on a stoichiometric approach employing 1,2:5,6-di-O-iso-
propylidene-a-D-allofuranose as a cheap chiral sugar aux-
iliary. As shown in Scheme 1, the enantiopure sulfonate 1
was deprotonated with n-butyllithium in THF and allowed
to react with the Knoevenagel acceptor 2a to give the
Michael adduct 3a in good yield (79%) and high diastereo-
selectivity (77%).
O
R2
2a–j
O
O
O
R1
=
EWG1 = CO2Me, CO2Et, CO2t-Bu
EWG2 = CO2Me, CO2t-Bu, CN
O
R
2 = aryl, alkyl
Scheme 1
We explored the generality of this reaction with a wide
range of Michael acceptors bearing different substituents.
The desired products 3a–j were obtained with one excep-
tion in good yields (10, 62–79%) and high diastereoselec-
tivities (ds = 69–96%). The results are summarized in
Table 1.
Encouraged by these results, we turned our attention to
coumarins as Michael acceptors. Coumarins and their de-
rivatives are important structural features of many natural
compounds, which show pharmacological activities and
of optical brighteners and laser dyes.5
We found that the reaction of sulfonate 1 with coumarin 4
proceeded well to give the corresponding Michael adduct
5 in good diastereoselectivity (ds = 63%) and moderate
yield (52%, Scheme 2). The relative configuration of the
SYNLETT 2009, No. 17, pp 2872–2874
x
x
.x
x
.2
0
0
9
Advanced online publication: 10.09.2009
DOI: 10.1055/s-0029-1218017; Art ID: G23509ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of a,b-Disubstituted g-Bisalkoxycarbonyl Sulfonates
2873
O
H3
O
OR1
O
1. n-BuLi, THF
–90 to 95 °C, 1 h
S
EtO2C
O
2.
O
H2
SO3R1
1
OEt
H1
O
O
5
4
52%
ds = 63% (98%, after HPLC)
Scheme 2
Michael adduct 5 was determined by NOE experiments,
coupling constants (J1,2 = 10.7 Hz; J2,3(eq) = 1.9 Hz), and
results obtained from related reactions of 1.4
The absolute configuration of the newly formed stereo-
genic centers was determined to be R,R,R by X-ray crys-
tal-structure analysis in the case of product 3i bearing a
cyano group as EWG2 and therefore a third stereocenter.
Thus, the hydrogen atoms at the a- and b-position of the
major diastereomer are anti to each other (Figure 1).6 This
stereochemical outcome is in agreement with the relative
topicity observed in previous electrophilic substitutions of
1.4
Figure 1 X-ray crystal structure of 3i6
Me
Me
CO2Me
CO2Me
MeO2C
MeO2C
1. MeOH–H2O, TFA
reflux, 15 h
SO3R1
SO3i-Pr
2. (i-PrO)3CH, CH2Cl2
reflux, 3 h
3b
6
The racemization-free cleavage of the chiral auxiliary to
form the corresponding sulfonic acid proceeded by reflux-
ing the stereoisomerically pure Michael adduct 3b, ob-
tained after preparative HPLC in a MeOH–H2O mixture
containing 2% TFA. To isolate the final product in a more
accessible form, the sulfonic acid was converted with tri-
isopropyl orthoformate to the corresponding sulfonate 6
(Scheme 3). The desired isopropyl sulfonate was obtained
in good overall yield (48%) and virtually complete diaste-
reomeric and enantiomeric purity (de, ee ≥ 98%).
48% (two steps)
de, ee = >98%
de = >98%
Scheme 3
chiral auxiliary to Knoevenagel acceptors with one excep-
tion in good yields (62–79%) and excellent diastereose-
lectivities (ds = 69–96%). The cleavage of the chiral
sugar auxiliary demonstrated in a typical case proceeded
without any epimerization or racemization to form the
corresponding isopropyl sulfonate in good overall yield
(48%) and excellent diastereomeric and enantiomeric ex-
cess (de, ee ≥ 98%).7
In summary, we have developed an efficient asymmetric
synthesis of a,b-disubstituted g-bisalkoxycarbonyl sul-
fonates via Michael addition of a lithiated sulfonate bear-
ing 1,2:5,6-di-O-isopropylidene-a-D-allofuranose as a
Table 1 Diastereoselective Synthesis of Sulfonates 3
Entry
3
R2
EWG1
EWG2
Yield (%)
ds (%)a
77
1
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CN
79
70
76
71
62
69
66
62
73
10
p-Tol
73 (98)b
76
3
4-MeOC6H4
3-ClC6H4
3-pyridyl
2-furyl
1-naphthyl
n-Pr
4
72
5
82
6
96
7
87
8
69
9
o-Tol
79
10
3j
p-Tol
CO2t-Bu
CO2t-Bu
92
a Determined by 1H NMR spectroscopy.
b After preparative HPLC.
Synlett 2009, No. 17, 2872–2874 © Thieme Stuttgart · New York

2874
D. Enders et al.
LETTER
solution was stirred for 1 h, after which the Michael acceptor
2 (1.0 mmol in 1 mL dry THF) was added dropwise. The
mixture was stirred for 4–6 h at –90 °C to – 95 °C. The
progress of the reaction was monitored by TLC. The mixture
was quenched with sat. NH4Cl (3 mL). After separation of
the organic layer, the aqueous phase was extracted with
CH2Cl2 (4 × 5 mL). The combined organic layers were dried
over MgSO4, evaporated, and the crude product was purified
by flash column chromatography (silica gel, Et2O–pentane,
1:2) to afford 3a–j.
Dimethyl 2-(2-{5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yloxy-
sulfonyl}-2-phenyl-1-p-tolylethyl)malonate (3b)
Yield 454 mg (70%); colorless solid; ds = 73%; the major
diastereomer was separated by preparative HPLC; de 98%;
mp 66–68 °C. 1H NMR (400 MHz, CDCl3): d = 1.32, 1.36,
1.37, 1.70 [4 × s, 12 H, (O)2C(CH3)2], 2.32 (s, 3 H, CH3),
3.33 (dd, J = 7.4, 8.5 Hz, 1 H, CHHOC), 3.44, 3.52 (2 × s, 6
H, OCH3), 3.72 (dd, J = 7.0, 8.5 Hz, 1 H, CHHOC), 3.76 [dd,
J = 2.5, 8.8 Hz, 1 H, CH(OC)CH(OC)CH2O], 3.81 [d,
J = 7.1 Hz, 1 H, CH(CO2)2], 4.13 [dt, J = 2.5, 7.0 Hz, 1 H,
CH(OC)CH2O], 4.20–4.26 [m, 2 H, CH(OC)CH(OC)2,
CHCH(CO2)2], 4.47 (dd, J = 4.7, 8.8 Hz, 1 H, CHOSO2),
5.60 (d, J = 9.6 Hz, 1 H, PhCHSO3), 5.64 [d, J = 3.6 Hz, 1
H, CH(OC)2], 7.11 (d, J = 8.0 Hz, 2 H, ArH), 7.38–7.46 (m,
7 H, ArH). 13C NMR (100 MHz, CDCl3): d = 21.1 (CH3),
25.3, 25.9, 26.4, 26.6 [O2C(CH3)2], 47.5 [CHCH(CO2)2],
52.1, 52.3 (OCH3), 54.7 [CH(CO2)2], 64.1 (CH2), 70.7
(PhCHSO3), 73.7 [CH(OC)CH2O], 76.0
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie.
Z.M. and H.S. thank the Ministry of Science of Iran and the DAAD
for a scholarship. We thank BASF AG for the donation of chemi-
cals.
References and Notes
(1) (a) Kalir, A.; Kalir, H. H. In The Chemistry of Sulfonic
Acids, Esters and their Derivatives; Patai, S.; Rappoport, Z.,
Eds.; Wiley: New York, 1991, 767. (b) Yoshikawa, M.;
Yamaguchi, S.; Kunimi, K.; Matsuda, H.; Kuno, Y.;
Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1994, 42,
1226. (c) Ovenden, S. P. B.; Capon, R. J. J. Nat. Prod. 1999,
62, 1246. (d) Minami, I.; Akimoto, H.; Kondo, M.; Nomura,
H. Chem. Pharm. Bull. 1983, 42, 482. (e) Dickson, J. K.;
Biller, S. A.; Magnin, D. R.; Petrillo, E. W. Jr.; Hillyer, J.
W.; Hsieh, D. C.; Lan, S.; Rinehart, J. K.; Gregg, R. E.;
Harrity, T. W.; Jolibois, K. G.; Kalinoski, S. S.;
Kunselmann, L. K.; Mookhtiar, K. A.; Ciosek, C. P. Jr.
J. Med. Chem. 1996, 39, 661. (f) Morimoto, S.;Nomura, H.;
Ishiguro, T.; Fugono, T.; Maeda, K. J. Med. Chem. 1972, 15,
1105.
(2) (a) Xie, M.; Widlanski, T. S. Tetrahedron Lett. 1996, 37,
4443. (b) Huang, J.; Widlanski, T. S. Tetrahedron Lett.
1992, 33, 2657.
(3) (a) Lawrence, R. M.; Biller, S. A.; Dickson, J. K.; Logan,
J. V. H.; Mignin, D. R.; Sulsky, R. B.; DiMarco, J. D.;
Gougoutas, J. Z.; Beyer, B. D.; Taylor, S. C.; Lan, S.;
Ciosek, C. P.; Harrity, T. W.; Jolibois, K. G.; Kunselman, L.
K.; Slusarchyk, D. A. J. Am. Chem. Soc. 1996, 118, 11668.
(b) Corey, E. J.; Cimprich, K. A. Tetrahedron Lett. 1992, 33,
4099.
(4) (a) Enders, D.; Vignola, N.; Berner, O. M. Angew. Chem.
Int. Ed. 2002, 41, 109. (b) Enders, D.; Berner, O. M.;
Vignola, N.; Bats, J. W. Chem. Commun. 2001, 2498.
(c) Enders, D.; Berner, O. M.; Vignola, N.; Harnying, W.
Synthesis 2002, 1945. (d) Enders, D.; Harnying, W.;
Vignola, N. Synlett 2002, 1727. (e) Enders, D.; Harnying,
W.; Vignola, N. Eur. J. Org. Chem. 2003, 3939. (f) Enders,
D.; Harnying, W. Synthesis 2004, 2910. (g) Enders, D.;
Harnying, W. ARKIVOC 2004, (ii), 181. (h) Enders, D.;
Harnying, W.; Raabe, G. Synthesis 2004, 590. (i) Enders,
D.; Adelbrecht, J.-C.; Harnying, W. Synthesis 2005, 2962.
(j) Harnying, W.; Kitisriworaphan, W.; Pohmakotr, M.;
Enders, D. Synlett 2007, 2529. (k) Enders, D.; Iffland, D.
Synthesis 2007, 1837. (l) Enders, D.; Iffland, D.; Raabe, G.
Synthesis 2009, 1683.
(5) (a) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural
Coumarins: Occurrence, Chemistry and Biochemistry;
Wiley: New York, 1982. (b) Zabradink, M. The Production
and Application of Fluorescent Brightening Agents; Wiley:
New York, 1992. (c) Yu, D.; Xie, M. L.; Morris-Natschke,
S. L.; Lee, K. H. Med. Res. Rev. 2003, 23, 322. (d) Wang,
C. J.; Hsieh, Y. J.; Chu, C. Y.; LinY, L.; Tseng, T. H. Cancer
Lett. 2002, 183, 163.
[CH(OC)CH(OC)CH2O], 76.6 [CH(OC)CH(OC)2], 76.9
(CHOSO2), 103.2 [CH(OC)2], 109.7, 113.2 [(O)2C(CH3)2],
128.2, 128.7, 129.2, 129.9, 130.2 (ArCH), 131.4, 132.7,
137.3 (ArC), 167.5, 167.9 (CO2). IR (KBr): 2954, 2986,
1736, 1602, 1516, 1436, 1370, 1163, 1017, 931, 833, 701
cm–1. MS (EI, 70 eV): m/z (%) = 633.6 (10) [M+ – CH3],
261.3 (37), 235.3 (66), 205.3 (40), 169.2 (89), 135.3 (100),
127.3 (66). Anal. Calcd for C32H40O12S (648.6): C, 59.25; H,
6.21. Found: C, 59.13; H, 6.12.
General Procedure for the Removal of the Chiral
Auxiliary
The sulfonate 3b (0.5 mmol) was dissolved in a solution of
2% TFA in MeOH–H2O (10:1 mL). The solution was
refluxed for 15 h and then evaporated to dryness. The
resulting oil was dissolved in CH2Cl2, (i-PrO)3CH (5 mmol)
was added dropwise, and the mixture was refluxed for 3 h.
The solvent was removed in vacuo, and the crude product
was purified by flash column chromatography (SiO2, Et2O–
pentane, 1:3) to yield the final product 6.
Dimethyl 2-[2-(Isopropoxysulfonyl)-2-phenyl-1-p-
tolylethyl]malonate (6)
Yield 107 mg (48%); colorless solid; mp 72–74 °C; de and
ee 98% (HPLC); [a]D22 +52.24 (c 0.67, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 0.89, 1.03 [2 × d, J = 6.0 Hz, 6 H,
(CH3)2CH], 2.32 (s, 3 H, CH3), 3.42, 3.54 (2 × s, 6 H,
OCH3), 3.95 [d, J = 8.0 Hz, 1 H, CH(CO2)2], 4.19 [dd,
J = 8.0, 9.1 Hz, 1 H, CHCH(CO2)2], 4.47 (sept, J = 6.0 Hz, 1
H, CHOSO2), 5.13 (d, J = 9.1 Hz, 1 H, PhCHSO3), 7.10 (d,
J = 8.0 Hz, 2 H, ArH), 7.30–7.42 (m, 7 H, ArH). 13C NMR
(100 MHz, CDCl3): d = 21.2 (CH3), 22.3, 23.1 [(CH3)2CH],
47.4 [CHCH(CO2)2], 52.3, 52.6 (OCH3), 55.1 [CH(CO2)2],
70.0 (CHSO3), 77.9 (CHOSO2), 128.6, 128.6, 129.0, 130.0,
130.1 (ArCH), 132.3, 132.7, 137.5 (ArC), 167.8, 168.2
(CO2). IR (KBr): 2987, 2954, 1738, 1596, 1436, 1370, 1213,
1165, 1017, 871, 840, 698 cm–1. MS (EI, 70 eV): m/z
(%) = 448.2 (5.7) [M+], 235.2 (43), 205.2 (21), 135.1 (100).
Anal. Calcd for C23H28O7S (448.2): C, 61.59; H, 6.29.
Found: C, 61.31; H, 6.78. HRMS: m/z calcd for C23H28O7S:
448.1550; found: 448.1552.
(6) CCDC-739752 (3i) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data–request/
cif.
(7) General Procedure for the Synthesis of a,b-Disubstituted
g-Alkoxycarbonyl Sulfonates 3a–j
To a solution of enantiopure sulfonate 1 (1.0 mmol) in dry
THF (10 mL), n-BuLi (1.6 M solution in hexane, 0.63 mL)
was added dropwise at –90 °C to – 95 °C under argon. The
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