Further studies toward himandrine via sequential oxidative amidation-intramolecular Diels-Alder reactions

Article abstract of DOI:10.1139/cjc-2012-0340

Exploratory work toward the alkaloid himandrine evaluated the directing ability of a pyrrolidine C-3 substituent in a diastereotopic group elective intramolecular Diels-Alder reaction of a spirodienone obtained by the oxidative amidation of a phenol. The

Full text of DOI:10.1139/cjc-2012-0340

82
Further studies toward himandrine via sequential
oxidative amidation – intramolecular Diels–Alder
reactions
Takahito Kasahara and Marco A. Ciufolini
Abstract: Exploratory work toward the alkaloid himandrine evaluated the directing ability of a pyrrolidine C-3 substituent
in a diastereotopic group elective intramolecular Diels–Alder reaction of a spirodienone obtained by the oxidative
amidation of a phenol. The study also defined a technique for the construction of ring D of the alkaloid.
Key words: alkaloids, Diels–Alder, himandrine, hypervalent iodine, phenols.
Résumé : Des travaux préliminaires en vue de la synthèse de l’alcaloïde himandrine ont permis d’évaluer la possibilité
d’un substituant en position C-3 d’une pyrrolidine d’orienter la réaction dans un groupe sélectif diastéréotope, d’une
réaction de Diels-Alder intramoléculaire d’une spirodiénone obtenue par amidation oxydante d’un phénol. L’étude a aussi
permis de définir une technique pour la formation du cycle D de l’alcaloïde.
Mots-clés : alcaloïdes, Diels-Alder, himandrine, iodure hypervalent, phénols.
[Traduit par la Rédaction]
It should be noted that the N-bearing tetrasubstituted carbon
atom in the dienone segment of compound 4 is chirotopic, but
not stereogenic.5 A generic addition reaction occurring selec-
tively at either the pro-R or the pro-S double bond of the
dienone, as exemplified in the conversion of anti-4 to 3,
induces a well-defined configuration, R or S, at the level of the
atom in question. The stereocontrolled generation of such
tetrasubstituted carbon centers is generally difficult, but ap-
proaches based on a selective addition to one of the diastereo-
topic carbon–carbon ␲ bonds in dienones of type 4 offers a
good solution.6 Of course, the honoree of the present issue of
the Canadian Journal of Chemistry has contributed signifi-
cantly to the development of this principle.7
A model study designed to address the feasibility of the
foregoing tandem sequence employed simplified substrate 7
(Scheme 3),8 wherein the N-bearing carbon is of opposite
configuration relative to the corresponding centre in 4. The
CH2OH group in 7 correlates with the R substituent in 4.
Relative to the latter, however, the (CH2)2Z unit is absent.
Oxidative cyclization2 of 7 with the hypervalent iodine re-
agent,9 (diacetoxyiodo)benzene (PhI(OAc)2; DIB), in trifluo-
roacetic acid (TFA), followed by dilution with toluene and
heating at reflux for 12 h, directly afforded the trans-fused
compound 1010 as the major component of an 8:1 mixture of
two cycloadducts.11 Evidently, epimerization of the primary
cycloadduct 9 had occurred in situ, probablybecause of revers-
ible enol formation promoted by TFA. A mere hydroxymethyl
Introduction
The architecturally interesting alkaloid himandrine (1)1 in-
vites the exploration of an approach that relies on a tandem
oxidative amidation2 – intramolecular Diels–Alder (IMDA)3
reaction of phenolic sulfonamide 5. According to the format of
Scheme 1, unraveling of the “northeastern” quadrant of 1
produces simplified structure 2, wherein substituent R and
functionality Z would ultimately permit the formation of rings
D–F of the natural product. Tricyclic compound 2 could be
obtained from 3, which is the result of an intramolecular
Diels–Alder reaction occurring selectively at the pro-S double
bond of dienone 4. The latter is recognized as the product of
oxidative cyclization4 of 5. Cycloadduct 3 exhibits the incor-
rect cis configuration of the decaline system relative to 2, but
the neighboring carbonyl group should enable epimerization
to the more energetically favorable trans diastereomer.
The expectation that a dienone such as 4 should selectively
undergo IMDA in the desired sense was rooted in the surmise
that a Diels–Alder reaction occurring at the pro-R double bond
(conformer syn-4, Scheme 2) would be impeded by steric
compression between the sulfonyl group and substituents R and
(CH2)2Z at the C-5 and C-3 position of the pyrrolidine ring,
respectively. Conversely, an IMDA reaction occurring at the
pro-S double bond (anti-4) would be relatively free of nonbond-
ing interactions. We describe product 6 as the syn cycloadduct
(disfavoured) and compound 3 as the anti cycloadduct (favoured).
Received 10 September 2012. Accepted 16 November 2012. Published at www.nrcresearchpress.com/cjc on 15 January 2013.
T. Kasahara and M.A. Ciufolini. Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T
1Z1, Canada.
Corresponding author: Marco A. Ciufolini (e-mail: ciufi@chem.ubc.ca).
This article is part of a Special Issue dedicated to Professor Derrick Clive. It is a pleasure to dedicate this work to our friend and colleague,
Professor Derrick L.J. Clive, in recognition of his many significant contributions to the field of organic chemistry.
Can. J. Chem. 91: 82–90 (2013)
doi:10.1139/cjc-2012-0340
Published by NRC Research Press

Kasahara and Ciufolini
83
Scheme 1.
H
H
R
R
F
C
N
tether
E
D
HN
C
H
O2S
N
H
H
H
H
OH
H
B
A
B
A
Z
Z
COOMe
H
H
MeO
OBz
H
1
3
2
MeO
O
MeO
O
epimerize
R
H
H
R
stereogenic
N
H
O2S
O2S
N
H
chirotopic, but
not stereogenic
Z
Z
5
4
MeO
OH
MeO
O
oxidative cyclization and IMDA reactions (Scheme 4). The
latter step could produce two pairs of diastereomeric adducts,
arising through reaction in an anti (desired) or a syn (unde-
sired) mode with either endo (presumably favoured on elec-
tronic grounds) or exo topology. These four compounds are
shown in Scheme 4 as structures 13–16. Base-promoted
isomerization of 13 and 14 would then provide compound 17,
which possesses the correct relative configuration of all ste-
reocentres as required for himandrine.
Scheme 2.
5
R
5
H
N
nonbonding
interactions
H
R
O2S
SO2
N
H
3
H
Z
3
MeO
OMe
Z
A computational study (MMϩ)12 carried out with simpli-
fied structures 18–21, which lack the tert-butyldimethylsiloxy
(OTBS) group relative to 13–16, revealed that the pair of endo
adducts 18 (an analog of the desired 13) and 20 (a surrogate of
the undesired 15) are virtually isoenergetic, whereas the anti-
exo adduct 19 (cf. the serviceable 14) was only slightly fa-
voured relative to its diastereomer, 21 (Fig. 1; tabulated
energies are relative to the least energetic compound, 18). This
result elicited some apprehension, in that, if the energies of the
transition states leading to the various cycloadducts were also
to be similar, then the crucial IMDA step would proceed with
modest diastereoselectivity. On the other hand, calculations
provided support for the prediction that structure 23, which
possesses a himandrine-like relative configuration, should be
favoured over its diastereomers 18–22 (Fig. 2; tabulated en-
ergies are relative to the least energetic isomer, 23). This
boded well for the planned route to compound 17.
syn-4
anti-4
O
H
O
R
opposite
configurations
5
5
R
H
Z
H
O2S
H
N
3
N
SO2
3
H
H
H
H
(S)
(R)
Z
H
MeO
H
OMe
H
H
O
O
3
6
anti-adduct: predicted
syn-adduct: predicted
major product
minor product
The experimental verification of these hypotheses com-
menced with a Tozer-type13 condensation of 24 (the prepara-
tion of this material is provided as Supplementary data) with
acrolein, followed by selective desilylation of the phenol,14
leading to dienic sulfonamide 11 (Scheme 5). Oxidative cycl-
ization with DIB in CH2Cl2, in the presence of 1.1 equiv of
TFA, afforded dienone 12. Whereas similar dienones had
previously been advanced directly to the Diels–Alder step,8
the present work revealed that greater overall efficiency was
attainable by purifying 12 prior to IMDA reaction. When a
toluene solution of pure 12 was refluxed for 5 h, an IMDA
reaction occurred, which led to a mixture of four compounds.
These were ultimately assigned as the anti-endo (13), anti-exo
(14), and syn-endo (15) adducts, plus some 17 (i.e., epi-13).
group at the C-5 position of the pyrrolidine moiety of 8 had
thus induced a satisfactory degree of diastereoinduction in the
cycloaddition step. Our continuing pursuit of himandrine re-
quired knowledge of the directing effect of a C-3 group, which
would correlate with the (CH2)2Z substitution in 4. Such
studies could also define an appropriate functionality Z that
might enable the formation of ring D of 1. Results of inves-
tigations in this sense are described herein.
Results and discussion
The present work centred on substrate (Ϯ)-11, which by
analogy with 4 and 7 would be processed through sequential
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84
Can. J. Chem. Vol. 91, 2013
Scheme 3.
5
H
H
N
HO
HO
PhI(OAc)2
("DIB")
N
H
SO2
SO2
3
TFA, rt, then
add toluene
reflux, 32%
7
8
OH
O
5
5
H
H
N
HO
HO
N
SO2
SO2
H
H
3
3
major
8:1 mixture
of regioisomers
H
H
9
10
O
O
Scheme 4.
O2S
O2S
N
H
N
H
H
DIB
heat
OTBS
OTBS
OH
O2S
O
H
11
12
SO2
N
N
H
H
H
Z
Z
TBSO
OTBS
H
H
O
O
15 Z = α-H (syn–endo)
16 Z = β-H (syn–exo)
13 Z = α-H (anti–endo)
14 Z = β-H (anti–exo)
O2S
H
N
H
H
base
[?]
OTBS
H
17
O
No evidence could be garnered for the presence of syn-exo
cycloadduct 16. A typical IMDA step would return an approx-
imately 1.2:1.0:1.1 mixture of 13, 14, and 15, respectively,
containing a small amount of 17. The extent of formation of
the latter varied from batch to batch of material, and ranged
from barely detectable to about 20%–25% of the product
mixture. The presence of increased quantities of 17 was al-
ways accompanied by a corresponding decrease in 13. We
surmise that trace amounts of residual TFA were responsible
for the in situ epimerization of 13 via acid-promoted enol
formation. Notice that only 13 can isomerize to 17 under
acidic conditions.
As anticipated, the action of a catalytic amount of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) upon the mixture of
IMDA adducts resulted in the conversion of 13 and 14 into the
desired 17, while 15 advanced to 25. Unsurprisingly, the
isomerization of endo-adduct 13 was considerably faster than
that of 14, which also must undergo epimerization at the less
Published by NRC Research Press

Kasahara and Ciufolini
85
Fig. 1. Estimated energies (MMϩ, kcal/mol) of model endo and exo adducts 18–21 (1 cal ϭ 4.194 J).
O2S
Z
SO2
N
N
H
H
H
H
Z
H
H
O
O
20 Z = α-H (syn–endo) Econf = 0.2
21 Z = β-H (syn–exo) Econf = 1.4
18 Z = α-H (anti–endo) Econf = 0.0
19 Z = β-H (anti–exo) Econf = 0.4
Fig. 2. Estimated energies (MMϩ, kcal/mol) of trans-decalin diastereomers of 18–19 (1 cal ϭ 4.194 J).
O2S
H
O2S
H
O2S
H
N
N
N
H
H
H
H
H
H
H
H
H
O
O
O
18 E = 4.4
19 E = 4.8
22 E > 10
O2S
H
N
H
H
H
23 E = 0.0
O
acidic ␣ position of the sulfonamide. The epimerization step
was best carried out in toluene at 60 °C over 2 h, at which time
approximately 30% of the starting 13 and 14 remained. Longer
reaction times and (or) higher temperatures promoted the
formation of two byproducts, assigned as vinylsulfonamides
26 and 27.15 Fortunately, the balance of 13 and 14 epimerized
to 17 during a subsequent O-deprotection step.
intermediate (vide infra). Dess–Martin oxidation of 33 fur-
nished the requisite 28 in a 72% yield. However, as of this
writing we have been unable to achieve cyclization of 28 to
either 29 or 30.
Nitrile 31 was obtained from 33 as outlined in Scheme 8.
Again, the final product was contaminated with approximately
15% of an isomer originating from 25. Attempted base-
promoted cyclization of 31 (t-BuOK) provided a mixture of
uncharacterized products. Suspecting that the problem was
due to preferential enolization of the ketone, an event that
might trigger numerous undesired side reactions, the cyano
group was converted into a more readily enolized aldehyde.
The action of diisobutylaluminum hydride (DIBAL) upon 31
induced reduction of the ketone to an alcohol and of the nitrile
to an aldehyde, necessitating a subsequent Dess–Martin oxi-
dation to create the desired 35 (also containing ~15% of an
isomer derived from 25). The intramolecular Michael reaction
of the latter under basic conditions was still problematic;
however, treatment with pyrrolidine triggered cyclization to
36, presumably through an enamine intermediate (Scheme 9).
Separation of isomeric materials emanating from syn adduct
25 was achieved at this stage. However, the final compound
was obtained as an essentially 1:1 mixture of epimeric
aldehydes. This detracted nothing from the valuable infor-
mation acquired, i.e., that ring D formation was achievable
through the enamine-mediated intramolecular conjugate ad-
dition of 35.
This preliminary phase of our study had determined that a
linear alkyl group at the C-3 position of the pyrrolidine is
weakly directing compared with a C-5 substituent, favouring
the production of anti adducts to the extent of ~2:1. Still, the
successful production of compound 17 enabled additional
investigations that defined a method for the formation of ring
D. To that end, we targeted aldehyde 28 and nitrile 31
(Scheme 6). The aldehyde appeared to be a substrate for
cyclization in a hydroacylation (cf. 29) or a reductive (cf. 30)
mode, whereas the nitrile might advance to 32 through an
intramolecular Michael reaction. The aldehyde was secured
starting with a tetrabutylammonium fluoride (TBAF) depro-
tection of 17 (Scheme 7). As alluded to earlier, such a treat-
ment promoted the epimerization of residual 13 and 14 (or
desilylated forms thereof). The resultant 33 was contaminated
with approximately 15% of epimerized syn adduct 25.16 The
separation of the two compounds was problematic given their
essentially identical mobility on chromatographic supports.
Accordingly, the mixture was used as follows in subsequent
operations: removal of the undesired regioisomeric material
was best achieved at the stage of a more advanced pentacyclic
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86
Can. J. Chem. Vol. 91, 2013
Scheme 5.
BOC
Ms
1. t-BuOK
DIB
TFA
N
toluene
H
acrolein
12
11
reflux
2. LiOAc•2H2O
72%
CH2Cl2
60%
OTBS
24
TBSO
OTBS
OTBS
O2S
H
O2S
Z
N
N
SO2
N
H
H
H
H
H
H
H
+
+
TBSO
H
H
Z
O
O
O
DBU
15 Z = α-H
25 Z = β-H
13 Z = α-H
14 Z = β-H
17
DBU
13:14:15 ≈ 1.2:1.0:1.1
OTBS
H
O2S
N
H
26 Z = α-H
27 Z = β-H
Z
O
Scheme 6.
Experimental section
Experimental protocols (additional details are provided
as Supplementary data)
O2S
H
N
H
O2S
H
N
H
H
hydro-
acylation
1
Unless otherwise stated, H NMR (300 MHz) and 13C
H
NMR (75 MHz) spectra were recorded at room temperature
(rt) from CDCl3 solutions. Chemical shifts are reported in
parts per million (ppm) on the ␦ scale and coupling con-
stants, J, are in hertz (Hz). Multiplicities are reported as s
(singlet), d (doublet), dd (doublet of doublets), ddd (doublet
of doublets of doublets), t (triplet), q (quartet), and m
(multiplet), and further qualified as app (apparent) and br
(broad). Flash chromatography was performed on 230–400
mesh silica gel.
CHO
H
O
Z
or SmI2
[ ? ]
H
H
O
N
28
29 Z = O
30 Z = H, OH
O2S
H
O2S
H
N
H
H
Michael
[ ? ]
H
H
(1E)-N-1-[[[5-(1,1-Dimethylethyl)dimethylsilyl]oxy]-3-[4-
(1,1-dimethylethyl)dimethylsilyl]-oxy]-phenyl]pentyl]-1,
3-butadiene-1-sulfonamide (11)
H
O
CN
CN
H
H
31
O
32
A freshly prepared tetrahydrofuran (THF) solution of
KO-t-Bu (23 mL, 46 mmol, 2.0 mol/L, 3.5 equiv) was added
dropwise to a solution of N-Boc sulfonamide 2416 (7.94 g,
13.2 mmol, 1.00 equiv) in THF (16 mL) at –78 °C. The
resulting pale yellow solution was stirred for 1 h at –78 °C and
a solution of acrolein (1.2 mL, 16.1 mmol, 1.2 equiv) in THF
(11 mL) was added dropwise. The light green mixture was
stirred for 1 h at –78 °C, then gradually warmed up to rt and
stirred overnight (12 h). The resulting brown solution was
quenched with sat. aq NH4Cl (10 mL) and diluted with EtOAc
(20 mL). The biphasic mixture was filtered through a pad of
In summary, exploratory work toward himandrine deter-
mined that a C-3 substituent on the pyrrolidine moiety of 12 is
weakly anti directing, and that the construction of ring D may
be achieved through cyclization of a transient enamine formed
in situ from aldehyde 35. These results are essential to the
progress of our ongoing effort toward the natural product.
Further results in that sense will be disclosed in due course.
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Kasahara and Ciufolini
87
Scheme 7.
O2S
H
N
TBAF
53% from
H
H
Dess-
28
29 or 30
17
12 over
3 steps
Martin
72%
OH
H
33
O
Scheme 8.
O2S
H
O2S
H
N
N
H
H
H
H
Et4N+ – CN
88%
t-BuOK
32
Z
CN
H
H
O
31
O
33 Z = OH
34 Z = I
I2, PPh3
87%
Scheme 9.
O2S
H
N
1. DIBAL
2. Dess-
O2S
H
H
N
H
H
N
H
H
31
H
O
42%
CHO
35
CHO
Martin
27%
H
H
O
36
Celite with EtOAc (60 mL). The mixture was separated and
the organic layer was rinsed again with sat. aq NH4Cl. The
combined aqueous phases were extracted twice with EtOAc
(10 mL). The organic fractions were combined, rinsed with
brine (10 mL), dried (Na2SO4), and concentrated to give a
brown oil that contained white solids. The crude product was
filtered through a pad of Celite with EtOAc (50 mL) and the
filtrate was evaporated. To the residual brown oil (6.83 g,
12.7 mmol, 1.0 equiv) in dimethylformamide (DMF; 35 mL)
was added LiOAc·2H2O (259 mg, 0.2 equiv) and water
(0.72 mL), and stirred at 75 °C for 6 h. The reaction was
cooled to rt, diluted with EtOAc (70 mL), and washed twice
with sat. aq NH4Cl (20 mL). The combined aqueous layers
were back-extracted three times with EtOAc (20 mL). The
combined organic fractions were rinsed three times with brine
(20 mL), dried (Na2SO4), and concentrated to furnish a brown
oil. Purification by column chromatography (20% ¡ 40%
EtOAc/hexanes) afforded compound 11 (4.03 g, 72%) as a
viscous pale yellow oil. IR: 3287, 2930, 2857, 1515. 1H NMR
␦: 7.01–6.90 (m, 3H), 6.77–6.70 (m, 2H), 6.34 (dt, J ϭ 16.9,
10.4 Hz, 1H), 6.15 (d, J ϭ 14.9 Hz, 1H), 6.02 (br s, 1H), 5.61
(d, J ϭ 16.9 Hz, 1H), 5.53 (d, J ϭ 10.2 Hz, 1H), 4.51 (br t, J ϭ
6.0 Hz, 1H), 3.52–3.33 (m, 2H), 2.83 (br q, J ϭ 6.7 Hz, 2H),
2.70 (app septet, J ϭ 4.9 Hz, 1H), 1.94–1.63 (m, 4H), 0.86 (s,
9H), –0.02 (s, 6H). 13C NMR ␦: 154.6, 141.8, 135.3, 132.7,
128.8, 128.3, 127.4, 115.7, 61.1, 41.5, 39.9, 38.9, 37.0, 26.2,
18.5, –5.10, –5.14. HR-MS calcd for C21H36NO4SSi [M ϩ H]ϩ:
426.2134; found: 426.2133.
(؎)-1-[1-((E)-1,3-Butadienyl)sulfonyl]-4-[1-[2-
[(1,1-dimethylethyl)dimethylsilyl]-oxy]ethyl]-
8-oxo-1-azaspiro[4.5]deca-6,9-diene (12)
The following procedure was performed with nonflame-
dried glassware and unpurified solvents. A solution of
sulfonamide 11 (3.01 g, 7.07 mmol, 1.0 equiv) in CH2Cl2
(35 mL) was added dropwise (addition funnel) over 8 min into
a cooled (0 °C) solution of DIB (2.56 g, 7.79 mmol, 1.1 equiv)
and TFA (600 ␮L, 7.79 mmol, 1.1 equiv) in CH2Cl2 (39 mL).
The addition funnel originally containing the solution of 11
was rinsed twice with CH2Cl2 (2 mL), and the washes were
added to the reaction mixture. The reaction was allowed to
warm up and stirred for an additional 45 min at rt. Anhydrous
K2CO3 (20 mg) was added, and the light brown suspension
was concentrated to give an orange oil, which was purified by
column chromatography (25% ¡ 30% EtOAc/hexanes) to
afford dienone 12 (1.57 g, 52%) as a viscous orange oil. IR:
1
2930, 2857, 1669, 1343. H NMR ␦: 7.00 (app dd, J ϭ 14.9,
10.9 Hz, 1H), 6.82 (app dd, J ϭ 9.9, 2.7 Hz, 1H), 6.67 (app dd,
J ϭ 10.6, 3.3 Hz, 1H), 6.39 (dt, J ϭ 16.9, 10.3 Hz, 1H),
6.32–6.26 (m, 2H), 6.19 (d, J ϭ 14.9 Hz, 1H), 5.66 (d, J ϭ
16.9 Hz, 1H), 5.58 (d, J ϭ 10.1 Hz, 1H), 3.65–3.52 (m, 4H),
2.52–2.30 (m, 2H), 1.84–1.67 (m, 1H), 1.41–1.29 (m, 1H),
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88
Can. J. Chem. Vol. 91, 2013
1.23–1.10 (m, 1H), 0.85 (s, 9H), –0.01 (s, 6H). 13C NMR ␦:
185.4, 151.3, 145.8, 142.8, 132.5, 130.2, 129.1, 127.9, 126.8,
66.6, 61.0, 47.9, 47.7, 31.7, 29.8, 26.0, 18.3, –5.27, –5.33.
HR-MS calcd for C21H33NO4SSiNa [M ϩ Na]ϩ: 446.1797;
found: 446.1801.
EtOAc (20 mL). The organic phase was separated and the
aqueous layer was extracted three times with EtOAc (3 mL).
The organic phases were combined, rinsed with water (5 mL)
and then with brine (5 mL), dried (Na2SO4), and concentrated.
Purification by column chromatography (90% EtOAc/hexanes
¡ EtOAc) afforded alcohol 33 (615 mg, 1.99 mmol, 53% over
three steps from 12) as a white foam. This material contained
approximately 15% of the isomer emanating from compound
(3aR*,8S*,8aS*,11aR*,11bR*)-1,3a,7,8,11a,11b-Hexahydro-
8-[[2-(1,1-dimethylethyl)-dimethylsilyl]-oxy)ethyl]-6H,11H-
naphtho[1,8-cd]pyrrolo[1,2-b]isothiazol-11-one-4,4-
1
25. IR: 3529, 2936, 2894, 1689, 1306, H NMR ␦: 6.47 (d,
dioxide (17)
J ϭ 10.4 Hz, 1H), 6.35–6.27 (m, 1H), 6.17 (d, J ϭ 10.4 Hz,
1H), 5.88–5.80 (m, 1H), 3.96–3.89 (m, 1H), 3.88–3.69 (m,
2H), 3.66–3.38 (m, 3H), 2.68 (dd, J ϭ 13.6, 7.1 Hz, 1H),
2.65–2.54 (m, 1H), 2.46–2.34 (m, 1H), 2.20–2.04 (m, 2H),
1.91–1.74 (m, 1H), 1.68 (br s, 1H), 1.60–1.35 (m, 2H). 13C
NMR ␦: 198.1, 142.6, 135.3, 130.0, 115.7, 68.9, 60.7, 57.8,
48.5, 45.6, 40.2, 38.7, 31.6, 30.0, 24.2. 1148. HR-MS calcd for
C15H19NO4SNa [M ϩ Na]ϩ: 332.0932; found: 332.0935.
A degassed (Ar bubbling, sonication, 15 min) solution of
dienone 12 (1.57 g, 3.71 mmol, 1.0 equiv) in toluene (9.0 mL)
was heated to 120 °C (oil bath temperature) for 5 h, where-
upon disappearance of the starting material was observed by
1H NMR. The solution was cooled to rt and diluted with more
toluene (9.6 mL). Neat DBU (165 ␮L, 1.10 mmol, 0.3 equiv)
was added; the solution was again degassed with Ar (5 min)
and then heated to 58 °C (oil bath temperature) for 2 h. The
mixture was cooled to rt, diluted with EtOAc (20 mL), and
washed with sat. aq NH4Cl (10 mL). The organic phase was
separated and washed with brine (5 mL), dried (Na2SO4), and
concentrated to give crude 17 (1.53 g, contaminated with
isomers as per the discussion) as a brown oil. This crude
material was used without further purification. A 70% pure
sample was prepared as follows: Upon completion of the IMDA
reaction, the solvent was evaporated and the residue was
subjected to column chromatography (20% EtOAc/hexanes).
Fractions containing the anti-endo adduct 13 and some anti-
exo adduct 14, plus compound 17 arising through in situ
epimerization of 13, were combined and evaporated to afford
an ~26:10:64 mixture of the three isomers, respectively. This
material was dissolved in enough toluene to furnish a
0.2 mol/L solution of substrates, to which DBU (0.4 equiv)
was added. The mixture was stirred at 40 °C (oil bath tem-
perature) for 3 h, then it was cooled to room temperature,
diluted with EtOAc (5 mL), rinsed with sat. aq NH4Cl solu-
tion, washed with brine, dried (Na2SO4), and concentrated.
Purification by column chromatography (20% EtOAc/hexanes)
afforded compound 17, clear film, contaminated with
about 15% each (1H NMR) of vinyl sulfonamides 26 and 27.
These produced characteristic signals at 6.83 ppm (app q, J ϭ
3.3 Hz) and 6.75 ppm (app q, J ϭ 3.3 Hz). IR: 2955, 2930,
2857, 1693, 1H NMR ␦: 6.48 (d, J ϭ 10.4 Hz, 1H), 6.35–6.27
(m, 1H), 6.18 (d, J ϭ 10.4 Hz, 1H), 5.89–5.81 (m, 1H),
3.92–3.78 (m, 2H), 3.71–3.40 (m, 4H), 2.69 (dd, J ϭ 13.7,
7.1 Hz, 1H), 2.65–2.55 (m, 1H), 2.43–2.31 (m, 1H), 2.19–2.03
(m, 2H), 1.92–1.74 (m, 1H), 1.51–1.40 (m, 2H), 0.85 (s, 9H),
0.02 (s, 3H), 0.01 (s, 3H). 13C NMR ␦: 198.1, 142.6, 135.3,
130.0, 115.9, 68.9, 60.8, 57.8, 48.5, 45.4, 40.2, 38.7, 32.0,
30.3, 25.97, 18.3, 24.3, –5.3. 1151. HR-MS calcd for
C21H33NO4SSiNa [M ϩ Na]ϩ: 446.1797; found: 446.1794.
(3aR*,8S*,8aS*,11aR*,11bR*)-1,3a,7,8,11a,11b-
Hexahydro-8-[[2-iodoethyl]-6H,11H-naphtho[1,8-cd]pyrrolo
[1,2-b]isothiazol-11-one-4,4-dioxide (34)
Solid I2 (506 mg, 1.99 mmol, 2.3 equiv) was added to a
chilled (0 °C) solution of alcohol 33 (265 mg, 867 ␮mol,
1.0 equiv), PPh3 (459 mg, 1.75 mmol, 2.0 equiv), and imida-
zole (148 mg, 2.17 mmol, 2.5 equiv) in THF (2.8 mL). After
5 min, the reaction flask was taken out of the ice bath and the
solution was stirred at rt for 2 h. The mixture was diluted with
EtOAc (10 mL) and rinsed twice with 10% aq Na2S2O3
solution (5 mL). The combined aqueous phases were back-
extracted once with ethyl acetate (3 mL). The combined or-
ganic phases were rinsed with brine (5 mL), dried (Na2SO4),
and concentrated. Purification of the residue by column chro-
matography (30% ¡ 40% EtOAc/hexanes) afforded the title
compound (318 mg, 87%) as a yellow solid; mp 189–192 °C
(dec.). This material contained approximately 15% of the
isomer emanating from compound 25. IR: 2934, 2898, 1689,
1306, 1137. 1H NMR ␦: 6.45 (d, J ϭ 10.4 Hz, 1H), 6.36–6.28
(m, 1H), 6.17 (d, J ϭ 10.4 Hz, 1H), 5.89–5.82 (m, 1H),
3.98–3.81 (m, 2H), 3.58–3.38 (m, 2H), 3.35–3.26 (m, 1H),
3.09–2.98 (m, 1H), 2.66–2.55 (m, 2H), 2.45–2.34 (m, 1H),
2.20–2.02 (m, 2H), 1.84–1.61 (m, 3H). 13C NMR ␦: 197.7,
142.1, 135.3, 130.2, 115.6, 68.5, 57.7, 49.2, 48.1, 40.1, 38.6,
32.6, 29.0, 24.2, 4.0. HR-MS calcd for C15H19INO3S [M ϩ
H]ϩ: 420.0130; found: 420.0130.
3-((3aR*,3a1R*,8R*,8aS*,11aR*)-1,3a,3a1,6,7,8,11,11a-
Octahydronaphtho[1,8-cd]pyrrolo[1,2-b]isothiazol-8-yl)-
11-oxo-propanenitrile-4,4-dioxide (31)
Solid Et4Nϩ –CN (132 mg, 0.794 mmol, 1.1 equiv) was
added in one portion to a chilled (0 °C) solution of iodide 34
(300 mg, 0.716 mmol, 1.0 equiv) in MeCN (2.4 mL). The
reaction flask was taken out of the ice bath and stirred at rt for
30 min. The suspension was diluted with EtOAc (5 mL) and
rinsed twice with 10% Na2S2O3 aqueous solution (2 mL). The
aqueous fractions were combined and extracted three times
with EtOAc (1 mL). The combined organic extracts were
washed with brine (2 mL), dried (Na2SO4), and concentrated.
Purification of the residue by column chromatography (60% ¡
65% EtOAc/hexanes) afforded 31 (200 mg, 88%) as a white
solid; mp 183–187 °C (dec.). This material contained approx-
imately 15% of the isomer emanating from compound 25. IR:
2936, 2248, 1690, 1307, 1148. 1H NMR ␦: 6.45 (d, J ϭ
(3aR*,8S*,8aS*,11aR*,11bR*)-1,3a,7,8,11a,11b-
Hexahydro-8-[[2-hydroxyethyl]-6H,11H-naphtho[1,8-cd]
pyrrolo[1,2-b]isothiazol-11-one-4,4-dioxide (33)
A cold (–25 °C) solution of the crude tetracycle 17 (1.53 g,
produced from 1.57 g (3.71 mmol) of dienone 12 as detailed
previously) in THF (7.2 mL) was treated with TBAF (com-
mercial 1 mol/L solution in THF; 11.0 mL, 11.0 mmol,
1.0 mol/L, 3.0 equiv). The resulting dark brown mixture was
stirred at –25 °C for 4 h, then water (10 mL) was added
dropwise and the mixture was warmed to rt and diluted with
Published by NRC Research Press

Kasahara and Ciufolini
89
10.5 Hz, 1H), 6.37–6.28 (m, 1H), 6.21 (d, J ϭ 10.5 Hz, 1H),
5.89–5.81 (m, 1H), 3.98–3.83 (m, 2H), 3.61–3.51 (m, 1H),
3.50–3.39 (m, 1H), 2.68–2.31 (m, 5H), 2.20–1.98 (m, 2H),
1.93–1.80 (m, 1H), 1.76–1.62 (m, 1H), 1.61–1.46 (m, 1H).
13C NMR ␦: 197.6, 141.5, 135.4, 130.6, 118.5, 115.5, 68.6,
57.7, 48.3, 47.9, 40.2, 39.0, 29.3, 25.1, 24.2, 16.5. HR-MS
calcd for C16H18N2O3SNa [M ϩ Na]ϩ: 341.0936; found:
341.0949.
3.86–3.76 (m, 1H), 3.58–3.08 (m, 9H), 2.75 (d, J ϭ 5.4 Hz,
1H), 2.69 (d, J ϭ 5.4 Hz, 1H), 2.60–2.28 (m, 7H), 2.27–2.17
(m, 3H), 2.14–2.00 (m, 3H), 1.98–1.78 (m, 4H), 1.66–1.55
(m, 2H). 13C NMR ␦: 209.6, 209.0, 200.7, 199.7, 134.5, 134.4,
115.7, 115.5, 79.7, 79.2, 60.54, 60.51, 56.0, 55.2, 52.1, 52.0,
51.7, 50.2, 44.52, 44.48, 43.5, 42.6, 41.7, 41.6, 41.3, 37.3,
32.9, 30.3, 28.7, 27.5, 24.4 (two signals). HR-MS calcd for
C16H20NO4S [M ϩ H]ϩ: 322.1113; found: 322.1109.
3-((3aR*,3a1R*,8R*,8aS*,11aR*)-1,3a,3a1,6,7,8,11,11a-
Octahydronaphtho[1,8-cd]pyrrolo[1,2-b]isothiazol-8-yl)-
11-oxo-propanal-4,4-dioxide (35)
Supplementary data
Supplementary data (experimental procedures for the prepara-
tion of compound 24 and characterization data) are available with
the article through the journal Web site at http://nrcresearchpress.
com/doi/suppl/10.1139/cjc-2012-0340.
Commercial DIBAL in hexanes (1 mol/L, 0.25 mL,
0.25 mmol, 3.0 equiv) was added dropwise to a cold (–78 °C)
solution of 31 (26 mg, 0.082 mmol, 1.0 equiv) in CH2Cl2
(0.3 mL). The mixture was stirred at –78 °C for 5 h, and then
it was quenched by careful addition of MeOH (0.1 mL). The
reaction was taken out of the cold bath, diluted with EtOAc
(2 mL), and treated with sat. aq Rochelle’s salt solution
(2 mL). The resulting biphasic mixture was vigorously stirred
overnight at rt. The organic phase was separated and the
aqueous layer was extracted three times with EtOAc (1 mL).
The combined organic phases were rinsed with brine, dried
(Na2SO4), and concentrated. The crude product, a mixture of
diastereomers of the secondary alcohol, was directly dissolved
in CH2Cl2 (0.35 mL) and Dess–Martin periodinane (52 mg,
0.12 mmol, 1.5 equiv) was added in one portion. The white
suspension was allowed to stir at rt for 2 h. The reaction was
diluted with EtOAc (2 mL) and rinsed twice with 1:1 (v/v)
10% aq Na2S2O3 / sat. aq NaHCO3 (1 mL). The combined
aqueous layers were back-extracted three times with EtOAc
(1 mL). The combined extracts were rinsed with brine (2 mL),
dried (Na2SO4), and concentrated. Purification of the residue
by column chromatography (75% ¡ 80% EtOAc/hexanes)
gave 35 as a clear film (7 mg, 27%). This material contained
approximately 15% of the isomer emanating from compound
25. IR: 2927, 1719, 1690, 1307, 1148. 1H NMR ␦: 9.76 (br s,
1H), 6.47 (d, J ϭ 10.5 Hz, 1H), 6.36–6.28 (m, 1H), 6.20 (d,
J ϭ 10.5 Hz, 1H), 5.89–5.81 (m, 1H), 3.93–3.76 (m, 2H),
3.56–3.37 (m, 2H), 2.74 (dd, J ϭ 13.6, 7.1 Hz, 1H), 2.68–2.48
(m, 3H), 2.35–2.25 (m 1H), 2.21–2.07 (m, 1H), 1.93–1.64 (m,
3H), 1.44–1.29 (m, 1H). 13C NMR ␦: 200.7, 197.8, 142.1, 135.3,
130.3, 115.6, 69.0, 57.8, 48.2, 48.0, 42.0, 40.2, 38.6, 29.7, 24.2,
21.1. HR-MS calcd for C17H24NO5S [M ϩ MeOH ϩ H]ϩ:
354.1375; found: 354.1387.
Acknowledgments
We thank the University of British Columbia, the Canada
Research Chair Program, the Canada Foundation for Innova-
tion (CFI), the British Columbia Knowledge Development
Fund (BCKDF), the Natural Sciences and Engineering Re-
search Council of Canada (NSERC), and the Canadian Insti-
tutes of Health Research (CIHR) for financial support.
References
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Compound 36
Pyrrolidine (49 ␮L, 593 ␮mol, 10 equiv) was added to
solution of aldehyde 35 (19 mg, 59 ␮mol, 1.0 equiv) in THF
(0.6 mL) at rt. The mixture was heated to 30 °C (oil bath
temperature) and stirred for 14 h, then it was quenched with
1 mol/L HCl (1 mL), stirred for 30 min at rt, and then diluted
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combined extracts were rinsed with brine (2 mL), dried
(Na2SO4), and concentrated. Purification of the residue by
column chromatography (70% EtOAc/hexanes) afforded pen-
tacyclic substance 36 (8 mg, 42%, clear film) as a 1:1 mixture
of ␣- and ␤-aldehyde diastereomers. This material was free of
isomeric products emanating from compound 25. IR: 2936,
1716, 1151. 1H NMR ␦: 9.79 (s, 1H) and 9.70 (s, 1H),
6.31–6.22 (m, 2H), 5.88–5.78 (m, 2H), 4.15–4.04 (m, 1H),
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90
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Published by NRC Research Press