Julia-Colonna stereoselective epoxidation of some α,β-unsaturated enones possessing a stereogenic centre at the γ-position: Synthesis of a protected galactonic acid derivative

Article abstract of DOI:10.1039/b007100p

The oxidation of enones 6-8 using peroxide or percarbonate and polyleucines as catalysts gave the corresponding diastereomers 9-12 in high yield. The compound 9 was converted into the galactonic acid derivative 16 in five steps and in an overall yield of nearly 60%. Polyleucines are shown to be catalysts powerful enough to overturn the intrinsic stereocontrol in the chosen substrates.

Full text of DOI:10.1039/b007100p

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Juliá–Colonna stereoselective epoxidation of some ꢀ,ꢁ-unsaturated
enones possessing a stereogenic centre at the ꢂ-position:
synthesis of a protected galactonic acid derivative
1
Peter C. Ray and Stanley M. Roberts
Department of Chemistry, The University of Liverpool, Liverpool, UK L69 7ZD
Received (in Cambridge, UK) 1st September 2000, Accepted 10th November 2000
First published as an Advance Article on the web 18th December 2000
The oxidation of enones 6–8 using peroxide or percarbonate and polyleucines as catalysts gave the corresponding
diastereomers 9–12 in high yield. The compound 9 was converted into the galactonic acid derivative 16 in five steps
and in an overall yield of nearly 60%. Polyleucines are shown to be catalysts powerful enough to overturn the
intrinsic stereocontrol in the chosen substrates.
Introduction
The stereoselective epoxidation of chalcone using aqueous
hydrogen peroxide in the presence of a polyamino acid was
invented by Juliá and Colonna.1 These workers found that
chalcone 1 afforded the 2S,3R-epoxide 2 in high enantiomeric
excess when poly--leucine (PDL) was used as the stereo-
selective catalyst, while the enantiomeric epoxide ent-2 was
obtained on using poly--leucine (PLL) (Scheme 1).
Fig. 1 Predictive model for polyleucine induced epoxidation.
Scheme 1 Reagents and conditions: i, H2O2, H2O, NaOH, toluene,
poly--leucine (PDL); ii, H2O2, H2O, NaOH, toluene, poly--leucine
employing (Ϫ)-diethyl tartrate enhances the sense of diastereo-
selection; the “mismatched” Katsuki–Sharpless stereoselective
(PLL).
epoxidation is clearly able to overcome the intrinsic substrate
Subsequently the Juliá–Colonna oxidation has been
developed and improved. Noteworthy modifications include the
control (Scheme 2).5 The ability of the Juliá–Colonna catalyst
following:
adsorption of the polyamino acid on silica for efficiency,
ease of use, simple recovery and ready recycling;2
use of urea hydrogen peroxide (UHP) as the oxidant with a
non-nucleophilic base (such as diazabicycloundecene (DBU))
in order to avoid aqueous hydroxide and hence to expand the
substrate range;3
introduction of percarbonate in dimethoxyethane as a cheap
oxidant/solvent for use in some polyamino acid-catalysed
epoxidations.4
The above work has resulted in a predictive model for the
enantioselective epoxidation of various (E)-enones on catalysis
using polyleucine (Fig. 1).
With a portfolio of optimised reaction conditions available
for the enantioselective epoxidation of (E)-enones it was of
interest to test the power of the polyamino acid catalysts. One
test, often used in this context previously, is to examine the
ability of a catalyst to overcome the sense of diastereoselection
for a reaction involving a substrate containing a pre-existing
stereogenic centre. For example oxidation of the allylic alcohol
3 using tert-butyl hydroperoxide and titanium() isopropoxide
gave the epoxide 4 and its diastereomer 5 in the ratio 2.3:1.
Addition of (Ϫ)-diethyl tartrate changed the ratio of 4:5 to
40:1 while on the other hand addition of (ϩ)-diethyl tartrate
altered the ratio to 1:14. The “matched” catalyst system
Scheme 2 Reagents: i, Ti(Oi-Pr)4, t-BuOOH.
to override the bias observed in the non-catalysed Weitz–
Scheffer oxidation of chiral enones was investigated using
(E)-enone 6, the corresponding (Z)-enone 7 and epoxide 8.6
Results and discussion
The ketones 6 and 7 (ratio 2:1) were prepared in 98% yield by
a two-step, one-pot procedure from 1,2:5,6-di-o-isopropyl-
DOI: 10.1039/b007100p
J. Chem. Soc., Perkin Trans. 1, 2001, 149–153
This journal is © The Royal Society of Chemistry 2001
149

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idene--mannitol using silica gel-supported sodium meta-
periodate7 followed by addition of the phenylcarbonyl-
methylenetriphenylphosphorane (Scheme 3). The two alkenes
Scheme 5
Scheme 3 Reagents and conditions: i, SiO2–NaIO4, Ph3PCHCOPh,
CH2Cl2.
Fig. 2 Selectivity for poly--leucine catalysed epoxidation of (E)-(4S)-
6 and (Z)-(4S)-7.
were separated by chromatography and independently sub-
jected to epoxidation using basic peroxide. The enantiomeric
purity of enones (E)-(4S)-6 and (Z)-(4S)-7 was determined by
comparison of the HPLC results to those obtained from the
corresponding racemates.8
Oxidation of enone (E)-(4S)-6 using UHP and DBU in tetra-
hydrofuran (THF) gave the syn-9 and anti-10 epoxides in the
ratio 1:2.2 (94%) (Scheme 4). Addition of poly--leucine,
the other hand the reaction catalysed by poly--leucine afforded
the diastereomers 9:10 in the ratio 3.6:1. The latter ratio was
improved slightly (to 4:1) on conducting a repeat run at 0 ЊC.
All three reactions gave excellent yields (>95%). It is especially
noteworthy that the polyleucine-catalysed epoxidations of the
(Z)-enone were faster than the corresponding reactions of the
(E)-enone, precluding the possibility that addition–elimination
reactions may have caused cis/trans-isomerization prior to
oxidation. Thus the poly--leucine catalysed reaction of both
the (Z)-enone and the (E)-enone involves attack of peroxide
from the same (Si) face (Fig. 2). In the case of the (Z)-enone
rotation about C2–C3 takes place prior to ring closure.
The third substrate (E)-(4S)-8 for study was made from
(S)-glycidol by a one-pot Swern oxidation/Wittig olefination
sequence,10 and the enantiomeric purity determined by com-
parison of the HPLC trace to that obtained from racemic
glycidol. The crystalline enone (E)-(4S)-8 was obtained in this
way in 80% yield (Scheme 6). The (Z)-enone was identified in
Scheme 4
expected to be the matched catalyst,1 did indeed alter the ratio
of 9 and 10 substantially in favour of the anti-10 isomer (ratio
1:30) (95% yield). The major component was crystallized and
the stereostructure of the compound was confirmed by X-ray
analysis. The mismatched catalyst, poly--leucine, was initially
disappointing, altering the ratio only to the extent of giving
equal quantities of the two diastereoisomers. However, on using
poly--leucine adsorbed onto silica, the ratio of syn-9 to anti-10
was improved to 2.2:1 (96% yield). This improvement was
attributed to the greater efficiency of the silica-based catalyst,
minimizing the background (non-catalysed) reaction.
Scheme 6 Reagents and conditions: i, DMSO, (COCl)2, Et3N, CH2Cl2,
Ph3PCHCOPh.
the crude mixture by 1H NMR spectroscopy, but it proved to be
difficult to isolate in a pure state.
Epoxidation of enone 8 using UHP and DBU in the absence
of catalyst gave the syn-isomer 11 and the anti-isomer 12 in the
ratio 1:1.7 (Scheme 7). Employment of poly--leucine as a
In the absence of polyleucine the previously documented
percarbonate conditions4 afforded the syn-9 and anti-10 iso-
mers in the ratio 1:2.7 (97%). Addition of poly--leucine to the
reaction mixture reversed the selectivity, to give the syn-9 iso-
mer as the major component (ratio 2.4:1; 94% yield). The
optimum conditions involved conducting the percarbonate
reaction at a lower temperature (0 to 3 ЊC) whereupon, on using
poly--leucine as the catalyst, the syn-9 and anti-10 isomers
were obtained in a 3.8:1 ratio (95%). Recrystallization of this
mixture afforded the pure syn-9 isomer, as evidenced by HPLC
analysis. Under the low temperature percarbonate conditions,
catalysis by poly--leucine furnished 9 and 10 in the ratio 1:30
(90% yield).
The Juliá–Colonna stereoselective epoxidation of (Z)-enones
has not been explored to any appreciable extent, thus it was of
particular interest to include the (Z)-enone (4S)-7 as a substrate
in the present study. Oxidation of 7 in THF using DBU and
UHP gave the epoxides 9 and 10 in the ratio 1:1.3 (Scheme 5).
The diminished anti-selectivity, compared to that observed for
the (E)-enone, is probably due to the increased importance of
reaction via an anti-Felkin transition state in which 1,3-allylic
strain is minimised.9
Scheme 7
catalyst for the oxidation gave a mixture which was highly
enriched in the anti-isomer 12 (ratio 11:12; 1:10) such that an
enantiomerically pure sample of 12 was readily obtained on
recrystallization from ethanol. The X-ray crystal data served to
confirm the stereostructure. Oxidation of substrate 8 under the
usual UHP–DBU–THF conditions, using poly--leucine as the
catalyst, furnished the two diastereomers 11 and 12 in the ratio
3.5:1.
The ready availability of highly functionalised compounds
such as 9 or 10 prompted an investigation of some aspects of
their chemistry. For example zinc borohydride reduction of the
epoxyketone 9 afforded alcohol 13 in a nearly quantitative
yield.11 This alcohol was converted into the corresponding
urethane 14 in 95% yield by reaction with phenyl isocyanate in
the presence of pyridine.12 The urethane was treated with boron
trifluoride diethyl ether complex at Ϫ20 ЊC for 1 h and the
intermediate iminium carbonate was then hydrolysed with
Conducting the reaction in the presence of poly--leucine
enhanced the amount of the anti-isomer (ratio 9:10, 1:8). On
150
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Scheme 8 Reagents and conditions: i, Zn(BH4)2, Et2O; ii, PhNCO, pyridine, CH2Cl2; iii, (a) BF3(OEt2), Et2O, H2SO4, (b) Ac2O, pyridine, DMAP,
CH2Cl2; iv, RuCl3, NaIO4, CCl4, CH3CN, H2O.
dilute sulfuric acid with concomitant removal of the iso-
propylidene group. The crude product was acetylated to give
the triester 15 in 96% yield. Finally, treatment of the cyclic
carbonate 15 in carbon tetrachloride and acetonitrile with
aqueous sodium metaperiodate containing ruthenium()
chloride or ruthenium() oxide13 furnished the carboxylic acid
16 in 65–68% yield. This acid is a differentially protected deriva-
tive of galactonic acid (Scheme 8).
Other polyoxygenated hexanoic acids would be available
from (R)- or (S)-glyceraldehydes using the appropriate poly-
amino acid in the key oxidation step.6 Thus in summary the
polyleucine catalysts are obviously powerful enough to over-
come the intrinsic senses of stereoselection to give different
diastereomers as major products when employed as catalysts
for the oxidation of enones 6, 7, and 8. Poly--leucine acted as
the “matched” catalyst, poly--leucine as the “mismatched”
catalyst in each case.
a E/Z mixture of (4S)-6 and (4S)-7 (1.72 g, 98%, E:Z [2:1] by
1H NMR). Flash chromatography of the residue over silica gel
(300 g) with ethyl acetate–hexane (1:9) as the eluent afforded
(Z)-(4S)-7 (>99% ee [chiral HPLC: ethanol–hexane (1:9);
Rt = 13.5 min]), mp 58–59 ЊC (from ethyl acetate) (Found:
C, 72.5; H, 7.0. C14H16O3 requires C, 72.4; H, 6.9%); [α]D 173
(c = 1, CHCl3); νmax(film)/cmϪ1 1743 (ketone CO); δH (300 MHz,
CHCl3) 1.40 and 1.48 (2 × 3H, 2 × s, C(CH3)2), 3.70 (1H, dd,
J 6.9 and 8.4 Hz, 5-H), 4.52 (1H, dd, J 7.2 and 8.4 Hz, 5-H),
5.37 (1H, m, 4-H), 6.49 (1H, dd, J 6.6 and 11.7 Hz, 3-H), 6.96
(1H, dd, J 1.5 and 11.7 Hz, 2-H), 7.38–7.94 (5H, m, C6H5);
δC (75 MHz, CHCl3) 25.3 and 26.6 (C(CH3)2), 69.7 (C-5), 74.6
(C-4), 109.8 (C(CH3)2), 124.8 (C-2), 128.5, 128.8, 133.2 and
137.7 (C6H5), 149.0 (C-3) and 190.9 (C-1); m/z (EI) 232 (Mϩ),
(CI) 233 [M ϩ H]ϩ and 250 [M ϩ NH4]ϩ, followed by (E)-(4S)-
6 (>99% ee [chiral HPLC: ethanol–hexane (1:9); Rt = 9.2 min]),
mp 48 ЊC (from ethyl acetate–hexane); [α]D 21 (c = 1, CHCl3),
νmax(CHCl3)/cmϪ1 1673 (ketone CO); δH (300 MHz, CDCl3)
1.45 and 1.49 (2 × 3H, 2 × s, C(CH3)2), 3.73 (1H, dd, J 7.2
and 8.4 Hz, 5-H), 4.24 (1H, dd, J 6.6 and 8.4 Hz, 5-H), 4.80
(1H, m, 4-H), 6.97 (1H, dd, J 5.1 and 15.0 Hz, 3-H), 7.19 (1H,
dd, J 1.2 and 15.0 Hz, 2-H), 7.48–7.96 (5H, m, C6H5); δC (75
MHz, CDCl3) 25.7 and 26.4 (C(CH3)2), 68.9 (C-5), 75.5 (C-4),
110.3 (C(CH3)2), 126.0 (C-2), 128.7, 133.1 and 137.7 (C6H5),
144.6 (C-3) and 190.3 (C-1); m/z (EI) 232 [M]ϩ, (CI) 233
[M ϩ H]ϩ and 250 [M ϩ NH4]ϩ.
Experimental
General
Melting points were measured using a Reichert-Jung Thermo-
var hot-stage microscope and are uncorrected. Microanalyses
were determined using a Carlo Elba elemental analyser
instrument. Nominal and accurate mass spectra were recorded
on VG7070E, CIPOS, Kratos Profile HV3 and TRIO1000
machines. Optical rotations ([α]) were measured at ambient
temperature (22 3 ЊC) from chloroform solutions using a
1 cm3 cell with 0.1 dm path length, on a Optical Activity
Ltd AA-1000 polarimeter, and are recorded in units of 10Ϫ1 deg
cm2 gϪ1. Infrared spectra were recorded in chloroform solutions
4,5-Epoxy-1-phenylpent-2-en-1-one 8
Dimethyl sulfoxide (2.55 cm3, 35.9 mmol) was added dropwise
to a solution of oxalyl chloride (8.5 cm3, 2.4 mol dmϪ3 solution
in dichloromethane) in anhydrous dichloromethane (38 cm3) at
Ϫ78 ЊC and under nitrogen. The mixture was vigorously stirred
for 5 min, after which a solution of racemic glycidol (1.11 cm3,
16.67 mmol) in anhydrous dichloromethane (15 cm3) was
added. The mixture was stirred for 15 min at Ϫ70 ЊC and then
triethylamine (10.5 cm3) was added. The mixture was stirred
for a further 5 min at Ϫ70 ЊC and then raised to room tem-
perature over a 1 h period. Phenylcarbonylmethylenetri-
phenylphosphorane (7 g, 18.4 mmol) and a further portion
of anhydrous dichloromethane (20 cm3) was added and the
mixture stirred for a further 20 h at room temperature. Water
(80 cm3) was added and the mixture was extracted with chloro-
form (40 cm3 × 3), and the combined extracts were washed with
brine, dried (Na2SO4) and evaporated under reduced pressure
to afford a crude residue (11 g). Selective recrystallisation of the
phosphine oxide was not possible. Flash chromatography of
the residue over silica gel (300 g) with ethyl acetate–petroleum
ether (3:17) as the eluent afforded an uncharacterised product
(100 mg), followed by epoxide (E)-rac-8 (2 g, 70%; the racemate
was separated on chiral HPLC: isopropyl alcohol–hexane
(1:99); Rt = 44 and 55 min respectively); νmax(CHCl3)/cmϪ1 1670
(ketone CO); δH (300 MHz, CDCl3) 2.76 (1H, dd, J 2.4 and 5.7
using
a
Perkin-Elmer 881 infrared spectrophotometer.
All NMR spectra were recorded on a Varian 300 Gemini
2000 (300 MHz) instrument. Chiral High Pressure Liquid
Chromatography was conducted using a Chiralpak AD column
(Daicel Chemical Industries), 0.46 × 25 cm. Column chroma-
tography was conducted with Merck Kieselgel 60: 230–400
mesh for flash chromatography, using the technique described
by W. C. Still.14
4,5-Isopropylidenedioxy-1-phenylpent-2-en-1-ones 6 and 7
1,2:5,6-Di-o-isopropylidene--mannitol (1 g, 3.8 mmol) was
added to a vigorously stirred suspension of silica gel-supported
sodium metaperiodate7 (7.6 g) in anhydrous dichloromethane
(40 cm3), followed by the addition of phenylcarbonyl-
methylenetriphenylphosphorane (3 g, 7.9 mmol). The mixture
was stirred for 2 h and then filtered over a pad of Na2SO4,
which was washed with dichloromethane. The filtrate was
evaporated under reduced pressure to afford a crude residue
(6 g). Flash chromatography of the residue over silica gel
(100 g) with ethyl acetate–hexane (2:3) as the eluent afforded
J. Chem. Soc., Perkin Trans. 1, 2001, 149–153
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Hz, 5-H), 3.10 (1H, dd, J 4.2 and 5.7 Hz, 5-H), 3.57 (1H, dddd,
J 0.6, 2.4, 4.2 and 6.9 Hz, 4-H), 6.76 (1H, dd, J 6.9 and 15.3 Hz,
3-H), 7.25 (1H, dd, J 0.6 and 15.3 Hz, 2-H), 7.48–7.95 (5H,
m, C6H5); δC (75 MHz, CDCl3) 49.6 (C-5), 50.8 (C-4), 127.7
(C-2), 128.7, 133.1 and 137.4 (C6H5), 144.7 (C-3) and 189.6
(C-1); m/z (EI) 174 [M]ϩ (Found: [M]ϩ, 174.0680. C11H10O2
requires [M], 174.0681).
The above reaction was repeated for enantiopure (S)-glycidol
(1.11 cm3) to afford (E)-(4S)-8 (2.3 g, 78%, >99% ee-chiral
HPLC: as above) mp 69 ЊC (from ethyl acetate–hexane) (Found:
C, 76.0; H, 5.8. C14H16O5 requires C, 75.8; H, 5.8%); [α]D Ϫ4.5
(c = 2, CHCl3).
(5H, m, C6H5); δC (75 MHz, CDCl3) 25.6 and 26.0 (C(CH3)2),
54.1 (C-3), 58.6 (C-2), 66.0 (C-5), 73.7 (C-4), 110.5 (C(CH3)2),
128.5, 128.9, 134.1 and 135.4 (C6H5) and 194.0 (C-1).
(2S,3R,4R)-2,3-Epoxy-4,5-isopropylidenedioxy-1-phenyl-
pentan-1-one 10. Reaction of enone 6 using poly--leucine
under biphasic conditions and work up as prescribed above
gave a residue. Purification by silica gel flash chromatography
(ethyl acetate–hexane 1:4) afforded 10 and 9 in the ratio 30:1
(203 mg, 95%); recrystallization furnished pure 10; mp 65 ЊC
(from ethyl acetate–hexane) (HPLC: syn:anti 1:>99) (Found:
C, 67.9; H, 6.5. C14H16O4 requires C, 67.7; H, 6.5%); [α]D Ϫ12.5
(CHCl3, c = 1); νmax(CHCl3)/cmϪ1 1694 (ketone CO); δH (300
MHz, CDCl3) 1.39 and 1.46 (2 × 3H, 2 × s, C(CH3)2), 3.25
(1H, dd, J 1.8 and 5.4 Hz, 3-H), 4.02 (1H, dd, J 4.8 and 8.1 Hz,
5-H), 4.09 (1H, ddd, J 4.8, 5.4 and 6.0 Hz, 4-H), 4.21 (1H, dd,
J 6.0 and 8.1 Hz, 5-H), 4.23 (1H, d, J 1.8 Hz, 2-H), 7.51–8.04
(5H, m, C6H5); δC (75 MHz, CDCl3) 25.1 and 26.6 (C(CH3)2),
55.6 (C-3), 59.2 (C-2), 67.0 (C-4), 75.3 (C-5), 110.4 (C(CH3)2),
128.4, 128.9, 134.1 and 135.5 (C6H5) and 193.6 (C-1); m/z (CI)
249 [M ϩ H]ϩ and 266 [M ϩ NH4]ϩ. X-Ray crystal data for
compound 9 are published elsewhere.15
General epoxidation procedures
Biphasic conditions. To a solution of substrate (0.86 mmol,
>99% ee) and activated polyleucine (400 mg) in anhydrous
tetrahydrofuran (1 cm3) was added urea hydrogen peroxide
(243 mg, 2.59 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene
(0.3 cm3, 2.50 mmol). The mixture was stirred at room
temperature for 4 h, and then filtered. The solid residue
(polyleucine) was washed with ethyl acetate (10 cm3 × 3) and
water (20 cm3). The filtrate was extracted with ethyl acetate
(20 cm3 × 3), and the combined extracts were dried (Na2SO4),
and evaporated under reduced pressure to afford a residue.
Chromatography over silica gel gave crude product which was
analysed by HPLC. Yields and isomer ratios are detailed in the
discussion.
(4R)-syn- and anti-2,3:4,5-Diepoxy-1-phenylpentan-1-one
Reaction of enone 8 under biphasic conditions, but in the
absence of catalyst, with work up as described, gave a residue.
Purification by silica gel flash chromatography (ethyl acetate–
hexane 3:7) afforded a mixture of 11 and 12 (25 mg, 94%, ratio
syn-11:anti-12 [1:1.7] by 1H NMR).
Percarbonate (Na2CO3ؒ1.5H2O2) conditions. To a mixture
of dimethoxyethane and water (1:2, 1 cm3) was added the
substrate (50 mg, 0.215 mmol) and polyleucine (400 mg). The
mixture was stirred for 10 min at room temperature, and
then Na2CO3ؒ1.5H2O2 (56 mg, 0.36 mmol) was added. The
mixture was stirred for 30 min and then worked up as above.
Chromatography over silica gel afforded crude product which
was analysed by HPLC. Yields and isomer ratios are given in
the discussion.
(2S,3R,4S)-2,3:4,5-Diepoxy-1-phenylpentan-1-one 12. Reac-
tion of enone 8 (196 mg) under biphasic conditions, using poly-
-leucine as catalyst and with work up as described, gave a
residue. Purification by silica gel flash chromatography (ethyl
acetate–hexane 3:7) afforded a crystalline residue (203 mg,
95%, syn-11:anti-12 [1:10] by 1H NMR); recrystallization
afforded pure 12; mp 58 ЊC (from ethanol) (Found: C, 69.3;
H, 5.3. C11H10O3 requires C, 69.5; H, 5.3%); [α]D Ϫ6 (CHCl3,
c = 1); νmax(CHCl3)/cmϪ1 1692 (ketone CO); δH (300 MHz,
CDCl3) 2.79 (1H, dd, J 2.7 and 5.1 Hz, 5-H), 2.94 (1H, dd, J 4.2
and 5.1 Hz, 5-H), 3.12 (1H, m, 4-H), 3.21 (1H, dd, J 2.1 and 4.8
Hz, 3-H), 4.25 (1H, d, J 2.1 Hz, 2-H), 7.51–8.02 (5H, m, C6H5);
δC (75 MHz, CDCl3) 45.5 (C-4), 50.0 (C-5), 54.7 (C-3), 58.1
(C-2), 128.4, 129.0, 134.2 and 135.4 (C6H5) and 193.3 (C-1);
m/z (CI) 191 ([M ϩ H]ϩ) and 208 ([M ϩ NH4]ϩ).
Silica adsorbed polyleucine (SCAT) conditions. To a solution
of silica adsorbed immobilized polyleucine (600 mg) and sub-
strate (100 mg, 0.43 mmol, >99% ee) in anhydrous tetrahydro-
furan (2 cm3) was added urea hydrogen peroxide (81 mg,
0.86 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 cm3,
0.43 mmol). The mixture was stirred at room temperature for
30 min, and then filtered. The solid residue was washed with
ethyl acetate (10 cm3 × 3). The filtrate was washed with water,
and the organic extract dried (Na2SO4), and evaporated under
reduced pressure to afford a residue. Chromatography over
silica gel afforded crude product which was analysed by HPLC.
Yields and isomer ratios are detailed in the discussion.
(1S,2S,3S,4R)-2,3-Epoxy-4,5-isopropylidenedioxy-1-phenyl-
pentan-1-ol 13
Zinc borohydride (4.5 cm3, 0.0629 mol dmϪ3 ethereal solution)
was added to a solution of syn-9 (187 mg, 0.75 mmol) in
anhydrous ether (10 cm3), at 0 ЊC and under argon. The mixture
was stirred at 0 ЊC for 10 min. Thereafter the mixture was
stirred at room temperature for 2 h. Water was added and the
resultant mixture stirred for 1 h after which time saturated
aqueous ammonium chloride (20 cm3) was added. The mixture
was extracted with ethyl acetate (20 cm3 × 4), and the combined
extracts dried (Na2SO4) and evaporated under reduced pressure
to afford a crude residue (420 mg). Flash chromatography of
the residue over silica gel (35 g) with ethyl acetate–hexane (2:3)
as the eluent afforded epoxy alcohol 13 (180 mg, 95%) as an oil;
[α]D 53 (CHCl3, c = 1); νmax(CHCl3)/cmϪ1 3451 (OH stretch);
δH (300 MHz, CDCl3) 1.31 and 1.36 (2 × 3H, 2 × s, C(CH3)2),
2.73 (1H, br s, exchanged by D2O, OH), 3.16 (1H, dd, J 2.1 and
2.7 Hz, 2-H), 3.27 (1H, dd, J 2.1 and 4.2 Hz, 3-H), 3.71 (1H, dd,
J 5.7 and 7.8 Hz, 5-H), 3.93–4.04 (2H, m, 4-H and 5-H), 4.88
(1H, d, J 2.7 Hz, 1-H) and 7.27–7.4 (5H, m, C6H5); δC (75 MHz,
CDCl3) 25.4 and 26.3 (C(CH3)2), 54.5 (C-3), 58.3 (C-2), 65.9
(C-5), 70.5 (C-4), 75.2 (C-1), 110.2 (C(CH3)2), 126.4, 128.4,
128.7 and 139.5 (C6H5).
(4R)-syn- and anti-2,3-Epoxy-4,5-isopropylidenedioxy-1-phenyl-
pentan-1-one
Reaction of enone 6 in the absence of catalyst, with work-up as
prescribed afforded a residue. Purification by silica gel flash
chromatography (ethyl acetate–hexane 1:4) afforded epoxides
9 and 10 (201 mg, 94%, syn:anti [1:2.2]-chiral HPLC: ethanol–
hexane (1:9); Rt = 14 and 22 min respectively).
(2R,3S,4R)-2,3-Epoxy-4,5-isopropylidenedioxy-1-phenyl-
pentan-1-one 9. Reaction of enone 6 with poly--leucine under
percarbonate conditions, with work-up as described, afforded
a residue. Purification by silica gel flash chromatography (ethyl
acetate–hexane 1:4) afforded 9 and 10 in the ratio 3.8:1
(203 mg, 95%); recrystallization afforded pure 9; mp 64 ЊC (ethyl
acetate–hexane) (HPLC: anti:syn >99:1); [α]D Ϫ35.9 (CHCl3,
c = 1); δH (300 MHz, CDCl3) 1.40 and 1.44 (2 × 3H, 2 × s,
C(CH3)2), 3.27 (1H, dd, J 2.1 and 3.3 Hz, 3-H), 3.97 (1H, dd,
J 6.0 and 8.4 Hz, 5-H), 4.19 (1H, dd, J 6.6 and 8.4 Hz, 5-H),
4.30 (1H, d, J 2.1 Hz, 2-H), 4.31–4.37 (1H, m, 4-H), 7.51–8.04
152
J. Chem. Soc., Perkin Trans. 1, 2001, 149–153

View Article Online
(1S,2R,3S,4R)-2,3-Epoxy-4,5-isopropylidenedioxy-1-phenyl-1-
[(N-phenyl)carbamoyloxy]pentane 14
(2S,3S,4S,5R)-2,3-Carbonyldioxy-4,5,6-triacetoxyhexanoic
acid 16
Phenyl isocyanate (0.75 cm3, 6.6 mmol) was added to a solution
of the epoxy alcohol 13 (670 mg, 2.68 mmol) in anhydrous
dichloromethane (21 cm3) and anhydrous pyridine (5.5 cm3).
The mixture was stirred for 24 h. The mixture was evaporated
under reduced pressure to afford a crude residue. The residue
was dissolved in acetone and water (2.5 cm3) was added. The
mixture was vigorously stirred and the organic solvents were
removed by evaporation under reduced pressure. Chloroform
(20 cm3) was added and the resultant mixture filtered to remove
the insoluble portion. Water (20 cm3) was added to the filtrate
and the mixture was extracted with chloroform (20 cm3 × 3),
and the combined extract dried (Na2SO4) and evaporated under
reduced pressure to afford a crude residue (1.5 g). Flash
chromatography of the residue over silica gel (50 g) with ethyl
acetate–hexane (3:7) as the eluent afforded the carbamate 14
(970 mg, 95%) as an amorphous solid, mp 163 ЊC (from
acetone-hexane) (Found: C, 68.4; H, 6.3; N, 3.8. C21H23NO5
requires C, 68.3; H, 6.3; N, 3.8%); νmax(CHCl3)/cmϪ1 1737 (CO),
2401 (CN) and 3438 (NH); δH (300 MHz, CDCl3) 1.34 and 1.38
(2 × 3H, 2 × s, C(CH3)2), 3.04 (1H, dd, J 2.1 and 3.9 Hz, 3-H),
3.33 (1H, dd, J 2.1 and 4.2 Hz, 2-H), 3.82 (1H, dd, J 6.3 and
7.8 Hz, 5-H), 4.02–4.15 (2H, m, 4-H and 5-H), 5.84 (1H, d,
J 4.2 Hz, 1-H), 6.73 (1H, br s, NH) and 7.04–7.42 (10H, m,
2 × C6H5); m/z (CI) 370 [M ϩ H]ϩ.
Sodium metaperiodate (2.8 g, 13.4 mmol) was added to a
stirred mixture of the phenyl carbonate 15 (340 mg, 0.89
mmol), carbon tetrachloride (3.7 cm3), acetonitrile (3.7 cm3)
and water (5.2 cm3). Ruthenium() chloride (414 mg, 2 mmol)
was added and the resultant mixture stirred for 24 h at room
temperature, at which point there was complete consumption
of the phenyl carbonate (TLC). The mixture was diluted with
an excess of diethyl ether, with vigorous stirring for 10 min to
precipitate ruthenium() oxide. Anhydrous magnesium sulfate
was added to the mixture. The resultant mixture was filtered
over anhydrous magnesium sulfate and washed thoroughly with
an excess of diethyl ether. The resultant filtrate was washed with
saturated aqueous sodium thiosulfate and evaporated under
reduced pressure to afford the title compound 16 (212 mg,
68%, 0.61 mmol) as an oil; νmax(CHCl3)/cmϪ1 1755 (CO stretch
of COOH), 1831 (CO stretches of OAc), and 2400 to 3500
(br OH stretch of COOH dimer); δH (300 MHz, CDCl3) 2.06,
2.11 and 2.17 (3 × 3H, 3 × s, 3 × OAc), 4.04 (1H, dd, J 6.0 and
11.7 Hz, 6-H), 4.30 (1H, dd, J 5.7 and 11.7 Hz, 6-H), 4.92 (1H,
t, J 2 × 4.2 Hz, 3-H), 5.18 (1H, d, J 4.2 Hz, 2-H), 5.40 (1H, ddd,
J 3.3, 5.7 and 6.0 Hz, 5-H), 5.57 (1H, dd, J 3.3 and 4.2 Hz, 4-H),
and 8.42 (1H, br s, exchanged by D2O, COOH); δC (75 MHz,
CDCl3) 20.3, 20.6 and 20.7 (3 × COCH3), 61.4 (C-6), 68.9
and 69.6 (C-4 and C-5), 73.4 and 77.7 (C-2 and C-3), 152.8
(CO3), 169.0 (COOH), 169.8, 170.3 and 171.0 (COCH3);
m/z (CI) 366 [M ϩ NH4]ϩ (Found: [M ϩ NH4]ϩ, 366.1045.
C13H20NO11 requires [M ϩ NH4]ϩ, 366.1036).
(1S,2S,3S,4R)-1,2-Carbonyldioxy-3,4,5-triacetoxy-1-phenyl-
pentane 15
Boron trifluoride–diethyl ether (0.074 cm3, 0.60 mmol)
was added to a solution of the epoxy urethane 14 (200 mg,
0.54 mmol) in anhydrous ether (12 cm3), at Ϫ20 ЊC and under
argon. The mixture was stirred for 1 h at Ϫ20 ЊC. Dilute
aqueous sulfuric acid (10 cm3, 1 mol dmϪ3) was added and the
mixture stirred for a further 5 h. The mixture was extracted with
ethyl acetate (20 cm3 × 3) and chloroform (20 cm3 × 1) and the
combined extracts were dried (Na2SO4) and evaporated under
reduced pressure to afford a crude residue (250 mg). The
residue was dissolved in anhydrous dichloromethane (8 cm3)
and acetic anhydride (0.6 cm3, 6.4 mmol), anhydrous pyridine
(0.4 cm3, 4.9 mmol) and 4-dimethylaminopyridine (10 mol%)
were added. The mixture was stirred for 24 h, saturated aqueous
sodium hydrogen carbonate (30 cm3) was added. The mixture
was extracted with chloroform (20 cm3 × 3), and the combined
extracts washed with dilute aqueous hydrochloric acid (10 cm3,
2 mol dmϪ3), dried (Na2SO4) and evaporated under reduced
pressure to afford a crude residue (290 mg). The residue
was flash chromatographed over silica (35 g); elution with ethyl
acetate–petroleum ether (3:17) afforded an unidentified
product (60 mg), followed by the title compound 15 (196 mg,
96%), as an oil; [α]D Ϫ20 (CHCl3, c = 1); νmax(CHCl3)/cmϪ1
1700–1840 (br CO stretch); δH (300 MHz, CDCl3) 2.02, 2.03
and 2.09 (3 × 3H, 3 × s, 3 × OAc), 3.98 (1H, dd, J 6 and 11.7
Hz, 5-H), 4.24 (1H, dd, J 6 and 11.7 Hz, 5-H), 4.74 (1H, t,
J 2 × 6 Hz, 2-H), 5.37 (1H, dt, J 3.9 and 2 × 6 Hz, 4-H), 5.53
(1H, d, J 6 Hz, 1-H), 5.56 (1H, dd, J 3.9 and 6 Hz, 3-H) and
7.32–7.49 (5H, m, C6H5); δH (300 MHz, C6D6) 1.48, 1.50 and
1.57 (3 × 3H, 3 × s, 3 × OAc), 3.81 (1H, dd, J 6 and 11.7 Hz,
5-H), 4.17 (1H, dd, J 5.4 and 11.7 Hz, 5-H), 4.35 (1H, t, J 2 ×
6 Hz, 2-H), 5.19 (1H, d, J 6 Hz, 1-H), 5.28–5.38 (2H, m, 3-H
and 4-H) and 6.89–6.94 (5H, m, C6H5); δC (75 MHz, CDCl3)
20.4, 20.5 and 20.6 (3 × COCH3), 61.0 (C-5), 68.7 and 70.1 (C-3
and C-4), 78.0 (C-1 and C-2), 126.5, 129.5, 130.2 and 135.5
(C6H5), 153.1 (CO3), 169.5, 169.6 and 170.3 (COCH3); δC (75
MHz, C6D6) 19.5, 19.5 and 19.8 (3 × COCH3), 61.2 (C-5),
68.8 and 70.3 (C-3 and C-4), 79.6 and 80.0 (C-1 and C-2),
126.5, 129.1, 129.6 and 136.0 (C6H6), 152.8 (CO3), 168.9, 168.9
and 169.5 (COCH3); m/z (CI) 398 [M ϩ NH4]ϩ (Found: [M ϩ
NH4]ϩ, 398.1439. C18H24NO9 requires [M ϩ NH4]ϩ, 398.1451).
Acknowledgements
We thank the Leverhulme Centre for Innovative Catalysis
(Liverpool) for a research studentship (to P. C. R).
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J. Chem. Soc., Perkin Trans. 1, 2001, 149–153
153