Preparation of chiral bipyridine bis-N-oxides by oxidative dimerization of chiral pyridine N-oxides

Article abstract of DOI:10.1016/j.tetasy.2005.12.039

The direct preparation of chiral 2,2′-bipyridine bis-N-oxides has been developed. The method involves two stages, first, the deprotonation of substituted chiral pyridine N-oxides and second, the oxidative dimerization of the resulting 2-lithiopyridine N-o

Full text of DOI:10.1016/j.tetasy.2005.12.039

Tetrahedron: Asymmetry 17 (2006) 687–707
Preparation of chiral bipyridine bis-N-oxides by
oxidative dimerization of chiral pyridine N-oxides
Scott E. Denmark* and Yu Fan
245 Roger Adams Laboratory, Box 18, Department of Chemistry, University of Illinois,
600 S. Mathews Avenue, Urbana, IL 61801, USA
Received 25 October 2005; accepted 21 December 2005
Available online 20 March 2006
Abstract—The direct preparation of chiral 2,20-bipyridine bis-N-oxides has been developed. The method involves two stages, first,
the deprotonation of substituted chiral pyridine N-oxides and second, the oxidative dimerization of the resulting 2-lithiopyridine
N-oxides. Optimization of the reaction conditions led to the selection of LiTMP in THF for the deprotonation and molecular iodine
as the oxidant. The corresponding 2-iodopyridine N-oxide is invariably formed as a by-product. A series of 11 chiral pyridine
N-oxides was prepared that bear substituents at the C(2) and C(5) positions. Oxidative dimerization of these mono-N-oxides
proceeded in 33–77% yield. In all cases, the dimerization was highly diastereoselective for the formation of the P-configuration
of the chiral axis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Background
Because of their strong electron-donating properties,
pyridine N-oxides have been widely applied as ligands
in the preparation of metal complexes.1 In addition, pyr-
idine N-oxides serve as useful oxygen atom transfer
agents for alkyl halides.2 However, it was not until
recently that the donor behavior of pyridine N-oxides
had been successfully harnessed for nucleophilic cata-
lysis.3 A number of chiral pyridine N-oxides have been
prepared and employed as Lewis-base catalysts for a
range of reactions involving silicon reagents such as:
(1) the allylation of aldehydes,4 (2) the enantioselective
ring opening of meso-epoxides,5 (3) the cyanosilylation
of ketones,6 and (4) the cyanosilylation of imine deriva-
tives.7 In addition to their application as Lewis-base
catalysts, these novel agents have also emerged as a
new class of ligands for Lewis acidic catalysts. Chiral
Lewis acids containing pyridine N-oxides have been
used for the addition of thiols8 or b-ketoesters9 to a,b-
unsaturated carbonyl compounds. Due to the growing
interest in this class of chiral agents, general synthetic
methods to access these highly functionalized hetero-
cycles are needed.
A survey of the current literature reveals that three
classes of chiral pyridine N-oxides have been developed.
Bis-N-oxides of type A that contain a chiral axis have
been prepared in racemic form and resolved (Chart 1).
Ph
HO
HO
N
N
Me Me
O
O
N
N
O
O
Ph
A
B
axial chirality
(Nakajima et al.)
axial chirality
(Hayashi et al.)
Me Me
N
Fe
O
R
R
N
N
R
R
O
Me
Me
Me
Me
R
R = 3,5-Me2C6H3
D
C
planar chirality
(Fu et al.)
central and axial chirality
(Kocovsky et al.)
*
Corresponding author. Tel.: +1 217 333 0066; fax: +1 217 333
3984; e-mail: denmark@scs.uiuc.edu
Chart 1.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.039

688
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
Nakajima et al. first described the resolution of this
compound by recrystallization of its hydrogen bonding
complex with enantiomerically pure BINOL.4d A con-
ceptually distinct approach has been reported recently
by Hayashi et al. who developed a method for the prep-
aration of a new class of 2,20-bipyrine bis-N-oxides B
(Chart 1). Herein, the 3,30-hydroxymethyl groups pro-
vide a handle for chemical resolution.4e These axially
chiral N-oxides provide excellent enantioselectivity in
the addition of allyltrichlorosilane to aromatic alde-
hydes at low catalyst loadings. Planar chiral pyridine
N-oxide C has been pioneered by Fu et al. for the
desymmetrization reactions of meso-epoxides (Chart
1).5a The enantiomers of this type of N-oxide were
resolved via chiral stationary phase HPLC and have
proven to be highly selective catalysts. Finally, bipyridyl
mono-N-oxide D (Chart 1), which embodies both cen-
tral and axial chirality, has been introduced by Kocov-
sky et al.4c By matching asymmetric induction from
two chiral elements, this catalyst proved to be highly
selective for the addition of allyltrichlorosilanes to aro-
matic aldehydes.
Me Me
Me Me
N
N
N
N
t-Bu
t-Bu t-Bu
t-Bu
O O
O O
O
O
O
O
R1
R1
R1
R1
(P)-(R,R)-5 R1 = n-Bu
(M )-(R,R)-5 R1 = n-Bu
(P)-(R,R)-6 R1 = 2,4,6-trimethylbenzyl
(P)-(R,R)-7 R1 = 2,4,6-triisopropylbenzyl
(P)-(R,R)-8 R1 = 1-naphthylmethyl
(P)-(R,R)-9 R1 = 2-naphthylmethyl
Me Me
X
X
N
N
N
N
R2
R2
t-Bu
t-Bu
O O
n-Bu
(P)-(R,R)-10 R2 = i-Pr
(P)-(R,R)-11 R2 = phenyldimethyl
(P)-(R,R)-12 R2 = t-heptyl
O O
n-Bu
(P)-(R,R)-13 X = Br
O
O
O
O
n-Bu
n-Bu
(P)-(R,R)-14 X = OMe
As part of our program to develop catalytic, enantio-
selective aldol additions of trichlorosilyl ketene acetals
to ketones, chiral bipyridine bis-N-oxide (R,R)-1 was
shown to be a highly reactive and selective catalyst
(Scheme 1).10 This catalyst can be prepared by bis-N-
oxidation of the parent chiral bipyridine as developed
by Bolm et al.11 In the presence of 10 mol % of this
N-oxide, the aldol addition of methyl trichlorosilyl
ketene acetal 2 to acetophenone 3 proceeds to comple-
tion within 150 min at 0 ꢁC, to afford the b-hydroxy
ester 4 in 92% yield with a 77.5/22.5 enantiomeric ratio.
Me Me
Me Me
Me
iPr
Me
iPr
N
N
N
N
O O
n-Bu
(P)-(R,R)-15
O O
n-Bu
16Aand 16B
O
O
O
O
n-Bu
n-Bu
Chart 2.
The high reactivity and promising selectivity observed
with this bis-N-oxide prompted further investigation of
this structural type.12 Structural modification of chiral
bis-N-oxides was formulated to examine the catalyst
structure/reactivity/selectivity relationship, including:
(1) the effect of fixing the chiral axis, (2) the steric effects
of substituents at the C(6,60)-centers, and (3) the elec-
tronic effects from the ring substituent at C(3,30). This
report details our full investigation on the development
of an efficient method for the synthesis of this class of
bis-N-oxides via direct dimerization of the correspond-
ing monomeric N-oxides and the application of this
method in the preparation of fifteen bis-N-oxide cata-
lysts (Chart 2) possessing both central and axial
chirality.
3. Results
3.1. Preparation of model mono-N-oxide 19
Although bis-N-oxidation of bipyridines provides facile
access to bis-N-oxides, the specific problems associated
with the preparation of 3,30-disubstituted 2,20-bipyridyls
prompted us to develop an alternative method. A more
direct approach was suggested by early studies from
Abramovitch et al.13 who showed that treatment of
2-lithiopyridine-1-oxides with bromine gives predomi-
nately bipyridyl compounds. The possibility of prepar-
ing chiral bis-N-oxides via dimerization of chiral
2-lithiopyridine N-oxide was therefore investigated. To
achieve this objective we first studied the conditions
for quantitative deprotonation of 2-substituted pyridine
N-oxides and then surveyed oxidants and conditions for
the dimerization. Pyridine N-oxide 19 was chosen as a
test substrate for these studies. The methyl ether was
readily prepared from commercially available 2-bromo-
5-methylpyridine 17. The three-step sequence outlined in
Scheme 2 afforded 19 in 81% overall yield via pyridyl
alcohol 18.
N
N
6'
6
t-Bu
t-Bu
Me
O O
OMe
MeO
(R,R)-1
OH
(S)
O
O
1. 10 mol% (R,R)-1
OSiCl3
+
OMe
Ph
2. sat. aq. NaHCO3
Ph
Me
OMe
3.1.1. The effects of base on the deprotonation of pyridine
N-oxide 19. Several lithium bases were initially sur-
veyed in the deprotonation of 19. A mixture of the pyr-
idine N-oxide and a base was stirred at low temperature
92% yield
77.5/22.5 er
2
3
4
Scheme 1.

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
689
MeO
t-Bu
1. NaH; MeI
0 oC, THF
89%
HO
N
t-Bu
Br
n-BuLi, Et2O, –73 oC
pivalaldehyde
O
N
N
92%
2. mCPBA
95%
Me
Me
Me
18
17
19
Scheme 2.
Table 1. The effects of base on deprotonation of pyridine N-oxide 19
MeO t-Bu
for the indicated period of time, before being quenched
with MeOD. The results are summarized in Table 1.
Although deprotonation of 19 took place when alkyl-
lithiums are used, the addition of the alkyllithiums to
19 was competitive (entries 1 and 2). Lithium amide
bases were also effective, but longer reaction times were
necessary (entries 3–6). A clean lithiation protocol was
established with the use of the bulky amide base LiTMP
at low temperature over 12 h (entry 5). Attempts to in-
crease the rate of lithiation with this reagent by increas-
ing the temperature led to lower chemical yields of 20
(entry 6).
MeO
t-Bu
O
O
MeOD
N
N
base
–74 oC, THF
D
H
Me
Me
20
19
Entry Base
1 n-BuLi
Time (h) Yield (%)a By-product yield (%)a
2 47
Me
t-Bu
N
n-Bu
3.1.2. The effects of oxidizing agents on dimeriza-
tion. With an effective lithiation protocol in hand, the
choice of oxidizing agent was investigated next. The
in situ generated 2-lithiopyridine N-oxide 21 was treated
with a variety of oxidizing agents at ꢀ74 ꢁC and the
reaction mixture was then allowed to warm to room
temperature before work-up. The results of the survey
of oxidizing agents are summarized in Table 2. The
use of molecular oxygen, Cu(OTf)2 and bromine
resulted in the formation of a complex mixture of
unidentified products that did not contain significant
amounts of the dimers (entries 1–3). When a full equiv-
alent of iodine was employed, diastereomeric dimeric
products 22 were formed in a combined yield of 43%
along with 39% of the corresponding 2-iodopyridine
N-oxide 23 (entry 4). This iodide was readily separated
from the dimers by column chromatography. Interest-
ingly, when half an equivalent of iodine was used, iodide
23 was found to be the major product (entry 5).
OMe
OMe
O
23
2
t-BuLi
2
64
Me
t-Bu
N
t-Bu
11
3
4
5
6c
LDA
LiTMP
LiTMP 12
LiTMP
5
4.5
77b
55b
95b
64b
—
—
—
—
5
a Yield of chromatographically pure material.
b % D incorporation.
c Reaction at ꢀ40 ꢁC.
Table 2. Effects of oxidizing agents on dimerization
3.1.3. The effects of solvent on dimerization. The effects
of solvent on the product ratio 22/23 were investigated
to improve the higher yield of the dimers. Under a
standard set of reaction conditions, weakly coordinating
solvents, such as toluene and diethyl ether were com-
pared with the strongly coordinating solvent, tetra-
hydrofuran in this reaction. The effect of HMPA
additive was also briefly investigated. These results are
summarized in Table 3.
Me Me
Me
oxidant
-74 oC, THF
Li
N
N
N
t-Bu
t-Bu
t-Bu
O
O
O
OMe
MeO
OMe
21
22
Entry
Oxidizing agent
22 Yield (%)a
23 Yield (%)
1
2
3
4
5b
O2
Cu(OTf)2
Br2
I2
I2
7
—
—
—
39
56
11
18
43
23
The use of non-coordinating solvents, such as toluene
and ether led to a dramatic decrease in the yield of
dimers 22 (Table 3, entries 1 and 2) while iodide 23
was obtained as the major product. In the coordinating
solvent THF, the dimer was produced in a slightly
higher yield than the iodide (Table 3, entry 3). However,
the addition of a strongly coordinating additive, such as
HMPA, did not lead to an improvement in the yield of
the dimer (Table 3, entry 4). Although the ratio of dimer
a Combined yields of three diastereomers.
b 0.5 equiv of I2 were used.
22 to iodide 23 is less than ideal, the direct dimerization
of lithiopyridine-N-oxides still provides a viable method

690
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
Table 3. Solvent effects on the product ratio 22/23
Me
Me
Me
(-)-(Ipc)2BCl
rt, 3 days
1. n-BuLi, Et2O;
-73 oC
2. pivaloyl chloride
Me
I
iodine (1.0 equiv)
84%,er 97.8/2.2
t-Bu
N
N
N
t-Bu
+
22
21
N
O
90%
t-Bu
Br
-74 oC to rt
THF
OMe
O
OH
(R)-18
23
17
24
Entry
Solvent
22 Yield (%)a
23 Yield (%)b
Me
Me
KH, THF
18-crown-6;
n-BuBr
1
2
3
4c
Toluene
Diethyl ether
THF
13
11
43
31
63
71
39
45
mCPBA
rt, CH2Cl2
(R)-18
N
N
84%
t-Bu
84%
t-Bu
THF
O
On-Bu
(R)-25a
On-Bu
(R)-26a
a Combined yields of three diastereomers of 21.
b Yields of chromatographically pure material.
c With 4 equiv of HMPA.
Scheme 3.
for the synthesis of bis-N-oxides considering that the by-
product iodide can be recycled or dimerized using the
Ullman protocol. Therefore, this method was chosen
for the synthesis of the collection of the bis-N-oxides
shown in Chart 2.
obtained in 48% yield along with 47% yield of iodide
(R)-27 (Scheme 4). Interestingly, the P-configured atrop-
isomer of 5 was produced with a diastereoselectivity
greater than 20/1. The configuration of (P)-(R,R)-5
was determined by X-ray crystallographic analysis of
its complex with silicon tetrachloride.14
3.2. Synthesis of bis-N-oxide (P)-(R,R)-5 and (M)-(R,R)-
5
Because (P)-(R,R)-5 was formed exclusively in the dim-
erization, it was necessary to employ a reduction/reoxi-
dation sequence for the preparation of (M)-(R,R)-5
(Scheme 5). Reduction of N-oxide (P)-(R,R)-5 with zinc
powder provided a good yield of bipyridine (R,R)-28.
Because of the absence of the N-oxide moiety, the
aryl–aryl bond in this compound is configurationally
labile. Bis-N-oxidation of (R,R)-28 provided a mixture
of two atropisomers that were separated by silica gel
column chromatography to afford (P)-(R,R)-5/(M)-
(R,R)-5 in 67% and 27% yields, respectively.
All of the optimization studies above were carried out
with racemic precursors 17.21 Consequently the products
were formed as mixtures of up to four diastereomers
arising from pair wise combinations of the stereogenic
centers, in addition to the newly formed chiral axis.
To prepare the enantiomerically pure bis-N-oxides
shown in Chart 2 for use as chiral catalysts, access to
enantiomerically enriched mono-oxides was needed.
This approach was illustrated for the pair atropisomers
(P)-(R,R)-5 and (M)-(R,R)-5, which were initially tar-
geted to study the effect of blocking rotation around
the aryl–aryl bond. The synthesis of (P)-(R,R)-5 re-
quired the preparation of an enantiomerically pure
mono-oxide (R)-26. The synthetic route began with
preparation of pyridyl ketone 24 by trapping 5-methyl-
2-pyridyllithium with excess pivaloyl chloride (Scheme
3). Subsequent enantioselective reduction of 24 provided
(R)-18 in good yield and high selectivity. The formation
of the butyl ether (R)-25a required the use of a sixfold
excess of potassium hydride and n-butyl bromide. Sub-
sequent oxidation of (R)-25a went smoothly and the
monomeric chiral N-oxide (R)-26a was obtained in high
yield.
3.3. Syntheses of bis-N-oxides (P)-(R,R)-(6–16)
To prepare the remaining variations of bis-N-oxides
compiled in Chart 1, a series of enantiomerically pure
chiral mono-N-oxides (R)-29 to (R)-39 was needed for
the final oxidative dimerization step. Under the assump-
tion that the size of the ether protecting group would
have a strong effect on enantioselectivity, the bis-N-
oxides (P)-(R,R)-(6–9) were prepared (Fig. 1).
Because of the difficulty of formation of the neopentyl
ether from alcohol (R)-18, reactive benzyl halides were
chosen as alkylating agents to obtain synthetically useful
yields in the etherification. The yields for each step
of the sequence in the preparation of bis-N-oxides
(P)-(R,R)-6–9 are summarized in Table 4. These prod-
When (R)-26a was lithiated with LiTMP and treated
with iodine following the procedure established for the
dimerization of 19, the bis-N-oxide (P)-(R,R)-5 was
1. LiTMP
- 74 oC, THF
Me
Me Me
2. I2, - 74 oC to rt
(R)-26a
t-Bu
+
N
O
I
N
N
O
t-Bu
t-Bu
On-Bu
O
O
n-Bu
On-Bu
48%
47%
(R)-27
(P)-(R,R)-5
Scheme 4.

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
Me Me Me Me
691
P-(R,R)-10R = i-Pr
P-(R,R)-11R = phenyldimethyl
P-(R,R)-12R = t-heptyl
Zn, CH3CO2H
91%
N
N
N
N
(P)-(R,R)-5
t-Bu
t-Bu
R
R
O
O
O
O
O
O
n-Bu
n-Bu
n-Bu
n-Bu
(R,R)-28
Figure 2. Structural variations of the alkyl groups at the 6,60-
stereocenters.
Me Me
mCPBA
(R,R)-28
3.4.1. Synthesis of (P)-(R,R)-10. The synthesis of (P)-
(R,R)-10 began with the preparation of the racemic alco-
hol ( )-29 from 2,5-dibromopyridine (Scheme 6). The
choice of 2,5-dibromopyridine instead of 2-bromo-5-
methylpyridine as a starting material was based on the
desire to have the ability to vary the substituent at the
3,30-positions of the bis-N-oxides. Thus, 2,5-dibromo-
pyridine was selectively lithiated at the 2-position using
the protocol developed by Wang et al.15 and reacted
with isobutyraldehyde to produce pyridyl alcohol ( )-
29 in good yield.
N
N
(P)-(R,R)-5
67%
+
t-Bu
t-Bu
O
O
O
O
27%
n-Bu
n-Bu
)-(R,R)-5
(M
Scheme 5.
Me Me
N
N
A two-step sequence converted racemic 29 to (R)-29 via
enantioselective reduction of pyridyl ketone 30. The for-
mation of butyl ether (R)-31 proceeded in good yield. In
order to have a direct comparison with bis-N-oxide (P)-
(R,R)-4, a methyl group was introduced at the 5-posi-
tion by a Kumada-type coupling reaction of (R)-31 with
methylmagnium bromide.16 Finally, N-oxide (R)-33 was
obtained in excellent yield by N-oxidation of (R)-32.
Subsequent dimerization provided a 38% yield of (P)-
(R,R)-10 along with 57% iodide (R)-34. The absolute
configuration of 10 was inferred by the sign of its specific
rotation, which was the same as that of (P)-(R,R)-5.
t-Bu
t-Bu
O O
O
R1
O
R1
(P)-(R,R)-6 R1 = 2,4,6-trimethylbenzyl
(P)-(R,R)-7 R1 = 2,4,6-triisopropylbenzyl
(P)-(R,R)-8 R1 = 1-naphthylmethyl
(P)-(R,R)-9 R1 = 2-naphthylmethyl
Figure 1. Structural variations of the ether protecting group.
ucts are inferred to be (P)-configured at the aryl–aryl
bond, on the basis of the sign of their specific rotation
as compared to (P)-(R,R)-5. The same sense of asym-
metric induction observed in the addition of 2 to
acetophenone provides additional evidence that the
configurations of these catalyst are the same as that in
(P)-(R,R)-5.
3.4.2. Synthesis of (P)-(R,R)-11. The synthesis of the
bis-N-oxide (P)-(R,R)-11 started with the preparation
of ( )-35 (Scheme 7). A two-step sequence converted
( )-35 to (R)-35 via enantioselective reduction of the
pyridyl ketone 36. High yields were achieved in the
reduction of hindered ketone 36. The etherification of
(R)-35 required the use of a large excess of the base
and alkylating agent under forcing conditions to provide
a good yield of the butyl ether (R)-37. Dimerization of
(R)-38, which was formed from the N-oxidation of butyl
ether (R)-37, delivered a 61% yield of the bis-N-oxide
3.4. Synthesis of bis-N-oxides (P)-(R,R)-10–12
This group of catalysts was prepared in order to assay
the effect of the size of the alkyl substituent at the
6,60-stereocenters on enantioselectivity (Fig. 2).
Table 4. Yields for preparations of bis-N-oxides (P)-(R,R)-(5–9)
RO
t-Bu
RO
N
t-Bu
1. LiTMP
KH, THF
RBr
-74 oC, THF
O
mCPBA
rt, CH2Cl2
(P)-(R,R)-6-9
N
(R)-18
2. I2
-74 oC to rt
Me
25b-e
Me
26b-e
R
Product yield (%)a
Product yield (%)a
Product yield (%)a
2,4,6-Trimethylbenzyl
2,4,6-Triisopropylbenzyl
1-Naphthylmethyl
25b, 87
25c, 82
25d, 69
25e, 87
26b, 94
26c, 86
26d, 79
26e, 91
(P)-(R,R)-6, 57
(P)-(R,R)-7, 52
(P)-(R,R)-8, 28
(P)-(R,R)-9, 39
2-Naphthylmethyl
a Yields of analytically pure material.

692
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
O
N
i-Pr
i-Pr
HO
N
1. n-BuLi, toluene, -78 oC
2. isobutyraldehyde
- 78 oC to rt
Br
PCC/SiO2
CH2Cl2
N
66%
90%
Br
Br
Br
( )-29
30
(-)-(Ipc)2BCl
rt, 2 days
yield 74%
er 95.2/4.8
BuO
i-Pr
mCPBA
BuO
i-Pr
Ni(dppp)2
BuO
i-Pr
HO
i-Pr
KH, THF
O
N
18-crown-6
n-BuBr
MeMgBr
N
N
N
94%
76%
87%
Me
(R)-33
Me
(R)-32
Br
Br
(R)-29
(R)-31
Me Me
Me
1. LiTMP
i-Pr
+
-74 oC, THF
N
O
I
N
N
(R)-33
2. I2, -74 oC to rt
OBu
i-Pr
i-Pr
O
O
O
O
57%
(R)-34
38%
(P)-(R,R)-10
n-Bu
n-Bu
Scheme 6.
Ph
Ph
O
Me
HO
N
Me
Br
N
1. n-BuLi, Et2O, –73 oC
Me
PCC/SiO2
rt, CH2Cl2
Me
Me
Me
N
2.
80%
Ph
CHO
90%
Me
Me
Me
36
( )-35
(-)-(Ipc)2BCl
rt, 3 days
yield 82%
er 97.5/2.5
Ph
Ph
Ph
HO
Me
Me
BuO
N
Me
Me
BuO
Me
mCPBA
Me
KOH, THF
18-crown-6
O
rt, CH2Cl2
N
N
92%
n-BuBr
74%
Me
Me
(R)-37
Me
(R)-38
(R)-35
Me Me
Me
1. LiTMP
-74 oC, THF
Me Me
(R)-38
+
Ph
N
I
2. I2, -74 oC to rt
N
N
OBu
O
R
R
O
O
O
O
Me Me
R =
61%
n-Bu
n-Bu
18%
(R)-39
Ph
(P)-(R,R)-11
Scheme 7.
(P)-(R,R)-11 along with a small amount of the iodide
(R)-39.
3.4.3. Synthesis of (P)-(R,R)-12. The synthesis of bis-
N-oxide (P)-(R,R)-12 began with the preparation of pyr-

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
693
Et
Et
Et
Et
Et
Et
O
N
HO
N
Br
(-)-(Ipc)2BCl
rt, 3 days
1. n-BuLi, Et2O, –73 oC
N
yield 67%
er 98/2
Et
Et
Et
O
2.
Me
Me
40
Me
(R)-41
Cl
85%
KOH, DMF
18-crown-6
n-BuBr
49%
Et
Et
Et
Et
Et
Et
Me Me
BuO
BuO
mCPBA
rt, CH2Cl2
1. LiTMP
-74 oC, THF
O
N
N
N
N
R
R
89%
O
2. I2, -74 oC to rt
77%
O
O
O
Me
(R)-42
Me
(R)-43
n-Bu
(P)-(R,R)-12
n-Bu
Et Et
R =
Et
Scheme 8.
idyl ketone 40 (Scheme 8). Highly enantiomerically en-
riched (R)-41 was obtained by (ꢀ)-Ipc2BCl reduction
of 40. Etherification of (R)-41 proved to be difficult
and only a modest yield was obtained, even with the
use of a large excess of reagents. Subsequent N-oxida-
tion of butyl ether (R)-42 went smoothly and provided
(R)-43 in good yield. Oxidative dimerization of (R)-43
gave the dimer (P)-(R,R)-12 in 77% yield. This is note-
worthy since it represents the highest yield in a coupling
step for any of the N-oxides.
tron-withdrawing bromine substituents would decrease
the electron density of the pyridine ring and thus dimin-
ish the electron-donating ability of the N-oxide donor.
The synthesis of (P)-(R,R)-13 began with the preparation
of the racemic alcohol ( )-44 by reacting pivaloyl alde-
hyde with 5-bromopyridyllithium, generated from selec-
tive mono-lithiation of 2,5-dibromopyridine (Scheme
9).13 A two-step sequence of converted ( )-44 to (R)-44
via the pyridyl ketone 45 afforded the product in good
yield. The formation of butyl ether (R)-46 proceeded in
a respectable yield under forcing conditions. Monomeric
N-oxide (R)-47 was obtained by mCPBA oxidation of
(R)-46. It was found that the deprotonation of (R)-47
with LiTMP was rapid and went to completion within
0.5 h at ꢀ74 ꢁC. This is much faster than the rate of
the 5-methyl substituted counterpart (R)-25, hinting at
enhanced acidity of the proton at the 6-position due to
the inductive effect from the bromine substituent. Upon
treatment of the lithiopyridine N-oxide (R)-48 with
iodine, a modest yield of the dimer (P)-(R,R)-13 was
obtained.
3.4.4. Synthesis of (P)-(R,R)-13 and (P)-(R,R)-14. Bis-
N-oxides (P)-(R,R)-13 and (P)-(R,R)-14 were investi-
gated in order to study the electronic effect of ring sub-
stituents on the reactivity of the catalyst (Fig. 3).
Although it would be ideal to compare the reactivity
of bis-N-oxides substituted with electron-withdrawing
or electron-donating groups at the 4,40-positions, due
to their well established influence on basicity, the 3,30-
positions were chosen as the site of substitution, since
it was expected that both catalysts (P)-(R,R)-13 and
(P)-(R,R)-14 could be readily obtained starting from
2,5-dibromopyridine.
3.4.6. Synthesis of (P)-(R,R)-14. Bis-N-oxide (P)-
(R,R)-14 was prepared in order to investigate the effect
of increasing the donor ability of the N-oxide on reactiv-
ity and selectivity. It was expected that the 3,30-di-
methoxy substituents would enhance the donor ability
of the N-oxide motif by donating electron density to
the pyridine ring.
3.4.5. Synthesis of (P)-(R,R)-13. Bis-N-oxide (P)-
(R,R)-13 was prepared in order to investigate the effect
of decreasing the donor ability of N-oxide moiety on
reactivity and selectivity. It was expected that the elec-
X
X
The monomeric N-oxide (R)-49 required for the synthe-
sis of (P)-(R,R)-14 was readily prepared by displacement
of the 5-bromo substituent of (R)-47 with potassium
methoxide in DMF (Scheme 10). The rate of the depro-
tonation of (R)-49 was found to be similar to that of
(R)-47, hinting at the electron-withdrawing influence
from the methoxy group.
N
N
P-(R,R)-13X = Br
t-Bu
t-Bu
O
O
P-(R,R)-14X = OMe
O
O
n-Bu
n-Bu
Figure 3. Structural variations at the 3,30-positions.

694
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
O
N
t-Bu
t-Bu
HO
N
Br
Br
PCC/SiO2
CH2Cl2
1. n-BuLi, Et2O, –73 oC
N
2. pivaloyl aldehyde
- 73 oC to rt
90%
Br
Br
( )-44
45
(-)-(Ipc)2BCl
rt, 3 days
yield 84%
er 96.8/3.2
HO
t-Bu
BuO
t-Bu
BuO
t-Bu
KH, THF
18-crown-6
n-BuBr
mCPBA
O
N
N
rt, CH2Cl2
N
79%
99%
Br
Br
Br
(R)-47
(R)-46
(R)-44
Br Br
BuO
t-Bu
I2
LiTMP
O
-74 oC to rt
33%
-74 oC
N
N
N
(R)-47
t-Bu
t-Bu
Li
O
O
0.5 h, THF
O
O
Br
n-Bu
n-Bu
(R)-48
(P)-(R,R)-13
Scheme 9.
MeO OMe
BuO
t-Bu
1. LiTMP
-74 oC, THF
KOMe
DMF
O
N
N
N
(R)-47
t-Bu
t-Bu
2. I2
O
O
79%
-74 oC to rt
O
O
OMe
(R)-49
n-Bu
(P)-(R,R)-14
n-Bu
51%
Scheme 10.
3.4.7. Synthesis of (P)-(R,R)-15, (P)-(R,R)-16, and (M)-
(R,R)-16. Bis-N-oxides (P)-(R,R)-15 and (P)-(R,R)-16
were selected as catalyst structures to study the effect
of the dihedral angle H(10)–C(60)–C(6)–N(1) on reactiv-
ity and selectivity (Fig. 4). The 5-methyl substituent in
catalyst (P)-(R,R)-15 was envisioned to rotate the
H(10)–C(60) bond away from the co-planarity with the
pyridine ring due to steric repulsion between the 5-
methyl substituent and the tert-butyl group. Comple-
mentarily, catalyst (P)-(R,R)-16 would rotate the bond
in the opposite direction through ring constriction.
Results from molecular mechanics modeling (PM3,
MM2) indicated that there was a slight increase of the
dihedral angle H–C(60)–C(6)–N in (P)-(R,R)-15ÆSiCl4 in
a clockwise direction as compared to that in (P)-(R,R)-
4ÆSiCl4. On the other hand, in (P)-(R,R)-16ÆSiCl4 there
is a drastic increase in the opposite direction (Fig. 5).
3.4.8. Synthesis of (P)-(R,R)-15. The synthesis of bis-
N-oxide (P)-(R,R)-15 started with the preparation of
pyridyl ketone 50 through reaction of pivaloyl chloride
with 3,5-dimethylpyridyllithium (Scheme 11). Subse-
quent enantioselective reduction of 50 with (ꢀ)-Ipc2BCl
provided alcohol (R)-51. Butyl ether (R)-52 was obtained
in good yield under the forcing conditions and mono-N-
oxide (R)-53 was obtained after N-oxidation of (R)-52.
Me
1'
Me
Me
H
Me
t-B
u
1
5
5
N
Me
Me
1
N
6
N
O
On-Bu
6
6
N
6'
6'
O
O
O
H
O
n-BuO
O
1'
t-Bu
H
n-Bu
(P)-(R,R)-16
H
n-Bu
(P)-(R,R)-15
Dimerization of (R)-53 provided (P)-(R,R)-15 in modest
yield (Scheme 12). Unfortunately, iodide (R)-54 was
obtained as the major product under these conditions.
Figure 4. Variation in the dihedral angle H(10)–C(60)–C(6)–N(1) for
(P)-(R,R)-15 and (P)-(R,R)-16.

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
Me Me
695
Me Me
Me Me
Me
Me
N
N
N
N
N
N
6
6
6'
6'
t-Bu
t-Bu
t-Bu
t-Bu
O
O
O
O
O
O
O
O
H O
O
H
O
O
Cl Si Cl
Cl
Cl
Cl Si Cl
n-Bu n-Bu
Cl Si Cl
n-Bu
n-Bu
n-Bu
n-Bu
Cl
Cl
Cl
Cl
•SiCl
4
(P)-(R,R)-16
(P)-(R,R)-4 •SiCl4
(P)-(R,R)-15•SiCl4
- 28.6o
-32.3o
72.6o
Figure 5. Dihedral angle H–C(60)–C(6)–N in PM3-calculated structures.
O
t-Bu
Me
HO
t-Bu
Me
1. n-BuLi, Et2O,- 73 oC
2. pivaloyl chloride
- 73 oC to rt
Br
(-)-(Ipc)2BCl
rt, 3 days
Me
N
N
N
yield 78%
er 98.2/1.8
86%
Me
Me
Me
(R)-51
50
KH, THF
18-crown-6
n-BuBr
4%
7
BuO
N
t-Bu
BuO
t-Bu
Me
CPBA
rt, CH2Cl2
m
Me
O
N
89%
Me
Me
(R)-53
(R)-52
Scheme 11.
Me Me
1. LiTMP
Me
t-Bu
Me
-74 oC, THF
Me
Me
+
2. I2, -74 oC to rt
N
I
N
N
(R)-53
t-Bu
t-Bu
OBu
O
O
O
O
O
n-Bu
n-Bu
47%
43%
(R)-54
(P)-(R,R)-15
Scheme 12.
3.4.9. Bis-N-oxides (P)-(R,R)-16 and (M)-(R,R)-16.
The synthesis of (P)-(R,R)-16 began with the prepara-
tion of pyridyl alcohol (R)-55 (Scheme 13). 3-Methyl-
6,7-dihydro-5H-quinolin-8-one17 was reduced with
(ꢀ)-Ipc2BCl at 0 ꢁC to provide (R)-55 in good yield
but with modest enantiomeric purity. The enantiomeric
purity of (R)-55 could be enhanced to greater than 99/1
by two recrystallizations of (R)-55 from tert-butyl methyl
ether. Enantiomerically pure (R)-55 was then trans-
formed to the monomeric N-oxide (R)-57 in two steps
via the butyl ether (R)-56.
(-)-(Ipc)2BCl
0 oC
Me
Me
yield 89%
er 88/12
recrystalized
to >99% ee
N
N
OH
(R)-55
O
KH, THF
18-crown-6
n-BuBr
91%
mCPBA
rt, CH2Cl2
Me
Me
96%
Surprisingly, the dimerization of (R)-57 was found to
proceed with low selectivity, providing a poor yield of
dimeric products. Again, the major product of the reac-
tion was found to be the iodide (R)-58 (Scheme 14).
Because of the poor yield of dimeric product, the iodide
N
N
O
(R)-57
OBu
OBu
(R)-56
Scheme 13.

696
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
line-derived mono-N-oxide (R)-39 delivered a mixture of
two atropisomers, in low yield (Table 5, entry 12).
Me
Me
O
1. LiTMP, -73 oC;
2. I2, -73 oC to rt
I
N
N
16 +
O
4. Discussion
23%
On-Bu
On-Bu
(R)-57
69%
(R)-58
Directed ortho-lithiation of heterocyclic N-oxides and
subsequent reactions of lithio N-oxides have been exten-
sively studied.18 However, examples of the formation of
bis-N-oxides by such a method are rare. Therefore, the
formation of bis-N-oxides from the monomeric N-oxi-
des of the structural type i represents a novel transfor-
mation, and hence raises the question of the mechanism.
Me Me
1. Cu, DMF, 150 oC
2. m CPBA, rt
N
N
(R)-58
O O
O
O
n-Bu
n-Bu
Three limiting scenarios can be formulated based on the
intermediacy of the 2-lithiopyridine-N-oxide ii, formed
by the deprotonation of the parent N-oxides: (1) addi-
tion of the 2-lithiopyridine to the neutral precursor i in
a slow step, followed by a secondary oxidation, (2) addi-
tion of ii to a radical formed by single electron oxidation
of ii and subsequent oxidation by iodine, and (3) iodin-
ation of ii and then addition of the 2-lithiopyridine pre-
cursor followed by loss of lithium iodide. These three
mechanisms are elaborated below.
(+)-16a(52%) and (-)-16b(22%)
Scheme 14.
(R)-58 was converted to the bis-N-oxide 16 by treatment
with copper powder in DMF at 150 ꢁC and then with
mCPBA at rt. The two isomers were separated by silica
gel column chromatography. The less polar isomer was
found to be the major isomer. Since both isomers
showed poor selectivities in the aldol reaction, their
absolute configurations were not assigned.14
In the first scenario, 2-lithiopyridine N-oxide ii (formed
by slow deprotonation of i) reacts with mono N-oxide i
to form stable adduct iii. Subsequent oxidation of iii
would provide dimer iv (Scheme 15). Such a mechanism
has been suggested for the formation of bisquinoline N-
oxide products.19 Herein, this mechanism might explain
the formation of a small amount of dimer when pyridine
N-oxide 17 was treated with LiTMP.
The results of the dimerizations of the enantiomerically
enriched mono N-oxides are summarized in Table 5.
The configurations of these bis-N-oxides were inferred
to be (P), on the basis of the sign of their specific rotation
as compared to (P)-(R,R)-5.14 The same sense of
asymmetric induction observed in the addition of 2 to
acetophenone, provides additional evidence that the
configurations of these catalysts are the same as those
in (P)-(R,R)-5. On the other hand, the tetrahydroquino-
In the second proposed mechanism, the 2-lithiopyridine
N-oxide ii was oxidized by iodine or bromine to give free
radical v (Scheme 16). As it is well known that lithio
anions generally exist as aggregates,20 it is reasonable
to propose that upon oxidation of the aggregated species
with a single electron oxidant, radical v might be gener-
ated and react with another molecule of ii in the imme-
diate proximity to produce radical vi. It is noteworthy
that the highest yields of bis-N-oxides were obtained
from mono-N-oxides having most sterically encumbered
oxygen substituents, such as phenyldimethyl and tert-
heptyl groups. One might expect that these bulky
Table 5. Dimerization of chiral pyridine-N-oxides
X
X X
O O
1. LiTMP
-74 oC, THF
2. I2, -74 oC to rt
R2
N
N
N
R2
R2
O
OR1
O
R1
O
R1
Entry
Mono-N-oxide
Bis-N-oxidea
Yield (%)b
1
2
3
4
5
6
7
8
(R)-26a
(R)-26b
(R)-26c
(R)-26d
(R)-26e
(R)-33
(R)-38
(R)-43
(R)-48
(R)-49
(R)-53
(R)-58
(P)-(R,R)-5
(P)-(R,R)-6
(P)-(R,R)-7
(P)-(R,R)-8
(P)-(R,R)-9
(P)-(R,R)-10
(P)-(R,R)-11
(P)-(R,R)-12
(P)-(R,R)-13
(P)-(R,R)-14
(P)-(R,R)-15
16a and16b
48
57
52
28
39
38
61
77
33
51
37
23c
R1 R1
R1
base; oxidants
R2
N
N
N
O
R2
R2
OR3
O
O
OR3
R3O
iv
i
LiTMP
R1
9
O
10
11
12
R1
R1
R2
+ i
N
O
Li
a These products are inferred to be (P)-configured at the aryl–aryl bond
based on comparison of the sign of their specific rotation as to that of
(P)-(R,R)-5.
b Yields of chromatographically pure material.
c Yields of a mixture of both diastereomers.
N
O
R
N
OR3
ii
O
H
R
iii
Li
Scheme 15.

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
697
R1
base; oxidants
iv
R2
N
O
Li
OR3
n
ii
- LiX
Br2
or I2
R1
Li
R1
R1
R1
R2
R2
+
N
O
N
O
N
R
N
OR3
OR3
O
O
R
vi
v
ii
Li
X = Br or I
Scheme 16.
R1
R1
substituents would facilitate deaggregation and lead to
the formation of a dimerization product.
R1
R1
I
iv
N
O
R
N
N
N
O
The third scenario invokes the intermediacy of an 2-iodo-
pyridine N-oxide vii, which was always isolated as a by
product (Scheme 17). Thus, the halogenation of addi-
tion of ii to form vii could be followed by an addition
to ii, analogous to the addition to radical v above. In this
case the intermediate viii would collapse with the loss of
lithium iodide to form dimer iv.
R2
R2
Li
O
O
I
R
OR3
R3O
Li
ix
viii
Scheme 18.
ing because the stereocenter at the 6-position is remote
from the generated chiral axis. In principle, the two
intermediates x and xi could lead to the formation of
the two atropisomers of iv (Scheme 19). Rotation
around the newly formed carbon–carbon bond intercon-
verts the intermediates x and xi. In the absence of a clear
mechanistic picture, it is difficult at best to formulate a
rationale for the near exclusive formation of the P-iso-
mers in the series 5–15. It is also unclear if the selectivity
arises from a kinetically controlled formation of inter-
mediates, such as x and xi or from their thermodynamic
equilibration. The poor selectivity in the dimerization of
(R)-58 suggests that the bulk and/or conformation of
the substituent at C(6,60) plays an important role in
the stereochemical outcome. However, this is difficult
to visualize by consideration of molecular models. On
If a hypervalent iodine intermediate21 is taken into
account, the formation of a complex of structure ix
might precede the carbon–carbon bond formation step
(Scheme 18). From studies by Reich and co-workers
on lithium–iodine exchange reactions it is known that
hypervalent iodine ‘ate’ complexes can be formed upon
mixing phenyllithium and iodobenzene and in a strong
coordinating solvent, such as HMPA.22 It is conceivable
that in the current case, the N-oxide donor might
coordinate to Li+ and thus facilitate the formation of
dipyridyliodinate anion.
The high diastereoselectivity observed in the formation
of the series of bis-N-oxides (P)-(R,R)-(5–15) is intrigu-
R1 R1
I
R
O
R2
O
N
R1
N
O
N
N
Li
R
R =
R
R1
O
R2
R2
N
OR3
O
O
N
n
OR3
R3O
R1
N
ii
O
I
iv
R
R
R1
)-iv
Li
- LiX
I2
x
OR2
R3
(M
R1
I
R1
R1
R1
R1
R1
ii
R2
R1
N
N
O
R
N
O
N
R
OR3
N
N
O
I
N
R
R
O
O
O
I
R
Li
viii
O
vii
Li
xi
)-iv
(P
Scheme 17.
Scheme 19.

698
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
the other hand, it is intriguing to consider the possible
role that chelation of a lithiated intermediate may play
in determining the preference (be it kinetic or thermo-
dynamic) for the formation or breakdown of xi, which
leads to the observed diastereomer (P)-iv.
tures (ABT) and are uncorrected. Analytical TLC was
performed on Merck silica gel plates with QF-254
indicator. Visualization was accomplished with potas-
sium permanganate. Analytical supercritical fluid
chromatography (SFC) was performed with a built-in
photometric detector (k = 220 or 258 nm) using Daicel
Chiralpak columns. Analytical capillary gas chromato-
graphy (GC) was performed with flame ionization detec-
tion (H2 carrier gas, 16 mL/min). The following columns
were used: Astec (Chiraldex) BPH 30 m · 0.25 mm ·
0.125 lm. The injector temperature was 225 ꢁC, the
detector temperature was 300 ꢁC. Retention times (tR)
and peak ratios were determined with a reporting inte-
grator. Analytical high pressure liquid chromatography
(HPLC) was performed with a built-in photometric
detector (k = 220 or 258 nm). Chiral separations were
performed using a Rexchrom (S,S) b-Gem 1 column.
Solvents for HPLC use were of spectroscopic grade
and filtered before use. Retention times (tR) and peak
ratios were determined with a reporting integrator. All
separation methods for chiral samples were calibrated
with racemic samples. Melting points (mp) were deter-
mined on a capillary melting point apparatus and are
5. Conclusion
A direct method for the synthesis of chiral bipyridine
bis-N-oxides has been developed. The key step of the
synthesis is an iodine-mediated dimerization reaction
of in situ-generated 2-lithiopyridine N-oxide. The facile
syntheses of these agents allow systematic structural
variations, which facilitate the elucidation of the rela-
tionship between catalyst structure, reactivity, and selec-
tivity for a variety of catalyzed reactions.
6. Experimental
6.1. General experimental
All reactions were performed in oven (140 ꢁC) or flame-
dried glassware under an inert atmosphere of dry N2. All
reaction temperatures corresponded to internal temper-
atures measured with Teflon-coated thermocouples
unless otherwise noted. Solvents for extraction and
chromatography were of technical grade and distilled
from the indicated drying agents: hexane (CaCl2); meth-
ylene chloride (CaCl2); ethyl acetate (K2CO3). Reaction
solvents were distilled from the indicated drying agents:
methylene chloride (P2O5); methanol (Mg). Diipropyl-
ethylamine was freshly distilled from CaH2. Flash col-
umn chromatography was performed using 230–400
mesh silica gel. 1,1,6,6-Tetramethylpiperidine was
freshly distilled before use. 2-Bromo-5-methylpyridine
was used as received. 2-Methyl-2-phenylpropionalde-
hyde,1 2,2-diethylbutyryl chloride,2 and 3-methyl-6,7-
dihydro-5H-quinolin-8-one3 were prepared according
to the literature procedures.
corrected. Optical rotations were obtained on a digital
T
polarimeter and are reported as follows: ½aꢁD, concentra-
tion (c g/100 mL), and solvent.
6.1.1. Preparation of (P)-(R,R)-3,30-Dimethyl-6,60-bis-
(1-butyloxy-2,2-dimethylpropyl)-2,20-bipyridine bis-N-oxide
(P)-(R,R)-5. 1-[2-(5-Methylpyridyl)]-2,2-dimethylpropa-
none 24. To a suspension of 2-bromo-5-methylpyridine
17 (5.02 g, 29.2 mmol) in Et2O (50 mL) was added n-
BuLi in hexane (20.0 mL, 31 mmol, 1.05 equiv) drop-
wise over 15 min at ꢀ73 ꢁC. The mixture was stirred
for 1 h at ꢀ73 ꢁC and the resulting deep red solution
transferred dropwise via a short cannula to a rapidly
stirred solution of pivaloyl chloride (7.2 mL, 61 mmol,
2.0 equiv) in THF (10 mL), which was pre-cooled to
ꢀ73 ꢁC. After being stirred for 4 h at ꢀ73 ꢁC, the red-
dish mixture was slowly brought to rt over 5 h and the
reaction quenched with cold water (20 mL). The mixture
was poured into cold aq NaOH solution (40%, 100 mL)
and stirred for 30 min. The aqueous layer was extracted
with Et2O (3 · 100 mL). The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. Purification of the semi-solid residue by silica
gel chromatography (hexane/EtOAc, 10/1) afforded
4.72 g of product (90%) as a colorless oil. An analyti-
cally pure sample was obtained after bulb-to-bulb distil-
1H NMR, 13C NMR, 19F NMR spectra were recorded
on 400 (1H, 400 MHz; 13C, 100 MHz; 19F, 376 MHz),
1
500 (1H, 500 MHz; 13C, 126 MHz). H NMR and 13C
NMR spectra are referenced to residual chloroform (d
1
7.26 ppm, H; d 77.0 ppm, 13C). 19F NMR spectra are
referenced externally to C6F6. Chemical shifts are given
in parts per million (d); multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), m (multi-
plet), or br (broadened). Coupling constants, J, are
1
lation. Data for 24: bp: 112 ꢁC ABT (7.3 mmHg); H
NMR (500 MHz, CDCl3): 8.43–8.44 (m, 1H, HC(50)),
7.82 (d, J = 8.0, 1H, HC(20)), 7.56–7.58 (m, 1H,
HC(30)), 2.38 (s, 3H, H3C(60)), 1.45 (s, 9H,
(H3C)3C(2)); 13C NMR (100 MHz, CDCl3): 206.6
(C(1)), 152.2 (C(20)), 148.1 (C(60)), 136.9 (C(40)), 136.0
(C(50)), 123.4 (C(30)), 44.1 (H3C(C(40))), 27.5 (C(3)),
18.6 (C(2)); IR (neat): 2955 (m), 2928 (m), 2867 (w),
1682 (s), 1566 (w), 1481 (m), 1297 (m), 1199 (s), 964
(s) 849 (w); TLC Rf 0.44 (hexane/EtOAc, 10/1); MS
(EI): 177 (14), 149 (11), 120 (10), 107 (10), 93 (100), 92
(39), 65 (18), 57 (15); Anal. Calcd for C11H15NO
(177.25): C, 74.54; H, 8.53; N, 7.90. Found: C, 74.55;
H, 8.68; N, 8.04.
1
reported in Hertz. All H and 13C NMR assignments
are corroborated by 2D experiments (HETCOR and
COSY).
Low-resolution electron impact (EI) mass spectra were
obtained with a typical ionization voltage of 70 eV.
Data are reported in the form m/z (intensity relative to
base = 100). Infrared spectra (IR) are reported in
cmꢀ1 with the following relative intensities: s (strong,
67–100%), m (medium, 34–66%), w (weak, 0–33%).
Bulb-to-bulb distillations were done on a Kugelrohr
apparatus; boiling points (bp) refer to air bath tempera-

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
699
6.1.2. 1-[2-(5-Methylpyridyl)]-2,2-dimethylpropanol ( )-
18. To a suspension of 2-bromo-5-methylpyridine
(344 mg, 2.0 mmol) in Et2O (5 mL) was added n-BuLi
in hexane (1.4 mL, 2.2 mmol, 1.1 equiv) dropwise over
15 min at ꢀ73 ꢁC. The mixture was stirred for 1 h at
ꢀ73 ꢁC and to the resulting deep-red solution was added
pivalaldehyde (240 lL, 2.2 mmol, 1.1 equiv). The mix-
ture was stirred for 1 h at ꢀ73 ꢁC and then warmed to
rt over 40 min. The reaction mixture was quenched with
cold water and the aqueous layer extracted with Et2O
(3 · 30 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure.
Purification of the semi-solid residue by silica gel chro-
matography (hexane/EtOAc, 5/1) afforded 331 mg of
product (91%) as white needles. Data for ( )-18: mp:
42–43 ꢁC; 1H NMR (500 MHz, CDCl3): 8.39 (s, 1H,
HC(60)), 7.48 (d, J = 7.9, 1H, HC(40)), 7.12 (d, J = 7.9,
1H, HC(30)), 4.36 (s, 1H, HC(1)), 4.31 (br s, 1H, HO),
2.35 (s, 3H, H3C(60)), 0.91 (s, 9H, (H3C)3C(2)).
2867 (s), 2740 (m), 1606 (w), 1573 (m), 1486 (s), 1454
(s), 1423 (m), 1388 (s), 1363 (s), 1348 (m), 1307 (w),
1240 (m), 1209 (m), 1182 (w), 1132 (w), 1079 (s), 1037
(s), 1018 (s), 910 (w), 837 (m), 798 (w); TLC Rf 0.20
(hexane/EtOAc, 5/1): MS (FI, 70 eV) 181 (3), 180 (31),
24
179 (100), 123 (6), 122 (73); Opt. Rot. ½aꢁD ¼ þ28:4 (c
0.89, EtOH): Anal. Calcd for C11H17NO (177.25): C,
73.10; H, 9.56; N, 7.81. Found: C, 73.05; H, 9.73; N,
7.83.
6.1.5. (R)-1-[2-(5-Methylpyridyl)]-2,2-dimethylpropyl tri-
fluoroacetate (R)-18a. To a solution of (R)-18 (180 mg,
1.0 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic
anhydride (160 lL, 1.1 mmol, 1.1 equiv) at 0 ꢁC under
N2. The resulting solution was stirred for 1 h at 0 ꢁC
and quenched by pouring the mixture into a cold, satu-
rated aqueous solution of NaHCO3 (20 mL). The aque-
ous layer was extracted with CH2Cl2 (3 · 20 mL). The
combined organic layers were washed with water
(20 mL), dried over MgSO4, and concentrated under
reduced pressure. The product (244 mg, 90%) was
obtained as a colorless oil after bulb-to-bulb distillation.
Data for (R)-18a: bp: 150 ꢁC ABT (0.3 mmHg); 1H
NMR (500 MHz, CDCl3): 8.40 (dd, J = 1.5, 0.8, 1H,
HC(60)), 7.49 (dd, J = 7.8, 1.4, 1H, HC(40)), 7.17 (d,
J = 7.8, 1H, HC(30)), 5.67 (s, 1H, HC(1)), 2.34 (s,
3H, H3C(50)), 1.01 (s, 9H, (H3C)3C(2)); 13C NMR
(100 MHz, CDCl3): 162.1 (q, J = 35.9, C(C@O)), 152.9
(C(20)), 149.1 (C(60)), 136.9 (C(40)), 132.9 (C(50)), 122.5
(C(30)), 116.6 (q, J = 271.8, CF3), 87.4 (C(1)), 35.3
(CH3C(50)), 25.8 (C(3)), 18.1 (C(2)); IR (neat): 2973
(s), 2874 (m), 1786 (s), 1601 (w), 1575 (m), 1486 (m),
1467 (m), 1399 (m), 1370 (s), 1337 (w), 1222 (s), 1157
(s), 1030 (m), 949 (m), 874 (w), 834 (m), 784 (m), 772
(w), 742 (w), 719 (m); TLC: Rf 0.32 (hexane/EtOAc,
10/1); GC: (R)-18a, tR 6.10 min (97.8%); (S)-18a, tR
7.37 min (2.2%) (Chiraldex GTA, 88 ꢁC, 18 psi); 19F
NMR (376 MHz, CDCl3): ꢀ75.55; Anal. Calcd for
C13H16F3NO2 (275.27): C, 56.72; H, 5.86; N, 5.09.
Found: C, 56.90; H, 5.91; N, 5.12.
6.1.3. 1-[2-(5-Methylpyridyl)]-2,2-dimethylpropyl trifluoro-
acetate ( )-18a. To a solution of ( )-18 (45 mg,
0.25 mmol) in 2 mL CH2Cl2 was added trifluoroacetic
anhydride (35 lL, 0.25 mmol, 1.0 equiv) at 0 ꢁC under
nitrogen. The resulting mixture was stirred for 30 min
at 0 ꢁC and quenched by pouring the mixture into a
cold, saturated NaHCO3 (20 mL) solution. The aqueous
layer was extracted with CH2Cl2 (3 · 20 mL). The com-
bined organic layers were washed with water (20 mL),
dried over MgSO4, and concentrated under reduced
pressure. The product (43 mg, 70%) was obtained as a
colorless oil after bulb-to-bulb distillation of the residue.
Data for ( )-18a: bp: 150 ꢁC ABT (0.3 mmHg): 1H
NMR (500 MHz, CDCl3): 8.40 (dd, J = 1.5, 0.8, 1H,
HC(60)), 7.49 (dd, J = 7.8, 1.4, 1H, HC(40)), 7.17 (d,
J = 7.8, 1H, HC(30)), 5.67 (s, 1H, HC(1)), 2.34 (s, 3H,
H3C(50)), 1.01 (s, 9H, (H3C)3C(2)); GC: (R)-18a, tR
6.10 min (50.1%); (S)-18a, tR 7.37 min (49.8%) (Chiral-
dex GTA, 88 ꢁC, 18 psi).
6.1.4. (R)-1-[2-(5-Methylpyridyl)]-2,2-dimethylpropanol
(R)-18. A mixture of (ꢀ)-(Ipc)2BCl (11.8 g, 36.8 mmol,
1.5 equiv) and 24 (4.34 g, 24.5 mmol) was stirred neat at
rt. The mixture became very viscous after 2 h, hence
5 mL THF was added to decrease the viscosity. After
stirring for 3 days at rt, Et2O (80 mL) was added into
the flask, followed by diethanolamine (12 g). The mix-
ture was stirred for 3 h at rt and the white precipitate fil-
tered off through Celite. The filtrate was dried over
Na2SO4 and concentrated under a reduced pressure.
Purification of the oily residue by silica gel column chro-
matography (hexane/EtOAc 5/1) afforded 3.68 g of
product (R)-18 (84%) as a colorless oil. An analytically
pure sample was obtained after bulb-to-bulb distillation.
Data for (R)-18: bp: 110 ꢁC ABT (0.5 mmHg); 1H NMR
(500 MHz, CDCl3): 8.37 (br s, 1H, HC(60)), 7.43 (dd,
J = 8.0, 1.7, 1H, HC(40)), 7.09 (d, J = 7.8, 1H,
HC(30)), 4.24–4.33 (AB quartet, J = 7.1, 2H, HC(1)
and OH), 2.33 (s, 3H, H3C(50)), 0.91 (s, 9H,
(H3C)3C(2)); 13C NMR (100 MHz, CDCl3): 156.9
(C(20)), 147.6 (C(60)), 136.6 (C(40)), 131.9 (C(50)), 122.5
(C(30)), 79.8 (C(1)), 36.2 (CH3C(50)), 25.8 (C(3)), 18.1
(C(2)); IR (KBr): 3161 (s), 2969 (s), 2948 (s), 2900 (s),
6.1.6. (R)-5-Methyl-1-(1-butyloxy-2,2-dimethylpropyl)-
pyridine (R)-25a.
A mixture of (R)-18 (880 mg,
4.9 mmol), potassium hydroxide (540 mg, 9.8 mmol,
2.0 equiv), n-BuBr (790 lL, 9.3 mmol, 1.9 equiv), 18-
crown-6 (130 mg, 0.49 mmol, 0.1 equiv) in DMF
(10 mL) was stirred in the presence of freshly dried
˚
molecular sieve power (2 g, 3 A) at rt. The second and
third portions of n-BuBr (each of 790 lL, 1.9 equiv),
and KOH (each of 540 mg, 2.0 equiv) were added after
4 and 8 h, respectively. After (R)-18 was consumed,
the reaction mixture was diluted with Et2O (40 mL)
and filtered through Celite. The filtrate was dried over
MgSO4 and concentrated under reduced pressure. Puri-
fication of the residue by column silica gel chromatogra-
phy (hexane/EtOAc, 5/1) afforded (R)-25a (967 mg,
84%) as a colorless oil. An analytically pure sample
was obtained after bulb-to-bulb distillation. Data for
(R)-25a: bp: 110 ꢁC ABT (0.1 mmHg); 1H NMR:
(400 MHz, CDCl3): 8.36 (dd, J = 1.5, 0.7, 1H, HC(6)),
7.46 (dd, J = 8.0, 1.2, 1H, HC(4)), 7.26 (d, J = 8.1,
1H, HC(3)), 4.00 (s, 1H, HC(10)), 3.19–3.31 (m, 2H,
H2C(100)), 2.32 (s, 3H, H3C(C(5))), 1.41–1.55 (m, 2H,

700
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
H2C(200)), 1.32–1.40 (m, 2H, H2C(300)), 0.90 (s, 9H,
(H3C)3(C(30))), 0.88 (t, J = 7.3, 3H, H3C(400)); 13C
NMR (100 MHz, CDCl3): 158.2 (C(2)), 148.4 (C(6)),
136.3 (C(4)), 131.3 (C(5)), 121.6 (C(3)), 90.57 (C(10)),
69.4 (C(100)), 35.6 (CH3(C(5))), 32.0 (C(200)), 26.2
(C(30)), 19.4 (C(300)), 18.1 (C(20)), 13.9 (C(400)); IR (neat):
2957 (s), 2932 (s), 2869 (s), 1601 (w), 1569 (w),1482 (m),
1462 (w), 1390 (w), 1100 (m), 1030 (w), 858 (w), 836 (w);
second portion of iodine (1.17 g, 5.0 mmol, 0.5 equiv)
in THF (10 mL) added into the flask. The cooling bath
was immediately removed and the reaction mixture was
brought up to rt over 40 min. During the warming per-
iod, the deep-red color reappeared. After being stirred at
rt for 2 h, cold water (10 mL) was added into the flask,
followed by satd aq NaHSO3 solution (10 mL). The
mixture was transferred to a separatory funnel, diluted
with NH4OH solution (50 mL), and was extracted thor-
oughly with CH2Cl2 (3 · 60 mL). The combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure. The brownish residue was purified
by silica gel column chromatography (pentane/ether,
2/1) to provide 3.0 g of a mixture of (P)-(R,R)-5 and
the by-product iodide (R)-27. The iodide (1.70 g, 47%)
was removed by recrystallization from pentane. From
the mother liquor, (P)-(R,R)-5 (1.20 g, 48%) was ob-
tained. An analytically pure sample was obtained after
recrystallization from hexane. Data for (P)-(R,R)-5:
mp: 135–135.5 ꢁC (hexane); 1H NMR (400 MHz,
CDCl3): 7.39 (d, J = 8.0, 2H, HC(5)), 7.16 (d, J = 8.1,
2H, HC(4)), 5.06 (s, 2H, HC(10)), 3.24–3.32 (m, 4H,
H2C(100)), 2.04 (s, 6H, H3C(C(3))), 1.44–1.51 (m, 4H,
H2C(200)), 1.26–1.40 (m, 4H, H2C(300)), 0.97 (s, 18H,
(H3C)3(C(30))), 0.88 (t, J = 7.3, 6H, H3C(400)); 13C
NMR (100 MHz, CDCl3): 149.5 (C(6)), 142.9 (C(2)),
134.6 (C(3)), 125.9 (C(4) or C(5)), 124.8 (C(5) or C(4)),
80.3 (C(10)), 70.0 (C(100)), 37.2 (CH3(C(3))), 32.1
(C(200)), 25.7 (C(30)), 19.4 (C(300)), 17.5 (C(20)), 14.0
(C(400)); IR (KBr): 2957 (s), 2871 (m), 1613 (w), 1503
(w), 1478 (w), 1461 (w), 1383 (m), 1285 (m), 1256 (w),
TLC: Rf 0.46 (hexane/EtOAc, 5/1); MS (EI): 234 (6),
24
179 (18), 178 (33), 122 (100), 92 (11); ½aꢁD ¼ þ37:8 (c
0.67, EtOH); Anal. Calcd for C15H25NO (235.37): C,
76.54; H, 10.71; N, 5.95. Found: C, 76.45; H, 10.89;
N, 6.11.
6.1.7. (R)-5-Methyl-1-(1-butyloxy-2,2-dimethylpropyl)-
pyridine N-oxide (R)-26a. General procedure 1. A solu-
tion of pyridine (R)-25a (1.67 g, 7.0 mmol) and mCPBA
(1.84 g, 10.6 mmol, 1.5 equiv) in CH2Cl2 (25 mL) was
prepared in a 50-mL round bottom flask fitted with a
magnetic stirrer bar and the mixture stirred overnight
at room temperature. Then, 10 mL of cold, 40% aque-
ous KOH solution was added into the flask and the
resulting slurry was stirred for 1 h at room temperature.
The biphasic mixture was diluted with water (50 mL)
and extracted thoroughly with CH2Cl2 (3 · 25 mL).
The combined organic layers were dried over MgSO4
and concentrated under reduced pressure to afford
1.82 g of white solid residue. Purification by silica gel
column chromatography (CH2Cl2/MeOH, 20/1) pro-
vided the product (1.49 g, 84%) as a colorless oil. An
analytically pure sample was obtained after bulb-to-bulb
distillation. Data for (R)-26a: bp: 150 ꢁC ABT
(0.1 mmHg); 1H NMR (400 MHz, CDCl3): 8.06 (s,
1H, HC(6)), 7.29 (d, J = 8.3, 1H, HC(3)), 7.05 (d,
J = 8.0, 1H, HC(4)), 5.02 (s, 1H, HC(10)), 3.15–3.29
(m, 2H, H2C(100)), 2.28 (s, 3H, H3C(C(5))), 1.34–1.49
(m, 2H, H2C(200)), 1.28–1.39 (m, 2H, H2C(300)), 0.96 (s,
9H, (H3C)3(C(30))), 0.86 (t, J = 7.3, 3H, H3C(400)); 13C
NMR (100 MHz, CDCl3): 149.3 (C(2)), 139.5 (C(6)),
134.4 (C(5)), 126.3 (C(3) or C(4)), 125.1 (C(3) or C(4)),
80.2 (C(10)), 69.9 (C(100)), 37.2 (CH3(C(5))), 31.9
(C(200)), 25.6 (C(30)), 19.4 (C(300)), 18.0 (C(20)), 13.8
(C(400)); IR (neat): 2957 (s), 2871 (m), 1613 (w), 1503
(w), 1478 (w), 1461 (w), 1383 (m), 1363 (m), 1339 (m),
1285 (m), 1256 (m), 1213 (m), 1199 (m), 1177 (s), 1095
(s), 1020 (w); TLC: Rf 0.42 (CH2Cl2/MeOH, 20/1);
1177 (m), 1095 (m); TLC Rf 0.32 (hexane/EtOAc, 5/1);
24
MS (FAB): 502 (34), 501 (100), 485 (22); ½aꢁD ¼ ꢀ39:7
(c 1.03, EtOH); Anal. Calcd for C30H48N2O4 (500.72):
C, 71.96; H, 9.66; N, 5.59. Found: C, 72.01; H, 9.90;
N, 5.64.
6.1.9. Preparation of (P)-(R,R)-3,30-dimethyl-6,60-bis(1-
butyloxy-2,2-dimethylpropyl)-2,20-bipyridine bis-N-oxide
(M)-(R,R)-5 and (R,R)-3,30-bismethyl-6,60-bis(1-butyloxy-
2,2-dimethylpropyl)-2,20-bipyridine (R,R)-28. A mixture
of (P)-(R,R)-5 (1.43 g, 2.85 mmol), Zn powder (1.86 g,
28.5 mmol, 10 equiv), and CH3CO2H (two drops) in
wet THF (20 mL) was stirred for 12 h at rt. Aqueous
NH4OH solution (50 mL) was added into the flask and
stirred for 30 min. The resulting precipitate was filtered
off through Celite. The filtrate was extracted thoroughly
with CH2Cl2 (3 · 30 mL). The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The brownish residue was purified by silica gel
column chromatography (hexane/EtOAc, 20/1) to pro-
vide 1.22 g (91%) of the product (R,R)-28 as a light yel-
low oil. Data for (R,R)-28: 1H NMR (400 MHz, CDCl3):
7.59 (d, J = 7.8, 2H, HC(5)), 7.35 (d, J = 8.0, 2H,
HC(4)), 4.11 (s, 2H, HC(10)), 3.18–3.38 (m, 4H,
H2C(100)), 2.13 (s, 6H, H3C(C(3))), 1.47–1.54 (m, 4H,
H2C(200)), 1.32–1.39 (m, 4H, H2C(300)), 0.94 (s, 18H,
(H3C)3(C(30))), 0.88 (t, J = 7.3, 6H, H3C(400)); 13C
NMR (100 MHz, CDCl3): 158.1 (C(6)), 155.7 (C(2)),
138.6 (C(4)), 130.2 (C(3)), 121.3 (C(5)), 90.2 (C(10)),
69.5 (C(100)), 35.7 (CH3(C(3))), 32.1 (C(200)), 26.3
(C(30)), 19.4 (C(4t300)), 18.8 (C(20)), 14.0 (C(400)); IR
(neat): 2957 (s), 2868 (s), 1584 (s), 1569 (s), 1479 (s),
MS (FAB): 253 (17), 252 (100), 236 (18), 195 (12), 178
24
(18), 119 (17); Opt. Rot.: ½aꢁD ¼ þ87:5 (c 0.535, EtOH);
Anal. Calcd for C15H25NO2 (251.37): C, 71.67; H, 10.02;
N, 5.57. Found: C, 71.55; H, 10.10; N, 5.76.
6.1.8. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-butyloxy-2,2-
dimethylpropyl)-2,20-bipyridine bis-N-oxide ((P)-(R,R)-
5). General procedure 2. To a suspension of (R)-26a
(2.51 g, 10 mmol) in Et2O (20 mL) was added freshly
prepared LiTMP solution (n-BuLi, 6.5 mL, 10 mmol,
1.0 equiv, and tetramethylpiperidine 1.70 mL, 10 mmol,
1.0 equiv) in THF (10 mL) at ꢀ73 ꢁC. After being stir-
red for 16 h at ꢀ73 ꢁC, a solution of iodine (1.17 g,
5.0 mmol, 0.5 equiv) in THF (10 mL) was added drop-
wise over 10 min into the resulting deep-red solution at
ꢀ73 ꢁC. The mixture was further stirred at ꢀ73 ꢁC for
1 h until the color of the mixture was discharged and a

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
701
1456 (s), 1390 (s), 1364 (s), 1303 (m), 1265 (m), 1244 (m),
1207 (m), 1101 (s), 1067 (m), 1036 (m), 994 (m), 970 (m),
841 (m), 737 (m); TLC Rf 0.37 (hexane/EtOAc, 20/1);
MS (EI, 70 eV): 469 (14), 468 (39), 413 (11), 412 (40),
411 (26), 356 (27), 355 (98), 282 (21), 281 (100), 265
(11), 241 (33).
1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383 (m), 1363
(m), 1339 (m), 1285 (m), 1256 (m), 1213 (m), 1199 (m),
1177 (s), 1095 (s), 1020 (w); TLC Rf 0.26 (Et2O); MS
24
(FAB): 329 (37), 328; ½aꢁD ¼ þ43:6 (c 0.79, EtOH).
Anal. Calcd for C21H29NO2 (327.46): C, 77.02; H,
8.93; N, 4.28. Found: C, 77.11; H, 9.04; N, 4.41.
6.1.10.
(M)-(R,R)-3,30-Dimethyl-6,60-bis-(1-butyloxy-
6.1.12. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-(2,4,6-trimeth-
yl)benzyloxy-2,2-dimethylpropyl)-2,20-bipyridine bis-N-
oxide (P)-(R,R)-6. Following general procedure 2,
from the reaction of (R)-26b (483 mg, 1.5 mmol),
277 mg (57%) of product (P)-(R,R)-6 was obtained as
a white solid after silica gel column chromatography
(Rf 0.27, hexane/EtOAc, 3/1). An analytically pure sam-
ple was obtained after crystallization from hexane. Data
for (P)-(R,R)-6: mp: 199–200 ꢁC (hexane); 1H NMR
(400 MHz, CDCl3): 7.51 (d, J = 8.3, 2H, HC(3)), 7.22
(d, J = 8.1, 2H, HC(4)), 6.85 (s, 4H, HC(400)), 5.21 (s,
2H, HC(10)), 4.35 (q, JAB = 15.3, 4H, H2C(100)), 2.31
(s, 12H, H3C(1000)), 2.26 (s, 6H, H3C(C(3))), 2.10 (s,
6H, H3C(2000)), 0.98 (s, 18H, H3C(30)); 13C NMR
(100 MHz, CDCl3): 149.13 (C(6)), 143.07 (C(2)),
138.08, 137.56, 135.97, 131.45, 128.73 (C(4)), 125.72,
124.71, 126.14 (C(3)), 125.08 (C(4) or C(5)), 80.57
(C(10)), 66.48 (C(100)), 37.28 (CH3(C(5))), 25.79
(C(1000)), 20.97 (C(2000)), 19.69 (C(30)), 17.58 (C(20)); IR
(KBr) 957 (s), 2871 (m), 1613 (w), 1503 (w), 1478 (w),
1461 (w), 1383 (m), 1363 (m), 1339 (m), 1285 (m),
1256 (m), 1213 (m), 1199 (m), 1177 (s), 1095 (s), 1020
2,2-dimethylpropyl)-2,20-bipyridine bis-N-oxide (M)-
(R,R)-5. A solution of pyridine (R,R)-28 (840 mg,
1.8 mmol) and mCPBA (864 mg, 5.0 mmol, 2.8 equiv)
in CH2Cl2 (20 mL) was prepared in a 50-mL round bot-
tom flask fitted with a magnetic stir bar and the mixture
stirred for 12 h at room temperature. Then, 5 mL of
cold, 40% aqueous KOH solution was added into the
flask and the resulting slurry stirred for 1 h at room tem-
perature. The biphasic mixture was diluted with water
(25 mL) and extracted thoroughly with CH2Cl2
(3 · 25 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure
to afford 1.11 g of white solid residue. Separation of
the two diastereomers by silica gel column chromatogra-
phy (hexane/EtOAc, 5/1) provided 601 mg (67%) of (P)-
(R,R)-5 and 242 mg (27%) of (M)-(R,R)-5. An analyti-
cally pure sample was obtained after recrystallization
from hexane. Data for (M)-(R,R)-5: mp: 141–141.5 ꢁC
(hexane); 1H NMR (400 MHz, CDCl3): 7.39 (d,
J = 8.0, 2H, HC(5)), 7.16 (d, J = 8.1, 2H, HC(4)), 5.06
(s, 2H, HC(10)), 3.24–3.32 (m, 4H, H2C(100)), 2.13 (s,
6H, H3C(C(3))), 1.44–1.51 (m, 4H, H2C(200)), 1.26–1.40
(m, 4H, H2C(300)), 0.97 (s, 18H, (H3C)3(C(30))), 0.88 (t,
J = 7.3, 6H, H3C(400)); 13C NMR (100 MHz, CDCl3):
149.5 (C(6)), 142.9 (C(2)), 134.6 (C(3)), 125.9 (C(4) or
C(5)), 124.8 (C(5) or C(4)), 80.3 (C(10)), 70.0 (C(100)),
37.2 (CH3(C(3))), 32.1 (C(200)), 25.7 (C(30)), 19.4
(C(300)), 17.5 (C(20)), 14.0 (C(400)); IR (KBr): 2957 (s),
2871 (m), 1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383
(m), 1285 (m), 1256 (w), 1177 (m), 1095 (m); TLC Rf
(w); TLC Rf 0.27 (hexane/EtOAc, 3/1); MS (FAB): 53
24
(18), 652 (100); ½aꢁD ¼ ꢀ101:7 (c 1.27, EtOH); HRMS
(ESI): Calcd for C42H59N2O4, 653.4319. Found:
653.4316.
6.1.13. (R)-5-Methyl-1-(1-(2,4,6-triisopryopyl)benzyloxy-
2,2-dimethylpropyl)pyridine N-oxide (R)-26c. Follow-
ing general procedure 1, pyridine (R)-25c (1.15 g,
2.8 mmol) and mCPBA (778 mg, 4.5 mmol, 1.6 equiv)
were dissolved in CH2Cl2 (20 mL) and the mixture was
stirred overnight at rt. The product (R)-26c (987 mg,
86%) was obtained as a white solid after silica gel col-
umn chromatography (diethyl ether). An analytically
pure sample was obtained after crystallization from hex-
ane. Data for (R)-26c: mp: 105–106 ꢁC (hexane); 1H
NMR (400 MHz, CDCl3): 8.42 (dd, J = 1.5, 1.0, 1H,
HC(6)), 7.53 (dd, J = 8.1, 2.0, 1H, HC(4)), 7.39 (d,
J = 8.1, 1H, HC(3)), 7.01 (s, 2H, HC(400)), 4.32 (q,
JAB = 14.9, 2H, H2C(100)), 4.22 (s, 1H, HC(10)), 3.18
(h, J = 6.8, 2H, H2C(600)), 2.88 (h, J = 6.8, 1H,
H2C(800)), 2.37 (s, 3H, H3C(C(5))), 1.25 (d, J = 6.8,
6H, HC(700)), 1.18 (d, J = 6.8, 3H, HC(900)), 0.92 (s,
18H, H3C(30)); 13C NMR (100 MHz, CDCl3): 158.33
(C(2)), 149.20 (C(6)), 148.88 (C(200) or C(500)), 148.77
(C(200) or C(500)), 148.71, 148.22, 136.40 (C(3)), 131.90
(300), 129.69 (C(4) or C(5)), 121.90, 121.50, 121.06,
92.16 (C(10)), 64.88 (C(100)), 57.51 (CH3(C(5))), 34.34
(C(800)), 29.21 (C(600)), 25.81 (C(700)), 25.33 (C(900)),
24.16 (C(30)), 17.15 (C(20)); IR (KBr): 2957 (s), 2871
(m), 1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383 (m),
0.23 (hexane/EtOAc, 5/1): MS (FAB): 502 (33), 501
24
(100), 485 (25); ½aꢁD ¼ þ125:9 (c 0.74, EtOH); Anal.
Calcd for C30H48N2O4 (500.72): C, 71.96; H, 9.66; N,
5.59. Found: C, 72.03; H, 9.88; N, 5.66.
6.1.11. (R)-5-Methyl-1-(1-(2,4,6-trimethyl)benzyloxy-2,2-
dimethylpropyl)pyridine N-oxide (R)-26b. Following
general procedure 1, from the reaction of (R)-25b
(4.26 g, 14.0 mmol) and mCPBA (3.19 g, 18.0 mmol,
1.3 equiv) in CH2Cl2 (100 mL), 3.79 g (94%) of product
(R)-26b was obtained as a white solid after silica gel col-
umn chromatography (Rf 0.27, CH2Cl2/i-PrOH, 20/1).
An analytically pure sample was obtained after crystal-
lization from hexane. Data for (R)-26b: mp: 175–
1
176 ꢁC (hexane); H NMR (400 MHz, CDCl3): 8.13 (s,
1H, HC(6)), 7.39 (d, J = 8.0, 1H, HC(3)), 7.10 (d,
J = 8.0, 1H, HC(4)), 6.84 (s, 6H, H3C(400)), 5.23 (s,
1H, HC(10)), 4.29 (q, JAB = 15.8, 2H, H2C(100)), 2.31
(s, 3H, H3C(C(3))), 2.26 (s, 9H, H3C(1000) and
H3C(2000)), 0.98 (s, 9H, H3C(30)); 13C NMR (100 MHz,
CDCl3): 149.00 (C(2)), 139.66 (C(6)), 137.89, 137.65,
134.63, 131.28, 134.63, 131.28, 128.78, 126.14 (C(5)),
125.08 (C(3) or C(4)), 80.45 (C(10)), 66.48 (C(100)),
37.21 (CH3(C(5))), 25.69 (C(1000)), 20.93 (C(2000)), 19.54
(C(30)), 17.99 (C(20)); IR (KBr): 2957 (s), 2871 (m),
1285 (m), 1256 (w), 1177 (m), 1095 (m); TLC Rf 0.17
24
(Et2O); Opt. Rot.: ½aꢁD ¼ þ41:1 (c 2.26, EtOH); HRMS
(ESI, 70 eV): Calcd for C27H40NO2, 411.3235. Found:
412.3228.

702
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
6.1.14. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-(2,4,6-triiso-
propyl)benzyloxy-2,2-dimethylpropyl)-2,20-bipyridine bis-
N-oxide (P)-(R,R)-7. Following general procedure 2,
from the reaction of (R)-26c (502 mg, 1.3 mmol), the
product (P)-(R,R)-7 (262 mg, 52%) was obtained as a
white solid after silica gel column chromatography (Rf
0.26, pentane/Et2O, 3/1). An analytically pure sample
was obtained after recrystallization from hexane. Data
for (P)-(R,R)-7: mp: 195–196 ꢁC (hexane); 1H NMR
(400 MHz, CDCl3): 7.52 (d, J = 8.2, 2H, HC(4)), 7.25
(d, J = 8.2, 2H, HC(3)), 7.01 (s, 4H, HC(400)), 5.34 (s,
2H, HC(10)), 4.40 (q, JAB = 15.9, 4H, H2C(100)), 3.23
(h, J = 6.8, 4H, H2C(600)), 2.88 (h, J = 6.8, 2H,
H2C(800)), 2.11 (s, 6H, H3C(C(3))), 1.26 (d, J = 6.8,
24H, HC(700)), 1.23 (d, J = 6.8, 12H, HC(900)), 0.98 (s,
18H, H3C(30)); 13C NMR (100 MHz, CDCl3): 149.19
(C(6)), 148.62 (C(200) or C(500)), 148.51 (C(200) or C(500)),
143.32 (C(2)), 135.11 (C(3)), 128.97 (300), 125.65 (C(4)
or C(5)), 124.70 (C(5) or C(4)), 120.82 (C(400)), 81.30
(C(10)), 64.96 (C(100)), 37.33 (CH3(C(3))), 34.19 (C(800)),
29.09 (C(600)), 25.80 (C(700)), 25.29 (C(900)), 24.07
(C(30)), 17.65 (C(20)); IR (KBr): 2957 (s), 2871 (m),
1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383 (m), 1285
(m), 1256 (w), 1177 (m), 1095 (m); TLC Rf 0.17 (pen-
cally pure sample was obtained after crystallization from
hexane. Data for (P)-(R,R)-8: mp: 195–196 ꢁC (hexane);
1H NMR (400 MHz, CDCl3): 7.48 (d, J = 8.1, 2H,
HC(5)), 7.23 (d, J = 8.1, 2H, HC(4)), 6.94–7.52 (m,
14H, naphthylH), 5.34 (s, 4H, HC(10)), 4.36–4.38 (q,
JAB = 14.9, 8H, H2C(100)), 2.13 (s, 6H, H3C(C(3))),
0.98 (s, 18H, H3C(30)); 13C NMR (100 MHz, CDCl3):
149.32 (C(6)), 148.53 (C(2) or C(5)), 148.44 (C(2) or
C(5)), 133.77, 133.44, 131.33, 128.4, 128.24, 126.15,
125.95, 125.79, 125.60, 125.26, 125.12, 123.87, 83.30
(C(10)), 66.14 (C(100)), 37.16 (CH3(C(3))), 24.01 (C(30)),
17.76 (C(20)); IR (KBr): 2957 (s), 2871 (m), 1613 (w),
1503 (w), 1478 (w), 1461 (w), 1383 (m), 1363 (m), 1339
(m), 1285 (m), 1256 (m), 1213 (m), 1199 (m), 1177 (s),
1095 (s), 1020 (w); TLC Rf 0.21 (Et2O); MS (FAB)
24
670 (13), 669 (100); ½aꢁD ¼ ꢀ80:9 (c 1.54, EtOH);
HRMS (ESI): Calcd for C44H49N2O4, 669.3691. Found:
669.3687.
6.1.17. (R)-5-Methyl-1-(1-(2-naphthylmethoxy)-2,2-di-
methylpropyl)pyridine N-oxide (R)-26e. Following gen-
eral procedure 1, pyridine (R)-25e (640 mg, 2.0 mmol)
and mCPBA (530 mg, 3.0 mmol, 1.5 equiv) were dis-
solved in CH2Cl2 (20 mL) and the mixture was stirred
overnight at rt. The product (R)-26e (610 mg, 91%)
was obtained as a white solid after silica gel column
chromatography (diethyl ether). An analytically pure
sample was obtained after recrystallization from hexane.
Data for (R)-32: mp: 99–100 ꢁC (hexane); 1H NMR
(400 MHz, CDCl3): 8.09 (s, 1H, HC(6)), 7.80 (d,
J = 8.3, 1H, HC(3)), 7.74 (s, HC(1100)), 7.02 (d,
J = 7.9, 1H, HC(4)), 7.38–7.84 (m, 6H, naphthylH),
5.30 (s, 1H, HC(10)), 4.46 (q, JAB = 16.3, 2H,
H2C(100)), 2.27 (s, 3H, H3C(C(5))), 1.04 (s, 9H,
(H3C)3(C(30))); 13C NMR (100 MHz, CDCl3): 148.86
(C(2)), 139.84 (C(6)), 135.98 (C(5)), 134.90, 133.43,
133.16, 128.18, 127.87, 126.56, 126.34, 126.28, 126.05,
125.99, 125.40, 80.65 (C(10)), 72.52 (C(100)), 37.63
(CH3(C(5))), 26.00 (C(30)), 18.29 (C(20)); IR (KBr):
2957 (s), 2871 (m), 1613 (w), 1503 (w), 1478 (w), 1461
(w), 1383 (m), 1363 (m), 1339 (m), 1285 (m), 1256 (m),
1213 (m), 1199 (m), 1177 (s), 1095 (s), 1020 (w); TLC
tane/Et2O, 5/1); MS (FAB): 822 (13), 217 (100);
24
½aꢁD ¼ ꢀ42:3 (c 0.50, MeOH). Anal. Calcd for
C54H80N2O4 (821.22): C, 78.98; H, 9.82; N, 3.42. Found:
C, 79.68; H, 10.02; N, 3.70. HRMS (ESI, 70 eV): Calcd
for C54H80N2O4, 822.6241. Found: 822.6237.
6.1.15. (R)-5-Methyl-1-(1-naphthylmethoxy-2,2-dimethyl-
propyl)pyridine N-oxide (R)-26d. Following general
procedure 1, pyridine (R)-25da (640 mg, 2.0 mmol) and
mCPBA (530 mg, 3.0 mmol, 1.5 equiv) were dissolved
in CH2Cl2 (20 mL) and the mixture was stirred over-
night at rt. The product (R)-31 (529 mg, 79%) was
obtained as a white solid after silica gel column
chromatography (diethyl ether). An analytically pure
sample was obtained after recrystallization from hexane.
1
Data for (R)-26d: mp: 115–116 ꢁC (hexane); H NMR
(400 MHz, CDCl3): 8.07 (s, 1H, HC(6)), 7.97 (d,
J = 7.3, 1H, HC(4)), 7.82 (d, J = 7.1, 1H, HC(3)),
6.94–7.52 (m, 7 H, naphthylH), 5.34 (s, 1H, HC(10)),
4.83 (q, JAB = 15.9, 2H, H2C(100)), 2.27 (s, 3H,
H3C(C(5))), 0.99 (s, 9H, H3C(30)); 13C NMR
(100 MHz, CDCl3): 148.53 (C(2)), 139.50 (C(6)),
135.54 (C(4)), 133.77, 133.44, 131.33, 128.4, 128.24,
126.15, 125.95, 125.79, 125.60, 125.26, 125.12, 123.87,
80.37 (C(10)), 70.38 (C(100)), 37.30 (CH3(C(5))), 25.72
(C(30)), 17.93 (C(20)); IR (neat): 2957 (s), 2871 (m),
1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383 (m), 1363
(m), 1339 (m), 1285 (m), 1256 (m), 1213 (m), 1199 (m),
Rf 0.32 (Et2O); MS (FAB): 337 (20), 336 (100);
24
½aꢁD ¼ þ41:3 (c 0.802, EtOH); Anal. Calcd for
C22H25NO2 (335.44): C, 78.77; H, 7.51; N, 4.18. Found:
C, 78.99; H, 7.68; N, 4.36.
6.1.18. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-(2-naphthyl-
methoxy)-2,2-dimethylpropyl)-2,20-bipyridine bis-N-oxide
(P)-(R,R)-9. Following general procedure 2, from (R)-
26e (402 mg, 1.2 mmol), 156 mg (39%) of the product
(P)-(R,R)-9 was obtained as a white solid after silica
gel column chromatography (diethyl ether). An analyti-
cally pure sample was obtained after crystallization from
hexane. Data for (P)-(R,R)-9: mp: 195–196 ꢁC (hexane);
1H NMR (400 MHz, CDCl3): 7.44 (d, J = 8.0, 2H,
HC(5)), 7.26 (d, J = 8.0, 2H, HC(4)), 7.74 (s,
HC(1100)), 6.94–7.52 (m, 12H, naphthyl), 5.32 (s, 4H,
HC(10)), 4.36–4.38 (q, JAB = 16.9, 8H, H2C(100)), 2.14
(s, 6H, H3C(C(3))), 0.97 (s, 18H, H3C(30)); 13C NMR
(100 MHz, CDCl3): 148.86 (C(6)), 139.84 (C(2) or
C(5)), 135.98 (C(2) or C(5)), 134.89, 133.44, 131.16,
128.18, 128.14, 127.87, 126.57, 126.34, 126.28, 126.05,
1177 (s), 1095 (s), 1020 (w); TLC Rf 0.21 (Et2O); MS
24
(FAB): 337 (17), 336; ½aꢁD ¼ þ34:7 (c 0.872, EtOH);
Anal. Calcd for C22H25NO2 (335.44): C, 78.77; H,
7.51; N, 4.18. Found: C, 78.91; H, 7.56; N, 4.40.
6.1.16. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-(1-naphthyl-
methoxy-2,2-dimethylpropyl))-2,20-bipyridine bis-N-oxide
(P)-(R,R)-8. Following general procedure 2, from (R)-
26d (402 mg, 1.2 mmol), 113 mg (28%) of the product
(P)-(R,R)-8 was obtained as a white solid after silica
gel column chromatography (diethyl ether). An analyti-

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
703
125.99, 125.40, 80.65 (C(10)), 72.59 (C(100)), 37.63
(CH3(C(3))), 26.06 (C(30)), 18.21 (C(20)); IR (KBr):
3007 (s), 2872 (m), 1616 (w), 1505 (w), 1479 (w), 1463
(w), 1383 (m), 1363 (m), 1339 (m), 1285 (m), 1256 (m),
1213 (m), 1199 (m), 1177 (s), 1095 (s), 1020 (w); TLC
6.1.21. (R)-5-Methyl-1-(1-butoxy-2-dimethyl-2-phenyl-
propyl)pyridine N-oxide (R)-38. Following general pro-
cedure 1, pyridine (R)-37 (1.16 g, 3.9 mmol) and
mCPBA (1.01 g, 5.9 mmol, 1.5 equiv) were dissolved in
CH2Cl2 (15 mL) and the mixture stirred overnight at
rt. Work-up provided 1.44 g of white solid residue. Puri-
fication by silica gel column chromatography (CH2Cl2/
MeOH, 20/1) provided the product (1.14 g, 92%) as a
colorless oil. An analytically pure sample was obtained
after bulb-to-bulb distillation. Data for (R)-38: bp:
180 ꢁC ABT (0.05 mmHg); 1H NMR (400 MHz,
CDCl3): 8.08 (s, 1H, HC(6)), 7.43 (d, J = 7.3, 2H,
HC(50)), 7.28 (t, 2H, J = 7.1, HC(60)), 7.19–7.22 (m,
1H, HC(70)), 6.87 (d, J = 8.0, 1H, HC(3)), 6.67 (d,
J = 8.3, 1H, HC(4)), 5.40 (s, 1H, HC(10)), 3.05–3.15
(m, 2H, H2C(80)), 2.26 (s, 3H, H3C(C(5))), 1.47 (s, 3H,
H3C(30)), 1.45 (s, 3H, H3C(30)), 1.31–1.37 (m, 2H,
H2C(90)), 1.15–1.22 (m, 2H, H2C(100)), 0.77 (t, J = 7.3,
3H, H3C(110)); 13C NMR (100 MHz, CDCl3): 148.70
(C(2)), 145.74 (C(6)), 139.23 (C(40)), 134.54 (C(5)),
127.56 (C(3)), 127.30 (C(50 or 60)), 126.15 (C(50 or 60)),
125.93 (C(70)), 125.36 (C(4)), 80.15 (C(10)), 69.72
(C(80)), 43.88 (C(20)), 31.65 (CH3(C(5)) or C(90)), 26.53
(CH3(C(5)) or C(90)), 22.60 (C(100)), 19.18 (C(30)),
17.95 (C(30)), 13.71 (C(110)); IR (neat): 3090 (w), 3058
(w), 3034 (w), 2959 (s), 2931 (s), 2871 (s), 1612 (m),
1553 (m), 1499 (s), 1476 (s), 1448 (s), 1384 (s), 1366
(m), 1339 (m), 1285 (s), 1258 (s), 1212 (m), 1182 (s),
1093 (s), 1032 (m), 1093 (s), 1020 (m), 955 (m), 881
(w), 827 (m), 809 (m), 769 (m), 752 (w); TLC Rf 0.52
(CH2Cl2/MeOH, 20/1); MS (FAB): 315 (22), 314
Rf 0.23 (Et2O); MS (FAB): 670 (16), 669 (100);
24
½aꢁD ¼ ꢀ61:4 (c 1.80, EtOH); HRMS (ESI): Calcd for
C44H49N2O4, 669.3691. Found: 669.3685.
6.1.19. (R)-5-Methyl-1-(1-butyloxy-2-dimethylpropyl)-
pyridine N-oxide (R)-33. Following general procedure
1, pyridine (R)-32 (2.43 g, 8.09 mmol) and mCPBA
(1.79 g, 10.1 mmol, 1.25 equiv) were dissolved in CH2Cl2
(25 mL) and the mixture was stirred overnight at rt.
Work-up provided 2.52 g of white solid residue. Purifi-
cation by silica gel column chromatography (CH2Cl2/
MeOH, 20/1) provided the product (2.40 g, 94%) as a
colorless oil. An analytically pure sample was obtained
after bulb-to-bulb distillation. Data for (R)-33: bp
220 ꢁC ABT (0.5 mmHg); 1H NMR (400 MHz, CDCl3):
8.34 (d, J = 1.7, 1H, HC(6)), 7.36 (dd, J = 8.6, 1.7, 1H,
HC(4)), 7.28 (d, J = 8.5, 1H, HC(3)), 4.94 (s, 1H,
HC(10)), 3.16–3.29 (m, 2H, H2C(100)), 1.44–1.51 (m,
2H, H2C(200)), 1.29–1.36 (m, 2H, H2C(300)), 0.96 (s, 9H,
H3C(30)), 0.87 (t, J = 7.3, 3H, H3C(400)); 13C NMR
(100 MHz, CDCl3): 151.43 (C(2)), 140.89 (C(6)),
127.73 (C(4)), 125.88 (C(3)), 118.20 (C(5)), 80.23
(C(10)), 70.12 (C(100)), 37.33 (C(20)), 31.84 (C(200)),
25.56 (C(30)), 19.33 (C(300)), 13.83 (C(400)); IR (neat):
3094 (w), 3036 (w), 2933 (s), 2871 (s), 1596 (m), 1532
(w), 1477 (s), 1370 (s), 1244 (s), 1094 (s), 901 (s); TLC
Rf 0.18 (hexane/Et2O, 3/1); MS (FAB): 318 (8), 316
(100), 298 (19), 240 (16), 122 (13), 119 (17);
24
24
(8), 244 (98), 242 (100); ½aꢁD ¼ þ27:1 (c 0.637, MeOH);
½aꢁD ¼ þ93:8 (c 1.15, EtOH); Anal. Calcd for
Anal. Calcd for C14H23NO2 (237.34): C, 70.84; H, 9.77;
N, 5.90. Found: C, 70.64; H, 9.98; N, 5.98.
C20H27N1O2 (313.44): C, 76.64; H, 8.68; N, 4.47. Found:
C, 76.67; H, 8.69; N, 4.69.
6.1.20. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-butyloxy-2-
methylpropyl)-2,20-bipyridine bis-N-oxide (P)-(R,R)-
10. Following general procedure 2, from (R)-33
(474 mg, 2.0 mmol), 179 mg (38%) of the product (P)-
(R,R)-10 was obtained as a white solid after silica gel
column chromatography (hexane/diethyl ether, 5/1).
An analytically pure sample was obtained after crystal-
lization from hexane. Data for (P)-(R,R)-10: mp: 112–
6.1.22. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-butyloxy-2-
methyl-2-phenylpropyl)-2,20-bipyridine bis-N-oxide (P)-
(R,R)-11. To
a
suspension of (R)-38 (880 mg,
2.8 mmol) in Et2O (3 mL) was added freshly prepared
LiTMP solution (n-BuLi, 1.8 mL, 2.9 mmol, 1.04 equiv,
and tetramethylpiperidine 500 lL, 2.9 mmol, 1.04 equiv)
in THF (3 mL) at ꢀ73 ꢁC. After being stirred for 16 h at
ꢀ73 ꢁC, a solution of iodine (369 mg, 1.5 mmol,
0.5 equiv) in THF (5 mL) was added dropwise over
5 min into the resulting deep-red solution at ꢀ73 ꢁC.
The mixture was further stirred at ꢀ73 ꢁC for 1 h until
the color of the mixture discharged and a second portion
of iodine (370 mg, 1.5 mmol, 0.5 equiv) in THF (5 mL)
was added into the flask. The cooling bath was immedi-
ately removed and the reaction mixture was brought up
to rt over 40 min. During the warming period, the deep-
red color reappeared. After being stirred at rt for 2 h,
cold water (10 mL) was added into the flask, followed
by saturated NaHSO3 solution (10 mL). The mixture
was transferred to a separatory funnel, diluted with
NH4OH solution (20 mL), and thoroughly extracted
with CH2Cl2 (3 · 30 mL). The combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The brownish residue was purified by silica gel
column chromatography (pentane/ether, 2/1) to provide
1.35 g of the mixture of (P)-(R,R)-11 and the by-product
iodide (R)-34d. The iodide (164 mg, 27%) was removed
1
113 ꢁC (hexane); H NMR (400 MHz, CDCl3): 7.39 (d,
J = 8.0, 2H, HC(5)), 7.16 (d, J = 8.1, 2H, HC(4)), 5.06
(s, 2H, HC(10)), 3.24–3.32 (m, 4H, H2C(100)), 2.16–2.25
(m, 2H, H2C(20)), 2.04 (s, 6H, H3C(C(3))), 1.44–1.51
(m, 4H, H2C(200)), 1.26–1.40 (m, 4H, H2C(300)), 1.02 (d,
J = 6.8, 3H, HC(30)), 0.91 (t, J = 7.3, 6H, H3C(400)),
0.82 (d, J = 6.8, 3H, HC(30)); 13C NMR (100 MHz,
CDCl3): 149.50 (C(6)), 142.87 (C(2)), 134.64 (C(3)),
125.90 (C(4) or C(5)), 124.82 (C(5) or C(4)), 80.34
(C(10)), 69.98 (C(100)), 37.24 (CH3(C(3))), 32.07 (C(200)),
25.71 (C(30)), 19.40 (C(300)), 17.53 (C(20)), 13.97
(C(400)); IR (CH2Cl2): 2957 (s), 2871 (m), 1613 (w),
1503 (w), 1478 (w), 1461 (w), 1383 (m), 1285 (m), 1256
(w), 1177 (m), 1095 (m); TLC Rf 0.15 (hexane/Et2O, 4/
1); MS (FAB): 474 (30), 473 (100), 337 (40);
24
½aꢁD ¼ þ39:7 (c 0.67, MeOH); Anal. Calcd for
C28H44N2O4 (472.66): C, 71.15; H, 9.38; N, 5.93. Found:
C, 71.63; H, 9.57; N, 6.00. HRMS (ESI, 70 eV): Calcd
for C28H45N2O4, 473.3389. Found: 473.3384.

704
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
by recrystallization from pentane. From the mother
liquor, (P)-(R,R)-11 (523 mg, 61%) was obtained. An
analytically pure sample was obtained after crystalliza-
tion from hexane. Data for (P)-(R,R)-11: mp: 149–
tetramethylpiperidine 230 lL, 1.35 mmol, 1.1 equiv) in
THF (0.5 mL) at ꢀ73 ꢁC. After being stirred for 16 h
at ꢀ73 ꢁC, a solution of iodine (340 mg, 1.35 mmol,
1.1 equiv) in THF (1.5 mL) was added dropwise over
10 min into the resulting deep-red solution at ꢀ73 ꢁC.
The mixture was further stirred at ꢀ73 ꢁC for 1 h until
the color of the mixture was discharged. The cooling
bath was immediately removed and the reaction mixture
brought up to rt over 30 min. During the warming per-
iod, the deep-red color reappeared. After being stirred at
rt for 40 min, cold water (10 mL) was added into the
flask, followed by satd NaHSO3 solution (15 mL). The
mixture was transferred to a separatory funnel, diluted
with NH4OH solution (50 mL), and extracted with
CH2Cl2 (3 · 20 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pres-
sure. The brownish residue was purified by silica gel col-
umn chromatography (pentane/ether, 2/1) to provide
330 mg of a mixture of (P)-(R,R)-12 and the by-product
iodide. The iodide (34 mg, 5%) was removed by recrys-
tallization from pentane. From the mother liquor, (P)-
(R,R)-12 (277 mg, 77%) was obtained. An analytically
pure sample was obtained after crystallization from pen-
tane. Data for (P)-(R,R)-12: mp: 112–113 ꢁC (pentane);
1H NMR (400 MHz, CDCl3); 7.45 (d, J = 8.2, 2H,
HC(5)), 7.16 (d, J = 8.4, 2H, HC(4)), 5.32 (s, 2H,
HC(10)), 3.19–3.28 (m, 4H, H2C(10)), 2.04 (s, 6H,
H3C(C(3))), 1.43–1.53 (m, 4H, H2C(20)), 1.29–1.43 (m,
16H, H2C(30) and H2C(300)), 0.88 (t, J = 7.5, 6H,
(H3C(40)3)), 0.81 (t, J = 7.5, 19H, H3C(400)); 13C NMR
(100 MHz, CDCl3): 150.24 (C(6)), 142.99 (C(2)),
134.49 (C(3)), 126.02 (C(4) or C(5)), 125.87 (C(5) or
C(4)), 77.73 (C(100)), 69.98 (C(10)), 44.84 (C(200)), 32.0
(C(20)), 25.19 (CH3(C(3))), 19.45 (C(300)), 17.58 (C(30)),
13.94 (C(40)), 8.49 (C(400)); IR (KBr): 2957 (s), 2871
(m), 1613 (w), 1503 (w), 1478 (w), 1461 (w), 1383 (m),
1285 (m), 1256 (w), 1177 (m), 1095 (m); TLC Rf 0.65
1
150.5 ꢁC (hexane); H NMR (400 MHz, CDCl3): 7.47
(dd, J = 7.3, 1.1, 4H, HC(50)), 7.27 (t, J = 7.3, 4H,
HC(60)), 7.28 (t, J = 7.0, 2H, J = 7.1, HC(70)), 7.09
(AB quartet, J = 8.3, 8H, HC(4) and HC(5)), 5.48
(s, 2H, HC(10)), 3.06–3.22 (m, 4H, H2C(80)), 2.05 (s,
6H, H3C(C(5))), 1.40 (s, 6H, H3C(30)), 1.36 (s, 6H,
H3C(30)), 1.29–1.33 (m, 4H, H2C(90)), 1.15–1.20 (m,
4H, H2C(100)), 0.77 (t, J = 7.3, 3H, H3C(110)); 13C
NMR (100 MHz, CDCl3): 149.08 (C(2)), 146.52 (C(6)),
142.62 (C(40)), 134.92 (C(3)), 127.38 (C(50 or 60)),
127.30 (C(50 or 60)), 125.84 (C(70)), 125.26 (C(4)),
80.38 (C(10)), 69.91 (C(80)), 44.02 (C(20)), 31.79
(CH3(C(5)) or C(90)), 26.33 (CH3(C(5)) or C(90)), 22.21
(C(100)), 19.20 (C(30)), 17.57 (C(30)), 13.81 (C(110)); IR
(KBr): 3090 (w), 3058 (w), 3023 (w), 2959 (s), 2932 (s),
2872 (s), 1740 (s), 1601 (m), 1497 (m), 1476 (s), 1446
(s), 1388 (s), 1369 (s), 1329 (s), 1269 (s), 1241 (s), 1096
(s), 1048 (s), 966 (w), 787 (m), 770 (m); TLC Rf 0.41
(hexane/EtOAc, 4/1); MS (FAB, 70 eV): 627 (11), 626
24
(44), 625 (100), 609 (19); ½aꢁD ¼ þ27:5 (c 1.01, EtOH);
Anal. Calcd for C40H52N2O4 (624.42): C, 76.94; H,
8.39; N, 4.49. Found: C, 76.64; H, 8.34; N, 4.57.
6.1.23. (R)-5-Methyl-1-(1-butyloxy-2,2-diethylbutyl)pyri-
dine N-oxide (R)-43. Following general procedure 1,
pyridine (R)-42 (486 mg, 1.75 mmol) and mCPBA
(450 mg, 2.63 mmol, 1.5 equiv) were dissolved in
CH2Cl2 (10 mL) and the mixture stirred overnight at
rt. Work-up provided 477 mg of white solid residue.
Purification by silica gel column chromatography
(CH2Cl2/MeOH, 20/1) provided the product (457 mg,
89%) as a colorless oil. An analytically pure sample
was obtained after bulb-to-bulb distillation. Data for
(R)-43: bp: 180 ꢁC ABT (0.1 mmHg); 1H NMR
(400 MHz, CDCl3): 8.05 (s, 1H, HC(6)), 7.36 (d,
J = 8.1, 1H, HC(3)), 7.03 (d, J = 8.1, 1H, HC(4)),
5.25 (s, 1H, HC(10)), 3.05–3.23 (m, 2H, H2C(100)), 2.27
(s, 3H, H3C(C(5))), 1.46–1.53 (m, 2H, H2C(200)), 1.44
(q, J = 7.3, 6H, 3 · H2C(30)), 1.29–1.42 (m, 2H,
H2C(300)), 0.85 (t, J = 7.3, 3H, H3C(400)), 0.82 (t,
J = 7.3, 9H, 3 · H3C(40)); 13C NMR (100 MHz,
CDCl3): 149.79 (C(2)), 139.45 (C(6)), 134.02 (C(5)),
126.21 (C(3) or C(4)), 125.99 (C(3) or C(4)), 78.04
(C(10)), 69.56 (C(100)), 44.51 (C(20)), 32.07 (C(200)),
25.40 (H3C(C(50))), 19.41 (C(30)), 17.94 (C(300)), 13.83
(C(400)), 8.39 (C(40)): IR (neat): 2965 (s), 2934 (s), 2878
(s), 1613 (w), 1503 (m), 1456 (m), 1379 (s), 1339 (m),
1284 (s), 1252 (m), 1212 (w), 1189 (m), 1165 (m), 1114
(m), 1093 (s), 1051 (s), 953 (m), 880 (w); TLC Rf 0.36
(hexane/EtOAc, 4/1); MS (FAB): 585 (100), 569 (20);
24
½aꢁD ¼ ꢀ30:7 (c 1.34, MeOH); Anal. Calcd for
C30H48N2O4 (584.88): C, 73.93; H, 10.34; N, 4.79.
Found: C, 73.89; H, 10.46; N, 4.74.
6.1.25. (R)-5-Bromo-1-(1-butyloxy-2,2-dimethylpropyl)-
pyridine N-oxide (R)-47. Following general procedure
1, pyridine (R)-46 (2.43 g, 8.09 mmol) and mCPBA
(1.79 g, 10.1 mmol, 1.25 equiv) were dissolved in CH2Cl2
(25 mL) and the mixture stirred overnight at rt. Work-
up provided 2.52 g of a white solid residue. Purification
by silica gel column chromatography (CH2Cl2/MeOH,
20/1) provided the product (2.45 g, 99%) as a colorless
oil. An analytically pure sample was obtained after
bulb-to-bulb distillation. Data for (R)-47: bp: 220 ꢁC
1
ABT (0.5 mmHg); H NMR (400 MHz, CDCl3): 8.34
(hexane/EtOAc, 3/1); MS (FAB): 294 (100);
(d, J = 1.7, 1H, HC(6)), 7.36 (dd, J = 8.6, 1.7, 1H,
HC(4)), 7.28 (d, J = 8.5, 1H, HC(3)), 4.94 (s, 1H,
HC(10)), 3.16–3.29 (m, 2H, H2C(100)), 1.44–1.51 (m,
2H, H2C(200)), 1.29–1.36 (m, 2H, H2C(300)), 0.96 (s, 9H,
H3C(30)), 0.87 (t, J = 7.3, 3H, H3C(400)); 13C NMR
(100 MHz, CDCl3): 151.43 (C(2)), 140.89 (C(6)),
127.73 (C(4)), 125.88 (C(3)), 118.20 (C(5)), 80.23
(C(10)), 70.12 (C(100)), 37.33 (C(20)), 31.84 (C(200)),
25.56 (C(30)), 19.33 (C(300)), 13.83 (C(400)); IR (KBr):
3094 (w), 3036 (w), 2933 (s), 2871 (s), 1596 (m), 1532
24
½aꢁD ¼ þ46:2 (c 0.59, MeOH); Anal. Calcd for
C18H31NO2 (293.44): C, 73.67; H, 10.65; N, 4.77.
Found: C, 73.94; H, 10.98; N, 4.81.
6.1.24. (P)-(R,R)-3,30-Dimethyl-6,60-bis-(1-butyloxy-2,2-
diethylbutyl)-2,20-bipyridine
bis-N-oxide
(P)-(R,R)-
12. To a suspension of (R)-43 (360 mg, 1.23 mmol) in
Et2O (1.0 mL) was added freshly prepared LiTMP solu-
tion (1.60 M n-BuLi, 840 lL, 1.35 mmol, 1.1 equiv, and

S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
705
(w), 1477 (s), 1370 (s), 1244 (s), 1094 (s), 901 (s); TLC Rf
cally pure sample was obtained after crystallization
from hexane. Data for (P)-(R,R)-15: mp: 167–169 ꢁC
(hexane); 1H NMR (400 MHz, CDCl3): 6.93 (s, 2H,
HC(4)), 5.27 (s, 2H, HC(10)), 3.28–3.37 (m, 4H,
H2C(100)), 2.53 (s, 6H, H3C(3) or H3C(5)), 1.97 (s, 6H,
H3C(3) or H3C(5)), 1.42–1.60 (m, 4H, H2C(200)), 1.29–
1.40 (m, 4H, H2C(300)), 1.02 (s, 18H, H3C(30)), 0.89 (t,
J = 7.3, 3H, H3C(400)); 13C NMR (100 MHz, CDCl3):
150.56 (C(6)), 143.09 (C(2)), 134.61 (C(3) or C(5)),
126.93 (C(3) or C(5)), 123.63 (C(4)), 79.75 (C(10)),
70.59 (C(100)), 32.27 (C(20)), 31.33 (C(200)), 19.64, 19.57,
17.69, 16.73, 14.19; TLC Rf 0.33 (hexane/EtOAc, 6/1);
IR (KBr): 3094 (w), 3036 (w), 2933 (s), 2871 (s), 1596
0.18 (hexane/Et2O, 3/1); MS (FAB): 318 (8), 316 (8), 244
24
(98), 242 (100); ½aꢁD ¼ ꢀ27:3 (c 0.22, MeOH); Anal.
Cacld for C14H22BrNO2 (316.23): C, 53.17; H, 7.01; N,
4.43. Found: C, 53.42; H, 7.19; N, 4.49.
6.1.26. (P)-(R,R)-3,30-Dibromo-6,60-bis-(1-butyloxy-2,2-
dimethylpropyl)-2,20-bipyridine bis-N-oxide (P)-(R,R)-
13. Following general procedure 2, from (R)-47
(948 mg, 3.0 mmol), 312 mg (33%) of the product (P)-
(R,R)-13 was obtained as a white solid after silica gel
column chromatography (pentane/ether, 2/1). An ana-
lytically pure sample was obtained after crystallization
from pentane. Data for (P)-(R,R)-13: mp: 175–179 ꢁC
(pentane); 1H NMR (400 MHz, CDCl3): 7.26 (dd,
J = 8.6, 1.7, 1H, HC(4)), 7.18 (d, J = 8.5, 1H, HC(5)),
4.92 (s, 1H, HC(10)), 3.16–3.29 (m, 2H, H2C(100)),
1.44–1.51 (m, 2H, H2C(200)), 1.29–1.36 (m, 2H,
H2C(300)), 0.96 (s, 9H, H3C(30)), 0.87 (t, J = 7.3, 3H,
H3C(400)); 13C NMR (100 MHz, CDCl3): 151.38 (C(6)),
128.15, 127.47, 127.41, 124.98, 82.54 (C(10)), 70.48
(C(100)), 37.74 (C(20)), 32.10 (C(200)), 25.97 (C(30)),
19.59 (C(300)), 14.09 (C(400)); TLC Rf 0.32 (hexane/
(m), 1532 (w), 1477 (s), 1370 (s), 1244 (s), 1094 (s), 901
24
(s); MS (FAB): 530 (18), 529 (100); ½aꢁD ¼ þ39:4 (c
0.89, EtOH); HRMS (ESI): Calcd for C32H57N2O4,
529.4005. Found: 529.3997.
6.1.29. (R)-3-Methyl-(8-(1-butyloxy)-(5,6,7,8)-tetrahydro)-
quinoline N-oxide (R)-57. Following general procedure
1, pyridine (R)-56 (5.02 g, 22.9 mmol) and mCPBA
(5.23 g, 29.2 mmol, 1.2 equiv) were dissolved in CH2Cl2
(50 mL) and the mixture stirred overnight at rt. Work-
up provided 5.09 g of an oily residue. Purification by sil-
ica gel column chromatography (Rf 0.35, CH2Cl2/
MeOH, 20/1) provided the product as colorless oil
(5.20 g, 96%). An analytically pure sample was obtained
after bulb-to-bulb distillation. Data for (R)-57 bp:
180 ꢁC ABT (0.5 mmHg); 1H NMR (400 MHz, CDCl3):
7.99 (d, J = 0.4, 1H, HC(2)), 6.80 (d, J = 0.4, 1H,
HC(4)), 4.94 (t, J = 4.7, 1H, HC(8)), 3.70–3.89 (m,
2H, H2C(10)), 2.57–2.81 (m, 2H, H2C(5)), 2.22 (s, 3H,
H3C(3)), 1.91–2.03 (m, 2H, H2C(20)), 1.72–1.77 (m,
2H, H2C(7)), 1.52–1.67 (m, 2H, H2C(30)), 1.31–1.41
(m, 2H, H2C(6)), 0.90 (t, J = 7.3, 3H, H3C(40)); 13C
NMR (100 MHz, CDCl3) 143.43 (C(9)), 137.39 (C(2)),
136.20 (C(3) or C(10)), 134.27 (C(3) or C(10)), 127.33
(C(4)), 70.79 (C(8)), 67.53 (C(10)), 32.29 (C(20)), 27.95,
27.52, 19.43, 18.03, 16.55, 13.95; IR (neat): 3094 (w),
3036 (w), 2933 (s), 2871 (s), 1596 (m), 1532 (w), 1477
(s), 1370 (s), 1244 (s), 1094 (s), 901 (s); TLC Rf 0.23
EtOAc, 5/1); MS (FAB): 634 (8), 633 (8), 632 (8), 631
24
(8), 244 (98), 242 (100); Opt. Rot.: ½aꢁD ¼ þ29:9 (c
0.28, EtOH); HRMS (ESI): Calcd for C28H43Br2N2O4,
629.1597. Found: 629.1590. Calcd for C28H42Br2N2-
Na1O2 651.1410. Found: 651.1413.
6.1.27.
(R)-3,5-Dimethyl-1-(1-butyloxy-2,2-dimethyl-
propyl)pyridine N-oxide (R)-53. Following general pro-
cedure 1, pyridine (R)-52 (2.90 g, 11.8 mmol) and
mCPBA (2.51 g, 14.2 mmol, 1.25 equiv) were dissolved
in CH2Cl2 (25 mL) and the mixture stirred overnight
at rt. Work-up provided 3.02 g of white solid residue.
Purification by silica gel column chromatography (Rf
0.33, CH2Cl2/MeOH, 20/1) provided the product
(2.77 g, 89%) as colorless oil. An analytically pure sam-
ple was obtained after bulb-to-bulb distillation. Data for
(R)-53: bp 220 ꢁC ABT (0.5 mmHg); 1H NMR
(400 MHz, CDCl3): 7.97 (s, 1H, HC(6)), 6.84 (s, 1H,
HC(4)), 5.50 (s, 1H, HC(10)), 3.50 (t, J = 8.3, 2H,
H2C(100)), 2.48 (s, 3H, H3C(3) or H3C(5)), 2.21 (s, 3H,
H3C(3) or H3C(5)), 1.44–1.52 (m, 2H, H2C(200)), 1.29–
1.36 (m, 2H, H2C(300)), 1.02 (s, 9H, H3C(30)), 0.87 (t,
J = 7.3, 3H, H3C(400)); 13C NMR (100 MHz, CDCl3):
147.58 (C(2)), 137.85 (C(6)), 136.62 (C(3) or C(5)),
133.24 (C(3) or C(5)), 130.87 (C(4)), 82.90 (C(10)),
70.57 (C(100)), 39.19 (C(20)), 32.12 (C(200)), 27.26
(C(30)), 19.67, 19.46, 17.86, 14.13; IR (neat): 3094 (w),
3036 (w), 2933 (s), 2871 (s), 1596 (m), 1532 (w), 1477
(Et2O/EtOH, 20/1): MS (FAB): 236 (100), 162 (60);
24
½aꢁD ¼ þ4:9 (c 0.61, MeOH); Anal. Calcd for
C14H21NO2 (235.32): C, 71.46; H, 8.99; N, 5.95. Found:
C, 71.23; H, 9.17; N, 6.06.
6.1.30. (R)-2-Iodo-3-methyl-(8-(1-butyloxy)-5,6,7,8-tetra-
hydro)quinoline (R)-58. To a suspension of (R)-57
(990 mg, 6.0 mmol) in Et2O (20 mL) was added freshly
prepared LiTMP solution (n-BuLi, 1.56 M, 4.5 mL,
6.6 mmol, 1.1 equiv, and tetramethylpiperidine 940 lL,
6.6 mmol, 1.1 equiv) in THF (10 mL) at ꢀ73 ꢁC. After
being stirred for 16 h at ꢀ73 ꢁC, a solution of iodine
(756 mg, 3.0 mmol, 0.5 equiv) in THF (5 mL) was added
dropwise over 10 min into the resulting deep-red solu-
tion at ꢀ73 ꢁC. The mixture was further stirred at
ꢀ73 ꢁC for 1 h until the color of the mixture discharged
and a second portion of iodine (756 mg, 3.0 mmol,
0.5 equiv) in THF (5 mL) was added into the flask.
The cooling bath was immediately removed and the
reaction mixture was brought up to rt over 40 min. Dur-
ing the warming period, the deep-red color was re-
charged. After being stirred at rt for 2 h, cold water
(s), 1370 (s), 1244 (s), 1094 (s), 901 (s); TLC Rf 0.18
24
(Et2O); MS (FAB): 266 (14), 265 (100); ½aꢁD ¼ þ31:7
(c 0.37, EtOH); Anal. Calcd for C16H27NO02 (265.39):
C, 72.41; H, 10.25; N, 5.28. Found: C, 72.07; H, 10.38;
N, 5.38.
6.1.28. (P)-(R,R)-3,30,5,50-Tetramethyl-6,60-bis-(1-butyl-
oxy-2,2-dimethylpropyl)-2,20-bipyridine bis-N-oxide (P)-
(R,R)-15. Following general procedure 2, using (R)-53
(530 mg, 2.0 mmol), 228 mg of the product (P)-(R,R)-15
(43%) was obtained as a white solid after silica gel col-
umn chromatography (pentane/ether, 2/1). An analyti-

706
S. E. Denmark, Y. Fan / Tetrahedron: Asymmetry 17 (2006) 687–707
(10 mL) was added into the flask, followed by satd
NaHSO3 solution (10 mL). The mixture was transferred
to a separatory funnel, diluted with NH4OH solution
(50 mL), and thoroughly extracted with CH2Cl2
(3 · 60 mL). The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure.
The brownish residue was purified by silica gel column
chromatography (pentane/ether, 2/1) to provide 1.32 g
of mixture of dimeric products and the iodide (R)-58.
The iodide (930 mg, 69%) was recrystallized from the
pentane solution of this mixture. From the mother li-
quor, a mixture of two dimers (207 mg, 23%) was ob-
(468.63): C, 71.76; H, 8.60; N, 5.98. Found: C, 71.64;
H, 8.75; N, 6.00.
1
Data for (ꢀ)-16b: mp: 153–155 ꢁC (hexane); H NMR
(400 MHz, CDCl3): 6.93 (s, 2H, HC(4)), 4.99 (s, 2H,
HC(8)), 3.69–3.87 (m, 2H, H2C(10)), 2.61–2.85 (m,
2H, H2C(5)), 2.05 (s, 3H, H3C(3)), 1.95–2.23 (m, 2H,
H2C(20)), 1.75–1.79 (m, 2H, H2C(7)), 1.51–1.67 (m,
2H, H2C(30)), 1.28–1.38 (m, 2H, H2C(6)), 0.87 (t,
J = 7.3, 3H, H3C(40)); 13C NMR (100 MHz, CDCl3):
145.46 (C(9)), 141.43 (C(2)), 135.86 (C(3) or C(10)),
126.99 (C(3) or C(10)), 116.51 (C(4)), 71.82 (C(8)),
71.05 (C(10)), 33.06 (C(20)), 28.52, 28.43, 28.06, 20.20,
1
tained. Data for (R)-58: mp: 106–109 ꢁC (pentane); H
NMR (400 MHz, CDCl3); 6.83 (s, 1H, HC(4)), 4.92 (t,
J = 4.7, 1H, HC(8)), 3.68–3.96 (m, 2H, H2C(10)),
2.54–2.79 (m, 2H, H2C(5)), 2.42 (s, 3H, H3C(3)), 2.22–
2.26 (m, 2H, H2C(20)), 1.91–2.03 (m, 2H, H2C(7)),
1.72–1.82 (m, 2H, H2C(30)), 1.28–1.64 (m, 2H,
H2C(6)), 0.90 (t, J = 7.3, 3H, H3C(40)); 13C NMR
(100 MHz, CDCl3): 144.68 (C(9)), 140.64 (C(2)),
135.08 (C(3) or C(10)), 126.23 (C(3) or C(10)), 115.73
(C(4)), 71.03 (C(8)), 69.25 (C(10)), 32.26 (C(20)), 27.72,
27.65, 27.26, 19.40, 16.41, 13.94; IR (KBr): 3094 (w),
3036 (w), 2933 (s), 2871 (s), 1596 (m), 1532 (w), 1477
17.21, 14.74; TLC Rf 0.29 (Et2O); MS (FAB): 469
24
(13), 468 (100); ½aꢁD ¼ ꢀ8:9 (c 3.19, MeOH); Anal.
Calcd for C28H40N2O4 (468.63): C, 71.76; H, 8.60; N,
5.98. Found: C, 71.57; H, 8.74; N, 6.05.
Acknowledgments
We are grateful to the National Science Foundation for
generous financial support (NSF CHE0105205 and NSF
CHE04144440). Y.F. thanks Boehringer Ingelheim
Pharmaceuticals Inc. for a graduate fellowship.
(s), 1370 (s), 1244 (s), 1094 (s), 901 (s); TLC Rf 0.35
24
(Et2O): MS (ESI): 362 (40); ½aꢁD ¼ ꢀ7:2 (c 1.16, EtOH);
Anal. Calcd for C14H20INO2 (361.22): C, 46.55; H, 5.58;
N, 3.88. Found: C, 46.83; H, 5.23; N, 3.86.
References
6.1.31. (P)- and (M)-(R,R)-3,30-Dimethyl-(8,80-bis-(1-
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2H, H2C(10)), 2.47–2.72 (m, 2H, H2C(5)), 2.09 (s, 3H,
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24
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