Synthesis of functionalized 1-azabicyclo[3.1.0]hexanes: Studies towards ficellomycin and its analogs

Article abstract of DOI:10.3987/COM-13-S(S)100

The molecule of antibiotic agent ficellomycin contains an intriguing array of functional groups assembled around a bicyclic aziridine core. To address the challenges of constructing ficellomycin derivatives, we have developed cycloamination methodology fo

Full text of DOI:10.3987/COM-13-S(S)100

HETEROCYCLES, Vol. 88, No. 2, 2014
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HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1299 - 1310. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 29th July, 2013, Accepted, 9th September, 2013, Published online, 19th September, 2013
DOI: 10.3987/COM-13-S(S)100
SYNTHESIS OF FUNCTIONALIZED 1-AZABICYCLO[3.1.0]HEXANES:
STUDIES TOWARDS FICELLOMYCIN AND ITS ANALOGS
Gang Chen, Zhi He, and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of
Toronto, 80 St. George Street, Toronto, Ontario, Canada, M5S 3H6. Email:
ayudin@chem.utoronto.ca
Abstract – The molecule of antibiotic agent ficellomycin contains an intriguing
array of functional groups assembled around a bicyclic aziridine core. To address
the challenges of constructing ficellomycin derivatives, we have developed
cycloamination methodology for the stereocontrolled transformation of
unprotected aziridine-containing olefins. The present paper discusses application
of this process towards synthesis of ficellomycin.
INTRODUCTION
Ficellomycin was isolated from Streptomyces ficellus in 1976.1 Initial structural assignment (structure 1,
Figure 1) was established by NMR and chemical degradation studies.2 The dipeptide molecule was found
to possess a rare azabicyclo[3.1.0]hexane core, a structural motif present in only a few natural products.3
The relative stereochemistry of the ficellomycin core was later revised to 2 (Figure 1).4 The
cis-relationship between the guanidine substituent and the aziridine methylene group has been suggested
in this structural variant. In addition to this apparent ambiguity, the stereochemistry beside the acid group
has not been rigorously elucidated. The absolute stereochemistry of the ficellomycin core is not clear
either.3b To date, there has been no report on a total synthesis of this naturally occurring antibiotic.
Figure 1

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Ficellomycin displays in vivo antibiotic activity against S. aureus and P. oxalicum in mice. Biochemical
studies indicate that ficellomycin selectively impairs semiconservative DNA replication in E. coli.5
Although the exact mechanism of action of ficellomycin is presently unknown, covalent modification of
DNA has been established as the mode of action for other aziridine-containing natural products such as
azinomycins, mitomycins, and FR900482. The azinomycin B/DNA interaction is based on covalent
modification of the 3’-CGG-5’ sequence,6 whereas mitomycin C and FR900482 make covalent links with
the 5’-CG-3’ sequence.7 The specificity of these interactions can be substantially improved by
introducing skeletal modifications. For instance, FK317, a semisynthetic derivative of FR 900482, has
shown reduced side effects without diminished potency. A fairly high IC50 value of 0.5 mM for
ficellomycin suggests that synthetic modifications may result in more selective compounds and may help
elucidate the mechanism of action for this antibiotic. A previously reported synthetic approach to the
ficellomycin core by Shipman and co-workers was based on an intramolecular 1,4-addition of an
unprotected aziridine to a -amino ,β-unsaturated ester.8 A 1,4-addition-elimination methodology was
earlier employed in an elegant total synthesis of azinomycin by Coleman and co-workers.9 As part of a
program directed towards complex amines, we have been interested in stereocontrolled construction of
ficellomycin derivatives.10,11
RESULTS AND DISCUSSION
Previously, stereospecific ring-opening reactions of bicyclic aziridines were found to afford piperidine
and pyrrolidine heterocycles.11 We were hopeful that this methodology could be further developed to
address the ficellomycin core synthesis by one of two strategies (Figure 2). If the aziridine moiety on the
bromo- substituted cycloamination product 3 is opened with a nitrogen nucleophile, the resulting
bromoamine intermediate can undergo tandem cyclization to afford the ficellomycin core (Route A). If
the aziridine ring-opening reaction proceeds in an SN2 fashion, the stereocenter beside the acid group can
be controlled by using trans- or cis-aziridine starting materials. The diastereomeric products of
cycloamination can lead to either of the two proposed ficellomycin core structures. On the other hand,
direct cycloamination of the aziridine-containing olefin 4 can afford the ficellomycin core if the
cyclization is followed by a nucleophilic displacement of bromine (Route B). In order to simplify the
synthesis and structural analysis, a protected alcohol was used in place of the guanidine group.12 The acid
functionality was kept in the ester or protected alcohol form.

HETEROCYCLES, Vol. 88, No. 2, 2014
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Figure 2
At the outset, ethyl acetate was treated with lithium diisopropylamide and the resulting lithium enolate
was reacted with acrolein to afford the aldol addition product (Scheme 1).13 After protection of the
alcohol functionality, ester 5 was reduced to the aldehyde and in situ reacted with the commercially
available Horner-Wadsworth-Emmons reagent to afford diene 6.14 Epoxidation of 6 with m-CPBA gave
the undesired terminal epoxide. Therefore, 6 was reduced to the allylic alcohol 7 in which the terminal
hydroxyl functionality allowed for a regioselective epoxidation. The epoxide was regioselectively
installed into 7 to afford intermediate 8. The epoxy alcohol 8 was formed as a mixture of two
diastereomers which were then converted into the acid form and esterfied in a one-pot process to give
epoxy methyl ester 9 in 71% yield. The epoxide was converted to the desired aziridine using a Staudinger
reaction.15 The two-step transformation led to a diasteromeric mixture of 10a and 10b in 76% yield based
on recovered starting material.
Scheme 1

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In order to arrive at the intermediate 4 (Figure 2), the terminal hydroxyl group of 7 was protected as a
p-methoxybenzyl ether and the silyl ether was removed to generate 11. The terminal olefin was
stereoselectively epoxidized using Sharpless kinetic resolution.16 A single enantiomer of 12 was obtained.
After protection of the secondary alcohol and a two-step aziridination, the desired aziridine-containing
olefin 14 was prepared as a single enantiomer (Scheme 2). Overall, the desired aziridine-containing olefin
starting materials 10 (Scheme 1) and 14 (Scheme 2) were prepared via common intermediate 7.
Scheme 2
To construct the ficellomycin core according to route A, the aziridine-containing olefins 10a and 10b
were subjected to cycloamination in dichloromethane. We have found that the starting material was
converted to the N-Br species 15 in the first few minutes of the reaction (Figure 3). The intermediate 15 is
relatively stable and can be purified by column chromatography. We were delighted to isolate and
characterize the desired diastereomer 16 as the major product of cyclization of 15. The stereochemistry of
compound 16 was confirmed by analysis of the ROESY spectra. The other three diastereomeric products
were isolated as an inseparable mixture epi-16 (Scheme 3). About 10% of unreacted starting material 10
was recovered after reductive workup. Interestingly, this material was identified as pure 10b, which
appears to be the less reactive diastereomer. The selectivity of this reaction can be explained by
considering relative energies of the four diastereomeric transition states A-D. The transition state A, in
which all substituents occupy equatorial positions of the pseudo-chair, is the lowest in energy. The
isolated yield of 16 is acceptable, considering that only one half of the starting material with correct
stereochemistry can be converted to the desired product.
Figure 3

HETEROCYCLES, Vol. 88, No. 2, 2014
1303
H
H
+
Br
H
O
O
CO2Me
CO2Me TBDPS
TBDPS
TBDPS
+
N
O
O
N
CO2Me
CO2Me
-
-
B
CO2Me
Br
TBDPS
TBDPS
H
NH
OTBDPS
10a
N
H
A
NBS
H
15a
Br
DCM
TBDPS
H
H
O
H
O
NH
CO2Me
H
CO2Me
H
OTBDPS
N
CO2Me
N
N
-
10b
-
H
15b
Br
H
+
Br
Br
+
H
D
C
TBDPSO
TBDPSO
+
TBDPSO
TBDPSO
H
H
H
H
CO2Me
+
+
N
H
N
N
N
CO2Me
CO2Me
CO2Me
H
H
H
Br
Br
Br
Br
16 (30%)
epi-16 (55%)
nOe observed
TBDPSO
OTs
CO2Me
TsOHH2O
(71%)
H
H
H
N
CO2Me
H
17
TBDPSO
N
H
Br
H
Scheme 3
The bicyclic aziridine 16 was subjected to an acid-catalyzed aziridine ring-opening. Under a variety of
conditions, the reaction was complicated by decomposition of the aziridine, direct substitution of bromide,
and other side reactions. Treatment of 16 with TsOH afforded 17 via clean SN2 aziridine ring-opening
with the sulfonate anion followed by an intramolecular substitution of bromide. This regioselectivity was
not observed in the previous examples of bicyclic aziridine ring openings and constitutes an attractive
route to sterochemically complex piperidines. Efforts to optimize the reaction in order to selectively form
the desired five-membered ring product along the SN2 pathway are ongoing.
The other enantiomerically pure aziridine-containing olefin 14 was converted to the corresponding
azabicycle in 57% yield following route B (Scheme 4). The two epimers were found to be separable by
column chromatography. Analysis of the ROESY spectra of product 18 was used in order to elucidate the
relative stereochemistry. Subsequently, nucleophilic displacement of bromide afforded the compound 19.
In this approach, the choice of 2,3-anti or 2,3-syn substituted aziridine starting material determines which
of the two proposed core structures will be constructed. Due to the anti mode of attack during cyclization,
the stereocenter beside the acid group can be controlled by using trans- or cis-olefin in the linear starting
material. The compound 19 can be converted to the final structure that will complete the total synthesis
through a series of transformations—peptide coupling to a valine residue upon reduction of azide to

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HETEROCYCLES, Vol. 88, No. 2, 2014
amine, adjustment of the oxidation state of terminal carbon to acid, and installation of the guanidine
group.
H
H
H
PMB
O
H
Br
H
N
H
H
nOe observed
PMBO
PMBO
H
CH2OPMB
H
CH2OPMB
Br
HN
NBS, TFA
OPMB
+
N
N
Br
DCM
OPMB
18
epi-18
57% (d.r. = 3:2)
14
NaN3
DMF
87%
H
N
HN
H
CO2H
NH
PMBO
H
CH2OPMB
N3
H2N
N
O
2
N
NH2
Ficellomycin
19
Scheme 4
In conclusion, our work demonstrates that oxidative cycloamination of aziridine-containing olefins can be
applied to the synthesis of the ficellomycin core. Compared to previous studies, the relative
stereochemistry of all four stereocenters around the core structure can now be controlled via
stereospecific cycloamination methodology. By using different readily available diastereomeric starting
materials and nucleophiles, synthesis of ficellomycin along with its analogs and their ring-opened
derivatives should be facilitated.
EXPERIMENTAL
General: Anhydrous solvents such as ether, toluene, acetonitrile, and dichloromethane were prepared
using the method described by Grubbs.17 Tetrahydrofuran was distilled from sodium-benzophenone ketyl
under nitrogen. Unless otherwise stated, all reactions were performed under nitrogen or argon atmosphere
using flame-dried glassware. Commercially available reagents were purchased and used without any
further purification.
13
Nuclear magnetic resonance spectra: 1H and C NMR spectra were recorded on Varian Mercury-400
1
spectrometer. H NMR spectra were referenced to residual CHCl3 ( 7.26), 13C NMR spectra were
referenced to CDCl3 ( 77.23), Peak multiplicities are designated by the following abbreviations: s,
singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; dt, doublet

HETEROCYCLES, Vol. 88, No. 2, 2014
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of triplets; br, broad; and J, coupling constant in Hz.
Chromatography: Analytical thin layer chromatography (TLC) was performed on Macherey Nagel
pre-coated glass-backed TLC plates (SIL G/UV254, 0.25 mm) and visualized by UV lamp (254 nm),
potassium permanganate stain, or iodine stain. Solvent ratios for Rf values are reported as v/v. Column
chromatography was carried out using 230-400 mesh silica gel.
Preparation of ethyl 3-(tert-butyldiphenylsilyloxy)pent-4-enoate (5): To a flask containing ethyl
3-hydroxypent-4-enoate18 (4.0 g, 28 mmol) in MeCN (25 mL), was added imidazole (3.6 g, 53 mmol) to
form a clear yellow solution. To the reaction mixture, tert-butyldiphenylsilyl chloride (10 mL, 38 mmol)
was added slowly with ice bath cooling. The mixture was stirred overnight. White precipitate was formed
in the course of the reaction. The mixture was filtered and concentrated. The residue was extracted with
1
hexanes and purified on a short silica gel plug to afford 5 (9.1 g, 85%) as a yellow oil. H NMR (400
MHz, CDCl3) δ 7.67-7.70 (m, 4H), 7.38-7.43 (m, 6H), 5.80-5.90 (m, 1H), 4.96-5.00 (m, 2H), 4.59-4.62
13
(m, 1H), 4.03-4.06 (m, 2H), 2.43-2.62 (m, 2H), 1.20 (t, J = 6.8 Hz, 3H), 1.07 (s, 9H); C NMR: (100
MHz, CDCl3) δ170.9, 139.6, 136.2, 136.1, 134.0, 129.8, 129.7, 127.7, 127.6, 115.5, 72.0, 60.5, 43.6, 27.1,
19.5, 14.3.
Preparation of (E)-ethyl 5-(tert-butyldiphenylsilyloxy)hepta-2,6-dienoate (6): To a solution of ethyl
o
3-(tert-butyldiphenylsilyloxy)pent-4-enoate (5, 5.3g, 13.8 mmol) in anhydrous Et2O (50 mL) at -78 C
was added DIBAL-H solution in toluene (1.5 M, 11 mL, 16.5 mmol) dropwise. The reaction mixture was
stirred at -78 oC for 1.5 h. To a suspension of NaH (0.55 g, 60% in mineral oil, 13.8 mmol) in anhydrous
THF(120 mL)at 0 oC, was added ethyl 2-(diethoxyphosphoryl)acetate (3.0 mL, 15.2 mmol). The resulting
solution was added slowly to the above DIBAL-H reaction maintained at -78 oC. The reaction was stirred
and allowed to reach room temperature overnight. The reaction was concentrated, extracted with pentane,
washed with brine, dried over MgSO4, concentrated again and purified on silica gel to afford 6 (5.2 g,
1
yield 89%). H NMR (400 MHz, CDCl3) δ 7.63-7.68 (m, 4H), 7.35-7.42 (m, 6H), 6.80-6.88 (m, 1H),
5.70-5.85 (m, 2H), 4.98-5.06 (m, 2H), 4.28-4.31 (m, 1H), 4.15 (q, J = 7.2, 2H), 2.30-2.32 (m, 2H), 1.26 (t,
J = 7.2 Hz, 3H), 1.07 (s, 9H); 13C NMR: (100 MHz, CDCl3) δ 166.5, 144.8, 139.8, 136.1 (2), 135.0, 134.2,
133.9, 130.0, 129.8, 127.8, 127.7, 123.9, 115.4, 73.5, 60.3, 40.8, 27.2, 19.5, 14.4.
Preparation of (E)-5-(tert-butyldiphenylsilyloxy)hepta-2,6-dien-1-ol (7): To a solution of (E)-ethyl
5-(tert-butyldiphenylsilyloxy)hepta-2,6-dienoate (6, 4.0 g, 10 mmol) in DCM (50 mL), was slowly added
diisobutylaluminium hydride solution (1.0 M in hexanes, 20 mL) at -78 oC over 30 min. The reaction was
stirred overnight and quenched by slow addition of tartaric acid solution (1.0 M in water, 15 mL). The
mixture was stirred for 30 min at room temperature until solid has formed on the bottom of flask. The
solution was filtered and concentrated. The residue was purified on a short silica gel plug to afford 7 as a
1
colorless oil (3.3 g, yield 90%) H NMR (400 MHz, CDCl3) δ 7.63-7.70 (m, 4H), 7.35-7.39 (m, 6H),

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HETEROCYCLES, Vol. 88, No. 2, 2014
5.78-5.82 (m, 1H), 5.12 (m, 2H), 4.98-5.03 (m, 2H), 4.19-4.21 (m, 1H), 4.95-4.99 (m, 2H), 2.18-2.21 (m,
13
2H), 1.06 (s, 9H); C NMR: (100 MHz, CDCl3) δ 140.5, 136.2 (2), 134.6, 134.3, 131.8, 129.9, 129.8,
128.7, 127.7, 127.6 , 114.7, 74.3, 63.9, 40.9, 27.2, 19.6.
Preparation of ((2S*,3S*)-3-(2-(tert-butyldiphenylsilyloxy)but-3-enyl)oxiran-2-yl) methanol (8): To a
solution of 7 (2.0 g, 5.5 mmol) and VO(acac)2 (160 mg, 10 mol %) in DCM (80 mL) at 0 oC, was added
tert-butyl hydroperoxide solution in decane (1.14 mL, 6.0 mmol). The reaction was allowed to reach
room temperature and was stirred overnight. After completion of the reaction, sodium sulfite (5.0 g) was
added. The mixture was filtered. The filtrate was concentrated and purified on silica gel to afford 8 as a
1
mixture of two diastereomers (1.9 g, yield 90%). H NMR (400 MHz, CDCl3) δ 7.62-7.68 (m, 4H),
7.35-7.38 (m, 6H), 5.58-5.95 (m, 1H), 4.95-5.10 (m, 2H), 4.31-4.42 (m, 1H), 3.25-3.36 (m, 1H),
13
3.47-3.57 (m, 1H), 2.95-2.98 (m, 1H), 2.74-2.80 (m, 2H), 1.58-1.82 (m, 3H), 1.08 (s, 9H); C NMR:
(100 MHz, CDCl3) δ (140.4, 140.1), (136.2,136.0), (134.0, 133.9), (130.0, 129.9), (127.8, 127.7), (115.3,
115.0), (72.7, 72.6), (61.8, 61.7), (58.9, 58.7), (52.9, 25.7), (40.2, 39.9), 27.2, (19.6, 19.5).
Preparation of (2R,3S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)but-3-enyl)oxirane-2-carboxylate (9):
o
To a solution of oxalyl chloride (182.7 µL, 2.1 mmol) in anhydrous DCM (6 mL) at -78 C was added
DMSO (297 µL, 4.2 mmol). The reaction was stirred for 5 min, ((2S*,3S*)-3-(2-(tert-
butyldiphenylsilyloxy)but-3-enyl)oxiran-2-yl) methanol (8, 680 mg, 1.78 mmol in 6 mL of DCM) was
o
added dropwise at -78 C followed by addition of triethylamine (1.79 mL, 13 mmol) after 15 min. The
reaction was allowed to reach room temperature and water (10 mL) was added. The aqueous layer was
extracted. The combined organic layer was washed with brine, dried, and concentrated to yield the crude
intermediate aldehyde. To the aldehyde intermediate (500 mg, 1.31 mmol) in t-BuOH (10 mL) were
added cyclohexene (689 mg, 8.4 mmol) and aqueous solution of NaH2PO4 (216 mg, 1.8 mmol) and
NaClO2 (163 mg, 1.8 mmol) in 5 mL water. The reaction was stirred overnight at room temperature. The
reaction was diluted with brine (50 mL), extracted with hexanes and EtOAc (1:1), the aqueous layer was
acidified to pH 2, and extracted one more time. The combined organic layer was concentrated, and
dissolved in DCM / MeOH (4:1, 10 mL). To the solution was added TMSCHN2 (2.0 M in hexanes, 1.0
mL 2.0 mmol). The reaction was quenched by addition of AcOH (0.5 mL), washed with NaHCO3
solution and concentrated. The residue was purified on silica gel to afford 9 (490 mg, yield 67%) as a
1
mixture of two diastereomers. H NMR (400 MHz, CDCl3) δ 7.64-7.69 (m, 4H), 7.36-7.42 (m, 6H),
5.76-5.90 (m, 1H), 4.98-5.10 (m, 2H), 4.17-4.20 (m, 1H), 3.75 (s, 3H), 3.07-3.22 (m, 2H), 1.62-1.81 (m,
13
2H), 1.07 (s, 9H); C NMR: (100 MHz, CDCl3) δ 169.7, (139.7, 139.4), (136.1, 136.0), (134.0, 133.8),
(130.0, 129.9), (127.9, 127.7), (115.8, 115.6), (72.4, 72.3), (55.5, 55.3), (53.3, 53.2), 52.6 (2C), (39.9,
39.7), 27.2, (19.5, 19.4).
Preparation of (2S*,3R*)-methyl 3-(2-(tert-butyldiphenylsilyloxy)but-3-enyl)aziridine-2-carboxylate

HETEROCYCLES, Vol. 88, No. 2, 2014
1307
(10): To a solution of (2R*,3S*)-methyl 3-(2-(tert-butyldiphenylsilyloxy)but-3-enyl)oxirane-2-
carboxylate (9, 450 mg, 1.1 mmol) in MeOH (15 mL) were added NaN3 (715 mg, 11 mmol) and NH4Cl
(594 mg, 11 mmol). The mixture was stirred at room temperature for 60 h. TLC indicated approximate
50% conversion to product. The mixture was filtered and concentrated under reduced pressure. The
residue was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 and
concentrated. The crude mixture was dissolved in MeCN (15 mL) followed by slow addition of
triphenylphosphine (222 mg, 0.8 mmol). The reaction was heated at 90 oC for 1 h until all azido-alcohol
was consumed. The reaction was concentrated and purified on a silica gel column to afford 10 (185 mg,
yield 41%) and recovered starting material (210 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 7.63-7.70 (m,
4H), 7.35-7.46 (m, 6H), 5.78-5.89 (m, 1H), 4.97-5.07 (m, 2H), 4.38-4.40 (m, 1H), 3.72 (s, 3H), 2.05-2.30
(m, 2H), 1.45-1.78 (m, 2H), 0.95-1.22 (m, 1H), 1.07 (s, 9H); 13C NMR: (100 MHz, CDCl3) δ 173.2,
(140.5, 140.0), (136.2, 136.1), 134.3, (129.9, 129.8), (127.8, 127.7), (115.3, 115.0), (73.3, 73.2), 52.6,
(41.3, 40.8), (36.4, 36.1), (35.7, 35.4), 27.2 (2), (19.6, 19.5). HR-MS (EI) m/z: calcd. for C24H31NO3Si
(M+) 409.2073, obsd 352.1362 (loss of t-butyl group).
Preparation
of
(E)-7-(4-methoxybenzyloxy)hepta-1,5-dien-3-ol
(11):
A
solution
of
(E)-5-(tert-butyldiphenylsilyloxy)hepta-2,6-dien-1-ol (7, 18.3 g, 50 mmol) in THF (70 mL) was added to
o
suspension of NaH (3.0 g, 60% in mineral oil, 75 mmol) in THF (125 mL) under nitrogen at 0 C. The
reaction was stirred for 30 min followed by a slow addition of 4-methoxybenzyl chloride (9.4 g, 60
mmol) in THF (50 mL). n-Bu4NI (1.85 g, 5 mmol) was added to the stirred mixture. The reaction was
allowed to reach room temperature and stirred for 48 h until all of the starting material 7 was consumed.
The reaction was concentrated, diluted with EtOAc (500 mL), and washed with brine (300 mL). The
combined organic layers were dried over MgSO4, concentrated and purified on a short silica gel plug to
give a yellow oil, which was redissolved in THF (250 mL). Tetrabutylammonium fluoride (TBAF, 1.0 M
solution in THF, 60 mL, 60 mmol) was added to the solution dropwise. The reaction mixture was stirred
overnight and concentrated. The residue was purified on a silica gel column to afford 11 as colorless oil
1
(11.1 g, yield 90% in two steps) H NMR (400 MHz, CDCl3) δ 7.27-7.25 (m, 2H), 6.88-6.86 (m, 2H),
5.92-5.84 (m, 1H), 5.72-5.70 (m, 2H), 5.27-5.23 (m, 1H), 5.14-5.11 (m, 1H), 4.43 (s, 2H), 4.16 (dd, J =
13
12.5 Hz, J = 7.0 Hz, 1H), 3.97-3.96 (m, 2H), 3.80 (s, 3H), 2.34-2.30 (m, 2H), 1.84 (br, 1H); C NMR:
(100 MHz, CDCl3) δ 159.4, 140.5, 130.5, 130.4, 129.6, 115.0, 114.0, 72.2, 71.9, 70.5, 55.5, 40.4.
Preparation of (S,E)-5-(4-methoxybenzyloxy)-1-((R)-oxiran-2-yl)pent-3-en-1-ol (12):16 A flask
o
charged with molecular sieves (4Å, powder, 3.5 g) was stirred and heated at 160 C under vacuum
o
overnight. To the activated molecular sieves, was added DCM (150 mL) and cooled to -20 C,
L-(+)-diisopropyl tartrate (1.18 mL, 5.6 mmol), titanium (IV) isopropoxide (1.10 mL, 3.76 mmol) and
tert-butyl hydroperoxide (4.8 mL, 5.5 M solution in decane, 26.4 mmol) were added under nitrogen. The

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HETEROCYCLES, Vol. 88, No. 2, 2014
o
resulting mixture was stirred at -20 C for 30 min. (E)-7-(4-Methoxybenzyloxy)hepta-1,5-dien-3-ol (11,
10.7 g, 43 mmol) was then added slowly to the mixture with the temperature maintained between -20 and
-15 oC. The reaction was moved to a freezer (-20 oC) and stirred for 3 days. The reaction was poured into
a mixture of FeSO4/tartaric acid solution (50 mL) in an ice bath. The mixture was stirred for 10 min. The
organic layer was separated and aqueous layer was extracted with Et2O (500 mL). The combined organic
o
layer was stirred with aqueous solution of NaOH (0.9g) and NaCl (0.2g) in 3 mL water at 0 C for 1 h,
then washed with water, dried over MgSO4, and concentrated. The residue was purified on a silica gel
column to afford the unreacted enantiomer (5.5 g) and 12 (5.1 g, yield 45%) 1H NMR (400 MHz, CDCl3)
δ 7.27-7.25 (m, 2H), 6.89-6.86 (m, 2H), 5.76-5.74 (m, 2H), 4.44 (s, 2H), 3.97 (d, J = 4.8 Hz, 2H), 3.81 (m,
13
1H), 3.80 (s, 3H), 3.02 (m, 1H), 2.79 (m, 1H), 2.74(m, 1H); 2.42-2.32 (m, 2H), 1.96 (s, 1H); C NMR:
(100 MHz, CDCl3) δ 159.4, 130.6, 130.4, 129.8, 128.9, 114.0, 72.1, 70.4, 68.6, 55.6, 54.3, 44.0, 36.9.
Preparation of (R)-2-((S,E)-1,5-bis(4-methoxybenzyloxy)pent-3-enyl)oxirane (13): 13 was prepared
1
according to the same procedure as preparation of 11 using 12 as the starting material (yield 85%). H
NMR (400 MHz, CDCl3) δ 7.26-7.22 (m, 4H), 6.88-6.83 (m, 4H), 5.78-5.59 (m, 2H), 4.56 (d, J = 11.2 Hz,
1H), 4.45 (d, J = 11.2 Hz, 1H), 4.42 (s, 2H), 3.96 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.31-3.29 (m, 1H),
2.97-2.95 (m, 1H), 2.77 (dd, J = 5.2 Hz, J = 4.0 Hz, 1H), 2.70 (dd, J = 2.6 Hz, J = 5.2 Hz, 1H), 2.44-2.37
(m, 2H);13C NMR: (100 MHz, CDCl3) δ 159.4, 159.3, 130.6, 130.6, 130.5, 130.0, 129.6, 129.5, 129.4,
113.9, 77.6, 72.0, 71.7, 70.6, 55.4, 53.3, 45.9, 35.9.
Preparation of (S)-2-((S,E)-1,5-bis(4-methoxybenzyloxy)pent-3-enyl)aziridine (14): 14 was prepared
according to the same procedure of preparation of 10 using 13 as the starting material (yield 50%, in two
steps). 1H NMR (400 MHz, CDCl3) δ 7.28-7.24 (m, 4H), 6.88-6.84 (m, 4H), 5.82-5.63 (m, 2H), 4.68 (d, J
= 11.2 Hz, 1H), 4.56 (d, J = 11.2 Hz, 1H), 4.42 (s, 2H), 3.95 (dd, J = 6.0 Hz, J = 0.8 Hz, 2H), 3.80 (s,
3H), 3.78 (s, 3H), 3.05 (m, 1H), 2.42-2.39 (m, 2H), 2.10-2.04 (m, 1H), 1.73-1.74 (m, 1H), 1.39 (s, 1H);
13C NMR: (100 MHz, CDCl3) δ 159.3 (2), 130.7, 130.1, 129.5, 129.4, 129.3, 113.9, 80.6, 71.8, 71.4, 70.6,
55.4, 36.9, 33.4, 21.6.
Preparation of (2S*,3S*,5R*,6S*)-methyl 2-(bromomethyl)-3-(tert-butyldiphenylsilyloxy)-1-aza-
bicyclo[3.1.0]hexane-6-carboxylate (16): To a solution of 10 (122 mg, 0.3 mmol) in anhydrous DCM
(50 mL) was added NBS (59 mg, 0.32 mmol). TLC indicated that the starting material 10 disappeared
o
within 2 min to form the N-Br species. The mixture was heated at 40 C for 48 h in the presence of 4Å
molecular sieves. The reaction mixture was filtered, washed with Na2SO3 aqueous solution, and dried.
The extract was concentrated and purified on a silica gel column to afford recovered starting material (13
mg), and a mixture of 16-epi (71 mg, 55% bsm, Rf 0.42 in 3:7 EtOAc/hexane) and the single diastereomer
16 (40 mg, 30% bsm, Rf 0.30 in 3:7 EtOAc/hexane). 16: 1H NMR (400 MHz, CDCl3) δ 7.62-7.68 (m, 4H),
7.40-7.44 (m, 6H), 4.33 (t, J = 4.8 Hz, 1H), 3.75 (s, 3H) 3.62-3.65 (m, 1H), 3.55 (d, J = 4.8 Hz, 2H) 3.14

HETEROCYCLES, Vol. 88, No. 2, 2014
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13
(d, J = 2.4 Hz, 1H), 2.7-2.75 (m, 1H), 2.20 (d, J = 15.2 Hz, 1H), 2.02 (m, 1H), 1.10 (s, 9H); C NMR:
(100 MHz, CDCl3) δ 170.9, 136.3, 136.2, 133.7, 132.2, 130.4, 130.2, 128.0, (2) 72.5, 71.2, 52.5, 45.8,
36.7, 27.9, 27.3, 19.4. HR-MS (ESI) m/z: calcd. for C24H31BrNO3Si [(M+H)+] 488.1251, obsd 488.1259.
Preparation of (2R*,3R*,5S*,6R*)-methyl 5-(tert-butyldiphenylsilyloxy)-3-(tosyloxy)-1-azabicyclo-
[4.1.0]heptane-2-carboxylate (17): To a solution of 16 (55 mg, 0.11 mmol) in DCM (2 mL), was added
p-toluenesulfonic acid monohydrate (26.6 mg, 0.14 mmol). The mixture was stirred at room temperature
for 16 h. The reaction mixture was concentrated and purified on a silica gel column to afford 17 (40 mg,
1
yield 61%) H NMR (400 MHz, CDCl3) δ 7.68-7.67 (m, 2H), 7.58-7.57 (m, 4H), 7.47-7.45 (m, 2H),
7.40-7.37 (m, 4H), 7.28-7.27 (m, 2H), 4.42-4.38 (m, 1H), 3.91-3.89 (m, 1H), 3.77-3.52 (m, 3H), 3.60 (s,
3H), 3.02-2.99 (m, 1H), 2.42 (s, 3H), 1.98-1.95 (m, 1H), 1.79-1.76 (m, 1H). 13C NMR: (100 MHz,
CDCl3) δ 170.3, 145.0, 135.9, 135.8, .133.9, 133.2, 132.9, 130.4, 130.3, 130.0, 128.2, 128.1, 128.0, 68.3,
57.5, 56.1, 52.8, 35.4, 31.8, 31.0, 27.1, 21.9, 19.4.
Preparation of (2S,4S,5S)-2-((S)-1-bromo-2-(4-methoxybenzyloxy)ethyl)-4-(4-methoxybenzyloxy)-1-
azabicyclo[3.1.0]hexane (18). To a mixture of 14 (200 mg, 0.52 mmol) in anhydrous DCM (150 mL) at
ice bath temperature, was added NBS (112 mg, 0.63 mmol). The mixture was stirred for 1 h at ice bath
temperature. TLC indicated all of the starting material was converted to the N-Br intermediate. To the
reaction mixture was added trifluoroacetic acid (24 µL, 0.313 mmol). The mixture was stirred
continuously at ice bath temperature for 8 h until most of the N-Br intermediate was consumed.
Triethylamine (30 µL, 0.22 mmol) was added. The reaction mixture was concentrated and purified on a
silica gel column to afford 18 (90 mg, the other diastereomeric product 62 mg, combined yield 57%). 1H
NMR (400 MHz, CDCl3) δ 7.31-7.27 (m, 4H), 6.90-6.87 (m, 4H), 4.57-4.40 (m, 4H), 4.09-3.99 (m, 2H),
3.81 (s, 3H), 3.80 (s, 3H), 3.80 (m, 1H), 3.62-3.59 (m, 1H), 2.60-2.59 (m, 1H), 2.22-2.18 (m, 1H),
1.86-1.85 (m, 1H), 1.54-1.42 (m, 2H), 13C NMR: (100 MHz, CDCl3) δ 159.6, 159.5, 130.2, 130.1, 129.7,
129.6, 114.1, 114.0, 78.1, 73.2, 72.5, 63.3, 55.5 (2C), 54.6, 41.3, 31.3, 22.0 HR-MS (ESI) m/z: calcd. for
C23H29BrNO4 462.1274, obsd 462.1282.
Preparation of (2S,4S,5S)-2-((R)-1-azido-2-(4-methoxybenzyloxy)ethyl)-4-(4-methoxybenzyloxy)-1-
azabicyclo[3.1.0]hexane (19): To a solution of 18 (25 mg, 0.054 mmol) in DMF (1 mL) was added NaN3
(35 mg, 0.54 mmol). The mixture was stirred at room temperature for 48 h. The reaction mixture was
diluted with brine (3 mL) and EtOAc (5 mL). The organic layer was separated, dried over MgSO4 and
concentrated. The resulting residue was purified on a silica gel column to afford 19 (20 mg, yield 88%).
1H NMR (400 MHz, CDCl3) δ 7.27-7.26 (m, 4H), 6.89-6.87 (m, 4H), 4.68-4.61 (m, 1H), 4.52-4.42 (m,
4H), 4.25-4.21 (m, 1H) 3.80 (s, 3H), 3.72 (s, 3H), 3.70-3.66 (m, 2H), 3.58-3.52 (m, 1H), 2.60-2.58 (m,
13
1H), 2.15-2.10 (m, 1H), 1.82 (d, J = 5.2 Hz, 1H), 1.72-1.67 (m, 2H) C NMR: (100 MHz, CDCl3) δ
159.6 (2), 130.5, 130.0, 129.6 (2), 114.1(2), 79.6, 73.1, 72.4, 71.7, 57.9, 55.5 (2), 42.7, 31.6, 28.3.

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HETEROCYCLES, Vol. 88, No. 2, 2014
HR-MS (ESI) m/z: calcd. for C23H29N4O4 425.2183, obsd 465.2180.
ACKNOWLEDGEMENTS
We thank NSERC, Canada Foundation for Innovation, ORDCF, and the University of Toronto for
financial support.
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