Copper-catalysed enantioselective stereodivergent synthesis of amino alcohols

Article abstract of DOI:10.1038/nature17191

The chirality, or 'handedness', of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug can

Full text of DOI:10.1038/nature17191

LEttER
doi:10.1038/nature17191
Copper-catalysed enantioselective stereodivergent
synthesis of amino alcohols
Shi-Liang Shi1, Zackary L. Wong1 & Stephen L. Buchwald1
The chirality, or ‘handedness’, of a biologically active molecule can two chiral catalysts sequentially perform an iminium/enamine catalysis
alter its physiological properties. Thus it is routine procedure in cascade to functionalize enals selectively. More recently, Carreira and
the drug discovery and development process to prepare and fully colleagues15,16 demonstrated an elegant dual catalyst system for inde-
characterize all possible stereoisomers of a drug candidate for pendently controlling the two stereocentres during the α-allylation
biological evaluation1,2. Despite many advances in asymmetric of branched aldehydes. Nonetheless, a rapid and predictable way
synthesis, developing general and practical strategies for obtaining to access complete stereoisomeric sets of products bearing multiple
all possible stereoisomers of an organic compound that has multiple stereocentres (for example, three contiguous stereocentres), using
contiguous stereocentres remains a challenge3. Here, we report readily available precursors and based on a single catalyst system,
a stereodivergent copper-based approach for the expeditious remains underdeveloped but is highly desirable.
construction of amino alcohols with high levels of chemo-, regio-,
Optically pure amino alcohols are important structural elements that
diastereo- and enantioselectivity. Specifically, we synthesized these are frequently found in pharmaceutical agents and biologically active
amino-alcohol products using sequential, copper-hydride-catalysed natural products (Fig. 1b)17. These compounds are also building blocks
hydrosilylation and hydroamination of readily available enals and for catalysts and auxiliaries in asymmetric synthesis. We speculated
enones. This strategy provides a route to all possible stereoisomers that our recently disclosed catalytic systems18–23 for enantioselective
of the amino-alcohol products, which contain up to three contiguous hydroamination24,25 based on copper hydride (CuH) intermediates26
stereocentres. We leveraged catalyst control and stereospecificity
a
simultaneously to attain exceptional control of the product
O
O
O
O
CF3
NH
CF3
NH
stereochemistry. Beyond the immediate utility of this protocol, our
strategy could inspire the development of methods that provide
complete sets of stereoisomers for other valuable synthetic targets.
Different stereoisomers of drugs can have distinct therapeutic prop-
erties or adverse effects, because of the chiral environments provided
by enzymes and receptors in biological systems. The most well known
example is thalidomide, the (R)-enantiomer of which was an effec-
tive sedative, while the (S)-enantiomer caused severe teratogenic side
effects and resulted in birth defects during the 1950s. Stereoisomers of
drugs can also have contrasting indications, as in the case of quinine
and quinidine, or even opposing biological activities (Fig. 1a, b). For
these reasons, regulatory agencies require the bioactivity of all stereo-
isomers of pharmaceutical candidates to be evaluated during the drug
discovery and development process1,2. Furthermore, manufacturers
must develop assays by which to determine stereochemical purity to
ensure drug safety. Consequently, all stereoisomers of a molecule must
be prepared for use in biological testing or as standard samples. Thus,
the construction of complete stereoisomeric sets represents a practically
important synthetic problem, as well as a fundamentally important
N
O
O2N
O N
COOMe
N
O
COOMe
2
O
O
N
N
H
H
(R)-thalidomide
(sleep-inducing)
(S)-thalidomide
(teratogenic)
(S)-BayK8644
(activator of
Ca2+ channel)
(R)-BayK8644
(antagonist of
Ca2+ channel)
b
N
N
O
O
O
OH
OH
Ph
Ph
O
O
O
N
N
N
N
Quinine
(antimalarial)
Quinidine
(antiarrhythmic)
Dextropropoxyphene
(analgesic)
Levopropoxyphene
(antitussive)
R2
O
Undesired
c
R2
OH
R4
R1
R4
R1
Conventional
1,4-addition
Over-reduction
R3
R2
O
R3
L*CuH
R1
R4
All stereoisomers
accessible
R3
R2
OH
R4
R5
R6
(E) or (Z)
Easily available
research topic1,2
.
N
OH
R4
R1
R3
Enantio- and
regioselective
1,2-addition
Regio- and
diastereoselective
hydroamination
R1
In the past few decades, there has been tremendous progress in the
field of asymmetric synthesis, providing numerous chiral biologically
active compounds with high levels of selectivity3. However, although
asymmetric catalysis has allowed enantiomers of a chiral molecule to be
obtained with equal ease, relatively few methods can provide a unified
route that leads to all possible stereoisomers of products containing
multiple contiguous stereocentres. Thus, full control of absolute and
relative stereochemical configuration remains an unmet synthetic
challenge3. Aside from classical techniques in asymmetric catalysis—
such as using additives4,5, modifying catalyst structure6–10, and varying
substrate-protecting groups11,12—multicatalytic approaches13–16 have
been advanced to access the full complement of stereoisomers for cer-
tain classes of compounds. For example, MacMillan and colleagues13,14
R2
R3
Figure 1 | Varying biological activity of some different stereoisomers,
and our strategy for constructing all stereoisomers of amino alcohols.
a, Different enantiomers give distinct activities in biological systems.
b, Stereoisomeric amino alcohols (esters) and their biological activities.
c, Bottom, our proposed one-pot synthesis protocol for forming
all stereoisomers of amino alcohols via selective hydrosilylation/
hydroamination reactions. The start point is an (E)- or (Z)-enal or
enone, which is chemoselectively reduced by a CuH-based catalyst to
yield corresponding allylic alcohols, which then undergo regio- and
stereoselective hydroamination to afford amino-alcohol products bearing
multiple contiguous stereocentres. Further details are in Fig. 2. Top,
undesired potential side reactions. ‘L’ denotes ‘ligand’. Red bonds highlight
described the novel concept of cycle-specific amino-catalysis, in which different stereocentres.
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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reSeArCH Letter
O
R3
R4
R3
R4
NEt2
N
O
O
O
PAr2
PAr2
N
O
5 mol% Cu(OAc) 2, 5.5 mol% (S)-L1
3–5.0 eq. (MeO) 2MeSiH,ꢀTHF, RT, 15 min;
R1
OH
R1
H
R2
R2
1.2-1.5 eq. ꢂH¶Q, 55 °C, 36–60 h
O
O
Enal (E)-ꢁH¶S
Ar = 3,5-(tBu)2-4-MeO-C6H2
Amino alcoholꢃꢀH¶U
Aminating reagent ꢂH¶Q
ꢂH: R3 = R4 = Bn
L1: DTBM-SEGPHOS
MeO
OMe
PMB
PMB
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
Bn
N
N
MeO
MeO
OH
OH
OH
OH
Me
Me
Me
F3CO
OH
OMe
ꢀJ, 92% yield
>20/1 d.r., >99% e.e.
ꢀH, 95%(96%)* yield
>20/1 d.r., >99% e.e.
ꢀI, 96% yield
>20/1 d.r., >99% e.e.
ꢁK, 67% yield
>20/1 d.r., 99% e.e.
ꢀL, 76% yield
>20/1 d.r., 95% e.e.
OH
Me
N
COOMe
N
N
Me
Me
OH
S
N
N
N
Bn
N
Bn
N
Bn
N
OH
HO
Me
OH
Me
OH
N
Et
OH
Me
Me
MeO
N
ꢀM, 78% yield
>20/1 d.r., >99% e.e.
ꢀN, 90% yield
>20/1 d.r., >99% e.e.
ꢀO, 66% yield
>20/1 d.r., >99% e.e.
ꢁP, 76% yield
>20/1 d.r., >99% e.e.
ꢀQ, 70% yield
>20/1 d.r., >99 % e.e.
from
Me
Bn
Bn
Bn
PMB
PMB
N
Me
N
O
Ph
N
Bn
N
Bn
NEt2
Cl
OH
Ph
N
O
OH
OH
HO
Me
Me
Si
OH
Me
Me
Me
Me Me
O
ꢀR, 64% yield
>20/1 d.r., 90% e.e.
ꢀS, 77% yield
>20/1 d.r., >99 % e.e.
ꢀT, 76% yield
>20/1 d.r., >99% e.e.
ꢀU, 65% yield
>20/1 d.r.
ꢁQ
Figure 2 | Asymmetric hydrosilylation/hydroamination of enals.
(e.e.) were determined by high-performance liquid-chomatography
(HPLC) analysis using chiral stationary phases. *Reaction was conducted
on 5 mmol scale. See Supplementary Information for details. Bn, benzyl;
PMB, p-methoxylbenzyl; RT, room temperature; THF, tetrahydrofuran.
Top row, the reaction studied here; bottom rows, substrate scope.
Isolated yields are reported (average of two runs on 0.5 mmol scale).
Diastereomeric ratios (d.r.) were determined by gas-chromatography (GC)
and nuclear magnetic resonance (NMR) analysis. Enantiomeric excesses
and electrophilic aminating reagents27 could be applied to the synthesis phosphino]-4,4′-bi-1,3-benzodioxole; (S)- L1) at room temperature
of this class of compounds. for 15 minutes. We observed neither the conventional 1,4-reduc-
We hypothesized that enals and enones, which are readily available tion product nor the over-reduced saturated alcohol, and the desired
as geometrically pure isomers, could be ideal precursors to amino 1,2-adduct was obtained in nearly quantitative yield. Further treat-
alcohols. In particular, we anticipated that, in one synthetic operation, ment of the reaction mixture with aminating reagent 2a at 55 °C
a CuH-based catalyst could reduce enals and enones chemoselectively effectively provided the amino alcohol 3a with a 95% yield and
to the corresponding allylic alcohols, which would then undergo regio- with complete diastereo- and enantioselectivity (diastereometric
and stereoselective hydroamination to afford amino-alcohol prod- ratio (d.r) >20/1; enantiomeric excess (e.e.) >99%). A thorough evalua-
ucts bearing multiple contiguous stereocentres (Fig. 1c). Because of tion of the electrophilic amine source indicated that 2a was the optimal
the synfacial nature of the hydroamination process, we reasoned that aminating reagent. We attributed the high efficiency of 2a to the pres-
this two-step sequence would be stereospecific with respect to olefin ence of its electron-rich para-diethylaminobenzoyl group. This group
geometry. Thus, effective catalyst control would allow all diastereomeric resulted in slower reductive decomposition of 2a, and presumably faster
possibilities to be generated through the appropriate choice of substrate regeneration of the CuH catalyst through σ-bond metathesis between
geometry (E or Z) and ligand enantiomer (R or S). Although the asym- the corresponding copper benzoate species and hydrosilane species22,23
.
metric hydrosilylation of ketones using a copper catalyst is a well known L1 was the best ligand among the phosphines screened in terms of both
process28, we were aware that 1,2-reduction of α,β-unsaturated carbonyl reactivity and selectivity (see Supplementary Information for details).
compounds by CuH is less favourable than 1,4-reduction, owing to the
With these optimized reaction conditions, we investigated the sub-
inherent preference of copper to coordinate to the olefin via soft-soft strate scope of this one-pot transformation. We found that an array
interactions26. Previous work29,30 suggested that control of the regiose- of β-aryl-substituted (E)-enals could be efficiently transformed to the
lectivity in the CuH reduction of Michael acceptors was sensitive to sub- corresponding chiral amino alcohols in a highly regio-, diastereo- and
tle variations in the steric and electronic properties of the ligand and of enantioselective manner (Fig. 2, 3a–3n). A diverse range of hydroxy-
the substituents of substrates. On the other hand, controlling the regio- lamine esters and enals with a variety of functional groups were suit-
and stereoselectivity of the hydroamination step is also non-trivial25, able coupling partners for this sequential transformation, including
because of the steric and electronic bias of the allylic silyl ether inter- phenols (3g, 3h), an aryl chloride (3k), an ester (3h), an acetal (3d),
mediates and potential matched/mismatched effects between substrates a trifluoromethoxyl (3e), cis-olefins (3f, 3l) and a trimethylsilanyl
and chiral catalysts. The copper-based catalyst system described here group (from the reaction of a vinyl silane) (3l). In addition to acy-
alleviates these problems, providing access to all possible amino-alcohol clic substrates, a cyclic enal and cyclic aminating reagents were both
stereoisomers in high chemo-, regio-, diastereo- and enantioselectivity, compatible, providing the products with high levels of stereocontrol
starting from readily available enals and enones.
(3d, 3i, 3k). Furthermore, substrates bearing a broad range of phar-
In initial efforts to implement this proposed hydrosilylation/ maceutically important heteroaromatic components—including an
hydroamination sequence, we first treated (E)-2-methyl-cinnamaldehyde indole (3g), a thiophene (3f), a pyridine (3h), a pyrrole (3j), a pyrim-
(Fig. 2; compound 1a) with an excess of dimethoxymethylsilane idylpiperidine (3i), and a chromene (3k)—could be readily converted to
in the presence of 5 mol% of copper acetate and (S)-DTBM- the desired products with excellent enantioselectivity. Additionally, an
SEGPHOS ((S)-(+)-5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl) enal substrate bearing a ketone functional group smoothly underwent
2
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Letter reSeArCH
NBn2 OH
O
a
NBn2
NBn2
NBn2
NBn2
5 mol% Cu(OAc)2, 5.5 mol% (S)-L1
5.0 eq. (MeO)2MeSiH, THF, 60 °C, 15 h;
R1
R3
R1
R3
Ph
OH
Ph
OH
Ph
OH
Ph
OH
R2
Amino alcohol 5a–h
R2
1.5 eq. 2a , 55 °C, 70 h
Me
Me
, 99% yield
(R,S)-3b
Me
Me
(E)-Enone 4a–h
, 96% yield
>20/1 d.r., >99% e.e.
(S,R)-3b
, 76% yield
, 78% yield
(S,S)-3b
>20/1 d.r., >99% e.e.
(R,R)-3b
>20/1 d.r., >99% e.e.*
>20/1 d.r., >99% e.e.*
†
†
NBn2 OH
NBn2 OH
NBn2 OH
F
NBn2 OH
Me
b
Cl
Me
Bn
N
Me
Bn
N
Me
Bn
N
Me
Bn
N
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
F3C
Ph
OH
Ph
OH
Ph
OH
Ph
OH
5a*, 76% yield,
>20/1 d.r., >99% e.e.
5b, 70% yield,
>20/1 d.r., >99% e.e.
5c, 72% yield,
>20/1 d.r., >99% e.e.
5d, 68% yield,
>20/1 d.r., >99% e.e.
Me
Me
Me
Me
(S,R,R)-3n
65% yield, >20/1 d.r.
(R,S,R)-3n
75% yield, >20/1 d.r.*
(S,R,S)-3n
(R,S,S)-3n
NBn2
OH
NBn2 OH
NBn2 OH
NBn2 OH
Me
76% yield, >20/1 d.r.#
64% yield, >20/1 d.r.*#
MeO
Me
Me
Et
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Ph
N
Ph
N
Ph
N
Ph
N
Me
5e, 71% yield,
>20/1 d.r., >99% e.e.
5f, 62% yield,
>20/1 d.r., >99% e.e.
5g, 67% yield,
10/1 d.r., >99% e.e.
5h, 82% yield,
5/1 d.r., >99% e.e.
Ph
OH
‡
Ph
OH
Ph
OH
Ph
OH
Me
Me
Me
Me
Figure 4 | Asymmetric hydrosilylation/hydroamination of enones.
Top row, the reaction studied here; bottom rows, substrate scope.
Isolated yields are reported (average of two runs on 1.0 mmol scale).
Diastereomeric ratios (d.r.) were determined by GC and NMR analysis.
Enantiomeric excesses (e.e.) were determined by HPLC analysis. The
asterisk indicates where the absolute and relative stereochemistry of 5a
was determined to be (S,S,R) by single-crystal X-ray diffraction. See
Supplementary Information for details.
(S,S,R)-3n
(R,R,R)-3n
72% yield, >20/1 d.r.*
(S,S,S)-3n
73% yield, >20/1 d.r.
(R,R,S)-3n
‡#
68% yield, >20/1 d.r.*
‡
‡#
64% yield, >20/1 d.r.
Figure 3 | All stereoisomers of amino alcohols from enals. a, Reaction
using (S)-L1 and (E)-2-amyl-cinnamaldehyde (1b) under the standard
conditions. Asterisks denote reactions using (R)-L1 instead of (S)-L1.
The dagger denotes a reaction using (Z)-1b instead of (E)-1b. b, Reaction
using (S)-L1, (E)-2-methyl-cinnamaldehyde (1a) and 2j under the
standard conditions. Asterisk denotes the use of (R)-L1 instead of (S)-L1.
The double dagger denotes the use of (Z)-1a instead of (E)-1a. The hash
symbol indicates reactions using ent-2j instead of 2j.
successfully to the respective amino-alcohol products (Fig. 4, 5a–5f)
with excellent absolute and relative stereoselectivity (>20/1 d.r., >99%
e.e.). In addition, a cyclic enone was converted into indanyl amino
the double hydrosilylation and hydroamination sequence under these alcohol (5g) with high diastereoselectivity (10/1 d.r.) and outstand-
conditions, furnishing amino diol (3m) bearing three stereocentres as a ing enantioselectivity (>99% e.e.) for both diastereomers. Lastly, we
single stereoisomer. Lastly, a reaction conducted on a 5mmol scale with found that α-substitution on the enone was not crucial for selective
decreased catalyst loading (1mol%) efficiently provided the desired 1,2-reduction. For instance, the less-substituted product 5h could
product (3a) in undiminished yield and stereoselectivity, demonstrat- be obtained with high enantioselectivity and a synthetically useful
ing the robustness and practicality of this process.
As described above, we were particularly interested in applying this
diastereomeric ratio from benzylidenacetone.
Subsequently, we wondered whether these conditions could be
approach to access all of the possible stereoisomers selectively, with adapted to the stereodivergent construction of all eight stereoisomers
high diasterero- and enantiocontrol for a given substrate. We felt that of 5a. Above (Fig. 4), we prepared (S,S,R)-5a from (E)-4a in a one-pot
using the (Z)-enal substrate would produce the pair of diastereomers sequence by using (S)-L1 as the ligand. To prepare (S,R,S)-5a, we devel-
that is complementary to the pair realized from the (E)-enal substrate. oped a modified protocol involving a ligand switch in which (E)-4a was
Accordingly, we subjected (Z)-2-amyl-cinnamaldehyde (1b) to the first hydrosilylated using (S)-L1 as the ligand, and then the resulting
reaction conditions described above, and produced the desired dias- chiral allylic alcohol was isolated and subjected to hydroamination con-
tereomeric syn-amino alcohol in high chemical yield with complete ditions using a copper catalyst based on (R)-L1. Use of enantiomeric
diastereo- and enantioselectivity. Thus, by correctly combining the ligands for the one-pot and ligand-switch protocols yielded (R,R,S)-5a
appropriate enantiomer of the CuH catalyst’s ligand with the olefin and (R,S,R)-5a, respectively, allowing four of the possible stereoisomers
geometry of the enal substrate, we could readily prepare all four ste- of 5a to be prepared from (E)-4a. We sought to prepare the four remain-
reoisomers of the corresponding amino alcohol with full control of ing stereoisomers of 5a from (Z)-4a by using a similar strategy. The
absolute and relative stereochemistry (Fig. 3a).
same ligand-switch protocol applied to (Z)-4a furnished (R,S,S)-5a and
We also found that amino alcohols bearing three stereogenic cen- (S,R,R)-5a. Initial attempts to prepare (S,S,S)-5a and (R,R,R)-5a were
tres could be generated with excellent catalyst-controlled diastereo- unsuccessful, presumably owing to the unfavourable steric interactions
selectivity when we used chiral hydroxylamine esters. The existing between the intermediate chiral (Z)-allylic alcohol and the L1-based
α-stereocentre on chiral aminating reagents did not interfere with the catalyst. Accordingly, we selected a less bulky ligand, DM-SEGPHOS
stereoselectivity when applied to our catalyst system. Thus, all eight (5,5′-bis[di(3,5-xylyl)phosphino]-4,4′-bi-1,3-benzodioxole; L2), for
stereoisomers of the amino alcohol 3n were easily constructed with the hydroamination step to obtain these products. Ultimately, all eight
good yield and excellent diastereoselectivity in one step, by selecting the stereoisomers of 5a were prepared expediently in one to two steps with
appropriate enantiomer of the chiral aminating reagent and geomet- useful isolated yields (33% to 76%), with complete enantioselectivity
ric isomer of the enal substrate as starting materials and using either (>99% e.e.) and good to excellent diastereoselectivity (7/1 to >20/1
enantiomer of the chiral catalyst (Fig. 3b).
produced in the reaction mixture before purification) (Fig. 5a). Upon
We then sought to examine the possibility of using enones as sub- isolation and chromatography, all isomers were obtained at >20/1 d.r.,
strates for the rapid synthesis of chiral amino alcohols with three con- as confirmed by the high-performance liquid-chromatography traces
tiguous stereocentres. Basing our protocol on Lipshutz and colleagues’ in Fig. 5b. Thus, the enantioselective hydroamination steps proceeded
work30 on the asymmetric CuH-catalysed 1,2-reduction of enones, we through excellent catalyst control in all eight cases.
found that the readily accessible enone 4a could be effectively converted
We have developed a unified and stereodivergent strategy for
to the corresponding chiral allylic alcohol in quantitative yield and 92% rapidly and predictably constructing amino alcohols that allows all
e.e. at −60°C in the presence of 5mol% of Cu(OAc)2–L1 complex. possible stereoisomers of a given product to be synthesized. This pro-
We added the aminating reagent to the reaction mixture while heating tocol assembles two or three contiguous stereocentres, using enal and
the mixture at 55°C, furnishing compound 5a at 76% chemical yield enone substrates, in a highly selective, copper-catalysed hydrosilyla-
with complete diastereo- and enantioselectivity (>20/1 d.r.; >99% e.e.). tion/hydroamination sequence. Essential to our approach were highly
Under these reaction conditions, a variety of enones were transformed effective catalyst control and the application of a stereospecific process
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© 2016 Macmillan Publishers Limited. All rights reserved

reSeArCH Letter
NBn2 OH
Me
NBn2 OH
Me
a
b
Ph
Ph
DAD1 D, Sig=220,2 Ref=360,100 (SSL\ATP 2015-07-30 21-19-25\SSL4-200LP-MP.D)
DAD1 D, Sig=220,2 Ref=360,100 (SSL\ATP 2015-09-25 19-59-33\SSL7-223-LP-MP.D)
Me
Me
120
80
40
0
150
(S,S,R)-5a
76% yield
>20/1 d.r.
>99% e.e.
(S,S,S)-5a
33% yield
7/1 d.r.
100
50
0
>99% e.e.
0
5
10
15
20
25
min
0
5
10
15
20
25
30
35
40 min
NBn2 OH
Me
NBn2 OH
DAD1 D, Sig=220,2 Ref=360,100 (SSL\ATP 2015-10-09 14-03-23\SSL7-137.D)
DAD1 C, Sig=210,8 Ref=360,100 (SSL\ATP 2015-10-06 21-00-30\SSL7-241.D)
Ph
Ph
Me
1) (S)-L1
500
400
300
200
100
0
(S)-L1
800
400
(R,R,S)-5a
(S,R,R)-5a
2) (S)-L2
Me
Me
(R,R,R)-5a
33% yield
7/1 d.r.
(R,R,S)-5a
75% yield
>20/1 d.r.
>99% e.e.
0
1) (R)-L1
2) (R)-L2
0
5
10
15
20
25
30
35
40
min
0
5
10
15
20
25
min
min
(R)-L1
O
Ph
O
DAD1 D, Sig=220,2 Ref=360,100 (SSL\ATP 2015-08-04 20-09-20\SSL7-162.D)
DAD1 C, Sig=210,8 Ref=360,100 (SSL\ATP 2015-10-07 10-28-06\SSL7-196A.D)
>99% e.e.
Ph
Me
Me
Me
Me
(R,S,R)-5a
200
100
80
40
0
(R,S,S)-5a
1) (S)-L1
2) (R)-L1
1) (S)-L1
2) (R)-L1
(E)-4a
(Z)-4a
0
NBn2 OH
NBn2 OH
0
5
10
15
20
25
0
5
10
15
20
25
30
35
40
min
Ph
Me
Ph
Me
DAD1 D, Sig=220,2 Ref=360,100 (SSL\NAOYUKI_LC 2015-11-14 02-41-55\SSL7-248B-MP.D)
DAD1 D, Sig=220,2 Ref=360,100 (ZLW\ATP 2015-09-04 19-10-21\SSL7-193.D)
Me
Me
1) (R)-L1
2) (S)-L1
1) (R)-L1
2) (S)-L1
200
150
(S,S,S)-5a
150
100
50
(S,R,R)-5a
64% yield
>20/1 d.r.
>99% e.e.
(S,R,S)-5a
60% yield
13/1 d.r.
(S,R,S)-5a
100
50
0
O
0
>99% e.e.
0
5
10
15
20
25
30
35
40
min
0
5
10
15
20
25
min
NBn2 OH
Me
NBn2 OH
Me
O
O
DAD1 D, Sig=220,2 Ref=360,100 (SSL\ATP 2015-10-09 18-35-13\SSL7-134.D)
PAr2
PAr2
DAD1 C, Sig=210,8 Ref=360,100 (SSL\NAOYUKI_LC 2015-11-14 02-41-55\SSL7-252.D)
Ph
Ph
400
300
200
100
0
400
300
(S,S,R)-5a
(R,R,R)-5a
Me
Me
200
100
0
O
(R,S,R)-5a
61% yield
13/1 d.r.
(R,S,S)-5a
62% yield
>20/1 d.r.
>99% e.e.
L1: DTBM-SEGPHOS
Ar = 3,5-(Me)2-C6H3
L2: DM-SEGPHOS
0
5
10
15
20
25
30
35
40
min
0
5
10
15
20
25
min
>99% e.e.
Time (min)
Figure 5 | All eight stereoisomers of amino alcohols synthesized from
enones. a, Access to all stereoisomers via a reaction using (E)- or (Z)-4a,
showing the catalyst permutations in each step. Isolated yields are
reported. Diastereomeric ratios (d.r.) were determined by NMR analysis
using a crude reaction mixture. b, HPLC traces of all stereoisomeric
amino-alcohol samples. See Supplementary Information for details.
to readily obtained pure geometric alkene isomers—factors that might 19. Shi, S.-L. & Buchwald, S. L. Copper-catalyzed selective hydroamination
reactions of alkynes. Nature Chem. 7, 38–44 (2015).
20. Zhu, S. & Buchwald, S. L. Enantioselective CuH-catalyzed anti-Markovnikov
hydroamination of 1, 1-disubstituted alkenes. J. Am. Chem. Soc. 136,
15913–15916 (2014).
21. Yang, Y., Shi, S.-L., Niu, D., Liu, P. & Buchwald, S. L. Catalytic asymmetric
be generally applicable to the development of other enantio- and dias-
tereodivergent hydrofunctionalization reactions.
received 24 November 2015; accepted 27 January 2016.
Published online 28 March 2016.
hydroamination of unactivated internal olefins to aliphatic amines. Science
349, 62–66 (2015).
1. Jozwiak, K., Lough, W. J. & Wainer, I. W. Drug Stereochemistry: Analytical
22. Niu, D. & Buchwald, S. L. Design of modified amine transfer reagents allows
Methods and Pharmacology 3rd edn (Informa, 2012).
the synthesis of α-chiral secondary amines via CuH-catalyzed hydroamination.
J. Am. Chem. Soc. 137, 9716–9721 (2015).
2. Wermuth, C. G. The Practice of Medicinal Chemistry 3rd edn (Elsevier, 2008).
3. Jacobsen, E. N., Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric
Catalysis Vol. I–III, Suppl. I–II (Springer, 1999).
4. Tian, X. et al. Diastereodivergent asymmetric sulfa-Michael additions of
α-branched enones using a single chiral organic catalyst. J. Am. Chem. Soc.
133, 17934–17941 (2011).
5. McInturff, E. L., Yamaguchi, E. & Krische, M. J. Chiral-anion-dependent
inversion of diastereo- and enantioselectivity in carbonyl crotylation via
ruthenium-catalyzed butadiene hydrohydroxyalkylation. J. Am. Chem. Soc.
134, 20628–20631 (2012).
6. Wang, B., Wu, F., Wang, Y., Liu, X. & Deng, L. Control of diastereoselectivity in tandem
asymmetric reactions generating nonadjacent stereocenters with bifunctional catalysis
by cinchona alkaloids. J. Am. Chem. Soc. 129, 768–769 (2007).
7. Yan, X.-X. et al. Highly diastereoselective switchable enantioselective Mannich reaction
of glycine derivatives with imines. J. Am. Chem. Soc. 130, 14362–14363 (2008).
8. Luparia, M. et al. Catalytic asymmetric diastereodivergent deracemization.
Angew. Chem. Int. Edn 50, 12631–12635 (2011).
9. Lu, G., Yoshino, T., Morimoto, H., Matsunaga, S. & Shibasaki, M. Stereodivergent
direct catalytic asymmetric mannich-type reactions of α-isothiocyanato ester
with ketimines. Angew. Chem. Int. Edn 50, 4382–4385 (2011).
10. Mechler, M. & Peters, R. Diastereodivergent asymmetric 1,4-addition of
oxindoles to nitroolefins by using polyfunctional nickel-hydrogen-bond-
azolium catalysts. Angew. Chem. Int. Edn 54, 10303–10307 (2015).
11. Lee, E. C., Hodous, B. L., Bergin, E., Shih, C. & Fu, G. C. Catalytic asymmetric
Staudinger reactions to form β-lactams: an unanticipated dependence of
diastereoselectivity on the choice of the nitrogen substituent. J. Am. Chem. Soc.
127, 11586–11587 (2005).
12. Huber, J. D. & Leighton, J. L. Highly enantioselective imine cinnamylation with a
remarkable diastereochemical switch. J. Am. Chem. Soc. 129, 14552–14553 (2007).
13. Huang, Y., Walji, A. M., Larsen, C. H. & MacMillan, D. W. C. Enantioselective
organo-cascade catalysis. J. Am. Chem. Soc. 127, 15051–15053 (2005).
14. Simmons, B., Walji, A. M. & MacMillan, D. W. C. Cycle-specific organocascade
catalysis: application to olefin hydroamination, hydro-oxidation, and
amino-oxidation, and to natural product synthesis. Angew. Chem. Int. Edn 48,
4349–4353 (2009).
23. Bandar, J. S., Pirnot, M. T. & Buchwald, S. L. Mechanistic studies lead to
dramatically improved reaction conditions for the Cu-catalyzed asymmetric
hydroamination of olefins. J. Am. Chem. Soc. 137, 14812–14818 (2015).
24. Miki, Y., Hirano, K., Satoh, T. & Miura, M. Copper-catalyzed intermolecular
regioselective hydroamination of styrenes with polymethylhydrosiloxane and
hydroxylamines. Angew. Chem. Int. Edn 52, 10830–10834 (2013).
25. Hannedouche, J. & Schulz, E. Asymmetric hydroamination: a survey of the
most recent developments. Chemistry 19, 4972–4985 (2013).
26. Deutsch, C., Krause, N. & Lipshutz, B. H. CuH-catalyzed reactions. Chem. Rev.
108, 2916–2927 (2008).
27. Barker, T. J. & Jarvo, E. R. Developments in transition-metal-catalyzed reactions
using electrophilic nitrogen sources. Synthesis 24, 3954–3964 (2011).
28. Lipshutz, B. H., Noson, K., Chrisman, W. & Lower, A. Asymmetric hydrosilylation
of aryl ketones catalyzed by copper hydride complexed by nonracemic
biphenyl bis-phosphine ligands. J. Am. Chem. Soc. 125, 8779–8789 (2003).
29. Chen, J.-X. et al. Highly chemoselective catalytic hydrogenation of unsaturated
ketones and aldehydes to unsaturated alcohols using phosphine-stabilized
copper(I) hydride complexes. Tetrahedron 56, 2153–2166 (2000).
30. Moser, R., Boskovic, Z. V., Crowe, C. S. & Lipshutz, B. H. CuH-catalyzed
enantioselective 1,2-reductions of α,β-unsaturated ketones. J. Am. Chem. Soc.
132, 7852–7853 (2010).
Supplementary Information is available in the online version of the paper.
Acknowledgements We thank the National Institutes of Health (grant GM-
58160 to S.L.B.). The content of this paper is solely our responsibility and does
not necessarily represent the official views of the National Institutes of Health.
We thank Y.-M. Wang and M. T. Pirnot for help preparing the manuscript. The
departmental X-ray diffraction instrumentation was purchased with the help of
funding from the National Science Foundation (CHE-0946721). We thank
P. Müller for X-ray crystallographic analysis of compound 5a.
Author Contributions S.-L.S. and S.L.B. conceived the idea and designed the
research. S.-L.S. and Z.L.W. performed the experiments. S.-L.S. and S.L.B. wrote
the manuscript. All authors commented on the final draft of the manuscript and
contributed to the analysis and interpretation of the data.
15. Krautwald, S., Sarlah, D., Schafroth, M. A. & Carreira, E. M. Enantio- and
diastereodivergent dual catalysis: α-allylation of branched aldehydes. Science
340, 1065–1068 (2013).
16. Schindler, C. S. & Jacobsen, E. N. A new twist on cooperative catalysis. Science
340, 1052–1053 (2013).
17. Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications
(Wiley VCH, 2010).
18. Zhu, S., Niljianskul, N. & Buchwald, S. L. Enantio- and regioselective CuH-catalyzed
hydroamination of alkenes. J. Am. Chem. Soc. 135, 15746–15749 (2013).
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the
paper. Correspondence and requests for materials should be addressed to
S.L.B. (sbuchwal@mit.edu).
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