Stereoselective synthesis of α-alkylidene- and substituted alkylidene- γ-lactones

Article abstract of DOI:10.1016/S0040-4039(00)00252-5

Cross-coupling reactions of (E)- and (Z)-tosylates of α- hydroxymethylene-γ-butyrolactone with aryl, heteroaryl, alkyl, and alkynylzinc chlorides under Pd(PPh₃)₄ catalysis were found to be a suitable synthetic method for stereoselective preparation of α-alkylidene- and substituted alkylidene-γ-lactones. The reactions, conducted under mild conditions, proceed with high stereoselectivity and moderate yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00252-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2741–2744
Stereoselective synthesis of α-alkylidene- and substituted
alkylidene-γ-lactones
∗
ˇ
Jakub Castulík and Ctibor Mazal
Department of Organic Chemistry, Faculty of Science, Masaryk University, Kotlárˇská 2, 611 37 Brno, Czech Republic
Received 21 December 1999; accepted 9 February 2000
Abstract
Cross-coupling reactions of (E)- and (Z)-tosylates of α-hydroxymethylene-γ-butyrolactone with aryl, heteroaryl,
alkyl, and alkynylzinc chlorides under Pd(PPh3)4 catalysis were found to be a suitable synthetic method for
stereoselective preparation of α-alkylidene- and substituted alkylidene-γ-lactones. The reactions, conducted under
mild conditions, proceed with high stereoselectivity and moderate yields. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: methylene lactones; coupling reactions; palladium; zinc compounds.
The α-methylene-γ-lactone moiety is an integral building block of many natural products exhibi-
ting a wide range of important biological activities, such as cytotoxicity,1 phytotoxicity,2 or antitu-
mor activity.3,4 However, possible application of such compounds is strongly limited by their high
cytotoxicity.5 One way to modify chemical and physical properties as well as the biological activity
of methylene lactones is alkylation and arylation of their exocyclic double bond.6 Such substituted α-
methylene-γ-lactones also occur in many natural compounds;7 normally, they can be synthesized via
two general ways. One, represented by a classical Claisen condensation, is based on introduction of the
alkylidene group on to the α-position of the lactone ring,8 the second yields α-alkylidene lactones by ring
closure reactions from acyclic, olefinic or acetylenic, precursors containing suitable functional groups.9
Although a number of methods have been reported, only a few of them can control the configuration of
the exocyclic double bond.10,11
Recently, a stereoselective preparation of sulfonates and carboxylates of α-hydroxymethylene lactones
has been developed in our department.12 Since it is well-known that vinylic sulfonates are suitable subs-
trates for coupling reactions with a variety of organometallic reagents, forming new C–C bonds with outs-
tanding stereoselectivity,13 we decided to investigate the potential of such reactions for stereoselective
synthesis of the title lactones. Organozinc compounds were chosen as coupling reagents because of their
easy accessibility and tolerance to many reactive groups including ester and lactone functionalities.14
∗
Corresponding author. Fax: +420 5 41211214; e-mail: mazal@chemi.muni.cz (C. Mazal)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00252-5
tetl 16532

2742
In this paper we report a novel, general method of stereoselective synthesis of α-alkylidene-
and substituted alkylidene-γ-butyrolactones by cross-coupling reactions of (E)- and (Z)-3-
(tosyloxymethylene)dihydro-2(3H)-furanones ((E)- and (Z)-1) with various aryl, heteroaryl,
alkyl, and alkynylzinc chlorides (Scheme 1). The reaction was catalyzed by 3–5 mol% of
tetrakis(triphenylphosphine)palladium(0). The starting organozinc compounds were prepared from
the corresponding Grignard (phenyl, naphthyl, and octyl) or organolithium (furyl, thienyl, butyl,
phenylethynyl, and trimethylsilylethynyl) reagents. With (E)-1, reactions have been carried out in THF
at 70°C, but with (Z)-1, the temperature has to be kept between 0–5°C in order to get satisfactory
stereoselectivity.15,16
Scheme 1.
Table 1 shows that the coupling gave the best results with arylzinc chlorides, entries 1, 2, 9, and 10,
where excellent stereoselectivity was obtained for both isomers of 1. Also very good stereoselectivity was
achieved in the reactions of heteroarylzinc chlorides. In the case of (E)-1, total retention of configuration
was observed (entries 3 and 4), whereas tosylate (Z)-1 gave small amounts of the thermodynamically
more stable8 (E)-products (5% entry 11, 7% entry 12). Similarly, the coupling of (Z)-1 with alkylzinc
chlorides, entries 13 and 14, gave only 4 and 5% of (E)-products, respectively. The amount of (E)-
product increased with reaction time in the order aryl<heteroaryl<alkyl<alkynyl. The largest extent
of stereochemical leakage, about 20%, was obtained in coupling of alkynylzinc chlorides with (Z)-1,
entries 15 and 16. The reason for thus could again lie in the higher thermodynamic stability of the
(E)-isomers of 2g and 2h and in a more facile isomerization of enyne lactone system in the presence
of Pd(II)-complexes. The only enyne lactone of this type in the literature was prepared by Ji et al.17
by Heck coupling of phenylacetylene with 3-bromomethylene-4-hydroxymethyl-5-pentyldihydro-2(3H)-
furanone. The starting lactone as well as the product had an (E)-configuration.
Table 1
Results of cross-coupling reactions of (E)-1, entries 1–8, and (Z)-1, entries 9–16, with organozinc
chlorides (Scheme 1)

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Quite surprisingly, reactions of (E)-1 with alkylzinc chlorides gave mixtures of isomers with about
10% of (Z)-products. Within the generally accepted mechanism of Pd-catalyzed cross-coupling reac-
tions, these results could be rationalized according to Scheme 2. Obviously, isomerization during the
oxidative addition step can be ruled out, because this reaction step does not involve RZnCl and is the
same as that which occurs in the reactions yielding complete retention of configuration. The reason
for the E–Z isomerization can, however, lie in the different character of Pd(II)-complex 5 formed
after transmetallation by RZnCl. Compared to other R substituents, alkyls are pure σ-donors without
possibility of π-interaction with orbitals on the palladium. Therefore, these orbitals can take part in
some kind of push–pull interaction with the methylene lactone system weakening the exocyclic double
bond and facilitating its rotation to the (Z)-configuration, which is stabilized by an additional, though
weak, chelating interaction of Pd with the lactone carbonyl oxygen. Reductive elimination of 6 would
then result in formation of the (Z)-isomer.
Scheme 2.
Our efforts to couple tosylates 1 with some vinyl- or allylzinc chlorides failed due to product
decomposition.
Acknowledgements
This work was supported by Grant-in-Aid (No. 391/99) from Fund of the Development of Universities.
The authors thank Prof. J. Jonas for his interest in this work.
References
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2744
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14. Erdik E. Tetrahedron 1984, 40, 641.
15. Typical procedure for coupling of 1 was as follows: A solution of (E)-1 (0.53 g, 2 mmol) and Pd(PPh3)4 (0.115 g, 0.1mmol)
in the THF (10 ml) was added via syringe to a solution of phenylethynylzinc chloride (4 mmol), prepared by the reaction of
phenylacetylene (0.4 ml, 4 mmol) and n-BuLi (4 mmol) in THF (10 ml) at 0–5°C and subsequent transmetallation with THF
solution of ZnCl2 (0.7 g, 5 mmol) at room temperature. The reaction mixture was then refluxed until (E)-1 was consumed.
Usual work-up with aqueous NH4Cl gave crude product that was chromatographed on silica gel (petroleum ether:ether, 3:2).
Recrystallization from petroleum ether gave 0.23 g (58 %) of (E)-2g: m.p. 109.5–110.2°C; 1H NMR: 7.50 (m, 2 H, arom);
7.39 (m, 3H, arom), 6.82 (t, J=3.2 Hz, 1H), 4.45 (t, J=7.3 Hz, 2H), 3.16 (dt, J=3.2 Hz, 7.3 Hz, 2H); 13C NMR: 170.2, 135.7,
131.8, 129.5, 128.5, 122.1, 116.9, 102.0, 85.7, 65.4, 27.3, IR: 2067, 1741, 1645, cm−1. Anal. calcd for C13H10O2: C, 78.8%;
H, 5.1%; found: C, 78.6%; H, 5.5%.
16. Selected physical and spectroscopic data of newly synthesized compounds: (E)-2d: m.p. 130.3–131.2°C; 1H NMR (CDCl3,
500 MHz) 7.76 (s, 1H), 7.56 (d, J=4.9 Hz, 1H), 7.33 (d, J=3.3 Hz, 1H), 7.16 (m, 1H), 4.49 (t, J=7.3 Hz, 2H), 3.15 (dt, J=2.7
Hz, 7.3 Hz, 2H); 13C NMR: 172.1, 139.1, 132.3, 130.2, 129.1, 128.1, 121.1, 65.3, 27.4; IR: 1736, 1641 cm−1. Anal. calcd
for C9H8O2S: C, 60 %; H, 4.5 %; found: C, 60.3%; H, 4.3%. (E)-2h: m.p. 44.2–45.1°C; 1H NMR (CDCl3, 500 MHz): 6.57
(t, J=3.1 Hz, 1H), 4.41 (t, J=7.2 Hz, 2H), 3.07 (dt, J=3.1 Hz, 7.2 Hz, 2H), 0.23 (s, 9H); 13C NMR: 170.1, 137.1, 116.7,
108.9, 100.6, 65.4, 27.3, −0.2; IR: 2197, 1751, 1646 cm−1. Anal. calcd for C10H14O2Si: C, 61.8%; H, 7.3%; found: C,
61.5%; H, 7.3%. (Z)-2c: m.p. 88–89°C; 1H NMR (CDCl3, 500 MHz) 7.78 (d, J=3.6 Hz, 1H), 7.45 (d, J=1.3 Hz, 1H), 6.85 (t,
J=2.3 Hz, 1H), 6.50 (m, 1H), 4.39 (t, J=7.4 Hz, 2H), 3.15 (dt, J=2.3 Hz, 7.4 Hz, 2H); 13C NMR: 169.9, 157.0, 143.9, 121.9,
120.9, 117.5, 106.7, 65.3, 28.4; IR: 1729, 1642 cm−1. Anal. calcd for C9H8O3: C, 65.8%; H, 4.9%; found: C, 65.5%; H,
5.0%. (Z)-2d: m.p. 96.5–97.3°C; 1H NMR (CDCl3, 500 MHz) 7.57 (d, J=3.5 Hz, 1H), 7.33 (d, J=5.1 Hz, 1H), 7.12 (s, 1H),
7.07 (m, 1H), 4.41 (t, J=7.4 Hz, 2H), 3.12 (dt, J=2.0 Hz, 7.4 Hz, 2H); 13C NMR: 169.5, 139.1, 136.9, 134.6, 131.1, 126.8,
119.1, 65.3, 30.5; IR: 1726, 1633 cm−1. Anal. calcd for C9H8O2S: C, 60%; H, 4.5%; found C, 60.3%; H, 4.3%. (Z)-2g: m.p.
75.4–76.5°C; 1H NMR (CDCl3, 500 MHz): 7.57 (m, 2H), 7.35 (m, 3H), 6.35 (t, J=2.6 Hz, 1H), 4.37 (t, J=7.3 Hz, 2H), 3.10
(dt, J=2.3 Hz, 7.3 Hz, 2H); 13C NMR: 167.3, 134.7, 130.8, 128.9, 128.4, 121.2, 115.9, 101.9, 84.7, 64.8, 26.6; IR: 2198,
1745, 1635 cm−1. Anal. calcd for C13H10O2: C, 78.8 %; H, 5.1%; found: C, 78.8%; H, 5.5%. (Z)-2h: m.p. 64.2–65.0°C;
1H NMR (CDCl3, 500 MHz): 6.14 (t, J=2.7 Hz, 1H), 4.32 (t, J=7.2 Hz, 2H), 3.03 (dt, J=2.7 Hz, 7.3 Hz, 2H), 0.20 (s, 9H);
13C NMR: 167.6, 135.5, 116.5, 108.9, 99.6, 64.7, 28.9, −0.2; IR: 2113, 1742, 1638 cm−1. Anal. calcd for C10H14O2Si: C,
61.8%; H, 7.3%; found: C, 61.5%; H, 7.3%.
17. Ji, J.; Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 1160.