Highly enantioselective synthesis of chiral imides and derived products via chiral base desymmetrisation

Article abstract of DOI:10.1016/S0040-4020(02)00367-8

The enantioselective deprotonation of several ring-fused imides with a chiral base, followed by electrophilic quenching, gives a range of chiral products in good yield and in ≥91% ee. The absolute stereochemistry of two of the products was determined by X-ray crystallography. A number of the imide products were subjected to further, highly regioselective, transformations, including enolate substitution, reduction and thionation.

Full text of DOI:10.1016/S0040-4020(02)00367-8

TETRAHEDRON
Pergamon
Tetrahedron 58 >2002) 4603±4615
Highly enantioselective synthesis of chiral imides and derived
products via chiral base desymmetrisation
David J. Adams, Alexander J. Blake, Paul A. Cooke, Christopher D. Gill and Nigel S. Simpkinsp
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 10 January 2002; accepted 14 February 2002
AbstractÐThe enantioselective deprotonation of several ring-fused imides with a chiral base, followed by electrophilic quenching, gives a
range of chiral products in good yield and in $91% ee. The absolute stereochemistry of two of the products was determined by X-ray
crystallography. A number of the imide products were subjected to further, highly regioselective, transformations, including enolate
substitution, reduction and thionation. q 2002 Published by Elsevier Science Ltd.
1. Introduction
In an effort to further extend this type of asymmetric
deprotonation approach to include more complex sub-
strates, especially those possessing multiple carbonyl
functions, we recently described reactions involving a
number of imide systems.9 This chemistry enables highly
enantioselective access to a range of imides and derived
products such as lactams and lactones, and is described in
full below.
The asymmetric desymmetrisation of various types of
prochiral substrate using chiral lithium amide bases is now
becoming an accepted method for the synthesis of certain
chiral products.1 Of particular importance in this regard
are the enolisation reactions of cyclic ketones,2 and the
rearrangement of epoxides to allylic alcohols,3 both of
which have been carried out with various ring sizes and
substitution patterns in the substrate.
2. Results and discussion
Other types of desymmetrisation are less well known, and
we have expended a substantial effort in establishing chiral
base reactions of a range of alternative types of substrate,
e.g. Fig. 1.
2.1. Chiral base reactions of ring fused imides
Preliminary studies focussed on the possible desymmetrisa-
tion of cyclopropyl imide systems of general structure 1.
Initial studies were not promising, attempted enolisation
reactions using several lithium amide bases, followed by
quenching with electrophiles, such as MeI, resulting only
in destruction of the starting material. We reasoned that
metallation was probably taking place but that the inter-
mediate anion was undergoing undesired side reactions
before addition of the electrophile. We therefore turned to
the use of in situ quenching conditions, involving addition
of a solution of chiral lithium amide base 2 to a mixture of
imide 1 and Me3SiCl at low temperature, Scheme 1.
These include sulfoxides,4 phosphine oxides,5 chromium
arene complexes,6 piperidine diesters7 and, most recently,
some bridged ketones that undergo enantioselective bridge-
head substitution.8
Figure 1.
Keywords: asymmetric synthesis; chiral lithium amide; imides.
Corresponding author. Fax: 144-115-9513564;
e-mail: nigel.simpkins@ nottingham.ac.uk
p
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020>02)00367-8

4604
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
This method gave excellent results, the desired mono-silylated
imides 3a±c being isolated in good yield and with very good
levels of enantioselectivity. In some cases small quantities of
doubly silylated by-products were also observed. The synth-
esis of 3a was repeated a number of times, on various scales,
and reproducibly gave ee values in the range indicated. We
found that this reaction could be applied to other simple imide
systems, giving silylated products 4±6 with excellent selec-
tivity >the chemical yields have not been optimised).10
conducted as an aside to the main programme of work, and to
date we have no proof of the absolute stereochemistry shown
>drawn as analogous to the imide results).
As indicated above, it proved impossible to carry out enolate
substitutions of the cyclopropylimide systems 1, except
using an in situ quench. The reactivity of the chiral enolate
from the norbornene system proved more controlled, and we
were able to carry out direct asymmetric substitution with
reactive electrophiles like MeI, allyl bromide and PhSSPh to
give products 12±14.
In each case clean C-silylation was observed with no sign of
the corresponding silylketene hemiaminals and very little, if
any, recovered starting material that might have come from
their hydrolysis.11 The chiral C-silylated compounds proved
to be stable and crystalline and, in the cases of 3a and 6, we
were able to secure X-ray crystal structures following
recrystallisation, Figs. 2 and 3.
The poor yields in these cases are presumably due to the
rather hindered nature of the system, the bulky enolate being
rather reluctant to form a quaternary centre.12 Pleasingly,
the reaction with PhSSPh was shown to occur with very
high enantioselectivity, indicating that we should, in prin-
ciple, be able to avoid recourse to the in situ quench pro-
cedure without loss of chiral base selectivity.
The structure determinations allowed us to assign the abso-
lute con®gurations as shown. These two structures indicate
an analogous mode of asymmetric desymmetrisation of the
starting imides, and we expect that the other products have
undergone the silylation in the same stereochemical sense,
although that has not been rigorously proven.
2.2. Manipulation of chiral ring fused imides
Since ef®cient direct substitution of the cyclic imides
appeared limited to silylation, we were keen to expand the
scope of this chemistry by exploring the synthetic repertoire
of the silylimide products. It was also important to discover
if the initial silylation would enable regiocontrolled imide
functional group conversions.
The asymmetric substitution of imides such as 1 was inter-
esting as a possible entry to cyclopropane natural products,
and at this point we carried out similar reactions with two
related systems 7 and 9, Scheme 2.
We ®rst examined further enolate chemistry using enantio-
merically enriched 3a and determined that substitution at
the remaining activated position was possible, Table 1.
Both the cis-diester 7 and the 1,3-diketone 9 gave good to
excellent levels of enantioselection under the standard chiral
base conditions. In the latter case, HPLC assay of the enan-
tiomeric purity of 10 proved dif®cult and so we ®rst converted
the silylated product into triketone 11. These reactions were
In all of these reactions the presence of LiCl seems to
enhance the yields, although we are uncertain of the
Figure 3. Structure of compound 6. The H atom bonded to C>9) is wholly
obscured by it.
Figure 2. Structure of compound 3a.

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4605
Scheme 2.
mechanism of this effect.13 It was interesting to note the
effectiveness of the enolate substitution chemistry using
the silylimide 3a, compared to the dif®culties experienced
with the parent compound 1. Presumably the silicon substi-
tuent has a protective effect that enables substitution to
compete with destructive side reactions involving self-
condensation. Although stereochemical scrambling by
some mode of silyl transfer >inter- or intramolecular)
appeared unlikely, we checked the ee of compound 15
formed this way, and found the value to be the same as
that of the starting imide 3a. The same is assumed to hold
for the other products.
to effect ¯uoride-mediated substitution of the silicon group
of the chiral silylimides.14 This idea was brie¯y explored,
and gave access to >2)-24, 26 and 27, starting from 3a, and
sul®de 14, starting with 6, Scheme 3.
In order to check that this type of substitution occurred
without erosion of enantiomeric purity we required to
analyse these compounds by HPLC. Unfortunately, analysis
of ketone 24 was thwarted by the extreme insolubility of this
compound in solvents suitable for HPLC separation, and the
formation of 26 as inseparable diastereomers also made
analysis dif®cult. Fortunately we were able to assay both
of the sulfur compounds 27 and 14, and in both cases the
ee was shown to be within 5% of the value for the corre-
sponding silyl compounds >3a of 95% ee gave 27 of 91% ee;
6 of 98% ee gave 14 of 93% ee), indicating minimal loss of
enantiomeric purity.
In a similar fashion, we carried out a single alkylation of
silylimide 6 >using a racemic sample), using MeI, to give the
methylated product 22 in moderate yield >48%). The reluc-
tance of this system to alkylate in high yield dissuaded us
from further exploration.
We were also interested to see if the silicon substituent
present in imides such as 3a and 6 could exert a useful
level of control on the reactions of the imide carbonyl func-
tions. Polonski and co-workers have demonstrated that
imide thionation of systems related to 3a using Lawesson's
reagent is highly selective for the CvO group at the least
substituted position.15 We subjected 3a and 6 to typical
thionation conditions and observed the formation of single
regioisomeric products, assigned the structures 28 and 29,
albeit in poor yield.
We considered that the substitution reactions listed in Table
1could give access to products that represent asymmetric C-
alkylation of parent imide 1, provided that the silyl group
could be removed. This proved reasonably straightforward,
using either CsF or TBAF in THF, and in the cases of 15, 20
and 21 gave the chiral imides 23±25 in the yields indicated.
An alternative strategy for accessing such compounds was
Table 1. Substitution of silylimide 3a
Electrophile
MeI
AllylBr
BnBr
PhSSPh
PhCHO
PhCOCl
>CH3)2CHCH2COCl
Compound >%)
15 >93)
16 >73)
17 >67)
18 >71)
19 >61)a
20 >57)
21 >47)
a
Formed as a mixture of diastereomers.

4606
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
Scheme 3.
Scheme 4.
By analogy with the literature precedent we believe that
these compounds arise by highly selective reaction of the
CvO group distal to the bulky silicon substituent. The
assignment is supported by the observation of substantial
down®eld shifts >ca. 0.5 ppm) in the H NMR spectrum
for the signal due to the methine adjacent to the newly
installed CvS group, compared to the starting imide.
The successful enantioselective synthesis of hydroxy-
lactams, shown in Scheme 4 also suggested an opportunity
for reduction or further substitution via N-acyliminium
chemistry.18 We found that this type of reaction could be
performed by activation of 30 using Me3SiOTf. Reduction
using triethylsilane, and allylation using allyltrimethylsi-
lane, could be effected in high yield to give 34 and 35,
respectively, Scheme 5.
1
Speckamp and Hiemstra had observed an analogous mode
of regioselective reduction on reaction of certain imides
with DIBAL.16 We used these conditions with silylated
imides 3a and 6 and observed high-yielding conversion
into the hydroxylactams 30 and 31, Scheme 4.
We also carried out the allylation starting with 31, and
obtained the desired product 36. Both of the allylated
products 35 and 36 were obtained as single diastereomers,
with the stereochemistry shown being readily assigned from
1
examination of coupling constants in the H NMR spectra.
In each case we were unable to detect the other possible
regioisomeric product. The reduction was also highly
stereocontrolled, giving solely 31, although we did observe
a small amount >ca. 4%) of the epimeric hydroxyl product in
the case of 30. Additional experiments showed that the use
of NaBH4 resulted in ring opening to give 32, which could
then be transformed by acid treatment into the silyllactone
33.17
Finally, we were interested in testing the possibility of
cyclopropane ring-opening reactions of various fused
imides, which might be effected using nucleophilic
reagents. The activation to such a process that would be
provided by an additional carbonyl substituent prompted
us to examine reactions of the ketone system 24. We
found that excellent results were obtained using the reagent
Scheme 5.

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4607
extracted with Et2O >5£100 mL), dried >MgSO4), ®ltered
and the solvent evaporated under reduced pressure to give
a crude product. Puri®cation by ¯ash column chromato-
graphy on silica gel >10% EtOAc±light petroleum) gave
the imide 3a as a white solid >1.10 g, 80%), mp 104±
28
1058C; [a]D ˆ288 >c 1.00 in CHCl3); >Found: C, 64.65;
H, 6.60; N, 5.24. Requires C, 64.83; H, 6.61; N, 5.40%);
nmax >CHCl3)/cm21 2958, 1768, 1707, 1599, and 1500; dH
>250 MHz, CDCl3) 0.21[9H, s, Si>C H3)3], 1.52 >1H, dd,
Jˆ7.5, 4.3 Hz, CHH), 1.66 >1H, dd, Jˆ4.3, 3.3 Hz, CHH),
2.43 >1H, dd, Jˆ7.5, 3.3 Hz, CH) and 7.20±7.47 >5H, m,
ArH); dC >68 MHz, CDCl3) 22.9 >SiCH3), 20.2 >C), 24.0
>CH2), 24.2 >CH), 126.3 >ArCH), 128.1 >ArCH), 128.9
>ArCH), 131.8 >ArC), 175.0 >CO) and 176.6 >CO); m/z
>EI) 259 >M1, 70%), 244 >100), 216 >4), 150 >10) and 73
>37) >HRMS: found M1, 259.1033. C14H17NO2Si requires
M, 259.1028). The ee was determined as 95% by HPLC
>OD column, 1% IPA in hexane), the retention times were
22.8 min >minor) and 25.0 min >major).
Scheme 6.
generated from diphenyldiselenide and sodium borohydride,
Scheme 6.19
The ring opened product 37 was obtained as a single
compound, assigned the trans stereochemistry shown. Pre-
liminary experiments to probe a number of alternative
methods for cyclopropane ring opening in such systems,
for example using cuprate reagents, have proved less fruitful
to date.
3. Conclusion
4.2.2. -1R,5S)-3-Benzyl-1-trimethylsilyl-3-azabicyclo[3.1.0]
hexane-2,4-dione 3b. This was prepared using the above
procedure, starting with 1b >500 mg, 2.48 mmol). The crude
product was puri®ed by ¯ash column chromatography on
silica gel >5% EtOAc±light petroleum) to yield imide 3b
The desymmetrisation of imides, described above, consti-
tutes another addition to the growing list of reactions that
can be ef®ciently carried out using chiral lithium amide
bases. The chiral imides formed are rather versatile, and
can be converted into diverse types of chiral product,
including lactams and lactones. We are actively pursuing
additional work in this area, along with applications to
target synthesis, and further results will be reported in due
course.
23
as a white solid >455 mg, 67%), mp 59±628C; [a]D ˆ262
>c 1.22 in CHCl3); >Found: C, 65.57; H, 7.02; N, 5.26.
Requires C, 65.90; H, 7.00; N, 5.12%); nmax >CHCl3)/
cm21 2928, 2855, 1762, 1698 and 1602; dH >400 MHz,
CDCl3) 0.14 [9H, s, Si>CH3)3], 1.31±1.35 >2H, m, CHH
and CHH), 2.25 >1H, dd, Jˆ7.2, 3.7 Hz, CH), 4.45 >1H, d,
Jˆ14.5 Hz, PhCHH), 4.50 >1H, Jˆ14.5 Hz, PhCHH), 7.21±
7.30 >5H, m, ArH); dC >100 MHz, CDCl3) 23.0 >SiCH3),
19.8 >C), 23.8 >CH), 24.0 >CH2), 41.5 >CH2), 127.5 >ArCH),
128.1 >ArCH), 128.5 >ArCH), 136.2 >ArC), 175.4 >CO) and
177.3 >CO); m/z >EI) 273 >M1, 74%), 259 >5), 258 >27), 245
>10), 232 >4), 91 >100) and 73 >38) >HRMS: found M1,
273.1195. C15H19NO2Si requires M, 273.1185). The ee
was determined as 91% by HPLC >OD column, 5% IPA
in hexane), the retention times were 8.7 min >major) and
9.4 min >minor).
4. Experimental
4.1. General details
General experimental details can be found in the accom-
panying paper. Starting imides 1 were prepared by conden-
sation of the commercially available cyclopropylanhydride
with the appropriate amine, according to the method of
Beckwith and Boate.20 The diester 7 was prepared using
the method of McCoy,21 and the diketone 9 by the route
described by Krief.22
4.2.3. -1R,5S)-3-Benzyloxy-1-trimethylsilyl-3-azabicyclo
[3.1.0]hexane-2,4-dione 3c. This was prepared using
the above procedure starting with imide 1c >540 mg,
2.49 mmol). The crude product was puri®ed by ¯ash column
chromatography on silica gel >10% EtOAc±light petroleum)
to yield imide 3c as a white solid >472 mg, 66%), mp 46±
4.2. Typical procedure for chiral base reactions using
Me3SiCl in situ quench
488C; [a]D ˆ285 >c 1.00 in CHCl3); nmax >CHCl3)/cm21
23
4.2.1. -1R,5S)-3-Phenyl-1-trimethylsilyl-3-azabicyclo[3.1.0]
hexane-2,4-dione 3a. Chiral lithium amide base 2 was
prepared from the corresponding chiral amine HCl salt
>1.68 g, 6.41 mmol) in THF >20 mL) at 2788C under an
2958, 2888, 1772, 1716, 1603 and 1497; dH >400 MHz,
CDCl3) 0.08 [9H, s, Si>CH3)3], 1.22 >1H, dd, Jˆ4.5,
3.5 Hz, CHH), 1.29 >1H, dd, Jˆ7.4, 4.5 Hz, CHH), 2.05
>1H, dd, Jˆ7.4, 3.5 Hz, CH), 5.02 >2H, s, PhCHH 1
PhCHH), 7.33±7.43 >5H, m, ArH); dC >100 MHz, CDCl3)
23.1>Si CH3), 16.7 >C), 20.1> CH), 24.5 >CH2), 78.2 >CH2),
128.4 >ArCH), 129.3 >ArCH), 130.0 >ArCH), 133.4 >ArC),
170.6 >CO) and 172.4 >CO); m/z >EI) 274 [>M2CH3)1, 2%],
184 >3), 168 >7), 140 >2), 91 >100), 77 >10) and 73 >8)
[HRMS: found >M2CH3)1, 274.0912. C15H19NO3Si±CH3
requires >M2CH3), 274.0899]. The ee was determined as
89% by HPLC >OD column, 1% IPA in hexane), the
retention times were 29.2 min >major) and 37.7 min
>minor).
n
atmosphere of nitrogen, by addition of BuLi >8.01mL of
a 1.6 M solution in hexanes, 12.8 mmol), followed by
warming to room temperature for 15 min. The resulting
solution of the chiral base 2 was cooled to 21008C before
being added dropwise over 1h to a stirred solution of the
imide 1a >1.00 g, 5.34 mmol) and chlorotrimethylsilane
>6.78 mL, 53.4 mmol) in THF >120 mL) maintaining a
temperature of 2107^28C. The solution was then allowed
to warm slowly over 4 h to room temperature before
quenching with saturated aqueous NaHCO3 >30 mL). Most
of the THF was evaporated in vacuo and then the solution

4608
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4.2.4. -1R,5S)-3-Benzyl-1-trimethylsilyl-3-azabicyclo[3.2.0]
heptane-2,4-dione 4. This was prepared using the above
procedure starting with N-benzyl-3-azabicyclo[3.2.0]hep-
tane-2,4-dione >50 mg, 0.23 mmol). The crude product
was puri®ed by ¯ash column chromatography on silica gel
>5% EtOAc±light petroleum) to yield imide 4 as a white
m/z >EI) 311 >M1, 67%), 245 >63), 105 >3) and 73 >100)
>HRMS: found M1, 311.1349. C18H21NO2Si requires M,
311.1342). The ee was determined as 98% by HPLC >OD
column, 0.25% IPA in hexane), the retention times were
38.8 min >minor) and 41.8 min >major).
28
solid >25 mg, 37%), mp 63±648C; [a]D ˆ265 >c 0.92 in
4.2.7. -1R,2S)-1-Trimethylsilyl-1,2-cyclopropanedicarbo-
xylic acid dimethyl ester 8. This was prepared using the
above procedure starting with 1,2-cyclopropanedicarbo-
xylic acid dimethyl ester 7. The crude product was puri®ed
by ¯ash column chromatography on silica gel >20%
EtOAc±light petroleum) to yield diester 8 as a colourless
CHCl3); nmax >CHCl3)/cm21 2959, 1756, 1689 and 1600; dH
>400 MHz, CDCl3) 0.07 [9H, s, Si>CH3)3], 2.15±2.25 >2H,
m, CH2CSi), 2.42±2.57 >2H, m, CH2), 3.07 >1H, dd, Jˆ10.1,
3.7 Hz, CH), 4.67 >1H, d, Jˆ14.1 Hz, PhCHH), 4.71>1H,
Jˆ14.1 Hz, PhCHH) and 7.23±7.36 >5H, m, ArH); dC
>100 MHz, CDCl3) 24.6 >SiCH3), 22.8 >CH2), 25.5 >CH2),
39.7 >C), 40.8 >CH), 42.5 >CH2), 127.7 >ArCH), 128.3
>ArCH), 128.6 >ArCH), 136.3 >ArC), 180.0 >CO) and
182.4 >CO); m/z >EI) 287 >M1, 56%), 272 >10), 160 >5),
91>010) and 73 >42) >HRMS: found M 1, 287.1337.
C16H21NO2Si requires M, 287.1342). The ee was deter-
mined as 93% by HPLC >OJ column, 1% IPA in hexane),
the retention times were 16.0 min >major) and 34.9 min
>minor).
22
oil >2.23 g, 77%); [a]D ˆ159 >c 1.04 in CHCl3); nmax
>CHCl3)/cm21 2953, 2901, 2843 and 1732; dH >250 MHz,
CDCl3) 0.06 [9H, s, Si>CH3)3], 1.10 >1H, dd, Jˆ7.2, 4.1Hz,
CHH), 1.72 >1H, dd, Jˆ5.1, 4.1 Hz, CHH), 1.80 >1H, dd,
Jˆ7.2, 5.1Hz, C H), 3.64 >3H, s, CH3) and 3.66 >3H, s,
CH3); dC >100 MHz, CDCl3) 23.2 >SiCH3), 16.0 >CH2),
22.4 >CH), 25.4 >C), 51.9 >CH3), 52.0 >CH3), 172.0 >CO)
and 172.05 >CO); m/z >EI) 215 [>M2CH3)1, 100%], 199
>32), 171 >14), 157 >1) and 89 >13) [HRMS: found
>M2CH3)1, 215.0731. C10H18O4Si±CH3 requires >M2CH3),
215.0740]. The ee was determined as 82% by HPLC >OD
column, 1% IPA in hexane), the retention times were
9.0 min >minor) and 10.0 min >major).
4.2.5. -1R,5S)-3-Benzyl-1-trimethylsilyl-3-azabicyclo
[3.3.0]octane-2,4-dione 5. This was prepared using the
above procedure starting with N-benzyl-3-azabicyclo[3.3.0]
octane-2,4-dione >0.15 g, 0.65 mmol). The crude product
was puri®ed by ¯ash column chromatography >5%
EtOAc±light petroleum) to yield imide 5 as a white solid
4.2.8.
-1R,5S)-3,3,6,6-Tetramethyl-1-trimethylsilylbi-
cyclo[3.1.0]hexane-2,4-dione 10. This was prepared using
the above procedure starting with 3,3,6,6-tetramethylbi-
cyclo[3.1.0]hexane-2,4-dione 9. The crude product was
puri®ed by ¯ash column chromatography on silica gel
>5% EtOAc±light petroleum) to give the required product
28
>0.14 g, 72%), mp 71±738C; [a]D ˆ260 >c 1.11 in
CHCl3); >Found: C, 67.33; H, 7.85; N, 4.63. Requires C,
67.73; H, 7.69; N, 4.65%); nmax >CHCl3)/cm21 2956,
2870, 1758, 1687, 1602 and 1449; dH >400 MHz, CDCl3)
0.01[9H, s, Si>C H3)3], 1.22 >1H, m, CHH), 1.58±1.80 >3H,
m, CH21CHH), 2.14 >1H, m, CHH), 2.25 >1H, m, CHH),
2.91>1H, m, C H), 4.60 >2H, m, PhCHH1PhCHH), 7.22±
7.36 >5H, m, ArH); dC >68 MHz, CDCl3) 24.2 >SiCH3),
25.7 >CH2), 31.3 >CH2), 33.1> CH2), 42.4 >CH2), 46.7 >C),
48.2 >CH), 127.6 >ArCH), 128.4 >ArCH), 128.5 >ArCH),
136.3 >ArC), 180.1 >CO) and 182.6 >CO); m/z >EI) 301
>M1, 74%), 273 >28), 91>88) and 73 >46) >HRMS: found
M1, 301.1489. C17H23NO2Si requires M, 301.1498). The ee
was determined as 91% by HPLC >OD column, 0.25% IPA
in hexane), the retention times were 14.4 min >minor) and
16.3 min >major).
27
10 as a colourless oil >1.02 g, 71%); [a]D ˆ220 >c 1.20 in
CHCl3); >Found: C, 65.27; H, 9.44. Requires C, 65.50; H,
9.30%); nmax >CHCl3)/cm21 2958, 2936, 2901, 2874, 1741
and 1704; dH >250 MHz, CDCl3) 0.17 [9H, s, Si>CH3)3],
1.03 >3H, s, CHCCH3), 1.05 >3H, s, CHCCH3), 1.12 >3H,
s, COCCH3), 1.30 >3H, s, COCCH3) and 2.29 >1H, s, CH);
dC >100 MHz, CDCl3) 20.5 >SiCH3), 15.5 >CH3), 20.4
>CH3), 24.5 >CH3), 25.7 >CH3), 32.8 >C), 40.7 >C), 44.4
>CH), 55.9 >C), 211.6 >CO) and 214.2 >CO); m/z >EI) 238
>M1, 28%), 223 >7), 195 >17), 168 >14) and 73 >100)
>HRMS: found M1, 238.1381. C12H22O2Si requires M,
238.1389).
4.2.6. -1R,2R,6S,7S)-4-Phenyl-2-trimethylsilyl-4-azatri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione 6. This was prepared
using the above procedure starting with N-phenyl-4-azatri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione >1.00 g, 4.18 mmol).
The crude product was puri®ed by ¯ash column chromato-
graphy on silica gel >10% EtOAc±light petroleum) to yield
imide 6 as a pale yellow solid >0.99 g, 76%), mp 132±
4.2.9. -1S,5R)-1-Benzoyl-3,3,6,6-tetramethylbicyclo[3.1.0]
hexane-2,4-dione 11. To a solution of ¯ame dried CsF
>48 mg, 0.31mmol) and 18-crown-6 >5 mg, 0.02 mmol) in
THF >1mL) at room temperature, under an atmosphere of
nitrogen, was added a mixture of diketone 10 >50 mg,
0.21mmol) and benzoyl ¯uoride >0.21mL, 1.93 mmol) in
THF >1mL). The solution was then stirred overnight before
quenching with saturated aqueous NH4Cl >4 mL) and
extracting with CH2Cl2 >3£30 mL). The combined extracts
were dried >MgSO4), ®ltered and the solvent evaporated in
vacuo to give crude product. This was then puri®ed by ¯ash
column chromatography >5% EtOAc±light petroleum) to
give the triketone 11 as a white solid >28 mg, 50%), mp
24
1338C; [a]D ˆ258 >c 1.11 in CHCl3); >Found: C, 69.13;
H, 6.53; N, 4.39. Requires C, 69.42; H, 6.80; N, 4.50%);
n
max >CHCl3)/cm21 2987, 2956, 2880, 1761, 1694, 1600 and
1500; dH >400 MHz, CDCl3) 0.27 [9H, s, Si>CH3)3], 1.62
>2H, s, CH2), 3.25 >1H, d, Jˆ4.4 Hz, COCH), 3.39 >1H, m,
CHCSi), 3.51>1H, m, COCHC H), 6.20 >1H, dd, Jˆ5.6,
2.9 Hz, CHvCH), 6.41>1H, dd, Jˆ5.6, 2.9 Hz, CHvCH)
and 7.10±7.44 >5H, m, ArH); dC >100 MHz, CDCl3) 22.4
>SiCH3), 46.4 >CH), 47.1> CH), 47.3 >C), 49.0 >CH), 50.8
>CH2), 126.6 >ArCH), 128.3 >ArCH), 129.0 >ArCH), 132.1
>ArC), 132.2 >CH), 138.5 >CH), 177.2 >CO) and 180.1 >CO);
23
69±708C; [a]D ˆ176 >c 0.76 in CHCl3); nmax >CHCl3)/
cm21 2977, 2933, 2873, 1756, 1719, 1667, 1598 and
1582; dH >400 MHz, CDCl3) 1.10 >3H, s, CHCCH3), 1.15
>3H, s, CHCCH3), 1.23 >3H, s, COCCH3), 1.33 >3H, s,
COCCH3), 2.97 >1H, s, CH), 7.55 >2H, t, Jˆ7.2 Hz, ArH),

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4609
7.66 >1H, t, Jˆ7.2 Hz, ArH) and 8.01>2H, d, Jˆ7.2 Hz,
ArH); dC >100 MHz, CDCl3) 15.4 >CH3), 19.3 >CH3), 23.4
>CH3), 24.5 >CH3), 35.2 >C), 42.6 >CH), 57.1> C), 57.7 >C),
128.5 >ArCH), 130.6 >ArCH), 134.1 >ArCH), 136.2 >ArC),
191.3 >PhCO), 205.2 >CO) and 208.6 >CO); m/z >EI) 270
>M1, 2%), 200 >3), 172 >4), 165 >2), 122 >8), 105 >100) and
77 >50) >HRMS: found M1, 270.1250. C17H18O3 requires M,
270.1256). The ee was determined as 97% by HPLC >OD
column, 1% IPA in hexane), the retention times were
9.9 min >major) and 15.1 min >minor).
>2H, d, Jˆ7.2 Hz, ArH), 7.36 >1H, t, Jˆ7.4 Hz, ArH) and
7.43 >2H, t, Jˆ7.2 Hz, ArH); dC >100 MHz, CDCl3) 39.8
>CH2), 46.2 >CH), 49.9 >CH), 50.5 >CH2), 50.6 >CH), 56.5
>C), 119.6 >CH2), 126.6 >ArCH), 128.6 >ArCH), 129.0
>ArCH), 131.9 >ArC), 132.6 >CH), 134.9 >CH), 136.7
>CH), 176.4 >CO) and 179.1 >CO); m/z >EI) 279 >M1,
30%), 238 >9), 213 >100), 77 >7) and 66 >66) >HRMS:
found M1, 279.1252. C18H17NO2 requires M, 279.1259).
Some diallylated product was also isolated.
4.3.3. -1R,2R,6S,7S)-4-Phenyl-2-thiophenyl-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione 14. The above typical pro-
cedure was followed using starting imide >240 mg,
1.0 mmol) and a solution of diphenyl disul®de >1.09 g,
5.0 mmol) in THF >10 mL), and the resulting crude product
was puri®ed by ¯ash column chromatography on silica gel
>20% EtOAc±light petroleum) to give 14 as a white solid
4.3. Typical procedure for chiral base reactions using
external quench
4.3.1. -1R,2S,6R,7S)-2-Methyl-4-phenyl-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione 12. Chiral lithium amide
base 2 was prepared from the corresponding chiral amine
HCl salt >131 mg, 0.50 mmol) in THF >4 mL) at 2788C
23
>175 mg, 50%), mp 130±1328C; [a]D ˆ245 >c 1.0 in
CHCl3); nmax >CHCl3)/cm21 2984, 2950, 2875, 1776,
1705, 1598, 1574 and 1499; dH >400 MHz, CDCl3) 1.96
>1H, dt, Jˆ9.1, 1.6 Hz, CHH), 2.39 >1H, d, Jˆ9.1Hz,
CHH), 3.29 >1H, m, CHCHCO), 3.37 >1H, d, Jˆ4.5 Hz,
CHCO), 3.57 >1H, m, CHCSPh), 6.31>2H, m, C HvCH),
6.88±7.68 >10H, m, ArH); dC >100 MHz, CDCl3) 46.7 >CH),
50.4 >CH), 51.3 >CH2), 53.6 >CH), 62.3 >C), 126.5 >ArCH),
128.6 >ArCH), 129.0 >ArCH), 129.3 >ArCH), 130.0 >ArCH),
131.6 >ArC), 135.9 >ArCH), 136.2 >CH), 136.4 >CH), 174.6
>CO) and 175.6 >CO); m/z >EI) 347 >M1, 11%), 134 >100)
and 77 >26) >HRMS: found M1, 347.0989. C21H17NO2S
requires M, 347.0980). The ee was determined as 97% by
HPLC >OJ column, 10% IPA in hexane), the retention times
were 31.5 min >minor) and 38.7 min >major).
n
under an atmosphere of nitrogen, by addition of BuLi
>0.63 mL of a 1.6 M solution in hexanes, 1.00 mmol),
followed by warming to room temperature for 15 min.
The resulting solution of the chiral base 2 was cooled to
2788C before being added dropwise over 15 min to a stirred
solution of the starting meso imide >100 mg, 0.42 mmol) in
THF >8 mL). The mixture was stirred for 1h before addition
of MeI >1.03 mL, 16.7 mmol). The solution was warmed
slowly overnight, and then quenched with saturated aqueous
NaHCO3 >4 mL). Most of the THF was evaporated in vacuo
and the remaining solution extracted with Et2O >3£50 mL),
dried >MgSO4), ®ltered and the solvent evaporated under
reduced pressure. The crude mixture was puri®ed by ¯ash
column chromatography on silica gel >10% EtOAc±light
petroleum) to yield imide 12 as a white solid >38 mg,
36%), mp 109±1128C, lit.12 mp 108±1108C; [a]D ˆ245
23
>c 1.18 in CHCl3); nmax >CHCl3)/cm21 2974, 2951, 2875,
1773, 1709, 1599 and 1500; dH >250 MHz, CDCl3) 1.63
>3H, s, CH3), 1.82 >1H, d, Jˆ1.6 Hz, CHH), 1.84 >1H, d,
Jˆ1.6 Hz, CHH), 2.99 >1H, d, Jˆ4.5 Hz, CHCO), 3.03 >1H,
m, CHCCH3), 3.46 >1H, m, CHCHCO), 6.24 >1H, dd,
Jˆ5.6, 2.6 Hz, CHvCH), 6.35 >1H, dd, Jˆ5.6, 2.6 Hz,
CHvCH), 7.14±7.47 >5H, m, ArH); dC >68 MHz, CDCl3)
21.4 >CH3), 46.2 >CH), 50.2 >CH2), 51.3 >CH), 51.4 >C),
52.9 >CH), 126.6 >ArCH), 128.5 >ArCH), 129.0 >ArCH),
131.8 >ArC), 134.2 >CH), 136.7 >CH), 176.4 >CO) and
180.0 >CO); m/z >EI) 253 >M1, 100%) and 103 >9)
>HRMS: found M1, 253.1101. C16H15NO2 requires M,
253.1103).
4.4. Typical procedure for substitution on 3a -Table 1)
4.4.1. -1R,5S)-5-Methyl-3-phenyl-1-trimethylsilyl-3-azabi-
cyclo[3.1.0]hexane-2,4-dione 15. LDA was prepared by
addition of nBuLi >0.58 mL of a 1.6 M solution in hexanes,
0.92 mmol) to a solution of DIPA >128 mL, 0.92 mmol) and
LiCl >38 mg, 0.92 mmol) in THF >6 mL) at 2788C and
warming to room temperature for 15 min before recooling
to 2788C. A solution of the cyclopropane 3a >200 mg,
0.77 mmol, 91% ee) in THF >2 mL) was added dropwise
over 10 min and the solution stirred for 45 min. Methyl
iodide >1.92 mL, 30.8 mmol) was then added and the solu-
tion warmed overnight to room temperature before quench-
ing with saturated aqueous NH4Cl >4 mL). The solution was
extracted with CH2Cl2 >3£30 mL) and the combined
extracts dried >MgSO4), ®ltered and the solvent evaporated
under reduced pressure to yield crude product. The resulting
crude mixture was puri®ed by ¯ash column chromatography
on silica gel >20% EtOAc±light petroleum) to give 15 as
4.3.2.
-1R,2S,6R,7S)-2-Allyl-4-phenyl-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione 13. The above typical
procedure was followed using starting imide >300 mg,
1.25 mmol) and allyl bromide >3.00 mL, 34.7 mmol), and
the resulting crude product was puri®ed by ¯ash column
chromatography on silica gel >10% EtOAc±light petroleum)
24
a white solid >195 mg, 93%), mp 113±1148C; [a]D ˆ244
>c 1.12 in CHCl3); nmax >CHCl3)/cm21 2957, 2900, 1766,
1702, 1600 and 1502; dH >250 MHz, CDCl3) 0.28 [9H, s,
Si>CH3)3], 1.44 >1H, d, Jˆ3.9 Hz, CHH), 1.60 >3H, s, CH3),
1.73 >1H, d, Jˆ3.9 Hz, CHH) and 7.21±7.46 >5H, m, ArH);
dC >100 MHz, CDCl3) 21.4 >SiCH3), 12.2 >CH3), 24.2 >C),
31.3 >CH2), 31.5 >C), 126.3 >ArCH), 128.0 >ArCH), 128.9
>ArCH), 132.1 >ArC), 177.2 >CO) and 177.4 >CO); m/z >EI)
273 >M1, 64%), 258 >77), 184 >4) and 73 >100) >HRMS:
found M1, 273.1180. C15H19NO2Si requires M, 273.1185).
23
to give 13 as a colourless oil >115 mg, 33%), [a]D ˆ260 >c
0.83 in CHCl3); nmax >CHCl3)/cm21 2982, 2949, 2877, 1774,
1706, 1641, 1599 and 1500; dH >400 MHz, CDCl3) 1.50
>2H, m, CHH1CHH), 2.40 >1H, dd, Jˆ13.7, 7.8 Hz,
CHHCHvCH2), 3.00 >1H, dd, Jˆ13.7, 7.1 Hz, CHHCHv
CH2), 3.07 >1H, m, CH), 3.11 >1H, d, Jˆ4.5 Hz, CHCO),
3.47 >1H, m, CH), 5.17±5.26 >2H, m, CH2CHvCH2), 5.77±
5.87 >1H, m, CH2CHvCH2), 6.26 >1H, dd, Jˆ5.7, 2.9 Hz,
CHvCH), 6.35 >1H, dd, Jˆ5.7, 2.9 Hz, CHvCH), 7.12

4610
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4.4.2. -1R,5S)-5-Allyl-3-phenyl-1-trimethylsilyl-3-azabi-
cyclo[3.1.0]hexane-2,4-dione 16. The above typical proce-
dure was followed using 3a >100 mg, 0.39 mmol, 91% ee)
and allyl bromide >1.00 mL, 11.6 mmol) and the resulting
crude mixture was puri®ed by ¯ash column chromatography
on silica gel >20% EtOAc±light petroleum) to give 16 as a
above typical procedure was followed using 3a >100 mg,
0.39 mmol, 95% ee) and benzaldehyde >0.20 mL,
1.93 mmol) and stirring at 2788C for 3 h before warming to
room temperature over 1h. This gave a crude mixture which
consisted of a 1:1 mixture of diastereomers of adduct 19, along
with a small amount of by-product which appeared to have
arisen by addition followed by silyl group transfer to oxygen.
Puri®cation by ¯ash column chromatography on silica gel
>10% EtOAc±light petroleum) allowed almost complete
separation of the diastereomers of 19, total yield >86 mg, 61%).
26
pale yellow oil >84 mg, 73%); [a]D ˆ236 >c 1.29 in
CHCl3); nmax >CHCl3)/cm21 2957, 1766, 1703, 1643, 1598
and 1501; dH >400 MHz, CDCl3) 0.27 [9H, s, Si>CH3)3],
1.43 >1H, d, Jˆ4.0 Hz, CHHCSi), 1.72 >1H, d, Jˆ4.0 Hz,
CHHCSi), 2.20 >1H, dd, Jˆ16.1, 6.0 Hz, CH2vCHCHH),
3.18 >1H, dd, Jˆ16.1, 6.3 Hz, CH2vCHCHH), 5.13 >1H, m,
CHHvCH), 5.17 >1H, m, CHHvCH), 5.91>H1, m,
CH2vCH) and 7.21±7.43 >5H, m, ArH); dC >100 MHz,
CDCl3) 21.5 Si>CH3), 23.7 >C), 29.6 >CH2), 30.7 >CH2),
36.3 >C), 117.4 >CH2), 126.3 >ArCH), 128.0 >ArCH),
128.9 >ArCH), 132.0 >ArC), 134.2 >CH), 176.2 >CO) and
177.2 >CO); m/z >EI) 299 >M1, 43%), 285 >18), 284 >79),
271>8) and 73 >010) >HRMS: found M 1, 299.1356.
C17H21NO2Si requires M, 299.1342).
Data for less polar diastereomer of 19: nmax >CHCl3)/cm21
3605 >OH), 2926, 2854, 1766, 1702, 1601 and 1496; dH
>250 MHz, CDCl3) 0.36 [9H, s, Si>CH3)3], 1.71 >1H, d,
Jˆ4.4 Hz, CHH), 1.89 >1H, d, Jˆ4.4 Hz, CHH), 2.85 >1H,
d, Jˆ8.0 Hz, OH), 4.87 >1H, d, Jˆ8.0 Hz, CH) and 7.21±
7.60 >10H, m, ArH); dC >100 MHz, CDCl3) 21.2 >SiCH3),
25.3 >C), 28.7 >CH2), 40.9 >C), 71.6 >CH), 126.4 >ArCH),
127.9 >ArCH), 128.1 >ArCH), 128.3 >ArCH), 128.4 >ArCH),
128.9 >ArCH), 131.7 >ArC), 141.6 >ArC), 175.0 >CO) and
176.4 >CO); m/z >EI) 365 >M1, 1%), 351 >1), 350 >9), 337
>24), 264 >32), 75 >100) and 73 >75) >HRMS: found M1,
365.1450. C21H23NO3Si requires M, 365.1447).
4.4.3. -1R,5S)-5-Benzyl-3-phenyl-1-trimethylsilyl-3-azabi-
cyclo[3.1.0]hexane-2,4-dione 17. The above typical proce-
dure was followed using 3a >100 mg, 0.39 mmol, 91% ee)
and benzyl bromide >0.92 mL, 7.71mmol) and the resulting
crude mixture was puri®ed by ¯ash column chromatography
on silica gel >7% EtOAc±light petroleum) to give 17 as a
Data for more polar diastereomer of 19 nmax >CHCl3)/cm21
3534 >OH), 2958, 1765, 1699, 1599 and 1495; dH
>250 MHz, CDCl3) 0.18 [9H, s, Si>CH3)3], 1.85 >1H, d,
Jˆ4.2 Hz, CHH), 2.00 >1H, d, Jˆ4.2 Hz, CHH), 4.16 >1H,
d, Jˆ11.2 Hz, OH), 4.65 >1H, d, Jˆ11.2 Hz, CH) and 7.22±
7.48 >10H, m, ArH); dC >100 MHz, CDCl3) 21.6 >SiCH3),
25.4 >C), 29.9 >CH2), 40.2 >C), 73.6 >CH), 126.2 >ArCH),
126.4 >ArCH), 128.3 >ArCH), 128.4 >ArCH), 128.7 >ArCH),
129.0 >ArCH), 131.3 >ArC), 141.2 >ArC), 176.5 >CO) and
177.3 >CO); m/z >EI) 365 >M1, 2%), 351>2), 350 >10), 337
>22), 264 >28), 75 >100) and 73 >71) >HRMS: found M1,
365.1462. C21H23NO3Si requires M, 365.1447).
26
colourless oil >87 mg, 67%); [a]D ˆ21 0 c> 0.46 in
CHCl3); nmax >CHCl3)/cm21 2958, 2927, 2872, 1766,
1702, 1600 and 1496; dH >400 MHz, CDCl3) 0.17 [9H, s,
Si>CH3)3], 1.53 >1H, d, Jˆ4.0 Hz, CHH), 1.78 >1H, d,
Jˆ4.0 Hz, CHH), 2.93 >1H, d, Jˆ16.4 Hz, PhCHH), 3.73
>1H, d, Jˆ16.4 Hz, PhCHH) and 7.20±7.44 >10H, m, ArH);
dC >100 MHz, CDCl3) 21.6 >SiCH3), 24.7 >C), 30.4 >CH2),
32.2 >CH2), 37.1> C), 126.3 >ArCH), 126.6 >ArCH), 128.0
>ArCH), 128.3 >ArCH), 128.5 >ArCH), 128.9 >ArCH), 132.1
>ArC), 138.4 >ArC), 176.8 >CO) and 177.0 >CO); m/z >EI)
349 >M1, 48%), 335 >14), 334 >53), 321 >66), 276 >10), 248
>73), 91>37) and 73 >100) >HRMS: found M 1, 349.1490.
C21H23NO2Si requires M, 349.1498).
4.4.6.
-1R,5R)-5-Benzoyl-3-phenyl-1-trimethylsilyl-3-
azabicyclo[3.1.0]hexane-2,4-dione 20. The above typical
procedure was followed using 3a >100 mg, 0.39 mmol,
95% ee) and benzoyl chloride >0.22 mL, 1.9 mmol) and
warming of the reaction mixture overnight to room tempera-
ture. Puri®cation of the crude mixture by ¯ash column
chromatography >7% EtOAc±light petroleum) gave the
imide 20 as a white solid >81mg, 57%), mp 168±170 8C;
4.4.4. -1R,5S)-3-Phenyl-1-thiophenyl-5-trimethylsilyl-3-
azabicyclo[3.1.0]hexane-2,4-dione 18. The above typical
procedure was followed using 3a >100 mg, 0.39 mmol,
95% ee) and a solution of diphenyl disul®de >420 mg,
1.93 mmol) in THF >1 mL) and the resulting crude mixture
was puri®ed by ¯ash column chromatography on silica gel
>5% EtOAc±light petroleum) to give 18 as a white solid
[a]D ˆ29.6 >c 1.23 in CHCl3); nmax >CHCl3)/cm21 2927,
25
1770, 1708, 1683, 1598, 1500, 1450, 1376 and 1342; dH
>250 MHz, CDCl3) 0.14 [9H, s, Si>CH3)3], 2.03 >1H, d,
Jˆ4.3 Hz, CHH), 2.33 >1H, d, Jˆ4.3 Hz, CHH) and 7.30±
7.97 >10H, m, ArH); dC >68 MHz, CDCl3), 22.1>Si CH3),
27.7 >CH2), 29.5 >C), 43.1> C), 126.2 >ArCH), 128.4
>ArCH), 128.8 >ArCH), 128.9 >ArCH), 129.1 >ArCH),
131.5 >ArC), 134.2 >ArCH), 135.7 >ArC), 172.7 >CO),
175.4 >CO) and 190.9 >COPh); m/z >EI) 363 >M1, 1%),
349 >26), 348 >100), 105 >35), 77 >35) and 73 >19)
>HRMS: found M1, 363.1281. C21H21NO3Si requires M,
363.1291).
25
>99 mg, 71%), mp 111±1138C; [a]D ˆ278 >c 1.10 in
CHCl3); >Found: C, 65.12; H, 5.84; N, 3.93. Requires C,
65.38; H, 5.77; N, 3.81%); nmax >CHCl3)/cm21 2957,
1770, 1708, 1600 and 1501; dH >250 MHz, CDCl3) 0.33
[9H, s, Si>CH3)3], 1.86 >1H, d, Jˆ4.3 Hz, CHH), 2.13
>1H, d, Jˆ4.3 Hz, CHH) and 7.28±7.54 >10H, m, ArH);
dC >100 MHz, CDCl3) 21.4 >SiCH3), 29.2 >C), 32.7
>CH2), 39.8 >C), 126.3 >ArCH), 127.3 >ArCH), 128.3
>ArCH), 128.9 >ArCH), 129.1 >ArCH), 130.0 >ArCH),
131.8 >ArC), 134.5 >ArC), 174.2 >CO) and 175.3 >CO); m/
z >EI) 367 >M1, 27%), 352 >7), 77 >5) and 73 >100) >HRMS:
found M1, 367.1048. C20H21NO2SSi requires M, 367.1062).
4.4.7.
-1R,5R)-5--30-Methyl-20-oxobutyl)-3-phenyl-1-
trimethylsilyl-3-azabicyclo[3.1.0]hexane-2,4-dione 21.
The above typical procedure was followed using 3a
>100 mg, 0.39 mmol) and isovaleryl methyl ester >0.15 mL,
1.2 mmol) and stirring the reaction mixture at 2788C for 1h
4.4.5. -1R,5R)-5--10-Hydroxyphenylmethyl)-3-phenyl-1-
trimethylsilyl-3-azabicyclo[3.1.0]hexane-2,4-dione 19. The

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4611
before quenching with saturated aqueous NH4Cl. Puri®ca-
tion by ¯ash column chromatography >5% EtOAc±light
petroleum) gave imide 21 as a white solid >62 mg, 47%),
cm21 2938, 1780, 1715, 1600 and 1500; dH >250 MHz,
CDCl3) 1.49 >1H, dd, Jˆ8.0, 4.7 Hz, CHH), 1 .59 >3H, s,
CH3), 1.69 >1H, dd, Jˆ4.7, 3.2 Hz, CHH), 2.43 >1H, dd,
Jˆ8.0, 3.2 Hz, CH), 7.23 >2H, d, Jˆ7.3 Hz, ArH), 7.36
>1H, t, Jˆ7.4 Hz, ArH) and 7.44 >2H, t, Jˆ7.4 Hz, ArH);
dC >68 MHz, CDCl3), 12.8 >CH3), 26.0 >CH), 26.9 >C), 26.9
24
mp 80±828C; [a]D ˆ161> c 1.02 in CHCl3); nmax >CHCl3)/
cm21 2960, 2933, 2901, 2874, 1770, 1707, 1683, 1598, and
1501; dH >400 MHz, CDCl3) 0.24 [9H, s, Si>CH3)3], 0.97
>3H, d, Jˆ6.7 Hz, CH3), 1.00 >3H, d, Jˆ6.7 Hz, CH3), 1.87
>1H, d, Jˆ3.9 Hz, CHHCSi), 2.24 >1H, m, CH), 2.31>1H, d,
Jˆ3.9 Hz, CHHCSi), 2.56 >1H, dd, Jˆ18.2, 6.7 Hz,
COCHH), 3.14 >1H, dd, Jˆ18.2, 6.7 Hz, COCHH), 7.24
>2H, d, Jˆ7.2 Hz, ArH), 7.37 >1H, t, Jˆ7.3 Hz, ArH) and
7.45 >2H, t, Jˆ7.3 Hz, ArH); dC >100 MHz, CDCl3) 21.4
>SiCH3), 22.6 >CH3), 22.6 >CH3), 23.8 >CH), 30.1> CH2),
31.2 >C), 44.0 >C), 51.3 >CH2), 126.3 >ArCH), 128.4
>ArCH), 129.0 >ArCH), 131.5 >ArC), 172.8 >CO), 175.0
>CO) and 200.3 >COCH2); m/z >EI) 328 [>M2CH3)1,
100%], 286 >30), 73 >10) and 57 >2) [HRMS: found
>M2CH3)1, 328.1367. C19H25NO3Si±CH3 requires >M 2
CH3), 328.1369].
>CH2), 126.4 >ArCH), 128.2 >ArCH), 129.0 >ArCH), 131.7
>ArC), 174.1 >CO) and 176.2 >CO); m/z >EI) 201>M
1
,
62%), 82 >100) and 77 >7) >HRMS: found M1, 201.0799.
C12H11NO2 requires M, 201.0790).
4.4.10. -1R,5S)-1-Benzoyl-3-phenyl-3-azabicyclo[3.1.0]-
hexane-2,4-dione -1)-24. To a solution of 20 >350 mg,
0.96 mmol, prepared from 3a of 95% ee) in THF >35 mL)
at 2788C was added TBAF >1.16 mL of a 1.0 M solution
in THF, 1.16 mmol) dropwise. The reaction mixture was
stirred for 1h at 2788C before quenching with water
>15 mL) and allowing to warm to room temperature. The
solution was extracted with CH2Cl2 >4£50 mL) then the
combined fractions dried >MgSO4), ®ltered and the solvent
removed in vacuo to give crude product. This was puri®ed
by ¯ash column chromatography >20% EtOAc±light petro-
leum) to give 24 as a white solid >252 mg, 90%), mp 217±
4.4.8. -1R,2R,6S,7S)-6-Methyl-4-phenyl-2-trimethylsilyl-
4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione 22. LDA was
prepared by addition of nBuLi >0.19 mL of a 1.6 M solution
in hexanes, 0.31mmol) to a solution of DIPA >44 mL,
0.31mmol) and LiCl >13 mg, 0.31mmol) in THF >3 mL)
at 2788C and warming to room temperature for 15 min
before recooling to 2788C. A solution of >^)-6 >80 mg,
0.26 mmol) in THF >2 mL) was then added dropwise over
10 min and the solution stirred for 1.5 h before the addition
of methyl iodide >0.63 mL, 10.3 mmol). The solution was
warmed overnight to room temperature before quenching
with saturated aqueous NH4Cl >4 mL). The solution was
extracted with CH2Cl2 >3£30 mL) and the combined
extracts dried >MgSO4), ®ltered and the solvent evaporated
under reduced pressure to yield crude product. This was
puri®ed by ¯ash column chromatography >10% EtOAc±
light petroleum) to yield the imide 22 as a colourless oil
>40 mg, 48%); nmax >CHCl3)/cm21 2985, 2955, 1759, 1691,
1600 and 1500; dH >400 MHz, CDCl3) 0.35 [9H, s,
Si>CH3)3], 1.66 >1H, dt, Jˆ9.1, 1.6 Hz, CHH), 1.70 >1H, s,
CH3), 1.85 >1H, d, Jˆ9.1Hz, CH H), 2.99 >1H, m, CHCSi),
3.40 >1H, m, CHCCH3), 6.26 >1H, dd, Jˆ5.5, 2.8 Hz,
CHvCH), 6.33 >1H, dd, Jˆ5.5, 2.8 Hz, CHvCH), 7.12
>2H, d, Jˆ7.2 Hz, ArH), 7.35 >1H, t, Jˆ7.4 Hz, ArH) and
7.42 >2H, t, Jˆ7.8 Hz, ArH); dC >68 MHz, CDCl3) 20.6
>SiCH3), 21.4 >CH3), 48.8 >CH), 49.6 >CH2), 50.7 >C),
53.7 >CH), 54.8 >C), 126.7 >ArCH), 128.4 >ArCH), 128.9
>ArCH), 132.2 >ArC), 133.9 >CH), 137.6 >CH), 180.1 >CO)
and 180.6 >CO); m/z >EI) 325 >M1, 82%), 310 >11), 259
>87), 231 >12), 142 >100) and 73 >81) >HRMS: found M1,
325.1485. C19H23NO2Si requires M, 325.1498).
2208C; [a]D ˆ158 >c 0.88 in CHCl3); nmax >CHCl3)/cm21
24
2926, 1778, 1722, 1679, 1599 and 1498; dH >250 MHz,
CDCl3) 2.11 >1H, dd, Jˆ4.7, 4.1Hz, C HH), 2.40 >1H, dd,
Jˆ8.4, 4.7 Hz, CHH), 3.15 >1H, dd, Jˆ8.4, 4.1Hz, C H) and
7.25±7.98 >10H, m, ArH); dC >68 MHz, CDCl3) 26.1> CH2),
27.9 >CH), 38.6 >C), 126.3 >ArCH), 128.6 >ArCH), 128.7
>ArCH), 129.0 >ArCH), 129.1 >ArCH), 131.1 >ArC), 134.1
>ArCH), 135.6 >ArC), 170.9 >CO), 171.7 >CO) and 190.4
>PhCO); m/z >EI) 291>M 1, 64%), 263 >3), 172 >1), 105
>100) and 91 >3) >HRMS: found M1, 291.0899.
C18H13NO3 requires M, 291.0895).
4.4.11. -1R,5S)-1-Isovalerylketone-3-phenyl-3-azabi-
cyclo[3.1.0]hexane-2,4-dione 25. To a solution of 21
24
>40 mg, 0.12 mmol) >[a]D ˆ161> c 1.02 in CHCl3)) in
THF >2 mL) at 2788C was added TBAF >0.14 mL of a
1.0 M solution in THF, 0.14 mmol) dropwise. The reaction
mixture was then stirred for 1h at 2788C before quenching
with water >3 mL) and allowing to warm to room tempera-
ture. The solution was extracted with CH2Cl2 >3£30 mL),
then the combined fractions dried >MgSO4), ®ltered and the
solvent removed in vacuo to give crude product. This was
puri®ed by ¯ash column chromatography >10% EtOAc±
light petroleum) to give 25 as a colourless oil >25 mg,
23
79%); [a]D ˆ1171 >c 1 .1 7 in CHC)l; nmax >CHCl3)/cm21
3
2961, 2874, 1782, 1721, 1598 and 1496; dH >400 MHz,
CDCl3) 0.97 >3H, d, Jˆ6.7 Hz, CH3), 1.00 >3H, d,
Jˆ6.7 Hz, CH3), 1.98 >1H, dd, Jˆ4.5, 4.2 Hz, CHHCSi),
2.23 [1H, m, CH>CH3)2], 2.33 >1H, dd, Jˆ8.5, 4.2 Hz,
CHHCSi), 2.84 >1H, dd, Jˆ16.7, 6.7 Hz, COCHH), 3.02
>1H, dd, Jˆ8.5, 4.5 Hz, COCH), 3.05 >1H, dd, Jˆ16.7,
6.7 Hz, COCHH), 7.23 >2H, d, Jˆ7.0 Hz, ArH), 7.40 >1H,
t, Jˆ7.1Hz, Ar H) and 7.47 >2H, t, Jˆ7.0 Hz, ArH); dC
>100 MHz, CDCl3) 22.5 >CH3), 24.4 >CH), 29.8 >CH2),
30.4 >CH), 38.7 >C), 50.9 >CH2), 126.4 >ArCH), 128.7
>ArCH), 129.2 >ArCH), 131.1 >ArC), 171.2 >CO), 171.3
>CO) and 200.4 >COCH2); m/z >EI) 271>M 1, 100%), 257
>12), 256 >81), 243 >24), 230 >3), 229 >28), 228 >20), 186
>12) and 95 >48) >HRMS: found M1, 271.1203. C16H17NO3
requires M, 271.1209).
4.4.9. -1R,5S)-1-Methyl-3-phenyl-3-azabicyclo[3.1.0]-
hexane-2,4-dione 23. A solution of 15 >50 mg, 0.1 8 mmol,
91% ee), CsF >42 mg, 0.27 mmol) and 18-crown-6 >5 mg,
0.02 mmol) in THF >2 mL) was stirred overnight before
quenching with saturated aqueous NH4Cl >4 mL). The solu-
tion was then extracted with CH2Cl2 >2£50 mL), washed with
brine >100 mL), dried >MgSO4), ®ltered and the solvent
removed in vacuo. The resulting crude product was then puri-
®ed by ¯ash column chromatography >20% EtOAc±light
petroleum) to yield 23 as a white solid >20 mg, 54%), mp
26
143±1458C; [a]D ˆ141> c 0.37 in CHCl3); nmax >CHCl3)/

4612
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4.5. Typical procedure for CsF mediated substitution
reactions of 3a
4.5.4. -1R,2R,6S,7S)-4-Phenyl-2-thiophenyl-4-azatri-
cyclo[5.2.1.02,6]dec-8-ene-3,5-dione 14. To a solution of
¯ame dried CsF >73 mg, 0.48 mmol) and 18-crown-6
>8 mg, 0.03 mmol) in THF >1mL) at room temperature
under an atmosphere of nitrogen was added a mixture of 6
>100 mg, 0.32 mmol, 98% ee) and diphenyl disul®de
>350 mg, 1.61 mmol) in THF >3 mL). The solution was
then stirred overnight before quenching with saturated
aqueous NH4Cl >4 mL) and extracting with CH2Cl2
>3£30 mL). The combined extracts were dried >MgSO4),
®ltered and the solvent evaporated in vacuo to give crude
product. This was puri®ed by ¯ash column chromatography
>10% EtOAc±light petroleum) to give 14 as a white solid
4.5.1.
-1S,5R)-1-Benzoyl-3-phenyl-3-azabicyclo[3.1.0]
hexane-2,4-dione -2)-24. To a solution of ¯ame dried
CsF >0.12 g, 0.77 mmol) and 18-crown-6 >10 mg,
0.04 mmol) in THF >1mL) at room temperature, under an
atmosphere of nitrogen, was added a mixture of 3a >0.10 g,
0.39 mmol, 95% ee) and benzoyl ¯uoride >0.21mL,
1.93 mmol) in THF >2 mL). The solution was stirred over-
night before quenching with saturated aqueous NH4Cl
>4 mL) and extracting with CH2Cl2 >3£30 mL). The
combined extracts were dried >MgSO4), ®ltered and the
solvent evaporated in vacuo to give crude product. This
was puri®ed by ¯ash column chromatography >5%
EtOAc±light petroleum) to give 24 as a white solid
24
>72 mg, 65%), mp 131±1338C; [a]D ˆ245 >c 0.85 in
CHCl3), other data as previously described. The ee was
determined as 93% by HPLC >OJ column, 10% IPA in
hexane), the retention times were 73 min >minor) and
83 min >major).
24
>49 mg, 44%), mp 217±2208C; [a]D ˆ262 >c 0.88 in
CHCl3) with data as described above.
4.5.2. -1S,5R)-1--10-Hydroxyphenylmethyl)-3-phenyl-3-
azabicyclo[3.1.0]hexane-2,4-dione 26. The above typical
procedure was followed using 3a >0.10 g, 0.39 mmol, 95%
ee), CsF >0.60 g, 0.39 mmol), 18-crown-6 >10 mg,
0.04 mmol) and benzaldehyde >0.20 mL, 1.93 mmol) and
the resulting crude mixture was puri®ed by ¯ash column
chromatography >10% EtOAc±light petroleum) to give a
white solid as a 1:1 mixture of inseparable diastereomers
26, total yield >77 mg, 68%); >Found: C, 73.50; H, 5.12; N,
4.76. Requires C, 73.69; H, 5.16; N, 4.78%); nmax >CHCl3)/
cm21 3606 >OH), 2897, 1779, 1714, 1598 and 1496; m/z
>EI) 293 >M1, 46%), 292 >23), 265 >10), 201 >10), 107 >3)
and 77 >44) >HRMS: found M1, 293.1054. C18H15NO3
requires M, 293.1052). For less polar diastereomer dH
>400 MHz, CDCl3) 1.62 >1H, dd, Jˆ4.7, 3.6 Hz, CHH),
1.72 >1H, dd, Jˆ8.3, 4.7 Hz, CHH), 2.35 >1H, dd, Jˆ8.3,
3.6 Hz, CH), 3.47 >1H, brs, OH), 5.59 >1H, s, CHOH) and
7.16±7.45 >5H, m, ArH). For more polar diastereomer dH
>400 MHz, CDCl3) 1.18 >1H, dd, Jˆ8.3, 4.9 Hz, CHH), 1.60
>1H, dd, Jˆ4.9, 3.6 Hz, CHH), 2.52 >1H, dd, Jˆ8.3, 3.6 Hz,
CH), 3.27 >1H, brs, OH), 5.59 >1H, s, CHOH) and 7.16±7.45
>5H, m, ArH).
4.5.5. -1R,5R)-3-Phenyl-1-trimethylsilyl-4-thioxo-3-azabi-
cyclo[3.1.0]hexan-2-one 28. To a solution of 3a >100 mg,
0.39 mmol, 95% ee) in toluene >5 mL) was added Lawesson's
reagent >78 mg, 0.19 mmol). The solution was then heated to
re¯ux for 4 h before being cooled and the toluene removed in
vacuo to give crude product. This was puri®ed by ¯ash
column chromatography >10% EtOAc±light petroleum) to
give pure product 28 as yellow solid >53 mg, 50%), mp
27
172±1738C; [a]D ˆ19 >c 1.27 in CHCl3); nmax >CHCl3)/
cm21 2956, 2926, 2853, 1742, 1601 and 1498; dH
>400 MHz, CDCl3) 0.22 [9H, s, Si>CH3)3], 1.65±1.70 >2H,
m, CHH1CHH), 3.10 >1H, dd, Jˆ7.2, 3.4 Hz, CH) and
7.16±7.50 >5H, m, ArH); dC >68 MHz, CDCl3) 23.0
>SiCH3), 23.1> C), 27.5 >CH2), 35.4 >CH), 127.7 >ArCH),
128.9 >ArCH), 129.1 >ArCH), 133.9 >ArC), 178.4 >CO) and
209.6 >CS); m/z >EI) 275 >M1, 74%), 260 >21), 127 >15) and
73 >100) >HRMS: found M1, 275.0799. C14H17NOSSi
requires M, 275.0800).
4.5.6. -1R,2R,6R,7S)-4-Phenyl-2-trimethylsilyl-5-thioxo-
4-azatricyclo[5.2.1.02,6]dec-8-en-3-one 29. To a solution
of 6 >100 mg, 0.32 mmol, 98% ee) in toluene >5 mL) was
added Lawesson's reagent >65 mg, 0.16 mmol). The solu-
tion was then heated to re¯ux for 4 days before cooling and
removal of the toluene in vacuo to give crude product. This
was puri®ed by ¯ash column chromatography on silica gel
>5% EtOAc±light petroleum) to give 29 as a yellow solid
4.5.3. -1R,5S)-3-Phenyl-1-thiophenyl-3-azabicyclo[3.1.0]
hexane-2,4-dione 27. The above typical procedure was
followed using 3a >0.10 g, 0.39 mmol, 95% ee), CsF
>0.60 g, 0.39 mmol), 18-crown-6 >10 mg, 0.04 mmol) and
diphenyl disul®de >0.42 g, 1.93 mmol) and the resulting
crude mixture was puri®ed by ¯ash column chromatography
>10% EtOAc±light petroleum) to give 27 as a white solid
24
>31mg, 30%); [ a]D ˆ245 >c 0.30 in CHCl3); nmax
>CHCl3)/cm21 2957, 2929, 2856, 1731, 1709, 1597 and
1498; dH >400 MHz, CDCl3) 0.27 [9H, s, Si>CH3)3], 1.60
>1H, dt, Jˆ8.9, 1.7 Hz, CHH), 1.68 >1H, d, Jˆ8.9 Hz,
CHH), 3.37 >1H, m, CHCSi), 3.62 >1H, m, CHCHCS),
3.72 >1H, d, Jˆ4.5 Hz, CHCS), 6.18 >1H, dd, Jˆ5.5,
2.9 Hz, CHvCH), 6.45 >1H, dd, Jˆ5.5, 2.9 Hz,
CHvCH), 7.04±7.49 >5H, m, ArH); dC >100 MHz,
CDCl3) 22.4 >SiCH3), 47.3 >CH), 49.1> C), 49.7 >CH),
50.1> CH2), 59.8 >CH), 127.7 >ArCH), 129.1 >ArCH),
129.3 >ArCH), 132.5 >CH), 134.8 >ArC), 139.0 >CH),
181.7 >CO) and 213.1 >CS); m/z >EI) 327 >M1, 100%), 73
>79) >HRMS: found M1, 327.1120. C18H21NOSSi requires
M, 327.1113).
24
>70 mg, 61%), mp 152±1548C; [a]D ˆ251> c 1.00 in
CHCl3); nmax >CHCl3)/cm21 2927, 2854, 1778, 1720,
1598, 1499, 1456 and 1375; dH >250 MHz, CDCl3) 2.01
>1H, dd, Jˆ8.5, 5.1Hz, C HH), 2.11 >1H, dd, Jˆ5.1,
4.0 Hz, CHH), 2.85 >1H, dd, Jˆ8.5, 4.0 Hz, CH) and
7.19±7.58 >10H, m, ArH); dC >68 MHz, CDCl3) 29.4
>CH2), 29.9 >CH), 34.8 >C), 126.4 >ArCH), 128.1 >ArCH),
128.5 >ArCH), 129.1 >ArCH), 129.3 >ArCH), 131.4 >ArCH),
133.1 >ArC), 172.0 >CO) and 172.9 >CO); m/z >EI) 295 >M1,
22%), 176 >44), 175 >5) and 147 >40) >HRMS: found M1,
295.0666. C17H13NO2S requires M, 295.0667). The ee was
determined as 91% by HPLC >OJ column, 15% IPA in
hexane), the retention times were 56 min >minor) and
74 min >major).
4.5.7. -1R,4R,5S)-4-Hydroxy-3-phenyl-1-trimethylsilyl-
3-azabicyclo[3.1.0]hexan-2-one 30. To a solution of 3a

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4613
>50 mg, 0.19 mmol, 95% ee) in CH2Cl2 >1mL) at 2788C
was added DIBAL >0.38 mL of a 1.0 M solution in CH2Cl2,
0.38 mmol). The reaction mixture was then stirred for
10 min before quenching with water >2 mL). The solution
was ®ltered to remove aluminium salts and the ®ltrate added
to CH2Cl2 >25 mL). Water was added >25 mL) and the
organic layer separated, dried >MgSO4), ®ltered and the
solvent evaporated off in vacuo to give crude product.
This was then puri®ed by ¯ash column chromatography
>20% EtOAc±light petroleum) to give 30 as a white solid
0.91±0.97 >2H, m, CHH1CHH), 1.45 >1H, m, CH), 3.13
>1H, t, Jˆ11.3 Hz, CHHOH), 3.85 >1H, br s, OH), 2.57 >1H,
dd, Jˆ11.3, 4.3 Hz, CHHOH), 7.10 >1H, t, Jˆ7.10 Hz,
ArH), 7.31>2H, t,
Jˆ7.8 Hz, ArH), 7.49 >2H, d,
Jˆ8.0 Hz, ArH) and 7.85 >1H, br s, NH); dC >100 MHz,
CDCl3) 23.1>Si CH3), 12.8 >CH2), 23.2 >CH), 24.8 >C),
65.4 >CH2), 119.9 >ArCH), 124.3 >ArCH), 129.0 >ArCH),
137.8 >ArC) and 172.5 >CO); m/z >FAB) 264 [>M1H)1,
55%], 246 >32), 93 >64),77 >30), 73 >100) [HRMS: found
>M1H)1, 264.1422. C14H4NO2Si1H requires >M1H),
264.1420].
28
>35 mg, 70 %), mp 121±1238C; [a]D ˆ2146 >c 0.48 in
CHCl3); nmax >CHCl3)/cm21 3584, 2957, 1694, 1600 and
1496; dH >400 MHz, CDCl3) 0.14 [9H, s, Si>CH3)3], 1.02
>1H, dd, Jˆ6.9, 4.4 Hz, CHH), 1.24 >1H, dd, Jˆ4.4, 4.1Hz,
CHH), 2.14 >1H, m, CH), 2.50 >1H, d, Jˆ8.5 Hz, OH), 5.85
>1H, dd, Jˆ8.5, 5.5 Hz, CHOH) and 7.16±7.37 >5H, m,
ArH); dC >68 MHz, CDCl3) 22.9 >SiCH3), 13.3 >CH2),
20.0 >C), 22.9 >CH), 81.5 >CH), 123.0 >ArCH), 125.4
>ArCH), 128.9 >ArCH), 136.6 >ArC) and 175.0 >CO); m/z
>EI) 261>M 1, 100%), 246 >17) and 73 >98) >HRMS: found
M1, 261.1186. C14H19NO2Si requires M, 261.1185).
4.5.10. -1R,5S)-1-Trimethylsilyl-3-oxabicyclo[3.1.0]-
hexan-2-one 33. A solution of 32 >90 mg, 0.34 mmol,
23
[a]D ˆ151> c 0.95 in CHCl3)), in 2 M H2SO4 >8 mL)
was heated at 808C for 2 h before cooling and extract-
ing with CHCl3 >3£50 mL). The combined extracts
were then dried >MgSO4), ®ltered and the solvent
removed in vacuo to give pure product 33 as a colourless
22
oil >58 mg, quantitative); [a]D ˆ284 >c 0.96 in CHCl3);
nmax >CHCl3)/cm21 2959, 2906, 1755; dH >400 MHz,
CDCl3) 0.1 1 [9H, s, SiH>C) ], 0.95 >1H, app. t, J ˆ
3 3
4.5.8. -1R,2R,5R,6S,7S)-5-Hydroxy-4-phenyl-2-trimethyl-
silyl-4-azatricyclo[5.2.1.02,6]dec-8-en-3-one 31. To a solu-
tion of 6 >100 mg, 0.32 mmol, 98% ee) in CH2Cl2 >2 mL) at
2788C was added DIBAL >0.64 mL of a 1.0 M solution in
CH2Cl2, 0.64 mmol). The reaction mixture was then stirred
for 8 min before quenching with water >2 mL). The solution
was ®ltered to remove aluminium salts and the ®ltrate added
to CH2Cl2 >25 mL). Water was added >25 mL) and the
organic layer separated, dried >MgSO4), ®ltered and the
solvent evaporated off in vacuo to give crude product.
This was then puri®ed by ¯ash column chromatography
>50% EtOAc±light petroleum) to give 31 as a white solid
4.3 Hz, CHH), 1.14 >1H, dd, Jˆ7.0, 4.3 Hz, CHH), 2.08
>1H, m, CH) and 4.24 >2H, m, CH2O); dC >100 MHz,
CDCl3) 23.1>Si CH3), 15.8 >CH2), 16.2 >C), 22.6 >CH),
68.4 >CH2) and 1 78.8 C> O); m/z >FAB) 171 [>M1H)1,
35%], 155 >70), 127 >29), 111 >52), 81 >100) and 73 >50)
[HRMS: found >M1H)1, 171.0840. C8H14O2Si1H
requires >M1H), 171.0841].
4.5.11. -1R,5S)-3-Phenyl-1-trimethylsilyl-3-azabicyclo
[3.1.0]hexan-2-one 34. To a stirred solution of 30
>50 mg, 0.19 mmol) in CH2Cl2 >2 mL) at 2788C was
added triethylsilane >61 mL, 0.38 mmol) and trimethyl-
silyltri¯ate >70 mL, 0.38 mmol). The reaction mixture
was stirred at 2788C for 2 h before allowing to warm to
room temperature and stirring overnight. The reaction was
then quenched with saturated aqueous NaHCO3 >2 mL)
before extracting with CH2Cl2 >4£10 mL). The combined
extracts were dried >MgSO4), ®ltered and the solvent
removed in vacuo to give crude product. This was puri®ed
by ¯ash column chromatography >5% EtOAc±light petro-
leum) to give pure 34 as a white solid >37 mg, 79%), mp
22
>83 mg, 83%) mp .2308C; [a]D ˆ139 >c 0.31in CHCl 3);
nmax >CHCl3)/cm21 3594 >OH), 2983, 2955, 2900, 1678,
1599 and 1496; dH >400 MHz, CDCl3) 0.19 [9H, s,
Si>CH3)3], 1.47 >1H, d, Jˆ1.6 Hz, CHH), 1.48 >1H, d,
Jˆ1.6 Hz, CHH), 2.29 >1H, br d, Jˆ6.8 Hz, OH), 3.06
>1H, dd, Jˆ7.6, 3.8 Hz, CHCHOH), 3.20 >1H, m, CHCSi),
3.26 >1H, m, CHCHCHOH), 5.62 >1H, br t, Jˆ6.8 Hz,
CHOH), 6.25 >1H, dd, Jˆ5.6, 2.8 Hz, CHvCH), 6.43
>1H, dd, Jˆ5.6, 2.8 Hz, CHvCH), 7.20 >1H, t, Jˆ7.2 Hz,
ArH), 7.30 >2H, d, Jˆ7.2 Hz, ArH) and 7.36 >2H, t,
Jˆ7.1Hz, Ar H); dC >100 MHz, CDCl3) 22.5 >SiCH3),
45.0 >CH), 46.6 >CH), 48.0 >CH), 50.2 >C), 50.3 >CH2),
82.6 >CH), 124.3 >ArCH), 126.1 >ArCH), 129.0 >ArCH),
133.3 >CH), 136.6 >ArC), 138.4 >CH) and 176.0 >CO); m/z
>EI) 313 >M1, 73%), 311 >14), 296 >26), 295 >100), 294 >19),
247 >68) and 73 >37) >HRMS: found M1, 313.1474.
C18H23NO2Si requires M, 313.1498).
22
74±768C; [a]D ˆ11 1 5c> 1.02 in CHCl3); nmax >CHCl3)/
cm21 2956, 2883, 1681, 1598 and 1492; dH >400 MHz,
CDCl3) 0.1 5 [9H, s, Si>CH3)3], 0.90 >1H, dd, Jˆ4.1,
4.0 Hz, CHH), 1.11 >1H, dd, Jˆ6.9, 4.1Hz, CH H), 1.87
>1H, m, CH), 3.81>1H, d, Jˆ9.9 Hz, CHHNPh), 4.02 >1H,
dd, Jˆ9.9, 5.8 Hz, CHHNPh), 7.08 >1H, dt, Jˆ7.5, 1.0 Hz,
ArH), 7.32 >2H, dt, Jˆ7.5, 0.8 Hz, ArH) and 7.56 >2H, dd,
Jˆ7.8, 0.9 Hz, ArH); dC >100 MHz, CDCl3) 22.8
>SiCH3), 16.0 >CH), 16.3 >CH2), 20.4 >C), 49.8 >CH2),
119.2 >ArCH), 123.7 >ArCH), 128.7 >ArCH), 139.7
>ArC) and 176.8 >CO); m/z >EI) 245 >M1, 78%), 230
>100), 156 >39), 145 >20) and 77 >9) >HRMS: found M1,
245.1263. C14H19NOSi requires M, 245.1236).
4.5.9. -1R,2S)-2-Hydroxymethyl-1--N-phenylcarbox-
amido)-1-trimethylsilylcyclopropane 32. To a solution
of 3a >50 mg, 0.19 mmol, 95% ee) in EtOH >10 mL) at
2788C was added NaBH4 >75 mg, 1.9 mmol). The reaction
was then stirred at 2788C for 4 h before quenching with
water >10 mL) and extracting with CHCl3 >3£30 mL). The
combined extracts were dried >MgSO4), ®ltered and the
solvent removed in vacuo to give 32 as a white solid
4.5.12. -1R,4S,5S)-4-Allyl-3-phenyl-1-trimethylsilyl-3-
azabicyclo[3.1.0]hexan-2-one 35. To a stirred solution
of 30 >100 mg, 0.38 mmol) in CH2Cl2 >3 mL) at 2788C
were added trimethylsilyltri¯ate >0.14 mL, 0.77 mmol)
and allyltrimethylsilane >0.12 mL, 0.77 mmol). After
stirring at 2788C for 1h the reaction mixture was allowed
23
>48 mg, 95%), mp 119±1228C; [a]D ˆ151> c 0.95 in
CHCl3); nmax >CHCl3)/cm21 3430 >OH), 2956, 1650, 1597
and 1500; dH >400 MHz, CDCl3) 0.12 [9H, s, Si>CH3)3],

4614
D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
to warm to room temperature and stirred overnight. The
reaction was then quenched with saturated aqueous
NaHCO3 >2 mL), extracted with CH2Cl2 >3£1 0 mL),
dried >MgSO4), ®ltered and the solvent removed in
vacuo to give crude product. This was puri®ed by ¯ash
column chromatography >2% EtOAc±light petroleum)
to give 35 as a white solid >70 mg, 64%), mp 78±
a further 30 min before quenching with 1M HCl >5 mL) and
adding water >30 mL). The solution was extracted with
CH2Cl2 >3£30 mL) and the combined extracts dried
>MgSO4), ®ltered and the solvent removed in vacuo. The
crude product obtained was puri®ed by ¯ash column
chromatography >20% EtOAc±light petroleum) to give
37 as a white solid >59 mg, 68%), mp 127±1298C;
22
24
818C; [a]D ˆ145 >c 0.99 in CHCl3); >Found: C, 71.11;
[a]D ˆ11 3 c> 0.91in CHCl 3); >Found: C, 64.25; H,
H, 8.15; N, 5.05. Requires C, 71.53; H, 8.12; N, 4.91%);
nmax >CHCl3)/cm21 2956, 2901, 1668, 1559 and 1492;
dH >250 MHz, CDCl3) 0.1 4 [9H, s, Si>CH3)3], 0.87 >1H,
dd, Jˆ4.1, 4.1 Hz, CHHCSi), 1.07 >1H, dd, Jˆ6.9, 4.1Hz,
CHHCSi), 1.70 >1H, dd, Jˆ6.9, 4.1Hz, C HCHNPh),
2.22±2.43 >2H, m, CH2vCHCH2), 4.29 >1H, dd, Jˆ6.5,
3.2 Hz, CHCH2CHvCH2), 5.05±5.16 >2H, m, CHvCH2),
5.76 >1H, m, CH2vCHCH2), 7.12 >1H, t, Jˆ7.3 Hz,
ArH), 7.32 >2H, t, Jˆ7.4 Hz, ArH) and 7.42 >2H, d,
Jˆ7.5 Hz, ArH); dC >100 MHz, CDCl3) 22.9 >SiCH3),
15.7 >CH2), 19.9 >C), 20.9 >CH), 38.0 >CH2), 59.8 >CH),
118.9 >CH2), 123.1 >ArCH), 124.8 >ArCH), 128.8 >ArCH),
132.4 >CH), 138.1 >ArC) and 176.3 >CO); m/z >EI) 285
>M1, 3%), 270 >4), 244 >100), 104 >7), 77 >14) and 73
>97) >HRMS: found M1, 285.1543. C17H23NOSi requires
M, 285.1549).
4.21; N, 2.92. Requires C, 64.29; H, 4.27; N, 3.12%); nmax
>CHCl3)/cm21 2927, 2855, 1781, 1716, 1684, 1598, 1580
and 1500; dH >400 MHz, CDCl3) 3.37 >1H, dd, Jˆ13.4,
7.2 Hz, CHH), 3.44 >1H, dd, Jˆ13.4, 4.6 Hz, CHH), 4.08
>1H, dt, Jˆ7.2, 4.6 Hz, CH2CH), 4.90 >1H, d, Jˆ4.6 Hz,
CHCOPh) and 7.18±7.93 >15H, m, ArH); dC >68 MHz,
CDCl3) 27.6 >CH2), 44.3 >CH), 54.9 >CH), 126.3 >ArCH),
126.5 >ArCH), 128.0 >ArC), 128.6 >ArCH), 128.8 >ArCH),
129.1 >ArCH), 129.6 >ArCH), 129.8 >ArCH), 131.5 >ArC),
133.5 >ArCH), 134.2 >ArCH), 133.5 >ArC), 170.9 >CO),
176.1 >CO) and 192.3 >PhCO); m/z >FAB) 450 [>M1H)1,
100%] [HRMS: found >M1H)1, 450.0616. C24H19NO3Se 1
H requires >M1H), 450.0608].
4.6. X-Ray crystallography
4.6.1. Cyclopropylimide 3a. Crystal data. C14H17NO2Si,
Mˆ259.38, orthorhombic, aˆ6.385>2), bˆ12.228>2),
4.5.13. -1R,2R,5S,6S,7S)-5-Allyl-4-phenyl-2-trimethyl-
a
silyl-4-azatricyclo[5.2.1.02,6]dec-8-en-3-one 36. To
Ê
Ê 3
cˆ17.906>3) A, Uˆ1398.0>5) A , Tˆ150>2) K, space group
P212121 >No. 19), Zˆ4, Dcˆ1.237 cm23, m>Mo Ka) ˆ
0.162 mm21, 2444 unique re¯ections corrected for absorp-
tion >Rint 0.023) and used in all calculations. Final R1
[2368F.4s>F)]ˆ0.0445 and wR>all F2) was 0.0969. The
Flack absolute structure parameter re®ned to 0.1>2). CCDC
deposition number 179331.
22
stirred solution of 31 >50 mg, 0.16 mmol, [a]D ˆ139 >c
0.31in CHCl )), in CH2Cl2 >2 mL) at 2788C were added
3
trimethylsilyltri¯ate >58 mL, 0.32 mmol) and allyltrimethyl-
silane >50 mL, 0.32 mmol). After stirring at 2788C for 2 h
the reaction mixture was allowed to warm to room tempera-
ture and stirred overnight before being quenched with satur-
ated aqueous NaHCO3 >2 mL), extracted with CH2Cl2
>3£10 mL), dried >MgSO4), ®ltered and the solvent
removed in vacuo to give crude product. This was puri®ed
by ¯ash column chromatography >10% EtOAc±light petro-
leum) to give 36 as a white solid >35 mg, 65%), mp 97±
4.6.2. Tricyclic imide 6. Crystal data. C18H21NO2Si,
Mˆ311.45, monoclinic, aˆ6.2395>4), bˆ14.8305>11),
Ê
Ê 3
cˆ9.4695>11) A, bˆ106.490>5)8, Uˆ840.22>13) A , T ˆ
298>2) K, space group P21 >No. 4), Zˆ2, Dcˆ1.231 cm23
,
1008C; [a]D ˆ133 >c 0.61in CHCl 3); nmax >CHCl3)/cm21
23
m>Mo Ka)ˆ0.146 mm21, 2953 unique re¯ections measured
>Rint 0.035) and used in all calculations. Final R1
[2608F.4s>F)]ˆ0.0358 and wR>all F2) was 0.0893. The
Flack absolute structure parameter re®ned to 0.00>14).
CCDC deposition number 179330.
2966, 1695, 1668, 1596 and 1493; dH >400 MHz, CDCl3)
0.26 [9H, s, Si>CH3)3], 1.43 >1H, dt, Jˆ8.5, 1.7 Hz, CHH),
1.46 >1H, d, Jˆ8.5 Hz, CHH), 2.00 >1H, m,
CH2vCHCHH), 2.46 >1H, m, CH2vCHCHH), 2.58 >1H,
dd, Jˆ4.1, 2.4 Hz, CHCHNPh), 3.10 >1H, m, CH), 3.26 >1H,
m, CH), 3.65 >1H, ddd, Jˆ10.8, 3.4, 2.4 Hz, CHNPh), 5.11±
5.16 >2H, m, CHvCH2), 5.74 >1H, m, CHvCH2), 6.21>1H,
dd, Jˆ5.6, 2.9 Hz, CHvCH), 6.41>1H, dd, Jˆ5.6, 2.9 Hz,
CHvCH), 7.16 >1H, t, Jˆ7.4 Hz, ArH), 7.23 >2H, d,
Jˆ7.3 Hz, ArH) and 7.33 >2H, t, Jˆ7.4 Hz, ArH); dC
>100 MHz, CDCl3) 21.7 >SiCH3), 38.9 >CH2), 44.7 >CH),
47.8 >CH), 47.9 >CH), 49.3 >CH2), 50.2 >C), 61.2 >CH),
118.1 >CH2), 124.5 >CH), 125.5 >CH), 128.8 >CH), 132.6
>CH), 133.8 >CH), 137.9 >C), 140.7 >CH) and 177.0 >CO);
m/z >EI) 337 >M1, 2%), 296 >35), 271 >10), 230 >100) and 73
>32) >HRMS: found M1, 337.1874. C21H27NOSi requires M,
337.1861).
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council >EPSRC) for support of C. D. G. and for the provi-
sion of a four-circle diffractometer, and we thank the
University of Nottingham for support of D. J. A. We
would also like to thank Professor Henk Hiemstra for the
gift of samples of the precursors to imides 4 and 5.
References
4.5.14. -3S,4R)-4-Benzoyl-3-phenylselenomethyl-1-phenyl-
pyrrolidine-2,5-dione 37. NaBH4 >22 mg, 0.58 mmol)
was added to a solution of diphenyl diselenide >90 mg,
0.29 mmol) in EtOH >1.5 mL) and the reaction mixture
stirred for 10 min before addition of a solution of 24
>50 mg, 0.19 mmol) in EtOH >3 mL). This was stirred for
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>b) Cox, P. J.; Simpkins, N. S. Tetrahedron: Asymmetry 1991,
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2001, 2915.

D.J.Adams et al./ Tetrahedron 58 '2002) 4603±4615
4615
3. For a recent example, see: de Sousa, S. E.; O'Brien, P.;
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Odriozola, J. M.; Oiarbide, M.; Palomo, C. J.Chem.Soc,.
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Ref. 6a.
N. S. J.Chem.Soc,. Perkin Trans.1
1999, 3177. For a more
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1998, 1729.
10. Precursors to imides 4 and 5 were kindly supplied to us by
Professor H. Hiemstra, but we did not have suf®cient quanti-
ties to optimise the chemical yields. See: Ostendorf, M.;
Romagnoli, R.; Pereiro, I. C.; Roos, E. C.; Moolenaar, M. J.;
Speckamp, W. N.; Hiemstra, H. Tetrahedron: Asymmetry
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11. This outcome presumably re¯ects the ring strain that would
result from O-silylation. Similar results have been observed
for small ring lactams, see for example >a) Cossio, F. P.;