Simple synthetic protocol for the preparation of enantiomeric 3-oxabicyclo[3.3.0]oct-6-en-2-ones

Article abstract of DOI:10.1016/j.tetasy.2008.04.001

Diastereomeric amides produced via the decomposition of easily available (±)-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one by treatment with (+)- or (-)-α-methylbenzylamines were transformed into bicyclic lactam-aminals, which can easily be separated using the column chromatography on SiO₂. The latter products lead to enantiomeric 3-oxabicyclo[3.3.0]oct-6-en-2-ones after the removal of the chiral auxiliary. Crown Copyright

Full text of DOI:10.1016/j.tetasy.2008.04.001

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 1094–1099
Simple synthetic protocol for the preparation of enantiomeric
3-oxabicyclo[3.3.0]oct-6-en-2-ones
Airat M. Gimazetdinov,* Nikolay S. Vostrikov and Mansur S. Miftakhov
Institute of Organic Chemistry of Ufa Research Centre, Russian Academy of Sciences, 450054 Ufa, Russian Federation
Received 13 March 2008; accepted 1 April 2008
Abstract—Diastereomeric amides produced via the decomposition of easily available ( )-7,7-dichlorobicyclo[3.2.0]hept-2-en-6-one by
treatment with (+)- or (ꢀ)-a-methylbenzylamines were transformed into bicyclic lactam-aminals, which can easily be separated using
the column chromatography on SiO2. The latter products lead to enantiomeric 3-oxabicyclo[3.3.0]oct-6-en-2-ones after the removal
of the chiral auxiliary.
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
1. Introduction
Brown Algae (Multifidenes, Viridiene, Caudoxirene) pher-
omones.11 Compound (+)-1 had not been described earlier,
probably, owing to the very strict stereoselectivity of
Bayer–Villiger microbiologic oxidation of bicyclic ketone
3, which leads only to (ꢀ)-1.
Functionalized chiral cyclopentenes are widely used as key
starting compounds for the synthesis of cyclopentenone
antibiotics,1 prostaglandins,2 carbanucleosides,3 amongst
others.4,5 Enantiomers of lactone 1 are the isomers of lac-
tone 2; these compounds are used in the classic syntheses
of prostaglandins, according to To¨mo¨sko¨zi6 via the Corey
lactone.7 Elaboration of 1 as a possible building block
seemed to be an interesting synthetic undertaking.
Herein, we report a simple and practical synthetic protocol
for the preparation of both enantiomers of lactone 1, using
easily available [2+2]-adduct of dichloroketene and cyclo-
pentadiene 4 and (+)- or (ꢀ)-a-methylbenzylamines as
the starting material.
The synthesis and use of racemic lactone 1 was described
by Hudlicky8 and Wang.9 Later, Furstoss worked out a
more convenient synthesis of racemic lactone 1,10,11 as well
as its (ꢀ)-enantiomer, applying a microbial Bayer–Villiger
oxidation of bicyclo [3.2.0]hept-6-en-2-one 3 (Scheme
1).10 Chiral lactones (ꢀ)-(1R,5S)-1 and (+)-(1S,5R)-2 were
obtained in 37% and 40% yields, respectively, by this ap-
proach. It should be noted that, in contrast to lactone 2,
chiral (ꢀ)-1 was used only in the synthesis of Marine
2. Results and discussion
Adduct 4 and related compounds (Scheme 2) is attractive
because its strained dichlorocyclobutane cycle may be the
cleavage by treatment with a host of different nucleo-
philes.12,13 As expected, both enantiomers of a-methyl-
benzylamines cleaved 4 to give diastereomeric amides 5a
and 5b and 6a and 6b in high yields, according to Scheme
2. The crystallization of the diastereomeric mixtures of 5
and 6 from benzene gave one of the individual isomers in
10–15% yield in each case. However, the given method of
the separation was not effective and was abandoned.
O
O
O
O
O
+
(+)-2
( )-3
(-)-1
The next important problem was the hydrolysis of gem-
dichloromethyl group in amides 5 and 6. Treatment of
these compounds with AgNO3 in boiling H2O–CH3CN
solution led to the slow transformation of 5 and 6 to bicy-
clic lactam-aminals 7a and 7b and 8a and 8b (Scheme 3). It
Scheme 1.
*
Corresponding author. E-mail: airopet@yandex.ru
0957-4166/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.001

A. M. Gimazetdinov et al. / Tetrahedron: Asymmetry 19 (2008) 1094–1099
1095
O
O
H2N Ph, C6H6, rt
>95%
N
Ph
N
Ph
H
H
+
CHCl2
5a
CHCl2
5b
O
Cl
Cl
O
O
( )-4
H2N Ph, C6H6, rt
>95%
N
Ph
N
Ph
H
H
+
CHCl2
CHCl2
6a
6b
Scheme 2.
O
O
2,1 eq. AgNO3,
MeCN-H2O(3:1),
reflux, 20 h, 95%
N
Ph
N
Ph
+
5a + 5b
or 3 eq. BaO
MeCN-H2O (3:1)
refl. 5h, >95%
H
OH
7b
OH
O
7a
O
2.1 eq. AgNO3,
MeCN-H2O(3:1),
reflux, 20 h, 95%
N
Ph
6a + 6b
N
Ph
+
OH
OH
8a
8b
Scheme 3.
was also possible to substitute AgNO3 with inexpensive
BaO.
ment with acid furnished the target structure (ꢀ)-(1R,5S)-
1. It should be noted that during the reduction with sodium
borohydride, the partial isomerization and formation of
the minor trans-amidoalcohol 10a (ꢁ3–5%) was observed.
However, at the stage of the acidic hydrolysis, 10a was
re-epimerized to (ꢀ)-(1R,5S)-1 while the formation of the
expected trans-acid 11 from 10a was not observed.14 Anal-
ogous transformations from 7b led to (+)-(1R,5S)-1.
Diastereoisomers 7a/7b or 8a/8b could be easily separated
by column chromatography on SiO2 without practically
any loss. Each of these bicyclic acetals was stereochemically
pure and did not contain any C3-epimer admixture. Com-
pounds 7a, 7b, 8a and 8b were characterized as the less hin-
dered exo-epimers. Thus, in the 1H NMR spectrum a
doublet resonance of the 3-H at 5.12 ppm appeared with
J3,3a = 3 Hz, which is characteristic for 7b. Naturally, the
pairs of amides 7a and 8a, as well as 7b and 8b can be com-
bined before the isolation of the corresponding lactones,
because after removal of the chiral auxiliary compound
(a-methylbenzylamine), the same lactone enantiomers
would be released.
3. Conclusion
The easily available [2+2]-adducts of cyclopentadiene and
dichloroketene as well as the commercially available and
inexpensive (+)- and (ꢀ)-a-methylbenzylamines were used
to develop a practical and scalable method for the prepara-
tion of both enantiomers of lactone 1.
Thus, there was no need to work with both enantiomers of
a-methylbenzylamine. The separation of ( )-dichlorode-
rivatives of 5 and 6 by crystallization would require both
enantiomers of the chiral auxiliary, but in the case of dia-
stereomeric 7 or 8, chromatography on SiO2 was sufficient
enough to bring about complete separation. From this
point on, only (+)-a-methylbenzylamine was used.
4. Experimental
4.1. General
Solvents were purified and dried by standard procedures
before use. Reagents were generally of the best quality
commercial grade and used without further purification
unless otherwise indicated. All reactions were carried in
oven-dried glassware. Dichloroacetyl chloride was pre-
pared as described in the literature (bp 107–108 °C).15
Cyclopentadiene was obtained by the thermal cracking of
The hydrolytic cleavage of amides 7 and 8 was found to be
a problem. Under the standard conditions of acidic and
alkali hydrolysis, the amides were highly stable. Only after
the borohydride reduction of 7a (Scheme 4) in dioxane/
water at reflux was amidoalcohol 9a produced. Its treat-

1096
A. M. Gimazetdinov et al. / Tetrahedron: Asymmetry 19 (2008) 1094–1099
O
O
NaBH4, dioxane-H2O
(5:1), reflux, 5h
N
Ph
N
Ph
H
H
7a
+
90%
OH
10a (minor)
OH
9a
O
O
9N H2SO4-dioxane,
(1:2), reflux, 4h
OH
O
88%
OH
(-)-(1R,5S)-1
11
Scheme 4.
dicyclopentadiene. TLC was performed using Sorbfil STC-
1A 110 lm layer, silica gel 5–17 precoated foil plates. Col-
umn chromatography was carried out using 210–280 mesh
silica gel. Optical rotations were measured using sodium D
line at 589 nm on a Perkin–Elmer, Model 241 MC polarim-
eter at 20 C. IR (infrared spectra) were recorded on a Shi-
madzu IRPrestige-21 spectrometer as nujol mull or as neat
thin films on KBr plates (film) and were reported in reci-
C7H6OCl2: C, 47.46; H, 3.38; Cl, 40.11. Found: C, 47.23;
H, 3.09; Cl, 39.96.
4.3. General protocol for 2-(dichloromethyl)-N-[(1R)-1-
phenylethyl]cyclopent-3-ene-1-carboxamides 5
To a stirred solution of 4 in benzene (40 mL) at room tem-
perature under nitrogen was added dropwise a solution of
(+)-[(1R)-1-phenylethyl]amine (1.09 g, 9 mmol) in benzene
(10 mL). The reaction was monitored by TLC (3:7 ethyl
acetate–petroleum ether) and after stirring 3–3.5 h at rt,
the solution was filtered to remove 5b (300 mg, 11.9%) as
a white solid, and the residue on the filter was washed with
two 10-mL portions of hexane. The filtrate was concen-
trated under reduced pressure, and the residue was diluted
with CH2Cl2 (50 mL) and washed with water, 5% aqueous
solution HCl, water and brine, then dried over MgSO4.
Removal of the solvent under reduced pressure afforded
1
procal centimeters (cmꢀ1). H and 13C NMR spectra were
1
obtained using a Bruker AM-300 (300 MHz for H and
75.47 MHz for 13C) as solutions in CDCl3 (Aldrich Chem-
ical Company; spectra grade). Chemical shifts are reported
in d unit-parts per million (ppm) downfield from tetra-
methyl silane (TMS) as the internal reference. Splitting pat-
terns are designated as s, singlet; br s, broad singlet; d,
doublet, t, triplet; q, quartet; quint., quintet. Mass spectra
were recorded on Shimadzu LCMS QP-2010EV (APCI)
spectrometer. Elemental analyses were carried on a Euro
EA 3000 CHNS-analyzer. Melting points were recorded
on a Mel-Temp apparatus and are uncorrected.
an unseparable 4/3 mixture of carboxamides 5a and 5b
20
(2.1 g, 83.1%) as a yellow solid, mp 114–122 °C; ½aꢃD
¼
þ108 (c 0.75, CH3OH).
4.2. General protocol for ( )-7-dichlorobicyclo[3.2.0]hept-2-
en-6-ones 4
4.3.1.
(1S,2R)-(Dichloromethyl)-N-[(1R)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 5b. Yield 11.9%; mp 139–
20
140 °C; ½aꢃD ¼ þ69 (c 0.5, CH3OH); IR (nujol mull)
To a flame-dried, nitrogen-purged flask were added hexane
(400 mL), cyclopentadiene (53 g, 0.8 mol) and dichloroace-
tyl chloride (60 g, 0.4 mol). Triethylamine (53 g, 0.8 mol) in
hexane (300 mL) was added via syringe and allowed to stir
for 15 h at room temperature. The triethylammonium
hydrochloride salt was removed by filtration through a
short pad of Celite and washed with hexane (2 ꢂ 50 mL).
The combined filtrates were concentrated under reduced
pressure and the residue was purified by distillation to
furnish 4 (55.23 g, 78%) as a yellow oil, bp 49–50 °C/
0.3 mmHg.
3312, 2951, 2853, 1922, 1635, 1618, 1548, 1456, 1446,
1392, 1375, 1240, 752, 709, 698 cmꢀ1
;
1H NMR
(300 MHz, CDCl3/TMS): d 1.51 (d, J = 6.8 Hz, 3H,
CH3), 2.53–2.73 (m, 2H, 5-H), 3.14 (q, J = 7.7, 8.3 Hz,
1H, 1-H), 3.61–3.75 (m, 1H, 2-H), 5.12 (quint.,
J = 7.1 Hz, 1H, CH–Ph), 5.78–5.94 (m, 2H, 4-H and N–
H), 5.95–6.05 (m, 1H, 3-H), 6.31 (d, J = 7.1 Hz, 1H,
CHCl2), 7.18–7.48 (m, 5H, Ph); 13C NMR (75 MHz,
CDCl3/CHCl3): d 21.29 (CH3), 36.49 (C5), 46.65 (C1),
48.70 (CHPh), 58.95 (C2), 74.33 (CHCl2), 126.13, 127.40,
128.65 (Ph), 128.89 (C4), 133.37 (C3), 142.8 (Ph), 171.07
(C@O). MS (APCI), m/z (%): 298 [MH+, 35Cl] (100), 149
(12.5). Anal. Calcd for C15H17Cl2NO: C, 60.40; H, 5.70;
N, 4.70; Cl, 23.83. Found: C, 60.32; H, 5.55; N, 4.69; Cl,
23.54.
4.2.1. ( )-7-Dichlorobicyclo[3.2.0]hept-2-en-6-ones 4. Yield
78%; bp 49–50 °C/0.3 mmHg; IR (film) 1805, 1028, 887,
814, 797, 754, 731, 631 cmꢀ1
;
1H NMR (300 MHz,
CDCl3/TMS): d 2.48–2.88 (m, 2H, 4-H), 4.04–4.22 (m,
1H, 5-H), 4.32–4.42 (m, 1H, 1-H), 5.78–5.90 (m, 1H, 3-
H), 6.03–6.17 (m, 1H, 2-H); 13C NMR (75 MHz, CDCl3/
CHCl3): d 35.21 (C4), 58.60 (C1), 59.53 (C5), 88.18 (C7),
128.41 (C3), 136.88 (C2), 197.79 (C6). MS (APCI), m/z
(%): 177 [MH+, 35Cl] (100), 149 (13.3). Anal. Calcd for
4.4. 2-(Dichloromethyl)-N-[(1S)-1-phenylethyl]cyclopent-3-
ene-1-carboxamides 6
These compounds were synthesized following a procedure
similar to the one described above for the preparation of

A. M. Gimazetdinov et al. / Tetrahedron: Asymmetry 19 (2008) 1094–1099
1097
5. To a stirred solution of 4 (1.0 g, 5.7 mmol) in benzene
(27 mL) was added dropwise a solution (ꢀ)-[(1S)-1-phenyl-
ethyl]amine (0.72 g, 5.95 mmol) in benzene (7 mL). The
reaction mixture gave 6a (210 mg, 12.5%) as a white crys-
talline residue on the filter. Removal of the solvent under
reduced pressure afforded an inseparable 3/4 mixture of
4.5.1. (3aS,6aR)-3R-Hydroxy-2-[(1R)-phenylethyl]-3,3a,6,
6a-tetrahydrocyclo-penta[c]pyrrol-1(2H)-one 7a. Yield
20
47%; mp = 105–107 °C; ½aꢃD ¼ þ142:4 (c 0.65, CH3OH);
IR (nujol mull) 3232, 2922, 2852, 1647, 1456, 1327, 1290,
1
1215, 1058, 802, 702 cmꢀ1; H NMR (300 MHz, CDCl3/
TMS): d 1.68 (d, J = 6.8 Hz, 3H, CH3), 2.54–2.84 (m,
2H, 6-H), 3.21–3.33 (m, 1H, 3a-H), 3.39 (t, J = 9.08 Hz,
1H, 6a-H), 3.73–4.03 (br s, 1H, OH), 4.63–4.73 (br s, 1H,
3-H), 5.34 (q, J = 7.1 Hz, 1H, CH–Ph), 5.35–5.49 (m, 1H,
5-H), 5.72–5.84 (m, 1H, 4-H), 7.13–7.35 (m, 5H, PhH);
13C NMR (75 MHz, CDCl3/CHCl3): d 18.66 (CH3),
35.70 (C6), 42.83 (C6a), 49.96 (CHPh), 54.17 (C3a), 84.83
(C3), 127.316, 127.43, 128.40 (Ph), 128.61 (C5), 132.30
(C4), 139.79 (Ph), 177.27 (C@O). MS (APCI), m/z (%):
244 [MH+] (100), 226 (43), 198 (33.3), 177 (16.7), 161
(15), 121 (11.7), 93 (16.7), 65 (8.3). Anal. Calcd for
C15H17NO2: C, 74.07; H, 6.99; N, 5.76. Found: C, 73.78;
H, 6.76; N, 5.25.
carboxamides 6a and 6b (1.39 g, 82.5%) as a yellow solid,
20
mp 114–122 °C; ½aꢃD ¼ ꢀ110 (c 1.0, CH3OH).
4.4.1.
(1R,2S)-(Dichloromethyl)-N-[(1S)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 6a. Yield 11.9%; mp =
20
139–140 °C. ½aꢃD ¼ ꢀ70 (c 1.0, CH3OH); IR (nujol mull)
3314, 2953, 2853, 1636, 1618, 1548, 1458, 1449, 1392,
1375, 1240, 754, 710, 698 cmꢀ1 1H NMR (300 MHz,
;
CDCl3/TMS): d 1.52 (d, J = 6.9 Hz, 3H, CH3), 2.54–2.72
(m, 2H, 5-H), 3.16 (q, J = 7.8, 8.2 Hz, 1H, 1-H), 3.64–
3.74 (m, 1H, 2-H), 5.15 (quint., J = 7.1 Hz, 1H, CH–Ph),
5.72–5.86 (m, 1H, N–H), 5.99–6.07 (m, 1H, 4-H), 5.99–
6.07 (m, 1H, 3-H), 6.33 (d, J = 7.1 Hz, 1H, CHCl2),
7.23–7.41 (m, 5H, Ph); 13C NMR (75 MHz, CDCl3/
CHCl3): d 21.28 (CH3), 36.49 (C5), 46.67 (C1), 48.69
(CHPh), 58.95 (C2), 74.33 (CHCl2), 126.13, 127.40,
128.68 (Ph), 128.91 (C4), 133.37 (C3), 142.50 (Ph), 171.07
(C@O). MS (APCI), m/z (%): 298 [MH+, 35Cl] (100), 149
(14.7). Anal. Calcd for C15H17Cl2NO: C, 60.40; H, 5.70;
N, 4.70; Cl, 23.83. Found: C, 60.35; H, 5.52; N, 4.67; Cl,
23.64.
4.5.2. (3aR,6aS)-3S-Hydroxy-2-[(1R)-phenylethyl]-3,3a,6,
6a-tetrahydrocyclo-penta[c]pyrrol-1(2H)-one 7b. Yield 48%;
20
mp = 120–121 °C; ½aꢃD ¼ þ37:8 (c 0.8, CH3OH). IR (nujol
mull) 3244, 2922, 2852, 1651, 1616, 1456, 1336, 1303,
1273, 1222, 1058, 805, 698 cmꢀ1 1H NMR (300 MHz,
;
CDCl3/TMS): d 1.56 (d, J = 5.7 Hz, 3H, CH3), 2.15–
2.35 (br s, 1H, OH), 2.54–2.84 (m, 2H, 6-H), 3.13–3.22 (m,
1H, 3a-H), 3.23 (t, J = 7.08 Hz, 1H, 6a-H), 5.11 (d,
J = 3.0 Hz, 1H, 3-H), 5.35 (q, J = 7.1 Hz, 1H, CH–Ph),
5.59–5.67 (m, 1H, 5-H), 5.75–5.85 (m, 1H, 4-H), 7.20–7.54
(m, 5H, PhH); 13C NMR (75 MHz, CDCl3/CHCl3): d
17.05 (CH3), 35.64 (C6), 42.85 (C6a), 49.94 (CHPh), 53.32
(C3a), 84.38 (C3), 126.96, 127.23, 128.07 (Ph), 128.73 (C5),
132.65 (C4), 141.21 (Ph), 177.35 (C@O). MS (APCI), m/z
(%): 244 [MH+] (100), 226 (39), 198 (35.3), 177 (13.7), 161
(18.1), 121 (12.8), 93 (13.2), 65 (9.3). Anal. Calcd for
C15H17NO2: C, 74.07; H, 6.99; N, 5.76. Found: C, 73.97;
H, 6.63; N, 5.35.
4.5. General protocol for (3a,6a)-3-hydroxy-2-[(1R)-phenyl-
ethyl]-3,3a,6,6a-tetrahydrocyclopenta[c]pyrrol-1(2H)-ones 7
Method A: To a stirred solution of 1/1 mixture of 5a and 5b
(2.7 g, 9 mmol) in CH3CN (40 mL) at room temperature
was added a solution of AgNO3 (3.21 g, 19 mol) in H2O
(14 mL). After being stirred at room temperature for
0.5 h, the reaction solution was refluxed for 20 h, moni-
tored by TLC (1:1 ethyl acetate–petroleum ether), cooled
to room temperature and concentrated under vacuum.
The residue was diluted with water (15 mL) and extracted
with 3 ꢂ 20 mL ethyl acetate. The combined ethyl acetate
extracts were washed with saturated brine, dried over anhy-
drous sodium sulfate and concentrated under vacuum.
Purification of the products by column chromatography
(3:7 ethyl acetate–petroleum ether) afforded 7a (1.04 g,
47%) as a yellow crystalline solid and 7b (1.06 g, 48%) as
a white crystalline solid.
4.6. General protocol for 2-(hydroxymethyl)-N-[(1R)-1-
phenylethyl]cyclopent-3-ene-1-carboxamides 9a and 10a
To
a suspension of sodium borohydride (130 mg,
3.4 mmol) in a water/dioxane mixture (1 mL/2 mL) was
added a solution of 7a in 3 mL of dioxane. The mixture
was heated at reflux for 5 h and monitored by TLC (1:1
ethyl acetate–petroleum ether). The excess hydride was
decomposed by the successive addition of 1 mL of water,
1.5 mL of 15% sodium hydroxide and 3 mL of water; the
suspension was filtered. The filtrate was extracted with
3 ꢂ 10 mL methylene chloride. The combined methylene
chloride extracts were washed with saturated brine, dried
over anhydrous sodium sulfate and concentrated under
vacuum. Purification of the product by column chromato-
graphy (1:1 ethyl acetate–petroleum ether) afforded an
inseparable ꢁ95/5 mixture of epimers 9a and 10a (77 mg,
90%) as a white crystalline solid.
Method B: To a stirred solution of a 1/1 mixture of 5a and
5b (1.0 g, 3.33 mmol) in CH3CN (20 mL) at room temper-
ature was added a solution of BaO (100 mg, 0.65 mmol) in
H2O (5 mL). After being stirred at room temperature for
0.5 h, the reaction solution was refluxed for 8 h, monitored
by TLC (1:1 ethyl acetate–petroleum ether), cooled to
room temperature and concentrated under vacuum. The
residue was diluted with water (10 mL) and extracted with
3 ꢂ 15 mL ethyl acetate. The combined ethyl acetate ex-
tracts were washed with saturated brine, dried over anhy-
drous sodium sulfate and concentrated under vacuum.
Purification of the products by column chromatography
(3:7 ethyl acetate–petroleum ether) afforded 7a (377 mg,
46%) as a white crystalline solid and 7b (385 mg, 47%) as
a yellow crystalline solid.
4.6.1. (1R,2S)-2-(Hydroxymethyl)-N-[(1R)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 9a. Yield 90%; mp =
20
115–117 °C; ½aꢃD ¼ þ168:5 (c 0.425, CH3OH); IR (nujol
mull) 3261, 2951, 2922, 2852, 1639, 1556, 1454, 1375,
1232, 1056, 759, 748, 698 cmꢀ1 1H NMR (300 MHz,
;

1098
A. M. Gimazetdinov et al. / Tetrahedron: Asymmetry 19 (2008) 1094–1099
CDCl3/TMS): d 1.53 (d, J = 9.0 Hz, 3H, CH3), 2.45–2.50
(m, 1H, 5-H), 2.70–2.80 (m, 1H, 5-H), 2.95–3.03 (m, 1H,
2-H), 3.05 (t, J = 9.0 Hz, 1H, 1-H), 3.41–3.61 (m, 3H,
OH and CH2–O), 5.18 (quint., J = 7.5, 6.0 Hz, 1H, CH–
Ph), 5.55–5.61 (m, 1H, 4-H), 5.86–5.92 (m, 1H, 3-H),
6.04–6.12 (m, 1H, N–H), 7.62–7.78 (m, 5H, PhH); 13C
NMR (75 MHz, CDCl3/CHCl3): d 21.64 (CH3), 36.79
(C5), 47.49 (C1), 49.08 (CHPh), 51.35 (C2), 62.62
(CH2O), 126.16, 127.45, 128.70 (Ph), 130.49 (C4), 131.21
(C3), 143.05 (Ph), 174.59 (C@O). MS (APCI), m/z (%):
246 [MH+] (100), 228 (91.3). Anal. Calcd for C15H19NO2:
C, 73.47; H, 7.76; N, 5.71. Found: C, 73.15; H, 7.67; N,
5.49.
ture and concentrated under vacuum. The residue was di-
luted with water (4 mL) and extracted with 3 ꢂ 7mL
ether. The combined ether extracts were washed with satu-
rated brine, dried over anhydrous sodium sulfate and con-
centrated under vacuum. Purification of the products by
column chromatography (1:1 ethyl acetate–petroleum
ether) afforded (ꢀ)-(1R,5S)-1 (43 mg, 88%) as a yellow oil.
4.8.1. (ꢀ)-(1R,5S)-3-Oxabicyclo[3.3.0]oct-6-en-2-one 1.
20
Yield 88%; ½aꢃD ¼ ꢀ68:0 (c 0.93, CH3Cl) (lit.10
20
½aꢃD ¼ ꢀ67:9 (c 2.3, CH3Cl)); IR (film) 3058, 2920, 2858,
1762, 1446, 1377, 1173, 1142, 1053, 996, 935, 789,
680 cmꢀ1 1H NMR (300 MHz, CDCl3/TMS): d 2.67–
;
2.86 (m, 2H, 8-H), 3.10–3.18 (td, J = 2.36, 7.76 Hz, 1H,
1-H), 3.54–3.65 (m, 1H, 5-H), 4.24 (d, J = 9.23 Hz, 1H,
4-H), 4.44 (ddd, J = 2.08, 8.30 Hz, 1H, 4-H), 5.63–5.69
(m, 1H, 7-H), 5.85–5.90 (m, 1H, 6-H); 13C NMR
(75 MHz, CDCl3/CHCl3): d 36.39 (C8), 41.53 (C1), 46.30
(C5), 71.98 (C4), 130.52 (C7), 132.20 (C6), 180.81 (C2).
MS (APCI), m/z (%): 125 [MH+] (100), 108 (1.8), 97
(9.1). Anal. Calcd for C7H8O2: C, 67.74; H, 6.45. Found:
C, 67.54; H, 6.10.
4.6.2. (1S,2S)-2-(Hydroxymethyl)-N-[(1R)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 10a. 13C NMR (75 MHz,
CDCl3/CHCl3): d 23.34 (CH3), 35.10 (C5), 48.05 (C1),
51.02 (CHPh), 53.51 (C2), 67.52 (CH2O), 126.01, 127.11,
128.58 (Ph), 128.97 (C4), 131.30 (C3), 144.01 (Ph), 174.23
(C@O).
4.7. General protocol for 2-(hydroxymethyl)-N-[(1R)-1-
phenylethyl]cyclopent-3-ene-1-carboxamides 9b and 10b
4.9. General protocol for (+)-(1S,5R)-3-oxabicyclo[3.3.0]-
oct-6-en-2-one 1
Compound 7b (130 mg, 0.54 mmol) was treated with so-
dium borohydride as described in the synthesis of 9a and
10a, and afforded an inseparable ꢁ95/5 mixture of epimers
9b and 10b (116 mg, 89%) as a white crystalline solid.
The ꢁ95/5 mixture of 9b and 10b (70 mg, 0.31 mmol), trea-
ted as described in the synthesis of (ꢀ)-(1R, 5S)-1, afforded
(+)-(1S,5R)-1 (31 mg, 89%) as a yellow oil.
4.7.1. (1S,2R)-2-(Hydroxymethyl)-N-[(1R)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 9b. Yield 89%; mp =
20
132–134 °C; ½aꢃD ¼ ꢀ1:8 (c 1.05, CH3OH); IR (nujol mull)
4.9.1. (+)-(1S,5R)-3-Oxabicyclo[3.3.0]oct-6-en-2-one 1.
20
3313, 2945, 2852, 1643, 1531, 1454, 1375, 1276, 1037, 764,
Yield 89%; ½aꢃD ¼ þ67:4 (c 0.92, CH3Cl); IR (film) 3059,
1
704, 547 cmꢀ1; H NMR (300 MHz, CDCl3/TMS): d 1.55
2920, 2858, 1763, 1446, 1377, 1174, 1141, 1053, 995, 935,
789, 680 cmꢀ1 1H NMR (300 MHz, CDCl3/TMS): d
;
(d, J = 9.0 Hz, 3H, CH3), 2.44–2.50 (m, 1H, 5-H), 2.70–
2.85 (m, 1H, 5-H), 2.98–3.10 (t, J = 6.0 Hz, 2H, 2-H and
1-H), 3.53–3.73 (m, 3H, OH and CH2–O), 5.19 (quint.,
J = 7.5, 6.0 Hz, 1H, CH–Ph), 5.58–5.65 (m, 1H, 4-H),
5.85–5.92 (m, 1H, 3-H), 6.01–6.12 (m, 1H, N–H), 7.27–
7.43 (m, 5H, PhH); 13C NMR (75 MHz, CDCl3/CHCl3):
d 21.28 (CH3), 36.64 (C5), 47.48 (C1), 49.07 (CHPh),
51.29 (C2), 62.61 (CH2O), 126.08, 127.43, 128.53 (Ph),
130.40 (C4), 131.14 (C3), 142.77 (Ph), 174.40 (C@O). MS
(APCI), m/z (%): 246 [MH+] (100), 228 (96.5). Anal. Calcd
for C15H19NO2: C, 73.47; H, 7.76; N, 5.71. Found: C,
72.85; H, 7.56; N, 5.49.
2.67–2.86 (m, 2H, 8-H), 3.10–3.18 (td, J = 2.36, 7.76 Hz,
1H, 1-H), 3.54–3.65 (m, 1H, 5-H), 4.24 (d, J = 9.23 Hz,
1H, 4-H), 4.44 (ddd, J = 2.08, 8.30 Hz, 1H, 4-H), 5.63–
5.69 (m, 1H, 7-H), 5.84–5.91 (m, 1H, 6-H); 13C NMR
(75 MHz, CDCl3/CHCl3): d 36.48 (C8), 41.62 (C1), 46.37
(C5), 71.98 (C4), 130.53 (C7), 132.37 (C6), 180.84 (C2).
MS (APCI), m/z (%): 125 [MH+] (100), 108 (1.5), 97
(8.7). Anal. Calcd for C7H8O2: C, 67.74; H, 6.45. Found:
C, 67.49; H, 6.19.
References
4.7.2. (1R,2R)-2-(Hydroxymethyl)-N-[(1R)-1-phenylethyl]-
cyclopent-3-ene-1-carboxamide 10b. 13C NMR (75 MHz,
CDCl3/CHCl3): d 23.12 (CH3), 36.64 (C5), 48.31 (C1),
48.81 (CHPh), 52.97 (C2), 66.51 (CH2O), 125.98, 127.09,
128.70 (Ph), 128.91 (C4), 131.26 (C3), 144.11 (Ph), 174.23
(C@O).
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´
´
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