An efficient synthesis of 3-alkyl-1,5,3-dioxazepanes and their use as electrophiles in double-Mannich reactions

Article abstract of DOI:10.1016/j.tet.2011.11.090

An efficient synthesis of 3-alkyl 1,5,3-dioxazepanes was developed for subsequent use in double-Mannich reactions with a variety of carbon-based nucleophiles. It was found that addition of methyltrichlorosilane to the dioxazepane led to a long-lasting rea

Full text of DOI:10.1016/j.tet.2011.11.090

Tetrahedron 68 (2012) 1017e1028
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An efficient synthesis of 3-alkyl-1,5,3-dioxazepanes and their use as electrophiles
in double-Mannich reactions
*
Kevin Sparrow, David Barker, Margaret A. Brimble
School of Chemical Sciences, University of Auckland, 23 Symonds St., Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 3-alkyl 1,5,3-dioxazepanes was developed for subsequent use in double-
Mannich reactions with a variety of carbon-based nucleophiles. It was found that addition of methyl-
trichlorosilane to the dioxazepane led to a long-lasting reactive species that reacted rapidly with acid-
Received 15 September 2011
Received in revised form 12 November 2011
Accepted 28 November 2011
Available online 7 December 2011
sensitive ketones and
b
-ketoesters to afford azabicyclo[3.3.1]nonanes in good yield.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Methyllycaconitine
Double-Mannich reactions
Dioxazepanes
Azabicyclo[3.3.1]nonanes
Bis(aminol)ethers
1. Introduction
2. Results and discussion
The use of N-alkyl bis(aminol)ethers 1 in double-Mannich re-
actions with -ketoester 2 has allowed the rapid, high-yielding
In order to improve the overall efficiency of the reaction se-
quence, alternative bis(iminium) ion precursors were desired. 3-
Alkyl-1,5,3-dioxazepanes were first reported by Kapnang and co-
workers2 and were later employed by that group as electrophiles in
double-Grignard additions, forming differentially-substituted ter-
tiary amines in good yields.3 More recently, a double-Mannich re-
action of 3-benzyl-1,5,3-dioxazepane with cyclopentanone
activated by iodotrimethylsilane was reported by Ooka et al.4 With
b
synthesis of bicyclic amines as AE ring analogues of methyl-
lycaconitine 3 (Scheme 1).1 To date, the reported syntheses of
bis(aminol)ethers have typically only proceeded in low to moder-
ate yield,1 have required distillation to isolate the product from
oligomeric impurities, and have exhibited low product stability.
These problems pose practical barriers for their use with expensive
or high molecular weight amines.
these encouraging precedents,
a
range of 3-alkyl-1,5,3-
OMe
OMe
A
O
R
i
ii
R
N
N
OEt
OEt
E
RNH2
A
O
O
N
E
OH
OH
N
O
EtO
O
1
O
H
O
OMe
O
EtO
O
Methyllycaconitine 3
2
Scheme 1. Reagents and conditions: (i) paraformaldehyde, K2CO3, EtOH, 3 d, 11e47%; (ii) 1þ2, MeSiCl3, 18 h, 75e99%.
dioxazepanes 4aeg were synthesized by modification of Kap-
nang’s method2 via condensation of a primary amine, excess
paraformaldehyde and ethylene glycol with azeotropic removal of
water (Table 1).
* Corresponding author. E-mail address: m.brimble@auckland.ac.nz (M.A.
Brimble).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.090

1018
K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
Table 1
Use of 1 equiv of SnCl4, BF3$OEt2, or 2 equiv of acetyl chloride
failed to effect the desired reaction whilst use of 0.1 equiv of
samarium(III) triflate (entry 5) gave 5e in moderate yield. Whilst
thionyl chloride (entry 6) also gave 5e in moderate yield it occurred
in a rapid exothermic reaction and was thus not investigated fur-
ther. Amongst the chlorosilane activators (entries 4, 7e9), meth-
yltrichlorosilane5 proved to be the most efficient in terms of
stoichiometry, reaction time and yield, consistent with related
work published in our group.1 The use of titanium(IV) chloride
(entries 10e12) as a Lewis acid activator initially appeared to afford
the highest yields. Unfortunately the crude mixture was contami-
nated with a closely related side product 6a and product isolation
proved difficult with a red gum also forming in the reaction mix-
ture, which complicated silica gel chromatography. The structure of
6a was determined after the related N-ethyl adduct 6b (Scheme 2)
was isolated and characterised in pure form.
Reagents and conditions: (i) paraformaldehyde (1.5 equiv), ethylene glycol
(1.1 equiv), amine (1 equiv), benzene or toluene, D, DeaneStark apparatus, 3e16 h
HO
RNH2 + 2 CH2O
HO
R
O 5
i
N
3
1
O
4a-g
Entry
R
Yield
Compound
1
2
3
4
5
6
7
Me
Et
n-Bu
t-Bu
Bn
54a
73b
97
4a
4b
4c
4d
4e
4f
70b
Quant.
97
Ph(CH2)3
(R)-
a
-MeBn
89
4g
a
Aqueous methylamine (40%) used.
Product distilled under reduced pressure.
b
O
Cl
N
TiCl4
N
N
CH2Cl2
O
CO2Et
2
O
CO2Et
5b
O
CO2Et
6b
Initially, the products were purified by distillation in good
O
yields (entries 2 and 4). It was subsequently discovered that nearly
quantitative yields of spectroscopically pure product could be
achieved through dilution of the crude reaction mixture with n-
hexane and washing with water, thereby eliminating the need for
distillation (entries 3, 5e7). The use of more polar solvents than n-
hexane in the extraction step, such as ethyl acetate or diethyl
ether, proved to be ineffective in removing impurities. The syn-
thesis of N-methyl-dioxazepane 4a proved to be low yielding
(entry 1), which was likely to be due to the use of a 40% aqueous
solution of methylamine for the reaction. The use of methylamine
hydrochloride with potassium carbonate however, also resulted in
low yields.
4b
Scheme 2. Reagents and conditions: TiCl4 (0.5 equi.), CH2Cl2, 0 ꢀC to rt, 18 h, 5b, 19%,
6b, 2.2%.
The incorporation of the chloromethyl substituent into 6b is
thought to occur via a methylenation product based on similar
reported examples.6,7 Having identified MeSiCl3 as the most effi-
cient Lewis acid activator, attention next focused on examining the
substrate scope of the reaction.
2.2. Reaction of N-alkyl-1,5,3-dioxazepanes 4beg with b-
ketoester 2
2.1. Selection of an efficient activator for N-alkyl-1,5,3-
dioxazepanes with b-ketoester 2
The results of the methyltrichlorosilane-activated double-
Mannich reaction of -ketoester 2 with a range of N-alkyl-1,5,3-
b
dioxazepanes 4beg are summarized in Table 3.
Having successfully optimized the synthesis of 3-alkyl-1,5,3-
dioxazepanes, several Lewis acids were evaluated as activators for
Table 3
the double-Mannich reaction of
dioxazepane 4e in dichloromethane (Table 2).
b
-ketoester
2
with 1,5,3-
Reagents and conditions: (i) 3-alkyl-1,5,3-dioxazepane (1.25 equiv), MeSiCl3
(1.0 equiv), CH2Cl2, 0 ꢀC to rt
O
i
RN
R
N
Table 2
Reagents and conditions: (i) activator, CH2Cl2
O
CO2Et
2
O
CO2Et
O
Ph
Ph
O
Cl
N
4b-g
5b-g
BnN
i
N
O
CO2Et
6a
O
CO2Et
2
O
CO2Et
5e
Entry
Dioxazepane
R
Yield (%)
Product
O
1
2
3
4
5
6
4b
4c
4d
4e
4f
Et
89
Quant.
69
5b
5c
5d
5e
5f
4e
n-Bu
t-Bu
Bn
Ph(CH2)3
(R)-
88
Entry
Activator
Equiv
Temperature (ꢀC)
Time (h)
Yield (%)
Quant.
1
2
3
4
5
6
7
8
SnCl4
BF3$OEt2
AcCl
Me2SiCl(OEt)
Sm(OTf)3
SOCl2
Me2SiCl2
Me3SiCl
MeSiCl3
TiCl4
1.0
1.0
2.0
1.0
0.1
1.0
1.5
3.0
1.0
0.25
0.5
1.0
0 ꢀC to rt
18
18
18
18
20
5
18
16
22
48
18
24
0
0
0
4g
a
-MeBn
Quant.a
5g
0 ꢀC to rt
a
Mixture (1:1) of diastereomers.
rt
rt
rt
55
66
67
72
85
88
90a
90a
90a
0 ꢀC to rt
rt
Yields were generally high with the exception of adduct 5d
(entry 3), which may be due to the highly acidic conditions cleaving
the N-tert-butyl group. Short-chain aliphatic amines (entries 1 and
2), afforded clean products after carrying out an acidebase wash
(see Experimental section). For N-benzyl adduct 5f (entry 4), a short
silica gel column purification was required to eliminate polar ma-
terial. Disappointingly, whilst giving a quantitative yield of adduct
rt
rt
9
10
11
12
0 ꢀC to rt
0 ꢀC to rt
0 ꢀC to rt
TiCl4
TiCl4
a
Crude yield with side product 6a ca. 2%.

K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
1019
Table 4
5g, the use of chiral 1,5,3-dioxazepane 4g, afforded no diaster-
Reagents and conditions: (i) 4e (1.25 equiv), MeSiCl3 (1.0 equiv), CH2Cl2, 0 ꢀC to rt,
18 h
eoselectivity in the double-Mannich reaction.
R3
N
R3 R4
R4
O
2.3. Reaction of chiral 1,5,3-dioxazepane 10 with b-ketoester 2
Bn
O
Bn
R2
i
N
R2
Disappointed with the lack of diastereoselectivity observed for
the double-Mannich reaction using chiral dioxazepane 4g, atten-
tion next focused on the use of chiral diol 7 to prepare chiral
dioxazepane 8 in order to probe the stereoselectivity upon reaction
O
O
R1
9a-d
R1
10a-10d
4e
with b-ketoester 2 (Scheme 3). Disappointingly, use of the meth-
Entry
1
Nucleophile
Product
Yield (%)
yltrichlorosilane-mediated conditions gave adduct 5e in 36% yield
with no enantioselectivity, as determined by chiral stationary
phase HPLC.
Ph
N
10a
9a
Quant.
O
O
Me
Me
Bn
HO
HO
O
N
Bn
N
i
ii
Ph
O
N
O
O
9b
2
3
88
EtO
O
O
10b
7
8
5e
EtO
O
EtO
O
Scheme 3. Reagents and conditions: (i) paraformaldehyde (1.5 equiv), diol (1 equiv),
benzylamine (1 equiv), toluene, , DeaneStark apparatus, 16 h, 27% (ii) 8 (1.25 equiv),
-ketoester 2 (1 equiv), MeSiCl3 (1 equiv), CH2Cl2, 0 ꢀC to rt, 36%.
D
b
Ph
N
Quant.
O
2.4. Reaction of N-alkyl-1,5,3-dioxazepane 4e with ketones
9aed
O
9c
10c
O
O
Attention next shifted to investigating the substrate scope of the
double-Mannich reaction using alternative carbon nucleophiles
(Table 4). The reaction proceeded well with ketone 9a, cyclic
ketoester 9b and diketone 9c all affording adducts 10aec in high
yields. Acyclic -ketoester 9d gave piperidone 10d as a single di-
b-
Ph
N
4
49
O
9d
b
O
10d
astereoisomer in modest 49% yield.
EtO
O
EtO
O
2.5. NMR study of the reaction of N-ethyl-1,5,3-dioxazepane
5b with methyltrichlorosilane
2.6. Application of the new addition protocol to acid-
sensitive enol precursors
A simple 1H and 13C NMR study was next carried out to examine
the effect of altering the order of addition by initially activating 3-
2.6.1. Use of
a-oxygenated ketone 11. The first sensitive substrate
attempted was 2-benzyloxycyclohexanone 11, a precursor to an AE
ring analogue 12 of lappaconitine 13 (Scheme 4).10 Prior attempts in
the literature to apply a double-Mannich reaction to 2-oxygenated
cyclohexanones have resulted in a very low 5% yield11 or a mixture
of isomeric products.12
ethyl-1,5,3-dioxazepane 4b in the absence of
a nucleophile.
Therefore 0.5,1.0 and 1.5 equiv of methyltrichlorosilane were added
to 4b in CDCl3 in three separate NMR tubes and their 1H NMR
spectra (Fig. 1) recorded. This latter method of activation would be
useful for subsequent reactions with acid-sensitive enols.
2-Benzyloxycyclohexanone 11 was synthesized in two steps by
copper(II) tetrafluoroborate-catalyzed opening of commercially
available cyclohexene oxide with excess benzyl alcohol.13 The pre-
activation methodology developed above was then applied to the
reaction of ketone 11 with N-ethyl-dioxazepane 5b affording the
double-Mannich adduct 12 in an improved 35% yield.
After 20 min with periodic agitation, the spectra for the reaction
using1.0and1.5 equivof MeSiCl3 werevirtuallyidenticaltoeachother
with a new single dominant species being observed. The 0.5 equiv
experiment afforded a more complex and line-broadened 1H spec-
trum compared to the other experiments with a weak 13C resonance
observed at circa d 160 ppmdwithin the typical range for an imine or
iminiumionspecies.8,9 Thespectraobtainedforthereactionsusing1.0
and 1.5 equiv of methyltrichlorosilane remained unchanged after 4
days inthe sealed NMR tubes and the presence ofanimineoriminium
ion was supported by a strong 13C resonance at w160 ppm.
2.6.2. Use of b-ketoester 16 containing a cyclic acetal for the syn-
thesis of C-6 oxygenated AE ring analogues of MLA. C-6 oxygenated
AE ring analogues of MLA 3 have yet to be synthesized via a double-
Mannich strategy (Fig. 3).14 The methyl ether present at C-1 in MLA
has been identified as participating in key non-covalent in-
teractions between MLA and Aplysia acetylcholine-binding protein;
‘a structural and functional surrogate’ for the receptor domain in
nAChRs.15 Incorporation of C-6 oxygenation into AE ring analogues
of MLA may therefore increase their potency.
It was anticipated that the bicyclic methyl ether 14 could be
synthesized diastereoselectively in two steps by reduction of the C-
6 ketone from the less-hindered top face, followed by methylation.
Protection of the C-6 ketone as a 1,3-dioxolane in 15 facilitates the
b-Ketoester 2 (1 equiv) was then added to the 1.0 equiv trial
reaction and the mixture agitated for ca. 5 min. The 1H NMR
spectrum subsequently indicated the absence of the previously
observed peaks, with the appearance of new resonances upfield
consistent with formation of an azabicyclo[3.3.1]nonane 5b (Fig. 2).
After workup of the reaction mixture a quantitative yield of
azabicyclo[3.3.1]nonane 5b was afforded. With this result in hand,
the synthesis of double-Mannich adducts using this order of ad-
dition of reagents, and stoichiometry, was next attempted with
acid-sensitive substrates.

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K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
Fig. 1. 1H NMR spectra of 3-ethyl-1,5,3-dioxazepane 4b and its activated species.
Fig. 2. Reaction of ethyl 2-oxocyclohexane-1-carboxylate 2 with the activated species.
selective functionalisation of the ketone and can be formed from 16
by double-Mannich reaction.
conjugate addition product 17 in 63% yield after purification by
fractional distillation.16 Intramolecular cyclization of diester 17
with sodium ethoxide afforded a crude mixture containing diketo
ester 18 that was used without purification in the next reaction.
Acetal formation with 1 equiv of ethylene glycol afforded a separa-
ble mixture of isomeric ketals 16 and 19 in a combined 58% yield.17
In order to examine this possibility,
b-ketoester 16 bearing
a cyclic acetal at the C-5 position was synthesized from methyl vinyl
ketone and diethyl malonate in a four-step sequence (Scheme 5).
Methyl vinyl ketone and diethyl malonate were condensed in
a sealed tube in the presence of potassium carbonate to give the
b-Ketoester 16 was then subjected to the titanium tetrachloride

K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
1021
Thus, silyl enol ether 24 was
subjected
to the
OMe
OMe
methyltrichlorosilane-activated double-Mannich reaction using N-
ethyl-1,5,3-dioxazepane 4b to afford the desired bicyclic amine 15.
The use of dichloromethane or THF gave modest yields of the de-
sired azabicyclo[3.3.1]nonane (entries 1 and 2). However, by
changing the solvent to dry dimethylformamide the adduct could
be obtained in 70% yield (entry 3). Dimethylformamide is known to
be an effective Lewis base for the enhancement of Lewis acidity in
chlorosilane complexes and the higher yield may be due to an
additional rate enhancement based on this effect.19
OMe
N
OH
OH
N
O
O
i
OBn
OBn
12
O
11
O
Lappaconitine 13
H
N
O
Adduct 15 was converted to the known ether 1414 using the
following standard transformations: Wittig olefination, acetal hy-
drolysis, reduction of the ketone and methylation. Previous double-
Mannich approaches to bicycles such as 14 have been unsuccessful
due to their incompatibility with acetal containing substrates. The
present approach also offers the advantage that bicycle 14 is formed
as a single diastereoisomer whilst previously mixtures of isomers
were produced.14
Scheme 4. Reagents and conditions: (i) 5b (1.25 equiv), MeSiCl3 (1.0 equiv), CH2Cl2, 0 ꢀ
to rt, 35%.
C
OMe
OMe
O
O
O
O
O
OMe
6
OMe
1
N
N
N
O
O
OH
OH
H
EtO
O
EtO
OMe
3 MLA Core Ring Structure
EtO
O
RO
14
15
16
3. Conclusion
Fig. 3. Proposed synthesis of oxygenated bicyclic analogues of MLA 3.
A simple modification of Kapnang’s method for the synthesis of
N-alkyl-1,5,3-dioxazepanes 4aeg involving an aqueous workup
procedure afforded quantitative yields of the products that were
free of impurities. The resultant N-alkyl-1,5,3-dioxazepanes were
activated double-Mannich reaction using the above optimized
conditions to afforded bicyclic amine 20 in 53% yield.
The formation of bicycle 20 can be rationalized if the ring
opening of the dioxolane ring to form conjugated vinyl enol ether
activated using a variety of Lewis acids and reacted with
b-
ketoesters to afford double-Mannich products 5aeg, with meth-
yltrichlorosilane providing the best results. Two chiral dioxaze-
panes were synthesized; one with chirality on the nitrogen 4g, and
another with chirality on the diol backbone 8. Unfortunately, both
chiral dioxazepanes induced no stereoselectivity in their reaction
21 is faster than the competing Mannich reaction with
b-ketoester
16 (Fig. 4). After the initial Mannich reaction of -ketoester in-
b
termediate 21, isomerization of 22 leads to homoenolate 23 that is
in close proximity to the pendant iminium ion enabling rapid
Mannich cyclization. The presence of the vinyl enol ether moiety
alpha to the ketone prevents the addition of the iminium ion to the
desired C-3 position.
with b-ketoester 2 under the optimized conditions. It was found
that in the absence of a nucleophile, 3-ethyl-1,5,3-dioxazepane 4b
and methyltrichorosilane formed a stable intermediate as observed
by 1H NMR. When exposed to
b-ketoesters, this intermediate
To test whether the use of a silyl enol ether could suppress this
reaction pathway by increasing the reaction rate of the Mannich
reaction over acetal cleavage, trimethylsilyl enol ether 24 was
reacted to form a double-Mannich adduct in high yield. This new,
pre-activation protocol was applied to double-Mannich reactions
with acid-sensitive carbonyl compounds 11, 16 and 24 to afford
azabicyclo[3.3.1]nonanes that are significant AE ring analogues of
MLA 3 and lappaconitine 13.
synthesized in 91% yield from b
-ketoester 16 (Scheme 6).18 In order
to suppress the ring opening of the dioxolane ring use of methyl-
trichlorosilane rather than titanium tetrachloride was examined.
O
O
O
O
O
O
i
ii
iii
+
O
CO2Et
CO2Et
17
O
CO2Et
18
O
O
CO2Et
CO2Et
16
19
iv
HO
O
Ph
N
O
EtO
O
20
Scheme 5. Reagents and conditions: (i) diethyl malonate (0.9 equiv), K2CO3 (0.1 equiv), neat, sealed tube, 18 h, 63%; (ii) NaOEt, EtOH, 0 ꢀC to rt to
glycol (1.0 equiv), toluene, cat. p-TsA,
, DeaneStark apparatus, 1 h, 16: 36%, 19: 22%; (iv) 4e (1.25 equiv), TiCl4 (1.0 equiv), CH2Cl2, 0 ꢀC to rt o/n, 54%.
D, 3 h, 94% crude; (iii) ethylene
D

1022
K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
H
HO
OH
OR
Bn
HO
Bn
HO
Bn
O
O
Cl
O
O
O
O
H
N
N
3
3
3
OH
CO2Et
16
O
O
N
O
N
OH
Bn
H
CO2Et
21
CO2Et
22
CO2Et
20
CO2Et
23
Fig. 4. Proposed mechanism for the formation of amine 20.
OMe
N
O O
O
O
O
O
O
i
ii
N
see Table
O
OTMS
O
CO2Et
16
EtO
O
EtO
EtO
O
24
15
14
Entry
1
2
Solvent
DCM
THF
Yield (%)
33
40
3
DMF
70
Scheme 6. Reagents and conditions: (i) Me3SiCl (1.5 equiv), NEt3 (1.5 equiv), toluene, rt 18 h, 91 %; (ii) 3-ethyl-1,5,3-dioxazepane 4b (1.25 equiv), MeSiCl3 (1.0 equiv), 24, solvent,
ꢀC to rt, 18 h.
0
4. Experimental section
4.1. General experimental
concentrated in vacuo to afford the title compound as a crude oil
(6.30 g, 54%, circa 90% pure); dH (400 MHz, CDCl3, Me4Si) 2.63 (3H,
s, NCH3), 3.83 (4H, s, H-6, H-7), 4.45 (4H, s, H-2, H-4); dC (100 MHz,
CDCl3) 37.2 (CH3), 69.1 (CH2, C-6, C-7), 85.2 (CH2, C-2, C-4); IR: nmax
(film)/cmꢁ1 2941, 2864, 1474, 1446, 1386, 1358, 1329, 1299, 1266,
1234, 1215, 1113, 1078, 1041, 1024, 951, 841, 792. LRMS m/z (ESI) 117
(Mþ, 100), 99 (8); HRMS (ESIþ) found: 117.0804, calculated:
117.0790.
All reactions were carried out in oven-dried glassware. HPLC-
grade THF and lab-grade DCM distilled from CaH2 were dried
ꢀ
over activated 3 A molecular sieves. Dried EtOH was freshly dis-
tilled from Mg(OEt)2. DMF, DMSO and Et3N were dried over CaH2
and distilled onto activated 4 A molecular sieves. All other reagents
ꢀ
were used as received. Thin-layer chromatography (TLC) was car-
ried out using Merck silica gel plates using UV light (254 nm) as the
primary visualisation method with supplementary visualisation by
staining with vanillin in 95% ethanol, iodine on silica gel or aqueous
potassium permanganate. Flash column chromatography was per-
formed using Davisil LC60A 40e63 micron amorphous silica.
Melting points were measured on a ReichertÔ stage apparatus,
ElectrothermalÔ capillary apparatus or a Stuart Scientific SMP3
melting point apparatus, with the melting points uncorrected.
Optical rotations were measured with a Perkin Elmer 341 polar-
imeter using the sodium D line (589 nm), with the concentration
measured in grams per 100 mL. Infrared (IR) spectra were recorded
using a Perkin Elmer Spectrum 1000 FT-IR spectrometer with the
absorption peaks expressed in wavenumbers (cmꢁ1) and recorded
between 450 cmꢁ1 and 4000 cmꢁ1. NMR spectra were recorded on
a Bruker Avance-300 or DRX400. High resolution mass spectra
were recorded using a VG70-SE spectrometer or microTOF-Q mass
spectrometer. Chiral stationary phase HPLC was carried out on
a Daicel ChiralpakÔ IC column using Dionex Ultimate 3000Ô HPLC
kit with Chromeleon software.
4.2.2. 3-Ethyl-1,5,3-dioxazepane 4b. Anhydrous ethylamine (9.50 g,
0.21 mol), ethylene glycol (12.5 g, 0.21 mol), and paraformaldehyde
(12.1 g, 0.40 mol) were mixed in a sealed tube at 0 ꢀC then heated to
140 ꢀC for 1.5 h. Benzene (100 mL) was added to the oil and heated
under reflux with a DeaneStark trap for 1 h. The solution was
concentrated in vacuo and the crude oil distilled under reduced
pressure to afford the title compound as a colourless oil (19.0 g,
73%); bp¼76e78 ꢀC, 30 mmHg; dH (300 MHz, CDCl3, Me4Si) 1.12
(3H, t, J¼7.2 Hz), 2.89 (2H, q, J¼7.2 Hz), 3.81 (4H, s, H-6, H-7), 4.49
(4H, s, H-2, H-4); dC (75 MHz, CDCl3) 13.3 (CH3), 43.0 (CH2), 69.1 (C-
6, C-7), 83.2 (C-2, C-4); IR: nmax (film)/cmꢁ1 2967, 2936, 2920, 2910,
2866, 1457, 1380, 1301, 1252, 1211, 1113, 1047, 976, 950, 844, 791,
652, 598; LRMS m/z (EIþ) 131 (Mþ, 2), 129 (2), 118 (7), 114 (3), 103
(2), 99 (2), 85 (66), 83 (100), 74 (5), 71 (6), 62 (3), 58 (37), 47 (31), 42
(23), 35 (14); HRMS (EIþ) found: 131.0946, calculated: 131.0946.
4.2.3. General procedure for the preparation of N-substituted dioxa-
zepanes 4ceg. To a mixture of the amine (1 equiv) and ethylene
glycol (1.2 equiv) in benzene or toluene was added para-
formaldehyde (2.5 equiv). The reaction mixture was heated under
reflux with a DeaneStark trap overnight. The solution was cooled,
washed once with deionized water and brine. The aqueous wash-
ings were extracted with n-hexane and the combined organic
layers dried over anhydrous MgSO4. The mixture was filtered and
concentrated in vacuo to afford the following dioxazepanes.
4.2. Preparation of N-substituted dioxazepanes 4aeg
4.2.1. 3-Methyl-1,5,3-dioxazepane
4a. Aq
methylamine
of
40%(10.0 g, 12.9 mmol), ethylene glycol (6.20 g, 10.0 mmol), and
paraformaldehyde (7.40 g, 24.6 mmol) were mixed in a sealed tube
at 0 ꢀC; heated to 140 ꢀC for 30 min then stirred at room temper-
ature overnight. Benzene (35 mL) was added to the oil and heated
under reflux with a DeaneStark trap for 66 h. The solution was
4.2.4. 3-n-Butyl-1,5,3-dioxazepane 4c. Following the general pro-
cedure, from n-butylamine (7.70 g, 0.11 mol) in benzene (60 mL):
97% yield as a colourless oil; dH (300 MHz, CDCl3, Me4Si) 0.92 (3H, t,

K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
1023
J¼7.2 Hz), 1.27e1.39 (2H, m), 1.43e1.53 (2H, m), 2.83 (2H, t,
J¼7.2 Hz), 3.80 (4H, s, H-6, H-7), 4.47 (4H, s, H-2, H-4); dC (75 MHz,
CDCl3) 13.8 (CH3), 20.1 (CH2), 30.3 (CH2), 48.4 (CH2), 69.2 (C-6, C-7),
83.7 (C-2, C-4); IR: nmax (film)/cmꢁ1 2930, 2863, 1456, 1375, 1302,
1269, 1208, 1112, 1059, 1041, 994, 947, 843, 791, 736, 658, 597; LRMS
m/z (EIþ) 159 (Mþ, 8), 116 (27), 98 (29), 86 (21), 72 (7), 57 (49), 42
(100). HRMS (ESI) found: 159.1262, calculated: 159.1259.
C-2, C-4), 127.0 (2ꢂCH, Ph), 127.1 (CH, Ph), 128.3 (2ꢂCH, Ph), 144.5
(C, Ph); IR: nmax (film)/cmꢁ1 3028, 2973, 2911, 2867, 1602, 1492,
1452, 1371, 1219, 1199, 1115, 1019, 971, 952, 845, 771, 750, 700, 613,
578, 542; LRMS m/z (EIþ) 207 (Mþ, 10), 192 (25), 162 (15), 147 (4),
130 (5), 118 (3), 105 (100), 102 (14), 91 (18), 79 (12), 77 (16), 58 (6),
56 (10), 42 (21); HRMS (EIþ) found: 207.12543, calculated:
207.12593.
4.2.5. 3-tert-Butyl-1,5,3-dioxazepane 4d20. Following the general
procedure, from tert-butylamine (7.70 g, 0.11 mol) in benzene
(40 mL): 70% yield as a colourless oil; bp: 80 ꢀC; 12 mmHg [lit. bp
4.2.10. (6R,7R)-3-Benzyl-6,7-dimethyl-1,5,3-dioxazepane
10. Following the general procedure, from benzylamine (3.2 g,
30.1 mmol), (1R,2R)-butane-1,2-diol (2.7 g, 29.9 mmol) in toluene
20
80 ꢀC; 12 mmHg]20
;
dH (400 MHz, CDCl3, Me4Si) 1.26 (9H, s), 3.86
(50 mL): 27% yield as a colourless oil; [
a]
ꢁ5.8 (c 1.5, CHCl3); dH
D
(4H, s, H-6, H-7), 4.63 (4H, s, H-2, H-4); dC (100 Hz, CDCl3) 29.9
((H3C)3C), 61.2 ((H3C)3C) 68.6 (C-6, C-7), 80.8 (C-2, C-4); HRMS (EIþ)
found: 159.1256, calculated: 159.1259.
(400 MHz, CDCl3, Me4Si) 1.17 (6H, d, J¼5.5 Hz, CH3), 3.57e3.63 (4H,
m, H-6, H-7), 4.06 (2H, s, CH2Ph), 4.32 (4H, d, J¼11.4 Hz, H-2, H-4),
4.61 (2H, d, J¼11.4 Hz, H-2, H-4), 7.20e7.25 (1H, m, Ph), 7.28e7.34
(4H, m, Ph); dC (100 MHz, CDCl3) 19.1 (2ꢂCH3), 53.8 (CH2Ph), 80.2
(2ꢂCH2, C-6, C-7), 82.6 (2ꢂCH2, C-2, C-4), 127.0 (CH, Ph), 128.3 (CH,
Ph), 128.7 (CH, Ph), 138.8 (C, Ph); IR: nmax (film)/cmꢁ1 3029, 2972,
2931, 2868, 1603, 1495, 1453, 1368, 1329, 1277, 1251, 1214, 1178,
1136, 1092, 1068, 1035, 1024, 982, 896, 837, 799, 740, 701, 612, 590,
530, 518; LRMS m/z (EIþ) 221 (Mþ, 0.5),133 (3),119 (16), 91 (100), 65
(11), 51 (4), 39 (6); HRMS (EIþ) found: 221.1416, calculated:
221.1416.
4.2.6. 3-Benzyl-1,5,3-dioxazepane 4e. Following the general pro-
cedure, from benzylamine (10.0 g, 93.3 mmol) in toluene (60 mL):
quantitative yield as a colourless oil; dH (300 MHz, CDCl3, Me4Si)
3.86 (4H, s, H-6, H-7), 4.01 (2H, s, CH2Ph), 4.46 (4H, s, H-2, H-4),
7.22e7.24 (1H, m, o-Ph), 7.25e7.27 (4H, m, Ph); dC (75 MHz, CDCl3)
53.1 (CH2Ph), 69.2 (C-6, C-7), 83.6 (C-2, C-4), 127.1 (CH, Ph), 128.3
(CH, Ph), 128.5 (CH, Ph), 138.3 (C, Ph); IR: nmax (film)/cmꢁ1 3063,
3029, 2911, 2862,1495,1476,1453,1370,1301, 1265,1210,1175,1111,
1076, 1036, 1025, 951, 873, 842, 792, 738, 698, 669, 600, 571, 535,
526, 517; LRMS m/z (EIþ) 193 (Mþ, 0.5),133 (1),119 (15), 91 (100), 65
(17), 51 (17), 41 (6), 39 (9); HRMS (EIþ) found: 193.1103, calculated:
193.1103.
4.3. General methods for the double-Mannich reaction
Method A: To a solution of the ketone (1.0 equiv) and the 3-alkyl-
1,5,3-dioxazepane (1.2 equiv) in dry CH2Cl2 (2 mL/mmol) was
added MeSiCl3 (1.2 equiv). The reaction mixture was stirred until
the consumption of the ketone was observed by thin-layer chro-
matography (3:1 hexane/ethyl acetate). The reaction was quenched
with 2 M HCl and diluted with Et2O. The organic layer was
extracted with 2 M HCl and the combined aqueous extracts were
basified with solid NaHCO3. The resulting mixture was extracted
with Et2O, dried over MgSO4, concentrated in vacuo, and if neces-
sary, purified by flash column chromatography, using the solvent
system stated, to afford the title compounds.
Method B: To a solution of the ketone (1.0 equiv) and the 3-alkyl-
1,5,3-dioxazepane (1.3 equiv) in dry CH2Cl2 (10 mL/mmol) was
added distilled TiCl4 (0.5 equiv) dropwise at 0 ꢀC. The reaction
mixture was stirred until the consumption of the ketone was ob-
served by thin-layer chromatography (3:1 hexane/ethyl acetate).
The reaction was quenched with satd NaHCO3, extracted with
CH2Cl2 (using a centrifuge at 3000 rpm for 5 min). The combined
organic extracts were dried over MgSO4, concentrated in vacuo and
purified by flash chromatography on silica gel, using the solvent
system stated, to afford the title compounds.
4.2.7. 3-(3-Phenylpropyl)-1,5,3-dioxazepane 4f. Following the gen-
eral procedure, from 3-phenylpropylamine (1.66 g, 12.3 mmol) in
toluene (40 mL): 97% yield as a colourless oil; dH (300 MHz, CDCl3,
Me4Si) 1.77e1.87 (2H, m, H-2’), 2.63 (2H, t, J¼7.2 Hz, H-1’), 2.86 (2H,
t, J¼6.9 Hz, H-3’), 3.79 (4H, s, H-6, H-7), 4.47 (4H, s, H-2, H-4),
7.15e7.19 (3H, m, Ph), 7.25e7.30 (2H, m, Ph); dC (75 MHz, CDCl3)
29.7 (CH2, C-2’), 33.1 (CH2, C-3’), 48.0 (CH2, C-1’), 69.1 (2ꢂCH2, C-6,
C-7), 83.7 (2ꢂCH2, C-2, C-4), 125.7, 128.3 (2ꢂCH, Ph), 141.9 (C, Ph);
IR: nmax (film)/cmꢁ1 3025, 2913, 2862, 1496, 1453, 1374, 1355, 1302,
1263, 1207, 1148, 1112, 1032, 978, 951, 843, 792, 744, 698, 656, 598,
523; LRMS m/z (EIþ) 221 (Mþ, 2), 147 (5), 146 (3), 117 (8), 103 (2), 91
(25), 77 (6), 65 (8), 57 (5), 51 (6), 43 (100), 42 (27), 39 (7); HRMS
(EIþ) found: 221.1419, calculated: 221.1416.
4.2.8. (R)-3-(1’-Phenylethyl)-1,5,3-dioxazepane 4g. Following the
general procedure, from (R)-1-phenylethanamine (1.40 g,
20
11.6 mmol) in toluene (60 mL): 89% yield as a colourless oil; [a]
D
þ54.0 (c 1.2, CHCl3); dH (300 MHz, CDCl3, Me4Si) 1.48 (3H, d,
J¼6.8 Hz, CH3), 3.88 (4H, s, H-6, H-7), 4.21 (1H, q, J¼6.8 Hz, CHPh),
4.38 (2H, d, J¼11.3 Hz, H-2A, H-4A), 4.60 (2H, d, J¼11.3 Hz, H-2B, H-
4B), 7.23e7.26 (1H, m, Ph), 7.29e7.34 (4H, m, Ph); dC (75 MHz,
CDCl3) 21.2 (CH3), 56.7 (CHPh), 69.4 (2ꢂCH2, C-6, C-7), 82.2 (2ꢂCH2,
C-2, C-4), 127.1 (2ꢂCH, Ph), 127.2 (CH, Ph), 128.4 (2ꢂCH, Ph), 144.6
(C, Ph); IR: nmax (film)/cmꢁ1 3028, 2973, 2911, 2865, 1602, 1492,
1452, 1371, 1219, 1199, 1115, 1019, 971, 952, 845, 770, 749, 700, 612,
578, 542, 519; LRMS m/z (EIþ) 207 (Mþ, 2), 192 (4), 162 (2), 133 (5),
118 (5), 105 (100), 91 (12), 79 (12), 77 (16), 51 (9), 40 (15); HRMS
(EIþ) found: 207.1260, calculated: 207.1259.
Method C: To
a solution of the 3-alkyl-1,5,3-dioxazepane
(1.2 equiv) in dry CH2Cl2 (circa 2 mL/mmol) was added CH3SiCl3
(1.2 equiv). The reaction mixture was stirred for 30 min followed by
addition of the ketone (1.0 equiv). The reaction mixture was then
stirred until the consumption of the ketone was observed by thin-
layer chromatography (3:1 hexane/ethyl acetate). The reaction was
quenched with 2 M HCl and diluted with Et2O. The organic layer
was extracted with 2 M HCl and the combined aqueous extracts
were basified with solid NaHCO3. The resulting mixture was
extracted with Et2O, dried over MgSO4, concentrated in vacuo, and
if necessary, purified by flash chromatography on silica gel, using
the solvent system stated, to afford the title compounds.
4.2.9. (S)-3-(1-Phenylethyl)-1,5,3-dioxazepane
ent-4g. Following
the general procedure, from (S)-1-phenylethanamine (2.5 g,
20
20.7 mmol) in toluene (40 mL): 88% yield as a colourless oil; [
a
]
4.3.1. (1R
*
,5R )-Ethyl 3-ethyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-
*
D
ꢁ53.0 (c 1.4, CHCl3); dH (400 MHz, CDCl3, Me4Si) 1.48 (3H, d,
J¼6.8 Hz, CH3), 3.86 (4H, s, H-6, H-7), 4.20 (1H, q, J¼6.8 Hz, CHPh),
4.37 (2H, d, J¼11.4 Hz, H-2A, H-4A), 4.59 (2H, d, J¼11.4 Hz, H-2B, H-
4B), 7.20e7.22 (1H, m, Ph), 7.24e7.25 (4H, m, Ph); dC (100 MHz,
CDCl3) 21.1 (CH3), 56.5 (CHPh), 69.3 (2ꢂCH2, C-6, C-7), 82.1 (2ꢂCH2,
carboxylate 5b. Using method A, from ethyl 2-oxocyclohexane-1-
carboxylate 2 (0.18 g, 1.10 mmol), 3-ethyl-1,5,3-dioxazepane 4b
(0.17 g, 1.31 mmol), CH2Cl2 (2.5 mL) and CH3SiCl3 (0.15 mL,
1.30 mmol). Colourless oil (0.25 g, 89%). The 1H and 13C NMR
spectra were in agreement with the literature;1 dH (300 MHz,

1024
K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
CDCl3, Me4Si) 1.10 (3H, t, J¼7.2 Hz, NCH2CH3), 1.29 (3H, t, J¼7.2 Hz,
OCH2CH3), 1.50e1.55 (1H, m, H-7eq), 2.04e2.18 (2H, m, H-6ax, H-
6eq), 2.21e2.27 (1H, m, H-8eq), 2.40 (1H, q, J¼7.2 Hz, NCHAHBCH3),
2.41 (1H, q, J¼7.2 Hz, NCHAHBCH3), 2.44e2.48 (1H, m, H-5),
2.49e2.57 (1H, m, H-8ax), 2.57 (1H, ddd, J¼0.8, 3.3, 11.4 Hz, H-4ax),
2.80e2.91 (1H, m, H-7ax), 2.94 (1H, dd, J¼1.8, 11.4 Hz, H-2ax), 3.15
(1H, dt, J¼2.3, 11.4 Hz, H-4eq), 3.22 (1H, dd, J¼2.3, 11.4 Hz, H-2eq),
4.21 (2H, q, J¼7.0 Hz, OCH2CH3); dC (75 MHz, CDCl3) 12.7
(eNCH2CH3), 14.1 (CH3, eOCH2CH3), 20.5 (CH2, C-7), 34.1 (CH2, C-6),
36.8 (CH2, C-8), 47.2 (CH2, C-5), 51.1 (eNCH2CH3), 58.8 (C, C-1), 59.9
(CH2, C-4), 61.0 (CH2, OCH2CH3), 61.6 (CH2, C-2), 171.2 (OC]O),
212.7 (C]O, C-9).
J¼7.2 Hz, OCHAHBCH3), 7.25e7.35 (5H, m, Ph); dC (75 MHz, CDCl3)
14.1 (CH3, eOCH2CH3), 20.7 (CH2, C-7), 34.0 (CH2, C-6), 36.6 (CH2, C-
8), 47.1 (CH2, C-5), 58.8 (C, C-1), 60.2 (CH2, C-4), 61.1 (CH2,
eOCH2CH3), 61.8 (CH2, C-2), 62.0 (CH2, eCH2Ph), 127.2 (CH, Ph),
128.2 (CH, Ph),128.7 (CH, Ph),138.3 (C, Ph),170.9 (C, C]O), 212.4 (C,
C]O, C-9); IR: nmax (film)/cmꢁ1 2928, 2860, 2813, 1732 (C]O), 1716
(C]O), 1585, 1494, 1455, 1365, 1242, 1186, 1163, 1110, 1072, 1052,
1027, 951, 912, 859, 797, 739, 698, 654, 606; LRMS m/z (EIþ) 301
(Mþ, 12), 300 (11), 284 (38), 272 (3), 258 (34), 256 (7), 226 (5), 212
(3), 210 (2), 182 (3), 164 (2), 132 (3), 120 (8), 106 (2), 91 (100), 81 (4),
65 (9), 55 (3), 42 (8), 41 (7); HRMS (EIþ) found: 301.1676, calculated:
301.1678.
4.3.2. (1R
*
,5R
*
)-Ethyl 3-butyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-
4.3.5. (1R
nonane-1-carboxylate 5f. Using method A, from ethyl 2-
oxocyclohexane-1-carboxylate (0.20 g, 1.20 mmol), 3-(3-
*
,5R )-Ethyl 3-(3-phenylpropyl)-9-oxo-3-azabicyclo[3.3.1]
*
carboxylate 5c. Using method A, from ethyl 2-oxocyclohexane-1-
carboxylate 2 (0.18 g, 1.1 mmol), 3-butyl-1,5,3-dioxazepane 4c
(0.20 g, 1.3 mmol), CH2Cl2 (2.5 mL) and CH3SiCl3 (0.15 mL,
1.3 mmol). Colourless oil (0.28 g, quantitative). The 1H and 13C NMR
spectra were in agreement with the literature;1 dH (300 MHz,
CDCl3, Me4Si) 1.10 (3H, t, J¼7.2 Hz, N(CH2)3CH3), 1.28 (3H, t,
J¼7.2 Hz, OCH2CH3), 1.29e1.59 (5H, m, eNCH2(CH2)2CH3, H-7eq),
2.01e2.28 (3H, m, H-6ax, H-6eq, H-8eq), 2.34 (2H, t, J¼6.9 Hz,
eNCH2(CH2)2CH3), 2.42e2.48 (1H, m, H-5), 2.49e2.59 (2H, m, H-
8ax, H-4ax), 2.78e2.94 (1H, m, H-7ax), 2.91 (1H, dd, J¼1.8, 11.7 Hz, H-
2ax), 3.14 (1H, dt, J¼2.4, 10.8 Hz, H-4eq), 3.20 (1H, dd, J¼2.4, 11.4 Hz,
H-2eq), 4.20 (2H, q, J¼7.2 Hz, eOCH2CH3); dC (75 MHz, CDCl3) 13.7
2
phenylpropyl)-1,5,3-dioxazepane 4f (0.33 g, 1.51 mmol), CH2Cl2
(2.5 mL) and CH3SiCl3 (0.17 mL, 1.39 mmol). Colourless oil (0.40 g,
quantitative). The 1H and 13C NMR spectra were in agreement with
the literature;1 dH (300 MHz, CDCl3, Me4Si) 1.28 (3H, t, J¼6.9 Hz,
eOCH2CH3), 1.54e1.61 (1H, m, H-7eq), 1.82 (2H, quin, J¼7.2 Hz,
eNCH2CH2Bn), 2.06e2.29 (3H, m, H-6ax, H-6eq, H-8eq), 2.35 (2H, t,
J¼6.9 Hz, eNCH2(CH2)2Ph), 2.45e2.61 (3H, m, H-5, H-8ax, H-4ax),
2.69 (2H, t, J¼7.5 Hz, eN(CH2)2CH2Ph), 2.86e2.97 (1H, m, H-7ax),
2.94 (1H, dd, J¼1.5, 11.7 Hz, H-2ax), 3.14 (1H, dt, J¼2.1, 11.1 Hz, H-
2eq), 3.21 (1H, dd, J¼2.1, 11.4 Hz, H-4eq), 4.21 (2H, q, J¼6.9 Hz,
eOCH2CH3), 7.16e7.25 (3H, m, Ph), 7.25e7.31 (2H, m, Ph); dC
(75 MHz, CDCl3) 14.1 (CH3, eOCH2CH3), 20.5 (CH2, C-7), 29.0 (CH2,
eNCH2CH2Bn), 33.4 (CH2, eN(CH2)2CH2Ph), 34.1 (CH2, C-6), 36.7
(CH2, C-8), 47.1 (CH, C-5), 56.3 (CH2, eNCH2(CH2)2Ph), 58.7 (C, C-1),
60.3 (CH2, eOCH2CH3), 61.0 (CH2, C-2), 61.9 (CH2, C-4), 125.8, 128.3
(2ꢂCH, Ph), 141.9 (C, Ph), 171.0 (C, C]O), 212.4 (C, C-9); IR: nmax
(film)/cmꢁ1 2929, 2860, 2808, 1732, 1715, 1602, 1496, 1454, 1365,
1259, 1187, 1162, 1115, 1053, 1028, 1008, 962, 909, 859, 731, 699,
655; LRMS m/z (EIþ) 329 (Mþ, 32), 312 (44), 300 (2), 286 (35), 224
(100), 196 (7), 180 (3), 160 (10), 152 (9), 117 (5), 91 (36), 55 (10), 43
(19); HRMS (EIþ) found: 329.1988, calculated: 329.1991.
(eN(CH2)3CH3),
13.9
(CH3,
eOCH2CH3),
20.2
(CH2,
eN(CH2)2CH2CH3), 20.3 (CH2, C-7), 29.1 (CH2, eNCH2CH2Et), 33.9
(CH2, C-6), 36.6 (CH2, C-8), 47.1 (CH2, C-5), 56.5 (eNCH2Pr), 58.6 (C,
C-1), 60.2 (CH2, C-4), 60.7 (CH2, eOCH2CH3), 61.8 (CH2, C-2), 170.8
(OC]O), 212.1 (C]O, C-9).
4.3.3. (1R
*
,5R )-Ethyl 3-tert-butyl-9-oxo-3-azabicyclo[3.3.1]nonane-
*
1-carboxylate 5d1. Using method A, from ethyl 2-oxocyclohexane-
1-carboxylate 2 (0.19 g, 1.1 mmol), 3-tert-butyl-1,5,3-dioxazepane
4d (0.20 g, 1.3 mmol), CH2Cl2 (2.5 mL) and CH3SiCl3 (0.15 mL,
1.3 mmol). Colourless oil (0.21 g, 69%). The 1H and 13C NMR spectra
were in agreement with the literature;1 dH (400 MHz, CDCl3, Me4Si)
1.13 (9H, s, t-Bu), 1.29 (3H, t, J¼7.2 Hz, OCH2CH3), 1.46e1.49 (1H, m,
H-7eq), 2.05e2.12 (2H, m, H-6ax, H-6eq), 2.21e2.25 (1H, m, H-8eq),
2.43e2.44 (1H, m, H-5), 2.49e2.57 (1H, m, H-8ax), 2.69e2.76 (2H,
m, H-4ax, H-7ax), 3.04 (1H, d, J¼11.3 Hz, H-2ax), 3.28 (1H, dd, J¼2.3,
11.0 Hz, H-4eq), 3.35 (1H, dd, J¼2.3, 11.3 Hz, H-2eq), 4.20 (1H, q,
J¼7.2 Hz, OCHAHBCH3), 4.21 (1H, q, J¼7.2 Hz, OCHAHBCH3); dC
(100 MHz, CDCl3) 14.1 (CH3, OCH2CH3), 20.5 (CH2, C-7), 26.3 (CH3, t-
Bu), 33.5 (CH2, C-6), 36.1 (CH2, C-8), 46.9 (CH2, C-5), 53.3 (CH2, C-4),
53.4 (C, t-Bu), 55.3 (CH2, C-2), 58.8 (C, C-1), 60.8 (CH2, eOCH2CH3),
171.4 (C, C]O), 213.3 (C, C]O, C-9); IR: nmax (film)/cmꢁ1 2971,
2928, 2862, 2821, 1732, 1715, 1458, 1393, 1359, 1299, 1262, 1239,
1219, 1202, 1188, 1162, 1097, 1069, 1040, 1024, 1006, 967, 657; LRMS
m/z (EIþ) 267 (Mþ, 15), 252 (100), 250 (25), 224 (10), 222 (7), 206
(35), 194 (10), 136 (5), 123 (6), 110 (5), 95 (4), 81 (10), 70 (26), 57
(26), 41 (38); HRMS (EIþ) found: 267.1838, calculated: 267.1834.
4.3.6. (1R
[3.3.1]nonane-1-carboxylate 5g. Using method A, from ethyl 2-
oxocyclohexane-1-carboxylate (0.19 g, 1.18 mmol), 3-((R)-1-
*
,5R
*
)-Ethyl 3-((R)-1-phenylethyl)-9-oxo-3-azabicyclo
2
phenylethyl)-1,5,3-dioxazepane 4g (0.30 g, 1.53 mmol), CH2Cl2
(2.5 mL) and CH3SiCl3 (0.17 mL, 1.39 mmol). Colourless oil (0.37 g,
quantitative). 1:1 Diastereomeric ratio. The 1H NMR was in agree-
ment with the literature;21 dH (300 MHz, CDCl3, Me4Si) 1.22 (3H, t,
J¼6.8 Hz, eOCH2CH3), 1.27 (3H, t, J¼7.2 Hz, eOCH2CH3
(6H, m, eCH(CH3)Ph, eCH(CH3)Ph ), 1.54e1.59 (2H, m, H-7eq, H-
7eq), 2.02e2.06 (2H, m, H-6ax, H-6eq), 2.06e2.29 (4H, m, H-6ax, H-
6eq, H-8eq, H-8eq), 2.34e2.45 (1H, m, H-5), 2.44e2.54 (4H, m, H-4ax
H-8ax, H-8ax, H-5 ), 2.87e2.98
(3H, m, H-7ax, H-7ax
J¼2.4, 11.6 Hz, H-2eq), 3.29 (1H, d, J¼10.8 Hz, H-4eq
J¼2.0, 11.0 Hz, H-2eq
(4H, m, eOCH2CH3, eOCH2CH3
*
), 1.37e1.41
*
*
*
*
*
,
*
*
), 2.63 (1H, dd, J¼2.4, 11.2 Hz, H-4ax
*
*
, H-4eq), 2.99e3.03 (1H, m, H-2ax
*
), 3.10 (1H, dd,
*
), 3.36 (1H, dd,
*
), 3.41 (1H, q, J¼6.8 Hz, eCH(CH3)Ph), 4.11e4.21
), 7.22e7.32 (10H, m, Ph).
*
4.3.4. (1R
*
,5R )-Ethyl 3-benzyl-9-oxo-3-azabicyclo[3.3.1]nonane-1-
*
carboxylate 5e. Using method A, from ethyl 2-oxocyclohexane-1-
carboxylate 2 (0.20 g, 1.20 mmol), 3-benzyl-1,5,3-dioxazepane 4e
(0.25 g, 1.32 mmol), CH2Cl2 (2.5 mL) and CH3SiCl3 (0.17 mL,
1.4 mmol). Colourless oil (0.35 g, 88%). The 1H and 13C NMR spectra
were in agreement with the literature;1 dH (300 MHz, CDCl3, Me4Si)
1.26 (3H, t, J¼7.7 Hz, OCH2CH3), 1.56e1.63 (1H, m, H-7eq), 2.01e2.15
(2H, m, H-6ax, H-6eq), 2.21e2.27 (1H, m, H-8eq), 2.43e2.46 (1H, m,
H-5), 2.47e2.55 (1H, m, H-8ax), 2.62 (1H, dd, J¼2.3, 11.5 Hz, H-4ax),
2.99 (1H, dd, J¼1.8, 11.4 Hz, H-2ax), 2.94e3.03 (1H, m, H-7ax), 3.12
(1H, dt, J¼2.3, 11.5 Hz, H-4eq), 3.20 (1H, dd, J¼2.4, 11.4 Hz, H-2eq),
3.51 (2H, s, eCH2Ph), 4.17 (1H, q, J¼7.2 Hz, OCHAHBCH3), 4.18 (1H, q,
4.3.7. (1R
*
,5R )-Ethyl 5-(chloromethyl)-3-ethyl-9-oxo-3-azabicyclo
*
[3.3.1]nonane-1-carboxylate 6b. Using method B, from ethyl 2-
oxocyclohexane-1-carboxylate 2 (0.18 g, 1.03 mmol), 3-ethyl-1,5,3-
dioxazepane 4b (0.18 g, 1.29 mmol), CH2Cl2 (2.5 mL) and TiCl4
(55 mL, 0.5 mmol). Purified by flash column chromatography (19:1
n-hexane/EtOAc). Colourless oil (30 mg, 2.2%); dH (400 MHz, CDCl3,
Me4Si) 1.12 (3H, t, J¼7.2 Hz, NCH2CH3), 1.29 (3H, t, J¼7.1 Hz,
OCH2CH3), 1.53e1.60 (1H, m H-7ax), 1.79 (1H, dddd, J¼2.0, 6.0, 11.6,
13.6 Hz, H-8ax), 2.21e2.27 (1H, m, H-6ax), 2.35 (1H, dd, J¼2.0,
10.8 Hz, H-4ax), 2.41e2.47 (1H, m, H-8eq), 2.45 (2H, q, J¼7.2 Hz,
NCH2CH3), 2.54 (1H, dddd, J¼2.0, 6.4, 12.0, 14.0 Hz, H-6eq),

K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
1025
2.84e2.95 (1H, m, H-7eq), 2.98 (1H, dd, J¼2.0, 11.6 Hz, H-2ax), 3.20
(1H, dd, J¼2.4, 11.6 Hz, H-2eq), 3.34 (1H, dd, J¼2.4, 10.8 Hz, H-4eq),
3.58 (2H, d, J¼2.8 Hz, CH2Cl), 4.22 (2H, q, J¼7.1 Hz, eOCH2CH3); dC
(100 MHz, CDCl3) 12.5 (CH3, eNCH2CH3), 14.1 (CH3, eOCH2CH3),
20.0 (CH2), 36.7 (CH2, C-6), 37.4 (CH2, C-8), 49.3 (CH2, CH2Cl), 49.9
(C, C-5), 51.0 (CH2, eNCH2CH3), 58.9 (C, C-1), 61.2 (CH2, eOCH2CH3),
61.5 (CH2, C-2), 62.6 (CH2, C-4), 170.7 (C, C]O), 211.5 (C, C-9); IR:
nmax (film)/cmꢁ1 2977, 2937, 2815, 1730, 1716, 1673, 1455, 1442,
1368, 1258, 1201, 1175, 1156, 1125, 1097, 1047, 1018, 985, 961, 910,
1072, 1028, 985, 948, 907, 829, 727, 698, 648, 614, 580; LRMS m/z
(EIþ) 287 (MHþ, 5), 272 (100), 260 (7), 134 (4).HRMS (EIþ) found:
272.1636, calculated: 272.1645.
4.3.11. (3R
carboxylate 10d. Using method A, from ethyl 2-methyl-3-
oxohept-6-enoate 9d (0.21 g, 1.2 mmol), 3-benzyl-1,5,3-
*
,5R
*
)-Ethyl 5-allyl-1-benzyl-3-methyl-4-oxopiperidine-3-
dioxazepane 4e (0.28 g, 1.48 mmol), CH2Cl2 (2.5 mL) and CH3SiCl3
(0.17 mL, 1.39 mmol). Purified by flash chromatography on silica gel
(9:1 n-hexane/EtOAc). Colourless oil (0.17 g, 49%). Rf (9:1 n-hexane/
EtOAc) 0.35; dH (400 MHz, CDCl3, Me4Si) 1.18 (3H, s, eCH3),1.22 (3H,
t, J¼6.8 Hz, eOCH2CH3), 1.94 (1H, dt, J¼7.3, 14.8 Hz, eCH2C]CH2),
2.02 (1H, d, J¼11.6 Hz, H-2), 2.05 (1H, t, J¼11.2 Hz, H-6), 2.59 (1H,
dtt, J¼1.2, 6.0, 14.4 Hz, eCH2C]CH2), 3.00e3.07 (1H, m, H-5), 3.16
(1H, ddd, J¼3.2, 6.4, 11.2 Hz, H-6), 3.48 (1H, d, J¼13.6 Hz,
eCHAHBPh), 3.50 (1H, dd, J¼3.2, 11.2 Hz, H-2), 3.66 (1H, d,
J¼13.6 Hz, eCHAHBPh), 4.10e4.18 (1H, m, eOCH2CH3), 4.19e4.27
(1H, m, eOCH2CH3), 4.98 (1H, d, J¼10.4 Hz, eCH]CH2), 5.02 (1H, d,
J¼1.2, 13.2 Hz, eCH]CH2), 5.71e5.81 (1H, m, eCH]CH2),
7.25e7.34 (5H, m, Ph); dC (100 MHz, CDCl3) 13.9 (CH3, eOCH2CH3),
17.6 (CH3), 31.0 (CH2, eCH2C]CH2), 47.6 (CH, C-5), 56.9 (C, C-3),
59.5 (CH2, C-6), 61.1 (CH2, eOCH2CH3), 61.5 (CH2, eCH2Ph), 62.8
(CH2, C-2), 116.2 (CH2, eCH]CH2), 127.1 (2ꢂCH, Ph), 128.1 (2ꢂCH,
Ph),128.6 (CH, Ph),135.7 (CH, eCH]CH2),137.6 (C, Ph),172.8 (C, C]
O), 206.6 (C, C]O, C-4); IR: nmax (film/cmꢁ1) 2979, 2804, 1716 (C]
O), 1657, 1585, 1489, 1469, 1452, 1361, 1272, 1252, 1206, 1118, 1152,
1114, 1066, 1025, 987, 915, 856, 829, 740, 698, 523; LRMS m/z (FABþ)
316 (MHþ, 100), 270 (2), 202 (8), 170 (53), 140 (5), 118 (1); HRMS
(FABþ) found: (MHþ) 316.1915, calculated: 316.1907.
859, 807, 731, 712; LRMS m/z (EIþ) 289 (Mþ 37Cl], 4), 287 (Mþ 35Cl],
[ [
5), 272 (3), 270 (4), 253 (15), 252 (100), 244 (7), 238 (14), 195 (5),
192 (3),183 (3),167 (4),137 (7), 93 (7), 83 (10), 51 (12), 44 (6); HRMS
(EIþ) Found: 287.1284, calculated: 287.1288.
4.3.8. (1S
*
,5R )-3-Benzyl-1-methyl-3-azabicyclo[3.3.1]nonan-9-one
*
10a. Using method A, from 2-methylcyclohexanone 9a (0.13 g,
1.14 mmol), 3-benzyl-1,5,3-dioxazepane 4e (0.26 g, 1.43 mmol),
CH2Cl2 (3 mL) and CH3SiCl3 (0.16 mL, 1.4 mmol). Colourless oil
(0.28 g, quantitative); dH (400 MHz, CDCl3, Me4Si) 0.87 (3H, d,
J¼1.6 Hz, CH3), 1.46e1.56 (1H, m, H-7eq), 1.67e1.75 (1H, m, H-8ax),
1.91e2.12 (3H, m, H-6ax, H-6eq, H-8eq), 2.21 (1H, br d, J¼9.2 Hz, H-
4ax), 2.38 (1H, br s, H-5), 2.49 (1H, d, J¼9.2 Hz, H-2ax), 2.98 (1H, d,
J¼9.2 Hz, H-4eq), 3.10e3.20 (1H, m, H-7ax), 3.13 (1H, dd, J¼1.6,
10.4 Hz, H-2eq), 3.40 (2H, s, eCH2Ph), 7.17e7.32 (5H, m, Ph); dC
(100 MHz, CDCl3) 20.8 (CH3), 21.2 (CH2, C-7), 34.6 (CH2, C-6), 42.4
(CH2, C-8), 46.9 (C, C-1), 47.7 (CH, C-5), 60.3 (CH2, C-2), 62.0 (CH2,
eCH2Ph), 66.7 (CH2, C-4), 126.9 (2ꢂCH, Ph), 128.7 (CH, Ph), 138.4 (C,
Ph), 218.3 (C]O, C-9); IR: nmax (film)/cmꢁ1 2971, 2926, 2856, 2821,
1721 (C]O), 1458, 1393, 1359, 1298, 1263, 1240, 1217, 1202, 1188,
1164, 1097, 1069, 1042, 1025, 1006, 657; LRMS m/z (ESIþ) 243 (Mþ,
100), 166 (13); HRMS (ESIþ) found: 243.1619, calculated: 243.1623.
4.4. Synthesis of 1-oxygenated-3-azabicyclo[3.3.1]nonan-9-
ones
4.3.9. (1R
*
,5R )-Ethyl 3-benzyl-8-oxo-3-azabicyclo[3.2.1]octane-1-
*
carboxylate 10b. Using method A, from ethyl 2-oxocyclopentane-
1-carboxylate 9b (0.16 g, 1.0 mmol), 3-benzyl-1,5,3-dioxazepane 4e
(0.23 g, 1.2 mmol), CH2Cl2 (2 mL) and CH3SiCl3 (0.13 mL, 1.1 mmol).
Colourless oil (0.30 g, 88%). The 1H NMR was in agreement with the
literature;1 dH (400 MHz, CDCl3, Me4Si) 1.25 (3H, t, J¼7.2 Hz,
eOCH2CH3), 1.92e2.05 (2H, m, H-6exo, H-6endo), 2.27e2.32 (1H, m,
H-7endo), 2.32e2.34 (1H, m, H-5), 2.41 (1H, ddd, J¼1.2, 4.8, 12.1 Hz,
H-7exo), 2.56 (1H, d, J¼10.4 Hz, H-4ax), 2.78 (1H, d, J¼11.0 Hz, H-2ax),
2.96 (1H, ddd, J¼1.4, 3.0, 10.4 Hz, H-4eq), 3.13 (1H, dd, J¼2.6, 11.0 Hz,
H-2eq), 3.60 (1H, d, J¼13.2 Hz, eCH2Ph), 3.66 (1H, d, J¼13.2 Hz,
eCH2Ph), 4.17 (2H, q, J¼7.2 Hz, eOCH2CH3), 7.24e7.36 (5H, m, Ph);
dC (100 MHz, CDCl3) 14.0 (CH3, eOCH2CH3), 21.8 (CH2, C-6), 27.6
(CH2, C-7), 46.4 (CH, C-5), 57.8 (C, C-1), 60.1 (CH2, eCH2Ph), 61.0
(CH2, eOCH2CH3), 61.1 (CH2, C-4), 62.4 (CH2, C-2), 127.2 (CH, Ph),
128.3 (CH, Ph), 128.5 (CH, Ph), 138.0 (C, Ph), 170.2 (C, C]O), 213.4
(C]O, C-8).
4.4.1. 2-(Benzyloxy)cyclohexanol22. To
a
suspension
of
Cu(BF4)2$xH2O (90 mg, w0.40 mmol) in benzyl alcohol (3.90 g,
36.0 mmol) under a nitrogen atmosphere was added cyclohexene
oxide (3.50 g, 36.2 mmol) dropwise. The reaction mixture was
stirred overnight and the crude mixture purified by flash column
chromatography (19:1 n-hexane/EtOAc) to afford the title com-
pound as a colourless oil (3.6 g, 49%). The 1H and 13C NMR spectra
were in agreement with the literature.23 Rf (9:1 n-hexane/EtOAc)
0.50; dH (300 MHz, CDCl3, Me4Si) 1.18e1.32 (4H, m, H-3B, H-4B, H-
5B, H-6B), 1.65e1.77 (2H, m, H-4A, H-5A), 1.98e2.17 (2H, m, H-3A,
H-6A), 2.78 (1H, br s, OH), 3.15e3.24 (1H, m, H-2), 3.45e3.54 (1H,
m, H-1), 4.48 (1H, d, J¼11.3 Hz, CH2Ph), 4.70 (1H, d, J¼11.3 Hz,
CH2Ph), 7.26e7.40 (5H, m, Ph); dC (75 MHz, CDCl3) 23.9 (CH2, C-4),
24.2 (CH2, C-5), 29.2 (CH2, C-3), 32.0 (CH2, C-6), 70.8 (CH2, CH2Ph),
73.8 (CH, C-1), 83.5 (CH, C-2), 127.7 (3ꢂCH, Ph), 128.5 (2ꢂCH, Ph),
138.5 (C, Ph).
4.3.10. (1S
*
,5R
*
)-1-Acetyl-3-benzyl-3-azabicyclo[3.3.1]nonan-9-one
4.4.2. 2-(Benzyloxy)cyclohexanone 11. Oxalyl chloride (1.5 mL,
17.4 mmol) was dissolved in dry CH2Cl2 (10 mL) under a nitrogen
atmosphere and cooled to ꢁ78 ꢀC. Dry DMSO (2.7 mL, 37.7 mmol)
in dry CH2Cl2 (30 mL) was added dropwise and stirred for 20 min.
2-(Benzyloxy)cyclohexanol (3.2 g, 15.5 mmol) in dry CH2Cl2 (7 mL)
was added dropwise to form a suspended white precipitate. The
mixture was stirred for 30 min, warmed to ꢁ60 ꢀC and dry Et3N
(11 mL, 78.9 mmol) was added dropwise. The reaction mixture was
held at ꢁ60 ꢀC for 5 min then warmed to room temperature. The
reaction was quenched with H2O (80 mL) and the organic layer
separated. The organic extract was washed with 2 M HCl (30 mL),
H2O (30 mL) and satd NaHCO3 (30 mL), dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (9:1 n-hexane/EtOAc) to afford the title
compound as a colourless oil (2.5 g, 75%). The 1H and 13C NMR
spectra were in agreement with the literature.24 Rf (9:1 n-hexane/
10c. Using method A, from 2-acetylcyclohexanone 9c (0.18 g,
1.3 mmol), 3-benzyl-1,5,3-dioxazepane 4e (0.33 g, 1.7 mmol),
CH2Cl2 (2.5 mL) and CH3SiCl3 (0.18 mL, 1.5 mmol). Colourless oil
(0.35 g, quantitative); dH (400 MHz, CDCl3, Me4Si) 1.57e1.61 (1H, m,
H-7eq), 2.02e2.17 (3H, m, H-6ax, H-6eq, H-8eq), 2.18 (3H, s, C(]O)
CH3), 2.26e2.34 (1H, m, H-8ax), 2.42e2.46 (1H, m, H-5), 2.61 (1H,
dd, J¼3.8, 11.5 Hz, H-4ax), 2.82e2.90 (1H, m, H-7ax), 2.89 (1H, d,
J¼11.1 Hz, H-2ax), 3.07 (1H, dt, J¼2.1, 11.1 Hz, H-2eq), 3.12 (1H, dd,
J¼2.1, 11.5 Hz, H-4eq), 3.47 (1H, d, J¼13.1 Hz, CH2Ph), 3.53 (1H, d,
J¼13.1 Hz, CH2Ph), 7.23e7.32 (5H, m, Ph); dC (100 MHz, CDCl3) 20.1
(CH2, C-7), 27.7 (CH3, C(]O)CH3), 33.6 (CH2, C-6), 35.7 (CH2, C-8),
47.2 (CH, C-5), 59.9 (CH2, C-4), 60.9 (CH2, C-2), 61.8 (CH2, CH2Ph),
62.6 (C, C-1), 127.1 (CH, Ph), 128.2 (CH, Ph), 128.5 (CH, Ph), 137.9 (C,
Ph), 207.1 (C, C]O), 214.7 (C, C-9); IR: nmax (film/cmꢁ1) 2928, 2859,
2806, 1704 (C]O), 1494, 1454, 1355, 1314, 1253, 1235, 1162, 1104,

1026
K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
EtOAc) 0.65; dH (300 MHz, CDCl3, Me4Si) 1.60e1.75 (2H, m),
1.77e1.86 (1H, m), 1.89e1.98 (2H, m), 2.14e2.32 (2H, m), 2.51e2.59
(1H, m), 3.88 (1H, ddd, J¼1.2, 5.5, 9.8 Hz), 4.48 (1H, d, J¼12.1 Hz,
CH2Ph), 4.76 (1H, d, J¼12.1 Hz, CH2Ph), 7.27e7.33 (1H, m, Ph),
7.34e7.39 (4H, m, Ph); dC (75 MHz, CDCl3) 23.1 (CH2, C-4), 27.6 (CH2,
C-5), 34.6 (CH2, C-3), 40.6 (CH2, C-6), 71.6 (CH2, CH2Ph), 81.7 (CH, C-
2), 127.7 (2ꢂCH, Ph), 127.8 (CH, Ph), 128.4 (2ꢂCH, Ph), 138.0 (C, Ph),
210.1 (C, C-1).
reaction mixture was allowed to warm to room temperature before
heating under reflux for 3 h. The crude material was dissolved in
brine (350 mL) and washed with Et2O (2ꢂ100 mL). The aqueous
layer was cooled to 0 ꢀC and acidified with 2 M H2SO4. The mixture
was extracted with Et2O (3ꢂ200 mL), the combined organic ex-
tracts were dried over MgSO4 and concentrated in vacuo to afford
the title compound as a colourless solid (17.7 g, 94%); mp 58e63 ꢀC
[lit. mp26 56e60 ꢀC]; multiple ketoeenol tautomers: dH (400 MHz,
CDCl3, Me4Si) 1.27e1.39 (3H, m, eOCH2CH3), 2.15e2.64 (4H, m, H-5,
H-6), 3.16 (0.6H, s, H-3), 3.36e3.67 (1H, m, H-1), 4.20e4.30 (2H, m,
eOCH2CH3), 5.39 (0.1H, s, H-3), 5.54 (0.4H, s, H-3), 7.82 (0.5H, br s,
OH enol), 12.22 (0.3H, s, OH, enol); dC (100 MHz, CDCl3) 14.1, 14.2
(CH3, eOCH2CH3), 20.1 (CH2), 21.5 (CH2), 24.2 (CH2), 27.3 (CH2), 29.4
(CH2), 37.8 (CH2), 38.9 (CH2), 42.9 (CH2), 49.0 (CH, C-1), 52.2 (CH, C-
1), 55.1 (CH, C-1), 57.8 (CH2), 60.8 (CH2, eOCH2CH3), 61.3 (CH2,
eOCH2CH3), 61.9 (CH2, eOCH2CH3), 64.7 (CH2, eOCH2CH3), 97.9 (C),
102.0 (CH), 104.9 (CH), 167.5 (C, C]O), 168.7 (C), 170.3(C), 170.8(C),
171.4 (C), 187.0 (C),188.2 (C),198.4 (C), 202.4 (C), 206.2 (C, C]O); IR:
nmax (film)/cmꢁ1 3156, 3063, 2983, 2955, 2914, 1728 (C]O), 1644,
1601, 1571, 1458, 1308, 1193, 1173, 1153, 1088, 1024, 845, 605; LRMS
m/z (EIþ) 184 (Mþ, 100), 156 (16), 142 (12), 138 (40), 127 (14), 114
(48), 110 (78), 96 (57), 86 (17), 82 (37), 68 (46), 55 (48), 42 (49), 39
(70); HRMS (EIþ) found: 184.0732, calculated: 184.0736.
4.4.3. (1R
*
,5R )-1-(Benzyloxy)-3-ethyl-3-azabicyclo[3.3.1]nonan-9-
*
one 12. To a solution of 2-(benzyloxy)cyclohexanone 11 (0.18 g,
0.88 mmol) and 3-ethyl-1,5,3-dioxazepane 4b (0.14 g, 1.03 mmol)
in dry CH2Cl2 (2 mL) was added CH3SiCl3 (0.13 mL, 1.12 mmol) un-
der a nitrogen atmosphere. The mixture was stirred for 90 min and
quenched with 2 M HCl (3 mL). The mixture was diluted with Et2O
(10 mL), the aqueous phase was separated and the organic phase
was extracted with 2 M HCl (3ꢂ10 mL). The combined aqueous
extracts were washed with Et2O (1ꢂ20 mL) and neutralized with
solid NaHCO3. The alkaline solution was extracted with Et2O
(3ꢂ20 mL), the combined extracts were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (9:1 n-hexane/EtOAc) to afford the title
compound as a colourless oil (85 mg, 35%); dH (400 MHz, CDCl3,
Me4Si) 1.08 (3H, t, J¼7.2 Hz, NCH2CH3), 1.57e1.64 (1H, m, H-7eq),
1.96e2.15 (2H, m, H-6ax, H-6eq), 2.19e2.34 (2H, m, H-8ax, H-8eq),
2.38 (1H, q, J¼7.2 Hz, eNCHAHBCH3), 2.39 (1H, q, J¼7.2 Hz,
NCHAHBCH3), 2.53e2.58 (2H, m, H-4ax, H-5), 2.62 (1H, dd, J¼1.6,
10.8 Hz, H-2ax), 2.85e2.97 (1H, m, H-7ax), 3.08 (1H, d, J¼10.8 Hz, H-
4eq), 3.22 (1H, dd, J¼1.6, 10.8 Hz, H-2eq), 4.68 (1H, d, J¼11.4 Hz,
eCH2Ph), 4.74 (1H, d, J¼11.4 Hz, eCH2Ph), 7.23e7.37 (3H, m, Ph),
7.41e7.42 (2H, m, Ph); dC (100 MHz, CDCl3) 12.6 (CH3, NCH2CH3),
21.3 (CH2, C-7), 33.8 (CH2, C-6), 39.3 (CH2, C-8), 49.0 (CH, C-5), 51.0
(CH2, NCH2CH3), 59.4 (C, C-4), 64.1 (CH2, C-2), 66.1 (CH2, eCH2Ph),
81.0 (C, C-1), 127.1 (2ꢂCH, Ph), 127.5 (CH, Ph), 128.1 (2ꢂCH, Ph),
139.2 (C, Ph), 214.6 (C, C-9); LRMS m/z (EIþ) 296 (MNaþ, 9), 274
(MHþ, 100),182 (1); HRMS (EIþ) found (MHþ): 274.1805, calculated:
274.1802.
4.5.3. Ethyl 7-oxo-1,4-dioxaspiro[4.5]decane-8-carboxylate 16 and
ethyl 9-oxo-1,4-dioxaspiro[4.5]decane-6-carboxylate 19. Ethyl 2,4-
dioxocyclohexane-1-carboxylate 18 (17.7 g, 96.1 mmol), ethylene
glycol (6.00 g, 96.7 mmol), p-TSA (0.20 g, 1.16 mmol) and toluene
(200 mL) were combined and heated under reflux in a DeaneStark
apparatus for 1 h. The crude mixture was concentrated in vacuo
and purified by flash column chromatography (9:1 n-hexane/
EtOAc) to afford the title compounds 16 (7.8 g, 36%) and 19 (4.8 g,
22%) as colourless oils.
A mixture of keto/enol tautomers. Compound 16: dH (400 MHz,
CDCl3, Me4Si) 1.26e1.40 (3H, m, eOCH2CH3), 1.73e1.78 (1.6H, m),
1.87e1.94 (0.3H, m), 1.87e1.94 (0.3H, m), 1.99e2.08 (0.7H, m),
2.20e2.27 (0.4H, m), 2.39e2.45 (1.4H, m), 2.53 (1.3H, m), 2.64
(0.3H, d, J¼13.9 Hz), 2.77 (0.3H, d, J¼13.9 Hz), 3.35 (0.3H, dd, J¼5.2,
8.1 Hz), 3.93e4.03 (4H, m), 4.16e4.25 (2H, m, eOCH2CH3), 12.20
(0.5H, s, OH enol); dC (100 MHz, CDCl3) 14.1, 14.2 (CH3, eOCH2CH3),
20.2 (CH2), 23.3 (CH2), 31.3 (CH2), 32.6 (CH2), 39.2 (CH2), 51.1 (CH2),
55.6 (CH), 60.3 (CH2), 61.3 (CH2), 64.5, 64.8 (2ꢂCH2, C-2, C-3), 96.9
(C), 107.2 (C), 109.6 (C), 168.5 (C), 169.4 (C), 172.2 (C), 201.7 (C, C-7);
IR: nmax (film)/cmꢁ1 2980, 2954, 2890, 1741, 1718, 1654, 1616, 1466,
1443,1404, 1365,1300,1262,1216,1175, 1153, 1107,1069,1036,1017,
947, 926, 823, 704; LRMS m/z (EIþ) 228 (Mþ, 22), 213 (1), 200 (2),
183 (6), 154 (3), 141 (3), 127 (2), 113 (10), 99 (31), 86 (100), 69 (5), 55
(8), 42 (14), 35 (5); HRMS (EIþ) found: 228.1001, calculated:
228.0998.
Compound 19: dH (400 MHz, CDCl3, Me4Si) 1.30 (3H, t, J¼7.2 Hz,
OCH2CH3), 2.09e2.18 (2H, m, H-7), 2.33 (1H, ddt, J¼1.6, 5.8, 14.1 Hz,
H-8), 2.52 (1H, dt, J¼1.5, 14.4 Hz, H-10), 2.59 (1H, ddd, J¼5.5, 9.2,
14.1 Hz, H-8), 2.95 (1H, dt, J¼1.2, 5.3 Hz, H-6), 3.14 (1H, dd, J¼1.0,
14.4 Hz, H-10), 3.94e3.98 (2H, m, C-2/C-3), 4.00e4.02 (2H, m, C-2/C-
3), 4.21 (2H, q, J¼7.2 Hz, OCH2CH3); dC (100 MHz, CDCl3) 14.1 (CH3,
eOCH2CH3), 23.2 (CH2 C-7), 37.3 (CH2, C-8), 47.9 (CH, C-6), 49.9 (CH2,
C-10), 60.8 (CH3, eOCH2CH3), 64.5, 64.8 (CH2, C-2, C-3), 109.4 (C, C-
5), 171.5 (C, C]O), 206.7 (C, C]O, C-9); IR: nmax (film)/cmꢁ1 2981,
2952, 2888,1756,1712,1654,1616,1469,1443,1363,1302,1260,1210,
1152, 1104, 1067, 1038, 1014, 947, 927, 824; LRMS m/z (EIþ) 228 (Mþ,
10), 212 (20), 183 (24), 171 (40), 167 (40), 155 (5), 139 (25), 128 (40),
112 (37), 99 (20), 86 (100), 84 (60), 69 (53), 68 (54), 55 (62), 43 (39);
HRMS (EIþ) found: 228.10058, calculated: 228.09977.
4.5. Synthesis of 1-oxygenated-3-azabicyclo[3.3.1]nonanes
4.5.1. Diethyl 2-(3’-oxobutyl)malonate 17. Diethyl malonate (65.6 g,
0.41 mol), K2CO3 (6.00 g, 0.04 mol) and methyl vinyl ketone (32.2 g,
0.46 mol) were stirred in a sealed tube [caution: exothermic] over-
night. The reaction was quenched with 2 M H2SO4 (21 mL) and di-
luted with Et2O (30 mL). The organic layer was separated and the
aqueous layer extracted with Et2O (50 mL). The combined organic
extracts were washed with H2O (50 mL), brine (20 mL) and dried
over MgSO4. The product was purified by distillation under reduced
pressure to afford the title compound as a colourless oil (59.4 g, 63%).
The 1H and 13C NMR spectra were in agreement with the litera-
ture;25 bp 124e126 ꢀC; 1 mmHg; dH (300 MHz, CDCl3, Me4Si) 1.27
(6H, t, J¼7.2 Hz, eOCH2CH3), 2.15 (3H, s, H-4’), 2.15 (2H, m, H-1’), 2.55
(2H, t, J¼7.2 Hz, H-2’), 2.55 (1H, t, J¼7.5 Hz, H-2), 4.18 (4H, dq, J¼0.9,
7.2 Hz, eOCH2CH3); dC (75 MHz, CDCl3) 13.9 (CH3, eOCH2CH3), 22.3
(CH2, C-1’), 29.8 (CH2, C-4’), 40.3 (CH2, C-2’), 50.6 (CH, C-2), 61.3 (CH2,
eOCH2CH3), 169.0 (C, eCO2CH2CH3), 207.0 (C, C-3’); IR: nmax (film)/
cmꢁ1 2984, 2941, 2905,1745,1726,1718,1466,1447,1415,1369,1249,
1227, 1176, 1151, 1096, 1026, 950, 860, 753; LRMS m/z (EIþ) 230 (Mþ,
5), 215 (3), 185 (43),173 (15), 169 (17),160 (81),156 (5), 139 (71),133
(17),127 (21),111 (21), 99 (8), 86 (10), 71 (6), 55 (26), 43 (100); HRMS
(EIþ) found: 230.11508, calculated: 230.11542.
4.5.2. Ethyl 2,4-dioxocyclohexanecarboxylate 1826. Diethyl 2-(3-
oxobutyl)malonate 17 (23.6 g, 0.1 mol) was added dropwise to
a solution of sodium ethoxide in EtOH [made from Na (2.3 g,
0.1 mol) and EtOH (42 mL)] at ꢁ12 ꢀC under a N2 atmosphere. The
4.5.4. (1R
*
,5R
*
)-Ethyl 3-benzyl-6-(2’-hydroxyethoxy)-8-oxo-3-
20. Ethyl 7-oxo-1,4-
azabicyclo[3.3.1]non-6-ene-1-carboxylate

K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
1027
dioxaspiro[4.5]decane-8-carboxylate 16 (0.32 g, 1.44 mmol) and 3-
benzyl-1,5,3-dioxazepane 4e (0.37 g, 1.92 mmol) were dissolved in
dry CH2Cl2 (5 mL) under a N2 atmosphere and cooled to 0 ꢀC. Dis-
tilled TiCl4 (0.15 mL, 1.4 mmol) was added dropwise and the mix-
ture was left to warm to room temperature overnight. The reaction
was quenched with satd NaHCO3 (10 mL), extracted [centrifuge]
with EtOAc (3ꢂ20 mL), dried over Na2SO4 and concentrated in
vacuo. The crude material was purified by flash column chroma-
tography (1:1 n-hexane/EtOAc) to afford the title compound as
a colourless gum (0.27 g, 54%). Rf (1:1 n-hexane/EtOAc) 0.2; dH
(400 MHz, CDCl3, Me4Si) 1.23 (3H, t, J¼7.1 Hz, eOCH2CH3), 1.76 (1H,
dd, J¼2.9, 12.5 Hz, H-9), 2.11 (1H, dd, J¼1.8, 11.0 Hz, H-4), 2.36 (1H,
d, J¼11.1 Hz, H-2), 2.59 (1H, br s, OH), 2.64 (1H, t, J¼2.5 Hz, H-5),
2.70 (1H, d, J¼12.5 Hz, H-9), 2.80 (1H, d, J¼11.0 Hz, H-4), 3.31 (1H, d,
J¼11.1 Hz, H-2), 3.49 (1H, d, J¼13.7 Hz, CH2Ph), 3.61 (1H, d,
J¼13.7 Hz, CH2Ph), 3.82e3.84 (2H, m, HOCH2CH2OR), 3.91e3.96
(1H, m, HOCH2CH2OR), 3.98e4.03 (1H, m, HOCH2CH2OR), 4.16 (2H,
q, J¼7.1 Hz, eOCH2CH3), 5.59 (1H, s, H-7), 7.16e7.32 (5H, m, Ph); dC
(100 MHz, CDCl3) 13.9 (CH3, eOCH2CH3), 35.0 (CH2, C-9), 35.9 (CH,
C-5), 51.5 (CH2, C-4), 54.1 (C, C-1), 56.8 (CH2, C-2), 60.1 (CH2,
HOCH2CH2OR), 60.9 (CH2, eOCH2CH3), 61.3 (CH2, CH2Ph), 70.1 (CH2,
HOCH2CH2OR), 104.2 (CH, C-7), 126.9 (CH, Ph), 128.1 (CH, Ph), 128.3
(CH, Ph), 137.8 (C, Ph), 171.3 (C, C]O), 178.4 (C, C-6), 196.8 (C, C-8);
IR: nmax (film)/cmꢁ1 3026, 2936, 2798, 1733, 1651, 1601, 1494, 1452,
1388, 1365, 1299, 1259, 1235, 1188, 1144, 1065, 1026, 902, 861, 835,
740, 699, 644; LRMS m/z (EIþ) 359 (Mþ, 31), 314 (45), 298 (3), 268
(22), 252 (2), 244 (2), 222 (2), 134 (9), 120 (6), 91 (100), 65 (7), 42
(14); HRMS (EIþ) found: 359.1727, calculated: 359.1733.
2.41 (2H, q, J¼7.2 Hz, eNCH2CH3), 2.39e2.46 (2H, m, H-4ax, H-8eq),
2.49e2.51 (1H, m, H-5), 2.93 (1H, dd, J¼2.1, 11.4 Hz, H-2ax),
3.18e3.29 (2H, m, H-2aq, H-7ax), 3.33 (1H, dt, J¼2.1, 11.4 Hz, H-4eq),
3.87e4.03 (4H, m, C-20, C-30, eO(CH2)2Oe), 4.22 (2H, q, J¼7.0 Hz,
eOCH2CH3); dC (75 MHz, CDCl3) 12.4 (CH3, eNCH2CH3), 14.0 (CH3,
eOCH2CH3), 29.6 (CH2, C-8), 31.9 (CH2, C-7), 50.6 (CH2, eNCH2CH3),
55.4 (CH, C-4), 56.5 (CH, C-5), 58.0 (C, C-1), 61.1 (CH2, eOCH2CH3),
61.8 (CH2, C-2), 64.4 (CH2, C-20/C-30), 64.8 (CH2, C-20/C-30), 112.6 (C,
C-6),170.5 (C, C]O), 206.8 (C, C-9); IR: nmax (film)/cmꢁ1 2975, 2936,
2808, 1733 (C]O), 1719 (C]O), 1596, 1475, 1452, 1426, 1367, 1308,
1259, 1232, 1164, 1138, 1095, 1024, 946, 906, 881, 860, 846, 776, 759,
732, 663; LRMS m/z (EIþ) 320 (MNaþ, 100), 298 (MHþ, 38), 252 (15),
186 (35), 141 (3); HRMS (EIþ) found: 298.1642, calculated:
298.1649.
4.5.7. (1S
*
,5S
*
)-Ethyl 3-ethyl-9-methylene-3-azaspiro[bicyclo[3.3.1]
suspension of
nonane-6,2’-[1,3]dioxolane]-1-carboxylate. To
a
methyltriphenylphosphonium bromide (2.1 g, 5.9 mmol) in dry
THF (20 mL) under a N2 atmosphere at ꢁ78 ꢀC was added n-BuLi in
n-hexane (3.2 mL, 1.6 M, 5.1 mmol). The mixture was warmed to
0 ꢀC then re-cooled to ꢁ78 ꢀC. Ketone 15 (0.7 g, 2.4 mmol) dis-
solved in dry THF (5 mL) was then added dropwise and the mixture
warmed to 0 ꢀC. After 1 h, the reaction mixture was warmed to
room temperature, quenched with satd NH4Cl (15 mL), extracted
with EtOAc (3ꢂ15 mL), dried over MgSO4 and concentrated in
vacuo. The crude material was purified by flash column chroma-
tography (9:1 n-hexane/EtOAc) to afford the title compound as an
amber oil (0.52 g, 74%); dH (300 MHz, CDCl3, Me4Si) 1.06 (3H, t,
J¼7.2 Hz, eNCH2CH3), 1.28 (3H, t, J¼7.6 Hz, eOCH2CH3), 1.71 (1H,
dd, J¼7.6, 11.4 Hz, H-7/8ax), 1.90 (1H, dd, J¼7.4, 12.0 Hz, H-7/8eq),
2.12 (1H, dd, J¼4.0, 11.6 Hz, H-4ax), 2.25 (1H, dtd, J¼1.2, 4.0, 14.8 Hz,
H-8/7ax), 2.33 (2H, q, J¼7.2 Hz, eNCH2CH3), 2.35 (1H, s, H-5), 2.57
(1H, dd, J¼4.0, 11.5 Hz, H-2ax), 3.04 (1H, dt, J¼8.0, 11.4 Hz, H-8/7eq),
3.07 (1H, d, J¼11.5 Hz, H-2aq), 3.22 (1H, d, J¼11.2 Hz, H-4eq),
3.89e3.96 (2H, m, C-40/C-50, eO(CH2)2Oe), 3.98e4.02 (2H, m, C-40/
C-50, eO(CH2)2Oe), 4.17e4.24 (2H, m, eOCH2CH3), 4.63 (1H, s, C]
CH2), 4.84 (1H, s, C]CH2); dC (75 MHz, CDCl3) 12.3 (CH3,
eNCH2CH3), 14.2 (CH3, eOCH2CH3), 32.0 (CH2, C-8/C-7), 32.1 (CH2,
C-7/C-8), 49.6 (CH, C-5), 49.8 (C, C-1), 51.5 (CH2, eNCH2CH3), 56.6
(CH, C-4), 60.6 (CH2, eOCH2CH3), 61.7 (CH2, C-2), 64.3 (CH2, C-20/C-
30), 64.5 (CH2, C-20/C-30), 106.5 (C]CH2), 111.1 (C, C-6), 148.2 (C, C-
9), 173.8 (C, C]O); IR: nmax (film)/cmꢁ1 2973, 2924, 2807, 1723,
1655, 1473, 1450, 1425, 1380, 1366, 1313, 1249, 1231, 1180, 1144,
1097, 1060, 1022, 949, 908, 891, 860, 840, 805, 754, 732, 692; LRMS
m/z (EIþ) 296 (MHþ, 100); HRMS (EIþ) found: 296.1849, calculated:
296.1862.
4.5.5. Ethyl 7-(trimethylsilyloxy)-1,4-dioxaspiro[4.5]dec-7-ene-8-
carboxylate 24. To a solution of ketone 16 (7.80 g, 34.2 mmol) in
dry toluene (140 mL) under a N2 atmosphere was added dry Et3N
(7.5 mL, 53.8 mmol) followed by chlorotrimethylsilane (6.5 mL,
51.5 mmol) and the mixture stirred overnight. The reaction was
quenched with satd NaHCO3 (40 mL), the aqueous layer extracted
with n-hexane (50 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo to afford the title compound
as a colourless oil (9.3 g, 91%); dH (300 MHz, CDCl3, Me4Si) 0.23 (9H,
s, eSi(CH3)3), 1.28 (3H, t, J¼7.1 Hz, eOCH2CH3), 1.73 (2H, t, J¼6.5 Hz,
H-10), 2.40 (2H, s, H-6), 2.45e2.49 (2H, t, J¼6.5 Hz, H-9), 3.97 (4H, s,
H-2, H-3), 4.17 (2H, q, J¼7.1 Hz, OCH2CH3); dC (75 MHz, CDCl3) 0.6
(Si(CH3)3), 14.4 (CH3, eOCH2CH3), 22.7 (CH2, C-9), 30.9 (CH2, C-10),
42.3 (CH2, C-6), 59.7 (CH2, eOCH2CH3), 64.5 (2ꢂCH2, C-2, C-3),107.5
(C, C-5), 108.7 (C, C-1), 155.7 (C, C-2), 167.0 (C, C]O); IR: nmax (film)/
cmꢁ1 2955, 2897, 1714, 1686, 1632, 1446, 1393, 1373, 1298, 1249,
1194, 1108, 1063, 1022, 1007, 984, 948, 931, 841, 787, 753, 688, 631,
578; LRMS m/z (CIþ) 301 (MHþ, 36), 285 (87), 271 (3), 265 (37), 228
(12), 214 (12), 199 (12), 185 (9), 171 (15), 141 (6), 113 (7), 99 (26), 91
(18), 86 (100), 75 (34), 73 (34); HRMS (CIþ) found: 301.1479; cal-
culated: 301.1471.
4.5.8. (1S
*
,5S )-Ethyl 3-ethyl-9-methylene-6-oxo-3-azabicyclo[3.3.1]
*
nonane-1-carboxylate. The above dioxolane (0.27 g, 0.9 mmol), ac-
etone (30 mL) and 10% HCl (20 mL) were mixed and heated under
reflux overnight. The reaction mixture was concentrated in vacuo to
ca. 20 mL volume, basified with solid NaHCO3 and extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic extracts were dried over
MgSO4 and concentrated in vacuo. The crude material was purified
by flash column chromatography (4:1 n-hexane/EtOAc) to afford
the title compound as an amber oil (0.11 g, 49%). Rf (4:1 n-hexane/
EtOAc) 0.35; dH (300 MHz, CDCl3, Me4Si) 0.99 (3H, t, J¼7.2 Hz,
NCH2CH3), 1.30 (3H, t, J¼7.6 Hz, eOCH2CH3), 1.98e2.06 (1H, m, H-
8), 2.35 (2H, t, J¼7.2 Hz, 7-CH2), 2.45e2.61 (2H, m, H-8, H-4ax), 2.63
(2H, t, J¼7.2 Hz, eNCH2CH3), 2.69 (1H, d, J¼8.8 Hz, H-2ax), 2.98 (1H,
s, H-5), 3.00 (1H, dd, J¼1.5, 14.4 Hz, H-4eq), 3.12 (1H, dt, J¼2.4,
8.8 Hz, H-2eq), 4.23 (2H, q, J¼7.6 Hz, OCH2CH3), 4.69 (1H, s, C]CH2),
4.87 (1H, s, C]CH2); dC (75 MHz, CDCl3) 12.1 (CH3, eNCH2CH3), 14.2
(CH3, eOCH2CH3), 29.9 (CH2, C-8), 39.0 (CH2, C-7), 49.8 (C, C-1), 51.2
(CH2, eNCH2CH3), 56.6 (CH, C-5), 58.4 (CH2, C-4), 61.0 (CH2,
eOCH2CH3), 62.4 (CH2, C-2), 108.6 (C]CH2), 145.2 (C, C-9), 173.5 (C,
*
4.5.6. (1R ,5R
*
)-Ethyl
3-ethyl-9-oxo-3-azaspiro[bicyclo[3.3.1]non-
ane-6,2’-[1,3]dioxolane]-1-carboxylate 15. To a solution of 3-ethyl-
1,5,3-dioxazepane 4b (0.14 g, 1.13 mmol) in dry DMF (2 mL) was
added CH3SiCl3 (0.13 mL). The mixture was stirred for 25 min, ethyl
7-(trimethylsilyloxy)-1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate
24 (0.33 g, 1.13 mmol) was added dropwise and then left to stir
overnight. The reaction was quenched with 2 M HCl (5 mL) and the
aqueous layer washed with Et2O (3ꢂ10 mL). The aqueous extract
was basified with solid NaHCO3, extracted with Et2O (3ꢂ20 mL)
and dried over MgSO4, The filtrate was concentrated in vacuo and
purified by flash column chromatography (4:1 n-hexane/EtOAc) to
afford the title compound as a colourless oil (0.23 g, 70%). Rf (4:1 n-
hexane/EtOAc) 0.25; dH (300 MHz, CDCl3; Me4Si) 1.09 (3H, t,
J¼7.0 Hz, eNCH2CH3), 1.28 (3H, t, J¼7.6 Hz, eOCH2CH3), 1.78 (1H,
dd, J¼6.9, 13.2 Hz, H-7ax), 2.02 (1H, ddd, J¼0.9, 6.9, 13.8 Hz, H-8eq),

1028
K. Sparrow et al. / Tetrahedron 68 (2012) 1017e1028
C]O), 212.6 (C, C-6); IR: nmax (film)/cmꢁ1 2976, 2934, 2866, 1743,
1726, 1657, 1470, 1410, 1365, 1304, 1253, 1220, 1177, 1149, 1101, 1065,
1018, 948, 805, 754; LRMS m/z (EIþ) 252 (MHþ, 16), 208 (17), 194
(10), 179 (25), 162 (100), 151 (42), 134 (24); HRMS (EIþ) [MHþ]
found: 252.1596, calculated: 252.1600.
literature.14 Rf (4:1 n-hexane/EtOAc) 0.6; dH (300 MHz, CDCl3,
Me4Si) 0.99 (3H, t, J¼7.2 Hz, eNCH2CH3), 1.19 (3H, t, J¼7.2 Hz,
eOCH2CH3), 1.56e1.74 (2H, m, H-7eq, H-8ax), 2.13e2.18 (2H, m, H-
4ax, H-8eq), 2.30 (2H, q, J¼7.2 Hz, eNCH2CH3), 2.45 (3H, d, J¼11.2 Hz,
H-2ax), 2.50 (1H, br s, H-5), 2.55e2.72 (1H, m, H-7ax), 2.86 (1H, d,
J¼11.2 Hz, H-2eq), 2.95 (1H, d, J¼11.4 Hz, H-4eq), 3.26 (3H, s, eOCH3),
3.44e3.45 (1H, m, H-6), 4.12 (2H, q, J¼7.2 Hz, eOCH2CH3), 4.56 (1H,
s, C]CH2), 4.77 (1H, s, C]CH2); LRMS m/z (EIþ) 268 (MHþ, 35), 236
(42), 208 (27), 194 (17), 179 (28), 162 (100), 151 (63), 134 (24), 119
(3), 105 (14); HRMS (EIþ) [MHþ] found: 268.1905, calculated:
268.1907.
4.5.9. (1S
*
,5S
*
,6S )-Ethyl 3-ethyl-6-hydroxy-9-methylene-3-
*
azabicyclo[3.3.1]nonane-1-carboxylate. To a solution of the above
ketone (66 mg, 0.26 mmol) in EtOH (5 mL) was added NaBH4
(30 mg, 0.79 mmol). After 1 h the reaction was quenched with satd
NH4Cl (10 mL). The aqueous layer was extracted with CH2Cl2
(5ꢂ10 mL), dried over Na2SO4 and concentrated in vacuo. The crude
material was purified by flash column chromatography (4:1 n-
hexane/EtOAc) to afford the title compound as an amber oil (40 mg,
60%). Rf (4:1 n-hexane/EtOAc) 0.25; dH (300 MHz, CDCl3, Me4Si)
0.99 (3H, t, J¼7.2 Hz, eNCH2CH3), 1.24 (3H, t, J¼7.2 Hz, eOCH2CH3),
1.56e1.74 (2H, m, H-7eq, H-8ax), 2.17e2.28 (2H, m, H-4ax, H-8eq),
2.29 (2H, q, J¼7.2 Hz, eNCH2CH3), 2.44 (1H, d, J¼11.2 Hz, H-2ax),
2.56 (1H, br s, H-5), 2.59e2.76 (1H, m, H-7ax), 2.87 (1H, d, J¼11.2 Hz,
H-2eq), 3.02 (1H, d, J¼11.4 Hz, H-4eq), 3.98e4.01 (1H, m, H-6), 4.14
(2H, q, J¼7.2 Hz, eOCH2CH3), 4.60 (1H, s, C]CH2), 4.82 (1H, s, C]
CH2); dC (75 MHz, CDCl3) 12.2 (CH3, NCH2CH3), 14.2 (CH3,
OCH2CH3), 28.7 (CH2, C-8), 39.2 (CH2, C-7), 49.6 (C, C-1), 51.1 (CH2,
eNCH2CH3), 56.6 (CH, C-5), 58.4 (CH2, C-4), 61.1 (CH2, eOCH2CH3),
62.3 (CH2, C-2), 70.5 (CH, C-6), 106.9 (C]CH2), 146.2 (C, C-9), 173.4
(C, C]O); IR: nmax (film)/cmꢁ1 3394 (OeH), 2973, 2917, 2807, 2770,
1726, 1652, 1473, 1450, 1381, 1367, 1301, 1249, 1230, 1185, 1155, 1131,
1040, 1061, 1022, 978, 951.7, 894, 861, 845, 804, 752, 721, 678, 652;
LRMS m/z (EIþ) 254 (MHþ, 26), 208 (20), 194 (14), 179 (22), 162
(100), 151 (54), 134 (31); HRMS (EIþ) [MHþ] found: 254.1768, cal-
culated: 254.1756.
Acknowledgements
We are grateful for the financial support from The University of
Auckland for a Doctoral Scholarship (K.S.).
References and notes
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4.5.10. (1S
*
,5S
*
,6S )-Ethyl 3-ethyl-6-methoxy-9-methylene-3-
*
azabicyclo[3.3.1]nonane-1-carboxylate 1414. NaH (60 wt %, 21 mg,
0.53 mmol) was washed with n-pentane (3ꢂ1 mL) and suspended
in dry THF (5 mL) under a N2 atmosphere. The mixture was cooled
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was added dropwise. The mixture was warmed to room tempera-
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0.19 mmol) was added dropwise, the reaction flask was sealed and
the reaction mixture left to warm to room temperature overnight.
The mixture was heated to 50 ꢀC in a sealed tube for a further 2 days
then quenched with satd NH4Cl (10 mL). The organic layer was
separated, dried over MgSO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (9:1 n-
hexane/EtOAc) to afford the title compound as a colourless oil
(10 mg, 25%). The 1H NMR spectrum was in agreement with the