CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications

Article abstract of DOI:10.1021/jacs.9b01784

Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We describe a mild and efficient method for the copper-catalyzed allylation of ketones using widely available 1,3-dienes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method was applied to the preparation of an important drug, (R)-procyclidine, and a key intermediate in the synthesis of several pharmaceuticals.

Full text of DOI:10.1021/jacs.9b01784

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Article
CuH-Catalyzed Enantioselective Ketone Allylation
with 1,3-Dienes: Scope, Mechanism, and Applications
Chengxi Li, Richard Y. Liu, Luke T. Jesikiewicz, Yang Yang, Peng Liu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Feb 2019
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CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes:
Scope, Mechanism, and Applications
Chengxi Li1, Richard Y. Liu1, Luke T. Jesikiewicz2, Yang Yang1, Peng Liu2,*, and Stephen L. Buch-
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wald1,*
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
2Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
ABSTRACT: Chiral tertiary alcohols are important building blocks for the synthesis of pharmaceutical agents and biologically
active natural products. The addition of carbon nucleophiles to ketones is the most common approach to tertiary alcohol synthesis,
but traditionally relies on stoichiometric organometallic reagents that are difficult to prepare, sensitive, and uneconomical. We de-
scribe a mild and efficient method for the copper-catalyzed allylation of ketones, using widely available 1,3-dienes as allylmetal
surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-
, and enantioselectivity. Mechanistic investigations using density functional theory (DFT) implicate the in situ formation of a rapidly
equilibrating mixture of isomeric copper(I) allyl complexes, from which Curtin-Hammett kinetics determine the major isomer of
product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process. Finally, this method
was applied toward the preparation of an important drug, (R)-Procyclidine, and a key intermediate in the synthesis of several phar-
maceuticals.
couplings (Ni,9 Ru,10 Rh11 and Ir12) with conjugated dienes, re-
actions involving ketones, rather than aldehydes, remain chal-
lenging, even in a non-stereoselective manner.
■
INTRODUCTION
Enantiomerically enriched tertiary alcohols and their deriv-
atives feature prominently in a variety of important pharmaceu-
tical agents and complex natural products.1 Consequently, their
efficient synthesis has attracted great attention from synthetic
chemists.2 Traditionally, the addition of organomagnesium
(Grignard) reagents to ketones has been a popular method to
obtain tertiary alcohols in racemic form.3 However, the harsh
methods required to prepare these organometallic reagents, as
well as their instability and Brønsted basicity, have limited the
tolerance of these reagents toward polar functional groups. Fur-
thermore, the necessity to use stoichiometric organometallic re-
agents, and often, chiral auxiliaries for enantioselective trans-
formations, is intrinsically inefficient and operationally compli-
cating. Thus, the development of highly efficient catalytic,
asymmetric strategies for constructing tertiary alcohols remains
a goal of high priority in organic synthesis.4
1,3-Dienes are important industrial raw materials that are
produced on an enormous scale annually (Figure 1a). These
chemicals include butadiene5 (about 13  106 ton/year produc-
tion), isoprene6 (about 8  105 ton/year) and myrcene7 (about
2500 ton/year). Recently, several groups have considered the
use of these inexpensive and stable compounds as surrogates for
stoichiometric organometallic reagents in carbonyl addition re-
actions. In 2005, a pioneering report by Gendre and Moïse8
demonstrated the first titanium-catalyzed aldehyde allylation
using conjugated dienes as reagents (Figure 1b), although due
to the highly reactive nature of the titanium-allyl species, the
functional group tolerance was limited. Subsequently,
Krische5b,c has developed ruthenium-catalyzed stereoselective
aldehyde (or alcohol) allylations with 1,3-butadiene (Figure 1c).
Unfortunately, the same method cannot be generally applied to
ketones for the synthesis of tertiary alcohols. Despite reports of
Figure 1. Overview of 1,3-dienes in industry and in catalytic
allylation processes.
Over the past several years, a number of research groups,
including ours, have reported approaches for the copper-cata-
lyzed hydroamination of unsaturated substrates through the in
situ generation of alkylcopper nucleophiles.13 Using this strat-
egy, activated pronucleophiles such as enynes and allenes were
a
number of other transition-metal-catalyzed reductive
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9
L3
L3
PhMe
PhMe
0
94
89
4:1
98:2
(97:3)
successfully engaged in nucleophilic addition reactions with ke-
tones.14 This reactivity pattern has since also been extended to
the reductive coupling of olefin pronucleophiles with
imines.2e,15
1
2
10
-20
1.8:1
98:2
(97:3)
3
4
5
6
7
8
9
Following this general concept, herein we describe a
highly regio- and enantioselective copper-catalyzed method for
the allylation of ketones using readily available 1,3-dienes (Fig-
ure 1d). Previously, we had reported a single, unoptimized ex-
ample of this transformation.14b In addition, we report a compu-
tational study of the mechanism of this class of transformations,
revealing a complex kinetic basis for diastereo- and enantiose-
lectivity resulting from an equilibrating mixture of allylcopper
intermediates of similar energy. Furthermore, we propose a ste-
reochemical model for these allylation processes using non-C2-
symmetric JOSIPHOS-derived chiral ligands. Finally, we apply
our method toward an efficient and concise synthesis of the
pharmaceutical agent (R)-procyclidine and key intermediates in
the synthesis of (R)-Oxyphencyclimine, (R)-Oxybutynin and
(R)-Oxyphenonium bromide.
aConditions: 0.2 mmol ketone (1 equiv), 1,3-butadiene (2 equiv),
copper(II) acetate (0.05 equiv), ligand (0.06 equiv), dimethoxy(me-
thyl)silane (4 equiv) in solvent (0.2 mL), ketone was added slowly
by syringe pump; see the Supporting Information for details. bYield
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1
and diastereomeric ratio were determined by H NMR spectros-
copy of the crude mixture, using dibromomethane as an internal
c
standard. Enantiomeric ratio was determined by HPLC or SFC
analysis on commercial chiral columns, and the relative configura-
tion of 1 was determined by comparing its NMR data with reported
data.17
■
RESULTS AND DISCUSSION
We began by studying the reaction between 4-methoxy-
Evaluation of the reaction solvent (Table 1, entry 4-7) in-
dicated that toluene was optimal for this transformation. The
results were very sensitive to the reaction temperature: the yield,
dr, and er were all diminished at slightly elevated temperatures
(40 ˚C, Table 1, entry 8). However, excellent yield (94%), dr
(4:1), and er (98:2 and 97:3 respectively for the major and minor
diastereomers) were achieved when the reaction was performed
at 0 ˚C (Table 1, entry 9). Further lowering of the reaction tem-
perature (-20 ˚C) significantly decreased the dr again (Table 1,
entry 10).
Next, the substrate scope of the asymmetric reductive cou-
pling of diverse ketones with acyclic 1,3-dienes was examined
(Table 2). A range of chiral homoallylic tertiary alcohols were
prepared with excellent yields and enantiomeric purity (>94:6
er). The reaction was compatible with ether (1), alcohol (2), sec-
ondary (3) and tertiary amine (4) groups, as well as aromatic
heterocycles (5, 6). Cyclic ketones such as 7a reacted with par-
ticularly good diastereoselectivity, as well as excellent yield
and enantioselectivity. Using acetylferrocene, we obtained en-
antiomerically enriched ferrocene 8. Substituted dienes were
also generally effective in our reductive coupling reaction. 2-
alkyl- (isoprene-derived 9 and myrcene-derived 10), 1-aryl-
(11), and 2-aryl-substituted (12) diene reactants were coupled
with ketones in moderate to good yield and with high stereose-
lectivity. Unfortunately, when 1-alkyl groups were introduced,
reactions resulted in complex mixtures of regioisomeric prod-
ucts, each in several diastereomeric forms.
We also surveyed the scope of ketone allylation using cy-
clic 1,3-dienes. However, under the conditions used for acyclic
dienes, the yield of the desired product was unsatisfactory, and
direct reduction of the ketone was instead the major reaction
that was observed (see Supporting Information for details). We
hypothesized that in the case of cyclic dienes, the L3-ligated
CuH is unable to react with the diene at a rate competitive with
direct ketone reduction. Revisiting our initial ligand evaluation
data, we noticed that the use of (S,S)-Ph-BPE (L2) provided less
ketone reduction byproduct than with L3 (Table 1, entries 2 and
3).14b Accordingly, we hypothesized that substituting L2 for L3
might be useful in these cases where ketone reduction is a prob-
lem: indeed, the catalyst derived from L2 provided greatly im-
proved yields with cyclic diene substrates.
acetophenone (1a) and 1,3-butadiene (1b) under conditions pre-
viously reported for Cu-catalyzed reductive coupling reactions
(Table 1, entry 1).14 With (R)-DTBM-SEGPHOS (L1) as the
ligand, homoallylic alcohol 1 was obtained with 44% yield,
1.2:1 dr and 83.5:16.5 er for the major diastereomer (65.5:34.5
er for the minor). Based on 1H NMR analysis of the crude reac-
tion mixture, the remainder of the ketone underwent direct re-
duction by copper hydride. When the ligand was exchanged for
(S,S)-Ph-BPE (L2), this reduction pathway was suppressed,14b
and a 96% yield of 1 was obtained with moderate dr and ee (Ta-
ble 1, entry 2). Further ligand screening revealed that use of the
commercially available JOSIPHOS16 derivative SL-J011-1 fur-
ther improved the stereoselectivity to 4:1 dr and 97:3 er (96:4
er for the minor diastereomer, Table 1, entry 3), while maintain-
ing high chemoselectivity for coupling over ketone reduction.
Table 1. Evaluation of Reaction Conditions for the CuH-Catalyzed
Allylation of 4-Methoxyacetophenone.a
En-
try
Lig-
and
Solvent
Temp
(°C)
Yieldb
1 (%)
dr
erc
major
(minor)
1
2
3
4
5
6
7
8
L1
L2
L3
L3
L3
L3
L3
L3
PhMe
PhMe
PhMe
CyH
25
25
25
25
25
25
25
40
44
96
90
71
88
83
55
75
1.2:1
3.1:1
4:1
83.5:16.5
(65.5:34.5)
86.5:13.5
(84:16)
97:3
(96:4)
3:1
96.5:3.5
(94:6)
THF
4:1
96.5:3.5
(94:6)
MTBE
Dioxane
PhMe
3.4:1
3.9:1
3.6:1
97:3
(94.5:5.5)
96.5:3.5
(94:6)
95:5
(93:7)
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Table 2. Evaluation of the Scope of the Ketone Allylation with
enantioselectivity (21, 22). Finally, a larger ring diene, 1,3-cy-
cloheptadiene, is also an effective reagent, providing 24 with
1
2
Acyclic Dienes.a
moderate yield and excellent stereoselectivity.
3
4
5
Table 3. Scope Evaluation of Ketone Allylation with Cyclic
Dienes. a
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aYields indicate the isolated yield of product as a mixture of two
diastereomers on a 1.0 mmol scale. Diastereomeric ratios were de-
termined by 1H NMR spectroscopy for both the crude and purified
products; enantiomeric ratios were determined by HPLC or SFC
analysis on commercial chiral columns; enantiomeric ratios of mi-
nor diastereomers are indicated in parentheses after those of the
major diastereomers. Yields, diastereomeric ratios, and enantio-
meric ratios are the averages for two identical runs. See Supporting
aYields indicate the isolated yield of product as a mixture of two
diastereomers on a 1.0 mmol scale. Diastereomeric ratios were de-
termined by 1H NMR spectroscopy for both the crude and purified
products; enantiomeric ratios were determined by HPLC or SFC
analysis on commercial chiral columns; enantiomeric ratios of mi-
nor diastereomers are indicated in parentheses after those of the
major diastereomers. Yields, diastereomeric ratios, and enantio-
meric ratios are the averages for two identical runs. See Supporting
Information for full details. bL2 was used instead of L3.
b
Information for full details. The yield was determined by 1H NMR
versus an internal standard due to the volatility of the product.
Using L2, several classes of ketones were coupled with cy-
clic 1,3-dienes in high regio- and enantioselectivity (Table 3).
The reaction is most efficient for aryl methyl ketones. A broad
range of aromatic carbonyl substituents, including an ortho-sub-
stituted arene (14), a pyridine (18), a pyrrole (19), a bromopy-
razole (20), and a ferrocene (23) were evaluated, all providing
good results. Several additional types of ketones were con-
verted with high yield and stereoselectivity under the same con-
ditions. For instance, a dialkyl ketone (16) and a vinyl methyl
ketone (17) underwent allylation with high enantioselectivity.
We proposed that the low diastereoselectivity observed in the
case of 16 may be due to the minimal steric differentiation be-
tween the methyl and methylene groups attached to the car-
bonyl. Accordingly, we found that our method can be particu-
larly useful on symmetric dialkyl ketones, which react to form
homoallylic alcohol products with exceptionally high yield and
■
MECHANISTIC STUDIES
The proposed catalytic cycle of this CuH-catalyzed allyla-
tion reaction is summarized in Figure 2. We envisioned that a
primary allylic copper intermediate (III) might be formed by
hydrocupration of a diene. Selectivity-determining nucleophilic
addition of III to the ketone would provide copper alkoxide V.
Subsequently, σ-bond metathesis with a hydrosilane VI should
rapidly regenerate the copper hydride catalyst I, with concomi-
tant formation of the silylated homoallylic alcohol (VII) in a
process that is well precedented.14b
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Figure 2. Proposed catalytic cycle.
We performed density functional theory (DFT) calcula-
tions to investigate several aspects of this proposed reaction
mechanism. First, a comparison of the candidate hydrocupra-
tion mechanisms was performed to understand the mechanism
of generation of the key allylcopper intermediate. Next, the en-
ergies and interconversion barriers of several possible allylic
complexes were evaluated. From here, a thorough consideration
of possible insertion transition states for the addition of the al-
lylcopper intermediate to ketones was undertaken to reveal the
origin the observed diastereoselectivity. Finally, we sought to
explain the -facial selectivity with respect to the ketone. While
the mechanism of chiral induction in enantioselective reactions
utilizing C2-symmetric ligands such as Ph-BPE has been fre-
quently rationalized using quadrant-diagrams,18a-c analogous in-
tuitive models for less symmetric ligands such as JOSIPHOS
derivatives are rare.18d Therefore, we focused on developing an
understanding of the high enantioselectivity observed with L3-
supported copper catalysts.
We started our computational investigation with a confor-
mational search on the L3-supported CuH catalyst. Two lowest-
energy conformers with almost identical energies (25a and 25b,
Figure 3) were located. These conformers differ in the arrange-
ment of the six-membered chelate ring. In 25a, the chiral carbon
center is puckered out-of-plane, while the two phosphorus at-
oms and the Cu are nearly co-planar with one of the Cp rings of
the ferrocene. In contrast, in 25b, the Cu is puckered out-of-
plane, while the two phosphorus atoms and the chiral carbon are
nearly co-planar with the ferrocene Cp ring. As a result, the P-
tBu and P-Ar substituents in 25a and 25b adopt different orien-
tations, and thus create distinct steric environments around the
Cu center. In 25a, the P-tBu group in quadrant IV and the P-
aryl group in quadrant II are placed in closer proximity to the
Cu center, while the P-tBu and P-aryl groups in quadrants I and
III are more distal from the Cu. Therefore, the steric environ-
ment of this conformer resembles those of C2-symmetric lig-
ands. In contrast, conformer 25b is pseudo-CS symmetric. The
P-tBu and P-aryl groups in quadrants IV and III are placed
closer to the Cu center, while quadrants I and II are relatively
unoccupied by the ligand as the P-substituents in these quad-
rants are placed further away from the Cu. Considering the sim-
ilar stability of 25a and 25b, both ligand conformations were
considered when locating the transition states in the proposed
catalytic cycle. Our calculations indicated the hydrocupration,
1,3-migration, and ketone addition transition states all are lower
in energy when the ligand adopts the conformation in 25a,
which has a pseudo-C2-symmetric steric environment (see be-
low). This is consistent with the high efficiency of CuH cata-
lysts with C2-symmetric ligands such as Ph-BPE in promoting
similar transformations.
Figure 3. Conformers of the CuH catalyst supported by the
SL-J011-1 ligand (L3). The P-Ar and P-tBu groups proximal
to the Cu center are highlighted in red.
Figure 4. Optimized geometries of the 1,2- and 1,4-hydrocu-
pration transition states. The diene is highlighted in yellow. The
P-aryl and P-tBu groups “proximal” to the Cu center are high-
lighted in red in Figure 4a.
We selected 2-acetonaphthone and 1,3-butadiene as the
model substrates for our computational investigation of the cat-
alytic cycle. Experimentally, this pair of substrates react with
95% yield, 2.5:1 dr, and 93:7 er (for the major diastereomer,
90.5:9.5 er for the minor diastereomer) under the standard reac-
tion conditions (see Supporting Information for details). We hy-
pothesized that, initially, the hydrocupration of 1,3-butadiene
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might proceed via either direct 1,4-hydrocupration of the diene in a pseudo-equatorial orientation, and the methyl substituent is
1
2
3
4
5
6
7
8
or via 1,2-hydrocupration followed by a 1,3-migration. Our cal-
culations suggest that this process strongly prefers to occur
through the 1,2-addition pathway (TS1a, Figure 4) to form a
secondary allylcopper intermediate (26, Figure 5). In compari-
son, the 1,4-hydrocupration of the diene requires 9.6 kcal/mol
higher activation energy (TS1c, Figure 4b). The 1,2-hydrocu-
pration proceeds with moderate -facial selectivity (∆∆G‡ = 0.8
kcal/mol, Figure 4a) leading initially to an (S)-allylcopper inter-
mediate. However, this stereocenter is rapidly ablated: the sec-
ondary allyl complex 26 undergoes facile 1,3-migration via ei-
ther TS2-cis or TS2-trans to form primary allylcopper interme-
diates 27-cis and 27-trans, which are similar in energy to each
other, and both more stable than 26 (Figure 5). This 1,3-migra-
tion step requires a very low barrier and is reversible. Therefore,
the cis/trans isomers of the primary allylcopper intermediates
exist in equilibrium with each other, and with the branched iso-
mers, prior to the nucleophilic addition to the ketone.
The enantio- and diastereoselectivity are both determined
in the subsequent ketone addition step. We found that the ketone
addition occurs through a six-membered Zimmerman-Traxler-
type transition state.19 After exhaustive computational investi-
gation of possible transition state isomers, TS3a and TS3b were
identified as the most favorable pathways for the ketone addi-
tions (see SI for other less favorable TS structures). In both
TS3a and TS3b, the bulkier aryl group on the ketone is placed
pseudo-axial. Counterintuitively, the preferred pathway for re-
action with the ketone takes place from the cis-allylcopper spe-
cies 27-cis via TS3a, which places the terminal methyl substit-
uent of the allyl group pseudo-axial.19b In comparison, the ke-
tone addition process from 27-trans, which involves a pseudo-
equatorial methyl substituent, requires an additional 1.3
kcal/mol of activation energy (TS3b). An examination of TS3b
reveals the origin of this destabilization: the methyl substituent
on the C=C double bond is placed between the aryl and methyl
groups of the ketone, and thus induces substantial gauche repul-
sions at the forming C−C bond. On the other hand, gauche re-
pulsions in TS3a are weaker because there is only one Me/Ar
interaction and the forming C−C bond distances in TS3a and
TS3b are both around 2.2 to 2.3 Å. In addition, the 1,3-diaxial
repulsions with the same methyl substituent in TS3a are rela-
tively weak because only one H…Me interaction is expected to
contribute.19b The most favorable ketone addition transition
state TS3a leads to the alkoxycopper intermediate 29a, from
which rapid -bond metathesis with a silane generates the ob-
served major product in silyl-protected form (30a). This step is
known to be very rapid for copper alkoxides, which renders the
ketone addition step effectively irreversible.14b
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Figure 5. Computed energy profiles of the CuH-catalyzed allylation of 2-acetonaphthone 28. The calculations were performed at the
M06-2X/SDD−6-311+G(d,p)/SMD(toluene)//B3LYP/SDD−6-31G(d) level of theory. All energies are with respect to the separate
L*CuH catalyst (25a) and reactants (1b and 28).
We next turned our attention to the enantioselectivity of
this process, which is determined by the -facial selectivity of
the ketone addition step as dictated by the ligand. Relative to
favored transition state structure TS3a, disfavored structures
TS3c and TS3c’ involves the addition to the opposite face of
the ketone (Figure 6). In TS3c, the -methylene group and the
pseudo-axial methyl group of the ketone are both placed in the
two quadrants occupied by the “proximal” P-aryl and P-tBu
groups (highlighted in red in Figure 6). As such, TS3c is
destabilized by the steric repulsions with the ligand. In contrast,
in the more stable transition state TS3a, the -methylene group
and the pseudo-axial methyl group are both placed in the “un-
occupied” quadrants, in which the P-substituents are further
away (“distal”) from the Cu center and the substrate. In TS3c’,
although such ligand-substrate repulsions are also minimized
by placing the -methylene group and the pseudo-axial aryl
substituent in the “unoccupied” quadrants, the greater 1,3-diax-
ial interactions with the aryl group destabilize this TS isomer.
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TS3c and TS3c’ are 4.0 and 2.6 kcal/mol less stable than TS3a, obtained in 53% overall yield and with over 99.5:0.5 er in a one-
1
2
3
4
5
6
7
8
respectively, which is in qualitative agreement with the high
levels of enantioselectivity observed in the experiment.
pot sequence without the need for chromatography.
We also applied our method toward a new synthetic route to
(R)-Procyclidine, a treatment for Parkinson’s disease.30 Biolog-
ical testing suggests that (R)-Procyclidine has a higher affinity
for the relevant muscarinic receptor both in humans and in ani-
mal models.22b,30 Thus, an efficient asymmetric synthesis of (R)-
Procyclidine would be valuable. We studied the copper-cata-
lyzed allylation of commercially available ketone 34, which
provided chiral tertiary alcohol 35. Again, without requiring
chromatographic purification, the mixture containing 35 was
subjected to simple hydrogenation and direct crystallization to
yield (R)-Procyclidine (36) in 58% overall yield and over
99.5:0.5 er.
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Scheme 1. Synthesis of a Key Tertiary α-Hydroxy Acid Intermedi-
ate.
Figure 6. Origin of enantioselectivity. All energies are with re-
spect to the separate L*CuH catalyst (25a) and reactants (1b
and 28).
aParenthetical data reflect results of an independent run for
which intermediates were isolated, purified, and characterized.
See the Supporting Information for details. bAfter recrystalliza-
tion. See the Supporting Information for details.
■
APPLICATIONS
To demonstrate the synthetic utility of this asymmetric
transformation, we sought to prepare chiral tertiary alcohol 33,
a key intermediate in the synthesis of anticholinergic agents (R)-
Oxybutynin,20 (R)-Oxyphenonium bromide21 and (R)-Oxy-
phencyclimine.22 Currently, these drugs are typically adminis-
tered in their racemic form, which is synthesized through the
addition of a cyclohexyl Grignard reagent to a ketone.23 How-
ever, motivated by the decreased side effects24 and higher effi-
ciency22,25 associated with the single enantiomer forms, several
groups have developed synthetic routes to enantioenriched key
chiral intermediate 33 using chiral auxiliaries,26 chiral pool syn-
thesis,20c an organocatalytic aldol-elimination-hydrogenation-
deprotection sequence,20b or palladium-catalyzed asymmetric
allylic alkylation followed by functional group interconver-
sions.20d Using our method, we devised an alternative, catalytic,
enantioselective synthetic route to this key chiral intermediate
(Scheme 1) that yields enantiopure product and does not require
the purification of intermediates. From commercially available
starting material 31, after CuH-catalyzed coupling with cyclo-
hexadiene, reduction, hydrolysis, and recrystallization, 33 was
Scheme 2. Synthesis of (R)-Procyclidine.
aParenthetical data reflect results of an independent run for
which intermediates were isolated, purified, and characterized.
See the Supporting Information for details.
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■
CONCLUSION
■
REFERENCES
In summary, we have developed a highly efficient copper-
catalyzed allylation of ketones with feedstock linear and cyclic
conjugated dienes. A large variety of chiral tertiary alcohols
were prepared in excellent yield, regio-, and enantioselectivity,
and with a high level of functional group compatibility. Guided
by DFT calculations, a rationale explaining the factors respon-
sible for the enantio- and diastereoselectivity of this transfor-
mation was derived. From a mixture of rapidly equilibrating al-
lylcopper intermediates of similar energy, selective reaction of
the cis-allyl complex generates the observed diastereomer. Fur-
thermore, a model for the enantioselectivity of the addition of
the allylcopper intermediates to ketones was proposed for cata-
lysts bearing the non-C2-symmetric JOSIPHOS ligands. Our
method also enabled a new, concise, and enantioselective syn-
thesis of pharmaceutically important drug (R)-Procyclidine and
a key intermediate for anticholinergic drugs (R)-Oxyphen-
cyclimine, (R)-Oxybutynin and (R)-Oxyphenonium bromide.
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■
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.
Experimental procedures and characterization data for all
compounds (PDF)
NMR spectra (PDF)
SFC and HPLC traces (PDF)
Computational details and Cartesian coordinates of opti-
mized geometries (PDF)
(3) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
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Chen, R.-Y.; Dhondge, A. P.; Lee, G.-H.; Chen, C. A Chiral
Bipyridyl Alcohol for Catalytic Enantioselective Nozaki–
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G.; Wang, Z.; Yu, X.; Deng, W.; Tang, W. Highly
■
AUTHOR INFORMATION
Corresponding Author
*sbuchwal@mit.edu, *pengliu@pitt.edu
ORCID
Chengxi Li: 0000-0003-3904-0299
Richard Y. Liu: 0000-0003-0951-6487
Luke T. Jesikiewicz: 0000-0002-8020-7006
Yang Yang: 0000-0002-4956-2034
Peng Liu: 0000-0002-8188-632X
Stephen L. Buchwald: 0000-0003-3875-4775
Notes
The authors declare no competing financial interest.
Enantioselective
Rhodium-Catalyzed
Addition
of
■
ACKNOWLEDGMENT
Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of
Escitalopram. Angew. Chem. Int. Ed. 2016, 55, 4527–4531. (f)
Khan, A.; Khan, S.; Khan, I.; Zhao, C.; Mao, Y.; Chen, Y.;
Zhang, Y. J. Enantioselective Construction of Tertiary C-O
Bond via Allylic Substitution of Vinylethylene Carbonates with
Water and Alcohols. J. Am. Chem. Soc. 2017, 139, 10733–
10741. (g) Brauns, M.; Mantel, M.; Schmauck, J.; Guder, M.;
Breugst, M.; Pietruszka, J. Highly Enantioselective Allylation
of Ketones: An Efficient Approach to All Stereoisomers of
Tertiary Homoallylic Alcohols. Chem. Eur. J. 2017, 23, 12136–
12140. (h) Robbins, D. W.; Lee, K.; Silverio, D. L.; Volkov, A.;
Torker, S.; Hoveyda, A. H. Practical and Broadly Applicable
Catalytic Enantioselective Additions of Allyl-B(pin)
Compounds to Ketones and α-Ketoesters. Angew. Chem. Int. Ed.
2016, 55, 9610–9614.
Research reported in this publication was supported by the Na-
tional Institutes of Health (GM122483, GM46059, GM058160-
17S1, GM128779). The content of this communication solely
reflects the research and opinion of the authors and does not
necessarily represent the official views of the NIH. Solvias AG
is acknowledged for a generous gift of SL-J011-1. R.Y.L.
acknowledges Bristol–Myers Squibb for a Fellowship in Syn-
thetic Organic Chemistry. We are grateful to Drs. Scott McCann,
Andy Thomas, and Christine Nguyen for advice on the prepa-
ration of this manuscript. DFT calculations were performed at
the Center for Research Computing at the University of Pitts-
burgh and the Extreme Science and Engineering Discovery En-
vironment (XSEDE) supported by the NSF.
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