The isopropylsulfinyl group: A useful chiral controller for the asymmetric aziridination of sulfinylimines and the organocatalytic allylation of hydrazones

Article abstract of DOI:10.1021/ol050080h

(Chemical Equation Presented) A comparative study shows that the isopropylsulfinyl group for which an enantiodivergent and highly diastereoselective approach is reported behaves better than the tert-butylsulfinyl and p-tolylsulfinyl groups, both in terms

Full text of DOI:10.1021/ol050080h

ORGANIC
LETTERS
2
005
Vol. 7, No. 7
307-1310
The Isopropylsulfinyl Group: A Useful
Chiral Controller for the Asymmetric
Aziridination of Sulfinylimines and the
Organocatalytic Allylation of Hydrazones
1
Inmaculada Fern a´ ndez,*,† Victoria Valdivia, Beatrice Gori, Felipe Alcudia,
†
†
†
‡
,‡
Eleuterio A
Ä
lvarez, and Noureddine Khiar*
Departamento de Qu ´ı mica Org a´ nica y Farmac e´ utica, Facultad de Farmacia,
UniVersidad de SeVilla, c/Profesor Garc ´ı a Gonz a´ lez, 2, 41012 SeVilla, Spain, and the
Instituto de InVestigaciones Qu ´ı micas, C.S.I.C.-UniVersidad de SeVilla,
c/. Am e´ rico Vespucio, 49, Isla de la Cartuja, 41092 SeVilla, Spain
inmaff@us.es; khiar@iiq.csic.es
Received January 14, 2005
ABSTRACT
A comparative study shows that the isopropylsulfinyl group for which an enantiodivergent and highly diastereoselective approach is reported
behaves better than the tert-butylsulfinyl and p-tolylsulfinyl groups, both in terms of reactivity and stereoselectivity in the Corey
−Chaykovsky
reaction of chiral sulfinylimines and the organocatalytic allylation of acyl hydrazones.
4
The past decades have witnessed an increased interest in the
preparation of chiral sulfinyl derivatives in relation to their
application in asymmetric synthesis. This interest was
bases in organocatalysis. On the other hand, the exceptional
behavior of the chiral sulfinyl group in sulfinylimine, as an
activator, a chiral controller, and finally as a useful protective
group makes the sulfinylimines a universal intermediate for
1
mainly directed toward the preparation of enantiomerically
pure sulfoxides as a consequence of their high efficiency,
as well as their wide applicability as chiral controllers in
asymmetric carbon-carbon and carbon-heteroatom bond
5
,6
the asymmetric synthesis of chiral amines. Due mainly to
(
3) (a) Evans, D. R.; Huang, M. S.; Seganish, W. M.; Fettinger, J. C.;
Williams, T. L. Inorg. Chem. Commun. 2003, 6, 462. (b) Khiar, N.; Ara u´ jo,
C. S.; Alcudia, F.; Fern a´ ndez, I. J. Org. Chem. 2002, 67, 345. (c) Pettinari,
C.; Pellei, M.; Cavicchio, G.; Crucianelli, M.; Panzeri, W.; Colapietro, M.;
Caseta, A. Organometallics 1999, 18, 555.
2
formation. Recent interesting applications of enantiomeri-
cally pure sulfoxides include inter alia their utilization as
chiral ligands or ligand precursors in metal-catalyzed asym-
(
4) (a) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem.
1
1,3
Soc. 2003, 125, 6610. (b) Massa, A.; Malkov, A. V.; Kocovky, P.; Scettri,
A. Tetrahedron Lett. 2003, 44, 7179. (c) Rowlands, G.; Barnes, W. K. Chem.
Commun. 2003, 2712.
(5) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984. (b) Ellman, J. A. Pure. Appl. Chem. 2003, 75, 39.
(6) (a) Davis, F. A.; Zhou, P.; Chen, B. C. Chem. Soc. ReV. 1998, 27,
13. (b) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
metric reactions, in coordination chemistry, and as Lewis
†
Universidad de Sevilla.
C.S.I.C.-Universidad de Sevilla.
‡
(
(
1) Fern a´ ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
2) Carre n˜ o, C. Chem. ReV. 1995, 95, 1717
1
0.1021/ol050080h CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/02/2005

a lack of synthetic methodologies, the main chemistry with
chiral sulfinyl derivatives has been carried out using a
p-tolylsulfinyl group.2,7 Nevertheless, recent studies have
demonstrated that hindered alkyl substituents on the sulfur
do confer better stereochemical control in different processes
compared to their aryl counterparts. Pioneering work from
Casey’s group has shown the superiority of tert-butyl
showed that the diastereomeric ratio of the final aziridines
is highly dependent on the nature of the chiral auxiliary. The
10
14
Ruano and Davis groups were the first to report on the
modest diastereocontrol exerted by aromatic sulfinyl auxil-
iaries. A subsequent study by Ruano and Fern a´ ndez showed
that the tert-butylsulfinyl group was the best chiral auxiliary
for this transformation, affording the final products with high
8
10
sulfoxide over the p-tolyl sulfoxide in Michael addition. The
de.
same trend was recently reported by Ellmann in the synthesis
The syntheses of both isomers of the isopropanesulfinate
esters, 2(R ) and 2(S ), have been carried out in high yield
S S
5
of chiral amines and in metal-catalyzed asymmetric syn-
9
thesis, by Ruano and Fern a´ ndez in the aziridination of
and diastereoslectivity applying our DAG methodology
10
13
sulfinylimine, and by Carretero in the Pauson-Khand
(Scheme 1). It is noteworthy that, in this case, we have
reaction.11
These results promoted an active search of new and more
12
hindered sulfinylating agents. Surprisingly, the synthesis
of sulfinyl auxiliaries with an intermediate size between the
p-tolylsulfinyl and the tert-butylsulfinyl group did not attract
much interest. Significantly, while the effect of the steric
hindrance on the stereoselectivity is always beneficial, there
are cases where the reaction becomes exceedingly slow if
not inhibited (vide infra).10 With these premises in mind,
we thought that the development of less sterically demanding
sulfinyl substituents such as the isopropyl derivatives might
present the advantages of lower molecular weight and higher
reactivity and could thus be a good alternative to the popular
tert-butyl sulfinyl group, provided that the enantioselectivity
achieved is equally high. In this communication, we have
found that this is indeed true for two important reactions,
the Corey-Chaykovsky reaction of chiral sulfinylimine (eq
Scheme 1
found that the glucose-derived dicyclohexylidene-D-glucose
(DCG) 1 gives better chemical yields and diastereoselec-
tivities than diacetone-D-glucose. Additionally, the DCG
isopropylsulfinate esters 2 were stable, as no decomposition
of these sulfinates was detected after months at 4 °C.
Treatment of 2(S
suspending the crude reaction mixture in silica gel afforded,
after filtration and crystallization, the sufinamide 3(S ) with
S
) with LHMDS at -78 °C followed by
1) and the organocatalytic allylation of acyl hydrazones with
ferrocenylsulfinyl derivatives (eq 2). In both processes, the
isopropylsulfinyl group behaves better than the tert-butyl-
sulfinyl and p-tolylsulfinyl groups, both in terms of reactivity
and stereoselectivity.
S
a good 80% isolated yield. Using Davis’ conditions for the
synthesis of chiral sulfinyl aldimine afforded in a one-pot
S
manner phenyl isopropylsulfinylimine 4(S ) in 75% yield
14
and in only 2 h. The absolute configuration of the obtained
sulfinylimine was S as shown by X-ray analysis (see
Supporting Information), confirming the S configuration at
sulfur in the starting sulfinate ester (Scheme 2).
Scheme 2
Our first comparative study was the Corey-Chakovsky
reaction of chiral sulfinylimine for the synthesis of chiral
aziridine. The synthetic importance of this reaction has
attracted the attention of different research groups, who
A comparative study on the asymmetric aziridination of
N-sulfinylaldimines 4, 5, and 6 employing either dimethyl-
sulfonium methylide (A) or dimethyloxosulfonium methylide
(B) as methylene transfer is presented in Table 1.
(7) Solladi e´ , G. Heteroat. Chem. 2002, 13, 443.
(
8) Casey, M.; Manage, A. C.; Nezhat, L. Tetrahedron Lett. 1988, 29,
As it can be seen from Table 1, both the tert-butyl and
isopropylsulfinyl groups are better chiral auxiliaries than the
5
821.
9) (a) Liu, G.; Cogan, D. A.; Owens, T. D.; Owens, T. D.; Tang, T. P.;
(
Ellman, J. A. J. Org. Chem. 1999, 64, 1278. (b) Owens, T. D.; Hollander,
F. J.; Oliver, A. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 1539.
(13) (a) Fern a´ ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem.
1992, 57, 6789. (b) Khiar, N.; Fer a´ ndez, I.; Alcudia, F. Tetrahedron Lett.
1994, 35, 5719. (c) Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodr ´ı guez, L.;
Fern a´ ndez, I. J. Am. Chem. Soc. 2000, 122, 7598 and references therein
(14) Davis, F. A.; Zhou, P.; Liang, C. H.; Reddy, R. E. Tetrahedron:
Asymmetry 1995, 6, 1511.
(
10) Garc ´ı a-Ruano, J. L.; Fern a´ ndez, I.; del Prado, M.; Alcudia, A.
Tetrahedron: Asymmetry 1996, 7, 3407.
(
11) Adrio, J. Carretero, J. C. J. Am. Chem. Soc. 1999, 121, 7441.
(12) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake,
C. H. J. Am. Chem. Soc. 2002, 124, 7880.
1308
Org. Lett., Vol. 7, No. 7, 2005

Table 1. Reaction of N-Sulfinylimines with Dimethylsulfonium Ylide (n ) 0, Reagent A) and with Dimethyloxosulfonium Ylide
n ) 1, Reagent B)10
(
reagenta
time (h)
aziridine
2S:2R ratio
b
dec
entry
R
N-sulfinylimine
1
2
3
4
5
6
p-Tol
p-Tol
t-Bu
t-Bu
i-Pr
6
6
5
5
4
4
A
B
A
B
A
B
2
48
48
168
1
9
9
8
8
7
7
40:60
73:27
15:85
95:5
15:85
91:9
20
46
70
90
70
86
i-Pr
48
a
Reagent generated in situ, (n ) 0 for A and n ) 1 for B). b C-2 configuration of the aziridine. c Determined by H NMR of the crude.
1
p-tolylsulfinyl group. When dimethylsulfonium methylide
was used for methylene transfer (reagent A), the isopropyl
sulfinyl and tert-butyl sulfinyl groups gave the (2R)-aziridine
with the same diastereomeric excess (entries 3 and 5), higher
than that obtained with the p-tolyl derivative 6 (entry 1).
Nevertheless, while 48 h was needed to complete the reaction
in the case of the tert-butyl group (entry 3), the reaction with
the isopropyl sulfinyl group was complete after only 1 h
sulfoxides 13, 14, and 15 as chiral Lewis bases. For the
synthesis of the unknown i-Pr-ferrocenylsulfoxide 15 in
optically pure form, we used the approximation pioneered
1
6
by Kagan for the synthesis of 13 and 14. Condensation of
1.5 equiv of ferrocenyllithium on 2(S ) at -78 °C, followed
by a rapid quench, afforded the desired sulfoxide 15 in 55%
S
16
yield and 90% ee. A simple recrystallization from hexanes
S
afforded optically pure 15(S ) in a 35% isolated yield
(entry 5). The same trend is observed when dimethyloxo-
(Scheme 3).
sulfonium methylide was used for methylene transfer (reagent
B). In this case, the isopropylsulfinyl group maintains the
same reactivity as the p-tolyl group (compare times of
reaction in entries 2 and 6), but with only a slightly lower
diastereomeric excess than the tert-butylsulfinyl group, for
which not less than 168 h was needed to complete the
reaction. A close look at the results in Table 1 allows us to
conclude that the isopropyl group combines the advantages
of both chiral auxilaries, the higher reactivity of the p-
tolylsulfinyl group with the better chiral discrimination of
the tert-butylsulfinyl group.
Scheme 3
Using the best conditions reported by Kobayashi for the
allylation of hydrazones with trichloroallyl silane,4a we
underwent a comparative study of the effect of the substituent
at the sulfinyl sulfur on the stereoselectivity, and the results
are reported in Table 2.
As it can be seen from Table 2, the sulfinylferrocenes are
good ligands for the allylation of hydrazone, as they all give
the product in high chemical yield and short reaction time.
With regard to the enantioselectivity, the p-tolylsulfinylfer-
rocene 13(R) gave the product in quantitative yield but with
quasiracemization (4% ee, Table 2, entry 1). The tert-
butylsulfinylferrocene 14(R), which has recently been suc-
cessfully used as a ligand precursor for asymmetric catalysis,1
gave the product in longer reaction time and 72% yield, with
a deceiving 26% ee (Table 2, entry 2). Remarkably enough,
the isopropylsulfinylferrocene 15(S) gave the (S)-allyl hy-
drazone in quantitative yield and 82% ee.
6b
One of the most appealing recent applications of enan-
tiomerically pure sulfoxides is their utilization as a chiral
Lewis base in the allylation of aldehydes and hydrazones
with allyl trichlorosilane.4,15 Even though the reason for the
ee observed is unknown, the apparent relation of enantiose-
lectivity and the size difference between the substituents on
the sulfinyl sulfur prompted us to carry out a study of the
allylation of N-(benzoyl)isobutylhydrazone 10 with trichlo-
roallyl silane 11 using the electronically rich ferrocenyl
The results presented in this work show that besides the
advantage of lower molecular weight, the isopropylsulfinyl
(16) (a) Rebi e` re, F.; Riant, O.; Ricard, L.; Kagan, H. B. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 568. (b) Garc ´ı a Manche n˜ o, O.; Priego, J.; Cabrera,
S.; G o´ mez-Array a´ s, R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003,
68, 3679
(15) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
Org. Lett., Vol. 7, No. 7, 2005
1309

These results make us optimistic about the behavior of the
isopropylsulfinyl group in other chiral transformations,
especially those using chiral sulfinyl derivatives as ligands
or ligand precursors in metal-catalyzed asymmetric trans-
formation. Work in this area is under active investigation in
our group.
Table 2. Asymmetric Allylation Using Various
Alkylsulfinylferrocenes as Neutral Coordinate Organocatalysts
Acknowledgment. We thank the Direcci o´ n General de
Investigaci o´ n Cient ´ı fica y T e´ cnica for financial support
(Grants PB BQU2003-00937 and CTQ2004-01057).
time
(h)
enantiomeric
ratio (%) S:R
yield
(%)b
a
entry
R
X
Y
1
2
3
p-Tol
t-Bu
i-Pr
O
O
1.5
1.0
1.0
48:52
37:63
91:9
g95
72
g95
Supporting Information Available: Representative ex-
perimental procedures for the synthesis of compounds 2(S),
O
2(R), 3(S), 4(S), and 15(S); general methods for aziridination
a
Determined by chiral HPLC. b Isolated yield.
and allylation; and listings of positional and thermal param-
eters for 4(S) and 15(S) with bond distances and angles for
the non-hydrogen atoms (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
group also confers higher chemical reactivity and better
enantiomeric discrimination than the p-tolylsulfinyl group
and similar or even much better reactivity and enantiomeric
discrimination than the most popular tert-butylsulfinyl group.
OL050080H
1310
Org. Lett., Vol. 7, No. 7, 2005