Enantiopure bicyclic piperidinones: Stereocontrolled conjugate additions leading to substituted piperidinones

Article abstract of DOI:10.1039/b404325a

The conjugate additions of Reformatsky reagents, organocuprate reagents, and hydroxylamines to a [4.3.0]-bicyclic enelactam derived from 6-oxopipecolic acid have been investigated, and found to be efficient, proceeding with excellent exo-stereocontrol, wi

Full text of DOI:10.1039/b404325a

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Enantiopure bicyclic piperidinones: stereocontrolled conjugate
additions leading to substituted piperidinones
Andrew G. Brewster,b Simon Broady,b Mark Hughes,a Mark G. Moloney*a
and Gordon Woodsa
a The Department of Chemistry, The University of Oxford, Central Research Laboratory,
Mansfield Road, Oxford, UK OX1 3TA
b AstraZeneca Pharmaceuticals, Mereside, Alderley Park, Macclesfield, UK SK10 4TG
Received 23rd March 2004, Accepted 21st April 2004
First published as an Advance Article on the web 26th May 2004
The conjugate additions of Reformatsky reagents, organocuprate reagents, and hydroxylamines to a [4.3.0]-bicyclic
enelactam derived from 6-oxopipecolic acid have been investigated, and found to be efficient, proceeding with
excellent exo-stereocontrol, with the exception of N-benzyl-O-benzylhydroxylamine, which gives predominantly the
product of endo-addition. These adducts can be readily converted to substituted piperidinones.
In the previous paper,1 we described a direct route for the
synthesis of enantiopure bicyclic piperidinones 1a,b and an
investigation of the alkylation of their derived enolates. Of
potentially greater interest, however, are the corresponding
unsaturated derivatives 2a,b which would permit manipulation
of C(7) and C(8) either separately or simultaneously, to give the
corresponding highly functionalised piperidinones. However, a
likely requirement for activation in such reactions is evident
from an earlier report by Overman that unsaturated δ-lactams
are not particularly susceptible to conjugate addition reac-
tions.2 Activation of these systems has been achieved in one of
three ways: an electron-withdrawing group may be attached
to nitrogen,3 the carbonyl group may be converted to a thiol-
actam,4,5 or an electron-withdrawing group may be attached to
the α-carbon.6 The latter strategy has proved to be effective in
the analogous [3.3.0] bicyclic system, which has permitted
highly diastereocontrolled modifications using carbon, oxygen
and nitrogen nucleophiles.7–11 A similar strategy has been
extensively developed for piperidinones by Amat and Bosch,12,13
who have achieved highly diastereoselective conjugate
additions14,15 in an enantiopure bicyclic oxazolopiperidinone
template.16 Significantly, in both of these [3.3.0] and [4.3.0]
bicyclic systems, exo-additions (i.e. sterically least encumbered
additions to the convex face of the template) are favoured,
although this preference can be overridden, at least in
unactivated [4.3.0] systems, by local substituent bulk effects, in
which case endo-additions have been observed.14 Conjugate
additions to α,β-unsaturated monocyclic γ-lactams of organo-
cuprates,15,17–19 nitroalkanes,20 stabilized enolates,15 and even
of phenylboronic acids under Rh() catalysis21 have since been
reported. The issue of stereocontrol in these additions has been
the subject of some investigation,22 and steric and A-strain
phenomena have been invoked to explain observed dia-
stereoselectivities.17,18,20 Alternative methodologies leading to
similar piperidinones from these conjugate addition reactions,
but instead using ring closure reactions,23,24 and zip-type
processes25 have been reported. The significance of sub-
stituted piperidines as conformational controlling elements is
becoming increasingly apparent, and methodology to access
these systems correspondingly more important.17,20,24,26
In this paper, we describe our work in the context of con-
jugate additions to unsaturated piperidinone systems, and the
application of these intermediates by further ring modifications
to highly functionalised heterocyclic systems.
Results and discussion
Synthesis of enone
We expected that the required enones 2a and 2b would be
readily available from selenides 3b and 3d (Scheme 1). Although
these compounds have been prepared by sequential conversion
Scheme 1 Reagents and conditions: (i) LiHMDS/THF/Ϫ78 ЊC then PhCH2OC(O)Cl then PhSeBr; (ii) NaIO4, NaHCO3, MeOH, H2O or H2O2, py,
CH2Cl2; (iii) 5 equiv. H2O2, CH2Cl2; (iv) NaIO4, H2O.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
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
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Fig. 1 NOE results for compounds 4, 6 and 8b.
Scheme 2 Reagents and conditions: (i) BrZnCH2CO2tBu, THF, DMPU (76%); (ii) p-X-C6H4Pb(OAc)3, py.
Fig. 2 Preferred conformations for 6, 8b, 13b and 17.
Table 1 Reaction of adduct 2 with lead complexes (Scheme 2)
of bicyclic lactams 1a,b to ester derivatives 3a,c and thence to
selenides 3b,d as described in our previous paper,1 we found that
a one-pot synthesis, based on successful similar conversions
which had been reported in the literature,27 was very effective.
Thus, treatment of lactam 1a with 2.2 equiv. LiHMDS,
followed successively by one equivalent each of benzyl chloro-
formate and phenylselenenyl bromide, gave the desired product
3b in 78% yield as approximately a 1 : 1 ratio of diastereomers.
Interestingly, application of this route to hemiaminal ether 1b
gave consistently lower yields of the corresponding selenide 3d
(9% at best over the two steps). Surprisingly, oxidative elimin-
ation of lactam 3b to its α,β-unsaturated derivative was highly
reagent-dependent: use of hydrogen peroxide–DCM gave only
epoxide 4 (stereochemistry established by NOE analysis
(Fig. 1)), but effective conversion of selenide 3b to enone 2a
could be achieved either by reaction with a mixture of NaIO4,
NaHCO3, MeOH, H2O (70% yield) or with H2O2 in a solution
of DCM and pyridine (88% yield). If the base was omitted from
these reactions, the unstable pyridone 5 was formed in low yield
(10%). Interestingly, application of the former conditions to
selenide 3d gave only a 45% yield of enone 2b.
Product
Aryllead triacetate
Yield (%)
Diastereomeric ratio
7a
7b
7c
PhPb(OAc)3
BrC6H4Pb(OAc)3
MeOC6H4Pb(OAc)3
69
93
59
3 : 1
5 : 1
2 : 1
7.5 Hz, suggests a boat-like piperidinone ring conformation as
indicated in Fig. 2. Similar trans-diastereoselectivity in con-
jugate addition reactions has been observed in the analogous
reactions of the [3.3.0] systems.10 This single step transform-
ation is noteworthy, introducing as it does a two-carbon unit
terminating in an ester, given that related conversions in the
literature using for example, ethyl 1,3-dithiolane-2-carb-
oxylate14 or allylcuprate,29 require two or more steps to achieve
the same outcome.
The value of these adducts as useful synthetic intermediates
was demonstrated as follows: it is well known that aryllead()
tricarboxylate complexes may be used to generate quaternary
carbon centres at β-dicarbonyl positions,30,31 although more
recently the application of palladium-based methodology has
also been reported.32 Reformatsky adduct 6 would be a suitable
substrate for such reactions, as it contains a highly activated site
at C-8. The expected products would be particularly interesting
as they could be considered to be homologues of kainic acid,
and of potential interest as glutamate agonists and/or antagon-
ists.33 Reaction of adduct 6 with preformed aryllead triacetates
(from the corresponding arylboronic acid and lead tetraacetate/
mercury() acetate34) in refluxing chloroform–pyridine gave the
corresponding α-arylated products 7a–c in good to excellent
yield, and as a mixture of diastereomers (Table 1). Hydro-
genolysis and decarboxylation (H2 at 4 bar, 10% palladium on
carbon, ethyl acetate, and a reaction time of 72 hours, followed
by heating of the crude product) of adducts 6 and 7c gave
Reformatsky conjugate additions
Because of our earlier success with the conjugate addition of
Reformatsky reagents,11,28 we examined similar reactions with
enone 2a and found that the adduct 6 was formed in 76% yield
as a single diastereomer as assigned by NOESY analysis
(Scheme 2 and Fig. 1). Addition of the Reformatsky reagent
occurred to the least hindered exo-face, as expected, but
the C(7)H/C(8)H relationship was more difficult to assign:
a mutual NOE enhancement upon irradiation of C(7)CH2 with
both C(8)H, C(6)H and C(5)H is consistent with their cis-
disposition and therefore the endo-location of the C(8) substi-
tuent; this, along with a C(7)H/C(8)H coupling constant of
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
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Scheme 3 Reagents and conditions: (i) H2, 4 bar, Pd/C then ∆; (ii) TFA, CH2Cl2; (iii) RuO2, NaIO4, CCl4, MeCN, H2O then CH2N2.
Fig. 3 NOE results for compounds 11a, 11b, 11c and 12a.
Table 2 Reactions of organocuprates with enone 2a (Scheme 4)
excellent yields of the decarboxylated products 8a and 8b
(84 and 67% respectively, Scheme 3). The C(7)CH2 exo-
stereochemistry was again confirmed by a NOE with C(5)H of
lactam 8b and the C(8)Hendo stereochemistry was suggested by
Product
R
Yield (%)
11a
11b
11c
Me
Bu
Ph
19
36
42
enhancements along the sequence of C(8)H, C(7)H, C(6)Hendo
,
C(4)Hendo and C(2)Ph which indicated their common endo-
configuration; interestingly the enhancement at C(6)Hexo (2.0%)
upon irradiation of C(7)H suggested a half-chair conformation
with the C-7 substituent pseudoaxial and the C-8 one pseudo-
equatorial (Figs. 1 and 2). Also suggestive of the C(8)exo
substituent stereochemistry is the fact that 8b exhibited a
large negative [α]D value, seen earlier in products of C(8) exo-
alkylation,1 and 3J7,8 was 5.5 Hz.
Deprotection of lactams 8a,b, using conditions established
earlier (TFA/DCM)1 gave simultaneous removal of the t-butyl
ester and oxazolidine protecting groups, to give the products
9a,b in excellent yield (98% and 100% respectively) which were
not purified, but used immediately (Scheme 3). Two-step con-
version (oxidation followed by immediate esterification of these
products using conditions reported earlier10) gave diesters 10a,b
in low (but unoptimised) yield (16 and 27%); their stereo-
chemistry is assumed from the structural assignments of their
precursors. Lactam 10b is the first example of a homokainoid
thus far reported.
Table
3
Reaction of lactams 2a and 2b with N,O-
dibenzylhydroxylamine (Scheme 5)
Reactant
Conditions
Product
Ratio 13 : 14
Yield (%)
2b
2b
2b
2a
MeOH, r.t.
13a,14a
13a,14a
13a,14a
13b,14b
9 : 1
—
9 : 1
8–10 : 1
30
—
63
45
MeOH, reflux
CHCl3, reflux
CHCl3, reflux
from NOESY analysis (Fig. 3), in which key enhancements were
C(7)Hendo/C(6)Hendo/C(4)Hendo and C(2)Me/C(5)H/C(8)H, and a
similar boat piperidinone ring conformation to adduct 2 was
suggested by 3J7,8 values of 7.0, 6.5 and 9.0 for 11a,b,c respect-
ively. This was a significantly higher level of diastereocontrol
than that obtained in the monocyclic systems of Mann,22 and is
in accord with the diastereoselectivity observed in the Reform-
atsky additions to the bicyclic system described above. By way
of demonstrating the value of these intermediates, deprotection
of lactam 11c (TFA, CHCl3) to give 12a and then removal of
the C-8 ester ((Bu3Sn)2O, toluene, reflux) gave lactam 12b in
32% yield over the two steps.
Cuprate conjugate additions
The success of Reformatsky reagents described above and of
literature precedent,22 suggested that organocuprates would
prove to be productive for conjugate additions to enone 2a.
Treatment of enone 2a with several diorganocopperlithium
reagents (Scheme 4 and Table 2) gave the corresponding
C(7)Hexo/C(8)Hendo adducts 11a–c in modest yields (compound
11a was obtained with 7% of the C(7) epimer, but 11b,c were
diastereomerically pure). Their stereochemistry was evident
Amine conjugate additions
Of further interest was examination of the addition of nitrogen
nucleophiles, to generate the corresponding β-aminoester
derivatives, a reaction which proved to be highly facile in the
[3.3.0] series.8,9 However, addition of N,O-dibenzylhydroxyl-
amine to both C-2 epimeric lactams 2a and 2b proved to be
sluggish although highly diastereoselective (Scheme 5 and
Table 3), giving best reaction in refluxing chloroform, and
favouring additions to the exo-face of both bicyclic systems.
Stereochemical assignment was by NOE analysis in the usual
way (Fig. 4) and a diequatorial conformation for each of 13a,
13b and 14b was indicated by 3J7,8 values of 8.0, 10.0 and 7.5 Hz
respectively. Key enhancements in lactam 13a were C(6)Hexo
and C(8)H
C(6)Hendo
C(4)Hendo
were C(6)Hendo
C(4)Hexo C(5)H
C(4)Hendo and C(2)Ph and C(8)H, and
Scheme 4 Reagents and conditions: (i) R2CuLi, ether; (ii) 15% TFA,
CHCl3 (52%); (iii) (Bu3Sn)2O, toluene, reflux (62%).
C(6)Hexo
C(7)H. The required trans-
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
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Scheme 5 Reagents and conditions: (i) PhCH2ONHCH2Ph; (ii) (Bu3Sn)2O, toluene, reflux (38%); (iii) 15% TFA, CHCl3 (63%).
Fig. 4 NOE results for compounds 13a, 13b, 14b, 16 and 17.
stereochemical arrangement of 13a and 13b could be supported
analysis of the crude reaction mixture showed the reaction had
gone to completion, and that the endo- : exo- ratio was again
2 : 1. Furthermore, refluxing either the pure exo-16 or pure
endo-adduct 17 in chloroform for 15 hours led to an endo- :
exo- ratio of 2 : 1 in both cases. It would therefore appear that
the endo-diastereomer 17, with the smaller C-7 substituent
when compared to 14b, is the thermodynamic product in this
case, favoured by the chair conformation of the piperidinone
ring which allows the bulky C(7) and C(8) substituents to adopt
diequatorial positions, and the exo-diastereomer 16 is the
kinetic one.
Although the diastereoselectivity for O-benzylhydroxylamine
addition was poorer than for N,O-dibenzylhydroxylamine, the
vastly superior yield for the former allowed full deprotection for
each of the exo-16 and endo-17 diastereomers (Scheme 6). Thus,
benzyl ester cleavage ((Bu3Sn)2O) gave lactams 18 and 19,
oxazolidine ring opening (TFA) gave alcohols 20a and 21a,
and hydrogenolysis (H2, 5 bar, 10% Pd/C) gave the amines
20b and 21b, in reactions which proceeded in good to excellent
yield.
in a trans-diequatorial chair-like piperidinone ring, as indicated
in Fig. 2. Single step hydrogenolytic deprotection of lactam 13b
was not successful, but sequential removal of ester ((Bu3Sn)2O,
toluene) and then oxazolidine (TFA) protecting groups
gave alcohol 15 in modest yield (25%) over the two steps
(Scheme 5).
Suspecting that this lack of reactivity may be a direct result
of steric hindrance of the bulky amine nucleophile, the reaction
of O-benzylhydroxylamine with lactam 2a was examined. In
this case, we were delighted to find that the reaction proceeded
in 91% yield within 3 hours. The most striking result from this
reaction, however, was the diastereomeric ratio. In direct con-
trast to the N,O-dibenzylhydroxylamine reaction, the C(7)Hexo
17 and not the C(7)Hendo diastereomer 16 dominated by a ratio
of 2 : 1. The stereochemistry and trans-substitution pattern of
both the exo-16 and endo-17 products were again confirmed by
1H NMR NOESY analysis (Fig. 4). Thus, the indicated
assignment for the minor isomer 16 was supported by the
enhancement sequence C(2)Ph
C(4)Hendo
C(6)Hendo and
C(7)H C(2)Ph; the C-8 stereochemistry was supported by an
enhancement between C(8)CH2Ph and C(2)Ph, and a coupling
constant for J7,8 of 6.0 Hz for 16 was observed. Similarly, for the
Stereochemical considerations
major isomer 17, key enhancements were C(2)Ph
C(6)Hendo C(7)NHOCH2Ph C(8)H, further supported
by a crosspeak between C(2)Ph and C(8)H. Furthermore,
coupling constant data (J6endo,5 = 10.5 Hz, J6endo,7 = 12.0 Hz, J8,7
C(4)Hendo
The stereochemistry of conjugate addition to unsaturated
piperidinones has attracted some recent attention. For mono-
cyclic systems using organometallic nucleophiles, the A1,3 strain
of the ring system and the size of the nucleophile appear to be
controlling factors,20,22 but more recent work suggests that
chelation control can become dominant in suitable substrates.17
In the case of [4.3.0] bicyclic systems, it would appear that
enone systems activated with ester substituents give exo-
addition in all cases,15 presumably since addition to the convex
face is favoured on steric grounds, but that unactivated enones
possessing an allylic substituent can proceed with endo-
=
8.0 Hz) suggested the diequatorial conformation for 17, in
which the piperidinone ring existed in a chair conformation as
indicated in Fig. 2.
To provide a direct comparison of reactivity with the
N,O-dibenzylhydroxylamine addition reactions examined
earlier (Scheme 5), the addition of O-benzylhydroxylamine was
carried out in refluxing chloroform. 1H-NMR spectroscopic
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
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THF (15 ml) was added dropwise via cannula and the reaction
mixture stirred for 1 hour. The reaction was then quenched with
5% NH4Cl(aq) (20 ml) and the aqueous layer was washed with
EtOAc (3 × 20 ml). The organic layers were combined, dried
(MgSO4) and the solvent removed in vacuo. Purification by
flash column chromatography (20% EtOAc : petroleum ether
(bp 60–80 ЊC)) on silica gel gave monobenzoylated material
(approx. 1%) along with the desired product 3b (78%) or 3d
(9%) as a mixture of diastereomers in a ratio of 1.3–1.6 : 1.
Data for both compounds are as reported in our previous
paper.1
(؊)-(2S,5S,7S,8S )-1-Aza-8-benzyloxycarbonyl-7,8-epoxy-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 4. To a solu-
tion of a mixture of the selenides 3b1 (64 mg, 0.12 mmol)
in DCM (12.5 ml) was added hydrogen peroxide (70 mg,
0.61 mmol). The mixture was then stirred vigorously for one
hour at 30 ЊC. The reaction was quenched with sat. aq.
NaHCO3 (5 ml), extracted with DCM (3 × 10 ml), and solvent
was removed in vacuo. The residue was purified using flash
column chromatography, eluting with 40% EtOAc : Petrol
to yield the product 4 as a colourless oil (46 mg, 99%); Rf
25
0.28 (40% EtOAc : Petrol); [α]D Ϫ77.5 (c 0.31, CHCl3);
νmax(film)/cmϪ1 1753s, 1669s; δH (500 MHz; CDCl3) 1.91 (1H,
dd, J 11.0 and 14.5, C(6)Hendo), 2.09 (3H, s, C(2)Me), 2.60 (1H,
ddd, J 3.5, 4.0 and 11.0, C(6)Hexo), 3.43 (1H, t, J 8.5, C(4)Hendo),
3.86 (1H, d, J 3.5, C(7)H), 3.97–4.04 (1H, m, C(5)H), 4.18 (1H,
dd, J 6.0 and 8.5, C(4)Hexo), 5.36 (2H, s, CO2CH2), 7.32–7.54
(10H, m, ArH); δC (125.8 MHz; CDCl3) 26.0 (C(2)Me), 26.6
(C(6)), 51.7 (C(5)), 58.1 (C(8)), 58.6 (C(7)), 68.2 (C(4)), 68.8
Scheme 6 Reagents and conditions: (i) PhCH2ONH2ؒHCl, NaOAc,
MeOH, r.t. (91%); (ii) (Bu3Sn)2O, toluene, reflux; (iii) 15% TFA, CHCl3;
(iv) 10% Pd–C/H2, glacial HOAc.
(CO2
CH ), 98.0 (C(2)), 126.1, 126.2, 128.7, 128.8, 128.9, 129.1
2
(ArCH), 135.5 (ArC), 141.4 (ArC), 160.9 (C᎐O), 165.7 (C᎐O);
᎐
᎐
addition.14 In the latter case, the global preference for convex
face addition appears to be overridden by a local preference for
reaction giving a (pseudo)diequatorial outcome.
m/z (APCIϩ) 380.2 (MHϩ, 100%); HRMS: 380.1499 (MHϩ,
ESϩ). C22H21NO5 requires 380.1498.
In the case of the [4.3.0] systems derived from oxopipecolic
acid as considered in this work, the same preference for exo-face
addition exists for bulky organometallic and amine nucleo-
philes, since this permits approach from the less hindered
convex face of the bicyclic system; however, although this
generates a product with (pseudo)diequatorial substituents,
the piperidinone ring would appear to be in a boat-like or half
chair conformation (e.g. compounds 6 and 13b in Fig. 2). In
the case of smaller nucleophiles, proceeding by a reversible
addition, such as hydroperoxide or O-benzylhydroxylamine,
endo-face addition becomes feasible, and this mode is favoured
(؊)-(2S,5S )-1-Aza-8-benzyloxycarbonyl-2-methyl-3-oxa-9-
oxo-2-phenylbicyclo[4.3.0]non-7-ene 2a. To
a solution of
selenides 3b1 (0.95 g, 1.8 mmol) in methanol (50 ml) was added
a solution of sodium periodate (0.78 g, 3.6 mmol) and sodium
bicarbonate (0.15 g, 1.8 mmol) in water (30 ml). The mixture
was stirred for 1 hour, when t.l.c. analysis suggested that
reaction was complete. A 1 : 1 mixture of sat. aq. NH4Cl and
EtOAc (30 ml) was added, and the organic layer separated. The
aqueous layer was extracted with EtOAc (3 × 25 ml), the
organic layers combined and dried with brine (25 ml) and over
MgSO4, and solvent was removed in vacuo. The residue was
separated by column chromatography eluting with 40%
EtOAc : Petrol to give the product 2a as a colourless oil (0.51 g,
by
a product in which the same (pseudo)diequatorial
disposition of substituents leaves the piperidinone ring in a
chair conformation, leading to a global energy minimum;
favourable chelation control might also assist in this facial
selectivity.
25
82%); Rf 0.24 (40% EtOAc : Petrol); [α]D Ϫ69.9 (c 1.09,
CHCl3); νmax(film)/cmϪ1 1735s, 1666s, 1246s; δH (500 MHz;
CDCl3) 2.10 (3H, s, C(2)Me), 2.27–2.33 (1H, m, C(6)Hendo),
2.50–2.56 (1H, m, C(6)Hexo), 3.46 (1H, t, J 9.0, C(4)Hendo), 4.06–
4.13 (1H, m, C(5)H), 4.16 (1H, dd, J 6.0 and 9.0, C(4)Hexo),
5.25–5.32 (2H, m, CO2CH2), 7.26–7.57 (11H, m, C(7)H and
ArH); δC (125.8 MHz; CDCl3) 26.1 (C(2)Me), 27.2 (C(6)), 55.4
(C(5)), 66.8 (C(4)), 68.4 (CO2CH2), 96.5 (C(2)), 125.6, 127.9,
128.0, 128.1, 128.2, 128.4 (ArCH), 131.1 (C(8)), 135.5 (ArC),
Conclusion
We have shown that highly stereoselective conjugate addition
reactions to bicyclic [4.3.0] lactams derived from 6-oxopiper-
idine carboxylic acid are possible, using organometallic and
amine nucleophiles, and that these adducts can be readily
elaborated to substituted enantiopure piperidinones.
142.0 (ArC), 145.7 (C(7)), 158.4 (C᎐O), 163.5 (C᎐O); m/z
᎐
᎐
(APCIϩ) 364 (MHϩ, 100%), 362 (19); HRMS: 364.1552 (MHϩ,
ESϩ). C22H21NO4 requires 364.1549.
The same compound could be obtained by the following
alternative procedure: Pyridine (0.18 ml, 2.24 mmol) was added
to a solution of a mixture of selenides 3b (583 mg, 1.12 mmol)
in DCM (10 ml) and cooled to 0 ЊC. 30% H2O2(aq) (0.34 ml,
2.99 mmol) was then added dropwise with rapid stirring. After
20 minutes, the reaction mixture was warmed to room
temperature and stirred for 20 min, before quenching with 1 : 1
DCM : 10% aq. NaHCO3 (20 ml). The aqueous layer was
washed with DCM (10 ml) and the organic layers combined,
washed with 10% aq. HCl (2 ml), brine (4 ml), dried (MgSO4)
Experimental
One-pot method for the preparation of selenides 3b and 3d. A
solution of lithium bis(trimethylsilyl)amide in hexanes (1.0 M,
2.2–4.0 equiv.) was added dropwise via cannula to a solution of
the lactam 1a or 1b1 (1 equiv.) in THF (40 ml) at Ϫ78 ЊC and
under an inert atmosphere. After stirring for 20 minutes a
solution of benzyl chloroformate (1.1 equiv.) in THF (15 ml)
was added dropwise via cannula. After stirring for 20 minutes at
Ϫ78 ЊC, a solution of phenylselenenyl bromide (1.4 equiv.) in
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
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and the solvent removed in vacuo. Purification by flash column
chromatography on silica gel (30% EtOAc : Petrol) gave only
the desired product 2a as a colourless oil (70 mg, 88%).
tBu), 1.84–1.89 (1H, m, C(6)Hexo), 1.94–2.02 (1H, m, C(6)Hendo),
2.03 (3H, s, C(2)Me), 2.33 (1H, dd, J 8.0 and 15.5, C(7)CH ),
2.44 (1H, dd, J 5.5 and 15.5, C(7)CH ), 2.93–2.97 (1H, m,
C(7)H), 3.42 (1H, t, J 9.0, C(4)Hendo), 3.47 (1H, d, J 7.5, C(8)H),
3.95–4.07 (1H, m, C(5)H), 4.14 (1H, dd, J 5.5 and 9.0,
C(4)Hexo), 5.23 (1H, d, J 12.5, PhCH ), 5.28 (1H, d, J 12.5,
PhCH ), 7.26–7.50 (10H, m, ArH); δC (100.6 MHz; CDCl3) 25.8
(Me), 28.0 (CMe3), 28.6 (C(6)), 32.0 (C(7)), 39.8 (C(7)CH2),
54.1 (C(5)), 54.3 (C(8)), 67.2 (C(4)), 69.1 (PhCH2), 81.4
(CMe3), 96.6 (C(2)), 125.5, 125.7, 128.1, 128.2, 128.3, 128.6
(؊)-(2S )-1-Aza-8-benzyloxycarbonyl-2-methyl-3-oxa-9-oxo-
2-phenylbicyclo[4.3.0]nona-5,7-diene 5. To a solution of selen-
ides 3b1 (1.42 g, 2.7 mmol) in methanol (50 ml) was added
a solution of sodium periodate (1.17 g, 5.5 mmol) in water
(30 ml). The mixture was stirred at room temperature for
3 hours, and then worked up with the addition of 50 ml of a
1 : 1 mixture of EtOAc and sat. aq. NH4Cl. The aqueous layer
was 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 (40% EtOAc :
Petrol) to give the product 5 as a colourless oil (98 mg, 10%)
that decomposed on standing to a brown gum. Rf 0.16 (40%
(ArCH), 135.5 (ArC), 141.4 (ArC), 163.9 (C᎐O), 169.7 (C᎐O),
᎐
᎐
170.4 (C᎐O); m/z (APCIϩ) 480 (MHϩ, 100%), 424 (73); HRMS:
᎐
480.2381 (MHϩ, CI). C28H33NO6 requires 480.2386.
(2S,5S,7R)-1-Aza-8-benzyloxycarbonyl-7-(tert-butyloxy-
carbonylmethyl)-2,8-diphenyl-2-methyl-3-oxa-9-oxobicyclo-
[4.3.0]nonane 7a. To a solution of the Reformatsky adduct 6
(61 mg, 0.1 mmol) in CHCl3 (10 ml) was added phenyllead
triacetate (0.117 g, 0.3 mmol) and pyridine (0.050 g, 0.6 mmol).
The mixture was heated to reflux for 72 hours, and then filtered
through Celite®, washed with 10% H2SO4 (5 ml), extracted with
CHCl3 (3 × 15 ml) and dried with brine (10 ml) and over
MgSO4. Solvent was removed in vacuo, and the residue purified
by flash column chromatography, eluting with 30% EtOAc :
Petrol to give the product 7a as a colourless oil as an insepar-
able mixture of two diastereomers in a 3 : 1 ratio (0.049 g, 69%);
22
EtOAc : Petrol); [α]D Ϫ212.0 (c 1.13, CHCl3); νmax(film)/cmϪ1
1734s, 1698m, 1667s, 1605m, 1554s, 666m; δH (400 MHz;
CDCl3) 2.30 (3H, s, C(2)Me), 4.94 (1H, dd, J 1.0 and 14.5,
C(4)H), 5.07 (1H, dd, J 1.0 and 14.5, C(4)H), 5.28–5.38 (2H, m,
CO2CH2), 6.12 (1H, dt, J 7.5 and 1.0, C(6)H), 7.18–7.54 (10H,
m, ArH), 8.22 (1H, d, J 7.5, C(7)H); δC (100.6 MHz; CDCl3)
25.1 (C(2)Me), 66.6 (C(4)), 68.3 (CO2CH2), 96.8 (C(6)), 103.3
(C(2)), 119.6 (C(5)), 125.8, 127.8, 128.2, 128.4, 128.6, 129.0
(ArCH), 136.1 (ArC), 139.2 (ArC), 146.2 (C(7)), 150.5 (C(8)),
157.4 (C᎐O), 164.2 (C᎐O); m/z 384 (MϩNaϩ, 33%), 362 (MHϩ,
᎐
᎐
100), 254 (20); HRMS: 384.1210 (MϩNaϩ, ESϩ). C22H19NO4
Rf 0.26 (40% EtOAc : Petrol); [α]D22 Ϫ23.5 (c 1.6, CHCl3); νmax
-
requires 384.1212.
(film)/cmϪ1 1729s, 1681s, 1369m, 1152s; δH (400 MHz; CDCl3)
1.37 (9H, s, CMe3 major), 1.41 (9H, s, CMe3 minor), 1.74–1.87
(1H, m, C(6)Hendo), 1.88 (3H, s, C(2)Me major), 1.99 (3H, s,
C(2)Me minor), 2.02–2.17 (2H, m, C(6)Hexo and C(7)CH ), 2.85
(1H, dd, J 11.0 and 16.5, C(7)CH ), 2.93–2.98 (1H, m, C(7)H),
3.40 (1H, t, J 8.5, C(4)Hendo major), 3.52–3.60 (1H, m, C(5)H
major), 3.77 (1H, t, J 8.0, C(4)Hendo minor), 3.82–3.90 (1H, m,
C(5)H minor), 3.99 (1H, dd, J 5.5 and 8.5, C(4)Hexo major), 4.07
(1H, dd, J 6.5 and 8.0, C(4)Hexo minor), 5.18 (1H, d, J 11.5,
PhCH2 major), 5.23–5.31 (2H, m, PhCH2 minor), 5.55 (1H, d,
J 11.5, PhCH2 major), 7.12–7.67 (15H, m, ArH); δC (100.6
MHz; CDCl3) 24.8 (C(2)Me minor), 25.1 (C(2)Me major), 27.8
(CMe3 minor), 28.0 (CMe3 major), 28.4 (C(6) major), 29.7
(C(6) minor), 37.8 (C(7)CH2 major), 37.9 (C(7)CH2 minor),
38.9 (C(7) major), 40.1 (C(7) minor), 52.1 (C(5) minor), 53.1
(C(5) major), 65.7 (C(8) major), 66.0 (C(8) minor), 67.6
(CO2CH2), 70.1 (C(4) major), 70.5 (C(4) minor), 80.6 (CMe3
major), 81.1 (CMe3 minor), 96.5 (C(2)), 125.3, 125.4, 125.5,
126.4, 127.6, 127.9, 128.0, 128.1, 128.2, 128.3, 128.5, 128.6,
128.8, 129.2 (ArCH), 134.7 (ArC), 136.0 (ArC), 136.1 (ArC),
141.8 (ArC), 142.2 (ArC), 166.5 (C᎐O), 169.7 (C᎐O major),
(؊)-(2R,5S )-1-Aza-8-benzyloxycarbonyl-2-methyl-3-oxa-9-
oxo-2-phenylbicyclo[4.3.0]non-7-ene 2b. The selenide 3d1
(95 mg, 0.2 mmol) was reacted with sodium periodate (78 mg,
0.4 mmol) and sodium bicarbonate (15 mg, 0.2 mmol) in water.
The mixture was stirred for 1 hour at room temperature before
quenching. The residue was separated by flash column chroma-
tography on silica gel, eluting with 40% EtOAc : Petrol, to give
the product 2b as an oil (30 mg, 45%); Rf 0.43 (50% EtOAc :
23
Petrol); [α]D ϩ38.7 (c 0.8, CHCl3); νmax(film)/cmϪ1 1736s,
1663s, 1422s; δH (500 MHz; CDCl3) 2.07 (3H, s, Me), 2.44–2.51
(1H, m, C(6)Hendo), 2.54–2.60 (1H, m, C(6)Hexo), 3.84–3.87 (1H,
m, C(4)Hendo), 4.04–4.10 (1H, m, C(5)H), 4.14–4.17 (1H, m,
C(4)Hexo), 5.24 (1H, d, J 12.5, PhCHHO), 5.29 (1H, d, J 12.5,
PhCHHO), 7.27–7.58 (9 H, m, C(7)H and ArCH), 7.38–7.42
(2H, m, ArH); δC (125.7 MHz; CDCl3) 25.7 (Me), 29.0 (C(6)),
55.3 (C(5)), 66.8 (CH2Ph), 69.9 (C(4)), 96.9 (C(2)), 125.8, 128.2,
128.2, 128.5 (ArCH), 130.8 (C(7)), 135.6, 141.6 (ArC), 144.8
(C(8)), 157.7 (CON), 163.6 (PhCH2OCO); m/z (APCIϩ)
364 (MHϩ, 100%); HRMS: 364.1549 (MHϩ, CI). C22H22NO4
requires 364.1554.
᎐
᎐
170.2 (C᎐O minor), 172.0 (C᎐O); m/z (APCIϩ) 556 (MHϩ,
᎐
᎐
87%), 500 (100), 114 (43); HRMS: 556.2694 (MHϩ, ES).
C34H37NO6 MHϩ requires 556.2699.
(؊)-(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-7-(tert-buty-
loxycarbonylmethyl)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo-
[4.3.0]nonane 6. To a solution of α-bromo tert-butyl acetate
(0.25 g, 1.3 mmol) and iodine (0.022 g, 0.09 mmol) in THF
(11 ml) was added zinc (0.14 g, 2.1 mmol). This mixture was
heated to 35 ЊC in an ultrasound bath for 15 minutes. The
suspension was then cooled to 0 ЊC in an ice bath, and DMPU
(1 ml) was added. A solution of the enone 2a (0.16 g, 0.43
mmol) in THF (2.5 ml) was then added by syringe. The reaction
mixture was then returned to the ultrasound bath for a further
15 minutes. The reaction was then quenched with ice/water
(2 ml), and sufficient sat. aq. NH4Cl was added to ensure that
the precipitate dissolved. The mixture was extracted with DCM
(3 × 15 ml), the organic fractions were recombined, and solvent
removed in vacuo. The residue was purified by flash column
chromatography eluting initially with 20% EtOAc : Petrol and
increasing the polarity gradually to 30% EtOAc : Petrol, to give
the product 6 as a colourless oil (0.16 g, 76%); Rf 0.48 (40%
(2S,5S,7R)-1-Aza-8-benzyloxycarbonyl-8-(p-bromophenyl)-7-
(tert-butyloxycarbonylmethyl)-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 7b. To a solution of adduct 6 (27 mg, 0.05
mmol) in CHCl3 (10 ml) was added bromophenyllead triacetate
(61 mg, 0.1 mmol) and pyridine (22 mg, 0.28 mmol). The mix-
ture was heated to reflux for 72 hours, and then filtered through
Celite®, washed with 10% H2SO4 (5 ml), extracted with CHCl3
(3 × 15 ml) and dried with brine (10 ml) and over MgSO4.
Solvent was removed in vacuo, and the residue purified by flash
column chromatography, eluting with 30% EtOAc : Petrol to
give the product 7b as a colourless oil as an inseparable mixture
of two diastereomers in a 5 : 1 ratio (0.033 g, 93%); Rf 0.30 (40%
22
EtOAc : Petrol); [α]D Ϫ12.9 (c 0.41, CHCl3); νmax(film)/cmϪ1
1732s, 1684s; δH (400 MHz; CDCl3) 1.37 (9H, s, CMe3 major),
1.40 (9 H, s, CMe3 minor), 1.75–1.82 (1H, m, C(6)Hendo), 1.87
(3H, s, C(2)Me major), 2.05 (3H, s, C(2)Me minor), 2.07–2.14
(2H, m, C(6)Hexo and C(7)CH ), 2.81 (1H, dd, J 11.0 and 16.5,
C(7)CH ), 2.86–2.91 (1H, m, C(7)H), 3.43 (1H, t, J 9.0,
EtOAc : Petrol); [α]D Ϫ70.5 (c 0.85, CHCl3); νmax(film)/cmϪ1
1728s, 1666s, 1440w, 1153s; δH (400 MHz; CDCl3) 1.43 (9 H, s,
22
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1805

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C(4)Hendo major), 3.54–3.60 (1H, m, C(5)H), 3.73 (1H, dd, J 8.0
and 11.0, C(4)Hendo minor), 4.00 (1H, dd, J 5.5 and 9.0, C(4)Hexo
major), 4.28 (1H, dd, J 6.0 and 8.0, C(4)Hexo minor), 5.18 (1H,
d, J 12.0, PhCH major), 5.14–5.26 (2H, m, PhCH2 minor), 5.50
(1H, d, J 12.0, PhCH major), 6.95–7.64 (14H, m, ArH); δC
(100.6 MHz; CDCl3) 25.0 (C(2)Me), 27.5 (CMe3), 28.4 and 29.7
(C(6)), 37.3 (C(7)CH2), 38.7 (C(7)), 53.1 (C(5) major), 56.1
(C(5) minor), 60.4 (C(8) minor), 65.2 (C(8) major), 67.8 (8-
CO2CH2), 70.2 (C(4)), 80.8 (CMe3 major), 81.2 (CMe3 minor),
96.5 (C(2) major), 97.3 (C(2) minor), 121.8, 125.3, 128.0, 128.1,
128.2, 128.3, 128.4, 128.5, 128.7, 128.9, 129.2, 130.1, 131.4,
132.3 (ArCH), 134.5 (ArC), 135.3 (ArC), 137.1 (ArC), 142.0
and 8.5, C(4)Hexo), 7.26–7.45 (5H, m, ArH); δC (100.6 MHz;
CDCl3) 25.8 (C(7)), 28.1 (CMe3), 28.5 (C(2)Me), 30.1 (C(6)),
38.8 (C(7)CH2), 41.1 (C(8)), 54.2 (C(5)), 69.2 (C(4)), 81.0
(CMe3), 96.0 (C(2)), 125.5, 128.0, 128.1 (ArCH), 141.9 (ArC),
167.9 (C᎐O), 170.9 (C᎐O); m/z(APCIϩ) 346 (MHϩ, 100%);
᎐
᎐
HRMS: 346.2012 (MHϩ, CI). C20H27NO4 requires 346.2018.
(؊)-(2S,5S,7R,8S )-1-Aza-7-(tert-butyloxycarbonylmethyl)-8-
(p-methoxyphenyl)-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 8b. To a solution of lactam 7c (0.24 g, 0.4
mmol) in EtOAc (30 ml) was added 10% Pd–C (0.24 g). The
mixture was degassed carefully, and then placed under a
hydrogen atmosphere (4 bar). The reaction was stirred for 72
hours, and then evacuated to remove excess hydrogen. The
suspension was filtered through Celite®, and solvent was
removed in vacuo. Crude NMR analysis revealed that decarb-
oxylation was not complete, so the residue was heated under
vacuum (200 ЊC, 1 mm) for two hours. The residue was purified
by flash column chromatography (40% EtOAc : Petrol) to give
the product 8b as a colourless oil (0.12 g, 67%); Rf 0.33 (40%
(ArC), 166.0 (C᎐O), 169.3 (CH C᎐O), 171.8 (C᎐O); m/z
᎐
᎐
᎐
2
(APCIϩ) 637 (MHϩ, 79Br, 88%), 636 (MHϩ, 81Br, 88%), 580 (80),
578 (100); HRMS: 634.1808 (MHϩ, ES). C34H36NO6Br requires
634.1804.
(2S,5S,7R)-1-Aza-8-benzyloxycarbonyl-7-(tert-butyloxy-
carbonylmethyl)-8-(p-methoxyphenyl)-2-methyl-3-oxa-9-oxo-2-
phenylbicyclo[4.3.0]nonane 7c. To a solution of the Reform-
atsky adduct 6 (0.35 g, 0.7 mmol) in CHCl3 (40 ml) was added
p-methoxyphenyllead triacetate (0.72 g, 1.5 mmol) and pyridine
(0.29 g, 3.7 mmol). The mixture was heated to reflux for
72 hours, and then filtered through Celite®, washed with 10%
H2SO4 (10 ml), extracted with CHCl3 (3 × 25 ml) and dried with
brine (20 ml) and over MgSO4. Solvent was removed in vacuo,
and the residue purified by flash column chromatography,
eluting with 30% EtOAc : Petrol to give the product 7c as a
colourless oil as an inseparable mixture of two diastereomers in
25
EtOAc : Petrol); [α]D Ϫ75.0 (c 1.18, CHCl3); νmax(film)/cmϪ1
1724s, 1654s, 1514s; δH (400 MHz; CDCl3) 1.41 (9 H, s, CMe3),
1.92–2.00 (1H, m, C(6)Hendo), 2.03–2.08 (1H, m, C(6)Hexo), 2.10
(3H, s, C(2)Me), 2.12–2.24 (2H, m, C(7)CH2), 2.80–2.86 (1H,
m, C(7)H), 3.66 (1H, dd, J 8.0 and 10.0, C(4)Hendo), 3.78 (3H, s,
OMe), 3.91 (1H, d, J 5.5, C(8)H), 4.09–4.26 (2H, m, C(4)Hexo
and C(5)H), 6.84–7.58 (9 H, m, ArH); δC (100.6 MHz; CDCl3)
25.0 (C(2)Me), 27.7 (C(6)), 28.0 (CMe3), 35.0 (C(7)), 36.5
(C(7)CH2), 52.7 (C(8)), 53.1 (C(5)), 55.2 (OMe), 70.0 (C(4)),
80.9 (CMe3), 95.7 (C(2)), 113.9, 125.6, 128.1 (ArCH), 128.4
24
a 2 : 1 ratio (0.25 g, 59%); Rf 0.10 (20% EtOAc : Petrol); [α]D
Ϫ59.7 (c 1.2, CHCl3); νmax(film)/cmϪ1 1732s, 1682s; δH (400
MHz; CDCl3) 1.36 (9 H, s, CMe3 major), 1.40 (9 H, s, CMe3
minor), 1.74–1.81 (1H, m, C(6)Hendo), 1.87 (3H, s, C(2)Me
major), 2.03–2.10 (2H, m, C(6)Hexo and C(7)CH ), 2.12 (3H, s,
C(2)Me minor), 2.79–2.93 (2H, m, C(7)CH, and C(7)H), 3.41
(1H, t, J 8.5, C(4)Hendo major), 3.46–3.56 (1H, m, C(5)H and
1H, m, C(4)Hendo minor), 3.80 (3H, s, OMe major), 3.82 (3H, s,
OMe minor), 3.98 (1H, dd, J 6.0 and 8.5, C(4)Hexo major), 4.06
(1H, dd, J 6.0 and 8.0, C(4)Hexo minor), 5.16 (1H, d, J 12.0,
PhCH ), 5.52 (1H, d, J 12.0, PhCH ), 6.86 (2H, d, J 9.0, ArH m
to OMe major), 6.88 (2H, d, J 9.0, ArH m to OMe minor), 7.03
(2H, d, J 9.0, ArH o to OMe major), 7.18 (2H, d, J 9.0, ArH
o to OMe minor), 7.21–7.51 (10H, m, ArH); δC (100.6 MHz;
CDCl3) 25.1 (C(2)Me), 28.0 (CMe3), 28.4 (C(6)), 37.7
(C(7)CH2), 38.8 (C(7)), 53.1 (C(5)), 55.2 (OMe), 65.0 (C(8)),
67.5 (CO2CH2), 70.1 (C(4)), 80.6 (CMe3), 96.5 (C(2)), 113.8
(ArC), 125.4 (ArC), 128.0, 128.2, 128.3, 128.6, 128.8, 129.2,
129.4, 130.0 (ArCH), 134.7 (ArC), 142.2 (ArC), 158.7 (ArC),
166.7 (C᎐O), 169.8 (C᎐O), 172.1 (C᎐O); m/z (APCIϩ) 587
(ArC), 130.6 (ArCH), 141.6 (ArC), 158.5 (ArC), 167.9 (C᎐O),
᎐
171.3 (C᎐O); m/z (APCIϩ) 452 (MHϩ, 100%); HRMS: 452.2442
᎐
(MHϩ, ES). C27H33NO5 requires 452.2437.
(؉)-(2S,4R)-(2-Hydroxymethyl-6-oxopiperidin-4-yl)acetic
acid 9a. To a solution of lactam 8a (0.061 g, 0.2 mmol) in DCM
(20 ml) was added TFA (0.5 ml). The reaction mixture was
stirred for 4 hours at room temperature, at which point t.l.c.
analysis indicated that no starting material was present. Solvent
was removed in vacuo, and the residue purified by flash column
chromatography eluting with 10% MeOH : EtOAc, to give the
product 9a as a brown oil (14 mg, 33%); Rf 0.25 (10% MeOH :
EtOAc); [α]D ϩ1.71 (c 0.35, CHCl3); νmax(film)/cmϪ1 3362br,
22
1686s, 1639s; δH (500 MHz; d4-MeOH) 1.45 (9 H, s, CMe3),
1.60–1.66 (1H, m, C(3)H), 1.84–1.87 (1H, m, C(3)H), 2.04–2.11
(1H, m, C(5)H), 2.26–2.28 (1H, m, C(5)H), 2.29–2.50 (3H, m,
C(4)H and C(4)CH2), 3.31 (1H, br, NH ), 3.48–3.60 (3H, m,
C(2)CH2, C(2)H); δC (125.8 MHz; d4-MeOH) 27.5 (C(4)), 28.3
(CMe3), 29.4 (C(5)), 41.4 (C(4)CH2), 52.9 (C(2)), 54.8 (C(5)),
65.7 (C(2)CH ), 82.0 (CMe ), 173.0 (C᎐O), 174.3 (C᎐O); m/z
᎐
᎐
᎐
(MHϩ, 100%), 531 (23), 114.0 (35); HRMS: 586.2795 (MHϩ,
ES). C35H39NO7 MHϩ requires 586.2805.
᎐
᎐
2
3
(APCIϩ) 244 (MHϩ, 100%), 230 (55), 216 (20), 189 (70),
158 (60); HRMS: 244.1552 (MHϩ, ES). C12H21NO4 requires
244.1549.
(؊)-(2S,5S,7R)-1-Aza-7-(tert-butyloxycarbonylmethyl)-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 8a. To a solu-
tion of adduct 6 (0.65 g, 1.3 mmol) in EtOAc (30 ml) was added
10% Pd–C (0.65 g). The mixture was degassed carefully, and
then placed under a hydrogen atmosphere (4 bar). The reaction
was stirred for 72 hours, and then evacuated to remove excess
hydrogen. The suspension was then filtered through Celite® to
remove the catalyst, and solvent was removed in vacuo. The
residue was purified by flash column chromatography (40%
EtOAc : Petrol) to give the product 8a as a colourless oil (0.40 g,
(2S,4S,5S )-(2-Hydroxymethyl-5-(4-methoxyphenyl)-6-oxo-
piperidin-4-yl)acetic acid 9b. To a solution of the product 8b
(0.121 g, 0.3 mmol) in DCM (10 ml) was added TFA (0.5 ml).
The reaction mixture was stirred with regular monitoring by
t.l.c. and mass spectrometry. After five minutes there was
evidence that the t-butyl group had been removed. The reaction
mixture was stirred for a further hour to ensure completion of
the reaction. Solvent was removed in vacuo to give the crude
product 9b, which was used immediately in the oxidation
reaction.
24
84%); Rf 0.26 (40% EtOAc : Petrol); [α]D Ϫ44.6 (c 1.25,
CHCl3); νmax(film)/cmϪ1 1726s, 1654s, 1151s; δH (400 MHz;
CDCl3) 1.45 (9 H, s, CMe3), 1.73–1.79 (1H, m, C(6)Hendo), 1.80–
1.85 (1H, m, C(6)Hexo), 2.05 (3H, s, C(2)Me), 2.27 (1H, dd, J 7.5
and 16.0, C(7)CH ), 2.33 (1H, dd, J 7.5 and 15.5, C(8)H), 2.39
(1H, dd, J 7.0 and 15.5, C(8)H), 2.58 (1H, dd, J 6.0 and 16.0,
C(7)CH ), 2.63–2.66 (1H, m, C(7)H), 3.41 (1H, dd, J 8.5 and
9.5, C(4)Hendo), 3.95–3.99 (1H, m, C(5)H), 4.13 (1H, dd, J 6.0
(؉)-(2S,4R)-2-Methoxycarbonyl-4-(methoxycarbonylmethyl)-
6-piperidinone 10a. To a solution of the alcohol 9a (57 mg, 0.3
mmol) in acetonitrile (1 ml) and carbon tetrachloride (2 ml) was
added a solution of sodium periodate (0.26 g, 1.2 mmol) and
ruthenium dioxide (2 mg) in water (1.5 ml). The reaction
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1806

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mixture was stirred for 72 hours, and then ethereal diazo-
methane solution (distilled from the dropwise addition of a
solution of Diazald®(2 g) in Et2O (19 ml) to a solution of KOH
(0.59 g) in water (0.98 ml), Et2O (2 ml) and EtOH (4 ml) heated
to 70 ЊC) was added until excess diazomethane was present, as
shown by the persistent yellow colour of the organic phase.
Acetic acid (2 drops) was then added to quench excess diazo-
methane. The reaction mixture was extracted with EtOAc (2 ×
15 ml), and solvent removed in vacuo. The residue was purified
by flash column chromatography eluting with EtOAc to give the
product 10a as a colourless oil (11 mg, 16%); Rf 0.54 (10%
CDCl3) 1.15 (3H, d, J 7.0, CH3CH), 1.68 (1H, dt, J 4.0, 13.5,
C(6)Hexo), 1.91–1.99 (1H, m, C(6)Hendo), 2.03 (3H, s, Me), 2.63–
2.69 (1H, m, C(7)H), 3.24 (1H, d, J 7.0, C(8)H), 3.43 (1H, dd,
J 9.0, 9.5, C(4)Hendo), 3.97–4.03 (1H, m, C(5)H), 4.13 (1H, dd,
J 6.0, 8.5, C(4)Hexo), 5.21 (2H, d, J 12.5, PhCHHO), 5.27 (2H,
d, J 12.5, PhCHHO), 7.25–7.51 (20 H, m, ArCH); δC (100.6
MHz, CDCl3) 20.9 (CH3CH), 25.7 (2-Me), 30.0 (C(7)), 30.2
(C(6)), 54.0 (C(5)), 56.6 (C(8)), 67.1 (PhCH2), 69.9 (C(4)), 96.4
(C(2)), 125.5, 128.0, 128.2, 128.3, 128.4, 128.5 (ArCH), 135.6,
141.5 (ArC), 164.4 (CON), 170.1 (PhCH2OCO); m/z (APCIϩ)
403 (MNaϩ, 70%), 380 (MHϩ, 15); HRMS: 380.1865 (MHϩ,
CI). C26H32O4N requires 380.1863.
24
MeOH : EtOAc); [α]D ϩ30.5 (c 0.55, CHCl3); νmax(film)/cmϪ1
1737s, 1659s; δH (400 MHz; CDCl3) 1.81–1.90 (1H, m,
C(3)Hexo), 2.11 (1H, dd, J 9.0 and 17.5, C(4)CH2), 2.22–2.26
(1H, m, C(3)Hendo), 2.34–2.44 (3H, m, C(4)H and 2 × C(5)H),
2.57 (1H, ddd, J 1.5, 5.0 and 17.5, C(4)CH ), 3.70 (3H, s, Me),
3.79 (3H, s, Me), 4.12–4.19 (1H, m, C(2)H), 6.26 (1H, br, NH );
δC (100.6 MHz; CDCl3) 26.9 (C(4)), 29.9 (C(3)), 37.0
(C(4)CH2), 39.1 (C(5)), 51.8 (CH2CO2Me), 52.8 (2-CO2Me),
53.1 (C(2)), 170.6 (C᎐O), 171.6, 171.7 (2 × C᎐O); m/z (APCIϩ)
(؊)-(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-7-n-butyl-2-
methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 11b. Using
the general organocuprate addition procedure, a solution of
lactam 2a (102 mg, 0.28 mmol) in Et2O was reacted with n-BuLi
in cyclohexanes (2.5 M, 0.54 ml, 1.12 mmol) and CuI (107 mg,
0.56 mmol) in Et2O. Purification by flash column chromato-
graphy on silica gel eluting with 15% EtOAc : Petrol yielded the
product 11b as a yellow oil and as a single diastereomer (42 mg,
36%); Rf 0.28 (15% EtOAc : Petrol); [α]D23 Ϫ99.2 (c 1.0, CHCl3);
vmax(film)/cmϪ1 2931s, 1741s, 1664s; δH (400 MHz; CDCl3) 0.89
(3H, t, J 6.2, CH3CH2), 1.28–1.32 (4 H, m, br, CH3CH2-
CH2CH2), 1.42–1.51 (2H, m, CH3CH2CH2CH2),1.76–1.82
(1H, m, C(6)Hexo), 1.85–1.93 (1H, m, C(6)Hendo), 2.03 (3H, s,
Me), 2.45–2.53 (1H, m, C(7)H), 3.31 (1H, d, J 6.5, C(8)H),
3.42–3.45 (1H, m, C(4)Hendo), 3.90–3.97 (1H, m, C(5)H), 4.09–
4.15 (1H, m, C(4)Hexo), 5.21 (1H, d, J 12.5, PhCHHO), 5.27
(1H, d, J 12.5, PhCHHO), 7.25–7.53 (10H, m, ArCH); δC (100.6
MHz, CDCl3) 13.9 (CH3CH2), 22.6 (CH3CH2), 25.7 (Me), 28.5
(C(6)), 28.8 (CH3CH2CH2), 35.3 (CH2CH2CH), 35.5 (C(7)),
54.2 (C(5)), 55.2 (C(8)), 67.1 (PhCH2), 69.1 (C(4)), 96.5 (C(2)),
125.5, 125.6, 128.0, 128.2, 128.2, 128.4, 128.5 (ArCH), 135.6,
141.4 (ArC), 164.3 (CON), 170.3 (PhCH2OCO); m/z (APCIϩ)
445 (MNaϩ, 100%), 422 (MHϩ, 30); HRMS: 422.2328 (MHϩ,
CI). C26H32O4N requires 442.2331.
᎐
᎐
230 (MHϩ, 100%), 202 (47), 138 (38); HRMS: 230.1024 (MHϩ,
ES). C10H15NO5 requires 230.1028.
(2S,4S,5S )-2-Methyloxycarbonyl-4-(methyloxycarbonyl-
methyl)-5-(p-methoxyphenyl)-6-piperidinone 10b. To a solution
of crude alcohol 9b in acetonitrile (2 ml) and ethyl acetate
(2 ml) was added RuCl3 (2 mg) and sodium periodate (0.24 g,
1.1 mmol) in water (3 ml). The reaction mixture was stirred for
2 hours, and then quenched with diazomethane as before. The
reaction mixture was extracted with EtOAc (2 × 10 ml) and
solvent was removed in vacuo. The residue was purified by two
flash columns (eluting with 10% MeOH : EtOAc) to give the
product 10b as a colourless oil (2 mg, 22%); Rf 0.23 (10%
MeOH : EtOAc); νmax(film)/cmϪ1 1737s, 1659s, 1212m; δH (400
MHz; CDCl3) 1.87 (1H, dd, J 8.5 and 16.0, C(4)CH2), 2.07 (1H,
dd, J 6.5 and 16.0, C(4)CH2), 2.11–2.23 (1H, m, C(3)H), 2.25–
2.51 (1H, m, C(3)H), 2.53–2.75 (1H, m, C(4)H), 3.64 (1H, d,
J 11.0, C(5)H), 3.79 (1H, s, OMe), 3.81 (1H, s, CO2Me), 3.82
(1H, s, CO2Me), 4.29–4.38 (1H, m, C(2)H), 6.62 (1H, br, NH ),
6.86 (2H, d, J 8.5, ArH m to OMe), 7.08 (2H, d, J 8.5, ArH o to
OMe); δC (100.6 MHz; CDCl3) 25.9 (C(3)), 32.0 (C(4)), 37.3
(C(4)CH2), 50.3 (CO2Me), 52.9 (C(5)), 53.2 (C(2)), 55.2 (OMe),
80.8 (CH2CO2Me), 114.0 (ArC), 126.4 (C(5)), 129.4 (ArC),
(؊)-(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-2,7-diphenyl-
2-methyl-3-oxa-9-oxobicyclo[4.3.0]nonane 11c. Using the gen-
eral organocuprate addition procedure, a solution of lactam 2a
(100 mg, 0.28 mmol) in Et2O was reacted with 1.6 M PhLi in
cyclohexane–Et2O (0.69 ml, 1.10 mmol) and CuI (105 mg, 0.55
mmol) in Et2O. Purification by flash column chromatography
(silica gel) eluting with 15% EtOAc : Petrol yielded the product
11c as a yellow oil and as a single diastereomer (52 mg, 42%);
136.1 (ArC), 158.8 (C᎐O), 170.9 (C᎐O), 171.7 (C᎐O); m/z
᎐
᎐
᎐
(APCIϩ) 336 (MHϩ, 28%), 322 (75), 308 (33), 294 (100);
HRMS: 336.1451 (MHϩ, ES). C17H21NO6 requires 336.1447.
23
Rf 0.23 (15% EtOAc : Petrol); [α]D Ϫ83.8 (c 0.8, CHCl3);
vmax(film)/cmϪ1 1743s, 1665s; δH (400 MHz; C6D6) 1.27 (1H, dt,
J 4.5, 13.5, C(6)Hexo), 1.59–1.67 (1H, m, C(6)Hendo), 2.17 (3H, s,
Me), 3.10 (1H, t, J 8.5, C(4)Hendo), 3.34–3.45 (2H, m, C(5)H,
C(4)Hexo), 3.61–3.67 (1H, m, C(7)H), 3.75 (1H, d, J 9.0, C(8)H),
4.99 (1H, d, J 12.5, PhCHHO), 5.03 (1H, d, J 12.5, PhCHHO),
7.00–7.78 (15H, m, ArCH); δC (100.6 MHz, C6D6) 27.0 (Me),
32.6 (C(6)), 41.4 (C(7)), 55.2 (C(5)), 56.2 (C(8)), 67.2 (PhCH2),
69.3 (C(4)), 97.2 (C(2)), 126.5, 127.3, 127.4, 127.7, 128.1, 128.2,
128.3, 128.5, 128.8, 129.3 (ArCH), 136.7, 143.4, 144.1 (ArC),
164.8 (CON), 169.7 (PhCH2OCO); m/z (APCIϩ) 442 (MHϩ,
100%); HRMS: 442.2024 (MHϩ, CI). C28H28O4N requires
442.2018.
Organocuprate general addition procedure
The required organolithium reagent (4.0 equiv.) was added
dropwise to a suspension of CuI (2.0 equiv.) in dry Et2O (8 ml)
at Ϫ78 ЊC and under an inert atmosphere. The temperature was
raised to Ϫ15 ЊC for 10 minutes and then lowered to Ϫ78 ЊC. A
solution of the lactam 2a (1.0 equiv.) in dry Et2O (5 ml) was
then added dropwise via cannula and the reaction mixture
warmed to Ϫ15 ЊC. After 2 h the reaction was quenched with
1 M aq. HCl (10 ml). The resulting precipitate was filtered off
and the organic layer washed with saturated aq. NH4Cl (2 × 5
ml), dried (MgSO4) and the solvent removed in vacuo.
(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-2,7-dimethyl-3-
oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 11a. Using the general
organocuprate addition procedure, a solution of lactam 2a (102
mg, 0.28 mmol) in Et2O was reacted with MeLi in Et2O (1.6 M,
0.70 ml, 1.12 mmol) and CuI (107 mg, 0.56 mmol) in Et2O.
Purification by flash column chromatography on silica gel
eluting with 15% EtOAc : Petrol yielded the product as a yellow
oil consisting mainly of lactam 11a, along with some of the C-7
epimer in a ratio of 14 : 1 (23 mg, 19%). Rf 0.15, 0.20 (20%
EtOAc : Petrol); vmax(film)/cmϪ1 1740s, 1661s; δH (400 MHz;
(؊)-(2S,4R,5S )-2-Hydroxymethyl-4-phenyl-5-benzyloxy-
carbonyl-6-piperidinone 12a. Trifluoroacetic acid (1 ml) was
added dropwise to a solution of adduct 11c (65 mg, 0.2 mmol)
in CHCl3 (10 ml) and the mixture stirred for 2 hours at room
temperature. Removal of the solvent in vacuo and purification
by flash column chromatography on silica gel eluting with 80%
EtOAc : Petrol yielded the product 12a as a white solid (26 mg,
23
52%); mp 145 ЊC; Rf 0.14 (15% EtOAc : Petrol); [α]D Ϫ23.5
(c 0.6, CHCl3); vmax(film)/cmϪ1 3393br, 1736m, 1665s, 1222s,
1160s; δH (400 MHz; MeOD) 2.06–2.11 (1H, m, C(3)Hendo),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1807

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2.15–2.20 (1H, m, C(3)Hexo), 3.52–3.56 (2H, m, C(2)H and
C(4)H), 3.65 (2H, d, J 6.5, CH2OH), 3.71 (1H, d, J 11.0,
C(5)H), 4.98 (1H, d, J 12.5, PhCHHO), 5.07 (1H, d, J 12.5,
PhCHHO), 7.06–7.32 (10H, m, ArCH); δC (100.6 MHz,
MeOD), 31.0 (C(3)), 40.2 (C(4)), 53.8 (C(2)), 57.2 (C(5)), 65.7
(CH2OH), 68.1 (PhCH2), 128.7, 128.9, 129.3, 129.4, 129.7,
129.8, 130.0, 130.3 (ArCH), 137.4, 143.2 (ArC), 170.0 (CON),
171.7 (PhCH2OCO); m/z (APCIϩ) 363 (MNaϩ, 90%), 340
(MHϩ, 25); HRMS: 340.1554 (MHϩ, CI). C20H22O4N (MHϩ)
requires 340.1549.
7-(benzyl(benzyloxy)amino)-2-methyl-3-oxa-9-oxo-2-phenyl-
bicyclo[4.3.0]nonane 14b. Using the general procedure, N,O-
dibenzylhydroxylamine (250 mg, 1.17 mmol) was added
dropwise to a solution of the lactam 2a (213 mg, 0.59 mmol) in
chloroform (15 ml) and the mixture heated under reflux for
48 hours. The solvent was removed in vacuo and purification by
flash column chromatography on silica gel, eluting with 20%
EtOAc : Petrol, yielded the product as a colourless oil and as
a separable mixture of two diastereomers in a 13b : 14b ratio of
8–10 : 1.
Major diastereomer 13b: (137 mg, 41%); Rf 0.31 (20%
25
EtOAc : Petrol); [α]D Ϫ96.7 (c 1.3, CHCl3); νmax(film)/cmϪ1
(؊)-(2S,4R)-2-Hydroxymethyl-4-phenyl-6-piperidinone 12b.
Bis(tributyltin) oxide (0.10 ml, 0.19 mmol) was added dropwise
to a solution of alcohol 12a (32 mg, 0.1 mmol) in toluene (5 ml)
and the mixture heated under reflux for 18 hours. The solvent
was removed in vacuo to furnish the crude product as a brown
oil. Purification by flash column chromatography on silica gel,
eluting with 2% MeOH : EtOAc, yielded the product 12b as a
1744m, 1672s, 1532m, 1210s; δH (400 MHz; C7D8) 1.00–1.10
(1H, m, br, C(6)Hendo), 1.96–2.00 (1H, m, br, C(6)Hexo), 2.07
(3H, s, Me), 3.00 (1H, t, J 9.0, C(4)Hendo), 3.50 (1H, d, J 13.0,
PhCHHN), 3.55 (1H, dd, J 6.5, 2.5, C(4)Hexo), 3.70–3.75 (1H,
m, C(5)H), 3.74 (1H, d, J 13.0, PhCHHN), 3.90–3.96 (1H, m,
C(7)H), 4.09 (1H, d, J 10.0, C(8)H), 4.26 (1H, d, J 10.0,
PhCHHON), 4.54 (1H, d, J 10.0, PhCHHON), 5.17 (1H, d,
J 12.3, PhCHHOCO), 5.37 (1H, d, J 12.3, PhCHHOCO), 7.01–
7.36 (18H, m, ArH), 7.66–7.68 (2H, m, ArH); δC (50.3 MHz,
CDCl3) 25.7 (C(6)), 26.4 (Me), 54.4 (C(8)), 56.2 (C(5)), 60.2
(PhCH2N), 61.3 (C(7)), 67.2 (PhCH2OCO), 69.2 (C(4)), 77.0
(PhCH2ON), 97.1 (C(2)), 125.6, 127.7, 128.0, 128.2, 128.2,
128.3, 128.4, 128.5, 128.5, 128.9, 129.0, 129.6 (ArCH), 135.9,
136.4, 136.5, 142.1 (ArC), 164.2 (CON), 169.3 (PhCH2OCO);
m/z (APCIϩ) 577 (MHϩ, 100%), 364 (70); HRMS: 577.2703
(MHϩ, CI). C36H36O5N2 (MHϩ) requires 577.2702.
23
clear oil (12 mg, 62%); Rf 0.25 (10% MeOH : EtOAc); [α]D
Ϫ8.2 (c 0.5, CHCl3); vmax(film)/cmϪ1 3289s, 1640s; δH (400 MHz;
MeOD) 2.03–2.07 (2H, m, C(3)H), 2.52 (1H, dd, J 8.5, 17.5,
C(5)Hexo), 2.62 (1H, dd, J 5.5, 17.5, C(5)Hendo), 3.30–3.37 (1H,
m, C(4)H), 3.41–3.47 (1H, m, C(2)H), 3.59 (2H, t, J 6.5,
CH2OH), 7.19–7.36 (5H, m, ArCH); δC (100.6 MHz, MeOD)
32.0 (C(3)), 36.1 (C(4)), 38.9 (C(5)), 53.5 (C(2)), 66.0 (CH2OH),
128.2, 128.2, 130.1 (ArCH), 145.3 (ArC), 175.3 (CON); m/z
(APCIϩ) 206 (MHϩ, 80%); HRMS: 206.1181(MHϩ, CI).
C12H16O2N requires 206.1183.
Minor diastereomer 14b: (15 mg, 4%); Rf 0.25 (20% EtOAc :
Petrol); [α]D Ϫ48.0 (c 0.8, CDCl3); νmax(CDCl3)/cmϪ1 1737s,
25
N,O-Dibenzylhydroxylamine general addition procedure
1663s; δH (400 MHz; C7D8) 1.41–1.44 (1H, m, br, C(6)Hendo),
1.64–1.69 (1H, m, br, C(6)Hexo), 2.12 (3H, s, Me), 3.02–3.07
(1H, m, C(4)Hendo), 3.30–3.38 (1H, m, C(5)H), 3.50–3.53 (1H,
m, C(4)Hexo), 3.59 (1H, d, J 13.0, PhCHHN), 3.76 (1H, d,
J 13.5, PhCHHN), 3.79–3.84 (1H, m, C(7)H), 4.05 (1H, d,
J 7.5, C(8)H), 4.42 (1H, d, J 10.5, PhCHHON), 4.54 (1H, s, br,
PhCHHON), 5.05 (1H, d, J 12.5, PhCHHOCO), 5.12 (1H, d,
J 12.5, PhCHHOCO), 7.01–7.30 (18H, m, ArH), 7.56–7.61
(2H, m, ArH); δC (100.6 MHz, CDCl3) 25.1 (Me) 25.6 (C(6)),
54.3 (C(8)), 55.4 (C(5)), 59.0 (PhCH2N), 62.7 (C(7)), 67.3
(PhCH2OCO), 69.0 (C(4)), 77.0 (PhCH2ON), 96.4 (C(2)),
125.6, 125.8, 127.7, 128.0, 128.1, 128.3, 128.3, 128.4, 128.5,
128.5, 128.9, 129.0, 129.5 (ArCH), 135.5, 136.5, 136.7, 141.0
(ArC), 162.9 (CON), 170.0 (PhCH2OCO); HRMS: 577.2703
(MHϩ, CI). C36H36O5N2 (MHϩ) requires 577.2702.
N,O-Dibenzylhydroxylamine (2 equiv.) was added dropwise to
a solution of unsaturated lactam (1 equiv.) in either chloroform
or MeOH and the mixture stirred for 24 hours. The solvent was
then removed in vacuo, and the residue purified by flash column
chromatography on silica, eluting with 20% EtOAc : Petrol.
(2R,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-7-(benzyl(benzyl-
oxy)amino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane
13a and (2R,5S,7S,8R)-1-aza-8-benzyloxycarbonyl-7-(benzyl-
(benzyloxy)amino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]-
nonane 14a. Using the general procedure, N,O-dibenzyl-
hydroxylamine (400 mg, 1.88 mmol) was added dropwise to a
solution of lactam 2b (340 mg, 0.94 mmol) in methanol (30 ml)
and the mixture stirred at room temperature for 24 hours. The
solvent was removed in vacuo, and the residue purified by flash
column chromatography on silica, eluting with 20% EtOAc :
Petrol, to yield the product as a colourless oil and an insepar-
able mixture of diastereomers in a 13a : 14a ratio of 10 : 1 (162
mg, 30%). Data for the major diastereomer 13a: Rf 0.22, 0.28
(20% EtOAc : Petrol); vmax(CHCl3)/cmϪ1 1740s, 1671s, 1496s,
1455s; δH (500 MHz; C7D8, 70 ЊC) 1.45–1.51 (1H, m, C(6)Hendo),
1.97–2.02 (1H, m, C(6)Hexo), 2.03 (3H, s, Me), 3.30–3.33 (1H,
m, C(4)Hendo), 3.55–3.60 (5H, m, C(5)H, C(4)), 3.62 (1H, d,
J 13.0, PhCHHN), 3.73–3.79 (1H, m, C(7)H), 3.80 (1H, d,
J 13.0, PhCHHN), 3.93 (1H, d, J 8.0, HЉ), 4.32 (1H, d, J 10.0,
PhCHHON), 4.40 (1H, d, J 10.0, PhCHHON), 5.05 (1H, d,
J 12.5, PhCHHOCO), 5.22 (1H, d, J 12.5, PhCHHOCO), 7.01–
7.62 (20 H, m, ArCH); δC (125.7 MHz, C7D8, 70 ЊC) 26.3 (Me),
28.2 (C(6)), 54.3 (C(8)), 54.9 (C(5)), 60.5 (PhCH2N), 61.2
(C(7)), 67.1 (PhCH2OCO), 69.6 (C(4)), 77.3 (PhCH2ON), 97.7
(C(2)), 125.0, 125.2, 125.4, 127.9, 128.0, 128.2, 128.2, 128.5,
128.6, 128.6, 128.8, 128.9, 129.1, 129.3 (ArCH), 137.0, 137.6,
143.8 (ArC), 164.2 (CON), 169.3 (PhCH2OCO); m/z (APCIϩ)
577 (MHϩ, 100%), 365 (20); HRMS: 577.2704 (MHϩ, CI).
C36H36O5N2 requires 577.2702.
(؉)-(2S,4R)-2-Hydroxymethyl-4-(benzyl(benzyloxy)amino)-
6-piperidinone 15. Bis(tributyltin) oxide (0.10 ml, 0.19 mmol)
was added dropwise to a solution of adduct 13b (55 mg,
0.1 mmol) in toluene (5 ml) and the mixture heated under reflux
for 18 hours. The solvent was removed in vacuo and purification
by flash column chromatography on silica gel, eluting with 30%
EtOAc : Petrol, yielded a colourless oil (15 mg, 38%); Rf 0.25
24
(30% EtOAc : Petrol); [α]D Ϫ75.1 (c 1.3, CHCl3); vmax(film)/
cmϪ1 1655s, 1469s, 1381s; δH (400 MHz; CDCl3) 1.55–1.67 (1H,
m, C(6)Hendo), 2.01 (3H, s, Me), 2.26–2.30 (1H, m, br, C(6)Hexo),
2.71 (1H, dd, J 6.0, 15.5, C(8)Hendo), 2.87 (1H, dd, br, J 8.0, 15.0,
C(8)Hexo), 3.36 (1H, t, J 9.0, C(4)Hendo), 3.42–3.48 (1H, m,
C(7)H), 3.93 (1H, d, J 13.0, PhCHHN), 4.01 (1H, d, J 13.0,
PhCHHN), 4.08–4.19 (2H, m, C(5)H, C(4)Hexo), 4.45 (2H, s, br,
PhCH2O), 7.18–7.48 (15H, m, ArCH); δC (100.63 MHz, CDCl3)
25.9 (Me), 27.1 (C(6)), 37.1 (C(8)), 55.1 (C(5)), 58.2 (C(7)), 59.8
(PhCH2N), 69.3 (C(4)), 78.2 (PhCH2ON), 96.1 (C(2)), 125.6,
127.6, 127.7 128.2, 128.4, 128.4, 128.5, 129.0, 129.5 (ArCH),
136.5, 136.9, 142.1 (ArC), 167.6 (CON); m/z (APCIϩ) 443
(MHϩ, 100%), 109.8(25); HRMS: 443.2337 (MHϩ, ES).
C28H30O3N2 requires 443.2335.
(؊)-(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-7-(benzyl-
(benzyloxy)amino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]-
nonane 13b, (؊)-(2S,5S,7S,8R)-1-aza-8-benzyloxycarbonyl-
Trifluoroacetic acid (0.75 ml) was added dropwise to the
above compound (40 mg, 0.1 mmol) in chloroform (10 ml) and
the reaction mixture stirred for 2 hours. The solvent was
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1808

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removed in vacuo and purification by flash column chromato-
graphy on silica gel, eluting with 10% MeOH : EtOAc, yielded
the product 15 as a colourless oil (19 mg, 63%); Rf 0.35 (10%
was added dropwise to a solution of adduct 16 and 17 (ratio of
1 : 2) (154 mg, 0.32 mmol) in toluene (10 ml) and the mixture
heated under reflux for 24 hours. The reaction was then
quenched with 1 : 1 saturated aqueous NaHCO3 : EtOAc (10
ml). The aqueous layer was washed with EtOAc (3 × 5 ml) and
the organic fractions combined, washed with water (10 ml),
dried (MgSO4) and the solvent removed in vacuo. Purification
by flash column chromatography on silica gel, eluting with 60%
EtOAc : Petrol, yielded the separable diastereomers 18 and 19
as a colourless oil.
24
MeOH : EtOAc); [α]D ϩ20.2 (c 0.9, CHCl3); vmax(film)/cmϪ1
3312m, 1651s; δH (400 MHz; CDCl3) 1.77–1.83 (1H, m,
C(3)Hendo), 2.00–2.07 (1H, m, C(3)Hexo), 2.53 (1H, dd, J 5.0,
17.5, C(5)Hendo), 2.74 (1H, d, br, J 14.0, C(5)Hexo), 3.22 (1H, s,
br, C(4)H), 3.46 (1H, dd, J 8.0, 11.0, CHHOH), 3.63 (1H, dd,
J 4.0, 11.0, CHHOH), 3.76 (1H, s, br, C(2)H), 3.87 (1H, d,
J 13.0, PhCHHN), 3.98 (1H, d, J 13.0, PhCHHN), 4.26 (1H, d,
br, J 8.0, PhCHHO), 4.35 (1H, d, J 10.0, PhCHHO), 7.01–7.42
(10H, m, ArCH); δC (100.6 MHz, CDCl3) 26.9 (C(3)), 34.7
(C(5)), 51.1 (C(2)), 57.1 (C(4)), 59.9 (PhCH2N), 66.2 (CH2OH),
77.3 (PhCH2O), 127.6 128.0, 128.3, 128.3, 129.0, 130.0 (ArCH),
136.3, 137.0, 142.1 (ArC), 172.0 (CON); m/z (APCIϩ) 341
(MHϩ, 100%), 272 (20), 128 (50); HRMS: 341.1869 (MHϩ, ES).
C20H25O3N2 requires 341.1865.
23
Lactam 19: (43 mg, 39%); Rf 0.22 (80% EtOAc : Petrol); [α]D
Ϫ37.9 (c 0.8, CHCl3); vmax(film)/cmϪ1 1651s, 1028s; δH (400
MHz; CDCl3) 1.37–1.45 (1H, ddd, J 10.0, 10.0, 12.0, C(6)Hendo),
2.05 (3H, s, Me), 2.29–2.34 (1H, ddd, J 4.0, 5.0, 13.0, C(6)Hexo),
2.49 (1H, dd, J 8.0, 17.0, C(8)Hendo), 2.64 (1H, dd, J 6.5, 17.0,
C(8)Hexo), 3.43 (1H, dd, J 9.0, 10.0, C(4)Hendo), 3.60 (1H, m,
C(7)H), 3.89 (1H, m, C(5)H), 4.10 (1H, dd, J 6.0, 9.0, C(4)Hexo),
4.76 (2H, s, PhCH2O), 5.49 (1H, s, br, NH), 7.27–7.43 (8 H, m,
ArH), 7.44–7.48 (2H, m, ArH); δC (100.6 MHz, CDCl3) 25.5
(Me), 29.9 (C(6)), 36.9 (C(8)), 55.2 (C(7)), 55.7 (C(5)), 68.8
(C(4)), 77.1 (PhCH2ON), 96.0 (C(2)), 125.8, 128.0, 128.1,
128.5, 128.5 (ArCH), 137.4, 141.3 (ArC), 166.3 (CON); m/z
(APCIϩ) 353 (MHϩ, 30%), 233 (100), 178 (15), 125 (40);
HRMS: 353.1862 (MHϩ, ES). C21H25O3N2 requires 353.1865.
(؊)-(2S,5S,7R,8S )-1-Aza-8-benzyloxycarbonyl-7-(benzyloxy-
amino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 16,
(؊)-(2S,5S,7S,8R)-1-aza-8-benzyloxycarbonyl-7-(benzyloxy-
amino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo[4.3.0]nonane 17.
To a solution of O-benzylhydroxylamine.HCl (62 mg, 0.4
mmol) in methanol (4 ml) at room temperature was added
NaOAc (32 mg, 0.4 mmol) with stirring. A solution of lactam
2a (128 mg, 0.4 mmol) in methanol (4 ml) was then added
dropwise and the reaction mixture stirred at room temperature
for 3 hours. The reaction was quenched with brine (20 ml) and
the aqueous layer extracted with EtOAc (3 × 20 ml). The
organic fractions were combined, washed with water (10 ml),
dried (MgSO4) and the solvent removed in vacuo. Purification
by flash column chromatography on silica gel, eluting with 20%
EtOAc : Petrol, yielded the product as a colourless oil and as a
separable mixture of two diastereomers 16 : 17 ratio of 1 : 2.
Major diastereomer 17: (111 mg, 65%); Rf 0.14 (30% EtOAc :
23
Lactam 18: (24 mg, 47%); Rf 0.35 (80% EtOAc : Petrol); [α]D
Ϫ63.8 (c 0.4, CHCl3); vmax(film)/cmϪ1 1651s, 1028s; δH (400
MHz; CDCl3) 1.54–1.60 (1H, ddd, J 5.0, 8.0, 13.5, C(6)Hendo),
2.03 (3H, s, Me), 2.12–2.16 (1H, m, C(6)Hexo), 2.31 (1H, dd,
J 4.0, 17.5, C(8)Hexo), 2.69 (1H, dd, J 6.5, 17.5, C(8)Hendo), 3.39–
3.44 (1H, m, C(4)Hendo), 3.69–3.73 (1H, m, C(7)H), 4.01 (2H, m,
C(5)H, C(4)Hexo), 4.72 (1H, d, J 12.0, PhCHHO), 4.76 (1H, d,
J 12.0, PhCHHO), 7.25–7.46 (10H m, ArH); δC (100.6 MHz,
CDCl3) 25.8 (Me), 29.0 (C(6)), 36.7 (C(8)), 53.4 (C(5)), 53.8
(C(7)), 69.5 (C(4)), 77.6 (PhCH2ON), 96.4 (C(2)), 126.1, 128.4,
128.6, 128.9, 129.3 (ArCH), 137.8, 142.1 (ArC), 166.6 (CON);
m/z (APCIϩ) 353 (MHϩ, 100%), 245 (20), 233 (30), 125 (40);
HRMS: 353.1865 (MHϩ, ES). C21H25O3N2 requires 353.1865.
22
Petrol); [α]D Ϫ38.0 (c 1.7, CHCl3); vmax(film)/cmϪ1 1738s,
1661s; δH (400 MHz; CDCl3) 1.55 (1H, ddd, J 10.5, 12.0, 12.5,
C(6)Hendo), 2.03 (3H, s, Me), 2.23–2.28 (1H, ddd, J 3.0, 5.0, 13.0,
C(6)Hexo), 3.43 (1H, dd, J 9.0, 10.0, C(4)Hendo), 3.74 (1H, d,
J 8.0, C(8)H), 3.86–3.96 (2H, m, C(7)H, C(5)H), 4.08 (1H, dd,
J 6.0, 8.5, C(4)Hexo), 4.67 (2H, s, PhCH2ONH), 5.20 (1H, d,
J 12.5, PhCHHOCO), 5.24 (1H, d, J 12.5, PhCHHOCO), 7.27–
7.40 (13H, m, ArH), 7.44–7.47 (2H, m, ArH); δC (50.3 MHz,
CDCl3) 25.2 (Me), 29.0 (C(6)), 54.7 (C(8)), 55.1 (C(5)), 58.7
(C(7)), 67.3 (PhCH2OCO), 69.0 (C(4)), 77.8 (PhCH2ON), 96.6
(C(2)), 125.9, 126.0, 128.1, 128.3, 128.4, 128.9 (ArCH), 135.8,
137.5, 141.4 (ArC), 162.9 (CON), 169.4 (PhCH2OCO); m/z
(APCIϩ) 487 (MHϩ, 30%), 364 (100); HRMS: 487.2225 (MHϩ,
ES). C29H31O5N2 requires 487.2233.
(؉)-(2S,4R)-2-Hydroxymethyl-4-(benzyloxyamino)-6-piper-
idinone 20a. Trifluoroacetic acid (0.5 ml) was added to a
solution of lactam 18 (36 mg, 0.1 mmol) in chloroform (3 ml).
After stirring for 2 hours, the solvent was removed in vacuo.
Purification by flash column chromatography on silica gel,
eluting initially with 4% MeOH : EtOAc and increasing the
polarity gradually to 8% MeOH : EtOAc, yielded the product
20a as a colourless oil (15 mg, 58%); Rf 0.24 (10% MeOH :
22
EtOAc); [α]D ϩ4.4 (c 0.8, CHCl3); vmax(film)/cmϪ1 3245m,
1651s; δH (400 MHz; acetone-d6) 1.68–1.75 (1H, ddd, J 3.0, 8.5,
13.5, C(3)Hendo), 1.92–2.03 (1H, m, C(3)Hexo), 2.22 (1H, ddd,
J 1.5, 4.5, 17.5, C(5)Hexo), 2.43 (1H, dd, J 5.0, 17.5, C(5)Hendo),
3.45 (1H, dd, J 7.0, 11.0, CHHOH), 3.49–3.55 (1H, m, C(4)H),
3.58 (1H, dd, J 5.0, 11.0, CHHOH), 3.61–3.69 (1H, m, C(2)H),
4.71 (2H, s, PhCH2O), 7.28–7.40 (5H, m, ArCH); δC (100.6
MHz, CDCl3) 27.1 (C(3)), 34.7 (C(5)), 50.9 (C(2)), 52.2 (C(4)),
66.2 (CH2OH), 77.4 (PhCH2O), 128.4, 128.9, 129.0, 130.2
(ArCH), 137.9 (ArC), 172.2 (CON); m/z (APCIϩ) 251 (MHϩ,
65%), 192 (50), 128 (100); HRMS: 251.1394 (MHϩ, ES).
C13H19O3N2 requires 251.1395.
Minor diastereomer 16: (44 mg, 26%); Rf 0.23 (30% EtOAc :
22
Petrol); [α]D Ϫ82.6 (c 0.7, CHCl3); vmax(film)/cmϪ1 1732s,
1651s, 1372s, 1323s, 1240s; δH (400 MHz; CDCl3) 1.77–1.85
(1H, ddd, J 7.0, 11.0, 14.0, C(6)Hendo), 1.95–2.00 (1H, ddd, J 4.5,
8.0, 11.5, C(6)Hexo), 2.01 (3H, s, Me), 3.36 (1H, dd, J 8.5, 9.0,
C(4)Hendo), 3.64 (1H, d, J 6.0, C(8)H), 3.95–4.04 (2H, m, C(7)H,
C(5)H), 4.06 (1H, dd, J 6.0, 8.0, C(4)Hexo), 4.66 (2H, d, J 3.0,
PhCH2ONH), 5.21 (1H, d, J 12.5, PhCHHOCO), 5.28 (1H, d,
J 12.5, PhCHHOCO), 7.25–7.43 (13H, m, ArH), 7.46–7.50
(2H, m, ArH); δC (100.6 MHz, CDCl3) 25.8 (Me), 28.6 (C(6)),
53.5(C(8)), 54.6 (C(5)), 56.8 (C(7)), 67.2 (PhCH2OCO), 68.7
(C(4)), 76.8 (PhCH2ON), 96.8 (C(2)), 125.6, 127.7, 128.0,
128.1, 128.2, 128.3, 128.4, 128.4, 128.5, 128.5, 128.9 (ArCH),
135.3, 137.1, 141.5 (ArC), 163.2 (CON), 169.3 (PhCH2OCO);
m/z (APCIϩ) 487 (MHϩ, 30%), 364 (100); HRMS: 487.2224
(MHϩ, ES). C29H31O5N2 requires 487.2233.
(؉)-(2S,4S )-2-Hydroxymethyl-4-(benzyloxyamino)-6-piper-
idinone 21a. Trifluoroacetic acid (0.5 ml) was added to a solu-
tion of adduct 19 (56 mg, 0.2 mmol) in chloroform (3 ml). After
stirring for 2 hours the solvent was removed in vacuo to yield a
yellow gum. Purification by flash column chromatography
on silica gel, eluting initially with 4% MeOH : EtOAc and
increasing the polarity gradually to 8% MeOH : EtOAc, yielded
the product 21a as a colourless oil (26 mg, 66%); Rf 0.23 (10%
(؊)-(2S,5S,7R)-1-Aza-7-(benzyloxyamino)-2-methyl-3-oxa-
9-oxo-2-phenylbicyclo[4.3.0]nonane 18 and (؊)-(2S,5S,7S )-1-
aza-7-(benzyloxyamino)-2-methyl-3-oxa-9-oxo-2-phenylbicyclo-
[4.3.0]nonane 19. Bis(tributyltin) oxide (0.32 ml, 0.62 mmol)
22
MeOH : EtOAc); [α]D ϩ14.6 (c 0.5, CHCl3); vmax(film)/cmϪ1
3248m, 1651s; δH (400 MHz; CDCl3) 1.23–1.31 (1H, q, J 12.0,
C(3)Hendo), 2.01–2.05 (1H, d, br, J 12.0, C(3)Hexo), 2.17 (1H, dd,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1809

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J 11.5, 17.0, C(5)Hendo), 2.58 (1H, dd, J 4.5, 17.0, C(5)Hexo),
3.32–3.37 (1H, m, C(4)H), 3.40 (1H, dd, J 3.0, 8.0, CHHOH),
3.49–3.53 (1H, m, C(2)H), 3.68 (1H, dd, J 3.0, 11.0, CHHOH),
4.69 (2H, s, PhCH2O), 7.27–7.53 (5H, m, ArCH); δC (100.6
MHz, CDCl3) 28.9 (C(3)), 35.1 (C(5)), 52.8 (C(2)), 53.7 (C(4)),
65.6 (CH2OH), 76.7 (PhCH2O), 128.0, 128.4 (ArCH), 137.3
(ArC), 172.2 (CON); m/z (APCIϩ) 251 (MHϩ, 100%); HRMS:
251.1398 (MHϩ, ES). C13H19O3N2 requires 251.1395.
EPSRC Chemical Database Service at Daresbury35 and
the EPSRC National Mass Spectrometry Service Centre at
Swansea.
References
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General hydrogenolysis procedure
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To a vigorously stirred solution of the starting material
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within Fischer–Porter apparatus, was added 10% palladium on
activated charcoal. The suspension was then evacuated and
flushed with H2(g) four times at room temperature. The reaction
was then subjected to H2(g) at the given pressure and stated
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(؉)-(2S,4R)-2-Hydroxymethyl-4-amino-6-piperidinone 20b.
Using the general hydrogenolysis procedure, adduct 20a
(120 mg, 0.48 mmol) was dissolved in glacial acetic acid (10 ml)
and then 10% Pd–C (120 mg) was added with vigorous stirring.
The mixture was degassed and then placed under an
atmosphere of hydrogen (5 bar) for 48 hours. Purification using
ion exchange chromatography (using water and then 2 M
ammonia in water as eluent) yielded the product 20b as a brown
22
oil (45 mg, 65%); [α]D ϩ25.8 (c 0.6, H2O); vmax(film)/cmϪ1
3420s, 1636s; δH (400 MHz; MeOD) 1.76–1.81 (1H, m,
C(3)Hendo), 1.89–1.93 (1H, m, C(3)Hexo), 2.20 (1H, dd, J 7.0,
17.5, C(5)exo), 2.58 (1H, dd, J 5.0, 17.5, C(5)Hendo), 3.45–3.48
(1H, m, C(4)H), 3.51 (1H, dd, J 6.0, 11.0, CHHOH), 3.58 (1H,
dd, J 5.5, 11.0, CHHOH), 3.61–3.67 (1H, m, C(2)H); δC (100.6
MHz, CDCl3) 29.7 (C(3)), 38.5 (C(5)), 42.1 (C(4)), 50.5 (C(2)),
64.4 (CH2OH), 174.6 (CON); m/z (APCIϩ) 145 (MHϩ, 100%),
128 (30); HRMS: 145.0978 (MHϩ, ES). C6H13O2N2 (MHϩ)
requires 145.0977.
18 C. Agami, S. Cheramy, L. Dechoux and E. Melaimi, Tetrahedron,
2001, 57, 195.
19 J. Cossy, O. Mirguet, D. G. Pardo and J. R. Desmurs, Tetrahedron
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1991.
(؉)-(2S,4S )-2-Hydroxymethyl-4-amino-6-piperidinone 21b.
Using the general hydrogenolysis procedure, adduct 21a (0.2
mmol) was dissolved in glacial acetic acid (10 ml) and then 10%
Pd–C (52 mg) was added with vigorous stirring. The mixture
was degassed and then placed under an atmosphere of
hydrogen (5 bar) for 48 hours. Purification using ion exchange
chromatography (using water and then 2 M ammonia in water
as eluent) yielded the product 21b as a green oil (26 mg, 93%);
[α]D22 Ϫ25.8 (c 0.6, H2O); vmax(film)/cmϪ1 3436s, 1646s; δH (400
MHz; D2O) 1.31 (1H, dd, J 12.0, 24.0, C(3)Hendo), 1.96 (1H, dd,
J 2.5, 23.0, C(3)Hexo), 2.06 (1H, dd, J 11.0, 17.5, C(5)Hendo),
2.47–2.54 (1H, m, C(5)Hexo), 3.17–3.25 (1H, m, C(4)H), 3.42
(1H, dd, J 5.5, 11.0, CHHOH), 3.46–3.52 (1H, m, C(2)H), 3.58
(1H, dd, J 4.0, 11.0, CHHOH); δC (100.6 MHz, D2O) 32.1
(C(3)), 38.4 (C(5)), 44.1 (C(4)), 52.7 (C(2)), 64.0 (CH2OH),
174.7 (CON); m/z (APCIϩ) 145 (MHϩ, 100%), 128 (50);
HRMS: 145.0977 (MHϩ, ES). C6H13O2N2 requires 145.0977.
21 T. Senda, M. Ogasawara and T. Hayashi, J. Org. Chem., 2001, 66,
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Acknowledgements
We thank EPSRC and Lancaster Synthesis for financial
support for GW, and AstraZeneca for a fully funded student-
ship to MH, and we gratefully acknowledge the use of the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 0 0 – 1 8 1 0
1810