Asymmetric azo-ene reactions using the chiral azo-enophile di-(-)- (1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate

Article abstract of DOI:10.1016/S0957-4166(98)00034-2

The preparation of di-(-)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate 4 is described. Reaction of (1R,2S)-2-phenyl-1- cyclohexanol 1 with excess phosgene in the presence of quinoline afforded chloroformate 2 which was treated directly with hydrazin

Full text of DOI:10.1016/S0957-4166(98)00034-2

Pergamon
Tetrahedron: Asymmetry 9 (1998) 873–884
Asymmetric azo-ene reactions using the chiral azo-enophile
di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate
Margaret A. Brimble ∗ and Connie K. Y. Lee
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
Received 15 January 1998; accepted 26 January 1998
Abstract
The preparation of di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazenedicarboxylate 4 is described. Reaction of
(1R,2S)-2-phenyl-1-cyclohexanol 1 with excess phosgene in the presence of quinoline afforded chloroformate
2 which was treated directly with hydrazine monohydrate (0.5 equiv.) to afford di-(−)-(1R,2S)-2-phenyl-1-
cyclohexyl diazanedicarboxylate 3. Oxidization of 3 to the azo-enophile 4 was then readily effected in high yield
using N-bromosuccinimide and pyridine. The azo-ene reactions of 4 with the alkenes cyclohexene 5, cyclopentene
6, trans-3-hexene7 and trans-4-octene 8 were carried out using the Lewis acid tin(IV) chloride. Use of cyclohexene
5 afforded the ene adduct 9 in 80% yield with a diastereomeric excess of >97:3 whilst the use of cyclopentene
6, trans-3-hexene 7 and trans-4-octene 8 afforded the ene adducts 10 (77%), 11 (71%) and 12 (92%) with a
diastereomeric excess of 86:14 in each case. Use of the conjugated aromatic acyclic alkene 13 afforded the product
of an ionic addition, namely, chloride 14 in 57% yield. Cleavage of the N–N bond of the ene adduct 9 was effected
using lithium in liquid ammonia affording the carbamate 16 in moderate yield. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
The preparation of allylic amines has been limited to the use of sulfur diimido compounds,1 N-
sulfonylimines,2 acylnitroso compounds3 or N-sulfinylbenzenesulfonamides.4 Whitesell and Yaser5
have reported asymmetric induction in the allylic amination of alkenes via ene reaction of an N-
sulfinylcarbamate bearing the chiral auxiliary trans-(1S)-2-phenylcyclohexanol followed by rearrange-
ment of the ene adducts to allylic carbamates. The azo-ene reaction offers an alternative method for
effecting allylic amination in that treatment of an alkene with an azo-diester affords a diacyl hydrazine
which upon N–N cleavage furnishes a carbamate. Subsequent hydrolysis of the carbamate provides an
allylic amine. Use of chiral diazenedicarboxylates offers an exciting opportunity for development of
∗
Corresponding author. E-mail: brimble@alf.chem.usyd.edu.au
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00034-2

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M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
an asymmetric variant of this azo-ene reaction thereby providing a method for stereoselective elec-
trophilic amination. The present study investigates the synthesis of di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl
diazenedicarboxylate 4 and its use as an azo-enophile in reactions with simple alkenes.
The ene reaction6 provides a powerful method for C–C bond formation with concomitant activation of
an allylic C–H bond. A variety of functionalised carbon skeletons can be constructed due to the range of
enophiles which can be used; for example carbonyl compounds give homoallylic alcohols7 and imino
derivatives of aldehydes afford homoallylic amines.8 Milder reaction conditions have been achieved
using Lewis acid promoters9 whilst the use of chiral binaphthol–titanium based Lewis acids developed
by Mikami et al.10 have provided an efficient catalytic asymmetric variant of the carbonyl-ene reaction.
A model for the enantioselectivity of this Mikami ene reaction has recently been proposed by Corey et
al.11 invoking complexation of the formyl group with the titanum catalyst and hydrogen bonding of the
formyl hydrogen.
Asymmetric carbonyl-ene reactions have also been developed using chiral auxiliaries. Thus, Whitesell
et al.12 have reported excellent asymmetric induction in carbonyl-ene reactions using 8-phenylmenthyl
glyoxylates whilst Mikami et al.13 reported high diastereoselectivity in imino-ene reactions of 1,1-
disubstituted alkenes with chiral α-iminoesters bearing the 8-phenylmenthyl auxiliary. More recently, the
use of an N-glyoxyloyl-(2R)-bornane-10,2-sultam in asymmetric carbonyl-ene reactions was reported.14
Despite the widespread use of chiral glyoxylate enophiles in ene reactions, the synthesis of chiral
diazenedicarboxylates as potential chiral electrophilic aminating agents has received little attention. Ved-
eras et al.15a synthesized a series of chiral bornyl, isobornyl and menthyl diazenedicarboxylates and re-
ported that their reaction with achiral enolates of esters and N,N-dimethyl amides afforded α-hydrazino-
acid derivatives with little or no selectivity. Attempts15b to use a macrocyclic diazenedicarboxylate based
on a steroid skeleton was unsuccessful whilst incorporation of a chiral azodicarboxamide unit into a
chiral bridging binaphthyl moiety afforded α-hydrazino-acid derivatives with high stereoselectivity in
reactions with achiral oxazolidinone anions.15c Evans and Nelson16 have recently reported the elegant
use of chiral magnesium bis(sulfonamide) complexes as catalysts for the enantioselective amination of
N-acyloxazolidinones using achiral diazenedicarboxylates.
The work carried out by Vederas et al.15 focused on the electrophilic amination of chiral diazenedicar-
boxylates with achiral ester enolates. The potential of these aminating agents as chiral azo-enophiles in
ene reactions, the subject of our investigations, was not pursued by these authors.
We have reported17 the use of tin(IV) chloride as a promoter for the azo-ene reaction of diethyl
diazenedicarboxylate (DEAD) with alkenes under mild conditions. Cleavage of the N–N bond in
the azo-ene adducts was effected using lithium in liquid ammonia. A method for allylic amination
was therefore developed which offered an alternative to the use of the more reactive azo-enophile
bis(2,2,2-trichloroethyl)azodicarboxylate.18 Extension of this reaction to the use of a chiral azo-enophile
initially focused on the use of di-(−)-menthyl diazenedicarboxylate.19 However, the level of asymmetric
induction achieved in Lewis acid mediated ene reactions with simple alkenes was not impressive.
Moreover, it proved difficult to cleave the N–N bond in the menthyl ester azo-ene adducts.
2. Results and discussion
As an extension to our earlier work, we next investigated the use of Whitesell’s auxiliary, (−)-(1R,2S)-
2-phenyl-1-cyclohexanol 1, for development of an asymmetric azo-ene reaction. Chloroacylation of
(−)-(1R,2S)-2-phenyl-1-cyclohexanol 1 with phosgene using triethylamine as the base afforded N,N-
diethylcarbamate 15 in 80% yield whereas use of pyridine as the base and subsequent reaction with

M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
875
hydrazine monohydrate only afforded the desired diazanedicarboxylate 3 in 11% yield. A successful
synthesis of 3 was finally realised when quinoline was used as the base (Scheme 1). The optimum
method involved a one-step procedure wherein chloroacylation of 1 by phosgene (3 equiv.) in the
presence of quinoline (1.1 equiv.) for 0.5 h afforded the chloroformate 2. Excess phosgene was removed
under reduced pressure and hydrazine monohydrate (0.5 equiv.) and quinoline (1.1 equiv.) were added
dropwise and alternately to 2 at 0–10°C over 10–15 min. After stirring at room temperature for 24 h,
diazanedicarboxylate 3 was furnished in 74% yield.
Scheme 1.
1
Owing to restricted rotation about the carbamate C–N bond on the NMR timescale, the H NMR
spectrum for 3 was broad and resolution was poor at 298 K (200 MHz, CDCl3). The resolution was
optimized by acquiring the 400 MHz spectrum at 360 K using deuterotoluene as the solvent.
Several oxidants were examined for conversion of the diazanedicarboxylate 3 to the diazenedicar-
boxylate 4. Whilst the use of [bis(trifluoroacetoxy)iodo]benzene20 in dichloromethane at 0°C readily
converted 3 to 4, the diazenedicarboxylate 4 isolated from this reaction proved unstable and underwent
conversion back to 3 upon standing at room temperature. Use of bromine and pyridine,21 fuming nitric
acid17 and N-bromosuccinimide15a and pyridine all effected smooth conversion of 3 to 4 in 80%, 90%
and 97% yields, respectively, and this latter reagent was used routinely.
The 1H NMR spectrum and elemental analysis for azo-enophile 4 were in agreement with the proposed
structure and the IR spectrum confirmed the presence of both a C_O stretch (1771 cm−1) and an
N_N stretch at (1449 cm−1). With azo-enophile 4 in hand, Lewis acid mediated azo-ene reactions were
investigated using a range of alkenes which could only afford one regioisomer of the corresponding ene
adduct.
Initial work focused on the ene reaction of 4 with cyclohexene 5 using tin(IV) chloride which had been
found to be the optimum Lewis acid in the reaction of di-(−)-menthyl diazanedicarboxylate with alkenes
(Table 1).19 Addition of tin(IV) chloride (1.1 equiv.) to a mixture of enophile 4 and cyclohexene 5 (1.6
equiv.) in dichloromethane at −60°C for 5 min afforded the ene adduct 9 in 80% yield after purification by
flash chromatography. Due to hindered rotation about the carbamate C–N bonds the 1H NMR spectrum
of adduct 9 acquired at 298 K in deuterated chloroform at 200 MHz, was very broad and complex. The
resolution was improved by acquiring the spectrum at elevated temperatures in deuterated toluene and
the optimum spectrum resolution was achieved at 380 K. Under these conditions the 1H NMR spectrum

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M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
Table 1
Reaction of azo-enophile 4 with alkenes using SnCl4
established the presence of only one diastereomer within the limits of detection by NMR spectroscopy
at 400 MHz (97:3). Further analysis of the ene adduct 9 by HPLC on a Whatman Partisil 5 normal phase
silica column using hexane:ethyl acetate (9:1) as eluent confirmed the presence of only one diastereomer,
Rt=12 min.
00x,100ax
Two double doublets, each integrating for one proton, resonating at δ 2.62 ppm (J2
10.4,
00
00
00 00 00 00
00ax,100ax
10.4, J2 ax,3 ax 10.4, J2 ax,3 eq 3.8) were
00ax,300ax
J2
10.4, J2 ax,3 eq 3.8) and δ 2.76 ppm (J2
assigned to the methine protons at C-200. A broad one-proton singlet at δ 4.66 ppm was assigned to the
CHN proton. Two double doublets, each integrating for one proton, resonating at δ 5.06 ppm (J1
00ax,200ax

M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
877
Fig. 1.
00
00
00
00
00
00
00
0
00
00
10.4, J1 ax,6 ax 10.4, J1 ax,6 eq 4.5) and δ 5.12 ppm (J1 ax,2 ax 10.4, J1 ax,6 ax 10.4, J1
4.5) were
ax,6 eq
assigned to the two methine protons at C-100. In the vinylic region, multiplets at δ 5.38–5.47 ppm and
δ 5.65–5.67 ppm, each integrating for one proton, were assigned to the vinylic protons H-30 and H-20
respectively. The presence of an NH proton was evident as a singlet at δ 5.58 ppm and a 10-proton
multiplet at δ 7.16–7.37 ppm was assigned to the aromatic protons.
The absolute stereochemistry at the newly formed stereogenic carbon of the major diastereomer of
the ene adduct 9 can be predicted by analysis of the transition model for the ene reaction (Fig. 1). The
(1R,2S)-2-phenyl-1-cyclohexyl chiral auxiliary adopts a chair conformation with equatorial placement
of the bulky phenyl group. Complexation of the carbonyl group to the Lewis acid affords the more
stable s-trans conformation about the C–N sigma bond. In this conformation the phenyl group shields
the Nβ-re-face therefore the cyclic olefin preferentially attacks from the less hindered Nβ-si-face. Ene
reaction proceeds through a six-membered cyclic transition state affording the (10R)-diastereomer of the
ene adduct. The origin of the diastereocontrol for this reaction is a consequence of the π-stacking of the
phenyl group of the auxiliary and the conjugated diazenedicarbonyl moiety.
The tin(IV) chloride promoted azo-ene reaction of 4 with cyclopentene 6 under similar conditions
to that used above afforded the ene adduct 10 in 77% yield. In this case two peaks were observed in
the HPLC chromatogram [Sorbax Sil normal phase silica column using hexane:ethyl acetate (85:15) as
eluent] at Rt=9.5 min and Rt=10 min which upon integration established an 86:14 ratio of diastereomers.
This ratio was also in agreement with that obtained from integration of the 1H NMR spectrum of the crude
ene adduct 10 acquired at elevated temperature in deuterotoluene at 400 MHz. The major diastereomer
was further purified by preparative HPLC.
The diastereomeric ratios observed for the ene adducts obtained after reaction of azo-enophile 4
with the cyclic alkenes, cyclohexene 5 (>97:3) and cyclopentene 6 (86:14), represent a significant
improvement over the 1:1 ratio of diastereomers observed in analogous reactions using di-(−)-menthyl
diazenedicarboxylate as the azo-enophile.19
Encouraged by the promising diastereomeric ratios achieved in the ene reaction of 4 with cyclic
alkenes, it was next decided to investigate the use of acyclic alkenes as the ene component. trans-3-
Hexene 7 and trans-4-octene 8 were reacted with 4 using the same conditions as for the analogous
reactions with cyclic alkenes. The ene adducts 11 and 12 were isolated in 71% and 92% yield respectively,
after flash chromatography. In both cases, HPLC analysis on a Whatman Partisil 5 normal phase column
using hexane:ethyl acetate (9:1) as eluent resolved the two diastereomers. For ene adduct 11, two peaks
were observed at Rt=19.5 min and Rt=21.5 min which upon integration established an 86:14 ratio of
diastereomers. Similarly for ene adduct 12 two peaks were observed at Rt=20.5 min and Rt=22 min
which upon integration also established an 86:14 ratio of diastereomers. Similar diastereomeric ratios
were obtained from integration of the 1H NMR spectrum of the crude ene adducts 11 and 12 acquired at
360 K in deuterotoluene at 400 MHz and were significantly better than the ratios observed for the ene

878
M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
Fig. 2.
reactions of acyclic alkenes 7 and 8 with di-(−)-menthyl diazenedicarboxylate as the azo-enophile (2.5:1
and 2:1 respectively).19
The major diastereomers of the ene adducts 11 and 12 were further purified by preparative HPLC.
Examination of the transition state model for the ene reaction using trans-3-hexene 7 and trans-4-octene
8 also allows a prediction of which diastereomer should be the favoured product (Fig. 2).
In view of the successful ene reactions observed with aliphatic cyclic and acyclic alkenes, it was
decided to examine the ene reaction of 4 with an acyclic alkene conjugated to an aromatic ring, namely,
trans-β-methylstyrene 13. With this more activated alkene, chloride 14 was formed in 57% yield after
treatment with tin(IV) chloride under similar conditions to those used for alkenes 5, 6, 7 and 8. Clearly in
this system an ionic mechanism involving a stepwise reaction with a carbocation intermediate is operating
rather than a pericyclic mechanism.
Given that the best asymmetric induction was observed in the formation of ene adduct 9, cleavage of
the N–N bond of the ene adduct 9 to the carbamate 16 was examined. Lithium in liquid ammonia had been
successfully used to cleave the N–N bond in ene adducts formed using DEAD,17 however, treatment of
ene adduct 9 with lithium in liquid ammonia resulted in formation of carbamate 16 in only in 10% yield
whereas the use of samarium diiodide was unsuccessful. Use of sodium and liquid ammonia, however,
afforded the desired carbamate 16 in 61% yield. The enantiomer of carbamate 16 has been prepared by
Whitesell and Yaser,5 who also demonstrated the facile hydrolysis of allylic trans-2-phenylcyclohexyl
carbamates to allylic amines under basic conditions. Carbamate 16 was a single diastereomer within the
limit of detection by 13C NMR spectroscopy and analytical HPLC as described by Whitesell and Yaser5
for the enantiomer of carbamate 16.
In summary the work described herein established that the use of a (1R,2S)-2-phenyl-1-cyclohexyl
chiral auxiliary rather than a menthyl ester affords much higher levels of asymmetric induction in the
Lewis acid mediated azo-ene reaction however subsequent cleavage of the N–N bond in the ene adduct
only proceeds in low yield.

M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
879
3. Experimental
3.1. General details
Melting points were determined using a Reichert heating stage with microscope and are uncorrected.
Elemental analyses were performed at either the Chemical Engineering Faculty, University of Sydney,
Sydney, the Central Services Laboratory, Hobart, Tasmania, Australia or the Microanalytical Laboratory,
University of Otago, Dunedin, New Zealand. Optical rotations were measured using a PolAAR 2001
polarimeter in chloroform at the temperature and concentration (g/100 mL) indicated. Specific rotations
are given in 10−1 deg cm2 g−1. Readings were taken using the 589.3 nm sodium line and a 1 dm cell.
Infrared absorption spectra were recorded using a Perkin–Elmer 1600 Series FTIR spectrometer as Nujol
mulls or as a thin film on a single sodium chloride plate seated in the apparatus on a custom-made perch.
1H NMR spectra were recorded using a Bruker AC200B spectrometer (200.13 MHz) or a Bruker AM400
spectrometer (400.12 MHz). 13C NMR spectra were recorded on a Bruker AC200 spectrometer (50.3
1
MHz) at ambient temperatures with complete decoupling. Variable temperature H NMR spectra were
recorded in deuterotoluene at 360 K or 380 K using toluene as an internal standard. Low resolution mass
spectra were recorded on a VG 70-SE, VG 70-250S, VG70-SD or an AEI model MS902 double focusing
magnetic sector mass spectrometer with an ionisation potential of 70 eV. The samples were inserted
through a solid direct injection probe with a source temperature of 200°C. Chemical ionisation (CI) mass
spectra were recorded on a Hewlett–Packard 5989A mass spectrometer using CH4 as the reagent gas, with
the sample dissolved in CH3OH and injected through an HPLC injection port with the sample passed to
the mass spectrometer source at 200°C by a particle beam interface. Liquid secondary ion mass spectra
(LSIMS) were recorded on a VG70-SE double focusing magnetic sector mass spectrometer operating
with an ionization potential of 20 keV using cesium as a secondary gas. Matrices used for LSIMS sample
preparation were m-nitrobenzyl alcohol (mnba) and polyethylene glycol. High resolution mass spectra
were recorded at a nominal resolution of 5000 or 10000 as appropriate, using EI, CI with ammonia or
LSIMS with mnba. High resolution CI and LSIMS mass spectra were recorded at the Central Services
Laboratory, Hobart, Australia. Thin layer chromatography (t.l.c) was carried out on Merck precoated
aluminium sheets coated with 0.2 mm silica gel 60F254 and flash chromatography on Merck silica
gel 60 (230–400 mesh ASTM). Solvent compositions specified are mixed v:v. High performance liquid
chromatography (HPLC) was performed using Waters and Associates HPLC instrumentation fitted with
a Whatman Partisil 5 normal phase silica column or a Sorbax Sil normal phase silica column (21.5
mm i.d.×25 mm) with a flow rate of 1.5 cm3/min and hexane–ethyl acetate as eluent (v:v). Hexane
was distilled from calcium hydride and tetrahydrofuran was distilled from benzophenone/sodium wire
immediately prior to use. Reaction temperatures were maintained at −70°C using dry ice/acetone; −60°C
using dry ice/chloroform; −20°C using dry ice/carbon tetrachloride and 0°C using ice/water cooling
baths. (−)-(1R,2S)-2-Phenyl-1-cyclohexanol was prepared from 1-phenylcyclohexene according to the
1
method of Sharpless and King.22 The H NMR spectrum, melting point and optical rotation of the
material prepared was in agreement with that reported in the literature.22
3.2. Di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazane-1,2-dicarboxylate 3
To phosgene (1.50 mL of a 12.5% w/w solution in benzene, 1.89 mmol) under an atmosphere of
nitrogen, were added dropwise and alternately over 10–15 min a solution of (−)-(1R,2S)-2-phenyl-1-
cyclohexanol 1 (100 mg, 0.567 mmol) in dry THF (1 mL) and quinoline (73 µL, 0.62 mmol). The
reaction mixture was stirred at room temperature for 30 min. Due to the instability of the chloroformate

880
M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
2, further purification was not attempted. Unreacted phosgene was removed under reduced pressure to
afford the crude chloroformate 2 as a viscous brown oil, δH (200 MHz, CDCl3) 1.25–1.70 (4H, m, H-40,
H-50), 1.76–2.01 (3H, m, H-30, H-60), 2.22–2.30 (1H, m, H-60), 2.74 (1H, ddd, J2 ax,1 ax 10.9, J2 ax,3 ax
0
0
0
0
10.9, J2 ax,3 eq 4.0, H-20), 4.98 (ddd, J1 ax,2 ax 10.9, J1 ax,6 ax 10.9, J1 ax,6 eq 4.5, H-10), 7.21–7.30 (5H, m,
Ph); m/z (EI) 238 [M+, 1], 194 [M−CO2, 16], 158 [M−CHO2Cl, 100].
0
0
0
0
0
0
0
0
To a solution of the crude chloroformate 2 in dry THF (1 mL) at 0−5°C, were added dropwise and
alternately hydrazine monohydrate (14 µL, 0.28 mmol) and quinoline (73 µL, 0.62 mmol) over 10–15
min with stirring under an atmosphere of nitrogen. The reaction mixture was warmed to room temperature
for 24 h then extracted with dichloromethane (3×8 mL), washed with water (0.5 mL) and dried over
anhydrous sodium sulfate. After removal of solvent under reduced pressure, the residue was purified
by flash chromatography using hexane:ethyl acetate (9:1) as eluent to afford the title compound 3 (92
mg, 74%) as a colourless solid, m.p. 43–44°C; [α]D −37.5 (c 1.07, CHCl3); νmax (thin film)/cm−1
3379 br (NH) and 1718 s (C_O); δH (400 MHz, [2H8]toluene, 360 K) 1.14–1.39 (8H, m, H-40, H-
50), 1.48–1.52 (2H, m, H-30), 1.56–1.59 (2H, m, H-30), 1.69–1.74 (2H, m, H-60), 2.14–2.18 (2H, m,
H-60), 2.48 (2H, ddd, J2 ax,1 ax 10.9, J2 ax,3 ax 10.9, J2 ax,3 eq 3.8, H-20), 4.84 (2H, ddd, J1 ax,2 ax 10.5,
0
0
0
0
0
0
0
0
J1 ax,6 ax 10.5, J1 ax,6 eq 4.4, H-10), 5.15 (2H, s, NH), 6.95–7.17 (10H, m, 2×Ph); δC (50 MHz, CDCl3)
24.7 (CH2, C-40), 25.7 (CH2, C-50), 32.5 (CH2, C-30), 34.2 (CH2, C-60), 49.7 (CH, C-20), 84.6 (CH, C-
10), 126.4, 127.5, 128.3 (CH, C-200, C-300, C-400), 143.3 (quat, C-10), 155.8 (quat, C_O); m/z (CI, CH4)
437 [(MH)+, 6], 279 [(MH)−C12H14, 16], 159 [(MH)−C14H18N2O4, 100]; [found: (MH)+, 437.2440;
C26H32N2O4 requires MH, 437.2443].
0
0
0
0
3.3. Di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl diazene-1,2-dicarboxylate 4
To a mixture of diazanedicarboxylate 3 (80 mg, 0.184 mmol) and pyridine (22 µL, 0.28 mmol) in dry
dichloromethane (1 mL) cooled to 0°C, was added a solution of N-bromosuccinimide (40 mg, 0.22 mmol)
in dry dichloromethane (0.3 mL). The reaction was protected from light and stirred under an atmosphere
of nitrogen at 0–5°C for 15 min The resultant mixture was extracted with dichloromethane (3×15
mL) and washed with water (1 mL). The organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford a yellow oil, which was purified by flash chromatography
using hexane:ethyl acetate (9:1) as eluent to give the title compound 4 (78 mg, 97%) as a yellow oil; [α]D
−56.9 (c 0.65, CHCl3); (found: C, 71.6; H, 7.0; N, 6.1; C26H30N2O4 requires C, 71.9; H, 7.0; N, 6.4%);
ν
max (thin film)/cm−1 1771 s (C_O), 1449 s (N_N); δH (400 MHz, CDCl3) 1.32–1.64 (8H, m, H-40, H-
50), 1.70–1.93 (6H, m, H-30, H-60), 2.10–2.20 (2H, m, H-60), 2.68 (2H, ddd, J2 ax,1 ax 10.6, J2 ax,3 ax 10.6,
0
0
0
0
J
2 ax,3 eq 3.9, H-20), 5.02 (2H, ddd, J1 ax,2 ax 10.6, J1 ax,6 ax 10.6, J1 ax,6 eq 4.6, H-10), 7.10–7.40 (10H, m,
0 0 0 0 0 0 0 0
2×Ph); δC (50 MHz, CDCl3) 24.6 (CH2, C-40), 25.4 (CH2, C-50), 31.8 (CH2, C-30), 33.5 (CH2, C-60),
49.2 (CH, C-20), 81.8 (CH, C-10), 126.7, 127.4, 128.4 (CH, C-200, C-300, C-400), 141.5 (quat, C-100) and
159.6 (quat, C_O); m/z (EI) 158 [M−C14H16N2O4, 95], 91 [M−C19H23N2O4, 100], 28 [M−C26H30O4,
99].
3.4. (−)-(1R,2S)-2-Phenyl-1-cyclohexyl N,N-diethylcarbamate 15
To phosgene (1.50 mL of a 12.5% w/w solution in toluene, 1.70 mmol) was added a solution of
(−)-(1R,2S)-2-phenylcyclohexanol 1 (100 mg, 0.57 mmol) in dry THF (0.8 mL) with stirring under an
atmosphere of nitrogen. After 45 min, triethylamine (87 µL, 0.62 mmol) was added dropwise resulting
in formation of a white precipitate. The resultant mixture was stirred for 18 h at room temperature under
an atmosphere of nitrogen. Excess phosgene and solvent were removed at reduced pressure and the

M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
881
residue extracted with dichloromethane (3×8 mL) and washed with water (0.5 mL). Purification by flash
chromatography using hexane:ethyl acetate (9:1) as eluent afforded the title compound 15 (126 mg, 80%)
as a pale yellow oil; [α]D −56.5 (c 0.32, CHCl3); νmax (thin film)/cm−1 1695 s (C_O); δH (200 MHz,
CDCl3) 0.85–0.91 (6H, br m, 2×CH2CH3), 1.31–1.69 (4H, m, H-40, H-50), 1.78–2.02 (2H, m, H-30),
2.28–2.33 (2H, m, H-60), 2.71 (1H, ddd, J2 ax,1 ax 11.2, J2 ax,3 ax 11.2, J2 ax,3 eq 3.7, H-20), 2.97–3.29
0
0
0
0
0
0
(4H, br m, 2×CH2CH3), 4.90 (1H, ddd, J1 ax,2 ax 11.2, J1 ax,6 ax 11.2, J1 ax,6 eq 4.1, H-10), 7.15–7.34 (5H,
m, Ph); δC (50 MHz, CDCl3) 13.2 (CH2CH3), 24.6 (CH2, C-40), 25.8 (CH2, C-50), 32.3 (CH2, C-30), 34.1
(CH2, C-60), 40.9 (CH2CH3), 50.2 (CH, C-20), 76.3 (CH, C-10), 125.9, 127.3, 130.0 (C-200, C-300, C-400),
143.5 (quat, C-100), 155.2 (quat, C_O); m/z (LSIMS, mnba) 276 [(MH)+, 84], 159 [(MH)−C5H11NO2,
100], 118 [(MH)−C12H14, 100]; [found: (MH)+ 276.1969; C17H25NO2 requires MH, 276.1885].
0
0
0
0
0
0
3.5. Di-(−)-(1R,2S)-2-phenylcyclohexyl 1-(20-cyclohexen-10-yl)-1,2-diazanedicarboxylate 9
To a solution of diazenedicarboxylate 4 (296 mg, 0.68 mmol) and cyclohexene 5 (86 µL, 0.83 mmol) in
dichloromethane (8 mL) cooled to −60°C under an atmosphere of nitrogen, was added tin(IV) chloride
(80 µL, 0.68 mmol). After 5 min, the yellow solution turned colourless and water (4 mL) was added.
After extraction with dichloromethane (3×25 mL), the combined organic extracts were dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resultant oil was purified by
flash chromatography using hexane:ethyl acetate (9:1) as eluent to afford the title compound 9 (281 mg,
80%) as a colourless solid. Further purification by HPLC on a Whatman Partisil 5 normal phase silica
column using hexane:ethyl acetate (9:1) as eluent afforded the major diastereomer as a colourless solid,
m.p. 138–139°C; [α]D −3.4 (c 0.65, CHCl3); νmax (thin film)/cm−1 3292 br (NH), 1749 s (C_O), 1713
s (C_O); δH (400 MHz, [2H8]toluene, 380 K) 1.30–1.58 (12H, m, H-50, H-60, H-400, H-500), 1.59–1.78
(2H, m, H-300), 1.79–1.90 (4H, m, H-300, H-40), 1.91–1.99 (2H, m, H-600), 2.35–2.44 (2H, m, H-600),
2.62 (1H, ddd, J2 ax,1 ax 10.4, J2 ax,3 ax 10.4, J2 ax,3 eq 3.8, H-200), 2.76 (1H, ddd, J2 ax,1 ax 10.4,
00
00
00
00
00
00
00
00
J2
J1
10.4, J2 ax,3 eq 3.8, H-200), 4.66 (1H, s, CHN), 5.06 (1H, ddd, J1 ax,2 ax 10.4, J1 ax,6 ax 10.4,
00
00
00 00 00 00 00 00
ax,3 ax
4.5, H-100), 5.12 (1H, ddd, J1 ax,2 ax 10.4, J1 ax,6 ax 10.4, J1 ax,6 eq 4.5, H-100), 5.38–5.47
00ax,600eq
00
00
00
00
00
00
(1H, br m, H-30), 5.58 (1H, s, NH), 5.65–5.67 (1H, m, H-20), 7.16–7.37 (10H, m, 2×Ph); m/z (LSIMS,
mnba), 649 [(MCs)+, 5], 517 [(MH)+, 29], 437 [(MH)−C6H8, 4], 279 [(MH)−C16H14O2, 17], 159
[(MH)−C20H26N2O4, 100]; [found (MH)+ 517.3064; C32H40N2O4 requires MH, 517.3068].
3.6. Di-(+)-(1R,2S)-2-phenylcyclohexyl 1-(20-cyclopenten-10-yl)-1,2-diazanedicarboxylate 10
To a solution of diazenedicarboxylate 4 (43 mg, 0.10 mmol) and cyclopentene 6 (14 µL, 0.15 mmol)
in dichloromethane (2 mL) cooled to −60°C under nitrogen, was added tin(IV) chloride (13 µL, 0.11
mmol). After 5 min the yellow solution turned colourless and water (0.5 mL) was added. After extraction
with dichloromethane (3×5 mL), the combined organic extracts were dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resultant oil was purified by flash chromatography
using hexane:ethyl acetate (9:1) as eluent to afford the title compound 10 (37 mg, 77%) as a colourless
solid and as an 86:14 mixture of diastereomers. Further purification by HPLC on a Sorbax Sil normal
phase silica column using hexane:ethyl acetate (85:15) as eluent afforded the major diastereomer as a
colourless solid, m.p. 134–135°C; [α]D +10.0 (c 0.44, CHCl3); νmax (thin film)/cm−1 3307 br (NH),
1717 br (C_O); δH (400 MHz, [2H8]toluene, 360 K) 1.10–1.41 (8H, m, H-400, H-500), 1.48–1.55 (2H, m,
H-300), 1.56–1.66 (2H, m, H-300), 1.67–1.78 (4H, m, H-50, H-600), 1.83–1.87 (1H, m, H-40), 1.91–1.96
(1H, m, H-40), 2.18–2.21 (2H, m, H-600), 2.40–2.47 (1H, ddd, J2 ax,1 ax 10.2, J2 ax,3 ax 10.2, J2
00
00
00
00
00ax,300eq
3.8, H-200), 2.60–2.67 (1H, ddd, J2 ax,1 ax 10.2, J2 ax,3 ax 10.2, J2 ax,3 eq 3.8, H-200), 4.93–5.08 (3H, m,
00
00
00
00
00
00

882
M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
H-100, CHN), 5.19–5.31 (1H, m, H-30), 5.42 (1H, s, NH), 5.56–5.61 (1H, m, H-20), 6.96–7.18 (10H, m,
2×Ph); m/z (LSIMS, mnba) 503 [(MH)+, 44], 437 [(MH)−C26H33N2O4, 4], 279 [(MH)−C15H12O2, 17],
159 [(MH)−C19H24N2O4, 100]; [found (MH)+ 503.2902; C31H38N2O4 requires MH, 503.2912].
3.7. Di-(−)-(1R,2S)-2-phenyl-1-cyclohexyl (E)-1-(20-hexen-40-yl)-1,2-diazanedicarboxylate 11
To a solution of diazenedicarboxylate 4 (22 mg, 0.051 mmol) and trans-3-hexene 7 (10 µL, 0.081
mmol) in dichloromethane (3 mL) cooled to −60°C under nitrogen, was added tin(IV) chloride (6
µL, 0.051 mmol). After 5 min the yellow solution turned colourless and water (0.5 mL) was added.
After extraction with dichloromethane (3×5 mL), the combined organic extracts were dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resultant oil was purified by
flash chromatography using hexane:ethyl acetate (9:1) as eluent to afford the title compound 11 (19 mg,
71%) as a colourless oil and as an 86:14 mixture of diastereomers. Further purification by HPLC on
a Whatman Partisil 5 normal phase silica column using hexane:ethyl acetate (9:1) as eluent afforded
the major diastereomer as a colourless oil; [α]D −38.9 (c 0.40, CHCl3); νmax (thin film)/cm−1 3385 br
(NH), 1754 s (C_O), 1712 s (C_O); δH (400 MHz, [2H8]toluene, 360 K) 0.70 (3H, t, J6 ,5 7.2, H-
00 00
600), 1.10–1.39 (10H, m, H-50, H-400, H-500), 1.43 (3H, dq, J1 ,2 6.7, J1 ,3 1.0, H-10), 1.50–1.54 (2H,
m, H-300), 1.60–1.64 (2H, m, H−300), 1.68–1.77 (2H, m, H−600), 2.18–2.26 (2H, m, H-600), 2.35 (1H,
0
0
0
0
ddd, J2 ax,1 ax 10.4, J2 ax,3 ax 10.4, J2 ax,3 eq 3.8, H-200), 2.58 (1H, ddd, J2 ax,1 ax 10.4, J2 ax,3 ax 10.4,
00
00
00
00
00
00
00
00
00
00
J2
3.8, H-200), 4.20 (1H, m, CHN), 4.82 (1H, ddd, J1 ax,2 ax 10.4, J1
10.4, J1
00
00
00ax,300eq
00ax,600ax 00ax,600eq
4.5, H-100), 4.96–5.14 (2H, m, H-30, H-100), 5.17 (1H, dq, J2 ,3 18.1, J2 ,1 6.4, H-20), 5.36 (1H, s,
NH), 6.97–7.18 (10H, m, 2×Ph); m/z (LSIMS, mnba) 519 [(MH)+, 41], 489 [(MH)−C2H5, 4], 437
[(MH)−C6H9, 36], 317 [(MH)−C13H14O2, 3], 279 [(MH)−C16H16O2, 27], 159 [(MH)−C20H28N2O4,
100]; [found: (MH)+, 519.3248; C32H42N2O4 requires MH, 519.3225].
0
0
0
0
3.8. Di-(−)-(1R,2S)-2-Phenyl-1-cyclohexyl (E)-1-(30-octen-50-yl)-1,2-diazanedicarboxylate 12
To a solution of diazenedicarboxylate 4 (38 mg, 0.087 mmol) and trans-4-octene 8 (13 µL, 0.087
mmol) in dichloromethane (2 mL) cooled to −60°C under nitrogen, was added tin(IV) chloride (10
µL, 0.087 mmol). After 5 min the yellow solution turned colourless and water (0.5 mL) was added.
After extraction with dichloromethane (3×5 mL), the combined organic extracts were dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resultant oil was purified by
flash chromatography using hexane:ethyl acetate (9:1) as eluent to afford the title compound 12 (44 mg,
92%) as a colourless oil and as an 86:14 diastereomeric mixture. Further purification by HPLC on a
Whatman Partisil 5 normal phase silica column using hexane:ethyl acetate (9:1) as eluent afforded the
major diastereomer as a colourless oil; [α]D −24.4 (c 0.65, CHCl3); νmax (thin film)/cm−1 3381 br (NH),
1750 s (C_O), 1710 s (C_O); δH (400 MHz, [2H8]toluene, 360 K) 0.80 (3H, t, J 7.1, H-10 or H-80), 0.85
(3H, t, J 7.4, H-80 or H-10), 1.07–1.46 (12H, m, H-60, H-70, H-400, H-500), 1.46–1.55 (2H, m, H-300),
1.56–1.65 (2H, m, H-300), 1.66–1.80 (2H, m, H-600), 1.81 (2H, p, J 7.6, H-20), 2.16–2.25 (2H, m, H-
600), 2.35 (1H, ddd, J2 ax,1 ax 10.9, J2 ax, 3 ax 10.9, J2 ax,3 eq 3.9, H-200), 2.57 (1H, ddd, J2 ax,1 ax 10.5,
00
00
00
00
00
00
00
00
J2 ax,3 ax 10.5, J2 ax,3 eq 3.9, H-200), 4.34–4.36 (1H, m, CHN), 4.81 (1H, ddd, J1 ax,2 ax 10.5, J1
00
00
00
00
00
00
00ax,600ax
10.5, J1 ax,6 eq 4.5, H-100), 4.97 (1H, ddd, J1 ax,2 ax 10.5, J1 ax,6 ax 10.5, J1
4.5, H-100), 5.05
00
00
00
00
00
00
00ax,600eq
(1H, dd, J4 ,3 15.5, J4 ,5 7.0, H-40), 5.29 (1H, ddt, J3 ,4 15.5, J3 ,2 4.3, J3 ,5 0.8, H-30), 5.38 (1H, s,
NH), 6.96–7.20 (10H, m, 2×Ph); m/z (LSMIS, mnba), 547 [(MH)+, 27], 437 [(MH)−C8H14N2O4, 16],
279 [(MH)−C18H20O2, 21], 159 [(MH)−C22H32N2O4, 100]; [found: (MH)+, 547.3584; C34H46N2O4
requires MH, 547.3538].
0
0
0
0
0
0
0
0
0
0

M. A. Brimble, C. K. Y. Lee / Tetrahedron: Asymmetry 9 (1998) 873–884
883
3.9. Di-(1R,2S)-2-phenylcyclohexyl 1-(10-chloro-10-phenyl)prop-20-yl-1,2-diazanedicarboxylate 14
To a solution of diazenedicarboxylate 4 (39 mg, 0.090 mmol) and trans-β-methylstyrene (24 µL,
0.18 mmol) in dichloromethane (2 mL) cooled to −60°C under nitrogen, was added tin(IV) chloride
(11 µL, 0.090 mmol). After 5 min the yellow solution turned colourless and water (0.5 mL) was
added. After extraction with dichloromethane (3×5 mL), the combined organic extracts were dried over
anhydrous sodium sulfate and concentrated under reduced pressure. The resultant oil was purified by
flash chromatography using hexane:ethyl acetate (9:1) as eluent to afford the title compound 14 (30 mg,
57%) as a colourless oil; νmax (thin film)/cm−1 3355 br (NH), 1756 s (C_O), 1716 s (C_O); δH (400
MHz, [2H8]toluene, 360 K) 1.19–1.47 (11H, m, H-400, H-500, H-30), 1.48–1.76 (8H, m, H-300, H-600),
2.25–2.30 (1H, m, H-200), 2.56–2.60 (1H, m, H-200), 4.43 (1H, d, J 9.4, H-10), 4.32–4.75 (1H, br m, H-
20), 4.84 (1H, ddd, J1 ax,2 ax 10.4, J1 ax,6 ax 10.4, J1
4.6, H-100), 5.02 (1H, ddd, J1 ax,2 ax 10.4,
00 00
00
00
00
00
00
00
ax,6 eq
10.4, J1 ax,6 eq 4.6, H-100), 5.59 (1H, s, NH), 6.95–7.16 (15H, m, 3×Ph); m/z (LSIMS, mnba)
00
J1
00
00
00
ax,6 ax
589 [(MH)+, 16], 553 [(MH)−Cl, 0.7], 237 [(MH)−C24H32O2, 30], 159 [(MH)−C23H27N2O4Cl, 100];
[found: (MH)+, 589.2851; C35H41ClN2O4 requires MH, 589.2836].
3.10. (−)-1-[N-(1R,2S)-2-Phenylcyclohexyloxycarbonylamino]-2-cyclohexene 16
To anhydrous liquid ammonia (15 mL) cooled to −78°C, was added a solution of the azo-ene adduct 9
(100 mg, 0.19 mmol) in dry THF (5 mL). Freshly cut sodium metal (50 mg, 2.17 mmol) was added to the
solution and a permanent blue colour developed. The cold bath was removed and the reaction mixture
stirred at reflux (−33°C) for 1.5 h. The reaction was quenched by the addition of solid ammonium
chloride (228 mg, 4.26 mmol) and the ammonia was allowed to evaporate. The residue was dissolved
in water (5 mL) and extracted with ethyl acetate (3×50 mL). The organic extracts were dried over
anhydrous sodium sulfate and concentrated under reduced pressure to afford an oil that was purified
by flash chromatography using hexane:ethyl acetate (8:2) as eluent to afford the title compound (35 mg,
61%) as a colourless oil, [α]D −7.6 (c 0.37, CHCl3); νmax (thin film)/cm−1 3384 br (NH), 1699 s (C_O);
δH (400 MHz, CDCl3) 1.28–1.93 (12H, br m, H-40, H-50, H-60, H-300, H-400, H-500), 2.20 (2H, br m, H-
600), 2.62 (1H, br m, H-200), 3.99 (1H, br s, NH), 4.31 (1H, br m, H-10), 4.90 (1H, ddd, J1 ax,2 ax 10.7,
00
00
00ax,600ax
J1
10.7, J1 ax,6 eq 4.2, H-100), 5.53 (1H, br m, H-20), 5.76 (1H, br m, H-30), 7.21–7.28 (5H, m,
00 00
Ph); m/z (EI) 299 (M+, 33), 158 (M−C7H11NO2, 100), 91 (M−C12H18NO2, 77).
Acknowledgements
We thank the Australian Research Council small grants scheme for financial support.
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