C1-Symmetric aminosulfoximines in copper-catalyzed asymmetric vinylogous mukaiyama aldol reactions

Article abstract of DOI:10.1002/chem.200903077

Vinylogous Mukaiyama-type aldol reactions have been catalyzed by a combination of Cu(OTf)₂ and readily available C₁-symmetric aminosulfoximines. After a fine-tuning of the reaction conditions and an optimization of the modularly assembled ligand structure, high stereoselectivities and excellent yields have been achieved in catalyzed reactions involving various electrophile/nucleophile combinations. The relative and absolute configurations of two products were assigned by X-ray single crystal structure analysis and a comparison of calculated and experimental CD spectra.

Full text of DOI:10.1002/chem.200903077

FULL PAPER
DOI: 10.1002/chem.200903077
C1-Symmetric Aminosulfoximines in Copper-Catalyzed Asymmetric
Vinylogous Mukaiyama Aldol Reactions
Marcus Frings,[a] Iuliana Atodiresei,[a] Yutian Wang,[b] Jan Runsink,[a]
Gerhard Raabe,[a] and Carsten Bolm*[a]
Abstract: Vinylogous Mukaiyama-type aldol reactions have been catalyzed by a
combination of CuACHTUNGTRENNUNG(OTf)2 and readily available C1-symmetric aminosulfoximines.
After a fine-tuning of the reaction conditions and an optimization of the modularly
assembled ligand structure, high stereoselectivities and excellent yields have been
achieved in catalyzed reactions involving various electrophile/nucleophile combi-
nations. The relative and absolute configurations of two products were assigned by
X-ray single crystal structure analysis and a comparison of calculated and experi-
mental CD spectra.
Keywords: aldol reaction · asym-
metric catalysis · copper · Mukaiya-
ma reaction · sulfoximine
Introduction
of the enormous feasibility the vinylogous aldol reaction is
still a highly challenging transformation because, in addition
to well-defined enantio- and diastereoselectivity of ordinary
aldol reactions, it appends the complexity of controlled re-
gioselectivity where due to two nucleophilic sites a and/or g
products can be formed (Scheme 1).
The Mukaiyama aldol reaction[1] is widely recognized as one
of the most versatile tools in organic synthesis for the link-
age of two (or more) carbons, and its enantioselective
metal-catalyzed version is attractive for both synthetic and
pharmaceutical chemists.[2] Catalyzed by chiral Lewis acids,
this reaction opens a convenient route to enantiomerically
enriched alcohols which frequently occur in natural or bio-
logically active compounds.[3]
By utilizing the concept of vinylogy,[4] which is understood
as the transmission of electronic effects through a conjugat-
ed p-system, the “normal aldol reaction” becomes its vinylo-
gous version, allowing the selective preparation of 1,5-di-
functional subunits. More precisely, in an elegant manner
the vinylogous aldol reaction provides access to d-hydroxy-
a,b-unsaturated carbonyl compounds. Thus, up to two ste-
reogenic centers and one double bond, which can easily be
further manipulated, are formed in a single step.[5] In spite
Scheme 1. Regioselective attacks in the vinylogous Mukaiyama aldol re-
action give g (left pathway) and/or a products (right pathway).
A general approach to circumvent the regioselectivity
issues and preferentially direct the electrophile attack to the
g-position is the use of O-silyl dienolates 1 (with M=SiR3)
in Lewis acid catalyzed vinylogous Mukaiyama-type aldol
reactions (VMAR). However, exceptions are known where
addition of aldehydes, acid anhydrides or nitroalkenes to O-
silyl dienolates led to the often undesired a-products either
in considerable amounts or even as sole products.[6] Further-
more, for high site selectivity electronic and steric effects of
both the dienolate and catalyst complex have to be taken
into account. In recent years, catalytic asymmetric VMAR
has attracted considerable attention and much effort has
[a] M. Frings, Dr. I. Atodiresei, Dr. J. Runsink, Prof. Dr. G. Raabe,
Prof. Dr. C. Bolm
Institut fꢀr Organische Chemie der RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-8092391
E-mail: carsten.bolm@oc.rwth-aachen.de
[b] Y. Wang
Institut fꢀr Anorganische Chemie der RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903077.
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4577

been made to overcome the remaining problems of regio-,
diastereo- and enantioselectivity.[6d,7]
hols and additional demand for high regio- and enantiose-
lectivities have hampered process development in this field.
For a considerable time, we have been interested in dem-
onstrating the applicability of various types of sulfoximines
as ligands in transition-metal-catalyzed asymmetric reac-
tions.[8,9] In particular, we have shown that C1-symmetric ox-
azolinyl- and aminosulfoximines are very effective ligands
for copper-catalyzed (V)MAR.[9a,10] In a recent communica-
tion we extended the catalytic system of aminosulfoximine
Development of the optimal reaction conditions: As depict-
ed in Scheme 3, commercially available TMSOF (2a) and
methyl pyruvate (3a) were chosen as starting materials for
the optimization of the reaction conditions. The initial ex-
periment was performed in dry diethyl ether at ambient
temperature using a catalyst composed of 10 mol% of Cu-
(S)-4aA and Cu
G
ACHTUNGRTENUN(NG OTf)2 and 10 mol% of sulfoximine (S)-4aA (Table 1,
electrophiles 3 (Scheme 2).[11] The resulting g-butenolides 5
were obtained in excellent yields and top-level diastereo-
and enantioselectivities. Additionally, the relative and abso-
lute configuration of a representative product was identified
beyond doubt.
entry 1). Satisfyingly, g-butenolide 5a was obtained in good
yield (83%) and high diastereoselectivity (94%) after five
hours. Moreover, a very promising ee of 83% was achieved.
Scheme 3. Synthesis of g-butenolide 5a by VMAR.
Because it is known that in Mukaiyama-type reactions ad-
ditives can dramatically affect enantioselectivities or catalyt-
ic turnover rates and thus enhance yields, the impact of vari-
ous additives was investigated next.[17] Indeed, when hexa-
fluoroisopropanol (HFIP) was applied the ee was increased
to 93% while the yield was slightly reduced to 78%
(entry 2). Fortunately, 2,2,2-trifluoroethanol (TFE) im-
proved the previous results, and 5a was isolated with 95%
ee in 88% yield (entry 3). In all cases the diastereoselectiv-
ity remained unaffected. TMSOTf (entry 4) was inadequate
in terms of yield (43%) and enantioselectivity (35%). Al-
though it can accelerate copper(II)-catalyzed Mukaiyama-
type aldol reactions,[16c] the competing role of the racemic
catalyst TMSOTf most probably decreased the enantioselec-
tivity. In none of the reactions an improved catalyst turn-
over was noticed. In contrast, a dramatic rate accelerating
effect was observed when BF3·Et2O was added, and full con-
version was reached in less than 45 min with g-butenolide
5a being isolated in 73% yield, and very good stereoselec-
tivities of 98% de and 91% ee (entry 5). Because TFE gave
the best results with respect to yield and ee, the subsequent
experiments were carried out with this additive.
Scheme 2. Highly enantio- and diastereoselective VMAR catalyzed by an
aminosulfoximine copper complex.
Here, we wish to summarize all results, present an over-
view on the optimization process and reveal the full scope
of the reaction. Furthermore, we will show that by structural
modifications of the aminosulfoximines 4 and careful selec-
tion of the optimal ligand in various reactions the yields and
stereoselectivities can be increased.
Results and Discussion
2-(Trimethylsilyloxy)furan (TMSOF, 2a) and its pyrrole-
and thiophene-based analogues are conformationally con-
strained cyclic enolates, that can act as vinylogous nucleo-
philes.[12] The stereoselective synthesis of the resulting g-bu-
tenolides 5 by means of VMAR is of great interest because
hydroxyl-bearing butenolides are important building
blocks[13] and common scaffolds in many natural products or
biologically active compounds.[14] Unlike the use of alde-
hydes, which has been thoroughly investigated,[15] the appli-
cation of ketonic substrates as electrophiles in VMAR has
been less explored, and the few examples involve pyruvates
as activated ketones.[15b,16] Apparently, various factors such
as the lower reactivity of the ketones compared with the al-
dehydes and the more challenging differentiation between
the diastereotopic faces of the former in combination with a
competing retro-aldol reaction of the resulting tertiary alco-
Table 1. Effect of additives on the test reaction to give g-butenolide 5a.
Entry
Additive[a]
Yield [%]
de [%][b]
ee [%][c]
1
2
3
4
5
none
83
78
88
43
73
94
94
94
96
98
83
93
95
35
91
1.2 equiv HFIP
1.2 equiv TFE
1.0 equiv TMSOTf
1.0 equiv BF3·Et2O
[a] Reaction conditions: 2a (0.22 mmol), 3a (0.2 mmol), CuACHTUNGTRENNUNG(OTf)2
(10 mol%), aminosulfoximine (S)-4aA (10 mol%), additive (0.20 or
0.24 mmol), dry Et2O (2 mL), RT. [b] Determined by 1H NMR analysis
of the crude reaction mixture, de refers to anti/syn ratio. [c] Determined
by CSP-HPLC for the anti (=major) diastereomer.
4578
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4577 – 4587

Copper-Catalyzed Asymmetric Aldol Reactions
FULL PAPER
Next, the effect of the solvent was explored; Table 2 sum-
marizes the results. When the test reaction was carried out
in dichloromethane or chloroform (Table 2, entries 1 and 2)
product 5a was isolated in slightly improved yields (89 and
91%, respectively) and almost unaffected diastereoselectivi-
ties (94 and 96% de, respectively), the enantioselectivities
were considerably lower (79 and 75% ee, respectively). Tol-
uene proved superior to chlorinated solvents and its use af-
forded 5a in very good yield (91%) with good stereoselec-
tivities (85% ee and 96% de, entry 3). To our surprise, the
yields and enantioselectivities varied significantly in the
group of ethereal solvents. Thus, when the reaction was con-
ducted in THF or 1,4-dioxane (compare entries 4 and 5 vs.
6) instead of diethyl ether the diastereoselectivity remained
unchanged, but the yields were slightly lower (83 and 75%,
respectively). Furthermore, the ee of g-butenolide 5a was
drastically reduced in both solvents (52% ee in THF and
74% ee in 1,4-dioxane). Aprotic or protic polar solvents
such as acetonitrile or methanol proved to be unsuitable for
this reaction (entries 7 and 8). In the case of acetonitrile, 5a
was obtained in only 5% yield with low stereoselectivities
(50% de and 10% ee), and use of methanol gave only traces
of the product. In contrast, 5a was isolated in 89% yield
when the fluorinated alcohol TFE was used as solvent
(Table 2, entry 9).[18] This result compared well with the one
obtained with TFE as additive, but unfortunately, the stereo-
selectivities (83% de and 45% ee) were significantly lower
here.
Use of ZnACHTGNUTRENNU(G OTf)2 and BiACTHUNGTREN(NUNG OTf)3 gave 5a in good yields
(Table 3, entries 3 and 7), but the enantioselectivities were
low (47 and 33% ee, respectively). Additionally, the reac-
tions were less diastereoselective. SnACHTUNTGRENNUG(OTf)2, MgACHTUNTGNER(NUGN OTf)2 and
Sc(OTf)3 were found to be unsuitable affording only race-
AHCTUNGTRENNUNG
mic 5a, albeit in moderate to good yields of 54–78% and
diastereoselectivities of 73–90% (Table 3, entries 2, 4 and
6).
Table 3. Screening of metal source, catalyst loading and temperature ef-
fects in the formation of g-butenolide 5a.[a]
Entry
M
G
T
Yield
[%]
de
ee
[%][b]
[%][c]
1
2
3
4
5
6
7
8
Fe
Sn
Zn
Mg
Cu(OTf)2 10
(OTf)3 10
(OTf)3 10
G
RT
RT
RT
RT
RT
RT
RT
RT
RT
86
78
81
54
88
78
43
88
20
89
90
86
73
94
81
72
94
46
95
91
12
0
47
0
95
0
33
83
32
94
51
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
E
Sc
Bi
ACHTUNGTRENNUNG
A
Cu
Cu
Cu
Cu
U
5
1
9
10
11
ACHTUNGTRENNUNG
E
ꢀ688C 88
AHCTUNGTRENNUNG
808C[d] 97
[a] Reaction conditions: 2a (0.22 mmol), 3a (0.2 mmol),
MACHTUNGTRENNUNG(OTf)2
AHCTUNGERTG(NNUN x mol%), aminosulfoximine (S)-4aA (x mol%), TFE (0.24 mmol), dry
Et2O (2 mL), temperature. [b] and [c] as in Table 1. [d] The reaction was
carried out in THF under microwave irradiation.
Because CuACTHNUGRTENUNG(OTf)2 gave the best results (Table 3, entry 5),
a reduction of the catalyst loading was studied next. The re-
action still proceeded smoothly when the amount of Cu-
Table 2. Influence of the solvent in the VMAR between dienol silane 2a
and pyruvate 3a.
Entry
Solvent[a]
Yield [%]
de [%][b]
ee [%][c]
AHCTUNGRTEGNUN(N OTf)2 and (S)-4aA was reduced from 10 to 5 mol% giving
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
toluene
THF
1,4-dioxane
Et2O
CH3CN
CH3OH
TFE
89
91
91
83
75
88
5
94
96
96
94
94
94
50
n. d.
83
79
75
85
52
74
95
10
n. d.
45
g-butenolide 5a in unchanged yield and de but decreased ee
(entry 8 vs. 5). Further lowering of the catalyst loading to
1 mol% had a detrimental effect and even after 24 h the
conversion was still incomplete. At that stage, the yield of
5a was only 20% and the products had been formed with
significantly reduced stereoselectivities (46% de and 32%
ee, entry 9).
traces
89
Varying the temperature did not lead to improved results
(Table 3, entry 10). Thus, VMAR product 5a was obtained
in essentially the same yield and with identical stereoselec-
tivity as at ambient temperature when the reaction was per-
formed at ꢀ688C, but the reaction time had to be prolonged
to 16 h for achieving full conversion. On the other hand,
when the reaction was carried out at 808C (in THF under
microwave irradiation) 5a was formed in excellent yield
(97%) after only 15 min (Table 3, entry 11). Whereas the de
of 5a was high (91%), its ee was only moderate (51%). Al-
though these results were not superior to the previous ones,
it is noteworthy that, to the best of our knowledge, this is
the first example of a microwave-accelerated stereoselective
Mukaiyama-type aldol reaction.[19]
[a] Reaction conditions: 2a (0.22 mmol), 3a (0.2 mmol), CuACTHNUTRGNEUNG(OTf)2
(10 mol%), aminosulfoximine (S)-4aA (10 mol%), TFE (0.24 mmol),
abs. or HPLC grade solvent (2 mL), RT. [b] and [c] as in Table 1.
In summary, weakly coordinating, nonpolar or aromatic
solvents such as toluene or diethyl ether were the best (en-
tries 3 and 6), and for the subsequent optimization diethyl
ether was selected as solvent.
Next, the effects of various metal triflates and variations
of other important parameters such as catalyst loading, tem-
perature and microwave irradiation on the reaction between
dienol silane 2a and electrophile 3a were investigated. Con-
sidering that the appropriate choice of the metal plays a cru-
cial role in catalysis, a test reaction was carried out with Fe-
A
Scope of the VMAR with Cu
ACHTUNGTRENNUNG
tion system being optimized to a CuAHCUTNGTRENNUNG
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4579

C. Bolm et al.
(S)-4aA ratio of 1:1 (10 mol% each) and TFE as additive
(1.2 equiv) in dry Et2O at ambient temperature, the sub-
strate scope was subsequently studied. In this screening, var-
ious ketonic electrophiles 3 or 6 and cyclic dienol silanes 2
(1.1 equiv) were applied. The findings are collected in
Table 4.
influence on the stereoselectivities (94–96% de and 95–98%
ee), but the yields for products 5n and 5o, bearing isopropyl
and benzyl substituents, respectively, were slightly lower
than for methyl ester 5a and ethyl ester 5 f (compare
Table 4, entries 1, 6, 14 and 15).
On the contrary, the ketonic substitution pattern played a
decisive role. For example, a trifluoromethyl group in the
ketoester proved not suitable (entries 3 and 9). Although
products 5c and 5i were obtained in good yields (75 and
88%, respectively) and high diastereoselectivities (92 and
83%, respectively), the major isomers of 5c and 5i were
almost racemic (4% ee for both). Unfortunately, the enan-
tioselectivity could not be raised by decreasing the reaction
temperature to 0 or even to ꢀ308C. Since the spatial
demand of a trifluoromethyl group corresponds approxi-
mately to those of an isopropyl or a tert-butyl group we
wondered whether the ee was low due to steric reasons.
However, as entries 7 and 8 indicate this was not the case.
Thus, g-butenolide 5g, stemming from 3-methyl-2-oxobuty-
rate (3g) and TMSOF (2a) was not only isolated in nearly
quantitative yield but also with 99% de and 99% ee
(entry 7). Roughly the same result was obtained for ethyl
3,3-dimethyl-2-oxobutyrate (3h) which gave VMAR product
5h with a tert-butyl substituent in 99% de and 99% ee
(entry 8). While the yield of 5h was rather low (16%), and
a considerable amount of undesired furan-2(5H)-one was
detected in the initial reaction at room temperature, it could
significantly be raised to 66% by performing the catalysis at
ꢀ208C. Also other experiments with ketoester 3c indicated
that not steric but electronic effects caused the low ee of
product 5c. Thus, in the absence of the copper–sulfoximine
complex the electron-withdrawing CF3 substituent of 3,3,3-
trifluoropyruvate (3c) sufficiently activated the keto func-
tionality to react with TMSOF (2a) and to generate racemic
5c.
In reactions with phenylpyruvic acid methyl ester (3e)
and TMSOF (2a) the resulting g-butenolide 5e was ob-
tained with high stereoselectivities (92% de and 93% ee),
but in only 20% yield (Table 4, entry 5). Like in the synthe-
sis of 5h a significant amount of furan-2(5H)-one was ob-
served in this catalysis which led to the hypothesis that
products with tert-butyl or benzyl substituents at the newly
generated stereogenic center had a high tendency to under-
go retro-aldol reactions (entries 5 and 8). Apparently, in the
reactions of TMSOF (2a) with other electrophiles (Table 4,
entries 10–12) retro-aldolization was less favorable, and the
resulting VMAR products could be isolated in high yields
(up to 96%) and with excellent diastereo- and enantioselec-
tivities (up to 99% de and 98% ee).
Table 4. Substrate scope in the VMAR between dienol silanes 2 and
electrophiles 3 or 6 to afford products 5 or 7, respectively.
Entry Dienol Electro- Product[a] Yield [%][b] de [%][c] ee [%][d]
silane
phile
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
5a
5b
5c
5d
5e
5 f
5g
5h
5i
88
79
75
99
20
92
99
66
88
95
96
91
91
84
84
38
52
46
87
87
94 (94)
98 (99)
92 (99)
94 (99)
92 (92)
96 (96)
99 (99)
99 (99)
83 (99)
96 (99)
85 (99)
99 (99)
–
95/n.d.
97/n.d.
4/3
97/70
93/n.d.
96/n.d.
99/n.d.
99/n.d.
4/4
98/n.d.
91/95
98/n.d.
28
98/n.d.
95/n.d.
8[e]
9
10
11
12
13
14
15
16
17[g]
18[e]
19[e]
20
3j
3k
3l
5j
5k
5l
3m
3n
3o
3d
3a
3a
3a
6
5m
5n
5o
5p
5q
5r
5s
7
94 (99)
96 (96)
16 (99)[f] 92/50
7 (7)
82/80
98/76
76/79
94/n.d.
91 (91)
90 (90)
99 (99)
[a] Reaction conditions:
2
(0.22 mmol),
3
(0.2 mmol), CuACHTNGUTERNNU(G OTf)2
(10 mol%), (S)-4aA (10 mol%), TFE (0.24 mmol), Et2O (2 mL), RT, 2–
6 h. [b] Yield of all stereoisomers after column chromatography. [c] De-
termined by 1H NMR analysis of the crude reaction mixture; in parenthe-
ses, de (referring to the anti/syn ratio) of the product after column chro-
matography. [d] Determined by CSP-HPLC; given for anti and syn iso-
mers. [e] Reaction conditions as in [a] but at ꢀ208C, overnight. [f] Dia-
stereomers were separated by preparative HPLC. [g] Reaction conditions
as in [a] but at ꢀ158C, overnight.
Subsequently, ketodiester 3m and pyruvic aldehyde di-
methyl acetal (6) were tested as electrophiles (Table 4, en-
tries 13 and 20). Although the reaction of 3m with dienol
silane 2a gave g-butenolide 5m in high yield (91%), the ee
was low (28%). Presumably, the asymmetric catalysis be-
tween activated ketodiester 3m and 2a could not compete
with an uncatalyzed background reaction leading to racemic
product. To our delight, ketone 6 with the adjacent masked
As can be deduced from the summarized data, most sub-
strates reacted well and the VMAR products were obtained
in excellent yields and stereoselectivities. In many cases the
major diastereomer could be isolated by chromatographic
techniques. Products from a-substitution were never detect-
ed. The steric demand of the ester group had only a minor
4580
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4577 – 4587

Copper-Catalyzed Asymmetric Aldol Reactions
FULL PAPER
aldehyde functionality reacted well with 2a, and product 7
was isolated in very good yield (87%) and excellent stereo-
selectivities (99% de and 94% ee).
lines 10 were isolated in up to 85% yield. Again, sulfox-
AHCTUNGTRENNUNG
imine 9d with R2 =tBu proved most problematic in this
step, and along with the desired 10d (22% yield) 2-aminoa-
niline, diphenyl disulfide and the ethyl ester of benzenesul-
finic acid were isolated as by-products. The direct reductive
amination of a broad range of aldehydes with anilines 10
under mild conditions with NaBH3CN gave aminosulfoxi-
mines 4 in high yields up to 92%.
Finally, our attention was directed to the variation of nu-
cleophiles 2. Replacing TMSOF (2a) with cyclic silyl dienol
ether 2b gave rise to a,b-unsaturated ketone 5p in moderate
yield (38%). While the diastereoselectivity was low (16%
de),[20] the ee of the major diastereomer (92%) was high
(Table 4, entry 16). Also replacing oxygen by sulfur and uti-
lizing 2-(trimethylsilyloxy)thiophene (TMSOT, 2c) as nucle-
ophile had a major influence on the catalysis (entry 17).
While only traces of 5q were isolated at room temperature,
the yield was significantly increased to 52% at ꢀ158C.
Albeit the reaction proceeded with low diastereoselectivity
(7% de), the ee of both diastereomers was good (82 and
80%, respectively). 1-(tert-Butoxycarbonyl)-2-(trimethylsilyl-
ACHTUNGTRENNUNGoxy)pyrrole (2d) could also be employed (entry 18). Again,
a reduced reaction temperature was needed to form VMAR
product 5r in an acceptable yield (46%). Then, however,
a,b-unsaturated lactam 5r was obtained with high diastereo-
(91%) and excellent enantioselectivity (98%). Due to the
rather low yield of 5r we hypothesized that the sterically de-
manding Boc group hampered the catalysis and, consequent-
ly, 1-methyl-2-(trimethylsilyloxy)pyrrole (2e, entry 19) was
tested. Indeed, the yield of the corresponding product 5s
almost doubled to 87% (compared to 46% for 5r). Howev-
er, while the change from Boc to methyl at the nitrogen had
no influence on the diastereoselectivity (90%), the ee of 5s
was lower (76%) than for Boc-containing 5r.
Scheme 4. Preparation of aminosulfoximines 4. a) 2-Iodonitrobenzene
(2.0 equiv), CuI (10 mol%), DMEDA (20 mol%), K2CO3 (2.5 equiv), tol-
uene, reflux, 16-24 h; 53–98%; b) Fe (4.5 equiv), AcOH (18 equiv),
EtOH/H2O, reflux, 4 h; 22–85%; c) aldehyde (1.0–2.5 equiv), NaBH3CN
(1.0 equiv), AcOH, MeOH, 08C to RT, 16 h; 52–92%.
Additionally, aminosulfoximine (R)-4 fB could be ob-
tained in very good yield (90%) by palladium-catalyzed
Suzuki coupling of (R)-4eB and phenylboronic acid, demon-
strating again the high versatility of this ligand class
(Scheme 5).
Structural variation of aminosulfoximines and their influ-
ence on the catalysis: Although most products shown in
Table 4 were formed with high stereoselectivities and isolat-
ed in good to excellent yields, some substrates were convert-
ed less efficiently and the resulting VMAR products could
only be obtained with yields, diastereo- or enantioselectivi-
ties below average. It was presumed that those results could
be improved by applying modified ligands with optimized
structures. In our previous work a straightforward synthesis
of the highly modular ligands 4 had been established.[10a,b]
This allowed to study the influence of the substitution pat-
tern of the 1,2-benzene linker and the N-benzyl group on
the stereoselectivity of the aldol reaction. Less attention was
paid to the variation of the alkyl or aryl moiety at the ste-
reogenic center. Consequently, it was decided to extend the
ligand portfolio by preparing new C1-symmetric aminosul-
foximines 4 with altered electronic or steric properties. For
their synthesis, the originally reported approach towards
aminosulfoximines 4 was modified, now using a CuI-cata-
lyzed N-arylation of enantiopure sulfoximines 8a–e[21] with
2-iodonitrobenzene and K2CO3 (instead of the more expen-
sive Cs2CO3) in the first step.[22] The resulting coupling prod-
ucts 9a–e (Scheme 4) were obtained in good to excellent
yields (53–98%). While arylated products 9a–c and e were
air-stable at room temperature, decomposition of 9d was ob-
served upon storage in air for 7–10 days. The reduction of
the nitro group proceeded well for most substrates, and ani-
Scheme 5. Palladium-catalyzed Suzuki coupling of (R)-4eB to afford (R)-
4 fB.
The 18 new C1-symmetric aminosulfoximines 4 (Table 5,
entries 3–20) were then tested in the synthesis of g-buteno-
lide 5a from TMSOF (2a) with methyl pyruvate (3a). As
reference points served the results obtained with sulfoxi-
mine (S)-4aA and known (S)-4aB[10a,b] (Table 5, entries 1
and 2). Apparently, the entire family of C1-symmetric ami-
nosulfoximines 4 was highly suitable and many compounds
were excellent ligands for the copper-catalyzed VMAR. As
long as the substitution pattern at the sulfoximine core re-
mained unchanged (Table 5, entries 1–11) the new com-
pounds compared well with the reference ligand (S)-4aA or
even outclassed it. Interestingly, mesitylene derivative (S)-
4aB was slightly better than (S)-4aA in terms of yield, dia-
stereo- and enantioselectivity (see entries 2 vs. 1). This was
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4581

C. Bolm et al.
unexpected because in the previously studied Mukaiyama
aldol reactions[10a,b] use of (S)-4aB gave the same enantiose-
lectivity but a lower yield than (S)-4aA. The new sulfox
imines (S)-4aC to (S)-4aK, which stemmed from aniline
10a and the corresponding aldehydes, formed 5a with excel-
lent stereoselectivities (de and ee up to 99%) in very good
yields (entries 3–11). The lowest ee (85%) was obtained in
the catalysis with 2-pyrrolyl derived sulfoximine (S)-4aJ
(entry 10).
selectivity could be improved by reducing the steric bulk of
the backbone of S-isobutyl sulfoximines and hence, use of
(S)-4cB and (S)-4cK afforded 5a with excellent de values
(98% for both) and yields (99 and 95%, respectively; see
entries 15 and 16).
Modifications on the S-aryl group also resulted in active
catalysts but did not lead to significant improvements. Thus,
from reactions with (R)-4eA, (R)-4eB and (R)-4 fB g-bute-
nolide 5a was isolated in very high yields and excellent ste-
reoselectivities (Table 5, entries 18–20).
AHCTUNGTRENNUNG
Since (R)-configured aminosulfoximines 4 (entries 18–20)
provide products with the opposite absolute configuration
both product enantiomers are accessible.
Table 5. Screening of aminosulfoximines 4 in the VMAR to give g-bute-
nolide 5a.[a]
Entry
Sulfoximine
Yield [%]
de [%][b]
ee [%][c]
The results from this ligand screening can be summarized
as follows: Most of the new aminosulfoximines 4 performed
well in the VMAR; three of them (Table 5, entries 3, 15 and
17) formed 5a in almost quantitative yield (99%), four (en-
tries 5–7 and 9) gave rise to a product with 99% de and one
sulfoximine (entry 11) led to almost enantiopure 5a (99%
ee).
1
2
3
4
5
6
7
8
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4aD
(S)-4aE
(S)-4aF
(S)-4aG
(S)-4aH
(S)-4aI
(S)-4aJ
(S)-4aK
(S)-4bA
(S)-4bB
(S)-4cA
(S)-4cB
(S)-4cK
(S)-4dB
(R)-4eA
(R)-4eB
(R)-4 fB
88
89
99
83
83
86
81
86
89
83
80
86
81
91
99
95
99
98
97
97
94
98
98
98
99
99
99
98
99
98
92
90
95
90
98
98
96
94
97
98
95
97
96
95
97
96
97
95
97
85
99
66
84
95
96
97
8
9
10
11
12
13
14
15
16
17
18
19
20
Fine adjustments for single substrates: Two screening strat-
egies had been followed up to this stage: First, a catalyst
bearing sulfoximine (S)-4aA as ligand had been tested in re-
actions of a variety of substrate combinations (enol ethers
and ketoesters), and second, various sulfoximine ligands had
been screened on their applicability in the catalyzed reac-
tion between TMSOF (2a) with methyl pyruvate (3a). In
many cases, the products were obtained with very high ste-
reoselectivities in excellent yields, but nevertheless, a few
substrate combinations remained problematic and did not
lead to satisfying results. It was therefore decided to focus
on an additional fine-adjustment between the catalyst
(ligand) structure and substrates. For this new optimization
(Table 6) sulfoximines (S)-4aB, (S)-4aC and (S)-4cB were
taken into consideration because before they had performed
in a well-balanced manner in terms of yields and stereose-
lectivities. The results from the catalyses with ligand (S)-
4aA were taken as reference.
Compared to the catalysis with (S)-4aA as ligand, the
yield (29%) and the diastereoselectivity (52%) in the for-
mation of g-butenolide 5c, obtained from 3,3,3-trifluoropyr-
uvate (3c) and TMSOF (2a), dropped significantly when
(S)-4aC was used (Table 6, entries 1 and 2). However, a
minor increase in the ee from 4 to 11% was observed. For
VMAR product 5e the yield remained very low (13%) in
the catalysis with (S)-4aB but an improvement of the de
(95%) with unchanged enantioselectivity was observed (see
entries 4 and 3). Employing ligands (S)-4aB, (S)-4aC and
(S)-4cB gave g-butenolide 5 f with excellent diastereo- and
enantioselectivities (each of them 99% de and 97–99% ee),
but the yields (79–85%) were slightly reduced (Table 6, en-
tries 6–8 vs. 5). The de of product 5k, stemming from 4-ni-
trophenylglyoxylate (3k) and TMSOF (2a), was only mod-
erate (85%) in the catalysis with the standard ligand (S)-
4aA (entry 9), but to our delight all three aminosulfoxi-
mines (S)-4aB, (S)-4aC and (S)-4cB led to significant im-
ꢀ92
ꢀ95
ꢀ96
[a] Reaction conditions: 2a (0.22 mmol), 3a (0.2 mmol), Cu
(10 mol%), aminosulfoximine (10 mol%), TFE (0.24 mmol), Et2O
(2 mL), RT. [b] and [c] as in Table 1.
ACHTUNGERTN(NUNG OTf)2
4
Next, the influence of the alkyl part of the sulfoximine
fragment was investigated. Increasing the steric bulk from
methyl [as in (S)-4aA] to isopropyl [as in (S)-4bA] resulted
in a product with reduced de (90%) and a significant loss of
enantioselectivity (66% ee; Table 5, entries 12 vs. 1). On the
other hand, when the benzylic part of the ligand was smaller
(having a 2,4,6-Me3Ph instead of a 2,4,6-iPr3Ph group), the
change from methyl to isopropyl at the stereogenic center
was beneficial for both diastereo- and enantioselectivity (see
entries 13 vs. 12). This result indicated a strong interaction
between the steric environment of the stereogenic center
and the backbone. A further increase in size of the alkyl
substituent to a tert-butyl group [(S)-4dB] resulted in almost
racemic 5a (8% ee), albeit the yield (99%) and the de
(96%) were excellent (entry 17). Previously, we had found
very high ee values and yields in catalyses with P,N-sulfoxi-
mines having a branching at the b-position of the alkyl
group,[23] and hence we expected the same positive effect for
similar aminosulfoximines 4. Indeed, when S-isobutyl sulfox-
imine (S)-4cA was utilized, product 5a was obtained with
increased yield (91%) and very high ee (95%), but unfortu-
nately, the de (90%) was low (entry 14). To our delight this
4582
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4577 – 4587

Copper-Catalyzed Asymmetric Aldol Reactions
FULL PAPER
Table 6. Sulfoximine-based optimization of selected VMAR products.
relevant in the synthesis of 5r (entries 24–26), it was impor-
tant for analogous product 5s (entries 27–30). Use of (S)-
4aB and (S)-4cB as ligands led to 5s with considerably in-
creased yields (98 and 97%, respectively) and higher enan-
tioselectivities (89 and 90%) at the cost of reduced de
values (80 and 78%; see entries 28 and 30 vs. 27). For prod-
uct 7 we aimed at increasing either yield or ee [an excellent
de of 99% was already obtained in the catalysis with (S)-
4aA; entry 31] and pleasingly we noticed that use of (S)-
4aC rose the yield (95%) with almost unaffected ee (92%,
entry 33). These reactions also indicated that a small sub-
stituent at the sulfoximine core (methyl rather than the
more bulky isobutyl) was essential for high enantioselectivi-
ties (entries 31–33 vs. 34). On the other hand the diastereo-
selectivities were not altered by the sulfoximine ligands.
In order to demonstrate potential conversions of the new
products 5 and considering that butyrolactones are common
structural motifs in natural products, g-butenolide 5g was
hydrogenated to give g-lactone 11 (Scheme 6). As expected,
the reaction proceeded smoothly, affording the reduced
product with excellent ee (99%) in very high yield (97%).[24]
Entry
Sulfoximine
Product[a]
Yield [%][b]
de [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
(S)-4aA
(S)-4aC
(S)-4aA
(S)-4aB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
(S)-4aA
(S)-4aB
(S)-4aC
(S)-4cB
5c
5c
5e
5e
5 f
5 f
5 f
5 f
5k
5k
5k
5k
5m
5m
5m
5m
5p
5p
5p
5q
5q
5q
5q
5r
5r
5r
5s
5s
5s
5s
7
75
29
20
13
92
85
79
85
96
89
95
96
91
82
63
84
38
17
19
52
47
21
19
46
42
52
87
98
67
97
87
57
95
87
92 (99)
52 (99)
92 (92)
95 (95)
96 (96)
99 (99)
99 (99)
99 (99)
85 (99)
95 (99)
98 (99)
94 (99)
–
4/3
11/n.d.
93/n.d.
93/n.d.
96/n.d.
98/n.d.
99/n.d.
97/n.d.
91/95
94/n.d.
92/n.d.
94/n.d.
28
9
10
11
12
13
14
15
16
17
18
19
20[e]
21[e]
22[e]
23[e]
24[f]
25[f]
26[f]
27[f]
28[f]
29[f]
30[f]
31
32
33
34
–
–
–
30
9
26
16 (16)
66 (66)
69 (69)
7 (7)
7 (7)
5 (5)
13 (13)
91 (91)
88 (88)
90 (90)
90 (90)
80 (80)
77 (77)
78 (78)
99 (99)
99 (99)
99 (99)
99 (99)
92/50
94/59
95/74
82/80
87/86
90/89
83/82
98/76
96/63
97/76
76/79
89/86
75/83
90/89
94/n.d.
89/n.d.
92/n.d.
80/n.d.
Scheme 6. Hydrogenation of g-butenolide 5g to give butyrolactone 11.
7
7
7
Determination of the relative and absolute configuration:
Previously, the absolute configuration of 5g stemming from
catalyses with S-configured sulfoximine 4aA was determined
as (R,R).[11] This enantiomer resulted from a preferential
attack of the nucleophile from the Si face on the Re face of
the electrophile (Scheme 7, top). Assuming that the reaction
took place in the same manner as above, namely from the
same sides of the reactants, a product with (S,R) configura-
tion was expected for 5p (Scheme 7, bottom).
[a] Reaction conditions: Dienol silane
2 (0.22 mmol), electrophile 3
(0.2 mmol), Cu(OTf)2 (10 mol%), aminosulfoximine 4 (10 mol%), TFE
ACHTUNGTRENNUNG
(0.24 mmol), Et2O (2 mL), RT, 2–6 h. [b], [c] and [d] as in Table 4.
[e] Reaction conditions as in [a] but at ꢀ158C, overnight. [f] Reaction
conditions as in [a] but at ꢀ208C, overnight.
provements (94–98% de, entries 10–12). Moreover, in all
three cases the ee was raised from 91 to 92–94%. Unfortu-
nately, this effect did not occur in the synthesis of 5m,
where (S)-4aA remained the ligand of choice (Table 6,
entry 13–16). The aminosulfoximine structure had a dramat-
ic impact in the optimization of the approach towards a,b-
unsaturated ketone 5p (entries 17–19). While only a low de
of 16% was reached with the reference ligand (S)-4aA, it
rose to 66 and 69% de, respectively, when (S)-4aB and (S)-
4cB were applied. It is noteworthy that while the ee of the
major diastereomer increased only slightly (94–95%) that of
the minor diastereomer reached up to 74%. Unfortunately,
this improvement in stereoselectivity was accompanied with
a drop in yield, which was reduced to 17–19% compared to
38% in the catalysis with (S)-4aA. Yield and de of VMAR
product 5q, derived from TMSOT (2c) and methyl pyruvate
(3a), remained problematic and could not be improved by
using (S)-4aB, (S)-4aC and (S)-4cB. However, these ligands
resulted in higher ee values for 5q with up to 90% (en-
tries 21–23 vs. 20). While the choice of the ligand was less
In order to validate this hypothesis the relative and abso-
lute configuration of 5p was determined by means of differ-
ent techniques.
Scheme 7. Simplified stereochemical models.
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4583

C. Bolm et al.
The relative stereochemistry[25] of 5p was shown by X-ray
single crystal structure analysis to be anti (Figure 1).
sition of the CD curves of the single conformers. The Boltzmann factors
(298 K) were calculated using the MP2/6-31+G** relative energies ob-
tained including the solvent (Table 7). The experimental and averaged
calculated[34] CD spectra are presented in Figure 2a and b, respectively.
The calculated CD spectrum has a positive Cotton effect of relatively
low intensity around 278 nm followed by a much stronger negative one at
around 234 nm. The first calculated Cotton effect is due to transitions
from a molecular orbital of p symmetry widely located on the phenyl
ring with small s and n contributions to a p* orbital located on the C=C-
C=O system of the non-aromatic six-membered ring. This band was as-
signed to the negative Cotton effect observed at 237 nm. The second cal-
culated Cotton effect is negative and we correlate it with the strongly
positive band observed at about 217 nm. The main contributions to this
band come from s+n ! p* transitions from HOMOꢀ4 to LUMO and
from p+n ! p* transitions from HOMOꢀ3 to LUMO. Compared to
their experimental counterparts the Cotton effects are shifted to the red.
The calculated CD spectrum of the (R,S)-enantiomer of 5p closely re-
sembles the mirror image of the measured spectrum. Therefore, we con-
clude that the absolute configuration of anti-5p is very likely (S,R), a
result which is in agreement with our initial assignment.
Figure 1. Structure of 5p in the solid state.[26]
The absolute configuration (S,R) was determined by com-
parison of calculated and experimental CD spectra.
Computational Details
A Monte–Carlo conformational search using the AM1 Hamiltonian[28] as
implemented in Spartan ꢂ02[29] provided the 62 initial geometries for the
arbitrarily chosen (R,S)-enantiomer of anti-5p. Subsequent ab initio ge-
ometry optimizations were performed for isolated molecules in the gas
phase employing the program Gaussian 03.[30] Accordingly, a number of
14 stationary points were located within a range of 5 kcalmolꢀ1 at the
MP2/6-31+G** level. Additionally, single point energy calculations
taking into account the effect of the solvent (acetonitrile, e=36.64) were
performed at PCM/MP2/6-31+G**//MP2/6-31+G** level. The seven
most stable conformers lying within a range of 2.0 kcalmolꢀ1 (Table 7)
were then included in the calculation of the CD curve of anti-5p.
Table 7. Relative energies (in kcalmolꢀ1) of the seven most stable con-
formers of anti-5p in acetonitrile as solvent and the corresponding Boltz-
mann factors.
Entry Conformer
DE [kcalmolꢀ1], CH3CN PCM/MP2/6-
31+G**//MP2/6-31+G**
w[a]
(anti)
Figure 2. a) Experimental CD spectrum of anti-5p. b) Averaged calculat-
ed CD spectrum of (R,S)-5p.
1
2
3
4
5
6
7
anti-5p
0.000
0.491
1.233
1.328
1.702
1.904
1.918
0.554731
0.241962
0.069150
0.058863
0.031301
0.022253
0.021740
anti-5p-a
anti-5p-b
anti-5p-c
anti-5p-d
anti-5p-e
anti-5p-f
Conclusion
In this full account we describe an efficient vinylogous Mu-
kaiyama-type aldol reaction. The catalytic system which
[a] w is the Boltzmann factor calculated at 298 K.
consists of CuACTHNUTRGNE(UNG OTf)2 and a C1-symmetric aminosulfoximine
tolerates numerous electrophiles/nucleophiles combinations
and affords the corresponding products with high stereose-
lectivities in excellent yields. A detailed study of the varia-
tion of the ligand backbone revealed that the applied sulfox-
imines are highly modular and that they can perfectly be ad-
justed to substrate requirements. The relative and absolute
configuration of two products was assigned by combined ex-
perimental and theoretical means.
Theoretical CD spectra for each of the seven conformers were obtained
using the time-dependent density functional theory (TDDFT)[31] employ-
ing the B3LYP functional[32] and a valence double zeta basis set, including
polarization as well as diffuse functions (6-31+G**). The rotational
strengths were calculated using the origin-independent dipole-velocity
formalism.[33] The solvent effect on the rotational strengths was also ac-
counted for by employing the Polarizable Continuum Model (PCM). The
calculated CD spectrum was obtained as a Boltzmann-weighted superpo-
4584
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4577 – 4587

Copper-Catalyzed Asymmetric Aldol Reactions
FULL PAPER
pressure gave the crude product, which was purified by flash column
chromatography.
Experimental Section
(S)-N-(2-Aminophenyl)-S-isopropyl-S-phenylsulfoximine [(S)-10b]: Pre-
pared from nitrosulfoximine (S)-9b (5.71 mmol). The product was puri-
fied by flash column chromatography (pentane/EtOAc=1:2) to give the
title compound. Yield: 70% (beige solid); m.p. 117–1208C; optical rota-
tion: [a]D =ꢀ14.4 (c=0.9 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
1.35 (d, J=6.8 Hz, 3H, CH3), 1.43 (d, J=6.8 Hz, 3H, CH3), 3.44 (sept.,
J=6.8 Hz, 1H, CH), 4.01 (brs, 2H, NH2), 6.44 (ddd, J=7.8 Hz, 5.8 Hz,
3.1 Hz, 1H, Ar-H), 6.68–6.71 (m, 2H, Ar-H), 6.84–6.89 (m, 1H, Ar-H),
7.46–7.61 (m, 3H, Ar-H), 7.82–7.87 (m, 2H, Ar-H); 13C NMR (75 MHz,
CDCl3): d=16.1 (CH3), 16.3 (CH3), 57.3 (CH), 114.7 (Ar-CH), 118.5 (Ar-
CH), 121.6 (Ar-CH), 122.0 (Ar-CH), 129.3 (2 Ar-CH), 130.2 (2 Ar-CH),
132.0 (Ar-C), 133.1 (Ar-CH), 135.5 (Ar-C), 140.5 (Ar-C); IR (KBr): n˜ =
3424 (s), 3336 (s), 1606 (s), 1497 (s), 1445 (m), 1342 (w), 1290 (s), 1248
(s), 1176 (s), 1093 (s), 1040 (m), 1012 (s), 757 (s), 690 (m), 566 (s); MS
(EI): m/z (%): 274 (55) [M]+, 213 (20), 182 (11), 137 (17), 125 (34), 107
(100), 78 (27); elemental analysis calcd (%) for C15H18N2OS: C 65.66, H
6.61, N 10.21; found C 65.69, H 6.65, N 10.18.
The analytical data for all other new compounds can be found in the
Supporting Information.
General procedure for the Cu-catalyzed VMAR: A dry Schlenk tube
under argon atmosphere was charged with CuACTHNURTGNENG(U OTf)2 (0.02 mmol,
0.1 equiv) and the aminosulfoximine (0.02 mmol, 0.1 equiv). Dry Et2O
(2.0 mL, 0.1m) was added and the green solution was stirred at RT for
30 min. Subsequently, 2,2,2-trifluoroethanol (0.24 mmol, 1.2 equiv), elec-
trophile 3 (0.2 mmol) and cyclic dienol silane 2 (0.22 mmol, 1.1 equiv)
were added and the Schlenk tube was sealed. After complete consump-
tion of starting material (2–6 h, TLC control), the solvent was evaporated
under reduced pressure, and the crude reaction mixture was analyzed by
1H NMR to determine the diastereomeric excess. Afterwards the product
was purified by flash column chromatography.
ACHTUNGTRENNUNG(R,R)-Methyl 2-hydroxy-2-(5-oxo-2,5-dihydrofuran-2-yl)butanoate (5b):
Prepared from methyl 2-oxo-butyrate (3b) and TMSOF (2a). The prod-
uct was purified by flash column chromatography (pentane/EtOAc 1:1)
to give the title compound as single diastereomer. Yield: 79% (light
yellow oil); de=98% (99% after chromatography); optical rotation:
[a]D =102.0 (c=1.8 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.92 (t,
J=7.4 Hz, 3H, CH3), 1.81–2.02 (m, 2H, CH2), 3.29 (brs, 1H, OH), 3.84
(s, 3H, CH3), 5.15 (dd, J=2.1 Hz, 1.6 Hz, 1H, CH), 6.21 (dd, J=5.8 Hz,
2.1 Hz, 1H, CH), 7.34 (dd, J=5.8 Hz, 1.6 Hz, 1H, CH); 13C NMR
(75 MHz, CDCl3): d=7.5 (CH3), 28.2 (CH2), 53.3 (CH3), 78.5 (C), 85.8
(CH), 123.3 (CH), 152.1 (CH), 172.3 (C), 173.1 (C); IR (CHCl3): n˜ =3485
(m), 3099 (w), 2961 (m), 2883 (w), 1754 (s), 1665 (m), 1602 (w), 1448
(m), 1309 (w), 1246 (s), 1162 (s), 1098 (m), 1052 (w), 1035 (w), 1012 (w),
892 (m), 845 (m), 812 (m), 757 (m), 693 (w); MS (EI): m/z (%): 141 (11)
[MꢀC2H3O2]+, 117 (23), 84 (55), 57 (100), 55 (11); HRMS: m/z: calcd
for C7H9O3: 141.0552, found 141.0550 [MꢀC2H3O2]+; HPLC: tR =
13.6 min [minor], tR =15.4 min [major] (Chiralpak AD column, flow rate
1.0 mLminꢀ1, heptane/iPrOH 90:10, l=210 nm, 208C); ee=97%.
General procedure for the N-arylation of sulfoximines:[22] A dry large
Schlenk tube under argon atmosphere was charged with sulfoximine 8, 2-
iodonitrobenzene (2.0 equiv), K2CO3 (2.5 equiv), CuI (0.1 equiv) and tol-
uene (0.5m). After addition of DMEDA (0.2 equiv) the Schlenk tube was
sealed with a stopper and heated to reflux for 16–20 h. The reaction mix-
ture was cooled to RT, diluted with CH2Cl2 and treated with aqueous
HCl (2.0m). After extracting the aqueous layer with CH2Cl2 (three times)
the combined organic extracts were dried over MgSO4. Filtration and
evaporation of the solvent under reduced pressure gave the crude prod-
uct, which was purified by flash column chromatography.
General procedure for the reductive amination with NaBH3CN:[10a,b]
A
round-bottom flask was charged with aniline 10 in MeOH (0.1–0.5m).
The corresponding aldehyde was added (1.0–2.5 equiv) and the reaction
mixture was cooled to 08C. After addition of NaBH3CN (1.0 equiv) and
3–6 drops of glacial acetic acid the reaction mixture was stirred at RT for
16–20 h. The reaction mixture was quenched with 10% aqueous K2CO3
and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2
(three times) and the combined organic extracts were dried over MgSO4.
Filtration and evaporation of the solvent under reduced pressure gave
the crude product, which was purified by flash column chromatography.
Caution: After column chromatography most of the aminosulfoximines 4
are obtained as oils, which suddenly solidify with strong foaming on the
rotary evaporator or at high vacuum.
(S)-N-[2-(9-Anthracenylmethyl)aminophenyl]-S-methyl-S-phenylsulfoxi-
mine [(S)-4aD)]: Prepared from aniline (S)-10a (0.50 mmol) and anthra-
cene-9-carboxaldehyde (1.00 mmol, 2.00 equiv). The product was purified
by flash column chromatography (pentane/EtOAc 4:1) to afford an in-
separable mixture of the product and the corresponding alcohol. A
second flash column chromatography (CH2Cl2/EtOAc 20:1) of the crude
product yielded the pure title compound. Yield: 68% (yellow solid); m.p.
144–1468C; optical rotation: [a]D =ꢀ161.7 (c=1.5 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=2.92 (s, 3H, CH3), 4.91 (brs, 1H, NH), 5.17 (d,
J=11.9 Hz, 1H, CHH), 5.25 (d, J=11.9 Hz, 1H, CHH), 6.54 (ddd, J=
7.8 Hz, 6.7 Hz, 2.3 Hz, 1H, Ar-H), 6.95–7.06 (m, 3H, Ar-H), 7.29–7.36
(m, 2H, Ar-H), 7.45–7.61 (m, 5H, Ar-H), 7.68 (dt, J=8.5 Hz, 1.6 Hz, 2H,
Ar-H), 8.07 (dd, J=8.6 Hz, 1.1 Hz, 2H, Ar-H), 8.38 (d, J=8.9 Hz, 2H,
Ar-H), 8.51 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): d=41.2 (CH2),
45.8 (CH3), 109.8 (Ar-CH), 117.0 (Ar-CH), 121.3 (Ar-CH), 122.9 (Ar-
CH), 124.6 (2 Ar-CH), 125.1 (2 Ar-CH), 126.2 (2 Ar-CH), 127.6 (Ar-
CH), 128.3 (2 Ar-CH), 129.0 (2 Ar-CH), 129.3 (2 Ar-CH), 130.4 (Ar-C),
130.6 (2 Ar-C), 131.3 (Ar-C), 131.6 (2 Ar-C), 133.0 (Ar-CH), 139.2 (Ar-
C), 142.7 (Ar-C); IR (KBr): n˜ =3047 (m), 2362 (s), 2342 (m), 1650 (w),
1581 (s), 1501 (s), 1420 (s), 1326 (m), 1253 (s), 1188 (m), 1122 (m), 1092
(m), 1019 (s), 960 (m), 878 (m), 837 (m), 737 (s), 687 (s), 614 (m), 523
(s); MS (EI): m/z (%): 436 (20) [M]+, 296 (100), 295 (81), 246 (13), 191
(84), 140 (34), 125 (33), 119 (32), 97 (33), 77 (21); elemental analysis
calcd (%) for C28H24N2OS: C 77.03, H 5.54, N 6.42, found C 76.88, H
5.73, N 6.08.
(S)-N-(2-Nitrophenyl)-S-isopropyl-S-phenylsulfoximine [(S)-9b] Pre-
pared from (S)-S-isopropyl-S-phenylsulfoximine [(S)-8b, 6.33 mmol]. The
product was purified by flash column chromatography (pentane/EtOAc
4:1) to give the title compound. Yield: 93% (red-brown oil); optical rota-
tion: [a]D =ꢀ25.4 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
1.35 (d, J=6.8 Hz, 3H, CH3), 1.39 (d, J=6.8 Hz, 3H, CH3), 3.44 (sept.,
J=6.8 Hz, 1H, CH), 6.85 (ddd, J=8.2 Hz, 7.0 Hz, 1.6 Hz, 1H, Ar-H),
7.10–7.20 (m, 2H, Ar-H), 7.49–7.57 (m, 2H, Ar-H), 7.59–7.65 (m, 2H,
Ar-H), 7.91–7.97 (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=15.8
(CH3), 16.0 (CH3), 58.2 (CH), 120.3 (Ar-CH), 123.6 (Ar-CH), 124.4 (Ar-
CH), 129.4 (2 Ar-CH), 130.2 (2 Ar-CH), 132.4 (Ar-CH), 133.6 (Ar-CH),
134.7 (Ar-C), 139.9 (Ar-C), 144.6 (Ar-C); IR (neat): n˜ =1601 (s), 1521
(s), 1478 (s), 1447 (m), 1355 (s), 1287 (s), 1199 (s), 1164 (m), 1097 (s),
1041 (w), 1015 (s), 855 (m), 750 (s), 721 (s), 692 (m); MS (EI): m/z (%):
304 (27) [M]+, 227 (2), 181 (12), 125 (100), 77 (18); HRMS for
C15H16N2O3S: calcd for 304.0882, found 304.0882.
General procedure for the reduction of the nitro group:[10a,b] A round-
bottom flask was charged with nitrosulfoximine 9 and iron turnings
(4.5 equiv) in EtOH/H2O (2:1, 0.05m). After addition of glacial acetic
acid (18 equiv) the reaction mixture was heated to reflux for 4 h, then
cooled to RT and diluted with CH2Cl2. The aqueous layer was extracted
with CH2Cl2 (three times) and the combined organic extracts were dried
over MgSO4. Filtration and evaporation of the solvent under reduced
General procedure for the reductive amination with NaBH4:[10a,b]
A
round-bottom flask was charged with aniline 10 in MeOH (0.1m), the
corresponding aldehyde (1.2 equiv) and glacial acetic acid (1.0 equiv).
After stirring at RT for 3 h NaBH4 (2.5 equiv) was added in small por-
tions at 08C and the reaction mixture was stirred additional 16 h at RT.
For work-up see the protocol described for the reductive amination with
NaBH3CN.
(S)-N-[2-(2,4,6-Triisopropylbenzyl)aminophenyl]-S-isobutyl-S-phenylsul-
foximine [(S)-4cA]: Prepared from aniline (S)-10c (1.46 mmol) and
2,4,6-triisopropylbenzaldehyde (1.75 mmol, 1.20 equiv). The product was
purified by flash column chromatography (pentane/EtOAc 10:1) to
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4585

C. Bolm et al.
afford an inseparable mixture of the product and the corresponding alco-
hol. A second flash column chromatography (CH2Cl2) of the crude prod-
uct yielded the pure title compound. Yield: 66% (beige solid); m.p. 100–
1028C; optical rotation: [a]D =ꢀ115.7 (c=1.5 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=0.96 (d, J=6.7 Hz, 3H, CH3), 1.04 (d, J=6.7 Hz,
3H, CH3), 1.37–1.48 (m, 18H, 6 CH3), 2.24–2.44 (m, 1H, CH), 2.99–3.16
(m, 2H, CHH and CH), 3.27 (dd, J=14.1 Hz, 6.0 Hz, 1H, CHH), 3.40–
3.53 (m, 2H, 2 CH), 4.35 (d, J=11.4 Hz, 1H, CHH), 4.46 (d, J=11.3 Hz,
1H, CHH), 4.70 (brs, 1H, NH), 6.52 (t, J=7.4 Hz, 1H, Ar-H), 6.85 (d,
J=7.7 Hz, 1H, Ar-H), 6.93–7.07 (m, 2H, Ar-H), 7.22 (s, 2H, Ar-H),
7.48–7.56 (m, 2H, Ar-H), 7.56–7.63 (m, 1H, Ar-H), 7.91 (d, J=7.5 Hz,
2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=22.8 (CH3), 23.0 (CH3),
24.3 (CH3), 24.4 (CH3), 24.5 (CH), 25.0 (4 CH3), 29.6 (2 CH), 34.5 (CH),
40.9 (CH2), 65.8 (CH2), 109.4 (Ar-CH), 116.5 (Ar-CH), 120.8 (Ar-CH),
121.2 (2 Ar-CH), 122.5 (Ar-CH), 128.9 (2 Ar-CH), 129.5 (2 Ar-CH),
130.5 (Ar-C), 131.5 (Ar-C), 133.0 (Ar-CH), 139.0 (Ar-C), 142.6 (Ar-C),
148.1 (2 Ar-C), 148.2 (Ar-C); IR (CHCl3): n˜ =3398 (m), 3058 (m), 2961
(s), 2872 (s), 2362 (w), 2336 (w), 1587 (m), 1502 (s), 1426 (m), 1256 (s),
1182 (w), 1119 (m), 1018 (m), 750 (s), 688 (w), 543 (m); MS (EI): m/z
(%): 504 (74) [M]+, 307 (62), 288 (100), 217 (12), 201 (8), 182 (6), 126
(21), 78 (9); elemental analysis calcd (%) for C32H44N2OS: C 76.14, H
8.79, N 5.55, found C 75.69, H 8.74, N 5.56.
[7] For recent contributions to catalytic asymmetric VMAR, see: a) B.
Bazꢅn-Tejeda, G. Bluet, G. Broustal, J.-M. Campagne, Chem. Eur. J.
2006, 12, 8358–8366; b) S. E. Denmark, J. R. Heemstra, Jr., J. Am.
Chem. Soc. 2006, 128, 1038–1039; c) S. Simsek, M. Horzella, M. Ka-
lesse, Org. Lett. 2007, 9, 5637–5639; d) L. V. Heumann, G. E. Keck,
Org. Lett. 2007, 9, 4275–4278; e) G. Broustal, X. Ariza, J.-M. Cam-
pagne, J. Garcia, Y. Georges, A. Marinetti, R. Robiette, Eur. J. Org.
Chem. 2007, 26, 4293–4297. For the importance of enantioselective
VMAR in natural product syntheses, see: f) I. Paterson, A. D. Fin-
dlay, G. J. Florence, Tetrahedron 2007, 63, 5806–5819; g) S. Shiroka-
wa, M. Shinoyama, I. Ooi, S. Hosokawa, A. Nakazaki, S. Kobayashi,
Org. Lett. 2007, 9, 849–852; h) X. Jiang, B. Liu, S. Lebreton, J. K.
De Brabander, J. Am. Chem. Soc. 2007, 129, 6386–6387; i) S.
Simsek, M. Kalesse, Tetrahedron Lett. 2009, 50, 3485–3488.
[8] For overviews on the use of sulfoximines as ligands in asymmetric
catalysis, see: a) M. Harmata, Chemtracts 2003, 16, 660–666; b) H.
Okamura, C. Bolm, Chem. Lett. 2004, 33, 482–487; c) C. Bolm in
Asymmetric Synthesis with Chemical and Biological Methods (Eds.:
D. Enders, K.-E. Jaeger), Wiley-VCH, Weinheim, 2007, pp. 149–
175; d) H. Pellissier, Tetrahedron 2007, 63, 1297–1330; e) C. Worch,
A. C. Mayer, C. Bolm in Organosulfur Chemistry in Asymmetric
Synthesis (Eds.: T. Toru, C. Bolm), Wiley-VCH, Weinheim, 2008,
pp. 209–229.
[9] For selected recent examples, see: a) J. Sedelmeier, T. Hammerer,
C. Bolm, Org. Lett. 2008, 10, 917–920; b) S.-M. Lu, C. Bolm, Adv.
Synth. Catal. 2008, 350, 1101–1105; c) S.-M. Lu, C. Bolm, Chem.
Eur. J. 2008, 14, 7513–7516; d) M. Frings, C. Bolm, Eur. J. Org.
Chem. 2009, 4085–4090.
[10] a) M. Langner, C. Bolm, Angew. Chem. 2004, 116, 6110–6113;
Angew. Chem. Int. Ed. 2004, 43, 5984–5987; b) M. Langner, P.
Rꢆmy, C. Bolm, Chem. Eur. J. 2005, 11, 6254–6265; c) P. Rꢆmy, M.
Langner, C. Bolm, Org. Lett. 2006, 8, 1209–1211. For other applica-
tions of C1-symmetric aminosulfoximines, see: d) M. Langner, P.
Rꢆmy, C. Bolm, Synlett 2005, 781–784; e) ref. [9d].
Acknowledgements
The authors are grateful to the Fonds der Chemischen Industrie for fi-
nancial support. We also thank Dr. A. C. Mayer for the donation of Fe-
ACHTUNGTRENNUNG(OTf)2, and A. Lçdden and W. Fegler are kindly acknowledged for prep-
arative work.
[1] a) T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett. 1973, 2,
1011–1014; b) T. Mukaiyama, K. Banno, K. Narasaka, J. Am. Chem.
Soc. 1974, 96, 7503–7509.
[11] M. Frings, I. Atodiresei, J. Runsink, G. Raabe, C. Bolm, Chem. Eur.
J. 2009, 15, 1566–1569.
[12] For reviews on vinylogous aldol reactions with heterocyclic silyloxy
dienes, see: a) G. Rassu, G. Casiraghi, Synthesis 1995, 607–626;
b) G. Rassu, F. Zanardi, L. Battistini, G. Casiraghi, Synlett 1999,
1333–1350; c) G. Casiraghi, F. Zanardi, G. Rassu, Pure Appl. Chem.
2000, 72, 1645–1648; d) G. Rassu, F. Zanardi, L. Battistini, G. Casir-
aghi, Chem. Soc. Rev. 2000, 29, 109–118; e) G. Casiraghi, F. Zanardi,
L. Battistini, G. Rassu, Synlett 2009, 1525–1542.
[2] For general reviews, see: a) T. Bach, Angew. Chem. 1994, 106, 433–
435; Angew. Chem. Int. Ed. Engl. 1994, 33, 417–419; b) T. K. Hollis,
B. Bosnich, J. Am. Chem. Soc. 1995, 117, 4570–4581; c) H. Grçger,
E. M. Vogl, M. Shibasaki, Chem. Eur. J. 1998, 4, 1137–1141; d) S. G.
Nelson, Tetrahedron: Asymmetry 1998, 9, 357–389; e) E. M. Car-
reira in Comprehensive Asymmetric Catalysis, Vol. 3 (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, pp. 997–
1065; f) C. Palomo, M. Oiarbide, J. M. Garcꢃa, Chem. Eur. J. 2002, 8,
36–44; g) See also in H. Yamamoto, K. Futatsugi, Angew. Chem.
2005, 117, 1958–1977; Angew. Chem. Int. Ed. 2005, 44, 1924–1942.
[3] For a short overview of applications of aldol reactions in natural
product syntheses, see: a) A. K. Ghosh, M. Shevlin in Modern Aldol
Reactions, Vol. 1 (Ed.: R. Mahrwald), Wiley-VCH, Weinheim, 2004,
pp. 105–119; b) I. Shiina in Modern Aldol Reactions, Vol. 2 (Ed.: R.
Mahrwald), Wiley-VCH, Weinheim, 2004, pp. 105–166.
[13] M. Enomoto, S. Kuwahara, Angew. Chem. 2009, 121, 1164–1168;
Angew. Chem. Int. Ed. 2009, 48, 1144–1148.
[14] Styryllactones: a) C. Mukai, S. Hirai, I. J. Kim, M. Kido, M. Hanao-
ka, Tetrahedron 1996, 52, 6547–6560; b) D. Matsuura, K. Takabe, H.
Yoda, Tetrahedron Lett. 2006, 47, 1371–1374; muricatacin and ana-
logues: c) G. Rassu, L. Pinna, P. Spanu, F. Zanardi, L. Battistini, G.
Casiraghi, J. Org. Chem. 1997, 62, 4513–4517; d) M. Szlosek, X.
Franck, B. Figadꢇre, A. Cavꢆ, J. Org. Chem. 1998, 63, 5169–5172;
e) M. Pichon, J.-C. Jullian, B. Figadꢇre, A. Cavꢆ, Tetrahedron Lett.
[4] a) R. C. Fuson, Chem. Rev. 1935, 16, 1–27; b) S. Krishnamurthy, J.
Chem. Educ. 1982, 59, 543–547; c) P. Bruneau, P. J. Taylor, A. J. Wil-
kinson, J. Chem. Soc. Perkin Trans. 2 1996, 2263–2269.
1998, 39, 1755–1758; iso-cladospolide
B and analogues: f) X.
Franck, M. E. Vaz Araujo, J.-C. Jullian, R. Hocquemiller, B. Figa-
dꢇre, Tetrahedron Lett. 2001, 42, 2801–2803; g) T. Hjelmgaard, T.
Persson, T. B. Rasmussen, M. Givskovc, J. Nielsen, Bioorg. Med.
Chem. 2003, 11, 3261–3271; micrandilactones B and C: h) R.-T. Li,
Q.-B. Han, Y.-T. Zheng, R.-R. Wang, L.-M. Yang, Y. Lu, S.-Q. Sang,
Q.-T. Zheng, Q.-S. Zhao, H.-D. Sun, Chem. Commun. 2005, 2936–
2938; (ꢀ)-rasfonin: i) R. K. Boeckman, Jr., J. E. Pero, D. J. Boehm-
ler, J. Am. Chem. Soc. 2006, 128, 11032–11033; (+)-1-epi-castano-
spermine: j) R. Hunter, S. C. M. Rees-Jones, H. Su, Beilstein J. Org.
Chem. 2007, 3, 38; k) T.-J. Wu, P.-Q. Huang, Tetrahedron Lett. 2008,
49, 383–386; Sapinofuranone B: l) P. Kumar, S. V. Naidu, P. Gupta,
J. Org. Chem. 2005, 70, 2843–2846; Freelingyne: m) F. von der Ohe,
R. Brꢀckner, New J. Chem. 2000, 24, 659–669; (ꢀ)-gymnodimine:
n) K. Kong, D. Romo, C. Lee, Angew. Chem. 2009, 121, 7538–7541;
Angew. Chem. Int. Ed. 2009, 48, 7402–7405.
[5] For reviews on vinylogous aldol reactions, see: a) G. Casiraghi, F.
Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929–
1972; b) S. E. Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew.
Chem. 2005, 117, 4760–4777; Angew. Chem. Int. Ed. 2005, 44, 4682–
4698; c) M. Kalesse, Top. Curr. Chem. 2005, 244, 43–76; d) S. Hoso-
kawa, K. Tatsuta, Mini-Rev. Org. Chem. 2008, 5, 1–18; e) T. Brod-
mann, M. Lorenz, R. Schꢄckel, S. Simsek, M. Kalesse, Synlett 2009,
174–192.
[6] a) I. Fleming, T. V. Lee, Tetrahedron Lett. 1981, 22, 705–708; b) J.
Hassfeld, M. Christmann, M. Kalesse, Org. Lett. 2001, 3, 3561–3564;
c) D. M. Speare, S. M. Fleming, M. N. Beckett, J.-J. Li, T. D. H.
Bugg, Org. Biomol. Chem. 2004, 2, 2942–2950; d) S. E. Denmark,
J. R. Heemstra, Jr., J. Org. Chem. 2007, 72, 5668–5688; e) S. E. Den-
mark, M. Xie, J. Org. Chem. 2007, 72, 7050–7053.
4586
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4577 – 4587

Copper-Catalyzed Asymmetric Aldol Reactions
FULL PAPER
[15] a) C. S. Lꢈpez, R. ꢉlvarez, B. Vaz, O. N. Faza, A. R. de Lera, J. Org.
Chem. 2005, 70, 3654–3659; b) M. De Rosa, L. Citro, A. Soriente,
Tetrahedron Lett. 2006, 47, 8507–8510; c) L. Palombi, M. R. Acocel-
la, N. Celenta, A. Massa, R. Villano, A. Scettri, Tetrahedron: Asym-
metry 2006, 17, 3300–3303; d) J. Barluenga, H. Vꢅzquez-Villa, I.
Merino, A. Ballesteros, J. M. Gonzꢅlez, Chem. Eur. J. 2006, 12,
5790–5805; e) J. Boukouvalas, P. P. Beltrꢅn, N. Lachance, S. Cꢊtꢆ, F.
Maltais, M. Pouliot, Synlett 2007, 219–222; f) H. Nagao, Y. Yamane,
T. Mukaiyama, Chem. Lett. 2007, 36, 8–9; g) T. Ollevier, J.-E. Bou-
chard, V. Desyroy, J. Org. Chem. 2008, 73, 331–334; h) C. Curti, A.
Sartori, L. Battistini, G. Rassu, F. Zanardi, G. Casiraghi, Tetrahedron
Lett. 2009, 50, 3428–3431.
[16] a) C. W. Jefford, D. Jaggi, G. Bernardinelli, J. Boukouvalas, Tetrahe-
dron Lett. 1987, 28, 4041–4044; b) D. A. Evans, M. C. Kozlowski,
J. A. Murry, C. S. Burgey, K. R. Campos, B. T. Connell, Richard J.
Staples, J. Am. Chem. Soc. 1999, 121, 669–685; c) D. A. Evans, C. S.
Burgey, M. C. Kozlowski, S. W. Tregay, J. Am. Chem. Soc. 1999, 121,
686–699; d) S. Naito, M. Escobar, P. R. Kym, S. Liras, S. F. Martin,
J. Org. Chem. 2002, 67, 4200–4208; e) K. Kong, D. Romo, Org. Lett.
2006, 8, 2909–2912; f) F. Zanardi, C. Curti, A. Sartori, G. Rassu, A.
Roggio, L. Battistini, P. Burreddu, L. Pinna, G. Pelosi, G. Casiraghi,
Eur. J. Org. Chem. 2008, 2273–2287; g) C. Curti, A. Sartori, L. Bat-
tistini, G. Rassu, P. Burreddu, F. Zanardi, G. Casiraghi, J. Org.
Chem. 2008, 73, 5446–5451; h) M. J. Fabra, J. M. Fraile, C. I. Herre-
rꢃas, F. J. Lahoz, J. A. Mayoral, I. Pꢆrez, Chem. Commun. 2008,
5402–5404.
102.62(1)8. A volume of V=654.0(3 ꢌ3, a molecular weight of M=
260.29 gmolꢀ1, and Z=2 result in a density of 1calcd =1.322 gcmꢀ3. A
total number of 4985 reflections was collected at room temperature
(298 K) on an Eraf-Nonius CAD4 diffractometer employing graph-
ite-monochromated CuKa radiation (l=1.54179 ꢌ, m=0.787 mmꢀ1
,
no absorption correction) in the range ꢀ10 ꢁ h ꢁ 10, ꢀ10 ꢁ k ꢁ
10, ꢀ10 ꢁ l ꢁ 10 (qmax =68.028). The structure was solved using
direct methods as implemented in Xtal3.7 package of crystallograph-
ic routines, a) employing GENSIN, b) to generate structure-invari-
ant relationships and GENTAN, c) for the general tangent phasing
procedure. 2377 observed reflections (I> 2s(I), Rint =0.06) were in-
cluded in the final full-matrix leas-squares refinement of 172 param-
eters on F, converging at R(Rw)=0.067 (0.083, w=1/35.0s2(F)), a
goodness of fit of 1.289, and a residual electron density of ꢀ0.39/
0.25 eꢌꢀ3. The coordinates of the hydrogen atoms were calculated
for idealized positions and their Ueq were fixed at 1.5 times the
value for the corresponding heavy atom. No hydrogen parameters
were refined. CCDC-742721 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[27] a) XTAL3.7 System (Eds.: S. R. Hall, D. J. du Boulay, R. Olthof-Ha-
zekamp), University of Western Australia, Perth, 2000; b) V. Subra-
manian, S. R. Hall, GENSIN, XTAL3.7 System (Eds.: S. R. Hall,
D. J. du Boulay, R. Olthof-Hazekamp), University of Western Aus-
tralia, Perth, 2000; c) S. R. Hall, GENTAN, XTAL3.7 System (Eds.:
S. R. Hall, D. J. du Boulay, R. Olthof-Hazekamp), University of
Western Australia, Perth, 2000.
[28] M. J. S. Dewar, E. G. Zoebisch, E. F. Healy, J. J. P. Stewart, J. Am.
Chem. Soc. 1985, 107, 3902–3909.
[29] Spartan (Version ’02), Wavefunction, Inc. 18401 Von Karman Ave.,
Suite 370, Irvine, CA 92612 (USA).
[17] a) H. Kitajima, T. Katsuki, Synlett 1997, 568–570; b) D. A. Evans,
D. S. Johnson, Org. Lett. 1999, 1, 595–598; c) D. A. Evans, K. A.
Scheidt, J. N. Johnston, M. C. Willis, J. Am. Chem. Soc. 2001, 123,
4480–4491; d) Y. Yamashita, H. Ishitani, H. Shimizu, S. Kobayashi,
J. Am. Chem. Soc. 2002, 124, 3292–3302; e) S. Onitsuka, Y. Matsuo-
ka, R. Irie, T. Katsuki, Chem. Lett. 2003, 32, 974–975.
[18] The authors acknowledge Prof. Dr. M. Tilet, University of Oslo, for
highlighting the stabilizing effect of TFE on metal cations in his pre-
sentation at ISOC09 in Camerino on September 6, 2009.
[19] For a Mukaiyama-type Mannich reaction under microwave irradia-
tion, see: H. Hagiwara, D. Iijima, B. Z. S. Awen, T. Hoshi, T. Suzuki,
Synlett 2008, 1520–1522.
[30] Gaussian 03, Revision D.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
ery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004.
[20] Remarkably, an exceptionally high de of 83% was observed when
the racemate of 5p was prepared under microwave conditions with
DMEDA as ligand: CuACHTNUGTRNEUNG(OTf)2 (10 mol%), DMEDA (20 mol%),
TFE (1.2 equiv), THF, 558C, MW, 1.5 h.
[21] Here, the absolute configuration of 8e was unambiguously assigned
as (R) by debromination of 8e and comparison of the optical rota-
tion and CSP-HPLC elution order of the resulting 8a with those
data of independently prepared samples of rac- and (S)-8a; a) for
the synthesis of 8e see: G. Y. Cho, H. Okamura, C. Bolm, J. Org.
Chem. 2005, 70, 2346–2349; b) Correction: G. Y. Cho, H. Okamura,
C. Bolm, J. Org. Chem. 2010, 75, 522.
[22] J. Sedelmeier, C. Bolm, J. Org. Chem. 2005, 70, 6904–6906.
[23] C. Moessner, C. Bolm, Angew. Chem. 2005, 117, 7736–7739; Angew.
Chem. Int. Ed. 2005, 44, 7564–7567.
[31] R. Bauernschmitt, R. Ahlrichs, Chem. Phys. Lett. 1996, 256, 454–
464.
[24] X-ray crystal structure of 11 is included in the Supporting Informa-
tion.
[25] By X-ray crystal structure analysis the relative stereochemistry of
two further derivatives (5d and 5r) has been determined to be anti.
For details see Supporting Information.
[32] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789;
b) B. Miehlich, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 1989,
157, 200–206; c) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[33] A. Moscowitz in Modern Quantum Chemistry Vol. 3 (Ed.: O. Sina-
noglu) Academic Press, New York, 1965, pp. 31–44.
[26] X-ray structure determination of compound 5p: A colourless plate-
like crystal (ca. 0.5ꢋ0.5ꢋ0.2 mm) suitable for single crystal structure
determination was obtained from diethyl ether. The compound
(C15H16O4) crystallizes in monoclinic space group P21 (4) with cell
constants a=8.519(2), b=8.800(2), c=8.940(2) ꢌ, and b=
[34] The averaged calculated CD spectrum of 5p has been obtained as
previously described in the Supporting Information associated with
ref. [11].
Received: November 9, 2009
Published online: March 12, 2010
Chem. Eur. J. 2010, 16, 4577 – 4587
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4587