Converting cycloalkanones into N-heterocycles: Formal synthesis of (-)-gephyrotoxin 287C

Article abstract of DOI:10.1021/jo402217e

The photochemical rearrangement of N-activated lactams enables their ring contraction concomitant with the migration of a carbon onto a nitrogen atom. When coupled with the Beckmann rearrangement, this photochemical ring contraction converts cycloalkanones into N-heterocycles in a few steps and in a stereospecific manner. To showcase the method, we performed an efficient formal synthesis of (-)-gephyrotoxin 287C.

Full text of DOI:10.1021/jo402217e

Article
pubs.acs.org/joc
Converting Cycloalkanones into N‑Heterocycles: Formal Synthesis of
(−)-Gephyrotoxin 287C
Simon Pichette, Dana K. Winter, Jean Lessard, and Claude Spino*
́ ́ ́
Departement de Chimie, Universite de Sherbrooke, Sherbrooke, Quebec, Canada J1K 2R1
S
* Supporting Information
ABSTRACT: The photochemical rearrangement of N-
activated lactams enables their ring contraction concomitant
with the migration of a carbon onto a nitrogen atom. When
coupled with the Beckmann rearrangement, this photo-
chemical ring contraction converts cycloalkanones into N-
heterocycles in a few steps and in a stereospecific manner. To
showcase the method, we performed an efficient formal
synthesis of (−)-gephyrotoxin 287C.
is then added to give the corresponding carbamate (3, Nu =
OR) or urea (3, Nu = NR2). The main difference among these
rearrangements is the nature of the primary amide derivative
that is used. In the Hofmann and Lossen rearrangements, the
nitrogen atom is oxidized (N−Br or N−OR) and a base is used
to generate the reactive intermediate, while in the Schmidt and
Curtius rearrangements, an acyl azide is generated and heated
to initiate the reaction, perhaps via a nitrene intermediate.4 In
all of these rearrangements, the starting amide, acyl azide, or
carbamic acid is necessarily primary. Secondary amides or
lactams could not contain the necessary functionalities for the
rearrangement to occur (eq 2).5 Recently, we have added a
unique complement to this list of reactions: the photochemical
and/or thermal rearrangement of N-activated lactams 6 to give
N-heterocycle 7 or a new lactam 8, depending on the carbon
that migrates (Scheme 1).6,7 This ring-contraction reaction
complements the Schmidt-type rearrangements because it
converts lactams 6a−c, thus secondary amide derivatives, to N-
heterocycle 7 or 8, and it is unique because its mechanism,
though not yet completely understood, is different, perhaps
involving a high-energy N-acylnitrenium ion.8 Notably, the
Beckmann rearrangement (a ring-expansion reaction) and our
INTRODUCTION
■
In the last 40 years, over 850 lipophilic alkaloids were reported
to have been isolated from the skin secretion of several species
of poison frogs.1 Those compounds were organized into several
classes on the basis of their respective structures.2 Even if the
carbon framework can differ greatly from one class to another,
there is one characteristic that can be found in each member of
all families: the presence of at least one stereogenic center α to
the nitrogen atom. In Figure 1 is represented a member of each
of the five largest classes of poison frog alkaloids, namely, the
disubstituted indolizidines (205A), the trisubstituted indolizi-
dines (193G), the tricyclics (205B), the pumiliotoxins (225F),
and the decahydroquinolines (195J). In addition to these main
categories, there are several other classes, each containing only
a small number of alkaloids. This is the case of the
gephyrotoxin family of alkaloids, which comprises only two
molecules, namely, gephyrotoxins 287C and 289B, differing
only by the nature of their side chain situated on the cis-
decaline fragment (Figure 1).
The Schmidt-type rearrangements, including the Lossen,
Hofmann, and Curtius rearrangements, are well-known
reactions that are frequently used in total syntheses of natural
alkaloids (eq 1).3 They reliably and stereospecifically convert a
Scheme 1. Rearrangements of N-Activated Lactams
carbon−carbon bond adjacent to a carbonyl (as in 1) into a
carbon−nitrogen bond (as in 2). Typically, an alcohol or amine
Received: October 5, 2013
© XXXX American Chemical Society
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Figure 1. Lipophilic alkaloids from poison frog skin secretion.
Scheme 2. Beckmann Ring-Expansion/Photochemical Ring-Contraction Sequence
Scheme 3. Retrosynthesis of (+)-Gephyrotoxin 287C by Kishi and His Group
Scheme 4. Retrosyntheses of (+)-Gephyrotoxin 287C by Three Different Research Groups
ring-contraction together constitute a formidable sequence
capable of transforming in three steps a cycloalkanone (9) into
an N-heterocycle of the same ring size (11) with retention of
the stereochemistry on either side of the starting carbonyl 9
(Scheme 2). We herein wish to showcase this strategy with a
short and efficient formal synthesis of (−)-gephyrotoxin 287C.
This neurotoxic alkaloid,9 isolated from skin extracts of the
neotropical frog Dendrobates histrionicus, was first named
B
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histrionicotoxin D (HTX-D) and then renamed gephyrotoxin
287C when analysis revealed its decahydroquinoline struc-
ture.10 It is in very short supply (<50 mg isolated from
thousands of frog skins), making its efficient synthesis a
worthwhile goal. ( )-Gephyrotoxin 287C was first synthesized
in the laboratory by Kishi and co-workers in 1980.11a Their
retrosynthesis is shown in Scheme 3. Daly and co-workers had
previously assigned the absolute configuration of natural
(−)-gephyrotoxin 287C as that shown in Scheme 3 for
(+)-gephyrotoxin 287C on the basis of X-ray analysis.10a Kishi’s
synthesis of (+)-gephyrotoxin 287C established the absolute
stereochemistry of natural (−)-gephyrotoxin 287C as the one
shown in Scheme 3.11b There have since been three other
formal syntheses of (+)-gephyrotoxin 287C, all of which
targeted Kishi’s intermediate 13, and their key steps are
summarized in Scheme 4.12,13 Lhommet’s approach involves a
highly diasteroselective reduction of pyrrolo[2,1-b]oxazole 16
into pyrrolidine 17 to achieve a 14-step synthesis of 13 starting
from allyl iodide (15).12a In their approach, Hsung and co-
workers used a poorly diastereoselective (3:2 ratio) intra-
molecular [3 + 2] cycloaddition of 19 to give 20 in order to
achieve an 11-step synthesis of 13 from alcohol 18.12b Lastly,
Trudell and his colleagues achieved the synthesis of 13 in 14
steps from (−)-cocaine (21) via pyrrolidine 22.12c
cyclopentanone 24 to the corresponding pyrrolidine 25 in three
chemical steps. Intermediate 25 could then be converted to 13
by a number of routes. The racemic version of the synthesis
began by alkylation of cyclopentanone 23 via its corresponding
N′,N′-dimethylhydrazone with benzyl-protected bromoethanol
26 to furnish the racemic alkylated product 27 (Scheme 6). At
this point, we decided not to optimize each reaction until the
pivotal photochemical rearrangement proved to proceed in
good yield. Alkylation of rac-27, this time with TBDPS-
protected bromoethanol 28, procured racemic product 29, for
which the ratio of cis and trans products was not determined,
although the presence of both stereoisomers could be detected
1
by H NMR spectroscopy. Only the cis product was required
for the synthesis of gephyrotoxin 287C, but we saw no harm in
testing both isomers in the photochemical ring contraction. We
thus made no effort to improve this diastereomeric ratio, as we
did not expect this to be an issue in the nonracemic version of
the alkylation using Enders’ hydrazone auxiliary. The
diastereomeric and enantiomeric ratios would then be
controlled by the chiral auxiliary.14 The Beckmann rearrange-
ment of 29 gave 30a and 30b as a mixture of regioisomers, a
fact that bore no consequence as both would give the same final
pyrrolidine derivative after the photochemical rearrangement.
Chlorination of amides 30a and 30b and irradiation of the
resulting N-chloroamides 31a and 31b at 254 nm gave a
disappointing 24% yield of the desired pyrrolidine 32 along
with 36% recovery of amides 30a and 30b. The latter were
expected, as the parent lactam nearly always accompanies, to
varying degrees, the ring-contraction product when N-
chlorolactams are used. The rest of the mass balance consisted
of a complex mixture of unidentified chlorinated products,
many having one or more chlorine atoms in their structure.
Those were also anticipated, but in smaller amounts than what
was actually observed.
RESULTS AND DISCUSSION
■
Our initial plan was to alkylate stereoselectively cyclopentanone
(23) with two different two-carbon chains using Enders’ chiral
hydrazones (Scheme 5).14 The syn stereochemistry of the two
Scheme 5. First Retrosynthetic Analysis of Kishi’s
Intermediate 13
The second unusual observation was that the benzyl-
protected alcohol had cyclized onto either the N-acylium ion
33a or the corresponding carbamoyl chloride to yield
carbamate rac-32 after dealkylation of the benzyl group in
33b (Scheme 7).7b While free alcohols and amines add readily
to such intermediates, weaker nucleophiles usually do not, and
the cyclization of the benzyl ether was a surprise.15 This in itself
was not a problem, but the low yield was. To try and improve
alkyl chains in 24 would be controlled by Enders’ hydrazones.
Our strategy then called for the conversion of the alkylated
Scheme 6. Synthesis of Pyrrolidine 32
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two alkyl chains at the 2- and 5-positions are tied together into
a more rigid bicyclic system. Rigid bicyclic N-chlorolactams
usually rearrange in higher yields.6a,b We decided to investigate
both solutions.
Scheme 7. Cyclization of the Benzyl Ether onto the N-
Acylium Ion in 33a
While making the required modifications to synthesize the
corresponding cyclic hydroxamic acid, we improved the yield of
the first steps of the synthetic sequence. The two successive
alkylations of cyclopentanone 23, which were previously
achieved in four steps and 29% overall yield, were combined
into a two-step process where the hydrazine intermediate
derived from 23 was alkylated twice, once with bromide 28 and
next with bromide 34, in a one-pot procedure to give the
required doubly alkylated product 35 as a mixture of cis and
trans isomers in 36% isolated yield (Scheme 8). Again, the
cis:trans ratio was difficult to determine because of overlapping
Scheme 8. Synthetic Sequence To Give Cyclic Hydroxamic
Acid Derivatives 38
1
signals, but both isomers were clearly present in the H NMR
spectrum. A Baeyer−Villiger ring expansion of cyclopentanones
35 to give the corresponding lactones 36a and 36b and
opening of these lactones with O-benzylhydroxylamine
supplied 37a and 37b as a mixture of regio- and stereoisomers.
Cyclization under the Mitsunobu conditions gave a surprising
result: one stereoisomer of 37 gave the cis-disubstituted cyclic
hydroxamic acids 38a and 38b, the result of an N-alkylation,
while the other stereoisomer of 37 afforded the trans-
disubstituted oximes 39a and 39b, the result of an O-alkylation.
The regioisomeric cyclic hydroxamic acids 38a and 38b were
later separately rearranged to the same cis-pyrrolidine, the
stereochemistry of which was established by NOESY (vide
infra). By inference, the stereochemistry of the regioisomeric
oximes 39a and 39b was determined to be anti. Not
surprisingly, oximes 39a and 39b did not rearrange upon
irradiation.
We have observed this phenomenon (O- vs N-alkylation) on
two other occasions (Scheme 9), and there are reported
examples of this occurrence in the literature.17 Hydroxamic acid
isomers 40a and 40b, for example, cyclized to give a 17% yield
of cis cyclic hydroxamic acid 41a, none of the trans isomer 41b,
and a 59% yield of oxime 42.6c The 41a:42 ratio corresponds to
the ratio of the starting isomers 40a and 40b. Cyclization of the
related alcohols 43a and 43b under the Mitsunobu conditions
also gave similar results, this time with a small amount of the
trans cyclic hydroxamic acid 41b accompanying oxime 42.6c
The desired regioisomeric cyclic hydroxamic acid derivatives
38a and 38b have the correct stereochemistry for the synthesis
of gephyrotoxin 287C, and we realized that this phenomenon
would help us procure pure cis-38 in the nonracemic version of
it, we made a number of derivatives in which the alcohols in 31
were protected with various groups, including acetates, MOM
ethers, and various silyl ether derivatives. All led to similarly low
yields of the desired ring-contraction product, a 30−40% yield
of the corresponding parent lactam, and an invariably larger
than expected quantity of chlorinated products.
We envisaged two ways to circumvent this problem. First, we
could use our second-generation ring-contraction methodology,
namely, the photochemical rearrangement of N-mesyloxylac-
tams: the yields of rearrangement products are invariably
higher, and no parent lactam or radical-derived products were
ever isolated in these cases.6 The caveat with this solution is
that it is not yet possible to directly and efficiently oxidize
lactams to cyclic hydroxamic acids.16 Therefore, a detour would
have to be taken to make the required cyclic hydroxamic acid
(vide infra). The second way to circumvent the problem of low
yield would be to use an N-chlorolactam derivative in which the
Scheme 9. N- versus O-Alkylation of Hydroxamic Acid
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Figure 2. O- or N-cyclization of the different stereoisomers of 37.
Scheme 10. Rearrangement of Hydroxamic Acids 45 and 46
the synthesis. Any amount of the wrong anti isomer of
nonracemic 35 produced would end up as the trans oxime 39
and could be removed.
Scheme 11. Synthesis of Carbamate 52
This phenomenon could arise from an unfavorable steric
interaction between R2 and OBn in the transition state leading
to trans-38 (Figure 2). This interaction is alleviated in the TS
leading to trans-oxime 39 and is not present in the TS leading
to cis-38.
The two regioisomers 38a and 38b were separately
debenzylated by hydrogenolysis and mesylated under standard
conditions to give N-mesyloxylactams 44a and 44b (Scheme
10). Separate irradiation of the regioisomers 44a and 44b gave
the same pyrrolidines 45 and 46 in a combined yield of 54%.
This yield was now acceptable, and we believed that we could
increase this yield by modifying the protecting groups for each
alcohol. Moreover, the selective cis-N-cyclization of the
Mitsunobu reaction would ensure a high stereochemical purity
in favor of the desired cis-disubstituted pyrrolidine 46. The only
drawback was the detour via the Baeyer−Villiger reaction
brought about by the difficulty in oxidizing lactams directly to
cyclic hydroxamic acids. As mentioned earlier, we decided also
to explore the next strategy, namely, the photochemical
rearrangement of a bicyclic N-chlorolactam. Often, these
more rigid structures give good yields of the product in the
photochemical rearrangement, and we could take advantage of
the direct chlorination of lactams. Another advantage is that a
bicyclic structure would also provide a pure cis stereochemical
relationship between the two carbon chains on the pyrrolidine
ring.
ketone 48 was increased to 87%, which compares favorably to
the 44% yield reported by Fohlisch and Joachimi.19
̈
Next, we initiated the Beckmann ring-expansion/photo-
chemical ring-contraction sequence (Scheme 11). After trying
several sets of reaction conditions, we found that we could
effect a direct Beckmann rearrangement to afford bicyclic
lactam 50 in 32% yield by treating bicyclic ketone 48 with
hydroxylamine-O-sulfonic acid in formic acid. We obtained a
higher yield using a two-step procedure: formation of oxime 49
from bicyclic ketone 48 followed by a Beckmann rearrange-
ment under basic conditions afforded lactam 50 in 55% yield
over two steps. Chlorination of lactam 50 under standard
conditions afforded the desired N-chlorolactam 51 in 79%
yield. This product was then dissolved in dichloromethane,
cooled to −78 °C, and irradiated with 254 nm UV light in order
to effect the desired ring contraction reaction (Scheme 11).
Evaporation and treatment with benzyl alcohol and base gave
benzyl carbamate 52 in 55% yield (65% brsm), one of the
highest yields obtained for the ring contraction of an N-
chlorolactam. The yield of rearrangement of 51 was the same as
Two methods for the synthesis of bicyclic ketone 48 have
been published. In the method published by Still in 1976, the
enamine of cyclopentanone reacts with cis-1,4-dichloro-2-
butene to yield the desired compound in 38%.18 Unfortunately,
this method proved to be ineffective in our hands. The second
method, published by Fohlisch and Joachimi in 1987, gave
̈
satisfactory results (Scheme 11).19 In the event, a [4 + 3]
cycloaddition took place between 1,3-butadiene and the
Favorskii intermediate generated from 2-chlorocyclopentanone
(47). After some optimization, in particular the fact that the
addition of the base must be really slow, the yield of bicyclic
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Scheme 12. Ozonolysis of 52 and Enzymatic Desymmetrization of Diol 53
Scheme 13. Formal Synthesis of (−)-Gephyrotoxin 287C
the yield of rearrangement of N-mesyloxylactams 44, its
synthesis was shorter, and no trans isomer or side products
were formed. Therefore, if the desymmetrization of 52 proved
to be possible, this synthetic strategy would be the better one.
Ozonolysis of the double bond present in benzyl carbamate
52 followed by a reductive quench afforded meso-diol 53 in
56% yield (Scheme 12). Room-temperature reduction of the
ozonide generated from 52 yielded a lactol intermediate that
was difficult to reduce. Heating the reaction mixture to reflux in
the presence of the hydride was necessary to ensure a complete
reduction to give 53. We then turned our efforts toward the
enzymatic desymmetrization of meso-diol 53. Our initial choice
of the reaction conditions was inspired by the results obtained
by other research groups that had successfully desymmetrized
similar diols.20 However, in their molecules both hydroxyl
groups were on the carbons next to the stereogenic centers. We
were concerned about obtaining poor results because the
hydroxyl groups in our case were two carbons removed from
the stereogenic centers. To the best of our knowledge, no
enzymatic desymmetrization of such substrates has been
reported in the literature. After much optimization with three
different enzymes (PS, PPL, and PFL), we were successful in
obtaining monoacetate 54 in 48% yield and 94:6 er using a
lipase isolated from Pseudomonas fluorescens (PFL) and vinyl
acetate. This was quite a remarkable result, as the other
enzymes afforded nearly racemic products. Some unreacted diol
53 remained, and the rest of the mass balance was mostly
composed of the corresponding diacetate product (not shown).
The recovered diol 53 was resubmitted to the desymmetriza-
tion conditions, thus further increasing the yield of 54 to 58%
after two desymmetrization runs.
conditions. It displayed a negative sign in its optical rotation
measurement, confirming the absolute stereochemistry shown
for the chiral structures in Schemes 12 and 13. This absolute
stereochemistry corresponds to the one needed to make natural
(−)-gephyrotoxin 287C.
In summary, we have developed a short and efficient
synthesis of Kishi’s intermediate to gephyrotoxin 287C,
compound (−)-13, using the powerful combination of the
Beckmann ring expansion and our photochemical ring
contraction to stereospecifically convert a cyclopentanone
into a pyrrolidine.
EXPERIMENTAL SECTION
■
All of the reactions were performed under an inert atmosphere of
argon in glassware that was flame-dried. Solvents were distilled neat
(hexanes), from potassium/benzophenone ketyl (THF), from calcium
hydride (CH2Cl2, toluene, benzene, Et3N), and from 4 Å molecular
sieves (MeOH) prior to use. Triflic anhydride and benzyl alcohol were
also freshly distilled before use. Proton nuclear magnetic resonance
(1H NMR) spectra were recorded on a 300 or 400 MHz spectrometer.
NMR samples were dissolved in chloroform-d (unless specified
otherwise), and chemical shifts are reported in parts per million
relative to the residual undeuterated solvent. Carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on a 75.5 or 100.7 MHz
spectrometer. NMR samples were dissolved in chloroform-d (unless
specified otherwise), and chemical shifts are reported in parts per
million relative to the solvent. LRMS analyses were performed on a
GC system spectrometer (30 m length, 25 μ OD, DB-5 ms column)
coupled with a mass spectrometer. High-resolution mass spectrometry
was performed by electrospray time-of-flight. Reactions were
monitored by thin-layer chromatography (TLC) on 0.25 mm silica
gel-coated UV254 glass plates. Silica gel (particle size 230−400 mesh)
was used for flash chromatography. Melting points are uncorrected.
((2-Bromoethoxy)methyl)benzene (26). Compound 26 was
prepared from 2-(benzyloxy)ethanol following the literature procedure
Oxidation of the alcohol in 54 using the Swern conditions
proceeded with a yield of 91% (Scheme 13). Following the
protocol utilized by Trudell,12c we synthesized compound 56 in
91% yield using a reductive Knoevenagel reaction starting from
aldehyde 55. Next, the benzyl carbamate in 56 was cleaved
using hydrogen and a palladium catalyst. The resulting
secondary amine immediately condensed onto one of the
carbonyl groups, affording a 60% yield of tricyclic compound
57. Kishi’s intermediate (−)-13 was obtained in 49% yield
(68% brsm) after methanolysis of the acetate under basic
of Hammerschmidt and Kahlig.21 1H NMR (300 MHz, CDCl3): δ
̈
7.44−7.28 (m, 5H), 4.60 (s, 2H), 3.79 (t, 2H, J = 6.3 Hz), 3.50 (t, 2H,
J = 6.3 Hz).
2-(2-(Benzyloxy)ethyl)cyclopentanone (27). N,N-Dimethylhy-
drazine hydrochloride (0.746 g, 7.73 mmol) and triethylamine (1.08
mL, 7.73 mmol) were added to a stirring solution of cyclopentanone
(23) (0.500 g, 5.94 mmol) in EtOH (20 mL). The resulting solution
was refluxed for 3.5 h. The solution was concentrated under reduced
pressure to give a brown-orange paste. The paste was dissolved in
F
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diethyl ether (200 mL) and washed with water (100 mL). The
aqueous layer was then extracted with diethyl ether twice (100 mL).
The organic layers were then combined, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to yield cyclo-
diastereomers. Note: only the major isomer is reported. 1H NMR (300
MHz, CDCl3): δ 7.80−7.77 (m, 4H), 7.52−7.25 (m, 11H), 4.62−4.52
(AB quartet, 2H), 3.92−3.77 (m, 2H), 3.71−3.54 (m, 2H), 2.43−2.09
(m, 6H), 1.73−1.37 (m, 4H), 1.16 (s, 9H). 13C NMR (75.5 MHz,
CDCl3): δ 221.7 (s), 138.5 (s), 135.6 (d), 133.8 (s), 129.7 (d), 128.4
(d), 127.8 (d), 127.6 (d), 72.8 (t), 68.3 (t), 62.1 (t), 46.6 (d), 46.5
(d), 33.1 (t), 30.1 (t), 28.0 (t), 27.0 (q), 22.8 (t), 19.3 (s). Note: one
carbon (d) was missing since it overlapped with another signal in the
aromatic region (138.5−127.6 ppm). IR (neat, NaCl) ν (cm−1): 3072,
3037, 2940, 2856, 1734, 1470, 1452, 1430, 1359, 1103. LRMS (m/z,
relative intensity): 500 (M+, 1), 336 (100), 275 (85), 199 (95), 182
(80). HRMS: calcd for C32H40O3Si 500.2747, found 500.2750.
6-(2-(Benzyloxy)ethyl)-3-(2-(tert-butyldiphenylsilyloxy)-
ethyl)piperidin-2-one (30a) and 3-(2-(Benzyloxy)ethyl)-6-(2-
(tert-butyldiphenylsilyloxy)ethyl)piperidin-2-one (30b). Sodium
acetate (0.375 g, 4.57 mmol) and hydroxylamine hydrochloride (0.318
g, 4.57 mmol) were added to a stirring solution of 29 (0.572 g, 1.14
mmol) in methanol (11 mL). The solution was stirred at rt for 20 h,
quenched with a 7.2 pH phosphate buffer (20 mL), and extracted with
DCM (3 × 100 mL). The organic layers were then combined, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure to give a clear oil. The oil was purified by flash
chromatography on silica gel (2:1 to 1:2 hexanes/diethyl ether) to
yield four oximes (two diastereomeric pairs, one for each regioisomer)
as a clear oil (0.546 g, 93%). Note: the four compounds were difficult
to separate, and their characterization as a mixture was difficult. We
therefore separated only one of them and report its characterization.
1H NMR (300 MHz, CDCl3): δ 8.94 (br s, 1H), 7.76−7.71 (m, 4H),
7.48−7.26 (m, 11H), 4.59−4.49 (AB quartet, 2H), 3.86−3.69 (m,
2H), 3.65−3.58 (m, 2H), 3.19−3.08 (m, 1H), 2.72−2.62 (m, 1H),
2.52−2.42 (m, 1H), 2.24−2.13 (m, 1H), 2.06−1.92 (m, 2H), 1.67−
1.24 (m, 4H), 1.10 (s, 9H). 13C NMR (100.7 MHz, CDCl3): δ 170.2
(s), 138.8 (s), 135.9 (d), 135.9 (d), 134.3 (s), 134.2 (s), 129.8 (d),
128.6 (d), 127.9 (d), 127.9 (d), 127.8 (d), 73.1 (t), 68.9 (t), 62.7 (t),
40.7 (d), 37.3 (d), 34.6 (t), 31.5 (t), 30.6 (t), 29.5 (t), 27.1 (q), 19.5
(s). IR (neat, NaCl) ν (cm−1): 3585−3108 (br), 3068, 2936, 2856,
1452, 1421, 1103. LRMS (m/z, relative intensity): 515 (M+, 1), 459
(100), 260 (30), 199 (20), 91 (25). HRMS: calcd for C32H41NO3Si
515.2856, found 515.2860.
Thionyl chloride (120 μL, 1.59 mmol) was added to a stirring
solution of the mixture of oximes (0.546 g, 1.06 mmol) in THF (11
mL) at 0 °C. The solution was stirred for 1 h and then quenched with
a saturated aqueous solution of NaHCO3 (10 mL). The solution was
allowed to stir for 1 h and then extracted three times with CHCl3 (50
mL). The organics were combined, washed with brine (50 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
give a light-yellow oil. The oil was purified by flash chromatography on
silica gel (2:1 to 1:1 hexanes: EtOAc) to yield 30a and 30b as a clear
oil (0.513 g, 94%). Note: the four compounds were difficult to
separate, and their characterization as a mixture was difficult. We
therefore separated only one of them and report its characterization.
1H NMR (300 MHz, CDCl3): δ 7.71−7.67 (m, 4H), 7.45−7.26 (m,
1
pentanone dimethylhydrazone as an orange oil (0.669 g, 89%). H
NMR (300 MHz, CDCl3): δ 2.48 (s, 6H), 2.38 (dt, 4H, J = 6.9, 15.1
Hz), 1.82−1.67 (m, 4H). This compound is known.22
n-BuLi in hexanes (11.6 mL, 2.40 M, 28.0 mmol) was added to a
stirring solution of cyclopentanone dimethylhydrazone (3.21 g, 25.4
mmol) in THF (85 mL) at 0 °C. The resulting mixture was allowed to
stir for 1 h at this temperature, and then a solution of bromide 26
(5.63 g, 26.2 mmol) in THF (40 mL) was added using a cannula. The
solution was then allowed to stir at rt for 45 min. The solution was
then quenched with water and extracted with diethyl ether (3 × 100
mL). The organic layers were combined, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure to give a
brown oil. The oil was dissolved in dichloromethane (500 mL) and
stirred with SiO2 (60 g) for 48 h. The solution was then filtered, and
the silica was washed with copious amounts of EtOAc. The resulting
solution was concentrated under reduced pressure to give a yellow oil.
The oil was purified by flash chromatography on silica gel (6:1 to 2:1
hexanes/diethyl ether) to yield rac-27 as a colorless solid (2.70 g,
49%). m.p. 39−41 °C. 1H NMR (300 MHz, CDCl3): δ 7.37−7.25 (m,
5H), 4.53−4.45 (AB quartet, 2H), 3.63−3.50 (m, 2H), 2.34−1.94 (m,
6H), 1.83−1.67 (m, 1H), 1.63−1.45 (m, 2H). 13C NMR (75.5 MHz,
CDCl3): δ 221.1 (s), 138.5 (s), 128.3 (d), 127.5 (d), 72.7 (t), 68.2 (t),
46.5 (d), 37.9 (t), 29.6 (t), 29.6 (t), 20.8 (t). Note: one carbon (d)
was missing in the aromatic region (128.3−127.5 ppm) since it
overlapped with another signal.
(2-Bromoethoxy)(tert-butyl)diphenylsilane (28). Compound
28 was prepared from 2-bromoethanol following the literature
procedure of Buchwald and co-workers.23 1H NMR (300 MHz,
CDCl3): δ 7.69−7.66 (m, 4H), 7.47−7.36 (m, 6H), 3.92 (t, 2H, J =
6.6 Hz), 3.42 (t, 2H, J = 6.6 Hz), 1.07 (s, 9H).
2-(2-(Benzyloxy)ethyl)-5-(2-(tert-butyldiphenylsilyloxy)-
ethyl)cyclopentanone (29). N,N-Dimethylhydrazine hydrochloride
(2.65 g, 27.4 mmol) and triethylamine (3.6 mL, 26 mmol) were added
to a stirring solution of 27 (3.99 g, 18.3 mmol) in EtOH (120 mL).
The resulting mixture was refluxed for 16 h. The solution was
concentrated under reduced pressure to give an orange paste. The
paste was dissolved in diethyl ether (200 mL) and washed with water
(100 mL). The aqueous layer was then extracted with diethyl ether
twice (100 mL). The organic layers were then combined, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure
to yield the corresponding hydrazone as a yellow oil (4.68 g, 98%). 1H
NMR (400 MHz, CDCl3): δ 7.33−7.23 (m, 5H), 4.52−4.45 (AB
quartet, 2H), 3.57 (t, 2H, J = 6.9 Hz), 2.53−2.37 (m, 2H), 2.44 (s,
6H), 2.29 (dtd, 1H, J = 18.1, 8.5, 1.5 Hz), 2.14−2.06 (m, 1H), 1.97−
1.91 (m, 1H), 1.85−1.76 (m, 1H), 1.64−1.54 (m, 2H), 1.42−1.33 (m,
1H). 13C NMR (100.7 MHz, CDCl3): δ 176.9 (s), 138.9 (s), 128.5
(d), 127.8 (d), 127.6 (d), 73.0 (t), 69.1 (t), 47.3 (q), 42.0 (d), 33.2
(t), 31.1 (t), 29.5 (t), 23.1 (t). IR (neat, NaCl) ν (cm−1): 3032, 2958,
2854, 2812, 1735, 1648, 1457, 1101. LRMS (m/z, relative intensity):
260 (M+, 20), 126 (100), 91 (75). HRMS: calcd for C16H24N2O
260.1889, found 260.1886.
n-BuLi in hexanes (4.0 mL, 2.4 M, 9.5 mmol) was added to a
stirring solution of the hydrazone (2.25 g, 8.64 mmol) in THF (30
mL) at 0 °C. The resulting mixture was stirred for 1 h at this
temperature, and then a solution of bromide 28 (3.45 g, 9.50 mmol) in
THF (10 mL) was added using a cannula. The solution was allowed to
stir at rt for 18 h. The solution was then quenched with water and
extracted with EtOAc (3 × 100 mL). The organic layers were
combined, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give an orange oil. The oil was dissolved in
dichloromethane (140 mL) and stirred with SiO2 (20 g) for 48 h. The
solution was filtered, and the silica was washed with copious amounts
of EtOAc. The resulting solution was concentrated under reduced
pressure to give an orange oil. The oil was purified by flash
chromatography on silica gel (4:1 to 2:1 hexanes/diethyl ether) to
yield rac-29 as a colorless oil (2.89 g, 67% (75% brsm)) as a mixture of
11H), 6.42 (br s, 1H), 4.52 (s, 2H), 3.84−3.71 (m, 2H), 3.68−3.48
(m, 3H), 2.48−2.37 (m, 2H), 1.99−1.52 (m, 7H), 1.06 (s, 9H). 13C
NMR (100.7 MHz, CDCl3): δ 174.5 (s), 138.1 (s), 135.8 (d), 134.2
(s), 134.1 (s), 129.8 (d), 128.7 (d), 128.0 (d), 127.9 (d), 127.9 (d),
73.5 (t), 68.4 (t), 61.9 (t), 53.2 (d), 38.2 (d), 37.0 (t), 34.2 (t), 29.8
(t), 27.1 (q), 26.6 (t), 19.5 (s). IR (neat, NaCl) ν (cm−1): 3209, 3072,
2931, 2865, 1659, 1465, 1421, 1112. LRMS (m/z, relative intensity):
515 (M+, 2), 500 (5), 440 (100). HRMS: calcd for C32H41NO3Si
515.2856, found 515.2855.
6-(2-(Benzyloxy)ethyl)-3-(2-(tert-butyldiphenylsilyloxy)-
ethyl)-1-chloropiperidin-2-one (31a) and 3-(2-(Benzyloxy)-
ethyl)-6-(2-(tert-butyldiphenylsilyloxy)ethyl)-1-chloropiperi-
din-2-one (31b). tert-Butyl hypochlorite (66 μL, 0.55 mmol) was
added dropwise to a stirring solution of 30a and 30b (0.191 g, 0.369
mmol) in dichloromethane (1.5 mL) in the dark at 0 °C. The solution
was stirred for 2 h, whereupon additional tert-butyl hypochlorite was
added (22 μL, 0.18 mmol) and the mixture was stirred for 15 min. The
solution was then concentrated under reduced pressure to give a light-
G
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yellow oil. The oil was purified by flash chromatography on silica gel
(2:1 to 1:1 hexanes/diethyl ether) to yield 31a and 31b as a clear oil
(0.128 g, 63%). Note: the four compounds were difficult to separate,
and their characterization as a mixture was difficult. We therefore
separated only two of them and report their characterization as a
to give a light-orange oil. The oil was dissolved in dichloromethane
(145 mL) and stirred with SiO2 (21 g) for 48 h. The solution was then
filtered from the silica. The silica was then washed with copious
amounts of EtOAc, and the resulting solution was concentrated under
reduced pressure to give a yellow oil. The oil was purified by flash
chromatography on silica gel (6:1 to 4:1 hexanes/diethyl ether) to
yield compound 35 as a clear oil (1.43 g, 36%) as a mixture of
inseparable diastereomers and 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-
cyclopentanone (the product of monoalkylation, 640 mg, 20%). One
of the two stereoisomers of 35 could be obtained stereoisomerically
pure: 1H NMR (300 MHz, CDCl3): δ 7.70−7.68 (m, 4H), 7.44−7.35
(m, 6H), 4.61 (s, 2H), 3.85−3.72 (m, 2H), 3.71−3.56 (m, 2H), 3.35
(s, 3H), 2.39−1.97 (m, 6H), 1.69−1.37 (m, 4H), 1.07 (s, 9H). 13C
NMR (75.5 MHz, CDCl3): δ 221.5 (s), 135.5 (d), 133.7 (d), 129.6
(d), 127.7 (d), 96.3 (t), 65.6 (t), 62.0 (t), 55.1 (q), 46.5 (d), 46.4 (d),
33.0 (t), 30.1 (t), 27.9 (t), 27.9 (t), 26.9 (q), 19.2 (s). IR (neat, NaCl)
ν (cm−1): 3072, 3053, 2900, 2862, 1735, 1469, 1424, 1151, 1113,
1042. LRMS (m/z, relative intensity): 397 (M+ − C4H9, 2), 365 (M+
− C5H14O, 100), 275 (25), 199 (80). HRMS: calcd for C23H29O4Si
(M+ − C4H9) 397.1835, found 397.1844.
1
mixture. H NMR (300 MHz, CDCl3): δ 7.69−7.67 (m, 8H), 7.46−
7.26 (m, 22H), 4.57−4.46 (AB quartet, 2H), 4.53−4.47 (AB quartet,
2H), 3.90−3.69 (m, 6H), 3.67−3.54 (m, 4H), 2.76−2.59 (m, 2H),
2.48−2.27 (m, 4H), 2.16−2.07 (m, 2H), 1.98−1.47 (m, 10H), 1.08 (s,
9H), 1.07 (s, 9H). 13C NMR (75.5 MHz, CDCl3): δ 171.3 (s), 171.2
(s), 138.4 (s), 138.0 (s), 135.6 (d), 135.6 (d), 133.7 (s), 133.4 (s),
129.8 (d), 129.8 (d), 129.7(d), 129.7 (d), 128.4 (d), 128.4 (d), 127.8
(d), 127.8 (d), 73.1 (t), 72.9 (t), 68.1 (t), 66.3 (t), 64.4 (d), 64,3 (d),
61.6 (t), 60.1 (t), 41.2 (d), 41.0 (d), 36.6 (t), 34.4 (t), 34.1 (t), 32.0
(t), 28.9 (t), 28.5 (t), 26.9 (q), 26.9 (q), 24.7 (t), 24.4 (t), 19.2 (s),
19.2 (s). IR (neat, NaCl) ν (cm−1): 3072, 3033, 2931, 2852, 1677,
1430, 1275, 1187, 1112. LRMS (m/z, relative intensity): 549 (M+, 1),
492 (M+ − C4H9, 2), 458 (M+ − C7H7, 100), 350 (30), 199 (25), 91
(85). HRMS: calcd for C28H31NO3SiCl (M+ − C4H9) 492.1762, found
492.1763.
7-(2-(tert-Butyldiphenylsilyloxy)ethyl)hexahydro-1H-
pyrrolo[1,2-c][1,3]oxazin-1-one (32). A mixture of 31a and 31b
(0.250 g, 0.454 mmol) was dissolved in dichloromethane (30 mL) in a
quartz reaction cell, which was lowered into into a Rayonet reactor
chamber equipped with sixteen 254 nm UV lamps and exposed to UV
light at −78 °C under a N2 atmosphere until no more starting material
was detected by TLC (2 h). The solution was then transferred to a
flask containing a mixture of MeOH (10 mL) and Et3N (1 mL). The
reaction mixture was allowed to stir overnight (18 h). The reaction
mixture was concentrated under reduced pressure to give an orange
oil. The oil was dissolved in dichloromethane (30 mL) and washed
with water (30 mL). The aqueous layer was extracted twice with
dichloromethane (30 mL). The organic layers were combined, dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give a light-yellow oil. The oil was taken up in
dichloromethane and purified by flash chromatography on silica gel
(4:1 to 1:1 hexanes/EtOAc) to yield 32 as colorless oil (47 mg, 24%)
and the parent amides 30a and 30b as a clear oil (85 mg, 36%). One of
3-(2-(tert-Butyldiphenylsilyloxy)ethyl)-6-(2-(methoxymeth-
oxy)ethyl)tetrahydro-2H-pyran-2-one (36a) and 6-(2-(tert-
Butyldiphenylsilyloxy)ethyl)-3-(2-(methoxymethoxy)ethyl)-
tetrahydro-2H-pyran-2-one (36b). mCPBA (2.74 g, 12.2 mmol)
and NaHCO3 (1.03 g, 12.2 mmol) were added to a stirring solution of
35 (0.928 g, 2.04 mmol) in DCM (70 mL). The resulting mixture was
stirred at rt for 24 h. The solution was then dissolved in DCM (50
mL) and washed with an aqueous solution of NaOH (25 mL, 1M).
The phases were separated, and the aqueous phase was extracted twice
with DCM (100 mL). The organic layers were then combined, dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to give a light-yellow oil. The oil was purified on by flash
chromatography on silica gel (2:1 to 1:1 hexanes/diethyl ether) to
yield the mixture of stereo- and regioisomeric compounds 36a and
36b as a clear oil (0.575 g, 60%) as a mixture of inseparable
regioisomers. Note: the four compounds were difficult to separate, and
their characterization as a mixture was difficult. We therefore separated
only one of them and report its characterization. 1H NMR (300 MHz,
CDCl3): δ 7.67−7.64 (m, 8H), 7.46−7.36 (m, 12H), 4.61 (s, 4H),
4.61−4.31 (m, 2H), 3.93−3.59 (m, 8H), 3.35 (s, 6H), 2.76−2.50 (m,
2H), 2.38−1.47 (m, 16H) 1.05 (s. 18H). 13C NMR (75.5 MHz,
CDCl3): δ 173.7 (s), 173.5 (s), 135.5 (d), 135.5 (d), 133.6 (s), 133.5
(s), 129.7 (d), 129.7 (d), 127.7 (d), 127.7 (d), 96.5 (t), 96.4 (t), 78.5
(d), 78.3 (d), 64.9 (t), 63.3 (t), 60.9 (t), 59.6 (t), 55.3 (q), 55.3 (q),
39.1 (t), 38.0 (d), 37.7 (d), 36.4 (t), 34.2 (t), 31.7 (t), 29.2 (t), 29.2
(t), 26.8 (q), 26.8 (q), 25.9 (t), 25.5 (t), 19.2 (s), 19.2 (s). IR (neat,
NaCl) ν (cm−1): 3076, 3050, 2930, 2885, 2855, 1731, 1473, 1428,
1185, 1151, 1113, 1035. LRMS (m/z, relative intensity): 439 (M+ −
OC1H3, 5), 413 (M+ − C4H9, 40), 351 (25), 291 (45), 213 (50), 199
(100), 91 (55). HRMS: calcd for C23H29O5Si (M+ − C4H9) 413.1784,
found 413.1776.
1
the two stereoisomers of 32 could be obtained reasonably pure: H
NMR (300 MHz, CDCl3): δ 7.68−7.65 (m, 4H), 7.45−7.35 (m, 6H),
4.29 (ddd, 1H, J = 11.0, 3.9, 1.9 Hz), 4.13−4.01 (m, 2H), 3.73 (t, 2H, J
= 6.3 Hz), 3.48 (ddd, 1H, J = 16.0, 11.0, 5.0 Hz), 2.41−2.31 (m, 1H),
2.18−2.04 (m, 3H), 1.72−1.54 (m, 3H), 1.44−1.31 (m, 1H), 1.04 (s,
9H). 13C NMR (100.7 MHz, CDCl3): δ 153.0 (s), 135.8 (d), 134.0
(s), 133.9 (s), 129.8 (d), 127.9 (d), 65.9 (t), 61.6 (t), 57.6 (d), 57.0
(d), 37.4 (t), 33.4 (t), 30.3 (t), 28.7 (t), 27.1 (q), 19.4 (s). IR (neat,
NaCl) ν (cm−1): 3064, 2936, 2861, 1695, 1470, 1430, 1112. LRMS
(m/z, relative intensity): 367 (M+ − C4H8, 100), 320 (10), 294 (15).
HRMS: calcd for C21H25NO3Si (M+ − C4H8) 367.1604, found
367.1605.
1-Bromo-2-(methoxymethoxy)ethane (34). Compound 34 was
prepared from 2-bromoethanol following the literature procedure of
Ito and co-workers.24 1H NMR (300 MHz, CDCl3): δ 4.68 (s, 2H),
3.87 (t, 2H, J = 6.1 Hz), 3.51 (t, 2H, J = 6.1 Hz), 3.39 (s, 3H).
2-(2-(tert-Butyldiphenylsilyloxy)ethyl)-5-(2-(methoxymeth-
oxy)ethyl)cyclopentanone (35). n-BuLi in hexanes (5.60 mL, 1.95
M, 10.9 mmol) was added to a stirring solution of cyclopentanone
dimethylhydrazone (prepared in the same way as in the synthesis of
compound 27) (1.10 g, 8.74 mmol) in THF (30 mL) at 0 °C. The
resulting mixture was allowed to stir for 30 min at this temperature,
and then a solution of bromide 28 (3.81 g, 10.5 mmol) in THF (10
mL) was added using a cannula. The solution was then allowed to stir
at rt for 30 min. The solution was then cooled down again to 0 °C, and
n-BuLi in hexanes (5.60 mL, 1.95 M, 10.9 mmol) was added. The
resulting mixture was allowed to stir for 30 min at this temperature,
and then a solution of bromide 34 (1.77 g, 10.5 mmol) in THF (10
mL) was added using a cannula. The solution was allowed to stir at rt
for 90 min and was then quenched with water and extracted into
EtOAc (3 × 100 mL). The organic layers were combined, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure
N-(Benzyloxy)-2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-hy-
droxy-7-(methoxymethoxy)heptanamide (37a) and N-(Benzyl-
oxy)-7-(tert-butyldiphenylsilyloxy)-5-hydroxy-2-(2-(methoxy-
methoxy)ethyl)heptanamide (37b). Trimethylaluminum (3.7 mL,
1.0 M in toluene, 3.7 mmol) was added to a stirring solution of O-
benzylhydroxylamine (596 mg, 3.73 mmol) in anhydrous THF (12
mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C and
30 min at rt and then cooled again to −10 °C. A solution of lactone
36a and 36b (586 mg, 1.24 mmol) in THF (12 mL) was transferred to
the reaction mixture using a cannula. The solution was allowed to stir
for 2 h at 0 °C. The resulting solution was cooled to 0 °C and then
quenched with a 0.5 N aqueous HCl solution (20 mL) portionwise
over 1 h. The resulting mixture was then extracted with EtOAc (3 ×
50 mL). The organic layers were then combined, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure to give a
clear oil. The oil was purified by flash chromatography on silica gel
(2:1 to 1:2 hexanes/diethyl ether) to yield 37a and 37b as a clear oil
(477 mg, 65% (73% brsm)) as a mixture of inseparable regioisomers
1
(3:2). H NMR (300 MHz, CDCl3): δ 8.77 (br s, 1H), 8.47 (br s,
H
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1H), 7.68−7.62 (m, 8H), 7.47−7.33 (m, 22H), 4.94−4.87 (AB
quartet, 2H), 4.87−4.78 (AB quartet, 2H), 4.61 (s, 2H), 4.51 (s, 2H),
3.90−3.54 (m, 8H), 3.46−3.38 (m, 2H), 3.35 (s, 3H), 3.30 (s, 3H),
2.32−2.21 (m, 2H), 2.01−1.66 (m, 10H), 1.63−1.40 (m, 6H), 1.04 (s,
9H), 1.02 (s, 9H). 13C NMR (75.5 MHz, CDCl3): δ 173.7 (s), 173.5
(s), 135.5 (d), 135.5 (d), 133.7 (s), 133.5 (s), 132.9 (s), 132.7 (s),
129.9 (d), 129.9 (d), 129.8 (d), 129.8 (d), 129.1 (d), 129.1 (d), 128.5
(d), 128.5 (d), 127.8 (d), 127.8 (d), 96.5 (t), 96.5 (t), 78.1 (t), 78.1
(t), 71.5 (d), 70.7 (d), 66.4 (t), 65.6 (t), 63.6 (t), 61.5 (t), 55.4 (q),
55.3 (q), 40.2 (d), 39.7 (d), 37.7 (t), 37.7 (t), 36.0 (t), 35.1 (t), 34.3
(t), 32.5 (t), 27.9 (t), 27.9 (t), 26.9 (q), 26.8 (q), 19.2 (s), 19.0 (s). IR
(neat, NaCl) ν (cm−1): 3653−3323 (br), 3323−3106 (br), 3076,
3035, 2934, 2855, 1656, 1473, 1432, 1110, 1038. LRMS (m/z, relative
intensity): 536 (M+ − C4H9, 2), 518 (M+ − C4H11O, 3), 413 (25),
291 (40), 199 (100), 91 (85). HRMS: calcd for C30H38NO6Si (M+ −
C4H9) 536.2468, found 536.2459.
cis-1-(Benzyloxy)-3-(2-(tert-butyldiphenylsilyloxy)ethyl)-6-
(2-(methoxymethoxy)ethyl)piperidin-2-one (38a), cis-1-(Benz-
yloxy)-6-(2-(tert-butyldiphenylsilyloxy)ethyl)-3-(2-(methoxy-
methoxy)ethyl)piperidin-2-one (38b), trans-3-(2-(tert-
Butyldiphenylsilyloxy)ethyl)-6-(2-(methoxymethoxy)ethyl)-
tetrahydro-2H-pyran-2-one O-Benzyl Oxime (39a), and trans-
6-(2-(tert-Butyldiphenylsilyloxy)ethyl)-3-(2-(methoxymeth-
oxy)ethyl)tetrahydro-2H-pyran-2-one O-Benzyl Oxime (39b).
DIAD (0.17 mL, 0.84 mmol) was added to a stirring solution of PPh3
(0.221 g, 0.843 mmol) in DCM (8 mL) at −10 °C. The solution was
stirred for 30 min at this temperature, and then a solution of alcohols
37a and 37b (0.477 g, 0.804 mmol) in DCM (8 mL) was added to the
reaction mixture using a cannula. The resulting solution was left to stir
at rt for 16 h and then concentrated under reduced pressure to give a
yellow oil. The oil was purified by flash chromatography on silica gel
(6:1 to 1:1 hexanes/EtOAc) to yield the separable isomers 38a and
38b as a clear oil (products of N-cyclization, 120 mg, 26%) and two
inseparable O-cyclization products 39a and 39b as a clear oil (146 mg,
38%).
1102, 1050. LRMS (m/z, relative intensity): 575 (M+, 2), 518 (M+ −
C4H9, 90), 293 (30), 199 (40), 91 (100). HRMS: calcd for
C34H45NO5Si 575.3067, found 575.3077.
cis-3-(2-(tert-Butyldiphenylsilyloxy)ethyl)-6-(2-(methoxy-
methoxy)ethyl)-2-oxopiperidin-1-yl Methanesulfonate (44a).
To a solution of 38a (77.1 mg, 0.134 mmol) in EtOH (13 mL) was
added Pd/C (∼25−50 mg, 10 wt % on activated carbon). The reaction
mixture was then allowed to stir at rt under a positive pressure of
hydrogen (1 atm) until no more starting material was seen by TLC
(10 h). The solution was then filtered through Celite and concentrated
under reduced pressure to give the cyclic hydroxamic acid as an orange
1
oil (65 mg). H NMR (300 MHz, CDCl3): δ 7.63−7.60 (m, 4H),
7.42−7.31 (m, 6H), 4.59−4.54 (AB quartet, 2H), 3.93−3.85 (m, 1H),
3.79−3.53 (m, 4H), 3.31 (s, 3H), 2.58−2.45 (m, 1H), 2.29−2.12 (m,
2H), 1.90−1.73 (m, 3H), 1.70−1.50 (m, 3H), 1.01 (s, 9H). 13C NMR
(75.5 MHz, CDCl3): δ 166.9 (s), 135.5 (d), 133.4 (s), 129.7 (d), 127.7
(d), 96.3 (t), 65.3 (t), 60.9 (t), 56.6 (d), 55.2 (q), 37.8 (d), 34.8 (t),
31.5 (t), 26.8 (q), 25.4 (t), 23.0 (t), 19.1 (s). IR (neat, NaCl) ν
(cm−1): 3469−3177 (br), 2982, 2941, 2881, 1626, 1514, 1237, 1106,
1035. LRMS (m/z, relative intensity): 485 (M+, 1), 470 (M+ − CH3,
1), 428 (M+ − C4H9, 100), 200 (20). HRMS: calcd for C27H39NO5Si
485.2597, found 485.2590.
Triethylamine (25 μL, 0.18 mmol), 4-dimethylaminopyridine (5.5
mg, 0.045 mmol), and methanesulfonyl chloride (13 μL, 0.17 mmol)
were added to a cooled (0 °C) stirring solution of the cyclic
hydroxamic acid (73 mg, 0.15 mmol) in dichloromethane (1.5 mL).
The resulting mixture was stirred at 0 °C for 1 h. The resulting
solution was quenched with a 0.5 N aqueous HCl solution (10 mL)
and extracted with dichloromethane (3 × 25 mL). The organic layers
were then combined, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to yield a pink oil. The oil was
purified by flash chromatography on silica gel (1:1 to 1:2 hexanes/
diethyl ether) to yield 44a as a clear oil (44 mg, 52% (86% brsm)). 1H
NMR (300 MHz, CDCl3): δ 7.66−7.64 (m, 4H), 7.46−7.37 (m, 6H),
4.63−4.58 (AB quartet, 2H), 4.28−4.24 (m, 1H), 3.77−3.56 (m, 4H),
3.35 (s, 3H), 3.22 (s, 3H), 2.74−2.64 (m, 1H), 2.34−2.21 (m, 2H),
2.17−2.02 (m, 2H), 1.93−1.83 (m, 1H), 1.72−1.56 (m, 3H), 1.05 (s,
9H). 13C NMR (75.5 MHz, CDCl3): δ 171.7 (s), 135.5 (d), 133.3 (s),
133.2 (s), 129.8 (d), 127.7 (d), 96.4 (t), 65.0 (t), 62.5 (d), 60.7 (t),
55.3 (q), 40.5 (d), 39.0 (q), 33.0 (t), 30.8 (t), 26.8 (q), 26.2 (t), 22.7
(t), 19.1 (s). IR (neat, NaCl) ν (cm−1): 3072, 3042, 2941, 2855, 1701,
1372, 1185, 1110, 1038. LRMS (m/z, relative intensity): 532 (M+ −
CH3O, 2), 506 (M+ − C4H9, 5), 366 (100). HRMS: calcd for
C24H32NO7SSi (M+ − C4H9) 506.1669, found 506.1654.
Data for 38a. 1H NMR (300 MHz, CDCl3): δ 7.70−7.67 (m, 4H),
7.47−7.33 (m, 11H), 4.94 (s, 2H), 4.57 (s, 2H), 3.87−3.60 (m, 3H),
3.56 (t, 2H, J = 6.3 Hz), 3.32 (s, 3H), 2.66−2.55 (m, 1H), 2.44−2.33
(m, 1H), 2.29−2.18 (m, 1H), 1.87−1.48 (m, 6H), 1.06 (s, 9H). 13C
NMR (75.5 MHz, CDCl3): δ 170.2 (s), 135.6 (d), 133.8 (s), 133.7 (s),
129.6 (d), 128.6 (d), 128.4 (d), 127.6 (d), 96.4 (t), 75.6 (t), 65.8 (t),
61.7 (t), 57.8 (d), 55.3 (q), 39.7 (d), 34.0 (t), 32.4 (t), 26.8 (q), 26.2
(t), 22.8 (t), 19.2 (s). IR (neat, NaCl) ν (cm−1): 3072, 3035, 2937,
2881, 2859, 1656, 1110, 1035. LRMS (m/z, relative intensity): 518
(M+ − C4H9, 100), 91 (60). HRMS: calcd for C30H36NO5Si (M+ −
C4H9) 518.2363, found 518.2368.
cis-6-(2-(tert-Butyldiphenylsilyloxy)ethyl)-3-(2-(methoxy-
methoxy)ethyl)-2-oxopiperidin-1-yl Methanesulfonate (44b).
To a solution of 38b (0.114 g, 0.197 mmol) in EtOH (7 mL) was
added Pd/C (∼25−50 mg, 10 wt % on activated carbon). The reaction
mixture was then allowed to stir at rt under a positive pressure of
hydrogen (1 atm.) until no more starting material was seen by TLC (6
h). The solution was then filtered through Celite and concentrated
under reduced pressure to give the cyclic hydroxamic acid as an orange
Data for 38b. 1H NMR (300 MHz, CDCl3): δ 7.61−7.59 (m, 4H),
7.42−7.26 (m, 11H), 4.89 (s, 2H), 4.62−4.57 (AB quartet, 2H), 3.73−
3.56 (m, 5H), 3.33 (s, 3H), 2.55−2.46 (m, 1H), 2.34−2.18 (m, 2H),
1.82−1.50 (m, 6H), 1.01 (s, 9H). 13C NMR (75.5 MHz, CDCl3): δ
169.8 (s), 135.5 (d), 135.3 (s), 133.4 (s), 129.7 (d), 129.5 (d), 128.5
(d), 128.3 (d), 127.7 (d), 96.3 (t), 75.4 (t), 65.5 (t), 60.9 (t), 57.5 (d),
55.2 (q), 29.8 (d), 34.5 (t), 31.3 (t), 26.8 (q), 25.8 (t), 22.9 (t), 19.1
(s). IR (neat, NaCl) ν (cm−1): 2986, 2937, 2877, 1653, 1510, 1465,
1110. LRMS (m/z, relative intensity): 544 (M+ − OMe, 5), 518 (M+
− C4H9, 15), 456 (25), 366 (50), 91 (100). HRMS: calcd for
C30H36NO5Si (M+ − C4H9) 518.2363, found 518.2352.
1
oil (94 mg, 98%). H NMR (300 MHz, CDCl3): δ 7.67−7.65 (m,
4H), 7.44−7.36 (m, 6H), 4.63−4.59 (AB quartet, 2H), 3.91−3.62 (m,
5H), 3.36 (s, 3H), 2.73−2.55 (m, 1H), 2.35−2.21 (m, 2H), 1.97−1.69
(m, 4H), 1.63−1.50 (m, 2H), 1.05 (s, 9H). 13C NMR (75.5 MHz,
CDCl3): δ 167.3 (s), 135.5 (d), 133.7 (s), 133.6 (s), 129.6 (d), 127.7
(d), 96.4 (t), 64.7 (t), 61.5 (t), 56.6 (d), 55.3 (q), 37.6 (d), 34.1 (t),
32.6 (t), 26.8 (q), 25.7 (t), 22.8 (t), 19.2 (s). IR (neat, NaCl) ν
(cm−1): 3398−3106 (br), 3068, 3050, 2934, 2859, 1731, 1634, 1473,
1102, 1038. LRMS (m/z, relative intensity): 485 (M+, 1), 470 (M+ −
CH3, 2), 428 (M+ − C4H9, 100), 199 (20). HRMS: calcd for
C27H39NO5Si 485.2597, found 485.2590.
Data for 39a/39b. 1H NMR (300 MHz, CDCl3): δ 7.70−7.68 (m,
8H), 7.52−7.26 (m, 22H), 5.00 (s, 2H), 4.97 (s, 2H), 4.63 (s, 2H),
4.60−4.55 (AB quartet, 2H), 4.38−4.32 (m, 1H), 4.32−4.22 (m, 1H),
3.98−3.90 (m, 1H), 3.84−3.60 (m, 5H), 3.58 (t, 2H, J = 6.3 Hz), 3.35
(s, 6H), 2.71−2.55 (m, 2H), 2.22−1.73 (m, 10H), 1.72−1.50 (m, 6H),
1.08 (s, 18H). 13C NMR (75.5 MHz, CDCl3): δ 157.1 (s), 156.7 (s),
138.6 (s), 138.4 (s), 135.6 (d), 135.6 (d), 134.0 (s), 133.9 (s), 133.8
(s), 133.6 (s), 129.6 (d), 129.6 (d), 128.1 (d), 128.1 (d), 127.7 (d),
127.7 (d), 127.4 (d), 127.4 (d), 96.5 (t), 96.5 (t), 75.7 (t), 75.7 (t),
75.0 (d), 74.8 (d), 65.4 (t), 63.8 (t), 61.5 (t), 60.0 (t), 55.2 (q), 55.2
(q), 38.1 (t), 35.5 (t), 34.2 (t), 33.3 (t), 31.2 (d), 31.0 (d), 26.9 (q),
26.9 (q), 25.2 (t), 25.2 (t), 24.9 (t), 24.9 (t), 19.2 (s), 19.2 (s). IR
(neat, NaCl) ν (cm−1): 3072, 3031, 2930, 2855, 1641, 1469, 1424,
Triethylamine (32 μL, 0.23 mmol), 4-dimethylaminopyridine (7.1
mg, 0.058 mmol), and methanesulfonyl chloride (16 μL, 0.21 mmol)
were added to a cooled (0 °C) stirring solution of the cyclic
hydroxamic acid (94 mg, 0.19 mmol) in dichloromethane (1.9 mL).
The resulting mixture was stirred at 0 °C for 1 h. The resulting
solution was quenched with a 0.5 N aqueous HCl solution (10 mL)
and extracted with dichloromethane (3 × 25 mL). The organic layers
I
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Article
were then combined, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to yield a pink oil. The oil was
purified by flash chromatography on silica gel (2:1 to 1:1 hexanes/
diethyl ether) to yield 44b as a clear oil (83 mg, 76%). 1H NMR (300
MHz, CDCl3): δ 7.66−7.64 (m, 4H), 7.46−7.33 (m, 6H), 4.62−4.57
(AB quartet, 2H), 4.22−4.18 (m, 1H), 3.85−3.62 (m, 2H), 3.60 (t,
2H, J = 6.3 Hz), 3.35 (s, 3H), 3.22 (s, 3H), 2.81−2.71 (m, 1H), 2.38−
2.25 (m, 2H), 2.19−1.95 (m, 2H), 1.93−1.53 (m, 4H), 1.05 (s, 9H).
13C NMR (75.5 MHz, CDCl3): δ 171.9 (s), 135.5 (d), 133.6 (s), 133.5
(s), 129.7 (d), 127.7 (d), 96.5 (t), 64.4 (t), 62.4 (d), 61.2 (t), 55.4 (q),
40.3 (d), 39.1 (q), 33.5 (t), 31.1 (t), 26.8 (q), 26.5 (t), 22.7 (t), 19.2
(s). IR (neat, NaCl) ν (cm−1): 3080, 3050, 2934, 2877, 1694, 1473,
1428, 1376, 1185, 1106, 1035. LRMS (m/z, relative intensity): 506
(M+ − C4H9, 100), 199 (30). HRMS: calcd for C24H32NO7SSi (M+ −
C4H9) 506.1669, found 506.1654.
extracts were combined, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using ethyl acetate and hexanes
(2.5:97.5) as the eluent to give a colorless oil (5.00 g, 87%). 1H NMR
(300 MHz, CDCl3): δ 5.70−5.56 (m, 2H), 2.59−2.49 (m, 2H), 2.31−
2.13 (m, 4H), 2.11−2.01 (m, 2H), 1.66 (AB quartet, 2H). 13C NMR
(75.5 MHz, CDCl3): δ 224.0 (s), 126.6 (d), 45.3 (d), 32.1 (t), 25.6
(t). IR (CHCl3) ν (cm−1): 3040, 2953, 2837, 1726, 1654, 1447, 1356,
1162, 1046. LRMS (m/z, relative intensity): 159 (MNa+, 100).
HRMS: calcd for C9H12ONa 159.0780, found 159.0784.
Bicyclo[4.2.1]non-3-en-9-one, oxime (49). To a solution of
ketone 48 (0.100 g, 0.734 mmol) in a 2:1 mixture of water (1.5 mL)
and MeOH (0.75 mL) at rt were added sodium acetate (0.300 g, 3.65
mmol) and hydroxylamine hydrochloride (61.2 mg, 0.881 mmol). The
reaction mixture was stirred at reflux for 18 h before being allowed to
cool to rt. Water (25 mL) was added, and the aqueous phase was
extracted with dichloromethane (3 × 25 mL). The organic extracts
were combined, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel using ethyl acetate and hexanes
(10:90) as the eluent to give compound 49 as a white solid (97.5 mg,
88%). 1H NMR (300 MHz, CDCl3): δ 5.60−5.50 (m, 2H), 3.61−3.51
(m, 1H), 2.95−2.85 (m, 1H), 2.53−2.39 (m, 1H), 2.32−2.11 (m, 4H),
2.05−1.86 (m, 2H), 1.65−1.50 (m, 2H). 13C NMR (75.5 MHz,
CDCl3): δ 172.0 (s), 126.8 (d), 126.5 (d), 40.0 (d), 35.8 (t), 34.9 (d),
32.4 (t), 28.4 (t), 28.4 (t). IR (CHCl3) ν (cm−1): 3513−3018, 2950,
2903, 2837, 1595, 1444, 1347, 1303, 1178, 1043. LRMS (m/z, relative
intensity): 174 (MNa+, 100). HRMS: calcd for C9H13NONa 174.0889,
found 174.0894. m.p. 92−94 °C.
7-Azabicyclo[4.2.2]dec-3-en-8-one (50). To a solution of oxime
49 (0.100 g, 0.661 mmol) in a 1:1 mixture of water (1.5 mL) and THF
(1.5 mL) at rt were added sodium hydroxide (0.264 g, 6.60 mmol) and
p-toluenesulfonyl chloride (0.628 g, 3.30 mmol). The reaction mixture
was stirred at reflux for 18 h before being allowed to cool to rt. Water
(25 mL) was added, and the aqueous phase was extracted with
dichloromethane (3 × 25 mL). The organic extracts were combined,
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified by flash
chromatography on silica gel using methanol and ethyl acetate
(5:95) as the eluent to give bicyclic lactam 50 as a white solid (62.1
mg, 62%). 1H NMR (300 MHz, CDCl3): δ 6.36 (br s, 1H), 5.44−5.24
(m, 2H), 3.81−3.72 (m, 1H), 2.84−2.67 (m, 2H), 2.64−2.33 (m, 3H),
2.10−1.94 (m, 2H), 1.93−1.74 (m, 2H). 13C NMR (75.5 MHz,
CDCl3): δ 177.6 (s), 124.5 (d), 123.8 (d), 47.7 (d), 39.5 (t), 38.4 (d),
36.6 (t), 24.6 (t), 23.7 (t). IR (CHCl3) ν (cm−1): 3497−3022, 3410,
3206, 2987, 2953, 2890, 2831, 1660, 1478, 1447, 1328, 1043. LRMS
(m/z, relative intensity): 174 (MNa+, 100). HRMS: calcd for
C9H13NONa 174.0889, found 174.0881. m.p. 130−132 °C.
cis-Methyl 2-(2-(tert-Butyldiphenylsilyloxy)ethyl)-5-(2-
(methoxymethoxy)ethyl)pyrrolidine-1-carboxylate (45) and
cis-7-(2-(tert-Butyldiphenylsilyloxy)ethyl)hexahydro-1H-
pyrrolo[1,2-c][1,3]oxazin-1-one (46). N-Mesyloxylactam 44a (70
mg, 0.12 mmol) was dissolved in DCM (20 mL) in a quartz reaction
cell, which was lowered into a Rayonet reactor chamber equipped with
sixteen 254 nm UV lamps. The reaction mixture was then exposed to
UV light at −78 °C under a N2 atmosphere until no more starting
material was seen by TLC (5.5 h). The solution was then transferred
to a flask containing a mixture MeOH (5 mL) and Et3N (0.5 mL). The
reaction mixture was allowed to stir overnight (16 h). The reaction
mixture was concentrated under reduced pressure to give an orange
oil. The solution was then concentrated to give a light-yellow oil. The
oil was dissolved in dichloromethane (30 mL) and washed with water
(30 mL). The aqueous layer was extracted twice with dichloromethane
(30 mL). The organic layers were then combined, dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure
to give a yellow oil. The oil was taken up in dichloromethane and
purified by flash chromatography on silica gel (4:1 to 1:2 hexanes/
EtOAc) to yield 45 as a clear oil (6 mg, 10%) and 46 as light-yellow oil
(23 mg, 44%). The same reaction starting from 44b gave identical
yields of products.
1
Data for 45. H NMR (300 MHz, CDCl3): δ 7.68−7.65 (m, 4H),
7.45−7.35 (m, 6H), 4.63−4.58 (AB quartet, 2H), 3.98−3.89 (m, 2H),
3.76−3.62 (m, 2H), 3.65 (s, 3H), 3.55 (t, 2H, J = 6.6 Hz), 3.36 (s,
3H), 2.27−1.99 (m, 4H), 1.95−1.44 (m, 4H), 1.05 (s, 9H). 13C NMR
(100.7 MHz, CDCl3): δ 156.2 (s), 135.8 (d), 134.1 (s), 129.8 (d),
127.9 (d), 96.6 (t), 65.6 (t), 61.9 (d), 61.9 (d), 55.4 (q), 52.3 (q), 52.3
(t), 35.9 (t), 35.9 (t), 30.1 (t), 27.1 (q), 26.3 (t), 19.4 (s). IR (neat,
NaCl) ν (cm−1): 2949, 2926, 2877, 2855, 1698, 1447, 1383, 1102.
LRMS (m/z, relative intensity): 442 (M+ − C4H9, 100), 412 (10), 366
(20), 294 (25), 213 (30), 183 (35). HRMS: calcd for C24H32NO5Si
(M+ − C4H9) 442.2050, found 442.2057.
1
Data for 46. H NMR (300 MHz, CDCl3): δ 7.67−7.65 (m, 4H),
Chloro-7-azabicyclo[4.2.2]dec-3-en-8-one (51). To a solution
of lactam 50 (0.500 g, 3.31 mmol) in THF (35 mL) at rt was added
sodium hydride (60% suspension in mineral oil, 0.172 g, 4.30 mmol).
The reaction mixture was stirred 15 min at rt, and N-
chlorosuccinimide (0.664 g, 4.97 mmol) was added. The solution
was shielded from light and stirred at rt for another 15 min, after which
a 1 N NaOH aqueous solution (100 mL) was added. The aqueous
phase was extracted with dichloromethane (3 × 75 mL), and the
organic extracts were combined, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel using ethyl acetate and
hexanes (25:75) as the eluent to give N-chlorolactam 51 as a white
7.44−7.36 (m, 6H), 4.37 (ddd, 1H, J = 12.9, 5.0, 1.1 Hz), 4.15 (ddd,
1H, J = 12.9, 12.9, 3.3 Hz), 3.98 (ddd, 1H, J = 8.8, 8.8, 2.2 Hz), 3.77−
3.63 (m, 2H), 3.47 (ddt, 1H, J = 16.0, 8.8, 3.3 Hz), 2.43−2.34 (m,
1H), 2.13−1.94 (m, 3H), 1.89−1.76 (m, 1H), 1.69−1.41 (m, 3H),
1.04 (s, 9H). 13C NMR (77.5 MHz, CDCl3): δ 151.8 (s), 135.6 (d),
133.6 (s), 129.6 (d), 127.6 (d), 67.1 (t), 62.1 (t), 56.8 (d), 56.7 (d),
35.0 (t), 30.6 (t), 29.0 (t), 28.3 (t), 26.8 (q), 19.1 (s). IR (neat, NaCl)
ν (cm−1): 3072, 3050, 2964, 2934, 2859, 1694, 1473, 1424, 1342,
1293, 1188, 1110, 1091 . LRMS (m/z, relative intensity): 366 (M+ −
C4H9, 100), 320 (15), 294 (60), 197 (30), 183 (35). HRMS: calcd for
C21H24NO3Si (M+ − C4H9) 366.1525, found 366.1533.
Bicyclo[4.2.1]non-3-en-9-one (48). 1,3-Butadiene (37 mL, 422
mmol) was condensed in a graduated cylinder at −78 °C before being
added to a solution of 2-chlorocyclopentanone (47) (4.22 mL, 42.2
mmol) in trifluoroethanol (42 mL) at −15 °C. A solution of sodium
trifluoroethoxide in trifluoroethanol (85 mL, 1.0 M, 84 mmol),
previously prepared by the addition of sodium to trifluoroethanol, was
added dropwise (7 h @ 0.2 mL/min), and the reaction mixture was
allowed to stir at −15 °C for 18 h. A 1 N aqueous HCl solution was
added until an acidic pH was obtained. The aqueous phase was
extracted with dichloromethane (3 × 150 mL), and the organic
1
solid (0.488 g, 79%). H NMR (300 MHz, CDCl3): δ 5.47−5.38 (m,
1H), 5.33−5.25 (m, 1H), 4.08−4.02 (m, 1H), 3.08−2.93 (m, 2H),
2.91−2.77 (m, 1H), 2.51−2.27 (m, 3H), 2.14−1.98 (m, 2H), 1.90−
1.78 (m, 1H). 13C NMR (75.5 MHz, CDCl3): δ 172.7 (s), 125.4 (d),
122.4 (d), 62.3 (d), 41.8 (d), 35.6 (t), 35.5 (t), 25.8 (t), 24.2 (t). IR
(CHCl3) ν (cm−1): 3000, 2956, 2893, 2831, 1660, 1406, 1284, 1240,
1165, 1134, 1093, 1043. LRMS (m/z, relative intensity): 186 (MH+,
15), 208 (MNa+, 100) . HRMS: calcd for C9H12ClNONa 208.0500,
found 208.0499. m.p. 55−57 °C.
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The Journal of Organic Chemistry
Article
Benzyl 9-Azabicyclo[4.2.1]non-3-ene-9-carboxylate (52). N-
Chlorolactam 51 (1.22 g, 6.57 mmol) was separated in four portions
of 305 mg each. Those portions were separately dissolved in
dichloromethane (110 mL). The solutions were transferred to quartz
cells, cooled to −78 °C, and irradiated with 254 nm UV light. After
irradiation at −78 °C for 45 min, the reaction mixtures were
transferred and combined in a round-bottom flask, and the solvent was
removed under reduced pressure. The residue was dissolved in THF
(40 mL), and the solution was cooled to 0 °C, after which benzyl
alcohol (0.36 mL, 3.4 mmol) was added. NaH (60% suspension in
mineral oil, 0.151 g, 3.78 mmol) was added portionwise, and the
reaction mixture was stirred at 0 °C for 15 min. A 1 N HCl aqueous
solution (100 mL) was added. The aqueous phase was extracted with
dichloromethane (3 × 75 mL), and the organic extracts were
combined, dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using ethyl acetate and hexanes (5:95) as
the eluent to give bicyclic compound 52 as a colorless oil (1.16 g,
55%). 1H NMR (300 MHz, CDCl3): δ 7.37−7.29 (m, 5H), 5.58−5.45
(m, 2H), 5.14 (AB quartet, 2H), 4.42 (d, 2H, J = 19.5 Hz), 2.71 (d,
1H, J = 20.6 Hz), 2.57 (d, 1H, J = 18.7 Hz), 2.21−2.02 (m, 4H), 1.69−
1.58 (m, 2H). 13C NMR (75.5 MHz, CDCl3): Rotamer A: δ 153.4
(s), 137.1 (s), 128.4 (d), 127.7 (d), 127.7 (d), 126.8 (d), 66.5 (t), 55.1
(d), 37.2 (t), 29.8 (t). Rotamer B: δ 153.4 (s), 137.1 (s), 128.4 (d),
127.7 (d), 127.7 (d), 126.2 (d), 66.5 (t), 54.8 (d), 36.4 (t), 29.0 (t). IR
(neat) ν (cm−1): 3063, 3010, 2957, 2895, 2834, 1694, 1420, 1328,
1208, 1102, 1001, 758. LRMS (m/z, relative intensity): 280 (MNa+,
100). HRMS: calcd for C16H19NO2Na 280.1308, found 280.1318.
Benzyl 2,5-Bis(2-hydroxyethyl)pyrrolidine-1-carboxylate
(53). Carbamate 52 (89 mg, 0.35 mmol) was dissolved in
dichloromethane (3 mL), and ozone was bubbled through the
solution until it turned pale blue (5 min). Argon was then bubbled for
10 min, and NaBH4 (0.132 g, 3.50 mmol) was added. The solution
was stirred at reflux for 1.5 h, and a 1 N HCl aqueous solution (10
mL) was added. The aqueous phase was extracted with dichloro-
methane (3 × 25 mL), and the organic extracts were combined, dried
over anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash chromatography on
silica gel using ethyl acetate as the eluent to give diol 53 as a colorless
oil (58 mg, 56%). 1H NMR (300 MHz, CDCl3): Rotamer A: δ 7.41−
7.29 (m, 5H), 5.24−5.08 (m, 2H), 4.32−4.18 (m, 1H), 4.13−4.03 (m,
1H), 3.70−3.49 (m, 4H), 2.16−1.34 (m, 8H). Rotamer B: δ 7.41−
7.29 (m, 5H), 5.24−5.08 (m, 2H), 4.32−4.18 (m, 1H), 4.03−3.90 (m,
1H), 3.70−3.49 (m, 4H), 2.16−1.34 (m, 8H). 13C NMR (75.5 MHz,
CDCl3): Rotamer A: δ 156.8 (s), 136.3 (s), 128.5 (d), 128.1 (d),
127.8 (d), 67.3 (t), 59.6 (t), 56.0 (d), 39.0 (t), 30.5 (t). Rotamer B: δ
156.8 (s), 136.3 (s), 128.5 (d), 128.1 (d), 127.8 (d), 67.3 (t), 59.1 (t),
55.7 (d), 38.8 (t), 30.2 (t). IR (neat) ν (cm−1): 3699−3094 (br),
2953, 2873, 1677, 1412, 1354, 1111, 1054, 736, 696. LRMS (m/z,
relative intensity): 316 (MNa+, 100). HRMS: calcd for C16H23NO4Na
316.1519, found 316.1527.
1107, 1041, 740, 696. LRMS (m/z, relative intensity): 358 (MNa+,
100). HRMS: calcd for C18H25NO5Na 358.1625, found 358.1635.
[α]2D0: + 8.12 (CHCl3, c = 0.5).
(2R,5S)-Benzyl 2-(2-Acetoxyethyl)-5-(2-oxoethyl)pyrrolidine-
1-carboxylate (55). Oxalyl chloride (0.11 mL, 1.2 mmol) was added
to a solution of DMSO (0.22 mL, 3.1 mmol) in CH2Cl2 (15 mL) at
−78 °C. The solution was stirred at that temperature for 15 min
before a solution of monoacetate 54 (0.349 g, 1.04 mmol) in CH2Cl2
(5 mL) was added. After the mixture was stirred at −78 °C for 45 min,
Et3N (1.0 mL, 7.3 mmol) was added, and the reaction mixture was
then allowed to stir at rt for 30 min. Water (20 mL) was added, and
the aqueous phase was extracted with CH2Cl2 (3 × 25 mL). The
organic extracts were combined, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash chromatography on silica gel using a mixture of ethyl
acetate and hexanes (35:65) as the eluent to give aldehyde 55 as a
1
colorless oil (314 mg, 91%). H NMR (300 MHz, CDCl3): δ 9.83−
9.63 (m, 1H), 7.41−7.28 (m, 5H), 5.20−4.98 (m, 2H), 4.36−4.25 (m,
1H), 4.18−3.92 (m, 3H), 3.16−2.76 (m, 1H), 2.52 (ddd, 1H, J = 16.6,
7.7, 1.5 Hz), 2.30−2.12 (m, 2H), 2.10−1.88 (m, 4H), 1.78−1.54 (m,
3H). 13C NMR (75.5 MHz, CDCl3): Rotamer A: δ 200.4 (s), 170.8
(s), 155.1 (s), 136.4 (s), 128.4 (d), 128.0 (d), 127.9 (d), 66.9 (t), 61.9
(t), 56.6 (d), 54.07 (d), 49.9 (t), 34.5 (t), 30.0 (t), 29.6 (t), 20.8 (q).
Rotamer B: δ 200.4 (s), 170.8 (s), 155.1 (s), 136.4 (s), 128.4 (d),
128.0 (d), 127.9 (d), 66.9 (t), 61.9 (t), 55.7 (d), 53.3 (d), 49.9 (t),
34.5 (t), 30.0 (t), 29.6 (t), 20.8 (q). IR (neat) ν (cm−1): 3038, 2964,
2885, 1739, 1694, 1409, 1353, 1244, 1106, 1031. LRMS (m/z, relative
intensity): 388 (MNa+ + MeOH, 100), 356 (MNa+, 60). HRMS: calcd
for C18H23NO5Na 356.1468, found 356.1479. [α]2D0: −18.0 (CHCl3, c
= 0.5).
(2R,5R)-Benzyl 2-(2-Acetoxyethyl)-5-(2-(2,6-dioxocyclo-
hexyl)ethyl)pyrrolidine-1-carboxylate (56). To a solution of
aldehyde 55 (0.295 g, 0.885 mmol) in CH2Cl2 (3 mL) were
successively added Hantzsch’s ester (0.360 g, 1.42 mmol), 1,3-
cyclohexanedione (0.159 g, 1.42 mmol), and L-proline (20.7 mg, 0.177
mmol). The reaction mixture was allowed to stir at rt for 3 h before
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel using a mixture of
ethyl acetate and hexanes (60:40) as the eluent to give product 56 as a
colorless oil (342 mg, 91%). 1H NMR (300 MHz, CDCl3): δ 10.25 (br
s, 1H), 7.39−7.28 (m, 5H), 5.16 (AB quartet, 2H), 4.16−4.02 (m,
2H), 4.01−3.93 (m, 1H), 3.86−3.74 (m, 1H), 2.61−2.34 (m, 5H),
2.31−2.11 (m, 2H), 2.05−1.87 (m, 4H), 1.93 (s, 3H), 1.84−1.50 (m,
6H). 13C NMR (75.5 MHz, CDCl3): δ 199.5 (s), 173.9 (s), 171.0 (s),
156.4 (s), 136.2 (s), 128.4 (d), 128.4 (d), 127.8 (d), 114.8 (s), 67.4
(t), 66.5 (t), 61.9 (t), 58.7 (d), 56.1 (d), 35.8 (t), 34.9 (t), 30.4 (d),
29.9 (d), 29.6 (d), 20.8 (t), 20.7 (q), 18.8 (t). IR (neat) ν (cm−1):
3495−3083 (br), 3027, 2960, 2881, 1735, 1698, 1409, 1353, 1237,
1106, 1027. LRMS (m/z, relative intensity): 452 (MNa+, 100), 430
(MH+, 10). HRMS: calcd for C24H31NO6Na 452.2044, found
452.2058. [α]2D0: +11.0 (CHCl3, c = 0.5)
2-((1R,3aR)-6-Oxo-1,2,3,3a,4,5,6,7,8,9-decahydropyrrolo[1,2-
a]quinolin-1-yl)ethyl Acetate (57). Diketone 56 (330 mg, 0.769
mmol) was dissolved in methanol (30 mL) at rt, and 5% Pd/C (100
mg) was added. After the solution was degassed with argon for 10 min,
the argon was replaced by hydrogen, and the latter was bubbled into
the solution for several seconds. The solution was stirred under
hydrogen for 1 h, and argon was bubbled into the solution for another
10 min. The reaction mixture was filtered over Celite, and the filter
cake was washed with methanol. The solvent was removed under
reduced pressure to yield the crude product, which was purified by
flash chromatography on silica gel using a mixture of methanol and
ethyl acetate (10:90) as the eluent to give tricyclic compound 57 as a
(2R,5S)-Benzyl 2-(2-Acetoxyethyl)-5-(2-hydroxyethyl)pyrrol-
idine-1-carboxylate (54). meso-Diol 53 (250 mg, 0.852 mmol) was
divided into five portions of 50 mg each. Those portions were
dissolved in benzene (1.7 mL) and hexanes (6.8 mL) before Celite
(500 mg), Amano lipase from P. fluorescens (Sigma-Aldrich, ≥20000
units/g, 500 mg), and vinyl acetate (0.018 mL, 0.20 mmol) were
added. After being stirred at rt for precisely 20 min, the reaction
mixtures were filtered using ethyl acetate. The solvent was removed
under reduced pressure, and the crude product was purified by flash
chromatography on silica gel using ethyl acetate and hexanes (75:25
and 100:0) as the eluent to give nonracemic 54 as a colorless oil (136
mg, 48%, 62% brsm). The enantiomeric excess was calculated to be
88% by HPLC using a chiral column. 1H NMR (300 MHz, CDCl3): δ
7.40−7.29 (m, 5H), 5.15 (s, 2H), 4.34−4.20 (m, 1H), 4.17−3.88 (m,
3H), 3.69−3.55 (m, 2H), 2.29−1.88 (m, 3H), 1.96 (s, 3H), 1.85−1.39
(m, 5H). 13C NMR (75.5 MHz, CDCl3): δ 170.9 (s), 156.9 (s), 136.3
(s), 128.5 (d), 128.1 (d), 127.9 (d), 67.4 (t), 61.8 (t), 59.0 (t), 56.0
(d), 55.6 (d), 38.8 (t), 35.4 (t), 30.5 (t), 30.2 (t), 20.8 (q). IR (neat) ν
(cm−1): 3637−3156 (br), 2957, 2878, 1734, 1685, 1412, 1354, 1239,
1
colorless oil (128 mg, 60%). H NMR (300 MHz, CDCl3): δ 4.15−
3.97 (m, 2H), 3.94−3.83 (m, 1H), 3.32−3.17 (m, 1H), 2.70−2.50 (m,
2H), 2.47−2.24 (m, 3H), 2.21−1.75 (m, 7H), 2.07 (s, 3H), 1.71−1.50
(m, 3H), 1.29−1.09 (m, 1H). 13C NMR (75.5 MHz, CDCl3): δ 193.7
(s), 170.8 (s), 158.3 (s), 107.2 (s), 61.6 (t), 59.1 (d), 55.5 (d), 36.1
(t), 34.6 (t), 29.4 (t), 28.8 (t), 28.2 (t), 27.0 (t), 21.8 (t), 21.2 (t), 20.8
(q). IR (neat) ν (cm−1): 2945, 2877, 1739, 1608, 1432, 1233, 1185,
K
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Article
1050. LRMS (m/z, relative intensity): 316 (MK+, 10), 300 (MNa+,
100), 278 (MH+, 50). HRMS: calcd for C16H23NO3Na 300.1570,
found 300.1579. [α]2D0: −343 (CHCl3, c = 0.49)
(7) The first examples of such rearrangement were reported by
Edwards as side reactions. See: (a) Edwards, O. E.; Grue-Sorensen, G.;
Blackwell, B. A. Can. J. Chem. 1997, 75, 857−872. For a recently
reported rearrangement of N-diazolactams, see: (b) Gu, P.; Kang, X.-
Y.; Sun, J.; Wang, B.-J.; Yi, M.; Li, X.-Q.; Xue, P.; Li, R. Org. Lett. 2012,
14, 5796−5799.
(8) Most cases reported involve an N-aryl-N-acylnitrenium ion.
However, see: (a) Ford, G. P.; Herman, P. S. J. Mol. Struct.:
THEOCHEM 1990, 204, 121−130. (b) Galliani, G.; Rindone, B. Nouv.
J. Chim. 1983, 7, 151−154.
(9) (a) Mesah-Dwumah, M.; Daly, J. W. Toxicon 1978, 16, 189−194.
(b) Witkop, B.; Gossinger, E. In The Alkaloids; Academic Press: New
York, 1983; Vol. 21, p 205. (c) Daly, J. W.; Spande, T. F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1986; Vol. 4, pp 95−122.
(10) (a) Daly, J. W.; Witkop, B.; Tokuyama, T.; Nishikawa, T.; Karle,
I. L. Helv. Chem. Acta 1977, 60, 1128−1140. (b) Tokuyama, T.;
Yenoyama, K.; Brown, G.; Daly, J. W.; Witkop, B. Helv. Chim. Acta
1974, 57, 2597−2604. For a review of alkaloids isolated from
Dendrobatidae, see ref 2.
(1R,3aR)-1-(2-Hydroxyethyl)-1,2,3,3a,4,5,8,9-octahydro-
pyrrolo[1,2-a]quinolin-6(7H)-one (13). To a solution of tricycle 57
(0.104 g, 0.375 mmol) in methanol (3 mL) was added K2CO3 (0.153
g, 1.12 mmol). The reaction mixture was stirred for 10 min at rt, and
the solvent was removed under reduced pressure. The crude product
was purified by flash chromatography on silica gel using a mixture of
methanol and ethyl acetate (15:85) as the eluent to give the
enantiomer of Kishi’s intermediate, (−)-13, as a white solid (43 mg,
1
49% (68% brsm)). H NMR (300 MHz, CDCl3): δ 4.13−4.07 (m,
1H), 3.80−3.73 (m, 1H), 3.66 (ddd, 1H, J = 11.0, 9.1, 4.6 Hz), 3.36−
3.23 (m, 1H), 2.74−2.58 (m, 2H), 2.55−2.31 (m, 4H), 2.26−2.04 (m,
5H), 2.00−1.75 (m, 5H), 1.72−1.48 (m, 2H), 1.33−1.11 (m, 1H).
LRMS (m/z, relative intensity): 258 (MNa+, 50), 236 (MH+, 100).
HRMS: calcd for C14H22NO2 236.1645, found 236.1653. [α]2D0: −422
(EtOH, c = 0.5) (lit11b +538 (EtOH, c = 1.4)).
ASSOCIATED CONTENT
* Supporting Information
■
S
(11) For the synthesis of racemic gephyrotoxin, see: (a) Fujimoto, R.;
Kishi, Y.; Blount, J. G. J. Am. Chem. Soc. 1980, 102, 7154−7156. For
the synthesis of nonracemic gephyrotoxin, see: (b) Fujimoto, R.; Kishi,
Y. Tetrahedron Lett. 1981, 42, 4197−4198.
Characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
́
(12) (a) Santarem, M.; Vannuci-Bacque, C.; Lhommet, G. J. Org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: Claude.Spino@USherbrooke.ca.
■
Chem. 2008, 73, 6466−6469. (b) Wei, L.-L.; Hsung, R. P.; Sklenicka,
H. M.; Gerasyuto, A. I. Angew. Chem., Int. Ed. 2001, 40, 1516−1518.
(c) Miao, L.; Shu, H.; Noble, A. R.; Fournet, S. P.; Stevens, E. D.;
Trudell, M. L. ARKIVOC 2010, 2010 (4), 6−14.
Notes
(13) For total syntheses of racemic gephyrotoxin, see: (a) Hart, D. J.;
Kanai, K. J. Am. Chem. Soc. 1983, 105, 1255−1263. (b) Overman, J. E.;
Lesuisse, D.; Hashimoto, M. J. Am. Chem. Soc. 1983, 105, 5373−5379.
For formal syntheses of racemic gephyrotoxin, see: (c) Hart, D. J. J.
Org. Chem. 1981, 46, 3576−3578. (d) Pearson, W. H.; Fang, W.-k. J.
Org. Chem. 2000, 65, 7158−7174. (e) Ito, Y.; Nakajo, E.; Nakatsuka,
M.; Saegusa, T. Tetrahedon Lett. 1983, 24, 2881−2884.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC), the Fonds de Recherche
́ ́
Quebecois Nature et Technologies (FRQ-NT), and the
Universite
Dr. Rene
enzymatic desymmetrization reaction.
́
de Sherbrooke for financial support. We also thank
Gagnon for helpful discussions regarding the
(14) (a) Enders, D.; Eichenauer, H.; Baus, U.; Schubert, H.; Kremer,
K. A. M. Tetrahedron 1984, 40, 1345−1359. (b) Enders, D.;
Eichenauer, H. Angew. Chem., Int. Ed. Engl. 1976, 15, 549−551.
(c) Enders, D.; Gatzweiler, W.; Jegelka, U. Synthesis 1991, 1137−1141.
(d) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253−2329. (e) Enders, D.; Zamponi, A.;
́
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