An asymmetric route to novel chiral cyclohexenones with spiro-connected cyclopentenes. Further utility of chiral bicyclic thiolactams and the [3,3] thio-Claisen products

Article abstract of DOI:10.1021/jo982426q

Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products 11. The stereoselectivity of the rearrangement was found to be on the order of 10-11:1, with the exo-endo products responsible for the mixture. Addition of hydride or methyllithium-cerium chloride gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs' catalyst.

Full text of DOI:10.1021/jo982426q

J . Org. Chem. 1999, 64, 3585-3591
3585
An Asym m etr ic Rou te to Novel Ch ir a l Cycloh exen on es w ith
Sp ir o-Con n ected Cyclop en ten es. F u r th er Utility of Ch ir a l Bicyclic
Th iola cta m s a n d th e [3,3] Th io-Cla isen P r od u cts
Rene´ M. Lemieux, Paul N. Devine, Mark F. Mechelke, and A. I. Meyers*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received December 11, 1998
Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products
11. The stereoselectivity of the rearrangement was found to be on the order of 10-11:1, with the
exo-endo products responsible for the mixture. Addition of hydride or methyllithium-cerium chloride
gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-
dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs’
catalyst.
We recently described the S-alkylation of R-alkanethio-
lactam 1 with various allylic halides and the subsequent
[3,3]-sigmatropic rearrangement of the resultant inter-
mediate N,S-ketene acetal to the thiolactam 2.1 This
resulted in the formation of compounds bearing stereo-
genic vicinal quaternary centers or vicinal quaternary-
tertiary centers. After removal of the chiral auxiliary,
access to 4,4-disubstituted enones such as 3 was realized.
As a testimony to the usefulness of this method, a more
complex system was devised in which vicinal stereogenic
quaternary centers were established via the thio-Claisen
rearrangement and, ultimately, led to the first complete
asymmetric synthesis of the sesquiterpene (-)-trichodi-
ene.2
asymmetric synthesis of diverse novel spirocyclic cyclo-
hexenones, including those bearing additional functional-
ity.
Bicyclic lactam 7, whose nonracemic chirality was
derived from (R)-phenylglycine,4 was thionated using
Belleau’s reagent5 in refluxing toluene to afford the
thiolactam 8 in 87% yield (Scheme 1). Treatment of 8
with LDA at -78 °C followed by addition of allyl bromide
provided a 6:1 mixture of the epimeric thiolactam 9. The
ratio was of no consequence since the next step will
generate the planar thioenolate 10a . When 9 was treated
with LDA at -78 °C followed by addition of crotyl
bromide a , the N,S-ketene acetal intermediate 10a was
formed. Subsequent heating of the reaction mixture in
refluxing THF allowed smooth [3,3]-sigmatropic rear-
rangement of 10a to 11a , as a 9:1 mixture of diastereo-
mers, in 72% isolated yield. The mixture, at this point of
our studies, was assumed to be due to exo-endo variants,
rather than the stereochemical position of the methyl
group in 11a (vide infra). Attempted ring-closing me-
tathesis of 11a to form the spirocyclopentene using
Grubbs’ catalyst6 led only to recovered starting material,
possibly due to the intolerance of sulfur by this catalyst.7
It was therefore decided to cleave the chiral thiolactam
to the cyclohexenone 15a and attempt the metathesis at
that stage. To reach cyclohexenone 15a , thiolactam 11a
was treated with Meerwein’s reagent in refluxing CH2-
Cl2. In this way, the S-iminium ion 12a was generated
and reduction of the latter with Red-Al furnished the N,S-
ketal 13a . Buffered hydrolysis (Bu4NH2PO4 or KH2PO4/
EtOH/H2O, reflux) of 13a liberated the ketoaldehyde 14a ,
which underwent in situ spontaneous aldol condensation
to the enone 15a in 73% yield for the three-step sequence.
Note that 12a -14a were not purified and were used
directly to reach ketone 15a . At this point, treatment of
As part of an ongoing research program aimed at
further developing the use of chiral nonracemic bicyclic
lactams, in their thiocarbonyl form 4, we were interested
in the possibility of performing sequential thio-Claisen
rearrangements to produce diastereomeric diallyl com-
pounds such as 5. The close proximity of the terminal
alkene moieties should lend themselves to olefin meta-
thesis3 to generate novel, chiral spirocyclic substances 6.
We report herein the results of our efforts toward the
(4) Lemieux, R. M.; Meyers, A. I. J . Org. Chem. 1998, submitted.
(5) Lajoie, G.; Le´pine, F.; Maziak, L.; Belleau, B. Tetrahedron Lett.
1983, 24, 3815-3818.
(1) Devine, P. N.; Meyers, A. I. J . Am. Chem. Soc. 1994, 116, 2633-
2634.
(2) Lemieux, R. M.; Meyers, A. I. J . Am. Chem. Soc. 1998, 120,
5453-5457.
(3) For recent reviews on olefin metathesis, see: (a) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036-2056. (b)
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (c)
Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371-388.
(6) (a) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R. H. J . Am. Chem.
Soc. 1992, 114, 3974-3975. (b) Nguyen, S. T.; Grubbs, R. H. J . Am.
Chem. Soc. 1993, 115, 9858-9859. (c) Schwab, P.; France, M. B.; Ziller,
J . W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039-
2041. (d) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100-110.
(7) Couturier, J . L.; Tanaka, K.; Leconte, M.; Basset, J . M.; Ollivier,
J . Angew. Chem., Int. Ed. Engl. 1993, 32, 112-115.
10.1021/jo982426q CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/16/1999

3586 J . Org. Chem., Vol. 64, No. 10, 1999
Lemieux et al.
Sch em e 1
enone 15a with Grubbs’ catalyst (5%) in 1,2-dichloroeth-
ane at room temperature for 30 min smoothly effected
the olefin metathesis to the desired spiro compound 16a
in 94% yield. It is noteworthy that this facile ring-closure
could also be effected with as little as 0.7% catalyst in 3
h at room temperature to provide 16a in comparable yield
(89%). Furthermore, no scrambling of the stereocenter
bearing the methyl group took place (NMR, GLC).
Continuing to explore the versatility of this asymmetric
route to novel spirocyclohexenones, the process above was
repeated with bifunctional allylic halides. Also, both cis
and trans allylic halides were investigated. Using trans-
4-bromo-2-butene 1-tert-butyldiphenylsilyl ether, the
thioenol ether 10b was obtained, which when heated in
refluxing THF underwent the [3,3]-rearrangement af-
fording 11b in 96% yield as an 11:1 mixture of diaster-
eomers. The latter ratio was again assumed at this time
to be due to the exo-endo facial rearrangement and not
the stereochemical positioning of the substituent (R )
CH2OSiPh2But) in 11b. However, it was not possible at
this juncture to separate the 11:1 mixture to verify this
fact. This stereochemical question will be addressed
below. As described for the crotyl series 11a , the siloxy-
containing lactam 11b was sequentially treated with
Meerwein’s reagent, Red-Al, and then KH2PO4. The
procedure, without purification of any of the three
intermediates, gave the 4,4-dialkylcyclohexenone 15b in
64% overall yield as a single diastereomer. When the
olefin metathesis was employed using Grubbs’ catalyst,
16b was obtained as a single diastereomer in 89% yield.
At this point, we felt we could make some progress
toward assigning the stereochemistry of the major isomer
in 11b by deprotecting the alcohol to 16c and determining
whether it would conjugatively add to the enone. The
siloxy group in 16b was therefore transformed into the
free hydroxyl 16c (R ) CH2OH) using TBAF, and
subsequently no conjugate addition was observed. Thus,
one can conclude that the hydroxy methyl group in 16c
is anti to the enone and could not cyclize to the five-
membered ring ether. However, this negative evidence
was deemed to be insufficient for firm stereochemical
assignment and would have to await further study.
When the cis-allylbromide derived from 1-bromo-4-
hydroxy-2-butene, as its tert-butyldiphenylsilyl ether, was
employed to alkylate 9, the rearrangement product 17
was obtained in 83% yield as a 5:1 ratio of diastereomers
Sch em e 2
(Scheme 2). Repeating the sequence as above, 17 was
transformed into the 4,4-dialkylcyclohexenone 18 (as a
10:1 diastereomeric mixture). There was present 10-15%
of tert-butyldiphenylsilanol that could not be separated
at this stage, and the mixture was carried on to the next
step. The crude product 18 was subjected to the meta-
thesis producing the spiroketone 19 in 75% yield as a
diastereomeric ratio of 10:1. The silanol impurity was
now absent, having been removed by column chroma-
tography. To add further support that the spiroketones
derived from the cis- and trans-allyl bromides differ only
at the siloxy methyl group, the silyl group in 19 was
cleaved with TBAF leading to a 71% yield of pure tricyclic
ether 20. Thus, it was now reasonably certain that the
major component in the two products obtained, 17 and
11b, was a result of exo-endo rearrangement.
The loss of the minor isomer accompanying 15b and
18 wherein it appeared that there was an increase in
diastereomeric ratios from 5:1f10:1 for 17f18 and 11:1
to > 99:1 for 11bf15b will now be addressed. The major
reason for these apparent increases may lie in the fact
that the thio-Claisen process takes place to produce a
small quantity of endo-rearranged product. This minor
component contains the large TBDPS substituent in the
endo-face that may, due to steric effects, inhibit thione
reduction such that only the major exo-substituted mate-
rial is reduced and hydrolyzed.
Finally, with regard to the stereochemical assignment,
another study was added to reaffirm the results. To
gather further insight into the stereo assignments result-
ing from the thio-Claisen rearrangement, the p-meth-
oxybenzyl ethers (PMB) of the cis- and trans-bro-

Chiral Cyclohexenones with Spiro-Connected Cyclopentenes
J . Org. Chem., Vol. 64, No. 10, 1999 3587
Sch em e 3
Sch em e 5
the desired diketone 22 in 40% yield overall from thio-
lactam 11a . The success of this addition to the thiocar-
bonyl group is undoubtedly due to the decreased basicity
of the organocerate reagents compared to that of alky-
lithium.
Sch em e 4
Having the key diketone 22 in hand, access to other
methyl-substituted spiro compounds (e.g., 25 and 27)
appeared to be within reach. Thus, treatment of 22 with
KOH in refluxing MeOH furnished the aldol condensa-
tion product 23 in 84% yield (Scheme 5). Similarly, when
diketone 22 was heated in refluxing benzene in the
presence of piperidine and acetic acid,10 the regioisomeric
enone 24 was obtained as a single compound in good yield
(75%). The ring-closure metathesis to these novel prod-
ucts was initially attempted with enone 23, since it was
anticipated that the methyl group in the â-position of the
enone would be less sterically demanding for the metal-
locycle than the corresponding â-methyl group in enone
24. Treatment of 23 with Grubbs’ catalyst (5% every 12
h; total of 20%) in refluxing 1,2-dichloroethane for 48 h
provided the spiroketone 25, albeit in low yield (32%).
As expected, the olefin metathesis proved very slow and
sluggish in these cyclohexenone systems. It was therefore
decided to reverse the order of the last two steps leading
to the spiro compound and perform the ring-closure
metathesis on the acyclic precursor to the enones, namely
diketone 22. Thus, when 22 was stirred at room temper-
ature in the presence of Grubbs’ catalyst (5%), conversion
of the starting material to the cyclopentene 26 was
complete in 2 h. It is interesting to note that a small
structural change in the substrate, i.e., 22 vs 23, allowed
the same transformation to be effected in a very facile
manner. It now remained only to cyclize diketone 26 to
the corresponding enones. When 26 was subjected to
piperidine and acetic acid in refluxing benzene for 15 h,
the spiro compound 27 was obtained in 67% yield.
Alternatively, treatment of 26 with KOH in refluxing
MeOH10 for 2 h generated a mixture of 25 (70%) and the
regioisomer 27 (20%).
mobutenols were used to alkylate the thiolactam 9 and
then subjected to the [3,3] rearrangement (Scheme 3).
The reason for utilizing another derivative of the allyl
bromide was based entirely on the fact that the major
and minor rearranged thiolactams could be readily
separated by chromatography unlike the silyl ethers, 11b
and 17.
As shown in Scheme 3, there are four possible stereo-
isomers (A-D) that could be obtained from each of the
Claisen rearrangements, using the cis- or trans-butenyl
bromides. However, each rearrangement gave only two
of the four possible products, indicating that all four may
indeed be different. As stated above, A-D could be
readily separated from their companion products (Scheme
1
3), and therefore, comparisons could be made of their H
NMR spectra. None of the products were the same,
supporting the conclusion made earlier that they indeed
were all different, and that the diastereomers obtained
with either cis or trans allylic bromides differed only at
the exo-endo face (A + B) and (C + D).
To further broaden the scope of this method, it was
desirable to add a carbon nucleophile, as opposed to a
hydride, to the S-iminium ion 12a , which would generate
a diketone instead of the ketoaldehydes after hydrolysis
(Scheme 4). Initial attempts to add MeLi to a solution of
the S-iminium ion 12a in THF at -78 °C only gave rise
to a complex mixture. It was then assumed that depro-
tonation of the benzylic proton in 12a could be respon-
sible for the absence of the desired carbonyl addition
product, a process observed earlier in a related system.8
Therefore, when the MeLi‚CeCl3 reagent9 was employed,
addition to the S-iminium ion occurred smoothly to
provide the alkylated intermediate 21. Buffered hydroly-
sis, using potassium dihydrogen phosphate, generated
In conclusion, we have shown that the sequential thio-
Claisen rearrangement can be utilized to introduce two
different allylic moieties in a diastereoselective fashion.
Furthermore, the presence of functionality (e.g., OH) on
the allylic bromide allows the rearrangement to proceed
(9) Paquette, L. A.; Learn, K. S.; Romine, J . L.; Lin, H. S. J . Am.
Chem. Soc. 1988, 110, 879-890.
(10) Meyers, A. I.; Lefker, B. A. Tetrahedron 1987, 43, 5663-5676.
(8) Fray, A. H.; Meyers, A. I. Bull. Soc. Chem. Fr. 1997, 134, 283-
298.

3588 J . Org. Chem., Vol. 64, No. 10, 1999
Lemieux et al.
room temperature and then was heated to reflux for 24 h. The
solution was cooled to room temperature and was diluted with
EtOAc (150 mL). The organic layer was washed with water
and brine, dried over MgSO4, and then filtered; the solvent
was removed under reduced pressure. 1H NMR analysis of the
crude product indicated a 9:1 mixture of diastereomers. The
oil thus acquired was subjected to flash chromatography (19:1
Hex/EtOAc) to afford 847 mg (72%) of an inseparable mixture
of two diastereomers (9:1) as a colorless solid: 1H NMR (300
MHz, CDCl3) δ 0.97 (d, J ) 6.7 Hz, 3H), 1.03 (s, 3H), 1.49 (s,
3H), 1.60-1.66 (m, 4H; therein 1.63 (s, 3H)), 1.78-2.14 (m,
3H), 2.28 (dd, J ) 13.2, 9.6 Hz, 1H), 2.89 (dq, J ) 8.9, 6.7 Hz,
1H), 3.12 (dd, J ) 13.2, 4.7 Hz, 1H), 4.89-4.96 (m, 1H), 5.01-
5.18 (m, 3H), 5.64-5.81 (m, 2H), 5.86 (s, 1H), 7.02-7.35 (m,
5H); 13C NMR (75 MHz, CDCl3); δ 16.4, 24.1, 27.66, 27.74, 33.2,
35.2, 51.0, 51.3, 53.1, 76.4, 81.6, 94.0, 117.0, 117.1, 126.2, 127.0,
128.2, 135.8, 137.4, 139.1, 205.2; IR (thin film) 1636, 1404 cm-1
; HRMS (FAB+) for C23H32NOS (M + H)+ calcd 370.2205, found
with a high degree of stereoselectivity. The S-iminium
ions, 12a and 12b, derived from the [3,3]-sigmatropic
rearrangement product, can undergo nucleophilic addi-
tion with a hydride or a carbon nucleophile to generate
the corresponding ketoaldehyde 14 or diketone 22. Fi-
nally, the combination of the aldol condensation-olefin
metathesis reaction sequence allows entry into a series
of chiral spiro[4.5]decane systems.
Exp er im en ta l Section
Thin-layer chromatography (TLC) and flash chromatogra-
phy were performed with E. Merck silica gel (230-400 mesh).
TLC grade flash chromatography was performed using Sigma
Type H silica gel (10-40 µm, no binder). All reagents were
purchased from Aldrich. All reactions were conducted under
an argon atmosphere in oven- or flame-dried apparatus. All
solvents and reagents were purified using established proce-
dures. Microanalyses were performed by Atlantic Microlab,
Inc., Norcross, GA.
370.2202; [R]25 -68.7 (c 1.57, CHCl3).
D
(4R)-4-Allyl-4-((3S)-bu t-1-en -3-yl)cycloh ex-2-en on e (15a).
To a stirred solution of thiolactam 11a (846 mg, 2.29 mmol),
as a 9:1 mixture of diastereomers, in anhydrous CH2Cl2 (25
mL) was added a solution of Et3OBF4 (2 M in CH2Cl2, 2.86
mL, 5.72 mmol). The reaction mixture was heated to reflux
for 2 h and then was cooled to -78 °C. A solution of Red-Al
(3.2 M in toluene, 0.86 mL, 2.8 mmol) was added via a syringe,
and the mixture was stirred for 25 min. The reaction mixture
was treated with MeOH (0.5 mL), was stirred for an additional
10 min at -78 °C, and then was warmed to room temperature.
The solution was diluted with EtOAc (100 mL), the organic
layer was washed with water (2 × 10 mL), and the solvent
was removed under reduced pressure. The residue acquired
was taken in EtOH-H2O (1:1, 46 mL total), and Bu4NH2PO4
buffer (1 M in H2O, 46 mL) was added. The reaction was
heated to reflux overnight and then was cooled to room
temperature, and the EtOH was removed under reduced
pressure. The residue was diluted with water and then was
extracted with Et2O. The combined organic layers were washed
successively with 1 M HCl, saturated aqueous NaHCO3, H2O,
and brine, dried over MgSO4, and then filtered; the solvent
was removed under reduced pressure. The residue acquired
was subjected to flash chromatography (7:1 Hex/EtOAc) to
afford 318 mg (73%) of the title compound as a light yellow oil
exhibiting a single diastereomer: 1H NMR (300 MHz, CDCl3)
δ 0.96 (d, J ) 7.0 Hz, 3H), 1.73 (dtd, J ) 13.8, 5.9, 1.3 Hz,
1H), 1.97 (ddd, J ) 13.8, 10.4, 5.9 Hz, 1H), 2.16-2.51 (m, 5H),
4.96-5.12 (m, 4H), 5.58-5.80 (m, 2H), 5.94 (d, J ) 10.0 Hz,
1H), 6.64 (dd, J ) 10.0, 2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 15.4, 27.8, 33.9, 40.2, 41.0, 44.1, 116.3, 118.5, 128.8, 133.5,
139.2, 157.0, 199.3; IR (thin film) 1681, 1638 cm-1; HRMS
(FAB+) for C13H19O (M + H)+ calcd 191.1436, found 191.1441;
Bicyclic Th iola cta m 8. To a stirred solution of lactam 74
(2.50 g, 9.64 mmol) in toluene (50 mL) was added Belleau’s
reagent5 (3.06 g, 5.78 mmol), and the reaction mixture was
heated to reflux for 20 h. The solution was cooled to room
temperature, the solvent was removed under reduced pressure,
and the acquired residue was subjected to flash chromatog-
raphy (9:1 Hex/EtOAc) to afford 2.30 g (87%) of the title
compound as a colorless solid: 1H NMR (300 MHz, CDCl3) δ
1.06 (s, 3H), 1.56 (s, 3H), 1.71 (s, 3H), 1.75-2.16 (m, 3H), 2.19-
2.28 (m, 1H), 2.93-3.06 (m, 1H), 3.24 (ddd, J ) 18.0, 9.1, 5.7
Hz, 1H), 5.63 (s, 1H), 7.02-7.19 (m, 2H), 7.24-7.38 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 16.5, 26.0, 27.2, 32.0, 36.5, 39.0,
74.8, 81.7, 95.1, 126.5, 127.2, 128.3, 136.7, 198.3; IR (thin film)
1438 cm-1; HRMS (EI) for C16H21NOS (M+) calcd 275.1344,
found 275.1344; [R]25 -147 (c 1.66, CHCl3).
D
Bicyclic Th iola cta m 9. To a cold (-78 °C) stirred solution
of LDA (11.1 mmol) in dry THF (100 mL) was added a solution
of the thiolactam 8 (2.90 g, 10.5 mmol) in THF (10 mL) via a
cannula. The reaction mixture was stirred at -78 °C for 20
min, and then allyl bromide (1.34 g, 0.96 mL, 11.1 mmol) was
added via a syringe. The mixture was stirred for 15 min,
warmed to room temperature, and then stirred for an ad-
ditional 20 min. The solution was diluted with EtOAc, and
the organic layer was washed with water and brine, dried over
MgSO4, and then filtered; the solvent was removed under
reduced pressure. 1H NMR analysis of the crude product
indicated a 6:1 mixture of epimers. The residue acquired was
subjected to flash chromatography (gradient elution from 19:1
to 6:1 Hex/EtOAc) to afford two fractions. The first epimer to
be eluted afforded 455 mg (14%) of a light yellow oil: 1H NMR
(300 MHz, CDCl3) δ 1.02 (s, 3H), 1.51 (s, 3H), 1.53-1.66 (m,
1H), 1.72 (s, 3H), 1.78-1.90 (m, 1H), 1.98-2.13 (m, 1H), 2.21
(ddd, J ) 12.5, 7.8, 2.8 Hz, 1H), 2.28-2.38 (m, 1H), 2.58-2.71
(m, 1H), 3.01-3.11 (m, 1H), 5.00-5.14 (m, 2H), 5.64 (s, 1H),
5.76-5.92 (m, 1H), 7.11-7.38 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 22.7, 26.6, 27.1, 31.7, 35.8, 40.1, 44.2, 75.1, 82.0, 95.3,
116.8, 126.7, 127.2, 128.3, 136.6, 136.8, 202.3; IR (thin film)
1639, 1417 cm-1. The second epimer to be eluted afforded 2.80
g (84%) of a yellow oil: 1H NMR (300 MHz, CDCl3) δ 1.06 (s,
3H), 1.55 (s, 3H), 1.65 (s, 3H), 1.67-1.83 (m, 2H), 1.93-2.03
(m, 1H), 2.17-2.25 (m, 1H), 2.62-2.73 (m, 1H), 2.74-2.84 (m,
1H), 3.12 (ddd, J ) 17.1, 8.6, 3.9 Hz, 1H), 5.10-5.13 (m, 1H),
5.14-5.19 (m, 1H), 5.70-5.85 (m, 2H; therein 5.80 (s, 1H)),
7.02-7.10 (m, 2H), 7.22-7.36 (m, 3H); 13C NMR (75 MHz,
CDCl3) δ 22.6, 26.7, 27.7, 32.8, 36.2, 43.2, 48.1, 75.5, 81.8, 94.5,
118.0, 126.0, 127.1, 128.4, 134.9, 137.0, 201.9; IR (thin film)
[R]25 +42.6 (c 1.72, CHCl3).
D
(1S,5R)-1-Meth yl-8-oxa sp ir o[4.5]d eca -2,6-d ien e (16a ).
To a degassed (three freeze-pump-thaw cycles) solution of
enone 15a (82.8 mg, 0.435 mmol) in 1,2-dichloroethane (60 mL)
was added Grubbs’ catalyst (17.9 mg, 0.022 mmol). The
reaction mixture was degassed (one cycle) and then was stirred
at room temperature for 30 min, at which time the starting
material had been completely consumed. The solvent was
removed under reduced pressure, the residue acquired was
filtered through Florisil (Et2O as eluant) and the solvent was
removed under reduced pressure. The derived oil was distilled
(bulb-to-bulb, 150-160 °C/0.5 mmHg) to afford 66.6 mg (94%)
of the title compound as a clear colorless oil: 1H NMR (300
MHz, CDCl3) δ 0.97 (d, J ) 7.2 Hz, 3H), 1.84-1.94 (m, 1H),
1.98-2.09 (m, 1H), 2.24-2.33 (m, 1H), 2.42 (t, J ) 6.6 Hz, 2H),
2.48 (dq, J ) 16.1, 2.0 Hz, 1H), 2.54-2.65 (m, 1H), 5.61-5.72
(m, 2H), 5.82 (d, J ) 10.0 Hz, 1H), 6.82 (d, J ) 10.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 15.3, 29.1, 35.5, 42.5, 45.6, 47.9,
126.5, 127.4, 136.0, 160.0, 199.8; IR (thin film) 1682, 1610
cm-1; HRMS (FAB+) for C11H15O (M + H)+ calcd 163.1123,
1640, 1422 cm-1
.
Th iola cta m 11a . To a cold (-78 °C) stirred solution of LDA
(3.51 mmol) in anhydrous THF (30 mL) was added thiolactam
9 (1.01 g, 3.19 mmol) in THF (5 mL) via a cannula. The
reaction mixture was stirred for 20 min, and then crotyl
bromide (85% isomeric purity, 0.46 mL, 0.60 g, 4.5 mmol) was
added via a syringe. The resulting mixture was warmed to
found 163.1118; [R]25 +103 (c 1.65, CHCl3).
D
(5S,6S)-5-Acetyl-5-a llyl-6-m eth yloct-7-en -2-on e (22). Ce-
rium trichloride heptahydrate (1.64 g, 4.40 mmol) was dried
overnight at 140 °C at 0.1 mmHg. The solids were cooled to

Chiral Cyclohexenones with Spiro-Connected Cyclopentenes
J . Org. Chem., Vol. 64, No. 10, 1999 3589
room temperature, and dry THF (20 mL) was added. The
resulting suspension was stirred at room temperature for 3 h
and was cooled to -78 °C, and then a solution of MeLi (1.40
M in Et2O, 2.83 mL, 3.96 mmol) was added and the slurry
was stirred for an additional 1 h at this temperature. In the
meantime, to a stirred solution of thiolactam 11a (615 mg, 1.66
mmol) in dry CH2Cl2 (20 mL) was added a solution of Et3OBF4
(2 M in CH2Cl2, 1.33 mL, 2.66 mmol), and the reaction mixture
was heated to reflux for 2 h. The solution was cooled to room
temperature and the solvent was removed in vacuo. The
residue was rapidly dissolved in dry THF (15 mL) and was
cooled immediately to -78 °C. The solution of S-iminium ion
was added, via a cannula, to the cerium slurry. The resulting
mixture was stirred at -78 °C for 10 min and warmed to 0 °C
and then was allowed to stir for an additional 1 h. The mixture
was diluted with Et2O and washed with water; the solvent was
removed under reduced pressure. The residue thus acquired
was dissolved in EtOH/H2O (1:1, 33 mL total), and a solution
of Bu4NH2PO4 (1 M in H2O, 33 mL, 33 mmol) was added. The
mixture was heated to reflux overnight and cooled to room
temperature, and the EtOH was removed under reduced
pressure. The aqueous layer was diluted with H2O and was
extracted with Et2O. The combined organic layers were washed
successively with 1 M HCl, saturated aqueous NaHCO3, H2O,
and brine, dried over MgSO4, and then filtered. The solvent
was removed under reduced pressure, and the resulting oil
was subjected to flash chromatography (6:1 Hex/EtOAc) to
afford 148 mg (40%) of the title compound as a clear colorless
oil: 1H NMR (300 MHz, CDCl3) δ 0.97 (d, J ) 6.9 Hz, 3H),
1.80 (ddd, J ) 14.6, 11.0, 5.5 Hz, 1H), 1.93 (ddd, J ) 14.6,
11.0, 4.8 Hz, 1H), 2.08 (s, 3H), 2.10 (s, 3H), 2.19-2.52 (m, 5H),
4.99-5.12 (m, 4H), 5.62-5.82 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 14.4, 25.3, 26.6, 29.1, 36.3, 38.0, 42.7, 55.4, 115.2,
117.1, 133.5, 138.5, 207.1, 210.9; IR (thin film) 1714, 1700,
1637 cm-1; HRMS (FAB+) for C14H23O2 (M + H)+ calcd
three drops), and the mixture was heated to reflux for 2 h.
The solution was cooled to room temperature, and the solvent
was removed under reduced pressure. The residue was sub-
jected to flash chromatography (19:1 then 9:1 Hex/EtOAc) to
afford 19.3 mg (70%) of the title compound as a clear colorless
oil and 5.5 mg (20%) of the regioisomeric enone 27 (vide
infra): 1H NMR (300 MHz, CDCl3) δ 0.91 (d, J ) 7.3 Hz, 3H),
1.80-1.96 (m, 5H; therein 1.91 (s, 3H)), 2.17-2.46 (m, 4H),
3.28-3.40 (m, 1H), 5.42-5.49 (m, 1H), 5.55-5.62 (m, 1H), 5.81
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 15.1, 23.9, 28.2, 28.9, 40.4,
43.2, 52.7, 125.0, 125.5, 136.4, 160.0, 202.4; IR (thin film) 1666
cm-1; HRMS (EI) for C12H16O (M+) calcd 176.1201, found
176.1201; [R]25 +167 (c 0.93, CHCl3).
D
(3S)-3-((2S)-2-Met h ylcyclop en t -3-en e-1,1-d iyl)h ep t a -
2,7-d ion e (26). To a degassed (three freeze-pump-thaw
cycles) solution of diketone 22 (90.1 mg, 0.405 mmol) in 1,2-
dichloroethane (60 mL) was added Grubbs’ catalyst (17 mg,
0.020 mmol). The solution was degassed (one cycle) and stirred
at room temperature for 2 h, and then the solvent was removed
under reduced pressure. The residue was filtered through
Florisil (Et2O as eluent), and the solvent was removed under
reduced pressure. The derived oil was subjected to flash
chromatography (6:1 Hex/EtOAc) to afford 63.3 mg (81%) of
the title compound as a clear colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.99 (d, J ) 7.3 Hz, 3H), 1.69-1.81 (m, 1H), 1.91-
2.14 (m, 8H; therein 2.07 (s, 3H), 2.09 (s, 3H)), 2.23 (t, J ) 7.9
Hz, 2H), 2.79-2.87 (m, 2H), 5.45-5.59 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 15.1, 25.6, 25.9, 29.9, 38.6, 39.8, 44.8, 60.3,
127.7, 135.0, 207.9, 211.5; IR (thin film) 1715, 1704 cm-1
;
HRMS (FAB+) for C12H19O2 (M + H)+ calcd 195.1385, found
195.1390; [R]25 +15.3 (c 1.43, CHCl3).
D
(1S,5S)-1,6-Dim eth yl-8-oxaspir o[4.5]deca-2,6-dien e (27).
To a stirred solution of the diketone 26 (25.2 mg, 0.130 mmol)
in benzene (5 mL) were added successively piperidine (two
drops) and glacial acetic acid (two drops), and the reaction
mixture was heated to reflux overnight. The solution was
cooled to room temperature and was diluted with Et2O. The
organic layer was washed with H2O and brine and dried over
MgSO4, and after filtration, the solvent was removed under
reduced pressure. The residue was subjected to flash chroma-
tography (9:1 Hex/EtOAc) to afford 15.3 mg (67%) of the title
compound as a clear colorless oil: 1H NMR (300 MHz, CDCl3)
δ 0.99 (d, J ) 7.4 Hz, 3H), 1.81-1.92 (m, 4H; therein 1.89 (d,
J ) 1.5 Hz, 3H)), 1.96-2.08 (m, 1H), 2.32-2.50 (m, 4H), 2.89-
223.1698, found 223.1692; [R]25 -33.0 (c 1.48, CHCl3).
D
(6S)-6-Allyl-6-((3S)-bu t-1-en -3-yl)-3-m eth ylcycloh ex-2-
en on e (23). To a stirred solution of diketone 22 (34.3 mg, 0.154
mmol) in MeOH (5 mL) was added a solution of KOH in MeOH
(10%, three drops), and the reaction mixture was heated to
reflux for 1 h. The solution was cooled to room temperature,
and the solvent was removed under reduced pressure. The
residue acquired was subjected to flash chromatography (19:1
Hex/EtOAc) to afford 26.4 mg (84%) of the title compound as
a clear colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.94 (d, J )
7.0 Hz, 3H), 1.78 (app dt, J ) 13.9, 5.8 Hz, 1H), 1.87 (s, 3H),
1.95 (ddd, J ) 13.9, 7.7, 5.9 Hz, 1H), 2.11 (dd, J ) 14.0, 7.7
Hz, 1H), 2.23-2.31 (m, 2H), 2.35 (dd, J ) 14.0, 6.6 Hz, 1H),
2.70 (app quint, J ) 7.0 Hz, 1H), 4.92-5.04 (m, 4H), 5.60-
5.79 (m, 3H; therein 5.77 (s, 1H)); 13C NMR (75 MHz, CDCl3)
δ 15.2, 24.0, 27.4, 28.0, 37.5, 40.0, 49.2, 115.7, 117.5, 126.5,
134.3, 139.4, 160.0, 201.8; IR (thin film) 1667 cm-1; HRMS
3.01 (m, 1H), 5.58-5.66 (m, 2H), 5.78 (d, J ) 1.5 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) δ 15.5, 21.1, 29.4, 35.0, 42.5, 45.8, 48.4,
127.0, 127.5, 136.2, 168.2, 199.5; IR (thin film) 1672, 1610
cm-1; HRMS (EI) for C12H16O (M+) calcd 176.1201, found
176.1202; [R]25 +90.1 (c 1.01, CHCl3).
D
4-Br om o-2(E)-bu ten e 1-ter t-Bu tyld ip h en ylsilyl Eth er .
A solution of known 4-tert-butyldiphenylsiloxy-2(E)-buten-1-
ol11 (1.01 g, 3.10 mmol) in CH2Cl2 (20 mL) was added dropwise
via cannula to a suspension of NBS (1.16 g, 6.51 mmol) and
dimethyl sulfide (0.58 mL, 7.90 mmol) with stirring in cold (0
°C) CH2Cl2 (15 mL). The mixture was allowed to warm to room
temperature and stirred for an additional 1 h. The resulting
suspension was diluted with ether and washed with brine, and
the combined organic extracts were concentrated in vacuo.
Purification by column chromatography (6:1 Hex/EtOAc) af-
forded the desired trans bromide (0.927 mg, 77%), which was
immediately carried on into the next reaction: 1H NMR (300
MHz, CDCl3) δ 1.06 (s, 9H), 3.98 (dd, J ) 7.5, 1.1 Hz, 2H),
4.20-4.24 (m, 2H), 5.84 (dt, J ) 15.0, 4.4 Hz, 1H), 6.02 (dtt, J
) 15.0, 7.5, 1.9 Hz, 1H), 7.33-7.46 (m, 6H), 7.67 (dd, J ) 7.7,
1.8 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 19.2, 26.8 (3C), 32.5,
63.2, 125.8, 127.7 (4C), 129.7 (2C), 133.4 (2C), 134.2, 135.5
(4C).
(EI) for C14H20O (M+) calcd 204.1514, found 204.1515; [R]25
-4.5 (c 1.39, CHCl3).
D
(4S)-4-Allyl-4-((3S)-bu t-1-en -3-yl)-3-m eth ylcycloh ex-2-
en on e (24). To a stirred solution of diketone 22 (23.7 mg, 0.107
mmol) in benzene (5 mL) were added successively piperidine
(two drops) and glacial acetic acid (two drops), and the reaction
mixture was heated to reflux overnight. The solution was
cooled to room temperature and then was diluted with Et2O,
and the organic layer was washed with H2O and brine, dried
over MgSO4, and then filtered; the solvent was removed under
reduced pressure. The residue was subjected to flash chroma-
tography (12:1 Hex/EtOAc) to afford 16.4 mg (75%) of the title
1
compound as a clear colorless oil. H NMR (300 MHz, CDCl3)
δ 0.93 (d, J ) 6.9 Hz, 3H), 1.70 (dt, J ) 14.1, 6.2 Hz, 1H), 1.91
(s, 3H), 1.99 (ddd, J ) 13.9, 10.6, 5.8 Hz, 1H), 2.26-2.55 (m,
5H), 4.97-5.14 (m, 4H), 5.64-5.84 (m, 2H), 5.96 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 16.3, 20.5, 27.3, 34.6, 42.8, 44.7, 44.8,
116.7, 117.9, 130.3, 134.7, 139.1, 165.2, 199.2; IR (thin film)
1668 cm-1; HRMS (EI) for C14H20O (M+) calcd 204.1514, found
Th iola cta m 11b. To a solution of LDA (2.42 mmol) in
anhydrous THF (15 mL) at -78 °C was added thiolactam 9
(548 mg, 1.74 mmol) in THF (10 mL) via cannula. After being
stirred for 40 min, the mixture was treated with 4-bromo-2(E)-
204.1512; [R]25 +53.2 (c 1.02, CHCl3).
D
(1S,5S)-1,8-Dim eth yl-6-oxaspir o[4.5]deca-2,7-dien e (25).
To a stirred solution of the diketone 23 (30.3 mg, 0.156 mmol)
in MeOH (5 mL) was added a solution of KOH in MeOH (10%,
(11) Roush, W. R.; Straub, J . A.; Van Nieuwenhze, M. S. J . Org.
Chem. 1991, 56, 1636-1648.

3590 J . Org. Chem., Vol. 64, No. 10, 1999
Lemieux et al.
butene 1-tert-butyldiphenylsilyl ether (898 mg, 2.31 mmol) as
described above. The resulting solution was warmed to room
temperature and allowed to stir until complete conversion to
N,S-ketene acetal 10b was observed by TLC analysis (1 h, 9:1
Hex/EtOAc). The reaction mixture was then heated to reflux
for 20 h. The resulting solution was cooled to room tempera-
ture, washed with H2O, and extracted with ether. Concentra-
tion of the organic extracts in vacuo provided a crude oil, which
indicated an 11:1 mixture of diastereomers by 1H NMR
analysis. Further purification by column chromatography (9:1
Hex/EtOAc) afforded 1.04 g (96%) of an inseparable mixture
of two diastereomers (11:1 thiolactam 11b/diastereomer) as a
white foam: 1H NMR of the 11:1 mixture with only the major
signals being reported (300 MHz, CDCl3) δ 1.00 (s, 3H), 1.04
(s, 9H), 1.42 (s, 3H), 1.49 (s, 3H), 1.77, (dt, J ) 13.8, 3.4 Hz,
1H), 1.88-2.14 (m, 3H), 2.36 (dd, J ) 13.2, 9.3 Hz, 1H), 3.01-
3.12 (m, 2H), 3.67 (dd, J ) 9.3, 8.4 Hz, 1H), 3.85 (dd, J ) 9.6,
4.1 Hz, 1H), 4.96 (br d, J ) 10.1 Hz, 1H), 5.08 (br d, J ) 17.0
Hz, 1H), 5.27 (dd, J ) 11.8, 2.0 Hz, 1H), 5.32 (dd, J ) 5.5, 2.0
Hz, 1H), 5.64-5.86 (m, 2H), 5.78 (s, 1H), 6.88 (d, J ) 7.5 Hz,
2H), 6.98-7.16 (m, 3H), 7.24-7.43 (m, 6H), 7.58-7.70 (m, 4H);
13C NMR selected (75 MHz, CDCl3) δ 19.3, 25.4, 26.9 (3C), 27.3,
27.7, 33.1, 35.2, 51.3, 51.9, 58.9, 64.0, 76.4, 81.6, 94.0, 117.3,
120.4, 125.9 (2C), 126.7, 127.6 (2C), 127.6 (2C), 128.2 (2C),
129.5, 129.6, 133.3, 134.0, 135.5, 135.7 (2C), 135.7 (2C), 135.9,
137.2, 204.4; IR (thin film) 1402 cm-1; HRMS (FAB+) for
was stirred at room temperature for 4 h, and the solvent was
subsequently removed under reduced pressure. Purification
by column chromatography (6:1 Hex/EtOAc) afforded the
desired spiro compound 16b as an oil (280 mg, 89%): 1H NMR
(300 MHz, CDCl3) δ 1.03 (s, 9H), 1.96 (ddd, J ) 13.3, 6.5, 6.5
Hz, 1H), 2.21 (dd, J ) 13.3, 6.6, 6.6 Hz, 1H), 2.31 (br d, J )
16.5 Hz, 1H), 2.41-2.48 (m, 2H), 2.57 (ddd, J ) 16.3, 4.3, 2.1
Hz, 1H), 2.70-2.77 (m, 1H), 3.65 (dd, J ) 10.4, 6.4 Hz, 1H),
3.70 (dd, J ) 10.6, 5.8 Hz, 1H), 5.63-5.68 (m, 1H), 5.76-5.81
(m, 1H), 5.85 (d, J ) 10.1 Hz, 1H), 6.84 (d, J ) 10.1 Hz, 1H),
7.34-7.46 (m, 6H), 7.62-7.67 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 19.1, 26.7 (3C), 28.6, 35.5, 43.3, 45.3, 56.0, 63.3, 126.4,
127.6 (4C), 129.7, 129.7, 129.9, 131.4, 133.2, 133.3, 135.5 (2C),
135.6 (2C), 159.7, 199.8; IR (thin film) 1674 cm-1; HRMS
(FAB+) for C27H33O2Si (M + H)+ calcd 417.2250, found 417.2260;
[R]25 +17.6 (c 1.06, CHCl3).
D
Alcoh ol 16c. Enone 16b (254 mg, 0.610 mmol) was dis-
solved in THF (8 mL) and treated with TBAF (1.6 mL of a 1
M solution in THF, 1.6 mmol). The reaction mixture was
allowed to stir for 2 h at room temperature, quenched by
additon of saturated NH4Cl, and extracted with ether. After
concentration in vacuo, purification of the resulting oil by
column chromatography (1.3:1.0 Hex/EtOAc) afforded the
desired alcohol 16c as a clear oil (92.5 mg, 85%): 1H NMR
(300 MHz, CDCl3) δ 2.00-2.11 (m, 2H), 2.25 (ddd, J ) 13.5,
8.7, 5.5 Hz, 1H), 2.34 (br d, J ) 16.4 Hz, 1H), 2.44-2.53 (m,
2H), 2.58 (ddd, J ) 16.5, 4.4, 2.2 Hz, 1H), 2.66-2.73 (m, 1H),
3.71 (d, J ) 5.1 Hz, 2H), 5.70-5.76 (m, 1H), 5.85 (d, J ) 10.0
Hz, 1H), 5.88-5.94 (m, 1H), 6.86 (d, J ) 10.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 28.9, 35.6, 43.8, 45.0, 55.5, 62.0,
126.3, 130.6, 131.2, 159.6, 199.9; IR (thin film) 3418 (br), 1668
cm-1; HRMS (FAB+) for C11H15O2 (M + H)+ calcd 179.1072,
C
39H49NO2SiS (M + H)+ calcd 624.3332, found 624.3310.
Cycloh exen on e 15b. To a stirred solution of thiolactam
11b (957 mg, 1.54 mmol), as an 11:1 mixture of diastereomers
in anhydrous CH2Cl2 (20 mL), was added a solution of Et3-
OBF4 (2 M in CH2Cl2, 1.92 mL, 3.84 mmol). The reaction
mixture was heated to reflux for 2 h and then was cooled to
-78 °C. A solution of Red-Al (3.12 M in toluene, 0.65 mL, 2.03
mmol) was added via syringe, and the mixture was stirred for
40 min. The latter was quenched with MeOH (0.5 mL), stirred
for an additional 10 min at -78 °C, and then warmed to room
temperature. The solution was diluted with EtOAc, and the
organic layer was washed with H2O. Concentration of the
organic extracts in vacuo provided a crude oil that was
dissolved in EtOH-H2O (1:1, 38 mL total) followed by the
addition of KH2PO4 buffer (1 M in H2O, 38 mL). The resulting
suspension was heated to reflux for 20 h and cooled to room
temperature, and the EtOH was removed under reduced
pressure. The residue was diluted with H2O and extracted with
ether. The combined organic layers were concentrated in
vacuo, and the resulting crude oil was shown by 1H NMR
analysis to be composed of a 2.8:1.0 mixture of aldehyde 14b/
enone 15b. This mixture was immediately dissolved in MeOH
(5 mL) and treated with 0.1 M KOH in MeOH (5 mL). The
mixture was heated to reflux for 2 h, cooled to room temper-
ature, and quenched with saturated NH4Cl. Extraction with
ether, concentration in vacuo, and purification by column
chromatography (6:1 Hex/EtOAc) afforded cyclohexenone 15b
(439 mg, 64%), which was a 4:1 mixture with tert-butyldiphen-
ylsilyl alcohol. These compounds were not readily separated
by column chromatography: 1H NMR (300 MHz, CDCl3) δ 1.03
(s, 9H), 1.78 (dddd, J ) 13.8, 5.7, 5.7, 1.2 Hz, 1H), 2.02 (ddd,
J ) 13.8, 10.8, 5.5 Hz, 1H), 2.25-2.32 (m, 2H), 2.33-2.45 (m,
3H), 3.71 (d, J ) 5.7 Hz, 2H), 4.98-5.10 (m, 2H), 5.15 (dd, J
) 17.0, 2.0 Hz, 1H), 5.24 (dd, J ) 10.3, 2.0 Hz, 1H), 5.60-5.82
(m, 2H), 5.89 (d, J ) 10.2 Hz, 1H), 6.61 (dd, J ) 10.4, 1.2 Hz,
1H), 7.35-7.45 (m, 6H), 7.61-7.66 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 19.2, 26.8 (3C), 28.6, 33.9, 40.4, 40.8, 52.8, 64.2, 118.8,
119.3, 127.7 (4C), 128.4, 129.7, 129.7, 129.7, 133.2, 133.3,
133.3, 135.6 (2C), 135.7 (2C), 157.5, 199.3; IR (thin film) 1682
cm-1; HRMS (FAB+) for C29H37O2Si (M + H)+ calcd 445.2563,
found 445.2566.
found 179.1075; [R]25 +46.3 (c 2.21, CHCl3).
D
4-Br om o-2(Z)-bu ten -1-ter t-bu tyld ip h en ylsilyl Eth er . A
solution of known 4-tert-butyldiphenylsiloxy-2(Z)-buten-1-ol11
(3.18 g, 9.74 mmol) in CH2Cl2 (20 mL) was added dropwise
via cannula to a suspension of NBS (3.64 g, 20.5 mmol) and
dimethyl sulfide (1.86 mL, 25.3 mmol) with stirring in cold
CH2Cl2 (0 °C, 40 mL). The mixture was allowed to warm to
room temperature and stirred for an additional 1 h. The
resulting suspension was diluted with ether and washed with
brine, and the combined organic extracts were concentrated
in vacuo. Purification by column chromatography (6:1 Hex/
EtOAc) afforded the desired cis bromide (3.26 g, 86%), which
was immediately carried on into the next reaction: 1H NMR
(300 MHz, CDCl3) δ 1.05 (s, 9H), 3.85 (dd, J ) 5.5, 2.0 Hz,
2H), 4.32 (d, J ) 4.2 Hz, 2H), 5.70-5.76 (m, 2H), 7.36-7.45
(m, 6H), 7.68 (dd, J ) 7.7, 1.8 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 19.1, 26.8 (3C), 26.8, 59.7, 126.2, 127.7 (4C), 129.7
(2C), 133.3, 133.7 (2C), 135.5 (4C).
Th iola cta m 17. To a solution of LDA (1.90 mmol) in
anhydrous THF (10 mL) at -78 °C was added thiolactam 9
(407 mg, 1.29 mmol) in THF (5 mL) via cannula. After being
stirred for 40 min, the reaction mixture was treated with
4-bromo-2(Z)-butene 1-tert-butyldiphenylsilyl ether (739 mg,
1.90 mmol) as described above. The resulting solution was
warmed to room temperature and allowed to stir until com-
plete conversion to the thioether intermediate was observed
by TLC analysis (9:1 Hex/EtOAc). The solution was subse-
quently diluted with ether, washed with saturated NH4Cl, and
dried over MgSO4, and the solvent was removed under reduced
pressure. The residual yellow oil was dissolved in dry DMF
(10 mL), anhydrous K2CO3 (270 mg, 1.95 mmol) was added,
and the resulting suspension was heated to 100 °C for 20 h.
The reaction mixture was then cooled to room temperature,
diluted with ether, and washed with H2O. The organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo.
1H NMR analysis of the resulting crude oil indicated a 5:1
mixture of diastereomers. Further purification by column
chromatography (9:1 Hex/EtOAc) afforded 669 mg (83%) of an
inseparable mixture of two diastereomers (5:1 thiolactam 17/
diastereomer) as a white foam: 1H NMR of the 5:1 mixture
with only the major signals reported (300 MHz, CDCl3) δ 1.05
(s, 9H), 1.06 (s, 3H), 1.52 (s, 3H), 1.57 (s, 3H), 1.78-2.20 (m,
4H), 2.39 (dd, J ) 13.1, 9.4 Hz, 1H), 3.05-3.18 (m, 2H), 3.84
ter t-Bu tyld ip h en ylsilyl a lcoh ol: 1H NMR (300 MHz,
CDCl3) δ 1.06 (s, 9H), 2.26 (br s, 1H), 7.32-7.41 (m, 6H), 7.68-
7.72 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 19.0, 26.5 (3C), 127.7
(2C), 129.6, 134.8 (2C), 135.2; IR (thin film) 3422 (br) cm-1
.
Cyclop en ten e 16b. To a solution of enone 15b (335 mg,
0.755 mmol) in degassed 1,2-dichloroethane (10.8 mL, de-
gassed by bubbling through Ar(g) for 30 min) was added
Grubbs’ catalyst (62.7 mg, 0.076 mmol). The reaction mixture

Chiral Cyclohexenones with Spiro-Connected Cyclopentenes
J . Org. Chem., Vol. 64, No. 10, 1999 3591
(dd, J ) 10.5, 6.7 Hz, 1H), 3.92 (dd, J ) 10.5, 4.6 Hz, 1H),
4.93-5.37 (m, 4H), 5.66-5.84 (m, 1H), 5.88 (s, 1H), 5.86-6.04
(m, 1H), 7.06-7.12 (m, 2H), 7.23-7.46 (m, 9H), 7.65-7.74 (m,
4H); 13C NMR (75 MHz, CDCl3) δ 19.2, 25.9, 26.8(3C), 27.4,
27.7, 33.2, 35.1, 49.6, 53.1, 57.1, 63.1, 76.0, 81.4, 93.9, 117.2,
119.6, 126.5, 127.0, 127.7(2C), 128.0, 129.7, 133.4, 133.5, 135.7,
135.7, 135.8, 135.9, 136.2, 137.2, 204.0; IR (thin film) 1407
cm-1; HRMS (FAB+) for C39H49NO2SiS (M + H)+ calcd 624.3332,
found 624.3319.
HRMS (FAB+) for C29H37O2Si (M + H)+ calcd 445.2563, found
445.2565.
Sp ir ocyclop en ten e 19. To a solution of enone 18 (331 mg,
0.745 mmol) in degassed 1,2-dichloroethane (10.6 mL) was
added Grubbs’ catalyst (61.6 mg, 0.075 mmol). The reaction
mixture was stirred at room temperature for 3 h, and the
solvent was subsequently removed under reduced pressure.
Purification by column chromatography (6:1 Hex/EtOAc) af-
forded the desired spiro compound 19 (232 mg, 75%) as a 10:1
1
Cycloh exen on e 18. To a stirred solution of the thiolactam
5:1 mixture 17 (1.48 g, 2.37 mmol), in anhydrous CH2Cl2 (20
mL), was added a solution of Et3OBF4 (2 M in CH2Cl2, 3.00
mL, 6.00 mmol). The reaction mixture was heated to reflux
for 2 h and then cooled to -78 °C. A solution of Red-Al (3.12
M in toluene, 0.96 mL, 3.00 mmol) was subsequently added
via syringe, and the reaction mixture was allowed to stir for
40 min. The resulting solution was quenched with MeOH (0.5
mL), stirred for an additional 10 min at -78 °C, and then
warmed to room temperature. The solution was then diluted
with EtOAc, and the organic layer was washed with H2O.
Concentration of the organic extracts in vacuo provided a crude
oil that was redissolved in EtOH-H2O (1:1, 60 mL total)
followed by the addition of KH2PO4 buffer (1 M in H2O, 60
mL). The resulting suspension was heated to reflux for 20 h
and cooled to room temperature with the EtOH being removed
under reduced pressure. The residue was diluted with H2O
and extracted with ether. The combined organic extracts were
concentrated in vacuo, and the crude oil obtained was shown
by 1H NMR analysis to be composed of a 1.4:1.0 mixture of
intermediate ketoaldehyde/enone 18. The crude oil was dis-
solved in MeOH (5 mL) and treated with 0.1 M KOH in MeOH
(5 mL). The resulting suspension was heated to reflux for 2 h,
cooled to room temperature, and quenched with saturated NH4-
Cl. Extraction with ether, concentration in vacuo, and purifica-
tion by column chromatography (6:1 Hex/EtOAc) afforded
cyclohexenone 18 (599 mg, 57%) as a 10:1 mixture of diaster-
mixture of diastereomers by H NMR analysis. This accounts
for an 81% yield of the diastereomeric mixture due to con-
tamination of the starting enone with tert-butyldiphenylsilyl
alcohol (7:1 enone 18/silyl alcohol): 1H NMR of the 10:1
mixture with only the major signals being reported (300 MHz,
CDCl3) δ 1.03 (s, 9H), 1.95 (ddd, J ) 13.2, 6.8, 6.8 Hz, 1H),
2.09 (ddd, J ) 13.2, 6.8, 6.8 Hz, 1H), 2.35-2.45 (m, 3H), 2.58
(ddd, J ) 16.5, 4.8, 2.4 Hz, 1H), 2.75-2.83 (m, 1H), 3.65 (d, J
) 5.7 Hz, 2H), 5.63-5.68 (m, 1H), 5.76-5.81 (m, 1H), 5.92 (d,
J ) 10.2 Hz, 1H), 7.03 (d, J ) 10.2 Hz, 1H), 7.33-7.44 (m,
6H), 7.60-7.67 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 19.1,
26.7(3C), 34.9, 35.8, 45.1, 46.0, 57.3, 63.9, 127.6(2C), 127.6,
128.2, 129.7, 129.7, 129.8, 131.0, 133.1, 133.3, 135.5(2C), 135.6-
(2C), 156.4, 199.7; IR (thin film) 1681 cm-1; HRMS (FAB+) for
C
27H33O2Si (M + H)+ calcd 417.2250, found 417.2252.
Cycloh exa n on e 20. The spirocyclopentene tert-butyldi-
phenylsilyl ether 19 (205 mg, 0.492 mmol) was dissolved in
THF (10 mL) and treated with TBAF (1.25 mL of a 1 M
solution in THF, 1.25 mmol). The mixture was allowed to stir
for 4 h at room temperature, quenched by addition of saturated
NH4Cl, and extracted with ether. After concentration of the
organic extracts in vacuo, purification of the resulting oil by
column chromatography (3:1 Hex/EtOAc) afforded the cyclized
product 20 as a single diastereomer by 1H NMR analysis (62.2
mg, 71%): 1H NMR (300 MHz, CDCl3) δ 1.87-2.07 (m, 2H),
2.24-2.52 (m, 4H), 2.61 (dd, J ) 16.5, 3.8 Hz, 1H), 2.70 (dd, J
) 16.6, 3.5 Hz, 1H), 3.12-3.21 (m, 1H), 3.42 (dd, J ) 8.8, 6.4
Hz, 1H), 3.85 (dd, J ) 3.6, 3.6 Hz, 1H), 4.19 (dd, J ) 8.4, 8.4
Hz, 1H), 5.62-5.70 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 32.1,
36.5, 41.8, 43.6, 51.7, 59.1, 72.5, 83.7, 129.1, 131.8, 210.4; IR
(thin film) 1715 cm-1; HRMS (FAB+) for C11H14O2 (M + H)+
1
eomers as observed by H NMR analysis. Enone 18 was also
not readily separated from tert-butyldiphenylsilyl alcohol (7:1
enone 18/silyl alcohol), which is a minor byproduct of the
hydrolysis reaction: 1H NMR of the 10:1 mixture with only
the major signals being reported (300 MHz, CDCl3) δ 1.04 (s,
9H), 1.84 (ddd, J ) 13.8, 6.8, 6.8 Hz, 1H), 1.96 (ddd, J ) 13.8,
6.8, 6.8 Hz, 1H), 2.18-2.51 (m, 5H), 3.70 (dd, J ) 10.5, 6.6
Hz, 1H), 3.80 (dd, J ) 10.5, 5.2 Hz, 1H), 5.02 (dd, J ) 16.8,
1.6 Hz, 1H), 5.07 (dd, J ) 10.2, 2.0 Hz, 1H), 5.12 (dd, J ) 17.0,
1.5 Hz, 1H), 5.20 (dd, J ) 10.4, 1.9 Hz, 1H), 5.86 (d, J ) 10.4
Hz, 1H), 5.60-5.91 (m, 2H), 6.79 (d, J ) 10.4 Hz, 1H), 7.34-
7.44 (m, 6H), 7.64 (dd, J ) 7.8, 1.8 Hz, 4H); 13C NMR (75 MHz,
CDCl3) δ 19.2, 26.8 (3C), 29.5, 33.6, 40.1, 40.3, 52.5, 63.6, 118.7,
118.7, 127.7 (4C), 127.9, 129.7, 129.8, 133.2, 133.6 (2C), 135.6
calcd 179.1072, found 179.1073; [R]25 +57.9 (c 1.39, CHCl3).
D
Ack n ow led gm en t. The authors are grateful to the
National Institutes of Health for generous financial
support of this program.
Su p p or tin g In for m a tion Ava ila ble: Spectral data (1H
and 13C) of all key intermediates. This material is available
free of charge via the Internet at http://pubs.acs.org.
(2C), 135.6 (2C), 136.0, 157.4, 199.2; IR (thin film) 1679 cm-1
;
J O982426Q