Chiral Br?nsted Acid as a True Catalyst: Asymmetric Mukaiyama Aldol and Hosomi-Sakurai Allylation Reactions

Article abstract of DOI:10.1021/jacs.5b04168

Highly diastereo- and enantioselective Mukaiyama aldol reaction catalyzed by a new chiral Br?nsted acid, N-(perfluorooctanesulfonyl)thiophosphoramide, is described. The perfluorooctyl substituent on the sulfonyl group of the catalyst plays an essential role in the stereoselection. The catalyst also allows the asymmetric Hosomi-Sakurai allylation, which has been considerably challenging due to the low reactivity of allylsilanes. ²⁹Si and ³¹P NMR monitoring reveals the characteristic feature of the thiophosphoramide catalyst, acting as a strong Br?nsted acid even in the presence of excess silyl nucleophiles, which cannot be found in other related phosphoric acid analogues.

Full text of DOI:10.1021/jacs.5b04168

Communication
pubs.acs.org/JACS
Chiral Brønsted Acid as a True Catalyst: Asymmetric Mukaiyama
Aldol and Hosomi−Sakurai Allylation Reactions
Masahiro Sai* and Hisashi Yamamoto*
Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
S
* Supporting Information
Scheme 1. Asymmetric Reactions of Aldehydes Catalyzed by a
New Chiral BINOL-Based Brønsted Acid
ABSTRACT: Highly diastereo- and enantioselective
Mukaiyama aldol reaction catalyzed by a new chiral
Brønsted acid, N-(perfluorooctanesulfonyl)-
thiophosphoramide, is described. The perfluorooctyl
substituent on the sulfonyl group of the catalyst plays an
essential role in the stereoselection. The catalyst also
allows the asymmetric Hosomi−Sakurai allylation, which
has been considerably challenging due to the low reactivity
of allylsilanes. 29Si and 31P NMR monitoring reveals the
characteristic feature of the thiophosphoramide catalyst,
acting as a strong Brønsted acid even in the presence of
excess silyl nucleophiles, which cannot be found in other
related phosphoric acid analogues.
Brønsted acid even in the presence of excess silyl enol ethers. We
also describe the synthesis of a new chiral N-(perfluoro-
octanesulfonyl)thiophosphoramide catalyst and the application
to the asymmetric Mukaiyama aldol and Hosomi−Sakurai
allylation reactions (Scheme 1). The longer perfluorooctyl
group of the catalyst plays a decisive role in the stereoselection.
To probe the actual catalyst of reactions involving chiral
BINOL-based phosphoric acid analogues10 and silyl enol ethers,
catalysts A1−D1 were treated with silyl enol ether 1a and
monitored by 29Si and 31P NMR spectroscopy (Scheme 2).11,12
Upon mixing the most acidic selenophosphoramide A1 with 1a,
the new signals appeared at 16.4 ppm (29Si NMR) and at 37.9
ppm (31P NMR), which would correspond to the silylated A1.13
In the case of thiophosphoramide B1, no new signal was
detected. The reaction of phosphoramide C1 with 1a generated
he addition of silyl enol ethers to carbonyl compounds,
Tknown as the Mukaiyama aldol reaction, has been the
subject of extensive investigation due to the usefulness of
products containing one new carbon−carbon bond and up to
two new stereogenic centers.1,2 Many successful examples of the
asymmetric version of this reaction have been developed
employing either Lewis acid3 or Lewis base4 catalysts. In
contrast, chiral Brønsted acid-catalyzed asymmetric reactions are
less explored. Rawal et al. reported a TADDOL-catalyzed
asymmetric Mukaiyama aldol reaction of aldehydes and
acylphosphonates with O-silyl-N,O-ketene acetals.5 Jørgensen
et al. described a chiral bis(sulfonamide) catalyst in an
asymmetric Mukaiyama aldol reaction of electron-deficient
aldehydes with ketene silyl acetals.6 However, these two-proton
systems generally require highly activated substrates for both
nucleophiles and electrophiles because such catalysts activate the
carbonyl group via weak hydrogen bonding. Thus, the
development of chiral single Brønsted acid catalysts with
enhanced acidity is highly desirable as they are expected to
activate carbonyl compounds for the addition of weak
nucleophiles. Recently, List et al. designed a new class of chiral
binaphthyl-derived disulfonimide catalysts7 and accomplished
the asymmetric Mukaiyama aldol reaction with a broad substrate
scope.7a In this reaction, the actual catalyst is shown to be the silyl
Lewis acid in situ generated by the reaction of the chiral
disulfonimide with ketene silyl acetals. Independently, we also
developed the asymmetric Mukaiyama aldol reaction using N-
triflylthiophosphoramides as the catalyst, which have expanded
the substrate scope by allowing the use of less reactive silyl enol
ethers.8,9 However, the mechanism and the true catalyst of the
reaction were not fully investigated. Here, we disclose the unique
feature of the thiophosphoramide catalyst, acting as a strong
TMS-C1, which exhibited 29Si NMR signal at 35.3 ppm (JSi−P
=
9.2 Hz) and 31P NMR signal at −9.1 ppm. Phosphoric acid D1
was also silylated, and new signals at 28.3 ppm (JSi−P = 4.5 Hz,
29Si NMR) and −8.6 ppm (31P NMR) were observed.14 As a
result, only thiophosphoramide B1 was not silylated by 1a. Silyl
enol ether 1a is considered to be protonated by the catalysts to
generate the oxonium ion 1a′ (Scheme 3). In the case of catalyst
B1, the counteranion causes the deprotonation of 1a′ to
regenerate catalyst B1 and 1a. On the other hand, in the case
of catalysts A1, C1, and D1, the counteranion can attack the
TMS group of 1a′ to generate the silyl Lewis acid and the
ketone.15 These results clearly demonstrate the unique feature of
the thiophosphoramide of activating the carbonyl group as a
Brønsted acid even in the presence of excess silyl enol ethers in
contrast to other phosphoric acid analogues.
Received: April 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b04168
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Journal of the American Chemical Society
Communication
Scheme 2. Investigation of the Actual Catalyst
Table 1. Optimization of Reaction Conditions
a
b
c
entry
catalyst
temp. (°C)
yield (%)
dr syn/anti
er syn
1
2
3
4
B1
B2
B3
B4
B4
B4
−78
−78
−78
−78
−100
−100
93
95
92
93
92
0
74:26
85:15
96:4
96:4
97:3
−
79:21
88:12
95:5
96:4
d
5
96.5:3.5
−
de
,
6
a
b
Isolated yield (containing syn- and anti-diastereomers). Determined
by H NMR analysis of the crude reaction mixture. Determined by
supercritical fluid chromatography on a chiral stationary phase. With
3 mol % catalyst B4 for 16 h. With 12 mol % 2,6-di-tert-butylpyridine.
c
1
d
e
Scheme 3. Reactivity Difference of the Catalysts
observation in Scheme 2 that the actual catalyst of the reaction is
the Brønsted acid itself, not the in situ generated silyl Lewis acid.
The absolute configuration of 3a was unambiguously established
by X-ray crystallography.
Having in hand the optimum conditions, we explored the
generality of the reaction in terms of aldehyde scope (Scheme 4).
Electron-rich and electron-neutral aldehydes underwent the
reaction with high stereoselectivities. Performing the reaction
with benzaldehyde gave the highest diastereo- and enantiose-
lectivity (3b, 99:1 dr and 99:1 er). An ortho-substituted aldehyde
could be used (3e). The reaction tolerated a variety of functional
groups such as fluoro, chloro, bromo, methoxy, ester, and
Knowing this characteristic feature of thiophosphoramides, we
next aimed at exploring their catalytic activity toward a diastereo-
and enantioselective Mukaiyama aldol reaction. To realize the
reaction, we synthesized chiral BINOL-based thiophosphor-
amides B2−B4 bearing bulky silyl groups onto the ortho aromatic
substituents. The carbon−silicon bond is longer than the
carbon−carbon bond, and thus such thiophosphoramides are
expected to effectively shield one enantiotopic face of the
aldehyde and influence the orientation of the approaching silyl
enol ether.16 We investigated the catalytic activities of several
chiral BINOL-derived thiophosphoramides B in the reaction of
silyl enol ether 1a with aldehyde 2a (Table 1). With catalyst B1,
the desired aldol product 3a was obtained but in poor
stereoselectivity (entry 1). As expected, catalyst B2, which
possesses tert-butyldiphenylsilyl (TBDPS) groups onto the ortho
aromatic substituents, enabled the reaction with a promising
diastereo- and enantioselectivity (entry 2). Next, trifluoromethyl
substituent on the sulfonyl group of the catalyst was replaced
with a more sterically demanding perfluorobutyl group (B3).
Surprisingly, the use of catalyst B3 led to a drastic improvement
in both diastereo- and enantioselectivity (96:4 dr and 95:5 er,
entry 3). To the best of our knowledge, this is the first report of
the RF group of the phosphoramide catalyst affecting the
stereoselectivity.17 Further optimization of the catalyst structure
revealed that thiophosphoramide B4, bearing a perfluorooctyl
substituent on the sulfonyl group, was the best catalyst (entry 4).
Catalyst B4 was highly active even at −100 °C, and the catalyst
loading could be reduced to 3 mol % without erosion of yield and
stereoselectivity (entry 5). It should be noted that the reaction of
1a with 2a under optimized conditions, but with a proton
scavenger, 2,6-di-tert-butylpyridine,18 resulted in no formation of
3a (entry 6). This result is consistent with the experimental
a
Scheme 4. Scope of Aldehydes
a
Reaction conditions: 2 (0.25 mmol), 1a (0.30 mmol), and catalyst B4
(3 mol %) in toluene (3.0 mL) at −100 °C for 16 h.
B
DOI: 10.1021/jacs.5b04168
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Journal of the American Chemical Society
Communication
a
Scheme 5. Scope of Silyl Enol Ethers
Scheme 6. Role of the Perfluorooctyl Group of the Catalyst in
the Stereoselection
a
Reaction conditions: benzaldehyde (0.25 mmol), silyl enol ether
(0.30 mmol), and catalyst B4 (3 mol %) in toluene (3.0 mL) at −100
b
°C for 16 h. With 7.5 mol % catalyst B4 and 1.5 equiv of silyl enol
ether 1b.
trifluoromethyl, maintaining excellent diastereo- and enantiose-
lectivities. Unfortunately, aliphatic aldehydes did not undergo
the reaction probably due to the low reactivity.
The scope of silyl enol ethers was then examined (Scheme 5).
A variety of silyl enol ethers were suitable for the reaction to give
the corresponding aldol products 4 in high yields and
stereoselectivities. Interestingly, the stereochemistry of the
major product (4h) was altered from syn to anti when silyl
enol ether Z-1b (E/Z = 1:24) was used.19 Additionally, anti-4h
was mainly obtained even when E-1b (E/Z = 1.7:1) was used.
This selectivity with E-1b is in contrast to that observed with
cyclic E-1a. Thus, we conducted control experiments and found
that the isomerization of E-1b to Z-1b occurred under Brønsted
acid catalysis.20,21
Although the exact role of the perfluorooctyl group of the
catalyst in the stereoselection is not yet clear, a plausible
stereochemical model is illustrated in Scheme 6. There are two
modes of the aldehyde coordination to the chiral Brønsted acid
catalyst (A and B). A is more favored than B as it avoids a steric
interaction between the phenyl group of the aldehyde and the
perfluorooctyl group of the catalyst. The si-face of the aldehyde in
A is effectively shielded by the bulky TBDPS-substituted aryl
group of the catalyst. Thus, the aldehyde is attacked preferentially
on its re-face. The role of the longer perfluorooctyl group of the
catalyst is likely to increase the steric interaction in B. When E-1a
is used as a nucleophile, the syn-selective aldol reaction via TS-1 is
operating exclusively. TS-2 is disfavored due to two simultaneous
steric repulsions between the TMS group of 1a and the bulky
perfluorooctyl group as well as the methylene group of 1a and the
aldehyde phenyl group. In the case of Z-1b, although TS-3 has an
unfavorable steric interaction between the methyl group of 1b
and the aldehyde phenyl group, TS-4 suffers a more severe steric
repulsion between the TMS group of 1b and the perfluorooctyl
group. Thus, the anti-aldol product via TS-3 is mainly obtained
with high enantioselectivity. The presence of the longer
perfluorooctyl group of the catalyst leads to the increased steric
congestion in TS-2 and TS-4, which contributes to the enhanced
diastereoselectivity.
The success of asymmetric Mukaiyama aldol reaction
prompted us to apply the catalytic system to the asymmetric
Hosomi−Sakurai allylation of carbonyl compounds,7d,22 which
was considerably more challenging because of the low reactivity
of allylsilanes. The asymmetric allylation of benzaldehyde with
various allylsilanes was examined using B4 as the catalyst. The
use of methallyltrimethylsilane gave full conversion to the desired
homoallylic alchohol 5a in 90% yield with 85:15 er at −70 °C
(Scheme 7).23 However, the reaction was highly sensitive to the
reaction temperature, and 5a was obtained in only 8% yield at
−78 °C. The replacement of the TMS group with the more
reactive SiMe2TMS group24 allowed the reaction at −78 °C,
a,b
Scheme 7. Asymmetric Hosomi−Sakurai Allylation
a
Reaction conditions: 2 (0.25 mmol), allylsilane (0.375 mmol), and
catalyst B4 (7.5 mol %) in toluene (2.5 mL) at −78 °C for 24 h.
b
Methallyltrimethylsilane (1.5 equiv) was used at −70 °C.
C
DOI: 10.1021/jacs.5b04168
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
́ ́
M. J. Org. Chem. 2011, 76, 7141. (l) Prevost, S.; Dupre, N.; Leutzsch, M.;
providing 5a in 90% yield and 91.5:8.5 er. Various functional
groups were tolerated, and the methallylated products were
obtained with high enantioselectivities.
Wang, Q.; Wakchaure, V.; List, B. Angew. Chem., Int. Ed. 2014, 53, 8770.
For a review, see: (m) van Gemmeren, M.; Lay, F.; List, B. Aldrichimica
Acta 2014, 47, 3.
In conclusion, we have designed and synthesized a new chiral
BINOL-based thiophosphoramide catalyst, which possesses
TBDPS groups onto the ortho aromatic substituents and the
perfluorooctyl substituent on the sulfonyl group. 29Si and 31P
NMR monitoring reveals the characteristic feature of the
thiophosphoramide catalyst, acting as a strong Brønsted acid
even in the presence of excess silyl enol ethers, which cannot be
found in other related phosphoric acid analogues. The catalyst is
highly effective to the asymmetric Mukaiyama aldol reaction, and
the reaction proceeds with excellent diastereo- and enantiose-
lectivities. The catalyst can be applied to the asymmetric
Hosomi−Sakurai allylation, which has been considerably
challenging due to the low reactivity of allylsilanes.
(8) Cheon, C. H.; Yamamoto, H. Org. Lett. 2010, 12, 2476.
(9) TMS silyl enol ether of acetophenone is 103 times less reactive than
TMS silyl ketene acetal of methyl isobutylate, see: Mayr, H.; Kempf, B.;
Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
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T. Chem. Rev. 2007, 107, 5744. (b) Terada, M. Chem. Commun. 2008,
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(11) For 29Si and 31P NMR spectra, see the Supporting Information.
(12) Computational study on the pKa values of various chiral Brønsted
acids, see: (a) Kaupmees, K.; Tolstoluzhsky, N.; Raja, S.; Rueping, M.;
Leito, I. Angew. Chem., Int. Ed. 2013, 52, 11569. (b) Yang, C.; Xue, X.-S.;
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ASSOCIATED CONTENT
* Supporting Information
■
S
(13) TMS-A1 and TMS-C1 may exist in equilibrium with their isomers
(P-N-SiMe3, P-Se/O-SiMe3, and S-O-SiMe3).
Experimental details and analytical and crystallographic data
(CIF). The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/jacs.5b04168.
(14) In situ generation of silyl Lewis acids by the reaction of chiral
phosphoric acids with silyl compounds, see: (a) Rowland, E. B.;
Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C. J. Am. Chem. Soc. 2007,
129, 12084. (b) Zamfir, A.; Tsogoeva, S. B. Org. Lett. 2010, 12, 188.
(c) Serdyuk, O. V.; Zamfir, A.; Hampel, F.; Tsogoeva, S. B. Adv. Synth.
Catal. 2012, 354, 3115.
(15) The reason for such a reactivity difference of the catalysts remains
unclear, and computational studies to rationalize this result are
underway.
(16) For the beneficial effect of bulky para substituents at the 3,3′-aryl
groups on enantioselectivity in chiral phosphoric acid catalysis, see:
(a) Cheng, X.; Goddard, R.; Buth, G.; List, B. Angew. Chem., Int. Ed.
2008, 47, 5079. (b) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am.
Chem. Soc. 2008, 130, 15786. (c) Cheon, C. H.; Yamamoto, H. J. Am.
Chem. Soc. 2008, 130, 9246. (d) Jiao, P.; Nakashima, D.; Yamamoto, H.
Angew. Chem., Int. Ed. 2008, 47, 2411.
AUTHOR INFORMATION
■
Corresponding Authors
*sai@isc.chubu.ac.jp
*hyamamoto@isc.chubu.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research (no. 23225002), Advanced Catalytic Transformation
Program for Carbon Utilization, Nippon Pharmaceutical
Chemicals Co., Ltd, and Advance Electric Co., Inc.
(17) It is reported that the substituent on the sulfonyl group of the
phosphoramide catalyst has a significant influence on the yield but not
on the enantioselectivity; see: ref 10f and references therein.
(18) For usage of this base to differentiate the reaction pathway
between Lewis acid and Brønsted acid catalysis, see: (a) Mathieu, B.;
Ghosez, L. Tetrahedron 2002, 58, 8219. (b) Hara, K.; Akiyama, R.;
Sawamura, M. Org. Lett. 2005, 7, 5621.
(19) This result implies that our new catalyst has the potential to
enable the asymmetric anti-selective Mukaiyama aldol reaction.
(20) Treatment of a 1.5:1 mixture of E- and Z-1b with 5 mol % of
catalyst B4 at −100 °C for 1 h resulted in a 1:7.7 mixture of E- and Z-1b,
see the Supporting Information.
(21) For examples of Brønsted acid-catalyzed isomerization of silyl
enol ethers, see: (a) Deyine, A.; Dujardin, G.; Mammeri, M.; Poirier, J.-
M. Synth. Commun. 1998, 28, 1817. (b) Ishihara, K.; Nakamura, H.;
Nakamura, S.; Yamamoto, H. J. Org. Chem. 1998, 63, 6444. (c) Inanaga,
K.; Ogawa, Y.; Nagamoto, Y.; Daigaku, A.; Tokuyama, H.; Takemoto,
Y.; Takasu, K. Beilstein J. Org. Chem. 2012, 8, 658.
(22) For reviews on catalytic asymmetric allylation of carbonyl
compounds with allylsilanes, see: (a) Denmark, S. E.; Almstead, N. G. In
Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
Germany, 2000; Chapter 10. (b) Denmark, S. E.; Fu, J. Chem. Rev. 2003,
103, 2763. (c) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed.
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DOI: 10.1021/jacs.5b04168
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