Synthesis of versatile chiral intermediates by enantioselective conjugate addition of alkenyl Grignard reagents to enamides deriving from (R)-(-)- or (S)-(+)-2-aminobutan-1-ol

Article abstract of DOI:10.1016/S0957-4166(98)00135-9

Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(-)-3, followed by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(-)-3-methyladipic acids 8, respectively. Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3-5, followed by hydrolysis, gave the alkenoic acids (S)-12-14, respectively. Iodolactonization of the latter led to the 5-iodomethyllactones (+)-15-17, which were reduced by means of n- Bu₃SnH into the trans-disubstituted 5-methyllactones (+)-19-21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe₂Cu or n- Bu₂CuLi furnished the trans-5-alkyl-4-phenyllactones (-)-22 or (+)-23.

Full text of DOI:10.1016/S0957-4166(98)00135-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1605–1614
Synthesis of versatile chiral intermediates by enantioselective
conjugate addition of alkenyl Grignard reagents to enamides
deriving from (R)-(−)- or (S)-(+)-2-aminobutan-1-ol
Eric Brown,∗ Christelle Deroye and Joël Touet
Laboratoire de Synthèse Organique (ESA-CNRS 6011), Faculté des Sciences, Avenue Messiaen, F-72085 Le Mans Cedex 9,
France
Received 12 March 1998; accepted 31 March 1998
Abstract
Conjugate addition of but-3-enylmagnesium bromide to the chiral crotonamide (R)-(+)- and (S)-(−)-3, followed
by hydrolysis and oxidation, afforded enantiopure (R)-(+)- and (S)-(−)-3-methyladipic acids 8, respectively.
Conjugate addition of vinylmagnesium chloride to the chiral crotonamide and cinnamamides (R)-(+)-3–5, fol-
lowed by hydrolysis, gave the alkenoic acids (S)-12–14, respectively. Iodolactonization of the latter led to the
5-iodomethyllactones (+)-15–17, which were reduced by means of n-Bu3SnH into the trans-disubstituted 5-
methyllactones (+)-19–21, respectively. Treatment of the iodomethyllactone (+)-16 with LiMe2Cu or n-Bu2CuLi
furnished the trans-5-alkyl-4-phenyllactones (−)-22 or (+)-23. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
In both previous papers in this series,1,2 we described the efficient diastereoselective conjugate addition
of alkyl Grignard reagents to the tertiary crotonamide (R)-(+)-3 and cinnamamide (R)-(+)-4 derived from
(R)-(−)-2-aminobutan-1-ol (R)-(−)-1, via the intermediate formation of the secondary amine (R)-(−)-2
(Scheme 1). Next we contemplated the possibility of carrying out the same reaction by means of alkenyl
Grignard reagents, since the resulting adducts could be potentially useful chiral intermediates.
2. Results and discussion
Reaction of p-chlorocinnamoyl chloride with the amine (R)-(−)-2 in biphasic conditions
(CH2Cl2/aqueous Na2CO3) gave high yields of the corresponding cinnamamide (R)-(+)-5. The
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00135-9

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E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
Scheme 1.
crotonamide (S)-(−)-3 was similarly prepared from crotonoyl chloride and the secondary amine
(S)-(+)-2 derived from (S)-(+)-1. Conjugate addition of but-3-enylmagnesium bromide (sixfold molar
excess) with the crotonamide (R)-(+)-3 in ether at 0°C stereoselectively1,2 afforded the corresponding
adduct (R,R)-(+)-6 in 82% yield, and having a d.e.=95.6% as shown from the 19F NMR spectrum. The
enantiomeric adduct (S,S)-(−)-6 was similarly prepared from the crotonamide (S)-(−)-3. Saponification

E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
1607
of both adducts (R,R)- and (S,S)-6 by means of KOH in aqueous ethanol yielded the corresponding free
acids (R)-(+)-7 and (S)-(−)-7, respectively. The e.e. of each acid 7 was assumed to be equal to the d.e.
of the starting adduct 6. The acid (R)-(+)-7 was used by McWilliams and Clardy3 in the synthesis of
the natural antitumour compound octalactin A, whereas the acid (S)-(−)-7 is an intermediate for various
immunostimulants or immunoregulators.4 Ozonolysis of the acids (R)-(+)- and (S)-(−)-7 was next
performed in acetone at −78°C followed by Jones’ oxidation at 0°C, thus giving crystalline (R)-(+)- and
(S)-(−)-3-methyladipic acids (R)-(+)- and (S)-(−)-8, respectively. The acid (R)-(+)-8 was used in the
synthesis of prostaglandins,5 whereas the acid (S)-(−)-8 is the precursor of an anticancer compound.6
Conjugate addition in ether/THF at 0°C of vinylmagnesium chloride (sixfold molar excess) with
the crotonamide (R)-(+)-3 and the cinnamamides (R)-(+)-4 and (R)-(+)-5 gave moderate yields of the
corresponding (20R,3S) adducts (+)-9, (−)-10 and (+)-11, having d.e.’s=95.4, 93.2 and 94%, respectively
(Scheme 2). Reaction of the crotonamide (R)-(+)-3 with a threefold molar excess of vinylmagnesium
chloride afforded diastereomerically pure adduct (20R,3S)-(+)-9 (d.e.=99%), albeit in poor yield (13%).
Alkaline hydrolysis of the above adducts 9–11, followed by mild acidification and evaporative distilla-
tion, furnished the corresponding (3S)-acids (+)-12, (−)-13 and (−)-14, respectively. Here again, the e.e.
of each acid was assumed to be equal to the d.e. of the starting adduct.
The enantiomerically enriched acids 12–14 were next used for the syntheses of various γ-
butyrolactones. Thus, iodolactonization of these acids was carried out under thermodynamic control, as
described by Bartlett et al.7 (3I2/acetonitrile/24 h/0°C) and gave the trans-disubstituted iodomethyl-γ-
lactones 15–17, respectively, contaminated by small amounts (2–8%) of the corresponding cis-isomer
as shown by the 1H NHR spectra: the proton at C5 gives a signal at ca. δ 4.1 ppm for the trans-isomer,
and at ca. δ 4.9 ppm for the cis-isomer (see Experimental section). The trans-lactone (+)-15 is an
intermediate in the syntheses of the antibiotics aplidiasphingosin8 and ambruticin.9 Iodolactonization
of the acid (−)-13 under kinetic control10 (I2/aqueous NaHCO3/6 h/0°C) gave a mixture of cis-lactone
(−)-18 and trans-lactone (+)-16 (cis:trans ratio=78:22). Recrystallization afforded the pure cis-lactone
(4R,5R)-(−)-18 in 25% yield.
Reduction of the iodomethyllactones (+)-15–17 with Bu3SnH in the presence of AIBN in refluxing
toluene for 24 h led to the corresponding 5-methylactones 19–21, respectively, and in fair yields after
purification. The diastereomerically pure lactones 20 and 21 were obtained by recrystallization. The
trans-dimethylactone (+)-19 is one of the components responsible for the aroma of whisky.11
Reaction of the iodomethylactone (+)-16 with 5 molar equivalents of Me2CuLi in THF at 0°C gave the
5-ethyllactone (−)-22 in 47% yield. Similarly, treatment of (+)-16 with 5 molar equivalents of n-Bu2CuLi
in THF at low temperature furnished the 5-n-pentyllactone (+)-23 in 25% yield. The enantiomer of the
latter is an intermediate for the antitumour antibiotic methylenolactocin.12
Since both the chiral vectors (R)-(−)-2 and (S)-(+)-2 are readily available, all the chiral intermediates
described above could be obtained in each enantiomeric form.
3. Experimental section
3.1. General
1
IR spectra were recorded with Nicolet 5DX and Genesis (Matteson) spectrophotometers. H NMR
(400 MHz) and 19F NMR spectra were recorded with a Bruker AC 400 spectrometer, using Me4Si
1
(for H) and CFCl3 (for 19F) as internal standards. Melting points were determined with a Reichert

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E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
Scheme 2.
microscope. Optical rotations were measured at 26°C with a Perkin–Elmer 241 micropolarimeter.
Elemental analyses were carried out at the I.C.S.N. (C.N.R.S., Gif-sur-Yvette).
(R)-(−)- and (S)-(+)-2-Aminobutan-1-ol, [α]D ꢀ10.0 (neat), were kindly provided by SmithKline
Beecham Laboratories (Mayenne).
3.2. (S)-(+)-N-(2-Fluorobenzyl)-2-aminobutan-1-ol (S)-(+)-2
This compound was prepared in the same way as its enantiomer (R)-(−)-2,2 by alkylation of (S)-(+)-2-
aminobutan-1-ol (S)-(+)-1, [α]D +10 (neat), with 2-fluorobenzyl chloride. The secondary amine (S)-(+)-2
was isolated in 95% yield, m.p. 48–54°C and [α]D +21 (c 2.31, MeOH). 1H NMR (CDCl3) δ: 7.35 (1H,
td); 7.25 (1H, td); 7.10 (1H, t); 7.01 (1H, t); 3.85 (1H, d); 3.80 (1H, d); 3.65 (1H, dd); 3.33 (1H, dd); 3.12
(1H); 2.60 (1H); 1.50 (2H); 0.92 (3H, t).

E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
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3.3. (S)-(−)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)crotonamide (S)-(−)-3
This compound was prepared in the same way as its enantiomer (R)-(+)-3,2 by N-acylation of the
enantiomer of the secondary amine (S)-(+)-2 with crotonoyl chloride. The crotonamide (S)-(−)-3 was
1
isolated in 83% yield, [α]D −18.6 (c 1.56, MeOH). IR (film): 3390, 1656 and 1603 cm−1. H NMR
(CDCl3) δ: 7.50–6.90 (5H); 6.40–6.10 (1H, d); 4.90 (d), 4.65 (d), 4.58 (d) and 4.38 (d) (total 2H);
4.0–3.40 (4H); 2.0–1.70 (3H); 1.70–1.50 (2H); 0.90 (3H, t). 19F NMR (CDCl3) δ: −118.6 (72%) and
−119.8 (28%) (Z/E amide conformers).
3.4. (R)-(+)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-p-chlorocinnamamide (R)-(+)-5
A solution of p-chlorocinnamoyl chloride (4.0 g; 19.9 mmol) in dichloromethane (12 mL) was added
at 0°C to the aminoalcohol (R)-(−)-2 (3.92 g; 19.9 mmol) in dichloromethane (19 mL), and the mixture
was treated with sodium carbonate (2.11 g; 19.9 mmol) in water (14 mL). The resulting biphasic medium
was stirred at 20°C for 4 h. Work-up in the usual manner2 gave an oil which was chromatographed
over silica gel (eluent: cyclohexane:ether=6:4 and elution gradient), thus affording the amide (R)-(+)-5
(6.47 g; 90%), [α]D +12.3 (c 1.06, MeOH). Anal. calc. for C20H21ClFNO2: C, 66.39; H, 5.85; N, 3.87.
1
Found: C, 66.38; H, 5.83; N, 3.71. IR (film): 3390, 1650 and 1600 cm−1. H NMR (CDCl3) δ: 7.65
(1H, d); 7.80–7.0 (8H); 6.75 (1H, d); 5.01 (d), 4.75 (d), 4.70 (d) and 4.45 (d) (total 2H); 4.25–3.50 (4H);
1.85 and 1.66 (2H); 0.95 (3H, t). 19F NMR (CDCl3) δ: −118.56 (68%) and −119.70 (32%) (Z/E amide
conformers).
3.5. (R,R)-(+)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-3-methylhept-6-enamide (R,R)-(+)-6
The crotonamide (R)-(+)-32 (0.70 g; 2.6 mmol) in dry ether (20 mL) was added at 0°C to a solution
of but-3-enylmagnesium bromide in dry ether (14 mL), prepared from 4-bromobut-1-ene (2.14 g; 15.9
mmol) and magnesium (0.433 g; 17.9 mmol). After stirring at 0°C for 19 h, the mixture was worked-up
in the usual way.2 The final residue was chromatographed over silica gel (eluent: cyclohexane:ether=5:5
and elution gradient), thus giving the adduct (R,R)-(+)-6 (0.698 g; 82%), [α]D +7.6 (c 1.12, MeOH). IR
1
(film): 3399, 1623 and 1587 cm−1. H NMR (CDCl3) δ: 7.50–6.90 (4H); 5.80 (1H); 4.95 (2H); 4.86
(d), 4.61 (d), 4.49 (d) and 4.35 (d) (total 2H); 4.0–3.40 (4H); 2.55 (1H); 2.35 (1H); 2.25–1.90 (2H);
1.90–1.20 (5H); 1.0 and 0.94 (3H); 0.91 (3H, t). 19F NMR (CDCl3) δ: −118.46 (R,R) (97.8%); −118.48
(S,R) (2.2%); −119.80 [(R,R)+(S,R)] (100%) (amide conformers and diastereomers), d.e.=95.6%.
3.6. (S,S)-(−)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-3-methylhept-6-enamide (S,S)-(−)-6
The adduct (S,S)-(−)-6, [α]D −7.5 (c 1.0, MeOH), was prepared in the same way as its enantiomer
(R,R)-(+)-6, starting from the crotonamide (S)-(−)-3. Anal. calc. for C19H28FNO2: C, 71.0; H, 8.78; N,
4.36. Found; C, 70.58; H, 8.78; N, 4.29. 19F NMR (CDCl3) δ: −118.47 (S,S) (96.8%); −118.5 (R,S)
(3.2%); −119.81 [(S,S)+(R,S)] (100%) (amide conformers and diastereomers), d.e.=93.5%.
3.7. (R)-(+)-3-Methylhept-6-enoic acid (R)-(+)-7
The adduct (R,R)-(+)-6 (0.589 g; 1.8 mmol), [α]D +7.6 (c 1.12, MeOH) and d.e.=95.6%, in ethanol
(4.5 mL) was treated with potassium hydroxide (0.421 g; 7.3 mmol) in water (1.5 mL). After stirring for
65 h at room temperature, the mixture was acidified with 10% aqueous hydrochloric acid, the ethanol was

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removed under reduced pressure and the aqueous residue was extracted with ether. The organic extracts
were dried (MgSO4) and evaporated. Distillation of the residue under reduced pressure afforded the acid
(R)-(+)-7 (0.221 g; 85%), b.p.20 135–140°C and [α]D +6.6 (c 0.98, CHCl3). Lit.3 (no characteristics
given). IR (film): 3500–2500, 1710 and 1643 cm−1. 1H NMR (CDCl3) δ: 5.80 (1H); 5.0 (2H); 2.37 (dd)
and 2.17 (dd) (total 2H); 2.15–1.90 (3H); 1.45 and 1.32 (2H); 1.0 (3H, d).
3.8. (S)-(−)-3-Methylhept-6-enoic acid (S)-(−)-7
The procedure is the same as for the enantiomeric acid (R)-(+)-7. The adduct (S,S)-(−)-6 (0.617 g;
1.9 mmol), [α]D −7.5 (c 1.0, MeOH) and d.e.=93.5%, in ethanol (4.7 mL) was treated with potassium
hydroxide (0.431 g; 7.7 mmol) in water (1.6 mL). Work-up followed by distillation gave the acid (S)-
(−)-7 (0.195 g; 72%), b.p.20 135–140°C and [α]D −6.7 (c 1.1, CHCl3). Lit.3 (no characteristics given).
3.9. (R)-(+)-3-Methyladipic acid (R)-(+)-8
A solution of the acid (R)-(+)-7 (0.142 g; 1.0 mmol), [α]D +6.6 (c 0.98, CHCl3), in dry acetone (50
mL) was ozonolyzed at −78°C for 5 min. After spontaneous warming to 0°C, Jones’ reagent was added
dropwise until the orange colour persisted. The mixture was filtered and evaporated, followed by addition
of ether (100 mL) and water (25 mL). The aqueous phase was extracted with ether (3×100 mL). The
combined ether extracts were dried (MgSO4) and evaporated. Evaporative distillation of the colourless
oily residue gave the acid (R)-(+)-8 as white crystals which were recrystallized from ether/pentane (0.100
g; 70%), m.p. 85–86°C, b.p.0.1 115–120°C and [α]D +11.67 (c 1.2, CHCl3). Lit.13 [α]D +11.5 (c 9.4,
1
CHCl3). IR (CHCl3): 3500–2500 and 1700 cm−1. H NMR (CDCl3) δ: 2.39 (2H); 2.33 (1H, dd); 2.21
(1H, dd); 2.01 (1H); 1.74 and 1.54 (2H); 0.98 (3H, d).
3.10. (S)-(−)-3-Methyladipic acid (S)-(−)-8
The acid (S)-(−)-8, m.p. 81–82°C and [α]D −11.1 (c 1.1, CHCl3) was prepared in the same way as its
enantiomer (R)-(+)-8, but starting from the ethylenic acid (S)-(−)-7. Lit.14 [α]D −10.98 (c 3.2, CHCl3).
3.11. (20R,3S)-(+)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-3-methylpent-4-enamide
(20R,3S)-(+)-9
The adduct (+)-9 was prepared in a similar manner as the adduct (+)-6. The crotonamide (R)-(+)-32
(0.700 g; 2.6 mmol) in dry ether (20 mL) was added at 0°C to vinylmagnesium chloride (1.370 g; 15.9
mmol; 15% solution in THF). After stirring at 0°C for 3 h, the mixture was worked-up in the usual
way.2 The final residue was chromatographed over silica gel (eluent: cyclohexane:ether=7:3 and elution
gradient), thus affording the adduct (20R 3S)-(+)-9 (0.540 g; 70%), [α]D +9.6 (c 1.1, MeOH). Anal. calc.
for C17H24FNO2: C, 69.60; H, 8.24; N, 4.77. Found: C, 69.61; H, 8.12; N, 4.76. IR (film): 3413, 1621
1
and 1587 cm−1. H NMR (CDCl3) δ: 7.50–6.95 (4H); 5.95–5.70 (1H); 5.06 (1H, dd); 4.98 (1H, dd);
4.88 (d), 4.59 (d), 4.52 (d) and 4.35 (d) (total 2H); 4.10–3.40 (4H); 3.00–2.50 (1H); 2.50–2.25 (2H);
1.90–1.50 (3H); 1.12 and 10.5 (3H); 0.90 (3H, t). 19F NMR (CDCl3) δ: −118.43 (R,R) (2.3%); −118.45
(S,R) (97.7%); −119.82 (S,R)+(R,R)] (100%) (amide conformers and diastereomers); d.e.=95.4%.

E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
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3.12. (20R,3S)-(−)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-3-phenylpent-4-enamide
(20R,3S)-(−)-10
The adduct (−)-10 was prepared in the usual manner. The cinnamamide (R)-(+)-41 (4.0 g; 12.2 mmol)
in dry ether (110 mL) was added at 0°C to vinylmagnesium chloride (6.37 g; 73.4 mmol; 15% solution
in THF). After stirring at 0°C for 3.5 h, the reaction mixture was worked-up1,2 and the final residue was
chromatographed over silica gel (eluent: cyclohexane:ether=7:3 and elution gradient), thus affording the
adduct (20R,3S)-(−)-10 (2.26 g; 52%), [α]D −3.47 (c 1.26, MeOH). Anal. calc. for C22H26FNO2: C,
1
74.34; H, 7.37; N, 3.94. Found: C, 74.16; H, 7.33; N, 3.69. IR (film): 3409, 1623 and 1585 cm−1. H
NMR (CDCl3) δ: 7.50–6.90 (9H); 6.20–5.9 (1H); 5.12 (2H); 4.75 (d), 4.52 (d), 4.39 (d) and 4.38 (d) (total
2H); 4.15 and 4.05 (1H); 3.80–3.40 (3H); 3.08 (dd), 2.93 (dd), 2.80 (dd) and 2.76 (dd) (total 2H); 1.70
(1H); 1.74 and 1.54 (2H); 0.86 and 0.81 (3H, 2t). 19F NMR (CDCl3) δ: −118.46 (S,R) (96.6%); −118.53
(R,R) (3.4%); −119.95 (S,R) (96.2%); −119.99 (R,R) (3.8%) (amide conformers and diastereomers);
d.e.=93.2%.
3.13. (20R,3S)-(+)-N-(1-Ethyl-2-hydroxy)ethyl-N-(2-fluorobenzyl)-3-(p-chlorophenyl)pent-4-enamide
(20R,3S)-(+)-11
The adduct (+)-11 was prepared in the usual manner. The p-chlorocinnamamide (R)-(+)-5 (3.55 g;
9.80 mmol) in dry ether (120 mL) was added at 0°C to vinylmagnesium chloride (5.11 g; 58.9 mmol;
15% solution in THF). After stirring at 0°C for 3.5 h, the reaction mixture was worked-up1,2 and the
final residue was chromatographed over silica gel (eluent: cyclohexane:ether=7:3 and elution gradient),
thus affording the adduct (20R,3S)-(+)-11 (2.08 g; 54%), [α]D +1.5 (c 1.2, MeOH). Anal. calc. for
C22H25ClFNO2: C, 67.77; H, 6.46; N, 3.59. Found: C, 67.72; H, 6.38; N, 3.37. IR (film): 3407, 1635
and 1587 cm−1. 1H NMR (CDCl3) δ: 7.40–6.90 (8H); 6.10–5.85 (1H); 5.10 (2H); 4.75 (d), 4.50 (d), 4.39
(d) and 4.31 (d) (total 2H); 4.15 and 4.05 (1H); 4.0–3.40 (3H); 3.05 (dd), 2.86 (dd), 2.70 (dd) and 2.63
(dd) (total 2H); 1.50 (1H); 1.75 and 1.49 (2H); 0.85 and 0.78 (3H, 2t). 19F NMR (CDCl3) δ: −118.42
(S,R) (97%); −118.54 (R,R) (3%); −119.93 (S,R) (94.2%); −120.00 (R,R) (5.8%) (amide conformers
and diastereomers); d.e.=94%.
3.14. (S)-(+)-3-Methylpent-4-enoic acid (S)-(+)-12
The procedure is the same as for the preparation of the acid (R)-(+)-7. The adduct (20R,3S)-(+)-9
(2.88 g; 9.80 mmol), [α]D +9.6 (c 1.1, MeOH) and d.e.=95.4%, in ethanol (21.6 mL) was treated with
potassium hydroxide (2.20 g; 39.3 mmol) in water (7.2 mL). Work-up followed by distillation gave the
acid (S)-(+)-12 (0.885 g; 79%), b.p.30 110–120°C and [α]D +15.14 (c 3.6, CHCl3). Lit.15 [α]D +17.3 (c
2.07, CHCl3). IR (film): 3400–2400, 1712 and 1643 cm−1. 1H NMR (CDCl3) δ: 5.80 (1H, ddd); 5.06 (d)
and 4.99 (d) (total 2H); 2.70 (1H); 2.42 (dd) and 2.32 (dd) (total 2H); 1.09 (3H, d).
3.15. (S)-(−)-3-Phenylpent-4-enoic acid (S)-(−)-13
The procedure is the same as above. The adduct (20R,3S)-(−)-10 (2.42 g; 6.8 mmol), [α]D −3.47 (c
1.3, MeOH) and d.e=93.2%, in ethanol (20 mL) was treated with potassium hydroxide (1.53 g; 27.3
mmol) in water (6.1 mL). Work-up followed by distillation gave the acid (S)-(−)-13 (1.20 g; 100%),
[α]D −12.2 (c 1.0, PhH). Lit.16 (described in racemic form). IR (film): 3500–2500, 1710, 1637 and 1602

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E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
1
cm−1. H NMR (CDCl3) δ: 7.40–7.20 (5H); 5.96 (1H); 5.10 (2H); 3.85 (1H, qd); 2.80 (1H, dd); 2.75
(1H, dd).
3.16. (S)-(−)-3-(p-Chlorophenyl)pent-4-enoic acid (S)-(−)-14
The procedure is the same as above. The adduct (20R,3S)-(+)-11 (2.04 g; 5.2 mmol), [α]D +1.5 (c 1.2,
MeOH) and d.e.=94%, in ethanol (16 mL) was treated with potassium hydroxide (1.17 g; 20.9 mmol) in
water (8 mL). Work-up followed by distillation gave the acid (S)-(−)-14 (0.757 g; 69%), m.p. 55–60°C
and [α]D −14.4 (c 1.39, PhH). Anal. calc. for C11H11ClO2: C, 62.72; H, 5.26. Found: C, 62.95; H, 5.21.
IR (film): 3400–2500, 1714, 1635 and 1616 cm−1. 1H NMR (CDCl3) δ: 7.35–7.00 (4H); 5.95 (1H, ddd);
5.08 (2H); 3.85 (1H); 2.80 (1H, dd); 2.70 (1H, dd).
3.17. (4S,5S)-(+)-trans-4,5-Dihydro-5-iodomethyl-4-methyl-(3H)-furan-2-one (4S,5S)-(+)-15
The acid (S)-(+)-12 (0.137 g; 1.20 mmol), [α]D +15.14 (c 3.6, CHCl3), in purified acetonitrile (4.4
mL) was treated at 0°C under nitrogen with iodine (0.91 g; 3.6 mmol). After stirring at 0°C in the dark
and under nitrogen for 24 h, ether (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5
mL) were added. The aqueous phase was extracted with ether and the combined organic solutions were
washed with 10% aqueous sodium thiosulphate solution until colourless, and then washed with water.
The organic phase was dried (MgSO4) and evaporated under reduced pressure. The brown oily residue
(0.247 g; 86%) was rapidly chromatographed over silica using ether as an eluent, thus affording the
lactone (+)-15 (0.227 g; 79%), [α]D +16.3 (c 1.45, CHCl3) with a trans:cis ratio=92:8 (from 1H NMR).
Lit.8 [α]D +18.14 (CHCl3). IR (film): 1778 cm−1. 1H NMR (CDCl3), major trans-isomer, δ: 4.05 (1H,
q) (92%); 3.40 (1H, dd); 3.35 (1H, dd); 2.81 (1H, dd); 2.45 (1H); 2.25 (1H, dd); 1.25 (3H, d). Minor
cis-isomer, δ: 4.67 (1H, q) (8%).
3.18. (4R,5S)-(+)-trans-4,5-Dihydro-5-iodomethyl-4-phenyl-(3H)-furan-2-one (4R,5S)-(+)-16
The acid (S)-(−)-13 (0.58 g; 3.30 mmol), [α]D −12.2 (c 1.0, PhH), in purified acetonitrile (14 mL) was
treated with iodine (2.49 g; 9.80 mmol) as above and was stirred at 0°C in the dark and under nitrogen for
24 h. Work-up as above gave a brown oil (0.860 g; 87%) which was rapidly chromatographed over silica
using ether as an eluent, thus affording the lactone (+)-16 (0.779 g; 79%), [α]D +39.7 (c 1.0 acetone),
1
1
with a trans:cis ratio=98:2 (from H NMR), Lit.7 (racemic form). IR (film): 1791 and 1602 cm−1. H
NMR (CDCl3), major trans-isomer, δ: 7.50–7.10 (5H); 4.32 (1H, dt) (98%); 3.60–3.50 (1H); 3.50 (1H,
dd); 3.36 (1H, dd); 3.10 (1H, dd); 2.85 (1H, dd). Minor cis-isomer, δ 4.96 (1H, dt) (2%).
3.19. (4R,5S)-(+)-trans-4-p-Chlorophenyl-4,5-dihydro-5-iodomethyl-(3H)-furan-2-one (4R,5S)-(+)-17
The acid (S)-(−)-14 (0.50 g; 2.4 mmol), [α]D −14.4 (c 1.39, PhH), in purified acetonitrile (9 mL) was
treated with iodine (1.80 g; 70 mmol) as above and was stirred at 0°C in the dark and under nitrogen
for 24 h. Work-up as above gave a brown oil (0.790 g; 99.6%) which was rapidly chromatographed over
silica (ether as eluent), thus affording the lactone (+)-17 (0.680 g; 86%), [α]D +38.2 (c 1.02, acetone),
with a trans:cis ratio=95:5 (1H NMR). Anal. calc. for C11H10ClIO2: C, 39.26; H, 2.99. Found: C, 39.44;
H, 3.09. IR (film): 1789 and 1596 cm−1. 1H NMR (CDCl3), major trans-isomer, δ: 7.50–7.10 (4H); 4.30
(1H, dt) (95%); 3.54 (1H); 3.47 (1H, dd); 3.34 (1H, dd); 3.10 (1H, dd); 2.80 (1H, dd). Minor cis-isomer,
δ: 4.95 (1H, dt) (5%).

E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
1613
3.20. (4R,5R)-(−)-cis-4,5-Dihydro-5-iodomethyl-4-phenyl-(3H)-furan-2-one (4R,5R)-(−)-18
Sodium hydrogen carbonate (0.141 g; 1.70 mmol) in water (3.2 mL) was added to the acid (S)-(−)-13
(0.148 g; 0.84 mmol), [α]D −12.2 (c 1.01, PhH), in purified dichloromethane (3.2 mL). The mixture was
treated at 0°C with iodine (0.427 g; 1.70 mmol) and was stirred at 0°C in the dark and under nitrogen
for 6 h. The organic phase was washed with 10% aqueous sodium thiosulphate solution until colourless,
then washed with water, and was finally dried (MgSO4) and evaporated. Rapid chromatography of the
residue over silica (eluent: CH2Cl2/ether) afforded a partially crystalline mixture (0.170 g; 67%) of
cis-lactone (−)-18 and trans-lactone (+)-16 (cis:trans ratio=78:22). Recrystallization from a mixture of
diisopropylether and CH2Cl2 gave the pure cis-lactone (4R,5R)-(−)-18 as white crystals (0.062 g; 25%),
m.p. 110–112°C and [α]D −119 (c 1.03, acetone). Lit.7 (racemic form). IR (Nujol): 1791 and 1602 cm−1
.
1H NMR (CDCl3) δ: 7.50–7.15 (5H); 4.96 (1H); 4.10 (1H, ddd); 3.10 (2H); 2.85 (1H, dd); 2.72 (2H, dd).
3.21. (4S,5R)-(+)-trans-4,5-Dihydro-4,5-dimethyl-(3H)-furan-2-one (4S,5R)-(+)-19
Tributyltin hydride (1.12 g; 3.9 mmol) and AIBN (0.014 g) were added to the iodomethyllactone
(+)-15 (0.500 g; 2.1 mmol), [α]D +15.2 (c 1.2, CHCl3) in dry toluene (43 mL). After refluxing for
24 h, the solvent was evaporated and the residue was distilled under reduced pressure, thus affording
the dimethyllactone (+)-19 (0.176 g; 74%), b.p.30 145–155°C and [α]D +37.1 (c 1.2, CHCl3) with a
trans:cis ratio=91:9 (1H NMR). Lit.11a +56.8 (c 1.6, CHCl3). IR (film): 1779 cm−1. 1H NMR (CDCl3),
major trans-isomer, δ: 4.15 (1H, dq) (91%); 2.65 (1H); 2.22 (1H); 2.18 (1H); 1.40 (3H, d); 1.15 (3H, d).
Minor cis-isomer, δ: 4.67 (1H, q) (9%).
3.22. (4R,5R)-(+)-trans-4,5-Dihydro-5-methyl-4-phenyl-(3H)-furan-2-one (4R,5R)-(+)-20
Tributyltin hydride (0.534 g; 1.8 mmol) and AIBN (0.010 g) were added to the iodomethyllactone (+)-
16 (0.300 g; 1.0 mmol), [α]D +38.8 (c 1.1, acetone), in dry toluene (20 mL). After refluxing for 24 h, the
solvent was evaporated under reduced pressure and the residue was treated with ether (17 mL) and 10%
aqueous potassium fluoride solution (17 mL). The aqueous phase was extracted with ether. The organic
extracts were pooled, dried (MgSO4) and evaporated, thus affording the trans-lactone (4R,5R)-(+)-20 as
white crystals (0.121 g; 70%), m.p. 56–59°C and [α]D +20.2 (c 1.0, MeOH), with a trans:cis ratio=99:1
1
(1H NMR). Lit.17 (racemic form). IR (Nujol): 1785 and 1604 cm−1. H NMR (CDCl3) δ: 7.50–7.20
(5H); 4.60 (1H) (99%); 3.25 (1H, dt); 2.95 (1H, dd); 2.78 (1H, dd); 1.45 (3H, d). Minor cis-isomer, δ:
4.95 (1H) (1%).
3.23. (4R,5R)-(+)-4-p-Chlorophenyl-4,5-dihydro-5-methyl-(3H)-furan-2-one (4R,5R)-(+)-21
Tributyltin hydride (0.800 g; 2.76 mmol) and AIBN (0.005 g) were added to the iodomethyllactone
(+)-17 (0.507 g; 1.5 mmol), [α]D +38.2 (c 1.0, acetone), in dry toluene (31 mL). After refluxing for 25 h,
the reaction mixture was worked-up as above, thus leading to the trans-lactone (4R,5R)-(+)-21 as white
crystals (0.201 g; 63.5%), m.p. 113–115°C and [α]D +15.5 (c 1.1, MeOH), with a trans:cis ratio=99:1
(1H NMR). Lit.18 (racemic form). IR (Nujol): 1785 and 1576 cm−1. 1H NMR (CDCl3) δ: 7.35 (2H); 7.20
(2H); 4.52 (1H, dq) (99%); 3.25 (1H, dt); 2.95 (1H, dd); 2.75 (1H, dd); 1.42 (3H, d). Minor cis-isomer,
δ: 4.92 (1H, dq) (1%).

1614
E. Brown et al. / Tetrahedron: Asymmetry 9 (1998) 1605–1614
3.24. (4R,5R)-(−)-4,5-Dihydro-5-ethyl-4-phenyl-(3H)-furan-2-one (4R,5R)-(−)-22
Lithium dimethylcuprate was generated at 0°C in dry THF (5 mL) from methyllithium (1.6 mol L−1
in ether; 6.5 mL; 10.4 mmol) and cuprous iodide (0.99 g; 5.2 mmol). The iodomethyllactone (4R,5S)-
(+)-16 (0.302 g; 1.0 mmol), [α]D +39.7 (c 1.0, acetone), in dry THF (10 mL) was added and the mixture
was stirred at 0°C for 5.5 h. Saturated aqueous ammonium chloride solution (20 mL) was added, the
resulting biphasic medium was filtered through Celite, the latter was washed with ether and the aqueous
phase was extracted with ether. The combined ethereal extracts were washed with brine, dried (MgSO4),
filtered and evaporated. Column chromatography of the final residue over silica gel (eluent: petroleum
ether:ether=9:1 and elution gradient) afforded the lactone (4R,5R)-(−)-22 (0.090 g; 47%), [α]D −11.7 (c
0.51, CHCl3). Lit.19 (no [α]D reported). IR (film): 1778 and 1602 cm−1. 1H NMR (CDCl3), δ: 7.50–7.0
(5H); 4.40 (1H, dt); 3.32 (1H); 2.95 (1H, dd); 2.75 (1H, dd); 1.90–1.60 (2H); 1.00 (3H, t).
3.25. (4R,5R)-(+)-4,5-Dihydro-5-pentyl-4-phenyl-(3H)-furan-2-one (4R,5R)-(+)-23
Lithium dibutylcuprate was generated at ca. −40°C in dry THF (7 mL) from n-butyllithium (1.6 mol
L
−1 in hexane; 8.6 mL; 13.8 mmol) and cuprous iodide (1.31 g; 6.9 mmol). After cooling down to −78°C,
the iodomethyllactone (4R,5S)-(+)-16 (0.400 g; 1.3 mmol), [α]D +39.7 (c 1.0, acetone), in dry THF (12
mL) was added. The mixture was stirred at −78°C for 3 h and at ca. −35°C for 2 h. Saturated aqueous
ammonium chloride solution (30 mL) was added, and the resulting biphasic medium was worked-up as
above. The final residue was chromatographed as above, thus affording the lactone (4R,5R)-(+)-23 (0.076
g; 25%), [α]D +26.7 (c 1.3, CHCl3). Lit.12b [α]D −25.6 (c 1.6, CHCl3), for the enantiomer (4S,5S)-(−)-
23. IR (film): 1778 and 1602 cm−1. 1H NMR (CDCl3) δ: 7.50–7.00 (5H); 4.45 (1H, dt); 3.30 (1H, dt);
2.95 (1H, dd); 2.75 (1H, dd); 1.65 (2H); 1.50–1.20 (6H); 0.85 (3H, t).
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