A new cycloheptenone annulation method: Use of the bifunctional reagent (Z)-5-iodo-l-tributylstannyIpent-l-ene in organic synthesis

Article abstract of DOI:10.1039/a909922k

A new seven-membered annulation method that employs (Z)-5-iodo-l-tributylstannylpent-l-ene (1) as a key reagent and that is exemplified by the conversion of compounds 6, 12, 13, 20, 25, and 26 into the annulation products 11, 18, 19, 24, 33, and 34, respe

Full text of DOI:10.1039/a909922k

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A new cycloheptenone annulation method: use of the bifunctional
reagent (Z)-5-iodo-1-tributylstannylpent-1-ene in organic synthesis
Edward Piers,* Shawn D. Walker and Ralph Armbrust
1
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver,
British Columbia, Canada V6T 1Z1. Fax: 1-604-822-2847; E:mail: epier@interchange.ubc.ca
Received (in Cambridge, UK) 21st December 1999, Accepted 1st February 2000
A new seven-membered annulation method that employs
(Z)-5-iodo-1-tributylstannylpent-1-ene (1) as a key reagent
and that is exemplified by the conversion of compounds 6,
12, 13, 20, 25, and 26 into the annulation products 11, 18,
19, 24, 33, and 34, respectively, is reported.
Seven-membered carbocycles commonly make up part of the
constitution of a variety of structurally novel, biologically
interesting natural products. Over the years, a number of
methods for the construction of seven-membered rings have
been devised and successfully employed in complex molecule
synthesis. Examples of such methods include the homo-Cope
rearrangement of 1,2-divinylcyclopropane systems,1 ring
expansion reactions,2 and cycloaddition processes [4 ϩ 3 (see
ref. 3) and 5 ϩ 2 (see ref. 4)]. In connection with another study
in progress in our laboratory, we wished to carry out a seven-
Scheme 2
membered ring annulation shown in general terms by the con-
version of a ketone A into a cycloheptenone B (Scheme 1). We
unit by treatment of 8 with ethanoic acid–sodium ethanoate in
aqueous THF at rt produced the ketone 9. It should be noted
that the three-step conversion of 6 into 9, which was easily and
conveniently performed without purification of the intermedi-
ates 7 and 8, was highly efficient and produced 9 in an overall
yield of 90%. Treatment of a cold (Ϫ78 ЊC) THF solution of
9 with BuLi (2.1 equiv.)12 produced, after a suitable work-up
procedure, the ring-closed product 10 in 84% yield as a single
diastereomer of undetermined configuration. The annulation
process (~64% overall yield, 6→11) was completed by treatment
of 10 with PCC13 in the presence of 3 Å molecular sieves.14
Typically, in this and subsequent oxidative conversions of ter-
tiary allylic alcohols to the corresponding cycloheptenones,
~0.85 g of molecular sieves per mmol of substrate was
employed. The sieves were powdered and flame-dried under
reduced pressure (vacuum pump) prior to use. In general, the
oxidative conversions in the presence of the molecular sieves
were superior (i.e., faster and more efficient) to those carried
out in the absence of the sieves.
Subjection of the dimethylhydrazones 12, 13, and 20 to the
alkylation–iododestannylation–hydrolysis protocol described
above provided the iodo ketones 14, 15, and 21, respectively, in
overall yields >90%. The product 21, which consisted of three
diastereomers, was equilibrated with sodium methoxide in
methanol. Purification of the resultant material by chromato-
graphy on silica gel afforded the most stable diastereomer 22 in
69% overall yield from 20. Butyllithium-induced ring closure12
of 14, 15, and 22 furnished the tertiary allylic alcohols (16, 17,
23, respectively) in good-to-excellent yields. Although 16 was
produced as a mixture of epimers (~5:1), the alcohols 17 and
23 were obtained in diastereomerically pure form. The relative
configurations at the newly formed ring junctions of these
materials are of no consequence to the overall annulation pro-
cesses and, consequently, were not determined. The only other
product detected in each of these reactions was uncyclized
material in which the iodine of the starting material was
replaced by a hydrogen. In each case, this (minor) product was
readily separated from the requisite alcohol by flash chromato-
Scheme 1
report herein the development of a new, concise protocol for
effecting such annulations. The novel bifunctional reagent
(Z)-5-iodo-1-tributylstannylpent-1-ene (1) played a pivotal role
in the elaboration of this new method.
The alkenylstannane 1 was prepared as shown in Scheme 2.
Commercial pent-4-yn-1-ol (2) was converted into the silyl
ether 3,† which, upon deprotonation with MeLi and reaction of
the resultant lithium acetylide with Bu3SnCl, afforded the
alkynylstannane 4. Subjection of 4 to hydrozirconation with
Schwartz’s reagent,5 followed by protonation of the resultant
intermediate,6 produced the required (Z)-alkenylstannane 5.
Routine fluoride-induced cleavage of the silyl ether of 5 and
reaction of the acquired alcohol with Ph3PؒI2–imidazole7 gave
the key bifunctional reagent 1. The overall yield of 1 from
pent-4-yn-1-ol (2) was ~70%. Substance 1 was stored in the
dark over copper wire and, under these conditions, has been
found to be stable for over one year at ambient temperature.
The new annulation protocol is illustrated initially by the
transformation of the dimethylhydrazone 68 into the bicyclic
cycloheptenone 11, as summarised in Scheme 3. Treatment of 6
with LDA in THF at Ϫ78 ЊC and then at 0 ЊC, followed by
addition of HMPT, cooling to Ϫ78 ЊC, addition of the electro-
phile 1, and warming of the reaction mixture to rt, provided the
alkylated9 hydrazone 7. In order to avoid the possibility of
protiodestannylation of the alkenylstannane function during
hydrolysis of the hydrazone moiety, the intermediate 7 was sub-
jected to iododestannylation,10 which provided, stereospecific-
ally, the iodide 8. At this stage, hydrolysis11 of the hydrazone
DOI: 10.1039/a909922k
J. Chem. Soc., Perkin Trans. 1, 2000, 635–637
This journal is © The Royal Society of Chemistry 2000
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Scheme 4 Reagents and conditions: (a) i, KH, THF, rt, 45 min; ii, 1,
THF, reflux, 15–17 h; (b) I2, CH2Cl2 rt, 15 min; (c) BuLi (2.1 equiv.),
THF, 0 ЊC, 45 min; (d) PCC (2–3 equiv.), 3 Å molecular sieves, CH2Cl2,
reflux, 5.5 h for 31; 2.5 h for 32.
products increased. It should be noted that, with respect to the
cyclisation process, the reactions were highly chemoselective.
No products that would have resulted from ring closure
involving the ester carbonyl functions could be detected in the
crude product mixtures.
Since any uncyclised by-products produced in the reactions
were difficult to separate chromatographically from the
required tertiary allylic alcohols 31 and 32, the crude products
were subjected directly to oxidation with PCC13 in refluxing
dichloromethane containing 3 Å molecular sieves.14 Subsequent
purification of the crude products by chromatography on silica
gel gave the enones 33 and 34 in moderate overall yields from
29 and 30, respectively.
The dramatic beneficial effect of using molecular sieves in the
PCC oxidation of 31 and 32 deserves emphasis. Oxidations of
the (crude) allylic alcohols 31 and 32 under other conditions
(e.g. PCC, NaOAc, CH2Cl2;13 PCC adsorbed on alumina15 in
refluxing CH2Cl2 or refluxing benzene) were very slow and
required long reaction times (~2 days) with a large excess
of PCC in order to drive the reaction to completion.
Unfortunately, these forcing conditions led to concomitant
formation of polar by-products and gave low yields of the
enones. These difficulties were largely circumvented when the
protocol outlined above (Scheme 4) was employed.
In summary, the bifunctional reagent 1 has been success-
fully employed in the development of a new cycloheptenone
annulation method. The individual reactions involved are
experimentally straightforward and the overall yields of the
annulation processes are good to excellent. Of particular note
are the high yields associated with the BuLi-mediated ring
closure of seven-membered rings in the transformations of 9,
14, 15, 22, 29, and 30 into 10, 16, 17, 23, 31, and 32, respectively.
Extensions of this method to natural product synthesis are
being investigated and the results will be reported in due course.
Scheme 3 Reagents and conditions: (a) i, LDA, THF, Ϫ78 ЊC, 5 min,
then 0 ЊC, 2 h; ii. 1, THF–HMPT, Ϫ78 ЊC to rt, 15 h; (b) I2, CH2Cl2, rt,
15 min; (c) HOAc, NaOAc, THF H2O, rt, 15 min for 9; 3 h for 14, 15,
and 21; (d) BuLi (2.1 equiv.), THF, Ϫ78 ЊC, 1 h; (e) PCC (2–3 equiv.), 3 Å
molecular sieves, CH2Cl2, rt, 2 h for 10; 23 h for 16; 1 h for 17; 3 h for 23;
(f) NaOMe, MeOH, rt, 15 h.
graphy of the mixture on silica gel. Exposure of each of the
compounds 16, 17, and 23 to PCC13 in the presence of 3 Å
molecular sieves14 provided the enone annulation products 18
(74%), 19 (82%), and 24 (86%), respectively. It should be noted
that the oxidative conversion 16→18 was slower than the trans-
formations 17→19 and 23→24. Monitoring the oxidation of 16
by TLC indicated that one diastereomer of 16 was transformed
into 18 at a rate slower than that of the other isomer. However,
the reaction was complete after the mixture had been stirred
overnight.
Application of the new method was extended to annulation
of cyclic β-keto ester substrates (Scheme 4). Reaction of iodide
1 with the potassium enolates of the keto esters 25 and 26 in
refluxing THF led to excellent yields of the alkylated products
27 and 28. Treatment of each of these substances with I2 in
dichloromethane smoothly effected iododestannylation to pro-
duce the iodides 29 and 30. Experimentation showed that,
compared with the substrates (9, 14, 15, 22) discussed above,
the BuLi-mediated cyclisations of the iodides 29 and 30 are
more efficiently carried out at 0 ЊC than at Ϫ78 ЊC. Thus, treat-
ment of 29 and 30 with BuLi under the conditions given in
Scheme 4 provided very good yields of the corresponding
bicycles 31 and 32. In each case, the desired alcohol (a single
diastereomer, configuration undefined) was accompanied by
minor amounts of uncyclised protiodeiodinated material. At
Ϫ78 ЊC, the amount of these synthetically unproductive by-
Experimental
Preparation of the keto iodide 9
To a cold (Ϫ78 ЊC), stirred solution of LDA (5.82 mmol) in dry
THF (15 ml) was added, via a cannula, a solution of the
dimethylhydrazone 6 (1.40 g, 5.82 mmol) in dry THF (3.5 ml).
The mixture was stirred for 5 min at Ϫ78 ЊC and then for 2 h at
0 ЊC. Dry HMPT (2.03 ml, 11.66 mmol) was added via a syringe
and the mixture was stirred at 0 ЊC for 10 min and then was
cooled to Ϫ78 ЊC. A solution of the bifunctional reagent 1 (1.41
g, 2.91 mmol) in dry THF (3 ml) was added dropwise via a
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cannula. The mixture was stirred at Ϫ78 ЊC for 2 h and then was
allowed to warm to rt overnight. The stirred mixture was treat-
ed sequentially with saturated aqueous NaHCO3 (30 ml), Et2O
(60 ml) and H2O (30 ml) and the layers were separated. The
aqueous layer was extracted with Et2O (2 × 50 ml) and the
combined organic extracts were washed (brine, 4 × 40 ml),
dried (MgSO4), and concentrated. The residual material was
dissolved in dry CH2Cl2 (30 ml). To the resultant vigorously
stirred solution at rt was added dropwise, by syringe, 30 ml of a
0.1 M solution of I2 in CH2Cl2 and stirring was continued for an
additional 15 min. The solution was treated with saturated
aqueous Na2S2O3 (30 ml), the layers were separated, and the
aqueous layer was extracted with Et2O (3 × 60 mL). The com-
bined organic extracts were washed (5% aqueous NaHCO3,
1 × 40 ml; brine, 2 × 60 ml), dried (MgSO4), and concentrated.
To the residual oil was added, sequentially, THF (3.8 ml), H2O
(0.85 ml), NaOAc (1.7 g), and HOAc (5.4 ml). The mixture was
stirred at rt for 15 min and then was neutralized by addition of
solid NaHCO3. Et2O (100 ml) and H2O (350 ml) were added
and the layers were separated. The aqueous layer was extracted
with Et2O (3 × 100 ml) and the combined organic extracts were
washed (brine, 75 ml), dried (MgSO4), and concentrated. The
crude product was purified by flash chromatography (100 g
TLC-grade silica gel, 9:1 and then 4:1 petroleum ether–Et2O)
and the acquired oil was distilled (bulb-to-bulb, 220–230 ЊC/0.5
Torr) to afford 1.03 g (90%) of compound 9, a pale yellow oil;
brown mixture was stirred at rt for 2 h. Et2O (10 ml) was added
and the mixture was stirred for 1 h at rt and then was filtered
through a thin pad of Florisil. The collected material was
washed with Et2O (~400 ml) and EtOAc (~100 ml) until no
UV-active product was detected in the eluate. The combined
eluate was concentrated and the crude product was purified by
flash chromatography (13 g of TLC-grade silica gel, 3:2 petrol-
eum ether–Et2O) to provide 115 mg (85%) of the enone 11, a
colourless oil that solidified to afford colourless crystals, mp
94.5–95 ЊC; νmax/cmϪ1 (KBr) 1636vs (CO); δH (CDCl3, 400
MHz) 0.91 (s, 3 H), 1.00 (s, 3 H), 1.37–1.48 (m, 3 H), 1.63–1.73
(m, 1 H), 1.78–1.87 (m, 1 H), 1.91–1.98 (m, 1 H), 2.17–2.23 (m,
2 H), 2.37–2.46 (m, 2 H), 2.50–2.64 (m, 3 H), 3.46 (d, 2 H, J 11
Hz), 3.52 (d, 1 H, J 11 Hz), 3.54 (d, 1 H, J 11 Hz), 5.89 (s, 1 H);
δC (CDCl3, 75.3 MHz) 20.1, 22.5, 22.7, 30.2, 32.0, 33.4, 34.8,
40.7, 41.5, 44.3, 70.2, 70.3, 96.8, 126.8, 158.9, 204.3 (Found: C,
72.6; H, 9.4. Calc. for C16H24O3: C, 72.7; H, 9.15%).
Acknowledgements
We thank the NSERC of Canada and the Merck Frosst Centre
for Therapeutic Research for financial support. Postgraduate
scholarships (to S. D. W.) from NSERC (Canada) and FCAR
(Quebec) are also gratefully acknowledged.
νmax/cmϪ1 (neat) 1713vs (CO), 1610 (C᎐C); δ (CDCl3, 400
Notes and references
᎐
MHz) 0.96 (s, 3 H), 1.00 (s, 3 H), 1.17–1.86 (m, H6 H), 2.09–2.15
(m, 2 H), 2.24–2.31 (m, 1 H), 2.45–2.55 (m, 4 H), 3.52 (s, 2 H),
3.54 (s, 2 H), 6.12–6.18 (m, 2 H); δC (CDCl3, 75.3 MHz) 22.5,
22.6, 25.2, 28.1, 30.1, 31.5, 34.6, 37.0, 38.1, 44.6, 70.3, 70.6,
82.6, 96.3, 140.8, 211.5 (Found: C, 48.9; H, 6.2. Calc. for
C16H25IO3: C, 49.0; H, 6.4%).
† All isolated and purified compounds reported herein exhibit spectra
in accord with the assigned structures and gave satisfactory elemental
(C, H) analyses and/or molecular mass determinations (high resolution
mass spectrometry).
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Preparation of the tertiary allylic alcohol 10
To a cold (Ϫ78 ЊC), stirred solution of compound 9 (475 mg,
1.21 mmol) in dry THF (70 ml) was added, in a single rapid
injection with a syringe, a solution of BuLi (2.54 mmol, 2.1
equiv.) in hexanes. The reaction mixture was stirred at Ϫ78 ЊC
for 1 h and then was treated with saturated aqueous NaHCO3
(20 ml). The mixture was warmed to rt, H2O (20 ml) and Et2O
(40 ml) were added, and the layers were separated. The aqueous
layer was extracted with Et2O (3 × 30 ml) and the combined
organic extracts were washed (brine, 1 × 30 ml), dried (MgSO4),
and concentrated. The crude product was purified by flash
chromatography (30 g of TLC-grade silica gel, 3:2 petroleum
ether–Et2O) to provide 271 mg (84%) of 10, a colourless oil that
solidified to give colourless crystals, mp 69–70 ЊC; νmax/cmϪ1
(KBr) 3495s (OH) 1654 (C᎐C); δ (CDCl3, 400 MHz) 0.89 (s,
᎐
3 H), 1.00 (s, 3 H), 1.24 (s, 1 H), 1H.45–1.91 (m, 10 H), 2.09–2.23
(m, 3 H), 3.40 (dd, 1 H, J 11, 1 Hz), 3.46 (dd, 1 H, J 11, 1 Hz),
3.47 (d, 1 H, J 11 Hz), 3.56 (d, 1 H, J 11 Hz), 5.48 (d, 1 H, J 12
Hz), 5.78 (ddd, 1 H, J 12, 6, 6 Hz); δC (CDCl3, 75.3 MHz) 22.6,
22.8, 25.8, 27.5, 27.6, 30.2, 32.8, 37.8, 37.9, 39.4, 70.0, 70.1,
72.0, 97.6, 133.4, 138.2 (Found: C, 72.0; H, 10.0. Calc. for
C16H26O3: C, 72.1; H, 9.8%).
Preparation of the bicyclic cycloheptenone 11
To a stirred solution of alcohol 10 (136 mg, 0.510 mmol) in dry
CH2Cl2 (2 ml) was added consecutively dry, powdered 3 Å
molecular sieves (434 mg) and PCC (220 mg, 2 equiv.) and the
15 Y.-S. Cheng, W.-L. Liu and S. Chen, Synthesis, 1980, 223.
Communication a909922k
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