1,3-Dipolar cycloadditions to unsymmetrical ketone-derived chiral stabilized azomethine ylides: Strategies for the synthesis of highly substituted amino acids

Article abstract of DOI:10.1055/s-2005-918487

We report herein, the first generation of unsymmetrical ketone-derived chiral stabilized azomethine ylides. Intramolecular and intermolecular cycloaddition strategies have been utilized to synthesize both an enantiomerically pure bicyclic proline derivati

Full text of DOI:10.1055/s-2005-918487

PAPER
3271
1,3-Dipolar Cycloadditions to Unsymmetrical Ketone-Derived Chiral
Stabilized Azomethine Ylides: Strategies for the Synthesis of Highly
Substituted Amino Acids
S
trategies for the
S
a
ynthesis of
v
H
ighly Subs
i
tituted
d
Amino
A
cids J. Aldous,a Michael G. B. Drew,b William N. Draffin,b Estelle M-N. Hamelin,b Laurence M. Harwood,*b
Sukanthini Thurairatnama
a
Rhône Poulenc Rhorer Limited, Rainham Road South, Dagenham, Essex RM10 7XS, UK
School of Chemistry, University of Reading, Whiteknights, Reading, Berkshire, RG6 6AD, UK
b
Fax +44(118)3786121; E-mail: l.m.harwood@reading.ac.uk
Received 14 September 2005
Dedicated to Professor Steven V. Ley FRS on the occasion of his 60th birthday
X
Abstract: We report herein, the first generation of unsymmetrical
Y
Y
X
Z
ketone-derived chiral stabilized azomethine ylides. Intramolecular
Ph
N
O
Z
and intermolecular cycloaddition strategies have been utilized to
synthesize both an enantiomerically pure bicyclic proline derivative
and an enantiomerically pure b-hydroxy-a-amino acid.
(i)
H
O
CO2H
N
H
H
4
5
Key words: azomethine ylide, b-hydroxy-a-amino acid, proline,
intramolecular, cycloaddition
Scheme 2 Reagents and conditions: (i) aq MeOH Pearlman’s cata-
lyst, TFA, H2 (5 atm)
A previous communication by this group has reported the
cycloaddition of acetone-derived azomethine ylides with
alkene dipolarophiles (Scheme 1).1 These cycloadducts
have been demonstrated to undergo degradation via cata-
lytic hydrogenolysis to furnish highly substituted diaste-
reomerically pure 5,5-dimethylprolines (Scheme 2). 5,5-
Disubstitution of proline derivatives remains an important
objective2 due the profound effect of such residues upon
cis peptide conformation3 and stabilization of type 1 b-
turn configuration.4
stereoselective syntheses of bicyclic prolines via intramo-
lecular cycloaddition of ylides derived from condensation
of the (5S)-phenylmorpholine-2-one (1) template with al-
dehydes possessing a terminal double or triple bond.6
Building on the success of this intramolecular strategy, a
strategy towards 5-substituted bicyclic prolines utilizing a
ketone equipped with an alkene tether was envisaged.
To this end, hept-6-en-2-one dimethyl ketal was synthe-
sized by protection of the respective ketone and reacted
with (5S)-phenylmorpholine-2-one (1) in the presence of
magnesium bromide etherate in THF at reflux using a
Soxhlet extractor loaded with 3Å molecular sieves to re-
move water. Gratifyingly this strategy resulted in the iso-
lation of a single cycloadduct 6 in 20% overall purified
The intramolecular 1,3-dipolar cycloaddition of azo-
methine ylides is a useful method for the construction of
biologically important heterocycles and has been the sub-
ject of a recent review.5 Our group has reported several
1
yield with the exo- configuration at C-4 (Scheme 3). H
and 13C NMR spectroscopic analyses were consistent with
the predicted gross structure of the new cycloadduct and
the configuration of the cycloadduct was confirmed by X-
ray crystal structure determination (Figure 1).7–10
H
H
N
H
Ph
(i)
Ph
N
O
O
O
Following the success of the synthesis of a bicyclic pro-
line derivative with a fused 5-membered ring, our atten-
tion turned to the synthesis of the six-membered bicyclic
proline analogue. Unfortunately, the reaction of (5S)-phe-
nylmorpholine-2-one (1) with oct-7-ene-2-one dimethyl
O
1
(ii)
H
X
H
X
8
7
H
9
8
7
H
9
Y
Ph
Y
N
Ph
N
1
1
Z
2
3
6
5
Z
2
3
6
5
H
H
4
4
O
O
O
O
H
2
3
H
Ph
N
O
Ph
N
Ph
N
O
(ii)
(i)
Scheme 1 Reagents and conditions: (i) D, THF, MgBr2·OEt2, ace-
tone dimethyl ketal; (ii) dipolarophile
H
O
O
O
O
6
1
SYNTHESIS 2005, No. 19, pp 3271–3278
Advanced online publication: 14.11.2005
DOI: 10.1055/s-2005-918487; Art ID: C07005SS
x
x.
x
x
.
2
0
0
5
Scheme
3
Reagents and conditions: (i) and (ii) D, THF,
MgBr2·OEt2 (1 or 10 equiv), hept-2-ene-6-one dimethyl ketal
© Georg Thieme Verlag Stuttgart · New York

3272
D. J. Aldous et al.
PAPER
sium bromide etherate in THF yielded three out of the four
possible cycloadducts. The stereochemistry of adduct 8a
was assigned by X-ray crystal structure determination as
C-9-syn-C-7-exo and the proton at C-6 was established to
be in the expected a-configuration (Figure 2).11 The struc-
1
tures of the other cycloadducts were determined by H
NMR NOE experiments as anti-exo 8b and anti-endo 8c.
No trace of the syn-endo adduct was detected on careful
examination of the crude reaction mixture (Scheme 5).
Figure 1 Crystal structure of cycloadduct 6
acetal using the same conditions as above led only to de-
composition of the starting materials; whereas use of a
lower boiling point solvent (diethyl ether) resulted in re-
covery of the starting materials. The problem here appears
to lie in the lack of stability of the ketal to the reaction con-
ditions needed to promote ylide formation.
Hydrogenolysis of the cycloadduct 6 was achieved by stir-
ring at room temperature in aqueous methanol using TFA
and Pearlman’s catalyst under five atmospheres of hydro-
gen for 48 hours. After work-up and removal of solvent,
trituration of the resultant residue with diethyl ether af-
forded the bicyclic proline derivative 7 in quantitative
yield (Scheme 4).
Figure 2 Crystal structure of cycloadduct 8a
H
Ph
N
H
O
O
(i)
H
H
Ph
N
O
H
(i)
H
O
O
O
H
O
CO2H
N
H
H
H
H
Ph
Me
Ph
H
Ph
Me
Ph
H
Ph
Me
Ph
H
NR
O
NR
O
NR
7
6
N
O
N
O
N
O
Scheme 4 Reagents and conditions: (i) aq MeOH TFA, Pearlman’s
O
H
H
H
H
H
catalyst, H2 (5 atm)
O
O
O
syn-exo
anti-exo
1 equivalent MgBr2×Et2O
anti-endo
We have observed that the presence of aromatic substitu-
ents on the azomethine ylide leads to stabilization of the
ylide. Thus our attention turned to ylides derived from
benzophenone in the hope that the two phenyl groups
would stabilize the resultant ylide and widen the range of
dipolarophiles that would react with these systems. How-
ever, reaction of benzophenone dimethyl acetal with (5S)-
phenylmorpholine-2-one and N-methylmaleimide in re-
fluxing THF in the presence of magnesium bromide ether-
ate failed to yield any expected cycloadduct. Possibly the
diphenyl-substituted ylide formed during this reaction is
too sterically hindered to form or to allow the approach of
the dipolarophile.
R = Me 8a: 10%
R = Ph
8b: 10%
9b: 10%
8c: 17%
9c: 12%
9a: 17%
10 equivalent MgBr2×Et2O
R = Me 8a: 15%
R = Ph
8b: 10%
9b: 10%
8c: –
9c: 1%
9a: 12%
Scheme 5 Reagents and conditions: (i) D, THF, MgBr2·OEt2, ace-
tophenone dimethyl ketal; (ii) dipolarophile
Reaction of (5S)-phenylmorpholin-2-one (1) with aceto-
phenone dimethyl acetal and N-phenylmaleimide in the
presence of magnesium bromide etherate likewise yielded
three adducts in the crude reaction mixture (Scheme 5).
The configuration of the anti-endo cycloadduct 9c was de-
termined by X-ray crystal structure analysis (Figure 3)11
and the two remaining adducts were assigned by 1H NMR
NOE experiments as the syn-exo 9a and anti-exo 9b cy-
cloadducts. In both cycloadditions the anti-endo cycload-
duct was the major product.
In order to reduce steric hindrance but still study the effect
of adding an aryl substituent to stabilize the ylide, reaction
between (5S)-phenylmorpholin-2-one (1) and acetophe-
none dimethyl acetal in the presence of dipolarophile was
next investigated. Refluxing 1 and acetophenone dimethyl
acetal in the presence of N-methylmaleimide and magne-
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York

PAPER
Strategies for the Synthesis of Highly Substituted Amino Acids
3273
H
Ph
Ph
CO2Me
CO2Me
H
H
Ph
N
O
H
H
N
Ph
N
Ph
(ii)
(i)
H
H
O
O
O
O
O
1
11c
Scheme 7 Reagents and conditions: (i) D, THF, MgBr2·OEt2, ace-
tophenone dimethyl ketal; (ii) dimethyl fumarate
Figure 3 Crystal structure of cycloadduct 9c
A study of the reaction of this ylide with non-maleimide
dipolarophiles showed a greater stereoselectivity. Thus,
reaction of (5S)-phenylmorpholin-2-one (1) with ace-
tophenone dimethyl acetal and dimethyl maleate in the
presence of magnesium bromide etherate in refluxing
THF yielded only one cycloadduct, albeit in poor isolated
yield (8%) (Scheme 6). Purification by flash column chro-
matography and X-ray crystal structure analysis of the cy-
cloadduct revealed it to be the anti-endo cycloadduct 10c
(Figure 4).11
Figure 5 Crystal structure of cycloadduct 11c
H
Ph
CO2Me
CO2Me
Ph
H
H
Ph
N
O
H
H
N
Ph
N
pholin-2-one (1) with acetophenone dimethyl acetal and
acrylonitrile in the presence of magnesium bromide ether-
ate, yielded a single adduct in 20% isolated yield
(Scheme 8), the configuration of which was determined to
be anti-endo- 12c by 1H NMR NOE investigation. The cy-
cloaddition was repeated using methyl acrylate as the di-
polarophile, furnishing a single cycloadduct 13 in 38%
yield upon purification by flash column chromatography
(Scheme 9) and this was again assigned the anti-endo
configuration 13c by NOE analysis. Although these yields
are modest, the reactions occur with very high diastereo-
selectivity. In addition, singly activated dipolarophiles are
normally unreactive with stabilized ylides derived from
the morpholinone template so this reactivity is notewor-
thy.
Ph
(ii)
(i)
H
H
O
O
O
O
O
10c
1
Scheme 6 Reagents and conditions: (i) D, THF, MgBr2·OEt2, ace-
tophenone dimethyl ketal; (ii) dimethyl maleate
Ph
H
Ph
CN
H
H
Ph
N
O
H
H
N
Ph
N
Ph
(ii)
(i)
H
Figure 4 Crystal structure of cycloadduct 10c
O
O
O
1
O
O
12c
Likewise, reaction of (5S)-phenylmorpholin-2-one (1)
with acetophenone dimethyl acetal and dimethyl fumarate
under the same conditions yielded a single cycloadduct in
43% yield (Scheme 7). X-ray crystal structure determina-
tion (Figure 5) also revealed this to be the anti-endo cy-
cloadduct 11c.11
Scheme 8 (i) Reagents and conditions: (i) D, THF, MgBr2·OEt2,
acetophenone dimethyl ketal; (ii) acrylonitrile, D
The favored formation of cycloadducts having the anti-
endo configuration can be rationalized by invoking a cy-
cloaddition pathway involving the anti ylide undergoing
endo cycloaddition by a type 1 interaction. This result is
in keeping with our previous studies with ylides derived
from benzaldehyde.12
In order to investigate the reactivity of this ylide further,
the cycloaddition of mono-activated alkene dipolaro-
philes was investigated. The reaction of (5S)-phenylmor-
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York

3274
D. J. Aldous et al.
PAPER
Ph
H
O
Ph
H
H
Ph
CO2Me
Ph
N
O
H
Ph
N
O
H
NO2
H
H
N
H
O
Ph
(ii)
N
Ph
H
H
N
(i)
Ph
H
14
O
(i)
O
O
O
O
O
1
O
1
13c
Ph
O
H
H
Scheme 9 (i) Reagents and conditions: (i) D, THF, MgBr2·OEt2,
Ph
N
acetophenone dimethyl ketal; (ii) methyl acrylate
NO2
H
O
O
15
In order to investigate the effect of switching the cycload-
dition from type 1 to type 3, the cycloadditions were re-
peated using 10 equivalents of magnesium bromide
etherate. In the case of the maleimide dipolarophiles a
preference was shown for exo cycloaddition but no pref-
erence for reaction via the syn or anti ylide. In the case of
dimethyl maleate or dimethyl fumarate dipolarophiles
only the anti-endo configuration was observed
(Schemes 6, 7). The hydrogenolysis of the major cycload-
ducts 8c–13c to yield their corresponding 5-methyl-5-
phenyl substituted prolines was attempted using the stan-
dard procedure [Pearlman’s catalyst, H2 (5 atm), MeOH–
H2O, TFA]. Unfortunately 1H NMR analysis of the crude
material resulting from the hydrogenolysis of the N-meth-
ylmaleimide cycloadduct 7c showed a complex mixture
of products and did not indicate the presence of the de-
sired amino acid. It is proposed that additional hydro-
genolysis of the second benzylamine is occurring.
Repetition of the hydrogenolysis at atmospheric pressure
showed two doublets d = 1.55 and 1.47 on 1H NMR anal-
ysis, which we assign to the C-5 methyl group suggesting
the both benzylamine bonds had been cleaved and that an
inseparable mixture of products was present.
Scheme 10 Reagents and conditions: (i) D, THF, MgBr2·OEt2, 1,1-
dimethoxyethylbenzene, p-nitrobenzaldehyde
Figure 6 Crystal structure of cycloadduct 15
Hydrogenolysis of both cycloadducts using standard pro-
cedures furnished the same product, (2S,3R)-2-amino-3-
hydroxy-3-(4-aminophenyl)propanoic
acid
(16)
(Scheme 11) showing the 14 and 15 to be epimeric at C-9
and indicating that stereochemical fidelity had been pre-
served at C-7. Thus both syn- and anti- ylides are involved
in cycloaddition.
1
Similarly, H NMR analysis of the crude reaction mix-
tures from the hydrogenolysis of the cycloadducts formed
by the cycloaddition of the other dipolarophiles revealed
none of the desired amino acids. It is clear that the pres-
ence of a second benzylamine prevents the use of the ace-
tophenone derived ylides for the synthesis of 5-methyl-5-
phenyl substituted prolines.
Ph
O
H
H
Ph
N
NO2
H
O
HO
O
14
H2N
(i)
To explore the reactivity of these acetophenone derived
ylides further, it was decided to investigate the cycloaddi-
tion with aldehyde dipolarophiles. As previously demon-
strated by our group with aldehyde derived cycloadducts,
the products resulting from the trapping of ylides derived
from (5S)-phenylmorpholin-2-one (1) with aldehydes fur-
nish b-hydroxy-a-amino acids upon hydrogenolysis of the
template.13
NO2
Ph
H
CO2H
O
H
H
16
Ph
N
O
NO2
H
O
15
Scheme 11 Reagents and conditions: (i) MeOH, HCl, D, 1 h, then
Pearlman’s catalyst, TFA, H2 (1 atm)
With this in mind, the reaction of (5S)-phenylmorpholin-
2-one (1) with acetophenone dimethyl acetal in the pres-
ence of magnesium bromide etherate in refluxing 1,4-di-
oxane with p-nitrobenzaldehyde was attempted. After 2
hours, work-up and chromatographic purification fur-
nished anti-exo 14 and syn-exo 15 cycloadducts in 42%
and 18% yield respectively (Scheme 10). The configura-
tion of the minor cycloadduct was confirmed by X-ray
crystal structure determination (Figure 6).11
In conclusion we have reported the first instance of gener-
ation and trapping of unsymmetrical ketone-derived
chiral stabilized azomethine yildes. In investigating the
reactivity of these ylides we have demonstrated an intrigu-
ing exo-stereoselective intramolecular dipolar cycloaddi-
tion. Hydrogenolysis of the template yields the
diastereomerically pure bicyclic proline derivative 7. The
reactivity of acetophenone derived ylides with alkene di-
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York

PAPER
Strategies for the Synthesis of Highly Substituted Amino Acids
3275
(1R,3S,5R)-2-Aza-1-methyl[3.3.0.1,5]bicyclooctane-3-carboxylic
Acid (7)
polarophiles with different catalyst loading has been dem-
onstrated. Finally a ketone derived ylide precursor has
been identified which favors reaction with an electron-de-
ficient aldehyde dipolarophile. This has been illustrated
with the synthesis of the enantiomerically pure b-hy-
droxy-a-amino acid 16.
The cycloadduct 6 (40 mg, 0.14 mmol, 1 equiv) was dissolved in
MeOH (2 mL) and H2O (0.1 mL) in a Fisher Porter bottle. TFA (11
mL, 0.12 mmol, 1 equiv) and Pearlman’s Catalyst [Pd(OH)2, 40 mg]
were added to the stirring suspension, which was then degassed and
subjected to hydrogen at 5 atm for 24 h. The solution was then
passed through a pad of Celite® to remove the catalyst and the sol-
vent was removed in vacuo. Trituration of the crude mixture with
Et2O led to precipitation of the amino acid, which was then recrys-
tallized from EtOH–PE and dried in vacuo to give a colorless pow-
Reagents were obtained from Aldrich, Fluka (Poole Dorset) and
used as supplied. All aldehydes were distilled under reduced pres-
sure before use. CH2Cl2 and MeCN were dried by distillation over
CaH2. THF and Et2O were dried by distillation over sodium ben-
zophenyl ketyl under dry N2. Petroleum ether (PE) used refers to the
fraction with boiling range 30–40 °C. TLC analysis was carried out
using Merck aluminum-backed plates coated with 0.2 mm silica and
were visualized either by fluorescence quenching or development
using 2% aq KMnO4. Flash column chromatography was carried
out using Merck 60 silica gel. IR spectra were recorded on a Perkin-
Elmer Paragon 1000 FT-IR spectrometer and recorded as KBr discs
or as a thin film between NaCl plates. NMR spectra were recorded
using a Bruker DPX250 or a Bruker AMX400 instrument. Peak po-
sitions are recorded in ppm. Deuterated solvents were purchased
from Goss Scientific and were >99% pure Specific rotation mea-
surements were recorded on a Perkin-Elmer 341 polarimeter, using
the sodium D line. Melting points were recorded using a Kofler
heated stage microscope and are uncorrected. Mass spectrometric
data were recorded using a VG Fisons Autospec, under conditions
of chemical ionization using ammonia as the ionizing source peaks
are quoted in the form of m/z (relative intensity).
25
der (23 mg, ~100%); mp 157–160 °C; [a]D –13.2 (c = 0.25,
MeOH).
1H NMR (250 MHz, CD3OD): d = 4.45 (1 H, dd, J = 7.6, 9.1 Hz,
2a-H), 2.42–2.15 (2 H, m), 2.14–1.90 (5 H, m), 1.88–1.58 (2 H, m),
1.55 (3 H, s, CH3).
13C NMR (62.5 MHz, CD3OD): d = 174.3 (C=O), 76.1 (C), 63.4
(CH), 51.0 (CH or CH3), 40.1 (CH2), 36.7 (CH2), 33.6 (CH2), 26.1
(CH2), 25.8 (CH3 or CH).
MS (CI): m/z (%) = 170 (100), 124 (51).
HRMS (CI): m/z calcd for (MH+) C9H15NO2: 170.1181; found:
170.1180.
Cycloadducts 8,9; General Procedure
Acetophenone dimethyl acetal (0.37 mL, 2.26 mmol, 2 equiv) was
added via syringe to a suspension of (5S)-5-phenylmorpholin-2-one
(1; 200 mg, 1.13 mmol, 1 equiv), the requisite dipolarophile (3.39
mmol, 3 equiv) and magnesium bromide etherate (290 mg, 1.13
mmol, 1 equiv) in THF (15 mL). The reaction mixture was refluxed
under N2 between 3 and 6 h, monitoring for disappearance of start-
ing material by TLC. The solution was then allowed to cool to r.t.
and filtered through a short pad of silica which was washed with
Et2O. Removal of the solvent in vacuo yielded the crude product.
Flash chromatography using gradient elution, typically PE–Et2O
(2:1) to pure Et2O, furnished the pure cycoladducts.
(2R,6R,8S,12S)-2-Methyl-12-phenyl-1-aza-10-
oxa[6.4.01,8.02,6]tricyclododecan-9-one (6)
(5S)-5-Phenylmorpholin-2-one (1; 200 mg, 1.13 mmol, 1 equiv)
and magnesium bromide etherate (290 mg, 1.13 mmol, 1 equiv)
were refluxed under N2 in anhyd THF for 1 h. The flask was fitted
with a Soxhlet extractor containing activated 3 Å molecular sieves
and with a condenser. Hept-6-en-2-one dimethyl ketal (535 mg,
3.39 mmol, 3 equiv), was added to the reaction mixture, which was
then refluxed for a further 2 h. The solution was then allowed to cool
down to r.t. and was filtered through a short pad of silica which was
washed with Et2O. The solvent was removed in vacuo to furnish the
crude cycloadduct, which was purified by flash chromatography on
silica using PE–Et2O (5:1) to give colorless needles (61 mg, 20%);
N-Methyl (2S,6S,7S,8R,9R)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (8a)
25
Colorless crystals (10%); mp 205–210 °C; [a]D +57.1 (c = 0.35,
CHCl3); Rf 0.45 (Et2O–PE, 1:1).
IR (KBr): 1777 (C=O), 1755 (C=O), 1703 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.47–7.18 (10 H, m, Ph-H), 4.71
(1 H, d, J = 1.7 Hz, 6a-H), 4.41 (1 H, dd, J = 1.7, 9.2 Hz, 7b-H), 4.05
(2 H, m, 3b-H, 3a-H), 3.86 (1 H, d, J = 9.2 Hz, 8-bH), 3.71 (1 H, dd,
J = 7.7, 9.4 Hz, 2b-H), 3.94 (3 H, s, NCH3), 1.26 (3 H, s, CH3);
NOE: H-2b → Ph-H (19.2%), H-7b → H-8b (11.1%), H-8b → H-
7b (9.6%) → Ph-H (19.2%).
13C NMR (63 MHz, CDCl3): d = 178.5 (C=O), 176.0 (C=O), 172.2
(C=O), 142.2 (C), 139.9 (C), 129.3 (Carom), 128.7 (Carom), 127.4 (Car-
om), 127.3 (Carom), 71.3 (C-3), 70.5 (C-9), 62.2 (C-6), 56.8 (C-8),
56.7 (C-2), 46.5 (C-7), 25.4 (CH3), 25.1 (CH3).
25
mp 103–105 °C; [a]D –44.4 (c = 0.5, CHCl3); Rf 0.35 (PE–Et2O,
5:1).
IR (KBr): 1747 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.37–7.21 (5 H, m, Ph-H), 4.24–
4.13 (3 H, m, 12b-H, 11b-H, 8a-H), 3.99 (1 H, dd, J = 9.9, 12.7 Hz,
11a-H), 2.60–2.51 (1 H, m, 7a-H), 2.19–2.15 (1 H, m, 6a-H), 1.86–
1.73 (2 H, m, 7b-H, 5a-H), 1.66–1.23 (1 H, m, 4b-H), 1.53–1.44 (1
H, m, 5b-H), 1.39–1.29 (1 H, m, 4a-H), 1.24–1.15 (1 H, m, 3b-H),
1.06 (3 H, s, CH3), 1.00–0.93 (1 H, m, 3a-H).
13C NMR (62.5 MHz, CDCl3): d = 175.0 (C=O), 141.1 (Carom),
129.0 (CHarom), 128.3 (CHarom), 127.3 (CHarom), 74.0 (C), 71.4
(CH2), 59.0 (CH or CH3), 56.6 (CH or CH3), 50.3 (CH or CH3), 39.4
(CH2), 33.7 (CH2), 30.8 (CH2), 21.6 (CH).
MS (CI): m/z (%) = 391 (100), 104 (25).
HRMS (CI): m/z calcd for (MH+) C23H22N2O4: 391.1658; found:
391.1676.
MS (CI): m/z (%) = 272 (100), 104 (62).
HRMS (CI): m/z calcd for (MH+) C17H22NO2: 272.1650; found:
272.1649.
N-Methyl (2S,6S,7S,8R,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (8b)
Oil (10%); mp 205–210 °C; [a]D25 –73.0 (c = 1.00, CHCl3); Rf 0.25
(Et2O–PE, 1:1).
Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C,
75.09; H, 7.83; N, 5.09.
IR (KBr): 1779 (C=O), 1752 (C=O), 1702 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.14–6.81 (10 H, m, Ph-H), 4.80
(1 H, s, 6a-H), 4.33 (1 H, dd, J = 6.5z, 11.7 Hz, 3b-H), 4.19 (1 H, t,
J = 11.7 Hz, 3a-H), 4.04 (1 H, d, J = 8.2 Hz, 7b-H), 3.64 (1 H, dd,
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York

3276
D. J. Aldous et al.
PAPER
J = 6.5, 11.7 Hz, 2b-H), 3.20 (1 H, d, J = 8.2 Hz, 8-bH), 2.78 (3 H,
s, NCH3), 1.70 (3 H, s, CH3); NOE: H-2b → CH3b (6.8%), H-6a →
H-3a (8.3%) → H-7b (7.9%), H-7b → H-6a (5.2%) → H-8b
(11.0%) → CH3 (6.8%), H-8b → H-7b (15.0%) → CH3 (4.9%).
13C NMR (63 MHz, CDCl3): d = 178.2 (C=O), 175.1 (C=O), 173.1
(C=O), 140.1 (C), 139.3 (C), 128.9 (Carom), 128.3 (Carom), 128.0
(Carom), 127.8 (Carom), 127.5 (Carom), 72.3 (C-9), 71.0 (C-3), 60.9 (C-
6), 57.6 (C-22 or C-8), 55.9 (C-8 or C-2), 45.5 (C-7), 25.5 (CH3),
23.3 (CH3).
H-2b (8.3%) → H-3a (30.2%), H-8b → H-7b (15.9%) → CH3b
(5.4%).
13C NMR (63 MHz, CDCl3): d = 177.8 (C=O), 174.2 (C=O), 173.1
(C=O), 140.6 (C), 139.3 (C), 132.0 (C), 129.5 (CHarom), 129.1
(CHarom), 128.9 (CHarom), 128.2 (CHarom), 127.4 (CHarom), 126.2
(CHarom), 72.6 (C-9), 71.1 (C-3), 61.2 (C-6), 57.4 (C-8 or C-2), 55.9
(C-2 or C-8), 45.9 (C-7), 24.0 (CH3).
MS (CI): m/z (%) = 453 (100).
HRMS (CI): m/z calcd for (MH+) C28H25N2O4: 453.1814; found:
453.1824.
MS (CI): m/z (%) = 391 (100), 104 (73).
HRMS (CI): m/z calcd for (MH+) C23H22N2O4: 391.1658; found:
391.1649.
N-Phenyl (2S,6S,7R,8R,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (9c)
Colorless crystals (12%); mp 254–260 °C; [a]D +23.4 (c = 0.25,
CHCl3); Rf 0.19 (PE–Et2O, 1:1).
IR (KBr): 1779 (C=O), 1752 (C=O), 1713 cm–1 (C=O).
13C NMR (250 MHz, CDCl3): d = 7.43–7.00 (15 H, m, Ph-H), 4.75
(1 H, d, J = 8.4 Hz, 6a-H), 4.31 (1 H, dd, J = 3.7, 9.6 Hz, 3b-H),
4.24–4.13 (2 H, m, 2b-H, 3a-H), 3.93 (1 H, dd, J = 8.4, 10.0 Hz, 7a-
H), 3.70 (1 H, d, J = 10.0 Hz, 8a-H), 1.18 (3 H, s, CH3).
13C NMNR (63 MHz, CDCl3): d = 174.8 (C=O), 174.2 (C=O),
171.0 (C=O), 145.4 (C), 139.3 (C), 132.3 (C), 129.6 (CHarom), 129.2
(CHarom), 129.0 (CHarom), 128.6 (CHarom), 128.4 (CHarom), 127.6
(CHarom), 127.5 (CHarom), 126.9 (CHarom), 126.8 (CHarom), 71.9 (C-
3), 71.2 (C-9), 60.4 (C-6), 58.2 (C-8), 56.2 (C-2), 46.3 (C-7), 19.0
(CH3).
25
N-Methyl (2S,6S,7R,8S,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (8c)
Colorless crystals (17%); mp 227–229 °C; [a]D –12.5 (c = 0.3,
CHCl3); Rf 0.12 (Et2O–PE, 1:1).
IR (KBr): 1753 (br, C=O), 1697 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.31–7.00 (10 H, m, Ph-H), 4.62
(1 H, d, J = 8.4 Hz, 6a-H), 4.29–3.99 (3 H, m, 3a-H, 3b-H, 2b-H),
3.75 (1 H, t, J = 8.4 Hz, 7a-H), 3.53 (1 H, d, J = 8.4 Hz, 8a-H), 3.00
(3 H, s, NCH3), 1.43 (3 H, s, CH3); NOE: H-3a → H-3b (24.3%) →
H-6a (9.3%), H-6a → H-3a (6.2%) → H-7a (14.6%), H-7a → H-
6a (11.9%) → H-8a (14.5%), H-8a → H-7a (11.3%) → Ph-H
(13.4%).
13C NMR (63 MHz, CDCl3): d = 175.8 (C=O), 175.0 (C=O), 170.4
(C=O), 145.4 (C), 139.4 (C), 129.0 (Carom), 128.6 (Carom), 128.4
(Carom), 127.6 (Carom), 127.4 (Carom), 126.7 (Carom), 72.0 (C-3), 71.0
(C-9), 60.1 (C-6), 57.9 (C-8), 56.3 (C-2), 46.6 (C-7), 25.6 (CH3),
19.6 (CH3).
25
MS (CI): m/z (%) = 453 (100), 104 (35).
HRMS (CI): m/z calcd for (MH+) C28H25N2O4: 453.1814; found:
453.1812.
MS (CI): m/z (%) = 391 (100), 104 (94).
HRMS (CI): m/z calcd for (MH+) C23H22N2O4: 391.1658; found:
391.1646.
Dimethyl (2S,6S,7R,8S,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboxylate (10c)
Colorless needles (8%); mp 210–212 °C; [a]D –88.8 (c = 0.20,
25
CHCl3); Rf 0.20 (Et2O–PE, 1:2).
N-Phenyl (2S,6S,7S,8R,9R)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (9a)
Colorless crystals (7%); mp 221–225 °C; [a]D –13.4 (c = 0.55,
CHCl3); Rf 0.64 (PE–Et2O, 1:1).
IR (KBr): 1779 (C=O), 1756 (C=O), 1714 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.45–7.14 (15 H, m, Ph-H), 4.75
(1 H, d, J = 1.5 Hz, 6a-H), 4.48 (1 H, dd, J = 1.5, 9.25 Hz, 7b-H),
4.06–3.96 (3 H, m, 3a-H, 3b-H, 8-bH), 3.67 (1 H, dd, J = 7.6 Hz,
J¢ = 9.7 Hz, 2b-H), 1.31 (3 H, s, CH3).
13C NMR (63 MHz, CDCl3): d = 177.5 (C=O), 175.1 (C=O), 171.9
(C=O), 142.2 (C), 139.9 (C), 132.1 (C), 129.8 (CHarom), 129.3
(CHarom), 128.8 (CHarom), 127.4 (CHarom), 126.7 (CHarom), 71.3 (C-3
and C-9), 62.6 (C-6), 56.8 (C-8), 56.6 (C-2), 46.7 (C-7), 25.7 (CH3).
IR (KBr): 1734 cm–1 (br, C=O).
1H NMR ( 250 MHz, CDCl3): d = 7.47–7.06 (10 H, m, Ph-H), 4.76
(2 H, m, 6a-H, 2b-H), 4.30 (1 H, t, J = 11.6 Hz, 3a-H), 4.14 (1 H,
dd, J = 3.7, 11.6 Hz, 3b-H), 3.75 (3 H, s, CO2CH3), 3.63 (3 H, s,
CO2CH3), 3.19 (1 H, dd, J = 6.0, 9.4 Hz, 7a-H), 2.96 (1 H, d, J = 6.0
Hz, 8a-H), 1.35 (3 H, s, CH3).
13C NMR (63 MHz, CDCl3): d = 173.3 (C=O), 170.8 (C=O), 169.7
(C=O), 148.1 (Carom), 140.0 (Carom), 129.0 (CHarom), 128.7 (CHarom),
128.3 (CHarom), 128.1 (CHarom), 127.4 (CHarom), 126.0 (CHarom),
71.6 (C-3), 71.4 (C-9), 61.7 (C-6), 58.3 (C-2), 56.8 (C-8), 52.6
(CO2CH3), 52.3 (CO2CH3), 47.2 (C-7), 20.9 (CH3).
25
MS (CI): m/z (%) = 424 (100), 104 (35).
HRMS (CI): m/z calcd for (MH+) C24H26NO6: 424.1760; found:
424.1747.
MS (CI): m/z (%) = 453 (100).
HRMS (CI): m/z calcd for (MH+) C28H25N2O4: 453.1814; found:
453.1800.
Dimethyl (2S,6S,7S,8S,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboxylate (11c)
Colorless crystals (43%); mp 128–140 °C; [a]D –17.0 (c = 1.00,
CHCl3); Rf 0.25 (Et2O–PE, 1:1).
IR (KBr): 1767–1719 cm–1 (br, C=O).
1H NMR (250 MHz, CDCl3): d = 7.18–6.88 (10 H, m, Ph-H), 4.74
(1 H, d, J = 5.0 Hz, 6a-H), 4.44 (1 H, dd, J = 5.0, 10.6 Hz, 7-bH),
4.31–4.20 (2 H, m, 3a-, 3b-H), 3.93 (1 H, dd, J = 5.4, 11.7 Hz, 2b-
H), 3.81 (3 H, s, CO2CH3), 3.61 (1 H, d, J = 10.6 Hz, 8a-H), 3.53 (3
H, s, CO2CH3), 1.43 (3 H, s, CH3).
13C NMR (62.5 MHz, CDCl3): d = 174.1 (C=O), 173.4 (C=O),
170.7 (C=O), 141.0 (Carom), 139.2 (Carom), 129.1 (CHarom), 128.9
25
N-Phenyl (2S,6S,7S,8R,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-7,8-dicarboximide (9b)
Colorless crystals (10%); mp 90–105 °C; [a]D –116.1 (c = 0.25,
CHCl3); Rf 0.35 (PE–Et2O, 1:1).
IR (KBr): 1779 (C=O), 1752 (C=O), 1714 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.31–6.88 (15 H, m, Ph-H), 4.94
(1 H, s, 6a-H), 4.35 (1 H, dd, J = 6.7, 12.8 Hz, 3b-H), 4.27–4.19 (2
H, m, 7b-H, 3a-H), 4.02 (1 H, dd, J = 6.7, 11.5 Hz, 2b-H), 3.35 (1
H, d, J = 8.5 Hz, 8b-H), 1.77 (3 H, s, CH3); NOE: H-2b → H-3b
(7.1%) → Ph-H (14.0%) → CH3b (6.5%), H-3b → H-3a (8.3%) →
25
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Strategies for the Synthesis of Highly Substituted Amino Acids
3277
(CHarom), 128.3 (CHarom), 127.9Carom), 127.8 (Carom), 127.7 (Carom),
127.6 (Carom), 127.4 (Carom), 70.7 (C-3), 69.6 (C-9), 60.0 (C-8), 59.8
(C-6), 56.9 (C-2), 53.2 (CO2CH3), 52.4 (CO2CH3), 45.3 (C-7), 14.1
(CH3).
(2S,6S,7R,9R)-9-Methyl-2,9-diphenyl-7-(4-nitrophenyl)-1-aza-
4,8-dioxa[4.3.01,6]bicyclononan-5-one (14)
Colorless needles (207 mg, 42%); mp 149–151 °C; [a]D –29.1
(c = 0.65, CHCl3); Rf 0.62 (PE–Et2O, 1:1).
25
MS (CI): m/z (%) = 424 (100).
IR (KBr): 1755 (C=O), 1522 (NO2), 1348 cm–1 (NO2).
HRMS (CI): m/z calcd for (MH+) C24H26NO6: 424.1760; found:
424.1747.
1H NMR (250 MHz, CDCl3): d = 8.33 (2 H, m, Ar-H), 7.86 (2 H, m,
Ar-H), 7.41–7.24 (5 H, m, Ph-H), 6.15 (1 H, d, J = 4.8 Hz, 6a-H),
4.32 (1 H, d, J = 4.8 Hz, 7b-H), 4.19–4.08 (2 H, m, 3a-, 3b-H), 3.95
(1 H, dd, J = 5.1, 10.25 Hz, 2b-H), 1.60 (3 H, s, CH3).
13C NMR (100 MHz, CDCl3): d = 170.7 (C=O), 148.8 (Carom), 147.8
(Carom), 139.8 (Carom), 138.0 (Carom), 128.9 (CHarom), 128.6 (CHarom),
128.5 (CHarom), 127.5 (CHarom), 127.0 (CHarom), 126.5 (CHarom),
124.0 (CHarom), 101.0 (C-9), 79.1 (C-6), 71.4 (C-3), 65.4 (C-7), 57.1
(C-2), 28.9 CH3).
(2S,6S,8S,9S)-9-Methyl-2,9-diphenyl-1-aza-4-oxa[4.3.01.6]bicy-
clononan-5-one-8-nitrile (12c)
25
Colorless crystals (20%); mp 170–175 °C; [a]D +15.0 (c = 0.35,
CHCl3); Rf 0.22 (PE–Et2O, 1:1).
IR (KBr): 2245 (C≡N), 1752 cm–1 (C=O).
1H NMR (250 MHz, CDCl3): d = 7.38–6.82 (10 H, m, Ph-H), 4.38
(1 H, dd, J = 5.5, 9.0 Hz, 6a-H), 4.27 (1 H, t, J = 11.9 Hz 3a-H),
4.16 (1 H, dd, J = 5.0, 11.9 Hz, 3b-H), 3.88 (1 H, dd, J = 5.0, 11.9
Hz, 2b-H), 3.17 (1 H, dd, J = 9.0, 11.0 Hz, 8a-H), 2.85 (1 H, m, 7b-
H), 2.62 (1 H, m, 7a-H), 1.57 (3 H, s, CH3). NOE: H-2b → H-3b
(5.0%), H-3a → H-3b (17.3%), H-3b → H-3a (15.6%) → H-8b
(8.3%), H-6a → H-7a (1.0%), H-7a → H-6a (1.4%) → H-7b
(16.1%) → H-8a (1.4%), H-7b → H-7a (62.3%) → CH3b (2.4%),
H-8a → (1.7%), Ph-H (6.9%).
13C NMR (63 MHz, CDCl3): d = 174.2 (C=O), 139.9 (Carom), 138.9
(Carom), 129.4 (CHarom), 128.6 (CHarom), 128.4 (CHarom), 128.1
(CHarom), 127.8 (CHarom), 127.6 (CHarom), 125.7 (CHarom), 119.0
(CN), 70.7 (C-3), 68.8 (C-9), 57.6 (C-2), 56.9 (C-6), 43.4 (C-8),
28.7 (C-7), 14.7 (CH3).
Anal. Calcd for C25H22N2O5: C, 69.76; H, 5.15; N, 6.50. Found: C,
69.47; H, 5.11; N,6.31.
MS (CI): m/z (%) = 431 (32), 280 (100).
HRMS (CI): m/z calcd for (MH+) C21H21N2O2: 431.1606; found:
431.1616.
(2S,6S,7R,9S)-9-Methyl-2,9-diphenyl-7-(4-nitrophenyl)-1-aza-
4,8-dioxa[4.3.01,6]bicyclononan-5-one (15)
25
Colorless needles (89 mg, 18%); mp 144–146 °C; [a]D –100.3
(c = 0.35, CHCl3); Rf 0.40 (PE–Et2O, 1:1).
IR (KBr): 1748 (C=O), 1522 (NO2), 1348 cm–1 (NO2).
1H NMR (250 MHz, CDCl3): d = 8.12 (2 H, m, Ar-H), 7.54 (2 H, m,
Ar-H), 7.42–7.07 (5 H, m, Ph-H), 5.48 (1 H, d, J = 7.6 Hz, 6a-H),
4.36–4.15 (4 H, m, 2b-H, 3a-H, 3b-H, 7b-H), 1.54 (3 H, s, CH3).
13C NMR (62.5 MHz, CDCl3): d = 170.2 (C=O), 148.3 (Carom),
147.2 (Carom), 143.1 (Carom), 137.4 (Carom), 128.9 (CHarom), 128.6
(CHarom), 128.5 (CHarom), 128.3 (CHarom), 128.2 (CHarom), 127.7
(CHarom), 126.8 (CHarom), 124.1 (CHarom), 100.4 (C-9), 78.6 (C-6),
72.6 (C-3), 66.1 (C-7), 57.5 (C-2), 23.0 CH3).
MS (CI): m/z (%) = 333 (100), 104 (35).
HRMS (CI): m/z calcd for (MH+) C21H21N2O2: 333.1603; found:
333.1615.
Methyl (2S,6S,8S,9S)-9-Methyl-2,9-diphenyl-1-aza-4-
oxa[4.3.01,6]bicyclononan-5-one-8-carboxylate (13c)
Yellow foam (38%); mp 45–50 °C; [a]D25 –21.8 (c = 0.90, CHCl3);
Rf 0.29 (PE–Et2O, 1:1).
MS (CI): m/z (%) = 431(15), 280 (100).
MS (CI): m/z calcd for (MH+) C21H21N2O2: 431.1606; found:
IR (KBr): 1748 cm–1 (br C=O).
1H NMR (250 MHz, CDCl3): d = 7.25–6.84 (10 H, m, Ph-H), 4.37
(1 H, dd, J = 5.1, 9.4 Hz, 6a-H), 4.22–3.97 (3 H, m, 2b-H, 3a-H, 3b-
H), 3.45 (3 H, s, CO2CH3), 3.17 (1 H, m, 8a-H,), 2.96 (1 H, m, 7b-
H), 2.41 (1 H, m, 7a-H), 1.34 (3 H, s, CH3).
431.1626.
(2S,3R)-2-Amino-3-hydroxy-3-(4-aminophenyl)propanoic Acid
(16)
To a solution of the cycloadduct 14 or 15 (90 mg, 0.2 mmol, 1
equiv) in MeOH (4 mL) was added 1 M HCl (1 mL) and the mixture
was refluxed for 1 h. The mixture was transferred into a Fisher Por-
ter bottle. TFA (16 mL, 0.2 mmol, 1 equiv) and Pearlman’s catalyst
(90 mg) were added to the solution, which was then degassed and
subjected to H2 at 1 atm. for 24 h with stirring. The solution was
then passed through a pad of Celite® to remove the catalyst and the
solvent was removed in vacuo. The crude mixture was purified on
an acidic ion-exchange column to yield the title compound in each
13C NMR (63 MHz, CDCl3): d = 174.9 (C=O), 172.3 (C=O), 143.0
(Carom), 139.8 (Carom), 128.4 (CHarom), 127.8 (CHarom), 127.7
(CHarom), 127.6 (CHarom), 127.5 (CHarom), 127.0 (CHarom), 70.9 (C-
3), 68.9 (C-9), 57.5 (C-6), 57.2 (C-2), 56.2 (C-8), 52.0 (CO2CH3),
27.6 (C-7), 14.8 (CH3).
MS (CI): m/z (%) = 366 (100), 104 (56).
HRMS (CI): m/z calcd for (MH+) C22H24NO4: 366.1705; found:
366.1699.
25
case as a pale yellow powder (60 and 68%, respectively); [a]D
–12.1 (c = 0.55, H2O) {Lit.13b [a]D24 –7.5 (c = 1.0, H2O)}.
Cycloadducts 14 and 15
Acetophenone dimethyl acetal (0.37 mL, 2.26 mmol, 2 equiv), (5S)-
5-phenylmorpholin-2-one (1; 200 mg, 1.13 mmol, 1 equiv) and
magnesium bromide etherate (290 mg, 1.13 mmol, 1 equiv) were re-
fluxed under nitrogen in 1,4-dioxane for 4 h. p-Nitrobenzaldehyde
(176 mg, 1.13 mmol, 1 equiv) was added to the reaction mixture,
which was then refluxed for a further 2 h. The solution was then al-
lowed to cool to r.t. and filtered through a short pad of silica and the
silica was washed with Et2O. The solvent was removed in vacuo and
the two cycloadducts were separated by flash chromatography on
silica using gradient elution (PE–Et2O, 4:1 to 2:1).
IR (KBr): 3420 (NH), 1653 cm–1 (C=O).
1H NMR (250 MHz, D2O): d = 7.15 (2 H, d, J = 8.37 Hz), 6.78 (2
H, d, J = 8.37 Hz), 5.05 (1 H, d, J = 4.75 Hz), 3.72 (1 H, d, J = 4.75
Hz).
13C NMR: (62.5 MHz, D2O): d = 172.4 (C=O), 130.8, 127.4, 117.3,
71.5, 61.2.
MS (CI): m/z (%) = 197 (20), 179 (100).
HRMS (CI): m/z calcd for (MH+) C9H13N2O3: 197.0926; found:
197.0920.
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York

3278
D. J. Aldous et al.
PAPER
was solved by direct methods using Shelx869 and refined on
F2 using Shelx10 to R1 0.0686, wR2 0.1937. 8a C23H22N2O4,
M = 390.43, orthorhombic, space group P212121–, Z = 4,
a = 9.510 (12), b = 9.934 (14), c = 21.23 (2), V = 2006 Å3,
d = 1.293 Mg/m3, 3554 independent reflections were
collected. The structure was solved by direct methods and
refined on F2 to R1 0.0834, wR2 0.2490. 9c C28H24N2O4,
M = 452.49, monoclinic, space group P21–, Z = 2,
a = 10.857 (12), b = 8.120 (10), c = 28.75 (3), b = 96.895
(i1)°, V = 2516 Å3, d = 1.194 Mg/m3, 4541 independent
reflections were collected. The structure was solved by
direct methods and refined on F2 to R1 0.1749, wR2 0.4199.
10c C24H25NO6, M = 423.45.31, orthorhombic, space group
P212121, Z = 4, a = 11.389 (15), b = 13.320 (14),
Acknowledgment
We thank Rhône Poulence Rohrer (E.M-N.H.) and the University of
Reading (W.N.D.) for financial support.
References
(1) Aldous, D. J.; Drew, M. G. B.; Hamelin, E. M.-N.; Harwood,
L. M.; Jahans, A. B.; Thurairatnam, S. Synlett 2001, 1836.
(2) For examples of the synthesis of substituted prolines, see:
(a) Koskinen, A. M. P.; Helaja, J.; Kumpulainen, T. T.;
Koivisto, J.; Mansikkamaki, H.; Rissanen, K. J. Org Chem.
2005, in press. (b) Seebach, D.; Boes, M.; Naef, R.;
Schwiezer, W. B. J. Am. Chem. Soc. 1983, 105, 5390.
(c) Wang, Q.; Tran Huu Dau, M.-E.; Saski, A.; Potier, P.
Tetrahedron 2001, 30, 6455. (d) Flamant-Rabin, C.; Wang,
Q.; Chiaroni, A.; Sasaki, A. Tetrahedron 2002, 58, 10475.
(e) Maeda, K.; Miller, R. A.; Szumigala, R. H. Jr.; Shafiee,
A.; Karady, S.; Armstrong, J. D. III Tetrahedron Lett. 2005,
46, 1545. (f) Xia, Q.; Ganem, B. Tetrahedron Lett. 2002, 43,
1597. (g) An, S. S. A.; Lester, C. C.; Peng, J.-L.; Li, Y.-J.;
Rothwarf, D. M.; Welker, E.; Thannhauser, T. W.; Zhang, L.
S.; Tam, J. P.; Scheraga, H. A. J. Am. Chem. Soc. 1999, 121,
11558. (h) Magaard, V. W.; Sanchez, R. M.; Bean, J. W.;
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(7) X-ray Crystal Data: 6 C17H21NO2, M = 271.35,
orthorhombic, space group P212121, Z = 4, a = 6.715 (10),
b = 13.502 (8), c = 16.73 (2), V = 1517 Å3, d = 1.188 Mg/m3,
1545 independent reflections were collected with MoKa
radiation on the MAR research Image Plate system. Data
analysis was carried out with the XDS program8 the structure
c = 15.080 (17), V = 2272 Å3, d = 1.238 Mg/m3, 2480
independent reflections were collected. The structure was
solved by direct methods and refined on F2 to R1 0.0488,
wR2 0.1277. 11c C24H25NO6, M = 423.45.31, orthorhombic,
space group P212121, Z = 4, a = 6.212 (10), b = 16.72 (2),
c = 20.33 (3), V = 2111 Å3, d = 1.332 Mg/m3, 6680
independent reflections were collected. The structure was
solved by direct methods and refined on F2 to R1 0.1078,
wR2 0.2857. 15 C25H22N2O5, M = 430.45, orthorhombic,
space group P212121, Z = 4, a = 7.481 (10), b = 13.464
(17), c = 21.72 (3), V = 2188 Å3, d = 1.307 Mg/m3, 6487
independent reflections were collected. The structure was
solved by direct methods and refined on F2 to R1 0.0996,
wR2 0.2057. Atomic co-ordinates, bond lengths and angles
and thermal parameters have been deposited with the
Cambridge Crystallographic Service.
(8) Kabsch, W. J. Appl. Cryst. 1988, 21, 916.
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University of Göttingen: Göttingen, 1993.
(11) Harwood, L. M.; Manage, A. C.; Robin, S.; Hopes, S. F. G.;
Watkin, D. J.; Williams, C. E. Synlett 1993, 777.
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Wong, L. F. Tetrahedron: Asymmetry 1991, 2, 1343.
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Wong, L. F. Tetrahedron: Asymmetry 1992, 3, 1127.
(b) Alker, D.; Hamblett, G.; Harwood, L. M.; Robertson, S.
M.; Watkin, D. J.; Williams, C. E. Tetrahedron 1998, 54,
6089.
Synthesis 2005, No. 19, 3271–3278 © Thieme Stuttgart · New York