Electrooxidation based strategy towards the core 3-amino-6-hydroxy-azepan- 2-one

Article abstract of DOI:10.1055/s-2004-820048

We describe a practical synthesis of protected (3S,6R)-6-hydroxy- cyclolysine derivatives starting from cyclic L-lysine. Evaluation of the electrochemical oxidation of various protected amino-caprolactams allowed a regioselective electromethoxylation at the α-position to the lactam nitrogen. Formation of the corresponding enamide by elimination of methanol followed by a diastereoselective dihydroxylation, diacetylation and subsequent regioselective reduction afford the orthogonally protected (3S,6R)-3-amino-6- hydroxy-azepan-2-one.

Full text of DOI:10.1055/s-2004-820048

LETTER
1029
Electrooxidation Based Strategy Towards the Core 3-Amino-6-Hydroxy-
azepan-2-one
E
lectrooxidation Based
a
StrategyT
r
owards
c
the Core 3-Amino
D
-
6-Hydroxyazepa
a
n-2-one vid, Hamid Dhimane*
Université René Descartes – Paris V – UMR 8601, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, 45,
rue des Saints Pères, 75270 Paris Cedex 06, France
Fax 33 (0) 1 42 86 83 87; E-mail: hamid.dhimane@univ-paris5.fr
Received 30 January 2004
Abstract: We describe a practical synthesis of protected (3S,6R)-6-
hydroxy-cyclolysine derivatives starting from cyclic L-lysine.
Evaluation of the electrochemical oxidation of various protected
amino-caprolactams allowed a regioselective electromethoxylation
at the a-position to the lactam nitrogen. Formation of the corre-
sponding enamide by elimination of methanol followed by a diaste-
reoselective dihydroxylation, diacetylation and subsequent
regioselective reduction afford the orthogonally protected (3S,6R)-
3-amino-6-hydroxy-azepan-2-one.
Key words: bengamides, diastereoselectivity, dihydroxylation,
electrooxidation, osmium
The 6-substituted 3-amino caprolactam is a common core
skeleton of various naturally occurring products
(Figure 1). Among them are Peritoxins A and B, isolated
from the soil-borne fungus Periconia circinata, which are
Figure 1 3-Amino-hydroxycaprolactam containing compounds
involved in the milo disease syndrome.1 Twenty-four
structurally related cyclolysine derivatives, bengamides,
were isolated from sponges of the genus Jaspus (family
Jaspidae).2 Some of these secondary metabolites, prin-
cipally bengamides bearing myristate group at C-6 of the
caprolactam core, were evaluated in vitro in the NCI 60
cell line screening and found to have a unique profile
compared to that of standard antitumor agents. Beng-
amide B and its analogues proved to have impressive in
vitro and in vivo antitumor activities against MDA-MB-
435 human breast carcinoma.2f,g,3
based on an enantioselective C-alkylation of an iminogly-
cine ester in the presence of a chiral phase-transfer cata-
lyst.
In this letter we report on the synthesis of protected
(3S,6R)-3-amino-6-hydroxy-azepan-2-ones 1, starting
from (S)-3-amino-azepan-2-one hydrochloride. As out-
lined in Scheme 2, our strategy relies on two key steps; a
diastereoselective dihydroxylation of enamides 2 derived
from aminoethers 3 which, in turn, were obtained by a
regioselective electrochemical oxidation of a judiciously
protected cyclic L-lysine.
Among bengamides and analogues those belonging to the
hydroxylysine derived category are considered the most
promising clinical candidates. One of this analogues de-
veloped by Novartis entered phase I trials in 2000.3c–d Me-
thionine aminopeptidases were very recently identified as
(unanticipated) intracellular molecular target of benga-
mides.4
The oxidation of amides leading to the corresponding a-
oxy-compounds is one of the most developed electro-
chemical methods in organic synthesis. While this reac-
All reported syntheses3,5 of bengamides and analogues
rely on the coupling of the polyol side chain and the 6-O-
acylated 3-amino-6-hydroxy caprolactam subunit
(Scheme 1). Kinder et al.5e reported on the shortest syn-
thesis of this heterocyclic core in three steps starting from
(5R)-hydroxy-L-lysine. Recently, Boeckman et al.5g,h de-
scribed an elegant approach to (3S,6S)-3-amino-6-hy-
droxycaprolactam in eight steps from D-aspartic acid
SYNLETT 2004, No. 6, pp 1029–1033
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820048; Art ID: G03804ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

1030
M. David, H. Dhimane
LETTER
in decreased chemical and electrical yields, probably due
to the competition between lactam and solvent oxidation.
Similar effect of yield improvement with electromethox-
ylations utilizing higher concentration of substrate was
reported by Steckhan.12 A possible explanation, as sug-
gested by Steckhan,12 would involve either a replacement
of solvent molecules by substrate within the Helmholtz-
layer, or an electron hopping mechanism between sub-
strate radical-cations inside the Helmholtz-layer with the
substrate outside this layer.
After screening various repported conditions,13 we pre-
pared the expected enamides 2b,c in acceptable and repro-
ducible yields (67 and 68% respectively) by refluxing the
corresponding methoxylated caprolactams 3 in toluene in
the presence of ca. ten equivalents of ammonium chloride
(Scheme 4).
Scheme 2
tion was extensively studied in the case of carbamates,6
particularly by Shono's group, amides and lactams were
less examined. A few examples of direct (anodic) or indi-
rect (anode-NaCl as catalyst) regioselective oxidation of
dipeptides were reported by Steckhan7 and Moeller.8 To
be successful, our strategy would require the previously
undemonstrated regioselective endocyclic electromethox-
ylation of exo N-acylated 3-aminocaprolactams.9 To dif-
ferentiate the two N-acyl groups during a direct a-
electromethoxylation, we envisioned modulating the
availability of the exocyclic nitrogen lone pair by means
of an appropriate electron withdrawing group to both
protect and deactivate the 3-amino substituent of the
caprolactam. To this end, five 3-N-acylated amino capro-
lactams 4a-e (Scheme 3) were prepared from L-lysine by
conventional methods.10 Preliminary experiments, per-
formed in an undivided cell with graphite electrodes,
revealed that only the pivaloyl and trifluoroacetyl deriva-
tives 4b and 4c gave the expected a-methoxylated com-
pounds 3b,c. Because of the very low solubility in
methanol, oxidation of substrates 4a and 4d could not be
examined, whereas, electrochemical oxidation of carbam-
ate 4e gives a complex mixture. Therefore, only substrates
4b,c were involved in further screening experiments
where various electrolysis conditions were examined
(electrolyte, temperature and concentration of electrolyte
and substrates).
Scheme 4
Previous reports showed that b-hydroxylation of en-
amides could be achieved by oxidative hydroboration.14
Unfortunately, treatment of enamides 2 with various
boranes [BH3·THF, BH3·SMe2, 9-BBN, HBCl2·SMe2,
HBBr2·SMe2 (free from BBr3)] affords either starting ma-
terial or, when excess borane is utilized, reduction of the
amide functionality. Next, we performed a regioselective
N-benzylation of the endocyclic amides 5 and submitted
the resulting N-benzyl derivatives 5b,c to the same oxida-
tive hydroboration procedures. No conversion of these
substrates was observed, except the formation (51%) of
the unexpected bridged aminal 6b (Figure 2) when enam-
ide 5b was treated with HBBr2·SMe2.
To avoid this intramolecular participation of the exocyclic
amide, 5c was converted in two steps to the phthalimido
analogue 5a (Scheme 4) which was submitted to the same
hydroboration/oxidation conditions. Regrettably, no hy-
droxylated compound could be obtained. Use of excess
HBBr2·SMe2 in methylene chloride, followed by an oxi-
dative treatment (H2O2/NaOH) resulted in the reduced
compound 6a15 (31%) (Figure 2).
Scheme 3
The best results were obtained when the electrolysis was
performed at –10 °C with sodium benzene sulfonate (0.05
mol·L–1) as supporting electrolyte11 using a substrate con-
centration of ca 0.3 mol·L–1 (Scheme 3). Electrolysis of
solutions with lower concentrations of substrates resulted
After these disappointing attempts, we explored less
straightforward oxidative methods. First, we examined
the conditions described by Correia and coworkers16 who
performed the hydroxymethoxylation of endocyclic en-
carbamates using m-CPBA in methanol. Unfortunately,
Synlett 2004, No. 6, 1029–1033 © Thieme Stuttgart · New York

LETTER
Electrooxidation Based Strategy Towards the Core 3-Amino-6-Hydroxyazepan-2-one
1031
Figure 2
Figure 3 The most significant observed nOe
under these conditions (with or without bicarbonate) 5 did
not react. The same absence of reactivity was observed
with other known conditions for epoxidation (H2O2/
Cl3CCN,17 H2O2/urea/TFAA18). Finally, enamide 5a was
oxidized using osmylation19 leading to 6,7-dihydroxylat-
ed caprolactam 7a, which was isolated in 30% yield.
However, when the crude diol 7a was acetylated prior to
purification, the corresponding diacetate 8a was isolated
in 49% overall yield (Scheme 5). The same sequence (di-
hydroxylation/acetylation) applied to enamide 5b afford-
ed the corresponding diacetate 8b in 45% overall yield.20
According to NMR data, both 8a and 8b are obtained as
single stereoisomers with a cis relative configuration of
both acetate substituents, indicating the absence of
epimerization of the hemiaminal carbon of diols 7.
The total diastereoselective dihydroxylation observed in
the case of 5a,b came as a pleasant surprise. Indeed, ow-
ing to the enamide moiety, the ring of enamides 5 was as-
sumed to be flattened (six atoms in the same plane C5-C6-
C7-N-C2-C3), and hence low or no diastereoselectivities
were expected to arise from addition reactions with enam-
ides 5. The observed diastereoselectivities suggest a non
fully conjugated C=C bond with the endocyclic amide
1
moiety23. Based on H and 13C NMR spectra, enamide
rings of 5a-c exist in a single conformation. Among the
possible conformations22b only the twisted-boat confor-
mation shown in Figure 4 is consistent with the observed
3J coupling constants values of H-3 and H-6. In this con-
formation (Figure 4) the pseudoaxial proton of C4 posi-
tion blocks the b-face of the carbon-carbon double bond
while the a-face seems more accessible to the dihydroxyl-
ation reagent.
Figure 4
The results obtained herein represent a novel and efficient
electrochemical based procedure to the orthogonally pro-
tected (3S,6S)-3-amino-6-hydroxy caprolactam, the aza-
heterocyclic subunit of bengamides. The synthetic appli-
cations of this methodology are under investigation.
Scheme 5
In order to reach the key caprolactam 1, we submitted de-
rivatives 8 to various conditions for the reduction of the
O-acetylated hemiaminal carbon (Scheme 5). The best
yields were obtained using triethylsilane as the reducing
agent with trifluoroacetic acid as the solvent and catalyst
Typical Experimental Procedures
(S)-3-Trifluoroacetamido-7-methoxy-azepan-2-one (3c)
An undivided beaker type cell with cooling mantle (-10 °C)
equipped with graphite electrodes plates (15 cm2) and charged with
for the generation of the transient iminium ion.21a Use of 4 g (17.9 mmol) of trifluoroacetimido caprolactam 4c, 540 mg (3.0
mmol) of sodium benzene sulfonate and 60 mL of MeOH. After
Lewis acids (BF3·OEt2, TiCl4) or TFA in methylene chlo-
ride as solvent resulted in poor conversions.21b
28500 Coulombs (16.5 F/mol, at 12 V) passed the reaction mixture
was concentrated under vacuum and chromatographied on silica gel
The relative trans stereochemistry of lactams 1a,b was es-
tablished by NOESY experiments (see Figure 3). The
coupling constants and the observed nuclear Overhauser
effect (nOe) are consistent with a chair-like conforma-
tion,22 where the amide carbon-nitrogen bond corresponds
to the 'flat' end with both substituents being in equatorial
orientations (Figure 3).
(1:1 EtOAc/cyclohexane) to afford 3.0 g (66%) of the desired meth-
oxylated compound 3c as a yellow solid: mp 109-111 °C; [a]16
=
D
1
– 87.3 (c 1.00, MeOH); H NMR (250 MHz, CDCl3): d 7.77 (bs,
NH), 7.00 (bs, NH), 4.75-4.55 (m, 1H), 4.45-4.30 (m, 1H), 3.34 (s,
3H), 2.20-2.12 (m, 3H); 1.81-1.70 (m, 1H); 1.60-1.23 (m, 2H); 13
C
NMR (62.5 MHz, CDCl3): d 174.5, 156.0 (q, J = 37 Hz), 115.7 (q,
J = 286 Hz), 83.1, 55.5, 53.4, 32.9, 30.1, 20.8; IR (neat): 3235,
2928, 1725, 1666, 1163 cm-1; HRMS: m/z calcd. for C9H14F3N2O3
(M+1): 255.0956. Found: 255.0952.
Synlett 2004, No. 6, 1029–1033 © Thieme Stuttgart · New York

1032
M. David, H. Dhimane
LETTER
(S)-3-Trifluoroacetamido-1,3,4,5-tetrahydro-azepin-2-one (2c)
A round bottom flask equipped with a condenser was charged with
3.3 g (13.0 mmol) of methoxy trifluoroacetimido caprolactam 3c, 8
g (149.53 mmol) of ammonium chloride and 80 mL of toluene. Af-
ter being refluxed for 64 h the mixture was concentrated under re-
duced pressure and the solid residue triturated with DCM.
Filtration, evaporation of the volatiles and column chromatography
on silica gel (1:1 EtOAc/cyclohexane) of the residue afforded 1.97
g (68%) of the enamide 2c as a white solid: mp 111-113 °C;
ternary system. This method afford 1.33 g (80% over 2 steps) of
the desired phtalimide 5a as a white solid: mp 42-44 °C; [a]16
=
D
– 226.3 (c 1.02, CH2Cl2); 1H NMR (250 MHz, CDCl3): d 7.85 (dd,
Jm = 3.1, Jo = 5.4 Hz, 2H), 7.70 (dd, Jm = 3.1, Jo = 5.4 Hz, 2H),
7.35-7.15 (m, 5H), 5.94 (dd, J1 = 1.7 Hz, J2 = 9.2 Hz, 1H), 5.39 (td,
Jt = 5.5, Jd = 9 Hz, 1H), 5.08 (dd, J1 = 3.6 Hz, J2 = 11.1 Hz, 1H),
4.81 and 4.53 (qAB, J = 14.8 Hz, 2H, Ph-CH2), 3.20-2.95 (m, 1H),
2.55-2.15 (m, 3H); 13C NMR (62.5 MHz, CDCl3): d 168.9, 168.3,
136.9, 134.0, 132.1, 128.9, 128.7, 128.0, 127.6, 123.5, 117.2, 53.6,
51.4, 30.5, 25.6; IR (neat): 3386, 2931, 1773, 1710, 1659, 1386,
716, 699 cm-1; HRMS: m/z calcd. for C21H19N2O3 (M+1): 347.1396.
Found: 347.1391.
1
[a]16D = - 155.3 (c 1.07, MeOH); H NMR (250 MHz, CDCl3): d
7.72 (bs, NH), 6.72 (bs, NH), 5.82 (apparent tdd, Jt = 2, Jd = 4.9,
Jd = 9.6 Hz, 1H), 5.25 (apparent qt, J = 4.6 Hz, 1H), 4.44 (ddd,
J1 = 2.5, J2 = 5, J3 = 10.6 Hz, 1H), 2.57-2.30 (m, 3H), 2.04-1.86 (m,
1H); 13C NMR (62.5 MHz, CDCl3): d 171.6, 156.4 (q, J = 37 Hz),
121.6, 115.8, 115.6 (q, J = 285 Hz), 53.2, 30.2, 26.2; IR (neat):
3230, 2923, 1730, 1662, 1176, 1151, 722 cm-1; HRMS: m/z calcd.
for C8H10F3N2O2 (M+1): 223.0694. Found: 223.0696.
(S)-1-Benzyl-6,7-diacetoxy-3-phtalimido-azepan-2-one (8a)
To a stirred solution of 490 mg (1.42 mmol) of phtalimidobenzyle
5a in 4 mL of a 1:1 mixture of acetone and acetonitrile were added
successively 2 mL of water, 380 mg (2.81 mmol) of NMO and drop-
wise 1.8 mL of a 1 wt.% aqueous solution of osmium tetroxide (5
mol%). After being stirred at room temperature overnight the reac-
tion mixture was diluted with EtOAc, solid Na2S2O3 (2 g) was add-
ed and stirring continued for 30 min. Filtration and evaporation
under reduced pressure afforded the desired diol 7a as a white liquid
(S)-1-Benzyl-3-trifluoroacetamido-1,3,4,5-tetrahydro-azepin-2-
one (5c)
To a suspension of 1.08 g of sodium hydride (45.00 mmol, 60% dis-
persion in oil) in 35 mL of THF was added dropwise at 0 °C a solu-
tion of 1.97 g (8.87 mmol) of trifluoroacetamido enamide 2c in 25
mL of THF. After 15 min 1.05 mL (8.78 mmol) of benzyl bromide
were added dropwise. The ice bath was removed 15 min later and
stirring continued overnight at room temperature. The reaction mix-
ture was then washed with a saturated aqueous NH4Cl solution and
the organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. Column chromatography on silica gel (1:1
EtOAc/cyclohexane) afforded 2.48 g (90%) of the expected com-
pound as a colorless oil : [a]20D = - 393.7 (c 1.04, MeOH); 1H NMR
(250 MHz, CDCl3): d 7.86 (bs, 1H), 7.40-7.10 (m, 5H), 5.92 (td,
Jt = 1.3, Jd = 8.7 Hz, 1H), 5.53 (td, Jt = 5.8, Jd = 8.6 Hz, 1H), 4.88
and 4.42 (qAB, J = 14.6 Hz, 2H, Ph-CH2), 4.71-4.62 (m, 1H), 2.52-
2.45 (m, 1H), 2.25-2.16 (m, 2H), 1.98-1.88 (m, 1H); 13C NMR (62.5
MHz, CDCl3): d 169.8, 156.1 (q, J = 37 Hz), 136.4, 128.7, 128.5,
127.9, 127.8, 120.1, 115.7, (q, J = 286 Hz), 52.2, 51.0, 34.2, 23.7;
IR (neat): 3285, 2938, 1721, 1645, 1208, 1149, 725, 699 cm-1;
HRMS: m/z calcd. for C15H16F3N2O2 (M+1): 313.1164. Found:
313.1159.
1
which was used in the next step without further purification: H
NMR (250 MHz, CDCl3): d 7.83 (dd, Jm = 3, Jo = 5.4 Hz, 2H), 7.69
(dd, Jm = 3, Jo = 5.4 Hz, 2H), 7.32-75.25 (m, 5H), 5.45 (bd, J = 11.7
Hz, 1H), 4.94 (bs, 1H), 4.71 and 4.51 (ABq, J = 14.8 Hz, 2H, Ph-
CH2), 3.93 (bs, 1H), 3.60-3.40 (m, 1H), 2.85-2.60 (m, 1H), 2.45-
2.20 (m, 1H), 2.20-1.90 (m, 3H); 13C NMR (62.5 MHz, CDCl3): d
171.0, 168.6, 137.3, 134.1, 132.1, 129.0, 128.4, 127.9, 123.5, 85.2,
72.1, 54.6, 52.1, 30.4, 27.3. To a solution of the previous diol in 8
mL of DCM were added successively 1.04 g (8.51 mmol) of DMAP
and 800 mL (8.55 mmol) of acetic anhydride at room temperature
and stirring is continued overnight. The reaction mixture was
washed with a saturated aqueous NH4Cl solution, the aqueous phase
is then extracted with DCM and the combined organic layers were
dried over MgSO4, filtered and concentrated under reduced pres-
sure. Column chromatography on silica gel (3:2 EtOAc/cyclohex-
ane) afforded 320 mg (49% over 2 steps) of the expected compound
8a as a white solid: mp 64-66 °C; [a]16D = - 48.4 (c 1.10, CH2Cl2);
1H NMR (250 MHz, CDCl3): d 7.83 (bd, J = 3 Hz, 2H), 7.01 (dd,,
Jm = 3, Jo = 5.4 Hz, 2H), 7.40-7.15 (m, 5H), 6.03 (d, J = 1.7 Hz,
1H), 5.37 (bd, J = 11.3 Hz, 1H), 5.00 and 4.46 (ABq, J = 14.6 Hz,
2H, Ph-CH2), 4.67 (ddd, J1 = 1.9 Hz, J2 = 4.7 Hz, J3 = 11.2 Hz, 1H),
2.95-2.70 (m, 1H), 2.30-1.85 (m including 2s at 2.19 and 1.96, 9H);
13C NMR (62.5 MHz, CDCl3): d 170.3, 169.6, 169.1, 168.2, 136.5,
134.1, 132.0, 128.8, 128.6, 127.9, 123.5, 81.1, 72.6, 54.3, 52.8,
27.6, 26.5, 20.8, 20.7; IR (neat): 2938, 1752, 1713, 1673, 1212, 718
cm-1; HRMS: m/z calcd. for C25H24N2O7 (M+1): 465.1662. Found:
465.1657.
(S)-1-Benzyl-3-Phtalimido-1,3,4,5-tetrahydro-azepin-2-one
(5a)
To a solution of 1.49 g (4.78 mmol) of benzylated trifluoroacetimi-
do enamide 5c in 200 mL of MeOH at 0 °C was added dropwise a
solution of 3.33 g (24.10 mmol) of potassium carbonate in 200 mL
of water. After 30 min the ice bath was removed and stirring contin-
ued overnight at room temperature. The reaction mixture was then
concentrated under vacuum, the residue dissolved in Et2O and po-
tassium carbonate was added. After 1 h of stirring the solid was fil-
tered off and rinsed with Et2O. Evaporation afforded 1.03 g (100%)
of the desired amine as a white liquid which was used in the next
(S)-1-Benzyl-6-acetoxy-3-phtalimido-azepan-2-one (1a)
To 222 mg (0.48 mmol) of diacetate 8a were added 550 mL (3.41
mmol) of triethylsilane and 2.8 mL of TFA. The mixture is stirred
for 75 min then diluted with DCM. A saturated NaHCO3 aqueous
solution and solid NaHCO3 were added. After evolution of CO2 has
ceased the organic phase was washed, separated and the aqueous
phase was reextracted with DCM. The combined organic layers
were dried over MgSO4, filtered and concentrated under reduced
pressure. Column chromatography on silica gel (1:1 EtOAc/cyclo-
hexane) afforded 145 mg (75%) of the expected monoacetate 1a as
1
step without further purification: H NMR (250 MHz, CDCl3): d
7.29-7.21 (m, 5H), 5.90 (dd, J1 = 1.9 Hz, J2 = 8.3 Hz, 1H), 5.60-
5.40 (m, 1H), 4.88 and 4.39 (qAB, J = 14.6 Hz, 2H, Ph-CH2), 3.92
(bs, 2H, NH2), 3.74 (apparent q, J = 5.3 Hz, 1H), 2.40-1.80 (m, 4H);
13C NMR (62.5 MHz, CDCl3): d 175.3, 137.2, 129.2, 128.6, 128.0,
127.5, 119.8, 53.4, 50.8, 37.9, 23.7; IR (neat): 3365, 2951, 1641,
1237, 1222, 749, 702 cm-1. To a solution of the amine thus obtained
(1.03 g, 4.77 mmol) in 30 mL of DMF was added 1.05 g (4.79
mmol) of N-carbethoxyphtalimide. After being stirred overnight the
solvent was evaporated off and the residue filtered through a plug
of silica gel (7:3 EtOAc/cyclohexane). After evaporation 25 mL of
water and 25 mL of abs EtOH were added to the residue and the sol-
vents were evaporated under reduced pressure. abs EtOH was added
and the mixture concentrated under vacuum. This procedure was
repeated at least three times in order to eliminate urethane via a
1
a colorless liquid: [a]18D = +95.6 (c 1.02, CH2Cl2); H NMR (250
MHz, CDCl3): d 7.84 (dd, Jm = 3, Jo = 5.4 Hz, 2H), 7.70 (dd, Jm = 3,
Jo = 5.4 Hz, 2H), 7.40-7.22 (m, 5H), 5.13 (dd, J1 = 2.3 Hz, J2 = 11.2
Hz, 1H, PhtN-CH), 5.03 and 4.23 (ABq, J = 14.6 Hz, 2H, Ph-CH2),
4.62 (tt, J1 = 3.5, J2 = 9.9 Hz, 1H, AcO-CH), 3.49 (dd, J1 = 9.9 Hz,
J2 = 15.0 Hz, 1H), 3.33 (bd, J = 15 Hz, 1H), 2.82 (apparent dq,
Jd = 2.4 Hz, Jq = 11.4 Hz, 1H), 2.27-2.20 (m, 1H), 2.20-2.13 (m,
Synlett 2004, No. 6, 1029–1033 © Thieme Stuttgart · New York

LETTER
Electrooxidation Based Strategy Towards the Core 3-Amino-6-Hydroxyazepan-2-one
1033
1H), 2.02 (s, 3H), 1.83 (apparent dq, Jd = 2.9 Hz, Jq = 13.0 Hz, 1H);
13C NMR (62.5 MHz, CDCl3): d 170.0 (2C), 168.2, 136.6, 134.1,
132.1, 128.8, 128.5, 127.8, 123.5, 70.1, 53.6, 52.0, 50.7, 33.4, 26.6,
21.1; IR (neat): 2963, 1777, 1710, 1664, 1387, 1087, 1030, 798, 717
cm-1; HRMS: m/z calcd. for C23H23N2O5 (M++1): 407.1607, found:
407.1604.
Tran, L. D.; Wang, R. M.; Weltchek, S.; Zabludoff, S. J.
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T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org. Chem.
1986, 51, 2590–2592. (c) Ludwig, C.; Wistrand, L. G. Acta
Chem. Scand. 1994, 48, 367–371.
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Synlett 2004, No. 6, 1029–1033 © Thieme Stuttgart · New York