A radical cyclization approach to the formal total syntheses of platencin

Article abstract of DOI:10.1039/c1ob06155k

Two different strategies leading to formal total syntheses of platencin are described. The first strategy involving Claisen rearrangement and radical cyclization provides a rapid access to the core structure of platencin, and also use minimum protective-g

Full text of DOI:10.1039/c1ob06155k

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PAPER
A radical cyclization approach to the formal total syntheses of platencin†
Kalanidhi Palanichamy, Ayyagari V. Subrahmanyam and Krishna P. Kaliappan*
Received 12th July 2011, Accepted 18th August 2011
DOI: 10.1039/c1ob06155k
Two different strategies leading to formal total syntheses of platencin are described. The first strategy
involving Claisen rearrangement and radical cyclization provides a rapid access to the core structure of
platencin, and also use minimum protective-group operations. The second strategy, a protecting
group-free route, utilizes a 6-exo-trig radical cyclization and aldol condensation as key steps leading to
the formal synthesis of platencin.
their advanced target-based whole-cell screening strategy using
Introduction
antisense differential sensitivity assay.
The “superbugs,” a set of bacterial strains, have been posing a
Being an unprecedented class of antibiotics, platensimycin and
serious threat to human lives by developing resistance to most of
platencin differ slightly in their mode of action though they both
the existing antibiotics, and hence there is a danger of the survival
are structurally related. While platensimycin is a selective inhibitor
of these superbugs. This is primarily due to the fact that most
of elongation condensing enzyme FabF, platencin is a balanced
dual inhibitor of FabF and initiation condensing enzyme FabH.5
Later, the Merck research group also reported the discovery of
several congeners of platensimycin and platencin from the same
cultural broth (Fig. 2, congeners of platencin).6
of the currently available antibiotics are either old discoveries or
synthetic modifications thereof. Consequently, there is an urgent
need for the discovery of new classes of antibiotics that work
with novel modes of action and also act on new targets. As many
of the existing antibiotics work by inhibiting cell wall synthesis,
protein synthesis, or nucleic acid synthesis of bacteria,1 discovery
of new antibiotics that work by unique modes of action is in
demand. Thus, bacterial fatty acid biosynthesis, which is essential
for bacterial survival is considered as an attractive target as there
are many interesting enzymes which could be targeted.2 To this
end, several inhibitors of these enzymes have appeared in the
literature, but none of them are suitable drug candidates due to
their poor penetration and lack of target selectivity. Nevertheless,
continued efforts on the discovery of new class of antibiotics
eventually rewarded the Merck research group to isolate two novel
potent antibiotics, platensimycin (1)3 and platencin (2)4 (Fig. 1)
from the strain of Streptomyces platensis through a systematic
screening of about 250 000 natural product extracts as part of
Fig. 1 Platensimycin and platencin.
Fig. 2 Natural congeners of platencin.
Department of Chemistry, Indian Institute of Technology Bombay, Powai,
Mumbai, 400 076, India. E-mail: kpk@chem.iitb.ac.in; Fax: (+91)22-2572-
3480; Tel: (+91)22-2576-7177
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06155k
However, none of them were found to exhibit superior activity
than the parent molecules. Thus, the fascinating molecular ar-
chitecture and the intriguing biological profile of platensimycin
and platencin inspired the synthetic community immediately after
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Scheme 1 Retrosynthetic analysis.
Fig. 3 Earlier synthetic approaches to platencin.
their isolation, and it has culminated in a few total (two for 1,
and four for 2) and several formal syntheses for both molecules
(Fig. 3 for platencin).7–9 In continuation of our earlier report
on a platensimycin analogue,8d and also in continuation of our
interest in the synthesis of biologically active natural and unnatural
products,10 herein we present our initial endeavours on synthesis
of platencin using two conceptually different approaches.
Results and discussion
First strategy
In the first approach, we planned to extend the radical cyclization
strategy utilized for the synthesis of the core structure of platen-
simycin, to achieve the formal synthesis of platencin. As per our
retrosynthetic analysis delineated in Scheme 1, we envisaged that
the tricyclic core 14,9a,b an advanced intermediate in the earlier
synthesis of platencin, could be constructed through a 6-exo-
dig radical cyclization from xanthate 15, which, in turn, could
be derived from alcohol 16. This alcohol 16 could be obtained
from g,d-unsaturated aldehyde 18 in a few steps, and aldehyde
18 was envisioned from the corresponding allylic alcohol through
Claisen rearrangement.11 The enone 1912 that would afford the
desired allylic alcohol could be derived from cyclohexanedione
monoethylene ketal 20 through a Robinson-type annulation.
Thus, as depicted in Scheme 2, the synthesis of enone 24
commenced with the construction of bicyclic enone 19. To this end,
cyclohexanedione monoethylene ketal 20 was treated with KOH
and methyl vinyl ketone to afford enone 19 in moderate yield
based on recovered starting material. A stereoselective DIBAL-
H reduction8d,13 of enone 19 furnished the corresponding allylic
alcohol as the precursor for Claisen rearrangement.
Scheme 2 Reagents and conditions: (a) KOH, methyl vinyl ketone, Et2O,
0 ◦C, 3 h, 60% (brsm); (b) DIBAL-H, CH2Cl2, -78 ◦C, 1 h, 99%; (c) NaH,
KH (cat.), phenylvinyl sulfoxide, THF, 0 ◦C to rt, 12 h, 98%; (d) NaHCO3,
decalin, 180 ◦C, 18 h, 69%; (e) diethyl 1-diazo-2-oxopropylphosphonate,
K2CO3, MeOH, 0 ◦C to rt, overnight, 73%; (f) PDC, tBuOOH, Celite,
benzene, 10 ◦C to rt, overnight, 44% (72% brsm); (g) p-TSA, MeOH/H2O,
rt, overnight, 85%; (h) CBr4, PPh3, Zn, CH2Cl2, 0 ◦C to rt, 12 h; (i) ethylene
glycol, p-TSA, benzene, reflux, 12 h, 88% (two steps); (j) nBuLi, THF,
-78 ◦C, 2 h, then TMSCl, -78 ◦C, 30 min, 73%; (k) PDC, tBuOOH, Celite,
benzene, 10 ◦C to rt, overnight, 62% brsm; (l) 5% aq. acetone, p-TSA,
60 ◦C, 10 h, 85%; (m) TBAF, THF, 0 ◦C to rt, 1 h, 82%.
18. Thus, the allylic alcohol was treated with NaH and phenyl
vinyl sulfoxide in the presence of catalytic amount of KH to
provide the sulfoxide 21, which upon heating with NaHCO3 in
decalin underwent elimination followed by Claisen rearrangement
to furnish the desired aldehyde 18. One-carbon homologation of
this aldehyde to afford alkyne 22 was carried out through a three-
step sequence, involving Corey–Fuchs olefination,15 treatment
After extensive experimentation, the modified Claisen rear-
rangement developed by Mandai14 was identified as the best
reaction conditions to afford the desired g,d-unsaturated aldehyde
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with nBuLi and TMSCl, and ketal formation. It was observed
that the Corey–Fuchs reaction was accompanied by deprotection
of the ketal group, presumably due to ZnBr2 formed during
the reaction conditions. Allylic oxidation of 22 with PDC and
tBuOOH,16 followed by ketal cleavage under acidic conditions
provided ketone 23, which upon cleavage of TMS group with
TBAF led to the formation of ketone 24. The lengthy nature of this
route to transform aldehyde 18 into ketone 24 forced us to improve
the efficiency of the strategy. Thus, treatment of aldehyde 18 with
Bestmann–Ohira reagent17 followed by allylic oxidation with PDC
and tBuOOH, and subsequent ketal deprotection furnished ketone
24 in three steps from 18.
A chemoselective reduction of ketone 24 with NaBH4 at -20 ◦C
afforded alcohol 16 as an inseparable mixture of diastereomers
(Scheme 3). To carry forward this inseparable mixture might not
encounter any difficulty as in principle they both would result in
a single radical intermediate. With this alcohol synthesized, the
final challenge was to successfully accomplish the core structure
of platencin by a 6-exo-dig radical cyclization. Towards this end,
alcohol 16 was treated with NaH and CS2, and subsequent
quenching with MeI, to afford xanthate 15. Unfortunately, all our
attempts to execute the key radical cyclisation of xanthate 15 were
unsuccessful18 under various reaction conditions with nBu3SnH
and AIBN, and revealing that xanthate 15 might be a poor radical
precursor.
Scheme 4 Retrosynthetic analysis.
as in the case of xanthate 15, all our efforts to execute the
radical cyclisation of iodide 26 failed to give the desired tricyclic
framework under various reaction conditions with nBu3SnH and
AIBN, resulting in only unidentified decomposition products.
Although fully consumed, the fate of the substrate under the
reaction conditions could not be determined.
The cumulative disappointment in realizing the radical cyclisa-
tion under various conditions called for an investigation on our
substrate. Thus, as observed by the Rawal’s group in their synthesis
of platencin,9b we eventually found that the rigid nature of iodide
26 due to the enone moiety might not permit the substrate to
adopt a suitable conformation in order to facilitate the radical
cyclisation. To answer this rigidity issue, enone 26 was reduced
with DIBAL-H to afford allylic alcohol 27 as an inseparable
mixure of diastereomers. Pleasingly, a slow addition of a solution
of nBu3SnH and AIBN in benzene to a refluxing solution of iodide
27 in benzene by a syringe pump over 2 h resulted in the formation
of the desired cyclised product, which was immediately treated
with MnO2 in CH2Cl2 to afford the tricyclic core 14 in 43% yield
over two steps, thus completing a formal synthesis of platencin.9a,b
Second strategy
In parallel, our constant efforts to develop a short and efficient
strategy that neglects protective-group operations led us to design
another route, as exemplified in Scheme 4, for the construction
of the tricyclic core structure of platencin. Accordingly, the
intermediate 14 was envisioned to be derived from ketoaldehyde 28
through an intramolecular aldol condensation,9a,d,h and compound
28, in turn, could be derived from 29 through a sequence of re-
ductions and oxidation. Horner–Wadsworth–Emmons reaction19
was envisioned as a means to derive enone 29 from ketoester 30,
which, in turn, could be constructed from compound 31 through
a 6-exo-trig radical cyclisation. Finally, compound 31 could be
traced back to the known ketoester 32.20
The synthesis of enone 14 commenced with the construction of
ketoester 30,21 which is a known compound from cyclohexanone
in seven steps. However, we intended to access this intermediate
through an alternative short route as shown in Scheme 5. To
this end, ketoester 32 which is readily accessible from cyclohex-
2-enone was subjected to propargylation with propargyl bromide
and K2CO3 to afford compound 31 in 72% yield. As anticipated,
the planned 6-exo-trig radical cyclisation underwent smoothly
by refluxing a solution of 31, nBu3SnH and AIBN in tBuOH
for 5 h, followed by destannation with PPTS, to afford the
Scheme 3 Reagents and conditions: (a) NaBH4, EtOH, -20 ◦C, 3 h, 77%;
(b) NaH, THF, 0 ◦C, 20 min, then CS2, rt, 30 min, then MeI, rt, 15 min,
91%; (c) PPh3, I2, Im, THF, 0 ◦C to RT, 1 h, 70%; (d) DIBAL-H, CH2Cl2,
-78 ◦C, 1 h, 63%; (e) nBu3SnH, AIBN, benzene, reflux, 2 h; (f) MnO2,
CH2Cl2, rt, overnight, 43% (over two steps).
This unexpected disappointment in accomplishing the radical
cyclization forced us to bring this strategy to a halt at this
stage, search for alternative conditions, and focus on the second
strategy (Scheme 4, vide infra). When we were working on the
second strategy, a report on the synthesis of platencin by the
Ghosh’s group9k appeared in the literature, wherein a similar such
problem had been encountered and circumvented by using the
corresponding iodide as the more reactive radical precursor. This
observation invited us to revisit our strategy, and thus, iodide
26 was envisioned to be a better reactive substrate that could be
conveniently obtained in good yield from alcohol 16 by treating
with PPh3, I2 and imidazole. However, once again to our dismay,
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Scheme 5 Reagents and conditions: (a) propargyl bromide, K2CO3,
acetone, reflux, 3.5 h, 72%; (b) nBu3SnH, AIBN, tBuOH, reflux, 5 h,
then PPTS, CH2Cl2, rt, overnight, 52% for two steps.
Scheme 7 Reagents and conditions: (a) LAH, Et2O, 0 ◦C, 52%; (b)
(COCl)2, DMSO, Et3N, CH2Cl2, -78 ◦C, 5 h, quant.; (c) diethyl 2-oxo-
propylphosphonate, NaH, THF, 0 ◦C, 30 min, 89%; (d) Ra-Ni, THF/H2O,
rt, 6.5 h, quant.; (e) NaOH, EtOH, rt, 12 h, 70%; (f) Ra-Ni, THF/H2O,
rt, 12 h, 85% (33:38 = 3 : 1).
bicyclic ketoester 30 in 52% yield. With enough supply of bicyclic
compound 30 in hand, our next task was to perform a three-carbon
homologation to obtain enone 29. Surprisingly, our various
attempts to execute the Horner–Wadsworth–Emmons olefination
under different conditions (NaH, KOH, nBuLi, DIPEA and LiCl,
and Wittig reaction with corresponding stabilized phosphorane)
at varying temperatures were unrewarding to deliver the desired
product, presumably due to the formation of chelated enolate 30a.
Due to the failure encountered in executing the Horner–
Wadsworth–Emmons reaction, we slightly modified the strategy
as shown in Scheme 6. Thus, enone 14 was envisaged to be
derived from b-disubstituted enone 34 through transposition of
the enone double bond. Further, an aldol condensation was
envisioned as a means to construct the tricyclic enone 34 from
the corresponding diketone, which, in turn, could be derived
from enone 35. A chemoselective Horner–Wadsworth–Emmons
reaction of corresponding ketoaldehyde that could be derived from
30 would give access to the formation of enone 35.
R
Raney Niꢀ (Ra-Ni) in THF allowed chemoselective reduction
of enone double bond to furnish dione 37 in quantitative yield.23
The closing of the ring was efficiently carried out through an
intramolecular aldol condensation to result in the formation of
tricyclic framework 34. The final challenge left over to complete
the synthesis was to accomplish a chemo- and stereoselective
reduction of the sterically challenged b-disubstituted enone double
bond of 34 in the presence of its exocyclic double bond. In our
search for various conditions to effect this transformation, we
eventually found that treatment of enone 34 with Ra-Ni in THF
caused the reduction to afford an inseparable mixture of the
desired tricyclic framework 33 and the other isomer 38 albeit in
3 : 1 ratio in favour of the desired one. Other attempted conditions
such as, hydosilylation,24,8m Stryker’s reduction,25 and Crabtree’s
reduction26 were unproductive, and left only the starting material
to be recovered. Nevertheless, construction of tricyclic ketone 33
thus constitutes a formal synthesis as this skeleton has previously
been elaborated into platencin.9g,k,n
Conclusions
In summary, we have successfully developed two different strate-
gies for the formal synthesis of platencin, by exploiting the radical
chemistry. While the first strategy utilizes Claisen rearrangement
and radical cyclisation for the construction of the tricyclic core
with the use of minimal protecting groups, the second one that
employs an aldol condensation along with the radical cyclisa-
tion, entirely avoids protective-group operations throughout the
strategy.
Scheme 6 Revised retrosynthetic analysis.
Accordingly, the synthetic strategy began with the reduction
of ketoester 30 with LAH to afford corresponding diol, which
upon oxidation under Swern conditions22 furnished ketoaldehyde
36 in quantitative yield (Scheme 7). The ketoaldehyde 36 was then
converted into enone 35 through Horner–Wadsworth–Emmons
reaction in 89% yield as a single diastereomer. It is worth mention-
ing that in this case also the keto group was highly unreactive under
the reaction conditions even in the presence of excess base and
phophonate reagent. With the enone 35 synthesized, our next task
was to selectively reduce the enone double bond in the presence
of an exocyclic double bond. Eventually, treatment of 35 with
Experimental section
General methods
Unless and otherwise noted, all starting materials and reagents
were obtained from commercial suppliers and used after further
purification. Tetrahydrofuran was distilled from sodium ben-
zophenone ketyl and toluene from sodium. Dichloromethane,
N,N-dimethylformamide, hexanes and pyridine were freshly dis-
tilled from calcium hydride. All solvents for routine isolation
of products and chromatography were of reagent grade and
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glass distilled. Reaction flasks were dried in oven at 100 ◦C
for 12 h. Air- and moisture-sensitive reactions were performed
under an argon/UHP nitrogen atmosphere. Chromatography was
performed using silica gel (100–200 mesh, Aceme, for gravity
column chromatography; 230–400 mesh, Aceme, for Biotage flash
column chromatography) with indicated solvents. All reactions
were monitored by thin-layer chromatography carried out on
0.25 mm E. Merck silica plates (60F-254) using UV light as
visualizing agent, and charring solution (prepared by dropwise
addition of conc. H2SO4 (5 mL) to a solution of phosphomolybdic
acid (1 g) and ceric sulphate (2 g) in water (95 mL)), alkaline
KMnO4 solution (prepared by dissolving KMnO4 (2 g) and
NaHCO3 (4 g) in water (100 mL)), and heat as developing
agents. Optical rotation was recorded on Autopol IV automatic
polarimeter. IR spectra were recorded on Thermo Nicolet Avater
320 FT-IR and Nicolete Impact 400 machine. Mass spectra
were obtained from Waters Micromass-Q-Tof microTM (YA105)
acetate–hexanes); mp 89–91 ◦C; 1H NMR (CDCl3, 400 MHz): d
5.47 (s, 1H), 4.24–4.0 (m, 1H), 3.96 (d, 4H, J = 2.0 Hz), 2.32–1.15
(m, 12H); 13C NMR (100 MHz, CDCl3): d 141.2, 124.4, 108.7,
67.0, 64.3, 64.2, 42.4, 35.3, 34.1, 31.7, 31.4, 27.4; IR (neat) cm-1:
3435, 2937, 2879, 1664, 1450, 1351, 1284, 1216, 1124, 1031, 947,
844, 758; HRMS (EI): calc. for C12H18O3Na m/z 233.1154, found
m/z 233.1156.
6¢-(2-(Phenylsulfinyl)ethoxy)-3¢,4¢,6¢,7¢,8¢,8a¢-hexahydro-1¢H-
spiro[[1,3]dioxolane-2,2¢-naphthalene] (21). A solution of allylic
alcohol 19a (0.3 g, 1.42 mmol) in THF (6 mL) was added dropwise
to a suspension of NaH (0.102 g, 2.14 mmol) in THF (2 mL) at 0 ◦C
and stirred for 20 min. Then, the reaction mixture was warmed
to room temperature and stirred for another 30 min. The reaction
◦
mixture was again cooled to 0 C and treated with a solution of
phenyl vinyl sulfoxide (0.65 g, 4.28 mmol) in THF (2 mL) followed
by the addition of a catalytic amount of (1 mg) of KH. After being
stirred at the same temperature for 10 min, the reaction mixture
was slowly warmed to room temperature and stirred for 12 h.
The mixture was treated with cold water and extracted with ethyl
acetate (3 ¥ 150 mL). The combined organic layers were washed
with water, brine and dried (Na2SO4). After concentration, the
resultant residue was purified by silica gel column chromatography
(25% ethyl acetate in hexanes) to afford the sulfoxide 21 (0.51 g)
in 98% yield as a yellow oil. Rf 0.26 (1 : 1 ethyl acetate–hexanes);
1H NMR (CDCl3, 400 MHz) d 7.67–7.64 (m, 2H), 7.54–7.47 (m,
3H), 5.53–5.44 (m, 1H), 3.99–3.66 (m, 6H), 3.56–3.51 (m, 1H),
3.01–2.98 (m, 2H), 2.32–2.18 (m, 3H), 1.99–1.76 (m, 4H), 1.60–
1.14 (m, 4H); 13C NMR (100 MHz, CDCl3): d 142.4, 142.1, 130.8,
129.1, 123.9, 121.6, 121.3, 108.7, 75.2, 74.9, 64.3, 64.2, 60.7, 60.6,
58.7, 58.5, 42.4, 42.3, 35.4, 35.3, 34.2, 34.2, 31.8, 31.7, 27.3, 27.3,
27.2, 27.1; IR (neat) cm-1 3054, 2935, 2859, 1714, 1664, 1477,
1444, 1354, 1283, 1174, 1068, 1035, 947, 751; HRMS (EI) calc. for
C20H26O4SNa m/z 385.1450, found m/z 385.1464.
1
spectrometer. H and 13C NMR spectra were recorded either on
Varian AS 400, Varian ASM 300 or Bruker 400. NMR data is in the
order of chemical shifts, multiplicity (s, singlet; br s, broad singlet;
d, doublet; t, triplet; q, quartet; qnt, quintet; m, multiplet), number
of protons and coupling constant in hertz (Hz). The processing
of NMR spectra was done using MestReNova NMR processing
software.
3¢,4¢,8¢,8a¢-Tetrahydro-1¢H-spiro[[1,3]dioxolane-2,2¢-naphthal-
en]-6¢(7¢H)-one (19)12. To a solution of ketone 20 (0.1 g, 0.64
mmol) in Et2O (1 mL) was added a solution of KOH (14.3 mg,
0.256 mmol) in ethanol (0.5 mL) at 0 ◦C, and the reaction mixture
was stirred for 30 min at the same temperature. A solution of
methyl vinyl ketone (0.061 mL, 0.742 mmol) in Et2O (1 mL) was
added to the reaction mixture at 0 ◦C over a period of 1 h. After
the addition was completed, the reaction mixture was stirred for
another 1 h. The reaction mixture was treated with water and the
aqueous layer was washed with ethyl acetate (2 ¥ 20 mL) and the
organic layer was washed with water (20 mL), brine, dried over
Na2SO4 and purified by silica gel column chromatography (20%
ethyl acetate in hexanes) to afford the enone 19 (0.08 g, 60%,
based on recovered starting material, brsm) as a white solid. Rf
0.52 (1 : 1 ethyl acetate–hexanes); mp 73–75 ◦C; 1H NMR (CDCl3,
400 MHz): d 5.87 (s, 1H), 4.01 (dd, 4H, J = 3.2, 4.8 Hz), 2.86–
1.57 (m, 9H), 1.48 (t, 2H, J = 17.2 Hz); 13C NMR (100 MHz,
CDCl3): d 199.6, 164.3, 124.9, 107.8, 64.5, 64.5, 41.5, 36.4, 35.1,
34.1, 32.2, 29.1; IR (neat) cm-1: 2950, 2886, 1671, 1622, 1452, 1334,
1127, 1065, 917, 733; HRMS (EI) calc. for C12H17O3 m/z 209.1178,
found m/z 209.1177.
2-(3¢,4¢,4a¢,7¢,8¢,8a¢-Hexahydro-1¢H-spiro[[1,3]dioxolane-2,2¢-
naphthalene]-4a¢-yl)acetaldehyde (18). A solution of sulfoxide 21
(2.85 g, 7.86 mmol) in decalin (35 mL) was treated with solid
NaHCO3 (25 g, 38.6 mmol) in one portion and heated at 180 ◦C
for 18 h. After being cooled to room temperature, the reaction
mixture was treated with ethyl acetate (150 mL) and water (50 mL).
The organic layer was separated and washed with water and
brine. After drying (Na2SO4), the solvent was removed and the
resultant yellow oil was loaded on a silica pad. The pad was
washed with hexanes to remove the decalin and then washed with
ethyl acetate which was concentrated and purified by a silica gel
column chromatography (10% ethyl acetate in hexanes) to yield
the aldehyde 18 (1.24 g, 69%) as a low melting solid. Rf 0.66 (1 : 2
3¢,4¢,6¢,7¢,8¢,8a¢-Hexahydro-1¢H-spiro[[1,3]dioxolane-2,2¢-naph-
thalen]-6¢-ol (19a). To a solution of enone 19 (0.1 g, 0.48 mmol)
in CH2Cl2 (5 mL) was added DIBAL-H (0.96 mL, 0.96 mmol,
1
ethyl acetate–hexanes); H NMR (CDCl3, 400 MHz): d 9.82 (t,
1H, J = 2.8 Hz), 5.79–5.70 (m, 1H), 5.51 (dd, 1H, J = 1.2, 9.6 Hz),
3.96 (s, 4H), 2.63 (dd, 1H, J = 2.8, 14.8 Hz), 2.33 (dd, 1H, J =
3.6, 14.8 Hz), 2.12–1.49 (m, 11H); 13C NMR (100 MHz, CDCl3):
d 203.0, 131.7, 128.5, 108.7, 64.1, 64.1, 55.6, 36.7, 36.1, 35.4, 34.4,
31.0, 23.1, 21.2; IR (neat) cm-1 3010, 2924, 2725, 1718, 1459, 1366,
1291, 1154, 1102, 1072, 1030, 947, 896, 771; HRMS (EI) calc. for
C14H21O3 m/z 237.1491, found m/z 237.1481.
◦
1 M in toluene) at -78 C. The solution was stirred at the same
temperature for 1 h. The reaction mixture was treated with a
saturated solution of sodium potassium tartarate, and the mixture
was stirred at rt until the solution became clear. The organic
layer was separated from the reaction mixture and the aqueous
layer was extracted with ethyl acetate (2 ¥ 20 mL). The combined
organic extracts were washed with water, brine and dried over
Na2SO4. Concentration of the solution followed by silica gel
column purification (20% ethyl acetate in hexanes) afforded the
alcohol 19a (0.096 g, 99%) as a white solid. Rf 0.52 (1 : 1 ethyl
(3-(3¢,4¢,4a¢,7¢,8¢,8a¢-Hexahydro-1¢H-spiro[[1,3]dioxolane-2,2¢-
naphthalene]-4a¢-yl)prop-1-ynyl)trimethylsilane (22). To a solu-
tion of aldehyde 18 (0.24 g, 1.04 mmol) in CH2Cl2 (15 mL) were
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added CBr4 (1.03 g, 3.126 mmol), PPh3 (0.82 g, 3.126 mmol) and
zinc powder (0.204 g, 3.126 mmol) at 0 ◦C. Then, the reaction
mixture was warmed to room temperature and stirred for 12 h.
The mixture was treated with cold water and extracted with ethyl
acetate (3 ¥ 10 mL). The combined organic layers were washed with
water, brine and dried (Na2SO4). After concentration, the resultant
residue 18a was directly used for the next reaction without further
purification.
to afford the enone 22a (0.18 g) in 62% (brsm) yield as a yellow oil.
Rf 0.58 (1 : 4 ethyl acetate–hexanes); 1H NMR (CDCl3, 400 MHz)
d 6.67 (dd, 1H, J = 1.6, 10.4 Hz), 6.02 (d, 1H, J = 10.4 Hz), 3.95–
3.88 (m, 4H), 2.74 (dd, 1H, J = 4.8, 17.2 Hz), 2.54 (dd, 2H, J =
17.2, 3.6 Hz), 2.39–2.28 (m, 2H), 1.97–1.82 (m, 2H), 1.72–1.42 (m,
4H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3): d 198.3, 154.7,
129.7, 107.8, 102.3, 88.6, 64.2, 64.1, 40.3, 38.8, 37.0, 36.8, 32.7,
31.4, 30.5, -0.09; IR (neat) cm-1 3016, 2917, 2123, 1670, 1410,
1259, 1217, 1094, 1017, 770; HRMS (EI) calc. for C18H27O3Si m/z
319.1729, found m/z 319.1724.
To a solution of enone 22a (0.045 g, 0.141 mmol) in 5%
aqueous acetone (5 mL) was added p-TSA (6 mg) and the reaction
mixture was heated at 60 ◦C for 10 h. After cooling to room
temperature, ethyl acetate (10 mL) was added and the organic layer
was separated. The aqueous layer was extracted with ethyl acetate
(2 ¥ 10 mL) and the combined organic layers were washed with
water, brine and dried (Na2SO4). After concentration, the resultant
compound was purified by silica gel column chromatography (10%
ethyl acetate in hexanes) to afford the ketone 23 (35 mg) in 85%
yield as a yellow oil. Rf 0.36 (1 : 4 ethyl acetate–hexanes); 1H NMR
(CDCl3, 400 MHz) d 6.85 (dd, 1H, J = 0.8, 10.2 Hz), 6.10 (d, 1H,
J = 10.2 Hz), 2.73–2.62 (m, 4H), 2.58–2.26 (m, 5H), 2.17–2.04 (m,
2H), 0.14 (s, 9H); 13C NMR (100 MHz, CDCl3): d 208.7, 196.8,
153.9, 129.8, 101.0, 89.5, 43.2, 40.2, 39.6, 38.7, 37.6, 33.6, 29.5,
29.5, -0.09; IR (neat) cm-1 3016, 2959, 2175, 1716, 1681, 1415,
1388, 1251, 1217, 1042, 1023, 911, 846, 759; HRMS (EI) calc. for
C16H23O2Si m/z 275.1467, found m/z 275.1468.
To a flask containing a Dean–Stark apparatus was placed a
solution of ethylene glycol (1 mL), benzene (20 mL) and p-TSA
(30 mg). The trace amount of water present initially was removed
from the reaction mixture via azeotropic distillation. Then the
compound 18a was added and the water generated from the
reaction mixture was removed during 12 h. After slowly warming
to room temperature, the mixture was treated with a saturated
solution of NaHCO3, and the organic layer was separated and the
aqueous layer was extracted with ethyl acetate (3 ¥ 150 mL). The
combined organic layers were washed with water, brine and dried
(Na2SO4). After concentration, the resultant residue was purified
by silica gel column chromatography (5% ethyl acetate in hexanes)
to afford the vinyl dibromide 18b (0.35 g) in 88% (two steps). Rf
0.56 (1 : 9 ethyl acetate–hexanes); 1H NMR (CDCl3, 400 MHz) d
6.42 (t, 1H, J = 8.0 Hz), 5.72 (dt, 1H, J = 3.6, 6.8 Hz), 5.35 (dd,
1H, J = 1.2, 10.0 Hz), 3.94–3.90 (m, 4H), 2.35 (dd, 1H, J = 6.8,
15.2 Hz), 2.14 (dd, 1H, J = 7.6, 15.2 Hz), 2.02–1.25 (m, 11H); 13
C
NMR (100 MHz, CDCl3): d 135.6, 132.7, 128.1, 109.0, 89.3, 64.1,
64.1, 45.1, 37.3, 35.7, 33.7, 31.0, 23.3, 21.4; IR (neat) cm-1 3011,
2925, 2879, 1613, 1439, 1367, 1290, 1215, 1186, 1152, 1092, 910,
757; HRMS (EI) calc. for C15H21O2Br2 m/z 390.9908, found m/z
390.9926.
4a-(Prop-2-ynyl)-4,4a,8,8a-tetrahydronaphthalene-2,7(1H,3H)-
dione (24). To a solution of ketone 23 (0.03 g, 0.109 mmol)
in THF (1 mL) was added a solution of TBAF (1 M in THF,
0.16 mL, 0.163 mmol) at 0 ◦C. The mixture was warmed to room
temperature and stirred for 1 h. The reaction mixture was treated
with water and extracted with ethyl acetate (10 mL), the organic
layer was separated and the aqueous layer was extracted with
ethyl acetate (2 ¥ 5 mL). The combined organic extracts were
washed successively with water, brine and dried (Na2SO4). After
concentration, the resultant product was purified by silica gel
column chromatography (10% ethyl acetate in hexanes) to afford
the alkyne 24 (12 mg) in 82% yield as a colorless oil. Rf 0.62 (1 : 2
To a solution of dibromo compound 18b (1.75 g, 4.46 mmol) in
THF (75 mL) was added nBuLi (8.36 mL, 1.6 M in hexane, 13.38
◦
mmol) at -78 C. After stirring at the same temperature for 2 h,
TMSCl (1.92 mL, 15.17 mmol) was added to the reaction mixture
and it was further stirred for 30 min. The mixture was then treated
with cold water and extracted with ethyl acetate (3 ¥ 50 mL). The
combined organic layers were washed with water, brine and dried
(Na2SO4). After concentration, the resultant residue was purified
by silica gel column chromatography (5% ethyl acetate in hexanes)
to afford the alkyne 22 (0.98 g) in 73% yield as a yellow oil. Rf 0.62
(1 : 9 ethyl acetate–hexanes); 1H NMR (CDCl3, 400 MHz) d 5.72
(dt, 1H, J = 3.2, 6.4 Hz), 5.44 (dd, 1H, J = 1.6, 10.0 Hz), 3.94–3.92
(m, 4H), 2.32 (d, 2H, J = 16.8 Hz), 2.22 (d, 1H, J = 16.8 Hz),
1.98–1.41 (m, 10H), 0.15 (s, 9H); 13C NMR (100 MHz, CDCl3): d
132.7, 127.7, 109.1, 104.6, 86.8, 64.0, 36.7, 35.6, 34.8, 33.4, 32.9,
31.1, 23.2, 21.3, 0.1; IR (neat) cm-1 3010, 2930, 2170, 1640, 1259,
1217, 1152, 1100, 1028, 844, 763; HRMS (EI) calc. for C18H29O2
Si m/z 305.1937, found m/z 305.1932.
1
ethyl acetate–hexanes); H NMR (CDCl3, 400 MHz) d 6.87 (dd,
1H, J = 0.8, 10.0 Hz), 6.11 (d, 1H, J = 10.2 Hz), 2.69–2.61 (m, 3H),
2.51–2.08 (m, 9H); 13C NMR (100 MHz, CDCl3): d 208.5, 196.7,
153.7, 130.0, 78.8, 72.6, 43.1, 40.2, 39.5, 38.6, 37.6, 33.5, 28.1; IR
(neat) cm-1 3269, 3016, 2923, 2340, 1717, 1674, 1412, 1218, 1034,
777, 669; HRMS (EI) calc. for C13H15O2 m/z 203.1072, found m/z
203.1072.
4a¢-(Prop-2-ynyl)-3¢,4¢,4a¢,7¢,8¢,8a¢-hexahydro-1¢H-spiro[[1,3]-
dioxolane-2,2¢-naphthalene] (25). To a solution of aldehyde 18
(0.21 g, 0.91 mmol) in MeOH (4 mL) was added a solution of
diethyl 1-diazo-2-oxopropylphosphonate (0.30 g, 1.36 mmol) in
MeOH (5 mL) followed by the addition of K2CO3 at 0 ◦C. After
addition, it was brought to rt and stirred overnight. The reaction
was quenched with sat. aq. NH4Cl solution (10 mL) and extracted
with ether (3 ¥ 20 mL). The combined organic layers were washed
with sat. aq. NaHCO3 solution (10 mL), water (10 mL) and
brine (10 mL) sequentially, dried and concentrated to afford
the crude product which was purified by silica gel flash column
chromatography (10–15% ethyl acetate in hexanes) to furnish
4a-(3-(Trimethylsilyl)prop-2-ynyl)-4,4a,8,8a-tetrahydronaphth-
alene-2,7(1H,3H)-dione (23). To a solution of alkene 22 (0.1 g,
0.328 mmol) in benzene (3 mL) were added PDC (0.423 g, 1.31
mmol), tert-butyl hydroperoxide (0.118 g, 1.31 mmol) and Celite
◦
(0.4 g) at 10 C. After being stirred at the same temperature for
10 min, the reaction mixture was slowly warmed to rt and stirred
for 4 h. The mixture was treated with diethyl ether, filtered through
a pad of Celite and the residue was washed with 40 mL of ethyl
acetate. After concentration, the resultant compound was purified
by silica gel column chromatography (8% ethyl acetate in hexanes)
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alkyne 25 (0.15 g) in 73% yield as a pale yellow oil. Rf 0.72 (1 : 3
ethyl acetate–hexanes); H NMR (CDCl3, 400 MHz) d 5.72 (dt,
40.2, 38.8, 37.6, 37.1, 35.4, 34.0, 31.8, 29.5, 28.9; IR (neat) cm-1
3425, 2928, 2346, 1701, 1669, 1415, 1053, 768; HRMS (EI) calc.
for C13H17O2 m/z 205.1229, found m/z 205.1227.
1
1H, J = 3.2, 6.4 Hz), 5.44 (dd, 1H, J = 1.6, 6.4 Hz), 3.96–3.92
(m, 4H), 2.32 (d, 2H, J = 16.8 Hz), 2.22 (d, 1H, J = 16.8 Hz),
1.99–1.42 (m, 11H); 13C NMR (100 MHz, CDCl3): d 132.7, 127.7,
109.1, 104.6, 86.8, 64.0, 36.7, 35.6, 34.8, 33.4, 32.9, 31.1, 23.2, 21.3;
IR (CHCl3) cm-1 3307, 3019, 2928, 2854, 2706, 2400, 2115, 1459,
1365, 1216, 1090, 757, 669; HRMS (EI) calc. for C15H21O2 m/z
233.1542, found m/z 233.1546.
S-Methyl O-7-oxo-4a-(prop-2-ynyl)-1,2,3,4,4a,7,8,8a-octahy-
dronaphthalen-2-yl carbonodithioate (15). To a stirred suspension
of NaH (4.9 mg, 0.204 mmol) in THF (2 mL) was added alcohol
16 (13 mg, 0.063 mmol) in THF (2 mL) at 0 ◦C. After stirring
for 20 min at the same temperature, CS2 (0.011 mL) was added
and again stirred for another 30 min at room temperature.
MeI (0.006 mL, 0.101 mmol) was added and was allowed to
stirr for 15 min. The reaction mixture was then treated with
1–2 drops of AcOH. The reaction mixture was filtered and
washed with ethyl acetate (2 ¥ 20 mL). The organic layer was
washed with water, brine and dried (Na2SO4). After evaporation
of the solvent the resultant residue was purified by silica gel
column chromatography (5% ethyl acetate in hexanes) to afford
compound 15 (17 mg, 91%) as a yellow oil. Rf 0.72 (1 : 4 ethyl
4a¢-(Prop-2-ynyl)-4¢,4a¢,8¢,8a¢-tetrahydro-1¢H -spiro[[1,3]di-
oxolane-2,2¢-naphthalen]-7¢(3¢H)-one (17). To
a solution of
alkene 25 (0.15 g, 0.66 mmol) and Celite (0.79 g) in benzene
(8 mL) were added PDC (0.998 g, 2.65 mmol), 70% tert-butyl
hydroperoxide (0.365 mL, 2.65 mmol) at 10 ◦C. After being stirred
at the same temperature for 10 min, the reaction mixture was
slowly warmed to rt and stirred overnight. The mixture was treated
with diethyl ether, filtered through a pad of Celite and the residue
was washed with 40 mL of ethyl acetate. After concentration,
the resultant compound was purified by silica gel flash column
chromatography (15–20% ethyl acetate in hexanes) to afford enone
17 (0.07 g) in 44% (72% brsm) yield as a yellow oil. Rf 0.54 (1 : 3
1
acetate–hexanes); H NMR (CDCl3, 400 MHz) d 6.66 (dd, 1H,
J = 2.0, 13.8 Hz), 6.05 (d, 1H, J = 10.0 Hz), 5.58–5.51 (m, 1H),
2.80 (dd, 1H, J = 5.2, 17.6 Hz), 2.61–1.52 (m, 14H); 13C NMR
(100 MHz, CDCl3): d 215.2, 197.6, 154.4, 131.8, 129.9, 80.6, 79.4,
78.2, 72.3, 72.0, 40.4, 39.9, 38.8, 36.8, 33.1, 32.7, 31.7, 29.3, 27.4,
26.0, 18.8, 17.9; HRMS (EI) calc. for C15H19O2S2 m/z 295.0826,
found m/z 295.0834.
1
ethyl acetate–hexanes); H NMR (CDCl3, 400 MHz) d 6.66 (dd,
1H, J = 1.5, 10.0 Hz), 6.02 (d, 1H, J = 10.0 Hz), 3.88 (s, 4H), 2.68–
2.58 (m, 1H), 2.49–2.28 (m, 5H), 2.08 (t, 1H, J = 2.7 Hz), 1.94–1.81
(m, 1H), 1.70–1.44 (m, 4H); 13C NMR (100 MHz, CDCl3): d 198.3,
155.0, 130.7, 107.8, 102.3, 88.6, 64.2, 64.1, 40.3, 38.8, 37.0, 36.8,
32.7, 31.4, 30.5; IR (CHCl3) cm-1 3307, 3019, 2927, 1676, 1216,
1092, 758, 669; HRMS (EI) calc. for C15H19O3 m/z 247.1334, found
m/z 247.1344.
7-Iodo-4a-(prop-2-ynyl)-4a,5,6,7,8,8a-hexahydronaphthalen-2-
(1H)-one (26). To a solution of alcohol 16 (0.022 g, 0.107 mmol)
in THF (2.2 mL) was added sequentially imidazole (0.0218 g,
0.321 mmol), PPh3 (0.0564 g, 0.215 mmol) and I2 (0.0547 g, 0.215
◦
mmol) at 0 C. After addition, the reaction was stirred at rt for
4a-(Prop-2-ynyl)-4,4a,8,8a-tetrahydronaphthalene-2,7(1H,3H)-
dione (24). To a solution of ketal 17 (0.08 g, 0.325 mmol) in
MeOH (6.5 mL) and water (6.5 mL) was added p-TSA (0.031 g,
0.163 mmol) at rt, followed by stirring overnight at the same
temperature. The reaction mixture was quenched with sat. aq.
NaHCO3 solution, and extracted with CH2Cl2 (3 ¥ 10 mL). The
combined organic layers were dried, concentrated, and purified by
silica gel column chromatography as above obtained from 23, to
afford ketone 24 (0.053 g, 85%) as a colorless oil.
1 h followed by the addition of 5% Na2SO3 solution (5 mL). The
reaction mixture was extracted with Et2O, and the organic layer
was dried and concentrated to afford the crude product, which
was purified by silica gel flash column chromatography (10–15%
ethyl acetate in hexanes) to afford iodide 26 (0.023 g, 70%) as an
inseparable diastereomers, and as a pale yellow oil. Rf 0.75 (1 : 3
1
ethyl acetate–hexanes); H NMR (CDCl3, 400 MHz) d 6.66 (d,
1H, J = 9.8 Hz), 6.00 (d, 1H, J = 10.1 Hz), 4.62 (br s, 1H), 2.69–
2.29 (m, 5H), 2.14–2.05 (m, 4H), 1.83–1.63 (m, 3H); 13C NMR
(100 MHz, CDCl3): d 198.2, 155.7, 129.3, 79.3, 72.2, 72.1, 39.5,
38.9, 36.6, 33.1, 32.5, 29.6, 29.0; IR (CHCl3) cm-1 3307, 3019,
2930, 2856, 1675, 1215, 758, 669; HRMS (EI) calc. for C13H16OI
m/z 315.0246, found m/z 315.0238.
7-Hydroxy-4a-(prop-2-ynyl)-4a,5,6,7,8,8a-hexahydronaphtha-
len-2(1H)-one (16). To a solution of ketone 24 (4.5 mg, 0.022
mmol) in ethanol (0.5 mL) was added NaBH4 (0.21 mg, 0.005
◦
mmol) in ethanol (0.5 mL) over a period of 2 h at -20 C. After
the addition was completed, the reaction mixture was stirred for
another 1 h at the same temperature. The mixture was treated
with glacial acetic acid (0.01 mL) and stirred for 5 min at the
same temperature. After solvent evaporation, the residue was
partitioned between ethyl acetate (2 ¥ 10 mL) and saturated
NaCl (2 ¥ 10 mL). The organic layer was dried over Na2SO4 and
evaporated and the resultant compound was purified by silica gel
column chromatography (15% ethyl acetate in hexanes) to afford
16 (3.5 mg, 77%) in 1 : 5 ratio as a yellow oil. Rf 0.36 (1 : 2 ethyl
7-Iodo-4a-(prop-2-ynyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-
2-ol (27). To a solution of enone 26 (110 mg, 0.35 mmol) in
CH2Cl2 (3 mL) was added DIBAL-H (0.385 mL, 0.385 mmol,
1 M in toluene) dropwise at -78 ◦C followed by stirring at the
same temperature for 1 h. Then the reaction mixture was quenched
with saturated aqueous sodium potassium tartrate solution (10
mL) at -78 ◦C and brought to room temperature. The reaction
mixture was extracted with CH2Cl2 (3 ¥ 10 mL), and the combined
organic layers were dried and concentrated. The crude product was
purified by flash column chromatography (10–25% ethyl acetate in
hexanes) to afford allylic alcohol 27 (70 mg, 63%) as an inseparable
mixture of diastereomers, and as a colorless oil. Rf 0.45 (1 : 3 ethyl
1
acetate–hexanes); H NMR (CDCl3, 400 MHz) d 6.63 (dd, 1H,
J = 2.0, 10.2 Hz), 6.04 (d, 1H, J = 10.2 H), 3.72–3.64 (m, 1H),
2.81 (dd, 1H, J = 5.2, 17.6 Hz), 2.51 (t, 1H, J = 2.8 Hz), 2.47 (dd,
1H, J = 2.4, 13.6 Hz), 2.39–2.23 (m, 2H), 2.10 (t, 1H, J = 2.8 Hz),
1.96–1.24 (m, 6H); 13C NMR (100 MHz, CDCl3): d 197.9, 195.7,
155.4, 154.9, 129.9, 129.3, 110.0, 79.7, 76.6, 71.9, 69.4, 65.5, 40.5,
1
acetate–hexanes); H NMR (CDCl3, 400 MHz) d 5.81–5.47 (m,
2H), 4.44–4.02 (m, 2H), 2.52–2.20 (m, 3H), 2.20–1.80 (m, 5H),
1.80–1.45 (m, 4H); 13C NMR (100 MHz, CDCl3): d 159.2, 138.2,
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136.5, 135.1, 131.4, 130.2, 81.0, 80.9, 80.8, 71.5, 71.4, 71.3, 64.9,
64.3, 41.6, 41.5, 40.7, 40.3, 38.4, 37.4, 37.0, 37.0, 36.9, 35.4, 34.6,
34.4, 33.9, 33.7, 33.4, 32.8, 32.1, 27.9, 27.6; IR (CHCl3) cm-1 3684,
3306, 3019, 2931, 2400, 1522, 1426, 1215, 1021, 929, 758; HRMS
(EI) calc. for C13H17ONaI m/z 339.0222, found m/z 339.0215.
oil. Rf 0.75 (12% ethyl acetate in hexanes); 1H NMR (CDCl3, 400
MHz) d 7.00–6.95 (m, 1H), 6.06 (dt, 1H, J = 10.2, 1.8 Hz), 4.18
(q, 2H, J = 7.0 Hz), 2.84 (dd, 1H, J = 16.8, 2.5 Hz), 2.72 (dd, 1H,
J = 16.8, 2.5 Hz), 2.66–2.51 (m, 2H), 2.45–2.34 (m, 1H), 2.28–2.20
(m, 1H), 2.03 (t, 1H, J = 2.5 Hz), 1.24 (t, 3H, J = 6.9 Hz); 13C
NMR (100 MHz, CDCl3): d 194.1, 170.0, 150.2, 128.6, 79.4, 71.1,
61.6, 55.9, 29.7, 23.9, 23.5, 13.9; IR (CHCl3) cm-1 3308, 3020,
2984, 2933, 2401, 2122, 1731, 1683, 1388, 1216, 1019, 758; HRMS
(EI) calc. for C12H14O3Na m/z 229.0841, found m/z 229.0845.
Core structure of platencin (14). To a solution of iodide 27
(70 mg, 0.22 mmol) in degassed dry benzene (50 mL) was added
a solution of nBu3SnH (154 mg, 0.53 mmol) and AIBN (8.7 mg,
0.052 mmol) in degassed dry benzene (5 mL) at reflux conditions
over a period of 2 h by a syringe pump. After addition, the reaction
mixture was cooled to room temperature, and the volatiles were
removed in a rotovapor to afford the crude cyclised product. To
a solution of the above crude allylic alcohol in CH2Cl2 (5 mL)
was added MnO2 (200 mg, 2.3 mmol) at room temperature. After
stirring overnight at the same temperature, the reaction mixture
was filtered through a pad of Celite and silica gel, washed with
CH2Cl2. The combined filtrates were concentrated and purified
by flash column chromatography (1–20% ethyl acetate in hexanes)
to afford the core structure of platencin 14 (18 mg, 43% for two
steps) as a colorless oil. Rf 0.65 (12% ethyl acetate in hexanes); 1H
NMR (CDCl3, 400 MHz) d 6.56 (d, 1H, J = 10.0 Hz), 5.87 (dd,
1H, J = 10.0, 0.9 Hz), 4.83 (dt, 1H, J = 3.0, 1.6 Hz), 4.69 (dd,
1H, J = 4.0, 1.8 Hz), 2.48–2.39 (m, 2H), 2.36–2.28 (m, 2H), 2.19–
2.07 (m, 2H), 2.04–1.97 (m, 1H), 1.80–1.65 (m, 3H), 1.54–1.48 (m,
1H), 1.20 (ddd, 1H, J = 12.6, 7.9, 1.5 Hz); 13C NMR (CDCl3, 100
MHz) d: 200.3, 156.9, 149.1, 127.9, 107.1, 41.8, 41.1, 36.2, 35.8,
35.7, 35.1, 26.6, 24.7; IR (CHCl3) cm-1 3020, 2928, 2857, 1682,
1464, 1216, 1084, 1026, 759; HRMS (EI) calc. for C13H17O m/z
189.1279, found m/z 189.1282. These data are in good agreement
with the literature reports.9b
Ethyl
5-methylene-2-oxobicyclo[2.2.2]octane-1-carboxylate
(30)21. To a solution of enone 31 (100 mg, 0.485 mmol) in
dry tBuOH (25 mL) were added AIBN (16 mg, 0.097 mmol)
and then nBu3SnH dropwise rt. After addition, the reaction
flash was immersed into an oil bath preheated to 120 ◦C, and
refluxed at that temperature for 5 h. After cooling to rt, the
solvent was evaporated, redissolved in CH2Cl2 (10 mL), and the
treated with PPTS (400 mg). After stirring overnight at rt, the
reaction mixture was quenched with saturated aqueous NaHCO3
solution, extracted with EtOAc. The combined organic layers
were dried and concentrated to afford the crude product, which
was purified by flash column chromatography (10–20% ethyl
acetate in hexanes) to furnish ketoester 30 (53 mg, 52%) as a
pale yellow oil. 1H NMR (400 MHz) d 4.92 (d, 1H, J = 0.9 Hz),
4.77 (q, 1H, J = 2.0 Hz), 4.18 (q, 2H, J = 7.2 Hz), 2.98 (dq, 1H,
J = 17.8, 2.6 Hz), 2.70 (t, 1H, J = 2.8 Hz), 2.64 (dt, 1H, J =
17.8, 2.1 Hz), 2.37 (dq, 2H, J = 2.8, 0.9 Hz), 2.34–2.26 (m, 1H),
1.94–1.73 (m, 3H), 1.28 (t, 3 H, J = 7.1 Hz); 13C NMR (100 MHz)
d 209.5, 170.9, 145.5, 108.2, 61.0, 55.9, 44.2, 38.2, 34.4, 25.5,
25.2, 14.0; IR (CHCl3) cm-1 3021,2938, 2873, 1746, 1450, 1249,
1216 cm-1; HRMS (EI) calc. for C12H17O3 m/z 209.1178, found
m/z 209.1174.
Ethyl 2-oxocyclohex-3-enecarboxylate (32)20. To a solution of
cyclohexenone (1 g, 10.4 mmol) in THF (33 mL) was added
a solution of LDA (16.66 mL, 12.5 mmol, 0.75 M solution in
THF) dropwise at -78 ◦C over 10 min. After stirring for 45 min,
ethylcyanoformate (1.13 g, 11.44 mmol) was added dropwise
1-(Hydroxymethyl)-5-methylenebicyclo[2.2.2]octan-2-ol (30b).
To a solution of ketoester 30 (120 mg, 0.576 mmol) in dry Et2O
(5 mL) was added LAH portion wise at 0 ◦C. After addition,
the reaction mixture was stirred for another 2 h at 0 ◦C, and then
quenched with wet Na2SO4/Celite (1 : 1 mixture with a little water)
at 0 ◦C. After stirring at rt for 2 h, the reaction mixture was filtered
through Celite, washed with EtOAc, and concentrated. The crude
material was purified by flash column chromatography (40–60%
ethyl acetate in hexanes) to afford diol 30b (50 mg, 52%) as a
◦
followed by stirring at -78 C for 4 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution and extracted
with EtOAc. The combined organic layers were washed with brine,
dried and concentrated. The crude product was purified by flash
column chromatography (15–25% ethyl acetate in hexanes) to
afford ketoester 32 (1.15 g, 66%) as a yellow oil. Rf 0.55 (12%
1
mixture of diastereomers, and as a colorless oil. H NMR (400
1
ethyl acetate in hexanes); H NMR (CDCl3, 400 MHz) d 7.03–
MHz) d 4.82–4.74 (m, 1H), 4.70–4.59 (m, 1H), 4.01–3.92 (m, 1H),
3.58–3.42 (m, 2H), 2.32–2.22 (m, 1H), 2.18–2.02 (m, 2H), 2.0–1.95
(m, 1H), 1.95–1.72 (m, 2H), 1.68–1.38 (m, 3H), 1.28–1.20 (m, 1H);
13C NMR (100 MHz) d 150.2, 149.6, 105.9, 105.7, 72.7, 72.7, 70.6,
70.5, 39.1, 38.9, 38.7, 38.2, 36.1, 36.1, 35.3, 30.6, 26.2, 25.9, 25.4,
21.1; IR (CHCl3) cm-1 3382, 2934, 1216, 1031, 909, 759; HRMS
(EI) calc. for C10H16O2Na m/z 191.1048, found m/z 191.1051.
6.99 (m, 1H), 6.07 (dt, 1H, J = 9.9, 1.8 Hz), 4.26–4.17 (m, 2H),
3.40 (dd, 1H, J = 9.9, 4.8 Hz), 2.56–2.45 (m, 1H), 2.40–2.33 (m,
2H), 2.27–2.17 (m, 1H), 1.34–1.20 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 193.9, 169.9, 150.5, 129.0, 61.1, 53.3, 25.5, 24.2, 14.0;
IR (CHCl3) cm-1 3021, 2984, 2939, 1735, 1684, 1446, 1426, 1389,
1373, 1308, 1219, 1170, 1125, 1096, 1080, 1072, 757.
Ethyl 2-oxo-1-(prop-2-ynyl)cyclohex-3-enecarboxylate (31).
To a solution of ketoester 32 (1.15 g, 6.84 mmol) in dry acetone
(41 mL) was added K2CO3 in one portion at rt. After stirring for
a few minutes, propargyl bromide (1.6 mL, 14.37 mmol, 80 wt%
in toluene) was introduced dropwise. After addition, the reaction
mixture was refluxed for 3.5 h followed by filtration through
Celite and concentration to afford the crude material, which was
purified by flash column chromatography (10–20% ethyl acetate
in hexanes) to provide enone ester 31 (1.0 g, 72%) as a pale yellow
5-Methylene-2-oxobicyclo[2.2.2]octane-1-carbaldehyde
(36).
To a solution of oxalyl chloride (218 mg, 1.72 mmol) in CH2Cl2
(2.1 ◦mL) was added DMSO (208 mg, 2.67 mmol) dropwise at
-78 C. After stirring for 30 min, a solution of diol 30b (50 mg,
0.297 mmol) in CH2Cl2 (2.1 mL) was added dropwise followed
by stirring for 3 h at the same temperature. Then, Et3N (344 mg,
3.41 mmol) was added dropwise at -78 ◦C, followed by stirring
for 2 h. The reaction mixture was quenched with aqueous NH4Cl
solution, extracted with EtOAc. The combined organic layers
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were dried and concentrated to provide the crude product, which
was purified by flash column chromatography (15–20% ethyl
acetate in hexanes) to afford ketoaldehyde 36 (50 mg, quantitative)
20.5; IR (CHCl3) cm-1 3019, 2929, 1660, 1216, 758, 669; HRMS
(EI) calc. for C13H17O m/z 189.1279, found m/z 189.1271.
Ketone 339g,k,n
. To a solution of enone 34 (20 mg, 0.106 mmol)
1
as a colorless oil. H NMR (400 MHz) d 9.89 (s, 1H), 5.01 (m,
in THF (3 mL) was added Ra-Ni (3 ¥ 0.5 g) three times after every
1 h at rt. After addition, the reaction mixture was stirred further
for 4 h, then diluted with ether, filtered through silica gel and
washed with ether. The combined filtrates were concentrated and
purified by flash column chromatography (30–35% ethyl acetate
in hexanes) to yield a 3 : 1 inseparable mixture of diastereomers 33
and 38 (17 mg, 85%) in favor of the desired isomer 33, as a colorless
sticky liquid. 1H NMR (400 MHz) d 4.74 (q, 1H, J = 2.3 Hz), 4.71
(q, 1H, J = 2.2 Hz, minor isomer) 4.60 (q, 1H, J = 2.0 Hz), 4.56
(q, 1H, J = 2.0 Hz, minor isomer), 2.79 (dq, 2H, J = 17.2, 2.0 Hz,
minor isomer), 2.42–2.08 (m, 7H), 1.98–1.88 (m, 2H), 1.88–1.72
(m, 1H), 1.68–1.58 (m, 3H), 1.53–1.40 (m, 1H), 1.28–1.14 (m,
1H), 1.12–1.02 (m, 1H); 13C NMR (100 MHz) d 211.9, 150.8,
105.7, 46.5, 43.3, 39.0, 38.6, 37.9, 37.7, 37.0, 35.6, 35.5, 34.3, 33.7,
32.5, 26.7, 26.5, 24.2; IR (CHCl3) cm-1 3068, 3015, 2928, 2862,
1714, 1651, 1451, 1356, 1237, 910, 878, 756, 667; HRMS (EI) calc.
for C13H19O m/z 191.1436, found m/z 191.1432. These data are
in good agreement with the previous literature reports.9g,k,n Only
clearly discernible peaks are reported for the minor isomer 38 in
the 1H NMR spectrum.
1H), 4.86 (m, 1H), 2.76 (dq, 2H, J = 17.6, 2.6 Hz), 2.58 (dt, 1H,
J = 17.6, 2.3 Hz), 2.43 (m, 2H), 2.22–2.08 (m, 1H), 2.02–1.75 (m,
3H); 13C NMR (100 MHz) d 212.7, 201.7, 144.8, 109.4, 57.6, 45.1,
38.3, 32.0, 25.1, 24.0; IR (CHCl3) cm-1 3019, 2944, 2874, 1718
(broad), 1430, 1400, 1216, 758; HRMS (EI) calc. for C10H12O2Na
m/z 187.0735, found m/z 187.0736.
(E)-5-Methylene-1-(3-oxobut-1-enyl)bicyclo[2.2.2]octan-2-one
(35). To a suspension of NaH (14.6 mg, 0.365 mmol) in THF
(0.8 mL) was added diethyl 2-oxopropylphosphonate (75.7 mg,
0.39 mmol) dropwise at rt. After 10 min, this solution was syringed
out and added to a solution of keto aldehyde 36 (50 mg, 0.30 mmol)
in THF (2.3 mL) at 0 ◦C. After stirring for 30 min at the same
temperature, the reaction mixture was diluted with brine solution,
and extracted with ether. The combined organic layers were dried
and concentrated to afford the crude product, which was purified
by flash column (20–25% ethyl acetate in hexanes) to yield enone
35 (55 mg, 89%) as a pale yellow oil. 1H NMR (400 MHz) d 7.10
(d, 1H, J = 16.9 Hz), 6.01 (d, 1H, J = 16.9 Hz), 4.99 (d, 1H, J =
0.8 Hz), 4.81 (d, 1H, J = 1.1 Hz), 2.78 (t, 1H, J = 2.9 Hz), 2.60
(q, 2H, J = 2.6 Hz), 2.43 (d, 2H, J = 2.9 Hz), 2.31 (s, 3H), 1.98–
1.76 (m, 4H); 13C NMR (75 MHz) d 212.4, 198.7, 147.0, 146.9,
145.6, 130.6, 108.5, 49.7, 44.6, 38.1, 36.4, 28.4, 26.6, 26.6, 25.7;
IR (CHCl3) cm-1 3019, 2943, 2876, 2400, 1720, 1676, 1630, 1259,
1216, 1100, 1032, 979, 908, 759; HRMS (EI) calc. for C13H17O2
m/z 205.1229, found m/z 205.1228.
Acknowledgements
We thank DST, New Delhi and SAIF, IIT Bombay for financial
support and the use of spectral facilities, respectively. K.P.K.
thanks DST for the award of the Swarnajayanti fellowship. K.P.
and A.V.S. thank CSIR, New Delhi for fellowships.
5-Methylene-1-(3-oxobutyl)bicyclo[2.2.2]octan-2-one (37). To
a solution of enone 35 (55 mg, 0.269 mmol) in THF (3 mL)
was added Ra-Ni (3 ¥ 0.5 g) three times after every 1 h at rt.
After addition, the reaction mixture was stirred further for 3.5 h,
then diluted with ether, filtered through a pad of silica gel and
washed with ether. The combined filtrates were concentrated and
purified by flash column chromatography (30–35% ethyl acetate in
hexanes) to yield diketone 37 (55 mg, quantitative) as a colorless
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oil. H NMR (400 MHz) d 4.89 (d, 1H, J = 1.1 Hz), 4.71 (d,
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