Copper-catalyzed asymmetric hydroboration of α-dehydroamino acid derivatives: Facile synthesis of chiral β-hydroxy-α-amino acids

Article abstract of DOI:10.1021/ol500219e

The Cu-catalyzed asymmetric conjugate hydroboration reaction of β-substituted α-dehydroamino acid derivatives has been established, affording enantioenriched syn- and anti-β-boronate-α-amino acid derivatives with excellent combined yields (83-99%, dr ≈ 1:

Full text of DOI:10.1021/ol500219e

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Asymmetric Hydroboration of α‑Dehydroamino
Acid Derivatives: Facile Synthesis of Chiral β‑Hydroxy-α-amino Acids
Zhi-Tao He, Yi-Shuang Zhao, Ping Tian,* Chuan-Chuan Wang, Han-Qing Dong,† and Guo-Qiang Lin*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The Cu-catalyzed asymmetric conjugate hydroboration reaction of β-substituted α-dehydroamino acid derivatives
has been established, affording enantioenriched syn- and anti-β-boronate-α-amino acid derivatives with excellent combined yields
(83−99%, dr ≈ 1:1) and excellent enantioselectivities (92−98% ee). The hydroboration products were expediently converted
into valuable β-hydroxy-α-amino acid derivatives, which were widely used in the preparation of chiral drugs and bioactive
molecules.
recious-metal-catalyzed asymmetric hydrogenation of α-
dehydroamino acid derivatives has been recognized as one
in Cu-catalyzed asymmetric hydroboration of α-dehydroamino
acid derivatives leading to chiral β-boronate-α-amino acids.
P
of the most important methods for the synthesis of various
chiral α-amino acids, which are of great synthetic importance in
the preparation of chiral drugs and natural products.1 However,
transition-metal-catalyzed asymmetric hydroboration of α-
dehydroamino acid derivatives has never been explored. As
shown in Scheme 1, this new approach can deliver a chiral β-
Scheme 1. Cu-Catalyzed Asymmetric Hydroboration of α-
Dehydroamino Acid Derivatives
Figure 1. Chiral drugs and bioactive molecules containing chiral β-
hydroxy-α-amino acid framework.
In the past 5 years, Cu-catalyzed asymmetric conjugate
hydroboration of α,β-unsaturated carboxylic derivatives with
bis(pinacolato)diboron (B2Pin2) as “boron” source and MeOH
as “hydrogen” source has been established, but the research was
mainly focused on the field of β-substituted8 and β,β-
disubstituted9 α,β-unsaturated compounds. With regard to
α,β-disubstituted α,β-unsaturated compounds, only α-methyl
α,β-unsaturated esters have been executed in the Cu-catalyzed
asymmetric hydroboration reaction with the enantiomeric
excess (ee) of the product generally below 70%.10
functionality, i.e., adding β-boronate into α-amino acids, which
should be quite attractive to chemists. These chiral β-boronate-
α-amino acids can be easily transformed by oxidation to β-
hydroxy-α-amino acids, which represent a unique amino acid
motif existing in numerous chiral drugs and bioactive
molecules, for instance, L-DOPS (Droxidopa),2 mugineic
acid,3 mcivicin,4 (3S,4S)-DHGA,5 L-(+)-furanomycin,6 and
hydroxyectoine7 (Figure 1). Herein, we present our findings
The existence of the electron-donating amino group at the
double bond of α,β-unsaturated esters will have great influence
Received: January 21, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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Table 1. Evaluation of Chiral Ligands for Cu-Catalyzed Asymmetric Hydroboration of α-Dehydroamino Acid Derivative (Z)-
a
1a
b
c
d
e
e
entry
L*
2 (x equiv)
time (h)
yield (%)
syn-3a (%)
anti-3a (%)
ee (syn-3a, %)
ee (anti-3a, %)
1
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
1.1
1.1
1.1
1.1
1.1
1.1
2.0
2.0
4.0
5.0
17
12
17
18
17
15
15
12
13
12
NR
51
f
2
3
4
5
6
7
8
9
20
67
20
20
16
22
24
50
54
31
7
60
9
62
−10
−33
−40
95
74
30
10
44
22
27
33
41
−22
−50
96
64
38
g
g
g
49
95
93
,
,
h
h
57
90
91
,
i
91
95
95
g,h,i
10
>99
46
97
96
a
b
c
d
Reactions were performed under argon atmosphere. Combined yield of syn-3a and anti-3a. Yield of the isolated product syn-3a. Yield of the
e
f
g
isolated product anti-3a. Determined by HPLC analysis using a chiral stationary phase. NaO-t-Bu (25 mol %) was used. MeOH (4.0 equiv) was
used. Molecular sieves (3 Å) were added. L6 (20 mol %) was used. B2Pin2 = bis(pinacolato)diboron, Boc = tert-butoxycarbonyl.
h
i
a
Table 2. Substrate Scope of β-Aryl-Substituted α-Dehydroamino Acid Derivatives (Z)-1
b
c
d
e
e
entry
1
(Ar =)
(C6H5−)
(4-Br-C6H4−)
(4-Cl-C6H4−)
(4-Me-C6H4−)
(4-Ph-C6H4−)
(3-Cl-C6H4−)
(3-F-C6H4−)
(3-MeO-C6H4−)
(3-Me-C6H4−)
(2-Me-C6H4−)
(2-naphthyl−)
(3-Br-5-Me-C6H3−)
(2,3-Me2-C6H3−)
(3,5-(t-Bu)2-C6H3−)
(3,4-(−OCH2O−)-C6H3−)
time (h)
yield (%)
syn-3 (%)
anti-3 (%)
ee (syn-3, %)
ee (anti-3, %)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
12
1
>99
93
54
42
45
44
37
41
33
45
50
35
49
43
50
50
47
46
51
47
52
55
50
50
49
50
65
50
51
50
45
49
97
98
98
92
96
96
96
95
95
97
98
98
95
98
91
96
96
96
94
94
97
96
94
92
98
95
97
94
97
2
3
1
92
4
5
96
5
4
92
6
11
2
91
7
g
h
i
83
8
2
94
9
12
4
>99
>99
99
10
11
12
13
14
15
j
k
m
n
o
p
24
16
4
94
>99
95
2
4
96
92
a
b
c
d
Reactions were performed under argon atmosphere. Combined yield of syn-3a and anti-3a. Yield of the isolated product syn-3a. Yield of the
isolated product anti-3a. Determined by HPLC analysis using a chiral stationary phase.
e
on the substrate reactivity. Meanwhile, the stereoselective
control remains quite challenging.
borylated product was observed for L1 ligand, and only 51%
combined yield of syn-3a and anti-3a in about 60% ee value
each was observed for L2 ligand in our case (Table 1, entries 1
and 2). Next, chiral N-heterocyclic carbene (NHC, L3),11
phosphoramidite ((R)-MonoPhos, L4),8i and phosphinooxazo-
line ((R)-i-Pr-PHOX, L5) ligands were subjected to this
reaction, although no promising outcomes were obtained
(Table 1, entries 3−5). To our delight, the ee values of syn-3a
and anti-3a dramatically raised to 96% and 95%, albeit in a low
With this mindset, a set of representative chiral ligands were
investigated for the Cu-catalyzed asymmetric hydroboration of
β-phenyl-α-dehydroamino acid methyl ester (Z)-1a, and the
screening results are summarized in Table 1. Chiral bi-
sphosphine ligands, (R,Sp)-Josiphos (L1) and (R,R)-QuinoxP*
(L2) have been successfully employed in the Cu-catalyzed
asymmetric conjugate hydroboration reaction.8,9 However, no
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yield, when (S,Sp)-ip-FOXAP (L6) served as ligand (Table 1,
entry 6).12 Increasing the B2Pin2 (2) loading led to great
improvement of yields (Table 1, entries 7−10). In particular,
quantitative yields of syn-3a and anti-3a (dr ≈ 1:1) were
accomplished, and their individual ee values reached 97% and
96% when 5 equiv of B2Pin2 and molecular sieve (3 Å) were
used.
Scheme 3. Transformations of the Hydroboration Products
With the optimal reaction conditions identified, various β-
aryl-substituted substrates were investigated, and the results are
summarized in Table 2. All 4-substituted and 3-substituted
phenyl substrates, regardless of the electron-donating or
electron-withdrawing property of the substitutent at the phenyl
ring, afforded the conjugate hydroboration products, syn-3 and
anti-3, in about 1:1 dr ratio with excellent yields and
enantioselectivities (Table 2, entries 2−9). Interestingly, 2-
methyl-substituted phenyl substrate (1j) gave the products syn-
3j and anti-3j in about 1:2 dr ratio, probably due to the steric
hindrance of the neighboring substituent in the stereocontrol
(Table 2, entry 10). As for 2-naphthyl and some disubstituted
phenyl substrates, the conjugate hydroboration reaction also
proceeded smoothly with about 1:1 dr ratio, excellent yields,
and enantioselectivities (Table 2, entries 11−15).
Given the highly enantioselective nature of this conjugate
hydroboration reaction, the E-isomer of β-phenyl-substituted
substrate, (E)-1a, was applied under the standard conditions.
Unfortunately, trace product was observed, which indicated
that the geometry of the double bond played an important role
in the substrate reactivity (Scheme 2).
°C generated β-hydroxyphenylalanine methyl ester hydro-
chloride salt 5a, of which absolute configurations were further
confirmed by comparing the NMR and optical rotation with the
known compound (2S,3R)-5a.13b According to the literature,13c
free (R)-β-hydroxy-L-phenylalanine 6a and (R)-β-hydroxy-L-
phenylalaninol 7a could be respectively achieved through a
simple hydrolytic and reductive procedure. In a similar way, the
oxidation reaction of syn-3p and subsequent N-Boc depro-
tection reaction of 4p also proceeded equally well to deliver the
chiral intermediate 5p, which can be used for the preparation of
chiral drug L-DOPS.14
Scheme 2. Cu-Catalyzed Asymmetric Hydroboration of (E)-
1a and (Z)-1q
It should be noted that the absolute configuration of other
conjugate hydroboration products were assigned on the basis of
their chemical correlation with syn-3a and anti-3a.15
In summary, the Cu-catalyzed asymmetric conjugate hydro-
boration reaction of β-substituted α-dehydroamino acid
derivatives with B2Pin2 and MeOH has been established.16
This reaction was conducted under convenient conditions,
simultaneously affording enantioenriched syn- and anti-β-
boronate-α-amino acid derivatives in about 1:1 dr ratio with
excellent yields and excellent enantioselectivities. The func-
tional group of β-boronate could be expediently converted into
the useful β-hydroxy derivatives, which could be applied in the
preparation of chiral drugs and bioactive molecules, thus
demonstrating their synthetic utility. The present results extend
the realm of the Cu-catalyzed asymmetric conjugate hydro-
boration reaction. Further studies on the applications of
hydroboration products are in progress in our laboratories
and will be reported in due course.
Next, β-alkyl-substituted substrate (Z)-1q was investigated in
this reaction. By utilizing (S,Sp)-ip-FOXAP (L6) as ligand, the
reaction afforded the desired products in high yield, but with
<30% ee for both syn-3q and anti-3q. After further screenings of
different ligands, a quantitative yield of syn-3q and anti-3q (dr =
1:1) was accomplished by using (R,R)-Ph-BPE (L7) as ligand,
and their ee values could reach −82% and −92%, respectively
(Scheme 2).12
The chiral β-boronate-α-amino acids could be readily
converted into the useful β-hydroxy-α-amino acids related to
chiral drugs and bioactive molecules (Scheme 3). For example,
syn-3a went through a mild oxidation with sodium perborate to
give β-hydroxyphenylalanine derivate 4a. The absolute
configurations of 4a were unambiguously assigned as 2S,3R
by chemical correlation (NMR and optical rotation) with the
known compound (2S,3R)-4a.13a Removal of the tert-
butoxycarbonyl (Boc) group in 4a under gaseous HCl at 80
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data for all new
compounds, and details of modification of reaction conditions.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Organic Letters
Letter
(11) Zhang, S.-S.; Zhao, Y.-S.; Tian, P.; Lin, G.-Q. Synlett 2013, 24,
437.
(12) For more chiral ligands screening, see the Supporting
AUTHOR INFORMATION
■
Corresponding Authors
Information (section 2).
*E-mail: tianping@sioc.ac.cn.
*E-mail: lingq@sioc.ac.cn.
Present Address
†Arvinas, Inc., 5 Science Park, New Haven, CT 06511.
(13) (a) Crich, D.; Banerjee, A. J. Org. Chem. 2006, 71, 7106.
(b) Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2010, 49, 6520.
(c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108,
6405.
(14) (a) Ishizumi, K.; Maejima, K.; Nagata, S.; Kojima, Y. (Sumitomo
Pharmaceuticals Co., Ltd.) JP61085380, 1986. (b) Ohashi, N.; Nagata,
S.; Ishizumi, K.; Maeshima, K. (Sumitomo Pharmaceuticals Co., Ltd.)
EP84928, 1983.
Notes
The authors declare no competing financial interest.
(15) The syn-3a isomer appeared in an upper position on the silica
gel TLC plate relative to the anti-3a isomer (eluent: ethyl acetate/
petroleum ether = 1/8).
(16) For the mechanistic studies, see the Supporting Information
(section 5).
ACKNOWLEDGMENTS
■
Financial support for this work was generously provided by the
National Natural Science Foundation of China (NSFC
21372243, 21232009, 21102161) and the Shanghai Municipal
Committee of Science and Technology (13JC1406900).
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