6-Spiro-1,4-diazepane-2,5-diones by head-to-tail N1/C2 amide bond formation

Article abstract of DOI:10.1002/ejoc.200400782

The synthesis of a series of 6-spiro-1,4-diazepane-2,5-diones containing an arylpropylamide moiety via head-to-tail cyclisation of a terminal amine and a terminal carboxylate ester is described. To induce ring closure of the dipeptide precursor, both lactamisation of the N4/C5 amide bond and N1/C2 amide bond were investigated. Whereas ring closure of the N4/ C5 amide bond proved unsuccessful, ring closure of the N1/ C2 amide bond was more viable. Furthermore, it was discovered that incorporation of a N,N-disubstituted amide bond in the peptide sequence was essential for cyclisation to occur. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400782

FULL PAPER
6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond
Formation
Leon W. A. Van Berkom,[a] René de Gelder,[b] and Hans W. Scheeren*[a]
Keywords: Spiroheterocycles / Cyclisation / Cyclic dipeptides / Diazepane
The synthesis of a series of 6-spiro-1,4-diazepane-2,5-diones
containing an arylpropylamide moiety via head-to-tail cyclis-
ation of a terminal amine and a terminal carboxylate ester is
described. To induce ring closure of the dipeptide precursor,
both lactamisation of the N4/C5 amide bond and N1/C2 am-
ide bond were investigated. Whereas ring closure of the N4/
C5 amide bond proved unsuccessful, ring closure of the N1/
C2 amide bond was more viable. Furthermore, it was discov-
ered that incorporation of a N,N-disubstituted amide bond in
the peptide sequence was essential for cyclisation to occur.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
azepane-2,5-diones I were envisioned to arise from the lin-
ear dipeptides II or III via lactamisation of the N4/C5 or
the N1/C2 amide bond (pathways A and B, Figure 1). In
turn, precursor II and III can be obtained from the cyclic
masked β-amino ester IV which can be prepared from 3-
aryl-2-cyanoprop-2-enoates V using a [4+2] cycloaddition
reaction. In this paper the structural requirements for a
head-to-tail cyclisation reaction via pathway A or B to give
6-spiro-1,4-benzodiazepane-2,5-diones containing an aryl-
propylamide moiety are described.
Introduction
The exploration of privileged structures in drug discov-
ery has gained significant popularity and relevance in recent
years.[1] An important example of these privileged struc-
tures, the 1,4-benzodiazepine-2,5-diones, have been re-
ported to possess a wide range of pharmacological activi-
ties.[2] Whereas many reports describe the synthesis of 1,4-
benzodiazepine-2,5-diones,[3] few describe the synthesis of
1,4-diazepane-2,5-diones.[4,5]
Usually, 1,4-diazepane-2,5-diones are synthesized
through head-to-tail cyclisation of the terminal amine and
carboxylic acid of a linear dipeptide, consisting of an α-
and a β-amino acid, using a carboxylate activating reagent.
Unfortunately, the cyclisation reaction is sometimes ac-
companied with dimerisation of the dipeptide precursor
and usually proceeds in low or moderate yields. Recently,
Van Maarseveen and co-workers succeeded to improve the
yield of 1,4-diazepane-2,5-dione formation using an intra-
molecular Staudinger ligation reaction.[4b] Remarkably,
scarce examples have been reported in which diazepane for-
mation was accomplished by direct lactamisation of the ter-
minal ester and amine functional groups without conver-
sion of the ester to an activated carboxylic acid followed by
ring closure.[5]
Results/Discussion
Pathway A
To prepare 6-spiro-1,4-diazepane-2,5-diones according to
the strategy outlined in Figure 1, methyl (E)-2-cyano-3-phe-
nylprop-2-enoate (1) was reacted with an excess of 2,3-di-
methylbuta-1,3-diene to give the cycloadduct 2 in quantita-
tive yield (Scheme 1). Although compound 1 can be con-
verted to a variety of five- or six-membered (hetero)cycles,[7]
in this paper the reactivity of cycloadduct 2 was studied,
because of a) the robustness of the resulting cycloadduct,
b) the ease of purification, and c) the ease of characteriza-
tion. The nitrile 2 was reduced using Raney nickel and hy-
drogen to give the amine 3 in quantitative yield.[8]
Fmoc-Gly-OH was coupled with the amine 3 using 1,3-
diisopropylcarbodiimide and a catalytic amount of N-
hydroxybenzotriazole to obtain the amide 4 in 98%. The
Fmoc group was removed using THF/MeOH/sodium hy-
droxide to obtain the amine 6 in a yield of 80%.
As continuation of our research on the application of
nitro- and cyanoalkenes in cycloaddition reactions leading
to rigid arylethyl/propylamines and derivatives thereof,[6] we
set out to study the preparation of compounds in which an
arylpropylamide moiety is fixed within a 6-spiro-1,4-di-
azepane-2,5-dione
I
(Figure 1). These 6-spiro-1,4-di-
Since the rate of cyclisation reactions is enhanced by the
[a] Department of Organic Chemistry, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
jsch@sci.kun.nl
[b] Department of Inorganic Chemistry, University of Nijmegen,
Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
gem-dialkyl effect,[9] compound
7
was synthesized
(Scheme 1). Compound 7 was obtained in a yield of 84%
by coupling of the amine 3 with Fmoc-Aib-OH using 1,3-
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L. W. A Van Berkom, R. de Gelder, H. W. Scheeren
FULL PAPER
Figure 1. General synthetic strategy towards 6-spiro-fused 1,4-diazepane-2,5-diones
rated in the peptide sequence.[11] For this purpose, substitu-
tion of the amide bond with a benzyl group appeared to be
the most versatile option since it has been demonstrated
that, if desired, the benzyl group can be removed using sev-
eral different procedures.[12]
To test this concept, the linear precursor 10 was synthe-
sized according to the route depicted in Scheme 2. The
amino ester 8 was obtained in a yield of 79% by reaction
of the amine 3 with benzaldehyde, followed by reduction
with sodium borohydride. The amino ester 8 was coupled
with Fmoc-Gly-OH to obtain the protected amine 9. The
protecting group was removed using sodium hydroxide to
obtain the amine 10 in a yield of 79%. Interestingly, NMR
assignment of the compounds 9 and 10 was hampered by
presence of two conformers in solution, which is indicative
for a conformationally unbiased amide bond in the peptide
sequence. Disappointingly, the cyclisation of compound 10
was not possible when using thermal conditions, basic con-
ditions or high pressure conditions.
The chemical inertness, with respect to diazepane forma-
tion, of the compounds 6, 7, or 10, is probably caused by
Scheme 1. Synthesis of amines 6 and 7. Reagents and conditions: (a)
2,3-dimethylbuta-1,3-diene, reflux, 40 h; (b) Raney nickel, 1 bar H2,
1 m NH3/MeOH, room temp., 9 h; (c) Fmoc-Gly-OH, DIPC, HOBt,
0 °C, 15 min then room temp., 17 h; or Fmoc-Aib-OH, DIPC, HOBt,
0 °C, 15 min then room temp., 24 h (d) THF/MeOH/1 m NaOH,
10:2:1.5, room temp., 1 h; or piperidine, THF, room temp., 1 h
diisopropylcarbodiimide followed by removal of the Fmoc
group under basic conditions.
A series of initial reactions was conducted in order to-
synthesise 6-spiro-1,4-diazepane-2,5-diones. Unfortunately,
reaction of neither the amine 6 nor 7 under thermal, acidic,
basic, nor high-pressure conditions resulted in 6-spiro-1,4-
diazepane-2,5-dione formation.
The failure of the amines 6 and 7 to react via head-to-
tail cyclisation, might be caused by the preferred trans con-
formation of the N-monosubstituted amide bond which
prevents the terminal amine group and ester group to come
in close proximity.[10] To solve this problem a conformation-
Scheme 2. Synthesis of amino ester 10. Reagents and conditions: (a)
benzaldehyde, MgSO4, Et2O, room temp., 1 h; (b) NaBH4, MeOH,
0 °C then room temp., 14 h; (c) Fmoc-Gly-OH, DIPC, HOBt,
15 min, 0 °C, then 8, room temp., 17 h; (d) THF/MeOH/1 m NaOH,
ally unbiased N,N-disubstituted amide bond was incorpo- 6:1:1, room temp., 1 h.
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6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond Formation
FULL PAPER
the lack of reactivity of the hindered carboxylate ester.[13]
To favour the diazepane formation, a N,N-disubstituted
However, this problem can be circumvented by following amide bond was incorporated in the dipeptide sequence
pathway B, which involves lactamisation of an unhindered (Scheme 4). For this reason, the acid 11 was coupled with
amine and ester group (Figure 1).
N-benzylglycine methyl ester. Instead of using 1,3-diisopro-
pylcarbodiimide as coupling reagent, the acid 11 was
treated with oxalyl chloride to obtain the corresponding
acid chloride.[14] The acid chloride was coupled with N-
benzylglycine methyl ester in the presence of an excess of
triethylamine to yield the desired amide 14 in 77%.
Unexpectedly, treatment of compound 14 with Raney
nickel and hydrogen in ammonia/methanol did not yield the
desired amine 15, but in stead compound 16 was formed.
Further research revealed that compound 16 was also
formed in the absence of Raney nickel by basic treatment
of the nitrile 14. When it was attempted to crystallise enam-
ine 16 by slow evaporation of a solution of 16 in dichloro-
methane/heptane, compound 17 was obtained in a yield of
63%.[15] The structure of compound 17 was determined
with X-ray crystallography (Figure 2).[16]
Pathway B
Hydrolysis of the ester 2 gave the acid 11 in nearly quan-
titative yield (Scheme 3). Upon coupling of 11 with glycine
methyl ester hydrochloride using 1,3-diisopropylcarbodiim-
ide, the amide 12 was obtained in 75%. After reduction of
compound 12 with Raney nickel to obtain the amino ester
13, a series of cyclisation reactions were attempted. How-
ever, again no cyclisation could be induced.
Figure 2. X-ray structure of compound 17[17]
To prevent the formation of compound 16, the reduction
of the nitrile 14 was performed under nonbasic reaction
conditions. Surprisingly, reaction of the nitrile 14 with
Raney nickel under 50 bar of hydrogen at 80 °C, did not
Scheme 3. Synthesis of amino ester 13. Reagents and conditions: (a)
THF/MeOH/LiOH, 2:1:1, room temp., 1 h; (b) DIPC, HOBt, THF,
0 °C, 15 min, then Et3N, H-Gly-OMe·HCl, room temp., 48 h; (c)
Raney nickel, 1 bar H2, 1 m NH3/MeOH, 4 h.
Scheme 4. Reagents and conditions: (a) (COCl)2, DMF, THF, 0 °C, 2 h, then Et3N, Bn-Gly-OMe, CH2Cl2, room temp., 20 h; (b) Et3N,
MeOH, room temp., 20 h; (c) Raney nickel, 50 bar H2, 80 °C, 17 h.
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L. W. A Van Berkom, R. de Gelder, H. W. Scheeren
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yield the amine 15 but instead spontaneous cyclisation oc-
curred to give the diazepane 18 in a yield of 72%.
Stimulated by these results, we were interested to investi-
gate diazepane formation for a more hindered precursor.
For this purpose, the acid 11 was coupled with N-benzylala-
nine methyl ester (19) using oxalyl chloride to yield the
compound 20 as a mixture of two diastereoisomers
(Scheme 5). Upon reduction of the nitrile group spontane-
ous cyclisation occurred leading to the diazepane 21 as a
mixture of two diastereoisomers in a yield of 98%.
Next, H-Pro-OtBu was coupled with the acid 11 to give
the diastereoisomers 22a and 22b in a yield of 93%
(Scheme 6). Then the nitrile of diastereoisomers 22a and
22b was hydrogenated using Raney nickel. Whereas the re-
duction of diastereoisomer 22a gave in good yield the di-
azepane (–)-23a, diastereoisomer 22b yielded in 85% the
amine 24.[18] To obtain the diazepane 23b, the amine 24 was
heated in the presence of triethylamine in methanol. After
3 days the reaction was finished and the products (+)-23b
and (+)-23a were formed in a ratio of 3.5:1, respectively. To
prevent epimerization of the α-proton of proline and thus
formation of diazepane (+)-23a, the cyclisation of amine
24 was attempted under nonbasic conditions. Refluxing a
Figure 3. X-ray structure of (–)-23a and (+)-23b[16]
solution of amine 24 in toluene for 5 days gave the di-
azepane (+)-23b in a yield of 88%. The crystal structures
of both the diazepanes (–)-23a and (+)-23b were determined
by X-ray structure analysis.[15]
Scheme 5. Only the diastereoisomers resulting from reaction of
(1R,6S)-11 with alanine are shown. Reagents and conditions: (a)
(COCl)2, DMF, THF, 0 °C, 2 h, then Et3N, Bn-Ala-OMe, CH2Cl2,
room temp., 20 h; (b) Raney nickel, 20 bar H2, 1 m NH3/MeOH,
room temp., 22 h
Conclusions
The present study has established an efficient synthesis
of spiro-1,4-diazepane-2,5-diones via a head-to-tail lac-
Scheme 6. Reagents and conditions: (a) (COCl)2, DMF, THF, 0 °C, 2 h, then Et3N, H-Pro-OtBu, CH2Cl2, room temp., 17 h; (b) Raney nickel,
40 bar H2, 1 m NH3/MeOH, room temp., 17 h; (c) toluene, reflux, 5 d.
910
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6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond Formation
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dryness to yield the amine 3 (882 mg, 100%). The crude product
was sufficiently pure for further reactions and was used as such.
1H NMR (300 MHz, CDCl3): δ = 1.05 (br. s, 2 H), 1.66 (s, 3 H),
1.72 (s, 3 H), 1.69 (br. d, J = 18.3 Hz, 1 H), 1.98 (br. d, J = 17.1 Hz,
1 H), 2.37–2.56 (m, 2 H), 2.46 (d, J = 12.9 Hz, 1 H), 2.78 (d, J =
12.9 Hz, 1 H), 3.43 (dd, J = 5.4 Hz, 5.4 Hz, 1 H), 3.64 (s, 3 H),
7.15–7.28 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.7,
19.1, 34.2, 35.8, 43.4, 46.1, 51.7, 52.2, 124.2, 124.7, 126.7, 128.2,
128.6, 142.5, 176.2 ppm. HRMS calcd. for [M]+ (C17H23N1O2):
tamisation of the terminal NH2 and the terminal carboxyl-
ate ester of a dipeptide consisting of a cyclic β-amino acid
and an α-amino acid. Whereas ring closure of N4/C5 amide
bond (pathway A) proved unsuccessful, ring closure of the
N1/C2 amide bond (pathway B) was more viable (Figure 1).
In addition, it was observed that for cyclisation to occur, it
is essential that a conformationally unbiased N,N-disubsti-
tuted amide bond is incorporated in the linear dipeptide
sequence. Currently research is in progress to translate the
approach outlined in this paper to the solid phase.
273.1729; found 273.1726. IR (film): ν = 2907, 1727, 1455, 1433,
˜
1200, 703 cm–1.
( )-Methyl
(1R,6S)-1-{[(2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]-
amino}acetyl)amino]methyl}-3,4-dimethyl-6-phenylcyclohex-3-ene-1-
carboxylate (4): Fmoc-Gly-OH (1.26 g, 4.23 mmol) was dissolved
in tetrahydrofuran (10 mL) and the solution was cooled to 0 °C.
The solution was stirred and 1,3-diisopropylcarbodiimide (691 µL,
4.41 mmol) and N-hydroxybenzotriazole (10.0 mg) were added. Af-
ter 15 minutes, a solution of the amine 3 (1.05 g, 3.84 mmol) in
tetrahydrofuran (6 mL) was added dropwise to the reaction mix-
ture. After addition of the amine, the reaction mixture was slowly
warmed to room temperature. After 17 h the solvents were evapo-
rated and the dry residue was dissolved in dichloromethane. The
organic layer was washed once with both saturated sodium hydro-
gen carbonate and 0.5 n potassium hydrogen sulfate. The organic
layer was dried (sodium sulfate), filtered and the solvents were
evaporated to dryness. The crude product was purified using col-
umn chromatography (CH2Cl2/MeOH, 50:1) to give the amide 4
Experimental Section
General Remarks:1H NMR and 13C NMR spectra were recorded
with a Bruker DMX-300 spectrometer. Chemical shifts are re-
ported in parts per million downfield relative to tetramethylsilane
(δ = 0.00 ppm) for 1H NMR and relative to CDCl3 (δ = 77.16 ppm)
for 13C NMR spectra. Optical rotations were measured with a Per-
kin–Elmer 241 polarimeter, using concentrations (c) in g/100 mL.
Mass spectra were recorded with a VG7070E double-focusing mass
spectrometer using EI and CI modes. IR spectra were recorded
with an Anadis Thermo Mattson IR300 spectrometer. Elemental
analysis was carried out with a Carlo Erba Instruments CHNSO
EA 1108 element analyzer. Thin layer chromatography (TLC) was
carried out on Merck precoated silica gel 60 F-254 plates. Spots
were visualised with UV or by dipping the TLC plate into a 6.2%
aqueous sulfuric acid solution containing ammonium molybdate
(42 g/L) and ceric ammonium sulfate (3.6 g/L) followed by char-
ring. Column chromatography was carried out with Acros silica gel
(0.035–0.070mm). Solid-phase extractions were performed using
isolute® SCX-2 columns which were purchased from Argonaut.
Melting points were determined with a Buchi B-545 melting point
apparatus and are uncorrected. When necessary, reactions were
performed under standard Schlenk conditions. Ethyl acetate and
heptane were distilled prior to use. Tetrahydrofuran was dried by
distillation from sodium and benzophenone. Raney® 2800 nickel
was purchased from Aldrich and was extensively washed with
methanol prior to use.
1
(2.10 g, 98%) as a white foam. H NMR (300 MHz, CDCl3): δ =
1.66 (s, 3 H), 1.68 (s, 3 H), 1.93 (d, J = 17.1 Hz, 1 H), 2.24 (dd, J
= 6.0 Hz, 18.0 Hz, 1 H), 2.39 (dd, J = 8.4 Hz, 18.0 Hz, 1 H), 2.56
(d, J = 17.1 Hz, 1 H), 3.25 (dd, J = 4.5 Hz, 13.2 Hz, 1 H), 3.41
(dd, J = 6.0 Hz, 8.4 Hz, 1 H), 3.56 (s, 3 H), 3.61 (dd, J = 7.8 Hz,
13.2 Hz, 1 H), 3.71–3.79 (m, 2 H), 4.19 (t, J = 6.9 Hz, 2 H), 4.37
(d, J = 6.9 Hz, 1 H), 5.33 (br. s, 1 H), 6.16 (br. s, 1 H), 7.10–7.40
(m, 7 H), 7.36 (t, J = 7.2 Hz, 2 H), 7.54 (d, J = 7.2 Hz, 2 H), 7.72
(d, J = 7.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1,
19.3, 34.9, 36.2, 40.3, 44.9, 47.3, 51.1, 52.2, 67.4, 120.0, 123.5,
124.1, 125.0, 127.0, 127.1, 127.7, 128.3, 128.5, 141.0, 141.2, 143.6,
168.5, 175.7. MS (EI): m/z (%) = 552 (7) [M]+, 330 (27) [M Ϫ
Fmoc]+, 178 (100). HRMS calcd. for [M]+ (C34H36N2O5):
Literature Preparations: Methyl (E)-2-cyano-3-phenylprop-2-enoate
(1) was prepared by condensation of benzaldehyde with methyl cy-
anoacetate in the presence of piperidine in ethanol solution.[19]N-
benzylglycine methyl ester and N-benzylalanine methyl ester{[α]2D0
= Ϫ40.6 (c = 1.0, methanol), ref.[20] [α]2D1 = –41.0 (c = 1.8, meth-
anol)} were prepared by reductive amination of the corresponding
amino acid methyl ester hydrochloride.[21]
552.2624; found 552.2628. IR (film): ν = 2910, 1718, 1671, 1519,
˜
1446, 1230, 906, 759, 728, 707 cm–1.
( )-Methyl (1R,6S)-1-{[(2-Aminoacetyl)amino]methyl}-3,4-dimeth-
yl-6-phenylcyclohex-3-ene-1-carboxylate (6): The protected amine 4
(272 mg, 494 µmol) was dissolved in a mixture of tetrahydrofuran
(10 mL), methanol (2 mL) and 1 m NaOH/H2O (1.5 mL). The reac-
tion mixture was stirred at room temperature for 1 hour and the
reaction was quenched with acetic acid (90 µL). The reaction was
concentrated to dryness in vacuo and the residue was dissolved
in dichloromethane. The organic layer was washed with saturated
sodium hydrogen carbonate. The organic layer was dried (sodium
sulfate), filtered and the solvents evaporated in vacuo. The crude
product was subjected to solid-phase extraction using an isolute®
SCX-2 column. The crude product was loaded on the column dis-
solved in dimethylformamide. The product was eluted from the col-
umn using first methanol and then 1 m ammonia/methanol. The
amine 6 (130 mg, 80%) was obtained as a clear oil. 1H NMR
( )-Methyl (1R,6S)-1-Cyano-3,4-dimethyl-6-phenylcyclohex-3-ene-
1-carboxylate (2): A mixture of cyanoalkene 1 (11.9 g, 63.6 mmol)
and 5-tert-butyl-4-hydroxy-2-methylphenyl sulfide (100 mg) was
heated to reflux in 2,3-dimethylbuta-1,3-diene (25.0 mL,
221 mmol). After 40 h the reaction mixture was evaporated to dry-
ness in vacuo. The crude product was crystallised from a small
amount of hot ethanol to give the cycloadduct 2 (15.6 g, 90%) as
white crystals. A second crop (1.60 g, 9%) was obtained by concen-
tration of the filtrate and crystallisation from hot ethanol. Analyti-
cal data were in agreement with literature.[23]
( )-Methyl (1R,6S)-1-(Aminomethyl)-3,4-dimethyl-6-phenylcyclo- (300 MHz, CDCl3): δ = 1.44 (br. s, 2 H), 1.68 (s, 6 H), 1.93 (d, J
hex-3-ene-1-carboxylate (3): Cycloadduct 2 (870 mg, 3.23 mmol)
was dissolved in 1 m ammonia/methanol (20 mL). Raney nickel
(spoontip) was added and the reaction mixture was stirred under
hydrogen (1 bar) for 9 h at room temperature. The reaction mixture
was filtered through Celite® and the filtrate was concentrated to
= 16.7 Hz, 1 H), 2.27–2.39 (m, 2 H), 2.56 (d, J = 16.7 Hz, 1 H),
3.23 (dd, J = 4.8 Hz, 13.2 Hz, 1 H), 3.23 (dd, J = 5.0 Hz, 13.0 Hz,
1 H), 3.26 (s, 2 H), 3.42–3.52 (m, 2 H), 3.61 (s, 3 H), 7.10–7.28 (m,
5 H), 7.37 (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1,
19.3, 35.3, 35.7, 41.0, 44.4, 44.9, 51.0, 52.1, 123.7, 124.2, 126.9,
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L. W. A Van Berkom, R. de Gelder, H. W. Scheeren
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128.2, 128.5, 141.4, 172.3, 175.5 ppm. HRMS calcd. for [M]+
The reaction was quenched with acetic acid (300 µL) and the reac-
tion mixture was concentrated in vacuo. The product was dissolved
in dichloromethane and the organic layer was washed once with
saturated sodium hydrogen carbonate. The water layer was then
extracted twice more with dichloromethane. The combined organic
layers were dried (magnesium sulfate), filtered, and the solvent was
removed under vacuo. The crude product was purified using col-
umn chromatography (EtOAc/heptane, 1:7) to give the secondary
amine 8 (1.36 g, 79%) as a clear oil that solified upon storage in
the fridge. M.p. (heptane) 63 °C. 1H NMR (300 MHz, CDCl3): δ
= 1.36 (s, 1 H), 1.63 (s, 3 H), 1.68 (s, 3 H), 1.99–2.18 (m, 2 H),
2.33–2.54 (m, 2 H), 2.36 (d, J = 11.4 Hz, 1 H), 2.63 (d, J = 11.4 Hz,
1 H), 3.45 (dd, J = 4.8 Hz, 6.6 Hz, 1 H), 3.47 (s, 3 H), 3.64 (s, 2
H), 7.12–7.28 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.1, 19.5, 35.3, 36.1, 43.7, 51.2, 52.0, 53.2, 54.4, 124.39, 124.43,
126.6, 126.7, 127.9, 128.0, 128.1, 128.7, 140.5, 142.7, 176.2 ppm.
MS (EI): m/z (%) = 363 (39) [M]+, 332 (1) [M Ϫ OCH3]+, 304 (1)
[M Ϫ CH3OOC]+, 197 (22) [M Ϫ CH3OOC Ϫ NH2CH2Ph]+, 120
(100) [CH2NHCH2Ph]+, 91 (93) [tropylium]+. HRMS calcd. for
(C H N O ): 330.1942; found 330.1944. IR (film): ν = 2907,
˜
19 26
2
3
1722, 1666, 1524, 1433, 1225, 1204, 1126, 1100, 728, 703 cm–1.
( )-Methyl (1R,6S)-1-{[(2-{[(9H-Fluoren-9-ylmethoxy)carbonyl]-
amino}-2-methylpropanoyl)amino]methyl}-3,4-dimethyl-6-phenyl-
cyclohex-3-ene-1-carboxylate (5): To a solution of 2-{[(9H-fluoren-
9-ylmethoxy)carbonyl]amino}-2-methylpropanoic acid (Fmoc-Aib-
OH) (292 mg, 897 µmol) in tetrahydrofuran (1 mL) at 0 °C was
added 1,3-diisopropylcarbodiimide (147 µL, 937 µmol) and N-
hydroxybenzotriazole (10.0 mg). The mixture was stirred for 15
minutes before a solution of the amine 3 (223 mg, 816 µmol) in
tetrahydrofuran (3 mL) was added dropwise to the reaction mix-
ture. The reaction mixture was warmed to room temperature and
stirred for 24 h. After evaporation of the solvent, the residue was
dissolved in dichloromethane and washed with saturated sodium
hydrogen carbonate and 0.5 n potassium hydrogen sulfate. The or-
ganic layer was dried with sodium sulfate, filtered, and the solvents
evaporated in vacuo. The crude product was purified using column
chromatography (EtOAc/heptane, 2:5). The product 5 (474 mg,
100%) was obtained as a white foam. Rf (EtOAc/heptane, 2:5) =
0.12. 1H NMR (300 MHz, CDCl3): δ = 1.44 (s, 3 H), 1.47 (s, 3 H),
1.66 (s, 3 H), 1.68 (s, 3 H), 1.99 (d, J = 16.8 Hz, 1 H), 2.24 (dd, J
= 6.0 Hz, 17.7 Hz, 1 H), 2.37 (dd, J = 8.1 Hz, 17.7 Hz, 1 H), 2.51
(br. d, J = 16.8 Hz, 1 H), 3.17 (dd, J = 4.2 Hz, 13.5 Hz, 1 H), 3.42
(dd, J = 6.0 Hz, 8.1 Hz, 1 H), 3.51 (s, 3 H), 3.66 (dd, J = 8.1 Hz,
13.5 Hz, 1 H), 4.16 (t, J = 6.6 Hz, 1 H), 4.34 (d, J = 6.6 Hz, 2 H),
5.33 (br. s, 1 H), 6.46 (br. s, 1 H), 7.12–7.39 (m, 7 H), 7.32–7.38
(m, 2 H), 7.53–7.56 (m, 2 H), 7.72 (d, J = 7.5 Hz, 2 H) ppm. MS
(EI): m/z (%) = 580 (8) [M]+, 549 (1) [M Ϫ OCH3]+, 520 (1) [M –
COOCH3]+, 384 (29), 178 (69) [9-methylfluor-9-ylium]+, 165 (100).
HRMS calcd. for [M]+ (C36H40N2O5): 580.2937; found 580.2936.
[M]+ (C H NO ): 363.2198; found 363.2198. IR (film): ν = 2911,
˜
24 29
2
1722, 1493, 1455, 1195, 1126, 1100, 737, 703 cm–1. C24H29NO2
(363.5): calcd. C 79.30, H 8.04, N 3.85, found C 79.25, H 8.16, N
3.92.
( )-Methyl (1R,6S)-1-{[Benzyl(2-[(9H-fluoren-9-ylmethoxy)carbon-
yl]amino)acetyl)amino]methyl}-3,4-dimethyl-6-phenylcyclohex-3-
ene-1-carboxylate (9): Fmoc-Gly-OH (930 mg, 3.13 mmol) was dis-
solved in tetrahydrofuran (5 mL). The solution was cooled and 1,3-
diisopropylcarbodiimide (513 µL, 3.28 mmol) and N-hydroxy-
benzotriazole (10.0 mg) were added to the reaction mixture. After
15 minutes, a solution of the amine 8 (1.08 g, 2.98 mmol) in tetra-
hydrofuran (5 mL) was added dropwise to the reaction mixture.
The reaction was allowed to reach room temperature. After 17 h
the solvent was removed, and the residue was dissolved in dichloro-
methane. The organic layer was washed with saturated sodium hy-
drogen carbonate and 0.5 n potassium hydrogen sulfate. The or-
ganic layer was dried (sodium sulfate), filtered, and the solvents
evaporated to dryness. The crude product was purified using col-
umn chromatography (EtOAc/heptane, 1:3) to give the protected
amine 9 (1.71 g, 85%) as a white solid. Compound 9 is present as
a mixture of two conformers (a/b) in a ratio of 0.8:0.2 respectively
in CDCl3. Selected signals[24] 1H NMR (300 MHz, CDCl3): δ (a/b)
= 1.65 (s, 3 H, 3 H), 1.74 (s, 3 H, 3 H), 1.92Ϫ2.27 (m, 2 H, 2 H),
2.33Ϫ2.72 (m, 2 H, 2 H), 3.15 (d, J = 15.9 Hz, 1 H), 3.26Ϫ3.47
(m, 2 H, 1 H), 4.10Ϫ4.40 (m, 5 H, 4 H), 4.80 (d, J = 15.3 Hz, 1
H), 6.85Ϫ7.77 (m, 18 H, 18 H) ppm. 13C NMR (300 MHz, CDCl3):
δ (a) = 19.1, 19.8, 33.8, 36.6, 43.2, 44.2, 47.4, 50.8, 51.6, 52.6, 53.3,
67.2, 119.9, 124.2, 125.1, 125.9, 127.0, 127.6, 127.7, 128.4, 128.9,
129.0, 135.5, 141.2, 142.2, 143.75, 143.82, 155.8, 169.3, 175.6 ppm.
MS (EI): m/z (%) = 642 (0.2) [M]+, 420 (10) [M Ϫ Fmoc]+, 390
(54) [M Ϫ Fmoc Ϫ NH2CH2]+, 91 (100). HRMS calcd. for [M]+
IR (film): ν = 2907, 1718, 1662, 1519, 1446, 1247, 1087, 906,
˜
737 cm–1.
( )-Methyl (1R,6S)-1-{[(2-Amino-2-methylpropanoyl)amino]meth-
yl}-3,4-dimethyl-6-phenylcyclohex-3-ene-1-carboxylate (7): The pro-
tected amine 5 (439 mg, 756 µmol) was dissolved in tetrahydrofu-
ran/piperidine, 4:1 (5 mL) and the reaction mixture was stirred at
room temperature. After 1 hour the reaction mixture was evapo-
rated to dryness and the crude product was subjected to solid-phase
extraction using an isolute® SCX-2 column. The desired amine 7
(229 mg, 84%) was obtained as a clear oil. 1H NMR (300 MHz,
CDCl3): δ = 1.30 (s, 6 H), 1.67 (s, 6 H), 1.90 (d, J = 16.5 Hz, 1 H),
2.28–2.35 (m, 2 H), 2.53 (br. d, J = 16.5 Hz, 1 H), 3.13 (dd, J =
4.8 Hz, 13.5 Hz, 1 H), 3.44 (d, J = 8.1 Hz, 1 H), 3.48 (d, J = 8.1 Hz,
1 H), 3.60 (s, 3 H), 7.13–7.27 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 19.0, 19.4, 29.5, 29.6, 35.3, 35.5, 41.3, 44.4, 51.0, 52.1,
55.0, 123.8, 124.2, 126.9, 128.2, 128.6, 141.5, 175.5, 177.2 ppm.
HRMS calcd. for [M]+ (C21H30N2O3): 358.2257; found 358.2257.
IR (film): ν = 2911, 1722, 1662, 1511, 1433, 1217, 1096, 914, 733,
˜
703 cm–1.
(C H N O ): 642.3094; found 642.3095. IR (film): ν = 3062,
˜
41 42
2
5
2898, 1722, 1658, 1495, 1450, 1265, 1210, 1048, 759, 735, 703 cm–1.
( )-Methyl (1R,6S)-1-[(Benzylamino)methyl]-3,4-dimethyl-6-phenyl-
cyclohex-3-ene-1-carboxylate (8): The amine 3 (1.29 g, 4.70 mmol)
and benzaldehyde (549 mg, 5.17 mmol) were dissolved in diethyl
ether (2 mL). Magnesium sulfate (1.0 g) was added and the reaction
mixture was stirred at room temperature for 1 hour. The reaction
mixture was filtered to remove the magnesium sulfate and the fil-
trate was evaporated to dryness. The crude imine was dissolved
in methanol (5 mL). The solution was stirred at 0 °C and sodium
borohydride (190 mg, 5.02 mmol) was added in small portions to
the reaction mixture to prevent excess foaming of the reaction mix-
ture. After addition of all sodium borohydride the reaction mixture
was allowed to reach room temperature and was stirred for 14 h.
( )-Methyl (1R,6S)-1-{[(2-Aminoacetyl)(benzyl)amino]methyl}-3,4-
dimethyl-6-phenylcyclohex-3-ene-1-carboxylate (10): The protected
amine 9 (1.68 g, 2.61 mmol) was dissolved in a mixture of tetrahy-
drofuran (30 mL), methanol (5 mL) and 1 m NaOH/H2O (5 mL).
The reaction mixture was stirred at room temperature for 1 hour.
The reaction mixture was evaporated to dryness and the residue
was partitioned between a solution of saturated sodium hydrogen
carbonate and dichloromethane. The organic layer was isolated and
the water layer was extracted twice with dichloromethane. The
combined organic layers were dried (magnesium sulfate), filtered,
and the solvents evaporated to dryness. The crude product was
912
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 907–917

6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond Formation
FULL PAPER
purified using column chromatography (CH2Cl2/MeOH, 9:1) to yi- Celite®. The filtrate was evaporated to dryness. The crude product
eld the amino ester 10 (870 mg, 79%) as a white foam. Compound was subjected to solid-phase extraction using an isolute® SCX-2
10 is present as a mixture of two conformers (a/b) in a ratio of column to obtain the desired amine 13 (105 mg, 93%) as an oil. Rf
0.8:0.2 respectively in CDCl3. Selected signals[24]1
H
NMR (CH2Cl2/MeOH, 9:1) = 0.26. 1H NMR (300 MHz, CDCl3): δ =
(300 MHz, CDCl3): δ (a/b) = 1.64 (s, 3 H), 1.74 (s, 3 H), 1.86–2.20 1.55 (s, 2 H), 1.69 (s, 3 H), 1.78 (s, 3 H), 1.97 (d, J = 17.7 Hz, 1
(m, 2 H, 2 H), 2.32Ϫ2.59 (m, 2 H, 2 H), 3.97 (d, J = 15.0 Hz, 1 H), 2.13 (d, J = 17.7 Hz, 1 H), 2.35 (d, J = 12.8 Hz, 1 H),
H), 4.27 (s, 2 H), 4.96 (d, J = 15.0 Hz, 1 H) ppm. 13C NMR 2.38Ϫ2.54 (m, 2 H), 2.88 (d, J = 12.8 Hz, 1 H), 3.39 (dd, J = 3.9,
(75 MHz, CDCl3): δ = (a) 19.3, 19.9, 34.0, 36.8, 43.9, 44.3, 51.0, J = 6.9 Hz, 1 H), 3.71 (s, 3 H), 3.87 (dd, J = 4.8, J = 18.0 Hz, 1
51.8, 52.7, 53.9, 124.3, 125.4, 125.9, 127.0, 127.6, 128.5, 129.1, H), 4.10 (dd, J = 6.0 Hz, 18.0 Hz, 1 H), 7.12Ϫ7.28 (m, 5 H), 7.61
136.5, 142.5, 174.3, 175.8 ppm. MS (EI): m/z (%) = 420 (40) [M]+, (br. s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.4, 19.6, 35.3,
390 (47) [M Ϫ NHCH2]+, 362 (9) [M Ϫ Gly]+, 91 (100). HRMS 36.4, 41.9, 44.1, 47.6, 50.4, 52.6, 123.7, 126.7, 128.3, 128.9, 142.9,
calcd. for [M]+ (C26H32N2O3): 420.2413; found 420.2412. IR (film): 170.7, 176.8 ppm. HRMS calcd. for [M]+ (C19H26N2O3): 330.1944;
ν = 2909, 1727, 1657, 1494, 1433, 1087, 735, 703 cm–1.
found 330.1942. IR (film): ν = 707, 728, 910, 1208, 1364, 1437,
˜
˜
1524, 1645, 1740, 2910 cm–1
( )-(1R,6S)-1-Cyano-3,4-dimethyl-6-phenylcyclohex-3-ene-1-car-
boxylic Acid (11): The ester 2 (2.08 g, g7.74 mmol) was stirred in ( )-Methyl
2-(Benzyl-{[(1R,6S)-1-cyano-3,4-dimethyl-6-phenyl-
tetrahydrofuran (20 mL), methanol (10 mL), and 1.25 m LiOH/ cyclohex-3-enyl]carbonyl}amino)acetate (14): The acid 11 (457 mg,
H2O (10 mL) at room temperature. After one hour the reaction 1.79 mmol) was dissolved in tetrahydrofuran (4 mL). A few drops
was quenched with acetic acid (750 µL). The reaction mixture was of dimethylformamide were added and the reaction mixture was
concentrated in vacuo. The residue was diluted with 0.5 n potas- cooled to 0 °C. Oxalyl chloride (312 µL, 3.58 mmol) in tetrahy-
sium hydrogen sulfate and the resulting solution was extracted drofuran (1.5 mL) was added dropwise and the reaction mixture
three times with diethyl ether. The combined organic layers were was stirred for 1 hour. The reaction mixture was evaporated to
dried (magnesium sulfate), filtered, and the solvents evaporated to dryness in vacuo and the residue was dissolved in dichloromethane
1
dryness to obtain the acid 11 (1.95 g, 99%). H NMR (300 MHz, (5 mL). The solution was cooled to 0 °C and triethylamine (498 µL,
CDCl3): δ = 1.71 (s, 6 H), 2.25 (dd, J = 5.1 Hz, 17.3 Hz, 1 H), 2.49 3.58 mmol) in dichloromethane (2 mL) was added dropwise. Next,
(d, J = 16.8 Hz, 1 H), 2.62–2.76 (m, 1 H), 2.84 (d, J = 16.8 Hz, 1 N-benzylglycine methyl ester (337 mg, 1.88 mmol) in dichlorometh-
H), 3.21 (dd, J = 5.1 Hz, 12.0 Hz, 1 H), 7.22–7.36 (m, 5 H), 8.88 ane (2 mL) was added dropwise. The reaction mixture was allowed
(s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.0, 19.3, 36.8, to reach room temperature. After 3 h the reaction mixture was di-
41.3, 46.0, 50.9, 118.0, 120.7, 126.7, 128.1, 128.8, 138.7, 174.1 ppm. luted with dichloromethane and the organic layer was washed with
HRMS calcd. for [M]+ (C16H17NO2): 255.1259; found 255.1259. saturated sodium hydrogen carbonate and 1 m ammonium chloride.
IR (film): ν = 2910, 2254, 1718, 906, 733, 703 cm–1.
The water layers were extracted twice more with dichloromethane.
The combined organic layers were dried (sodium sulfate), filtered,
and the solvents evaporated to dryness. The crude product was
purified using column chromatography (EtOAc/heptane, 1:4) to
give the amide 14 (573 mg, 77%) as an oil. The amide is present as
a mixture of conformers a/b in a ratio of 0.53:0.47 respectively in
CDCl3. Selected signals[24] 1H NMR (300 MHz, CDCl3): δ = (a/b)
1.74 (s, 6 H, 6 H), 2.18Ϫ2.39 (m, 1 H, 1 H), 2.43Ϫ2.85 (m, 3 H, 3
H), 3.02 (br. s, J = 16.1 Hz, 1 H), 3.18Ϫ3.77 (m, 5 H, 6 H),
3.80Ϫ4.03 (m, 1 H, 1 H), 4.25 (br. d, J = 18.2 Hz, 1 H), 4.62 (br.
d, J = 15.5 Hz, 1 H), 4.85–5.14 (m, 1 H, 1 H). 6.75–7.56 (m, 10 H,
10 H). MS (EI): m/z (%) = 416 (36) [M]+, 385 (2) [M Ϫ OMe]+,
357 (5) [M – COOMe]+, 325 (21) [M Ϫ benzyl]+, 210 (46), 91 (100).
HRMS calcd. for [M]+ (C26H28N2O3): 416.2100; found 416.2101.
˜
( )-Methyl 2-({[(1R,6S)-1-Cyano-3,4-dimethyl-6-phenylcyclohex-3-
enyl]carbonyl}amino)acetate (12): The acid 11 (1.00 g, 3.71 mmol)
and N-hydroxybenzotriazole (10.0 mg) were dissolved in tetrahy-
drofuran (5 mL). While stirring at 0 °C, 1,3-diisopropylcarbodiim-
ide (640 µL, 4.09 mmol) was added. After 15 minutes, triethylamine
(432 mg, 4.27 mmol) was added to the reaction mixture. Next, gly-
cine methyl ester hydrogenchloride (512 mg, 4.09 mmol) was added
in small portions to the reaction mixture. After 3 h the reaction
mixture was slowly warmed to room temperature. After 48 h, the
reaction mixture was concentrated in vacuo. The residue was dis-
solved in dichloromethane and the organic layer was washed once
with saturated sodium hydrogen carbonate and once with 0.5 n po-
tassium hydrogen sulfate. The water layers were extracted two times
with dichloromethane. The combined organic layers were dried
(magnesium sulfate), filtered, and the solvents evaporated to dry-
IR (film): ν = 2907, 2252, 1754, 1647, 1496, 1433, 1365, 1208, 959,
˜
912, 770, 737, 702, 648 cm–1.
ness. The crude product was purified using column chromatogra- Preparation of Compounds 16 and17: The nitrile 14 (28.9 mg, 69.4
phy (EtOAc/heptane, 1:4) to obtain the amide 12 (903 mg, 75%). µmol) was dissolved in 1 m triethylamine/methanol (1 mL) and
1
Rf (EtOAc/heptane, 1:4) = 0.24. H NMR (300 MHz, CDCl3): δ = stirred at room temperature. After 20 h the reaction mixture was
1.71 (s, 6 H), 2.24 (dd, J = 5.1 Hz, 18.6 Hz, 1 H), 2.38 (d, J = concentrated to dryness to obtain the compound 16 (28.9 mg,
17.3 Hz, 1 H), 2.68Ϫ2.79 (m, 1 H), 3.02 (d, J = 17.3 Hz, 1 H), 3.28 100%) as a white solid. Upon attempted crystallization of com-
(dd, J = 5.1 Hz, 12.3 Hz, 1 H), 3.50 (dd, J = 4.8 Hz, 18.0 Hz, 1 H), pound 16 from dichloromethane/heptane, compound 17 (18.1 mg,
3.63 (s, 3 H), 3.86 (dd, J = 5.4 Hz, 18.0 Hz, 1 H), 6.44 (br. s, 1 H), 63%) was obtained.
7.18Ϫ7.36 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 18.9,
( )-Methyl (5R,10S)-4-Amino-2-benzyl-7,8-dimethyl-1-oxo-10-phe-
19.2, 36.3, 40.9, 41.9, 45.8, 51.2, 52.7, 120.2, 121.5, 125.9, 127.9,
nyl-2-azaspiro[4.5]deca-3,7-diene-3-carboxylate (16):1H NMR
128.1, 128.6, 139.1, 167.0, 168.8 ppm. HRMS calcd. for [M]+
(300 MHz, CDCl3): δ = 1.75 (s, 6 H), 2.08 (d, J = 17.1 Hz, 1 H),
2.38 (dd, J = 6.3 Hz, 18.9 Hz, 1 H), 2.65–2.83 (m, 1 H), 2.91 (d, J
= 17.1 Hz, 1 H), 3.46 (dd, J = 6.3 Hz, 12.0 Hz, 1 H), 3.49 (s, 3 H),
(C H N O ): 326.1631; found 326.1630. IR (film): ν = 3382,
˜
19 22
2
3
1748, 1679, 1524, 1433, 1368, 1208, 703 cm–1.
( )-Methyl 2-({[(1R,6S)-1-(Aminomethyl)-3,4-dimethyl-6-phenyl- 4.43 (d, J = 15.3 Hz, 1 H), 4.85 (d, J = 15.3 Hz, 1 H), 5.85 (s, 2
cyclohex-3-enyl]carbonyl}amino)acetate (13): The nitrile 12 (111 mg, H), 6.24–6.33 (m, 2 H), 6.93–7.08 (m, 3 H), 7.16–7.32 (m, 5 H)
340 µmol) was dissolved in 1 m NH3/MeOH (7 mL). After addition ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1, 19.2, 36.5, 39.8, 45.2,
of a catalytic amount of Raney nickel it was stirred at room tem- 45.9, 50.6, 53.5, 103.2, 124.3, 126.0, 126.2, 126.2, 127.3, 127.9,
perature under hydrogen (1 bar) for 4 h and then filtered through 128.3, 128.6, 137.9, 139.7, 153.1, 162.0, 173.4 ppm. HRMS calcd.
Eur. J. Org. Chem. 2005, 907–917
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
913

L. W. A Van Berkom, R. de Gelder, H. W. Scheeren
FULL PAPER
for [M]+ (C H N O ): 416.2100; found 416.2097. IR (film): ν =
OCH3), 3.44–3.57 (m, CH-Ala), 3.67 (s, OCH3), 4.25–4.73 (m,
CH2-benzyl), 7.00–7.54 (m, aromats) ppm. MS (EI): m/z (%) = 430
(50) [M]+, 371 (11) [M – COOMe]+, 339 (27) [M Ϫ benzyl]+, 210
(65), 91 (100). HRMS calcd. for [M]+ (C27H30N2O3): 430.2257;
˜
26 28
2
3
2947, 1727, 1612, 1491, 1451, 1273, 1241, 1193, 1149, 910, 731,
699 cm–1.
( )-Methyl (3S,5R,10S)-2-Benzyl-3-hydroxy-4-imino-7,8-dimethyl-
1-oxo-10-phenyl-2-azaspiro[4.5]dec-7-ene-3-carboxylate (17): M.p.
(CH2Cl2/heptane) 185 °C. 1H NMR (300 MHz, CDCl3): δ = 1.70
(s, 3 H), 1.78 (s, 3 H), 2.13 (d, J = 16.8 Hz, 1 H), 2.34–2.50 (m, 1
H), 2.67–2.93 (m, 2 H), 2.76 (s, 3 H), 3.52 (dd, J = 6.3 Hz, 11.7 Hz,
1 H), 3.85 (d, J = 15.3 Hz, 1 H), 4.91 (d, J = 15.3 Hz, 1 H), 6.67–
6.78 (m, 2 H), 6.97–7.13 (m, 3 H), 7.14–7.30 (m, 5 H) ppm. 13C
found 430.2255. IR (film): ν = 2902, 1744, 1648, 1496, 1454, 1432,
˜
1330, 1219, 1115, 770, 737, 701 cm–1.
(5SR,6RS,9S)-8-Benzyl-2,3,9-trimethyl-5-phenyl-8,11-diazaspiro-
[5.6]dodec-2-ene-7,10-dione (21): The amide 20 (511 mg, 1.19 mmol)
was dissolved in 1 m NH3/MeOH (5 mL) in an autoclave. A cata-
lytic amount of Raney nickel was added and the reaction mixture
NMR (75 MHz, CDCl3): δ = 19.1, 19.2, 35.1, 41.5, 42.6, 43.9, 50.8, was hydrogenated under 20 bar of hydrogen at room temperature.
53.1, 86.5, 125.7, 127.0, 127.1, 127.7, 127.9, 128.4, 129.7, 135.1,
After 22 h the reaction mixture was filtered through Celite® and
the filtrate was evaporated to dryness. To remove minor impurities,
the crude product was purified over a small silica column (EtOAc/
139.7, 169.5, 175.3, 175.3 ppm. HRMS calcd. for [M]+
(C H N O ): 432.2049; found 432.2051. IR (film): ν = 1753,
˜
26 28
2
4
1714, 1670, 1453, 1436, 1391, 1351, 1263, 1138, 911, 734, 699 cm–1. heptane, 1:1) to obtain the desired diazepane 21 (467 mg, 98%) as
C26H28N2O4 (432.5): calcd. C 72.20, H 6.53, N 6.48; found C 71.80,
H 6.33, N 6.16.
a white foam. According to NMR analysis the diazepane was pres-
ent as a mixture of diastereoisomers in a ratio of 0.56:0.44. Rf
(EtOAc/heptane, 1:1) = 0.33. 1H NMR (300 MHz, CDCl3): δ =
(major/minor) 0.77 (d, J = 7.5 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H),
1.65 (br. s, 3 H, 3 H), 1.69 (s, 3 H, 3 H), 2.04–2.18 (m, 2 H, 1 H),
2.26 (d, J = 17.4 Hz, 1 H), 2.33–2.53 (m, 1 H, 1 H), 2.85 (br. d, J
= 16.8 Hz, 1 H), 3.07 (d, J = 17.5 Hz, 1 H), 3.13 (dd, J = 7.2 Hz,
15.0 Hz, 1 H), 3.26 (dd, J = 6.6 Hz, 15 Hz, 1 H), 3.56 (dd, J =
5.4 Hz, 12.9 Hz, 1 H), 3.67–3.83 (m, 3 H), 3.84–3.94 (m, 2 H), 4.30
(d, J = 15.0 Hz, 1 H), 4.41 (d, J = 15.9 Hz, 1 H), 4.62 (d, J =
15.9 Hz, 1 H), 4.78 (d, J = 15.0 Hz, 1 H), 6.74 (br. s, 1 H, 1 H),
6.85–7.46 (m, 10 H, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
13.6, 17.5, 19.0, 19.08, 19.18, 19.24, 33.7, 33.8, 37.6, 39.7, 40.5,
42.1, 46.0, 46.3, 47.7, 49.7, 53.4, 52.7, 53.1, 60.7, 122.9, 123.3,
123.6, 124.0, 126.4, 126.5, 126.9, 127.1, 127.2, 127.6, 128.0, 128.1,
128.3, 128.4, 129.3, 129.4, 136.7, 138.7, 140.1, 140,2, 173.2, 173.7,
175.0, 175.3 ppm. HRMS calcd. for [M]+ (C26H30N2O2): 402.2307;
( )-(5S,6R)-8-Benzyl-2,3-dimethyl-5-phenyl-8,11-diazaspiro[5.6]do-
dec-2-ene-7,10-dione (18): The nitrile 14 (120 mg, 288 µmol) was
dissolved in methanol (5 mL) in an autoclave. To the solution was
added a catalytic amount of Raney nickel followed by hydrogena-
tion at 50 bar H2 and 80 °C. After 17 h the reaction was stopped
and the reaction mixture was filtered through Celite®. The filtrate
was evaporated to dryness and the crude product was subjected to
column chromatography (EtOAc/heptane, 1:1). After the column
the diazepane 18 (80.7 mg, 72%) was obtained as a white solid. Rf
(EtOAc/heptane, 1:1) = 0.34. 1H NMR (300 MHz, CDCl3): δ =
1.59 (s, 3 H), 1.61 (s, 3 H), 1.98–2.17 (m, 2 H), 2.25–2.36 (m, 1 H),
2.87 (d, J = 17.7 Hz, 1 H), 3.02 (dd, J = 1.5 Hz, 13.2 Hz, 1 H),
3.21 (dd, J = 6.9 Hz, 15.0 Hz, 1 H), 3.53–3.64 (m, 2 H), 3.76 (dd,
J = 5.1 Hz, 14.7 Hz, 1 H), 4.00 (d, J = 14.9 Hz, 1 H), 4.98 (d, J =
14.9 Hz, 1 H), 6.46 (br. s, 1 H), 6.54–6.71 (m, 2 H), 7.00–7.26 (m,
8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1, 19.3, 34.3, 40.1,
40.4, 46.5, 50.8, 52.5, 53.9, 123.0, 124.2, 127.0, 127.2, 127.6, 128.38,
128.39, 129.5, 136.1, 140.3, 171.6, 174.0 ppm. HRMS calcd. for
found 402.2307. IR (film): ν = 1687, 1616, 1494, 1450, 1388, 1358,
˜
1273, 766, 734, 702 cm–1.
Preparation of Compounds 22a and 22b: The acid 11 (2.00 g,
7.83 mmol) was dissolved in tetrahydrofuran (10 mL). A few drops
[M]+ (C H N O ): 338.2151; found 388.2150. IR (film): ν = 2912,
˜
25 28
2
2
1691, 1624, 1494, 1472, 1454, 1403, 1359, 1224, 911, 733, 703 cm–1. of dimethylformamide were added and the reaction mixture was
cooled to 0 °C. Oxalyl chloride (1.30 mL, 1.9 equiv.) in tetrahy-
drofuran (2 mL) was added dropwise to the reaction mixture. After
2 h the reaction mixture was evaporated to dryness in vacuo. The
Methyl (2S)-2-(Benzyl-{[(1RS,6SR)-1-cyano-3,4-dimethyl-6-phenyl-
cyclohex-3-enyl]carbonyl}amino)propanoate (20): The acid 11
(1.15 g, 4.51 mmol) was dissolved in tetrahydrofuran (5 mL). A few
crude acid chloride was dissolved in dichloromethane (10 mL) and
drops of dimethylformamide were added and the reaction mixture
the solution was cooled to 0 °C. Triethylamine (3.0 mL, 2.8 equiv.)
was cooled to 0 °C. Oxalyl chloride (745 µL, 1.9 equiv.) in tetrahy-
drofuran (2 mL) was added dropwise to the reaction mixture. After
in dichloromethane (3 mL) was added dropwise to the reaction
mixture. Next, H-Pro-OtBu (1.34 g, 1.0 equiv.) in dichloromethane
2 h the reaction mixture was evaporated to dryness in vacuo. The
(4 mL) was added dropwise to the reaction mixture. The reaction
crude acid chloride was dissolved in dichloromethane (6 mL) and
mixture was allowed to reach room temperature. After 17 h, the
the solution was cooled to 0 °C. Triethylamine (1.19 mL, 1.9 equiv.)
reaction mixture was diluted with dichloromethane and washed
in dichloromethane was added dropwise to the reaction mixture.
Next, N-benzylalanine methyl ester (867 mg, 1.0 equiv.) in dichloro-
with saturated sodium hydrogen carbonate and 1 m ammonium
chloride. The water layers were extracted twice with dichlorometh-
methane (3 mL) was added dropwise to the reaction mixture. The
ane. The combined organic layers were dried (sodium sulfate), fil-
reaction mixture was stirred at 0 °C for 1 hour and then 20 h at
tered and the solvents evaporated to dryness. The crude product
room temperature. The reaction mixture was diluted with dichloro-
was purified using column chromatography (EtOAc/heptane, 1:7)
methane and washed with saturated sodium hydrogen carbonate
and 1 m ammonium chloride. The water layers were extracted twice
with dichloromethane. The combined organic layers were dried (so-
to yield the amides 22a (1.51 g, 47%) and 22b (1.47 g, 46%) as a
white solids.
dium sulfate), filtered and the solvents evaporated to dryness. The
crude product was purified using column chromatography (EtOAc/
(–)-tert-Butyl (2S)-1-{[(1S,6R)-1-Cyano-3,4-dimethyl-6-phenylcyclo-
hex-3-enyl]carbonyl}tetrahydro-1H-pyrrole-2-carboxylate (22a):[α]2D0
heptane, 1:4) to yield the amide 20 (1.63 g, 84%) as a white solid. = –113 (c = 1.03, CH2Cl2). Rf (EtOAc/heptane, 1:4) = 0.27. The
The amide is formed as a mixture of two diastereoisomers which
are both present in solution as a mixture of conformers. Selected
amide is present as a mixture of conformers a/b in CDCl3 in a ratio
of 0.59:0.41. Selected signals[24]1H NMR (300 MHz, CDCl3): δ (a/
signals[24]1H NMR (300 MHz, CDCl3): δ = 1.02–1.34 (m, CH3- b) = 1.28 (s, CH3), 1.43 (s, CH3), 1.70 (s, tBu), 2.14–2.33 (m, 1 H,
Ala), 1.71 (s, CH3-ring), 2.20–2.36 (m, CH-ring), 2.42–2.56 (m,
CH-ring), 2.58–2.86 (m, CH-ring), 2.88–3.14 (m, CH-ring), 3.39 (s,
1 H), 2.35–2.47 (m, 1 H, 1 H), 2.59–2.94 (m, 1 H, 2 H), 3.17–3.22
(m, 1 H), 3.26–3.40 (m, 2 H), 3.42–3.58 (m, 1 H, 2 H), 3.77 (ddd,
914
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 907–917

6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond Formation
J = 6.6 Hz, 6.6 Hz, 10.2 Hz, 1 H), 4.20 (dd, J = 5.1 Hz, 8.4 Hz, 1 (s, 3 H), 1.74 (s, 3 H), 1.70–2.07 (m, 5 H), 2.15 (d, J = 17.6 Hz, 1
FULL PAPER
H), 4.31 (dd, J = 1.8 Hz, 8.1 Hz, 1 H), 7.15–7.47 (m, 5 H, 5 H)
ppm. MS (EI): m/z (%) = 408 (34) [M]+, 352 (89) [M – tBu]+, 335
(14) [M Ϫ OtBu]+, 307 (88) [M – COOtBu]+, 210 (74) [M Ϫ Boc
H), 2.28 (d, J = 13.8 Hz, 1 H), 2.33–2.46 (m, 1 H), 2.79 (d, J =
17.6 Hz, 1 H), 3.12 (d, J = 13.8 Hz, 1 H), 3.37–3.49 (m, 1 H), 3.52
(dd, J = 4.5 Hz, 5.1 Hz, 1 H), 3.77–3.88 (m, 1 H), 4.40–4.53 (m, 1
Ϫ Pro]+, 91 (93), 70 (100). HRMS calcd. for [M]+ (C25H32N2O3): H), 7.12–7.27 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 19.1,
408.2413; found 408.2414. IR (film): ν = 2976, 2911, 1735, 1632, 19.4, 26.3, 27.8, 28.3, 36.0, 36.2, 43.0, 46.8, 48.1, 53.1, 62.5, 81.1,
˜
1398, 1364, 1152, 910, 698 cm–1.
123.6, 125.5, 126.7, 128.1, 128.8, 142.5, 171.9, 173.3 ppm. HRMS
calcd. for [M]+ (C H N O ): 412.2726 found 412.2725. IR (film): ν
˜
25 36
2
3
(+)-tert-Butyl (2S)-1-{[(1R,6S)-1-Cyano-3,4-dimethyl-6-phenylcy-
clohex-3-enyl]carbonyl}tetrahydro-1H-pyrrole-2-carboxylate (22b):
[α]2D0 = +14.7 (c = 0.99, CH2Cl2). Rf (EtOAc/heptane, 1:4) = 0.34.
1H NMR (300 MHz, CDCl3): δ = 1.20–1.30 (m, 1 H), 1.43 (s, 9
= 2976, 1733, 1612, 1451, 1390, 1366, 1222, 1153, 767, 737, 704 cm–1.
(–)-3,4-Dimethyl-6-phenyl-2Ј,3Ј,7Ј,8Ј,9Ј,9aЈ-hexahydro-1ЈH,5ЈH-spiro[-
cyclohex-3-ene-1,4Ј-pyrrolo[1,2-a][1,4]diazepine-1,5-dione] (23a): Com-
H), 1.60–1.87 (m, 3 H), 1.71 (s, 3 H), 1.73 (s, 3 H), 2.21 (dd, J = pound 22a (168 mg, 411 µmol) was dissolved in 1 m ammonia/meth-
4.8 Hz, 17.7 Hz, 1 H), 2.44 (d, J = 17.4 Hz, 1 H), 2.74–2.90 (m, 1
H), 3.09–3.23 (m, 2 H), 3.35 (dd, J = 5.1 Hz, 12.3 Hz, 1 H), 3.62
(ddd, J = 6.9 Hz, 6.9 Hz, 10.2 Hz, 1 H), 4.09 (dd, J = 5.7 Hz,
anol (5 mL) in an autoclave. A catalytic amount of Raney nickel was
added and the reaction mixture was stirred under 40 bar H2. After
17 h the reaction mixture was filtered through Celite® and the filtrate
7.8 Hz, 1 H), 7.17–7.32 (m, 3 H), 7.35–7.44 (m, 2 H) ppm. 13C was concentrated to dryness in vacuo. The crude product was purified
NMR (75 MHz, CDCl3): δ = 18.8, 19.0, 25.6, 28.17, 28.23, 35.4,
42.1, 46.1, 48.5, 48.6, 62.0, 81.2, 119.8, 121.2, 125.2, 127.6, 128.2,
128.3, 139.5, 165.1, 170.4 ppm. MS (EI): m/z (%) = 408 (4) [M]+,
352 (79) [M – tBu]+, 335 (14) [M Ϫ OtBu]+, 307 (38) [M – COOt-
using column chromatography (CH2Cl2/MeOH, 20:1) to give the di-
azepane 23a (118 mg, 85%). An analytical sample was obtained by
crystallisation of the product from CH2Cl2/heptane. [α]2D0 = –66.7 (c
=
1.23, CH2Cl2). M.p. (CH2Cl2/heptane) 229 °C. 1H NMR
Bu]+, 210 (40) [M Ϫ Boc Ϫ Pro]+, 91 (79), 70 (100). HRMS calcd. (300 MHz, CDCl3): δ = 1.23–1.41 (m, 1 H, H-8), 1.46–1.60 (m, 1 H,
for [M]+ (C H N O ): 408.2413; found 408.2401. IR (film): ν =
H-7), 1.61–1.73 (m, 1 H, H-8), 1.66 (s, 3 H, H-11), 1.69 (s, 3 H, H-
10), 2.01–2.16 (m, 2 H, H-1, H-2), 2.19–2.32 (m, 1 H, H-7), 2.36–
2.53 (m, 1 H, H-2), 3.00 (d, J = 17.4 Hz, 1 H, H-1), 3.13–3.28 (m, 2
H, H-4, H-9), 3.40–3.62 (m, 3 H, H-3, H-6, H-9), 3.71–3.83 (m, 1 H,
H-4), 6.73 (dd, J = 6.0 Hz, 6.0 Hz, NH), 7.16–7.34 (m, 5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 19.1, 19.2, 22.3, 27.6, 32.9, 39.35,
39.37, 46.1, 48.6, 51.5, 55.2, 123.2, 123.7, 126.7, 127.0, 127.9, 128.8,
139.9, 172.3, 172.5 ppm. HRMS calcd. for [M]+ (C21H26N2O2):
˜
25 32
2 3
2976, 2911, 1735, 1636, 1398, 1368, 1148, 910, 728, 698 cm–1.
(–)-tert-Butyl (2S)-1-{[(1R,6S)-1-(Aminomethyl)-3,4-dimethyl-6-phe-
nylcyclohex-3-enyl]carbonyl}pyrrolidine-2-carboxylate (24): Com-
pound 22b (530 mg, 1.30 mmol) was dissolved in 1 m ammonia/meth-
anol (7 mL) in an autoclave. A catalytic amount of Raney nickel was
added and the reaction mixture was stirred under hydrogen (40 bar).
After 17 h the reaction mixture was filtered through Celite® and the
filtrate was concentrated to dryness in vacuo. The crude product was
purified using column chromatography (CH2Cl2/MeOH, 24:1) to yi-
eld the amine 24 (444 mg, 83%). [α]D20 = –43.9 (c = 1.08, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9 H), 1.52 (s, 2 H), 1.66
338.1994; found 388.1996. IR (film): ν = 2915, 1689, 1616, 1410,
˜
1268, 768, 740, 703 cm–1.
(+)-3,4-Dimethyl-6-phenyl-2Ј,3Ј,7Ј,8Ј,9Ј,9aЈ-hexahydro-1ЈH,5ЈH-spiro-
[cyclohex-3-ene-1,4Ј-pyrrolo[1,2-a][1,4]diazepine-1,5-dione] (23b): The
Table 1. Crystallographic data and parameters for the compounds 17, 23a, and 23b
Compound
17
23a
23b
Emperical formula
Molecular mass
C26H28N2O4
432.50
C21H26N2O2
338.44
C21H26N2O2
338.44
Temperature [K]
Wavelength [Å]
Crystal system
Space group
208(2)
293(2)
0.71073
orthorhombic
P212121
208(2)
0.71073
orthorhombic
P212121
0.71073
monoclinic
P21/n
Unit cell dimension [Å, °]
a
b
c
16.0418(12)
7.5508(5)
19.0123(7)
90
9.4452(5)
13.6480(13)
29.921(3)
90
7.01380(10)
12.3349(7)
20.6112(11)
90
α
β
γ
98.032(5)
90
2280.3(2)
4
1.260
0.085
90
90
3857.1(5)
8
1.166
0.075
90
90
1783.17
4
1.261
Volume [3]
Z
Density, calculated [mg/m3]
µ [mm–1]
0.081
F(000)
Crystal size [mm]
θ range [°]
920
1456
728
0.46 × 0.31 × 0.22
2.16Ϫ27.50
45674
0.26 × 0.18 × 0.13
3.06Ϫ27.50
43704
0.29 × 0.20 × 0.18
3.06Ϫ27.50
61751
Reflections collected
Independent reflections [Rint
Refinement method
Data/restraint/parameters
Goodness-of-fit on F2
R1, wR2 indices [I Ͼ 2σ(I)]
R1, wR2 indices (all data)
]
5236 [0.0506]
8833 [0.0513]
full-matrix least-squares on F2
8833/0/465
1.000
4092 [0.0433]
5236/0/401
1.041
0.0552, 0.1078
0.0887, 0.1194
0.290 and –0.249
4092/0/330
1.075
0.0405, 0.0851
0.0499, 0.0887
0.224 and –0.218
0.0628, 0.1235
0.1729, 0.1576
0.227 and –0.159
Largest diff. peak and hole [e·–3]
Eur. J. Org. Chem. 2005, 907–917
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
915

L. W. A Van Berkom, R. de Gelder, H. W. Scheeren
FULL PAPER
5814–5819; j) M. Akssira, M. Boumzebra, H. Kasmi, A. Dah-
douh, Tetrahedron 1994, 50, 9051–9060.
amine 24 (104 mg, 252 µmol) was dissolved in toluene (3 mL) and
heated at reflux. The progress of the reaction was monitored using
TLC and NMR spectroscopy. After 5 days the reaction was finished
and the reaction mixture was evaporated to dryness. The crude pro-
duct was purified using column chromatography (CH2Cl2/MeOH,
20:1) to obtain the desired diazepane 23b (75.1 mg, 88%) as a light
yellow oil. An analytical sample was obtained by crystallisation from
EtOAc/heptane to give small sugar-like crystals. [α]2D0 = +52 (c = 0.08,
CH2Cl2). M.p. (EtOAc/heptane) 195 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.65 (s, 3 H), 1.71 (s, 3 H), 1.64–1.96 (m, 4 H), 2.24–
2.38 (m, 2 H), 2.52–2.67 (m, 1 H), 2.95–3.07 (m, 1 H), 3.43–3.74 (m,
5 H), 4.33 (dd, J = 6.9 Hz, 6.9 Hz, 1 H), 5.36 (dd, J = 6.9 Hz, 6.9 Hz,
1 H), 7.10–7.33 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
19.05, 19.07, 22.2, 28.4, 33.5, 42.8, 43.0, 44.2, 49.4, 51.6, 56.3, 122.9,
123.9, 126.6, 128.0, 128.2, 141.2, 170.4, 173.2 ppm. HRMS calcd. for
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[M]+ (C H N O ): 338.1994; found 388.1995. IR (film): ν = 2911,
˜
21 26
2
2
1687, 1599, 1402, 1153, 911, 733, 702, 647 cm–1. C21H26N2O2 (338.5):
calcd. C 74.53, H 7.74, N 8.28; found C 74.35, H 7.54, N 8.11.
Crystal Structure Determinations:[16] Crystals suitable for X-ray dif-
fraction studies were grown by slow evaporation from CH2Cl2/hep-
tane for 17 and 23a, and EtOAc/heptane for 23b. Single crystals were
mounted in air on glass fibres. Intensity data were collected at room
temperature for 23a and at Ϫ65 °C for 17 and 23b. A Nonius Kappa
CCD single-crystal diffractometer was used (φ and ω scan mode),
using graphite-monochromated Mo-Kα radiation. The structures
were solved by the program CRUNCH[25] and were refined with stan-
dard methods using SHELXL97[26] with anisotropic parameters for
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lated positions and were refined riding on the parent atoms. For 17
and 23b the hydrogens were initially placed at calculated positions
and were freely refined subsequently. Crystallographic data and
parameters of the refinements are listed in Table 1.
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using various reaction conditions failed.
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3-cyclohexenyl)carbonyl]-N,NЈ-diisopropylurea upon application
of 1,3-diisopropylcarbodiimide, the acid 11 was converted to
compound 14 using oxalyl chloride.
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[16]
Upon standing in CDCl3 for 22 h the same reaction was ob-
served. The conversion of 16 to 17 probably involves molecular
oxygen. The details of the reaction mechanism are currently un-
der investigation.
Crystallographic data for the structures 17, 23a and 23b have
been deposited with the Cambridge Crystallography Data Centre
as supplementary publication numbers CCDC-252852, -252850
and -252851 contain the supplementary crystallographic data for
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6-Spiro-1,4-diazepane-2,5-diones by Head-to-Tail N1/C2 Amide Bond Formation
FULL PAPER
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Eur. J. Org. Chem. 2005, 907–917
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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