Co-catalyst enhancement of enantioselective PTC Michael additions involving glycine imines

Article abstract of DOI:10.1016/j.tetlet.2009.02.123

In this Letter we demonstrate that the use of 2,4,6-trimethylphenol (mesitol) as a co-catalyst facilitates highly enantioselective addition of benzophenone glycine imine tert-butyl ester to a range of Michael acceptors.

Full text of DOI:10.1016/j.tetlet.2009.02.123

Tetrahedron Letters 50 (2009) 3363–3365
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Tetrahedron Letters
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Co-catalyst enhancement of enantioselective PTC Michael additions
involving glycine imines
a
a
a
b
Barry Lygo a, , Christopher Beynon , Christopher Lumley , Michael C. McLeod , Charles E. Wade
*
a School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
b GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we demonstrate that the use of 2,4,6-trimethylphenol (mesitol) as a co-catalyst facilitates
highly enantioselective addition of benzophenone glycine imine tert-butyl ester to a range of Michael
acceptors.
Received 22 December 2008
Revised 5 February 2009
Accepted 16 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
In recent years, a number of chiral quaternary ammonium
phase transfer catalysts (PTCs) have been found to promote highly
enantioselective alkylation of glycine imine 2.1,2 This has led to the
development of effective methods for the synthesis of a wide range
Table 1
Alkylation versus Michael addition of imine 2
E+
Ph2C=N
CO2t-Bu
Ph2C=N
CO2t-Bu
of a
-amino acid derivatives.3 The corresponding reactions of imine
9 M aq. KOH
PhMe, 25 oC
PTC 1 (10 mol%)
3
2
2 with Michael acceptors have proved to be more challenging.4–6
These often result in lower enantioselectivities and lower yields
than the corresponding alkylations.
E
Electrophile
Yielda (%)
eeb (%)
Et
PhCH2Br
n-BuI
MVK
93
88
87
<10
94 (S)
93 (S)
12 (S)
—
N
N+
H
OBn
t-Butyl acrylate
a
Determined by 1H NMR.
Determined by HPLC.
Br-
b
1
quaternary ammonium salts with appropriate basic counterions.
A0s a result, we decided to investigate the possibility of generating
R4 N+ ꢀOR species 6 in situ. In principle this should be possible sim-
ply by mixing an alkoxide (e.g., KOR, 5) with a quaternary ammo-
nium salt such as 1. As long as the alkoxide is sufficiently lipophilic
the ion exchange equilibrium should favour the desired ion-pair
combination. To further simplify the experimental protocol we
envisaged that the alkoxide species might also be generated
in situ by reaction of the corresponding alcohol (ROH, 4) with
KOH (Scheme 1). The advantage of this approach is that the quater-
nary ammonium alkoxide need never be isolated, but it suffers
from the potential disadvantage that both KOH and KOR could pro-
mote non-selective Michael addition.
For example, we have found that the cinchona alkaloid-derived PTC
1 will promote highly enantioselective asymmetric alkylations of
imine 2 with a wide range of alkyl halides.7 However, under the
same conditions, Michael acceptors such as methyl vinyl ketone
(MVK) and tert-butyl acrylate give disappointing results (Table 1).
Clearly the differing transition states for these processes could
account for these observations, but an additional factor may be
that the Michael additions can also proceed via base-catalyzed
(non-selective) background pathways.
We considered that it might be possible to control the latter by
employing a quaternary ammonium salt catalyst with a basic
counterion (e.g., R04 N+ ꢀOR).8 In this instance, it should be unnec-
essary to add additional base, and hence background reaction path-
ways should be minimized. This approach has so far been
unsuccessful, mainly due to difficulties in isolating and purifying
KOH(s)
R'4NBr
K
+ -OR
R'4N+ -OR
ROH
4
5
6
* Corresponding author. Tel.: +44 0 115 9513526; fax: +44 0 115 9513564.
E-mail address: b.lygo@nottingham.ac.uk (B. Lygo).
Scheme 1. In situ generation of R04 N+ ꢀOR species.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.123

3364
B. Lygo et al. / Tetrahedron Letters 50 (2009) 3363–3365
Table 2
Of the solvents investigated, only CH2Cl2, THF and 1,3-dioxolane
gave complete reaction within 10 h at ꢀ78 °C, and of these, only
CH2Cl2 resulted in high enantioselectivity. The majority of the
other solvents gave either no reaction or a racemic product. In
the case of t-BuOMe, the reaction was found to proceed signifi-
cantly faster than in other solvents. This was found to be due to
a fast background reaction mediated by the potassium salt of mes-
itol. It was also found that use of CH2Cl2/PhMe (1:1) resulted in
similar levels of enantioselectivity to CH2Cl2 alone, but the rate
of reaction was slowed. Interestingly, when t-BuOMe/PhMe (1:1)
was used the opposite enantiomer of 7a was produced in 30% ee.
These results clearly indicate that CH2Cl2 is the best solvent for
this process, so we next moved on to probe the scope of this pro-
cess by investigating the reaction of imine 2 with other Michael
acceptors (Table 4).
It was found that the optimized reaction conditions would suc-
cessfully promote addition of imine 2 to a range of enones (Table 4,
entries b–e) as well as acrylonitrile (entry f) and phenyl vinyl sul-
fone (entry g). Addition to the less electrophilic vinylphosphonates
and amides was not successful, even at higher temperatures. In all
cases, the levels of enantioselectivity were high.
Under the standard conditions, reaction with phenyl vinyl ke-
tone (entry e) gave significant amounts of the double addition
product 8. This could be minimized by slow addition of the enone
to the reaction mixture. Similar improvements to the yield of the
acrylonitrile adduct 7f could also be achieved via slow addition
of the electrophile.
Effect of phenol additives on the enantioselective Michael addition of imine 2 to
methyl acrylate
CO2Me
t-BuO2C
CO2Me
2
KOH, CH2Cl2, -78 oC
ROH (10 mol%)
PTC 1 (10 mol%)
7a
Ph2C=N
ROH
Time (h)
Yielda (%)
eeb (%)
None
Phenol
4-Methylphenol
2,6,-Dimethylphenol
Mesitol
24
10
10
10
8
<10c
40c
93
93
95
—
81
92
98
98
91
2,4,6-Tri-tert-butylphenol
10
82
a
Determined by 1H NMR.
b
Determined by HPLC.
c
Conversion after 10 h by 1H NMR.
To probe this further we decided to investigate the application
of this approach in the Michael addition of imine 2 to methyl acry-
late. We were able to establish that this reaction was not promoted
by 10 mol % PTC 1 in conjunction with solid KOH9 at ꢀ78 °C. How-
ever, if 10 mol % phenol was included, the resulting mixture was
capable of promoting the desired Michael addition. After 10 h,
the reaction had proceeded to 40% conversion and the resulting ad-
duct 7a was produced in 81% ee. In an effort to improve on this, a
range of other phenol additives were examined (Table 2). This
study identified mesitol (2,4,6-trimethylphenol) as a highly effec-
tive co-catalyst10,11 for the Michael addition, generating the prod-
uct 7a in 95% yield and 98% ee.
Further investigation into the reaction conditions established
that for reproducible results, the three catalyst components
(KOH, mesitol and PTC 1) need to be pre-mixed at 0 °C for
30 min. In addition, all three are required to be present during
the Michael addition. If the solid KOH is removed prior to addition
of imine 2 and methyl acrylate, then low conversions are observed.
This suggests that the reaction mechanism is not as simple as ini-
tially envisaged.
Ph2C=N
CO2t-Bu
O
8
Ph
O
Ph
The absolute stereochemistry of product 7a was established as (S)
by conversion to tert-butyl pyroglutamate and comparison of the
sign of rotation with that previously published.16 We were able to
demonstrate that 7d was also obtained as the (S)-isomer by conver-
sion of this product into (2S,5S)-5-butyl-2-(tert-butoxycar-
bonyl)pyrrolidine and by comparison of the sign of rotation with
that previously reported for this material.17 Product 7f was also
shown to be the (S)-isomer by comparison of the sign of rotation
As we have previously found that the nature of the solvent can
have profound effects on quaternary ammonium salt-catalyzed
Michael additions,4e,12 we next investigated the effect of changing
the reaction solvent (Table 3).
Table 4
Enantioselective addition of glycine imine 2 to various Michael acceptors13,14
Table 3
Effect of solvent on the enantioselective Michael addition of imine 2 to methyl
acrylate
EWG
t-BuO2C
EWG
2
CO2Me
KOH, CH2Cl2, -78 oC
mesitol (10 mol%)
PTC 1 (10 mol%)
7a
2
7
KOH, solvent, -78 oC
mesitol (10 mol%)
PTC 1 (10 mol%)
Ph2C=N
Entry
EWG
Time (h)
Yield (%)a
eeb (%)
Solvent
Time (h)
Yielda (%)
eeb (%)
a
b
c
d
e
CO2Me
COMe
COEt
COn-Bu
COPh
8
2.5
6
95
80
87
65
63
99
58
77
90
<10
<10
98 (ꢀ) (S)
95 (ꢀ) (S)
95 (ꢀ)
CH2Cl2
PhMe
i-Pr2O
THF
8
10
10
7
95
98
—
—
0
0
<10c
<10c
89
5
91 (ꢀ) (S)
9115 (ꢀ)
8915 (ꢀ)
95 (ꢀ) (S)
96 (ꢀ) (S)
92 (ꢀ)
1.5
2.5c
5
t-BuOMe
3
10
3
10
10
68
TAMEd
32c
85
0
f
CN
1,3-Dioxolane
CH2Cl2/PhMe (1:1)
t-BuOMe/PhMe (1:1)
34
98
ꢀ30
8c
90c
50c
g
h
i
SO2Ph
P(O)(OEt)2
CONMe2
1.5
10
10
—
—
a
Determined by 1H NMR.
Determined by HPLC.
Determined by 1H NMR.
Determined by HPLC.
Slow addition of Michael acceptor.
b
c
a
b
c
Conversion after 10 h by 1H NMR.
d
TAME = tert-amylmethylether.

B. Lygo et al. / Tetrahedron Letters 50 (2009) 3363–3365
3365
with previously reported data4g and 7b by comparison of HPLC
retention times with previously published data.6c As yet, we have
not been able to unambiguously establish the absolute stereochem-
istry of Michael adducts 7c, 7e and 7g and so the signs of rotation
are given in Table 4. It should be noted that PTC 1 also gives (S)-
selectivity in the corresponding alkylation reactions (Table 1) and
so the Michael additions may be proceeding via similar ion-pair
intermediates to those proposed previously for the corresponding
alkylation reactions.1
In conclusion, we have shown that use of a co-catalyst can
greatly enhance the effectiveness of KOH-mediated asymmetric
PTC Michael additions involving glycine imine 2. The enantioselec-
tivities obtained using this method generally exceed those previ-
ously reported for the same substrates using alternative cinchona
alkaloid PTC procedures.4g,h,5 We are currently investigating the
application of this chemistry in target synthesis.
involving silylketene acetals see: Tozawa, T.; Yamane, Y.; Mukaiyama, T.
Chem. Lett. 2006, 35, 56.
9. Reagent grade KOH pellets were purchased from Fisher Scientific, UK and used
as supplied.
10. For an example of crown ethers as co-catalysts for PTC asymmetric alkylations
see: Shirakawa, S.; Yamamoto, K.; Kitamura, M.; Ooi, T.; Maruoka, K. Angew.
Chem., Int. Ed. 2005, 44, 625.
11. For an example of mesitol as a co-catalyst for PTC eliminations see: Makoswa,
M.;
Chesnokov, A. Tetrahedron 2000, 56, 3553.
12. (a) Lygo, B.; Gardiner, S.; McLeod, M. C.; To, D. C. M. Org. Biomol. Chem. 2007, 5,
2283; (b) Lygo, B.; To, D. C. M. Tetrahedron Lett. 2001, 42, 1343.
13. Representative procedure: Potassium hydroxide (19 mg, 0.34 mmol) was added
to a solution of PTC 1 (10.5 mg, 10 mol %) and mesitol (2.3 mg, 10 mol %) in
dichloromethane (1 mL) at 0 °C and the mixture was stirred for 30 min. During
this time a colour change from yellow to orange/brown was observed. The
mixture was then cooled to ꢀ78 °C and a solution of glycine imine 2 (50 mg,
0.17 mmol) in dichloromethane (1 mL) was added, followed by methyl acrylate
(23
lL, 0.26 mmol). The reaction mixture was stirred at ꢀ78 °C until complete
by TLC (8 h), and then immediately filtered through a plug of magnesium
sulfate. After warming to room temperature the solution was concentrated
under reduced pressure to afford the crude product 7a. Yields were calculated
by 1H NMR using veratrole as an internal standard. An aliquot of the crude
product was purified by flash column chromatography on silica gel (90:9:1,
Acknowledgements
petroleum ether/EtOAc/Et3 N) to give 7a as
a colourless oil, Rf 0.25 (9:1
petroleum ether/EtOAc); ½a D
ꢁ
ꢀ96.0 (98% ee, c 0.7 in CHCl3); mmax (film)/cmꢀ1
2977, 1736, 1623, 1445, 1368, 1152; 1H NMR (400 MHz, CDCl3)4h 7.66–7.64
(2H, m, ArH), 7.46–7.31 (6H, m, ArH), 7.20–7.18 (2H, m, ArH), 3.98 (1H, dd, J
7.0, 5.5, CHCO2), 3.60 (3H, s, OCH3), 2.41–2.37 (2H, m, CH2), 2.26–2.20 (2H, m,
CH2), 1.45 (9H, s, (CH3)3); 13C NMR (100 MHz, CDCl3) 173.6 (C), 170.8 (C), 139.5
(C), 136.5 (C), 130.3 (CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.0 (CH), 127.8
(CH), 81.2 (C), 64.8 (CH), 51.5 (CH3), 30.5 (CH2), 28.7 (CH2), 28.0 (CH3); m/z
(ESI+) found [M+H]+ 382.1996; C23H27NO4 requires 382.2013. Rt HPLC
(Chiralcel OD–H column, 97.5:2.5 hexane/iso-propyl alcohol, 0.5 mL/min,
254 nm) 12.9 min (R)-isomer, 15.8 min (S)-isomer.
Financial support for this work was provided by EPSRC and
GlaxoSmithKline.
References and notes
1. For reviews covering recent developments in asymmetric phase-transfer
catalysis see: (a) Maruoka, K. Org. Proc. Res. Dev. 2008, 12, 679; (b)
Hashimoto, T.; Maruoka, K. Chem. Rev. 2007, 107, 5656; (c) Ooi, T.; Maruoka,
K. Angew. Chem., Int. Ed. 2007, 46, 4222; (d) Vachon, J.; Lacour, J. Chimia 2006,
60, 266; (e) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506; (f) Lygo, B.; Andrews,
B. I. Acc. Chem. Res. 2004, 37, 518; (g) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103,
3013.
14. Analytical data for previously unreported compounds: Compound 7d. Pale yellow
oil, Rf 0.45 (9:1 petroleum ether/EtOAc); [
a
]
ꢀ53.4 (91% ee, c 0.7 in CHCl3);
D
mmax (CHCl3)/cmꢀ1 3006, 2962, 2934, 2874, 1726, 1153; 1H NMR (400 MHz,
CDCl3) 7.63 (2H, d, J 9.0, ArH), 7.48–7.42 (3H, m, ArH), 7.36–7.31 (3H, m, ArH),
7.18–7.15 (2H, m, ArH), 3.95 (1H, app t, J 6.0, CHCO2), 2.59–2.47 (2H, m, CH2),
2.41 (2H, app t, J 7.5, COCH2), 2.21–2.15 (2H, m, CH2), 1.58–1.50 (2H, m, CH2),
1.44 (9H, s, (CH3)3) 1.35–1.25 (2H, m, CH2), 0.88 (3H, t, J 7.0, CH3). 13C NMR
(100 MHz, CDCl3) 210.7 (C), 171.1 (C), 170.4 (C), 139.5 (C), 136.5 (C), 130.3
(CH), 128.8 (CH), 128.6 (CH), 128.5 (CH), 128.0 (CH), 127.7 (CH), 81.1 (C), 64.8
(CH), 42.6 (CH2), 38.9 (CH2), 28.1 (CH2), 27.8 (CH2), 25.9 (CH2), 22.4 (CH2), 13.9
(CH3); m/z (ESI+) found [M+H]+ 408.2518; C26H34NO3 requires 408.2460. Rt
HPLC (Chiralcel OD–H column, 99:1 hexane/ethanol, 0.5 mL/min, 254 nm)
12.3 min (R)-isomer, 14.9 min (S)-isomer.
2. For a review of glycine imine chemistry see: O’Donnell, M. J. Aldrichim. Acta.
2001, 34, 3.
3. For examples of application in target synthesis see: (a) Wang, Y.-G.; Ueda, M.;
Wang, X.; Han, Z.; Maruoka, K. Tetrahedron 2007, 63, 6042; (b) Lee, J.-H.; Jeong,
B.-S.; Ku, J.-M.; Jew, S.-S.; Park, H.-G. J. Org. Chem. 2006, 71, 6690; (c) Lygo, B.;
Slack, D.; Wilson, C. Tetrahedron Lett. 2005, 46, 6629; (d) Fukuta, Y.; Ohshima,
T.; Gnanadesikan, V.; Shibuguchi, T.; Nemoto, T.; Kisugi, T.; Okino, T.; Shibasaki,
M. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5433; (e) Lygo, B.; Humphreys, L. D.
Synlett 2004, 2809; (f) Kim, S.; Lee, J.; Lee, T.; Park, H.-G.; Kim, D. Org. Lett. 2003,
5, 2703; (g) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331; (h) Lygo, B.;
Andrews, B. I. Tetrahedron Lett. 2003, 44, 4499; (i) Boeckman, R. K., Jr.; Clark, T.
J.; Shook, B. C. Org. Lett. 2002, 4, 2109.
4. For examples of highly enantioselective PTC Michael additions involving
glycine imines see: (a) Elsner, P.; Bernardi, L.; Salla, G. D.; Overgaard, J.;
Jorgensen, K. A. J. Am. Chem. Soc. 2008, 130, 4897; (b) Bernardi, L.; Lopez-
Cantarero, J.; Niess, B.; Jorgensen, K. A. J. Am. Chem. Soc. 2007, 129, 5772; (c)
Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Chem.
Asian J. 2007, 2, 794; (d) Arai, S.; Takahashi, F.; Tsuji, R.; Nishida, A.
Heterocycles 2006, 67, 495; (e) Lygo, B.; Allbutt, B.; Kirton, E. H. M.
Tetrahedron Lett. 2005, 46, 4461; (f) Akiyama, T.; Hara, M.; Fuchibe, K.;
Sakamoto, S.; Yamaguchi, K. Chem. Commun. 2003, 1734; (g) Corey, E. J.;
Zhang, F-Y. Org. Lett. 2000, 2, 1097; (h) Corey, E. J.; Noe, M. C.; Xu, F.
Tetrahedron Lett. 1998, 39, 5347.
5. For highly enantioselective Michael additions of imine 2 mediated by cinchona
alkaloid-derived quaternary ammonium salts in conjunction with phosphazine
bases see: O’Donnell, M. J.; Delgado, F.; Dominguez, E.; de Blas, J.; Scott, W. L.
Tetrahedron: Asymmetry 2001, 12, 821.
6. For other examples of highly enantioselective Michael additions of glycine
imines see: (a) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am.
Chem. Soc. 2008, 130, 13321; (b) Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.;
Nakanishi, W.; Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73,
133; (c) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T.
Chem. Commun. 2001, 245.
Compound 7e. Pale yellow oil, Rf 0.2 (9:1 petroleum ether/EtOAc); [
a
]
ꢀ15.6
D
(91% ee, c 0.7 in CHCl3);
m
max (film)/cmꢀ1 3059, 2976, 2933, 1731, 1685, 1150;
1H NMR (400 MHz, CDCl3) 7.97–7.94 (2H, m, ArH), 7.67–7.64 (2H, m, ArH),
7.58–7.53 (1H, m, ArH), 7.48–7.30 (8H, m, ArH), 7.17–7.13 (2H, m, ArH), 4.08
(1H, dd, J 6.5, 5.5, CHCO2), 3.18–2.99 (2H, m, CH2), 2.36–2.22 (2H, m, CH2), 1.46
(9H, s, (CH3)3); 13C NMR (100 MHz, CDCl3) 199.7 (C), 171.1 (C), 170.6 (C), 139.5
(C), 136.9 (C), 136.5 (C), 132.9 (CH), 130.3 (CH), 128.8 (CH), 128.6 (CH), 128.6
(CH), 128.5 (CH), 128.1 (CH), 128.0 (CH), 127.7 (CH), 81.2 (C), 64.8 (CH), 34.7
(CH2), 28.2 (CH2), 28.1 (CH3); m/z (ESI+) found [M+H]+ 428.2207; C29H30NO3
requires 428.2220.
15. The enantiomeric excess of 7e was determined by conversion to 2-tert-
butoxycarbonyl-5-phenyl-3,4-dihydro-2H-pyrrole, followed by HPLC analysis:
the crude imine 7e was hydrolyzed by addition of a solution of 15% aqueous
citric acid (1 mL) and tetrahydrofuran (2 mL). The resulting solution was
stirred at rt for 2 h then diluted with dichloromethane (2 mL). The organic
layer was washed with brine (3 ꢂ 3 mL), dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (9:1 petroleum ether/EtOAc) to afford 2-tert-
butoxycarbonyl-5-phenyl-3,4-dihydro-2H-pyrrole (69% overall from 2) as a
colourless oil, Rf 0.2 (9:1 petroleum ether/EtOAc); [a] +88.0 (91% ee, c 0.7 in
D
CHCl3); mmax (film)/cmꢀ1 2978, 1732, 1154; 1H NMR (400 MHz, CDCl3) 7.90–
7.88 (2H, m, ArH), 7.47–7.38 (3H, m, ArH), 4.84–4.80 (1H, m, H-2), 3.17–3.08
(1H, m, H-4a), 3.02–2.95 (1H, m, H-4b), 2.37–2.28 (1H, m, H-3a), 2.21–2.12 (1H,
m, H-3b), 1.50 (9H, s, (CH3)3); 13C NMR (100 MHz, CDCl3) 175.8 (C), 172.3 (C),
134.1 (C), 130.8 (CH), 128.5 (CH), 128.1 (CH), 81.1 (C), 75.4 (CH), 35.4 (CH2),
28.1 (CH3), 26.8 (CH2); m/z (ESI+) found [M+H]+ 246.1487; C15H19NO2 requires
246.1489. Rt HPLC (Chiralcel OD–H column, 90:10 hexane/iso-propyl alcohol,
0.5 mL/min; 254 nm) 11.3 min (major), 19.8 min (minor).
7. (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595; (b) Lygo, B.;
Crosby, J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G. Tetrahedron 2001, 57,
2403.
8. For an example of the use of
a cinchona alkaloid-derived quaternary
16. Besson, M.; Delbecq, F.; Gallezot, P.; Neto, S.; Pinel, C. Chem. Eur. J. 2000, 6, 949.
17. Ibrahim, H. H.; Lubell, W. D. J. Org. Chem. 1993, 58, 6438.
ammonium phenoxide as catalyst for homogeneous Michael additions
a