L-proline-catalyzed direct intermolecular asymmetric aldol reactions of 1-phenylthiocycloalkyl carboxaldehydes with ketones. Easy access to spiro-and fused-cyclobutyl tetrahydrofurans and cyclopentanones

Article abstract of DOI:10.1021/ol063084a

Acid-catalyzed ring expansion of chiral cyclopropyl and cyclobutyl derivatives for the synthesis of carbo- and heterocyclic compounds is reported. The starting materials have been successfully prepared by i-proline-catalyzed direct asymmetric aldol reacti

Full text of DOI:10.1021/ol063084a

ORGANIC
LETTERS
2007
Vol. 9, No. 3
541-544
L
-Proline-Catalyzed Direct Intermolecular
Asymmetric Aldol Reactions of
1-Phenylthiocycloalkyl Carboxaldehydes
with Ketones. Easy Access to Spiro-
and Fused-Cyclobutyl Tetrahydrofurans
and Cyclopentanones
Angela M. Bernard,† Angelo Frongia,*,† Regis Guillot,‡ Pier P. Piras,*,†
Francesco Secci,† and Marco Spiga†
Dipartimento di Scienze Chimiche, UniVersita` degli studi di Cagliari, Complesso
UniVersitario di Monserrato, S.S. 554, BiVio per Sestu, I-09042 Monserrato (Cagliari),
Italy, and UMR 8182, Institut de Chimie Moleculaire et des Materiaux d’Orsay, Baˆt.
420 UniVersite´ Paris-Sud, 91405 Orsay Cedex, France
pppiras@unica.it
Received December 20, 2006
ABSTRACT
Acid-catalyzed ring expansion of chiral cyclopropyl and cyclobutyl derivatives for the synthesis of carbo- and heterocyclic compounds is
reported. The starting materials have been successfully prepared by
carboxaldehydes with ketones.
L-proline-catalyzed direct asymmetric aldol reactions of 1-phenylthiocycloalkyl
The proline-catalyzed direct enantioselective aldol reaction
between aldehydes and ketones is one of the most important
catalytic approaches to asymmetric synthesis of new C-C
bonds.1 A major limitation of the proline-promoted aldol
reactions is the rather narrow substrate scope. As a matter
of fact, organic catalysts that initiate asymmetric aldol
reactions of thio-substituted aldehydes have scarcely been
investigated,2 notwithstanding the great number of biologi-
cally relevant compounds that feature sulfur-containing
groups and the wide range of synthetic opportunities offered
by their manipulation.3 Furthermore, the synthesis of sulfur-
carrying cyclopropyl- and cyclobutylcarbinols is a useful
target as they are known to be efficient precursors of
cyclobutanones4 and cyclopentanones5 and of new carbo- and
heterocyclic cyclobutyl derivatives.6 For the above reasons,
we planned the study of the proline-catalyzed asymmetric
† Universita` degli Studi di Cagliari.
(2) (a) Baker-Glenn, C.; Ancliff, R.; Gouverneur, V. Tetrahedron 2004,
60, 7607. (b) Storer, R. I.; MacMillan, D. W. C. Tetrahedron 2004, 60,
7705.
(3) Organic Sulfur Chemistry: Theoretical and Experimental AdVances;
Bernardi, F., Csizmadia, I. G., Mangini, A., Eds.; Elsevier: Amsterdam,
1985.
(4) Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Bogdanowicz, M. J. J.
Am. Chem. Soc. 1977, 99, 3088.
(5) Fitjer, L.; Schlotmann, W.; Noltemeyer, M. Tetrahedron Lett. 1995,
36, 4985.
‡ Universite´ de Paris-Sud.
(1) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
Soc. 2001, 123, 5260. For reviews on organocatalysis, see: (b) List, B.
Tetrahedron 2002, 58, 5573; (c) Acc. Chem. Res. 2004, 37, special issue
on organocatalysis. (d) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138. (e) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (f) Seayad, J.; List, B. Org. Biomol. Chem.
2005, 3, 719. (g) List, B. Chem. Commun. 2006, 819. (h) Marigo, M.;
Jorgensen, K. A. Chem. Commun. 2006, 2001.
10.1021/ol063084a CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

direct aldol reactions of the R-phenylsulfanyl aldehydes 1-3
with ketones as donors under the List-Barbas conditions1a
(Scheme 1). Moreover, following our current research interest
tion products (see the Supporting Information). For the study
of the acid-catalyzed ring expansion of 1a-d and 2a,b, we
used as a model compound the aldols 1a and 2a whose
absolute configuration (R) was known by X-ray analysis (see
the Supporting Information). A preliminary attempt, in
different acid conditions, led only to the corresponding
dehydration products by an elimination reaction. For this
reason, we reduced 1a and 2a to the corresponding optically
pure syn- and anti-diols 4 and 9 using either the Prasad’s
reduction protocol10 or NaBH4 without chelating Lewis acid
and then separating the two diastereoisomers by column
chromatography.
Scheme 1
After screening different acids, we treated the cyclopropyl
diols 4 with SnCl4 in CH2Cl2 at rt, and unexpectedly, we
did not isolate the corresponding cyclobutanones. As a matter
of fact, (1R,3S)-anti-4 gave a mixture of two cis-fused (see
Supporting Information) cyclobutyl tetrahydrofuran diaste-
reoisomers (1R,3S,5S)-6 and (1S,3S,5R)-6 in a 14:86 ratio,
while the (1R,3R)-syn-4 led to the corresponding enantiomers
(1S,3R,5R)-8 and (1R,3R,5S)-8 in a 60:40 ratio.
We suppose that the ring expansion could occur through
two concurrent paths: (a) formation of an episulfonium ion
(path “a”) that allows preservation of the stereochemical
integrity11 of the migrating terminus through two consecutive
inversions during the ring expansion to the cyclobutylth-
ionium ion 5 or 7, that are finally captured by the oxygen
atom of the 3-hydroxyl group; (b) intermediacy of a
carbocation (path “b”) that causes a loss of stereochemical
integrity of the migrating terminus and consequent formation
of both 5 and 5′ or 7 and 7′ (Scheme 2).
in the preparation of carbocyclic7 and heterocyclic8 com-
pounds using cyclopropyl or cyclobutyl derivatives, we were
also interested in the study of the acid-catalyzed ring
expansion of the corresponding cyclopropyl and cyclobutyl
aldols, obtainable from 1 and 2, hopefully in an enantioen-
riched form.
The reaction of 1-3 with different ketones in the presence
of proline led to the corresponding aldol products 1a-d,
2a,b, and 3a,b in moderate to good yields and with ee values
in the range of 95-99% (Scheme 1).
The chiral discrimination increased with the increasing
bulkiness of the ring sizes (Table 1, entries 1-6), while a
Table 1. Direct Asymmetric Aldol Reactions Catalyzed by
L-proline.
entry aldol
n
R
R′
time (h) yielda (%) eeb (%)
If we make the reasonable hypothesis that the stereochem-
istry of the carbon carrying the 3-hydroxy group in both the
diols 4 is preserved, it is evident that a different amount of
epimerization of the migrating terminus is occurring in the
two isomers, during the ring expansion. This fact should be
a consequence of the different importance of the two possible
reaction paths for the two diols 4.
In Scheme 2, it appears that the reactions following path
“a” with the anti-diol 4 should lead to the corresponding
tetrahydrofuran (1S,3S,5R)-6 with the two large group in a
trans position, while the syn-diol 4 should lead to the tetra-
hydrofuran (1S,3R,5R)-8 with the two large substituents in
a less stable cis position. This fact could imply that path “a”
will be more important in the reaction of the anti-diol 4 rather
than in the syn-diol 4, with a consequent high level of
preservation of the stereochemistry of the migrating terminus.
Therefore, the reaction of the syn-diol 4 will have a higher
percentage of the ionic mechanism (path “b”) with major
erosion of the stereochemical integrity of the migrating
terminus.
1
2
3
4
5
6
7
8
1a
2a
3a
1b
2b
3b
1c
1d
1
2
3
1
2
3
1
1
H
H
H
H
H
H
H
Me
Me
Me
Et
Et
Et
16
16
24
24
24
48
48
16
80
95
98
>99
96
99
>99
96
88
56c
51c
44c
21c
Pr
21c
-(CH2)3-
syn: 29
anti: 51
>99
89
a Isolated yields after column chromatography. b The ee was determined
by chiral-phase HPLC analysis. c Moderate yield due to low conversion.
very small amount of condensation product was isolated only
in the case of entry 1. The preferential formation of the aldol
rather than the condensation products was very likely dictated
from the steric hindrance of the phenylsulfanyl group that
could render more difficult the Mannich-elimination se-
quence.9 In fact, the same reaction with acetone and the
corresponding cycloalkyl carboxaldehydes, lacking the R-phen-
ylsulfanyl group, led exclusively or mainly to the condensa-
Interestingly, when we treated the diols (1R,3R)-syn-9 and
(1R,3S)-anti-9 with SnCl4 we did not obtain the correspond-
ing cyclopentanones5 but the spiro-cyclobutyl tetrahydro-
furans (6R,8S)-syn-10 and (6S,8S)-trans-10, diastereoiso-
merically pure by stereospecific [1,2]-PhS migration.
(6) (a) Bernard, A. M.; Cadoni, E.; Frongia, A.; Secci, F.; Piras, P. P.
Org. Lett. 2002, 4, 2565. (b) Alberti, G.; Bernard, A. M.; Frongia, A.; Piras,
P. P.; Secci, F.; Spiga, M. Synlett 2006, 2242.
(7) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P. J. Chem. Soc.,
Chem. Commun. 2005, 3853.
(8) Bernard, A. M.; Frongia, A.; Secci, F.; Piras, P. P.; Spiga, M. Org.
Lett. 2005, 7, 4565.
(9) (a) Kreher, U. P.; Rosamilia, A. E.; Raston, C. L.; Scott, J. L.; Strass,
C. R. Org. Lett. 2003, 5, 3107. (b) Wang, W.; Mei, Y.; Li, H.; Wang, J.
Org. Lett. 2005, 7, 601.
(10) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.;
Repic, O.; Shapiro, M. J. Chem. Lett. 1987, 1923.
(11) Hiroi, K.; Ogata, T. Chem. Lett. 1990, 527.
542
Org. Lett., Vol. 9, No. 3, 2007

Scheme 2. Synthesis of Cis-Fused Cyclobutyl Tetrahydrofurans
Stereochemistry as reported by Warren for analogous sys-
temswas presumably inverted at the migrating terminus12
(Scheme 3).
iodide gave the cyclopentanone 12. This transformation15 is
here reported for the first time with a chiral nonracemic
oxaspirohexane to obtain 12 diastereoisomerically pure with
no loss of stereochemical integrity through inversion16 of
configuration at the migrating terminus (Scheme 4).
Scheme 3. Synthesis of Spirocyclic Tetrahydrofurans
Scheme 4. Synthesis of Cyclopentanones
In conclusion, we have presented the first successful proline-
catalyzed direct asymmetric aldol reactions of 1-phenylthio-
cycloalkyl carboxaldehydes with ketones. Some of the obtained
cycloalkyl carbinols are useful substrates for subsequent acid-
catalyzed transformation into the corresponding cis-fused or
spirocyclic tetrahydrofurans and cyclopentanones.
Depending upon the size of the carbocyclic ring of the
starting diols, the reaction with SnCl4 can give either the cis-
fused or the spirocyclic tetrahydrofurans. This remarkably
different behavior represents a further evidence that, despite
the almost equal strain energies, dissimilar effects are at work
in cyclopropanes and cyclobutanes in determining the chemi-
cal reactivity and the outcome of chemical transformations.13
Finally we have investigated an alternative approach to cy-
clopentanones. Thus, the diol (1R,3R)-syn-9 was transformed14
into the oxaspirohexane 11 that by reaction with lithium
Acknowledgment. Financial support from the MIUR,
Rome, by the University of Cagliari (National Project
“Stereoselezione in Sintesi Organica Metodologie ed appli-
cazioni”), and from CINMPIS is gratefully acknowledged.
We thank Dr. Jean Ollivier (Laboratoire de Synthe`se
(14) Solladie, G.; Solom-Roig, X. J.; Hanquet, G. Tetrahedron Lett. 2000,
41, 551.
(15) (a) Leriverend, M. L.; Leriverend, P. C. R. Acad. Sci., Ser. C 1975,
280, 791. (b) Trost, B. M.; Latimer, L. H. J. Org. Chem. 1978, 43, 1031.
(c) Krief, A.; Halazy, S. J. Chem. Soc., Chem. Commun. 1982, 1200.
(16) Chevtchouk, T.; Ollivier, J.; Salaun, J. Tetrahedron: Asymmetry
1997, 8, 1011.
(12) Eames, J.; Warren, S. Tetrahedron Lett. 1996, 37, 3525.
(13) Roberts, J. D.; Chambers, V. J. Am. Chem. Soc. 1951, 73, 5034.
Org. Lett., Vol. 9, No. 3, 2007
543

organique et de Me´thodologie, UMR 8122, ICMMO, Paris-
Sud, XI) for the crystallization of samples for the X-ray
analysis.
13C NMR spectra, and CIF files of 1a, 2a, and the
corresponding sulfones of (1S*,3R*,5R*)-8 and (1R*,3R*,5S*)-
8. This material is available free of charge via the Internet
at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures, stereochemical proofs, representative 1H NMR and
OL063084A
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Org. Lett., Vol. 9, No. 3, 2007