ORGANIC CHEMISTRY
Deracemization through photochemicalE/Z
isomerization of enamines
Mouxin Huang^1 †, Long Zhang1,2†, Tianrun Pan^1 , Sanzhong Luo1,2*
Catalytic deracemization ofa-branched aldehydes is a direct strategy to construct enantiopure
a-tertiary carbonyls, which are essential to pharmaceutical applications. Here, we report a
photochemicalE/Zisomerization strategy for the deracemization ofa-branched aldehydes by using
simple aminocatalysts and readily available photosensitizers. A variety of racemica-branched aldehydes
could be directly transformed into either enantiomer with high selectivity. Rapid photodynamicE/Z
isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that
underlie the enantioenrichment. This study presents a distinctive photochemicalE/Zisomerization
strategy for externally tuning enamine catalysis.
C
arbonyl transformations are textbook
chemical reactions, and subjecting them
to asymmetric catalysis can provide
enantiomerically pure products essen-
tial to pharmaceutical applications ( 1 , 2 ).
Most of these methods involve stereogenic
C–C/C–X bond formations featuring enol(ate)-
or enamine-based processes, in which the
geometry of the intermediate and associated
facial selectivity during bond formation dic-
tate the stereoselectivity (Fig. 1A) ( 3 , 4 ). In the
construction of enantiopurea-tertiary carbonyls,
catalytic deracemization is arguably the most
atom-economical strategy ( 5 ). However, this
transformation remains elusive despite tre-
mendous progress in steering stereogenic
carbonyl reactivity more generally ( 6 , 7 ). The
challenges are threefold. First, deracemization
is inherently endergonic with a negative entropy
change. In addition, according to the principle
of microscopic reversibility ( 8 ), the backward
and forward pathways are identical for a given
chiral catalyst cycle. Hence, the degree of enantio-
enrichment of the starting material cannot be
adjusted without exogenous chemical or phys-
ical inputs (Fig. 1A). Recent seminal works by
Bach ( 9 , 10 ) and Knowles and Miller ( 11 ) have
demonstrated that light absorption can supply
the necessary external perturbation to surmount
the thermodynamic and kinetic constraints. Ac-
cordingly, photomediated energy transfer and
electron transfer were found to work effectively in
tandem with chiral catalysts to facilitate enantio-
selective deracemization of allenes or cyclic
ureas, respectively (Fig. 1B). The final challenge
is thata-tertiary carbonyls are easily racemized
through undesired alternative pathways, add-
ing a potentially complex time constraint to
catalytic deracemization strategies ( 12 , 13 ).
Bearing these challenges in mind, we report
a photochemicalE/Zisomerization strategy
for the deracemization ofa-branched alde-
hydes by using simple aminocatalysts and
readily available photosensitizers (Fig. 1C).
Photoisomerization was found to perturb the
E/Zdistribution of the in situ generated
enamine intermediates. This photochemical
strategy together with our previous finding
( 14 , 15 ), that enamine of certain configuration
(EorZ) could be stereospecifically formed
from the corresponding enantiopure aldehyde
with chiral primary amine catalysts such as1a,
makes possible a highly enantioselective dera-
cemization process. Although visible light–
promotedE/Zisomerization of double bonds
has been widely applied in chemical ( 16 ) and
materials science ( 17 ), such a process with a
transient catalytic intermediate in the pursuit
of stereoselective catalysis has not been reported.
Photochemical tuning of enamine intermedi-
ates has been explored in pioneering studies
by MacMillan ( 18 , 19 ) and Melchiorre ( 20 , 21 )
using photoinduced electron transfer, which
greatly expanded the capacity of nucleophilic
enamine catalysis. Our current strategy com-
plements these known processes by harness-
ing theE/Zphotoisomerization of an enamine
double bond.
We first investigated the deracemization of
2-phenylpropionaldehyde2ausing a chiral
primary amine catalyst ( 14 ). Screening of
photocatalysts showed large variations of optical
enrichment outcomes (table S3), and Ir(ppy) 3
was identified as the optimal one. The addi-
tion of a weak acid such as benzoic acid could
significantly improve the enantioselectivity
(table S1, entry 2), which is consistent with
our previous finding on stereoselective enamine
protonation ( 15 ). With Ir(ppy) 3 , benzoic acid,
and primary-tertiary amine (S)-1a/HNTf 2 , the
deracemization proceeded rapidly in 1 hour to
afford (R)-2ain 77% yield (73% isolated yield)
and 94% enantiomeric excess (ee). Control
experiments indicated that aminocatalyst,
photocatalyst, and light irradiation were all
essential, and their absence led to no enrich-
ment or rather poor enantioselectivity (tableS1, entry 1 versus entries 3 and 4). The minor yet
noticeable enantioselectivity observed under
thermodynamic conditions (table S1, entries 3
and 4) could be accounted for by considering
kinetic resolution through selective trapping
of aldehyde by aminocatalyst (~10%) (figs. S12
and S13). A small extent of homo-coupling
side-reaction (~3%), (fig. S11) was also observed,
which may explain the loss of aldehyde during
deracemization. We next examined the re-
actions with optically pure aldehydes. Both
(R)- and (S)-2aled to (R)-selectivity with com-
parable enantioselectivity (table S1, entries 7
and 8). By contrast, racemization was observed
without light irradiation in these cases. This
observation strongly suggests that light sup-
plies the major driving force for the current
deracemization reaction. Addition ofE-stilbene
or the presence of ambient oxygen, well-known
energy transfer quenchers, completely inhibited
the deracemization (table S1, entries 5 and 6),
which is a strong indication of the energy trans-
fer mechanism.
The scope of this deracemization was next
examined (Fig. 2A). 2-Arylpropanals bearing
alkyl or aryl groups on the aromatic ring—
such as Me,i-Bu, and Ph (2a-e)—gave high
enantioselectivities. A 5-mmol-scale reaction
of2awas also successful. The enantioen-
riched aldehydes can be isolated by simply
filtering through a pad of silica gel without ee
erosion (table S6 and figs. S2 and S3). Both
electron-deficient substituents—such as halogen,
trifluoromethyl, and ester (2f-m)—and electron-
donating groups—such as alkoxyl, aryloxy, and
methylenedioxy (2n-s)—gave consistently high
enantioselectivity. Functional groups such as
methylthio (2t) and dimethylamino (2u) also
worked well. When aldehyde and ketone func-
tionality coexisted in the same compound,
deracemization would occur preferentially at
thea-carbon of the aldehyde, whereas ketone
moiety remained unchanged (2v). Expanding
the aromatic ring or increasing the size of the
branched chain led to a slight reduction of
enantioselectivity (2w-aa). The deracemiza-
tioncouldalsobeappliedtocomplexarylal-
dehydes bearing functional groups such as
amides and alkynes (2aband2ac) and distinct
chiral centers as in steroids and amino acids
(2adand2ae).a-Heteroaromatic groups—such
as thiophene, dibenzofuran, and pyridine—
were compatible with good to excellent enantio-
selectivity (2af-ah). Aldehydes other than 2-
arylacetaldehyde showed low enantioenrichment
(2ai), which we rationalized on the basis of
the need for an aryl alkene chromophore in the
enamine to achieve effective photoisomerization
( 22 ).a-Branched ketones were also examined
but unfortunately showed no enantioenrich-
ment (2ajand2ak). We executed simple oxi-
dation of selected products to obtain nonsteroidal
anti-inflammatory drug compounds without
loss of enantiopurity. The aldehydes could alsoSCIENCEscience.org 25 FEBRUARY 2022•VOL 375 ISSUE 6583 869
(^1) Center of Basic Molecular Science, Department of Chemistry,
Tsinghua University, Beijing 100084, China.^2 Haihe Laboratory of
Sustainable Chemical Transformations, Tianjin 300192, China.
*Corresponding author. Email: [email protected]
These authors contributed equally to this work.
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