Catalytic asymmetric acetalization of carboxylic acids for access to chiral phthalidyl ester prodrugs

Article abstract of DOI:10.1038/s41467-019-09445-x

Carboxylic acids are common moieties in medicines. They can be converted to phthalidyl esters as prodrugs. Unfortunately, phthalidyl esters are now mostly prepared in racemic forms. This is not desirable because the two enantiomers of phthalidyl esters likely have different pharmacological effects. Here we address the synthetic challenges in enantioselective modification of carboxylic acids via asymmetric acetalizations. The key reaction step involves asymmetric addition of a carboxylic acid to the catalyst-bound intermediate. This addition step enantioselectively constructs a chiral acetal unit that lead to optically enriched phthalidyl esters. A broad range of carboxylic acids react effectively under mild and transition metal-free conditions. Preliminary bioactivity studies show that the two enantiomers of chlorambucil phthalidyl esters exhibit different anti-cancer activities to inhibit the growth of Hela cells. Our catalytic strategy of asymmetric acetalizations of carboxylic acids shall benefit future development of chiral phthalidyl ester prodrugs and related molecules.

Full text of DOI:10.1038/s41467-019-09445-x

A RT ICLE
https://doi.org/10.1038/s41467-019-09445-x
OPEN
Cat a ly t ic a s y mm e tr i c ac et aliz a tio n of ca rb oxy lic
a c id s f o r a cc es s to ch ir al ph t ha lidy l es t er pr o dr ugs
1
1
2
2
1
1
1
Yi n gg u o Li u , Q iao C he n , C he ng l i Mo u , L ut ai Pa n , Xi ao yong D uan , Xi n gk uan Ch en , H on gzh ong Chen ,
1
1
3
1,3
Ya n li Zh ao , Yu np en g L u , Zh i ch ao J i n & Yo nggu i R obi n Ch i
C arb o xy l ic a cid s a re c om m on m oi e ti e s in m e di cin e s . T h ey can b e co n ve rt e d t o p ht h alid yl
e st e rs a s p ro d r ug s . Un fort un at e ly, ph th al idy l e s te r s ar e n ow mo s tl y p re p are d in r ace mic
f or ms. Th i s i s n o t d es i rab le be c au s e t he t wo e na nt iom er s o f p ht h alid yl e st er s lik ely h av e
d iff e r e nt p h ar m aco l o g ic al e ffe c ts . H e re we ad dre ss th e sy nt h et ic ch alle n g es in e nan t io se -
le ct ive m o di fica ti on of c arb oxy lic ac id s vi a as ym m e t ri c ace t aliz at io n s. T h e ke y r eac ti on st e p
in vo lve s a sy m me tr ic ad dit io n of a c arb oxy lic ac id t o t h e cat al yst -b o un d in t er me di at e. T h is
ad d iti o n s te p e n an ti o s e le c ti ve ly c ons t ru ct s a c hir al ac et al u ni t t h at le ad t o o pt ic ally e nr ich e d
p ht h al i d yl e s te rs . A b r oad ra ng e of c arb oxy lic ac id s re ac t e ff ect iv e ly u nd e r mi ld an d t ra ns it io n
me t al- fr e e co n d it io n s . Pr e lim in ary bi oac t ivit y s tu di e s sh o w t h at t h e t wo e nan t io me rs o f
ch lo ra mb u c il p h th al i dy l e s te r s e xh ibi t di ffe re n t an ti -ca n cer act iv it ie s t o in h ibi t t h e g r ow t h o f
He la ce l ls . Ou r ca ta ly tic s tr at e g y of as ym m e t ri c ac e ta liz at io n s o f car b ox yli c aci ds sh all b en e fit
f ut ur e d e ve l o p me n t of c hir al ph th al idy l e s te r pr od rug s an d r elat e d mo le cu les .
1
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
2
3
School of Pharmacy, Guiyang University of Chinese Medicine, Huaxi District, Guiyang 550025, China. Laboratory Breeding Base of Green Pesticide and
Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang
50025, China. Correspondence and requests for materials should be addressed to L.P. (email: ltpan@sina.cn) or to Y.R.C. (email: robinchi@ntu.edu.sg)
5
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(2 0 1 9) 1 0 : 1 67 5 | h t t p s :/ /d o i . o r g /1 0 . 1 0 3 8 /s 4 1 4 67 - 0 1 9- 0 9 4 4 5- x | w ww . na tu r e . c o m /n atu r e c o m mu n i ca ti o n s
1

A R T I C L E
N AT URE CO M MU N ICAT IO N S | ht t ps: //doi .or g /1 0 .10 38/s 41 467 - 0 19- 0944 5 -x
hemical modification on medicinally significant natural chemotherapy drug. Our results show that the (R)-enantiomer of
1
–5
products or drug molecules
develop chemical entities and prodrugs for improving growth of Hela cells than the corresponding (S)-enantiomer,
drug performance or introducing alternative clinical applica- racemic mixture and the unmodified chlorambucil. With our
is a proven strategy to the phthalidyl ester derivative have better activities to inhibit the
C
6
–8
tions . Approximately one out of five chemical entity approvals catalytic approach we achieve enantioselective addition of car-
9
,10
by FDA are prodrugs in recent three years . Carboxylic acids boxylic acid to catalytically generated NHC-bound intermediates.
are among the most common moieties in pharmaceuticals. They Given the wide presence of carboxylic acid moieties in bioactive
are typically converted to the corresponding esters for better drug molecules, we expect our enantioselective approach for phthalidyl
efficacy and/or lower side effects . Among the different types of ester synthesis to bring significant values for both discovery and
esters, phthalidyl esters as promoieties were found with manufacturing of better pharmaceuticals.
impressive success12 (Fig. 1a). Representative examples of
1
1
phthalidyl ester prodrugs include talosalate, talniflumate, talam-
Results
1
3–15
picilin, and talmetacin
. These phthalidyl esters contain an
Condition optimization. We chose aspirin (acetylsalicylic acid,
acetal moiety with a stereogenic carbon center that is difficult to
be installed enantioselectively (Fig. 1b). To date, phthalidyl esters
are routinely prepared via reactions of carboxylic acids with 3-
1
) as a model carboxylic acid to react with o-phthalaldehyde (2)
in searching for suitable NHC catalysts and conditions (Table 1).
Both aspirin and the corresponding phthalidyl ester (talosalate)
are commercial drugs for several decades. Key results from
extensive optimizations (see Supplementary Table 1, 2 and 3) are
shown in Table 1. A typical reaction was performed with azolium
1
6
bromophthalides (Fig. 1b) . This method is efficient but unfor-
tunately has no controls over the stereoselectivity for the newly
created chiral center. It is challenging to directly modify car-
boxylic acid and related heteroatom functional groups in an
2
8
salt as an NHC pre-catalyst, quinone as an oxidant , and K CO
2
3
enantioselective manner to form chiral acetal moieties and their
as the base. When N-mesityl substituted triazolium salt A29 was
analogs1
7–19
. Thus, the phthalidyl esters are afforded as a racemic
used as the NHC pre-catalyst, the reaction carried out in CH Cl2
2
mixture of two enantiomers. Related efforts for enantioselective
synthesis of phthalidyl esters also remain unsuccessful. The lim-
ited examples via kinetic resolutions used carboxylic anhydrides
as the substrates and gave poor to moderate enantioselectivities
at room temperature with LiCl as an additive gave desired
phthalidyl ester product 3 in 66% yield and encouraging 60:40 er
value (entry 1). Replacing the NHC pre-catalyst A with N-
trichlorophenyl substituted triazolium B led to product 3 with
improvements on both yield and er value (84% yield, 77:23 er;
entry 2). Encouraged by this improvement, we modified the pre-
catalyst B to obtain a pre-catalyst C, the congener earlier reported
by Yamada . Changing the pre-catalyst to C resulted in a further
increase on er value (85:15, entry 3). Additional optimizations
were then performed with C as a pre-catalyst. Replacing CH Cl2
with CHCl as the solvent improved the er of 3 to 90:10 (entry 4).
3
0
2
0
with narrow substrate scopes .
Recent studies have further shown that such prodrugs exhibit
medicinal applications. For example, talniflumate, an anti-
inflammatory phthalidyl ester drug sold on the market for over
thirty years, has extended its use in treatment of rheumatoid
arthritis to cystic fibrosis, chronic obstructive pulmonary dis-
ease (COPD) and asthma, and is now identified as a novel
3
1
2
3
inhibitor that improves responsiveness of pancreatic tumors to
Decreasing the reaction temperature to −20 °C led to product 3
with 89% yield and 95:5 er (entry 5). The presence of NHC pre-
catalyst was essential for this reaction (entry 6). The use of LiCl as
gefitinib2
1–24
. In these cases, phthalidyl esters were used in
racemic form while FDA guidelines and policies have required
that each enantiomer shall be meticulously studied in phar-
3
2–35
an additive
offered a small while consistent increase on
2
5,26
macology and toxicology before reaching the market
. It’s
product er value (entry 7). The quinone oxidant could be replaced
by MnO with reaction yield and er values remained (entry 8).
worthy to note that chiral phthalidyl esters are also found in
2
bioactive natural products isolated from the marine plants, such
2
7
as luteorosin and macfarlandin A . Unfortunately, efficient
methods for asymmetric access to optically enriched phthalidyl Substrate scope. With an optimized set of conditions in hand, we
esters are not available. evaluated the generality of our reactions (Fig. 2). We first studied
Here we disclose a highly enantioselective organic catalytic aryl carboxylic acids (4–21). Various substituents (such as halo-
strategy for carboxylic acid functionalization and efficient access gen and amine moieties) or substitution patterns for benzoic acid
to optically enriched phthalidyl esters (Fig. 1c). Our approach were all well tolerated (4–14). Multiple substituents can be pre-
involves an N-heterocylcic carbene (NHC)-catalyzed activation of sent on the benzoic acid (15, 16). The use of sterically bulky aryl
a phthalaldehyde that subsequently reacts with a carboxylic acid carboxylic acid could typically give higher product er values (e.g.,
to form phthalidyl ester products. The main pathway involves a 16; 97:3 er). Hetero aryl carboxylic acids worked effectively (19).
dynamic kinetic resolution process (Fig. 1c). Oxidation of the one The absolute configurations of our catalytic reaction products
aldehyde moiety-derived Breslow intermediate generates azolium were confirmed based on X-ray structures of ferrocenecarboxylic
ester intermediate I. An addition of carboxylic acid to another acid (20) and para-iodobenzoic acid (21).
aldehyde moiety of chiral NHC-bound intermediate I affords
We next evaluated aliphatic acids (22–44) (Fig. 3). Notably,
diastereomeric intermediate II and III. Intermediate III pre- aliphatic acids are widely present in small molecule pharmaceu-
ferentially undergoes the intermolecular annulation to give chiral ticals, peptides and proteins. They are increasingly recognized as
36
phthalidyl esters with high enantiomeric ratio. The reaction signaling molecules and hold significant therapeutic potentials .
enantioselectivity is controlled by the NHC catalyst. In our We were very delighted to find that higher enantioselectivities
approach the operational condition is mild, and no transition were obtained with aliphatic acids, when compared with aryl
metals are involved. A broad range of substrates and functional carboxylic acids. For example, when acetic acid is the substrate
groups are well tolerated. Both aryl and aliphatic carboxylic acids (22), the corresponding phthalidyl ester was obtained with 82%
bearing various substituents work effectively. Several natural yield and 97:3 er. The length of the alkyl chain in the acids has
products and drug molecules (e.g., valproic acid, chlorambucil, little influence on the reaction yield and er values (22–26).
and naproxen) bearing carboxylic acid moieties can be enantio- Primary (22–32), secondary (33–40), and tertiary (41–44) alkyl
selectively modified using this approach. We also performed carboxylic acids all worked well to give the corresponding
preliminary evaluations on the bioactivities of the phthalidyl ester products with excellent enantioselectivities. For cyclic (34–37, 40,
derivatives of chlorambucil, an anti-cancer agent and and 44), heterocyclic (38, 39, 42), and bridging (43) alkyl acids,
2
N
A
T
U
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E
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A
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x
A
R
T
I
C
L
E
a Acetal moietyꢀcontaining phthalidyl esters as prodrugs (marketed as racemates)
O
O
O
O
O
O
O
O
O
O
O
N
NH
R
O
OAc
Talniflumate
analgesic)
Talosalate
(
(
antiꢀinflammatory)
Phthalidyl ester
O
CF3
Cl
O
O
O
O
N
O
O
O
O
N
HN
O
H N
O
2
S
Talmetacin
analgesic)
Talampicillin
antibacterial)
(
O
(
b Asymmetric acetalization and phthalidyl ester synthesis is challenging
O
OH
O
O
Widely present
Drug
O
O
Drug
OH
Asymmetric synthesis
challenging
O
Numerous drugs
Phthalidyl ester prodrugs
contain carboxylic acid unit (better pharmacological effect)
Acetal moiety
O
O
O
Previous methods
O
O
O
Racemic synthesis
R
OH + Br
enantioselectivity control difficult
R
O
Not desired for prodrugs
Carboxylic
acids
(
±)ꢀphthalidyl ester
racemate
c NHCꢀcatalyzed enantioselective acetalization and chrial phthalidyl ester synthesis (This work)
O
This work
enantioselective strategy
N
N
Cl
N
O
O
O
O
O
Cl
Cl
*
R
O
Br
+
1–10 mol% NHC cat.
R
OH
O
Up to 99:1er
Oxidative condition
Carboxylic
acids
♦
Carboxylic acid modification > 60 examples; gram scale
♦
Asymmtric acetalization
NHC
[O]
–
NHC
♦
Optically enriched phthalidyl esters & prodrugs
NHC+
NHC+
NHC+
O
O
O
O–
O–
O
RCOO–
RCOO–
RCOO
Intermediate II
RCOO
Intermediate III
Intermediate I
Fig. 1 P ht ha l id y l e st e r pr o dr ug s an d sy nt he t i c me t hods . a Ac et a l moie t y-c ont ai ning pht ha lidy l e st e rs as pr odrug s (mar k e ted as ra ce ma t es) b Asy mmet ri c
a c et al iz a t ion a nd ph t ha l idyl e st e r sy nt he si s i s ch al l en gi ng . c N HC-c atal yz e d e nant i ose le ct iv e ac e t ali z at ion and c hri al pht al idyl e st e r syn th e sis ( t hi s wo rk)
the ring size and steric hindrance have little influence on the demonstrated that gram scale of acid 32 could be effectively
reaction outcomes. Unsaturated carboxylic acids are effective transformed to the corresponding ester with 97:3 er by using 1
substrates as well (45–48). Our catalytic reactions are mol% of NHC catalyst. However, when we tried stronger acids,
amenable for scalable synthesis with low catalyst loadings. We such as trifluoracetic acid, the reaction became messy and no
N A TU RE C OMM U N IC AT I ON S |
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3

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R
T
I
C
L
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N
A
T
U
R
E
C
O
M
M
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C
A
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Table 1 Condition optimization
Entry
condition
A , CH Cl
Cl
Cl
Isolated yield(%)
e.r.
1
2
2
, RT
, RT
66
84
92
91
89
n. r.
85
83
60: 40
7 7 :2 3
85 :1 5
90: 10
95 :5
—
2
3
4
5
6
7
8
B , CH
C, CH
2
2
2
2
, RT
C, CH Cl
C, CH Cl
3
, RT
, −2 0 °C
3
W it h out N HC
As e nt r y 5 , w/ o Li Cl ad di t iv e
As e nt r y 5 , e x ce pt M nO
93 :7
94: 6
2
as
ox i dan t
Re
a
c
t
io
n
c
o
n
di
t
i
on
s
: 1
(0
.
1
mm
o
l)
, 2 (0. 15 m mo l ), s ol ve nt (2 m L), r t , 12 h. Y ie l d s de t e r mi ne d by i sol a ti on er de t e r mi ne d by HP L , n.r. no r e ac ti o n
O
O
O
0
.1 equiv. NHC C
O
O
OH
1equiv. quinone
R
+
O
O
R
0
.6 equiv. K CO , 0.5 equiv. LiCl
2 3
CHCl (2.0 mL), overnight
3
X = F, 4, 88%, 95:5 er
CO H
CO H
CO H
CO H
2
CO H
2
2
2
2
CH , 5, 72%, 94:6 er
3
Ph
C(CH ) , 6, 82%, 90:10 er
3
3
N(CH ) , 7, 75%, 94:6 er
3
2
b
CN, 8, 90%, 92:8 er
Cl, 9, 81%, 93:7 er
11, 90%, 95:5 er 12, 91%, 89:11 er 13, 94%, 92:8 er
14, 82%, 92:8 er
X
Ph, 10, 77%, 96:4 er
Me
CO2H
CO H
O
O
2
CO H
CO H
2
2
CO H
2
O
Me
Me
15, 79%, 94:6 er
16, 69%, 97:3 er
17, 58%, 91:9 era
18, 66%, 93:7 era
19, 64%, 93:7 era
O
O
O
I
O
(R)
O (R)
O
Fe
O
O
20, 88%, 97:3 er
21,68%, 91:9 er
Fig. 2 S c ope of a r oma t i c ac i ds. Re a ct i on co ndi t io ns: ar o mat i c ac i d (0 . 1 mmol ), o-pht h alalde hyde (0 . 15 mmol ), 0 .1 e quiv . N H C C, 1 e quiv . qui none , 0. 6 eq u iv.
a
b
K
2
CO
3
, 0. 5 e qui v. L iC l, CH Cl
3
(
2
m
L
)
,
r
t
,
1
2
h
.
Y
i
e
l
d
s
d
e
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e
d
b
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l
a
t
i
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n
.
e
r
d
e
t
e
r
m
i
n
e
d
b
y
H
P
L
C
.
u
n
d
e
r
−
3
0
°
C
.
t
o
l
u
e
n
e
a
s
s
o
l
v
e
n
t
desired product was obtained (see Supplementary Fig. 187). The
Substituted phthaldehydes tested here all reacted effectively to
main reasons likely include lower nucleophilicity of the give the corresponding ester products with excellent er values and
trifluoracetic anion, and the poor stabilities of the intermediates good yields (49–52). Regioselectivity studies of unsymmetrical
resulted from reactions between trifluoracetic anion and the dialdehydes were investigated (Fig. 4b 52a:52b = 2.2:1, 95:5 er),
dialdehyde substrates.
The addition of carboxylate to aldehyde favors the sterically less
4
N AT U R E CO M MU NI C A TI O N S |
( 2 0 1 9 ) 1 0 : 1 67 5 | h tt p s : / /d o i . o r g /1 0 . 1 0 3 8/ s 41 4 67 - 0 1 9- 0 94 4 5 - x | w ww . na tu r e . c o m /n atu r e c o m m u n ic a tio n s

NA TUR E COMM UNICAT IO NS | ht t ps ://doi .or g / 10 .1 0 38/ s 41 46 7 -019- 0 944 5 -x
A R T I C L E
O
O
O
0
1
.1 equiv. NHC C
equiv. quinone
O
O
+
R
OH
O
R
O
0
.6 equiv. K CO , 0.5 equiv. LiCl
2 3
CHCl (2.0 mL), overnight
R = alkyl group
3
CO H
CO2H
CH3
R= H, 22 82%, 97:3 er
CH3, 23, 90%, 95:5 er
2
Ph
CO H
2
CO H
2
C H , 24, 95%, 97:3 er
2
5
H C
CH3
3
H C
3
CH3
O
R
C H , 25, 68%, 98:2 er
3 7
2
7, 55%, 97:3 er
28, 76%, 98:2 er
29, 96%, 94:6 er
C H , 26, 56%, 98:2 er
4
9
CH O H
CO2H
2
2
CO H
CO H
2
Br
CO H
2
2
H C
CH3
3
3
2, 85%, 97:3 erb
NH
(1.48 g, with 1% catalyst loading)
3
3, 78%, 97:3 er
34, 90%, 95:5 er
Cl
3
0, 92%, 97:3 er 31, 68%, 95:5 era
CO H
HO C
2
CO H
2
CO H
2
CO H
2
2
Fmoc
N
N
FmocꢀProꢀOH
Fmoc
35, 80%, 97:3 er
36, 91%, 95:5 er
37, 90%, 95:5 er
38, 80%, >13:1 dra
39, 86%, 98:2 er
CO H
2
CO H
HO C
CO H
2
CO H
2
2
2
O
H C
CH3
H C
3
3
CH3
O
NHBoc
H C
3
4
1, 66%,97:3 er
4
0, 80%, >30:1 dra
42, 75%, 94:6 er
43, 82%, 97:3 er
44, 70%, 91:9 era
H3C
R
CO H
2
CO H
R = CH , 45, 91%, 92:8 er
R = H, 47, 75%, 95:5 er
2
3
R
C H , 46, 65%, 97:3 er
CH , 48, 78%, 97:3 er
6
5
3
2
3
a
b
0
3
.5 eq ui v. L iC l, CHCl ( 2 mL) , r t , 1 2 h. Yi e l ds de t e r min ed by i sol at i on. e r de t e rmi ned by H P LC , unde r −30 ° C. unde r −10 ° C
a
O
O
O
O
O
O
O
O
O
O
O
O
O
Br
Br
Br
O
O
O
49, 82%, 97:3 er
50, 79%, 96:4 er
51, 78%, 98:2 er
b
OMe
MeO
OMe
O
O
O
CO H
OMe
2
OMe
O
O
O
O
MeO
0.1 equiv. NHC C
equiv. quinone, –20 °C
O
1
O
O
0.6 equiv. K CO , 0.5 equiv. LiCl
2 3
CHCl3 (2.0 mL), overnight
Br
Br
Br
5
2a, 59%, 95:5 er
5
2b, 27%, 95:5 er
confirmed by Xꢀray
Fig. 4 S c ope of di a ld eh y de s an d r e gi os el ect i v i ty st u dy. a su bst i t ut e d al de hyde s. b unsy mme t ic dia lde hyd e (r e gi ose le c t iv it y st udy)
N
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N AT URE CO M MU N ICAT IO N S | ht t ps: //doi .or g /1 0 .10 38/s 41 467 - 0 19- 0944 5 -x
congested site of the dialdehydes. For the reaction between diastereoselectivities and identical chirality for the newly formed
aldehyde and NHC, (to eventually form azolium ester inter- center. Relatively sophisticated natural products and drugs
mediate under oxidative condition), the carbene addition step is (abietic acid 55, dehydrocholic acid 56) with multiple fused rings
not the rate-determine step and thus the substituents have little and chiral centers are well tolerated in our condition. In addition
influence. These results (Figs. 2, 3, and 4) clearly illustrate the to talosalate (3), we have also demonstrated that our methods can
broad applicability of our strategy for enantioselective modifica- be used to prepare optically enriched versions of several
tion of various carboxylic acids.
phthalidyl ester prodrugs sold on the market, including
To further demonstrate the generality and utility of our talmetacin, talniflumate, and talampicillin (60–62) (Fig. 5b).
strategy, several natural products bearing carboxylic acid moieties
(Fig. 5) were modified under our standard catalytic condition
(
53–55). Multiple commercially used drug molecules bearing Bioevaluation. It is well established that the two enantiomers of a
3
7
carboxylic acid moieties were also modified to give the molecule can have different pharmacological effects . Chlor-
corresponding ester products (56–59, 63). In all cases, the ambucil is an anti-cancer drug with applications mainly in
reaction worked effectively. The newly created chiral center chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma (HL),
3
8,39
during phthalidyl ester formation is well-controlled by the NHC and non-Hodgkin lymphoma (NHL)
. We performed pre-
catalyst. The chiral centers present in the natural products liminary bioactivity studies using the two phthalidyl ester enan-
and drugs have nearly no influence over the stereochemistry tiomers of Chlorambucil (Fig. 5c). Our results show that at the
during the catalytic reaction. For example, the use of drug R-57 concentration of 100 μg/mL (See Supplementary Fig. 188). The
and S-57 under otherwise identical catalytic conditions both (R)-enantiomer (R-63, >99:1 er, IC : 53.6 mg/mL) phthalidyl
50
give the corresponding ester products with exceptional ester is more effective to inhibit Hela cells than the corresponding
a
CO H
2
CO H
Ph
CO H
2
2
H C
3
CO H
2
Sorbic acid
3, 75%, 95:5
(R)ꢀHydratropic acid
O
H C
CH3
Valproic acid
(against epilepsy)
8, 79%, 98:2
54, 76% >20:1 dra
3
5
CO H
2
(
R)ꢀNaproxen
CO H
2
O
H
b
H
H
R-57, 87%, >20:1 dr
5
CO H
CO H
2
2
H
H
O
N
O
Abietic acid
O
Nicotinamide
(vitamine)
59, 62%, 89:11
(
S)ꢀNaproxen
5, 64%, >20:1 dra
Dehydrocholic acid
b
5
6, 72%, >20:1 dra
S-57, 82%, >20:1 dr
5
b
O
O
O
O
O
N
O
O
Cl
O
O
O
O
N
NH
3
HN
O
O
O
Cl
N
NH
Talniflumate
analgesic)
S
O
(
Talampicillin
antibacterial)
2, 58%, 6:1 dr
6
1, 96%, 95:5
Talmetacin
(analgesic)
(
6
O
c
CF3
60, 80%, 98:2
c Cl
Chlorambucil
Racꢀ63
Rꢀ63
1
50
00
50
0
CO H
N
2
O
O
Cl
Chlorambucil
antiꢀtumor)
Sꢀ63
1
(
Cl
O
N
N
O
O
Cl
Cl
Rꢀ63, 87%, >99:1
O
O
O
1
10
Concentration mg/mL
100
Cl
S-63, 90%, 3:97
Fig. 5 Na t ur a l pr o duc ts a nd me di ci na l mol e cul es. a N at ur a l pr od uc t s modifie d usi ng our appr oac h. b M ark e t e d pr odrug s syn th e siz e d vi a our a pp ro ach .
Rea c t i o n c on di ti on : a c id ( 0.1 mmol ), o- pht ha la l dehy de (0 .1 5 mmol ), 0 .1 e quiv . N H C C, 1 e quiv . qui none , 0 .6 e quiv . K CO , 0 .5 e quiv . L iCl, CH Cl ( 2 mL) , rt ,
2 h . d r de t er mi ne d by H N MR; dr de t e r min ed by H PL C. w it h ac e t one as sol ve nt , yi e ld f or 2 st e ps; . c B ioeva luat i on of c hir al pht ha lidy l e s t er
p ro d r ugs a ga in st t he gr owt h of H el a ce l l s ( n = 3 bi ol og ic al r e pl ica t e s, M e an ± SD), Rac -63(R-63:S- 63 = 1: 1), I C f or Chlo rambu ci l: 15 7 . 0 mg / mL; Ra c-63:
2
3
3
a
1
b
c
1
5
0
83 .6 mg / mL ; R- 63: 5 3.6 mg / mL, S- 63: 91 .7 mg / mL. S our c e da t a ar e pr ovid ed as a So urc e D at a file
6
N
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NA TUR E COMM UNICAT IO NS | ht t ps ://doi .or g / 10 .1 0 38/ s 41 46 7 -019- 0 944 5 -x
A R T I C L E
(
6
S)-enantiomer (S-63, 3:97 er, IC : 83.6 mg/mL), racemate (Rac- References
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In summary, we have addressed the challenges in enantioselective
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1
1
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Received: 5 December 2018 Accepted: 12 March 2019
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7

A R T I C L E
N AT URE CO M MU N ICAT IO N S | ht t ps: //doi .or g /1 0 .10 38/s 41 467 - 0 19- 0944 5 -x
dition optimizations and substrate scope studies. H.C., Y.Z., L.P. contributed in discus-
sion, design, and experimentations regarding bioactivity studies. Y.Lu. discussed about
the reaction mechanism. Y.R.C. conceptualized and directed the project and drafted the
manuscript with assistance from all co-authors. All authors contributed to discussions.
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019-09445-x.
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Competing interests: The authors declare no competing interests.
Reprints and permission information is available online at http://npg.nature.com/
reprintsandpermissions/
Journal peer review information: Nature Communications thanks Jeffrey Bode and the
other anonymous reviewer(s) for their contribution to the peer review of this work.
4
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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
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(
1976).
Acknowledgements
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
We acknowledge financial support by the Singapore National Research Foundation
NRF-NRFI2016-06), the Ministry of Education of Singapore (MOE2013-T2-2-003;
(
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
MOE2016-T2-1-032; RG108/16), A*STAR Individual Research Grant (A1783c0008),
Nanyang Research Award Grant, Tier 1 grants RG8/15 and RG116/15, and Nanyang
Technological University; Guizhou Province First-Class Disciplines Project (Yiliu Xueke
Jianshe Xiangmu)-GNYL(2017)008, Guiyang College of Traditional Chinese Medicine,
China; National Natural Science Foundation of China (No. 21772029, 21472028),
National Key Technologies R&D Program (No. 2014BAD23B01), “Thousand Talent
Plan”, The 10 Talent Plan (Shicengci) of Guizhou Province, and Guizhou University.
Author contributions
Y.Liu. conducted most of the experiments. Q.C. Conducted scope studies on some of the
alkyl acids. C.M., L.P., X.D., X.C. and Z.J. conducted some experiments regarding con-
© The Author(s) 2019
8
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