A practical approach towards the asymmetric synthesis of α,γ-substituted γ-sultones

Article abstract of DOI:10.1055/s-2002-34229

The first auxiliary controlled synthesis of enantiopure α,γ-substituted γ-sultones via α-allylated chiral sulfonates is described. The high asymmetric inductions of the α-allylations were reached with our previously described auxiliary 1,2:5,6-di-O-isopro

Full text of DOI:10.1055/s-2002-34229

LETTER
1727
A Practical Approach Towards the Asymmetric Synthesis of , -Substituted
-Sultones
A
symmetric Synth
i
esis of
e
,
-Substit
t
uted
-
e
S
ultones r Enders,* Wacharee Harnying, Nicola Vignola
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 22 July 2002
Synthetic applications of chiral sultones, which were syn-
Abstract: The first auxiliary controlled synthesis of enantiopure
thesized by the intramolecular Diels–Alder reaction of
enantiopure vinylsulfonates, have been demonstrated in
several syntheses of natural products. For example, chiral
, -substituted -sultones via -allylated chiral sulfonates is de-
scribed. The high asymmetric inductions of the -allylations were
reached with our previously described auxiliary 1,2:5,6-di-O-iso-
propylidene- -D-allofuranose (de≥98%). Cleavage of the auxiliary sultones have been used as intermediates for the total syn-
thesis of the macrodiolide antibiotic pamamycin-607.10 A
and successive diastereoselective ring closure of the sulfonic acid
intermediates led to the title compounds in high selectivities (de,
further application has been reported by Winterfeldt et al.,
ee≥98%) and good to excellent yields (52–90%). Enantiopure , -
who used a chiral sultone as intermediate for the total syn-
substituted -sultones are interesting intermediates in the reaction
thesis of (–)-myltaylenol.11
with various nucleophiles.
Considering all the reported methods, no auxiliary con-
trolled method is known for an efficient asymmetric syn-
thesis of sultones, bearing one or more stereogenic centers
on the ring.
Key words: asymmetric synthesis, sugar auxiliary -allylation,
sulfonates, sultones
Over the past several years, sultones have emerged as
valuable heterocyclic intermediates.1 Both - and -sul-
tones are very reactive to nucleophiles, which cleave the
carbon-oxygen bond. Thus they behave as sulfoalkylating
agents.2 Many materials containing nucleophilic function-
alities have been modified by propane sultone, producing
fungicides, fire resistant polymers, lubricating oil addi-
tives and emulsifying agents.3 Very interesting is the use
of propanesultone as a cellulose modifier for the produc-
tion of cation exchange membranes.4
In previous communications we have shown highly effi-
cient asymmetric conversions of enantiopure -lithiated
sulfonates with various alkylhalides and nitroolefins for
the enantioselective synthesis of -substituted methyl sul-
fonates.12 In all cases the sugar derivative 1,2:5,6-di-O-
isopropylidene- -D-allofuranose was used as chiral auxil-
iary.
We have now extended this alkylation procedure to the
enantioselective synthesis of enantiopure , -substituted
-sultones.
Diastereoselective syntheses of chiral sultones have been
carried out by several groups. For example, Yamamoto et
al. reported on the stereoselective synthesis of -sultones
by an intramolecular Michael reaction starting from -
alkylsulfonyloxy- , -unsaturated esters.5 Lee et al. inves-
tigated the Diels–Alder reaction of unsaturated -sultones
with various dienes in excellent endo-selectivities and
good to excellent yields.6 An intramolecular stereocon-
trolled Diels–Alder reaction of vinylsulfonates bearing a
1,3-diene unit in the alcohol component was performed by
Metz et al. and led to alkyl substituted -sultones.7 On the
contrary to the reported methods, only a few synthetic
routes to enantiopure sultones and their applications in
synthesis have been reported. Various mixed disulfonate
ester derivatives of carbohydrates led to chiral products in
which a sultone is fused to a sugar ring via intramolecular
displacement reactions.8 In the same manner nucleoside
sultones have been prepared as synthons for the prepara-
tion of novel nucleotide analogues.9
As shown in Scheme 1, the enantiopure sulfonates 1 were
lithiated with 1 equivalent of n-butyllithium in tetrahydro-
furan at 90 °C to –95 °C. In analogy to the procedure re-
ported in the previous communications any side reactions
are minimized by using low temperature, mainly the at-
tack upon the sulfonate moiety by n-butyllithium. The
lithiated sulfonic esters were allowed to react with differ-
ent allylic halides at 90 °C to –95 °C for 2 hours and then
at –78 °C for 15 hours. Work up and purification gave
the -allylated sulfonates (R)-2a–e in good to excellent
yields (72–98%) and high diastereomeric excesses of
de = 82–95% (Table 1).13 In all cases diastereomerically
pure -allylated sulfonates could be obtained by recrystal-
lization from 2-propanol (de≥98%).
The absolute configuration of the newly formed stereo-
genic centre was assigned to be R in analogy to the results
shown in the previous report on the synthesis of the -
alkylated analogues.12
The racemization-free cleavage of the chiral auxiliary to
form the corresponding sulfonic acids 3 proceeded by re-
fluxing the diastereomerically pure sulfonates (R)-2a–e in
an EtOH solution containing 2% TFA. After removal of
the auxiliary the resulting crude sulfonic acids 3 were not
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1727,1729,ftx,en;G20002ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1728
D. Enders et al.
LETTER
R3
occured in a lower yield of 29%, which could be improved
by increasing the amount of TFA in the CH2Cl2 solution.
In this manner the ring closure to the sultones 4c–e was
then achieved by refluxing the sulfonates (R)-2c–e in a
CH2Cl2 solution containing 20% TFA for 24 hours giving
the corresponding -sultones in good yields and satisfying
diastereomeric excesses of de = 54–80%. In the case of
the cleavage of (R)-2e, 21% of a -sultone was found in
the product mixture. The diastereomerically pure sultones
4c–e could be obtained by flash column chromatography
or HPLC (de≥98%).
R2
SO3R*
O
S
R1
O
O
R1
1
4
ee ≥ 98%, de = 54-80%
(de ≥ 98% after chromatography)
a
72-98%
R2
52-90%
c
(2 steps)
R2
R3
R3
Table 2 Removal of the Chiral Auxiliary and Cyclization to the
Sultones 4a–e
-
b
SO3R*
SO3H
4
R1
R2
R3
Yield
[%]
dea,b [%] eec [%]
R1
R1
81d
90d
29d
72e
64e
52e,f
–
98
98
98
98
98
98
(R)-2
de = 82-95%
(de ≥ 98% after recrystallization)
3
a
b
c
H
CH3
CH3
H
H
t-Bu
H
H
–
O
H
78 ( 98)
80 ( 98)
78 ( 98)
54 ( 98)
O
H3C
H3C
O
R* =
O
c
H
H
H
CH3
O
CH3
d
e
t-Bu
t-Bu
H
H
Scheme 1 Reagents and conditions: (a) 1. n-BuLi, THF, –90 °C →
–95 °C,1 h; 2. XCH2C(R2)=CHR3, –90 °C → –95 °C, 2 h then –78 °C
for 15 h; (b) TFA/EtOH, reflux, 24 h; (c) TFA/CH2Cl2, reflux.
H
CH3
a Determined by 13C NMR spectroscopy.
b In brackets after flash column chromatography or HPLC.
c Determined by HPLC on chiral stationary phase (Daicel AD, n-hep-
tane/2-propanol 95:5).
d Cyclization condition: 2% TFA in CH2Cl2, reflux, 20 h.
e Cyclization condition: 20% TFA in CH2Cl2, reflux, 24 h.
f Product mixture consisted of 21% of -sultone.
Table 1 Asymmetric -Allylation of Chiral Sulfonates 1 to Afford
the Products (R)-2a–e
(R)-2
R1
H
Allylic halide
Yield [%] dea,b [%]
a
72
88 ( 98)
CH2
NOE experiments on compound 4c revealed that the pro-
tons at the and position are cis to each other (Figure 1).
Br
Br
I
CH3
CH2
Due to the known R-configuration of the stereogenic cen-
ter generated in the -allylation, the absolute configura-
tion could be assigned as R,R. The stereochemistry of the
major diastereomers of the examples 4c–e is expected to
be also R,R since we can postulate a uniform reaction
mechanism.
b
t-Bu
80
90 ( 98)
CH3
CH2
c
d
e
H
98
98
93
94 ( 98)
95 ( 98)
82 ( 98)
t-Bu
t-Bu
CH2
I
In summary, this methodology allows the first auxiliary
controlled asymmetric synthesis of enantiopure , -sub-
stituted -sultones.15 Applications of these enantiopure
compounds as chiral synthetic intermediates will be the
subject of further investigations.
Br
CH3
a Determined by 13C NMR spectroscopy.
b In brackets after recrystallization from 2-propanol.
purified, but directly refluxed in a TFA/CH2Cl2 solution
to yield the -sultones 4 in moderate to excellent yields,
good diastereoselectivities and excellent enantiomeric ex-
cesses (Table 2).14 As shown in Table 2 the sultones 4a,b
were obtained in very good yields (81–90%) and enantio-
selectivities (ee 98%) by refluxing the corresponding sul-
fonates (R)-2a,b in a CH2Cl2 solution containing 2% TFA
for 20 hours. On the contrary the reaction of (R)-2c to 4c
H
CH3
H
H
O
S
H
O
O
Figure 1 Selected NOE enhancements on 4c.
Synlett 2002, No. 10, 1727–1729 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of , -Substituted -Sultones
1729
(13) General Procedure for the -Allylation of Chiral
Acknowledgement
Sulfonates 1: To a solution of enantiopure sulfonate 1 (5.0
mmol) in dry THF (50 mL), n-butyllithium (1.0 equiv) was
added dropwise at –(90–95) °C under an argon atmosphere.
After stirring at –(90–95) °C for 1 h, the allylic halide (1.5
equiv) was added dropwise. The reaction mixture was stirred
for additional 2 h and then stirring was continued at –78 °C
over night. The mixture was quenched with water. After
separation of the organic layer the aq phase was extracted
with CH2Cl2 (3 20 mL). The combined organic layers were
washed with water, brine and dried over MgSO4. The solvent
was evaporated under reduced pressure and the crude
product was purified by flash column chromatography
(SiO2, n-pentane/diethyl ether 5:1) to afford (R)-2.
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG and Bayer AG for the
donation of chemicals. NOE-measurements by Dr. J. Runsink are
gratefully acknowledged.
References
(1) Metz, P. J. Prakt. Chem. 1998, 340, 1.
(2) Fischer, R. F. Ind. Eng. Chem. 1964, 56, 41.
(3) For reviews on sultone chemistry see: (a) Buglass, A. J.;
Tillet, J. G. In The Chemistry of Sulfonic Acids, Esters and
their Derivatives; Patai, S.; Rappoport, Z., Eds.; Wiley:
Chichester, New York, 1991, Chap. 19. (b) Roberts, D. W.;
Williams, D. L. Tetrahedron 1987, 43, 1027.
(4) Van der Velden, P. M.; Rijpkema, B.; Smolders, C. A.;
Bantjes, A. Eur. Polym. J. 1977, 13, 37.
(5) Asao, N.; Meguro, M.; Yamamoto, Y. Synlett 1994, 185.
(6) Jiang, L. S.; Chan, W. H.; Lee, A. W. M. Tetrahedron 1999,
55, 2245.
(7) (a) Metz, P.; Fleischer, M. Synlett 1993, 399. (b) Metz, P.;
Fleischer, M.; Fröhlich, R. Tetrahedron 1995, 51, 711.
(8) Fraser-Reid, B.; Sun, K. M.; Tsang, R. Y.-K. Can. J. Chem.
1981, 59, 260.
(9) Crooks, P. A.; Reynolds, R. C.; Maddry, J. A.; Rathore, A.;
Akhtar, M. S.; Montgomery, J. A.; Secrist, J. A. III J. Org.
Chem. 1992, 57, 2830.
(14) General Procedure for the Removal of the Chiral
Auxiliary: The sulfonates (R)-2 (1.0 mmol) were dissolved
in a 2% TFA/EtOH solution (40 mL). The solution was
refluxed for 24 h after which the solvent was removed under
reduced pressure and the crude sulfonic acid was used in the
next reaction step without further purification.
General Procedure for the Cyclization: The crude product
3 was dissolved in a TFA/CH2Cl2 solution (20 mL). The
reaction mixture was refluxed for 24 h. After separation of
the organic layer the aq phase was extracted with CH2Cl2 (3
20 mL). The combined organic layers were washed with
sat. aq NaHCO3-solution and brine. After drying over
MgSO4 the solvent was evaporated and the crude product
was purified by flash column chromatography (SiO2, n-
pentane/diethyl ether 4:1) to afford 4.
(R,R)-4c: IR (KBr): 3035, 2995, 2973, 1498, 1459, 1387,
1331 (s), 1252, 1194, 1165 (s), 1130, 1113, 1026 (s), 942,
910, 858, 820 (s), 795 (s), 770, 698 (s), 598 cm–1. 1H NMR
(400 MHz, CDCl3): = 1.56 (d, J = 6.0 Hz, 3 H, CH3), 2.56
(ddd, J = 10.4, 13.2, 13.2 Hz, 1 H, CHH), 2.79 (ddd, J = 5.5,
6.9, 13.2 Hz, 1 H, CHH), 4.54 (dd, J = 6.9, 13.2 Hz, 1 H,
CHPh), 4.78 (m, 1 H, CHO), 7.36–7.45 (m, 5 H, ArH) ppm.
13C NMR (100 MHz, CDCl3): = 20.8 (CH3), 37.6 (CH2),
63.25 (CHPh), 77.4 (CHO), 128.6, 128.8, 129.25 (PhCH),
129.3(PhC) ppm. MS (EI, 70eV): m/z = 212 (10)[M+], 148
(14), 104 (100), 91 (5), 78 (10).
(10) (a) Bernsmann, H.; Hungerhoff, B.; Fechner, R.; Fröhlich,
R.; Metz, P. Tetrahedron Lett. 2000, 41, 1721.
(b) Bernsmann, H.; Fröhlich, R.; Metz, P. Tetrahedron Lett.
2000, 41, 4347. (c) Bernsmann, H.; Gruner, M.; Metz, P.
Tetrahedron Lett. 2000, 41, 7629. (d) Wang, Y.;
Bernsmann, H.; Gruner, M.; Metz, P. Tetrahedron Lett.
2001, 42, 7801.
(11) (a) Doye, S.; Hotopp, T.; Winterfeldt, E. Chem. Commun.
1997, 1491. (b) Doye, S.; Hotopp, T.; Wartchow, R.;
Winterfeldt, E. Chem.–Eur. J. 1998, 4, 1480.
(12) (a) Enders, D.; Vignola, N.; Berner, O. M. Angew. Chem.
Int. Ed. 2002, 41, 109; Angew. Chem. 2002, 114, 116.
(b) Enders, D.; Berner, O. M.; Vignola, N. Chem. Commun.
2001, 2498.
(15) All new compounds showed suitable spectroscopic data
(NMR, MS, IR) and correct elemental analyses.
Synlett 2002, No. 10, 1727–1729 ISSN 0936-5214 © Thieme Stuttgart · New York