Diastereocontrolled synthesis of hydroxylated lactams

Article abstract of DOI:10.1039/b108056n

Highly diastereoselective reductions and organometallic additions in bicyclic lactams have been observed, which appear to result either from a stereoelectronic interaction of the pyramidalised nitrogen lone pair or from steric interactions in the bicyclic

Full text of DOI:10.1039/b108056n

View Article Online / Journal Homepage / Table of Contents for this issue
Diastereocontrolled synthesis of hydroxylated lactams
Mark. D. Andrews,a Andrew G. Brewsterb and Mark G. Moloney*a
a The Department of Chemistry, The Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, UK OX1 3QY. E-mail: mark.maloney@chem.ox.ac.uk
b Zeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
1
Received (in Cambridge, UK) 5th September 2001, Accepted 2nd November 2001
First published as an Advance Article on the web 5th December 2001
Highly diastereoselective reductions and organometallic additions in bicyclic lactams have been observed, which
appear to result either from a stereoelectronic interaction of the pyramidalised nitrogen lone pair or from steric
interactions in the bicyclic system. These products can be readily deprotected to give hydroxylated lactams.
Highly substituted lactam rings possess diverse biological
activity, and much recent attention has focussed on excitatory
amino acid chemistry, particularly as a result of the drive
to better understand CNS function in mammalian systems.1
It has recently also been shown that densely functionalised
pyrrolidinones, such as lactacystin,2 exhibit potent and selective
activity in proteasome inactivation; there has therefore been
considerable interest in the rapid construction of the pyr-
rolidinone framework,3 since such compounds may find
application in the development of selective therapeutic agents
Scheme 1
for important parasitic infections.4,5
Our interest in this area has been concerned with the appli-
required β-dicarbonyl unit and then cyclised to the tetramic
cation of bicyclic lactams for the synthesis of diversely sub-
stituted lactam rings. Two lactam templates 1 and 2, derived
from pyroglutamic or pyroadipic acids respectively, have been
used to access a variety of kainoid analogues as well as novel
aminolactams, and make use of the inherent facial selectivity
which comes from the bicyclic system.6–9 Another template 3,
derived from serine,10 has also been found to be applicable for
the preparation of diversely functionalised lactams of well-
defined stereochemistry. In this series, ring closure of 3a–c by
Dieckmann, Aldol or intramolecular cyclisation reactions
respectively led to functionalised lactam systems which possess
a quaternary α-amino centre with high diastereo- and enantio-
control.11–14 We wished to further develop this chemistry to
permit the introduction of hydroxy functionality around the
ring periphery, and describe here that highly diastereo-
controlled ring modifications using hydride or organometallic
nucleophiles in bicyclic lactams are possible using steric,
chelation or stereoelectronic control.
acid by treatment with potassium tert-butoxide in tert-butyl
alcohol.
Ketone reductions
Our initial investigations were concerned with selective reduc-
tions in the bicyclic lactams 5a,b; for this purpose, sodium
triacetoxyborohydride appeared to be the reagent of choice,
since Poncet and co-workers had earlier reported that reduction
of the related bicyclic tetramic acid 6 with this reagent
generated in situ from sodium borohydride and acetic acid in
dichloromethane gave the alcohols 7a,b in the ratio 95 : 5
(Scheme 2).15 This corresponds to preferential attack of the
Scheme 2
ketone carbonyl by borohydride from the sterically more
hindered endo-face of the bicyclic system, anti to the nitrogen
lone pair, and from a study of several substrates, the authors
concluded that this was a general phenomenon.
Application of this method to the reduction of dicarbonyl
compound 5a gave a very similar result. Thus, reduction
with sodium borohydride in a 1 : 9 mixture of acetic acid and
dichloromethane gave a 63 : 1 mixture of the epimeric alcohols
8 and 9, along with 0.1% of the acetate 10 (Scheme 3). That the
major product was the alcohol 8, with the indicated relative
stereochemistry, was initially assumed on the basis of the
results obtained by Poncet, but this was later confirmed by
single crystal X-ray analysis of a derivative (vide infra).
Recrystallisation from chloroform–petrol gave the major
Results and discussion
Starting material synthesis
Lactams 5a,b were prepared by our previously reported meth-
odology (Scheme 1);11,12 oxazolidine 4, itself readily obtained
from serine and pivaldehyde in 90% yield, was acylated with the
80
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b108056n

View Article Online
Scheme 3
epimer 8 in a yield of 81%. The relative stereochemistry of
oethanol gave alcohol 15a in 97% yield. Attempted N-Boc pro-
compound 10 was assumed to be the same as the major
reduction product 8, from which it was presumably formed
under the reaction conditions.
tection in fact gave the crystalline carbonate 15b in 92% yield,
whose relative stereochemistry was confirmed by single crystal
X-ray structural analysis.17 This important result confirmed the
earlier tentative stereochemical assignments of compounds 8, 9
and 10. O,N-Diprotection, using triethylamine as a base, with a
catalytic amount of DMAP as a nucleophilic catalyst, in fact
gave the elimination product 16 in 58% yield along with a 31%
yield of the carbonate 15b.
In view of the success of these reductions, it was of interest
to examine the diastereocontrol of more elaborate systems of
type 5b.† Reduction of dicarbonyl 5b with sodium borohydride
in acetic acid and dichloromethane as described above gave,
in addition to 29% of unreacted starting material, three
diastereomeric alcohols 17a, 17b and 17c, which were obtained,
after careful purification, in yields of 32, 16 and 4% respectively
(Scheme 5). Interestingly, it was found that this reduction
Deprotection of lactam 8 to diol 11 was achieved in quan-
titative yield in a mixture of propane-1,3-dithiol and acidic
trifluoroethanol.16 This synthesis of ester 11, which was without
recourse to column chromatography, was achieved in an excel-
lent total yield of 42% from -serine. Alternatively, both the
oxazolidine and lactam rings of alcohol 8 could be cleaved by
heating in methanolic HCl at reflux; after removal of solvent
in vacuo and purification by column chromatography, the
glutamate ester 12, contaminated with 8% of the diol 11, was
obtained. Diol 11 could also be synthesised, in lower overall
yield, by reversing the order of the last two steps in the
synthesis above. Thus, deprotection of dicarbonyl 5a as
described above gave the unstable keto alcohol 13 in 87%
yield.11 Treatment of the crude product with sodium triac-
etoxyborohydride in acetic acid then led to the diol 11 in
58% yield.
Confirmation of the stereochemical assignment above was
possible by successful derivatisation to a crystalline compound.
Alcohol 8 was protected in quantitative yield with benzoyl
chloride and pyridine to give the benzoate ester 14 (Scheme 4)
and deprotection with propane-1,3-dithiol in acidic trifluor-
Scheme 5
needed to be carried out in the absence of oxygen to prevent
autoxidation, otherwise the diol product 18 was obtained in low
yield.11 The relative stereochemistries of these three alcohols
were established by a series of NOE experiments (Fig. 1). For
17a and 17b, a sequence of irradiations easily gave the relative
stereochemistry around the bicyclic ring system, but for the
minor product 17c only one enhancement gave any exact
information and the overall stereochemistry was therefore
assumed from the earlier assignments of isomers 17a,b.
Hydride addition, predominantly from the endo-face, which is
anti to the nitrogen lone pair gives the major products 17a,b.
† This compound exists as the enol tautomer, but is drawn in the keto
form for convenience.
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
81

View Article Online
Scheme 7
with 4 equivalents of a solution of DIBAL-H in hexane in THF
at 0 ЊC, giving the crude alcohol 22a in 85% yield (Scheme 7),
although this compound was found to be unstable to chrom-
atography. Attempts to oxidise this material to the aldehyde 22b
with TPAP or PCC were unsuccessful, and although evidence
Fig. 1
1
for successful Swern oxidation could be obtained by H NMR
analysis of the crude product, this material also proved to be
unstable to isolation. Further reduction of 22a with sodium
triacetoxyborohydride in acetic acid gave diol 23 as a single
diastereomer in 70% yield; the stereochemistry of this product
was assumed to be as shown because of the presumed
intramolecular chelated delivery of the hydride in the tri-
acetoxyborohydride reduction, forcing hydride attack from
the Si face of the ketone of 22a.
The low overall yield for the reduction can probably be
explained by steric hindrance from the C(7) methyl group.
In order to gain some information concerning the stability of
these reduction products, epimerisation studies of the epimeric
alcohols 17a or 17b were undertaken with sodium methoxide in
methanol. For the former, no change was observed on stirring
with base but lactam 17b gave almost complete epimerisation
to its C(7) epimer 17a (de 94%), clearly indicating that alcohol
17a is the thermodynamically more stable. Epimerisation at
C(6) of the alcohols 17a and 17b was also attempted under the
Mitsunobu conditions,18 but treatment with benzoic acid,
triphenylphosphine and DEAD in THF gave none of the
desired products, with the only compound isolated being the
alkene 19. Alcohol 17a gave a 36% yield of this elimination
product with 53% of starting material being recovered, while
alcohol 17b gave alkene 19 in 33% yield along with 38%
recovered starting material.
In several of the above compounds, it was noted that con-
1
sistent trends were observed in the H NMR spectra which
facilitated assignment of stereochemistry. Thus, for the
C(6)Hendo compounds 8, 10, 17a and 17b, the difference in
the C(4)Hendo and C(4)Hexo chemical shift values were typically
1.1–1.4 ppm, and were much larger than in the C(6)Hexo
compounds 9, 17c and 23, for which the difference was only
0.3 ppm. Conversely, the difference in C(7)Hendo and C(7)Hexo
chemical shift values for the C(6)Hendo compounds 8 and 10
were typically only 0.4 ppm, significantly lower than the 0.9
ppm observed for the C(6)Hexo compounds 9, 17c and 23.
Similar trends in NMR data in functionalised pyrrolidinones
have been ascribed to steric compression of the different proton
nuclei around the periphery of the heterocyclic system.19
In an attempt to improve the reduction of dicarbonyl com-
pound 5b, it was decided to change the order of the steps in the
synthesis by cleaving the oxazolidine ring before attempting the
reduction of the ketone. Accordingly, dicarbonyl compound 5b
was converted to the unstable keto alcohol 20 as reported
previously (Scheme 6).11 Reaction with sodium triacetoxy-
Organometallic additions
In view of the success of the diastereoselective reductions, it
was also of interest to examine the possibility of introducing
alcohol functionality using organometallic additions. Kikkawa
and Yorifuji reported that, in the presence of triethylamine,
aliphatic Grignard reagents react with esters to form the
corresponding ketones in good yield.20 Unfortunately, lactams
5a,b were unreactive with isopropylmagnesium bromide, even
on heating in THF at reflux, but with the more reactive alkyl-
lithium species (5 equivalents in THF–petrol at Ϫ78 ЊC21,22),
ester 5a gave an inseparable 3 : 1 mixture of ketone 24a and the
secondary alcohol 25a in a total yield of 85% (Scheme 8). No
tertiary alcohol due to reaction of ketone 24a with another
equivalent of isopropyllithium was observed in this reaction,
presumably since this is a particularly hindered ketone. The
ketone 24a–alcohol 25a product could be entirely converted to
the alcohol product 25a using lithium in ammonia–ethanol in
70% yield for the two steps from ester 5a. Similarly, ester 5b was
reacted with excess isopropyllithium to give a partially separ-
able 7 : 1 mixture of ketone 24b and secondary alcohol 25b. The
formation of the secondary alcohols 25a,b was due to reduction
of the ketones 24a,b by excess lithium metal in the reaction.23
Reduction of the ketone 24a–alcohol 25a mixture with alk-
aline sodium borohydride in ethanol (in which the β-dicarbonyl
enolate was formed, thereby protecting the ketone from reduc-
tion) gave 3 products: (S)-alcohol 26 was obtained in 36% yield,
along with 19% of (R)-alcohol 25a, present as a contaminant in
the starting material, and a 20% yield of the over-reduction
product, diol 27. The yields of these products are quoted for the
two steps from ester 5a, and their stereochemistry was assigned
Scheme 6
borohydride then gave diol 21 as an inseparable 3 : 2 mixture of
two diastereomers in 51% yield. It was assumed that these diols
were epimeric at C(4) rather than C(3) because of the excellent
diastereocontrol exhibited previously in the sodium triacetoxy-
borohydride reduction of lactam 13.
In view of the good to high levels of diastereoselectivity
exhibited in ring carbonyl reductions, it was of interest to
examine manipulation of the pyrrolidinone ring side-chains.
Reduction of the C(5) ester function of 5a proved to be possible
82
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90

View Article Online
Scheme 8
Fig. 2
by a consideration of their IR spectral data. Thus, the product
25a, also obtained by dissolving metal reduction (Li, NH3,
EtOH) of ketone 24a as described above, exhibited a broad
peak from 3600 to 2200 cmϪ1 and peaks at 1680, 1650 and
1610 cmϪ1, consistent with the presence of an intramolecular
hydrogen bond. For the epimer 26, the IR spectrum showed no
evidence for such intramolecular hydrogen bonding, with the
OH signal occurring at 3600–3100 cmϪ1 and the carbonyl signal
occurring at 1770 and 1710 cmϪ1. These observations are con-
sistent with reduction of the H-bonded ketone 24a (or its metal
chelated enolate, Fig. 2) which in the case of dissolving metal
reduction, leads to the thermodynamically more stable H-
bonded product 25a in which steric interactions between the
iBu and iPr groups are minimised. On the other hand, reduc-
tion of 24a by NaBH4 occurs by attack of hydride at the least
hindered face, as indicated, to give the product 26 in which
intramolecular hydrogen bonding is not possible, without
causing unfavourable steric interactions between the iBu and
iPr groups. That compounds 26 and 27 possessed the same
side-chain stereochemistry (S) was established by the conver-
sion of ketone 26 to alcohol 27 by catalytic hydrogenation with
platinum oxide in ethyl acetate at 5 atm; under these conditions,
the reaction was slow and gave only a low yield (25%) of
product 27, along with recovered starting material. The stereo-
chemistry of 27 was in part determined by NOE (Fig. 3), which
established the side-chain stereochemistry, and in part by use of
Fig. 3
Reduction of ketone 24b was similarly achieved; treatment
with sodium methoxide in ethanol followed by addition of
sodium borohydride under nitrogen led to the (S)-alcohol 28
in 91% yield (Scheme 9). This reaction was performed under
1
the H NMR patterns discussed above; thus, the ∆δ of each
of the H(4) signals, at 1.0 ppm, was consistent with the exo
orientation of the C(6) hydroxy as indicated. Such a stereo-
chemistry would have required hydrogen attack anti to
the nitrogen lone pair, which, as noted above, appears to be
the kinetically preferred mode of attack, and in any case the
alternative exo-face reduction is clearly blocked by the bulky
iPr group.
Scheme 9
nitrogen because both product alcohols 28 and 25b were found
to be extremely sensitive to autoxidation. On the other hand,
dissolving metal reduction of ketone 24b with lithium in liquid
ammonia gave only the (R)-alcohol 25b in 89% yield. Use of
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
83

View Article Online
sodium in liquid ammonia, however, led to a mixture of the (R)-
and (S)-alcohols, the (R)-alcohol 25b predominating, in a
combined yield of 57%. The stereochemistries of the (R)- and
(S)-alcohols 25b and 28 were assigned by analogy with those
of alcohols 25a and 26.
acid derivatives, which in the best cases proceed with excellent
diastereocontrol. Deprotection permits rapid access to highly
functionalised pyrrolidinones.
Experimental
Again, useful patterns in the 1H NMR spectra were observed:
the appearance of the methine proton of the isopropyl side-
Lactams 5a,b were prepared by our previously reported
methodology.11
1
chain in the H NMR spectra of these compounds proved to
be diagnostic of the alcohol stereochemistry. For those com-
pounds assigned the (S)-stereochemistry, this methine proton
appeared as an octet, with the coupling constants to the
isopropyl methyl groups and the proton at the alcohol centre
all being approximately 6.5 or 7.0 Hz. For those compounds
assigned the (R)-stereochemistry, however, this methine proton
appeared as a doublet of septets or a septet, the coupling con-
stant to the proton at the alcohol centre being 2.0 Hz or less.
As noted above, alcohols 25b and 28 were found to be
unusually sensitive to aerial oxidation, and attempted recrystal-
lisation of alcohol 28 from chloroform led to a decomposition
owing to this instability. Purification of this decomposition
mixture by column chromatography enabled the isolation of
diol 29 in 7% yield. That the oxidation product was indeed the
diol 29 was confirmed by mass spectrometry, both chemical
ionisation and positive electrospray spectra showing peaks at
317 and 300 Da corresponding to M ϩ NH4ϩ and M ϩ Hϩ ions
respectively. Storage of alcohol 25b in deuterochloroform
solution for 20 days led to relatively clean oxidation to give a
single product as shown by 1H NMR spectroscopy. Purification
by column chromatography gave unchanged starting material
in 50% recovery and a 30% yield of the peroxide 30. That this
compound was the peroxide and not the diol analogous to
compound 29 was established from a positive starch iodide test.
This was supported by mass spectrometry, and the positive
electrospray spectrum of compound 30 clearly showed a peak
at 316 Da indicating that the peroxide was indeed the product
formed.
(2R,5R,6S)- and (2R,5R,6R)-2-tert-Butyl-6-hydroxy-5-
methoxycarbonyl-8-oxo-3-oxa-1-azabicyclo[3.3.0]octane 8 and
9 and (2R,5R,6S)-6-acetoxy-2-tert-butyl-5-methoxycarbonyl-8-
oxo-3-oxa-1-azabicyclo[3.3.0]octane 10
To a solution of lactam 5a (9.0 g, 35.3 mmol) in 10% AcOH in
DCM (175 ml) at 0 ЊC was added, portionwise over 15 min,
NaBH4 (2.93 g, 77.6 mmol). The mixture was stirred at 0 ЊC for
a further 15 min, at room temperature for 1.5 h and the solvent
was then removed in vacuo. The residue was partitioned
between EtOAc (250 ml) and sat. NaHCO3 (aq) (250 ml) and
the aqueous layer was re-extracted with EtOAc (2 × 100 ml).
The aqueous layer was then acidified with 1M HCl and
extracted with EtOAc (250 ml), the EtOAc layer being washed
with brine (200 ml), dried (MgSO4) and evaporated in vacuo to
give recovered starting material 5a (0.25 g, 2.8%). The neutral
organic extracts were washed with brine (300 ml), dried
(MgSO4) and evaporated in vacuo to give a crude mixture of
epimeric alcohols 8 and 9 (ratio 63 : 1). Recrystallisation from
CHCl3–hexane gave alcohol 8 (7.36 g, 81%), contaminated with
traces (<1.5%) of alcohol 9, as a colourless crystalline solid;
mp 129–130.5 ЊC; Rf = 0.07 (EtOAc–DCM, 1 : 3); [α]2D0 = ϩ72.4
(c = 0.98 in CHCl3); found: C, 55.9; H, 7.3; N, 5.3; C12H19NO5
requires: C, 56.0; H, 7.4; N, 5.5%; νmax (Nujol) 3325 (br m), 1740
(s), 1690 (s) and 1680 (s) cmϪ1; δH (200 MHz, CDCl3) 0.87 (9H,
s, C(CH3)3), 2.83 (1H, dd, J = 16.0 Hz, JЈ = 8.0 Hz, CHHЈCH),
3.05 (1H, br s, OH), 3.16 (1H, dd, J = 16.0 Hz, JЈ = 10.5 Hz,
CHHЈCH), 3.57 (1H, d, J = 8.5 Hz, C(4)HHЈ), 3.83 (3H, s,
t
CO2CH3), 4.57 (1H, m, CHHЈCH), 4.87 (1H, s, BuCH) and
4.89 (1H, d, J = 8.5 Hz, C(4)HHЈ); δC (50.3 MHz, CDCl3) 24.7
(C(CH3)3), 36.0 (C(CH3)3), 43.0 (C(7)H2), 52.6 (CO2CH3),
75.6 (C(4)H2 and C(6)H), 77.5 (C(5)), 96.2 (tBuCH) and 170.7
and 175.2 (carbonyls); m/z (CI) 258 (M ϩ Hϩ, 100%) and 200
(M ϩ Hϩ Ϫ tBuH, 48).
Purification of the residue by careful column chroma-
tography (EtOAc–petrol, 2 : 3) gave alcohols 8 (0.75 g, 8.3%)
and 9 (0.04 g, 0.4%) as a crystalline solid; mp 104–105.5 ЊC; Rf
= 0.12 (EtOAc–DCM, 1 : 3); [α]2D5 = ϩ29.4 (c = 0.35 in CHCl3);
found: C, 56.03; H, 7.68; N, 5.40; C12H19NO5 requires: C, 56.02;
H, 7.44; N, 5.45%; νmax (CHCl3) 3605 (w), 3500–3100 (br w),
2960 (m), 1740 (m), 1720 (s) and 1085 (s) cmϪ1; δH (200 MHz,
CDCl3) 0.89 (9H, s, C(CH3)3), 2.46 (1H, d, J = 17.0 Hz,
CHHЈCH), 3.38 (1H, dd, J = 17.0 Hz, JЈ = 6.0 Hz, CHHЈCH),
3.81 (3H, s, CO2CH3), 4.24 (1H, d, J = 9.0 Hz, C(4)HHЈ),
4.41 (1H, t, J = 6.0 Hz, CHHЈCH), 4.58 (1H, d, J = 9.0 Hz,
t
C(4)HHЈ) and 4.92 (1H, s, BuCH); δC (125.7 MHz, CDCl3)
24.88 (C(CH3)3), 36.21 (C(CH3)3), 44.65 (C(7)H2), 52.92
(CO2CH3), 67.30 and 71.16 (C(4)H2 and C(6)H), 77.89 (C(5)),
96.38 (tBuCH) and 171.9 and 177.2 (CO); m/z (CI) 275 (M ϩ
NH4ϩ, 9%), 258 (M ϩ Hϩ, 100) and 200 (25), along with acetate
10 (5.11) (0.01 g, 0.1%) as a colourless oil, Rf = 0.24 (EtOAc–
petrol, 3 : 7); νmax (CHCl3) 2960 (m), 1750 (s), 125 (s) and 1080
(m) cmϪ1; δH (200 MHz, CDCl3) 0.86 (9H, s, C(CH3)3), 2.02
(3H, s, CH3CO2), 2.80 (1H, dd, J = 15.5 Hz, JЈ = 8.0 Hz,
CHHЈCH), 3.27 (1H, dd, J = 15.5 Hz, JЈ = 11.0 Hz, CHHЈCH),
3.72 (1H, d, J = 9.5 Hz, C(4)HHЈ), 3.79 (3H, s, CO2CH3), 4.82
In view of the successful modification of the C(5) ester
function of 5 by organometallic addition, it was of interest
to investigate the reactions of the corresponding aldehyde.
However, attempted oxidation of alcohol 15a to the aldehyde
31 using Swern conditions gave not this product, but the corre-
sponding dimer 32 in 42% yield; disappointingly, although this
compound gave an acceptable yield (56%) of product 33 (along
with 5% of the Z-isomer) by reaction with the stabilised Wittig
reagent, non-stabilised ylides and Grignards, with or without
Lewis acid activation, gave none of the desired products.
t
(1H, d, J = 9.5 Hz, C(4)HHЈ), 4.86 (1H, s, BuCH) and 5.22
(1H, dd, J = 11.0 Hz, JЈ = 8.0 Hz, CHHЈCH); δC (125.7 MHz,
CDCl3) 20.41 (CH3CO2), 24.76 (C(CH3)3), 36.06 (C(CH3)3),
40.00 (C(7)H2), 52.73 (CO2CH3), 73.39 and 73.91 (C(4)H2, C(5)
and C(6)H), 95.99 (tBuCH) and 169.5, 170.0 and 173.1 (CO);
m/z (GCMS) 300 (M ϩ Hϩ, 2%), 240 (100) and 182 (70).
Conclusion
We have shown that hydroxylated pyrrolidinones are available
by reduction or organometallic addition to protected tetramic
84
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90

View Article Online
(2R,3S)-3-Hydroxy-2-hydroxymethyl-2-methoxycarbonyl-
pyrrolidin-5-one 11
(EtOAc–petrol, 3 : 7); [α]2D5 = ϩ7.2 (c = 0.61 in CHCl3); found: C,
63.23; H, 5.97; N, 3.76; C19H23NO6 requires: C, 63.14; H, 6.42;
N, 3.88%; νmax (CHCl3) 2960 (m), 2870 (w), 1745 (m), 1725 (s)
and 1600 (w) cmϪ1; δH (200 MHz, CDCl3) 0.90 (9H, s, C(CH3)3),
2.99 (1H, dd, J = 15.5 Hz, JЈ = 8.0 Hz, C(7)HHЈ), 3.46 (1H, dd,
J = 15.5 Hz, JЈ = 11.0 Hz, C(7)HHЈ), 3.69 (3H, s, CO2CH3), 3.85
(1H, d, J = 9.0 Hz, C(4)HHЈ), 4.94 (1H, s, tBuCH), 4.95 (1H, d,
J = 9.0 Hz, C(4)HHЈ), 5.50 (1H, dd, J = 11.0 Hz, JЈ = 8.0 Hz,
C(6)H), 7.43–7.51 (2H, m, ArH), 7.58–7.66 (1H, m, ArH) and
7.98 (2H, d, J = 7.0 Hz, ArH); δC (50.3 MHz, CDCl3) 24.6
(C(CH3)3), 35.8 (C(CH3)3), 40.1 (C(7)H2), 52.7 (CO2CH3), 73.7,
73.8 and 75.7 (C(4)H2, C(5) and C(6)H), 96.0 (tBuCH), 128.5,
128.8, 129.7 and 133.9 (aromatic) and 165.7, 169.6 and 173.6
(CO); m/z (CI) 379 (M ϩ NH4ϩ, 5%), 362 (M ϩ Hϩ, 100)
and 304 (24).
To a solution of alcohol 8 (1.0 g, 3.89 mmol) in acidic 2,2,2-
trifluoroethanol (2% w/v HCl) (15 ml) was added propane-1,3-
dithiol (0.4 ml, 0.43 g, 4.0 mmol). The mixture was stirred at
room temperature for 5 h and silica (5 ml) was added before the
solvent was removed in vacuo. The silica loaded material was
placed on top of a silica filled (50 ml) sinter funnel and eluted
with EtOAc–hexane 1 : 1 (200 ml) followed by MeOH–EtOAc,
1 : 4 (200 ml) to give diol 11 (0.73 g, 99%) as an off-white,
hygroscopic crystalline solid; mp 45–47 ЊC; Rf = 0.09 (MeOH–
EtOAc, 1 : 9); [α]2D5 = ϩ16.9 (c = 1.13 in MeOH); found: C,
44.1; H, 6.1; N, 7.4; C7H11NO5 requires: C, 44.4; H, 5.9; N,
7.4%; νmax (Nujol) 3340 (br s), 3290 (br s), 1735 (s) and 1685 (s)
cmϪ1; δH (200 MHz, CD3OD) 2.27 (1H, dd, J = 17.0 Hz, JЈ = 3.5
Hz, C(4)HHЈ), 2.73 (1H, dd, J = 17.0 Hz, JЈ = 7.0 Hz,
C(4)HHЈ), 3.71 (1H, d, J = 11.0 Hz, CHHЈOH), 3.76 (3H, s,
CO2CH3), 3.91 (1H, d, J = 11.0 Hz, CHHЈOH) and 4.36 (1H,
dd, J = 7.0 Hz, JЈ = 3.5 Hz, C(3)HOH); δC (50.3 MHz, CD3OD)
(2R,3S)-3-Benzoyloxy-2-hydroxymethyl-2-methoxycarbonyl-
pyrrolidin-5-one 15a
To a solution of crude bicycle 14 (400 mg, 1.11 mmol) in acidic
trifluoroethanol (1.5% w/v HCl) (15 ml) was added propane-
1,3-dithiol (0.12 ml, 129 mg, 1.20 mmol). The mixture was
stirred at room temperature for 22 h and solvent was then
removed in vacuo at room temperature. Purification by column
chromatography (EtOAc increasing polarity to MeOH–EtOAc,
1 : 9) gave amido alcohol 15a (315 mg, 97%) as a crystalline
solid; mp 138–139.5 ЊC; Rf = 0.29 (EtOAc); [α]2D5 = ϩ61.9 (c =
1.11 in CHCl3); found: C, 57.21; H, 4.93; N, 4.57; C14H15NO6
requires: C, 57.33; H, 5.16; N, 4.78%; νmax (CHCl3) 3420 (w),
3500–3150 (br w), 1725 (s), 1600 (w) and 1270 (s) cmϪ1; δH (200
MHz, CDCl3) 2.53 (1H, dd, J = 18.0 Hz, JЈ = 2.5 Hz, C(4)HHЈ),
3.06 (1H, dd, J = 18.0 Hz, JЈ = 7.0 Hz, C(4)HHЈ), 3.65 (3H,
s, CO2CH3), 3.94 (1H, d, J = 11.5 Hz, CHHЈOH), 4.08 (1H, d,
J = 11.5 Hz, CHHЈOH), 4.72 (1H, br s, OH), 5.71 (1H, dd,
J = 7.0 Hz, JЈ = 2.5 Hz, C(3)H), 7.39–7.46 (2H, m, ArH), 7.54–
7.61 (1H, m, ArH) and 7.91–7.99 (3H, m, ArH and NH);
δC (50.3 MHz, CDCl3) 38.0 (C(4)H2), 52.7 (CO2CH3), 65.2, 71.8
and 72.4 (CH2OH, C(2) and C(3)H), 128.4, 128.8, 129.7 and
133.9 (ArC) and 164.8, 169.4 and 175.9 (CO); m/z (CI) 311
(M ϩ NH4ϩ, 30%) and 294 (M ϩ Hϩ, 100).
40.9 (C(4)H2), 52.8 (CO2CH3), 65.6 (CH2OH), 71.2 (C(3)H),
ϩ
75.5 (C(2)) and 171.9 and 178.5 (CO); m/z (CI) 207 (M ϩ NH4
,
6%), 190 (M ϩ Hϩ, 100) and 130 (8).
(2R,3S)-3-Hydroxy-2-hydroxymethylglutamic acid dimethyl
ester 12
A solution of alcohol 8 (200 mg, 0.78 mmol) in methanolic HCl
(5% w/v HCl) (10 ml) was heated at reflux for 7.5 h. After
cooling to room temperature the solvent was removed in vacuo
and the residue was purified by column chromatography
(MeOH–EtOAc, 1 : 9) giving glutamate 12 as a white foam
contaminated with 8% of pyroglutamate 11 (170 mg); Rf = 0.17
(MeOH–EtOAc, 1 : 9); νmax (Nujol) 3350 (br s), 1740 (s), 1440
(m) and 1250 (m) cmϪ1; δH (200 MHz, CD3OD) 2.49 (1H, dd,
J = 16.0 Hz, JЈ = 10.0 Hz, C(4)HHЈ), 2.71 (1H, dd, J = 16.0 Hz,
JЈ = 3.5 Hz, C(4)HHЈ), 3.71 (3H, s, CO2CH3), 3.72 (1H, d, J =
11.5 Hz, CHHЈOH), 3.85 (3H, s, CO2CH3), 3.96 (1H, d, J = 11.5
Hz, CHHЈOH) and 4.52 (1H, dd, J = 10.0 Hz, JЈ = 3.5 Hz,
C(3)H); δC (125.7 MHz, CD3OD) 37.99 (CH2CO2Me), 52.46
and 53.93 (2 × CO2CH3), 62.18 (CH2OH), 68.75 (CHOH),
70.21 (CNH2) and 170.7 and 172.6 (ester CO); m/z (CI) 222
(M ϩ Hϩ, 100%) and 190 (17).
(2R,3S)-3-Benzoyloxy-2-tert-butoxycarbonyloxymethyl-2-
methoxycarbonylpyrrolidin-5-one 15b
To a solution of amido alcohol 15a (50 mg, 0.17 mmol) and
pyridine (28 µl, 27 mg, 0.35 mmol) in DCM (3 ml) was added
(BOC)2O (75 mg, 0.34 mmol). The mixture was stirred at room
temperature for 5 h and solvent was then removed in vacuo.
Purification by column chromatography (EtOAc–petrol 2 : 3)
gave carbonate 15b (62 mg, 92%) as colourless needles;
mp 144.5–146 ЊC; Rf = 0.09 (EtOAc–petrol, 3 : 7); [α]2D2 = ϩ63.9
(c = 1.08 in CHCl3); found: C, 58.28; H, 5.67; N, 3.30;
C19H23NO8 requires: C, 58.01; H, 5.89; N, 3.56%; νmax (CHCl3)
3430 (w), 1745 (s) and 1725 (s) cmϪ1; δH (200 MHz, CDCl3) 1.47
(9H, s, C(CH3)3), 2.56 (1H, dd, J = 17.5 Hz, JЈ = 3.5 Hz,
C(4)HHЈ), 2.99 (1H, dd, J = 17.5 Hz, JЈ = 7.0 Hz, C(4)HHЈ),
3.68 (3H, s, CO2CH3), 4.29 (1H, d, J = 11.0 Hz, CHHЈOBoc),
4.61 (1H, d, J = 11.0 Hz, CHHЈOBoc), 5.70 (1H, dd, J = 7.0 Hz,
JЈ = 3.5 Hz, C(3)H), 6.70 (1H, br s, NH), 7.44 (2H, t, J = 7.5 Hz,
ArH), 7.59 (1H, t, J = 7.5 Hz, ArH) and 7.94 (2H, d, J = 7.5 Hz,
ArH); δC (50.3 MHz, CDCl3) 27.6 (C(CH3)3), 37.1 (C(4)H2),
53.1 (CO2CH3), 68.0, 69.1 and 71.6 (CH2OBoc, C(2) and
C(3)H), 83.4 (C(CH3)3), 128.6, 129.6 and 133.8 (ArC), 152.7
(carbonate CO) and 164.8, 168.4 and 173.7 (amide and ester
CO); m/z (CI) 411 (M ϩ NH4ϩ, 2%), 394 (M ϩ Hϩ, 2), 294
(100), 142 (50) and 105 (48).
Alcohol 11 from lactam 13 by sodium triacetoxyborohydride
reduction
To AcOH (3 ml) cooled in a water bath was added portionwise
NaBH4 (38 mg, 1 mmol) and the mixture was stirred until H2
evolution ceased (about 10 min). A solution of keto alcohol 13
(90 mg, 0.48 mmol) in AcOH (2 ml) was then added dropwise
and the mixture was stirred at room temperature for 5.5 h.
Solvent was removed in vacuo and the residue was purified
by column chromatography (EtOAc increasing polarity to
MeOH–EtOAc, 1 : 4) to give diol 11 (52 mg, 58%) as a hygro-
scopic, off-white crystalline solid. Data as described above.
(2R,5R,6S)-6-Benzoyloxy-2-(tert-butyl)-5-methoxycarbonyl-8-
oxo-3-oxa-1-azabicyclo[3.3.0]octane 14
To a solution of alcohol 8 (1.0 g, 3.89 mmol) and pyridine (1 ml,
0.72 g, 9.13 mmol) in DCM (25 ml) was added dropwise
benzoyl chloride (1.0 ml, 1.22 g, 8.6 mmol). The mixture was
heated at reflux for 24 h, allowed to cool to room temperature
then partitioned between DCM (30 ml) and NH4Cl (aq)
(40 ml). The organic layer was washed with 5% aq NaHCO3
(40 ml), water (40 ml) and brine (40 ml), dried (MgSO4) and
evaporated in vacuo to give a quantitative yield of the title
compound 14 as colourless needles contaminated with benzoic
acid. An analytical sample was prepared by column chroma-
tography (EtOAc–petrol, 1 : 19 increasing polarity to EtOAc–
petrol, 1 : 4) (93% recovery); mp 174.5–175.5 ЊC; Rf = 0.56
(2S)-1-tert-Butoxycarbonyl-2-tert-butoxycarbonyloxymethyl-2-
methoxycarbonyl-2,5-dihydro-1H-pyrrol-5-one 16
To a solution of amido alcohol 15a (100 mg, 0.34 mmol),
triethylamine (48 µl, 35 mg, 0.34 mmol) and DMAP (42 mg,
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
85

View Article Online
0.34 mmol) in DCM (5 ml) was added (Boc)2O (150 mg, 0.69
mmol). The mixture was stirred at room temperature for 5 h
and solvent was then removed in vacuo. Purification by column
chromatography (EtOAc–petrol, 1 : 3 increasing polarity to
EtOAc–petrol 2 : 3) gave carbonate 15b (41 mg, 31%) as colour-
less needles and alkene 16 (73 mg, 58%) as a colourless oil;
Rf = 0.34 (EtOAc–petrol, 3 : 7); [α]2D2 = ϩ34.7 (c = 2.39 in
CHCl3); νmax (CHCl3) 2985 (m), 1790 (s), 1745 (s), 1370 (m) and
1330 (s) cmϪ1; δH (200 MHz, CDCl3) 1.41 and 1.51 (18H, 2 × s,
2 × C(CH3)3), 3.74 (3H, s, CO2CH3), 4.76 (1H, d, J = 12.0 Hz,
CHHЈOBoc), 4.87 (1H, d, J = 12.0 Hz, CHHЈOBOC), 6.22 (1H,
3400–3200 (br), 1715 (s), 1600 (m) and 1130 (s) cmϪ1; δH (200
MHz, CDCl3) 0.91 (9H, s, C(CH3)3), 1.18 (3H, d, J = 7.5 Hz,
CHCH3), 3.31 (1H, dq, Jd = 5.0 Hz, Jq = 7.5 Hz, CHCH3), 3.82
(3H, s, CO2CH3), 4.23 (1H, d, J = 9.0 Hz, C(4)HHЈ), 4.40 (1H,
d, J = 5.0 Hz, CHOH), 4.55 (1H, d, J = 9.0 Hz, C(4)HHЈ) and
t
4.92 (1H, s, BuCH); δC (125.7 MHz, CDCl3) 7.77 (CHCH3),
24.91 (C(CH3)3), 36.27 (C(CH3)3), 44.77 (CHCH3), 52.88
(CO2CH3), 67.71 (CHOH), 74.40 (C(4)H2), 75.75 (C(5)), 96.45
ϩ
,
(tBuCH) and 172.0 and 178.9 (CO); m/z (CI) 289 (M ϩ NH4
3%), 272 (M ϩ Hϩ, 100) and 214 (40).
d, J = 6.5 Hz, CH᎐CHЈ) and 7.00 (1H, d, J = 6.5 Hz, CH᎐CHЈ);
Epimerisation of 17b with sodium methoxide
᎐
᎐
δC (50.3 MHz, CDCl3) 27.3 and 27.7 (2 × C(CH3)3), 53.1
(CO2CH3), 63.5 and 72.3 (CH2OBoc and C(2)), 83.0 and
84.1 (2 × C(CH3)3), 128.8 and 145.8 (vinylic), 148.2 and 153.1
(2 × carbonate CO) and 167.2 and 168.6 (amide and ester CO);
m/z (CI) 389 (M ϩ NH4ϩ, 10), 372 (M ϩ Hϩ, 12), 216 (100) and
142 (100).
A solution of alcohol 17b (20 mg, 0.07 mmol) and NaOMe
(40 mg, 0.74 mmol) in MeOH (3 ml) was stirred at room
temperature for 15.75 h and then partitioned between EtOAc
(10 ml) and brine (5 ml), the organic layer being dried (MgSO4)
and evaporated in vacuo to give 20 mg of a 30 : 1 mixture of
alcohol 17a–alcohol 17b.
(2R,5R,6S,7S)-, (2R,5R,6S,7R)- and (2R,5R,6R,7S)-2-tert-
Butyl-6-hydroxy-5-methoxycarbonyl-7-methyl-8-oxo-3-oxa-1-
azabicyclo[3.3.0]octane 17a, 17b and 17c
Epimerisation of 17a with sodium methoxide
A solution of alcohol 17a (15 mg, 0.06 mmol) and NaOMe
(30 mg, 0.55 mmol) in MeOH (2.5 ml) was stirred at 0 ЊC for
5.25 h and then partitioned between EtOAc (10 ml) and brine
(5 ml), the organic layer being dried (MgSO4) and evaporated
in vacuo to give 15 mg of alcohol 17a, no other diastereomers
being seen in the NMR spectrum.
To a deoxygenated solution of lactam 5b (617 mg, 2.3 mmol) in
10% AcOH in DCM (20 ml) under N2 was added, portionwise
over 45 min, NaBH4 (265 mg, 7 mmol). The mixture was stirred
at room temperature for 20 h, the solvent was evaporated
in vacuo and the residue was partitioned between EtOAc (40 ml)
and 5% NaHCO3 (aq) (40 ml). The aqueous layer was acidified
with 2 M HCl and extracted with EtOAc (2 × 20 ml). The
EtOAc extracts were washed with brine (30 ml), dried (MgSO4)
and evaporated in vacuo to give unreacted starting material
(5b) (181 mg, 29%). The organic layer was washed with brine
(30 ml), dried (MgSO4) and evaporated in vacuo. Purification by
careful multiple column chromatography (DCM–EtOAc, 1 : 4
increasing polarity to DCM–EtOAc, 1 : 1) gave the alcohols 17c
(26 mg, 4%), 17a (197 mg, 32%) and 17b (100 mg, 16%) as
colourless crystalline solids.
(2R,5S)-2-tert-Butyl-5-methoxycarbonyl-7-methyl-8-oxo-3-oxa-
1-azabicyclo[3.3.0]oct-6-ene 19
To a solution of triphenylphosphine (17 mg, 0.065 mmol),
benzoic acid (8 mg, 0.066 mmol) and alcohol 17b (16 mg,
0.059 mmol) in THF (2.5 ml) under N2 was added dropwise a
solution of diethyl azodicarboxylate (11 mg, 0.063 mmol)
in THF (1.5 ml). The mixture was stirred at room temperature
for 24 h and then partitioned between ether (5 ml) and 5%
NaHCO3 (aq) (5 ml). The ether layer was washed with brine
(5 ml), dried (MgSO4) and evaporated in vacuo. Purification
by column chromatography (DCM increasing polarity to EtO-
Ac–DCM, 1 : 3) gave starting material 17b (6 mg, 38%) (after
recrystallisation from CHCl3–hexane to remove triphenyl-
phosphine oxide) and alkene 19 (5 mg, 33%) as a viscous oil;
Rf = 0.13 (DCM); [α]2D2 = ϩ210 (c = 0.22 in CHCl3); νmax (CHCl3)
2960 (m), 2870 (w), 1745 (s) and 1715 (s) cmϪ1; δH (200 MHz,
CDCl3) 0.97 (9H, s, C(CH3)3), 1.92 (3H, d, J = 1.5 Hz,
Data for 17a. Mp 104–105.5 ЊC; Rf = 0.18 (EtOAc–DCM,
1 : 9); [α]2D5 = ϩ32.0 (c = 1.10 in CHCl3); found: C, 57.8; H, 7.7;
N, 5.2; C13H12NO5 requires: C, 57.6; H, 7.8; N, 5.2%; νmax
(CHCl3) 3685 (w), 3605 (w), 2975 (m), 1720 (s), 1600 (w) and
1105 (m) cmϪ1; δH (200 MHz, CDCl3) 0.88 (9H, s, C(CH3)3),
1.23 (3H, d, J = 7.0 Hz, CHCH3), 2.60 (1H, br s, CHOH),
3.22 (1H, dq, Jd = 10.5 Hz, Jq = 7.0 Hz, CHCH3), 3.52 (1H, d,
J = 9.0 Hz, C(4)HHЈ), 3.83 (3H, s, CO2CH3), 4.04 (1H, dd, J =
CH᎐CCH ), 3.26 (1H, d, J = 8.5 Hz, C(4)HHЈ), 3.76 (3H, s,
᎐
3
t
t
CO2CH3), 4.69 (1H, s, BuCH), 4.78 (1H, d, J = 8.5 Hz,
10.5 Hz, JЈ = 6.0 Hz, CHOH), 4.89 (1H, s, BuCH) and 4.92
C(4)HHЈ) and 6.73 (1H, d, J = 1.5 Hz, CH᎐CCH ); δ (125.7
᎐
3
C
(1H, d, J = 9.0 Hz, C(4)HHЈ); δC (50.3 MHz, CDCl3) 11.9
(CHCH3), 24.5 (C(CH3)3), 35.9 (C(CH3)3), 46.8 (CHCH3), 52.6
(CO2CH3), 74.0 (C(4)H2), 75.4 (C(5)), 81.2 (CHOH), 96.0
(tBuCH) and 171.0 and 177.4 (carbonyls); m/z (CI) 289 (M ϩ
NH4ϩ, 4%), 272 (M ϩ Hϩ, 100) and 214 (M ϩ Hϩ Ϫ tBuH, 30).
MHz, CDCl ) 11.04 (CH᎐CCH ), 24.83 (C(CH ) ), 35.23
᎐
3
3
3 3
(C(CH3)3), 52.90 (CO2CH3), 71.11 (C(4)H2), 75.60 (C(5)), 96.85
(tBuCH), 138.6 and 139.3 (CH᎐CCH ) and 169.9 and 178.3
᎐
3
(carbonyls); m/z (GCMS) 254 (M ϩ Hϩ, 100%) and 196 (15).
(2R,3S)-3-Hydroxy-2-hydroxymethyl-2-methoxycarbonyl-4-
methylpyrrolidin-5-one 21
Data for 17b. Mp 112–115 ЊC; Rf = 0.15 (EtOAc–DCM, 1 : 9);
[α]2D5 = ϩ66.4 (c = 1.15 in CHCl3); νmax (CHCl3) 3685 (w), 3610
(w), 2960 (m), 1715 (s), 1600 (w) and 1090 (m) cmϪ1; δH (200
MHz, CDCl3) 0.90 (9H, s, C(CH3)3), 1.42 (3H, d, J = 7.5 Hz,
CHCH3), 2.68 (1H, br d, J = 7.0 Hz, CHOH), 2.97 (1H, dq,
Jd = 9.0 Hz, Jq = 7.5 Hz, CHCH3), 3.45 (1H, d, J = 8.5 Hz,
C(4)HHЈ), 3.82 (3H, s, CO2CH3), 4.54 (1H, dd, J = 9.0 Hz, JЈ =
7.0 Hz, CHOH), 4.87 (1H, s, BuCH) and 4.93 (1H, d, J = 8.5
Hz, C(4)HHЈ); δC (125.7 MHz, CDCl3) 11.97 (CHCH3), 25.65
(C(CH3)3), 36.40 (C(CH3)3), 47.21 (CHCH3), 53.34 (CO2CH3),
To AcOH (2 ml) cooled in a water bath was added portionwise
NaBH4 (30 mg, 0.79 mmol) and the mixture was stirred until H2
evolution ceased (about 10 min). A solution of keto alcohol 20
(80 mg, 0.40 mmol) in AcOH (0.5 ml) was then added dropwise
and the mixture was stirred at room temperature for 2.75 h.
Solvent was removed in vacuo and the residue was purified
by column chromatography (EtOAc increasing polarity to
MeOH–EtOAc, 1 : 4) to give a 3 : 2 mixture of the epimers of
diol 21 (41 mg, 51%) as a colourless glass; Rf = 0.49 and 0.41
(MeOH–EtOAc, 1 : 3); νmax (KBr) 3700–2600 (br s), 1730 (s)
and 1695 (s) cmϪ1; δH (200 MHz, D2O) (major epimer) 1.00 (3H,
d, J = 7.5 Hz, CHCH3), 2.40 (1H, quin, J = 7.5 Hz, C(4)H), 3.56
(1H, d, J = 12.0 Hz, CHHЈOH), 3.61 (3H, s, CO2CH3), 3.89
(1H, d, J = 7.5 Hz, C(3)HOH) and 3.93 (1H, d, J = 12.0 Hz,
t
73.15, 75.14 and 78.55 (CHOH, C(4)H2 and C(5)), 97.66
ϩ
(tBuCH) and 171.8 and 181.6 (CO); m/z (CI) 289 (M ϩ NH4
1%), 272 (M ϩ Hϩ, 100) and 214 (20).
,
Data for 17c. Mp 115–117 ЊC; Rf = 0.23 (EtOAc–DCM, 1 : 9);
[α]2D5 = ϩ28 (c = 0.1 in CHCl3); νmax (CHCl3) 3690 (w), 3610 (w),
86
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90

View Article Online
CHHЈOH); (minor epimer) 0.89 (3H, d, J = 7.5 Hz, CHCH3),
2.67 (1H, quin, J = 7.0 Hz, C(4)H), 3.55 (1H, d, J = 11.0 Hz,
CHHЈOH), 3.61 (3H, s, CO2CH3), 3.85 (1H, d, J = 11.0 Hz,
CHHЈOH) and 4.18 (1H, d, J = 6.0 Hz, C(3)HOH); m/z (CI)
221 (M ϩ NH4ϩ, 6%), 204 (M ϩ Hϩ, 100) and 144 (18).
(40 ml), dried (MgSO4) and evaporated in vacuo to give an
inseparable 3 : 1 mixture of ketone 24a and alcohol 25a (0.89 g)
as a pale yellow crystalline solid; mp 191–192.5 ЊC; Rf = 0.32
(ketone), 0.36 (alcohol) (AcOH–EtOAc–DCM, 1 : 20 : 80); νmax
(KBr) 3600–3300 (br w), 3590 (w), 2980 (m), 2800–2100 (br w),
1730 (s), 1650 (s), 1575 (s), 1480 (s), 1315 (s) and 1295 (s) cmϪ1
;
δH (500 MHz, CD3OD) 0.87 (9H, s, C(CH3)3), 1.087 (3H,
d, J = 7.1 Hz, CH(CH3)(CH3)Ј), 1.09 (3H, d, J = 6.5 Hz,
CH(CH3)(CH3)Ј), 3.33 (1H, sept, J = 6.8 Hz, CH(CH3)2), 3.42
(1H, d, J = 8.5 Hz, C(4)HHЈ), 4.58 (1H, s, BuCH) and 4.84
(1H, d, J = 8.5 Hz, C(4)HHЈ); δC (125.7 MHz, CD3OD) 19.47
(2R,5R)-2-tert-Butyl-5-hydroxymethyl-6,8-dioxo-3-oxa-1-aza-
bicyclo[3.3.0]octane 22a
To a solution of ester 4a (95 mg, 0.37 mmol) in THF (5 ml) at
0 ЊC was added a solution of DIBAL-H (0.94 M in hexane,
1.6 ml, 1.50 mmol). The reaction was stirred at 0 ЊC for 1 h,
then quenched by the cautious addition of MeOH (1 ml) before
partitioning between ether (20 ml) and 2 M HCl (20 ml). The
aqueous layer was saturated with NaCl and re-extracted with
EtOAc (20 ml), the combined organic extracts being washed
with brine (30 ml), dried (MgSO4) and evaporated in vacuo to
give crude alcohol 22a (72 mg, 85%) as a brown oil; δH (200
MHz, CDCl3) 0.96 (9H, s, C(CH3)3), 3.05 (1H, d, J = 21.5 Hz,
C(7)HHЈ), 3.53 (1H, d, J = 21.5 Hz, C(7)HHЈ), 3.56 (1H, d,
J = 9.0 Hz, C(4)HHЈ), 3.78 (1H, d, J = 9.0 Hz, C(4)HHЈ), 3.82
(1H, d, J = 11.0 Hz, CHHЈOH), 3.98 (1H, d, J = 11.0 Hz,
t
and 21.78 (CH(CH3)2), 25.80 (C(CH3)3), 35.53 (CH(CH3)2),
35.85 (C(CH ) ), 68.95 (C(4)H ), 76.68 (C(5)), 96.34 (CD᎐
᎐
3
3
2
COH, JCD = 27 Hz), 99.03 (tBuCH), 178.8 (amide CO), 183.8
ϩ
(CD᎐COD) and 209.1 (ketone CO); m/z (CI) 285 (M ϩ NH
,
᎐
4
3%), 268 (M ϩ Hϩ, 100), 210 (24) and 197 (26).
Data for 25a are given below.
(2R,5R)-2-tert-Butyl-6-hydroxy-7-methyl-8-oxo-5-(2Ј-methyl-
propanoyl)-3-oxa-1-azabicyclo[3.3.0]oct-6-ene 24b
To a suspension of Li (0.5% Na, 30% dispersion in mineral oil)
(230 mg, 9.94 mmol) in petrol (10 ml) was added isopropyl
chloride (100 µl, 86 mg, 1.1 mmol). The flask was placed in a
sonicator for 5 minutes and isopropyl chloride (300 µl, 238 mg,
3.3 mmol) was then added in 3 portions over 30 min. After
stirring for a further 1.5 h the reaction was cooled to Ϫ78 ЊC
and a solution of ester 5b (237 mg, 0.88 mmol) in THF (10 ml)
was added dropwise over 10 min. After 2 h at Ϫ78 ЊC the reac-
tion was quenched by the cautious addition of water. After
warming to room temperature the mixture was partitioned
between ether (40 ml) and water (40 ml). The aqueous layer was
acidified with 2 M HCl and extracted with ether (2 × 25 ml), the
ether extract being washed with brine (40 ml), dried (MgSO4)
and evaporated in vacuo. Recrystallisation from EtOAc–
CHCl3–petrol gave ketone 24b (62 mg, 25%) as colourless
crystals. A second crop (82 mg, 33%) was obtained containing
alcohol 25b as a minor component (<4%). The residue was a
3 : 2 mixture of ketone 24b–alcohol 25b [65 mg, 16% ketone
(24b), 10% alcohol (25b)]; mp 188–190.5 ЊC; [α]2D3 = ϩ286 (c =
0.94 in MeOH); νmax (KBr) 3440 (br s), 2980 (s), 2680 (br m),
1730 (s), 1655 (s), 1605 (s), 1325 (s) and 1175 (s) cmϪ1; δH (200
MHz, CD3OD) 0.87 (9H, s, C(CH3)3), 1.04 (3H, d, J = 7.0 Hz,
CH(CH3)(CH3)Ј), 1.06 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј),
t
CHHЈOH) and 4.98 (1H, s, BuCH); δC (50.3 MHz, CDCl3)
25.3 (C(CH3)3), 35.0 (C(CH3)3), 46.9 (C(7)H2), 63.7 and 67.2
(CH2OH and C(4)H2), 79.7 (C(5)), 98.5 (tBuCH), 174.5 (amide
CO) and 206.1 (ketone CO).
(2R,5R,6R)-2-tert-Butyl-6-hydroxy-5-hydroxymethyl-8-oxo-3-
oxa-1-azabicyclo[3.3.0]octane 23
NaBH4 (63 mg, 1.67 mmol) was added to AcOH (1.5 ml) and
stirred at room temperature for 15 min. After H2 evolution had
ceased a solution of crude alcohol 22a (38 mg, 0.17 mmol) in
acetone (1.5 ml) was added and the mixture was stirred at room
temperature for 2.5 h. Solvent was removed in vacuo and the
residue was partitioned between EtOAc (10 ml) and 5% aq
NaHCO3 (5 ml). The aqueous layer was re-extracted with
EtOAc (10 ml) and the combined organic layers were washed
with brine (10 ml), dried (MgSO4) and evaporated in vacuo.
Purification by column chromatography (EtOAc–petrol, 3 : 1
increasing polarity to EtOAc) gave diol 23 (27 mg, 70%) as
colourless crystals; mp 183–184.5 ЊC (decomp.); Rf = 0.17
(EtOAc); [α]2D1 = ϩ77.3 (c = 0.33 in MeOH); found: C, 57.3; H,
8.6; N, 5.8; C11H19NO4 requires: C, 57.6; H, 8.4; N, 6.1%; νmax
(KBr) 3410 (m), 3365 (m), 2970 (m), 1695 (s) and 1080 (m)
cmϪ1; δH (200 MHz, CD3OD) 0.93 (9H, s, C(CH3)3), 2.21 (1H,
d, J = 16.5 Hz, C(7)HHЈ), 3.28 (1H, dd, J = 16.5 Hz, JЈ = 5.5 Hz,
C(7)HHЈ), 3.60 (1H, d, J = 11.0 Hz, CHHЈOH), 3.70 (1H, d, J =
11.0 Hz, CHHЈOH), 3.78 (1H, d, J = 9.0 Hz, C(4)HHЈ), 4.03
(1H, d, J = 9.0 Hz, C(4)HHЈ), 4.41 (1H, d, J = 5.5 Hz, C(6)H)
and 4.73 (1H, s, tBuCH); δC (50.3 MHz, CD3OD) 26.2
(C(CH3)3), 36.5 (C(CH3)3), 46.0 (C(7)H2), 64.9, 67.9 and 70.6
(CH2OH, C(4)H2 and C(6)H), 77.2 (C(5)), 97.3 (tBuCH) and
180.5 (amide CO); m/z (CI) 230 (M ϩ Hϩ, 100%) and 172 (33).
1.69 (3H, s, CH C᎐COH), 3.24 (1H, sept, J = 7.0 Hz, CH-
᎐
3
(CH3)2), 3.33 (1H, d, J = 8.5 Hz, C(4)HHЈ), 4.83 (1H, s, tBuCH)
and 4.95 (1H, d, J = 8.5 Hz, C(4)HHЈ); δC (50.3 MHz, CDCl3)
4.8 (CH C᎐COH), 18.0 and 20.2 (CH(CH ) ), 24.3 (C(CH ) ),
᎐
3
3
2
3 3
33.6 and 34.3 (CH(CH3)2 and C(CH3)3), 67.4 (C(4)H2), 79.0
(C(5)), 97.4 (tBuCH), 103.8 (CH C᎐COH), 170.5 (amide CO),
᎐
3
183.1 (CH3C = COH) and 208.9 (ketone CO); m/z (CI) 299
(M ϩ NH4ϩ, 8%) and 282 (M ϩ Hϩ, 100).
(2R,5S,1ЈR)-2-tert-Butyl-6,8-dioxo-5-(1Ј-hydroxy-2Ј-methyl-
propyl)-3-oxa-1-azabicyclo[3.3.0]octane 25a
(2R,5R)-2-tert-Butyl-6,8-dioxo-5-(2Ј-methylpropanoyl)-3-oxa-
1-azabicyclo[3.3.0]octane 24a
Ammonia (12 ml) was condensed in a flask fitted with a dry ice
condenser at Ϫ78 ЊC and Li metal (0.35 g, 50.4 mmol) was then
added. After 15 min at Ϫ78 ЊC a solution of ketone 24a (con-
taminated with 25% alcohol 25a) (100 mg, 0.37 mmol) in THF
(4 ml) was added to the bronze solution and followed after
a further 5 min by ethanol (1 ml). The mixture was allowed to
warm to Ϫ33 ЊC over 10 min and further ethanol (1 ml) was
added. After 30 min at Ϫ33 ЊC the reaction was quenched by
the addition of excess ethanol (5 ml) and the mixture was
allowed to warm to room temperature. The reaction mixture
was partitioned between ether (15 ml) and water (15 ml), the
ether layer being extracted with sat. NaHCO3 (aq) (2 × 15 ml).
The combined aqueous layers were acidified with conc. HCl
and extracted with ether (2 × 20 ml), the ether layers being
washed with brine (25 ml), dried (MgSO4) and evaporated
To a suspension of Li (0.5% Na, 30% dispersion in mineral oil)
(1.00 g, 43.2 mmol) in petrol (15 ml) was added isopropyl
chloride (0.3 ml, 0.26 g, 3.3 mmol). The flask was placed in a
sonicator for 5 minutes and isopropyl chloride (1.5 ml, 1.29 g,
16.4 mmol) was then added over 1 h so as to keep the mixture at
a gentle reflux. After stirring for a further 1 h the reaction was
cooled to Ϫ78 ЊC and a solution of ester 5a (0.89 g, 3.49 mmol)
in THF (15 ml) was added dropwise over 10 min. After 3 h at
Ϫ78 ЊC the reaction was quenched by the cautious addition of
water. After warming to room temperature the mixture was
partitioned between ether (50 ml) and water (50 ml). The
aqueous layer was acidified with 2 M HCl and extracted with
ether (2 × 30 ml), the ether extract being washed with brine
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
87

View Article Online
in vacuo to give alcohol 25a (74 mg, 70% from ester 5a) as a pale
pink crystalline solid; mp 168–170 ЊC; Rf = 0.36 (AcOH–
EtOAc–DCM, 1 : 20 : 80); [α]2D3 = ϩ98.2 (c = 1.14 in CHCl3); νmax
(KBr) 3600–2200 (br m), 2960 (s), 1680 (s), 1650 (s), 1610 (s)
and 1290 (s) cmϪ1; δH (200 MHz, CDCl3) 0.84 (3H, d, J = 7.0
Hz, CH(CH3)(CH3)Ј), 0.99 (9H, s, C(CH3)3), 1.07 (3H, d, J =
7.0 Hz, CH(CH3)(CH3)Ј), 2.14 (1H, d sept, Jsept = 7.0 Hz,
Jd = 1.5 Hz, CH(CH3)2), 2.56 (1H, br s, OH), 3.22 (1H, d,
J = 22.0 Hz, C(7)HHЈ), 3.46 (1H, d, J = 9.0 Hz, C(4)HHЈ),
3.54 (1H, d, J = 22.0 Hz, C(7)HHЈ), 3.77 (1H, br s, CHOH(iPr)),
4.51 (1H, d, J = 9.0 Hz, C(4)HHЈ) and 4.97 (tBuCH); δC (50.3
MHz, CDCl3) 16.2 and 21.7 (CH(CH3)2), 25.6 (C(CH3)3), 27.9
(CH(CH3)2), 34.9 (C(CH3)2), 46.5 (C(7)H2), 69.1, 77.0 and 79.3
(C(4)H2, C(5) and CHOH(iPr)), 99.7 (tBuCH), 174.2 (amide
CO) and 208.0 (ketone CO); m/z (CI) 270 (M ϩ Hϩ, 63%), 198
(59) and 140 (100).
evaporated in vacuo. Purification by column chromatography
(EtOAc–petrol, 1 : 4 increasing polarity to EtOAc) gave alcohol
26 (58 mg, 36% from ester (5a)), as a colourless oil, and a
mixture of alcohol 25a and diol 27. The crude alcohol–diol
mixture was partitioned between EtOAc (20 ml) and sat.
NaHCO3 (aq) (20 ml), the EtOAc layer being washed with brine
(15 ml), dried (MgSO4) and evaporated in vacuo. Precipitation
from EtOAc–petrol gave diol 27 (32 mg, 20% from ester (5a)) as
an amorphous solid. The aqueous layer was acidified with conc.
HCl and extracted with EtOAc (2 × 10 ml), the organic extracts
being washed with brine (15 ml), dried (MgSO4) and evaporated
in vacuo to give crude alcohol 25a (31 mg, 19% from ester 5a).
Method B. To a solution of crude ketone 24a (32 mg)
(contaminated with 25% alcohol (25a)) in EtOH (3 ml) was
added NaOMe (7 mg, 0.13 mmol). After stirring at room tem-
perature for 10 min NaBH4 (7 mg, 0.19 mmol) was added and
the mixture was stirred for a further 14 h. After partitioning
between ether (20 ml) and 2 M HCl (20 ml) the aqueous layer
was washed with ether (15 ml) and the combined organic
extracts were washed with brine (25 ml), dried (MgSO4) and
evaporated in vacuo. Purification by column chromatography
(EtOAc–petrol, 1 : 4 increasing polarity to EtOAc–petrol, 1 : 1)
gave diol 27 (2 mg) and alcohol 26 (15 mg) as a colourless oil;
Rf = 0.23 (EtOAc–petrol, 3 : 7); [α]2D3 = ϩ97.4 (c = 1.48 in
CHCl3); found: C, 62.40; H, 8.92; N, 5.05; C14H23NO4 requires:
C, 62.43; H, 8.61; N, 5.20%; νmax (film) 3600–3100 (br m), 3585
(m), 2960 (m), 1770 (m) and 1710 (s) cmϪ1; δH (200 MHz,
CDCl3) 1.02 (9H, s, C(CH3)3), 1.04 (3H, d, J = 7.0 Hz,
CH(CH3)(CH3)Ј), 1.07 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј),
1.87 (1H, oct, J = 7.0 Hz, CH(CH3)2), 2.53 (1H, br s, OH), 3.03
(1H, d, J = 20.0 Hz, C(7)HHЈ), 3.46 (1H, d, J = 7.5 Hz, CHOH),
3.68 (1H, d, J = 9.5 Hz, C(4)HHЈ), 3.68 (1H, dd, J = 20.0 Hz, JЈ
= 0.5 Hz, C(7)HHЈ), 4.15 (1H, d, J = 9.5 Hz, C(4)HHЈ) and
(2R,5R,1ЈR)-2-tert-Butyl-6-hydroxy-7-methyl-8-oxo-5-(1Ј-
hydroxy-2Ј-methylpropyl)-3-oxa-1-azabicyclo[3.3.0]octane 25b
Li reduction. Ammonia (5 ml) was condensed in a flask fitted
with a dry ice condenser and Li metal (7 mg, 1.0 mmol) was
then added. After 10 min at Ϫ33 ЊC a solution of ketone 24b
(20 mg, 0.07 mmol) in THF (3 ml) was added to the blue solu-
tion. After 10 min at Ϫ33 ЊC the reaction was quenched by the
addition of excess solid NH4Cl (0.5 g) and the mixture was
allowed to warm to room temperature. The reaction mixture
was partitioned between ether (15 ml) and water (15 ml), the
water layer being re-extracted with ether (15 ml). The combined
ether layers were washed with brine (25 ml), dried (MgSO4) and
evaporated in vacuo to give alcohol 25b (18 mg, 89%) as a light
brown foam; mp 135–138 ЊC; Rf = 0.09 (EtOAc–petrol, 3 : 7);
[α]2D3 = ϩ81.0 (c = 0.42 in CHCl3); νmax (film) 3600–3100 (br m),
2960 (m), 2800–2600 (br w) and 1660 (s) cmϪ1; δH (200 MHz,
CDCl3) 0.91 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј), 0.97 (9H, s,
C(CH3)3), 1.00 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј), 1.65 (3H,
t
4.97 (1H, s, BuCH); δC (50.3 MHz, CDCl3) 19.8 and 20.9
(CH(CH3)2), 25.5 (C(CH3)3), 30.5 (CH(CH3)2), 35.2 (C(CH3)3),
48.9 (C(7)H2), 68.4 (C(4)H2), 77.3 (CHOH), 82.1 (C(5)), 97.7
(tBuCH), 173.5 (amide CO) and 203.7 (ketone CO); m/z (CI)
287 (M ϩ NH4ϩ, 10%), 270 (M ϩ Hϩ, 100) and 212 (15).
s, CH C᎐COH), 2.23 (1H, sept, J = 7.0 Hz, CH(CH ) ), 3.37
᎐
3
3 2
(1H, d, J = 8.5 Hz, C(4)HHЈ), 3.62 (1H, br s, CHOH), 4.06
(1H, br s, CHOH(iPr)), 4.37 (1H, d, J = 8.5 Hz, C(4)HHЈ), 4.57
(1H, s, tBuCH) and 8.32 (1H, br s, CH C᎐COH); δ (50.3 MHz,
᎐
3
C
CDCl ) 5.5 (CH C᎐COH), 15.1 and 21.4 (CH(CH ) ), 25.3
᎐
3
3
3 2
(2R,5S,6S,1ЈS)-2-tert-Butyl-6-hydroxy-8-oxo-5-(1Ј-hydroxy-2Ј-
methylpropyl)-3-oxa-1-azabicyclo[3.3.0]octane 27
(C(CH3)3), 27.6 (CH(CH3)2), 34.6 (C(CH3)3), 71.0, 72.6 and
78.0 (C(4)H2, C(5) and CHOH(iPr)), 97.7 (tBuCH), 103.9
(CH C᎐COH), 172.7 (amide CO) and 182.2 (CH C᎐COH);
A solution of alcohol 26 (24 mg, 0.09 mmol) and PtO2 (10 mg)
in EtOAc (3 ml) was stirred at room temperature under 4–5 atm
pressure of H2 (Fischer bottle) for 16.5 h. The crude reaction
mixture was then filtered through Celite® to remove PtO2 and
evaporated in vacuo. Purification by column chromatography
(EtOAc–petrol, 3 : 7 increasing polarity to EtOAc–petrol, 1 : 1)
gave unreacted starting material 26 (18 mg, 75%) and diol 27
(6 mg, 25%) as an amorphous solid; mp 144–146 ЊC (decomp.);
Rf = 0.18 (EtOAc–petrol, 1 : 1); [α]2D3 = ϩ95.3 (c = 0.30 in
CHCl3); νmax (CHCl3) 3555 (m), 3315 (br m), 1670 (s) and 1350
(m) cmϪ1; δH (200 MHz, CDCl3) 1.00 (9H, s, C(CH3)3, 1.07 (6H,
d, J = 6.5 Hz, CH(CH3)2), 2.25 (1H, oct, J = 6.5 Hz, CH(CH3)2),
2.67 (1H, br d, J = 5.0 Hz, CHOH(iPr)), 2.85 (1H, dd, J = 16.5
Hz, JЈ = 8.5 Hz, C(7)HHЈ), 3.04 (1H, dd, J = 16.5 Hz, JЈ = 9.5
Hz, C(7)HHЈ), 3.32 (1H, d, J = 9.5 Hz, C(4)HHЈ), 3.41 (1H, br
d, J = 10.5 Hz, C(6)HOH), 3.85 (1H, dd, J = 6.5 Hz, JЈ = 5.0 Hz,
CHOH(iPr)), 4.38 (1H, d, J = 9.5 Hz, C(4)HHЈ), 4.41 (1H, q,
J = 9.0 Hz, C(6)HOH) and 4.78 (1H, s, tBuCH); δC (50.3 MHz,
CDCl3) 18.9 and 23.1 (CH(CH3)2), 26.0 (C(CH3)3, 30.2
(CH(CH3)2), 35.1 (C(CH3)3, 46.3 (C(7)H2), 73.6, 74.4, 76.7 and
79.2 (C(4)H2, C(5), C(6)H and CHOH(iPr)), 97.0 (tBuCH) and
177.4 (amide CO); m/z (CI) 272 (M ϩ Hϩ, 100%) and 214 (15).
᎐
᎐
3
3
m/z (CI) 317 (M ϩ O ϩ NH4ϩ, 3%), 300 (M ϩ O ϩ Hϩ, 10), 284
(M ϩ Hϩ, 100).
Na reduction. Ammonia (5 ml) was condensed in a flask
at Ϫ78 ЊC, fitted with a dry ice condenser, containing NH4Cl
(105 mg, 1.96 mmol). A solution of ketone 24b (33 mg,
0.12 mmol) in THF (3 ml) was added to the mixture, Na (40 mg,
1.74 mmol) was then added in four portions over 15 min and
the mixture was allowed to warm to room temperature. The
reaction mixture was partitioned between ether (15 ml) and
2 M HCl (15 ml), the aqueous layer being re-extracted with
ether (15 ml). The combined ether layers were washed with
brine (25 ml), dried (MgSO4) and evaporated in vacuo. Purifica-
tion by column chromatography (EtOAc–petrol, 1 : 3) gave
alcohol 25b (16 mg, 48%) and its epimer 28 (3 mg, 9%).
(2R,5S,1ЈS)-2-tert-Butyl-6,8-dioxo-5-(1Ј-hydroxy-2Ј-methyl-
propyl)-3-oxa-1-azabicyclo[3.3.0]octane 26
Method A. To a solution of crude ketone 24a (contaminated
with 25% alcohol 25a) (154 mg) in EtOH (8 ml) was added
NaOMe (43 mg, 0.80 mmol). After stirring at room tem-
perature for 20 min, NaBH4 (63 mg, 1.67 mmol) was added and
the mixture was stirred for a further 12 h. After partitioning
between ether (40 ml) and 2 M HCl (40 ml), the aqueous
layer was washed with ether (30 ml), the combined organic
extracts being washed with brine (50 ml), dried (MgSO4) and
(2R,5R,1ЈS)-2-tert-Butyl-6-hydroxy-7-methyl-8-oxo-5-(1Ј-
hydroxy-2Ј-methylpropyl)-3-oxa-1-azabicyclo[3.3.0]oct-6-ene 28
To a solution of ketone 24b (50 mg, 0.18 mmol) in degassed
EtOH (5 ml) under N2 was added NaOMe (10 mg, 0.19 mmol).
88
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90

View Article Online
After stirring at room temperature for 10 min NaBH4 (14 mg,
0.37 mmol) was added and the mixture was stirred for a further
15 h. After partitioning between ether (20 ml) and 2 M HCl
(20 ml) the aqueous layer was washed with ether (15 ml), the
combined organic extracts being washed with brine (25 ml),
dried (MgSO4) and evaporated in vacuo. The crude material was
triturated with cold ether, and the ether washings were con-
centrated in vacuo and purification of this material by column
chromatography (EtOAc–petrol, 3 : 7) gave further alcohol 28
(2 mg, 4%) as a white powder; mp 173–174.5 ЊC; Rf = 0.19
(EtOAc–petrol, 3 : 7); [α]2D5 = ϩ94.0 (c = 0.72 in MeOH); νmax
(KBr) 3565 (m), 3435 (br m), 2960 (s), 1655 (m) and 1610 (s)
cmϪ1; δH (200 MHz, CD3OD) (enol tautomer) 1.00 (9H, s,
C(CH3)3, 1.03 (6H, d, J = 6.5 Hz, CH(CH3)2), 1.62 (3H, s,
CDCl3) 15.07, 19.06 and 21.20 (CH(CH3)2 and C(7)CH3),
25.56 (C(CH3)3, 29.68 (CH(CH3)2), 35.32 (C(CH3)3, 69.08,
75.60, 77.40 and 78.91 (C(4)H2, C(5), C(7) and CHOH), 97.65
(tBuCH), 175.0 (amide CO) and 204.2 (ketone CO); m/z (CI)
317 (M Ϫ O ϩ NH4ϩ, 9%), 300 (M Ϫ O ϩHϩ, 28), 298 (M ϩ
Hϩ Ϫ H2O, 11) and 200 (100); m/z (electrospray) 316 (M ϩ Hϩ,
75%), 270 (72) and 200 (100).
(3S,4S,9S,10S)-4,10-Dibenzoyloxy-2,8-dihydroxy-3,9-dimeth-
oxycarbonyl-6,12-dioxo-1,7-diazatricyclo[7.3.0.03,7]dodecane 32
To a solution of (COCl)2 (35 µl, 51 mg, 0.40 mmol) in DCM
(3 ml) under N2 at Ϫ78 ЊC was added DMSO (45 µl, 50 mg,
0.63 mmol). The mixture was stirred at Ϫ78 ЊC for 15 min and
then a solution of alcohol 15a (100 mg, 0.34 mmol) in DCM
(1.5 ml) was added dropwise. After a further 15 min at Ϫ78 ЊC
triethylamine (140 µl, 102 mg, 1.0 mmol) was added and the
mixture was allowed to warm to room temperature over 10 min.
After stirring at room temperature for 3 h the mixture was par-
titioned between DCM (10 ml) and H2O (10 ml). The aqueous
layer was re-extracted with DCM (10 ml) and the combined
organic layers were dried (MgSO4) and evaporated in vacuo.
Purification by column chromatography (EtOAc–petrol, 1 : 1
increasing polarity to EtOAc–petrol, 3 : 1) gave dimer 32
(42 mg, 42%) as an off-white solid; mp 185.5–188 ЊC (decomp.);
Rf = 0.20 (EtOAc–petrol, 1 : 1); [α]2D2 = ϩ50.3 (c = 1.49 in
CHCl3); νmax (CHCl3) 3560 (w), 3440 (br w), 2960 (w), 1730 (s)
and 1605 (w) cmϪ1; δH (200 MHz, CDCl3) 2.95 (4H, d, J =
9.5 Hz, 2 × CH2CH), 3.54 (6H, s, 2 × CO2CH3), 5.55 (2H, d,
exchangeable, J = 8.0 Hz, 2 × CHOH), 6.03 (2H, t, J = 9.5 Hz,
2 × CH2CH), 6.36 (2H, d, J = 8.0 Hz, 2 × CHOH), 7.41–7.48
(4H, m, ArH), 7.57–7.64 (2H, m, ArH) and 7.94 (4H, d,
J = 7.0 Hz, ArH); δC (50.3 MHz, CDCl3) 35.4 (CH2CH), 53.7
(CO2CH3), 70.6 and 73.2 (CH2CH and CHOH), 72.3
(NCCO2CH3), 128.3 (ArC), 128.8, 129.7 and 134.1 (ArC) and
165.9, 168.6 and 172.7 (CO); m/z (CI) 583 (M ϩ Hϩ, <1%), 309
(M/2 ϩ NH4ϩ, 100), 292 (M/2 ϩ Hϩ, 93), 142 (76) and 105 (85);
CH C᎐COH), 2.12 (1H, oct, J = 6.5 Hz, CH(CH ) ), 3.44 (1H,
᎐
3
3 2
d, J = 9.0 Hz, C(4)HHЈ), 3.62 (1H, d, J = 6.5 Hz, CHOH(iPr)),
t
4.27 (1H, d, J = 9.0 Hz, C(4)HHЈ) and 4.45 (1H, s, BuCH);
(keto tautomer) 0.95 (3H, d, J = 6.5 Hz, CH(CH3)(CH3)Ј), 1.88
(1H, oct, J = 6.5 Hz, CH(CH3)2), 3.57 (1H, d, J = 6.5 Hz,
CHOH(iPr)), 3.63 (1H, m, C(4)HHЈ) and 4.14 (1H, d, J =
9.5 Hz, C(4)HHЈ); δC (50.3 MHz, CD3OD) (enol tautomer)
6.5 (CH C᎐COH), 20.8 and 22.7 (CH(CH ) ), 26.6 (C(CH ) ,
᎐
3
3
2
3 3
31.7 (CH(CH3)2), 36.1 (C(CH3)3, 71.6, 76.9 and 77.5 (C(4)H2,
C(5) and CHOH(iPr)), 98.7 (tBuCH), 104.5 (CH C᎐COH),
᎐
3
174.2 (amide CO) and 184.2 (CH C᎐COH); (keto tautomer)
᎐
3
7.1 (C(7)CH3), 19.4 and 22.5 (CH(CH3)2), 26.3 (C(CH3)3, 32.0
(CH(CH3)2) and 69.8 and 78.0 (C(4)H2 and CHOH(iPr));
m/z (CI) 284 (M ϩ Hϩ, 100%), 226 (M ϩ Hϩ Ϫ tBuH, 54) and
212 (46); exact mass 284.1859, C15H25NO4 (MHϩ) requires
284.1862.
(2R,5S,1ЈS)-2-tert-Butyl-7-hydroxy-7-methyl-6,8-dioxo-5-(1Ј-
hydroxy-2Ј-methylpropyl)-3-oxa-1-azabicyclo[3.3.0]octane 29
Attempted recrystallisation of crude alcohol 25b (38 mg,
0.14 mmol), formed by the NaBH4 reduction of ketone 24b,
from hot CHCl3 gave decomposition. Purification of the resi-
due by column chromatography (EtOAc–petrol, 1 : 4) gave,
apart from starting material, the autoxidation product 29
(3 mg, 7%) as a colourless oil; Rf = 0.55 (EtOAc–petrol, 3 : 7);
[α]2D3 = ϩ71 (c = 0.12 in CHCl3); νmax (film) 3600–3100 (br m),
2960 (m), 1770 (m) and 1705 (s) cmϪ1; δH (200 MHz, CDCl3)
1.04 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј), 1.05 (9H, s, C(CH3)3,
1.13 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј), 1.36 (3H, s,
C(7)CH3), 1.94 (1H, oct, J = 7.0 Hz, CH(CH3)2), 2.96 (1H, br s,
CHOH), 3.55 (1H, br d, J = 7.0 Hz, CHOH(iPr)), 3.60 (1H, d,
J = 9.5 Hz, C(4)HHЈ), 4.22 (1H, d, J = 9.5 Hz, C(4)HHЈ), 4.95
(1H, s, tBuCH) and 5.23 (1H, br s, OH); δC (125.7 MHz, CDCl3)
16.61, 16.71 and 22.26 (CH(CH3)2 and C(7)CH3), 25.87
(C(CH3)3, 28.04 (CH(CH3)2), 34.69 (C(CH3)3, 68.98, 76.58 and
86.94 (C(4)H2, C(5), C(7) and CHOH), 100.9 (tBuCH), 177.6
(amide CO) and 209.7 (ketone CO); m/z (CI) 317 (M ϩ NH4ϩ,
18%), 300 (M ϩ Hϩ, 91), 245 (77) and 228 (100); m/z (electro-
spray) 317 (M ϩ NH4ϩ, 6%) and 300 (M ϩ Hϩ, 100).
exact mass 292.0828, C14H14NO6 (M/2
292.0821.
ϩ
Hϩ) requires
(2R,3S,E )-3-Benzoyloxy-2-methoxycarbonyl-2-(2Јethoxycarb-
onylvinyl)pyrrolidin-5-one 33
To a solution of dimer 32 (72 mg, 0.12 mmol) in toluene (10 ml)
was added ethoxycarbonylmethylenetriphenylphosphorane
(90 mg, 0.26 mmol). The mixture was heated at reflux for 4 h,
cooled to room temperature and partitioned between ether
(25 ml) and NH4Cl (aq) (25 ml). The organic layer was washed
with brine (20 ml), dried (MgSO4) and evaporated in vacuo.
Purification by column chromatography gave a 2 : 9 mixture of
(Z)-alkene–(E)-alkene 33 (22 mg, 26%) as a pale yellow oil and
pure (E)-alkene 33 (28 mg, 33%) as a pale yellow glass; Rf = 0.42
(EtOAc–petrol, 1 : 1); [α]2D5 = ϩ54.7 (c = 1.35 in CHCl3); νmax
(CHCl3) 3430 (w), 1725 (s) and 1270 (s) cmϪ1; δH (200 MHz,
CDCl3) 1.30 (3H, t, J = 7.0 Hz, CO2CH2CH3), 2.50 (1H, d, J =
17.5 Hz, C(4)HHЈ), 2.87 (1H, dd, J = 17.5 Hz, JЈ = 5.5 Hz,
C(4)HHЈ), 3.68 (3H, s, CO2CH3), 4.22 (2H, q, J = 7.0 Hz,
CO2CH2CH3), 5.73 (1H, d, J = 5.5 Hz, C(3)H), 6.21 (1H, d,
(2R,5S,1ЈR)-2-tert-Butyl-7-methyl-6,8-dioxo-7-peroxy-5-(1Ј-
hydroxy-2Ј-methylpropyl)-3-oxa-1-azabicyclo[3.3.0]octane 30
A solution of alcohol 25b (12 mg, 0.04 mmol) in CDCl3 (0.5 ml)
was left at room temperature for 20 days. Purification by
column chromatography (EtOAc–petrol, 1 : 4) gave starting
material (6 mg, 50%) and peroxide 30 (4 mg, 30%) as a yellow
oil (positive peroxide test with starch/KI paper); Rf = 0.30
(EtOAc–petrol, 3 : 7); [α]2D3 = ϩ48 (c = 0.10 in CHCl3); νmax (film)
3600–3100 (br m), 2965 (m), 1770 (m) and 1715 (s) cmϪ1; δH
(200 MHz, CDCl3) 0.86 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј),
1.02 (9H, s, C(CH3)3, 1.08 (3H, d, J = 7.0 Hz, CH(CH3)(CH3)Ј),
1.47 (3H, s, C(7)CH3), 1.93 (1H, d sept, Jsept = 7.0 Hz, Jd =
2.0 Hz, CH(CH3)2), 2.50 (1H, br s, CHOH), 3.60 (1H, d,
J = 8.5 Hz, C(4)HHЈ), 3.75 (1H, br s, CHOH(iPr)), 4.60 (1H, d,
J = 8.5 Hz, C(4)HHЈ) and 5.02 (1H, s, tBuCH); δC (125.7 MHz,
J = 15.5 Hz, CH᎐CHЈ), 7.26 (1H, d, J = 15.5 Hz, CH᎐CHЈ),
᎐ ᎐
7.41–7.48 (3H, m, ArH and NH), 7.56–7.64 (1H, m, ArH)
and 7.95 (2H, d, J = 7.0 Hz, ArH); δC (50.3 MHz, CDCl3) 14.1
(CO2CH2CH3), 36.3 (C(4)H2), 53.4 (CO2CH3), 61.2 (CO2-
CH2CH3), 71.1 and 74.1 (C(2) and C(3)H), 123.8 and 142.5
(vinylic), 128.5, 128.6, 129.7 and 133.9 (ArC) and 164.7, 165.0,
167.8 and 174.3 (CO); m/z (CI) 379 (M ϩ NH4ϩ, 100%), 362
(M ϩ Hϩ, 46), 257 (94), 240 (100), 208 (89) and 105 (70); exact
mass 362.1234, C18H20NO7 (MHϩ) requires 362.1240.
(Z)-isomer: Rf = 0.38 (EtOAc–petrol, 1 : 1); δH (200 MHz,
CDCl3) 1.28 (3H, t, J = 7.0 Hz, CO2CH2CH3), 2.71 (1H, dd,
J = 17.0 Hz, JЈ = 6.0 Hz, C(4)HHЈ), 2.95 (1H, dd, J = 17.0 Hz,
JЈ = 7.5 Hz, C(4)HHЈ), 3.65 (3H, s, CO2CH3), 4.20 (2H, q,
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90
89

View Article Online
8 J. H. Bailey, A. T. J. Byfield, P. J. Davis, A. C. Foster, M. Leech,
M. G. Moloney, M. Muller and C. K. Prout, J. Chem Soc, Perkin
Trans. 1, 2000, 1977.
9 C. E. M. Davis, T. D. Heightman, S. A. Hermitage, M. G. Moloney
and G. A. Woods, Tetrahedron Lett., 1998, 39, 1025.
10 D. Seebach and J. D. Aebi, Tetrahedron Lett., 1984, 25, 2545.
11 M. D. Andrews, A. G. Brewster, K. M. Crapnell, A. J. Ibbett,
T. Jones, M. G. Moloney, C. K. Prout and D. Watkin, J. Chem. Soc.,
Perkin Trans. 1, 1998, 223.
12 M. D. Andrews, A. G. Brewster and M. G. Moloney, Synlett, 1996,
612.
13 M. D. Andrews, A. G. Brewster, J. Chuhan, A. J. Ibbett,
M. G. Moloney, K. Prout and D. Watkin, Synthesis, 1997, 305.
14 M. D. Andrews, A. G. Brewster, M. G. Moloney and K. L. Owen,
J. Chem. Soc., Perkin Trans. 1, 1996, 227.
J = 7.0 Hz, CO2CH2CH3), 5.79 (1H, dd, J = 7.5 Hz, JЈ = 6.0 Hz,
C(3)H), 6.08 (1H, d, J = 11.5 Hz, CH᎐CHЈ), 6.68 (1H, d,
᎐
J = 11.5 Hz, CH᎐CHЈ), 7.4–8.0 (6H, ArH and NH).
᎐
Acknowledgements
We thank EPSRC and AstraZeneca for funding of a student-
ship to MDA, and we wish to gratefully acknowledge the use
of the EPSRC Chemical Database Service at Daresbury24 and
the EPSRC National Mass Spectrometry Service Centre at
Swansea.
15 N. Galeotti, J. Poncet, L. Chiche and P. Jouin, J. Org. Chem., 1993,
58, 5370.
16 E. J. Corey and G. A. Reichard, J. Am. Chem. Soc., 1992, 114, 10677.
17 M. D. Andrews, A. G. Brewster, J. Chuhan, M. G. Moloney and
C. K. Prout, unpublished results.
18 D. L. Hughes, Org. React. (N. Y.), 1992, 42, 335.
19 R. W. Armstrong and J. A. DeMattei, Tetrahedron Lett., 1991, 32,
5749.
20 I. Kikkawa and T. Yorifuji, Synthesis, 1980, 877.
21 D. Bryce-Smith and E. E. Turner, J. Chem. Soc., 1953, 861.
22 B. J. Wakefield, Organolithium Methods, Academic, London, 1988.
23 J. W. Huffman, in Comprehensive Organic Synthesis; Pergamon,
Oxford, 1991, p. 107.
References
1 M. G. Moloney, Nat. Prod. Rep., 1999, 16, 485.
2 S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi,
H. Tanaka and Y. Sasaki, J. Antibiot., 1991, 44, 113.
3 E. J. Corey, W. Li and T. Nagamistu, Angew. Chem., Int. Ed., 1998,
37, 1676.
4 S. N. Crane and E. J. Corey, Org. Lett., 2001, 3, 1395.
5 E. J. Corey, W.-D. Z. Li, T. Nagamitsu and G. Fenteany, Tetrahedron
Lett., 1999, 55, 3305.
6 J. H. Bailey, D. Cherry, J. Dyer, M. G. Moloney, M. J. Bamford,
S. Keeling and R. B. Lamont, J. Chem. Soc., Perkin Trans. 1, 2000,
2783.
7 J. Dyer, S. Keeling, A. King and M. G. Moloney, J. Chem. Soc.,
Perkin Trans. 1, 2000, 2793.
24 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf.
Comput. Sci., 1996, 36, 746.
90
J. Chem. Soc., Perkin Trans. 1, 2002, 80–90