Total synthesis of AI-77-B: Stereoselective hydroxylation of 4-alkenylazetidinones

Article abstract of DOI:10.1039/a900334g

A stereoselective synthesis of the anti-ulcer compound AI-77-B 1 is described. The 4-formylazetidinone 6 was converted into the 4-(Z)-alkene 23 using a phosphonate condensation, and dihydroxylation using osmium tetroxide and N-methylmorpholine W-oxide gav

Full text of DOI:10.1039/a900334g

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Total synthesis of AI-77-B: stereoselective hydroxylation of
4-alkenylazetidinones
Simon D. Broady, Jost E. Rexhausen and Eric J. Thomas*
The Department of Chemistry, The University of Manchester, Manchester, UK M13 9PL
Received (in Glasgow) 3rd December 1998, Accepted 13th January 1999
A stereoselective synthesis of the anti-ulcer compound AI-77-B 1 is described. The 4-formylazetidinone 6 was
converted into the 4-(Z)-alkene 23 using a phosphonate condensation, and dihydroxylation using osmium tetroxide
and N-methylmorpholine N-oxide gave a mixture of the diols 24 and 25 in an 80:20, ratio. After protection of the
diol 24 as its acetonide, hydrogenolysis gave the acid 27. The oxazoline 45 was deprotonated using butyllithium,
and the lithiated oxazoline added to Cbz-protected leucinal 29, which had previously been deprotonated by tert-
butylmagnesium chloride, to give the lactones 30 and 31, ratio 85:15, after treatment with silica in dichloromethane.
Hydrogenolysis gave the aminolactone hydrochloride 52 which was condensed with the acid 27 to give the protected
dipeptide 54. Deprotection under acidic conditions gave the dihydroxyazetidinone 55. Treatment with sodium
hydroxide followed by acidification then gave the aminolactone hydrochloride 56 which on further treatment with
sodium hydroxide followed by acid gave AI-77-B methyl ether 58. Demethylation of the phenolic methyl ether 30
followed by hydrogenolysis of the Cbz-protecting group gave the aminophenol 60 which was coupled with the
acid 27 and the product taken through to AI-77-B 1 following the sequence used to prepare the methyl ether 58.
The AI-77’s are a small family of 3,4-dihydroisocoumarins and
derivatives isolated from a culture broth of Bacillus pumilus
AI-77.1 The most abundant member of the series, AI-77-B 1,
shows activity against stress ulcers in rats yet is also non-central
suppressive, non-anticholinergic and non-antihistaminergic.2
Similar compounds, the amicoumacins, have been isolated
from Bacillus pumilus BN-103.3 Aspects of the chemistry of
the AI-77’s have been studied and analogues prepared for
biological evaluation.2 The first total synthesis of AI-77-B was
reported in 19894 and two other total syntheses and several
syntheses of the dihydroxyamino acid component have been
described since.5,6 We here report full details of a total synthesis
of AI-77-B 1 which features the use of the oxazoline (4,5-
dihydrooxazole) 45 in the synthesis of the 3,4-dihydroiso-
coumarin 30 and the azetidinone 23 in the preparation of the
protected hydroxyamino acid 27.7
Formally AI-77-B is a dipeptide derived from the 3,4-
dihydroisocoumarin 2 and the β-amino acid 3. It was decided to
investigate the synthesis of this amino acid from an azetidinone
5 which would provide simultaneous protection of the amino
group and one of the carboxy functions and give scope for
the stereoselective introduction of the vicinol diol moiety. At
the onset of our work, it was intended to prepare the 3,4-
dihydroisocoumarin by chelation controlled addition of a
derivative of 2-methoxy-6-methylbenzoic acid 4 (P = Me) to a
protected leucinal, as had been carried out in other syntheses of
AI-77-B 1, albeit with some difficulty.5
OH
O
+
O
H
H
N
OH
NH3
–
CO2
O
OH
1
OH
O
O
H
+
OH
NH3
NH2
+
–
CO2
HO2C
OH
2
3
OP
O
RO2C
PN
CO2R
5
4
onate rather than potassium hexamethyldisilazide as the base
because of increased β-lactam decomposition in the presence
of the stronger base. The structures of the alkenes 7 and 8
followed from their spectroscopic data and hydrogenation to
the saturated ester 10.
The stereoselectivity of hydroxylation of the (Z)-alkene 7
was investigated using both osmium tetroxide–N-methyl-
morpholine N-oxide and osmium tetroxide in the presence
of quinine and quinidine ligands.10 In all cases the preferred
product was the (1ЈS,2ЈS)-diastereoisomer 11 with reasonable
stereoselectivity being obtained using osmium tetroxide–N-
methylmorpholine N-oxide, 11:12 = 82:18. This selectivity was
enhanced, 11:12 = 92:8, when matched with the quinine ligand
Results and discussion
The 4-formylazetidinone 6 was prepared following the liter-
ature procedure,8 and its conversion into the (Z)- and (E)-
alkenes 7 and 8 investigated. The (E)-alkene 8 was the major
product using (methoxycarbonylmethylene)triphenylphosphor-
ane in methanol at 0 ЊC and was the exclusive product with this
ylide or trimethyl phosphonoacetate and sodium hydride in
tetrahydrofuran. However, the (Z)-alkene 7 was prepared in
good yield using the bis(trifluoroethyl) phosphonate 99
although better results were obtained using potassium carb-
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094
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tBuMe2Si
OHC
O
tBuMe2Si
O
tBuMe2Si
O
OsO4
N
N
N
+
MeO2C
MeO2C
CO2Me
H
6
O
H
7
8
N
Isolated yields (%)
SiMe2But
Reagents and conditions
Ph3P᎐CHCO2Me in MeOH, 0 ЊC
(MeO)2P(O)CH2CO2Me, NaH in THF, 0 ЊC
9, K2CO3, 18-C-6, THF, 0 ЊC
7
8
Fig. 1 Preferred approach of osmium tetroxide to the alkene 7.
30
—
70
58
70
—
᎐
R
O
N
OHC
N3
tBuMe2Si
O
O
P
O
N
t
13 R = CH(CO2 Bu)P(O)(OEt)2
CF3CH2O
OMe
MeO2C
CF3CH2O
OsO4 H2O2
9
10
R
O
R
O
OH
N
OH
N
tBuMe2Si
O
+
OHC
N3
N
OHC
N3
OH
MeO2C
OH
75
: 25
14
15
7
8
OsO4 NMO
tBuMe2Si
OH
O
tBuMe2Si
OH
O
N
N
+
tBuMe2Si
OH
O
tBuMe2Si
OH
O
MeO2C
MeO2C
N
N
+
OH
OH
12
MeO2C
MeO2C
11
OH
16
OH
80
: 20
Combined
yields (%)
17
Ratio
Reagents and conditions
of 11 and 12
11:12
presence of a trace of toluene-p-sulfonic acid as catalyst, but
attempts to convert this into the corresponding carboxylic acid
20 were unsuccessful. Attempts at saponification of the ester,
e.g. by using lithium hydroxide in aqueous methanol or sodium
hydroxide in aqueous methanol–tetrahydrofuran, or attempts
to effect an SN2 type of displacement of the methyl ester using
lithium iodide or trimethylsilyl iodide all resulted in the form-
ation of very polar decomposition products.
1% OsO4, 25% dihydroquinine p-chloro-
benzoate, N-methylmorpholine N-oxide
Stoichiometric OsO4, dioxane
5% OsO4, N-methylmorpholine N-oxide,
acetone, water
1% OsO4, 25% dihydroquinidine p-chloro
benzoate, N-methylmorpholine N-oxide
80
92:8
86
71
83:17
82:18
80
75:25
and slightly reduced, but not overturned, 11:12 = 75:25, by the
presence of the mismatched quinidine ligand.
O
O
The structures assigned to the diols 11 and 12 were supported
by their spectroscopic data. The (1ЈS,2ЈS)-configuration was
assigned to the major product 11 by analogy with the reported
hydroxylation of the 4-alkenylazetidinone 13,11 which gave the
diols 14 and 15, ratio 75:25, and is consistent with the matching
and mismatching observed using the quinine and quinidine
ligands. The stereoselectivity is consistent with approach of
the osmium tetroxide on the less hindered face of the pre-
ferred conformation of the alkene as indicated in Fig. 1. Inter-
estingly reasonable stereoselectivity was also observed for
the hydroxylation of the (E)-alkene 8 using osmium tetroxide–
N-methylmorpholine N-oxide with the two diastereoisomeric
diols 16 and 17 being obtained in a ratio of 80:20. Structure
16 was assigned to the major product in this case also by
analogy with the reported stereoselectivity of hydroxylation
of 13.11
HN
OH HN
RO2C
MeO2C
O
O
OH
18
19 R = Me
20 R = H
The corresponding benzyl ester was prepared to avoid this
methyl ester cleavage. Bis(trifluoroethyl) phosphonate 21 was
prepared from phosphonic dichloride and 2,2,2-trifluoro-
ethanol,12 and was alkylated using benzyl bromoacetate to give
the benzyl bis(trifluoroethyl) phosphonoacetate 22. Condens-
ation with the aldehyde 6 was achieved using potassium
carbonate in the presence of 18-crown-6 and gave the (Z)-
benzyl ester 23 together with its (E)-isomer, ratio ca. 85:15,
respectively. Hydroxylation of the (Z)-ester 23 using a catalytic
amount of osmium tetroxide and N-methylmorpholine N-oxide
N-Desilylation of the diol 11 using an acidic Dowex ion
exchange resin gave 18 which was converted into the NH-
acetonide 19 using 2,2-dimethoxypropane and acetone in the
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O
P
O
heated together to give the amide 34 which was cyclised to the
i
oxazoline 35 by treatment with base, see Scheme 2.14 The oxazo-
line was then deprotonated using butyllithium and the lithiated
oxazoline added to Cbz-protected leucinal 2915 which had been
deprotonated using tert-butylmagnesium chloride. On work-up
of this reaction, a mixture of four products was obtained which
was believed to include the oxazolines 36 and 37 together with
the iminolactones 38 and 39 (combined yield 32%). Rather than
attempt to separate this mixture, it was hydrolysed by aqueous
hydrogen chloride to give a mixture of the lactones 40 and 41,
ratio 87:13, respectively, from which the major diastereoisomer
40 was isolated in a 62% yield (based on the mixture of 36–39).
The structures of the lactones 40 and 41 were consistent with
their spectroscopic data, and 40 was identified as the major
product on the basis of chelation control of the addition to the
Cbz-leucinal 29.4–6 Although the yields of products 36–39 from
the reaction between the oxazoline 35 and the Cbz-protected
leucinal 29 were only modest, it was decided to see whether
this procedure could be applied to synthesize the required
lactone 30.
(F3CCH2O)2P(O)H
F3CCH2O
OBn
F3CCH2O
21
22
ii
tBuMe2Si
tBuMe2Si
OH
O
O
iii
N
N
BnO2C
BnO2C
OH
24
23
+
tBuMe2Si
O
tBuMe2Si
OH
O
N
N
iv, v
RO2C
BnO2C
O
O
OH
2-Methoxy-6-methylbenzoic acid 4213 was converted into
its acid chloride which was treated with oxazolidin-2-one 33
followed by sodium hydroxide to give the N-hydroxyethyl amide
43 (Scheme 3). Treatment of this with thionyl chloride and then
with sodium hydroxide gave the oxazoline 45. Deprotonation of
this oxazoline using butyllithium followed by the addition of an
excess of methyl iodide gave an excellent yield of the methylated
product 46 so confirming the conditions required for efficient
oxazoline deprotonation.
25
26 R = Bn
27 R = H
Scheme 1 Reagents and conditions: i, NaH, BrCH2CO2Bn (45%); ii, 6,
K2CO3, 18-C-6 [76%; (Z):(E) = 85:15]; iii, OsO4 (cat.), NMO, acetone–
water (75%; 24:25 = 80:20); iv, Me2C(OMe)2, TsOH (cat.) (75%); v, H2
(1 atm), Pd/C, EtOH (97%).
gave the vicinal diols 24 and 25, ratio 80:20, and protection
using 2,2-dimethoxypropane followed by hydrogenolysis gave
an excellent yield of the required acid 27. In this sequence,
see Scheme 1, the stereoselectivity of the phosphonate conden-
sation was established by 1H NMR, and the facial selectivity in
the hydroxylation reaction was assigned by analogy with the
stereoselectivity of hydroxylation of the methyl ester 7 and by
comparison of the 1H NMR spectra of the diols 24 and 25 with
those of 11 and 12.
In other synthetic approaches to the AI-77’s, the 3,4-dihydro-
isocoumarin is usually obtained by chelation controlled add-
ition of a lithiated 2-alkoxy-6-methylbenzoate to a protected
leucinal.4–6 However in our hands, deprotonation of the ethyl
2-methoxy-6-methylbenzoate 2813 using lithium diisopropyl-
amide followed by addition of benzyloxycarbonyl protected
leucinal 29 gave variable yields of the lactones 30 and 31,
although the stereoselectivity was good, ca. 92:8, in favour of
the required stereoisomer 30.
Addition of the lithiated oxazoline to Cbz-leucinal 29 which
had been previously deprotonated using tert-butylmagnesium
chloride gave a mixture of products believed to include the
oxazolines 47 and 48 together with the iminolactones 49 and
50. This mixture was most conveniently converted into the
required lactones by treatment with a suspension of silica gel
in dichloromethane to give a mixture of the lactones 30 and
31 in a 44% yield from Cbz-leucinal 29, ratio 30:31 = 87:13.
The lactone 30 required for the synthesis of AI-77-B was
isolated as a single diastereoisomer in a yield of 30% from
Cbz-leucinal. Although the yields in this sequence were not
significantly better than those obtained by the direct addition
of the lithiated ester 28 to Cbz-leucinal 29, in our hands it was
a more reliable procedure and amenable to scaling up. The
optical purity of the lactone 30 was estimated to correspond
to an enantiomeric excess (ee) greater than 90% by com-
1
parison of its H NMR spectra in the presence of the shift
reagent 1-(9-anthryl)-2,2,2-trifluoroethanol 5116 with those of
material with low ee in which peaks due to both enantiomers
were clearly distinguished. At this point it was decided to
develop the conditions for the final stages of a synthesis of
AI-77-B by attempting a synthesis of its phenolic methyl
ether.
O
OMe
NHCbz
CO2Et
H
+
Hydrogenolysis of the benzyloxycarbonyl protected amino-
lactone 30 was carried out under acidic conditions to avoid
rearrangement to the corresponding hydroxylactam, and gave
the amino-lactone hydrochloride salt 52 (Scheme 4). Using
dicyclohexylcarbodiimide and 4-dimethylaminopyridine, this
was coupled with isobutyric acid to give the amide 53 so
establishing conditions for amide formation. The hydrochloride
salt 52 was then coupled with the acid 27 to give the protected
dipeptide 54. To get a consistent yield (65%) for this reaction
it was necessary to use redistilled dicyclohexylcarbodiimide
and recrystallized 4-dimethylaminopyridine. Other coupling
procedures, e.g. using mixed anhyrides, were less successful in
our hands. Deprotection under acidic conditions followed by a
sodium bicarbonate work-up gave a product identified as the
dihydroxyalkylazetidinone 55 rather than the amine corre-
sponding to the hydrochloride salt 56 on the basis of two differ-
28
29
LDA
OMe
O
OMe O
O
O
H
+
NHCbz
NHCbz
H
30
31
It was decided to study the addition of heterocyclic synthetic
equivalents of the ester 28 to protected leucinal to see whether a
more reliable procedure could be obtained. To evaluate this
possibility, o-toluoyl chloride 32 and oxazolidin-2-one 33 were
1
ent NH-protons evident in its H NMR spectrum in dimethyl
sulfoxide-d6. Treatment of the azetidinone 55 with sodium
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094
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O
O
N
O
Cl
N
H
O
Cl
i
ii
+
HN
O
34
32
33
35
iii
N
N
O
O
HO
HO
+
NHCbz
NHCbz
O
O
36
37
O
iv
O
H
+
NHCbz
+
NHCbz
OH
OH
N
H
N
O
H
O
40
NHCbz
41
+
NHCbz
H
38
39
Scheme 2 Reagents and conditions: i, heat to 140 ЊC; ii, NaOH, EtOH (59% from 31); iii, BuLi, 29ؒMgCl (32%); iv, aq. HCl then sat. aq. NaHCO3
(77%; 40:41 = 87:13; isolated yield of 40, 62%).
MeO
N
MeO
N
MeO
O
MeO
O
iv
iii
O
i, ii
X
O
OH
N
H
45
46
42
43 X = OH
44 X = Cl
v
MeO
N
MeO
N
O
O
HO
HO
+
NHCbz
NHCbz
47
48
vi
+
30
+
31
OH
OH
MeO
N
MeO
N
O
H
O
NHCbz
+
NHCbz
H
49
50
Scheme 3 Reagents and conditions: i, thionyl chloride then 33, 65 ЊC followed by NaOH, EtOH; ii, thionyl chloride, heat under reflux 1.5 h; iii,
NaOH, EtOH, heat under reflux 1.5 h (65% of 45 based on acid 42); iv, BuLi, Ϫ78 ЊC, 30 min, then MeI (96%); v, BuLi, 29ؒMgCl; vi, silica gel,
CH2Cl2 (44% of 30 and 31 based on 45; 30:31 = 87:13; 30% of 30 isolated as a single diastereoisomer).
hydroxide followed by acidic methanol then gave the amino-
lactone hydrochloride salt 56. The structure of this bis-lactone
was consistent with its spectroscopic data including an absorb-
ance in its IR spectrum at 1788 cmϪ1 which agrees with that
reported for amicoumacin C 57.3 Presumably in this conversion
of the azetidinone 55 into the bis-lactone 56, both the δ-lactone
and the azetidinone are being cleaved by the sodium hydroxide
with bis-lactonisation occurring on treatment with acid. No
attempt was made to open the azetidinone selectively. It
remained to hydrolyse selectively the γ-lactone ring of the
bis-lactone 56 in the presence of the δ-lactone. Following the
literature procedure,2 this was achieved by treatment with
sodium hydroxide at pH 9 followed by careful acidification, and
gave AI-77-B methyl ether 58 in a yield of 70% based on the
dihydroxyalkylazetidinone 55. The spectroscopic data of the
synthetic methyl ether 58 agreed fully with those reported for
material prepared from natural AI-77-B.2
Cleavage of the methyl ether of the amido-lactone 30 was
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J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094

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achieved by rapid treatment at low temperature with boron tri-
bromide17 and gave the corresponding phenol 59 (Scheme 5).
Hydrogenolysis under acidic conditions gave the amine
hydrochloride 60 which was coupled with the acid 27 using
dicyclohexylcarbodiimide to give the amide 61. The sequence
developed for the synthesis of AI-77-B methyl ether 58 was then
used to convert the azetidinone 61 through to AI-77-B 1. Thus
hydrolysis under acidic conditions gave the dihydroxyalkyl-
azetidinone 62. This azetidinone 62 was converted into the
amino-lactone hydrochloride 573 by treatment with sodium
hydroxide and then with methanolic hydrogen chloride. Further
treatment with sodium hydroxide followed by mild acidification
finally gave synthetic AI-77-B 1.
CF3
H
OH
51
30
i
MeO
O
MeO
O
The structure of the synthetic AI-77-B 1 was confirmed by
1
O
H
direct comparison of its H and 13C NMR, IR, UV and MS
O
H
H
N
ii
data with those of an authentic sample of the natural product.
The only discrepancies between our data and those reported for
the natural product were the coupling constants reported for
the diastereotopic protons at C(5) and the proton at C(4). In
our spectra of the synthetic AI-77-B and the sample of the
natural product, which were the same within experimental error
in both methanol-d4 and in dimethyl sulfoxide-d6, the higher
field H(5) had the larger coupling to H(4) (ca. 10 Hz) whereas in
the spectrum reported1 for AI-77-B 1 in dimethyl sulfoxide-d6,
it is the lower field H(5) which has the larger coupling to H(4) (9
Hz).
The chemical shift of H-4 of the synthetic amino-lactone
hydrochloride 57, which is itself a natural product, amicou-
macin C,3 was also different from that reported for material
prepared from AI-77-B (δ 4.18 cf. δ 3.72).2 However, its IR
spectrum is identical to that reproduced3 for amicoumacin C,
and treatment of natural AI-77-B with acidic methanol gave
amino-lactone hydrochloride 57 which was identical to that
obtained from rearrangement of the dihydroxyazetidinone 62.
Treatment of this hydrochloride with sodium carbonate gave
the free amino-lactone 63 which had spectra identical to those
reported2 for the amino-lactone hydrochloride 57 and which,
on reprotonation with methanolic hydrogen chloride, regener-
ated the amino-lactone hydrochloride 57. It would appear that
the published data for the amino-lactone hydrochloride 57 may
well refer to the free amino-lactone 63.
NH3Cl
O
52
53
iii
MeO
O
tBuMe2Si
O
O
O
H
N
H
N
O
O
54
iv
MeO
O
H
O
O
H
N
OH
N
H
O
OH
55
Summary and conclusions
v
This work describes a stereoselective synthesis of the anti-ulcer
compound AI-77-B 1. Of interest is the stereoselectivity of the
hydroxylation of the (E)- and (Z)-4-alkenylazetidinones 8 and
7/23, and the use of the oxazolines 35 and 45 in the syntheses
of the 1H-2-benzopyran-1-ones 30/31 and 40/41. This work
provides additional access to AI-77’s and related dipeptides and
may be useful for the synthesis of analogues.
RO
O
O
H
N
OH
NH3Cl
H
O
O
O
Experimental
56 R = Me
57 R = H
1H NMR spectra were recorded on Varian Unity 500, Bruker
AC 300, Varian XL 300, JEOL GX 270 and Varian Gemini 200
spectrometers in chloroform-d1 unless otherwise stated. 13C
NMR spectra were recorded on a Bruker AC 300 spectrometer
operating at 75 MHz. J Values are given in Hz. IR spectra were
recorded on a Perkin-Elmer 1710FT spectrometer as liquid
films unless otherwise stated. Mass spectra were recorded on a
Kratos MS25 mass spectrometer using electron impact (EI),
chemical ionisation (CI) and fast atom bombardment (FAB)
ionisation. Ultraviolet spectra were recorded on a Shimadzu
UV260 spectrometer. Melting points were determined on a
Kofler Block apparatus and are uncorrected. Optical rotations
were recorded on an Optical Activity AA100 polarimeter and
are given in units of 10Ϫ1 deg cm2 gϪ1. Flash column chrom-
atography was carried out using Merck silica gel 60H (40–63 µ,
230–300 mesh) or May and Baker Sorbsil C60 (40–60 µ) silica
vi
MeO
O
+
O
H
N
OH
NH3
–
CO2
H
O
OH
58
Scheme 4 Reagents and conditions: i, H2, Pd/C, HCl, EtOH (100%); ii,
PriCO2H, DCC, DMAP, CH2Cl2 (70%); iii, 27, DCC, DMAP (65%);
iv, 1:1 aq. HCl (3 M)–THF (82%); v, NaOH, pH 12 then HCl, MeOH;
vi, NaOH, pH 9 then aq. HCl, pH 6.5 (70% from 55).
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OH
O
OH
O
OH
O
tBuMe2Si
O
O
O
H
i
O
H
O
H
N
H
ii
iii
30
NHCbz
NH3Cl
N
O
O
59
60
61
iv
OH
O
OH
O
OH
O
H
O
+
O
H
N
OH
NH3
vi
O
H
OH
NH3Cl
O
H
H
N
OH
N
v
–
CO2
N
vii
4
4
H
5
H
O
OH
O
O
O
OH
O
1
62
57
viii
ix
OH
O
O
H
H
OH
NH2
N
O
O
O
63
Scheme 5 Reagents and conditions: i, BBr3, CH2Cl2, Ϫ78 ЊC, 3 min (72%); ii, H2, Pd/C, EtOH (95%); iii, 27, DCC, DMAP, CH2Cl2 (54%); iv, 1:1 aq.
HCl (3 M)–THF (74%); v, NaOH, pH 12 then HCl, MeOH; vi, NaOH, pH 9 then HCl, MeOH, pH 6.5 (72% from 62); vii, HCl, MeOH; viii, aq.
Na2CO3 (40%); ix, HCl, MeOH.
gel as the stationary phase. Light petroleum refers to the
fraction boiling between 40 and 60 ЊC and was redistilled before
use. All reagents and solvents were purified and/or dried by
standard procedures.
acetate (6:1 to 2:1) as eluent gave (4S)-1-tert-butyldimeth-
ylsilyl-4-(2-methoxycarbonylethyl)azetidin-2-one 10 (270 mg,
100%), [α]D20 Ϫ51.8 (c 0.7, CHCl3); νmax/cmϪ1 1740, 1322, 1302,
1255, 1192, 841 and 824; δH 0.25 and 0.27 (each 3 H, s,
SiCH3), 0.97 [9 H, s, SiC(CH3)3], 1.71 (1 H, m, 1Ј-H), 2.29
(3 H, m, 1Ј-HЈ, 2Ј-H2), 2.59 (1 H, dd, J 15, 3, 3-H), 3.13
(1 H, dd, J 15, 6, 3-HЈ), 3.57 (1 H, m, 4-H), 3.70 (3 H, s,
CO2CH3); m/z (CI) 273 (30%), 272 (Mϩ ϩ 1, 100), 230 (50) and
214 (35).
(4S,1ЈZ)-1-tert-Butyldimethylsilyl-4-(2-methoxycarbonyl-
ethenyl)azetidin-2-one 7
A slurry of finely-ground potassium carbonate (643 mg, 4.66
mmol) and 18-crown-6 (2.36 g, 8.94 mmol) in dry toluene
(5 cm3) was stirred at room temperature for 24 h then cooled to
Ϫ25 ЊC and a solution of the 4-formylazetidinone 68 (500 mg,
2.35 mmol) and the bis(trifluoroethyl) phosphonate 9 (795 mg,
25 mmol) in toluene (5 cm3) was added. The mixture was
allowed to warm to 0 ЊC and was stirred for 1 h. Saturated
aqueous ammonium chloride (10 cm3) was added and the mix-
ture extracted with ether. The combined organic extracts were
washed with water and brine, dried (MgSO4) and concentrated
under reduced pressure. Chromatography using light
petroleum–ethyl acetate (3:1) as eluent gave the title compound
7 (442 mg, 70%), [α]D20 Ϫ48 (c 1, CHCl3); νmax/cmϪ1 1750, 1720,
1645, 1465, 1438, 1410, 1285, 1252, 1200, 1180, 990, 837 and
820; δH 0.15 and 0.21 (each 3 H, s, SiCH3), 0.96 [9 H, s,
SiC(CH3)3], 2.72 (1 H, dd, J 15, 3, 3-H), 3.47 (1 H, dd, J 15, 6,
3-HЈ), 3.72 (3 H, s, CO2CH3), 5.2 (1 H, m, 4-H), 5.90 (1 H, dd,
J 11.5, 1, 2Ј-H) and 6.25 (1 H, dd, J 11.5, 9, 1Ј-H); m/z (CI) 270
(Mϩ ϩ 1, 100%).
(4S,1ЈE)-1-tert-Butyldimethylsilyl-4-(2-methoxycarbonyl-
ethenyl)azetidin-2-one 8
Trimethyl phosphonoacetate (0.21 cm3, 1.29 mmol) in tetra-
hydrofuran (3 cm3) was added dropwise to a suspension of
sodium hydride (60% dispersion in mineral oil; 51.5 mg, 1.29
mmol) in tetrahydrofuran (5 cm3) at 0 ЊC. The mixture was
allowed to warm to room temperature and was stirred for 15
min. A solution of the formylazetidinone 6 (250 mg, 1.17
mmol) in tetrahydrofuran (5 cm3) was added dropwise and the
mixture stirred for a further 18 h. Saturated aqueous ammo-
nium chloride (10 cm3) was added and the mixture was
partitioned between water and ether. The aqueous layer was
extracted with ether, and the combined organic extracts were
washed with water then brine, dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ethyl acetate (3:1) as eluent gave the title com-
pound 8 (220 mg, 70%) as a colourless oil, [α]D20 Ϫ78 (c 0.5,
CHCl3) (Found: Mϩ, 269.1445. Cl3H23NO3Si requires M,
269.1447); νmax/cmϪ1 1735, 1660, 1465, 1435, 1355, 1295, 1180,
985, 841 and 770; δH 0.15 and 0.23 (each 3 H, s, SiCH3), 0.95
[9 H, s, SiC(CH3)3], 2.83 (1 H, dd, J 15, 2, 3-H), 3.37 (1 H, dd,
J 15, 5, 3-H), 3.76 (3 H, s, OCH3), 4.12 (1 H, m, 4-H), 6.01 (1 H,
The (Z)-4-alkenylazetidinone 7 (269 mg, 1 mmol) was dis-
solved in ethyl acetate (20 cm3), palladium (10% on charcoal; 21
mg, 0.02 mmol) was added and the mixture stirred under an
atmosphere of hydrogen (14 bar) for 16 h. The catalyst was
filtered off and the filtrate concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl
1088
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094

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d, J 16, 2Ј-H) and 6.90 (1 H, dd, J 16, 9, 1Ј-H); m/z (CI) 270
(Mϩ ϩ 1, 100%).
Hydrogenation of the (E)-alkene 8 gave (4S)-1-tert-butyl-
dimethylsilyl-4-(2-methoxycarbonylethyl)azetidin-2-one 10 in
quantitative yield.
2.59 (2 H, br s, 2 × OH), 3.03 (1 H, dd, J 16, 5, 3-H), 3.18 (1 H,
dd, J 16, 3, 3-HЈ), 3.77 (1 H, m, 4-H), 3.85 (3 H, s, OCH3) and
4.19 (2 H, m, 1Ј-H and 2Ј-H); m/z (CI) 306 (12%), 305 (40) and
304 (Mϩ ϩ 1, 100); and the (1ЈR,2ЈS)-isomer of the title com-
pound 17 (9 mg, 14%), mp 118–120 ЊC (Found: Mϩ ϩ H,
304.1586. C13H26NO5Si requires M, 304.1580); νmax/cmϪ1 3338,
1756, 1708, 1279, 1252, 1199, 1123, 1065 and 843; δH 0.27 (6 H,
s, 2 × SiCH3), 1.00 [9 H, s, SiC(CH3)3], 1.67 and 2.33 (each 1 H,
br s, 2 × OH), 2.80 (1 H, dd, J 15, 3, 3-H), 3.17 (1 H, dd, J 15, 5,
3-HЈ), 3.74 (1 H, m, 4-H), 3.87 (3 H, s, OCH3) and 3.92 and 4.22
(each 1 H, m, 1Ј-H and 2Ј-H); m/z (CI) 305 (22%) and 304
(Mϩ ϩ 1, 100).
(1ЈS,2ЈS,4S- and 1ЈR,2ЈR,4S)-1-tert-Butyldimethylsilyl-4-(1,2-
dihydroxy-2-methoxycarbonylethyl)azetidin-2-ones 11 and 12
N-Methylmorpholine N-oxide monohydrate (818 mg, 5.97
mmol) was added to the (Z)-4-alkenylazetidinone 7 (1.07 g,
3.98 mmol) in acetone (85 cm3) followed by a solution of
osmium tetroxide (51 mg, 0.2 mmol) in water (34 cm3). The
reaction vessel was sealed under argon and the flask shaken
for four days in the dark, the progress of the reaction being
monitored by TLC. Aqueous sodium bisulfite was added and
the mixture stirred overnight then filtered. The filtrate was
extracted with chloroform (5 × 50 cm3) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (2:1) as eluent gave the title compounds
11 and 12 (857 mg, 71%), ratio 11:12 = 82:18. Repeated
chromatography using chloroform–methanol (250:1→50:1)
as eluent separated the diastereoisomers to give the (1ЈR,2ЈR)-
isomer of the title compound 12 (146 mg, 12%), [α]D20 Ϫ45.5
(c 0.4, CHCl3) (Found: C, 51.7; H, 8.4; N, 4.5. C13H25NO5Si
requires C, 51.45; H, 8.3; N, 4.6%); νmax/cmϪ1 3350 and 1730;
δH 0.27 and 0.29 (each 3 H, s, SiCH3), 0.99 [9 H, s, SiC(CH3)3],
2.60 (2 H, br s, 2 × OH), 2.68 (1 H, dd, J 15, 3, 3-H), 3.12 (1 H,
dd, J 15, 5, 3-HЈ), 3.7 (1 H, ddd, J 7, 5, 3, 4-H), 3.8 (1 H, dd,
J 7.3, 1Ј-H), 3.86 (3 H, s, CO2CH3) and 4.25 (1 H, d, J 3, 2Ј-H);
m/z (CI) 305 (25%), 304 (Mϩ ϩ 1, 100). The more polar product
was the (1ЈS,2ЈS)-isomer of the title compound 11 (693 mg,
57%), mp 94–95 ЊC, [α]D20 Ϫ59 (c 0.25, CHCl3); νmax/cmϪ1 (KBr
disc) 3540, 3500, 3380, 1740, 1705, 1650, 1465, 1440, 1345,
1255, 1215, 1195, 1100, 1055, 1005, 960, 845 and 822; δH 0.26
(6 H, s, 2 × SiCH3), 0.98 [9 H, s, SiC(CH3)3], 2.47 (1 H, d, J 4.5,
OH), 2.94 (1 H, dd, J 15, 5, 3-H), 2.95 (1 H, d, J 5, OH), 3.13
(1 H, dd, J 15, 3, 3-HЈ), 3.78 (1 H, m, 4-H), 3.86 (3 H, s,
CO2CH3), 4.12 (1 H, t, J 4.5, 1Ј-H) and 4.20 (1 H, t, J 4.5, 2Ј-H);
m/z (CI) 305 (24%) and 304 (Mϩ ϩ 1, 100).
Dowex was freshly acidified with aqueous hydrogen chloride
(10 M) and washed with water and methanol. The acidified
Dowex resin (5 g) was added to a solution of the N-silyl-
azetidinone 11 (306 mg, 1.01 mmol) in methanol (25 cm3) and
the mixture stirred at room temperature until the reaction
was complete as indicated by TLC. The mixture was filtered
and the filtrate concentrated under reduced pressure. Chrom-
atography of the residue using chloroform–methanol as eluent
gave (1ЈS,2ЈS,4S)-4-(1,2-dihydroxy-2-methoxycarbonylethyl)-
azetidin-2-one 18 (183 mg, 96%), [α]D20 Ϫ8.0 (c 0.2, MeOH);
νmax/cmϪ1 3300 and 1730; δH (D2O shake) 2.71 (1 H, dd, J 15, 2,
3-H), 2.89 (1 H, dd, J 15, 5, 3-HЈ), 3.64 (3 H, s, CO2CH3), 3.73
(1 H, td, J 5, 2, 4-H), 3.78 (1 H, m, NH), 3.87 (1 H, t, J 5, 1Ј-H)
and 4.20 (1 H, d, J 5, 2Ј-H); m/z (CI) 191 (13%) and 190
(Mϩ ϩ 1, 100).
Benzyl [bis(2,2,2-trifluoroethyl)phosphono]acetate 22
A solution of tert-butyl alcohol (1.85 g, 25 mmol) in dichloro-
methane (5 cm3) was added slowly to a solution of phosphorus
trichloride (2.18 cm3, 25 mmol) in dichloromethane (5 cm3) and
the mixture stirred at 0 ЊC for 30 min. 2,2,2-Trifluoroethanol
(5.0 g, 50 mmol) in dichloromethane (5 cm3) was added over
a 10 min period and the mixture allowed to warm to room
temperature and stirred for 18 h. The solvent was removed by
distillation at atmospheric pressure and the product purified by
distillation through a Vigreux column to give the bis(2,2,2-
trifluoroethyl) phosphonate 21 (4.43 g, 72%); νmax/cmϪ1 2485,
1250, 1150 and 1080; δH 2.32 [1 H, s, P(O)H] and 4.42 (4 H, dq,
J 11, 8, 2 × CF3CH2O).
Benzene (30 cm3) was added to sodium hydride (0.79 g of
60% w/w suspension in mineral oil, 19.8 mmol) which had been
washed with light petroleum (3 × 20 cm3) followed by bis(tri-
fluoroethyl) phosphonate (4.43 g, 18.0 mmol) in benzene (20
cm3). The mixture was stirred for 30 min at room temperature
while hydrogen gas was evolved. The reaction vessel was cooled
to 5 ЊC and benzyl bromoacetate (4.53 g, 19.8 mmol) in tetra-
hydrofuran (20 cm3) was added slowly. The mixture was allowed
to warm to room temperature and stirred for 48 h before etha-
nol (5 cm3), water (100 cm3) and ether (100 cm3) were added.
The aqueous layer was extracted with ether and the ethereal
extracts washed with water and brine and dried (MgSO4). After
concentration under reduced pressure, chromatography of the
residue using light petroleum–ethyl acetate as eluent (2:1) gave
the title compound 22 (3.18 g, 45%) (Found: Mϩ, 394.0412.
C13H13O5PF6 requires M, 394.0405); νmax/cmϪ1 3478, 3037,
1740, 1457, 1420, 1378, 1268, 1173, 1073 and 964; δH 3.20 (2 H,
d, J 21, PCH2), 4.38 (4 H, dq, J 7, 6, 2 × CF3CH2), 5.20 (2 H, s,
CH2Ph) and 7.36 (5 H, br s, ArH); m/z (CI) 412 (Mϩ ϩ 18,
100%).
(4S,1ЈZ)-1-tert-Butyldimethylsilyl-4-(2-benzyloxycarbonyl-
ethenyl)azetidin-2-one 23
A slurry of finely-ground potassium carbonate (518 mg, 3.75
mmol) and 18-crown-6 (1.98 g, 7.50 mmol) in toluene (3 cm3)
was stirred at room temperature for 24 h. The mixture was then
cooled to Ϫ25 ЊC and a solution of the 4-formylazetidinone 6
(399 mg, 1.87 mmol) and the benzyl phosphonate 22 in toluene
(4 cm3) was added. The mixture was allowed to warm to 0 ЊC
and was stirred for a further 60 min. Saturated aqueous
ammonium chloride (10 cm3) was added and the mixture
extracted with ether. The combined organic extracts were
washed with water and brine, dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ethyl acetate (3:1) as eluent gave the title
compound 23 (419 mg, 65%) (Found: Mϩ ϩ H, 346.1836.
C19H28NO3Si requires M, 346.1838); νmax/cmϪ1 1749, 1720,
1646, 1417, 1285, 1255, 1186, 1083, 968 and 754; δH 0.15 and
0.21 (each 3 H, s, SiCH3), 0.94 [9 H, s, SiC(CH3)3], 2.62 (1 H, dd,
J 15, 3, 3-H), 3.45 (1 H, dd, J 15, 5, 3-HЈ), 5.18 (2 H, s, CH2Ph),
5.27 (1 H, m, 4-H), 5.93 (1 H, dd, J 11.5, 1, 2Ј-H), 6.28 (1 H, dd,
J 11, 9, 1Ј-H), 7.8 (5 H, m, ArH); m/z 346 (Mϩ ϩ 1, 54%) and
206 (100).
(4S)-1-tert-Butyldimethylsilyl-4-(1,2-dihydroxy-2-methoxy-
carbonylethyl)azetidin-2- ones 16 and 17
Following the procedure outlined for the synthesis of the diols
11 and 12, N-methylmorpholine N-oxide (36 mg, 0.308 mmol),
osmium tetroxide (5 mg, 0.02 mmol) in water (0.3 cm3) and the
(E)-alkene 8 (56 mg, 0.208 mmol) in acetone (2 cm3) gave, after
shaking for three days and chromatography using methanol
(4%) in chloroform, the diols 16 and 17 (48 mg, 76%). Further
chromatography using methanol (2%) in chloroform separated
the two isomers to give the (1ЈS,2ЈR)-isomer of the title
compound 16 (34 mg, 54%) as a white solid, mp 78–80 ЊC
(Found: Mϩ ϩ H, 304.1569. C13H26NO5Si requires M,
304.1580); νmax/cmϪ1 3387, 1735, 1718, 1256, 1138, 841 and 826;
δH 0.24 and 0.27 (each 3 H, s, SiCH3), 0.96 [9 H, s, SiC(CH3)3],
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094
1089

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(1ЈS,2ЈS,4S- and 1ЈR,2ЈR,4S)-1-tert-Butyldimethylsilyl-4-(1,2-
dihydroxy-2-benzyloxycarbonylethyl)azetidin-2-ones 24 and 25
line was added by cannula to the solution of the deprotonated
aldehyde and the mixture stirred for 1 h. Saturated aqueous
ammonium chloride was added and the mixture allowed to
warm to room temperature and extracted with chloroform. The
organic extracts were washed with water and brine, dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography using light petroleum–ethyl acetate (1:1) as eluent
gave a mixture of the oxazolines 36 and 37 together with the
imino esters 38 and 39 (155 mg).
Following the procedure outlined for the preparation of diols
11 and 12, N-methylmorpholine N-oxide monohydrate (176
mg, 1.52 mmol), osmium tetroxide (21 mg, 0.09 mmol) in water
(5 cm3) and the (Z)-alkene 23 (350 mg, 1.01 mmol) in acetone
(4 cm3) gave, after shaking in the dark for three days at room
temperature and chromatography using methanol (1%) in
chloroform as eluent, the (1ЈR,2ЈR)-isomer of the title com-
pound 25 (58 mg, 15%); δH 0.20 and 0.23 (each 3 H, s, SiCH3),
0.93 [9 H, s, SiC(CH3)3], 2.62 (1 H, dd, J 15, 3, 3-H), 2.82 (1 H,
br s, OH), 3.03 (1 H, dd, J 15, 5, 3-HЈ), 3.45 (1 H, br s, OH),
3.62 (1 H, m, 4-H), 3.79 (1 H, dd, J 10, 2, 1Ј-H), 4.25 (1 H, d,
J 2, 2Ј-H), 5.24 and 5.26 (each 1 H, d, J 10, HCHPh) and 7.37
(5 H, m, ArH); followed by the more polar (1ЈS,2ЈS)-isomer of
the title compound 24 (218 mg, 58%) (Found: Mϩ ϩ H,
380.1894. C19H30NO5Si requires M, 380.1893); δH 0.19 (6 H, s,
2 × SiCH3), 0.93 [9 H, s, SiC(CH3)3], 2.86 (1 H, dd, J 17, 6,
3-H), 3.09 (1 H, dd, J 17, 3, 3-HЈ), 3.7 (1 H, m, 4-H), 4.09 (1 H,
dd, J 4.5, 2, 1Ј-H), 4.22 (1 H, d, J 4.5, 2Ј-H), 5.25 and 5.27 (each
1 H, d, J 10, HCHPh) and 7.38 (5 H, m, ArH); m/z (CI) 380
(Mϩ ϩ 1, 100%).
Aqueous hydrogen chloride (3.5 M; 2 cm3) was added drop-
wise to a solution of a mixture of the oxazolines 36 and 37 and
the imino esters 38 and 39 (70 mg) in tetrahydrofuran (6 cm3)
and the mixture stirred for 18 h. Saturated aqueous sodium
bicarbonate was added and the mixture extracted with dichlo-
romethane. The organic extracts were washed with water and
brine, dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using light petroleum–ethyl
acetate (4:1) as eluent gave a mixture of the diastereoisomeric
lactones 40 and 41 (48 mg, 77%), ratio 40:41 = 7:1. Further
chromatography gave the (3S)-isomer of the title compound 40
(39 mg, 62%) (Found: Mϩ, 367.1784. C22H25NO4 requires M,
367.1783); νmax/cmϪ1 3324, 1723, 1606, 1534, 1460, 1231, 1119,
1087, 1031, 743 and 697; δH 0.95 and 0.97 (each 3 H, d, J 6,
3Ј-CH3 and 4Ј-H3), 1.46 (1 H, m, 2Ј-H), 1.75 (2 H, m, 2Ј-HЈ and
3Ј-H), 2.84 (1 H, dd, 15, 2, 4-H), 3.18 (1 H, dd, J 15, 12, 4-HЈ),
4.08 (1 H, m, 1Ј-H), 4.54 (1 H, m, 3-H), 5.00 (1 H, br d, J 9,
NH), 5.13 (2 H, s, CH2Ph), 7.24–7.42 (7 H, m, ArH), 7.53 (1 H,
t, J 7, ArH) and 8.07 (1 H, d, J 7, ArH); m/z (CI) 385 (Mϩ ϩ 18,
74%), 369 (72), 368 (Mϩ ϩ 1, 98), 334 (82), 277 (95), 260 (70)
and 234 (100). The minor product was identified as the (3R)-
isomer of the title compound 41; δH (C6D6) 0.88 and 0.98 (each
3 H, d, J 7, 3Ј-CH3 and 4Ј-H3), 1.04 (1 H, m, 2Ј-H), 1.47–1.62
(2 H, m, 2Ј-HЈ and 3Ј-H), 2.02 (1 H, dd, J 16, 3, 4-H), 2.43 (1 H,
dd, J 15, 12, 4-HЈ), 3.76 (1 H, m, 3-H), 3.94 (1 H, m, 1Ј-H), 4.51
(1 H, br d, J 11, N-H), 5.12 and 5.19 (each 1 H, d, J 12,
HCHPh), 6.67 (1 H, d, J 7, ArH), 6.94–7.33 (7 H, m, ArH) and
8.26 (1 H, d, J 7, ArH).
(1ЈS,2ЈS,4S)-1-tert-Butyldimethylsilyl-4-[1,2-(dimethylmethyl-
enedioxy)-2-benzyloxycarbonylethyl]azetidin-2-one 26
The diol 24 (283 mg, 0.75 mmol) was added to stirred solution
of dimethoxypropane (5 cm3) in chloroform (12 cm3), toluene-
p-sulfonic acid (10 mg, 0.05 mmol) was added and the mixture
stirred for 18 h. Saturated aqueous sodium bicarbonate was
added and the aqueous layer extracted with dichloromethane.
The organic extracts were washed with water and brine, dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography of the residue using light petroleum–ethyl acetate
(5:1) as eluent gave the title compound 26 (252 mg, 76%), as a
white solid, mp 93–95 ЊC (Found: C, 63.2; H, 8.1; N, 3.1;
Mϩ ϩ H, 420.2203. C22H33NO5Si requires: C, 63.0; H, 7.95; N,
3.35%; C22H34NO5Si requires M, 420.2206); νmax/cmϪ1 1739,
1473, 1382, 1255, 1213, 1095, 991 and 775; δH 0.22 and 0.24
(3 H, s, SiCH3), 0.93 [9 H, s, SiC(CH3)3], 1.37 and 1.59 (each
3 H, s, CH3), 2.45 (1 H, dd, J 15, 5, 3-H), 2.89 (1 H, dd,
J 15, 3, 3-HЈ), 3.71 (1 H, m, 4-H), 4.57 (1 H, dd, J 7, 1, 1Ј-H),
4.67 (1 H, d, J 7, 2Ј-H), 5.13 and 5.17 (each 1 H, d, J 14,
HCHPh) and 7.49 (5 H, m, ArH); m/z (CI) 421 (31%) and 420
(Mϩ ϩ 1, 100).
Palladium on activated charcoal (10% Pd; 13 mg, 0.01 mmol)
was added to a solution of the benzyl ester 26 (50 mg, 0.12
mmol) in ethanol (2 cm3) and the mixture stirred under an
atmosphere of hydrogen for 18 h. Chloroform (5 cm3) was
added and the mixture filtered through Celite and concentrated
under reduced pressure to give (1ЈS,2ЈS,4S)-1-tert-butyldi-
methylsilyl-4-[1,2-(dimethylmethylenedioxy)-2-carboxyethyl]-
azetidin-2-one 27 (36.5 mg, 95%) used without further purifi-
cation; νmax/cmϪ1 3939, 1724, 1640, 1464, 1382, 1316, 1256, 1212
and 1165; δH 0.25 and 0.27 (3 H, s, SiCH3), 0.98 [9 H, s,
SiC(CH3)3], 1.41 and 1.65 (each 3 H, s, CH3), 2.88 (1 H, dd, J 15,
5, 3-H), 2.99 (1 H, dd, J 15, 2, 3-HЈ), 4.00 (1 H, m, 4-H), 4.24
(1 H, br s, OH) and 4.68 (2 H, m, 2Ј-H and 3Ј-H); m/z (CI) 331
(11%), 330 (Mϩ ϩ 1, 52), 233 (6) and 216 (8).
N-(2-Hydroxyethyl)-2-methoxy-6-methylbenzamide 43
A solution of 2-methoxy-6-methylbenzoic acid 4213 (5.5 g, 33.1
mmol) in thionyl chloride (22 cm3) was stirred and heated under
reflux for 50 min, then allowed to cool to room temperature.
The excess of thionyl chloride was removed under reduced
pressure. Oxazolidin-2-one 33 (2.88 g, 33.1 mmol) was added
and the mixture was stirred and heated to 65 ЊC for 2 h. The
mixture was allowed to cool to room temperature and aqueous
sodium hydroxide (10%; 35 cm3) and ethanol (35 cm3) were
added. The mixture was heated under reflux for 2 h then
allowed to cool to room temperature and acidified to pH 5 by
addition of dilute aqueous hydrogen chloride. The mixture was
extracted with dichloromethane, and the organic extracts
washed with water and brine, dried (MgSO4) and concentrated
under reduced pressure to give the hydroxyethyl benzamide 43
(6.34 g). Chromatography of a sample using ethyl acetate–light
petroleum (2:1) as eluent gave the title compound 43 as a
white solid, mp 105–106 ЊC (Found: C, 62.9; H, 7.1; N, 6.7.
C11H15NO3 requires C, 63.1; H, 7.2; N, 6.7%); νmax/cmϪ1 3440,
3325, 1631, 1601, 1585, 1545, 1472, 1264, 1082 and 787; δH 2.25
(3 H, s, ArCH3), 3.46 (2 H, m, CH2), 3.67 (2 H, t, J 5, CH2), 3.76
(3 H, s, OCH3), 6.58 (1 H, br s, NH), 6.70 and 6.75 (each 1 H, d,
J 7, ArH), 7.18 (1 H, t, J 7, ArH); m/z (CI) 210 (Mϩ ϩ 1, 100%)
and 149 (36).
(3S- and 3R)-[(1S)-1-Benzyloxycarbonylamino-3-methylbutyl]-
3,4-dihydro-1H-2-benzopyran-1-ones 40 and 41
Butyllithium (1.6 M in hexanes; 0.73 cm3, 1.17 mmol) was
added to a solution of the oxazoline 3514 (188 mg, 1.17 mmol)
in tetrahydrofuran (7 cm3) at Ϫ78 ЊC and this solution stirred
for 30 min. Ethereal tert-butylmagnesium chloride (2 M; 0.59
cm3, 1.17 mmol) was added to a solution of Cbz-leucinal 29
(291 mg, 1.17 mmol) in tetrahydrofuran (8 cm3) at Ϫ78 ЊC and
the solution stirred for 3 min. The solution of lithiated oxazo-
4,5-Dihydro-2-(2-methoxy-6-methylphenyl)oxazole 45
Thionyl chloride (17 cm3) was added to the crude hydroxyethyl
amide 43 (6.34 g) and the mixture stirred under reflux for 1.5 h.
After cooling to room temperature, the excess of thionyl
chloride was removed under reduced pressure and the residue
partitioned between dichloromethane and saturated aqueous
1090
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094

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sodium bicarbonate. The aqueous layer was extracted with
dichloromethane and the combined organic phase washed with
water and brine, dried (MgSO4) and concentrated under
reduced pressure to give the amide 44 (5.59 g). Chromatography
of a sample using light petroleum–ethyl acetate (3:1) as elu-
ent gave the chloroethyl amide 44 as a white solid, mp 120–
122 ЊC; νmax/cmϪ1 3279, 1646, 1597, 1584, 1546, 1472, 1459,
1438, 1425, 1367, 1320, 1293, 1263, 1247 and 783; δH 2.32 (3
H, s, ArCH3), 3.70 (4 H, m, 2 × CH2), 3.80 (3 H, s, OCH3),
6.40 (1 H, br s, NH), 6.74 and 6.79 (each 1 H, d, J 7, ArH)
and 7.21 (1 H, t, J 7, ArH); m/z (EI) 227 ( Mϩ, 20%), 192
(13) and 149 (100).
CHCl3) (Found: Mϩ, 397.1885. C23H27NO5 requires M,
397.1889); λmax 243.2, 306.0 nm; νmax/cmϪ1 3328, 1719, 1599,
1586, 1531, 1477, 1234, 1089 and 1061; δH (C6D6) 0.88 and 0.98
(each 3 H, d, J 7, 3Ј-CH3, 4Ј-H3), 1.05 (1 H, m, 2Ј-H), 1.55 (2 H,
m, 2Ј-HЈ and 3Ј-H), 2.31 (1 H, dd, J 16, 2, 4-H), 2.85 (1 H, dd,
J 16, 13, 4-HЈ), 3.43 (3 H, s, OCH3), 3.78 (1 H, m, 1Ј-H), 4.01
(1 H, m, 3-H), 4.81 (1 H, br d, J 10, NH), 5.13 and 5.19 (each 1
H, d, J 13, HCHPh), 6.37 and 6.42 (each 1 H, d, J 7, 5-H and
7-H) and 7.03–7.3 (6 H, m, 6-H and ArH); δC 22.1, 23.0, 24.7,
31.8, 41.1, 51.4, 56.2, 66.9, 79.5, 110.8, 113.5, 119.5, 127.8,
128.1, 128.5, 134.7, 136.4, 142.1, 156.5, 161.2 and 162.3;
m/z (CI) 398 (Mϩ ϩ 1, 0.6%), 330 (4), 328 (4), 252 (47) and 248
(66).
Aqueous sodium hydroxide (10%; 17.5 cm3) was added to
a solution of the crude 2-(chloroethyl)amide 44 (5.59 g) in
ethanol (17.5 cm3) and the mixture stirred and heated under
reflux for 1.5 h. The mixture was extracted with dichloro-
methane, and the combined organic extracts were washed with
water and brine, dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ethyl acetate (1:2) as eluent gave the title compound
45 (4.09 g, 65%) as a white solid, mp 103–104 ЊC (Found: Mϩ,
191.0945. C11H13NO2 requires M, 191.0946); λmax 280.2, 228.8
nm; νmax/cmϪ1 1673, 1585, 1475, 1275, 1081 and 1049; δH 2.32
(3 H, s, ArCH3), 3.82 (3 H, s, OCH3), 4.10 and 4.42 (each 2 H, t,
J 10, CH2), 6.76 (1 H, d, J 7.5, ArH), 6.83 (1 H, d, J 6.5, ArH)
and 7.26 (1 H, dd, J 7.5, 6.5, ArH); δC 19.1, 54.9, 55.6, 67.0,
108.1, 118.4, 122.0, 130.2, 138.5, 157.6 and 162.7; m/z (EI)
192 (19%), 191 (Mϩ, 100), 190 (32), 162 (49), 146 (33) and 133
(32).
(1S,3ЈS)-[1-(3,4-Dihydro-8-methoxy-1-oxo-1H-2-benzopyran-3-
yl)-3-methylbutyl]ammonium chloride 52
Aqueous hydrogen chloride (3 M; 2 drops) and palladium on
charcoal (10% Pd, 16 mg, 0.015 mmol) were added to a suspen-
sion of lactone 30 (60 mg, 0.15 mmol) in ethanol (3 cm3) and
the reaction mixture stirred under an atmosphere of hydrogen
for 6 h. The catalyst was removed by filtration through Celite
and the filtrate concentrated under reduced pressure to leave the
title compound 52 (46 mg, 100%) as an off-white solid; νmax/cmϪ1
3500, 3400, 1730, 1600, 1515, 1485, 1460, 1260, 1240 and 1060;
δH (CD3OD) 1.02 and 1.05 (each 3 H, d, J 6, 3-CH3 and 4-H3),
1.61–1.98 (3 H, m, 2-CH2 and 3-H), 3.14 (2 H, m, 4Ј-CH2), 3.55
(1 H, m, 1-H), 3.91 (3 H, s, OCH3), 4.56 (1 H, m, 3Ј-H), 6.98
and 7.12 (each 1 H, d, J 7, 5Ј-H and 7Ј-H) and 7.60 (1 H, t, J 7,
6Ј-H); m/z (CI) 264 (52%), 194 (19) and 118 (100).
4,5-Dihydro-2-(6-ethyl-2-methoxyphenyl)oxazole 46
Butyllithium (1.55 M in hexanes; 0.38 cm3, 0.59 mmol) was
added dropwise to the oxazoline 45 (101 mg, 0.53 mmol) in
tetrahydrofuran (2 cm3) at Ϫ78 ЊC. The solution was stirred
for 30 min then iodomethane (0.2 cm3) was added dropwise.
Saturated aqueous ammonium chloride (3 cm3) was added and
the mixture was allowed to warm to room temperature then
extracted with dichloromethane. The organic extracts were
washed with water and brine, dried (MgSO4) and concentrated
under reduced pressure to give the title compound 46 (105 mg,
96%); νmax/cmϪ1 1665, 1583, 1472, 1439, 1268, 1050 and 939;
δH 1.21 (3 H, t, J 7, CH2CH3), 2.64 (2 H, q, J 7, CH2CH3),
3.81 (3 H, s, OCH3) 4.09 and 4.42 (each 2 H, t, J 10, CH2), 6.75
and 6.86 (each 1 H, d, J 7, ArH) and 7.29 (1 H, t, J 7, ArH);
m/z (EI) 205 (Mϩ, 100%), 204 (60), 191 (23), 176 (63) and 148
(50).
(1ЈS,3S)-3-[1-(2-Methylpropanoylamino)-3-methylbutyl]-3,4-
dihydro-8-methoxy-1H-2-benzopyran-1-one 53
4-Dimethylaminopyridine (33 mg, 0.27 mmol) in dichloro-
methane (1 cm3), isobutyric acid (0.011 cm3, 0.12 mmol) and
the amine hydrochloride 52 (38 mg, 0.12 mmol) in dichloro-
methane (2 cm3) were added to a solution of N,NЈ-dicyclo-
hexylcarbodiimide (27 mg, 0.13 mmol) in dichloromethane
(1 cm3) at 0 ЊC and the reaction mixture stirred for 10 min at
0 ЊC then at room temperature for 18 h. Ether (10 cm3) was
added and the mixture filtered through Celite then concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ethyl acetate (2:1 ) as eluent gave the title com-
pound 53 (29.8 mg, 70%) as a colourless oil (Found: Mϩ,
333.1946. C19H27NO4 requires M, 333.1940); νmax/cmϪ1 3315,
1720, 1645, 1598, 1536, 1236, 1097, 1058 and 1036; δH 0.92 and
0.94 (each 3 H, d, J 6, 3Ј-CH3 and 4Ј-H3), 1.17 and 1.18 (each
3 H, d, J 9, 2Љ-CH3 and 3Љ-H3), 1.4–2.0 (3 H, m, 2Ј-H2 and
3Ј-H), 2.41 (1 H, septet, J 9, 2Љ-H), 2.79 (1 H, dd, J 16, 2, 4-H),
2.98 (1 H, dd, J 16, 12, 4-HЈ), 3.96 (3 H, s, OCH3), 4.38 (2 H, m,
3-H and 1Ј-H), 5.72 (1 H, br d, J 8, NH), 6.82 and 6.91 (each 1
H, d, J 7, 5-H and 7-H) and 7.46 (1 H, t, J 6, 6-H); m/z (CI) 334
(Mϩ ϩ 1, 80%), 226 (36) and 225 (100).
(1ЈS,3S)-3-(1-Benzyloxycarbonylamino-3-methylbutyl)-3,4-
dihydro-8-methoxy-1H-2-benzopyran-1-one 30
Butyllithium (2.5 M; 0.96 cm3, 2.17 mmol) was added to a solu-
tion of the oxazoline 45 (500 mg, 2.62 mmol) in tetrahydro-
furan (15 cm3) at Ϫ78 ЊC and the mixture stirred for 20 min.
Ethereal tert-butylmagnesium chloride (2 M; 1.09 cm3, 2.18
mmol) was added to a solution of Cbz-leucinal 29 (542 mg, 2.18
mmol) in tetrahydrofuran (15 cm3) at Ϫ78 ЊC and the mixture
stirred for 3 min. The solution of the lithiated oxazoline was
added by cannula to the solution of the deprotonated aldehyde
and the mixture stirred for 5 min at Ϫ78 ЊC. Saturated aqueous
ammonium chloride was added and the mixture allowed to
warm to room temperature and extracted with chloroform. The
organic extracts were washed with water and brine, dried
(MgSO4) and concentrated under reduced pressure. The residue
was dissolved in dichloromethane (20 cm3) and silica (5 g) was
added. The slurry was stirred for 18 h then filtered and the
filtrate concentrated under reduced pressure. Chromatography
of the residue using light petroleum–ethyl acetate (2:1) as
eluent gave a mixture of the lactones 30 and 31 (383 mg, 44%),
ratio 30:31 = 87:13. Further chromatography gave the (3S)-
lactone 305,6 (261 mg, 30%) as a colourless oil, [α]D20 Ϫ137 (c 1,
(4S)-1-tert-Butyldimethylsilyl-4-{(1S,2S)-1,2-(dimethylmeth-
ylenedioxy)-3-{1-[(3S)-3,4-dihydro-8-methoxy-l-oxo-1H-2-
benzopyran-3-yl]-3-methylbutyl}amino-3-oxopropyl}azetidin-2-
one 54
4-Dimethylaminopyridine (76 mg, 0.69 mmol) in dichloro-
methane (3 cm3), the acid 27 (94 mg, 0.28 mmol) in dichloro-
methane (3 cm3) and the amine hydrochloride 52 (94 mg, 0.32
mmol) in dichloromethane (5 cm3) were added to a solution of
N,NЈ-dicyclohexylcarbodiimide (70 mg, 0.34 mmol) in dichloro-
methane (3 cm3) at 0 ЊC and the reaction mixture stirred for 10
min at 0 ЊC then at room temperature for 18 h. Ether (20 cm3)
was added and the mixture filtered through Celite. After con-
centration under reduced pressure, chromatography of the
residue using light petroleum–ethyl acetate (3:2) as eluent gave
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094
1091

View Article Online
the title compound 54† (107 mg, 65%) as a colourless oil, [α]D20
Ϫ135 (c 1, CHCl3) (Found: Mϩ ϩ H, 575.3150. C30H47N2O7Si
requires M, 575.3152); νmax/cmϪ1 3410, 3325, 1740, 1680, 1630,
1600, 1585, 1515, 1475, 1280, 1255, 1215, 1090, 1060, 840 and
820; δH (C6D6) 0.14 and 0.26 (each 3 H, s, SiCH3), 0.75 and 0.82
(each 3 H, d, J 6, 3Љ-CH3 and 4Љ-H3), 1.01 [9 H, s, SiC(CH3)3],
1.04 (3 H, s, CH3), 1.20 (1 H, m), 1.26 (3 H, s, CH3), 1.55 (2 H,
m), 2.28 (1 H, dd, J 16, 3, 4ٞ-H), 2.72 (1 H, dd, J 16, 12, 4ٞ-HЈ),
3.03 (1 H, dd, J 15, 5, 3-H), 3.17 (1 H, dd, J 15, 3, 3-HЈ), 3.34
(3 H, s, OCH3), 3.79 (1 H, m, 1Љ-H), 4.15 (1 H, m, 3ٞ-H), 4.36
(2 H, m, 1Ј-H, 4-H), 4.53 (1 H, dd, J 8, 1, 2Ј-H), 6.33 and
6.36 (each 1 H, d, J 7, 5ٞ-H and 7ٞ-H), 6.87 (1 H, d, J 10, NH)
and 7.46 (1 H, t, J 6, 6ٞ-H); m/z (FAB) 575 (Mϩ ϩ 1, 21%) and
532 (13).
Al-77-B methyl ether 58
Aqueous sodium hydroxide (0.05 M) was added dropwise to
solution of the azetidinone 55 (15 mg, 0.036 mmol) in ethanol–
water (1:1; 4 cm3) until the pH of the solution reached 12. The
pH was maintained at 12 by further addition of base until the
starting material could no longer be detected by TLC (ca. 18 h).
The reaction mixture was then cooled to 0 ЊC and acidified to
pH 1.3 by addition of methanolic hydrogen chloride (3 M). The
mixture was stirred at this temperature for 2 h then concen-
trated under reduced pressure to give the amine hydrochloride
56 (17 mg); νmax/cmϪ1 3360br, 1788, 1708, 1657, 1600, 1528,
1477, 1250 and 1069; δH (CD3OD) 0.92 and 0.98 (each 3 H, d,
J 6, 3Ј-CH3 and 4Ј-H3), 1.40 (1 H, m, 2Ј-H), 1.69 (2 H, m, 2Ј-HЈ
and 3Ј-H), 2.71 (1 H, dd, J 15, 12, 5-H), 3.00 (2 H, m, 4Љ-H2),
3.22 (1 H, dd, J 16, 8, 5-HЈ), 3.90 (3 H, s, OCH3), 4.0 (1 H, m),
4.19–4.36 (2 H, m), 4.51 (2 H, m), 6.94 and 7.09 (each 1 H, d,
J 7, 5Љ-H and 7Љ-H) and 7.56 (1 H, t, J 7, 6Љ-H).
(4S)-4-{(1S,2S)-1,2-dihydroxy-3-{1-[(3S)-3,4-dihydro-8-meth-
oxy-l-oxo-1H-2-benzopyran-3-yl]-3-methylbutyl}amino-3-oxo-
propyl}azetidin-2-one 55
Aqueous sodium hydroxide (0.02 M) was added dropwise
to a solution of the amine hydrochloride 56 (17 mg) in ethanol–
water (1:1; 4 cm3) until the pH reached 9. The pH was main-
tained at this level by further addition of base until the starting
material could no longer be detected by TLC (ca. 18 h). The pH
was then adjusted to 6.5 by dropwise addition of aqueous
hydrogen chloride (0.02 M). The reaction mixture was then
loaded directly onto a column of Amberlite XAD-2 resin
packed with water. The column was washed with water–
methanol (4:1) and the product isolated by eluting with water–
methanol (1:4) to give the title compound 5817† (11 mg,
70%) as a white solid, mp 135–138 ЊC; λmax 241.4, 306.6 nm;
νmax/cmϪ1 3279, 1721, 1657, 1599, 1585, 1477, 1243 and 1076;
δH (CD3OD) 0.94 and 0.99 (each 3 H, d, J 7, 3Ј-CH3 and 4Ј-H3),
1.42 (1 H, m, 2Ј-H), 1.63–1.87 (2 H, m, 2Ј-HЈ and 3Ј-H), 2.51
(1 H, dd, J 16, 11, 5-H), 2.63 (1 H, dd, J 16, 3, 5-HЈ), 2.87 (1 H,
dd, J 15, 2, 4Љ-H), 3.04 (1 H, dd, J 15, 12, 4Љ-HЈ), 3.62 (1 H, m,
4-H), 3.89 (3 H, s, OCH3), 3.96 (1 H, m, 3-H), 4.16 (1 H, d, J 8,
2-H), 4.33 and 4.49 (each 1 H, m, 1Ј-H and 3Љ-H), 6.90 and 7.06
(each 1 H, d J 8, 5Љ-H and 7Љ-H) and 7.54 (1H, t, J 8, 6Љ-H);
m/z (FAB) 440 (24%) and 439 (Mϩ ϩ 1, 100).
Aqueous hydrogen chloride (3.5 M; 10 cm3) was added drop-
wise to a solution of the acetonide 54 (55 mg, 0.096 mmol) in
tetrahydrofuran (10 cm3) at 0 ЊC and the mixture stirred for 30
min at 0 ЊC then at room temperature for 6 h. The reaction was
cooled to 0 ЊC and saturated aqueous sodium bicarbonate
(20 cm3) was added. The mixture was extracted with chloroform
and the organic extracts washed with water and brine then
dried (MgSO4). After concentration under reduced pressure,
chromatography of the residue using chloroform–methanol
(93:7) as eluent gave the title compound 55† (33 mg, 82%) as a
white solid, mp 105–106 ЊC, [α]D20 Ϫ153 (c 1, CHCl3) (Found: C,
59.7; H, 6.9. C21H28N2O7 requires C, 60.0; H, 6.7%; Found:
Mϩ ϩ H, 421.1971. C21H29N2O7 requires M, 421.1975); νmax
/
cmϪ1 3400, 3320, 1740, 1660, 1605, 1480, 1240, 1085, 1060 and
800; δH (CD3OD) 0.93 and 0.97 (each 3 H, d, J 6, 3Љ-CH3 and
4Љ-H3), 1.42 (1 H, m, 2Љ-H), 1.8 (2 H, m, 2Љ-HЈ and 3Љ-H), 2.83–
3.10 (4 H, m, 4ٞ-CH2 and 3-CH2), 3.77 (1 H, m, 4-H), 3.90 (4 H,
m, OCH3 and 1Ј-H), 4.10 (1 H, d, J 5, 2Ј-H), 4.13 (1 H, m,
1Љ-H), 5.10 (1 H, dt, J 10, 2, 3ٞ-H), 6.91 and 7.06 (each 1 H, d,
J 7, 5ٞ-H and 7ٞ-H) and 7.46 (1 H, t, J 7, 6ٞ-H); δH (dimethyl
sulfoxide-d6, 55 ЊC) 0.87 and 0.90 (each 3 H, d, J 6, 3Љ-CH3 and
4Љ-H3), 1.35 (1 H, m, 2Љ-H), 1.66 (2 H, m, 2Љ-HЈ and 3Љ-H), 2.73
(2 H, m, 3-CH2), 2.79 (1 H, dd, J 18, 3, 4ٞ-H), 2.93 (1 H, dd,
J 18, 12 4ٞ-HЈ), 3.57 (1 H, m, 4-H), 3.72 (1 H, q, J 5, 1Ј-H), 3.83
(3 H, s, OCH3), 3.97 (1 H, t, J 5, 2Ј-H), 4.17 (1 H, m, 1Љ-H), 4.42
(1 H, dt, J 13, 2, 3ٞ-H), 5.02 (1 H, d, J 5, OH), 5.53 (1 H, d, J 6,
OH), 6.91 and 7.05 (each 1 H, d, J 8, 5ٞ-H and 7ٞ-H), 7.37 (1 H,
br d, J 10, NH) and 7.52 (2 H, m, 6ٞ-H and NH); m/z (FAB)
421 (Mϩ ϩ 1, 32%).
(1ЈS,3S)-3-(1-Benzyloxycarbonylamino-3-methylbutyl)-3,4-
dihydro-8-hydroxy-1H-2-benzopyran-1-one 59
Boron tribromide (1 M in dichloromethane; 1.48 cm3, 1.48
mmol) was added dropwise to a solution of the methyl ether 30
(280 mg, 0.705 mmol) in dichloromethane (14 cm3) at Ϫ78 ЊC
over 3 min. The mixture was stirred for 3 min then saturated
aqueous ammonium chloride (10 cm3) was added. After
warming to room temperature, the mixture was extracted into
dichloromethane and the organic extracts washed with water
then brine and dried (MgSO4). After concentration under
reduced pressure, chromatography of the residue using light
petroleum–ethyl acetate (7:1) as eluent gave the title compound
59 (194 mg, 72%) as a white solid, mp 113–114 ЊC, [α]D20 Ϫ75.6
(c 1, CHCl3) (Found: C, 69.1; H, 6.5; N, 3.7; Mϩ, 383.1740.
C22H25NO5 requires C, 68.9; H, 6.6; N, 3.65%; M, 383.1733);
λmax 246.0, 314.4 nm; νmax/cmϪ1 3324, 3064, 1679, 1620, 1585,
1534, 1256, 1231, 1114, 1048, 737 and 698; δH (C6D6) 0.91 and
1.00 (each 3 H, d, J 6, 3Ј-CH3 and 4Ј-H3), 1.1 (1 H, m), 1.55
(2 H, m), 2.18 (1 H, dd, J 18, 3, 4-H), 2.72 (1 H, dd, J 18, 13,
4-HЈ), 3.68 (1 H, m, 3-H), 3.89 (1 H, dt, J 10, 3, 1Ј-H), 4.42 (1 H,
d, J 10, NH), 5.17 (2 H, s, CH2Ph), 6.20 (1 H, d, J 8, 7-H), 6.92
(1 H, d, J 8, 5-H), 7.00 (1 H, t, J 8, 6-H), 7.14–7.36 (5 H, m,
ArH) and 11.68 (1 H, s, ArOH); m/z (CI) 401 (Mϩ ϩ 18, 4%).
Aqueous hydrogen chloride (3 M; 2 drops) and palladium on
charcoal (10% Pd; 19 mg, 0.018 mmol) were added to a suspen-
sion of the protected aminolactone 59 (70 mg, 0.18 mmol) in
ethanol (3 cm3) and the reaction mixture stirred under an
atmosphere of hydrogen for 3.5 h. The mixture was then filtered
and concentrated under reduced pressure to leave the (1S,3ЈS)-
† The numbering scheme used in this paper for the azetidinone contain-
ing dipeptides is indicated in i and that for AI-77-B and derivatives in ii.
OH
O
tBuMe2Si
O
O
1
2
7"'
6"'
1"'
O
H
N
H
3"'
4"'
N
1"
2' 1'
4
3
5"'
2"
O
O
3"
4"
i
OH
O
+
1"
7"
O
H
N
OH
NH3
–
3"
1
3
CO2
1'
5
6"
4
2
4"
5"
H
2'
O
OH
3'
4'
ii
1092
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094

View Article Online
[1-(3,4-dihydro-8-hydroxy-1-oxo-1H-2-benzopyran-3-yl)-3-
methylbutyl]ammonium chloride 60 (49 mg, 95%) as an off-
white solid which was used without purification; νmax/cmϪ1
3350br, 1681, 1619, 1518, 1463, 1234, 1165 and 1113;
δH (CD3OD) 0.93 and 0.98 (each 3 H, d, J 6, 3Ј-CH3 and 4Ј-H3),
1.60 (2 H, m), 1.75 (1 H, m), 3.01–3.27 (2 H, m, 4-CH2), 3.52
(1 H, m, 1Ј-H), 4.68 (1 H, m, 3-H), 6.79 and 6.82 (each 1 H, d,
J 7, 5-H and 7-H) and 7.43 (1 H, t, J 7, 6-H); m/z (CI) 278
(13%), 251 (19) and 250 (100).
pH was maintained at this level by further addition of base
until the starting material could no longer be detected by TLC
(ca. 18 h). The mixture was then cooled to 0 ЊC, acidified to pH
1.3 by addition of methanolic hydrogen chloride (3 M) and
stirred at this temperature for 2 h. Concentration gave the bis-
lactone hydrochloride 57 (24 mg).
Aqueous sodium hydroxide (0.02 M) was added dropwise to
the bis-lactone hydrochloride 57 (24 mg) in ethanol–water (1:1;
5 cm3) until the pH reached 9. The pH was maintained at this
level by further addition of base until the starting material
could no longer be detected by TLC (ca. 18 h). The pH was then
adjusted to 6.5 by dropwise addition of aqueous hydrogen
chloride (0.02 M). The reaction mixture was loaded directly
onto a column of Amberlite XAD-2 resin packed with water.
The column was washed with water–methanol (4:1) and the
product isolated by eluting with water–methanol (1:4) to give
title compound 11 † (15 mg, 72%) as a white solid, mp 137–
138 ЊC (lit.,1 mp 139.5 ЊC); λmax 246.6, 314.6 nm; [α]D20 Ϫ68 (c 0.1,
MeOH) (lit.,1 Ϫ72.2; Ϫ78); νmax/cmϪ1 3258br, 1667, 1620, 1584,
1463, 1392, 1232, 1164 and 1112; δH (CD3OD) 0.91 and 0.97
(each 3 H, d, J 6, 3Ј-CH3 and 4Ј-H3), 1.35 (1 H, m, 2Ј-H), 1.74 (2
H, m, 2Ј-HЈ and 3Ј-H), 2.52 (1 H, dd, J 16, 10, 5-H), 2.6 (1 H,
dd, J 16, 3, 5-HЈ), 2.91 (1 H, dd, J 16, 3, 4Љ-H), 3.08 (1 H, dd,
J 16, 12, 4Љ-HЈ), 3.60 (1 H, m, 4-H), 3.93 (1 H, dd, J 8, 4, 3-H),
4.12 (1 H, d, J 7, 2-H), 4.31 (1 H, dt, J 10, 2, 1Ј-H), 4.65 (1 H, dt,
J 11, 3, 3Љ-H), 6.76 and 6.81 (each 1 H, d, J 7, 5Љ-H and 7Љ-H)
and 7.5 (1 H, t, J 7, 6Љ-H); δH (dimethyl sulfoxide-d6; 60 ЊC) 0.87
and 0.91 (each 3 H, d, J 6.5, 3Ј-CH3 and 4Ј-H3), 1.38 (1 H, m,
2Ј-H), 1.67 (2 H, m, 2Ј-HЈ and 3Ј-H), 2.17 (1 H, dd, J 16, 9,
5-H), 2.35 (1 H, dd, J 16, 3, 5-HЈ), 2.90 (1 H, dd, J 17, 3, 4Љ-H),
3.05 (1 H, dd, J 17, 12, 4Љ-HЈ), 3.23 (1 H, m, 4-H), 3.66 (1 H, dd,
J 7, 4, 3-H), 3.99 (1 H, d, J 7, 2-H), 4.21 (1 H, m, 1Ј-H), 4.65
(1 H, dt, J 12, 3, 3Љ-H), 6.81 (1 H, d, J 8, 5Љ-H), 6.85 (1 H, d, J 8,
7Љ-H), 7.48 (1 H, t, J 8, 6Љ-H) and 7.65 (1 H, br d, J 9, N-H);
δC (dimethyl sulfoxide-d6) 21.5, 23.3, 23.9, 29.0, 33.6, 48.0,
50.1, 71.6, 72.3, 80.9, 108.3, 115.2, 118.4, 136.2, 140.6, 160.8,
169.0 and 172.6; m/z (FAB) 425 (Mϩ ϩ 1, 32%), 413 (15) and
329 (35).
Natural Al-77-B 1 (2 mg, 0.005 mmol) was dissolved in
methanol (2 cm3) and methanolic hydrogen chloride was
added (3 M; 1 drop). Concentration under reduced pressure
gave the bis-lactone hydrochloride 57; νmax/cmϪ1 3245, 1783,
1665, 1619, 1584, 1462, 1230, 1163 and 1110; δH (CD3OD)
0.92 and 0.98 (each 3 H, d, J 6, 3Ј-CH3 and 4Ј-H3), 1.43
(1 H, m, 2Ј-H), 1.69 (1 H, m, 3Ј-H), 1.80 (1 H, m, 2Ј-HЈ), 2.56 (1
H, dd, J 18, 2, 5-H), 3.03 (2 H, m, 4Љ-CH2), 3.22 (1 H, dd, J 18,
9, 5-HЈ), 4.18 (2 H, m, 1Ј-H and 4-H), 4.46 (1 H, d, J 4, 2-H),
4.72 (1 H, m, 3Љ-H), 4.87 (1 H, t, J 4, 3-H), 6.82 and 6.86 (each
1 H, d, J 7, 5Љ-H and 7Љ-H) and 7.47 (1 H, t, J 7, 6Љ-H); m/z
(FAB) 442 (Mϩ, 20%), 439 (20), 413 (45), 407 (55), 393 (60) and
322 (75).
(4S)-1-tert-Butyldimethylsilyl-4-{(1S,2S)-1,2-(dimethylmethyl-
enedioxy)-3-{1-[(3S)-3,4-dihydro-8-hydroxy-l-oxo-1H-2-benzo-
pyran-3-yl]-3-methylbutyl}amino-3-oxopropyl}azetidin-2-one 61
4-Dimethylaminopyridine (60 mg, 0.49 mmol) in dichloro-
methane (3 cm3), the acid 27 (72 mg, 0.23 mmol) in dichloro-
methane (3 cm3) and the amine hydrochloride 60 (65 mg, 0.227
mmol) in dichloromethane (5 cm3) were added to a solution of
N,NЈ-dicyclohexylcarbodiimide (56 mg, 0.27 mmol) in dichloro-
methane (3 cm3) at 0 ЊC and the mixture stirred for 10 min at
0 ЊC then at room temperature for 18 h. Ether (20 cm3) was
added and the mixture filtered through Celite. After concen-
tration under reduced pressure, chromatography of the residue
using light petroleum–ethyl acetate (1:1) as eluent gave the title
compound 61† (68 mg, 54%) as a colourless oil, [α]D20 Ϫ75.6
(c 0.7, CHCl3) (Found: Mϩ, 561.3011. C29H45N2O7Si requires
M, 561.2996); νmax/cmϪ1 3413, 1741, 1677, 1620, 1586, 1516,
1464, 1231, 1214 and 1069; δH 0.21 and 0.37 (each 3 H, s,
SiCH3), 0.83 and 0.90 (each 3 H, d, J 6, 3Љ-CH3 and 4Љ-H3), 1.2
(1 H, m), 1.12 [9 H, s, SiC(CH3)3], 1.14 and 1.31 (each 3 H, s,
CH3), 1.55 (2 H, m), 2.22 (1 H, dd, J 13, 2, 4ٞ-H), 2.72 (1 H, dd,
J 13, 11, 4ٞ-HЈ), 3.07 (1 H, dd, J 11, 5, 3-H), 3.21 (1 H, dd, J 11,
2, 3-HЈ), 3.77 (1 H, m, 3ٞ-H), 4.2 (1 H, m, 1Љ-H), 4.40 (1 H, d,
J 8, 2Ј-H), 4.43 (1 H, m, 4-H), 4.61 (1 H, dd, J 8, 1, 1Ј-H), 6.21
(1 H, d, J 7, 7ٞ-H), 6.76 (1 H, d, J 11, N-H), 6.89 (1 H, d, J 7,
5ٞ-H), 6.99 (1 H, t, J 7, 6ٞ-H) and 11.53 (1 H, s, ArOH); m/z
(FAB) 561 (Mϩ ϩ 1, 65%), 545 (15), 519 (50) and 503 (80).
(4S)-4-{(1S,2S)-1,2-Dihydroxy-3-{1-[(3S)-3,4-dihydro-8-
hydroxy-1-oxo-1H-2-benzopyran-3-yl]-3-methylbutyl}amino-3-
oxopropyl}azetidin-2-one 62
Aqueous hydrogen chloride (3.5 M; 5 cm3) was added dropwise
to a stirred solution of the acetonide 61 (32 mg, 0.057 mmol)
in tetrahydrofuran (5 cm3) at 0 ЊC and the reaction mixture
stirred for 30 min at 0 ЊC then at room temperature for 6 h. The
reaction was cooled to 0 ЊC and saturated aqueous sodium
bicarbonate (10 cm3) added slowly. The mixture was extracted
into chloroform, and the organic extracts washed with water
and brine then dried (MgSO4). After concentration under
reduced pressure, chromatography of the residue using
chloroform–methanol (95:5) as eluent gave the title compound
62 (17 mg, 74%) as a white solid, mp 99–101 ЊC, [α]D20 Ϫ103.4
(c 1, CHCl3) (Found: Mϩ ϩ H, 407.1826. C20H27N2O7 requires
M, 407.1818); νmax/cmϪ1 3337, 1737, 1670, 1620, 1585, 1531,
1464, 1232, 1165, 1113 and 756; δH (CD3OD) 0.94 and 0.98
(each 3 H, d, J 6, 3Љ-CH3 and 4Љ-H3), 1.43 (1 H, m, 2Љ-H), 1.77
(2 H, m, 2Љ-HЈ and 3Љ-H), 2.82–3.10 (3 H, m, 4ٞ-H and 3-CH2),
3.10 (1 H, dd, J 14, 11, 4ٞ-HЈ), 3.76 (1 H, m, 4-H), 3.88 (1 H, t,
J 5, 1Ј-H), 4.10 (1 H, d, J 5, 2Ј-H), 4.33 (1 H, m, 1Љ-H), 4.66
(1 H, dt, J 11, 2, 3ٞ-H), 6.77 and 6.84 (each 1 H, d, J 8, 5ٞ-H
and 7ٞ-H) and 7.44 (1 H, t, J 8, 6ٞ-H); δC 21.9, 23.3, 24.9, 30.5,
39.6, 40.6, 49.5, 49.7, 72.6, 72.7, 81.5, 108.2, 116.5, 118.5, 136.8,
139.5, 162.2, 169.8, 169.9 and 172.9; m/z (FAB) 405 (Mϩ Ϫ 1,
21%).
The bis-lactone hydrochloride 57 (5 mg, 0.012 mmol) was
dissolved in saturated aqueous sodium carbonate (2 cm3). The
solution was immediately extracted with ethyl acetate and the
organic extracts washed with water and dried (MgSO4). Con-
centration under reduced pressure gave the amino-bis-lactone
63 (2 mg, 40%); δH (CD3OD) 0.91 and 0.98 (each 3 H, d, J 6, 3Ј-
CH3 and 4Ј-H3), 1.33–1.91 (3 H, m, 2Ј-H2 and 3Ј-H), 2.72 (1 H,
dd, J 18, 3, 5-H), 2.93 (3 H, m, 4Љ-H2 and 5-H), 3.66 (1 H, m,
4-H), 4.31 (1 H, m, 1Ј-H), 4.37 (1 H, d, J 3, 2-H), 4.54 (1 H, t,
J 3, 3-H), 4.63 (1 H, m, 3Љ-H), 6.77 and 6.82 (each 1 H, d, J 7,
5Љ-H and 7Љ-H) and 7.43 (1 H, t, J 7, 6Љ-H).
On addition of methanolic hydrogen chloride (3 M; 1 drop)
the hydrochloride 57 was reformed.
AI-77-B 1
Acknowledgements
Aqueous sodium hydroxide (0.05 M) was added dropwise to a
solution of the azetidinone 62 (20 mg, 0.05 mmol) in ethanol–
water (1:1; 5 cm3) until the pH of the mixture reached 12. The
This paper is dedicated to Ralph Raphael an excellent chemist
and an outstanding teacher, who brought humour into his
lectures.
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094
1093

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Tetrahedron Lett., 1989, 30, 6503; H. Kotsuki, A. Miyazaki and
M. Ochi, Chem. Lett., 1992, 1255.
7 S. D. Broady, J. E. Rexhausen and E. J. Thomas, J. Chem. Soc.,
Chem. Commun., 1991, 708.
8 T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen and F. A.
Bouffard, J. Am. Chem. Soc., 1980, 102, 6161; R. Labia and
C. Morin, Chem. Lett., 1984, 1007.
We thank Zeneca Pharmaceuticals and the EPSRC for a
CASE Award (to S. D. B.), the Deutscher Akademischer
Austauschdienst was a scholarship (to J. E. R.) and Dr Y.
Shimojima, The Technical Research Laboratory, The Asahi
Chemical Industry Limited, Japan, for a sample of authentic
AI-77-B.
9 W. C. Still and C. Gennari, Tetrahedron Lett., 1983, 24, 4405.
10 E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schroder and K. B.
Sharpless, J. Am. Chem. Soc., 1988, 110, 1968; J. S. M. Wai,
I. Marko, J. S. Svendsen, M. G. Finn, E. N. Jacobsen and K. B.
Sharpless, J. Am. Chem. Soc., 1989, 111, 1123.
11 H. Saito, F. Suzuki and T. Hirata, Chem. Pharm. Bull., 1989, 37,
2298.
12 D. E. Gibbs and C. Larsen, Synthesis, 1984, 410.
13 F. M. Hauser and S. A. Pogany, Synthesis, 1980, 814.
14 A. I. Meyers, M. A. Hanagan, L. M. Trefonas and R. J. Baker,
Tetrahedron, 1983, 39, 1991; J. A. Frump, Chem. Rev., 1971, 71,
483.
References
1 Y. Shimojima, H. Hayashi, T. Ooka, M. Shibukawa and Y. Iitaka,
Tetrahedron, 1984, 40, 2519; Y. Shimojima, H. Hayashi, T. Ooka,
M. Shibukawa and Y. Iitaka, Tetrahedron Lett., 1982, 23, 5435.
2 Y. Shimojima and H. Hayashi, J. Med. Chem., 1983, 26, 1370;
Y. Shimojima, T. Shirai, T. Baba and H. Hayashi, J. Med. Chem.,
1985, 28, 3.
3 J. Itoh, T. Shomura, S. Omoto, S. Miyado, Y. Yuda, U. Shibata and
S. Inouye, Agric. Biol. Chem., 1982, 46, 1255; J. Itoh, S. Omoto, N.
Nishizawa, Y. Kodama and S. Inouye, Agric. Biol. Chem., 1982, 46,
2659.
4 Y. Hamada, A. Kawai, Y. Kohno, O. Hara and T. Shioiri, J. Am.
Chem Soc., 1989, 111, 1524; Y. Hamada, O. Hara, A. Kawai,
Y. Kohno and T. Shioiri, Tetrahedron, 1991, 47, 8635.
5 R. A. Ward and G. Procter, Tetrahedron Lett., 1992, 33, 3359; R. A.
Ward and G. Procter, Tetrahedron, 1995, 51, 12301; J.-M. Durgnat
and P. Vogel, Helv. Chim. Acta, 1993, 76, 222.
15 A. Ito, R. Takahashi and Y. Baba, Chem. Pharm. Bull., 1975, 23,
3081.
16 W. H. Pirkle, D. L. Sikkenga and M. S. Pavlin, J. Org. Chem., 1977,
42, 384.
17 J. F. W. McOmie, M. L. Watts and D. E. West, Tetrahedron, 1968, 24,
2289.
6 A. Kawai, O. Hara, Y. Hamada and T. Shioiri, Tetrahedron Lett.,
1988, 29, 6331; J. P. Gesson, J. C. Jacquesy and M. Mondon,
Paper 9/00334G
1094
J. Chem. Soc., Perkin Trans. 1, 1999, 1083–1094