An entry to functionalized 2,8-ethanonoradamantane derivatives

Article abstract of DOI:10.1021/jo302398c

The synthesis of a functionalized derivative containing the 2,8-ethanonoradamantane carbocyclic skeleton, whose key-step consists of an intramolecular Diels-Alder reaction, is described. Chemoselective reduction of an intermediate enone required protection of the maleimide function through their Diels-Alder adducts with furan.

Full text of DOI:10.1021/jo302398c

Article
pubs.acs.org/joc
An Entry to Functionalized 2,8-Ethanonoradamantane Derivatives
Pelayo Camps,* Tania Gomez, and Claudio Monasterolo
̀
́
̀ ̀
Laboratori de Química Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia and Institut de Biomedicina (IBUB),
Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain
S
* Supporting Information
ABSTRACT: The synthesis of a functionalized derivative containing the 2,8-ethanonoradamantane carbocyclic skeleton, whose
key-step consists of an intramolecular Diels−Alder reaction, is described. Chemoselective reduction of an intermediate enone
required protection of the maleimide function through their Diels−Alder adducts with furan.
under study at different levels, as neuroactive, anticancer, anti-
infective, antihypertensive and anti-inflammatory agents.1
Drugs containing other cage structures are very limited,
probably due to the lack of readily available cage precursors.
However, several compounds containing cage structures
different from adamantane have been studied as neuro-
protective agents,2−5 HIV-1 protease inhibitors6,7 and anti-
virals8−10 (Figure 2).
In connection with the preparation of novel cage compounds
with potential biological activity, we were interested in the
synthesis of functionalized 2,8-ethanonoradamantane deriva-
tives as key synthetic intermediates. Literature about 2,8-
ethanonoradamantane or tetracyclo[6.2.1.02,6.05,10]undecane
derivatives is very limited, and so far only three type of
synthetic approaches have been described, in all cases from very
specific precursors and leading to a limited number of
functionalized derivatives, namely, (1) by intramolecular keto
carbene insertion,11 (2) by formic acid induced rearrange-
ment,12 and (3) by BF3·Et2O catalyzed transannular cycliza-
tion13 (Figure 3).
INTRODUCTION
■
Compounds containing carbocyclic cage structures, such as
adamantyl groups, are of significant interest in medicinal
chemistry. At present, seven drugs containing the adamantane
skeleton are being used clinically (Figure 1): Amantadine,
rimantadine and tromantadine as antiviral agents, amantadine
for the treatment of Parkinson’s disease, memantine for the
treatment of Alzheimer’s disease, adapalene for the treatment of
acne vulgaris, and vildagliptin and saxagliptin for the treatment
of type 2 diabetes. Also, many other adamantane derivatives are
Herein we report a rationally designed entry into a
polyfunctionalized compound containing this carbocyclic
skeleton, based on the retrosynthetic analysis shown in Scheme
1, whose key-step consists of an intramolecular Diels−Alder
reaction.
RESULTS AND DISCUSSION
■
The starting compound 4 was recently described by our
group.14 To transform compound 4 into alkylating agent 3, we
first submitted 4 to hydroboration with 9-borabicyclo[3.3.1]-
nonane (9-BBN) followed by oxidation with aqueous 35%
H2O2 under basic conditions. Although we obtained the desired
alcohol 5 as a mixture of stereoisomers, we could not separate it
from the cis-cyclooctane-1,5-diol, formed as a byproduct.
Received: October 29, 2012
Published: November 30, 2012
Figure 1. Drugs in clinical use, containing the adamantane skeleton.
© 2012 American Chemical Society
11270
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
Figure 3. Structure of 2,8-noradamantane or tetracyclo[6.2.1.02,6.05,10]-
undecane and known procedures to prepare compounds containing
this carbocyclic skeleton.
Scheme 1. Retrosynthetic Analysis of 2,8-Noradamantane
Derivative 1
Figure 2. Biologically active cage derivatives.
Hydroboration of 4 with BH3·THF complex followed by H2O2
oxidation gave an essentially 1:1 mixture of alcohol 5 plus its
C5 epimer in 55% yield. Although both stereoisomers of 5
might be converted into 3, for analytical reasons we preferred
to carry out first this transformation by working with one
stereoisomer. To this end, we carried out the hydroboration
with dicyclohexylborane, generated in situ by reaction of the
BH3·THF complex with cyclohexene (Scheme 2). The method
of Brown et al.15 was followed, except for the use of BH3·THF
complex instead of BH3·SMe2. By using this reagent, after H2O2
oxidation of the reaction mixture and column chromatography
of the crude product, we obtained pure alcohol 5 and mixtures
of 5 and its C5 epimer. Altogether we obtained both alcohols in
55% yield with a calculated ratio of about 88:12 (1H NMR).
The configuration of the main stereoisomer was established to
be that shown for 5 with the hydroxymethyl group in an exo
H−C5−C4−Hx and H−C5−C6−Hx close to 180°. Also, a
stronger NOE among the 3a-H/4-Hx and 6a-H/6-Hx than
among the 3a-H/4-Hn and 6a-H/6-Hn pairs of protons was
observed in the NOESY experiment.
Protection of the hydroxyl group of the stereoisomerically
pure 5 as t-butyldimethylsilyl ether was performed in high yield
using a standard procedure.16 For the introduction of the
unsaturation at the C3a−C6a position, we decided to use the
benzeneselenenylation/H2O2 oxidation procedure, which is
well established for the introduction of a CC bond in the
α,β-position of carbonyl compounds, such as ketones, esters,
nitriles, amides or lactams,17 although we only find application
1
arrangement on the basis of the H NMR and NOESY data.
This compound seems to exist preferentially with the
cyclopentane ring in the shown envelope conformation with
the hydroxymethyl group in a pseudoequatorial position, as
shown by the observed coupling constants (J3aH/4‑Hn ∼ 0 Hz;
J3aH/4‑Hx ∼ 9.6 Hz; J4‑Hx/4‑Hn = 13.2 Hz; J4‑Hx/5‑H = 12.0 Hz;
J4‑Hn/5‑H = 5.7 Hz), the fourth one suggesting dihedral angles
11271
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
Scheme 2. Preparation of Compounds 7 and 8 from the Starting Imide 4
Scheme 3. Preparation of Tosylates 10 and 14
of this procedure to transform succinimide derivatives to the
corresponding maleimides, in the case of α-acylsuccinimides.18
Benzeneselenenylation of succinimide 6 was carried out by
reaction with lithium hexamethyldisilazide (LHMDS), prepared
in situ by reaction of hexamethyldisilazane (HMDS) with n-
BuLi in hexanes, followed by reaction with benzeneselenenyl
chloride.17 The benzeneselenenylated product 7 was obtained
in only 35% yield, the elimination product 8 was also isolated in
3% yield, and much starting compound 6 was recovered (37%),
in spite of using an excess of base. Formation of 8 might take
place by base-induced elimination of benzeneselenol from 7.
Hydrogen peroxide oxidation of 7 gave in good yield maleimide
8. More conveniently, oxidation of the crude mixture from the
benzeneselenenylation of 6 gave compound 8 in 28% yield. The
relative configuration of 7 and its derivatives was established as
correspond to the first enantiomer described by their IUPAC
names (see the Experimental Section).
Reaction of 7 with tetrabutylammonium fluoride (TBAF)16
gave in good yield the corresponding alcohol 9, which on
reaction with tosyl chloride gave tosylate 10 (Scheme 3).
Column chromatography of the crude tosylate allowed us to
isolate pure tosylate 10 in 78% yield and a mixture of chlorides
1
11 and 12 in a ratio about 4.4:1 (by H NMR) in 7% yield.
1
From the H NMR spectrum of tosylate 10, the following
coupling constants were obtained: J4‑Hx/4‑Hn = 13.2 Hz, J4‑Hx/5‑H
∼ 11.8 Hz, J4‑Hn/5‑H ∼ 6.0 Hz, J5‑H/CH2OTs = 6.0 Hz, J4‑Hn/6‑Hn
∼
1.2 Hz, J5‑H/6‑Hx ∼ 10.4 Hz, J5‑H/6‑Hn ∼ 6.0 Hz, J6‑Hx/6‑Hn = 12.6
Hz, J6‑Hx/6a‑H ∼ 10.4 Hz, J6‑Hn/6a‑H ∼ 0 Hz). Also, a NOE among
6a-H/6-Hx stronger than among 6a-H/6-Hn was observed. All
these data suggest that the configuration and the preferred
conformation of 10 is that shown, in which the cyclopentane
ring is in an envelope conformation with the tosyloxymethyl
group in a pseudoequatorial arrangement. Although chloride 12
(1.3% yield) might be formed from chloride 11 by pyridine-
induced elimination of phenylselenol, we cannot discard the
possibility that the starting alcohol 9 contained a small amount
of alcohol 13.
1
before on the basis of the H NMR and NOESY data for its
derived tosylate 10 (Scheme 3). The cis relationship among the
benzeneselenenyl group at C3a and 6a-H is required to allow
the syn-elimination of phenylselenenic acid from the
intermediate selenoxide during the transformation of 7 to 8.
Compound 7 and its derivatives (9, 10, 11, 15, 16, 23 and 24)
are racemic compounds, and the configurations shown for them
11272
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
Surprisingly, reaction of 8 with TBAF gave the expected
alcohol 13 in only 30% yield. Hydrolysis of the imide function
was observed when deprotection of 8 was attempted with 1 M
HCl in a mixture of THF and MeOH at room temperature for
3 d.19 Fortunately treatment of 8 with 1 M HCl in THF gave
alcohol 13 in high yield. Tosylation of 13 gave mainly tosylate
14, chloride 12 being also formed in low yield. Both
compounds could be separated by column chromatography
and fully characterized. Alternatively, tosylate 14 was obtained
in high yield from tosylate 10 by oxidation with H2O2 and
elimination of the benzeneselenenyl group.
Reaction of tosylate 14 with sodium cyclopentadienide in
THF at low temperature (−40 °C or from 0 °C to room
temperature) gave a mixture of products in which neither the
expected substitution product 2 (R = H) or tautomers nor the
desired intramolecular Diels−Alder adduct 1 (R = H) were
detected by 1H NMR. Alternatively, reaction of tosylate 10 with
sodium cyclopentadienide in THF at −40 °C gave in 46% yield
a mixture of the substitution products 15 and 16 in a ratio
about 3:2, established by integration of the fully differentiated
signals corresponding to the cyclopentadienyl group of both
tautomers (Scheme 4).20 However, oxidation of this mixture
To favor the intramolecular cycloaddition in compound 2,
we then planned the preparation of 2 (R = COOMe) using a
methodology we had previously used to prepare methyl 1-
benzylcyclopenta-2,4-diene-1-carboxylate.21 Reaction of alcohol
13 with mesyl chloride in CH2Cl2 in the presence of Et3N22
gave mesylate 17 in 97% yield (Scheme 5). In this case,
formation of the corresponding chloride 12 was not observed.
To favor C-alkylation in the alkylation step leading to
compound 19, mesylate 17 and tosylate 14 were transformed
in high yield into iodide 18 by reaction with NaI in acetone
under reflux.23 Reaction of iodide 18 with the sodium salt of
methyl 2-oxocyclopentane-1-carboxylate in DMF at 0 °C for 4
h gave product 19 in 78% yield, after purification by column
chromatography. Reaction of 19 with trimethylsilyl triflate
(TMSOTf) in CH2Cl2 in the presence of Et3N gave the
corresponding trimethylsilyl enol ether 20, which was used as
such in the next step. Oxidation of 20 with Pd(OAc)2 in
DMSO at room temperature for 16 h gave enone 21 in 87%
global yield from ketone 19, after purification by column
chromatography (Scheme 5).24 Worthy of note and contrarily
to our previous experience,21 oxidation of 20 by using a
catalytic amount of Pd(OAc)2 (5−10%) and oxygen,25,26 or by
using Pd(OAc)2 (0.5 equiv) plus benzoquinone (0.5 equiv) as
in the original method of Saegusa,27,28 gave a low yield of 21
(25 and 53% yield, respectively).
Scheme 4. Attempted Preparation of Tetracycle 1 (R = H)
Reduction of the ketone function of 21 with NaBH4 in the
presence of CeCl3·7H2O (Luche conditions),29 under similar
conditions to those used for the preparation of a related
compound,21,26 gave a stereoisomeric mixture 22, derived from
the reduction not only of the ketone but also of the imide
functions (Scheme 6). To study the possibility of carrying out a
chemoselective reduction of 21, we performed this trans-
formation under different conditions, using an excess of
CeCl3·7H2O, taking into account the possible preferential
coordination of the imide function, and reducing the amount of
NaBH4 until 0.5 mol NaBH4/mol 21, always working at −40
°C for 15 min. When the molar ratio NaBH4/21 was 1.0 or 0.5,
mixtures of all possible products derived from the reduction of
the enone, the imide or both functions of 21 plus starting
compound were obtained in different ratio.
We observed that tosylate 10, which contains a succinimide
function instead of the maleimide function, was not reduced
with NaBH4/CeCl3·7H2O at −40 °C for 15 min. Con-
sequently, we planned the transformations shown in Scheme
with H2O2 gave a complex mixture of products not containing
(1H NMR) the expected compound 1 (R = H) or its precursor
2 (R = H) or its tautomers. The last products might have
polymerized through intermolecular Diels−Alder reactions.
Scheme 5. Preparation of Enone 21
11273
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
as a mixture of two diastereoisomeric racemic pairs. However,
reaction of 24 with TMSOTf did not give the corresponding
silyl enol ether, from which allylic alcohol 25 might have been
prepared (Scheme 6).
Scheme 6. Thwarted Attempts to Prepare Compound 25
Alternatively, we could prepare alcohol 25 as shown in
Scheme 7, by protecting the imide function of 21 as a Diels−
Alder adduct with furan. Reaction of 21 with an excess of furan
in a closed glass vessel at 80 °C for 24 h gave quantitatively a
stereoisomeric mixture of four possible racemic pairs in
1
different ratio (1H NMR). From the H NMR data (δ 6.13−
6.18 and 7.72−7.80 ppm, cyclopentenone 3-H and 4-H,
respectively), it was clear that the cyclopentenone moiety was
present, and thus, this moiety had not reacted with furan.
Reduction of the stereoisomeric mixture 26 with NaBH4/
CeCl3·7H2O at −40 °C for 1 h gave a stereoisomeric mixture of
1
allylic alcohols 27. From the H NMR data (δ 5.75−5.79 and
5.87−5.95 ppm, cyclopentenol 4-H and 3-H, respectively, and
4.85−5.09 ppm, cyclopentenol 2-H plus allylic H from the
dihydrofuran moiety), it was clear that the enone function had
been reduced, while the absence of signals around δ 4.4−4.8
ppm (MeN-CHOH- type of proton) was indicative that the
imide function had not been reduced. Upon heating the
stereoisomeric mixture 27 in an open vessel in toluene under
reflux, after 4 days, most of the Diels−Alder adducts had
experienced a retro-Diels−Alder reaction. When working in
xylene under reflux, much degradation of the product was
observed. Worthy of note, the more abundant stereoisomers 27
experienced this retro-Diels−Alder process faster than the less
abundant ones, so that they became the main starting
stereoisomers 27 remaining in the reaction mixture when the
retrocycloaddition was stopped. From the reaction mixture, the
6 from tosylate 10, which was transformed as before into the
corresponding iodide 23 and reacted with the sodium salt of
methyl 2-oxocyclopentanecarboxylate to give 24 in good yield,
Scheme 7. Alternative Preparations of Compound 25 and Conversions to Polycycle 1 (R = COOMe)
11274
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
(gHSQC sequence) and H/13C multiple bond correlation (gHMBC
sequence) experiments and also, for certain compounds, on NOESY
spectra information. Infrared spectra were obtained by using the
attenuated total reflectance (ATR) technique. Absorption values are
given as wavenumbers (cm−1), and the intensities of the absorptions
are given as strong (s), medium (m) or weak (w). High-resolution
mass spectra (HRMS) were obtained with electrospray ionization
using a TOF mass analyzer (ESI-MS) and are reported as m/z
(relative ratio). Flash column chromatography was performed on silica
gel 60 A C.C (35−70 mesh). The eluents employed are reported as
volume/volume percentages. For the thin layer chromatography
(TLC), aluminum-backed sheets with silica gel 60 F254 were used,
and spots were visualized with UV light and/or 1% aq KMnO4.
(3aR,5s,6aS)-2-Methyl-5-(hydroxymethyl)-4,5,6,6a-tetra-
hydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione, 5. To a cold (0
°C, ice−water bath) solution of cyclohexene (3.7 mL, 3.0 g, 36.5
mmol) in anhydrous THF (15 mL), a solution of the BH3·THF
complex in THF (1M, 17.7 mL, 17.7 mmol) was added dropwise.
Then, the reaction mixture was stirred for 15 min at 0 °C and for 2 h
at room temperature. After cooling again to 0 °C, a solution of 4 (1.01
g, 6.10 mmol) in THF (67 mL) was added dropwise, and the reaction
mixture was stirred for 4 h at this temperature. Absolute EtOH (12
mL) was added dropwise, and the mixture was stirred for 10 min at
room temperature, until no more hydrogen evolution was observed.
The mixture was cooled to 0 °C, and aqueous solutions of H2O2 (35%,
8 mL) and NaOH (3N, 10.6 mL) were simultaneously added
dropwise, keeping the temperature at around 0 °C. The reaction
mixture was concentrated, the residue was treated with water (40 mL)
and EtOAc (50 mL), the organic phase was separated, and the
aqueous one was extracted with EtOAc (2 × 50 mL). The combined
organic phases were dried (anhydrous Na2SO4) and concentrated in
vacuo. The oily residue (3.63 g) was subjected to column
chromatography (silica gel, 90 g, hexane/EtOAc mixtures). On elution
with EtOAc, in order of elution 5 (253 mg) and mixtures of 5 and its
C5 epimer 10:2 (271 mg) and 10:4 (91 mg) were obtained as light
yellow oils. Total 614 mg, 55% yield of 5 plus its C5 epimer, 5/C5
epimer ratio 88:12 (by 1H NMR). Analytical and spectroscopic data of
5: Rf = 0.27 (silica gel, 4.9 cm, EtOAc); IR (ATR) ν 3600−3200 (max.
at 3432, m), 2949 (m), 2922 (m), 2853 (m), 1771 (w), 1686 (s), 1678
(s), 1432 (m), 1381 (m), 1307 (m), 1281 (m), 1160 (w), 1087 (m),
1
main alcohol 25 plus mixtures of 25 and its C2 epimer were
isolated in 74% yield by column chromatography. By analogy
with previous results,21 the main stereoisomer must be the one
shown, in which the hydroxyl function is trans with respect to
the methoxycarbonyl group. This three-step transformation is
worthy of note, since the retro Diels−Alder reaction leading to
the maleimide product 25 takes place in toluene under reflux.
The protection of 2,3-unsubstituted maleimides as furan
adducts and its deprotection in refluxing anisole has been
described.30 However, to the best of our knowledge, a similar
deprotection of 2,3-disubstituted maleimides31 or maleic
anhydrides32,33 from their Diels−Alder adducts has usually
been effected under flash vacuum pyrolysis (FVP) conditions at
temperatures close to 400 °C.
p-Toluenesulfonic acid catalyzed dehydration of alcohol 25
in refluxing benzene, under similar conditions to those used for
the preparation of methyl 1-benzylcyclopenta-2,4-dienecarbox-
ylate,21 led in good yield to the desired product 1 (R =
COOMe), reasonably formed by intramolecular Diels−Alder
reaction from cyclopentadiene maleimide 2 (R = COOMe).
This product was also obtained in an alternative less
convenient way from the stereoisomeric mixture 22 by
controlled oxidation with MnO2 in CH2Cl2.34 This oxidation
is not chemoselective, and using a limited amount of MnO2 led
to a mixture of products, which on column chromatography
gave mixtures of the two less polar products 21 and 25 and of
the two more polar starting compound 22 and a product
containing the enone function, whose probable structure
corresponds to hydroxylactam 28. From the integral of the
olefinic and CH−OH protons of the different products in these
fractions and their weight, the following yields of formed
products could be calculated: alcohol 25 (43%), enone 21
(12%), hydroxylactam 28 (13%), recovered 22 (10%).
Acetylation of a mixture of the main stereoisomer of allylic
alcohol 25 and enone 21 (ratio alcohol 25/enone 21 = 3:1)
with acetic anhydride in CH2Cl2 in the presence of pyridine and
a catalytic amount of 4-dimethylaminopyridine (DMAP) gave a
mixture of acetate 29 and enone 21, which could be easily
separated by column chromatography yielding stereoisomeri-
cally pure acetate 29 in 92% global yield from the amount of
alcohol 25 in the starting mixture. Acid catalyzed elimination of
acetic acid from acetate 29 as described before for the
dehydration of alcohol 25 led in high yield to the same
polycyclic product 1 (R = COOMe).
1026 (m), 996 (m), 972 (m), 603 (m) cm−1; H NMR δ 1.62−1.77
1
[m, 2H, 4(6)-Hx], 1.87 (ttt, J = 12.0 Hz, J′ = 5.7 Hz, J″ = 5.7 Hz, 1H,
5-H), 1.90−2.05 (br s, 1H, OH), 2.19 [dd, J′ = 13.2 Hz, J″ = 6.0 Hz,
2H, 4(6)-Hn], 2.94 (s, 3H, N-CH3), 3.16−3.22 [m, 2H, 3a(6a)-H],
3.57 (d, J′ = 5.6 Hz, 2H, CH2OH); 13C NMR δ 25.0 (CH3, N-CH3),
32.9 [CH2, C4(6)], 40.6 (CH, C5), 44.8 [CH, C3a(6a)], 64.5 (CH2,
CH2OH), 180.3 [C, C1(3)]. HRMS (ESI) (m/z) calcd for
[C9H13NO3 + H]+: 184.0968. Found: 184.0968. Anal. Calcd for
C9H13NO3·0.1H2O (185.01): C, 58.43; H, 7.19; N, 7.57. Found: C,
58.36; H, 7.41; N, 7.29.
CONCLUSION
(3aR,5s,6aS)-2-Methyl-5-[(t-butyldimethylsilyloxy)methyl]-
4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-dione, 6.
To a solution of 5 (490 mg, 2.68 mmol) in anhydrous THF (6 mL),
imidazole (432 mg, 6.34 mmol) was added. After the mixture was
stirred for 10 min at room temperature, t-butyldimethylsilyl chloride
(98% content, 487 mg, 3.23 mmol) was added, and the mixture was
stirred for 48 h under an Ar atmosphere. The reaction mixture was
filtered through a short pad of silica gel and Celite washing the solid
with EtOAc (20 mL). The combined filtrate and washings were
concentrated in vacuo, and the residue was taken in EtOAc (8 mL),
washed with water (3 × 4 mL) and brine (2 × 4 mL), dried
(anhydrous Na2SO4) and concentrated in vacuo to give 6 (739 mg,
93% yield) as a yellow oil, which was used as such in the next step: Rf =
0.55 (silica gel, 8 cm, EtOAc); IR (ATR) ν 2955 (w), 2928 (w), 2886
(w), 2856 (w), 1774 (w), 1698 (s), 1431 (m), 1383 (m), 1281 (m),
1252 (m), 1117 (m), 1089 (m), 1001 (m), 977 (m), 834 (s), 774 (s)
■
In conclusion, we have developed a synthetic entry to a highly
functionalized 2,8-ethanonoradamantane derivative, whose key
step consists of an intramolecular Diels−Alder reaction.
Protection of a maleimide function during the NaBH4/
CeCl3·7H2O reduction of an enone has been nicely achieved
by selective cycloaddition of the maleimide with furan,
deprotection after enone reduction being effected in refluxing
toluene. This polycyclic compound might be a new scaffold for
the preparation of compounds with potential biological activity.
EXPERIMENTAL SECTION
■
General Methods. Melting points were determined in open
capillary tubes. Chemical shifts (δ) are reported in ppm related to
internal TMS or CDCl3. Multiplicities are reported using the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad or their combinations. Assignments given for the NMR
spectra are based on DEPT, 1H/13C single quantum correlation
1
cm−1; H NMR δ 0.01 [s, 6H, Si(CH3)2], 0.86 [s, 9H, SiC(CH3)3],
1.70−1.77 [m, 2H, 4(6)-Hx], 1.85 (ttt, J = 11.2 Hz, J′ = 5.6 Hz, J″ =
5.6 Hz, 1H, 5-H), 2.14 [dd, J = 13.2 Hz, J′ = 6.0 Hz, 2H, 4(6)-Hn],
2.96 (s, 3H, N-CH3), 3.15−3.21 [m, 2H, 3a(6a)-H], 3.54 (d, J = 9.2
11275
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
1
Hz, 2H, CH2−O); 13C NMR δ −5.5 [CH3, Si(CH3)2], 18.3 [C,
SiC(CH3)3], 25.0 (CH3, N-CH3), 25.8 [CH3, SiC(CH3)3], 32.8 [CH2,
C4(6)], 40.7 (CH, C5), 45.0 [CH, C3a(6a)], 64.5 (CH2, CH2O−),
180.5 [C, C1(3)]. HRMS (ESI) (m/z) cacld for [C15H27NO3Si + H]+:
298.1833. Found: 298.1829. Anal. Calcd for C15H27NO3Si (297.47):
C, 60.57; H, 9.15; N, 4.71. Found: C, 60.51; H, 9.26; N, 4.54.
(3aRS,5RS,6aSR)-5-(t-Butyldimethylsilyloxymethyl)-2-meth-
yl-3a-(phenylselanyl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-
1,3(2H,3aH)-dione, 7. To a cold solution (−78 °C, acetone−CO2
bath) of hexamethyldisilazane (HMDS, 0.74 mL, 3.55 mmol) in
anhydrous THF (10 mL), a solution of n-BuLi in hexane (2.2 M, 1.34
mL, 2.95 mmol) was added dropwise. The reaction mixture was
allowed to warm to 0 °C (ice−water bath) and was stirred for 1 h at
this temperature. The mixture was again cooled to −78 °C, and a
solution of 6 (695 mg, 2.34 mmol) in anhydrous THF (3 mL) was
added dropwise. The reaction mixture was stirred at this temperature
for 15 min, allowed to warm to 0 °C, stirred for 1 h at this temperature
and cooled again to −78 °C. To the above reaction mixture, a solution
of benzeneselenenyl chloride (95% content, 570 mg, 2.83 mmol) in
anhydrous THF (5.2 mL) was added. The mixture was stirred for 30
min at −78 °C, allowed to warm to 0 °C, stirred for 30 min at this
temperature and then overnight at room temperature. The reaction
mixture was quenched with saturated aqueous NH4Cl solution (5
mL), water (5 mL) and Et2O (5 mL) were added, the organic phase
was separated, and the aqueous one was extracted with Et2O (2 × 5
mL). The combined organic phases were washed with water, dried
(anhydrous Na2SO4) and concentrated in vacuo. The residue (1.06 g)
was subjected to column chromatography (silica gel, 42.6 g, hexane/
EtOAc mixtures). On elution with hexane/EtOAc 9:1, in order of
elution, compound 8 (18 mg, 3% yield, 5% yield taking into account
the recovered starting compound) and 7 (368 mg, 35% yield, 56%
yield taking into account the recovered starting compound) and
starting compound 6 (260 mg) were isolated as light yellow oils.
Analytical and spectroscopic data of 7: Rf = 0,32 (silica gel, 5 cm,
hexane/EtOAc 9:1); IR (ATR) ν 2952 (w), 2923 (w), 2886 (w), 2855
(w), 1775 (w), 1700 (s), 1429 (m), 1379 (m), 1283 (m), 1252 (m),
1088 (m), 1021 (m), 1005 (m), 834 (s), 775 (s), 742 (s), 693 (m)
(m), 846 (s), 831 (s), 777 (s), 726 (m), 705 (m), 664 (m) cm−1; H
NMR δ 0.03 [s, 6H, Si(CH3)2], 0.86 [s, 9H, SiC(CH3)3], 2.43−2.58
(m, 2H) and 2.67−2.77 (m, 2H) [4(6)-Hcis and 4(6)-Htrans], 2.95 (s,
3H, N-CH3), 2.99−3.07 (m, 1H, 5-H), 3.59 (d, J = 6.0 Hz, 2H,
CH2O); 13C NMR δ −5.5 [CH3, Si(CH3)2], 18.2 [C, SiC(CH3)3],
23.7 (CH3, N-CH3), 25.8 [CH3, SiC(CH3)3], 29.5 [CH2, C4(6)], 44.8
(CH, C5), 65.6 (CH2, CH2O), 152.3 [C, C3a(6a)], 167.5 [C, C1(3)].
HRMS (ESI) (m/z) calcd for [C15H26NO3Si + H]+: 296.1676. Found:
296.1669. Anal. Calcd for C15H25NO3Si (295.45): C, 60.98%; H,
8.53%; N, 4.74. Found: C, 60.93; H, 8.67; N, 4.48.
One-Pot Preparation of 8 from 6. To a cold solution (−78 °C,
acetone−CO2 bath) of HMDS (2.77 mL, 13.2 mmol) in anhydrous
THF (40 mL), a solution of n-BuLi in hexane (2.15 M, 5.1 mL, 11.0
mmol) was added dropwise. The reaction mixture was allowed to
warm to 0 °C (ice−water bath) and was stirred for 1 h at this
temperature. The mixture was again cooled to −78 °C, and a solution
of 6 (2.60 g, 8.74 mmol) in anhydrous THF (15 mL) was added
dropwise. The reaction mixture was stirred at this temperature for 15
min, allowed to warm to 0 °C, stirred for 1 h at this temperature and
cooled again to −78 °C. To the above reaction mixture, a solution of
benzeneselenenyl chloride (98% content, 2.07 g, 10.6 mmol) in
anhydrous THF (20 mL) was added. The mixture was stirred for 30
min at −78 °C, allowed to warm to 0 °C, stirred for 30 min at this
temperature and then overnight at room temperature. The reaction
mixture was quenched with saturated aqueous NH4Cl solution (18
mL), water (18 mL) and Et2O (30 mL) were added, the organic phase
was separated, and the aqueous one was extracted with Et2O (2 × 30
mL). The combined organic phases were washed with water, dried
(anhydrous Na2SO4) and concentrated in vacuo. The residue (4.10 g)
was used as such for the next step.
To a cold (0 °C, ice−water bath) and stirred solution of the above
crude product (4.10 g) in CH2Cl2 (60 mL), a solution of H2O2 35%
(2.8 mL) in water (5.5 mL) was added dropwise, keeping the
temperature around 0 °C. The reaction mixture was allowed to warm
to room temperature and stirred for 1 h at this temperature. A
saturated aqueous NaHCO3 solution (7 mL) was added, the organic
phase was separated, and the aqueous one was extracted with CH2Cl2
(2 × 11 mL). The combined organic phases were washed with water,
dried (anhydrous Na2SO4) and concentrated in vacuo. The residue
(2.73 g) was subjected to column chromatography (silica gel, 82 g,
hexane/EtOAc mixtures). In order of elution, product 8 (725 mg, 28%
total yield from 6, 53% yield taking into account the recovered starting
6, hexane/EtOAc 9:1), as light yellow oil, and starting compound 6
(1.23 g, hexane/EtOAc 85:15) were isolated.
1
cm−1; H NMR δ 0.00 [s, 6H, Si(CH3)2], 0.86 [s, 9H, SiC(CH3)3],
1.73 (dd, J = 12.0 Hz, J′ = 12.8 Hz, 1H, 4-Hx), 1.82−1.91 (complex
signal, 2H, 5-H and 6-Hx), 1.98−2.11 (m, 1H, 6-Hn), 2.45−2.50 (m,
1H, 4-Hn), 2.74 (s, 3H, N-CH3), 3.20 (d, J = 9.6 Hz, 1H, 6a-H), 3.52
(d, J = 4.8 Hz, 2H, CH2−O), 7.27−7.39 [tm, J = 7.4 Hz, 2H, Ar-3(5)-
H], 7.36−7.40 (tm, J = 7.4 Hz, 1H, Ar-4-H), 7.59−7.61 [dd, J = 8.2
Hz, J′ = 1.2 Hz, 2H, Ar-2(6)-H]; 13C NMR δ −5.5 [CH3, Si(CH3)2],
18.3 [C, SiC(CH3)3], 25.1 (CH3, N-CH3), 25.8 [CH3, SiC(CH3)3],
32.3 (CH2, C4), 39.4 (CH2, C6), 41.6 (CH, C5), 53.2 (CH, C6a),
53.9 (C, C3a), 64.0 (CH2, CH2−O), 125.9 (C, Ar−C1), 129.2 [CH,
Ar−C3(5)], 129.8 (CH, Ar−C4), 137.3 [CH, Ar−C2(6)], 178.2 (C,
C3), 179.1 (C, C1). HRMS (ESI) (m/z) calcd for [C21H32NO380SeSi
+ H]+: 454.1326. Found: 454.1311. Anal. Calcd for C21H31NO3SeSi
(452.52): C, 55.74; H, 6.90; N, 3.10. Found: C, 56.21; H, 7.05; N,
3.12.
5-{[(t-Butyldimethylsilyl)oxy]methyl}-2-methyl-5,6-dihydro-
cyclopenta[c]pyrrole-1,3(2H,4H)-dione, 8. To a cold (0 °C, ice−
water bath) and stirred solution of 11 (408 mg, 0.90 mmol) in CH2Cl2
(10 mL), a solution of H2O2 35% (0.63 mL) in water (1.26 mL) was
added dropwise, keeping the temperature around 0 °C. The reaction
mixture was allowed to warm to room temperature and stirred for 1 h
at this temperature. A saturated aqueous NaHCO3 solution (1.2 mL)
was added. The organic phase was separated, and the aqueous one was
extracted with CH2Cl2 (3 × 5 mL). The combined organic phases
were washed with water, dried (anhydrous Na2SO4) and concentrated
in vacuo. The residue (261 mg) was subjected to column
chromatography (silica gel, 6.5 g, hexane/EtOAc mixtures). On
elution with hexane/EtOAc 95:5, product 8 (210 mg, 79% yield) was
isolated as light yellow oil. An analytical sample of 8 was obtained as a
white solid on drying at 10−2 Torr: mp 38−40 °C; Rf = 0.26 (silica gel,
7.4 cm, hexane/EtOAc 9:1); IR (ATR) ν 2951 (w), 2923 (w), 2881
(w), 2852 (w), 1769 (w), 1713 (s), 1704 (s), 1470 (w), 1432 (m),
1375 (m), 1366 (m), 1246 (m), 1103 (m), 1082 (m), 1061 (m), 982
(3aRS,5RS,6aSR)-5-(Hydroxymethyl)-2-methyl-3a-(phenylse-
lanyl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-
dione, 9. To a cold (0 °C, ice−water bath) solution of 7 (234 mg,
0.52 mmol) in anhydrous THF (7 mL), a solution of tetrabuty-
lammonium fluoride (TBAF) in THF (1M, 0.67 mL, 0.67 mmol) was
added dropwise, and the mixture was stirred for 2 h at room
temperature under an Ar atmosphere. Saturated aqueous NH4Cl
solution (0.4 mL) was added, the mixture was stirred for 10 min, the
solvents were evaporated under reduced pressure, and the residue
(450 mg) was subjected to column chromatography (silica gel, 9 g,
hexane/EtOAc mixtures). On elution with hexane/EtOAc 4:6, product
9 (144 mg, 82% yield) was isolated as a brown oil: Rf = 0.25 (silica gel,
6 cm, hexane/EtOAc 4:6); IR (ATR) ν 3300−3600 (w, OH st), 2939
(w), 2872 (w), 1770 (w), 1691 (s), 1430 (m), 1379 (m), 1283 (m),
1085 (m), 1021 (m), 743 (m), 693 (m) cm−1; H NMR δ 1.56 (br s,
1
1H, OH), 1.66 (s, H2O), 1.73 (dd, J = 13.2 Hz, J′ = 11.6 Hz, 1H, 4-
Hx), 1.80−1.88 (m, 1H, 6-Hx), 1.87−1.97 (m, 1H, 5-H), 2.09−2.14
(ddm, J = 12.7 Hz, J′ = 5.8 Hz, 1H, 6-Hn), 2.52−2.57 (ddm, J = 13.2
Hz, J′ = 4.0 Hz, 1H, 4-Hn), 2.74 (s, 3H, N-CH3), 3.21−3.24 (dm, J =
9.2 Hz, 1H, 6a-H), 3.58 (d, J = 3.2 Hz, 2H, CH2OH), 7.28−7.32 [tm, J
= 7.6 Hz, 2H, Ar-3(5)-H], 7.37−7.44 (tm, J = 7.4 Hz, 1H, Ar-4-H),
7.59−7.62 [dm, J = 7.6 Hz, 2H, Ar-2(6)-H]; 13C NMR δ 25.1 (CH3,
N-CH3), 32.5 (CH2, C6), 39.5 (CH2, C4), 41.6 (CH, C5), 53.1 (CH,
C6a), 53.7 (C, C3a), 64.2 (CH2, CH2OH), 125.8 (C, Ar−C1), 129.2
[CH, Ar−C3(5)], 129.9 (CH, Ar−C4), 137.1 [CH, Ar−C2(6)], 178.0
(C, C3), 179.0 (C, C1). HRMS (ESI) (m/z) calcd for
11276
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
[C15H17NO380Se + H]+: 340.0446. Found: 340.0449. Anal. Calcd for
C15H17NO3Se (338.26): C, 53.26; H, 5.07; N, 4.14. Found: C, 52.92;
H, 5.24; N, 3.96.
product 13 (398 mg, 91% yield) was isolated as light yellow oil: Rf =
0.15 (silica gel, 6.5 cm, hexane/EtOAc 4:6); IR (ATR) ν 3600−3150
(m, OH st), 2941 (w), 2863 (w) 1772 (w), 1688 (s), 1432 (m), 1376
1
(3aRS,5RS,6aSR)-2-Methyl-3a-(phenylselanyl)-5-(tosyloxy-
methyl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-
dione, 10, and (3aRS,5RS,6aSR)-5-(Chloromethyl)-2-methyl-3a-
(phenylselanyl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3-
(2H,3aH)-dione, 11. To a cold (0 °C, ice−water bath) solution of
alcohol 9 (708 mg, 2.09 mmol) in anhydrous pyridine (7 mL), tosyl
chloride (599 mg, 3.14 mmol) was slowly added in 20 min, and the
reaction mixture was stirred at room temperature overnight. Aqueous
HCl (2N, 50 mL) was added, and the mixture was extracted with
EtOAc (3 × 50 mL). The combined organic extracts were washed with
water (30 mL) and brine (30 mL), dried (anhydrous Na2SO4) and
concentrated in vacuo. The residue (1.01 g) was subjected to column
chromatography (silica gel, 30 g, hexane/EtOAc mixtures). On elution
with hexane/EtOAc 7:3, a mixture of chlorides 11 and 12 as orange oil
(m), 1242 (m), 1067 (m), 1032 (m), 983 (m), 723 (m) cm−1; H
NMR δ 2.43−2.50 (m, 2H) and 2.70−2.79 (m, 2H) [4(6)-Hcis and
4(6)-Htrans], 2.54−2.66 (br s, 1H, OH), 2.91 (s, 3H, N−CH3), 2.99−
3.09 (m, 1H, 5-H), 3.62 (d, J = 6.4 Hz, 2H, CH2OH); 13C NMR δ
23.7 (CH3, N−CH3), 29.4 [CH2, C4(6)], 44.4 (CH, C5), 65.3 (CH2,
CH2OH), 152.2 [C, C3a(6a)], 167.4 [C, C1(3)]. HRMS (ESI) (m/z)
calcd for [C9H11NO3 + H]+: 182.0812. Found: 182.0815. Anal. Calcd
for C9H11NO3·0.4H2O (188.40): C, 57.38; H, 6.31; N, 7.43. Found: C,
57.65; H, 6.42; N, 7.23.
b. By Reaction of Compound 8 with Tetrabutylammonium
Fluoride. To a cold (0 °C, ice−water bath) solution of 8 (110 mg, 0.37
mmol) in anhydrous THF (4 mL), a solution of tetrabutylammonium
fluoride (TBAF) in THF (1M, 0.48 mL, 0.48 mmol) was added
dropwise, and the mixture was stirred for 2 h at room temperature
under an Ar atmosphere. Saturated aqueous NH4Cl solution (0.3 mL)
was added, the mixture was stirred for 10 min, the solvents were
evaporated under reduced pressure, and the residue (271 mg) was
subjected to column chromatography (silica gel, 6 g, hexane/EtOAc
mixtures). On elution with hexane/EtOAc 1:1, impure product 13 (20
mg, 30% yield) was isolated as a brown oil.
2-Methyl-5-(tosyloxymethyl)-5,6-dihydrocyclopenta[c]-
pyrrole-1,3(2H,4H)-dione, 14, and 5-(Chloromethyl)-2-methyl-
5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione, 12. To a
cold (0 °C, ice−water bath) solution of alcohol 13 (526 mg, 2.90
mmol) in anhydrous pyridine (9.1 mL), tosyl chloride (830 mg, 4.35
mmol) was slowly added in 25 min, and the reaction mixture was
stirred at room temperature overnight. Aqueous HCl (1 N, 60 mL)
was added, and the mixture was extracted with EtOAc (3 × 70 mL).
The combined organic extracts were washed with water (60 mL) and
brine (60 mL), dried (anhydrous Na2SO4) and concentrated in vacuo.
The yellow solid residue (870 mg) was subjected to column
chromatography (silica gel, hexane/EtOAc mixtures). In order of
elution, chloro compound 12 (116 mg, 20% yield, hexane/EtOAc 8:2)
and tosylate 14 (750 mg, 77% yield, hexane/EtOAc 7:3) were
obtained as a light yellow oil and a beige solid, respectively. The
analytical sample of tosylate 14 (39 mg) was obtained as a white solid
by crystallization of a sample of 14 (62 mg) from EtOAc (0.6 mL): mp
134−136 °C.
Analytical and Spectroscopic Data of 14. Rf = 0.36 (silica gel, 8.5
cm, hexane/EtOAc 1:1); IR (ATR) ν 2954 (w), 2911 (w), 1773 (w),
1711 (m), 1697 (s), 1596 (w), 1435 (m), 1380 (m), 1357 (s), 1307,
1187 (m), 1173 (s), 989 (m), 952 (s), 880 (m), 842 (m), 823 (m),
807 (m), 790 (m), 765 (m), 721 (m), 667 (s) cm−1; 1H NMR δ 2.37−
2.46 (m, 2H) and 2.74−2.83 (m, 2H) [4(6)-Hcis and 4(6)-Htrans], 2.45
(s, 3H, Ar−CH3), 2.94 (s, 3H, N−CH3), 3.14−3.25 (m, 1H, 5-H),
4.04 (d, J = 6.4 Hz, 2H, CH2OTs), 7.36 (d, J = 8.2 Hz, 2H, Ar-3(5)-
H), 7.78 (dm, J = 8.2 Hz, 2H, Ar-2(6)-H); 13C NMR δ 21.6 (CH3,
Ar−CH3), 23.8 (CH3, N-CH3), 29.6 [CH2, C4(6)], 41.4 (CH, C5),
71.7 (CH2, CH2OTs), 127.9 [CH, Ar−C2(6)], 130.0 [CH, Ar−
C3(5)], 132.6 (C, Ar−C1), 145.2 (C, Ar−C4), 151.5 [C, C3a(6a)],
166.7 [C, C1(3)]. HRMS (ESI) (m/z) calcd for [C16H17NO5S + H]+:
336.0900. Found: 336.0908. Anal. Calcd for C16H17NO5S (335.37): C,
57.30; H, 5.11; N, 4.18; S, 9.56. Found: C, 57.11; H, 4.97; N, 4.17; S,
9.38.
1
(approximate ratio by H NMR: 4.4:1, 50 mg, 7% yield) and tosylate
10 as yellow oil (800 mg, 78% yield) were obtained.
Analytical and Spectroscopic Data of 10. Rf = 0.51 (silica gel, 4.5
cm, hexane/EtOAc 1:1); IR (ATR) ν 3058 (w), 2949 (w), 2890 (w),
1772 (w), 1697 (s), 1597 (w), 1430 (m), 1379 (m), 1361 (m), 1287
(m), 1188 (m), 1174 (s), 1094 (m), 1020 (w), 963 (m), 813 (m), 743
(m), 693 (m), 665 (m) cm−1; 1H NMR δ 1.60 (s, H2O), 1.65 (dd, J =
13.0 Hz, J′ = 11.8 Hz, 1H, 4-Hx), 1.76 (dt, J = 12.0 Hz, J′ = 10.4 Hz,
1H, 6-Hx), 1.99 (ttt, J = 11.6 Hz, J′ = 6.0 Hz, J″ = 6.0 Hz, 1H, 5-H),
2.04−2.09 (ddm, J = 12.6 Hz, J′ = 5.8 Hz, 1H, 6-Hn), 2.45 (s, 3H, Ar−
CH3), 2.49 (ddd, J = 13.2 Hz, J′ = 5.6 Hz, J″ = 1.2 Hz, 1H, 4-Hn), 2.72
(s, 3H, N-CH3), 3.17 (d, J = 10.4 Hz, 1H, 6a-H), 3.93 (d, J = 5.6 Hz,
2H, CH2OTs), 7.28−7.32 [m, 2H, Ar-3(5)-H Ar−Se], 7.34 [d, J = 8.2
Hz, 2H, Ar-3(5)-H, Ts], 7.38−7.42 (tm, J = 7.4 Hz, 1H, Ar-4-H, Ar−
Se), 7.55−7.58 [dm, J = 8.0 Hz, 2H, Ar-2(6)-H, Ar−Se], 7.75 [d, J =
8.2 Hz, 2H, Ar-2(6)-H, Ts]; 13C NMR δ 21.6 (CH3, Ar−CH3), 25.2
(CH3, N-CH3), 32.3 (CH2, C6), 38.4 (CH, C5), 39.2 (CH2, C4), 52.7
(CH, C6a), 53.0 (C, C3a), 70.4 (CH2, CH2OTs), 125.5 (C, Ar−C1,
PhSe), 127.9 [CH, Ar−C2(6), Ts], 129.3 [CH, Ar−C3(5), PhSe],
129.9 [CH, Ar−C3(5), Ts], 130.0 (CH, Ar−C4, PhSe), 132.6 (C, Ar−
C1, Ts), 137.9 [CH, Ar−C2(6), PhSe], 145.1 (C, Ar−C4, Ts), 177.3
(C, C3), 178.4 (C, C1). HRMS (ESI) (m/z) calcd for
[C22H23NO5S80Se + H]+: 494.0534. Found: 494.0543. Anal. Calcd
for C22H23NO5SSe (492.45): C, 53.66; H, 4.71; N, 2.84. Found: C,
54.06; H, 4.77; N, 2.65.
Analytical and Spectroscopic Data of 11 from the Spectra of Its
Mixture with 12. Rf = 0.62 (silica gel, 4,5 cm, hexane/EtOAc 1:1); IR
(ATR) ν 2946 (w), 2860 (w), 1772 (w), 1696 (s), 1429 (m), 1378
(m), 1292 (m), 1278 (m), 1087 (m), 1020 (m), 741 (m), 729 (m),
693 (m) cm−1; 1H NMR δ 1.80 (dd, J = 12.6 Hz, J′ = 11.6 Hz, 1H, 4-
Hx), 1.83−1.94 (ddd, J = 12.4 Hz, J′ = 12.0 Hz, J″ = 10.4 Hz, 1H, 6-
Hx), 2.02−2.15 (dt, J = 12.0 Hz, J′ = 6.0 Hz, 1H, 5-H), 2.15−2.20
(ddm, J = 12.8 Hz, J′ = 6.0 Hz, 1H, 6-Hn), 2.49 (ddd, J = 12.8 Hz, J′ =
5.6 Hz, J″ = 1.6 Hz, 1H, 4-Hn), 2.76 (s, 3H, N-CH3), 3.23 (d, J = 9.6
Hz, 1H, 6a-H), 3.47 (dd, J = 12.0, J′ = 6.0 Hz, 1H) and 3.49 (dd, J =
12.0, J′ = 6.0 Hz, 1H) (CH2Cl), 7.29−7.33 [m, 2H, Ar-3(5)-H Ar−
Se], 7.40 (tm, J = 7.4 Hz, 1H, Ar-4-H, Ar−Se), 7.59−7.63 [dm, J = 8.0
Hz, 2H, Ar-2(6)-H, Ar−Se]; 13C NMR δ 25.2 (CH3, N-CH3), 33.4
(CH2, C6), 40.4 (CH2, C4), 41.1 (CH, C5), 45.9 (CH2, CH2Cl), 52.9
(CH, C6a), 53.3 (C, C3a), 125.6 (C, Ar−C1, PhSe), 129.3 [CH, Ar−
C3(5), PhSe], 130.0 (CH, Ar−C4, PhSe), 137.1 [CH, Ar−C2(6),
PhSe], 177.6 (C, C1), 177.7 (C, C3). HRMS (ESI) (m/z) calcd for
[C15H16ClNO280Se + H]+: 358.0113. Found: 358.0106.
Analytical and Spectroscopic Data of 12. Rf = 0.49 (silica gel, 8.5
cm, hexane/EtOAc 1:1); IR (ATR) ν 2954 (w), 2922 (w), 2847 (w),
1773 (w), 1694 (s), 1431 (m), 1375 (m), 1243 (w), 983 (m), 728 (m)
1
cm−1; H NMR δ 2.54−2.63 (m, 2H) and 2.83−2.92 (m, 2H) [4(6)-
5-(Hydroxymethyl)-2-methyl-5,6-dihydrocyclopenta[c]-
pyrrole-1,3(2H,4H)-dione, 13. a. By Reaction of Compound 8
with 1 N HCl. To a solution of 8 (715 mg, 2.42 mmol) in THF (18
mL), HCl (1M, 24.2 mL, 24.2 mmol) was added dropwise, and the
reaction mixture was stirred for 2 h at room temperature. Saturated
aqueous NaHCO3 solution (28 mL) was added, and the mixture was
extracted with EtOAc (3 × 60 mL). The combined organic extracts
were dried (anhydrous Na2SO4) and concentrated in vacuo. The
residue (521 mg) was subjected to column chromatography (silica gel,
10.5 g, hexane/EtOAc mixtures). On elution with hexane/EtOAc 4:6,
Hcis and 4(6)-Htrans], 2.96 (s, 3H, N-CH3), 3.25−3.32 (m, 1H, 5-H),
3.63 (d, J = 6.0 Hz, 2H, CH2Cl); 13C NMR δ 23.8 [CH3, N-CH3],
30.9 [CH2, C4(6)], 44.4 [CH, C5], 48.2 [CH2, CH2Cl], 151.6 [C,
C3a(6a)], 167.0 [C, C1(3)]. Anal. Calcd for C9H10ClNO2: C, 54.15;
H, 5.05; N, 7.02; Cl, 17.76. calcd for C9H10ClNO2·0.1H2O·0.1hexane
(210.06): C, 54.89; H, 5.57; N, 6.67; Cl, 16.88. Found: C, 54.69; H,
5.46; N, 6.62; Cl, 16.79.
Tosylate 14 from 10. To a cold (0 °C, ice−water bath) and
stirred solution of 10 (190 mg, 0.39 mmol) in CH2Cl2 (3 mL), a
11277
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
solution of H2O2 35% (0.27 mL) in water (0.54 mL) was added
dropwise, keeping the temperature around 0 °C. The reaction mixture
was allowed to warm to room temperature and stirred for 1 h at this
temperature. A saturated aqueous NaHCO3 solution (0.5 mL) was
added. The organic phase was separated, and the aqueous one was
extracted with CH2Cl2 (3 × 3 mL). The combined organic phases
were washed with water, dried (anhydrous Na2SO4) and concentrated
in vacuo. The residue (132 mg) was subjected to column
chromatography (silica gel, 3.3 g, hexane/EtOAc mixtures). On
elution with hexane/EtOAc 8:2, product 14 (128 mg, 99% yield) was
isolated as light yellow solid.
C5), 42.9 (CH2, C4), 43.5 (CH2, C3′), 53.3 (CH, C6a), 53.8 (C,
C3a), 125.8 (C, Ar−C1), 128.1 (CH, C2′), 129.2 [CH, Ar−C3(5)],
129.8 (CH, Ar−C4), 131.1 (CH, C4′), 132.3 (CH, C5′), 137.1 [CH,
Ar−C2(6)], 146.4 (C, C1′), 178.1 (C, C1), 179.1 (C, C3).
H2O2 Oxidation of the Mixture of 15 and 16. To a cold (0 °C,
ice−water bath) and stirred solution of the tautomeric mixture 15 and
16 (113 mg, 0.29 mmol) in CH2Cl2 (20 mL), a solution of H2O2 35%
(0.20 mL) in water (0.40 mL) was added dropwise, keeping the
temperature around 0 °C. The reaction mixture was allowed to warm
to room temperature and stirred for 1 h at this temperature. A
saturated aqueous NaHCO3 solution (0.5 mL) and water (1 mL) were
added. The organic phase was separated, and the aqueous one was
extracted with CH2Cl2 (2 × 3 mL). The combined organic phases
were washed with water, dried (anhydrous Na2SO4) and concentrated
in vacuo. The residue (90 mg) was subjected to column
chromatography (silica gel, 6.5 g, hexane/EtOAc mixtures). None of
the obtained fractions contained the expected product 1 (R = H) or its
precursor 2 (R = H).
Reaction of Tosylate 14 with Sodium Cyclopentadienide. A
1.08 M THF solution of sodium cyclopentadienide was prepared by
dropwise addition of freshly distilled cyclopentadiene (0.88 mL, 10.8
mmol) to a cold (0 °C, ice−water bath) mixture of NaH (275 mg,
95% content, 10.9 mmol) in anhydrous THF (10 mL). The above
solution (1.05 mL, 1.1 mmol) was added dropwise under an Ar
atmosphere to a cold (−41 °C, cryocool) solution of 14 (316 mg, 0.94
mmol) in anhydrous THF (4 mL), and the mixture was stirred at −41
°C for 1.5 h. The reaction mixture was concentrated in vacuo, and the
residue (566 mg) was subjected to column chromatography (silica gel,
11 g, hexane/EtOAc mixtures). None of the obtained fractions showed
5-(Methanesulfonyloxymethyl)-2-methyl-5,6-dihydrocyclo-
penta[c]pyrrole-1,3(2H,4H)-dione, 17. To a cold (0 °C, ice−water
bath) solution of alcohol 13 (205 mg, 1.13 mmol) and anhydrous
Et3N (0.36 mL, 262 mg, 2.6 mmol) in CH2Cl2 (12 mL), mesyl
chloride (0.11 mL, 155 mg, 1.35 mmol) was added dropwise, and the
reaction mixture was stirred at 0 °C for 7 h and allowed to stand at 4
°C overnight. Saturated aqueous NaHCO3 solution (1.5 mL) and
water (5 mL) were added. The organic phase was separated, and the
aqueous one was extracted with CH2Cl2 (2 × 7 mL). The combined
organic extracts were washed with water (10 mL) and brine (10 mL),
dried (anhydrous Na2SO4) and concentrated in vacuo to give mesylate
17 (284 mg, 97% yield) as a thick light yellow oil that solidified on
standing. On trituration of part of the above product (256 mg) with
EtOAc (0.7 mL), a white solid (125 mg) was obtained: mp 104−105
°C; Rf = 0.29 (silica gel, 8.3 cm, hexane/EtOAc 2:3); IR (ATR) ν 2940
(w), 1772 (w), 1695 (s), 1432 (m), 1375 (m), 1347 (s), 1170 (s), 977
(s), 950 (s), 838 (m), 813 (m), 725 (m) cm−1; 1H NMR δ 2.50−2.58
(m, 2H) and 2.84−2.93 (m, 2H) [4(6)-Hsyn and 4(6)-Hanti], 2.96 (s,
3H, N−CH3), 3.03 (s, 3H, CH3SO2), 3.25−3.35 (m, 1H, 5-H), 4.24
(d, J = 6.8 Hz, 2H, CH2OMs); 13C NMR δ 23.9 (CH3, N-CH3), 29.6
[CH2, C4(6)], 37.5 (CH3, CH3SO2), 41.6 (CH, C5), 70.9 (CH2,
CH2OMs), 151.5 [C, C3a(6a)], 166.7 [C, C1(3)]. HRMS (ESI) (m/
z) calcd for [C10H13NO5S + H]+: 260.0587. Found: 260.0582. Anal.
Calcd for C10H13NO5S (259.28): C, 46.32; H, 5.05; N, 5.40; S, 12.37.
Found: C, 45.98; H, 4.93; N, 5.31; S, 12.19.
1
by H NMR the presence of the expected polycycle 1 (R = H), its
precursor 2 (R = H), tautomers or other derivatives of 2 (R = H).
Mixture of (3aRS,5SR,6aSR)-5-[(Cyclopenta-1,3-dien-1-yl)-
methyl]-2-methyl-3a-(phenylselanyl)-4,5,6,6a-tetrahydro-
cyclopenta[c]pyrrole)-1,3(2H,3aH)-dione, 15, and (3aRS,5S-
R,6aSR)-5-[(Cyclopenta-1,4-dien-1-yl)methyl]-2-methyl-3a-
(phenylselanyl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole)-1,3-
(2H,3aH)-dione, 16. A 1.08 M THF solution of sodium cyclo-
pentadienide was prepared by dropwise addition of freshly distilled
cyclopentadiene (0.88 mL, 10.8 mmol) to a cold (0 °C, ice−water
bath) mixture of NaH (275 mg, 95% content, 10.9 mmol) in
anhydrous THF (10 mL). The above solution (1 mL, 1.08 mmol) was
added dropwise under an Ar atmosphere to a cold (−41 °C, cryocool)
solution of 10 (443 mg, 0.90 mmol) in anhydrous THF (4 mL), and
the mixture was stirred at −41 °C for 1.5 h and then at room
temperature for 1.5 h. The reaction mixture was concentrated in
vacuo, and the residue (1.1 g) was subjected to column
chromatography (silica gel, 14 g, hexane/EtOAc mixtures) to give
on elution with hexane/EtOAc 95:5 a mixture of products 15 and 16
in an approximate ratio of 15/16 = 3:2 (1H NMR) (160 mg, 46%
yield) as yellow oil: Rf = 0.64 (silica gel, 6.4 cm, hexane/EtOAc 1:1)
Spectroscopic Data of the Tautomeric Mixture 15 and 16. IR
(ATR) ν 3060 (w), 2949 (w), 1772 (w), 1697 (s), 1428 (m), 1377
(m), 1281 (m), 1086 (m), 1020 (m), 742 (m), 692 (m), 673 (m)
cm−1. HRMS (ESI) (m/z) calcd for [C20H21NO280Se + H]+: 388.0810.
Found: 388.0812.
5-(Iodomethyl)-2-methyl-5,6-dihydrocyclopenta[c]pyrrole-
1,3(2H,4H)-dione, 18. a. From Tosylate 14. A magnetically stirred
mixture of tosylate 14 (710 mg, 2,12 mmol) and NaI (3.18 g, 21.2
mmol) in anhydrous acetone (30 mL) was heated at 56 °C for 13 h
under an Ar atmosphere. The mixture was allowed to cool to room
temperature, the precipitate was filtered through a pad of Celite, and
the solid was washed with EtOAc (40 mL). The combined filtrate and
washings were concentrated in vacuo, and the residue (3.35 g) was
subjected to column chromatography (silica gel, 15 g, hexane/EtOAc
mixtures) to give iodide 18 (603 mg, 98% yield), as a light yellow
solid. The analytical sample of 18 (422 mg) was obtained as white
solid, mp 89−90 °C, by crystallization of the above product from
EtOAc (1.5 mL): Rf = 0.58 (silica gel, 9.5 cm, hexane/EtOAc 1:1); IR
(ATR) ν 2952 (w), 2928 (w), 2902 (w) and 2833 (w) (C−H st),
1766 (w), 1711 (s), 1692 (s) and 1652 (m) (CO st), 1428 (s),
1373 (s), 1237 (m), 1206 (m), 1184 (m), 984 (s), 756 (m), 725 (m),
NMR Data of 15 Obtained from the Spectra of Its Mixture with
1
16. H NMR δ 1.55−1.63 (m, 1H, 4-Hx), 1.65−1.75 (m, 1H, 6-Hx),
1.79−1.93 (m, 1H, 5-H), 2.10−2.16 (m, 1H, 6-Hn), 2.37−2.44 (m,
2H, CH2-C5H5), 2.54−2.60 (m, 1H, 4-Hn), 2.72 (s, 3H, N-CH3), 2.91
(q, J = 1.5 Hz, 2H, 5′-H2), 3.19 (br s, 1H, 6a-H), 5.96−5.98 (m, 1H,
2′-H), 6.29−6.32 (dq, J = 4.8 Hz, J′ = 1.5 Hz, 1H, 4′-H), 6.36−6.39
(m, 1H, 3′-H), 7.27−7.31 [m, 2H, Ar-3(5)-H], 7.39 (tm, J = 7.2 Hz,
1H, Ar-4-H), 7.56−7.59 [dm, J = 8.0 Hz, 2H, Ar-2(6)-H]; 13C NMR δ
25.1 (CH3, N-CH3), 33.9 (CH2, C5-CH2), 35.8 (CH2, C6), 39.1 (CH,
C5), 41.3 (CH2, C5′), 42.8 (CH2, C4), 53.3 (CH, C6a), 53.9 (C,
C3a), 125.8 (C, Ar−C1), 127.6 (CH, C2′), 129.2 [CH, Ar−C3(5)],
129.8 (CH, Ar−C4), 134.2 (CH, C3′), 134.4 (CH, C4′), 137,1 [CH,
Ar−C2(6)], 144.3 (C, C1′), 178.2 (C, C1), 179.1 (C, C3).
1
692 (m) cm−1; H NMR δ 2.43−2.51 (m, 2H) and 2.84−2.93 (m,
2H) [4(6)-Hcis and 4(6)-Htrans], 2.97 (s, 3H, N-CH3), 3.07−3.18 (m,
1H, 5-H), 3.34 (d, J = 6.4 Hz, 2H, CH2I); 13C NMR δ 12.3 (CH2,
CH2I), 23.9 (CH3, N-CH3), 34.1 [CH2, C4(6)], 44.4 (CH, C5), 151.4
[CH, C3a(6a)], 167.1 [C, C1(3)]. HRMS (ESI) (m/z) calcd for
[C9H10INO2 + H]+: 291.9829. Found: 291.9832. Anal. Calcd for
C9H10INO2 (291.09): C 37.14, H 3.46, N 4.81, I 43.60. Found: C
37.49, H 3.50, N 5.14, I, 43.77.
NMR Data of 16 Obtained from the Spectra of Its Mixture with
1
15. H NMR δ 1.55−1.63 (m, 1H, 4-Hx), 1.65−1.75 (m, 1H, 6-Hx),
1.79−1.93 (m, 1H, 5-H), 2.10−2.16 (m, 1H, 6-Hn), 2.37−2.44 (m,
2H, CH2-C5H5), 2.54−2.60 (m, 1H, 4-Hn), 2.73 (s, 3H, N-CH3), 2.79
(q, J = 1.5 Hz, 2H, 3′-H2), 3.21 (br s, 1H, 6a-H), 6.11−6.13 (m, 1H,
2′-H), 6.22−6.24 (dq, J = 5.2 Hz, J′ = 1.5 Hz, 1H, 4′-H), 6.36−6.39
(m, 1H, 5′-H), 7.27−7.31 [m, 2H, Ar-3(5)-H], 7.39 (tm, J = 7.2 Hz,
1H, Ar-4-H), 7.56−7.59 [dm, J = 8.0 Hz, 2H, Ar-2(6)-H]; 13C NMR δ
25.1 (CH3, N-CH3), 34.9 (CH2, C5-CH2), 36.0 (CH2, C6), 39.8 (CH,
b. From Mesylate 17. A magnetically stirred mixture of mesylate 17
(105 mg, 0,40 mmol) and NaI (607 mg, 4.0 mmol) in anhydrous
acetone (5 mL) was heated at 56 °C for 16 h under an Ar atmosphere.
11278
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
The mixture was allowed to cool to room temperature, the precipate
was filtered through a pad of Celite, and the solid was washed with
EtOAc (15 mL). The combined filtrate and washings were
concentrated in vacuo, and the residue (664 mg) was subjected to
column chromatography (silica gel, 4 g, hexane/EtOAc mixtures). On
elution with hexane/EtOAc 4:1, iodide 18 (116 mg, 98% yield) was
obtained as a light yellow solid.
content, 1.50 mmol) was added, and the mixture was stirred for 16 h at
room temperature. The suspension was filtered through a pad of
Celite, and the solid was washed with EtOAc. The combined filtrate
and washings were concentrated in vacuo; the residue was taken in
EtOAc (20 mL) and washed with water (12 mL). The organic phase
was extracted with EtOAc (2 × 18 mL). The combined organic phase
and washings were washed with brine (2 × 7 mL), dried (anhydrous
Na2SO4) and concentrated in vacuo. The brown oily residue (480 mg)
was subjected to column chromatography (silica gel, 24 g, hexane/
EtOAc mixtures. On elution with hexane/EtOAc 3:1, keto ester 19 (47
mg) was recovered. On elution with hexane/EtOAc 7:3 to 6:4, enone
21 (396 mg, 87% yield from keto ester 19) was obtained as a light
brown solid. Crystallization of a sample (265 mg) of the above product
from EtOAc (0.7 mL) and pentane (3 drops) gave the analytical
sample of 21 (158 mg) as white solid: mp 87−89 °C; Rf = 0.22 (silica
gel, 9 cm, hexane/EtOAc 1:1); IR (ATR) ν 3063 (w), 2948 (w), 2912
(w), 2844 (w), 1768 (w), 1744 (w), 1701 (s) and 1693 (s), 1590 (w),
1433 (m), 1374 (m), 1352 (w), 1273 (w), 1243 (m), 1205 (m), 1177
(m), 1164 (m), 982 (m), 829 (w), 753 (m), 723 (m) cm−1; 1H NMR
δ 2.12 (dd, J = 14.4 Hz, J′ = 7.2 Hz, 1H, C5′-CHa), 2.28−2.38
(complex signal, 3H, 4′-Ha, 6′-Ha and C5′-CHb, contains at 2.35, dd, J
= 14.4 Hz, J′ = 5.8 Hz), 2.67 (dt, J = 19.2 Hz, J′ = 2.4 Hz, 1H, 5-Ha),
2.66−2.87 (complex signal, 3H, 4′-Hb, 5′-H and 6′-Hb), 2.93 (s, 3H,
N-CH3), 3.33 (dt, J = 19.2 Hz, J′ = 2.4 Hz, 1H, 5-Hb), 3.71 (s, 3H,
COOCH3), 6.20 (dt, J = 10.0 Hz, J′ = 5.8 Hz, 1H, 3-H), 7.80 (dt, J =
10.0 Hz, J′ = 6.4 Hz, 1H, 4-H); 13C NMR δ 23.7(CH3, N-CH3), 33.81
(CH2) and 33.83 (CH2) (C4′ and C6′), 39.4 (CH2, C5), 39.8 (CH2,
C5′-CH2), 40.6 (CH, C5′), 52.9 (CH3, COOCH3), 57.6 (C, C1),
132.2 (CH, C3), 151.9 (C) and 152.2 (C) (C3a′ and C6a′), 163.6
(CH, C4), 167.1 (C, C1′ and C3′), 170.8 (C, COOMe), 204.8 (C,
C2). HRMS (ESI) (m/z) calcd for [C16H17NO5 + H]+: 304.1179.
Found: 304.1174. Anal. Calcd for C16H17NO5 (303.31): C 63.36, H
5.65, N 4.62. Found: C 63.29, H 5.80, N 4.56.
Methyl (1RS)-1-[(2-methyl-1,3-dioxo-1,2,3,4,5,6-hexahydro-
cyclopenta[c]pyrrol-5-yl)methyl]-2-oxocyclopentanecarboxy-
late, 19. To a cold (0 °C, ice−water bath), magnetically stirred
suspension of NaH (49 mg, 95% content, 1.93 mmol) in anhydrous
DMF (2 mL), a solution of methyl 2-oxocyclopentanecarboxylate (359
mg, 0.33 mL del 95%, 2.66 mmol) was added dropwise, and the
mixture was stirred for 1 h at this temperature. Then, a solution of
iodide 18 (402 mg, 1.38 mmol) in anhydrous DMF (4 mL) was added
dropwise, and the reaction mixture was stirred for 4 h at 0 °C. A
saturated aqueous solution of NH4Cl (2 mL) and water (1.5 mL) were
added, and the mixture was extracted with EtOAc (3 × 12 mL). The
combined organic extracts were dried (anhydrous Na2SO4) and
concentrated in vacuo. The obtained residue (2.05 g) was subjected to
column chromatography (silica gel, 40 g, hexane/EtOAc mixtures).
On elution with hexane/EtOAc 3:1, product 19 (327 mg, 78% yield)
was isolated as light yellow oil: Rf = 0.35 (silica gel, 9 cm, hexane/
EtOAc 1:1); IR (ATR) ν 2951 (w), 2918 (w), 2844 (w), 1749 (m),
1707 (s) and 1696 (s), 1603 (w), 1505 (w), 1431 (m), 1377 (m),
1304 (w), 1282 (w), 1230 (m), 1175 (m), 1126 (m), 983 (m), 731
(m) cm−1; 1H NMR δ 1.78−1.85 (complex signal, 2H, 5-Ha and C5′-
CHa), 1.92−2.00 (complex signal, 2H, 4-Ha and 4-Hb), 2.19−2.36
(complex signal, 4H, 3-Ha, 4′-Ha, 6′-Ha and C5′-CHb), 2.41 (ddt, J =
19.0 Hz, J′ = 1.4 Hz, J″ = 7.0 Hz, 1H, 3-Hb), 2.61 (ddt, J = 12.6 Hz, J′
= 1.4 Hz, J″ = 5.2 Hz, 1H, 5-Hb), 2.72−2.80 (m, 2H, 4′-Hb and 6′-Hb),
2.82−2.93 (m, 1H, 5′-H), 2.91 (s, 3H, N-CH3), 3.70 (s, 3H, OCH3);
13C NMR δ 19.5 (CH2, C4), 23.7 (CH3, N-CH3), 33.4 (CH2, C5),
Stereoisomeric Mixture of Methyl 2-hydroxy-1-[(1-hydroxy-
2-methyl-3-oxo-1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-
yl)methyl)cyclopent-3-enecarboxylate, 22. To a cold (0 °C, ice−
water bath) of enone 21 (112 mg, 0.37 mmol) and CeCl3·7H2O (380
mg, 1.02 mmol) in a mixture of THF (3.3 mL) and MeOH (3.7 mL),
NaBH4 (54.6 mg, 1.44 mmol) was added portionwise, and the solution
was stirred at room temperature for 1 h. A saturated aqueous solution
of NaHCO3 (1,5 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 8 mL). The combined organic phases were dried
(anhydrous Na2SO4) and concentrated in vacuo to give a stereo-
isomeric mixture of at least four diastereomeric racemic pairs of diol 22
(97.5 mg, 86% yield) as a beige solid. Crystallization of the above
product from EtOAc (0.4 mL) gave an analytical sample of 22 (52
mg) as a white solid: mp 80−82 °C (EtOAc); Rf = 0.21 (silica gel, 9.5
cm, EtOAc); IR (ATR) ν 3500−3000 (max. at 3284) (m), 2920 (m),
2850 (w), 1724 (m), 1677 (s), 1653 (s), 1432 (s), 1396 (s), 1348 (m),
1316 (m), 1289 (m), 1228 (s), 1199 (m), 1166 (s), 1085 (s), 1018
(s), 980 (m), 752 (m), 729 (m), 704 (m), 661 (m) cm−1; 1H NMR δ
1.60−1.99 (complex signal, 2H, 4′-Ha and OH), 2.08−2.27 (complex
signal, 3H, 4′-Hb, C5′-CHa and 6′-Ha), 2.29−2.38 (complex signal,
1H, 5-Ha), 2.54−2.98 (complex signal, 4H, 5-Hb, 5′-H, C5′-CHb, 6′-
Hb) 2.91 (s, 3H, N-CH3), 3.20−3.60 (br, 1H, OH), 3.70 (s) 3.737 (s)
and 3.742 (s) (total 3H, OCH3), 4.93 (br s), 4.95 (br s) and 4.97 (br
s) (total 1H, 2-H), 5.07 (br s) and 5.11 (br s) (total 1H, 1′-H), 5.78−
5.82 (complex signal, 1H, 4-H), 5.91−5.96 (complex signal, 1H, 3-H);
13C NMR (the groups of signals for each carbon atom of different
stereoisomers are given in order of relative intensity) δ 26.32 and
26.36 (CH3, N-CH3), 33.3, 32.9, 33.4, and 33.9 (CH2, C6′), 35.4, 35.7,
35.1, and 34.5 (CH2, C5′-CH2), 39.2, 38.9, 39.1, and 38.8 (CH2, C4′),
40.1, 39.3, 39.7, and 39.2 (CH2, C5), 41.5, 40.9, 41.4, and 40.9 (CH,
C5′), 52.2 and 52.3 (CH3, OCH3), 57.0, 57.5, 57.2, and 57.3 (C, C1),
79.4, 80.1, 79.9, and 80.4 (CH, C2), 81.9, 81.8, 82.01, and 81.95 (CH,
C1′), 132.1, 131.82, 132.0, and 131.76 (CH, C4), 133.6, 134.0, 133.9,
and 134.2 (CH, C3), 142.1, 142.29, 142.35, 142.0 (C, C3a′), 162.6,
162.8, 162.5, and 163.0 (C, C6a′), 167.44, 167.6, 167.39, 167.5 (C,
C3′), 177.0 and 177.1 (C, COOCH3). HRMS (ESI) (m/z) calcd for
[C16H21NO5 + H]+ 308.1492. Found: 308.1494. Anal. Calcd for
33.55 (CH2) and 33.59 (CH2) (C4′ and C6′), 37.3 (CH2, C3), 39.7
(CH2, C5′-CH2), 40.6 (CH, C5′), 52.7 (CH3, OCH3), 60.4 (C, C1),
151.97 (C), 152.04 (C) (C3a′ and C6a′) 167.1 (C, C1′ and C3′),
170.8 (C, COOCH3), 213.8 (C, C2). HRMS (ESI) (m/z) calcd. for
[C16H19NO5 + H]+: 306.1336. Found: 306.1333. Anal. Calcd for
C16H19NO5·0.5H2O (314.34): C 61.14, H 6.41, N 4.46. Found: C
61.27, H 6.27, N 4.74.
Methyl (1RS)-1-[(2-methyl-1,3-dioxo-1,2,3,4,5,6-
hexahydrocyclopenta[c]pyrrol-5-yl)methyl]-2-(trimethylsilyl-
oxy)cyclopent-2-enecarboxylate, 20. To a cold (0 °C, ice−water
bath) solution of keto ester 19 (458 mg, 1.50 mmol) and anhydrous
Et3N (1.04 mL, 758 mg, 7.50 mmol) in anhydrous CH2Cl2 (4.5 mL),
trimethylsilyl trifluoromethanesulfonate (0.42 mL, 98% content, 500
mg, 2.25 mmol) was added at once under an Ar atmosphere, and the
mixture was stirred for 30 min at this temperature. A saturated
aqueous solution of NaHCO3 (1.5 mL) was added, the organic phase
was separated, and the aqueous one was extracted with CH2Cl2 (3
mL). The combined organic phases were dried (anhydrous Na2SO4)
and concentrated in vacuo. The residue was taken in EtOAc (6 mL);
the solution was washed with water (2 × 2 mL), dried (anhydrous
Na2SO4) and concentrated in vacuo. The red-brown oily residue
corresponding to 20 (548 mg), Rf = 0.63 (silica gel, 9 cm, hexane/
EtOAc 1:1), was used as such in the next step: 1H NMR δ 0.19 [s, 9H,
Si(CH3)3], 1.76−1.88 (m, 1H), 1.97 (dd, J = 14.0 Hz, J′ = 7.4 Hz,
1H), 2.16−2.43 (complex signal, 6H) (4-Ha, 4-Hb, 4′-Ha, 5-Ha, 5-Hb,
6′-Ha, C5′-CHa and C5′-CHb), 2.75−2.83 (complex signal, 2H, 4′-Hb
and 6′-Hb), 2.84−2.94 (m, 1H, 5′-H), 2.95 (s, 3H, N-CH3), 3.67 (s,
3H, OCH3), 4.71 (s, 1H, 3-H); 13C NMR δ −0.2 [CH3, Si(CH3)3],
23.7 (CH3, N-CH3), 26.4 (CH2, C5), 32.5 (CH2, C4), 33.7 (CH2) and
34.2 (CH2) (C4′ and C6′), 40.5 (CH2, C5′-CH2), 40.6 (CH, C5′),
51.9 (CH3, OCH3), 57.9 (C, C1), 103.4 (CH, C3), 152.2 (C) and
152.8 (C) (C3a′ and C6a′), 154.0 (C, C2), 167.5 (C, C1′ and C3′),
175.4 (C, COOCH3).
Methyl (1RS)-1-[(2-methyl-1,3-dioxo-1,2,3,4,5,6-hexahydro-
cyclopenta[c]pyrrol-5-yl)methyl]-2-oxocyclopent-3-ene-
carboxylate, 21. To a solution of the above trimethylsilyl ether 20
(548 mg) in anhydrous DMSO (5.4 mL), Pd(OAc)2 (344 mg, 98%
11279
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
C16H21NO5·0.25H2O (311.85): C 61.62, H 6.95, N 4.49. Found: C
61.70, H 7.11, N 4.34.
Anal. Calcd for C22H25NO5Se (462.40): C, 57.14; H, 5.45; N, 3.03.
Found: C, 57.31; H, 5.73; N, 2.85.
Methyl (1RS,2RS)-2-hydroxy-1-[(2-methyl-1,3-dioxo-
1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)methyl]-
cyclopent-3-enecarboxylate, 25. a. Reaction of Enone 21 with
Furan. A solution of enone 21 (104 mg, 0,34 mmol) in furan (3.2 mL)
was heated at 80 °C for 24 h in a closed glass vessel. The solution was
allowed to cool to room temperature and was concentrated in vacuo to
give a mixture of four diastereomeric pairs of the Diels−Alder adduct
26 (145 mg, quantitative yield), which was used as such in the next
step.
(3aRS,5RS,6aSR)-5-(Iodomethyl)-2-methyl-3a-(phenylselan-
yl)-4,5,6,6a-tetrahydrocyclopenta[c]pyrrole-1,3(2H,3aH)-
dione, 23. A magnetically stirred mixture of tosylate 10 (252 mg, 0.51
mmol) and NaI (765 mg, 5.1 mmol) in anhydrous acetone (30 mL)
was heated at 56 °C for 16 h under an Ar atmosphere. The mixture
was allowed to cool to room temperature; the precipitate was filtered
through a pad of Celite, washing the solid with EtOAc (20 mL). The
combined filtrate and washings were concentrated in vacuo, and the
residue (919 mg) was subjected to column chromatography (silica gel,
5 g, hexane/EtOAc mixtures). On elution with hexane/EtOAc 4:1,
iodide 23 (220 mg, 96% yield) was obtained as a light yellow oil: Rf =
0.57 (silica gel, 9 cm, hexane/EtOAc 1:1); IR (ATR) ν 2928 (w), 1771
(w), 1695 (s), 1428 (m), 1377 (m), 1288 (m), 1274 (m), 1179 (m),
1
Significant H NMR data of the stereoisomeric mixture 26 (the
given values for each kind of proton are given in decreasing relative
ratio): 2.80/2.96/2.82/3.00 (s, N-CH3), 3.70/3.68/3.69/3.67 (s,
COOCH3), 6.13−6.18 (complex signal, cyclopentenone 3-H), 6.43/
6.59/6.38/6.40 (t, J = 1.2 Hz, olefinic protons from the dihydrofuran
moiety), 7.72−7.80 (complex signal, cyclopentenone 4-H).
1
1086 (m), 1006 (m), 742 (m), 692 (m), 634 (m) cm−1; H NMR δ
1.69 (dd, J = 12.8 Hz, J′ = 12.0 Hz, 1H, 4-Hx), 1.75 (dt, J = 10.4 Hz, J′
= 12.0 Hz, 1H, 6-Hx), 1.80−1.90 (m, 1H, 5-H), 2.18−2.24 (ddm, J =
12.8 Hz, J′ = 5.6 Hz, 1H, 6-Hn), 2.63 (ddd, J = 12.8 Hz, J′ = 5.6 Hz, J″
= 1.4 Hz, 1H, 4-Hn), 2.76 (s, 3H, N-CH3), 3.11 (dd, J = 10.4 Hz, J′ =
6.0 Hz, 1H) and 3.16 (dd, J = 10.4 Hz, J′ = 6.0 Hz, 1H) (CH2I), 3.25
(dd, J = 10.4 Hz, J′ = 1.2 Hz, 1H, 6a-H), 7.29−7.33 [m, 2H, Ar-3(5)-
H], 7.41 (tm, J = 7.2 Hz, 1H, Ar-4-H), 7.61 [dm, J = 8.0 Hz, 2H, Ar-
2(6)-H]; 13C NMR δ 7.4 (CH2, CH2I), 25.2 (CH3, N-CH3), 36.3
(CH2, C6), 41.0 (CH, C5), 43.1 (CH2, C4), 53.1 (CH, C6a), 53.5 (C,
C3a), 125.5 (C, Ar−C1), 129.3 [CH, Ar−C3(5)], 130.0 (CH, Ar−
C4), 137.2 [CH, Ar−C2(6)], 177.5 (C, C1), 178.6 (C, C3). HRMS
(ESI) (m/z) calcd for [C15H16INO280Se + H]+ 449.9463. Found:
449.9475. Anal. Calcd for C15H16INO2Se·0.05hexane (452.47): C
40.61, H 3.72, N 3.10; I, 28.05. Found: C 40.90, H 3.75, N 3.18; I,
28.11.
Mixture of Methyl (1RS)- and (1SR)-1-{[(3aRS,5SR,6aSR)-2-
methyl-3a-(phenylselanyl)-1,3-dioxooctahydrocyclopenta[c]-
pyrrol-5-yl]methyl}-2-oxocyclopentanecarboxylate, 24. To a
cold (0 °C, ice−water bath), magnetically stirred suspension of NaH
(14 mg, 60% content, 0.36 mmol) in anhydrous DMF (0.5 mL), a
solution of methyl 2-oxocyclopentanecarboxylate (66 mg, 60 μL, 95%
content, 0.44 mmol) was added dropwise, and the mixture was stirred
for 1 h at this temperature. Then, a solution of iodide 23 (80.3 mg,
0.18 mmol) in anhydrous DMF (0.8 mL) was added dropwise, and the
reaction mixture was stirred at 0 °C for 2 h and at room temperature
for 67 h. A saturated aqueous solution of NH4Cl (0.5 mL) and water
(0.8 mL) were added, and the mixture was extracted with EtOAc (3 ×
4 mL). The combined organic extracts were washed with water, dried
(anhydrous Na2SO4) and concentrated in vacuo. The obtained residue
(331 mg) was subjected to column chromatography (silica gel, 15 g,
hexane/EtOAc mixtures). On elution with hexane/EtOAc 1:1, product
24 (59.2 mg, 71% yield) was isolated as a thick yellow oil: Rf = 0.36
(silica gel, 9.5 cm, hexane/EtOAc 1:1); IR (ATR) ν 2952 (w), 1770
(w), 1749 (w), 1697 (s), 1429 (m), 1378 (m), 1283 (m), 1222 (m),
1147 (m), 1119 (m), 1088 (m), 1021 (m), 744 (m), 694 (m) cm−1;
1H NMR δ 1.51−1.60 (complex signal, 2H, 4′-Hx and C5′-CHa),
1.62−1.75 (complex signal, 3H, 5-Ha, 5′-H and 6′-Hx), 1.82−1.99
(complex signal, 2H, 4-Ha and 4-Hb), 2.02−2.14 (complex signal, 2H,
4′-Hn and 6′-Hn), 2.14−2.26 (m, 1H, 3-Ha), 2.33−2.43 (m, 1H, 3-Hb),
2.43−2.54 (complex signal, 2H, 5-Hb and C5′-CHb), 2.72 (s) and 2.73
(s) (total 3H, N−CH3), 3.13 (br s) and 3.15 (br s) (total 1H, 6a′-H),
3.64 (s) and 3.65 (s) (total 3H, OCH3), 7.27−7.31 [complex signal,
2H, Ar-3(5)-H], 7.38 (tm, J = 7.4 Hz, 1H, Ar-4-H), 7.56−7.59
[complex signal, 2H, Ar-2(6)-H]; 13C NMR δ 19.5 (CH2, C4), 25.1
(CH3) and 25.2 (CH3) (N-CH3), 32.8 (CH2) and 32.9 (CH2) (C5),
35.8 (CH, C5′), 36.1 (CH2) and 36.4 (CH2) (C6′), 37.3 (CH2, C3),
37.57 (CH2) and 37.64 (CH2) (C4′), 43.1 (CH2) and 43.4 (CH2)
(C5′-CH2), 52.7 [CH3, OCH3], 52.9 (CH) and 53.1 (CH) (C6a′),
53.3 (C) and 53.6 (C) (C3a′), 60.0 (C, C1), 125.6 (C) and 125.7 (C)
(Ar−C1), 129.2 [CH, Ar−C3(5)], 129.87 (CH) and 129.90 (CH)
(Ar−C4), 137.1 [CH, Ar−C2(6)], 170.7 [C, COOCH3], 177.79 (C)
and 177.83 (C) (C1′), 178.8 (C, C3′), 213.8 (C, C2). HRMS (ESI)
(m/z) calcd for [C22H25NO5Se + H]+: 464.0970. Found: 464.0968.
b. Reduction of the Mixture of Diels−Alder Adducts 26 with
NaBH4/CeCl3·7H2O. To a cold (−40 °C, cryocool) solution of the
above mixture of Diels−Alder adducts 26 (127 mg, 0.34 mmol) and
CeCl3·7H2O (357 mg, 0.96 mmol) in a mixture of THF (3.1 mL)/
MeOH (3.4 mL), NaBH4 (50 mg, 1.33 mmol) was added portionwise,
and the mixture was stirred at this temperature for 1 h. Then, saturated
aqueous NaHCO3 solution (1.3 mL) and water (1.5 mL) were added,
and the mixture was extracted with CH2Cl2 (3 × 12 mL). The
combined organic phases were dried (anhydrous Na2SO4) and
concentrated in vacuo to give a mixture of diastereomeric alcohols
27 (135 mg, quantitative yield) as a white solid, which was used as
such in the next step.
1
Significant H NMR data of the stereoisomeric mixture 27 (the
given values for each kind of proton are given in decreasing relative
ratio): 2.80/2.96/2.83/3.02 (s, N-CH3), 3.70/3.74/3.680/3.683/other
minor signals (s, COOCH3), 4.93/5.09/4.85/5.04/5.04/5.01 (br,
cyclopentenol 2-H plus allylic protons from the dihydrofuran moiety),
5.75−5.79 (complex signal, cyclopentenol 4-H), 5.88−5.95 (complex
signal, cyclopentenol 3-H), 6.43/6.60/6.38/6.58 (br s, olefinic protons
from the dihydrofuran moiety).
c. Retro-Diels−Alder Reaction from the Reduced Adducts 27. A
solution of the above stereoisomeric mixture 27 in toluene (17 mL)
was heated under reflux for 4 d. The solution was allowed to cool to
room temperature and concentrated in vacuo, and the residue (113
mg) was subjected to column chromatography (silica gel 35−70 μm, 7
g, hexane/EtOAc mixtures). On elution with hexane/EtOAc 65:35,
stereoisomerically pure alcohol 25 (48.4 mg) and a mixture of 25 and
its epimer at the cyclopentene C2 carbon atom (28.5 mg, ratio 25/C2
epimer about 2:1 by 1H NMR), both as thick white oils, were
successively isolated (total 76.9 mg, 74% yield from enone 21). On
increasing the polarity of the eluent until hexane/EtOAc 4:6, a
stereoisomeric mixture of the two originally minor adducts 27 (22.5
mg) was recovered as brown oil.
Analytical and Spectroscopic Data of the Main Diastereoisomer
25. Thick white oil: Rf = 0.33 (silica gel, 8 cm, hexane/EtOAc 4:6); IR
(ATR) ν 3600−3300 (m), 2947 (w), 1770 (w), 1695 (s), 1432 (m),
1377 (m), 1230 (m), 1203 (m), 1167 (m), 1031 (m), 982 (m), 728
(m) cm−1; 1H NMR δ 1.80 (s, 1H, OH), 1.98 (dd, J = 14.4 Hz, J′ = 5.6
Hz, 1H, C5′-CHa), 2.23 (dd, J = 14.4 Hz, J′ = 7.2 Hz, 1H, C5′-CHb),
2.32−2.37 (complex signal, 3H, 4′-Ha, 5-Htrans and 6′-Ha), 2.70−2.87
(complex signal, 3H, 4′-Hb, 5′-H and 6′-Hb), 2.93 (s, 3H, N-CH3),
2.93−2.99 (dm, J = 16.8 Hz, 1H, 5-Hcis), 3.66 (s, 3H, COOCH3),
4.92−4.95 (br s, 1H, 2-H), 5.80 (dq, J = 6.0 Hz, J′ = 2.0 Hz, 1H, 4-H),
5.92−5.95 (m, 1H, 3-H); 13C NMR δ 23.7 (CH3, N−CH3), 33.2
(CH2) and 34.0 (CH2) (C4′ and C6′), 38.5 (CH2, C5′-CH2), 39.2
(CH2, C5), 41.3 (CH, C5′), 52.3 (CH3, COOCH3), 57.3 (C, C1),
80.2 (CH, C2), 132.0 (CH, C4), 133.9 (CH, C3), 152.1 (C) and
152.4 (C) (C3a′ and C6a′), 167.3 (C, C1′ and C3′), 176.5 (C,
COOMe). HRMS (ESI) (m/z) calcd for [C16H19NO5 + NH4]+
323.1601. Found: 323.1593. Anal. Calcd for C16H19NO5 (305.33): C
62.94, H 6.27, N 4.59. Found: C 63.24, H 6.45, N 4.27.
Significant NMR Data of the Minor Diastereoisomer of 25 from
the Spectra of the Diastereomeric Mixture. 1H NMR δ 1.87 (dd, J =
11280
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
13.8 Hz, J′ = 5.8 Hz, 1H, C5′-CHa), 2.14 (dd, J = 13.8 Hz, J′ = 7.8 Hz,
1H, C5′-CHb), 2.97 (s, 3H, N−CH3), 3.07−3.14 (dm, J = 17.6 Hz,
1H, 5-Hcis), 3.75 (s, 3H, COOCH3), 4.48−4.52 (br s, 1H, 2-H); 13C
NMR δ 23.8 (CH3, N-CH3), 33.3 (CH2) and 34.2 (CH2) (C4′ and
C6′), 38.3 (CH2, C5′-CH2), 41.0 (CH, C5′), 43.0 (CH2, C5), 52.1
(CH3, COOCH3), 57.6 (C, C1), 83.5 (CH, C2), 130.9 (CH, C4),
134.0 (CH, C3), 151.9 (C) and 152.3 (C) (C3a′ and C6a′), 167.20
and 167.22 (C, C1′ and C3′), 175.2 (C, COOCH3).
and was filtered. Concentration of the filtrate in vacuo gave a white
solid (41.4 mg), which was subjected to column chromatography
(silica gel, 2.0 g, hexane/EtOAc mixtures). On elution with hexane/
EtOAc 85:15, product 1 (R= COOMe) (20.7 mg, 90% yield) was
obtained as a white solid. The analytical sample of 1 (R = COOMe)
was obtained as white solid: mp 166−167 °C, by sublimation at 110
°C/0.2−0.5 Torr; Rf = 0.32 (silica gel, 10 cm, hexane/EtOAc 1:1); IR
(ATR) ν 2953 (w), 2860 (w), 1754 (w), 1731 (m), 1691 (s), 1424
(m), 1374 (m), 1327 (m), 1307 (m), 1253 (s), 1145 (m), 1110 (m),
1053 (m), 780 (m), 730 (m) cm−1; 1H NMR δ 1.88−1.89 (dm, J = 2.8
Hz, 2H, 6-H2), 1.93−1.97 [ddm, J = 11.6 Hz, J′ = 3.6 Hz, 2H, 4(12)-
Hb], 2.04−2.07 [dm, J = 11.6 Hz, 2H, 4(12)-Ha], 2.62−2.65 (m, 1H,
5-H), 2.81 (s, 3H, N-CH3), 3.25 [t, J = 2.0 Hz, 2H, 8(11)-H], 3.59 (s,
3H, OCH3), 6.17 [t, J = 2.0 Hz, 2H, 9(10)-H]; 13C NMR δ 24.4 (CH3,
N-CH3), 35.3 (CH2, C6), 38.2 (CH, C5), 38.6 [CH2, C4(12)], 52.0
(CH3, OCH3), 55.5 [CH, C8(11)], 59.5 [C, C3a(8a)], 72.2 (C, C7),
135.5 [C, C9(10)], 173.3 (C, COOCH3), 177.3 [C, C1(3)]. HRMS
(ESI) (m/z) calcd for [C16H17NO4 + H]+ 288.1230. Found: 288.1217.
Anal. Calcd for C16H17NO4 (287.31): C 66.89, H 5.96, N 4.88. Found:
C 66.80, H 6.15, N 4.67.
b. From Alcohol 25. To a solution of alcohol 25 (33.5 mg, 0.11
mmol) in benzene (16 mL), p-TsOH·H2O (4.2 mg, 22 μmol) was
added, and the solution was heated under reflux with azeotropic
distillation of water with a Dean−Stark equipment for 24 h. The
solution was allowed to cool to room temperature, treated with solid
K2CO3 (about 60 mg) and was filtered. Concentration of the filtrate in
vacuo gave a brown solid (39.7 mg), which was subjected to column
chromatography (silica gel, 2.0 g, hexane/EtOAc mixtures). On
elution with hexane/EtOAc 85:15, product 1 (R = COOMe) (28.6
mg, 91% yield) was obtained as a white solid. A similar reaction
starting from a mixture of 25 and its C2 epimer (134 mg, 0.44 mmol)
gave 1 (R = COOMe) in 85% yield.
Methyl (1RS,2RS)-2-acetoxy-1-[(2-methyl-1,3-dioxo-
1,2,3,4,5,6-hexahydrocyclopenta[c]pyrrol-5-yl)methyl]-
cyclopent-3-enecarboxylate, 29. a. Oxidation of the Stereo-
isomeric Mixture 22 with MnO2. To a solution of the stereoisomeric
mixture of diols 22 (210 mg, 0.68 mmol) in anhydrous CH2Cl2 (130
mL), MnO2 (418 mg, 85% content, 4.1 mmol) was added at once
under an Ar atmosphere, and the mixture was heated under reflux for
36 h. The solution was allowed to cool to room temperature, filtered
through a pad of Celite, and the solid was washed with CH2Cl2 (3 ×
35 mL). Concentration in vacuo of the combined filtrate and washings
gave a residue (204 mg), which was subjected to column
chromatography (silica gel 35−70 μm, 12 g, hexane/EtOAc mixtures).
In order of elution, a mixture of the main stereoisomeric allylic alcohol
25 and enone 21 (hexane/EtOAc 4:1, 75 mg, approximate ratio by 1H
NMR alcohol 25/enone 21 = 3:1), a mixture of alcohol 25, its C2
epimer and enone 21 (hexane/EtOAc 7:3, 28 mg, approximate ratio
1
by H NMR alcohol 25/C2 epimer of 25/enone 21 = 4:3:1.5) and a
mixture of starting diol 22 and hydroxylactam 28 (hexane/EtOAc 1:1,
1
48.5 mg, approximate ratio by H NMR diol 22/hydroxylactam 28 =
3:4) were obtained. Altogether, the approximate yield for the different
compounds were alcohol 25 and its C2 epimer (43%), enone 21
(12%), hydroxylactam 28 (13%) and starting diol 22 (10%).
b. Acetylation of the Mixture of Alcohol 25 and Enone 21. To a
solution of the above mixture of alcohol 25 and enone 21 (75 mg,
ratio alcohol 25/enone 21 = 3:1, 0.18 mmol alcohol 25) in anhydrous
CH2Cl2 (1.5 mL) under an Ar atmosphere, anhydrous pyridine (0.11
mL, 1.35 mmol), acetic anhydride (0.11 mL, 1.16 mmol) and DMAP
(14.9 mg, 0.122 mmol) were successively added, and the solution was
stirred at room temperature for 15 h. The solution was made acidic by
addition of an aqueous 0.1 N HCl solution (4.5 mL); the organic
phase was separated and washed with aqueous 0.1 N HCl solution (2
× 4.5 mL), brine (6 mL), saturated aqueous NaHCO3 solution (2 × 6
mL) and brine (6 mL), dried (anhydrous Na2SO4) and concentrated
in vacuo to give a yellowish oily residue (76 mg), which was subjected
to column chromatography (silica gel 35−70 μm, 4.0 g, hexane/EtOAc
mixtures). In order of elution, pure acetate 29 as colorless oil (hexane/
EtOAc 9:1, 59 mg, 92% yield) and enone 21 (hexane/EtOAc 4:1, 18
mg) were isolated. Spectroscopic data of acetate 29: IR (ATR) ν 3055
(w), 2946 (w), 1771 (w), 1695 (s), 1428 (m), 1377 (m), 1288 (m),
1275 (m), 1180 (m), 1086 (m), 1006 (m), 742 (m), 692 (m), 633
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +34+934024536. Fax: +34+934035941. E-mail:
camps@ub.edu.
Notes
The authors declare no competing financial interest.
1
(m) cm−1; H NMR δ 2.00 (dd, J = 14.0 Hz, J′ = 6.4 Hz, 1H, C5′-
ACKNOWLEDGMENTS
■
CHa), 2.06 (s, 3H, CH3COO), 2.18 (dd, J = 14.0 Hz, J′ = 5.6 Hz, 1H,
C5′-CHb), 2.20−2.34 (m, 2H, 4′-Ha and 6′-Ha), 2.38 (dq, J = 16.8 Hz,
J′ = 2.0 Hz, 1H, 5-Hcis), 2.71−2.83 (complex signal, 3H, 4′-Hb, 6′-Hb
and 5′-H), 2.93 (s, 3H, N-CH3), 3.06 (dt, J = 16.8 Hz, J′ = 2.0 Hz, 1H,
5-Htrans), 3.71 (s, 3H, COOCH3), 5.78−5.81 (m, 1H, 4-H), 5.94−5.96
(m, 1H, 2-H), 6.06 (dt, J = 5.6 Hz, J′ = 2.0 Hz, 1H, 3-H); 13C NMR δ
21.0 (CH3, CH3COO), 23.7 (CH3, N-CH3), 33.7 (CH2) and 33.9
(CH2) (C4′ and C6′), 38.8 (CH2, C5′-CH2), 40.3 (CH2, C5), 41.2
(CH, C5′), 52.5 (CH3, COOCH3), 56.4 (C, C1), 81.5 (CH, C2),
128.9 (CH, C4), 136.5 (CH, C3), 152.05 (C) and 152.12 (C) (C3a′
and C6a′), 167.2 (C, C1′ and C3′), 170.2 (C, CH3COO), 175.3 (C,
COOCH3). HRMS (ESI) (m/z) calcd for [C18H21NO6 + NH4]+
365.1707. Found: 365.1709. Anal. Calcd for C18H21NO6 (347.36): C
62.24, H 6.09, N 4.03. Found: C 62.54, H 6.39, N 3.80.
Financial support from Direccion
́
General de Investigacion
́
of
́
Ministerio de Economıa y Competitividad and FEDER
[Projects CTQ2008-03768/PPQ and CTQ2011-22433 and
́
fellowship to T. Gomez (FPI program)] is gratefully acknowl-
edged. C. Monasterolo thanks the Faculty of Industrial
Chemistry of the University of Bologna for financial support.
́
We also thank the Centre Cientıfic i Tecnolog
̀
ic of the
University of Barcelona (CCiTUB) for NMR and MS facilities,
́
̀
and Ms. P. Domenech from the Institut de Quımica Avanca̧ da
de Catalunya (IQAC, CSIC, Barcelona, Spain) for carrying out
the elemental analyses.
REFERENCES
■
Methyl 2-methyl-1,3-dioxo-1,2,3,4,5,6,7,8-octahydro-3a,7,8-
(epiprop[2]ene[1,1,3]triyl)-5,8a-methanocyclohepta[c]pyrrole-
7-carboxylate, 1 (R = COOMe). a. From Acetate 29. To a solution
of acetate 29 (27.8 mg, 80 μmol) in benzene (16 mL), p-TsOH·H2O
(3.0 mg, 16 μmol) was added, and the solution was heated under
reflux in a Dean−Stark equipment for 24 h. The solution was allowed
to cool to room temperature, treated with solid K2CO3 (about 60 mg)
(1) Liu, J.; Obando, D.; Liao, V.; Lifa, T.; Codd, R. Eur. J. Med. Chem.
2011, 46, 1949−1963.
(2) Geldenhuys, W. J.; Malan, S. F.; Bloomquist, J. R.; Van der Schyf,
C. J. Bioorg. Med. Chem. 2007, 15, 1525−1532.
(3) Camps, P.; Duque, M. D.; Vaz
́
quez, S.; Naesens, L.; De Clerq, E.;
̀
ez-Querol, M.; Camins, A.; Pallas, M.; Prathalingam,
Sureda, F. X.; Lop
́
11281
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282

The Journal of Organic Chemistry
Article
S. R.; Kelly, J. M.; Romero, V.; Ivorra, D.; Cortes
Chem. 2008, 16, 9925−9936.
(4) Duque, M. D.; Camps, P.; Profire, L.; Montaner, S.; Vaz
́
, D. Bioorg. Med.
(33) Rickborn, B. Org. React. 1998, 52, 1−393.
(34) Brenna, E.; Fuganti, C.; Fronza, G.; Gatti, F. G.; Sala F. Serra, S.
Tetrahedron 2007, 63, 2351−2356.
́
quez, S.;
Sureda, F. X.; Mallol, J.; Lop
Prathalingam, S. R.; Kelly, J. M. Bioorg. Med. Chem. 2009, 17, 3198−
3206.
́
ez-Querol, M.; Naesens, L.; De Clerq, E.;
(5) Duque, M. D.; Camps, P.; Torres, E.; Valverde, E.; Sureda, F. X.;
Lop
́
ez-Querol, M.; Camins, A.; Prathalingam, S. R.; Kelly, J. M.;
́
Vazquez, S. Bioorg. Med. Chem. 2010, 18, 46−57.
(6) Honarparvar, B.; Makatini, M. M.; Pawar, S. A.; Petzold, K.;
Soliman, M. E. S.; Arvidsson, P. I.; Sayed, Y.; Govender, T.; Maguire,
G. E. M.; Kruger, H. G. ChemMedChem 2012, 7, 1009−1019.
(7) Makatini, M. M.; Petzold, K.; Arvidsson, P. I.; Honarparvar, B.;
Govender, T.; Maguire, G. E. M.; Parboosing, R.; Sayed, Y.; Soliman,
M. E. S.; Kruger, H. G. Eur. J. Med. Chem. 2012, 57, 459−467.
(8) Bailey, T. R.; Rippin, S. R.; Opsitnick, E.; Burns, C. J.; Pevear, D.
C.; Collett, M. S.; Rhodes, G.; Tohan, S.; Huggins, J. W.; Baker, R. O.;
Kern, E. R.; Keith, K. A.; Dai, D.; Yang, G.; Hruby, D.; Jordan, R. J.
Med. Chem. 2007, 50, 1442−1444.
(9) Torres, E.; Duque, M. D.; Camps, P.; Naesens, L.; Calvet, T.;
Font-Bardia, M.; Vaz
(10) Duque, M. D.; Chunglong, M.; Torres, E.; Wang, J.; Naesens,
L.; Juarez-Jimenez, J.; Camps, P.; Luque, F. J.; DeGrado, W. F.; Lamb,
R. A.; Pinto, L. H.; Vaz
́
quez, S. ChemMedChem 2010, 5, 2072−2078.
́
́
́
quez, S. J. Med. Chem. 2011, 54, 2646−2657.
(11) Godleski, S. A.; Schleyer, P. v. R.; Osawa, E.; Inamoto, Y.;
Fujikura, Y. J. Org. Chem. 1976, 42, 2596−2605.
(12) Ipaktschi, J.; Herber, J.; Kalinowski, H.-O.; Amme, M.; Boese, R.
Chem. Ber. 1990, 299−304.
(13) Mehta, G.; Reddy, K. S.; Ravikumar, K. Indian J. Chem. Sect. B:
Org. Chem. Incl. Med. Chem. 1996, 35B, 524−527.
(14) Camps, P.; Fernan
Chem. 2009, 3081−3087.
́ ́
dez, J. A.; Rull, J.; Vazquez, S. Eur. J. Org.
(15) Brown, H. C.; Prasad, J. V. N. V.; Zee, S.-H. J. Org. Chem. 1985,
50, 1582−1589.
(16) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190−6191.
(17) Reich, H. J.; Wollowitz, S. Org. React. 1993, 44, 1−296.
(18) Durrant, M. L.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1984,
901−904.
(19) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. J. Org. Chem. 2010, 75, 4872−4875.
(20) Pelletier, F.; Comte, V.; Massard, A.; Wenzel, M.; Toulot, S.;
Richard, P.; Picquet, M.; Le Gendre, P.; Zava, O.; Edafe, F.; Casini, A.;
Dyson, P. J. J. Med. Chem. 2010, 53, 6923−6933.
́
(21) Camps, P.; Gomez, T. ARKIVOC 2011, iii, 128−139.
(22) Ibrahim-Ouali, M.; Romero, E.; Bouleghlem, H. Tetrahedron
2011, 67, 3668−3676.
(23) Polo, E.; Forlini, F.; Bertolasi, V.; Boccia, A. C.; Sacchi, M. C.
Adv. Synth. Catal. 2008, 350, 1544−1556.
(24) Angeles, A. R.; Waters, S. P.; Danishefsky, S. J. J. Am. Chem. Soc.
2008, 130, 13765−13770.
(25) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng,
D. Tetrahedron Lett. 1995, 36, 2423−2426.
(26) Kumamoto, H.; Haraguchi, K.; Tanaka, H.; Nitanda, T.; Baba,
M.; Dutschman, G. E.; Cheng, Y.-C.; Kato, K. Nucleosides, Nucleotides
Nucleic Acids 2005, 24, 73−83.
(27) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011−
1013.
(28) Ito, Y.; Suginome, M. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-VCH:
Weinheim, Germany, 2002; Vol. 2, pp 2873−2879.
(29) Luche, J. L.; Gemal, A. L. J. Am. Chem. Soc. 1979, 101, 5848−
5849.
(30) Clevenger, R. C.; Turnbull, K. D. Synth. Commun. 2000, 30,
1379−1388.
(31) Margetic, D.; Butler, D. N.; Warrener, R. N.; Murata, Y.
Tetrahedron 2011, 67, 1580−1588.
(32) Margetic, D.; Warrener, R. N.; Sun, G.; Butler, D. N.
Tetrahedron 2007, 63, 4338−4346.
11282
dx.doi.org/10.1021/jo302398c | J. Org. Chem. 2012, 77, 11270−11282