Preparation of intermediates for the synthesis of polycyclic alkaloids: A new access to the azabicyclic core of the Stemona alkaloids

Article abstract of DOI:10.1002/ejoc.200400322

Several isoxazolidines, derived from the 1,3-dipolar cycloaddition of α,β-hexenolides to cyclic nitrones, were converted into the corresponding piperidine- and pyrrolidine-oxepinones by reduction of the nitrogen-oxygen bond. The potential of the resulting amino alcohols as synthetic precursors of polycyclic alkaloids was explored. These intermediates provide a new access to the 1-azabicyclo[5.3.0]decane core of the Sfemona alkaloids. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400322

FULL PAPER
Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids:
A New Access to the Azabicyclic Core of the Stemona Alkaloids
Pau Cid,[a] Montserrat Closa,[a] Pedro de March,[a] Marta Figueredo,*[a] Josep Font,[a]
Elena Sanfeliu,[a] and Angeles Soria[a]
Dedicated to the memory of Dr. Juan Carlos del Amo[‡]
Keywords: Isoxazolidine / Oxepinone / Piperidine / Pyrrolidine / Polycyclic alkaloids / Stemona
Several isoxazolidines, derived from the 1,3-dipolar cycload- polycyclic alkaloids was explored. These intermediates pro-
dition of α,β-hexenolides to cyclic nitrones, were converted
vide a new access to the 1-azabicyclo[5.3.0]decane core of
into the corresponding piperidine- and pyrrolidine-oxepi- the Stemona alkaloids.
nones by reduction of the nitrogen−oxygen bond. The poten- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tial of the resulting amino alcohols as synthetic precursors of
Germany, 2004)
Introduction
dipolar cycloaddition of nitrones to (E)-α,β-unsaturated
esters[3] and also to five, six and seven membered α,β-un-
The 1,3-dipolar cycloaddition reaction of nitrones to ole- saturated lactones[3c,4] with
a variety of substitution
fins is an effective procedure for the preparation of chiral patterns. As a result of these studies, we prepared a series
isoxazolidines.[1] These compounds have been used as inter- of piperidine and pyrrolidine fused isoxazolidines, some of
mediates in the synthesis of many nitrogen containing tar- which were further elaborated yielding useful synthetic in-
get molecules. In particular, the cycloaddition of five and termediates.
six membered cyclic nitrones to olefins has been success-
One of the purposes of this work was to investigate if
fully employed as a key step in the preparation of various the procedure outlined in Scheme 1, which is already firmly
indolizidine and pyrrolizidine alkaloids[2] by the general established for the construction of the indolizidine and pyr-
strategy shown in Scheme 1, developed by Tufariello in the rolizidine frameworks, could be extended to the formation
mid-nineteen seventies. In this approach, after the cyclo- of the 1-azabicyclo[5.3.0]decane core common to most alka-
addition reaction, the formation of the pyrrolidine ring loids of the Stemona class (Scheme 2).[5]
is accomplished by reduction of the isoxazolidine
In a previous paper, we described the reduction of several
nitrogenϪoxygen bond, followed by intramolecular nucleo- piperidineisoxazolidines derived from ester type di-
philic displacement of a leaving group previously intro- polarophiles.[6] Herein we present the study of the reduction
duced at the appropriate position in the starting olefin. In of several tricyclic adducts derived from α,β-hexenolides
connection with a program of polycyclic alkaloid synthesis, and further elaboration of the products towards the 1-aza-
we have studied in detail the stereoselectivity of the 1,3- bicyclo[5.3.0]decane system.
Results and Discussion
Reduction of the N؊O Bond
Scheme 1. The ‘‘cyclic nitrone approach’’ to indolizidine and pyrro-
lizidine alkaloids.
The reductive cleavage of nitrogenϪoxygen bonds has
been performed using a variety of procedures and reagents
[a]
including catalytic hydrogenation, various metals in differ-
ent solvents, hydrides, and metal complexes.[1c] The pro-
cedure of choice depends on what other functional groups
are present in the substrate and also on its particular struc-
´
`
Departament de Quımica, Universitat Autonoma de Barcelona,
08193 Bellaterra, Spain
Fax (intrenat.): ϩ34-935811265
E-mail: marta.figueredo@uab.es
[‡]
Victim of the terrorist attack on March 11, 2004 in Madrid
Eur. J. Org. Chem. 2004, 4215Ϫ4233
DOI: 10.1002/ejoc.200400322
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Scheme 2. The designed ‘‘cyclic nitrone approach’’ to Stemona alkaloids.
tural features. Figure 1 shows the piperidine and pyrrolidine Products and yields are shown in Table 1. The reductive
fused isoxazolidines 1Ϫ11,[4] which were the subject of our cleavage of the nitrogenϪoxygen bond furnished the ex-
investigation.
pected amino alcohols for seven of the eleven studied isox-
Some preliminary attempts at catalytic hydrogenation in azolidines. The substrates 5 and 9 bearing the phenylthio
the presence of Pd[2aϪ2e,7] or molybdenum hexacarbonyl[8] substituent gave the best yield in both the piperidine and
rendered either unchanged starting material or unidentified pyrrolidine series. The amino alcohols 12Ϫ17 were fully
products, while the reduction with zinc in acidic media[2e,9] characterized according to their spectroscopic data. All the
1
emerged as the most appropriate method for our substrates. signals in their H NMR spectra were assigned with the
After extensive experimentation with variable molar pro- help of bidimensional experiments. Subsequently, the coup-
portions of activated zinc, either in acetic or hydrochloric ling constant values were examined to deduce the preferred
acid over a range of concentrations, we found that the best conformation of these compounds in solution and in order
conditions for the reduction are obtained by using 10 equiv- to confirm their relative configuration. For instance, in the
alents of zinc powder in 10% aqueous HCl under sonication 1H NMR spectrum of compound 15, the signal of the α-
at room temperature. Absence of sonication gave slightly carbonyl proton (3-H) appears at δ ϭ 3.12 as a broad sing-
slower substrate conversions and significantly lower yields. let, while 5-H displays a false quadruplet at δ ϭ 3.75 (J ഠ
Figure 1. The isoxazolidine substrates studied, products of the NϪO bond reduction, and related derivatives.
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Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
Instead of the expected amino alcohols, the parent pyr-
rolidineisoxazolidine 7 and the thioesters 6 and 10 only gave
complex mixtures of unidentified products when they were
subjected to the same reduction conditions. For substrate 6,
the NϪO reduction was accomplished in AcOH/H2O (1:1)
as solvent and, avoiding basic workup conditions, the piper-
idinium acetate 20 could be isolated in 51% yield, although
the corresponding free amine decomposed rapidly. Anal-
ogous reaction conditions failed when applied to pyrroli-
dines 7 and 10.
Since we intended to explore the potential of the amino
alcohols 12Ϫ17 as synthetic intermediates for polycyclic al-
kaloids, we thought that the presence of a free secondary
amine could be problematic for further transformations es-
pecially in reactions involving the hydroxyl group. This pre-
sumption was soon confirmed when the deoxygenation of
compound 14 was attempted by passing either through a
sulfonate or a thiocarbonate. Thus, treatment of 14 with
tosyl chloride in pyridine furnished the sulfonamide 22 in
86% yield, while the reaction of 14 with thiocarbonyldiimid-
azole delivered the thiocarbamate 23 in 60% yield. The
necessity for protection of the nitrogen atom led us to con-
sider the possibility of improving the yields of the NϪO
reduction by initial N-benzylation of the substrates, as has
been reported previously.[11]
Table 1. Reduction of isoxazolidines 1Ϫ11 with Zn in 10% aque-
ous HCl.
Substrate
Products (yield)
1
12 (51%)
18 (59%), 19 (6%)
13 (50%)
14 (75%)
15 (80%)
20 (51%)
none
16 (60%)
17 (83%)
none
2
3
4
5
6[a]
7
8
9
10
11
21 (77%)
[a]
Reduction performed in AcOH/H2O, 1:1.
3.1 Hz, due to its coupling with 4-H and the two protons
at C-6) denoting its equatorial orientation. These data are
in agreement with a chair conformation of the oxepinone
with the piperidine substituent equatorial and the hydroxyl
and phenylthio groups axial, favouring the formation of an
intramolecular hydrogen bond. In such a conformation, the
protons at C-3 and C-4 are near orthogonal and hence pre-
sent a coupling constant close to zero. These considerations
can be extended to the other related amino alcohols. The
reduction of the bromo derivative 2 led to the isolation of
the β-lactam 18 as the major product, along with a minor
quantity of the α,β-hexenolide 19. Decisive spectroscopic
data for the identification of 18 are given by the olefin pro-
ton signals at δ ϭ 5.33 and 5.82 ppm with a vicinal coupling
N-Benzylation and Further Reactions
Accordingly, the benzylisoxazolidinium bromides 24Ϫ31
(Figure 2) were prepared in quantitative yields by reaction
of the corresponding isoxazolidines 1 and 4Ϫ10 with benzyl
bromide in THF at room temperature. Although the N-
benzylation generates a new stereogenic centre at the nitro-
gen atom, a unique diastereoisomer was obtained in all
cases. We know from previous studies that the tricyclic pyr-
rolidine substrates such as 7 exist in solution as a unique
cis-fused invertomer, while the piperidine derivatives of type
1 present a conformational equilibrium with a clear pre-
dominance of the trans-fused invertomer, and so we were
intrigued by the stereochemistry of the isoxazolidinium bro-
mides 24Ϫ31.
1
of 10.8 Hz in the H NMR spectrum, and the lactam ab-
sorption at 1780 cmϪ1 in the IR spectrum. The formation
of 18 and 19 can be explained using the mechanistic path-
way depicted in Scheme 3. A metal-induced reductive de-
bromination[10] with a concomitant opening of the isoxazol-
idine ring is followed by cleavage of the nitrogenϪoxygen
bond to give a piperidine. This piperidine can then evolve
either by intramolecular acyl group transfer to the lactam
18, or by double bond migration to the conjugate lactone
19.
1
A detailed H NMR study revealed that all these com-
pounds are cis-fused. Most spectra were obtained from
CDCl3 solutions, but the salts 29 and 31 have low solubility
in most common organic solvents and their spectra had to
be measured in [D6]DMSO. The signals were assigned with
the assistance of homo- and hetero-nuclear bidimensional
experiments. Table 2 and Table 3 show the most significant
data. It is noticeable that the signal of the proton at the α-
carbonyl position (H11b or H10b for the piperidine or pyr-
rolidine series, respectively) appears more downfield shifted
(cfr. last columns of Table 2Ϫ3) than any of the others on
going from the original isoxazolidine to the corresponding
N-benzylisoxazolidinium cation. A possible anisotropic ef-
fect caused by its proximity to the aromatic residue was
discarded, since the N-methylisoxazolidinium iodide 32,
prepared by reaction of 10 with methyl iodide, exhibits a δ
for H11b (see Figure 3 for numbering) similar to that of its
analogue 27. Therefore, the deshielding of H11b must orig-
Scheme 3. Proposed mechanism for the formation of 18 and 19
from 2 by treatment with Zn/aqueous HCl.
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Figure 2. Prepared isoxazolidinium salts and products of their NϪO bond reduction.
1
Table 2. Chemical shifts of important resonances in the H NMR spectra (CDCl3) of 24Ϫ27 and 32.
Compound
δ H3α
δ H3β
δ H5
δ H5a
δ H8α
δ H8β
δ H11a
δ H11b
[δ H11b, c and t][a]
24
25
26
27
32
5.00
5.15
5.12
5.17
5.18
4.25
4.25
4.21
4.27
4.32
5.58
5.55
5.50
5.53
5.48
4.92
4.77
4.95
4.80
5.03
3.37
3.40
3.39
3.28
3.46
4.21
4.30
4.21
4.41
4.35
5.44
5.71
5.71
5.69
5.55
3.88 c, 3.46 t (1)
3.97 c, 3.59 t (4)
3.95 c, 3.50 t (5)
3.63 t (6)
5.10
3.29
3.80
3.82
3.63 t (6)
[a]
Chemical shift for the cis (c) and trans (t) invertomer of the corresponding precursors (indicated in parenthesis).
1
Table 3. Chemical shifts of important resonances in the H NMR spectra of 28Ϫ31.
[a]
Compound
Solvent
δ H3α
δ H3β
δ H5
δ H5a
δ H8
δ H10a
δ H10b
[δ H10b]
28
28
29
30
30
31
CDCl3
5.02
4.44
4.52
5.08
4.44
4.53
4.31
4.33
4.41
4.32
4.32
4.39
5.52
5.11
5.35
5.32
5.07
5.23
3.65, 4.38
3.65, 4.06
4.06, 3.68
4.18, 3.16
4.07, 3.66
4.07, 3.60
5.52
5.23
5.32
5.49
5.29
5.33
5.52
4.63
4.80
5.86
4.75
4.77
3.39 (7)
[D6]DMSO
[D6]DMSO
CDCl3
[D6]DMSO
[D6]DMSO
4.95
3.72
3.35
3.60
3.50 (8)[b]
3.49 (9)
3.53 (10)[b]
[a]
[b]
Chemical shift for the corresponding precursors (indicated in parenthesis). In CDCl3 solution.
tween the isoxazolidine and the piperidine (or pyrrolidine)
rings, despite the fact that the piperidine precursors exist in
solution mainly or exclusively as their trans invertomers.
When the isoxazolidinium salts 24Ϫ31 were treated with
activated zinc powder in 10% aqueous HCl under the stand-
ard conditions established for their amine precursors, the
parent oxepinones (24 and 28) and the acetoxyoxepinones
(25 and 29) rendered the expected N-benzylamino alcohols
in excellent yields (Table 4). The sulfides 26 and 30 fur-
nished the NϪO reduction products in moderate yields, in
contrast with the previous results (see Table 3, substrates 5
Figure 3. NOE correlations for compound 27.
inate in the polarization of the CϪH11b bond, as a conse- and 9). From the reduction of 26, besides the expected am-
quence of the electric field induced by the positive charge ino alcohol 35, we also isolated a minor amount of its ep-
on the nitrogen atom.[12] Once all proton signals were as- imer at the α-carbonyl centre, 40. The reduction of the ace-
signed, the cis stereochemistry was determined by a tylthiolates 27 and 31 furnished unstable products and, al-
NOESY experiment performed on 27 (Figure 3), where though the formation of the amino alcohol 39 was observed
crossed signals between H5a and H8α and between H11a and by NMR analysis of the crude reaction mixture, all at-
one of the benzylic protons were observed.
tempts to purify this compound led to decomposition. We
Considering the strong similarities in their NMR spectra, also studied the NϪO reduction of the N-benzyl derivative
we assume that all the salts 24Ϫ31 present a cis fusion be- of the tricyclic furanone 11, but the only identifiable prod-
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Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
and also on their evolution pathway under the reduction
conditions. Hydrogenolysis of the N-benzylamines 46 and
47 was accomplished using Pd(OH)2 as catalyst in methanol
with the secondary amines 52 and 53 being isolated in 93%
and 96% yield, respectively.
Table 4. Reduction of isoxazolidinium bromides 24Ϫ31 with Zn in
10% aqueous HCl.
Substrate
Product (yield)
24
25
26
27
28
29
30
31
33 (100%)
34 (100%)
35 (50%), 40 (14%)
none
Construction of the 1-Azabicyclo[5.3.0]decane Skeleton
The results obtained hitherto indicate that the reductive
cleavage of the nitrogenϪoxygen bond of the oxepinoisox-
azolopiperidine framework is a convenient entrance to a
variety of piperidine-oxepinones with different substitution
patterns, but that their pyrrolidine analogues are very sensi-
tive to minor structural changes and chemical manipulation
often ends in their decomposition. We were then confronted
with the problem of avoiding these unstable intermediates
during construction of the 1-azabicyclo[5.3.0]decane system
(Scheme 2) . Since the isoxazolium salts proved in most
cases better substrates than their amine precursors towards
the NϪO reduction, we thought that it would be advan-
tageous to firstly construct the azepine ring by intramolecu-
lar N-alkylation and then proceed with the NϪO cleavage
(Scheme 4). The analogous approach for the construction
of the indolizidine skeleton using the appropriate homoallyl
derivatives is well documented.[14]
36 (99%)
37 (97%)
38 (51%)
39 (85%)[a]
[a] Yield refers to crude material; compound 39 decomposes rapidly.
uct that could be isolated from this reaction was the dehy-
drated compound 41 (22% yield).
To examine the effectiveness of the benzylic protection,
we then studied the deoxygenation of the N-benzylamino
alcohols. Compounds 33, 34, 36 and 37 were selected as
substrates and the BartonϪMcCombie procedure[13] as the
methodology. Treatment of 33 with TCDIm in refluxing
THF furnished the expected thiocarbamate 42 (Figure 4),
but attempted chromatographic purification over silica gel
led to the elimination product 49 (60% yield). Fortunately,
the thiocarbamate 42 could be purified and isolated in 83%
yield by crystallization from acetone/hexane.The thiocarba-
mate 43 was prepared analogously in 73% yield from the
corresponding precursor 34. Reaction of 42 with Bu3SnH,
in the presence of AIBN in refluxing toluene, gave the re-
duction product 46 in 70% yield together with a small quan-
tity of the α,β-unsaturated lactone 49. The same procedure
applied to the thiocarbamate 43 rendered the corresponding
reduction product 47 in 76% yield. The reaction of the pyr-
rolidine substrates 36 and 37 with TCDIm provided the thi-
ocarbamates 44 and 45, respectively, as revealed by NMR
analyses of the crude reaction products, but all attempts to
purify these compounds were unsuccessful. Therefore, the
crude materials were used in the following step. Treatment
of 44 with Bu3SnH delivered the elimination product 50
(49% yield), while the same reaction conditions applied to
45 gave a poor yield of the deoxygenation product 48 (9%),
along with the olefin 51 (19%) and the alcohol 37 (20%).
Thus, it became clear that the size of the nitrogen ring has
a decisive influence on the stability of the thiocarbamates
Scheme 4. The ‘‘cyclic nitrone approach’’ to the 1-azabicyclo[5.3.0]-
decane system.
To this end, the olefins 54 (Scheme 5) and 59 (Scheme 6)
were considered the most suitable dipolarophiles and so
their cycloadditions to nitrone 55[4b,15] were investigated.
The reaction between the unsaturated ester 54, prepared by
mesylation of methyl (E)-6-hydroxyhex-2-enoate,[16] and
nitrone 55 in refluxing chloroform furnished directly the
tricyclic isoxazolidinium mesylate 56, whose stereochem-
istry was assigned assuming that the primary adduct must
derive from an endo (CO2Me) transition state.[3] Treatment
of 56 with zinc in 10% aqueous HCl effected clean NϪO
reduction to give the azabicycle 57 in 83% overall yield.
These findings demonstrate that Tufariello’s ‘‘cyclic nitrone
approach’’ to indolizidine and pyrrolizidine systems is equ-
ally efficient for the construction of the 1-azabicyclo[5.3.0]-
decane core present in most Stemona alkaloids, opening a
new pathway to these natural products. When reductive de-
oxygenation of 57 was attempted by consecutive treatment
with TCDIm and Bu3SnH, traces of the olefin 58 were de-
Figure 4. Prepared thiocarbamates and products of their reaction
with Bu3SnH and subsequent debenzylation
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aqueous HCl reduction followed by treatment with NaOMe
in refluxing methanol, the azabicycle 61 was isolated in 53%
overall yield (cycloaddition-reduction-epimerization) as a
single isomer, along with another compound identified as
66 (4% yield). The incomplete reduction of the isoxazolidin-
ium salt 60 may account for the formation of this unexpec-
ted compound, with an intermediate iminium alkoxide be-
ing generated under basic conditions (Scheme 7).
Scheme 5. (a) CHCl3, reflux, 24 h; (b) Zn/10% aqueous HCl, sonic-
ation, room temp., 40 min, 83% (two steps); (c) (i) TCDIm; (ii)
Bu3SnH/AIBN, toluene, 100 °C; (d) (i) MsCl, CH2Cl2, 0 °C to
room temp., 5 h, 84%; (ii) KtBuO, CH2Cl2, reflux, 3 h, 75%.
Scheme 7. Proposed mechanism for the formation of 66.
tected exclusively. For characterization purposes, this olefin
was independently synthesized in 75% yield by mesylation
of 57, followed by reaction with potassium tert-butoxide.
The bicyclic ketone 61 was also prepared from oxepinone
Ketone 59[17] was prepared from 4-chlorobutanol, by 7, the exo adduct derived from nitrone 55 and α,β-hexenol-
PCC oxidation followed by Wittig olefination, in 58% yield. ide, by treatment with MeLi, followed by mesylation and
Its cycloaddition to nitrone 55 in refluxing chloroform NϪO reduction in 53% overall yield (Scheme 8). Despite
turned out to be quite complicated. The resulting mixture extensive experimentation, the competitive formation of the
of products was partitioned between ether and water. The alcohol 69 during the nucleophilic addition of the or-
water soluble fraction contained the isoxazolidinium chlo- ganometallic reagent could not be completely avoided.
ride 60, as a mixture of epimers at the α-carbonyl centre. When subjected to the usual deoxygenation protocol, ke-
From the organic fraction we isolated the primary re- tone 61 showed a similar behavior to the analogous ester
gioisomeric adduct 64 (5% yield), the exo isomer 65 (4% 57 so that only the elimination product 62 was detected in
yield) and some unchanged 59 (17% recovery). When per- this experiment. Enone 62 proved to be highly unstable al-
forming the same reaction in refluxing toluene, the primary though it could be prepared independently from 61 by con-
endo cycloadduct 63 could be isolated (50% yield), but the secutive mesylation and basic treatment as above (79%
regio- and stereo-selectivity of the cycloaddition was dimin- yield).
ished (21% of 64 and 9% of 65). Moreover, the cycloadduct
In view that any structural modification of our substrates
63 cyclizes on standing and the resulting tricyclic product could critically affect their evolution towards a specific re-
epimerizes rapidly. When the salt 60 was subjected to Zn/ agent, we decided to prepare the ester 72 (epimer of 57 at
Scheme 6. (a) CHCl3, reflux, 48 h; (b) (i) Zn/10% aqueous HCl, sonication, room temp., 45 min; (ii) NaMeO/MeOH, reflux, 2.5 h, 53%
(three steps); (c) (i) TCDIm; (ii) Bu3SnH/AIBN, toluene, 100 °C; (d) (i) MsCl, CH2Cl2, 0 °C to room temp., 5 h, 84%; (ii) KtBuO,
CH2Cl2, reflux, 3 h, 79%.
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Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
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derivatives for further elaboration of their functional
groups. This point is of major importance for synthetic
routes to the Stemona alkaloids following the present ap-
proach. In 57, an elimination pathway may be favored by
the trans relationship between the leaving oxygen residue
and the α-carbonyl proton, facilitating an antiperiplanar ar-
rangement, consistent with an E2 type mechanism, which
is poorly accessible by the diastereomer 72. The feasibility
of following the elimination pathway observed for the
methyl ketone 61, which has a relative stereochemistry
identical to 72, may be explained by operation of an E1cb
type mechanism, caused by the stronger acidity of its α-
carbonyl proton.
Conclusion
In summary, the reduction of the nitrogenϪoxygen bond
of a series of tricyclic isoxazolidines bearing a variety of
additional functionalities was performed effectively by
treatment with Zn in 10% aqueous HCl under sonication.
In most cases, the formation of the N-benzylisoxazolidin-
ium salts prior to the reduction improves notably the yield
Scheme 8. (a) MeLi, THF, Ϫ100 °C, 2 h, 57%; (b) MsCl, pyridine, of amino alcohol and ends with an N-protected derivative,
CH2Cl2, 0 °C to room temp., 6 h; (c) Zn/10% aqueous HCl, sonic-
which is more suitable for further synthetic elaboration. Ac-
cording to our results, the reductive cleavage of the
ation, room temp., 45 min, 93% (two steps).
nitrogenϪoxygen bond of the oxepinoisoxazolopiperidine
framework is a convenient entrance to a variety of piperi-
dine-oxepinones, although their pyrrolidine analogues are
the α-carbonyl position) and attempt the Barton-McCom-
bie deoxygenation of this isomer (Scheme 9). To this end,
very sensitive to minor structural changes and often of low
oxepinone 7 was subjected to methanolysis, followed by me-
stability. We have also shown that ‘‘the cyclic nitrone strat-
sylation of the resulting hydroxy ester 70, with concomitant
egy’’, previously developed for indolizidine and pyrrolizid-
cyclization, and then reductive cleavage of the isoxazolidin-
ine alkaloids,[2] can be successfully applied to the synthesis
ium salt 71, with an overall yield of 78%. The amino al-
cohol 72 was converted into the corresponding thiocarba-
mate 73, which upon treatment with Bu3SnH furnished the
deoxygenation product 74, isolated in 67% yield over the
of intermediates containing the 1-azabicyclo[5.3.0]decane
core of the Stemona alkaloids, with the relative stereochem-
istry of these bicyclic polysubstituted derivatives being of
crucial importance in successive synthetic transformations.
two steps. This result confirms the relevance of the relative
stereochemistry of the substituted 1-azabicyclo[5.3.0]decane
Experimental Section
General Remarks: Reaction mixtures were stirred magnetically. The
organic extracts were dried over anhydrous magnesium sulfate. Re-
action solutions were concentrated using a rotary evaporator at
5Ϫ10 Torr. Tlc was performed on Alugram Sil G/UV254 plates of
0.25 mm thickness (purchased from MachereyϪNagel). Flash chro-
matography was performed using Merck silica gel (230Ϫ400 mesh).
Infrared spectra were recorded on a Nicolet 5 ZDX spectrophoto-
meter. 1H and 13C NMR spectra were recorded by Servei de
`
`
`
Ressonancia Magnetica Nuclear de la Universitat Autonoma de Bar-
celona, on Bruker AC-250-WB or AM-400-WB instruments at 250
or 400 MHz and 62.5 or 100 MHz, respectively, in CDCl3 solutions
(unless otherwise stated). Tetramethylsilane (δ ϭ 0.00) or CHCl3
(δ ϭ 7.27 for 1H and 77.2 for 13C) were used as internal standards
for H and 13C NMR spectra. The assignment of the signals was
1
assisted by DEPT, COSY and 1H-13C correlation experiments.
Mass spectra were performed on a HewlettϪPackard 5985B instru-
ment at 70 eV; only peaks of intensity greater than 20% are re-
ported, unless they were molecular ions or significant fragments.
Scheme 9. (a) MeOH, TsOH, reflux, 6 h, 91%; (b) MsCl, pyridine,
CH2Cl2, 0 °C to room temp., 6 h; (c) Zn/10% aqueous HCl, sonic-
ation, room temp., 30 min, 86% (two steps); (d) (i) TCDIm, THF,
room temp., overnight; (ii) Bu3SnH/AIBN, toluene, 100 °C 30 min,
67% (two steps).
`
MS and Microanalyses were performed by Servei d’Analisi
Eur. J. Org. Chem. 2004, 4215Ϫ4233
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4221

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
´
`
Quımica de la Universitat Autonoma de Barcelona. HRMS were
J7β,7α ϭ 13.0, J7β,6α ഠ 4.6, J7β,6β ϭ 2.3, J7β,5 ϭ 0.6 Hz, 1 H, 7β-
H), 4.22 (d, J4,5 ϭ 4.4 Hz, 1 H, 4-H), 4.41 (dd, J7α,7β ϭ 13.0,
J7α,6β ϭ 11.7 Hz, 1 H, 7α-H), 5.03 (m, 1 H, 5-H) ppm. 13C NMR
(100 MHz): δ ϭ 21.0 (CH3), 24.4 (C-4Ј), 25.0 (C-5Ј), 28.4 (C-6),
29.3 (C-3Ј), 46.7 (C-6Ј), 47.4 (C-3), 56.8 (C-2Ј), 62.6 (C-7), 65.5 (C-
4), 70.8 (C-5), 169.2 (CH3CO), 174.5 (C-2) ppm. EIMS: m/z ϭ 272
(1) [M ϩ1]ϩ, 228 (2), 211 (1), 171 (1), 124 (10), 84 (100), 43 (15).
C13H21NO5 (271.31) calcd. C 57.55, H 7.80, N 5.16; found C 57.57,
H 7.66, N 5.06.
´
performed by Servei de Masses del Centre d’Investigacio i Desenvo-
lupament de Barcelona CSIC, using a VG AutoSpec-Q instrument.
Compounds 1Ϫ11 were prepared as described previously: see ref.[4c]
for 1, 2, 4, 6, ref.[4d] for 3, 5, 8, 9, 10, ref.[4b] for 7, and ref.[4a] for
11. The elemental analysis data for isoxazolium bromides 26Ϫ29,
31, amines 35, 52, 53, 58, 72, 74 and isoxazolidines 67, 70 were
erratic.
(3RS,4RS)-4-Hydroxy-3-[(2RS)-2-piperidyl]oxepan-2-one (12). Gen-
eral Reduction Procedure Using Activated Zn in 10% Aqueous HCl: (3RS,4SR,5SR)-4-Hydroxy-5-phenylthio-3-[(2RS)-2-piperidyl]-
Activated zinc powder (4.69 g, 71.7 mmol) was added to a solution
of 1 (210 mg, 1.00 mmol) in 10% aqueous HCl (20 mL). The mix-
oxepan-2-one (15): Following the general procedure described for
12, reduction of 5 (200 mg, 0.63 mmol) rendered 15 (160 mg,
ture was immersed in an ultrasound bath and reaction progress was 0.50 mmol, 80% yield) as a white solid. M.p. 156Ϫ158 °C (CHCl3/
monitored by TLC analysis (eluent: CH2Cl2/MeOH/NH3 saturated
solution in MeOH, 10:1/0.1). When the starting material had been
consumed (25 min), the mixture was filtered and the solid washed
hexane). IR (KBr): ν˜ ϭ 3600Ϫ2500 (br), 3311, 3065, 2924, 2854,
1729, 1152, 1054 cmϪ1 1H NMR (400 MHz): δ ϭ 1.29 (m, 4 H,
3Ј,3Ј,4Ј, 5Ј-H), 1.53 (m, 1 H, 5Ј-H), 1.72 (m, 1 H, 4Ј-H), 1.92 (ddd,
.
with 10% aqueous HCl and water. The solution was brought to pH J6α,6β ϭ 15.9, J6α,7β ϭ 4.9, J6α,5 ϭ 2.7 Hz, 1 H, 6α-H), 2.53 (dddd,
9Ϫ10 by addition of 30% aqueous NH3. A white solid appeared
which was filtered under vacuum. The solution was then extracted
with CHCl3 (4 ϫ 50 mL), the combined organic extracts were dried
and the solution was concentrated to furnish a white solid residue
J6β,6α ഠ 15.5, J6β,7α ϭ 11.6, J6β,7β ϭ 4.3, J6β,5 ϭ 1.5 Hz, 1 H, 6β-
H), 2.61 (td, J6Јax,6Јeq ഠ J6Јax,5Јax ഠ 11.9, J6Јax,5Јeq ഠ 2.7 Hz, 1 H,
6Јax-H), 2.97 (br. d, J6Јeq,6Јax ϭ 11.6 Hz, 1 H, 6Јeq-H), 3.12 (br. s,
1 H, 3-H), 3.22 (br. d, J2Ј,3Јax ഠ 11.6 Hz, 1 H, 2Ј-H), 3.75 (q, J5,4
ഠ
identified as 12 (108 mg, 0.51 mmol, 51% yield). M.p. 152Ϫ154 °C J5,6α ഠ J5,6β ഠ 3.1 Hz, 1 H, 5-H), 4.12 (br. dd, J7β,7α ϭ 12.8,
(from CHCl3/hexane). IR (KBr): ν˜ ϭ 3325, 3170, 2931, 2854, 2812, 7β,6α ϭ 4.3 Hz, 1 H, 7β-H), 4.33 (d, J4,5 ϭ 3.7 Hz, 1 H, 4-H), 4.56
1715, 1166 cmϪ1 1H NMR (400 MHz): δ ϭ 1.30Ϫ1.82 (m, 8 H, (dd, J7α,7β ϭ 12.8, J7α,6β ϭ 11.0 Hz, 1 H, 7α-H), 7.29 (m, 3 H, Ar-
5,5,3Ј,3Ј,4Ј,4Ј,5Ј,5Ј-H), 2.15 (m, 2 H, 6,6-H), 2.64 (ddd, J6Јax,6Јeq
H), 7.39 (m, 2 H, Ar-H) ppm. 13C NMR (62.5 MHz): δ ϭ 24.4 (C-
J6Јax,5Јax ഠ 11.9, J6Јax,5Јeq ϭ 2.7 Hz, 1 H, 6Јax-H), 2.65 (br. s, 1 H, 4Ј), 25.1 (C-5Ј), 28.2 (C-6), 29.5 (C-3Ј), 46.7 (C-6Ј), 47.8 (C-3), 50.2
3-H), 3.08 (m, J6Јeq,6Јax ഠ 11.6 Hz, 1 H, 6Јeq-H), 3.21 (ddd, (C-5), 56.9 (C-2Ј), 63.5 (C-7), 67.1 (C-4), 127.5/129.2/131.6/132.9
J2Ј,3Јax ഠ 11.3, J2Ј,3Јeq ഠ J2Ј,3 ഠ 2.1 Hz, 1 H, 2Ј-H), 4.16 (dd, (C-Ar), 174.8 (C-2) ppm. EIMS: m/z ϭ 321 (1) [M]ϩ, 293 (2), 212
7α,7β ϭ 12.5, J7α,6β ϭ 11.0 Hz, 1 H, 7α-H), 4.31 (ddt, J7β,7α ഠ 12.4, (1), 84 (100). C17H23NO3S (321.43) calcd. C 63.52, H 7.22, N 4.36,
J
.
ഠ
J
J7β,6α ഠ 4.7, J7β,6β ഠ J7β,5 ഠ 1.8 Hz, 1 H, 7β-H), 4.45 (t, J4,3
ഠ
S 9.96; found C 63.48, H 7.24, N 4.36, S 9.84.
J4,5 ഠ 3.5 Hz, 1 H, 4-H) ppm. 13C NMR (62.5 MHz): δ ϭ 22.9 (C-
6), 24.4 (C-4Ј), 25.2 (C-5Ј), 29.6 (C-3Ј), 35.0 (C-5), 46.5 (C-6Ј), 52.1
(C-3), 56.8 (C-2Ј), 64.3 (C-4), 68.7 (C-7), 175.0 (C-2) ppm. EIMS:
m/z ϭ 213 (1) [M]ϩ, 170 (6), 152 (8), 84 (100). C11H19NO3 (213.27)
calcd. C 61.93, H 8.98, N 6.57; found C 61.85, H 8.97, N 6.55.
(3RS,4SR,5SR)-5-Acetoxy-4-hydroxy-3-[(2RS)-2-pyrrolidyl]oxepan-
2-one (16): Following the general procedure described for 12, re-
duction of 8 (206 mg, 0.81 mmol) rendered 16 (125 mg, 0.49 mmol,
60% yield) as a white solid. M.p. 138Ϫ140 °C (acetone/hexane). IR
(KBr): ν˜ ϭ 3600Ϫ2500 (br), 3276, 3002, 2952, 2924, 1743, 1244,
(3RS,4SR,5SR)-4-Hydroxy-3-[(2RS)-2-piperidyl]-5-(tosyloxy)- 1068 cmϪ1 1H NMR (400 MHz): δ ϭ 1.41 (m, 1 H, 3Ј-H), 1.77
.
oxepan-2-one (13): Following the general procedure described for
12, reduction of 3 (54 mg, 0.14 mmol) rendered the unstable com-
pound 13 (27 mg), contaminated by other products. Attempted
crystallisation or column chromatography resulted in total de-
(m, 2 H, 4Ј,4Ј-H), 1.94 (m, 2 H, 3Ј,6α-H), 2.08 (s, 3 H, CH3), 2.35
(ddt, J6β,6α ഠ 16.2, J6β,7α ഠ 11.3, J6β,7β ഠ J6β,5 ഠ 2.4 Hz, 1 H, 6β-
H), 2.91 (m, 2 H, 5Ј,5Ј-H), 3.08 (br. s, 1 H, 3-H), 3.88 (t, J2Ј,3Ј
ഠ
8.2 Hz, 1 H, 2Ј-H), 4.02 (d, J4,5 ϭ 4.3 Hz, 1 H, 4-H), 4.10 (ddd,
composition of 13. 1H NMR (250 MHz): δ ϭ 1.20Ϫ1.48 (m, 4 H), J7β,7α ഠ 12.8, J7β,6 ഠ 4.6, 1.5 Hz, 1 H, 7β-H), 4.43 (dd, J7α,7β
ϭ
1.58 (m, 1 H), 1.76 (m, 1 H), 1.88 (dt, J6α,6β ϭ 16.1, J6α,7β ഠ J6α,5
ഠ
12.8, J7α,6β ϭ 11.6 Hz, 1 H, 7α-H), 5.18 (q, J5,4 ഠ J5,6α ഠ J5,6β
ഠ
4.0 Hz, 1 H, 6α-H), 2.28 (m, 1 H, 6β-H), 2.44 (s, 3 H, CH3), 2.64 3.3 Hz, 1 H, 5-H) ppm. 13C NMR (62.5 MHz): δ ϭ 21.1 (CH3),
(m, 1 H, 6Ј-H), 2.97 (s, 1 H, 3-H), 3.04 (br. d, J6Ј,6Ј ഠ 11.7 Hz, 1 25.9 (C-4Ј), 28.6/28.7 (C-3Ј/C-6), 46.5/46.8 (C-3/C-5Ј), 57.8 (C-2Ј),
H, 6Ј-H), 3.19 (br. d, J2Ј,3 ഠ 8.8 Hz, 1 H, 2Ј-H), 4.07 (br. dd, 62.4 (C-7), 66.7 (C-4), 70.5 (C-5), 169.3 (CH3CO), 174.7 (C-2) ppm.
J7β,7α ϭ 13.2, J7β,6β ϭ 2.2 Hz, 1 H, 7β-H), 4.21 (d, J4,5 ഠ 4.4 Hz,
1 H, 4-H), 4.45 (t, J7α,7β ഠ J7α,6β ഠ 12.4 Hz, 1 H, 7α-H), 4.66 (m, 70 (100), 43 (34). C12H19NO5 (257.28) calcd. C 56.00, H 7.45, N
EIMS: m/z ϭ 258 (1) [M ϩ1]ϩ, 214 (2), 198 (1), 197 (1), 186 (2),
1 H, 5-H), 7.36 (d, Jm,o ϭ 8.4 Hz, 2 H, m-Ph-H), 7.77 (d, Jo,m
ϭ
5.45; found C 56.01, H 7.41, N 5.39.
8.4 Hz, 2 H, o-Ph-H) ppm.
(3RS,4SR,5SR)-4-Hydroxy-5-phenylthio-3-[(2RS)-2-pyrrolidyl]-
(3RS,4SR,5SR)-5-Acetoxy-4-hydroxy-3-[(2RS)-2-piperidyl]oxepan- oxepan-2-one (17): Following the general procedure described for
2-one (14): Following the general procedure described for 12, re-
duction of 4 (200 mg, 0.74 mmol) rendered 14 (150 mg, 55.3 mmol,
75% yield) as a white solid (crystallized from acetone) decomp.
145Ϫ155 °C. IR (KBr): ν˜ ϭ 3318, 3100, 2983, 1740, 1720, 1372,
12, reduction of 9 (201 mg, 0.66 mmol) rendered 17 (168 mg,
0.55 mmol, 83% yield) as a white solid. M.p. 99Ϫ101 °C (CHCl3/
hexane). IR (KBr): ν˜ ϭ 3600Ϫ2800 (br), 3344, 2976, 2960, 2944,
2928, 2880, 2816, 1728, 1408, 1152 cmϪ1 1H NMR (400 MHz):
.
1273, 1226, 1218, 1174, 1155, 1083 cmϪ1 1H NMR (400 MHz): δ ϭ 1.36 (m, 1 H, 3Ј-H), 1.61 (m, 1 H, 4Ј-H), 1.68 (m, 1 H, 4Ј-H),
.
δ ϭ 1.33 (m, 4 H, 3Јax,3Јeq,4Јax,5Јax-H), 1.54 (m, 1 H, 5Јeq-H), 1.86 (m, 1 H, 3Ј-H), 1.92 (ddd, J6α,6β ϭ 15.9, J6α,7β ϭ 5.5, J6α,5
ϭ
1.75 (m, 1 H, 4Јeq-H), 1.89 (dt, J6α,6β ϭ 16.3, J6α,7α ഠ J6α,7β 3.0 Hz, 1 H, 6α-H), 2.57 (dddd, J6β,6α ഠ 16.2, J6β,7α ϭ 11.3, J6β,5
ഠ
ഠ
4.2 Hz, 1 H, 6α-H), 2.03 (s, 3 H, CH3), 2.34 (ddt, J6β,6α ϭ 16.3, 4.0, J6β,7β ഠ 1.7 Hz, 1 H, 6β-H), 2.85 (m, 2 H, 5Ј,5Ј-H), 3.29 (br.
J6β,7α ϭ 11.7, J6β,7β ϭ J6β,5 ϭ 2.3 Hz, 1 H, 6β-H), 2.60 (td, s, 1 H, 3-H), 3.77 (q, J5,4 ഠ J5,6α ഠ J5,6β ഠ 3.2 Hz, 1 H, 5-H), 3.87
J6Јax,6Јeq ϭ J6Јax,5Јax ϭ 11.6, J6Јax,5Јeq ϭ 2.5 Hz, 1 H, 6Јax-H), 2.90 (td, J2Ј,3Ј ഠ 8.7, J2Ј,3 ഠ 0.9 Hz, 1 H, 2Ј-H), 4.07 (d, J4,5 ഠ 3.4 Hz,
(d, J3,2Ј ϭ 1.3 Hz, 1 H, 3-H), 2.99 (br. d, J6Јeq,6Јax ഠ 11.0 Hz, 1 H, 1 H, 4-H), 4.12 (ddt, J7β,7α ϭ 13.1, J7β,6α ϭ 4.9, J7β,6β ഠ J7β,5
6Јeq-H), 3.14 (br. d, J2Ј,3Јax ഠ 10.0 Hz, 1 H, 2Ј-H), 4.07 (dddd, 1.4 Hz, 1 H, 7β-H), 4.56 (dd, J7α,7β ϭ 13.1, J7α,6β ϭ 11.3 Hz, 1 H,
ഠ
4222
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4215Ϫ4233

Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
7α-H), 7.28 (m, 3 H, Ar-H), 7.39 (m, 2 H, Ar-H) ppm. 13C NMR as 2(RS)-2-[(3RS,4SR,5SR)-5-acetylthio-4-hydroxy-2-oxooxepin-3-
(62.5 MHz): δ ϭ 25.8 (C-4Ј), 28.4 (C-6 ϩ C-3Ј), 46.4/47.0 (C-3/C- yl]piperidinium acetate (20): 1H NMR (400 MHz, [D6]acetone):
5Ј), 49.2 (C-5), 57.8 (C-2Ј), 63.3 (C-7), 67.8 (C-4), 127.4/129.2/ δ ϭ 1.60Ϫ1.83 (m, 5 H, 3Ј,3Ј,4Ј,4Ј,5Ј-H), 1.86 (m, 1 H, 6α-H), 1.87
131.4/132.9 (C-Ar), 174.8 (C-2). EIMS: m/z ϭ 307 (2) [M]ϩ, 279
(s, 3 H, CH3CO2Ϫ), 2.07 (m, 1 H, 5Ј-H), 2.35 (s, 3 H, CH3COS),
(3), 238 (1), 110 (15), 70 (100) ppm. C16H21NO3S (307.41) calcd. C 2.63 (dddd, J6β,6α ഠ 15.6, J6β,7α ഠ 11.5, J6β,5 ഠ 3.8, J6β,7β ഠ 1.9 Hz,
62.52, H 6.89, N 4.56, S 10.41; found C 62.48, H 6.84, N 4.45,
1 H, 6β-H), 2.92 (td, J6Јax,6Јeq ഠ J6Јax,5Јax ഠ 12.8, J6Јax,5Јeq ഠ 3.1 Hz,
S 10.34.
1 H, 6Јax-H), 3.23 (d, J3,2Ј ϭ 1.7 Hz, 1 H, 3-H), 3.43 (dt, J2Ј,3Јax
12.5, J2Ј,3Јeq ഠ J2Ј,3 ഠ 2.1 Hz, 1 H, 2Ј-H), 3.47 (ddt, J6Јeq,6Јax
ഠ
ഠ
Reduction of 2: Activated zinc powder (542 mg, 8.28 mmol) was
added to a solution of 2 (290 mg, 0.69 mmol) in a 1:1 mixture of
AcOH and H2O (32 mL). The mixture was stirred at room tem-
perature and reaction progress was monitored by TLC analysis
(eluent: CH2Cl2/diethyl ether/MeOH/NH3 saturated solution in
MeOH, 10:1/1:0.1). When the starting material had been consumed
(3 h), the mixture was filtered and the solid washed with AcOH/
H2O (1:1). The solution was brought to pH 8Ϫ9 by addition of
30% aqueous NH3 and then it was extracted with CHCl3 (6 ϫ
40 mL). The combined organic extracts were dried and the solution
was concentrated to furnish an oily residue. Purification by flash
column chromatography (same eluent as TLC) gave the following
fractions: 2 (97 mg, 33% recovery), (1RS,7aSR)-1-[(Z)-4-hydroxy-
butenyl]azetidino[1,2-a]piperidin-2-one (18) (80 mg, 0.40 mmol,
59% yield, 88% considering unrecovered 2) and 6,7-dihydro-3-(pip-
eridin-2-yl)-2(5H)-oxepinone (19) (8 mg, 0.04 mmol, 6% yield, 9%
over unrecovered 2).
13.0, J6Јeq,5Јax ഠ 4.1, J6Јeq,5Јeq ഠ J6Јeq,4Ј ഠ 2.2 Hz, 1 H, 6Јeq-H),
3.80 (q, J5,4 ഠ J5,6α ഠ J5,6β ഠ 3.5 Hz, 1 H, 5-H), 4.18 (dddd,
J7β,7α ഠ 13.5, J7β,6α ഠ 5.1, J7β,6β ഠ 2.0, J7β,5 ഠ 1.2 Hz, 1 H, 7β-
H), 4.37 (d, J4,5 ϭ 4.2 Hz, 1 H, 4-H), 4.39 (dd, J7α,7β ഠ 13.5,
J7α,6β ഠ 11.5 Hz, 1 H, 7α-H) ppm. 13C NMR (100 MHz, [D6]ace-
tone): δ ϭ 22.5 (C-4Ј), 22.9 (CH3CO2Ϫ), 24.0 (C-5Ј), 27.7 (C-3Ј),
29.7 (C-6), 31.1 (CH3COS), 47.3 (C-6Ј), 48.1 (C-5), 49.1 (C-3), 59.8
(C-2Ј), 66.0/66.1 (C-4/C-7), 175.8/176.3 (CH3CO2Ϫ/C-2), 194.3
(CH3COS) ppm. Compound 20 decomposes on standing.
(3RS,4SR,5RS)-
and
(3RS,4SR,5SR)-5-(2-Benzyloxy)ethyl-4-
hydroxy-3-[(2RS)-piperidin-2-yl]-3,4-dihydro-2(5H)-furanone (21):
Following the general procedure described for 12, reduction of 11
(300 mg, 0.95 mmol) rendered 21 (232 mg, 0.73 mmol, 77% yield)
as a mixture of two diastereomers, which could not be separated
by crystallisation or flash chromatography.
21: IR (KBr): ν˜ ϭ 3283, 3200Ϫ2600 (br), 3093, 3072, 3044, 2980,
2938, 2854, 2798, 2755, 2699, 1764, 1363, 1173, 1124, 1103, 1075,
18: IR (KBr): ν˜ ϭ 3416 (br), 2942, 2858, 1779, 1161, 1124, 1055
1026 cmϪ1 1H NMR (400 MHz): δ ϭ 1.30Ϫ1.50 (m), 1.53Ϫ1.97
.
1
cmϪ1. H NMR (400 MHz, [D6]acetone): δ ϭ 1.32 (m, 1 H, 6ax-
(m), 2.08 (m), 2.53 (td, J ϭ 12.2, 2.4 Hz), 2.59 (m), 2.88 (m), 3.03
(m), 3.36 (dt, J ϭ 11.6, 3.0 Hz), 3.62 (m), 4.07 (t, J ϭ 7.6 Hz) and
4.09 (dd, J ϭ 7.8, 4.6 Hz) (4-H), 4.46 (d, J ϭ 6.0 Hz) and 4.59 (dd,
J ϭ 8.5, 4.9 Hz) (5-H), 4.47 (d, J ϭ 11.6 Hz) 4.50 (d, J ϭ 11.6 Hz)
and 4.53 (s) (OCH2Ph), 7.32 (m, Ar) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 24.1, 24.4, 25.0, 25.9, 29.2, 29.5, 32.3, 33.2, 46.3, 46.8,
47.4, 52.6, 53.7, 56.0, 65.9, 66.5, 73.2, 73.5, 74.3, 82.0, 85.7, 127.56,
127.61, 127.8, 128.0, 128.3, 128.5, 137.2, 137.9, 174.6, 176.0. EIMS:
m/z ϭ 301 (2) [M Ϫ H2O]ϩ, 256 (1), 228 (2), 210 (6), 180 (14), 167
(12), 91 (87), 84 (100) ppm. C18H25NO4 (319.40) calcd. C 67.67, H
7.89, N 4.39; found C 67.65, H 7.89, N 4.50.
H), 1.53 (m, 2 H, 6eq,7ax-H), 1.62 (m, 3 H, 5ax,5eq,7eq-H), 2.31
(m, 2 H, 3Ј,3Ј-H), 2.68 (ddd, J4ax,5ax ϭ 11.8, J4ax,4eq ϭ 8.7,
J4ax,5eq ϭ 3.0 Hz, 1 H, 4ax-H), 2.79 (ddd, J7a,1 ϭ 12.5, J7a,7ax
ϭ
11.1, J7a,7eq ϭ 2.3 Hz, 1 H, 7a-H), 3.49 (m, 1 H, 4eq-H), 3.55 (m,
2 H, 4Ј,4Ј-H), 3.67 (ddd, J1,7a ϭ 12.5, J1,1Ј ϭ 9.3, J1,2Ј ϭ 1.0 Hz, 1
H, 1-H), 3.94 (t, JOH,4Ј ϭ 5.4 Hz, 1 H, O-H), 5.33 (ddt, J1Ј,2Ј
ϭ
10.8, J1Ј,1 ϭ 9.3, J1Ј,3 ϭ 1.6 Hz, 1 H, 1Ј-H), 5.82 (dtd, J2Ј,1Ј ϭ 10.8,
J2Ј,3Ј ϭ 7.5, J2Ј,1 ϭ 1.0 Hz, 1 H, 2Ј-H) ppm. 13C NMR (100 MHz,
[D6]acetone): δ ϭ 23.7 (C-6), 25.4 (C-5), 28.5 (C-7), 32.1 (C-3Ј),
47.3 (C-1), 55.9 (C-4), 61.7 (C-4Ј), 74.2 (C-7a), 123.1 (C-1Ј), 134.3
(C-2Ј), 174.7 (C-2) ppm. CIMS (NH3): m/z ϭ 229 (26) [M ϩ 34]ϩ,
212 (100) [M ϩ17]ϩ. C11H17NO2 (195.26) calcd. C 67.66, H 8.78,
N 7.17; found C 67.78, H 8.51, N 7.07.
(3RS,4SR,5SR)-5-Acetoxy-4-hydroxy-3-[(2RS)-N-tosylpiperidin-2-
yl]oxepan-2-one (22): Tosyl chloride (194 mg, 1.02 mmol) was ad-
ded to a stirred solution of 14 (55 mg, 0.20 mmol) in anhydrous
pyridine (2.5 mL). The mixture was heated at 60 °C and reaction
progress was monitored by TLC analysis (eluents: CH2Cl2/MeOH/
NH3 saturated solution in MeOH, 10:1/0.1, and hexane/EtOAc,
1:1). After all the starting material had been consumed (60 h), the
cold reaction mixture was concentrated under vacuum and the resi-
due (577 mg) was purified by flash column chromatography (hex-
ane/EtOAc, 1:1), furnishing 22 (74 mg, 0.17 mmol, 86% yield) as a
yellowish solid. M.p. 135Ϫ137 °C (CHCl3/hexane). IR (KBr): ν˜ ϭ
3472 (br), 2960, 2880, 1744, 1728, 1344, 1240, 1216, 1184, 1152,
19: IR (KBr): ν˜ ϭ 3325, 2931, 2854, 1715, 1469, 1441, 1398, 1349,
1
1286, 1230, 1180, 1152, 1110 cmϪ1. H NMR (250 MHz, [D6]ace-
tone): δ ϭ 1.30Ϫ2.10 (m, 8 H, 6,6,3Ј,3Ј,4Ј,4Ј,5Ј,5Ј-H), 2.30 (q, J ഠ
7.1 Hz, 2 H, 5,5-H), 2.68 (td, J6Јax,6Јeq ϭ J6Јax,5Јax ϭ 11.8,
J6Јax,5Јeq ϭ 2.9 Hz, 1 H, 6Јax-H), 3.09 (m, 1 H, 6Јeq-H), 3.44 (br.
d, J2Ј,3Ј ϭ 10.6 Hz, 1 H, 2Ј-H), 4.19 (m, 2 H, 7,7-H), 6.33 (td,
J4,5 ϭ 6.7, J4,2Ј ϭ 1.3 Hz, 1 H, 4-H) ppm. 13C NMR (62.5 MHz,
[D6]acetone): δ ϭ 23.1/24.6/25.8/26.1/31.9 (C-6/C-3Ј/C-4Ј/ C-5Ј/C-
5), 47.1 (C-6Ј), 58.1 (C-2Ј), 65.9 (C-7), 131.8 (C-3), 138.6 (C-4),
171.7 (C-2) ppm. EIMS: m/z ϭ 195 (4) [M]ϩ, 167 (91), 152 (50),
84 (100), 56 (42), 42 (39), 41 (60).
1
1064 cmϪ1. H NMR (400 MHz): δ ϭ 1.11 (m, 2 H, 3Ј,5Ј-H), 1.29
(m, 1 H, 4Ј-H), 1.46 (m, 3 H, 3Ј,4Ј,5Ј-H), 2.04 (dt, J6α,6β ϭ 16.4,
Reduction of 6: Activated zinc powder (562 mg, 8.59 mmol) was J6α,7β ഠ J6α,5 ഠ 4.3 Hz, 1 H, 6α-H), 2.09 (s, 3 H, CH3CO2), 2.32
added to a solution of 6 (102 mg, 0.36 mmol) in a 1:1 mixture of
AcOH and H2O (16 mL). The mixture was stirred at room tem-
(ddt, J6β,6α ϭ 16.4, J6β,7α ϭ 11.5, J6β,7β ഠ J6β,5 ഠ 2.2 Hz, 1 H, 6β-
H), 2.41 (s, 3 H, CH3-Ar), 2.67 (td, J6Јax,6Јeq ഠ J6Јax,5Јax ഠ 14.1,
perature and reaction progress was monitored by TLC analysis J6Јax,5Јeq ഠ 2.6 Hz, 1 H, 6Јax-H), 3.47 (d, J3,2Ј ϭ 11.0 Hz, 1 H, 3-
(eluent: CH2Cl2/MeOH/NH3 saturated solution in MeOH, 10:1/ H), 3.49 (d, JOH,4 ഠ 6.7 Hz, 1 H, OH), 4.05 (br. dd, J6Јeq,6Јax
0.1). When the starting material had been consumed (24 h), the 13.9, J6Јeq,5Јeq ഠ 2.1 Hz, 1 H, 6Јeq-H), 4.10 (ddd, J7β,7α ϭ 13.1,
ഠ
mixture was filtered, the solid washed with AcOH/H2O (1:1) The
solution was brought to pH 7Ϫ8 by addition of 30% aqueous NH3
and then it was extracted with CHCl3 (4 ϫ 50 mL). The combined
organic extracts were dried and the solution was concentrated to
furnish a yellowish solid (64 mg, 0.18 mmol, 51% yield) identified
J7β,6α ϭ 4.8, J7β,6β ϭ 1.3 Hz, 1 H, 7β-H), 4.18 (t, J4,5 ഠ J4,OH ഠ
4.9 Hz, 1 H, 4-H), 4.47 (dd, J7α,7β ഠ 13.0, J7α,6β ഠ 11.7 Hz, 1 H,
7α-H), 4.50 (dd, J2Ј,3 ഠ 10.6, J2Ј,3Ј ഠ 7.1 Hz, 1 H, 2Ј-H), 5.20 (q,
J5,4 ഠ J5,6β ഠ J5,6α ഠ 3.4 Hz, 1 H, 5-H), 7.30 (d, J ϭ 8.0 Hz, 2 H,
Ar-H), 7.74 (d, J ϭ 8.0 Hz, 2 H, Ar-H) ppm. 13C NMR
Eur. J. Org. Chem. 2004, 4215Ϫ4233
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4223

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
(62.5 MHz): δ ϭ 18.7 (C-3Ј), 21.2 (CH3CO2), 21.5 (CH3-Ar), 23.9 125.8/128.7/130.6/132.0 (Ph), 169.5 (C-1) ppm. EIMS: m/z ϭ 211
(C-4Ј), 25.8 (C-5Ј), 28.3 (C-6), 41.9 (C-6Ј), 42.1 (C-3), 50.5 (C-2Ј), (6) [M Ϫ BnBr]ϩ, 174 (20), 91 (100). C18H24BrNO3 (382.29) calcd.
61.9 (C-7), 65.8 (C-4), 70.8 (C-5), 126.6/130.0/138.0/143.6 (Ar),
C 56.68, H 6.35, Br 20.71, N 3.67; found C 56.53, H 6.31, Br 20.68,
168.8 (CH3CO), 171.4 (C-2) ppm. EIMS: m/z ϭ 316 (8) [M Ϫ H2O N 3.68.
Ϫ CH3C6H4]ϩ, 270 (24), 238 (46), 179 (30), 155 (31), 135 (66), 91
(47), 57 (33), 55 (43), 43 (100). C20H27NO7S (425.50) calcd. C
56.46, H 6.40, N 3.29, S 7.53; found C 56.44, H 6.40, N 3.11,
S 7.25.
(5RS,5aRS,7RS,11aSR,11bSR)-5-Acetoxy-N-benzyl-1-oxo-deca-
hydro-1H-oxepino[3Ј,4Ј:4,5]isoxazolo[2,3-a]pyridinium Bromide (25):
Following the general procedure described for 24, treatment of 4
(103 mg, 0.38 mmol) with benzyl bromide (46 µL, 0.38 mmol)
rendered 25 (169 mg, 0.38 mmol, 100% yield) as a yellowish solid
(crystallized from acetone/hexane) decomp. 169Ϫ177 °C. IR (KBr):
ν˜ ϭ 2976, 2952, 2880, 1746, 1733, 1238, 1218, 1054 cmϪ1. 1H NMR
(400 MHz): δ ϭ 1.80 (m, 2 H), 1.83 (m, 1 H), 1.98 (m, 1 H), 2.10
(s, 3 H, CH3CO2), 2.14 (m, 1 H), 2.30 (m, 1 H), 2.40 (m, 1 H), 2.50
(m, 1 H), 3.40 (br. d, J8eq,8ax ϭ 12.8 Hz, 1 H, 8eq-H), 4.25 (dd,
(5RS,5aRS,12aSR,12bSR)-5-Acetoxy-7-thioxo-decahydro-1H,7H-
oxepino[3,4-e]pyrido[1,2-c][1,3]oxazin-1-one (23):
A solution of
TCDI (50 mg, 0.28 mmol) in THF (2 mL) was added dropwise to
a stirred solution of 14 (38 mg, 0.14 mmol) in anhydrous THF
(10 mL) under nitrogen, and heated at reflux. Reaction progress
was monitored by TLC analysis (eluent: CH2Cl2/MeOH/NH3 satu-
rated solution in MeOH, 10:1/0.1). After all the starting material
had been consumed (2 h), the cooled reaction mixture was concen-
trated under vacuum. The oily residue was dissolved in CH2Cl2
(25 mL) and the solution washed with water (2 ϫ 25 mL). The
organic extracts were dried and the solvent evaporated, furnishing
a brown solid (65 mg). Purification by flash chromatography (hex-
ane/EtOAc, 1:3) gave 23 (21 mg, 0.07 mmol, 60% yield) as a white
solid. M.p. 181Ϫ183 °C. IR (KBr): ν˜ ϭ 3009, 2952, 2931, 2861,
J3β,3α ϭ 14.0, J3β,4 ϭ 6.7 Hz, 1 H, 3β-H), 4.30 (br. d, J11a,11b
ϭ
10.4 Hz, 1 H, 11a-H), 4.72 (d, J ϭ 13.4 Hz, 1 H, CH2Ph), 4.77 (td,
J8ax,8eq ഠ J8ax,9ax ഠ 12.9, J8ax,9eq ഠ 2.5 Hz, 1 H, 8ax-H), 5.00 (d,
J ϭ 13.4 Hz, 1 H, CH2Ph), 5.10 (q, J5,5a ഠ J5,4 ഠ 9.1 Hz, 1 H, 5-
H), 5.15 (td, J3α,3β ഠ J3α,4 ഠ 13.4, J3α,4 ϭ 3.1 Hz, 1 H, 3α-H), 5.55
(t, J ഠ 10.4 Hz, 1 H, 5a/11b-H), 5.71 (t, J ഠ 10.4 Hz, 1 H, 5a/11b-
H), 7.34 (d, J ϭ 7.3 Hz, 2 H, Ar), 7.41 (t, J ϭ 7.3 Hz, 2 H, Ar),
7.50 (t, J ϭ 7.3 Hz, 1 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 15.6
(C-9), 20.8 (CH3CO2), 22.6/24.0 (C-10/C-11), 29.7 (C-4), 47.6 (C-
11b), 57.8 (C-8), 64.1 (C-3), 66.1 (CH2Ph), 68.6 (C-5), 73.2 (C-
11a), 78.6 (C-5a), 125.4/129.4/131.5/132.1 (Ph), 168.9/169.4 (C-1/
CH3CO2) ppm. EIMS: m/z ϭ 269 (3) [M Ϫ BnBr]ϩ, 226 (1), 172
(6), 170 (6), 124 (20), 91 (100), 43 (22). C20H26BrNO5 (440.33)
calcd. C 54.66, H 5.97, Br 17.97, N 3.19; found C 54.49, H 5.94,
Br 17.84, N 3.17.
1
1736, 1497, 1237, 1173 cmϪ1. H NMR (400 MHz): δ ϭ 1.64 (m,
4 H, 10,10,11,12-H), 1.82 (m, 1 H, 12-H), 1.97 (m, 1 H, 11-H), 2.11
(s, 3 H, CH3CO2), 2.12 (dt, J4α,4β ഠ 17.1, J4α,3β ഠ J4α,5 ഠ 4.9 Hz,
1 H, 4α-H), 2.33 (ddt, J4β,4α ϭ 16.5, J4β,3α ϭ 11.0, J4β,3β ഠ J4β,5
1.8 Hz, 1 H, 4β-H), 3.13 (td, J9ax,9eq ഠ J9ax,10ax ഠ 12.8, J9ax,10eq
2.7 Hz, 1 H, 9ax-H), 3.21 (br. s, 1 H, 12b-H), 4.04 (dd, J12a,12
11.9, 2.7 Hz, 1 H, 12a-H), 4.19 (br. dd, J3β,3α ഠ 12.8, J3β,4α
ഠ
ഠ
ഠ
ഠ
4.9 Hz, 1 H, 3β-H), 4.32 (br. d, J5a,5 ϭ 3.7 Hz, 1 H, 5a-H), 4.49
(dd, J3α,3β ϭ 13.4, J3α,4β ϭ 10.4 Hz, 1 H, 3α-H), 5.09 (dt, J9eq,9ax ϭ
(5RS,5aRS,7RS,11aSR,11bSR)-N-Benzyl-1-oxo-5-phenylthio-deca-
hydro-1H-oxepino[3Ј,4Ј:4,5]isoxazolo[2,3-a]pyridinium Bromide (26):
Following the general procedure described for 24, treatment of 5
(501 mg, 1.57 mmol) with benzyl bromide (187 µL, 1.57 mmol)
rendered 26 (770 mg, 1.57 mmol, 100% yield) as a yellowish solid
(crystallized from CHCl3/hexane) decomp. 144Ϫ152 °C. IR (KBr):
13.4, J9eq,10ax ഠ J9eq,10eq ഠ 1.8 Hz, 1 H, 9eq-H), 5.46 (q, J5,4α
ഠ
J5,4β ഠ J5,5a ഠ 3.1 Hz, 1 H, 5-H) ppm. 13C NMR (62.5 MHz): δ ϭ
20.9 (CH3CO2), 24.0 (C-11), 25.4 (C-12), 29.1 (C-4), 31.7 (C-10),
43.6 (C-12b), 53.2 (C-9), 60.0 (C-12a), 61.9 (C-3), 68.4 (C-5), 72.1
(C-5a), 168.7 (CH3CO), 169.2 (C-1), 185.5 (C-7) ppm. EIMS: m/
z ϭ 313 (80) [M]ϩ, 280 (11), 238 (11), 220 (38), 210 (15), 194 (36),
83 (87), 82 (100), 55 (55), 43 (95). C14H19NO5S (313.37) calcd. C
53.66, H 6.12, N 4.47, S 10.21; found C 53.38, H 6.12, N 4.33,
S 9.96.
1
ν˜ ϭ 2938, 2868, 1729, 1173 cmϪ1. H NMR (400 MHz): δ ϭ 1.77
(m, 1 H), 1.89 (m, 2 H), 2.23 (m, 3 H), 2.37 (m, 1 H), 2.55 (m, 1
H), 3.29 (td, J5,5a ϭ J5,4 ϭ 11.0, J5,4 ϭ 6.1 Hz, 1 H, 5-H), 3.39 (br.
d, J8eq,8ax ഠ 12.2 Hz, 1 H, 8eq-H), 4.21 (m, 2 H, 3β,11a-H), 4.64
(d, J ϭ 13.7 Hz, 1 H, CH2Ph), 4.84 (d, J ϭ 13.7 Hz, 1 H, CH2Ph),
4.95 (br. t, J8ax,8eq ഠ J8ax,9ax ഠ 11.9 Hz, 1 H, 8ax-H), 5.12 (td,
(5aRS,7RS,11aSR,11bSR)-N-Benzyl-1-oxo-decahydro-1H-oxepino-
[3Ј,4Ј:4,5]isoxazolo[2,3-a]pyridinium Bromide (24). General Pro-
cedure for the Benzylation of Isoxazolidines: Benzyl bromide (72 µL,
0.60 mmol) was added dropwise to a stirred solution of 1 (127 mg,
0.60 mmol) in anhydrous THF (25 mL) at room temperature. Reac-
tion progress was monitored by 1H NMR analysis of aliquot
samples. When all the starting material had been consumed (3
days), the solvent was removed furnishing 24 (228 mg, 0.60 mmol,
J3α,3β ϭ J3α,4 ϭ 13.4, J3α,4 ϭ 3.7 Hz, 1 H, 3α-H), 5.50 (t, J5a,5
ഠ
J5a,11b ഠ 11.0 Hz, 1 H, 5a-H), 5.71 (t, J11b,11a ഠ J11b,5a ഠ 10.4 Hz,
1 H, 11b-H), 7.25Ϫ7.51 (m, 10 H, Ar) ppm. 13C NMR (62.5 MHz):
δ ϭ 15.5 (C-9), 22.7/24.0 (C-10/C-11), 31.5 (C-4), 44.3 (C-5), 49.4
(C-11b), 58.1 (C-8), 65.1 (C-3), 66.0 (CH2Ph), 72.2 (C-11a), 79.9
(C-5a), 125.5/128.5/129.4/131.4/132.1/133.1 (Ph), 169.5 (C-1) ppm.
(5RS,5aRS,7RS,11aSR,11bSR)-5-Acetylthio-N-benzyl-1-oxo-deca-
99% yield) as a yellowish solid (crystallized from acetone/hexane) hydro-1H-oxepino[3Ј,4Ј:4,5]isoxazolo[2,3-a]pyridinium Bromide (27):
decomp. 197Ϫ204 °C. IR (KBr): ν˜ ϭ 2976, 2949, 2880, 1733, 1187 Following the general procedure described for 24, treatment of 6
cmϪ1. 1H NMR (400 MHz): δ ϭ 1.56 (m, 1 H), 1.78 (m, 1 H), 1.90 (100 mg, 0.35 mmol) with benzyl bromide (42 µL, 0.35 mmol)
(m, 2 H), 2.05 (m, 1 H), 2.12 (m, 1 H), 2.20 (m, 1 H), 2.27 (m, 2 rendered 27 (163 mg, 0.35 mmol, 100% yield) as a yellowish solid
H), 2.47 (m, 1 H), 3.37 (br. d, J8eq,8ax ϭ 11.6 Hz, 1 H, 8eq-H), 4.21 (crystallized from acetone/hexane) decomp. 142Ϫ150 °C. IR (KBr):
(dd, J11a,11b ϭ 10.4, J11a,11 ϭ 2.4 Hz, 1 H, 11a-H), 4.25 (dd, J3β,3α ϭ ν˜ ϭ 3021, 2962, 2944, 2920, 2880, 1750, 1715, 1272, 1181, 1072
13.4, J3β,4 ϭ 6.4 Hz, 1 H, 3β-H), 4.74 (d, J ϭ 13.4 Hz, 1 H, cmϪ1 1H NMR (400 MHz): δ ϭ 1.80 (m, 1 H, 9-H), 1.93 (td,
4α,4β ϭ J4α,5 ϭ 13.4, J4α,3α ഠ 3.1 Hz, 1 H, 4α-H), 2.16 (m, 1 H, 9-
.
CH2Ph), 4.89 (d, J ϭ 13.4 Hz, 1 H, CH2Ph), 4.92 (td, J8ax,8eq
J8ax,9ax ഠ 13.1, J8ax,9eq ϭ 3.1 Hz, 1 H, 8ax-H), 5.00 (td, J3α,3β
J3α,4 ഠ 13.4, J3α,4 ϭ 3.7 Hz, 1 H, 3α-H), 5.44 (t, J11b,11a ഠ J11b,5a
ഠ
ഠ
ഠ
J
H), 2.28 (m, 1 H, 11-H), 2.32Ϫ2.50 (m, 4 H, 4β,10,10,11-H), 2.42
(s, 3 H, CH3COS), 3.28 (br. d, J8eq,8ax ϭ 12.2 Hz, 1 H, 8eq-H), 3.80
10.0 Hz, 1 H, 11b-H), 5.58 (ddd, J5a,5 ϭ 12.2, J5a,11b ϭ 9.8, J5a,5 ϭ (td, J5,5a ϭ J5,4α ϭ 11.6, J5,4β ഠ 6.7 Hz, 1 H, 5-H), 4.27 (dd,
2.7 Hz, 1 H, 5a-H), 7.46 (m, 5 H, Ar) ppm. 13C NMR (62.5 MHz):
J3β,3α ϭ 13.4, J3β,4β ϭ 6.1 Hz, 1 H, 3β-H), 4.41 (dd, J11a,11b ϭ 10.4,
δ ϭ 15.2 (C-9), 21.8/23.2/24.6 (C-4/C-5/C-10/C-11), 49.0 (C-11b), J11a,11 ϭ 4.9 Hz, 1 H, 11a-H), 4.62 (d, J ϭ 13.7 Hz, 1 H, CH2Ph),
57.4 (C-8), 65.3 (C-3), 65.6 (CH2Ph), 71.5 (C-11a), 77.5 (C-5a), 4.80 (br. t, J8ax,8eq ഠ J8ax,9ax ഠ 12.8 Hz, 1 H, 8ax-H), 4.90 (d, J ϭ
4224
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4215Ϫ4233

Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
13.7 Hz, 1 H, CH2Ph), 5.17 (td, J3α,3β ϭ J3α,4β ϭ 13.4, J3α,4α
FULL PAPER
ഠ
Decomp. 175Ϫ185 °C. IR (KBr): ν˜ ϭ 2988, 2945, 1743, 1237, 1188,
3.7 Hz, 1 H, 3α-H), 5.53 (t, J5a,5 ഠ J5a,11b ഠ 10.7 Hz, 1 H, 5a-H), 1047 cmϪ1. H NMR (250 MHz, [D6]DMSO): δ ϭ 1.81 (m, 1 H,
1
5.69 (t, J11b,11a ϭ J11b,5a ϭ 10.4 Hz, 1 H, 11b-H), 7.30 (d, J ഠ
4-H), 2.00Ϫ2.60 (m, 5 H, 4,9,9,10,10-H), 2.05 (s, 3 H, CH3CO2),
7.6 Hz, 2 H, Ar), 7.43 (t, J ഠ 7.6 Hz, 2 H, Ar), 7.52 (t, J ഠ 7.6 Hz, 3.68 (dt, J8,8 ഠ 12.4, J8,9 ഠ 5.9 Hz, 1 H, 8-H), 4.06 (dt, J8,8 ϭ 12.4,
1 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 15.5 (C-9), 22.2/23.9 J8,9 ഠ 7.7 Hz, 1 H, 8-H), 4.41 (dd, J3β,3α ഠ 13.2, J3β,4 ϭ 8.8 Hz, 1
(C-10/C-11), 30.2 (C-4), 30.4 (CH3COS), 39.4 (C-5), 49.3 (C-11b),
56.9 (C-8), 64.8 (C-3), 66.1 (CH2Ph), 73.5 (C-11a), 78.4 (C-5a),
125.8/129.2/131.1/131.9 (Ph), 169.1 (C-1), 193.1 (CH3COS) ppm.
H, 3β-H), 4.52 (td, J3α,3β ഠ J3α,4 ഠ 12.4, J3α,4 ഠ 7.3 Hz, 1 H, 3α-
H), 4.80 (dd, J10b,5a ϭ 8.0, J10b,10a ϭ 2.2 Hz, 1 H, 10b-H), 4.92 (d,
J ϭ 13.2 Hz, 1 H, CH2Ph), 4.95 (td, J5,5a ഠ J5,4 ഠ 11.0, J5,4
ഠ
6.6 Hz, 1 H, 5-H), 5.12 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.32 (m, 1
H, 10a-H), 5.35 (t, J5a,5 ഠ J5a,10b ഠ 8.8 Hz, 1 H, 5a-H), 7.50 (m, 5
H, Ph) ppm. 13C NMR (62.5 MHz, [D6]DMSO): δ ϭ 20.8
(CH3CO2), 23.6/27.3/29.7 (C-4/C-9/C-10), 51.8 (C-10b), 63.4 (C-3),
66.6 (CH2Ph), 69.0 (C-8), 70.0 (C-5), 79.8 (C-5a), 83.1 (C-10a),
128.3/128.9/130.7/132.7 (Ph), 169.4/169.6 (C-1/ CH3CO2) ppm.
(5RS,5aRS,7RS,11aSR,11bSR)-5-Acetylthio-N-methyl-1-oxo-
decahydro-1H-oxepino[3Ј,4Ј:4,5]isoxazolo[2,3-a]pyridinium Iodide
(32): Methyl iodide (700 µL, 11.2 mmol) was added dropwise to a
stirred solution of 6 (105 mg, 0.37 mmol) in anhydrous THF
(5 mL) at room temperature. Reaction progress was monitored by
1H NMR analysis of aliquot samples. When all the starting mate-
rial had been consumed (3 days), the solution was concentrated
(5RS,5aRS,7RS,10aSR,10bSR)-N-Benzyl-5-phenylthio-1-oxo-
furnishing 32 (157 mg, 0.37 mmol, 100% yield) as a yellowish solid octahydro-3H-oxepino[3,4:d]pyrrolo[1,2-b]isoxazolium Bromide (30):
Following the general procedure described for 24, treatment of 9
(crystallized from CHCl3/hexane) decomp. 185Ϫ201 °C. IR (KBr):
ν˜ ϭ 3008, 2984, 2956, 2933, 2900, 2873, 1736, 1688, 1280, 1176, (200 mg, 0.66 mmol) with benzyl bromide (78 µL, 0.66 mmol)
1
1108 cmϪ1. H NMR (400 MHz): δ ϭ 1.75 (m, 2 H, 9,10-H), 1.93 rendered 30 (310 mg, 0.66 mmol, 100% yield) as a white solid. De-
(ddd, J4α,4β ϭ 14.6, J4α,5 ϭ 11.6, J4α,3α ϭ 3.1 Hz, 1 H, 4α-H), 2.13
comp. 152Ϫ166 °C. IR (KBr): ν˜ ϭ 2981, 2938, 2903, 1743, 1181
(m, 1 H, 9/11-H), 2.23Ϫ2.51 (m, 4 H, 4β,10,11,9/11-H), 2.34 (s, 3 cmϪ1. 1H NMR (250 MHz, [D6]DMSO): δ ϭ 1.79 (dt, J4,4 ϭ 13.5,
H, CH3COS), 3.46 (m, 1 H, 8eq-H), 3.47 (s, 3 H, CH3-N), 3.82 (td, J4,3α ഠ J4,5 ഠ 5.1 Hz, 1 H, 4-H), 2.12 (m, 2 H, 9,9-H), 2.28 (m, 1
J5,5a ϭ J5,4 ϭ 11.6, J5,4 ϭ 6.7 Hz, 1 H, 5-H), 4.32 (dd, J3β,3α
13.4, J3β,4β ഠ 6.1 Hz, 1 H, 3β-H), 4.35 (dd, J11a,11b ഠ 10.4, J11a,11
5.5 Hz, 1 H, 11a-H), 5.03 (td, J8ax,8eq ഠ J8ax,9ax ഠ 13.7, J8ax,9eq
3.4 Hz, 1 H, 8ax-H), 5.18 (td, J3α,3β ϭ J3α,4α ϭ 13.4, J3α,4β
ഠ
ഠ
ഠ
ϭ
H, 10-H), 2.40 (m, 1 H, 4-H), 2.53 (m, 1 H, 10-H), 3.35 (m, 1 H,
5-H), 3.66 (dt, J8,8 ഠ 12.4, J8,9 ഠ 5.9 Hz, 1 H, 8-H), 4.07 (dt, J8,8 ϭ
12.4, J8,9 ഠ 7.6 Hz, 1 H, 8-H), 4.32 (dd, J3β,3α ഠ 13.2, J3β,4
ϭ
8.0 Hz, 1 H, 3β-H), 4.44 (td, J3α,3β ഠ J3α,4 ഠ 12.4, J3α,4 ϭ 5.1 Hz,
3.7 Hz, 1 H, 3α-H), 5.48 (t, J5a,5 ഠ J5a,11b ഠ 10.7 Hz, 1 H, 5a-H), 1 H, 3α-H), 4.75 (dd, J10b,5a ഠ 8.0, J10b,10a ഠ 1.5 Hz, 1 H, 10b-H),
5.55 (t, J11b,11a ഠ J11b,5a ഠ 10.1 Hz, 1 H, 11b-H) ppm. 13C NMR
4.95 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.07 (dd, J5a,5 ഠ 10.2, J5a,10b ϭ
(62.5 MHz): δ ϭ 15.5 (C-9), 22.8/23.9 (C-10/C-11), 29.7 (C-4), 30.4 8.0 Hz, 1 H, 5a-H), 5.14 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.29 (m, 1
(CH3COS), 39.3 (C-5), 49.7 (C-11b), 51.9 (CH3-N), 62.4 (C-8), 65.0 H, 10a-H), 7.36Ϫ7.55 (m, 10 H, Ar) ppm. 13C NMR (62.5 MHz,
(C-3), 74.7 (C-11a), 78.6 (C-5a), 168.6 (C-1), 193.1 (CH3COS) ppm. [D6]DMSO): δ ϭ 23.6/29.6 (C-4/C-9/C-10), 45.0 (C-5), 53.1 (C-
C14H22INO4S (427.30) calcd. C 39.34, H 5.19, N 3.28, S 7.49;
found C 39.47, H 5.28, N 3.19, S 7.40.
10b), 64.4 (C-3), 66.3 (CH2Ph), 68.8 (C-8), 80.0 (C-5a), 84.6 (C-
10a), 128.5/128.9/129.6/130.5/131.0/132.7/134.4 (Ar), 169.7 (C-1)
ppm. C23H26BrNO3S (476.43) calcd. C 58.10, H 5.52, Br 16.61, N
2.95, S 6.73; found C 58.02, H 5.55, Br 16.56, N 2.99, S 6.69.
(5aRS,7SR,10aRS,10bRS)-N-Benzyl-1-oxo-octahydro-3H-oxepino-
[3,4:d]pyrrolo[1,2-b]isoxazolium Bromide (28): Following the general
procedure described for 24, treatment of 7 (200 mg, 1.01 mmol)
(5RS,5aRS,7RS,10aSR,10bSR)-5-Acetylthio-N-benzyl-1-oxoocta-
with benzyl bromide (120 µL, 1.02 mmol) rendered 28 (350 mg, hydro-3H-oxepino[3,4:d]pyrrolo[1,2-b]isoxazolium Bromide (31):
0.95 mmol, 94% yield) as a yellowish solid. IR (KBr): ν˜ ϭ 3037, Following the general procedure described for 24, treatment of 10
2994, 2952, 2924, 2875, 1736, 1405, 1279, 1173 cmϪ1 1H NMR (203 mg, 0.75 mmol) with benzyl bromide (89 µL, 0.75 mmol)
(400 MHz): δ ϭ 1.66 (td, J ϭ 12.9, 6.2 Hz, 1 H), 2.04 (m, 3 H), rendered 31 (332 mg, 0.75 mmol, 100% yield) as a yellowish solid.
.
2.39 (m, 2 H), 2.79 (m, 1 H), 2.91 (m, 1 H), 3.65 (dt, J8,8 ϭ 11.7, Decomp. 161Ϫ170 °C. IR (KBr): ν˜ ϭ 2931, 1743, 1715, 1694, 1181
J8,9 ഠ 5.7 Hz, 1 H, 8-H), 4.31 (m, 2 H, 3,8-H), 4.90 (d, J ϭ 13.2 Hz,
1 H, CH2Ph), 5.02 (td, J3,3 ϭ J3,4 ϭ 12.6, J3,4 ϭ 5.9 Hz, 1 H, 3-
H), 5.45 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.52 (m, 3 H, 5a,10a,10b-
cmϪ1. 1H NMR (250 MHz, [D6]DMSO): δ ϭ 2.00 (dt, J4,4 ϭ 13.9,
J4,3 ϭ J4,5 ϭ 5.1 Hz, 1 H, 4-H), 2.12 (m, 2 H, 9,9-H), 2.25 (m, 2
H, 4,10-H), 2.39 (s, 3 H, CH3COS), 2.50 (m, 1 H, 10-H), 3.60 (m,
H), 7.40 (t, J ϭ 7.0 Hz, 2 H, Ar), 7.46 (t, J ϭ 7.0 Hz, 1 H, Ar), 2 H, 5,8-H), 4.06 (dt, J8,8 ഠ 12.4, J8,9 ഠ 7.3 Hz, 1 H, 8-H), 4.39
7.58 (d, J ϭ 7.0 Hz, 2 H, Ar) ppm. 1H NMR (400 MHz,
(dd, J3β,3α ϭ 13.2, J3β,4 ϭ 8.8 Hz, 1 H, 3β-H), 4.53 (td, J3α,3β
[D6]DMSO): δ ϭ 1.50 (m, 1 H), 1.69 (m, 1 H), 2.07Ϫ2.25 (m, 5 J3α,4 ഠ 12.4, J3α,4 ഠ 5.5 Hz, 1 H, 3α-H), 4.77 (dd, J10b,5a ഠ 7.7,
H), 2.53 (m, 1 H), 3.65 (dt, J8,8 ϭ 13.0, J8,9 ϭ 6.4 Hz, 1 H, 8-H), 10b,10a ϭ 1.5 Hz, 1 H, 10b-H), 4.88 (d, J ϭ 13.2 Hz, 1 H, CH2Ph),
4.06 (dt, J8,8 ϭ 13.0, J8,9 ϭ 7.3 Hz, 1 H, 8-H), 4.33 (dd, J3,3 ϭ 13.2, 5.10 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.23 (dd, J5a,5 ഠ 10.6, J5a,10b
ഠ
J
ഠ
J
3,4 ϭ 8.8 Hz, 1 H, 3-H), 4.44 (td, J3,3 ഠ J3,4 ഠ 12.6, J3,4 ഠ 5.3 Hz, 7.7 Hz, 1 H, 5a-H), 5.33 (ddd, J10a,10 ഠ 7.3, 5.1, J10a,10b ഠ 1.5 Hz,
1 H, 3-H), 4.63 (br. d, J10b,5a ϭ 7.9 Hz, 1 H, 10b-H), 4.90 (d, J ϭ
1 H, 10a-H), 7.40Ϫ7.53 (m, 5 H, Ph) ppm. 13C NMR (62.5 MHz,
13.2 Hz, 1 H, CH2Ph), 5.09 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 5.11 [D6]DMSO): δ ϭ 23.7/29.2/29.7 (C-4/C-9/C-10), 30.6 (CH3COS),
(m, 1 H, 5a-H), 5.23 (m, 1 H, 10a-H), 7.48 (m, 3 H, Ar), 7.57 (m, 39.7 (C-5), 53.2 (C-10b), 64.4 (C-3), 66.2 (CH2Ph), 69.0 (C-8), 80.8
2 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 20.5/24.1/26.1/29.8 (C-
4/C-5/C-9/C-10), 54.7 (C-10b), 66.1/66.4 (CH2Ph/C-3), 69.7 (C-8),
79.9 (C-5a), 83.4 (C-10a), 127.7/129.0/130.7/132.4 (Ph), 170.7 (C-1)
ppm. EIMS: m/z ϭ 288 (1) [M Ϫ Br]ϩ, 197 (3), 91 (100).
(C-5a), 83.1 (C-10a), 128.3/128.8/130.6/132.7 (Ph), 169.8 (C-1),
193.4 (CH3COS) ppm.
(3RS,4RS)-3-[(2RS)-N-Benzylpiperidin-2-yl]-4-hydroxyoxepan-2-
one (33). General Procedure for the Reduction of N-Benzylisoxazoli-
dinium Salts: Activated zinc powder (5.33 g, 81.4 mmol) was added
to a solution of 24 (432 mg, 1.13 mmol) in 10% aqueous HCl
(40 mL) and the mixture was sonicated for 15 min. Then the sus-
(5RS,5aRS,7RS,10aSR,10bSR)-5-Acetoxy-N-benzyl-1-oxoocta-
hydro-3H-oxepino[3,4:d]pyrrolo[1,2-b]isoxazolium Bromide (29):
Following the general procedure described for 24, treatment of 8
(213 mg, 0.84 mmol) with benzyl bromide (100 µL, 0.84 mmol) pension was filtered, the solid washed with 10% aqueous HCl and
rendered 29 (356 mg, 0.84 mmol, 100% yield) as a yellowish solid. water and the solution brought to pH 9Ϫ10 by addition of 30%
Eur. J. Org. Chem. 2004, 4215Ϫ4233
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4225

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
aqueous NH3. A white solid appeared which was filtered under
vacuum. The solution was then extracted with CHCl3 (4 ϫ 50 mL),
the combined organic extracts were dried and the solution was con-
centrated to furnish 33 (343 mg, 81.4 mmol, 100% yield) as a white
solid. M.p. 129Ϫ130 °C (from acetone/hexane). IR (KBr): ν˜ ϭ
(3RS,4RS)-3-[(2RS)-N-Benzylpyrrolidin-2-yl]-4-hydroxyoxepan-2-
one (36): Following the general procedure described for 33, re-
duction of 28 (175 mg, 0.47 mmol) gave an oily residue (171 mg),
which was purified by flash chromatography (eluent: CHCl3/
MeOH, 9:1), affording 36 (136 mg, 0.47 mmol, 99% yield) as a
3472, 2976, 2944, 2880, 1728, 1296, 1184 cmϪ1
.
1H NMR white solid. M.p. 129Ϫ131 °C. IR (KBr): ν˜ ϭ 3416 (br), 2952, 2924,
(400 MHz): δ ϭ 1.38 (m, 2 H), 1.60Ϫ1.84 (m, 5 H), 1.89 (m, 1 H),
2.01 (m, 1 H), 2.71 (dt, J6Јeq,6Јax ഠ 14.3, J6Јeq,5Јax ഠ J6Јeq,5Јeq
4.0 Hz, 1 H, 6Јeq-H), 2.81 (ddd, J6Јax,6Јeq ϭ 14.0, J6Јax,5Јax ϭ 9.8,
J6Јax,5Јeq ϭ 3.4 Hz, 1 H, 6Јax-H), 3.37 (dd, J3,2Ј ϭ 11.0, J3,4
1729, 1447, 1398, 1286, 1230, 1166, 1103, 1061, 1019 cmϪ1 1H
.
ഠ
NMR (400 MHz): δ ϭ 1.50 (m, 1 H), 1.64 (m, 1 H), 1.73 (m, 3 H),
2.18 (m, 3 H), 2.70 (m, 2 H, 5Ј,5Ј-H), 2.80 (s, 1 H, 3-H), 3.45 (d,
J ϭ 13.1 Hz, 1 H, CH2Ph), 3.69 (t, J2Ј,3 ϭ 7.6 Hz, 1 H, 2Ј-H), 4.14
(t, J7,7 ഠ J7,6 ഠ 11.9 Hz, 1 H, 7-H), 4.24 (br. s, 1 H, 4-H), 4.29 (dd,
J7,7 ϭ 12.8, J7,6 ϭ 4.3 Hz, 1 H, 7-H), 4.63 (d, J ϭ 13.1 Hz, 1 H,
ϭ
2.1 Hz, 1 H, 3-H), 3.44 (dt, J2Ј,3 ഠ 10.5, J2Ј,3Ј ഠ 4.1 Hz, 1 H, 2Ј-
H), 3.81 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), 3.95 (d, J ϭ 13.1 Hz, 1 H,
CH2Ph), 4.21 (m, 2 H, 7,7-H), 4.44 (m, 1 H, 4-H), 7.25 (m, 1 H, CH2Ph), 5.56 (br. s, 1 H, OH), 7.22 (m, 5 H, Ph) ppm. 13C NMR
Ar), 7.30 (m, 4 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 18.6/21.0/
21.8 (C-3Ј/C-4Ј/C-5Ј), 23.5 (C-5), 33.2 (C-6), 46.4 (C-6Ј), 48.6 (C-
(62.5 MHz): δ ϭ 23.4/24.0 (C-4Ј/C-5), 32.3/35.1 (C-3Ј/C-6), 53.6
(C-3), 54.3 (C-5Ј), 61.4 (CH2Ph), 64.8/65.2 (C-2Ј/C-4), 68.8 (C-7),
3), 54.7 (C-2Ј), 55.4 (CH2Ph), 65.2 (C-4), 67.2 (C-7), 127.3/128.5/ 126.8/128.4/128.8/140.2 (Ph), 174.6 (C-2) ppm. EIMS: m/z ϭ 290
128.8/139.1 (Ph), 172.8 (C-2) ppm. EIMS: m/z ϭ 303 (1) [M]ϩ, 174 (1) [M ϩ1]ϩ, 289 (1) [M]ϩ, 160 (100), 91 (94). C17H23NO3 (289.37)
(85), 91 (100). C18H25NO3 (303.40) calcd. C 71.24, H 8.31, N 4.62;
found C 71.20, H 8.44, N 4.60.
calcd. C 70.56, H 8.01, N 4.84; found C 70.68, H 8.04, N 4.83.
(3RS,4SR,5SR)-5-Acetoxy-3-[(2RS)-N-benzylpyrrolidin-2-yl]-4-
hydroxyoxepan-2-one (37): Following the general procedure de-
scribed for 33, reduction of 29 (105 mg, 0.25 mmol) rendered 37
(83 mg, 0.24 mmol, 97% yield) as a white solid (crystallized from
CHCl3/pentane). M.p. 117Ϫ120 °C. IR (KBr): ν˜ ϭ 3423, 2973,
(3RS,4SR,5SR)-5-Acetoxy-3-[(2RS)-N-benzylpiperidin-2-yl]-4-
hydroxyoxepan-2-one (34): Following the general procedure de-
scribed for 33, reduction of 25 (164 mg, 0.37 mmol) rendered 34
(135 mg, 0.37 mmol, 100% yield) as a white solid. M.p. 141Ϫ143
°C (from CHCl3/hexane). IR (KBr): ν˜ ϭ 3395, 2945, 2868, 1729,
1708, 1370, 1244, 1173, 1068 cmϪ1. 1H NMR (400 MHz): δ ϭ 1.34
(m, 1 H), 1.43 (m, 1 H), 1.52Ϫ1.70 (m, 3 H), 1.92 (m, 1 H), 1.92
(dt, J6α,6β ϭ 16.5, J6α,7β ϭ J6α,5 ϭ 4.3 Hz, 1 H, 6α-H), 2.00 (s, 3 H,
2959, 2924, 2882, 1715, 1377, 1265, 1166, 1061 cmϪ1 1H NMR
.
(400 MHz): δ ϭ 1.41 (m, 1 H, 3Ј/4Ј-H), 1.73 (m, 2 H, 3Ј/4Ј,4Ј-H),
1.96 (dt, J6α,6β ഠ 15.9, J6α,7β ഠ J6α,5 ഠ 4.3 Hz, 1 H, 6α-H), 2.08 (s,
3 H, CH3CO2), 2.21 (m, 1 H, 3Ј-H), 2.39 (ddt, J6β,6α ഠ 15.9,
J6β,7α ഠ 11.6, J6β,5 ഠ J6β,7β ഠ 2.4 Hz, 1 H, 6β-H), 2.72 (m, 2 H,
5Ј,5Ј-H), 3.03 (d, J3,2Ј ഠ 1.8 Hz, 1 H, 3-H), 3.47 (d, J ϭ 13.1 Hz,
1 H, CH2Ph), 3.74 (td, J2Ј,3Ј ഠ 8.8, J2Ј,3 ഠ 1.8 Hz, 1 H, 2Ј-H), 4.07
(d, J4,5 ϭ 4.3 Hz, 1 H, 4-H), 4.12 (ddt, J7β,7α ഠ 13.1, J7β,6α ഠ 4.9,
CH3CO2), 2.29 (ddt, J6β,6α ഠ 16.2, J6β,7α ഠ 11.3, J6β,7β ഠ J6β,5
ഠ
2.4 Hz, 1 H, 6β-H), 2.68 (m, 2 H, 6Ј,6Ј-H), 3.22 (dt, J2Ј,3 ϭ 10.4,
J2Ј,3Ј ഠ 4.3 Hz, 1 H, 2Ј-H), 3.48 (d, J3,2Ј ϭ 10.4 Hz, 1 H, 3-H), 3.75
(d, J ϭ 13.1 Hz, 1 H, CH2Ph), 3.95 (d, J ϭ 13.1 Hz, 1 H, CH2Ph),
4.08 (ddd, J7β,7α ϭ 13.4, J7β,6α ϭ 4.9, J7β,6β ϭ 1.8 Hz, 1 H, 7β-H),
4.50 (t, J7α,7β ഠ J7α,6β ഠ 12.2 Hz, 1 H, 7α-H), 4.63 (d, J4,5 ϭ 4.9 Hz,
1 H, 4-H), 5.13 (q, J5,4 ഠ J5,6α ഠ J5,6β ഠ 4.0 Hz, 1 H, 5-H), 7.22
(m, 1 H, Ar), 7.29 (m, 4 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ
19.4/21.3/21.9 (C-3Ј/C-4Ј/C-5Ј), 21.0 (CH3CO2), 28.7 (C-6), 43.5
(C-3), 46.8 (C-6Ј), 53.8 (C-2Ј), 55.6 (CH2Ph), 62.1 (C-7), 65.1 (C-
4), 70.9 (C-5), 127.3/128.6/139.9 (Ph), 169.3 (CH3CO2), 172.4 (C-
2) ppm. EIMS: m/z ϭ 361 (0.4) [M]ϩ, 301 (2.5), 174 (100), 91 (57).
C20H27NO5 (361.43) calcd. C 66.45, H 7.53, N 3.88; found C 66.39,
H 7.56, N 3.88.
J7β,6β ഠ J7β,5 ഠ 1.2 Hz, 1 H, 7β-H), 4.44 (t, J7α,7β ഠ J7α,6β
ഠ
12.2 Hz, 1 H, 7α-H), 4.63 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), 5.17 (q,
J5,4 ഠ J5,6α ഠ J5,6β ഠ 3.4 Hz, 1 H, 5-H), 7.25 (m, 5 H, Ph) ppm.
13C NMR (62.5 MHz): δ ϭ 20.9 (CH3CO2), 23.8 (C-4Ј), 28.6 (C-
6), 31.8 (C-3Ј), 49.0 (C-3), 54.1 (C-5Ј), 61.2 (CH2Ph), 62.2/64.3 (C-
2Ј/C-7), 66.8 (C-4), 70.5 (C-5), 126.8/128.3/128.6/140.0 (Ph), 169.2
(CH3CO2), 174.0 (C-2) ppm. EIMS: m/z ϭ 347 (0.3) [M]ϩ, 304
(0.8), 287 (1), 256 (1), 160 (100), 91 (91). C19H25NO5 (347.41) calcd.
C 65.67, H 7.26, N 4.03; found C 65.53, H 7.39, N 3.93.
(3RS,4SR,5SR)-3-[(2RS)-N-Benzylpyrrolidin-2-yl]-4-hydroxy-5-
phenylthiooxepan-2-one (38): Following the general procedure de-
scribed for 33, reduction of 30 (251 mg, 0.53 mmol) gave an oily
residue (208 mg), which was purified by flash chromatography. Elu-
tion with hexane/EtOAc, 2:1, afforded 38 (107 mg, 0.27 mmol, 51%
yield). Elution with CHCl3/MeOH, 9:1, afforded 40 (30 mg,
0.08 mmol, 14% yield).
(3RS,4SR,5SR)-3-[(2RS)-N-Benzylpiperidin-2-yl]-4-hydroxy-5-
phenylthiooxepan-2-one (35): Following the general procedure de-
scribed for 33, reduction of 26 (658 mg, 1.34 mmol) rendered 35
(275 mg, 0.67 mmol, 50% yield) as a white solid (crystallized from
CHCl3/hexane) decomp. 155Ϫ170 °C. IR (KBr): ν˜ ϭ 3395, 2924,
2861, 1715, 1166, 1068, 1026 cmϪ1. 1H NMR (400 MHz): δ ϭ 1.30 38: White solid (crystallized from CHCl3/pentane). M.p. 94Ϫ95 °C.
(m, 1 H), 1.45 (m, 1 H), 1.61 (m, 3 H), 1.91 (m, 2 H), 2.45 (dddd,
J6β,6α ഠ 16.2, J6β,7α ഠ 10.7, J6β,5 ഠ 3.5, J6β,7β ഠ 1.7 Hz, 1 H, 6β- 1701, 1406, 1314, 1174, 1061, 1026 cmϪ1
H), 2.60 (br. d, J6Јeq,6Јax ഠ 14.3 Hz, 1 H, 6Јeq-H), 2.91 (ddd, δ ϭ 1.41 (m, 2 H, 3Ј,4Ј-H), 1.61 (m, 1 H, 4Ј-H), 1.90 (ddd, J6,6
IR (KBr): ν˜ ϭ 3466, 3058, 3023, 2959, 2924, 2861, 2812, 2791,
.
1H NMR (400 MHz):
ϭ
J6Јax,6Јeq ഠ 14.3, J6Јax,5Јax ഠ 11.3, J6Јax,5Јeq ഠ 2.9 Hz, 1 H, 6Јax-H), 16.5, J6,7 ϭ 5.0, J6,5 ϭ 2.7 Hz, 1 H, 6-H), 2.11 (m, 1 H, 3Ј-H), 2.54
3.17 (m, 1 H, 2Ј-H), 3.62 (d, J3,2Ј ϭ 10.4 Hz, 1 H, 3-H), 3.67 (q, (m, 1 H, 6-H), 2.58 (m, 2 H, 5Ј,5Ј-H), 3.22 (d, J3,2Ј ഠ 1.8 Hz, 1 H,
J5,4 ഠ J5,6 ഠ 4.0 Hz, 1 H, 5-H), 3.75 (d, J ϭ 13.1 Hz, 1 H, CH2Ph),
3.94 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), 4.09 (br. dd, J7β,7α ϭ 13.1, 6.7, J2Ј,3 ϭ 1.8 Hz, 1 H, 2Ј-H), 3.73 (q, J5,4 ഠ J5,6 ഠ 3.1 Hz, 1 H,
J7β,6α ϭ 4.3 Hz, 1 H, 7β-H), 4.60 (dd, J7α,7β ϭ 13.1, J7α,6β 5-H), 4.05 (d, J4,5 ഠ 3.0 Hz, 1 H, 4-H), 4.08 (m, 1 H, 7β-H), 4.50
3-H), 3.38 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), 3.67 (ddd, J2Ј,3Ј ϭ 8.5,
ϭ
11.0 Hz, 1 H, 7α-H), 4.71 (d, J4,5 ϭ 3.7 Hz, 1 H, 4-H), 7.17Ϫ7.40 (dd, J7α,7β ഠ 13.1, J7α,6 ഠ 11.3 Hz, 1 H, 7α-H), 4.61 (d, J ϭ
(m, 10 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 19.4/20.8/21.8 (C-
3Ј/C-4Ј/C-5Ј), 28.6 (C-6), 44.1 (C-3), 46.6 (C-6Ј), 49.8 (C-5), 53.8
13.1 Hz, 1 H, CH2Ph), 7.20 (m, 8 H, Ar), 7.34 (m, 2 H, Ar) ppm.
13C NMR (62.5 MHz): δ ϭ 23.9 (C-4Ј), 28.5 (C-6), 31.9 (C-3Ј), 49.4
(C-2Ј), 56.8 (CH2Ph), 62.9 (C-7), 66.6 (C-4), 127.0/127.2/128.4/ (C-5), 49.5 (C-3), 54.5 (C-5Ј), 61.3 (CH2Ph), 63.3 (C-7), 64.6 (C-
128.7/129.1/131.2/133.3/140.1 (Ar), 172.8 (C-2) ppm. EIMS: m/z ϭ
2Ј), 68.3 (C-4), 126.8/127.5/128.3/128.8/129.2/131.4/133.0/140.1
411 (1) [M]ϩ, 302 (5), 174 (100), 91 (53).
(Ar), 174.3 (C-2) ppm. EIMS: m/z ϭ 288 (2) [M Ϫ PhS]ϩ, 160
4226
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4215Ϫ4233

Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
(100), 91 (90). C23H27NO3S (397.53) calcd. C 69.49, H 6.85, N 3.53,
S 8.05; found C 69.49, H 6.90, N 3.42, S 8.00.
(100). C25H29NO3 (391.50) calcd. C 76.68, H 7.47, N 3.58; found
C 76.76, H 7.55, N 3.68.
40: White solid (crystallized from acetone/hexane) decomp.
150Ϫ168 °C. IR (KBr): ν˜ ϭ 3402, 3051, 3030, 2959, 2931, 2875,
(3RS,4RS)-3-[(2RS)-N-Benzylpiperidin-2-yl]-4-(imidazol-2-yl-
thiocarbonyloxy)oxepan-2-one (42). General Procedure for the Thio-
2861, 1729, 1602, 1462, 1377, 1272, 1124, 1075 cmϪ1 1H NMR carbonylation of the Alcohols: A solution of TCDI (676 mg,
.
(400 MHz): δ ϭ 1.86 (m, 3 H, 3Ј,3Ј,4Ј-H), 2.12 (m, 3 H, 6,6,4Ј-H), 3.79 mmol) in THF (3 mL) was added dropwise to a stirred solu-
2.47 (dt, J5Ј,5Ј ഠ 11.0, J5Ј,4Ј ഠ 8.0 Hz, 1 H, 5Ј-H), 2.99 (d, J ϭ
13.1 Hz, 1 H, CH2Ph), 3.30 (dd, J3,4 ഠ 9.0, J3,2Ј ഠ 4.5 Hz, 1 H, 3-
tion of 33 (769 mg, 2.53 mmol) in anhydrous THF (30 mL) heated
at reflux under nitrogen, and reaction progress was monitored by
H), 3.40 (m, 2 H, 2Ј,5Ј-H), 3.47 (td, J5,6 ϭ 6.7, J5,4 ϭ 1.8 Hz, 1 H, TLC analysis (eluent: hexane/EtOAc, 2:1). When all the starting
5-H), 3.84 (ddd, J7,7 ϭ 11.0, J7,6 ഠ 7.0, 4.0 Hz, 1 H, 7-H), 3.92 material had been consumed (6 h), the cooled solution was concen-
(ddd, J7,7 ϭ 11.0, J7,6 ഠ 7.1, 3.9 Hz, 1 H, 7-H), 4.15 (dd, J4,3
ϭ
trated under vacuum. The oily residue (1.40 g) was dissolved in
8.9, J4,5 ϭ 1.8 Hz, 1 H, 4-H), 4.19 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), CH2Cl2 (40 mL) and the solution washed with water (4 ϫ 30 mL).
7.27 (m, 8 H, Ar), 7.46 (m, 2 H, Ar) ppm. 13C NMR (62.5 MHz): The organic layer was dried, the solvent removed and the residue
δ ϭ 22.2 (C-3Ј), 26.6 (C-4Ј), 35.8 (C-6), 45.0 (C-3), 48.2 (C-5), 51.4 crystallised in acetone/hexane to furnish 42 (867 mg, 2.10 mmol,
(C-5Ј), 55.7 (CH2Ph), 59.3 (C-7), 64.2 (C-2Ј), 72.0 (C-4), 126.4/
83% yield) as a white solid. M.p. 139Ϫ141 °C. IR (KBr): ν˜ ϭ 3135,
129.2/129.3/130.1/132.0/136.5 (Ar), 177.0 (C-2) ppm. EIMS: m/z ϭ 3114, 3065, 3037, 2988, 2945, 2861, 1729, 1469, 1384, 1328, 1293,
1
248 (3), 160 (76), 91 (100).
1237, 1159, 1110, 1047 cmϪ1. H NMR (400 MHz): δ ϭ 1.27 (m,
1 H), 1.43 (m, 1 H), 1.52 (m, 1 H), 1.67 (m, 3 H), 1.88 (m, 2 H),
1.98 (m, 1 H), 2.61 (ddd, J6Јax,6Јeq ഠ 14.3, J6Јax,5Јax ഠ 11.1,
J6Јax,5Јeq ഠ 3.1 Hz, 1 H, 6Јax-H), 2.72 (m, J6Јeq,6Јax ഠ 13.7 Hz, 1 H,
6Јeq-H), 2.91 (m, 1 H, 6-H), 3.18 (dt, J2Ј,3 ഠ 11.0, J2Ј,3Ј ഠ 3.7 Hz,
1 H, 2Ј-H), 3.51 (d, J3,2Ј ϭ 11.3 Hz, 1 H, 3-H), 3.78 (d, J ϭ 12.9 Hz,
1 H, CH2Ph), 3.83 (d, J ϭ 12.9 Hz, 1 H, CH2Ph), 4.38 (m, 2 H,
7,7-H), 6.39 (dd, J4,5 ഠ 3.8, 2.6 Hz, 1 H, 4-H), 6.93 (m, 1 H, Im-
H), 7.02 (t, J ϭ 7.3 Hz, 1 H, Ph-H), 7.12 (t, J ഠ 7.5 Hz, 2 H, Ph-
H), 7.27 (d, J ഠ 7.0 Hz, 2 H, Ph-H), 7.38 (br. s, 1 H, Im-H), 8.17
(br. s, 1 H, Im-H) ppm. 13C NMR (62.5 MHz): δ ϭ 18.8 (C-5Ј),
20.65/20.74 (C-3Ј/C-4Ј), 23.7/30.9 (C-5/C-6), 45.6/46.4 (C-3/C-6Ј),
53.5 (C-2Ј), 56.1 (CH2Ph), 67.7 (C-7), 75.8 (C-4), 117.5/127.0/128.0/
129.0/130.6/137.2/138.8 (Im/Ph), 171.6 (C-2), 182.5 (ImCSO) ppm.
EIMS: m/z ϭ 194 (8) [M Ϫ ImCSOH Ϫ Bn]ϩ, 174 (60), 91 (100).
C22H27N3O3S (413.53) calcd. C 63.90, H 6.59, N 10.17, S 7.74;
found C 63.89, H 6.57, N 10.05, S 7.58.
Reduction of 31: Following the general procedure described for 33,
reduction of 31 (80 mg, 0.18 mmol) gave an oily residue (68 mg),
containing mainly (3RS,4SR,5SR)-5-acetylthio-3-[(2RS)-N-benzyl-
pyrrolidin-2-yl]-4-hydroxyoxepan-2-one (39) according to NMR
analysis: 1H NMR (250 MHz): δ ϭ 1.42 (m, 1 H, 3Ј/4Ј-H), 1.65
(m, 2 H, 3Ј/4Ј,4Ј-H), 1.84 (m, 1 H, 6-H), 2.17 (m, 1 H, 3Ј-H), 2.35
(s, 3 H, CH3COS), 2.71 (m, 3 H, 5Ј,5Ј,6-H), 2.88 (d, J3,2Ј ϭ 2.2 Hz,
1 H, 3-H), 3.48 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 3.71 (td, J2Ј,3Ј
ഠ
8.8, J2Ј,3 ഠ 1.8 Hz, 1 H, 2Ј-H), 4.08 (s, 2 H, 4,5/7-H), 4.22 (m, 2
H, 5/7,7-H), 4.62 (d, J ϭ 13.2 Hz, 1 H, CH2Ph), 7.25 (m, 5 H, Ar)
ppm. 13C NMR (62.5 MHz) observed signals: δ ϭ 45.8 (C-5), 50.8
(C-3), 54.4 (C-5Ј), 61.4 (CH2Ph), 64.6/64.8 (C-2Ј/C-7), 68.6 (C-4),
127.0/128.5/128.9/140.0 (Ph), 173.8 (C-2) ppm. Attempts to purify
this compound either by crystallisation or flash chromatography
resulted in decomposition.
(5RS)-3-[(2RS)- and (5RS)-3-[(2SR)-N-Benzylpiperidin-2-yl]-5-[2-
(benzyloxy)ethyl]-2(5H)-furanone (41): Benzyl bromide (410 µL,
3.45 mmol) was added dropwise to a stirred solution of 11 (703 mg,
2.22 mmol) in anhydrous THF (10 mL) at room temperature and
3-[(2RS)-N-Benzylpiperidin-2-yl]-6,7-dihydro-2(5H)-oxepinone (49):
When the crude product from the previous reaction was submitted
to flash chromatography (eluent: hexane/EtOAc, 2:1), a product
identified as 49 (60% yield) was isolated as a white solid (crys-
tallized from acetone/hexane). M.p. 87Ϫ88 °C. IR (KBr): ν˜ ϭ 3088,
3072, 3040, 2976, 2960, 2928, 2864, 2832, 2816, 2800, 2720, 1712,
1
reaction progress was monitored by H NMR analysis of aliquot
samples. When all the starting isoxazolidine had been consumed (3
days), the solvent was removed affording an oily residue (1.28 g).
This material (504 mg) was dissolved in 10% aqueous HCl (50 mL),
activated zinc powder (3.13 g, 47.9 mmol) was added and the mix-
ture was sonicated for 30 min. Subsequently, the reaction mixture
was filtered, the solid washed with 10% aqueous HCl and water,
and the solution brought to pH 9Ϫ10 by addition of 30% aqueous
NH3. A white solid appeared which was filtered under vacuum. The
solution was then extracted with CHCl3 (4 ϫ 50 mL), the combined
organic extracts were dried and the solution was concentrated fur-
nishing an oily residue (230 mg). Purification of this material by
flash chromatography (eluent: hexane/EtOAc, 3:1) furnished 41
(77 mg, 0.20 mmol, 22% yield) as a colorless oil which solidifies on
standing. IR (film): ν˜ ϭ 3065, 3030, 2931, 2854, 2798, 1757, 1455,
1
1184, 1104, 1040 cmϪ1. H NMR (400 MHz): δ ϭ 1.20Ϫ1.50 (m,
4 H, 3Ј,4Јax,5Ј,5Ј-H), 1.66 (m, J4Јeq,4Јax ϭ 12.2 Hz, 1 H, 4Јeq-H),
1.85 (m, 3 H, 6,3Ј,6Ј-H), 2.01 (dqn, J6,6 ഠ 13.7, J6,7 ഠ J6,5
6.7 Hz, 1 H, 6-H), 2.33 (m, 2 H, 5,5-H), 2.85 (br. d, J6Ј,6Ј ഠ 11.6 Hz,
1 H, 6Ј-H), 2.90 (d, J ϭ 13.4 Hz, 1 H, CH2Ph), 3.05 (dd, J2Ј,3Ј
ഠ
ഠ
10.7, 2.7 Hz, 1 H, 2Ј-H), 4.00 (d, J ϭ 13.4 Hz, 1 H, CH2Ph), 4.17
(m, 2 H, 7,7-H), 6.66 (t, J4,5 ഠ 6.7 Hz, 1 H, 4-H), 7.17 (m, 1 H,
Ar), 7.23 (m, 4 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 24.2 (C-
5), 24.7 (C-4Ј), 25.4 (C-5Ј), 26.4 (C-6), 35.4 (C-3Ј), 53.3 (C-6Ј), 59.2
(CH2Ph), 64.7 (C-2Ј), 66.1 (C-7), 126.6/128.1/128.3 (Ar), 134.9 (C-
4), 138.0/139.6 (C-3/Ar), 171.7 (C-2) ppm. EIMS: m/z ϭ 194 (100)
[M Ϫ Bn]ϩ, 174 (23), 91 (60). C18H23NO2 (285.38) calcd. C 75.74,
H 8.13, N 4.91; found C 75.77, H 8.20, N 4.88.
1
1103, 1075 cmϪ1. H NMR (400 MHz): δ ϭ 1.23Ϫ1.53 (m, 4 H),
1.64 (m, 1 H, 3Ј/4Ј/5Ј-H), 1.76Ϫ2.03 (m, 4 H, 3Ј,6Јax,1ЈЈ,1ЈЈ-H), (3RS,4SR,5SR)-5-Acetoxy-3-[(2RS)-N-benzylpiperidin-2-yl]-4-
2.84 (br. d, J6Јeq,6Јax ഠ 12.2 Hz, 1 H, 6Јeq-H), 2.96 (d, J ϭ 13.4 Hz, (imidazol-2-ylthiocarbonyloxy)oxepan-2-one (43): Following the
1 H, N-CH2Ph), 3.10 (br. d, J2Ј,3Ј ഠ 9.2 Hz, 1 H, 2Ј-H), 3.55 (m, 2 general procedure described for 42, treatment of 34 (148 mg,
H, 2ЈЈ-H), 3.80 (d, J ϭ 13.4 Hz, 1 H, N-CH2Ph), 4.43 (s, 2 H, O-
0.41 mmol) with TCDI rendered 43 (140 mg, 0.30 mmol, 73%
CH2Ph), 5.04 (m, J5,4 ഠ J5,1ЈЈ ഠ 6.4 Hz, 1 H, 5-H), 7.13Ϫ7.32 (m, yield) as a white solid (crystallized from acetone/hexane). M.p.
11 H, Ar,4-H) ppm. 13C NMR (62.5 MHz): δ ϭ 24.2/25.6 (C-4Ј/C- 149Ϫ152 °C. IR (KBr): ν˜ ϭ 3160, 3120, 3088, 3032, 2992, 2944,
5Ј), 33.7/33.9 (C-1ЈЈ/C-3Ј), 53.2 (C-6Ј), 58.6 (C-2Ј), 59.6 (N-
CH2Ph), 65.7 (C-2ЈЈ), 73.2 (O-CH2Ph), 79.1 (C-5), 126.8/127.68/ 1008 cmϪ1
127.74/128.2/128.37/128.43/136.8/139.2 (Ar), 137.9 (C-3), 149.7 (C- (m, 1 H), 1.64 (m, 3 H), 1.90Ϫ2.20 (m, 3 H), 2.03 (s, 3 H, CH3CO2),
4), 173.1 (C-2) ppm. EIMS: m/z ϭ 391 (12) [M]ϩ, 300 (30), 91 2.69 (m, 2 H, 6Ј,6Ј-H), 3.17 (dt, J2Ј,3 ഠ 11.0, J2Ј,3Ј ഠ 3.7 Hz, 1 H,
2864, 1760, 1744, 1392, 1344, 1296, 1248, 1216, 1168, 1056, 1040,
.
1H NMR (400 MHz): δ ϭ 1.32 (m, 1 H, 5Ј-H), 1.46
Eur. J. Org. Chem. 2004, 4215Ϫ4233
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4227

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
2Ј-H), 3.78 (d, J ϭ 13.1 Hz, 1 H, CH2Ph), 3.84 (d, J ϭ 13.1 Hz, 1
H, CH2Ph), 3.87 (d, J3,2Ј ϭ 10.4 Hz, 1 H, 3-H), 4.19 (dt, J7,7
13.1, J7,6 ഠ 3.1 Hz, 1 H, 7-H), 4.63 (ddd, J7,7 ഠ 12.5, J7,6 ഠ 8.2,
4.0 Hz, 1 H, 7-H), 5.76 (m, 1 H, 5-H), 6.29 (br. d, J4,5 ϭ 4.3 Hz, 1 9.8 Hz, 1 H, 3-H), 2.97 (ddd, J2Ј,3 ഠ 9.5, J2Ј,3Ј ϭ 6.1, 3.7 Hz, 1 H,
3.6 Hz, 1 H, 5-H), 2.41 (ddd, J6Ј,6Ј ϭ 14.0, J6Ј,5Ј ϭ 7.3, 3.7 Hz, 1
ഠ
H, 6Ј-H), 2.52 (t, J4,4 ϭ 14.0, J4,5 ഠ 4.0 Hz, 1 H, 4-H), 2.65 (ddd,
J6Ј,6Ј ϭ 14.0, J6Ј,5Ј ϭ 7.9, 3.7 Hz, 1 H, 6Ј-H), 2.85 (t, J3,2 ഠ J3,4
ഠ
H, 4-H), 6.93 (s, 1 H, Im-H), 7.02 (t, J ഠ 7.0 Hz, 1 H, Ph-H), 7.12
(t, J ഠ 7.6 Hz, 2 H, Ph-H), 7.25 (d, J ϭ 8.0 Hz, 2 H, Ph-H), 7.36
2Ј-H), 3.59 (d, J ϭ 13.7 Hz, 1 H, CH2Ph), 3.77 (d, J ϭ 13.7 Hz, 1
H, CH2Ph), 4.19 (m, 2 H, 7,7-H), 7.20 (m, 5 H, Ar) ppm. 13C
(s, 1 H, Im-H), 8.13 (s, 1 H, Im-H) ppm. 13C NMR (62.5 MHz): NMR (62.5 MHz): δ ϭ 20.2 (C-5Ј), 22.6 (C-4Ј), 24.0 (C-3Ј), 24.9
δ ϭ 18.7 (C-5Ј), 20.7/21.0 (C-3Ј/C-4Ј/CH3CO2), 29.2 (C-6), 40.9 (C- (C-4), 28.4 (C-5), 28.9 (C-6), 44.2 (C-3), 48.0 (C-6Ј), 55.5 (CH2Ph),
3), 45.9 (C-6Ј), 53.1 (C-2Ј), 55.3 (CH2Ph), 61.7 (C-7), 65.6 (C-5),
58.9 (C-2Ј), 68.3 (C-7), 126.7/128.2/128.5/140.2 (Ph), 176.7 (C-2)
74.6 (C-4), 117.6/126.9/128.0/128.8/130.8/137.2/138.6 (Im/Ph), ppm. EIMS: m/z ϭ 287 (0.6) [M]ϩ, 174 (100), 91 (45). C18H25NO2
168.4 (CH3CO2), 171.0 (C-2), 182.8 (ImCSO) ppm. EIMS: m/z ϭ
284 (6) [M Ϫ ImCSOH Ϫ OAc]ϩ, 252 (26), 174 (89), 91 (100), 43
(37). C24H29N3O5S (471.57) calcd. C 61.12, H 6.20, N 8.92, S 6.74;
found C 61.04, H 6.31, N 8.85, S 6.60.
(287.40) calcd. C 75.21, H 8.77, N 4.88; found C 75.16, H 8.81,
N 4.92.
(3RS,5SR)-5-Acetoxy-3-[(2SR)-N-benzylpiperidin-2-yl]oxepan-2-
one (47): Following the general procedure described above, re-
duction of 43 (150 mg, 0.31 mmol) furnished 47 (84 mg, 0.24 mmol,
76% yield) as a white solid (crystallized from CHCl3/pentane). M.p.
109Ϫ111 °C. IR (KBr): ν˜ ϭ 3065, 3030, 2945, 2924, 2847, 2826,
(3RS,4RS)-3-[(2RS)-N-Benzylpyrrolidin-2-yl]-4-(imidazol-2-yl-
thiocarbonyloxy)oxepan-2-one (44): Following the general pro-
cedure described for 42, treatment of 36 (50 mg, 0.17 mmol) with
1729, 1377, 1244, 1159, 1117, 1061, 1033 cmϪ1 1H NMR
.
1
TCDI rendered an oily material (100 mg). H NMR analysis indi-
cated a mixture with the main component identified as 44: 1H
NMR (250 MHz): δ ϭ 1.47 (m, 1 H), 1.76 (m, 4 H), 2.17 (m, 2 H),
2.44 (m, 1 H), 2.74 (m, 3 H, 3,5Ј,5Ј-H), 3.32 (td, J ϭ 9 and 2.5 Hz,
1 H, 2Ј-H), 3.50 (d, J ϭ 12.6 Hz, 1 H, CH2Ph), 3.77 (d, J ϭ
12.6 Hz, 1 H, CH2Ph), 4.31 (m, 2 H, 7,7-H), 6.32 (br. s, 1 H, 4-H),
6.95 (s, 1 H, Im-H), 7.16Ϫ7.32 (m, 5 H, Ph-H), 7.49 (s, 1 H, Im-
H), 8.24 (s, 1 H, Im-H) ppm. All attempts to purify this compound
led to decomposition.
(400 MHz): δ ϭ 1.36Ϫ1.69 (m, 6 H, 4,3Ј,4Ј,4Ј,5Ј,5Ј-H), 1.78 (m, 1
H, 3Ј-H), 1.92 (s, 3 H, CH3CO2), 1.97 (m, 1 H, 6-H), 2.07 (m, 1
H, 6-H), 2.47 (ddd, J6Ј,6Ј ϭ 13.7, J6Ј,5Ј ഠ 7.0, 3.7 Hz, 1 H, 6Ј-H),
2.72 (ddd, J6Ј,6Ј ϭ 13.7, J6Ј,5Ј ഠ 7.6, 3.6 Hz, 1 H, 6Ј-H), 2.90 (m, 1
H, 4-H), 2.99 (ddd, J2Ј,3 ഠ 9.7, J2Ј,3Ј ϭ 6.2, 3.5 Hz, 1 H, 2Ј-H), 3.34
(t, J3,2Ј ഠ J3,4 ഠ 10.4 Hz, 1 H, 3-H), 3.70 (d, J ϭ 13.7 Hz, 1 H,
CH2Ph), 3.80 (d, J ϭ 13.7 Hz, 1 H, CH2Ph), 4.10 (ddd, J7,7 ϭ 13.1,
J7,6 ഠ 4.1, 2.3 Hz, 1 H, 7-H), 4.57 (t, J7,7 ϭ J7,6 ϭ 12.2 Hz, 1 H,
7-H), 5.30 (m, 1 H, 5-H), 7.27 (m, 5 H, Ar) ppm. 13C NMR
(62.5 MHz): δ ϭ 19.9 (C-5Ј), 21.1 (CH3CO2), 22.7 (C-4Ј), 23.5 (C-
3Ј), 29.5 (C-4), 33.5 (C-6), 37.1 (C-3), 47.6 (C-6Ј), 54.8 (CH2Ph),
58.1 (C-2Ј), 62.5 (C-7), 68.3 (C-5), 126.8/128.28/128.34/139.8 (Ph),
169.6 (CH3CO2), 176.2 (C-2) ppm. EIMS: m/z ϭ 174 (100), 91 (70),
43 (15). C20H27NO4 (345.43) calcd. C 69.53, H 7.88, N 4.06; found
C 69.50, H 7.90, N 4.29.
(3RS,4RS,5SR)-5-Acetoxy-3-[(2RS)-N-benzylpyrrolidin-2-yl]-4-
(imidazol-2-ylthiocarbonyloxy)oxepan-2-one (45): Following the
general procedure described for 42, treatment of 37 (51 mg,
0.15 mmol) with TCDI rendered an oily material (120 mg). 1H
NMR analysis indicated a mixture with the main component ident-
ified as 45: 1H NMR (250 MHz): δ ϭ 1.52 (m, 1 H), 1.62Ϫ1.88 (m,
2 H), 2.00Ϫ2.30 (m, 3 H), 2.13 (s, 3 H, CH3CO2), 2.51 (dt, J5Ј,5Ј
11.4, J5Ј,4Ј ഠ 6.8 Hz, 1 H, 5Ј-H), 2.75 (dt, J5Ј,5Ј ഠ 11.4, J5Ј,4Ј
ഠ
ഠ
3-(N-Benzylpyrrolidin-2-yl)-6,7-dihydro-2(5H)-oxepinone (50): Fol-
lowing the general procedure described above, treatment of 44
(100 mg of crude material) with Bu3SnH (190 µL, 0.71 mmol) fur-
nished an oil (291 mg). Flash chromatography of this material (elu-
ent: hexane; then hexane/EtOAc, 1:1; then EtOAc) allowed the sep-
aration of most of the impurities. The fraction containing the prod-
uct was dissolved in CHCl3 and extracted with 10% aqueous HCl.
The aqueous phase was basified with 30% aqueous NH3 and then
extracted with CHCl3, furnishing 50 (23 mg, 0.08 mmol, 49%
yield). IR (film): ν˜ ϭ 3065, 3030, 2959, 2868, 2791, 1722, 1462,
6.8 Hz, 1 H, 5Ј-H), 3.21 (d, J3,2Ј ഠ 9.1 Hz, 1 H, 3-H), 3.32 (td,
J2Ј,3 ഠ J2Ј,3Ј ഠ 9.1, J2Ј,3Ј ഠ 3.2 Hz, 1 H, 2Ј-H), 3.54 (d, J ϭ 13.6 Hz,
1 H, CH2Ph), 3.75 (d, J ϭ 13.6 Hz, 1 H, CH2Ph), 4.15 (dt, J7,7
ഠ
12.7, J7,6 ഠ 4.1 Hz, 1 H, 7-H), 4.50 (ddd, J7,7 ഠ 12.3, J7,6 ഠ 8.6,
3.6 Hz, 1 H, 7-H), 5.60 (m, 1 H, 5-H), 6.21 (d, J4,5 ഠ 2.3 Hz, 1 H,
4-H), 6.97 (s, 1 H, Im-H), 7.13Ϫ7.33 (m, 5 H, Ph-H), 7.45 (s, 1 H,
Im-H), 8.22 (s, 1 H, Im-H) ppm. All attempts to purify this com-
pound led to decomposition.
1398, 1356, 1321, 1279, 1223, 1173, 1103, 1068, 1040 cmϪ1 1H
.
(3RS)-3-[(2SR)-N-Benzylpiperidin-2-yl]oxepan-2-one (46). General
Procedure for the Reduction of Thiocarbonyl Derivatives: A solution
of 42 (114 mg, 0.28 mmol) in toluene (2 mL) was added over a
30 min period to a stirred solution of Bu3SnH (1.1 mL, 4.1 mmol)
and AIBN (5 mg, 0.03 mmol) in anhydrous toluene (11 mL), heated
at the reflux temperature under nitrogen, and reaction progress was
monitored by TLC analysis (eluent: hexane/EtOAc, 2:1). When all
the starting material had been consumed (35 min), the mixture was
cooled and then concentrated under vacuum, affording a yellow
oily residue (1.52 g), which was redissolved in acetonitrile (40 mL).
This solution was washed with hexane (2 ϫ 50 mL) and then con-
centrated to give a yellowish oil (108 mg). Purification by flash
chromatography (eluent: hexane/EtOAc, 2:1) rendered a fraction of
pure 46 (55 mg, 0.19 mmol, 70% yield) and another fraction of a
1.2:1 mixture of 46 and 49.
NMR (400 MHz): δ ϭ 1.71 (m, 3 H), 1.90 (m, 1 H), 2.00 (m, 1 H),
2.20 (m, 2 H), 2.36 (m, 2 H), 3.02 (ddd, J5Ј,5Ј ϭ 11.1, J5Ј,4Ј ϭ 7.3,
2.1 Hz, 1 H, 5Ј-H), 3.27 (d, J ϭ 13.5 Hz, 1 H, CH2Ph), 3.39 (br. t,
J2Ј,3Ј ϭ 7.5 Hz, 1 H, 2Ј-H), 3.90 (d, J ϭ 13.5 Hz, 1 H, CH2Ph),
4.12 (m, 2 H, 7,7-H), 6.66 (td, J4,5 ϭ 6.5, J ϭ 0.9 Hz, 1 H, 4-H),
7.25 (m, 5 H, Ar) ppm. 13C NMR (62.5 MHz): δ ϭ 22.8/24.2/26.5/
33.3 (C-5/C-6/ C-3Ј/C-4Ј), 53.8 (C-5Ј), 58.8 (CH2Ph), 65.8 (C-2Ј),
66.1 (C-7), 126.8/128.2/128.4 (Ph), 133.5 (C-4), 137.0/139.8 (C-3/
Ph), 171.7 (C-2) ppm. EIMS: m/z ϭ 272 (3) [M ϩ1]ϩ, 271 (2) [M]ϩ,
180 (97), 160 (31), 91 (100). C17H21NO2 (271.35) calcd. C 75.25, H
7.80, N 5.16; found C 75.19, H 7.90, N 5.03.
Reduction of 45: Following the general procedure described above,
treatment of 45 (194 mg of crude material) with Bu3SnH (940 µL,
3.39 mmol) furnished an oil (98 mg), which was purified by flash
46: White solid. M.p. 62Ϫ63 °C. IR (KBr): ν˜ ϭ 2931, 2854, 1722, chromatography (eluent: hexane/EtOAc, 2:1) affording the follow-
1152 cmϪ1. 1H NMR (400 MHz): δ ϭ 1.22 (m, 1 H, 4-H), 1.32 (m,
ing fractions: (5RS)-5-acetoxy-3-[(2SR)-N-benzylpyrrolidin-2-yl]-
1 H, 5Ј-H), 1.38Ϫ1.54 (m, 4 H, 5,3Ј,4Ј,5Ј-H), 1.56Ϫ1.73 (m, 3 H, 6,7-dihydro-2(5H)-oxepinone (51) (15 mg, 0.05 mmol, 19% yield for
6,3Ј,4Ј-H), 1.83 (m, 1 H, 6-H), 1.94 (dqn, J5,5 ഠ 14.1, J5,4 ഠ J5,6 the two steps), (3RS,5SR)-5-acetoxy-3-[(2SR)-N-benzylpyrrolidin-
ഠ
4228
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4215Ϫ4233

Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
2-yl]oxepan-2-one (48) (7 mg, 0.02 mmol, 9% yield for the two 21.4 (CH3CO2), 22.2 (C-5Ј), 22.7 (C-4Ј), 24.0 (C-3Ј), 30.1 (C-4),
steps), a mixture of 48 and 51 (6 mg), and 37 (17 mg, 0.05 mmol, 32.8 (C-6), 37.6 (C-3), 46.0 (C-6Ј), 59.0 (C-2Ј), 63.8 (C-7), 67.2 (C-
20% recovering).
5), 170.3 (CH3CO2), 175.6 (C-2) ppm.
51: 1H NMR (250 MHz): δ ϭ 1.67 (m, 2 H, 3Ј,4Ј-H), 1.92 (ddt,
Methyl (E)-6-Mesyloxyhex-2-enoate (54): A solution of methyl (E)-
6-hydroxyhex-2-enoate[16] (400 mg, 2.78 mmol) in CH2Cl2 (65 mL)
was added dropwise to a stirred solution of MsCl (1.7 mL,
22.0 mmol) in pyridine (6.5 mL) at 0 °C under nitrogen. After the
addition (1.5 h), the mixture was stirred at room temperature for
20 h. Then the solution was washed with portions of 10% aqueous
HCl (until the aqueous solution maintained an acidic pH) and with
brine. The organic phase was dried and the solvent removed under
vacuum. Purification of the remaining oil by flash chromatography
(eluent: hexane/EtOAc, 1:1) furnished 54 (560 mg, 2.52 mmol, 91%
yield) as a white solid. M.p. 30Ϫ31 °C. IR (film): ν˜ ϭ 3030, 2952,
J6,6 ϭ 15.4, J ϭ 6.6, 4.4 Hz, 1 H, 6-H), 2.00Ϫ2.30 (m, 3 H, 3Ј,4Ј,5Ј-
H), 2.02 (s, 3 H, CH3CO2), 2.45 (m, 1 H, 6-H), 3.03 (ddd, J5Ј,5Ј
ഠ
9.0, J5Ј,4Ј ഠ 6.2, 2.2 Hz, 1 H, 5Ј-H), 3.30 (d, J ϭ 13.2 Hz, 1 H,
CH2Ph), 3.46 (dd, J2Ј,3Ј ϭ 8.8, 5.9 Hz, 1 H, 2Ј-H), 3.82 (d, J ϭ
13.2 Hz, 1 H, CH2Ph), 4.10 (m, 2 H, 7,7-H), 5.49 (m, 1 H, 5-H),
6.55 (d, J4,5 ϭ 4.4 Hz, 1 H, 4-H), 7.24 (m, 5 H, Ar) ppm. 13C NMR
(62.5 MHz): δ ϭ 20.9 (CH3CO2), 23.0 (C-4Ј), 32.9/33.1 (C-6/C-3Ј),
53.9 (C-5Ј), 59.0 (CH2Ph), 64.1/65.6 (C-7/C-2Ј), 69.2 (C-5), 126.9/
128.2/128.7 (Ar), 133.4/136.3/139.4 (C-3/C-4/Ar), 169.9 (CH3CO2
and C-2) ppm. EIMS: m/z ϭ 270 (7) [M Ϫ AcO]ϩ, 238 (27), 160
(27), 91 (100). C19H23NO4 (329.39) calcd. C 69.27, H 7.04, N 4.25;
found C 69.23, H 7.12, N 4.32.
2854, 1722, 1659, 1441, 1356, 1279, 1209, 1173 cmϪ1 1H NMR
.
(250 MHz): δ ϭ 1.87 (qn, J ϭ 6.9 Hz, 2 H, 5,5-H), 2.29 (q, J ϭ
6.9 Hz, 2 H, 4,4-H), 2.96 (s, 3 H, CH3SO2), 3.67 (s, 3 H, CH3O),
4.18 (t, J ϭ 6.2 Hz, 2 H, 6,6-H), 5.82 (d, J ϭ 15.5 Hz, 1 H, 2-H),
6.87 (dt, J ϭ 15.5, 6.9 Hz, 1 H, 3-H) ppm. 13C NMR (62.5 MHz):
δ ϭ 27.4/27.9 (C-4/C-5), 37.3 (CH3SO2), 51.4 (CH3O), 68.6 (C-6),
122.1 (C-2), 146.7 (C-3), 166.6 (C-1) ppm. EIMS: m/z ϭ 233 (1)
[M ϩ1]ϩ, 191 (12), 111 (71), 98 (79), 95 (35), 94 (43), 79 (37), 67
(100). C8H14SO5 (222.26) calcd. C 43.23, H 6.35, S 14.40; found C
43.34, H 6.33, S 14.30.
48: Oil. IR (film): ν˜ ϭ 3072, 3032, 2959, 2924, 2875, 2861, 2798,
1736, 1370, 1244, 1159, 1061 cmϪ1. 1H NMR (400 MHz): δ ϭ 1.60
(m, 2 H), 1.74 (m, 2 H), 1.92 (ddt, J6,6 ഠ 16.2, J6,7 ഠ 11.3, J6,7
ഠ
J6,5 ഠ 2.4 Hz, 1 H, 6-H), 2.00Ϫ2.10 (m, 2 H), 2.08 (s, 3 H,
CH3CO2), 2.36 (m, 1 H), 2.48 (m, 1 H, 4-H), 2.88 (m, 2 H, 5Ј,5Ј-
H), 3.03 (td, J ഠ 7.6, 4.3 Hz, 1 H, 2Ј-H), 3.58 (d, J ϭ 13.4 Hz, 1
H, CH2Ph), 3.80 (d, J ϭ 13.4 Hz, 1 H, CH2Ph), 4.04 (ddd, J7,7
12.8, J7,6 ഠ 4.6, 2.4 Hz, 1 H, 7-H), 4.36 (dd, J7,7 ഠ 12.2, J7,6
ഠ
ഠ
Methyl (5RS,6SR,7RS)-5-Hydroxy-1-azabicyclo[5.3.0]decane-6-car-
boxylate (57): A stirred solution of ester 54 (541 mg, 2.44 mmol)
and nitrone 55[4b,15] (475 mg, 5.59 mmol) in CHCl3 (10 mL) was
heated at the reflux temperature for 24 h. The solvent was removed
under vacuum and the formation of the expected mesylate 56 was
confirmed by 1H NMR analysis of the residue: (250 MHz, CDCl3):
δ ϭ 2.16Ϫ2.51 (m, 8 H), 2.73 (s, 3 H), 3.72 (m, 3 H), 3.75 (s, 3 H),
4.l6 (m, 1 H), 4.79 (dd, J ϭ 12.4, 5.5 Hz, 1 H), 5.23 (br. s, 1 H),
5.79 (td, J ϭ 9.7, 4.8 Hz, 1 H) ppm. Activated zinc powder (6.00 g,
91.74 mmol) was added to a solution of this residue in 10% aque-
ous HCl (40 mL) and the mixture was sonicated for 40 min. The
mixture was then filtered, the solid washed with 10% aqueous HCl
and water and the solution brought to pH 9Ϫ10 by addition of
30% aqueous NH3. A white solid appeared which was filtered un-
der vacuum. The solution was then extracted with CHCl3 (5 ϫ
50 mL), the combined organic extracts were dried and the solution
was concentrated to furnish an oily material (717 mg). Purification
by flash chromatography (eluent: CHCl3/MeOH, 9:1) furnished 57
(430 mg, 2.02 mmol, 83% yield) as an oil. B.p. 80 °C (oven)/
0.08 Torr. IR (film): ν˜ ϭ 3381 (br), 2931, 2875, 2798, 2748, 1743,
11.6 Hz, 1 H, 7-H), 5.22 (m, 1 H, 5-H), 7.20Ϫ7.32 (m, 5 H, Ar)
ppm. 13C NMR (62.5 MHz): δ ϭ 21.2 (CH3CO2), 23.5 (C-4Ј), 30.3/
30.4/33.4 (C-4/C-6/C-3Ј), 40.8 (C-3), 54.4 (C-5Ј), 61.3 (CH2Ph),
62.3 (C-2Ј), 64.9 (C-7), 68.3 (C-5), 126.8/128.2/128.4/140.5 (Ph),
169.7 (CH3CO2), 176.2 (C-2) ppm. EIMS: m/z ϭ 240 (1) [M Ϫ
Bn]ϩ, 160 (62), 91 (100), 43 (20).
(3RS)-3-[(2SR)-Piperidin-2-yl]oxepan-2-one (52). General Procedure
for N-Debenzylation: 20% Pd(OH)2 (20 mg) was added to a solu-
tion of 46 (21 mg, 0.07 mmol) in MeOH (10 mL), and the mixture
was submitted to a hydrogen pressure of 30 psi at room tempera-
ture. After 45 h of reaction, the mixture was filtered through Ce-
lite, the solvent was evaporated under vacuum and the oily resi-
due (23 mg) was purified by flash chromatography (eluent: CHCl3/
MeOH, 9:1) affording 52 (13 mg, 0.07 mmol, 93% yield): IR (film):
ν˜ ϭ 3500Ϫ2300 (br), 3205, 2945, 2868, 2713, 2579, 2495, 2404,
1
1722, 1173 cmϪ1. H NMR (400 MHz): δ ϭ 1.45 (m, 1 H, 4Ј-H),
1.56 (m, 1 H, 4-H), 1.72 (m, 2 H), 1.87 (m, 2 H, 3Ј,5Ј-H), 1.95 (m,
3 H, 6,4Ј,5Ј-H), 2.05 (m, 3 H), 2.92 (td, J6Јax,6Јeq ഠ J6Јax,5Јax ഠ 13.1,
J6Јax,5Јeq ഠ 3.3 Hz, 1 H, 6Јax-H), 3.23 (ddd, J ഠ 12.2, 4.9, 2.7 Hz,
1 H, 2Ј-H), 3.62 (m, 1 H, 6Јeq-H), 3.65 (m, 1 H, 3-H), 4.29 (dd,
1440, 1201, 1159, 1096, 1054 cmϪ1
1.50Ϫ1.70 (m, 3 H, 3,3,8-H), 1.70Ϫ2.02 (m, 4 H, 4,8,9,9-H), 2.17
(m, 1 H, 4-H), 2.37 (m, 2 H, 2,10-H), 2.84 (dd, J6,7 ϭ 5.9, J6,5
.
1H NMR (250 MHz): δ ϭ
J7,7 ഠ 13.3, J7,6 ഠ 4.9 Hz, 1 H, 7-H), 4.39 (dd, J7,7 ഠ 12.8, J7,6
ഠ
10.4 Hz, 1 H, 7-H) ppm. 13C NMR (62.5 MHz): δ ϭ 22.4 (C-5Ј),
22.8 (C-4Ј), 24.5 (C-3Ј), 26.2/27.5/28.2 (C-4/C-5/C-6), 44.3 (C-3),
45.8 (C-6Ј), 59.2 (C-2Ј), 69.6 (C-7), 176.0 (C-2) ppm. EIMS: m/z ϭ
197 (1) [M]ϩ, 154 (11), 84 (100).
ϭ
2.7 Hz, 1 H, 6-H), 2.91Ϫ3.10 (m, 3 H, 2,7,10-H), 3.69 (s, 3 H,
CH3O), 4.18 (dt, J5,4 ഠ 7.5, J5,4 ഠ J5,6 ഠ 2.4 Hz, 1 H, 5-H)ppm.
13C NMR (62.5 MHz): δ ϭ 22.8/24.1 (C-3/C-9), 30.0/33.9 (C-4/C-
8), 51.3 (CH3O), 52.0 (C-6), 53.6/56.5 (C-2/C-10), 62.7 (C-7), 71.5
(C-5), 173.3 (CO2Me) ppm. EIMS: m/z ϭ 214 (12) [M ϩ1]ϩ, 213
(15) [M]ϩ, 196 (13), 154 (8), 110 (36), 97 (34), 96 (30), 84 (43), 83
(100), 70 (32). C11H19NO3 (213.27) calcd. C 61.93, H 8.98, N 6.57;
found C 61.87, H 9.07, N 6.55.
(3RS,5SR)-5-Acetoxy-3-[(2SR)-piperidin-2-yl]oxepan-2-one
(53):
Following the same procedure described for hydrogenolysis of 46,
hydrogenolysis of 47 (37 mg, 0.11 mmol) furnished 53 (26 mg,
0.10 mmol, 96% yield): IR (film): ν˜ ϭ 3500Ϫ2400 (br), 3206, 3149,
2938, 2868, 2706, 2573, 2502, 1729, 1377, 1244, 1230, 1173, 1061
cmϪ1. H NMR (400 MHz): δ ϭ 1.47 (m, 1 H, 4Ј-H), 1.72 (m, 1 Methyl 1-Azabicyclo[5.3.0]dec-5-ene-6-carboxylate (58): A solution
1
H, 3Ј-H), 1.86Ϫ2.21 (m, 8 H, 4,4,6,6,3Ј,4Ј,5Ј,5Ј-H), 2.17 (s, 3 H,
of 57 (45 mg, 0.21 mmol) in anhydrous CH2Cl2 (200 µL) was added
CH3CO2), 2.95 (td, J6Јax,6Јeq ഠ J6Јax,5Јax ഠ 12.8, J6Јax,5Јeq ഠ 4.3 Hz, dropwise to a stirred solution of MsCl (17 µL, 0.22 mmol) in
1 H, 6Јax-H), 3.18 (dt, J2Ј,3Ј ϭ 12.8, J2Ј,3 ഠ J2Ј,3Ј ഠ 2.4 Hz, 1 H,
2Ј-H), 3.61 (m, 1 H, 6Јeq-H), 4.16 (m, 1 H, 3-H), 4.20 (ddd, J7,7
13.4, J7,6 ഠ 4.0, 2.7 Hz, 1 H, 7-H), 4.71 (t, J7,7 ഠ J7,6 ഠ 12.1 Hz,
CH2Cl2 (50 µL) at 0 °C under nitrogen. The cooling bath was re-
moved and the reaction mixture stirred at room temperature for
5 h. The reaction mixture was then poured into a saturated aqueous
ϭ
1 H, 7-H), 5.25 (m, 1 H, 5-H) ppm. 13C NMR (62.5 MHz): δ ϭ NaHCO3 solution at 0 °C, the product was extracted with CH2Cl2,
Eur. J. Org. Chem. 2004, 4215Ϫ4233
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4229

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
and the organic extracts were dried. The solvent was removed un-
solid washed with 10% aqueous HCl and water, the solution
der vacuum and the formation of the expected mesylate (51 mg, brought to pH 9Ϫ10 by addition of 30% aqueous NH3, and ex-
1
0.18 mmol, 84% yield) was confirmed by H NMR analysis of the
tracted with CHCl3 (5 ϫ 100 mL). The combined organic extracts
residue (250 MHz, CDCl3): δ ϭ 1.50Ϫ1.80 (m, 4 H), 2.00 (m, 4 H), were dried and the solution was concentrated to furnish an oily
2.37 (m, 1 H), 2.51 (m, 1 H), 2.99 (s, 3 H), 2.90Ϫ3.20 (m, 4 H), residue (950 mg). This material was dissolved in MeOH (5 mL) and
3.68 (s, 3 H), 4.75 (m, 1 H) ppm. Potassium tert-butoxide (18 mg,
sodium methoxide (26 mg, 0.50 mmol) was added. The mixture was
0.16 mmol) was added to a stirred solution of the crude mesylate heated at reflux for 2.5 h. The methanol was evaporated under vac-
(48 mg, 0.16 mmol) in CH2Cl2 (2.5 mL) and the mixture was heated uum, the remaining oil was redissolved in CHCl3 and the solution
at the reflux temperature for 3 h. Water was then added, the organic
washed with saturated aqueous NaHCO3 (2 ϫ 2 mL). The organic
layer was separated and the aqueous phase extracted with CH2Cl2 phase was dried and the solvent removed, affording a residue
(3 ϫ 3 mL). The combined organic extracts were dried and the
solvent evaporated under vacuum to furnish a residue (31 mg),
which was purified by flash chromatography (eluent: EtOAc), af-
(820 mg), which furnished a by-product identified as (11-oxa-2-
azatricyclo[6.2.1.02,6]undec-7-yl) methyl ketone (66) (45 mg,
0.23 mmol, 4% yield, 5% over unrecovered 59) and 61 (588 mg,
fording 58 (24 mg, 0.12 mmol, 75% yield): 1H NMR (250 MHz): 2.99 mmol, 53% yield, 64% over unrecovered 59) following separ-
δ ϭ 1.45Ϫ1.95 (m, 5 H, 3,3,8,9,9-H), 2.10 (m, 1 H, 4-H), 2.37 (m, ation by flash chromatography (eluent: EtOAc/30% aqueous
3 H, 2,8,10-H), 2.66 (m, 1 H, 4-H), 3.16 (m, 2 H, 2,10-H), 3.44 (m, NH3, 99:1).
1 H, 7-H), 3.67 (s, 3 H, CH3O), 6.85 (ddd, J ϭ 8.6, 3.7, 1.9 Hz, 1
61: IR (film): ν˜ ϭ 3381 (br), 3022, 2938, 2818, 1707, 1440, 1356,
H, 5-H) ppm. 13C NMR (62.5 MHz): δ ϭ 22.0/25.0/26.0 (C-3/C-8/
1215 cmϪ1. 1H NMR (250 MHz): δ ϭ 1.37 (m, 1 H, 8-H), 1.49 (m,
1 H, 3-H), 1.66 (m, 3 H, 4,9,9-H), 1.95 (m, 3 H, 3,4,8-H), 2.17 (s,
C-9), 33.1 (C-4), 51.3 (CH3O), 53.4/56.8 (C-2/C-10), 64.2 (C-7),
135.9 (C-6), 142.0 (C-5), 168.4 (CO2Me) ppm. EIMS: m/z ϭ 195
3 H, CH3CO), 2.34 (m, 2 H, 2,10-H), 2.82 (dd, J6,7 ϭ 9.1, J6,5
ϭ
(33) [M]ϩ, 180 (73), 136 (100), 108 (31), 96 (42), 80 (26), 55 (24),
41 (25). HRMS (EI, 70 eV, C11H17NO2): calcd. 195.1259; found
195.1257.
4.2 Hz, 1 H, 6-H), 3.01 (m, 3 H, 2,7,10-H), 4.08 (ddd, J5,4 ϭ 7.7,
J5,6 ϭ 4.2, J5,4 ϭ 1.5 Hz, 1 H, 5-H) ppm. 13C NMR (62.5 MHz):
δ ϭ 22.6/23.4 (C-3/C-9), 31.00/32.6 (C-4/C-8), 31.05 (CH3CO),
55.7/56.9 (C-2/C-10), 63.5/66.1 (C-6/C-7), 71.3 (C-5), 209.5
(CH3CO) ppm. EIMS: m/z ϭ 197 (9) [M]ϩ, 180 (9), 154 (18), 110
(34), 83 (100). HRMS (EI, 70 eV, C11H19NO2): calcd. 197.1416;
found 197.1412.
(E)-7-Chlorohept-3-en-2-one (59): A solution of 4-chlorobutanol
(3.00 g, 27.7 mmol) in anhydrous CH2Cl2 (9 mL) was added drop-
wise to a stirred suspension of pyridinium chlorochromate (7.30 g,
33.2 mmol) in anhydrous CH2Cl2 (72 mL) at room temperature un-
der nitrogen. After the addition was complete, reaction progress
was monitored by TLC analysis (eluent: hexane/Et2O, 1:1). When
all the starting alcohol had been consumed (5 h), diethyl ether was
added (200 mL) and stirring was continued for 10 min. The liquid
phase was decanted and the remaining solid washed with Et2O (2
ϫ 100 mL). The combined organic fractions were filtered, the solu-
tion was concentrated under vacuum (to about 80 mL) and then
filtered again through Celite. The filtrate was transferred to a
reaction vessel and 1-(triphenylphosphoranylidene)propan-2-one
(13.20 g, 41.5 mmol) was added during a 1 h period, while stirring.
The mixture was then stirred at room temperature overnight. Then
the solvent was removed under vacuum and the remaining solid
was washed with a copious amount of a warm mixture of hexane
and EtO2 (1:1). The resulting extracts were filtered and the solvent
removed under vacuum, affording a yellowish oil (6.80 g), which
furnished 59[17] (2.34 g, 12.9 mmol, 58%) following purification by
flash chromatography (eluent: hexane/diethyl ether, 2:1).
64: 1H NMR (250 MHz):
δ
ϭ
1.45Ϫ2.10 (m,
8
H,
4,4,5,5,1Ј,1Ј,2Ј,2Ј-H), 2.15 (s, 3 H, CH3CO), 2.18 (m, 1 H, 3-H),
2.89 (ddd, J6,6 ϭ 13.9, J6,5 ϭ 8.8, 7.1 Hz, 1 H, 6-H), 3.25Ϫ3.40 (m,
2 H, 3a,6-H), 3.48 (br. t, J ഠ 5.9 Hz, 2 H, 3Ј,3Ј-H), 3.91 (d, J2,3
ϭ
8.0 Hz, 1 H, 2-H) ppm. 13C NMR (62.5 MHz): δ ϭ 23.7/30.3/30.7/
31.4 (C-4/C-5/C-1Ј/C-2Ј), 26.2 (CH3CO), 44.5 (C-3Ј), 53.1 (C-3),
56.6 (C-6), 72.0 (C-3a), 88.0 (C-2), 206.9 (CH3CO) ppm. EIMS: m/
z ϭ 234Ϫ232 (19Ϫ60) [M ϩ1]ϩ, 233Ϫ231 (15Ϫ25) [M]ϩ, 196 (4),
190Ϫ188 (7Ϫ14), 162Ϫ160 (14Ϫ42), 124 (23), 96 (31), 86 (28), 85
(65), 70 (72), 68 (39), 55 (52), 43 (100). HRMS (EI, 70 eV,
C11H18ClNO2): calcd. 231.1026; found 231.1029.
65: 1H NMR (250 MHz):
δ
ϭ
1.50Ϫ2.00 (m,
8
H,
4,4,5,5,1Ј,1Ј,2Ј,2Ј-H), 2.21 (s, 3 H, CH3CO), 2.75 (dd, J3,2 ϭ 8.3,
J3,3a ϭ 5.0 Hz, 1 H, 3-H), 2.86 (m, 1 H, 6-H), 3.33 (m, 1 H, 6-H),
3.53 (m, 2 H, 3Ј,3Ј-H), 3.78 (dt, J3a,4 ϭ 8.2, J3a,3 ഠ J3a,4 ഠ 5.0 Hz,
1 H, 3a-H), 4.03 (dt, J2,3 ϭ 8.3, J2,1Ј ϭ 3.2 Hz, 1 H, 2-H) ppm. 13
C
NMR (62.5 MHz): δ ϭ 23.9/29.2/30.3/32.1 (C-4/C-5/C-1Ј/C-2Ј),
29.4 (CH3CO), 44.7 (C-3Ј), 56.7 (C-6), 68.8/69.2 (C-3/C-3a), 79.1
(C-2), 206.1 (CH3CO) ppm. EIMS: m/z ϭ 234Ϫ232 (8Ϫ23) [M
ϩ1]ϩ, 233Ϫ231 (7Ϫ11) [M]ϩ, 112 (15), 110 (26), 86 (78), 85 (100),
55 (55), 43 (90).
(5RS,6RS,7RS)-5-Hydroxy-1-azabicyclo[5.3.0]dec-6-yl Methyl Ke-
tone (61): A stirred solution of ketone 59 (830 mg, 5.66 mmol) and
nitrone 55[4b,15] (720 mg, 8.47 mmol) in CHCl3 (30 mL) was heated
at reflux for 48 h. Removal of the solvent under vacuum rendered
a brown oil (1.98 g) to which water (10 mL) and diethyl ether
(10 mL) were added. The layers were separated, the organic phase
was dried and the solvent removed under vacuum, affording an oily
residue (343 mg). Purification of this material by flash chromatog-
raphy (eluent: hexane/EtOAc, 1:1) furnished the following
fractions: unchanged 59 (143 mg, 0.98 mmol, 17% recovery);
(2RS,3RS,3aRS)-3-(3-chloropropyl)hexahydropyrrolo[1,2-b]-
isoxazol-2-yl methyl ketone (64) (71 mg, 0.31 mmol, 5% yield, 7%
over unrecovered 59); and (2RS,3SR,3aSR)-2-(3-chloropropyl)-
hexahydropyrrolo[1,2-b]isoxazol-3-yl methyl ketone (65) (54 mg,
0.23 mmol, 4% yield, 5% over unrecovered 59). The aqueous phase
was poured into a reaction vessel, 10% aqueous HCl (128 mL) and
activated zinc powder (18.6 g, 0.28 mol) were added, and the mix-
ture was sonicated for 45 min. The mixture was then filtered, the
1
66: H NMR (250 MHz): δ ϭ 1.22 (m, 1 H), 1.70Ϫ2.10 (m, 7 H),
2.09 (s, 3 H, CH3CO), 2.84 (m, 2 H, 3,7-H), 3.07 (q, J ϭ 8.8 Hz, 1
H, 3-H), 3.61 (br. t, J ഠ 8.8 Hz, 1 H, 6-H), 4.57 (m, 1 H, 8-H),
4.96 (d, J1,10 ϭ 6.6 Hz, 1 H, 1-H) ppm. 13C NMR (62.5 MHz): δ ϭ
22.6/23.7/29.6/29.8 (C-4/C-5/C-9/C-10), 30.0 (CH3CO), 47.7 (C-3),
50.8 (C-7), 54.9 (C-6), 74.9 (C-8), 88.4 (C-1), 207.7 (CH3CO) ppm.
EIMS: m/z ϭ 195 (10) [M]ϩ, 152 (100), 124 (43), 110 (60), 96 (79),
83 (85), 70 (97), 55 (42), 43 (40), 41 (45).
Preparation of 61 from 7: a) A solution of MeLi (1.5  in diethyl
ether, 2.8 mL, 4.2 mmol) was added to a stirred solution of 7
(686 mg, 3.48 mmol) in anhydrous THF (70 mL) at Ϫ100 °C, under
nitrogen and the mixture was stirred at the same temperature for
2 h. The solution was then poured carefully into a saturated aque-
4230
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4215Ϫ4233

Preparation of Intermediates for the Synthesis of Polycyclic Alkaloids
FULL PAPER
ous solution of NH4Cl (100 mL) at 0 °C, with vigorous stirring.
The organic layer was separated and the aqueous phase extracted
was washed with water, the organic layer was separated and the
aqueous phase was extracted with CH2Cl2 (2 ϫ 3 mL). The com-
with CH2Cl2 (3 ϫ 75 mL). The combined organic extracts were bined organic extracts were dried and the solvent removed under
dried and the solvent evaporated under vacuum. Purification of
the residue by flash chromatography (eluent: EtOAc) furnished the
following fractions: unchanged 7 (76 mg, 0.39 mmol, 11% recov-
ery), (2RS,3RS,3aRS)-2-(3-hydroxypropyl)hexahydropyrrolo[1,2-
b]isoxazol-3-yl methyl ketone (67) (422 mg, 1.98 mmol, 57% yield,
64% over unrecovered 7), a 1:1.25 mixture (150 mg) of 67 and
3-[(2RS,3RS,3aRS)3-(1-hydroxy-1-methylethyl)hexahydro-
pyrrolo[1,2-b]isoxazol-2-yl]propan-1-ol (69).
vacuum affording a residue (38 mg), which furnished 62 (30 mg,
0.17 mmol, 79% yield) after purification by flash chromatography
(eluent: CHCl3/MeOH/30% aqueous NH3, 9:1/0.1). 1H NMR
(250 MHz): δ ϭ 1.40Ϫ1.90 (m, 5 H, 3,3,8,9,9-H), 2.04Ϫ2.50 (m, 4
H, 2,4,8,10-H), 2.24 (s, 3 H, CH3), 2.77 (m, 1 H, 4-H), 3.05 (m, 2
H, 2,10-H), 3.37 (m, 1 H, 7-H), 6.77 (m, 1 H, 5-H) ppm. 13C NMR
(62.5 MHz): δ ϭ 22.0/25.3/26.1 (C-3/C-8/C-9), 26.8 (CH3), 33.0 (C-
4), 53.3/56.7 (C-2/C-10), 64.1 (C-7), 142.0 (C-5), 147.5 (C-6), 200.8
(CH3CO) ppm. Compound 62 is of low stability.
67: IR (film): ν˜ ϭ 3423 (br), 2966, 2931, 2875, 1714, 1595, 1525,
Methyl (2RS,3RS,3aRS)-2-(3-Hydroxypropyl)hexahydropyrrolo[1,2-
b]isoxazole-3-carboxylate (70): p-Toluenesulfonic acid (1.16 g,
6.10 mmol) was added to solution of 7 (400 mg, 2.03 mmol) in
MeOH (40 mL) and the mixture was heated at the reflux tempera-
ture for 6 h. The cold solution was concentrated under vacuum,
the residue was redissolved in CH2Cl2 (25 mL), and the solution
washed with saturated aqueous NaHCO3 (20 mL). The organic
layer was separated, dried and the solvent removed, affording an
oily residue (524 mg). Purification of this material by flash chroma-
tography (eluent: EtOAc/MeOH, 9:1) rendered 70 (425 mg,
1
1426, 1356, 1046 cmϪ1. H NMR (250 MHz): δ ϭ 1.30Ϫ2.10 (m,
8 H, 4,4,5,5,1Ј,1Ј,2Ј,2Ј-H), 2.20 (s, 3 H, CH3CO), 2.84 (br. s, 1 H,
OH), 3.11 (m, 3 H, 3,6,6-H), 3.64 (m, 2 H, 3Ј,3Ј-H), 4.06 (dt, J3a,3 ϭ
7.3, J3a,4 ϭ 5.1 Hz, 1 H, 3a-H), 4.28 (m, 1 H, 2-H) ppm. 13C NMR
(62.5 MHz): δ ϭ 23.8 (C-2Ј), 25.7 (C-1Ј), 29.7 (C-5), 30.1 (CH3CO),
31.7 (C-4), 57.1 (C-6), 62.1 (C-3Ј), 65.8 (C-3), 67.3 (C-3a), 78.2 (C-
2), 205.8 (COMe) ppm. EIMS: m/z ϭ 214 (1) [M ϩ1]ϩ, 213 (1)
[M]ϩ, 196 (1), 86 (100), 85 (31), 70 (75).
69: IR (film): ν˜ ϭ 3620, 3402 (br), 2966, 2931, 2868, 1447, 1377,
1060, 1011 cmϪ1 1H NMR (250 MHz): δ ϭ 1.28 (s, 3 H, CH3), 1.85 mmol, 91% yield): IR (film): ν˜ ϭ 3381 (br), 2952, 2875, 1736,
.
1.29 (s, 3 H, CH3), 1.50Ϫ2.00 (m, 8 H, 1,1,2,2,4Ј,4Ј,5Ј,5Ј-H), 2.12
1440, 1377, 1286, 1201, 1166, 1061 cmϪ1 1H NMR (400 MHz):
.
(t, J3Ј,2Ј ϭ J3Ј,3aЈ ϭ 6.3 Hz, 1 H, 3Ј-H), 2.75 (br. s, 1 H, OH), 2.94 δ ϭ 1.44 (m, 1 H, 1Ј-H), 1.54Ϫ1.70 (m, 5 H, 4,5,1Ј,2Ј,2Ј-H), 1.83
(m, 1 H, 6Ј-H), 3.15 (m, 1 H, 6Ј-H), 3.65 (m, 3 H, 3,3,3aЈ-H), 4.05 (m, 1 H, 5-H), 1.95 (m, 1 H, 4-H), 2.82 (br. s, 1 H, OH), 3.03 (m,
(ddd, J2Ј,1 ϭ 9.2, J2Ј,3Ј ϭ 6.3, J2Ј,1 ϭ 2.8 Hz, 1 H, 2Ј-H) ppm. 13C
3 H, 3,6,6-H), 3.59 (m, 2 H, 3Ј,3Ј-H), 3.66 (s, 3 H, CH3O), 4.03
NMR (62.5 MHz): δ ϭ 23.8 (C-2), 26.0 (C-1), 29.5 (CH3), 29.9 (C- (dt, J ϭ 8.5, 4.1 Hz, 1 H, 3a-H), 4.23 (ddd, J ϭ 9.8, 6.9, 3.7 Hz, 1
5Ј), 30.3 (CH3), 33.5 (C-4Ј), 56.8 (C-6Ј), 62.4 (C-3), 63.8/65.4 (C-
3Ј/C-3aЈ), 70.5 (Me2COH), 80.0 (C-2Ј) ppm. EIMS: m/z ϭ 230 (1)
[M ϩ1]ϩ, 229 (2) [M]ϩ, 86 (100), 70 (69).
H, 2-H) ppm. 13C NMR (62.5 MHz): δ ϭ 23.5 (C-2Ј), 25.8 (C-1Ј),
29.3 (C-5), 31.2 (C-4), 51.9 (CH3O), 56.5 (C-6), 58.7 (C-3), 61.9 (C-
3Ј), 66.6 (C-3a), 78.3 (C-2), 171.0 (CO2Me) ppm. EIMS: m/z ϭ 230
(1) [M ϩ1]ϩ, 229 (1) [M]ϩ, 149 (18), 86 (100), 85 (30), 70 (68).
HRMS (EI, 70 eV, C11H19NO4): calcd. 229.1314; found 229.1310.
b) A solution of 67 (348 mg, 1.63 mmol) in anhydrous CH2Cl2
(45 mL) was slowly added to a solution of mesyl chloride (640 µL,
8.21 mmol) in pyridine (4 mL) at 0 °C, under nitrogen. After ad-
dition was complete, the cooling bath was removed and the mixture
stirred at room temperature for 6 h. Then the solvent was evapo-
rated under vacuum, the remaining oil was redissolved in 10%
aqueous HCl (37 mL), activated zinc powder (5.39 g, 82.4 mmol)
was added, and the mixture was sonicated for 45 min. Then the
mixture was filtered, the solid washed with 10% aqueous HCl and
water and the solution brought to pH 9Ϫ10 by addition of 30%
aqueous NH3. This solution was extracted with CHCl3 (5 ϫ
50 mL) and the combined organic extracts were dried, then concen-
trated to furnish an oily residue (378 mg). Purification of this mate-
rial by flash chromatography (eluent: EtOAc/30% aqueous NH3,
99:1) furnished 61 (300 mg, 1.52 mmol, 93% yield).
Methyl (5RS,6RS,7RS)-5-Hydroxy-1-azabicyclo[5.3.0]decane-6-car-
boxylate (72): A solution of 70 (425 mg, 1.85 mmol) in CH2Cl2
(50 mL) was added dropwise to a stirred solution of MsCl (720 µL,
9.24 mmol) in pyridine (4.5 mL) under nitrogen and the mixture
was stirred at room temperature for 6 h. Evaporation of the solvent
under vacuum afforded the mesylate 71: 1H NMR (250 MHz): δ ϭ
1.79Ϫ2.29 (m, 8 H), 2.80 (s, 3 H), 3.75 (s, 3 H), 3.84 (m, 3 H), 4.45
(m, 1 H), 4.80 (dd, J ϭ 12.3, 5.5 Hz, 1 H), 5.08 (br. s, 1 H), 5.42
(br. t, J ഠ 7.1 Hz, 1 H) ppm. Activated zinc powder (6.07 g,
92.8 mmol) was added to a solution of this material in 10% aque-
ous HCl (42 mL) and the mixture was sonicated for 30 min. The
the mixture was filtered, the solid washed with 10% aqueous HCl
and water, and the solution brought to pH 9Ϫ10 by addition of
30% aqueous NH3. A white solid appeared which was filtered un-
der vacuum. Then the solution was extracted with CHCl3 (5 ϫ
1-Azabicyclo[5.3.0]dec-5-en-6-yl Methyl Ketone (62): A solution of
61 (110 mg, 0.56 mmol) in anhydrous CH2Cl2 (250 µL) was added 35 mL), the combined organic extracts were dried, and the solution
dropwise to a solution of mesyl chloride (46 µL, 0.59 mmol) in
anhydrous CH2Cl2 (250 µL) at 0 °C, under nitrogen. The cooling
bath was removed and the mixture was stirred at room temperature
for 5 h. The reaction mixture was treated with saturated aqueous
NaHCO3 at 0 °C, the organic layer was separated and the aqueous
was concentrated affording an oily residue (533 mg). Purification
of this oil by flash chromatography (eluent: EtOAc) furnished 72
(341 mg, 1.60 mmol, 86% yield) as an oil. B.p. 80 °C (oven)/
0.06 Torr. IR (film): ν˜ ϭ 3402 (br), 2945, 2875, 2812, 1736, 1440,
1342, 1314, 1258, 1208, 1159, 1096 cmϪ1 1H NMR (400 MHz):
.
phase extracted with CH2Cl2 (2 ϫ 2 mL). The combined organic δ ϭ 1.55 (m, 2 H, 3,8-H), 1.76 (m, 3 H, 8,9,9-H), 1.98 (m, 3 H,
extracts were dried and the solvent evaporated under vacuum af- 3,4,4-H), 2.40 (m, 2 H, 2,10-H), 2.67 (dd, J6,7 ϭ 9.1, J6,5 ϭ 5.0 Hz,
fording the expected mesylate (126 mg, 0.46 mmol, 82% yield), 1 H, 6-H), 3.00 (m, 3 H, 2,7,10-H), 3.66 (s, 3 H, CH3O), 4.09 (ddd,
which was used in the next step without further purification. 1H J5,4 ϭ 7.0, J5,6 ϭ 5.0, J5,4 ϭ 2.0 Hz, 1 H, 5-H) ppm. 13C NMR
NMR (250 MHz): δ ϭ 1.35Ϫ2.20 (m, 8 H), 2.18 (s, 3 H), 2.37 (m, (62.5 MHz): δ ϭ 22.8/23.5 (C-3/C-9), 30.9/32.7 (C-4/C-8), 51.7
2 H), 2.81 (s, 3 H), 2.93 (m, 4 H), 4.76 (m, 1 H) ppm. Potassium (CH3O), 55.8/57.1 (C-2/C-10), 58.8 (C-6), 64.3 (C-7), 71.8 (C-5),
tert-butoxide (24 mg, 0.21 mmol) was added to a solution of the 173.8 (CO2Me) ppm. EIMS: m/z ϭ 213 (14) [M]ϩ, 196 (20), 182
crude mesylate (59 mg, 0.21 mmol) in CH2Cl2 (3 mL) and the mix- (14), 110 (50), 97 (47), 96 (41), 84 (50), 83 (100). HRMS (EI, 70 eV,
ture was stirred at room temperature for 3 h. The reaction mixture C11H19NO3): calcd. 213.1365; found 213.1364.
Eur. J. Org. Chem. 2004, 4215Ϫ4233
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4231

P. Cid, M. Closa, P. de March, M. Figueredo, J. Font, E. Sanfeliu, A. Soria
FULL PAPER
Torssell, Nitrile Oxides, Nitrones, and Nitronates in Organic
Synthesis, VCH Verlagsgesellschaft, Weinheim, 1988.
Methyl
(5RS,6RS,7RS)-5-(Imidazol-2-ylthiocarbonyloxy)-1-aza-
bicyclo[5.3.0]decane-6-carboxylate (73): TCDI (98 mg, 0.55 mmol)
was added to a stirred solution of 73 (65 mg, 0.30 mmol) in anhy-
drous THF (6 mL) under nitrogen, and the mixture was stirred at
room temperature overnight. Then, the solvent was evaporated un-
der vacuum and the residue re-dissolved in CHCl3 (3 mL). This
solution was washed with water (2 ϫ 2 mL), dried, and the solvent
removed affording a crude material (135 mg) which was used in the
next step without further purification. An analytical sample of 73
was obtained by flash chromatography of this material (eluent:
EtOAc/MeOH, 9:1), followed by separation of the imidazole resi-
dues by crystallisation from EtOAc/pentane and a second chroma-
tography of the remaining oil. IR (film): ν˜ ϭ 3128, 2938, 2868,
[2] [2a]
J. J. Tufariello, J. P. Tette, J. Org. Chem. 1975, 40,
[2b]
3866Ϫ3869.
J. J. Tufariello, S. A. Ali, Tetrahedron Lett.
1979, 46, 4445Ϫ4448. [2c] J. J. Tufariello, Acc. Chem. Res. 1979,
[2d]
12, 396Ϫ403.
J. J. Tufariello, G. E. Lee, J. Am. Chem. Soc.
[2e]
1980, 102, 373Ϫ374.
Kibayashi, J. Org. Chem. 1984, 49, 2412Ϫ2418.
H. Iida, Y. Watanabe, M. Tanaka, C.
[2f]
J. J. Tufari-
ello, K. Winzenberg, Tetrahedron Lett. 1986, 27, 1645Ϫ1648.
[2g]
D. Lathbury, T. Gallagher, J. Chem. Soc., Chem. Commun.
1986, 13, 1017Ϫ1018. [2h] F. M. Cordero, B. Anichini, A. Goti,
[2i]
A. Brandi, Tetrahedron 1993, 49, 9867Ϫ9876.
A. Goti, V.
Fedi, L. Nannelli, F. De Sarlo, A. Brandi, Synlett 1997,
577Ϫ579. [2j] A. E. McCaig, K. P. Meldrum, R. H. Wightman,
Tetrahedron 1998, 54, 9429Ϫ9446. [2k] A. Goti, S. Cicchi, F. M.
2805, 1736, 1469, 1391, 1328, 1286, 1237, 1159, 1096 cmϪ1 1H
.
NMR (400 MHz): δ ϭ 1.67 (m, 3 H, 3,8,9-H), 1.81 (m, 1 H, 3-H),
1.92 (m, 2 H, 8,9-H), 2.15 (m, 2 H, 4,4-H), 2.47 (m, 2 H, 2,10-H),
2.82 (ddd, J7,6 ϭ 9.7, J7,8 ഠ 7.9, 6.5 Hz, 1 H, 7-H), 2.96 (t, J6,7
J6,5 ϭ 9.7 Hz, 1 H, 6-H), 3.08 (m, 2 H, 2,10-H), 3.58 (s, 3 H,
CH3O), 5.69 (td, J5,4 ϭ J5,6 ϭ 8.9, J5,4 ϭ 3.8 Hz, 1 H, 5-H), 6.95
(s, 1 H, Im-H), 7.53 (s, 1 H, Im-H), 8.24 (s, 1 H, Im-H) ppm. 13C
NMR (62.5 MHz): δ ϭ 22.4/22.9 (C-3/C-9), 29.3/31.0 (C-4/C-8),
51.9 (CH3O), 53.5/57.2 (C-2/C-10), 57.8 (C-6), 61.4 (C-7), 85.5 (C-
5), 117.8/130.7/136.7 (Im), 172.6 (CO2Me), 182.7 (CϭS) ppm.
EIMS: m/z ϭ 196 (52) [M Ϫ ImCSO]ϩ, 195 (50), 180 (89), 139 (25),
136 (100), 134 (34), 108 (28), 96 (41), 83 (31), 82 (32). C15H21N3O3S
(323.41) calcd. C 55.71, H 6.54, N 12.99; found C 55.69, H 6.65,
N 12.71.
[2l]
Cordero, V. Fedi, A. Brandi, Molecules 1999, 4, 1Ϫ12.
Goti, M. Cacciarini, F. Cardona, A. Brandi, Tetrahedron Lett.
1999, 40, 2853Ϫ2856.
Org. Chem. 2003, 7, 585Ϫ628.
A.
[2m]
A. E. Koumbis, J. K. Gallos, Curr.
ϭ
[3] [3a]
P. de March, M. Figueredo, J. Font, M. Monsalvatje, Rec.
Trav. Chim. Pays-Bas 1995, 114, 357Ϫ360. [3b] F. Busque, P. de
´
March, M. Figueredo, J. Font, M. Monsalvatje, A. Virgili, A.
´
Alvarez-Larena, J. F. Piniella, J. Org. Chem. 1996, 61,
[3c]
8578Ϫ8585.
P. de March, M. Figueredo, J. Font, A. Sal-
[3d]
´
R. Alibes, F.
gado, Tetrahedron 1998, 54, 6947Ϫ6956.
Busque, P. de March, M. Figueredo, J. Font, T. Parella, Tetra-
hedron 1998, 54, 10857Ϫ10878.
March, M. Figueredo, J. Font, M. E. Gambino, B. A. Keay,
´
[3e]
´ ´
R. Alibes, F. Busque, P. de
Tetrahedron: Asymmetry 2001, 12, 1747Ϫ1756.
[4] [4a]
´
P. Cid, P. de March, M. Figueredo, J. Font, S. Milan, A.
[4b]
Soria, A. Virgili, Tetrahedron 1993, 49, 3857Ϫ3870.
D.
Methyl (6RS,7SR)-1-Azabicyclo[5.3.0]decane-6-carboxylate (74): A
solution of crude 73 (prepared from 115 mg, 0.54 mmol, of 72) in
anhydrous toluene (11 mL) was added to a solution of Bu3SnH
(580 µL, 2.16 mmol) and AIBN (13 mg, 0.08 mmol) in anhydrous
toluene (4 mL) at 100 °C and the mixture was heated at this tem-
perature for 30 min. The cold solution was extracted with 10%
aqueous HCl (4 ϫ 6 mL). The combined aqueous extracts were
basified to pH 9Ϫ10 with 30% aqueous NH3 and extracted with
CHCl3 (5 ϫ 10 mL). These organic extracts were dried and the
solvent evaporated under vacuum affording an oily residue
(118 mg), which furnished 74 (71 mg, 0.36 mmol, 67% yield for the
two steps) after purification by flash chromatography (eluent:
EtOAc/MeOH, 9:1). IR (film): ν˜ ϭ 2931, 2868, 2798, 1736, 1441,
Alonso-Perarnau, P. de March, M. Figueredo, J. Font, A. So-
[4c]
´
F. Busque, P. Cid, P.
ria, Tetrahedron 1993, 49, 4267Ϫ4274.
de March, M. Figueredo, J. Font, Heterocycles 1995, 40,
[4d]
387Ϫ399.
M. Closa, P. de March, M. Figueredo, J. Font,
A. Soria, Tetrahedron 1997, 53, 16803Ϫ16816.
For a recent review on Stemona alkaloids see: R. A. Pilli, M.
C. Ferreira de Oliveira, Nat. Prod. Rep. 2000, 17, 117Ϫ127.
[5]
[6]
´
´
R. Alibes, F. Busque, P. de March, M. Figueredo, J. Font,
Tetrahedron 1998, 54, 11581Ϫ11588.
[7] [7a]
P. M. Wovkulich, M. R. Uskokovic, J. Am. Chem. Soc.
1981, 103, 3956Ϫ3958. [7b] C. M. Tice, B. Ganem, J. Org. Chem.
[7c]
1983, 48, 5048Ϫ5050.
I. Panfil, M. Chmielewski, C.
Belzecki, Heterocycles 1986, 24, 1609Ϫ1617. [7d] J. D. White, R.
A. Badger, H. S. Kezar III, A. J. Pallenberg, G. A. Schiehser,
1321, 1258, 1202, 1159, 1103, 1068, 1026 cmϪ1 1H NMR
.
[7e]
Tetrahedron 1989, 45, 6631Ϫ6644.
A. Brandi, F. Cordero,
C. Querci, J. Org. Chem. 1989, 54, 1748Ϫ1750. [7f] S.-I. Murah-
ashi, Y. Imada, M. Kohno, T. Kawakami, Synlett 1993,
395Ϫ396.
(250 MHz): δ ϭ 1.50 (m, 1 H), 1.60Ϫ2.06 (m, 9 H), 2.37 (m, 3 H,
2,6,10-H), 2.70 (ddd, J ഠ 10.0, 8.4, 6.0 Hz, 1 H, 7-H), 3.02 (m, 2
H, 2,10-H), 3.64 (s, 3 H, CH3O) ppm. 13C NMR (62.5 MHz): δ ϭ
23.1/23.9 (C-3/C-9), 29.2/30.6/32.0 (C-4/C-5/C-8), 51.3/52.2 (C-6/
CH3O), 55.4/57.9 (C-2/C-10), 66.0 (C-7), 176.2 (CO2Me) ppm.
EIMS: m/z ϭ 197 (17) [M]ϩ, 110 (47), 97 (30), 96 (89), 83 (100).
HRMS (EI, 70 eV, C11H18NO2 [M Ϫ 1]ϩ): calcd. 196.1337; found
196.1329.
[8]
S. Cicchi, A. Goti, A. Brandi, A. Guarna, F. De Sarlo, Tetra-
hedron Lett. 1990, 31, 3351Ϫ3354.
[9] [9a]
J. J. Tufariello, G. B. Mullen, J. J. Tegeler, E. J. Trybulski,
S. C. Wong, S. A. Ali, J. Am. Chem. Soc. 1979, 101,
2435Ϫ2442. [9b] H. Otomasu, N. Takatsu, T. Honda, T. Kamet-
[9c]
ani, Tetrahedron 1982, 38, 2627Ϫ2633.
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Acknowledgments
We gratefully acknowledge financial support by the Ministerio de
Ciencia y Tecnologıa (Project BQU2001Ϫ2600) and CIRIT (Pro-
ject 2001SGR 00178). We are also thankful for grants from the
Ministerio de Educacion y Ciencia (to P. C.), CIRIT (to A. S.) and
Universitat Autonoma de Barcelona (to M. C.).
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