Stereoselective synthesis of hydroxylated 3-aminoazepanes using a multi-bond forming, three-step tandem process

Article abstract of DOI:10.1039/c2ob26544c

A multi-bond forming, three-step tandem process involving a palladium(II)-catalysed Overman rearrangement and a ring closing metathesis reaction has been utilised for the efficient synthesis of a 2,3,6,7-tetrahydro- 3-amidoazepine. Substrate directed epoxidation or dihydroxylation of this synthetic intermediate has allowed the diastereoselective synthesis of hydroxylated 3-aminoazepanes including the syn-diastereomer of the balanol core. Asymmetric synthesis of the 2,3,6,7-tetrahydro-3-amidoazepine motif was also achieved using a chiral palladium(II)-catalyst during the Overman rearrangement.

Full text of DOI:10.1039/c2ob26544c

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PAPER
Stereoselective synthesis of hydroxylated 3-aminoazepanes using a multi-bond
forming, three-step tandem process†
Sajjad Ahmad and Andrew Sutherland*
Received 5th August 2012, Accepted 30th August 2012
DOI: 10.1039/c2ob26544c
A multi-bond forming, three-step tandem process involving a palladium(II)-catalysed Overman
rearrangement and a ring closing metathesis reaction has been utilised for the efficient synthesis of a
2,3,6,7-tetrahydro-3-amidoazepine. Substrate directed epoxidation or dihydroxylation of this synthetic
intermediate has allowed the diastereoselective synthesis of hydroxylated 3-aminoazepanes including the
syn-diastereomer of the balanol core. Asymmetric synthesis of the 2,3,6,7-tetrahydro-3-amidoazepine
motif was also achieved using a chiral palladium(II)-catalyst during the Overman rearrangement.
Introduction
The azepane ring system is an important structural motif found
in many pharmaceutically active compounds and natural pro-
ducts.1 Amino-substituted azepane rings in particular, make up
the core of several important natural products and medicinal
agents such as (−)-balanol (1), a metabolite of the fungi Verticil-
lium balanoides and a potent inhibitor of human protein kinase
C (Fig. 1).2 Other important aminoazepanes include azelastine
(2),3 a selective histamine antagonist and zilpaterol (3), a β-adre-
nergic agonist used as a feed additive for cattle.4 Due to the
interest in using amino-substituted azepanes as pharmacologi-
cally active building blocks and as conformationally constrained
peptidomimetics,5 there has been much focus on developing
methods for their synthesis.6,7 For example, Braga and co-
workers prepared a trihydroxylated aminoazepane from D-gluci-
Fig. 1 Structures of aminoazepane containing compounds.
tol via an aziridine ring opening reaction,7c while Würdemann
and Christoffers utilised an intramolecular 1,3-dipolar cyclo-
addition between a nitrone and an allylic amine to generate a cis-
5-aminoazepan-3-ol.7e Most synthetic methods developed for the
preparation of aminoazepanes have focused on the generation of
the trans-3-amino-4-hydroxyazepane core of balanol (1)8 and
include samarium iodide mediated cyclisation of oxime ethers8b,c
as well as ring closing metathesis (RCM) of amino-substituted
dienes to form the azepane ring system.8d,e,h,i
While many of these synthetic methods allow the efficient
stereoselective synthesis of amino-substituted azepane rings,
they all rely on traditional single-step transformations that
require their own set of reagents, solvents and conditions as well
as the yield reducing isolation and purification of each intermedi-
ate. Cascade, domino or tandem processes overcome many limit-
ations of single-step transformations and allow the formation of
multiple bonds and molecular complexity, all in a single pot
operation.9 We now report the efficient preparation of a 2,3,6,7-
tetrahydro-3-amidoazepine using a multi-bond forming, three-
step tandem process. We also demonstrate how this flexible syn-
thetic intermediate can be subjected to substrate directed oxi-
dation reactions for the diastereoselective preparation of
hydroxylated 3-aminoazepanes including the syn-diastereomer of
the balanol core.
WestCHEM, School of Chemistry, The Joseph Black Building, University
of Glasgow, Glasgow, UK, G12 8QQ.
E-mail: Andrew.Sutherland@glasgow.ac.uk; Fax: +44 (0)141 330 4888;
Tel: +44 (0)141 330 5936
Results and discussion
†Electronic supplementary information (ESI) available: NOE data for
compounds 15, 18 and 20 and, 1H and 13C NMR spectra for all new
compounds. See DOI: 10.1039/c2ob26544c
Our synthesis of hydroxylated 3-aminoazepanes is outlined in
Scheme 1. It was proposed that allylic alcohol 5 could be easily
This journal is © The Royal Society of Chemistry 2012
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Boc-protection of the secondary amine. Removal of the silyl pro-
tecting group under standard conditions gave alcohol 9 which
was then subjected to a one-pot Swern oxidation and Horner–
Wadsworth–Emmons reaction under Masamune–Roush con-
ditions.10,11 This gave exclusively E-α,β-unsaturated ester 11 in
94% yield over the two steps. DIBAL-H reduction of 11 was
attempted but gave E-allylic alcohol 5 in only 37% yield along
with a complex mixture of compounds. It is well-known that
α,β-unsaturated esters containing adjacent heteroatoms can
undergo competing 1,4-addition rather than 1,2-reduction due to
complexation of the metal hydride with the heteroatom.12 This
can be overcome using the Moriwake modification that involves
addition of a Lewis acid to protect the heteroatom.12 However,
attempted reduction of 11 using DIBAL-H in the presence of
boron trifluoride diethyl etherate gave 11 in only a slightly
improved yield of 41%. Due to the issues associated with
reduction of 11, a more efficient route to E-allylic alcohol 5 was
achieved via α,β-unsaturated aldehyde 12. Primary alcohol 9 was
subject to a Swern oxidation which gave aldehyde 10 in 94%
yield. Wittig reaction of 10 with (triphenylphosphoranylidene)
acetaldehyde followed by reduction of the aldehyde moiety with
sodium borohydride reduction gave E-allylic alcohol 5 in 88%
yield. This seven-step synthesis was particularly amenable to
scale-up (∼5 g) giving allylic alcohol 5 in 53% overall yield
from 2-aminoethanol (6).
Scheme 1 Proposed route to hydroxylated 3-aminoazepanes.
Allylic alcohol 5 was then subjected to the three-step tandem
process for the preparation of 2,3,6,7-tetrahydro-3-amidoazepine
4 (Scheme 3).13 Allylic alcohol 5 was converted to allylic tri-
chloroacetimidate 13 under standard conditions, followed by
rearrangement with bis(acetonitrile)palladium(II) chloride.14,15
As part of the one-pot tandem process, 14 was initially treated
with Grubbs 1st generation catalyst.16 However, this required a
RCM reaction time of 96 hours giving 2,3,6,7-tetrahydro-3-
amidoazepine 4 in 49% from 5. The RCM step of the tandem
process was improved substantially using Grubbs 2nd generation
catalyst,17 which gave 2,3,6,7-tetrahydro-3-amidoazepine 4 after
only 12 hours and in 79% overall yield.
Having developed the tandem process for the facile synthesis
of 2,3,6,7-tetrahydro-3-amidoazepine 4, the programme of
research then focused on the diasteroselective oxidation of this
Scheme 2 Reagents and conditions: (i) 4-bromo-1-butene, NaI,
MeOH, Δ, 100%; (ii) TBDPSCl, imidazole, THF, rt, 86%; (iii) Boc2O,
Et3N, DMAP, CH2Cl2, rt, 100%; (iv) TBAF, THF, 0 °C, 100%; (v)
(COCl)2, DMSO, Et3N, CH2Cl2, −78 °C, 94%; (vi) (EtO)2P(O)-
CH2CO2Et, DBU, LiCl, MeCN, rt, 94% from 9; (vii) DIBAL-H,
BF3OEt2, CH2Cl2, −78 °C, 41%; (viii) Ph3PvCHCHO, toluene, 80 °C,
75%; (ix) NaBH4, MeOH, 0 °C, 88%.
generated using inexpensive, readily available 2-aminoethanol
(6). A three-step tandem process involving a palladium(II)-cata-
lysed Overman rearrangement and a RCM reaction was then
envisaged for the preparation of 2,3,6,7-tetrahydro-3-amido-
azepine 4. Subsequent stereoselective oxidation of the alkene
using the trichloroacetamide substituent as a directing group
would lead to the hydroxylated 3-aminoazepanes.
Initially, a synthetic route was developed for the efficient prep-
aration of allylic alcohol 5 (Scheme 2), the substrate for the
tandem process. 2-Aminoethanol (6) was coupled with 4-bromo-
1-butene in the presence of sodium iodide to give 7 in quantitat-
ive yield. Silyl protection of the primary alcohol then allowed
Scheme 3 Reagents and conditions: (i) Cl3CCN, DBU (25 mol%),
CH2Cl2, rt; (ii) PdCl2(MeCN)2 (10 mol%), CH2Cl2, rt; (iii) Grubbs II
(10 mol%), Δ, 79% over three steps.
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Scheme 4 Reagents and conditions: (i) m-CPBA, CH2Cl2, rt, 58%; (ii)
LiAlH4, THF, Δ; (iii) 6N HCl, MeOH, rt, 61% over two steps.
Scheme 5 Reagents and conditions: (i) OsO4, TMEDA, CH2Cl2,
−78 °C, 81%; (ii) 2 M NaOH, MeOH, 40 °C then 2 M HCl, 78%; (iii)
N-iodosuccinimide, CHCl3, rt, 78%; (iv) 0.5 M HCl, MeOH, rt, 77%.
synthetic intermediate using the allylic trichloroacetamide
moiety as a directing group. Initial studies focused on the prep-
aration of the syn-diastereomer of the balanol core. Directed
epoxidation of 4 using m-CPBA18,19 gave 15 as a single diaster-
eomer in 58% yield (Scheme 4). The relative stereochemistry
was confirmed by difference NOE experiments which clearly
showed the syn-relationship of the 3-, 3a- and 4a-hydrogen
atoms.20 Regioselective reductive ring opening of the epoxide
was performed using LiAlH4 which gave bicyclic oxazolidinone
16. Without purification, removal of the Boc-protecting group
and hydrolysis of the oxazolidinone ring was achieved under
acid mediated conditions to give the syn-diastereomer of the
balanol core, (3S*,4R*)-3-aminoazepin-4-ol (17) in 61% yield
from 15.
In an effort to generate azepines with a higher level of substi-
tution, conditions for the directed dihydroxylation of 4 were next
investigated. Donohoe and co-workers have shown that highly
stereoselective substrate directed dihydroxylation of cyclic allylic
trichloroacetamides can be achieved using a reagent generated
from osmium tetroxide and N,N,N′,N′-tetramethylethylenedi-
amine (TMEDA).21 This method proved particularly effective
for the selective dihydroxylation of cycloheptenes.21c Using
2,3,6,7-tetrahydro-3-amidoazepine 4 as a substrate for this reac-
tion gave syn-diol 18 in 81% yield and as a single diastereomer
(Scheme 5). Difference NOE experiments confirmed the relative
stereochemistry of 18 with clear correlation between the hydro-
gen atoms at C-3 and C-4.20 Removal of the protecting groups
under standard conditions gave (3S*,4S*,5R*)-3-aminoazepane-
4,5-diol (19) in 78% yield.
Biologically active compounds incorporating an iodine atom
are important both as synthetic intermediates in organic chem-
istry and as molecular tracers for single photon emission com-
puted tomography (SPECT) imaging.22 It was proposed that
2,3,6,7-tetrahydro-3-amidoazepine 4 could be used in a substrate
directed iodination to access an iodinated stereoisomer of 17.
Reaction of 4 with N-iodosuccinimide gave 4,5-dihydro-1,3-
oxazole 20 in 78% yield (Scheme 5).23 As is well precedented
for this reaction, generation of the iodonium intermediate takes
place anti to the trichloroacetamide group.13e,23 This is followed
by syn-formation of the 4,5-dihydro-1,3-oxazole ring, ultimately
yielding 20 as a single diastereomer.20 Acid mediated hydrolysis
of the 4,5-dihydro-1,3-oxazole ring and concurrent removal of
Scheme 6 Reagents and conditions: (i) Cl3CCN, DBU, CH2Cl2, rt; (ii)
(S)-COP-Cl (5 mol%), CH2Cl2, rt; (iii) Grubbs II (10 mol%), Δ, 92%
over three steps; (iv) (R)-COP-Cl (5 mol%), CH2Cl2, rt; (v) Grubbs II
(10 mol%), Δ, 84% over three steps.
the Boc-group was achieved under mild conditions to give
(3S*,4S*,5S*)-3-amino-5-iodoazepane-4-ol (21) in 77% yield.
While the oxidation of 2,3,6,7-tetrahydro-3-amidoazepine 4
using these reactions leads to the highly efficient preparation of
functionalised aminoazepanes as single diastereomers, these
compounds are racemic due to the formation of 4 as a racemate
during the three-step tandem process. We therefore wanted to
demonstrate the enantioselective synthesis of 4. The groups of
Richards and Overman have developed a series of chiral palla-
dium(II) complexes such as (S)-COP-Cl 22 which have been
shown to effect the rearrangement of allylic trichloroacetimidates
in excellent yields and with high enantioselectivity.24 Using
commercially available (S)-COP-Cl 22 (5 mol%) to catalyse the
Overman rearrangement during the three-step tandem process
gave (R)-2,3,6,7-tetrahydro-3-amidoazepine 4 in 92% yield and
in 92% enantiomeric excess (Scheme 6).25 In a similar fashion,
use of (R)-COP-Cl gave the (S)-enantiomer in 84% yield and in
This journal is © The Royal Society of Chemistry 2012
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92% ee. Having demonstrated the asymmetric synthesis of 4,
these products now have the potential to be used for the enantio-
selective preparation of highly functionalised aminoazepanes.
mixture was heated under reflux for 2 h, then cooled to room
temperature and evaporated in vacuo. The residue was parti-
tioned between saturated aqueous ammonium chloride solution
(20 mL) and ethyl acetate (20 mL). The aqueous layer was made
basic with 40% sodium hydroxide and extracted with ethyl
acetate (3 × 15 mL). The combined organic layers were dried
(MgSO4) and concentrated to afford N-[2′-(hydroxy)ethyl]-1-
aminobut-3-ene (7) (4.26 g, 100% yield) as a colourless oil. This
oil was dissolved in tetrahydrofuran (200 mL) and tert-butyldi-
phenylsilyl chloride (14.44 mL, 55.6 mmol) and imidazole
(5.04 g, 74.1 mmol) were added. The reaction mixture was
stirred overnight at room temperature. A white precipitate was
removed by filtration and washed with diethyl ether (70 mL).
The combined filtrate was concentrated, dried (MgSO4) and
purified by flash column chromatography on silica gel (elution
with dichloromethane/ethyl acetate, 1 : 5) to give N-[2′-(tert-
butyldimethylsilyloxy)ethyl]-1-aminobut-3-ene (9.43 g, 86%) as
a colourless oil. νmax/cm−1 (neat) 3071 (NH), 2932 (CH), 1465,
1080, 910, 702; δH (400 MHz, CDCl3) 1.08 (9H, s, SiC(CH3)3),
2.31 (2H, qt, J 6.8, 0.8 Hz, 2-H2), 2.72 (2H, t, J 6.8 Hz, 1-H2),
2.79 (2H, t, J 5.4 Hz, 1′-H2), 3.81 (2H, t, J 5.4 Hz, 2′-H2),
5.06–5.18 (2H, m, 4-H2), 5.17 (1H, ddt, J 17.1, 10.2, 6.8 Hz,
3-H), 7.38–7.49 (6H, m, ArH), 7.68–7.72 (4H, m, ArH);
δC (101 MHz, CDCl3) 19.2 (C), 26.9 (3 × CH3), 34.4 (CH2),
48.6 (CH2), 51.5 (CH2), 63.1 (CH2), 116.4 (CH2), 127.7 (4 ×
CH), 129.7 (2 × CH), 133.7 (2 × C), 135.6 (4 × CH), 136.5
(CH); m/z (CI) 354.2254 (MH+. C22H32NOSi requires
354.2253), 312 (6%), 257 (8), 193 (5), 137 (7), 113 (28), 85
(89), 69 (100).
Conclusions
In summary, a highly efficient, multi-bond forming, three-step
tandem process has been developed for the racemic and asym-
metric synthesis of a 2,3,6,7-tetrahydro-3-amidoazepine. The
utility of this compound as a key intermediate for the diastereo-
selective preparation of a range of hydroxylated aminoazepanes
was also demonstrated, including the synthesis of the syn-diaster-
eomer of the balanol core. These studies have shown how the
combination of an efficient multi-step tandem process followed
by substrate directed reactions of the tetra-hydroaminoazepine
ring system can allow rapid access to highly functionalised
azepane analogues. Work is currently underway to fully explore
the asymmetric functionalisation of the chiral 2,3,6,7-tetrahydro-
3-amidoazepines for the preparation of more complex com-
pounds with potential biological application.
Experimental
Reactions were performed in flame-dried glassware under a posi-
tive atmosphere of argon. All reagents and starting materials
were obtained from commercial sources and used as received.
Dry solvents were purified using a PureSolv 500 MD solvent
purification system or tetrahydrofuran and diethyl ether were dis-
tilled from sodium and benzophenone, whilst dichloromethane
was distilled from calcium hydride. Flash column chromato-
graphy was carried out using Fisher matrix silica 60. Macherey–
Nagel aluminium-backed plates pre-coated with silica gel 60
(UV254) were used for thin layer chromatography and were visu-
N-2′-(tert-Butyldiphenylsilyloxy)ethyl-N-(tert-butoxycarbonyl)-1-
aminobut-3-ene (8)
1
alised by staining with KMnO4. H NMR and 13C NMR spectra
To a solution of N-[2′-(tert-butyldimethylsilyloxy)ethyl]-1-amino-
but-3-ene (4.00 g, 11.3 mmol) in dichloromethane (100 mL)
at 0 °C was added triethylamine (3.31 mL, 23.7 mmol), 4-
dimethylaminopyridine (0.14 g, 1.30 mmol) and di-tert-butyl
dicarbonate (4.93 g, 22.6 mmol). The reaction mixture was
warmed to room temperature and stirred overnight. The reaction
mixture was washed with brine (2 × 30 mL), dried (MgSO4) and
concentrated in vacuo. Purification by flash column chromato-
graphy (elution with ethyl acetate–diethyl ether, 1 : 10) gave N-
2′-(tert-butyldiphenylsilyloxy)ethyl-N-(tert-butoxycarbonyl)-1-
aminobut-3-ene (8) (5.1 g, 100%) as a colourless oil. νmax/cm−1
(neat) 2932 (CH), 1690 (CO), 1474, 1412, 1265, 1157, 1111,
825; NMR spectra showed a 1 : 1 mixture of rotomers, only
signals for one rotomer is recorded: δH (400 MHz, CDCl3) 1.05
(9H, s, SiC(CH3)3), 1.37 (9H, s, OC(CH3)3), 2.20–2.29 (2H, m,
2-H2), 3.25–3.40 (4H, m, 1-H2 and 1′-H2), 3.25–3.39 (2H, m,
2′-H2), 4.96–5.06 (2H, m, 4-H2), 5.66–5.81 (1H, m, 3-H),
7.33–7.44 (6H, m, ArH), 7.63–7.67 (4H, m, ArH); δC
(101 MHz, CDCl3) 19.2 (C), 26.9 (3 × CH3), 28.5 (3 × CH3),
32.7 (CH2), 45.6 (CH2), 49.5 (CH2), 62.5 (CH2), 83.0 (C), 116.4
(CH2), 127.7 (4 × CH), 129.7 (2 × CH), 133.6 (2 × C), 135.3
(4 × CH), 135.8 (CH), 155.4 (C); m/z (CI) 454.2772 (MH+.
C27H40NO3Si requires 454.2777), 398 (18%), 354 (28), 340
(12), 320 (8), 257 (8), 179 (5), 139 (6), 97 (28), 85 (87),
69 (100).
were recorded on a Bruker DPX 400 spectrometer with chemical
shift values in ppm relative to TMS (δH 0.00 and δC 0.0) or
residual chloroform (δH 7.28 and δC 77.2) as standard. Assign-
1
ment of H and 13C NMR signals are based on two-dimensional
COSY and DEPT experiments, respectively. Mass spectra were
obtained using a JEOL JMS-700 spectrometer. Infrared spectra
were recorded using Golden Gate apparatus on a JASCO FTIR
410. Melting points were determined on a Reichert platform
melting point apparatus. Optical rotations were determined as
solutions irradiating with the sodium D line (λ = 589 nm) using
an Auto pol V polarimeter. [α]D values are given in units
10−1 deg cm2 g−1. The chiral HPLC methods were calibrated
with their corresponding racemic mixtures. (S)-COP-Cl 22 refers
to di-μ-chlorobis[η5-(S)-(ρR)-2-(2′-(4′-methylethyl)oxazolinyl)-
cyclopentadienyl, 1-C, 3′-N)(η4-tetraphenylcyclobutadiene)-
cobalt]dipalladium and (R)-COP-Cl refers to di-μ-chlorobis[η5-
(R)-(ρR)-2-(2′-(4′-methylethyl)oxazolinyl)cyclopentadienyl, 1-C,
3′-N)(η4-tetraphenylcyclobutadiene)cobalt]dipalladium.
N-[2′-(tert-Butyldiphenylsilyloxy)ethyl]-1-aminobut-3-ene
Sodium iodide (0.55 g, 3.70 mmol) was added to a solution of
4-bromo-1-butene (5.00 g, 37.1 mmol) and 2-aminoethanol (6)
(8.85 mL, 185.3 mmol) in methanol (80 mL). The reaction
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N-2′-(Hydroxy)ethyl-N-(tert-butoxycarbonyl)-1-aminobut-3-ene
(9)
1′-H2), 4.23 (2H, q, J 7.3 Hz, OCH2CH3), 5.02–5.14 (2H, m,
4-H2), 5.71–5.80 (1H, m, 3-H), 5.88 (1H, dt, J 15.6, 1.8 Hz, 3′-
H), 6.89 (1H, dt, J 15.6, 4.7 Hz, 2′-H); δC (101 MHz, CDCl3)
14.2 (CH3), 28.4 (3 × CH3), 33.1 (CH2), 46.8 (CH2), 47.8
(CH2), 60.5 (CH2), 80.0 (C), 116.9 (CH2), 121.8 (CH), 135.2
(CH), 144.2 (CH), 155.3 (C), 166.1 (C); m/z (CI) 284.1862
(MH+. C15H26NO4 requires 284.1862), 228 (94%), 184 (62),
142 (10), 113 (32), 97 (35), 85 (82), 71 (100).
A solution of n-tetrabutylammonium fluoride (1.0 M in tetra-
hydrofuran) (13.6 mL, 13.6 mmol) was added to a solution of N-
2′-(tert-butyldiphenylsilyloxy)ethyl-N-(tert-butoxycarbonyl)-1-
aminobut-3-ene (8) (5.12 g, 11.3 mmol) in tetrahydrofuran
(100 mL) at 0 °C. The reaction mixture was warmed to room
temperature and stirred overnight. The reaction mixture was then
concentrated and the resulting residue was re-suspended in
diethyl ether (80 mL). The solution was washed with water
(40 mL) and the aqueous layer was then extracted with diethyl
ether (3 × 40 mL). The combined organic extracts were dried
(MgSO4), concentrated and then purified by flash column
chromatography (petroleum ether–diethyl ether, 1 : 5) to give N-
2′-(hydroxy)ethyl-N-(tert-butoxycarbonyl)-1-aminobut-3-ene (9)
(2.42 g, 100%) as a colourless oil. νmax/cm−1 (neat) 3742 (OH),
2978 (CH), 1690 (CO), 1474, 1412, 1250, 1157, 910, 733; δH
(400 MHz, CDCl3) 1.48 (9H, s, OC(CH3)3), 2.30 (2H, q, J
6.8 Hz, 2-H2), 3.25–3.35 (2H, m, 1-H2), 3.40 (2H, t, J 4.8 Hz,
1′-H2), 3.80 (2H, t, J 4.8 Hz, 2′-H2), 5.03–5.12 (2H, m, 4-H2),
5.71–5.84 (1H, m, 3-H); δC (101 MHz, CDCl3) 28.4 (3 × CH3),
33.3 (CH2), 48.5 (CH2), 50.6 (CH2), 62.8 (CH2), 80.2 (C), 116.8
(CH2), 135.3 (CH), 155.5 (C); m/z (CI) 216.1603 (MH+.
C11H22NO3 requires 216.1600), 202 (5%), 174 (8), 160 (100),
116 (6), 85 (21), 69 (28).
(2E)-N-(Butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-
2′-en-4′-ol (5)
A stirred solution of (2′E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycar-
bonyl)-1′-aminobut-2′-enoate (11) (0.25 g, 0.90 mmol) in
dichloromethane (30 mL) was cooled to −78 °C before boron
trifluoride diethyl etherate (0.15 mL, 1.17 mmol) was added
dropwise. The mixture was stirred at −78 °C for 0.5 h before di-
isobutylaluminium hydride solution (1.0 M in hexanes, 2.7 mL,
2.7 mmol) was added dropwise. The reaction mixture was then
stirred at −78 °C for 3 h before being quenched by the addition
of 5.0 M acetic acid solution in dichloromethane (10 mL). The
mixture was poured into 10% aqueous tartaric acid solution
(10 mL), and the organic layers were extracted using dichloro-
methane (2 × 20 mL). The combined organic layers were
washed with a saturated aqueous solution of sodium hydrogen
carbonate (15 mL) before being dried (MgSO4), filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether–diethyl ether, 2 : 5) to
give (2E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-amino-
but-2′-en-4′-ol (5) (0.09 g 41%) as a colourless oil. νmax/cm−1
(neat) 3433 (OH), 2978 (CH), 1674 (CO), 1474, 1412, 1366,
1242, 1165, 918; δH (400 MHz, CDCl3) 1.38 (9H, s, OC
(CH3)3), 2.18 (2H, q, J 7.5 Hz, 2-H2), 3.06–3.22 (2H, m, 1-H2),
3.66–3.79 (2H, m, 1′-H2), 4.13 (2H, d, J 4.1 Hz, 4′-H2),
4.89–5.02 (2H, m, 4-H2), 5.49–5.76 (3H, m, 3-H, 2′-H and
3′-H); δC (101 MHz, CDCl3) 28.5 (3 × CH3), 32.5 (CH2), 46.3
(CH2), 48.3 (CH2), 63.1 (CH2), 79.5 (C), 116.5 (CH2), 127.9
(CH), 131.0 (CH), 135.5 (CH), 155.4 (C); m/z (CI) 242.1752
(MH+. C13H24NO3 requires 242.1756), 224 (8%), 200 (9), 186
(100), 168 (72), 160 (12), 113 (14), 85 (28), 73 (38).
Ethyl (2′E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-
aminobut-2′-enoate (11)
Dimethyl sulfoxide (2.36 mL, 33.2 mmol) was added to a stirred
solution of oxalyl chloride (1.58 mL, 18.6 mmol) in dichloro-
methane (50 mL) at −78 °C. The reaction mixture was stirred for
0.3 h before N-2′-(hydroxy)ethyl-N-(tert-butoxycarbonyl)-1-ami-
nobut-3-ene (9) (2.86 g, 13.3 mmol) in dichloromethane
(50 mL) was slowly added. The mixture was stirred for a further
0.3 h before triethylamine (9.27 mL, 66.5 mmol) was added.
This reaction mixture was stirred for 0.5 h at −78 °C and then
allowed to warm to room temperature and stirred for a further
2 h. Meanwhile, a solution of lithium chloride (1.01 g,
23.9 mmol), triethyl phosphonoacetate (4.75 mL, 23.9 mmol)
and 1,8-diazabicyclo[5,4,0]undec-7-ene (3.58 mL, 23.9 mmol)
in acetonitrile (100 mL) was prepared and stirred for 1.0 h. The
Swern solution was concentrated in vacuo, then the Horner–
Wadsworth–Emmons solution was added and the reaction
mixture was stirred at room temperature overnight. The reaction
was quenched by the addition of a saturated solution of
ammonium chloride (50 mL) and concentrated to give an orange
residue, which was then extracted with diethyl ether (4 ×
75 mL). The organic layers were combined, dried (MgSO4) and
concentrated to give an orange oil. Purification by flash column
chromatography (diethyl ether–petroleum ether, 2 : 3) gave ethyl
(2′E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-
2′-enoate (11) (2.90 g, 94%) as colourless oil. νmax/cm−1 (NaCl)
2978 (CH), 1690 (CO), 1466, 1412, 1366, 1273, 1165, 910,
725; NMR spectra showed a 1 : 1 mixture of rotomers, only
signals for one rotomer is recorded: δH (400 MHz, CDCl3) 1.32
(3H, t, J 7.3 Hz, OCH2CH3), 1.49 (9H, s, OC(CH3)3), 2.25–2.35
(2H, m, 2-H2), 3.19–3.36 (2H, m, 1-H2), 3.93–4.06 (2H, m,
N-(2′-Oxoethyl)-N-(tert-butoxycarbonyl)-1-aminobut-3-ene (10)
Dimethyl sulfoxide (4.20 mL, 59.2 mmol) was added to a stirred
solution of oxalyl chloride (3.10 mL, 35.5 mmol) in dichloro-
methane (50 mL) at −78 °C. The reaction mixture was stirred for
0.3 h before N-2′-(hydroxy)ethyl-N-(tert-butoxycarbonyl)-1-ami-
nobut-3-ene (9) (5.10 g, 23.7 mmol) in dichloromethane
(25 mL) was slowly added. The mixture was stirred for a further
0.3 h before triethylamine (16.5 mL, 118.4 mmol) was added.
This reaction mixture was stirred for 0.5 h at −78 °C and then
allowed to warm to room temperature and stirred for a further
2 h. The reaction mixture was concentrated in vacuo, and
purified by flash column chromatography (petroleum ether–
diethyl ether, 2 : 5) to give N-(2′-oxoethyl)-N-(tert-butoxycarbo-
nyl)-1-aminobut-3-ene (10) (4.74 g, 94%) as a colourless oil.
νmax/cm−1 (neat) 2982 (CH), 1736 (CO), 1686 (CO), 1424,
1370, 1216, 1153, 907, 729; NMR spectra showed
a
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1 : 1 mixture of rotomers, only signals for one rotomer is
recorded: δH (400 MHz, CDCl3) 1.45 (9H, s, OC(CH3)3),
2.23–2.33 (2H, m, 2-H2), 3.30 (2H, t, J 7.1 Hz, 1-H2), 3.80 (2H,
br s, 1′-H2), 5.02–5.11 (2H, m, 4-H2), 5.68–5.83 (1H, m, 3-H),
9.56 (1H, br s, 2′-H); δC (101 MHz, CDCl3) 28.2 (3 × CH3),
33.0 (CH2), 48.5 (CH2), 57.7 (CH2), 80.8 (C), 117.2 (CH2),
135.1 (CH), 155.0 (C), 199.4 (C); m/z (CI) 214.1440 (MH+.
C11H20NO3 requires 214.1443), 200 (10%), 196 (8), 158 (100),
114 (9), 85 (7), 69 (12).
undec-7-ene (0.02 mL, 0.14 mmol) was added to the solution
followed by trichloroacetonitrile (0.08 mL, 0.81 mmol). The
reaction mixture was then warmed to room temperature and
stirred for 2 h. The reaction mixture was filtered through a short
pad of silica gel and washed with diethyl ether (100 mL). The
resulting filtrate was then concentrated to give allylic trichloro-
acetimidate 13, which was used without further purification.
Allylic trichloroacetimidate 13 was then dissolved in dichloro-
methane (10 mL). Bis(acetonitrile)palladium(II) chloride
(0.014 g, 0.05 mmol) was added to the solution and the reaction
mixture was stirred at room temperature for 3 h. Grubbs first gen-
eration catalyst (0.044 g, 0.05 mmol) was then added and the
reaction mixture was heated under reflux for 96 h. The reaction
mixture was cooled to room temperature and then filtered
through a short pad of Celite® and washed with diethyl ether
(100 mL). Concentration of the filtrate, followed by flash column
chromatography (petroleum ether–diethylether, 2 : 1) gave
1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloro-
methylcarbonylamino)azepine (4) (0.09 g, 49% over three steps)
as a white solid. Mp 103–105 °C; νmax/cm−1 (NaCl) 3330 (NH),
2978 (CH), 1690 (CO), 1419, 1366, 1165, 756; NMR spectra
showed a 1 : 1 mixture of rotomers, only signals for one rotomer
is recorded: δH (400 MHz, CDCl3) 1.47 (9H, s, OC(CH3)3),
2.17–2.42 (2H, m, 6-H2), 3.03–3.16 (1H, m, 7-HH), 3.32 (1H,
dd, J 14.9, 2.6 Hz, 2-HH), 3.72–3.81 (1H, m, 7-HH), 4.05 (1H,
br d, J 14.9 Hz, 2-HH), 4.43–4.59 (1H, m, 3-H), 5.53–5.93 (2H,
m, 4-H and 5-H), 8.30 (1H, br s, NH); δC (101 MHz, CDCl3)
27.9 (CH2), 28.4 (3 × CH3), 47.7 (CH2), 48.7 (CH2), 54.2 (CH),
80.7 (C), 92.1 (C), 128.6 (CH), 129.5 (CH), 157.2 (C), 163.7
(C); m/z (CI) 359.0511 (MH+. C13H2035Cl237ClN2O3 requires
359.0512), 301 (100%), 267 (34), 257 (18), 223 (7), 163 (8),
85 (13), 69 (19).
(2′E)-N-(Butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-
2′-en-4′-al (12)
To a solution of N-(2′-oxoethyl)-N-(tert-butoxycarbonyl)-1-ami-
nobut-3-ene (10) (1.60 g, 7.51 mmol) in toluene (80 mL) was
added (triphenylphosphoranylidene)acetaldehyde (3.42 g,
11.3 mmol) and the reaction mixture was heated at 80 °C and
stirred for 24 h. The solution was allowed to cool to room temp-
erature and concentrated in vacuo. The resulting residue was
purified with flash column chromatography (petroleum ether–
diethyl ether, 2 : 5) to give (2′E)-N-(butyl-3-en-1-yl)-N-(tert-
butoxycarbonyl)-1′-aminobut-2′-en-4′-al (12) (1.35 g, 75%) as
colourless oil. νmax/cm−1 (neat) 2982 (CH), 2361, 1678 (CO),
1416, 1215, 1169, 918, 745; NMR spectra showed
a
1 : 1 mixture of rotomers, only signals for one rotomer is
recorded: δH (400 MHz, CDCl3) 1.51 (9H, s, OC(CH3)3),
2.26–2.36 (2H, m, 2-H2), 3.22–3.38 (2H, m, 1-H2), 4.05–4.19
(2H, m, 1′-H2), 5.05–5.15 (2H, m, 4-H2), 5.71–5.85 (1H, m,
3-H), 6.17 (1H, ddt, J 15.8, 7.9, 1.6 Hz, 3′-H), 6.72–6.86 (1H,
m, 2′-H), 9.62 (1H, d, J 7.9 Hz, 4′-H); δC (101 MHz, CDCl3)
28.4 (3 × CH3), 33.2 (CH2), 47.2 (CH2), 48.3 (CH2), 80.3 (C),
117.0 (CH2), 125.3 (CH), 129.1 (CH), 132.3 (CH), 153.4 (C),
193.2 (C); m/z (CI) 240.1595 (MH+. C13H22NO3 requires
240.1600), 236 (19%), 210 (96), 184 (100), 158 (40), 116 (58),
69 (12).
1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-
trichloromethylcarbonylamino)azepine (4)
The reaction was carried out as described above except using
(2E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-2′-
en-4′-ol (5) (0.13 g, 0.54 mmol) and Grubbs second generation
catalyst (0.044 g, 0.05 mmol) for the RCM step which was com-
plete in 12 h. Purification by flash column chromatography
(petroleum ether–diethylether, 2 : 1) gave 1-(tert-butoxycarbo-
nyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloromethylcarbonylamino)-
azepine (4) (0.15 g, 79% over three steps) as a white solid. Spec-
troscopic data as reported above.
(2E)-N-(Butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-
2′-en-4′-ol (5)
To a solution of (2′E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbo-
nyl)-1′-aminobut-2′-en-4′-al (12) (0.30 g, 1.28 mmol) in metha-
nol (35 mL) at 0 °C was added sodium borohydride (0.09 g,
2.56 mmol). After 1 h, the reaction mixture was quenched with
1.0 M hydrochloric acid (5 mL) and then concentrated in vacuo.
The residue was dissolved in dichloromethane (20 mL), washed
with saturated sodium hydrogencarbonate solution (10 mL),
dried (MgSO4), and concentrated in vacuo. The crude product
was purified by flash column chromatography (petroleum ether–
diethyl ether, 2 : 5) to give (2E)-N-(butyl-3-en-1-yl)-N-(tert-
butoxycarbonyl)-1′-aminobut-2′-en-4′-ol (5) (0.26 g 88%) as a
colourless oil. Spectroscopic data as reported above.
2′,2′,2′-Trichloro-N-[(3S*,3aS*,4aR*)-1-tert-butoxycarbonylamino-
4-oxobicyclo[5.1.0]octa-3a-yl]acetamide (15)
1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloro-
methylcarbonylamino)azepine (4) (0.19 g, 0.53 mmol) was dis-
solved in dichloromethane (15 mL) and to the stirred suspension
was added meta-chloroperoxybenzoic acid (0.18 g 1.05 mmol)
at room temperature. The resulting suspension was stirred vigor-
ously for 19 h. A 20% aqueous solution of sodium sulfite
(10 mL) was added and the resulting two-phase mixture was
stirred vigorously for 0.25 h. The two layers were separated and
the aqueous layer was extracted with dichloromethane (2 ×
1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloro-
methylcarbonylamino)azepine (4)
(2E)-N-(Butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-2′-
en-4′-ol (5) (0.13 g, 0.54 mmol) was dissolved in dichloro-
methane (20 mL) and cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]-
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20 mL). The combined organic layers were washed with a 20%
aqueous solution of sodium sulfite (10 mL) and a 5% aqueous
solution of sodium hydrogencarbonate (2 × 20 mL), dried
(MgSO4) and evaporated under reduced pressure. Purification by
flash column chromatography (elution with petroleum ether–
diethyl ether, 2 : 5) gave 2′,2′,2′-trichloro-N-[(3S*,3aS*,4aR*)-1-
tert-butoxycarbonylamino-4-oxobicyclo[5.1.0]octa-3a-yl]aceta-
aqueous sodium sulfite (10 mL). The reaction mixture was
stirred and heated under reflux for 12 h. The solvent was
removed in vacuo to afford a dark solid. Flash column chromato-
graphy (elution with ethyl acetate) afforded (3S*,4S*,5R*)-1-
(tert-butoxycarbonyl)-3-(2′,2′,2′-trichloromethyl
carbonyl-
amino)-4,5-dihydroxyazepane (18) (0.042 g, 81%) as a white
solid. Mp 153–155 °C; νmax/cm−1 (NaCl) 3390 (NH/OH), 2967
(CH), 1672 (CO), 1471, 1249, 956; NMR spectra showed a
1 : 1 mixture of rotomers, only signals for one rotomer is
recorded: δH (400 MHz, CDCl3) 1.45 (9H, s, OC(CH3)3),
1.64–1.75 (1H, m, 6-HH), 2.06–2.17 (1H, m, 6-HH), 2.77 (1H,
br s, OH), 3.25–3.92 (4H, m, 4-H, 5-H and 7-H2), 4.11–4.31
(2H, m, 2-H2), 4.67–4.79 (1H, m, 3-H), 5.37 (1H, br s, NH); δC
(126 MHz, CDCl3) 28.4 (3 × CH3), 29.7 (CH2), 31.6 (CH2),
47.6 (CH2), 53.1 (CH), 70.1 (CH), 77.3 (CH), 80.6 (C), 92.3
(C), 155.4 (C), 158.4 (C); m/z (EI) 390.0523 (M+.
C13H2135Cl3N2O5 requires 390.0516), 354 (11%), 339 (20), 283
(8), 216 (28), 191 (100), 172 (9), 111 (18), 83 (35), 57 (98).
mide (15) (0.11 g, 58%) as white solid. Mp 160–162 °C; νmax
/
cm−1 (NaCl) 3293 (NH), 2974 (CH), 1697 (CO), 1518, 1414,
1368, 1165, 943, 821; NMR spectra showed a 2 : 1 mixture of
rotomers, only signals for major rotomer is recorded: δH
(400 MHz, CDCl3) 1.50 (9H, s, OC(CH3)3), 2.21–2.37 (2H, m,
5-H2), 2.78–2.93 (1H, m, 2-H2), 3.26–3.33 (2H, m, 6-H2), 3.83
(1H, dd, J 13.6, 4.4 Hz, 3a-H), 3.86–3.93 (1H, m, 4a-H), 4.59
(1H, td, J 9.2, 4.4 Hz, 3-H), 6.90 (1H, br d, J 9.2 Hz, NH); δC
(101 MHz, CDCl3) 27.6 (CH2), 28.4 (3 × CH3), 43.2 (CH2),
46.5 (CH2), 50.7 (CH), 55.4 (CH), 58.7 (CH), 80.7 (C), 92.3
(C), 154.3 (C), 161.4 (C); m/z (CI) 375.0453 (MH+.
C13H2035Cl237ClN2O4 requires 375.0461), 319 (100%), 283
(76), 273 (10), 239 (8), 211 (8), 155 (10), 81 (6), 69 (11).
(3S*,4S*,5R*)-3-Aminoazepane-4,5-diol (19)
To
a solution of (3S*,4S*,5R*)-1-(tert-butoxycarbonyl)-3-
(3S*,4R*)-3-Aminoazepin-4-ol (17)8h
(2′,2′,2′-trichloromethylcarbonylamino)-4,5-dihydroxyazepane
(18) (0.023 g, 0.051 mmol) in methanol (5 mL) was added
2.0 M sodium hydroxide (3 mL) and the reaction mixture was
stirred at 40 °C for 12 h. 2.0 M Hydrochloric acid (10 mL) was
added and the reaction was stirred for 1 h. The reaction mixture
was concentrated in vacuo. The resulting residue was dissolved
in chloroform (20 mL) and washed with water (10 mL). The
organic layer was dried (MgSO4) and concentrated under
vacuum to give (3S*,4S*,5R*)-3-aminoazepane-4,5-diol (19) as
a white solid (0.07 g, 78%). Mp 172–174 °C (decomposition);
νmax/cm−1 (NaCl) 3379 (NH/OH), 2931 (CH), 1649, 1448,
1211, 970; δH (500 MHz, D2O) 2.33–2.41 (1H, m, 6-HH),
2.49–2.61 (1H, m, 6-HH), 3.51–3.60 (1H, m, 7-HH), 3.80–3.88
(2H, m, 2-HH and 7-HH), 3.96–4.04 (1H, m, 3-H), 4.29–4.40
(2H, m, 2-HH and 5-H), 4.59–4.65 (1H, m, 4-H); δC (126 MHz,
CD3OD) 28.4 (CH2), 43.4 (CH2), 43.6 (CH2), 50.0 (CH), 72.0
(CH), 73.0 (CH); m/z (CI) 147.1140 (MH+. C6H15N2O2 requires
147.1133), 127 (100), 113 (4), 101 (12), 81 (8), 69 (11).
2′,2′,2′-Trichloro-N-[(3S*,3aS*,4aR*)-1-tert-butoxycarbonyl-
amino-4-oxobicyclo[5.1.0]octa-3a-yl]acetamide (15) (0.05 g,
0.14 mmol) was dissolved in tetrahydrofuran (10 mL) and
cooled to 0 °C. Lithium aluminium hydride (0.03 g, 0.71 mmol)
was then added and the slurry was heated under reflux for 12 h.
The solution was cooled to room temperature and concentrated
in vacuo. The crude material was dissolved in methanol (2 mL)
and 6.0 N hydrochloric acid (2 mL) was added. The reaction
mixture was stirred at room temperature for 12 h and then con-
centrated in vacuo. Purification by ion exchange column chrom-
atography (Dowex® 50WX8-100), eluting with 0.5 M ammonia
solution gave (3S*,4R*)-3-aminoazepin-4-ol (17) (0.01 g 61%
over two steps) as a viscous oil. Spectroscopic data as previously
reported.8h νmax/cm−1 (neat) 3369 (NH/OH), 2922 (CH), 1637,
1544, 1463, 1016; δH (500 MHz, CDCl3) 1.86–1.96 (2H, m,
6-H2), 2.17–2.25 (1H, m, 5-HH), 2.42–2.48 (1H, m, 2-HH),
2.57 (1H, td, J 10.0, 1.8 Hz, 7-HH), 2.76–2.86 (2H, m, 2-HH
and 5-HH), 3.09–3.14 (2H, m, 4-H and 7-HH), 3.17–3.21 (1H,
m, 3-H); δC (126 MHz, CDCl3) 29.7 (CH2), 31.7 (CH2),
45.3 (CH2), 54.3 (CH), 54.5 (CH2), 62.3 (CH); m/z (CI) 131
(MH+, 4%), 121 (100), 117 (70), 113 (15), 85 (18), 61 (19).
(3aS*,8S*,8aS*)-1-Oxo-2-trichloromethyl-3,5-diaza-5-(tert-
butoxycarbonyl)-8-iodo-1,3a,4,5,6,7,8,8a-octahydroazulene (20)
To a solution of 1-(tert-butoxycarbonyl)-3-(2′,2′,2′-trichloro-
methylamino)azapin-4-ene (4) (0.05 g, 0.139 mmol) in chloro-
form (8 mL), N-iodosuccinimide (0.05 g, 0.230 mmol) was
added and the mixture stirred for 18 h. The solvent was then
removed in vacuo. The resulting residue was dissolved in ethyl
acetate (20 mL) and the organic layer washed with water (4 ×
30 mL). The organic layer was then dried (MgSO4) and the
solvent removed in vacuo. Purification by flash column chrom-
atography (elution with petroleum ether–diethyl ether, 5 : 1)
gave (3aS*,8S*,8aS*)-1-oxo-2-trichloromethyl-3,5-diaza-5-(tert-
butoxycarbonyl)-8-iodo-1,3a,4,5,6,7,8,8a-octahydroazulene (20)
(0.052 g, 78%) as a white solid. Mp 130–133 °C; νmax/cm−1
(NaCl) 2933 (CH), 1684 (CO), 1417, 1243, 1164, 754; δH
(500 MHz, CDCl3) 1.47 (9H, s, OC(CH3)3), 1.98–2.15 (1H, m,
(3S*,4S*,5R*)-1-(tert-Butoxycarbonyl)-3-(2′,2′,2′-
trichloromethylcarbonylamino)-4,5-dihydroxyazepane (18)
1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloro-
methylcarbonylamino)azepine (4) (0.048 g, 0.134 mmol) was
dissolved in dichloromethane (8 mL) at −78 °C. Tetramethyl-
ethylenediamine (0.024 mL, 0.147 mmol) was added and the
reaction mixture stirred for 0.1 h before the addition of osmium
tetroxide (0.04 g, 0.157 mmol). The dark coloured solution was
stirred for 1 h at −78 °C before warming to room temperature.
The reaction mixture was stirred for a further 1 h. The solvent
was removed in vacuo and the dark coloured solid was dissolved
in 1 : 1 mixture of tetrahydrofuran and a saturated solution of
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7-HH), 2.25–2.39 (1H, m, 7-HH), 3.31–4.03 (4H, m, 6-H2 and
4-H2), 4.51–4.62 (1H, m, 8-H), 4.63–4.75 (1H, m, 3a-H), 5.26
(1H, t, J 8.2 Hz, 8a-H); δC (126 MHz, CDCl3) 26.3 (CH2), 28.4
(3 × CH3), 29.9 (CH2), 36.2 (CH), 48.1 (CH2), 68.9 (CH), 80.6
(CH), 86.2 (C), 89.6 (C), 154.7 (C), 161.0 (C); m/z (CI)
482.9496 (MH+. C13H1935Cl3IN2O3 requires 482.9506), 427
(38%), 393 (8), 301 (6), 199 (4), 164 (13), 100 (100).
previously reported above for 1-(tert-butoxycarbonyl)-2,3,6,7-
tetrahydro-3-(2′,2′,2′- trichloromethylcarbonylamino)azepine (4).
(3S)-1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-
trichloromethylcarbonylamino)azepine
The reaction was performed as described above, except using
(2E)-N-(butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-2′-
en-4′-ol (5) (0.06 g, 0.26 mmol) and (R)-COP-Cl (0.019 g,
0.013 mmol). Purification by flash column chromatography (pet-
roleum ether–diethylether, 2 : 1) gave (3S)-1-(tert-butoxycarbo-
nyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-trichloromethylcarbonylamino)-
azepine (0.08 g, 84% over three steps) as a white solid. Chiral
HPLC (Chiralcel IB column) analysis using 5% isopropanol in
hexane as the elution solvent indicated 92% ee. [α]2D4 +140.7
(c 0.7, CHCl3). All other spectroscopic data as previously
reported above for 1-(tert-butoxycarbonyl)-2,3,6,7-tetrahydro-3-
(2′,2′,2′- trichloromethylcarbonylamino)azepine (4).
(3S*,4S*,5S*)-3-Amino-5-iodoazepane-4-ol (21)
To a solution of (3aS*,8S*,8aS*)-1-oxo-2-trichloromethyl-3,5-
diaza-5-(tert-butoxycarbonyl)-8-iodo-1,3a,4,5,6,7,8,8a-octa-
hydroazulene (20) (0.047 g, 0.097 mmol) in methanol (5 mL)
was added 0.5 M hydrochloric acid (5 mL) and the reaction
mixture was stirred at room temperature for 0.5 h. The reaction
mixture was then diluted with a saturated solution of sodium
hydrogencarbonate (10 mL) and extracted with ethyl acetate (3 ×
20 mL). The organic layers were combined, dried (MgSO4) and
concentrated in vacuo to give (3S*,4S*,5S*)-3-amino-5-iodoaze-
pane-4-ol (21) (0.03 g, 77%) as a white solid. Mp 154–155 °C;
νmax/cm−1 (NaCl) 3450 (OH), 3337 (NH), 2957 (CH), 1665,
1463, 1272, 741; δH (500 MHz, CD3OD) 2.21–2.29 (1H, m,
6-HH), 2.55–2.62 (1H, m, 6-HH), 3.36 (1H, dd, J 13.5, 3.2 Hz,
2-HH), 3.41–3.49 (2H, m, 7-H2), 3.72 (1H, dd J 13.5, 10.0 Hz,
2-HH), 4.24 (1H, dt, J 10.0, 3.2 Hz, 3-H), 4.42–4.45 (1H, m,
4-H), 4.61 (1H, dt, J 6.1, 3.5 Hz, 5-H); δC (126 MHz, CD3OD)
29.2 (CH2), 30.7 (CH), 41.5 (CH2), 45.9 (CH2), 49.8 (CH), 74.8
(CH); m/z (CI) 257.0158 (MH+. C6H14IN2O requires 257.0151),
217 (20), 173 (12), 146 (8), 113 (8), 73 (22).
Acknowledgements
Financial support from the HEC, Pakistan and the University of
Glasgow is gratefully acknowledged.
Notes and references
1 G. R. Proctor and J. Redpath, Monocyclic Azepines: the Synthesis and
Chemical Properties of the Monocyclic Azepines, John Wiley and Sons,
New York, 1996.
2 P. Kulanthaivel, Y. F. Hallock, C. Boros, S. M. Hamilton, W. P. Janzen,
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(3R)-1-(tert-Butoxycarbonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′-
trichloromethylcarbonylamino)azepine
(2E)-N-(Butyl-3-en-1-yl)-N-(tert-butoxycarbonyl)-1′-aminobut-2′-
en-4′-ol (5) (0.07 g, 0.31 mmol) was dissolved in dichloro-
methane (15 mL) and cooled to 0 °C. 1,8-Diazabicyclo[5.4.0]-
undec-7-ene (0.06 mL, 0.47 mmol) was added to the solution
followed by trichloroacetonitrile (0.05 mL, 0.47 mmol). The
reaction mixture was then warmed to room temperature and
stirred for 2 h. The reaction mixture was filtered through a short
pad of silica gel and washed with diethyl ether (100 mL). The
resulting filtrate was then concentrated to give allylic trichloro-
acetimidate 13, which was used without further purification.
Allylic trichloroacetimidate 13 was then dissolved in dichloro-
methane (10 mL). (S)-COP-Cl 22 (0.023 g, 0.016 mmol) was
added to the solution and the reaction mixture was stirred at
room temperature for 72 h. Grubbs second generation catalyst
(0.03 g, 0.03 mmol) was then added and the reaction mixture
was heated under reflux for 24 h. The reaction mixture was
cooled to room temperature and then filtered through a short pad
of Celite® and washed with diethyl ether (100 mL). Concen-
tration of the filtrate, followed by flash column chromatography
(petroleum ether–diethylether, 2 : 1) gave (3R)-1-(tert-butoxycar-
bonyl)-2,3,6,7-tetrahydro-3-(2′,2′,2′- trichloromethylcarbonyl-
amino)azepine (0.10 g, 92% over three steps) as a white solid.
Chiral HPLC (Chiralcel IB column) analysis using 5% isopropa-
nol in hexane as the elution solvent indicated 92% ee. [α]D26
−120.8 (c 1.0, CHCl3). All other spectroscopic data as
8258 | Org. Biomol. Chem., 2012, 10, 8251–8259
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by chiral HPLC. See experimental for full details.
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