A concise synthesis of (S)-(+)-5,6-2H-pyran-2-one via hydrozirconation- carbonylation-demetallation of O-benzyl (S)-(-)-4-pentyn-2-ol

Article abstract of DOI:10.1016/S0957-4166(98)00054-8

A simple synthetic approach to α,β-unsaturated δ-lactones has been devised from the hydrozirconation of O-protected homopropargyl alcohols followed by carbonylation and quenching with iodine. The synthesis of (S)- (+)-5,6-2H-pyran-2-one (parasorbic acid)

Full text of DOI:10.1016/S0957-4166(98)00054-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 949–954
A concise synthesis of (S)-(+)-5,6-2H-pyran-2-one via
hydrozirconation–carbonylation–demetallation of O-benzyl
(S)-(−)-4-pentyn-2-ol
Jairton Dupont ∗ and Augusto J. Donato
Grupo de Catálise, Instituto de Química, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500, 91501-970
Porto Alegre RS, Brazil
Received 2 January 1998; accepted 22 January 1998
Abstract
A simple synthetic approach to α,β-unsaturated δ-lactones has been devised from the hydrozirconation of O-
protected homopropargyl alcohols followed by carbonylation and quenching with iodine. The synthesis of (S)-
(+)-5,6-2H-pyran-2-one (parasorbic acid) from easily available O-benzylated (S)-(−)-4-pentyn-2-ol was chosen to
exemplify the approach. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
α,β-Unsaturated δ-lactones are represented in many natural products and are synthetically versatile
precursors of other molecules of considerable interest, and their synthesis has attracted attention over
the years.1,2 In this respect, the naturally occurring (S)-(+)-5,6-2H-pyran-2-one (parasorbic acid) 1e
(Scheme 1) has served as a convenient starting material for the synthesis of various natural products
and as a chiral building block.3–22
Although, the synthesis of the lactone 1e has been reported several times in racemic and enantiomer-
ically enriched forms, to our knowledge, no expedient method is available.3–22 Herein, we report that
1e and other δ-lactones can be easily prepared in essentially one-pot procedures with the key step
being the hydrozirconation–carbonylation–demetallation of O-protected homopropargyl alcohols. This
approach is based on previous findings that the hydrozirconation–carbonylation–demetallation of O-
protected propargyl alcohols leads selectively to 3,5-disubstituted butenolides.23 In order to extend
this method to the synthesis of α,β-unsaturated δ-lactones, we have investigated the hydrozircona-
tion–carbonylation–demetallation of a series of homopropargyl alcohols and then applied this to the
synthesis of (S)-(+)-1e.
∗
Corresponding author. E-mail: dupont@if.ufrgs.br
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00054-8

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Scheme 1.
Table 1
(a) The stereochemistry at the C_C bond of 2 was assigned from NOE experiments. (b) Isolated yield.
(c) Reaction performed in the presence of 1.5 equiv. of the Schwartz reagent.
2. Results and discussion
The hydrozirconation–carbonylation–demetallation procedure was first exploited with various racemic
O-protected homopropargyl alcohols listed in Table 1. The addition of equimolar amounts of the O-
protected homopropargyl alcohols 3a–3g to a suspension of the Schwartz reagent Cp2Zr(H)Cl in benzene
at room temperature yields after 12–15 h a light yellow solution. Without isolation, the carbonylation of
these hydrozirconated alkynes under 1.1 atm of carbon monoxide affords after 5–6 h an orange solution,
which was treated with iodine for 2–3 h. Aqueous workup and column chromatography of the reaction
mixture produces the lactones 1 and/or 2 in good yields together with benzyl alcohol and trimethyl- or
triphenylsilanol (Scheme 1).
The reaction scheme can be understood based on mechanisms proposed for the formation of 3,5-
disubstituted butenolides.23 In the first step, the hydrozirconation of the alkyne will lead to the
vinyl–zirconium compounds. This is followed by insertion of CO into the Zr–alkenyl bond and demet-
allation with iodine to give the α,β acyl iodide. Intramolecular nucleophilic attack by the ether oxygen

J. Dupont, A. J. Donato / Tetrahedron: Asymmetry 9 (1998) 949–954
951
on the electrophilic acyl iodide group leads to the γ- or δ-lactone (Scheme 2). The formed benzyl iodide
and iodo trimethyl or triphenyl silane are hydrolyzed to the corresponding alcohols during the aqueous
workup.
Scheme 2. [Zr]=Cp2ZrCl
The formation of the γ- or δ-lactones is controlled during the hydrometallation step. In most of the
cases, the relative steric bulkiness of the substituents at the C^C bond (R1 vs R2) dictates the preferred
direction of the Zr–H cis-β addition.24,25 This addition of Zr–H gives mixtures of vinyl Zr complexes
with the less-hindered complex predominating. Moreover, equilibration of this mixture with an excess of
Cp2Zr(H)Cl should enrich less-hindered complexes.24,25
In the reactions with alkynes containing a 1,2-disubstituted cyclohexane moiety (3a–3c) or H (3d
and 3e) six-membered heterocyclic compounds were formed selectively. In contrast, the five-membered
lactone is formed as the only product in the case of the alkyne 3h (R2=t-Bu). However, for the alkynes
3f and 3g, where the differences in the steric bulkiness of R1 and R2 are not so pronounced, a mixture
of the γ- and δ-lactones were formed. Nevertheless, in the case of alkyne 3g, an excess of the Schwartz
reagent increased the selectivity of 1g from 1.2:1 to 3.2:1.
In the demetallation step, E α,β-unsaturated acyl iodides are formed and an equilibrium with their Z
isomers in the presence of an excess of iodide (Scheme 2) can be assumed. This isomerization process
is essential in the case of δ-lactone formation. However, only γ-lactones with trans-stereochemistry at
the C_C bond (with respect to R2 and the acyl group) have been obtained. This clearly indicates that the
reaction leading to the five-membered lactones is faster than the E–Z isomerization process. The nature
of the alcohol protecting group (CH2Ph, SiMe3 and SiPh3) has no significant influence on the selectivity
or yield of the lactone formation (compare entries 5–7 and 8–9 of Table 1).
On the basis of the above results, the methodology has been applied to the synthesis of (S)-(+)-1e.
The addition of the lithium acetylide ethylene diamine complex to a solution of (S)-(−)-propylene oxide
affords (S)-(−)-4-pentyn-2-ol that has been transformed without isolation into (S)-(−)-3e ([α]25589=−9.8

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J. Dupont, A. J. Donato / Tetrahedron: Asymmetry 9 (1998) 949–954
(c=2.85, Et2O)) in 60% overall yield by reaction with benzylbromide. Using the same protocol described
for the preparation of racemic 1e, the (S)-(+)-5,6-2H-pyran-2-one was prepared in 62% yield (Scheme 3).
Scheme 3.
In summary, a simple and efficient route to non-racemic α,β-unsaturated δ-lactones has been devel-
oped. The availability of both enantiomers of homopropargyl alcohols from chiral epoxides should allow
the concise and enantiospecific synthetic route to various substituted α,β-unsaturated δ-lactones.
3. Experimental
3.1. General considerations
All manipulations were performed under dry, oxygen-free argon using standard techniques. All
solvents were dried and distilled under argon prior to use. Infrared spectra (Nujol mulls or KBr pellets)
1
were recorded in the region 4000–400 cm−1 using a Mattson 3020 FT-IR spectrometer. The H and
13C–{1H} NMR spectra were recorded at 200 or 300 MHz and 50 or 75 MHz, respectively, using
Varian VXR-200 or Varian 300 Inova instruments. Proton and carbon shifts (δ/ppm, J/Hz), are positive
downfield relative to external SiMe4. Elemental analyses were carried out by the Central Analítica
IQ/UFRGS (Porto Alegre, Brazil). Mass spectra were obtained with a GC–MS HP 5988A (EI, 70 eV).
Optical rotations were measured using a Perkin–Elmer 341 polarimeter with a 1.0 dm tube (1.0 mL). The
racemic homopropargyl alcohols 3a–3f were obtained from the reaction of the acetylide anions with the
corresponding epoxides26 and protected according to the procedure described for O-benzyl-(S)-(−)-4-
pentyn-2-ol (3e). All other reagents were obtained from Aldrich and used as purchased.
3.2. General procedure for the preparation of the lactones
A solution of the O-protected homopropargyl alcohol (3 mmol) in benzene (10 mL) was added to a
white suspension of Cp2Zr(H)Cl (0.8 g, 3.1 mmol) in benzene (25 mL) at room temperature. The reaction
mixture was stirred at room temperature for 12–16 h. The resulting yellow solution was treated with
carbon monoxide (1.1 atm) for 6–8 h at room temperature to produce an orange–red solution. A solution
of iodide (0.78 g, 3.1 mmol) in benzene (20 mL) was added and the reaction mixture was stirred at room
temperature for 2 h. The reaction was quenched by the addition of a suspension of sodium disulfide (2–3
g) in water (2 mL) and the organic phase was immediately extracted with diethyl ether (3×50 mL). The
organic phase was dried over magnesium sulfate and the volatiles were removed under reduced pressure
(15 mmHg). Column chromatography (hexane/diethyl ether) affords the lactone.
Compound 1a: Calculated for C9H12O2: C, 71.03; H, 7.95; found: C, 71.29; H, 7.89. IR (KBr pellets):
1
1707 cm−1 (ν C_O). H NMR (CDCl3, 300 MHz, RT), δ 6.68 (dd, 1H, HC_CH); 6.01 (dd, 1H,
CH_CH); 4.01 (m, 1H, CH–O); 2.32–1.24 (4m, 9H, CH+CH2). 13C–{1H} NMR (CDCl3, 75 MHz,
RT), δ 164.5 (C_O); 150.6 (HC_C); 120.9 (HC_CH); 81.9 (CH–O); 39.5 (CH–C); 31.1, 28.8, 25.2 and
23.9 (CH2).

J. Dupont, A. J. Donato / Tetrahedron: Asymmetry 9 (1998) 949–954
953
Compound 1b: M.p. (DSC): 140°C. Calculated for C15H16O2: C, 78.92; H, 7.06; found: C, 78.79; H,
1
6.89. IR (KBr pellets): 1709 cm−1 (ν C_O); 1599 cm−1 (ν C_C). H NMR (CDCl3, 300 MHz, RT),
δ 7.47–7.31 (m, 5H, aromatic H); 6.71 (d, 1H, 3JHH=1.47 Hz, HC_C); 4.07 (m, 1H, CH–O); 2.41 (m,
1H, CH–C); 2.20–1.20 (4m, 8H, CH2). 13C–{1H} NMR (CDCl3, 75 MHz, RT), δ 165.2 (C_O); 146.5
(HC_C); 135.7 (HC_C); 133.1 (Cipso); 128.0–129.1 (CH aromatic); 81.8 (CH–O); 40.4 (CH–C); 31.5,
29.5, 25.5 and 24.3 (CH2). GC–MS (EI, 70 eV): 228 (46, M+); 200 (91); 129 (97); 105 (100).
Compound 1c: Calculated for C13H20O2: C, 74.96; H, 9.68; found: C, 74.78; H, 9.81. IR (KBr pellets):
1717 cm−1 (ν C_O); 1599 cm−1 (ν C_C). 1H NMR (CDCl3, 200 MHz, RT), δ 6.32 (s br, 1H, HC_C);
3.90 (m, 1H, CH–O); 2.33–1.20 (m, 15H, CH+CH2); 0.93 (t, 3H, 3JHH=1.47 Hz, 7.8 Hz, CH3). 13C–{1H}
NMR (CDCl3, 50 MHz, RT), δ 165.7 (C_O); 143.7 (HC_C); 132.5 (HC_C); 81.6 (CH–O); 39.6
(CH–C); 31.0, 30.3, 30.2, 29.1, 25.1, 23.9, and 22.2 (CH2), 13.8 (CH3).
Compound 1d: IR and NMR data identical to literature values.27
Compound 1e: [α]25589=+219.2 (c=0.96, CHCl3) compared to the literature values ([α]25589=+224.2
(c=0.98, CHCl3)3 and [α]25589=+213.4 (c=1.0, CHCl3)6, also IR and NMR data are identical to literature
values.6
Compound 1f: Calculated for C11H10O2: C, 75.84; H, 5.79; found: C, 75.64; H, 6.01. IR (KBr pellets):
1
1715 cm−1 (ν C_O); 1625 cm−1 (ν C_C). H NMR (CDCl3, 200 MHz, RT), δ 7.50–7.31 (m, 5H,
aromatic H); 7.02 (t, 1H, 3JHH=4.50 Hz, HC_C); 4.50 (t, 2H, 3JHH=4.5 Hz, CH2O); 2.64 (m, 2H, CH2).
13C–{1H} NMR (CDCl3, 50 MHz, RT), δ 164.0 (C_O); 141.6 (HC_C); 135.8 (C_CH); 134.0 (Cipso
aromatic); 128.6 and 128.5 (CH aromatic); 66.7 (CH2O); 25.2 (CH2). GC–MS (EI, 70 eV): 174 (100,
M+); 144 (65); 129 (12); 115 (99). Compound 2f was observed only by gas chromatography. GC–MS
(EI, 70 eV): 174 (M+, 96); 173 (100, M+−1); 129 (45).
Compound 1g: IR (KBr pellets): 1718 cm−1 (ν C_O); 1681 cm−1 (ν C_C). 1H NMR (CDCl3, 200
MHz, RT), δ 6.61 (m, 1H, HC_C); 4.36 (t, 2H, 3JHH=7.7 Hz, CH2O); 2.45 (m, 2H, CH2); 1.94 (d, 3H,
3JHH=1.9 Hz). 13C–{1H} NMR (CDCl3, 50 MHz, RT), δ 165.8 (C_O); 139.9 (HC_C); 128.9 (C_CH);
67.0 (CH2O); 24.7 (CH2); 17.6 (CH3). GC–MS (EI, 70 eV): 112 (100, M+); 82 (56); 67 (15); 54 (77).
Compound 2g: IR (KBr pellets): 1756 cm−1 (ν C_O); 1H NMR (CDCl3, 200 MHz, RT), δ 6.80 (m,
3
3
1H, HC_C); 4.35 (t, 2H, JHH=6.2 Hz, CH2O); 2.86 (m, 2H, CH2); 1.91 (d, 3H, JHH=2.7 Hz, CH3).
13C–{1H} NMR (CDCl3, 50 MHz, RT), δ 172.0 (C_O); 136.0 (HC_C); 126.0 (C_CH); 65.7 (CH2O);
25.2 (CH2); 16.1 (CH3). GC–MS (EI, 70 eV): 112 (100, M+); 97 (9); 94 (12); 82 (63); 67 (32).
Compound 2h: Calculated for C10H16O2: C, 71.39; H, 9.59; found: C, 71.21; H, 9.45. IR (KBr pellets):
1756 cm−1 (ν C_O); 1H NMR (CDCl3, 300 MHz, RT), δ 6.74 (t, 1H, 3JHH=2.8 Hz, HC_C); 4.64 (m,
1H, CHO); 3.15 and 2.60 (2m, 2H, CH2); 1.41 (d, 3H, 3JHH=6.2 Hz, CH3); 1.17 (s, 9H, CH3). 13C–{1H}
NMR (CDCl3, 50 MHz, RT), δ 172.5 (C_O); 150.6 (HC_C); 123.0 (C_CH); 74.1 (CHO); 33.7 (CH2);
29.6 and 22.6 (CH3).
3.3. Synthesis of O-benzyl (S)-(−)-4-pentyn-2-ol 3e
To a suspension of solid lithium acetylide ethylenediamine complex (3.17 g, 34.5 mmol) in DMSO (15
mL), a solution of (S)-(−)-propylene oxide (1.0 g, 17.2 mmol) in DMSO (3 mL) was added dropwise at
0°C. After stirring at room temperature for 30 h the brown solution was diluted with a saturated aqueous
solution of NH4Cl (30 mL). The organic phase was extracted with diethyl ether (3×30 mL) and dried
over magnesium sulfate. Evaporation of the volatiles at atmospheric pressure afforded an orange oil (1.11
g). The alkyne thus obtained was dissolved in THF (30mL) and sodium hydride (0.8 g, 20 mmol) was
added at room temperature. After stirring at room temperature for 0.2 h, benzyl bromide (2.4 mL, 20
mmol) was added and the reaction mixture was stirred for 2 h. Addition of water (200 mL), extraction

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J. Dupont, A. J. Donato / Tetrahedron: Asymmetry 9 (1998) 949–954
of the organic phase with MTBE (3×40 mL) that was dried over magnesium sulfate and removing the
volatiles under reduced pressure afforded a yellow oil. Column chromatography (hexane/diethyl ether
3%) gave 3e as a colourless oil (1.79 g, 60% overall yield).
Compound 3e: Calculated for C12H14O: C, 82.72; H, 8.10; found: C, 82.59; H, 8.45. [α]25589=−9.8
1
(c=2.85, Et2O). IR (KBr pellets): 3298 cm−1 (ν C–H); 2119 cm−1 (ν C^C); H NMR (CDCl3, 200
MHz, RT), δ 7.37–7.24 (m, 5H, CH aromatic); 4.56 (s, 2H, CH2O); 3.70 (m, 1H, CH); 2.45 (m, 2H,
3
CH2); 2.01 (m, 1H, CH); 1.31 (d, 3H, JHH=6.1 Hz, CH3). 13C–{1H} NMR (CDCl3, 50 MHz, RT), δ
138.3 (Cipso); 129.5, 1128.2 and 127.5 (CH aromatic); 81.5 and 69.1 (C^C); 73.1 (CH); 70.6 (CH2O);
25.9 (CH2); 19.4 (CH3).
Acknowledgements
Financial support by CNPq and FAPERGS is gratefully acknowledged. A.J.D. expresses his apprecia-
tion for a fellowship from the CAPES (Brazil) and CPG-Química — UNESP.
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