Synthesis and palladium-catalyzed coupling reactions of enantiopure p-bromophenyl methyl sulfoximine

Article abstract of DOI:10.1021/jo047940c

(Chemical Equation Presented) The asymmetric synthesis and chemical modification of p-bromophenyl methyl sulfoximine (2) is described. Starting from p-bromophenyl menthyl sulfinate (5), enantiopure 2 can be obtained in a short reaction sequence involving

Full text of DOI:10.1021/jo047940c

approaches have been commonly used. The first one
involves the synthesis of racemic sulfoximines, which are
then resolved into their enantiomers.6 The second relies
on the stereospecific imination of enantiopure sul-
foxides.7,8 Both ways have the disadvantage that they are
rather limited in scope and that only a narrow range of
enantiopure sulfoximines can be accessed. For that
reason, many applications of sulfoximines utilize phenyl
methyl sulfoximine (1) as starting material, since this
compound is readily available by the resolution process.6
Unfortunately, attempts to expand the scope of this type
of enantiomer separation remained largely unsuccessful.9
By the sulfoxide imination route a larger variety of
enantiopure sulfoximines can be prepared, but in this
case the limitation stems from the fact that each sul-
foximine requires the intermediacy of the corresponding
sulfoxide, and often those compounds are not easy to
prepare in enantiopure form either.10 In the context of
our studies on sulfoximine-containing pseudopeptides
(such as 3)3 we became particularly interested in the
modification of the aryl group of sulfoximines. By varying
the electronic (and steric) properties of this substituent
we hoped to be able to fine-tune the chemical stability of
the pseudopeptides toward peptidases and eventually
develop interesting candidates for a prodrug approach.
Furthermore, sulfoximine derivatives with modified aryl
groups would also be of interest for the synthesis of novel
ligands, since in several cases sulfoximines with substi-
tuted aryls showed improved properties in catalytic
asymmetric reactions compared to their phenyl
analogues.2c,d
Synthesis and Palladium-Catalyzed
Coupling Reactions of Enantiopure
p-Bromophenyl Methyl Sulfoximine
Gae Young Cho, Hiroaki Okamura, and Carsten Bolm*
Institut fu¨r Organische Chemie der RWTH Aachen,
Professor-Pirlet-Str. 1, D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received November 19, 2004
The asymmetric synthesis and chemical modification of
p-bromophenyl methyl sulfoximine (2) is described. Starting
from p-bromophenyl menthyl sulfinate (5), enantiopure 2 can
be obtained in a short reaction sequence involving a well-
established substitution reaction followed by stereospecific
imination with O-mesitylenesulfonylhydroxylamine (MSH).
Palladium-catalyzed Buchwald/Hartwig, Suzuki, and Stille
coupling reactions allow a broad variation of the sulfoximine
aryl group, which is otherwise difficult to achieve. The
incorporation of a p-morpholino-substituted derivative into
a pseudotripeptide demonstrates the applicability of the
novel sulfoximine derivatives.
In recent years, sulfoximines have been widely used
as building blocks in chiral ligands1,2 and structural units
in pseudopeptides.3,4 All of those applications require
enantiopure sulfoximines.5 For their preparation two
With the intention to develop a more flexible synthetic
strategy, which allowed the introduction of a high
structural diversity, we focused our attention on the
search of a single key intermediate, which should readily
be available on a large scale and easily be modified. On
that basis, p-bromophenyl methyl sulfoximine (2) was
* To whom correspondence should be addressed. Fax: (Int.) +49
241 809 2391. Phone: (Int.) +49 241 809 4675.
(1) Reviews: (a) Okamura, H.; Bolm, C. Chem. Lett. 2004, 33, 482.
(b) Harmata, M. Chemtracts 2003, 16, 660.
(2) For recent representative examples, see: (a) Bolm, C.; Simic, O.
J. Am. Chem. Soc. 2001, 123, 3830. (b) Harmata, M.; Ghosh, S. K.
Org. Lett. 2001, 3, 3321. (c) Bolm, C.; Martin, M.; Simic, O.; Verrucci,
M. Org. Lett. 2003, 5, 427. (d) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi,
P. G.; Raabe, G.; Okamura, H. Chem. Commun. 2003, 2816. (e) Bolm,
C.; Martin, M.; Gescheidt, G.; Palivan, C.; Neshchadin, D.; Bertagnolli,
H.; Feth, M. P.; Schweiger, A.; Mitrikas, G.; Harmer, J. J. Am. Chem.
Soc. 2003, 125, 6222. (f) Langner, M.; Bolm, C. Angew. Chem., Int.
Ed. 2004, 43, 5984.
(3) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997,
38, 1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001,
7, 1118. (c) Tye, H.; Skinner, C. L. Helv. Chim. Acta 2002, 85, 3272.
(d) Bolm, C.; Mu¨ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4,
893. (e) Bolm, C.; Mu¨ller, D.; Dalhoff, C.; Hackenberger, C. P. R.;
Weinhold, E. Bioorg. Med. Chem. Lett. 2003, 13, 3207. (f) In this
context, see also: Hackenberger, C. P. R.; Schiffers, I.; Runsink, J.;
Bolm, C. J. Org. Chem. 2004, 69, 739.
(4) For very early work in this area, see: (a) Mock, W. L.; Tsay,
J.-T. J. Am. Chem. Soc. 1989, 111, 4467. (b) Mock, W. L.; Zhang, J. Z.
J. Biol. Chem. 1991, 266, 6393.
(5) Reviews: (a) Reggelin, M.; Zur, C. Synthesis 2000, 1. (b)
Mikolajczk, M.; Drabowicz, J.; Kielbasinski, P. Chiral Sulfur Reagents;
CRC Press: Boca Raton, 1997. (c) Pyne, S. Sulfur Rep. 1992, 12, 57.
(d) Haake, M. In Houben-Weyl; Klamann, D., Eds.; VCH Thieme:
Stuttgart, 1985; Vol. E11, p 1299. (e) Johnson, C. R. Acc. Chem. Res.
1973, 6, 341. (f) Johnson, C. R. Aldrichim. Acta 1985, 18, 3.
(6) (a) Fusco, R.; Tericoni, F. Chem. Ind. (Milan) 1965, 47, 61. (b)
Johnson. C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. (c)
Johnson, C. R.; Schroeck, C. W.; Shanklin, J. R. J. Am. Chem. Soc.
1973, 95, 7424. (d) Shiner, C. S.; Berks, A. H. J. Org. Chem. 1988, 53,
5542. (e) Brandt, J.; Gais, H. J. Tetrahedron: Asymmetry 1997, 8, 909.
(7) (a) Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda,
M. J. Org. Chem. 1973, 38, 1239. (b) Johnson, C. R.; Kirchhoff, R. A.;
Corkins, H. G. J. Org. Chem. 1974, 39, 2458. (c) Tamura, Y.;
Matushima, H.; Minamikawa, J.; Ikeda, M.; Sumoto, K. Tetrahedron
1975, 31, 3035.
(8) Cu salts: (a) Mu¨ller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998,
39, 4805. (b) Lacoˆte, E.; Amatore, M.; Fensterbank, L.; Malacria, M.
Synlett 2002, 116. (c) Cren, S.; Kinahan, T. C.; Skinner, C. L.; Tye, H.
Tetrahedron Lett. 2002, 43, 2749. (d) Tomooka, C. S.; Carreira, E. M.
Helv. Chim. Acta 2003, 85, 3773. (e) Takada, H.; Ohe, K.; Uemura, S.
Angew. Chem., Int. Ed. 1999, 38, 1288. Fe salts: (f) Bach, T.; Ko¨rber,
C. Tetrahedron Lett. 1998, 39, 5015. (g) Bach, T.; Ko¨rber, C. Eur. J.
Org. Chem. 1999, 1033. (h) Bolm, C.; Kesselgruber, M.; Mun˜iz, K.;
Raabe, G. Organometallics 2000, 19, 1648. (i) Nakayama, J.; Otani,
T.; Sugihara, Y.; Sano, Y.; Ishii, A.; Sakamoto, A. Heteroatom Chem.
2001, 12, 333. Rh complexes: (j) Okamura, H.; Bolm, C. Org. Lett. 2004,
6, 1305.
(9) Cho, G. Y.; Bolm, C. Unpublished results.
10.1021/jo047940c CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/10/2005
2346
J. Org. Chem. 2005, 70, 2346-2349

SCHEME 1a
TABLE 1. Palladium-Catalyzed (Buchwald/Hartwig)
Aminations of 7 and 8 with Amino Derivatives
a Reagents and conditions: (a) (-)-menthol, P(OMe)3, Et3N,
CH2Cl2; (b) CH3MgBr, toluene, 5 °C; (c) MSH, CH2Cl2, rt; (d) (S)-
Boc-PheOH, DCC, HOBt, CH2Cl2 rt; (e) (Boc)2O, NaH, THF, rt.
a In reactions with (S,S)-7 and Cs2CO3 diastereomers were
formed (see text). b Values for reactions with K2CO3 instead of
Cs2CO3 are given in parentheses. Single diastereomers were
obtained in these reactions (see text). c Reaction conditions:
Pd(OAc)2 (2 mol %), BINAP (4 mol %), and Cs2CO3 (1.4 equiv),
toluene, reflux. d A 1:1 mixture of diastereomers was obtained with
both bases Cs2CO3 and K2CO3. e As a mixture of diastereomers.
identified as the target compound. The bromo substituent
in the para position was expected to allow the introduc-
tion of various other groups by palladium catalysis, and
the synthesis of 2 appeared practical, since Naso and co-
workers recently prepared the corresponding sulfoxide
6 in enantiopure form.11 Here, we report on the realiza-
tion of this concept. Enantiopure 2 was synthesized by a
short reaction sequence and subsequent palladium-
catalyzed Buchwald/Hartwig,12 Suzuki,13 and Stille cou-
plings14 led to various para-substituted sulfoximines. One
of those modified derivatives was finally incorporated into
a pseudopeptidic structure.
As chemical transformations of 7 and 8 (and with the
intention to increase the electron-donating ability of the
sulfoximine aryl group) we first investigated palladium-
catalyzed (Buchwald/Hartwig) amination reactions (Table
1). Although (S)-8 could be prepared in good yield,
racemic 8 was used in most of the reactivity studies. An
optimization of various reaction parameters revealed that
a combination of Pd2(dba)3, BINAP, and Cs2CO3 was the
best system for the coupling reactions with primary
amines. For the reactions with morpholine (Table 1,
entries 2 and 7) use of Pd(OAc)2 instead of Pd2(dba)3
proved superior. The same trend was found in reactions
of sulfoximine (S)-1 with (S,S)-7 and rac-8 (Table 1,
entries 4 and 10). There, with Pd(OAc)2 as metal source
the corresponding products (S,S,S)-9d and rac-9j were
obtained in 95 and 72% yield, respectively. Applying Pd2-
(dba)3 in the coupling of (S,S)-7 and sulfoximine (S)-1
gave the product in only 40% yield. Most reactions
proceeded to completion within less than 24 h and gave
high yields.
Although the yields in the palladium-catalyzed amine
couplings were satisfying, another aspect of the trans-
formation was problematic. Thus, under the reaction
conditions described above, (S,S)-7 was converted well,
but unfortunately a significant amount of epimerization
(ca. 40%) occurred. Since the diastereomers could not be
separated by column chromatography, the application of
the new amino-substituted sulfoximines as building
blocks in pseudopeptide synthesis appeared to be critical.
On the basis of previous results,16 we assumed that the
loss of the stereochemical integrity involved the amino
acid part of the products. To confirm this hypothesis, (S)-
9h [the coupling product of (S)-8 and aniline] was
specifically converted into both diastereomers of 9c
(Scheme 2), and a comparison of the product NMR
spectra confirmed the assumed formation of (S,S)-9c and
Following Naso’s protocol,11 p-bromophenyl menthyl
sulfinate (5) was prepared by reaction between p-bro-
mobenzenesulfonyl chloride (4) and (-)-menthol in the
presence of trimethyl phosphite as reducing agent (Scheme
1). The diastereomer with S-configuration at the stereo-
genic center of sulfur was isolated by crystallization and
subsequently treated with methylmagnesium bromide
affording (S)-p-bromophenyl methyl sulfoxide [(S)-6].
Finally, imination of (S)-6 with MSH gave sulfoximine
(S)-2 in 86% yield with >99% ee (after crystallization).
To demonstrate the potential introduction of functional
groups at the imine nitrogen, (S)-2 was coupled with (S)-
N-Boc-phenylalanine and treated with Boc-anhydride to
give amino acid derivative (S,S)-7 (96% yield) and N-Boc-
protected (S)-8 (74% yield), respectively.15
(10) Reviews: (a) Kagan, H. B.; Luukas, T. In Transition Metals
for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 2004; p 479. (b) Kagan, H. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Eds.; Wiley-VCH: New York, 2000; p
327. (c) Bolm, C.; Mun˜iz, K.; Hildebrand, J. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; p 697.
(11) (a) Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Spina, G.;
Tortorella, P. J. Org. Chem. 2001, 66, 5933. (b) For a review, see:
Capozzi, M. A. M.; Cardellicchio, C.; Naso, F. Eur. J. Org. Chem. 2004,
1855.
(12) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219,
131. (b) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2000; p 195. (c) Hartwig, J. F. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley-Interscience: New York, 2002; p 1051.
(13) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c) Stanforth, S. P.
Tetrahedron 1998, 54, 263. (d) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron 2002, 58, 9633. (e) Miyaura, N. Top. Curr. Chem. 2002,
219, 11. (f) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419. (g)
See also: Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201 and
references therein.
(15) The 1H NMR spectra of sulfoximines coupled to N-Boc-phenyl-
alanine indicated the presence of rotamers in a ratio of ca. 6:1. For
example, compound (S,S)-7 showed two separate sets of signals at 5.14/
4.97 ppm and 4.60-4.55/4.41 ppm for the NH and CHN protons,
respectively. Only one set of signals was found in a spectrum taken at
55 °C (in CDCl3).
(14) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Farina, V.; Krishnamurthy, V.; Scott, W. Org. React. 1997, 50, 1. (c)
Handy, S. T.; Zhang, X. Org. Lett. 2001, 3, 233. (d) Mitchel, T. N. In
Metal Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 1998; p 167 and references therein.
(16) Hackenberger, C. P. R.; Raabe, G.; Bolm, C. Chem. Eur. J. 2004,
10, 2942.
J. Org. Chem, Vol. 70, No. 6, 2005 2347

SCHEME 2a
TABLE 3. Palladium-Catalyzed (Stille) Coupling
Reactions of 7 and 8
a Reagents and conditions: (a) TFA/CH2Cl2 ) 1:3; (b) (S)-Boc-
Phe-OH, DCC, HOBt, CH2Cl2; (c) (R)-Boc-Phe-OH, DCC, HOBt,
CH2Cl2.
71%, respectively). Furthermore, both the yield and the
degree of epimerization appeared to be affected by the
ratio of acetonitrile and water. For example, 11c was
obtained as an 11:1 mixture of diastereomers in 42% yield
when the ratio of CH3CN/water was 1:1. In a 3:1 mixture
of these solvents, however, the yield of 11c increased to
75% and the dr was now 8:1 (Table 2, entry 3).
TABLE 2. Palladium-Catalyzed (Suzuki) Couplings of 7
and 8 with Boronic Acids
To introduce other unsaturated functional groups in
the para position of the sulfoximine aryl, palladium-
catalyzed Stille coupling reactions with 7 and 8 were
examined. As shown in Table 3, all reactions proceeded
well giving the corresponding products 12 in high yields
(up to 98%). No epimerization was observed. As ligand
BINAP was more effective than P(t-Bu)3 and P(o-Tol)3.
In most reactions full conversion was achieved in less
than 24 h.
After having established that a broad range of com-
pounds with various substituents in the para position of
the sulfoximine aryl group was accessible by this coupling
route, the attention was focused on the incorporation of
the novel building blocks into pseudopeptidic structures.
As representative substrate morpholino-substituted sul-
foximine (S)-9g was chosen. This compound was regarded
as particularly interesting, since the amino substitutent
in the para position was expected to have a significant
electronic effect on the sulfoximine unit. Furthermore,
amine protonation could enhance the water solubility of
such modified pseudopeptides. To allow a comparison
with our previous studies,3a,b both R-amino acids next to
the new sulfoximine unit in target compound 15 were
protected valines. To our surprise, the standard reaction
sequence for the synthesis of pseudopeptides of this type
(route A) involving carboxylation of (S)-9g at the sul-
foximine methyl group followed by DCC coupling of the
resulting ammonium salt with the R-amino acid benzyl
ester proved inefficient here giving (S,S)-13 in only 14%
yield (Scheme 3). Deprotection of (S,S)-13 at the sul-
foximine nitrogen, and subsequent DCC coupling with
N-Boc-valine gave (S,S,S)-15 in 67% yield over two steps.
The alternative reaction sequence for the synthesis of 15,
route B, in which the sulfoximine nitrogen is first
connected with N-Boc-valine and the carbon chain then
extended by carboxylation, also required significant
optimization. In this case, the second step was the most
critical one. Thus, the Boc cleavage and the subsequent
DCC coupling of the resulting NH-sulfoximine (not
shown) proceeded well and gave (S,S)-14 in good yield
(88% over two steps). The following carboxylation of (S,S)-
14 and the subsequent DCC coupling of the resulting
ammonium salt with benzyl-protected valine, however,
gave (S,S,S)-15 in only 16% yield. After an extensive
a The epimer ratio is given in parentheses. b Single stereoiso-
mer. c After recrystallization dr > 30:1.
(S,R)-9c in the palladium-catalyzed coupling starting
from (S,S)-7.
Suspecting that the epimerization was most likely
caused by the base (Cs2CO3) in toluene under reflux, a
brief base screening was performed which revealed that
K2CO3 could also be applied in the coupling reactions.
As shown by the data presented in Table 1 (entries 1-5),
a slight decrease in yield had to be accepted in some
cases, but most significantly, with K2CO3 as base the
epimerization was suppressed. Only in the coupling with
tert-butyl carbazate (entry 5) were two diastereomers of
9e still observed.
Next, palladium-catalyzed (Suzuki) couplings of 7 and
8 with boronic acids were investigated. For both com-
pounds, a system consisting of Pd(PPh3)4 and K2CO3 in
acetonitrile/water (3:1) proved optimal. Under those
conditions, the base-induced epimerization of products
stemming from (S,S)-7 was reduced to a minimum (Table
2).
Attempts to use Pd(OAc)2, P(o-Tol)3, and K2CO3 in
dioxane in Suzuki-type couplings of 8 gave 11 in lower
yields. Interestingly, with the same catalyst system
reactions between (S,S)-7 and p-biphenylboronic acid led
to the coupling product 11a in 91% yield. In this case,
however, more of the undesired epimer [(S,R)-11a] was
formed (dr ) 1.6:1). Other reagent combinations {[Pd-
(PPh3)4] and Cs2CO3 in CH3CN/water or [Pd(PPh3)4] and
K2CO3 in DME/water} led to lower yields of 11a (69 and
2348 J. Org. Chem., Vol. 70, No. 6, 2005

SCHEME 3a
1H, J ) 8.0 Hz), 5.02 (s, br, 1H), 4.55 (dd, 1H, J ) 5.8, 13.2 Hz),
4.38 (s, br, 2H), 3.27 (s, 3H), 3.24-3.07 (m, 2H), 1.40 (s, 9H);
13C NMR (CDCl3, 100 MHz) δ 179.7, 155.2, 152.4, 137.6, 137.2,
129.7, 129.1, 128.8, 128.1, 127.7, 127.2, 126.4, 123.8, 112.2, 79.1,
57.4, 47.4, 44.5, 38.7, 28.3; IR (neat, cm-1) 3376, 2978, 1706,
1596; MS (CI, m/z) 508 (MH+). Anal. Calcd for C28H33N3O4S: C,
66.25; H, 6.55; N, 8.28. Found: C, 66.03; H, 6.59; N, 8.22.
General Procedure (GP 2) for Palladium-Catalyzed
Suzuki Coupling of (S,S)-7 and rac-8. To a mixture of (S,S)-7
(96 mg, 0.2 mmol) or rac-8 (100 mg, 0.3 mmol) and Pd(PPh3)4 (2
mol %) in acetonitrile (3 mL) was added the aryl boronic acid
(1.2 equiv), followed by K2CO3 (1.5 equiv) in H2O (1 mL). The
mixture was heated to reflux until the starting material was
completely consumed (TLC analysis). After being cooled to room
temperature, the reaction mixture was partitioned between ethyl
acetate and brine. The organic phase was separated, dried
(MgSO4), and concentrated. The product was purified by column
chromatography (SiO2).
Synthesis of 11a. Following GP 2 using (S,S)-7 and 4-bi-
phenylboronic acid gave 89.5 mg (78%) of 11a as a white solid
and as a mixture of diastereomers (>10:1): 1H NMR (CDCl3,
400 MHz) δ 7.83 (d, 2H, J ) 8.5 Hz), 7.73-7.71 (m, 2H), 7.67-
7.56 (m, 6H), 7.42-7.38 (m, 2H), 7.34-7.29 (m, 1H), 7.23-7.13
(m, 5H), 5.12 (d, 1H, J ) 7.7 Hz), 4.57-4.52 (m, 1H), 3.30/3.24
(s, 3H), 3.21-3.04 (m, 2H), 1.35 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 179.9, 155.3, 146.5, 141.7, 140.1, 137.6, 137.2, 136.7,
129.7, 128.9, 128.2, 128.0, 127.8, 127.7, 127.0, 126.5, 79.3, 57.4,
44.1, 38.6, 28.3 (signal pairs of diastereomers are indicated by
/; two Caryl signals could not be assigned); IR (neat, cm-1) 3375,
2928, 1648, 1501; MS (CI, m/z) 555 (MH+). Anal. Calcd for
C33H34N2O4S: C, 71.45; H, 6.18; N, 5.05. Found: C, 71.67; H,
6.18; N, 4.75.
a Reagents and conditions: (a) LCHIPA, THF, -78 °C, then
CO2; (b) (S)-H-Val-OBn, DCC, DMAP, CH2Cl2; (c) TFA/CH2Cl2 )
1:3; (d) (S)-Boc-Val-OH, DCC, HOBt, CH2Cl2; (e) (S)-H-Val-OBn,
EEDQ, DMAP, CH2Cl2.
search for new conditions (involving the use of other
bases such as n-BuLi and KHMDS for the metalation
before the introduction of CO2 and the exchange of DCC
by EDC and HBTU)17 it was found that the best yield
could be achieved when the standard carboxylation
protocol with LCHIPA (lithium cyclohexylisopropyl amide)
as base was applied and when the following reaction with
the benzyl-protected valine was performed in the pres-
ence of EEDQ17 as coupling reagent. Under these condi-
tions pseudotripeptide (S,S,S)-15 was obtained in 55%
yield over two steps [starting from (S,S)-14].
In conclusion, we have synthesized enantiomerically
pure p-bromophenyl methyl sulfoximine (2) and used it
as a key intermediate for the preparation of a variety of
novel sulfoximines with a functionalized aryl group.
Palladium-catalyzed Buchwald/Hartwig, Suzuki, and
Stille coupling reactions gave the corresponding products
in high yields. By fine-tuning of the reaction conditions
the observed epimerization in couplings of (S,S)-7 was
mimimized. Finally, the potential application of these
new sulfoximines in the synthesis of pseudotripeptides
was demonstrated. Further investigations are now fo-
cused on incorporating these products into other peptidic
structures and ligands for asymmetric catalysis.
General Procedure (GP 3) for Palladium-Catalyzed
Stille Coupling of (S,S)-7 and rac-8. Under argon, (S,S)-7 (96
mg, 0.2 mmol) or rac-8 (100 mg, 0.3 mmol), Pd2(dba)3 (1 mol %),
and rac-BINAP (2.2 mol %) were dissolved in toluene (2 mL).
After addition of the stannane (1.2 equiv), the mixture was
heated to reflux until the starting material was completely
consumed (TLC analysis). The solution was concentrated in
vacuo, and the resulting product was isolated by column chro-
matography (SiO2).
Synthesis of (S,S)-12a. Following GP 3 using (S,S)-7 and
tributyl(vinyl)tin gave 86.4 mg (97%) of (S,S)-12a as a white solid
and as a single isomer: mp 153-154 °C; [R]D -41.42 (c 1.26,
1
MeOH); H NMR (CDCl3, 400 MHz) δ 7.78 (d, 2H, J ) 8.2 Hz),
7.56 (d, 2H, J ) 8.5 Hz), 7.29-7.20 (m, 5H), 6.76 (dd, 1H, J )
11.0, 17.6 Hz), 5.92 (d, 1H, J ) 17.6 Hz), 5.48 (d, 1H, J ) 11.0
Hz), 5.16 (d, 1H, J ) 7.4 Hz), 4.61-4.56 (m, 1H), 3.33 (s, 3H),
3.25-3.08 (m, 2H), 1.41(s, 9H); 13C NMR (CDCl3, 100 MHz) δ
179.9, 155.3, 143.2, 137.2, 136.9, 135.0, 129.7, 128.2, 127.5, 127.1,
126.5, 118.4, 79.2, 57.4, 44.1, 38.6, 28.4; IR (neat, cm-1) 3384,
2930, 1623, 1525; MS (CI, m/z) 429 (MH+). Anal. Calcd for
Experimental Section
General Procedure (GP 1) for the Palladium-Catalyzed
Amination of (S,S)-7 and rac-8. A solution of (S,S)-7 (96 mg,
0.2 mmol) or rac-8 (100 mg, 0.3 mmol), amine (1.2 equiv),
potassium carbonate or cesium carbonate (1.4 equiv), tris-
(dibenzylideneacetone)dipalladium(0) or palladium(II) acetate (2
mol %), and rac-BINAP (1.5 equiv/Pd) in toluene (0.2 M) was
heated to reflux under argon until the starting material com-
pletely disappeared (TLC analysis). After the mixture was cooled
to room temperature, aq HCl (1 N, ca. 20 mL) and ethyl acetate
(ca. 30 mL) were added, and the organic phase was separated,
dried (MgSO4), and concentrated. The product was purified by
column chromatography (SiO2).
Synthesis of (S,S)-9a. Following GP 1 using (S,S)-7, ben-
zylamine, K2CO3, rac-BINAP, and Pd2(dba)3 gave 89.2 mg (88%)
of (S,S)-9a as a colorless oil (and as a single isomer): [R]D -32.4
(c 1.01, MeOH); H NMR (CDCl3, 400 MHz) δ 7.55 (d, 2H, J )
8.8 Hz), 7.38-7.15 (m, 10H), 6.62 (d, 2H, J ) 8.8 Hz), 5.20 (d,
C
23H28N2O4S: C, 64.46; H, 6.59; N, 6.54. Found: C, 64.33; H,
6.70; N, 6.48.
Acknowledgment. This work was supported by the
Fonds der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG) within the Collabora-
tive Research Center (SFB) 380 “Asymmetric Synthesis
by Chemical and Biological Methods” and the “Gra-
duiertenkolleg” (GRK) 440 “Methods in Asymmetric
Synthesis”. H.O. is grateful to the Alexander von
Humboldt Foundation for a postdoctoral fellowship. We
also thank Dr. J. Runsink for helping in the interpreta-
1
tion of the H NMR spectra.
1
Supporting Information Available: Full experimental
details and spectral characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) HBTU: O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium
hexafluorophosphate. EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-
quinoline ethyl 1,2-dihydro-2-ethoxy-1-quinolinecarboxylate.
JO047940C
J. Org. Chem, Vol. 70, No. 6, 2005 2349