Stereocontrolled formation of spiro enones by radical cyclization of bromo acetals

Article abstract of DOI:10.1016/S0040-4020(01)00226-5

Aldol condensation of ketones with 2-[[(1,1-(dimethylethyl)diphenylsilyl]oxy]propanal (7), dehydration, NaBH₄ reduction and treatment of the resulting alcohols with ethyl vinyl ether in the presence of NBS gives bromo acetals (e.g. 11) that undergo 5-exo-trigonal radical cyclization, affording compounds that are easily converted into spiro enones (e.g. 16). The stereochemistry at the spiro center is controlled by the stereochemistry at the hydroxyl-bearing carbon of the intermediate alcohol.

Full text of DOI:10.1016/S0040-4020(01)00226-5

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 3845±3858
Stereocontrolled formation of spiro enones by radical cyclization
of bromo acetals
Derrick L. J. Clivep and Xiaojun Huang
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Dedicated to the memory of Professor R. U. Lemieux,FRS
Received 8 January 2001; accepted 23 February 2001
AbstractÐAldol condensation of ketones with 2-[[01,1-0dimethylethyl)diphenylsilyl]oxy]propanal 07),dehydration,NaBH 4 reduction and
treatment of the resulting alcohols with ethyl vinyl ether in the presence of NBS gives bromo acetals 0e.g. 11) that undergo 5-exo-trigonal
radical cyclization,affording compounds that are easily converted into spiro enones 0e.g. 16). The stereochemistry at the spiro center is
controlled by the stereochemistry at the hydroxyl-bearing carbon of the intermediate alcohol. q 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction and discussion
Radical cyclizations of halo acetals onto fully substituted
sp2 centers are known,as illustrated by the examples of Eqs.
01),3 02)4 and 03),5 but the process6 does not appear to have
been exploited speci®cally as a general and stereo-
chemically controllable method for the preparation of
spiro compounds. In developing the cyclization for this
purpose,we felt that closure onto an exocyclic double
bond,rather than one that is endocyclic,would be more
convenient,because in the former case the requisite alkenes
should be available easily by aldol condensation and
dehydration.7 On this basis,our initial approach 0Scheme
2) called for conversion of cyclohexanone into the conju-
gated ketone 5,which was prepared 0though,without full
characterization) by aldol condensation with aldehyde 3,8
followed by mesylation and treatment with DBU.
We describe a method for making spiro enones of type 1,in
such a way that the stereochemistry at the spiro center is
controlled by the stereochemistry of an adjacent hydroxyl
group.1,2
AcO
O
R
1
Our approach is based on the cyclization of Stork bromo
acetals,as summarized in Scheme 1,where R is a group that
is convertible into a methyl ketone unit [MeC0O)].
OEt
Br
O
O
HO
O
O
R
R
R
OEt
O
OEt
HO
HO
O
•
R
R
O
O
Scheme 1.
Keywords: spiro compounds; radical cyclization; enones.
Corresponding author. Tel.: 11-780-492-3251; fax: 11-780-492-8231; e-mail: derrick.clive@ualberta.ca
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00226-5

3846
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
O
O
NaBH4,
CeCl3.7H2O,
86%
O
O
O
OH
O
O
3
O
O
i MsCl, Et3N,
CH2Cl2, 85%
O
OH
O
O
ii DBU, THF,
74%
LDA, THF
2
4
5
6
Scheme 2.
OEt
O
We therefore modi®ed the process to that summarized in
Scheme 3,and found that this revised approach could be
implemented quite easily.
OEt
Br
O
ꢀ1†
CO2Et
CO2Et
Aldol condensation of cyclohexanone with the readily avail-
able aldehyde 79 gave the expected aldols 810 and these were
easily dehydrated by mesylation,followed by treatment
with DBU. Enone 9 was obtained with the E geometry,as
shown. Reduction with NaBH4±CeCl3´7H2O afforded the
expected alcohols 10. The yield of the major alcohol was
65%,while that of the minor isomer was 16%; only the
major alcohol was taken further. Treatment with ethyl
vinyl ether in the presence of NBS served to generate the
required bromo acetals 11 066%) and these were best
cyclized 011!12) by rapid heating 01158C) with a mixture
of Bu3SnH 0ca. 2 equiv.) and AIBN in PhMe,rather than by
slow addition of the stannane. Under these optimized condi-
tions,11 the desired cyclization products 12 were isolated in
high yield 092%),with the ring fusion stereochemistry being
necessarily12 as shown. The phenylseleno acetal corre-
sponding to 11 0PhSe instead of Br),which was available
in comparable yield to the bromo acetal 0ethyl vinyl ether,
PhSeBr,70%) underwent radical cyclization in much poorer
yield,and so only bromo acetals were used in subsequent
work. Desilylation of 12 0Bu4NF) and PCC oxidation
converted the angular substituent into a methyl ketone,
OEt
EtO
EtO
O
Br
O
O
•
H
ꢀ2†
OEt
EtO
Br
O
O
O
O
H
ꢀ3†
H
H
H
H
H
In the event,the derived alcohol 6 was very sensitive and it
was not possible to attach the bromo acetal unit ef®ciently;
the same was true in the corresponding diethyl ketal series.
OSiPh2Bu-t
O
O
8a
O
OH
O
H
LDA,
THF
MsCl, Et3N, 81%;
DBU, THF, 76%
7
O
OSiPh2Bu-t
OSiPh2Bu-t
92%
2
9
NaBH4,
CeCl3.7H2O; 81%
OEt
OEt
2
Br
2
OH
H
O
OSiPh2Bu-t
Bu3SnH,
AIBN, 92%
ethyl vinyl ether,
NBS, 66%
OSiPh2Bu-t
OSiPh2Bu-t
12d
TBAF,
92%
OEt
11c
10a,bb
OEt
2
2
O
O
O
AcO
TsOH, Ac2O,
PhH, heat,
69%
PCC, CH2Cl2
4Å sieves,
82%
O
OH
O
3M HCl,
THF, 74%f
O
13d
14a,be
15
16
Scheme 3. a One main isomer 0ca. 80% of total). b Major isomer 010a) isolated in 65% yield,minor isomer 0 10b) isolated in 16% yield. Only major isomer was
taken further. c Mixture 0ca. 1:1) of two isomers differing in stereochemistry at C02). Relative stereochemistry of ring and side chain stereogenic centers not
e
assigned. d Two inseparable isomers 0ca. 4:3) differing in stereochemistry at C02). Major isomer 014a) isolated in 41% yield,minor isomer 0 14b) in 31%
yield. Compounds 14a and b differ in stereochemistry at C02). f Mixture of 14a and b used.

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
OSiPh2Bu-t
3847
O
O
OH
O
H
MsCl, Et3N, 94%, 54%;c
DBU, THF, 89%, 66%c
LDA,
THF
7
O
OSiPh2Bu-t
OSiPh2Bu-t
57%a, 20%b
17
18a,b
19
NaBH4,
CeCl3.7H2O; 98%
OEt
OEt
2
Br
2
O
OH
H
O
OSiPh2Bu-t
Bu3SnH,
ethyl vinyl ether,
NBS, 65%
AIBN, 90%
OSiPh2Bu-t
OSiPh2Bu-t
Only major isomer
processed further.
22e
21e
20a,bd
TBAF,
83%
OEt
2
OEt
2
PCC, CH2Cl2
TsOH, Ac2O,
PhH, heat,
74%
O
O
O
AcO
4Å sieves,
74%,g 71%h
3M HCl,
THF, 74%i
OH
O
O
O
23a,bf
24, 24'
25
26
Scheme 4. a Yield of major aldol 018a),which contains trace impurities. b Yield of minor aldol 018b),which contains trace impurities. c First yield in each case
corresponds to major aldol series. d Major isomer 020a) isolated in 55% yield,minor isomer 0 20b) isolated in 43% yield. Only major isomer was taken further.
e Mixture 01:1) of two inseparable isomers differing in stereochemistry at C02). f Major isomer 023a) isolated in 44% yield,minor isomer 0 23b) in 39% yield.
The isomers differ in stereochemistry at C02). g Yield of 24 from 23a 0major isomer of 23). h Yield of 240 from 23b 0minor isomer of 23). Compounds 24 and
240 differ in stereochemistry at C02). i Mixture of 24 and 240 used.
and then exposure to mineral acid caused hydrolysis of the
lactol ethyl ethers to the corresponding lactols,and induced,
formally,aldol condensation,dehydration and intramolecu-
lar Michael addition,leading to 15. Finally,the enone
system was liberated13 015!16) by heating in PhH with
Ac2O and a catalytic amount of TsOH´H2O.
complex stereoisomer mixtures have to be handled,
the silyl ether series based on 7 has the important
advantage that it does not involve any especially sensitive
intermediates.
We then repeated the sequence,starting from cyclo-
pentanone; the results were entirely comparable,and are
summarized in Scheme 4.
Although use of 7,as opposed to 3,means that more
OSiPh2Bu-t
Me2CuLi;
ZnCl2,
THF
O
27
O
O
OH
O
H
MsCl, Et3N, 81%;
DBU, THF, 62%b
7
O
OSiPh2Bu-t
OSiPh2Bu-t
80%
28a,ba
29a,b
NaBH4,
CeCl3.7H2O; 96%
OEt
OEt
OSiPh2Bu-t
Br
O
OH
H
Bu3SnH,
AIBN, 73%
ethyl vinyl ether,
NBS, 64%
1
3
OSiPh2Bu-t
OSiPh2Bu-t
32e
31d
30c
TBAF,
86%
OEt
OEt
PCC, CH2Cl2
4Å sieves,
81%, 87%g
2
O
O
O
AcO
TsOH, Ac2O,
PhH, heat,
62%
O
OH
O
3M HCl,
THF, 77%h
O
33a,bf
34, 34'
35
36
Scheme 5. a Major isomer 028a) isolated in 72% yield,minor isomer 0 28b) isolated in 8% yield. b Mixture of isomers of 28 used. Yield of major fraction 029a,
two isomers 0ca. 8:1),both with E geometry) 53%,yield of minor fraction 0 29b,two isomers 0ca. 5:1),both with Z geometry) 9%. Only major fraction 029a)
taken forward. c Two inseparable isomers 0ca. 8:1). d Four isomers 0ca. 8:8:1:1). e Four isomers. f Yield of major fraction 033a) 44%,yield of minor fraction
033b) 42%,each fraction consisting of two isomers 0both ca. 6:1). g Yield from 33a 0major fraction of 33) was 81%; yield from 33b 0minor fraction of 33) was
87%. Both 34 and 340 were single isomers differing in stereochemistry at C02). h A 1:1 mixture of 34 and 340 was used.

3848
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
p-O2NC6H4CO2H,
OEt
OEt
OSiPh2Bu-t
Ph3P, DEAD;
KOH, MeOH,
48%, 12%b
Br
ethyl vinyl
ether, NBS,
63%
Bu3SnH,
AIBN,
73%
2
OH
H
OH
37a,b
O
O
O
OSiPh2Bu-t
OSiPh2Bu-t
OSiPh2Bu-t
38c
30a
39a,bd
TBAF, 80%, 76%e
OEt
2
OEt
PCC, CH2Cl2
2
TsOH, Ac2O,
PhH, heat,
O
AcO
O
O
OH
O
4A sieves,
81%, 78%f
3M HCl,
THF, 85%g
34% (or 49%
O
based on
conversion)
40, 40'
41, 41'
42
43
Scheme 6. a An 8:1 mixture of isomers. b Yield of major isomer 037a) 48% overall. Yield of minor isomer 037b) 12%. Only major isomer was taken further.
c
Two isomers 0ca. 1:1) differing in stereochemistry at C02). d Yield of major isomer 039a) 49%,yield of minor isomer 0 39b) 24%. e Yield of 40 from 39a
0major isomer of 39) 80%,yield of 400 from 39b 0minor isomer of 39) 76%. Isomers 40 and 400 differ in stereochemistry at C02). f Yield of 41 from 40 0major
isomer series) 81%,yield of 410 from 400 0minor isomer series) 78%. g Ketones 41 and 410 were mixed 0ca. 2:1) before treatment with HCl.
The experiments leading to 16 and 26 suggest that the
method is general,and so we next established that the
stereochemistry of the spiro center could indeed be reversed
by appropriate manipulation of the stereochemistry of the
adjacent oxygen function. To this end,the route of Scheme
3 was modi®ed so as to incorporate a methyl group as a
stereochemical marker in the 6-membered ring 0see Scheme
5). A conjugate addition-aldol condensation served to
convert 2-cyclohexenone into 28a,b 0Scheme 5),and from
that point,our standard sequence of reactions was applied,
as shown. The presence of the methyl group increased the
number of isomers in the intermediate stages,but this
complication disappears,of course,near the end of the
sequence. Both isomers of aldol 28 and the major fraction
of enone 29 053% yield,consisting of two isomers,each
with E geometry) were used for the subsequent steps. The
E geometry for 29a was established by the characteristic
chemical shift of the vinylic hydrogen 0d 6.4). Both isomers
of the minor fraction of 29 had Z geometry 0d 5.6).
Compound 30 was obtained as an 8:1 mixture of E isomers,
and the relative stereochemistry at C01) and C03) of each
component was inferred by observation of an NOE 0ca. 5%)
between C01)H and the C03)CH3 hydrogens. For compari-
son,alcohol 37a 0see later) was also examined,and in this
case,no NOE enhancement between the corresponding
hydrogens was observed. The trans relationship of the
hydroxyl and methyl groups in 30 is that expected for the
usual axial hydride delivery in NaBH4 reduction of ketones
29a. The bromo acetals 31 were obtained as a mixture
of four isomers 0ca. 8:8:1:1). The corresponding product
of radical cyclization 032) was also obtained as a mixture
of four isomers. In this case,however,the isomer ratio
35. This was converted under the standard conditions into
spiro enone 36.
We have also shown that 30 can serve as a common inter-
mediate for generating both stereochemistries at the spiro
carbon. To do this,alcohols 30 0as an 8:1 isomer mixture)
were subjected to Mitsunobu inversion 0Scheme 6,
30!37a,b),and the major alcohol 0 37a) was converted
into bromo acetals 38. These were subjected to radical cycli-
zation and the individual products 039a,49% and 39b,24%)
were separately desilylated. Oxidation of the resulting
alcohols 040!41 and 400!410) gave the expected ketones.
Samples of these were mixed and converted into the poly-
cyclic ketone 42 by the action of hydrochloric acid. Finally,
treatment with Ac2O in the presence of TsOH´H2O yielded
spiro enone 43,isomeric with that 0 36) obtained from
alcohols 30.
2. Conclusion
The above experiments show that the present methodology
can be used to make spiro enones in a manner that allows
control of the stereochemistry of the spiro center so that
either stereochemistry can be generated.
3. Experimental
3.1. General
The same general procedures as used previously14 were
followed. The symbols s,d,t and q used for 13C NMR
signals indicate zero,one,two and three attached hydro-
gens,respectively. In cases where the number of signals is
less than expected,we assume this is due to coincident
chemical shifts.
1
could not be determined from the H NMR spectrum,but
the presence of two major and two minor isomers was
clear from the 13C NMR spectrum. Desilylation 0Bu4NF)
afforded alcohols 33 as a separable mixture of two
fractions in yields of 44 and 42%,each consisting of two
isomers,and in both cases,the isomer ratio was ca. 6:1.
After oxidation,each fraction gave a single isomer of
general structure 34/340 in good yield 0.80%),and both
the ketones 34 and 340,which differ only in the stereo-
chemistry at C02),then afforded the same tricyclic product
3.1.1.
2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-
hydroxypropyl]cyclohexanone (8). A solution of cyclo-
hexanone 00.90 mL,8.67 mmol) in THF 015 mL) was
added dropwise to a stirred and cooled 02788C) solution

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3849
of LDA [generated by dropwise addition of BuLi 02.5 M,in
and CeCl3´7H2O 065 mg,0.17 mmol) in MeOH 01.5 mL)
and THF 00.4 mL). After 1 h,the mixture was quenched
with saturated aqueous NH4Cl 00.3 mL),diluted with Et O
2
hexane,3.9 mL,9.7 mmol) to i-Pr2NH 01.4 mL,10.0 mmol)
in THF 060 mL) at 08C,followed,after 15 min,by cooling
to 2788C]. After 1 h,aldehyde 79 01.384 g,4.428 mmol) in
THF 020 mL) was added quickly. Stirring was continued for
50 min at 2788C,and the reaction was quenched with satu-
rated aqueous NH4Cl 09 mL). The cooling bath was
removed and stirring was continued until the mixture had
reached room temperature. The mixture was diluted with
Et2O 0150 mL),washed with water and brine,dried
0MgSO4),and evaporated. Flash chromatography of the
residue over silica gel 02£20 cm),using 1:6 EtOAc±hexane,
gave alcohols 8 as a mixture of four isomers 0one isomer
being the major component,ca. 80% of the total) 0 13C NMR)
020 mL),and ®ltered through a pad 02 £2 cm) of silica gel,
using Et2O 020 mL) as a rinse. The organic ®ltrate was
washed with brine,dried 0MgSO ),and evaporated. Flash
4
chromatography of the residue over silica gel 01£20 cm),
using 1:10 EtOAc±hexane,gave alcohols 10 as two separ-
able isomers, 10a 0less polar) 029.2 mg,65%) and 10b
0more polar) 07.3 mg,16%).
Isomer 10a: FTIR 0CH2Cl2,cast) 3387,2931,2892,2857,
;
1589 cm21 1H NMR 0CDCl3,300 MHz) d 0.96 0d,
Jˆ4.3 Hz,1H),1.05 0s,9H),1.10±1.50 0m,7H,including
01.669 g,92%): FTIR 0CH Cl2,cast) 3520,2932,2857,
2
a doublet at d 1.20, Jˆ6.2 Hz),1.55±1.78 0m,3H),1.80±
1696 cm21; exact mass 0HR electrospray) m/z calcd for
C25H34NaO3Si 433.217493,found 433.216764.
2.05 0m,1H),3.81±3.91 0m,1H),4.65 0dq,
Jˆ8.3,6.2 Hz,
1H),5.37 0dd, Jˆ8.3,1.0 Hz,1H),7.30±7.50 0m,6H),
7.65±7.75 0m,4H); 13C NMR 0CDCl3,75.5 MHz) d 19.2
0s),22.6 0t),25.0 0q),26.0 0t),26.7 0t),27.0 0q),35.6 0t),66.1
0d),73.1 0d),126.5 0d),127.4 0d),127.6 0d),129.46 0d),
129.54 0d),134.6 0s),134.9 0s),135.9 0d),136.1 0d),139.5
0s); exact mass 0HR electrospray) m/z calcd for
C25H34NaO2Si 417.222579,found 417.222943.
3.1.2. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]cyclohexanone (9). )a) Methanesulfonic acid
2-[[)1,1-dimethylethyl)diphenylsilyl]oxy]-1-)2-oxocyclo-
hexyl)propyl ester. MeSO2Cl 00.96 mL,12.4 mmol) was
added dropwise to a stirred and cooled 008C) solution of
alcohols 8 01.6334 g,3.9778 mmol) and Et 3N 02.8 mL,
20 mmol) in CH2Cl2 064 mL). The cooling bath was left in
place,but was not recharged. Stirring was continued for 6 h,
the solution was quenched with saturated aqueous NaHCO3
Isomer 10b: FTIR 0CH2Cl2,cast) 3358,2931,2892,2857,
1
1589 cm21; H NMR 0CDCl3,200 MHz) d 1.07 0s,9H),
1.11±1.61 0m,including a doublet at d 1.21, Jˆ6.2 Hz,
015 mL),diluted with Et O 0200 mL),washed with water
2
and brine,dried 0MgSO 4),and ®ltered through a pad
9H in all),1.61±1.88 0m,2H),1.95±2.15 0m,1H),3.84±
3.95 0m,1H),4.65 0dq,
Jˆ8.3,6.2 Hz,1H),5.44 0d,
04£3 cm) of silica gel,using Et O 0100 mL) as a rinse.
Jˆ8.3 Hz,1H),7.27±7.50 0m,6H),7.60±7.78 0m,4H);
13C NMR 0CDCl3,50.3 MHz) d 19.2 0s),22.8 0t),25.0
0q),26.3 0t),26.9 0t),27.0 0q),35.7 0t),65.9 0d),73.2 0d),
126.1 0d),127.3 0d),127.5 0d),129.4 0d),129.5 0d),134.6
0s),134.7 0s),135.8 0d),135.9 0d),139.9 0s); exact mass 0HR
electrospray) m/z calcd for C25H34NaO2Si 417.222579,
found 417.222279.
2
Evaporation of the ®ltrate gave the crude mesylates
01.5785 g,81%),which were used immediately for next
step.
)b) )E)-2-[2-[[)1,1-Dimethylethyl)diphenylsilyl]oxy]propyl-
idene]cyclohexanone )9). DBU 01.0 mL,6.7 mmol) was
added dropwise to a stirred solution of the above mesylates
01.5785 g,3.2298 mmol) in THF 026 mL). After 1 h,the
mixture was diluted with Et2O 0200 mL) and washed with
water,5% hydrochloric acid,and brine,dried 0MgSO 4),and
evaporated. Flash chromatography of the residue over silica
3.1.4. (E)-[[1-[2-(2-Bromo-1-ethoxyethoxy)cyclohexyl-
idene]-2-propyl]oxy](1,1-dimethylethyl)diphenylsilane
(11). NBS 00.7472 g,4.198 mmol),dry CH 2Cl2 018.5 mL)
and ethyl vinyl ether 01.35 mL,14.1 mmol) were mixed
under Ar in a 50-mL round-bottomed ¯ask until a homo-
geneous solution was obtained. This solution was added
dropwise by syringe to a stirred and cooled 008C) solution
of alcohol 10a 0i.e. major isomer) 00.5523 g,1.3995 mmol)
in CH2Cl2 07.5 mL),the reaction mixture being protected
from light by aluminum foil. The cold bath was left in place,
and stirring was continued for 25 h. The mixture was then
diluted with CH2Cl2 0100 mL),washed with 10% aqueous
Na2S2O3,water and brine,dried 0MgSO 4),and evaporated.
Flash chromatography of the residue over silica gel
02£20 cm),using 1:25 EtOAc±hexane,gave bromo acetals
gel 02.5£25 cm),using 1:10 EtOAc±hexane,gave enone
9
00.9631 g,76%): FTIR 0CH Cl2,cast) 2931,2889,2857,
2
1691,1624 cm 21; H NMR 0CDCl3,400 MHz) d 1.07 0s,
9H),1.22 0d, Jˆ6.3 Hz,3H),1.26±1.40 0m,1H),1.50±1.62
0m,1H),1.62±1.82 0m,2H),2.00 0ddd, Jˆ7.0,6.0,2.0 Hz,
1
2H),2.26 0ddd, Jˆ17.6,9.0,5.6 Hz,1H),2.40 0dt,
Jˆ17,
Jˆ8,
13C
5 Hz,1H),4.52 0dq,
1.2 Hz,1H),7.3±7.5 0m,6H),7.62±7.74 0m,4H);
Jˆ8,6.3 Hz,1H),6.54 0dt,
NMR 0CDCl3,100.6 MHz) d 19.2 0s),23.0 0q),23.3 0t),
23.4 0t),26.7 0t),26.9 0q),66.0 0d),127.5 0d),127.6 0d),
129.6 0d),129.7 0d),133.8 0s),133.9 0s),134.1 0s),135.8 0d),
135.9 0d),141.5 0d),201.3 0s); exact mass 0HR electrospray)
m/z calcd for C25H32NaO2Si 415.206929,found
415.207259. The E geometry was assigned by comparison
of the chemical shift of the vinyl hydrogen with values
reported for the model compounds 0E)-2-ethylidenecyclo-
hexanone15 and 0Z)-2-ethylidenecyclohexanone.15
1
11 00.4925 g,66%) as a mixture [1:1 0 H NMR)] of two
1
isomers: FTIR 0CH2Cl2,cast) 2965,2931,2857 cm 21; H
NMR 0C6D6,300 MHz) d 0.8±1.10 0m,4H),1.10±1.56 0m,
15H),1.56±2.10 0m,4H),3.10±3.60 0m,4H),3.70±3.78
0m,0.5H),3.98±4.07 0m,0.5H),4.52±4.62 0m,1H),
4.62±4.78 0m,1H),5.63 0d,
Jˆ8.2 Hz,0.5H),5.67 0d,
Jˆ8.3 Hz,0.5H),7.16±7.35 0m,6H),7.72±7.88 0m,4H);
13C NMR 0C6D6,75.5 MHz) d 15.5 0q),15.6 0q),19.4 0s),
21.5 0t),22.2 0t),25.3 0q),26.2 0t),27.2 0q),27.4 0t),27.7 0t),
32.7 0t),32.9 0t),34.0 0t),34.3 0t),61.8 0t),62.0 0t),66.3 0d),
66.4 0d),77.4 0d),78.1 0d),98.9 0d),100.6 0d),127.9 0d),
3.1.3. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]cyclohexanol (10a,b). NaBH4 06.9 mg,
0.18 mmol) was added in small portions to a stirred and
cooled 008C) solution of enone 9 044.6 mg,0.114 mmol)

3850
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
128.0 0d),129.0 0d),129.9 0d),130.0 0d),131.5 0d),134.56
0s),134.61 0s),134.96 0s),134.99 0s),136.2 0d),136.3 0d),
136.8 0s),137.9 0s); exact mass 0HR electrospray) m/z calcd
for C29H4179BrNaO3Si 567.190605,found 567.191218.
and 14b 0more polar) 08.2 mg,31%),differing in stereo-
chemistry at C02).
Isomer 14a: FTIR 0CH2Cl2,cast) 2974,2933,2862,
1
1712 cm21; H NMR 0C6D6,300 MHz) d 0.96±1.24 0m,
3.1.5. (3aRp,7aSp)-3a-[2-[[(1,1-Dimethylethyl)diphenyl-
1H),1.17±1.24 0t, Jˆ7.0 Hz,3H),1.24±1.45 0m,4H),
1.55±1.72 0m,1H),1.65 0s,3H),1.72±1.85 0m,2H),1.92
0dd, Jˆ13.6,4 Hz,1H),1.95±2.07 0m,1H),2.35 0d,
Jˆ16.0 Hz,1H),2.42 0dd, Jˆ13.6,6 Hz,1H),3.41 0dq,
silyl]oxy]propyl]-2-ethoxyoctahydrobenzofuran
(12).
Bu3SnH 00.37 mL,1.37 mmol) and AIBN 021 mg,
0.13 mmol) were added to a stirred solution of bromo
acetals 11 00.3952 g,0.7243 mmol) in PhMe 050 mL). The
¯ask was then lowered into a preheated oil bath set at 1158C
0continued stirring). After 1.5 h,the mixture was cooled to
room temperature and the solvent was evaporated. Flash
chromatography of the residue over silica gel
01.5£20 cm),using 1:30 EtOAc±hexane,gave acetals 12
Jˆ9.6,7.0 Hz,1H),3.72 0t,
Jˆ9.6,7.0 Hz,1H),5.15 0dd,
Jˆ3 Hz,1H),3.93 0dq,
Jˆ6,4 Hz,1H); 13C NMR
0C6D6,75.5 MHz) d 15.3 0q),20.1 0t),21.6 0t),25.5 0t),30.3
0t),30.7 0q),41.5 0s),46.3 0t),46.8 0t),63.4 0t),79.5 0d),
103.0 0d),205.0 0s); exact mass m/z calcd for C13H22O3
226.15689,found 226.15672.
1
00.3100 g,92%) as a mixture [ca. 4:3 0 H NMR)] of two
isomers,differing in stereochemistry at C02): FTIR
1H NMR 0C6D6,
Isomer 14b: FTIR 0CH2Cl2,cast) 2973,2931,2862,
21
1
0CH2Cl2,cast) 2931,2857 cm
;
1716 cm21; H NMR 0C6D6,300 MHz) d 1.09±1.31 0m,
300 MHz) d 0.80±1.80 0m,24H),1.85±2.15 0m,3H),
3.30±3.45 0m,1H),3.45±3.96 0m,2H),3.96±4.12 0m,
1H),5.05±5.18 0two t, Jˆ5.1,4.5 Hz,1H),7.15±7.28 0m,
6H),7.63±7.9 0m,4H); 13C NMR 0C6D6,75.5 MHz) d 15.4
0q),15.5 0q),16.8 0s),19.2 0s),20.2 0t),21.3 0t),21.6 0t),21.7
0t),25.2 0t),25.5 0q),25.8 0q),27.0 0q),27.5 0t),30.5 0t),31.8
0t),41.1 0s),42.1 0s),43.4 0t),44.8 0t),46.2 0t),47.7 0t),63.2
0t),63.5 0t),68.1 0d),79.4 0d),82.8 0d),103.0 0d),103.8 0d),
127.8 0d),128.0 0d),129.5 0d),129.7 0d),134.2 0s),135.2
0s),136.0 0d),136.1 0d); exact mass 0HR electrospray) m/z
calcd for C29H42NaO3Si 489.280094,found 489.280630.
2H),1.21 0t, Jˆ7 Hz,3H),1.31±1.45 0m,1H),1.45±1.60
0m,2H),1.60±1.72 0m,1H),1.70 0s,3H),1.84 0d,
1H),1.90±2.17 0m,3H),2.19±2.29 0m,2H),3.41 0dq,
Jˆ16 Hz,
Jˆ10,7 Hz,1H),3.58 0t,
Jˆ5 Hz,1H),3.94 0dq, Jˆ10,
7.0 Hz,1H),5.11 0dd,
Jˆ6.5,3.0 Hz,1H);
13C NMR
0C6D6,75.5 MHz) d 15.4 0q),21.5 0t),21.7 0t),28.0 0t),
30.4 0t),31.1 0q),41.7 0s),43.5 0t),49.1 0t),63.6 0t),81.8
0d),103.9 0d),205.4 0s); exact mass m/z calcd for C13H22O3
226.15689,found 226.15692.
3.1.8. (1Rp,6Rp,8Sp)-7-Oxatricyclo[6.3.1.01,6]dodecan-10-
one (15). A solution of ketones 14a and b 0ca. 4:3)
00.1359 g,0.6004 mmol) in a mixture of 3 M HCl
030 mL) and THF 06 mL) was re¯uxed 0858C) for 24 h,
cooled to room temperature,and extracted with EtOAc
0100 mL). The aqueous layer was washed with EtOAc
02£50 mL),and the combined organic extracts were washed
with water and brine,dried 0MgSO 4),and evaporated. Flash
chromatography of the residue over silica gel 01£20 cm),
3.1.6. 1-[(3aRp,7aSp)-2-Ethoxyoctahydrobenzofuran-3a-
yl]-2-propanol (13). Bu4NF 01.0 M in THF,3.5 mL,
3.5 mmol) was added dropwise to a stirred solution of
acetals 12 00.4090 g,0.8763 mmol) in THF 030 mL). The
stirred mixture was warmed to 458C for 150 min,cooled to
room temperature,diluted with Et 2O 0120 mL),and washed
with water and brine,dried 0MgSO 4),and evaporated. Flash
chromatography of the residue over silica gel 01£20 cm),
using 1:4 EtOAc±hexane,gave alcohols 13 0185 mg,92%)
as a chromatographically inseparable mixture [ca. 4:3 01H
using 1:1 EtOAc±hexane,gave tricyclic ketone
15
080.1 mg,74%) as a solid: FTIR 0CH 2Cl2,cast) 2934,
1
2861,1716 cm 21; H NMR 0C6D6,360 MHz) d 0.64±0.90
NMR)] of two isomers,differing in stereochemistry at C02):
;
1H
0m,3H),0.91±1.10 0m,2H),1.17±1.27 0m,1H),1.29±1.45
0m,2H),1.73±1.84 0m,1H),1.84 0t, Jˆ16.8 Hz,2H),1.99±
2.07 0m,1H),2.16 0dt, Jˆ16.8,2.6 Hz,1H),2.60±2.71 0m,
1H),3.49 0dd, Jˆ10.4,4.4 Hz,1H),4.15±4.21 0m,1H); 13C
NMR 0C6D6,75.5 MHz) d 21.4 0t),23.2 0t),32.0 0t),32.5 0t),
36.1 0t),42.1 0s),49.3 0t),56.4 0t),73.4 0d),82.1 0d),207.1
0s); exact mass m/z calcd for C11H16O2 180.11504,found
180.11500.
21
FTIR 0CH2Cl2,cast) 3443,2969,2931,2861 cm
NMR 0C6D6,300 MHz) d 0.92±1.50 0m,13H),1.50±1.75
0m,1.5H),1.77±2.12 0m,4H),2.63 0brs,0.5H),3.25±3.45
0m,1H),3.55±3.95 0m,3H),5.05±5.20 0m,1H);
13C NMR
0C6D6,75.5 MHz) d 15.3 0q),15.4 0q),20.3 0t),21.5 0t),21.7
0t),21.9 0t),25.2 0t),25.4 0q),25.6 0q),28.1 0t),31.27 0t),
31.33 0t),42.0 0s),42.3 0s),42.6 0t),43.8 0t),47.4 0t),63.3 0t),
63.6 0t),64.2 0d),64.3 0d),79.7 0d),82.8 0d),103.2 0d),104.4
0d); exact mass m/z calcd for C13H24O3 228.17255,found
228.17290.
3.1.9. Acetic acid (1Rp,6Rp)-10-oxospiro[5.5]undec-8-en-
1-yl ester (16). A solution of ketone 15 050.2 mg,
0.279 mmol),TsOH´H O 047 mg,0.27 mmol),and Ac 2O
2
3.1.7. 1-[(3aRp,7aRp)-2-Ethoxyoctahydrobenzofuran-3a-
yl]-2-propanone (14a,b). A solution of alcohols 13
026.8 mg,0.117 mmol) in CH Cl2 01 mL) was added drop-
00.40 mL,4.2 mmol) in PhH 055 mL) was heated at 85 8C
for 40 h,cooled,and evaporated. The residue was diluted
with Et2O 0100 mL),washed with water,saturated aqueous
2
wise to a stirred mixture of PCC 038.0 mg,0.176 mmol),
Ê
powdered 4 A molecular sieves 0150 mg) and CH2Cl2
NaHCO3 and brine,dried 0MgSO ),and evaporated. Flash
4
chromatography of the residue over silica gel 01£15 cm),
using 1:4 EtOAc±hexane,gave spiro enone 16 042.5 mg,
69%): FTIR 0CH2Cl2,cast) 3035,2938,2864,1734,1680,
01 mL). After 3 h,the mixture was diluted with Et 2O
010 mL),and ®ltered through a pad 02 £1.5 cm) of silica
1
gel,using Et O 020 mL) as a rinse. Evaporation of the
2
1621 cm21; H NMR 0C6D6,400 MHz) d 0.85±1.14 0m,
®ltrate and ¯ash chromatography of the residue over silica
gel 00.6£15 cm),using 1:9 EtOAc±hexane,gave ketones 14
as two separable isomers, 14a 0less polar) 011.0 mg,41%)
4H),1.24±1.42 0m,2H),1.45±1.55 0m,1H),1.55±1.65
0m,1H),1.68 0s,3H),1.82 0dt,
0dt, Jˆ19.0,3.0 Hz,1H),2.15 0d, Jˆ15.4 Hz,1H),2.37 0d,
Jˆ19.0,1.5 Hz,1H),2.11

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3851
Jˆ15.4 Hz,1H),4.63 0dd, Jˆ9.0,4.0 Hz,1H),5.96±6.02
13C NMR
0CDCl3,75.5 MHz) d 20.6 0t),21.1 0q),23.0 0t),26.3 0t),
30.1 0t),32.2 0t),40.3 0s),47.6 0t),77.0 0d),128.9 0d),147.5
0d),170.2 0s),198.8 0s); exact mass m/z calcd for C13H18O3
222.12560,found 222.12578.
75.5 MHz) d 19.1 0s),19.8 0t),23.1 0q),26.4 0t),26.9 0q),
38.1 0t),67.8 0d),127.5 0d),127.6 0d),129.66 0d),129.70
0d),133.8 0s),134.0 0s),134.6 0s),135.8 0d),135.9 0d),138.0
0d),207.5 0s); exact mass 0HR electrospray) m/z calcd for
C24H30NaO2Si 401.191279,found 401.191571. The
geometry was assigned on the basis of the chemical shift
0m,1H),6.16 0ddd, Jˆ9.6,5.2,2.8 Hz,1H);
E
arguments used for 9.
3.1.10. 2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-
hydroxypropyl]cyclopentanone (18a,b). The procedure
described for 8 was followed,using cyclopentanone
01.72 mL,19.5 mmol) in THF 034 mL),LDA 021.4 mmol)
in THF 0140 mL),aldehyde 79 03.0450 g,9.7446 mmol) in
THF 048 mL),and a ®nal reaction time of 1 h. Flash
chromatography of the crude product over silica gel
02.5£25 cm),using 1:10 EtOAc±hexane,gave aldols 18 as
two fractions, 18a 0more polar) 02.2118 g,57%) and 18b
0less polar) 00.7671 g,20%),each of which contained trace
impurities 01H NMR).
3.1.12. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]cyclopentanone (19) from 18b (minor
isomer of 18). )a) Methanesulfonic acid 2-[[)1,1-dimethyl-
ethyl)diphenylsilyl]oxy]-1-)2-oxocyclopentyl)propyl ester.
The procedure described for mesylation of 8 was followed,
using MeSO2Cl 00.45 mL,5.8 mmol),alcohol 18b
0i.e. minor isomer of 18) 00.7485 g,1.887 mmol),Et 3N
01.3 mL,9.3 mmol) and CH Cl2 036 mL),and a reaction
2
time of 6 h. The crude mesylate 00.4875 g,54%) was used
immediately for next step.
Fraction 18a: FTIR 0CH2Cl2,cast) 3491,2961,2931,2886,
2857,1723 cm 21; 1H NMR 0CDCl3,400 MHz) d 0.97±2.30
)b) )E)-2-[2-[[)1,1-Dimethylethyl)diphenylsilyl]oxy]propyl-
idene]cyclopentanone )19). The procedure described for 9
was followed,using DBU 00.32 mL,2.1 mmol),the above
mesylates 00.4875 g,1.027 mmol) in THF 010 mL),and a
reaction time of 45 min. Flash chromatography of the crude
product over silica gel 01.5£20 cm),using 1:15 EtOAc±
hexane,gave enone 19 00.2560 g,66%),spectroscopically
identical with material obtained from the major isomer
series.
0m,7H),1.10 0s,9H),1.12 0d,
Jˆ8.5,2.8 Hz,1H),3.77 0dd,
Jˆ7.0 Hz,3H),3.62 0dt,
Jˆ2.5,0.6 Hz,1H),3.89
0dq, Jˆ6.3,2.8 Hz,1H),7.35±7.47 0m,6H),7.69±7.79
0m,4H); 13C NMR 0CDCl3,100.6 MHz) d 17.0 0q),19.1
0s),20.4 0t),26.5 0t),26.9 0q),38.0 0t),50.2 0d),71.0 0d),
75.8 0d),127.4 0d),127.44 0d),129.47 0d),129.5 0d),133.8
0s),134.1 0s),135.7 0d),222.3 0s); exact mass 0HR electro-
spray) m/z calcd for C24H32NaO3Si 419.201843,found
419.202002.
3.1.13. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]cyclopentanol (20a,b). The procedure
described for 10a,b was followed,using NaBH 00.3680 g,
Fraction 18b: 1H NMR 0CDCl3,400 MHz) d 0.96±2.42 0m,
10H),1.08 0s,9H),3.66 0ddd, Jˆ8.0,4.0,2.0 Hz,1H),4.01
0dq, Jˆ7.5,3.6 Hz,1H),4.07 0d, Jˆ2.0 Hz,1H),7.35±7.50
0m,6H),7.65±7.78 0m,4H); 13C NMR 0CDCl3,100.6 MHz)
d 18.7 0q),19.3 0s),21.0 0t),27.1 0q),27.2 0t),78.7 0t),50.1
0d),70.9 0d),76.1 0d),127.5 0d),127.8 0d),129.7 0d),129.8
0d),133.6 0s),134.3 0s),135.75 0d),135.8 0d),136.0 0d),
223.7 0s).
4
9.725 mmol),enone
19 02.4240 g,6.4027 mmol),
CeCl3´7H2O 03.4210 g,9.1817 mmol)a, nd MeOH 074 mL).
Flash chromatography of the crude product over silica gel
02.5£25 cm),using 1:8 EtOAc±hexane,gave alcohols 20 as
two separable isomers, 20a 0less polar) 01.3555 g,55%) and
20b 0more polar) 01.0530 g,43%).
Isomer 20a: FTIR 0CH2Cl2,cast) 3432,2962,2930,2891,
3.1.11. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]cyclopentanone (19) from 18a (major
isomer of 18). )a) Methanesulfonic acid 2-[[)1,1-dimethyl-
ethyl)diphenylsilyl]oxy]-1-)2-oxocyclopentyl)propyl ester.
The procedure described for mesylation of 8 was followed,
2857 cm21 1H NMR 0CDCl3,400 MHz) d 0.64 0d,
;
Jˆ6.0 Hz,1H),1.07 0s,9H),1.18±1.58 0m,3H),1.27 0d,
Jˆ6.0 Hz,3H),1.63±1.84 0m,3H),4.15 0q, Jˆ6.0 Hz,1H),
4.43 0dq, Jˆ8.0,6.0 Hz,1H),5.47 0dq, Jˆ8.0,2.0 Hz,1H),
7.33±7.48 0m,6H),7.66±7.75 0m,4H); 13C NMR 0CDCl3,
100.6 MHz) d 19.1 0s),21.5 0t),23.9 0q),26.5 0t),27.0 0q),
35.1 0t),68.1 0d),75.2 0d),127.4 0d),127.6 0d),128.3 0d),
129.6 0d),134.3 0s),135.0 0s),135.8 0d),136.0 0d),144.3 0s);
exact mass 0HR electrospray) m/z calcd for C24H32NaO2Si
403.206929,found 403.207043.
using MeSO2Cl 00.44 mL,5.7 mmol),alcohol
major isomer of 18) 00.7360 g,1.8557 mmol),Et
18a 0i.e.
3N
01.3 mL,9.3 mmol) and CH Cl2 035 mL),and a reaction
2
time of 4 h. The crude mesylate 00.8280 g,94%) was used
immediately for next step.
)b) )E)-2-[2-[[)1,1-Dimethylethyl)diphenylsilyl]oxy]propyl-
idene]cyclopentanone )19). The procedure described for 9
was followed,using DBU 00.54 mL,3.6 mmol) and the
above mesylates 00.8280 g,1.744 mmol) in THF 017 mL).
Flash chromatography of the crude product over silica gel
01.5£20 cm),using 1:10 EtOAc±hexane,gave enone 19
Isomer 20b: FTIR 0CH2Cl2,cast) 3340,2962,2930,2892,
1
2857 cm21; H NMR 0CDCl3,400 MHz) d 1.08 0s,9H),
1.26 0d, Jˆ6.0 Hz,3H),1.30±1.43 0m,1H),1.46±1.60
0m,3H),1.62±1.75 0m,2H),1.91±2.03 0m,1H),4.25 0s,
1H),4.39 0dq, Jˆ8.0,6.0 Hz,1H),5.61 0dd, Jˆ8.0,1.0 Hz,
1H),7.32±7.48 0m,6H),7.66±7.75 0m,4H);
13C NMR
00.5850 g,89%): FTIR 0CH Cl2,cast) 2963,2930,2891,
0CDCl3,100.6 MHz) d 19.2 0s),22.1 0t),24.1 0q),26.3
0t),27.0 0q),35.0 0t),68.0 0d),75.6 0d),127.3 0d),127.5
0d),128.7 0d),129.4 0d),129.5 0d),134.46 0s),134.50 0s),
135.86 0d),135.93 0d),144.4 0s); exact mass 0HR electro-
spray) m/z calcd for C24H32NaO2Si 403.206929,found
403.207247.
2
2857,1722,1657 cm 21; H NMR 0CDCl3,300 MHz)
1.06 0s,9H),1.25 0d, Jˆ6.4 Hz,3H),1.50±1.70 0m,1H),
1.70±1.80 0m,1H),1.92±2.06 0m,1H),2.12±2.30 0m,3H),
4.44 0dq, Jˆ7.6,6.4 Hz,1H),6.50 0dt, Jˆ8.2,2.7 Hz,1H),
d
1
7.30±7.50 0m,6H),7.62±7.75 0m,4H); 13C NMR 0CDCl3,

3852
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3.1.14. (E)-[[1-[2-(2-Bromo-1-ethoxyethoxy)cyclopentyl-
idene]-2-propyl]oxy](1,1-dimethylethyl)diphenylsilane
(21). The procedure described for 11 was followed,using
NBS 01.8235 g,10.245 mmol),dry CH 2Cl2 046 mL),ethyl
of the crude product over silica gel 01£20 cm),using 1:6
EtOAc±hexane,gave alcohols 23 as two isomers, 23a 0more
polar) 099.8 mg,44%) and 23b 0less polar) 088.0 mg,39%),
differing in stereochemistry at C02).
vinyl ether 03.3 mL,34 mmol),alcohol
20a 0i.e. major
21
isomer) 01.3000 g,3.4155 mmol) in 18 mL CH 2Cl2
018 mL),and a reaction time of 18 h. Flash chromatography
of the crude product over silica gel 02£20 cm),using 1:40
EtOAc±hexane,gave bromo acetals 21 01.1870 g,65%) as a
chromatographically inseparable mixture [ca. 1:1 01H
NMR) of two isomers: FTIR 0CH2Cl2,cast) 2965,2930,
Isomer 23a: FTIR 0CH2Cl2,cast) 3432,2967,2908 cm
1H NMR 0C6D6,400 MHz) d 1.01 0d, Jˆ6.2 Hz,3H),1.15±
1.44 0m,4H),1.19 0t, Jˆ7.1 Hz,3H),1.51±1.65 0m,2H),
;
1.87±1.96 0m,1H),1.96±2.06 0m,1H),2.08 0dd,
Jˆ13.7,
1.8 Hz,1H),2.17±2.30 0m,2H),3.36 0dq,
Jˆ9.4,7.1 Hz,
1H),3.61±3.72 0m,1H),3.89 0dq, Jˆ9.4,7.1 Hz,1H),4.30
0d, Jˆ4.7 Hz,1H),5.16 0dd, Jˆ5.9,1.85 Hz,1H); 13C NMR
0C6D6,100.6 MHz) d 15.4 0q),24.2 0t),25.5 0q),34.2 0t),
38.6 0t),46.3 0t),49.6 0t),52.1 0s),63.0 0t),65.8 0d),92.2 0d),
105.8 0d); exact mass 0HR electrospray) m/z calcd for
C12H22NaO3 237.146665,found 237.146728.
1
2891,2857 cm 21; H NMR 0C6D6,360 MHz) d 1.12 0t,
Jˆ7.0 Hz,1.5H),1.13 0t, Jˆ7.0 Hz,1.5H),1.23 0s,4.5H),
1.24 0s,4.5H),1.30 0d, Jˆ6.2 Hz,2H),1.32 0d, Jˆ6.2 Hz,
2H),1.38±1.58 0m,2H),1.58±1.80 0m,3H),3.15±3.31 0m,
2H),3.31±3.42 0m,1H),3.42±3.53 0m,1H),4.12±4.20 0m,
1H),4.44±4.58 0m,1H),4.70 0t, Jˆ5.5 Hz,0.5H),4.77 0t,
Jˆ5.5 Hz,0.5H),5.85 0d, Jˆ8.5 Hz,0.5H),5.90 0dq, Jˆ8.5,
21
Isomer 23b: FTIR 0CH2Cl2,cast) 3455,2960 cm
;
1H
2.0 Hz,0.5H),7.15±7.30 0m,6H),7.75±7.85 0m,4H);
13C
NMR 0C6D6,300 MHz) d 1.10±1.25 0m,1H),1.12 0t,
Jˆ7.1 Hz,3H),1.21 0d, Jˆ6.2 Hz,3H),1.29±1.52 0m,
4H),1.52±1.74 0m,3H),1.92±2.03 0m,1H),2.34 0d,
Jˆ13.8 Hz,1H),3.28 0dq, Jˆ9.6,7.1 Hz,1H),3.31 0s,
4.68 0d, Jˆ5.0 Hz,1H),5.03 0d, Jˆ5.4 Hz,1H); 13C NMR
0C6D6,75.5 MHz) d 15.2 0q),24.2 0t),24.7 0q),33.6 0t),43.1
0t),44.9 0t),48.6 0t),51.1 0s),62.6 0t),65.0 0d),89.3 0d),
105.0 0d); exact mass 0HR electrospray) m/z calcd for
C12H22NaO3 237.146665,found 237.146457.
NMR 0C6D6,100.6 MHz) d 15.2 0q),19.2 0s),21.6 0t),22.0
0t),23.9 0q),24.0 0q),25.8 0t),26.3 0t),26.8 0q),27.0 0q),
32.1 0t),32.2 0t),32.3 0t),33.4 0t),60.7 0t),60.8 0t),68.2 0d),
79.0 0d),79.8 0d),99.6 0d),100.1 0d),127.56 0d),127.6 0d),
129.3 0d),129.5 0d),129.59 0d),129.63 0d),130.3 0d),134.3
0s),134.4 0s),134.6 0s),134.7 0s),136.0 0d),136.1 0d),136.2
0d),140.4 0s),141.0 0s); exact mass 0HR electrospray) m/z
calcd for C28H3979BrNaO3Si 553.174955,found
553.175107.
1H),3.75 0dq, Jˆ9.6,7.1 Hz,1H),3.92±4.08 0m,1H),
3.1.15. (3aRp,7aSp)-3a-[2-[[(1,1-Dimethylethyl)diphenyl-
silyl]oxy]propyl]-2-ethoxyhexahydrocyclopenta[b]furan
(22). The procedure described for 12 was followed,using
Bu3SnH 00.57 mL,2.11 mmol),AIBN 033 mg,0.20 mmol),
bromo acetals 21 00.6860 g,1.290 mmol),PhMe 090 mL),
and a reaction time of 1 h. Flash chromatography of the
crude product over silica gel 01.5£20 cm),using 1:40
EtOAc±hexane,gave acetals 22 00.5290 g,90%) as a chro-
matographically inseparable mixture [ca. 1:1 01H NMR)] of
3.1.17. 1-[(3aRp,7aRp)-2-Ethoxyhexahydrocyclopenta[b]-
furan-3a-yl]-2-propanone (24) from 23a (major isomer
of 23). The procedure described for 14a,b was followed,
using alcohol 23a 0i.e. major isomer) 087.0 mg,
0.406 mmol) in CH2Cl2 03.6 mL),PCC 00.1326 g,0.6149
Ê
mmol),powdered 4 A molecular sieves 0704 mg),CH Cl2
2
03.6 mL),and a reaction time of 3 h. Flash chromatography
of the crude product over silica gel 01£15 cm),using 1:4
EtOAc±hexane,gave ketone 24 064.0 mg,74%),whose
stereochemistry at C02) with respect to the quaternary center
was not established. Compound 24 had: FTIR 0CH2Cl2,
two isomers,differing in stereochemistry at C02): FTIR
;
1H NMR
21
0CH2Cl2,cast) 2961,2931,2898,2857 cm
1
0C6D6,400 MHz) d 1.10 0d, Jˆ6.0 Hz,1.5H),1.11 0d,
Jˆ6.0 Hz,1.5H),1.16 0t, Jˆ7.0 Hz,1.5H),1.17 0t, Jˆ7.0,
1.5H),1.19±2.24 0m,9H),1.22 0s,4.5H),1.25 0s,4.5H),
2.43 0d, Jˆ13 Hz,0.5H),2.51 0dd, Jˆ14,6.0 Hz,0.5H),
3.30±3.41 0m,1H),3.74±3.90 0m,1H),4.04 0sextet,
Jˆ6.0 Hz,0.5H),4.14 0sextet, Jˆ6.0 Hz,0.5H),4.19 0d,
Jˆ5.0 Hz,1H),5.06 0dd, Jˆ5.6,2.0 Hz,0.5H),5.13 0d,
Jˆ5.0 Hz,0.5H),7.15±7.30 0m,6H),7.75±7.90 0m,4H);
13C NMR 0C6D6,100.6 MHz) d 15.2 0q),15.3 0q),19.15 0s),
19.20 0s),24.3 0t),24.5 0t),25.2 0q),25.4 0q),27.0 0q),27.1
0q),32.8 0t),34.0 0t),38.8 0t),39.5 0t),46.0 0t),46.1 0t),49.9
0s or t),50.9 0s or t),51.29 0s or t),51.35 0s or t),62.0 0t),
62.7 0t),68.9 0d),69.1 0d),90.7 0d),92.8 0d),104.7 0d),105.2
0d),127.6 0d),127.7 0d),129.5 0d),129.6 0d),129.65 0d),
129.7 0d),134.3 0s),134.4 0s),135.0 0s),135.3 0s),136.0 0d),
136.07 0d),136.12 0d); exact mass 0HR electrospray) m/z
calcd for C28H40NaO3Si 475.26444,found 475.264908.
cast) 2971,2901,1718 cm 21; H NMR 0C6D6,300 MHz)
d 1.17 0t, Jˆ7.1 Hz,3H),1.32±1.74 0m,3H),1.64 0s,3H),
1.92±2.06 0m,1H),1.94 0dd, Jˆ13.5,5.8 Hz,1H),2.04 0s,
2H),2.06±2.26 0m,2H),2.29 0dd, Jˆ13.5,1.8 Hz,1H),3.37
0dq, Jˆ9.4,7.1 Hz,1H),3.86 0dq, Jˆ9.4,7.1 Hz,1H),4.18
0dd, Jˆ5.7,1.3 Hz,1H),5.11 0dd, Jˆ5.8,1.8 Hz,1H); 13C
NMR 0C6D6,75.5 MHz) d 15.4 0q),24.5 0t),30.4 0q),34.5
0t),39.2 0t),46.7 0t),50.6 0s),53.5 0t),63.0 0t),91.4 0d),
105.4 0d),205.1 0s); exact mass m/z calcd for C12H20O3
212.14125,found 212.14062.
3.1.18. 1-[(3aRp,7aRp)-2-Ethoxyhexahydrocyclopenta[b]-
furan-3a-yl]-2-propanone (240) from 23b (minor isomer
of 23). The procedure described for 14a,b was followed,
using alcohol 23b 0i.e. minor isomer) 074.0 mg,
0.345 mmol) in CH2Cl2 03 mL),PCC 00.1117 g,0.5180
Ê
mmol),powdered 4 A molecular sieves 0500 mg),CH Cl2
2
03 mL),and a reaction time of 3.5 h. Flash chromatography
of the crude product over silica gel 01£15 cm),using 1:4
EtOAc±hexane,gave ketone 240 00.0521 g,71%),whose
stereochemistry at C02) with respect to the quaternary center
was not established. Compounds 24 and 240 have different
stereochemistry at C02). Compound 240 had: FTIR 0CH2Cl2,
3.1.16. 1-[(3aRp,7aSp)-2-Ethoxyhexahydrocyclopenta[b]-
furan-3a-yl]-2-propanol (23a,b). The procedure described
for 13 was followed,using Bu NF 01.0 M in THF,2.5 mL,
2.5 mmol),acetals 22 00.4750 g,1.049 mmol) in THF
044 mL),and a reaction time of 4 h. Flash chromatography
4

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3853
21
cast) 2941,2902,2868,1718 cm
400 MHz) d 1.14 0t, Jˆ7.1 Hz,3H),1.34 0ddd, Jˆ6.1 Hz,
1H),1.51±1.75 0m,3H),1.64 0s,3H),1.78 0dd,
Jˆ13.4,
4.9 Hz,1H),1.81±1.88 0m,1H),1.93±2.00 0m,1H),2.16
0d, Jˆ13.4 Hz,1H),2.41 0d, Jˆ17.8 Hz,1H),2.79 0d,
Jˆ17.8 Hz,1H),3.31 0dq, Jˆ9.6,7.1 Hz,1H),3.74 0dq,
;
1H NMR 0C6D6,
rated. Flash chromatography of the residue over silica gel
02£15 cm),using 1:10 EtOAc±hexane,gave aldols 28 as
two fractions, 28a 0less polar) 00.4619 g,72%) and 28b
0more polar) 054.7 mg,8%),each consisting 0 1H and 13C
NMR) of a single isomer.
Jˆ9.6,7.1 Hz,1H),4.28 0d,
Jˆ4.8 Hz,1H),5.06 0d,
Isomer 28a: FTIR 0CH2Cl2,cast) 3515,2957,2932,2858,
Jˆ4.9 Hz,1H); 13C NMR 0C6D6,100.6 MHz) d 15.5 0q),
24.5 0t),30.3 0q),33.2 0t),39.7 0t),46.7 0t),50.2 0s),53.2 0t),
62.2 0t),89.4 0d),104.5 0d),205.8 0s); exact mass m/z calcd
for C12H20O3 212.14125,found 212.14120.
1695,1589 cm 21; H NMR 0CDCl3,400 MHz) d 1.06 0s,
1
9H),1.12 0d, Jˆ6.5 Hz,3H),1.21 0d, Jˆ6.1 Hz,3H),1.29±
1.42 0m,1H),1.55±2.19 0m,6H),2.58 0dd, Jˆ10.5,1.8 Hz,
1H),3.13 0brs,1H),3.49 0dd, Jˆ8.0,1.8 Hz,1H),4.07 0dq,
Jˆ8.0,6.1 Hz,1H),7.30±7.50 0m,6H),7.60±7.72 0m,4H);
13C NMR 0CDCl3,100.6 MHz) d 19.3 0s),20.2 0q),20.6 0q),
26.4 0t),27.0 0q),33.8 0t),36.6 0d),42.6 0t),56.6 0d),71.2
0d),74.8 0d),127.5 0d),127.6 0d),129.6 0d),129.7 0d),133.8
0s),134.2 0s),135.8 0d),135.9 0d),216.3 0s); exact mass 0HR
electrospray) m/z calcd for C26H36NaO3Si 447.233143,
found 447.233532.
3.1.19. (1Rp,5Rp,7Sp)-6-Oxatricyclo[5.3.1.01,5]undecan-9-
one (25). The procedure described for 15 was followed,
using ketones 24 and 240 0ca. 1:1) 074.0 mg,0.349 mmol),
3 M HCl 017 mL),THF 03.6 mL),and a re¯ux time of 36 h.
Flash chromatography of the crude product over silica gel
01£15 cm),using 1:3 EtOAc±hexane gave ketone 25
043 mg,74%): FTIR 0CH 2Cl2,cast) 2954,2877,
1715 cm21; H NMR 0C6D6,360 MHz) d 0.84±0.95 0m,
Isomer 28b: FTIR 0CH2Cl2,cast) 3462,2957,2931,2858,
1
1
1H),1.15 0d, Jˆ11.2 Hz,1H),1.23±1.45 0m,2H),1.48±
1.62 0m,3H),1.64 0ddt, Jˆ11.2,5.6,2.8 Hz,1H),1.80
0dd, Jˆ17.8,2.8 Hz,1H),2.16 0d, Jˆ17 Hz,1H),2.26 0dt,
Jˆ17,2.0 Hz,1H),2.58 0dq, Jˆ17.8,2.0 Hz,1H),3.91 0t,
Jˆ5.6 Hz,1H),4.17 0dt, Jˆ5.4,2.7 Hz,1H); 13C NMR
0CDCl3,100.6 MHz) d 23.6 0t),33.2 0t),34.0 0t),40.6 0t),
48.3 0t),50.9 0s),53.5 0t),76.4 0d),88.5 0d),209.8 0s); exact
mass m/z calcd for C10H14O2 166.09938,found 166.09960.
1702,1589 cm 21; H NMR 0CDCl3,400 MHz) d 0.98 0d,
Jˆ6.7 Hz,3H),1.01 0d, Jˆ6.2 Hz,3H),1.08 0s,9H),1.34±
1.46 0m,1H),1.68±2.08 0m,4H),2.22±2.48 0m,3H),2.74
0brs,1H),3.67 0t, Jˆ5.0 Hz,1H),4.09 0dq, Jˆ6.2,5.0 Hz,
1H),7.30±7.50 0m,6H),7.60±7.80 0m,4H);
13C NMR
0CDCl3,100.6 MHz) d 19.4 0s),20.0 0q),20.3 0q),24.4
0t),27.1 0q),31.1 0t),35.4 0d),41.8 0t),58.2 0d),71.1 0d),
75.3 0d),127.5 0d),127.7 0d),129.6 0d),129.8 0d),133.5 0s),
134.4 0s),135.9 0d),214.1 0s); exact mass 0HR electrospray)
m/z calcd for C26H36NaO3Si 447.233143,found
447.233639.
3.1.20. Acetic acid (1Rp,5Rp)-9-oxospiro[5.4]dec-7-en-1-
yl ester (26). The procedure described for 16 was followed,
using ketone 25 015.2 mg,0.091 mmol),TsOH´H
2O
015.5 mg,0.089 mmol),Ac 2O 00.13 mL,1.4 mmol),PhH
018 mL),and a reaction time of 20 h. Flash chromatography
of the crude product over silica gel 00.6£10 cm),using 1:3
3.1.22. (E)-2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]-3-methylcyclohexanone (29). )a) Methane-
sulfonic acid 2-[[)1,1-dimethylethyl)diphenylsilyl]oxy]-1-
)6-methyl-2-oxocyclohexyl)propyl ester. The procedure
described for mesylation of 8 was followed,using MeSO 2Cl
EtOAc±hexane,gave enone 26 014.1 mg,74%): FTIR
21
0CH2Cl2,cast) 2958,2879,1736,1680 cm
;
1H NMR
0CDCl3,400 MHz) d 1.56±1.86 0m,5H),2.06 0s,3H),
2.08±2.19 0m,1H),2.27 0dd, Jˆ16.0,1.0 Hz,1H),2.29
01.2 mL,15 mmol),alcohols
4.8108 mmol),Et 3N 03.4 mL,24 mmol),and CH
080 mL),and a reaction time of 4 h. The crude mesylates
were obtained 01.9542 g,ca. 81%) were used immediately
for next step.
28a and
b
02.0430 g,
2Cl2
0ddt, Jˆ19.0,5.0,1.4 Hz,1H),2.46 0d,
2.57 0dt, Jˆ19.0,2.8 Hz,1H),4.85 0dd,
Jˆ16.0 Hz,1H),
Jˆ6.4,4.0 Hz,
1H),6.04 0dq, Jˆ10.0,2.0 Hz,1H),6.93 0ddd,
Jˆ10.0,
5.0,3.3 Hz,1H); 13C NMR 0CDCl3,100.6 MHz) d 20.1
0t),21.1 0q),29.9 0t),31.8 0t),34.4 0t),47.3 0t),47.6 0s),
80.6 0d),129.5 0d),148.7 0d),170.4 0s),198.4 0s); exact
mass m/z calcd for C12H16O3 208.10994,found 208.11036.
)b) )E)-2-[2-[[)1,1-Dimethylethyl)diphenylsilyl]oxy]propyl-
idene]-3-methylcyclohexanone )29a,b). The procedure
described for 9 was followed,using DBU 01.8 mL,
12 mmol),the above mesylates 01.9542 g,3.8870 mmol)
in THF 040 mL),and a reaction time of 24 h. Flash chroma-
tography of the crude product over silica gel 03£20 cm),
using 1:10 EtOAc±hexane,gave enone 29 as two fractions,
29a 0more polar) 00.8343 g,53%) and 29b 0less polar)
00.1450 g,9%),each fraction consisting of two isomers
01H NMR).
3.1.21. 2-[2-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-1-
hydroxypropyl]-3-methylcyclohexanone (28a,b). MeLi
01.4 M in Et2O,4.28 mL,6.0 mmol) was added dropwise
to a stirred and cooled 008C) suspension of CuI 00.571 g,
3.00 mmol) in Et2O 030 mL). After 5 min,2-cyclohexenone
00.145 mL,1.5 mmol) was added,and stirring was con-
tinued at 08C for 30 min. ZnCl2 solution 01.0 M in Et2O,
3.0 mL,3.0 mmol) was then added,the mixture was cooled
to 2788C,and aldehyde 79 00.94 g,3.0 mmol) in Et 2O
010 mL) was added dropwise. Stirring at 2788C was con-
tinued for 1 h,and saturated aqueous NH 4Cl 020 mL),
followed by water 030 mL) were added. The cooling bath
was removed,and stirring was continued until the mixture
attained room temperature. The mixture was extracted with
Et2O 03£50 mL),and the combined organic extracts were
Fraction 29a [two isomers,ca. 8:1 0 1H NMR)]: FTIR
0CH2Cl2,cast) 3071,3049,2960,2931,2891,2857,1691,
1
1629,1589 cm 21; H NMR 0CDCl3,360 MHz) d 0.61 0d,
Jˆ7.2 Hz,0.3H),0.81 0d, Jˆ7.3 Hz,2.7H),1.02 0s,8.0H),
1.04 0s,1.0H),1.20 0d, Jˆ6.4 Hz,0.3H),1.25 0d, Jˆ6.3 Hz,
2.7H),1.20±2.80 0m,7H),4.48±4.60 0m,1H),6.32 0dd,
Jˆ9.0,1.0 Hz,0.9H),6.45 0dd,
Jˆ8.0,0.7 Hz,0.1H),
7.30±7.50 0m,6H),7.60±7.72 0m,4H); 13C NMR 0CDCl3,
100.6 MHz) d 18.5 0t),18.8 0t),19.1 0s),19.2 0q),21.0 0q),
washed with water and brine,dried 0MgSO ),and evapo-
4

3854
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
24.1 0q),24.15 0q),26.88 0q),26.9 0q),30.27 0d),30.3 0t),
30.4 0t),30.9 0d),40.6 0t),40.7 0t),65.5 0d),66.0 0d),127.5
0d),127.6 0d),129.6 0d),129.67 0d),129.7 0d),133.5 0s),
134.0 0s),134.1 0s),134.2 0s),135.8 0d),135.82 0d),135.9
0d),136.0 0d),139.3 0s),139.7 0d),140.1 0d),201.9 0s),
203.0 0s); exact mass 0HR electrospray) m/z calcd for
alcohols 30 00.3570 g,0.8735 mmol) in CH Cl2 05 mL),
2
and a reaction time of 24 h. Flash chromatography of the
crude product over silica gel 02£20 cm),using 1:20 EtOAc±
hexane,gave bromo acetals 31 00.315 g,64%) as a mixture
[ca. 8:8:1:1 01H NMR)] of four isomers: FTIR 0CH2Cl2,cast)
3070,3048,2965,2930,2889,2858 cm 21; 1H NMR 0C6D6,
300 MHz) d 0.50±0.78 0m,3H),0.90±1.45 0m,20H),1.78±
1.98 0m,1H),2.35±2.55 0m,1H),3.05±3.56 0m,4H),3.88±
4.10 0m,1H),4.55±4.88 0m,2H),5.86±6.10 0m,1H),7.18±
C26H34NaO2Si 429.222579,found 429.222573. The
E
geometry for both components of this 0major) fraction was
inferred from the characteristic chemical shift 0d 6.45) of
the vinyl hydrogen.
7.32 0m,6H),7.74±7.90 0m,4H);
13C NMR 0C6D6,
75.5 MHz) d 15.4 0q),15.42 0q),18.67 0q),18.7 0q),19.5
0s),20.0 0t),20.1 0t),20.2 0t),25.6 0q),25.7 0q),27.2 0q),
31.6 0d),31.7 0d),31.8 0d),32.0 0t),32.3 0t),32.4 0t),32.6 0t),
33.2 0t),35.0 0t),35.6 0t),36.0 0t),36.5 0t),61.0 0t),61.3 0t),
66.6 0d),66.63 0d),67.1 0d),73.1 0d),73.7 0d),73.8 0d),73.9
0d),100.6 0d),100.9 0d),101.1 0d),101.3 0d),125.5 0d),
125.7 0d),126.0 0d),127.8 0d),127.9 0d),129.7 0d),129.9
0d),130.2 0d),134.8 0s),135.1 0s),136.2 0d),136.3 0d),
136.35 0d),136.45 0d),136.47 0d),140.7 0s),141.0 0s);
exact mass 0HR electrospray) m/z calcd for
C30H4379BrNaO3Si 581.206255,found 581.206942.
Fraction 29b [two isomers,ca. 5:1 0 1H NMR)]: FTIR
21
0CH2Cl2,cast) 3515,2957,2932,2858,1695,1589 cm
1H NMR 0CDCl3,400 MHz) d 0.90±1.90 0m,20H),2.05±
2.60 0m,2H),4.65±4.85 0m,1H),5.54±5.65 0m,1H),7.25±
;
7.42 0m,6H),7.60±7.68 0m,4H);
13C NMR 0CDCl3,
100.6 MHz) d 18.3 0q),19.2 0t),20.2 0t),20.9 0q),23.5
0s),24.1 0q),24.4 0q),26.9 0q),27.0 0q),31.3 0t),33.6 0t),
27.5 0d),38.3 0d),42.0 0t),42.2 0t),67.2 0d),67.8 0d),127.4
0d),127.43 0d),127.5 0d),127.54 0d),129.4 0d),129.5 0d),
133.3 0s),134.6 0s),135.8 0d),135.86 0d),135.9 0d),138.0
0d),139.9 0s),140.4 0s),141.3 0d),203.7 0s),204.1 0s); exact
mass 0HR electrospray) m/z calcd for C26H34NaO2Si
429.222579,found 429.223320. The Z geometry for both
components of this 0minor) fraction was inferred from the
characteristic chemical shift 0d 5.54±5.65) of the vinyl
hydrogen.
3.1.25.
(3aRp,4Sp,7aSp)-3a-[2-[[(1,1-Dimethylethyl)di-
phenylsilyl]oxy]propyl]-2-ethoxyoctahydro-4-methyl-
benzofuran (32). The procedure described for 12 was
followed,using Bu 3SnH 00.20 mL,0.74 mmol),AIBN
012.5 mg,0.08 mmol),bromo acetals
31 00.2702 g,
0.4828 mmol),PhMe 035 mL),and a reaction time of
1.5 h. Flash chromatography of the crude product over silica
gel 01.5£20 cm),using 1:25 EtOAc±hexane,gave acetals
3.1.23. (1Rp,E,3Rp)-2-[2-[[(1,1-Dimethylethyl)diphenyl-
silyl]oxy]propylidene]-3-methylcyclohexanol (30). The
procedure described for 10a,b was followed,using NaBH
053.5 mg,1.41 mmol),enones 29a 0two isomers,major frac-
tion of 29) 00.3790 g,0.9320 mmol),CeCl 3´7H2O 00.498 g,
1.34 mmol),and MeOH 010 mL). Flash chromatography of
the crude product over silica gel 02£20 cm),using 1:8
EtOAc±hexane,gave alcohols 30 as a chromatographically
inseparable mixture [ca. 8:1 01H NMR)] of two isomers
1
32 00.170 g,73%) as a mixture of four isomers 0 H NMR):
4
21
FTIR 0CH2Cl2,cast) 3070,3049,2959,2931,2858 cm
1H NMR 0C6D6,400 MHz) d 0.55±2.40 0m,29H),3.25±
3.55 0m,1H),3.75±4.20 0m,3H),4.95±5.06 0m,1H),7.15±
;
7.30 0m,6H),7.70±7.90 0m,4H);
13C NMR 0C6D6,
50.3 MHz) d 13.7 0q),15.6 0q),15.8 0q),16.0 0q),16.4
0q),17.0 0s),19.39 0s),19.41 0s),20.4 0q),20.9 0t),21.0
0t),25.4 0t),25.5 0t),25.6 0q),25.9 0q),26.4 0q),26.5 0t),
27.0 0t),27.2 0q),27.3 0q),28.6 0t),29.8 0t),29.9 0t),34.5 0d),
34.7 0d),36.0 0d),36.7 0d),37.1 0t),37.7 0t),37.8 0t),37.9 0t),
41.8 0s),42.3 0s),43.0 0t),43.26 0t),43.34 0t),45.2 0t),45.6
0t),63.2 0t),63.4 0t),64.0 0t),67.9 0d),68.2 0d),68.3 0d),76.4
0d),77.5 0d),79.9 0d),80.3 0d),102.4 0d),102.8 0d),103.3
0d),127.8 0d),128.3 0d),129.8 0d),129.85 0d),129.9 0d),
130.0 0d),130.1 0d),134.3 0s),134.5 0s),134.56 0s),134.6
0s),135.16 0s),135.2 0s),136.2 0d),136.3 0d); exact mass
00.3665 g,96%): FTIR 0CH Cl2,cast) 3380,3070,3048,
2
1
2964,2930,2857 cm 21; H NMR 0CDCl3,400 MHz)
d
0.72 0d, Jˆ7.3 Hz,0.3H),0.89 0d, Jˆ7.4 Hz,2.7H),0.92±
1.70 0m,6H),1.06 0s,9H),1.22 0d,
2.08 0m,1H),2.50±2.68 0m,1H),4.08 0t,
4.73 0dq, Jˆ8.3,6.2 Hz,1H),5.44 0dd,
Jˆ6.2 Hz,3H),1.97±
Jˆ5.4 Hz,1H),
Jˆ7.9,1.8 Hz,
0.1H),5.49 0dd, Jˆ8.3,1.9 Hz,0.9H),7.30±7.50 0m,6H),
7.62±7.78 0m,4H); 13C NMR 0CDCl3,50.3 MHz) d 19.0
0q),19.2 0s),19.6 0t),25.3 0q),27.0 0q),31.2 0d),31.8 0t),
37.6 0t),66.1 0d),68.7 0d),123.8 0d),127.4 0d),127.5 0d),
129.4 0d),129.5 0d),134.7 0s),134.8 0s),135.8 0d),136.0
0d),143.6 0s); the spectrum showed some peaks from minor
isomer: d 17.5 0q),19.5 0t),25.4 0q),31.0 0d),32.8 0t),66.5
0d),68.4 0d),123.3 0d),127.4 0d),143.3 0s); exact mass 0HR
electrospray) m/z calcd for C26H36NaO2Si 431.238229,
found 431.238955.
0HR electrospray) m/z calcd for C30H44NaO3Si 503.295744,
found 503.295796.
3.1.26. 1-[(3aRp,4Sp,7aSp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanol (33a,b). The procedure
described for 13 was followed,using Bu NF 01.0 M in
4
THF,1.0 mL,1.0 mmol),acetals
32 0four isomers)
00.1615 g,0.3359 mmol) in THF 015 mL),and a reaction
time of 4 h. Flash chromatography of the crude product
over silica gel 01£20 cm),using 1:4 EtOAc±hexane,gave
alcohol 33 as two fractions, 33a 0less polar) 036.0 mg,44%)
and 33b 0more polar) 034.5 mg,42%),each fraction
consisting two isomers.
As described in Section 1,NOE measurements established
that the OH and ring CH3 groups are trans for both the major
and minor isomers of 30.
3.1.24. [[1-[(2Rp,E,6Rp)-2-(2-Bromo-1-ethoxyethoxy)-6-
methylcyclohexylidene]-2-propyl]oxy](1,1-dimethyl-
ethyl)diphenylsilane (31). The procedure described for 11
was followed,using NBS 00.4663 g,2.620 mmol),dry
CH2Cl2 012 mL),ethyl vinyl ether 00.84 mL,8.8 mmol),
Fraction 33a [0two isomers,ca. 6:1 0 1H NMR)]: FTIR
1
0CH2Cl2,cast) 3438,2960,2931 cm 21; H NMR 0C6D6,
400 MHz) d 0.73 0d, Jˆ7.0 Hz,3H),0.78 0s,1H),0.95 0d,

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3855
Jˆ6.2 Hz,3H),1.06±1.23 0m,2H),1.25 0t, Jˆ7.1 Hz,3H),
1.29±1.62 0m,4H),1.74±2.50 0m,5H),3.48 0dq,
Jˆ9.5,
7.1 Hz,1H),3.74±3.87 0m,1H),4.01 0dq,
Jˆ9.5,7.1 Hz,
7.1 Hz,1H),3.91 0t,
7.1 Hz,1H),5.13 0dd,
0C6D6,100.6 MHz) d 15.7 0q),17.0 0q),20.7 0t),26.8 0t),
30.0 0t),31.8 0q),34.2 0d),41.5 0t),41.9 0t),44.3 0s),64.1 0t),
80.5 0d),103.6 0d),206.3 0s); exact mass m/z calcd for
C14H24O3 240.17255,found 240.17227.
Jˆ3.4 Hz,1H),3.94 0dq,
Jˆ7.1,1.9 Hz,1H);
Jˆ9.6,
13C NMR
1H),4.49 0t, Jˆ2.8 Hz,1H),5.15 0dd, Jˆ5.8,4.0 Hz,1H);
13C NMR 0C6D6,100.6 MHz) 0signals for major isomer
only) d 15.6 0q),16.2 0q),21.1 0t),25.5 0t),26.3 0q),30.0
0t),36.2 0d),36.6 0t),43.0 0t),45.9 0s),63.4 0t),64.5 0d),77.7
0d),102.5 0d); exact mass
242.18820,found 242.18760.
m/z calcd for C14H26O3
3.1.29.
(1Rp,2Rp,6Rp,8Sp)-2-Methyl
7-oxatricyclo-
[6.3.1.01,6]dodecan-10-one (35). The procedure described
for 15 was followed,using ketones 34 and 340 0ca. 2:1)
016.0 mg,0.067 mmol),3 M HCl 03.3 mL),THF
Fraction 33b [0two isomers,ca. 6:1 0 1H NMR)]: FTIR
21
0CH2Cl2,cast) 3438,2961,2931,2875 cm
0C6D6,360 MHz) d 0.69 0brs,1H),0.81 0d,
;
1H NMR
Jˆ7.0 Hz,
00.68 mL),and a re¯ux time of 36 h. Flash chromatography
of the crude product over silica gel 00.6£20 cm),using
3H),0.94 0d, Jˆ6.2 Hz,3H),0.94±1.50 0m,9H),1.60±
EtOAc±hexane,gave tricyclic ketone 35 010 mg,77%):
FTIR 0CH2Cl2,cast) 2939,2867,1716 cm
21
2.17 0m,4H),2.26±2.56 0m,1H),3.49 0dq,
Jˆ9.6,7.0 Hz,
;
1H NMR
1H),3.50±3.62 0m,1H),4.01 0dq, Jˆ9.6,7.0 Hz,1H),4.14
0t, Jˆ3.5 Hz,1H),5.18 0dd, Jˆ6.8,2.2 Hz,1H); 13C NMR
0C6D6,50.3 MHz) 0signals for major isomer only) d 15.8 0q),
16.5 0q),21.0 0t),26.3 0q),26.7 0t),30.0 0t),34.4 0d),38.1 0t),
41.9 0t),44.0 0s),63.9 0t),64.7 0d),80.9 0d),103.4 0d); exact
mass m/z calcd for C14H26O3 242.18820,found 242.18790.
0CD2Cl2,400 MHz) d 0.96 0d, Jˆ7.2 Hz,3H),1.20±1.82
0m,7H),1.92±2.04 0m,1H),2.22 0d, Jˆ17.5 Hz,1H),2.28
0d, Jˆ17.5 Hz,1H),2.40±2.58 0m,3H),3.75 0dd,
Jˆ11.0,
6.0 Hz,1H),4.47 0ddd, Jˆ6.4,3.7,1.6 Hz,1H); 13C NMR
0CD2Cl2,100.6 MHz) d 16.7 0q),18.4 0t),28.1 0t),30.4 0t),
34.1 0d),39.0 0t),45.9 0s),49.6 0t),52.1 0t),73.6 0d),87.7
0d),210.4 0s); exact mass m/z calcd for C12H18O2 194.13068,
found 194.13115.
3.1.27. 1-[(3aRp,4Rp,7aRp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanone (34) from 33a (major
fraction of 33). The procedure described for 14a,b was
followed,using alcohols 33a 0two isomers,major fraction
3.1.30. Acetic acid (1Rp,5Rp,6Rp)-5-methyl-10-oxospiro-
[5.5]undec-8-en-1-yl ester (36). The procedure described
for 16 was followed,using ketone 35 04.8 mg,0.025 mmol),
of 33) 030.0 mg,0.124 mmol) in CH 2Cl2 03 mL),PCC
Ê
041 mg,0.19 mmol),powdered 4 A molecular sieves
0180 mg),CH Cl2 01.2 mL),and a reaction time of 2 h.
TsOH´H2O 04.0 mg,0.02 mmol),Ac
2O 00.04 mL,
0.4 mmol,PhH 04.5 mL),and a reaction time of 28 h.
Flash chromatography of the crude product over silica gel
00.6£25 cm),using 2:5 EtOAc±hexane,gave spiro enone 36
03.6 mg,62%): FTIR 0CH 2Cl2,cast) 2938,2868,1734,
2
Flash chromatography of the crude product over silica gel
01£15 cm),using 1:2 EtOAc±hexane,gave ketone 34 as a
single isomer 024 mg,81%): FTIR 0CH Cl2,cast) 2932,
2
1719 cm21
;
1H NMR 0C6D6,360 MHz)
d
0.69 0d,
1680 cm21
;
1H NMR 0C6D6,360 MHz)
d 0.66 0d,
Jˆ7.0 Hz,3H),0.89 0dq, Jˆ13.2,3.2 Hz,1H),1.19±1.51
0m,4H),1.21 0t, Jˆ7.1 Hz,3H),1.68±1.80 0m,1H),1.73 0s,
3H),1.83 0d, Jˆ15.5 Hz,1H),1.98±2.07 0m,1H),2.17 0d,
Jˆ15.5 Hz,1H),2.23 0dd, Jˆ13.9,4.4 Hz,1H),2.38 0dd,
Jˆ13.9,6.0 Hz,1H),3.43 0dq, Jˆ9.4,7.1 Hz,1H),3.94 0dq,
Jˆ9.4,7.1 Hz,1H),4.02 0t, Jˆ2.8 Hz,1H),5.10 0dd, Jˆ5.9,
4.5 Hz,1H); 13C NMR 0C6D6,50.3 MHz) d 15.5 0q),17.1
0q),20.7 0t),25.5 0t),30.0 0t),31.6 0q),35.7 0d),41.8 0t),43.1
0t),46.0 0s),63.6 0t),79.0 0d),102.9 0d),205.7 0s); exact
mass m/z calcd for C14H24O3 240.17255,found 240.17280.
Jˆ7.2 Hz,3H),0.87±1.02 0m,1H),1.12±1.58 0m,5H),
1.62±1.74 0m,1H),1.69 0s,3H),1.88±2.05 0m,2H),2.27
0d, Jˆ16.0 Hz,1H),2.29 0d, Jˆ16.0 Hz,1H),5.06 0dd,
0dt, Jˆ10.1,4.2 Hz,1H); 13C NMR 0C6D6,50.3 MHz) d
15.7 0q),19.5 0t),20.3 0q),25.8 0t),28.5 0t),31.1 0t),33.8
0d),42.1 0s or t),42.8 0s or t),72.9 0d),129.2 0d),146.3 0d),
168.8 0s),196.6 0s); exact mass m/z calcd for C14H20O3
236.14125,found 236.14145.
Jˆ6.5,3.5 Hz,1H),6.02 0dt,
Jˆ10.1,2.1 Hz,1H),6.19
3.1.31. (1Rp,E,3Sp)-2-[2-[[(1,1-Dimethylethyl)diphenyl-
silyl]oxy]propylidene]-3-methylcyclo-hexanol (37a,b).
)a) 4-Nitrobenzoic acid )1Rp,E,3Sp)-2-[2-[[)1,1-dimethyl-
ethyl)diphenylsilyl]oxy]propylidene]-3-methylcyclohexyl
ester. Ph3P 00.802 g,3.06 mmol) and 4-nitrobenzoic acid
00.5117 g,3.06 mmol) were added successively to a stirred
and cooled 008C) solution of allylic alcohols 30 08:1 mixture
of isomers) 00.6253 g,1.530 mmol) in dry THF 015 mL).
DEAD 00.48 mL,3.05 mmol) was added dropwise,and stir-
ring was continued for 90 min at 08C. The mixture was then
diluted with Et2O 0150 mL),washed successively with satu-
rated aqueous NaHCO3,water and brine,dried 0MgSO 4),
and evaporated. Flash chromatography of the residue over
silica gel 01.5£30 cm),using 1:15 EtOAc±hexane,gave the
crude nitrobenzoates 00.785 g),which were used directly in
next step.
3.1.28. 1-[(3aRp,4Rp,7aRp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanone (340) from 33b (minor
fraction of 33). The procedure described for 14a,b was
followed,using alcohols
010.0 mg,0.0413 mmol) in CH Cl2 01 mL),PCC 014 mg,
33b 0i.e. minor fraction)
2
Ê
0.065 mmol),powdered 4 A molecular sieves 060 mg),
CH2Cl2 00.5 mL),and a reaction time of 5 h. Flash chroma-
tography of the crude product over silica gel 00.6£15 cm),
using 1:5 EtOAc±hexane,gave ketone 340 as a single
isomer 08.6 mg,87%). Compounds 34 and 340 have
different stereochemistry at C02).
Compound 340: FTIR 0CH2Cl2,cast) 2932,2874,
1716 cm21
;
1H NMR 0C6D6,400 MHz)
d
0.73 0d,
Jˆ7.0 Hz,3H),0.87±1.01 0m,1H),1.20 0t,
Jˆ7.1 Hz,
3H),1.32±1.44 0m,3H),1.70 0s,3H),1.76±1.92 0m,1H),
1.91 0d, Jˆ16.0 Hz,1H),2.01±2.11 0m,1H),2.15 0d,
Jˆ16.0 Hz,1H),2.21 0d, Jˆ1.9 Hz,1H),2.35±2.46 0m,
)b) )1Rp,E,3Sp)-2-[2-[[)1,1-Dimethylethyl)diphenylsilyl]oxy]-
propylidene]-3-methylcyclohexanol )37a,b). KOH 00.79 g,
14 mmol) was added to a stirred solution of the above crude
1H),2.49 0dd, Jˆ13.6,7.1 Hz,1H),3.42 0dq,
Jˆ9.6,

3856
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
nitrobenzoates 0ca. 0.785 g,ca. 1.407 mmol) in MeOH
050 mL),and stirring was continued for 4 h. The solvent
was evaporated and the residue was diluted with water
050 mL) and extracted with Et2O 02£50 mL). The combined
organic extracts were washed with brine,dried 0MgSO 4),and
evaporated. Flash chromatography of the residue over silica
gel 01.5£40 cm),using 1:8 EtOAc±hexane,gave alcohols 37
as two separable isomers, 37a 0more polar) 00.299 g,48%)
and 37b 0less polar) 00.0765 g,12%).
phenylsilyl]oxy]propyl]-2-ethoxyoctahydro-4-methyl-
benzofuran (39a,b). The procedure described for 12 was
followed,using Bu 3SnH 00.15 mL,0.56 mmol),AIBN
09.0 mg,0.055 mmol),bromo acetals
38 00.194 g,
0.3466 mmol),PhMe 025 mL),and a reaction time of 1 h.
Flash chromatography of the crude product over silica gel
01.5£30 cm),using 1:40 EtOAc±hexane gave acetals 39 as
two separable isomers, 39a 0more polar) 082 mg,49%) and
39b 0less polar) 040 mg,24%),differing in stereochemistry
at C02).
Isomer 37a: FTIR 0CH2Cl2,cast) 3387,3070,3048,2931,
2857,1589 cm 21; 1H NMR 0CDCl3,400 MHz) d 1.00±1.48
Isomer 39a: FTIR 0CH2Cl2,cast) 3070,3048,2931,
;
0m,8H),1.06 0s,9H),1.23 0d,
Jˆ6.2,3H),1.78±1.98 0m,
2857 cm21
1H NMR 0C6D6,400 MHz)
d
0.82 0d,
Jˆ13.5,
2H),2.26±2.38 0m,1H),4.12 0t, Jˆ2.5 Hz,1H),4.64 0dq,
Jˆ8.3,6.2 Hz,1H),5.45 0d, Jˆ8.3 Hz,1H),7.28±7.48 0m,
6H),7.60±7.75 0m,4H); 13C NMR 0CDCl3,50.3 MHz) d
15.0 0t),19.1 0s),21.4 0q),25.0 0q),26.9 0q),29.9 0d),31.9
0t),33.5 0t),65.3 0d),74.9 0d),127.4 0d),127.5 0d),129.4 0d),
129.5 0d),133.0 0d),134.4 0s),134.5 0s),135.8 0d),135.9
0d),141.9 0s); exact mass 0HR electrospray) m/z calcd for
C26H36NaO2Si 431.238229,found 431.237534.
Jˆ7.0 Hz,3H),0.87±1.73 0m,24H),2.07 0dd,
6.2 Hz,1H),2.34 0dd,
Jˆ9.4,7.1 Hz,1H),3.96 0dq,
Jˆ14.5,5.0 Hz,1H),3.42 0dq,
Jˆ9.4,7.1 Hz,1H),4.02±
4.13 0m,2H),5.09 0dd, Jˆ6.1,2.6 Hz,1H),7.16±7.28 0m,
6H),7.75±7.90 0m,4H); 13C NMR 0C6D6,50.3 MHz) d 15.3
0q),16.9 0q),17.2 0t),19.1 0s),25.5 0q),26.7 0t),27.0 0q),
28.1 0t),31.3 0d),42.0 0t),45.6 0t),46.7 0s),63.0 0t),68.3
0d),80.6 0d),103.2 0d),127.5 0d),128.0 0d),129.5 0d),129.6
0d),134.5 0s),135.2 0s),136.1 0s); exact mass 0HR electro-
spray) m/z calcd for C30H44NaO3Si 503.295744,found
503.295658.
Isomer 37b: FTIR 0CH2Cl2,cast) 3578,3463,3070,3049,
2931,2857,1589 cm 21; 1H NMR 0CDCl3,300 MHz) d 0.72
0s,1H),0.78 0d, Jˆ7.3,3H),1.07 0s,9H),1.18±1.52 0m,
4H),1.22 0d, Jˆ7.2 Hz,3H),1.74±1.95 0m,2H),2.32±2.45
0m,1H),3.98 0t, Jˆ2 Hz,1H),4.65 0dq, Jˆ7.8,6.3 Hz,1H),
5.32 0d, Jˆ7.8 Hz,1H),7.30±7.52 0m,6H),7.60±7.80 0m,
4H); 13C NMR 0CDCl3,75.5 MHz) d 15.0 0t),19.2 0s),19.9
0q),24.9 0q),27.0 0q),29.4 0d),32.7 0t),33.3 0t),66.1 0d),
74.4 0d),127.4 0d),127.6 0d),129.6 0d),132.9 0d),134.3 0s),
134.8 0s),135.9 0d),136.1 0d),136.3 0d),141.0 0s); exact
mass 0HR electrospray) m/z calcd for C26H36NaO2Si
431.238229,found 431.237429.
Isomer 39b: FTIR 0CH2Cl2,cast) 3070,3048,2965,2931,
2857 cm21; 1H NMR 0C6D6,360 MHz) d 0.68 0d, Jˆ6.7 Hz,
3H),0.85±1.75 0m,22H),1.84±2.07 0m,2H),2.05 0dd,
Jˆ13.4,5.4 Hz,1H),2.23 0dd,
Jˆ14.6,5.4 Hz,1H),3.44
0dq, Jˆ9.5,7.0 Hz,1H),3.97 0dq,
Jˆ9.5,7.0 Hz,1H),
4.12±4.23 0m,2H),5.18 0t, Jˆ5.7 Hz,1H),7.16±7.30 0m,
6H),7.75±7.92 0m,4H); 13C NMR 0C6D6,50.3 MHz) d 15.7
0q),17.4 0q),19.4 0s),23.3 0t),26.4 0q),27.31 0q),30.6 0t),
31.5 0t),34.5 0d),39.3 0t),47.7 0s or t),49.2 0s or t),63.7 0t),
68.3 0d),80.2 0d),104.6 0d),127.8 0d),128.3 0d),129.8 0d),
129.9 0d),134.7 0s),135.6 0s),136.4 0d); exact mass 0HR
electrospray) m/z calcd for C30H44NaO3Si 503.29519,found
503.29536.
3.1.32. [[1-[(2Rp,E,6Sp)-2-(2-Bromo-1-ethoxyethoxy)-6-
methylcyclohexylidene]-2-propyl]oxy]-(1,1-dimethyl-
ethyl)diphenylsilane (38). The procedure described for 11
was followed,using NBS 00.353 g,1.98 mmol),dry CH 2Cl2
09 mL),ethyl vinyl ether 00.64 mL,6.6 mmol),alcohol 37a
0i.e. major isomer) 00.2702 g,0.6612 mmol) in CH 2Cl2
04 mL),and a reaction time of 26 h. Flash chromatography
of the crude product over silica gel 01.5£40 cm),using 1:20
EtOAc±hexane,gave bromo acetals 38 as a chromato-
graphically inseparable mixture [ca. 1:1 01H NMR)] of
3.1.34. 1-[(3aRp,4Rp,7aSp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanol (40) from 39a (major
isomer of 39). The procedure described for 13 was
followed,using Bu 4NF 01.0 M in THF,0.5 mL,
0.5 mmol),acetals 39a 0i.e. major isomer) 080 mg,
0.17 mmol) in THF 07 mL),and a reaction time of 6 h.
isomers 00.2319 g,63%): FTIR 0CH Cl2,cast) 3070,3048,
2
Flash chromatography of the crude product over silica gel
01£30 cm),using 1:4 EtOAc±hexane,gave alcohol
2964,2931,2857 cm 21; 1H NMR 0C6D6,400 MHz) d 0.66±
1.46 0m,22H),1.83±2.06 0m,2H),2.28±2.42 0m,1H),
40
032 mg,80%): FTIR 0CH 2Cl2,cast) 3439,2960,
2930 cm21
3.05±3.4 0m,4H),3.84 0t,
Jˆ1.5 Hz,0.5H),4.05 0t,
;
1H NMR 0C6D6,360 MHz)
d
0.77 0d,
Jˆ7.1 Hz,
Jˆ2 Hz,0.5H),4.58 0t, Jˆ5.4 Hz,0.5H),4.72 0dd, Jˆ6.0,
4.7 Hz,0.5H),4.74±4.88 0m,1H),5.54 0d, Jˆ8.3 Hz,0.5H),
5.60 0d, Jˆ8.3 Hz,0.5H),7.16±7.28 0m,6H),7.72±7.88 0m,
4H); 13C NMR 0C6D6,100.6 MHz) d 15.2 0q),15.4 0q),15.8
0t),15.9 0t),19.4 0s),20.6 0q),20.7 0q),25.2 0q),25.5 0q),
27.16 0q),27.2 0q),30.3 0d),30.6 0d),32.2 0t),32.3 0t),32.5
0t),32.9 0t),33.4 0t),60.6 0t),61.3 0t),65.9 0d),78.3 0d),80.0
0d),98.8 0d),100.9 0d),127.8 0d),127.9 0d),129.8 0d),130.0
0d),133.4 0d),134.7 0s),134.76 0s),134.8 0s),135.4 0d),
136.1 0d),136.2 0d),137.8 0s),139.9 0s); exact mass 0HR
electrospray) m/z calcd for C30H4379BrNaO3Si 581.206255,
found 581.205692.
Jˆ6.8 Hz,3H),1.05±1.75 0m,8H),1.15 0t,
3H),1.18 0d, Jˆ6.1 Hz,3H),1.89 0dd, Jˆ13.8,1.6 Hz,
1H),1.98 0dd, Jˆ13.8,6.0 Hz,1H),2.08 0dd,
Jˆ14.7,
Jˆ9.5,7.1 Hz,1H),
9.7 Hz,1H),2.81 0brs,1H),3.34 0dq,
3.84 0dq, Jˆ9.5,7.1 Hz,1H),4.01±4.13 0m,1H),4.29 0dd,
Jˆ5.4,4.1 Hz,1H),5.04 0dd, Jˆ6.0,1.6 Hz,1H); 13C NMR
0C6D6,50.3 MHz) d 15.3 0q),16.9 0q),18.3 0t),25.7 0q),
26.1 0t),27.4 0t),34.6 0d),38.7 0t),45.5 0s or t),47.8 0s or t),
63.0 0t),64.5 0d),80.7 0d),103.3 0d); exact mass m/z calcd
for C14H26O3 242.18820,found 242.18826.
3.1.35. 1-[(3aRp,4Rp,7aSp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanol (400) from 39b (minor
isomer of 39). The procedure described for 13 was
3.1.33.
(3aRp,4Rp,7aSp)-3a-[2-[[(1,1-Dimethylethyl)di-

D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
3857
followed,using Bu 4NF 01.0 M in THF,0.25 mL,
0.25 mmol),acetals 39b 0i.e. minor isomer) 038 mg,
0.08 mmol) in THF 04 mL),and a reaction time of 6 h.
Jˆ10.7,6.7 Hz,1H),5.14 0dd, Jˆ6.1,5.2,1H); 13C NMR
0C6D6,100.6 MHz) d 15.6 0q),17.7 0q),23.1 0t),30.6 0t),
31.3 0t),32.0 0q),35.0 0d),37.8 0t),49.5 0t),50.7 0s),63.8 0t),
81.1 0d),104.6 0d),206.8 0s); exact mass m/z calcd for
C14H24O3 240.17255,found 240.17271.
Flash chromatography of the crude product over silica gel
400
01£30 cm),using 1:4 EtOAc±hexane,gave alcohol
014.5 mg,76%). Compounds 40 and 400 have different
stereochemistry at C02).
3.1.38. (1Rp,2Sp,6Rp,8Sp)-2-Methyl-7-oxatricyclo[6.3.1.01,6]-
dodecan-10-one (42). The procedure described for 15 was
followed,using ketones 41 and 410 0ca. 2:1 mixture of
isomers) 017.5 mg,0.073 mmol),3 M HCl 03.6 mL),THF
00.75 mL),and a re¯ux time of 6 h. Flash chromatography
of the crude product over silica gel 00.6£30 cm),using 1:3
Compound 400: FTIR 0CH2Cl2,cast) 3417,2960,2930,
2874 cm21
;
1H NMR 0C6D6,360 MHz)
d
0.73 0d,
Jˆ6.2 Hz,
Jˆ6.8 Hz,3H),0.96±1.18 0m,3H),1.02 0d,
3H),1.21±1.36 0m,2H),1.25 0t,
Jˆ7.1 Hz,3H),1.48±
EtOAc±hexane,gave tricyclic ketone 42 012 mg,85%):
1.61 0m,2H),1.65 0dd, Jˆ13.3,6.1 Hz,1H),1.70 0dd,
Jˆ14.9,9.2 Hz,1H),1.86±2.10 0m,2H),2.11 0dd,
Jˆ13.2,5.4 Hz,1H),3.47 0dq, Jˆ9.5,7.1 Hz,1H),3.80±
21
FTIR 0CH2Cl2,cast) 2933,2859,1718 cm
;
1H NMR
0C6D6,360 MHz) d 0.65 0d, Jˆ6.7 Hz,3H),0.70±1.40
0m,7H),1.74±1.84 0m,3H),2.02 0dt,
1H),2.27 0d, Jˆ16.9 Hz,1H),2.66 0ddt,
Jˆ16.9,2.6 Hz,
Jˆ16.4,4.0,
3.90 0m,1H),4.00 0dq,
Jˆ9.5,7.1 Hz,1H),4.35 0dd,
Jˆ5.7 Hz,1H); 13C NMR
Jˆ10.8,6.6 Hz,1H),5.29 0t,
2.0 Hz,1H),3.54 0d,
Jˆ10.5,6.4 Hz,1H),4.20 0ddd,
13C NMR 0C6D6,100.6 MHz) d
0C6D6,50.3 MHz) d 15.7 0q),17.5 0q),23.4 0t),26.2 0q),
30.7 0t),31.5 0t),34.6 0d),39.3 0t),46.7 0s or t),49.0 0s or t),
63.8 0t),64.9 0d),80.9 0d),104.9 0d); exact mass m/z calcd
for C14H26O3 242.18820,found 242.18795.
Jˆ6.7,4.3,1.1 Hz,1H);
17.6 0q),22.7 0t),30.8 0t),32.5 0t),32.7 0t),36.7 0d),47.0
0s),49.5 0t),54.2 0t),73.5 0d),83.5 0d),207.7 0s); exact mass
m/z calcd for C12H18O2 194.13068,found 194.13072.
3.1.36. 1-[(3aRp,4Rp,7aSp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanone (41) from 40 (major
isomer series). The procedure described for 14a,b was
followed,using alcohol 40 0major isomer series) 026 mg,
0.11 mmol) in CH2Cl2 02.6 mL),PCC 036 mg,
3.1.39. Acetic acid (1Rp,5Sp,6Sp)-5-methyl-10-oxospiro-
[5.5]undec-8-en-1-yl ester (43). The procedure described
for 16 was followed,using ketone 42 011 mg,0.06 mmol),
TsOH´H2O 010 mg,0.057 mmol),Ac
2O 00.08 mL,
Ê
0.9 mmol),PhH 012 mL),and a reaction time of 23 h.
Flash chromatography of the crude product over silica gel
00.6£30 cm),using 1:6 EtOAc±hexane,gave spiro enone 43
04.5 mg,34% or 49% after correction for recovered starting
material): FTIR 0CH2Cl2,cast) 3034,2938,2863,1739,
0.17 mmol),powdered 4 A molecular sieves 0156 mg),
CH2Cl2 01 mL),and a reaction time of 3 h. Flash chromato-
graphy of the crude product over silica gel 00.6£25 cm),
using 1:2 EtOAc±hexane,gave ketone 41 020.8 mg,81%):
FTIR 0CH2Cl2,cast) 2931,2872,1715 cm
21
;
1H NMR
1678 cm21
;
1H NMR 0C6D6,360 MHz)
d
0.50 0d,
Jˆ13.7,
0C6D6,360 MHz) d 0.77 0d, Jˆ6.9 Hz,3H),0.98±1.08
Jˆ6.7 Hz,3H),0.65±1.22 0m,5H),1.27 0dt,
0m,1H),1.19 0t,
1.44±1.65 0m,2H),1.46 0dd, Jˆ13.5,1.4 Hz,1H),1.69
0s,3H),1.88±1.99 0m,1H),2.10±2.20 0m,1H),2.12 0dd,
Jˆ7.1 Hz,3H),1.26±1.39 0m,2H),
3.8 Hz,1H),1.56±1.73 0m,2H),1.58 0s,3H),2.00 0ddd,
Jˆ16.3 Hz,1H),2.29 0d,
Jˆ20,3.6,2.6 Hz,1H),2.16 0d,
Jˆ16.3 Hz,1H),4.46 0dd, Jˆ10.7,4.1 Hz,1H),5.94 0dt,
Jˆ13.5,6.2 Hz,1H),2.37 0d,
Jˆ17.5 Hz,1H),3.05 0d,
Jˆ10.2,2.3 Hz,1H),6.13 0dt,
Jˆ10.2,4.1 Hz,1H); 13C
Jˆ17.5 Hz,1H),3.38 0dq, Jˆ9.5,7.1 Hz,1H),3.89 0dq,
NMR 0C6D6,75.5 MHz) d 17.5 0q),20.5 0q),22.8 0t),25.1
0t),26.7 0t),29.1 0t),40.7 0d),43.2 0s),46.6 0t),79.3 0d),
Jˆ9.5,7.1 Hz,1H),4.52 0dd,
Jˆ6.9,5.0 Hz,1H),5.07
d
0dd, Jˆ6.2,1.4 Hz,1H); 13C NMR 0C6D6,50.3 MHz)
15.6 0q),17.3 0q),19.1 0t),28.6 0t),29.0 0t),31.3 0d or q),
31.6 0d or q),39.6 0t),45.9 0s or t),49.5 0s or t),63.3 0t),81.4
129.5 0d),146.7 0d),169.3 0s),197.4 0s); exact mass
calcd for C14H20O3 236.14125,found 236.14138.
m/z
0d),103.0 0d),206.6 0s); exact mass m/z calcd for C14H24O3
240.17255,found 240.17226.
Acknowledgements
3.1.37. 1-[(3aRp,4Rp,7aSp)-2-Ethoxyoctahydro-4-methyl-
benzofuran-3a-yl]-2-propanone (410) from 400 (minor
isomer series). The procedure described for 14a,b was
followed,using alcohol 400 0minor isomer series) 013 mg,
0.05 mmol) in CH2Cl2 01.5 mL),PCC 018 mg,0.08 mmol),
We thank the Natural Sciences and Engineering Research
Council of Canada,Merck Frosst 0Montreal),and
AnorMED 0Langley,BC) for ®nancial support,and Prof.
M. Shimizu 0Mie University,Japan) for details of the
preparation of 3.
Ê
powdered 4 A molecular sieves 080 mg),CH Cl2 00.5 mL),
2
and reaction time of 3 h. Flash chromatography of the crude
product over silica gel 00.6£30 cm),using 1:2 EtOAc±
hexane,gave ketone 410 010 mg,78%). Compounds 41
and 410 have different stereochemistry at C02).
References
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0a) Sannigrahi,M.
1
Compound 410: FTIR 0CH2Cl2,cast) 2931,1716 cm 21; H
Tetrahedron 1999, 55,9007±9071.
NMR 0C6D6,360 MHz) d 0.70 0d, Jˆ6.8 Hz,3H),0.90±
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Jˆ9.5,7.1 Hz,1H),3.93 0dq, Jˆ9.5,7.1 Hz,1H),4.26 0dd,
Jˆ13.5,5.2 Hz,1H),

3858
D. L. J. Clive, X. Huang / Tetrahedron 57 )2001) 3845±3858
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