Direct enantio-convergent transformation of racemic substrates without racemization or symmetrization

Article abstract of DOI:10.1038/nchem.801

Asymmetric reactions that transform racemic mixtures into enantio-enriched products are in high demand, but classical kinetic resolution produces enantiopure compounds in <50% yield even in an ideal case. Many deracemization processes have thus been devel

Full text of DOI:10.1038/nchem.801

ARTICLES
PUBLISHED ONLINE: 29 AUGUST 2010 | DOI: 10.1038/NCHEM.801
Direct enantio-convergent transformation of
racemic substrates without racemization or
symmetrization
Hajime Ito1,2 , Shun Kunii1 and Masaya Sawamura1
*
Asymmetric reactions that transform racemic mixtures into enantio-enriched products are in high demand, but classical
kinetic resolution produces enantiopure compounds in <50% yield even in an ideal case. Many deracemization processes
have thus been developed including dynamic kinetic resolution and dynamic kinetic asymmetric transformation, which can
provide enantio-enriched products even after complete conversion of the racemic starting materials. However, these
dynamic processes require racemization or symmetrization of the substrates or intermediates. We demonstrate a direct
chemical enantio-convergent transformation without a racemization or symmetrization process. Copper(I)-catalysed
asymmetric allylic substitution of a racemic allylic ether afforded a single enantiomer of an a-chiral allylboronate with
complete conversion and high enantioselectivity (up to 98% enantiomeric excess). One enantiomer of the substrate
undergoes an anti-SN2′-type reaction whereas the other enantiomer reacts via a syn-SN2′ pathway. The products, which
cannot be prepared by dynamic procedures, have been used to construct all-carbon quaternary stereocentres.
fficient methods to produce enantiopure compounds from complexes with chiral catalysts. The new chiral centre is then
racemic starting materials are in high demand, especially in established by the subsequent enantioselective step (kA ≫ kB,
E
the pharmaceutical and agricultural industries, as are enantio- Fig. 1c)10–18. However, the majority of racemic compounds
selective catalysis methods that convert pro-chiral starting materials have significantly robust chiral centres, and reaction procedures
to desired enantio-enriched products (Fig. 1)1–4. The reaction of a such as DKR or DYKAT are therefore ineffective: most racemic
racemic substrate with a chiral catalyst usually results in kinetic res- starting materials have no suitable means for racemization, which
olution where the two enantiomers of the racemate react at different is essential for DKR; and DYKAT requires the disappearance of
rates (Fig. 1a)4–6. When the reaction rate of one enantiomer of the the stereogenic centre in the reaction intermediate, but many
starting material (SA) is significantly higher than the other chiral compounds cannot take symmetrical structures (pseudo
(kA ≫ kB), that enantiomer is converted far more rapidly than meso- or C2-symmetric) even in the transformation pathway to
the opposite enantiomer. An enantio-enriched product (PA) is other chiral products. Deracemization of racemates with such
thus obtained with high selectivity; however, the other substrate robust chiral centres remains an unsolved problem in the field of
enantiomer with lower reactivity (SB) remains unreacted and the asymmetric synthesis.
theoretical maximum yield of the desired product (PA) is only
50% even in an ideal case.
If each enantiomer of a racemic mixture is converted into the
same enantiomer of the product through different reaction path-
To overcome the limitation caused by this incomplete conver- ways, the problems raised by racemization or symmetrization can
sion, many elegant deracemization processes have been designed be circumvented (Fig. 1d)1,2,19,20. However, the requirements to
that can transform both enantiomers of the racemic starting achieve such a reaction in a single operation with a single catalyst
materials into a single enantiomer of the product. Dynamic are challenging. The catalyst should promote two distinctive reac-
kinetic resolution (DKR)7–9 and dynamic kinetic asymmetric trans- tion pathways with opposite enantiomeric preference of the sub-
formation (DYKAT)10–18 are examples (Fig 1b,c). Dynamic kinetic strate (kAA ≫ kAB and kBA ≫ kBB), and each pathway should have
resolution can be achieved by combining an enantioselective opposite stereoselectivity to produce the same enantiomer of the
reaction with the rapid racemization of the starting materials products. Furthermore, the two preferred pathways should
(Fig. 1b). In this case, the less reactive substrate enantiomer (SB) proceed at similar reaction rates (kAA ≈ kBA) to avoid kinetic resol-
can be converted into the more reactive enantiomer (SA) through ution of the substrate. Studies describing such direct enantio-con-
the racemization process; when the reaction rate of the vergent reactions are scarce and are limited to a few biocatalytic
racemization is much higher than the favourable enantioselective reactions19,20. To our knowledge, artificial catalysts that can
step (from SA to PA) and the rate of the favourable enantioselective promote this type of transformation with a practically useful level
step is sufficiently larger than that of the disfavoured one (kA ≫ kB), of selectivity are unknown. We recently reported the copper(I)-cat-
the desirable enantiomer (PA) can be obtained with high enantio- alysed enantioselective boryl substitution of pro-chiral allylic car-
meric purity after complete conversion of the starting material. bonates to produce enantio-enriched allylboronates, which are
For dynamic kinetic asymmetric transformation (Fig. 1c), both useful building blocks for the asymmetric preparation of com-
enantiomers are initially converted into a common intermediate pounds with multiple chiral centres21–23. This is the first direct
(I) in which the substrate stereogenic centre disappears. This is chemical enantio-convergent transformation to occur without a
typically achieved by forming pseudo meso- or C2-symmetric racemization or symmetrization process when the substrate
1Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan, 2PRESTO, Japan Science and Technology Agency (JST),
Honcho, Kawaguchi, Saitama 332-0012, Japan. e-mail: hajito@sci.hokudai.ac.jp
*
972
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
© 2010 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.801
ARTICLES
a
instead of Cu(O-t-Bu), but a longer reaction time was required
(entry 2, 96 h). Reaction with (R,R)-Me-Duphos (2b) instead of
(R,R)-QuinoxP* (2a) also proceeded as the enantio-convergent
transformation with a lower enantioselectivity (99%, 88% e.e.,
entry 3). Reaction with (R)-BINAP (2c) did not reach completion
even after a long reaction time and gave poor enantioselectivity
(59 h, 54%, 18% e.e., entry 4). Reactions of enantiopure substrates,
(þ)-1a and (–)-1a, also afforded the same enantiomer of the
product (S)-4a with a high degree of enantiomeric excess (97%
e.e., entries 5 and 6). These results represent the successful derace-
mization of the robust chiral compound (rac)-1a.
b
cat*
cat*
kA
PA
PA
SA
SA
SB
kA
Desired
product
cat*
cat*
kB
SB
PB
PB
kB
Racemization
Unreactive
c
kAA
kBA
d
PA
PA
cat*
cat*
cat*
SA
SA
kA
kB
We next applied this enantio-convergent transformation cataly-
sis to the secondary allylic ether 1b to investigate details of the reac-
tion stereochemistry; the use of 1b eases the stereochemical
characterization of the starting material and the product. Reaction
of (rac)-1b using the enantio-convergent transformation catalysis
approach gave the corresponding allylboronate (S)-4b in good
yield with high enantiomeric purity (92% yield, 92% e.e.; entry 7).
The reaction of deuterium-labelled (rac)-1c exclusively afforded
the allylboronate (S)-4c with high enantioselectivity (92% e.e.;
entry 8) without transposition of the deuterium atom. This indicates
that the reaction does not include a pseudo-meso p allylmetal inter-
mediate, which is observed in other transition-metal-catalysed
DYKAT processes (entry 8)10,11,17,18. In addition, both enantio-
enriched forms of the starting material, (S)-1b (93% e.e.) or (R)-1b
(94% e.e.) were converted into the same enantiomer, (S)-4b (entries
9 and 10). The reaction of (S)-1b resulted in a higher enantiomeric
excess (99% e.e.) than that obtained from (rac)-1b, and the reaction
of (R)-1b gave a lower enantiomeric excess (85% e.e.). The stereo-
chemical outcomes indicate that the reactions of (S)-1b and (R)-
1b proceed via two distinct pathways, anti-SN2′ with higher enantio-
selectivity and syn-SN2′ with slightly lower enantioselectivity. The
enantiomeric excess of the product prepared from (rac)-1b (92%;
entry 7) is roughly the average of the values from (S)-1b (99% e.e.;
entry 9) and (R)-1b (85% e.e.; entry 10). The reaction of (S)-1b
with a low amount of 3 (0.6 equivalents), where the reaction did
not reach completion, gave (S)-4b in 46% yield with 99% e.e.; (S)-
1b was recovered in 44% yield with a slightly lower enantiomeric
purity (89% e.e.) compared with the starting material (entry 11).
Conversely, a similar reaction of (R)-1b with 0.6 equivalents of 3
gave (S)-4b with a lower product enantiomeric purity (43%,
85% e.e.) and the recovered (R)-1b showed a higher enantiomeric
purity (45%, 98% e.e.) than that of the starting material
(entry 12). The enantiomeric excess values of the recovered 1b indi-
cate that the reaction does not involve racemization of the starting
material and that the consumption rate of (S)-1b is slightly higher
than that of (R)-1b, resulting in partial kinetic resolution (entries
11, 12). Reaction of (rac)-1b with 0.6 equivalents of 3 resulted in
50% yield of (S)-4b with high enantioselectivity (95% e.e.) and
48% recovery of the starting material with moderate enantiomeric
excess (34% e.e. (R); entry 13). This result is consistent with the
assumption that (S)-1b reacts slightly faster than (R)-1b.
I
cat*
kAB
kBB
SB
SB
PB
PB
Desymmetrization
Figure 1 | Conceptual schemes for asymmetric reactions of racemic chiral
substrates for production of enantio-enriched compounds. Solid arrows
represent faster reaction pathways and dotted arrows show slower ones.
Racemization and desymmetrization processes are shown by blue arrows.
a, Kinetic resolution. One of the substrate enantiomers (SA) is converted
into the product (PA) at a higher reaction rate in the presence of a chiral
catalyst (cat*), whereas the other substrate enantiomer (SB) reacts at a
much lower rate (kA ≫ kB). b, Dynamic kinetic resolution. The rapid
racemization process of the substrate enables the conversion of two
enantiomers (SA and SB) into one enantiomer of the product (PA).
c, Dynamic kinetic asymmetric transformation. A desymmetrization process
first converts the two substrate enantiomers (SA and SB) into an
intermediate (I), where the substrate chiral centre disappears. The
subsequent enantioselective path produces one enantiomer (kA ≫ kB).
d, Direct enantio-convergent transformation. One substrate enantiomer
(SA) is converted preferentially into one product enantiomer (PA) (red arrow,
kAA ≫ kAB) and the other enantiomer (SB) is also converted into the same
product (PA) (kBA ≫ kBB) through a different reaction pathway (green arrow).
racemic allylic ethers have a ‘robust’ chiral centre that cannot be
treated by known deracemization processes such as DKR or
DYKAT. The synthetic use of the allylboronates, which can only
be prepared by this direct enantio-convergent transformation, was
demonstrated by construction of all-carbon quaternary stereocen-
tres through stereoselective aldehyde allylation24–26
.
Results
Direct enantio-convergent reaction. Racemic allylic ether 1a has a
cyclic structure with an asymmetric substituent pattern around the
allylic system (Table 1). This appears to be an example of a compound
that cannot be applied to the known deracemization procedures.
There are no efficient ways to racemize such tertiary ethers,
indicating that DKR is not applicable. Although DYKAT of some
racemic allylic esters have been reported in transition-metal-
catalysed asymmetric allylic alkylation10,11,13–18, successful cases are
limited to the acyclic allylic esters or cyclic ones bearing
symmetrical substituents about the allylic system or an electron
withdrawing group. Such structures enable DYKAT by racemization
through p2s2p isomerization10,11,15,16 or symmetrization via the
The reaction of enantiomerically pure (S)-4b with an achiral
ligand BDPB (2d), which has a similar backbone structure to
chiral ligands 2a and 2b, proceeded via anti-SN2′ to afford (S)-4b
(84%, 77% e.e. (S); entry 14). Conversely, the reaction with
Xantphos (2e), which showed high reactivity in our former
copper(I)/diboron catalyst systems, preferentially gave a syn-SN2′
product with a low enantiomeric excess (17% e.e. (R); entry 15).
We suppose that the steric interaction between the catalyst with
BDPB (2d) and the benzyloxy group is responsible for the anti-
stereoselectivity, whereas the catalyst with Xantphos (2e) has no
significant difference in the steric interactions in both pathways.
formation of pseudo-meso p allylmetal complexes10,11,17,18
.
The reaction of (rac)-1a was first carried out with bis(pinacola-
to)diboron 3 ((pin)B–B(pin), pin ¼ pinacolato; 1.5 equivalents) in
the presence of 5 mol% of Cu(O-t-Bu) and a chiral phosphine
ligand [(R,R)-QuinoxP* (2a)]27 in diethyl ether at 30 8C (Table 1).
Complete conversion of (rac)-1a was reached within 24 h and the
corresponding allylboronate (S)-4a, the SN2′ product of boryl
substitution, was obtained in high yield (98%) with a high enantios-
electivity (97% enantiomeric excess (e.e.); entry 1). The reaction was Mechanism. Further experiments with deuterated substrates clearly
also performed with the readily available catalyst CuCl/K(O-t-Bu) showed that the two enantiomers were converted via distinct
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
© 2010 Macmillan Publishers Limited. All rights reserved.
973

NATURE CHEMISTRY DOI: 10.1038/NCHEM.801
ARTICLES
Table 1 | Examination of direct enantio-convergent transformation in copper(I)-catalysed asymmetric allylic boryl
substitution.
t-Bu
P
P
N
P
P
PPh2
PPh2
Cu(O-t-Bu) (5 mol%)
or CuCl/K(O-t-Bu) (20 mol%)
ligand 2 (5 mol%)
R1
R1
OR2
N
t-Bu
(R,R)-QuinoxP* (2a)
Et2O, 30°C
B(pin)
1
(R,R)-Me-Duphos (2b)
(R)-BINAP (2c)
PPh2
O
O
O
4
B
B
PPh2
1a: R1 = –CH2CH2Ph, R2 = Me
1b: R1 = H, R2 = –CH2Ph
1c: R1 = D, R2 = –CH2Ph
(S)-4a: R1 = –CH2CH2Ph
(S)-4b: R1 = H
O
PPh2
O
3 (0.6–2.0 equiv.)
(S)-4c: R1 = D
PPh2
BDPB (2d)
Xantphos (2e)
Entry Substrate
Ligand 2
Equiv. of 3 Time (h) Yield of 4 (%)* e.e. of 4 (%)† Recovery of 1 (%)* e.e. of 1 (%)‡
1
(rac)-1a
(rac)-1a
(rac)-1a
(rac)-1a
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-Me-Duphos (2b) 2.0
(R)-BINAP (2c)
(R,R)-QuinoxP* (2a)
1.5
2.0
24
96
16.5
59
24
24
12
98
98
99
54
95
92
92
91
88
90
46
43
50
84
88
97 (S)
95 (S)
88 (S)
18 (S)
97 (S)
97 (S)
92 (S)
92 (S)
99 (S)
85 (S)
99 (S)
85 (S)
95 (S)
77 (S)
17 (R)
0
0
0
46
0
0
0
0
0
0
–
–
–
28
–
–
–
–
2§
3
4
5
6
7
2.0
1.5
1.5
1.5
1.5
1.5
1.5
0.6
0.6
0.6
1.5
1.5
(þ)-1a (99% e.e.)
(2)-1a (.99% e.e.) (R,R)-QuinoxP* (2a)
(rac)-1b
(rac)-1c
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
(R,R)-QuinoxP* (2a)
8
12
9ꢀ
10ꢀ
11ꢀ
12ꢀ
13
14}
15}
(S)-1b (93% e.e.)
(R)-1b (94% e.e.)
(S)-1b (93% e.e.)
(R)-1b (94% e.e.)
(rac)-1b
10
10
7.5
7
5.5
9
–
–
44
45
48
0
89 (S)
98 (R)
34 (R)
–
(S)-1b (.99% e.e.) BDPB (2d)
(S)-1b (.99% e.e.) Xantphos (2e)
8
0
–
Reaction conditions: 1 (0.5 mmol), Cu(O-t-Bu) (0.025 mmol), ligand 2 (0.025 mmol), 3 (0.75 mmol) in diethyl ether at 30 8C. *Yield of the allylboronate and recovery of the starting material were determined
by 1H NMR of an unpurified reaction mixture using an internal standard. †The value of the enantiomeric excess was determined by HPLC analysis of an oxidative derivative or a carbonyl addition product of the
allylboronate. ‡Enantiomeric ratio was determined by HPLC analysis. §CuCl (0.1 mmol) and K(O-t-Bu) (0.1 mmol) were used instead of Cu(O-t-Bu). ꢀThe reaction was carried out at a 0.25 mmol scale with
5 mol% of catalyst. }The reaction was carried out at a 0.20 mmol scale with 10 mol% of catalyst.
pathways, anti-SN2′ and syn-SN2′ (Fig. 2a,b). The reaction of chiral centres around the deuteride remained unchanged. This led
(1S,5R)-1d, deuterated at the 5-position, gave the anti-SN2′ to the formation of two product diastereomers from two substrate
product, (1S,4R)-4d, without regio- and stereochemical enantiomers. This stereo-divergent behaviour is characteristic of
disposition of the deuterium (Fig. 2a). (1R,5S)-1d, which is the this type of enantio-convergent transformation when the substrate
enantiomer of (1S,5R)-1d, afforded the diastereomeric syn-SN2′ racemates have multiple chiral centres1.
product, (1S,4S)-4d (Fig. 2b). The two opposite stereogenic
As shown in Fig. 2c, the experimental results are clearly
centres at the a-carbon of the alkoxy group in the allylic systems explained by assuming a direct enantio-convergent reaction. The
in 1d disappeared and a new chiral centre at the g-carbon with substrate (S)-1b is attacked by the borylcopper(I), a catalytic inter-
the same absolute configuration was formed in 4d. However, the mediate generated from alkoxycopper(I) and diboron 3. When
c
a
d
b
e
OBn
1
OR2
R1
OBn
1
Cu(O-t-Bu) (5 mol%)
2a (5 mol%)
Cu(O-t-Bu) (5 mol%)
2a (5 mol%)
4
4
D
R1
D
5
C
5
D
D
1
1
3 (1.5 equiv.)
Et2O, 30°C, 13h
anti-SN2'
3 (1.5 equiv.)
Et2O, 30°C, 13h
L*Cu
B(pin)
B(pin)
"99% e.e."
(1S,5R)-1d
>99% e.e.
(1R,5S)-1d
>99% e.e.
(1S,4R)-4d
94%, 99% de
(1S,4S)-4d
92%, 88% de
(pin)B
anti-SN2'
B(pin)
(S)-4b, 92% e.e.
syn-SN2'
(S)-1b
syn-SN2'
"85% e.e."
R1 = H
L* = QuinoxP* (2a)
OR2
R1
R1
C
OR2
R1
R1
R1
C
R2O
syn-SN2'
anti-SN2'
C
L = BDPB (2d)
R1 = H
L = Xantphos (2e)
R1 = H
CuL
LCu
L*Cu
B(pin)
(S)-4b, 77% e.e.
B(pin)
(pin)B
B(pin)
(pin)B
(S)-1b
(R)-4b, 17% e.e.
(S)-1b
(R)-1b
Figure 2 | Experimental studies and plausible schematic explanations on the mechanism of the direct enantio-convergent transformation. a, The reaction
of a deuterium-labelled substrate, (1S,5R)-1d, resulted in anti-SN2′ product (1S,4R)-4d. b, The reaction of (1R,5S)-1d, which is the enantiomer starting material
in a, afforded the syn-SN2′ product (1S,4S)-4d, which is the diastereomer of the product in a. c, The mechanistic scheme for the direct enantio-convergent
transformation. The chiral borylcopper(I) intermediate with the chiral ligand (2a) reacts with (S)-1b via an anti-SN2′ pathway (red arrow) and with (R)-1b via
a syn-SN2′ pathway (green arrow). The same product, (S)-4b, is produced from both substrate enantiomers by the two distinct pathways. d, Reaction of
borylcopper(I) with achiral ligand BDPB (2d) via an anti-SN2′ route. e, Reaction of borylcopper(I) with achiral ligand Xantphos (2e) tends to proceed via an
syn-SN2′ route.
974
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
© 2010 Macmillan Publishers Limited. All rights reserved.

NATURE CHEMISTRY DOI: 10.1038/NCHEM.801
ARTICLES
R1
C
5 mol%
Cu(O-t-Bu)
/(R,R)-QuinoxP*
R1
R3
OH
H
R1
OR2
R3
R1
R1
R3CHO (5)
Hydrolysis
H
R3
O
n
(pin)B B(pin) (3)
Aldehyde
addition
conditions
H
O
n
n
B(pin)
Et2O, 30°C
B
OR
n
n
B(pin)
rac-1
New
stereocentres
6
RO
4
1a: n = 1, R1 = –CH2CH2Ph, R2 = CH3
1b: n = 1, R1 = H, R2 = –CH2Ph
1e: n = 1, R1 = CH3, R2 = –CH2Ph
1f: n = 1, R1 = –CH(CH3)2, R2 = CH3
1g: n = 2, R1 = H, R2 = –CO2CH3
Stereocentre
formed by DECT
Six-membered
transition state
5a: R3 = Ph
5b: R3 = –CH=CHPh
5c: R3 = –CH2CH2Ph
OH
OH
Ph
OH
OH
OH
OH
H
Ph
Ph
H
H
Ph
Ph
Ph
Ph
Ph
(S,S)-6aa, 85%
97% e.e. d.r. >99:1
(S,R)-6ea, 80%
98% e.e. d.r. >99:1
(R,S)-6ab, 72%
97% e.e. d.r. >97:3
(S,R)-6ba, 91%
93% e.e. d.r. >99:1
(R,R)-6bc, 86%
93% e.e. d.r. >99:1
(S,R)-6ga, 84%
91% e.e. d.r. >99:1
Figure 3 | Synthesis of enantio-enriched homoallylic alcohols with an all-carbon quaternary or tertiary stereocentre. The direct enantio-convergent reaction
of allylic ether or carbonate (rac-1) with diboron 3 was first conducted in the presence of a Cu(O-t-Bu)/QuinoxP* catalyst at 30 8C. After completion of the
copper(I)-catalysed reaction and rough purification of the allylboronate 4, a subsequent reaction with aldehyde 5 was carried out in either the presence
.
(BF3 OEt2, –78 8C in CH2Cl2) or absence of a Lewis acid catalyst (30 8C in toluene). The addition reaction proceeded via a six-membered ring transition state
to produce homoallylic alcohol 6 with two newly formed chiral stereocentres after hydrolysis. The enantiomeric excess values of 6 were determined by
high-performance liquid chromotography analysis with a chiral stationary phase. In the case of substrate 1f, the best result was obtained by using
(R,R)-Me-Duphos as ligand—product (S)-4f was obtained in 78% yield and 85% e.e. DECT ¼ direct enantio-convergent transformation.
(R,R)-QuinoxP* (2a) was used as the ligand, in the reaction of (S)- substituent (1f) gave the corresponding allylboronate in good yield
1b, the nucleophilic attack took place on the opposite face (of the with slightly lower enantioselectivity (78%, 85% e.e.) when a (R,R)-
carbon–carbon double bond) to the leaving alkoxy group (OR2) Me-Duphos ligand (2b) was used; however the subsequent aldehyde
to afford (S)-4b via an anti-SN2′-type pathway with 99% e.e. addition was very slow. A carbonate with cyclohexenyl structure (1g)
(Fig. 2c). In contrast, the same borylcopper(I) intermediate also gave a good result with 10 mol% catalyst (84%, 91% e.e., d.r. .
approaches (R)-1b from the same side as the leaving alkoxy group 99:1); however the reaction with a similar seven-membered ring
(OR2) to give (S)-4b through a syn-SN2′-type reaction with 85% e.e. substrate, 2-cyclohepten-1-yl methyl carbonate, resulted in a poor
As shown in Fig. 2c,d the reaction of (S)-1b predominantly pro- enantioselectivity (65%, 44% e.e.). Interestingly, the reaction of a
ceeds through an anti-SN2′ pathway when an achiral BDPB ligand is linear substrate with unsymmetrical substituents, (Z)-methyl
used, whereas when Xantphos is used the reaction tends to proceed (6-phenylhex-3-en-2-yl) carbonate, proceeded in a typical kinetic
via a syn-SN2′ pathway (Table 1, entries 14 and 15). These results resolution manner (allylboronate product, 47%, 80% e.e.; recovered
indicate that the anti- or syn-SN2′-type reaction route is flexible starting material, 46%, 82% e.e.; see Supplementary Information).
and controllable by the ligand structure. Thus, it is reasonable to
Discussion
assume that catalysts with the (R,R)-QuinoxP* ligand have sound
face selectivity on the double bond and that this overcomes the
inherent stereoselectivity (anti- or syn- SN2′) of the borylcopper(I)
intermediate toward the allylic substrate. Density functional theory
calculations (M05-2X/6-31G(d)) using model compounds were
carried out for four distinct reaction pathways (anti- or syn-SN2′ path-
ways from (S)-1 or (R)-1). The results support our proposed mechan-
ism. For the reaction of (S)-1, anti-SN2′ is favourable over syn-SN2′;
for the reaction of (R)-1, syn-SN2′ is favourable over the anti-SN2′
reaction (see Supplementary Information).
The present transformation shows interesting similarity to a class of
asymmetric reactions called ‘divergent reactions on a racemic
mixture’ by Kagan3, which may include parallel kinetic resolution,
regio- and stereo-divergent reactions31–37. In such reactions, two
enantiomers of a racemic mixture were converted into ‘distinct’
enantio-enriched products through different pathways. Contrary
to this, the present reaction transforms the substrate enantiomers
into the ‘same’ enantio-enriched product through different pathways.
The divergent or parallel asymmetric reactions are advantageous
compared with classical kinetic resolution in terms of efficiency
Construction of all-carbon quaternary stereocentre. The enantio- because the efficiency of the resolution is the simple sum of the selec-
enriched allylboronates prepared by the enantio-convergent tivity of the two independent pathways when the two pathways have
transformation through copper(I)-catalysed asymmetric boryl similar reaction rates3,31. A similar feature was observed in the present
substitution are valuable synthetic reagents28–30. In particular, a- transformation (Table 1, entries 11–13). This enantio-convergent
chiral cyclic allylboronates bearing a substituent at the 3-position can transformation can be considered as a special ‘convergent’ case of
be prepared only by this reaction, and these can be used to produce the ‘divergent reactions on a racemic mixture’.
homoallylic alcohols with an all-carbon quaternary stereocentre by
The key to success in the present enantio-convergent reaction, as
stereoselective aldehyde allylation; selective construction of such well as other divergent-type reactions, is the ability of the external
molecules is a challenging issue in synthetic chemistry. The racemic chiral reactive species to control the selectivity. This is significantly
substrates 1a–e were initially subjected to the copper(I)-catalysed superior to the influence of the internal chiral structure of the
enantio-convergent transformation to afford enantio-enriched racemic substrate. Tomioka et al. reported a relevant two-step
allylboronates, which were subsequently reacted with aldehydes enantio-convergent procedure, which includes a reagent-controlled
(Fig. 3). The aldehyde addition proceeded in a highly stereoselective reaction38. In our reaction, the single catalytic reaction promotes the
manner through a six-membered transition state to give homoallylic reagent-controlled enantioselective addition and the elimination of
alcohols 6 with an all-carbon quaternary or tertiary stereocentre in the stereogenic leaving groups.
high yields with high diastereo- and enantioselectivities (72–91%,
In summary, we have presented the first direct chemical enantio-
93–98% e.e., diastereomeric ratio (d.r.) .99:1– . 97:3). The convergent transformation promoted by an artificial catalyst
borylation reaction with a substrate with a bulky isopropyl without a racemization or symmetrization process. The known
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
© 2010 Macmillan Publishers Limited. All rights reserved.
975

NATURE CHEMISTRY DOI: 10.1038/NCHEM.801
ARTICLES
17. Trost, B. M., Dudash, J. & Hembre, E. J. Asymmetric induction of conduritols via
AAA reactions: synthesis of the aminocyclohexitol of hygromycin A. Chem.
Eur. J. 7, 1619–1629 (2001).
dynamic processes (for example, DKR and DYKAT) require racemi-
zation or symmetrization of the substrates or the intermediates and
can thus only treat ‘labile’ racemates. In contrast, the present reac-
tion can access racemates with structural features that are not suit-
able for racemization or symmetrization. Reaction of such ‘robust’
racemic compounds with a chiral catalyst usually results in kinetic
resolution because the substrate-controlled stereoselectivity and
reagent-controlled enantioselectivity of the catalyst are in conflict
with the conversion of the less reactive substrate enantiomer. In
18. Langlois, J. & Alexakis, A. Dynamic kinetic asymmetric transformation in
copper-catalyzed allylic alkylation. Chem. Commun. 3868–3870 (2009).
19. Pedragosa-Moreau, S., Archelas, A. & Furstoss, R. Microbiological
transformations 28. Enantiocomplementary epoxide hydrolyzes as a preparative
access to both enantiomers of styrene oxide. J. Org. Chem. 58, 5533–5536 (1993).
20. Kroutil, W., Mischitz, M. & Faber, K. Deracemization of (þ/-)-2,3-disubstituted
oxiranes via biocatalytic hydrolysis using epoxide hydrolases: kinetics of an
enantioconvergent process. J. Chem. Soc., Perkin Trans. 1 3629–3636 (1997).
our direct enantio-convergent reaction, convergence of both sub- 21. Ito, H. et al. Copper-catalyzed enantioselective substitution of allylic carbonates
with diboron: An efficient route to optically active a-chiral allylboronates. J. Am.
Chem. Soc. 129, 14856–14857 (2007).
22. Ito, H. et al. Synthesis of optically active boron-silicon bifunctional cyclopropane
strate enantiomers into the single chiral product is enabled
because of the decisive superiority of reagent-controlled enantio-
selectivity over substrate-controlled stereoselectivity. Although the
derivatives through enantioselective copper(I)-catalyzed reaction of allylic
present reaction is effective on rather limited substrates, we believe
that our study provides a novel principle for the development of
chemical enantio-convergent reactions for the robust racemates
that cannot be treated by known dynamic methods.
carbonates with a diboron derivative. Angew. Chem. Int. Ed. 47, 7424–7427 (2008).
23. Ito, H., Okura, T., Matsuura, K. & Sawamura, M. Desymmetrization of meso-2-
alkene-1,4-diol derivatives through copper(I)-catalyzed asymmetric boryl
substitution and stereoselective allylation of aldehydes. Angew. Chem. Int. Ed.
49, 560–563 (2010).
24. Corey, E. & Guzman-Perez, A. The catalytic enantioselective construction of
molecules with quaternary carbon stereocenters. Angew. Chem. Int. Ed. 37,
388–401 (1998).
25. Christoffers, J. & Baro, A. (eds) Quaternary Stereocenters: Challenges and
Solutions for Organic Synthesis (Wiley-VCH, 2006).
26. Trost, B. & Jiang, C. Catalytic enantioselective construction of all-carbon
quaternary stereocenters. Synthesis 369–396 (2006).
27. Imamoto, T., Sugita, K. & Yoshida, K. An air-stable P-chiral phosphine ligand
for highly enantioselective transition-metal-catalyzed reactions. J. Am. Chem.
Soc. 127, 11934–11935 (2005).
Methods
In a nitrogen-filled glove box, copper(I) tert-butoxide (3.4 mg, 0.025 mmol), the
ligand 2 (0.025 mmol) and bis(pinacolato)diboron 3 (190 mg, 0.75 mmol) were
placed into a vial and mixed with dry diethyl ether (0.5 ml) with stirring. After being
sealed with a rubber septum, the reaction vial was removed from the glovebox and
connected to an argon line through a needle. Allylic ether 1 (0.5 mmol) was added
dropwise to the mixture at 30 8C. After the reaction was complete, the reaction
mixture was directly subjected to column chromatography (SiO2, hexane:diethyl
ether ¼ 100:0–99.0:1.0) to give the crude allylboronate 4 as a colourless oil. The yield
was estimated by 1H NMR using mesitylene as the internal standard.
28. Hall, D. G. (ed) Boronic Acids: Preparation and Applications in Organic Synthesis
and Medicine (Wiley-VCH, 2005).
29. Ramachandran, R. V. Pinane-based versatile “allyl”boranes. Aldrichimica Acta
35, 23–35 (2002).
Received 22 January 2010; accepted 10 July 2010;
published online 29 August 2010
30. Hall, D. G., Lewis and Brønsted acid catalyzed allylboration of carbonyl compounds:
from discovery to mechanism and applications. Synlett, 1644–1655 (2007).
31. Vedejs, E. & Chen, X. H. Parallel kinetic resolution. J. Am. Chem. Soc. 119,
2584–2585 (1997).
32. Tanaka, K. & Fu, G. C. Parallel kinetic resolution of 4-alkynals catalyzed by
Rh(I)/Tol-BINAP: synthesis of enantioenriched cyclobutanones and
cyclopentenones. J. Am. Chem. Soc. 125, 8078–8079 (2003).
33. Webster, R., Boing, C. & Lautens, M. Reagent-controlled regiodivergent
resolution of unsymmetrical oxabicyclic alkenes using a cationic rhodium
catalyst. J. Am. Chem. Soc. 131, 444–445 (2009).
References
1. Faber, K. Non-sequential processes for the transformation of a racemate into a
single stereoisomeric product: proposal for stereochemical classification. Chem.
Eur. J. 7, 5004–5010 (2001).
2. Steinreiber, J., Faber, K. & Griengl, H. De-racemization of enantiomers versus
de-epimerization of diastereomers-classification of dynamic kinetic asymmetric
transformations (DYKAT). Chem. Eur. J. 14, 8060–8072 (2008).
3. Kagan, H. B. Various aspects of the reaction of a chiral catalyst or reagent with a
racemic or enantiopure substrate. Tetrahedron 57, 2449–2459 (2001).
4. Vedejs, E. & Jure, M. Efficiency in nonenzymatic kinetic resolution. Angew.
Chem. Int. Ed. 44, 3974–4001 (2005).
34. Wu, B., Parquette, J. R. & RajanBabu, T. V. Regiodivergent ring opening of chiral
aziridines. Science 326, 1662–1662 (2009).
5. Gao, Y. et al. Catalytic asymmetric epoxidation and kinetic resolution: modified
procedures including in situ derivatization. J. Am. Chem. Soc. 109, 5765–5780 (1987).
6. Tokunaga, M., Larrow, J. F., Kakiuchi, F. & Jacobsen, E. N. Asymmetric catalysis
with water: efficient kinetic resolution of terminal epoxides by means of catalytic
hydrolysis. Science 277, 936–938 (1997).
7. Noyori, R., Tokunaga, M. & Kitamura, M. Stereoselective organic synthesis via
dynamic kinetic resolution. Bull. Chem. Soc. Jpn. 68, 36–55 (1995).
8. Huerta, F. F., Minidis, A. B. E. & Ba¨ckvall, J. E. Racemization in asymmetric
synthesis. Dynamic kinetic resolution and related processes in enzyme and metal
catalysis. Chem. Soc. Rev. 30, 321–331 (2001).
35. Reetz, M. T., Strack, T. J., Mutulis, F. & Goddard, R. Asymmetric dihydroxylation
of chiral gamma-amino a, b-unsaturated esters: turning the mismatched into the
matched case via protective group tuning. Tetrahedron Lett. 37, 9293–9296 (1996).
36. Matsumura, K., Hashiguchi, S., Ikariya, T. & Noyori, R. Asymmetric transfer
hydrogenation of a, b-acetylenic ketones. J. Am. Chem. Soc. 119, 8738–8739 (1997).
37. Ohmura, T. & Suginome, M. Asymmetric silaboration of terminal allenes
bearing a-stereogenic centers: stereoselection based on “reagent control”. Org.
Lett. 8, 2503–2506 (2006).
38. Chen, O. et al. Asymmetric synthesis of 5-arylcyclohexenones by rhodium(I)-
catalyzed conjugate arylation of racemic 5-(trimethylsilyl)cyclohexenone with
arylboronic acids. Org. Lett. 7, 4439–4441 (2005).
9. Pellissier, H. Recent developments in dynamic kinetic resolution. Tetrahedron
64, 1563–1601 (2008).
10. Trost, B. M. Pd asymmetric allylic alkylation (AAA). A powerful synthetic tool.
Chem. Pharm. Bull. 50, 1–14 (2002).
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (B) (JSPS) and the
PRESTO program (JST). We thank T. Inabe for his assistance in X-ray analysis. Nippon
Chemical Industrial is acknowledged for a gift of (R,R)-QuinoxP*. We also acknowledge
DAICEL chemical industries for their help on the optical resolution of some
starting materials.
11. Trost, B. M. & Crawley, M. L. Asymmetric transition-metal-catalyzed allylic
alkylations: Applications in total synthesis. Chem. Rew. 103, 2921–2943 (2003).
12. Hayashi, T. et al. Chiral (b-aminoalkyl)phosphines. Highly efficient phosphine
ligands for catalytic asymmetric Grignard cross-coupling. J. Org. Chem. 48,
2195–2202 (1983).
13. Norinder, J. & Ba¨ckvall, J. Dynamic processes in the copper-catalyzed
substitution of chiral allylic acetates leading to loss of chiral information. Chem.
Eur. J. 13, 4094–4102 (2007).
14. Lu, Z. & Ma, S. Metal-catalyzed enantioselective allylation in asymmetric
synthesis. Angew. Chem. Int. Ed. 47, 258–297 (2008).
15. Trost, B. M., Bunt, R. C., Lemoine, R. C. & Calkins, T. L. Dynamic kinetic
asymmetric transformation of diene monoepoxides: A practical asymmetric
synthesis of vinylglycinol, vigabatrin, and ethambutol. J. Am. Chem. Soc. 122,
5968–5976 (2000).
16. Trost, B. M. & Toste, F. D. Palladium-catalyzed kinetic and dynamic
kinetic asymmetric transformation of 5-acyloxy-2-(5H)-furanone.
Enantioselective synthesis of (-)-aflatoxin B lactone. J. Am. Chem. Soc. 121,
3543–3544 (1999).
Author contributions
H.I. directed this study. Experiments were carried out by S.K. and H.I. Density functional
theory calculations (Supplementary Information) were carried out by H.I. M.S. gave
comments on the reaction mechanism and the preparation of the enantio-enriched
starting materials.
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to H.I.
976
NATURE CHEMISTRY | VOL 2 | NOVEMBER 2010 | www.nature.com/naturechemistry
© 2010 Macmillan Publishers Limited. All rights reserved.