Totally regio- and stereoselective behavior of mono- and diactivated cyclic alkenes in the Lu reaction: Synthesis of enantiopure functionalized cyclopentanes

Article abstract of DOI:10.1021/jo801896a

(Chemical Equation Presented) 5-Alkoxyfuran-2(5H)-ones optically pure 3-p-tolylsulfinyl derivatives, synthetic equivalents of the acyclic esters, react with dipoles generated from allenoates and PPh₃ (Lu reaction), in a completely regioselective, π-facial selective and endo-selective manner, yielding bicyclic adducts, which are easily converted into optically pure highly substituted cyclopentane derivatives.

Full text of DOI:10.1021/jo801896a

Totally Regio- and Stereoselective Behavior of Mono- and
Diactivated Cyclic Alkenes in the Lu Reaction: Synthesis of
Enantiopure Functionalized Cyclopentanes
Jose´ L. Garc´ıa Ruano,* Alberto Nu´n˜ez, Jr., M. Rosario Mart´ın,* and Alberto Fraile
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
joseluis.garcia.ruano@uam.es; rosario.martin@uam.es
ReceiVed August 27, 2008
5-Alkoxyfuran-2(5H)-ones and their optically pure 3-p-tolylsulfinyl derivatives, synthetic equivalents of
the acyclic esters, react with dipoles generated from allenoates and PPh3 (Lu reaction), in a completely
regioselective, π-facial selective and endo-selective manner, yielding bicyclic adducts, which are easily
converted into optically pure highly substituted cyclopentane derivatives.
Introduction
highly regio- and stereoselective manner8 but the efficiency of
the intermolecular ones, mainly studied on acyclic and exocyclic
alkenes, is usually lower and clearly dependent on the structure
of the dipolarophile. Moreover, only dual activated or terminal
alkenes can be used as the two-carbon partner (except for
intramolecular processes) due to reactivity and regioselectivity
problems.1a,2 The asymmetric version of the intermolecular Lu
reaction has been reported by using chiral phosphines,9 chiral
1,3-dipoles derived from butynoic acid derivatives,5b,c and chiral
dipolarophiles.4d,5b,10 Antecedents in this field are scarce and
most of the cases are enones with exocyclic double bonds.
Concerning acyclic unsaturated esters, only unsubstituted acry-
lates and diethyl maleate react with the allene with high
enantiomeric excess in the presence of some chiral phosphines.9a
On the other hand, although it could be expected that electron-
poor endocyclic olefins exhibited better dipolarophilic features
(higher reactivity, and better regio- and stereoselectivity) than
their corresponding acyclic ones, they have also been scarcely
used in the Lu reaction.11 Consequently, reactions with unsatur-
ated esters have not been widely exploited in the synthesis of
Nucleophilic catalysis by phosphines has emerged as a good
synthetic tool in organic chemistry.1 In 1995 Lu reported the
first [3+2] cycloaddition of electron-deficient olefins with the
1,3-dipoles generated by conjugate addition of phosphines to
2-butynoates or 2,3-butadienoates2 to afford cyclopentenes.
Since this disclosure, allene cycloaditions to a wide range of
electron-poor CdC bonds3-5 and polarized CdX bonds (X )
N,6 O7) have been studied. Intramolecular processes work in a
(1) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot,
J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035.
(2) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.
(3) (a) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed 2006, 45, 1426. (b)
Lu, Z.; Zheng, S.; Zhang, X.; Lu, X. Org. Lett. 2008, 10, 3267.
(4) For the acyclic two-carbon component see: (a) References 2 and 3. (b)
Xu, Z.; Lu, X. Tetrahedron Lett. 1999, 40, 549. (c) Lu, X.; Lu, Z.; Zhang, X.
Tetrahedron 2006, 62, 457. (d) Ung, A. T.; Schafer, K.; Lindsay, K. B.; Pyne,
S. G.; Amornraksa, K.; Wouters, R.; Van der Linden, I.; Biesmans, I.; Lesage,
A. S. J.; Skelton, B. W.; White, A. H. J. Org. Chem. 2002, 67, 227.
(5) For the cyclic two-carbon component see: (a) References 3 and 4d. (b)
Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White,
A. H.; Turner, P. Tetrahedron 2005, 61, 8120. (c) Pham, T. Q.; Pyne, S. G.;
Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70, 6369. (d) Du, Y.; Lu, X.;
Yu, Y. J. Org. Chem. 2002, 67, 8901. (e) Wallace, D. J.; Sidda, R. L.; Reamer,
R. A. J. Org. Chem. 2007, 72, 1051.
(8) Kwon, O.; Henry, C. E. Org. Lett. 2007, 9, 3069. For examples of alkyne/
alkene [3 + 2] intramolecular cycloaddition, see: Wang, J.; Ng, S.; Krische, M.
J. Am. Chem. Soc. 2003, 125, 3682.
(6) (a) Fleury-Bre´geot, N.; Jean, L.; Retailleau, P.; Marinetti, A. Tetrahedron
2007, 63, 11920. (b) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
5660.
(7) Creech, G. S.; Kwon, O. Org. Lett. 2008, 10, 429, and references cited
therein.
(9) (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836. (b) Reference 3. (c) Cowen, B. J.; Miller, S. J.
J. Am. Chem. Soc. 2007, 129, 10988.
(10) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6465.
9366 J. Org. Chem. 2008, 73, 9366–9371
10.1021/jo801896a CCC: $40.75 2008 American Chemical Society
Published on Web 10/28/2008

Synthesis of Enantiopure Functionalized Cyclopentanes
TABLE 1. Reaction of (()-1 with 3
TABLE 2. Reactions of 5-Ethoxy-3-p-tolylsulfinylfuran-2(5H)-ones
2a and 2b with Ethyl 2,3-Butadienoate (3) under PPh3 Catalysis
entry equiv of (()-1 equiv of PPh3 time (h) isolated yield (%)
1
2
3
4
1.5
1.5
2.0
2.0
0.15
0.30
0.30
0.40
14
14
14
61
68
75
69
equiv
of 3
equiv of
PPh3
time
(h)
cycloadduct
(isolated yield, %)
entry
furanone
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2b
2b
1.5
1.5
2.0
2.0
1.5
1.5
2.0
0.15
0.30
0.20
0.30
0.30
0.20
0.30
12
6a (84)
6a (91)
6a (75)
6a (96)
6b (47)
6b (33)
6b (75)
6.5
3.3
6.5
3
3.5
5.5
2.5
optically pure cyclopentane carboxylic derivatives, despite their
wide occurrence in natural products.
The excellent features as dipolarophiles exhibited by 5-meth-
oxyfuran-2(5H)-one (1) and its 3-p-tolylsulfinyl derivatives (2a
and 2b) in many [3+2] dipolar cycloadditions,12 and the scarce
knowledge about the dipolarophilic behavior of endocyclic
double bonds in Lu reactions, prompted us to study the behavior
of these compounds in their reactions with the allenyl esters 3
and 4 in the presence of PPh3. Furanones 1 and 2 can be
considered as synthetic equivalents of 3-formylacrylate, leading
to adducts that can be easily transformed into highly function-
alized cyclopentanes. In this paper we report the results obtained
in the reactions of ethyl allenoates 3 and 4 with furanones 1 or
2, which provide a new entry to optically pure highly substituted
cyclopentanes.
SCHEME 1. Reaction of Furanone 1 with Allenoate (()-4
are collected in Table 2. The regio- and stereoselectivity of these
reactions were also complete and compounds 6a and 6b were
isolated as the sole adducts of their respective reactions. They
are the result of the anti approach of the dipole to the 5-ethoxy
group, regardless of the configuration at sulfur,13 which indicates
that C-5 is the controller of the facial selectivity.
Results and Discussions
Under the optimal conditions, the isolated yield for 6a was
excellent (96%, entry 4, Table 2), whereas it was high but lower
for 6b (75%, entry 7, Table 2). It could be presumably due to
the different stability of the starting furanones and/or adducts
(lower for b isomers) in the presence of PPh3.14
The role of the sulfinyl group in these reactions is limited to
an enhancement of the reactivity of the dipolarophile (compare
reaction times in Tables 1 and 2), which was confirmed by a
competitive experiment. Thus, the reaction of a 1:1 mixture of
1 and 2a (2 equiv) with allenoate 3 (1 equiv) and PPh3 (0.3
equiv), at room temperature for 1 h, afforded a 1:8 mixture of
adducts 5/6a.
We first studied the reaction of racemic furanone 1 with
commercially available ethyl 2,3-butadienoate (3) in the presence
of catalytic amounts of PPh3 (Table 1). The reaction evolved
1
in benzene at room temperature. The H NMR spectra of the
crude reaction revealed the presence of a sole adduct [(()-5],
easily isolated by flash column chromatography, along with the
signals corresponding to the unreacted furanone 1. The ratios
allene/catalyst and allene/furanone slightly modified the reaction
rate (it seems to be faster on increasing the amount of catalyst,
entry 4) and the yields (see Table 1), with the conditions of
entry 3 being the most efficient.
The complete regioselectivity observed in reactions from
(()-1 is worth mentioning, in contrast with the mixture of
regioisomers usually obtained from acyclic dipolarophiles, which
suggests that the endocyclic character of the double bond
improves the dipolarophilic features of the olefins. The stereo-
selectivity is also completely controlled by the orientation of
the OMe group at C-5, which hinders the approach of the dipole,
only affording the anti adduct. Moreover, as the reaction of 3
with ethyl crotonate does not work,2 the formation of adduct 5
from (()-1 indicates that the cyclic compound is much more
reactive than the acyclic analogues.
Finally, we have studied the reactions of the cyclic dipolaro-
philes with ethyl pent-2,3-dienoate [(()-4] in the presence of
PPh3. Reactions of 4 with (()-1 (Scheme 1) also evolved in a
completely regioselective and π-facial selective manner but with
a moderate endo/exo selectivity,15 thus yielding a 2:1 mixture
of two anti adducts, 8-endo being the major one. Under the
best conditions (1.5 equiv of 4 and 0.3 equiv of PPh3, for 14 h)
isolated yields were 45% (8-endo) and 24% (8-exo). The
influence of the methyl group on the reactivity of the allene
was scarce as it could be established by competitive experi-
ments.16
We then studied the reactions of the allenoate 3 with the
optically pure sulfinylfuranones 2a and 2b. The obtained results
(13) Though we have used only the sulfoxide of S configuration, we can say
“regardless of the configuration at sulfur”, because 2b [(S)S,5R-isomer] is the
enantiomer of (S)R,5S-isomer, and the (S)R,5R-stereoisomer is the enantiomer
of 2a [(S)S,5S-isomer].
(14) It is noteworthy that a small amount (5%) of ethyl 3-(p-tolylsulfinyl)but-
3-enoate 7 could be isolated in the reaction from epimer 2b, which could be the
result of the addition of sulfenic acid (resulting from the syn-pyrolitic elimination
from 6b) to the allene 3. See: (a) Grainger, R. S.; Tisselli, P.; Steed, J. W. Org.
Biomol. Chem. 2004, 2, 151. (b) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P. Curr. Org. Chem. 2007, 11, 1034.
(11) To our knowledge, only 3-formylchromones and 4-quinolone-1,3-
dicarboxylate have been studied. See: Kumar, K.; Kapoor, R.; Kapur, A.; Ishar,
M. P. S. Org. Lett. 2000, 2, 2023. Al-Soud, Y. A.; Al-Masoudi, N. A.; Hass, T.;
Beifuss, U. Lett. Org. Chem 2008, 5, 55.
(12) (a) Garc´ıa Ruano, J. L.; Fraile, A.; Gonza´lez, G.; Mart´ın, M. R.;
Clemente, F. R.; Gordillo, R. J. Org. Chem. 2003, 68, 6522. (b) Garc´ıa Ruano,
J. L.; Fraile, A.; Mart´ın, M. R. Tetrahedron 1999, 55, 14491. (c) Garc´ıa Ruano,
J. L.; Fraile, A.; Mart´ın Castro, A. M.; Mart´ın, M. R. J. Org. Chem. 2005, 70,
8825. (d) Garc´ıa Ruano, J. L.; Fraile, A.; Mart´ın, M. R.; Nun˜ez, A. J. Org.
Chem. 2006, 71, 6536.
(15) Endo/exo selectivity refers to the orientation of the methyl group on
the bicyclic structure.
J. Org. Chem. Vol. 73, No. 23, 2008 9367

Garc´ıa Ruano et al.
TABLE 3. Reactions of 2a and 2b with (()-4 under PPh3
Catalysis
FIGURE 1. Rationalization of the endo-selectivity.
equiv
of 4
equiv of
PPh3
endo/exo
time
(h)
yield
(%)
entry
furanone
ratioa
SCHEME 3. Transformations toward to Cyclopentanes
1
2
2a
2a
2a
2b
2b
3
2
1.5
1.5
2
0.30
0.30
0.30
0.30
0.20
97:<3
97:<3
97:<3
97:<3
97:<3
1
2
1.5
3.5
1
9a (44)
9a (34)
9a (47)
9b (29)
9b (24)
3
4b
5
a Ratio determined by 1H NMR. b P(p-ClC6H4)3 was used instead of
PPh3.
SCHEME 2. Desulfinylation of Adducts 6 and 9 with
Al(Hg)a
a a ) Al(Hg), THF/H2O, rt.
Only one adduct (9a or 9b) was isolated in the reactions of
4 with furanones 2a and 2b (Table 3). This means that the endo/
exo selectivity was completely controlled by the sulfinyl group,
which also increased the reactivity. Under the best conditions
(entries 3 and 4, respectively) the isolated yields are moderate
(47% for 9a, entry 3) or low (29% for 9b, entry 4), but no other
adduct could be isolated from the reaction mixture.
The adducts 6 and 9 were efficiently desulfinylated with Al/
Hg. Thus, 6a and 6b afforded enantiomers (-)-10 and (+)-10,
respectively, both in optically pure form (Scheme 2). 6-Methyl
derivatives 9a and 9b also were efficiently desulfinylated into
(-)-11 and (+)-11, respectively.17 Therefore, compounds 2a
and 2b can be considered as the enantiomerically pure synthetic
equivalents of furanone (()-1.
reported for ethyl acrylate (75:25 mixture),2 acrylonitrile (83:
17 mixture),2 and methyl vinyl ketone (63:37 mixture),2 which
reveals the positive influence of the furanone moiety.20
The complete π-facial selectivity observed in reactions from
1 and 2 can be easily explained by assuming that the syn-
approach is strongly destabilized with respect to the anti-
approach by steric and stereoelectronic interactions of the dipole
with the 5-alkoxy group. Moreover, the exclusive formation of
anti-adducts both from 2a and 2b indicates that the orientating
character of the alkoxy group at C-5 is higher than that of the
sulfinyl function at C-3. However, the sulfinyl group completely
controls the endo-selectivity, which is very low in reactions from
1. This control can be explained taking into account the higher
stability of intermediate IA with respect to that of IB, unsta-
bilized by the Me/SOTol interaction (Figure 1).
The presence of the R,ꢀ-unsaturated ester moiety in the
obtained adducts offers multiple synthetic possibilities to obtain
polysubstituted rings. Additionally, their bicyclic structure
suggests an efficient control of the stereoselectivity, which open
interesting possibilities in the synthesis of optically pure
cyclopentanes. Our initial studies in this field concern the
hydrogenation focused to the preparation of all-cis tri- and
tetrasubstituted cyclopentanes. Hydrogenation of (()-5 or (-)-
10 catalyzed by Pd(C) yielded 82:18 mixtures of two stereoi-
somers (A and B) of 12 and 13, respectively (Scheme 3). The
A isomers can be epimerized into B isomers with NaH. The
major A isomer results from the approach of the hydrogen to
the less hindered face, as has been demonstrated by NOESY
experiments. Under similar conditions, (-)-11 or (()-8-endo
evolved with higher selectivity (95:5) to afford adducts 14A
(Scheme 3) and 15A. The major compounds, (()-12A, 13A,
Although many stereochemical features of these compounds
could be established from NMR studies, their unequivocal
configurational assignment required the X-ray diffraction studies
of compounds 6b and 9b.18 The chemical correlation of these
compounds with 6a and 9a, through their desulfinylated products
10 and 11, allowed the stereochemical assignment of the adducts
derived from furanones 2a and 2b. The comparison of the NMR
spectra of compounds 10 and 11 with (()-5 and (()-8-endo,
respectively, revealed their structural similarities.
The complete regioselectivity19 observed in reactions of the
furanones with 3 and 4 contrasts with the modest regioselectivity
(16) Reaction of a 1:1:1 mixture of 1, 3, and 4 yielded a 3:2 mixture of 5
and 8 (determined by 1H NMR analysis of the crude reaction mixture).
(17) The ee values were determined by HPLC employing a Daicel Chiralpack
AD column and with hexane and isopropyl alcohol as eluent.
(18) Crystallographic data (excluding structure factors) for 6b and 9b have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 695572 and 695573. Copies of
the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax +44(0)-1223-366033 or e-mail
deposit@ccdc.cam.ac.uk].
(19) Regioselectivity of these reactions with acrylate esters has been explained
by theoretical calculations at the B3LYP/6-31G(d) level. See: Dudding, T.; Kwon,
O.; Mercier, E. Org. Lett. 2006, 8, 3643.
(20) Other examples of regioselective Lu reactions are reported, see refs 5b
and 11.
9368 J. Org. Chem. Vol. 73, No. 23, 2008

Synthesis of Enantiopure Functionalized Cyclopentanes
and 7.31 (AA′BB′ system, 4H), 6.74 (m, 1H), 5.23 (d, 1H, J ) 1.3
Hz), 4.20 (m, 2H), 3.82 (m, 1H), 3.55 (ddd, 1H, J ) 1.7, 2.5 and
19.8 Hz), 3.36 (dt, 1H, J ) 2.5 and 19.8 Hz), 3.28 (m, 2H), 2.41
(s, 3H), 1.28 (t, 3H, J ) 7.1 Hz), 0.85 (t, 3H, J ) 7.1 Hz). 13C
NMR (CDCl3, 75 MHz) δ 173.6 (C), 162.7 (C), 142.6 (C), 141.9
(CH), 135.2 (C), 134.0 (C), 129.7 (CH), 125.8 (CH), 107.0 (CH),
75.7 (C), 65.6 (CH2), 61.0 (CH2), 51.1 (CH), 41.5 (CH2), 21.5
(CH3), 14.4 (CH3), 14.1 (CH3). Anal. Calcd for C19H22O6S: C,
60.30; H, 5.86; S, 8.47. Found: C, 60.08; H, 5.90; S, 8.50.
Ethyl (()-3-[(4-Methylphenyl)sulfinyl]but-3-enoate (7). This
product was obtained as a byproduct from ethyl 2,3-butadienoate
(3), sulfinylfuranones 2, and triphenylphosphine. 1H NMR (CDCl3,
300 MHz) δ 7.51 and 7.29 (AA′BB′ system, 4H), 6.22 (s, 1H),
5.88 (s, 1H), 4.01 (q, 2H, J ) 7.2 Hz), 3.13 and 2.93 (AB system,
2H, J ) 16.8 Hz), 2.40 (s, 3H), 1.17 (t, 3H, J ) 7.2 Hz). 13C NMR
(CDCl3, 75 MHz) δ 169.0 (C), 147.5 (C), 142.0 (C), 138.6 (C),
129.9 (CH), 125.4 (CH), 120.8 (CH2), 61.2 (CH2), 32.9 (CH2), 21.4
(CH3), 14.0 (CH3). MS (FAB+) (m/z) 253 (M+ + 1) 100%.
b. Cycloaddition of Ethyl 2,3-Pentadienoate (4) to Furano-
nes Catalyzed by Triphenylphosphine. To a stirred solution of
0.2 M furanone 1, 2a, or 2b in benzene, under positive pressure of
argon, was added at room temperature allene 424 and finally a
benzene solution of triphenylphosphine. The reaction was monitored
by TLC. The amounts of reactants and catalyst are indicated in
each case. The solvent was removed in vacuo and the crude reaction
14A, and (()-15A, were transformed into the all-cis trisubsti-
tuted and tetrasubstituted methyl cyclopentanecarboxylates (18
and 19), by reaction with ethanodithiol catalyzed by BF3 ·OEt2,21
and further reaction with diazomethane.
In summary 5-alkoxyfuran-2(5H)-ones react efficiently with
allenoates with complete regioselectivity and anti-selectivity.
The incorporation of the sulfinyl group to the furanones increases
the reactivity and controls the endo-selectivity thus affording
optically pure bicyclic adducts, which have been selectively
transformed into all-cis functionalized cyclopentane carboxylic
acids. Application of adducts obtained from furanones and
allenes in the stereoselective synthesis of cyclopentanes with
great functional diversity will be reported in due course.
Experimental Section
a. Cycloaddition of Ethyl 2,3-Butadienoate (3) to Furano-
nes Catalyzed by Triphenylphosphine. To a stirred solution of
0.2 M furanone 1,22 2a,23 or 2b23 in benzene, under positive
pressure of argon, was added at room temperature allene 3 (2 equiv)
and finally 0.3 equiv of triphenylphosphine (solution 0.6 M) in
benzene. The reaction was monitored by TLC. The solvent was
removed in vacuo and the crude reaction was analyzed by 1H NMR
and immediately purified by column chromatography.
1
was analyzed by H NMR and immediately purified by column
Ethyl (()-(R3,S3a,S6a)-3-Methoxy-1-oxo-3,3a,6,6a-tetrahydro-
1H-cyclopenta[c]furan-4-carboxylate (5). 5 was obtained by
reaction of 5-methoxyfuran-2(5H)-one (1) (0.53 mmol), commercial
ethyl 2,3-butadienoate (1.05 mmol), and PPh3 (0.13 mmol) after
14 h. It was isolated by column chromatography (hexane-ethyl
acetate, 4:1) as a colorless oil. Yield 75%. IR (neat) 1780, 1716,
1632, 1270, 1201, 1102, 948 cm-1. 1H NMR (CDCl3, 300 MHz) δ
6.82 (q, 1H, J ) 2.3 Hz), 5.49 (s, 1H), 4.23 (m, 2H), 3.66 (m, 1H),
3.53 (s, 3H), 3.35 (dt, 1H, J ) 2.8 and 7.7 Hz), 2.91 (m, 2H), 1.31
(t, 3H, J ) 7.2 Hz). 13C NMR (CDCl3, 75 MHz) δ 179.4 (C), 163.4
(C), 144.7 (CH), 133.6 (C), 106.6 (CH), 60.8 (CH2), 56.8 (CH3),
53.1 (CH), 41.0 (CH), 36.6 (CH2), 14.2 (CH3). Anal. Calcd for
C11H14O5: C, 58.40; H, 6.24. Found: C, 58.69; H, 6.07.
chromatography.
Ethyl (()-3-Methoxy-6-methyl-1-oxo-3,3a,6,6a-tetrahydro-
1H-cyclopenta[c]furan-4-carboxylates (8). These compounds were
obtained as a mixture 60:40 endo/exo, from 5-methoxyfuran-2(5H)-
one (1) (0.79 mmol), 4 (1.19 mmol), and PPh3 (0.24 mmol in 4
mL), after 14 h. These isomers were separated by column
chromatography (hexane-ethyl acetate, 9:1). Overall yield 69%.
(()-(R3,S3a,R6,S6a)-8-exo: Colorless oil. TLC Rf (hexane-ethyl
acetate, 6:1) 0.26. Yield 24%. IR (neat) 1780, 1714, 1630, 1454,
1266, 1217, 1102, 956 cm-1. H NMR (CDCl3, 300 MHz) δ 6.78
1
(t, 1H, J ) 2.3 Hz), 5.47 (s, 1H), 4.23 (m, 2H), 3.71 (dt, 1H, J )
2.3 and 7.5 Hz), 3.52 (s, 3H), 3.25 (m, 1H), 2.97 (dd, 1H, J ) 1.1
and 7.5 Hz), 1.31 (t, 3H, J ) 7.1 Hz), 1.19 (d, 3H, J ) 7.3 Hz).
13C NMR (CDCl3, 75 MHz) δ 178.9 (C), 163.7 (C), 149.9 (CH),
132.0 (C), 106.5 (CH), 60.8 (CH2), 56.7 (CH3), 52.0 (CH), 48.5
(CH), 44.4 (CH), 20.1 (CH3) 14.2 (CH3). Anal. Calcd for C12H16O5:
C, 59.99; H, 6.71. Found: C, 60.10; H, 6.78.
Ethyl (S3,R3a,S6a,SS)-3-Ethoxy-6a-[(4-methylphenyl)sulfinyl]-
1-oxo-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-carboxy-
late (6a). 6a was obtained from furanone 2a (0.20 mmol), ethyl
2,3-butadienoate (0.38 mmol), and PPh3 (0.06 mmol) after 3.3 h.
It was isolated by column chromatography (hexane-ethyl acetate,
(()-(R3,S3a,S6,S6a)-8-endo: Colorless oil. TLC Rf (hexane-ethyl
3:1) as a colorless oil. Yield 91%. [R]20 +93.3 (c 0.60, CHCl3).
D
acetate, 6:1) 0.21. Yield 45%. IR (neat) 1779, 1713, 1638, 1343,
IR (neat) 1772, 1714, 1635, 1208, 1157, 1115, 944 cm-1. 1H NMR
(CDCl3, 300 MHz) δ 7.56 and 7.33 (AA′BB′ system, 4H), 6.71
(m, 1H), 5.69 (s, 1H), 4.23 (m, 2H), 4.16 (m, 1H), 3.92 (m, 1H),
3.74 (m, 1H), 3.22 (dt, 1H, J ) 2.3 and 19.1 Hz), 2.45 (dt, 1H, J
) 2.5 and 19.1 Hz), 2.43 (s, 3H), 1.31 (t, 3H, J ) 7.1 Hz), 1.30 (t,
3H, J ) 7.2 Hz). 13C NMR (CDCl3, 75 MHz) δ 173.1 (C), 162.8
(C), 143.0 (C), 142.9 (CH), 135.7 (C), 132.6 (C), 129.4 (CH), 125.9
(CH), 104.8 (CH), 72.3 (C), 65.8 (CH2), 61.0 (CH2), 55.4 (CH),
34.9 (CH2), 21.6 (CH3), 14.9 (CH3), 14.2 (CH3). Anal. Calcd for
C19H22O6S: C, 60.30; H, 5.86; S, 8.47. Found: C, 59.96; H, 6.03;
S, 8.41.
1264, 1166, 1121, 941 cm-1. H NMR (CDCl3, 300 MHz) δ 6.68
1
(t, 1H, J ) 1.9 Hz), 5.39 (s, 1H), 4.23 (m, 2H), 3.69 (m, 1H), 3.51
(s, 3H), 3.39-3.25 (m, 2H), 1.31 (t, 3H, J ) 6.9 Hz), 1.30 (d, 3H,
1
J ) 6.8 Hz). H NMR (C6D6, 300 MHz) δ 6.28 (t, 1H, J ) 2.1
Hz), 5.26 (d, 1H, J ) 0.9 Hz), 3.96 (m, 2H), 3.44 (dtd, 1H, J )
0.9, 2.1 and 8.2 Hz), 3.18 (s, 3H), 2.82 (dd, 1H, J ) 8.2 and 9.3
Hz), 2.62 (m, 1H), 1.06 (d, 3H, J ) 7.5 Hz), 0.99 (t, 3H, J ) 7.1
Hz). 13C NMR (CDCl3, 75 MHz) δ 175.6 (C), 163.7 (C), 150.1
(CH), 132.0 (C), 106.0 (CH), 60.8 (CH2), 56.7 (CH3), 53.8 (CH),
44.1 (CH), 42.3 (CH), 15.1 (CH3), 14.2 (CH3). HRMS (FAB+) calcd
for C12H17O5 [M + H] 241.1076, found 241.1077.
Ethyl (R3,S3a,R6a,SS)-3-Ethoxy-1-oxo-6a-[(4-methylphenyl)-
sulfinyl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-4-carboxy-
late (6b). 6b was obtained from furanone 2b (0.20 mmol), ethyl
2,3-butadienoate (0.40 mmol), and PPh3 (0.06 mmol) after 2.5 h.
It was isolated by column chromatography (hexane-ethyl acetate,
Ethyl (S3,R3a,R6,S6a,SS)-3-Ethoxy-6-methyl-1-oxo-6a-[(4-me-
thylphenyl)sulfinyl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-
4-carboxylate (9a). 9a was obtained from sulfinylfuranone 2a (0.40
mmol), ethyl 2,3-pentadienoate (4) (0.60 mmol), and PPh3 (0.12
mmol in 2 mL), after 1 h. It was isolated by column chromatography
3:1) as a white yellow solid: mp 130-131 °C. [R]20 +91.5 (c
(hexane-ethyl acetate, 3:1) as a colorless oil. Yield 47%. [R]20
D
D
0.82, CHCl3). Yield 75%. IR (KBr) 1765, 1710, 1631, 1597, 1340,
+100.1 (c 1.40, CHCl3). IR (neat) 1771, 1721, 1644, 1179, 1055
1
1236, 1115, 1084, 944 cm-1. H NMR (CDCl3, 300 MHz) δ 7.54
cm-1 1H NMR (CDCl3, 300 MHz) δ 7.64 and 7.33 (AA′BB′
.
system, 4H), 6.54 (t, 1H, J ) 2.1 Hz), 5.52 (d, 1H, J ) 1.1 Hz),
4.23 (m, 2H), 4.18 (m, 1H), 3.88 (m, 1H), 3.68 (m, 1H), 3.56 (tq,
1H, J ) 1.9 and 7.5 Hz), 2.43 (s, 3H), 1.30 (t, 3H, J ) 7.2 Hz),
(21) Farin˜a, F.; Mart´ın, M. R.; Parellada, M. D. J. Chem. Res. (S) 1984,
250, 2213.
(22) Schenck, G. O. Liebigs Ann. 1953, 584, 156.
(23) Carretero, J. C.; Garc´ıa Ruano, J. L.; Lorente, A.; Yuste, F. Tetrahedron:
Asymmetry 1993, 4, 177.
(24) Lang, R. W.; Hansen, H. J. Org. Synth. 1984, 62, 202.
J. Org. Chem. Vol. 73, No. 23, 2008 9369

Garc´ıa Ruano et al.
1.27 (t, 3H, J ) 7.1 Hz), 0.74 (d, 3H, J ) 7.5 Hz). 13C NMR
(CDCl3, 75 MHz) δ 169.9 (C), 162.9 (C), 148.7 (CH), 143.1 (C),
135.0 (C), 130.6 (C), 129.3 (CH), 126.4 (CH), 104.2 (CH), 74.3
(C), 65.7 (CH2), 61.0 (CH2), 56.5 (CH), 41.7 (CH), 21.1 (CH3),
15.8 (CH3), 14.9 (CH3), 14.2 (CH3). Anal. Calcd for C20H24O6S:
C, 61.21; H, 6.16; S, 8.17. Found: C, 61.53; H, 6.30; S, 8.17.
Ethyl (R3,S3a,S6,R6a,SS)-3-Ethoxy-6-methyl-1-oxo-6a-[(4-me-
thylphenyl)sulfinyl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]furan-
4-carboxylate (9b). 9b was obtained from sulfinylfuranone 2b (0.20
mmol), ethyl 2,3-pentadienoate (4) (0.30 mmol), and PPh3 (0.06
mmol in 1 mL), after 1 h. It was isolated by column chromatography
(hexane-ethyl acetate, 3:1) as a yellow pale solid, mp 103-105
(CDCl3, 300 MHz) δ 6.69 (t, 1H, J ) 2.0 Hz), 5.50 (d, 1H, J )
0.9 Hz), 4.23 (m, 2H), 3.88 (m, 1H), 3.65 (m, 2H), 3.34 (m, 2H),
1.31 (t, 3H, J ) 7.0 Hz), 1.30 (d, 3H, J ) 6.8 Hz), 1.25 (t, 3H, J
) 7.1 Hz). 1H NMR (C6D6, 300 MHz) δ 6.27 (t, 1H, J ) 2.1 Hz),
5.49 (d, 1H, J ) 0.8 Hz), 3.95 (m, 2H), 3.67 (m, 1H), 3.52 (dtd,
1H, J ) 0.8, 2.2 and 8.3 Hz), 3.32 (m, 2H), 2.81 (dd, 1H, J ) 8.3
and 9.3 Hz), 2.48 (m, 1H), 1.09 (d, 3H, J ) 7.4 Hz), 1.00 (t, 3H,
J ) 7.1 Hz), 0.94 (t, 3H, J ) 7.1 Hz). 13C NMR (C6D6, 75 MHz)
δ 175.5 (C), 164.2 (C), 150.5 (CH), 133.0 (C), 105.1 (CH), 65.6
(CH2), 61.0 (CH2), 54.8 (CH), 44.6 (CH) 42.8 (CH), 15.8 (CH3),
15.6 (CH3), 14.7 (CH3). HRMS (EI) calcd for C13H18O5 [M]
254.1154, found 254.1167.
°C. Yield 24%. [R]20 +128.9 (c 0.46, CHCl3). IR (neat) 1761,
D
Ethyl (S3,R3a,R6,R6a)-3-Ethoxy-6-methyl-1-oxo-3,3a,6,6a-tet-
rahydro-1H-cyclopenta[c]furan-4-carboxylate [(-)-11]. (-)-11
was obtained following the general procedure from cycloadduct
9a and isolated by column chromatography (pentane-diethyl ether,
1715, 1644, 1263, 1084, 938 cm-1. 1H NMR (CDCl3, 300 MHz) δ
7.56 and 7.32 (AA′BB′ system, 4H), 6.66 (t, 1H, J ) 2.1 Hz),
5.17 (d, 1H, J ) 1.7 Hz), 4.21 (m, 2H), 3.90 (m, 1H), 3.84 (m,
1H), 3.28 (q, 2H, J ) 7.1 Hz), 2.41 (s, 3H), 1.41 (d, 3H, J ) 7.6
Hz), 1.29 (t, 3H, J ) 7.1 Hz), 0.83 (t, 3H, J ) 7.0 Hz). 13C NMR
(CDCl3, 75 MHz) δ 170.6 (C), 163.0 (C), 147.6 (CH), 142.6 (C),
135.0 (C), 131.9 (C), 129.7 (CH), 126.2 (2CH), 106.0 (CH), 79.0
(C), 65.4 (CH2), 61.0 (CH2), 51.8 (CH), 46.9 (CH), 21.5 (CH3),
15.7 (CH3), 14.5 (CH3), 14.2 (CH3). HRMS (FAB+) calcd for
C20H25O6S [M + H] 393.1372, found 393.1385. Anal. Calcd for
C20H24O6S: C, 61.21; H, 6.16; S, 8.17. Found: C, 61.47; H, 6.06.
c. Desulfinylation of Primary Adducts with Aluminum Amal-
gam: General Procedure. To a vigorously stirred 0.01 M solution
of sulfinylcycloadduct in a 9:1 mixture of THF-water was added
aluminum amalgam (obtained from aluminum kitchen foil)25 in
small portions. Reaction is monitored by TLC and when the starting
material was not observed the reaction mixture was filtered through
celite and the solid was washed with dichloromethane. The solution
was evaporated at reduced pressure to dryness. The product was
isolated as indicated in each case.
4:1). Yield 93%. [R]20 -95.8 (c 0.50, CHCl3), ee >99.5%
D
(hexane-isopropyl alcohol, 95/5, Rt ) 8.7 min). HRMS (FAB+)
calcd for C13H19O5 [M + H] 255.1232, found 255.1229.
d. Catalytic Hydrogenation of Cyclopentenes. A solution of
(()-5 or (-)-10 (0.28 mmol) in ethyl acetate (4.2 mL) containing
10% Pd(C) (25.3 mg) was stirred under positive pressure of
hydrogen at room temperature. After 14 h the suspension was
filtered through celite, the solid residue was washed with ethyl
acetate, and the solvent was removed in vacuo. The residue analyzed
1
by H NMR contains a mixture 82:18 of A and B isomers, which
were isolated diastereoisomerically pure by column chromatography
(hexane-ethyl acetate, 6:1).
Ethyl 3-Methoxy-1-oxo-hexahydro-1H-cyclopenta[c]furan-4-
carboxylates (12). Compounds 12 were obtained from (()-5.
(()-(3R,3aR,4R,6aS)-12A: Colorless oil. TLC Rf (hexane-ethyl
acetate, 6:1) 0.18. Yield 60%. IR (neat) 1780, 1731, 1190, 1116
1
cm-1. H NMR (CDCl3, 300 MHz) δ 5.16 (d, 1H, J ) 1.6 Hz),
All desulfinylated adducts were analyzed by HPLC with a Daicel
Chiralpack AD column and with hexane and isopropyl alcohol as
eluents with a continuous flow of 1 mL/min. Conditions and
retention times are indicated in each case.
4.19 (m, 2H), 3.46 (s, 3H), 3.19 (m, 1H), 2.97 (m, 2H), 2.20 (m,
1H), 1.93 (m, 2H), 1.69 (m, 1H), 1.28 (t, 3H, J ) 7.1 Hz). 13C
NMR (CDCl3, 75 MHz) δ 178.7 (C), 172.0 (C), 106.2 (CH), 60.9
(CH2), 56.9 (CH3), 47.9 (CH), 47.7 (CH), 44.1 (CH), 29.9 (CH2),
27.8 (CH2), 14.2 (CH3). Anal. Calcd for C11H16O5: C, 57.88; H,
7.07. Found: C, 57.62; H, 7.06.
Ethyl (S3,R3a,R6a)-3-Ethoxy-1-oxo-3,3a,6,6a-tetrahydro-1H-
cyclopenta[c]furan-4-carboxylate [(-)-10]. (-)-10 was obtained
following the general procedure from cycloadduct 6a and was
isolated by column chromatography (hexane-ethyl acetate, 5:1).
(()-(3R,3aR,4S,6aS)-12B: Colorless oil. TLC Rf (hexane-ethyl
acetate, 6:1) 0.25. Yield 15%. IR (neat) 1781, 1730, 1184, 1115,
Yield 88%. White solid, mp 70-72 °C. [R]20 -33.2 (c 0.72,
D
1
946, 928 cm-1. H NMR (CDCl3, 300 MHz) δ 5.21 (s, 1H), 4.17
CHCl3), ee >99.5% (hexane-isopropyl alcohol, 90/10, Rt ) 7.6
min). IR (KBr) 1793, 1711, 1621, 1271, 1099, 1043, 948 cm-1. 1H
NMR (CDCl3, 300 MHz) δ 6.83 (q, 1H, J ) 2.4 Hz), 5.61 (s, 1H),
4.24 (m, 2H), 3.88 (m, 1H), 3.73-3.62 (m, 3H), 3.38 (td, 1H, J )
2.6 and 7.9 Hz), 2.92 (m, 2H), 1.31 (t, 3H, J ) 7.1 Hz), 1.26 (t,
3H, J ) 7.1 Hz). 13C NMR (CDCl3, 75 MHz) δ 179.6 (C), 163.5
(C), 144.7 (CH), 133.7 (C), 105.4 (CH), 65.2 (CH2), 60.8 (CH2),
53.2 (CH), 41.1 (CH), 36.6 (CH2), 14.9 (CH3), 14.2 (CH3). Anal.
Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 59.73; H, 6.32.
Ethyl (R3,S3a,S6a)-3-Ethoxy-1-oxo-3,3a,6,6a-tetrahydro-1H-
cyclopenta[c]furan-4-carboxylate [(+)-10]. (+)-10 was obtained
following the general procedure from furanone 2b and ethyl 2,3-
butadienoate and subsequent desulfinylation with aluminum amal-
gam. It was isolated by column chromatography (hexane-ethyl
acetate, 5:1) and crystallized from diethyl ether and hexane. Overall
(q, 2H, J ) 7.2 Hz), 3.49 (s, 3H), 3.22 (dt, 1H, J ) 3.3 and 8.6
Hz), 3.02 (dd, 1H, J ) 6.4 and 8.6 Hz), 2.72 (dd, 1H, J ) 6.4 and
13.8 Hz), 2.01 (m, 4H), 1.27 (t, 3H, J ) 7.2 Hz). 13C NMR (CDCl3,
75 MHz) δ 179.5 (C), 173.4 (C), 107.8 (CH), 61.1 (CH2), 56.6
(CH3), 50.1 (CH), 48.1, (CH), 43.8 (CH), 29.7 (CH2), 28.7 (CH2),
14.2 (CH3).
Ethyl 3-Ethoxy-1-oxo-hexahydro-1H-cyclopenta[c]furan-4-
carboxylate (13). Compounds 13 were obtained from (-)-10.
(3S,3aS,4S,6aR)-13A: Colorless oil. TLC Rf (hexane-ethyl
acetate, 6:1) 0.18. Yield 66%. [R]20D +32.4 (c 1.9, CHCl3). IR (neat)
1
1775, 1734, 1191, 1159, 1118, 959 cm-1. H NMR (CDCl3, 300
MHz) δ 5.26 (d, 1H, J ) 1.8 Hz), 4.18 (m, 2H), 3.83 (qd, 1H, J )
7.1 and 9.6 Hz), 3.56 (qd, 1H, J ) 7.1 and 9.6 Hz), 3.20 (m, 1H),
2.97 (m, 2H), 2.21 (m, 1H), 1.91 (m, 2H), 1.67 (m, 1H), 1.28 (t,
3H, J ) 7.1 Hz), 1.20 (t, 3H, J ) 7.1 Hz). 13C NMR (CDCl3, 75
MHz) δ 178.8 (C), 172.0 (C), 104.9 (CH), 65.4 (CH2), 60.8 (CH2),
48.1 (CH), 47.8 (CH), 44.2 (CH), 29.9 (CH2), 27.8 (CH2), 14.9
(CH3), 14.2 (CH3).
yield 60%. White solid, mp 71-73 °C. [R]20 +34.0 (c 0.25,
D
CHCl3), ee >99.5% (hexane-isopropyl alcohol, 90/10, Rt ) 6.5
min).
Ethyl (R3,S3a,S6,S6a)-3-Ethoxy-6-methyl-1-oxo-3,3a,6,6a-tet-
rahydro-1H-cyclopenta[c]furan-4-carboxylate [(+)-11]. (+)-11
was obtained following the general procedure from cycloadduct
9b and was isolated by column chromatography (hexane-diethyl
(3S,3aS,4S,6aR)-13B: Colorless oil. TLC Rf (hexane-ethyl
acetate, 6:1) 0.25. Yield 15%. [R]20D +10.0 (c 0.5, CHCl3). IR (neat)
1
1782, 1731, 1191, 1114, 1045, 926 cm-1. H NMR (CDCl3, 300
ether, 5:2) as a colorless oil. Yield 92%. [R]20 +93.5 (c 0.80,
MHz) δ 5.31 (s, 1H), 4.17 (q, 2H, J ) 7.1 Hz), 3.86 (qd, 1H, J )
7.1 and 9.5 Hz), 3.69 (qd, 1H, J ) 7.1 and 9.5 Hz), 3.24 (dt, 1H,
J ) 3.2 and 8.6 Hz), 3.02 (dd, 1H, J ) 6.5 and 8.6 Hz), 2.72 (dd,
1H, J ) 6.5 and 13.8 Hz), 2.01 (m, 4H), 1.27 (t, 3H, J ) 7.1 Hz),
1.24 (t, 3H, J ) 7.1 Hz). 13C NMR (CDCl3, 75 MHz) δ 179.6 (C),
D
CHCl3), ee >99.5% (hexane-isopropyl alcohol, 95/5, Rt ) 7.3
min). IR (neat) 1782, 1714, 1638, 1373, 1340, 941 cm-1. 1H NMR
(25) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345.
9370 J. Org. Chem. Vol. 73, No. 23, 2008

Synthesis of Enantiopure Functionalized Cyclopentanes
173.4 (C), 106.6 (CH), 65.1 (CH2), 61.1 (CH2), 50.3 (CH), 48.2,
(CH), 43.9 (CH), 29.7 (CH2), 28.7 (CH2), 14.9 (CH3), 14.2 (CH3).
(3S,3aS,4S,6R,6aR)-Ethyl 3-Ethoxy-6-methyl-1-oxohexahy-
dro-1H-cyclopenta[c]furan-4-carboxylate (14). 14 was obtained
from (-)-11 after 14 h. The residue analyzed by 1H NMR contains
a mixture of (+)-14 and the other stereoisomer in 95:5 ratio. (+)-
14 was isolated by column chromatography (hexane-ethyl acetate,
pure form from 14A and ethane-1,2-dithiol. Yield. 82%. [R]20
D
+26.2 (c 1.3, CHCl3). IR (neat) 3500-2500, 1727, 1705, 1184
1
cm-1. H NMR (CDCl3, 300 MHz) δ 5.11 (d, 1H, J ) 11.8 Hz),
4.15 (q, 2H, J ) 7.1 Hz), 3.30-3.10 (m, 5H), 3.07 (m, 1H), 2.62
(ddd, 1H, J ) 6.3, 9.9 and 11.8 Hz), 2.32-2.03 (m, 3H), 1.27 (t,
3H, J ) 7.2 Hz), 1.10 (d, 3H, J ) 6.4 Hz). 13C NMR (CDCl3, 75
MHz) δ 176.2 (C), 174.8 (C), 61.0 (CH2), 56.2 (CH), 53.4 (CH),
52.6 (CH), 45.3 (CH), 38.8 (CH2), 38.1 (CH2), 37.4 (CH), 36.8
(CH2), 15.8 (CH3), 14.1 (CH3).
6:1) in 67% yield as a colorless oil. [R]20 +37.5 (c 1.2, CHCl3).
D
1
IR (neat) 1778, 1731, 1186, 1121, 961 cm-1. H NMR (CDCl3,
The racemic compound was obtained from (()-15.
300 MHz) δ 5.26 (d, 1H, J ) 2.7 Hz), 4.18 (m, 2H), 3.84 (qd, 1H,
J ) 7.1 and 9.5 Hz), 3.55 (qd, 1H, J ) 7.1 and 9.5 Hz), 3.06 (m,
2H), 2.96 (m, 1H), 2.30 (m, 1H), 2.05 (m, 1H), 1.44 (q, 1H, J )
12.9 Hz), 1.28 (t, 3H, J ) 7.2 Hz), 1.20 (t, 3H, J ) 7.1 Hz), 1.18
(d, 1H, J ) 7.0 Hz). 13C NMR (CDCl3, 75 MHz) δ 175.4 (C),
172.0 (C), 105.0 (CH), 65.6 (CH2), 60.8 (CH2), 49.3 (CH), 47.5
(CH), 46.5 (CH), 36.9 (CH), 35.8 (CH2), 15.5 (CH3), 14.9 (CH3),
14.2 (CH3).
f. Methylation of Acids with Diazomethane. Carboxylic acids
16 and 17 were treated with an excess of diazomethane at 0 °C in
diethyl ether giving the corresponding methyl esters in quantitative
yield. They were analyzed by HPLC with a Daicel Chiralcell OD
column with hexane and isopropyl alcohol as eluents (97/3) with a
continuous flow of 1 mL/min. Retention times are indicated in each
case.
Ethyl 3-Methyl-(1S,2R,3R)-2-(1,3-dithiolan-2-yl)cyclopentane-
1,3-dicarboxylate (18). 18 was obtained in optically pure form from
16. Quantitative yield. [R]20D +1.8 (c 1.0, CHCl3), ee >99.5% (Rt
(()-(3R,3aR,4R,6S,6aS)-Ethyl 3-Methoxy-6-methyl-1-oxo-
hexahydro-1H-cyclopenta[c]furan-4-carboxylate (15A). 15A was
1
obtained from (()-8-endo after 14 h. The residue analyzed by H
1
) 13.4 min). IR (neat) 1726, 1175, 933 cm-1. H NMR (CDCl3,
NMR contains a mixture of (()-15A and the other stereoisomer in
95:5. It was isolated by column chromatography (hexane-ethyl
acetate, 6:1) in 65% yield. White solid, mp 38-40 °C. IR (neat)
1780, 1731, 1189, 1123, 965 cm-1. 1H NMR (CDCl3, 300 MHz) δ
5.14 (d, 1H, J ) 2.3 Hz), 4.18 (m, 2H), 3.45 (s, 3H), 3.09-2.90
(m, 2H), 2.29 (m, 1H), 2.05 (td, 1H, J ) 5.6 and 12.8 Hz), 1.42 (q,
1H, J ) 12.8 Hz), 1.26 (t, 3H, J ) 7.1 Hz), 1.17 (d, 3H, J ) 7.0
Hz). 13C NMR (CDCl3, 75 MHz) δ 175.3 (C), 171.9 (C), 106.3
(CH), 60.8 (CH2), 57.1 (CH3), 49.1 (CH), 47.4 (CH), 46.5 (CH),
36.9 (CH), 35.8 (CH2), 14.3 (CH3), 14.2 (CH3). Anal. Calcd for
C12H18O5: C, 59.49; H, 7.49. Found: C, 59.13; H, 7.49.
300 MHz) δ 5.13 (d, 1H, J ) 11.8 Hz), 4.13 (m, 2H), 3.67 (s, 3H),
3.21 (m, 4H), 3.07 (m, 2H), 2.47 (td, 1H, J ) 7.7 and 11.8 Hz),
2.22 (m, 2H), 1.90 (m, 2H), 1.28 (t, 3H, J ) 7.2 Hz). 13C NMR
(CDCl3, 75 MHz) δ 174.1 (C), 173.7 (C), 60.5 (CH2), 57.1 (CH),
52.4 (CH), 51.6 (CH), 46.2 (CH), 46.1 (CH), 38.4 (2CH2), 28.3
(CH2), 28.2 (CH2), 14.2 (CH3). HRMS (FAB+) calcd for
C13H21O4S2 [M + H] 305.0881, found 305.0880.
The racemic compound was obtained from (()-16 (Rt ) 13.5
and 14.5 min).
1-Ethyl 3-Methyl-(1S,2S,3R,4R)-2-(1,3-dithiolan-2-yl)-4-me-
thylcyclopentane-1,3-dicarboxylate (19). 19 was obtained from
e. Furanone Ring-Opening. A solution 0.2 M of (()-12A, (+)-
13A, (+)-14, or (()-15 and ethane-1,2-dithiol (5 equiv) in dry
dichloromethane was added dropwise to a 0.1 M solution of boron
trifluoride-diethyl ether (2 equiv) in the same solvent, kept under
stirring at 0 °C. The solution was stirred at 0 °C over 6 h
(monitorized by TLC). Water was added to the reaction mixture,
and the aqueous layer was extracted several times with ethyl acetate.
The combined organic layer was washed with brine then dried over
MgSO4 and the solvent was removed in vacuo. The crude material
17 in quantitative yield and optically pure form. [R]20 +40.4 (c
D
0.8, CHCl3), ee >99.5% (Rt ) 11.5 min). IR (neat) 1730, 1171,
1
1029 cm-1. H NMR (CDCl3, 300 MHz) δ 5.09 (d, 1H, J ) 11.7
Hz), 4.17 (q, 2H, J ) 7.1 Hz), 3.67 (s, 3H), 3.31-3.07 (m, 5H),
3.03 (m, 1H), 2.59 (ddd, 1H, J ) 6.2, 9.9 and 11.8 Hz), 2.28-2.12
(m, 3H), 1.29 (t, 3H, J ) 7.2 Hz), 1.03 (d, 3H, J ) 6.3 Hz). 13C
NMR (CDCl3, 75 MHz) δ 173.7 (C), 172.6 (C), 60.5 (CH2), 56.5
(CH), 53.1 (CH), 52.9 (CH), 51.1 (CH3), 45.2 (CH), 38.9 (CH2),
37.9 (CH2), 37.3 (CH), 36.4 (CH2), 15.9 (CH3), 14.2 (CH3). HRMS
(FAB+) calcd for C14H23O4S2 [M + H] 319.1038, found 319.1033.
The racemic compound was obtained from (()-17 (Rt ) 11.6
and 14.2 min).
1
was analyzed by H NMR and the cyclopentanes was purified by
column chromatography (hexane-acetone, 4:1).
(1R,2R,3S)-2-(1,3-Dithiolan-2-yl)-3-(ethoxycarbonyl)cyclopen-
tanecarboxylic Acid (16). 16 was obtained in optically pure form
from 13A and ethane-1,2-dithiol. Yield 79%, colorless oil. [R]20
D
Acknowledgment. We thank DGICYT (Grant CTQ2006-
06741/BQU) and Comunidad Auto´noma de Madrid (CCG07-
UAM/PPQ-1849) for financial support. We thank Universidad
Auto´noma de Madrid for a Predoctoral Fellowship to Alberto
Nu´n˜ez.
+11.3 (c 1.7, CHCl3). IR (neat) 3400-2600, 1725, 1702, 1184
1
cm-1. H NMR (CDCl3, 300 MHz) δ 5.16 (d, 1H, J ) 11.8 Hz),
4.14 (m, 2H), 3.22 (s, 4H), 3.28-3.06 (m, 2H), 2.51 (td, 1H, J )
7.8 and 11.8 Hz), 2.33-2.17 (m, 2H), 2.04-1.84 (m, 2H), 1.27 (t,
3H, J ) 7.2 Hz). 13C NMR (CDCl3, 75 MHz) δ 178.6 (C), 174.1
(C), 60.8 (CH2), 56.8 (CH), 52.1 (CH), 46.5 (CH), 46.2 (CH), 38.5
(CH2), 38.4 (CH2), 28.4 (2CH2), 14.1 (CH3). Anal. Calcd for
C12H18O4S2: C, 49.63; H, 6.25; S, 22.08. Found: C, 49.83; H, 6.42;
S, 21.39.
The racemic compound was obtained from (()-12A.
(1R,2S,3S,5R)-2-(1,3-Dithiolan-2-yl)-3-(ethoxycarbonyl)-5-me-
thylcyclopentanecarboxylic Acid (17). 17 was obtained in optically
Supporting Information Available: NMR spectra of all new
compounds and crystallographic data for compounds 6b and
9b (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
JO801896A
J. Org. Chem. Vol. 73, No. 23, 2008 9371