Synthesis of δ-lactones from 2-alkynyl epoxides and 4-alkynyl-1,3-dioxolan-2-ones by palladium catalysed carbonylation and conjugate nucleophilic addition

Article abstract of DOI:10.1039/b006927m

Synthesis of δ-lactones from 2-alkynyl epoxides and 4-alkynyl-1,3-dioxolan-2-ones by palladium catalysed carbonylation and conjugate nucleophilic addition was investigated. The stereocontrolled conjugate addition of nucleophiles to the electron deficient

Full text of DOI:10.1039/b006927m

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Synthesis of ꢀ-lactones from 2-alkynyl epoxides and 4-alkynyl-1,3-
dioxolan-2-ones by palladium catalysed carbonylation and
conjugate nucleophilic addition
1
Julian G. Knight,* Simon W. Ainge, Carl A. Baxter, Timothy P. Eastman and
Simon J. Harwood
Department of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne,
UK NE1 7RU. E-mail: J.G.Knight@ncl.ac.uk
Received (in Liverpool, UK) 21st July 2000, Accepted 24th August 2000
First published as an Advance Article on the web 11th September 2000
Palladium catalysed carbonylation of both 4-alkynyl-1,3-
dioxolan-2-ones and alkynyl epoxides occurs under mild
conditions to give methyl 5-hydroxy-2,3-dienoates which
are converted to ꢁ,ꢀ-unsaturated ꢀ-lactones by tandem
conjugate addition–cyclisation with lithium dimethyl-
cuprate or to methyl (E)-5-hydroxypent-3-enoates by
stereoselective reduction with sodium borohydride.
Scheme 2 Reagents and conditions: (a) MCPBA (1.3 eq.), CH2Cl2, 0 ЊC
δ-Lactones are found in a wide variety of biologically import-
ant natural products1 and have been isolated from organisms
carrying genetically modified polyketide synthases.2 We have
recently reported3 the synthesis of γ,δ-unsaturated δ-lactams
by palladium catalysed carbonylation of 5-vinyloxazolidinones
and were interested in extending our studies to the synthesis of
the corresponding δ-lactones. This lactam formation, which is
thought to involve the carbonylation of a π-allyl palladium
intermediate, occurs at high pressures (70 atm CO). In contrast,
the carbonylation of vinylpalladium intermediates occurs
under much milder conditions,4 and so we planned to use the
alkynyl dioxolanones 3 rather than the corresponding vinyl
species. Palladium catalysed carbonylation of 4-alkynyl-1,3-
dioxolan-2-ones 3 and the corresponding epoxides 5 is known5,6
to lead to alkyl 5-hydroxypenta-2,3-dienoates 6. In this Com-
munication we report the stereocontrolled conjugate addition
of nucleophiles to the electron deficient 2,3-double bond of
allenes 6 to give γ,δ-unsaturated δ-lactones in the case of
lithium dimethylcuprate, and methyl (E)-5-hydroxypent-3-
enoates in the case of sodium borohydride. Dioxolanones 3a–c
were prepared by the addition of 1-lithioalkynes to α-hydroxy
ketones 1 to give the corresponding diols 2 followed by cyclis-
ation7 by treatment with methyl chloroformate (Scheme 1).
to rt.
Dixneuf and co-workers5 used harsher conditions [Pd(dba)2 (2
mol%), PBu3 (10 mol%), CO (50 atm)] for highly substitued
alkynyldioxolanones and Piotti and Alper6 reported the carbo-
nylation of alkynyl epoxides [Pd(Ph2PMe)4 (1 mol%), CO (20
atm), MeOH, rt]. We found that the palladium catalysed carbo-
nylation of alkynyldioxolanones 3a–d and alkynyl epoxides 5a–
c proceeds in good yields under very mild conditions [Pd(PPh3)4
(1 mol%), CO (1 atm), MeOH, rt, 18 h] (Table 1, Scheme 3).
Scheme 3 Reagents and conditions: (a) Pd(PPh3)4 (1 mol%), CO
(1 atm), MeOH, rt, 18 h; (b) Me2CuLi (2.2 eq.), Et2O, Ϫ78 to Ϫ40 ЊC.
3
᎐
Scheme 1 Reagents and conditions: (a) R C᎐CLi (2.2 eq.), THF,
᎐
The dioxolanone 3d gave the allene 6d in 70% yield whereas the
corresponding epoxide 5c gave the same allene in just 53% yield
under our conditions (Table 1). As expected,6 the carbonylation
appeared to proceed with high diastereoselectivity. A 2.5:1 mix-
ture of diasteroisomers of dioxolanone 3c was transformed into
a 2.5:1 mixture of diastereoisomers of allene 6c. Similarly, the
carbonylation of dioxolanone 3d (a single diastereoisomer) and
epoxide 5c both gave the allene 6d as a single diastereoisomer
(by 1H NMR).
0 ЊC to rt, 2 h (2c was produced as a 2.5:1 mixture of diastereoisomers);
(b) Et3N (8 eq.), MeOCOCl (6 eq.), CH2Cl2, rt, 20 h.
Oxidation of enynes 4 with MCPBA6 (Scheme 2) gave the
corresponding alkynyl epoxides 5a–c in very variable yields
which were not improved by the use of buffered conditions. On
one attempt, the oxidation of hex-1-ynylcyclohexene 4c gave the
diols 2d (10%) and 2e (8%) as the only identifiable products. The
syn-diol 2d was converted to the corresponding dioxolanone 3d
in 47% yield by treatment with methyl chloroformate.
Although nucleophilic addition to allene esters (most com-
monly to dimethyl penta-2,3-dienoate) has been reported9 there
are to our knowledge no reports concerning the addition of
Tsuji and Mandai have reported8 the carbonylation of alk-2-
ynyl carbonates [Pd(PPh3)4 (2 mol%), CO (1–30 atm), MeOH].
3188
J. Chem. Soc., Perkin Trans. 1, 2000, 3188–3190
This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b006927m

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Table 1
11b in 69% yield. In this case none of the corresponding
α,β-unsaturated ester was detected. The alkene is assumed to be
E by analogy to the stereochemistry of 11a. Reduction of allene
6d gave the β,γ-unsaturated ester 11c in 71% yield as a 1:1
mixture of diastereoisomers (these are assumed to be E-alkenes
differing in the relative stereochemistry of C2 and C5 resulting
from a non-stereoselective enolate protonation). The selective
formation of E-alkenes can be explained on the basis of initial
deprotonation of the OH group by borohydride, followed by
internal delivery of hydride by the resulting alkoxyborohydride
species 12.
Allene
Lactone
SMa
R1
R2
R3
(% yield)b
(% yield)b
3a
3b
3cc
3d
5a
5b
5c
H
H
Me
Me
Me
Me
Bu
Ph
Ph
Bu
(CH2)3Ph
Et
Bu
6a (76)
6b (49)
6c (51)c
6d (70)d
6e (52)
6f (78)
7a (60)
7b (56)
7c (55)e
7d (53)e
7e (54)
7f (53)
(CH2)4
H
H
H
Me
(CH2)4
6d (53)d
a Starting material. b Isolated yield. c A 2.5:1 mixture of diastereoi-
somers (1H NMR). d A single diastereoisomer (1H NMR). e A 1:1 mix-
ture of diastereoisomers (1H NMR).
nucleophiles to alkyl 5-hydroxy-2,3-dienoates. We were pleased
to find that addition of two molar equivalents of lithium
dimethylcuprate to the allenes 6a–f gave rise to the correspond-
ing δ-lactones 7a–f in 53–60% yields (Table 1, Scheme 3).10 This
process (Scheme 4) may involve11 the stereoselective cuprate
We are currently investigating the mechanisms of these
reactions, the control of stereoselectivity, and the elaboration
of the products to sugar-derived targets.
Acknowledgements
We thank GlaxoWellcome (Dr D. M. Hollinshead) for CASE
support (S. W. A.) and the EPSRC for studentship support
(S. J. H.).
Notes and references
1 (a) A. Nangia, G. Prasuna and P. B. Rao, Tetrahedron, 1997, 53,
14507; (b) J. M. Harris and G. A. O’Doherty, Tetrahedron Lett.,
2000, 41, 183; (c) A. M. Gómez, B. López de Uralde, S. Valverde
and J. C. López, Chem. Commun., 1997, 1647; (d) H. Toshima,
H. Sato and A. Ichihara, Tetrahedron, 1999, 55, 2581; (e) C. Clissold,
C. L. Kelly, K. W. M. Lawrie and C. L. Willis, Tetrahedron Lett.,
1997, 38, 8105.
2 J. Staunton and B. Wilkinson, Chem. Rev., 1997, 97, 2611.
3 J. G. Knight, S. W. Ainge, A. M. Harm, S. J. Harwood, H. I.
Maughan, D. R. Armour, D. M. Hollinshead and A. A. Jaxa-
Chamiec, J. Am. Chem. Soc., 2000, 122, 2944.
4 J. Tsuji and T. Mandai, Angew. Chem., Int. Ed. Engl., 1996, 34, 2589.
5 C. Darcel, C. Bruneau and P. H. Dixneuf, Synlett, 1996, 218.
6 M. E. Piotti and H. Alper, J. Org. Chem., 1997, 62, 8484.
7 T. Bando, S. Tanaka, K. Fugami, Z.-I. Yoshida and Y. Tamaru,
Bull. Chem. Soc. Jpn., 1992, 65, 97.
8 J. Tsuji and T. Mandai, J. Organomet. Chem., 1993, 451, 15.
9 (a) H. F. Schuster and G. M. Coppola, Allenes in Organic Synthesis,
Wiley, New York, 1984, 179; (b) Y. Naruse, S. Kakita and
A. Tsunekawa, Synlett, 1995, 711.
Scheme 4
addition to the less hindered face of the 2,3-double bond of the
alkoxide 8 (the size of the R1CHOϪ group may well be increased
by metal ion coordination to the alkoxide) to give the (3Z)-
enolate 9. Protonation of this species occurs in the work-up
since quenching the reaction of 6a with D2O gave the pyran-2-
one 7a deuterated at the 3-position. No hydroxy ester inter-
mediate 10 is observed and, if formed, it must cyclise rapidly to
the lactone 7. The cuprate addition appears to be Z-stereo-
selective since we did not observe any of the E-hydroxy ester
(corresponding to 10), which would be unable to cyclise.
Protonation of the enolate 9 is not stereoselective since lactones
7c and 7d are formed as 1:1 mixtures of diastereoisomers
(Table 1).
10 Typical procedure; the synthesis of 4,5-dimethyl-3-phenyl-3,6-
dihydropyran-2-one 7b: MeLi (2.2 ml of 1.6 M solution in Et2O, 3.6
mmol) was added to copper() iodide (344 mg, 1.8 mmol) in Et2O (10
ml), under nitrogen at 0 ЊC. The suspension was stirred for 2 min,
then cooled to Ϫ78 ЊC and a solution of methyl 5-hydroxy-4-methyl-
2-phenylpenta-2,3-dienoate 6b (197 mg, 0.9 mmol) in Et2O (3 ml)
was added. The reaction mixture was stirred for 45 min, and then a
solution of NH4Cl(aq)–MeOH–NH3(aq) [15:10:4] (15 ml) was
added to quench the reaction. The layers were separated and the
aqueous phase was extracted with Et2O (3 × 10 ml). The combined
organic layers were washed with H2O (30 ml), brine (2 × 30 ml),
dried (MgSO4), filtered and the solvent was removed under reduced
pressure. Purification of the crude material by column chromato-
graphy (EtOAc–petrol, 1:6) afforded the δ-lactone 7b (100 mg, 56%)
as a yellow oil. νmax/cmϪ1 (film) 2916, 1741, 1650, 1597, 1495; δH (500
In order to extend this scheme to the synthesis of naturally
occurring sugar derivatives, we were interested in using a
hydride nucleophile. Naruse et al. have reported9b the reduction
of dimethyl penta-2,3-dienoate with LiAlH4–AlCl3. We chose
to investigate the use of sodium borohydride as a more conveni-
ent alternative (Scheme 5). Reduction of allene 6e [NaBH4 (2.2
MHz, CDCl3) 1.66 (3H, s, one of CH3C᎐CCH3), 1.80 (3H, s, one of
᎐
CH3C᎐CCH3), 4.12 (1H, s, PhCHO), 4.63 (1H, d, J 16, one of
᎐
CH2O), 4.88 (1H, d with fine splitting, J 16, one of CH2O), 7.26–
7.35 (5H, m, Ar-H); δC (125MHz, CDCl3) 14.26, 16.77, 51.48, 71.99,
123.65, 125.56, 127.80, 127.94, 128.99, 136.11, 170.53; m/z 202 (Mϩ,
27.5%), 158 (62), 143 (100), 128 (41), 91 (11), 77 (7); Found: (Mϩ)
202.0990. C13H14O2 requires 202.0994.
Scheme 5 Reagents and conditions: (a) NaBH4 (2.2 eq.), EtOH, rt, 2 h.
eq.), EtOH, rt, 2 h]12 gave in 53% yield a mixture of the
β,γ-unsaturated ester 11a together with the corresponding
α,β-unsaturated isomer in a ratio of 5:1. The E-alkene geom-
etry of 11a was assigned on the basis of the coupling constant
(14.5 Hz) between the protons on the double bond. Allene
6f was reduced to the corresponding β,γ-unsaturated ester
11 For a discussion of the mechanism of cuprate addition to an allenic
ketone see: J. Berlan, J.-P. Battioni and K. Koosha, Tetrahedron
Lett., 1976, 3355.
12 Typical procedure; the synthesis of methyl (E)-2-ethyl-5-hydroxy-4-
methylpent-3-enoate 11b: NaBH4 (53.3 mg, 1.41 mmol) was added
J. Chem. Soc., Perkin Trans. 1, 2000, 3188–3190
3189

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to methyl 2-ethyl-5-hydroxy-4-methylpenta-2,3-dienoate 6f (100 mg,
0.588 mmol) in dry ethanol (5 ml) under nitrogen at room temper-
ature. The reaction mixture was stirred for 2 h, quenched with
NH4Cl (5 ml), and the product extracted into EtOAc (10 ml). The
organic layer was removed and washed with NH4Cl (5 ml), sat.
NaHCO3 (5 ml), brine (5 ml), dried (MgSO4), filtered and the sol-
vent was removed under reduced pressure. Purification of the crude
material by column chromatography (EtOAc–petrol, 1:10 to 1:1)
gave the ester 11b as a clear oil (70 mg, 69%). δH (500 MHz, CDCl3)
0.82 (3H, t, J 7.5, CH3CH2), 1.43–1.75 (2H, m, CH3CH2CH), 1.63
(3H, d, J 1.5, CH3C᎐CH), 1.97 (1H, br s, OH), 3.13 (1H, dt, J 7.0,
᎐
9.5, CH3CH2CHCH᎐C), 3.6 (3H, s, CH3OCO), 3.95 (2H, s,
᎐
CH2OH), 5.35 (1H, qd, J 1.5, 9.5, HC᎐C); δC (125 MHz, CDCl3)
᎐
11.6, 13.9, 26.0, 45.8, 51.7, 68.1, 123.0, 137.9, 175.0; νmax/cmϪ1 (film)
3421 (br), 2964, 2875, 1736; m/z 172 (Mϩ, 0.3%) 155 (3), 140 (100);
Found (Mϩ) 172.10964. C9H16O3 requires 172.10994.
3190
J. Chem. Soc., Perkin Trans. 1, 2000, 3188–3190