An umpolung-enabled copper-catalysed regioselective hydroamination approach to α-amino acids

Article abstract of DOI:10.1039/d1sc03692k

A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding α-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as

Full text of DOI:10.1039/d1sc03692k

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An umpolung-enabled copper-catalysed
regioselective hydroamination approach to a-
amino acids†
Cite this: DOI: 10.1039/d1sc03692k
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have been paid for by the Royal Society
of Chemistry
b
a
Soshi Nishino,a Masahiro Miura
and Koji Hirano
*
A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and
hydroxylamines has been developed to afford the corresponding a-amino acids in good yields. The key
to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent.
Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of
remote steric hindrance enables the otherwise challenging C–N bond formation at the a position to the
carbonyl. The point chirality at the b-position is successfully controlled by the Xyl-BINAP or DTBM-
SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary,
(ꢀ)-8-phenylmenthol, also induces stereoselectivity at the a-position to form the optically active
unnatural a-amino acids with two adjacent stereocentres.
Received 7th July 2021
Accepted 27th July 2021
DOI: 10.1039/d1sc03692k
rsc.li/chemical-science
coupling of phenylacetates and free NH amines through the
transient formation of a-bromo esters.11 The copper-catalysed
Introduction
electrophilic amination of ketene silyl acetals with hydroxyl-
amines12 or chloroamines13 can also access a-amino acids and
was independently developed by our group and the Miura/
Murakami research group (Scheme 1b). Kiyokawa and Mina-
kata recently designed (diarylmethylene)amino-substituted
hypervalent iodine(III) reagents and succeeded in the amination
of the same ketene silyl acetals under catalyst-free conditions.14
Yazaki and Ohshima achieved the copper-catalysed direct a-
amination of acylpyrazoles as the carboxylic acid surrogates with
the PhI ¼ NTs nitrenoid source (Scheme 1c).15 Wasa16 and
Sawamura/Shimizu17 groups independently developed boron-
based catalyst systems for the a-amination of esters, amides,
and free carboxylic acids with azodicarboxylates (Scheme 1d).
Despite these certain advances, there are still several drawbacks;
the substrates are limited to the relatively acidic C–H of
a-Amino acids are prevalent structural motifs in many biologi-
cally active compounds and pharmaceutical agents, especially
peptide drugs. In particular, unnatural a-amino acids have
received signicant attention because when they replace natural
a-amino acids in the original drug structure, the potential for
activity improvement and the discovery of new functions
increases.1 Multicomponent couplings such as the Strecker, Ugi,
and Petasis reactions are classical but the most powerful
approaches to the aforementioned target structures.2 The cata-
lytic hydrogenation of a-dehydroamino acid derivatives also
provides promising access to unnatural a-amino acids.3 Addi-
tionally, the decoration of naturally occurring a-amino acids by
the C–C bond forming reactions under phase-transfer,4 palla-
dium,5 copper,6 and iridium/copper dual catalysis7 as well as
cross-dehydrogenative-coupling (CDC) conditions8 has also been
explored. On the other hand, the C–N bond formation at the
a position to the carbonyl in carboxylic acid derivatives can also
be a good alternative (Scheme 1). Vedejs reported the KO-t-Bu-
mediated direct a-amination of phenylacetates with the electro-
philic amination reagent (4-MeOC6H4)2(O)PO–NH2 (Scheme 1a).9
Shi also revealed that the related a-amination was possible with
di-tert-butyldiaziridinone in the presence of copper salts.10 Mac-
Millan developed the CuBr2/O2-catalysed ideal C–H/N–H
aDepartment of Applied Chemistry, Graduate School of Engineering, Osaka University,
Suita, Osaka 565-0871, Japan. E-mail: k_hirano@chem.eng.osaka-u.ac.jp
bInnovative Catalysis Science Division, Institute for Open and Transdisciplinary
Research Initiatives (ICS-OTRI), Osaka University, Suita, Osaka 565-0871, Japan
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc03692k
Scheme 1 C–N bond forming approaches to a-amino acids. (a)
Amination of phenylacetates, (b) amination of ketene silyl acetals, (c)
amination of acylpyrazoles, and (d) amination with azo reagents. LG ¼
leaving group, Ts ¼ p-toluenesulfonyl.
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phenylacetates (Scheme 1a); the preactivation of carboxylic acids
by strong bases/silyl halides is inevitable (Scheme 1b); conden-
sation with a special pyrazole-based directing group is necessary
(Scheme 1c); the initial product is the hydrazine derivative, and
thus the resultant N–N bond should be reductively cleaved to
obtain the targeted a-amino acids (Scheme 1d). Moreover, the
highly stereocontrolled process remains largely elusive. Thus, the
concise and efficient synthesis of a-amino acids based on C–N
bond formation is still a formidable challenge.18
Meanwhile, the catalytic hydroamination of readily available
a,b-unsaturated carboxylic acid derivatives such as acrylic acids
also seems to be an attractive approach to amino acids. However,
because of the innate polarity of a,b-unsaturated carbonyls and
amines, the nucleophilic amino group generally adds at the
electrophilic b-position, thus delivering the b-amino acids
selectively (Scheme 2a).19 Therefore, in spite of its potential, a-
amino acids are generally difficult to prepare by conventional
hydroamination reactions. Herein, we report a copper-catalysed
regioselective hydroamination of a,b-unsaturated esters with
hydrosilanes and hydroxylamines to form a-amino acid deriva-
tives with high regioselectivity (Scheme 2b). The key to successful
regioselectivity control is the introduction of a polarity inversion
concept, that is an umpolung strategy;20 the hydrosilane and
hydroxylamine work as the nucleophilic hydrogen (hydride) and
amino electrophile, respectively, to induce the desired a-amina-
tion selectivity. The judicious choice of the CsOPiv base and
bisphosphine ligands of remote steric hindrance enables the
otherwise challenging C–N bond formation at the a position to
the carbonyl. The asymmetric induction at the b position is also
possible by a similarly bulky Xyl-BINAP or DTBM-SEGPHOS
chiral ligand. Moreover, the point chirality at the a-position is
also successfully controlled by using an (ꢀ)-8-phenylmenthol
auxiliary. Thus, unnatural a-amino acids with adjacent two
stereocentres are obtained with high enantioselectivity. The
detailed optimization studies, substrate scope, application to
conjugation with bioactive amines, and preliminary mechanistic
studies are disclosed herein.
Scheme 3 Working hypothesis.
hydroamination of alkenes with hydrosilanes and hydroxyl-
amines, which was originally and independently developed by
our group21 and the Buchwald research group.22 Our working
hypothesis is shown in Scheme 3. A copper hydride species A is
initially formed from the starting copper salt CuX2 and hydro-
silane Si–H with the assistance of an external base. The acrylate
1 undergoes the regioselective 1,4-addition with the LnCu–H A
to afford the O-bound copper enolate B, where the regiose-
lectivity is controlled by the innate electronic bias of acrylate 1
toward the nucleophilic copper hydride.23 Subsequent electro-
philic amination24 with the O-benzoylhydroxylamine 2 delivers
the desired a-amino acid derivative 3.25 The concurrently
formed copper benzoate C is converted back to the catalytically
active copper hydride A via direct metathesis with the hydro-
silane Si–H or base-assisted stepwise ligand exchange. If the
appropriate chiral ligand (L) is employed, enantioselectivity is
induced in the 1,4-addition step (A to B) to control the point
chirality at the b-position. The additional point chirality at the
a-position can also be controlled by the proximal chirality at the
b-position (substrate control), the chirality of the ligand on
copper (catalyst control), or both, giving optically active a-
amino acids with two adjacent stereocentres. However, there is
a considerable challenge associated with the aforementioned
reaction design; Guo and Buchwald recently reported the
related attempt of the copper-catalysed regioselective hydro-
amination of cinnamates with 1,2-benzisoxazole as the elec-
trophilic amino source (Scheme 4).26a While the (S,S)-Ph–BPE
ligand successfully gave the corresponding b-amino acid
derivative, the a-amino acid was not obtained at all, and instead
Results and discussion
The blueprint for the regioselective hydroamination of acrylates
is based on the recent advances of copper-catalysed net
Scheme 2 Hydroamination approaches to amino acids. (a) Usual
hydroamination and (b) umpolung hydroamination. Bz ¼ benzoate, Piv Scheme
4 Attempt to synthesize a-amino acids by Guo and
Buchwald.
¼ tert-butylcarbonyl.
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the simply reduced byproduct 4 was observed exclusively. 2-H). Namely, the copper hydride A should react with the
Around the same time, the research group of Xiong, Guan, and unsaturated ester 1 preferably over the hydroxylamine 2.
Zhang also reported the related hydroamination of cinnamates,
Our optimization studies commenced with (E)-b-methyl-
in which the corresponding a-amino acids were detected but as cinnamate (E)-1a and O-benzoly-N,N-dibenzylhydroxylamine
the minor product.26b Thus, the development of suitable reac- (2a) to identify the suitable ligand, base, and solvent in the
tion conditions for the suppression of the undesired proton- presence of Cu(OAc)2 and polymethylhydrosiloxane (PMHS;
ation from the copper enolate B is the most important but Table 1). The initial attempt to apply our previous optimal
challenging issue (B to 4). An additional potent side reaction is conditions for the styrene hydroamination (CF3-dppbz (dppbz
the reductive N–O bond cleavage of 2 with the copper hydride A, ¼ 1,2-bis(diphenylphosphino)benzene) ligand and the LiO-t-Bu
just consuming the electrophilic amination reagent (A and 2 to base)21a remained unsuccessful; similar to the aforementioned
result in Scheme 4, just saturated ester 4a was observed (entry
Table 1 Optimization studies for copper-catalysed regioselective hydroamination of acrylate (E)-1a with O-benzoylhydroxylamine 2a for
synthesis of a-amino acid 3aa a
Entry
Ligand
Base
Yield of 3aa (%), syn/antib
Yield of 4a c (%)
1
2
3
4
5
6
7
8
9
10
11
12
CF3-dppbz
LiO-t-Bu
CsOAc
KOAc
NaOAc
CsOPiv
KOPiv
NaOPiv
Cs2CO3
CsF
0, —
9
43
57
63
29
30
0
59
64
55
51
49
30
27
67
0
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
DTBM-dppbz
dppbz
62, 44 : 56
38, 47 : 53
26, 50 : 50
71, 42 : 58
70, 44 : 56
0, —
30, 37 : 67
34, 44 : 56
22, 32 : 68
0, —
None
LiO-t-Bu
NaO-t-Bu
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
0, —
13d
14d,e
15d,e
16d,e
17d,e
18d,e
19d,e
20d,e
21d,e
22d,e
23d,e,f
24d,e,f,g
71, 38 : 62
77, 42 : 58
10, 40 : 60
0, —
21, 48 : 52
0, —
32, 41 : 59
46, 41 : 59
47, 38 : 62
26, 42 : 58
82, 44 : 56
99, 38 : 62 (92, 42 : 58)
o-Me-dppbz
MeO-dppbz
p-CF3-dppbz
p-t-Bu-dppbz
CF3-dppbz
80
0
73
55
53
65
19
84
t-Bu-dppbz
TMS-dppbz
DTBM-dppbz
DTBM-dppbz
a
Conditions: Cu(OAc)2 (0.025 mmol), ligand (0.025 mmol), (E)-1a (0.25 mmol), 2a (0.38 mmol), PMHS (0.75 mmol based on Si–H), base (0.75 mmol),
solvent (1.5 mL), RT, 4 h, N2. b Estimated by 1H NMR based on 0.25 mmol with CH2Br2 as the internal standard. The syn/anti ratio is determined in
c
d
the crude mixture. Isolated yield is in parentheses. Estimated by 1H NMR based on 0.25 mmol with CH2Br2 as the internal standard. With
e
f
g
(EtO)3SiH instead of PMHS. With Cu(OAc)2$H2O instead of anhydrous Cu(OAc)2. In 1,4-dioxane (1.0 mL). With 1a (0.50 mmol) and 2a (0.25
mmol).
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1). Additional screening of ligands and solvents was also per- we then switched attention to conditions including the bulky
formed, but the use of LiO-t-Bu only afforded the simply dppbz-type ligand, namely, DTBM-dppbz,27 the CsOAc base, and
reduced product regardless of other reaction parameters. Thus, 1,4-dioxane solvent, which were uniquely effective for the
Scheme 5 Scope of copper-catalysed regioselective hydroamination of acrylates 1 with O-benzoylhydroxylamines 2 for synthesis of a-amino
acids 3. Conditions: Cu(OAc)2$H2O (0.015 mmol), DTBM-dppbz (0.015 mmol), 1 (0.30 mmol), 2 (0.15 mmol), (EtO)3Si–H (0.45 mmol), CsOPiv
(0.45 mmol), 1,4-dioxane (0.60 mL), RT, 4 h, N2. Isolated yields are shown. a On a 0.25 mmol scale. b On a 1.0 mmol scale.
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related hydroamination of 1-triuoromethylalkenes.21f Gratify- methyltryptophan30 3ka was accessible. The copper catalysis
ingly, the desired b-methyl-a-amino acid derivative 3aa 28 was accommodated some other bulkier alkyl substituents at the b-
formed in 62% 1H NMR yield (syn/anti ¼ 44 : 56) albeit with the position; the ethyl-, chloropropyl-, and cyclopropyl-substituted
concomitant formation of 4a in 43% (entry 2). Prompted by this cinnamates underwent the regioselective hydroamination
preliminary but intriguing result, several acetate-type bases smoothly (3la–na). Moreover, the cyclic systems could also be
were investigated (entries 3–7), with CsOPiv proving to be best employed (3oa and 3pa). The successful conversion of b,b-
in terms of efficiency and diastereoselectivity. As a general dialkyl-substituted acrylates to deliver the corresponding
trend, the yield increased with increasing the size of the counter isoleucine derivatives 3qa and 3ra in synthetically useful yields
cation (Cs > K > Na). Other cesium bases such as Cs2CO3 and is particularly notable. The b,b-diaryl substitution pattern was
CsF showed lower performance (entries 8 and 9). The reaction also viable (3sa–ua) albeit with somewhat lower efficiency. The
also proceeded even in the absence of external bases, but the ester, boryl, and silyl functionalities at the b-position were
yield of 3aa largely dropped (entry 10). Even with the DTBM- amenable to the regioselective hydroamination, and the bio-
dppbz ligand, the Li- or NaO-t-Bu bases totally shut down the logically interesting aspartic acid 3va, b-boryl-a-amino acid
formation of 3aa (entries 11 and 12). We next examined the 3wa,31 and b-silyl-a-amino acid 3xa 32 were obtained in accept-
effect of hydrosilanes; some alkoxy-substituted hydrosilanes able yields. Uniquely in the case of 3wa and 3xa, the syn-isomer
provided the desired 3aa, with (EtO)3SiH giving the a-amino was mainly formed because of the intramolecular oxygen to
acid 3aa in a comparable yield with a slightly better syn/anti boron or silicon coordination in the O-bound copper enolate
ratio (entry 13). As far as we tested, the reaction was less intermediate (B in Scheme 3).33 On the other hand, the reaction
dependent on the copper catalyst precursor, but Cu(OAc)2$H2O of the simple cinnamate and crotonate also proceeded without
slightly improved the yield (entry 14). On the other hand, the any difficulties to form 3ya and 3za in high yields. Different
substituent on the aromatic ring in the dppbz-type ligand was from the work by Guo and Buchwald,26 the regioisomeric b-
critical; the parent dppbz and ortho-substituted o-Me-dppbz amino acid was not detected at all in the hydroamination of
resulted in much less productivity (entries 15 and 16) whereas cinnamate 1y. The a,b,g,d-unsaturated sorbate was also appli-
para- and meta-substituted dppbzs gave the a-amino acid 3aa in cable, and the corresponding 1,4-adduct 3Aa was formed
moderate to good yields, except for the electron-withdrawing p- exclusively.
CF3-dppbz (entries 17–22). The observed better performance of
Several acyclic and cyclic O-benzoylhydroxylamines 2
dppbzs of remote steric hindrance can be associated with the underwent copper-catalysed hydroamination; N-benzyl-N-
attractive London dispersion,29 which accelerates the C–N bond methylamine, N,N-diallylamine, piperidine, morpholine, thio-
formation (B to C and 3 in Scheme 3) as well as the addition step morpholine, and piperazine all were adopted in the reaction to
(A to B in Scheme 3). The yield of 3aa further increased at afford the corresponding a-amino acids 3ab–ae, 3bf, and 3ag in
a higher reaction concentration (entry 23). The nal investiga- good to excellent yields. Additionally it is worth noting that (1)
tion of reaction stoichiometry revealed that the use of 2a as the the reaction could also be conducted on a 1.0 mmol scale (3aa);
limiting agent was the best, and the desired 3aa was isolated in (2) when the (Z)-type substrate was employed, the yield was
92% yield with 42 : 58 syn/anti ratio (entry 24). Additional slightly lower, but the same syn/anti ratio was observed (3aa),
observations are to be noted; other bidentate/monodentate thus supporting the intermediacy of the common O-bound
phosphine and NHC ligands mainly formed the reduced 4a or copper enolate (B in Scheme 3).34
recovered the starting 1a intact; the solvent screening uncov-
The aforementioned success prompted us to explore enan-
ered that 3aa was formed uniquely in 1,4-dioxane; no conver- tioselective conditions by the judicious choice of ancillary chiral
sion was observed in the absence of any copper salts or ancillary ligands (Table 2). Given the positive effects of the DTBM
ligands; other leaving groups on the nitrogen were tested, but substituent observed in Table 1, we rst investigated (R)-DTBM-
OBz was identied to be the best in terms of reactivity and BINAP, -SEGPHOS, and -MeO-BIPHEP in conjunction with
availability (see the ESI† for more detailed optimization
a
Cu(OAc)2$H2O catalyst. The DTBM-SEGPHOS ligand
studies).
promoted the reaction to form 3aa in 60% isolated yield with
With optimal conditions in hand (entry 24 in Table 1), we 42 : 56 syn/anti ratio and 99 : 1 e.r. for each diastereomer (entry
next examined the substrate scope of the umpolung-enabled 2), while no conversion occurred in the presence of DTBM-
regioselective hydroamination of acrylates toward a-amino BINAP and -MeO-BIPHEP (entries 1 and 3). Intriguingly, the
acids (Scheme 5). The reaction was compatible with the relatively small (R)-DM-SEGPHOS also showed high enantiose-
electron-donating
methoxy,
electron-withdrawing
tri- lectivity (98 : 2 e.r.) albeit with somewhat lower yield of 3aa
uoromethyl, and chloro groups at the para position of the (entry 4). On the other hand, the parent (R)-SEGPHOS largely
phenyl ring in the model substrate 1a to form the correspond- decreased the yield (entry 5). Inspired by the comparable
ing b-methylphenylalanine derivatives 3ba–da in good yields. performance of DM-SEGPHOS, (R)-Xyl-BINAP and parent (R)-
The methylenedioxy substituent was also tolerated (3ea), while BINAP were also tested (entries 6 and 7). Gratifyingly, the better
the ortho-substitution was somewhat detrimental to the reac- isolated yield and similarly high enantioselectivity were ob-
tion (3fa). The substrates that bear higher fused naphthalene tained with the (R)-Xyl-BINAP ligand (81% yield and 97 : 3 e.r.;
and heteroaromatic benzofuran, thiophene, and pyridine all entry 6). Additional screening of copper salts revealed that the
worked well to deliver the targeted a-amino acids 3ga–ja in 77– combination of CuCl/(R)-DTBM-SEGPHOS resulted in better
95% yields. Additionally, the biologically interesting b- conversion than that of Cu(OAc)2$H2O/(R)-DTBM-SEGPHOS
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Table 2 Optimization studies for copper-catalysed regio- and enantioselective hydroamination of (E)-1a with 2a for asymmetric synthesis of a-
amino acid 3aa a
e.r.c
Entry
Cu/ligand
Yield of 3aa (%), syn/antib
syn
anti
1
2
3
4
5
6
7
8
9f
Cu(OAc)2$H2O/(R)-DTBM-BINAP
Cu(OAc)2$H2O/(R)-DTBM-SEGPHOS
Cu(OAc)2$H2O/(R)-DTBM-MeO-BIPHEP
Cu(OAc)2$H2O/(R)-DM-SEGPHOS
Cu(OAc)2$H2O/(R)-SEGPHOS
Cu(OAc)2$H2O/(R)-Xyl-BINAP
Cu(OAc)2$H2O/(R)-BINAP
0, —
60, 44 : 56
0, —
42, 44 : 56
18,d 44 : 56
81, 43 : 57 (31, 41)e
23, 44 : 56
73, 42 : 58
65, 43 : 57
—
99 : 1
—
98 : 2
n.d.
97 : 3
94 : 6
96 : 4
97 : 3
—
99 : 1
—
98 : 2
n.d.
97 : 3
94 : 6
96 : 4
97 : 3
Cu(OAc)2$H2O/(R)-DTBM-SEGPHOS
CuCl/(R)-Xyl-BINAP
a
Conditions: Cu (0.015 mmol), ligand (0.015 mmol), (E)-1a (0.30 mmol), 2a (0.15 mmol), (EtO)3Si–H (0.45 mmol), CsOPiv (0.45 mmol), 1,4-dioxane
b
c
(0.60 mL), RT, 18 h, N2. Isolated yields are shown. The syn/anti ratio is determined in the crude mixture. The enantiomeric ratios (e.r.) were
determined by HPLC analysis on a chiral stationary phase. d 1H NMR yield. The isolated yields of syn-3aa and anti-3aa aer the separation.
e
f
4 h. n.d. ¼ not determined.
(entries 8 vs. 1) whereas in the case of (R)-Xyl-BINAP, CuCl heteroaromatic substituents were also compatible to deliver the
showed slightly lower activity than Cu(OAc)2$H2O (entries 9 vs. hydroaminated products with high enantioselectivity, except for
6). On the basis of the above optimization studies, conditions the benzofuran substrate (3ha–ka). The asymmetric catalysis
with Cu(OAc)2$H2O and (R)-Xyl-BINAP were identied to be the accommodated several other alkyl substituents at the b-position
best from the viewpoints of catalytic activity and enantiose- (3la–na and 3pa) as well as the b,b-dialkyl substitution (3qa and
lectivity (entry 6).35 The syn/anti ratio was low, but both isomers 3ra). In particular, both diastereomers of isoleucine derivative
could be separated to each other by chromatographic purica- 3qa were obtained with high enantiopurity. In the reaction of
tion. The relative and absolute congurations were assigned by b,b-diaryl-substituted acrylates, the yield was somewhat lower,
1
comparison of H NMR spectra and specic rotation with the but the high enantiomeric ratio still remained (3sa–ua). More-
reported values aer the derivatization. Given the high enan- over, the b-boryl- and b-silyl-a-amino acids 3wa and 3xa were
tioselectivity also in the reduced byproduct 4a, the point successfully synthesized in enantioenriched forms. In contrast,
chirality at the b-position was well controlled but not at the a- the simple methyl cinnamate formed the completely racemic
position (see the ESI† for details).
product 3ya, thus suggesting almost no control of point chirality
Under conditions of entry 6 in Table 2, a variety of b-meth- at the a-position by the catalyst. As the amino sources, not only
ylcinnamates underwent regio- and enantioselective hydro- the acyclic but also cyclic hydroxylamines were readily and
amination to form the corresponding b-methylphenylalanine stereoselectively coupled with the b-methylcinnamates to afford
derivatives 3ba–ga in good yields with 92 : 8–98 : 2 e.r. (Scheme the corresponding optically active a-amino acids 3ab–ae, 3bf,
6). Similarly under the nonenantioselective conditions, and 3ag with high enantiomeric ratios (96 : 4–99 : 1 e.r.). In
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Scheme 6 Scope and limitation of copper-catalysed regio- and enantioselective hydroamination of acrylates 1 with O-benzoylhydroxylamines
2 for asymmetric synthesis of a-amino acids 3. Conditions: Cu(OAc)2$H2O (0.015 mmol), (R)-Xyl-BINAP (0.015 mmol), 1 (0.30 mmol), 2 (0.15
mmol), (EtO)3Si–H (0.45 mmol), CsOPiv (0.45 mmol), 1,4-dioxane (0.60 mL), RT, 18 h, N2. Isolated yields are shown. a On a 1.0 mmol scale. b With
CuCl/(R)-DTBM-SEGPHOS instead of Cu(OAc)2$H2O/(R)-Xyl-BINAP.
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Fig. 1 Modification of biologically active amines by conjugation with acrylate 1a through coper-catalysed enantioselective hydroamination. For
conditions, see the footnote in Scheme 6. a With (S)-Xyl-BINAP instead of (R)-Xyl-BINAP.
Scheme 7 Attempts to control point chirality at the a-position. (a) Identification of alkyl groups in acrylate 1, (b) removal of auxiliary and
additional transformations, and (c) substrate scope.
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some cases (3qa, 3sa, and 3ta), the combination of CuCl/(R)- corresponding chiral 1,2-aminoalcohol, and the major anti-5
DTBM-SEGPHOS instead of Cu(OAc)2$H2O/(R)-Xyl-BINAP could be isolated in a pure form with recovery of the chiral
showed better performance from the viewpoints of efficiency auxiliary (Scheme 7b). Subsequent protecting group exchange
and enantioselectivity. The enantioselective reaction could also on nitrogen and TEMPO oxidation afforded the Boc-protected b-
be performed on a 1.0 mmol scale (3aa), indicating the good methylphenylalanine anti-6 with >99 : 1 d.r. and >99 : 1 e.r. (see
reliability and reproducibility of the asymmetric copper the ESI† for detailed stereochemical assignment). Given the
catalysis.
absolute conguration of anti-6, the Si-face of copper enolate is
On the other hand, the stereoisomeric (Z)-1a was converted efficiently blocked by the bulky PhMe2C group, and the
to the opposite enantiomers with a moderate enantiomeric ratio hydroxylamine 2a selectively approaches from the Re-face to
(3aa), supporting that the enantioface selection in the reaction produce the observed stereoisomer. The Xyl-BINAP/8-
of the copper hydride and acrylate 1 (A to B in Scheme 3) occurs phenylmenthol double asymmetric induction strategy was
in the 1,4-addition manner rather than the 1,2-insertion.36
applicable to the cyclic amine (3Gd) as well as other b-alkyl-
The newly developed asymmetric copper catalysis was substituted cinnamate derivatives (3Ha–Ja) to furnish the cor-
applicable to the derivatization of several biologically active responding a-amino acids with good diastereoselectivity
alkylamines (Fig. 1). Nortriptyline and maprotiline, antide- (>10 : 90; Scheme 7c). The b,b-dialky and -diaryl substrates (3Ka
pressant drugs, were conjugated with the b-methylcinnamate 1a and 3La) could also be employed albeit with slightly reduced
and 1b under the (R)-Xyl-BINAP-ligated asymmetric copper stereoselectivity. On the other hand, the simple crotonate
catalysis to form the corresponding a-amino acids 3ah and 3bi, resulted in moderate stereochemical induction (3Ma). Even
respectively, with high enantioselectivity. In a similar manner, with the achiral DTBM-dppbz, the b-monosubstituted 1M gave
desloratadine, an antihistamine agent, was successfully modi- 3Ma with the same 31 : 69 d.r. (data not shown), thus suggest-
ed with 1b, where the heterocyclic pyridine and aryl-Cl moiety ing that the point chirality at the a-position is controlled just by
were tolerated (3bj). Moreover, the chiral amines including the steric repulsion between the 8-phenylmenthol auxiliary and
duloxetine (antidepressant and anticonvulsant), paroxetine, the substituent at the b-position without inuence of the
and sertraline (selective serotonin reuptake inhibitors) were phosphine ligand on copper.
viable substrates, giving the highly functionalized a-amino
Finally mechanistic studies were implemented. In Scheme 3,
acids 3ak, 3al, and 3bm with acceptable diastereomeric ratios we propose C–N bond formation by the reaction of the hydrox-
(d.r.). Notably, the a-chiral amine, sertraline, showed a signi- ylamine 2 and copper enolate B directly formed through the 1,4-
cant match/mismatch phenomenon and resulted in almost no addition of the copper hydride A to the acrylate 1, but there are
formation of the aminated product in the presence of (S)-Xyl- two other potential pathways: one is the stepwise conjugate
BINAP, while the reaction of paroxetine that bears the chiral reduction/enolization/electrophilic amination (Scheme 8a) and
centres at the remote positions proceeded smoothly even with another is the hydrosilylation/transmetalation from Si to Cu/
(S)-Xyl-BINAP to furnish the product with the opposite electrophilic amination (Scheme 8b). To investigate these
stereoselectivity.
possibilities, we performed some control experiments. When the
As mentioned above, the Cu/Xyl-BINAP catalyst system independently prepared simply reduced 4a was subjected to
successfully controlled the point chirality at the b-position but reaction conditions including the copper catalyst, base, and 2a,
not at the a-position. Given the intermediacy of the O-bound
copper enolate (B in Scheme 3), the steric and electronic effects
of the alcohol moiety in 1 (R3 of B in Scheme 3) can affect the
stereochemical outcome. Accordingly, several alkyl and aryl
esters were prepared and subjected to the enantioselective
conditions (Scheme 7a). Unfortunately, the ethyl, tert-butyl, and
diphenylmethyl esters showed negligible effects on the stereo-
selectivity, and the corresponding a-amino acids were formed
with low to moderate diastereomeric ratios similar to the
methyl ester model substrate (3Ba–Da vs. 3aa). The additionally
coordinating pyridyl ester did not undergo hydroamination at
all (3Ea). We then switched attention to the use of chiral
alcohol, namely, the chiral auxiliary for improvement of the
diastereoselectivity. Pleasingly, the L-(ꢀ)-menthol skeleton was
found to be the promising candidate to increase the diaste-
reomeric ratio to 25 : 75 (3Fa), only when combined with (S)-Xyl-
BINAP. The value of d.r. was further improved to 9 : 91 with the
assistance of readily prepared (ꢀ)-8-phenylmenthol37 (3Ga). The
achiral DTBM-dppbz resulted in poor reactivity and moderate
stereoselectivity, thus suggesting the necessity of double
asymmetric induction arising from the chiral ligand and
Conjugate reduction/enolization/electrophilic amination pathway and
auxiliary. Treatment with LiAlH4 readily converted 3Ga to the (b) hydrosilylation/transmetalation/electrophilic amination pathway.
Scheme 8 Two other possible pathways in C–N bond formation. (a)
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Scheme 10 Effects of external bases under silane-free, stoichiometric
conditions with [(Ph3P)CuH]6.
Scheme 11 Effects of external bases in the decomposition of
hydroxylamine 2a.
amination/protonation selectivity under silane-free, stoichio-
metric conditions on CuH in the absence and presence of
CsOPiv (Scheme 10); upon treatment of unsaturated ester 1N
with Stryker's reagent, [(PPh3)CuH]6,40 and the hydroxylamine
2a, the corresponding a-amino acid derivative 3Na was formed
in 21% yield along with 34% of the simply reduced 4N. The
addition of CsOPiv was almost negligible, delivering 3Na and
4N in similar 15 and 47% yields, respectively. Thus, acceleration
of the C–N bond forming step (B to C and 3 in Scheme 3) by the
action of CsOPiv is unlikely. On the other hand, LiO-t-Bu totally
shut down the formation of 3Na, which is consistent with the
optimization studies in entries 1 and 11 of Table 1.
The aforementioned results prompted us to check the
dependence of the hydroxylamine decomposition side pathway
(A and 2 to 2-H in Scheme 3)22e,f on the external base (Scheme
11). Under the external-base free conditions, 80% of the
hydroxylamine 2a was decomposed within 4 h. In sharp
contrast, the rate of decomposition dramatically decreased in
the presence of CsOPiv, and 72% of 2a was retained aer 4 h.
These outcomes suggest that the CsOPiv base suppresses the
competitive N–O bond cleavage by the CuH species to keep the
concentration of the hydroxylamine higher and increase the
amination product over the protonation byproduct.41 Other
bases also suppressed the decomposition to some extent, except
for strongly basic LiO-t-Bu, but with CsOPiv proving to be best.
Scheme 9 Control experiments. (a) Possibility of 4a as intermediate
and (b)–(d) possibilities of ketene silyl acetal as intermediate.
no aminated product 3aa was observed with 4a le intact
(Scheme 9a). The additional use of (EtO)3SiH also gave no 3aa,
thus excluding the possibility demonstrated in Scheme 8a. The
intermediacy of the ketene silyl acetal (Scheme 8b) was also
examined by the following experiments; the copper-catalysed
reaction of 1a with (EtO)3SiH in the absence of 2a (4 h) was
followed by the addition of D2O to afford the deuterated 4a-d in
99% yield with 82% D content (Scheme 9b).38 This result
suggests in situ formation of the ketene silyl acetal. However, the
quenching with the hydroxylamine 2a instead of D2O only
formed the protonated 4a without any detectable amount of the
aminated product 3aa (Scheme 9c). Thus, the ketene silyl acetal
can be generated under the optimal catalytic conditions but as
nonproductive species, just en route to the protonated byprod-
uct; under optimal conditions, the transmetalation from Si to Cu
in the ketene silyl acetal might be unfavored.39 Actually, also
under catalytic optimal conditions, the D2O quenching afforded
the partial but a signicant amount of deuterated 4a-d along
with the aminated product 3aa (Scheme 9d). On the basis of the
ndings in Scheme 9, the originally proposed direct electrophilic
amination of the rstly generated copper enolate with hydrox-
ylamines is most favourable.
Conclusions
We have developed an umpolung-enabled copper-catalysed
regioselective hydroamination of a,b-unsaturated esters with
hydrosilanes and hydroxylamines to deliver the corresponding
a-amino acid derivatives. The judicious choice of the CsOPiv
To gain insight into the origin of the positive effects of the
CsOPiv base (Table 1, entries 5 vs. 10), we then investigated the
Chem. Sci.
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external base and supporting ligand with remote steric bulki-
ness promotes the otherwise challenging C–N bond formation
at the a position to the carbonyl. The asymmetric induction at
the b-position is possible by using the suitable chiral Xyl-BINAP
or DTBM-SEGPHOS bisphosphine ligand. Moreover, combined
with the 8-phenylmenthol chiral auxiliary, the point chirality at
the a-position can also be controlled, giving optically active
unnatural a-amino acids with two adjacent stereocentres.
Asymmetric copper catalysis is also applied to the conjugation
of a-amino acids with biologically active complex amines. Some
mechanistic experiments suggest the pivotal role of the copper
enolate in the C–N forming step and the unique effect of CsOPiv
to suppress the competitive but nonproductive decomposition
pathway of the hydroxylamines. The obtained results can
provide a new repertoire of C–N bond formation approaches to
unnatural and complicated chiral a-amino acid derivatives.
More detailed mechanistic studies and further development of
related copper catalysis for more complicated and densely
functionalized a-amino acids are ongoing in our laboratory and
will be reported in due course.
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Data availability
All experimental procedures and spectroscopic data can be
found in the ESI.†
6 Y. Matsumoto, J. Sawamura, Y. Murata, T. Nishikata,
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Author contributions
S. N. and K. H. conceived the idea. S. N. performed all experi-
ments including condition optimizations and exploring the
scope. K. H. supervised the project. M. M. supported other
authors to perform the project well. All the authors discussed
the results and commented on the manuscript.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by JSPS KAKENHI Grant no. JP
17H06092 (Grant-in-Aid for Specially Promoted Research) to
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MM and 18K19078 (Grant-in-Aid for Challenging Research 10 B. Zhao, H. Du and Y. Shi, J. Am. Chem. Soc., 2008, 130, 7220.
(Exploratory)) to KH. KH also acknowledges Toyota Riken 11 R. W. Evano, J. R. Zbieg, S. Zhu, W. Li and
Scholar for nancial support. We thank Mr Tatsuaki Takata
(Osaka University) for his initial experimental assistance.
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35 See the ESI for more detailed optimization studies for
enantioselective conditions.
conversion even in the presence of
amount of [(Ph3P)CuH]6.
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CsOPiv also accelerates the C–N bond forming step in the
case of b,b-disubstituted substrates such as 1a.
© 2021 The Author(s). Published by the Royal Society of Chemistry
Chem. Sci.