Phase-transfer-catalyzed asymmetric alkylation with epoxy triflates as alkylating agents: Highly stereoselective synthesis of γ,δ-epoxy- α-amino acids

Article abstract of DOI:10.1246/cl.2011.1115

Although alkyl sulfonates are commonly used for alkylating agents, there are very few reports on phase-transfer-catalyzed asymmetric alkylation with alkyl sulfonates. Herein, we report that the asymmetric reaction using glycine Schiff base 1 and optically pure epoxy triflates op-2 proceeded smoothly in the presence of phase-transfer catalyst (S,S)-4a to furnish γ,δ-epoxy- α-amino acids 3 in good yield with high enantioselectivity.

Full text of DOI:10.1246/cl.2011.1115

doi:10.1246/cl.2011.1115
Published on the web September 23, 2011
1115
Phase-transfer-catalyzed Asymmetric Alkylation with Epoxy Triflates as Alkylating Agents:
Highly Stereoselective Synthesis of £,¤-Epoxy-¡-amino Acids
Satoru Arimitsu, Daisuke Kato, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
(Received July 15, 2011; CL-110609; E-mail: maruoka@kuchem.kyoto-u.ac.jp)
Although alkyl sulfonates are commonly used for alkylating
agents, there are very few reports on phase-transfer-catalyzed
asymmetric alkylation with alkyl sulfonates. Herein, we report
that the asymmetric reaction using glycine Schiff base 1 and
optically pure epoxy triflates op-2 proceeded smoothly in the
presence of phase-transfer catalyst (S,S)-4a to furnish £,¤-
epoxy-¡-amino acids 3 in good yield with high enantioselec-
tivity.
transfer-catalyzed asymmetric alkylation of glycine Schiff
base 1 with epoxy triflates 2 for the stereoselective synthesis
of £,¤-epoxy-¡-amino acid derivatives, which are frequently
encountered as important scaffolds in several total syntheses.5
First, the effect of the sulfonate moiety of rac-2 was
examined (Table 1). Attempted treatment of 1 and rac-2a
(2 equiv) using catalyst (S,S)-4a in toluene with CsOH¢H2O6 at
0 °C for 2 h gave £,¤-epoxy-¡-amino acid derivative 3a in only
36% yield with poor diastereo- and enantioselectivity (Entry 1).
Other substituted aryl sulfonate groups with an electron-with-
drawing or -donating group did not give any improvements
(Entries 2-5). In contrast, reaction with epoxy triflate with rac-2f
gave 3a in moderate yield with low diastereoselectivity but
better enantioselectivity. Furthermore, by lowering the reaction
temperature to ¹20 °C, sufficient enantioselectivities for each
diastereomers (dr = 57:43) were observed (Entry 7).
Alkylation has been utilized as the one of the most
fundamental, yet versatile reactions for carbon-carbon bond
formation in synthetic organic chemistry, and asymmetric
alkylation has been developed with several types of phase-
transfer catalysts.1 However, asymmetric alkylation under phase-
transfer conditions is strictly limited to only alkyl halides
(i.e., R-X; X = Br and I), and this fact is always inherently
problematic when the required alkyl halides are not easily
available. For a particular example, the preparation of epoxy
halides is relatively cumbersome, and especially the synthesis
of chiral epihalohydrin requires multiple steps, thereby often
resulting in low yields (eq 1, Figure 1).2
On the other hand, although alkyl sulfonates are utilized as
useful alkylating agents and easily prepared by one step from the
corresponding alcohols,3 there are sparse examples of phase-
transfer-catalyzed asymmetric alkylation with alkyl sulfonates,
which give unsatisfactory results.4 If alkyl sulfonates can be
applied as alkylating agents under phase-transfer conditions, it
will certainly expand the synthetic value of phase-transfer
catalysis. In order to realize our strategy, we focus our attention
on the use of epoxy sulfonates as alkylating agents, which can be
prepared from the corresponding alcohols concisely by the
Sharpless asymmetric epoxidation in two steps as shown in eq 2
(Figure 1). Here, we wish to report a first practical phase-
Next, we investigated the effect on structures of catalysts to
attain higher reactivity and selectivity. The aryl groups at the
3,3¤-position of binaphthyl subunits turned out to influence
crucially the enantioselective outcome (Table 2). Thus, the
Table 1. Effects of sulfonate moieties of epoxy sulfonates
rac-2a
O
O
O
(S,S)-4a (2 mol%)
Ph2C
N
*
OBut
3a
+
OSO2R1
Ph2C
N
OBut
toluene-CsOH·H2O,
0 °C
O
1
rac-2
*
Ar
Br
(S,S)-4a; Ar = 3,4,5-trifluorophenyl
N
Ar
Time Yieldb
eed,e
/%
Entry R1
drc
/h
/%
1
2
3
4
5
6
7f
p-ClC6H4 (2a)
p-BrC6H4 (2b)
p-NO2C6H4 (2c)
m-NO2C6H4 (2d)
p-MeC6H4 (2e)
CF3 (2f)
2
36
55:45
®
®
55:45
®
3 (11)
®
®
5 (11)
®
O
OH
2.5 no rxn.
2
5
3
2
HO
O
O
O
(1)
H
O
X
trace
41
trace
52
O
*
O
OH
R3
epihalohydrin
multistep
O
O
R1
R2
R1
R2
R1
OH
SAE
57:43 47 (43)
57:43 80 (77)
OH
OSO2R'
(2)
* *
* *
R3
R3
two-step
CF3 (2f)
23
52
R2
SAE = Sharpless Asymmetric Epoxidation
aUnless otherwise noted, the reaction was conducted with 2
equiv of rac-2, 2 mol % of (S,S)-4a, and 5 equiv of CsOH¢H2O
in toluene at 0 °C for given reaction time. bIsolated yield.
cDetermined by 1H NMR. dEnantiopurity of 3a was determined
by HPLC analysis using a chiral column with hexane-
isopropanol as a solvent after derivatization to N-benzoate
(See Supporting Information; SI6). The value in parentheses
is enantiopurity of the minor diastereomer. fPerformed at
¹20 °C.
(R1, R2, R3 = H, Alkyl, Ar)
Phase-Transfer
Catalyst
O
O
Ph2C
N
OBut
*
R-X
+
Ph2C
N
OBut
X = halides, known
X = sulfonates, this work
R
e
Figure 1. Preparation of optically active epihalohydrin and
epoxy sulfonates for asymmetric alkylation of glycine deriva-
tives under phase-transfer conditions.
Chem. Lett. 2011, 40, 1115-1117
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1116
Table 2. Screening of catalyst structuresa
Table 3. The reaction of glycine Shiff base 1 and optically pure
epoxides op-2a
O
O
catalyst (2 mol%)
O
Ph2C
N
*
O
OBut
3a
+
Ph2C
N
OTf
rac-2f
toluene-CsOH·H2O,
–20 °C
OBut
Ph2C
R2
N
*
O
*
O
O
R2
R3
(S,S)-4a (2 mol%)
OBut
1
+
OTf
Ph2C
N
O
*
*
*
OBut
toluene-CsOH·H2O,
–20 °C
R4
op-2
Ar
Ar
*
R3
R4
1
3
Br
Br
Bu
op-2
R2, R3, R4
Time Yieldb
eed
/%
Entry
drc
N
N
/h
/%
Bu
1
2
3
4
5
H, H, H (R)
H, H, H (S)
Me, H, H (2R, 3S)
H, Me, H (2R, 3R)
H, H, Me (S)
10
10
8
8
8
80
84
71
74
82
13:87
92:8
90:10
89:11
87:13
99
99
98
97
95
Ar
Ar
(S,S)-4a; Ar = 3,4,5-trifluorophenyl
(S,S)-4b; Ar = 4-(trifluoromethyl)phenyl
(S,S)-4c; Ar = 3,5-di-tert-butylphenyl
(S)-4e; Ar = 3,4,5-trifluorophenyl
(S,S)-4d; Ar = 3,5-bis(3,5-di-tert-butylphenyl)phenyl
Time
/h
Yieldb
/%
eed,e
/%
Entry
Catalyst 4
drc
aUnless otherwise noted, the reaction was conducted with 2
equiv of op-2, 2 mol % of (S,S)-4a, and 5 equiv of CsOH¢H2O
in toluene at ¹20 °C for given reaction time. Isolated yield.
cDetermined by H NMR. Enantiopurity of the major isomer
was determined by HPLC analysis using chiral column with
hexane-isopropanol as solvent after derivatization to the
corresponding N-benzoate (See SI6).
b
1
2
3
4
5
(S,S)-4a
(S,S)-4b
(S,S)-4c
(S,S)-4d
(S)-4e
23
24
23
4
52
64
67
58
70
57:43
54:46
52:48
51:49
48:52
80 (77)
43 (43)
63 (47)
23 (6)
1
d
29
76 (75)
aUnless otherwise noted, the reaction was conducted with 2
equiv of rac-2f, 2 mol % of catalysts, and 5 equiv of CsOH¢
H2O in toluene at ¹20 °C for given reaction time. Isolated
yield. cDetermined by 1H NMR. dEnantiopurity of 3a was
determined by HPLC analysis using chiral column with
hexane-2-propanol as solvent after derivatization to the
corresponding N-benzoate (See SI6). eThe value in parentheses
is the enantiopurity of the minor diastereomer.
The work was supported by a Grant-in-Aid for Specially
Promoted Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
b
References and Notes
1
Selected recent reviews on asymmetric phase-transfer-cata-
lyzed alkylations: a) T. Shioiri, S. Arai, in Stimulating
Concepts in Chemistry, ed. by F. Vögtle, J. F. Stoddart, M.
Shibasaki, Wiley-VCH, Weinheim, 2000, p. 123. b) M. J.
O’Donnell, in Catalytic Asymmetric Synthesis, 2nd ed., ed.
by I. Ojima, Wiley-VCH, New York, 2000, Chap. 10. c)
M. J. O’Donnell, Aldrichimica Acta 2001, 34, 3. d) K.
Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013. e) M. J.
O’Donnell, Acc. Chem. Res. 2004, 37, 506. f) B. Lygo, B. I.
Andrews, Acc. Chem. Res. 2004, 37, 518. g) J. Vachon, J.
Lacour, Chimia 2006, 60, 266. h) T. Ooi, K. Maruoka,
Angew. Chem., Int. Ed. 2007, 46, 4222. i) T. Hashimoto, K.
Maruoka, Chem. Rev. 2007, 107, 5656. j) T. Ooi, K.
Maruoka, Aldrichimica Acta 2007, 40, 77. k) K. Maruoka,
Org. Process Res. Dev. 2008, 12, 679. l) Asymmetric Phase
Transfer Catalysis, ed. by K. Maruoka, Wiley-VCH,
Weinheim, 2008. m) S. Shirakawa, K. Maruoka, in Catalytic
Asymmetric Synthesis, 3rd ed., ed. by I. Ojima, John Wiley
& Sons, Hoboken, New Jersey, 2010, Chap. 2C. n) K.
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catalyst (S,S)-4b possessing 4-(trifluoromethyl)phenyl group led
to deterioration of the enantioselectivity (Entry 2, Table 2), and
other catalysts possessing bulkier substituents such as (S,S)-4c
and (S,S)-4d, lowered the enantioselectivity (Entries 3 and 4).
Additionally, structurally simpler catalyst (S)-4e showed similar
catalytic efficiency as (S,S)-4a, which was found to be the most
efficient catalyst among all.
Although the enantioselectivity was further increased by
judiciously tuning catalysts and reaction conditions, the dia-
stereoselectivity still remained at unsatisfactory levels. From
comparison of the reaction with glycine Schiff base 1 and
racemic secondary alkyl halides, where the catalyst invoked
kinetic resolution of racemic secondary alkyl halides to provide
excellent diastereoselectivity,7 it is assured that catalysts 4 are
unable to differentiate the stereochemistry of epoxides rac-2,
and therefore we turned to utilize optically pure epoxides op-2.8
As we expected, with the optimal conditions in hand, it showed
marked enhancements of diastereoselectivity with excellent
enantioselectivity, and also the smoother reaction led to
increasing product yields in shortened reaction times (Table 3).
Other optically pure epoxides having different stereochemistry
and substituents were all tolerant to furnish the corresponding
products9 in good yield with good diastereoselectivity and
excellent enantioselectivity.10
2
3
Synthesis of chiral epihalohydrins: a) J. J. Baldwin, A. W.
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In conclusion, we have successfully demonstrated the first
practical example of asymmetric alkylation using alkyl sulfo-
nates, especially epoxy triflates as notable examples in this letter,
under phase-transfer catalysis conditions. This research provides
a new entry to phase-transfer-catalyzed asymmetric reaction.
Chem. Lett. 2011, 40, 1115-1117
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1117
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the best base to effectively suppress hydrolysis of n-hexyl
triflate. For more details, see the Supporting Information
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See, ref. 3. The enantiopurities of utilized epoxy triflates in
Table 3 were 97% (Entries 1 and 2), 95% (Entry 3), 93%
(Entry 4), and 92% (Entry 5), respectively.
It has been reported that nucleophilic reactions with epoxy
triflates take place highly regioselectively through the direct
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4
5
7
8
9
6
The effect of base was examined preliminarily on the
reaction with Shiff base 1 and n-hexyl triflate as a model
reaction. Of the bases screened, CsOH¢H2O was found as
10 The little decreased enantioselectivities in Entries 4 and 5 of
Table 3 were due to slightly lower enantiopurities of utilized
epoxy triflates. See, ref. 8.
Chem. Lett. 2011, 40, 1115-1117
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/