Enantiopure bicyclic piperidinones: Stereoselectivity in lactam enolate alkylations

Article abstract of DOI:10.1039/b316037h

The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6-oxopipecolic acid, have been investigated. Alkylation can proceed with predominantly exo-diastereoselectivity, but the efficiency of this process depends on the substitution at the hemiaminal ether system. These products can be readily deprotected to give substituted hydroxymethyl lactams in good yield.

Full text of DOI:10.1039/b316037h

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Enantiopure bicyclic piperidinones: stereoselectivity in lactam
enolate alkylations
Andrew G. Brewster,b Simon Broady,b Catherine E. Davies (née Mills),a
Thomas D. Heightman,a Stephen A. Hermitage,a Mark Hughes,a Mark G. Moloney*a and
Gordon Woodsa
a The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford,
South Parks Road, Oxford, UK OX1 3QY. E-mail: mark.moloney@chem.ox.ac.uk
b AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
Received 10th December 2003, Accepted 5th February 2004
First published as an Advance Article on the web 3rd March 2004
The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6-oxopipecolic acid, have been investigated.
Alkylation can proceed with predominantly exo-diastereoselectivity, but the efficiency of this process depends on the
substitution at the hemiaminal ether system. These products can be readily deprotected to give substituted
hydroxymethyl lactams in good yield.
The synthesis of substituted piperidines, piperidinones and
indolizidines1–5 is of importance because of their wide-
spread occurrence in nature, their wide-ranging biological
activity, and more recently for their conformational controlling
properties.6–14 Although a number of routes to these com-
pounds have been reported, involving, for example, the elabor-
ation of amino acids15–19 or other chiral starting materials,20–26
and chiral auxiliary mediated,27–30 catalytic31,32 or desymmetri-
sation processes,33–35 the most general strategies for piperidine
synthesis appear to be the CN(R,S) method developed by
Husson and Royer,36 the 2,3-dihydro-4-pyridone strategy exten-
sively developed by Comins,37,38 the bicyclic lactam method-
ology developed by Meyers,39–41 and the chiral deprotonation
mediated approach of Beak.42 Of interest to us are such general
approaches, enabling the preparation of piperidines, substi-
tuted at any or all of the ring carbons, in a diastereoselective
and enantioselective manner, which are applicable to combin-
atorial or parallel synthetic technologies. We have recently
described that racemic or enantiopure 6-oxo-2-hydroxymethyl-
piperidine 1 is readily available in 5 steps from lysine and in 60%
overall yield.43 Herein we describe the synthesis of bicyclic
lactams 2a–e derived from this alcohol, and report on their
diastereoselective functionalisation via the lactam enolate;
some of this work has been previously published in preliminary
form.44,45 A similar strategy, applied to the analogous [3.3.0]
bicyclic system, has proved to be very successful, permitting
ring manipulations in a highly diastereocontrolled sense,46–52
and providing access to analogues of natural products48,50,53
and conformationally restricted systems.54 That such a protocol
is robust has been demonstrated by its recent application by
Boehringer-Ingelheim Pharmaceuticals for the synthesis of
multi-kilo quantities of 3,5-disubstituted-2-pyrrolidinones for
evaluation as collagen-induced thrombocyte aggregation
inhibitors.55 We expected all of these advantages to be directly
transferable to the [4.3.0] series, and that ready functionalis-
ation of the piperidine ring would be possible; a similar strategy
has recently been extensively developed by Amat and Bosch,56,57
who have achieved diastereoselective alkylations58 and conju-
gate additions58–60 in an enantiopure bicyclic oxazolopiper-
idinone template.61
(as a separable mixture of diastereomers) or 2c in 22% and 54%
yield respectively. The diastereomers 2a and 2b were assigned as
exo- and endo- respectively by a series of NOE experiments
(Fig. 1); the C(2)Hendo stereochemistry of 2a was evident from
the enhancement series C(6)Hendo
the C(2)Hexo stereochemistry of 2b from the enhancement series
C(5)H C(4)Hexo C(2)H. Noteworthy is that similar cyclis-
C(4)Hendo
C(2)H and
ations in the related [3.3.0] pyrrolidinone series are reported to
give only the exo-diastereomer.62 Of significance in the 1H
NMR COSY spectrum of 2a was a strong long range W-coup-
ling between C(6)Hexo and C(8)Hexo and this is consistent with a
preferred half chair conformation established by MM analysis
(Chem 3D with PM3 parameters) (Fig. 2). When we began this
work, these systems were not well-known, but since then a
related bicyclic piperidine has been reported63 and similar
bicyclic piperidinones, in which the methylene and oxygen of
the oxazolidine ring are transposed relative to 2, have been
investigated for their synthetic utility.61 Surprisingly, however,
the ratio of 2a : 2b was found to depend upon the purity of the
starting lactam 1.44 This was traced to the catalytic activity of
boric acid, present as an impurity from the sodium borohydride
reduction step leading to the formation of alcohol 1, which
mediated a reaction in which the kinetic product 2b equilibrates
to 2a, the thermodynamic product; therefore, all further cyclis-
ation reactions were conducted in the presence of catalytic
boric acid/p-toluenesulfonic acid; the equilibration of related
epimeric oxazolidines by ring chain tautomerism has been
reported.64 Conversion of enantiopure lactam 143 to the bicyclic
derivative (S,S)-2a was accomplished in better yield (82%) than
in the racemic series as described above using benzaldehyde
dimethyl acetal (Scheme 1).45
Reaction of enantiopure lactam 143 with acetophenone
dimethyl acetal65 gave the corresponding hemiaminal ether
(S,S)-2d, but with variable amounts of its C(2) epimer 2e, and
in variable (30–64%) yield. The stereochemistry of this com-
pound was established by NOE analysis (Fig. 1), in which an
enhancement from C(5)H to C(2)Me indicated the stereo-
chemistry at C(2); simple molecular modeling (Chem 3D with
PM3 parameters) indicated a distorted boat conformation for
the piperidinone ring (Fig. 2) with the phenyl ring orientated in
such a way that steric effects were minimized on the endo-face
of the bicyclic system.
Results and discussion
However, we rapidly found lack of reproducibility in this
reaction, obtaining low yields and highly variable ratios of 2d
and 2e; this forced a detailed examination of the formation of
these compounds. From our previous work in this area,44 we
Reaction of racemic lactam 143 with benzaldehyde or 2-meth-
oxypropene in toluene at reflux and catalytic p-toluenesulfonic
acid gave the corresponding racemic hemiaminal ethers 2a, b
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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Scheme 1 Reagents and conditions: (i) PhCHO or PhCH(OMe)2, cat. p-TsOH, toluene, reflux (for 2a–2b), or MeC(OMe)᎐CH2, cat. p-TsOH,
᎐
toluene, reflux (for 2c), or PhCH(OMe)2, cat. p-TsOH, B(OH)3 (1 equiv.), reflux (for (S,S)-2d/(R,S)-2e); (ii) LDA/THF/Ϫ78 ЊC then R3X.
Fig. 1
Fig. 2
were aware that a p-TsOH/B(OH)3 catalytic system gave most
efficient conversion of alcohol 1 to hemiaminal ether 2a, and so
a detailed examination of the reaction leading to (2S)-2d : (2R)-
2e was undertaken by GC. When alcohol 1 and acetophenone
dimethyl acetal was heated at reflux with the same catalyst mix-
ture in toluene at 110 ЊC, the (2S) 2d : (2R) 2e product ratio was
1.5 : 1 after 30 minutes, and this slowly reversed over 27 h to
1 : 2; a similar outcome was observed in the absence of boric
acid. Significantly, however, reduction of temperature of this
reaction to 80 ЊC gave an entirely different outcome: after 2 h at
this temperature, the (2S) : (2R) product ratio was 4.8 : 1 and
this was virtually unaltered after 22 h (4.4 : 1). These results
indicated that the (2S) kinetic product 2d could be converted to
the (2R) 2e thermodynamic product under appropriate condi-
tions, although this product distribution of 2d,e was critically
dependent on very small changes to the reaction parameters.
Pyridinium p-toluenesulfonate (PPTS) was found to be par-
ticularly effective as the acid catalyst, and the results of a study
using three different solvents (toluene, chloroform, and di-
chloromethane) and reaction times are given in Table 1. When
toluene at reflux was used as the solvent, a mixture of diastereo-
mers was obtained, and although the diastereoselectivity was
highest in dichloromethane, chloroform gave the best combin-
ation of yield and stereochemical outcome. By way of confirm-
ation of previous results, and since we now had pure (2S)-2d
lactam in hand, this material was subjected to more vigorous
conditions (acetophenone dimethyl acetal, PPTS, toluene,
reflux), and interconversion of this isomer to a (2S) 2d : (2R) 2e
product mixture (1 : 2) was observed after 24 hours. Although
the (2S) 2d isomer is clearly the kinetic product, the energy
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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Table 1 GC analysis for formation of lactams 2d,e from alcohol 1 with PPTS, PhMeC(OMe)2 in various solvents and temperatures
Entry
1
Solvent
Toluene
Temperature
Reaction time
Ratio (2S) 2d : (2R) 2e
Yield 2d
110 ЊC
45 min
23.4 : 1.0
9.5 : 1.0
1.0 : 1.6
Not determined
Not determined
Not determined
Not determined
3 hours
20 hours
40 hours
20 min
2 hours
18 hours
20 min
1.0 : 2.2
2
3
Chloroform
DCM
70 ЊC
40 ЊC
(2S) only
(2S) only
70.0 : 1
No product observed
(2S) only
150.0 : 1
78%
50%
2 hours
18 hours
Table 2 Reaction of bicyclic lactam (S,S)-2d with electrophiles
difference is very small; molecular modeling calculations
(Chem 3D, MOPAC PM3 parameters) suggest only a 0.1 kJ
molϪ1 difference in energy, and this compares with a 1.6 kJ
molϪ1 difference for 2a,b, for which the former is clearly the
more stable. Thus, the most reliable procedure, giving 2d
exclusively, proved to be alcohol 1 and acetophenone dimethyl
acetal in chloroform and PPTS at reflux.
That hemiaminal ethers 2a–e were useful synthetic inter-
mediates was demonstrated by their elaboration to substituted
bicyclic piperidinone derivatives by generation of the lactam
enolate.66–70 At the time we began this work, lactam enolate
formation in piperidinones was not well precedented, although
it has since been developed in oxopipecolic acids,71,72 and more
recently stereocontrolled enolate generation has become pos-
sible using chiral lithium amides.73 Thus, treatment of the major
diastereomer ( )-2a with LDA in THF at Ϫ78 ЊC, followed by
the addition of p-nitrobenzyl bromide, gave the corresponding
alkylated product as a mixture of two diastereomers 3a and 3b
at the new chiral carbon (C(8)), in a ratio of 5 : 1 (assignments
made by NOE analysis, with crucial mutual enhancements for
according to Scheme 2
Electrophile
Product
Yield (%)
Ratio exo : endo
Methyl iodide
Benzyl bromide
para-Nitrobenzyl bromide
Allyl bromide
8a,b
9a,b
80
69
28
95
44
51
52
28
72
1 : 1
10 : 1
3 : 2
2 : 1
5 : 3
5 : 3
7 : 4
1 : 1
1 : 1
11a,b
12a,b
13a,b
13a,b
14a,b
15a,b
15a,b
Tosyl chloride
Tosyl chloridea
Phenyl selenenyl chloride
Benzyl chloroformate
Benzyl chloroformatea
a Reverse addition: see main text.
workers have reported similar difficulties in the alkylation of a
closely related bicyclic system, which they were unable to alkyl-
ate after deprotonation with either LDA or s-BuLi75 (later work
by Amat58 was able to achieve the alkylation of this system
readily with LDA and either methyl iodide or benzyl bromide,
in moderate yield (40%) but with excellent diastereoselectivity,
while Young has also reported acylation in simple piperidinone
derivatives,72 and Puschl76 has achieved hydroxylations using
LiHMDS for the deprotonation step). The lack of reactivity of
lactam 2d may be due to developing A-strain77 in its enolate.
However, reaction of this lactam with s-BuLi in THF at
Ϫ78 ЊC, followed by warming to Ϫ30 ЊC, gave the distinctive
red colour of the enolate, and this could be readily reacted with
electrophiles to give a mixture of exo-isomers 8a–15a and
endo-isomers 8b–15b (Table 2); separation, however, of these
diastereomeric products was not always straightforward due
to their similar polarity, and the presence of unreacted start-
ing material, but their ratio was readily established by NMR
spectroscopic analysis (C(2)Me) of the crude reaction products.
Benzylation gave, in addition to 9a,b, significant amounts (18%)
of dibenzyl adduct 10a. In the case of tosyl chloride and benzyl
chloroformate, it was found that reverse addition, namely addi-
tion of the enolate to a solution of the alkylating agent, gave
improved yields of 13a,b and 15a,b respectively, since this
minimized the formation of disubstituted products 10b and
16a respectively. Unfortunately, none of these products were
crystalline, and stereochemical assignment relied upon NOE
difference and NOESY spectra (Fig. 3), although their stereo-
chemistry could also be deduced from characteristic chemical
shift patterns observed in 1H NMR spectra. Thus, for example,
mutual enhancements of C(8)H, C(7)Hendo, C(6)Hendo, C(4)Hendo
and of C(7)Hexo, C(6)Hexo, C(5)H, C(4)Hexo for compounds 9a,
11a, and 12a indicated the exo-stereochemistry of the C(8) sub-
stituent, and the enhancements between C(8)H and C(6)Hendo
and of C(7)Hexo with C(5)H suggested that the conformation of
the piperidinone ring was such that the C(8) substituent was in
a pseudoequatorial position (Fig. 2) as might be expected. For
all of compounds 8–13 and 15, the endo-isomer has a more
positive value of [α]D and the major (exo-) isomer was more
polar. Furthermore, it was observed that the endo-isomers con-
sistently exhibited larger values for J(C(5)H/C(4)Hexo) than for
3a of C(8)H
and C(7)Hexo
C(7)Hendo and C(6)Hendo
C(5)Hexo C(4)Hexo (see Fig. 1)), with a total
C(4)Hendo
C(2)H,
yield of 43%. The predominance of product 3a is presumably
due to steric factors, with the electrophile approaching from the
exo-face of the bicyclic ring system, as the phenyl substituent at
C(2) would appear to be too far removed to directly influence
the stereochemistry of alkylation at C(8). When methyl iodide
was used as the electrophile in the above sequence, a better yield
of 60% of the methylated products 4a and 4b was obtained, but
in a poorer (2 : 1) diastereomeric ratio, demonstrating that the
diastereoselectivity was dependent on the bulk of the incoming
electrophile. When the dimethyl derivative ( )-2c was treated
with LDA and either p-nitrobenzyl bromide or methyl iodide,
derivatives 5a,b and 6a,b were obtained in modest yields of 28%
and 43% respectively but with no diastereocontrol. Related
bicyclo[4.3.0] heterocycles have been shown to exhibit signifi-
cant conformational fluxionality,74 and this may account for the
lack of diastereoselectivity observed in the alkylations of 2c: for
this compound, the presence of two methyl substituents at C(2)
means that no steric advantage is achieved in a conformational
equilibrium, unlike 2a, where the C(2)Ph is presumably in a
(pseudo)equatorial position. That disubstitution was feasible
was evident by the initial introduction of an ester function
(NaH, diethyl carbonate) to give 7a in 81% yield followed by
selenenylation (NaH, PhSeCl, 70%) leading to 7b, but without
diastereocontrol, or by direct double selenenylation (LiHMDS,
PhSeCl, 50%) leading to 7c. However, unlike the successful
deprotonation and subsequent alkylations of exo-2a and 2c,
neither starting material nor product could be recovered from a
similar reaction involving ( )-endo-2b; for this reason, as well as
the generally low yields and diastereoselectivity in the reactions
of 2a, we examined the reactions of hemiaminal ether 2d in
some detail.
Initial investigations of enantiopure (S,S)-2d established that
formation of the enolate and subsequent alkylation, contrary to
lactams 2a and 2c, was not straightforward. Husson and co-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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Scheme 2 Reagents and conditions: (i) s-BuLi/THF/Ϫ78 ЊC then RX (Table 1); (ii) NaH then PhCH2Br for 16b, or PhSeBr for 16c.
Fig. 3
Scheme 3 Reagents and conditions: (i) s-BuLi/THF/Ϫ78 ЊC then RX; (ii) NaH the PhSeCl (20b only).
Table 3 Reaction of bicyclic lactam (R,S)-2e with electrophiles
the exo-isomers, and this probably reflects the fact that the
according to Scheme 3
endo-substituted systems are less concave, by virtue of intra-
molecular steric interactions. The diastereoselectivity of these
reactions is clearly dependent on the size of the incoming
electrophile, with the small methyl iodide showing the least
selectivity, and the large benzyl bromide the greatest. Interest-
ingly, similar alkylations performed on the related Amat–Bosch
[4.3.0] template are reported to give the exo- diastereomer as the
sole product.58
Electrophile
Product
Yield(%)
exo : endo ratio
Methyl iodide
17a,b
18a,b
19a,b
46
25
50
0 : 1
2 : 1
1 : 1
Benzyl bromide
Benzyl chloroformatea
a Reverse addition: see main text.
Since significant quantities of the 2R bicyclic lactam 2e had
been synthesised in the course of investigations of the 2S
bicyclic lactam 2d, investigation of differences in reactivity of
their respective enolates was made. Two alkylation reactions
were therefore performed on bicyclic lactam (R,S)-2e using the
same conditions as shown in Scheme 2; in this case, the yields of
the products 17b and 18a,b were significantly lower than in the
case of lactam 2d (Scheme 3 and Table 3), and more surpris-
ingly, gave only the endo-product 17b for methylation, and a
much lower preference for the exo-isomer 18a in the benzyl-
ation. The endo-stereochemistry followed from NOESY
analysis, in which key significant enhancements were observed
C(6)Hexo, C(5)H, and C(4)Hexofor compounds 17b, 18a and 18b
(Fig. 4). Lactam 2e, with the more bulky methyl substituent at
the C(2) position on the endo- face, therefore leads to a much
higher proportion of the endo-isomer compared to the lactam
2d in a contra-steric alkylation process. We have observed simi-
lar selectivity in the [3.3.0] series, and ascribed this to a stronger
stereoelectronic directing effect from the nitrogen atom when
the bicyclic system is forced into a more planar conformation
by a bulky substituent on the concave face49 and a similar
explanation seems likely for the [4.3.0] system. Interestingly,
application of the reverse addition protocol, so successfully
applied for 2d for the synthesis of benzyloxycarbonyl deriv-
between C(7)Hendo, C(6)Hendo, C(4)Hendo and of C(8)H, C(7)Hexo
,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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Fig. 4
atives 15a,b, proved to be less effective, giving the product
19a,b as a diastereomeric mixture in low and variable (6–14%)
yield, along with 25–46% yield of the diacylated product
20a.
Lactams 15a,b could be further alkylated or selenylated after
deprotonation with sodium hydride; the products 16b,c were
obtained in yields of 55 and 70% and diastereoselectivities of
4 : 1 and 1 : 1 respectively, although the diastereomers were
not separable. Interestingly, a similar procedure applied to
lactam 19a,b gave the expected product 20b as a mixture of
diastereomers, but in highly variable yield (37–66%).
Trio-1 spectrometer. Major peaks are listed with intensities
quoted as percentages of the base peak. Microanalyses were
performed by the microanalytical service of the Dyson Perrins
Laboratory. Melting points were recorded on a Stuart Scientific
SMP1 melting point device and are uncorrected. Thin layer
chromatography (TLC) was performed using Merck aluminium
foil backed sheets precoated with Kieselgel 60 F254. Plates were
visualised using UV light (254 nm) or a solution of 5% w/v
dodeca-molybdophosphoric acid in EtOH followed by heat.
Flash column chromatography was carried out using Sorbsil
C60 H(40–60 mm) silica gel. THF was distilled from sodium/
benzophenone under N2 prior to use. Toluene, hexane, DCM
and EtOAc were purified by distillation before use. Light
petroleum refers to that fraction of light petroleum ether boil-
ing at 30–40 ЊC, and this was purified by distillation before use.
n-Butyllithium was used as a solution in hexanes and was
standardised with diphenylacetic acid prior to use. All other
reagents were used as obtained from commercial sources. NMR
signals for the major diastereomer of a given product are
labeled as A and the minor as B whenever they could be
resolved; otherwise, both signals are superimposed.
Deprotection
In order to demonstrate the synthetic utility of these com-
pounds, representative deprotections were undertaken. Thus,
treatment of lactams 9a and 16a with 20% trifluoroacetic acid
in dichloromethane gave 73 and 74% yield of the corresponding
alcohols 21a,b (Scheme 4).
( )-(2R*,5S*) and (2R*,5R*)-1-Aza-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 2a and 2b
To a solution of lactam 1 (0.38 g, 2.94 mmol) in toluene (30 ml)
were added benzaldehyde (0.70 g, 5.4 mmol) and p-toluene-
sulfonic acid (0.01 g, 0.05 mmol), and the mixture heated at
reflux for 72 h using a Dean–Stark condenser. The solvent was
removed in vacuo to afford a crude mixture of two diastereo-
meric products 2a and 2b in approx. 5 : 1 ratio. This residue was
purified by flash column chromatography in 50% light petrol-
eum/50% EtOAc, which afforded pure O,N-hemiaminal ether
2a (0.100 g, 16%), and 2b (0.036 g, 6%), although the latter
compound could not be obtained free from 2a.
Lactam 2a: Rf (EtOAc) 0.40; Found: C, 72.1; H, 6.97; N,
6.31. Calc. for C13H15NO2: C, 71.9; H, 6.96; N, 6.45%. νmax
(CHCl3)/cmϪ1 1640s; δH (500 MHz, CDCl3) 1.29–1.37 (1H, m,
C(6)Hendo), 1.69–1.80 (1H, m, C(7)Hexo), 1.94–2.00 (1H, m,
C(7)Hendo), 2.10–2.17 (1H, m, C(6)Hexo), 2.28–2.37 (1H, m,
C(8)Hexo), 2.45–2.51 (1H, m, C(8)Hendo), 3.55 (1H, m, C(4)Hendo),
3.82 (1H, m, C(5)H), 4.37 (1H, m, C(4)Hexo), 6.42 (1H, s,
C(2)H), 7.32–7.43 (3H, m, ArH ), 7.46–7.57 (2H, m, ArH );
δC(50.3 MHz, CDCl3) 20.1 (C(7)), 25.4 (C(6)), 31.4 (C(8)), 56.2
(C(5)), 72.9 (C(4)), 88.5 (C(2)), 126.5, 128.2, 128.5 (ArC), 139.1
(4Њ ArC), 168.0 (C(9)); m/z (DCI GCMS) 218 (M ϩ Hϩ, 100%).
Material prepared from enantiopure lactam 1 gave identical
spectroscopic data, with [α]22 ϩ129 (c 1, CHCl3).
Scheme 4 Reagents and conditions: (i) TFA, CH2Cl2, rt.
Conclusion
The convenient synthesis and elaboration of hemiaminal ethers
derived from 6-oxopipecolic acid opens up their potential
application to the synthesis of a wide range of substituted
piperidines and piperidinones, and successes in this direction
will be reported in subsequent papers.
Experimental
1H NMR spectra were recorded on Varian Gemini 200
(200 MHz) and Bruker AM-500 (500 MHz) spectrometers.
13C NMR spectra were recorded on the same spectrometers at
50.3 MHz and at 125.8 MHz respectively. Chemical shifts (d)
are reported in parts per million (ppm) and were referenced to
the residual solvent peak. Multiplicities are reported as broad
(br), singlet (s), doublet (d), triplet (t), quartet (q) and multiplet
(m). Coupling constants (J) are reported in Hertz (Hz) to the
nearest 1 Hz when obtained from 200 MHz spectra, and to the
nearest 0.1 Hz when obtained from 500 MHz spectra. Infra-red
spectra were recorded as thin films, in CHCl3 solution or as a
Nujol® mull, using a Perkin-Elmer 1750 FT-IR spectrometer.
Only selected peaks are reported, and absorption maxima (in
cmϪ1) are described as strong (s), medium (m), weak (w) or
broad (br). Mass spectra (m/z) were recorded on VG Micro-
mass ZAB 1F and VG Masslab 20–250 spectrometers using
ammonia desorption chemical ionisation (DCI), chemical ion-
isation (CI) or fast atom bombardment (FAB) techniques. Gas
chromatography mass spectra (GCMS) were recorded on a VG
Lactam 2b: Rf (EtOAc) 0.31; νmax (CHCl3)/cmϪ1 1657s;
δH (500 MHz, CDCl3) 1.50–1.70 (1H, m, C(6)Hendo), 1.75–2.0
(1H, m, C(7)Hexo), 2.05–2.25 (2H, m, C(7)Hendo and C(6)Hexo),
2.35–2.55 (2H, m, C(8)Hexo and C(8)Hendo), 3.65–3.75 (1H, m,
C(4)Hendo), 3.75–3.95 (1H, m, C(5)H), 4.15–4.25 (1H, m,
C(4)Hexo), 6.22 (1H, m, C(2)H), 7.32–7.39 (5H, m, ArH );
δC(50.3 MHz, CDCl3) 21.0 (C(7)), 24.9 (C(6)), 31.2 (C(8)), 57.8
(C(5)), 70.2 (C(4)), 89.8 (C(2)), 126.6, 128.7, 128.9 (ArC), 138.8
(4Њ ArC), 168.2 (C(9)); m/z (DCI GCMS) 218 (M ϩ Hϩ, 100%);
HRMS: 218.1811 (MHϩ). C13H16NO2 requires 218.1181.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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Material prepared from enantiopure lactam 1 gave identical
spectroscopic data, with [α]22 Ϫ39 (c 1, CHCl3).
(77), 216 (100); HRMS: 232.1334 (MHϩ, ESϩ). C14H17NO2
requires 232.1338.
An improved method gave lactam 2d exclusively: to a solu-
tion of alcohol 1 (4.37 g, 34.0 mmol) in chloroform (200 ml)
was added pyridinium p-toluenesulfonate (0.85 g, 3.40 mmol)
and acetophenone dimethyl acetal (7.26 ml, 44.0 mmol). The
suspension was heated at 70 ЊC for 18 hours, and then allowed
to cool to room temperature before the solvent was removed in
vacuo. The residue was then purified by flash column chrom-
atography on silica gel, eluting with EtOAc, to give exclusively
the diastereomer 2d as a white solid (6.13 g, 78%).
( )-1-Aza-2,2-dimethyl-3-oxa-9-oxobicyclo[4.3.0]nonane 2c
2-Methoxypropene (2.50 g, 34.7 mmol) was added to a suspen-
sion of lactam 1 (0.49 g, 3.8 mmol) in dry toluene, to which
p-toluenesulfonic acid (0.01 g, 0.05 mmol) was added. The mix-
ture was heated at 100 ЊC for 18 h, and after cooling, the tolu-
ene was removed in vacuo and the residue partitioned between
EtOAc and water. The organic layer was separated and dried
over MgSO4. Filtration and removal of the solvent under vac-
uum afforded the crude product, which was purified by flash
column chromatography using 20% EtOAc/80% light petrol-
eum as the eluent, to afford the product 2c (0.35 g, 54%); Rf
(EtOAc) 0.40; νmax (CHCl3/cmϪ1) 1630s; δH (200 MHz, CDCl3)
1.20–1.40 (1H, m, C(6)Hendo), 1.55 (6H, 2 × s, CH3), 1.6–1.8
(1H, m, CH2), 1.88–2.04 (2H, m, CH2), 2.25–2.37 (2H,
m, C(8)H), 3.42 (1H, m, C(4)Hendo), 3.5–3.7 (1H, m, C(5)H),
4.16 (1H, m, C(4)Hexo); δC (50.3 MHz, CDCl3) 20.9 (C(7)),
24.0 (CH3), 25.5 (C(6)), 25.6 (CH3), 31.9 (C(8)), 57.5 (C(5)),
69.4 (C(4)), 94.6 (C(2)), 167.3 (C(9)); m/z (DCI GCMS) 170
(M ϩ Hϩ, 100%), 154 (22); HRMS: 170.1181 (MHϩ); C9H16-
NO2 requires 170.1181.
( )-(2R*,5S*,8S*)-1-Aza-8-(p-nitrobenzyl)-3-oxa-9-oxo-2-
phenylbicyclo[4.3.0]nonane 3a
To a solution of LDA (0.13 g, 1.2 mmol) in THF (10 ml) under
nitrogen at Ϫ78 ЊC was added lactam 2a (0.18 g, 0.83 mmol),
and the solution stirred for 30 min. p-Nitrobenzyl bromide
(0.22 g, 1.0 mmol) was added in a 2 ml portion of THF, and the
reaction mixture stirred for a further 2 h. After allowing the
solution to warm to room temperature, the reaction was
quenched by adding saturated ammonium chloride in methanol
(5 ml). The resulting liquor was partitioned between EtOAc
and water, the organic layer separated and the solvent removed
in vacuo. Purification by flash column chromatography, using
10% EtOAc/90% light petroleum, increasing the EtOAc propor-
tion slowly to 100%, gave 3a as the major product (0.10 g, 34%).
Rf (EtOAc) 0.55; νmax (CHCl3)/cmϪ1 1640s; δH (500 MHz,
CDCl3) 1.32–1.40 (1H, m, C(6)Hendo), 1.44–1.52 (1H, m,
C(7)Hexo), 1.87–1.92 (1H, m, C(7)Hendo), 2.08–2.12 (1H, m,
C(6)Hexo), 2.67–2.73 (1H, m, C(8)Hendo), 3.10–3.18 (2H, m,
ArCH2), 3.51–3.54 (1H, m, C(4)Hendo), 3.67–3.73 (1H, m,
C(5)H), 4.32–4.35 (1H, m, C(4)Hexo), 6.38 (1H, s, C(2)H), 7.21–
7.27 (2H, d, J 8.7, p-NO2C6H4), 7.36–7.41 (5H, m, ArH ), 7.98–
8.00 (2H, d, J 8.7, p-NO2C6H4); δC (500 MHz, CDCl3) 25.0 and
25.4 (C(6), C(7)), 37.5 (ArCH2), 43.0 (C(8)), 56.8 (C(5)), 72.9
(C(4)), 88.9 (C(2)), 123.4, 123.4, 126.6, 128.3, 128.8, 130.3
(ArC), 138.8 (4Њ ArC), 146.7 and 146.8 (4Њ ArC), 169.0 (C(9));
m/z (DCI) 370 (M ϩ NH4ϩ, 5%), 353 (M ϩ Hϩ, 100). HRMS:
353.1501 (MHϩ). C20H21N2O4 requires 353.1501.
(؊)-(2S,5S )-1-Aza-2-methyl-3-oxa-9-oxo-2-phenylbicyclo-
[4.3.0]nonane 2d and (؊)-(2R,5S )-1-aza-2-methyl-3-oxa-9-oxo-
2-phenylbicyclo[4.3.0]nonane 2e
To a suspension of the lactam 1 (3.52 g, 27.3 mmol) in toluene
(125 ml) was added p-toluenesulfonic acid (1.3 g, 6.8 mmol) and
pre-dried boric acid (0.42 g, 6.8 mmol), and the mixture heated
to reflux with continuous removal of water using a Dean–Stark
apparatus. After 5 hours the mixture was cooled to room tem-
perature and the Dean–Stark apparatus was removed. Aceto-
phenone dimethyl acetal (10 ml, excess) was then added, and
the mixture was again brought to reflux for a further 19 hours.
The mixture was then allowed to cool to room temperature and
partitioned between EtOAc : water. The aqueous layer was then
extracted with ethyl acetate (3 × 30 ml). The combined organic
extracts were then washed with sat. aq. NaHCO3 (30 ml), water
(30 ml) and dried with brine (40 ml) and over MgSO4 and the
solvent was removed in vacuo. Acetophenone dimethyl acetal
was then removed by Kugelrohr distillation, and the residue
purified by flash column chromatography on silica gel, eluting
progressively with 20% EtOAc : petrol, 40% EtOAc : petrol,
60% EtOAc : petrol and EtOAc to yield two products, lactam 2e
as a yellow oil (1.50 g, 24%) and lactam 2d as a white solid
(1.97 g, 31%).
( )-(2R*,5S*,8R*)-1-Aza-8-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 4a
Lactam 2a (0.14 g, 0.63 mmol) was added to a solution of LDA
(0.094 g, 0.88 mmol) in THF (10 ml) at Ϫ78 ЊC under nitrogen,
and the solution stirred for 30 min. MeI (0.200 g) was added,
and the new solution stirred for a further 1 h. The solution was
quenched by adding saturated ammonium chloride in MeOH
(5 ml). Organic products were extracted into EtOAc and the
two layers separated. The organic layer was washed with water,
separated and dried over MgSO4. Filtration and removal of the
solvent afforded a mixture of products and starting materials.
The product was obtained as a mixture of diastereomers of
approx. ratio 2 : 1, from which lactam 4a was isolated by flash
column chromatography (0.069 g, 47%). Diastereomer 4b was
not recovered in pure form. Data for 4a: Rf (EtOAc) 0.60;
Found: C, 72.4; H, 7.3; N, 6.0. Calc. for C14H17NO2: C, 72.7; H,
7.4; N, 6.1%; νmax (CHCl3)/cmϪ1 1635s; δH (200 MHz, CDCl3)
1.26 (3H, d, CH3), 1.38–1.61 (2H, m, CH2), 2.03–2.20 (2H, m,
CH2), 2.30–2.49 (1H, m, C(8)H), 3.57 (1H, m, C(4)Hendo), 3.81–
3.96 (1H, m, C(5)H), 4.38 (1H, m, C(4)Hexo), 6.41 (1H, s,
C(2)H), 7.33–7.56 (5H, m, ArH); δC (500 MHz, CDCl3) 17.8
(CH3), 25.3 (C(7)), 29.0 (C(6)), 37.1 (C(8)), 56.9 (C(5)), 73.2
(C(4)), 88.7 (C(2)), 126.7, 128.5 and 128.8 (ArC), 139.5 (ArC)
and 171.9 (C(9)); m/z (DCI) 232 (M ϩ Hϩ, 100%).
Lactam 2d: mp 116–117 ЊC; Rf 0.32 (EtOAc); [α]2D6 Ϫ6.86
(c 0.51, CHCl3); Found: C, 73.2; H 7.9; N, 5.6. C14H17NO2
requires C, 72.7; H, 7.4; N, 6.1%; νmax (film)/cmϪ1 1651s; δH(200
MHz; CDCl3) 1.47–1.53 (1 H, m, C(6)Hendo), 1.80–1.90 (1 H, m,
C(7)Hexo), 2.01–2.15 (5 H, m, C(6)Hexo, C(7)Hendo and CH3),
2.38–2.51 (2 H, m, C(8)Hendo and C(8)Hexo), 3.47 (1 H, dd, J 8.0
and 10.0, C(4)Hendo), 3.79–3.89 (1 H, m, C(5)H), 4.11 (1 H, dd,
J 5.0 and 8.0, C(4)Hexo), 7.31–7.46 (3 H, m, ArH), 7.57–7.62
(2 H, m, ArH); δC (200 MHz, CDCl3) 20.9 (C(6)), 24.8 (C(7)),
25.2 (CH3), 32.1 (C(8)), 57.7 (C(5)), 69.1 (C(4)), 95.9 (C(2)),
125.8, 126.0, 128.1, 128.3 (Aryl CH), 141.9 (Aryl C), 168.0 (C-
9); m/z (GCMS) 232 (MHϩ, 100%).
Lactam 2e: Rf 0.36 (EtOAc); [α]2D4 ϩ161.1 (c 1.0, CHCl3); νmax
(film)/cmϪ1 3503m, 1649s, 1408m, 1325w; δH (400 MHz; CDCl3)
1.27–1.49 (1 H, m, C(6)Hendo), 1.69–1.81 (1 H, m, C(7)Hexo),
1.96–2.04 (1 H, m, C(7)Hendo), 2.05 (1 H, s, Me), 2.06–2.18 (1 H,
m, C(6)Hexo), 2.34–2.49 (2 H, m, C(8)H), 3.38–3.78 (2 H, m,
C(5)H and C(4)Hendo), 4.24 (1 H, dd, J 5.5 and 7.5, C(4)Hexo),
7.28–7.49 (3 H, m, Ph), 7.56–7.59 (2H, m, Ph); δC(100.6 MHz;
CDCl3) 20.8 (C(6)), 24.9 (Me), 26.3 (C(7)), 32.3 (C(8)), 57.5
(C(5)), 70.2 (C(4)), 96.1 (C(2)), 123.1, 125.7 and 128.0 (ArCH),
142.5 (ArC), 167.3 (C(9)); m/z (APCIϩ) 232 (MHϩ, 56%), 232
( )-(5S*,8S*) and (5S*,8R*)-1-Aza-2,2-dimethyl-8-
( p-nitrobenzyl)-3-oxa-9-oxobicyclo[4.3.0]nonane 5a,b
To a solution of LDA (0.23 g, 2.1 mmol) in THF (10 ml) under
nitrogen at Ϫ78 ЊC was added lactam 2c (0.26 g, 1.5 mmol), and
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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the solution stirred for 30 min. p-Nitrobenzyl bromide (0.39 g,
1.8 mmol) was added in a 2 ml portion of THF, and the reac-
tion mixture stirred for a further 2 h. After allowing the solu-
tion to warm up slowly to room temperature the reaction was
quenched by adding saturated ammonium chloride in methanol
(5 ml). The resulting liquor was partitioned between EtOAc and
water, the organic layer separated and the solvent removed
in vacuo. Purification using flash column chromatography with
10 : 90 EtOAc/light petroleum, increasing the EtOAc propor-
tion slowly to 100%, gave 5a,b (mixture of diastereomers in a
ratio of approx. 3 : 2) as a yellow oil (0.130 g, 28%). Rf (EtOAc)
0.69 and 0.90; νmax (CHCl3)/cmϪ1 1635s, 1520s; δH (200 MHz,
CDCl3) 1.21–1.47 (2H, m, C(7)H), 1.61 and 1.63 (6H, 2s,
C(CH3)2), 1.67–1.98 (2H, m, C(6)H), 2.92–3.04 (2H, m,
C(4)Hendoand C(8)H), 3.28–3.56 (3H, m, C(5)H and ArCH2),
4.02–4.14 (1H, m, C(4)Hexo), 7.37 (2H, m, ArH), 8.14 (2H, m,
ArH); δC (50.3 MHz, CDCl3) 23.9 (CH3), 25.1 and 26.6 (C(7)),
25.7 (CH3), 26.6 (C(6)), 37.4 and 37.7 (ArCH2), 42.0 and 43.4
(C(8)), 56.6 and 57.8 (C(5)), 69.3 and 69.5 (C(4)), 94.78 and
94.9 (C(2)), 123.7 (ArC), 130.0 (ArC), 146.8 and 148.1 (ArC),
168.0 and 169.1 (C(9)); m/z (DCI GCMS) 305 (M ϩ Hϩ, 100%),
275 (50); HRMS: 305.1501 (MHϩ), C16H21N2O4 requires
305.1501.
C(2)H), 7.30–7.37 (3H, m, ArH), 7.45–7.50 (1H, m, ArH),
7.50–7.52 (1H, m, ArH); δC (200 MHz, CDCl3) 13.88, 13.97
(CH3CH2) 22.2 (C(6)), 24.0, 24.6 (C(7)), 47.0, 49.29 (C(8)),
56.2, 56.3 (C(5)), 61.5 (CH3CH2), 72.8 (C(4)), 88.8, 89.0 (C(2)),
126.5, 127.0, 128.5, 128.6, 128.9, 129.0, 129.2 (ArCH), 138.6,
139.0 (ArylC), 164.4 (C-9), 170.9, 171.3 (C᎐O); m/z (CI(NH ))
᎐
3
290 (MHϩ, 100%).
(2R,5S )-8-Ethoxycarbonyl-9-oxo-2-phenyl-8-phenylselenenyl-1-
aza-3-oxabicyclo[4.3.0]nonane 7b
To a stirred suspension of NaH (0.074 g, 1.2 eq, 60% disper-
sion) in dry THF (5 ml) under a N2 atmosphere was added, via a
syringe at 0 ЊC, a solution of the lactam 7a (0.448 g, 1.55 mmol)
in dry THF (5 ml). After 10 min, a solution of phenylselenyl
chloride (0.341 g, 1.15 eq) in dry THF (5 ml) was added, via
syringe, at room temperature. The solution was heated to reflux
for 15 hours. This solution was carefully poured into saturated
NH4Cl (15 ml)/EtOAc (15 ml) and the organic layer washed
with water (15 ml) and brine (15 ml). After drying over MgSO4,
the solvent was removed in vacuo to give an orange oil. Purifi-
cation by flash column chromatography, eluting with 4 : 1
petrol/EtOAc gave lactam 7b as two separable diastereoisomers
as yellow oils (0.48 g, 70%) in a ratio of 0.4 : 0.6.
25
Minor diastereoisomer: Rf 0.58 (1 : 1 petrol/EtOAc); [α]D
( )-(5S*,8R*) and (5S*,8S*)-1-Aza-2,2,8-trimethyl-3-oxa-9-
oxobicyclo[4.3.0]nonane 6a,b
ϩ13.8 (c 0.99, CHCl3); vmax (CHCl3/cmϪ1) 1724s, 1651s; δH (500
MHz, CDCl3) 1.21–1.24 (3H, t, J 7.1, CH3CH2), 1.70–1.77 (1H,
m, C(6)H), 1.91–1.97 (1H, m, C(6)H), 2.09–2.14 (1H, m,
C(7)H), 2.28–2.33 (1H, m, C(7)H), 3.50–3.53 (1H, dd, J 8.4,
C(4)H), 3.78–3.84 (1H, m, C(5)H), 4.18–4.22 (2H, q, J 7.1,
CH3CH2), 4.24–4.27 (1H, dd, J 6.0, 8.1, C(4)H), 6.45 (1H, s,
C(2)H), 7.30–7.37, 7.40–7.41, 7.42–7.48, 7.73–7.74 (10H, m,
ArH); m/z (CI(NH3)) 446 (MHϩ, 80%), 290 (100%).
Lactam 2c (0.13 g, 0.77 mmol) was added to a solution of LDA
(0.12 g, 1.1 mmol) in THF (10 ml) at Ϫ78 ЊC under nitrogen,
and the solution stirred for 30 min. MeI (0.20 g, 1.4 mmol) was
added, and the new solution stirred for a further 1 h. The solu-
tion was quenched by adding saturated ammonium chloride in
MeOH (5 ml), the solution extracted with EtOAc and the layers
separated. The organic layer was washed with water, separated
and dried over MgSO4. Filtration and removal of the solvent,
purification (flash column chromatography) afforded the prod-
uct as a mixture of diastereomers 6a and 6b of approx. ratio
5 : 4 by 13C NMR spectroscopic analysis (0.060 g, 43%). Rf
(EtOAc) 0.66; νmax (CHCl3)/cmϪ1 1645; δH (200 MHz, CDCl3)
1.22–1.27 (3H, m, CH3), 1.36–1.52 (2H, m, C(7)H), 1.52–1.60
(6H, 2s, (CH3)2), 1.84–2.07 (2H, m, C(6)H), 2.25–2.45 (1H, m,
C(8)H), 3.40–3.52 (1H, m, C(4)Hendo), 3.61–3.76 (1H, m,
C(5)H), 4.00–4.13 (1H, m, C(4)Hexo); δC (50.3 MHz, CDCl3)
17.3 and 18.8 (8-CH3), 22.7 and 25.4 (C(7)), 23.9, 24.1, 25.5 and
25.8 (2 × (CH3)2), 27.9 and 30.1 (C(6)), 35.6 and 37.1 (C(8)),
56.9 and 58.0 (C(5)), 69.4 and 69.6 (C(4)), 94.4 and 94.6 (C(2)),
170.4 and 171.4 (C(9)); m/z (DCI GCMS) 184 (M ϩ Hϩ, 100%);
HRMS: 184.1338 (MHϩ). C10H18NO2 requires 184.1338.
25
Major diastereoisomer: Rf 0.51 (1 : 1 petrol/EtOAc); [α]D
Ϫ2.97 (c 0.16, CHCl3); vmax (CHCl3/cmϪ1) 1727s, 1651s; δH (500
MHz, CDCl3) 1.31–1.34 (3H, t, J 7.1, CH3CH2), 1.57–1.66 (1H,
m, C(6)H), 1.89–1.94 (1H, m, C(6)H), 2.03–2.09 (1H, m,
C(7)H), 2.42–2.46 (1H, m, C(7)H), 3.42–3.47 (1H, m, C(5)H),
3.51–3.54 (1H, dd, J 8.1, 9.6, C(4)H), 4.23–4.37 (3H, m, C(4)H
and CH3CH2), 6.42 (1H, s, C(2)H), 7.03–7.06, 7.27–7.31, 7.34–
7.41, 7.49–7.51 (10H, m, ArH); δC DEPT (200 MHz, CDCl3)
14.1 (CH3), 23.8 (C-6), 32.8 (C-7), 56.3 (C-5), 62.7 (CH2), 72.9
(C-4), 89.4 (C-2), 126.5, 127.3, 128.3, 128.9, 129.3, 138.0 (ArC),
126.2 (C-8), 138.3 (ArC), 165.1 (C-9), 170.5 (C᎐O); m/z
᎐
(CI(NH3)) 446 (MHϩ, 80%), 290 (100).
(؉)-(2R,5S )-1-Aza-3-oxa-9-oxo-2-phenyl-8,8-bis(phenyl-
selenenyl)bicyclo[4.3.0]nonane 7c
To a solution of lactam 2a (0.38 g, 1.7 mmol) in THF (15 ml)
under nitrogen at Ϫ78 ЊC was added LiHMDS (3.6 ml × 1 M in
THF) dropwise, and the solution stirred for 15 minutes. Phenyl
selenenyl chloride (0.696 g, 3.63 mmol) was added in THF
(10 ml) under nitrogen and the solution allowed to stir for
30 minutes at Ϫ78 ЊC. The solution was allowed to warm to
room temperature over 1 hour, then quenched with water
(20 ml). The product was extracted with CH2Cl2 (3 × 20 ml),
washed with brine (25 ml) then dried over Na2SO4. The solvent
was removed in vacuo to afford a crude product which was
recrystallised from EtOAc/petrol giving the title compound 7c
as a white crystalline solid (0.458 g, 50%). Rf 0.66 (50 : 50
EtOAc : petrol); Found C, 57.03; H, 4.49; N, 2.22; required for
C25H23NO2Se2 C, 56.71; H, 4.38; N, 2.65%; [α]D25 ϩ109.4 (c 1.0,
CHCl3); νmax (CHCl3)/cmϪ1 1641(s); δH (500 MHz, CDCl3)
1.64–1.71 (2H, m, C(6)H), 1.95–2.05 (2H, m, C(7)H), 3.47–3.54
(2H, m, C(4)H and C(5)H), 4.28–4.30 (1H, m, C(4)H), 6.38
(1H, s, C(2)H), 6.96–7.81 (15H, m, ArH); δC (50.3 MHz,
CDCl3) 22.8 (C(6)), 33.0 (C(7)), 56.9 (C(5)), 72.9 (C(4)), 89.7
(C(2)), 126.9, 127.5, 128.0, 128.5, 128.8, 129.0, 129.1, 129.4,
129.9, 130.0, 135.5, 136.9, 138.2 (ArC), 138.6 (C-8), 168.09
(C(9)); m/z (DCI, NH3) 530 (MHϩ, 10%), 374 (65), 218 (100).
(2R,5S )-8-Ethoxycarbonyl-9-oxo-2-phenyl-1-aza-3-oxa-
bicyclo[4.3.0]nonane 7a
A solution of lactam 2a (1.00 g, 4.62 mmol) and diethyl
carbonate (2.86 ml, 5 eq) in toluene (20 ml) was heated at reflux
for 5 hours using a Dean–Stark trap. Prewashed sodium
hydride (0.407 g, 2.2 eq, 60% dispersion) was carefully added
at 0 ЊC and the solution brought back to reflux for a further
16 hours. The mixture was cooled to 0 ЊC, quenched with gla-
cial acetic acid (0.48 ml) and the suspension filtered. The sol-
vent was removed in vacuo and the resulting yellow oil purified
by flash column chromatography, eluting with 3 : 1 petrol/
EtOAc and gradually increasing polarity to 2 : 1 petrol/EtOAc.
This gave the product 7a as an inseparable diastereoisomeric
mixture (1.08 g, 81%) in the ratio 11 : 14. Rf 0.26, 0.39 (1 : 1
petrol/EtOAc); vmax (CHCl3/cmϪ1) 1734s, 1651s, 1175; δH (500
MHz, CDCl3) 1.24–1.27 and 1.29–1.31 (3H, 2 × t, J 7.1,
CH3CH2), 1.40–1.47 and 1.76–1.83 (1H, m, C(6)H), 1.97–2.30
(3H, m, C(7)H2 and C(6)H), 3.42–3.45 (1H, 2 × t, J 6.9, C(8)H),
3.57–3.65 (1H, 2 × dd, C(4)H, J 8.2, 9.6), 3.82–3.95 (1H, m,
C(5)H), 4.18–4.28 (2H, 2 × q, CH3CH2O), 4.34–4.37 and 4.40–
4.43 (1H, 2 × dd, J 6.0, 8.2 and J 5.7, 8.1, C(4)H), 6.43 (1H, s,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
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(2S,5S,8R) and (2S,5S,8S )-1-Aza-2-methyl-8-methyl-3-oxa-9-
oxo-2-phenylbicyclo[4.3.0]nonane 8a,b
C(6)Hexo), 2.07 (3 H, s, C(2)Me), 2.59–2.65 (1H, m, C(8)H), 2.73
(1H, dd J 10.0 and 13.5, PhCH ), 3.33 (1H, dd J 4.0 and 13.5,
PhCH ), 3.67 (1H, dd J 8.0 and 8.0, C(4)Hendo), 3.72–3.78 (1H,
m, C(5)H), 4.16 (1H, dd J 6.0 and 8.0, C(4)Hexo), 7.00–7.61
(10H, m, ArH); m/z (APCIϩ) 322 (MHϩ, 100%); HRMS:
322.1807 (MHϩ, CI). C21H23NO2 requires 322.1807.
To a stirred flask of THF (20 ml) under N2 at Ϫ78 ЊC was
added s-BuLi (0.68 ml, 0.66 mmol). A solution of the lactam 2d
(0.10 g, 0.44 mmol) in THF (10 ml) was then added slowly.
After five minutes a dark brown colour was observed. Methyl
iodide (0.04 ml, 0.66 mmol) was then added by syringe, and the
reaction mixture was seen to turn pink. The reaction mixture
was allowed to warm to room temperature over 30 minutes,
when TLC indicated that reaction was complete. The reaction
was then quenched with sat. aq. NH4Cl (20 ml), extracted with
EtOAc (4 × 25 ml) and dried over MgSO4. Solvent was removed
in vacuo, and the residue purified by flash column chromato-
graphy on silica eluting with 40% EtOAc : petrol to yield an
inseparable mixture of 8a,b as a colourless oil (0.089 g, 82%); Rf
0.26 and 0.13 (40% EtOAc : petrol); νmax(film)/cmϪ1 3583m,
1649s, 1420m, 1325m, 1240m, 1028m, 764m, 697m and 666s;
δH(500 MHz; CDCl3) 1.26 (3H, d, J 3.5, C(8)Me (B)), 1.27 (3H,
d, J 3.5, C(8)Me (A)), 1.51–1.73, 1.94–1.99, 2.05–2.12 and 2.17–
2.21 (4H, m, C(6)H and C(7)H (A) and (B)), 2.03 (3H, s,
C(2)Me (B)), 2.04 (3H, s, C(2)Me (A)), 2.43–2.53 (1H, m,
C(8)H), 3.39 (1H, dd, J 8.5 and 10.0, C(4)Hendo (B)), 3.52 (1H,
dd, J 8.5 and 10.5, C(4)Hendo (A)), 3.87–3.97 (1H, m, C(5)H),
4.08 (1H, dd, J 5.5 and 8.5, C(4)Hexo (A)), 4.13 (1H, dd, J 6.0
and 8.5, C(4)Hexo (B)), 7.26–7.57 (5H, m, ArH); δC(125.8 MHz;
CDCl3) 16.9 (C(8)Me (B)), 17.0 (C(8)Me (A)), 23.3 (C(7) (B)),
24.9 (C(2)Me (A)), 25.3 (C(7) (A)), 25.8 (C(2)Me (B)), 28.1
(C(6) (B)), 30.5 (C(6) (A)), 36.3 (C(8) (B)), 37.3 (C(8) (A)),
56.8 (C(5) (B)), 58.2 (C(5) (A)), 69.3 (C(4)), 95.5 (C(2)
(B)), 96.0 (C(2) (A)), 125.5, 125.6, 125.7, 127.8, 128.1, 128.1
(ArCH), 141.7 (ArH (B)), 142.3 (ArH (A)), 170.2 (C(9) (A)),
171.7 (C(9) (B)); m/z (APCIϩ) 268 (M ϩ NH4ϩ, 26%), 246
(MHϩ, 100); HRMS: 246.1492 (MHϩ, CI). C15H20NO2 requires
246.1494.
Dialkylated lactam 10a: Yield 0.047 g (18%); Rf 0.38 (20%
25
EtOAc : petrol); [α]D ϩ2.41 (c 0.79, CHCl3); νmax(film)/cmϪ1
1636s, 1419m; δH(500 MHz; CDCl3) 0.77–0.86 (1H, m,
C(6)Hendo), 0.88–0.95 (1H, m, C(7)Hexo), 1.56–1.60 (1H, m,
C(7)Hendo), 1.87–1.95 (1H, m, C(6)Hexo), 1.94 (3H, s, C(2)Me),
2.39 (1H, d, J 13.0, PhCH ), 2.67 (1H, d, J 13.0, PhCH ), 3.02–
3.09 (1H, m, C(5)H), 3.34 (1H, dd, J 8.5 and 10.5, C(4)Hendo),
3.38 (1H, d, J 13.0, PhCH ), 3.48 (1H, d, J 13.0, PhCH ), 3.86
(1H, dd, J 6.0 and 8.5, C(4)Hexo), 7.00–7.48 (15H, m, ArH);
δC(125.8 MHz; CDCl3) 23.29 and 24.31 (C(6) and C(7)), 28.4
(C(2)Me), 45.7 (PHCH), 47.1 (PHCH), 48.7 (C(8)), 57.3 (C(5)),
69.9 (C(4)), 95.9 (C(2)), 126.3, 126.5, 126.6, 127.8, 127.9, 128.1,
128.1, 130.7, 132.0 (ArCH), 137.7 (ArC), 141.8 (ArC), 170.5
(C(9)); m/z (APCIϩ) 412 (MHϩ, 100%), 292 (31); HRMS:
412.2277 (MHϩ, CI). C28H29NO2 requires 412.2277.
(؊)-(2S,5S,8R)-1-Aza-2-methyl-8-(p-nitrobenzyl)-3-oxa-9-oxo-
2-phenylbicyclo[4.3.0]nonane 11b and (؊)-(2S,5S,8S )-1-aza-2-
methyl-8-(p-nitrobenzyl)-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]-
nonane 11a
To a solution of the lactam 2d (0.59 g, 2.5 mmol) in THF
(50 ml) cooled to Ϫ78 ЊC under nitrogen was added s-BuLi
(3.1 ml, 2.5 mmol), and the reaction mixture was allowed to
warm to Ϫ30 ЊC over fifteen minutes. The enolate solution was
then added to a solution of freshly recrystallised p-nitrobenzyl
bromide (0.66 g, 3.1 mmol) in THF (10 ml) at Ϫ78 ЊC by
cannula. After 45 minutes the reaction was quenched by the
addition of sat. aq. NH4Cl (25 ml), and extracted with EtOAc
(3 × 25 ml), dried with brine (25 ml) and over MgSO4. Solvent
was then removed in vacuo. The residue was separated on silica
gel eluting with 40% EtOAc : petrol to yield the products as
yellow oils.
(؉)-(2S,5S )-1-Aza-8-dibenzyl-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 10a, (2S,5S,8R)-1-Aza-8-benzyl-2-
methyl-3-oxa-9-oxo-2-phenyl-bicyclo[4.3.0]nonane 9b and
(؊)-(2S,5S,8S )-1-Aza-8-benzyl-2-methyl-3-oxa-9-oxo-2-
phenyl-bicyclo[4.3.0]nonane 9a
Major diastereomer (exo) 11a: Yield 0.16 g (18%); Rf 0.14
25
(40% EtOAc : petrol); [α]D Ϫ65.5 (c 1.0, CHCl3); νmax(film)/
To stirred THF (30 ml) cooled to Ϫ78 ЊC under N2 was added
s-BuLi (0.75 ml, 0.98 mmol). Lactam 2d (0.15 g, 0.65 mmol) in
dry THF (5 ml) was then added slowly and the reaction was
allowed to warm to Ϫ30 ЊC. Benzyl bromide (0.670 g, 3.92
mmol) in dry THF (5 ml) was then added slowly. After 15 min,
the reaction mixture was quenched with distilled water (25 ml),
extracted with EtOAc (3 × 25 ml) and dried with brine (25 ml)
and over MgSO4. Solvent was removed in vacuo and the residue
separated by column chromatography eluting with 20% EtOAc
: petrol to yield three products.
cmϪ1 1647s, 1603w, 1518s, 1494w, 1427m, 1370w, 1346s, 1323m,
1244m; δH(400 MHz; CDCl3) 1.46–1.59 (2H, m, C(6)Hexo and
C(7)Hendo), 1.91–2.00 (1H, m, C(6)Hendo), 2.02–2.09 (1H, m,
C(7)Hexo), 2.04 (3H, s, C(2)Me), 2.66–2.79 (1H, m, C(8)H), 2.98
(1H, dd, J 9.0 and 14.0, PhCH ), 3.40 (1H, dd, J 4.0 and 14.0,
PhCH ), 3.50 (1H, dd, J 8.5 and 10.5, C(4)Hendo), 3.71–3.78 (1H,
m, C(5)H), 4.04 (1H, dd, J 5.5 and 8.5, C(4)Hexo), 7.27–8.15
(9H, m, ArH); δC(100.6 MHz; CDCl3) 24.8 (C(2)Me), 24.9
(C(7)), 26.9 (C(6)), 37.1 (C(2)CH2), 43.4 (C(8)), 56.4 (C(5)),
69.1 (C(4)), 95.7 (C(2)), 123.6, 125.5, 128.0, 128.2, 128.5, 130.2
(ArCH), 141.3 (ArC), 136.6 (ArC), 147.8 (ArCNO2), 167.8
(C(9)); m/z (APCIϩ) 367.2 (MHϩ, 100%), 337 (23), 247 (98);
HRMS: 367.1653 (MHϩ, ESϩ). C21H22N2O4 requires 367.1658.
Minor diastereomer (endo) 11b: Yield 0.10 g (11%); Rf 0.07
Major diastereomer (exo) 9a: Yield 0.132 g (63%); Rf 0.13
25
(20% EtOAc : petrol); [α]D Ϫ25.8 (c 1.03, CHCl3); νmax(film)/
cmϪ1 1648s, 1495w, 1445w, 1424m; δH(500 MHz; CDCl3) 1.50–
1.60 (1H, m, C6(H)endo), 1.55–1.62 (1H, m, C(7)Hexo), 1.94–1.99
(1H, m, C(7)Hendo), 2.00–2.06 (1H, m, C(6)Hexo), 2.07 (3 H, s,
C(2)Me), 2.65–2.71 (1H, m, C(8)H), 2.84 (1H, dd, J 9.0 and
13.5, PhCH ), 3.35 (1H, dd, J 4.0 and 13.5, PhCH ), 3.50 (1H,
dd, J 8.5 and 10.5, C(4)Hendo), 3.70–3.76 (1H, m, C(5)H), 4.04
(1H, dd, J 5.5 and 8.5, C(4)Hexo), 7.21–7.50 (10H, m, ArH);
δC(125.8 MHz; CDCl3) 24.9 (C(2)CH3), 25.1 and 26.9 (C(6) and
C(7)), 37.4 (CH2Ph), 43.8 (C(8)), 57.9 (C(5)), 69.2 (C(4)), 95.8
(C(2)), 125.6, 126.2, 127.9, 128.1, 128.3, 129.4 (ArCH), 139.7,
141.6 (ArC), 168.7 (C(9)); m/z (APCIϩ) 322 (MHϩ, 100%),
202 (94); HRMS: 322.1807 (MHϩ,CI). C21H23NO2 requires
322.1807.
25
(40% EtOAc : petrol); [α]D Ϫ52.1 (c 1.04, CHCl3); νmax(film)/
cmϪ1 1648s, 1559w, 1519w, 1494w, 1426m, 1370m, 1345m,
1324m, 1243m, 1182m; δH(400 MHz; CDCl3) 1.50–1.62 (1H, m,
C(6)Hendo), 1.81–1.85 (1H, m, C(7)Hexo), 1.97–2.00 (1H, m,
C(7)Hendo), and 2.34–2.49 (1H, m, C(6)Hexo), 2.05 (3H, s,
C(2)Me), 2.85–3.00 (1H, m, C(8)H), 3.35 (1H, t, J 10.0,
PhCH ), 3.45 (1H, dd, J 8.0 and 10.0, PhCH ), 3.56 (1H, dd,
J 8.5 and 10.5, C(4)Hendo), 3.90–3.98 (1H, m, C(5)H), 4.16 (1H,
dd, J 6.0 and 8.5, C(4)Hexo), 7.26–7.53 (9H, m, ArH); δC(100.6
MHz; CDCl3) 20.6 (C(6)), 24.9 (C(2)Me), 25.8 (C(7)), 32.1
(PhCH), 44.0 (C(8)), 58.0 (C(5)), 69.5 (C(4)), 96.4 (C(2)),
123.6, 125.4, 125.5, 125.6, 125.7, 127.9, 128.2, 130.2 (ArCH),
140.8 (ArC), 142.4 (ArC), 163.3 (C(9)), 170.3 (ArCNO2); m/z
(APCIϩ) 367 (MHϩ, 100%), 337 (19), 247 (99); HRMS:
367.1661 (MHϩ, ESϩ). C21H22N2O4 requires 367.1658.
Minor diastereomer (endo) 9b: Yield 0.013 g (6%); Rf 0.26
(20% EtOAc : petrol); νmax(film)/cmϪ1 1644s, 1422m; δH(500
MHz; CDCl3) 1.39–1.48 (1H, m, C(6)Hendo), 1.65–1.71 (1H, m,
C(7)Hexo), 1.75–1.81 (1H, m, C(7)Hendo), 1.82–1.89 (1H, m,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
1038

View Article Online
(2S,5S,8S )-8-Allyl-1-aza-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 12b and (؊)-(2S,5S,8R)-8-allyl-1-aza-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 12a
s, C(2)Me), 2.09–2.18 (2H, m, C(6)H), 2.81–2.87 (1H, m,
C(7)H), 3.06 (1H, dt, J 4.0 and 15.0, C(7)H), 3.59 (1H, dd, J 8.5
and 10.0, C(4)Hendo), 4.03–4.09 (1H, m, C(5)H), 4.12 (1H, dd,
J 5.5 and 8.5, C(4)Hexo), 7.30–7.49 (5H, m, ArH); δC(125.8
MHz; CDCl3) 22.7 (C(6)), 25.0 (C(2)Me), 44.1 (C(7)), 58.2
(C(5)), 68.9 (C(4)), 83.3 (C(8)), 96.4 (C(2)), 125.4, 128.3 and
128.4 (ArCH), 140.5 (ArC), 160.2 (C(9)); m/z (APCIϩ) 300.1
(MHϩ, 100%), 301.9 (MHϩ 35Cl 37Cl, 50%), 304 (MHϩ 37Cl
37Cl), 266 (32), 232 (44), 180 (38), 146 (38), 122 (52); HRMS:
300.0559 (MHϩ,CI). C14H15NO2Cl2 requires 300.0558.
To a stirred flask of THF (20 ml) cooled to Ϫ78 ЊC under nitro-
gen was added sBuLi (1.08 ml, 0.98 mmol). The lactam 2d
(0.15 g, 0.65 mmol) was then dissolved in THF (10 ml) and
added slowly to the mixture using a syringe. The reaction was
allowed to warm slightly to Ϫ30 ЊC. Freshly distilled allyl
bromide (0.12 g, 0.98 mmol) dissolved in THF (5 ml) was then
added and the dark red colour of the anion disappeared. After
30 minutes the reaction was quenched with sat. aq. NH4Cl
(30 ml). The aqueous layer was separated and extracted with
EtOAc (3 × 30 ml). The organic extracts were then combined
and dried with brine (25 ml) and over MgSO4. Solvent was
removed in vacuo. The residue was then separated by column
chromatography on silica gel, eluting with 20% EtOAc : petrol
to give two colourless oils.
Major diastereomer (exo) 13a: Rf 0.19 (40% EtOAc : petrol);
25
[α]D Ϫ30.4 (c 0.58, CHCl3); νmax(film)/cmϪ1 1666s, 1494w,
1446m, 1427m, 1371m, 1244m, 1222m; δH(500 MHz; CDCl3)
1.92–2.04 (2H, m, C(6)H and C(7)H), 2.05 (3H, s, C(2)Me),
2.30–2.41 (2H, m, C(6)H and C(7)H), 3.51 (1H, dd, J 8.5 and
10.5, C(4)Hendo), 3.84–3.90 (1H, m, C(5)H), 4.09 (1H, dd, J 5.5
and 8.5, C(4)Hexo), 4.45 (1H, dd, J 3.5 and 4.5, C(8)H), 7.27–
7.59 (5H, m, ArH); δC(125.8 MHz; CDCl3) 20.3 (C(6)), 24.9
(C(2)Me), 31.4 (C(7)), 55.2 (C(5)), 57.9 (C(8)), 68.8 (C(4)), 95.6
(C(2)), 125.3, 128.1, 128.2 (ArCH), 140.8 (ArC), 163.1 (C(9));
m/z (APCIϩ) 266 (MHϩ, 11%), 268 (MHϩ 37Cl, 3), 232 (100);
HRMS: 266.0948 (MHϩ, CI). C14H16NO2Cl requires 266.0948.
Minor diastereomer (endo) 13b: Rf 0.28 (40% EtOAc : petrol);
Major diastereomer (exo) 12a: Yield 0.11 g (64%); Rf 0.28
25
(20% petrol : EtOAc); [α]D Ϫ60.0 (c 0.09, CHCl3); νmax(film)/
cmϪ1 1660s, 1559m, 1540m, 1522m, 1506m, 1457m, 1420m;
δH(500 MHz; CDCl3) 1.58–1.69 (2H, m, C(6)Hendo and
C(7)Hexo), 2.06 (3H, s, C(2)Me), 2.09–2.17 (2H, m, C(6)Hexo and
C(7)Hendo), 2.35–2.41 (1 H, m, CH ᎐CHCH ), 2.46–2.52 (1H, m,
᎐
25
[α]D ϩ47.2 (c 0.11, CHCl3); νmax(film)/cmϪ1 1664s, 1494w,
2
C(8)H), 2.66–2.71 (1H, m, CH ᎐CHCH ), 3.52 (1H, dd, J 8.5
᎐
2
1446m, 1426m, 1370m, 1325m, 1270m, 1211m, 1180m; δH(500
MHz; CDCl3) 1.59–1.68 (1H, m, C(6)H), 2.03 (3H, s, C(2)Me),
2.11–2.21 (2H, m, C(6)H and C(7)H), 2.45–2.52 (1H, m,
C(7)H), 3.71 (1H, t, J 8.5, C(4)Hendo), 3.96–4.02 (1H, m, C(5)H),
4.18 (1H, dd, J 6.5 and 8.5, C(4)Hexo), 4.48 (1H, dd, J 6.0 and
8.0, C(8)H), 7.26–7.79 (5H, m, ArH); δC(125.8 MHz; CDCl3)
25.0 (C(6) and C(2)Me), 30.8 (C(7)), 55.7 and 55.9 (C(5) and
C(8)), 69.9 (C(4)), 96.7 (C(2)), 125.5, 128.2, 128.2 (ArCH),
141.6 (ArC), 163.4 (C(9)); m/z(APCIϩ) 266 (MHϩ, 21%),
268 (MHϩ, 37Cl, 7), 232 (100), 146 (94); HRMS: 266.0948
(MHϩ,CI). C14H16NO2Cl requires 266.0948.
and 10.5, C(4)Hendo), 3.83–3.89 (1H, m, C(5)H), 4.08 (1H, dd,
J 5.5 and 8.5, C(4)Hexo), 5.08–5.14 (2H, m, CH᎐CH ), 5.75–5.83
᎐
2
(1H, m, CH᎐CH ), 7.28–7.47 (5H, m, ArH); δ (125.8 MHz;
᎐
2
C
CDCl ) 24.8 (C(2)Me), 25.0 (C(7)), 26.9 (C(6)), 35.7 (CH ᎐
᎐
2
3
CHCH2), 41.4 (C(8)), 57.8 (C(5)), 69.1 (C(4)), 95.5 (C(2)), 117.0
(CH᎐CH ), 125.5, 127.7, 127.9 (ArCH), 135.7 (CH᎐CH ),
᎐
᎐
2
2
141.5 (ArC), 168.7 (C(9); m/z (APCIϩ) 272 (MHϩ, 100%), 152
(81); HRMS: 272.1651 (MHϩ, CI). C17H21NO2 requires
272.1650.
Minor diastereomer (endo) 12b: Yield 0.054 g (30%); Rf 0.32
(20% EtOAc : petrol); νmax(film)/cmϪ1 1654s. 1419m, 764m;
δH(500 MHz; CDCl3) 1.48–1.57 (1H, m, C(6)Hendo), 1.72–
1.80 (1H, m, C(7)Hexo), 1.92–2.02 (1H, m, C(7)Hendo), 2.21–2.27
(؊)-(2S,5S,8S )-1-Aza-2-methyl-3-oxa-9-oxo-2-phenyl-8-
phenylselenylbicyclo[4.3.0]nonane 14b and (؊)-(2S,5S,8R)-1-
aza-2-methyl-3-oxa-9-oxo-2-phenyl-8-phenylselenylbicyclo-
[4.3.0]nonane 14a
(1H, m, C(6)Hexo), 2.63–2.72 (3H, m, C(8)H and CH ᎐CHCH ),
᎐
2
2.02 (3H, s, C(2)Me), 3.39 (1H, dd, J 9.0 and 10.0, C(4)Hendo),
3.89–3.93 (1H, m, C(5)H), 4.11 (1H, dd, J 6.0 and 9.0,
C(4)Hexo), 5.05–5.12 (2H, m, CH᎐CH ), 5.82–5.89 (1H, m,
᎐
2
To a stirred flask of THF (20 ml) cooled to Ϫ78 ЊC under nitro-
gen was added s-BuLi (0.94 ml, 0.84 mmol). The lactam 2d
(0.13 g, 0.56 mmol) was then dissolved in THF (10 ml) and
added slowly to the mixture using a syringe. The reaction
was allowed to warm slightly to Ϫ30 ЊC. Phenylselenenyl
chloride (0.16 g, 0.84 mmol) dissolved in THF (10 ml) was then
added and the dark red colour of the anion disappeared. After
30 minutes the reaction was quenched with sat. aq. NH4Cl
(25 ml). The aqueous layer was separated and extracted with
EtOAc (3 × 25 ml). The organic extracts were then combined
and dried with brine (25 ml) and over MgSO4, and the solvent
removed in vacuo. The residue was then separated by column
chromatography on silica gel, eluting initially with 20% EtOAc :
petrol and increasing the polarity to 40% EtOAc : petrol to give
the products as two yellow oils.
CH᎐CH ), 7.25–7.44 (5 H, m, ArH); δ (125.8 MHz; CDCl )
᎐
2
C
3
23.2 (C(7)), 24.7 (C(6)), 25.6 (C(2)Me), 35.7 (CH ᎐CHCH ),
᎐
2
2
40.9 (C(8)), 56.7 (C(5)), 69.2 (C(4)), 96.0 (C(2)), 116.8
(CH CH᎐CH ), 125.5, 127.8, 128.1 (ArCH), 136.5 (CH CH᎐
᎐
᎐
2
2
2
CH2), 142.1 (ArC), 170.4 (C(9)); m/z (APCIϩ) 272 (MHϩ,
100%); HRMS: 272.1644 (MHϩ, CI). C17H21NO2 requires
272.1650.
(؊)-(2S,5S )-1-Aza-8-dichloro-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 10b, (؉)-(2S,5S,8S )-1-aza-8-chloro-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 13b and
(؊)-(2S,5S,8R)-1-aza-8-chloro-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 13a
To a solution of lactam 2d (0.332 g, 1.4 mmol) in THF (20 ml)
cooled to Ϫ78 ЊC under nitrogen was added s-BuLi (1.69 ml,
1.7 mmol). The solution was stirred for 15 minutes and allowed
to warm slightly to Ϫ30 ЊC. The enolate was then transferred by
syringe to a solution of tosyl chloride (0.410 g, 2.2 mmol) in
THF (20 ml) cooled to Ϫ78 ЊC. After 1.5 h the reaction was
quenched using sat. aq. NH4Cl (25 ml), and the mixture
extracted with EtOAc (3 × 25 ml). The organic extracts were
then dried with brine (25 ml) and over MgSO4. Solvent was
removed in vacuo and the residue separated by column chrom-
atography on silica gel (40% EtOAc : petrol) to give two
colourless oils 13b (74 mg, 19%) and 13a (123 mg, 32%).
Major diastereomer (exo) 14a: Yield 71 mg (33%); Rf 0.06
25
(20% EtOAc : petrol); [α]D Ϫ26.8 (c 0.37, CHCl3); νmax(film)/
cmϪ1 1652s, 1578w, 1494w, 1477w, 1447m, 1438m, 1423m,
1375m, 1322m; δH(500 MHz; CDCl3) 1.88–1.96 (1H, m,
C(6)Hendo), 2.01–2.06 (1H, m, C(7)Hexo), 2.11 (3H, s, C(2)Me),
2.30–2.38 (2H, m, C(6)Hexo and C(7)Hendo), 3.59 (1H, dd, J 8.5
and 10.5, C(4)Hendo), 3.93–3.99 (1H, m, C(5)H), 4.09 (1H, t,
J 5.0, C(8)H), 4.15 (1H, dd, J 5.5 and 8.5, C(4)Hexo), 7.30–7.70
(10H, m, ArH); δC(125.8 MHz; CDCl3) 22.2 (C(6)), 25.0
(C(2)Me), 28.9 (C(7)), 43.5 (C(8)), 58.0 (C(5)), 69.2 (C(4)), 95.5
(C(2)), 125.6, 128.0, 128.2, 129.1 and 129.2 (ArCH), 131.57
(ArC), 141.4 (ArC), 166.6 (C(9)); m/z (APCIϩ) 388 (MHϩ,
100%), 386 (50); HRMS: 388.0820 (MHϩ, CI). C20H21NO2Se
requires 388.0815.
25
Dichlorolactam 10b: Rf 0.32 (40% EtOAc : petrol); [α]D
Ϫ75.5 (c 0.65, CHCl3); νmax(film)/cmϪ1 1686s, 1495w, 1447m,
1422m, 1378m, 1325m, 1226m; δH(500 MHz; CDCl3) 2.08 (3H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
1039

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Minor diastereomer (endo) 14b: Yield 41 mg (19%); Rf
0.11 (20% EtOAc : petrol); [α]D Ϫ120.5 (c 0.39, CHCl3);
(؉)-(2R,5S,8S )-1-Aza-2-methyl-8-methyl-3-oxa-9-oxo-2-
phenylbicyclo[4.3.0]nonane 17b
25
νmax(film)/cmϪ1 1650s, 1416m, 1370m, 1322m, 1241m; δH(500
MHz; CDCl3) 1.53–1.60 (1H, m, C(6)Hendo), 2.00–2.14
(2H, m, C(6)Hexo and C(7)Hexo), 2.02 (3H, s, C(2)Me), 2.41–2.46
(1H, m, C(7)Hendo), 3.44 (1H, dd, J 9.0 and 10.0, C(4)Hendo),
3.82–3.87 (1H, m, C(5)H), 4.03 (1H, t, J 7.5, C(8)H), 4.09
(1H, dd, J 6.0 and 9.0, C(4)Hexo), 7.28–7.71 (10H, m, ArH);
δC(125.8 MHz; CDCl3) 25.1 (C(7) and C(2)Me), 29.0
(C(6)), 41.8 (C(8)), 56.6 (C(5)), 69.0 (C(4)), 96.5 (C(2)), 125.7,
127.9, 128.1, 128.4, 129.0 and 135.8 (ArCH), 131.5 (ArC),
141.4 (ArC), 166.4 (C(9)); m/z (APCIϩ) 388 (MHϩ, 100%), 386
(51); HRMS: 388.0819 (MHϩ, CI). C20H21NO2Se requires
388.0816.
To a solution of the lactam 2e (0.21 g, 0.90 mmol) in THF
(10 ml) cooled to Ϫ78 ЊC under nitrogen was added sBuLi
(1.1 ml, 0.99 mmol). The reaction mixture was stirred for
30 minutes, and then methyl iodide (0.07 ml, 1.1 mmol)
was added by syringe. The reaction mixture was stirred for
30 minutes, and then allowed to return to room temperature,
and quenched with sat. aq. NH4Cl (25 ml). The biphasic system
was then extracted with EtOAc (3 × 25 ml), dried with brine
(20 ml) and over MgSO4. Solvent was removed in vacuo, and the
residue separated by flash column chromatography on silica gel,
eluting with 40% EtOAc : petrol to yield the title compound 17b
as a colourless oil (0.102 g, 46%). Rf 0.33 (40% EtOAc : petrol);
25
[α]D ϩ126.1 (c 0.53, CHCl3); νmax(film)/cmϪ1 2937m, 1648s,
(؉)-(2S,5S )-1-Aza-8,8-dibenzyloxycarbonyl-2-methyl-3-oxa-9-
oxo-2-phenylbicyclo[4.3.0]nonane 16a, (2S,5S,8S ) and
(2S,5S,8R)-1-aza-8-benzyloxycarbonyl-2-methyl-3-oxa-9-oxo-
2-phenylbicyclo[4.3.0]nonane 15a and 15b
1420m, 1324m, 1237m, 1028m; δH(400 MHz; CDCl3) 1.26 (3H,
d, J 7.0, C(8)Me), 1.58–1.67 (2H, m, C(6)H and C(7)H), 1.94–
2.11 (2H, m, C(6)H and C(7)H), 2.03 (3H, s, C(2)Me), 2.44–
2.48 (1H, m, C(8)H), 3.71–3.80 (2H, m, C(5)H and C(4)Hendo),
4.15 (1H, dd, J 5.5 and 7.5, C(4)Hexo), 7.28–7.57 (5H, m, ArH);
δC(100.6 MHz; CDCl3) 17.5 (C(8)Me), 24.4 (C(6)), 25.6
(C(8)Me), 27.5 (C(7)), 35.9 (C(8)), 56.5 (C(5)), 69.8 (C(4)), 96.3
(C(2)), 125.6, 128.0 and 128.1 (ArCH), 142.6 (ArC), 171.4
(C(9)); m/z (APCIϩ) 246 (MHϩ); HRMS: 246.1490 (MHϩ, CI).
C15H19NO2 requires 246.1494.
To a solution of the lactam 2d (1.59 g, 6.9 mmol) in THF
(50 ml) at Ϫ78 ЊC under nitrogen was added s-BuLi (8.2 ml,
8.2 mmol). The mixture was stirred for 15 minutes and allowed
to warm to Ϫ30 ЊC. The enolate solution was then trans-
ferred by cannula into a solution of benzyl chloroformate
(2.34 g, 13.7 mmol) in THF (10 ml) at Ϫ78 ЊC. The reaction
was stirred for three hours, and then quenched with sat. aq.
NH4Cl (25 ml), extracted with EtOAc (3 × 30 ml), dried with
brine (30 ml) and over MgSO4, and solvent was removed in
vacuo. Separation of the residue by flash column chromato-
graphy (20% EtOAc : petrol) on silica gel gave 0.335 g (10%) of
the diacylated product and 1.128 g (45%) of a mixture of
diastereomers of the monoacylated product. An improved
purification method, whereby the residue was separated on an
alumina column gave 9.17 g (72%) of a mixture of the
diastereomers 15a,b.
Diastereomeric mixture 15a,b: Rf 0.32 and 0.22 (40% EtOAc :
petrol); νmax(film)/cmϪ1 1736s, 1655s, 1497w, 1430m, 1372m;
δH(500 MHz; CDCl3) 1.51–1.59, 1.80–1.88, 1.96–2.01, 2.07–
2.17, 2.20–2.34 (4H, m, C(6)H and C(7)H), 2.03 and 2.05 (3H,
2 × s, C(2)Me), 3.44 (1H, dd, J 8.5 and 10.0, C(4)Hendo (B)), 3.46
(1H, dd, J 8.5 and 10.0, C(4)Hendo (A)), 3.55 (1H, dd, J 2.0 and
9.5, C(8)H (B)), 3.56 (1H, dd, J 4.0 and 11.0, C(8)H (A)), 3.81–
3.91 (1H, m, C(5)H), 4.08 (1H, dd, J 5.5 and 8.5, C(4)Hexo (A)),
4.10 (1H, dd, J 6.0 and 8.5, C(4)Hexo (B)), 5.16–5.26 (2H, m,
CO2CH2), 7.24–7.51 (10H, m, ArH); δC(125.8 MHz; CDCl3)
22.5 (C(7) (A)), 24.3 (C(7) (B)), 25.0 (C(6) (B)), 25.1 (C(6) (A)),
25.1 (C(2)Me (A)), 25.2 (C(2)Me (B)), 48.1 (C(5) (A)), 50.0
(C(5) (B)), 57.1 (C(8) (A)), 57.7 (C(8) (B)), 66.8 (C(4) (B)),
67.1 (C(4) (A)), 68.7 (CO2CH2 (A)), 69.1 (CO2CH2 (B)),
96.2 (C(2) (A)), 96.3 (C(2) (B)), 125.6, 127.9, 128.0, 128.1,
128.2, 128.5, 128.5 (ArCH), 135.5 (ArC), 140.9 (CH2CO2C
(؉)-(2R,5S,8R)-1-Aza-8-benzyl-2-methyl-3-oxa-9-oxo-2-
phenylbicyclo[4.3.0]nonane 18b and (؉)-(2R,5S,8S )-1-aza-8-
benzyl-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 18a
To a solution of the lactam 2e (0.21 g, 0.90 mmol) in THF
(10 ml) cooled to Ϫ78 ЊC under nitrogen was added s-BuLi
(1.1 ml, 0.99 mmol). The reaction mixture was stirred for
30 minutes, and then a solution of benzyl bromide (0.18 g,
1.08 mmol) in THF (20 ml) was added by syringe. The reaction
mixture was stirred for 30 minutes, and then allowed to return
to room temperature, and quenched with sat. aq. NH4Cl
(25 ml). The biphasic system was then extracted with EtOAc
(3 × 25 ml), dried with brine (20 ml) and over MgSO4. Solvent
was removed in vacuo, and the residue separated by flash
column chromatography on silica gel, eluting initially with 20%
EtOAc : petrol and increasing the polarity to 40% EtOAc :
petrol to yield the title compounds as two colourless oils.
Major diastereomer (exo) 18a: Yield 48 mg (16%); Rf 0.48
25
(40% EtOAc : petrol); [α]D ϩ25.0 (c 1.4, CHCl3); νmax(film)/
cmϪ1 3503w, 1645s, 1495w, 1446w, 1421m, 1377w, 1319w,
1230w, 1077w; δH(400 MHz; CDCl3) 1.36–1.57 (2H, m,
C(6)Hendo and C(7)Hexo), 1.86–1.92 (1H, m, C(7)Hendo), 1.97–
2.02 (1H, m, C(6)Hexo), 2.10 (3H, s, C(2)Me), 2.62–2.70 (1H, m,
C(8)H), 2.90 (1H, dd, J 8.5 and 13.5, PhCH ), 3.23 (1H, dd,
J 4.0 and 13.5, PhCH ), 3.62–3.69 (2H, m, C(5)H and
C(4)Hendo), 4.18 (1H, m, C(4)Hexo), 7.10–7.55 (10H, m, ArH);
δC(100.6 MHz; CDCl3) 24.4 (C(2)Me), 26.0 (C(7)), 26.3 (C(6)),
37.4 (PhCH), 43.9 (C(8)), 58.1 (C(5)), 70.2 (C(4)), 96.2 (C(2)),
(A)), 141.3 (CH CO C (B)), 163.3 (C(9)), 170.6 (C᎐O, (B)),
᎐
2
2
170.9 (C᎐O (A)); m/z (APCIϩ) 366 (MHϩ, 100%), 246 (27),
᎐
156 (27); HRMS: 366.1711 (MHϩ,CI). C22H23NO4 requires
366.1705.
126.2, 126.3, 128.1, 128.3 and 129.5 (ArCH), 139.5 (ArC),
142.2 (ArC), 168.8 (C(9)); m/z (APCIϩ) 344 (M ϩ NH4
,
ϩ
Diacylated lactam 16a: Rf 0.53 (40% EtOAc : petrol); [α]D
100%); HRMS: 322.1815 (MHϩ, ESϩ). C21H23NO2 requires
322.1807.
25
ϩ46.0 (c 2.1, CHCl3); νmax(film)/cmϪ1 1732s, 1673s, 1221s;
δH(500 MHz; CDCl3) 1.55–1.63 (1H, m, C(6)Hendo), 1.93–
2.00 (1H, m, C(6)Hexo), 1.98 (3H, s, C(2)Me), 2.60–
2.70 (2H, m, C(7)H), 3.38 (1H, dd, J 8.5 and 10.0, C(4)Hendo),
3.58–3.67 (1H, m, C(5)H), 4.04 (1H, dd, J 5.5 and 8.5,
Minor diastereomer (endo) 18b: Yield 27 mg (9%); Rf 0.58
25
(40% EtOAc : petrol); [α]D ϩ134.6 (c 1.2, CHCl3); νmax(film)/
cmϪ1 1647s, 1496w, 1420m, 1370m, 1320w, 1238m; δH(400
MHz; CDCl3) 1.38–1.48 (1H, m, C(6)Hendo), 1.64–1.71 (1H, m,
C(7)Hendo), 1.73–1.81 (1H, m, C(7)Hexo), 1.82–1.89 (1H, m,
C(6)Hexo), 2.07 (3H, s, C(2)Me), 2.58–2.65 (1H, m, C(8)H), 2.73
(1H, dd, J 10.0 and 13.5, PhCH ), 3.32 (1H, dd, J 4.0 and 13.5,
PhCH ), 3.67 (1H, t, J 8.0, C(4)Hendo), 3.72–3.79 (1H, m,
C(5)H), 4.16 (1H, dd, J 6.0 and 8.0, C(4)Hexo), 7.19–7.61 (10H,
m, ArH); δC(100.6 MHz; CDCl3) 23.7 (C(7)), 23.9 (C(6)), 25.2
(C(2)Me), 37.7 (ArCH2), 56.7 (C(5)), 69.9 (C(4)), 96.3 (C(2)),
125.8, 126.3, 128.1, 128.4 and 129.2 (ArCH), 139.9 (CH2CAr),
C(4)Hexo), 5.15–5.32 (4H, m,
2 × CO2CH2), 7.24–7.52
(15H, m, ArH); δC(125.8 MHz; CDCl3) 22.1 (C(6)), 25.3
(C(2)Me), 28.3 (C(7)), 56.3 (C(5)), 64.6 (C(8)), 67.9 and
68.1 (2 × CH2Ph), 69.4 (C(4)), 96.7 (C(2)), 125.6, 127.9,
128.1, 128.2, 128.4, 128.5 (ArCH), 134.9 and 135.1 (2 × ArC),
162.3 (C(9)), 167.5, 167.6 (C᎐O); m/z (APCIϩ) 500 (MHϩ,
᎐
100%); HRMS: 500.2070 (MHϩ,CI). C30H29NO6 requires
500.2073.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
1040

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ϩ
142.4 (ArC), 170.2 (C(9)); m/z (APCIϩ) 344 (M ϩ NH4
,
135.2, 138.3, 138.4, 140.9, 141.9 (ArC), 163.3 (C(9) (B), 164.7
100%), 229 (23), 202 (18); HRMS: 322.1811 (MHϩ, ESϩ).
C21H23NO2 requires 322.1807.
((C(9) (A)), 169.4 (C᎐O (A)), 170.7 (C᎐O (B)); m/z (APCIϩ) 522
᎐ ᎐
(MHϩ, 100%), 520 (62), 366 (57); HRMS: 522.1181 (MHϩ,
APCIϩ). C28H27NO480Se requires 522.1184.
(2S,5S,8RS )-1-Aza-8-benzyl-8-benzyloxycarbonyl-2-methyl-3-
oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 16b
(2R,5S,8R)- and (2R,5S,8S )-1-Aza-8-benzyloxycarbonyl-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 19a,b and
(؉)-(2R,5S )-1-aza-8-dibenzyloxycarbonyl-2-methyl-3-oxa-9-
oxo-2-phenylbicyclo[4.3.0]nonane 20a
Prewashed sodium hydride (8 mg, 0.34 mmol) was suspended in
THF (10 ml) and cooled to 0 ЊC under nitrogen. A solution of
lactams 15a,b (0.11 g, 0.31 mmol) in THF (5 ml) was then
added, and the mixture stirred for 45 minutes. Benzyl bromide
(58 mg, 0.34 mmol) was then added, and the reaction stirred
for four hours, until TLC indicated that no starting material
was present. The reaction was then quenched with 50 ml 1 : 1
EtOAc : sat. aq. NH4Cl, extracted with EtOAc (3 × 30 ml),
dried with brine (25 ml) and over MgSO4, and the solvent
removed in vacuo. The residue was separated by flash column
chromatography on silica gel, eluting with 20% EtOAc : petrol
to give 16b as an inseparable mixture of diastereomers (77 mg,
55%); Rf 0.23 and 0.18 (20% EtOAc : petrol); νmax(film)/cmϪ1
1740s, 1653s, 1496w, 1423m, 1370m, 1323w, 1223m; δH(500
MHz; CDCl3) 0.93–1.01(1 H, m, C(6)Hendo), 1.78–1.84(1 H, m,
C(7)Hexo), 1.97–2.06 (1 H, m, C(7)Hendo) and 2.26–2.33 (1 H, m,
C(7)Hexo), 2.96 (1H, d, J 13.5, PhCH (B)), 3.24 (1H, d, J 13.5,
PhCH (A)), 3.31 (1H, dd, J 8.5 and 9.5, C(4)Hendo (A)), 3.37
(1H, t, J 8.5, C(4)Hendo (B)), 3.47 (1H, d, J 13.5, PhCH (A)),
3.62–3.69 (1H, m, C(5)H), 3.79 (1H, d, J 13.5, PhCH (B)), 3.82
(1H, dd, J 6.5 and 8.5, C(4)Hexo (B)), 4.00 (1H, dd, J 6.0 and 8.5,
C(4)Hexo (A)), 5.10 (1H, d, J 12.5, CO2CH2 (B)), 5.19 (1H, d,
J 12.0, CO2CH2 (A)), 5.23 (1H, d, J 12.0, CO2CH2 (A)), 5.34
(1H, d, J 12.5, CO2CH2 (B)), 7.06–7.51 (15H, m, ArH); δC(125.8
MHz; CDCl3) 22.9 (C(7) (B)), 23.2 (C(7) (A)), 24.5 (C(2)Me),
29.3 (C(6) (A)), 29.8 (C(6) (B)), 40.5 (PhCH (B)), 41.0 (PhCH
(A)), 55.8 (C(5) (A)), 55.9 (C(5) (B)), 67.3 (CO2CH2(A)), 68.2
(CO2CH2 (B)), 69.8 (C(4)), 96.2 (C(2)), 125.6, 125.9, 126.8,
127.0, 127.9, 128.1, 128.3, 128.4, 128.5, 128.6, 130.3, 130.5,
131.1 (ArCH), 135.3 (ArC), 136.5 (ArC), 141.6 (ArC), 166.1
To a solution of the lactam 2e (1 eq) in THF (50 ml) at Ϫ78 ЊC
under an inert atmosphere was added sec-BuLi (1.15 eq). The
mixture was stirred for 15 minutes and allowed to warm to
Ϫ30 ЊC. The enolate solution was then transferred by cannula
into a solution of the benzyl chloroformate (1.2 eq) in THF
(10 ml) at Ϫ78 ЊC. The reaction was stirred for 3 hours, and
then quenched with saturated NH4Cl (aq) (25 ml). The aqueous
layer was extracted with EtOAc (3 × 30 ml), washed with brine
(30 ml), dried (MgSO4), and the solvent removed in vacuo.
Purification by flash column chromatography (20% EtOAc :
petrol) on silica gel gave the diacylated product 20a as a brown
oil (25–46%) and the monoacylated product as an inseparable
mixture of two diastereomers 19a,b in a 1 : 1 ratio and 6–14%
1
yield (estimated from H-NMR spectrum) along with 25–46%
of unreacted starting material. The yield of the monoacyl
adduct could be improved to 36–50% by using benzyl
cyanoformate.
Monoacylated diastereomers 19a,b; Rf 0.23 (40% EtOAc :
petrol); νmax(film)/cmϪ1 1738s, 1659s, 1265s; δH(500 MHz; C6D6)
0.47–0.54 (1 H, m, C(6)Hendo (A)), 0.83–0.87 (1 H, m, C(6)Hexo
,
(B)), 0.92–0.99 (1 H, m, C(6)Hexo (A)), 1.12–1.20 (2 H, m,
C(6)Hendo, C(7)Hexo (B)), 1.41–1.48 (1 H, m, C(7)Hendo (A)),
1.64–1.72 (2 H, m, C(7)Hexo(A), C(7)Hendo (B)), 1.93, 1.95 (3 H,
2 × s, Me), 2.78 (1 H, dd, J 8.5, 10.0, C(4)Hendo (A)), 2.84 (1 H,
dd, J 8.0, 10.0, C(4)Hendo (B)), 2.88–2.91 (1 H, m, C(5)H (B)),
3.08–3.10 (1 H, m, C(5)H (A)), 3.12 (1 H, dd, J 4.0, 7.0, C(8)H
(B)), 3.15 (1 H, dd, J 7.5, 10.0, C(8)H (A)), 3.24–3.30 (2H, m,
C(4)Hexo), 4.78–4.90 (4H, m, PhCH2O), 6.82–7.51 (20H, m,
ArCH); δC(100.6 MHz C6D6) 21.2 (C(6) (B)), 22.8 (C(6) (A)),
23.6 (C(7) (A)), 24.1 (C(7) (B)), 24.5, 24.5, (2 × Me), 47.2 (C(8)
(B)), 49.0 (C(8) (A)), 55.9 (C(5) (A)), 56.2 (C(5) (B)), 65.6, 65.6
(2 × PhCH2O), 67.3, 67.6 (2 × C(4), 94.7, 95.1 (2 × C(2)), 124.8,
125.0, 125.1, 126.5, 126.7, 126.7, 126.9, 126.9, 127.0, 127.0,
127.1, 127.1, 127.1, 127.2, 127.3, 127.3 (ArCH), 134.5, 135.0,
141.1, 141.2 (ArC), 161.9, 162.1 (2 × CON), 169.5, 169.7
(2 × PhCH2OCO); m/z (APCIϩ) 366 (MHϩ 100%), 232 (15), 112
(50); HRMS: 366.1710 (MHϩ). C22H24NO4 requires 366.1705.
Lactam 20a: Rf 0.53 (40% EtOAc : petrol); [α]D23 ϩ86.9 (c 1.0,
CHCl3); νmax(film)/cmϪ1 1735s, 1670s, 1455s; δH(400 MHz;
CDCl3) 1.47–1.56 (1 H, m, C(6)Hendo), 1.93–2.01 (1 H, m,
C(6)Hexo), 2.02 (3 H, s, Me), 2.50–2.58 (1 H, m, C(7)Hexo), 2.60–
2.68 (1 H, m, C(7)Hendo), 3.57–3.64 (2 H, m, C(4)Hendo and
C(5)H), 4.01–4.06 (1 H, m, C(4)Hexo), 5.15–5.34 (4 H, m, 2 ×
PhCH2O), 7.24–7.54 (15 H, m, ArCH); δC(100.6 MHz; CDCl3)
22.3 (C(6)), 25.4 (Me), 28.4 (C(7)), 56.3 (C(5)), 64.3 (C(8)), 67.9,
68.1 (2 × CH2Ph), 69.9 (C(4)), 97.2 (C(2)), 125.6, 127.9, 128.1,
128.3, 128.4, 128.5, 128.6 (ArCH), 134.9, 135.2, 141.9 (ArC),
161.7 (CON), 167.7, 167.8 (2 × PhCH2OCO); m/z (APCIϩ) 500
(MHϩ 20%); HRMS: 500.2078 (MHϩ). C30H30NO6 requires
500.2073.
(C(9)), 172.0 (C᎐O); m/z (APCIϩ) 456 (MHϩ, 100%); HRMS:
᎐
456.2178 (MHϩ, APCIϩ). C29H29NO4 requires 456.2175.
(2S,5S,8RS )-1-Aza-8-benzyloxycarbonyl-2-methyl-3-oxa-9-
oxo-2-phenyl-8-phenylselenylbicyclo[4.3.0]nonane 16c
Prewashed sodium hydride (29 mg, 1.2 mmol) was suspended in
THF (10 ml) and cooled to 0 ЊC under nitrogen. The lactam
15a,b (0.29 g, 0.80 mmol) was dissolved in THF (5 ml) and
added to the reaction mixture. This mixture was then stirred for
1 hour, after which phenylselenenyl chloride (0.17 g, 0.88 mmol)
in THF (5 ml) was added. The reaction was monitored by TLC
and quenched after 5 hours by the addition of 50 ml 1 : 1
EtOAc : sat. aq. NH4Cl. The mixture was then extracted with
EtOAc (3 × 25 ml), dried with brine (25 ml) and over MgSO4,
and solvent was removed in vacuo. The residue was then separ-
ated on silica gel eluting with 20% EtOAc : petrol to give the
products 16c in an inseparable diastereomeric mixture (0.29 g,
70%); Rf 0.23 and 0.18 (20% EtOAc : petrol); νmax(film)/cmϪ1
1736s, 1655, 1438m, 1246m; δH(500 MHz; CDCl3) 1.47–1.56
(1H, m, C(6)Hendo), 1.81–1.88 (1H, m, C(7)Hexo), 2.13–2.33 (1H,
m, C(7)Hendo), 2.25–2.53 (1 H, m, C(6)Hexo), 1.96 (3H, s, C(2)Me
(A)), 1.99 (3H, s, C(2)Me (B)), 3.31 (1H, t, J 8.5, C(4)Hendo (A)),
3.37 (1H, dd, J 4.5 and 7.0, C(4)Hendo (B)), 3.42–3.50 (1H, m,
C(5)H), 3.93 (1H, dd, J 4.0 and 7.0, C(4)Hexo (B)), 3.98 (1H, dd,
J 6.0 and 8.5, C(4)Hexo (A)), 5.15 (1H, d, J 12.0, CO2CH2 (A)),
5.23 (2H, s, CO2CH2), 5.33 (1H, d, J 12.0, CO2CH2), 7.12–7.68
(15H, m, ArH); δC(125.8 MHz; CDCl3) 23.2 (C(6) (A)), 24.0
(C(6) (B)), 24.8 (C(2)Me (B)), 25.7 (C(2)Me (A)), 30.5 (C(7)
(A)), 24.8 (C(7) (B)), 55.4 (C(5) (A)), 56.9 (C(8) (A)), 57.9 (C(5)
(B)), 60.4 (C(8) (B)), 67.7 (CO2CH2 (A)), 67.9 (CO2CH2 (B)),
68.7 (C(4) (B)), 69.5 (C(4) (A)), 96.6 (C(2) (B)), 96.9 (C(2) (A)),
125.5, 125.8, 126.1, 126.5, 126.6, 127.9, 128.1, 128.3, 128.5,
128.5, 128.6, 128.7, 128.8, 128.9, 129.2, 129.6, 129.7 (ArCH),
(2R,5S,8R) and (2R,5S,8S )-1-Aza-8-benzyloxycarbonyl-2-
methyl-3-oxa-9-oxo-2-phenyl-8-phenylselenylbicyclo[4.3.0]-
nonane 20b
Prewashed sodium hydride (1.5 eq.) was suspended in THF
(5 ml) and cooled to 0 ЊC under an inert atmosphere. A solution
of lactam 19a (160 mg, 0.44 mmol) in THF (5 ml) was then
added. After stirring for 1 hour at 0 ЊC, phenylselenyl chloride
(92 mg, 0.48 mmol) in THF (5 ml) was added dropwise via
cannula. The reaction was then stirred for 5 hours at 25 ЊC
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 0 3 1 – 1 0 4 3
1041

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before it was quenched with 1 : 1 saturated NH4Cl (aq) : EtOAc
(20 ml) The aqueous layer was washed with EtOAc (3 × 10 ml)
and the organic fractions were combined, washed with brine
(10 ml), dried (MgSO4) and solvent removed in vacuo. The
residue was then purified by flash column chromatography on
silica gel, eluting with 20% EtOAc : petrol. Purification by flash
column chromatography yielded the product 20b as a 1.6 : 1.0
ratio of diastereomers in 66% overall yield.
CHCl3); νmax(film)/cmϪ1 3348br, 1732s, 1673s, 1498w, 1456m,
1379w, 1647w, 1322w, 1271m, 1222m 1186m, 1090m; δH(500
MHz; CDCl3) 1.26–1.35 (1 H, m, C(3)H), 1.71–1.77 (1H, m,
C(3)H), 2.39 (1H, dt, J 3.5 and 13.5, C(4)H), 2.53 (1H, ddd,
J 3.5, 5.5 and 13.5, C(4)H), 2.92 (1H, br, OH ), 3.29 (1H, dd,
J 8.0 and 12.0, OCH2), 3.50–3.55 (2H, m, OCH2and C(2)H),
5.22 (4H, s, 2 × CO2CH2), 7.28–7.37 (10H, m, ArH), 7.45 (1H,
br, NH ); δC(125.8 MHz; CDCl3) 20.5 (C(3)), 27.4 (C(4)), 54.5
(C(2)), 63.2 (C(5)), 65.3 (OCH2), 67.9, 68.0 (2 × CO2CH2),
128.0, 128.2, 128.3, 128.4, 128.5 (ArCH), 135.0, 135.1 (ArC),
23
Major diastereomer: Rf 0.25 (20% EtOAc : petrol); [α]D
Ϫ12.7 (c 0.7, CHCl3); νmax(film)/cmϪ1 1724s, 1656s, 1421s,
1256s, 1236s; δH(500 MHz; CDCl3) 1.42–1.50 (1 H, m,
C(6)Hendo), 1.84–1.88 (1 H, m, C(6)Hexo), 2.02 (3 H, s, Me), 2.04–
2.13 (1 H, m, C(7)Hendo), 2.34–2.38 (1 H, m, C(7)Hexo), 3.49–3.58
(1 H, m, C(4)Hendo and C(5)H), 4.16–4.20 (1 H, m, C(4)Hexo),
5.26 (1 H, d, J 12.0, PhCH ), 5.37 (1 H, d, J 12.0, PhCH ), 7.17–
7.66 (15 H, m, ArCH ); δC(125.7 MHz; CDCl3) 24.2 (Me), 24.6
(C(6)), 33.6 (C(7)), 55.3 (C(8)), 57.4 (C(5)), 67.9 (CH2Ph), 70.0
(C(4)), 96.6 (C(2)), 126.0, 126.6, 128.1, 128.2, 128.4, 128.5,
128.8, 129.3 (ArCH), 135.3, 138.1, 141.9 (ArC), 163.4 (CO),
170.8 (PhCH2OC); m/z(APCIϩ) 524 (MHϩ, 30%), 524 (MHϩ,
20), 522 (MHϩ, 50), 522 (MHϩ, 100), 520 (MHϩ, 60), 518
(MHϩ, 30), 232 (30); HRMS: 522.1177 (MHϩ, CI). C28H28-
N80SeO4 requires 522.1184.
166.3 (C(6)) 167.4, 167.8 (2 × C᎐O); m/z (APCIϩ) 398 (MHϩ,
᎐
100%), 156 (41); HRMS: 398.1613 (MHϩ,CIϩ). C23H23NO6
requires 398.1604.
Acknowledgements
We thank EPSRC and Lancaster Synthesis for financial
support for GW, and we gratefully acknowledge the use of
the EPSRC Chemical Database Service at Daresbury78 and
the EPSRC National Mass Spectrometry Service Centre at
Swansea.
Minor diastereomer: mp 110 ЊC; Rf 0.31 (20% EtOAc :
petrol); [α]D23 ϩ79.4 (c 1.1, CHCl3); Found: C, 64.5; H, 5.3; N,
2.5. C28H27N80SeO4 requires C, 64.5; H, 5.3; N, 2.5%; νmax(film)/
cmϪ1 1724s, 1661s, 1417s, 1374s, 1261s; δH(500 MHz; CDCl3)
1.72–1.78 (1 H, m, C(6)Hendo), 1.88–1.98 (1 H, m, C(6)Hexo), 2.08
(3 H, s, Me), 2.10–2.18 (1 H, m, C(7)Hendo), 2.35–2.41 (1 H, m,
C(7)Hexo), 3.35–3.40 (1 H, m, C(5)H), 3.70–3.73 (1 H, m,
C(4)Hendo), 3.92–3.95 (1 H, m, C(4)Hexo), 5.20 (1 H, d, J 12.0,
PhCH ), 5.24 (1 H, d, J 12.0, PhCH ), 7.24–7.67 (15 H, m,
ArCH); δC(125.7 MHz; CDCl3) 25.2 (C(6)), 26.4 (Me), 29.9
(C(7)), 54.5 (C(5)), 56.8 (C(8)), 67.9 (CH2Ph), 69.4 (C(4)), 97.5
(C(2)), 125.5, 126.6, 128.1, 128.2, 128.4, 128.5, 128.8, 129.6
(ArCH), 135.0, 138.3, 141.8 (ArC), 164.4 (CO), 169.7
(PhCH2OC); m/z (APCIϩ) 524.3 (MHϩ, 20%), 524 (MHϩ, 30),
522 (MHϩ, 40), 522 (MHϩ, 100), 520 (MHϩ, 60), 518 (MHϩ,
20), 232 (30); HRMS: 522.1173 (MHϩ, CI). C28H28N80SeO4
requires 522.1184.
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