Asymmetric synthesis of α-acyl-γ-butyrolactones possessing all-carbon quaternary stereocenters by phase-transfer-catalyzed alkylation

Article abstract of DOI:10.1002/adsc.200606064

The enantioselective construction of all-carbon quaternary stereocenters on α-acyl-γ-butyrolactones has been achieved by the N-spiro chiral quaternary ammonium bromide 1-catalyzed alkylation under mild phase-transfer conditions. The resulting α-alkylated

Full text of DOI:10.1002/adsc.200606064

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DOI: 10.1002/adsc.200606064
Asymmetric Synthesis of a-Acyl-g-butyrolactones Possessing All-
Carbon Quaternary Stereocenters by Phase-Transfer-Catalyzed
Alkylation
Takashi Ooi,a Takashi Miki,a Kazuhiro Fukumoto,a and Keiji Maruokaa,*
a
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax : (+81)-75-753-4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
Received: February 28, 2006; Accepted: May 2, 2006
Abstract: The enantioselective construction of all-
carbon quaternary stereocenters on a-acyl-g-butyro-
lactones has been achieved by the N-spiro chiral
quaternary ammonium bromide 1-catalyzed alkyla-
tion under mild phase-transfer conditions. The re-
sulting a-alkylated keto lactones serve as valuable
chiral building blocks in organic synthesis as clearly
demonstrated by the facile conversion to optically
active a,a-dialkyl-a-amino acid derivatives via
Schmidt rearrangement.
meric excess of 3a was revealed to be quite promising
(89% ee), and thus different bases were examined for
rate enhancement without sacrificing the stereoselec-
tivity. Fortunately, the benzylation was completed in
9 h when Cs2CO3 was employed, giving rise to 3a in
85% with 88% ee (entry 2). Here, use of other sol-
vents such as mesitylene, o-xylene and more polar
tert-butyl methyl ether (TBME) did not lead to an im-
provement of the enantioselectivity (entries 3–5). We
also evaluated the steric effect of the 3,3’-aromatic
substituents (Ar) of the catalyst using 1b[4d] and
1c,[4b,c] which showed the superiority of 1a in terms of
both reactivity and selectivity (entries 6 and 7). Final-
ly, the highest enantioselectivity (91% ee) was found
to be attainable by performing the alkylation at
À208C, although a prolonged reaction time was re-
quired (entry 8).[5]
Keywords: a-acyl-g-butyrolactones; chiral quaterna-
ry ammonium bromide; organic catalysis; phase-
transfer alkylation; quaternary carbon centers
The asymmetric construction of all-carbon quaternary
stereocenters on highly functionalized organic mole-
cules, particularly in a catalytic manner, represents a
very challenging yet important task in current organic
synthesis.[1] We recently contributed to this rapidly
growing area by achieving phase-transfer-catalyzed
asymmetric alkylation and Michael reaction of b-keto
esters with N-spiro C2-symmetric chiral quaternary
ammonium salt 1a as catalyst.[2] During our continu-
ous efforts for expanding the synthetic utility of our
approach, we sought to extend the substrate range to
heterocyclic donors such as lactones in view of their
potential usefulness as chiral building blocks.[3]
Herein we report the highly enantioselective alkyla-
tion of a-acyl-g-butyrolactones catalyzed by 1 under
mild phase-transfer conditions, providing a direct
access to enantiomerically enriched a-alkylated keto
lactones 3 (Scheme 1).
Attempted reaction of a-benzoyl-g-butyrolactone
(2a) with benzyl bromide in the presence of K2CO3 (5
equivs.) and (S,S)-1a[2,4a] (1 mol%) in toluene pro-
ceeded sluggishly at 08C and the desired alkylation
product 3a was obtained in only 12% yield after 24 h
Scheme 1. Asymmetric alkylation of a-acyl-g-butyrolactones
of stirring (entry 1 in Table 1). However, the enantio- 2 under phase-transfer conditions using (S,S)-1 as catalyst.
Adv. Synth. Catal. 2006, 348, 1539 – 1542
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Takashi Ooi et al.
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Table 1. Screening of the reaction parameters in the phase-transfer-catalyzed benzylation of a-benzoyl-g-butyrolactone (2a)
using (S,S)-1 as catalyst.[a]
Entry
Catalyst
Base
Solvent
toluene
Temperature [8C]
Reaction time [h]
Yield [%][b]
% ee[c]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1c
1a
K2CO3
Cs2CO3
0
0
0
0
0
0
0
À20
24
9
18
12
36
9
12
85
80
83
89
80
90
91
89
88
80
83
88
61
66
91
mesitylene
o-xylene
TBME
toluene
20
84
[a]
The reaction was carried out with 1.2 equivs. of benzyl bromide in the presence of 5 equivs. of base and 1 mol% of (S,S)-1
in an appropriate solvent under the given reaction conditions.
[b] Isolated yield.
[c]
Enantiopurity of 3a was determined by HPLC analysis using a chiral column (DAICEL Chiralpak AD-H) with hexane-2-
propanol as solvent. Absolute configuration of the major enantiomer of 3a was assigned to be S.[5]
On the basis of the results, the catalysis of (S,S)-1a the resulting 4 as a synthetic intermediate was also
in toluene at 08C was applied to further investigations highlighted by the subsequent facile aminolysis with
on the substrate scope.[6] As summarized in Table 2, methylamine,[8] affording the optically active, func-
the alkylation was relatively less sensitive to the char- tionalized a,a-dialkyl-a-amino amide 5 in high yield
acter of the benzylic bromide aromatic moiety in as indicated in Scheme 2.
terms of both enantioselectivity and reaction efficien-
In summary, we have successfully demonstrated
cy. Electron-withdrawing and -donating substituents that the present phase-transfer-catalyzed alkylation
at the para position afforded a marginal effect on the strategy for the asymmetric construction of all-carbon
selectivity (entries 1 and 2). In addition, 2-naphthyl- quaternary stereocenters on 1,3-dicarbonyl com-
and 2-pyridylmethyl bromides were tolerated for the pounds can nicely accommodate a-acyl-g-butyrolac-
reaction (entries 3 and 4). Unfortunately, however, tones. This finding certainly expands the synthetic
the use of allylic bromides and propargyl bromide as utility of our approach based on the use of N-spiro
an elecrophilic partner led to an erosion of the stereo- chiral quaternary ammonium bromide 1a as an effi-
selectivity (entries 5–7).
cient phase-transfer catalyst, and provides a practical
Structural variation in the a-acyl-g-butyrolactone access to a variety of optically active a-alkylated keto
component was also possible without loss of enantio- lactones as well as a,a-dialkyl-a-amino acid deriva-
selectivity as evident from the results of the benzyla- tives.
tion of the substrates bearing para-substituted benzoyl
groups (entries 8–10). It is noteworthy that the butyr-
olactone possessing an alkylcarbonyl moiety appeared
to be a good candidate for this phase-transfer-cata-
lyzed asymmetric quaternization, and the correspond-
ing a-alkylated keto lactone was obtained with good
enantiomeric excess (entry 11).
The a-alkylated keto lactones of high enantiomeric
purity can be readily transformed to the protected a-
alkyl-a-amino lactones by Schmidt rearrangement
with complete retention of the configuration of the a-
quaternary stereocenters.[7] For instance, treatment of
3a [88% ee (S)] with sodium azide in methanesulfonic
acid at room temperature for 5 h resulted in the for-
mation of a-(N-benzoylamino)-a-benzyl-g-butyrolac-
tone (4) in 67% yield without loss of the enantiomer-
Scheme 2. Facile conversion of of 3a to a,a-dialkyl-a-amino
ic excess [88% ee (R)] (Scheme 2). The usefulness of acid derivatives 4 and 5.
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Asymmetric Synthesis of a-Acyl-g-butyrolactones
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Table 2. Phase-transfer-catalyzed asymmetric quaternization of
2.[a]
Representative Procedure for the
Phase-Transfer-Catalyzed Alkylation of 2 (Entry 2 in
Table 1)
Entry 2 (R1)
R2Br
Reaction Yield %
time [h] [%][b] ee[c]
To a mixture of a-benzoyl-g-butyrolactone (2a; 57.2 mg,
0.30 mmol) and (S,S)-1a (3.2 mg, 0.003 mmol, 1 mol%) in
toluene (3 mL) was added benzyl bromide (43 mL,
0.36 mmol) and Cs2CO3 (488 mg, 1.5 mmol) sequentially at
08C under an argon atmosphere, and the mixture was stirred
for 9 h at the same temperature. The resulting mixture was
diluted with water and extracted with AcOEt (3 times). The
combined organic extracts were washed with brine and then
dried over Na2SO4. Evaporation of solvents and purification
of the residual crude products by column chromatography
on silica gel (hexane/AcOEt=6:1 as eluent) gave the corre-
sponding alkylation product 3a;[10] yield: 72.1 mg
(0.257 mmol, 85%); [a]D29: +5.88 (c 0.96, CHCl3) [88% ee
(S)]; 1H NMR (400 MHz, CDCl3, room temperature): d=
8.03 (2H, d, J=7.6 Hz, Ph), 7.57 (1H, t, J=7.6 Hz, Ph), 7.47
(2H, dd, J=7.6, 7.6 Hz, Ph), 7.29–7.22 (3H, m, Ph), 7.17–
7.11 (2H, m, Ph), 4.23 (1H, ddd, J=8.8, 8.0, 6.8 Hz, CH2O),
3.68 (1H, ddd, J=8.8, 8.8, 5.6 Hz, CH2O), 3.50 (1H, d, J=
13.6 Hz, CH2Ph), 3.45 (1H, d, J=13.6 Hz, CH2Ph), 2.88
(1H, ddd, J=13.6, 8.0, 5.6 Hz, CH2CH2O), 2.34 (1H, ddd,
J=13.6, 8.8, 6.8 Hz, CH2CH2O); 13C NMR (100 MHz,
CDCl3, room temperature): d=195.1, 176.1, 135.1, 132.9,
129.8, 129.0, 128.5, 128.5, 127.2, 66.3, 60.5, 40.8, 31.6; HPLC
conditions: DAICEL Chiralpak AD-H, hexane/i-PrOH=
10:1, flow rate=0.5 mLminÀ1, retention times: 21.3 min (S),
1
2
Ph
Ph
6
9
80
85
87
83
3
4
Ph
Ph
15
12
87
83
80
83
5
6[d]
Ph
Ph
10
72
82
89
56
61
7
Ph
48
40
29
8
PhCH2Br
PhCH2Br
24
97
88
9
24
94
90
10
PhCH2Br
PhCH2Br
24
24
79
82
88 23.4 min (R).
11
i-Pr
78
[a]
The reaction was carried out with 1.2 equivs. of R2Br in the Acknowledgements
presence of 1 mol% of (S,S)-1a and 5 equivs. of Cs2CO3 in
toluene at 08C for the given reaction time.
This work was partially supported by a Grant-in-Aid for Sci-
entific Research on Priority Areas “Advanced Molecular
Transformation of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
[b] Isolated yield.
[c]
Enantiopurity of 3 was determined by HPLC analysis using a
chiral column (DAICEL Chiralpak AD-H or Chiralcel OD-
H) with hexane-2-propanol as solvent.
[d] Performed at À108C.
References
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Experimental Section
Preparation of a-Benzoyl-g-butyrolactone (2a)[9]
To a solution of lithium diisopropylamide (12.5 mmol) in
THF (20 mL) was added g-butyrolactone (384 mL,
5.0 mmol) at À788C under an argon atmosphere and the
mixture was stirred for 1 h at the same temperature. Then,
benzoyl chloride (640 mL, 5.5 mmol) was added at À788C
and stirring was continued for 15 min. The reaction mixture
was diluted with 1 N HCl and extracted with AcOEt (3
times). The combined organic extracts were washed with
brine and dried over Na2SO4. Evaporation of solvents and
purification of the residual crude products by column chro-
matography on silica gel (hexane/AcOEt=4:1 as eluent)
gave a-benzoyl-g-butyrolactone (2a); yield: 808 mg
(4.25 mmol, 85%).
Adv. Synth. Catal. 2006, 348, 1539 – 1542
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www.asc.wiley-vch.de
1541

Takashi Ooi et al.
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[5] For the assignment of the absolute configuration, 3a
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6
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1
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Adv. Synth. Catal. 2006, 348, 1539 – 1542