P-chirogenic organocatalysts: Application to the aza-Morita-Baylis-Hillman (aza-MBH) reaction of ketimines

Article abstract of DOI:10.1039/c3cc44549f

The P-chirogenic organocatalysts were found to promote the enantioselective aza-Morita-Baylis-Hillman reaction of ketimines derived from acyclic α-keto esters. In the P-chirogenic organocatalyzed aza-MBH reactions, α,α-disubstituted α-amino acid derivativ

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P-Chirogenic organocatalysts: Application to the aza-Morita-Baylis-
Hillman (aza-MBH) reaction of ketimines
Shinobu Takizawa,a Emmanuelle Rémond,b Fernando Arteaga Arteaga,a Yasushi Yoshida,a Vellaisamy
Sridharan,a,c Jérôme Bayardon,b Sylvain Jugé,*b and Hiroaki Sasai*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
As the first step in the development of the azaꢀMBH reaction
of ketimines, the reaction of methyl vinyl ketone (3a) with ethyl
55 2ꢀphenylꢀ2ꢀ(tosylimino)acetate (4a) was attempted using 10
mol% of achiral LB catalysts. Among the catalysts we examined,
PPh3 was found to promote the reaction efficiently to give the
azaꢀMBH adduct 5a in 74% yield. The reaction in tertꢀbutyl
methyl ether (TBME) gave good result to afford 5a in 96%
60 yield.9
The P-chirogenic organocatalysts were found to promote the
enantioselective aza-Morita-Baylis-Hillman reaction of
ketimines derived from acyclic α-keto esters. In the P-
10 chirogenic organocatalyzed aza-MBH reactions, α,α-
disubstituted α-amino acid derivatives were obtained in high
yields with high enantioselectivities (up to 97% ee).
Chiral α,αꢀdisubstituted unnatural amino acids are important
building blocks for biologically important compounds and natural
15 products.1 The catalytic enantioselective addition of carbon
nucleophiles to ketimines2 is an efficient and straightforward
method to construct chiral unnatural amino acids. However,
ketimines are considerably less reactive than aldimines, and
enantioface differentiation of ketimines is more difficult because
20 of the smaller steric and electronic differences between the two
substituents on prochiral carbons. Therefore, construction of
tetrasubstituted carbon stereogenic centers is still a subject of
intensive research in asymmetric organic chemistry.2.3
NHTs
O
O
NTs
1a-f
2
or (10-20 mol%)
CO2R2
R1
R1
TBME, 5 or 10 o
C
R2O2C
Ar
Ar
3
4
5
up to 97% ee
65
HO
P
X
(
S)-1a: X = CH OH
1b
(S)- : X = CH2CH3
1c
(S)- : X = CH3
1d
(S)- : X = CH2OCH3
2
Fe
P
Ph
MeO
Ph
2
2
(
(
S)-1e: X = OH
S ,S)-1f: X = (S)-CHOHPh
(Rp,R)-
(Rp,S)-
70
The azaꢀMorita–Baylis–Hillman (aza–MBH) reaction is known
25 to be a useful and atomꢀeconomical C–C bond–forming reaction
of electronꢀdeficient alkenes with imines catalyzed by Lewis
bases (LBs). The azaꢀMBH adducts are highly functionalized βꢀ
amino acid derivatives and are valuable building blocks in
medicinal chemistry.4 Despite a number of attractive systems
30 have been developed for the azaꢀMBH reaction,5 a few reports on
reaction of ketimines have been published. In 2001 Burger
reported that the mixed reagent 1,4ꢀdiazabicyclo[2.2.2]octane
(DABCO) (100 mol%) and CaH2 (70 mol%) promoted the
reaction of acrylates with Nꢀbenzoyl or Nꢀtertꢀbutoxycarbonyl
35 ketimines derived from hexafluoroacetone to afford β,βꢀ
bis(trifluoromethyl) βꢀamino acids in up to 65% yield.6 In 2012,
Ye reported achiral LBꢀcatalyzed cycloaddition reactions of
allenoates with cyclic ketimines for the synthesis of trisubstituted
Nꢀheterocycles.7 As the first enantioselective azaꢀMBH studies of
40 ketimines, in 2013 Shi and Li group and Chen group
independently reported azaꢀMBH reaction of ketimines promoted
by acidꢀbase organocatalysts such as βꢀICD.8 Effective and
enantioselective construction of tetrasubstituted carbon
stereogenic centers via the azaꢀMBH reaction of ketimines has
45 been a challenge in asymmetric synthetic chemistry. Herein we
report the enantioselective azaꢀMBH reaction of ketimines, alkyl
2ꢀarylꢀ2ꢀ(tosylimino)acetates 4, producing multifunctional α,αꢀ
disubstituted unnatural amino acid derivatives 5. The newly
developed Pꢀchirogenic organocatalysts 1a-f or 2 promote the
50 reaction of enones 3 with ketimines 4 to give the corresponding
α,αꢀdisubstituted amino acid derivatives 5 in high yields with
moderate to high enantioselectivities (Figure 1).
p
1f
(Sp,R)- : X = ( )-CHOHPh
R
Figure 1. PꢀChirogenic organocatalyzed azaꢀMBH reaction of
enones 3 with ketimines 4.
75
Next, various chiral catalysts such as (S)ꢀ(+)ꢀNMDPP, (R)ꢀ(S)ꢀ
PPFA, (S)ꢀBINAP, (R)ꢀMeOꢀMOP, βꢀICD and compounds (S) or
(R)ꢀ6ꢀ9, were tested as shown in Table 1. Some of them which
are known to mediate the enantioselective MBHꢀtype
processes,5,10 showed no activity with ketimine 4a (entries 1
–5).
80 A mixed reagent of (S)ꢀBINOL (10 mol%) with PPh3 (10 mol%)
or chiral organocatalyst (R)ꢀ10 possessing highly nucleophilic
phosphine led to racemic products (entries 6 and 7). The acid–
base organocatalyst (S)ꢀ11[10e] promoted the reaction to give 5a in
25% yield with 38% ee (entry 8), along with ethyl 2ꢀoxoꢀ2ꢀ
85 phenylacetate generated from the hydrolysis of 4a.11 During this
screening process, Pꢀchirogenic12,13 organocatalysts were found
to promote the azaꢀMBH reaction of ketimine 4a to give adduct
5a without the decomposition of 4a (entries 9–12). The synthesis
of Pꢀchirogenic oꢀ(hydroxyalkyl)phenyl phosphine such as (S)ꢀ1a
90 or (Sp,S)ꢀ1f, were achieved by hydroxyalkylation of their
corresponding oꢀbromophenylphosphines (free or borane
complex).12f,13d Thus, the ferrocenyl Pꢀchirogenic organocatalysts
(S)ꢀ1a promoted the reaction in 87% yield with 96% ee9 (entry 9),
whereas (S)ꢀ1c with a methyl and (S)ꢀ1d with a methoxymethyl
95 as orthoꢀsubstituents exhibited low asymmetric inductions
(entries 11 and 12). No catalytic activity was observed when
using Pꢀchirogenic acidꢀbase organocatalyst (S)ꢀ1e bearing an
orthoꢀhydroxy substituent (entry 13). Since the organocatalyst
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DOI: 10.1039/C3CC44549F
40 Table 2. Scope of substratesa
(S)ꢀ1b having an ethyl substituent afforded 5a with high
enantioselectivity (entry 10), the steric effect of the
hydroxymethyl group or the ethyl substituent on the catalysts 1a
and 1b would be important to promote the reaction with high
enantiocontrol. However, catalyst 1a exhibited higher activity
than 1b because the hydroxy group in 1a could work as a protonꢀ
shuttle in a protonꢀtransfer rate determining step.5
5
°C/ yield ee
1 or 2
entry
3, R1
4, R2, R3
4a, Ph, Et
4b, 4ꢀMeꢀC6H4,Et
4c, 4ꢀMeOꢀC6H4, Et
4d, 4ꢀClꢀC6H4, Et
4e, Ph, CH2CF3
4f, Ph, Bn
4g, 3,4ꢀ(OCH2O)ꢀC6H3¸Et
4h, 4ꢀBrꢀC6H4, Et
4i, 2ꢀthiophenyl, Et
4a
day (%)b (%)c
1
2
3
4
5
6
7
8
3a, Me
3a
3a
3a
3a
3a
3a
3a
3a
3b, Et
3a
3a
3a
3a
3a
3a
3a
3a
1a
1a
1a
1a
1a
1a
1a
10/2 5a, 87 96
5/4 5b, 81 89
10/2 5c, 79 80
5/2 5d, 59 88
5/3 5e, 89 97
5/7 5f, 98 41
10/2 5g, 86 96
5/10 5h, 91 96
5/3 5i, 81 76
5/4 5j, 83 85
10/5 5a, 70 89
5/9 5b, 87 96
10/4 5c, 92 94
5/4 5d, 95 88
5/3 5k, 93 93
Table 1. Enantioselective azaꢀMBH reaction of 3a with 4a using
10 organocatalystsa
1ac
1a
9
entry
1
2
3
4
chiral organocatalyst
yield (%)b
trace
trace
trace
trace
trace
13
ee (%)c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1a
(S)ꢀ(+)ꢀNMDPP
(R)ꢀ(S)ꢀPPFA
(S)ꢀBINAP
(R)ꢀMeOꢀMOP
βꢀICD, (S) or (R)-6-9
PPh3 + (S)ꢀBINOL
(R)ꢀ10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4a
4b
4c
4d
1b
1b
1b
1b
4j, 2ꢀnaphthyl, Et
4j
4k, 3ꢀMeꢀC6H4, Et
4k
4l, PhCH=CH2, Et
4l
4m, Ph, Me
4m
4n, 2ꢀMeꢀC6H4, Et
4o, 2ꢀBrꢀC6H4, Me
4p, tꢀBu, Et
(Sp,S)ꢀ1e
5
6d
7
0
0
(Sp,R)ꢀ1e 5/9 5k, 55 52
(Rp,R)ꢀ2d 5/10 5l, 70 64
29
(Rp,S)ꢀ2d
5/9 5l, 63 54
(Rp,R)ꢀ2d 5/9 5m, 67 72
(Rp,S)ꢀ2d
5/8 5m, 96 53
(Rp,R)ꢀ2 5/3.5 5n, 90 93
(Rp,S)ꢀ2 5/2.5 5n, 98 56
1 or 2 5/10
8
9
10
11
12
13
(S)ꢀ11
(S)ꢀ1a
(S)ꢀ1b
(S)ꢀ1c
(S)ꢀ1d
(S)ꢀ1e
25
87
36
42
52
trace
38
96
89
15
17
ꢀ
3a
3a
3a
3a
3a
3a
3a
nr
nr
nr
ꢀ
ꢀ
ꢀ
aConditions: 3a (0.12 mmol), 4a (0.040 mmol), catalyst (10 mol%) in
TBME (0.2 mL). bIsolated yield. cDetermined by HPLC (Daicel
Chiralpak IC). dPPh3 (10 mol%) and (S)ꢀBINOL (10 mol%) were used.
1 or 2 5/10
1 or 2 5/10
aConditions: 3a (0.12 mmol), 4 (0.040 mmol), catalyst (10 mol%) in TBME (0.2
b
c
OH
4m5 L). Isolated yield. Determined by HPLC (Daicel Chiralpak IC for 5a; Daicel
Me
PPh2
O
Chiralpak AS for 5b and 5i; Daicel Chiralpak IB for 5c; Daicel Chiralpak IA for
5d; Daicel Chiralcel ODꢀH for 5g; Daicel Chiralpak ASꢀH for 5e, f, 5h, and 5j–n).
d20 mol% of catalyst was used. nr = no reaction.
PPh2
PPh2
PPh2
OR
NMe2
PPh2
N
Fe
N
(S)-(+)-NMDPP
(R)-(S)-PPFA
(S)-BINAP
( )-MeO-MOP (R = Me)
R
6 (R = H)
-ICD
50
N
PPh2
PPh2
OH
N
PPh2
OH
OH
OH
S)-7
OH
Ph2P
NH2
OH
OH
11
(S)-
(
(S)-8
(S)-9
(R)-10
Scheme 1. Enantioselective azaꢀMBH reaction of 3a with 4q.
15
55
With the optimized conditions, we focused on the substrate
scope (Table 2). In the Pꢀchirogenic organocatalyzed azaꢀMBH
reaction of ketimines, moderate to high enantioselectivities were
obtained irrespective of the electronic nature of the substituent on
20 the aromatic ring of 4. In the reactions of ketimines 4j–m,
diastereomeric catalysts (Sp,S)ꢀ1e or (Sp,R)ꢀ1e and (Rp,R)ꢀ2 or
(Rp,S)ꢀ2 were used (entries 15–22). The reactions using catalysts
(Sp,R)ꢀ1e and (Rp,S)ꢀ2 exhibited enantioselectivites lower than
those using (Sp,S)ꢀ1e and (Rp,R)ꢀ2.14ꢀ16 In terms of
25 enantioselectivities, the Pꢀchirogenic organocatalyst 1a afforded
the best outcome (97% ee) for substrate 4e (entry 5). The
compounds 2ꢀthiophenyl ketimine 4i, 2ꢀnaphthyl ketimine 4j and
ketimine 4q derived from cyclic αꢀketo amide were also found to
be suitable substrates (entries 9, 15 and Scheme 1). The reaction
30 of ethyl vinyl ketone (3b) with 4a afforded the adduct 5j with
high enantioselectivity (entry 10).17 However, the introduction of
substituent in ortho position of the aromatic ring (R2 = Ar) and
bulky aliphatic substitution (R2 = tꢀBu) of 4 led to no reaction,
probably because of steric hindrance (entries 23ꢀ25). Examining
35 the substituent R3 on Nꢀtosylketimine 4, the catalyst 1a gave
adducts 5 in good yields with high enantioselectivities, except for
benzyl ester 4f (entries 1, 5 and 6).
60
65
Conditions: a) 10% Pd/C, MeOH, H2 (1 atm), RT, 2 h; b) BuLi (2.2 equiv.),
CuI (2.2 equiv.), THF, −78°C, overnight; c) diethyl malonate (1.2 equiv.),
K2CO3 (2.5 equiv.), DMSO, RT, 2.5 h; d) LiOH (1.5 equiv) in H2O/THF (1:1),
70 RT, 10 h; d.r. = diastereomeric ratio determined by 1HꢀNMR or HPLC.
Scheme 2. Transformations of α,αꢀdisubstituted amino acid
derivatives (R)ꢀ5.
75 were performed (Scheme 2). The αꢀmethyl ketone 12 was
obtained in good yield by hydrogenation of 5a using 10% Pd/C
under H2 without over reduction of the ketone moiety.
Furthermore, the Michael addition of nꢀbutylcopper reagent or
To demonstrate the synthetic utility of the highly
functionalized azaꢀMBH product 5, a variety of transformations
2
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6
7
8
N. N. Sergeeva, A. S. Golubev and K. Burger, Synthesis 2001,
281.
diethyl malonate to 5d produced the cyclic product 13 or 14 via
sequential 1,4ꢀaddition/lactonization with over 85% yields,
respectively. Finally, 5a could be hydrolyzed to the amino acid
15 by exposure to aqueous LiOH/THF, accompanied by a fiveꢀ
membered ring product 16.
In summary, we have developed the first highly
enantioselective Pꢀchirogenic organocatalyzed CꢀC bondꢀforming
reaction to produce the tetrasubstituted carbon stereogenic
centers. The products obtained were transformed reliably into a
10 variety of α,αꢀdisubstituted αꢀamino acid derivatives. Further
investigation of the reaction mechanism and the reaction scope
and application of the protocol to the enantioselective synthesis
of biologically active compounds is currently underway.
This work was supported by the Japan Science and Technology
15 Corporation and the Ministry of Education, Culture, Sports,
Science and Technology, Japan. This research was also supported
by the CNRS (Centre National de la Recherche Scientifique), the
“Ministère de l’Education National et de la Recherche”, and the
Agence Nationale de la Recherche for funding (ANR BLAN
20 MetChirPhos). We acknowledge Y. Rousselin (ICMUBꢀ Dijon)
for the Xꢀray structure and the technical staff of the
Comprehensive Analysis Center of ISIR, Osaka Univ. (Japan).
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90
Notes and references
a
The Institute of Scientific and Industrial Research (ISIR), Osaka
11 To suppress the decomposition of the moisture–sensitive
ketimine, molecular sieve (MS) 4 A was added to the reaction
25 University, Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan. E-mail:
sasai@sanken.osaka-u.ac.jp; Fax: +81 6 6879 8465; Tel: +81 6 6879
8469
95
media. Although the addition of MS
4
A
improved
b
Université de Bourgogne, ICMUB-StéréochIM- 9 av. A. Savary, BP
enantioselectivity (80% ee), the desired product 5a was obtained
in only 17% yield.
47870-21078 Dijon Cedex, France. E-mail: sylvain.juge@u-bourgogne.fr
30 c V.S. present address: Department of Chemistry, School of Chemical and
Biotechnology, SASTRA University, Thanjavur - 613401, Tamil Nadu,
India
† Electronic Supplementary Information (ESI) available: Experimental
procedures and analytical data. See DOI: 10.1039/b000000x/
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2
120 14 In the reactions of ketimines 4j, k and 4m with catalyst 1a or 1b,
the lower enantioselectivities (5k: 84 % ee with 1a, 79% ee with
1b; 5l: 50 % ee with 1a, 45% ee with 1b; 5n: 83 % ee with 1a,
75% ee with 1b) were obtained than those using catalyst (Sp,R)ꢀ1e
or (Rp,S)ꢀ2.
125 15 The reaction of 3a and 4l mediated by the Pꢀchirogenic catalysts 1
gave the known tetrahydropyridines via azaꢀRauhutꢀCurrier
process, see: (a) Z. Shi, P. Yu, T.ꢀP. Loh and G. Zhong, Angew.
Chem. Int. Ed. 2012, 51, 7825. (b) Z. Jin, R. Yang, Y. Du, B.
Tiwari, R. Ganguly and Y. R. Chi, Org. Lett. 2012, 14, 3226.
130 16 The absolute configuration of 5 was assigned by comparison with
an optical rotation of the synthetic analog reported in the
literature.8
3
4
J. Clayden, M. Donnard, J. Lefranc and D. J. Tetlow, Chem.
Commun. 2011, 47, 4624.
For recent reviews on applications of MBH adducts to bioactive
molecules, see: (a) V. Declerck, J. Martinez and F. Lamaty,
Chem. Rev. 2009, 109, 1. (b) D. Basavaiah, B. S. Reddy and S.
Badsara, Chem. Rev. 2010, 110, 5447. (c) C. G. Lima–Junior and
M. L. A. A. Vasconcellos, Bioorg. Med. Chem. 2012, 20, 3954.
For recent reviews on enantioselective MBH reaction, see: (a) G.
Masson, C. Housseman and J. Zhu, Angew. Chem. Int. Ed. 2007,
46, 4614. (b) Y. Wei and M. Shi, Acc. Chem. Res. 2010, 43, 1005.
(c) S.ꢀX. Wang, V. Han, F. Zhong, Y. Wang and Y. Lu, Synlett
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5
17 When the 2ꢀnaphthyl acrylate (3c) was used for a coupling of 4a,
the corresponding adduct 5p was obtained in 75% yield with 53%
135
ee.
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