β-Substituted γ-butyrolactams from mucochloric acid: Synthesis of (±)-baclofen and other γ-aminobutyric acids and useful building blocks

Article abstract of DOI:10.1039/c3ra42201a

In the course of our exploration of the application of mucohalic acids in organic synthesis, we reported the synthesis of α,β-dihalo-α, β-unsaturated γ-butyrolactams by reductive amination of a suitable mucohalic acid and a suitable amine. However, the functionalization of the α- and/or β-halogen was found to be elusive under Suzuki conditions that worked well with the corresponding γ-lactones. Although the corresponding β-aryl derivative was obtained under some of the modified Suzuki conditions tried, the yields were found to be very low. Next, the Suzuki coupling was performed on mucochloric acid prior to the reductive amination step. By careful control of the reaction conditions, only β-substitution was achieved to yield the corresponding β-aryl mucochloric acid. This could then be converted to the corresponding β-substituted γ-butyrolactam by reductive amination with 2,4-dimethoxybenzylamine (DMB-NH₂) followed by reduction by nickel boride and subsequent deprotection of the DMB group. The resulting γ-butyrolactam could either be alkylated or hydrolyzed resulting in the corresponding β-substituted γ-aminobutyric acid. This methodology was extended to synthesize (±)-baclofen in five steps starting from mucochloric acid.

Full text of DOI:10.1039/c3ra42201a

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b-Substituted g-butyrolactams from mucochloric
acid: synthesis of (ꢀ)-baclofen and other
Cite this: RSC Adv., 2014, 4, 2538
g-aminobutyric acids and useful building blocks†
Kallolmay Biswas, Rajesh Gholap, Padakanti Srinivas, Sachin Kanyal
*
and Koushik Das Sarma
In the course of our exploration of the application of mucohalic acids in organic synthesis, we reported the
synthesis of a,b-dihalo-a,b-unsaturated g-butyrolactams by reductive amination of a suitable mucohalic
acid and a suitable amine. However, the functionalization of the a- and/or b-halogen was found to be
elusive under Suzuki conditions that worked well with the corresponding g-lactones. Although the
corresponding b-aryl derivative was obtained under some of the modified Suzuki conditions tried, the
yields were found to be very low. Next, the Suzuki coupling was performed on mucochloric acid prior to
the reductive amination step. By careful control of the reaction conditions, only b-substitution was
achieved to yield the corresponding b-aryl mucochloric acid. This could then be converted to the
corresponding b-substituted g-butyrolactam by reductive amination with 2,4-dimethoxybenzylamine
(DMB-NH2) followed by reduction by nickel boride and subsequent deprotection of the DMB group. The
resulting g-butyrolactam could either be alkylated or hydrolyzed resulting in the corresponding
b-substituted g-aminobutyric acid. This methodology was extended to synthesize (ꢀ)-baclofen in five
steps starting from mucochloric acid.
Received 3rd May 2013
Accepted 17th October 2013
DOI: 10.1039/c3ra42201a
www.rsc.org/advances
synthesis of a- and/or b-substituted g-butyrolactams of biolog-
ical relevance is relatively unexplored.
Introduction
In an effort to extend the reductive amination methodology
further, we planned the regioselective synthesis of a- and/or b-
substituted g-butyrolactams starting from mucohalic acids. We
reasoned that the reactivity difference between the a- and b-halo
groups could potentially be used for regioselective arylation as
was the case for g-butenolides (option 1, Scheme 1).7 Recently,
the synthesis of b-aryl-a,b-unsaturated g-butyrolactams was
reported by stepwise Suzuki coupling on a g-lactam generated
Highly functionalized and inexpensive mucohalic acids have
found usage in organic synthesis.1 In recent times, mucohalic
acids chemistry has been extended toward the synthesis of
compounds of biological interest. For example, derivatives of
mucohalic acids have been reported for their antibacterial and
antiprotozoal activities.2 Chiral 2,5-disubstituted 1,3,4-thiadia-
zoles possessing a g-butenolide moiety have been reported for
their anticancer properties.3 A new class of compounds based
on a g-hydroxybutenolide scaffold have been reported for their
anti-inammatory properties by virtue of inhibiting microsomal
prostaglandin E synthase 1 expression.4
In general, the main utilization of mucohalic acids chemistry
has been in the area of synthesis of g-butenolide derivatives.
Mucohalic acids can easily be converted into a,b-unsaturated
a,b-dihalo-g-butyrolactam by reductive amination with a suit-
able amine.5 Extending this method further, one of the present
authors reported the synthesis of novel g-butyrolactams, short
peptides and antiseizure agent levetiracetam (Keppra®).6
However, utilization of mucohalic acids chemistry in the
Jubilant Chemsys Ltd., B-34, Sector-58, Noida, UP, 201301, India. E-mail: kdsarma@
gmail.com; koushik_sarma@jchemsys.com; Tel: +91 120-4093300
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
Scheme
1 Potential use of b-substituted g-butyrolactams and
NMR spectra for all compounds. See DOI: 10.1039/c3ra42201a
proposed retrosynthetic analysis.
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Table 1 Optimization of Suzuki conditions on g-lactam 1
from
mucobromic
acid
and
p-methoxybenzylamine
(PMB-NH2).8 However, unlike in the case of g-butyrolactones,7
ꢁ
the reaction required elevated temperature (60 C), and use of
an additional ligand (PA-Ph9). Not only that, despite using a
controlled amount (1 equiv.) of the boronic acid, a small
amount of diarylation product formation was reported.
In the present study, we set out to develop a novel method for
generating b-substituted g-butyrolactams regioselectively using
simple and mild conditions. We report the extension of this
method to generate interesting building blocks. Finally, a novel
method to synthesize GABA receptor agonist (ꢀ)-baclofen10 and
other g-aminobutyric acids is reported.
Entry Catalyst
Ligand Base
Solvent
% Yielda
1
2
3
4
5
6
7
8
9
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Cy3P
Ph3P
Cy3P
Cy3P
Cy3P
Cy3P
—
Cs2CO3
KF
CsF
Cs2CO3
Cs2CO3
K3PO4
2 M NaOH Toluene
CsF
K3PO4
KF
CsF
K2CO3
CsF
THF
THF
THF
DMF
1,4-Dioxane
1,4-Dioxane
—
—
—
—
—
—
—
—
—
—
—
—
Results and discussion
We initiated our studies with the Bn-lactam 1 generated from
mucochloric acid due to better stability of these lactams
compared to the corresponding ones with mucobromic acid.
The rst attempt of coupling with p-tolylboronic acid resulted in 11
no conversion to the monoarylated product 3 using the condi-
tions reported earlier for g-butyrolactones (Scheme 2).7
Increasing the catalyst loading to 10 mol% did not alter the
outcome of the reaction. Several conditions were screened next
to nd out the best possible conditions for arylation of 17
g-butyrolactams by Suzuki coupling.
As seen in Table 1, only the Pd(PPh3)4-catalyzed reaction
resulted in a modest yield of the desired product 3. No diary-
lated product was observed in spite of using excess boronic acid.
Encouraged by this result, we screened several boronic acids
under these reaction conditions (Table 2). However, the yields
were found to be in the range of 30–35% and could not be
improved any further by changing the catalyst and/or ligand.
Changing the amine component to 2,4-dimethoxyaniline or
2,4,6-trimethylaniline did not have any favorable impact on the
conversion.
1,4-Dioxane
DMF
Toluene
1,4-Dioxane
1,4-Dioxane
10
12
13
14
15
1,4-Dioxane 35
—
KF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
THF
1,4-Dioxane
8
—
—
—
15
—
—
—
—
Cs2CO3
K3PO4
CsF
16
18
19
20
—
CsF
—
—
Et3N
CsF
1,4-Dioxane 20
a
Isolated yield.
acids. There was no need for any protection/deprotection
strategy. Interestingly, the conversions were successful with
mucochloric acid, which is cheaper than mucobromic acid.
Table 2 Suzuki coupling of 1 with different arylboronic acidsa
As a next step, we wanted to evaluate the feasibility of per-
forming the arylation prior to reductive amination (option 2,
Scheme 1). There was no report of monoarylation by Suzuki
coupling on mucohalic acids in the literature. In the earlier
reported method utilizing mucochloric acid, only the diarylated
product was isolated.7 The reported methods on mucobromic
acid utilized the O-MEM or O-TBS derivative as a substrate
rather than unprotected mucobromic acid.4,11 The rst attempt
at coupling mucochloric acid 5 with p-tolylboronic acid resulted
in 72% isolated yield of the corresponding monoarylated
product 6a under mild conditions, as reported previously for
g-butyrolactones.7 As seen in Table 3, monoarylated
mucochloric acid could be generated from various arylboronic
Compd #
Ar
% Yieldb
4a
4b
31
36
4c
33
32
4d
a
Reaction conditions: 1 equiv. of 1, 3 equiv. of Ar-B(OH)2, 2 equiv. of CsF,
10 mol% Pd(PPh3)4 in 1,4-dioxane heated at 120 ꢁC for 18 h. b Isolated
yields.
Scheme 2 Initial attempts with Suzuki coupling on g-lactam 1.
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Table 3 Suzuki coupling of 5 with different arylboronic acidsa
Scheme 3 Synthesis of a,b-unsaturated g-butyrolactams by reductive
amination.
Compd #
Ar
% Yieldb
6a
6b
72
68
Several a,b-unsaturated g-butyrolactam derivatives were
synthesized using DMB-NH2 in moderate to good isolated yields
(Table 4).
The DMB group of a,b-unsaturated g-butyrolactams was
removed by treatment with TFA. Thus g-butyrolactam 9a
resulted in 10a in 82% isolated yield. Compound 10a was
reduced to the corresponding g-butyrolactam 11a using nickel
boride in high yield (Scheme 4).12 The g-butyrolactam 11a can
serve as a common starting point for both alkylation and
hydrolysis to give g-aminobutyric acid. Thus, alkylation at the
amide nitrogen by benzyl bromide resulted 12 (Scheme 4) and
6c
6d
6e
6f
68
70
51
48
6g
6h
68
58
20
a
Table 4 Reductive amination of 5-hydroxy furanones with DMB-NH2
6i
6j
47
55
Compd #
Ar
% Yieldb
9a
9b
68
55
6k
a
Reaction conditions: 1 equiv. of 5, 2 equiv. of Ar-B(OH)2, 2 equiv. of CsF,
10 mol% PdCl2(PPh3)2, 10 mol% Bu4NCl, 1 : 1 PhMe–H2O, rt, 18 h.
b
Isolated yields.
9c
9d
9e
9f
50
52
40
40
Thus, from a scale-up point of view, these conversions were
found to be cost efficient. The Suzuki coupling was also
successful with vinylboronic acids (6j and 6k).
With the success of monoarylation via Suzuki coupling,
these g-hydroxyfuranones were studied for their propensity
toward reductive amination. Using the conditions reported
before,6,7 the corresponding g-butyrolactam 7 could be formed
from 6 with benzylamine (Scheme 3) in 48% isolated yield. The
conversion was studied further with PMB-NH2 and DMB-NH2.
Although the yield with PMB-NH2 for 8 was comparable to that
for 7, the yield with DMB-NH2 was improved to 68% for 9a.
The advantage of DMB and PMB is that these can be removed
under acidic conditions, making the N available for further
alkylation.
9g
43
45
9h
a
Reaction conditions: 1 equiv. of 6, 1.5 equiv. of DMB-NH2, 1.5 equiv. of
NaBH(OAc)3, 0.1 equiv. AcOH, CHCl3, rt, overnight. b Isolated yields.
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follows: chemical shi (in ppm on the d scale), multiplicity (s ¼
singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), the
coupling constant (J, in hertz) and integration. The 13C data is
reported as the ppm on the d scale followed by the interpreta-
tion. Electrospray and electron impact high resolution mass
spectrometry was performed using a Waters® Q-TOF Micro™
instrument. The data is recorded as the ionisation method
followed by the calculated and measured masses. TLC was
performed on Merck 60F254 silica plates and visualized by UV
light and/or anisaldehyde or potassium permanganate stains.
The compounds were puried by ash chromatography using
Merck Kieselgel 60 (particle size 35–70) silica under a positive
pressure. All solvents were dried before use unless otherwise
stated. Mucochloric acid (5) and caesium uoride (CsF) were
purchased from Sigma-Aldrich Co. All other chemicals were
purchased from a chemical supplier and used as received.
General procedure (for entries in Table 2) for arylation
reactions
Scheme 4 Synthetic utilization of a,b-unsaturated g-butyrolactams.
To a solution of Bn-lactam 1 (2.9 mmol, 1.0 equiv.) in 1,4-
dioxane (10 mL) was slowly added arylboronic acid (8.7 mmol,
3.0 equiv.) under N2 at room temperature. The reaction mixture
was then degassed for 10 min under the ow of nitrogen. To it
were added Pd(PPh3)4 (0.29 mmol, 0.1 equiv.) and CsF
(5.8 mmol, 2.0 equiv.). The whole reaction mixture was heated
hydrolysis using 6 M HCl under reux resulted in the corre-
sponding g-aminobutyric acid 13a. Similarly, g-aminobutyric
acid 13b was synthesized starting from 9b.
The use of nickel boride in a,b-unsaturated g-butyrolactam
reduction allowed us to use this method to synthesize
(ꢀ)-baclofen starting from 4-chlorophenylboronic acid and
mucochloric acid in ve steps (16, Scheme 5).
ꢁ
at 120 C for 18 h. It was then ltered through a pad of Celite.
The ltrate was extracted with ethyl acetate (3 ꢂ 50 mL). The
combined organic layer was dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was
puried by ash chromatography on silica gel (dry loading)
from a mixed solvent of hexane–ethyl acetate (7 : 1) as an eluent
to give the corresponding arylation products.
Experimental
General methods
Melting points are uncorrected. H and 13C NMR spectra were
recorded on a Bruker Ultrashield™ (400 MHz) instrument and
calibrated to residual solvent peaks: proton (CDCl3 7.26 ppm)
and carbon (CDCl3 77.0 ppm). The 1H data is presented as
1
General procedure for arylation reactions (6)
To a solution of mucochloric acid 5 (2.9 mmol, 1.0 equiv.) in
toluene–water (10 mL, 1 : 1) was slowly added arylboronic acid
(5.8 mmol, 2.0 equiv.) under N2 at room temperature. The
reaction mixture was then degassed for 10 min under a ow of
nitrogen. To it were added tetrabutylammonium chloride
(TBAC) (0.29 mmol, 0.1 equiv.), PdCl2(PPh3)2 (0.29 mmol,
0.1 equiv.) and CsF (5.8 mmol, 2.0 equiv.). The whole reaction
mixture was stirred at room temperature for 18 h. It was then
ltered through a pad of Celite. The ltrate was extracted with
ethyl acetate (3 ꢂ 50 mL). The combined organic layer was dried
over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude was puried by ash chromatography on
silica gel from a mixed solvent of hexane–ethyl acetate as an
eluent to afford the corresponding arylation products.
3-Chloro-5-hydroxy-4-(p-tolyl)furan-2(5H)-one (6a). Flash
chromatography (silica gel, hexane–ethyl acetate ¼ 10 : 1)
1
ꢁ
afforded 6a (469 mg, 72%); white solid; mp 63–65 C. H NMR
(400 MHz, DMSO-d6): d 8.33 (d, J ¼ 9.0 Hz, 1H), 7.62 (d, J ¼ 8.0
Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H), 6.16 (d, J ¼ 9.0 Hz, 1H), 2.36
(s, 3H); 13C NMR (100 MHz, DMSO-d6): d 167.6, 149.1, 139.6,
129.2, 128.3, 126.5, 124.4, 96.5, 21.0; HRMS (ESI+) calcd for
(M + H)+ C11H10ClO3: 225.0313, found: 225.0314.
Scheme 5 Synthesis of (ꢀ)-baclofen.
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1H), 6.22 (d, J ¼ 8.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d
167.1, 151.5, 132.5, 129.9, 129.2 (q, J ¼ 255.8 Hz, CF3), 128.3,
127.9, 125.2, 122.5, 119.8, 125.6, 124.8, 96.7; HRMS (ESI+) calcd
for (M + H)+ C11H7ClF3O3: 279.0030, found: 279.0040.
3-Chloro-5-hydroxy-4-(o-tolyl)furan-2(5H)-one (6i). Flash
chromatography (silica gel, hexane–ethyl acetate ¼ 10 : 1)
afforded 6i (130 mg, 20%) as a light yellow liquid. 1H NMR (400
MHz, CDCl3): d 7.33–7.36 (m, 1H), 7.23–7.29 (m, 2H), 7.17–7.19
(m, 1H), 6.14 (s, 1H), 2.25 (s, 3H); 13C NMR (100 MHz, DMSO-
d6): d 167.3, 152.3, 136.7, 130.4, 129.7, 128.5, 127.0, 125.8, 96.6,
19.1; HRMS (ESI+) calcd for (M + H)+ C11H10ClO3: 225.0313,
found: 225.0316.
(E)-3-Chloro-5-hydroxy-4-styrylfuran-2(5H)-one (6j). Flash
chromatography (silica gel, hexane–ethyl acetate ¼ 15 : 1)
afforded 6j (322 mg, 47%); grey solid; mp 135–138 ꢁC. 1H NMR
(400 MHz, DMSO-d6): d 8.31 (d, J ¼ 9.0 Hz, 1H), 7.79 (d, J ¼ 16.4
Hz, 1H), 7.66 (d, J ¼ 7.2 Hz, 2H), 7.35–7.43 (m, 3H), 6.87 (d, J ¼
16.4 Hz, 1H), 6.13 (d, J ¼ 9.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d 167.1, 148.7, 136.4, 135.6, 129.3, 128.9, 127.2,
124.3, 119.2, 115.6, 114.1, 96.4; HRMS (ESI+) calcd for (M + H)+
C12H10ClO3: 237.0313, found: 237.0315.
3-Chloro-5-hydroxy-4-phenylfuran-2(5H)-one (6b). Flash
chromatography (silica gel, hexane–ethyl acetate ¼ 9 : 1) affor-
1
ded 6b (415 mg, 68%); light yellow solid; mp 109–111 ꢁC. H
NMR (400 MHz, DMSO-d6): d 8.36 (d, J ¼ 8.8 Hz, 1H), 7.71 (t, J ¼
8.0 Hz, 2H), 7.47–7.55 (m, 3H), 6.19 (d, J ¼ 8.8 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d 167.5, 149.9, 134.1, 130.0, 129.7, 128.6,
127.3, 126.7, 96.6; HRMS (ESI+) calcd for (M + H)+ C10H8ClO3:
211.0156, found: 211.0165.
3-Chloro-4-(4-chlorophenyl)-5-hydroxyfuran-2(5H)-one (6c).
Flash chromatography (silica gel, hexane–ethyl acetate ¼ 12 : 1)
afforded 6c (483 mg, 68%); off-white solid; mp 93–96 ꢁC. 1H
NMR (400 MHz, DMSO-d6): d 8.40 (d, J ¼ 8.5 Hz, 1H), 7.78 (d, J ¼
8.6 Hz, 2H), 7.61 (d, J ¼ 8.6 Hz, 2H), 6.19 (d, J ¼ 8.5 Hz, 1H); 13
C
NMR (100 MHz, DMSO-d6): d 167.3, 150.5, 135.9, 134.5, 130.3,
128.8, 127.4, 126.1, 125.6, 96.6; HRMS (ESI+) calcd for (M + H)+
C10H7Cl2O3: 244.9767, found: 244.9770.
3-Chloro-5-hydroxy-4-(4-methoxyphenyl)furan-2(5H)-one (6d).
Flash chromatography (silica gel, hexane–ethyl acetate ¼ 10 : 1)
ꢁ
afforded 6d (488 mg, 70%); light yellow solid; mp 118–120 C.
1H NMR (400 MHz, DMSO-d6): d 8.30 (d, J ¼ 8.9 Hz, 1H), 7.72
(distorted doublet, J ¼ 8.9 Hz, 2H), 7.09 (distorted doublet, J ¼
8.9 Hz, 2H), 6.15 (d, J ¼ 8.9 Hz, 1H), 3.81 (s, 3H); 13C NMR (100
MHz, DMSO-d6): d 167.7, 160.2, 147.8, 129.9, 125.9, 119.4, 114.1,
96.4, 55.3; HRMS (ESI+) calcd for (M + H)+ C11H10ClO4: 241.0262,
found: 241.0270.
3-Chloro-5-hydroxy-4-(2-methylprop-1-en-1-yl)furan-2(5H)-one
(6k). Flash chromatography (silica gel, hexane–ethyl acetate ¼
15 : 1) afforded 6k (301 mg, 55%); a pale yellow liquid. 1H NMR
(400 MHz, DMSO-d6): d 8.22 (d, J ¼ 8.8 Hz, 1H), 6.07 (d, J ¼ 8.8
Hz, 1H), 5.62 (s, 1H), 1.88 (s, 3H), 1.69 (s, 3H); 13C NMR (100
MHz, DMSO-d6): d 167.9, 149.5, 144.7, 126.9, 110.8, 96.7, 25.8,
21.1; HRMS (ESI+) calcd for (M + H)+ C8H10ClO3: 189.0313,
found: 189.0311.
3-Chloro-5-hydroxy-4-(4-(triuoromethyl)phenyl)furan-2(5H)-
one (6e). Flash chromatography (silica gel, hexane–ethyl acetate
¼ 15 : 1) afforded 6e (412 mg, 51%); off-white solid; mp 105–107
ꢁC. 1H NMR (400 MHz, DMSO-d6): d 8.33 (d, J ¼ 9.2 Hz, 1H), 7.62
(d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.0 Hz, 2H), 6.16 (d, J ¼ 8.8 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d 167.1, 151.9, 131.3, 129.9
(q, J ¼ 255.8 Hz, CF3), 129.3, 127.9, 125.2, 122.5, 119.8, 125.8,
125.5, 125.5, 96.7; HRMS (ESI+) calcd for (M + H)+ C11H7ClF3O3:
279.0030, found: 279.0034.
3-Chloro-5-hydroxy-4-(4-(triuoromethoxy)phenyl)furan-2(5H)-
one (6f). Flash chromatography (silica gel, hexane–ethyl acetate
¼ 15 : 1) afforded 6f (410 mg, 48%); light yellow solid; mp 90–92
ꢁC. 1H NMR (400 MHz, DMSO-d6): d 8.42 (d, J ¼ 8.8 Hz, 1H), 7.85
(d, J ¼ 9.2 Hz, 2H), 7.55 (d, J ¼ 8.4 Hz, 2H), 6.21 (d, J ¼ 8.8 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d 167.3, 150.8, 148.9, 130.7,
126.5, 125.6, 121.1, 96.7, 123.8, 120.6 (q, J ¼ 255.8 Hz, CF3);
HRMS (ESI+) calcd for (M + H)+ C11H7ClF3O4: 294.9979, found:
294.9984.
3-Chloro-4-(3-chlorophenyl)-5-hydroxyfuran-2(5H)-one (6g).
Flash chromatography (silica gel, hexane–ethyl acetate ¼ 12 : 1)
afforded 6g (483 mg, 68%); light yellow solid; mp 102–104 ꢁC. 1H
NMR (400 MHz, DMSO-d6): d 8.43 (d, J ¼ 8.8 Hz, 1H), 7.70–7.73
(m, 1H), 7.66–7.69 (m, 1H), 7.55–7.60 (m, 2H), 6.20 (d, J ¼ 8.8
Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d 167.2, 151.2, 133.4,
130.6, 129.7, 129.4, 128.1, 127.2, 125.6, 96.7; HRMS (ESI+) calcd
for (M + H)+ C10H7Cl2O3: 244.9767, found: 244.9776.
3-Chloro-5-hydroxy-4-(3-(triuoromethyl)phenyl)furan-2(5H)-
one (6h). Flash chromatography (silica gel, hexane–ethyl acetate
¼ 15 : 1) afforded 6h (468 mg, 58%); off-white solid; mp 124–126
ꢁC. 1H NMR (400 MHz, DMSO-d6): d 8.47 (d, J ¼ 8.8 Hz, 1H), 8.02
(d, J ¼ 6.8 Hz, 2H), 7.89 (d, J ¼ 7.7 Hz, 1H), 7.79 (d, J ¼ 8.0 Hz,
General procedure for reductive amination reactions (7–9)
To a solution of 3-chloro-5-hydroxy-4-arylfuran-2(5H)-one 6
(2.0 mmol) in chloroform (20 mL) was slowly added amine
(3.0 mmol, 1.5 equiv.) at room temperature before cooling to 0–
5 ꢁC. Acetic acid (0.2 mmol, 0.1 equiv.) was then added and the
reaction mixture was allowed to warm at room temperature.
Stirring was continued for one additional hour. Finally, sodium
triacetoxyborohydride (3.0 mmol, 1.5 equiv.) was slowly added
to the reaction mixture and it was kept stirring at room
temperature overnight. Water was added to the reaction
mixture and extracted with chloroform. The organic phases
were dried over anhydrous Na2SO4, and concentrated under
reduced pressure. The crude was puried by ash chromatog-
raphy on silica gel (dry loading) from a mixed solvent of ethyl
acetate and hexane to give the corresponding reductive ami-
nation products.
1-Benzyl-3-chloro-4-phenyl-1H-pyrrol-2(5H)-one (7). Flash
chromatography (silica gel, hexane–ethyl acetate ¼ 4 : 1)
afforded 7 (409 mg, 48%) as a colourless oil. 1H NMR (400
MHz, DMSO-d6): d 7.69–7.71 (m, 2H), 7.46–7.48 (m, 2H),
7.42–7.44 (d, J ¼ 7.2 Hz, 1H), 7.35–7.39 (m, 3H), 7.28–7.31
(m, 2H), 4.63 (s, 2H), 4.23 (s, 2H); 13C NMR (100 MHz, DMSO-
d6): d 167.8, 141.7, 137.6, 130.9, 129.9, 129.8, 129.2, 129.1,
129.1, 128.9, 128.7, 128.6, 128.5, 128.3, 93.5, 54.1, 45.7;
HRMS (ESI+) calcd for (M + H)+ C17H15ClNO: 284.0837,
found: 284.0844.
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3-Chloro-1-(4-methoxybenzyl)-4-phenyl-1H-pyrrol-2(5H)-one
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13C NMR (100 MHz, DMSO-d6): d 166.7, 160.3, 158.1, 150.7,
143.0, 133.5 (q, J ¼ 255.8 Hz, CF3), 129.6, 129.5, 129.3, 129.0,
125.5, 116.7, 104.4, 98.4, 55.4, 55.2, 54.1, 41.2; HRMS (ESI+)
calcd for (M + H)+ C20H18ClF3NO3: 412.0922, found: 412.0931.
3-Chloro-1-(2,4-dimethoxybenzyl)-4-(4-(triuoromethoxy)-
phenyl)-1H-pyrrol-2(5H)-one (9f). Flash chromatography (silica
gel, hexane–ethyl acetate ¼ 7 : 1) afforded 9f (343 mg, 40%) as a
viscous liquid. 1H NMR (400 MHz, DMSO-d6): d 7.84 (d, J ¼ 8.4
Hz, 2H), 7.48 (d, J ¼ 8.0 Hz, 2H), 7.08 (d, J ¼ 8.4 Hz, 1H), 6.49–
6.58 (m, 2H), 4.51 (s, 2H), 4.20 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H);
13C NMR (100 MHz, DMSO-d6): 166.8, 160.2, 158.0, 148.2, 141.8,
130.7, 130.6, 130.1, 129.2, 128.6 (q, J ¼ 255.8 Hz, CF3), 120.7,
119.4, 116.9, 114.1, 104.5, 98.4, 55.5, 55.3, 53.9, 40.1; HRMS
(ESI+) calcd for (M + H)+ C20H18ClF3NO4: 428.0871, found:
428.0874.
3-Chloro-4-(3-chlorophenyl)-1-(2,4-dimethoxybenzyl)-1H-pyr-
rol-2(5H)-one (9g). Flash chromatography (silica gel, hexane–
ethyl acetate ¼ 7 : 1) afforded 9g (326 mg, 43%) as a light yellow
oil. 1H NMR (400 MHz, DMSO-d6): d 7.75 (s, 1H), 7.68 (d, J ¼ 6.4
Hz, 1H), 7.51 (d, J ¼ 6.4 Hz, 2H), 7.10 (d, J ¼ 8.4 Hz, 1H), 6.59 (d,
J ¼ 2.0 Hz, 1H), 6.50 (d, J ¼ 8.4 Hz, 1H), 4.55 (s, 2H), 4.20 (s, 2H),
3.81 (s, 3H), 3.75 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 166.7,
160.3, 158.0, 142.3, 132.9, 131.4, 130.2, 129.0, 128.6, 128.1,
127.1, 116.7, 104.7, 98.4, 55.5, 55.2, 54.0, 40.3; HRMS (ESI+)
calcd for (M + H)+ C19H18Cl2NO3: 378.0658, found: 378.0662.
3-Chloro-1-(2,4-dimethoxybenzyl)-4-(3-(triuoromethyl)-
phenyl)-1H-pyrrol-2(5H)-one (9h). Flash chromatography (silica
gel, hexane–ethyl acetate ¼ 9 : 1) afforded 9h (371 mg, 45%) as a
light yellow oil. 1H NMR (400 MHz, DMSO-d6) d 8.05 (s, 1H), 8.01
(d, J ¼ 6.9 Hz, 1H), 7.80 (d, J ¼ 7.8 Hz, 1H), 7.73 (t, J ¼ 7.7 Hz,
1H), 7.11 (d, J ¼ 8.5 Hz, 1H), 6.59 (s, 1H), 6.49–6.59 (m, 1H), 4.52
(s, 2H), 4.23 (s, 2H), 3.82 (s, 3H), 3.75 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 167.8, 161.1, 158.7, 141.8, 132.2, 131.7,
130.6, 130.4, 129.3 (q, J ¼ 255.8 Hz, CF3), 128.8, 125.9, 125.8,
117.2, 104.6, 98.7, 55.6, 55.6, 54.5, 40.8; HRMS (ESI+) calcd for
(M + H)+ C20H18ClF3NO3: 412.0922, found: 412.0929.
(8). Flash chromatography (silica gel, hexane–ethyl acetate ¼
5 : 1) afforded 8 (471 mg, 50%) as a light yellow oil. 1H NMR (400
MHz, DMSO-d6): d 7.69–7.71 (m, 2H), 7.48–7.50 (m, 3H), 7.23 (d,
J ¼ 8.6 Hz, 2H), 6.92 (d, J ¼ 8.6 Hz, 2H), 4.58 (s, 2H), 4.16 (s, 2H),
3.73 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 167.1, 158.6,
141.0, 130.4, 130.1, 129.3, 129.2, 129.1, 129.0, 128.6, 128.5,
128.4, 128.3, 114.3, 96.5, 55.1, 53.4, 44.7; HRMS (ESI+) calcd for
(M + H)+ C18H17ClNO2: 314.0942, found: 314.0946.
3-Chloro-1-(2,4-dimethoxybenzyl)-4-phenyl-1H-pyrrol-2(5H)-
one (9a). Flash chromatography (silica gel, hexane–ethyl acetate
1
¼ 5 : 1) afforded 9a (468 mg, 68%) as a colourless oil. H NMR
(400 MHz, DMSO-d6) 7.68 (d, J ¼ 8.0 Hz, 2H), 7.39–7.52 (m, 3H),
7.09 (d, J ¼ 8.4 Hz, 1H), 6.59 (s, 1H), 6.50 (d, J ¼ 8.8 Hz, 1H), 4.50
(s, 2H), 4.18 (s, 2H), 3.81 (s, 3H), 3.75 (s, 3H); 13C NMR (100
MHz, DMSO-d6): d 167.1, 160.2, 158.0, 140.9, 130.5, 130.2, 129.7,
129.4, 128.7, 128.6, 128.5, 128.2, 116.9, 104.7, 98.4, 55.5, 55.2,
53.9, 40.2; HRMS (ESI+) calcd for (M + H)+ C19H19ClNO3:
344.1048, found: 344.1055.
3-Chloro-1-(2,4-dimethoxybenzyl)-4-(p-tolyl)-1H-pyrrol-2(5H)-
one (9b). Flash chromatography (silica gel, hexane–ethyl acetate
¼ 5 : 1) afforded 9b (394 mg, 55%) as a yellow solid; mp 107–109
ꢁC. 1H NMR (400 MHz, DMSO-d6): d 7.59–7.61 (m, 2H), 7.27 (d, J
¼ 8.0 Hz, 2H), 7.08 (d, J ¼ 8.4 Hz, 1H), 6.58 (d, J ¼ 2.4 Hz, 1H),
6.48–6.51 (m, 1H), 4.49 (s, 2H), 4.15 (s, 2H), 3.81 (s, 3H), 3.75 (s,
3H); 13C NMR (100 MHz, DMSO-d6): d 167.2, 160.2, 158.0, 149.1,
140.1, 139.5, 138.2, 130.2, 129.1, 128.9, 128.4, 126.5, 116.9,
104.7, 98.4, 55.5, 55.2, 53.8, 40.2; HRMS (ESI+) calcd for (M + H)+
C20H21ClNO3: 358.1204, found: 358.1212.
3-Chloro-4-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-1H-pyr-
rol-2(5H)-one (9c). Flash chromatography (silica gel, hexane–
ethyl acetate ¼ 7 : 1) afforded 9c (379 mg, 50%) as a colourless
oil. 1H NMR (400 MHz, DMSO-d6): d 7.74 (d, J ¼ 8.8 Hz, 2H), 7.55
(d, J ¼ 8.4 Hz, 2H), 7.09 (d, J ¼ 8.4 Hz, 1H), 6.59 (d, J ¼ 2.4 Hz,
1H), 6.50 (dd, J ¼ 8.4 and 6.4 Hz, 1H), 4.50 (s, 2H), 4.19 (s, 2H),
3.81 (s, 3H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3): d 167.0,
160.9, 158.6, 140.7, 134.7, 131.6, 130.2, 130.2, 130.1, 128.8,
128.5, 128.0, 117.2, 104.5, 98.7, 55.5, 55.4, 54.4, 40.7; HRMS
(ESI+) calcd for (M + H)+ C19H18Cl2NO3: 378.0658, found:
378.0662.
General procedure for the synthesis of 3-chloro-4-ayrl-1H-
pyrrol-2(5H)-one (10a, 10b, 14)
To a solution of 3-chloro-1-(2,4-dimethoxybenzyl)-4-aryl-1H-
pyrrol-2(5H)-one (1.5 mmol) in dichloroethane (10.0 mL) was
added TFA (4.5 mL) and the reaction mixture was stirred at 80
ꢁC for 2 h. Aer monitoring by TLC, the reaction mixture was
evaporated to dryness. It was then puried over silica gel
column chromatography using the solvent system hexane–ethyl
acetate to afford the corresponding pyrrol-2(5H)-one.
3-Chloro-1-(2,4-dimethoxybenzyl)-4-(4-methoxyphenyl)-1H-
pyrrol-2(5H)-one (9d). Flash chromatography (silica gel,
hexane–ethyl acetate ¼ 7 : 1) afforded 9d (389 mg, 52%) as a
1
colourless oil. H NMR (400 MHz, DMSO-d6): d 7.81 (d, J ¼ 8.8
Hz, 2H), 6.86–7.09 (m, 3H), 6.58 (s, 1H), 6.49–6.51 (m, 1H), 4.49
(s, 2H), 4.14 (s, 2H), 3.81 (s, 6H), 3.75 (s, 3H); 13C NMR (100
MHz, DMSO-d6): d 167.3, 160.2, 159.4, 158.01, 147.7, 139.0,
130.0, 125.9, 121.7, 119.4, 116.9, 114.1, 113.6, 104.7, 98.4, 55.5,
55.1, 53.7, 40.1; HRMS (ESI+) calcd for (M + H)+ C20H21ClNO4:
374.1154, found: 374.1161.
3-Chloro-4-phenyl-1H-pyrrol-2(5H)-one (10a). Flash chroma-
tography (silica gel, hexane–ethyl acetate ¼ 3 : 1) afforded 10a
1
ꢁ
(198 mg, 68%) as a brown solid; mp 149–151 C. H NMR (400
MHz, DMSO-d6): d 8.63 (bs, 1H), 7.66 (d, J ¼ 7.2 Hz, 2H), 7.46 (t, J
3-Chloro-1-(2,4-dimethoxybenzyl)-4-(4-(triuoromethyl)phenyl)-
1H-pyrrol-2(5H)-one (9e). Flash chromatography (silica gel,
hexane–ethyl acetate ¼ 7 : 1) afforded 9e (330 mg, 40%) as a
¼ 8.0 and 6.8 Hz, 2H), 7.39 (d, J ¼ 7.2 Hz, 1H), 4.20 (s, 2H); 13
C
NMR (100 MHz, DMSO-d6): d 169.7, 142.8, 130.7, 129.4, 128.6,
128.5, 128.1 49.6; HRMS (ESI+) calcd for (M + H)+ C10H9ClNO:
194.0367, found: 194.0370.
1
colourless oil. H NMR (400 MHz, DMSO-d6): d 7.94 (d, J ¼ 8.4
Hz, 2H), 7.68 (d, J ¼ 8.4 Hz, 2H), 7.25 (t, J ¼ 8.4 Hz, 1H), 6.45 (d, J
¼ 8.4 Hz, 2H), 4.64 (s, 2H), 4.05 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H);
3-Chloro-4-(p-tolyl)-1H-pyrrol-2(5H)-one (10b). Flash chro-
matography (silica gel, hexane–ethyl acetate ¼ 3 : 1) afforded
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1
ꢁ
10b (218 mg, 70%) as a light yellow solid; mp 126–129 C. H one 11a (70 mg, 0.43 mmol) in THF (0.50 mL) and benzyl
NMR (400 MHz, DMSO-d6): d 8.58 (s, H), 7.59 (d, J ¼ 8.0 Hz, 2H), bromide (74 mg, 0.43 mmol) in THF (0.50 mL). The whole
7.27 (d, J ¼ 8.0 Hz, 2H), 4.17 (s, 2H), 2.33 (s, 2H); 13C NMR (100 reaction mixture was stirred at room temperature for 0.5 h. It
MHz, DMSO-d6): d 169.8, 142.0, 138.0, 130.5, 128.7, 128.4, 126.6, was then quenched with ice cold water (2.0 mL) and extracted
49.5, 20.9; HRMS (ESI+) calcd for (M + H)+ C11H11ClNO: with ethyl acetate (3 ꢂ 5 mL). The combined organic layer was
208.0524, found: 208.0533.
dried over Na2SO4, ltered and concentrated under reduced
3-Chloro-4-(4-chlorophenyl)-1H-pyrrol-2(5H)-one (14). Flash pressure. The crude was puried over silica gel from a mixed
chromatography (silica gel, hexane–ethyl acetate ¼ 3 : 1) affor- solvent of hexane–ethyl acetate (5 : 1) as an eluent to give 12 as a
1
ded 14 (257 mg, 75%) as a light yellow solid; mp 178–180 ꢁC. 1H yellow viscous liquid, yield (54 mg, 52%). H NMR (400 MHz,
NMR (400 MHz, DMSO-d6): d 8.67 (s, H), 7.73 (d, J ¼ 8.80 Hz, DMSO-d6): d 7.35–7.26 (m, 10H), 4.60 (d, J ¼ 14.4 Hz, 1H), 4.47
2H), 7.55 (d, J ¼ 8.40 Hz, 2H), 4.20 (s, 2H); 13C NMR (100 MHz, (d, J ¼ 14.4 Hz, 1H), 3.73 (t, J ¼ 8.8 and 8.4 Hz, 1H), 3.27–3.39
DMSO-d6): d 169.4, 143.4, 133.2, 130.3, 129.5, 128.2, 49.71; (m, 2H), 2.46–2.54 (m, 1H), 2.06–2.13 (m, 1H); 13C NMR (100
HRMS (ESI+) calcd for (M + H)+ C10H8Cl2NO: 227.9977, found: MHz, CDCl3): d 174.9, 140.0, 136.6, 128.8, 128.3, 128.0, 127.7,
227.9980.
127.1, 48.3, 47.2, 45.0, 27.9; LCMS: 252.14 (M
purity: 98.9%.
+
H)+,
General procedure for the synthesis of 4-ayrlpyrrolidin-2-one
(11a, 11b, 15)
General procedure for the synthesis of 4-amino-3-arylbutanoic
acid hydrochloride (13a, 13b, 16)
To a solution of 3-chloro-4-aryl-1H-pyrrol-2(5H)-one (1.0 mmol,
1.0 equiv.) in MeOH–THF (8 mL, 1 : 1) was slowly added NiCl2
(6.0 mmol, 6.0 equiv.) at 0 ꢁC followed by the addition of sodium
borohydride (6.0 mmol, 6.0 equiv.) and the reaction mixture was
allowed to warm at room temperature. The reaction was
monitored by TLC. It was then ltered through a pad of Celite.
The ltrate was concentrated under reduced pressure to obtain
a gummy residue which was then washed with pentane to
remove the unwanted impurities. This affords the correspond-
ing pyrrolidin-2-one product.
A solution of 4-arylpyrrolidin-2-one (1.0 mmol) in 6 M HCl (5.0
mL) was reuxed for 16 h. Aer the completion of reaction (TLC
monitoring), the reaction mixture was concentrated under
reduced pressure to obtain a gummy residue. It was triturated
with isopropanol to obtain corresponding butanoic acid as a
pure product.
4-Amino-3-phenylbutanoic acid hydrochloride (13a).15
General procedure described above was followed to obtain 13a
1
ꢁ
(99 mg, 55%) as a brown solid; mp 176–178 C. H NMR (400
MHz, DMSO-d6): d 12.57 (s, 1H), 8.021 (bs, 2H), 7.34–7.37 (m,
2H), 7.27–7.29 (m, 3H), 3.70–3.73 (m, 1H), 2.50–2.71 (m, 2H),
2.18–2.27 (m, 1H) and 1.90–1.99 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): d 174.0, 138.7, 128.6, 127.7, 127.2, 47.6, 36.9, 30.3;
LCMS: 180.11 (M + H)+, purity: 98.3%.
4-Phenylpyrrolidin-2-one
(11a).13
General
procedure
described above was followed to obtain 11a (149 mg, 92%) as an
1
ꢁ
off-white solid; mp 73–75 C. H NMR (400 MHz, DMSO-d6): d
7.81 (bs, 1H), 7.11 (t, J ¼ 8.0 and 6.8 Hz, 2H), 7.22 (t, J ¼ 6.8 and
6.4 Hz, 3H), 3.51 (t, J ¼ 18 and 9.2 Hz, 1H), 3.24–3.31 (m, 2H),
2.43–2.50 (m, 1H), 2.01–2.11 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): d 176.9, 140.6, 128.3, 128.1, 126.4, 46.9, 39.6, 30.1;
HRMS (ESI+) calcd for (M + H)+ C10H12NO: 162.0913, found:
162.0921.
4-Amino-3-(p-tolyl)butanoic acid (13b).16 General procedure
described above was followed to obtain 13b (120 mg, 62%) as a
1
ꢁ
brown solid; mp 203–205 C. H NMR (400 MHz, DMSO-d6): d
12.54 (bs, 1H), 7.94 (bs, 2H), 7.16 (appeared as bs, 4H), 3.63–3.70
(m, 1H), 2.67–2.73 (m, 1H), 2.55–2.59 (m, 1H), 3.14 (s, 3H), 2.19–
2.24 (m, 1H) and 1.90–1.96 (m, 1H); 13C NMR (100 MHz, DMSO-
d6): d 174.1, 136.3, 135.7, 129.2, 127.6, 47.2, 36.9, 30.3, 20.6;
LCMS: 193.92 (M + H)+, purity: 97.5%.
4-(p-Tolyl)pyrrolidin-2-one
(11b).
General procedure
described above was followed to obtain 11b (90 mg, 51%) as an
off-white solid; mp 137–139 ꢁC. 1H NMR (400 MHz, DMSO-d6): d
7.76 (s, 1H), 7.11 (appeared as bs, 4H), 3.43–3.50 (m, 1H), 3.23–
3.32 (m, 2H), 2.40–2.45 (m, 1H), 1.98–2.07 (m, 1H); 13C NMR
(100 MHz, DMSO-d6): d 176.9, 137.5, 135.3, 128.8, 127.8, 47.4,
39.6, 30.1, 20.5; HRMS (ESI+) calcd for (M + H)+ C11H14NO:
176.1070, found: 176.1077.
4-Amino-3-(4-chlorophenyl)butanoic acid (16).17 General
procedure described above was followed to obtain 16 (173 mg,
81%) as a brown solid; mp 188–190 ꢁC. 1H NMR (400 MHz,
DMSO-d6): d 12.67 (bs, 1H), 7.85 (bs, 2H), 7.43 (d, J ¼ 8.4 Hz,
2H), 7.31 (d, J ¼ 8.4 Hz, 2H), 3.75 (t, J ¼ 8.0 and 7.6 Hz, 1H),
2.70–2.75 (m, 1H), 2.50–2.58 (m, 1H), 2.19–2.21 (m, 1H), 1.92–
1.95 (m, 1H); 13C NMR (100 MHz, DMSO-d6): d 173.7, 137.7,
131.8, 129.7, 128.6, 47.6, 36.8, 30.2; LCMS: 213.80 (M + H)+,
purity: 95.9%.
4-(4-Chlorophenyl)pyrrolidin-2-one (15). General procedure
described above was followed to obtain 15 (112 mg, 57%) as an
off-white solid; mp 151–153 ꢁC. 1H NMR (400 MHz, DMSO-d6): d
7.85 (s, 1H), 7.38 (d, J ¼ 8.40 Hz, 2H), 7.27 (d, J ¼ 8.40 Hz, 2H),
3.51–3.58 (m, 1H), 3.23–3.32 (m, 2H), 2.42–2.49 (m, 1H), 2.02–
2.09 (m, 1H); 13C NMR (100 MHz, DMSO-d6): d 176.4, 139.5,
131.1, 129.9, 128.2, 128.2, 126.4, 46.9, 39.5, 30.1; HRMS (ESI+)
calcd for (M + H)+ C10H11ClNO: 196.0524, found: 196.0526.
Conclusion
1-Benzyl-4-phenylpyrrolidin-2-one (12).14 To
a
stirred In summary, we have successfully developed a novel method to
suspension of sodium hydride (16 mg, 0.645 mmol) in dry THF generate regioselectively b-substituted g-butyrolactams using
(1.0 mL) at 0 ꢁC were added sequentially solution of 18-crown-6 simple and mild conditions starting from mucochloric acid.
(56 mg, 0.215 mmol) in THF (0.20 mL), 4-phenylpyrrolidin-2- The nitrogen of the reduced lactam can be used for alkylation.
2544 | RSC Adv., 2014, 4, 2538–2545
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The reduced lactams can easily be converted to g-aminobutyric
acids by acid hydrolysis. This method was utilized further to
synthesize (ꢀ)-baclofen starting from mucochloric acid. We are
exploring further application of these building blocks, espe-
cially enantioselective synthesis. The results will be reported in
due course.
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M. D. Guerrero, M. C. Terencio, M. Paya and R. Riccio,
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9 1,3,5,7-Tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo
[3.3.1.13,7]decane.
Acknowledgements
The authors thank Jubilant Chemsys management for support.
Analytical support from Mr Narendra Pratap Singh is gratefully
acknowledged. K.D.S. thanks past colleagues from Pzer, Ann
Arbor, Drs Ji Zhang (presently at King Kai-Ray Pharma) and Tim
Curran (presently at Vertex) for their encouragement in
continuing research in mucohalic acids chemistry. The
reviewers are gratefully acknowledged for their feedback.
10 (a) J. Lei, M. Yuheng, L. Jin, Z. Liangren and Z. Lihe,
Tetrahedron Lett., 2009, 50, 6166; (b) T. Ibuka,
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