Synthesis of the diazatricyclic core of madangamines via cyclic N,O-acetalization-bridgehead reduction

Article abstract of DOI:10.3987/COM-07-11276

A new approach to synthesize the diazatricyclic core of the madangamine alkaloids is described. The synthesis involves intramolecular N,O-acetalization of the keto-aminophenol which enables rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton. Red

Full text of DOI:10.3987/COM-07-11276

HETEROCYCLES, Vol. 75, No. 6, 2008
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HETEROCYCLES, Vol. 75, No. 6, 2008, pp. 1329 - 1354. © The Japan Institute of Heterocyclic Chemistry
Received, 24th November, 2007, Accepted, 25th February, 2008, Published online, 26th February, 2008. COM-07-11276
SYNTHESIS OF THE DIAZATRICYCLIC CORE OF MADANGAMINES
VIA CYCLIC N,O-ACETALIZATION–BRIDGEHEAD REDUCTION
Yuta Yoshimura, Takahiko Kusanagi, Chihiro Kibayashi, Naoki Yamazaki,*†
and Sakae Aoyagi*
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi, Hachioji, Tokyo 192-0392, Japan
Abstract – A new approach to synthesize the diazatricyclic core of the
madangamine alkaloids is described. The synthesis involves intramolecular
N,O-acetalization of the keto-aminophenol which enables rapid construction of
the 2-azabicyclo[3.3.1]nonane skeleton. Reductive C–O bond cleavage of the
N,O-acetal has been accomplished by using AlH3 as the source of nucleophilic
hydrogen as well as the Lewis acid character. This strategy also demonstrates
the utility of such approach in the stereoselective construction of the central
2,6-diazatricyclo[6.2.2.04,9]dodecane core with a quaternary carbon center at C-4
found in the madangamine alkaloids.
INTRODUCTION
Madangamine A (1) is a novel pentacyclic alkaloid that was isolated from the marine sponge
Xestospongia ingens in 1994.1 Soon after, structural variations in the D-ring of this alkaloid class,
madangamines B–E (2–5), were isolated.2 More recently, madangamine F (6) that was the first example
of the E-ring variant, was added to this class.3 In addition to the novel pentacyclic structure, the
diazatricyclic core, i.e., 2,6-diazatricyclo[6.2.2.04,9]dodecane (7), which commonly composes these
alkaloids, is of a considerable interest to utilize as a molecular scaffold in drug discovery as well as a
conventional synthetic target.4–7
During the course of our investigations on the synthesis of nitrogenous natural products, we have
demonstrated the use of cyclic N,O-acetals for the elaboration of bridgehead alkylation of
2-azabicyclo[3.3.1]nonane employing a combination of Lewis acids (LA) and nucleophilic alkylmetal
reagents (M–R), or alkylaluminum compounds (AlR3) as Lewis acids with nucleophilic alkyl groups as

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HETEROCYCLES, Vol. 75, No. 6, 2008
depicted in Scheme 1 (9→10 →11).8,9 In this context, we intended to examine the use of alane (AlR3, R
= H) for the synthesis of 2-azabicyclo[3.3.1]nonane 12, the AC-ring of madangamines, by reductive
cleavage of cyclic N,O-acetal 9 via bridgehead iminium ion 10.
34
13
1
9
1
X
D
9
N
D
A
N
B
7N
A
B
E
C
7N
C
E
22
3
3
H OH
madangamine F (6)
madangamines A–E (1–5)
A (1): NX =
B (2): NX =
C (3): NX =
D (4): NX =
E (5): NX =
N
N
N
N
N
NH
HN
7
M–R
LA
N+
N
NH
N
or
AlR3
O
OH
OH
XO
10
R
O
8
11
9
X = LA–, Al–R3
M–H
N
OH
H
12
Scheme 1

HETEROCYCLES, Vol. 75, No. 6, 2008
1331
RESULTS AND DISCUSSION
Synthesis of 2-azabicyclo[3.3.1]nonane.
The cyclic N,O-acetal (16) was prepared by the following two-step process which we had previously
reported.8 Reductive amination of the (formylmethyl)cyclohexane 1310 and 2-(aminomethyl)phenol (14)
was carried out in the presence of sodium borohydride in methanol to yield the secondary amine 15 in a
good yield (Scheme 2). Cleavage of the cyclic acetal 15 and intramolecular N,O-acetalization were
carried out consecutively under acidic conditions (3.0 M hydrochloric acid–methanol, then
p-toluenesulfonic acid, benzene at reflux) to give 16 as crystals suitable for X-ray crystallography.11 The
X-ray crystal structure of 16 revealed the 2-azabicyclononane ring and trans-fused quinolizidine system
Figure 1. X-Ray crystallographic structure of 16.
O
O
H2N
+
N
N
c
O
HO
14
CHO
OH
13
17
16
a
b
d
e
O
O
OH
N
H
N
NH
•HCl
Me
15
18
19
Scheme 2. Reagents and conditions: (a) NaBH4, MeOH, 77%; (b) 3.0 M HCl,
MeOH, then p-TsOH, reflux, 80%; (c) AlH3,Et2O, 0 °C, 85%; (d) HCO2H,
10% Pd–C, then HCl, 48%; (e) 35% HCHO, H2, 10% Pd–C, 86%.

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HETEROCYCLES, Vol. 75, No. 6, 2008
to be in the chair–chair conformation as well as convincing evidence for the skeletal structure 16 (Figure
1). Treatment of 16 with AlH3 as a Lewis acid with nucleophilic hydrogens provided the hydrogenated
product 17 via the bridgehead iminium ion through the sequence (9→10→12) depicted in Scheme 1.
The resulting hydrogenated product 17 was treated with formic acid in the presence of 10% palladium on
carbon to give 2-azabicyclo[3.3.1]nonane (18), isolated as the hydrochloride salt in 48% yield. In the
case of catalytic hydrogenation using 10% palladium on carbon in the presence of formaldehyde,
2-methyl-2-azabicyclo[3.3.1]nonane (19) was obtained in 86% yield.
The results obtained above prompted our efforts to develop a synthetic route to the
2,6-diazatricyclo[6.2.2.04,9]dodecane derivative 20, which includes quaternary carbon center at C–4, via
bridgehead reduction. Our strategy for 20 involves cyclization of 2-azabicyclononane derivative 21,
which is prepared through N,O-acetalization of 23 and Lewis acid mediated reduction of the resulting
tetracyclic N,O-acetal 22 (Scheme 3).
OR1
OR1
NH
R1O
HN
R2O
R3O
R2O
R3O
4
OR1 NH OH
N
NH
O
R2O
AlH3
O
22
20
21
R3O
23
Scheme 3
Synthesis of 2,6-Diazatricyclo[6.2.2.04,9]dodecane.
The cyclohexenone 24, which was prepared from cyclohexenone according to the protocol of
Danishefsky,12 was treated with cyanoethylacetate at 0 °C for 2 h to give a 9:4 diastereomeric mixture of
the cis-Michael adduct 25 in 73% yield as a more polar component with accompanying a 3:1
diastereomeric mixture of the trans-adduct 26 in 22% yield as a less polar component.13 These adducts
were easily separated by column chromatography on silica gel. The cis-adduct 25 was treated with
ethylene glycol in the presence of p-toluenesulfonic acid to give the cyclic acetal 27 maintaining the same
diastereoisomeric ratio. The acetal 27 was exposed to 35% aqueous formaldehyde in the presence of
catalytic amount of potassium bicarbonate to yield the carbinol 28, which was protected as a MOM ether
in the usual manner to give 29. The cyanoester 29 thus obtained as a 9:4 diastereomeric mixture was
treated with LiBH4 to give 30, of which primary alcohol was protected as a MOM ether to give the
biscarbinol derivative 31 as a single diastereomer. Reduction of nitrile moiety by DIBAL-H reduction
yielded the primary amine 32, which underwent reductive amination using salicylaldehyde and NaBH4 to

HETEROCYCLES, Vol. 75, No. 6, 2008
1333
give the amino phenol 33. Upon treatment of 33 with pyridinium p-toluenesulfonate in acetone–H2O at
reflux, the transiently formed keto-aminophenol 34 was dehydrated to give the tetracyclic N,O-acetal 35
including the 2-azabicyclo[3.3.1]nonane skeleton.
With the tetracyclic N,O-acetal in hand, we next examined the bridgehead reduction established above.
Treatment of 35 with AlH3 in Et2O at rt led to reductive C–O bond cleavage of the N,O-acetal and
selective deprotection of one of the two MOM ethers in one step, providing the amino alcohol 37 in good
O
O
O
a
+
CO2Et
CN
CO2Et
CN
H
H
OTBDMS
TBDMSO
TBDMSO
3.3:1
25 (d.r. = 2.3:1)
26 (d.r. = 3:1)
24
b
O
O
O
O
H
O
O
H
c
e
CN
CN
CO2Et
CN
OMOM
OR
H
TBDMSO
TBDMSO
TBDMSO
CO2Et
OR
27
28: R = H
30: R = H
d
f
29: R = MOM
31: R = MOM
HO
O
O
H
O
O
H
H
N
g
h
i
NH2
OMOM
OMOM
OMOM
OMOM
TBDMSO
TBDMSO
33
32
OMOM
N
MOMO
MOMO
MOMO
NH OH
O
O
TBDMSO
H
35
TBDMSO
34
Scheme 4. Reagents and conditions: (a) CH2(CN)CO2Et, t-BuOK, toluene, 0
°C, 95% total yield: (b) (CH2OH)2, p-TsOH, benzene, reflux, 99%; (c) 35%
HCHO, KHCO3, rt, 90%; (d) MOMCl, i-Pr2EtN, CH2Cl2, rt, 90%; (e) LiBH4 in
THF, EtOH/Et2O, reflux, 83%; (f) MOMCl, i-Pr2EtN, CH2Cl2, rt, 90%; (g)
DIBAL-H in hexane, CH2Cl2, 0 °C, 83%; (h) salicylaldehyde, EtOH, rt, then
NaBH4, 0 °C ! rt, 98%; (i) PPTS, acetone/H2O, reflux, 48 h, 75% for 35.

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HETEROCYCLES, Vol. 75, No. 6, 2008
yield (Scheme 5). The latter process involves selective deprotection of the MOM ether in which the
chemically equivalent MOM ethers were efficiently differentiated, being suitable to perform the
subsequent cyclization for the construction of the diazatricyclic core skeleton. This process presumably
occurred via a chelated phenoxyaluminum hydride intermediate such as 36 where the hydride delivery
preferentially occurred at the methoxymethyl group connected to the axially oriented C–4
methoxymethylene group.
MeO
H
O
O
Al
N
AlH3
H
MOMO
4
35
Et2O, rt, 10 h
84%
TBDMSO
36
OH
MOMO
N
OH
TBDMSO
37
Scheme 5
Removal of a (2-hydroxyphenyl)methyl group from 37 was performed by catalytic hydrogenation using
palladium on charcoal in MeOH to give the amino alcohol 38. Compound 38 was converted to the
secondary alcohol 41 by sequential protection as the Boc carbamate and the benzyl ether followed by
deprotection of the TBDMS ether with Bu4NF (Scheme 6). The secondary alcohol 41 was oxidized with
PCC and the resulting ketone 42 was converted to the exo-methylene product 43 by using the Tebbe
reagent. Hydroboration of 43 with 9-BBN from the less congested convex β-face followed by an
oxidative workup with basic peroxide led to the primary alcohol 44 as a single diastereomer. Mitsunobu
reaction with phthalimide afforded 45, which on acidic treatment underwent deprotection of the MOM
and Boc groups to yield 46. After Boc-protection of the secondary amine as 47, the phthaloyl unit was
removed with hydrazine to give the amino alcohol 48. The primary amino group was protected as
Cbz-group to give the alcohol 49. The primary alcohol 49 was mesylated and the resulting mesylate was
exposed to t-BuOK in THF at rt to produce the expecting diazatricyclic compound 50.

HETEROCYCLES, Vol. 75, No. 6, 2008
1335
OR
OH
MOMO
MOMO
d
b
a
NH
N
Boc
37
TBDMSO
TBDMSO
38
39: R = H
40: R = Bn
c
OBn
OBn
N
OBn
MOMO
f
MOMO
HO
MOMO
N
e
Boc
N
Boc
Boc
O
43
42
41
OBn
OBn
MOMO
HO
MOMO
g
h
i
N
N
Boc
Boc
PhthN
45
44
OBn
OBn
BnO
N
HO
HO
k
m
N
N
N
R
Boc
Boc
Cbz
PhthN
RHN
50
48: R = H
49: R = Cbz
46: R = H
l
j
47: R = Boc
Scheme 6. Reagents and conditions: (a) H2, Pd–C, MeOH, 86%; (b) (Boc)2O, 0.5 M
NaOH, dioxane, rt, 99%; (c) BnBr, NaH, Bu4NI, DMF, rt, 87%; (d) TBAF, THF, rt, 99%;
(e) PCC, CH2Cl2, rt, 99%; (f) Tebbe reagent, THF, rt, 8 h, 73%; (g) (i) 9-BBN, THF, rt;
(ii) NaOH, H2O2, rt, 91% over 2 steps; (h) PhthNH, DEAD, Ph3P, THF, rt, 72%; (i) HCl,
MeOH, 60 °C, 83%; (j) (Boc)2O, 0.5 M NaOH, dioxane, rt, 76%; (k) H2NNH2·H2O,
EtOH, reflux, 96%; (l) CbzCl, Na2CO3, dioxane/H2O, rt, 70%; (m) (i) MsCl, Et3N,
CH2Cl2, rt; (ii) t-BuOK, THF, rt, 72% from 49.
Conclusion
In summary, an efficient synthesis of the diazatricyclic core of the madangamine alkaloids has been
accomplished. Our studies have shown that N,O-acetalization of the keto-aminophenol 15 enables the
rapid construction of the 2-azabicyclo[3.3.1]nonane skeleton 16. Reductive C–O bond cleavage of the
N,O-acetal has been accomplished by reduction using AlH3 as the source of nucleophilic hydrogen as well
as the Lewis acid character to give 17.
This strategy applied to the synthesis of the
2-azabicyclo[3.3.1]nonane skeleton 37 with a quaternary carbon center at C–4 demonstrates the utility of

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HETEROCYCLES, Vol. 75, No. 6, 2008
such approach in the stereoselective construction of the central diazatricyclic core found in the
madangamine alkaloids. The strategy developed for stereocontrolled synthesis of 50 is amenable to the
efficient synthesis of madangamines by using the keto-aminophenol with an appropriate functionality.
EXPERIMENTAL
Melting points (uncorrected) were determined by using a Yanagimoto micro melting point apparatus.
1H NMR spectra were recorded at 400 MHz or 300 MHz using residual CHCl3 (7.26 ppm) as reference.
13C NMR spectra were recorded at 100.6 MHz with CDCl3 (77.05 ppm) as reference. IR spectra were
taken with an FTIR instrument. Mass spectra were measured at an ionizing voltage of 70 eV or
performed on a spectrometer equipped with a positive electrospray ionization mode (ESI). Organic
solvents used were dried by standard methods. Silica gel 60 (230–400 mesh, Merck) was used for
column chromatography, and precoated silica gel 60F254 plates (0.25 mm, Merck) were used for TLC.
2-({[2-(1,4-Dioxaspiro[4.5]dec-7-yl)ethyl]amino}methyl)phenol (15). To a stirred ice-cold solution of
13 (2.30 g, 12.5 mmol) in MeOH (100 mL) was added 2-(aminomethyl)phenol (14) (2.00 g, 16.2 mmol),
and the reaction mixture was allowed to warm to rt, stirred for 1h, and then cooled to 0 °C. Sodium
borohydride (0.85 g, 22.5 mmol) was added and the mixture was stirred at rt for 30 min. Water (50 mL)
was added and the mixture was extracted with Et2O (3 x 50 mL). The combined organic phases were
dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on
silica gel (CHCl3–MeOH–concentrated NH4OH, 400:9:1) to give 15 (2.82 g, 77%) as a colorless oil: IR
(neat) 3290, 2932, 2349, 1614 cm-1;1H NMR (400 MHz, CDCl3) δ 0.87 (1H, qd, J = 12.1, 4.0 Hz), 1.18
(1H, t, J = 12.1 Hz), 1.35–1.58 (4H, m), 1.59–1.78 (5H, m), 2.69 (2H, t, J = 7.9 Hz), 3.87–3.96 (4H, m),
3.98 (2H, m), 6.76 (1H, td, J = 8.0, 1.0 Hz), 6.82 (1H, dd, J = 8.0, 1.0 Hz), 6.97 (1H, dd, J = 8.0, 1.0 Hz),
13
7.16 (1H, td, J = 8.1, 1.6 Hz); C NMR (100.6 MHz, CDCl3) δ 23.2 (CH2), 31.8 (CH2), 33.5 (CH), 34.9
(CH2), 36.8 (CH2), 41.8 (CH2), 46.4 (CH2), 52.9 (CH2), 64.3 (CH2), 64.4 (CH2), 109.1 (C), 116.5 (CH),
119.0 (CH), 122.6 (C), 128.3 (CH), 128.7 (CH), 158.4 (C); EIMS m/z (relative intensity) 291 (M+, 8), 246
(30), 136 (75), 107 (100); HRMS (ESI) calcd for C17H26NO3 [M+H]+ 292.1913, found 292.1930. Anal.
Calcd for C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.75; H, 8.51; N, 4.71.
2-Oxa-10-azatetracyclo[11.3.1.01,10.03,8]heptadeca-3(8),4,6-triene (16). To a solution of 15 (2.30 g,
7.90 mmol) in MeOH (25 mL) was added 3.0 M HCl (25 mL) at once and the mixture was refluxed for 3
h, The mixture was neutralized with a saturated aqueous NaHCO3 and extracted with CHCl3 (3 x 80 mL).
The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was redissolved in
benzene (150 mL) including p-toluenesulfonic acid (115 mg) and the resulting solution was refluxed for 4

HETEROCYCLES, Vol. 75, No. 6, 2008
1337
h with continuous azeotropic water removal using a Dean-Stark apparatus. Evaporation of the solvent
and purification of the residue by column chromatography on silica gel (CHCl3–MeOH–concentrated
NH4OH, 1000:9:1) gave 16 (1.45 g, 80%) as white crystals. A part of the resulting crystals was
recrystallized form EtOAc–hexane to afford colorless needles for analytical measurements: mp
92–93 °C; IR (KBr) 2921 cm-1;1H NMR (400 MHz, CDCl3) δ 1.51 (1H, td, J = 13.4, 6.4 Hz), 1.59–1.97
(7H, m), 2.15 (tdd, J = 13.4, 7.8, 4.8 Hz), 2.36 (1H, br s), 2.42 (1H, d quint, J = 13.9, 2.7 Hz), 3.05 (1H,
td, J = 12.6, 5.5 Hz), 3.19 (1H, dd, J = 11.7, 7.8 Hz), 3.79 (1H, A part of ABq, J = 15.3 Hz), 3.80 (1H, B
part of ABq, J = 15.3 Hz), 6.79 (1H, d, J = 7.6 Hz), 6.83 (1H, t, J = 7.6 Hz), 6.99 (1H, d, J = 7.6 Hz), 7.09
(1H, t, J = 7.6 Hz); 13C NMR (100.6 MHz, CDCl3) δ 22.1 (CH2), 29.5 (CH2), 29.9 (CH2), 30.3 (CH), 30.4
(CH2), 40.9 (CH2), 49.7 (CH2), 51.8 (CH2), 86.1 (C), 116.9 (CH), 119.9 (CH), 120.3 (C), 126.5 (CH),
127.7 (CH), 151.8 (C); EIMS m/z (relative intensity) 229 (M+, 15), 200 (10), 186 (100); HRMS (ESI)
calcd for C15H20NO [M+H]+ 230.1545, found 230.1549. Anal. Calcd for C15H19NO: C, 78.56; H, 8.35;
N, 6.11. Found: C, 78.41; H, 8.25; N, 5.96.
[(2-Azabicyclo[3.3.1]nonan-2-yl)methyl]phenol (17). Aluminum chloride (814 mg, 6.11 mmol) was
added to a stirred ice-cold suspension of lithium aluminum hydride (695 mg, 18.3 mmol) in Et2O (20 mL)
under argon atmosphere. After stirring at rt for 5 min, a solution of 16 (1.40 g, 6.11 mmol) in Et2O (10
mL) was added and stirring was continued at rt for 2 h. The reaction mixture was quenched by addition
of 10% aqueous NaOH solution (10 mL) and filtered through Celite. The filtrate was concentrated in
vacuo and the residue was purified by column chromatography on silica gel (CHCl3–MeOH–concentrated
NH4OH, 1000:9:1) to give 17 (1.20 g, 85 %) as a colorless oil: IR (neat) 2920, 2350 cm-1;1H NMR (400
MHz, CDCl3) δ 1.38–1.50 (1H, m), 1.62–1.88 (7H, m), 1.96–2.20 (3H, m), 2.88–2.95 (3H, m), 3.82 (1H,
A part of ABq, J = 14.1 Hz), 3.93 (1H, B part of ABq, J = 14.1 Hz), 6.75–6.79 (2H, m), 6.97 (1H, dd, J =
7.4, 1.3 Hz), 7.12–7.17 (1H, td, J = 7.4, 1.1 Hz); 13C NMR (100.6 MHz, CDCl3) δ 21.9 (CH2), 24.5 (CH2),
25.4 (CH), 30.3 (CH2), 30.6 (CH2), 34.6 (CH2), 48.6 (CH2), 50.9 (C), 59.3 (CH2), 115.8 (CH), 118.7 (CH),
121.7 (C), 128.3 (CH), 128.4 (CH), 158.6 (C); EIMS m/z (relative intensity) 231 (M+, 51), 188 (100);
HRMS (ESI) calcd for C15H22NO [M+H]+ 232.1701, found 232.1684. Anal. Calcd for C15H21NO: C,
77.88; H, 9.15; N, 6.05. Found: C, 78.19; H, 9.24; N, 5.80.
2-Azabicyclo[3.3.1]nonane (18). To a stirred solution of 17 (750 mg, 3.07 mmol) in MeOH (44 mL)
were added 10% Pd–C (750 mg) and formic acid (4.4 mL) under argon atmosphere at rt for 14 h. The
reaction mixture was filtered and the filtrate was evaporated in vacuo. To the residue was added
potassium carbonate and water (50 mL) and the mixture was extracted with CHCl3 (3 x 100 mL). The
combined organic extracts were dried (MgSO4) and 1.0 M HCl in MeOH (2 mL) was added. After

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HETEROCYCLES, Vol. 75, No. 6, 2008
concentration in vacuo, the residue was recrystallized from EtOH–acetone to give 18·HCl (238 mg, 48%)
as colorless needles: mp 287–289 °C (lit.14 288 °C); IR (neat) 2945, 2754 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.64 (1H, dd, J = 13.9, 2.4 Hz), 1.71–1.92 (6H, m), 2.06 (1H, s), 2.16–2.25 (2H, m), 2.35–2.38
(1H, m), 3.29 (1H, dd, J = 13.2, 6.9 Hz), 3.45 (1H, td, J = 13.2, 5.6 Hz), 3.65 (1H, br s);13C NMR (100.6
MHz, CDCl3) δ 20.4 (CH2), 24.0 (CH), 26.8 (CH2), 27.3 (CH2), 29.5 (CH2), 30.3 (CH2), 40.0 (CH2), 47.1
(CH); EIMS m/z (relative intensity) 125 (M+–HCl, 18), 82 (100). Anal. Calcd for C8H16ClN: C, 59.43;
H, 9.98; N, 8.66. Found: C, 59.63; H, 9.71; N, 8.26.
2-Methyl-2-azabicyclo[3.3.1]nonane (19). A mixture of 17 (1.00 g, 4.33 mmol), 10% Pd–C (1.00 g),
and 35% formalin (0.5 mL) was stirred under a balloon pressure of hydrogen for 14 h, filtered, and
concentrated in vacuo. To the residue was added 3.0 M HCl (20 mL) and the resulting mixture was
washed with Et2O (2 x 20 mL) and concentrated in vacuo. Saturated aqueous sodium bicarbonate (20
mL) was added and the mixture was extracted with CHCl3 (3 x 20 mL). The combined extracts were
washed with water (10 mL) and brine (10 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified column chromatography (CHCl3–MeOH–concentrated NH4OH, 100:9:1) to give 19 (519 mg,
86%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ 1.36–1.39 (1H, m), 1.54–1.71 (6H, m),
1.83–1.89 (2H, m), 2.00–2.17 (2H, m), 2.42 (3H, s), 2.78–2.82 (2H, m), 2.88 (1H, td, J = 12.4, 5.1 Hz);
13C NMR (125 MHz, CDCl3) δ 22.2 (CH2), 24.6 (CH2), 25.2 (CH), 30.5 (CH2), 30.7 (CH2), 34.7 (CH2),
43.3 (CH3), 51.5 (CH2), 53.3 (CH); EIMS m/z (relative intensity) 139 (M+, 32), 96 (100).
Ethyl (2R*)- and (2S*)-((1S*,2S*)-2-{[tert-Butyl(dimethyl)silyl]oxy}-5-oxocyclohexyl)(cyano)acetate
(25) and Ethyl (2R*)- and (2S*)-((1R*,2S*)-2-{[tert-Butyl(dimethyl)silyl]oxy}-5-oxocyclohexyl)-
(cyano)acetate (26). To a stirred ice-cold suspension of t-BuOK (118 mg, 1.05 mmol) in toluene (7
mL) was added CH2(CN)CO2Et (119 mg, 1.05 mmol). After 15 min, a solution of 24 (226 mg, 1.00
mmol) in toluene (3 mL) was added to the mixture and the stirring was continued for 2 h. After addition
of water (10 mL), the mixture was extracted with Et2O (3 x 15 mL). The combined organic phases were
washed with brine (20 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (hexane–EtOAc, 10:1) to give as the first fraction 26 (74.7 mg,
22%) as colorless needles (CHCl3–hexane): mp 85.3–86.8 °C; 1H NMR (300MHz, CDCl3) δ 0.13 and
0.15 (total 3H in 1:3 ratio, s each), 0.14 and 0.19 (total 3H in 1:3 ratio, s each), 0.89 and 0.91 (total 9H in
1:3 ratio, s each), 1.33 (3H, td, J = 7.1, 0.8 Hz), 1.68–1.91 (1H, m), 2.16–2.30 (1H, m), 2.31–2.70 (5H, m),
3.71 (0.25H, d, J = 4.0 Hz), 3.96 (0.75H, ddd, J = 10.0, 10.0, 4.5 Hz), 4.13 (0.75H, d, J = 2.5 Hz),
4.16–4.35 (2.25H, m, including 2H at δ 4.28, q, J = 7.1 Hz). The second fraction gave 25 (248 mg,
1
73%) as colorless oil: IR (neat) 2248, 1747, 1718 cm-1; H NMR (400 MHz, CDCl3) δ 0.10 and 0.17

HETEROCYCLES, Vol. 75, No. 6, 2008
1339
(total 3H in 4:9 ratio, s, each), 0.12 and 0.22 (total 3H in 4:9 ratio, s, each), 0.93 and 0.94 (total 9H in 4:9
ratio, s, each), 1.32 and 1.33 (total 3H in 4:9 ratio, t, J = 7.1 Hz, each), 1.82 and 1.86 (total 1H in 4:9 ratio,
tdd, J = 14.2, 4.8, 1.9 Hz, and tdd, J = 14.4, 4.7, 1.8 Hz, respectively), 2.09–2.70 (6H, m), 3.45 and 3.64
(total 1H in 4:9 ratio, dt, J = 10.2, 5.5 Hz and d, J = 8.6 Hz, respectively), 4.12 and 4.39 (total 1H in 4:9
ratio, br s each), 4.22–4.33 (2H, m); 13C NMR (100.6 MHz, CDCl3) δ –5.2 and –5.0 (CH3, total 1 carbon
in 4:9 ratio), –4.3 (CH3), 14.0 (CH3), 18.1 (C), 25.8 (CH3, 3 carbons), 31.7 and 31.9 (CH2, total 1 carbon
in 4:9 ratio), 34.8 and 35.0 (CH2, total 1 carbon in 4:9 ratio), 39.5 and 40.7 (CH, total 1 carbon in 4:9
ratio), 39.8 and 39.9 (CH2, total 1 carbon in 4:9 ratio), 42.7 and 44.0 (CH, total 1 carbon in 4:9 ratio), 63.2
(CH2), 65.8 and 66.0 (CH, total 1 carbon in 4:9 ratio), 115.0 and 115.4 (C, total 1 carbon in 4:9 ratio),
164.8 and 165.0 (C, total 1 carbon in 4:9 ratio), 207.7 (C); EIMS m/z (relative intensity) 340 (M+ + 1, 22),
282 (43), 169 (60), 142 (36), 99 (18), 73 (100). Anal. Calcd for C17H29NO4Si: C, 60.14; H, 8.61; N,
4.13. Found: C, 60.22; H, 8.56; N, 4.11.
Ethyl (2R*)- and (2S*)-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-
(cyano)acetate (27). A solution of 25 (diastereomeric mixture of β-cyano/α-cyano = 9:4, 19.0 g, 56.0
mmol), p-toluenesulfonic acid (533 mg, 2.80 mmol), and ethylene glycol (5.21 g, 84.0 mmol) in benzene
(190 mL) was stirred for 1 h at reflux with continuous azeotropic water removal using a Dean–Stark
apparatus. Evaporation of the solvent and purification by column chromatography on silica gel
(hexane–EtOAc, 10:1) gave 27 (diastereomeric mixture of 27β/27α = 9:4, 21.3 g, 99%) as a colorless oil:
1
IR (neat) 2248, 1746 cm-1; H NMR (400 MHz, CDCl3) δ 0.02 and 0.10 (total 3H in 4:9 ratio, s each),
0.05–0.14 (total 3H in 4:9 ratio, s each), 0.88 and 0.89 (total 9H in 4:9 ratio, s each), 1.30 (3H, t, J = 7.1
Hz), 1.38–1.95 (6H, m), 2.31–2.43 (1H, m), 3.36 and 3.56 (total 1H in 9:4 ratio, d, J = 11.2 Hz and d, J =
10.0 Hz, respectively), 3.85–4.01 (4H, m), 4.16–4.32 (3H, m); 13C NMR (100.6 MHz, CDCl3) δ –5.3 and
–5.1 (CH3, total 1 carbon in 4:9 ratio), –4.3 (CH3), 14.0 (CH3), 18.1 (C), 25.8 (CH3, 3 carbons), 28.4 and
28.7 (CH2, total 1 carbon in 9:4 ratio), 30.3 (CH2), 33.2 and 33.3 (CH2, total 1 carbon in 9:4 ratio), 39.4
and 39.5 (CH, total 1 carbon in 9:4 ratio), 40.5 and 40.8 (CH, total 1 carbon in 9:4 ratio), 41.9 and 43.4
(CH, total 1 carbon in 9:4 ratio), 62.6 and 62.7 (CH2, total 1 carbon in 9:4 ratio), 64.3 (CH2), 64.4 (CH2),
66.1 and 66.2 (CH, total 1 carbon in 4:9 ratio), 108.1 and 108.2 (C, total 1 carbon in 9:4 ratio), 115.9 and
116.0 (C, total 1 carbon in 4:9 ratio), 165.5 (C); EIMS m/z (relative intensity) 384 (M++1, 16), 326 (100),
282 (24), 142 (42), 99 (56), 75 (56), 57 (44). Anal. Calcd for C19H33NO5Si: C, 59.50; H, 8.67; N, 3.65.
Found: C, 59.63; H, 8.67; N, 3.62.
Ethyl (2R*)- and (2S*)-2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-2-
cyano-3-hydroxypropanoate (28). A mixture of 27 (diastereomeric mixture of 27β/27α = 9:4, 200 mg,

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0.52 mmol), 35% formalin (0.15 mL, 1.95 mmol), and KHCO3 (16 mg, 0.16 mmol) were stirred
vigorously at rt for 4 h. After addition of water (15 mL), the mixture was extracted with Et2O (3 x 20
mL). The combined extracts were washed with brine (30 mL), dried (MgSO4), and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc, 3:1) to give
28 (diastereomeric mixture of 28β/28α = 9:4, 193 mg, 90%) as a colorless oil: IR (neat) 3456, 2247,
1744 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.08 and 0.11 (total 3H in 4:9 ratio, s each), 0.09 and 0.14 (total
3H in 4:9 ratio, s each), 0.92 (9H, s), 1.32 and 1.33 (total 3H in 9:4 ratio, t, J = 7.2 Hz, each), 1.50–1.95
(5H, m), 2.09 and 2.18 (total 1H in 4:9 ratio, t, J = 12.7 Hz, each), 2.28 and 2.36 (total 1H in 4:9 ratio, d,
13
J = 12.8 Hz, each), 2.65–2.80 (1H, m), 3.86–4.10 (7H, m), 4.20–4.37 (2H, m); C NMR (100.6 MHz,
CDCl3) δ –4.6 and –4.1 (CH3, total 1 carbon in 4:9 ratio), –4.3 and –3.9 (CH3, total 1 carbon in 4:9 ratio),
14.0 (CH3), 18.2 (C), 26.0 (CH3, 3 carbons), 28.6 and 28.8 (CH2, total 1 carbon in 9:4 ratio), 31.0 (CH2),
31.4 and 32.3 (CH2, total 1 carbon in 9:4 ratio), 43.3 and 43.5 (CH, total 1 carbon in 9:4 ratio), 54.1 and
54.4 (C, total 1 carbon in 4:9 ratio), 62.9 and 63.0 (CH2, total 1 carbon in 9:4 ratio), 63.8 and 65.5 (CH2,
total 1 carbon in 9:4 ratio), 64.3 (CH2, 2 carbons), 65.9 and 67.2 (CH, total 1 carbon in 4:9 ratio), 108.3
and 108.4 (C, total 1 carbon in 4:9 ratio), 117.5 and 117.6 (C, total 1 carbon in 4:9 ratio), 168.0 and 168.5
(C, total 1 carbon in 4:9 ratio); EIMS m/z (relative intensity) 414 (M++1, 15), 356 (80), 326 (100), 284
(32), 214 (24), 139 (44). Anal. Calcd for C20H35NO6Si: C, 58.08; H, 8.53; N, 3.39. Found: C,
58.14; H, 8.52; N, 3.38.
Ethyl (2R*)- and (2S*)-2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-2-
cyano-3-(methoxymethoxy)propanoate (29). To a stirred solution of 28 (diastereomeric mixture of
28β/28α = 9:4, 11.8 g, 28.5 mmol) in CH2Cl2 (100 mL) were added diisopropylethylamine (9.20 g, 71.3
mmol) and chloromethyl methyl ether (4.59 g, 57.0 mmol) under argon atmosphere. After 24 h, water
(100 mL) was added to the mixture, then the the mixture was extracted with CHCl3 (3 x 100 mL). The
combined extracts were washed with brine (150 mL), dried (MgSO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel (hexane–EtOAc, 10:1) to give 29
(diastereomeric mixture of 29β/29α = 9:4, 11.8 g, 90%) as a colorless oil: IR (neat) 2245, 1745 cm-1;
1H NMR (400 MHz, CDCl3) δ 0.07 and 0.14 (total 3H in 4:9 ratio, s each), 0.09 and 0.15 (total 3H in 4:9
ratio, s each), 0.92 (9H, s), 1.31 and 1.32 (total 3H in 9:4 ratio, t, J = 7.0 Hz, each), 1.47–2.36 (7H, m),
3.35 (3H, s), 3.80–3.98 (6H, m), 4.03 and 4.10 (total 1H in 4:9 ratio, br s each), 4.21–4.36 (2H, m), 4.77
13
(2H, s); C NMR (100.6 MHz, CDCl3) δ –4.6 and –4.1 (CH3, total 1 carbon in 4:9 ratio), –4.4 and –3.9
(CH3, total 1 carbon in 4:9 ratio), 14.0 and 14.1 (CH3, total 1 carbon in 4:9 ratio), 18.2 (C), 26.0 (CH3, 3
carbons), 28.7 and 28.8 (CH2, total 1 carbon in 9:4 ratio), 31.0 and 31.1 (CH2, total 1 carbon in 9:4 ratio),
31.5 and 32.4 (CH2, total 1 carbon in 9:4 ratio), 43.9 and 44.0 (CH, total 1 carbon in 9:4 ratio), 52.7 and

HETEROCYCLES, Vol. 75, No. 6, 2008
1341
52.8 (C, total 1 carbon in 9:4 ratio), 55.7 (CH3), 62.7 and 62.8 (CH2, total 1 carbon in 9:4 ratio), 64.2
(CH2), 64.3 (CH2), 65.7 and 67.2 (CH, total 1 carbon in 9:4 ratio), 68.2 and 69.8 (CH2, total 1 carbon in
4:9 ratio), 96.4 and 96.5 (CH2, total 1 carbon in 9:4 ratio), 108.3 and 108.4 (C, total 1 carbon in 4:9 ratio),
117.4 and 117.6 (C, total 1 carbon in 4:9 ratio), 167.4 and 167.5 (C, total 1 carbon in 9:4 ratio); EIMS m/z
(relative intensity) 426 (M++1, 4), 400 (20), 370 (16), 356 (8), 296 (8), 258 (8), 57, (44), 45 (100). Anal.
Calcd for C22H39NO7Si: C, 57.74; H, 8.59; N, 3.06. Found: C, 57.69; H, 8.50; N, 2.91.
(2R*)-
and
(2S*)-2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-3-
hydroxy-2-[(methoxymethoxy)methyl]propanenitrile (30). To a stirred ice-cold solution of 29
(diastereomeric mixture of 29β/29α = 9:4, 18.5 g, 40.4 mmol) in Et2O (100 mL) were added EtOH (6.80
mL, 121 mmol) and LiBH4 (2.0 M solution in THF, 60.6 mL, 121 mmol). After being stirred at reflux
for 1.5 h, the reaction was quenched by addition of 1 M NaOH (10 mL). The mixture was filtered
through Celite. The filtrate was added water (100 mL), and the mixture was extracted with Et2O (3 x
150 mL). The combined extracts were washed with brine (200 mL), dried (MgSO4), and concentrated in
vacuo. The residue was purified by column chromatography on silica gel (hexane–EtOAc, 3:1) to give
30 (diastereomeric mixture of 30β/30α = 9:4, 14.0 g, 83%) as white crystals: IR (neat) 2245, 1745 cm-1;
1H NMR (400 MHz, CDCl3) δ 0.12 (3H, s), 0.16 (3H, s), 0.92 (9H, s), 1.50–1.71 (3H, m), 1.78–2.22 (4H,
m), 2.66 and 2.73 (total 1H in 4:9 ratio, t, J = 6.0 Hz, each), 3.38 (3H, s), 3.65–3.98 (8H, m), 4.21 and
13
4.27 (total 1H in 9:4 ratio, br s each), 4.65 (2H, s); C NMR (100.6 MHz, CDCl3) δ –4.4 (CH3), –3.9
(CH3), 18.2 (C), 26.0 (CH3, 3 carbons), 28.8 (CH2), 31.0 (CH2), 31.4 (CH2), 40.8 and 40.9 (CH, total 1
carbon in 9:4 ratio), 46.3 and 46.4 (C, total 1 carbon in 9:4 ratio), 55.8 (CH3), 63.0 and 63.1 (CH2 total 1
carbon in 4:9 ratio), 64.3 (CH2), 64.4 (CH2), 66.8 and 66.9 (CH, total 1 carbon in 4:9 ratio), 67.3 and 67.6
(CH2, total 1 carbon in 9:4 ratio), 96.7 (CH2), 108.6 (C), 120.4 (C); EIMS m/z (relative intensity) 416
(M++1, 16), 384 (10), 358 (44), 326 (20), 252 (20), 168 (24), 57 (60), 45 (100). Anal. Calcd for
C20H37NO6Si: C, 57.80; H, 8.97; N, 3.37. Found: C, 57.80; H, 8.75; N, 3.31.
2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-3-(methoxymethoxy)-2-
[(methoxymethoxy)methyl]propanenitrile (31).
In the same manner describe above for the
preparation of 29, 30 (diastereomeric mixture of 30β/30α = 9:4, 11.8 g, 28.4 mmol) was
methoxymethylated. Workup and column chromatography on silica gel (hexane–EtOAc, 10:1) gave 31
1
(11.7 g, 90%) as white crystals: mp 59.5–61.0 °C; IR (KBr) 2238 cm-1; H NMR (400 MHz, CDCl3) δ
0.12 (3H, s), 0.16 (3H, s), 0.93 (9H, s), 1.50–1.56 (1H, m), 1.58–1.70 (2H, m), 1.82 (1H, dq, J = 14.2, 3.0
Hz), 1.93 (1H, td, J = 13.5, 4.2 Hz), 2.05 (1H, t, J = 12.8 Hz), 2.23 (1H, dt, J = 12.9, 2.2 Hz), 3.38 (6H, s),
3.63 (1H, A part of ABq, J = 9.7 Hz), 3.74 (1H, A’ part of ABq, J = 9.6 Hz), 3.83 (1H, B’ part of ABq, J

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HETEROCYCLES, Vol. 75, No. 6, 2008
= 9.6 Hz), 3.88–3.98 (5H, m, including 1H at δ 3.90, B part of ABq, J = 9.7 Hz), 4.61–4.67 (4H, m); 13C
NMR (100.6 MHz, CDCl3) δ –4.5 (CH3), –3.9 (CH3), 18.2 (C), 26.0 (CH3, 3 carbons), 28.9 (CH2), 31.1
(CH2), 31.2 (CH2), 40.7 (CH), 45.2 (C), 55.6 (CH2, 2 carbons), 64.3 (CH2), 64.4 (CH2), 65.9 (CH2), 66.4
(CH2), 66.8 (CH), 96.6 (CH2, 2 carbons), 108.7 (C), 120.5 (C); EIMS m/z (relative intensity) 460 (M++1,
2), 459 (M+, 1), 402 (100), 372 (24), 340 (20), 260 (32), 89 (36), 45 (16). Anal. Calcd for C22H41NO7Si:
C, 57.49; H, 8.99; N, 3.05. Found: C, 57.54; H, 9.13; N, 3.07.
2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-3-(methoxymethoxy)-2-
[(methoxymethoxy)methyl]-1-propanamine (32). To a stirred ice-cold solution of 31 (5.90 g, 12.8
mmol) in CH2Cl2 (90 mL) under argon atmosphere was added diisobutylaluminum hydride (0.95 M
solution in hexane, 40.4 mL, 38.4 mmol). After being stirred for 1 h, the reaction was quenched by
addition of water (0.7 mL). The mixture was filtered through celite. The filtrate was rinsed with THF
(400 mL). The combined filtrates were concentrated in vacuo. The residue was purified by column
chromatography on silica gel (CHCl3–MeOH–concentrated NH4OH, 300:9:1) to give 32 (4.92 g, 83%) as
a colorless oil: IR (neat) 3397 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.08 (3H, s), 0.09 (3H, s), 1.38 (2H,
br s), 1.48–1.53 (1H, m), 1.55–1.67 (2H, m), 1.76 (1H, dq, J = 13.8, 2.8 Hz), 1.89 (2H, t, J = 12.8 Hz),
2.00 (1H, d, J = 13.4 Hz), 2.83 (1H, A part of ABq, J = 13.6 Hz), 2.96 (1H, B part of ABq, J = 13.6 Hz),
3.33 (6H, s), 3.58 (1H, A’ part of ABq, J = 9.6 Hz), 3.60 (1H, A’’ part of ABq, J = 9.3 Hz), 3.68 (1H, B’
part of ABq, J = 9.6 Hz), 3.69 (1H, B’’ part of ABq, J = 9.3 Hz), 3.88–3.98 (4H, m), 4.22 (1H, br s), 4.56
13
(2H, s), 4.57 (2H, s); C NMR (100.6 MHz, CDCl3) δ –4.4 (CH3), –3.6 (CH3), 18.2 (C), 26.1 (CH3, 3
carbons), 29.1 (CH2), 30.7 (CH2), 32.0 (CH2), 41.5 (CH), 43.5 (C), 46.2 (CH2), 55.3 (CH3), 55.4 (CH3),
64.2 (CH2), 64.3 (CH2), 67.0 (CH), 69.6 (CH2), 70.5 (CH2), 96.9 (CH2), 97.0 (CH2), 109.6 (C); EIMS m/z
(relative intensity) 460 (M++1, 48), 418 (73), 330 (24), 315 (32), 201 (40), 193 (62), 132 (96), 99 (90), 73
(93), 45 (100); HRMS Calcd for C22H45NO7Si [M+] 463.2965, found 463.2954. Anal. Calcd for
C22H45NO7Si: C, 56.99; H, 9.78; N, 3.02. Found: C, 56.73; H, 9.61; N, 3.01.
2-[({2-((7S*,8S*)-8-{[tert-Butyl(dimethyl)silyl]oxy}-1,4-dioxaspiro[4.5]dec-7-yl)-3-(methoxymethoxy)-
2-[(methoxymethoxy)methyl]propyl}amino)methyl]phenol (33). To a stirred ice-cold solution of 32
(1.90 g, 4.10 mmol) in EtOH (20 mL) was added salicylaldehyde (550 mg, 4.51 mmol), and the reaction
mixture was allowed to warm to rt. After being stirred at rt for 30 min, the mixture was cooled to 0 °C
and sodium borohydride (310 mg, 4.51 mmol) was added. The mixture was stirred at rt for 30 min,
added water (20 mL), and extracted with Et2O (3 x 50 mL). The combined extracts were washed with
brine (100 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (CHCl3–MeOH–concentrated NH4OH, 1000:9:1) to give 33 (2.29 g, 98%)

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1343
1
as a colorless oil: IR (neat) 3317 cm-1; H NMR (400 MHz, CDCl3) δ 0.07 (3H, s), 0.08 (3H, s), 0.90
(9H, s), 1.48–1.83 (4H, m), 1.89 (2H, t, J = 12.9 Hz), 2.12 (1H, d, J = 12.9 Hz), 2.82 (1H, A part of ABq,
J = 11.7 Hz), 2.94 (1H, B part of ABq, J = 11.7 Hz), 3.31 (3H, s), 3.33 (3H, s), 3.57 (1H, A’ part of ABq,
J = 9.7 Hz), 3.65 (1H, A’’ part of ABq, J = 9.7 Hz), 3.74 (1H, B’’ part of ABq, J = 9.7 Hz), 3.75 (1H, B’
part of ABq, J = 9.7 Hz), 3.86–4.00 (6H, m), 4.23 (1H, br s), 4.54–4.60 (4H, m), 6.75 (1H, td, J = 7.4, 1.1
13
Hz), 6.81 (1H, dd, J = 8.0, 1.0 Hz), 6.97 (1H, dd, J = 7.4, 1.2 Hz), 7.14 (1H, td, J = 7.7, 1.6 Hz); C
NMR (100.6 MHz, CDCl3) δ –4.4 (CH3), –3.7 (CH3), 18.2 (C), 26.1 (CH3, 3 carbons), 29.1 (CH2), 30.7
(CH2), 31.8 (CH2), 41.4 (CH), 42.8 (C), 53.5 (CH2), 55.4 (CH3, 2 carbons), 64.3 (CH2, 2 carbons), 66.9
(CH), 69.7 (CH2), 70.6 (CH2), 96.9 (CH2, 2 carbons), 109.4 (C), 116.3 (CH), 118.8 (CH), 123.2 (C), 128.2
(CH), 128.6 (CH), 158.4 (C); EIMS m/z (relative intensity) 570 (M++1, 24), 524 (5), 464 (2), 418 (2), 299
(24), 238 (84), 136 (100), 107 (58), 45 (12); HRMS calcd for C29H51NO8Si [M+] 569.3384, found
569.3389. Anal. Calcd for C29H51NO8Si: C, 61.13; H, 9.02; N, 2.46. Found: C, 60.82; H, 8.87; N,
2.36.
(1S*,13R*,14S*)-14-{[tert-Butyl(dimethyl)silyl]oxy}-12,12-bis[(methoxymethoxy)methyl]-2-oxa-10-
azatetracyclo[11.3.1.01,10.03,8]heptadeca-3,5,7-triene (35). To a solution of 33 (1.00 g, 1.76 mmol) in
acetone–water (5:1, 24 mL) was added pyridinium p-toluenesulfonate (4.42 g, 17.6 mmol), and the
mixture was heated under reflux for 48 h. After cooling to rt, water (30 mL) was added. The mixture
was extracted with CHCl3 (3 x 30 mL). The combined extracts were washed with brine (50 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel
(hexane–EtOAc, 3:1) to give 35 (670 mg, 75%) as colorless needles: mp 92.5–93.0 °C; IR (KBr) 3427,
2936, 2884 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.06 (3H, s), 0.09 (3H, s), 0.91 (9H, s), 1.56 (1H, td, J =
14.0, 6.8 Hz), 1.75–1.83 (2H, m), 1.91 (1H, qd, J = 13.5, 5.9 Hz), 2.25 (1H, dt, J = 13.0, 3.5 Hz), 2.42
(1H, dt, J = 14.0, 3.7 Hz), 2.50 (1H, br d, J = 2.9 Hz), 2.98 (1H, A part of ABq, J = 12.8 Hz), 3.03 (1H, B
part of ABq, J = 12.8 Hz), 3.34 (3H, s), 3.35 (3H, s), 3.72 (1H, A’ part of ABq, J = 10.2 Hz), 3.76 (2H, s),
3.78 (1H, A’’ part of ABq, J = 9.8 Hz), 3.98 (1H, B’’ part of ABq, J = 9.8 Hz), 4.06 (1H, B’ part of ABq,
J = 10.2 Hz), 4.08–4.14 (1H, m), 4.58 (2H, s), 4.63 (2H, s), 6.76 (1H, d, J = 8.1 Hz), 6.84 (1H, t, J = 7.4
Hz), 6.99 (1H, d, J = 7.4 Hz), 7.09 (1H, t, J = 7.6 Hz); 13C NMR (100.6 MHz, CDCl3) δ –4.9 (CH3), –4.7
(CH3), 18.0 (C), 25.9 (CH3, 3 carbons), 27.8 (CH2), 31.3 (CH2), 36.3 (CH2), 38.4 (CH), 42.4 (C), 49.5
(CH2), 55.0 (CH3), 55.2 (CH3), 58.6 (CH2), 68.5 (CH2), 71.0 (CH2), 74.9 (CH2), 86.0 (C), 96.8 (CH2), 96.9
(CH2), 116.7 (CH), 119.9 (C), 120.0 (CH), 126.6 (CH), 127.7 (CH), 151.8 (C); EIMS m/z (relative
intensity) 507 (M+, 8), 462 (16), 432 (4), 364 (8), 335 (16), 334 (100), 330 (4), 258 (6). Anal. Calcd for
C27H45NO6Si: C, 63.87; H, 8.93; N, 2.76. Found: C, 63.67; H, 8.87; N, 2.74.

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2-({(4S*,5R*,6S*)-6-{[tert-Butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-4-[(methoxymethoxy)-
methyl]-2-azabicyclo[3.3.1]non-2-yl}methyl)phenol (37). Aluminum chloride (493 mg, 3.70 mmol)
was added to a stirred ice-cold suspension of lithium aluminum hydride (421 mg, 11.1 mmol) in Et2O (30
mL) under argon atmosphere. After being stirred at rt for 5 min, a solution of 35 (1.88 g, 3.70 mmol) in
Et2O (7.0 mL) was added to the mixture and the stirring was continued at rt for 10 h. The reaction
mixture was quenched by addition of 10% aqueous NaOH (0.8 mL). The mixture was filtered through
celite and the solvent was evaporated in vacuo. The residue was purified by column chromatography on
silica gel (CHCl3–MeOH–concentrated NH4OH, 1000:9:1) to give 37 (1.44 g, 84%) as a colorless oil:
IR (neat) 3476 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.04 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.35 (1H, qd,
J = 11.0, 4.2 Hz), 1.47 (1H, dt, J = 13.6, 2.6 Hz), 1.79–1.88 (2H, m), 2.06 (1H, br d, J = 2.9 Hz), 2.20 (2H,
br d, J = 13.9 Hz), 2.79 (1H, A part of ABq, J = 12.8 Hz), 2.84 (1H, br s), 2.88 (1H, B part of ABq, J =
12.8 Hz), 3.32 (3H, s), 3.78–3.93 (6H, m), 3.96 (1H, td, J = 9.0, 3.9 Hz), 4.54 (2H, s), 6.76 (1H, td, J =
7.4, 1.1 Hz), 6.80 (1H, dd, J = 8.0, 0.8 Hz), 6.97 (1H, dd, J = 7.4, 1.1 Hz), 7.15 (1H, td, J = 7.7, 1.5 Hz);
13C NMR (100.6 MHz, CDCl3) δ –4.8 (CH3), –4.7 (CH3), 18.0 (C), 22.8 (CH2), 25.9 (CH3, 3 carbons),
31.1 (CH2), 32.5 (CH2), 35.5 (CH), 42.6 (C), 49.6 (CH), 54.1 (CH2), 55.4 (CH3), 58.7 (CH2), 66.2 (CH2),
73.6 (CH2), 75.1 (CH), 96.9 (CH2), 115,9 (CH), 119.0 (CH), 121.3 (C), 128.4 (CH), 128.7 (CH), 158.3
(C); EIMS m/z (relative intensity) 465 (M+, 64), 408 (16), 376 (8), 331 (8), 292 (100), 200 (4), 107 (22),
57 (16); HRMS calcd for C25H43NO5Si [M+] 465.2911, found 465.2926.
{(1R*,4S*,5R*,6S*)-6-{[tert-Butyl(dimethyl)silyl]oxy}-4-[(methoxymethoxy)methyl]-2-azabicyclo-
[3.3.1]non-4-yl}methanol (38). A solution of N-(2-hydroxyphenyl)methyl compound 37 (3.85 g, 8.27
mmol) in MeOH (80 mL) was hydrogenated (H2, 1 atm) over Pd–C (10%, 3.85 g) for 48 h. The mixture
was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica
gel (CHCl3–MeOH–concentrated NH4OH, 50:9:1) to give 38 (2.56 g, 86%) as white crystals: mp
1
98.0–99.0 °C; IR (KBr) 3289, 3124 cm-1; H NMR (400 MHz, CDCl3) δ 0.03 (6H, s), 0.88 (9H, s), 1.34
(1H, br d, J = 13.5 Hz), 1.69–2.09 (6H, m), 2.43 (2H, br s), 2.96 (1H, br s), 3.00 (1H, A part of ABq, J =
14.0 Hz), 3.23 (1H, B part of ABq, J = 14.0 Hz), 3.34 (3H, s), 3.74 (1H, A’ part of ABq, J = 10.0 Hz),
13
3.80 (2H, s), 3.90 (1H, B’ part of ABq, J = 10.0 Hz), 3.92–3.98 (1H, m), 4.55 (2H, s); C NMR (100.6
MHz, CDCl3) δ –4.8 (CH3), –4.7 (CH3), 18.0 (C), 25.9 (CH3, 3 carbons), 31.1 (CH2), 31.8 (CH2), 32.8
(CH2), 37.1 (CH), 41.4 (C), 45.6 (CH), 46.8 (CH2), 55.3 (CH3), 67.3 (CH2), 75.1 (CH2), 75.7 (CH), 96.9
(CH2); EIMS m/z (relative intensity) 360 (M++1, 92), 314 (16), 302 (20), 279 (80), 266 (100), 224 (12),
186 (36). Anal. Calcd for C18H37NO4Si: C, 60.12; H, 10.37; N, 3.90. Found: C, 60.01; H, 10.35; N,
3.87.

HETEROCYCLES, Vol. 75, No. 6, 2008
1345
tert-Butyl
(1R*,4S*,5R*,6S*)-6-{[tert-Butyl(dimethyl)silyl]oxy}-4-(hydroxymethyl)-4-[(methoxy-
methoxy)methyl]-2-azabicyclo[3.3.1]nonane-2-carboxylate (39). To a stirred ice-cold solution of 38
(920 mg, 2.56 mmol) in dioxane–0.5 M NaOH solution (1:1, 10.4 mL) was added di-tert-butyl
dicarbonate (615 mg, 2.82 mmol). After 30 min, water (10 mL) was added and the mixture was
extracted with Et2O (3 x 20 mL). The combined extracts were washed with brine (50 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silca gel
(hexane–EtOAc, 5:1) to give 39 (1.17 g, 99%) as white crystals: mp 98.5–99.8 °C; IR (KBr) 3475, 1662
cm-1; 1H NMR (400 MHz, CDCl3) δ 0.04 (6H, s), 0.88 (9H, s), 1.40 (1H, br t, J = 14.1 Hz), 1.44 (9H, s),
1.56–1.91 (6H, m), 2.59 and 2.66 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br
s), 3.26 (1H, t, J = 15.0 Hz), 3.35 and 3.36 (total 3H, respectively, in ca. 1:1 due to the carbamate
rotamers, each s), 3.56–3.75 (3H, m), 3.84–3.97 (3H, m), 4.04 and 4.21 (total 1H, respectively, in ca. 1:1
due to the carbamate rotamers, each s), 4.56 (2H, br s); 13C NMR (100.6 MHz, CDCl3) δ –4.8 (CH3), –4.7
(CH3), 18.1 (C), 25.9 (CH3, 3 carbons), 28.5 (CH3, 3 carbons), 29.2 (CH2), 29.9 and 30.7 (CH2, total 1
carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 31.3 (CH2), 35.0 and 35.6 (CH, total 1
carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 41.6 and 41.7 (C, total 1 carbon,
respectively, in ca. 1:1 due to the carbamate rotamers), 44.4 and 45.4 (CH, total 1 carbon, respectively, in
ca. 1:1 due to the carbamate rotamers), 46.2 and 46.5 (CH2, total 1 carbon, respectively, in ca. 1:1 due to
the carbamate rotamers), 55.4 (CH3), 66.4 (CH2), 73.1 and 73.3 (CH2, total 1 carbon, respectively, in ca.
1:1 due to the carbamate rotamers), 75.1 (CH), 79.4 and 79.5 (C, total 1 carbon, respectively, in ca. 1:1
due to the carbamate rotamers), 96.9 (CH2), 155.6 (C); EIMS m/z (relative intensity) 460 (M++1, 7), 379
(6), 323 (8), 310 (100), 270 (14), 266 (34), 240 (8). Anal. Calcd for C23H45NO6Si: C, 60.09; H, 9.87; N,
3.05. Found: C, 59.93; H, 9.80; N, 3.07.
tert-Butyl (1R*,4S*,5R*,6S*)-4-[(Benzyloxy)methyl]-6-{[tert-butyl(dimethyl)silyl]oxy}-4-[(methoxy-
methoxy)methyl]-2-azabicyclo[3.3.1]nonane-2-carboxylate (40). To a stirred ice-cold solution of 39
(1.93 g, 4.20 mmol) in DMF (17 mL) were added NaH (672 mg, 16.8 mmol), tetrabutylammonium iodide
(155 mg, 0.42 mmol), and benzyl bromide (1.08 g, 6.31 mmol). After being stirred at rt for 8 h, water
(30 mL) was added carefully and the mixture was extracted with Et2O (3 x 30 mL). The combined
extracts were washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane–EtOAc, 20:1) to give 40 (2.01 g, 87%) as white
1
crystals: mp 81.1–83.1 °C; IR (KBr) 1691 cm-1; H NMR (400 MHz, CDCl3) δ 0.05 (3H, s), 0.07 (3H,
s), 0.90 (9H, s), 1.32 (1H, br t, J = 14.9 Hz), 1.44 (9H, s), 1.55–2.00 (5H, m), 2.32 (1H, br s), 3.29–4.02
(10H, m, including total 3H at δ 3.29 and 3.31, respectively, in ca. 1:1 due to the carbamate rotamers,
each s), 4.03 and 4.20 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br s),

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HETEROCYCLES, Vol. 75, No. 6, 2008
4.43–4.58 (4H, m), 7.30–7.40 (5H, m); 13C NMR (100.6 MHz, CDCl3) δ –4.8 (CH3), –4.7 (CH3), 18.0 (C),
25.9 (CH3, 3 carbons), 28.5 (CH3, 3 carbons), 28.9 (CH2), 30.1 and 30.8 (CH2, total 1 carbon, respectively,
in ca. 1:1 due to the carbamate rotamers), 31.4 (CH2), 34.9 and 35.3 (CH, total 1 carbon, respectively, in
ca. 1:1 due to the carbamate rotamers), 41.9 (C), 44.4 and 45.3 (CH, total 1 carbon, respectively, in ca.
1:1 due to the carbamate rotamers), 47.8 and 48.2 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the
carbamate rotamers), 55.0 (CH3), 70.2 (CH2), 71.0 (CH2), 73.1 (CH2), 75.1 (CH), 79.3 and 79.4 (C, total 1
carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 96.7 (CH2), 127.1 (CH, 2 carbons), 127.2
(CH), 128.2 (CH, 2 carbons), 139.0 (C), 155.7 (C); EIMS m/z (relative intensity) 550 (M++1, 32), 462
(10), 448 (12), 379 (100), 366 (40), 311 (20), 310 (92), 266 (40). Anal. Calcd for C30H51NO6Si: C,
65.54; H, 9.35; N, 2.55. Found: C, 65.37; H, 9.28, N; 2.55.
tert-Butyl (1R*,4S*,5R*,6S*)-4-[(Benzyloxy)methyl]-6-hydroxy-4-[(methoxymethoxy)methyl]-2-aza-
bicyclo[3.3.1]nonane-2-carboxylate (41). Tetrabutylammonium fluoride (1.0 M solution in THF, 36.0
mL, 36.0 mmol) was added to a stirred solution of 40 (1.98 g, 3.60 mmol) in THF (36 mL) at rt and the
stirring was continued at rt for 48 h. Water (50 mL) was added and the mixture was extracted with Et2O
(3 x 50 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4), and
concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(hexane–EtOAc, 2:1) to give 41 (1.55 g, 99%) as white crystals: mp 78.0–79.5 °C; IR (KBr) 3456, 1691
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.37 (1H, t, J = 13.3 Hz), 1.43 and 1.44 (total 9H, respectively, in ca.
1:1 due to the carbamate rotamers, each s), 1.55–1.70 (1H, m), 1.82–1.99 (4H, m), 2.13 and 2.24 (total 1H,
respectively, in ca. 1:1 due to the carbamate rotamers, each br s), 3.21–3.49 (6H, m, including 3H at δ
3.35, s), 3.65–3.97 (5H, m), 4.05 and 4.25 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers,
13
each br s), 4.41–4.53 (2H, m), 4.63 (2H, s), 7.26–7.33 (5H, m); C NMR (100.6 MHz, CDCl3) δ 28.5
(CH3, 3 carbons), 29.6 (CH2), 29.8 and 30.5 (CH2, total 1 carbon, respectively, in ca 1:1 due to the
carbamate rotamers), 30.4 (CH2), 36.4 (CH), 41.0 and 41.1 (C, total 1 carbon, respectively, in ca. 1:1 due
to the carbamate rotamers), 43.9 (CH), 45.1 (CH2), 45.2 (CH), 55.8 (CH3), 70.3 and 71.3 (CH2, total 1
carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 72.0 (CH2), 73.3 (CH2), 74.1 (CH), 79.4
and 79.5 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 97.0 (CH2), 127.3
(CH), 127.4 (CH), 127.5 (CH), 128.3 (CH, 2 carbons), 138.4 (C), 155.6 and 155.7 (C, total 1 carbon,
respectively, in ca. 1:1 due to the carbamate rotamers); EIMS m/z (relative intensity) 436 (M++1, 20), 348
(10), 265 (20), 209 (20), 196 (64), 152 (30), 91 (78), 57 (100); HRMS calcd for C24H37NO6 [M+] 435.2621,
found 435.2614. Anal. Calcd for C24H37NO6: C, 66.18; H, 8.56; N, 3.22. Found: C, 65.91; H, 8.54,
N; 2.96.

HETEROCYCLES, Vol. 75, No. 6, 2008
1347
tert-Butyl (1R*,4S*,5R*)-4-[(Benzyloxy)methyl]-4-[(methoxymethoxy)methyl]-6-oxo-2-azabicyclo-
[3.3.1]nonane-2-carboxylate (42). To a stirred solution of 41 (1.40 g, 3.21 mmol) in CH2Cl2 (30 mL)
was added pyridinium chlorochromate (1.40 g, 6.42 mmol), and the stirring was continued at rt for 1.5 h.
MgSO4 (5.6 g) and Et2O (30 mL) were added and stirred for 10 min. The mixture was filtered through
celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
on silica gel (hexane–EtOAc, 3:1) to give 42 (1.38 g, 99%) as white crystals: mp 71.6–73.5 °C; IR
1
(KBr) 1692 cm-1; H NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.64–1.75 (1H, br m), 1.96 (1H, br s),
2.05–2.17 (2H, m), 2.46–2.82 (3H, m), 3.24–3.39 (5H, m), 3.41–3.53 (3H, m), 3.83 (1H, d, J = 14.5 Hz),
4.30 and 4.40 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br s), 4.41–4.55 (4H,
m), 7.26–7.35 (5H, m); 13C NMR (100.6 MHz, CDCl3) δ 28.5 (CH3, 3 carbons), 30.2 (CH2), 31.0 (CH2),
39.1 (CH2), 40.2 (C), 43.6 and 44.9 (CH, total 1 carbon, respectively, in ca. 1:1 due to the carbamate
rotamers), 44.0 and 44.2 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 46.9
and 47.4 (CH, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 55.4 (CH3), 69.6
(CH2), 70.5 and 70.7 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 73.4
(CH2), 80.1 (C), 96.9 (CH2), 127.4 (CH), 127.5 (CH), 127.6 (CH), 128,4 (CH, 2 carbons), 138.1 (C),
155.5 (C), 211.5 (C); EIMS m/z (relative intensity) 434 (M+, 15), 376 (10), 332 (25), 263 (100), 207 (50),
194 (78), 150 (23), 91 (18), 57 (18). Anal. Calcd for C24H35NO6: C, 66.49; H, 8.14; N, 3.23. Found:
C, 66.34; H, 8.13; N, 3.29.
tert-Butyl
(1R*,4S*,5S*)-4-[(Benzyloxy)methyl]-4-[(methoxymethoxy)methyl]-6-methylene-2-aza-
bicyclo[3.3.1]nonane-2-carboxylate (43). To a stirred ice-cold solution of 42 (1.10 g, 2.54 mmol) in
THF (8 mL) was added Tebbe reagent (0.5 M in toluene, 7.62 mL, 3.81 mmol) as dropwise under argon
atmosphere. The mixture was allowed to warm to rt and stirred at the same temperature for 1 h. The
reaction mixture was diluted with Et2O (30 mL), and 0.1 M NaOH solution was added until gas evolution
ceased. MgSO4 (5.0 g) was added and the mixture was filtered through celite. The filtrate was
concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(hexane–EtOAc, 10:1) to give 43 (800 mg, 73%) as white crystals: mp 108.5–109.7 °C; IR (KBr) 1690,
1645 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.48 (1H, br s), 1.57–1.72 (1H, m), 1.84–2.06 (2H,
m), 2.28–2.39 (1H, m), 2.40–2.53 (1H, m), 2.65 (1H, br d, J = 12.4 Hz), 3.07 (1H, A part of ABq, J =
14.5 Hz), 3.22–3.45 (4H, m, including total 3H at δ 3.29 and 3.31, respectively, in ca. 1:1 due to the
carbamate rotamers, each s), 3.40–3.51 (2H, m), 3.52–3.63 (1H, m), 3.74 (1H, B part of ABq, J = 14.5
Hz), 4.18 and 4.37 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each s), 4.46–4.60
13
(4H, m), 4.76 (2H, m), 7.26–7.37 (5H, m); C NMR (100.6 MHz, CDCl3) δ 28.5 (CH3, 3 carbons), 29.9
(CH2), 30.7 (CH2), 31.4 and 32.2 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate

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HETEROCYCLES, Vol. 75, No. 6, 2008
rotamers), 38.1 and 38.7 (CH, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 39.4
and 39.7 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 44.7 and 45.9 (CH,
total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 46.3 and 46.4 (CH2, total 1 carbon,
respectively, in ca. 1:1 due to the carbamate rotamers), 55.1 (CH3), 69.5 (CH2), 70.2 and 70.7 (CH2, total
1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 73.2 and 73.3 (CH2, total 1 carbon,
respectively, in ca. 1:1 due to the carbamate rotamers), 79.5 (C), 96.8 (CH2), 111.3 (CH2), 127.3 (CH),
127.5 (CH, 2 carbons), 128.3 (CH, 2 carbons), 138.7 (C), 147.5 (C), 155.8 (C); EIMS m/z (relative
intensity) 432 (M++1, 2.3), 344 (1.6), 261 (2), 192 (13), 148 (6), 91 (44), 57 (100); HRMS calcd for
C25H37NO5 [M+] 431.2672, found 431.2664. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25.
Found: C, 69.26; H, 8.45, N; 3.22.
tert-Butyl
(1R*,4S*,5S*,6S*)-4-[(Benzyloxy)methyl]-6-(hydroxymethyl)-4-[(methoxymethoxy)-
methyl]-2-azabicyclo[3.3.1]nonane-2-carboxylate (44). To a stirred ice-cold solution of 43 (200 mg,
0.46 mmol) in THF (3 mL) was added 9-BBN (0.5 M solution in THF, 1.39 mL, 0.70 mmol), and the
stirring was continued at rt for 3 h. The mixture was cooled to ice-cold temperature, then the reaction
was quenched by addition of EtOH (1 mL). To the mixture were added 3.0 M NaOH (0.30 mL, 0.90
mmol) and 30% H2O2 (0.3 mL) at rt. After 1 h, water (10 mL) was added, and the mixture was extracted
with Et2O (3 x 10 mL). The combined extracts were washed with brine (20 mL), dried (MgSO4), and
concentrated in vacuo.
The residue was purified by column chromatography on silica gel
1
(hexane–EtOAc, 1:1) to give 44 (190 mg, 91%) as a colorless oil: IR 3454, 1682 cm-1; H NMR (400
MHz, CDCl3) δ 1.42 and 1.45 (total 9H, respectively, in ca. 3:2 due to the carbamate rotamers, each s),
1.50–2.13 (8H, m), 2.90 (1H, d, J = 14.0 Hz), 3.18 and 3.28 (total 1H, respectively, in ca. 2:3 due to the
carbamate rotamers, each br s), 3.31–3.38 (4H, m, including total 3H at δ 3.35 and 3.36, respectively, in
ca. 2:3 due to the carbamate rotamers, each s), 3.48–3.60 (3H, m), 3.61–3.72 (2H, m), 3.78–3.88 (1H, m),
4.15 and 4.36 (total 1H, respectively, in ca. 2:3 due to the carbamate rotamers, each s), 4.43–4.54 (2H, m),
13
4.56–4.64 (2H, m), 7.26–7.36 (5H, m); C NMR (100.6 MHz, CDCl3) δ 24.3 and 24.4 (CH2, total 1
carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 28.5 (CH3, 3 carbons), 28.8 (CH), 30.5
and 31.3 (CH2, total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers), 32.0 (CH2), 42.0
and 42.2 (C, total 1 carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 44.7 (CH2), 45.2 and
46.4 (CH, total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers), 46.7 (CH), 55.8 (CH3),
67.0 (CH2), 69.5 and 69.9 (CH2, total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers),
71.3 and 71.6 (CH2, total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers), 73.2 and 73.3
(CH2, total 1 carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 79.3 and 79.4 (C, total 1
carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 97.3 (CH2), 127.3 (CH), 127.4 (CH),

HETEROCYCLES, Vol. 75, No. 6, 2008
1349
127.5 (CH), 128.3 (CH, 2 carbons), 138.4 and 138.5 (C, total 1 carbon, respectively, in ca. 3:2 due to the
carbamate rotamers), 155.5 (C); EIMS m/z (relative intensity) 450 (M++1, 22), 350 (14), 279 (29), 210
(100), 166 (42), 91 (19), 57 (11); HRMS calcd for C25H39NO6 [M+] 449.2777, found 449.2771. Anal.
Calcd for C25H39NO6: C, 66.79; H, 8.74; N, 3.12. Found: C, 66.85; H, 8.66, N; 2.96.
tert-Butyl
(1R*,4S*,5S*,6S*)-4-[(Benzyloxy)methyl]-6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-
methyl]-4-[(methoxymethoxy)methyl]-2-azabicyclo[3.3.1]nonane-2-carboxylate (45). To a stirred
ice-cold solution of 44 (92.0 mg, 0.20 mmol) in THF (2 mL) were added triphenylphosphine (68.2 mg,
0.26 mmol), phthalimide (38.3 mg, 0.26 mmol), and diethyl azodicarboxylate (40% in toluene, 0.10 mL,
0.26 mmol) under argon atmosphere. After being stirred at rt for 30 min, saturated aqueous NaHCO3 (5
mL) was added and the mixture was extracted with Et2O (3 x 10 mL). The combined organic phases
were washed with brine (20 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified
by column chromatography (hexane–EtOAc, 7:1) to give 45 (85 mg, 72%) as a white amorphous solid:
IR (neat) 2930, 1771, 1713, 1686 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.35–1.68 (12H, m, including 9H at
δ 1.43, s), 1.70–2.04 (3H, m), 2.05–2.18 (1H, m), 2.23 and 2.31 (total 1H, respectively, in ca. 1:1 due to
the carbamate rotamers, each br s), 3.15 and 3.18 (total 1H, respectively, in ca. 1:1 due to the carbamate
rotamers, each br d, J = 9.5 Hz), 3.34 (3H, s), 3.42 and 3.44 (total 1H, respectively, in ca. 1:1 due to the
carbamate rotamers, each s), 3.52–3.90 (6H, m), 4.09 and 4.25 (total 1H, respectively, in ca. 1:1 due to
the carbamate rotamers, each br s), 4.44–4.57 (2H, m), 4.58–4.66 (2H, m), 7.26–7.36 (5H, m), 7.67–7.72
(2H, m), 7.81–7.86 (2H, m); 13C NMR (100.6 MHz, CDCl3) δ 25.7 (CH2), 28.5 (CH3, 3 carbons), 30.8 and
31.4 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 32.4 (CH2), 32.7 and
33.1 (CH, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 42.2 (C), 43.6 (CH2),
44.2 (CH), 44.9 and 46.0 (CH, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 45.9
(CH2), 55.5 (CH3), 69.5 and 70.1 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate
rotamers), 71.2 and 71.3 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 73.3
(CH2), 79.3 and 79.4 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 96.9
(CH2), 123.2 (CH, 2 carbons), 127.3 (CH, 2 carbons), 127.5 (CH), 128.3 (CH, 2 carbons), 132.1 (C, 2
carbons), 133.9 (CH, 2 carbons), 138.6 (C), 155.6 (C), 168.5 (C, 2 carbons); EIMS m/z (relative intensity)
579 (M++1, 2.4), 491 (8), 479 (13), 339 (78), 295 (100), 91 (58), 57 (38); HRMS calcd for C33H42N2O7
[M+] 578.2992, found 578.2994. Anal. Calcd for C33H42N2O7: C, 68.49; H, 7.32; N, 4.84. Found: C,
68.26; H, 7.12; N, 4.68.
2-{[(1R*,4R*,5S*,6S*)-4-[(Benzyloxy)methyl]-4-(hydroxymethyl)-2-azabicyclo[3.3.1]non-6-yl]-
methyl}-1H-isoindol-1,3(2H)-dione (46). To a stirred ice-cold solution of 45 (320 mg, 0.55 mmol) in

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MeOH (5.5 mL) was added concentrated HCl (0.18 mL, 2.21 mmol). After being stirred at 60 °C for 8
h, the mixture was cooled to 0 °C and saturated aqueous NaHCO3 (5 mL) was added. The mixture was
extracted with CHCl3 (3 x 10 mL). The combined extracts were washed with brine (20 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified by column chromatography on silica gel
(CHCl3–MeOH–concentrated NH4OH, 150:9:1) to give 46 (198 mg, 83%) as white crystals: mp
161.7–162.7 °C; IR (KBr) 3462, 3060, 2911, 1769, 1710 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.42 (1H, dt,
J = 13.3, 2.5 Hz), 1.56–1.71 (2H, m), 1.81–2.03 (3H, m), 2.11–2.23 (1H, m), 2.45 (1H, br s), 2.52 (1H, A
part of ABq, J = 13.6 Hz), 2.98 (1H, br s), 3.10 (1H, B part of ABq, J = 13.6 Hz), 3.52 (1H, A’ part of
ABq, J = 9.1 Hz), 3.63 (1H, A’’ part of ABq, J = 11.3 Hz), 3.70 (1H, B’’ part of ABq, J = 11.3 Hz),
3.90–4.03 (3H, m, including 1H at δ 3.95, B’ part of ABq, J = 9.1 Hz), 4.53–4.60 (2H, m), 7.27–7.39 (5H,
m), 7.66–7.72 (2H, m), 7.78–7.85 (2H, m); 13C NMR (100.6 MHz, CDCl3) δ 27.3 (CH2), 32.0 (CH), 33.1
(CH2), 33.8 (CH2), 42.0 (C), 43.9 (CH2), 44.3 (CH), 46.6 (CH), 46.7 (CH2), 69.1 (CH2), 73.7 (CH2), 76.7
(CH2), 123.2 (CH, 2 carbons), 127.7 (CH, 2 carbons), 127.9 (CH), 128.6 (CH, 2 carbons), 132.1 (C, 2
carbons), 133.8 (CH, 2 carbons),137.8 (C), 168.6 (C, 2 carbons); EIMS m/z (relative intensity) 345 (M++1,
5), 343 (18), 308 (14), 295 (32), 232 (28), 168 (20), 160 (52), 91 (100); HRMS calcd for C26H30N2O4 [M+]
434.2206, found 434.2206. Anal. Calcd for C26H30N2O4: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.70; H, 7.07; N, 6.30.
tert-Butyl
(1R*,4R*,5S*,6S*)-4-[(Benzyloxy)methyl]-6-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)-
methyl]-4-(hydroxymethyl)-2-azabicyclo[3.3.1]nonane-2-carboxylate (47). To a stirred ice-cold
solution of 46 (198 mg, 0.46 mmol) in dioxane–0.5 M NaOH (1:1, 4.6 mL) was added di-tert-butyl
dicarbonate (131 mg, 0.60 mmol) and the stirring was continued at rt for 20 min. Water (4.6 mL) was
added and the mixture was extracted with Et2O (3 x 5 mL). The combined organic phases were washed
with brine (10 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane–EtOAc, 3:1) to give 47 (186 mg, 76%) as a colorless oil: IR
(neat) 3466, 2929, 1770, 1712, 1685, cm-1; 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 1.63–1.93 (5H, m),
2.15 (1H, br s), 2.44 and 2.55 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each s),
2.85 and 2.95 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br s), 3.02 and 3.10
(total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each d, J = 14.4 Hz), 3.43–3.52 (2H, m),
3.71–3.75 (3H, m), 3.95 and 4.26 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br
s), 3.96–4.09 (2H, m), 4.48 (1H, A part of ABq, J = 12.1 Hz), 4.58 (1H, B part of ABq, J = 12.1 Hz),
7.31–7.35 (5H, m), 7.68–7.72 (2H, m), 7.81–7.84 (2H, m); 13C NMR (100.6 MHz, CDCl3) δ 25.8 (CH2),
28.4 (CH3, 3 carbons), 30.7 and 31.3 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate
rotamers), 30.8 (CH), 31.5 (CH), 32.0 (CH2), 41.8 and 42.1 (C, total 1 carbon, respectively, in ca.1:1 due

HETEROCYCLES, Vol. 75, No. 6, 2008
1351
to the carbamate rotamers), 43.5 (CH2), 43.7 (CH), 45.0 and 46.2 (CH, total 1 carbon, respectively, in ca.
1:1 due to the carbamate rotamers), 45.5 and 46.0 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the
carbamate rotamers), 68.0 and 68.8 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate
rotamers), 73.6 and 73.7 (CH2, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 75.9
(CH2), 79.5 and 79.6 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 123.2 (CH,
2 carbons), 127.6 (CH), 127.9 (CH), 128.5 (CH, 2 carbons), 133.9 (CH, 2 carbons), 132.0 (C, 2 carbons),
137.52 and 137.56 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 155.4 and
155.5 (C, total 1 carbon, respectively, in ca. 1:1 due to the carbamate rotamers), 168.6 (C, 2 carbons);
HRMS (ESI) calcd for C31H39N2O6 [M+H]+ 535.2808, found 5235.2784.
tert-Butyl (1R*,4R*,5S*,6S*)-6-(Aminomethyl)-4-[(benzyloxy)methyl]-4-(hydroxymethyl)-2-azabi-
cyclo[3.3.1]nonane-2-carboxylate (48). To a stirred solution of 47 (220 mg, 0.41 mmol) in EtOH (4.1
mL) was added hydrazine monohydrate (80.1 µL, 0.82 mmol). After being stirred at 70 °C for 2.5 h, the
mixture was cooled to rt and Et2O (10 mL) was added. The resulting precipitates were filtered off, and
the filtrate was concentrated. The residue was purified by column chromatography on silica gel
(CHCl3–MeOH–concentrated NH4OH, 150:9:1) to give 48 (159 mg, 96%) as a colorless oil: IR (neat)
3360, 3293, 3192 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.41–1.59 (10H, m, including 9H at δ 1.43, s),
1.59–1.66 (3H, m), 1.90–2.10 (4H, m), 2.72–2.84 (3H, m), 3.13 (2H, br s), 3.49 (2H, m), 3.57 and 3.66
(total 2H, respectively, in ca. 2:3 ratio due to the carbamate rotamers, each d, J = 11.8 Hz), 3.79 and 3.90
(total 1H, respectively, in ca. 2:3 ratio due to the carbamate rotamers, each d, J = 13.9 Hz), 4.35 and 4.47
(total 1H, respectively, in ca. 2:3 ratio due to the carbamate rotamers, each br s), 4.49 (1H, A part of ABq,
J = 12.2 Hz), 4.56 (1H, B part of ABq, J = 12.2 Hz), 7.22–7.31 (5H, m); 13C NMR (100.6 MHz, CDCl3) δ
26.4 and 26.8 (CH2, total 1 carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 27.8 and 28.0
(CH, total 1 carbon, respectively, in ca. 2:3 due to the carbamate rotamers), 28.5 (CH3, 3 carbons), 30.9
(CH2), 31.7 (CH2), 42.9 and 43.3 (C, total 1 carbon, respectively, in ca. 2:3 due to the carbamate
rotamers), 44.7 (CH2), 45.1 (CH), 46.3 (CH), 46.8 (CH2), 64.8 and 65.9 (CH2, total 1 carbon, respectively,
in ca. 3:2 due to the carbamate rotamers), 72.1 (CH2), 73.4 (CH2), 79.4 (C), 127.1 (CH), 127.25 (CH),
127.33 (CH), 128.2 (CH, 2 carbons), 138.8 and 138.9 (C, total 1 carbon, respectively, in ca. 2:3 due to the
carbamate rotamers), 155.7 (C); EIMS m/z (relative intensity) 405 (M++1, 76), 349 (23), 278 (31), 265
(48), 209 (70), 148 (54), 91 (98), 57 (100); HRMS (ESI) calcd for C23H37N2O4 [M+H]+ 405.2753, found
405.2744.
tert-Butyl
(1R*,4R*,5S*,6S*)-6-({[(Benzyloxy)carbonyl]amino}methyl)-4-[(benzyloxy)methyl]-4-
(hydroxymethyl)-2-azabicyclo[3.3.1]nonane-2-carboxylate (49). To a stirred ice-cold mixture of 48

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(12.0 mg, 29.7 µmol) in dioxane–water (1:1, 0.3 mL) were added Na2CO3 (3.46 mg, 32.7 µmol) and
benzyloxycarbonyl chloride (5.65 mg, 33.1 µmol). After being stirred at rt for 30 min, water (5 mL)
was added and the mixture was extracted with Et2O (3 x 10 mL). The combined organic phases were
washed with brine (30 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (hexane–EtOAc, 3:1) to give 49 (11.2 mg, 70%) as a colorless oil:
IR (neat) 3413, 2928, 1777, 1686 cm-1;1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 1.53–1.67 (3H, m),
1.89 (2H, m), 2.11 (1H, m), 2.29 and 2.39 (total 1H, respectively, in ca. 2:3 due to the carbamate rotamers,
each br s), 2.87–3.01 (2H, m), 3.00 and 3.18 (total 1H, respectively, in ca. 2:3 due to the carbamate
rotamers, each br s), 3.40 (2H, m), 3.55 (1H, t, J = 14.5 Hz), 3.58 (1H, dd, J = 2.4, 14.5 Hz), 3.65 (2H, m),
4.14 and 4.32 (total 1H, respectively, in ca. 3:2 due to the carbamate rotamers, each s), 4.45–4.57 (2H, m),
5.05 (1H, A part of ABq, J = 12.7 Hz), 5.13 (1H, B part of ABq, J = 12.7 Hz), 6.16 and 6.29 (total 1H,
13
respectively, in ca. 2:3 due to the carbamate rotamaers, each d, J = 5.0 Hz), 7.27–7.39 (10H, m); C
NMR (100.6 MHz, CDCl3) δ 26.0 (CH2), 26.6 and 27.5 (CH, total 1 carbon, respectively, in ca. 2:3 due to
the carbamate rotamers), 28.5 (CH3, 3 carbons), 30.7 (CH2), 31.4 (CH2), 41.9 and 42.3 (C, total 1 carbon,
respectively, in ca. 3:2 due to the carbamate rotamers), 43.4 and 43.7 (CH, total 1 carbon, respectively, in
ca. 3:2 due to the carbamate rotamers), 45.4 (CH2), 45.8 and 46.0 (CH2, total 1 carbon, respectively, in ca.
2:3 due to the carbamate rotamers), 46.6 (CH), 66.4 (CH2), 68.4 (CH2), 69.5 (CH2), 73.6 and 73.7 (CH2,
total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers), 79.7 (C), 127.5 (CH), 127.6 (CH),
128.0 (CH), 128.1 (CH), 128.5 (CH, 3 carbons), 128.6 (CH, 3 carbons), 136.9 (C), 137.3 and 137.4 (C,
total 1 carbon, respectively, in ca. 3:2 due to the carbamate rotamers), 155.3 and 155.7 (C, total 1 carbon,
respectively, in ca. 3:2 due to the carbamate rotamers), 156.6 (C); HRMS (ESI) calcd for C31H42N2O6Na
[M+H]+ 561.2941, found 561.2931.
6-Benzyl-2-tert-butyl (1R*,4S*,8S*,9S*)-4-[(Benzyloxy)methyl]-2,6-diazabicyclo[6.2.2.04,9]dodecane-
2,6-dicarboxylate (50). To a stirred ice-cold solution of 49 (10.0 mg, 18.6 µmol) in CH2Cl2 were added
Et3N (2.26 mg, 22.3 µmol) and methanesulfonyl chloride (2.35 mg, 20.5 µmol) at rt under argon
atmosphere. After being stirred at rt for 30 min, water (10 mL) was added and the mixture was extracted
with CHCl3 (3 x 10 mL). The combined phases were washed with brine (20 mL), dried (MgSO4), and
concentrated in vacuo. The residue was dissolved in THF (0.4 mL), t-BuOK (5.20 mg, 46.5 µmol) was
added at 0 °C, and stirring was continued at rt for 1 h. Water (5 mL) was added and the mixture was
extracted with Et2O (3 x 10 mL). The combined extracts were concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane–EtOAc, 5:1) to give 50 (7.0 mg, 72%) as a pale
yellow oil: IR (neat) 3030, 2926, 2869, 1687 cm-1;1H NMR (400 MHz, CDCl3) δ 1.36 (1H, br t J = 12.2
Hz), 1.44 (9H, s), 1.49–1.79 (3H, m), 1.80-2.08 (4H, m), 2.79–3.03 (2H, m), 3.08–3.70 (4H, m),

HETEROCYCLES, Vol. 75, No. 6, 2008
1353
3.77–4.14 (2H, m), 4.09 and 4.29 (total 1H, respectively, in ca. 1:1 due to the carbamate rotamers, each br
s), 4.40–4.53 (2H, m), 5.14 (2H, br s), 7.24–7.40 (10H, m); 13C NMR (100.6 MHz, CDCl3) δ 24.2 (CH2),
28.6 (CH3, 3 carbons), 28.9 (CH), 29,8 (CH2), 30.5 (CH2), 31.0 and 31.7 (CH, total 1 carbon, respectively,
in ca. 1:1 due to the carbamate rotamers), 34.3 (CH), 36.8 and 37.2 (C, total 1 carbon, respectively, in ca.
1:1 due to the carbamate rotamers), 44.8 (CH), 46.0 (CH2), 49.4 and 50.0 (CH2, total 1 carbon,
respectively, in ca. 1:1 due to the carbamate rotamers), 67.2 (CH2), 73.3 (CH2), 79.6 (CH), 127.4 (CH),
127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH). 128.4 (CH), 128.5 (CH, 3 carbons), 136.9
(C), 138.3 (C), 155.8 (C), 156.4 (C); EIMS m/z (relative intensity) 521 (M++1, 11), 419 (68), 321 (75),
265 (100), 221 (51), 91 (68), 57 (24); HRMS (ESI) calcd for C31H41N2O5 [M+H]+ 521.3015, found
521.2988.
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for Scientific Research on Priority Areas from the
Ministry of Education, Science, Sports and Culture of Japan.
REFERENCES AND NOTES
†Present address: Faculty of Pharmacy, Iwaki Meisei University, 5-5-1 Chuodai-Iino, Iwaki, Fukushima
970-8551, Japan.
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11. Crystal data: C30H38O2N2, Mr = 458.00, triclinic, P¯1, a = 10.014 (4) Å, b = 11.191 (4) Å, c = 12.561
(2) Å, α = 64.53 (2)°, β = 79.05 (2)°, γ = 74.74 (1) °, V = 1221.32 (0) Å3, Z = 2.
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13. The cis stereochemistry of the major adducts 24 and the trans stereochemistry of the minor adducts
25 were established by X-ray crystallographic analysis and spectroscopic analysis. For these
descriptions, see: ref. 5.
14. D. Ginsburg, J. Org. Chem., 1950, 15, 1003.