Diastereoselective synthesis of enantiomerically pure 1,2-disubstituted cyclopropanols from allylic sulfones

Article abstract of DOI:10.1055/s-2002-19749

Enantiomerically pure 1,2-disubstituted cyclopropanols have been obtained from allylic sulfones derived from (R)-glyceraldehyde, in good yield.

Full text of DOI:10.1055/s-2002-19749

LETTER
355
Diastereoselective Synthesis of Enantiomerically Pure 1,2-Disubstituted
Cyclopropanols from Allylic Sulfones
D
iastereoselective
.
Synthesis of
D
1,2-Disubstituted
i
Cyclop
e
ropanols z,* P. García, M. P. Pacheco, I. S. Marcos, N. M. Garrido, P. Basabe, J. G. Urones
Dpto. de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: ddm@usal.es
Received 27 November 2001
In order to preserve and use the stereogenic center present,
to obtain cyclic compounds in enantiomeric pure form in-
stead of dienes in the above reaction, it was clearly neces-
sary to establish differences between the hydroxyl groups.
For this reason the primary alcohol was converted into a
good leaving group and the secondary hydroxyl group
protected with a very stable group. For the protection of
the secondary alcohol the tetrahydropiranyl function was
chosen, due to its stability under basic conditions.9 Tosy-
lation of the primary alcohol or replacement with iodide
were selected due to ease of synthesis and difference in re-
activity, (hardness).
Abstract: Enantiomerically pure 1,2-disubstituted cyclopropanols
have been obtained from allylic sulfones derived from (R)-glyceral-
dehyde, in good yield.
Key words: cyclopropanols, sulfones, cyclization, synthesis
There are many biologically important compounds that
have a three-member carbocyclic ring,1 so the develop-
ment of an asymmetric approach to these rings is of con-
siderable interest. The unique reactivity of cyclopropanes2
due to the high level of strain, offers considerable utility
in organic synthesis and have been widely studied during
the last years.1 Among cyclopropanes 1,2-disubstituted
cyclopropanols are quite rare and its chemistry offers
great potential,3 especially vinylic ones.4
The use of enantiomerically pure olefins derived from R
or S-glyceraldehyde acetonide to introduce absolute con-
figuration into cyclopropane systems has received consid-
erable attention in the last years,5 but surprisingly
asymmetric induction of unprotected glyceraldehyde has
been little explored.
As part of our ongoing study of the reactivity6 and syn-
thetic applications7 of allylic sulfones we report a new and
very interesting application of these compounds. The
elimination reactions of certain allyl sulfones with various
protecting groups, these being the same for the primary
and the secondary hydroxy group, to give 1-hydroxyme-
thyl-4-sulfonylbutadienes, have being studied by us.6 This
kind of compound presents very interesting reactivity8
(Scheme 1).
Scheme 2 a) HCI 2 N, MeOH (97%); b) TsCI. Pyridine (70%);
c) NaI, Acetone, 80 °C; d) DHP, p-TsOH, DCM (95%)
Compound 1, previously synthesised by us6, was depro-
tected with 2 N HCl in MeOH, to obtain diol 3. This com-
pound reacts selectively with tosyl chloride in pyridine to
give 4, which was transformed under the usual conditions
into iodide 5, thus increasing the difference in reactivity
already present. Compound 4 was protected as its tetrahy-
dropyranyl derivative to give 6 and thence transformed
into iodide 7, that could be obtained directly from 5
(Scheme 2).
Once the starting materials had been obtained, they were
treated separately with LDA as base. Compound 6 gave a
large number of compounds under the reaction conditions,
perhaps tosylate (hard) is not displaced by the allylic an-
ion (soft), while 7, iodide (soft) gave in good yield a 7: 3
mixture of cyclopropanols 8 and 9 respectively10
(Scheme 3). The same ratio was obtained using one or two
equivalents of base, but better yield was obtained in the
last case. When these compounds were hydrolysed with
careful work up, extraction under neutral conditions, alde-
Scheme 1
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
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© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

356
D. Diez et al.
LETTER
hyde 10 was obtained in both cases. This result can be un-
derstood by protonation of the double bond and opening
of the cyclopropane ring to give the aldehyde function
with isomerisation of the double bond to the conjugate po-
sition. The stereochemistry of the double bond was as-
signed by the coupling constant of hydrogen at C2 (J =
15.8 Hz).6 The 8/9 ratio, has been explained in a similar
system by de Meijere et al, by a deprotonation in position
2 and a chelate effect with the oxygen of the cyclopropyl
group11 (Scheme 3).
Acknowledgement
We thank the CICYT, Junta de Castilla y León (SA 13/00B) and
MEC for financial support of this research. We gratefully acknow-
ledge the Mass and NMR Spectrometry Services of Universidad de
Salamanca, Dr. H. B. Broughton (Lilly S.A., Alcobendas, Madrid),
and Dr. Jorg Pietruszka, University of Stuttgart for helpful discussi-
ons and Universidad de Salamanca for a doctoral fellowship to P. G.
G.
References
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(4) McGaffin, G.; Grimm, B.; Heinecke, U.; Michaelsen, H.; de
Meijere, A.; Walsh, R. Eur. J. Org. Chem. 2001, 3559; and
references cited therein.
Scheme 3 a) LDA, 2 equiv THF; b) AcOH–THF–H2O, 4:1:1
Reactivity of protected cyclopropanols has received con-
siderable attention in the literature due to the facile and re-
giocontrolled ring opening.12 So even despite of losing the
stereogenic centers this methodology is a convenient pro-
cedure to obtain , -unsaturated aldehydes with a sulfone
in -position (Scheme 3).
In order to stop the ring expansion, due to the double
bond, this function was suppressed by hydrogenation un-
der the usual conditions to obtain the cyclopropanes 11
and 12. These were conveniently deprotected to give in
good yield the cyclopropanols 13 and 14,13 which are
good cyclopropane scaffolds for synthesis (Scheme 4).
(5) (a) Morikawa, T.; Saski, H.; Hanai, R.; Shibuya, A.;
Taguchi, T.; Muray, E. J. Org. Chem. 1994, 59, 97.
(b) Evans, D. A.; Burch, J. D. Org. Lett. 2001, 3, 503.
(c) Alvarez-Larena, A.; Piniella, J. F.; Branchadell, V.;
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Cao, Y.; Yang, Y.; Cheng, D. Org. Lett. 1999, 1, 285.
(6) (a) Urones, J. G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.;
Bastida, A. J.; San Feliciano, S. G.; Díez Martín, D.;
Goodman, J. M. Synlett 1998, 1361. (b) Díez Martín, D.;
San Feliciano, S. G.; Marcos, I. S.; Basabe, P.; Garrido, N.
M.; Urones, J. G. Synthesis 2001, 1069.
(7) (a) Urones, J. G.; Díez Martín, D.; Marcos, I. S.; Garrido, N.
M.; Basabe, P.; San Feliciano, S. G.; Coca, R. Synlett 1998,
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Scheme 4 a) H2, PtO2, AcOEt; b) p-TsOH, MeOH
The stereochemistry of these compounds was determined
by 1H NMR studies of the coupling constants J1,2 = 2.8 Hz
for 13 and J1,2 = 6.4 Hz for 14, and extensive NOE studies.
In conclusion, we have developed a convenient method of
synthesis for enantiomerically pure 1,2-disubstituted cy-
clopropanols that present a great synthetic potential and
will be reported in due course.
(9) Kociénski, P. J. Protecting Groups; Thieme Verlag:
Stuttgart/New York, 1994.
Synlett 2002, No. 2, 355–357 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Synthesis of 1,2-Disubstituted Cyclopropanols
357
(10) Experimental Details for the Transformation of 7: LDA was
generated by the addition of n-butyllithium 1.6 M (0.25 mL,
0.38 mmol) to a solution of diisopropylamine (54 L, 0.38
mmol) in THF (1.0 mL) at -78 ºC. After 5 minutes, the
mixture was allowed to warm to room temperature, and then
recooled to -78 ºC. Compound 7 (80 mg, 0.18 mmol) was
then added to the reaction flask via cannula as a solution in
THF (1 mL). The reaction mixture was left to stir for one
hour at -78 ºC under argon before the addition of saturated
ammonium chloride solution (1 mL). The product was
extracted into ethyl acetate three times. The organic extracts
were combined, washed with water and saturated brine, then
dried over anhydrous sodium sulfate, filtered and removed
the solvent in vacuo. The mixture was purified by flash silica
column chromatography (hexane–ethyl acetate, 9:1)
(C-2’), 57.0 (C-1), 62.6 and 62.8 (C-5’), 99.3 (C-1’) 127.7
(Corto, -SO2Ph), 128.6 (CH -SO2Ph), 129.3 (Cmeta, -SO2Ph),
133.2 (Cpara, -SO2Ph), 141.4 (Cipso, -SO2Ph), 146.8 and 147.4
(CH=CH -SO2Ph). EIMS m/z (rel. int.): 308 (M+, 3), 224(5),
195(8), 125(15), 85(100). HRMS C16H20O4S requires
308,1082, found 308,1092. IR (film, cm–1): 2945, 1618,
1447, 1317, 1144.
(11) Militzer, H.-C.; Schömenauer, S.; Otte, C.; Puls, C.; Hain, J.;
Bräse, S.; de Meijere, A. Synthesis 1993, 998; and references
cited therein.
(12) (a) For general review see: Wong, H. N. C.; Hon, M.-Y.;
Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev.
1989, 89, 165. (b) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2,
147; and references cited therein.
(13) Selected data for compound 13: [ ]20D =–17.2º, (c = 0.40,
CHCl3), 1H NMR (400 MHz, CDCl3) 0.37 (1 H, q, J = 6.0
Hz, H -3), 0.76 (1 H, ddd, J = 9.2, 5.6 and 2.8 Hz, H -3), 0.95
(1 H, m, H-2), 1.56–1.73 (3 H, m, CH2-CH2 -SO2Ph, -OH),
3.18 (2 H, m, -CH2 -SO2Ph), 3.25 (1 H, dt, J = 6.0, 2.8, 2.8
Hz, H-1), 7.58 (2 H, m, -SO2Ph), 7.65 (1 H, m, -SO2Ph), 7.91
(2 H, m, -SO2Ph), 13C NMR (50 MHz, CDCl3) 14.9 (C-3),
19.6 (C-2), 25.2 (CH2-CH2 -SO2Ph), 52.8 (C-1), 56.0 (CH2 -
SO2Ph), 128.2 (Corto, -SO2Ph), 129.5 (Cmeta, -SO2Ph), 133.9
(Cpara, -SO2Ph), 139.5 (Cipso, -SO2Ph). EIMS m/z (rel. int.):
226 (M+, 5), 184(10), 143(65), 125(30), 84(85), 77(100).
HRMS C11H14O3S requires 226.0664, found 226.0669. IR
(liquid film, cm–1): 3200–3600, 2926, 1447, 1304, 1142,
1086, 689. Selected data for compound 14: [ ]20D = –8.5º, (c
= 0.46, CHCl3), 1H NMR (400 MHz, CDCl3) 0.21 (1 H, m,
H -3), 0.72 (1 H, m, H -3), 1.20 (1 H, m, H-2), 1.90 (2 H, m,
CH2-CH2 -SO2Ph), 3.25 (2 H, m, CH2 -SO2Ph), 3.53 (1 H, dt,
J = 6.4, 6.4 and 3.2 Hz, H-1), 7.63 (3 H, m, -SO2Ph), 7.92 (2
H, m, -SO2Ph). 13C NMR (100 MHz, CDCl3) 13.0 (C-3),
16.5 (C-2), 20.4 (CH2-CH2 -SO2Ph), 49.6 (C-1), 56.4 (CH2 -
SO2Ph), 127.9 (Corto, -SO2Ph), 129.2 (Cmeta, -SO2Ph), 133.6
(Cpara, -SO2Ph), 139.7 (Cipso, -SO2Ph). EIMS m/z (rel. int.):
226 (M+, 13), 184(12), 143(70), 125(30), 77(100). HRMS
C11H14O3S requires 226.0664, found 226.0684. IR (liquid
film, cm–1): 3200–3600, 3063, 2926, 2855, 1447, 1304,
1144, 1086.
isolating 53 mg, 94% of a mixture 7:3 of cyclopropanes 8
and 9. Selected data for compound 8: [ ]20D = +17.2º, (c =
0.79, CHCl3), 1H NMR (200 MHz, CDCl3) 0.93 (1 H, m,
H -3), 1.04 (1 H, q, J = 6.4 Hz, H -3), 1.24 (1 H, m, H-2),
1.38–1.90 (6 H, m, H-2’, H-3’, H-4’), 3.57 (1 H, m, HA-5’),
3.71 (1 H, m, H-1), 3.86 (1 H, m, HB-5’), 4.68 (1 H, m, H-
1’), 6.22 and 6.30 (1 H, d, J = 15 Hz, CH=CH-SO2Ph), 6.54
(1 H, dd, J = 15.0 and 10.0 Hz, CH=CH-SO2Ph), 7.56 (3 H,
m, -SO2Ph), 7.86 (2 H, m, -SO2Ph). 13C NMR (50 MHz,
CDCl3) 16.0 and 17.1 (C-3), 19.3 and 19.4 (C-3’), 21.5 and
22.2 (C-2), 25.5 (C-4’), 29.9 and 30.6 (C-2’), 59.0 (C-1),
62.6 and 62.8 (C-5’), 99.1 (C-1’), 127.5 and 128.2 (CH=CH-
SO2Ph), 127.7 (Corto, -SO2Ph), 129.5 (Cmeta, -SO2Ph), 133.4
(Cpara, -SO2Ph), 141.1 (Cipso, -SO2Ph), 147.9 and 148.0
(CH=CH-SO2Ph). EIMS m/z (rel. int.): 309 (M+ + 1, 3),
279(5), 195(5), 167(10), 125,(10), 85(100). HRMS
C16H20O4S requires 308,1082, found, 308,1082. IR (liquid
film, cm–1): 3063, 2942, 1620, 1447, 1308, 1146, 1086.
Selected data for compound 9: [ ]20D = –41.7º, (c = 0.87,
CHCl3), 1H NMR (200 MHz, CDCl3) 0.91 (2 H, m, H-3),
1.08–1.89 (7 H, m, H-2’, H-3’, H-4’, H-2), 3.57 (1 H, m, HA-
5’), 3.76–4.02 (2 H, m, HB-5’, H-1), 4.42 and 4.75 (1 H, m,
H-1’), 6.42 (1 H, m, CH -SO2Ph), 6.80 (1 H, m, CH=CH -
SO2Ph), 7.56 (3 H, m, -SO2Ph), 7.88 (2 H, m, -SO2Ph), 13
C
NMR (50 MHz, CDCl3) 15.8 and 17.0 (C-3), 19.3 and 19.5
(C-3’), 20.5 and 21.1 (C-2), 25.6 (C-4’), 30.3 and 30.6
Synlett 2002, No. 2, 355–357 ISSN 0936-5214 © Thieme Stuttgart · New York