Phase-transfer catalyzed enantioselective α-alkylation of α-acyloxymalonates: Construction of chiral α-hydroxy quaternary stereogenic centers

Article abstract of DOI:10.1039/c6ra15121c

The enantioselective synthesis of α-acyloxy-α-alkylmalonates was developed as an efficient method for producing chiral α-tertiary alcohols, which are potentially valuable intermediates in the synthesis of natural products and pharmaceuticals. The efficient enantioselective α-alkylation of diphenylmethyl tert-butyl α-acyloxymalonates was accomplished via phase-transfer catalysis in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide to afford the corresponding α-acyloxy-α-alkylmalonates at high chemical (up to 99%) and optical (up to 93% ee) yields, which could be readily converted to versatile chiral intermediates with a chiral α-tertiary alcohol group.

Full text of DOI:10.1039/c6ra15121c

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Phase-transfer catalyzed enantioselective a-
alkylation of a-acyloxymalonates: construction of
chiral a-hydroxy quaternary stereogenic centers†
Cite this: RSC Adv., 2016, 6, 77427
Min Woo Ha,a Sujee Choi,a Seek Kim,a Jun Young Lee,a Jae Kyun Lee,b Jeeyeon Lee,a
Received 10th June 2016
Accepted 3rd August 2016
a
a
*
*
Suckchang Hong and Hyeung-geun Park
DOI: 10.1039/c6ra15121c
www.rsc.org/advances
The enantioselective synthesis of a-acyloxy-a-alkylmalonates was ammonium salts. We successfully demonstrated the usefulness
developed as an efficient method for producing chiral a-tertiary of these synthetic methods by applying them to synthesize
alcohols, which are potentially valuable intermediates in the synthesis various chiral building blocks with tertiary or quaternary carbon
of natural products and pharmaceuticals. The efficient enantiose- centers.6
lective a-alkylation of diphenylmethyl tert-butyl a-acyloxymalonates
We planned to develop a new synthetic method of chiral
was accomplished via phase-transfer catalysis in the presence of (S,S)- quaternary a-hydroxymalonates using the well-established
3,4,5-trifluorophenyl-NAS bromide to afford the corresponding enantioselective phase-transfer catalytic a-alkylation of malo-
a-acyloxy-a-alkylmalonates at high chemical (up to 99%) and optical nates (Scheme 1B).7 The incorporation of a hydroxyl group into
(up to 93% ee) yields, which could be readily converted to versatile the a-position of malonates and the subsequent enantiose-
chiral intermediates with a chiral a-tertiary alcohol group.
lective a-alkylation under phase-transfer catalysis conditions,
which is a key step for the asymmetric induction, would yield
chiral quaternary a-hydroxymalonates which is a reverse
Chiral a-hydroxymalonates and their related compounds are
potentially valuable intermediates for the synthesis of natural
products and pharmaceuticals (Fig. 1).1 Furthermore,
a-hydroxymalonate can be easily modied to a,b-dihydroxy
esters or glycerols via the chemical conversion of two esters.
There are many enantioselective synthetic methods for the
a-hydroxy-b-ketoester system.2,3 However, the enantioselective
synthetic methods of a-hydroxymalonates have been mostly
achieved by the enzymatic desymmetrization of prochiral
malonates,4 and there is only one chemical synthetic method
via the enantioselective direct a-hydroxylation of prochiral
malonate, which uses oxazine as an oxidant in the presence of
Ni complex of (R,R)-DBFOX-Ph as an organometallic catalyst
and was reported by Shibata group.5
Recently, we reported new synthetic methods to produce
chiral malonates in high chemical yields and enantioselectiv-
ities via the phase-transfer catalytic (PTC) desymmetrizing
malonates system in the presence of chiral quaternary
Fig. 1 Bioactive ingredients with an a-hydroxy quaternary stereogenic
center.
aResearch Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul
National University, Seoul 151-742, Korea. E-mail: hgpk@snu.ac.kr; bfgfgf@daum.
net
bNeuro-Medicine Center, Korea Institute of Science and Technology, PO Box 131, Seoul
130-650, Cheongyang, Republic of Korea
† Electronic supplementary information (ESI) available: Representative
experimental procedures and spectroscopic characterization of all new
compounds. See DOI: 10.1039/c6ra15121c
Scheme 1 Strategy for synthesizing chiral a-hydroxymalonates.
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Table 1 Enantioselective PTC allylation of a-acyloxymalonatesa
strategy to that used in the Shibata group's work (Scheme 1A).5
The advantage of our strategy is that various chiral compounds
are easily available only by changing the alkylating reagents.
Herein, we report a new and highly efficient enantioselective
synthetic method for a-acyloxy-a-alkylmalonates via asymmetric
phase-transfer catalysis.
First, we designed enantiotopic unsymmetrical a-hydrox-
ymalonates as the substrates for PTC a-alkylation. Because both
the diphenylmethyl ester group and the tert-butyl ester group
were essential for the high enantioselectivity in previous enan-
tioselective PTC a-alkylations of the malonate system,6a we used
diphenylmethyl tert-butyl malonate (2) as a template of the
substrates with benzyl tert-butyl malonate (1) (Scheme 2).
a-Acyloxymalonates 5–7 were prepared from malonates 1 and 2
in 2 steps. The a-bromination of malonates 1 and 2 using
N-bromosuccinimide (NBS) in the presence of magnesium
perchlorate under acetonitrile produced a-bromomalonates 3
and 4, respectively.3k Substitutions of a-bromides with sodium
acetate or sodium benzoate successfully produced the corre-
sponding a-acyloxymalonates 5–7.
In a preliminary study, the substrate efficiency of the
prepared substrates were examined by a-allylation under typical
PTC conditions based on previous reports.6 Enantioselective
PTC allylation of 5–7 was performed in the presence of the
chiral quaternary ammonium salts (8–11) (Fig. 2),8 allyl bromide produced a-allylated products. Malonate 6 showed a higher
(5.0 equiv.) and 50% KOH (aq., 5.0 equiv.) at room temperature enantioselectivity than malonate 5 in the presence of (S,S)-3,4,5-
Entry Malonate
1
Cat. Time (h) Yieldb (%) eec (%)
5
6
8
8
2
4
98
90
42
76
2
3
4
5
6
8
9
10
11
2
4
6
6
89
80
62
32
79
12
24
21
7
a
Reactions were performed with 5.0 equiv. of allyl bromide and 5.0
b
equiv. of 50% KOH (aq.) under the given conditions. Isolated yields.
c
Enantiopurity was determined by HPLC analysis using a chiral
column (DAICEL Chiralpak AD-H).
As shown in Table 1, all malonate substrates successfully
in toluene (Table 1).
triuorophenyl-NAS bromide (8) (entries 1 and 2). One more
phenyl ring may be responsible for the higher enantioselectivity
via the p–p stacking interaction between the substrate and PTC
catalyst 8. In the case of the a-acyloxy group, the a-benzoate
group showed a slightly higher enantioselectivity than the acetate
group, with comparable chemical yield in the presence of (S,S)-
3,4,5-triuorophenyl-NAS bromide (8). However, N,N-dibutyl-
binaphthyl-derived catalyst 9 and cinchona-derived catalysts (10
and 11) have signicantly lower enantioselectivities than 8, which
is consistent with the previous result (entries 3–6).6a
Next, we selected malonate 7 to optimize the reaction
conditions. The PTC allylation of 7 was performed in the pres-
ence of the best catalyst 8 under variable base, solvent and
temperature conditions. As shown in Table 2, in general, the
enantioselectivity did not signicantly depend on the base
conditions. However, the solid CsOH exhibited notably lower
chemical yields (entry 4, 9%). The variation of the reaction
solvent also could not signicantly increase both enantiose-
lectivity and chemical yield (entry 2, entries 5–7). In case of
temperature conditions, the lower reaction temperatures
resulted in the higher enantioselectivity except ꢀ40 ꢁC (entry 2,
entries 8–9). However, the reaction time increased with
a decrease in temperature, which resulted in a notably longer
reaction time at ꢀ40 ꢁC (entry 10). Finally, 50% CsOH base
under toluene at ꢀ20 ꢁC were selected as the optimized reaction
conditions, considering the enantioselectivity, chemical yield,
and reaction time (entry 9; 94%, 87% ee).
Scheme
malonates.
2 Preparation of diphenylmethyl tert-butyl a-acyloxy
Under the optimized reaction condition (Table 2, entry 9), the
scope and limitations of the enantioselective PTC alkylation of 7
with various electrophiles were studied (Table 3). The activated
allylic and benzylic halides yielded high enantioselectivities.
Fig. 2 Representative chiral phase-transfer catalysts.
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a
Table 2 Optimization of the PTC benzylation of a-benzyloxy malonates 7
Entry
Base
T (ꢁC)
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
50% KOH
50% CsOH
KOH (s)
rt
rt
rt
rt
rt
rt
rt
0
Toluene
Toluene
Toluene
Toluene
Xylene
Mesitylene
Cyclopentylmethyl ether
Toluene
2
2
15
15
4
4
4
4
5
89
90
72
9
99
86
81
90
94
71
79
80
80
80
78
79
79
86
87
75
CsOH (s)
50% CsOH
50% CsOH
50% CsOH
50% CsOH
50% CsOH
50% CsOH
ꢀ20
Toluene
Toluene
ꢀ40
16
a
b
c
Reactions were performed with 5.0 equiv. of allyl bromide and 5.0 equiv. under the given conditions. Isolated yields. Enantiopurity was
determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H).
However, unactivated hexyl iodide showed slightly lower enan- 1,2-diol (17), as exemplied in Schemes 3 and 4. Catalytic
tioselectivity at 0 ꢁC with relatively longer reaction time (Table 3, hydrogenation of 7e with Pd/C–H2 in methanol afforded the
entry 1). The high enantioselectivities (up to 93% ee) in Table 3 corresponding mono acid 12 that was converted to the corre-
indicate that this reaction system is a notably efficient enantio- sponding methyl ester 13 by the treatment of trimethylsi-
selective synthetic method for a-benzoyloxy-a-alkylmalonates.
lyldiazomethane. The reduction of 13 using LiAl(Ot-Bu)3H,
The synthetic potential of this method was demonstrated via followed by basic hydrolysis using 50%-KOH provided diol 14.
the synthesis of a,b-dihydroxyester (14), a,b-epoxyester (16), and Finally, the mono mesylation of 14, followed by intramolecular
epoxidation in the presence of K2CO3 under acetonitrile affor-
ded epoxide 16 (Scheme 3). The absolute conguration of 7e
Table
3 Enantioselective synthesis of a-benzoyloxy-a-alkylmalo- was assigned as R by the chemical conversion to a known
nates via PTC alkylationa
compound (17). The reduction of 16 using LiAlH4 successfully
afforded diol (S)-17 {[a]D20 ¼ ꢀ9.6ꢁ (c 1.0, EtOH 95%); lit.9 (R)-17,
[a]2D0 ¼ +11.4ꢁ (c 1.0, EtOH 95%), 94% ee} (Scheme 4).
Entry
RX
Time (h)
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3(CH2)4CH2I (a)
CH2]CHCH2Br (b)
CH2]C(CH3)CH2Br (c)
CH2]C(Br)CH2Br (d)
PhCH2Br (e)
4-Me-PhCH2Br (f)
4-t-Bu-PhCH2Br (g)
3-CH3O-PhCH2Br (h)
3,5-(CH3O)2-PhCH2Br (i)
4-F-PhCH2Br (j)
19
2
2
15
3
3
4
2
2
3
99
94
75
89
99
93
95
91
93
90
92
88
92
72
75
87
91
93
91(R)e
91
91
93
91
85
80
93
81
88
Scheme 3 Derivatizations of chiral malonate 7e.
4-Cl-PhCH2Br (k)
4-Br-PhCH2Br (l)
4-NO2-PhCH2Br (m)
b-Naphthyl-CH2Br (n)
3
3
2
3
a
Reactions were performed with 5.0 equiv. of alkyl bromides and 5.0
b
equiv. of 50% CsOH (aq.) under the given conditions. Isolated
yields. Enantiopurity was determined by HPLC analysis using
c
d
a
chiral column (DAICEL Chiralpak AD-H).
The reaction was
e
performed under 0 ꢁC. Absolute conguration of 7e was conrmed
as R based on the (S)-17 prepared from 7e (Scheme 4).
Scheme 4 Conversion of 16 into (S)-17 to confirm the absolute
configuration of 7e.
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In conclusion, an enantioselective synthetic method for a-
benzoyloxy-a-alkylmalonates via PTC alkylation was developed.
The asymmetric PTC a-alkylation of diphenylmethyl-tert-butyl a-
benzoyloxy-malonates produced the corresponding a-benzoy-
loxy-a-alkylmalonates with high chemical (up to 99%) and
optical (up to 93% ee) yields. Our new catalytic system provides
an attractive synthetic method for versatile chiral building
blocks, which can be readily converted to chiral target molecules
with a-hydroxy quaternary stereogenic centers. Further applica-
tions and extension to the a-acylthiomalonate system are
currently under investigation and will be reported in due date.
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Acknowledgements
This work was supported by the National Research Foundation
of Korea (2016R1A2B2008109, 2009-0083533) and BK21 Plus
Program in 2016.
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