Geminal bis(sulfoximine)s: Synthesis and applications in asymmetric catalysis

Article abstract of DOI:10.1002/adsc.200404164

A number of C₂-symmetrical geminal bis-(sulfoximine)s have been prepared for the first time and used as ligands in boron-mediated reductions of acetophenone and copper complex-catalyzed 1,4-additions of diethylzinc to 2-cyclohexenone. The coppe

Full text of DOI:10.1002/adsc.200404164

FULL PAPERS
Geminal Bis(sulfoximine)s: Synthesis and Applications in
Asymmetric Catalysis
M. Reggelin,a,* H. Weinberger,b V. Spohra
a
Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Petersenstraße 22,
64287 Darmstadt, Germany
Fax: (þ49)-6151-16-5531, e-mail: re@punk.oc.chemie.tu-darmstadt.de
b
Baxter Oncology, Chemical Development, Daimlerstraße 40, 60314 Frankfurt/Main, Germany
Fax: (þ49)-69-9686-7919, e-mail: heinz_weinberger@baxter.com
Received: June 9, 2004; Accepted: July 29, 2004
Dedicated to Prof. J. Mulzer on the occasion of his 60th anniversary.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A number of C2-symmetrical geminal bis- Cu(OTf)2 a copper complex was isolated and charac-
(sulfoximine)s have been prepared for the first time terized by X-ray structural analysis. A mixture of
and used as ligands in boron-mediated reductions of SES-Cl and NaN3 in acetonitrile was found to behave
acetophenone and copper complex-catalyzed 1,4-ad- like SES-N3 in FeCl2-mediated iminations of sulfox-
ditions of diethylzinc to 2-cyclohexenone. The copper ides, affording the corresponding sulfoximines with
complex of bis(sulfoximine) 46 was found to be highly complete retention of the sulfur configuration.
active in this type of reaction, furnishing the addition
product in nearly quantitative yield even at À908C. Keywords: 1,4-addition; asymmetric catalysis; copper;
From the reaction of bis(sulfoximine) 42 with sulfoximines
Introduction
Since their discovery in the early 1950 s[1–5] sulfoximines
have developed to a powerful tool in organic synthesis.[6]
This is especially true for the chiral non-racemic mem-
bers of this uncommonly versatile class of compounds.
Early work focused on the development of asymmetric
alkylidene transfer reagents[7,8] and ketone resolutions
based on the reversible formation of b-hydroxysulfox-
imines.[9–11] More recently, titanated 2-alkenylsulfox-
imines have been developed to highly diastereoselective
allyl transfer reagents[12–17] and as tools for the synthesis
Figure 1. Sulfoximine-based ligands.
of a broad range of isomerically pure oxa-[18–21] and aza-
heterocycles.[22–27]
Nowadays sulfoximine chemistry is characterized by a tion as well as in Diels–Alder and hetero-Diels–Alder
transition from stoichiometric to catalytic applications. reactions.[29–32] The very interesting bis(benzothiazine)
This metamorphosis is reflected by an increasing num- ligand 2 was synthesized by Harmata[33] and performed
ber of publications describing the synthesis of sulfox- well again in the Pd-catalyzed asymmetric allylation
imine-based ligands as depicted in Figure 1.
(up to 86% ee). Common structural features of the bis-
Most of the work emanated and still emanates from (sulfoximine) ligands 2–4 are their C2-symmetry and the
the laboratories of Bolm. In 1996 he introduced the two-carbon bridge linking the two sulfoximine nitrogen
monosulfoximine 1 as a ligand in a Pd complex-cata- atoms. This structural motive resembles the bonding sit-
lyzed asymmetric allylation reaction affording the prod- uation in the successful salen-type ligands which obvi-
uct with up to 73% ee.[28] Later on he developed a num- ously was the initial motivation for the synthesis of li-
ber of C2-symmetrical bis(sulfoximine)s of types 3 and 4 gands 3 and 4. On the other hand, facing the immense
with impressive results in the already-mentioned reac- importance of the chiral, C2-symmetrical bis(oxazo-
Adv. Synth. Catal. 2004, 346, 1295–1306
DOI: 10.1002/adsc.200404164
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1295

M. Reggelin et al.
FULL PAPERS
line)s 5 and 6 as ligands in asymmetric catalysis[34–48] we
became curious to explore the corresponding potential
of the structurally related bis(sulfoximine)s 7 and 8 in
this area (Figure 2).
Results and Discussion
At the time we began our studies only two racemic S,S-
linked bis(sulfoximine)s were known. The ethylene-
bridged derivative 9 had been synthesized by Johnson
1980 as a vinylsulfoximine precursor[49] and 10 was pre-
pared as early as 1954 in 9% yield to explore the suspect-
Scheme 1. Retrosynthetic analysis of target structure 7; LG¼
leaving group.
ed intrinsic toxicity of the sulfoximine group.[50] The tar- and quite a number of successful stereoselective imina-
get C1-bridged bis(sulfoximine)s comprise a class of tions of other sulfoxides, especially with MSH, have
hitherto unknown compounds.
been described.[51,60,61]
À
Strategy B relies on a C S bond formation between a
sulfur(VI) nucleophile generated from 12 and a sul-
fur(VI) electrophile 13. The major problem with this ap-
proach was the non-availability of the latter in enantio-
Synthesis of Geminal Bis(sulfoximine)s
To tackle the problem of their synthesis in enantiomeri- merically pure state at the time we started our investiga-
cally pure state we envisaged two major strategies tions. For that reason we strongly favoured path A and
(Scheme 1).
therefore our efforts in that area will be discussed first.
Strategy A is based on the possibility to oxidatively
iminate chiral sulfoxides with retention of their configu-
ration using reagents acting like nitrenes. The most Route A
prominent representatives here are mesitylenesulfonyl-
hydroxylamine (MSH),[51] BOC azide,[52] N-amino- The synthesis of the S,S-enantiomer 11 has been describ-
phthalimide,[53,54] or N-tosyliminophenyliodinane.[55] ed several times in the literature.[58,59] Kunieda was the
Hydrazoic acid itself is less appropriate due to its incom- first who used the Andersen reagent 15 for that purpose
plete stereoselectivity.
furnishing 11 with 35% yield (Scheme 2).[59] To improve
Route A seemed to be a rather promising entry to the this yield it was necessary to account for the increased
geminal bis(sulfoximine)s last but not least because the acidity of the methylene protons in the product 11 com-
starting bis(sulfoxide) 11 was a known compound[56–59] pared to those in the starting sulfoxide 14.
Indeed with an excess of lithium hexamethyldisilazide
(LHMDS, 3.3 equivs.) it was possible to obtain 11 as a
pure isomer with 91% yield. Next we tried the two-
fold imination reaction to prepare bis(sulfoximine)s 7a
(Figure 2), which appeared to be especially useful due
to its free NH groups allowing further derivatization.
For that purpose we employed MSH as a reagent
(Scheme 3).
To our surprise only the monosulfoximine 16 was iso-
lated with 79% yield. As a possible explanation for this
finding, we suspected the intermediate S-aminosulfoxo-
nium salt[61] (not shown) to reduce the nucleophilicity of
the second sulfur, thus preventing it from being attacked
by MSH [a similar explanation has been put forward by
Appel for the failure of the bis-imination of a C1-bridged
Figure 2. Structural comparison of bis(oxazoline)s 5, 6 and
geminal S,S-linked bis(sulfoximine)s 7, 8 as well as the only
two racemic S,S-linked bis(sulfoximine)s 9, 10 known prior
to this work.
Scheme 2. Improved synthesis of bis(sulfoxide) 11.
1296
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306

Geminal Bis(sulfoximine)s: Synthesis and Applications
FULL PAPERS
Scheme 5. Action of different nitrene precursors to bis(sulf-
oxide) 11. Path B: A new route to SES-protected sulfox-
imines.
Scheme 3. Attempts to synthesize the geminal bis(sulfox-
imine) 7a via imination of sulfoxides.
bis(phosphane)].[62] We therefore N-protected 16 by disappointing result, we tried a modification of Bachꢁs
acetylation yielding 18 and synthesized the benzyl-pro- imination reaction[52] replacing BOC-azide by trime-
tected derivative 17 by application of our LHMDS- thylsilylethanesulfonyl azide (SES azide) to avoid acidic
based method from 19 and sulfinate 15 with 91% yield. deprotection conditions in the final step to the “free”
To our disappointment both protected derivatives sulfoximine 7a. SES azide has never been described be-
failed to react with MSH in the desired manner. The ace- fore and for safety reasons we tried to generate it in situ
tylated derivative was completely unreactive whereas from SES-Cl and sodium azide in CH3CN. In the event
the benzylated one underwent a rather surprising trans- SES-Cl was stirred with NaN3 in CH3CN for 16 h at
formation to the starting bis(sulfoxide) 11 (34% yield) which point the bis(sulfoxide) 11 and anhydrous FeCl2
with complete retention of the S-configuration. In addi- were added. Alkaline work-up followed by flash column
tion to that 16% of debenzylated 16 and 31% of the chromatography furnished the SES-protected monosulf-
starting material were isolated (Scheme 4).
oximine 23 in 66% yield as a pure isomer. Although
As a plausible mechanistic interpretation of this un- again only monoimination was observed, we were
usual process we propose an electrophilic attack of pleased to see that this new stereoselective reaction,
MSH onto the electron-rich sulfoximine nitrogen yield- leading to sulfoximines with a fluoride ion-cleavable
ing the S-aminosulfoxonium salt 20 which may cyclize to protecting group, worked.
the thiadiaziridine S-oxide 21. This latter compound fi-
nally undergoes a [1,2]-cycloreversion affording bis still unresolved, and therefore we focused our attention
(sulfoxide) 11 with retention of the configuration. on the Pb(OAc)4-mediated oxidative imination proce-
Nevertheless our problem to doubly iminate 11 was
As a consequence of these disappointing results, we dure with N-aminophthalimide as the nitrogen source
decided to explore the reactivity of 11 towards various (Scheme 5, Path C).
“nitrene” sources (Scheme 5).
This time we isolated an easy to separate mixture of
The first experiment in this series was a Raney copper- the desired bis(sulfoximine) 24 (23%) and the corre-
mediated tosyl-imination following the classical proce- sponding monosulfoximine (not shown). Unfortunately
dure developed by Kwart and Kahn in 1967.[63] Again it turned out that 24 could not be deprotected. Neither
no bis-imination was observed and only 19% of the mono- H2/PtO2 nor Zn/HOAc worked in the anticipated man-
sulfoximine 22 was isolated instead. Despite this rather ner and therefore we had to give up this first promising
entry to geminal bis(sulfoximine)s.
Route B
As discussed earlier this strategy relies on the availabil-
ity of a suitable sulfur(VI) electrophile 25 (Scheme 6).
Obvious candidates are sulfonimidoyl halides such as
27 or sulfonimidates 26. Both types of compounds are
problematic from a stereochemical point of view. First
of all their synthesis in enantiomerically pure state is
rather tedious and the removal of the chiral N-bound
auxiliary is difficult, if not impossible.[64] Furthermore
sulfonimidoyl halides are rather prone to epimerization
and finally the nucleophilic displacement reaction with
Scheme 4. Mechanistic proposal for the formation of 11 from
monosulfoximine 17.
Adv. Synth. Catal. 2004, 346, 1295–1306
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1297

M. Reggelin et al.
FULL PAPERS
Scheme 6. Solutions for sulfur(VI) electrophiles.
carbon nucleophiles is vulnerable to reduction and not
completely stereoselective.[64]
Scheme 8. Successful coupling and failed deprotection.
Facing this situation we found it best to employ a rac-
emic sulfonimidoyl fluoride (the chlorides tend to get re-
duced or to give chlorinated products in their reactions
with carbanions)[65–67] with a sterically non-demanding
protecting group at nitrogen (Scheme 7). The attempted
preparation of the attractive menthyl ester 32 as a sul-
fur(VI) analogon of the Andersen reagent[68] via a nucle-
ophilic displacement reaction with rac-30 as electrophile
failed.
As second building block we used N-allylsulfoximine
34 which was obtained in 89% yield from the known sulf-
oximine 33[51] (synthesized via the MSH route from the
corresponding sulfoxide in 90% yield).
Scheme 9. A stereoselective one-pot-procedure to enantio-
merically pure geminal bis(sulfoximine)s via sulfonimidate
37.
To facilitate the NMR spectroscopic analysis of the
coupling products we chose identical N-protecting
In the course of an attempted fluorination of a sulfon-
groups on both components. This way the desired com- imidoyl chloride (not shown) the hitherto unknown het-
pound 35 with identical absolute configuration of both erocycle 37 was obtained as a major product.[70–73] Later
sulfur atoms is C2-symmetrical with homotopic hydro- on this compound was elaborated to a central starting
gens at the methylene carbon, whereas in the Cs-sym- material for the synthesis of enantiomerically pure 2-al-
metrical meso compound 36 these hydrogens are dia- kenylsulfoximines as powerful asymmetric allyl transfer
stereotopic (Scheme 8).
Under the optimized coupling conditions developed
reagents.[12,16,18,19,23]
The cyclic sulfonimidate 37 turned out to be the miss-
for 11 and 17 we were able to isolate 19% of an insepa- ing chiral non-racemic sulfur(VI) electrophile. More-
rable 1:1 mixture of the target bis(sulfoximine)s 35 and over, contrasting the behaviour of sulfonimidates 26,[64]
36. Unfortunately again the intended deprotection, this 37 reacts readily with carbon nucleophiles, including sul-
time via Rh-catalyzed isomerization of the double fonimidoyl-substituted derivatives, without reduction
bond,[69] failed under a variety of conditions.
and with complete inversion of the sulfur configuration.
The unexpected breakthrough in this chemistry came Reacting 37 with MeLi affords the methylsulfoximine 38
by serendipity (Scheme 9)!
which can be deprotonated by an excess of LHMDS and
reacted with a second equivalent of the sulfonimidate
yielding the desired bis(sulfoximine) 40 in a one-pot se-
quence with 62% yield. Alternatively, the O-silylated
methylsulfoximine 39 can be reacted in a separate step
with 37 furnishing 40 with 74% yield after deprotection.
It is worth mentioning here that ent-40 can easily be ob-
tained starting from ent-37.
Structural Modifications of 40
Having found a simple, high yielding entry to bis(sulfox-
imine) 40 starting from commercially available 37, we
explored possibilities to structurally modify the parent
compound. This was regarded as necessary for at least
two reasons. Firstly, it is known from the chemistry of
the related bis(oxazoline)s 5 and 6 that a replacement
of the acidic methylene protons by alkyl groups has a
Scheme 7. Synthesis of the sulfur(VI) electrophile rac-31 and
the sulfur(VI) nucleophile (R)-34.
1298
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306

Geminal Bis(sulfoximine)s: Synthesis and Applications
FULL PAPERS
major influence in catalyst performance.[36,74] This can be 48 was isolated besides 20% of the dichlorobis(sulfox-
traced back to variations of the “bite angle”[74] and to the imine) 46 (Scheme 11).
avoidance of deprotonated species. Indeedthe most use-
A plausible explanation for this finding is the forma-
ful applications of bis(oxazoline) ligands rely on the tion of an aziridinium cation 49, which undergoes ring
geminal dimethylated derivatives.[37,40] Secondly, the opening by chloride ion to yield the observed chlorinat-
two hydroxy groups from the valine side-chains offer ad- ed product 46. A much better access to that compound
ditional possibilities for ligand design. On the one hand (47% yield) was found by application of the Appel reac-
their mere existence in a free or blocked state has proved tion using PPh3 and CCl4 (Scheme 10). In the context of
to have a major impact on the sense of asymmetric in- our objective to design ligands suitable for heterobime-
duction.[45] Furthermore, these two additional function- tal catalysis we tried to replace chlorine by phosphorus.
al groups can possibly be exploited to construct ligands This should give access to a new class of N,P ligands with
for two-centre catalysis.[75–80] For these reasons we syn- the relatively hard nitrogen centres being combined
thesized a number of derivatives as depicted in with the soft phosphorus atoms. This kind of ligand
Scheme 10.
should be able to complex early and late transition met-
The bis(sulfoximine) 40 can be silylated either using als simultaneously. With this in mind, chlorinated bis
dimethylaminotrimethylsilane or TBSCl to yield 41 or (sulfoximine) 46 was reacted with the borane complex
42, respectively. The potassium salts of both protected of lithium diphenylphosphane in THF at À788C. Al-
derivatives prepared by deprotonation with potassium though the yield of isolated 47 was only 16% we were
t-butoxide react readilyto the corresponding geminaldi-
methylated bis(sulfoximine)s 43 and 45. The diol 44 was
generated either by fluoride ion-mediated desilylation
or by a solvolysis reaction employing K2CO3 in
MeOH. The best way to prepare 44 is the route via the
bis-TMS derivative 43, which was not isolated, affording
the target compound in almost 99% overall yield. The
application of potassium t-butoxide as a base was found
to be crucial to get high yields of the methylated prod-
ucts.
In order to convert the OH groups into leaving groups
we tried to mesylate 40 under standard conditions. Inter-
estingly only minor amounts of the mesylated product
Scheme 11. Unexpected formation of the dichlorobis(sulfox-
imine) 46.
Scheme 10. Derivatization of the parent bis(sulfoximine) 40.
Adv. Synth. Catal. 2004, 346, 1295–1306
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1299

M. Reggelin et al.
FULL PAPERS
Table 1. Stoichiometric and catalytic reduction of acetophe-
pleased to realize that the reaction worked, at least in
principle. As an explanation for the low yield we suspect
the presence of the rather acidic protons in the starting
material.
none with boron complexes CA to CC.[a]
Application of the NewLigands: Stoichiometric and
Catalytic Reactions
Despite the long history of b-hydroxysulfoximines as li-
gands in boron-mediated reduction reactions[81–83] noth-
ingis knowntodate abouttheapplicability ofN-hydroxy-
ethyl-functionalized sulfoximines for that purpose.
Therefore we were curious to see whether different bor-
on complexes of 40 can be used to asymmetrically re-
duce ketones. To answer that question we reacted 40
with three different boron sources as depicted in
Scheme 12.
For the preparation of complex CA bis(sulfoximine)
40 was reacted with 2 equivs. of BH3 ·THF complex in
toluene at ambient temperature. After 40 min reaction
time the solvent was removed under vacuum to leave a
[a]
All reactions were run for 10 min at 08C.
Compound 50 was added as a toluene solution over a time
period of 60 min.
10 mol % of complex CB.
[b]
[c]
[d]
The ee was determined by chiral GC (RT-BDex cst-TM,
Restek, see Experimental Section). The configuration
was deduced by comparison of the value of the optical ro-
tation with literature data.[84]
white solid which was used in stoichiometric amounts 0.66 equivs. of the boron heterocycle with respect to the
to reduce ketone 50 (Table 1). ligand. With stoichiometric amounts of CC and 1 equiv.
As reducing agent 0.5 equivs. of BH3 ·THF were add- of BH3 ·THF 51 was isolated with 58% yield and 48% ee
ed whereupon an almost quantitative reduction was ob- [(R)-51], again after 10 min at 08C.
served within 10 min, affording the alcohol (R)-51 with
Although we tried to get some structural information
39% ee. This rather low ee could not be improved by var- about complexes CA – CC by NMR (1H, 13C, 11B) and
iation of the amount of BH3 ·THF used for complexa- MS no consistent picture emerged from these analyses.
tion and/or the amount of BH3 ·THF used for the reduc- For the time being any attempt to assign structures to
tion.
the complexes would be highly speculative and is there-
For that reason we changed the boron source to meth- fore avoided. On the other hand, the encouraging results
ylboronic acid[85] (Table 1) which was reacted with 40 in especially from the experiments with complex CC
toluene to produce complex CB. This time the reduction stimulated further efforts to learn more about the spe-
using 0.6 equivs. of BH3 ·THF was performed in THF cies formed. These studies are currently in progress.
with only 10 mol % of CB. Again alcohol (R)-51 was
We next turned our attention to the question of a pos-
produced in quantitative yield after 10 min at 08C but sible complexation of copper by our new bis(sulfox-
the ee was even lower (28%). Surprisingly the reaction imine)s. For that purpose the three ligands 40, 42 and
was very much slower in toluene yielding only around 45 were reacted with CuCl2 and Cu(OTf)2 in different
10% 51 within 10 min (not shown).
Finally, we tried complex CC which was prepared
solvents (Table 2).
Although in all cases complete dissolution of the add-
from trimethylboroxine[85,86] and 40 (Table 1). The ed copper(II) salt could be observed, only the reaction
most active and selective catalyst was obtained by using of the bis-protected ligand 42 with copper(II) triflate
led to crystalline material (Table 2, entry 7). This copper
complex was isolated in 80% yield after the addition of
hexanes to induce crystallization. Interestingly the
slightly turbid dichloromethane solution generated af-
ter combining the ligand with copper triflate at room
temperature became clear upon cooling to À788C. A
similar effect has been observed by Evans during copper
complexation by a bis(oxazoline).[39,87] To our delight the
crystals obtained were suited for an X-ray structural
analysis (Figure 3).[88]
Surprisingly, this copper complex derived from C2-
symmetrical bis(silylated) 42 was found to be desymme-
trized due to loss of one silyl substituent! Much like the
Scheme 12. Boron complexes from 40.
situation in copper-BOX complexes,[40] the copper atom
1300
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306

Geminal Bis(sulfoximine)s: Synthesis and Applications
FULL PAPERS
Table 2. Complexation experiments with the ligands 40, 42
and 45.
Figure 4. Least squares fit of six bis(oxazoline)-copper com-
plexes (grey sticks) and sulfoximine complex 52. (coloured
ball and stick representation; yellow: S; red: O; cyan: Si;
blue: N; dark grey: C; orange: Cu). The counterions and hy-
drogen atoms have been omitted for clarity.
[a]
CuX2:Ligand¼1: 1, room temperature, after complete dis-
solution of the copper(II) salt the solution was filtered and
overlayed with hexanes to induce crystallization.
For that purpose a least squares fit of six Cu-BOX-
complexes (CSD-Ref.-Codes: CUHCEN,[42] GIQ-
LUN,[87] GIWHID,[89] GIWHID01,[90] LOXWOK,[91]
[b]
2 equivs. AgSbF6 then filtration.
Dry stirring of Cu(OTf)2 and ligand under vacuum for
[c]
MISHOL[90]) and 52 with respect to the central
Cu N2 –C3 six-membered ring has been calculated.
30 min prior to solvent addition.
Slow evaporation of the solvent by a stream of argon bub-
bled through the solution.
[92]
À
[d]
From this fit it is obvious that due to the inverted direc-
À À À
tion of the N C C O chain of the amino acid derived
portion of the molecule the space blocked by the i-Pr-
groups of 52 is inverted too. This entails the expectation
is coordinated in a distorted square pyramidal fashion in that any asymmetrical reaction occurring in the coordi-
which one of the triflate ligands is weakly bound in the nation sphere of the copper atom should lead to prod-
1
À
apical position (Cu OTf ¼2.33 Š) whereas the other ucts with opposite absolute configuration as compared
2
À
one is fully dissociated (Cu OTf ¼3.30 Š). The dis- to the induction from BOX ligands, although the abso-
tance of the copper atom from the N2O2 plane is lute configuration of the underlying amino acid is un-
0.233 Š. A comparison with the X-ay structure of the changed.[93] Moreover, the structure of 52 reveals that
metal-free ligand 42 displays only minor structural the sulphur-bound p-Tol groups should have only a mi-
À
changes. Most notable is a slight decrease of the C S nor influence on the asymmetric induction of this com-
bond lengths (from 1.83 to 1.73, 1.79 Š) and a minor en- plex. To verify these expectations and, of course, to an-
largement of the S C S angle (from 118.78 to 1228 in the swer the question whether copper complexes of the bis
À À
complex).
(sulfoximine)s 40, 44 and 46 (Scheme 10) are able at
À
Much more interesting is a structural comparison of 52 all to asymmetrically catalyze C C bond forming reac-
with a number of Cu-BOX-complexes (Figure 4).
tions, we chose the Et2Zn-mediated 1,4-addition to 2-cy-
Figure 3. (a) X-ray structure of copper complex 52. (b) X-ray structure of the uncomplexed ligand 42. Colour code: yellow: S;
red: O; cyan: Si; blue: N; dark grey: C; magenta: fluorine; orange: Cu.
Adv. Synth. Catal. 2004, 346, 1295–1306
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1301

M. Reggelin et al.
FULL PAPERS
clohexenone as a model reaction (Table 3). This choice oximine)s. Due to the commercially availability of the
was made because copper complexes of bis(oxazoline)s starting materials 37 and ent-37, their synthesis is ex-
with unfunctionalized side chains failed to give useful tremely easy and short. Moreover, structural modifica-
stereoselectivities in these reactions.[36] On the other tions, not only on the valine-derived side chain leading
hand bis(oxazoline)s bearing hydroxy groups in the b- to derivatives such as 41, 46 and 47 but also on the bridg-
position of the nitrogens perform much better, an obser- ing carbon have been achieved. Future work will be di-
vation that has been traced back to a precoordination of rected towards the synthesis of other phosphinylated li-
the Zn-atom to these oxygens.[36]
gands as indicated in structure 55, not only to have ac-
To our delight all ligand-copper complexes were cess to systems suited for the synthesis of bimetallic
found to be highly active catalysts delivering the ethyl complexes but also to improve the asymmetric environ-
group of Et2Zn in a 1,4-fashion onto the substrate. ment of the complexed metal(s) (Figure 5).
This was especially true for the dichloro-substituted li-
Following these lines we are currently working on the
gand 46. A nearly quantitative yield was achieved even problem to completely remove the N-side chain and to
at À908C using only 2.4 mol % of the catalyst and exploit the ortho-directinggroup properties ofthe sulfon-
CuCl2 as the copper source.
imidoyl moiety[70,94–96] to phosphinylate the ortho-posi-
On the other hand the enantioselectivities were rather tions of the tolyl rings.
disappointing, with 36% ee as the best value. As expect-
Beside these constitutional modifications it is impor-
ed from the analysis discussed above the major enan- tant to mention that the described syntheses of the
tiomer was (R)-(þ)-54 in all cases. Interestingly, the di- bis(sulfoximine)s are flexible enough to allow configu-
methylated ligand 44 performed even worse contrasting rational adjustments on both the C- and S-centred con-
the experiences made with the corresponding dimethy- figurations. This opens the opportunity to develop li-
lated bis(oxazoline) complexes.[36]
gands with a “matched” relative configuration on these
Based on the results achieved so far, it is difficult to an- stereogenic units, a situation which might not have been
alyze the potential role of the ligandsꢁ oxygen atoms as a established at the moment.
possible coordination site for zinc. This interesting pos-
sibility has been discussed by Reiser et al. to explain the
effect of O-substituents and various additives upon the
stereoselection observed with copper complexes of 6a
in the 1,4-addition reaction discussed above (Fig-
ure 2).[36]
In summary, we have synthesized for the first time
enantiomerically pure C2-symmetrical geminal bis(sulf-
Figure 5. Possible sites of phosphinylation and bond cleavage
in bis(sulfoximine)s 55.
Table 3. Copper complex-catalyzed 1,4-additions to 2-cyclo-
hexenone.
Conclusion
The cyclic sulfonimidates 37 and ent-37 offer the oppor-
tunity to synthesize new C2-symmetrical bis(sulfox-
imine)s for the first time. Due to the acidic protons in
the C1-bridge of these compounds and their functional-
ized N-side chains numerous structural modifications
are easy to perform. Furthermore dialkylated deriva-
tives such as 43 or 45 are expected to take part in direct-
ed ortho-metallation reactions which in turn renders fur-
ther modifications possible. The boron complex from 40
and trimethylboroxine reduces acetophenone to the cor-
responding (R)-alcohol with 48% ee, whereas the cop-
per complex from the dichloro-substituted ligand 46
was found to be a highly active catalyst for the 1,4-addi-
tion reaction of diethylzinc to 2-cyclohexenone. Even at
À908C a nearly quantitative yield of the addition prod-
uct was observed with only 2.4 mol % of the catalyst.
Given the manifold ways for constitutional and configu-
rational changes of the ligand structure, it seems just a
[a]
Determined by chiral GC (Beta-Dex120, Supelco, see Ex-
perimental Section).
1302
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306

Geminal Bis(sulfoximine)s: Synthesis and Applications
FULL PAPERS
CDCl3): d¼0.005 [9H, s, Si(CH3)3], 1.163 (2H, m, Si-CH2),
2.382 (3H, s, SO-C6H4-CH3), 2.477 (3H, s, SON-C6H4-CH3),
3.201 (2H, m, SO2-CH2), 4.495 (1H, d, 2J¼13.3 Hz, SCHHS),
5.112 (1H, d, 2J¼13.3 Hz, SCHHS), 7.300 (2H, d, 3J¼8.2 Hz,
3J¼8.2 Hz, SO-o-CH), 8.015 (d, 3J¼8 Hz, SON-o-CH);
13C NMR (50.3 MHz, CDCl3): d¼ À1.384 [Si(CH3)3], 10.35
(Si-CH2), 21.44 (SO-C6H4-CH3), 21.84 (SON-C6H4-CH3),
54.14 (SO2-CH2), 81.36 (S-CH2-S), 124.09 (SO-o-CH), 128.91
(SON-o-CH), 130.40 (SO-m-CH), 130.41 (SON-m-CH),
132.37 (SO-ipso-C), 138.54 (SON-ipso-C), 142.73 (SO-p-C),
146.91 (SON-p-C); anal. calcd. for C20H29NO4S3Si: C 50.92, H
6.20, N 2.97; found: C 50.92, H 6.21, N 2.93.
matter of time to improve the selectivity of the system
which is, at the time being, not yet sufficient for prepara-
tive purposes (36% ee for the above-mentioned reac-
tion).
Current work focuses on the synthesis of various phos-
phinylated derivatives (with or without the N-side
chain) to improve the selectivity and to design ligands
suited for hetero-bimetal catalysis.[76,80]
3
SO-m-CH), 7.449 (2H, d, J¼8 Hz, SON-m-CH), 7.549 (d,
Experimental Section
General Remarks
All manipulations except work-up and chromatographic puri-
fication were performed under an atmosphere of dry, oxygen-
free argon with Schlenk and syringe techniques. Na2SO4 or
MgSO4 were applied to dry organic layers. Solvents were puri-
fied and dried prior to use by distillation from an appropriate
drying agent. Diethyl ether (ether) and tetrahydrofuran
(THF) were distilled from sodium benzophenone ketyl. Di-
chloromethane (CH2Cl2) was distilled from calcium hydride.
Starting materials were obtained from commercial sources
and used without further purification unless otherwise stated.
The assay from n-BuLi was obtained by titration with menthol
in THF in the presence of 1,10-phenanthroline.[97] Analytical
thin layer chromatography (TLC): Macherey & Nagel precoat-
ed TLC plates (SilG/UV 254). Flash chromatography: E.
Merck silica gel 60 (15–40 mm). Enantiomeric excesses were
determined by GC analysis of the crude reaction mixture using
a Thermo-Finnigan GC 8360 equipped with an appropriate op-
tically active column, as described in the footnotes of the corre-
sponding tables and in the corresponding section of the exper-
imental part. Melting points (mp): Gallenkamp apparatus, un-
corrected. Optical rotations: Perkin Elmer 241 polarimeter. IR
spectra: Perkin Elmer, FT-IR-Spectrometer 1720X. Elemental
analysis; Elementar, Vario EL. 1H and 13C NMR spectra: Bruk-
er DRX 500, AM 300, AC 300, AMX 300, AC 200. 1H NMR
and 13C NMR spectra are reported in ppm relative to tetrame-
thylsilane or for DMSO-d6 as solvent dH ¼2.50 ppm and dC ¼
39.5 ppm.
Bis(sulfoximine) 40
Method A: One-pot-procedure: The donor flask of an inverse
apparatus (see Supporting Information) was charged with
239 mg (1.0 mmol) 37 dissolved in 3 mL THF, the acceptor
flask with 383 mg (1.6 mmol) 37 dissolved in 4.8 mL THF.
The solutions were cooled to À788C. Then 750 mL
(1.2 mmol) of an ether solution of MeLi (1.6 molar) were add-
ed via syringe to the donor flask and 30 min later a freshly pre-
pared solution of 200.5 mg (1.2 mmol) LHMDS in 2.5 mLTHF
was added dropwise into the same flask. After 35 min of stir-
ring at À788C the colourless reaction mixture was transferred
to the acceptor flask using an Ar-filled balloon. After 5 min the
reaction mixture was allowed to reach 08C and was stopped
20 min later by adding 2 mL saturated NH4Cl solution. After
extraction with diethyl ether (3ꢀ10 mL) and drying of the or-
ganic layers with MgSO4 the solvent was removed under vac-
uum and the crude product was purified by flash chromatogra-
phy (EtOAc/hexanes, 3:1) affording 40 as a colourless solid;
yield: 309 mg (62%); Rf ¼0.27 (EtOAc/hexanes, 3:1); mp
1098C; [a]2D0: À54.80 (c 0.98, CH2Cl2); IR (KBr): n¼3500
(OH), 1260, 1130 cmÀ1 (N S O); 1H NMR (270 MHz,
¼ ¼
CDCl3): d¼0.945 (6H, d, i-Pr CH3, 3J¼7.2 Hz), 0.971 (6H, d,
3
3
i-Pr CH3, J¼7.2 Hz), 1.802 (2H, dqq, i-Pr CH, J¼7.2 Hz,
3J¼5.2 Hz), 2.423 (6H, s, C6H4-CH3), 2.902 (2H, dd, OH, 3J¼
3
3
3
9.5 Hz), 3.227 (2H, ddd, N-CH, J¼8.2 Hz, J¼3.1 Hz, J¼
3
3
¼
5.2 Hz), 3.457 (2H, ddd, CHH-OH, J 11.0 Hz, J¼4.0 Hz),
3
3
¼
3.584 (2H, ddd, CHH-OH, J¼9.5 Hz, J 11.0 Hz), 4.847
(2H, s, S-CH2-S), 7.245 (4H, d, m-CH), 7.752 (4H, d, o-CH);
13C NMR (62.5 MHz, CDCl3): d¼18.68 (i-Pr CH3), 19.78 (i-
Pr CH3), 21.53 (C6H4-CH3), 31.72 (i-Pr CH), 64.23 (N-CH),
65.07 (CH2-OH), 70.24 (S-C-S), 129.29 (m-CH), 129.49 (o-
CH), 135.06 (S-C), 144.27 (C6H4-C); MS (Cl, isobutane): m/
e¼496 (27.9%[Mþ1]þ), 495 (100%[M]þ); anal. calcd. for
C25H38N2O4S2: C 60.70, H 7.74, N 5.66; found: C 60.85, H 7.57,
N 5.70.
Sulfinylsulfoximine 23
In a25-mL Schlenk flask 0.803 g (4.0 mmol) trimethylsilyletha-
nesulfonyl chloride (SES-Cl) were dissolved in 4 mL acetoni-
trile at room temperature. Under vigorous stirring 0.364 g
(5.6 mmol) NaN3 were added within 30 min after which the sol-
ution was stirred for another 14 h. Then a solution of 0.292 g
(1.0 mmol) 11 in 2 mL acetonitrile was added followed by
0.507 g (4.0 mmol) dry FeCl2. After 3 h the reaction mixture
was poured onto ice and ether (20 g and 30 mL, respectively).
The aqueous layer was extracted with ether (3ꢀ30 mL), the
combined organic layers were washed first with aqueous 10%
NaOH (30 mL) then with brine (30 mL) and finally dried
over MgSO4. Removal of the solvent under reduced pressure
furnished 0.7 g crude product, which was purified by flash chro-
matography (EtOAc/hexanes 1:2) affording 23 as a white sol-
id; yield: 311 mg (66%); Rf ¼0.62 (EtOAc/hexanes, 1:2); mp
Method B: In a 25-mL inverse apparatus (see Supporting In-
formation) the donor flask was charged with 655 mg 39
(2.0 mmol, for the preparation of 39 from 37, see Supporting
Information) and the acceptor flask with 239 mg 37
(1.0 mmol) dissolved in dry THF (3 mL) each. After cooling
to À788C 747 mg (2.0 mmol) of a hexane solution containing
2.67 mmol/g n-BuLi were added to the donor flask via syringe.
After 40 min of stirring at this temperature the mixture in that
flask was transferred dropwise to the solution in the acceptor
flask using an Ar-filled balloon. 5 min later the mixture was al-
lowed to reach room temperature, stirred for another 80 min
1
628C; [a]2D0: þ264.64 (c 0.9, CH2Cl2); H NMR (200.13 MHz,
Adv. Synth. Catal. 2004, 346, 1295–1306
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1303

M. Reggelin et al.
FULL PAPERS
and then the reaction was stopped by adding 1.5 mL of a satu-
rated NH4Cl solution. After extraction of the reaction mixture
with diethyl ether (3ꢀ10 mL) and drying of the combined or-
ganic layers with MgSO4 the solvent was removed under vac-
uum affording 965 mg of a colourless crude product which
was dissolved in 6 mL MeOH containing 180 mg (3.0 mmol)
K2CO3. After 35 min of stirring the solvent was removed, the
residue was triturated with 10 mL diethyl ether and evaporated
again. This procedure was repeated twice and finally the ether
suspension was filtered, the filtrate evaporated and the residue
was purified by flash chromatography (EtOAc/hexanes, 2:1)
affording 40 as a colourless solid; yield: 367 mg (74%).
Dichlorobis(sulfoximine) 46
In a Schlenk tube 6 mL dry CCl4 were cooled to 08C and then
100.0 mg (0.202 mmol, 1.0 equiv.) 40 and 106.0 mg
(0.404 mmol, 2.0 equiv.) triphenylphosphane were added. Af-
ter stirring for 2 h at 08C the reaction mixture was heated to re-
flux for 40 h. Then 10 mL of diethyl ether were added inducing
precipitation of triphenylphosphane oxide which was filtered
off. After removal of all volatiles the remaining yellow oil
was purified by flash chromatography (EtOAc/hexanes,
10:1) affording 46 as a colourless solid; yield: 50 mg (47%);
Rf ¼0.75 (EtOAc/hexanes, 1:1); mp 838C; [a]2D0: À40.65 (c
1
0.31, CH2C12); H NMR (500.1 MHz, CDCl3): d¼0.873 (6H,
3
3
d, i-Pr CH3, J¼6.8 Hz), 0.947 (6H, d, i-Pr CH3, J¼6.8 Hz),
3
3
2.074 (2H, dqq, i-Pr CH, J¼3.8 Hz, J¼6.8 Hz), 2.440 (6H,
s, C6H4-CH3), 3.206 (2H, ddd, N-CH, 3J¼3.8 Hz, 3J¼6.5 Hz),
Dimethylbis(sulfoximine) 44
3
3.424 (4H, d, CH2-Cl, J¼6.5 Hz), 4.803 (2H, s, S-CH2-S),
3
3
7.291 (4H, d, m-CH, J¼8.2 Hz), 7.763 (4H, d, o-CH, J¼
8.2 Hz); 13C NMR (125.7 MHz, CDCl3): d¼16.34 (i-Pr CH3),
20.10 (i-Pr CH3), 21.72 (C6H4-CH3), 30.45 (i-Pr CH), 47.39
(CH2-Cl), 61.31 (N-CH), 71.83 (S-C-S), 129.32 (o-CH),
129.72 (m-CH), 135.40 (S-C), 144.50 (C6H4-C); MS (ESI, meth-
anol): m/z¼553.2 (100%, [MþNa]þ), 531.3 (23%, [Mþ1]þ);
anal. calcd. for C25H36Cl2N2O2S2: C 56.49, H 6.83, N 5.27; found:
C 56.49, H 6.82, N 5.24.
In a 25-mL round-bottom flask with a magnetic stirring bar
145 mg (0.293 mmol, 1.0 equiv.) 40 were dissolved in 3 mL
N,N-dimethylaminotrimethylsilane (DMA-TMS) and the re-
sulting solution was heated to 808C. After 3.5 h no more start-
ing material could be detected by TLC in the clear, colourless
reaction mixture. The excess DMA-TMS was condensed in a
cryo-trap (cooled by N2) furnishing the bis-silylated sulfox-
imine 41 in quantitative yield.
78 mg (0.122 mmol, 1 equiv.) of this crude product were dis-
solved in 1 mL dry THF in a 10-mL round-bottom flask and
cooled to 08C. At this temperature 28.76 mg (0.256 mmol,
2.1 equivs.) potassium t-butoxide dissolved in 1 mL dry THF
were added. After stirring for 15 min 0.03 mL (0.488 mmol,
4.0 equivs.) methyl iodide were added dropwise via syringe.
The reaction was allowed to reach room temperature within
4 h and stirred for another 24 h. Aqueous work-up (10 mL di-
ethyl ether and 10 mL water) followed by diethyl ether extrac-
tion (2ꢀ10 mL) and washing of the combined organic layers
with 20 mL of a saturated NaCl solution afforded after drying
with Na2SO4 and concentration under vacuum 43 as a yellow oil
which was not further purified for deprotection; yield: 81 mg
(99.4%).
Cu Complex 52
In a Schlenk tube 200 mg (0.276 mmol, 1.0 equiv.) 42 and
100 mg (0.276 mmol, 1.0 equiv.) Cu(OTf)2 were stirred for
30 min under vacuum. Then under an atmosphere of dry argon
0.7 mL dry dichloromethane were added via syringe. The re-
sulting suspension was stirred for 1 h at room temperature
and then filtered using an argon flushed hydrophobic 0.45 mm
PTFE syringe filter. The obtained green solution was transfer-
red into a dry 25-mL flask and overlayed with dry hexanes. 24 h
later turquoise crystals of 52 had formed; yield: (240 mg, 80%).
A single crystal of this material was characterized by X-ray
structural analysis.
In a round-bottom flask 64 mg (0.096 mmol, 1.0 equiv.) of
the crude product 43 were dissolved in 2 mL methanol contain-
ing 27.8 mg (0.201 mmol, 2.1 equivs.) potassium carbonate.
The resulting suspension was stirred for 2 h at room tempera-
ture. Then the solvent was removed under vacuum and the re-
sulting residue was triturated with 5 mL water and 5 mL dieth-
yl ether. After separation of the phases the aqueous phase was
extracted with diethyl ether (2ꢀ10 mL) and the combined or-
ganic phases were washed with 15 mL of a saturated NaCl sol-
ution. After drying over Na2SO4 and removal of the solvent un-
der reduced pressure 44 was obtained as a colourless solid;
yield: 46 mg (92%); Rf ¼0.41 (ether/hexanes, 5:1); mp 878C;
Reduction of Acetophenone (Table 1, Entry 3)
In a 25-mL Schlenk flask 100 mg (0.202 mmol, 1.0 equiv.) 40
were dissolved in 2 mL toluene, followed by 16.9 mg
(0.134 mmol, 0.66 equivs.) trimethylboroxine. After 30 min
stirring at room temperature another 10 mL of toluene were
added and distilled off under an Ar atmosphere to leave a vol-
ume of 2 mL. This procedure was repeated two more times.
The third distillation was stopped after reduction of the solu-
tion to 3 mL volume at which point the flask was cooled to
08C and 0.202 mL (0.202 mmol, 1 equiv.) BH3 ·THF (1 M in
THF) were added. 10 min later 24.28 mg (0.202 mmol, 1.0
equiv.) acetophenone were added and again after 10 min the
reaction was stopped by adding 1.5 mL of methanol. After re-
moval of all volatiles under vacuum the yield and the enantio-
meric excess [48% ee in favour of (þ)-(R)-phenylethan-1-ol]
were determined by chiral GC [RT-BDex cst-TM, Restek;
oven: 608C to 2308C, 48/min; flow N2: 2 mL/min; Injec. and
FID: 2308C; split 1:100; tR: acetophenone: 15.82 min, (þ)-
(R)-1-phenylethan-1-ol: 19.63 min, (À)-(S)-1-phenylethan-1-
1
[a]2D0: þ7.0 (c 1.1, CH2Cl2); H NMR (500.1 MHz, CDCl3):
d¼0.960 (6H, d, i-Pr CH3, 3J¼6.9 Hz), 0.995 (6H, d, i-Pr
3
CH3, J¼6.9 Hz), 1.569 [6H, s, S(CH3)2], 1.921 (2H, m, i-Pr
CH), 2.426 (6H, s, C6H4-CH3), 3.604 (2H, m, N-CH), 3.677
(4H, m, CH2-OH), 4.352 (2H, br, s, OH), 7.296 (4H, d, m-
3
3
CH, J¼8.2 Hz), 7.877 (4H, d, o-CH, J¼6.9 Hz); 13C NMR
(125.7 MHz, CDCl3): d¼19.05 (i-Pr CH3), 19.27 (i-Pr CH3),
21.63 (C6H4-CH3), 21.96 (S-CH3), 32.45 (i-Pr CH), 63.86 (N-
CH), 64.48 (CH2-OH), 90.01 (S-C-S), 129.31 (m-CH), 131.72
(o-CH), 134.57 (S-C), 144.11 (C6H4-C); MS (ESI, methanol)
m/z¼545.3 (100%, [MþNa]þ); anal. calcd. for C27H42N2O4S2:
C 62.03, H 8.10, N 5.36; found: C 62.12, H 8.06, N 5.14.
1304
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306

Geminal Bis(sulfoximine)s: Synthesis and Applications
FULL PAPERS
ol: 20.10 min]. The spectroscopic data of the reduction product
corresponded to those described in the literature.[84]
[12] M. Reggelin, H. Weinberger, M. Gerlach, R. Welcker, J.
Am. Chem. Soc. 1996, 118, 4765.
[13] R. Hainz, H.-J. Gais, G. Raabe, Tetrahedron: Asymmetry
1996, 7, 2505.
1,4-Addition of Diethylzinc to 2-Cyclohexenone
(Table 3, Entry 6)
[14] H.-J. Gais, R. Hainz, H. Muller, P. R. Bruns, N. Giesen,
G. Raabe, J. Runsink, S. Nienstedt, J. Decker, M.
Schleusner, J. Hachtel, R. Loo, C.-W. Woo, P. Das, Eur.
J. Org. Chem. 2000, 3973.
[15] H.-J. Gais, H. Mueller, J. Decker, R. Hainz, Tetrahedron
Lett. 1995, 36, 7433.
[16] M. Reggelin, H. Weinberger, Angew. Chem. Int. Ed.
Engl. 1994, 33, 444.
[17] M. Reggelin, H. Weinberger, Phosphorus, Sulfur Silicon
Relat. Elem. 1994, 95–96, 341.
[18] M. Reggelin, M. Gerlach, M. Vogt, Eur. J. Org. Chem.
1999, 1011.
[19] M. Reggelin, H. Weinberger, T. Heinrich, Liebigs Ann./
Recl. 1997, 1881.
[20] H.-J. Gais, G. S. Babu, M. Guenter, P. Das, Eur. J. Org.
Chem. 2004, 1464.
[21] H.-J. Gais, L. R. Reddy, G. S. Babu, G. Raabe, J . Am.
Chem. Soc. 2004, 126, 4859.
In a Schlenk tube were dissolved 13.0 mg (0.024 mmol, 1.0
equiv.) 46 in 0.4 mL dichloromethane at room temperature.
Then 3.28 mg (0.024 mmol, 1.0 equiv.) dry CuCl2 were added
and the resulting green solution was cooled to À908C. At
this temperature 96.13 mg (1.0 mmol) 2-cyclohexen-1-one
and 2 mL (2 mmol) of a 1 M solution of ZnEt2 in hexane
were added via syringe. After 18 h the reaction mixture was
poured onto 20 mL of a vigorously stirred solution of NH4Cl
at 08C. The phases were separated and the organic layer was
extracted with 10 mL of a NH3/NH4Cl (pH 9) solution. The
aqueous layer was extracted with diethyl ether (3ꢀ15 mL)
and the combined organic layers were washed with 20 mL of
saturated NaCl solution. After drying with Na2SO4 the yield
and the enantiomeric excess were determined by chiral GC
[Beta-Dex120, Supelco; oven: 808C; flow N2 1 mL/min; Injec.
and FID 2308C; split 1:100; tR: 2-cyclohexen-1-on 24.26 min,
(þ)-(R)-3-ethylcylohexanone: 52.56 min; (À)-(S)-3-ethylcylo-
hexanone: 53.44 min]. The spectroscopic data of the product
corresponded to those described in the literature for the enan-
tiomer.[98] Its absolute configuration was determined by meas-
uring the optical rotation ([a]2D0: þ2.0 (c 0.15, toluene)).[98,99]
[22] M. Reggelin, T. Heinrich, B. Junker, J. Antel, U. Preusch-
off, (Solvay Pharmaceuticals GmbH., Germany), PCT
Int. Appl. 1998.
[23] M. Reggelin, T. Heinrich, Angew. Chem. Int. Ed. Engl.
1998, 37, 2883.
[24] H. J. Gais, R. Loo, P. Das, G. Raabe, Tetrahedron Lett.
2000, 41, 2851.
[25] M. Schleusner, H. J. Gais, S. Koep, G. Raabe, J. Am.
Chem. Soc. 2002, 124, 7789.
[26] H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe, Eur. J.
Org. Chem. 2003, 1500.
[27] S. Koep, H.-J. Gais, G. Raabe, J. Am. Chem. Soc. 2003,
125, 13243.
Acknowledgements
Thanks are due to Mrs. Foro (Institut für Organische Chemie
und Biochemie, TU-Darmstadt, Germany) and Mr. J. Bats (In-
stitut für Organische Chemie, Universität Frankfurt, Germany)
for their careful work on the X-ray structures published in this
paper.
[28] C. Bolm, D. Kaufmann, M. Zehnder, M. Neuburger, Tet-
rahedron Lett. 1996, 37, 3985.
[29] C. Bolm, O. Simic, M. Martin, Synlett 2001, 1878.
[30] C. Bolm, O. Simic, J. Am. Chem. Soc. 2001, 123, 3830.
[31] C. Bolm, C. P. R. Hackenberger, O. Simic, M. Verrucci,
D. Muller, F. Bienewald, Synthesis 2002, 879.
[32] C. Bolm, M. Martin, O. Simic, M. Verrucci, Org. Lett.
2003, 5, 427.
[33] M. Harmata, S. K. Ghosh, Org. Lett. 2001, 3, 3321.
[34] B. Fu, D.-M. Du, J. Wang, Tetrahedron: Asymmetry 2004,
15, 119.
[35] D. Rechavi, M. Lemaire, Chem. Rev. 2002, 102, 3467.
[36] M. Schinnerl, M. Seitz, A. Kaiser, O. Reiser, Org. Lett.
2001, 3, 4259.
[37] D. A. Evans, K. A. Scheidt, J. N. Johnston, M. C. Willis, J.
Am. Chem. Soc. 2001, 123, 4480.
References and Notes
[1] H. R. Bentley, E. E. McDermott, J. Pace, J. K. White-
head, T. Moran, Nature 1949, 163, 675.
[2] H. R. Bentley, E. E. McDermott, J. Pace, J. K. White-
head, T. Moran, Nature 1950, 165, 150.
[3] H. R. Bentley, E. E. McDermott, J. K. Whitehead, Na-
ture 1950, 165, 735.
[4] H. R. Bentley, J. K. Whitehead, J. Chem. Soc. D 1950,
2081.
[5] H. R. Bentley, J. K. Whitehead, J. Chem. Soc. 1952, 1572.
[6] M. Reggelin, C. Zur, Synthesis 2000, 1.
[7] C. R. Johnson, R. A. Kirchhoff, R. J. Reischer, J. Am.
Chem. Soc. 1973, 95, 4287.
[8] C. R. Johnson, C. W. Schroeck, J. R. Shanklin, J. Am.
Chem. Soc. 1973, 95, 7424.
[38] D. A. Evans, J. S. Johnson, E. J. Olhava, J. Am. Chem.
Soc. 2000, 122, 1635.
[39] D. A. Evans, T. Rovis, M. C. Kozlowski, C. W. Downey,
J. S. Tedrow, J. Am. Chem. Soc. 2000, 122, 9134.
[40] J. S. Johnson, D. A. Evans, Acc. Chem. Res. 2000, 33, 325.
[41] D. A. Evans, T. Rovis, J. S. Johnson, Pure Appl. Chem.
1999, 71, 1407.
[9] C. R. Johnson, J. R. Zeller, J. Am. Chem. Soc. 1982, 104,
4021.
[10] C. R. Johnson, J. R. Zeller, Tetrahedron 1984, 40, 1225.
[11] W. L. Mock, J. Z. Zhang, C. Z. Ni, J. Clardy, J . Org.
Chem. 1990, 55, 5791.
Adv. Synth. Catal. 2004, 346, 1295–1306
asc.wiley-vch.de
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1305

M. Reggelin et al.
FULL PAPERS
[42] D. A. Evans, J. S. Johnson, C. S. Burgey, K. R. Campos,
Tetrahedron Lett. 1999, 40, 2879.
[43] D. A. Evans, D. M. Barnes, J. S. Johnson, T. Lectka, P.
von Matt, S. J. Miller, J. A. Murry, R. D. Norcross, E. A.
Shaughnessy, K. R. Campos, J. Am. Chem. Soc. 1999,
121, 7582.
[44] D. A. Evans, S. J. Miller, T. Lectka, P. von Matt, J. Am.
Chem. Soc. 1999, 121, 7559.
[45] O. Hoarau, H. Aiet-Haddou, J.-C. Daran, D. Cramailere,
G. G. A. Balavoine, Organometallics 1999, 18, 4718.
[46] A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1.
[73] M. Reggelin, B. Junker, Chem. Eur. J. 2001, 7, 1232.
[74] S. E. Denmark, C. M. Stiff, J. Org. Chem. 2000, 65, 5875.
[75] Y. Zhong, Q. D. You, Chin. J. Org. Chem. 2002, 22, 453.
[76] G. J. Rowlands, Tetrahedron 2001, 57, 1865.
[77] M. Shibasaki, Enantiomer 1999, 4, 513.
[78] E. K. van den Beuken, B. L. Feringa, Tetrahedron 1998,
54, 12985.
[79] M. Shibasaki, H. Sasai, Adv. Asymm. Synth. 1998, 3, 191.
[80] H. Steinhagen, G. Helmchen, Angew. Chem. Int. Ed.
Engl. 1996, 35, 2339.
[81] C. R. Johnson, C. J. Stark, Jr., Tetrahedron Lett. 1979,
#20#4713.
[47] O. Hoarau, H. Ait-Haddou, M. Castro, G. G. A. Bala-
voine, Tetrahedron: Asymmetry 1997, 8, 3755.
[48] E. J. Corey, K. Ishihara, Tetrahedron Lett. 1992, 33, 6807.
[49] C. R. Johnson, J. P. Lockard, E. R. Kennedy, J . Org.
Chem. 1980, 45, 264.
[50] D. Jerchel, L. Dippelhofer, D. Renner, Chem. Ber. 1954,
87, 947.
[51] C. R. Johnson, R. A. Kirchhoff, H. G. Corkins, J. Org.
Chem. 1974, 39, 2458.
[52] T. Bach, C. Korber, Tetrahedron Lett. 1998, 39, 5015.
[53] S. Colonna, C. J. M. Stirling, J. Chem. Soc. D. 1971, 1591.
[54] S. Colonna, C. J. M. Stirling, J. Chem. Soc. Perkin Trans.
1 1974, 2120.
[55] D. Leca, K. Song, M. Amatore, L. Fensterbank, E. La-
cote, M. Malacria, Chem. Eur. J. 2004, 10, 906.
[56] N. Khiar, I. Fernandez, F. Alcudia, Tetrahedron Lett.
1993, 34, 123.
[57] G. Asensio, P. A. Aleman, M. Medio-Simon, Tetrahe-
dron: Asymmetry 1997, 8, 3647.
[58] M. Cinquini, S. Colonna, Int. J. Sulfur Chem. 1976, 8, 603.
[59] N. Kunieda, J. Nokami, M. Kinoshita, Bull. Chem. Soc.
Jpn. 1976, 49, 256.
[82] C. Bolm, M. Felder, Synlett 1994, 655.
[83] C. Bolm, J. Mueller, Tetrahedron 1994, 50, 4355.
[84] J. L. Von dem Bussche-Huennefeld, D. Seebach, Tetrahe-
dron 1992, 48, 5719.
[85] H. C. Brown, T. E. Cole, Organometallics 1985, 4, 816.
[86] D. J. Mathre, A. S. Thompson, A. W. Douglas, K. Hoogs-
teen, J. D. Carroll, E. G. Corley, E. J. J. Grabowski, J.
Org. Chem. 1993, 58, 2880.
[87] D. A. Evans, G. S. Peterson, J. S. Johnson, D. M. Barnes,
K. R. Campos, K. A. Woerpel, J. Org. Chem. 1998, 63,
4541.
[88] Crystallographic data (excluding structure factors) for
the structures 42, 46 and 52 reported in this paper have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC-
239332, 235551, 233648 respectively. Copies of the data
can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: int. codeþ44(1223)336–033; E-mail: deposit@
ccdc.cam.ac.uk].
[89] D. A. Evans, E. J. Olhava, J. S. Johnson, J. M. Janey, An-
gew. Chem. Int. Ed. Engl. 1998, 37, 3372.
[60] H. Tye, C. L. Skinner, Helv. Chim. Acta 2002, 85, 3272.
[61] Y. Tamura, J. Minamikawa, M. Ikeda, Synthesis 1977, 1.
[62] R. Appel, R. Kleinstueck, K. D. Ziehn, F. Knoll, Chem.
Ber. 1970, 103, 3631.
[63] H. Kwart, A. A. Kahn, J. Am. Chem. Soc. 1967, 89, 1950.
[64] M. R. Jones, D. J. Cram, J. Am. Chem. Soc. 1974, 96,
2183.
[90] J. Thorhauge, M. Roberson, R. G. Hazell, K. A. Jorgen-
sen, Chem. Eur. J. 2002, 8, 1888.
[91] C. M. Reynoso-Paz, M. M. Olmstead, M. J. Kurth, N. E.
Schore, Acta Crystallographica, Section E: Structure Re-
ports Online 2002, E58, m310.
[92] S. Immel, MolArchþ– MOLecular ARCHitect program,
V 7.35, TU-Darmstadt, Germany, 2004.
[65] C. R. Johnson, E. U. Jonsson, C. C. Bacon, J. Org. Chem.
1979, 44, 2055.
[66] C. R. Johnson, A. Wambsgans, J. Org. Chem. 1979, 44,
2278.
[67] C. R. Johnson, K. G. Bis, J. H. Cantillo, N. A. Meanwell,
M. F. D. Reinhard, J. R. Zeller, G. P. Vonk, J. Org. Chem.
1983, 48, 1.
[68] K. K. Andersen, Tetrahedron Lett. 1962, 93.
[69] B. C. Laguzza, B. Ganem, Tetrahedron Lett. 1981, 22,
1483.
[70] M. Reggelin, Ph. D. Thesis, University of Kiel (Germa-
ny), 1989.
[71] M. Reggelin, H. Weinberger, Tetrahedron Lett. 1992, 33,
6959.
[72] M. Reggelin, R. Welcker, Tetrahedron Lett. 1995, 36,
5885.
[93] Effects like these have been observed with other reac-
tions and Ph-BOX ligands but the reasoning for that is
necessarily completely different. See refs.[89,90]
[94] R. F. W. Jackson, A. D. Briggs, P. A. Brown, W. Clegg,
M. R. J. Elsegood, C. Frampton, J. Chem. Soc. Perkin
Trans. 1 1996, 1673.
[95] J. F. K. Muller, M. Neuburger, M. Zehnder, Helv. Chim.
Acta 1997, 80, 2182.
[96] V. Levacher, B. L. Eriksen, M. Begtrup, G. Dupas, G.
Queguiner, J. Duflos, J. Bourguignon, Tetrahedron Lett.
1999, 40, 1665.
[97] E. Vedejs, D. A. Engler, J. E. Telschow, J. Org. Chem.
1978, 43, 188.
[98] M. Shi, W. Zhang, Tetrahedron: Asymmetry 2004, 15, 167.
[99] E. J. Corey, R. Naef, F. J. Hannon, J. Am. Chem. Soc.
1986, 108, 7114.
1306
ꢀ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1295–1306