Highly enantioselective regiodivergent allylic alkylations of MBH carbonates with phthalides

Article abstract of DOI:10.1021/ja303115m

Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of chiral 3,3-disubstituted phthalides. Highly enantioselective regiodivergent synthesis of γ-selective or β-selective allylic alkylation products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine-thioureas as the catalyst, respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an S_N2′- S_N2′ pathway and an addition-elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomerically pure form.

Full text of DOI:10.1021/ja303115m

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Article
Highly Enantioselective Regiodivergent Allylic
Alkylations of MBH Carbonates with Phthalides
Fangrui Zhong, Jie Luo, Guo-Ying Chen, Xiaowei Dou, and Yixin Lu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja303115m • Publication Date (Web): 23 May 2012
Downloaded from http://pubs.acs.org on May 29, 2012
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Journal of the American Chemical Society
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Highly Enantioselective Regiodivergent Allylic Alkylations of
MBH Carbonates with Phthalides
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Fangrui Zhong, Jie Luo, GuoꢀYing Chen, Xiaowei Dou and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Sciꢀ
ence Drive 3, Singapore 117543 (Singapore)
Supporting Information Placeholder
ABSTRACT: Phthalides were used for the first time in the allylic alkylation reactions with MBH carbonates for the creation of
chiral 3,3ꢀdisubstituted phthalides. Highly enantioselective regiodivergent synthesis of γꢀselective or βꢀselective allylic alkylation
products was achieved by employing bifunctional chiral phosphines or multifunctional tertiary amine−thioureas as the catalyst,
respectively. It was demonstrated that proper selection of catalysts and reaction conditions would differentiate an SN2’−SN2’ pathꢀ
way and an addition−elimination process, yielding different regioisomers of the allylic alkylation products in a highly enantiomeriꢀ
cally pure form.
with the MBH adducts in the AAA reaction. Herein, we docꢀ
ument highly enantioselective and regiodivergent allylic alkylꢀ
1. INTRODUCTION
Asymmetric allylic alkylation (AAA) is one of the most
useful reactions in organic synthesis which allows easy access
to chiral allylic intermediates. Approaches via transition metal
catalysis have been intensively investigated and wellꢀ
established for the AAA reaction.1 Alternatively, organocataꢀ
lytic methods utilizing Morita−Baylis−Hillman (MBH) adꢀ
ducts2 as an electrophilic allylation reaction partner has recentꢀ
ly emerged as a powerful strategy. Majority of reactions in this
category made use of a cascade SN2’−SN2’ pathway initiated
by a nucleophilic phosphine3 or amine catalyst.4 On the other
hand, the nucleophile can also attach to the βꢀcarbon, usually
via an addition−elimination pathway, leading to the formation
of allylation products with different regioselectivity (Scheme
1). While vast majority of literature examples described the
formation of γꢀproducts, methods for the construction of βꢀ
selective allylation products are scarce.5 Given the high imꢀ
portance of the allylic alkylation products, versatile catalytic
AAA reactions yielding different regioisomers are certainly
very appealing and are of enormous synthetic value.
ations of phthalides with the MBH carbonates, via either Lewꢀ
is base or Brønsted baseꢀcatalyzed reaction pathway.
O
O
O
O
Me
COOH
MeO
MeO
R1
R2
MeO
H
N
O
O
O
O
N
H
O
O
O
OH
(-)-Arnottin II
Y5 receptor antagonists
Altenuic acid II
OH
Cl
O
O
O
N
N
H
H
O
OH
NH2
H2N
COOMe
Ph
Me
HN
O
OH
O
O
O
Dermacozine D (4)
Isochlortetracycline
Figure 1. Selected examples of biologically important phthalides.
2. RESULTS AND DISCUSSION
2.1. γ-Selective Asymmetric Allylic Alkylation of
Phthalides.
Scheme 1. Regioselective Allylic Alkylation Reactions of the
MBH Adducts
We initiated our studies by examining the allylation reaction
of MBH carbonates 2, using 3ꢀcarboxylate phthalide 1a as a
prenucleophile. In order to selectively form the γꢀselective
allylic alkylation products, we reasoned nucleophilic phosꢀ
phines might promote an SN2’−SN2’ reaction sequence. We
recently introduced a series of novel amino acidꢀderived chiral
phosphines9 in asymmetric catalysis. Our amino acidꢀbased
phosphines were found to be very powerful in a number of
enantioselective organic transformations, including: MBH
reaction,10a azaꢀMBH reaction,10b [3 + 2] cycloaddition of alꢀ
lenoates with acrylates,10c imines,10d maleimide10e and acrylaꢀ
mides,10f [4 + 2] annulation of allenoates with olefins10g as well
as [3 + 2] annulation using MBH adducts as a C3 synthon.10h
The phosphine functional groups in these catalysts were highly
Enantiomerically pure 3,3ꢀdisubstituted phthalides are atꢀ
tractive structural motifs due to their wide occurrence in natuꢀ
ral products and biologically important molecules6 (Figure 1).
However, asymmetric synthetic methods for phthalides with a
3ꢀquaternary chiral center have met with limited success.7 In
conjunction with our continuous efforts for the creation of
quaternary chiral centers,8 we set out to explore the applicaꢀ
tion of 3ꢀsubstituted phthalides as a novel reaction partner
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nucleophilic as they were connected to a primary carbon atom.
8
>99:1
>99:1
>99:1
>99:1
93
91
96
90
96
94
98
88
5d
5e
5c
5c
2a
2a
2b
2c
1
2
3
4
5
6
7
8
The Brønsted acid moieties in the catalyst structures could be
tuned easily to enable suitable interactions with substrates and
thus contribute to the stereochemical control. Given their
proven efficiency in asymmetric induction, we anticipated
amino acidꢀbased chiral phosphines may be very suitable for
the projected enantioselective allylic alkylation of phthalides.
The bifunctional phosphines investigated in this study are
shown in Figure 2.
9
10
11
a Reactions were performed with 1a (0.05 mmol), 2 (0.075 mmol)
b
and the catalyst (0.005 mmol) in toluene (0.5 mL) under argon.
Determined by 1H NMR analysis of the crude products. c Isolated
d
yield. Determined by HPLC analysis on a chiral stationary
phase.
9
F
PPh2
PPh2
PPh2
Ph2P
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11
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60
S
Generality of this γꢀselective AAA reaction of MBH carꢀ
bonates with phthalides 1 was next studied (Table 2). All the
reactions were completed within 2 h, and the γꢀallylic alkylaꢀ
tion products were obtained in excellent yields. The aryl moieꢀ
ties in the MBH carbonates 2 were wellꢀtolerated, regardless
of their electronic nature and substitution pattern (entries
1−13). Heterocyclic rings and 2ꢀnaphthyl group were also
suitable (entries 14−16). Moreover, the less reactive alkyl
MBH carbonates could be employed, albeit with moderate
diastereoselectivity (entries 17−18). It should be noted that
alkyl MBH carbonates were found to be unsuitable substrates
in related literature reports.3,4 Substitutions on the aromatic
ring of phthalides 1 could also be wellꢀtolerated (entries
19−21). However, the trisubstituted alkenes such as the MBH
adduct of cyclohexenone were found to be unsuitable for the
reaction, and no allylation product was observed. The absolute
configuration of the allylation products were determined based
on Xꢀray crystal structural analysis of an acid derivative of 3w
(see the Supporting Information for details).
N
R
N
NHAc
4a
NHTs
4b
NHBoc
H
4c
4d
4d'
: R = CH3
: R = H;
CF3
Ph2P
RO
F
S
Ph2P
TBSO
S
N
N
N
N
CF3
H
H
H
H
5a: R = TBS; 5b: R = TBDPS
5c 5d
5e
: R = TIPS; : R = TDS
Figure 2. Amino acidꢀderived chiral phosphines examined.
All the phosphines examined were effective in promoting
the reaction, affording the desired γꢀselective products in exꢀ
cellent yields (Table 1). Among various Brønsted acid moieꢀ
ties investigated, thioureas were found superior in stereochemꢀ
ical control (entries 1−4). Consistent with our previous findꢀ
ings, threonineꢀbased catalysts proved to be privileged,11 offerꢀ
ing further improvement in enantioselectivity. The sterically
hindered silyloxy groups were generally effective, and TIPS
protection led to the best results (entries 5−8). Notably, thiouꢀ
rea bearing a pꢀFꢀphenyl was slightly better than the thiourea
with a 3,5ꢀdiꢀtrifluoromethylphenyl group (entry 9). The ester
moiety of the MBH carbonates also had influence on the reacꢀ
tion, and the ethyl ester gave the highest ee (entries 10−11).
The reactions described proceeded rapidly to full conversion
in 2 h, in contrast to much longer reaction time for the amineꢀ
catalyzed reactions.4 Under the optimized reaction conditions,
γꢀselective allylation product 3a was obtained in 96% yield
and with 98% ee in a diasteromericallly pure form.
Table 2. Substrate Scope of the γ-Regioselective Allylic
Alkylation Reaction of Phthalidesa
O
O
OBoc
5c (10 mol%)
R1
O
R1
O
CO2Et
+
R2
toluene, RT, 2 h
CO2Et
tBuO2C
CO2tBu
R2
2
1
3
entry R1/R2 (3)
d.r.b
yield (%)c ee (%)d
1
H/C6H5 (3a)
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96:4
96
95
92
96
93
97
91
92
92
93
93
95
92
94
92
90
82
98
99
98
97
99
98
98
98
95
98
97
95
97
96
97
99
99/30
2
H/4ꢀMeꢀC6H4 (3d)
H/4ꢀBrꢀC6H4 (3e)
H/4ꢀFꢀC6H4 (3f)
H/4ꢀClꢀC6H4 (3g)
H/4ꢀCF3ꢀC6H4 (3h)
H/4ꢀNO2ꢀC6H4 (3i)
H/4ꢀCNꢀC6H4 (3j)
H/3ꢀMeꢀC6H4 (3k)
H/3ꢀBrꢀC6H4 (3l)
H/2ꢀMeꢀC6H4 (3m)
H/2ꢀBrꢀC6H4 (3n)
H/2,4ꢀClꢀC6H4 (3o)
H/2ꢀthiophenyl (3p)
H/3ꢀfuryl (3q)
3
Table 1. Asymmetric Allylic Alkylation of MBH Car-
bonates 2 with Phthalide 1a Catalyzed by Bifunctional
Phosphinesa
4
5
6
7
8
9
10
11
12
13
14
15
16
17
entry
cat.
4a
4b
4c
d.r.b
yield (%)c
ee (%)d
25
2
1
2
3
4
5
6
7
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
94
90
91
94
92
90
92
2a
2a
2a
2a
2a
2a
2a
>99:1
>99:1
>99:1
97:3
20
3
87
4d
5a
5b
5c
96
H/2ꢀnathphyl (3r)
H/Me (3s)
>99:1
67:33
95
97
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suggested that another mechanism might be in operation with
the simple switch of reaction medium from toluene to CH3CN,
which prompted us to further investigate the influence of solꢀ
vents on our reaction.
18
H/iꢀPr (3t)
75:25
>99:1
>99:1
>99:1
92
93
92
91
98/53
>99
98
1
2
3
4
5
6
7
8
19
20
21
a
5ꢀBr/Ph (3u)
5ꢀCN/Ph (3v)
5ꢀBr/2,4ꢀClꢀC6H4 (3w)
98
We performed the allylation reaction between 1a and 2b
catalyzed by bifunctional phosphine 4d in a number of comꢀ
mon aprotic organic solvents, and the results are summarized
in Table 3. The ee values of the γꢀproducts plotted against the
βꢀselectivity of the reaction are illustrated in Figure 3. A clear
correlation between regioselectivity and solvent polarity was
observed. When solvents with low polarity12 (e.g. toluene)
were utilized, the γꢀregioisomer 3b was formed in high enantiꢀ
omeric excess. Increase of solvent polarity favoured the forꢀ
mation of the βꢀproduct 3b’, but such an increase in βꢀ
selectivity was coupled with a decrease in enantioselectivity of
the γ product. When the reaction was carried out in DMSO, a
β (3b’) to γ (3b) ratio of 92:8 could be obtained, however, the
γꢀallylation product was formed with only 4% ee. It should
also be noted that although more polar solvents favoured the
formation of βꢀproducts, such βꢀproducts were obtained in
nearly racemic form.
Reactions were performed with 1 (0.05 mmol), 2 (0.075 mmol)
b
and 5c (0.005 mmol) in toluene (0.5 mL) under argon. Deterꢀ
mined by 1H NMR analysis of the crude products. c Isolated yield.
d Determined by HPLC analysis on a chiral stationary phase.
9
10
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2.2. Mechanistic Considerations and Solvent Effects
on Regioselectivity and Enantioselectivity.
A mechanism involving a tandem SN2’−SN2’ pathway was
postulated to account for the formation of the observed γꢀ
selectivity (Scheme 2, pathway 1). The first SN2’ reaction is
initiated via nucleophilic attack of phosphine 5c on the MBH
carbonate 2b, and the phosphonium intermediate A is generatꢀ
ed with concurrent release of CO2. The tertꢀbutoxide generated
then deprotonates phthalide 1a, which undergoes a second
SN2’ with phosphonium A to yield γꢀallylation product 3b.
We propose that the hydrogen bonding interactions between
thiourea moiety of the catalyst and the ester group of phthalide
are crucial for the observed stereoselectivity.
The above results suggested that employment of more polar
solvents resulted in a switch of reaction mechanism; a new βꢀ
selective and nonꢀenantioselective pathway is likely in operaꢀ
tion. When the in situ generated tertꢀbutoxide abstracted the
proton from the phthalide 1a, the resulting anion could either
add to intermediate A or the MBH carbonate 2b. Intermediate
A was a favoured reaction partner when the reaction was run
in toluene, due to the high electrophilicity of the phosphonium
alkene A and intramolecular like reaction facilitated by the
hydrogen bonding interactions. However, when the polar aproꢀ
tic solvent (e.g. DMSO) was used, the polar group of the solꢀ
vent not only stabilized the phosphonium intermediate, but
also disrupted the hydrogen bonding interactions, and such
disruption resulted in decreased ee values of the γꢀproduct
formed. Indeed, when methylated thiourea phosphine 4d’
(Scheme 3) was employed, the ratio of γ to β products reꢀ
mained unchanged. Nevertheless, the ee of γꢀproduct 3b deꢀ
creased to 21%, comparing with a 54% ee when thiouꢀ
rea−phosphine 4d was used as a catalyst under otherwise same
conditions. These results clearly showed the importance of
hydrogen bonding interactions in stereochemical formation of
γꢀproduct via pathway 1. When the solvent was switched to
polar aprotic solvents, such as DMSO, the MBH carbonate 2b
became a predominant acceptor to trap the phthalide anion,
yielding the βꢀallylic alkylation product 3b’. Such an addiꢀ
tion−elimination process is independent of steric or electronic
control, and thus is apparently nonꢀstereoselective, affording
nearly racemic products (Scheme 2, pathway 2).
Scheme 2. Diverse Reaction Pathways
O
TIPSO
Pathway 1
O
O
A
( )
S
Ph
Ph
CO2Et
Ph
N
P
O
N
H
O
CO2
TIPSO
H
F
2b
O
O
O
PPh2
S
O
Ph
CO2Et
HN
5c
tBuO2
C
Ph
(γ-product)
O
5c
HN
3b
O
1a
)
(
t-BuO
H
F
TIPSO
Pathway 2
S
(A)
N
O
N
BocO
Ph
CO2Et
H
F
H
Ph
O
∗
O
O
2b
tBuO2C
CO2Et
β
-product)
O
3b'
(
O
(1a)
t-BuO
H
Scheme 3. The AAA Reaction Catalyzed by 4d or 4d’ in
CH3CN
O
O
O
4d or 4d'
OBoc
(10 mol%)
O
Ph
O
+
O
CO2Et
+
Ph
CH3CN, RT, 2h
tBuO2C
Ph
3b (γ-product)
CO2Et
tBuO2C
3b'
CO2Et
CO2tBu
1a
2b
(β-product)
: 46% yield, <5% ee;
4d
4d'
4d
4d'
: 48% yield, 54% ee;
: 45% yield,
21%
ee
: 42% yield, <5% ee
Solvents are known to play important roles in organic reacꢀ
tions. Given the involvement of ionic intermediates in our
reaction system, solvent effect is thus anticipated to be proꢀ
found. Intriguingly, when phosphine 4dꢀcatalyzed reaction
between phthalide 1a and the MBH carbonate 2b was carried
out in CH3CN, the βꢀproduct 3b’ and γꢀselective 3b were
formed in a 1:1 ratio (Scheme 3). In stark contrast, the γꢀ
selective 3b was the only product observed when toluene was
used as the solvent (Table 1, entry 4). This experimental result
Table 3. The Influence of Various Aprotic Solvents on the
Regioselectivities and Enantioselectivitiesa
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εrb
β : γc
ee (γ)d
87
the enantioselectivity of the reaction, a screening of catalysts
entry solvent
1
2
3
4
5
6
7
8
was performed. Tryptophanꢀbased catalyst 10 was ineffective
(entry 4), and our previously developed trifunctional cataꢀ
lysts8d offered fantastic results (entries 5−9). Under the optiꢀ
mized reaction conditions,13 threonineꢀincorporated 12c proꢀ
moted the allylation reaction of phthalide 1a with 6a in a highꢀ
ly enantioselective and regioselective manner, affording the βꢀ
product 7a in 91% yield and with 98% ee (entry 8).
1
2
3
4
5
6
7
8
a
toluene
CHCl3
THF
2.38
4.89
7.58
8.93
0:100
0:100
87
4.3:95.6
4.5:95.5
5.6:94.4
5.7:94.3
46.0:54.0
92.0:8.0
85
CH2Cl2
80
ClCH2CH2Cl 10.36
78
acetone
CH3CN
DMSO
20.56
35.90
44.00
57
9
54
Table 4. Reaction Condition Optimization for β-Selective
Allylation Reaction of Phthalidesa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4
O
O
Reactions were performed with 1a (0.05 mmol), 2b (0.075
OBoc
cat. (10 mol%)
R1
Ph
R1
O
+
mmol) and the 4d (0.005 mmol) in the solvent specified (0.5 mL)
under argon. b Dielectric constant εr values are referred as empiriꢀ
cal parameter of solvent polarity. c Evaluated by 1H NMR analysis
of the crude products. d The ee values of 3b, determined by HPLC
analysis on a chiral stationary phase. The ee values of 3b‘ were all
below 5%.
Ph
O
toluene, RT, 36 h
: R1 = CO2Et
tBuO2
C
2b
CO2tBu
1a
6a: R1 = CN
3b': R1 = CO2Et
R
1 = CN
7a:
OMe
H
OMe
N
H
N
N
CF3
HN
HN
S
HO
N
HN
S
N
N
H
CF3
H
8
N
9
10
F3C
CF3
DMSO
92
100
toluene
87
CHCl3
87
H
N
THF
H
N
85 CH2Cl2
80
90
80
70
60
50
40
30
20
10
0
DCE
78
NH
H
N
H
N
NH
O
H
N
H
N
N
CF3
O
N
CF3
S
acetone
57
S
RO
CH3CN
54
CF3
CF3
12a: R = TBS; 12b: R = TDS
11
12c
12d
: R = TIPS
entry
cat.
8
R1
Z/Eb : R = TyBDiPeSl;d (%)c
ee (%)d
ꢀ
46
1
2
3
4
5
6
7
8
9
CO2Et
CO2Et
CN
ꢀ
<10
<10
94
ꢀ
ꢀ
9
5.7
5.6
4.5
4.3
4
0
0
15:1
15:1
14:1
17:1
17:1
18:1
18:1
72
35
85
93
93
98
94
9
0
5
10
15
20
25
30
35
40
45
50
polarity (er)
CN
87
10
11
12a
12b
12c
12d
CN
90
Figure 3. Correlation of ee of γ isomer (orange) and β:(γ+β) ratio
(blue) with solvent polarity.
CN
90
CN
92
2.3. β-Selective Asymmetric Allylic Alkylation of
Phthalides.
CN
91
CN
92
Having established a stereoselective pathway for deriving γꢀ
selective allylation products, we next focused on the formation
of βꢀselective phthalides in an enantioselective manner. The
aforementioned pathway 2 implies that Brønsted baseꢀinitiated
addition−elimination sequence may be utilized for selective
formation of the βꢀproduct. Given the high acidity of the proꢀ
ton at the C3 position of phthalide, we reasoned an appropriate
chiral Brønsted base may provide sufficient activation. We
hypothesized that utilization of multiꢀfunctional tertiary
amineꢀbased catalysts may lead to an enantioselective variant
of βꢀselective allylic alkylation of phthalides .
a Reactions were performed with 1a (0.05 mmol), 2b or 6a (0.075
mmol) and the catalyst (0.005 mmol) in toluene (0.5 mL) under
c
argon. b Determined by 1H NMR analysis of the crude products.
Isolated yield. d Determined by HPLC analysis on a chiral stationꢀ
ary phase.
The above βꢀselective allylation reactions were general for
MBH carbonates with different substituents (Table 5), includꢀ
ing electron rich/poor aryls with different substitution patterns
(entries 1−14), 1ꢀnaphthyl (entry 15), heteroaromatic ring (enꢀ
try 16), vinylic group (entry 17). Notably, in contrast to reꢀ
ported systems with substrates scope limited to aromatic subꢀ
stituted MBH adducts,3,4 our current catalytic system also
worked nicely for MBH carbonates with aliphatic group (entry
18), or simply hydrogen (derived from formaldehyde, entry
19). Moreover, different substituents on the aromatic part of
phthalides 1 could also be tolerated (entries 20−21). In all
cases, good to excellent Z/E ratios were attainable. The absoꢀ
lute configurations of products 7 were determined based on Xꢀ
ray crystal structural analysis of 7m (see the Supporting Inꢀ
formation for details).
The reaction between phthalides 1a and the MBH carꢀ
bonates in the presence of tertiary amine−thiourea catalysts
was examined, and the results are summarized in Table 4.
Neither quinidine
8
nor quinidineꢀderived tertiary
amine−thiourea 9 could effectively promote the reaction (enꢀ
tries 1−2). Suspecting the esterꢀcontaining MBH carbonate
may not have sufficient reactivity, we then utilized carbonate
6a as a reaction partner. Indeed, the allylation proceeded
smoothly with 6a, affording the βꢀselective product in excelꢀ
lent yield and with moderate ee (entry 3). To further improve
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making the reaction catalytic. When the MBH acetate was
Table 5. Asymmetric β-Selective Allylic Alkylation of
Phthalidesa
1
2
employed, the reaction was not catalytic anymore as the aceꢀ
tate was unable to facilitate the regeneration of the catalyst.
The combination of the MBH acetate 6b and the phosphine
catalyst 5c did not lead to the product formation, which clearly
supported that the tertꢀbutoxide was required for the deprotoꢀ
nation of phthalide in an SN2’−SN2’ mechanism (Scheme 2).
On the other hand, when carbonate 6a was used in the presꢀ
ence of phosphine 5c, only the βꢀproduct 7a was isolated. In
contrast to γꢀselectivity for carbonate 2b, the observed βꢀ
selectivity with 6a as a substrate under phosphine catalysis
suggested that the cyano group in 6a exerted a strong inducꢀ
tive effect and enhanced electrophilicity of the terminal alꢀ
kene, and led to the formation of βꢀproduct.
3
4
5
6
7
Entry R1/R2, 7
Z/Eb
Yield
(%)c
ee (%)d
8
9
1
H/C6H5, 7a
18:1
12:1
15:1
9:1
91
90
92
94
95
93
90
95
92
93
92
91
86
88
92
80
85
75
78
93
88
98
98
98
98
98
98
98
98
99
97
97
96
98
98
97
91
91
95
93
98
97
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
H/4ꢀOMeꢀC6H4, 7b
H/4ꢀClꢀC6H4, 7c
H/4ꢀFꢀC6H4, 7d
H/4ꢀNO2ꢀC6H4, 7e
H/3ꢀCNꢀC6H4, 7f
H/3ꢀMeꢀC6H4, 7g
H/3ꢀBrꢀC6H4, 7h
H/3ꢀClꢀC6H4, 7i
H/3ꢀFꢀC6H4, 7j
3
4
5
9:1
Scheme 4. The Formation of β-Selective Allylation Product
6
>25:1
12:1
10:1
18:1
21:1
>25:1
11:1
11:1
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
a
H/2ꢀMeꢀC6H4, 7k
H/2ꢀClꢀC6H4, 7l
H/3,4ꢀClꢀC6H3, 7m
H/3ꢀNO2ꢀ4ꢀClꢀC6H3, 7n 14:1
H/1ꢀnaphthyl, 7o
H/2ꢀthiophenyl, 7p
H/(E)ꢀPhCH=CH, 7q
H/C6H4CH2CH2, 7r
H/H, 7s
7:1
25:1
5:1
>25:1
ꢀ
5ꢀBr/4ꢀClꢀC6H4, 7t
5ꢀCN/C6H5, 7u
>25:1
10:1
Reactions were performed with 1 (0.05 mmol), 6 (0.075 mmol)
b
and 12c (0.005 mmol) in toluene (0.5 mL) under argon. Deterꢀ
mined by 1H NMR analysis of the crude products. c Isolated yield.
d Determined by HPLC analysis on a chiral stationary phase.
Scheme 5. Employment of MBH Acetate in the Reaction
O
O
OR
12c
5c
(30 mol%)
or
CN
We believe selective formation of the βꢀselective product
resulted from a Brønsted baseꢀinitiated addition−elimination
reaction sequence (Scheme 4, pathway B). It is postulated that
the hydrogen bonding network between catalyst 12c and the
substrate was crucial for the observed enantioselectivity.
However, it should be noted that the same product could also
be formed via an SN2’−SN2 tandem reaction, in which tertiary
amine catalysts serve as a nucleophilic catalyst (Scheme 4,
pathway A).
O
+
Ph
Ph
CN
O
toluene, RT, 36 h
CO2tBu
6a: R = Boc
: R = Ac
tBuO2C
1a
6b
7a
H
N
12c
F
Ph2P
TIPSO
S
NH
H
H
N
H
N
H
N
N
N
CF3
O
5c
S
TBDPSO
To gain further mechanistic insights, we performed the
same allylic alkylation experiment by utilizing the MBH aceꢀ
tate 6b (Scheme 5). In the presence of 30 mol% 12c, 7a was
obtained in 30% yield, in contrast to a 91% yield when the
MBH carbonate 6a was employed under otherwise identical
reaction conditions. These experimental results support that
pathway B is more likely for our reaction. Had the reaction
proceed via pathway A, the allylation product would not be
formed as the acetate anion is not basic enough to deprotonate
1a. In pathway B, the in situ generated tertꢀbutoxide deprotoꢀ
nates the ammonium species to reꢀgenerate the catalyst, hence
R = Boc (6a), 7a: 89% yield,
Z/E = 17:1, 13%ee (2 h)
R = Ac (6b), no product
CF3
R = Boc (6a), 7a: 91% yield, Z/E = 18:1, 98%ee;
R = Ac (6b), 7a: 30% yield, Z/E = 16:1, 96%ee,
3. CONLUSIONS
In conclusion, we have used phthalides for the first time in
the AAA reaction with MBH carbonates to access optically
enriched 3,3ꢀdisubstituted phthalides. By employing bifuncꢀ
tional chiral phosphines or multifunctional tertiary
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C.; Wang, R. Org. Lett. 2010, 12, 3914. (f) Hong, L.; Sun, W.; Liu,
amine−thioureas as the catalyst, we developed highly reꢀ
giodivergent approach to enantioselectively prepare γꢀselective
or βꢀselective allylic alkylation products, respectively. Our
results also demonstrated that proper selection of catalysts and
reaction conditions would differentiate an SN2’ꢀSN2’ pathway
and an additionꢀelimination process, yielding different regioiꢀ
somers of the allylic alkylation products in a highly enantioꢀ
merically pure form. Applications of the approaches described
here to other allylation reactions, biological evaluation of our
synthetic phthalides and DFT calculations to understand our
catalytic systems are in progress in our laboratory.
C.; Zhao, D.; Wang, R. Chem. Commun. 2010, 46, 2856. (g) Liu, C.;
Tan, B.ꢀX.; Jin, J.ꢀL.; Zhang, Y.ꢀY.; Dong, N.; Li, X.; Cheng, J.ꢀP. J.
Org. Chem. 2011, 76, 5838. (h) Yang, W.; Wei, X.; Pan, Y.; Lee, R.;
Zhu, B.; Liu, H.; Yan, L.; Huang, K.ꢀW.; Jiang, Z.; Tan, C.ꢀH. Chem.
Eur. J. 2011, 17, 8066. (i) Furukawa, T.; Kawazoe, J.; Zhang, W.;
Nishimine, T.; Tokunaga, E.; Matsumoto, T.; Shiro, M.; Shibata, N.
Angew. Chem. Int. Ed. 2011, 50, 9684. (j) Li, Y.; Liang, F.; Li, Q.;
Xu, Y.ꢀC.; Wang, Q.ꢀR.; Jiang, L. Org. Lett. 2011, 13, 6082. (k) Cho,
C.ꢀW.; Krische, M. J. Angew. Chem. Int. Ed. 2004, 43, 6689. (l)
Baidya, M.; Remennikov, G. Y.; Mayer, P.; Mayr, H. Chem. Eur. J.
2010, 16, 1365. (m) Lin, A,; Mao, H.; Zhu, X.; Ge, H.; Tan, R.; Zhu,
C.; Cheng, Y. Adv. Synth. Catal. 2011, 353, 3301. (n) Lin, A.; Mao,
H.; Zhu, X.; Ge, H.; Tan, R.; Zhu, C.; Cheng, Y. Chem. Eur. J. 2011,
17, 13676.
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ASSOCIATED CONTENT
(5) (a) Ramachandran, P. V.; Madhi, S.; BlandꢀBerry, L.; Reddy,
M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450. (b)
Chen, G.ꢀY.; Zhong, F.; Lu, Y. Org. Lett. 2011, 13, 6070.
Supporting Information. Representative experimental proceꢀ
dures, determinations of absolute configurations, Xꢀray crystalloꢀ
graphic data, HPLC chromatograms and NMR spectral data for all
the compounds described. This material is available free of charge
via the Internet at http://pubs.acs.org.
(6) (a) Beck, J. J.; Chou, S.ꢀC. J. Nat. Prod. 2007, 70, 891. (b)
Xiong, M. J.; Li, Z. H. Curr. Org. Chem. 2007, 11, 833. (c) Tayone,
W. C.; Honma, M.; Kanamaru, S.; Noguchi, S.; Tanaka, K.; Nehira,
T.; Hashimoto, M.; J. Nat. Prod. 2011, 74, 425. (d) Tymiak, A. A.;
Aklonis, C.; Bolgar, M. S.; Kahle, A. D.; Kirsch, D. R.; O’Sullivan,
J.; Porubcan, M. A.; Principe, P.; Trejo, W. H.; Ax, H. A.; Wells, J.
S.; Andersen, N. H.; Devasthale, P. V.; Telikepalli, H.; Vander Velde,
D.; Zou, J.ꢀY.; Mitscher, L. A. J. Org. Chem. 1993, 58, 535. (e) Baba,
Y.; Ogoshi, Y.; Hirai, G.; Yanagisawa, T.; Nagamatsu, K.; Mayumi,
S.; Hashimoto, Y.; Sodeoka, M.; Bioorg. Med. Chem. Lett. 2004, 14,
2963. (f) Williams, D. J.; Thoms, R. Tetrahedron Lett. 1973, 9, 639.
(g) Ogino, Y.; Ohtake, N.; Nagae, Y.; Matsuda, K.; Ishikawa, M.;
Moriya, M.; Kanesaka, M.; Mitobe, Y.; Ito, J.; Kanno, T.; Ishihara,
A.; Iwaasa, H.; Ohe, T.; Kanatani, A.; Fukami, T. Bioorg. Med.
Chem. Lett. 2008, 18, 4997. (h) AbdelꢀMageed W. M, Milne B. F,
Wagner M, Schumacher M, Sandor P, Pathomꢀaree W, Goodfellow
M, Bull A. T, Horikoshi K, Ebel R, Diederich M, Fiedler H.ꢀP, Jasꢀ
pars M. Org. Biomol. Chem., 2010, 8, 2352.
AUTHOR INFORMATION
Corresponding Author
chmlyx@nus.edu.sg
ACKNOWLEDGMENT
Financial support from the National University of Singapore (Rꢀ
143ꢀ000ꢀ469ꢀ112) is gratefully acknowledged.
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1
2
L
(a) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y. Chem.
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solvent effects in organic chemistry, WileyꢀVCH, 2010, 4th edition,
p375ꢀ377.
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5
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(13) For the complete optimization study, see the Supporting Inꢀ
formation.
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1
2
3
4
5
6
7
8
O
O
O
OBoc
R3
12c
(10 mol%)
R2
CN
5c
R1
O
(10 mol%)
R1
O
+
R2
R1
O
toluene, RT, 36 h
toluene, RT, 2 h
CO2Et
R3 = CO2Et or CN
tBuO2
C
tBuO2
C
R2
CO2tBu
β-selective
γ-selective
21 entries
75-95% yields
91-99% ee
21 entries
82-97% yields
95-99% ee
TIPSO
H
12c
N
PPh2
S
HN
HN
NH
H
H
N
N
N
CF3
O
5c
S
TBDPSO
F
CF3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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