Enantioselective phospha-michael reaction of diphenyl phosphonate with nitroolefins utilizing conformationally flexible guanidinium/bisthiourea organocatalyst: Assembly-state tunability in asymmetric organocatalysis

Article abstract of DOI:10.1002/adsc.201100219

A catalytic enantioselective phospha-Michael reaction of diphenyl phosphonate to nitroolefins was achieved by utilizing a 1,3-diamine-tethered guanidinium/bisthiourea organocatalyst. The procedure is applicable to nitroolefins having various aromatic and

Full text of DOI:10.1002/adsc.201100219

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DOI: 10.1002/adsc.201100219
Enantioselective Phospha-Michael Reaction of Diphenyl
Phosphonate with Nitroolefins Utilizing Conformationally
Flexible Guanidinium/Bisthiourea Organocatalyst:
Assembly-State Tunability in Asymmetric Organocatalysis
Yoshihiro Sohtome,a,b,* Natsuko Horitsugi,a Rika Takagi,a and Kazuo Nagasawaa,*
a
Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology,
2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Fax : (+81)-42-388-7295; e-mail: knaga@cc.tuat.ac.jp
Present address: RIKEN Advanced Science Institute, 2–1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
b
Fax : (+81)-48-467-4666; e-mail: sohtome@riken.jp
Received: March 28, 2011; Revised: May 19, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100219.
Abstract: A catalytic enantioselective phospha-Mi-
chael reaction of diphenyl phosphonate to nitroole-
fins was achieved by utilizing a 1,3-diamine-teth-
ered guanidinium/bisthiourea organocatalyst. The
procedure is applicable to nitroolefins having vari-
ous aromatic and aliphatic substituents, and enables
an efficient access to phospha-Michael products
with 90–98% ee. Monomeric or oligomeric active
species of the catalyst can be utilized, depending on
the presence or absence of water.
text, our attention has been directed to the develop-
ment of a catalytic system enabling the construction
of versatile chiral environments by using a conforma-
tionally flexible organocatalyst, 1 or 2 (Figure 1).[5–8]
We have successfully developed unique catalytic pro-
cesses, such as retro-free,[5a,9] enantiodivergent[10] and
entropy-controlled organocatalysis,[11] by exploiting
the conformational flexibility of our catalysts.
Given the encouraging catalytic activity of 1,3-di-
AHCTUNGTREGaNNNU mine-tethered guanidine/bisthiourea organocatalyst
2,[12–14] which can selectively promote the Michael re-
action of phenol enolates to nitroolefins,[11] we plan-
ned to extend this strategy to the asymmetric forma-
Keywords: asymmetric synthesis; guanidinium spe-
cies; organocatalysis; phospha-Michael reaction;
thioureas
À
tion of phosphorus-carbon (P C) bonds. The conju-
gate addition of phosphonates to nitroolefins (phos-
pha-Michael reactions)[15–19] is a useful P C bond-
À
forming reaction that provides b-nitrophosphonates,
which are precursors for the preparation of b-amino-
Hydrogen-bonding catalysis has recently emerged as phosphonic acids.[20] However, only a few organocata-
an important strategy in asymmetric organocataly- lytic approaches to the phospha-Michael reaction, in-
sis.[1,2] Although many H-bonding catalysts have been volving the use of conformationally constrained orga-
designed based on inspiration drawn from molecular nocatalysts (i.e., quinines,[16a] axially chiral guani-
recognition processes in enzyme-catalyzed reactions,[3]
in general, their stereoselection processes are gov-
erned by a fundamentally different principle.[4] Since
enzymes are conformationally flexible, their selectivi-
ties are controlled by the kinetically favored confor-
mation, which affords substantial rate acceleration
relative to competing reaction pathways via other
conformations.[3] In sharp contrast, the vast majority
of the H-bonding catalysts reported to date are predi-
cated on the use of rigid chiral templates in order to
reduce the number of distinct possible diastereomeric
dines[16b] and squaramides that have chiral cyclohex-
ACHTUNGTRENNUNG
transiton states that can be involved.[1,2] In this con- Figure 1. Structures of 1 and 2.
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Table 1. Optimization studies.[a]
ACHTUNGTRENNUNG
[20]
À
the diverse biological activities of P C compounds,
additional studies to develop organocatalytic phos-
pha-Michael reactions are desirable. Herein, we show
that the conformationally flexible guanidinium/bis-
thiourea organocatalyst 2a·HCl permits a highly enan-
tioselective phospha-Michael reaction of diphenyl
phosphonate with nitroolefins in 77–95% yield with
90–98% ee. The assembly-state tunability of the cata-
lyst[21] by water in the reaction solution is also pre-
sented as a new aspect of guanidinium/bisthiourea or-
ganocatalysts.
Because the conformationally flexible organocata-
lyst can potentially provide many different diastereo-
meric transition states,[10] it is important to kinetically
control the stereoselectivity of bond formation
through the ideal transition state of the catalyst in
order to attain the maximum enantioselectivity with
conformationally flexible organocatalysts. According-
ly, efforts directed at exploring the phospha-Michael
reaction by utilizing conformationally flexible organo-
catalyst 2a·HCl[22] were first focused on the solvent
effect on the conjugate addition of diphenyl phospho-
nate (3) with b-nitrostyrene (4a). As shown in
Table 1, the cooperative procedure using 2a·HCl and
potassium carbonate[23] promoted the smooth phos-
pha-Michael reaction, giving the corresponding phos-
pha-Michael adduct 5a in 85–99% yield. A feature of
this catalytic system is that (R)-5a predominates re-
gardless of the solvent used (entries 1–6); these re-
sults contrast with the solvent-dependent enantio-
[a]
Reactions were carried out on a 0.1-mmol scale in
1.0 mL of the solvent.
Isolated yield.
Determined by chiral HPLC analysis.
The absolute configuration of 5a was determined to be
(R) on the basis of its optical rotation.[16]
Reactions were carried out on a 0.1-mmol scale in
1.0 mL of toluene and 0.5 mL H2O.
[b]
[c]
[d]
[e]
[f]
The reaction was carried out on a 5-mmol scale in 50 mL
of toluene and 25 mL H2O.
The ee value after single recrystallization.
ACHTUNGTRENNUNGswitching in previously developed Mannich-type reac-
tions[10] and Friedel–Crafts alkylations.[11,24] In compar-
ison with polar solvents (entries 1–3: 7–42% ee), non-
polar solvents (entries 4–6: 88–89% ee) gave better
[g]
enantioselectivities. Among the solvents tested, tolu- tion rate (entries 7–11) led to high enantioselectivity
ene gave the best enantioselectivity (entry 6, 89% ee). for the reactions involving both aromatic and aliphat-
A significant improvement of the enantioselectivity ic nitroolefins. For example, p-substituted aromatic ni-
was seen upon addition of water, and the ee value was troolefins including an electron-withdrawing or elec-
increased to 95% ee (entry 7). The reaction proceeded tron-donating group gave the corresponding phospha-
with as little as 1 mol% of 2a·HCl to give 5a without Michael adducts in 88–90% yield with 90–96% ee (en-
loss of reactivity and enantioselectivity (entry 8, 99% tries 1–3). Disubstituted aromatic nitroolefin 4e was
yield, 95% ee). As shown in entry 9, the developed also available as a substrate, giving the product 5e in
catalytic enantioselective phospha-Michael reaction 81% yield with 96% ee (entry 4). Naphthyl-, 2-thien-
was successfully performed on a 5-mmol scale with yl- and 2-furyl-substituted nitroolefins also afforded
1 mol% catalyst, giving the product 5a in 99% yield the corresponding phospha-Michael adducts in 77–
with 95% ee. A single recrystallization of 5a (95% ee) 84% yield with 95–98% ee (entries 5–8). Among the
provided the optically pure compound in 91% yield most challenging substrates reported to date in orga-
by vapor diffusion of hexane into dichloromethane so- nocatalytic phospha-Michael reactions are sterically
lution at 48C
bulky aliphatic nitroolefins, which are well known to
Next, the scope of catalytic phospha-Michael reac- be poorly reactive.[16] Indeed, only one organocatalyt-
tion with a range of nitroalkenes 4 was examined ic approach has been reported to afford a highly
(Table 2). For operational convenience, all reactions enantioselective reaction (>90% ee), and it required
were performed with 5 mol% of 2a·HCl under bipha- 20 mol% catalyst loading.[16c] As can be seen in en-
sic conditions. Fine-tuning of the reaction conditions tries 9 and 10, 2a displayed extraordinary high catalyt-
by changing the amount of potassium carbonate or ic activity for 4j and 4k, attaining high enantioselec-
the reaction temperature in order to control the reac- tivities with 5 mol% catalyst loading: 4j: 98% yield,
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Enantioselective Phospha-Michael Reaction of Diphenyl Phosphonate with Nitroolefins
Table 2. Catalytic phospha-Michael reactions with various
nitroolefins using 2a·HCl.[a]
Scheme 1. The phospha-Michael reaction of 3 with 4a utiliz-
ing 6 or 7·HCl.
[a]
Reactions were carried out on a 0.1-mmol scale in
1.0 mL of toluene.
Isolated yield.
Determined by chiral HPLC analysis.
The absolute configuration of 5 was determined to be
(R) on the basis of the optical rotation.[16]
The reactions were carried out in 0.5 mL toluene and
0.25 mL H2O.[f] The reactions were carried out in 0.5 mL
toluene and 0.1 mL H2O.
[b]
[c]
[d]
served in the reaction using guanidinium 7·HCl. Thus,
the guanidinium cation in the catalyst plays a key role
in enhancement of the reaction rate of the phospha-
Michael reaction under biphasic conditions in the
[e]
[g]
presence of water,[26] suggesting that the P C bond-
À
Ice was formed in the reaction media.
forming reaction might take place through the inter-
action of guanidinium/phosphite at the interfacial
layer.[22]
The unique solvent/water effects described
92% ee (entry 9) and 4k: 95% yield, 92% ee above,[24,26] along with our wish to explore assembly-
(entry 10).
state-tunable organocatalysis, stimulated us to investi-
To gain insight into the reaction mechanism, we gate the relationship between the ee of the catalyst
next investigated the structure/catalytic activity rela- 2a·HCl and the ee of the phospha-Michael product 5a
tionship with respective to possible catalytic sites in the presence or absence of water.[27] A linear rela-
(Scheme 1). Use of the structural variants 6 and tionship between the % ee of 2a·HCl and that of 5a
7·HCl under the same reaction conditions as em- was obtained for the reaction in the absence of water,
ployed in Table 1, entry 6 (conditions A) and entry 7 suggesting that the stereoselectivity in this process is
(conditions B) resulted in a drastic decline of the controlled by the inherent structure of monomeric
enantioselectivity (7–14% ee). These observations 2a·HCl.[10,11] In contrast, a negative non-linear effect
strongly suggest that the stereodiscrimination process was observed upon addition of water.[9c] These obser-
in catalytic phospha-Michael reactions using 2a·HCl is vations indicate the importance of catalyst assembly
governed by cooperative activation of the sub- for the construction of a favorable chiral environment
strates[25] by guanidinium and thiourea in 2a·HCl for attainment of higher ee of (R)-5a in the phospha-
under both homogeneous and biphasic conditions. As Michael reaction of 3 with 4a (Table 1, entry 6 vs.
regards reactivity, a significant difference between 6 entry 7). Thus, the results shown in Figure 2 support
and 7·HCl was observed. For example, the addition of the idea that the assembly state of the 2a·HCl can be
water drastically decreased the reactivity of 6, in tuned depending on the presence or absence of water.
which the guanidinium group in 2a·HCl is replaced by We believe that assembly-state tunability of the cata-
a thiourea group (toluene: 87% yield vs. toluene/ lyst[21] is a potentially useful strategy for modulation
H2O=2/1: 16% yield). On the other hand, significant- of the chiral environments of conformationally flexi-
ly higher reactivity upon addition of water (toluene: ble guanidinium/bisthiourea organocatalysts. Further
46% yield vs. toluene/H2O=2/1: 78% yield) was ob- mechanistic studies are ongoing.
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Acknowledgements
This work was supported by a Grant-in-Aid for Encourage-
ment of Young Scientists (B) and a grant from The Uehara
Memorial Foundation.
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n-hexane/ethanol=80/20,
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17.9 min, minor; 13.6 min.
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COMMUNICATIONS
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Adv. Synth. Catal. 2011, 353, 2631 – 2636