Intermolecular [3+2] MIRC reactions with alkynoates. Asymmetric Michael addition leading to a nonracemic cyclopentene-annulated α,β-butenolide

Article abstract of DOI:10.1016/S0040-4039(00)00867-4

A novel Michael-initiated ring closure reacton involving allylic chlorosulfone (2) and γ-alkoxy-α,β-ynoates to afford 4- methylenecyclopentenecarboxylates is reported, while with γ-alkylynoates no reaction occurred. With chiral phenyl ynoates 4, the reaction proceeds by 1,3-asymmetric induction and leads further to a nonracemic annulated α,β- butenolide (7). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00867-4

Tetrahedron Letters 41 (2000) 5583±5587
Intermolecular [3+2] MIRC reactions with alkynoates.
Asymmetric Michael addition leading to a nonracemic
cyclopentene-annulated a,b-butenolidey1
Philippe Nakache, Eugene Ghera* and Alfred Hassner*
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Received 27 March 2000; accepted 23 May 2000
Abstract
A novel Michael-initiated ring closure reaction involving allylic chlorosulfone (2) and g-alkoxy-a,b-
ynoates to a€ord 4-methylenecyclopentenecarboxylates is reported, while with g-alkylynoates no reaction
occurred. With chiral phenyl ynoates 4, the reaction proceeds by 1,3-asymmetric induction and leads fur-
ther to a nonracemic annulated a,b-butenolide (7). # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: Michael reactions; cyclopentenecarboxylates; butenolides; asymmetric induction; lithium ion chelation.
The emergence of widespread targets containing ®ve-membered carbon rings, such as quinane
terpenes, has led to continuous interest in new pentannulation strategies. Among the [3+2] dis-
connections leading to cyclopentanes, utilization of trimethylenemethane (TMM) equivalents as
the three-carbon units have been extensively used.2 Within this context, the intermolecular
Michael-initiated ring closure (MIRC) reaction was e€ectively utilized for the regio- and stereo-
selective synthesis3 as well as the asymmetric synthesis4 of methylenecyclopentanes.
Limited success, however, was achieved in the application of intermolecular [3+2] schemes
involving acetylenic acceptors to obtain 4-methylenecyclopentenes. Using mainly methylenecy-
clopropanes as the TMM synthons, such routes were of limited scope5 or presented experimental
restrictions.6 The Pd-complexed TMM species, successful in cycloadditions with ole®ns, failed
when applied to acetylene acceptors.7
* Corresponding authors. Fax: +972-3-5351250; e-mail: hassna@mail.biu.ac.il
y
Dedicated to Professor Richard Neidlein on the occasion of his 70th birthday.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00867-4

5584
We report herein the synthesis of 4-methylenecyclopentenes by a simple MIRC route from
2-(chloromethyl)-3-phenylsulfonyl-1-propene (2)8 (as the TMM synthon) and readily available
g-alkoxy-a,b-alkynoates 4. The results are summarized in Table 1.9 By contrast, we found that in
the absence of oxygen substitution at C-4, the g-alkylated or arylated ynoates do not undergo
addition of lithiated allylic sulfones 1±3.10,11 Formation of open-chain adducts, via protonation
of the reversible intermediate 5, was not observed. The use of phenyl instead of ethyl ynoates
resulted mostly in improved yields and better diastereoselectivity (entries 7 and 8, Table 1).
Moreover, the nonracemic (S)-ethyl ynoate 4j,12 a€orded with 2 a 1:1 stereomeric mixture of
cyclopentenecarboxylates (6j), whereas the corresponding phenyl ester 4k gave under the same
conditions a single diastereoisomer 6k (entries 10 and 11).13 This 1,3-asymmetric induction
resulting from conjugate addition to a chiral ynoate may be attributed to a preferred facial
approach due to additional chelation between the Li cation and the aryl group of the ester. The
e€ect of aryl±Li ion chelation on remote asymmetric induction has recently been reported by us.14
Utilization of a bulky, nonaromatic ester (4l) resulted in a 1:1 stereomeric mixture of cyclo-
pentenes (6l, entry 12), thus eliminating the steric factor as accounting for the stereoselective
formation of 6k.
Table 1
[3+2] MIRC reaction of chlorosulfone 2 with ynoates 4

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Acid treatment of phenyl ester 6k a€orded the a,b-butenolide 7 in which the given stereo-
chemistry is based on NOE measurements (Eq. (1)).15 By contrast, the less strained unsaturated
d-lactones 8 were obtained from the diastereomeric ethyl esters 6j (Eq. (2)).16 The kinetic pref-
erence for the formation of 7 rather than of d-lactones 8 may be due to the better leaving (phenoxy)
group in 6k.
ꢀ1†
ꢀ2†
The cyclopentenation route provides an entry to annulated a,b-butenolides such as 9, which,
on exposure to an aqueous base, can be converted to an annulated cyclopentadiene 10 (Eq. (3)).17
ꢀ3†
It is noteworthy that lithiated methallyl sulfone 1 reacted more e€ectively than chlorosulfone 2
with g-oxygenated ynoates and a€orded 82% of 1:1 conjugate adducts (30 min, ^60ꢁC), including
an isolated 53% of 11 arising from cis addition of the organometallic to the double bond. Though
lithiated 1 underwent chloride displacement with methallyl chloride, it led solely to proton
transfer when exposed to chloroallylsulfone 2, to a€ord 12 and 1 upon D2O quenching. The

5586
higher stability of the lithio derivative of 2 is attributed to Li±Cl coordination (A), hence its lower
reactivity in conjugate additions.18
In conclusion, the coordination between the g-alkoxy group of ynoates 4 and the Li cation has
proven critical for successful MIRC reaction utilizing the lithiated allyl sulfone 2, presumably by
displacement of the equilibrium toward 5, thus promoting the ring closure. Additional coordination
of the lithium cation with the aromatic group of the ester in 4 contributes to the stereoselectivity
of the conjugate additions.
Acknowledgements
The authors wish to thank the US±Israel Science Foundation and the Marcus Center for
Pharmaceutical and Medicinal Chemistry at Bar-Ilan University for ®nancial support, and Dr.
Hugo E. Gottlieb for his valuable help in NMR analysis.
References
1. Stereochemistry. Part 91. For part 90 see: Gottlieb, L.; Hassner, A. Synth. Commun. 2000, in press.
2. For reviews, see: Chan, D. M. T. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp. 287±313; Hudlicky, T. Chem. Rev. 1989, 89, 1457.
3. Ghera, E.; Yechezkel, Y.; Hassner, A. J. Org. Chem. 1996, 61, 4959, and references cited therein.
4. Yechezkel, T.; Ghera, E.; Hassner, A. Tetrahedron: Asymmetry 1996, 2422.
5. Binger, P.; Buch, H. M. Top Curr. Chem. 1987, 135, 77; Binger, P.; Lu, Q.-H.; Wedemann, P. Angew. Chem., Int.
Ed. Engl. 1985, 24, 316.
6. Yamago, S.; Ejiri, S.; Nakamura, E. Angew. Chem., Int. Ed. Engl. 1995, 34, 2154; see also: van der Louw, J.; van
der Baan, F.; Bickelhaupt, F.; Klumpp, G. W. Tetrahedron Lett. 1987, 28, 2889.
7. Trost, B. M.; Balkovek, J. M.; Angle, S. R. Tetrahedron Lett. 1986, 27, 1445.
8. Breuilles, P.; Uguen, D. Tetrahedron Lett. 1987, 28, 6053.
9. In a typical experiment, BuLi in hexane (1.2 mmol) was added to a stirred solution of 2 (1.3 mmol) in anhydrous
THF (4 ml) and DMPU (1 ml) under argon, at ^78ꢁC; After 15 min the alkynoate (4, 1 mmol in 1 ml THF) was
added and stirring of the mixture continued at ^60ꢁC for about 4 h and the reaction was quenched (aqueous
NH4Cl) after all the alkynoate reacted (TLC). The crude product, after extraction with ether, was rapidly ®ltered
via a short silica column (ethyl acetate±ether) to separate unreacted 2 and the polymerized polar material and then
puri®ed by silica gel (¯ash) chromatography (petroleum ether±ethyl acetate).
10. Reaction of 2 with unsubstituted ethyl propiolate a€orded, however, the open-chain adduct; see also: Alonso,
D. A.; Flavello, L. R.; Mancheno, B.; Najera, C.; Tomas, M. J. Org. Chem. 1996, 61, 5004.
11. Stabilized carbanions are poor donors for intermolecular Michael reactions with g-alkyl or aryl ynoates unless the
adduct intermediate is trapped by strong electrophiles: see, e.g.: Jung, M. E. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, p. 41; Bury, A.; Joay, S. D.; Stirling, C. J. M.
J. Chem. Soc., Chem. Commun. 1986, 124.

5587
12. For the preparation of a similar ester, see: Boeckman, R. K.; Charette, A. B.; Asberom, T.; Johnston, B. H. J. Am.
Chem. Soc. 1991, 113, 5337.
13. Data for 6k: mp=117ꢁC; [ꢀ]D=^69.3 (c=1.5, CHCl3). 1H NMR (600 MHz, CDCl3) ꢁ=1.41 (s, 3H), 1.63 (s, 3H),
3.19 (dq, J=18.2, 2.4 Hz, 1H), 3.29 (d, J=19.3 Hz, 1H), 4.26 (dd, J=7.20, 7.10 Hz, 1H), 4.47 (t, J=7.19 Hz, 1H),
4.71 (s, 1H), 5.12 (s, 2H), 5.52 (t, J=7.1 Hz, 1H), 7.05±7.13 (m, 2H), 7.26 (m, 1H), 7.42 (m, 2H), 7.57 (m, 2H),
7.66±7.71 (m, 1H), 7.86±7.89 (m, 2H).
14. Ghera, E.; Kleiman, V.; Hassner, A. J. Org. Chem. 1999, 64, 8; for subsequent similar observations, see: Juaristi,
E.; Leon-Romo, J. L.; Ramirez-Quiros, Y. J. Org. Chem. 1999, 64, 2914; Harris, C. R.; Kuduk, S. D.; Balog, A.;
Savin, K.; Glunz, P. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 7050.
20
15. Data for 7: mp=81ꢁC; ‰ꢀŠD =^70 (CHCl3); IR (®lm): 1636, 1756 cm^1; H NMR (600 MHz, CDCl3) ꢁ 2.68 (d,
J=20 Hz, 1H), 3.07 (dq, J=20, 2 Hz, 1H), 3.98 (dd, J=12.5, 3.8 Hz, 1H), 4.07 (dd, J=12.5, 3.8 Hz, 1H), 5.02 (m,
1H), 5.39 (m, 1H), 5.43 (m, 1H), 5.50 (m, 1H), 7.56 (m, 2H), 7.71 (m, 1H), 7.79 (m, 2H); 13C NMR: ꢁ 31.68, 61.20,
73.09, 81.07, 118.96, 129.17, 129.72, 134.73, 134.87, 135.30, 142.94, 143.21, 163.21; NOE: strong interaction for
H1±CH2OH, very weak for H1±H2.
1
16. Data for 8: IR: 1722 cm^1; The 13C NMR spectrum (600 MHz, CDCl3) exhibits a long range interaction between
the CˆO group (ꢁ 161.1) and one of the protons of the oxymethylene group (ꢁ 4.56) which is missing in the
spectrum of 7; other spectral data agree with the given structure.
17. Data for 9: 1H NMR (300 MHz, CDCl3: ꢁ 2.60 (d, J=10 Hz, 1H), 3.10 (d, J=10 Hz, 1H), 5.02 (m, 2H), 5.16 (d,
J=9 Hz, 1H), 5.44 (s, 1H), 5.53 (s, 1H), 7.52±7.57 (m, 2H), 7.68±7.78 (m, 3H); 13C NMR: ꢁ 31.80, 69.37, 73.52,
77.00, 118.98, 128.28, 128.43, 134.72, 135.07, 142.06, 143.09, 162.96. MS: 294 (MNH4+, 227 (MH+). Compound
1
10: H NMR (300 MHz, CDCl3): ꢁ 2.52 (s, 3H), 3.44 (t, J=3.1 Hz, 2H), 5.10 (t, J=3.1 Hz, 2H), 7.58±7.94 (m,
5H).
18. In contrast with the well-known e€ects of Li cation coordination with heteroatoms, the in¯uence of Li±Cl
coordination was not suciently explored; see, however: Gschwend, H. W.; Rodriguez, H. R. In Org. Reactions;
Vol. 26, 1979; pp. 74±75; Najera, C.; Sansano, J. M. Tetrahedron Lett. 1992, 33, 6543. For an example of F±Li
coordination e€ects, see: Gilday, J. P.; Widdowson, D. A. Tetrahedron Lett. 1986, 27, 5525. We are indebted to
Prof. G. H. Posner for valuable comments.