Catalytic enantioselective alkene epoxidation using novel spirocyclic N-carbethoxy-azabicyclo[3.2.1]octanones

Article abstract of DOI:10.1016/j.tet.2010.04.004

A general synthetic route allowing access to several spirocyclic N-carbethoxy-azabicyclo[3.2.1]octanones is developed. These novel ketones efficiently catalyse alkene epoxidation using Oxone with up to 91.5% ee.

Full text of DOI:10.1016/j.tet.2010.04.004

Tetrahedron 66 (2010) 6309–6320
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic enantioselective alkene epoxidation using novel spirocyclic
N-carbethoxy-azabicyclo[3.2.1]octanonesq
*
Alan Armstrong , Michela Bettati, Andrew J.P. White
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general synthetic route allowing access to several spirocyclic N-carbethoxy-azabicyclo[3.2.1]octanones is
developed. These novel ketones efficiently catalyse alkene epoxidation using OxoneÒ with up to 91.5% ee.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 February 2010
Accepted 1 April 2010
Available online 7 April 2010
Keywords:
Epoxidation
Asymmetric
Ketone
Dioxirane
1. Introduction
enantioselectivities (up to 98% ee) have been obtained for trans-
and trisubstituted olefins, but generally poor results for terminal
Enantioselective alkene epoxidation catalysed by chiral ketones,
using Oxone as stoichiometric oxidant, has been intensively studied
over the past decade and has resulted in the design of several
effective novel ketone architectures.1,2 In particular, a comprehen-
sive series of inventive contributions from Shi and co-workers has
demonstrated chiral ketones derived from carbohydrates to be
exceptionally selective and practical members of the asymmetric
synthesis toolbox.1,3–5 The fructose-derived ketone 1 is now widely
employed for the epoxidation of trans- and trisubstituted alkenes.
Interestingly, Shi has extended the applicability of his catalysts to
a wide range of alkene substitution patterns, including challenging
terminal olefins,5 by modifying the catalyst structure. Catalysts 2
incorporating a fused spirocyclic oxazolidinone moiety have been
especially effective for this purpose, and several interesting elec-
tronic effects have been noted upon variation of the oxazolidinone
N-substituent.4 As well as their synthetic utility, chiral ketone
catalysts have provided outstanding insights into the mechanisms
of asymmetric induction with computational studies providing
satisfying agreement with experimental data.6
alkenes. Nevertheless, the enantioselectivities afforded are notable
given the simple nature of the ketone alpha-substituents (e.g., Y¼F
or OAc). In view of the remarkable effectiveness and tunability of
the alpha-oxazolidinone-bearing spirocyclic systems developed by
Shi, we were keen to incorporate this more complex motif onto our
own bicyclic system. In addition, we reasoned that the markedly
different synthetic routes available for catalyst synthesis from
non-carbohydrate precursors might allow access to novel spi-
rocyclic moieties that have not previously been explored. The
synthesis of several novel catalysts of this type (4–6) and their
effectiveness for enantioselective epoxidation of a range of alkenes
is reported herein. A new alternative spirocycle, the sulfamidate
unit, is also prepared and tested.
2. Results and discussion
2.1. Catalyst synthesis
Our previous studies on bicyclo[3.2.1]octanone catalysts7
employed chiral base-mediated desymmetrisation of the parent
In our own work, we have introduced 2-substituted-bicy-
clo[3.2.1]octanones 3 as a family of chiral catalysts, which are
generally stable to Baeyer–Villiger reaction,7 allowing the
development of solid supported variants.7c Good-to-excellent
ketone
7 to access enantiomerically enriched material. This
approach relied on enantiomeric enrichment by recrystallisation
for access to enantiomerically pure catalysts. In the present study,
we prepared catalysts initially in racemic form and resolved them
on a chiral stationary phase (vide infra) to facilitate catalyst
screening. We identified enone 8 as a key potential intermediate for
the synthesis of a wide range of our target spirocyclic ketones. We
q
With congratulations to Prof. Steve Ley on the award of the Tetrahedron Prize.
* Correspondingauthor. E-mail address: a.armstrong@imperial.ac.uk (A. Armstrong).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.004

6310
A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
therefore temporarily reduced by Luche reduction9 of 8 to give the
O
allylic alcohol followed by epoxidation with m-CPBA; the sequence
occurred stereoselectively to afford 10 as confirmed by NOE studies.
Epoxide 10 could then be opened by nucleophilic addition of
several primary amines at the less hindered carbon to give amino
alcohols 11 (Scheme 2). The regiochemical outcome of the epoxide
opening was confirmed in one case (11d, R¼Bn) by HMBC studies,
notably a three-bond correlation between the benzylic protons and
the CH2 carbon of the amino alcohol moiety. The other examples
were assumed to follow the same regiochemical outcome. Since
attempts to selectively engage the tertiary alcohol and amine in
oxazolidinone formation with triphosgene proved problematic, we
sought to oxidise the secondary alcohol group first. Several com-
mon methods (TPAP, PCC, Jones or Dess–Martin reagents) proved
unsuccessful. An effective method was eventually found to be the
use of IBX in the presence of acid (TFA),10 under which conditions
protonation of the amino group is presumed to protect it from
oxidation. Attempts to use this route to prepare 5g (R¼Ph) failed at
the IBX oxidation step: as an alternative, the Swern oxidation was
successful in this case. Finally, cyclisation with triphosgene in
pyridine afforded ketones 5. Where a chiral, enantiomerically pure
O
O
O
N R
O
O
O
O
O
O
O
O
1
2
EtO2C
O
X
N
Y
O
X
O
O
3
4 X = O
X = NCO2Et, O
5 X = NR
6 X = CH2
Y = e.g. F, OAc
amine (S-a-methyl benzylamine) was used in the epoxide opening
have previously reported a synthesis of 8 from commercially
available 7.7d However, we were keen to develop a superior route
since the earlier approach, involving cyclopropanation of the
trimethylsilyl enol ether of 7, was quite lengthy and low yielding
(33% from 7). A better approach was found to involve silyl enol
ether formation and reaction with Eschenmoser’s salt, followed by
N-quaternization and base-mediated elimination (Scheme 1).8
After some experimentation to identify optimal conditions, the
process provided reproducible yields of ca. 60% of 8, with the main
side-product (10–20%) being dienone. We have previously repor-
ted7d dihydroxylation of 8 to give diol 9; the derived acetonide was
found to be a poor epoxidation catalyst, undergoing decomposition
by Baeyer–Villiger reaction. We reasoned that the corresponding
carbonate 4 would be less susceptible to this side-reaction, and
would present a novel spirocyclic motif not tested in the Shi
systems. Treatment of 9 with triphosgene yielded racemic 4
(Scheme 1).
step, the final product was obtained as a mixture of two separable
diastereomers, the configuration of one of which (5e) was
determined by X-ray crystallography (vide infra).
EtO2C
EtO2C
N
N
O
OH
HN
R
c
a, b
8
OH
OH
10
11
a R = Me
b R = iPr
c R = tBu
d R = Bn
e R = (S)-CH(CH3)Ph
f R = (S)-CH(CH3)Ph*
g R = Ph
O
EtO2C
N
O
R
N
d, e
30-52%
O
5
EtO2C
EtO2C
N
N
a, b
c
*derived from ent-11
Scheme 2. (a) NaBH4, CeCl3$7H2O, MeOH, 0 ꢁC, 95%; (b) m-CPBA, DCM, 0 ꢁC, 70%; (c)
RNH2 (1 equiv), EtOH, 80 ꢁC; (d) For 11a–f: IBX, TFA, DMSO. For 11g: (COCl)2, DMSO,
then Et3N; (e) triphosgene, pyridine, DCM.
7
8
O
O
We wished to evaluate the steric and electronic effects of
replacing the oxazolidinone nitrogen with a tetrahedral carbon
atom. The required lactone was prepared as shown in Scheme 3.
Silylation of epoxy alcohol 10 was followed by epoxide opening
O
EtO2C
EtO2C
N
N
HO
O
OH
O
d
EtO2C
O
N
4
9
O
O
O
a, b
Scheme 1. (a) (i) LiHMDS, THF, ꢀ78 ꢁC; (ii) TMSCl, ꢀ78 ꢁC; (b) (i) Eschenmoser’s salt
(Me2NCH2I), DMF, rt, 1.5 h; (ii) MeI, 50 ꢁC, sealed tube; (iii) NaHCO3, DMF, 95 ꢁC,
60–65%; (c) K2OsO4$2H2O, quinuclidine, NMO, acetone/H2O, 86%; (d) triphosgene,
pyridine, DCM, 60%.
10
OH
12
EtO2C
O
For the synthesis of further fused heterocycles including oxa-
zolidinones, epoxidation of 8 followed by ring opening with an
appropriate nucleophile was an attractive strategy. However,
attempts to effect direct epoxidation of 8 were generally low
yielding and afforded mixtures of diastereomers. While diol 9 could
be converted cleanly to the diastereomerically pure ketoepoxide,
exploratory experiments indicated that some of the later ketone
intermediates in this synthetic route were unstable. The ketone was
N
c
O
O
6
Scheme 3. (a) Et3N, TMSOTf, DCM, ꢀ78 ꢁC/ꢀ30 ꢁC, quantitative; (b) (i) NaH, diethyl
malonate, THF; (ii) NaCl, DMSO, H2O, 150 ꢁC, 35%; (c) TPAP, NMO, DCM, 53%.

A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
6311
with the anion of diethyl malonate and concomitant lactonisation
and desilylation. Krapcho decarboxylation followed by TPAP oxi-
dation12 of the secondary alcohol 12 delivered the target racemic
ketone 6.
Finally, we decided to investigate the effect of replacing the
oxazolidinone carbonyl with SO2. To the best of our knowledge,
ketones bearing the spirocyclic cyclic sulfate or sulfamidate motif
have not previously been tested in asymmetric epoxidation. The
former was found to be too unstable under the Oxone epoxidation
conditions to allow proper evaluation. The cyclic sulfamidate 14
was prepared from the amino alcohol 13, an intermediate in the
synthesis of oxazoidinone 5a, by reaction with thionyl chloride
followed by oxidation (Scheme 4).
tested in Table 1 (entries 11–14), whilst showing variations in
reactivity, displayed remarkably similar levels of enantioselectivity.
Indeed, the five catalysts 4, 5a, 5g, 6, 14, with cyclic carbonate,
N-methyl- and N-phenyl oxazolidinone, lactone and sulfamidate
spiro systems all afforded E-stilbene oxide in the narrow range of
87–91.5% ee. This suggests that in this catalyst family, specific
interactions with particular elements of the spirocycle are not
significant factors in controlling enantioselectivity.
Table 1
Catalytic asymmetric epoxidation of E-stilbenea
Entry Catalyst
X
t (h) Conversionc Yield eed Epoxide
(%)
(%)
(%) configurationd
1
2
3
4
5
6
7
8
4
O
O
N-Me
18 100
18 100
85
83
85
85
90
41
17
50
50
20
74
68
nd
nd
87 (R,R)
89 (S,S)
91.5 (R,R)
91.5 (S,S)
87 (R,R)
79 (S,S)
82 (S,S)
82 (S,S)
87 (R,R)
69 (S,S)
87 (R,R)
88 (S,S)
90 (R,R)
87 (R,R)
EtO2C
EtO2C
O
S
ent-4
5a
ent-5a N-Me
O
N
N
N
12
12
18
18
24
18
87
86.5
90
41
37
50
52
24
76
69
95
95
HO
O
a,b
HN
O
5b
N-iPr
ent-5c N-tBu
ent-5d N-Bn
ent-5db N-Bn
O
14
13
9
5e
5f
5g
(S)-NCH(CH3)Ph 12
(S)-NCH(CH3)Ph 12
N-Ph
Scheme 4. (a) SOCl2, pyridine, DCM, 48%; (b) RuCl3xH2O, NaIO4, CH3CN, H2O, 55%.
10
11
12
13
14
12
12
24
8
ent-5g N-Ph
6
14
With the exception of 5e/5f derived from
a-methyl benzyl-
CH2
SO2
amine, all catalysts in Schemes 1–4 were prepared as racemates.
These were resolved by supercritical fluid chromatography (SFC) on
chiral stationary phases to give enantiomerically pure catalysts for
testing. The relative configuration of 5e was confirmed by X-ray
crystallography (vide infra), and the absolute configuration for the
other ketones was assigned based on correlation of the results for
asymmetric epoxidation of E-stilbene (see later discussion).
Overall, we have developed a versatile, six-step approach from
commercially available N-carbethoxytropinone 7, which offers the
great advantage of reacting the advanced intermediate epoxide 10
with various nucleophiles at a late stage, thus allowing ready access
to a wide range of substituted derivatives. The route could poten-
tially be rendered enantioselective by desymmetrisation of 7 using,
for example, deprotonation with chiral bases, as in our earlier
work.7
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst
(10 mol %).
b
Catalyst (20 mol %).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
d
Product ee and configuration determined by chiral HPLC analysis.
In each case, the enantiomer of the ketone catalyst that afforded
(R,R)-stilbene oxide was assigned the configuration depicted in the
schemes based on the well established spiro-TS model1,6 in Figure 1,
which has been found to operate with our previous related cata-
lysts.7 In the case of 5e, the catalyst configuration was confirmed by
X-ray crystallography. In this crystal structure (Fig. 2), 5e adopts
a conformation in which the benzylic hydrogen almost eclipses the
oxazolidinone carbonyl. This places the Me-substituent towards the
catalyst region approached by the olefin in the epoxidation TS. If
the diastereomer 5f adopts a similar conformation, this would
place the Ph-substituent in this position, with a resulting steric
clash with the incoming olefin, offering a possible explanation for
the lower reactivity and enantioselectivity observed for this cata-
lyst. Similar steric interactions may account for the slightly lower ee
value obtained with the N-tBu catalyst ent-5c (entry 6).
2.2. Catalyst evaluation
Catalyst screening under standard Oxone/NaHCO3/CH3CN/H2O
conditions13 began with E-stilbene as test substrate, since this
would allow comparison to results with our earlier catalysts. As
a benchmark, the fluoroketone 3 (X¼NCO2Et, Y¼F) has been
reported to epoxidize E-stilbene with 76% ee.7d The carbonate 4 was
screened first (Table 1, entry 1). Complete conversion was observed
using 10 mol % of 4, and the epoxide was obtained in excellent ee
(87%). Similar results were obtained with the opposite catalyst
enantiomer (entry 2). Turning to the oxazolidinone catalysts, the
N-Me-derivative 5a was screened first. Although a small decrease in
conversion was noted, this catalyst displayed a slightly higher
enantioselectivity (91.5% ee, entries 3 and 4). The effect of increased
steric hindrance in the N-substituent was now probed. Moving to
N]iPr derivative 5b resulted in a slight drop in conversion and
enantioselectivity (entry 5), while the NtBu analogue 5c performed
more poorly in both regards (entry 6). The NBn counterpart 5d
provided similar results (entry 7), with incomplete conversion even
at 20 mol % loading, suggesting that this substituent does not
provide beneficial aromatic-aromatic interactions with the alkene
substrate. The related catalysts 5e and 5f provided an interesting
test of the effect of an additional element of central chirality. The
former performed better both in terms of conversion and enan-
tioselectivity (87 vs 69% ee, entries 9 and 10). The final derivatives
EtO2C
O
N
H
H
O
X
O
Ph
Ph
Ph
Ph
(R,R)
O
O
Figure 1. Epoxidation TS model.
A selection of the catalysts was screened with two other trans-
disubstituted olefins. With E- -methyl styrene (Table 2), the N-Me-
derivative 5a afforded best results (73.5% ee, entry 2). Catalysts
with distinct cyclic motifs were again found to afford epoxides in
a narrow range of enantioselectivity (compare entries 1, 3, 6 and 7).
Cinnamate esters represent more challenging, less reactive
b

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A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
Phenyl cyclohexene has proved to be a particularly interesting
substrate in epoxidation reactions with Shi’s carbohydrate-derived
catalysts. The first generation catalyst 1 afforded (R,R)-phenyl
cyclohexene oxide in excellent ee. This sense of selectivity is in
accord with the spiro-TS model similar to that shown in Figure 1.
However, Shi has reported a reversal of enantioselectivity for some
N-aryl- and N-Boc-oxazolidinone-containing spirocyclic ketones
(e.g., 15, Fig. 3).4 This was attributed to an attractive interaction
between the oxazolidinone N-substituent and the phenyl ring on
the alkene, resulting in predominant reaction via a planar-TS. With
our own catalysts (Table 4), the major enantiomer was in all cases in
accord with the spiro-TS model (cf. Fig.1), suggesting that attractive
interactions between the substrate-phenyl and our own spirocyclic
substituents do not exert a significant influence.
O
Figure 2. The molecular structure of one of the two crystallographically independent
molecules present in the crystals of 5e.11
Boc
O
N
O
O
Ph
O
Ph
(S,S)
(R,R)
O
O
enantiomer
(39% ee)
enantiomer
(98% ee)
O
O
O
O
O
O
substrates, the epoxides of which are synthetically useful. While
moderate conversions were obtained, promising levels of enan-
tioselectivity were observed (up to 82% ee, Table 3). For both of
these trans-disubstituted substrates, the major epoxide enantiomer
obtained is again consistent with the model in Figure 1.
Ketone 1:
Spiro TS
Ketone 15:
Planar TS
Figure 3. Enantiomeric excesses for epoxidation of phenyl cyclohexene with ketones 1
and 15.
Table 2
Catalytic asymmetric epoxidation of E-b
-methylstyrenea
Entry Catalyst
X
t (h) Conversionc Yield eed Epoxide
Table 4
(%) configurationd
Catalytic asymmetric epoxidation of 1-phenylcyclohexenea
(%)
(%)
1
2
3
4
5
6
7
ent-4
5ab
O
N-Me
N-iPr
1
100
25
71
53
69
70
90
nd
63 (S,S)
73.5 (R,R)
62 (R,R)
45 (S,S)
57 (R,R)
64 (S,S)
67 (S,S)
Entry Catalyst
X
t (h) Conversionc Yield eed Epoxide
18 100
18
15
(%)
(%)
(%) configurationd
5bb
95
83
85
96
100
ent-5db N-Bn
1
2
3
4
5
6
7
8
ent-4
5ab
O
N-Me
N-iPr
1
18
1
98
100
95
100
100
100
88
63
65
54
58
69
86
nd
nd
73 (S,S)
74 (R,R)
71 (R,R)
51 (S,S)
64 (R,R)
58 (S,S)
45 (R,R)
69 (R,R)
5eb
ent-5gb N-Ph
ent-6 CH2
(S)-NCH(CH3)Ph 18
5bb
18
8
ent-5db N-Bn
15
5eb
ent-5gb N-Ph
(S)-NCH(CH3)Ph 18
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
18
8
8
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst
(10 mol %).
6
14
CH2
SO2
65
b
Reaction conditions: alkene (0.2 mmol), OxoneÒ (2.0 mmol KHSO5), ketone
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
(10 mol %), NaHCO3 (3.01 mmol), CH3CN (3 ml), aq Na2EDTA (2 ml of 0.4 mM
solution).
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst
(10 mol %).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
Product ee and configuration determined by chiral HPLC analysis.
b
Reaction conditions: alkene (0.2 mmol), OxoneÒ (2.0 mmol KHSO5), ketone
d
(10 mol %), NaHCO3 (3.01 mmol), CH3CN (3 ml), aq Na2EDTA (2 ml of 0.4 mM
solution).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
Product ee and configuration determined by chiral HPLC analysis.
d
Table 3
Catalytic asymmetric epoxidation of E-ethyl cinnamatea
Direct enantioselective epoxidation of terminal alkenes remains
an important challenge, and the highly encouraging results repor-
ted by Shi with his spirocyclic ketones5 prompted us to screen our
Entry Catalyst
X
t (h) Conversionc Yield eed Epoxide
(%)
(%)
(%) configurationd
1
2
3
4
5
6
7
ent-4
O
N-Me
18
18
15
55
44
20
28
40
23
17
48
41
17
21
35
nd
nd
74 (2R,3S)
80 (22,3R)
61 (2R,3S)
73 (22,3R)
82 (2R,3S)
78 (2R,3S)
81 (2R, 3S)
5ab
own catalysts. Epoxidation of styrene with fluoroketone
3
(X¼NCO2Et, Y¼F) affords styrene oxide in poor ee (29%).7d The
majority of the new catalysts improve on this (Table 5), with 5f
again affording lower enantioselectivity than its diastereomer 5e
(entries 6 and 7). The best result (59% ee) was with the N-Ph-de-
rivative 5g (entry 8), suggesting that exploration of the effect of
substituents on the catalyst’s aromatic ring may be worthwhile.
Finally, the particularly challenging 1,1-disubstituted alkene class
was examined (Table 6), but enantioselectivities were poor, and
again within a relatively narrow range, suggesting an absence of
specific TS-interactions between the various spirocyclic sub-
stituents and the alkene.
ent-5a N-Bn
5b
ent-5db N-Ph
ent-6 CH2
ent-14 SO2
(S)-NCH(CH3)Ph 18
18
18
18
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst
(10 mol %).
b
Reaction conditions: alkene (0.2 mmol), OxoneÒ (2.0 mmol KHSO5), ketone
(10 mol %), NaHCO3 (3.01 mmol), CH3CN (3 ml), aq Na2EDTA (2 ml of 0.4 mM
solution).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
Product ee and configuration determined by chiral HPLC analysis.
d

A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
6313
Table 5
and needles were oven-dried. Anhydrous THF, DMF, Et2O and
MeOH were purchased from Aldrich Chemical Co. All commercially
reagents were used without further purification. Flash chroma-
tography was performed on silica gel Merck Kieselgel (230–400)
mesh or on Varian Mega Be–Si pre-packed cartridges or on
pre-packed Biotage silica cartridges. In a number of preparations,
purification was performed using either Biotage manual flash
chromatography (Flashþ) or automatic flash chromatography
(Horizon, SP1) systems. All these instruments work with Biotage
Silica cartridges.
SPE-SCX cartridges are ion exchange solid phase extraction
columns supplied by Varian. The eluent used with SPE-SCX
cartridges is methanol followed by 2 M ammonia solution in
methanol.
In a number of preparations, ‘dried’ refers to a solution dried
over anhydrous sodium sulfate (when organic solvents as diethyl
ether or ethyl acetate are used) or by phase separator cartridge
(when DCM is used). Phase separation cartridges were supplied by
Whatman (PTFE, 5 mM pore size).
Catalytic asymmetric epoxidation of styrenea
Entry Catalyst
X
t (h) Conversionc Yield eed Epoxide
(%)
(%)
(%) configurationd
1
2
3
4
5
6
7
8
9
ent-4
5ab
O
N-Me
N-iPr
1
12
18
18
24
100
100
88
>30
89
94
63
93
100
nd
79
35
8
68
66
40
29
nd
46 (S)
58 (R)
54 (R)
43 (S)
43 (S)
55 (R)
27 (S)
59 (S)
50 (S)
5bb
ent-5cb N-tBu
ent-5db N-Bn
5eb
5fb
(S)-NCH(CH3)Ph 12
(S)-NCH(CH3)Ph 12
ent-5gb N-Ph
24
18
ent-6
CH2
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst (10%
mol).
b
Reaction conditions: alkene (0.2 mmol), OxoneÒ (2.0 mmol KHSO5), ketone
(10 mol %), NaHCO3 (3.01 mmol), CH3CN (3 ml), aq Na2EDTA (2 ml of 0.4 mM
solution).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
Product ee and configuration determined by chiral HPLC analysis.
d
Thin layer chromatography (TLC) was carried out on Merck
5ꢂ10 cm plates with silica gel 60 F254 as sorbant. Visualisation of
reaction components was achieved with UV lamp (254 nm) and
with ceric ammonium nitrate or potassium permanganate stains.
Preparative thin layer chromatography was carried out using
20ꢂ20 cm silica gel GF tapered plates supplied by Analtech Inc,
Newark. IR spectra were recorded on a Perkin–Elmer FT-IR spec-
trometer, Spectrum 1000 or on Nicolet FT-IR Magna 760 spec-
trometer. Samples were run as thin films (produced by the
evaporation of chloroform or DCM) on aluminium oxide plates or
on Nujol. Absorption maxima are reported in wavenumber (cmꢀ1).
1H and 13C NMR spectra were recorded in CDCl3 unless stated
otherwise on either a Bruker spectrometer at 500, 400 or 360 MHz,
or on Varian instruments at 300, 400 or 500 MHz. Chemical shifts
Table 6
Catalytic asymmetric epoxidation of
a
-methylstyrenea
Entry Catalyst
X
t
Conversionc Yield eed Epoxide
(h) (%)
(%)
(%) configurationd
1
2
3
4
5
6
ent-4b
5ab
O
N-Me
N-iPr
1
100
30
90
27
45
49
67
19 (S)
17 (R)
15 (R)
16 (S)
12 100
10 100
18
18
24
5bb
ent-5cb N-tBu
ent-5db N-Bn
55
81
69
6
(S)
5eb
(S)-
13 (R)
NCH(CH3)Ph
7
8
ent-5gb N-Ph
24
8
97
81
52
nd
12 (S)
13 (R)
6
CH2
are reported in parts per million (d) downfield from tetrame-
a
Conditions: alkene (0.1 mmol), OxoneÒ (1.0 mmol KHSO5), NaHCO3
thylsilane as internal standard and coupling constants are quoted in
hertz (Hz). Splitting patterns are abbreviated as follows: singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), broad (br) and
combinations of the above. The NMR spectra were recorded at
a temperature ranging from 25 to 90 ꢁC.
Mass spectra were recorded using a HP1100 flow inject system
(50:50 1% formic acid–H2O/CH3CN) into an electrospray source of
a Waters ZMD2000 or on a 4 II triple quadrupole Mass Spectrom-
eter (Micromass UK) or on an Agilent MSD 1100 Mass Spectrometer,
operating in ES(þ) and ES(ꢀ) ionisation mode. Accurate mass was
recorded using a HP1100 flow injection into an electrospray source
of a Waters Q-Tof micro or a Waters LCT Premier mass spectrometer
equipped with a Z-spray source and coupled to a Waters UPLC
(Ultra Performance Liquid Chromatography). Leucine Enkephalin
was used as external standard and infused with a reference probe.
Optical rotations were recorded on a Perkin–Elmer Polarimeter 241,
with a path length of 5 cm or on an Optical-Activity AA-5 Polar-
(1.55 mmol), CH3CN (1.5 ml), aq Na2EDTA (1 ml of 0.4 mM solution), catalyst (10%
mol).
b
Reaction conditions: alkene (0.2 mmol), OxoneÒ (2.0 mmol KHSO5), ketone
(10 mol %), NaHCO3 (3.01 mmol), CH3CN (3 ml), aq Na2EDTA (2 ml of 0.4 mM
solution).
c
Estimated from the 1H NMR spectrum of the crude reaction mixture.
Product ee and configuration determined by chiral HPLC analysis.
d
3. Conclusions
We have developed an efficient synthetic approach to a range of
spirocyclic ketones, which has allowed access to several novel
derivatives from a common synthetic intermediate. These new
ketones are efficient catalysts for alkene epoxidation using Oxone,
and can be used at low loadings (10 mol %). Enantioselectivities are
very good for epoxidation of E-stilbene, and the new spirocyclic
catalysts afford higher ee for epoxidation of styrene than does the
simpler ketone 3. The results for epoxidation of phenylcyclohexene,
and the generally low variation of product ee with catalyst sub-
stitution, suggest that specific interactions with the spirocyclic
substituents are not significant contributors to the observed
imeter with a path length of 5 cm, in chloroform or methanol. [a]
D
values are given in 10ꢀ1 deg cm2 gꢀ1. Concentrations (c) are given in
grams per 100 cm3. Melting points were obtained using a Buchi
melting point B-540 hot stage apparatus or a Gallenkamp melting
point apparatus and are quoted as uncorrected.
enantioselectivities. Syntheses of
a wider range of ketones,
Separations of racemic ketones into single enantiomers were
performed using Supercritical Fluid Chromatography (Chiralpak IA,
Chiralpak AS or AS-H, Chiralpak AD-H column) on a Berger Mini-
gram system with UV/VIS detector at 220 nm using CO2/methanol
as mobile phase. Alternatively, they were performed by chiral
chromatography (Chiralpak AS-H, ACE C8, Chiralpak AD-H or
Chiralcel OJ-H column) on an Agilent HP1100 system with UV/VIS
detector at 254 or 220 nm using iso-propanol/n-hexane or meth-
anol/n-hexane as eluent; retention times are quoted in minutes.
The absolute configuration of the ketones was assumed based on
including more highly substituted variants, are ongoing and will be
reported in due course.
4. Experimental
4.1. General details
All reactions requiring dry or inert conditions were conducted in
oven-dried equipment under an atmosphere of nitrogen. Syringes

6314
A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
the observed major enantiomer of E-stilbene oxide obtained when
they were used as catalysts, i.e., the catalyst enantiomers depicted
in the schemes give (R,R)-stilbene oxide, whilst the ent-series gives
(S,S)-stilbene oxide. This is consistent with the spiro-TS model in
Figure 1, with the results for earlier catalysts,7 and was confirmed
by X-ray crystallography in the case of 5e.11
Epoxide enantiomeric excesses (ee) were determined by chiral
HPLC HP1100 (Chiralpak AS, Chiralcel OD or Chiralcel OJ-H column)
on an Agilent HP1100 system with UV/VIS detector at 254 or
220 nm using iso-propanol/n-hexane or methanol/n-hexane as
eluent.
CCH2OH), 3.56–3.54 (1H, m, CCH2OH), 3.15 (1H, d, J¼20.6 Hz,
CHCH2axCO), 2.41 (1H, br s, COH), 2.22 (1H, d, J¼20.6 Hz, CHCH2eqCO),
2.05–2.00 (2H, m, CHCH2exoCH2exoCH), 1.64 (1H, br s, CH2OH), 1.61–
1.57 (2H, m, CHCH2endoCH2endoCH),1.31 (3H, m, OCH2CH3); 13C NMR dC
(ppm) (CDCl3, 91 MHz): 208.4 (C, C]Oketone),155.7 (C, C]Ocarbamate),
80.0 (C, CCH2OH), 62.9 (CH2, CCH2OH), 62.2 (CH2, OCH2CH3), 59.4(CH,
NCHC), 54.1 (CH, NCHCH2CO), 46.4 (CH2, CHCH2CO), 28.3 (CH2,
CHCH2CH2CHCH2), 23.9 (CH2, CHCH2CH2CHCH2), 15.0 (CH3,
OCH2CH3); m/z (ESþ) 244 ([MþH]þ,100%); m/z (ESþ) found: [MþH]þ,
244.1189. C11H18NO5 requires: [MþH]þ, 244.1185.
4.2.3. (1R
*
,2S
*
,5S
)-Ethyl 20,3-dioxo-8H-spiro[8-azabicyclo[3.2.1]octane-
*
4.2. Synthesis of ketone catalysts
2,40-[1,3]dioxolane]-8-carboxylate (ꢃ)-4. Compound (ꢃ)-4, and reso-
lution to give 4 and ent-4. To a stirred solution of diol (ꢃ)-9 (150 mg,
6.15 mmol) and pyridine (0.5 ml, 6.15 mmol) in DCM (3 ml) a solu-
tion of triphosgene (0.182 mg, 6.15 mmol) in DCM (0.4 ml) was
added at 0 ꢁC under a nitrogen atmosphere. The mixture was stirred
between 0 ꢁC and rt for 8 h. It was then quenched with H2O (2 ml).
The organic phase was diluted with DCM (20 ml), separated, dried
over MgSO4 and concentrated. The residue was purified by flash
chromatography on silica gel eluting with 50% EtOAc in n-hexane to
give (ꢃ)-4 as a colourless solid (100 mg, 60%); mp: 113.4–114.3 ꢁC;
nmax/cmꢀ1 (CHCl3): 1806, 1692, 1426, 1335, 1047; 1H NMR dH (ppm)
(CDCl3, 500 MHz): 5.04–4.99 (1H, m, CCH2O), 4.85–4.64 (2H, m,
NCHC and NCHCH2CO), 4.27–4.18 (2H, m, OCH2CH3), 4.00 (1H, d,
J¼8.8 Hz, CCH2O), 3.15–3.01 (1H, br m, CHCH2axCO), 2.52 (1H, dd,
J¼15.2 and 2.2 Hz, CHCH2eqCO), 2.16–2.08 (2H, m, CHCH2exoCH2ex-
oCH), 1.63–1.61 (1H, m, CHCH2endoCH2endoCHCH2), 1.33–1.24 (4H, m,
OCH2CH3 and CHCH2endoCH2endoCHCH2); 13C NMR dC (ppm) (CDCl3,
91 MHz): 199.6 (C, C]Oketone), 154.4 (C, C]Ocarbamate), 152.6 (C,
C]Ocarbonate), 85.2 (C, CCH2O), 65.8 (CH2, CCH2O), 62.4 (CH2,
OCH2CH3), 59.4 (CH, NCHC), 54.0 (CH, NCHCH2CO), 47.1 (CH2,
4.2.1. (1R
*
,5S )-Ethyl 2-methylene-3-oxo-8-azabicyclo[3.2.1]octane-
*
8-carboxylate (ꢃ8). Under a nitrogen atmosphere, LiHMDS 1.0 M in
THF (83 ml, 0.08 mol) was added dropwise to a stirred solution of
ketone 7 (15.0 g, 0.08 mol) in THF (150 ml) cooled at ꢀ78 ꢁC. After
stirring at ꢀ78 ꢁC for 30 min, Me3SiCl (14.4 ml, 0.11 mol) was
1
added, and stirring was continued for ⁄2 h. The reaction mixture
was quenched with a saturated solution of NH4Cl (50 ml) at 0 ꢁC;
then the organic layer was diluted with EtOAc (100 ml) and
extracted with EtOAc (3ꢂ20 ml). The combined organics were
washed with a saturated solution of NaHCO3 (50 ml), dried over
MgSO4 and concentrated. The crude silyl enol ether intermediate
was dissolved in DMF (150 ml), under a nitrogen atmosphere, and
Eschenmoser’s salt (15.4 g, 0.08 mol) was added. The reaction
mixture was stirred at rt for 1.5 h and then MeI (23 ml, 0.38 mol)
was added. After stirring at 50 ꢁC overnight in a sealed tube,
NaHCO3 (47.0 g, 0.56 mol) was added and the reaction mixture
diluted with DMF (100 ml). It was heated to 95 ꢁC overnight and
then cooled to rt, diluted with EtOAc (100 ml), washed with H2O
(50 ml), extracted with EtOAc (3ꢂ30 ml) and separated. The
combined organics were dried over MgSO4 and concentrated. The
residue was purified by flash chromatography over silica gel eluting
with 25% EtOAc in n-hexane to give (ꢃ)-8 as a colourless oil (10.1 g,
63%); nmax/cmꢀ1 (CHCl3): 2977, 1693, 1622, 1410, 1380, 1106, 946,
768; 1H NMR dH (ppm) (CDCl3, 500 MHz): 5.91 (1H, s, C]CH2), 5.24
(1H, br s, C]CH2), 4.91 (1H, br s, NCHC), 4.57 (1H, br s, NCHCH2CO),
4.18–4.14 (2H, q, J¼7.1 Hz, OCH2CH3), 2.78 (1H, br s, CHCH2axCO),
2.46 (1H, d, J¼18.0 Hz, CHCH2eqCO), 2.29–2.17 (2H, m, CHCH2ex-
oCH2exoCH), 1.80–1.68 (2H, m, CHCH2endoCH2endoCH), 1.26 (3H, t,
J¼7.1 Hz, OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz): 198.5
(C, C]Oketone), 154.0 (C, C]Ocarbamate), 146.8 (C, C]CH2), 119.6
(CH2, C]CH2), 61.8 (CH2, OCH2CH3), 58.6 (CH, NCHC), 52.8 (CH,
NCHCH2CO), 47.9 (CH2, CHCH2CO), 31.4 (CH2, CHCH2CH2CH), 29.5
(CH2, CHCH2CH2CH), 15.0 (CH3, OCH2CH3); m/z (ESþ) 210 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 210.1138. C11H16NO3 requires:
[MþH]þ, 210.1130.
CHCH2CO),
27.9
(CH2,
CHCH2CH2CHCH2),
23.8
(CH2,
CHCH2CH2CHCH2), 14.9 (CH3, OCH2CH3); m/z (ESþ) 270 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 270.0976. C12H16NO6 requires:
[MþH]þ, 270.0978.
The racemic compound was separated into single enantiomers
by SFC (Chiralpak AD-H column, 220 nm, 90:10 CO2/iso-propanol,
10 ml/min, 35 ꢁC, outlet P¼100 bar).
Compound ent-4: enantiomer 1, tR¼5.20 min, colourless solid,
20
mp: 126.5–128.1 ꢁC; [
a
]
ꢀ25.2 (c 1, CHCl3); 99% ee.
D
Compound 4: enantiomer 2, tR¼6.35 min, colourless solid, mp:
20
116.1–120.2 ꢁC; [
a
]
þ21.0 (c 0.3, CHCl3); 97% ee.
D
4.2.4. (1R ,2S ,3S ,5S )-Ethyl 3-hydroxy-8H-spiro[8-azabicyclo[3.2.1]octane-
*
*
*
*
2,20-oxirane]-8-carboxylate (ꢃ)-10. CeCl3$7H2O (7.8 g, 0.02 mol) was
added to a solution of enone (ꢃ)-8 (4.0 g, 0.02 mol) in MeOH (30 ml).
The mixture was cooled to 0 ꢁC and then NaBH4 (0.79 g, 0.02 mol)
was added portionwise. After stirring at 0 ꢁC for 1 h, the mixture was
quenched with water (3 ml). The organic solvent was evaporated in
vacuo and the residue diluted with EtOAc(30 ml), washed with0.1 M
HCl (10 ml), brine (10 ml), dried over MgSO4 and concentrated. It was
then purified by flash chromatography on silica gel eluting with 50%
EtOAc in n-hexane and thenwith 5% MeOH in DCM to yield the allylic
alcohol as a colourless oil (3.8 g, 95%); nmax/cmꢀ1 (CHCl3): 3518,1697,
908; 1H NMR dH (ppm) (DMSO-d6, 500 MHz): 4.92 (1H, d, J¼6.5 Hz,
OH), 4.90–4.89 (1H, m, C]CH2), 4.80 (1H, br s, C]CH2), 4.46 (1H, d,
J¼6.3 Hz, NCHC), 4.32–4.29 (1H, m, CHCH2CHOH), 4.16 (1H, br s,
NCHCH2CHOH), 4.01 (2H, q, J¼7.0 Hz, OCH2CH3), 1.91–1.87 (3H, m,
4.2.2. (1R
*
,2S
*
,5S )-Ethyl 2-hydroxy-2-(hydroxymethyl)-3-oxo-8-aza-
*
bicyclo[3.2.1]octane-8-carboxylate (ꢃ9). To a stirred suspension of
K2OsO4$2H2O (5.2 mg, 0.01 mmol), quinuclidine (7.8 mg, 0.07 mmol)
and N-methylmorpholine-N-oxide (336 mg, 2.87 mmol) in H2O
(0.64 ml) a solution of enone (ꢃ)-8 (300 mg, 1.40 mmol) in acetone
(3.36 ml) was added. The reaction mixture was stirred vigorouslyat rt
for 3 days, then solid sodium metabisulfite (w1.5 g) was added and
vigorous stirring was continued for a further hour. The reaction
mixture was diluted with DCM (10 ml). The solid was removed by
filtration through a pad of CeliteÔ and washed with DCM (20 ml). The
combinedfiltrate andwashingsweredriedand evaporatedtodryness
and the residue purified by flash chromatography on silica gel eluting
with3%MeOHinDCMtogive(ꢃ)-9asa paleyellowoil(300 mg, 86%);
nmax/cmꢀ1 (CHCl3): 3526, 3410, 2978, 1726, 1676,1115,1068; 1H NMR
dH (ppm) (CDCl3, 500 MHz): 4.61 (1H, br s, NCHCH2CO), 4.50 (1H, br s,
NCHC), 4.22 (2H, m, OCH2CH3), 4.06 (1H, dd, J¼18.5 and 5.5 Hz,
CHCH2CHOH and CHCH2exoCH2exoCH), 1.76–1.67 (1H, m, CHCH2endo
-
CH2endoCHCH2), 1.66–1.57 (1H, m, CHCH2endoCH2endoCHCH2), 1.55–
1.40(1H, m, CHCH2CHOH),1.16 (3H, t, J¼7.1 Hz,OCH2CH3);1H NMR dH
(ppm) (CDCl3, 500 MHz): 5.08–4.79 (2H, br m, C]CH2), 4.75–4.51
(1H, br m, NCHC), 4.50–4.40 (1H, br s, CHCH2CHOH), 4.39–4.28 (1H,
br s, NCHCH2CHOH), 4.15–4.02 (2H, m, OCH2CH3), 2.65–1.97 (4H, br
m, OH, CHCH2CHOH and CHCH2exoCH2exoCH), 1.76–1.52 (3H, br m,

A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
6315
CHCH2endoCH2endoCHandCHCH2CHOH),1.25–1.20(3H, m, OCH2CH3);
13C NMR dC (ppm) (CDCl3, 91 MHz): 154.5 (C, C]Ocarbamate),150.4 (C,
C]CH2), 106.3 (CH2, C]CH2), 66.5 (CH, CHCH2CHOH), 61.4 (CH2,
OCH2CH3), 60.3 (CH, NCHC), 53.9 (CH, NCHCH2CHOH), 43.1
(CH2, CHCH2CHOH), 29.4 (CH2, CHCH2CH2CHCH2), 28.1 (CH2,
CHCH2CH2CHCH2),15.1 (CH3, OCH2CH3); m/z (ESþ) 166 ([MþH (ꢀOH
and ꢀC2H5)]þ 100%); m/z (ESþ) found: [MþH]þ, 212.1287. C11H18NO3
requires: [MþH]þ, 212.1287.
2.17 (1H, dd, J¼14.6 and 1.9 Hz, CHCH2eqCO), 1.99–1.96 (2H, m,
CHCH2exoCH2exoCH), 1.55–1.49 (2H, m, CHCH2endoCH2endoCH), 1.30
(3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz):
209.3 (C, C]Oketone), 155.2 (C, C]Ocarbamate), 78.3 (C, CCH2NH), 61.8
(CH2, OCH2CH3), 61.4 (CH, NCHC), 53.7 (CH, NCHCH2CO), 52.8 (CH2,
CCH2NH), 46.2 (CH2, CHCH2CO), 37.3 (CH3, NHCH3), 28.2 (CH2,
CHCH2CH2CH), 23.5 (CH2, CHCH2CH2CH), 15.0 (CH3, OCH2CH3); m/z
(ESþ) 257 ([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ, 257.1494.
C12H21N2O4 requires: [MþH]þ, 257.1501.
The allylic alcohol (4.9 g, 0.02 mol) was dissolved in DCM
(60 ml) and cooled to 0 ꢁC. Then m-CPBA 75% wt (6.2 g, 0.03 mol)
was added portionwise and the mixture stirred at 0 ꢁC for 3 h.
A white solid formed during the reaction. The suspension was
diluted with DCM (20 ml); it was washed with a 10% solution of
sodium thiosulfate (40 ml), then with 1.0 M NaOH (40 ml) and
finally with brine (40 ml). The organic layer was dried over
MgSO4 and then concentrated under vacuum. The residue was
purified by flash chromatography on silica gel eluting with 50%
EtOAc in n-hexane and then with 5% MeOH in DCM to yield
(ꢃ)-10 as a colourless oil (3.7 g, 70%); nmax/cmꢀ1 (CHCl3): 3525,
1707, 1487, 1123; 1H NMR dH (ppm) (DMSO-d6, 500 MHz): 4.33
(1H, d, J¼9.0 Hz, OH), 4.26 (1H, br s, NCHCH2CHOH), 4.08–4.00
(3H, m, OCH2CH3 and CHCH2CHOH), 3.78 (1H, br s, NCHC), 2.82
(1H, d, J¼5.3 Hz, CCH2O), 2.66 (1H, d, J¼5.3 Hz, CCH2O), 1.92–1.86
(3H, m, CHCH2CHOH and CHCH2exoCH2exoCH), 1.76–1.69 (2H, m,
CHCH2endoCH2endoCH), 1.59 (1H, m, CHCH2CHOH), 1.17 (3H, br t,
OCH2CH3); 1H NMR dH (ppm) (CDCl3, 500 MHz): 4.44 (1H, br s,
NCHCH2CHOH), 4.17–4.10 (3H, m, OCH2CH3 and CHCH2CHOH),
4.09–3.90 (1H, m, NCHC), 3.04 (1H, d, J¼5.3 Hz, CCH2O), 2.76 (1H,
The ketone (0.4 g, 1.56 mmol) was dissolved in DCM (20 ml);
pyridine (1.6 ml, 0.02 mol) was added and the mixture cooled to
0 ꢁC. Triphosgene (0.51 g, 1.72 mmol) was subsequently added por-
tionwise and the final mixture was stirred at rt for 6 h. It was then
diluted with DCM (20 ml), washed with 0.1 M HCl (20 ml), H2O
(20 ml), brine (20 ml), dried over MgSO4 and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with EtOAc to yield (ꢃ)-5a as a pale yellow oil that solidified at rt
(210 mg, 48%); mp: 110.3–113.2 ꢁC; nmax/cmꢀ1 (CHCl3): 2981, 1784,
1716,1695,1441,1337,1122,1037, 934, 755; 1H NMR dH (ppm) (CDCl3,
500 MHz): 4.76–4.48 (2H, m, NCHCH2CO and NCHC), 4.33–4.14 (3H,
m, OCH2CH3 and CCH2N), 3.17–3.02 (2H, m, CHCH2axCO and CCH2N),
2.91 (3H, s, NCH3), 2.45 (1H, dd, J¼14.8 and 1.6 Hz, CHCH2eqCO), 2.18–
2.00 (2H, m, CHCH2exoCH2exoCH), 1.63–1.55 (1H, m, CHCH2endo
-
CH2endoCHCH2), 1.36–1.25 (4H, m, CHCH2endoCH2endoCHCH2 and
OCH2CH3); 1H NMR dH (ppm) (CDCl3, 360 MHz, 56 ꢁC): 4.75–4.55
(2H, m, NCHCH2CO and NCHC), 4.34–4.20 (2H, m, OCH2CH3), 4.17
(1H, d, J¼8.9 Hz, CCH2N), 3.16 (1H, br d, J¼14.8 Hz, CHCH2axCO), 3.04
(1H, d, J¼8.9 Hz, CCH2N), 2.92 (3H, s, NCH3), 2.46 (1H, dd, J¼14.8 and
1.9 Hz, CHCH2eqCO), 2.19–2.03 (2H, m, CHCH2exoCH2exoCH),1.68–1.60
br s, CCH2O), 2.16–2.12 (1H, m, J¼13.0, 6.1 and 2.9 Hz, CHCH2eq
-
CHOH), 2.08–1.96 (2H, m, CHCH2exoCH2exoCH), 1.84–1.76 (2H, m,
CHCH2endoCH2endoCH and CHCH2CHOH), 1.74–1.70 (2H, m,
CHCH2axCHOH and CHCH2endoCH2endoCH), 1.26 (3H, t, J¼7.1 Hz,
OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz): 154.3 (C,
C]Ocarbamate), 61.9 (CH, CHCH2CHOH), 61.6 (CH2, OCH2CH3), 61.2
(C, CCH2O), 58.8 (CH, NCHC), 52.7 (CH, NCHCH2CHOH), 48.8 (CH2,
CCH2O), 40.2 (CH2, CHCH2CHOH), 26.6 (CH2, CHCH2CH2CH), 26.4
(CH2, CHCH2CH2CH), 14.7 (CH3, OCH2CH3); m/z (ESþ) 250
([MþNa]þ, 100%); m/z (ESþ) found: [MþH]þ, 228.1247. C11H18NO4
requires: [MþH]þ, 228.1236.
(1H, m, CHCH2endoCH2endoCHCH2), 1.36–1.27 (4H, m, CHCH2endo
-
CH2endoCHCH2 and OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz):
201.0 (C, C]Oketone), 155.8 (C, C]Ocyclic carbamate), 154.6 (C, C]Ocar-
bamate), 82.3 (C, CCH2N), 62.3 (CH2, OCH2CH3), 60.2 (CH, NCHC), 54.0
(CH, NCHCH2CO), 47.9 (CH2, CCH2N), 46.8 (CH2, CHCH2CO), 31.5 (CH3,
NCH3), 27.9 (CH2, CHCH2CH2CHCH2), 23.8 (CH2, CHCH2CH2CHCH2),
15.0 (CH3, OCH2CH3); m/z (ESþ) 283 ([MþH]þ, 100%); m/z (ESþ)
found: [MþH]þ, 283.1292. C13H19N2O5 requires: [MþH]þ, 283.1294.
The racemic compound was then separated into single enan-
tiomers by SFC (Chiralpak AD-H column, 220 nm, 85:15 CO2/MeOH,
10 ml/min, 35 ꢁC, outlet P¼100 bar).
*
4.2.5. (1R ,2R
*
,5S
*
)-Ethyl 30-methyl-20,3-dioxo-8H-spiro[8-azabicy-
Compound 5a: enantiomer 1, tR¼3.74 min; 70 mg, colourless
20
clo[3. 2.1]octane-2, 50-[1, 3]oxazolidine]-8-carboxylate
(ꢃ)-5a. Compound (ꢃ)-5a, and resolution to give 5a and ent-5a.
Epoxide (ꢃ)-10 (500 mg, 2.2 mmol) was dissolved in EtOH (5 ml)
and then methylamine 33% wt in EtOH (0.27 ml, 2.2 mmol) was
added. The solution was heated to 70 ꢁC overnight in a sealed tube.
The reaction mixture was cooled to rt and concentrated under re-
duced pressure. The residue was purified by SCX cartridge eluting
first with MeOH and then with 2.0 M NH3 in MeOH to yield (ꢃ)-11a
as a colourless oil. It was dissolved in DMSO (20 ml) and TFA
(180 ml, 2.39 mmol) was added followed by IBX (1.82 g, 6.5 mmol).
The reaction mixture was stirred at rt overnight. Then 3 ml of water
was added and after 20 min stirring a white solid was filtered. The
filtrate was diluted with EtOAc (15 ml) and purified by SCX car-
tridge eluting first with MeOH and then with 2.0 M NH3 in MeOH.
The ammonia fractions were further purified by flash chromatog-
raphy on silica gel eluting with 5% MeOH in DCM to yield the ketone
as a colourless oil (0.4 g, 72% slightly impure).
solid, mp 119.1–120.0 ꢁC; [
a
]
D
ꢀ49.3 (c 1, CHCl3); >99% ee.
Compound ent-5a: enantiomer 2, tR¼4.31 min; 70 mg, colour-
20
less solid, mp 119.1–120.0 ꢁC; [
a
]
þ49.2 (c 1, CHCl3); >99% ee.
D
4.2.6. (1R ,2R ,5S
*
*
*
)-Ethyl 30-iso-propyl-20,3-dioxo-8H-spiro[8-azabi-
cyclo[3.2.1]octane-2,50-[1,3]oxazolidine]-8-carboxylate
(ꢃ)-5b. Compound (ꢃ)-5b, and resolution to give 5b and ent-5b.
Epoxide (ꢃ)-10 (0.4 g, 1.76 mmol) was dissolved in EtOH (7 ml) and
then iso-propylamine (0.12 ml, 1.41 mmol) was added. The solution
was heated to reflux temperature overnight. The reaction mixture
was cooled to rt and concentrated under reduced pressure. The
residue was purified by SCX cartridge eluting first with MeOH and
then with 2.0 M NH3 in MeOH to yield the amino alcohol (ꢃ)-11b as
a colourless oil. It was then dissolved in DMSO (10 ml) and TFA
(0.1 ml, 1.35 mmol) was added followed by IBX (1.03 g, 3.70 mmol).
The reaction mixture was stirred at rt overnight. Then 3 ml of water
was added and after 10 min stirring a white solid was filtered. The
solid was washed with further EtOAc and then volatiles were
concentrated under reduced pressure. The residue was purified by
SCX cartridge eluting first with MeOH and then with 2.0 M NH3 in
MeOH. The ammonia fractions were concentrated, diluted with
EtOAc (20 ml), washed with water (20 ml), dried over Na2SO4 and
concentrated. They were further purified by flash chromatography
on silica gel eluting with 5% MeOH in DCM to yield the ketone as
a colourless oil (210 mg, 60%); nmax/cmꢀ1 (CHCl3): 3316, 2966, 1697,
A small portion was further purified by chromatography on
silica gel eluting with 5% MeOH in DCM to get full characterisation
data while all the rest of the material was taken through the next
step: nmax/cmꢀ1 (CHCl3): 2981, 1697, 1430, 1332, 1108, 1034, 765; 1H
NMR dH (ppm) (CDCl3, 500 MHz): 4.57 (1H, br s, NCHCH2CO),
4.48–4.26 (1H, br s, NCHC), 4.25–4.18 (2H, m, OCH2CH3), 3.24 (1H, d,
J¼12.2 Hz, CCH2NH), 3.18 (1H, br d, J¼14.6, CHCH2axCO), 3.00 (2H,
br s, OH and NH), 2.49 (3H, s, NHCH3), 2.30–2.24 (1H, br s, CCH2NH),

6316
A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
1424, 1382, 1314, 1106, 1022, 765; 1H NMR dH (ppm) (CDCl3,
500 MHz): 4.56 (1H, br s, NCHCH2CO), 4.42–4.18 (3H, m, NCHC and
OCH2CH3), 3.24–3.17 (2H, m, CCH2NH and CHCH2axCO), 2.82–2.74
(1H, m, J¼6.3 Hz, NHCH(CH3)2), 2.21–2.14 (2H, m, CCH2NH and
CHCH2eqCO), 1.97–1.91 (2H, m, CHCH2exoCH2exoCH), 1.54–1.46 (2H,
m, CHCH2endoCH2endoCH), 1.28 (3H, t, J¼7.1 Hz, OCH2CH3), 1.09 (3H,
d, J¼6.3 Hz, NHCH(CH3)2), 1.05 (3H, d, J¼6.3 Hz, NHCH(CH3)2); 1H
NMR dH (ppm) (CDCl3, 360 MHz, 56 ꢁC): 4.55 (1H, br s, NCHCH2CO),
4.33 (1H, br s, NCHC), 4.27–3.80 (4H, m, OCH2CH3, NH and OH),
3.27–3.17 (2H, m, CCH2NH and CHCH2axCO), 2.82–2.74 (1H, m,
J¼6.3 Hz, NHCH(CH3)2), 2.34 (1H, d, J¼12.3 Hz, CCH2NH), 2.15 (1H,
dd, J¼11.6 and 1.8 Hz, CHCH2eqCO), 2.06–1.87 (2H, m, CHCH2ex-
oCH2exoCH), 1.58–1.44 (2H, m, CHCH2endoCH2endoCH), 1.28 (3H, t,
J¼7.1 Hz, OCH2CH3), 1.54–1.08 (6H, m, NHCH(CH3)2); 13C NMR dC
(ppm) (CDCl3, 91 MHz): 209.4 (C, C]Oketone), 154.7 (C, C]Ocarba-
mate), 77.8 (C, CCH2NH), 61.4 (CH2, OCH2CH3), 61.1 (CH, NCHC), 53.4
(CH, NCHCH2CO), 49.9 (CH, NHCH(CH3)2), 47.2 (CH2, CCH2NH), 45.9
(CH2, CHCH2CO), 27.8 (CH2, CHCH2CH2CH), 23.3 (CH2,
CHCH2CH2CH), 22.2 (CH3, NHCH(CH3)2), 22.0 (CH3, NHCH(CH3)2),
14.7 (CH3, OCH2CH3); m/z (ESþ) 285 ([MþH]þ, 100%); m/z (ESþ)
found: [MþH]þ, 285.1822. C14H25N2O4 requires: [MþH]þ, 285.1814.
The above ketone (0.21 g, 0.74 mmol) was dissolved in DCM
(10 ml); pyridine (0.75 ml, 7.4 mmol) was added and the mixture
cooled to 0 ꢁC. Triphosgene (241 mg, 0.81 mmol) was slowly added
portionwise and the final mixture was stirred at rt for 7 h. It was then
diluted with DCM (10 ml), washed with 0.1 M HCl (10 ml), H2O
(20 ml), brine (20 ml), dried over MgSO4 and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 3% MeOH in DCM and, after evaporation of the volatiles, was
triturated with Et2O to yield (ꢃ)-5b as a colourless solid (180 mg,
78%); mp: 148.5–150.0 ꢁC; nmax/cmꢀ1 (CHCl3): 2974, 2364, 1750,
1695, 1412, 1332, 1275, 1101, 1034, 930, 755; 1H NMR dH (ppm)
(DMSO-d6, 360 MHz): 4.70–4.41 (2H, br m, NCHCH2CO and NCHC),
4.19–4.01 (2H, m, OCH2CH3), 3.96–3.81 (2H, m, CCH2N and
NCH(CH3)2), 3.23 (1H, d, J¼9.3 Hz, CCH2N), 2.90 (1H, dd, J¼15.3 Hz
and 4.0, CHCH2axCO), 2.44 (1H, dd, J¼15.3 Hz and 1.8, CHCH2eqCO),
(ppm) (CDCl3, 500 MHz): 4.38–4.26 (1H, br s, NCHCH2CHOH),
4.24–3.98 (3H, m, NCHC and OCH2CH3), 3.88–3.75 (1H, m,
CHCH2CHaxOH), 2.78–2.68 (2H, m, CCH2NH), 1.99–1.84 (2H, m,
CHCH2exoCH2exoCH), 1.83–1.65 (2H, m, CHCH2CHOH), 1.65–1.49
(2H, m, CHCH2endoCH2endoCH), 1.31–1.16 (3H, m, OCH2CH3), 1.13–
0.95 (9H, m, NHC(CH3)3); 13C NMR dC (ppm) (CDCl3, 91 MHz):
155.6 (C, C]Ocarbamate), 73.8 (C, CCH2NH), 69.5 (CH,
CHCH2CHOH), 61.5 (CH2, OCH2CH3), 59.9 (CH, NCHC), 52.4 (CH,
NCHCH2CHOH), 50.8 (C, NHC(CH3)3), 49.1 (CH2, CCH2NH), 36.4
(CH2, CHCH2CHOH), 29.3 (CH3, NHC(CH3)3), 27.8 (CH2,
CHCH2CH2CH), 25.1 (CH2, CHCH2CH2CH), 15.1 (CH3, OCH2CH3);
m/z (ESþ) 301 ([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ,
301.2125. C15H29N2O4 requires: [MþH]þ, 301.2127.
Intermediate (ꢃ)-11c (0.69 g, 2.3 mmol) was dissolved in
DMSO (30 ml) and TFA (0.2 ml, 2.53 mmol) was added followed
by IBX (1.9 g, 6.9 mmol). The reaction mixture was stirred at rt
overnight. Then 5 ml of water was added and after 10 min
stirring a white solid was filtered. The solid was washed with
further EtOAc and then volatiles were concentrated under re-
duced pressure. The residue was purified by SCX cartridge
eluting first with MeOH and then with 2.0 M NH3 in MeOH to
yield the ketone as a yellow oil (0.6 g, 88%); nmax/cmꢀ1 (CHCl3):
3327, 2964, 1694, 1425, 1313, 1108, 1022, 748; 1H NMR dH
(ppm) (CDCl3, 500 MHz): 4.56 (1H, br s, NCHCH2CO), 4.37 (1H,
br s, NCHC), 4.24–4.20 (2H, m, OCH2CH3), 3.27–3.02 (2H, m,
CHCH2axCO and CCH2NH), 2.30–2.19 (1H, br d, CCH2NH), 2.16
(1H, dd, J¼20.0 and 3.6 Hz, CHCH2eqCO), 1.98–1.96 (2H, m,
CHCH2exoCH2exoCH), 1.51–1.49 (2H, m, CHCH2endoCH2endoCH), 1.29
(3H, m, J¼7.1 Hz, OCH2CH3), 1.1 (9H, s, NHC(CH3)3); 13C NMR dC
(ppm) (CDCl3, 91 MHz): 210.0 (C, C]Oketone), 155.1 (C,
C]Ocarbamate), 77.4 (C, CCH2NH from HMBC), 61.7 (CH2,
OCH2CH3 and CH, NCHC), 53.7 (CH, NCHCH2CO), 51.1 (C,
NHC(CH3)3), 46.3 (CH2, CHCH2CO), 43.7 (CH2, CCH2NH), 29.4
(CH3, NHC(CH3)3), 28.3 (CH2, CHCH2CH2CHCH2), 23.0 (CH2,
CHCH2CH2CHCH2), 15.1 (CH3, OCH2CH3); m/z (ESþ) 299
([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ, 299.1966.
C15H27N2O4 requires: [MþH]þ, 299.1971.
2.15–1.95 (2H, m, CHCH2exoCH2exoCH), 1.57–1.45 (1H, m, CHCH2endo
-
CH2endoCHCH2), 1.40–1.28 (1H, m, CHCH2endoCH2endoCHCH2), 1.22
(3H, t, J¼7.3 Hz, OCH2CH3), 1.16 (3H, d, J¼6.7 Hz, NCH(CH3)2), 1.13
(3H, d, J¼6.7 Hz, NCH(CH3)2); 13C NMR dC (ppm) (DMSO-d6,
91 MHz): 201.9 (C, C]Oketone), 154.1 (C, C]Ocarbamate and C]Ocyclic
carbamate), 82.1 (C, CCH2N), 61.2 (CH2, OCH2CH3), 59.5 (CH, NCHC),
53.6 (CH, NCHCH2CO), 45.8 (CH2, CHCH2CO), 45.0 (CH, NCH(CH3)2),
40.8 (CH2, CCH2N), 27.6 (CH2, CHCH2CH2CHCH2), 23.2 (CH2,
CHCH2CH2CHCH2), 19.8 (CH3, NCH(CH3)2), 19.7 (CH3, NCH(CH3)2),
14.8 (CH3, OCH2CH3); m/z (ESþ) 311 ([MþH]þ, 100%); m/z (ESþ)
found: [MþH]þ, 311.1600. C15H23N2O5 requires: [MþH]þ, 311.1607.
The racemic compound was then separated into single enan-
tiomers by SFC (Chiralpak AD-H column, 220 nm, 80:20 CO2/MeOH,
10 ml/min, 35 ꢁC, outlet P¼100 bar).
The ketone (0.6 g, 2.02 mmol) was dissolved in DCM (20 ml);
pyridine (2 ml, 0.02 mol) was added and the mixture cooled to
0 ꢁC. Triphosgene (660 mg, 2.2 mmol) was subsequently added
portionwise and the final mixture was stirred at rt for 2 h. It was
then diluted with DCM (10 ml), washed with 0.1 M HCl, H2O
(20 ml), brine (20 ml), dried over MgSO4 and concentrated. The
residue was purified by flash chromatography on silica gel elut-
ing with 50% EtOAc in n-hexane to yield (ꢃ)-5c as a colourless oil
(250 mg, 38%); nmax/cmꢀ1 (CHCl3): 2978, 1760, 1704, 1408, 750;
1H NMR dH (ppm) (CDCl3, 360 MHz, 56 ꢁC): 4.70–4.52 (2H, br m,
NCHCH2CO and NCHC), 4.26–4.17 (3H, m, OCH2CH3 and CCH2N),
3.12 (1H, br dd, J¼14.7 and 1.9 Hz, CHCH2axCO), 3.05 (1H, d,
J¼9.1 Hz, CCH2N), 2.41 (1H, dd, J¼14.7 and 1.9 Hz, CHCH2eqCO),
2.10–2.00 (2H, m, CHCH2exoCH2exoCH), 1.68–1.52 (1H, m,
CHCH2endoCH2endoCHCH2), 1.40 (9H, s, NC(CH3)3), 1.35–1.26 (4H,
m, CHCH2endoCH2endoCHCH2 and OCH2CH3); 13C NMR dC (ppm)
(CDCl3, 91 MHz): 201.4 (C, C]Oketone), 154.8 (C, C]Ocarbamate),
154.0 (C, C]Ocarbamate), 81.3 (C, CCH2N), 62.1 (CH2, OCH2CH3),
60.1 (CH, NCHC), 54.3 (C, NC(CH3)3), 54.0 (CH, NCHCH2CO), 46.7
Compound 5b: enantiomer 1, tR¼2.38 min; 50 mg, colourless
20
solid, mp 147.4–148.1 ꢁC; [
a]
þ125.5 (c 1, CHCl3); >99% ee.
D
Compound ent-5b: enantiomer 2, tR¼3.16 min; 50 mg, colour-
20
less solid, mp 147.4–148.1 ꢁC; [
a
]
ꢀ125.6 (c 1, CHCl3); >99% ee.
D
4.2.7. (1S ,2S ,5R
*
*
*
)-Ethyl 30-tert-butyl-20,3-dioxo-8H-spiro[8-azabi-
cyclo[3.2.1]octane-2,50-[1,3]oxazolidine]-8-carboxylate
(ꢃ)-5c. Compound (ꢃ)-5c, and resolution to give ent-5c. Epox-
ide (ꢃ)-10 (0.6 g, 2.64 mmol) was dissolved in EtOH (5 ml) and
then tert-butylamine (0.28 ml, 2.64 mmol) was added. The so-
lution was heated to 70 ꢁC overnight in a sealed tube. The re-
action mixture was cooled to rt and concentrated under reduced
pressure. The residue was purified by SCX cartridge eluting first
with MeOH and then with 2.0 M NH3 in MeOH to yield (ꢃ)-11c
(CH2,
CHCH2CH2CHCH2),
CCH2N),
44.4
27.8
(CH2,
(CH3,
CHCH2CO),
NC(CH3)3),
28.0
23.8
(CH2,
(CH2,
CHCH2CH2CHCH2), 14.9 (CH3, OCH2CH3); m/z (ESþ) 325 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 325.1764. C16H25N2O5 requires:
[MþH]þ, 325.1763.
The racemic compound was then separated into single enan-
tiomers by SFC (Chiralpak IA column, 220 nm, 87:13 CO2/iso-
propanol, 10 ml/min, 35 ꢁC, outlet P¼100 bar).
as
a
colourless oil (0.79 g, quantitative yield); nmax/cmꢀ1
Compound ent-5c: enantiomer 1, tR¼3.45 min; colourless oil,
20
(CHCl3): 3374, 2964, 1688, 1434, 1314, 1109, 764; 1H NMR dH
[a
]
ꢀ35.3 (c 1, CHCl3); >99% ee.
D

A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
6317
4.2.8. (1R
*
,2R
*
,5S
*
)-Ethyl 30-benzyl-20,3-dioxo-8H-spiro[8-azabicy-
CHCH2eqCO), 2.08–1.98 (2H, m, CHCH2exoCH2exoCH), 1.53 (1H, m,
CH2CHCH2endoCH2endoCH), 1.37–1.27 (3H, m, OCH2CH3), 1.26–1.20
(1H, m, CH2CHCH2endoCH2endoCH); 13C NMR dC (ppm) (91 MHz,
CDCl3): 200.8 (C, C]Oketone), 155.7 (C, C]O), 154.7 (C, C]O),
135.8 (C, CAr), 129.4 (CH, CHAr), 128.6 (CH, CHAr), 128.4 (CH, CHAr),
82.7 (C, CCH2N), 62.3 (CH2, OCH2CH3), 60.2 (CH, NCHC), 54.0
(CH, NCHCH2CO), 48.8 (CH2, NCH2Ar), 46.8 (CH2, CHCH2CO), 45.3
(CH2, NCH2C), 27.9 (CH2, CH2CHCH2CH2CH), 23.9 (CH2,
CH2CHCH2CH2CH), 15.0 (CH3, OCH2CH3); m/z (ESþ) 359 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 359.1619. C19H23N2O5 requires:
[MþH]þ, 359.1607.
clo[3. 2.1]octane-2, 50-[1, 3]oxazolidine]-8-carboxylate
(ꢃ)-5d. Compound (ꢃ)-5d, and resolution to give 5d and ent-5d.
Epoxide (ꢃ)-10 (0.5 g, 2.2 mmol) was dissolved in EtOH (5 ml) and
benzylamine (0.24 ml, 2.2 mmol) was added. The solution was
heated to reflux temperature overnight. The reaction mixture was
cooled to rt and concentrated under reduced pressure. The residue
was purified by SCX cartridge eluting first with MeOH and then
with 2.0 M NH3 in MeOH to yield (ꢃ)-11d as a colourless oil
(0.73 g, quantitative yield); nmax/cmꢀ1 (CHCl3): 3405, 1690, 1113;
1H NMR dH (ppm) (CDCl3, 500 MHz): 7.34–7.25 (5H, m, CHAr), 4.31
(1H, br s, NCHCH2CHOH), 4.19–4.09 (3H, m, OCH2CH3 and NCHC),
3.85–3.77 (3H, m, NCH2Ar and CHCH2CHOH), 3.19 (3H, br s, OH,
OH, NH), 2.82 (1H, d, J¼12.1 Hz, CCH2NH), 2.78 (1H, d, J¼12.1 Hz,
CCH2NH), 1.92–1.69 (4H, m, CHCH2exoCH2exoCH and CHCH2CHOH),
1.57–1.49 (2H, m, CHCH2endoCH2endoCH), 1.26 (3H, t, J¼7.1 Hz,
OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz): 155.6 (C, C]Ocar-
bamate), 139.6 (C, CAr), 129.0 (CH, CHAr), 128.5 (CH, CHAr), 127.8 (CH,
CHAr), 74.6 (C, CCH2NH), 69.4 (CH, CHCH2CHOH), 61.6 (CH2,
OCH2CH3), 59.9 (CH, NCHC), 55.5 (CH2, CCH2NH), 54.6 (CH2,
NHCH2Ar), 52.5 (CH, NCHCH2CHOH), 36.5 (CH2, CHCH2CHOH), 27.7
(CH2, CHCH2CH2CH), 25.0 (CH2, CHCH2CH2CH), 15.1 (CH3,
OCH2CH3); m/z (ESþ) 335 ([MþH]þ, 100%); m/z (ESþ) found:
[MþH]þ, 335.1974. C18H27N2O4 requires: [MþH]þ, 335.1971.
Amino alcohol (ꢃ)-11d (0.73 g, 2.2 mmol) was dissolved in
DMSO (20 ml) and TFA (0.18 ml, 2.3 mmol) was added followed by
IBX (1.85 g, 6.6 mmol). The reaction mixture was stirred at rt
overnight. Then 3 ml of water was added and after 10 min of
stirring a white solid was filtered. The filtrate was diluted with
EtOAc (30 ml), washed with water, dried over Na2SO4 and con-
centrated. It was then purified by SCX cartridge eluting first with
MeOH and then with 2.0 M NH3 in MeOH. The ammonia fractions
were further purified by flash chromatography on silica gel eluting
with 3% MeOH in DCM to yield the ketone as a yellow oil (0.44 g,
63%); nmax/cmꢀ1 (CHCl3): 3404, 2978, 1681, 1422, 1314, 1105, 747;
1H NMR dH (ppm) (CDCl3, 500 MHz): 7.34–7.25 (5H, m, CHAr), 4.56
(1H, br s, NCHCH2CO), 4.45–4.18 (3H, m, OCH2CH3 and NCHC), 3.84
(1H, d, J¼13.4 Hz, NCH2Ar), 3.80 (1H, d, J¼13.4 Hz, NCH2Ar), 3.25
(1H, d, J¼12.2 Hz, CCH2N), 3.17 (1H, br d, CHCH2axCO), 2.28 (1H, d,
J¼12.2 Hz, CCH2NH), 2.16 (1H, dd, J¼14.6 and 1.7 Hz, CHCH2eqCO),
1.97–1.89 (2H, m, CHCH2exoCH2exoCH), 1.52–1.42 (2H, m,
CHCH2endoCH2endoCH), 1.30 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR dC
(ppm) (CDCl3, 91 MHz): 209.5 (C, C]Oketone), 155.2 (C, C]Ocarba-
mate), 140.0 (C, CAr), 128.9 (CH, CHAr), 128.4 (CH, CHAr), 127.6 (CH,
CHAr), 77.7 (C, CCH2NH), 61.8 (CH2, OCH2CH3), 61.4 (CH, NCHC),
54.6 (CH2, NCH2Ar), 53.7 (CH, NCHCH2CO), 50.3 (CH2, CCH2NH),
46.2 (CH2, CHCH2CO), 28.3 (CH2, CHCH2CH2CHCH2), 23.4 (CH2,
CHCH2CH2CHCH2), 15.1 (CH3, OCH2CH3); m/z (ESþ) 333 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 333.1820. C18H25N2O4 requires:
[MþH]þ, 333.1814.
The racemic compound was then separated into single enan-
tiomers by SFC (Chiralpak AS-H column, 220 nm, 85:15 CO2/MeOH,
10 ml/min, 40 ꢁC, outlet P¼100 bar).
Compound ent-11d: enantiomer 1; tR¼3.60 min; colourless
20
solid, 80 mg, mp 82.5–88.3 ꢁC; [
a]
ꢀ5.0 (c 1, CHCl3); >99% ee.
D
Compound 11d: enantiomer 2, tR¼4.19 min, colourless solid,
20
80 mg, mp 88.5–90.7 ꢁC; [
a
]
þ4.6 (c 1, CHCl3); >99% ee.
D
4.2.9. (1R,2R,5S)-(ꢀ)-Ethyl 20,3-dioxo-30-[(1S)-1-phenylethyl]-8H-
spiro[8-azabicyclo[3.2.1]octane-2,50-[1,3]oxazolidine]-8-carboxylate
5e and (1S,2S,5R)-(ꢀ)-ethyl 20,3-dioxo-30-[(1S)-1-phenylethyl]-8H-
spiro[8-azabicyclo[3.2.1]octane-2,50-[1,3]oxazolidine]-8-carboxylate
5f. Epoxide (ꢃ)-10 (0.5 g, 2.2 mmol) was dissolved in EtOH (5 ml)
and then (S)-(ꢀ)-
a-methyl benzylamine (0.24 ml, 2.2 mmol) was
added. The solution was heated to 70 ꢁC overnight in a sealed tube.
The reaction mixture was cooled to rt and concentrated under
reduced pressure. The residue was purified by SCX cartridge eluting
first with MeOH and then with 2.0 M NH3 in MeOH to yield
a mixture of 11e and 11f as a colourless oil. The crude reaction was
used immediately in the following step. It was dissolved in DMSO
(20 ml) and TFA (0.18 ml, 2.3 mmol) was added followed by IBX
(1.85 g, 6.6 mmol). The reaction mixture was stirred at rt overnight.
Then 5 ml of water was added; after 10 min of stirring a white solid
was filtered. The filtrate was diluted with EtOAc (30 ml), washed
with water, dried over MgSO4 and concentrated. The residue was
purified by SCX cartridge eluting first with MeOH and then with
2.0 M NH3 in MeOH. The ammonia fractions were further purified
by flash chromatography on silica gel eluting with 5% MeOH in DCM
to yield the ketone (0.4 g, 53%) as a yellow oil and as a 0.8:1 mixture
of diastereoisomers A/B; nmax/cmꢀ1 (CHCl3): 3328, 2977,1699,1432,
1186, 1112, 762; 1H NMR dH (ppm) (CDCl3, 500 MHz): 7.36–2.24
(10H, m, CHAr AþB), 5.54 (2H, br s, NCHCH2CO AþB), 4.38–4.10 (6H,
m, NCHC and OCH2CH3 AþB), 3.88–3.77 (1H, q, J¼6.6 Hz, NCHCH3
B), 3.75–3.64 (1H, q, J¼6.6 Hz, NCHCH3 A), 3.25–3.07 (3H, m,
CHCH2CO AþB and CCH2NH B), 3.02 (1H, d, J¼12.2 Hz, CCH2NH A),
2.25–2.02 (4H, m, CHCH2CO AþB and CCH2NH AþB), 2.00–1.77
(4H, m, CHCH2exoCH2exoCH AþB), 1.52–1.41 (2H, m, CHCH2endo
-
CH2endoCHCH2 AþB), 1.40–1.19 (14H, m, NCHCH3 AþB, OCH2CH3
AþB and CHCH2endoCH2endoCHCH2 AþB); 13C NMR dC (ppm) (CDCl3,
91 MHz): 209.5 (C, C]Oketone AþB), 155.3 (C, C]Ocarbamate AþB),
145.4 (C, CAr A/B), 145.0 (C, CAr A/B), 129.1 (CH, CHAr A/B), 129.0 (CH,
CHAr A/B), 127.6 (CH, CHAr A/B), 127.5 (CH, CHAr A/B), 127.2 (CH, CHAr
A/B), 126.5 (CH, CHAr A/B), 78.5 (C, CCH2NH AþB), 61.8
(CH2, OCH2CH3 AþB), 61.2 (CH, NCHC AþB), 59.5 (CH, NCHCH3 A),
58.6 (CH, NCHCH3 B), 53.8 (CH, NCHCH2CO A/B), 53.6 (CH,
NCHCH2CO A/B), 49.3 (CH2, CCH2NH A), 48.4 (CH2, CCH2NH B), 46.2
(CH2, CHCH2CO AþB), 28.2 (CH2, CHCH2CH2CHCH2 AþB), 24.9 (CH3,
NCHCH3 A/B), 24.7 (CH3, NCHCH3 A/B), 23.4 (CH2, CHCH2CH2CHCH2
AþB), 15.1 (CH3, OCH2CH3 A/B), 15.0 (CH3, OCH2CH3 A/B); m/z (ESþ)
347 ([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ, 347.1976.
C19H27N2O4 requires: [MþH]þ, 347.1971.
The ketone (0.44 g, 1.35 mmol) was dissolved in DCM (20 ml);
pyridine (1.3 ml, 0.01 mol) was added and the mixture cooled to
0 ꢁC. Triphosgene (432 mg, 1.46 mmol) was subsequently added
portionwise and the final mixture was stirred at rt for 7 h. It was
then diluted with DCM (10 ml), washed with 0.1 M HCl (10 ml),
H2O (20 ml), brine (20 ml), dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on silica gel
eluting with 50% EtOAc in n-hexane to yield 330 mg (70%) of
(ꢃ)-11d as a pale yellow solid; mp: 123.0–123.9 ꢁC; nmax/cmꢀ1
(CHCl3): 2968, 1760, 1698, 1418, 1332, 1106; 1H NMR dH (ppm)
(CDCl3, 500 MHz): 7.40–7.26 (5H, m, CHAr), 4.65 (1H, br s,
NCHCH2CO), 4.51–4.47 (2H, m, NCH2Ar and NCHC), 4.39 (1H, d,
J¼15.0 Hz, NCH2Ar), 4.30–4.21 (2H, m, OCH2CH3), 4.03 (1H, d,
J¼8.8 Hz, CCH2N), 3.21–3.07 (1H, br d, J¼14.8 Hz, CHCH2axCO),
2.86 (1H, br d, J¼8.8 Hz, CCH2N), 2.43 (1H, d, J¼14.8 Hz,
The mixture of ketone diastereomers (0.4 g, 1.16 mmol) was
dissolved in DCM (20 ml); pyridine (1.2 ml, 0.016 mol) was added
and the mixture cooled to 0 ꢁC. Triphosgene (0.38 g,1.27 mmol) was

6318
A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
subsequently added portionwise and the final mixture was stirred
at rt for 4 h. It was then diluted with DCM (10 ml), washed with
0.1 M HCl (10 ml), H2O (20 ml), brine (20 ml), dried over MgSO4 and
concentrated. The residue was purified by flash chromatography on
silica gel eluting with 40% EtOAc in n-hexane to yield the two single
diastereoisomers 5e and 5f as pale yellow solids.
aniline (0.2 ml, 2.2 mmol) was added. The solution was heated to
70 ꢁC overnight in a sealed tube. The reaction mixture was then
cooled to rt and concentrated under reduced pressure. The residue
was purified by SCX cartridge eluting first with MeOH and then
with 2.0 M NH3 in MeOH to yield (ꢃ)-11g as a colourless oil (0.7 g,
quantitative yield); nmax/cmꢀ1 (CHCl3): 3370, 2978, 1670, 1603,
1438, 1314, 1115; 1H NMR dH (ppm) (CDCl3, 500 MHz): 7.19 (2H, t,
J¼7.9 Hz, CHAr-meta), 6.76 (1H, t, J¼7.3 Hz, CHAr-para), 6.71 (2H, d,
J¼7.9, CHAr-ortho), 4.45 (1H, br d, NCHC), 4.36 (1H, br s,
NCHCH2CHOH), 4.20–4.13 (2H, m, OCH2CH3), 3.73–3.70 (1H, dd,
J¼11.4 and 6.0 Hz, CHCH2CHaxOH), 3.49 (1H, d, J¼12.8 Hz, CCH2NH),
3.20 (1H, d, J¼12.8 Hz, CCH2NH), 1.97–1.89 (3H, m, CHCH2ex-
oCH2exoCH and CHCH2CHOH), 1.83–1.65 (2H, m, CHCH2CHOH and
CHCH2endoCH2endoCH), 1.65–1.49 (1H, m, CHCH2endoCH2endoCH), 1.27
(3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz):
155.5 (C, C]Ocarbamate), 148.7 (C, CAr), 129.7 (CH, CHAr-meta), 118.9
(CH, CHAr-para), 114.4 (CH, CHAr-ortho), 75.3 (C, CCH2NH), 67.5 (CH,
CHCH2CHOH), 61.5 (CH2, OCH2CH3), 58.8 (CH, NCHC), 52.7 (CH,
NCHCH2CHOH), 48.0 (CH2, CCH2NH), 37.2 (CH2, CHCH2CHOH), 27.3
(CH2, CHCH2CH2CHCH2), 24.7 (CH2, CHCH2CH2CHCH2), 14.7 (CH3,
OCH2CH3); m/z (ESþ) 321 ([MþH]þ, 100%); m/z (ESþ) found:
[MþH]þ, 321.1824. C17H25N2O4 requires: [MþH]þ, 321.1814.
Less polar 5e, pale yellow solid (100 mg, 23% of the overall
20
yield); mp 91.8–92.4 ꢁC; [
a]
ꢀ120.0 (c 1, CHCl3); tR¼5.47 min;
D
nmax/cmꢀ1 (CHCl3): 2981, 1769, 1731, 1713, 1417,1334, 1220, 1113,
1022, 702; 1H NMR dH (ppm) (CDCl3, 500 MHz): 7.41–7.32 (5H, m,
CHAr), 5.22–5.17 (1H, q, J¼7.1 Hz, NCHCH3), 4.63 (1H, br s,
NCHCH2CO), 4.58–4.19 (3H, m, NCHC and OCH2CH3), 4.09 (1H, br d,
J¼8.5 Hz, CCH2N), 3.17–3.05 (1H, m, CHCH2axCO), 2.56 (1H, br d,
J¼8.5 Hz, CCH2N), 2.42 (1H, d, J¼14.9 Hz, CHCH2eqCO), 2.04–1.98
(2H, m, CHCH2exoCH2exoCH), 1.66–1.53 (4H, m, NCHCH3 and
CHCH2endoCH2endoCHCH2), 1.32–1.27 (3H, m, OCH2CH3), 1.16–1.14
(1H, m, CHCH2endoCH2endoCHCH2); 1H NMR dH (ppm) (CDCl3,
360 MHz, 55 ꢁC): 7.40–7.13 (5H, m, CHAr), 5.21–5.15 (1H, q, J¼7.1 Hz,
NCHCH3), 4.67 (1H, br s, NCHCH2CO), 4.46–4.15 (3H, m, NCHC and
OCH2CH3), 4.09 (1H, d, J¼9.0 Hz, CCH2N), 3.13 (1H, br d, J¼15.0 Hz,
CHCH2axCO), 2.56 (1H, d, J¼9.0 Hz, CCH2N), 2.39 (1H, d, J¼15.0 Hz,
CHCH2eqCO), 2.14–1.88 (2H, m, CHCH2exoCH2exoCH), 1.61–1.48 (4H,
m, NCHCH3 and CHCH2endoCH2endoCHCH2), 1.32–1.27 (3H, t,
COCl2 (0.21 ml, 2.42 mmol) in DCM (17 ml) was cooled to
ꢀ60 ꢁC; DMSO (0.34 ml, 4.84 mmol) in DCM (1 ml) was added at
ꢀ60 ꢁC and the mixture stirred for 10 min. Then intermediate
(ꢃ)-11g (0.7 g, 2.2 mmol) in DCM (2 ml) was added over 5 min at
ꢀ60 ꢁC. After 15 min stirring at this temperature, Et3N (1.5 ml,
0.011 mol) was added. The cooling bath was removed and slowly
warmed to rt. Then H2O (3 ml) was added and the mixture stirred at
rt for 10 min. The two phases were then separated; the organic
layer was dried over Na2SO4 and concentrated. Purification by flash
chromatography on silica gel eluting with 3% MeOH in DCM yielded
a yellow oil that was further purified by SCX cartridge eluting first
with MeOH and then with 2.0 M NH3 in MeOH. The ketone was
obtained as a pale yellow oil, (550 mg, 79%); nmax/cmꢀ1 (CHCl3):
3381, 2979, 1684, 1603, 1438, 1112, 748; 1H NMR dH (ppm) (CDCl3,
500 MHz): 7.20 (2H, t, J¼7.6 Hz, CHAr-meta), 6.78 (1H, t, J¼7.3 Hz,
CHAr-para), 6.73 (2H, d, J¼7.9, CHAr-ortho), 4.63–4.56 (2H, br m,
NCHCH2CO and NCHC), 4.26–4.20 (2H, m, OCH2CH3), 4.01 (1H, br s,
NH), 3.70 (1H, br s, OH), 3.58 (1H, d, J¼13.4 Hz, CCH2NH), 3.24–3.17
(2H, m, CCH2NH and CHCH2axCO), 2.25 (1H, dd, J¼14.7 and 2.0 Hz,
CHCH2eqCO), 2.04–2.01 (2H, m, CHCH2exoCH2exoCH), 1.63–1.59 (2H,
m, CHCH2endoCH2endoCH), 1.30 (3H, t, J¼7.1 Hz, OCH2CH3); 13C NMR
dC (ppm) (CDCl3, 91 MHz): 208.1 (C, C]Oketone), 155.8 (C, C]Ocar-
bamate), 148.8 (C, CAr), 129.7 (CH, CHAr), 119.0 (CH, CHAr), 114.5 (CH,
CHAr), 79.7 (C, CCH2NH), 62.2 (CH2, OCH2CH3), 60.5 (CH, NCHC),
54.2 (CH, NCHCH2CO), 46.3 and 46.2 (CH2, CCH2NH and CH2,
CHCH2CO), 28.4 (CH2, CHCH2CH2CH), 24.0 (CH2, CHCH2CH2CH), 15.1
(CH3, OCH2CH3); m/z (ESþ) 319 ([MþH]þ, 100%); m/z (ESþ) found:
[MþH]þ, 319.1650. C17H23N2O4 requires: [MþH]þ, 319.1658.
J¼7.1 Hz, OCH2CH3), 1.18–1.12 (1H, m, CHCH2endoCH2endoCHCH2); 13
C
NMR dC (ppm) (CDCl3, 91 MHz): 201.0 (C, C]Oketone), 155.0 (C,
C]O), 154.8 (C, C]O), 139.7 (C, CAr), 129.3 (CH, CHAr), 128.5 (CH,
CHAr), 127.3 (CH, CHAr), 82.8 (C, CCH2N), 62.2 (CH2, OCH2CH3), 60.1
(CH, NCHC), 54.0 (CH, NCHCH2CO), 52.0 (CH, NCHCH3), 46.7 (CH2,
CHCH2CO), 41.4 (CH2, CCH2N), 27.9 (CH2, CHCH2CH2CHC), 23.8 (CH2,
CHCH2CH2CHC), 16.5 (CH3, NCHCH3), 14.9 (CH3, OCH2CH3); m/z
(ESþ) 373 ([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ, 373.1772.
C20H25N2O5 requires: [MþH]þ, 373.1763. Structure and absolute
configuration confirmed by X-ray of a sample obtained by crystal-
lisation from ether.
More polar diastereoisomer 5f, pale yellow solid (135 mg, 31% of
20
the overall yield); mp 125.0–126.2 ꢁC; [
a
]
ꢀ67.0 (c 1, CHCl3);
D
tR¼5.62 min; nmax/cmꢀ1 (CHCl3): 2980, 1728, 1752, 1700, 1420,1110,
1022, 752, 701; 1H NMR dH (ppm) (CDCl3, 500 MHz): 7.41–7.28 (5H,
m, CHAr), 5.21–5.13 (1H, q, J¼7.1 Hz, NCHCH3), 4.77–4.44 (2H, m,
NCHCH2CO and NCHC), 4.35–4.14 (2H, m, OCH2CH3), 3.81 (1H, br d,
J¼9.1 Hz, CCH2N), 3.20–3.01 (1H, m, CHCH2eqCO), 3.00–2.85 (1H, m,
CCH2N), 2.39 (1H, d, J¼15.7 Hz, CHCH2axCO), 2.17–1.94 (2H, m,
CHCH2exoCH2exoCH), 1.67–1.49 (4H, m, NCHCH3 and CHCH2endo
-
CH2endoCHCH2), 1.39–1.15 (4H, m, OCH2CH3 and CHCH2endoCH2en-
doCHCH2); 1H NMR dH (ppm) (CDCl3, 360 MHz, 56 ꢁC): 7.38–7.27
(5H, m, CHAr), 5.17–5.11 (1H, q, J¼7.1 Hz, NCHCH3), 4.62–4.50 (2H,
m, NCHCH2CO and NCHC), 4.26–4.16 (2H, m, OCH2CH3), 3.81 (1H, d,
J¼8.9 Hz, CCH2N), 3.11 (1H, br d, J¼14.7 Hz, CHCH2axCO), 2.90 (1H, d,
J¼8.9 Hz, CCH2N), 2.36 (1H, d, J¼14.7 Hz, CHCH2eqCO), 2.10–1.96
(2H, m, CHCH2exoCH2exoCH), 1.61–1.52 (4H, m, NCHCH3 and
CHCH2endoCH2endoCHCH2), 1.34–1.19 (4H, m, OCH2CH3 and
CHCH2endoCH2endoCHCH2); 13C NMR dC (ppm) (CDCl3, 91 MHz):
200.8 (C, C]Oketone), 155.1 (C, C]O), 154.7 (C, C]O), 139.3 (C, CAr),
129.1 (CH, CHAr), 128.4 (CH, CHAr), 127.3 (CH, CHAr), 82.8 (C, CCH2N),
62.3 (CH2, OCH2CH3), 60.3 (CH, NCHC), 54.0 (CH, NCHCH2CO), 52.2
(CH, NCHCH3), 46.7 (CH2, CHCH2CO), 42.1 (CH2, CCH2N), 27.9 (CH2,
CHCH2CH2CHCH2), 23.9 (CH2, CHCH2CH2CHCH2), 17.3 (CH3,
NCHCH3), 15.0 (CH3, OCH2CH3); m/z (ESþ) 373 ([MþH]þ, 100%); m/z
(ESþ) found: [MþH]þ, 373.1766. C20H25N2O5 requires: [MþH]þ,
373.1763.
The amino alcohol (0.55 g, 1.73 mmol) was dissolved in DCM
(10 ml); pyridine (1.76 ml, 0.02 mol) was added and the mixture
cooled to 0 ꢁC. Triphosgene (0.56 g, 1.90 mmol) was subsequently
added portionwise and the final mixture was stirred at rt for 4 h. It
was then diluted with DCM (20 ml), washed with 0.1 M HCl (10 ml),
H2O (20 ml), brine (20 ml), dried over MgSO4 and concentrated. The
residue was purified by flash chromatography on silica gel eluting
with 50% EtOAc in n-hexane to yield (ꢃ)-5g as a colourless solid
(0.39 g, 66%); mp: 169.1–172.4 ꢁC; nmax/cmꢀ1 (CHCl3): 2981, 1759,
1729, 1699, 1403, 1316, 1111, 757; 1H NMR dH (ppm) (CDCl3,
500 MHz): 7.56 (2H, d, J¼8.1 Hz, CHAr-ortho), 7.39 (2H, t, J¼8.1 Hz,
CHAr-meta), 7.17 (1H, t, J¼7.4 Hz, CHAr-para), 4.90–4.60 (3H, m,
NCHCH2CO, NCHC and CCH2N), 4.31–4.20 (2H, m, OCH2CH3), 3.48
(1H, br d, J¼12.9 Hz, CCH2N), 3.24–3.20 (1H, m, CHCH2axCO), 2.51
4.2.10. (1R
*
,2R
*
,5S
)-Ethyl 20,3-dioxo-30-phenyl-8H-spiro[8-azabicy-
*
clo[3. 2.1]octane-2, 50-[1, 3]oxazolidine]-8-carboxylate
(ꢃ)-5g. Compound (ꢃ)-5g, and resolution to give 5g and ent-5g.
Epoxide (ꢃ)-10 (0.5 g, 2.2 mmol) was dissolved in EtOH (5 ml) and
(1H,
d,
J¼20.5 Hz,
CHCH2eqCO),
2.14–2.01
(2H,
m,

A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
6319
CHCH2exoCH2exoCH), 1.68–1.56 (1H, m, CHCH2endoCH2endoCHCH2),
1.45–1.33 (4H, m, CHCH2endoCH2endoCHCH2 and OCH2CH3); 13C NMR
dC (ppm) (CDCl3, 91 MHz): 200.4 (C, C]Oketone), 154.3 (C, C]Ocar-
bamate), 151.7 (C, C]Ocyclic carbamate), 137.7 (C, CAr), 129.2 (CH, CHAr-
meta), 124.6 (CH, CHAr-para), 118.3 (CH, CHAr-ortho), 81.6 (C, CCH2N),
62.0 (CH2, OCH2CH3), 60.0 (CH, NCHC), 53.8 (CH, NCHCH2CO), 46.4
(CH2, CHCH2CO), 46.0 (CH2, CCH2N), 27.6 (CH2, CHCH2CH2CHCH2),
25.1 (CH2, CHCH2CH2CHCH2), 14.6 (CH3, OCH2CH3); m/z (ESþ) 345
([MþH]þ, 100%); m/z (ESþ) found: [MþH]þ, 345.1442. C18H21N2O5
requires: [MþH]þ, 345.1450.
mixture was stirred at rt for 3 h and then was filtered through a pad
of CeliteÔ. The solvent was removed under reduced pressure and
the residue was purified by chromatography on silica gel eluting
with a gradient from 30 to 80% ethyl acetate in cyclohexane to yield
(ꢃ)-6 as a colourless solid (90 mg, 53%); mp: 111.5–112.5 ꢁC; nmax
/
cmꢀ1 (Nujol): 1795,1724,1694,1113,1016, 956, 932, 769; 1H NMR dH
(ppm) (CDCl3, 400 MHz): 4.74–4.40 (2H, m, NCHCH2CO and NCHC),
4.35–4.14 (2H, m, OCH2CH3), 3.23–2.98 (1H, m, CHCH2axCO), 2.92–
2.80 (1H, m, CCH2CH2), 2.78–2.59 (2H, m, CCH2CH2), 2.46 (1H, d,
J¼16.0 Hz, CHCH2eqCO), 2.23–1.99 (2H, m, CHCH2exoCH2exoCH),
1.86–1.71 (1H, m, CCH2CH2), 1.67–1.57 (1H, m, CHCH2endoCH2en-
doCHCH2), 1.54–1.42 (1H, m, CHCH2endoCH2endoCHCH2), 1.31 (3H, t,
J¼7.1 Hz, OCH2CH3); 13C NMR dC (ppm) (CDCl3, 100 MHz): 202.3 (C,
C]Oketone), 174.4 (C, C]Olactone), 154.2 (C, C]Ocarbamate), 88.8 (C,
CCH2CH2), 61.8 (CH2, OCH2CH3), 60.4 (CH, NCHC), 53.5 (CH,
NCHCH2CO), 46.4 (CH2, CHCH2CO), 28.5 (CH2, CCH2CH2), 27.6 (CH2,
CHCH2CH2CH), 23.6 and 23.4 (CH2, CCH2CH2 and CHCH2CH2CH),
14.6 (CH3, OCH2CH3); m/z (ESþ) 268 ([MþH]þ, 100%); m/z (ESþ)
found: [MþH]þ, 268.1172. C13H18NO5 requires: [MþH]þ, 268.1185.
Racemate resolved by semi-preparative chiral chromatography
(column: Chiralpak AD-H (25ꢂ2.0 cm); mobile phase: n-hexane/
ethanol 70:30 v/v; flow rate: 14.0 ml/min; DAD: 225 nm).
The racemic compound was resolved by SFC (Chiralpak AS-H
column, 220 nm, 85:15 CO2/MeOH, 10 ml/min, 35 ꢁC, outlet
P¼100 bar).
Compound ent-5g: enantiomer 1, tR¼3.32 min; colourless solid,
20
70 mg, mp 162.2–163.4 ꢁC; [
a
]
ꢀ53.5 (c 1, CHCl3); 99% ee.
D
Compound 5g: enantiomer 2, tR¼4.23 min; colourless solid,
20
70 mg, mp 163.8–164.2 ꢁC [
a
]
þ46.5 (c 1, CHCl3); 98% ee.
D
4.2.11. (1R
*
,2R
*
,3S
*
,5S
*
)-Ethyl 3-hydroxy-50-oxodihydro-30H,8-azas-
(ꢃ)-12. Epoxy
piro[bicyclo[3.2.1]octane-2,20-furan]-8-carboxylate
alcohol (ꢃ)-10 (0.8 g, 3.5 mmol) was dissolved in DCM (30 ml)
and cooled to ꢀ78 ꢁC. Et3N (2.45 ml, 18 mmol) was added fol-
lowed by TMSOTf (1.6 ml, 8.8 mmol). After stirring at this
temperature for 30 min, the reaction mixture was slowly
warmed to ꢀ30 ꢁC and stirred at this temperature for further
30 min. It was then quenched with a saturated solution of
NH4Cl (10 ml). The organic layer was washed with brine, dried
and concentrated under vacuum. The crude trimethylsilyl ether,
as a colourless oil, was used in the following step without
further purification.
Compound ent-6: enantiomer 1: tR: 18.75 min; 32 mg, colour-
20
less solid, mp145.9–146.7 ꢁC; [
a
]
þ25.0 (c 0.16, CH3OH); 100% ee.
D
Compound 6: enantiomer 2: tR: 22.15 min; 32 mg, colourless
20
solid, mp: 145.9–146.7 ꢁC; [
a
]
ꢀ33.3 (c 0.18, CH3OH); 100% ee.
D
4.2.13. (1R ,2R ,5S
*
*
*
)-Ethyl 30-methyl-3-oxo-8H-spiro[8-azabicy-
clo[3.2.1]octane-2,50-[1,2,3]oxathiazolidine]-8-carboxylate 20,2’-
dioxide (ꢃ)-14. Compound (ꢃ)-14, and resolution to give 14 and
ent-14. Amino alcohol (ꢃ)-13 was prepared from (ꢃ)-10, via
(ꢃ)-11a, as described in the procedure for the synthesis of 5a.
Amino alcohol (ꢃ)-13 (0.7 g, 2.7 mmol) was dissolved in DCM
(20 ml) and cooled to 0 ꢁC. Pyridine (2.21 ml, 27 mmol) was added
followed by thionyl chloride (0.22 ml, 3 mmol) in DCM (1 ml). The
reaction mixture was stirred at 0 ꢁC for 30 min and then slowly
warmed to rt. It was stirred at rt for further 48 h and then quenched
by addition of a saturated solution of NH4Cl. The organic phase was
diluted with DCM (20 ml), washed with a 0.1 M HCl solution
(20 ml), brine (20 ml), dried over MgSO4 and concentrated. Purifi-
cation by chromatography on silica gel eluting with a gradient from
50% to 100% EtOAc in cyclohexane delivered the diastereomeric
mixture of cyclic sulfamidites as a colourless solid (400 mg, 48%);
m/z (ESþ) 303 ([MþH]þ 100%); m/z (ESþ) found: [MþH]þ, 303.1003.
C12H19N2O5S requires: [MþH]þ, 303.1015. This intermediate
(400 mg, 1.32 mmol) was dissolved in CH3CN (10 ml) and cooled to
0 ꢁC. RuCl3xH2O (catalytic amount) was added followed by NaIO4
(420 mg, 1.98 mmol) dissolved in H2O (2 ml). The mixture was
stirred at rt for 30 min and then partitioned between DCM (20 ml)
and H2O (20 ml). The organic layer was washed with a saturated
solution of NaHCO3 (20 ml), brine (20 ml), dried over MgSO4 and
concentrated. Purification by chromatography on silica gel eluting
with a gradient from 50% to 100% ethyl acetate in cyclohexane
delivered a solid that was triturated with diethyl ether to afford
(ꢃ)-14 as a colourless solid (230 mg, 55%); mp: 127.1–128.2 ꢁC;
nmax/cmꢀ1 (Nujol): 1731, 1689, 1348, 1214, 1178; 1H NMR dH (ppm)
(CDCl3, 360 MHz): 4.79–4.77 (1H, m, NCHC), 4.68–4.66 (1H, m,
NCHCH2CO), 4.27–4.19 (2H, m, OCH2CH3), 4.10 (1H, d, J¼10.4 Hz,
CCH2N), 3.18–3.09 (2H, m, CCH2N and CHCH2axCO), 2.82 (3H, s,
NCH3), 2.50 (1H, dd, J¼14.7, 2.1 Hz, CHCH2eqCO), 2.21–1.98 (2H, m,
CHCH2exoCH2exoCH), 1.62–1.54 (1H, m, CHCH2endoCH2endoCHCH2),
1.35–1.27 (4H, m, OCH2CH3 and CHCH2endoCH2endoCHCH2); 13C NMR
dC (ppm) (CDCl3, 91 MHz): 199.2 (C, C]Oketone), 154.2 (C, C]Ocar-
bamate), 86.9 (C, CCH2N), 62.4 (CH2, OCH2CH3), 60.2 (CH, NCHC), 54.1
(CH, NCHCH2CO), 50.7 (CH2, CCH2N), 46.9 (CH2, CHCH2CO), 35.6
NaH (60% dispersed in mineral oil, 87 mg, 2.2 mmol) was sus-
pended in THF (10 ml) and cooled to 0 ꢁC. Diethyl malonate
(0.33 ml, 2.2 mmol) in THF (1 ml) was added dropwise and the
reaction mixture was stirred at 0 ꢁC for 30 min. The silyl ether
(540 mg, 1.8 mmol) in THF (2 ml) was added dropwise and then the
mixture heated to reflux for 3 h. The volatiles were evaporated
under reduced pressure to give a mixture of diastereomers. This
mixture (250 mg) was dissolved in DMSO (5 ml) and water added
(0.5 ml) followed by NaCl (56 mg). The mixture was heated to
160 ꢁC for 7 h. After this period of time the mixture was cooled to rt
and partitioned between DCM and water. The organic layer was
washed with brine, dried and concentrated. Purification by chro-
matography on silica gel eluting with a gradient from 50% to 100%
ethyl acetate in cyclohexane afforded (ꢃ)-12 as a colourless oil
(170 mg, 35% over two steps); nmax/cmꢀ1 (film): 3440, 1772, 1684,
1437, 1336, 1385, 1217, 1111, 964, 772; 1H NMR dH (ppm) (CDCl3,
400 MHz): 4.46–4.32 (1H, br s, NCHCH2CHOH), 4.27–4.02 (3H, m,
NCHC and OCH2CH3), 3.73 (1H, dd, J¼11.24 and 6.06 Hz, CHOH),
2.79–2.53 (2H, m, CCH2CH2), 2.51–2.09 (2H, m, CCH2CH2 and
CHOH), 2.08–1.75 (5H, m, CHCH2exoCH2exoCH, CCH2CH2, and
CHCH2CHOH), 1.70–1.53 (2H, m, CHCH2endoCH2endoCH), 1.32–1.16
(3H, m, OCH2CH3); 13C NMR dC (ppm) (CDCl3, 91 MHz): 176.4 (C,
C]Olactone), 154.2 (C, C]Ocarbamate), 87.9 (C, CCH2CH2), 68.1 (CH,
CHCH2CHOH), 61.3 (CH2, OCH2CH3), 59.3 (CH, NCHC), 52.3 (CH,
NCHCH2CHOH), 37.6 (CH2, CHCH2CHOH), 28.8 (CH2, CCH2CH2), 27.1
(CH2, CHCH2CH2CH), 26.5 (CH2, CCH2CH2), 24.9 (CH2,
CHCH2CH2CH), 14.6 (CH3, OCH2CH3); m/z (ESþ) 270 ([MþH]þ 100%),
m/z (ESþ) found: [MþH]þ, 270.1337. C13H20NO5 requires: [MþH]þ,
270.1341.
4.2.12. (1R
*
,2R
*
,5S
)-Ethyl 3,50-dioxodihydro-30H,8H-spiro[8-azabi-
*
cyclo[3.2.1]octane-2,20-furan]-8-carboxylate
(ꢃ)-6, and resolution to give 6 and ent-6. Lactone (ꢃ)-12 (170 mg,
0.63 mmol) was dissolved in DCM (5 ml). NMO (111 mg,
0.95 mmol) was added followed by TPAP (10 mg). The reaction
(ꢃ)-6. Compound

6320
A. Armstrong et al. / Tetrahedron 66 (2010) 6309–6320
(CH3, NCH3), 27.7 (CH2, CHCH2CH2CHCH2), 23.6 (CH2,
CHCH2CH2CHCH2), 14.8 (CH3, OCH2CH3); m/z (ESþ) 319 ([MþH]þ,
100%); m/z (ESþ) found: [MþH]þ, 319.0970. C12H19N2O6S requires:
[MþH]þ, 319.0964.
products were assigned by comparison with literature retention
times or optical rotations, as described previously.7a
Acknowledgements
The racemic mixture (110 mg) was resolved by semi-preparative
chiral chromatography, column: Chiralpak AD-H (25ꢂ0.46 cm);
mobile phase: n-hexane/iso-propanol 85:15 v/v; flow rate: 14.0 ml/
min; DAD: 225 nm.
We are extremely grateful to Merck Sharp and Dohme (Dr. Luis
Castro) and GlaxoSmithKline for their support of this work. We
particularly thank Dr. Ian Churcher for many helpful discussions.
Compound ent-14: enantiomer 1: tR¼15.23 min; 40 mg, colour-
20
less solid, mp: 108.3–110.1 ꢁC; [
a
]
þ40.0 (c 0.1, CH3OH); 100% ee.
D
Compound 14: enantiomer 2: tR¼18.53 min; 40 mg, colourless
Supplementary data
20
solid, mp: 113.5–114.8 ꢁC; [
a]
ꢀ40.0 (c 0.1, CH3OH);100% ee.
D
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.004. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.3. General procedure for alkene epoxidation13
To a solution of ketone and alkene (0.1 mmol) in acetonitrile
(1.5 ml) was added aqueous Na2EDTA solution (1.0 ml of a 0.4 mM
aqueous solution). OxoneÒ (307 mg, 1.0 mmol KHSO5) and
NaHCO3 (130 mg, 1.55 mmol) were added in portions simulta-
neously over 30 min. The reaction mixture was stirred vigorously
until completion (by TLC analysis) or for 24 h, then diluted with
water (10 ml).
Two different work-up procedures (A and B) were employed.
Work-up B is highly efficient when epoxidation reactions are run
in parallel. No difference in the enantioselectivity has been ob-
served, for example, where both work-up A and work-up B has
been used.
Work-up A (used for Table 1, entries 1, 2, 6–8; Table 2, entries 2,
4–6; Table 3, entries 1–5; Table 4, entries 2, 4–6; Table 5, entries 4,
5, 8; Table 6, entries 2, 4–7): the reaction mixture was extracted
into diethyl ether (3ꢂ25 ml). The combined organic extracts were
dried (Na2SO4), filtered and evaporated to dryness under reduced
pressure. Flash column chromatography (gradient from 5 to 10%
diethyl ether in cyclohexane) on silica or purification by pre-
parative thin layer chromatography afforded the relevant
epoxide.
Work-up B (used for Table 1, entries 3, 4, 5, 9–14; Table 2, entries
1, 3, 7; Table 3, entries 6, 7; Table 4, entries 1, 3, 7, 8; Table 5, entries
1–3, 6, 7, 9; Table 6, entries 1, 3, 6): the reaction mixture was
extracted into DCM (25 ml). The organic phase was separated using
a phase separation cartridge and evaporated to dryness under
reduced pressure or under a steam of nitrogen. Flash column
chromatography (gradient from 5 to 10% diethyl ether in cyclo-
hexane) on silica or purification by preparative thin layer chro-
matography afforded the relevant epoxide.
References and notes
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1EZ, UK (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk). Details
are also provided as Supplementary data to this paper.
4.4. Determination of epoxide enantiomeric purity
Epoxides gave 1H NMR data in accord with literature values.7a
Epoxide enantiomeric excesses were determined by HPLC on chi-
ral stationary phases and the absolute configuration of the major
12. Ley, S. V.; Norman, J.; Griffith, W. P. Synthesis 1994, 639–666.
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