Asymmetric NaBH4 1,4-reduction of C3-disubstituted 2-propenoates catalyzed by a diamidine cobalt complex

Article abstract of DOI:10.1002/cctc.201500260

A new Co complex of a unique diamidine ligand catalyzes asymmetric NaBH₄ reduction of C3-disubstituted (E)- and (Z)-2-propenoates, including C3-oxygen- and nitrogen-substituted substrates with high enantioselectivity. Analysis by X-ray diffract

Full text of DOI:10.1002/cctc.201500260

DOI: 10.1002/cctc.201500260
Communications
Asymmetric NaBH4 1,4-Reduction of C3-Disubstituted
2-Propenoates Catalyzed by a Diamidine Cobalt Complex
Yoshihiro Shuto,[a] Tomoya Yamamura,[a] Shinji Tanaka,[a] Masahiro Yoshimura,[b] and
Masato Kitamura*[a]
A new Co complex of a unique diamidine ligand catalyzes
asymmetric NaBH4 reduction of C3-disubstituted (E)- and (Z)-2-
propenoates, including C3-oxygen- and nitrogen-substituted
substrates with high enantioselectivity. Analysis by X-ray dif-
a,b-unsaturated carboxylic esters by NaBH4;[4] however, this de-
velopment did not result in a significant advance in the field.[5]
This may be due to the lower atom efficiency, as well as the
higher E factor, of NaBH4 compared with that of the H2 system.
However, hydrogenation often requires a high-pressure-resist-
ance stainless autoclave in a dedicated laboratory with special-
ized techniques for manipulating the air-sensitive catalyst pre-
cursor. By contrast, the operational simplicity of NaBH4 reduc-
tion makes experiments very easy, enabling not only small-
scale reactions, but also industrial-scale production.[6] Reconsid-
ering the advantages, we have reinvestigated the NaBH4 reduc-
tion of 1 with the CoCl2 complexes (R,R)- and (S,S)-3, as a step
towards the development of the utility of our chiral diamidine
sp2N ligand, Naph-diPIM-dioxo-R.[7]
1
fraction, H NMR spectroscopy, ring-opening radical-clock and
D-labeling reactions, and the structure/selectivity relationship
suggest that a mechanism of CoH-involved non-single-electron
transfer 1,4-addition differentiates the C2 enantioface. Involve-
ment of CoH species has been supported by quantitative isola-
tion of a new type of CoH2(BH3)2 complex.
Asymmetric 1,4-reduction of a,b-unsaturated carboxylic esters
is an important and versatile unit operation in multistep syn-
theses of natural products and pharmaceuticals.[1] In particular,
stereo- and olefin-selective reduction of C3-disubstituted 2-
propenoates 1, yielding the saturated prenyl-type motif 2 has
considerable importance (Scheme 1). Asymmetric hydrogena-
The substrate (E)-1a was selected as the standard, and the
concentrations were set to [(E)-1a]=250 mm, [(R,R)-3]=
2.5 mm, and [NaBH4]=500 mm. The complex (R,R)-3 was pre-
pared by mixing CoCl2 and (R,R)-Naph-diPIM-dioxo-R (R=iPr,
Me, and H) in CH3OH at 258C for 1 h, followed by concentra-
tion (see below). To the cooled CH2Cl2 suspension of NaBH4
containing (R,R)-3A and (E)-1a, CH3OH at 08C was added to
achieve a 1:1 CH3OH/CH2Cl2 solvent system. After 1 h at 258C,
the yield and enantiomeric ratio (er) of the product 2a were
analyzed.[8] The results are shown in Table 1. The standard con-
ditions quantitatively afforded 2a with an R/S er of >99:1.
Switching the chirality of the catalyst to (S,S)-3A gave almost
enantiopure (S)-2a. The concentration of (R,R)-3A could be re-
duced from 2.5 mm to 0.125 mm (substrate/catalyst (S/C) ratio
of 2000) without loss of enantioselectivity. A 1:1 CH3OH/CH2Cl2
solvent system with the Co complex provided the best results
of the conditions investigated.[8] Replacement of iPr in Naph-
diPIM-dioxo-R with Me ((S,S)-3B) resulted in a reduction of the
er to 2:98; this decrease in er was more significant with (S,S)-
3C (R=H). Bisoxazoline ligands, L1 and L2, and BINAP (L3),
which are recognized as privileged ligands,[9] were not effective
in this particular reaction.
Scheme 1. Asymmetric 1,4-reduction of C3-disubstituted 2-propenoates.
tion has been the major approach to this reduction since 1987,
when the first success using Ru(OCOCH3)2(binap) (binap=2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl) was reported.[2,3] Two
years later, Pfaltz and co-workers reported an excellent chiral
Co semicorrin catalyst affecting asymmetric 1,4-reduction of
[a] Y. Shuto, T. Yamamura, Dr. S. Tanaka, Prof. M. Kitamura
Graduate School of Pharmaceutical Sciences
Graduate School of Science
and Research Center for Materials Science
Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
E-mail: kitamura@os.rcms.nagoya-u.ac.jp
[b] Dr. M. Yoshimura
Division of Liberal Arts and Sciences
Aichi Gakuin University
Iwasaki, Nisshin 470-0195 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500260.
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Communications
possessed a tert-butyl group (entries 1–5). The C3-diaryl substi-
tuted substrates 1 f and 1g were reduced with reasonable
enantioselectivity (entries 6 and 7). The C3-dialkyl-substituted
substrates 1h–j were efficiently reduced to give the corre-
sponding saturated products with high enantioselectivities,
even with a tert-butyl substituent (entries 8–10). With the dia-
stereomeric substrates (Z)-1a and (Z)-1h, the enantioselectivity
was reversed without any negative effect on the er (entries 11
and 12). The present asymmetric catalysis could be also ap-
plied to C3-heterosubstituted 1. Thus, C3-CH3CONH-substitut-
ed ethyl cinnamate 1k and crotonate 1l were quantitatively
reduced to the corresponding b-amino acid derivatives with
R/S ratios of >97:3 (entries 13 and 14).[10] The tert-butyldi-
methylsilyl (TBDMS)-protected enol of a b-keto ester, 1m, was
also reduced with a R/S er of >99:1 (entry 15). The esters of
tiglic acid and angelic acid were found to be poor substrates.[8]
The stereochemical outcome obtained by the substrate-struc-
ture/enantioface-selectivity relationship (Table 2) is outlined in
Scheme 2, and implies that the Naph-diPIM-dioxo-iPr–Co spe-
Table 1. Co-catalyzed asymmetric NaBH4 1,4-reduction.
Catalyst
S/C
100
100
2000
10000
100
100
100
100
100
NMR yield [%]
R/S
(R,R)-3A
(S,S)-3A
(R,R)-3A[a]
(R,R)-3A[b]
(S,S)-3B
>99
>99
88
>99:1
1:>99
99:1
91:9
53
>99
>99
54
35
9
2:98
(S,S)-3C
10:90
42:58
35:65
70:30
L1/CoCl2
L2/CoCl2
L3/CoCl2
[a] [(R,R)-3A]=0.125 mm; 7 h. [b] [(E)-1a]=1 m; [NaBH4]=2 m; [(R,R)-
3A]=0.1 mm; 24 h.
Table 2. (R,R)-Naph-diPIM-dioxo-iPr–Co-catalyzed asymmetric NaBH4 1,4-
reduction of C3-disubstituted methyl 2-propenoates.[a]
Substrate
Product
er[c]
Entry
R1
R2
Yield
[%][b]
Config.
Scheme 2. General rule of enantioface selection. R2 >CH2CO2R3 >R1.
1[d]
2
3
4
5[f]
6[f]
7
8
9
10
11
12
13[h,i]
14[h,i]
15[h,i]
(E)-1a
(E)-1b
(E)-1c
(E)-1d
(E)-1e
(E)-1 f
(E)-1g
(E)-1h
(E)-1i
(E)-1j
(Z)-1a
(Z)-1h
(Z)-1k
(Z)-1l
CH3
C6H5
C6H5
C6H5
C6H5
98
93
92
98
<5
95[g]
97
94
90
72
90
93
89
86
98
99:1
98:2
98:2
>99:1
–
94:6
92:8
99:1
97:3
98:2
99:1
99:1
97:3
98:2
>99:1[j]
R
R
S
–
–
C2H5
i-C3H7
c-C3H5
t-C4H9
C6H5
C6H5
CH3
cies differentiates the C2 enantiofaces at a certain stage of the
catalysis. Both R and S enantiomers are accessible either by
changing the geometry of the olefin or by switching the chiral-
ity of the catalysts.
[e]
C6H5
4-CH3OC6H4
4-CF3C6H4
C6H5(CH2)2
c-C6H11
t-C4H9
CH3
S
–
[e]
S
–
–
We assume that the Naph-diPIM-dioxo-iPr–CoHn (n=1 or 2)
species is generated by the action of NaBH4 on the CoIICl2 pre-
cursor,[11] and that the hydride is delivered to C3 of 1 in a 1,4-
addition manner by a two-electron-transfer mechanism, rather
than by single-electron transfer (SET), to generate the corre-
sponding Co enolate,[4g,12] as suggested by the following four
observations. i) The reaction of (E)-1a with (R,R)-3A under stan-
dard conditions using NaBD4/1:1 CH3OH/CH2Cl2 gave (R)-[3-2H]-
2a as the sole product within the error range, and under the
conditions of NaBH4/1:1 CH3OD/CH2Cl2 gave (2S,3R)-[2-2H]-2a
and (2R,3R)-[2-2H]-2a in a 1:1 ratio. ii) The electronic effect on
the reactivity observed for (E)-1 f/(E)-1g (Table 2, entries 6 and
7) is in agreement with a 1,4-addition mechanism. iii) Both the
SET mechanism[13] and H addition onto the C2 atom can be ex-
cluded by the fact that the C3-cyclopropyl-substituted sub-
strate 1d (Table 2, entry 4) and ethyl 2-cyclopropylideneacetate
(4) are quantitatively converted to the corresponding 1,4-re-
duction products 5 without cleavage of the cyclopropyl ring.
iv) A Co hydride complex, CoH2(BH3)2((R,R)-Naph-diPIM-dioxo-
iPr), with the same catalyst performance as that of (R,R)-3A,
was quantitatively prepared by reaction of the CoCl2 precursor
[e]
CH3
CH3
[e]
C6H5
C6H5(CH2)2 CH3
CH3CONH
CH3CONH
S
R
R
C6H5
CH3
CH3
[e]
–
(Z)-1m TBDMSO
R
[a] Unless specified otherwise, all reactions were carried out in 1:1
CH3OH/CH2Cl2 under conditions on a 0.5 mmol scale; [1]=250Æ10 mm;
[NaBH4]=500 mm; [(R,R)-3A]=2.5 mm; 258C; 1 h. [b] Isolated yield.
[c] Chiral HPLC or GC analyses of the product 2, or 1H NMR analyses of
the diastereomeric amides derived from 2.[8] [d] 50 mmol scale; S/C=
1000. [e] Not determined. [f] 28 h. [g] 1H NMR yield. [h] Ethyl esters (R3 =
C2H5) were used in 1:1 C2H5OH/CH2Cl2. [i] 3 h. [j] Determined by chiral
HPLC analysis after desilylation.[8]
As summarized in Table 2, the Naph-diPIM-dioxo-iPr–Co
complex (R,R)-3A exhibited a high level of enantio-differentiat-
ing ability in the reduction of C3-disubstituted 2-propenoates
with alkyl, aryl, and heteroatom substitution patterns. The C3-
CH3 substituent of 1a could be replaced by a primary or sec-
ondary alkyl group, but no reaction occurred with 1e, which
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Communications
(R,R)-3A with a 2 mol amount of NaBH4 in dimethoxyethane
(DME).[8,14]
lyst is ascribed to the following characteristics of Naph-diPIM-
dioxo-R, which differ from those of conventional sp2N-based
bidentate ligands: i) high s-donating ability derived from two
amidine units fixed to the same side on the highly rigid and
planar ligand, enhancing the hydride properties of the CoH
species; ii) an almost 908 bite angle to stabilize the CoH com-
plex; iii) an extended p-conjugated system to accept the back
donation from the low-valence CoH species; and iv) clear chir-
ality constructed by the C2-iPr-substituted dioxolane rings
pointing up and down on the core 5,5,6,6,5,5 ring system. The
reaction pathway, as well as the mechanism of enantioface se-
lection, has been assumed on the basis of the substrate-struc-
ture/enantioselectivity relationship, deuterium-labeling experi-
ments, radical-clock experiments, and X-ray crystallographic
analysis of a new type of CoH2(BH3)2 complex. The present
method is operationally simple, and will provide organic syn-
thetic chemists with a powerful tool for the multistep synthe-
ses of natural products and pharmaceuticals.
Considering these results together with the molecular struc-
tures of (R,R)-3A and CoH2(BH3)2((R,R)-Naph-diPIM-dioxo-iPr)
complexes in the crystals (Figure 1),[8,15] the enantioface of 1 is
Experimental Section
A solution of (R,R)-3A (5.00 mm in CH3OH, 10.0 mL, 50.0 mmol) was
added to a 1000 mL Young-type Schlenk flask and concentrated in
vacuo, leaving a blue solid in the tube. NaBH4 (3.78 g, 100 mmol),
CH2Cl2 (100 mL), and (E)-methyl 3-phenylbut-2-enoate ((E)-1a)
(8.81 g, 50.0 mmol) were then added. After cooling the mixture to
08C, CH3OH (100 mL) was slowly added. After removal from the ice
bath, the mixture was stirred at RT for 1 h. After this time the reac-
tion was quenched by the addition of 1m aqueous HCl (200 mL)
and extracted by CH2Cl2 (3”100 mL). The aqueous layer was con-
centrated to half its volume and extracted by CH2Cl2 (3”100 mL).
The combined organic layers were concentrated to give a crude
product (9.25 g, >99%), which was dissolved in diethyl ether and
passed through a short silica gel column (5 cmf”10 cm; 25 g;
eluent; ether). The filtrate was concentrated to give (R)-methyl 3-
phenylbutanoate ((R)-2a) (8.72 g, 98% yield) with a 99:1 R/S er as
Figure 1. Molecular structures of a) CoCl2((R,R)-Naph-diPIM-dioxo-iPr)·thf
((R,R)-3A·thf) (thf omitted) and b) CoH2(BH3)2((R,R)-Naph-diPIM-dioxo-
iPr)·ether (ether omitted). Hydrogen atoms on Co and B were located by
Fourier differences and isotropically refined.
thought to be selected by the catalyst/substrate complexes
cat/subSiSi and cat/subReRe (R2 >=CHCO2R3 > R1; X=H, H(BH3),
Cl, solvent, substrate, product). The CoH species would interact
with the C2=C3 bond of 1 in parallel to the CoÀH bond. In this
case, cat/subSiSi is more stereo-complementary than cat/
subReRe, which is affected by steric repulsion from the dioxo-
lane ring of the R,R ligand, yielding (R)-2 (R2 >CH2CO2R3 >R1)
as the major product. The higher enantioselectivity achieved
with 3A can be ascribed to the W-shape conformation of the
five-carbon system of the two iPr groups (Figure 1, side view),
which extend a methyl group toward the reaction site. Swap-
ping R1 and R2 leads to formation of the enantiomeric product,
because only the Si C2 enantioface is recognized by (R,R)-3A.
Neither the configuration nor the valency of Co[11] is clear, and
the involvement of a CoH/BH3 bridged species[11d] cannot be
a colorless oil (½aŠ25 =À29.4 (c=1.0 in CHCl3)).
D
Acknowledgements
This work was supported by an Advanced Catalytic Transforma-
tion Program for Carbon Utilization (ACT-C) from Japan Science
and Technology Agency (JST).
excluded. Nevertheless, by assuming cat/subSiSi and cat/subReRe
the stereochemical outcome in Scheme 2 can be well ex-
plained. A detailed mechanistic study is now underway.
,
Keywords: asymmetric catalysis · carboxylic esters · cobalt ·
reduction · sodium borohydride
In summary, we have developed a high-performance molec-
ular asymmetric catalyst for the 1,4-reduction of various C3-di-
substituted 2-propenoates by NaBH4. The success of this cata-
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[15] CCDC 1049568 ((R,R)-3A·thf) and CCDC 1049569 (CoH2(BH3)2((R,R)-Naph-
diPIM-dioxo-iPr)·ether) contain the supplementary crystallographic data
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[7] (R,R)-Naph-diPIM-dioxo-iPr: (3aR,11aR,14aS,16bS)-2,2,13,13-tetraisoprop-
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Received: March 11, 2015
Published online on April 27, 2015
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