Enantioselective synthesis of cocaine C-1 analogues using sulfinimines (N -sulfinyl imines)

Article abstract of DOI:10.1021/jo202652f

The first examples of cocaine analogues having substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at the C-1 position of the cocaine tropane skeleton were prepared by heating sulfinimine-derived α,β-unsaturated pyrrolidine nitrones. In the presence of the Lewis acid Al(O ^tBu)₃ the nitrones undergo an intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines that were transformed in three steps to the cocaine analogues. In the absence of the Lewis acid, lactams were formed resulting from rearrangement of the nitrone to an oxaziridine. A novel Pd- and base-promoted rearrangement of methanesulfonate salts of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was discovered.

Full text of DOI:10.1021/jo202652f

Article
pubs.acs.org/joc
Enantioselective Synthesis of Cocaine C-1 Analogues using
Sulfinimines (N-Sulfinyl Imines)
Franklin A. Davis,* Narendra V. Gaddiraju, Naresh Theddu, Joshua R. Hummel, Sandeep K. Kondaveeti,
and Michael J. Zdilla
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
S
* Supporting Information
ABSTRACT: The first examples of cocaine analogues having
substituents (methyl, ethyl, n-propyl, n-pentyl, and phenyl) at
the C-1 position of the cocaine tropane skeleton were
prepared by heating sulfinimine-derived α,β-unsaturated
pyrrolidine nitrones. In the presence of the Lewis acid
Al(OtBu)3 the nitrones undergo an intramolecular [3 + 2]
cycloaddition to give tricyclic isoxazolidines that were
transformed in three steps to the cocaine analogues. In the
absence of the Lewis acid, lactams were formed resulting from
rearrangement of the nitrone to an oxaziridine. A novel Pd-
and base-promoted rearrangement of methanesulfonate salts
of isoxazolidine to bridge bicyclic[4.2.1]isoxazolidines was
discovered.
focused on modifications of the C-2 and C-3 substituents,
which are prepared from (−)-1. Although useful information
on the cocaine-binding site has resulted from these studies, to
date there are no therapeutically useful cocaine analogues.3 The
introduction of groups at other positions of the cocaine tropane
skeleton is much more problematic, often requiring multistep
syntheses and resolutions to access enantiopure materials.3
Recently Shing et al. described the enantioselective synthesis of
C-6,7 and C-7 cocaine analogues from D-(−)-ribose.6e In 2010
we disclosed the first synthesis of enantiopure cocaine
analogues having substituents at the C-1 or bridgehead position
of the cocaine tropane skeleton in addition to (S)-(+)-2 the
enantiomer of cocaine (R)-(−)-1 (Figure 1).7 Here we describe
full details of the enantioselective synthesis of C-1 substituted
cocaine analogues and their related chemistries.
INTRODUCTION
Tropane alkaloids such as (R)-(−)-cocaine (1) have often
served as lead compounds in drug discovery (Figure 1). This is
■
Our synthesis of C-1 cocaine analogues builds on Tufariello’s
synthesis of racemic cocaine described in the late 1970s.8 His
procedure employed a novel [3 + 2] cycloaddition reaction of a
pyrrolidine nitrone to give a tricyclic isoxazolidine, which
determines the cis relationship of the C-2 and C-3 substituents
in the tropane skeleton. Unfortunately, an enantioselective
route could not be adapted to this method, and the
introduction of functionality at other positions of the skeleton
was impractical. Our asymmetric synthesis of C-1 cocaine
analogues, which employs an enantiopure-masked oxo-
sulfinimine, is given in Figure 2. Here the tricyclic isoxazolidine
and the enantiopure nitrone are prepared from an N-sulfinyl β-
amino ketal ester derived from a masked oxo-sulfinimine.9,10
Figure 1. Cocaine and C-1 cocaine analogues.
because cocaine targets the three monoamine transporters:
dopamine (DAT), serotonin (SERT), and norepinephrin
(NET).1 Modification in the dopamine transporter function
may have a role in Alzheimer’s disease, Parkinson’s disease,
attention deficit hyperactivity disorder, aging, depression, and
cocaine’s powerful stimulator and addictive properties.2,3 For
these reasons there is continuing interest in the asymmetric
synthesis of cocaine-like compounds that can selectively target
the monoamine transporters and DAT in particular.3,4
The difficulty encountered in the stereoselective synthesis of
cocaine analogues is the requirement that the C-2 and C-3
substituents have a cis relationship. Additionally, of cocaine’s
eight stereoisomers only the R-isomer (−)-1 is addictive.3,5,6
For these reasons most nonracemic analogues of cocaine have
Received: December 22, 2011
Published: February 2, 2012
© 2012 American Chemical Society
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Scheme 2
Figure 2. Retrosynthetic analysis of C-1 cocaine analogues from
masked oxo-sulfinimines.
yields. Acid-catalyzed ketalization followed by reduction of the
Weinreb amides using lithium aluminum hydride (LiAlH4) gave
the desired aldehydes 3 in good yields (Scheme 2).
(S)-(+)-Dehydropyrrolidines. Treatment of sulfinimines
(S)-(+)-6 and (S)-(+)-7 with an excess of the sodium enolate
of methyl acetate in Et2O at −78 °C afforded the
corresponding β-amino esters (SS,3S)-(+)-12 and (SS,3S)-
(+)-13 as single diastereoisomers in good to excellent yields
(Scheme 3). Reduction of (+)-12 and (+)-13 with DIBAL-H in
RESULTS AND DISCUSSION
■
Masked Oxo-sulfinimines. Our synthesis of C-1 cocaine
analogues begins with the preparation of the masked oxo-
sulfinimine, a sulfinimine-derived chiral building block.11 The
sulfinimines were prepared in the usual manner by condensing
(S)-(+)-p-toluenesulfinamide (4) or (S)-(−)-tert-butanesulfina-
mide (5) with the appropriate ketal aldehyde 3 in the presence
of excess Ti(OEt)4 as shown in Scheme 1.10 The bulkier and
Scheme 3
Scheme 1
more nucleophilic (S)-(−)-tert-butanesulfinamide (5) gave the
product within 24 h, but (S)-(+)-4 required longer times (24 to
48 h). In general yields using (S)-(−)-5 were also improved
compared to (S)-(+)-4 (Scheme 1).
The ketal aldehydes 3a (R = Me) and 3e (R = Ph) were
prepared as previously described.11a,12 Ketal aldehydes 3b (R =
Et), 3c (R = n-Pr), and 3d (R = n-C5H11) were prepared from
the corresponding commercially available lactones 8 as shown
in Scheme 2. Reaction of lactone 8 with in situ generated
magnesium N,O-dimethyhydroxylamine13 afforded the corre-
sponding Weinreb amides 9 in 85−89% yields. Swern oxidation
of 9c (R = n-Pr) failed to give the ketone, but oxidation using
iodoxybenzoic acid (IBX) gave the ketones 10 in 70−85%
toluene at −78 °C gave the desired aldehydes (SS,3S)-(+)-14
and (SS,3S)-(+)-15 in good yield, but over-reduction to the
alcohols was problematic. Careful control of the reaction time
and equivalents of DIBAL-H were necessary to minimize over-
reduction. Best yields were observed using 1.8 equiv of DIBAL-
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H and a time of approximately 45 min for (+)-12 and only 10
min for (+)-13 (Scheme 3). Importantly, epimerization at the
C−N chiral center in (+)-14 and (+)-15 was not observed.
Conversion of (+)-14 and (+)-15 into the (E)-α,β-
unsaturated N-sulfinyl β-amino ketals was next explored.
Reaction of aldehyde (+)-14a with methyl (triphenylphosphor-
anylidene) acetate for 10 h gave the α,β-unsaturated N-sulfinyl
δ-amino ketal (SS,5S)-(+)-16a in 92% yield (Scheme 4). The
In the absence of LiCl with 2 equiv of trimethyl
phosphonoacetate/DBU, N-p-toluenesulfinyl aldehydes
(+)-14a (R = Me), (+)-14c (R = n-Pr), and (+)-14e (R =
Ph) were converted into α,β-unsaturated esters (+)-16a,
(+)-16c, and (+)-16e in less than 1 h and in >90% yield
with exclusive (E)-geometry for the olefin. Olefination of the
N-tert-butanesulfinyl β-amino aldehydes (+)-15 under similar
reaction conditions resulted in formation of the α,β-unsaturated
ester ketals (+)-17a (R = Me), (+)-17b (R = Et), and (+)-17d
(R = n-C5H11) in excellent yield without isomerization.
However, ester (+)-17e (R = Ph) was isolated as 95:5 mixture
of inseparable E:Z isomers.
Scheme 4
An alternative strategy was briefly explored to access α,β-
unsaturated ester ketals (+)-17a (R = Me) and 17e (R = Ph)
(Scheme 5).15 This procedure treats oxo-sulfinimines (+)-7a
and (+)-7e with 2 equiv of allylmagnesium bromide at −50 °C
to give allyl amines (SS4S)-(+)-18a and (SS4S)-(+)-18b in 82%
and 85% yields, respectively. Cross metathesis (CM) using
Hoveyda−Grubbs catalyst II for 12 h in DCM afforded the
desired α,β-unsaturated ester ketals (+)-17a and (+)-17e in
79% and 71% yields, respectively, but the E:Z ratios were 92:8
and 93:7, respectively. All attempts to improve the ratios by
using Grubbs I or Grubbs II were unsuccessful.
Hydrolysis of the α,β-unsaturated δ-amino ester ketals
(+)-16 and (+)-17 with 3 N HCl in THF/MeOH (1:1) gave
the corresponding dehydropyrrolidines (S)-(+)-19a−e in
excellent yields without E:Z isomerization (Scheme 6).
However, with excess methanol/THF (3:1) isomerization of
the α,β-unsaturated ester was observed, and in THF hydrolysis
of the ester functionality was noted in addition to isomer-
ization. Importantly, even when the α,β-unsaturated δ-amino
ester ketals were not single isomers, after purification the
dehydropyrrolidines (S)-(+)-19a−e were obtained as single
isomers (Scheme 6).
Preparation of Nitrones. With the dehydropyrrolidines
(+)-19 in hand it was next necessary to selectively oxidize them
to the corresponding nitrones (S)-20 (Scheme 6). Oxidation of
imines with reagents such as m-CPBA can give nitrones or
oxaziridines.16 The selective oxidation of imines to nitrones by
urea hydrogen peroxide (UHP) catalyzed by methyltrioxo-
rhenium (MTO) has recently been described by Goti and co-
workers.17 Oxidation of (+)-19a (R = Me) with 3.3 equiv of
UHP and cat. MTO (2 mol %) in anhydrous MeOH for 1 h
resulted in no reaction and recovery of starting material.
16 Hz coupling constant observed for the olefinic protons in
(+)-16a is consistent with the major isomer having the desired
(E)-geometry.14 To overcome the longer reaction times, β-
amino aldehyde (+)-14a (R = Me) was subjected to the
Roush−Masamune modification of the Horner−Wadsworth−
Emmons (HWE) reaction with nucleophilic trimethylphospho-
noacetate and DBU-LiCl.12 However, these conditions resulted
in the formation of (Ss,5S)-(+)-16a as an inseparable 9:1 E:Z
mixture of isomers in 80% yield within 5−6 h. Prolonged
reaction times and the presence of LiCl were thought to be
causing isomerization of olefin geometry. Importantly, only the
(E)-isomer (+)-16a was obtained in >90% yield when LiCl was
omitted from the HWE reaction.
Scheme 5
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Scheme 6
Increasing the amount of catalyst from 2 to 6 mol % and the
reaction time to 16 h resulted in conversion of the imine to the
nitrone (S)-20a (R = Me) in quantitative yield. Nitrone
formation was confirmed by 1H NMR analysis of crude reaction
mixture in which the C-2 hydrogen of the pyrrole ring was
shifted downfield to δ 4.20 ppm as compared to δ 4.05 ppm in
the imine. In the 13C NMR the C-5 carbon in 20a was shifted
upfield to δ 150.5 ppm as compared to δ 175.0 ppm for the
imine. Using the optimized conditions, dehydropyrrolidines
(+)-19b−e were converted to the corresponding nitrones (S)-
Table 1. Intramolecular [3 + 2] Cycloaddition of Nitrones
20 to Isoxazolidines (−)-21 and Lactam (S)-(−)-22
products (% yield)
isoxazoline 21,
lactam 22
nitrone 20
solvent,
Al(OtBu)3,
mol %
entry
1
(R =)
°C
time, h
24
20a (Me)
PhMe,
110
none
21a (20)
2
3
48
24
21a (45−50)
decomp
xylene,
143
4
5
PhH
24
24
10
10
21a (<10)
21a (25)
1
20b−e in quantitative yield. While the H NMR results of the
PhMe,
110
crude nitrones were clean, attempts to purify them by
chromatography resulted in decomposition. For this reason
the nitrones were used without purification in the [3 + 2]
cycloaddition reactions discussed below.
6
PhMe,
110
72
72
24
48
96
48
72
48
96
48
72
50
100
10
21a (70)
21a (40)
decomp
7
PhMe,
110
Formation of Isoxazolidines and Lactams. Heating
nitrone 20a (R = Me) in toluene for 24 h gave less than 20%
yield of tricyclic isoxazolidines (1S,2R,3R,6S)-(−)-21a (Scheme
6, Table 1, entry 1). The yield improved to 45−50% on heating
for 48 h (Table 1, entry 2). In xylene at 143 °C 20a
decomposed (Table 1, entry 3). In these experiments a
considerable amount of a dark residue was produced. Since it
was shown that (−)-21a was stable under these reaction
conditions, it suggests that the nitrone was decomposing. Due
to the difficulty associated with isolation of the volatile
isoxazolidine (−)-21a (R = Me), it was converted into a
water-soluble hydrochloride salt by treating with aqueous 5%
HCl. Neutralization of the aqueous phase with solid sodium
carbonate and extraction into diethyl ether afforded isoxazoli-
dine (−)-21a in moderate yield (Table 1, entries 1−8). The
structure of (1S,2R,3R,6S)-(−)-21a is supported by character-
istic proton resonances at δ 4.93 ppm for the C-1 proton
(doublet) and at δ 2.44 ppm for the C-2 proton (singlet) in the
1H NMR spectra.8
8
xylene,
143
a
9
20b (Et)
PhMe,
110
21b:22b 1:1
22b (32)
10
11
12
13
14
15
16
PhMe,
110
50
50
50
21b (64)
20c (n-Pr) PhMe,
22c (40)
21c (65)
22d (62)
21d (68)
110
PhMe,
110
20d
(n-C5H11)
PhMe,
110
PhMe,
110
a
20e (Ph)
PhMe,
110
21e:22e 1:3
22e (50)
PhMe,
110
50
21e (50), 22e
(40)
a
1
Ratio of isoxazolidine:amide determined by H NMR on the crude
reaction mixture.
lactam (Table 1, entry 15). The olefin protons at δ 6.9 and 5.90
ppm in the 1H NMR and the carboxylic carbons at
approximately 179−178 ppm in the 13C NMR support the
lactam structures (see below).
Nitrones on heating can rearrange to oxaziridines, and
oxaziridines can rearrange to amides.17 To verify the source of
the lactams, the corresponding oxaziridines, oxaziridine 23c (R
= n-Pr) and 23d (R = n-C5H11) were prepared as mixtures of
isomers by oxidation of dehydropyrrolidines (+)-19c and
Heating nitrone 20b (R = Et) under the optimized
conditions, toluene at 110 °C for 48 h, resulted in formation
of both the tricyclic isoxazolidine (−)-21b and the lactam
(−)-22b in a 1:1 ratio. Upon purification only the lactam
(−)-22b was isolated in 32% yield (Scheme 6, Table 1, entry
9). Under similar conditions nitrones (S)-20c (R = n-Pr) and
(S)-20d (R = n-C5H11) gave only the corresponding lactams
(−)-22c,d (Table 1, entries 11, and 13). Interestingly nitrone
(S)-20e (R = Ph) afforded a 1:3 mixture of isoxazolidine and
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(+)-19d with m-CPBA (Scheme 7). However, heating
oxaziridine 23c under the cycloaddition reaction conditions
(−)-21d by variation of the temperature and time were also
unsuccessful.
Because the Lewis acid can also coordinate to the nitrone, it
was thought that a bulky Lewis acid might preferentially
activate the α,β-unsaturated ester group in the nitrone. Indeed,
heating nitrone 20a (R = Me) with 10 mol % of commercially
available aluminum tert-butoxide [Al(OtBu)3] for 24 h gave the
desired tricyclic isoxazolidine (−)-21a in 25% yield (Table 1,
entry 5). The optimum conditions were heating for 72 h with
50 mol % of Al(OtBu)3 affording a 70% yield of (−)-21a,
(Table 1, entry 6). Significantly, when these conditions were
applied to nitrones 20b (R = Et), 20c (R = n-Pr), and 20d (R =
n-C5H11), none of the corresponding lactams 22 were detected,
but 72 to 96 h of heating was required (Table 1, entries 10, 12,
and 14). However, even under these conditions phenyl nitrone
20e gave about equal amounts of the isoxazolidine (−)-21e and
lactam (+)-22e (Table 1, entry 16).
Scheme 7
The reaction mixtures were treated with 5% HCl and
neutralization of the aqueous phase to give isoxazolidines
(−)-21a−c. Isoxazolidine (−)-21d (R = n-C5H11) failed to be
extracted into the aqueous phase and was isolated from the
toluene solution. Isoxazolidine (−)-21e (R1 = Ph) with
aqueous 5% HCl resulted in decomposition. Repeated washings
of the reaction mixture with water to remove the Al(OtBu)3,
resulted in a 1:1 mixture of (−)-21e and amide (+)-22d in 95%
combined yield, which were separated by chromatography
affording the isoxazolidine (−)-21e as a white solid in 50%
yield.
The X-ray crystallographic structure of (−)-21e (see
Supporting Information) reveals that the molecule is best
described as a C7ON tricyclic core with a pendant phenyl group
on C(3), and a carbomethoxy group on C(2). These groups are
both oriented “vertically” such that the C(10)−C(2)−C(3)−
C(12) dihedral angle is nearly zero (2.1°), and the phenyl and
carbomethoxy groups are oriented approximately parallel such
that planar faces of the carbomethoxy and the phenyl group are
oriented toward one another. The angle between the least-
squares fitted planes defined by the phenyl ring and by the
carbomethoxy group is 41.6° and is entirely the result of the
angle between the C(3)−C(12) and C(2)−C(10) bond
vectors. The planes defined by the phenyl and carbomethoxy
groups are nearly perpendicular to the C(2)−C(3) bond vector
(82.2° and 82.0°, respectively). The proximity of the
carbomethoxy group to the phenyl ring is further supported
by the upfield shift of the methyl protons of the carbomethoxy
group to δ 3.04 ppm compared to δ 3.68 ppm for this group in
isoxazolidines (−)-21a−d.
Heating isoxazolidine (−)-21a−d with 10 equiv of
methylmethanesulfonate in DCM for 48 h gave the quaternary
ammonium salts 24 in quantitative yield (Scheme 8). However,
(−)-21e (R = Ph) required 72 h. Attempts to increase the
reaction rate using higher boiling solvents such as benzene
resulted in decomposition. The salts were dissolved in water to
separate the excess methylmethanesulfonate from the iso-
xazolidinium salts 24, and the latter were recovered from the
aqueous solution by lyophilized. Cleavage of the N−O bond in
24 was accomplished by hydrogenolysis with palladium on
charcoal (5% Pd−C) to give ecgonine methyl ester derivatives
25 in excellent yield (Table 2). As can be seen from the results
summarized in Table 2, at 1 atm of H2 24a−c took 48 h for
completion (Table 2, entries 1, 3 and 5) and at 4 atm for 15−
30 h (Table 3, entries 2 and 4). Isoxazolidinium salt 24e (R =
Ph) at 1 atm of H2 for 48 h gave a complex mixture of products
resulted in no reaction. When 23c was refluxed in toluene for
96 h in the presence of a catalytic amount of peroxorhenium
complex, prepared by reacting 2 mol % MTO with UHP,
lactam (S)-(−)-22c was obtained in 51% yield (Scheme 7). By
contrast oxaziridine 23d afforded the lactam (−)-22d in 68%
yield after 48 h in the absence of the catalyst. Both lactams were
identical to those obtained on heating nitrones 20c and 20d
(Table 1, entries 11 and 13).
As shown in transition state TS-1 in Scheme 7 a possible
rationale for the formation of amide rather than isoxazolidine
assumes a steric interaction between the substituent at C-5 in
the cyclic nitrones and the carbomethoxy group inhibiting
cycloaddition and leading to oxaziridine formation. If this is
correct, the amount of the amide formed should increase with
increasing size of the C-5 substituent. Indeed nitrone 20a (R =
Me) gave only the isoxazolidine, while nitrone 20b (R = Et)
gave mixtures of isoxazolidine and amide. Nitrones 20c (n-Pr)
and 20d (R = n-C5H11) gave only the amides (Table 1, entries
2, 9, 11, and 13). However, nitrone 20e (R = Ph) having the
bulky C-5 phenyl group gave both isoxazolidine and amide
(Table 1, entry 15). The reason for this is not readily apparent
but may be related to a stabilizing interaction between the
phenyl group and the antibonding orbital of the carbonyl in the
carbomethoxy group at C-2.20
Nitrone 1,3-dipolar cycloadditions are favored by Lewis acids
that can coordinate to the α,β-unsaturated carbonyl moiety.20
Initial attempts using 10 mol % of Lewis acids such as BF3·OEt2
and Ti(OiPr)4 to catalyze the reaction of nitrone 20d (R =
C5H11) in toluene at 110 °C resulted in decomposition.
However, 10 mol % of La(OTf)3, Cu(OTf)3, or Sc(OTf)3
under similar conditions resulted in the formation of both
isoxazolidine (−)-21d and amide (−)-22d in about equal
amounts, but only the amide could be isolated in poor yield,
i.e., <30%. Higher amounts of these Lewis acids, 20 mol %,
resulted in decomposition. Attempts to improve the yield of
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Scheme 8
Table 3. Rearrangement of Isoxazolidinum Salts 24 to 26
and 27 in MeOH at 25 °C
ratio
27 (%
a
a
entry
(R =)
conditions
time, h
48
24:26
yield)
1
2
24a (Me) 5% Pd−C
NR
1:1 MeOH/Et3N
18
27a
(95)
3
4
6
1:1 MeOH/pyridine
1:1 MeOH/pyridine
5% Pd−C/MeOH
18
48
48
NR
NR
24b (Et)
24d (n-
C5H11)
1:0.48 27d
b
(32)
7
8
5% Pd−C
5% Pd−C
96
48
(reflux)
1:0.52
1:0.5
9
5% Pd−C
48 and
1:0.5
27d
c
48
9
MeOH
48
48
48
48
18
NR
NR
NR
NR
d
10
11
12
13
pyridine
1:1 MeOH/pyridine
MeOH/satd K2CO3
1:1 MeOH/Et3N
Table 2. Hydrogenolysis of Isoxazolidinium Salts 24 with 5%
Pd−C in MeOH
27d
(83)
27d
(100)
27d
(84)
entry
24 (R =)
24a (Me)
H2, atm time, h
25 (% yield)
25a (100)
14
15
1:1 MeOH/Et3N
4
6
1
2
3
4
5
6
7
8
9
1
4
1
4
1
1
4
1
1
48
30
48
15
48
48
6
5% Pd−C, 4 atm H2
25a (100)
e
24b (Et)
25b (100)
f
16
17
MeCN, DABCO
18
6
25b (100)
24c (n-Pr)
25c (100)
5% Pd−C, 4 atm H2/1
25d
(99)
g
a
atm H2
24d (n-C5H11)
24d (n-C5H11)
24e (Ph)
(+)-24d [27, (32%)]
25d (100)
18
19
24e (Ph)
5% Pd−C
1:1 MeOH/pyridine
48
18
NR
27e
(84)
48
complex mixture
b
10
25e (<80)
20
1:1 MeOH/Et3N
18
27e
(81)
a
b
See Table 3 and discussion below. Mixture containing predom-
inantly 25e and other unidentified materials.
a
Determined by 1H NMR on the crude reaction mixture by
integration of the protons at δ 5.2 ppm for 26 and δ 5.29 ppm for
b
and less than 20% of 25e was formed (Table 2, entry 8).
Hydrogenation for 10 h (Table 2, entry 9) gave mostly 25e, but
it could not be purified and was taken on to the next step
without additional purification. Unexpectedly isoxazolidinium
salt 24d (R = n-C5H11) at 1 atm of H2 and 48 h gave bridged
bicyclo[4.2.1]isoxazolidine salt 26d (Table 2, entry 6). Its
formation will be discussed in detail below. Fortunately, at 4
atm of H2 and 6 h 24d gave a quantitative yield of alcohol
(+)-25d (Table 2, entry 7).
24d. Isolated by treatment of the crude reaction mixture with satd
c
K2CO3. Reaction run for 48 h and a second addition of 5% Pd.
d
e
f
g
Pyridine as the solvent. See Table 2. DABCO, 4 equiv. Pd
saturated with H2 at 4 atm followed by addition of 24d at 1 atm H2.
there was no reaction (Table 3, entries 10, 11 and 12).
However, with Et3N an 83% isolated yield of (+)-27d was
obtained (Table 2, entries 13 and 14). Similar results were
observed for (−)-24a (R = Me) (Table 3, entry 2). Whereas
isoxazolidinium salts 24a (R = Me) and 24b (R = Et) did not
react with pyridine, (+)-24e (R = Ph) did affording (+)-27e in
84% yield (Table 3, entries 3. Four and 15). Isoxazolidines are
important intermediates in the synthesis of natural product and
other biologically important compounds.21 Bridged
bicyclo[4.2.1]isoxazolidines such as (+)-27 are rare, with the
few known examples being employed in the synthesis of
glycoside inhibitors22,23 and cocaine analogues.6e
The reason that (+)-24d (R = n-C5H11) is the only
isoxazolidinum salt to form bridged bicyclo[4.2.1]isoxazolidine
(+)-27d under the hydrogenolysis conditions, 5% Pd−C at 1
atm of H2 but cleavage of the N−O bond to give alcohol
(+)-25d at 4 atm of H2 is not readily apparent (Table 1, entries
6 and 7). Furthermore, as can be seen from Table 3, entry 6,
this transformation does not require hydrogen. Palladium-
catalyzed dehydrogenation of secondary alcohols to ketones,24
oximes to nitriles,25 amines to imines,26 and aromatization of
cyclic dienes27 is well-known. We speculate that the C-1 n-
pentyl group in (+)-24d sterically inhibits coordination of the
Pd−H2 species with the N−O bond favoring coordination at
In the preceding section hydrogenolysis of isoxazolidinium
salt 24d (R = n-C5H11) at 1 atm gave a new compound
1
tentatively identified as salt 26d. In the crude H NMR two
new doubles appeared at δ 5.2 (J = 8.8 Hz) and δ 1.88 (J = 12
Hz). The ratio of 24d:26d determined by 1H NMR was
estimated to be 1:0.5 (Table 2, entry 6). Treatment of the
mixture with satd K2CO3 solution gave a 32% isolated yield of
an oil identified as bridged bicyclo[4.2.1]isoxazolidine
(E,1S,6S)-(+)-27d based on 2D NMR analysis (Scheme 9).
1
The H NMR of (+)-27d is characterized by doublets at δ 5.2
ppm (J = 8.8 Hz) and at 1.88 ppm (J = 2 Hz) for the C-1
proton and C-9 protons. In the 13C NMR the C-2 and C-3
olefinic carbons are at δ 157.4 and δ 131.8 ppm, respectively,
and there were seven methylene carbons and two methine units
(see Experimental Section).
A reasonable mechanism for the formation of (+)-27d is
base-catalyzed elimination of the C-2 carbomethoxy proton as
shown in Scheme 9. The driving force for this reaction is relief
of ring strain and formation of the C−C double bond. When
(+)-24d (R = n-C5H11) was treated with pyridine or K2CO3
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Scheme 9
the C-2 carbomethoxy group leading to (+)-27d. At higher
pressures of H2 Pd is likely to be completely saturated,
preventing coordination with the CO2Me group resulting in
N−O bond cleavage to give alcohol (+)-25d. Indeed when the
catalyst was hydrogenated in MeOH at 4 atm for 12 h to
saturate the Pd and the reaction vessel exposed to the
atmosphere, followed by addition of (+)-24d and hydro-
genation at 1 atm of H2 for 6 h, a quantitative isolated yield of
alcohol (+)-25d was realized (Table 3, entry 17).
Cocaine C-1 Analogues. The first examples of C-1
substituted cocaine analogues were prepared by benzoylation
of the secondary alcohol in tropanes 25 with 1.5 equiv of
benzoyl chloride in pyridine at rt affording (−)-28a (R = Me),
(−)-28b (R = Et), (−)-28c (R = n-Pr), (+)-28d (R = n-C5H11),
and (+)-28e (R = Ph) as pale yellow oils in good to excellent
yields (Scheme 10).
studies of the hydrogenation of isoxazolidine (+)-24d. These
heterocycles are potentially useful new chiral scaffolds for
enantioselective synthesis. Our new methodology has the
potential for the enantioselective syntheses of a wide variety of
new and novel cocaine analogues not only having varied
substituents at the C-1 position, but at other positions as well
because of the diverse groups that can be introduced using
sulfinimine chemistry.
EXPERMENTAL SECTION
■
Ketal aldehydes 3-(2-methyl-1,3-dioxolan-2-yl)propanal (3a),11a 3-(2-
propyl-1,3-dioxolan-2-yl)propanal (3c),28 3-(2-phenyl-1,3-dioxolan-2-
yl)propanal (3e),12 and (SS)-(+)-3-(2-methyl-1,3-dioxolan-2-yl)-
propylidene-p-toluenesulfinamide (6a)11c were prepared as previously
described.
4-Hydroxy-N-methoxy-N-methylhexanamide (9b). Typical
Procedure. In a 100 mL, oven-dried, single-necked round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and argon
inlet were placed N,O-dimethyl hydroxylamine hydrochloride (2.9 g,
29.8 mmol) and dihydro-5-ethyllfuran-2(3H)-one (8b) (2.2 g, 19.3
mmol) in THF (96 mL), and the solution was cooled to −15 °C in an
salt−ice mixture. Isopropylmagnesuim chloride (2.0 M solution in
THF, 28.8 mL, 57.6 mmol) was added slowly via syringe, and the
reaction mixture was stirred at −20 °C for 20 min. At this time the
solution was quenched with satd NH4Cl solution (20 mL) and
extracted with EtOAc (3 × 25 mL). The combined organic phases
were washed with brine (2 × 50 mL), dried (MgSO4), and
concentrated. Flash chromatography (60% EtOAc/hexanes) gave
Scheme 10
1
2.87 g (85%) of a colorless oil: IR (neat) 3418, 1648 cm−1; H NMR
(CDCl3) δ 0.943 (t, J = 7.2 Hz, 3H), 1.49 (m, 2H), 1.72 (m, 1H), 1.85
(m, 1H), 2.58 (m, 3H), 3.18 (s, 3H), 3.54 (b, 1H), 3.69 (s, 3H); 13C
NMR (CDCl3) δ 9.9, 28.5, 30.4, 31.1, 61.2, 72.9, 82.0, 175.1. HRMS
calcd for C8H18NO3 (M + H) 176.1287, found 176.1279.
SUMMARY AND CONCLUSIONS
4-Hydroxy-N-methoxy N-methylheptamide (9c). Prepared
■
from γ-heptalactone. Flash chromatography (50% EtOAc in hexanes)
The first examples of cocaine analogues 28 having methyl,
ethyl, n-propyl, n-pentyl, and phenyl at the bridgehead or C-1
position of the cocaine tropane skeleton were prepared in nine
steps from sulfinimine-derived masked oxo-sulfinimines (+)-6
and (+)-7. The key step in the synthesis was a highly
stereoselective [3 + 2] cycloaddition reaction of α,β-
unsaturated pyrrolidine nitrones (S)-20. In the presence of
the Lewis acid Al(OtBu)3 the nitrones gave tricyclic
isoxazolidines (−)-21, which were transformed in three steps
to the cocaine analogues. In the absence of the Lewis acid the
nitrones gave lactams resulting from rearrangement of the
nitrone to an intermediate oxaziridine, which rearranged on
heating to the lactam. An unusual Pd- and base-promoted
rearrangement of methanesulfonate salts of isoxazolidine 24 to
bridge bicyclic[4.2.1] isoxazolidines (+)-27 was discovered in
1
afforded a clear oil: IR (film) 3440, 1640 cm−1; H NMR (CDCl3) δ
0.92 (t, J = 7.1 Hz, 3H), 1.45 (m, 4H), 1.72 (m, 1H), 1.84 (m, 1H),
2.57 (m, 3H), 3.18 (s, 3H), 3.64 (m, 1H), 3.69 (s, 3H); 13C NMR
(CDCl3) δ 14.1, 18.8, 28.5, 31.6, 32.2, 39.9, 61.2, 71.3, 175.1. HRMS
calcd for C9H20NO3 (M + H) 190.1443, found 190.1436.
4-Hydroxy-N-methoxy-N-methylnonanamide (9d). Prepared
from dihydro-5-pentylfuran-2(3H)-one. Flash chromatography (40%
1
EtOAc/hexanes) gave a colorless oil: IR (neat) 3418, 1648 cm−1; H
NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.31 (b, 5H), 14.3(b, 3H),
1.70 (m, 1H), 1.86 (m, 1H), 2.56 (m, 3H), 3.18 (s, 3H), 3.62 (b, 1H),
3.69 (s, 3H); 13C NMR (CDCl3) δ 14.0, 22.6, 25.3, 28.4, 31.5, 31.8,
32.1, 37.6, 175.0. HRMS calcd for C11H24NO3 (M + H) 218.1756,
found 218.1753.
N-Methoxy-N-methyl-4-oxonohexanamide (10b). Typical
Procedure. In a 250 mL, oven-dried, single-necked round-bottom
flask equipped with a magnetic stirring bar, rubber septum, and argon
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inlet were placed IBX (13.44 g, 48 mmol) in dry EtOAc (80 mL, and
the mixture was cooled to 0 °C. A solution of 9b (2.8 g, 16 mmol) in
EtOAc (80 mL) was added, and the reaction mixture was refluxed for
3 h, cooled to rt, and filtered. The filter cake was washed with EtOAc
(2 × 30 mL), and the combined organic phase combined organic
phases were washed with brine (50 mL), dried (MgSO4), and
concentrated. Flash chromatography (40% EtOAc/hexanes) gave 2.07
NMR(CDCl3) δ 7.8, 29.1, 30.0, 37.9, 64.7, 110.8, 201,6. HRMS calcd
for C8H15O3 (M + H) 159.1021, found 159.1014.
3-(2-Pentyl-1,3-dixoxlan-2-yl)propanal (3d). Flash chromatog-
raphy (10% EtOAc/hexanes) gave a colorless oil: IR (neat) 1704, 1646
1
cm−1; H NMR (CDCl3) δ 0.86 (t, J = 6.8 Hz, 3H), 1.26 (m, 6H),
1.56 (m, 2H), 2.01 (t, J = 6.8 Hz, 2H), 2.42 (m, 2H), 3.90 (m, 4H),
9.69 (t, J = 2.72 Hz, 1H); 13C NMR(CDCl3) δ 14.0, 22.6, 23.6, 29.8,
32.0, 37.6, 38.3, 65.0, 111.0, 202.2. HRMS calcd for C11H21O3 (M +
H) 201.1491, found 201.1482.
1
g (75%) of a colorless oil: IR (neat) 1698, 1645 cm−1; H NMR
(CDCl3) δ 1.06 (t, J = 7.2 Hz, 3H), 2.50 (q, J = 7.3 Hz, 2H), 2.72 (b,
4H), 3.16 (s, 3H), 3.72 (s, 3H); 13C NMR (CDCl3) δ 7.6, 25.7, 32.0.
35.9, 36.0, 61.0, 173.1, 210.3. HRMS calcd for C8H16NO3 (M + H)
174.1130, found 174.1123.
(S)-(+)-3-(2-Propyl-1,3-dioxalan-2-yl)propylidene-p-toluene-
sulfinamide (6c). Typical Procedure. To a 500 mL round-
bottomed flask equipped with magnetic stirring bar and argon inlet
was placed 3c (2.22 g, 12.88 mmol) in dry CH2Cl2 (100 mL). (S)-
(+)-p-Toluenesulfinamide (1.99 g, 12.88 mmol) was added followed
by Ti(OEt)4 (14.71 g, 64.45 mmol), and the reaction was stirred at rt
for 24−48 h until complete. At this time, the reaction mixture was
cooled to 0 °C and then quenched with H2O (6 mL). After 5 min of
stirring, the solids were filtered, the filter cake was washed with DCM
(3 × 50 mL), and the combined organic phases were washed with
brine (100 mL), dried (MgSO4), and concentrated. Flash chromatog-
raphy (25% EtOAc/hexanes) gave 2.79 g (70%) of slightly yellow oil:
N-Methoxy-N-methyl-4-oxoheptamide (10c). Flash chroma-
tography (50% EtOAc in hexanes) afforded a clear oil: IR (film) 1715,
1
1640 cm−1; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.58 (m,
2H), 2.42 (t, J = 7.3 Hz, 2H), 2.71 (bm, 4H), 3.13 (s, 3H), 3.69 (s,
3H); 13C NMR (CDCl3) δ 13.6, 17.1, 25.6, 32.1, 36.3, 44.7, 61.0,
173.1, 209.8. HRMS calcd for C9H18NO3 (M + H) 188.1287, found
188.1279.
N-Methoxy-N-methyl-4-oxononanamide (10d). Flash chroma-
tography (20% EtOAc/hexanes) gave a colorless oil: IR (neat) 1698,
1
1645 cm−1; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.29 (m,
IR (film) 1625 cm−1; [α]20 +230.2 (c 0.6, CHCl3); 1H NMR
D
4H), 1.57 (m, 2H), 2.46 (t, J = 7.6 Hz, 2H), 2.73 (s, 4H), 3.16 (s, 3H),
3.72 (s, 3H); 13C NMR (CDCl3) δ 13.8, 22.4, 23.4, 25.7, 31.3, 32.1,
36.5, 42.9, 61.1, 173.2, 210.1. HRMS calcd for C11H22NO3 (M + H)
216.1600, found 216.1595
(CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H), 1.36 (m, 2H), 1.55 (m, 2H), 1.96
(m, 2H), 2.39 (s, 3H), 2.55 (m, 2H), 3.86 (m, 4H), 7.29 (bd, J = 7.8
Hz, 2H), 7.56 (bd, J = 8.1 Hz, 2H), 8.23 (t, J = 4.4 Hz, 1H); 13C NMR
(CDCl3) δ 14.3, 17.1, 30.5, 32.5, 39.7, 64.9, 65.0, 110.8, 124.6, 129.7,
141.6, 141.8, 167.3; HRMS calcd for C16H24NO3S (M + H) 310.1477,
found 310.1473.
N-Methoxy-N-methyl-3-(2-ethyl-1,3-dioxolan-2-yl)-
propanamide (11b). Typical Procedure. In a 250 mL, oven-dried,
single-necked round-bottom flask equipped with a magnetic stirring
bar and rubber septum were placed 10b (2.0 g, 11.56 mmol), ethylene
glycol (1.07 g, 17.34 mmol), PTSA.H2O (0.0679 g, 0.34 mmol), and
benzene (140 mL). The reaction mixture was refluxed using a Dean−
Stark column for 12 h and concentrated, and the residue was diluted
with EtOAc (100 mL). The organic phase was washed with satd
NaHCO3 (3 × 30 mL), H2O (2 × 20 mL), and brine (2 × 25 mL),
dried (MgSO4), and concentrated. Flash chromatography (40%
EtOAc/hexanes) gave 2.00 g (80%) of a colorless oil: IR (neat)
(S)-(+)-3-(2-Phenyl-1,3-dioxolan-2-yl)propylidene-p-toluene-
sulfinamide (6e). Flash chromatography (12% EtOAc/hexanes)
yielded 0.710 g (65%) of a slightly yellow oil: [α]20 +206.0 (c 1.30,
D
CHCl3); IR (neat) 3051, 1635, 1213 cm−1; 1H NMR (CDCl3) δ 2.16
(m, 2H) 2.33 (s, 3H), 2.53 (dt, J = 7.6 Hz, 4.4 Hz, 2H), 3.66 (m, 2H),
3.88 (m, 2H), 7.24 (m, 5H), 7.35 (m, 2H), 7.48 (d, J = 10.0 Hz, 2H),
8.18 (t, J = 5.5 Hz, 1H); 13C NMR (CDCl3) δ 21.4, 30.6, 35.9, 64.5,
109.5, 124.6, 125.6, 128.0, 128.2, 129.7, 141.5, 142.1, 167.1. HRMS
calcd for C19H21NNaO3S (M + Na) 366.1140, found 366.1139
(S)-(+)-3-(2-Ethyl-1,3-dioxolan-2-yl)propylidene-tert-butyl-
sulfinamide (7b). Typical Procedure. In a 250 mL, oven-dried,
single-necked round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon inlet were placed 3b (1.2 g, 7.59 mmol)
in THF (76 mL) and (S)-(+)-tert-butylsulfinamide (0.919 g, 7.59
mmol), and Ti(OEt)4 (5.19 g, 22.78 mmol) were added. The reaction
mixture was stirred at rt for 24 h, cooled to 0 °C, and quenched by
addition of brine solution (75 mL). The solution was filtered through
Celite, the filter cake was washed with EtOAc (2 × 75 mL), and the
combined organic phases were washed with brine (75 mL), dried
(MgSO4), and concentrated. Flash chromatography (25% EtOAc/
1
1642 cm−1; H NMR (CDCl3) δ (t, J = 7.6 Hz, 3H), 1.63 (q, J = 7.6
Hz, 2H), 1.96 (m, 2H), 2.47 (m, 2H), 3.15 (s, 3H), 3.67 (s, 3H), 3.93
(s, 4H); 13C NMR (CDCl3) δ 7.9, 26.4, 29.8, 30.9, 32.3, 35.9, 36.1,
61.2, 64.4, 111.3, 174.4. HRMS calcd for C10H20NO4 (M + H)
218.1392, found 218.1386.
N-Methoxy-N-methyl-3-(2-propyl-1,3-dioxolan-2-yl)-
propanamide (11c). Flash chromatography (70% EtOAc in hexanes)
afforded a clear oil: IR (film) 1640 cm−1; 1H NMR (CDCl3) δ 0.86 (t,
J = 7.3 Hz, 3H), 1.35 (m, 2H), 1.55 (m, 2H), 1.93 (m, 2H), 2.44 (t, J =
7.6 Hz, 2H), 3.12 (s, 3H), 3.64 (s, 3H), 3.89 (m, 4H); 13C NMR
(CDCl3) δ 14.2, 16.9, 26.3, 31.3, 32.2, 39.3, 61.1, 64.7, 110.9, 174.3.
HRMS calcd for C11H22NO4 (M + H) 232.1549, found 232.1544.
N-Methoxy-N-methyl-3-(2-pentyl-1,3-dioxolan-2-yl)-
propanamide (11d). Flash chromatography (15% EtOAc/hexanes)
afforded 75% of a colorless oil: IR (neat) 1642 cm−1; 1H NMR
(CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.31 (b, 6H), 1.61 (m, 2H), 1.97
(m, 2H), 2.48 (m, 2H), 3.17 (s, 3H), 3.68 (s, 3H), 3.94 (s, 4H); 13C
NMR (CDCl3) δ 13.9, 22.5, 23.3, 26.4, 31.3, 32.0, 32.2, 37.0, 61.1,
64.8, 111.1, 174.4. HRMS calcd for C13H26NO4 (M + H) 260.1862,
found 260.1860.
hexanes) gave 1.58 g (80%) of a colorless oil: [α]20 +163.4 (c 2.085,
D
CHCl3); IR (neat) 1623 cm−1; 1H NMR (CDCl3) 0.917 (t, J = 7.6 Hz,
3H), 1.18 (s, 9H), 1.64 (m, 3H), 1.97 (m, 2H), 2.57 (m, 2H), 3.94 (s,
4H), 8.08 (t, J = 4.4 Hz, 1H); 13C NMR (CDCl3) 8.0, 22.1, 30.0, 30.5,
31.9, 56.3, 64.9, 65.0, 111.0, 169.3. HRMS calcd for C12H24NO3S (M
+ H) 262.1477, found 262.1477
(S)-(+)-3-(2-Methyl-1,3-dioxalan-2-yl)propylidene-tert-butyl-
sulfinamide (7a). Flash chromatography (40% EtOAc/hexanes) gave
85% of a clear oil: [α]20D +228.9 (c 1.59, CHCl3); 1H NMR (CDCl3)
δ 1.19 (s, 9H), 1.35 (s, 3H), 2.01 (m, 2H), 2.61 (m, 2H), 3.95 (m,
4H), 8.09 (t, J = 4.8 Hz, 1H); 13C NMR (CDCl3) δ 22.2, 23.9, 30.7,
34.4, 56.3, 64.5, 64.6, 109.0, 169.1. HRMS calcd for C11H22NO3S (M
+ H) 248.3623, found 248.3620.
3-(2-ethyl-1,3-dixoxlan-2-yl)propanal (3b).29 Typical Proce-
dure. In a 100 mL, oven-dried, single-necked round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and argon inlet,
was placed LiAlH4 (0.525 g, 13.82 mmol) in THF (40 mL), and the
reaction mixture was cooled to −78 °C. A solution of 11b (2.0 g, 9.21
mmol) in THF (52 mL) was added slowly, and the reaction mixture
was stirred at −78 °C for 1 h, quenched with H2O (50 mL), and
extracted with EtOAc (3 × 75 mL). The combined organic phases
were washed with H2O (2 × 50 mL) and brine (2 × 30 mL), dried
(MgSO4), and concentrated. Flash chromatography (25% EtOAc/
hexanes) gave 1.23 g (85%) of a colorless oil: IR (neat) 1704, 1646
(S)-(+)-3-(2-Pentyl-1,3-dioxolan-2-yl)propylidene-tert-butyl-
sulfinamide (7d). Flash chromatography (25% EtOAc/hexanes) gave
1.59 g (70%) of a colorless oil: [α]20 +156.6 (c 3.56, CHCl3); IR
D
(neat) 1623 cm−1; 1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.18
(s, 9H), 1.31 (m, 6H), 1.59 (m, 2H), 1.98 (m, 2H), 2.57 (m, 2H), 3.94
(m, 4H), 8.08 (t, J = 4.4 Hz, 1H); 13C NMR(CDCl3) δ 13.9, 22.2,
22.4, 23.4, 30.6, 31.9, 32.4, 37.2, 56.4, 64.8, 64.9, 110.8, 169.3. HRMS
calcd for C15H30NO3S (M + H) 304.1946, found 304.1945.
1
cm−1; H NMR (CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.57 (m, 2H),
2.00 (m, 2H), 2.41 (m, 2H), 3.90 (s, 4H), 9.67 (t, J = 1.6, 1H); 13C
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(S)-(+)-3-(2-Phenyl-1,3-dioxalan-2-yl)propylidene-tert-butyl-
sulfinamide (7e). Flash chromatography (40% EtOAc/hexanes) gave
(SS,3S)-(+)-Methyl N-(tert-Butylsulfinyl)-3-amino-5-(2-pentyl-
1,3-dioxolan-2-yl)pentanoate (13d). Flash chromatography (70%
85% of a white solid: mp 60−61 °C; [α]20 +155.5 (c 0.55, CHCl3);
EtOAc/hexanes) gave a colorless oil: [α]20 +34.8 (c 1.375, CHCl3);
D
D
1
IR (neat) 1741 cm−1; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H),
1H NMR (CDCl3) δ 1.17 (s, 3H), 2.24 (m, 2H), 2.60 (m, 2H), 3.78
1.21 (s, 9H), 1.27 (m, 6H), 1.55 (m, 3H), 1.62 (m, 1H), 2.61 (dd, J =
16.1, 5.6 Hz, 1H), 2.79 (dd, J = 16.1, 5.6 Hz, 1H), 3.53 (b, 1H), 3.68
(s, 3H), 3.92 (m, 4H), 4.18 (d, J = 8.8 Hz, 1H); 13C NMR(CDCl3) δ
13.9. 22.5, 22.6, 23.4, 29.8, 31.9, 33.2, 37.0, 40.3, 51.6, 54.0, 55.8, 64.8
(2 C’s), 111.4, 172.2. HRMS calcd for C18H36NO5S (M + H)
378.2314, found 378.2314.
(m, 2H), 4.02 (m, 2H), 7.35 (m, 3H), 7.45 (m, 2H), 8.08 (t, J = 4.4
Hz, 1H); 13C NMR (CDCl3) δ 22.3, 30.7, 35.9, 56.5, 64.5, 64.6, 109.6,
125.6, 128.1, 128.2, 142.1, 169.2. HRMS calcd for C16H24NO3S (M +
H) 310.1477, found 310.1477.
(SS,3S)-(+)-Methyl N-(p-Toluenesulfinyl)-3-amino-5-(2-meth-
yl-1,3-dioxolan-2-yl)pentanoate (12a). Typical Procedure. To a
500 mL round-bottomed flask equipped with magnetic stirring bar and
argon inlet was added NaHMDS (53.63 mL, 53.63 mmol, 1.0 M
solution in THF) in anhydrous ether (300 mL). To this solution
methyl acetate (3.61 g, 48.75 mmol) was added dropwise at −78 °C
slowly via syringe, and the reaction mixture was stirred at this
temperature for 1 h. At this time (+)-6a (5.48 g, 19.50 mmol) in THF
(20 mL) was added to the above solution slowly via cannula. After 2 h
of stirring at −78 °C, the reaction mixture was quenched by adding
satd NH4Cl solution (30 mL), and H2O (100 mL) was added. The
phases were separated, and the aqueous phase was extracted with
EtOAc (3 × 100 mL). The combined organic phases were washed
with brine (100 mL), dried (MgSO4), and concentrated. Flash
chromatography (hexanes/EtOAc, 50:50) gave 6.92 g (75%) of a clear
(SS,3S)-(+)-Methyl N-(tert-Butylsulfinyl)-3-amino-5-(2-phe-
nyl-1,3-dioxolan-2- yl)pentanoate (13e). Flash chromatography
(hexanes/EtOAc, 50:50) gave 0.60 g (93%) of a clear oil (dr >99:1):
1
IR (film) 3230, 1740 cm−1; [α]20 +31.3 (c 2.35, CHCl3); H NMR
D
(CDCl3) δ 1.19 (s, 9H), 1.62 (m, 2H), 1.94 (m, 1H), 2.03 (m, 1H),
2.65 (m, 2H), 3.55 (m, 1H), 3.65 (s, 3H), 3.75 (m, 2H), 4.00 (m, 2H),
4.09 (d, J = 8.8 Hz, 1H), 7.32 (m, 3H), 7.41 (m, 2H); 13C NMR
(CDCl3) δ 22.5, 29.4, 36.5, 40.2, 51.5, 53.7, 55.7, 64.3, 64.4, 109.9,
125.4, 127.7, 128.0, 142.2, 172.1. HRMS calcd for C19H30NO5S
384.1845, found 384.1842.
(Ss,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-methyl-1,3-di-
oxolan-2-yl)pentanal (14a). Typical Procedure. In a 250 mL,
oven-dried, single-neck round-bottomed flask equipped with magnetic
stirring bar, and a rubber septum was placed (Ss,3S)-(+)-12a (2.64 g,
7.42 mmol) in toluene (75 mL). The solution was cooled to −78 °C,
and diisobutylaluminumhydride (13.36 mL, 13.36 mmol, 1.0 M
solution in toluene) was added slowly via syringe. After 1 h of stirring,
the reaction mixture was quenched with saturated aqueous NH4Cl (15
mL) at −78 °C and warmed to rt. The reaction mixture was diluted
with EtOAc (50 mL) and water (40 mL). This mixture was filtered
through a Celite pad, and the aqueous phase was extracted with EtOAc
(3 × 60 mL). The combined organic phases were washed with brine
(100 mL), dried (MgSO4), and concentrated. Chromatography (80%
oil (dr >99:1): IR (film) 3230, 1740 cm−1; [α]20 +80.4 (c 1.49,
D
1
CHCl3); H NMR (CDCl3) δ 1.32 (s, 3H), 1.73 (m, 3H), 1.87 (m,
1H), 2.40 (s, 3H), 2.60 (dq, J = 5.4 Hz, J = 16.4 Hz, 2H), 3.65 (s, 3H),
3.68 (m, 1H), 3.94 (m, 4H), 4.62 (d, J = 8.8 Hz, 1H), 7.28 (bd, J = 8.4
Hz, 2H), 7.57 (td, J = 1.6 Hz, J = 8.0 Hz, 2H); 13C NMR(CDCl3) δ
21.3,23.9, 30.0, 35.4, 40.5, 51.7, 52.6, 64.6, 64.7, 109.7, 125.4, 129.5,
41.3, 142.4, 171.9. HRMS calcd for C17H25NNaO5S (M + Na)
378.1351, found 378.1333.
(SS,3S)-(+)-Methyl N-(p-Toluenesulfinyl)-3-amino-5-(2-prop-
yl-1,3-dioxolan-2-yl)pentanoate (12c). Flash chromatography
(hexanes/EtOAc, 50:50) gave a clear oil (dr >99:1): IR (film) 3226,
1736, cm−1; [α]20D +66.8 (c 0.9, CHCl3); 1H NMR (CDCl3) δ 0.91 (t,
J = 7.3 Hz, 3H), 1.38 (m, 2H), 1.58 (m, 2H), 1.69 (m, 3H), 1.83 (m,
1H), 2.40 (s, 3H), 2.60 (dq, J = 16.6 Hz, J = 5.6 Hz, 2H), 3.65 (s, 3H),
3.68 (m, 1H), 3.92 (bs, 4H), 4.61 (d, J = 9.0 Hz, 1H), 7.28 (bd, J = 8.1
Hz, 2H), 7.58 (td, J = 8.1 Hz, J = 1.7 Hz, 2H); 13C NMR (CDCl3) δ
14.3, 17.1, 21.3, 29.8, 33.3, 39.4, 40.5, 51.6, 52.7, 64.9 (2C), 111.4,
125.4, 129.5, 141.3, 142.4, 171.9. HRMS calcd for C19H29NNaO5S (M
+ Na) 406.1664, found 406.1665.
EtOAc/hexanes) afforded 2.3 g (95%) of a clear oil: IR (film) 3424,
1
1725 cm−1; [α]20 +78.3 (c 1.68, CHCl3); H NMR (CDCl3) δ 1.31
D
(s, 3H), 1.75 (m, 4H), 2.39 (s, 3H), 2.68 (m, 1H), 3.76 (m, 1H), 3.93
(m, 4H), 4.43 (d, J = 8.8 Hz, 1H), 7.27 (bd, J = 8.0 Hz, 2H), 7.54 (td,
J = 2.0 Hz, J = 8.0 Hz, 2H), 9.61 (t, J = 1.2 Hz, 1H); 13C NMR
(CDCl3) δ 21.3, 23.8, 30.5, 35.4, 49.9, 50.6, 64.6, 64.7, 109.6, 125.4,
129.5, 141.5, 141.9, 200.7. HRMS calcd for C16H24NO4S (M + H)
326.1421, found 326.1424.
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-propyl-1,3-di-
oxolan-2-yl)pentanal (14c). Chromatography (80% EtOAc/hex-
anes) afforded a clear oil: IR (film) 3440, 1721 cm−1; [α]20D +73.7 (c
1.56, CHCl3); 1H NMR (CDCl3) δ 0.91 (t, J = 7.3 Hz, 3H), 1.37 (m,
2H), 1.57 (m, 2H), 1.69 (m, 3H), 1.83 (m, 1H), 2.40 (s, 3H), 2.67 (m,
2H), 3.75 (m, 1H), 3.92 (bs, 4H), 4.41 (d, J = 8.8 Hz, 1H), 7.28 (bd, J
= 7.8 Hz, 2H), 7.55 (td, J = 8.1 Hz, J = 1.7 Hz, 2H); 13C NMR
(CDCl3) δ 14.3, 17.1, 21.3, 30.3, 33.2, 39.4, 49.9, 50.7, 64.9(2C),
111.3, 125.4, 129.5, 141.4, 142.0, 200.7; HRMS calcd for
C18H27NNaO4S (M + Na) 376.1558, found 376.1557.
(SS,3S)-(+)-Methyl N-(p-Toluenesulfinyl)-3-amino-5-(2-phe-
nyl-1,3-dioxolan-2-yl)pentanoate (12e). Flash chromatography
(hexanes/EtOAc, 50:50) gave a clear oil (dr >99:1): IR (film) 3230,
1
1740 cm−1; [α]20 +62.6 (c 1.02, CHCl3); H NMR (CDCl3) δ 1.62
D
(m, 1H), 1.94 (m, 1H), 2.01 (m, 1H), 2.32 (s, 3H), 2.49 (m, 2H), 3.54
(s, 3H), 3.61 (m, 1H), 3.67 (m, 2H), 3.92 (m, 2H), 4.50 (d, J = 9.2
Hz, 1H), 7.23 (m, 5H), 7.37 (m, 3H), 7.47 (m, 2H); 13C NMR
(CDCl3) δ 21.3, 29.5, 36.6, 40.6, 51.5, 52.5, 64.4, 64.5, 109.9, 125.4,
125.5, 127.8, 128.1, 129.4, 141.1, 142.3, 142.4, 171.7. HRMS calcd for
C22H28NO5S (M + H) 418.1688, found 418.1687.
(SS,3S)-(+)-N-(p-Toluenesulfinyl)-3-amino-5-(2-phenyl-1,3-di-
oxolan-2-yl)pentanal (14e). Chromatography afforded a clear oil:
(SS,3S)-(+)-Methyl N-(tert-Butylsulfinyl)-3-amino-5-(2-meth-
yl-1,3-dioxolan-2-yl)pentanoate (13a). Flash chromatography
1
IR (film) 3430, 1730 cm−1; [α]20 +69.3 (c 2.0, CHCl3); H NMR
D
(CDCl3) δ 1.63 (m, 2H), 1.88 (m, 1H), 2.15 (m, 1H), 2.32 (s, 3H),
2.56 (dt, J = 5.4 Hz, J = 1.2 Hz, 2H), 3.67 (m, 3H), 3.93 (m, 2H), 4.33
(d, J = 8.8 Hz, 1H), 7.18 − 7.28 (m, 5H), 7.36 (m, 2H), 7.45 (m, 2H);
13C NMR (CDCl3) δ 21.3, 30.1, 36.6, 49.9, 50.5, 64.4, 64.5, 109.9,
125.4, 125.5, 127.9, 128.1, 129.5, 141.3, 141.9, 142.2, 200.7. HRMS
calcd for C21H26NO4S (M + H) 388.1583. A satisfactory HRMS could
not be obtained due to decomposition.
(hexanes/EtOAc, 50:50) gave a clear oil (dr >99:1): IR (film) 3235,
1
1730 cm−1; [α]20 +44.0 (c 1.78, CHCl3); H NMR (CDCl3) δ 1.19
D
(s, 9H), 1.27 (s, 3H), 1.63 (m, 3H), 1.78 (m, 1H), 2.68 (m, 2H), 3.54
(m, 1H), 3.66 (s, 3H), 3.91 (m, 4H), 4.16 (d, J = 8.4 Hz, 1H); 13C
NMR (CDCl3) δ 22.5, 23.6, 29.9, 35.3, 40.2, 51.5, 53.8, 55.7, 64.4,
64.5, 109.5, 172.1. HRMS calcd for (M + H) C14H28NO5S 322.1688,
found 322.1682.
(SS,3S)-(+)-Methyl N-(tert-butylsulfinyl)-3-amino-5-(2-ethyl-
1,3-dioxolan-2-yl)pentanoate (13b). Flash chromatography (80%
EtOAc/hexanes) gave a colorless oil: [α]20D +29.2 (c 1.60, CHCl3); IR
(neat) 1741 cm−1; 1H NMR (CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.21
(s, 9H), 1.60 (m, 5H), 1.79 (m, 1H), 2.62 (dd, J = 16.0, 5.2 Hz, 1H),
2.79 (dd, J = 16.0, 5.2 Hz, 1H), 3.53 (b, 1H), 3.68 (s, 3H), 3.92 (s,
4H), 4.17 (d, J = 8.8 Hz, 1H); 13C NMR (CDCl3) δ 8.0, 22.6, 29.7,
32.8, 40.3, 51.6, 54.0, 55.8, 64.8, 64.9, 111.6, 172.2. HRMS calcd for
C15H30NO5S (M + H) 336.1845, found 336.1837.
(SS,3S)-(+)-N-(tert-Butylsulfinyl)-3-amino-5-(2-ethyl-1,3-diox-
olan-2yl)pentanal (15b). Typical Procedure. In a 100 mL, oven-
dried, single-necked round-bottom flask equipped with magnetic
stirring bar and rubber septum was placed (+)-7 (1.84 g, 5.49 mmol)
in toluene (55 mL), and the solution was cooled to −78 °C. DIBAL-H
in toluene (1.0 M solution in toluene, 9.9 mL, 9.88 mmol) was added
slowly via syringe, and the solution was stirred for 10 min at −78 °C,
and quenched by the addition of satd NH4Cl (30 mL). The solution
was extracted with EtOAc (3 × 30 mL), dried (MgSO4), and
2353
dx.doi.org/10.1021/jo202652f | J. Org. Chem. 2012, 77, 2345−2359

The Journal of Organic Chemistry
Article
concentrated. Flash chromatography (90% EtOAc/hexanes) provided
111.3, 124.0, 125.5, 129.5, 141.3, 141.9, 144.2, 166.4. HRMS calcd for
C21H31NNaO5S (M + Na) 432.1821, found 432.1820.
1.25 g (75%) of colorless oil: [α]20D +35.5 (c 1.46, CHCl3); IR (film)
1
3435, 1723 cm−1; H NMR (CDCl3) δ 0.89 (t, J = 7.6 Hz, 3H), 1.20
(SS,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-
phenyl-1,3-dioxolan-2-yl)-hept-2-enoate (16e). Chromatography
(50% EtOAc/hexanes) afforded 95% of a colorless oil: IR (film) 3440,
1725, 1660 cm−1; [α]20D +35.4 (c 0.87, CHCl3); 1H NMR (CDCl3) δ
1.56 (m, 1H), 1.67 (m, 1H), 1.98 (m, 1H), 2.05 (m, 1H), 2.26 (m,
1H), 2.34 (m, 1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s, 3H), 3.75 (m,
2H), 4.00 (m, 2H), 4.04 (d, J = 8.0 Hz, 1H), 5.77 (td, J = 15.6 Hz, J =
1.6 Hz, 1H), 6.77 (td, J = 15.7 Hz, J = 7.6 Hz, 1H), 7.26 − 7.35 (m,
5H), 7.43 (m, 2H), 7.54 (m, 2H); 13C NMR (CDCl3) δ δ 21.3, 29.3,
36.3, 39.1, 51.4, 53.3, 64.4, 64.5, 110.0, 123.9, 125.5, 125.6, 127.9,
128.1, 129.4, 141.3, 141.9, 142.2, 144.2, 166.4. HRMS calcd for
C24H30NO5S (M + H) 444.1845, found 444.1841.
(s, 9H), 1.65 (m, 5H), 1.80 (m, 1H), 2.89 (d, J = 5.6 Hz, 2H), 3.62 (b,
1H), 3.75 (d, J = 8.8 Hz, 1H), 3.93 (s, 4H), 9.78 (s, 1H); 13C NMR
(CDCl3) δ 8.0, 22.5, 29.7, 30.0, 32.7, 49.8, 52.8, 55.8, 64.8 (2 C’s),
111.5, 200.9; HRMS calcd for C14H28NO4S (M + H) 306.1739, found
306.1737.
(SS,3S)-(+)-N-(tert-Butylsulfinyl)-3-amino-5-(2-methyl-1,3-di-
oxolan-2-yl)pentanal (15a). Chromatography (80% EtOAc/hex-
anes) afforded a clear oil: IR (film) 3435, 1725 cm−1; [α]20 +43.0 (c
D
1
1.85, CHCl3); H NMR (CDCl3) δ 1.18 (s, 9H), 1.28 (s, 3H), 1.67
(m, 3H), 1.81 (m, 1H), 2.86 (dd, J = 5.4 Hz, J = 1.0 Hz, 2H), 3.62 (m,
1H), 3.75 (d, J = 8.8 Hz, 1H), 3.91 (m, 4H), 9.76 (bs, 1H); 13C NMR
(CDCl3) δ 22.6, 23.8, 30.3, 35.5, 49.9, 52.8, 55.9, 64.5, 64.6, 109.6,
200.9. HRMS calcd for C13H26NO4S (M + H) 292.1583, found
292.1580.
(SS,5S,2E)-(+)-Methyl-N-(tert-butylsulfinyl)-5-amino-7-(2-
methyl-1,3-dioxolan-2-yl)-hept-2-enoate (17a). Chromatography
(80% EtOAc/hexanes) afforded 95% of a clear oil. The product was
isolated as 95:5 mixture of E:Z isomers: IR (film) 3430, 1720, 1650
(SS,3S)-(+)-N-(-tert-Butylsulfinyl)-3-amino-5-(2-pentyl-1,3-di-
oxolan-2yl)pentanal (15d). Flash chromatography (90% EtOAc/
hexanes) gave a colorless oil: [α]20D +32.5 (c 1.64, CHCl3); IR (film)
1
cm−1; [α]20 +20.3 (c 0.87, CHCl3); H NMR (CDCl3) δ 1.16 (s,
D
9H), 1.25 (s, 3H), 1.51 (m, 1H), 1.63 (m, 2H), 1.76 (m, 1H), 2.54 (m,
2H), 3.17 (d, J = 7.6 Hz, 1 H), 3.35 (m, 1H), 3.68 (s, 3H), 3.89 (m,
4H), 5.89 (bd, J = 16.0 Hz, 1H), 6.87 (m, 1H); 13C NMR (CDCl3) δ
22.5, 23.7, 29.5, 35.1, 39.2, 51.4, 55.7, 55.9, 64.5, 64.6, 109.6, 124.3,
144.0, 166.4. HRMS calcd for (M + H) C16H30NO5S 348.1845, found
348.1841.
1
3435, 1723 cm−1; H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.20
(s, 9H), 1.28 (m, 6H), 1.63 (b, 5H), 1.772 (b, 1H), 2.89 (d, J = 5.6 Hz,
2H), 3.62 (b, 1H), 3.75 (d, J = 8.8 Hz, 1H), 3.92 (m, 4H), 9.78 (s,
1H); 13C NMR(CDCl3) δ 13.9, 22.6, 23.5, 30.1, 32.0, 33.3, 37.1, 50.0,
53.0, 56.0, 64.8, 64.9, 111.4, 201.0. HRMS calcd for C17H34NO4S (M
+ H) 348.2209, found 348.2208.
(SS,5S,2E)-(+)-Methyl-N-(-tert-butylsulfinyl)-5-amino-7-(2-
ethyl-1,3-dioxolan-2yl)-hept-2-enoate (17b). Flash chromatog-
(SS,3S)-(+)-N-(tert-Butylsulfinyl)-3-amino-5-(2-phenyl-1,3-di-
oxolan-2-yl)pentanal (15e). Chromatography (80% EtOAc/hex-
raphy (80% EtOAc/hexanes) afforded 93% of a colorless oil: [α]20
D
1
1
anes) afforded a clear oil: [α]20 +32.5 (c 1.77, CHCl3); H NMR
+20.0 (c 1.74, CHCl3); IR (film) 3428, 1716, 1651 cm−1; H NMR
D
(CDCl3) δ 1.18 (s, 9H), 1.66 (m, 1H), 1.93 (m, 1H), 2.06 (m, 1H),
2.83 (dd, J = 5.4 Hz, J = 1.0 Hz, 2H), 3.63 (m, 1H), 3.68 (d, J = 8.4
Hz, 1H), 3.76 (m, 2H), 3.99 (m, 2H), 7.33 (m, 3H), 7.41 (m, 2H),
9.74 (bs, 1H); 13C NMR (CDCl3) δ 22.6, 29.9, 36.7, 49.9, 52.7, 55.9,
64.4, 64.5, 109.9, 125.5, 127.9, 128.1, 142.2, 200.9. HRMS calcd for
(M + H) C18H28NO4S 354.1739. A satisfactory HRMS could not be
obtained due to decomposition.
(SS,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-
methyl-1,3-dioxolan-2-yl)-hept-2-enoate (16a). Typical Proce-
dure. In a 50 mL, oven-dried, single-neck round-bottomed flask
equipped with magnetic stirring bar, and a rubber septum was placed
trimethylphosphonoacetate (2.11 g, 11.60 mmol) in anhydrous
acetonitrile (20 mL) under argon. To this solution was added DBU
(1.76 g, 11.60 mmol) at rt, and the solution was stirred for 15 min. At
this time, a solution of (+)-14a (1.89 g, 5.80 mmol) in dry acetonitrile
(20 mL) was added to the mixture via cannula, and the reaction
mixture was monitored for completion by TLC (typically 2 h). At this
time the reaction mixture was quenched by addition of water (80 mL),
the phases were separated, and the aqueous phase was extracted with
EtOAc (4 × 60 mL). The combined organic phases were washed with
brine (2 × 100 mL), dried (MgSO4), and concentrated. Chromatog-
(CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.20 (s, 9H), 1.61 (m, 5H), 1.70
(b, 1H), 2.54 (m, 1H), 2.61 (m, 1H), 3.16 (d, J = 8.0 Hz, 1H), 3.39 (b,
1H), 3.73 (s, 3H), 3.92 (m, 4H), 5.94 (td, J = 1.5 Hz, 15.7 Hz, 1H),
6.82 (td, J = 7.1 Hz, 15.7 Hz, 1H); 13C NMR (CDCl3) δ 8.30. HRMS
calcd for C17H32NO5S (M + H) 362.2001, found 362.1997.
(SS,5S,2E)-(+)-Methyl-N-(-tert-butylsulfinyl)-5-amino-7-(2-
pentyl-1,3-dioxolan-2yl)-hept-2-enoate (17d). Flash chromatog-
raphy (75% EtOAc/hexanes) afforded 89% of a colorless oil: [α]20
D
1
+16.9 (c 1.31, CHCl3); IR (film) 3428, 1716, 1651 cm−1; H NMR
(CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.20 (s, 9H), 1.28 (m, 6H), 1.596
(m, 5H), 1.76 (m, 1H), 2.57 (m, 2H), 3.15 (d, J = 8.0 Hz, 1H), 3.38
(bm, 1H), 3.73 (s, 3H), 3.92 (m, 4H), 5.94 (td, J = 1.5 Hz, 15.7 Hz,
1H), 6.91 (td, J = 7.1 Hz, 15.7 Hz, 1H); 13C NMR (CDCl3) δ 13.9,
22.5, 22.6, 23.4, 29.3, 31.9, 32.9, 37.0, 39.0, 51.4, 55.8, 56.0, 64.8 (2
C’s), 111.4, 124.4, 144.0, 166.4. HRMS calcd for C20H38NO5S (M +
H) 404.2471, found 404.2470.
(SS,5S,2E)-(+)-Methyl-N-(tert-butylsulfinyl)-5-amino-7-(2-
phenyl-1,3-dioxolan-2-yl)-hept-2-enoate (17e). Chromatography
(60% EtOAc/hexanes) afforded 90% of clear oil. The product was
isolated as a 95:5 mixture of E:Z isomers: IR (film) 3430, 1730, 1665
cm−1; [α]20D +14.4 (c 2.2, CHCl3); 1H NMR (CDCl3) δ 1.10 (s, 9H),
1.42 (m, 1H), 1.58 (m, 1H), 1.87 (m, 1H), 1.95 (m, 1H), 2.40 (m,
1H), 2.51 (m, 1H), 3.03 (d, J = 7.6 Hz, 1H), 3.29 (m, 1H), 3.65 (s,
3H), 3.68 (m, 2H), 3.92 (m, 2H), 5.82 (td, J = 15.6 Hz, J = 1.6 Hz,
1H), 6.79 (td, J = 15.7 Hz, J = 7.1 Hz, 1H), 7.24 (m, 3H), 7.33 (m,
2H); 13C NMR (CDCl3) δ 22.6, 29.1, 36.3, 39.3, 51.4, 55.6, 56.0, 64.3,
64.4, 110.0, 124.3, 125.5, 127.9, 128.1, 142.2, 144.1, 166.4. HRMS
calcd for (M + H) C21H32NO5S 410.2001, found 410.1997.
(SS,4S)-(+)-N-(tert-Butylsulfinyl)-4-amine 6-(2-methyl-1,3-di-
oxolan-2-yl)hex-1-ene (18a). Typical Procedure. To a 500 mL
round-bottom flask equipped with magnetic stirring bar and argon
inlet was added (S)-(+)-7a (1.903 g, 7.693 mmol) in anhydrous ether
(256 mL). The solution was cooled to −50 °C, and allylmagnesium
bromide (15.4 mL, 15.39 mmol, 1.0 M solution in ether) was added
dropwise via syringe. After 1 h of stirring at this temperature the
reaction mixture was quenched with satd aqueous NH4Cl (18 mL) at
−50 °C and warmed to rt. The phases were separated, and the
aqueous phase was extracted with EtOAc (3 × 50 mL). The combined
organic phases were washed with brine (50 mL), dried (MgSO4), and
concentrated. Flash chromatography (50% EtOAc/hexanes) afforded
1.83 g (82%) of a clear oil: IR (film) 3385 cm−1; [α]20D +48.9 (c 1.69,
raphy (80% EtOAc/hexanes) afforded 2.10 g (95%) of a colorless oil:
1
IR (film) 3440, 1720,1660 cm−1; [α]20 +34.9 (c 1.07, CHCl3); H
D
NMR (CDCl3) δ 1.31 (s, 3H), 1.57 (m, 1H), 1.74 (m, 2H), 1.84 (m,
1H), 2.30 (m, 1H), 2.39 (s, 3H), 3.49 (m, 1H), 3.71 (s, 3H), 3.94 (m,
4H), 4.07 (d, J = 8.0 Hz, 1H), 5.80 (td, J = 1.6 Hz, J = 15.2 Hz, 1H),
6.80 (td, J = 7.2 Hz, J = 15.6 Hz, 1H), 7.27 (bd, J = 8.0 Hz, 2H), 7.56
(td, J = 2.0 Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3) δ 21.2, 23.8, 29.7,
35.0, 39.0, 51.4, 53.2, 64.5, 64.6, 109.6, 123.9, 125.5, 129.4, 141.2,
141.9, 144.2, 166.4. HRMS calcd for C19H28NO5S (M + H) 382.1683,
found 382.1695.
(SS,5S,2E)-(+)-Methyl-N-(p-toluenesulfinyl)-5-amino-7-(2-
propyl-1,3-dioxolan-2yl)-hept-2-enoate (16c). Chromatography
(50% EtOAc/hexanes) afforded 95% of a colorless oi: IR (film) 3431,
1722, 1657 cm−1; [α]20D +26.6 (c 2.83, CHCl3); 1H NMR (CDCl3) δ
0.90 (t, J = 7.3 Hz, 3H), 1.40 (m, 2H), 1.56 (m, 3H), 1.66 (m, 2H),
1.84 (m, 1H), 2.26 (m, 1H), 2.36 (m, 1H), 2.39 (s, 3H), 3.48 (m, 1H),
3.71 (s, 3H), 3.92 (bs, 4H), 4.07 (d, J = 8.1 Hz, 1H), 5.81 (td, J = 15.7
Hz, J = 1.2 Hz, 1H), 6.80 (td, J = 15.7 Hz, J = 7.6 Hz, 1H), 7.27 (bd, J
= 8.1 Hz, 2H), 7.56 (td, J = 8.1 Hz, J = 1.7 Hz, 2H); 13C NMR
(CDCl3) δ 14.3, 17.1, 21.3, 29.5, 32.9, 39.1, 39.4, 51.4, 53.3, 64.8(2C),
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1
1
CHCl3); H NMR (CDCl3) δ 1.19 (s, 9H), 1.30 (s, 3H), 1.66 (m,
1698 cm−1; H NMR (CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.31 (m,
4H), 1.50 (m, 3H), 2.03 (m, 1H), 2.40 (m, 5H), 2.63 (m, 1H), 3.72 (s,
3H), 4.09 (m, 1H), 5.88 (td, J = 1.5, 15.7 Hz, 1H), 6.96 (td, J = 7.3,
15.7 Hz, 1H); 13C NMR (CDCl3) 13.9, 22.4, 26.2, 27.9, 31.6, 33.8
37.2, 39.0, 51.3, 71.0, 122.7, 146.3, 166.8, 178.5; HRMS calcd for
C14H24NO2 (M + H) 238.1807, found 238.1805.
4H), 2.36 (m, 2H), 3.24 (d, J = 6.3 Hz, 1H), 3.32 (m, 1H), 3.92 (m,
4H), 5.15 (dd, J = 2.3 Hz, J = 14.4 Hz, 2H), 5.78 (m, 1H); 13C NMR
(CDCl3) δ 22.7, 23.8, 29.3, 34.9, 40.4, 54.9, 55.8, 64.6 (2C), 109.8,
119.0, 134.0. HRMS calcd for C14H27NO3S (M + H) 290.1790, found
290.1788
(SS,4S)-(+)-N-(tert-Butylsulfinyl)-4-amino-6-(2-phenyl-1,3-di-
oxolan-2-yl)hex-1-ene (18b). Flash chromatography (40% EtOAc/
hexanes) afforded 85% of a colorless oil that crystallized to a white
solid, mp 33 °C, on cooling to −20 °C: IR (film) 854 cm−1, 1059
cm−1, 3233 cm−1; [α]20D +42.0 (c 1.37, CHCl3); 1H NMR (CDCl3) δ
1.17 (s, 9H), 1.51 (m, 1H), 1.62 (m, 1H), 1.96 (m, 2H), 2.32 (m, 2H),
3.17 (d, J = 6.6 Hz, 1H), 3.30 (m, 1H), 3.76 (m, 2H), 4.00 (m, 2H),
5.09 (d, J = 3.9 Hz, 1H), 5.13 (s, 1H), 5.73 (m, 1H), 7.31 (m, 3H),
7.41 (m, 2H); 13C NMR (CDCl3) δ 22.7, 28.8, 36.2, 40.5, 54.9, 55.8,
64.5 (2C), 110.2, 119.0, 125.6, 127.9, 128.1, 134.0, 142.4. HRMS calcd
for C14H27NO3S (M + H) 352.1946, found 352.1944.
(5S,2E)-(+)-Methyl-(3,4-dihydro-5-phenyl-2H-pyrrol-2-yl)-
but-2-enoate (19e). Chromatography (30% EtOAc/hexanes) gave
90) of a clear oil: IR (film) 1735, 1663, 1650 cm−1; [α]20 +27.5 (c
D
1.78, CHCl3); 1H NMR (CDCl3) δ 1.65 (m, 1H), 2.20 (m, 1H), 2.45
(m, 1H), 2.75 (m, 1H), 2.94 (m, 1H), 3.01 (m, 1H), 3.72 (s, 3H), 4.33
(m, 1H), 5.93 (td, J = 15.6 Hz, J = 1.6 Hz, 1H), 7.04 (td, J = 15.6 Hz, J
= 7.6 Hz, 1H), 7.41 (m, 3H), 7.83 (m, 2H); 13C NMR (CDCl3) δ
28.0, 35.1, 39.1, 51.4, 71.7, 122.8, 127.7, 128.4, 130.5, 134.3, 146.3,
166.8, 172.9. HRMS calcd for C15H18NO2 (M + H) 244.1338, found
244.1329.
(5S,2E)-Methyl-(3,4-dihydro-5-methyl-2H-pyrrol-2-yl)-but-2-
enoate-N-oxide (20a). In a 50 mL, oven-dried, single-neck round-
bottomed flask equipped with magnetic stirring bar, and a rubber
septum was placed urea hydrogen peroxide (0.743 g, 7.898 mmol) in
anhydrous MeOH (30 mL) under argon. Methyltrioxorhenium (0.041
g, 0.165 mmol) was added, the solution was stirred for 15 min, and
(S)-18a (0.440 g, 2.43 mmol) in MeOH (20 mL) was added via
cannula. The yellow solution was stirred at rt for 15 h, concentrated,
and the residue was dissolved in CH2Cl2 (20 mL). The suspended
urea crystals were filtered; the filtrate was concentrated to give 0.47 g
(98%) of a yellow oil, which was taken to the next step without further
purification. The C-2 hydrogen in the nitrone was shifted downfield to
δ 4.20 ppm as compared to 4.06 ppm in the dehydropyrrolidine. The
C-5 carbon in the nitrone was shifted upfield to δ 150.5 ppm as
compared to 175.0 ppm for its precursor. This procedure was followed
in the synthesis of nitrones 20b−e.
(SS,5S,2E)-(+)-Methyl-N-(tert-butylsulfinyl)-5-amino-7-(2-
methyl-1,3-dioxolan-2-yl)-hept-2-enoate (17a). Typical Proce-
dure Using Cross-Metathesis. To a 100 mL round-bottomed flask
equipped with magnetic stirring bar and argon inlet were placed (S)-
(+)-18a (0.182 g, 0.629 mmol) and methyl acrylate (283 μL, 3.14
mmol) in DCM (62.9 mL), followed by a solution of Hoveyda−
Grubbs II catalyst (19.7 mg, 0.0314 mmol) in DCM (2 mL) added
dropwise via cannula. The reaction mixture was refluxed for 12 h and
concentrated. Chromatography (60% EtOAc/hexanes) afforded 0.173
g (79%) of a colorless oil identical to (+)-17a prepared above; [α]20
D
+20.5 (c 2.02, CHCl3).
(SS,5S,2E)-(+)-Methyl-N-(tert-butylsulfinyl)-5-amino-7-(2-
phenyl-1,3-dioxolan-2-yl)-hept-2-enoate (17e). Prepared using
cross metathesis to give (+)-17e with properties identical to (+)-17e
prepared above; [α]20 +14.2 (c 1.21, CHCl3).
D
(5S,2E)-(+)-Methyl-(3,4-dihydro-5-methyl-2H-pyrrol-2-yl)-
but-2-enoate (19a). Typical Procedure. In a 250 mL, oven-dried,
single-neck round-bottomed flask equipped with magnetic stirring bar,
and a rubber septum was placed (+)-16a (0.12 g, 0.31 mmol) in
MeOH (15 mL) and THF (15 mL). To this solution was added 3.0 N
HCl (1.05 mL) slowly via syringe at rt. This reaction mixture was
stirred at rt for 16 h, concentrated, and the residue was dissolved in
CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3
solution (2 × 20 mL), brine (30 mL), dried (MgSO4), and
concentrated. Chromatography (70% EtOAc/hexanes) gave 0.55 g
General Procedure for the Synthesis of (1S,2R,3R,6S)-
(−)-Methyl-3-methyl-7-aza-8-oxatricyclo[4.2.1.0]nonane-2-car-
boxylate (21a) by Heating. In a 500 mL, oven-dried, single-neck
round-bottomed flask equipped with magnetic stirring bar and a
rubber septum was placed nitrone 20a (0.400 g, 2.028 mmol) in
anhydrous toluene (400 mL,) and the solution was refluxed (while
maintaining the oil bath temperature at 150 °C for 48 h and
concentrated. Purification by flash column chromatography gave 0.180
g (45%) of a low melting solid: IR (film) 1740 cm−1; [α]20D −56.5 (c
1
0.42, CHCl3); H NMR (CDCl3) δ 1.24 (s, 3H), 1.81 (m, 3H), 2.18
(100%) of a clear oil: IR (film) 1720, 1655, 1650 cm−1; [α]20 +39.7
(m, 3H), 2.44 (s, 1H), 3.61 (m, 1H), 3.68 (s, 3H), 4.94 (d, J = 4.8 Hz,
1H); 13C NMR (CDCl3) δ 22.0, 26.0, 33.8, 42.0, 51.5, 61.2, 62.7, 75.7,
81.5, 171.6. HRMS calcd for C10H16NO3 (M + H) 198.1130, found
198.1124.
D
1
(c 1.21, CHCl3); H NMR (CDCl3) δ 1.45 (m, 1H), 2.00 (d, J = 1.6
Hz, 3H), 2.02 (m, 1H), 2.33 (m, 1H), 2.45 (m, 2H), 2.58 (m, 1H),
3.69 (s, 3H), 4.05 (m, 1H), 5.87 (td, J = 1.6 Hz, J = 16.0 Hz, 1H), 6.95
(td, J = 7.2 Hz, J = 15.6 Hz, 1H); 13C NMR (CDCl3) δ 19.6, 28.4,
38.9, 39.0, 51.3, 71.2, 122.6, 146.3, 166.8, 175.0. HRMS calcd for
C10H16NO2 (M + H) 182.1176, found 182.1172.
(1S,2R,3R,6S)-(−)-Methyl-3-methyl-7-aza-8-oxatricyclo-
[4.2.1.0]nonane-2-carboxylate (21a) using the Lewis Acid
Aluminum tert-Butoxide. Typical Procedure. In a 500 mL,
oven-dried, single-neck round-bottomed flask equipped with magnetic
stirring bar and a rubber septum was placed nitrone 20a (0.370 g,
1.876 mmol) in anhydrous toluene (200 mL). To this solution was
added Al(OtBu)3 (0.230 g, 0.938 mmol), and the solution was stirred
at rt for 6 h. At this time the reaction mixture was refluxed for 96 h,
cooled to rt, and extracted with aqueous 5% HCl solution (4 × 50
mL). The combined aqueous phases were carefully neutralized by slow
addition of solid Na2CO3 until the solution became slightly basic (pH
8). This aqueous solution was extracted with DCM (4 × 50 mL), and
the combined organic phases were washed with brine, dried (MgSO4),
and concentrated. Chromatography gave 0.260 g (70%) of a low
(5S,2E)-(+)-Methyl-(3,4-dihydro-5-ethyl-2H-pyrrol-2-yl)-but-
2-enoate (19b). Flash chromatography (60% EtOAc/hexanes)
afforded 100% of a oil: [α]20 +43.4 (c 1.9, CHCl3); IR (neat)
D
1
1636, 1698 cm−1; H NMR (CDCl3) δ 1.14 (t, J = 7.6 Hz, 3H), 1.46
(m, 1H), 2.04 (m, 1H), 2.33 (m, 3H), 2.49 (m, 2H), 2.65 (m, 1H),
3.72 (s, 3H), 4.09 (m, 1H), 5.89 (td, J = 1.6, 15.7 Hz, 1H), 6.96 (td, J
= 7.6, 15.7 Hz, 1H); 13H NMR (CDCl3) δ 10.6, 26.7, 27.7, 36.7, 38.8,
51.1, 70.7, 122.5, 146.1, 166.6, 179.2. HRMS calcd for C11H18NO2 (M
+ H) 196.1338, found 196.1334.
(5S,2E)-(+)-Methyl-(3,4-dihydro-5-propyl-2H-pyrrol-2-yl)-
but-2-enoate (19c). Flash chromatography (60% EtOAc/hexanes)
afforded 93% of a clear oil: IR (film) 1730, 1660, 1653 cm−1; [α]20
+39.1 (c 0.9, CHCl3); H NMR (CDCl3) δ 0.93 (t, J = 7.3 Hz, 3H),
melting white solid: IR (film) 1740 cm−1; [α]20 −56.47 (c 0.42,
D
D
1
1
CHCl3); H NMR (CDCl3) δ 1.24 (s, 3H), 1.81 (m, 3H), 2.18 (m,
1.46 (m, 1H), 1.59 (m, 1H), 2.03 (m, 1H), 2.33 (m, 3H), 2.46 (m,
2H), 2.65 (m, 1H), 3.70 (s, 3H), 4.09 (m, 1H), 5.88 (td, J = 15.7 Hz, J
= 1.5 Hz, 1H), 6.95 (td, J = 15.7 Hz, J = 7.3 Hz, 1H); 13C NMR
(CDCl3) δ 13.9, 19.8, 27.9, 35.7, 37.1, 39.0, 51.4, 70.9, 122.7, 146.3,
166.8, 178.3. HRMS calcd for C12H20NO2 (M + H) 210.1494, found
210.1489.
(5S,2E)-(+)-Methyl-(3,4-dihydro-5-pentyl-2H-pyrrol-2-yl)-
but-2-enoate (19d). Flash chromatography (50% EtOAc/hexanes)
afforded 83% of an oil: [α]20D +31.1 (c 3.15, CHCl3); IR (neat) 1636,
3H), 2.44 (s, 1H), 3.61 (m, 1H), 3.68 (s, 3H), 4.94 (d, J = 4.8 Hz,
1H); 13C NMR (CDCl3) δ 22.0, 26.0, 33.8, 42.0, 51.5, 61.2, 62.7, 75.7,
81.5, 171.6. HRMS calcd for C10H16NO3 (M + H) 198.1130, found
198.1124.
(1S,2R,3R,6S)-(−)-Methyl-3-ethyl-7-aza-8-oxatricyclo-
[4.2.1.0]nonane-2-carboxylate (21b). The toluene solution was
extracted with 5% HCl solution (4 × 50 mL, the combined aqueous
phases were neutralized by slow addition of solid Na2CO3 until the
solution was slightly basic. At this time the aqueous solution was
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Article
extracted with DCM (4 × 50 mL), and the combined organic phases
were washed with brine, dried, and concentrated to give 0.192 g (52%)
of a clear oil: [α]20D −27.3 (c 0.495, CHCl3); IR (film) 1738 cm−1; 1H
NMR (CDCl3) 0.95 (t, J = 7.6 Hz, 3H), 1.26 (dd, J = 11.8, 2.4 Hz,
1H), 1.57 (q, J = 7.6 Hz, 3H), 1.85 (m, 1H), 1.98 (m, 2H), 2.14 (m,
2H), 2.48 (s, 1H), 3.619 (m, 1H), 3.69 (s, 3H), 4.90 (d, J = 4.8 Hz,
1H); 13C NMR (CDCl3) 8.7, 25.8, 26.1, 29.3, 41.9, 51.5, 62.2, 62.8,
77.3 81.6, 171.8. HRMS calcd for C11H18NO3 (M + H) 212.1287,
found 212.1282.
(1S,2R,3R,6S)-(−)-Methyl-3-propyl-7-aza-8-oxatricyclo-
[4.2.1.0]nonane-2-carboxylate (21c). Clear oil; IR (film) 1738
cm−1; [α]20D −56.6 (c 0.71, CHCl3); 1H NMR (CDCl3) δ 0.88 (t, J =
7.1 Hz, 3H), 1.25 (dd, J = 11.5 Hz, J = 2.2 Hz, 1H), 1.31 (m, 1H), 1.49
(m, 3H), 1.80 (m, 1H), 1.99 (m, 2H), 2.15 (m, 2H), 2.46 (s, 1H), 3.60
(m, 1H), 3.68 (s, 3H); 13C NMR (CDCl3) δ 14.6, 17.7, 25.9, 30.1,
35.9, 42.0, 51.6, 62.3, 62.8, 79.0, 81.6, 171.9. HRMS calcd for
C12H19NNaO3 (M + Na) 248.1263, found 248.1260.
cm−1; 1H NMR (CDCl3) 0.88 (t, J = 6.8 Hz, 3H), 1.35 (m, 4H), 15.6
(m, 2H), 2.03 (m, 1H), 2.39 (m, 6H), 2.64 (m, 1H), 3.71 (s, 3H), 4.1
(m, 1H), 5.88 (td, J = 1.5, 17.7 Hz, 1H), 6.95 (td, J = 7.3, 15.7 Hz,
1H); 13C NMR (CDCl3) 13.9, 22.4, 26.2, 27. 9, 31.6, 33.7, 37.2, 39.0,
51.4, 70.8, 122.78, 146.3, 166.8, 178.7. HRMS calcd for C14H24NO3(
M + H) 254.1756, found 254.1752.
(E)-(S)-(+)-Methyl-4-(5-oxo-1-phenylpyrrolidin-2-yl)-but-2-
enoate (22e). Flash chromatography (35% EtOAc/hexanes) gave a
1
brown oil: [α]20 +27.9 (c 1.53, CHCl3); H NMR (CDCl3) δ 1.65
D
(m, 1H), 2.21 (m, 1H), 2.45 (m, 1H), 2.75 (m, 1H), 2.93 (m, 1H),
3.01 (m, 1H), 3.73 (s, 3H), 4.34 (m, 1H), 5.94 (td, J = 15.6 Hz, J = 1.6
Hz, 1H), 7.04 (td, J = 15.6 Hz, J = 7.6 Hz, 1H), 7.41 (m, 3H), 7.83 (m,
2H); 13C NMR (CDCl3) δ 28.1, 35.1, 39.1, 51.4, 71.7, 122.8, 127.7,
128.4, 130.5, 134.4, 146.3, 166.8, 172.8. HRMS calcd for (M + H)
C15H18NO3 260.1287, found 260.1281.
(E)-Methyl-4((2S)-(+)-5-propyl-6-oxa-1-aza-bicyclo[3.1.0]-
hexan-2-yl)-but-2-enoate (23c). Typical Procedure. In a 25 mL,
oven-dried, single-neck round-bottomed flask equipped with magnetic
stirring bar and a rubber septum was placed (+)-19c (0.054 g, 0.259
mmol) in anhydrous dichloromethane (5.0 mL) under argon. To this
solution was added m-CPBA (0.067 g, 0.388 mmol, ≥77%) at 0 °C,
and the reaction mixture was stirred for 0.5 h and quenched by adding
a saturated solution of NaHCO3/Na2S2O3 (1:1) (10 mL). The
aqueous phase was extracted with EtOAc (2 × 30 mL), and the
combined organic phases were washed with satd NaHCO3 solution (2
× 30 mL) and brine (30 mL), dried (MgSO4), and concentrated. Flash
chromatography (30% EtOAc in hexanes) afforded 0.045 g (77%) of a
yellow oil as 2.5:1 mixture of isomers: IR (film) 1724, 1650 cm−1;
[α]20D +60.3 (c 1.53, CHCl3); major isomer 1H NMR (CDCl3) δ 0.93
(t, J = 7.4 Hz, 3H), 1.45 (m, 3H), 1.81 (m, 4H), 2.29 (m, 1H), 2.39
(m, 1H), 2.70 (m, 1H), 3.19 (m, 1H), 3.70 (s, 3H), 5.92 (td, J = 15.6
Hz, J = 1.5 Hz, 1H), 7.01 (td, J = 15.6 Hz, J = 7.3 Hz, 1H); δ minor
isomer 0.94 (t, J = 7.3 Hz, 3H), 1.28 (m, 3H), 1.67 (m, 4H), 2.10−
2.24 (m, 2H), 2.39 (m, 1H), 3.58 (m, 1H), 3.71 (s, 3H), 5.87 (td, J =
15.6 Hz, J = 1.5 Hz, 1H), 6.91 (td, J = 15.6 Hz, J = 7.3 Hz, 1H); major
isomer 13C NMR (CDCl3) δ 14.1, 17.9, 25.3, 29.3, 34.6, 35.3, 51.4,
65.8, 90.2, 122.7, 145.6, 166.7; δ minor isomer 14.2, 17.9, 24.4, 27.5,
34.7, 35.3, 51.5, 64.5, 90.3, 123.3, 144.8, 166.5. HRMS calcd for
C12H20NO3 (M + H) 226.1443, found 226.1441.
(1S,2R,3R,6S)-(−)-Methyl-3-pentyl-7-aza-8-oxatricyclo-
[4.2.1.0]nonane-2-carboxylate (21d). At this time the toluene
solution was extracted with 5% HCl solution (4 × 50 mL), and the
organic layer was washed satd Na2CO3 solution (2 × 30 mL), brine
(40 mL), dried (MgSO4) and concentrated to give 0.328 g (58%) of
1
clear oil: [α]20 −45.6 (c 1.275, CHCl3); IR (film) 1738 cm−1; H
D
NMR (CDCl3) δ 0.86 (t, J = 6.8 Hz, 3H), 1.25 (b, 6H), 1.49 (b, 4H),
1.81 (m, 1H), 2.0 (m, 2H), 2.18 (m, 2H), 2.46 (s, 1H), 3.60 (m, 1H),
3.69 (s, 3H), 4.89 (d, J = 4.8 Hz, 1H); 13C NMR (CDCl3) δ 14.0, 22.6,
24.2, 25.9, 30.1, 32.4, 33.7, 42.0, 51.5, 62.2, 62.8, 79.1, 81.6, 171.8.
HRMS calcd for C14H24NO3 (M + H) 254.1756, found 254.1752.
(1S,2R,3R,6S)-(−)-Methyl-3-phenyl-7-aza-8-oxatricyclo-
[4.2.1.0]nonane-2-carboxylate (21e). The crude reaction mixture
was washed with H2O (3 × 20 mL), and the organic phase was dried
(MgSO4) and concentrated. Chromatography (35% EtOAc/hexanes)
gave 0.31 g (40%) of a white solid, mp 136−138 °C, and 0.30 g (38%)
of lactam (S)-(+)-22e (see below): IR (film) 1750 cm−1; [α]20D −54.7
1
(c 0.88, CHCl3); H NMR (CDCl3) δ 1.38 (dd, J = 11.7 Hz, J = 2.4
Hz, 1H), 1.93 (m, 1H), 2.22 (m, 2H), 2.28 (m, 1H), 2.73 (m, 1H),
2.81 (s, 1H), 3.04 (s, 3H), 3.75 (m, 1H), 4.95 (d, J = 4.9 Hz, 1H), 7.14
(m, 1H), 7.23 (m, 2H), 7.45 (m, 2H); 13C NMR (CDCl3) δ 25.4,
34.1, 42.2, 50.9, 63.0, 64.5, 80.7, 81.2, 126.6, 126.8, 127.3, 141.5, 170.6.
HRMS calcd for (M + H) C15H18NO3 260.1287, found 260.1281.
(E)-(S)-(+)-Methyl-4-(5-oxo-1ethylpyrrolidini-2-yl)-but-2-
enoate (22b). Typical Procedure. In a 100 mL round-bottom flask
equipped with magnetic stirring bar and argon inlet was placed nitrone
20b (0.05 g, 0.226 mmol) in anhydrous toluene (23 mL), and the
solution was refluxed for 96 h. At this time, the reaction mixture was
cooled to rt and concentrated. Flash chromatography (90% EtOAc/
hexanes) gave 0.016 g (32%) of slightly brownish oil: IR (film) 1726,
1651, 1640 cm−1; [α]20D +36.0 (c 0.40, CHCl3); 1H NMR (CDCl3) δ
1.14 (t, J = 7.6 Hz, 3H), 2.04 (m, 2H), 2.35 (m, 3H), 2.51 (m, 2H),
2.65 (m, 1H), 3.72 (s, 3H), 4.10 (m, 1H), 5.89 (td, J = 1.6, 15.7 Hz,
1H), 6.97 (td, J = 7.6, 15.7 Hz, 1H); 13C NMR (CDCl3) δ 10.8, 26.9,
28.0, 37.0, 39.0, 51.3, 71.1, 122.8, 146.3, 166.8, 179.8. HRMS calcd for
C11H18NO3 (M + H) 212.1287, found 212.1280
(E)-(S)-(+)-Methyl-4-(5-oxo-1-propylpyrrolidin-2-yl)-but-2-
enoate (22c). Typical Procedure. In a 100 mL round-bottomed
flask equipped with magnetic stirring bar and argon inlet was placed
nitrone 20c (0.100 g, 0.444 mmol) in anhydrous toluene (45.0 mL),
and the solution was refluxed for 96 h. At this time, the reaction
mixture was cooled to rt and concentrated. Flash chromatography
(25% EtOAc/hexanes) yielded 0.04 g (40%) of slightly yellow oil: IR
(film) 1724, 1657, 1642 cm−1; [α]20D +25.1 (c 0.45, CHCl3); 1H NMR
(CDCl3) δ 0.95 (t, J = 7.1 Hz, 3H), 1.49 (m, 1H), 1.61 (m, 2H), 2.06
(m, 1H), 2.35 (m, 3H), 2.51 (m, 2H), 2.66 (m, 1H), 3.72 (s, 3H), 4.15
(m, 1H), 5.90 (bd, J = 15.7 Hz, 1H), 6.96 (td, J = 15.7 Hz, J = 7.3 Hz,
1H); 13C NMR (CDCl3) δ 13.9, 19.8, 27.7, 35.6, 37.1, 38.8, 51.4, 70.6,
122.9, 146.0, 166.8, 179.5. HRMS calcd for C12H20NO3 (M + H)
226.1443, found 226.1436.
(E)-Methyl-4((2S)-(+)-5-pentyl-6-oxa-1-aza-bicyclo[3.1.0]-
hexan-2-yl)-but-2-enoate (23d). Flash chromatography (50%
EtOAc/hexanes) provided a colorless oil as a 2.6:1 mixture of
oxaziridines isomers: [α]20 +46.2 (c 2.03, CHCl3); IR (film) 1728,
D
1
1651 cm−1; H NMR (CDCl3) major isomer: δ 0.87 (t, J = 6.7 Hz,
3H), 1.29 (m, 5H), 1.45 (m, 2H), 1.74 (m, 1H), 2.43 (m, 6H), 2.71
(m, 1H), 3.71 (s, 3H), 4.2 (b, 1H), 5.92 (td, J = 1.5, 15.7 Hz, 1H),
7.06 (td, J = 7.6, 15.7 Hz, 1H); minor isomer: δ (t, J = 6.7 Hz, 3H),
1.29 (m, 5H), 1.74 (m, 1H), 2.39 (m, 6H), 2.71 (m, 1H), 3.72 (s, 3H),
5.86 (td, J = 1.5, 15.7 Hz, 1H), 6.92 (td, J = 7.6, 15.7 Hz, 1H); 13C
NMR (CDCl3) major isomer: δ 13.9, 22.5, 22.3, 24.8, 25.3, 27.5, 29.4,
31.8, 32.6, 35.4, 51.4, 65.9, 90.3, 122.8, 145.7, 166.8; minor isomer: δ
15.2, 23.3, 24.4, 24.7, 29.7, 32.5, 34.7, 51.5, 64.5, 90.5, 123.3, 144.8,
166.5. HRMS: calcd for C14H24NO3 (M + H) 254.1756, found
254.1750.
(E)-(S)-(+)-Methyl-4-(5-oxo-1-propylpyrrolidin-2-yl)-but-2-
enoate (22c) from Oxaziridine 23c. In a 50 mL single-necked
round-bottom flask were added MeReO3 (0.001 g, 0.005 mmol) and
UHP (0.021 g, 0.224 mmol) in methanol (2.0 mL). The reaction
mixture was stirred for 0.5 h under an argon atmosphere and
concentrated, and the residue was dissolved in CH2Cl2 (10 mL). The
solids were removed by filtration, and the filtrate was concentrated to
give the methylperoxorhenium complex. The complex was dissolved in
anhydrous toluene (4.0 mL) and added to a solution of (+)-23c
(0.015 g, 0.069 mmol) in anhydrous toluene (4.0 mL). The solution
was refluxed for 96 h, and concentrated. Flash chromatography (25%
EtOAc/hexanes) gave 0.008 g (51%) of slightly yellow oil with spectral
properties identical to that prepared from 20c; [α]20 +27.5 (c 0.4,
D
(E)-(S)-Methyl-4-(5-oxo-1-pentylpyrrolidin-2-yl)-but-2-
CHCl3).
enoate (22d). Flash chromatography (50% EtOAc/hexanes) gave
Methane Sulfonate Salt of Methyl (1S,2R,3R,6S)-(−)-3-
45% of an oil: [α]20 −33.9 (c 1.28, CHCl3); IR (film) 1720, 1656
Methyl-7-aza-8-oxatricyclo[4.2.1.0]nonane-2-carboxylate
D
2356
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The Journal of Organic Chemistry
Article
(24a). Typical Procedure. In a 50 mL, oven-dried, single-neck
round-bottomed flask equipped with magnetic stirring bar and a reflux
condenser was placed (−)-21a (0.06 g, 0.304 mmol) in anhydrous
benzene (20 mL) under argon. Methylmethanesulfonate (0.335 g, 3.04
mmol) was added via syringe, and the solution was heated at refluxed
for 24 h. At this time the solution was concentrated, the residue was
dissolved in H2O (20 mL). The aqueous solution was extracted with
CH2Cl2 (3 × 10 mL), to the aqueous phase was added acetonitrile/
water (2:1, 20 mL), and the solution was lyophilized to give 0.92 g
(98%) of a white sticky material: IR (film) 1745 cm−1; [α]20D −2.9 (c
0.7, CHCl3); 1H NMR (CD3OD) δ 1.45 (s, 3H), 2.12 (dd, J = 2.4 Hz,
J = 12.7 Hz, 1H), 2.28 (m, 2H), 2.50 (m, 1H), 2.58 (m, 1H), 2.62 (s,
3H), 2.77 (m, 1H), 3.42 (s, 3H), 3.50 (s, 1H), 3.71 (s, 3H), 4.43 (tq, J
= 8.6 Hz, J = 2.0 Hz, 1H), 5.36 (d, J = 5.2 Hz, 1H); 13C NMR
(CD3OD) δ 18.2, 25.6, 34.1, 39.7, 41.6, 41.7, 53.1, 60.8, 78.3, 84.0,
88.1, 170.2. HRMS calcd for C11H18NO3 (M+) 212.1281, found
212.1279.
Methanesulfonate Salt of Methyl (1S,2R,3R,6S)-(+)- 3-Ethyl-
7-methyl-7-aza-8-oxatricyclo[4.2.1.0]nonane-2-carboxylate
(24b). Sticky material: [α]20D +10.7 (c 3.975, MeOH); IR (film) 1748
cm−1; 1H NMR (CD3OD) δ 0.617 (t, J = 7.6 Hz, 3H), 1.69 (m, 2H),
1.87 (dd, J = 12.8, 2.8 Hz, 1H), 2.02 (m, 2H), 2.18 (m, 1H), 2.33 (m,
1H), 2.38 (s, 3H), 2.51 (m, 1H), 3.01 (s, 1H), 3.16 (s, 3H), 3.22 (s,
1H), 3.41 (s, 3H), 4.14 (m, 1H), 5.02 (d, J = 4.8 Hz, 1H); 13C NMR
(CD3OD) δ 8.98, 25.2, 25.75, 32.64, 39.65, 41.54, 42.0, 53.20, 59.8,
79.10, 84.97, 92.0, 171.0. HRMS calcd for C12H20NO3 (M+) 226.1443,
found 226. 1438.
20.8, 25.3, 32.4, 36.4, 36.5, 39.6, 53.2, 57.0, 63.1, 66.8, 71.8, 175.7.
HRMS calcd for C11H20NO3 214.1434, found 214.1434.
Methanesulfonate Salt of Methyl (1R,2R,3S,5S)-(−)-1-Ethyl-
3-(hydroxyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxy-
late (25b). Sticky solid: [α]20 −7.6 (c 4.055, MeOH); IR (film)
D
1
3380, 1749 cm−1; H NMR (CD3OD) 0.89 (t, J = 7.6 Hz, 3H), 1.56
(m, 1H), 1.80 (m, 1H), 1.99 (m, 3H), 2.10 (m, 2H), 2.25 (m, 1H),
2.59 (s, 3H), 2.62 (s, 3H), 3.22 (s, 1H), 3.27 (d, J = 6.8 Hz, 1H), 3.68
(s, 3H), 3.81 (b, 1H), 4.22 (m, 1H); 13C NMR (CD3OD) 9.4, 25.0,
28.1, 30.4, 36.4, 39.7, 52.8, 53.2, 63.1, 67.0, 75.3, 175.4. HRMS calcd
for C12H22NO3(M+) 228.16, found 228.1592.
Methanesulfonate Salt of Methyl (1R,2R,3S,5S)-(+)-1-Propyl-
3-(hydroxy)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate
(25c). Sticky solid: IR (film) 3340, 1745 cm−1; [α]20 +1.7 (c 0.82,
D
MeOH); 1H NMR (CD3OD) δ 0.85 (t, J = 7.3 Hz, 3H), 1.15 (m, 1H),
1.35−1.71 (m, 7H), 1.97 (m, 1H), 2.10 (m, 1H), 2.12 (s, 3H), 2.60 (s,
3H), 2.89 (d, J = 6.6 Hz, 1H), 3.17 (m, 1H), 3.57 (s, 3H), 3.88 (m,
1H); 13C NMR (CD3OD) δ 15.4, 19.5, 27.2, 33.7, 36.6, 37.7, 39.6,
39.9, 51.6, 55.6, 64.3, 65.7, 69.1, 173.6. HRMS calcd for C13H24NO3
(M+) 242.1751, found 242.1751.
Methanesulfonate Salt of Methyl (1R,2R,3S,5S)-(+)-1-Pentyl-
3-(hydroxyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxy-
late (25d). A hydrogen atmosphere (50 atm) was applied, and the
reaction mixture was stirred at rt for 6 h. At this time the solution was
filtered through a short pad of Celite, and the Celite was washed with
MeOH (2 × 5 mL) and concentrated to give 0.295 g (98%) of a sticky
1
solid: [α]20 +3.5 (c 0.43, MeOH); IR (film) 3380, 1749 cm−1; H
D
NMR (CD3OD) δ 0.82 (t, J = 7.2 Hz, 3H), 1.20 (b, 6H), 1.48 (m,
8H), 1.94 (m, 1H), 2.09 (3, 3H), 2.60 (s, 3H), 2.88 (d, J = 6.4 Hz,
1H), 3.14 (m, 1H), 3.24 (s, 1H), 3.55 ((s, 3H), 3.87 (m, 1H); 13C
NMR (CD3OD) δ 14.4, 23.6, 25.7, 27.2, 33.8, 33.9, 36.6, 36.3, 37.5,
37.7, 39.5, 51.5, 55.6, 64.2, 65.7, 68.9, 173.5. HRMS calcd for
C15H28NO3 (M+) 270.2064, found 270.2066.
Methanesulfonate Salt of Methyl (1R,2R,3S,5S)-(−)-3-(Hy-
droxy)-1-phenyl-8-methyl-8-azabicyclo[3.2.1]octane-2-carbox-
ylate (25e). In a 50 mL, oven-dried, single-neck round-bottomed flask
equipped with magnetic stirring bar and a rubber septum was placed
(1S,2R,3R,6S)-(+)-23e (0.160 g, 0.433 mmol) in anhydrous MeOH
(10 mL), and Pd−C (0.01 g, 5% Pd on carbon) was added. A
hydrogen atmosphere (1 atm) was maintained using a balloon, and the
reaction mixture was stirred at rt for 10 h. At this time the solution was
filtered through a short pad of Celite, and concentrated to give 0.159 g
(99%) of sticky material. This crude reaction mixture was taken further
in the synthesis because it could not be purified.
(1S,6S,E)-(+)-Methyl 7-methyl-3-pentyl-8-oxa-7-aza-bicyclo-
[4.2.1]non-2-ene-2-carboxylate (27d) from Palladium. In a 25
mL, oven-dried, single-necked round-bottom flask equipped with
magnetic stirring bar and rubber septum was placed 24d (0.030 g,
0.083 mmol) and 5% Pd/C (20% w/w) in methanol (10 mL). The
reaction mixture was stirred at rt for 48 h, the solution was filtered
through Celite, washed using methanol (2 × 7 mL), and concentrated.
The residue was dissolved in anhydrous pyridine (5 mL) and stirred at
rt for 20 h under an argon atmosphere. At this time the solution was
concentrated, the residue was dissolved in satd K2CO3 (10 mL) and
extracted with DCM (2 × 7 mL), and the combined organic phases
were washed with brine (8 mL), dried (MgSO4) and concentrated.
Flash chromatography (60% EtOAC in hexanes) yielded 0.014 g
(63%) of oil: [α]20D +66.5 (c 0.4, CHCl3); IR (CHCl3) 1719 cm−1; 1H
NMR (CDCl3) δ 0.87 (t, J = 6.8 Hz, 3H), 1.28 (m, 4H), 1.46 (m, 3H),
1.98 (m, 3H), 2.20 (m, 1H), 2.40 (m, 1H), 2.65 (m, 4H), 3.17 (m,
1H), 3.45 (t, J = 6.0 Hz, 1H), 3.70 (s, 3H), 5.20 (d, J = 8.8 Hz, 1H);
13C NMR (CDCl3) δ 13.9, 22.4, 27.5, 31.1, 31.8, 33.1, 37.8, 39.3, 46.5,
Methanesulfonate Salt of Methyl (1S,2R,3R,6S)-(+)-3-Propyl-
7-aza-8-oxatricyclo[4.2.1.0]nonane-2-carboxylate (24c). Sticky
1
solid: IR (film) 1750 cm−1; [α]20 +14.3 (c 0.77, CHCl3); H NMR
D
(CD3OD) δ 0.87 (t, J = 7.3 Hz, 3H), 1.13 (m, 1H), 1.28 (m, 1H), 1.82
(m, 2H), 2.08 (dd, J = 12.5 Hz, J = 2.7 Hz, 1H), 2.25 (m, 2H), 2.41
(m, 1H), 2.52 (m, 1H), 2.58 (m, 1H), 2.59 (s, 3H), 2.74 (m, 1H), 3.41
(s, 3H), 3.42 (s, 1H), 3.66 (s, 3H), 4.36 (m, 1H), 5.26 (d, J = 4.9 Hz,
1H); 13C NMR (CD3OD) δ 14.8, 19.0, 25.4, 32.9, 34.7, 39.6, 41.7,
41.9, 53.2, 60.0, 78.9, 85.0, 91.5, 171.1. HRMS calcd for C13H22NO3
(M+) 240.1594, found 240.1598.
Methanesulfonate Salt of Methyl (1S,2R,3R,6S)-(+)-3-Pentyl-
7-methyl-7-aza-8-oxatricyclo[4.2.1.0]nonane-2-carboxylate
(24d). Sticky material: [α]20 +13.9 (c 1.06, MeOH); IR (film) 1748
D
1
cm−1; H NMR (CD3OD) δ 0.82 (t, J = 7.2 Hz, 3H), 1.20 (m, 6H),
1.81 (dt, J = 4.4, 12.4 Hz, 1H), 1.94 (m, 1H), 2.08 (dd, J = 2.7, 12.5
Hz, 1H), 2.23 (m, 2H), 2.39 (m, 1H), 2.55 (m, 1H), 2.60 (s, 3H), 2.73
(m, 1H), 3.41 (s, 3H), 3.42 (s, 1H), 3.66 (s, 3H), 4.36 (m, 1H), 5.26
(d, J = 5.2 Hz, 1H); 13C NMR (CD3OD) δ 14.3, 23.4, 25.2, 25.4, 32.7,
33.0, 33.3 39.6, 41.6, 41.9, 53.2, 60.0. 78.9, 85.0, 91.6, 171.1. HRMS
calcd for C15H26NO3 (M+) 268.1907, found 268.1912.
Methanesulfonate Salt of Methyl (1S,2R,3R,6S)-(+)-3-Phenyl-
7-aza-8-oxatricyclo[4.2.1.0]nonane-2-carboxylate (24e). Iso-
lated as a white sticky material: IR (film) 1760 cm−1; [α]20 +38.9
D
(c 1.62, CH3OH); 1H NMR (CD3OD) δ 2.21 (dd, J = 12.5 Hz, J = 1.7
Hz, 1H), 2.40 (m, 1H), 2.55 (s, 3H), 2.65 (m, 1H), 2.77 (m, 1H), 2.88
(m, 1H), 2.91 (s, 3H), 2.99 (m, 1H), 3.21 (s, 3H), 3.85 (s, 1H), 4.59
(m, 1H), 5.60 (d, J = 4.6 Hz, 1H), 7.36 (m, 3H), 7.45 (m, 2H); 13C
NMR (CD3OD) δ 25.8, 31.3, 39.7, 42.7, 42.9, 52.7, 62.9, 80.1, 83.8,
91.8, 129.6, 130.2, 131.9, 133.5, 169.7. HRMS calcd for C16H20NO3
(M+) 274.1443, found 274.1440.
Methanesulfonate Salt of Methyl (1R,2R,3S,5S)-(−)-3-(Hy-
droxy)-1,8-dimethyl-8-azabicyclo[3.2.1]octane-2-carboxylate
(25a). Typical Procedure. In a 50 mL, oven-dried, single-neck
round-bottomed flask equipped with magnetic stirring bar and a
rubber septum was placed (−)-24a (0.030 g, 0.097 mmol) in
anhydrous MeOH (10 mL), and Pd−C (0.01 g, 5% Pd on carbon) was
added. A hydrogen atmosphere (1 atm) was maintained using a
balloon, and the reaction mixture was stirred at rt for 48 h. At this time
the solution was filtered through a short pad of Celite and
concentrated to give 0.03 g (99%) of a white sticky solid: IR (film)
3400, 1750, cm−1; [α]20D −24.2 (c 1.17, MeOH); 1H NMR (CD3OD)
δ 1.38 (s, 3H), 1.99 (m, 1H), 2.07 (m, 4H), 2.28 (m, 1H), 2.63 (s,
3H), 2.71 (s, 3H), 3.12 (d, J = 6.8 Hz, 1H), 3.73 (s, 3H), 3.84 (m,
1H), 4.28 (td, J = 6.6 Hz, J = 11.0 Hz, 1H); 13C NMR (CD3OD) δ
51.3, 64.4, 76.8, 131.8, 157.4, 168.4. HRMS calcd for C15H26 NO3 (M
+ H) 268.1913, found 268.1909.
(1S,6S,E)-(+)-Methyl 7-Methyl-3-pentyl-8-oxa-7-aza-bicyclo-
[4.2.1]non-2-ene-2-carboxylate (27d). Typical Procedure from
Triethylamine. In a 25 mL, oven-dried, single-necked round-bottom
flask equipped with magnetic stirring bar and rubber septum was
placed salt 24d (0.020 g, 0.055 mmol) in methanol (1 mL), and
triethylamine was added (1 mL). The reaction mixture was stirred at rt
for 12 h, and the solution was concentrated. The residue was taken
2357
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The Journal of Organic Chemistry
Article
into satd K2CO3 (5 mL) and extracted with DCM (2 × 5 mL), the
combined organic phases were washed with brine (8 mL), dried
(MgSO4), and concentrated. Flash chromatography (60% EtOAC in
hexanes) gave 0.0132 g (90%) of oil identical to that prepared above.
(1S,6S,E)-(+)-Methyl 3,7-Dimethyl-8-oxa-7-aza-bicyclo-
[4.2.1]non-2-ene-2-carboxylate (27a). Flash chromatography
1H); 13C NMR (CDCl3) δ 15.0, 18.2, 26.3, 32.9, 33.4, 36.1, 38.5, 51.1,
51.4, 62.4, 67.8, 68.6, 128.3, 129.6, 130.2, 132.9, 165.9, 170.6. HRMS
calcd for C20H28NO4 (M + H) 346.2018, found 346.2019.
Methyl (1R,2R,3S,5S)-(+)-1-Pentyl-3-(benzoyloxy)-8-methyl-
8-azabicyclo[3.2.1]octane-2-carboxylate (28d). Flash chromatog-
raphy (1% NH4OH:EtOAc) gave 82% of an oil: [α]20 +6.7 (c 1.2,
D
CHCl3); IR (film) 1721, 1646 cm−1; 1H NMR (CDCl3) δ 0.89 (t, J =
6.8 Hz, 3H), 1.37 (b, 4H), 1.62 (b, 5H), 1.77 (m, 2H), 1.84 (b, 1H),
2.09 (b, 1H), 2.30 (s, 3H), 2.54 (dt, J = 2.7, 12.2 Hz, 1H), 3.16 (d, J =
6.8 Hz, 1H), 3.39 (b, 1H), 3.62 (s, 3H), 5.34 (m, 1H), 7.41 (m, 2H),
7.52 (m, 1H), 7.96 (m, 2H); 13C NMR (CDCl3) δ 13.9, 22.4, 24.4,
26.2, 32.6, 32.9, 33.2, 36.0, 36.1, 51.0, 51.3, 62.4, 67.7, 68.6, 128.2,
129.5, 130.1, 132.9, 165.8, 170.5; HRMS calcd for C22H32NO4 (M +
H) 374.2331, found 374.2327.
(70% EtOAC in hexanes) yielded 0.013 g (95%) of oil: [α]20
D
+73.7 (c 2.195, CHCl3); IR (CHCl3) 1719 cm−1
;
1H NMR
(CDCl3) δ 1.55 (m, 1H), 1.95 (m, 3H), 2.04 (s, 3H), 2.65 (m,
4H), 3.22 (m, 1H), 3.44 (t, J = 6.0 Hz, 1H), 3.71 (s, 3H), 5.24 (d, J =
8.8 Hz, 1H); 13C NMR (CDCl3) δ 24.7, 29.6, 32.6, 33.0, 39.1, 46.5,
51.3, 64.3, 77.2, 131.9, 154.2, 168.3. HRMS calcd for C11H18NO3 (M +
H) 211.1208, found 212.1284.
(1S,6S,E)-(+)-Methyl-7-methyl-3-phenyl-8-oxa-7-aza-bicyclo-
[4.2.1]non-2-ene-2-carboxylate (27e). In a 50 mL, oven-dried,
single-neck round-bottomed flask equipped with magnetic stirring bar
and a rubber septum was placed 24e (0.028 g, 0.076 mmol) in
anhydrous MeOH (1.0 mL) under argon. To this solution was added
pyridine (1.0 mL), and the mixture was stirred at rt for 16 h. At this
time, the solvent was removed, satd aqueous potassium carbonate (30
mL) was added, and the solution was stirred for 10 min. At this time
the aqueous solution was extracted with CHCl3 (3 × 30 mL), and the
combined organic phases were dried (MgSO4) and concentrated.
Methyl (1R,2R,3S,5S)-(+)-1-Phenyl-3-(benzyloxy)-1-phenyl-
8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate (28e). Chro-
matography (40% EtOAc/hexanes) gave 80% of a syrupy oil: IR (film)
1
1710, 1635 cm−1; [α]20 +33.1 (c 1.8, CHCl3); H NMR (CDCl3) δ
D
1.81 (m, 1H), 1.97 (m, 1H), 2.09 (s, 3H), 2.21 (m, 2H), 2.34 (m, 1H),
2.58 (m, 1H), 2.98 (d, J = 6.8 Hz, 1H), 3.22 (s, 3H), 3.52 (m, 1H),
5.38 (td, J = 11.6 Hz, J = 6.3 Hz, 1H), 7.17 (m, 2H), 7.27 (m, 5H),
7.45 (m, 1H), 7.80 (m, 2H); 13C NMR (CDCl3) δ 25.1, 32.3, 34.3,
38.4, 50.9, 58.1, 62.9, 68.3, 73.1. 127.1, 127.7, 128.1, 128.3, 128.4,
129.5, 129.9, 133.0, 133.3, 165.7, 169.7. HRMS calcd for C23H26NO4
(M + H) 380.1862, found 380.1859.
Chromatography (50% EtOAc/hexanes) gave 0.019 g (96%) of a
1
syrupy oil: [α]20 +97.1 (c 0.38, CHCl3); H NMR (CDCl3) δ 1.74
D
(ddt, J = 13.4 Hz, J = 3.4 Hz, J = 1.0 Hz, 1H), 2.04 (m, 1H), 2.15 (d, J
= 12.4 Hz, 1H), 2.33 (td, J = 16.4 Hz, J = 3.9 Hz, 1H), 2.71 (s, 3H),
2.76 (m, 1H), 3.36 (s, 3H), 3.50 (m, 2H), 5.26 (d, J = 9.2 Hz, 1H),
7.08 (m, 2H), 7.27 (m, 3H); 13C NMR (CDCl3) δ 32.7, 33.2, 39.1,
46.6, 51.2, 64.5, 77.2, 126.4, 127.1, 127.9, 134.9, 144.5, 153.1, 169.2.
HRMS calcd for C16H20NO3 (M + H) 274.1443, found 274.1440.
Methyl (1R,2R,3S,5S)-(−)-3-(Benzyloxy)-1,8-dimethyl-8-
azabicyclo[3.2.1]octane-2-carboxylate (28a). Typical Proce-
dure. In a 25 mL, oven-dried, single-neck round-bottomed flask
equipped with magnetic stirring bar and a rubber septum was placed
(−)-25a (0.03 g, 0.097 mmol) in anhydrous pyridine (1.0 mL) under
argon. Benzoyl chloride (0.020 g, 0.145 mmol) was slowly added, and
the solution was stirred at rt for 20 h. At this time the solvent was
removed, satd aqueous potassium carbonate (30 mL) was added, and
the solution was stirred for 10 min. At this time the mixture was
extracted with CHCl3 (3 × 20 mL), and the combined organic phases
were dried (MgSO4) and concentrated. Chromatography (1%
NH4OH in 40% EtOAc/hexanes) gave 0.029 g (94%) of a syrupy
oil: IR (film) 1720, 1645 cm−1; [α]20D −8.3 (c 1.25, CHCl3); 1H NMR
(CDCl3) δ 1.27 (s, 3H), 1.72 (m, 1H), 1.81 (m, 2H), 1.89 (m, 1H),
2.14 (m, 1H), 2.26 (s, 3H), 2.50 (dt, J = 2.7 Hz, J = 12.0 Hz, 1H), 2.94
(d, J = 6.8 Hz, 1H), 3.36 (m, 1H), 3.64 (s, 3H), 5.36 (td, J = 6.4 Hz, J
= 11.7 Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 7.95 (m, 2H); 13C NMR
(CDCl3) δ 22.7, 26.7, 34.2, 34.5, 36.8, 51.1, 55.5, 62.8, 64.9, 68.4,
128.3, 129.5, 130.1, 132.9, 165.9, 170.4. HRMS calcd for C18H24NO4
(M + H) 318.1705, found 318.1701.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental general procedures and 1H and 13C NMR
spectroscopic data for all new compounds; ORTEP/X-ray
structure of tricyclic isoxazolidine (−)-21e in CIF format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: fdavis@temple.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professors David Dalton and William Wuest and Mr.
Gopal Sirasani of Temple University for helpful discussions.
This research was supported in part by the National Institutes
of General Medicinal Sciences (GM 57870).
REFERENCES
■
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