Enantioselective electrophilic amination of α-cyanothioacetates with azodicarboxylates catalyzed by an axially chiral guanidine base

Article abstract of DOI:10.1002/adsc.200900594

An enantioselective electrophilic amination of α-substituted cyanothioacetates with azodicarboxylate is demonstrated using an axially chiral guanidine as a chiral Bronsted base catalyst. The corresponding product, having a quaternary stereogenie center at

Full text of DOI:10.1002/adsc.200900594

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DOI: 10.1002/adsc.200900594
Enantioselective Electrophilic Amination of a-Cyanothioacetates
with Azodicarboxylates Catalyzed by an Axially Chiral Guanidine
Base
Masahiro Terada,a,* Daisuke Tsushima,a and Megumi Nakanoa
a
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Fax : (+81)-22-795-6602; phone: (+81)-22-795-6602; e-mail: mterada@mail.tains.tohoku.ac.jp
Received: August 28, 2009; Published online: November 13, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900594.
Abstract: An enantioselective electrophilic amina-
tion of a-substituted cyanothioacetates with azodi-
carboxylate is demonstrated using an axially chiral
guanidine as a chiral Brønsted base catalyst. The
corresponding product, having a quaternary stereo-
genic center at the a-carbon atom, is formed in ex-
cellent enantioselectivity.
stituted a-cyanoacetates have not been established to
date,[4a,c,6] despite the potential for further elaboration
of the corresponding amination products.
Recently, we successfully developed the novel axial-
ly chiral guanidines 1[4e,7] as highly efficient Brønsted
base catalysts for promotion of enantioselective trans-
formations.[4e,7–9] Specifically, we reported on the
enantioselective electrophilic amination of unsymmet-
rical 1,3-dicarbonyl compounds with di-tert-butyl azo-
dicarboxylate catalyzed by a chiral guanidine catalyst
(1a), which afforded excellent enantioselectivity and
catalytic efficiency for cyclic b-keto esters; however,
for the acyclic b-keto esters, the enantioselectivities
were highly dependent on the alkyl substituent at the
Keywords: amination; amino acids; asymmetric cat-
alysis; organocatalysis; quaternary stereocenters
a-Amino acids having
a
quaternary stereogenic a-position of the keto ester.[4e] In this context, we
center at the a-position are attractive compounds aimed to develop the enantioselective electrophilic
owing to their potent biological activities as non-pro- amination of a-alkyl-substituted a-cyanoacetate deriv-
teinogenic analogues of natural a-amino acids and atives 2 with azodicarboxylate 3. Herein, we report
their increasing importance as constituents for prepar- that the guanidine catalyst 1 exhibited excellent per-
ing conformationally restricted peptides.[1] Catalysis of formance for the amination of a-cyanothioacetates 2
the enantioselective electrophilic amination of a,a- having a variety of primary alkyl substituents at the
disubstituted carbonyl compounds using azodicarbox- a-position, giving the products 4 in excellent enantio-
ylates has emerged as an efficient strategy to address selectivity and chemical yield (Scheme 1).
the challenging issue of constructing a nitrogen-substi-
Our investigation began by using thioacetate 2 as a
tuted quaternary stereogenic center at the a-position substrate in the present electrophilic amination be-
of a carbonyl compound.[2–4] Recently, several excel- cause of the potential for further derivatization of the
lent enantioselective catalytic reactions for electro- thioester moiety in the obtained products (4). An ini-
philic amination of a-substituted b-keto esters and tial attempt at electrophilic amination was performed
their analogues have been developed using chiral using benzyl-substituted cyanothioacetates 2a, di-tert-
metal-based catalysts[3] or organocatalysts.[2,4] Among butyl azodicarboxylate (3), and 1 mol% of guanidine
these, the enantioselective amination of a-substituted catalyst 1a in THF at À808C. To our delight, 1a
a-cyanoacetates is a powerful method to construct a worked efficiently and afforded the desired 4a quanti-
densely functionalized quaternary stereogenic center, tatively in good enantioselectivity, as shown in Table 1
and hence is a substantial step toward the enantiose- (entry 1). Screening of ethereal solvents showed a sig-
lective synthesis of a-amino acid derivatives having a nificant rate enhancement and completion of the re-
quaternary a-carbon atom.[3d,4a,c,d,f,g,5] However, the action within 20 min when either diethyl ether or 1,2-
methods are applicable to a-cyanoacetates with an ar- dimethoxyethane (DME) was employed (entries 2
omatic group at the a-position. General approaches and 3). More importantly, an increase in enantioselec-
to the highly enantioselective amination of alkyl-sub- tivity was achieved in these reaction media. Interest-
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Table 2. Enantioselective electrophilic amination of various
a-cyanothioacetates 2 with azodicarboxylate 3 catalyzed by
(R)-1a.[a]
Entry
2 (R)
t [h]
4
Yield [%]
% ee[b]
1
2b: Me
2b
2b
1
1
4b
4b
4b
4a
4c
4d
4e
4f
98
98
85
89
91
87
97
94
97
54
41
88
98
Scheme 1. Electrophilic amination of a-alkyl-substituted a-
cyanothioacetates 2 catalyzed by axially chiral guanidines 1.
2[c]
3[c,d]
4[c,d]
5
3.5
8
0.5
4.5
1
3.5
48
6
>98
>98
96
>98
91
>98
65
>98
92
2a: Bn
2c: Et
2d: iBu
2e: allyl
2f: iPr
2g: Ph
2g’: Ph
2a: Bn
Table 1. Enantioselective electrophilic amination of a-cyano-
thioacetate 2a with azodicarboxylate 3 catalyzed by by (R)-
1a.[a]
6
7
8[e]
9
4g
4g’
4a
10
11[f]
48
[a]
Unless otherwise noted, all reactions were carried out
with 0.22 mmol of 2, 0.2 mmol of 3, and 0.002 mmol of
(R)-1a (1 mol%), in 2 mL of DME/Et2O=3:1 mixed sol-
vent at À808C.
Entry Solvent
Time
4 h
20 min >98
15 min 98
3.5 h
2.5 h
Yield [%] % ee[b]
[b]
1
THF
>98
88
96
95
88
98
98
Enantiomeric excess was determined by chiral stationary
phases HPLC analysis.
2
Et2O
3[c]
4
DME[d]
[c]
[d]
[e]
[f]
In DME/acetone=3:1 mixed solvent.
1 mol% of catalyst (R)-1b.
acetone
DME/Et2O=3:1
98
5
>98
97
In DME at À508C.
6
DME/acetone=3:1 2.5 h
4.4 mmol of 2a (0.96 g), 4.0 mmol of 3 (0.92 g), and
0.004 mmol of (R)-1a (0.1 mol%), in 12 mL of DME/
Et2O=3:1 mixed solvent.
[a]
Unless otherwise noted, all reactions were carried out
with 0.22 mmol of 2a, 0.2 mmol of 3, and 0.002 mmol of
(R)-1a (1 mol%), in 2 mL of the indicated solvent at
À808C.
[b]
Enantiomeric excess was determined by chiral stationary
phases HPLC analysis.
subsequent investigations as it gave the amination
product 4a quantitatively.
Having identified the optimal reaction conditions,
we then investigated the substrate scope of the enan-
tioselective amination of a-cyanothioacetates 2 bear-
ing a variety of substituents at the a-position. As
[c]
[d]
Reaction run at À508C.
DME: 1,2-dimethoxyethane.
ingly, acetone was also applicable to the present cata- shown in Table 2, the present enantioselective cataly-
lytic reaction, affording 4a in nearly quantitative yield sis is applicable to a range of aliphatic substituents. It
with good enantioselectivity (entry 4). Among the sol- is noteworthy that excellent enantioselectivities were
vents examined, DME is particularly effective, giving achieved for primary alkyl substituents (entries 1–
an enantioselectivity that was as high as that obtained 7).[10] The methyl-substituted cyanothioacetate 2b ex-
in diethyl ether even at an elevated reaction tempera- hibited slightly lower enantioselectivity under the op-
ture of À508C. We therefore attempted to employ a timized conditions (entry 1), however, the selectivity
mixed solvent system to avoid freezing of DME (mp could be improved by further screening of solvents
À588C). As expected, mixing of DME with other sol- and catalysts 1 (entries 2 and 3), with the DME/ace-
vents, not only diethyl ether but also acetone, resulted tone mixed solvent system giving the highest enantio-
in an increase in enantioselectivity (entries 5 and 6), selectivity (entry 2). In addition, modification of the
reaching 98% ee at À808C in both cases. The DME/ catalyst by introduction of a trimethylsilyl substituent
diethyl ether mixed solvent system was employed for at the 3,5-positions of the terminal phenyl of the bi-
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Enantioselective Electrophilic Amination of a-Cyanothioacetates with Azodicarboxylates
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phenyl, giving 1b, further improves the enantioselec-
tivity (entry 3), reaching 91% ee. Unfortunately, the
catalyst 1b was not useful in reaction of the benzyl-
substituted 2a, giving a lower enantioselectivity (87%
ee) than that observed in catalysis by 1a (98% ee: see
Table 1, entries 5 and 6). In contrast to the primary
alkyl substituents, the amination of cyanothioacetates
having secondary alkyl and aromatic substituents, iso-
propyl (2f) and phenyl (2g), respectively, was serious-
ly compromised, giving the products (4f and 4g) in
moderate enantioselectivities (entries 8 and 9). More-
over, the reaction of 2g proceeded sluggishly, giving
the product 4g in moderate yield even for a prolonged
reaction period. This observation is in striking con-
trast to the parent cyanoacetate 2g’, the oxygen ana-
logue of 2g, which underwent the reaction to comple-
tion within 6 h, giving the product 4g’ in 88% ee
(entry 10). This enantioselectivity was much higher
Scheme 2. Transformation of amination product 4a to an a-
amino acid derivative. Reagents and conditions: a) NaBH4,
EtOH, room temperature, 1 h (83%); b) HCl, MeOH,
reflux, 48 h; c) H2, PtO2, MeOH, room temperature, 15 h; d)
Boc2O, MeOH, room temperature, 12 h (15% from 6).
than that obtained in the reaction of the correspond- N-Boc protective groups in MeOH, to afford the HCl
ing thioester 2g (entry 9). To evaluate the catalytic ef- salt of the a-hydrazinyl ester 7. Subsequent hydroge-
ficiency of 1a, we attempted a large-scale experiment nolysis of the hydrazine moiety was conducted using
with reductions in catalyst loading (entry 11). Gratify- PtO2 catalyst to give the serine derivative 8.[1a] Intro-
ingly, the reaction proceeded smoothly without any duction of a Boc group to the nitrogen atom of 8 then
detrimental effect even on a gram scale of 2a and the afforded the N-Boc-protected serine derivative 5. The
catalyst loading could be decreased to 0.1 mol%, absolute stereochemistry of 5 was determined to be
giving 4a in high yield with excellent enantioselectivi- the (S)-configuration by comparison of the optical ro-
ty. To further expand the scope of the present enan- tation with the literature value.[11] Thus it was con-
tioselective amination, we turned our attention to a- firmed that the electrophilic amination catalyzed by
cyanothioacetates 2 having a functionalized primary (R)-1a gave the (R)-isomer as the major product.
alkyl substituent (Figure 1). Excellent yields and
The stereochemical outcome of catalysis by the ax-
enantioselectivities were achieved under the opti- ially chiral guanidine 1 is highly dependent on the
mized conditions [1 mol% of (R)-1a, DME/Et2O= steric demand of the substituent introduced at the a-
3:1, À808C] in all cases.
position of the cyanothioacetate. When a primary
In order to demonstrate the synthetic potential of alkyl substituent was used, excellent enantioselectivi-
this methodology and to determine the absolute con- ties were observed for a variety of substituent pat-
figuration of the amination product, we transformed terns, including those having functionalized alkyl ter-
4b to the stereochemically known N-Boc-protected mini. Moreover, an entirely different effect was ob-
amino acid derivative 5 via a four-step chemical trans- served for the a-substituent of the parent cyanoace-
formation (Scheme 2). Derivatization of 4b was per- tates, oxygen analogues of thioesters 2 (see Table 2,
formed by reduction of the thioester moiety by entries 9 and 10).[10] Although the precise mechanism
NaBH4, followed by acid hydrolysis of the nitrile and of the enantiofacial selection has not yet been clari-
fied, the fact that subtle differences in not only steric
congestion but also the electronic property at the re-
action site, that is, the a-position of the cyano-
AHCTUNGTREG(NNUN thio)acetates, affect the stereochemical outcome
would be ascribed to the intrinsic flexibility of the
O···H···N hydrogen bond formed between the enolate
of the cyanothioacetate and the chiral guanidinium
ion.
In conclusion, we have demonstrated the highly
enantioselective electrophilic amination of a-cyano-
thioacetates with azodicarboxylates catalyzed by ax-
ially chiral guanidines. The method facilitates the
highly enantioenriched synthesis of a-amino acid de-
rivatives having a quaternary stereogenic center at
the a-position, an important class of compounds for
the preparation of peptide analogues and biologically
Figure 1. Enantioselective amination of functionalized a-cy-
anothioacetates.
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be explored in due course.
Experimental Section
General Procedure
To a test-tube equipped with a magnetic stirring bar was
added dimethoxyethane (1.5 mL), diethyl ether (0.5 mL), S-
ethyl
2-cyano-3-phenylpropanethioate
(2a;
48.3 mg,
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[6] During preparation of this manuscript, Deng and co-
workers reported the highly enantioselective amination
reaction of a-methyl substituted trifluoroethyl a-cya-
noacetate, see ref.[4g]
0.22 mmol), and (R)-1a (1.73 mg, 0.002 mmol). The tube was
capped, and stirred at room temperature for 15 min. After
that, the mixture was cooled to À808C and di-tert-butyl azo-
dicarboxylate (DBAD, 3; 46.1 mg, 0.20 mmol) was added.
The resulting yellow solution was stirred until the yellow
color had disappeared. After completion of the reaction, the
resulting solution was quenched with saturated aqueous
NH4Cl solution (a few drops) and solvent was removed. The
residue was purified by column chromatography (hexane/
AcOEt 12/1 to 6/1) to afford 4a; yield: >98%. The enantio-
meric excess was determined to be 98% ee by chiral station-
ary phase HPLC analysis.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas “Advanced Molecular Transforma-
tions of Carbon Resources” (Grant No. 19020006) from
MEXT, Japan. We acknowledge the JSPS Research Fellow-
ship for Young Scientists (M.N.). We also thank Prof. Li
Deng and co-workers for communicating their results prior
to publication.[4g]
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Enantioselective Electrophilic Amination of a-Cyanothioacetates with Azodicarboxylates
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