Enantioselective synthesis of hexahydroisobenzofuran and hexahydro-isoindole derivatives with quaternary stereocenters

Article abstract of DOI:10.1055/s-0030-1258419

Oxo esters with pyrrolidine and tetrahydrofuran rings were converted into optically active isobenzofuran and isoindole derivatives. The key step of the sequence was a copper-catalyzed asymmetric Michael reaction with methyl vinyl ketone and en-amines prepared from the oxo esters and l-valine diethylamide. The chiral auxiliary was cleaved from the products during workup and 1,5-diketones with a quaternary stereocenter are obtained with 97-99% ee. Subsequent annulation reactions were achieved in two steps via the intermediate aldol products. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258419

PAPER
895
Enantioselective Synthesis of Hexahydroisobenzofuran and Hexahydro-
isoindole Derivatives with Quaternary Stereocenters
O
ptically A
e
ctive Isob
n
e
nzofuran an
s
d
Isoindole Deri
Cvatives hristoffers,* Jonas Sluiter, Jan Schmidt
Institut für Reine und Angewandte Chemie, Carl von Ossietzky-Universität Oldenburg, 26111 Oldenburg, Germany
Fax +49(441)7983873; E-mail: jens.christoffers@uni-oldenburg.de
Received 3 November 2010; revised 16 December 2010
Dedicated to Professor Siegfried Blechert on the occasion of his 65th birthday
N
Abstract: Oxo esters with pyrrolidine and tetrahydrofuran rings
O
N
N
H
H
Ph
were converted into optically active isobenzofuran and isoindole
derivatives. The key step of the sequence was a copper-catalyzed
asymmetric Michael reaction with methyl vinyl ketone and en-
amines prepared from the oxo esters and L-valine diethylamide. The
chiral auxiliary was cleaved from the products during workup and
1,5-diketones with a quaternary stereocenter are obtained with 97–
99% ee. Subsequent annulation reactions were achieved in two
steps via the intermediate aldol products.
H
H
N
N
N
CO2H
O
O
tandospirone
mitiglinide
N
Me
Key words: tetrahydrofurans, pyrrolidines, isoindoles, isobenzo-
furans, chirality, Michael addition, quaternary stereocenters
H
H
H
O
O
N
O
N
O
The isoindole moiety is a common structural motif in het-
erocyclic compounds,1 and one of the privileged struc-
tures in medicinal chemistry.2 In contrast, isobenzofurans
are less frequently reported.3 Prominent examples of phar-
maceutically active isoindoles are the antidepressant tan-
dospirone,4 the hypoglycemic mitiglinide (diabetes),5 and
the antiviral tecovirimat (ST-246) (Figure 1).6 Examples
for pharmaceutically active isobenzofurans are the topo-
isomerase II-inhibitor etoposide7 and the thrombolytic
SCH 530348,8 an analogue of the natural product himba-
cine.9
H
H
CF3
O
tecovirimat
OH
himbacine
F
HO
O
O
O
O
O
O
N
O
H
H
H
O
A couple of years ago we reported on the asymmetric syn-
thesis of optically active octahydroisoquinolone 2 from
enamine 1 (Scheme 1).10 The key step of this reaction was
a copper-catalyzed Michael reaction with methyl vinyl
ketone (MVK) using L-valine diethylamide as chiral aux-
iliary.11 Since then, compound 2 bearing a quaternary
stereocenter12 has continuously been used by us13 and
others14 as a valuable chiral building block for the synthe-
sis of various heterocyclic compounds, mainly in a medi-
cinal chemistry context. For this reason, we decided to
prepare also compound 3a with a pyrrolidine ring instead
of the piperidine moiety as well as its tetrahydrofuran con-
gener 3b. In order to obtain both products 3a and 3b in op-
tically pure form, the enamines 4 derived from L-valine
diethylamide were chosen as the starting materials in the
copper-catalyzed Michael reaction with MVK.
O
MeO
OMe
EtO2CHN
H
OH
etoposide
O
SCH 530348
Figure 1 Prominent examples of pharmaceutically active com-
pounds with isoindole and isobenzofuran moieties
pared it in a one-pot protocol by conjugate addition of N-
Boc-GlyOMe (7)16 to methyl acrylate followed by
Dieckmann condensation (90% yield). Tetrahydrofuran
derivative 5b was reported before and prepared accord-
ingly.17 In order to develop suitable tools for enantiomeric
analyses, racemic products were prepared prior to asym-
metric Michael reactions. Therefore, b-oxo esters 5a and
5b were converted, with MVK and catalytic amounts of
FeCl3·6H2O,18 into the racemic 1,5-diketones 6a and 6b in
84% and 87% yield, respectively (Scheme 2). While the
product rac-6b gave sufficient baseline resolution in GLC
on a chiral phase, pyrrolidine derivative rac-6a did not.
For this reason we were seeking for a suitable derivative
for GLC analysis and found that the trifluoroacetamide 6c
fulfilled these requirements. The compound rac-6c was
The starting material 5a was mentioned before as a by-
product,15 but never isolated and characterized. We pre-
SYNTHESIS 2011, No. 6, pp 0895–0900
x
x
.
x
x
.2
0
1
1
Advanced online publication: 01.03.2011
DOI: 10.1055/s-0030-1258419; Art ID: T21410SS
© Georg Thieme Verlag Stuttgart · New York

896
J. Christoffers et al.
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CONEt2
O
which were subsequently hydrolyzed with hydrochloric
acid or aqueous citric acid to give the diketones 6a and 6b
in 42% and 83% yield, respectively. The product 6b was
directly submitted to enantiomeric analysis by GLC on a
chiral phase. Only one isomer was detectable (>99% ee)
and based on our experience with product 2 (Scheme 1)20
and other cyclopentanone carboxylates19 we presume it to
be the S-enantiomer. Analysis of carbamate 6a was per-
formed after conversion of a small sample into trifluoro-
acetamide 6c; GLC on a chiral phase gave 97% ee for this
derivative. Again, compounds 6a and 6c should have the
S-configuration.
O
i-Pr
NH
CO2Me
1. cat. Cu(OAc)2⋅H2O
2. pyrrolidine–AcOH
CO2Me
N
N
Boc
Boc
2 (99% ee)
1
O
CONEt2
NH
i-Pr
CO2Me
CO2Me
X
X
CONEt2
CONEt2
3a, X = N-Boc
3b, X = O
4a, X = N-Boc
4b, X = O
O
i-Pr
NH
i-Pr
NH2
CO2Me
CO2Me
Scheme 1 Synthesis of optically active octahydroisoquinolone 2
from enamine 1 and the synthetic plan for isoindole 3a and isobenzo-
furan 3b from enamines 4
(a)
X
X
5a, X = N-Boc
5b, X = O
4a, X = N-Boc, 77%
4b, X = O, 63%
obtained on a preparative as well as on an analytical scale.
Treatment of carbamate 6a with TFA led to cleavage of
the Boc-group. The N-unprotected pyrrolidine turned out
to be an unstable compound and was therefore not isolat-
ed. Subsequent conversion with TFAA formed the amide
6c. The resulting crude reaction mixture could directly be
submitted to GLC analysis.
O
cat. Cu(OAc)2⋅H2O
(b)
O
O
O
O
for 6a
CO2Me
CO2Me
O
O
O
(c)
O
N
X
F3C
CO2Me
(S)-6a, X = N-Boc, 42%
(S)-6b, X = O, 83%
O
CO2Me
cat. FeCl3⋅6H2O
(S)-6c
X
X
(b)
5a, X = N-Boc
5b, X = O
rac-6a, X = N-Boc, 84%
rac-6b, X = O, 87%
Scheme 3 Synthesis of enamines 4 and asymmetric Michael reac-
tions. Reagents and conditions: (a) cat. HCl–H2O, mol. sieves, tolu-
ene, 60 °C, 16 h, 77% (4a), 63% (4b); (b) for (S)-6a: 1.
Cu(OAc)2·H2O (5 mol%), MVK (2 equiv), acetone, 23 °C, 18 h, 2.
HCl–H2O–acetone, 23 °C, 2 h, 42%; for (S)-6b: 1. Cu(OAc)2·H2O (5
mol%), MVK (3 equiv), acetone, 23 °C, 1 h; 2. citric acid–acetone–
H2O, 23 °C, 1 h, 83%, >99% ee; (c) 1. TFA, CH2Cl2, 23 °C, 1 h, 2.
TFAA, Et3N, CH2Cl2, –10 → 23 °C, 1.5 h, 97% ee (analytical scale,
32% conversion).
for 5a
(90%)
(a)
(c)
for 6a
CO2Me
O
O
BocHN
CO2Me
CO2Me
7
N
F3C
Annulation reactions were performed with a mixture of
pyrrolidine and AcOH for racemic as well as optically ac-
tive 1,5-diketones 6a and 6b. In contrast to our previous
observations21 regarding this reaction, it stopped at the
stage of the tertiary alcohols 8a and 8b, which were iso-
lated in 91% and 67% yield, respectively (Scheme 4). The
relative configuration was established to be cis in the case
of isobenzofuran derivative 8b by X-ray analysis
(Figure 2).22 Elimination reaction of carbamate 8a was
achieved with TFAA and Et3N (93% yield of product 3a).
The more robust tetrahydrofuran derivative 8b was con-
verted to the hexahydroisobenzofuranone 3b with con-
centrated sulfuric acid (73% yield).
O
rac-6c, 29%
Scheme 2 Synthesis of starting material 5a, racemic Michael reac-
tions, and derivatization of product 6a. Reagents and conditions: (a)
t-BuOK (1.1 equiv), methyl acrylate (1 equiv), THF, 23 °C, 16 h, 90%
(for 5a); (b) FeCl3·6H2O (10 mol%), MVK (3 equiv), CH2Cl2, 23 °C,
3 d, 84% (for rac-6a), 16 h, 87% (for rac-6b); (c) 1. TFA, CH2Cl2,
23 °C, 1 h, 2. TFAA, Et3N, CH2Cl2, –10 → 23 °C, 1.5 h, 29%.
The reaction of the oxo esters 5a and 5b with the chiral
auxiliary19 gave the enamines 4a and 4b in 77% and 63%
yield, respectively (Scheme 3). Their conversion with
MVK in the presence of 5 mol% copper catalyst proceed-
ed smoothly to furnish imines as intermediate products,
Synthesis 2011, No. 6, 895–900 © Thieme Stuttgart · New York

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Optically Active Isobenzofuran and Isoindole Derivatives
897
ganic layers were dried (MgSO4), and after filtration, the solvent
was evaporated. The residue was chromatographed (SiO2, hexane–
MTBE, 1:2, Rf = 0.35) to yield the title compound 5a (29.0 g,
119 mmol, 90%) as a red oil.
O
O
O
O
(a)
(b)
HO
CO2Me
X
CO2Me
CO2Me
NMR spectra showed doubled signal sets due to the presence of
keto and enol tautomers (ratio 2:1). Because of E- and Z-isomers of
the carbamate moieties, these two signals sets are further doubled in
part (ratio 1:1).
X
X
6a, X = N-Boc
6b, X = O
8a, X = N-Boc, 91%
8b, X = O, 67%
3a, X = N-Boc, 93%
3b, X = O, 73%
Scheme 4 Annulation reaction. Reagents and conditions: (a) pyrro-
lidine (0.3 equiv), AcOH (0.3 equiv), DMSO, 23 °C, 2 h, 91% (for
8a), 67% (for 8b); (b) for 3a: TFAA (1.5 equiv), Et3N (1 equiv),
DMAP (0.05 equiv), CH2Cl2, 23 °C, 16 h, 93%; for 3b: concd H2SO4
(4 equiv), CH2Cl2, 23 °C, 1 h, 73%.
IR (ATR): 2973 (w), 2900 (w), 2871 (w), 1682 (s), 1629 (s), 1404
(s), 1366 (s), 1325 (s), 1226 (s), 1167 (s), 1113 (s), 1044 (s), 875
(m), 855 (m), 770 cm–1 (s).
1H NMR (500 MHz, CDCl3): d = 1.48 (s, 18 H), 1.49 (s, 18 H),
3.57–3.65 (m, 2 H), 3.79 (s, 12 H), 3.81–3.96 (m, 6 H), 3.98–4.04
(m, 2 H), 4.04–4.13 (m, 2 H), 4.16–4.25 (m, 6 H), 10.00 (s, 1 H),
10.04 (s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d (enol tautomer) = 28.7
(3 CH3), 28.8 (3 CH3), 48.7 (CH2), 49.1 (CH2), 51.4 (CH2), 51.7
(CH2), 53.36 (2 CH3), 80.5 (C), 81.2 (C), 97.49 (C), 97.54 (C),
154.4 (C), 154.5 (C), 168.1 (C), 168.4 (C), 168.5 (C), 168.7 (C);
d (keto tautomer) = 28.7 (3 CH3), 28.8 (3 CH3), 45.9 (CH2), 46.4
(CH2), 52.1 (CH), 52.5 (CH), 52.7 (CH2), 53.0 (CH2), 53.39
(2 CH3), 80.5 (C), 81.2 (C), 154.3 (C), 154.4 (C), 167.5 (2 C), 204.0
(C), 204.6 (C).
HRMS (ESI): m/z calcd for C11H17NO5 + MeOH + Li: 282.1529;
found: 282.1537 [M + MeOH + Li+].
N-(1-tert-Butyloxycarbonyl-3-methoxycarbonyl-2,5-dihydro-
pyrrol-4-yl)-L-valine Diethylamide (4a)
Anhyd molecular sieves (4 Å, ca. 5 g), L-valine diethylamide (793
mg, 4.60 mmol), and a catalytic amount of concd HCl (ca. 30 mg)
were subsequently added under an inert atmosphere to a solution of
oxo ester 5a (1.12 g, 4.60 mmol) in anhyd toluene (8 mL). The mix-
ture was heated to 60 °C under an inert atmosphere for 16 h and sub-
sequently filtered through a glass frit. The residue was washed with
CH2Cl2 (20 mL), the filtrates were evaporated and submitted to
chromatography [neutral Al2O3, hexane–EtOAc, 2:1, Rf = 0.30
(SiO2, hexane–EtOAc, 1:1)] to yield the title compound 4a (1.41 g,
3.55 mmol, 77%) as a colorless resin; [a]D20 +24 (c = 10 g/L in
CH2Cl2).
Figure 2 ORTEP-representation of the structure of compound 8b in
the solid state
Preparative column chromatography was carried out using Merck
SiO2 (0.035–0.070 mm, type 60 A) with hexane, EtOAc, or tert-bu-
tyl methyl ether (MTBE) as eluents. TLC was performed on Merck
SiO2 F254 plates on aluminum sheets. 1H and 13C NMR spectra were
recorded on a Bruker Avance DRX 500 spectrometer. Multiplicities
of carbon signals were determined with DEPT experiments. Spectra
of all Boc-protected compounds showed broad, partly doubled sig-
nal sets due to hindered rotation along the carbamate C–N bond
(E,Z-isomers). MS and HRMS spectra were obtained with a Finni-
gan MAT 95 (CI with isobutane and EI) and a Waters Q-TOF Pre-
mier (ESI, positive mode) spectrometer. IR spectra were recorded
on a Bruker Tensor 27 spectrometer equipped with a ‘GoldenGate’
diamond-ATR unit. Elemental analyses were measured with a Euro
EA-CHNS from HEKAtech. GLC analysis on a chiral phase was
performed with a Focus/Triplus (Thermo Electron) with FID on a
column Lipodex E (25 m × 0.25 mm) with H2 as carrier gas (+0.4
bar). N-Boc-GlyOMe (7)16 and oxo ester 5b17 were prepared ac-
cording to literature procedures. L-Valine diethylamide was pre-
pared as reported previously.19 All other starting materials were
commercially available.
IR (ATR): 3334 (w, br), 2975 (m), 2938 (m), 2877 (w), 1780 (m),
1739 (m), 1684 (s), 1623 (s), 1368 (s), 1281 (s), 1153 (s), 985 (m),
889 (m), 853 (m), 774 cm–1 (s).
1H NMR (500 MHz CDCl3): d = 0.97 (d, J = 6.8 Hz, 3 H), 0.98 (d,
J = 6.8 Hz, 3 H), 1.12 (t, J = 7.0 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H),
1.47 (s, 9 H), 2.01 (oct, J = 6.1 Hz, 1 H), 3.09–3.18 (m, 1 H), 3.19–
3.28 (m, 1 H), 3.33–3.41 (m, 1 H), 3.60–3.68 (m, 1 H), 3.72 (s, 3 H),
3.78 (dd, J = 10.3, 5.6 Hz, 1 H), 4.17–4.23 (m, 3 H), 4.29–4.35 (m,
1 H), 7.58 (br s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 13.3 (CH3), 15.2 (CH3),
17.5 (CH3), 20.2 (CH3), 28.8 (3 CH3), 33.1 (CH), 40.6 (CH2), 42.1
(CH2), 50.86 (CH2), 50.92 (CH3), 51.8 (CH2), 60.0 (CH), 80.3 (C),
90.3 (C), 154.0 (C), 154.8 (C), 166.5 (C), 170.3 (C).
HRMS (EI, 70 eV): m/z calcd for C20H35N3O5: 397.2577; found:
397.2569 [M+].
1-tert-Butyl 3-Methyl 4-Oxopyrrolidine-1,3-dicarboxylate (5a)
Methyl acrylate (11.4 g, 133 mmol, 1 equiv) and powdered t-BuOK
(17.9 g, 146 mmol, 1.1 equiv) were subsequently added to a cooled
(ice-water bath) solution of carbamate 7 (25.1 g, 133 mmol) in an-
hyd THF (250 mL). The reaction mixture was stirred under an inert
atmosphere for 16 h at 23 °C and then evaporated. The residue was
redissolved in CH2Cl2 (250 mL) and acidified with HCl (ca. 150
mL, c = 2 mol L–1). The layers were separated and the aqueous
phase was extracted with CH2Cl2 (2 × 100 mL). The combined or-
N-(3-Methoxycarbonyl-2,5-dihydro-4-furyl)-L-valine Diethyl-
amide (4b)
According to the procedure given above for product 4a, anhyd mo-
lecular sieves (4 Å, ca. 5 g), L-valine diethylamide (979 mg,
5.68 mmol), a catalytic amount of concd HCl (ca. 50 mg), and oxo
ester 5b (910 mg, 5.68 mmol) were converted in anhyd toluene
(10 mL) to give the title compound 4b (1.13 g, 3.60 mmol, 63%) as
a colorless solid after chromatography [neutral Al2O3, hexane–
EtOAc, 2:1, Rf = 0.21 (SiO2, hexane–EtOAc, 1:1)]; mp 70 °C. De-
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898
J. Christoffers et al.
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composition occurred during storage even at –20 °C, but the mate-
rial could be repurified by recrystallization from hexane–MTBE
(10:1); [a]D20 –3.3 (c = 10 g/L in CH2Cl2).
Enantiopure: Cu(OAc)2·H2O (16 mg, 0.082 mmol, 5 mol%) was
added to a solution of enamine 4b (490 mg, 1.64 mmol) in acetone
(3 mL). After stirring for 0.5 h at 23 °C, MVK (346 mg, 4.93 mmol,
3 equiv) was added and the resulting mixture stirred for further 1 h.
Subsequently, all volatile materials were removed under vacuum
and the residue redissolved in a mixture of acetone (2 mL), H2O
(2 mL), and citric acid (345 mg, 1.64 mmol, 1 equiv). After stirring
for 1 h at 23 °C, the mixture was extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with sat. aq NaHCO3
(10 mL) and dried (MgSO4). After filtration, all volatile materials
were removed under vacuum and the residue was chromatographed
(SiO2, hexane–EtOAc, 1:1, Rf = 0.34) to give the optically active
(S)-6b (292 mg, 1.36 mmol, 83%) as a colorless oil; [a]D20 +81
(c = 13 g/L in CH2Cl2).
IR (ATR): 3342 (w, br), 2968 (m), 2935 (m), 2875 (m), 1670 (s),
1630 (s), 1596 (vs), 1460 (s), 1430 (s), 1273 (vs), 1196 (s), 1122 (s),
1062 (s), 912 (m), 771 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 0.99 (d, J = 6.9 Hz, 6 H), 1.13 (t,
J = 7.1 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.97–2.07 (m, 1 H), 3.10–
3.17 (m, 1 H), 3.18–3.28 (m, 1 H), 3.35–3.44 (m, 1 H), 3.60–3.68
(m, 2 H), 3.71 (s, 3 H), 4.59–4.66 (m, 1 H), 4.69–4.80 (m, 3 H), 7.31
(br s, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 12.8 (CH3), 14.6 (CH3),
17.2 (CH3), 19.7 (CH3), 32.6 (CH), 40.2 (CH2), 41.5 (CH2), 50.4
(CH3), 60.1 (CH), 72.1 (CH2), 73.9 (CH2), 90.8 (C), 156.5 (C),
165.5 (C), 169.8 (C).
GLC (Lipodex E, 5 min at 50 °C, then 1.5 K min–1 to 180 °C): tR
(S) = 64.37 min, tR (R) = 65.07 min, >99% ee.
HRMS (EI, 70 eV): m/z calcd for C15H26N2O4: 298.1893; found:
IR (ATR): 2657 (w), 2886 (w), 1770 (s), 1714 (vs), 1433 (m), 1359
(m), 1237 (s), 1165 (s), 1066 (s), 925 cm–1 (m).
298.1895 [M+].
1H NMR (500 MHz, CDCl3): d = 2.02 (ddd, J = 14.7, 9.2, 5.7 Hz, 1
H), 2.09 (s, 3 H), 2.16 (ddd, J = 14.6, 9.2, 5.9 Hz, 1 H), 2.45 (ddd,
J = 14.9, 9.2, 5.7 Hz, 1 H), 2.67 (ddd, J = 15.1, 9.2, 5.9 Hz, 1 H),
3.70 (s, 3 H), 3.97 (d, J = 9.8 Hz, 1 H), 3.97 (B-part of an AB-
system, J = 17.1 Hz, 1 H), 4.03 (A-part of an AB-system, J = 17.1
Hz, 1 H), 4.49 (d, J = 9.7 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 25.3 (CH2), 29.8 (CH3),
38.2 (CH2), 52.9 (CH3), 58.1 (C), 71.0 (CH2), 75.3 (CH2), 169.4 (C),
206.8 (C), 210.2 (C).
1-tert-Butyl 3-Methyl 4-Oxo-3-(3-oxobutyl)pyrrolidine-1,3-di-
carboxylate (6a)
Racemic: FeCl3·6H2O (3.2 g, 12 mmol, 10 mol%) was added to a
solution of oxo ester 5a (29.0 g, 119 mmol) in CH2Cl2 (60 mL). Af-
ter stirring for 5 min at 23 °C, MVK (25.1 g, 358 mmol, 3 equiv)
was added and the resulting mixture stirred for further 3 d at 23 °C.
Subsequently, all volatile materials were removed under vacuum
and the residue was chromatographed (SiO2, hexane–MTBE, 1:2,
Rf = 0.23) to yield rac-6a (31.3 g, 100 mmol, 84%) as a light yellow
oil.
HRMS (CI): m/z calcd for C10H15O5: 215.0919; found: 215.0916 [M
Enantiopure: Cu(OAc)2·H2O (27 mg, 0.13 mmol, 5 mol%) was
added to a solution of enamine 4a (1.06 g, 2.68 mmol) in acetone
(10 mL). After stirring for 45 min at 23 °C, MVK (0.45 mL,
5.35 mmol, 2 equiv) was added and the resulting mixture stirred for
further 18 h. Subsequently, all volatile materials were removed un-
der vacuum and the residue was redissolved in a mixture of acetone
(1 mL) and HCl (5 mL, c = 1 mol L–1). After stirring for 2 h at 0 °C,
the mixture was extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with sat. aq NaHCO3 (50 mL) and dried
(MgSO4). After filtration, all volatile materials were removed under
vacuum and the residue was chromatographed (SiO2, hexane–
MTBE, 1:2, Rf = 0.23) to yield the optically active (S)-6a (353 mg,
1.13 mmol, 42%) as a light yellow oil; [a]D20 –12.4 (c = 7.3 g/L in
CHCl3).
+ H+].
Anal. Calcd for C10H14O5 (214.22): C, 56.07; H, 6.59. Found: C,
55.90; H, 6.91.
Methyl 4-Oxo-3-(3-oxobutyl)-1-trifluoroacetylpyrrolidine-3-
carboxylate (6c)
TFA (1.2 mL, 16 mmol, 10 equiv) was added to a solution of 1,5-
diketone 6a (500 mg, 1.60 mmol) in CH2Cl2 (2 mL). After stirring
for 1 h at 23 °C, all volatile materials were removed under vacuum.
The residue was redissolved in CH2Cl2 (4 mL) and cooled to –10 °C
(NaCl/ice bath). TFAA (2.2 mL, 16 mmol, 10 equiv) and Et3N
(3.3 mL, 24 mmol, 15 equiv) were added and the resulting mixture
was stirred for 1.5 h at 23 °C. Subsequently, the solution was
washed with H2O (20 mL) and sat. aq NaHCO3 (20 mL). The com-
bined aqueous layers were extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried (MgSO4), and after filtration,
the solvent was evaporated. The residue was chromatographed
(SiO2, hexane–EtOAc, 1:1, Rf = 0.30) to yield the title compound 6c
(144 mg, 0.466 mmol, 29%) as a light yellow oil; [a]D20 –35.9
(c = 1.7 g/L in EtOAc).
IR (ATR): 2977 (w), 2933 (w), 1768 (m), 1696 (s), 1400 (s), 1367
(s), 1256 (m), 1163 (s), 1125 (s), 884 (m), 770 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 1.46 (s, 9 H), 1.99–2.06 (m, 1 H),
2.11 (s, 3 H), 2.14–2.22 (m, 1 H), 2.41–2.49 (m, 1 H), 2.60–2.71 (m,
1 H), 3.49–3.61 (m, 1 H), 3.71 (s, 3 H), 3.82 (d, J = 19.6 Hz, 1 H),
3.86–3.99 (m, 1 H), 4.15 (d, J = 11.9 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 26.2 (CH2), 28.3 (3 CH3),
29.8 (CH3), 38.3 (CH2), 52.0 (CH2), 52.8 (CH2), 53.0 (CH3), 58.9
(C), 80.8 (C), 154.1 (C), 169.5 (2 C), 206.7 (C).
GLC (Lipodex E, 5 min at 70 °C, then 0.3 K min–1 to 120 °C, 1 min
at 120 °C, then 0.6 K min–1 to 180 °C): tR (R) = 232.78 min, tR (S) =
234.61 min, 97% ee.
The NMR spectra showed doubled signal sets due to E- and Z-iso-
mers of the amide moiety (ratio A/B = 1.3:1).
HRMS (ESI): m/z calcd for C15H23NO6 + Na: 336.1423; found:
336.1425 [M + Na+].
IR (ATR): 2960 (w), 2922 (m), 2852 (w), 1773 (w), 1694 (s), 1461
(w), 1375 (w), 1141 (s), 1021 (w), 966 (w), 799 (w), 757 (w), 719
cm–1 (w).
Methyl 4-Oxo-3-(3-oxobutyl)tetrahydrofuran-3-carboxylate
(6b)
Racemic: FeCl3·6H2O (608 mg, 2.25 mmol, 10 mol%) was added to
a solution of oxo ester 5b (3.25 g, 22.5 mmol) in CH2Cl2 (4 mL).
After stirring for 5 min at 23 °C, MVK (3.16 g, 45.1 mmol, 3 equiv)
was added and the resulting mixture stirred for further 16 h. Subse-
quently, all volatile materials were removed under vacuum and the
residue distilled through a Vigreux column (bp 91–93 °C/0.2 mbar)
to yield the title compound rac-6b (4.20 g, 19.6 mmol, 87%) as a
colorless oil.
1H NMR (500 MHz, CDCl3): d = 2.05–2.13 (m, 2 × 1 H, A and B),
2.14 (s, 3 H, A), 2.15 (s, 3 H, B), 2.24–2.31 (m, 2 × 1 H, A and B),
2.45–2.54 (m, 2 × 1 H, A and B), 2.66–2.80 (m, 2 × 1 H, A and B),
3.76 (s, 3 H, A), 3.77 (s, 3 H, B), 3.79–3.85 (m, 2 × 1 H, A and B),
4.01 (d, J = 20.2 Hz, 1 H, A), 4.19–4.26 (m, 1 H + 2 H, A and 2 B),
4.44 (d, J = 13.1 Hz, 1 H, A), 4.55 (d, J = 12.0 Hz, 1 H, B).
Synthesis 2011, No. 6, 895–900 © Thieme Stuttgart · New York

PAPER
Optically Active Isobenzofuran and Isoindole Derivatives
899
13C{1H} NMR (125 MHz, CDCl3): d (isomer A) = 26.1 (CH2), 29.9
(CH3), 38.18 (CH2), 52.4 (CH2), 52.9 (CH2), 53.5 (CH3), 57.5 (C),
115.8 (q, J = 287.1 Hz, C), 155.9 (q, J = 37.1 Hz, C), 168.7 (C),
202.6 (C), 206.8 (C): d (isomer B) = 25.8 (CH2), 29.9 (CH3), 38.15
(CH2), 52.3 (CH2), 53.0 (CH2), 53.6 (CH3), 59.6 (C), 115.9 (q,
J = 286.9 Hz, C), 155.9 (q, J = 37.1 Hz, C), 168.3 (C), 203.6 (C),
206.5 (C).
1H NMR (500 MHz, CDCl3): d = 1.93–2.00 (m, 1 H), 2.34–2.42 (m,
2 H), 2.48–2.57 (m, 1 H), 2.75 (d, J = 15.0 Hz, 1 H), 2.92 (d,
J = 15.0 Hz, 1 H), 3.31 (s, 1 H), 3.74 (d, J = 10.0 Hz, 1 H), 3.83 (s,
3 H), 3.85 (d, J = 10.0 Hz, 1 H), 3.85 (d, J = 8.5 Hz, 1 H), 4.35 (d,
J = 8.5 Hz, 1 H).
13C{1H} NMR (125 MHz, CDCl3): d = 29.3 (CH2), 36.8 (CH2),
47.5 (CH2), 52.6 (CH3), 55.4 (CH2), 74.2 (C), 77.2 (CH2), 81.4 (C),
173.0 (C), 207.1 (C).
HRMS (CI): m/z calcd for C12H15F3NO5: 310.0902; found:
310.0906 [M + H+].
HRMS (EI, 70 eV): m/z calcd for C10H14O5: 214.0841; found:
214.0839 [M+].
2-tert-Butyl 3a-Methyl cis-7a-Hydroxy-6-oxooctahydro-1H-
isoindole-2,3a-dicarboxylate (8a)
Anal. Calcd for C10H14O5 (214.22): C, 56.07; H, 6.59. Found: C,
55.65; H, 6.80.
Pyrrolidine (2.05 g, 28.9 mmol, 30 mol%) and AcOH (1.73 g, 28.9
mmol, 30 mol%) were added subsequently to a cooled (ice-water
bath) solution of diketone 6a (30.2 g, 96.3 mmol) in DMSO
(70 mL). After warming to r.t., the mixture was stirred for 16 h, sub-
sequently diluted with EtOAc (150 mL), and washed with brine
(250 mL). The layers were separated and the aqueous phase was ex-
tracted twice with EtOAc (2 × 150 mL). The combined organic lay-
ers were dried (MgSO4) and evaporated after filtration. The residue
was chromatographed (SiO2, hexane–EtOAc, 1:2, Rf = 0.35) to
yield the title compound 8a (27.6 g, 87.9 mmol, 91%) as a colorless
solid; mp 126 °C (racemic) or oil (enantiopure); [a]D20 –15
(c = 11.2 g/L in CH2Cl2).
Methyl 6-Oxo-2,3,3a,4,5,6-hexahydro-1H-isoindole-3a-carbox-
ylate (3a)
DMAP (47.4 mg, 0.388 mmol, 0.05 equiv), Et3N (785 mg, 7.76
mmol, 1 equiv), and TFAA (2.44 mg, 11.6 mmol, 1.5 equiv) were
subsequently added to a cooled (ice-water bath) solution of alcohol
8a (2.43 mg, 7.76 mmol, 1 equiv) in CH2Cl2 (7 mL). After warming
to r.t., the mixture was stirred for 16 h, then diluted with EtOAc (7
mL), and chromatographed (SiO2, hexane–EtOAc, 1:1, Rf = 0.29)
to yield the title compound 3a (2.12 g, 7.19 mmol, 93%) as a color-
less oil; [a]D20 +34 (c = 8.5 g/L in CHCl3).
GLC (Lipodex E, 5 min at 50 °C, then 1.5 K min–1 to 180 °C):
tR (R) = 96.68 min, tR (S) = 97.86 min, 96% ee.
The NMR spectra show doubled signal sets due to E- and Z-isomers
of the carbamate moiety (ratio 1:1).
The NMR spectra showed a partly doubled signal set due to E,Z-iso-
mers of the carbamate moiety.
IR (ATR): 3355 (m, br), 2977 (w), 1722 (s), 1656 (s), 1421 (s), 1403
(s), 1363 (m), 1290 (s), 1141 (s), 1087 (s), 1016 (s), 880 (m), 771
cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 1.44 (s, 9 H), 1.45 (s, 9 H), 1.75–
1.87 (m, 2 H), 2.29–2.39 (m, 4 H), 2.41–2.51 (m, 2 H), 2.67–2.79
(m, 2 H), 2.95 (s, 1 H), 2.98 (s, 1 H), 3.21–3.34 (m, 2 H), 3.41–3.54
(m, 4 H), 3.59–3.69 (m, 2 H), 3.80–3.83 (m, 2 H), 3.84 (s, 6 H).
IR (ATR): 2976 (w), 2932 (w), 2873 (m), 1783 (w), 1732 (s), 1678
(vs), 1476 (w), 1396 (s), 1366 (m), 1344 (w), 1305 (w), 1271 (w),
1256 (m), 1226 (w), 1203 (s), 1163 (vs), 1115 (s), 1081 (w), 985
(w), 967 (w), 903 (w), 991 (w), 949 (w), 772 (m), 731 (s), 698 (w),
647 cm–1 (w).
1H NMR (500 MHz, CDCl3): d = 1.42 (s, 9 H), 1.91 (td,
J = 12.8, 6.6 Hz, 1 H), 2.35–2.45 (m, 2 H), 2.54–2.62 (m, 1 H), 3.15
(d, J = 11.5 Hz, 1 H), 3.71 (s, 3 H), 4.07 (br d, J = ca. 16 Hz, 1 H),
4.12 (d, J = 11.5 Hz, 1/2 H), 4.19 (d, J = 11.5 Hz, 1/2 H), 4.36 (d,
J = 15.9 Hz, 1/2 H), 4.38 (d, J = 15.9 Hz, 1/2 H), 5.96 (s, 1/2 H), 5.99
(s, 1/2 H).
13C{1H} NMR (125 MHz, CDCl3): d = 28.1 (3 CH3), 30.5 (CH2),
33.95 (1/2 CH2), 34.04 (1/2 CH2), 49.9 (1/2 CH2), 50.3 (1/2 CH2), 51.7
(1/2 C), 52.5 (1/2 C), 52.97 (1/2 CH3), 53.00 (1/2 CH3), 55.4 (1/2 CH2),
56.1 (1/2 CH2), 80.4 (C), 123.0 (1/2 CH), 123.2 (1/2 CH), 153.9 (C),
160.5 (1/2 C), 161.3 (1/2 C), 171.7 (1/2 C), 171.9 (1/2 C), 197.3 (1/2 C),
197.4 (1/2 C).
13C{1H} NMR (125 MHz, CDCl3): d = 28.25 (3 CH3), 28.29
(3 CH3), 29.7 (2 CH2), 37.1 (CH2), 37.2 (CH2), 48.1 (CH2), 48.3
(CH2), 51.7 (CH2), 52.3 (CH2), 52.5 (CH3), 52.6 (CH3), 53.3 (C),
53.9 (C), 55.4 (CH2), 55.7 (CH2), 79.4 (C), 80.0 (2 C), 80.3 (C),
154.3 (2 C), 172.9 (C), 173.2 (C), 206.4 (C), 206.8 (C).
HRMS (ESI): m/z calcd for C15H23NO6 + Na: 336.1423; found:
336.1422 [M + Na+].
Anal. Calcd for C15H23NO6 (313.35): C, 57.50; H, 7.40; N 4.47.
Found: C, 57.68; H, 7.76; N, 4.47.
Methyl cis-7a-Hydroxy-6-oxooctahydroisobenzofuran-3a-car-
boxylate (8b)
HRMS (EI, 70 eV): m/z calcd for C15H22NO5: 296.1498; found:
Pyrrolidine (26 mg, 0.36 mmol, 30 mol%) and AcOH (22 mg,
0.36 mmol, 30 mol%) were subsequently added to a cooled (ice-
water bath) solution of diketone 6b (260 mg, 1.21 mmol) in DMSO
(1 mL). After warming to r.t., the mixture was stirred for 2 h, diluted
with EtOAc (5 mL), and washed with brine (10 mL). The layers
were separated and the aqueous phase was extracted twice with
EtOAc (2 × 5 mL). The combined organic layers were dried
(Na2SO4) and evaporated after filtration. The residue was chromato-
graphed (SiO2, hexane–EtOAc, 1:1, Rf = 0.15) to yield the title
compound 8b (174 mg, 0.813 mmol, 67%) as a colorless solid; mp
104 °C (racemic); mp 88 °C (S,S-isomer); [a]D20 –17 (c = 8 g/L in
CHCl3).
296.1504 [M + H+].
Methyl 6-Oxo-1,3,3a,4,5,6-hexahydroisobenzofuran-3a-car-
boxylate (3b)
Concd H2SO4 (251 mg, 2.56 mmol, 4 equiv) was added to a cooled
(ice-water bath) solution of alcohol 8b (137 mg, 0.640 mmol) in
CH2Cl2 (2 mL). After warming to r.t., the mixture was stirred for 1
h. Then sat. aq NaHCO3 (15 mL) was added and the stirring contin-
ued for 10 min. The layers were separated and the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and evaporated. The residue was
chromatographed (SiO2, hexane–EtOAc, 1:1, Rf = 0.22) to yield
the title compound 3b (92 mg, 0.47 mmol, 73%) as a colorless oil,
if optically active. The racemate was a colorless solid; mp 87 °C;
[a]D20 +158 (c = 10 g/L in CHCl3).
GLC (Lipodex E, 5 min at 50 °C, then 1.5 K min–1 to 180 °C):
tR (S,S) = 84.55 min, tR (R,R) = 85.22 min, >99% ee.
IR (ATR): 3465 (m, br), 2988 (w), 2955 (m), 2897 (w), 2878 (w),
1724 (s), 1435 (m), 1325 (m), 1287 (s), 1210 (s), 1090 (m), 1043 (s),
1017 (s), 915 (s), 743 (m), 709 cm–1 (m).
GLC (Lipodex E, 5 min at 50 °C, then 1.5 K min–1 to 180 °C):
tR (R) = 72.08 min, tR (S) = 75.57 min, >99% ee.
Synthesis 2011, No. 6, 895–900 © Thieme Stuttgart · New York

900
J. Christoffers et al.
PAPER
IR (ATR): 3048 (w), 2951 (m), 2868 (m), 1723 (s), 1665 (s), 1450
(m), 1372 (m), 1257 (s), 1229 (s), 1195 (s), 1104 (m), 1043 (s), 911
(s), 723 cm–1 (m).
1H NMR (500 MHz, CDCl3): d = 1.93 (ddd, J = 13.9, 13.2, 5.1 Hz,
1 H), 2.39 (ddd, J = 17.7, 13.9, 5.0 Hz, 1 H), 2.48 (dddd,
J = 17.9, 5.1, 1.8, 0.7 Hz, 1 H), 2.57 (ddd, J = 13.1, 4.9, 2.2 Hz, 1
H), 3.55 (d, J = 9.1 Hz, 1 H), 3.77 (s, 3 H), 4.48 (ddd, J = 16.0, 2.7,
J = 1.7 Hz, 1 H), 4.49 (d, J = 9.1 Hz, 1 H), 4.75 (dd, J = 15.9,
2.2 Hz, 1 H), 5.98 (t, J = 2.1 Hz, 1 H).
(8) (a) Chackalamannil, S.; Wang, Y.; Greenlee, W. J.; Hu, Z.;
Xia, Y.; Ahn, H.-S.; Boykow, G.; Hsieh, Y.; Palamanda, J.;
Agans-Fantuzzi, J.; Kurowski, S.; Graziano, M.; Chintala,
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Chackalamannil, S. J. Med. Chem. 2006, 49, 5389.
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Doller, D.; Wong, J.; Leone, D.; McPhail, A. T. J. Org.
Chem. 1999, 64, 1932.
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(11) Review: Christoffers, J. Chem. Eur. J. 2003, 9, 4862.
(12) Review: Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005,
347, 1473.
13C{1H} NMR (125 MHz, CDCl3): d = 29.3 (CH2), 34.1 (CH2),
53.0 (CH3), 54.3 (C), 69.7 (CH2), 77.2 (CH2), 121.5 (CH), 163.7
(C), 172.2 (C), 197.3 (C).
(13) (a) Christoffers, J.; Scharl, H.; Frey, W.; Baro, A. Eur. J.
Org. Chem. 2004, 2701. (b) Christoffers, J.; Scharl, H.;
Frey, W.; Baro, A. Org. Lett. 2004, 6, 1171. (c) Diedrich,
C. L.; Haase, D.; Christoffers, J. Synthesis 2008, 2199.
(d) Wache, N.; Christoffers, J. Synlett 2009, 3016.
(14) (a) Clark, R. D.; Ray, N. C.; Williams, K.; Blaney, P.; Ward,
S.; Crackett, P. H.; Hurley, C.; Dyke, H. J.; Clark, D. E.;
Lockey, P.; Devos, R.; Wong, M.; Porres, S. S.; Bright, C.
P.; Jenkins, R. E.; Belanoff, J. Bioorg. Med. Chem. Lett.
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Hurley, C. A.; Williams, K. Patent WO 2005/087769 A1,
2005; Chem. Abstr. 2005, 143, 306309. (c) Clark, R. D.;
Ray, N. C.; Blaney, P.; Hurley, C.; Williams, K.; Hunt, H.;
Clark, D. Patent WO 2005/070893, 2005; Chem. Abstr.
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Surivet, J.-P.; Zumbrunn Acklin, C. Patent WO 2009/
034546, 2009; Chem. Abstr. 2009, 150, 352177.
(15) Knight, D. W.; Sibley, A. W. J. Chem. Soc., Perkin Trans. 1
1997, 2179.
(16) Morandeau, L.; Remaud-Le Saec, P.; Ouadi, A.; Bultel-
Riviere, K.; Mougin-Degraef, M.; de France-Robert, A.;
Faivre-Chauvet, A.; Gestin, J.-F. J. Labelled Compd.
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(b) See also: Pflantz, R.; Sluiter, J.; Krička, M.; Saak, W.;
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(18) Review: Christoffers, J.; Frey, H. Chimica Oggi/Chem.
Today Suppl. 2008, 26, 26.
HRMS (EI, 70 eV): m/z calcd for C10H12O4: 196.0736; found:
196.0739 [M+].
Anal. Calcd for C10H12O4 (196.20): C, 61.22; H, 6.16. Found: C,
60.85; H, 6.35.
Acknowledgment
We are grateful to Elisabeth Jaskulska for assistance, to Wolfgang
Saak and Detlev Haase for X-ray crystallography, and Dr. Herbert
Frey for helping us with the manuscript.
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Synthesis 2011, No. 6, 895–900 © Thieme Stuttgart · New York