Hydrogen-bond-mediated asymmetric cascade reaction of stable sulfur ylides with nitroolefins: Scope, application and mechanism

Article abstract of DOI:10.1002/chem.201104021

A hydrogen-bond-mediated asymmetric [4+1] annulation/rearrangement cascade of stable sulfur ylides and nitroolefins was developed. This reaction provides a facile route to enantioenriched 4,5-substituted oxazolidinones in moderate to excellent isolated yields (65-96 %) with excellent stereocontrol (up to more than 95:5 d.r. and 97:3 e.r.). This methodology was successfully applied to the concise synthesis of two bioactive molecules. The stereocontrolled modes and mechanism have been proposed to explain the origin of this stereochemistry. Controlled cascade: A hydrogen-bond-mediated asymmetric [4+1] annulation/rearrangement cascade of stable sulfur ylides and nitroolefins was developed (see scheme). This reaction provides a facile route to enantioenriched 4,5-substituted oxazolidinones. Stereocontrolled modes and a mechanism are proposed to explain the origin of the stereochemistry. Copyright

Full text of DOI:10.1002/chem.201104021

FULL PAPER
DOI: 10.1002/chem.201104021
Hydrogen-Bond-Mediated Asymmetric Cascade Reaction of Stable Sulfur
Ylides with Nitroolefins: Scope, Application and Mechanism
Liang-Qiu Lu, Fang Li, Jing An, Ying Cheng, Jia-Rong Chen, and Wen-Jing Xiao*[a]
Abstract: A hydrogen-bond-mediated asymmetric [4+1] annulation/rearrangement
cascade of stable sulfur ylides and nitroolefins was developed. This reaction pro-
vides a facile route to enantioenriched 4,5-substituted oxazolidinones in moderate
to excellent isolated yields (65–96%) with excellent stereocontrol (up to more
than 95:5 d.r. and 97:3 e.r.). This methodology was successfully applied to the con-
cise synthesis of two bioactive molecules. The stereocontrolled modes and mecha-
nism have been proposed to explain the origin of this stereochemistry.
Keywords: annulation · asymmetric
synthesis · hydrogen bonds · re-
AHCTUNGTERGaNNUN rrangement · sulfur · ylides
Introduction
involving this active intermediate have been developed.[4–7]
For instance, the groups of Borhan,[5a,b] Aggarwal[5c–e] and
Tang[4b,6a,b] have recently performed elegant studies on cas-
cade reactions with active or semistable sulfur ylides as the
key intermediates that can be used to efficiently construct
complex cyclic molecules. In this field, we are interested in
the design and implementation of novel cascade reactions
involving stable sulfur ylides that provide new routes to oxa-
zolidinones, pyrrolines, and some other important heterocy-
cles.[7] At the same time, asymmetric processes that take
place in cascade reactions and involve sulfur ylides is anoth-
er research topic of importance. However, to the best of our
knowledge, most studies have largely relied on the use of
stoichiometric chiral sources, that is, enantiopure substrates
(e.g., Scheme 2a)[5a,b] or chiral sulfides (e.g., Sche-
me 2b).[5c–f,7c,d] Therefore, the development of asymmetric
cascade reactions involving sulfur ylides that use simpler
and more economical substoichiometric stereocontrol ele-
ments, is still highly desirable.[8] Moreover, the asymmetric
construction of chiral oxazolidinones has attracted remark-
able research interest due to the biological and synthetic sig-
nificance of such heterocyclic motifs.[9,10]
Over the last decade, cascade reactions, particularly those
including dipole-type intermediates, have been identified as
one of the most powerful tools available to access a variety
of functional cyclic compounds.[1,2] For example, 1,3-dipole
intermediates generated in situ, trimethylenemethane
(TMM) reagents,[2c] and 2,3-butadienoates[2d] have been
widely used as versatile building blocks to construct five- to
seven-membered or even larger cyclic compounds
(Scheme 1). These key zwitterionic intermediates, which
couple nucleophilic and electrophilic components, can react
with other reaction partners consecutively. From this stand-
point, sulfur ylides were believed to possess similar charac-
teristics[3] and thus many unprecedented cascade reactions
Scheme 1. Typical character of dipole-type intermediates: the electrophile
and nucleophile coexist in one molecule.
[a] Dr. L.-Q. Lu, Dr. F. Li, J. An, Y. Cheng, Dr. J.-R. Chen,
Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (P.R. China)
Fax : (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Scheme 2. Traditional methods applied to asymmetric cascade reactions
of sulfur ylides: stoichiometric chiral sources, such as a) enantiopure sub-
strates or b) chiral sulfides.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201104021.
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Based on one of our previous reports, referring to the
[4+1] annulation/rearrangement cascade of stable sulfur
ylides with nitroolefins,[7a,d] we further developed an asym-
metric process that allows facile synthesis of chiral 4,5-sub-
stituted oxazolidinones with good chemoselectivity (65–96%
yield) and good stereoselectivity (up to 95:5 d.r. and 97:3
e.r.). This study features 1) the use of inexpensive and recov-
erable C2-symmetric multiple hydrogen-bonding catalysts
that can be obtained by a one-step procedure from readily
available commercial materials; 2) successful application to
the asymmetric synthesis of (+)-epi-cytoxazone[11] and vali-
noctin A;[12] and 3) a rational explanation for the stereo-
chemical course.
enantiomeric ratio (Figure 1; 55% yield, 52:48 e.r.). Chang-
ing the dimethyl amino group to a primary amino group
(4b) resulted in the formation of a completely racemic prod-
uct. We therefore moved our attention to other hydrogen-
bonding catalysts, that is, the bis-sulfonamide 4c, which fa-
cilitated excellent stereocontrol in our previous work;[14b]
however, in this case, the use of 4c did not result in any im-
provement in enantioselectivity. We assumed that if the
stronger hydrogen-bonding ability of stable sulfur ylides re-
sulted in this disappointing enantioinducement, the addition
of hydrogen-bonding donors would reverse this situation.
With this consideration in mind, other multiple hydrogen-
bonding catalysts were further examined. We were pleased
to find that the use of the triple hydrogen-bonding catalyst
4d gave product 3aa with encouraging enantioselectivity
(91% yield, 66:34 e.r.); when the quadruplex hydrogen-
bonding catalyst 4e was employed, to our delight, the enan-
tiomeric ratio further increased to 87:13, albeit in reduced
yield (37%). Encouraged by this result, we continued to
screen a wide array of multiple hydrogen-bonding catalysts
to further improve the enantio- and chemoselectivity. As
highlighted in Figure 1, we observed that: 1) among the
three chiral backbones, for example, cyclohexyl (4e: 37%
yield and 83:17 e.r.), diphenylethyl (4k: 66% yield and
90:10 e.r.) and binaphthyl (4n: 22% yield and 53:47 e.r.)
units, the second was the best choice; 2) compared with
thiourea-type hydrogen-bonding catalysts, urea-type cata-
lysts generally exhibited better stereoinduction abilities (4e
vs. 4i and 4k vs. 4l); and 3) after examining the effects of
electronic factors and steric hindrance on the catalytic activ-
ity, we found that the 3,5-bis(trifluoromethyl)benzyl sub-
stituent proved to be superior (4e vs. 4 f–h, 4i vs. 4j and 4l
vs. 4m). As a result, the C2-symmetric chiral urea 4l was
found to be the most efficient catalyst for this cascade reac-
tion (4l: 81% yield, 93:7 e.r.). Careful evaluation of many
other reaction parameters, such as the solvent, concentration
and temperature (see the Supporting Information for de-
tails) further improved the reaction efficiency in terms of
both enantio- and chemoselectivities (88% yield, 95:5 e.r.).
However, the catalyst-loading study showed that either a fur-
ther decrease or an increase in the amount of catalyst 4l did
not have any positive effect on enantioselectivity.
Considering the efficiency of hydrogen-bonding donors
such as thiourea, urea and amide to direct and activate ni-
troolefins in their asymmetric Michael addition re-
ACHTUNGTRENNUNG
actions,[13,14] we proposed that the asymmetric [4+1] annula-
tion/rearrangement cascade of nitroolefins with sulfur ylides
might be realised through asymmetric hydrogen-bond con-
trol (Scheme 3). However, we also recognised a vital chal-
Scheme 3. Proposal and challenge: hydrogen-bonding-mediated asym-
metric [4+1] annulation/rearrangement cascade of stable sulfur ylides
with nitroolefins.
lenge that must be addressed for this proposal to be real-
ised: stable acyl sulfur ylides would coordinate with hydro-
gen-bonding catalysts, possibly in preference to nitroolefins,
due to their zwitterionic character, which would make these
catalysts ineffective in the asymmetric cascade reaction. This
was indeed confirmed by the results of our hydrogen-bond-
ing titration experiments that were conducted with a thio-
Scope of the reaction: With the optimum conditions in
hand, we began to explore the substrate scope of this hydro-
gen-bond-mediated asymmetric cascade reaction. As high-
lighted in Scheme 4, this strategy proved to be tolerant of
a wide range of nitroolefin partners, and various enantioen-
riched oxazolidinones were obtained in moderate to excel-
lent yields with high stereoselectivities (65–96% yields,
>95:5 d.r., up to 97:3 e.r.). Electronic and steric variation of
nitrostyrenes were accommodated with good yields and high
enantiomeric ratios (Scheme 4, 3aa–ai: 74–88% yields,
>95:5 d.r. and 90:10–95:5 e.r.). It should be noted that halo-
gen atoms and methoxyl groups on the aryl rings could be
easily removed or transformed into other groups through
the use of transition-metal catalysts;[17] product 3aj is an im-
ACHTUNGTRENNUNG
Results and Discussion
Optimisation of reaction conditions: To validate this propos-
al, we carried out the cascade reaction of sulfur ylide 1a and
nitroolefin 2a with 50 mol% of Takemotoꢁs catalyst (4a) in
xylene at À258C for 72 h. The desired oxazolidinone prod-
uct 3aa was obtained in moderate yield, but with a very low
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Reactions of Sulfur Ylides with Nitroolefins
FULL PAPER
reaction could deliver the de-
sired products with a good level
of chemo- and stereoselectivity
(Scheme 5, 3ba–fa: 89–91%
yields, >95:5 d.r. and up to
94:6 e.r.). Remarkably, signifi-
cant variation in the steric
demand of the sulfur ylide was
also possible. For example, the
meta-bromo-substituted sulfur
ylide 1g could take part in the
reaction efficiently to give the
desired product 3ga in 89%
yield with 95:5 d.r. and 95:5
e.r.; for the ortho-methoxyl
sulfur ylide 1h, the correspond-
ing oxazolidinone 3ha could be
obtained in good yield with
a slight decrease in the enantio-
meric ratio (Scheme 5, 3ha:
86% yield, >95:5 d.r. and
88:12 e.r.). To our delight,
heteroaromatic
compounds,
which are valuable in medicinal
chemistry, were also found to
be suitable reaction compo-
nents for this asymmetric cas-
cade reaction. For example,
treatment of 2-thiophenyl-sub-
stituted sulfur ylide 1i with ni-
troolefin 2a under the optimum
reaction conditions generated
the heteroarene-containing oxa-
zolidinone 3ia in 96% yield
with 95:5 d.r. and 94:6 e.r. In
addition to aryl- and heteroar-
yl-substituted acyl sulfur ylides,
the cascade reaction of alkyl-
substituted sulfur ylides also
proved
to
be
feasible
(Scheme 5, 3ja: 72% yield,
95:5 d.r. and 90:10 e.r.).
Figure 1. Optimisation of the hydrogen-bond-mediated asymmetric cascade reaction conditions: screening hy-
drogen-bonding catalysts. Reagents and conditions: 2a (0.10 mmol, 1.0 equiv) and 1a (0.11 mmol, 1.1 equiv)
were used. Enantiomeric ratios (e.r.) (anti) were determined by chiral HPLC analysis. [a] N,N-dimethylpyri-
din-4-amine (DMAP) was not added. [b] 10 mol% 2-chlorophenylthiourea (2-CTU) was added.[16]
Synthetic applications of the re-
action: To illustrate the synthet-
ic utility of this asymmetric cas-
portant intermediate that allows access to a family of poten-
tial a-adrenoceptor antagonists.[18] In addition, alkenyl-
(Scheme 4, 3aj: 87% yield, >95:5 d.r. and 91:9 e.r.) and
alkyl-substituted nitroolefins (Scheme 4, 3ak: 65% yield
and 95:5 e.r.; 3al: 67% yield and 97:3 e.r.) could also be suc-
cessfully used for the enantioselective construction of opti-
cally active oxazolidinones.
As outlined in Scheme 5, the same conditions were also
compatible with a wide range of stable sulfur ylides.
Through the introduction of electron-donating or electron-
withdrawing substituents on the benzene ring, this cascade
cade reaction, we performed two reactions on millimolar
scales (Scheme 6). The corresponding aryl- or alkyl-substi-
tuted chiral products were provided efficiently with good
enantiocontrol (3bf: 80% yield, >95:5 d.r. and 94:6 e.r.;
3bm: 66% yield, >95:5 d.r. and 92:8 e.r.). It is worth noting
that the stereocontroller, chiral urea 4l, could be easily re-
covered during the purification of the product. Moreover,
starting from these oxazolidinones, (+)-epi-cytoxazone and
a vital intermediate of the natural dipeptide valinoctin A,
which respectively possess significant bioactivities in terms
of selectively modulating Th2 cytokine secretion[11a] and in-
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W.-J. Xiao et al.
Scheme 5. Scope of the hydrogen-bond-mediated asymmetric [4+1] annu-
lation/rearrangement cascade with respect to stable sulfur ylides. For the
optimum conditions: see Figure 1. Yield is given as the isolated yield.
Diastereomeric ratios (d.r.) (anti/syn) values were determined by
1H NMR spectroscopic analysis of the reaction mixture and e.r. (anti)
values were determined by chiral HPLC analysis. OMP: o-methoxyphen-
yl.
Scheme 4. Scope of the hydrogen-bond-mediated asymmetric [4+1] annu-
lation/rearrangement cascade with respect to nitroolefins. For the opti-
mum conditions: see Figure 1. Yield is given as the isolated yield. Diaste-
reomeric ratios (d.r.) (anti/syn) were determined by 1H NMR spectro-
scopic analysis of the reaction mixture and e.r. (anti) values were deter-
mined by chiral HPLC analysis.
hibiting farnesyl transferase,[12a] could be accessed through
a straightforward two-step routine.
Possible stereochemical course of reaction: To address the
hydrogen-bond-mediated mechanism, a series of experi-
ments, such as in situ IR experiments, the Job method, and
hydrogen bonding titration experiments, were performed
(see details in the Supporting Information).[15] As a result,
we concluded that: 1) the in situ IR experiment implied that
only the [4+1] annulation could be observed at low temper-
atures and that the subsequent reaction process to generate
oxazolidinones occurred only at higher temperature (358C);
2) the Job method experiments, not only confirmed the exis-
tence of hydrogen-bonding interactions between the starting
materials and the nitronate intermediates, but also implied
that one molecule of the quadruplex hydrogen-bonding cat-
alyst 4k could coordinate two molecules of sulfur ylides or
nitroolefins, but only one molecule of the nitronate inter-
mediate; and 3) according to the results of hydrogen-bond-
ing titration experiments, we speculated that the thiourea
catalyst 4k exhibited the strongest binding ability with
sulfur ylides and the weakest with nitroolefin (ka1 =25, ka2 =
3.2, ka3 =5.4, where ka1, ka2 and ka3 are defined as the bind-
ing constants of sulfur ylide 1a, nitroolefin 2a and the nitro-
nate analogue Me-7ae with the thiourea catalyst 4k).
Scheme 6. Synthetic application: concise asymmetric synthesis of (+)-epi-
cytoxazone and valinoctin A. PMP=p-methoxyphenyl. Conditions:
1) 1 mmol scale: 50 mol% 4l, 10 mol% 2-CTU, 10 mol% DMAP,
0.0125 m in xylene, À358C, 96 h, then 24 h at 358C; 2) NaH2PO4·2H2O,
meta-chlorobenzoperoxoic acid (m-CPBA), 1,2-dichloroethane (DCE),
608C, 6 h; 3) NaBH4, HOAc, THF, 08C–RT, 2 h; 4) K2CO3, EtOH; 5) See
ref. [12b].
In light of previous work on asymmetric multiple hydro-
gen-bonding catalysis,[19] two efficient modes were estab-
lished to understand the origin of stereodiscrimination in
this asymmetric cascade reaction (Scheme 7): in mode A,
two urea segments coordinate to the oxygen atom of the
acyl sulfur ylide and nitroolefin, functioning as a Lewis acid
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Reactions of Sulfur Ylides with Nitroolefins
FULL PAPER
II. Although the second complexation process is thermody-
namically disadvantageous (ka2’<ka1’),[20] the cooperative
Lewis acid/base activation served by the C2-symmetric urea
catalyst 4l in mode B would make the asymmetric Michael
addition of sulfur ylide to nitroolefin proceed efficiently.
Subsequently, the hydrogen-bonding complex of the nitro-
nate intermediate and catalyst 4l (complex IV) gradually
forms through an intramolecular chemoselective O-alkyla-
tion of the zwitterionic intermediate complex (complex III).
Finally, presumably because of its stronger binding ability
(ka1’ > ka3’), the unreacted sulfur ylide preferentially coordi-
nates with catalyst 4l, replacing nitronate intermediate 7 to
ensure the turnover of the hydrogen-bonding catalyst and
the release of intermediates at low temperature. After most
of the starting material was consumed, the reaction system
was warmed to promote the rearrangement of chiral nitro-
nate intermediates 7 into the final enantioenriched oxazoli-
dinones 3. Consequently, stepwise operation at a tempera-
ture that ensures the high enantioselectivity of this cascade
reaction would be explained by this proposed mechanism.
Tentatively, the relatively high catalyst loading in this asym-
metric cascade reaction arises either from a competing cata-
lyst-free cascade process or possibly from inhibitory action
of intermediates on hydrogen catalysts as depicted in com-
plex III and complex IV.
Scheme 7. Rationalising the stereocontrolled course of this hydrogen-
bond-mediated asymmetric cascade reaction.
to activate and/or direct the two reactants; in mode B, one
urea unit imposed on the nitroolefin functions as a Lewis
acid, whereas the other plays the role of a Lewis base to ac-
tivate and direct the acyl sulfur ylide. The involvement of
these two modes was convincingly supported by the above
experiments and theoretical calculations;[19b] the absolute
configuration deduced from these two modes are in accord-
ance with those obtained in the chemical transformation of
3bf or 3bm.[11b,12b] However, at the current stage, Mode B is
believed to be favoured, possibly as a result of activation
energy.
Based on these results, we also propose a possible catalyt-
ic cycle for the hydrogen-bond-mediated asymmetric cas-
cade [4+1] annulation/rearrangement reaction of stable
sulfur ylides with nitroolefins. As illustrated in Scheme 8,
catalyst 4l incorporates sulfur ylide 1 with the charge-sepa-
rated isomer into complex I through strong hydrogen-bond-
ing interactions; this complex could further transiently coor-
dinate with another molecule of nitroolefin to form complex
Conclusion
In this full paper, we have developed a hydrogen-bond-
mediated asymmetric [4+1] annulation/rearrangement cas-
cade of stable sulfur ylides with
nitroolefins. A readily available,
inexpensive and recoverable
C2-symmetric chiral urea cata-
lyst could efficiently promote
this cascade reaction and the
optically active oxazolidinones
were provided with good re-
AHCTUNGTERGaNNUN ction efficiency and high ste-
reoselectivities. Moreover, the
corresponding products can be
applied in the concise synthesis
of (+)-epi-cytoxazone and vali-
noctin A, and a possible stereo-
control mode of the hydrogen-
bonding cooperative catalysis
was proposed on the basis of
reliable experiments. Further
studies directed toward the ap-
plication of this strategy to
other stable sulfur-ylide-partici-
pating cascade reactions for the
enantioselective construction of
other heterocyclic adducts will
be reported in due course.
Scheme 8. Mechanistic proposals for the hydrogen-bond-mediated asymmetric cascade reaction of stable sulfur
ylides with nitroolefins.
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W.-J. Xiao et al.
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Representative procedure: To a 25 mL flask equipped with a magnetic
stir bar was added nitroolefin 2a (0.1 mmol, 1.0 equiv, 17.9 mg), 2-CTU
(0.01 mmol, 10 mol%, 1.87 mg), DMAP (0.01 mmol, 10 mol%, 1.22 mg),
catalyst 4l (0.05 mmol, 50 mol%, 36.13 mg) and xylene (8.0 mL), and the
mixture was stirred at À358C for 30 min. Sulfur ylide 1a (0.11 mmol,
1.1 equiv, 20.5 mg) was added directly to the above system. After 96 h,
the reaction mixture was slowly warmed to 358C and stirring was contin-
ued for 24 h. The desired chiral product 3aa was obtained in 88% yield
by flash chromatography (silica: 200–300; petroleum ether/CH2Cl2/ace-
tone). The diastereomeric ratio and enantiomeric ratio were determined
by 1H NMR spectroscopic analysis and chiral stationary phase HPLC
analysis of the reaction mixture, respectively. White solid; diastereomeric
ratio: >95:5, enantiomeric ratio: 95:5 (Daicel Chirapak OD-H; hexane/
isopropanol=80:20; flow rate: 0.7 mLminÀ1; T=258C; 254 nm; tR =17.79
(minor), 22.25 min (major)). [a]2D7 = +108 (c=1.3 in CHCl3); 1H NMR
(600 MHz, CDCl3): d=7.98 (d, J=7.5 Hz, 2H), 7.62 (t, J=7.4 Hz, 1H),
7.49 (t, J=7.7 Hz, 2H), 7.42–7.29 (m, 2H), 7.04 (t, J=7.4 Hz, 1H), 6.89
(d, J=8.2 Hz, 1H), 5.59 (d, J=4.5 Hz, 1H), 5.52 (d, J=4.3 Hz, 2H),
3.64 ppm (s, 3H); 13C NMR (100 MHz, CDCl3 + [D6]DMSO): d=192.6,
157.7, 155.4, 133.6, 133.4, 128.9, 128.3, 128.1, 127.1, 125.7, 120.1, 109.9,
79.8, 54.2, 52.5 ppm; MS: m/z: 297.6 [M]+; elemental analysis calcd (%)
for C17H15NO4: C 68.68, H 5.09, N 4.71; found: C 68.57, H 5.02, N 4.62.
Acknowledgements
We are grateful to the National Science Foundation of China (NO.
21072069 and 21002036) and the National Basic Research Programme of
China (2011CB808600) for support of this research.
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4078
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Chem. Eur. J. 2012, 18, 4073 – 4079

Reactions of Sulfur Ylides with Nitroolefins
FULL PAPER
d) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Re-
smerita, N. K. Garg, V. Percec, Chem. Rev. 2011, 111, 1346.
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catalyst 4k, where ka1’, ka2’ and ka3’ are defined as the binding con-
stants of sulfur ylide 1a, nitroolefin 2a and nitronate analogue
Me-7ae with the corresponding urea-type hydrogen-bonding cata-
lysts, respectively. According to ref [19b], 4l is reported to have
larger binding constants than thiourea-catalyst 4k.
[20] We speculated that the urea-catalyst 4l could exhibit the same trend
with respect to the binding strength (ka1’>ka3’>ka2’) as the thiourea-
Received: December 22, 2011
Published online: February 23, 2012
Chem. Eur. J. 2012, 18, 4073 – 4079
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4079