Introduction of C(5/6) side chains onto 2-azabicyclo[2.1.1]hexanes via a 6-anti -bromo-5-anti-hydroxy derivative

Article abstract of DOI:10.1139/v11-112

Oxidation of the title bromoalcohol provided the strained ketone, 5-bromo-6-oxo-2-azabicyclo[2.1.1]hexane. Additions of nucleophiles to either this or the debrominated ketone have been used to introduce 5(6)-syn-alkyl and aryl groups, 5(6)-alkylidene link

Full text of DOI:10.1139/v11-112

121
Introduction of C(5/6) side chains onto 2-
azabicyclo[2.1.1]hexanes via a 6-anti-bromo-5-
anti-hydroxy derivative
Grant R. Krow, Fang Yu, Matthew Sender, Deepa Gandla, Guoliang Lin,
Charles DeBrosse, and Charles W. Ross III
Abstract: Oxidation of the title bromoalcohol provided the strained ketone, 5-bromo-6-oxo-2-azabicyclo[2.1.1]hexane. Addi-
tions of nucleophiles to either this or the debrominated ketone have been used to introduce 5(6)-syn-alkyl and aryl groups,
5(6)-alkylidene linkages, and 5(6)-anti-alkyl and acyl substituents. Facial selectivity is for additions to the 6-bromo-5-ketone
and 5-alkylidene azabicycles to occur from the face syn to the nitrogen atom. The bromine atom of the title alcohol has also
been replaced by a 6-anti-(1-hydroxyethyl) substituent using a directed radical addition process. The stereoselective function-
alization reactions expand the range of available methano-bridged pyrrolidines.
Key words: methanopyrrolidine, 6-oxo-2-azabicyclo[2.1.1]hexane, directed radical addition, facial selectivity and nucleo-
philic addition, strained ketone.
Résumé : L’oxydation du bromoalcool mentionné dans le titre conduit à une cétone tendue, le 5-bromo-6-oxo-2-azabicyclo
[2.1.1]hexane. L’addition de nucléophiles aussi bien à ce produit qu’à la cétone débromée a été utilisée pour introduire des
groupes 5(6)-syn-alkyles ou aryles, des liaisons 5(6)-alkylidènes et des substituants 5(6)-anti-alkyles ou acyles. La sélectivité
faciale conduit à des additions sur les azabicycles avec des substituants 6-bromo et 5-cétone ou une chaîne 5-alkylidène qui
se produisent par la face syn par rapport à l’atome d’azote. On a aussi remplacé l’atome de brome de l’alcool mentionné
dans le titre par un substituant 6-anti-(1-hydroxyéthyle) en faisant appel à un processus d’addition radicalaire orienté. Les
réactions de fonctionnalisations sélectives étendent la plage de pyrrolidines à pont méthano disponibles.
Mots‐clés : méthanopyrrolidine, 6-oxo-2-azabicyclo[2.1.1]hexane, addition radicalaire orientée, sélectivité faciale, addition
nucléophile, cétone tendue.
[Traduit par la Rédaction]
Introduction
Pyrrolidines 1 substituted with alkyl,1,2 aryl,3 or acyl4 sub-
stituents at the 3-position, b to the nitrogen, are found in a
number of molecules with interesting biological or structural
properties. A 5-substituted 2-azabicyclo[2.1.1]hexane ring
system (2) is a mimic of a pyrrolidine that has been con-
strained to exist in a single conformation in which a 2,4-
2-Azabicyclo[2.1.1]hexanes 2 with alkyl, acyl, or aryl side
chains attached at C5(6) are known, but effective syntheses for
5(6)-syn orientation of these groups predominate. Examples
where only the C5 bridge and the nitrogen atom have sub-
stituents are shown as follows.7 The synthetic approaches to
introduce alkyl groups include skeletal rearrangement (R =
6-syn-methyl, with heteroatoms in the other methylene
bridge);8 ring closure and subsequent manipulation (R = 5-
syn-CH2OH 3a and R = 6-syn-CH2NH2, with a heteroatom
in the 5-bridge).9 There are photochemical cycloaddition
b
methylene bridge forces the substituted C atom to be puck-
ered out of the plane described by the other four atoms of its
pyrrolidine ring. As part of a strategy to incorporate key
pharmacophoric units into inflexible structures,5 practical
methods to introduce substituents in defined spatial orienta-
tions at one or both positions C5(6) of azabicycles such as 2
are of interest. Such molecules may prove to be valuable
scaffolds for drug discovery and for incorporation into novel
b-amino acids.6
Received 11 March 2011. Accepted 10 July 2011. Published at www.nrcresearchpress.com/cjc on 16 November 2011.
G.R. Krow, F. Yu, M. Sender, D. Gandla, G. Lin, and C. DeBrosse. Department of Chemistry, Temple University, Philadelphia, PA
19122, USA.
C.W. Ross III. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486-004, USA.
Corresponding author: Grant R. Krow (e-mail: Grkrow@temple.edu).
This article is part of a Special Issue dedicated to Professor Tak-Hang Chan.
Can. J. Chem. 90: 121–130 (2012)
doi:10.1139/V11-112
Published by NRC Research Press

122
Can. J. Chem. Vol. 90, 2012
routes that introduce R/H = Me2, along with a 1-aryl
group;10 R = C(OR)3 or CH2SiMe3 along with acyl in the
other methylene bridge;11,12 and R = syn- or anti-oriented cy-
clohexane rings fused from C5 to C4 or cyclohexanone rings
fused from C5 to C1.13 Recently, alkylester 4b, accompanied
by some extended chain addition products, was prepared by
methyl acrylate addition to radicals generated at C5 from ei-
ther a 5-syn-acid (5b) or 5-iodo-2-azabicyclo[2.1.1]hexane.14
Phenyl substitution (R = 6-syn-Ph along with a 5-anti-hetero-
atom) was effected via a rearrangement route,8 and also a 6:1
syn/anti-Ph mixture of 6b and 7 were synthesized using a
lead tetraacetate-initiated decarboxylative radical arylation of
acid 5b.14 For 5-syn/anti-carbonyl substitution several photo-
chemical syntheses introduced a 5-acetyl group11,12,15 or 1,5-
fused cyclohexanone ring systems.16 Three routes to 5-carboxy
azabicycles have been described. One somewhat lengthy
route to the R = 5-syn-acid 5a involves ring closure and
subsequent modification of substituents.9 A 6-acetyl-5-ester,
of undefined stereochemistry, has been prepared from an
azabicycle with an R = 5-syn-orthoester and a 6-syn-acetyl
substituent using a photochemical ring closure sequence
and subsequent synthetic modification of the orthoester.11
We have described17 a shorter approach to the preparation of
R = 5-syn-5b and 5-anti-carboxy-2-azabicyclo[2.1.1]hexane
(8b), useful for multigram quantities of the 5-syn-acid 5b,
from readily prepared and separable (9:1) 5-syn/anti-acetyl-2-
azabicyclo[2.1.1]hexanes 9b/10 first described by Kwak and
Winkler.15 There remains a need for stereoselective syn-
thetic routes that introduce 5-anti-alkyl and 5-anti-carboxy
substituents onto 2-azabicyclo[2.1.1]hexanes.
of substituents at the C5 position, although the stereochemis-
try of the addition to the ketone is an issue.5a The corre-
sponding carbocycle (bicyclo[2.1.1]hexan-5-one 13) has been
synthesized18 in an optimized 54% yield by alcohol oxida-
tion,18c but only two nucleophilic addition reactions have
been reported. Reduction of 13 gives and 82:18 exo/endo
mixture of alcohols 14/15 in which the major product derives
from hydride attack on the side of the ethylene bridge.18a,18b
The only carbon nucleophile reported for reaction with ke-
tone 13 was diethyl(diazomethyl)phosphonate; the transient
alkylidene carbene 16 from this reaction does not retain evi-
dence for the initial facial selectivity of nucleophilic attack.19
In this paper we show how a readily available pyridine-
derived alcohol 17 can be oxidized to ketone 18, and how
subsequent carbonyl addition reactions provide solutions to
the stereochemical problems outlined previously.20 Stereo-
controlled syntheses of tertiary alcohols with 5-syn-alkyl or
5-syn-aryl substituents, 5-anti-alkyl and 5-anti-carboxy com-
pounds, as well as 5-exo-alkylidenes will be described. Ad-
ditionally, we show how the bromoalcohol 17 can be used
to incorporate a 6-anti-alkyl group onto the 2-azabicyclo
[2.1.1]hexane skeleton to give diol 19 using a radical trap-
ping process. Since 5(6)-substituents in these azabicycles
are often compatible with subsequent introduction of sub-
stituents at the C1 and C3 positions, the functional group
modifications described herein should prove useful in the
preparation of more highly functionalized 5-substituted 2-
azabicyclo[2.1.1]hexanes.21
A second synthetic challenge is the preparation of 2-azabi-
cyclo[2.1.1]hexanes with functional groups and substituents
on the same methylene bridge. There are two examples of
such structures. These are the 6-syn-fluoro-6-anti-methyl-5-
anti-alcohol 11 and the 6-syn-hydroxy-6-anti-methyl-5-anti-
alcohol 12.8 There are no similar structures reported with the
reversed stereochemistry at the tertiary carbon.
Z
Z
N
N
R
a Z = Cbz
b Z = BOC
R
3 R = CH2OH
7 R = Ph
4 R = CH2CH2CO2Me
5 R = COOH
6 R = Ph
8 R = COOH
10 R = COCH3
9 R = COCH3
Results and discussion
OH
X
Hydrolysis of the bromoacetate 20, prepared in three steps
from pyridine,20 afforded bromoalcohol 17 (90%), which was
oxidized using Swern conditions (oxalyl chloride / DMSO /
CH2Cl2 / Et3N) to give the bromoketone 18 in 90% yield.22
The ketone showed an IR carbonyl band at 1818 cm–1. De-
bromination of bromoalcohol 17 using tributyltin hydride23
gave alcohol 21 that was also oxidized to ketone 22 using
the Swern procedure. The ketone 22 has an IR carbonyl
stretch band at 1809 cm–1. The parent carbocycle 13 has its
carbonyl band at 1799 cm–1.18a
Cbz
N
Me
11 X = F
12 X = OH
A disconnection of tertiary alcohol 12 suggested that an
azabicyclic ketone might be a useful synthon for introduction
Published by NRC Research Press

Krow et al.
123
X
X
As part of an effort to prepare b-amino acids based on
conformationally constrained pyrrolidines,6 we desired a ster-
eocontrolled synthetic route to the 5-anti-carboxylic acid 8b.
Toward this end, we attempted, unsuccessfully, to prepare 5-
exo-methylene derivative 30 by dehydration of alcohol 24 us-
ing POCl3/pyridine. Successful preparation of 5-anti-bromo-
6-exo-methylene derivative 31 was achieved by reacting bro-
moketone 18 with the Tebbe reagent (48 h).27 The Wittig re-
action of bromoketone 18 with triphenylphosphonium
methylide was unsuccessful as a route to 6-exo-methylene 31.
17 or 21
(COCl)2/DMSO
Cbz
Cbz
N
N
Y
CH2Cl2/Et3N
O
18 X = Br (90%)
22 X = H (84%)
20 X = Br, Y = OAc
17 X = Br, Y = OH
21 X = H, Y = OH
Et3N/
MeOH
(90%)
Bu3SnH/
AIBN
(54%)
18 + MeLi
66%
½1ꢀ
H6syn
Cbz
X
24 +
BAST/CH2Cl2
Cbz
N
N
F
OH
Me
(89%)
Me
H3
Bu3SnH/
AIBN
(96%)
X
25
Br
23 X = Br
24 X = H
POCl3
0%
Tebbe
43%
CH2
Cbz
Cbz
Cbz
N
N
OH
Me
N
½3ꢀ
O
24
30 X = H
31 X = Br
18
Addition of MeLi to ketone 18 afforded a single adduct 23
that was shown to have 6-syn-Me stereochemistry by NOE
interaction of the methyl and an H3 proton. Reductive re-
moval of the bromine of 23 using tributyltin hydride23 gave
the alcohol 24. Notably, the 5-syn-methyl and 5-anti-hydroxyl
groups in 23 and 24 have complementary (inverted) stereo-
chemistry relative to the tertiary alcohol 12 formed by a re-
arrangement pathway. The alcohol 24 was converted to the
fluoride 25 by reaction with bis(2-methoxylethyl)aminosul-
fur trifluoride (BAST).24 The absence of W-coupling
between the 5-anti-fluorine atom and H6syn enabled a ster-
eochemical assignment for fluoride 25 that is consistent
with precedent for retention of stereochemistry for an anti-
alcohol displacement in this azabicyclic ring system.25
Addition of phenylmagnesium bromide or 2-chloro-pyridyl-
5-lithium26 to bromoketone 18 provided the arylalcohols 26
or 27, respectively. The stereochemical assignment for both
26 and 27 were shown to be 6-syn-aryl by NOE interaction
between H2 of the respective aryl and pyridyl rings and H3.
The bromine atoms of 26 and 27 were reductively removed
to give alcohols 28 and 29; in the latter case with retention
of the pyridyl chlorine atom. The syn relationship of the ni-
trogen atom in the attached chloropyridyl group at C6 and
the b-amino group embedded in the bicyclic ring is found
also in epibatidine.5a
Alkene 31 was best converted to bromoalcohol 32 (94%)
with 9-BBN at room temperature for 7 h, followed by basic
hydrogen peroxide.28 The 5-anti-6-anti- stereochemistry for
32 was shown by a W-plan coupling (J = 7.2 Hz) between
H5syn and H6syn. Debromination of 32 with tris(trimethylsilyl)
silane (TTMSS) gave alcohol 33 (69%)29; subsequent oxida-
tion with NaOCl/TEMPO afforded the desired 5-anti-acid
8a.30
H5syn
Br
Br
Cbz
N
Cbz
CH2OH
H6syn
32
(1) 9-BBN
N
(2) NaOH,
HOOH
(94%)
CH2
31
TTMSS,
½4ꢀ
AIBN
(69%)
NaOCl
Cbz
Cbz
TEMPO
(63%)
N
CH2OH
N
COOH
H
H
Br
Br
8a
33
A. PhMgBr or
Cbz
Cbz
N
N
OH
B. 2-Cl-pyridyl-5-Li
O
H2
H3
18
N
The difficulty in isolating useful product from the reaction
of bromoketone 18 with Ph3P=CH2 was noted previously
(see eq. [3]). Surprisingly, ketones 18 and 21 reacted with
the conjugated ylide methyl(triphenylphosphoranylidene)ace-
tate in CH2Cl2 to give mixtures of stereoisomeric esters
34a–34b and 35a–35b, respectively (eq. [5]).31 This stable
ylide generally reacts poorly, if at all, with ketones. The ma-
jor isomers in both cases have the ester oriented toward C4
(E-ester) as indicated by NOE experiments in which the vi-
nylidene hydrogen interacts with H1. In the minor isomer
34b, NOE experiments indicate the vinylidene hydrogen is
closer to H4, whereas in the minor isomer 35b, the Z-ester
stereochemistry could not be confirmed by NOE experiments
because of the overlap between H1 and the vinylidene hydro-
gen.
Y
26 N = CH, Y = H (72%)
27 Y = Cl (59%)
Bu3SnH/
AIBN
½2ꢀ
Cbz
N
OH
N
Y
28 N = CH, Y = H (60%)
29 Y = Cl (60%)
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124
Can. J. Chem. Vol. 90, 2012
X
X
preparation of b-amino acid oligomers with useful func-
tionalities.
H1
Cbz
Cbz
Ph3P=CHCOOMe
CH2Cl2
N
N
H
O
H4
Experimental section
34a:34b
MeOOC
1.5:1 (70%)
35a:35b
18 X = Br
21 X = H
General procedures
34a X = Br
35a X = H
2.0:1 (94%)
Thin layer chromatography (TLC) was performed on pre-
coated plates of silica gel GF 250–1000 µm. Column chro-
matography was performed on silica gel Merck grade 60
(230–400 mesh). Reagent chemicals were obtained from
commercial suppliers, and reagent grade solvents were used
½5ꢀ
X
H1
Cbz
N
COOMe
H4
1
without further purification. Both the H and 13C NMR spec-
H
tra (see Supplementary data) are often complicated by the
presence of carbamate conformers, and resonances are often
presented as pairs. Chemical shifts are expressed in ppm rel-
ative to internal TMS (1H) or solvent CDCl3 (13C). High-
resolution mass spectra were performed at Merck Research
Laboratories (West Point, Pennsylvania) using FAB ioniza-
tion methods.
34b X = Br
35b X = H
The 5-anti-6-anti- substituents in bromoalcohol 17 are
ideally situated to take advantage of an intramolecular cycli-
zation approach to introduce a functionalized 5-syn-alkyl sub-
stituent by use of a silicon-containing tether.32 Accordingly,
alcohol 17 was reacted with dimethylvinylchlorosilane to af-
ford the vinylsilyl ether 36. The radical generated by abstrac-
tion of the bromine of 36 with tributyltin hydride (1.5 equiv)
at reflux afforded tethered silyl ether 37 formed by 5-exo-
cyclization (83%). Tamao oxidation of 37 gave a 1:1 mixture
of alcohols 19a–19b (40%), epimeric at the side-chain hy-
droxyl position.33
N-Benzyloxycarbonyl-6-anti-bromo-5-anti-hydroxy-2-
azabicyclo[2.1.1]hexane (17)20
Triethylamine (20 mL) was added to the known20 bromo-
acetate 20 (2.0 g, 5.6 mmol) in MeOH (10 mL) at room tem-
perature (RT). The resulting mixture was stirred for 12 h. The
solvent was removed, and purification of the resulting crude
oil by column chromatography gave the known alcohol 17
1
(1.57 g, 90%) at Rf = 0.35 (2:1 hexanes/ether). H NMR d:
Br
Br
7.26 (s, 5H), 5.07 (s, 2H), 4.37 (d, J = 5.4 Hz, 1H), 4.19 (d,
J = 7 Hz, 1H), 4.01 (d, J = 7.5 Hz, 1H), 3.53 (d, J = 8.8 Hz,
1H), 3.47 (d, J = 8.8 Hz, 1H), 3.5–3.4 (br, 1H), 2.92 (d, J =
7 Hz, 1H). 13C NMR d: 155.7, 136.5, 129.0, 128.7, 128.5,
85.4, 67.8, 66.4, 65.9, 52.4, 50.4, 49.7.
CH2=CH-SiMe2Cl
Si
Cbz
Cbz
N
N
OH
O
imidazole/DMF
(66%)
36
17
Bu3SnH
AIBN (83%)
½6ꢀ
N-Benzyloxycarbonyl-5-anti-bromo-6-oxo-2-azabicyclo
[2.1.1]hexane (18) — General procedure
OH
OH
Si
O
H2O2, KF, KHCO3
Oxalyl chloride (360 mg, 2.76 mmol) dissolved in CH2Cl2
(10 mL) was placed in a 50 mL flask. The contents of the
flask were cooled to –78 °C and DMSO (452 mg,
5.25 mmol) in CH2Cl2 (3 mL) was added dropwise over
5 min. Stirring was continued at –78 °C for 10 min followed
by addition of the alcohol 17 (730 mg, 2.3 mmol) in CH2Cl2
(3 mL) over 10 min. The reaction mixture was stirred for
30 min, and triethylamine (1.16 g, 11.5 mmol) was added in
over 10 min with stirring at –78 °C for 1 h. The cooling bath
was removed and the reaction was stirred for an additional
3 h. Water (20 mL) was added at RT. After 10 min of stir-
ring, the organic layer was separated. The aqueous layer was
extracted with CH2Cl2 (3 × 20 mL), and the combined or-
ganic extracts were washed with brine, dried over MgSO4,
and filtered. The solvent was removed in vacuo. Column
chromatography gave pure ketone 18 (642 mg, 90%) at Rf =
0.32 (1:1 hexanes / diethyl ether). 1H NMR (500 MHz,
CDCl3) d: 7.36 (m, 5H), 5.16 (s, 2H), 4.76 (d, J = 6.6 Hz,
1H, H1), 3.90 (s, 1H, H5), 3.77 (dd, J = 9.1, 1.4 Hz, 1H,
H3), 3.61 (dd, J = 9.0, 0.9 Hz, 1H, H3), 3.49 (dbr, J =
6.6 Hz, 1H, H4). 13C NMR (100 MHz, CDCl3) d: 189.2
(C6), 154.9 (C=O), 136.1, 129.1, 128.9, 128.7, 75.3 (C1),
68.2 (CH2Ph), 64.9 (C4), 47.5 (C5), 40.8 (C3). HRMS m/z
found: 310.0074; calcd for C13H1379BrNO3 (M + H)
Cbz
Cbz
N
N
THF/MeOH (40%)
1:1 mixture
19a and 19b
37
Conclusion
Addition reactions with bromoketone 18 and ketone 22
have been shown to extend the stereochemical diversity of
alkyl-, acyl-, and aryl-substituted 2-azabicyclo[2.1.1]hexanes.
It is now possible to access 2-azabicyclo[2.1.1]hexanes
with 5(6)-anti-carboxy (or alkyl) groups and also 5(6)-syn-
alkyl (or aryl) tertiary alcohols. Organolithium and organo-
magnesium carbonyl additions, as well as 9-BBN addition
and catalytic hydrogenation of exo-alkylidines, have been
shown to be stereoselective for attack from the face syn
to the nitrogen-containing bridge.34 In separate experiments
the usefulness of the bromine substituent of bromoalcohol
17 for the introduction of 5-anti-alkyl groups by a tether-
ing process has been demonstrated. The 5-bromine sub-
stituents in products derived from ketone 18 should prove
useful in further synthetic manipulations of this azabicyclic
ring system.5a,35 The results have implications for develop-
ment of bridged pyrrolidine-based pharmaceuticals and the
Published by NRC Research Press

Krow et al.
125
310.0078; m/z found: 312.0053; calcd for C13H1381BrNO3
3.48 (d, J = 9.2 Hz, 1H, H3), 2.83 (d, J = 6.8 Hz, 1H, H4),
1.24, 1,21 (2 s, 3H, CH3). 13C NMR (100 MHz, CDCl3) d:
155.7, 136.4, 128.8, 128.5, 128.4, 128.2, 127.9, 86.9, 86.7
(C6), 68.0, 67.8 (C1), 67.4, 67.2 (CH2Ph), 52.3 (C3), 50.6,
50.3 (C4), 49.2, 49.0 (C5), 20.3 (CH3). HRMS m/z found:
348.0203; calcd for C14H1679BrNNaO3 (M + Na): 348.0211;
m/z found: 350.0185; calcd for C14H1681BrNNaO3 (M + Na):
350.0191. The stereochemistry at C6 was confirmed by an
NOE experiment that showed a Me/H3 interaction.
(M + H): 312.0058.
N-Benzyloxycarbonyl-6-anti-hydroxy-2-azabicyclo[2.1.1]
hexane (21) — General procedure
Bromoalcohol 17 (300 mg, 0.96 mmol) dissolved in tol-
uene (17 mL) was degassed for 30 min with argon. AIBN
(16 mg, 0.96 mmol) and tristrimethylsilylsilane (0.59 mL,
1.92mmol)wereaddedandthereactionwasheatedto100°C for
2 h under argon.23 The reaction was allowed to come to
RT and the solvent was removed in vacuo. The resultant
oil was purified by preparative silica gel TLC to yield alcohol
N-Benzyloxycarbonyl-5-anti-hydroxy-5-syn-methyl-2-
azabicyclo[2.1.1]hexane (24)
1
21 (150 mg, 67%) at Rf = 0.38 (1:1 ethyl acetate / hexanes). H
Following the general procedure, AIBN (12 mg,
0.07 mmol) was added to the bromoalcohol 23 (480 mg,
1.47 mmol) in benzene (20 mL) with argon protection. The
resulting mixture was refluxed for 5 min, and Bu3SnH
(595 µL, 2.20 mmol) was added by syringe. The reaction
was refluxed for an additional 10 h. The solvent was re-
moved in vacuo and column chromatography of the residue
gave alcohol 24 (350 mg, 96%) at Rf = 0.18 (1:2 hexanes /
NMR (300 MHz, CDCl3) d: 7.39 (m, 5H), 5.19 (s, 2H),
4.26, 4.26 (2 d, J = 7.2, 7.5 Hz, 1H, H1), 4.12 (d, J =
7.2 Hz, 1H, H6), 3.45 (s, 2H, 2H3), 3.08 (br, 1H, OH),
2.97 (2 br, 1H, H4), 2.72, 2.71 (2 d, J = 7.2, 7.2 Hz, 2H,
H5x), 1.68 (dd, J = 7.2, 7.2 Hz, H5n). 13C NMR (100 MHz,
CDCl3) d: 156.2, 137.1, 128.9, 128.4, 128.2, 81.5 (C6),
67.2 (CH2Ph), 63.9 (C1), 48.7 (C3), 44.3 (C4), 37.3 (C6).
HRMS m/z found: 256.0946: calcd for C13H15NO3Na (M +
Na) m/z: 256.0950.
1
diethyl ether). H NMR (400 MHz, CDCl3) d: 7.36 (m, 5H),
5.16 (s, 2H), 4.18, 4.15 (2 d, J = 6.8 Hz, 1H, H1), 3.37 (d,
J = 9.2 Hz, 1H, H3), 3.34 (d, J = 9.2 Hz, 1H, H3), 2.85 (d, J =
7.2 Hz, 1H, H6), 2.55 (br, 1H, H4), 2.42 (br, 1H, OH), 1.43
(d, J = 7.2 Hz, 1H, H6), 1.17 (s, 3H, Me). 13C NMR
(100 MHz, CDCl3) d: 156.5, 155.9 (C=O), 137.0, 128.6,
128.1, 128.0, 83.8, 83.5 (C5), 67.0, 66.9 (CH2Ph), 65.9,
65.4 (C1), 48.5 (C3), 46.5 (C4), 36.2, 36.0 (C6), 19.1.
HRMS m/z found: 248.1285; calcd for C14H18NO3 (M +
H): 248.1281; m/z found: 270.1090; calcd for C14H17NNaO3
(M + Na): 270.1100.
N-Benzyloxycarbonyl-5-oxo-2-azabicyclo[2.1.1]hexane (22)
According to the general procedure, oxalyl chloride
(0.055 mL, 0.63 mmol) in dry CH2Cl2 (2 mL) was cooled
to –78 °C. DMSO (0.09 mL, 1.26 mmol) was added by sy-
ringe, then stirred for 15 min. To this the alcohol 21 (74 mg,
0.32 mmol) dissolved in CH2Cl2 (1 mL) was added slowly
over 15 min, followed by NEt3 (0.18 mL, 1.26 mmol) over
10 min. After 15 min at –78 °C, the mixture was allowed to
stir in a 0 °C bath for 2 h. The reaction was diluted with
CH2Cl2 (6 mL) and washed with dilute HCl (3 × 3 mL,
0.1 N). Workup afforded ketone 22 as a pale yellow oil
(64 mg, 84%) that remained at the origin when eluted with
N-Benzyloxycarbonyl-5-anti-fluoro-5-syn-methyl-2-
azabicyclo[2.1.1]hexane (25)
A 50 wt % BAST solution in THF (299 µL, 0.8 mmol)
was added dropwise to a solution of tertiary alcohol 24
(100 mg, 0.4 mmol) in CH2Cl2 (20 mL) at RT. The solution
was stirred for 16 h. The solvent was removed in vacuo and
column chromatography of the residue gave the fluoride 25
1
ether on a silica gel TLC plate. H NMR (500 MHz, CDCl3)
d: 7.37–7.30 (m, 5H), 5.16–5.14 (m, 2H, benzyl CH2), 4.67
(d, J = 6.3 Hz, 1H, H1), 3.62 (m, 2H, H3), 3.30 (dd, J =
6.5, 3.2 Hz, 1H, H4), 1.97 (dm, 1H, J = 8.9 Hz, H6anti), 1.79
(bd, 1H, J = 8.9 Hz, H6syn). 13C NMR (126 MHz, CDCl3) d:
189.3, 155.2, 136.1, 128.5, 128.0, 69.6, 67.2, 55.8, 46.4,
29.6. HRMS m/z found: 232.0971; calcd for C13H14NO3
(M + H) m/z: 232.0968.
1
(90 mg, 89%) at Rf = 0.44 (1:1 hexanes / diethyl ether). H
NMR (300 MHz, CDCl3) d: 7.34 (m, 5H), 5.17 (s, 2H),
4.34. 4.30 (2 d, J = 7.2 Hz, 1H, H1), 3.42 (d, J = 9.3 Hz,
1H, H3), 3.34 (d, J = 9.3 Hz, 1H, H3), 2.77 (br, 2H, H4 and
H6), 1.56, 1.53 (2 d, J = 7.8 Hz, 1H, H6), 1.30, 1.28 (2 d,
J = 22.2 Hz, 3H, Me). 13C NMR (100 MHz, CDCl3) d:
156.6, 156.0 (C=O), 137.1, 128.9, 128.8, 128.7, 128.6,
128.5, 128.3, 105.4, 103.4 (C5), 67.4 (CH2Ph), 64.8, 64.5,
64.2, 64.0 (C1), 48.3 (C3), 46.3, 46.2, 46.0 (C4), 35.7, 35.6
(C6), 15.9, 15.6 (CH3). HRMS m/z found: 250.1233; calcd
for C14H17FNO2 (M + H): 250.1238.
N-Benzyloxycarbonyl-6-anti-bromo-5-anti-hydroxy-5-syn-
methyl-2-azabicyclo[2.1.1]hexane (23)
MeLi (10.6 mg, 0.48 mmol) was added to cooled ether
(5 mL, dry) at 0 °C with argon protection. After stirring for
5 min, bromoketone 18 (100 mg, 0.32 mmol) dissolved in
ether (5 mL) was added dropwise over 10 min. Stirring was
continued for 2 h. The cooling bath was removed and concd
NH4Cl (10 mL) was added at RT. The reaction mixture was
stirred for an additional 5 min. The organic layer was sepa-
rated, and the aqueous layer was extracted with ether (3 ×
10 mL). The combined organic extracts were washed with
brine, dried over MgSO4, and filtered. The solvent was re-
moved in vacuo and chromatography of the residue gave al-
cohol 23 (69 mg, 66%) at Rf = 0.31 (1:2 hexanes / diethyl
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-hydroxy-6-syn-
phenyl-2-azabicyclo-[2.1.1]hexane (26)
Anhydrous diethyl ether (3 mL, dry) was added to bromo-
ketone 18 (100 mg, 0.32 mmol) at 0 °C with argon protec-
tion. PhMgBr (87 mg, 0.48 mmol) was added to the mixture
over 5 min. After stirring for 1 h, the cooling bath was re-
moved and concd NH4Cl (5 mL) was added at RT. The or-
ganic layer was separated, and the aqueous layer was
extracted with diethyl ether (3 × 10 mL). The combined ether
layers were dried over MgSO4 and then filtered. Solvent
1
ether). H NMR (400 MHz, CDCl3) d: 7.26 (m, 5H), 5.16
(m, 2H), 4.36, 4.31 (2 d, J = 6.8 Hz, 1H, H1), 4.01 (s, 1H,
H5), 3.62, 3.61 (2 s, 1H, OH), 3.53 (d, J = 9.2 Hz, 1H, H3),
Published by NRC Research Press

126
Can. J. Chem. Vol. 90, 2012
removal in vacuo and column chromatography of the residue
gave pure bromide 26 (90 mg, 72%) at Rf = 0.45 (1:2 hex-
anes / diethyl ether). 1H NMR (400 MHz, CDCl3) d:
7.33∼6.96 (m, 10H, H on Ph), 5.09, 4.94, 4.93, 4.84 (4 d,
J = 12.4, 12.4, 12.8, 12.8 Hz, 2H, CH2Ph), 4.78, 4.74 (2 d,
J = 7.2 Hz, 1H, H1), 4.07, 4.05 (2 s, 1H, H5), 3.40, 3.38 (2
br, 1H, OH), 3.33 (d, J = 9.2 Hz, 1H, H3), 3.22, 3.21 (2 d, J =
7.2 Hz, 1H, H6). 13C NMR (100 MHz, CDCl3) d: 155.4,
155.3 (C=O), 140.1, 137.3, 137.2, 129.1, 128.9, 128.7,
128.5, 128.4, 128.3, 128.0, 127.6, 126.5, 126.3, 87.3, 87.1
(C6), 67.1, 66.5 (CH2Ph), 64.4, 63.8 (C1), 48.3, 48.1 (C3),
46.1, 45.8 (C4), 35.5, 35.3 (C5). HRMS m/z found:
332.1251; calcd for C19H19NNaO3 (M + Na): 332.1257.
1
N-Benzyloxycarbonyl-5-syn-(6-chloro-3-pyridyl)-5-anti-
hydroxy-2-azabicyclo[2.1.1]hexane (29)
7.2 Hz, 1H, H4), 2.98 (d, J = 9.2 Hz, 1H, H3). H NMR
(400 MHz, CDCl3, 60 °C) d: 7.21 (m, 5H), 5.11∼4.86 (m,
2H), 4.78, 4.74 (2 d, J = 7.0, 7.1 Hz, 1H, H1), 4.09 (s, 1H,
H5), 3.44, 3.42 (2 br, 1H, OH), 3.38 (d, J = 9.0 Hz, 1H,
H3), 3.24, 3.22 (2 d, J = 7.2 Hz, 1H, H4), 3.03 (d, J =
9.0 Hz, 1H, H3). 13C NMR (100 MHz, CDCl3) d: 154.5,
154.4 (C=O), 140.1, 140.0, 136.6, 136.5, 129.2, 129.0,
128.7, 128.6, 128.5, 128.4, 128.2, 127.7, 125.9, 125.7 (C
on Ph), 89.7, 89.5 (C6), 67.6, 67.0 (CH2Ph), 66.6, 65.9
(C1), 51.7, 51.4 (C4), 49.2, 49.0 (C5), 48.9, 48.7 (C3).
HRMS m/z found: 388.0565; calcd for C19H1979BrNO3
(M + H): 388.0543.
Following the general procedure, AIBN (2 mg, 0.05 equiv)
was added to bromoalcohol 27 (0.130 g, 0.31 mmol) in
15 mL benzene with argon protection and Bu3SnH
(0.124 mL, 0.46 mmol) was added. After 10 h reflux,
workup and column chromatography gave the alcohol 29
1
(60 mg, 60%) at Rf = 0.13 (1:2 hexanes / diethyl ether). H
NMR (400 MHz, CDCl3) d: 8.03, 7.99 (2 s, 1H, H2′), 7.29
(m, 5H), 7.02 (m, 2H, H4′ and H5′), 5.02, 4.95, 4.82 (3 d,
J = 12.0, 12.0, 12.8 Hz, 2H, CH2Ph), 4.58, 4.56 (2 d, J =
7.2 Hz, 1H, H1), 3.60∼3.00 (br, 1H, OH), 3.25, 3.24 (2 d,
J = 9.2 Hz, 1H, H3n), 2.98 (m, 2H, H4 and H6), 2.76 (d, J =
9.2 Hz, 1H, H3x), 1.55 (d, J = 7.2 Hz, 1H, H6). 13C NMR
(100 MHz, CDCl3) d: 155.3 (C=O), 151.2, 148.3, 148.1,
137.6, 137.4, 136.9, 134.8, 129.0, 128.6, 128.4, 127.9,
124.7, 84.8, 84.7 (C5), 67.4, 66.9 (CH2Ph), 64.4, 63.7 (C1),
48.1, 47.9 (C3), 46.4, 46.0 (C4), 36.1, 35.8 (C6). HRMS m/z
found: 345.0989; calcd for C18H1835ClN2O3 (MH): 345.1001.
The stereochemistry on C5 was confirmed by NOE. When
H2’ was irradiated, the signals of H1, H4, and H3x were in-
creased.
N-Benzyloxycarbonyl-5-anti-bromo-6-syn-(6-chloro-3-
pyridyl)-6-anti-hydroxy-2-azabicyclo[2.1.1]hexane (27)
At –78 °C, n-butyllithium in hexane (1.6 mol/L) (0.40 mL,
0.65 mmol) was added dropwise to a solution of 2-chloro-5-
iodopyridine (0.155 g, 0.65 mmol) in dry THF (10 mL). The
reaction was stirred for 30 min at –78 °C, whereupon the ke-
tone 18 (0.200 g, 0.65 mmol) in dry THF (10 mL) was
added slowly. The reaction was stirred at –78 °C for 0.5 h
followed by 2 h at RT. The reaction was quenched with sat.
aq ammonium chloride (10 mL), diluted with water (10 mL),
and extracted with EtOAc (3 × 30 mL). The combined or-
ganic layers were washed with water, dried, and solvent was
evaporated in vacuo to give the crude product. Column chro-
matography on silica gel, eluting with 1:1 hexanes / diethyl
ether, gave the alcohol 27 (160 mg, 59%) at Rf = 0.27 (1:2
Attempted dehydration of alcohol 24 to give olefin 30
The tertiary alcohol 24 (200 mg, 0.6 mmol) in pyridine
(5 mL) was placed in a 50 mL flask. To this stirred solution,
phosphorus oxychloride (270 µL) was added at 0–5 °C, and
the mixture was stirred for 14 h at RT. The reaction mixture
was diluted with diethyl ether (10 mL) and slowly quenched
with water (10 mL) to hydrolyze the excess phosphorus oxy-
chloride. The layers were separated and the aqueous layer
was extracted with diethyl ether (3 × 10 mL). The combined
organic layers were washed with brine, dried over MgSO4,
and filtered. Solvent removal gave only 10 mg of crude oil
that did not contain the desired alkene 30.
1
hexanes / diethyl ether). H NMR (400 MHz, CDCl3) d: 8.11,
8.08 (2 br, 1H, H2′), 7.30 (m, 5H), 7.04 (m, 2H, H4′ and
H5′), 4.95 (3 d, J = 12.0, 12.4, 12.8 Hz, 2H, CH2Ph), 4.76
(br, 1H, H1), 4.29 (br, 1H, OH), 4.08 (s, 1H, H5), 3.40 (d,
J = 9.2 Hz, 1H, H3n), 3.25 (br, 1H, H4), 2.88 (d, J =
9.2 Hz, 1H, H3x). 13C NMR (100 MHz, CDCl3) d: 154.6
(C=O), 151.4, 148.1, 137.2, 136.9, 136.3, 134.7, 129.2,
129.0, 128.7, 128.2, 125.9, 124.8, 87.6 (C6), 68.1, 67.6
(CH2Ph), 66.6, 65.9 (C1), 52.0, 51.7 (C4), 49.2 (C3), 49.1,
48.7 (C5). HRMS m/z found: 423.0105; calcd for
C18H1779Br35ClN2O3 (MH): 423.0106.
N-Benzyloxycarbonyl-5-anti-bromo-6-methylene-2-
azabicyclo[2.1.1]hexane (31)
To a solution of ketone 18 (1.26 mmol, 390 mg) in dry
THF (15 mL) at 0 °C was added a toluene solution of the
Tebbe reagent (2.52 mL of 0.5 mol/L solution,
1.26 mmol).27 The mixture was allowed to warm to RT and
stirred for 2 days, whereupon Et2O (20 mL) was added fol-
lowed slowly followed by 5 drops of aq NaOH (0.1 mol/L).
After gas evolution ceased, the mixture was dried (Na2SO4)
and filtered using a Celite pad. The solvent was removed in
vacuo and purification of the residue by chromatography on
silica gel (4:1 hexanes / diethyl ether) gave the bromoalkene
31 (165 mg, 43%) at Rf = 0.41 (1:1 hexanes / diethyl ether).
1H NMR (400 MHz, CDCl3) d: 7.27 (m, 5H), 5.08 (s, 2H),
4.87 (br, 1H, =CH2), 4.81 (s, 1H, =CH2), 4.57 (br, 1H, H1),
3.85 (s, 1H, H5), 3.53 (d, J = 8.5 Hz, 1H, H3), 3.42 (d, J =
8.5 Hz, 1H, H3), 3.19 (d, J = 6.4 Hz, 1H, H4). 13C NMR
(100 MHz, CDCl3) d: 155.7 (C=O), 148.5 (C6), 136.7,
N-Benzyloxycarbonyl-5-anti-hydroxy-5-syn-phenyl-2-
azabicyclo[2.1.1]hexane (28)
Following the general procedure, AIBN (18 mg,
0.05 equiv) was added to the bromoalcohol 26 (0.84 g,
2.16 mmol) in benzene (25 mL) with argon protection. The
resulting mixture was refluxed for 5 min and Bu3SnH
(0.87 mL, 1.5 equiv) was added. The reaction was refluxed
for an additional 10 h. Workup and column chromatography
gave the alcohol 28 (400 mg, 60%) at Rf = 0.32 (1:2 hex-
anes / diethyl ether). 1H NMR (400 MHz, CDCl3) d: =
7.27∼6.91 (m, 10H), 5.00, 4.87, 4.86, 4.74 (4 d, J =
12.8 Hz, 2H, CH2Ph), 4.51 (multiple d, J = 7.2 Hz, 1H,
H1), 3.19 (br, 1H, OH), 3.13, 3.10 (2 d, J = 8.8 Hz, 1H,
H3), 2.89∼2.80 (m, 3H, H3, H4, and H6), 1.43 (d, J =
Published by NRC Research Press

Krow et al.
127
128.9, 128.8, 128.7, 128.5, 128.4 (Ph), 100.9 (=CH2), 69.4
(C1), 67.6, 67.4 (CH2Ph), 54.5 (C4), 50.2 (C6), 49.6 (C3).
HRMS m/z found: 330.0094 (79Br), 332.0070 (81Br); calcd
for C14H14BrNO2Na (MNa): 330.0100 (79Br), 332.0080
(81Br).
H5), 1.73 (br, 1H, OH), 1.51 (dd, J = 8.0, 7.6 Hz, 1H,
H6). 13C NMR (100 MHz, CDCl3) d: 156.1, 137.1, 128.7,
128.5, 128.3, 128.1, 127.9, 66.9 (OCH2), 61.7, 61.2 (C1),
61.0 (CH2Ph), 56.6 (C3), 50.9 (C5), 39.7 (C4), 38.0 (C6).
HRMS m/z found: 248.1274; calcd for C14H18NO3 (M + H):
248.1281.
Wittig reaction of ketone 18 — Attempted synthesis of
alkene 31
N-Benzyloxycarbonyl-5-anti-carboxy-2-azabicyclo[2.1.1]
hexane (8a)
To a suspension of CH3 PPh3Br– (77 mg, 0.22 mmol) in
+
dry THF (1.1 mL) at –78 °C was added n-BuLi (135 µL,
0.215 mmol, 1.6 mol/L) by syringe, resulting in the appear-
ance of a bright yellow color. After 30 min at –78 °C, ketone
18 (63 mg, 0.20 mmol) in dry THF (1.01 mL) was added
slowly and allowed to rise to RT overnight. The reaction was
quenched with water, and the solvent was removed in vacuo.
The mixture was taken up in CH2Cl2 (6 mL) and washed
with water (3 × 2 mL) and once with brine (1 × 2 mL). The
solvent was removed in vacuo, and the resultant oil was puri-
fied by preparative TLC (4:1 hexanes/ether). Eight UV active
bands were collected as fractions (63 mg total). No fraction
corresponded to either starting material or the desired alkene
31.
To a stirred solution of alcohol 33 (60 mg, 0.24 mmol) in
CH2Cl2 (3 mL) containing TEMPO (1 mg) was added
NaHCO3 (aq) (0.74 mL) containing KBr (3.0 mg) and
Bu4NCl (4.0 mg). The mixture was cooled to 0 °C and a sol-
ution of NaOCl (0.60 mL), NaHCO3 (0.51 mL), and brine
(0.55 mL) was added dropwise. After 1 h, the layers were
separated. The organic layer was extracted with water (4 ×
5 mL). The combined aqueous solution was acidified with
10% HCl. The resulting solution was extracted with EtOAc
(4 × 10 mL). The combined organic solution was dried over
Na2SO4. Removal of solvent and purification of the residue
by column chromatography gave acid 8a (40 mg, 63%) at
Rf
=
0.32 (90:10:1 CH2Cl2/MeOH/TFA). 1H NMR
(300 MHz, CD3OD) d: 7.41 (m, 5H), 5.20 (s, 2H), 4.58 (br,
1H, H1), 3.48 (br, 2H, 2H3), 3.08, 3.06 (2 br, 1H, H4), 2.61
(br, 2H, H6x and H5), 2.32 (t, J = 7.8 Hz, 1H, H6n). 13C
NMR (100 MHz, CDCl3) d: 177.6 (COOH), 156.1 (C=O),
137.3, 137.0, 128.8, 128.6, 128.3, 128.1 (C on Ph), 67.1
(CH2Ph), 63.3 (C1), 58.7 (C5), 50.8 (C3), 42.3 (C4), 39.4
(C6). HRMS m/z found: 284.0898; calcd for C14H15NO4Na
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-
(hydroxymethyl)-2-azabicyclo[2.1.1]-hexane (32)
To a stirred solution of olefin 31 (150 mg, 0.49 mmol) in
THF (10 mL) at 0 °C under an argon atmosphere was added
9-BBN (2.94 mL, 1.47 mmol, 0.5 mol/L solution in hexane).
After the solution was stirred at RT for 7 h, 6 mol/L NaOH
(1.3 mL) and 30% H2O2 (1.3 mL) were added at 0 °C. After
stirring at RT overnight, the reaction mixture was diluted
with water and extracted with diethyl ether (3 × 15 mL).
The organic phase was washed with water, dried over
Na2SO4, and concentrated under reduced pressure. Column
chromatography of the residue (2:3 hexanes / diethyl ether)
gave the alcohol 32 (150 mg, 94%) at Rf = 0.27 (1:1 hex-
1
(M + Na): 284.0893. H COSY showed couplings between
H1 and H4 and H6x and H6n.
N-Benzyloxycarbonyl-5-[(methoxycarbonyl)methylene]-6-
anti-bromo-2-azabicyclo[2.1.1]hexane (stereoisomers E-
34a and Z-34b)
Methyl(triphenylphosphoranylidene)acetate
(582
mg,
1
anes / ethyl acetate). H NMR (400 MHz, CDCl3) d: 7.36 (m,
1.74 mmol) was added to a solution of ketone 18 (360 mg,
1.16 mmol) in 20 mL CH2Cl2 at RT. The reaction mixture
was stirred for 2 days. The solvent was removed in vacuo
and purification of the residue by column chromatography
on silica gel (4:1 hexanes / diethyl ether) provided stereo-
isomer 34a (110 mg, 27%), stereioisomer 34b (170 mg,
42%), and starting material (20 mg). Analytical data for prod-
5H), 5.16 (s, 2H), 4.54 (d, J = 7.2 Hz, 1H, H1), 4,51 (d, J =
7.2 Hz, 2H, OCH2), 3.96 (d, J = 7.2 Hz, 1H, H5syn), 3.61 (d,
J = 8.8 Hz, 1H, H3), 3.54 (d, J = 8.8 Hz, 1H, H3), 3.06 (d,
J = 7.2 Hz, 1H, H4), 2.44 (td, J = 7.2, 7.2 Hz, 1H, H6syn),
2.00 (2 br, 1H, OH). 13C NMR (100 MHz, CDCl3) d: 155.6
(C=O), 136.7, 128.9, 128.7, 128.5, 128.3, 67.5 (OCH2),
65.3, 64.8 (C1), 61.4 (CH2Ph), 58.8 (C3), 53.5 (C5), 52.3
(C4), 47.0 (C6). HRMS m/z found: 326.0382; calcd for
C14H1779BrNO3 (M + H): 326.0387.
1
uct 34a at Rf = 0.37 (1:1 hexanes / diethyl ether): H NMR
(400 MHz, CDCl3) d: 7.24 (m, 5H), 5.72 (s, 1H, =CH), 5.08
(s, 2H), 4.68 (br, 1H, H1), 3.96 (d, J = 6.8 Hz, 1H, H4), 3.94
(s, 1H, H5), 3.67 (s, 3H, CH3), 3.60 (d, J = 8.4 Hz, 1H, H3),
3.50 (d, J = 8.4 Hz, 1H, H3). 13C NMR (100 MHz, CDCl3)
d: 167.2, 159.7 (C6), 155.5 (CO2Bn), 136.5, 129.0, 128.8,
128.7, 128.6, 128.5, 108.4 (=CH), 68.9 (C1), 67.8 (CH2Ph),
55.2 (C4), 52.0 (CH3), 49.2 (C3), 48.8 (C5). HRMS m/z
found: 388.0152; calcd for C16H1679BrNO4Na (M + Na):
388.0155; m/z found: 390.0132; calcd for C16H1681BrNO4Na
(M + Na): 390.0134. Analytical data for product 34b at Rf =
0.29 (1:1 hexanes / diethyl ether): 1H NMR (400 MHz,
CDCl3) d: 7.27 (m, 5H), 5.64 (s, 1H, =CH), 5.28 (d, 1H,
J = 6.8 Hz, H1), 5.09 (m, 2H, CH2Ph), 3.93 (s, 1H, H5),
3.61 (s, 3H, CH3), 3.60 (d, J = 8.8 Hz, 1H, H3), 3.59 (d, J =
8.8 Hz, 1H, H3), 3.33 (d, J = 6.4 Hz, 1H, H4). 13C NMR
(100 MHz, CDCl3) d: 165.8, 157.8 (C6), 155.5 (CO2Bn),
136.6, 128.9, 128.8, 128.7, 128.6, 128.3, 108.3 (=CH),
N-Benzyloxycarbonyl-5-anti-(hydroxymethyl)-2-azabicyclo
[2.1.1]hexane-2-carboxylate (33)
To a toluene (15 mL) solution of bromide 32 (250 mg,
0.77 mmol) was added TTMSS (1.18 mL, 3.83 mmol) and a
catalytic amount of AIBN. The resulting solution was re-
fluxed under argon for 12 h until no starting material re-
mained. The solvent was removed and purification of the
residue by silica gel flash column chromatography gave alco-
hol 33 (130 mg, 69%) at Rf = 0.13 (1:1 hexanes / ethyl acetate).
1H NMR (400 MHz, CDCl3) d: 7.34 (m, 5H), 5.16 (s, 2H,
CH2Ph), 4.35 (d, J = 7.2 Hz, 1H, H1), 3.89 (d, J = 7.6 Hz,
2H, OCH2), 3.46 (d, J = 8.4 Hz, 1H, H3), 3.42 (d, J =
8.4 Hz, 1H, H3), 2.74, 2.73 (2 d, J = 7.2 Hz, 1H, H4),
2.41 (d, J = 8.0 Hz, 1H, H6), 2.15 (td, J = 7.6, 7.6 Hz,
Published by NRC Research Press

128
Can. J. Chem. Vol. 90, 2012
68.9 (C1), 67.7, 67.6 (CH2Ph), 54.7 (C4), 52.0 (CH3), 49.4
calcd for C17H2279BrNaNO3Si (M + Na): 418.0451; m/z
found: 420.0423; calcd for C17H2281BrNO3SiNa (M + Na):
420.0430.
(C3), 48.6 (C5). HRMS m/z found: 388.0145; calcd for
C16H1679BrNO4Na (M
+ Na): 388.0155; m/z found:
390.0124; calcd for C16H1681BrNO4Na (M + Na): 390.0134.
N-Benzyloxycarbonyl-5-anti-oxy-6-anti-(1-ethyl)-2-
azabicyclo[2.1.1]hexyl-dimethylsilane (37) (a 2,2,3-
trimethyl-1,2-oxasilepane)
N-Benzyloxycarbonyl-5-[(methoxycarbonyl)methylene]-2-
azabicyclo[2.1.1]hexane (stereoisomers E-35a and Z-35b)
According to the preceding procedure, methyl(triphenyl-
phosphoranylidene)acetate (430 mg, 1.29 mmol) was added
to a solution of ketone 21 (210 mg, 0.86 mmol) in CH2Cl2
(20 mL) at RT. After 36 h, workup and column chromatogra-
phy on silica gel (3:1 hexanes / diethyl ether) provided alkene
35a (155 mg, 62%) and alkene 35b (80 mg, 32%). Analytical
data for product 35a at Rf = 0.34 (1:1 hexanes / diethyl
AIBN (3.0 mg, 0.02 mmol) was added to a solution of
compound 36 (150 mg, 0.38 mmol) in benzene (20 mL)
under argon. The resulting mixture was refluxed for 5 min
and tributyltin hydride (165 mg, 0.57 mmol) was added im-
mediately. The mixture was refluxed for an additional 5 h.
The solvent was removed in vacuo to give a residue that after
column chromatography gave tethered silane 37 (100 mg,
83%) at Rf = 0.32 (2:1 hexanes / diethyl ether). 1H NMR
(400 MHz, CDCl3) d: 7.30 (m, 5H), 5.11 (s, 2H), 4.15, 4.13
(2 d, J = 7.6, 7.2 Hz, 1H, H6), 4.15, 4.08 (2 br, 1H, H1),
3.40 (m, 2H, 2H3), 2.55 (br, 1H, H5), 2.32, 2.30 (2 d, J =
7.6 Hz, 1H, H4), 1.46 (m, 1H, CHSi), 1.05, 1.03 (2 d, J =
8.4, 7.6 Hz, 3H, CH3), 0.20, 0.17, 0.16, 0.15 (4 s, 6H,
2CH3). 13C NMR (100 MHz, CDCl3) d: 156.0 (C=O),
137.2, 128.9, 128.4, 128.2, 127.9, 84.5, 84.3 (C6), 67.1
(CH2Ph), 66.3, 65.7, 63.2, 62.6 (C1), 57.9 (C3), 49.5, 49.4
(C4), 48.7, 48.2, 44.8, 44.5 (C5), 19.6, 18.7 (SiCH), 15.8,
15.3 (CH3), 1.87, 1.42 (CH3), –1.12, –1.29 (CH3). HRMS
m/z found: 340.1344; calcd for C17H23NO3SiNa (M + Na):
340.1345.
1
ether): H NMR (400 MHz, CDCl3) d: 7.25 (m, 5H), 5.38
(br, 1H, =CH), 5.07 (s, 2H), 4.66 (br, 1H, H1), 3.89, 3.88 (2
d, J = 6.4, 6.8 Hz, 1H, H4), 3.63 (s, 3H, CH3), 3.45 (d, J =
8.0 Hz, 1H, H3), 3.41 (d, J = 8.0 Hz, 1H, H3). 1.89, 1.88 (2
d, J = 7.6 Hz, 1H, H6), 1.68, 1.67 (2 d, J = 7.6 Hz, 1H, H6).
13C NMR (100 MHz, CDCl3) d: 167.2, 159.7 (C5), 156.2,
137.0, 129.0, 128.9, 128.7, 128.6, 128.4, 128.3, 101.5
(=CH), 67.3 (CH2Ph), 64.3 (C1), 51.7 (CH3), 49.2 (C3), 47.3
(C4), 36.9 (C6). HRMS m/z found: 288.1229; calcd for
C16H17NO4Na (M + Na): 288.1231. Analytical data for prod-
1
uct 35b at Rf = 0.27 (1:1 hexanes / diethyl ether): H NMR
(400 MHz, CDCl3) d: 7.26 (m, 5H), 5.29 (m, 2H, =CH and
H1), 5.09 (m, 2H, CH2Ph), 3.60 (br, 3H, CH3), 3.44 (d, J =
8.4 Hz, 1H, H3), 3.36 (d, J = 8.4 Hz, 1H, H3), 3.24 (2 d, J =
6.6 Hz, 1H, H4), 1.89, 1.88 (2 d, J = 7.2 Hz, 1H, H5), 1.68
(d, J = 7.2 Hz, 1H, H5). 13C NMR (100 MHz, CDCl3) d:
166.5, 158.9 (C5), 156.2 (CO2Bn), 137.1, 128.8, 128.6,
128.4, 128.3, 128.2 (C on Ph), 101.4 (=CH), 67.2 (CH2Ph),
64.4 (C1), 51.7 (CH3), 49.2 (C3), 46.8 (C4), 36.9 (C6). HRMS
m/z found: 288.1230; calcd for C16H17NO4Na (M + Na):
288.1231.
N-Benzyloxycarbonyl-5-anti-hydroxy-6-anti-(1-
hydroxyethyl)-2-azabicyclo[2.1.1]hexane stereoisomers
(19)
Route A: To silylether 37 (30 mg, 0.095 mmol) in 1:1
THF/MeOH (0.2 mL) was added KHCO3 (10 mg,
0.10 mmol) and KF (12 mg, 0.21 mmol). To this stirred sus-
pension was added 30% H2O2 (50 mL, 0.45 mmol).33 The
suspension was stirred at RT open to the air for 28 h. Be-
cause of the small reaction volume, two additional portions
of 1:1 THF/MeOH were added as the reaction solvent evapo-
rated. The reaction was quenched by addition of 50% NaS2O3
(0.5 mL), and the solution (0.7 mL) was applied to a prepa-
rative silica gel TLC plate that was allowed to dry. Elution
with 1:1 hexanes/Et2O gave 6 mg (20%) of unreacted 37
(Rf = 0.5, 1:1 hexanes/Et2O). A second elution with 2:1
EtOAc/hexanes yielded 17 mg (65%) of diols 19a + 19b at
Rf = 0.3 (2:1 EtOAc/hexanes) taken as one fraction. The ratio
N-Benzyloxycarbonyl-5-anti-bromo-6-anti-[dimethyl(vinyl)
silyloxy]-2-azabicyclo[2.1.1]hexane (36)
Dimethylvinylchlorosilane (0.77 g, 6.4 mmol) was added
to bromoalcohol 17 (2.0 g, 6.4 mmol) in DMF (1 mL) at RT
followed by addition of imidazole (0.44 g, 6.4 mmol). The
resulting mixture was stirred for 2 days. Diethyl ether
(20 mL) and distilled water (20 mL) were added. The organic
layer was separated and the aqueous layer was extracted with
ether (3 × 20 mL). The combined organic extracts were
washed with brine and then dried over MgSO4. After filtra-
tion, the solvent was removed in vacuo and purification of
the residue by column chromatography gave vinylsilane 36
1
of isomers was 45:55 by H NMR based on integrations of
unique peaks at d 2.81 and 2.60. Route B: To a solution of
compound 37 (520 mg, 1.64 mmol) in THF/MeOH (1:1,
15 mL), KHCO3 (492 mg, 4.92 mmol), KF (190 mg,
3.28 mmol), and 90% H2O2 (0.78 mL, 39.36 mmol) were
successively added. The resulting solution was stirred at RT
for 20 h and then diluted with Et2O. The solvent was filtered
over Celite and concentrated in vacuo. Column chromatogra-
phy gave diol 19a (90 mg, 20% at Rf = 0.17, 2:1 ethyl ace-
tate / hexanes) and diol 19b (90 mg, 20% at Rf = 0.12, 2:1
ethyl acetate / hexanes). Spectral data for 19a: 1H NMR
(400 MHz, CDCl3) d: 7.35 (br, 5H), 5.10 (br, 2H, CH2Ph),
4.96, 4.84 (2 br, 1H, H6), 4.34 (d, J = 7.2 Hz, 1H, H1), 4.12
(d, J = 7.2 Hz, 1H, OCH), 3.85, 3.10 (2 br, 1H, OH), 3.49
(d, J = 8.8 Hz, 1H, H3), 3.44 (d, J = 8.8 Hz, 1H, H3), 2.60
(d, J = 7.2 Hz, 1H, H4), 2.24 (br, 1H, OH), 2.14 (m, 1H,
1
(1.68 g, 66%) at Rf = 0.29 (4:1 hexanes / diethyl ether). H
NMR (400 MHz, CDCl3) d: 7.35 (m, 5H), 6.16 (dd, J =
20.0, 14.8 Hz, 1H, =CH), 6.05, 6.04 (2 d, J = 14.8,
14.4 Hz, 1H, =CH2cis), 5.82, 5.81 (2 d, J = 20.0, 20.4 Hz,
1H, =CH2trans), 5.14 (m, 2H, CH2Ph), 4.36 (br, 1H, H6),
4.27 (d, J = 6.4 Hz, 1H, H1), 4.04 (d, J = 7.2 Hz, 1H, H5),
3.53, 3.52 (2 d, J = 9.2, 8.8 Hz, 1H, H3), 3.47 (d, J =
8.8 Hz, 1H, H3), 2.90 (d, J = 6.4 Hz, 1H, H4), 0.25 (s, 6H).
13C NMR (100 MHz, CDCl3) d: 155.7, 155.2 (C=O), 137.0,
136.6 (=CH), 134.4 (=CH2), 128.9, 128.5, 128.3, 83.7 (C6),
67.5 (CH2Ph), 66.4, 65.7 (C1), 50.7 (C4), 50.0 (C5), 49.3
(C3), –1.26, –1.55 (2CH3). HRMS m/z found: 418.0436;
Published by NRC Research Press

Krow et al.
129
H5), 1.24 (d, J = 5.6 Hz, 3H, CH3). 13C NMR (100 MHz,
CDCl3) d: 156.0, 137.0, 128.9, 128.4, 128.2, 83.3 (C6), 67.3
(C1), 66.5 (OCH), 63.7 (CH2Ph), 63.0 (C3), 50.8 (C4), 46.0
(C5), 23.2 (CH3). HRMS m/z found: 300.1196; calcd for
C15H19NaNO4 (M + Na): 300.1206. Spectral data for 19b:
1H NMR (400 MHz, CDCl3) d: 7.34 (br, 5H), 5.14 (s, 2H),
4.79 (br, 1H, OCH), 4.14 (2 d, J = 7.2 Hz, H1 and H6), 3.53
(d, J = 8.8 Hz, 1H, H3), 3.45 (d, J = 8.8 Hz, 1H, H3), 3.00
(br, 1H, OH), 2.83 (d, J = 7.2 Hz, 1H, H4), 2.16 (m, 1H,
H5), 1.82 (br, 1H, OH), 1.26 (d, J = 6.0 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3) d: 156.0, 137.0, 128.8, 128.6,
128.4, 128.2, 83.4 (C6), 67.2 (OCH), 65.9 (C1), 64.5
(CH2Ph), 62.5 (C3), 50.7 (C4), 44.9 (C5), 23.9 (CH3). HRMS
m/z found: 300.1217; calcd for C15H19NaNO4 (M + Na):
300.1206.
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Supplementary data
Supplementary data (copies of reported H NMR and 13C
NMR spectra for all new compounds) are available with this
article through the journal Web site at http://nrcresearchpress.
com/doi/suppl/10.1139/v11-112.
1
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Acknowledgment
Financial support was provided by the National Science
Foundation (NSF, CHE 0515635 and CHE-0111208) and
the donors of the Petroleum Research Fund, administered by
the American Chemical Society. M.S. was supported by a
Der Min Fan Fellowship and NSF (DGE-0841377) through
a grant to Temple University. We thank A. Suffian for techni-
cal assistance.
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