Stereocontrolled ring-opening of some enantiomerically enriched epoxy ketones and epoxy alcohols using trimethylaluminium: Synthesis of (S)-2-arylpropanoic acids

Article abstract of DOI:10.1039/b000996m

Poly-(D)-leucine-catalysed epoxidation of chalcone furnished epoxide (+)-6; treatment of this epoxide with trimethylaluminium followed by zinc borohydride reduction and oxidative cleavage furnished (S)-2-phenylpropanoic acid 11. In a complementary sequence epoxy ketones (-)-6 and 25 were converted into (S)-2-phenylpropanoic acid and (S)-fenoprofen 5 respectively by reduction with zinc borohydride, reaction with trimethylaluminium and oxidative cleavage. Similarly epoxy ketones (-)-6, 21 and 28 were treated with methylmagnesium iodide, trimethylaluminium and the resultant alcohols subjected to oxidative cleavage to afford (S)-2-phenylpropanoic acid (from the first two substrates) and (S)-naproxen 1.

Full text of DOI:10.1039/b000996m

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Stereocontrolled ring-opening of some enantiomerically enriched
epoxy ketones and epoxy alcohols using trimethylaluminium:
synthesis of (S)-2-arylpropanoic acids
1
Lydia Carde,a D. Huw Daviesb and Stanley M. Robertsa
a Department of Chemistry, Liverpool University, Liverpool, UK L69 7ZD
b AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire,
UK SK10 4TG
Received (in Cambridge, UK) 7th February 2000, Accepted 17th March 2000
Published on the Web 2nd May 2000
Poly-()-leucine-catalysed epoxidation of chalcone furnished epoxide (ϩ)-6; treatment of this epoxide with
trimethylaluminium followed by zinc borohydride reduction and oxidative cleavage furnished (S)-2-phenyl-
propanoic acid 11. In a complementary sequence epoxy ketones (Ϫ)-6 and 25 were converted into (S)-2-
phenylpropanoic acid and (S)-fenoprofen 5 respectively by reduction with zinc borohydride, reaction with
trimethylaluminium and oxidative cleavage. Similarly epoxy ketones (Ϫ)-6, 21 and 28 were treated with
methylmagnesium iodide, trimethylaluminium and the resultant alcohols subjected to oxidative cleavage
to afford (S)-2-phenylpropanoic acid (from the first two substrates) and (S)-naproxen 1.
Introduction and background information
2-Arylpropionic acids are well known as anti-inflammatory
agents and, as such, are widely used to control the symptoms of
arthritis and related connective tissue disorders.1 Typical
examples of these non-steroidal anti-inflammatory agents
include naproxen 1, ibuprofen 2, flurbiprofen 3, ketoprofen 4,
and fenoprofen 5.
Fig. 2 Reagents and conditions: (i) [O], poly-()-leucine; (ii) [O],
poly-()-leucine; (iii) Me3Al; (iv) oxidative cleavage.
aluminium reagents proceeds regio- and stereo-selectively with
inversion of configuration at the C-3 position.6
It is now well established that the major therapeutic activity
of many, if not all, of these compounds resides in the (S)-
enantiomer. For example, in the case of naproxen 1, the
(S)-enantiomer is twenty-eight times more potent than the
(R)-enantiomer.2 Several methods for obtaining the (S)-
enantiomers of arylpropanoic acids, free of contaminating (R)-
enantiomers, are known. These include asymmetric chemical
synthesis as well as classical chemical resolutions and bio-
catalysis.3
Contemporaneously, there has been an increased interest in
the chemistry surrounding the ring-opening of epoxides using
trimethylaluminium (Fig. 1). In most cases ring-opening occurs
with inversion of configuration4 except when R2 is an electron-
donating unit capable of stabilising an intermediate carbo-
cation (e.g., R2 = aryl) when retention of configuration at the
reacting carbon centre can be observed.5 It has been shown,
moreover, that reaction of 2,3-epoxyalkan-1-ols with trialkyl-
We reasoned that if the ring-opening reaction with trimethyl-
aluminium could extend to suitably substituted enantiopure
2,3-epoxy ketones, oxidative cleavage of the resultant vicinal
hydroxy ketone unit would provide rapid access to (S)-aryl-
propionic acids (Fig. 2). The requisite optically active epoxy
ketones were anticipated to be readily available by Juliá–
Colonna asymmetric epoxidation7 of the corresponding
unsaturated ketones using, as the chiral catalyst, poly-()-
leucine or poly-()-leucine (as appropriate to complement the
stereochemistry of the epoxide-ring opening).
As described hereunder, after some modification, the above
strategy did provide rapid, high yielding reactions leading to a
small selection of (S)-arylpropanoic acids.8
Results and discussion
Synthesis of (S)-2-phenylpropanoic acid
Exploratory studies focused on the synthesis of (S)-(ϩ)-
phenylpropanoic acid. Thus chalcone was converted into the
epoxide (Ϫ)-6 (95% ee) using poly-()-leucine adsorbed onto
silica,9 together with urea–hydrogen peroxide and diazabicyclo-
undecene (DBU) in tetrahydrofuran (THF).
Fig. 1
DOI: 10.1039/b000996m
J. Chem. Soc., Perkin Trans. 1, 2000, 2455–2463
This journal is © The Royal Society of Chemistry 2000
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Alkylation with epoxide ring-opening was accomplished
using trimethylaluminium under conditions recommended by
Miyashita et al.10,11 Thus trimethylaluminium (10 mol equiv.)
was added dropwise to a stirred solution of epoxychalcone
(Ϫ)-6 (1 equiv.) in 1,2-dichloroethane at Ϫ30 ЊC and water (6
equiv.) was added to the reaction mixture. After reaction (30
min) and work-up a mixture of anti-7 and syn-9 alcohols was
obtained in the ratio 3:1 and a combined yield of 66%. (The
relative stereochemistry within 7 and 9 was ascertained by
further experimentation, vide infra.) Optimisation of the
reaction led to the employment of just two equiv. of trimethyl-
aluminium with 1.2 equiv. of water in dichloromethane at
Ϫ78 ЊC, reaction conditions which furnished hydroxy ketones 7
and 9 in the ratio 10:1 and a yield of 83%.
of 12 with trimethylaluminium in dry hexane at 0 ЊC gave
diol 10 in 93% yield through a reaction involving essentially
complete retention of configuration at C-3 (Scheme 1). It seems
The presence of water was important, otherwise most of the
epoxychalcone 6 was recovered unchanged with only small
Scheme 1 Reagents and conditions (yields in parenthesis): (i) Zn(BH4)2
(0.3 equiv.), Et2O, 0 ЊC, 30 min (95%); (ii) Me3Al (3 equiv.), hexane,
0 ЊC (93%).
that the aluminium species, acting as a Lewis acid, coordinates
to both oxygen atoms, creating a benzylic carbocation which
allows delivery of the methyl group from the face previously
occupied by the oxirane moiety.5,6
Thus (S)-phenylpropanoic acid 11 was available by oxidation
of chalcone in the presence of poly-()-leucine to afford (Ϫ)-6
and then either treatment with trimethylaluminium, separation
of the minor component 9, reduction to the diol 10 and oxid-
ative cleavage (overall 4% yield) or zinc borohydride reduction
of ketone (Ϫ)-6 to give epoxy alcohol 12, reaction with the
alkylating agent and cleavage (overall yield from the epoxy
ketone 57%).
In an alternative pathway chalcone was oxidised to (ϩ)-6
using poly-()-leucine on silica (92% yield, 97% ee). Treat-
ment of (ϩ)-6 with trimethylaluminium, then zinc borohydride,
followed by the usual oxidative cleavage protocol, gave (S)-2-
phenylpropanoic acid11 in 48% overall yield. Once again the
overall yield was compromised by the mandatory separation of
(ϩ)-11 from benzoic acid.
In order to overcome this separation problem trimethyl-
aluminium-promoted ring-opening of some related epoxy ter-
tiary alcohols was investigated. Reaction of epoxychalcone
with organocerium reagents has been shown to result in tertiary
alcohols with the major diastereoisomer being formed by
nucleophilic attack on the carbonyl group from the re-face
(Table 1: Entries 1,2).17 Even better selectivity has now been
obtained, simply by treating the epoxy ketone with methyl-
magnesium iodide (Entry 3) or n-butylmagnesium bromide
(Entry 4), giving epoxy tertiary alcohols 13 and 14 as pure
amounts of unidentified materials being formed. It is mooted
that the water probably reacts with Me3Al to give species
such as R2AlOAlR2 and R3AlO which are potent methylating
agents.11 It should be noted that under these conditions the
reaction occurred with inversion of configuration, predomin-
antly.
In passing it should be noted that triethylaluminium also
reacted with racemic epoxide ( )-6 under the same conditions
to give only anti-2-hydroxy-1,3-diphenylpentan-1-one ( )-8 in a
highly respectable 85% yield. While the chemistry of the ethyl
compound was not investigated further it is clear that, by
analogy with the work described hereunder, such species, if
prepared in single enantiomer form, could be converted into
optically active α-arylbutanoic acids, for example indobufen12
and analogues.
Notwithstanding literature precedent,13 attempts to cleave
the anti-7 and syn-hydroxy ketone 9 (using sodium periodate on
silica14 followed by Jones oxidation) were disappointing, afford-
ing the desired arylpropanoic acid in very low yield. However,
zinc borohydride reduction of the hydroxy ketone 9 gave
the diol 10 (95% yield) which, in contrast, was readily cleaved
with periodate on silica; subsequent Jones oxidation furnished
(ϩ)-2(S)-phenylpropanoic acid 11 in 71% yield over two steps.
The yield of the oxidative cleavage was relatively low because
the desired product 11 could only be separated from the simul-
taneously formed benzoic acid by column chromatography. The
absolute configuration of the acid 11 was ascertained by com-
parison of the optical rotation {[α]D20 ϩ72.5 (c 1.0, CHCl3) with
the literature value ([α]D20 ϩ72.8 (c 1.0, CHCl3) for 99% ee (S)-
acid15} and the enantiomeric excess was confirmed as 95% by
conversion of the acid 11 into the corresponding methyl ester
and then application of NMR spectroscopy using the chiral
shift reagent Eu(hfc)3.†
single compounds. The epoxy alcohol 15 was available as the
major product, but contaminated with diastereomer 13, by
reaction of epoxide 17 with phenylmagnesium bromide
(Entry 5).18
Treatment of the epoxy alcohol 13 with trimethylaluminium
in hexane at Ϫ78 ЊC gave the diol 18 (the product of alkylation
with retention of configuration) in 82% yield. Cleavage of the
diol using sodium periodate–silica followed by Jones oxidation
gave (S)-2-phenylpropanoic acid in 86% yield; the acid was
readily separated from the acetophenone produced concur-
rently. Thus (S)-2-phenylpropanoic acid was prepared from
chalcone in 58% overall yield.
The diol 10 was obtained from chalcone epoxide by a second
route, namely reduction of (Ϫ)-6 using zinc borohydride, a
reaction known to give only the epoxy alcohol 12.16 Treatment
† Eu(hfc)3 = europium tris(heptafluorobutynylcamphorate).
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Table 1 Reactions of some 2,3-epoxy ketones with organocerium and organomagnesium reagents
Entry
Substrate
Reagent
Reaction time (t/h)
Products (Ratio)
Yield (%)
1
2
3
4
5
(Ϫ)-6
(Ϫ)-6
(Ϫ)-6
(Ϫ)-6
17
MeLi–CeI3
BuLi–CeI3
MeMgI
BuMgBr
PhMgBr
2
2
1.5
4
1.5
13,15 (4:1)
91
80
90
60
70
14,16 (9:1)
13,15 (>99:<1)
14,16 (>99:<1)
13,15 (1:6)
Similar treatment of the diastereoisomeric mixture rich in
epoxy alcohol 15 (see Table 1, Entry 5) with trimethyl-
aluminium gave the alcohol 19 as the major product (with
using (ϩ)-α-methylbenzylamine to resolve, in classical fashion,
the racemic carboxylic acid.19
Aldol condensation of 3-phenoxybenzaldehyde with aceto-
phenone gave the E-enone 24 in 91% yield (Scheme 3).
retention of configuration at the reacting carbon atom) since
oxidative cleavage gave, once more, (S)-2-phenylpropanoic acid
in 84% yield. Thus the configuration of the tertiary alcohol
group had no bearing on the stereochemistry of the epoxide
ring-opening reaction.
We were also minded to try to improve the atom efficiency in
these new routes to optically active 2-arylpropanoic acids. To
this end the dienone 20 was prepared from benzaldehyde
and acetone and then the optically pure bis-epoxide 21 was
prepared in 90% yield using poly-()-leucine on silica as the
catalyst for the asymmetric epoxidation (Scheme 2).
Scheme 3 Reagents and conditions (yields in parenthesis): (i) Poly-()-
leucine adsorbed onto silica, urea–hydrogen peroxide, DBU, THF, 2 h
(98% yield, 94% ee); (ii) Zn(NH4)2 (0.3 equiv.), Et2O, 0 ЊC, 3 h (95%);
(iii) Me3Al (3 equiv.), hexane, Ϫ78 ЊC, 2 h (85%); (iv) NalO4/SiO2,
CH2Cl2; then Jones oxidation (64%).
Polyleucine-catalysed asymmetric oxidation of 24 was highly
efficient, furnishing the epoxy ketone 25 in 98% yield and 94%
enantiomeric excess. Zinc borohydride reduction followed by
treatment with trimethylaluminium gave diol 26 in 81% yield
over the two steps. Oxidative cleavage gave (S)-(ϩ)-fenoprofen
5, [α]D20 ϩ46 (c 1.0, CHCl3) (identical to the literature value)
in 64% yield. Thus (S)-(ϩ)-fenoprofen is available from
3-phenoxybenzaldehyde in 46% overall yield.
Synthesis of (S)-(؉)-naproxen 1
The synthesis of naproxen in its enantiomerically pure (S)-form
has attracted considerable attention over the years20 but we
believe our new asymmetric synthesis, described below, is as
efficient as any of the other, pre-existing methodologies.
Aldol condensation of 6-methoxy-2-naphthaldehyde with
acetophenone gave the enone 27 in 90% yield (Scheme 4).
Stereoselective epoxidation of this enone using poly-()-leucine
on silica as the chiral catalyst furnished the epoxide 28 in 97%
yield and 94% ee. Treatment of this epoxy ketone with methyl-
magnesium iodide formed the tertiary alcohol 29 which was
ring-opened (with retention of configuration) using trimethyl-
aluminium to give the diol 30 (66% yield over two steps). The
diol was cleaved in the usual manner to give naproxen 1 (88%
yield) and acetophenone.
Confirmation of the absolute stereochemistry of compound
1 was provided by comparison of the optical activity {[α]D20 ϩ68
(c 1.0 (CHCl3)} with data published previously {[α]D20 ϩ67.5
(c 1.0 (CHCl3)}.21 Thus (S)-(ϩ)-naproxen 1 is available from
6-methoxy-2-naphthaldehyde in six steps (five-pots) in a non-
optimised overall yield of 51%.
Scheme 2 Reagents and conditions (yields in parenthesis): (i) Poly-()-
leucine adsorbed onto silica, tert-butyl methyl ether containing urea–
hydrogen peroxide and DBU, Ϫ10 ЊC (90%); (ii) MeMgI, THF, Et2O,
Ϫ78 ЊC (88%); (iii) Me3Al, hexane, Ϫ78 ЊC (71%); (iv) NaIO4/SiO2,
CH2Cl2; then Jones oxidation (69%).
Reaction of the ketone 21 with methylmagnesium iodide
gave the tertiary alcohol 22 which reacted with excess of tri-
methylaluminium so as to undergo a double alkylation reac-
tion to give the triol 23. Retention of configuration during
alkylation was confirmed by oxidative cleavage to afford (S)-
2-phenylpropanoic acid in 39% overall yield from dienone 20;
acetic acid (which was lost on work-up) was the only other
product.
Synthesis of (S)-(؉)-fenoprofen 5
Conclusions
After establishing viable routes to (S)-2-phenylpropanoic acid,
attention was switched to the synthesis of two anti-inflam-
matory drugs in optically active form. The first target was (S)-
(ϩ)-fenoprofen 5, a compound prepared by the Lilly group
The routes to (S)-2-phenylpropanoic acid 11, (S)-fenoprofen 5
and (S)-naproxen 1, described in Schemes 2, 3 and 4 respect-
ively, are efficient and high yielding. The fact that polyleucine-
J. Chem. Soc., Perkin Trans. 1, 2000, 2455–2463
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mg, 1 mmol) and poly-()-leucine adsorbed onto silica [1:3
ratio poly-()-leucine to silica]9 (1.5 g) were stirred with exclu-
sion of light in THF (10 cm3) and DBU (0.15 cm3, 1 mmol) was
added. After 30 min, the reaction mixture was filtered and the
filtrate was diluted with ethyl acetate (100 cm3) and washed
successively with aq. sodium sulfite (20%) (2 × 20 cm3) and
brine (20 cm3). The organic layer was dried over magnesium
sulfate and the solvent was evaporated under reduced pressure.
Purification by flash column chromatography (SiO2; petroleum
spirit–ethyl acetate, 9:1) afforded the pure trans-epoxychalcone
(Ϫ)-6 (191 mg, 95%, 97% ee), mp 61–62 ЊC (from diethyl ether);
[α]D Ϫ205 (c 1.0, CHCl3) (Found: C, 80.2; H, 5.3. C15H12O2
requires C, 80.35; H, 5.4%); νmax(CHCl3)/cmϪ1 1690 (C᎐O),
᎐
1292, 835 (C–O, epoxide); δH (400 MHz; CDCl3) 4.08 (1H, d,
J 1.9, H-3), 4.25 (1H, d, J 1.9, H-2), 7.15–8.10 (10H, m, ArH);
δC (75 MHz; CDCl3) 59.4 and 61.1 (C-2 and -3), 125.9, 128.4,
128.8, 128.9 and 129.1 (C-12, -13, -14, -32, -33 and -34), 134.0 and
135.1 (C-11 and -31), 186.0 (C-1); m/z (EI) 224 (Mϩ, 11%), 105
(PhC᎐O, 100).
᎐
Scheme 4 Reagents and conditions (yields in parenthesis): (i) Poly-()-
leucine adsorbed onto silica, urea–hydrogen peroxide, DBU, THF, 1.5 h
(97% yield, 94% ee); (ii) MeMgI, THF, Et2O, Ϫ78 ЊC, 2.5 h (85%); (iii)
Me3Al (3 equiv.), hexane, Ϫ78 ЊC, 4 h (78%); (iv) NaIO4/SiO2, CH2Cl2;
then Jones oxidation (88%).
anti-(2R,3R)- and syn-(2R,3S)-2-Hydroxy-1,3-diphenyl-
butanone 7 and 9. To a solution of epoxychalcone (Ϫ)-6 (200
mg, 0.89 mmol) in dichloromethane (35 cm3) under an argon
atmosphere at Ϫ78 ЊC was added dropwise a solution of tri-
methylaluminium (2 M solution in hexane; 0.9 cm3, 1.78 mmol)
followed by water (19.2 × 10Ϫ3 cm3, 0.373 mmol). After 30 min,
the reaction was quenched by slow addition of water and the
resulting mixture was filtered over a pad of Celite and washed
with dichloromethane. The aqueous layer was extracted with
dichloromethane (3 × 20 cm3) and the combined organic layers
were washed successively with water (2 × 15 cm3) and brine
(2 × 15 cm3), dried over magnesium sulfate, filtered and evapor-
ated under reduced pressure to afford a yellow oil. Purification
by flash column chromatography [SiO2; petroleum spirit–ethyl
acetate, 9:1) yielded the syn-hydroxy ketone 9 as an oil (18 mg,
8%), Rf (isohexane–ethyl acetate, 9:1) 0.26 (Found: C, 80.0, H,
6.8. C16H16O2 requires C, 80.0; H, 6.7); νmax(NaCl)/cmϪ1 3470
catalysed asymmetric oxidations of enones can be applied so as
to match the retention or inversion of configuration in the
subsequent alkylation process allows a small portfolio of routes
to these important compounds to be constructed. Obviously
(R)-arylpropanoic acids could be made available, if and when
required, by application of the same technologies. To the chem-
ical purist some of the transformations (for example conversion
of triol 23 into the acid 11 and acetic acid) may seem wasteful in
terms of the loss of well defined stereogenic centres, so it is also
of interest to us to use such 2,4,6-trisubstituted heptane-3,4,5-
triols in synthetic sequences where the array of contiguous
stereogenic centres is not subsequently lost. These later studies
will be the subject of another full paper.
(OH), 3060, 3025 (᎐CH), 1687 (C᎐O), 1595, 1580 (C᎐C, Ar);
᎐
᎐
᎐
δH (300 MHz; CDCl3) 1.15 (3H, d, J 7.1, H3-4), 3.12 (1H, qd,
J 7.1 and 0.1, H-3), 3.80 (1H, d, J 6.0, OH), 5.23 (1H, m, H-2),
7.15–7.65 (8H, m, ArH), 7.85–8.12 (2H, m, ArH); δC (75 MHz;
CDCl3) 13.1 (C-4), 43.5 (C-3), 76.7 (C-2), 126.9 (C-34), 127.8,
128.6, 128.7 and 129.0 (C-12, -13, -32 and -33), 133.8 (C-14),
Experimental
Diethyl ether and THF were distilled over sodium metal and
benzophenone. Petroleum spirit (distillation range 40–60 ЊC)
and dichloromethane were distilled over calcium hydride. Other
reagents and solvents were obtained commercially and used as
received without further purification. Reactions were moni-
tored by TLC, performed on glass-backed silica plates coated
with Merck 60F-254. Visualisation was achieved either by
treatment with potassium permanganate, cerium(IV) ammo-
nium molybdate (CAM), or p-anisaldehyde, followed by heat-
ing and/or UV light (254 nm). Flash column chromatography
was performed using Merck 60 silica gel (40–63 µm). Mps were
measured on a Gallenkamp melting point apparatus, and are
uncorrected. IR spectra were recorded on a Perkin-Elmer 881
infrared spectrometer. Low-resolution EI mass spectra were
measured on a Fisons Trio 1000 instrument; CI and accurate
mass spectra were measured on a VG Analytical 7070E double-
134.0 and 144.1 (C-11 and -31), 201 (C᎐O); m/z (EI) 105
᎐
(PhC᎐O, 100%), 77 (Ph, 35); followed by its major diastereo-
᎐
isomer anti-hydroxy ketone 7 as an oil (163 mg, 75%), Rf
(isohexane–ethyl acetate, 9:1) 0.21 (Found: C, 80.2, H, 6.6%)
νmax(NaCl)/cmϪ1 3480 (OH), 3090, 3072 (᎐CH), 1685 (C᎐O),
᎐
᎐
1600, 1580 (C᎐C, Ar); δ (300 MHz; CDCl ) 1.52 (3H, d, J 7.2,
᎐
H
3
H3-4), 3.32 (1H, qd, J 7.2 and 2.7, H-3), 3.50 (1H, d, J 7.0, OH),
5.20 (1H, dd, J 7.0 and 2.7, H-2), 6.88–7.60 (10H, m, ArH);
δC (75 MHz; CDCl3) 18.1 (C-4), 44.2 (C-3), 76.6 (C-2), 127.0
(C-34), 127.9, 128.2, 128.5, 128.7 and 128.9 (C-12, -13, -32 and
-33), 133.7 (C-14), 134.8 and 139.8 (C-11 and -31), 201.0 (C᎐O);
᎐
m/z (EI) 105 (PhC᎐O, 100%), 77 (Ph, 39). Diastereoisomer
᎐
ration (dr) of the crude mixture (determined by NMR
analysis), 7:9, 10:1.
1
focusing mass spectrometer. H NMR spectra were measured
[CDCl3 as a solvent using tetramethylsilane (TMS) as internal
reference] with a Brucker AC200 instrument at 200 MHz or a
Varian Gemini 300 at 300 MHz. 13C NMR spectra were
recorded on a Varian Gemini 3000 at 75 MHz. All chemical
shifts are quoted in ppm relative to TMS (0.0 ppm) and to
residual CHCl3 (77.0 ppm) for 13C analysis. Optical rotations
were measured on an Optical Activity Ltd. AA-1000 polar-
anti-(2R,3R)-2-Hydroxy-1,3-diphenylpentan-1-one rac-8. The
same procedure as above was followed using ( )-epoxychalcone
( )-6 (200 mg, 0.89 mmol) in dichloromethane (35 cm3) with
triethylaluminium (1 M solution in hexane; 1.78 cm3, 1.78
mmol) and water (19.2 × 10Ϫ3 cm3, 0.373 mmol). After 1 h, the
reaction was complete and quenched as for the alkylation with
trimethylaluminium (see above). Purification by flash column
chromatography (SiO2; petroleum spirit–ethyl acetate, 9:1)
afforded the hydroxy ketone ( )-8 (193 mg, 85%) as a white
solid, mp 85–87 ЊC (from hexane); Rf (isohexane–ethyl acetate,
9:1) 0.35 (Found: C, 80.15, H, 7.0. C17H18O2 requires C, 80.3;
imeter, and [α]D-values are given in units of 10Ϫ1 deg cm2 gϪ1
.
Synthesis of (S)-2-phenylpropanoic acid 11
(2R,3S)-2,3-Epoxy-1,3-diphenylpropan-1-one (؊)-6. (E)-
Chalcone (180 mg, 0.9 mmol), urea–hydrogen peroxide (100
H, 7.0); νmax(NaCl)/cmϪ1 3480 (OH), 3075, 3072, 3030 (᎐CH),
᎐
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1685 (C᎐O), 1600, 1575 (C᎐C, Ar); δH (300 MHz; CDCl3) 0.96
argon atmosphere. After stirring of the solution for 1 h at 0 ЊC,
᎐
᎐
(3H, t, J 8.0, H3-5), 2.10 (2H, m, H2-4), 2.96 (1H, dt, J 2.5 and
3.2, H-3), 3.58 (1H, d, J 7.0, OH), 5.33 (1H, dd, J 7.0 and 2.5,
H-2), 6.98–7.63 (8H, m, ArH), 7.8–7.92 (2H, m, H-12); δC (75
MHz; CDCl3) 12.0 (C-5), 25.3 (C-4), 51.6 (C-3), 75.5 (C-2),
126.8 (C-34), 127.7–128.7 (C-32, -33, -12 and -13), 133.6 (C-14),
the resulting mixture was diluted with dichloromethane (45
cm3), and treated with sodium fluoride (5.5 g, 0.13 mol) and
water (2.5 cm3). Vigorous stirring of the resulting suspension
was continued at room temperature for another 30 min. The
semi-solid was filtered off and washed with diethyl ether (3 × 30
cm3). The filtrate and washings were dried over magnesium
sulfate and concentrated under reduced pressure. Purification
by flash column chromatography (SiO2; petroleum spirit–ethyl
acetate, 4:1) furnished the diol 10 as a white solid (0.94 g, 93%),
[α]D ϩ63.47 (c 1.05, CHCl3); mp 90–91 ЊC (from ethyl acetate–
hexane).
134.4 and 138 (C-11 and -31), 200.9 (C᎐O); m/z (EI) 105
᎐
(Ph-C᎐O, 100%), 77 (Ph, 29).
᎐
Reduction of hydroxy ketone 9. Preparation of zinc boro-
hydride [Zn(BH4)2]. An ethereal solution of zinc chloride (5 g,
36 mmol) and distilled diethyl ether (70 cm3) was added drop-
wise to a stirred suspension of sodium borohydride (3.375 g,
90 cm3) in distilled diethyl ether (180 cm3). The mixture was
stirred at room temperature under argon atmosphere for 12 h.
The solid formed (NaCl) was allowed to settle and the liquid
was removed and stored in a stoppered bottle under an argon
atmosphere at Ϫ18 ЊC and was used as a 0.144 M Zn(BH4)2
solution in diethyl ether.
Oxidative cleavage of diol 10. Synthesis of (2S)-2-phenyl-
propanoic acid 11. To a solution of diol 10 (400 mg, 1.65 mmol)
in dichloromethane (9 cm3) was added sodium periodate sup-
ported on silica gel (1.2 mmol gϪ1; 4.96 mmol, 4.13 g). After 1 h,
the reaction was complete and the mixture was filtered through
sodium sulfate and concentrated under reduced pressure to give
a mixture of phenylpropanal and benzaldehyde which was used
without any further purification for the next step. To a solution
of the crude product (380 mg) in acetone (15 cm3) at 0 ЊC was
added dropwise a solution of Jones reagent (2.7 M; 0.76 cm3).
After 1 h the reaction was judged to be complete and the excess
of oxidant was destroyed by addition of propan-2-ol (10 cm3).
The solid residue was filtered off, and washed with acetone
(3 × 5 cm3). The combined filtrates were diluted with water (20
cm3) and concentrated to ca. 20 cm3. The remaining aqueous
residue was extracted with ethyl acetate (5 × 10 cm3). The com-
bined organic extracts were washed with 1 M NaHCO3 (3 × 10
cm3). The combined aqueous extracts were acidified with a
solution of hydrochloric acid (1 M) and re-extracted with
ethyl acetate (3 × 10 cm3). The combined organic extracts
were dried over sodium sulfate and evaporated under reduced
pressure to give a mixture of benzoic acid and phenylpropan-
oic acid. Purification by flash column chromatography (SiO2;
dichloromethane–methanol, 49:1) furnished (2S)-phenyl-
propanoic acid 11 as a colourless liquid (176 mg, 71%), [α]D
ϩ72.5 (c 1.0, CHCl3) {lit.,14 [α]D ϩ72.8 (c 1.0, CHCl3), 99% ee};
Rf (dichloromethane–methanol, 97:3) 0.23 (Found: Mϩ,
150.06813; C, 72.3; H, 6.9. C9H10O2 requires M, 150.06808; C,
72.0; H, 6.7%); νmax(NaCl)/ cmϪ1 2600–3600 (OH), 1705 (CO);
δH (300 MHz; CDCl3) 1.60 (3H, d, J 5.8, H3-3), 3.82 (1H, q,
J 5.8, H-2), 7.35–7.43 (5H, m, ArH), 11.90 (1H, br s, COOH);
δC (75 MHz, CDCl3) 18.2 (C-3), 45.55 (C-2), 127.6 (C-24),
127.8 and 128.9 (C-22 and -23), 139.9 (C-21), 181.9 (COOH);
m/z (EI).
(1S,2R,3S)-1,2-Dihydroxy-1,3-diphenylbutane 10. To an
ice-cold solution of the hydroxy ketone 9 (200 mg, 0.83 mmol)
in diethyl ether (5 cm3) was added, dropwise, a solution of zinc
borohydride (0.144 M in diethyl ether; 1.75 cm3, 0.25 mmol).
After 1 h, the reaction was quenched with water (1 cm3). The
solution was then stirred for another 30 min. The aqueous layer
was extracted with diethyl ether (3 × 15 cm3) and the combined
organic layers were dried over magnesium sulfate and filtered
under reduced pressure to afford a yellow oil. Purification by
flash column chromatography (SiO2; petroleum spirit–ethyl
acetate, 9:1) furnished the pure diol 10 as a white solid (194 mg,
95%), mp 90–92 ЊC (from ethyl acetate–hexane); [α]D ϩ63.5
(c 1.04, CHCl3); Rf (petroleum spirit–ethyl acetate, 4:1) 0.18
(Found: C, 79.2; H, 7.3. C16H18O2 requires C, 79.3; H, 7.4%);
νmax(NaCl)/cmϪ1 3609 (OH), 1602, 1644 (C᎐C, Ar); δ (300
᎐
H
MHz; CDCl3) 1.33 (3H, d, J 6.9, H3-4), 1.85 (1H, s, OH), 2.22
(1H, s, OH), 2.82 (1H, quint, J 6.9, H-3), 4.02 (1H, t, J 6.9,
H-2), 4.53 (1H, d, J 6.9, H-1), 7.09–7.29 (10H, m, ArH); δC (75
MHz; CDCl3) 16.6 (C-4), 41.5 (C-3), 75.2 (C-2), 78.8 (C-1),
126.6 and 128.2 (C-14 and -34), 127.7, 128.0, 128.4 and 128.6
(C-12, -13, -32 and -33), 140.7 and 144.7 (C-11 and -31); m/z (EI)
135 (M Ϫ PhCOH, 13%), 108 [M Ϫ PhCH(CH3)COH, 100],
105 (PhC᎐O, 91), (Ph, 40).
᎐
anti-(1S,2S,3S)-2,3-Epoxy-1,3-diphenylpropan-1-ol 12. To an
ice-cold solution of epoxychalcone (Ϫ)-6 (1 g, 4.46 mmol) in
distilled diethyl ether (20 cm3) was added dropwise a cold solu-
tion of Zn(BH4)2 (0.144 M solution in diethyl ether; 9.3 cm3,
1.34 mmol). After 30 min, the reaction was quenched with
water (5 cm3) and stirred vigorously for another 30 min. The
aqueous layer was extracted with diethyl ether (3 × 15 cm3) and
the combined organic phases were dried over magnesium sul-
fate, filtered and evaporated under reduced pressure. Crystal-
lisation of the crude compound from hexane afforded the epoxy
alcohol 12 as a white solid (0.96 g, 95%), mp 114–115 ЊC (from
ethyl acetate–hexane); [α]D Ϫ12.65 (c 1.0, CHCl3); Rf (petrol-
eum spirit–ethyl acetate 4:1) 0.37 (Found: C, 79.8; H, 6.1.
C15H14O2 requires C, 79.6; H, 6.2%); νmax(NaCl)/cmϪ1 3430
(OH), 1220, 870, (C–O, epoxide); δH (300 MHz; CDCl3) 2.54
(1H, d, J 2.0, OH), 3.28 (1H, dd, J 1.65 and 2.75, H-2), 4.13
(1H, d, J 1.65, H-3), 4.98 (1H, d, J 2.75, H-1), 7.23–7.44 (10H,
m, ArH); δC (75 MHz; CDCl3) 55.0 (C-2), 64.9 (C-3), 71.3
(C-1), 125.8, 126.5, 128.5 and 128.7 (C-12, -13, -33 and -32),
128.2 and 128.3 (C-14 and -34), 136.5 and 139.2 (C-11 and -31);
Synthesis of (2S)-2-phenylpropanoic acid 11 from epoxychalcone
(؉)-6
In parallel experiments to those described above the epoxy-
chalcone (ϩ)-6 was prepared from chalcone using poly-()-
leucine on silica as the catalyst. Treatment of (ϩ)-6 with tri-
methylaluminium, reduction using zinc borohydride, separation
of the major diastereoisomer and two-step oxidative cleavage
gave the desired product 11 in 48% overall yield. The physical
properties of product 11 were found to be exactly the same as
those described above.
Synthesis of tertiary epoxy alcohols
Alkylation of epoxychalcone (؊)-6 with MeMgI. Synthesis of
(2S,3R,4S)-3,4-epoxy-2,4-diphenylbutan-2-ol 13. Diethyl ether
(10 cm3) and THF (7 cm3) were added to a nitrogen-filled flask
and the vessel was cooled to Ϫ78 ЊC. Epoxychalcone (448 mg, 2
mmol) as a solution in THF (2 cm3) was then added, followed
by methylmagnesium iodide (2 M solution in diethyl ether; 1.6
cm3, 3.2 mmol). After 1.5 h, the reaction was quenched with
saturated aq. ammonium chloride and extracted with diethyl
ether (3 × 50 cm3). The combined organic layers were washed
m/z (EI) 118 (M Ϫ PhCHCOH,81%), 105 (PhC᎐O, 91), 91
᎐
(C7H7, 100), 77 (Ph, 55).
Alkylation of epoxy alcohol 12 with trimethylaluminium. A
solution of epoxy alcohol 12 (1 g, 4.42 mmol) in hexane (20
cm3) was added dropwise to a solution of trimethylaluminium
(2 M solution in hexane, 6.6 cm3, 13.27 mmol) at 0 ЊC under an
J. Chem. Soc., Perkin Trans. 1, 2000, 2455–2463
2459

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successively water (50 cm3) and brine (50 cm3), dried over
magnesium sulfate and evaporated under reduced pressure.
Purification by flash column chromatography (SiO2; petroleum
spirit–diethyl ether, 6:1) afforded the diastereomerically pure
epoxy alcohol 13 (432 mg, 90%) as white crystals, mp 101–
102 ЊC (from hexane); [α] Ϫ47 (c 0.5, CHCl3); Rf (petroleum
spirit–diethyl ether, 3:1) 0.3 (Found: C, 79.9; H, 6.7. C16H16O2
requires C, 80.0; H, 6.7%); νmax(NaCl)/cmϪ1 3495 (OH), 1630,
1212, 981, 870 (C–O, epoxide); δH(400 MHz; CDCl3) 1.70 (3H,
s, H3-1), 2.84 (1H, s, OH), 3.25 (1H, d, J 2.2, H-3), 4.05 (1H, d,
J 2.2, H-4), 7.18–7.50 (10H, m, ArH); δC (75 MHz; CDCl3) 27.8
(C-1), 55.8 (C-3, 68.3 (C-4), 71.3 (C-2), 128.6–125.2 (CH, Ar),
136.9 (C, Ar), 143.8 (C, Ar); m/z (EI) 121 (M Ϫ PhCHOCH,
Reaction of epoxy ketone 17 with PhMgBr. Synthesis of
(2R,3R,4S)-3,4-epoxy-2,4-diphenylbutan-2-ol 15. To a stirred
suspension of magnesium turnings (77.8 mg, 3.2 mmol) in
diethyl ether (10 cm3) was added bromobenzene (0.337 cm3, 3.2
mmol) under a nitrogen atmosphere at such a rate as to main-
tain reflux. After complete reaction of the magnesium, THF
(10 cm3) was added and the contents of the flask were cooled
to Ϫ78 ЊC. trans-Epoxy ketone 17 (324 mg, 2 mmol) was added
via a solid-addition tube. After 2 h the reaction had gone to
completion and was quenched with saturated aq. ammonium
chloride before being extracted with dichloromethane (3 × 50
cm3). The combined organic layers were washed successively
with water (2 × 25 cm3) and brine (2 × 25 cm3), then dried over
sodium sulfate, filtered, and evaporated under reduced pressure.
Purification by flash column chromatography (SiO2; petroleum
spirit–diethyl ether, 8:2) afforded an inseparable mixture of
13 and 15 as a white solid (336 mg, 70%), mp 102–103 ЊC; Rf
(petroleum spirit–diethyl ether, 3:1) 0.35 (Found: C, 79.8; H,
6.6. C16H16O2 requires C, 80.0; H, 6.7%); νmax(NaCl)/cmϪ1 3497
(OH), 1212, 991, 881 (C–O, epoxide). The diastereomeric ratio
determined by 1H NMR analysis was found to be 13:15, 1:6.
36%), 120 (PhCHOCH , 86), 105 (PhC᎐O, 91), 91 (C H , 100),
᎐
2
7
7
77 (Ph, 53).
n
Alkylation of epoxychalcone (؊)-6 with BuMgBr. Synthesis
of (1S,2R,3S)-1,2-epoxy-1,3-diphenylheptan-3-ol 14. To
a
stirred suspension of magnesium turnings (108 mg, 4.46 mmol)
in diethyl ether (10 cm3) was added 1-bromobutane (0.48 cm3,
4.5 mmol) under a nitrogen atmosphere at such a rate as to
maintain reflux. After complete reaction of the magnesium,
THF (10 cm3) was added and the contents of the flask were
cooled to Ϫ78 ЊC. trans-Epoxychalcone (Ϫ)-6 (500 mg, 2.23
mmol) was added via a solid-addition tube. After 4 h, the
reaction was quenched by addition of saturated aq. ammon-
ium chloride (10 cm3), allowed to warm to room temperature
and extracted with diethyl ether (3 × 50 cm3). The combined
organic extracts were washed successively with water (50 cm3)
and brine (50 cm3) and dried over magnesium sulfate.
Removal of the solvent under reduced pressure gave a crude
reaction mixture which contained the desired tertiary alcohol
with a diastereomeric ratio of >99:1. Purification by flash
column chromatography (SiO2; petroleum ether spirit–diethyl
ether, 6:1) and recrystallisation from hexane afforded the
alcohol 14 (378 mg, 60%) as white crystals, mp 81–83 ЊC
(from hexane); [α]D Ϫ51.0 (c 1.0, CHCl3); Rf (petroleum
spirit–Et2O, 3:1) 0.4 (Found: C, 80.8; H, 7.8. C19H22O2
requires C, 80.8; H, 7.9%); νmax (KBr)/cmϪ1 3495 (OH), 1210,
961 and 881; δH (300 MHz; CDCl3) 0.88 (3H, m, H-7), 1.18–
1.48 (2 × 2H, m, H-5 and H-6), 1.94–2.09 (2H, m, H-4), 2.36
(1H, s, OH), 3.36 (1H, d, J 2.2, H-2), 3.92 (1H, d, J 2.2,
H-1), 7.17–7.47 (10H, m, ArH); δC (75 MHz; CDCl3) 14.6
(C-7), 23.7 and 25.9 (C-6 and -5), 41.7 (C-4), 55.7 (C-2), 68.6
(C-1), 73.9 (C-3), 125.7, 126.4, 127.7, 128.8, 129.0 and 129.0
and 136.8 142.6 (Ar); m/z (EI) 163 (20%), 120 (83), 105 (100), 91
(81), 77 (59).
Synthesis of (2S,3R,4S)-2,3-dihydroxy-2,4-diphenylpentane 18
To a solution of tertiary epoxy alcohol 13 (500 mg, 2.08 mmol)
in hexane (10 cm3) was added dropwise a solution of trimethyl-
aluminium (2 M solution in hexane; 3.12 cm3, 6.24 mmol) at
Ϫ78 ЊC under an argon atmosphere. After stirring for 1 h at
Ϫ78 ЊC, the resulting mixture was diluted with dichloro-
methane (25 cm3), and treated with sodium fluoride (2.75 g, 65
mmol) and water (1.25 cm3). Vigorous stirring of the resulting
suspension was continued at room temperature for another 30
min. The semi-solid was filtered off and washed with diethyl
ether (3 × 20 cm3). The filtrate and washings were dried over
magnesium sulfate and concentrated under reduced pressure.
Purification by flash column chromatography (SiO2; petroleum
spirit–ethyl acetate, 4:1) furnished the diol 18 as an oil (454.
mg, 82%) [α]D ϩ36 (c 1.0, EtOH); Rf (petroleum spirit–ethyl
acetate, 9:1) 0.18 (Found: C, 79.5; H, 7.9. C17H20O2 requires C,
79.7; H, 7.8%); νmax(NaCl)/cmϪ1 3619 (OH), 1602, 1654 (C᎐C,
᎐
Ar); δH (300 MHz; CDCl3) 1.17 (3H, d, J 6.9, H3-5), 1.56 (3H, s,
H3-1), 2.16 (1H, br s, OH), 2.44 (1H, br s, OH), 2.59–2.68 (1H,
dq, J 6.9 and 3.0, H-4), 3.88 (1H, d, J 3.0, H-3), 7.04–7.48 (10H,
m, ArH); δC (75 MHz; CDCl3) 14.25 (C-5), 29.05 (C-1), 40.45
(C-4), 60.15 (C-2), 81.1 (C-3), 125.1, 127.4, 128.3 and 128.5
(C-42, -43, -22 and -23), 126.2 and 126.9 (C-44 and -24), 145 and
146.5 (C-41 and -21), m/z (CI) (Found: [M ϩ NH4]ϩ, 274.18052,
C17H24NO3 requires m/z, 274.18071), 121 (PhCCH3OH, 100%),
105 (PhCO, 45), 91 (C7H7, 21), 43 (CH3CO, 83).
(3R,4S)-3,4-Epoxy-4-phenylbutan-2-one 17. (E)-4-Phenyl-
but-3-en-2-one (180 mg, 0.9 mmol), urea–hydrogen peroxide
(100 mg, 1 mmol) and poly-()-leucine on silica (1.550 g) were
stirred in tert-butyl methyl ether (10 cm3) at Ϫ10 ЊC, and DBU
(150 × 10Ϫ3 cm3, 1 mmol) was added. After 10 h, the reaction
was complete and the solution was filtered (glass sinter, porosity
3) and the residue was rinsed with ethyl acetate (3 × 50 cm3).
The filtrate was washed successively with aq. sodium sulfite
(20%; 20 cm3) and brine (20 cm3), dried over magnesium sulfate
and evaporated under reduced pressure. Purification by flash
column chromatography (SiO2; petroleum spirit–ethyl acetate,
9:1) followed by crystallisation from hexane afforded the pure
enantiomeric trans-epoxide 17 (124 mg, 85%), mp 42–43 ЊC;
(2R,3R,4S)-2,3-Dihydroxy-2,4-diphenylpentane 19
The mixture of epoxy alcohols 13 and 15 (500 mg, 2.08 mmol;
15:13. 6:1) was alkylated as above with a solution of trimethyl-
aluminium (2 M solution in hexane; 3.12 cm3, 6.24 mmol).
Purification by flash column chromatography (SiO2; petroleum
spirit–ethyl acetate, 4:1) furnished an inseparable mixture of
the diastereomers 19 and 18 whose ratio was found to be 19:18,
6:1. Crystallisation, from hexane, of the resulting solid fur-
nished the two diastereomers 19 and 18 in a 12:1 ratio (393 mg,
71%). Diol 19: δH (300 MHz; CDCl3) 1.30 (3H, d, J 7.0, H3-5),
1.49 (3H, s, H3-1), 2.20 (1H, br s, OH), 2.26 (1H, br s, OH), 3.03
(1H, dq, J 7.0 and 4.1, H-4), 3.94 (1H, d, J 4.1, H-3), 7.04–7.48
(10H, m, ArH); δC (75 MHz; CDCl3) 16.4 (C-5), 25.1 (C-1), 40.6
(C-4), 60.5 (C-2), 81.3 (C-3), 125.1–128.5 (CH, Ar), 146.5 and
146.7 (C-41 and -21).
[α]D Ϫ203 (c 1.0, CHCl3); νmax(CHCl3)/cmϪ1 1712 (C᎐O), 1203
᎐
and 886 (C–O, epoxide), 1411, 1368 (Found: C, 74.2; H, 6.25.
C10H10O2 requires C, 74.1; H, 6.2%); δH (300 MHz; CDCl3) 2.16
(3H, s, H3-1), 3.47 (1H, d, J 2.2, H-2), 3.99 (1H, d, J 2.2, H-3),
7.23–7.27 (5H, m, ArH); δC (75.5 MHz, CDCl3) 24.7 (C-1), 57.7
(C-2), 63.5 (C-3), 125.8 and 128.8 (C-42 and -43), 129.1 (C-44),
135.2 (C-41), 204.1 (C-4); m/z (EI) 162 (Mϩ, 19%), 91 (C7H7,
100). ee > 90% determined by NMR spectroscopy [chiral shift
reagent Eu(hfc)3].
trans, trans-(1S,2R,4R,5S)-1,2,4,5-Diepoxy-1,5-diphenylpentan-
3-one 21
(E,E)-1,5-Diphenylpenta-1,4-dien-3-one 20 (600 mg, 2.56
mmol), urea–hydrogen peroxide (289 mg, 3.1 mmol) and poly-
2460
J. Chem. Soc., Perkin Trans. 1, 2000, 2455–2463

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()-leucine on silica (2 g, 0.5 g of polymer) were stirred at
Ϫ10 ЊC in tert-butyl methyl ether (90 cm3) with exclusion of
light, and DBU (464 × 10Ϫ3 cm3, 3.1 mmol) was added. After
1 h the reaction was complete, the solution was filtered (glass
sinter, porosity 3) and the residue rinsed with ethyl acetate
(3 × 20 cm3). The filtrate was washed successively with aq.
sodium sulfite (20%; 20 cm3) and brine (20 cm3), dried over
magnesium sulfate and evaporated under reduced pressure.
Purification by flash column chromatography (SiO2; petroleum
spirit–ethyl acetate, 9:1) followed by crystallisation from
hexane, afforded the pure bis-epoxide 21 as white needles (613
mg, 90%), mp 117–119 ЊC (from hexane) [lit.,22 118–118.5 ЊC
(from ethanol)] [α]D Ϫ253 (c 1.0, EtOH); Rf (petroleum spirit–
ethyl acetate, 4:1) 0.56 (Found: C, 76.7; H, 5.3. C17H14O3
requires C, 76.7; H, 5.3%); νmax(NaCl)/cmϪ1 1220, 870 (C–O,
epoxide); δH (300 MHz; CDCl3) 3.80 (2H, d, J 1.65, H-1 and -5),
4.08 (2H, d, J 1.65, H-2 and -4), 7.24–7.37 (10H, m, ArH);
δC (75 MHz; CDCl3) 59.0 (C-1 and -5), 61.0 (C-2 and -4), 125.9
and 128.9 (C-12, -13, -52 and -53), 129.4 (C-14 and -54), 134.4
(C-11 and -51), 199.4 (C-3); m/z (EI) 180 (PhCHOCH2, 40%),
and -61); m/z (CI) (Found: [M ϩ NH4]ϩ, 332.22288. C20H30NO3
requires m/z, 332.22288), 147 (23%), 105 (PhC᎐O, 100), 91
᎐
(C7H7, 20), 77 (Ph, 15), 43 (CH3CO, 46.5).
Cleavage of triol 23. Synthesis of (S)-2-phenylpropanoic acid 11
The usual 2-step oxidative cleavage procedure was carried out
on triol 23. Purification by flash column chromatography (SiO2;
dichloromethane–methanol, 49:2) furnished (2S)-2-phenyl-
propanoic acid 11 as a colourless liquid (314 mg, 69%), [α]D
ϩ72.5 (c 1.0, CHCl3).
Synthesis of (S)-(؉)-fenoprofen 5
(E)-3-(3-Phenoxyphenyl)-1-phenylpropenone 24. To a solu-
tion of acetophenone (0.9 cm3, 7.56 mmol) and 3-phenoxy-
benzaldehyde (1.5 g, 7.65 mmol) in absolute methanol (7.6 cm3;
1 cm3 per mmol of ketone), under an argon atmosphere, were
added 3 pellets of sodium hydroxide and the mixture was
stirred vigorously. The reaction was monitored by TLC (petrol-
eum spirit–ethyl acetate, 4:1) and visualised by UV light and
CAM. A yellow precipitate was formed during the reaction
which appeared to be complete after 24 h. The reaction mixture
was evaporated under reduced pressure and the yellow solid
obtained was washed successively with cold ethanol and water.
Crystallisation from hexane–ethyl acetate, (10:1) afforded the
pure (E)-enone 24 as a yellow solid (2.6 g, 91), mp 62–64 ЊC
(from hexane–ethyl acetate); Rf (petroleum spirit–ethyl acetate,
9:1) 0.24 (Found: Mϩ, 300.11477; C, 84.1 H, 5.4. C21H16O2
requires M, 300.11505; C, 84.0; H, 5.35%); νmax(CHCl3)/cmϪ1
105 (PhC᎐O, 43), 77 (Ph, 77). ee 99%, de 95% (before crystal-
᎐
lisation), de 99% (after crystallisation).
Synthesis of (1S,2R,4R,5S)-1,2,4,5-diepoxy-3-methyl-1,5-
diphenylpentan-3-ol 22
To a solution of the diepoxy ketone 21 (500 mg, 1.879 mmol) in
freshly distilled diethyl ether (25 cm3) and THF (20 cm3) was
added dropwise a solution of methylmagnesium iodide (3 M
solution in diethyl ether; 2 cm3, 6 mmol) under a nitrogen
atmosphere at Ϫ78 ЊC. After 1 h, the reaction mixture was
quenched with saturated aq. ammonium chloride and the solu-
tion extracted with diethyl ether (3 × 50 cm3). The combined
organic layers were washed successively with water (30 cm3) and
brine (30 cm3), dried over magnesium sulfate and evaporated
under reduced pressure. Purification by flash column chrom-
atography (SiO2; petroleum spirit–ethyl acetate, 9:1) followed
by crystallisation from hexane–ethyl acetate, 10:1, furnished
the diepoxy alcohol 22 (466 mg, 88%). [α]D 93 (c 1.0, EtOH); mp
116–118 ЊC (from ethyl acetate–hexane); Rf (petroleum spirit–
ethyl acetate, 9:1) 0.15 (Found: C, 76.55; H, 6.35. C18H18O3
requires C, 76.6; H, 6.4%); νmax(CHCl3)/cmϪ1 3625 (OH), 3025
(ArH), 1205, 905 and 849 (C–O, epoxide); δH (300 MHz;
CDCl3) 1.41 (3H, s, CH3), 2.24 (1H, br s, OH), 3.12 and 3.15
(each 1H, d, J 2.2, H-1 and -5), 3.95 and 4.02 (each 1H, d,
J 2.2, H-2 and H-4), 7.33–7.37 (10H, m, ArH); δC (75
MHz; CDCl3) 20.2 (CH3), 54.3 and 55.8 (C-1 and -5), 65.2 and
66.3 (C-2 and -4), 125.8 (C-14 and -54), 128.5 and 128.6 (C-12,
-13, -52 and -53), 136.4 (C-11 and -51); m/z (CI) (Found: [M ϩ
NH4]ϩ, 300.15997. C18H22NO3 requires m/z 300.15997); m/z
3060, 1615, 1581, 980 (C᎐C), 1690 (C᎐O); δ (300 MHz;
᎐
᎐
H
CDCl3) 6.88–8.0 (16H, m, ArH, H-2 and -3; δC (75 MHz;
CDCl3) 106.15, 119.6, 121.3, 124.5, 127.6, 128.56, 128.66,
130.3, 132.7, 136.0, 138.6, 145.3, 156.9, 159.1, (C-2, -3 and Ar),
191.5 (C-1); m/z (EI) 300 (Mϩ, 100%), 207 (M Ϫ OPh, 60.2),
105 (PhC᎐O, 35), 77 (Ph, 67).
᎐
2R,3S)-2,3-Epoxy-3-(3-phenoxyphenyl)-1-phenylpropan-1-
one 25. To a solution of enone 24 (2.0 g, 6.67 mmol) in THF
(100 cm3) were added urea–hydrogen peroxide (753 mg, 8
mmol), poly-()-leucine on silica (6 g, (1.39 g of PLL)) and
DBU (1.2 cm3, 8 mmol). After 1 h, the reaction was com-
plete, the mixture was filtered and the solid residue washed
with ethyl acetate (5 × 20 cm3). The filtrate was quenched
with aq. sodium sulfite (20%). The organic phase was washed
with brine, dried over magnesium sulfate and evaporated
under reduced pressure. Crystallisation from hexane–ethyl
acetate, 10:1, afforded the pure epoxide 25 as a white solid (2
g, 98%, 94% ee), [α]D Ϫ223 (c 1.0, CHCl3); mp 74–76 ЊC
(from hexane–ethyl acetate); Rf (petroleum spirit–ethyl acet-
ate, 9:1) 0.19 (Found: Mϩ, 316.10995; C, 79.85; H, 5.1. C21H16O3
requires M, 316.11000; C, 79.75; H, 5.05%); νmax(CHCl3)/cmϪ1
(EI) 147 (PhCHOCHCO, 77%), 105 (PhC᎐O, 14), 91 (C H ,
᎐
7
7
84), 43 (CH3CO, 100).
3012 (ArH), 1691 (C᎐O), 1204 and 831 (C–O, epoxide); δ (300
᎐
H
MHz; CDCl3) 4.05 (1H, d, J 1.9, H-2), 4.25 (1H, d, J 1.9, H-3),
6.99–8.0 (14 H, m, ArH); δC (75 MHz; CDCl3) 60.9 (C-3), 58.75
Synthesis of (2S,3R,5R,6S)-3,4,5-trihydroxy-4-methyl-2,6-
diphenylheptane (23)
(C-2), 115.5–133.8 (Ar); m/z (EI) 105 (PhC᎐O, 100%), 77 (Ph,
᎐
Diepoxy tertiary alcohol 22 was alkylated with a solution of
trimethylaluminium as described above. Purification by flash
column chromatography (SiO2; petroleum spirit–ethyl acetate,
4:1) furnished the triol 23 as a colourless oil (446 mg, 71%); [α]D
ϩ12 (c 1.0, EtOH); Rf (petroleum spirit–ethyl acetate, 4:1) 0.12
(Found: C, 76.5; H, 8.25. C20H26O3 requires C, 76.4; H, 8.3%);
νmax(NaCl)/cmϪ1 3455 (OH), 1320 (OH); δH (300 MHz; CDCl3)
0.84 (3H, s, 4-CH3), 1.31 and 1.34 (each 3H, d, J 7.2, H-1 and
-7), 2.55 (1H, br s, 4-OH), 2.89 (1H, quint, J 7.2, H-2 or -6),
2.97 (2H, br s, 3-OH and -OH), 3.06 (1H, dq, J 7.2 and 3.3, H-6
or -2), 3.6 (1H, d, J 7.2, H-3 or -5), 4.0 (1H, d, J 3.3, H-5 or -3),
7.17–7.36 (10H, m, ArH); δC (75 MHz; CDCl3) 14.8 (4-CH3),
18.9 and 22.5 (C-1 and -7), 40.7 and 42.1 (C-2 and -6), 76.2 and
78.3 (C-3 and -5), 83.75 (C-4), 126.5 and 126.6 (C-24 and -64),
127.7 and 128.7 (C-22, -23, -62 and -63), 145.9 and 146.1 (C-21
67).
(1S,2R,3S)-1,2-Dihydroxy-3-(3-phenoxyphenyl)-1-phenyl-
butane 26. The usual reduction procedure with Zn(BH4)2 was
carried out on epoxy ketone 25 to afford (1S,2S,3S)-2,3-epoxy-
3-(3-phenoxyphenyl)-1-phenylpropan-1-ol as an oil (382 mg,
95%), [α]D Ϫ15.2 (c 1.0, CHCl3); Rf (petroleum spirit–ethyl
acetate, 8.5:1.5) 0.22 (Found: Mϩ, 318.12502; C, 79.3; H, 5.8.
C21H18O3 requires M, 318.12558; C, 79.25; H, 5.7%); νmax(NaCl)/
cmϪ1 3425 (OH), 1220, 890 (C–O epoxide); δH (300 MHz;
CDCl3) 2.33 (1H, br s, OH), 3.25 (1H, dd, J 2.98 and 2.0, H-2),
4.1 (1H, d, J 2.0, H-3), 4.94 (1H, d, J 2.98, H-1), 6.87–7.93
(14H, m, ArH); δC (75 MHz; CDCl3) 54.8 (C-2), 64.97 (C-3),
71.3 (C-1), 116.0, 118.6, 120.6, 123.6, 126.6, 128.5, 128.8 and
129.9 (CH, Ar), 138.8, 138.9, 156.9 and 157.8 (C, Ar); m/z (EI)
J. Chem. Soc., Perkin Trans. 1, 2000, 2455–2463
2461

View Online
212 (M Ϫ PhCOH, 58%), 183 (M Ϫ PhCHOHCO, 61.4), 105
123.2, 125.8, 127.6, 128.4, 128.7, 128.9 and 129.5 (CH, Ar),
(PhC᎐O, 60.4), 77 (Ph, 100).
130.6, 134.0, 135.0 and 135.7 (C-32, -34a and -38a), 158.4 (C-36),
᎐
Alkylation of the epoxy alcohol with trimethylaluminium
gave diol 26 as a colourless oil (85%); [α]D ϩ63.46 (c 1.04,
CDCl3); Rf (petroleum spirit–ethyl acetate, 4:1) 0.18 (Found:
Mϩ, 334.15695; C, 79.2; H, 6.3. C22H22O3 requires M, 334.15689;
C, 79.0; H, 6.6%); νmax(NaCl)/cmϪ1 3612 (OH), 3075, 3030
193.3 (C-1); m/z (EI) 304 (Mϩ, 37%), 171 (MeOC8H6CHOH,
62), 105 (PhC᎐O, 100), 77 (Ph, 47.4).
᎐
(2S,3R,4S)-3,4-Epoxy-4-(6-methoxynaphthalen-2-yl)-2-
phenylbutan-2-ol 29. To a solution of epoxy ketone 28 (1.5 g,
4.9 mmol) in freshly distilled diethyl ether (40 cm3) and THF
(32 cm3) was added dropwise a solution of methylmagnesium
iodide (3 M solution in diethyl ether; 2.6 cm3, 7.84 mmol) at
Ϫ78 ЊC under an argon atmosphere. After 2.5 h, the reaction
mixture was quenched with saturated aq. ammonium chloride
and extracted with diethyl ether (3 × 50 cm3). The combined
organic layers were washed successively with water (50 cm3) and
brine (50 cm3), dried over magnesium sulfate and evaporated
under reduced pressure. Purification of the residue by flash
column chromatography (SiO2; petroleum spirit–diethyl ether,
9:1) furnished the diastereomerically pure epoxy alcohol 29 as
a white solid (1.3 g, 85%); [α]D Ϫ38 (c 1.0, CHCl3); mp 130–
132 ЊC (from hexane); Rf (petroleum spirit–diethyl ether, 4:1)
0.31 (Found: Mϩ, 320.14158; C, 78.8; H, 6.4. C21H20O3 requires
M, 320.1421; C, 78.75; H, 6.25%); νmax(CHCl3)/cmϪ1 3495
(OH), 1210, 975 and 875 (C–O, epoxide); δH (300 MHz; CDCl3)
1.78 (3H, s, H3-1), 2.33 (1H, s, OH), 3.80 (1H, d, J 2.1, H-3), 3.90
(3H, s, OMe), 4.17 (1H, d, J 2.1, H-4), 7.09–7.69 (11H, m, Ar);
δC (75 MHz; CDCl3) 27.85 (C-1), 55.3 (OMe), 56.2 (C-4), 68.4
(C-3), 105.8, 119.3, 123.6, 125.1, 125.3, 127.2, 127.6, 128.5,
129.1, 131.8, 134.0, 141.8, 144.0 and 157.5 (Ar); m/z (EI) 200
(M Ϫ Ph COCH3, 26%), 171 [M Ϫ PhC(OH)CH3CO, 100], 105
(᎐CH), 1602, 1654 (C᎐C, Ar); δH (300 MHz; CDCl3) 1.28 (3H,
᎐
᎐
d, J 7.15, H3-4), 1.85 (1H, br s, OH), 2.21 (1H, br s, OH), 2.70
(1H, m, H-3), 3.95 (1H, dd, J 6.6 and 5.3, H-2), 4.50 (1H, d,
J 5.3, H-1), 6.8–7.30 (14H, m, ArH); δC (75 MHz; CDCl3) 16.6
(C-4), 41.4 (C-3), 75.1 (C-2), 78.5 (C-1), 116.9, 118.7, 118.9,
122.8, 123.3, 127.6, 128.3, 128.5 and 129.8 (CH, Ar), 140.5,
146.9, 157.4 and 157.5 (C, Ar); m/z (EI) 227 (M Ϫ PhCHOH,
22%), 197 (M Ϫ PhCHOHCHOH, 22.3), 108 (PhCHOH, 100),
77 (Ph, 44.3).
(S)-(؉)-Fenoprofen 5. The usual oxidative cleavage procedure
was carried out on diol 26. Purification of the residue by flash
column chromatography (SiO2; dichloromethane–methanol,
49:1) afforded (S)-fenoprofen 5 as a colourless liquid (64%),
[α]D ϩ46 (c 1.0, CHCl3) {lit.,19 [α]D ϩ45.7 (c 1.0, CHCl3)}; Rf
(dichloromethane–methanol, 49:1) 0.17 (Found: C, 74.5; H,
5.8. Calc. for C15H14O3: C, 74.4; H, 5.75); νmax(NaCl)/cmϪ1
2700–3100 (OH), 1720 (C᎐O); δH (300 MHz; CDCl3) 1.36 (3H,
᎐
d, J 7, -3), 3.50 (1H, q, J 7, H-2), 6.79–7.31 (9H, m, ArH3), 8.40
(1H, br s, COOH); δC (75 MHz; CDCl3) 18.2 (C-3), 45.75 (C-2),
117.3, 118.5, 118.9, 122.5, 123.3 and 129.8 (CH, Ar), 142.5,
157.2 and 157.4 (C, Ar), 180.75 (COOH).
(PhC᎐O, 85), 77 (Ph, 47).
᎐
Synthesis of (S)-naproxen 1
(2S,3R,4S)-2,3-Dihydroxy-4-(6-methoxynaphthalen-2-yl)-2-
phenylpentane 30. Tertiary epoxy alcohol 29 was alkylated in
the usual manner with a solution of trimethylaluminium. Puri-
fication of the residue by flash column chromatography (SiO2;
petroleum spirit–ethyl acetate, 9:1) furnished the diol 30 as a
colourless oil (815 mg, 78%); [α]D ϩ68 (c 1.0, CHCl3); Rf (pet-
roleum spirit–ethyl acetate, 4:1) 0.14 (Found: Mϩ, 336.17298;
C, 78.65; H, 7.1. C22H24O3 requires M, 336.17255; C, 78.6; H,
7.15%); νmax(NaCl)/cmϪ1 3400 (OH), 1320 (OH); δH (300 MHz;
CDCl3) 1.24 (3H, d, J 7.0, H3-5), 1.53 (3H, s, H3-1), 2.01 (1H, s,
OH), 2.35 (1H, s br, OH), 2.76 (1H, dq, J 7.0 and 3.3, H-4), 3.87
(3H, s, OMe), 3.93 (1H, d, J 3.3, H-3), 7.07–7.64 (11H, m,
ArH); δC (75 MHz; CDCl3) 14.4 (C-5), 29.2 (C-1), 40.5 (C-4),
55.3 (C-2), 81.05 (C-3), 105.8 , 118.8, 125.25, 125.5, 127.0, 127.0
and 128.4, 129.2 (CH, Ar), 133.4, 141.7 and 145.2 (C-48a, -42
and -44a); m/z (EI) 185 [M Ϫ PhC(Me)(OH)CHOH, 76%], 122
[PhC(CH3)OH, 100], 77 (Ph, 44.3%).
(E)-3-(6-Methoxynaphthalen-2-yl)-1-phenylpropenone
27.
To a stirred solution of acetophenone (2.1 cm3, 16.11 mmol)
and 6-methoxy-2-naphthaldehyde (3 g, 15.3 mmol) in absolute
methanol (16 cm3; 1 cm3 per mmol of ketone) were added 3
pellets of sodium hydroxide. After 20 h, the resulting yellow
solid was washed successively with cold ethanol and water and
was then crystallised from hexane–ethyl acetate, 10:1 to afford
(E)-enone 27 (4.10 g, 90%) as a colourless crystalline solid, mp
148–149 ЊC (from ethyl acetate–hexane); Rf (petroleum spirit–
ethyl acetate, 9:1) 0.24 (Found: Mϩ, 300.11477; C, 84.05 H, 5.4.
C21H16O2 requires M, 300.11505; C, 84.0; H, 5.35.); νmax(CHCl3)/
cmϪ1 3060, 1615, 1581, 980 (C᎐C), 1690 (C᎐O); δ (300 MHz;
᎐
᎐
H
CDCl3) 3.94 (3H, s, CH3) 6.88–8.0 (13H, m, ArH, H-2 and -3);
δC (75 MHz; CDCl3) 55.3 (CH3, OCH3), 106.2, 119.4, 121.3,
124.5, 127.6, 128.6, 128.8, 130.3, 130.4, 130.4, 132.7, 136.0,
138.6, 145.3 (C-2, -3, C-Ar and CH-Ar), 159 (C-36) 190.7 (C-1);
m/z (EI) 300 (Mϩ, 100%), 207 (M Ϫ OPh, 60.2), 105 (PhC᎐O,
᎐
35), 77 (Ph, 67).
(S)-Naproxen 1. The usual 2-step oxidative cleavage was car-
ried out on diol 30. Purification by flash column chroma-
tography (SiO2; dichloromethane–methanol, 98:2) afforded
(S)-naproxen 1 as a white solid (88%, mp 154–156 ЊC (from
hexane–ethyl acetate) (lit.,21 154–157 ЊC); [α]D ϩ68 (c 1.0,
CHCl3) {lit.,21 [α]D ϩ67.5 (c 1.0, CHCl3)} (Found: Mϩ, 230.094
31; C, 73.1; H, 6.1, C14H14O3 requires M, 230.9428; C, 73.05; H,
6.1%); νmax(NaCl)/cmϪ1 2750–3100 (OH), 1780 (C᎐O); δ (300
MHz; CDCl3) 1.57 (3H, d, J 7.0, H3-3), 3.87 (1H, q, J 7.0, H-2),
3.90 (3H, s, OMe), 7.09–7.17 (2H, m, ArH), 7.40 (1H, m, ArH),
7.63–7.78 (3H, m, ArH); δC (75 MHz; CDCl3) 18.1 (C-3), 45.3
(OMe), 55.3 (C-2), 105.7, 119.2, 126.3, 127.3 and 129.4 (CH,
ArH), 129.0 and 133.9 (C-24a and -28a), 135.0 and 157.9 (C-22
and -26), 180.5 (COOH); m/z (EI) 230 (Mϩ, 40%), 185 (M Ϫ
COOH, 100), 170 (MeOC8H6CH, 18).
(2R,3S)-2,3-Epoxy-3-(6-methoxynaphthalen-2-yl)-1-phenyl-
propan-1-one 28. To a solution of enone 27 (2.0 g, 6.94 mmol)
in THF (80 cm3) were added urea–hydrogen peroxide (784 mg,
8.34 mmol), poly-()-leucine adsorbed onto silica (6.4 g, 1.44 g
of polymer) and DBU (1.25 cm3, 8.34 mmol). After 1.5 h the
reaction mixture was filtered and the solid residue washed with
ethyl acetate (5 × 20 cm3). The filtrate was quenched with aq.
sodium sulfite (20%). The organic phase was washed with brine,
dried over magnesium sulfate and evaporated under reduced
pressure. Crystallisation from hexane–ethyl acetate, 10:1,
afforded the pure epoxy ketone 28 as a white solid (2.0 g, 97%,
94% ee). [α]D Ϫ310 (c 1.0, CHCl3); mp 101–103 ЊC (from
hexane–ethyl acetate); Rf (petroleum spirit–ethyl acetate, 9:1)
0.35 (Found: Mϩ, 304.11101; C, 78.9; H, 5.3. C20H16O3 requires
M, 304.10995; C, 78.95; H, 5.25%); νmax(CHCl3)/cmϪ1 3011
᎐
H
(Ar-H), 1691 (C᎐O), 1269 and 854 (C–O, epoxide); δ (300
᎐
H
Acknowledgements
We thank AstraZeneca and the Eden Fund (University of
Liverpool) for financial support (to L. C.).
MHz; CDCl3) 3.90 (3H, s, OMe), 4.39 (1H, d, J 1.8, H-2), 4.20
(1H, d J 1.8, H-3), 7.15–8.0 (11 H, m, ArH); δC (75 MHz;
CDCl3) 55.4 (OMe), 59.8 (C-3), 61.25 (C-2), 105.95, 119.6,
2462
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10 M. Miyashita, T. Shiratani, K. Kawamine, S. Hatakeyama and
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8 Initial investigations have been reported in a communication: L.
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2463