Tandem alkylation-cyclization process via an O,C-dianion

Article abstract of DOI:10.1016/j.tet.2005.01.097

A general protocol for preparing densely functionalized cyclopentenones through a tandem nucleophilic addition-deprotonation-alkylation-cyclization process is described. Addition of lithioallene 2 to enamides 1 generates tetrahedral intermediate 3. Deprotonation of the γ carbon atom of the allene function in situ, followed by trapping by a suitable electrophile and cyclization during workup leads to C6 substituted cyclopentenones 6.

Full text of DOI:10.1016/j.tet.2005.01.097

Tetrahedron 61 (2005) 3419–3428
Tandem alkylation–cyclization process via an O,C-dianion
April R. Banaag,a Gideon O. Berger,a Francis Dhoro,a Derrick B. delos Santos,a Darryl D. Dixon,a
James P. Mitchell,a Bradley K. Tokeshia and Marcus A. Tiusa,b,
*
aDepartment of Chemistry, 2545 The Mall, University of Hawaii, Honolulu, Hawaii, HI 96822, USA
bThe Cancer Research Center of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii, HI 96813, USA
Received 18 October 2004; revised 13 December 2004; accepted 21 January 2005
Abstract—A general protocol for preparing densely functionalized cyclopentenones through a tandem nucleophilic addition–deprotonation–
alkylation–cyclization process is described. Addition of lithioallene 2 to enamides 1 generates tetrahedral intermediate 3. Deprotonation of
the g carbon atom of the allene function in situ, followed by trapping by a suitable electrophile and cyclization during workup leads to C6
substituted cyclopentenones 6.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
following the protocol that is summarized in Eq. 1.
In a preliminary communication we described the triply
convergent process whereby morpholino enamide 1 (Eq. 1)
is first combined with lithio allene 2 to give tetrahedral
intermediate 3.1 The acidity of the allenic protons in 3
makes it possible to deprotonate 3 by exposure to a strong
base. Lithio allene 4 is a good nucleophile, and can be
trapped by a number of different types of electrophiles to
produce 5, which is cyclized upon workup with acid to give
cross conjugated cyclopentenone 6 bearing a substituent on
exocyclic carbon atom C6. This strategy makes it possible to
combine three large fragments, the allene, the enamide and
the electrophile, and for this reason we have described the
process as being ‘triply’ convergent.
2. Discussion
(1)
There are several advantages inherent to this approach in
addition to the high degree of convergency. The alternative
approach to structures such as 6 is by means of a lithioallene
analogous to 2, but bearing a substituent at the g carbon
atom. Whereas the preparation of 2 is completely straight-
forward, the preparation of homologs of 2 requires several
additional steps, and is not always efficient.2 Some allene
substituents may interfere with the generation of the
lithioallene, or may inhibit the clean addition of the
morpholino enamide. These problems are avoided by
There are some potential difficulties in implementing such a
process efficiently. Whenever a number of sequential
processes is attempted in a single operation, it is important
that each step proceed to completion (if possible) and that
each step not be plagued by the creation of undesired side
products. Whereas these shortcomings might be tolerable in
a reaction that proceeds in a single step, it is clear that in a
process that encompasses a series of linked steps this would
result in a low yield of product, and in the generation of
complex product mixtures.
Keywords: Allene; Nazarov; Cyclization.
* Corresponding author. Tel.: C1 808 956 2779; fax: C1 808 956 5908;
e-mail: tius@gold.chem.hawaii.edu
In our preliminary communication we described the
reactions of a single morpholino enamide derived from
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.097

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A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
Table 1. Alkyl halide electrophiles
commercially available trans-a-methylcinnamic acid with a
representative panel of electrophiles. The question we
wished to answer with the work described herein is whether
the method can be applied to other morpholino enamides
and to other electrophiles. In addition, we hoped to be able
to define optimum conditions for the process. Our results
with enamides 7–12 and an expanded panel of electrophiles
are summarized in Tables 1–3.
Table 2. Ketone electrophiles

A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
3421
Table 3. Trialkylsilyl chloride electrophiles
alkyllithium, since the sec-butyllithium solution had been
titrated immediately prior to its use. There are apparently
two reasons to which the low product yields may be
attributed. First, when the titer of the sec-butyllithium falls
much below 1 M, the volume of the solution that must be
added increase, as does the proportion of hydrocarbon
solvent (cyclohexane) in the reaction medium (THF). This
may have an effect on the kinetics of the subsequent steps
leading to 6. Second, the reduction in the observed sec-
butyllithium titer is probably caused by introduction of
small amounts of air through leaks in the septum closure.
This suggests the presence of hydroperoxides in aged
sec-butyllithium solutions that may be able to degrade
O,C-dianion 4 through oxidative processes. The progress of
the reactions was not monitored by TLC so as to avoid
introducing moisture.
Morpholino enamides 7, 8, and 11 were prepared from the
commercially available carboxylic acids in two steps.
Exposure to oxalyl chloride and catalytic DMF led to the
acid chlorides that were treated with morpholine and
pyridine to give the amides. Amides 9 and 10 were prepared
from cyclohexanone and cycloheptanone, respectively. The
ketones were first converted to the corresponding cyano-
hydrins with potassium cyanide and acetic acid, then
dehydrated with phosphorus oxychloride according to the
published procedure.3 The resulting a,b-unsaturated nitriles
were hydrolyzed to the corresponding carboxylic acids by
exposure to aqueous ethanolic sodium hydroxide at reflux,
in the presence of catalytic tetra-n-butylammonium hydro-
gen sulfate. The carboxylic acids were converted to
enamides in the same way as 7, 8 and 11. Enamide 12
was prepared in two steps from commercially available
5-methylfurfural. Horner–Emmons reaction with triethyl
2-phosphonopropionate led to the expected enoate as a
single geometrical isomer. Exposure of the ester to
morpholine and trimethylaluminum gave enamide 12.4
In all cases the quality of the allene that is used for the
preparation of 2 is important. The allene undergoes some
discoloration upon standing. Discolored samples of allene
should be distilled before use. The allene is prepared from
the isomerization of methoxymethyl propargyl ether with
freshly sublimed potassium tert-butoxide,5 a procedure that
can result in contamination of the allene by variable
amounts of tert-butanol. Distilling the allene from potas-
sium hydride leads to dry, alcohol-free material.
In all reactions that proceed by means of carbanion
intermediates it is critical to take pains to exclude
adventitious proton sources. In the present case, it is
necessary that conversion of tetrahedral intermediate 3 to
lithioallene 4 be complete, and that the electrophile be dry
and acid free. If either of these two conditions is not met, the
reaction mixture at the end of the process will be derived
from cyclization of a mixture of 3 and 5, resulting in a
mixture of the desired product 6 and of the corresponding
protio compound (6, EZH). Another way in which this
byproduct can be formed is if the kinetics for the alkylation
step (Eq. 1, 4/5) are slow. In this case, premature
quenching of the mixture of 4 and 5 again leads to the same
product mixture. Separation of the byproduct by means of
flash column chromatography is tedious.
The critical alkylation step (Eq. 1, 4/5) must be performed
at K78 8C. The solution of the electrophile was cooled
and transferred rapidly by cannula to the solution of
O,C-dianion 4.
There is some variation allowed in the conditions for the
cyclization step. The conditions on which we have con-
verged call for transferring the solution of 5 to 5% HCl in
ethanol, stirring for no more than 5–10 min at rt, and
neutralizing the solution with pH 7 phosphate buffer.
Contact with ethanolic HCl for times longer than 10 min
often resulted in diminished yields of product. It is impor-
tant that addition of the solution of 5 to the acid be
performed as rapidly as possible, otherwise the yield of
product was lower.
During the course of the execution of this research we made
a number of observations that have an important bearing on
the outcome of these reactions. In all cases the amides were
dried by azeotropic distillation with benzene, then stored in
˚
THF over 4 A molecular sieves prior to use. Best results
were obtained when a fresh solution of sec-butyllithium was
used for the generation of O,C-dianion 4. The use of aged
solutions invariably led to erosion of the yield of product.
This was not due to any uncertainty regarding the titer of
What emerges from the discussion above is a protocol that
is sensitive to essentially all of the reaction parameters.
While it is true that the procedure is quite unforgiving of

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A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
inattention to experimental detail, if the precautions that
have been delineated above are followed, it is easy to
reproduce. Table 1 shows that there is some variability in
the yields, but that in all cases they are within the
synthetically useful range. The reactions with allyl bromide,
methallyl chloride and n-butyl iodide were surprisingly
sluggish compared to the reaction with iodomethane. The
addition of HMPA, and of several equivalents of LiI in the
case of allyl bromide and methallyl chloride was necessary
in order to achieve the results that are reported in Table 1.
The alkyl halides were distilled and passed through a short
column of basic alumina prior to use. The liquid ketones,
3-pentanone and cyclohexanone, were distilled and dried
Eq. 2 summarizes our results with a single tetrasubstituted
enamide. Addition of lithioallene 2 to enamide 51 took place
during 1.5 h at K5 8C. The solution was cooled to K78 8C,
deprotonated to generate the O,C-dianion, and exposed to
excess iodomethane. Cyclization led to cyclopentenone 52 in
64% yield as a ca. 1/1 mixture of geometrical isomers. These
were separated with difficulty by means of column
chromatography on silica gel.
3. Conclusions
˚
over 4 A molecular sieves prior to use, whereas no such
The scope of a tandem alkylation–cyclization process for
preparing highly substituted cyclopentenones has been
expanded. The structures of the products that are shown in
Tables 1–3 would be challenging to prepare by other means,
and would require several discrete steps. A large degree of
molecular complexity can be created in a single step. On the
basis of the results that are summarized in (Eq. 2) it appears
likely that the synthesis of cyclopentenones such as 52
bearing a quaternary ring carbon atom is also amenable
through this method. Applications to natural products total
synthesis as well as to diversity-oriented synthesis can be
anticipated.
precaution was necessary in the case of cyclododecanone, a
crystalline solid. tert-Butyldimethylsilyl chloride was sub-
limed, then treated with anhydrous potassium carbonate as a
˚
solutioninTHF, followedby4 Amolecularsievespriortouse.
Triisopropylsilyl chloride was used as received from Acros.
For reasons that we have discussed in earlier work,6,7 the
kinetic products of cyclization are the Z isomers at the
exocyclic double bond. Longer contact times with acid
during cyclization can lead to isomerization to the E isomer,
when that isomer is thermodynamically favored. For
example, most of the cyclopentenones shown in Table 1
were isolated as the E isomer. When the substituent at C6
has a large steric requirement, the Z isomer is often
thermodynamically, as well as kinetically favored. For
example, as shown in Table 2, cyclopentenones 27–41 that
bear a tertiary group at C6 were all isolated as the Z isomer.
The situation is the same in the case of trialkylsilyl
cyclopentenones 42–50 (Table 3). It is noteworthy that
cyclopentenones 18–20 and 24–26 (Table 1) were isolated
as skipped dienes. Conjugation of the terminal double bond
on the side chain did not take place to any large extent. This
testifies to the mildness of the reaction conditions. Products
35 and 48 were converted to the corresponding benzoate
esters for ease of purification. In both cases the reported
yield is of the benzoate derivative. All reaction products
were fairly stable to storage under neutral conditions,
however, some decomposition took place on standing at rt.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on either a
Varian Mercury Plus 300 operating at 300 MHz (1H) or
75 MHz (13C) or on a Varian Unity Inova 500 operating at
500 MHz (1H) or 126 MHz (13C). Infrared spectra were
recorded on a Perkin–Elmer IR 1430 spectrometer. Electron
impact mass spectra were recorded on a VG-70SE mass
spectrometer. Thin-layer chromatography (TLC) was per-
formed on Sigma-Aldrich TLC plates, 250 mm, particle size
˚
5–17 mm, pore size 60 A. Flash column chromatography
was performed on Natland International Corporation silica
gel, 200–400 mesh and Sorbent Technologies silica gel,
˚
premium Rf, 60 A, 40–75 mm. Anhydrous THF was taken
Amides 7–12 bear a single substituent at the b carbon atom.
Limited work with b-disubstituted morpholino enamides
suggested that the tandem alkylation–cyclization process
would take place with this class of substrates, however, the
efficiency of such a process was open to question.8 In the
few examples that we examined, yields for the simple cycli-
zation had been modest. Part of the reason for this appears to
be related to the fact that addition of the allene nucleophile
to b-disubstituted enamides is much slower, a fact that we
had not fully appreciated. Although the slow kinetics for the
addition can be easily accommodated by a longer reaction
time in a process that takes place in a single step, it was less
clear that it would be practical to do so in the tandem process.
from a solvent purification system from GlassContour
(www.glasscontour.com). Reagents were purified as
described in text or were used as received. All moisture
sensitive reactions were performed under a static nitrogen or
argon atmosphere in oven-dried or flame-dried glassware.
A general method for the preparation of compounds 13–17
is described in section 4.1.1, compounds 18–26 is described
in section 4.1.6, compounds 27–41 is described in section
4.1.15, compounds 42–45 is described in section 4.1.30,
compounds 46–50 is described in section 4.1.34.
4.1.1. (5E)-5-Ethylidene-2-hydroxy-3,4-diphenylcyclo-
pent-2-enone 16. A solution of allenyllithium 2 was
prepared in 3 mL THF at K78 8C from 43 mg
(0.43 mmol) of allene and 155 mL n-BuLi (2.91 M in
hexanes, 0.45 mmol). After 45 min, a solution of amide 11
(105 mg, 0.36 mmol) in 2 mL THF was added at K78 8C
via cannula. After 10 min at K78 8C, the reaction mixture
was warmed from K78 to K30 8C over 30 min, and stirred
(2)

A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
3423
further for 30 min at K30 8C. sec-BuLi (415 mL, 1.35 M in
cyclohexane, 0.56 mmol) was added dropwise at K78 8C.
After 45 min, MeI (110 mL, 1.77 mmol) in 2 mL THF was
added at K78 8C via cannula. The reaction mixture was
warmed from K78 to K30 8C over 15 min, and stirred
further for 1 h at K30 8C; then quenched by rapid addition
through a large bore cannula to 5% (v/v) aqueous HCl in
EtOH (7 mL). After 10 min, it was neutralized with pH 7
buffer, and extracted with EtOAc (3!). The combined
organic extracts were washed with brine (2!) and dried
over MgSO4. Purification by flash column chromatography
on silica gel (10% EtOAc in hexanes) gave cyclopentenone
16 as a white crystalline solid (83 mg, 84% yield): mp 196–
198 8C; RfZ0.32 (20% EtOAc in hexanes). IR (film): 3222
(85), 135 (20), 107 (20). HREIMS calcd for C12H16O2
192.1150, found 192.1166.
4.1.5.
(5E)-5-Ethylidene-2-hydroxy-3-methyl-4-(5-
methylfuran-2-yl)cyclopent-2-enone 17. Isolated as a
white crystalline solid (97 mg, 70% yield): mp 188 8C. IR
(film): 3243, 2980, 1678 cmK1 1H NMR (300 MHz,
.
CDCl3): dZ6.67 (qd, JZ8.0, 1.8 Hz, 1H), 5.95 (d, JZ
3.0 Hz, 1H), 5.85 (dt, JZ3.0, 0.9 Hz, 1H), 4.30 (bs, 1H),
2.19 (d, JZ0.9 Hz, 3H), 1.88 (s, 3H), 1.75 (d, JZ8.0 Hz,
3H). 13C NMR (75 MHz, CDCl3): dZ189.3, 153.8, 150.6,
150.4, 149.9, 145.7, 137.2, 132.6, 101.1, 43.8, 14.0, 13.2,
11.9. HREIMS calcd for C13H14O3 218.0943, found
218.0943.
(br), 3018, 1683, 1655, 1401 cmK1
.
1H NMR (300 MHz, CDCl3): dZ7.90–7.82 (m, 2H), 7.36–
7.10 (m, 8H), 6.98 (bs, 1H), 6.80 (qd, JZ7.3, 1.3 Hz, 1H),
4.93 (d, JZ1.3 Hz, 1H), 1.71 (d, JZ7.3 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dZ190.0, 150.7, 140.6, 138.3, 135.5,
132.7, 132.4, 128.9 (2), 128.6 (2), 128.4 (2), 128.1 (2), 126.9
(2), 45.8, 14.2. MS: m/z (%)Z276 (MC, 100), 261 (2), 258
(13), 232 (3), 199 (3). HREIMS calcd for C19H16O2
276.1150, found 276.1179.
4.1.6. (5Z)-2-Hydroxy-5-(3-methylbut-3-enylidene)-3,4-
diphenylcyclopent-2-enone 26. A solution of allenyl-
lithium 2 was prepared in 3 mL THF at K78 8C from
40 mg (0.40 mmol) of allene and 140 mL n-BuLi (2.91 M in
hexanes, 0.41 mmol). After 45 min, a solution of amide 11
(97 mg, 0.33 mmol) in 2 mL THF was added at K78 8C via
cannula. After 10 min at K78 8C, the reaction mixture was
warmed from K78 to K30 8C over 30 min and stirred
further for 30 min at K30 8C. sec-BuLi (380 mL, 1.35 M in
cyclohexane, 0.51 mmol) was added dropwise at K78 8C.
After 45 min, a solution of methallyl chloride (165 mL,
1.67 mmol), LiI (225 mg, 1.68 mmol), and HMPA (115 mL,
0.66 mmol) in 3 mL THF was added at K78 8C via cannula.
The reaction mixture was warmed from K78 to K30 8C
over 15 min and stirred further for 2 h at K30 8C; then
quenched by rapid addition through a large bore cannula to
5% (v/v) aqueous HCl in EtOH (7 mL). After 10 min, it was
neutralized with pH 7 buffer and extracted with EtOAc (3!).
The combined organic extracts were washed with brine (2!)
and dried over MgSO4. Purification by crystallization of the
crude in 3% EtOAc in hexanes gave cyclopentenone 26 as a
yellow crystalline solid (97 mg, 93% yield): mp 164–
166 8C; RfZ0.58 (20% EtOAc in hexanes).
Compounds 13, 14, 15 and 17 were prepared according to
the general procedure described above for 16.
4.1.2. (5E)-5-Ethylidene-2-hydroxy-3,4-dimethylcyclo-
pent-2-enone 13. Isolated as a white crystalline solid
(106 mg, 69% yield): mp 132–134 8C. IR (film): 3270 (br),
1
1675, 1630, 1405 cmK1. H NMR (300 MHz, C6D6): dZ
7.86 (bs, 1H), 6.57 (qd, JZ7.2, 1.5 Hz, 1H), 2.54 (bq, JZ
6.9 Hz, 1H), 1.69 (s, 3H), 1.34 (d, JZ7.2 Hz, 3H), 0.77 (d,
JZ6.9 Hz, 3H). 13C NMR (75 MHz, C6D6): dZ189.8,
151.3, 142.5, 139.7, 129.6, 36.7, 17.3, 14.3, 11.5. MS: m/z
(%)Z152 (MC, 100), 137 (65), 109 (60). HREIMS calcd
for C9H12O2 152.0837, 152.0868.
4.1.3. (3E)-3-Ethylidene-3a,4,5,6-tetrahydro-1-hydroxy-
1H-inden-2(4H)-one 14. Isolated as a white amorphous
solid (111 mg, 62% yield): mp 132 8C. IR (film): 3300 (br),
2935, 2856, 1682, 1630, 1444, 1399, 1202, 1119, 1050,
1H NMR (300 MHz, CDCl3): dZ7.90–7.82 (m, 2H), 7.35–
7.14 (m, 8H), 6.61 (bs, 1H), 5.95 (t, JZ7.9 Hz, 1H), 4.79 (s,
1H), 4.70 (s, 1H), 4.54 (s, 1H), 3.62 (dd, JZ15.9, 8.1 Hz,
1H), 3.46 (dd, JZ15.9, 7.8 Hz, 1H), 1.67 (s, 3H). 13C NMR
(75 MHz, CDCl3): dZ190.4, 151.6, 143.6, 141.7, 141.2,
136.8, 132.8, 132.4, 129.2 (2), 128.9 (2), 128.4 (2), 127.4
(2), 127.0 (2), 111.3, 47.6, 35.9, 22.8. MS: m/z (%)Z316
(MC, 100), 301 (30), 298 (7), 287 (4), 259 (3). HREIMS
calcd for C22 H20O2 316.1463, found 316.1477.
1
972 cmK1. H NMR (300 MHz, CDCl3): dZ6.64 (dq, JZ
7.2, 4.2 Hz, 1H), 5.95 (bs, 1H), 3.01 (dd, JZ12.0, 4.5 Hz,
2H), 2.41–2.35 (dm, 1H), 2.12–1.83 (m, 6H), 1.52 (qt, JZ
13.2, 3.3 Hz, 1H), 1.34 (qt, JZ12.6, 3.3 Hz, 1H), 1.04 (qd,
JZ12.9, 3.6 Hz, 1H). 13C NMR (75 MHz, CDCl3): dZ
189.4, 107.0, 144.4, 137.5, 130.8, 39.5, 32.7, 26.2 (2), 25.2,
14.6. MS: m/z (%)Z178 (MC, 96), 160 (21), 149 (17), 135
(100), 79 (58). HREIMS calcd for C11H14O2 178.0994,
found 178.0996.
Compounds 18–25 were prepared according to the general
procedure described above for 26.
4.1.4.
(3E)-3-Ethylidene-3a,4,5,6,7,8-hexahydro-1-
4.1.7. (3Z)-3-(But-3-enylidene)-3a,4,5,6,7,8-hexahydro-
1-hydroxyazulen-2(1H)-one 18. Isolated as a white
amorphous solid (75 mg, 68% yield). IR (neat): 3584,
hydroxyazulen-2(1H)-one 15. Isolated as a white crystal-
line solid (61 mg, 63% yield): decomposition at 73 8C. IR
(film): 3292 (br), 2927, 1671, 1626, 1404, 953 cmK1. H
3383 (br), 2924, 1670, 1613, 1407, 1078 cmK1. H NMR
1
1
NMR (300 MHz, C6D6): dZ7.45 (bs, 1H), 6.59 (q, JZ
7.3 Hz, 1H), 2.74 (d, JZ9.9 Hz, 1H), 2.70–2.44 (m, 2H),
1.89–1.78 (m, 1H), 1.60–1.44 (m, 2H), 1.35 (d, JZ7.3, 3H),
1.30–0.76 (m, 5H). 13C NMR (75 MHz, C6D6): dZ188.9,
150.5, 147.2, 139.3, 128.6, 41.4, 34.3, 30.3, 29.5, 28.1, 25.5,
14.0. MS: m/z (%)Z192 (MC, 100), 174 (20), 164 (10), 149
(300 MHz, C6D6): dZ5.60–5.45 (m, 1H), 5.33 (t, JZ
7.6 Hz, 1H), 4.84–4.68 (m, 2H) 3.54–3.32 (m, 2H), 2.40–
2.32 (m, 1H) 2.18–2.10 (m, 2H), 1.45–1.34 (m, 1H), 1.34–
1.90 (m, 3H), 0.96–0.55 (m, 5H). 13C NMR (75 MHz,
C6D6): dZ190.1, 151.3, 146.2, 137.2, 136.2, 136.2, 115.9,
43.8, 35.1, 32.0, 30.7, 29.8, 28.1, 25.9. MS: m/z (%)Z218

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A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
(MC, 25), 105 (10), 91 (10), 84 (100), 70 (10). HREIMS
calcd for C14H18O2 218.1307, found 218.1297.
1660 cmK1. 1H NMR (300 MHz, CDCl3): dZ6.57 (td, JZ
8.1, 1.8 Hz, 1H), 5.92 (d, JZ3.0 Hz, 1H), 5.80 (dt, JZ3.0,
0.9 Hz, 1H), 4.24 (bs, 1H), 2.15 (d, JZ0.9 Hz, 3H), 1.92–
2.06 (m, 2H), 1.82 (s, 3H), 1.04–1.65 (m, 4H), 0.75 (t, JZ
7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ188.5, 153.2,
151.5, 150.4, 149.9, 141.4, 138.5, 131.1, 106.1, 42.2, 30.3,
28.2, 22.3, 13.8, 13.5, 11.8. HREIMS calcd for C16H20O3
260.1412, found 260.1415.
4.1.8. (5Z)-5-(But-3-enylidene)-2-hydroxy-3,4-diphenyl-
cyclopent-2-enone 19. Isolated as a yellow crystalline solid
(65 mg, 61% yield): mp 158–160 8C. IR (film): 3248 (br),
2915, 1668, 1398 cmK1. 1H NMR (300 MHz, CDCl3): dZ
7.90–7.82 (m, 2H), 7.40–7.10 (m, 8H), 6.77 (bs, 1H), 5.93
(t, JZ7.5 Hz, 1H), 5.80 (m, 1H), 5.00 (s, 1H), 4.95 (m, 1H),
4.78 (s, 1H), 3.82–3.62 (m, 1H), 3.52–3.34 (m, 1H). 13C
NMR (75 MHz, CDCl3): dZ190.4, 151.6, 141.6, 140.7,
136.4, 135.2, 133.0, 132.4, 129.2 (2), 128.9 (2), 128.4 (2),
127.4 (2), 127.0 (2), 116.1, 47.5, 32.1. MS: m/z (%)Z302
(MC, 100), 273 (6), 284 (10), 245 (5). HREIMS calcd for
C21H18O2 302.1307, found 302.1337.
4.1.13. (5Z)-2-Hydroxy-3,4-dimethyl-5-(3-methylbut-3-
enylidene)cyclopent-2-enone 24. Isolated as an oil
(114 mg, 59% yield). IR (neat): 3314, 2967, 2932, 2871,
1
1679, 1626, 1650, 1409, 1357 cmK1. H NMR (300 MHz,
CDCl3): dZ6.02 (td, JZ7.8, 1.2 Hz, 1H), 4.72 (s, 1H), 4.76
(s, 1H), 3.54 (d, JZ7.8 Hz, 2H), 3.02 (q, JZ7.2 Hz, 1H),
1.96 (d, JZ1.2 Hz, 3H), 1.75 (s, 3H), 1.20 (d, JZ7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3): dZ190.5, 150.9, 148.9,
144.3, 141.0, 137.1, 111.3, 38.6, 35.8, 22.9, 17.9, 11.7.
HREIMS calcd for C12H16O2 192.1150, found 192.1146.
4.1.9. (5E)-5-(But-3-enylidene)-2-hydroxy-3-methyl-4-
(5-methylfuran-2-yl)cyclopent-2-enone 20. Isolated as a
yellow oil (80 mg, 58% yield). IR (film): 3280, 1673,
1490 cmK1. 1H NMR (300 MHz, CDCl3): dZ6.64 (m, 1H),
6.05 (dt, JZ3.0, 0.9 Hz, 1H), 5.87 (d, 0.9 Hz, 1H), 5.70–
5.59 (m, 1H), 5.31 (bs, 1H), 4.98 (d, JZ10.0 Hz, 1H), 4.89
(d, JZ17.0 Hz, 1H), 4.35 (bs, 1H), 2.91–2.80 (m, 2H), 2.24
(d, JZ0.9 Hz, 3H), 1.95 (s, 3H). 13C NMR (75 MHz,
CDCl3): dZ189.9, 161.3, 153.2, 152.5, 150.2, 146.8, 138.4,
134.8, 116.0, 112.1, 108.2, 44.8, 31.0, 13.7, 12.9. HREIMS
calcd for C15H16O3 244.1099 found 244.1089.
4.1.14. (3Z)-3a,4,5,6-Tetrahydro-1-hydroxy-3-(3-methyl-
but-3-enylidene)-1H-inden-2(4H)-one 25. Isolated as an
oil (104 mg, 51% yield). IR (film): 3315, 2933, 2855, 1687,
1623, 1445, 1400, 1361.2 cmK1 1H NMR (300 MHz,
.
CDCl3): dZ6.35 (bs, 1H), 5.99 (t, JZ7.8 Hz, 1H), 4.76
(s, 1H), 4.70 (s, 1H) 3.53 (d, JZ7.8 Hz, 2H), 2.97 (dd, JZ
13.8, 4.2 Hz, 1H), 2.82 (dd, JZ11.7, 5.4 Hz, 1H) 2.26–2.14
(m, 1H), 2.10–1.80 (m, 3H), 1.74 (s, 3H), 1.56–1.38 (m,
1H), 1.36–1.15 (m, 1H), 1.15–0.80 (m, 1H). 13C NMR
(75 MHz, CDCl3): dZ190.9, 148.1, 144.3, 142.9, 136.8,
136.5, 111.3, 40.9, 35.7, 33.2, 25.5, 25.2, 25.1, 22.9.
HREIMS calcd for C14H18O2 218.2915, found 260.1334.
4.1.10. (5E)-2-Hydroxy-3,4-dimethyl-5-pentylidene-
cyclopent-2-enone 21. Isolated as a pale amber oil
(57 mg, 29% yield). The Z isomer was isolated as an
amorphous solid (67 mg, 37% yield). IR Z isomer: (neat)
3310 (br), 2960, 2930, 2870, 1770, 1680, 1625 cmK1; E
isomer: (neat) 3310 (br), 2960, 2930, 2870, 1680, 1625,
1410 cmK1. 1H NMR (300 MHz, C6D6). Z isomer: dZ7.12
(s, 1H), 5.62 (td, JZ7.8, 0.9 Hz, 1H), 2.93 (m, 2H), 2.52
(bq, JZ7.0 Hz, 1H), 1.64 (s, 3H), 1.28 (m, 4H), 1.25 (t, JZ
6.9 Hz, 3H), 0.86 (d, JZ7.0 Hz, 3H); E isomer: dZ6.61 (td,
JZ8.1, 1.5 Hz, 1H), 2.63 (bq, JZ6.9 Hz, 1H), 1.89 (m, 2H),
1.68 (s, 3H), 1.13 (m, 4H), 0.83 (d, JZ6.9 Hz, 3H), 0.80 (m,
3H). 13C NMR (75 MHz, CDCl3): Z isomer: dZ190.5,
151.7, 139.8, 139.7, 137.2, 38.4, 31.8, 27.5, 22.6, 17.6, 14.2,
11.1; E isomer: dZ189.4, 150.7, 141.6, 138.2, 134.6, 36.5,
30.9, 28.4, 22.6, 17.3, 13.9, 11.0. Z isomer HREIMS calcd
for C12H18O2 194.1307, found 194.1297. E isomer
HREIMS calcd for C12H18O2 194.1307, found 194.1250.
4.1.15. (5Z)-2-Hydroxy-5-((1-hydroxycyclohexyl)methyl-
ene)-3,4-diphenylcyclopent-2-enone 36. A solution of
allenyllithium 2 was prepared in 3 mL THF at K78 8C
from 44 mg (0.44 mmol) of allene and 160 mL n-BuLi
(2.91 M in hexanes, 0.47 mmol). After 45 min a solution of
amide 11 (108 mg, 0.37 mmol) in 2 mL THF was added at
K78 8C via cannula. After 10 min at K78 8C, the reaction
mixture was warmed from K78 to K30 8C over 30 min and
stirred further for 30 min at K30 8C. sec-BuLi (430 mL,
1.35 M in cyclohexane, 0.58 mmol) was added dropwise at
K78 8C. After 45 min, a solution of cyclohexanone
(170 mL, 1.64 mmol) in 2 mL THF was added at K78 8C
via cannula. The reaction mixture was warmed from K78 to
K30 8C over 15 min, and stirred further for 1 h at K30 8C;
then quenched by rapid addition through a large bore
cannula to 5% (v/v) aqueous HCl in EtOH (7 mL). After
10 min, it was neutralized with pH 7 buffer, and extracted
with EtOAc (3!). The combined organic extracts were
washed with brine (2!) and dried over MgSO4. Purification
by flash column chromatography on silica gel (10% EtOAc
in hexanes) gave cyclopentenone 36 as a yellow, crystalline
solid (90 mg, 68% yield): mp 184–186 8C; RfZ0.18 (20%
EtOAc in hexanes).
4.1.11. (5E)-2-Hydroxy-5-pentylidene-3,4-diphenyl-
cyclopent-2-enone 22. Isolated as a yellow crystalline
solid (74 mg, 63% yield): mp 200–202 8C. IR (film): 3208
(br), 2958, 1655, 1401 cmK1. 1H NMR (300 MHz, CDCl3):
dZ7.82 (d, JZ7.3 Hz, 2H), 7.40–7.10 (m, 8H), 6.82 (bs,
1H), 6.71 (t, JZ7.9 Hz, 1H), 4.93 (s, 1H), 2.25–1.95 (m,
2H), 1.30–0.90 (m, 4H), 0.76 (t, JZ7.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dZ190.5, 150.9, 141.2, 138.3, 137.4,
135.6, 132.7, 129.2 (2), 128.9 (2), 128.6 (2), 128.4 (2), 127.1
(2), 46.1, 30.3, 28.5, 22.6, 14.0. MS: m/z (%)Z318 (MC,
100), 300 (13), 289 (10). HREIMS calcd for C22 H22O2
318.1620, found 318.1589.
1
IR (film): 3372 (br), 2938, 1651, 1451 cmK1. H NMR
(300 MHz, CDCl3): dZ7.84–7.74 (m, 2H), 7.40–7.00 (m,
8H), 6.47 (bs, 1H), 6.12 (bs, 1H), 6.04 (s, 1H), 4.75 (s, 1H),
1.84–1.10 (m, 10H). 13C NMR (75 MHz, CDCl3): dZ190.6,
153.1, 151.7, 141.0, 136.1, 135.7, 132.1, 129.5 (2), 129.0
(2), 128.4 (2), 127.4 (2), 127.2 (2), 71.9, 47.8, 37.5, 37.2,
4.1.12. (5E)-2-Hydroxy-3-methyl-4-(5-methylfuran-2-
yl)-5-pentylidenecyclopent-2-enone 23. Isolated as a pale
yellow wax (65 mg, 52% yield). IR (neat): 3300, 2960,

A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
3425
25.3, 21.9, 21.8. MS: m/z (%)Z360 (MC, 100), 342 (57),
248 (47). HREIMS calcd for C24H24O3 360.1726, found
360.1685.
CDCl3): dZ6.43 (d, JZ1.8 Hz, 1H), 6.05 (d, JZ3.0 Hz,
1H), 5.86 (dt, JZ3.0, 0.9 Hz, 1H), 4.69 (bs, 1H), 4.22 (bs,
1H), 2.20 (d, JZ0.9 Hz, 3H), 1.95 (s, 3H), 1.41–1.72 (m,
4H), 1.11 (t, JZ7.4 Hz, 3H), 0.80 (t, JZ7.4 Hz, 3H). 13C
NMR (75 MHz, CDCl3): dZ189.9, 154.0, 152.1, 151.8,
150.7, 139.2, 118.1, 106.6, 104.3, 55.9, 46.2, 38.0, 33.4,
13.6, 12.7, 8.1, 8.0. HREIMS calcd for C17H22O4 290.1518,
found 290.1522.
Compounds 27–35 and 37–41 were prepared according to
the general procedure described above for 36.
4.1.16. (5Z)-2-Hydroxy-5-(2-hydroxy-2-ethylbutyl-
idene)-3,4-dimethylcyclopent-2-enone 27. Isolated as a
pale yellow oil (70 mg, 59% yield). IR (film): 3306 (br),
4.1.21. (5Z)-2-Hydroxy-5-((1-hydroxycyclohexyl)methyl-
ene)-3,4-dimethylcyclopent-2-enone 32. Isolated as a
colorless oil (123 mg, 56% yield). IR (film): 3300, 2932,
1
2966, 1661, 1616, 797 cmK1. H NMR (300 MHz, C6D6):
dZ7.11 (bs, 1H), 5.75 (s, 1H), 5.65 (bs, 1H), 2.45–2.32 (m,
1H), 1.86–1.70 (m, 2H), 1.66–1.52 (m, 2H), 1.50 (d, JZ
1.2 Hz, 3H), 1.12–0.96 (m, 6H), 0.67 (d, JZ7.2 Hz, 3H) 13C
NMR (75 MHz, C6D6): dZ190.8, 151.7, 147.6, 143.5,
138.0, 77.0, 38.9, 34.4, 17.5, 11.5, 8.7. HREIMS calcd for
C13H20O3 224.2961, found 224.1416.
2855, 1659, 1613, 1446, 1403, 1350 cmK1 1H NMR
.
(300 MHz, C6D6): dZ6.64 (bs, 1H), 6.14 (bs, 1H), 5.89
(s, 1H), 3.24–3.16 (m, 1H), 3.14–3.06 (m, 1H), 2.42–2.30
(m, 1H), 2.08–1.90 (m, 3H), 1.52 (s, 3H), 1.50–1.38 (m,
3H), 1.18–1.15 (m, 2H), 0.69 (d, JZ6.9 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dZ190.3, 150.8, 148.9, 144.2, 136.6,
71.7, 38.9, 37.9, 37.8, 25.6, 25.4, 22.3, 17.8, 12.0. HREIMS
calcd for C14H20O3 236.1412, found 236.1440.
4.1.17.
(3Z)-3a,4,5,6-Tetrahydro-1-hydroxy-3-(2-
hydroxy-2-ethylbutylidene)-1H-inden-2(4H)-one 28.
Isolated as a pale yellow crystalline solid (150 mg, 60%
yield): mp 90–93 8C. IR (film): 3294 (br), 2934, 1664, 1616,
4.1.22. (5Z)-4-Ethyl-2-hydroxy-5-((1-hydroxycyclohex-
yl)methylene)-3-methylcyclopent-2-enone 33. Isolated as
a clear oil (107 mg, 64% yield). IR (film): 3329 (br), 2933,
1753, 1659, 1612 cmK1. 1H NMR (300 MHz, CDCl3): dZ
6.76 (s, 1H), 5.92 (d, JZ0.9 Hz, 1H), 2.52 (m, 1H), 1.93–
2.06 (m, 4H), 1.54 (d, JZ1.5 Hz, 3H), 1.53–1.20 (m, 8H),
0.41 (t, JZ7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ
191.1, 152.8, 147.9, 141.8, 134.2, 71.8, 43.7, 38.1, 37.9,
25.9, 22.9, 22.3 (2), 11.5, 7.3. HREIMS calcd for C15H22O3
250.1569, found 250.1600.
1
1457, 1403, 1255, 1204, 1095 cmK1. H NMR (300 MHz,
CDCl3): dZ6.59 (s, 1H), 6.05 (s, 1H), 3.01–2.95 (m, 1H),
2.87 (dd, JZ12.0, 5.1 Hz, 1H), 2.21 (m, 1H), 2.24–1.86 (m,
4H), 1.74–1.41 (m, 5H), 1.28 (qt, JZ12.9, 3.9 Hz, 1H), 1.06
(qd, JZ12.9, 3.3 Hz, 1H), 0.92 (t, JZ7.5 Hz, 3H), 0.90 (t,
JZ7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ190.8,
147.7, 147.6, 145.5, 136.1, 76.7, 41.2, 33.8, 33.8, 33.0, 25.2,
25.1, 24.8, 8.3, 8.2. MS: m/z (%)Z250 (MC, 2), 222 (13),
221 (100), 193 (17). HREIMS calcd for C15H22O3
250.1569, found 250.1565.
4.1.23.
(3Z)-3a,4,5,6-Tetrahydro-1-hydroxy-3-((1-
4.1.18. (3Z)-3a,4,5,6,7,8-Hexahydro-1-hydroxy-3-(2-
hydroxy-2-ethylbutylidene)azulen-2(1H)-one 29. Isolated
as a white crystalline solid (135 mg, 51% yield): mp 140–
142 8C. IR (neat): 3310, 2960, 1715, 1666, 1610, 1457,
1415, 1359 cmK1. 1H NMR (300 MHz, CDCl3): dZ6.71 (s,
1H), 6.09 (s, 1H), 3.19 (dd, JZ10.2, 1.8 Hz, 1H), 2.82–2.58
(m, 2H), 2.10 (dd, JZ14.0, 2.7 Hz, 1H), 2.00–1.80 (m, 3H),
1.76–1.40 (m, 6H), 1.38–1.20 (m, 2H), 0.90 (t, JZ7.5 Hz,
3H), 0.91 (t, JZ7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
dZ190.0, 150.3, 149.9, 148.5, 137.2, 44.8, 35.6 (2), 34.2,
34.1, 30.8, 29.9, 28.5, 25.9, 8.5 (2). MS: m/z (%)Z264
(MC, 2), 246 (9), 235 (100). HREIMS calcd for C16 H24O3
264.1725, found 264.1742.
hydroxycyclohexyl)methylene)-1H-inden-2(4H)-one 34.
Isolated as a white crystalline solid (157 mg, 60% yield):
mp 281–282 8C. IR (neat): 3300, 2932, 2855, 1659, 1613,
1446, 1403, 1350 cmK1. 1H NMR (300 MHz, CDCl3): dZ
6.23 (d, JZ3.0 Hz, 1H), 5.70 (bs, 1H), 3.05–2.92 (m, 1H),
2.83 (dd, JZ12.0, 5.4 Hz, 1H), 2.26–1.05 (m, 17H), 1.05
(qd, JZ12.6, 3.3 Hz, 1H). 13C NMR (75 MHz, CDCl3): dZ
190.7, 148.6, 147.9, 146.2, 135.3, 71.8, 41.1, 37.9 (2), 33.0,
25.6, 25.4 (2), 25.1, 22.3 (2). MS: m/z (%)Z262 (MC, 100),
244 (56), 150 (79). HREIMS calcd for C16H22O3 262.1569,
found 262.1572.
4.1.24. (1Z)-1,2,4,5,6,7,8,8a-Octahydro-1-((1-hydroxy-
cyclohexyl)methylene)-2-oxoazulen-3-yl benzoate 35.
Isolated as a clear oil (88 mg, 46% yield). IR (film): 3442
4.1.19. (5Z)-2-Hydroxy-5-(2-hydroxy-2-ethylbutyl-
idene)-3,4-diphenylcyclopent-2-enone 30. Isolated as a
yellow crystalline solid (98 mg, 76% yield): mp 144–
(br), 2931, 1745, 1681, 1633, 707 cmK1 1H NMR
.
(300 MHz, C6D6): dZ8.19 (d, JZ8.3 Hz, 2H), 7.30–6.95
(m, 3H), 6.72 (bs, 1H), 6.25 (s, 1H), 2.67 (d, JZ7.5 Hz, 1H),
2.37–2.16 (m, 2H), 2.10–1.90 (m, 4H), 1.74–0.80 (m, 14H).
13C NMR (75 MHz, CDCl3): dZ188.8, 164.5, 163.0, 150.8,
147.4, 139.6, 136.2, 133.6, 132.9, 130.2, 128.5, 126.0, 71.3,
45.1, 38.1, 37.9, 34.6, 30.2, 29.5, 28.4, 25.9, 25.2, 22.2,
20.5. HREIMS calcd for C24H28O4 380.1988, found
380.1961.
1
145 8C. IR (film): 3321 (br), 2939, 1644, 1405 cmK1. H
NMR (300 MHz, CDCl3): dZ7.90–7.76 (m, 2H), 7.40–7.10
(m, 8H), 6.88 (bs, 1H), 6.53 (bs, 1H), 5.94 (s, 1H), 4.78 (s,
1H), 1.80–1.38 (m, 4H), 0.94 (t, JZ7.5 Hz, 3H), 0.57 (t, JZ
7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): dZ190.9, 153.0,
151.6, 141.2, 136.7, 135.8, 132.0, 129.5 (2), 129.0 (2), 128.4
(2), 127.4 (2), 127.2 (2), 77.2, 48.0, 34.0, 33.8, 8.3, 8.0.
HREIMS calcd for C23H24O3 348.1725, found 348.1738.
4.1.25. (5Z)-2-Hydroxy-5-((1-hydroxycyclohexyl)methyl-
ene)-3-methyl-4-(5-methylfuran-2-yl)cyclopent-2-enone
37. Isolated as a clear oil (143 mg, 64% yield). IR (film):
3316, 1678 cmK1. 1H NMR (300 MHz, CDCl3): dZ6.15 (d,
JZ1.8 Hz, 1H), 6.02 (d, JZ3.0 Hz, 1H), 5.88 (dt, JZ3.0,
4.1.20. (5Z)-2-Hydroxy-5-(2-hydroxy-2-ethylbutyl-
idene)-3-methyl-4-(5-methylfuran-2-yl)cyclopent-2-
enone 31. Isolated as a clear oil (77 mg, 48% yield).
1
IR (neat): 3312, 1676, 1482 cmK1. H NMR (300 MHz,

3426
A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
0.9 Hz, 1H), 5.40 (bs, 1H), 4.31 (d, JZ1.8 Hz, 1H), 2.23 (d,
JZ0.8 Hz, 3H), 1.96 (s, 3H), 1.82–1.40 (m, 10H). 13C NMR
(75 MHz, CDCl3): dZ189.2, 153.4, 152.1, 151.4, 150.2,
138.7, 118.2, 108.0, 106.1, 57.0, 43.4, 33.4, 25.3, 25.2, 20.9,
18.5, 13.2, 11.7. HREIMS calcd for C18H22O4 302.1518
found 302.1537.
K78 8C via cannula. After 10 min at K78 8C, the reaction
mixture was warmed from K78 to K30 8C over 30 min and
stirred further for 30 min at K30 8C. sec-BuLi (420 mL,
1.35 M in cyclohexane, 0.57 mmol) was added dropwise at
K78 8C. After 45 min, a solution of freshly sublimed tert-
butyldimethylsilyl chloride (218 mg, 1.45 mmol) in 2 mL
THF was added at K78 8C via cannula. The reaction
mixture was warmed from K78 to K30 8C, stirred further
for1.5 hatK30 8C;thenquenchedbyrapidadditionthrougha
large bore cannula to 5% (v/v) aqueous HCl in EtOH (7 mL).
After 10 min, it was neutralized with pH 7 buffer, and
extracted with EtOAc (3!). The combined organic extracts
were washed with brine (2!) and dried over MgSO4.
Purification by flash column chromatography on silica (1%
EtOAc in hexanes) gave cyclopentenone 44 as a yellow
crystalline solid (107 mg, 79% yield): mp 136–138 8C.
4.1.26. (5Z)-2-Hydroxy-5-((1-hydroxycyclododecyl)-
methylene)-3,4-dimethylcyclopent-2-enone 38. Isolated
as a white crystalline solid (198 mg, 62% yield): mp 149–
151 8C. IR (film): 3340 (br), 2930, 2860, 1680, 1660, 1615,
1
1110 cmK1. H NMR (300 MHz, C6D6): dZ6.80 (s, 1H),
6.50 (bs, 1H), 5.96 (bs, 1H), 2.42 (q, JZ7.0 Hz, 1H), 2.05–
1.80 (m, 4H), 1.57 (d, JZ0.6 Hz, 3H), 1.50–1.30 (m, 18H),
0.75 (d, JZ7.0 Hz, 3H). 13C NMR (75 MHz, C6D6): dZ
190.3, 151.6, 148.6, 143.1, 136.2, 75.2, 38.6, 35.4, 35.3,
26.8, 26.4, 22.8, 22.3, 20.3, 20.1, 17.3, 11.3. HREIMS calcd
for C20H32O3 320.2351, found 320.2390.
1
IR (film): 3272 (br), 2927, 1668, 1398 cmK1. H NMR
(300 MHz, CDCl3): dZ7.84–7.74 (m, 2H), 7.40–7.10 (m,
8H), 6.18 (s, 1H), 4.76 (s, 1H), 0.83 (s, 9H), 0.23 (s, 3H), 0.20
(s, 3H). 13C NMR (75 MHz, CDCl3): dZ190.2, 152.1, 151.8,
141.6, 140.9, 133.9, 132.6, 129.4 (2), 128.8 (2), 128.5 (2),
128.4 (2), 127.5 (2), 49.4, 26.4(3), 17.2, K5.6, K5.9. MS: m/z
(%)Z361 (MC–CH3, 3), 343 (1), 319 (100). HREIMS calcd
for C24H28O2Si (MC–CH3) 361.1624, found 361.1604.
4.1.27.
(3Z)-3a,4,5,6-Tetrahydro-1-hydroxy-3-((1-
hydroxycyclododecyl)methylene)-1H-inden-2(4H)-one
39. Isolated as a white crystalline solid. (119 mg, 58%
yield): mp 154–156 8C. IR (neat): 3310, 2960, 1714, 1665,
1610, 1457, 1414, 1359 cmK1 1H NMR (300 MHz,
.
CDCl3): dZ6.39 (bs, 1H), 6.19 (s, 1H), 3.05–2.90 (m,
1H), 2.81 (dd, JZ11.7, 5.4 Hz, 1H), 2.24–0.80 (m, 29H).
13C NMR (75 MHz, CDCl3): dZ190.7, 148.8, 147.9, 146.2,
134.9, 75.4, 41.2, 35.1, 35.0, 33.1, 26.6, 26.3, 25.4 (2), 25.1
(2), 22.7 (2), 22.3 (2), 20.2, 19.9. MS: m/z (%)Z346 (MC,
100), 328 (51), 150 (86). HREIMS calcd for C22H34O3
346.2508, found 346.2487.
Compounds 42, 43 and 45 were prepared according to the
general procedure described above for 44.
4.1.31. (3Z)-3-((tert-Butyldimethylsilyl)methylene)-3a,4,
5,6-tetrahydro-1-hydroxy-1H-inden-2(4H)-one 42. Iso-
lated as a white crystalline solid (140 mg, 50% yield): mp
118–121 8C. IR (film): 3326 (br), 2930, 2855, 1686, 1657,
4.1.28. (3Z)-3a,4,5,6,7,8-Hexahydro-1-hydroxy-3-((1-
hydroxycyclododecyl)methylene)azulen-2(1H)-one 40.
Isolated as a white crystalline solid (120 mg, 67% yield):
mp 160–162 8C. IR (neat): 3345, 2927, 2850, 1667, 1610,
1
1607, 1401, 1250, 1087, 1070, 860, 825, 768 cmK1. H
NMR (300 MHz, CDCl3): dZ6.16 (d, JZ0.9 Hz, 1H), 6.06
(bs, 1H), 2.98 (dm, JZ14.2 Hz, 1H), 2.82 (dd, JZ11.8,
5.3 Hz, 1H), 2.27–2.21 (m, 1H), 2.11–1.86 (m, 3H), 1.48
(qt, JZ13.2, 3.0 Hz, 1H), 1.29 (qt, JZ12.0, 3.6 Hz, 1H),
1.01 (qd, JZ9.6, 3.0 Hz, 1H), 0.92 (s, 9H), 0.21 (s, 3H),
0.20 (s, 3H). 13C NMR (75 MHz, CDCl3): dZ189.8, 152.3,
148.0, 143.7, 135.7, 42.3, 32.6, 26.4 (3), 25.3, 25.1, 24.9,
17.0, K5.8, K5.9. MS: m/z (%)Z221 (MC–C4H9, 100), 75
(23). HREIMS calcd for C16H26O2Si (–C4H9) 221.0998,
found 221.0999.
1470, 1419 cmK1. H NMR (300 MHz, CDCl3): dZ6.43
1
(bs, 1H), 6.24 (s, 1H), 5.65 (bs, 1H), 3.14 (d, JZ9.9 Hz,
1H), 2.82–2.58 (m, 2H), 2.08 (d, JZ11.7 Hz, 1H), 2.00–
1.71 (m, 5H), 1.70–1.57 (m, 3H) 1.50–1.20 (m, 21H). 13C
NMR (75 MHz, CDCl3): dZ189.5, 150.2, 149.9, 149.1,
135.5, 75.1, 44.3, 35.1, 34.9, 34.8 (2), 30.6, 29.7, 28.3, 26.4
(2), 26.0, 25.6, 22.5 (2), 22.0, 19.9, 19.8. HREIMS calcd for
C23H36O3 360.2664, found 360.2700.
4.1.32. (3Z)-3-((tert-Butyldimethylsilyl)methylene)-3a,4,
5,6,7,8-hexahydro-1-hydroxyazulen-2(1H)-one 43. Iso-
lated as a white crystalline solid (86 mg, 65% yield): mp
128–133 8C. IR (film): 3339, 2923, 1671, 1601, 1407,
4.1.29. (5Z)-2-Hydroxy-5-((1-hydroxycyclododecyl)-
methylene)-3,4-diphenylcyclopent-2-enone 41. Isolated
as a yellow crystalline solid (106 mg, 66% yield): mp
200–202 8C. IR (film): 3417 (br), 2939, 1665, 1405 cmK1
.
1
825 cmK1. H NMR (300 MHz, C6D6): dZ6.83 (s, 1H),
1H NMR (300 MHz, CDCl3): dZ7.90–7.76 (m, 2H), 7.40–
7.10 (m, 8H), 6.79 (bs, 1H), 6.25 (bs, 1H), 6.08 (s, 1H), 4.73
(s, 1H), 1.90–0.80 (m, 22H). 13C NMR (75 MHz, CDCl3):
dZ190.5, 153.6, 151.6, 141.0, 135.0, 135.1, 132.1, 129.5
(2), 129.0 (2), 128.5 (2), 127.4 (2), 127.2 (2), 75.5, 47.8,
34.8, 34.7, 26.3, 26.3, 26.0, 22.4 (2), 22.0, 21.9, 19.5 (2).
HREIMS calcd for C30H36O3 444.2664, found 444.2687.
6.14 (s, 1H), 2.73–2.69 (m, 1H), 2.54–2.49 (m, 2H), 1.92–
1.82 (m, 1H), 1.62–1.40 (m, 3H), 1.24–1.14 (m, 2H), 1.12
(s, 9H), 1.00–0.80 (m, 2H), 0.51 (s, 3H), 0.50 (s, 3H). 13C
NMR (75 MHz, C6D6): dZ189.6, 154.3, 151.9, 148.7,
134.9, 45.5, 35.1, 30.7, 30.1, 28.4, 26.7 (3), 25.8, 17.4, K5.3
(2). HREIMS calcd for C17H28O2Si 292.18586, found
292.1875.
4.1.30. (5Z)-5-((tert-Butyldimethylsilyl)methylene)-2-
hydroxy-3,4-diphenylcyclopent-2-enone 44. A solution
of allenyllithium 2 was prepared in 3 mL THF at K78 8C
from 44 mg (0.44 mmol) of allene and 155 mL n-BuLi
(2.91 M in hexanes, 0.45 mmol). After 45 min a solution of
amide 11 (106 mg, 0.36 mmol) in 2 mL THF was added at
4.1.33. (5Z)-5-((tert-Butyldimethylsilyl)methylene)-2-
hydroxy-3-methyl-4-(5-methylfuran-2-yl)cyclopent-2-
enone 45. Isolated as an amorphous solid (95 mg, 75%
yield): mp 140–142 8C. IR (film): 3400, 1680, 1410 cmK1
.
1H NMR (300 MHz, CDCl3): dZ6.21 (d, JZ1.2 Hz, 1H),

A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
3427
5.98 (d, JZ3.0 Hz, 1H), 5.87 (dt, JZ3.0, 1.2 Hz, 1H), 5.51
(s, 1H), 4.23 (bs, 1H), 2.22 (d, JZ0.9 Hz, 3H), 1.93 (d, JZ
1.2 Hz, 3H), 0.83 (s, 9H), 0.21 (s, 3H), 0.20 (s, 3H). 13C
NMR (75 MHz, CDCl3): dZ189.3, 151.9, 151.8, 151.0,
149.0, 138.2, 107.9, 106.1, 94.7, 45.9, 26.3 (3), 17.2, 13.5,
12.1, K5.6, K5.8. HREIMS calcd for C18H26O3Si
318.1651, found 318.1642.
(d, JZ7.4 Hz, 9H), 0.64 (t, JZ7.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3): dZ189.7, 151.7 (2), 139.4, 133.9, 45.4,
22.7, 19.1 (2),† 12.3, 11.5, 7.7. HREIMS calcd for C15H22O3
250.1569, found 250.1590.
4.1.36. (3Z)-3a,4,5,6-Tetrahydro-1-hydroxy-3-((triiso-
propylsilyl)methylene)-1H-inden-2(4H)-one 47. Isolated
as a white amorphous solid (142 mg, 50% yield): mp 118–
1
121 8C. IR (neat): 3373 (br), 2934, 1681, 1402 cmK1. H
4.1.34. (1Z)-1,2,4,5,6,7,8,8a-Octahydro-1-((triisopropyl-
silyl)methylene)-2-oxoazulen-3-yl benzoate 48. To a
solution of methoxymethyl allene ether (76 mg,
0.76 mmol) in 2 mL of THF at K78 8C was added n-BuLi
(0.31 mL, 2.49 M in hexanes, 0.78 mmol). After 30 min, a
solution of amide 10 (99 mg, 0.47 mmol) in 2 mL THF was
added at K78 8C via cannula and the reaction mixture was
allowed to warm from K78 to K30 8C over 1 h, added with
sec-BuLi (0.57 mL, 1.68 M in cyclohexane, 0.95 mmol) and
was stirred at K78 8C for an additional 30 min. TIPSCl
(0.30 mL, 1.40 mmol) in 1 mL THF was then added at
K78 8C via cannula and the reaction was allowed to warm
from K78 to K30 8C over 1 h, was quenched with 5% HCl
in EtOH, allowed to warm to rt over 20–30 min and was
then neutralized with pH 7 buffer. The mixture was
extracted with EtOAc (3!) and the combined organic
extracts were washed with brine, dried over MgSO4. The
crude mixture was dissolved into 2 mL of DCM and was
followed by the addition of Hu¨nig’s base (0.25 mL,
1.42 mmol). The mixture was cooled to 0 8C, added with
benzoyl chloride (0.06 mL, 0.52 mmol) dropwise, stirred at
rt for 1 h, was quenched with NaHCO3(aq), washed with
brine and was isolated via flash column chromatography on
silica gel (1% EtOAc in hexanes) to yield a pale yellow oil
(112 mg, 71% yield): RfZ0.39 (3% EtOAc in hexanes).
NMR (300 MHz, CDCl3): dZ6.07 (d, JZ0.9 Hz, 1H), 5.70
(bs, 1H), 3.00–2.94 (m, 1H), 2.87 (dd, JZ11.7, 5.5 Hz, 1H),
2.28 (m, 1H), 2.09 (ddd, JZ12.7, 5.5, 1.5 Hz, 1H), 1.98–
1.86 (m, 2H), 1.53–1.47 (m, 1H), 1.45–1.36 (m, 3H), 1.34–
1.25 (m, 2H), 1.05 (d, JZ3.3 Hz, 12H), 1.02 (d, JZ3.3 Hz,
6H). 13C NMR (75 MHz, CDCl3): dZ189.6, 153.2, 147.9,
143.0, 134.3, 42.8, 33.2, 25.5, 25.4, 25.1, 19.3, 12.4. MS
m/z: 277 (MC, –C3H7, 100), 145 (14), 117 (11), 115 (10), 74
(10), 68 (3). HREIMS calcd for C19H32O2Si (MC–C3H7)
277.1624, found 277.1618.
4.1.37. (5Z)-2-Hydroxy-5-((triisopropylsilyl)methylene)-
3,4-diphenylcyclopent-2-enone 49. Isolated as a low
melting solid (118 mg, 76% yield). IR (film): 3273 (br),
2948, 1667, 1402 cmK1. 1H NMR (300 MHz, CDCl3): dZ
7.96–7.88 (m, 2H), 7.40–7.10 (m, 8H), 6.10 (bs, 1H), 6.05
(s, 1H), 4.83 (s, 1H), 1.56–1.36 (m, 3H), 1.20–0.90 (m,
18H). 13C NMR (75 MHz, CDCl3): dZ190.6, 152.9, 141.9,
139.9, 134.7, 132.7, 129.4 (2), 129.0 (2), 128.7 (2), 128.3
(2), 127.3 (2), 126.8, 49.6, 18.5 (6), 17.6 (3). HREIMS calcd
C24H27O2Si (MC–C3H8) 375.1780, found 375.1761.
4.1.38. (5Z)-2-Hydroxy-5-((triisopropylsilyl)methylene)-
3-methyl-4-(5-methylfuran-2-yl)cyclopent-2-enone 50.
Isolated as a colorless oil (123 mg, 75% yield). IR (neat):
3315, 2935, 1681, 1652 cmK1 1H NMR (300 MHz,
.
IR (film): 2929, 1747, 1702, 1608, 1257, 882, 706 cmK1. 1H
NMR (300 MHz, C6D6): dZ8.13 (d, JZ8.1 Hz, 2H), 7.13–
6.95 (m, 3H), 6.10 (s, 1H), 2.88 (brd, JZ9.0 Hz, 1H), 2.36–
2.28 (m, 2H), 1.99–1.89 (m, 1H), 1.70–1.23 (m, 6H), 1.23–
1.14 (m, 20H), 1.14–0.84 (m, 2H). 13C NMR (75 MHz,
C6D6): dZ186.7, 163.0, 162.0, 154.6, 148.2, 133.4, 133.3,
130.5, 129.3, 128.6, 46.7, 35.1, 30.4, 29.7, 28.3, 25.5, 19.5,
12.6. HREIMS calcd for C27H38O3Si (MC – C3H8)
395.2042, found 395.2040.
CDCl3): dZ6.10 (d, JZ1.5 Hz, 1H), 6.01 (d, JZ2.7 Hz,
1H), 5.86 (dt, JZ3.0, 0.9 Hz, 1H), 4.75 (bs, 1H), 2.20 (d,
JZ0.9 Hz, 3H), 1.94 (s, 3H), 1.38 (m, 3H), 1.03–1.89 (m,
18H). 13C NMR (75 MHz, CDCl3): dZ189.3, 151.9, 151.7,
151.1, 149.6, 137.8, 108.1, 105.9, 94.4, 45.9, 18.9 (6), 17.7
(3), 13.5, 12.8. HREIMS calcd for C21H32O3Si 360.2121,
found 360.2134.
4.1.39. (5Z)-5-Ethylidene-2-hydroxy-3,4-dimethyl-4-
phenylcyclopent-2-enone 52. To a solution of methoxy-
methyl allene ether (88 mg, 0.88 mmol) in 2 mL of THF at
K78 8C was added n-BuLi (0.30 mL, 2.78 M in hexanes,
0.83 mmol). After 20 min, a solution of amide 51 (108 mg,
0.44 mmol) in 1 mL THF was added at K78 8C via syringe
and the reaction mixture warmed to K5 8C and maintained
for 90 min. The reaction was then recooled to K78 8C, sec-
BuLi (0.70 mL, 1.33 M in cyclohexane, 0.92 mmol) added
and stirred at K78 8C for an additional 20 min. MeI
(373 mg, 2.6 mmol) in 3 mL THF was then added at
K78 8C via cannula and the reaction stirred at K78 8C for
30 min and K30 8C for 30 min and followed by quench
with 5% HCl in EtOH at K5 8C. The reaction mixture was
allowed to warm to rt over 7 min and was then neutralized
with pH 7 buffer. The mixture was extracted with EtOAc
(3!) and the combined organic extracts were washed with
brine, dried over MgSO4 and concentrated. The crude
residue was purified via flash column chromatography
on silica gel (10–25% Et2O in hexanes) to provide 52
Compounds 46, 47, 49 and 50 were prepared according to
the general procedure described above for 48.
4.1.35. (5Z)-4-Ethyl-2-hydroxy-5-((triisopropylsilyl)-
methylene)-3-methylcyclopent-2-enone 46. Isolated as a
white crystalline solid (150 mg, 68% yield): mp 83–85 8C.
IR (neat): 3316 (br), 2939, 2864, 1684, 1656, 1606 cmK1
.
1H NMR (300 MHz, CDCl3): dZ6.08 (d, JZ1.2 Hz, 1H),
5.98 (s, 1H), 3.16 (m, 1H), 1.95 (d, JZ1.2 Hz, 3H), 1.71–
1.92 (m, 2H), 1.43 (m, 2H), 1.04† (d, JZ7.4 Hz, 9H), 1.04
† For this substrate the methyl groups of the isopropyl group displayed
unusual asymmetry in the 1H NMR at 300 and 500 MHz and the 13C
NMR at 125 MHz. For this compound, at these field strengths, there are
1
exactly two types of isopropyl methyls. Thus, in the H NMR there are
two doublets of equal intensity and in the 13C NMR there are two signals
for the methyl carbons. It had been anticipiated that methyl groups on a
given isopropyl group would be equivalent and if there was any
asymmetry, it would give rise to different types of isopropyl group rather
than different types of methyl groups. This, however, was not the case.

3428
A. R. Banaag et al. / Tetrahedron 61 (2005) 3419–3428
(Z isomer) as a clear oil and 52 (E isomer) as a white
crystalline solid (33 mg of Z isomer, 26 mg of E isomer,
5 mg of a mixture, 64% yield): mp (E isomer) 134–136 8C;
RfZ0.42 (Z), 0.31 (E) (25% Et2O in hexanes).
Cancer Research Program (DAMD17-03-1-0685) for gen-
erous support of this research.
IR Z isomer: (neat) 3310 (br), 2969, 2932, 1676, 1627 cmK1
;
E isomer: (neat) 3292 (br), 2922, 1679, 1630 cmK1. H
NMR (300 MHz, CDCl3) Z isomer: dZ7.18–7.32 (m, 5H),
5.84 (q, JZ7.4 Hz, 1H), 2.19 (d, JZ7.4, 3H), 1.69 (s, 3H),
1.63 (s, 3H); E isomer: dZ7.18–7.34 (m, 5H), 6.62 (q, JZ
7.4 Hz, 1H), 5.85 (s, 1H), 1.69 (s, 3H), 1.65 (s, 3H), 1.48 (d,
JZ7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) Z isomer: dZ
191.2, 150.6, 143.7, 143.1, 142.8, 136.7, 128.4, 126.5,
126.5, 48.9, 23.2, 14.3, 9.4; E isomer: dZ189.8, 149.3,
146.4, 143.5, 142.4, 130.7, 128.4, 126.6 (2), 48.2, 21.2,
13.9, 8.9. HREIMS calcd for C15H16O2 228.1150 (E
isomer), found 228.1132.
1
References and notes
1. Bee, C.; Tius, M. A. Org. Lett. 2003, 5, 1681–1684.
2. For an example, see: Tius, M. A.; Busch-Petersen, J.;
Yamashita, M. Tetrahedron Lett. 1998, 39, 4219–4222.
3. Baldwin, J. E.; Barton, D. H. R.; Dainis, I.; Pereira, J. L. C.
J. Chem. Soc. (C) 1968, 2283–2289.
4. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171–4174. See also: Huang, P.-Q.; Zheng, X.; Deng, X.-M.
Tetrahedron Lett. 2001, 42, 9039–9041.
5. Hoff, S.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas
1968, 87, 916–924.
6. Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem. Soc.
1999, 121, 9895–9896.
Acknowledgements
7. Tius, M. A. Acc. Chem. Res. 2003, 36, 284–290.
8. Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem.
Soc. 2002, 124, 10091–10100.
Acknowledgement is made to the National Institutes of
Health (GM-57873) and the Department of Defense Breast