Dynamic Kinetic Resolution of Aldehydes by Hydroacylation

Article abstract of DOI:10.1002/anie.201900545

We report a dynamic kinetic resolution (DKR) of chiral 4-pentenals by olefin hydroacylation. A primary amine racemizes the aldehyde substrate via enamine formation and hydrolysis. Then, a cationic rhodium catalyst promotes hydroacylation to generate α,γ-disubstituted cyclopentanones with high enantio- and diastereoselectivities.

Full text of DOI:10.1002/anie.201900545

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Accepted Article
Title: Dynamic Kinetic Resolution of Aldehydes by Hydroacylation
Authors: Zhiwei Chen, Yusuke Aota, Hillary My Ha Nguyen, and Vy
Dong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900545
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10.1002/anie.201900545
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COMMUNICATION
Dynamic Kinetic Resolution of Aldehydes by Hydroacylation
Zhiwei Chen, Yusuke Aota, Hillary M. H. Nguyen, and Vy M. Dong*
Abstract: We report a dynamic kinetic resolution (DKR) of chiral 4-
a) Previous resolutions of chiral aldehydes via hydroacylation
pentenals by olefin hydroacylation. A primary amine racemizes the
aldehyde substrate via enamine formation and hydrolysis. Then, a
O
O
EtS
R1
O
cationic Rh-catalyst promotes hydroacylation to generate α,γ-
disubstituted cyclopentanones with high enantio- and
diastereoselectivities.
Ph
Me
H
H
H
R2
MeO
R1 = H or R2 = H
R
Kinetic Resolution
(James)
Parallel Kinetic Resolution
(Fu)
Kinetic Resolution
(Willis)
By merging epimerization with asymmetric catalysis,
chemists have developed powerful ways to convert racemic
reagents into enantiopure precursors, including those used for
making natural products and medicinal targets.[1] While most
dynamic kinetic resolutions (DKR’s) feature hydrogenation[2a-c] or
acylation,[2d,e] variants that exploit C–C bond formation remain
rare.[3] Olefin hydroacylation is an atom-economical[4] route to
ketones that achieves both C–H bond activation and C–C bond
formation.[5] Herein, we disclose a DKR strategy to prepare α,γ-
disubstituted cyclopentanones by intramolecular hydroacylation.
The first kinetic resolution of an α-chiral aldehyde was
fortuitously discovered by James in 1983. While attempting to
develop an enantioselective decarbonylation, the authors
b) Proposal: Dynamic kinetic resolution via dual catalysis
O
O
R1
R1
Rh(I)
H
kR (fast)
R2
R2
krac
H
x
amine
R1
amine
R1
O
O
Rh(I)
H
observed
that
2-methyl-2-phenylpent-4-enal
underwent
kS (slow)
intramolecular hydroacylation to furnish the corresponding
cyclopentanone in up to 69% ee (Figure 1a).[6a,b] Fu described a
parallel kinetic resolution of racemic 4-alkynals to generate a
R2
R2
H
mixture
of
enantioenriched
cyclopentenones
and
Figure 1. Resolutions of chiral aldehydes by hydroacylation.
cyclobutanones.[6c] Most recently, Willis disclosed an kinetic
resolution of β-thio aldehydes by intermolecular alkyne
hydroacylation.[6d] Aldehydes bearing either α- or β-
stereocenters undergo kinetic resolution. These early studies
contribute to emerging kinetic resolutions that occur by C–H
bond activation,[7] however, the theoretical yield for the
enantiopure ketone products is limited to fifty percent. Despite
the first resolution over three decades ago, the DKR of
aldehydes by hydroacylation had yet to be achieved. In light of
this challenge, we imagined combining aldehyde racemization
with formyl C–H bond functionalization to invent DKR’s via
hydroacylation.[8]
We propose using an amine organocatalyst and a Rh-
catalyst in tandem to produce α,γ-disubstituted cyclopentanones,
a motif not yet accessible by hydroacylation (Figure 1b). Given
that branched aldehydes readily undergo epimerization,[9] we
reasoned a DKR variant of hydroacylation would be feasible.
Since the substrate and product have similar acidities, one
challenge would be to identify a catalyst that would rapidly and
selectively epimerize the aldehyde reagent, in preference to the
ketone product. If successful, this DKR by C–C bond formation
would complement Buchwald’s DKR of cyclopentenones by
asymmetric reduction.[10]
To test our hypothesis, we investigated the cyclization of
aldehyde 1a (Table 1). Our initial studies included various bases,
such as alkoxides and tertiary amines. The use of pyridine A1
and
a
Segphos-derived
ligand
(Segphos
=
5,5’-
bis(diphenylphosphino)-4,4’-bi-1,3-benzodioxole) provided an
early lead (Table 1a), where bulkier phosphine substituents
afforded higher reactivity (L2 and L3), presumably due to
increased dispersive interactions.[11] The combination of L3 and
A1 led to cyclopentanone 2a in 33% yield with high
stereoselectivities (>20:1 dr, 94% ee). Aldehydes are known to
form enamines with primary amines, and this reactivity has been
used by List to achieve a DKR by reductive amination using
aniline A2.[9b] We found that A2 promoted the hydroacylation
with excellent reactivity (96%) but gave only 4:1 dr. However,
aliphatic primary amines provided higher diastereocontrol with
increased steric bulk: n-butylamine (A3) (65%, 10:1 dr),
cyclohexylamine (A4) (50%, 16:1 dr), and 1-adamantylamine
(A5) (73%, 14:1 dr). By using a lower loading of A5 (10 mol%)
and switching the catalyst counter-ion to SbF6, 2a was obtained
in high yield and stereocontrol (94%, >20:1 dr, >99% ee). The
absolute configuration of 2a was determined to be (2R,4R) by X-
ray crystallography.[12] To demonstrate the scalability of this DKR,
we cyclized 1a on a gram-scale and obtained 2a in high yield
and stereocontrol (89%, >20:1 dr, >99% ee).
[*]
Z. Chen, Y. Aota, H. M. H. Nguyen, Prof. Dr. V. M. Dong
Department of Chemistry
University of California, Irvine
Irvine, California 92697 (United States)
E-mail: dongv@uci.edu
Y. Aota
Department of Chemistry
We next examined the cyclization of various α-alkyl
aldehydes (Table 2). These branched aldehydes undergo DKR
with moderate to high reactivity (2b–2k, 52–94%),
diastereocontrol (11–>20:1 dr), and enantiocontrol (82–>99%
Graduate School of Sciences, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
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10.1002/anie.201900545
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ee). This hydroacylation is chemoselective for the terminal olefin
as styrenyl olefins (1g) and internal alkynes (1h), remain intact
to afford cyclopentanones 2g and 2h (11–>20:1 dr, 94–95% ee).
Placing bulkier alkyl substituents on the olefin led to diminished
reactivity and diastereoselectivity (2j, 21%, 1:1 dr, 88% ee).
However, high reactivity and stereoselectivities were restored by
using JoSPOphos (L4) as the chiral ligand (89%, >20:1 dr,
>99% ee). We also prepared a monosubstituted cyclic ketone
(2k, 52%, 82% ee). A substrate containing an internal olefin (1l)
failed to cyclize.
high selectivity (>20:1 dr, >99% ee), albeit with low yield (24%).
Switching to other biaryl ligand scaffolds produced similar results.
Table 2. Hydroacylation Scope with α-Alkyl Aldehydes[a]
O
O
O
[Rh(COD)Cl]2 (4 mol%)
R
R
L3 (8 mol%)
O
O
H
PAr2
PAr2
AgSbF6 (10 mol%)
A5 (10 mol%)
PhMe (0.20 M), 50 °C, 24 h
Me
Me
O
1
2
L3 (Ar = 3,5-tBu2-4-OMePh)
Table 1. Ligand and Amine Evaluation with α-Alkyl Aldehyde 1a[a]
O
O
O
O
Me
S
Bn
8
O
O
O
[Rh(COD)Cl]2 (4 mol%)
ligand (8 mol%)
PMB
PMB
PMB
Me
Me
Me
Me
H
+
2b, 94%
2c, 86%
2d, 94%
2e, 65%[b]
AgBF4 (10 mol%)
A1 (20 mol%)
PhMe (0.20 M), 60 °C, 24 h
>20:1 dr, 96% ee[c]
>20:1 dr, 93% ee
>20:1 dr, 93% ee >20:1 dr, 93% ee
Me
Me
Me
O
O
O
O
1a
2a
epi-2a
Ph
PMB
Ph
a) Ligand evaluation
O
Me
Me
nHex
Me
Me
tBu
OMe
2f, 63%[b]
2g, 69%
>20:1 dr, 94% ee
2h, 68%[b]
2i, 66%
>20:1 dr, >99% ee[c]
11:1 dr, 95% ee
>20:1 dr, >99% ee
O
PAr2
Ar =
O
PAr2
O
O
O
PMB
Me
L2, 21%,
tBu
L3, 33%,
PMB
PMB
O
L1, N.R.
Me
>20:1 dr, 91% ee >20:1 dr, 94% ee
Cy
ꢀꢁ ꢂꢃꢄꢅꢀꢁꢆꢇꢈꢀꢅꢉꢃꢂꢅꢀꢊꢁ
2j, 21%[b], 1:1 dr, 88% ee
89%[d], >20:1 dr, >99% ee
2k, 52%
82% ee
2l, 0%
b) Amine evaluation (with L3)
Me
[a] With 0.10 mmol of 1. Isolated yields are given. Diastereoselectivities were
determined by 1H NMR analysis of the unpurified reaction mixture.
Enantioselectivities (ee’s) were determined by chiral SFC analysis. [b]
Reaction performed at 60 °C. [c] SFC analysis performed with the tertiary
alcohol after treatment with PhMgBr. [d] Reaction performed with L4 at 60 °C.
H2N
OMe
Me
N
Me
A1, 33%,
>20:1 dr, 94% ee
A2, 96%,
4:1 dr, 99% ee[b]
(2R,4R)-2a
Table 3. Hydroacylation Scope with Styrenyl Olefins[a]
O
O
H2N
[Rh(COD)Cl]2 (4 mol%)
O
H2N
PMB
PMB
Ph2P
H2N
Me
L4 (8 mol%)
H
P
Fe
H
tBu
Me
AgSbF6 (10 mol%)
A5 (10 mol%)
PhMe (0.20 M), 60 °C, 24 h
Ar
Ar
A3, 65%,
10:1 dr, 94% ee
A4, 50%,
16:1 dr, 96% ee
A5, 73%, 14:1 dr, 92% ee
94%, >20:1 dr, >99% ee[b]
89%, >20:1 dr, >99% ee[c]
JoSPOphos (L4)
3
4, >20:1 dr
O
O
ꢀꢁ ꢂꢃꢄꢅꢀꢁꢆꢇꢅꢋꢃꢂꢀ ꢇꢌꢀꢁꢈꢂꢄꢁ ꢃ
O
O
PMB
PMB
PMB
PMB
[a] With 0.050 mmol of 1a. Yields and diastereoselectivities were determined
by 1H NMR analysis of the unpurified reaction mixture using triphenylmethane
as an internal standard. Enantioselectivities (ee’s) were determined by chiral
SFC analysis. [b] With 0.10 mmol of 1a. Reaction performed at 50 °C using
AgSbF6 (10 mol%) and 10 mol% of the amine. [c] Isolated yield of 2a (4.6
mmol scale) using 2 mol% [Rh(COD)Cl]2, 4 mol% L3, 10 mol% AgSbF6, and
10 mol% A5 for 48 h. PMB = p-methoxybenzyl. COD = 1,5-cyclooctadiene.
Me
Me
4a, 76%
>99% ee
4b, 90%
95% ee
4c, 80%
>99% ee
4d, 88%
96% ee
O
O
O
O
Aldehydes with styrenyl olefins (e.g. 3a) were slow to react
with ligand L3 (Table 3). To overcome this limitation, we used
amine A5 and ligand L4. This combination enabled the
resolution of chiral aldehydes bearing a range of styrenyl olefins
with excellent stereocontrol (4a–4h, >20:1 dr, 74–>99% ee). The
absolute configuration of 4a is analogous to that of 2a, as
determined by X-ray crystallography.[12a]
PMB
PMB
PMB
PMB
O
O
Cl
O
F
4e, 77%
94% ee
4f, 91%
>99% ee
4g, 83%
96% ee
4h, 53%
74% ee
In contrast to the previous aldehydes, we found that the DKR
of α-aryl aldehydes 5 requires an aniline co-catalyst (Table 4).
Using A5 and L3, 5a transformed into cyclopentanone 6a with
[a] With 0.10 mmol of 3. Isolated yields are given. Diastereoselectivities were
determined by 1H NMR analysis of the unpurified reaction mixture.
Enantioselectivities (ee’s) were determined by chiral SFC analysis. (RP)-1-[(S)-
tert-Butylphosphinoyl]-2-[(S)-1-(diphenylphosphino)ethyl]ferrocene
(L4) is
abbreviated as JoSPOphos.
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In contrast, changing the amine to 2,6-disubstituted anilines A7
and A8 resulted in improved reactivity and diastereocontrol (78–
80%, 13–14:1 dr).[13] Aniline A9, which is more sterically
hindered, provided higher diastereocontrol (16:1 dr) but lower
yield (68%). Using A8, we found that Garphos-derived ligand L5
promoted the formation of 6a in 87% yield with high
Cyclopentanols containing aryl halides (7e–7g) can be accessed
with high stereoselectivities (>20:1:1:1 dr, 98–>99% ee).
Electron-deficient (7g) and electron-rich arenes (7h and 7i) are
tolerated. Cyclopentanols bearing heterocycles (7j) are obtained
with excellent stereocontrol (>20:1:1:1 dr, >99% ee). By merging
DKR
with
desymmetrization,[15]
the
α,β,γ-trisubstituted
stereoselectivities (>20:1 dr, >99% ee) (Garphos
bis(diphenylphosphino)-4,4’,6,6’-tetramethoxybiphenyl).
=
2,2’-
cyclopentanone 9 can be generated in 53% yield as a single
stereoisomer (>20:1:1:1 dr, >99% ee) [Eq. (1)]. This example
illustrates enantioselective construction of three contiguous
stereocenters via a single C–H oxidation.
Table 4. Ligand and Amine Evaluation with α-Aryl Aldehyde 5a[a]
O
Table 5. Hydroacylation Scope with α-Aryl Aldehydes[a]
O
O
[Rh(COD)Cl]2 (4 mol%)
Ph
Ph
Ph
L3 (8 mol%)
H
+
O
OH
Me
L-Selectride〉
(3 equiv)
O
AgSbF6 (10 mol%)
amine (10 mol%)
PhMe (0.20 M), 60 °C, 24 h
[Rh(COD)Cl]2 (4 mol%)
Ar
Ar
Ar
L5 (8 mol%)
H
Me
Me
Me
5a
AgSbF6 (10 mol%)
A8 (10 mol%)
PhMe (0.20 M), 65 °C, 24 h
THF (0.50 M)
4 °C, 16 h
6a
epi-6a
yield
Me
Me
R1
Me
Me
Et
R2
amine
A6
dr
6
7
5
>20:1 dr
>20:1:1:1 dr
NH2
H
Me
Et
5:1
13:1
14:1
16:1
61%
78%
80%
68%
R1
R2
Me
OH
OH
A7
OH
A8
Me
amine
iPr
iPr
A9
Me
Me
Me
7a (87%)
76%, >99% ee
7b (92%)
65%, >99% ee
7c (68%)
48%, 95% ee
OMe
NH2
X
OH
Et
Et
MeO
MeO
PAr2
PAr2
OH
X = Cl 7e (81%), 57%, 99% ee
= Br 7f (74%), 57%, 98% ee
= F 7g (85%), 56%, >99% ee
A8
Me
7d (84%)
51%, 97% ee
Me
87%, >20:1 dr, >99% ee
(with L5 at 65 °C)[b]
OMe
L5 (Ar = 3,5-tBu2-4-OMePh)
MeO
O
S
OH
Me
OH
Me
OH
O
[a] With 0.050 mmol 5a. Yields and diastereoselectivities were determined by
1H NMR analysis of the unpurified reaction mixture using triphenylmethane as
an internal standard. Enantioselectivities (ee’s) were determined by chiral SFC
analysis. [b] Using 0.10 mmol of 5a.
Me
7h (77%)
7i (76%)
51%, 99% ee
7j (83%)
51%, >99% ee
50%, 99% ee
We found that 6a epimerizes on silica and decomposes to
form hydroxyketone 6aa and keto acid 6ab, which we isolated
as the methyl ester (Scheme 1).[12a] This observation is
consistent with those reported by Houminer and others that α-
aryl cyclopentanones undergo oxidation via a hydroperoxide
intermediate.[14] To circumvent this oxidation, we treat the
reaction mixture with L-Selectride® to produce the all-syn
cyclopentanol 7a with high diastereoselectivity (>20:1:1:1 dr)
(Table 5). The absolute configuration of 7a was determined by
X-ray crystallography after derivatization to the corresponding
3,5-dinitrobenzoic ester.[12a]
[a] With 0.10 mmol of 5. 1H NMR yields of 6 are given in parentheses. Isolated
yields over two steps are given of 7. Diastereoselectivities of each step were
determined by 1H NMR analysis of the unpurified reaction mixture.
Enantioselectivities (ee’s) were determined by chiral SFC analysis.
O
O
[Rh(COD)Cl]2 (4 mol%)
PMB
PMB
L3 (8 mol%)
H
(1)
AgSbF6 (10 mol%)
A5 (10 mol%)
PhMe (0.20 M), 60 °C, 44 h
53%, >20:1:1:1 dr, >99% ee
Me
Me Me
Me
8
9
We propose a mechanism involving two catalysts (Scheme
2). The primary amine catalyst condenses with aldehyde 1 to
form an achiral enamine (A) that then undergoes hydrolysis. The
R-enantiomer ((R)-1) undergoes oxidative addition with the Rh-
catalyst to generate the Rh-acyl-hydride B. Subsequent
migratory insertion makes metallacycle C, which undergoes
reductive elimination to afford cyclopentanone 2. When 1a was
subjected to the Rh-catalyst in the absence of amine A5, we
observed hydroacylation with the same diastereo- and
enantiocontrol (>20:1 dr, >99% ee), although in lower yield as
O
O
O
HOO
O2 Ph
HO
Ph
Ph
O
Ph
OH
+
O
Me
6ab
Me
Me
Me
6a
6aa
Scheme 1. Decomposition of 6a.
With this two-step protocol, various cyclopentanols can be
prepared (7a–7j, >20:1:1:1 dr, 95–>99% ee) (Table 5).
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10.1002/anie.201900545
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COMMUNICATION
R2
O
O
HN
R1
R1
R1
H
Rh
Rh
H
insertion
H2O
H2O
Me H
A
B
C
Me
Me
hydroacylation
racemization
O
O
O
R1
R1
R1
oxidative
addition
reductive
elimination
H
H
H
Me
(S)-1
(R)-1
2
Me
Me
Rh
H2N R2
Scheme 2. Amine-catalyzed racemization and Rh-catalyzed hydroacylation
expected (38%) (Scheme 3a). This experiment points to the
aldehyde as being the substrate for hydroacylation, as opposed
to the imine intermediate.[16] In the absence of aldehyde, 2a can
be epimerized. When 2a (>20:1 dr) was subjected to the
standard reaction conditions with L3 and A5, it was recovered
with lower diastereoselectivity (14:1 dr). (Scheme 3b). When
treated with n-butylamine (A3), 2a epimerized more rapidly (5:1
dr). Due to unfavorable steric interactions, enamine formation
with the product should be more challenging with bulky amines.
Moreover, the bulky amine should favor the less substituted
enamine 2ab to avoid allylic strain (Scheme 3c).
O
a)
O
[Rh(COD)Cl]2 (4 mol%)
PMB
PMB
L3 (8 mol%)
D
AgSbF6 (10 mol%),
A5 (10 mol%)
PhMe (0.20 M), 50 °C, 18 h
83%
D
Me
2a-d
Me
1a-d
>99% D
O
O
b)
O
O
PMB
PMB
PMB
PMB
as above
H
D
+
+
1 h, 18%
H
D
kH/kD = 1.1
Me
2a
Me
2a-d
Me
Me
1a
1a-d
Scheme 4. Isotopic labeling and KIE experiments.
O
a)
O
[Rh(COD)Cl]2 (4 mol%)
PMB
PMB
By using tandem catalysis,[18] we have added a dynamic
twist to hydroacylation. The empirical trends we observed for
catalyst choice provides a useful guide for accessing a wide
range of enantiopure cyclopentanones that are relatively
unique.[19] Our study contributes to a growing class of DKR’s that
feature aldehyde racemization.[9] The identification of an efficient
amine-catalyst for racemization will impact future studies that
feature DKR of aldehydes.
L3 (8 mol%)
H
AgSbF6 (10 mol%),
PhMe (0.20 M), 30 °C, 18 h
38%, >20:1 dr, >99% ee
Me
O
Me
O
1a
2a
b)
conditions A:
standard conditions
with L3 and A5 for 24 h
PMB
PMB
or
conditions B: A3 (10 mol%)
PhMe (0.20 M), 50 °C, 18 h
Me
Me
2a (>20:1 dr)
2a + epi-2a
Acknowledgements
conditions A
conditions B
14:1 dr, 97% recovery
5:1 dr, 84% recovery
Funding provided by UC Irvine and the National Institutes of
Health (R35GM127071). Z.C. and H.M.H.N. are grateful for
Allergan Fellowships. We thank Kyle B. Brook and Alexander Y.
Jiu for help with initial studies and characterization data. We
acknowledge Dr. Curtis Moore and Dr. Arnold Rheingold (UC
San Diego) for X-ray crystallographic analysis.
Ad
NH
Ad
N
Ad
NH
c)
PMB
PMB
PMB
Me
Me
Me
2ac
2aa
2ab
Scheme 3. Amine-free hydroacylation and product epimerization.
Conflict of interest
An isotope labeling experiment with 1a-d showed that the
deuterium label is fully incorporated at the γ-position (Scheme
4a). This result is consistent with a highly regioselective olefin
insertion step. We reason that reductive elimination is the
turnover-limiting step. When a 1:1 mixture of 1a and 1a-d was
used for the reaction, no primary kinetic isotope effect (KIE) was
observed (Scheme 4b), which suggests that oxidative addition
and migratory insertion are not turnover-limiting.[17]
The authors declare no conflict of interest.
Keywords: dynamic kinetic resolution • hydroacylation • dual
catalysis • C–H activation • rhodium
[1]
For selected reviews on dynamic kinetic resolution, see: a) V. Bhat, E.
R. Welin, X. Guo, B. M. Stoltz, Chem. Rev. 2017, 117, 4528–4561; b) K.
Nakano, M. Kitamura in Separation of Enantiomers: Synthetic Methods
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10.1002/anie.201900545
Angewandte Chemie International Edition
COMMUNICATION
(Ed. M. Todd), Wiley-VCH: Weinheim, 2014, pp. 161–216; c) O. Verho,
J.-E. Bäckvall, J. Am. Chem. Soc. 2015, 137, 3996–4009; d) O. Pàmies,
J.-E. Bäckvall, Chem. Rev. 2003, 103, 3247–3262.
Hong, Angew. Chem. Int. Ed. 2000, 39, 3070–3072; c) C.-H. Jun, H.
Lee, J.-B. Hong, J. Org. Chem. 1997, 62, 1200–1201
[17] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066–
3072.
[2]
For selected examples using hydrogenation, see: a) K. M. Steward, E.
C. Gentry, J. S. Johnson, J. Am. Chem. Soc. 2012, 134, 7329–7332; b)
D. S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou, X. Zhang, J. Am.
Chem. Soc. 2010, 132, 8909–8911; c) J.-H. Xie, S. Liu, W.-L. Kong,
W.-J. Bai, X.-C. Wang, L.-X. Wang, Q.-L. Zhou, J. Am. Chem. Soc.
2009, 131, 4222–4223. For selected examples using acylation, see: d)
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10.1002/anie.201900545
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Zhiwei Chen, Yusuke Aota, Hillary M. H.
Nguyen, Vy M. Dong*
dynamic kinetic resolution
O
O
R1
R1
H
RNH2 Rh
Page No. – Page No.
R2
Dynamic Kinetic Resolution of
Aldehydes by Hydroacylation
R2
H
Dynamic duo: Racemic α-allyl aldehydes undergo stereoconvergent
hydroacylation to generate α,γ-disubstituted cyclopentanones with high diastereo-
and enantioselectivities. In this dynamic kinetic resolution, a primary amine catalyst
racemizes the aldehyde substrate via enamine formation and hydrolysis, while a
Rh-catalyst promotes cyclization.
This article is protected by copyright. All rights reserved.