Synthesis of bicyclo[3.2.2]nonadienones via enantioselective cyclopropanation of racemic cyclohexen-3-yl diazoacetate

Article abstract of DOI:10.1016/S0957-4166(02)00105-2

Optically active (1S,5R)-(+)-3-azabicyclo[3.2.2]non-6-en-2-one (+)-7 was synthesized via enantioselective intramolecular cyclopropanation of racemic cyclohexen-3-yl diazoacetate 10 in the presence of [Rh₂({(2S)-meox}₄] catalyst. The

Full text of DOI:10.1016/S0957-4166(02)00105-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 551–558
Synthesis of bicyclo[3.2.2]nonadienones via enantioselective
cyclopropanation of racemic cyclohexen-3-yl diazoacetate
Paul Mu¨ller,* Ge´rald Bernardinelli and Patrice Nury
Department of Organic Chemistry, University of Geneva 30, Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
Received 19 February 2002; accepted 28 February 2002
Abstract—Optically active (1S,5R)-(+)-3-azabicyclo[3.2.2]non-6-en-2-one (+)-7 was synthesized via enantioselective intramolecular
cyclopropanation of racemic cyclohexen-3-yl diazoacetate 10 in the presence of [Rh2({(2S)-meox}4] catalyst. The cyclopropanation
product (−)-9 was converted to the azide 8, which underwent successive Curtius and 3-aza-Cope rearrangements to afford 18,
which was reduced to the bicyclic azepinone (+)-7. An analogous sequence based on Cope rearrangement of the SEM-protected
enol ether 20 afforded (1S,5R)-bicyclo[3.2.2]nona-3,6-dien-2-one 22. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
in a fully stereospecific manner.10 On the grounds of
these results an approach towards chiral non-racemic
bicyclic azepinones was envisaged. Thus, the azepinone
7 should be available from azide 8 via sequential Cur-
tius- and aza-Cope rearrangement followed by reduc-
tion. The azide 8, in turn, was expected to be accessible
by eliminative opening followed by azidation (Scheme
2).
The Cope rearrangement1 and the related Claisen
rearrangement2 are both concerted suprafacial [3,3]-sig-
matropic processes.3 Owing to their high degree of
stereospecificity,4 both reactions have found numerous
synthetic applications.5 A few examples of Cope rear-
rangements containing nitrogen atoms in the rearrang-
ing framework are also known, mostly using
isocyanates;6 however, this ‘aza-Cope’ rearrangement is
mechanistically much less established, and its synthetic
potential has not been widely exploited.
The key step of the sequence is the known enantioselec-
tive cyclopropanation of racemic cyclohexen-3-yl diazo-
acetate 10.11 The intramolecular nature of the
cyclopropanation ensures the endo-orientation of the
Recently, we reported the asymmetric synthesis of (+)-
dictyopterene C% 2a7 via Cope rearrangement of an
appropriately substituted divinylcyclopropane 1a
which, in turn, was accessible by intermolecular enan-
tioselective cyclopropenation of diethoxypropyne.8 The
analogous aza-Cope rearrangement of the enantioen-
riched isocyanate 1b was expected to afford the
azepinone 2b and, subsequently, its tautomer 3. How-
ever, contrary to the rearrangement of 1a which was
fully stereospecific, that of 1b was accompanied by ca.
30% racemization (Scheme 1).9
The cause for this partial racemization could not be
established; however, it was found that the benzannu-
lated isocyanate 4, in which the vinyl group is locked in
the conformation required for Cope rearrangement,
could be converted thermally to 5 and, ultimately to 6
* Corresponding author. E-mail: paul.muller@chiorg.unige.ch
Scheme 1.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00105-2

552
P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
spontaneous recyclization to 9 upon work-up. How-
ever, ring opening occurred smoothly with
methoxymethylamine (MeMeONH·HCl) in the pres-
13
14
ence of AlMe3 and Et2NH/AlCl3 to afford the
hydroxy amides 11a and 11b in 95 and 97% yield,
respectively. Their dehydration to 13a,b was effected in
an overall yield of ca. 75% by reaction with phenyl-
selenocyanate/Bu3P15 to initially form 12a,b, followed
by oxidation of the resulting selenides with H2O2 in
pyridine. The N-methoxyamide 13a was hydrolyzed
with aqueous KOH to afford the acid 15. In contrast,
the diethylamide 12b was unreactive under these condi-
tions, while more vigorous conditions ((t-BuOK/THF/
H2O or KOH/DMSO)13 resulted in epimerization to the
exo-isomer 14. The endo-acid 15 was transformed to
the azide 8 with (PhO)2PON3,16 and the azide was
converted in refluxing toluene to the isocyanate 16. The
isocyanate was not isolated, but rearranged to the
bicyclic imine 17, which was trapped in situ with n-
Scheme 2.
carboxylate group, which is required for the
Cope-rearrangement.
2. Results and discussion
In our hands, the intramolecular cyclopropanation of
racemic 10 in the presence of [Rh2{(2S)-meox)4]12
afforded the lactone (−)-9 in 29% yield and with enan-
tiomeric excess of 94%, in good agreement with the
results reported in the literature.11 Our original plan
envisaged a one-pot conversion of the lactone 9 to the
unsaturated acid 15. However, this reaction could not
be realized, although a large number of systems were
tried, so that an indirect route had to be devised. The
lactone resisted hydrolysis under acidic and basic condi-
tions. It did react with aqueous base; however, the
resulting hydroxyacid could not be isolated owing to its
BuOH and isolated as
a
60:40 mixture of
diastereomeric N,O-acetals 18. Reduction of 18 with
Et3SiH afforded the bicyclic lactam 7 in 76% yield.
Recrystallization from hexane produced (+)-7 having
97% e.e. The absolute configuration of (+)-7 is (1S,5R)-
3-azabicyclo[3.2.2]non-6-en-4-one, attributed on the
grounds of the known absolute configuration of (−)-9
and the known stereochemical course of the reactions,
which in turn, have been established for the synthesis of
6 (Scheme 3).9
Scheme 3.

P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
553
21b occurred in satisfactory yield with CsF in HMPA
at 140°C.18 Oxidation of 21b with PDC afforded the so
far unknown optically active bicyclic ketone 22 with an
e.e. of 94%. Racemic 22 has been used as intermediate
for the synthesis of isosesquicarene19 and a formal
synthesis of sirenin.20
Since the conversion of (−)-9 to (−)-20 and the Cope
rearrangement of 20 are stereospecific, the absolute
configuration of 22 is expected to be (1S,5R). This was
verified by X-ray crystallography of the ester 23,
obtained by the reaction of 21b with (−)-camphanic
acid chloride. This establishes unambiguously the
(1S,5R)- configuration of 21a,b and also that of 22
(Fig. 1).
3. Experimental
3.1. General
See Ref. 21. All reactions were carried out under a
nitrogen atmosphere.
3.2. Synthesis of (1S,5R)-(+)-3-aza-bicyclo[3.2.2]non-6-
en-2-one (+)-7
Scheme 4.
The availability of 13a also allowed access to the hith-
erto unknown optically active bicyclo[3.2.2]nona-2,6-
diene-2-one (Scheme 4). The methoxyamide 13a was
reduced with DIBAL-H to the aldehyde 19. Wittig
reaction of the aldehyde 19 with SEM-triphenylphos-
phonium ylide17 afforded the diene 20 as an inseparable
Z/E mixture. Heating of the Z/E-mixture to 100°C in
CCl4 led to rearrangement of Z-20 to 21, which could
be separated from E-20. Rearrangement of E-20, in
turn, required heating to 190°C, and was accompanied
by partial decomposition of the starting material. Both
stereoisomers of 20 afforded the same rearrangement
product 21a, in an overall yield of 65%, indicating
E/Z-interconversion under the reaction conditions. The
deprotection of the SEM ethers 21a was initially
effected with Bu4N+F− in HMPA at 100°C in the
presence of molecular sieves. Under these conditions,
the desired alcohol 21b was isolated in poor yield. The
major product was the ether 21c. However, cleavage to
3.2.1. Intramolecular cyclopropanation of racemic cyclo-
hexen-3-yl diazoacetate 10: (1S,2R,6S,9R)-(−)-7-oxatri-
cyclo[4.3.0.02,9]nonan-8-one
9.
A
solution
of
cyclohexen-3-yl diazoacetate 810 (2.50 g, 15.0 mmol) in
CH2Cl2 (60 mL) was added at rt over 15 h to [Rh2{4S)-
meox}4] (107 mg, 0.14 mmol) in CH2Cl2 (200 mL).
After the addition, the solvent was evaporated, and the
residue was purified by flash chromatography (SiO2,
pentane/AcOEt 3:2) to afford (−)-9 (593 mg, 29%) as
colorless crystals, mp 35–37°C (lit.10 36–37°C). [h]D21=
−1.8 (c=2.50, MeOH), for 93% e.e. (Lipodex E, 120°C,
T1=10.3 min, T2=11.3 min (major enantiomer). IR
1
(CHCl3): 2955w, 1758s, 1343w, 1206s, 971m. H NMR
(500 MHz, CDCl3): 1.60–1.81 (m, 3H); 1.84–1.92 (m,
3H); 1.95–2.22 (m, 1H); 2.05–2.14 (m, 1H); 2.26 (s, 2H);
3.44 (s, 2H); 5.30–5.34 (m, 1H); 5.69–5.74 (m, 1H);
5.96–6.00 (m, 1H). 13C NMR: (125 MHz, CDCl3): 18.7
(t); 24.8 (t); 28.1 (t); 30.1 (q); 50.4 (t); 69.2 (d); 125.6
(d); 133.3(d); 166.8 (s); 200.7 (s).
Figure 1. X-Ray structure of 23.

554
P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
3.2.2. (1S,2S,6R,7R)-2-Hydroxy-N-methoxy-N-methyl-
bicyclo[4.1.0]heptane-7-carboxamide 11a. AlMe3 (2.83
mL, 2 M in heptane, 5.67 mmol) was added at rt within
20 min to N,O-dimethylhydroxylamine (422 mg, 4.33
mmol) in CH2Cl2 (18 mL). After stirring for 30 min,
compound 9 (200 mg, 1.45 mmol) was added to the
homogeneous solution, which was then stirred
overnight. After cooling to 0°C the mixture was treated
with 10% HCl (15 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with CH2Cl2
(3×20 mL). The combined organic layers were dried
(Na2SO4), evaporated, and the residue was purified by
flash chromatography (SiO2; pentane/AcOEt, 4:1) to
give 11a (274 mg, 95%) as a colorless oil, which soli-
dified upon standing, mp <25°C. [h]2D1=−122.8 (c=
1.04, CHCl3). IR (CHCl3): 3460mbr, 3022s, 2940m,
1636s, 1042m. 1H NMR (500 MHz, CDCl3, 50°C):
0.93–1.02 (m, 1H); 1.08–1.16 (m, 2H); 1.42–1.48 (m,
1H); 1.52–1.58 (m, 1H); 1.64–1.72 (m, 1H); 1.88–2.05
(m, 3H); 3.26 (s, 3H); 3.73 (s, 3H); 4.10–4.17 (m, 1H);
4.30 (s large, 1H). 13C NMR (125 MHz, CDCl3) 20.0
(5), 67 (13), 66 (5), 65 (5), 58 (100), 57 (7), 56 (13), 55
(32), 54 (5), 53 (19). HRMS: 211.1549 (C12H21O2N ,
calcd: 211.1572).
+
’
3.2.4. (1S,2R,6R,7R)-N-Methoxy-N-methyl-2-phenyl-
seleno bicyclo[4.1.0]heptane-7-carboxamide 12a. To a
mixture of 11a (166 mg, 0.83 mmol) and Bu3P (337 mg,
1.67 mmol) in refluxing THF (3.5 mL) was added
PhSeCN (303 mg, 1.67 mmol) in THF (1.0 mL) over 10
min. After heating under reflux for 14 h the volatiles
were removed by evaporation in vacuo, and the residue
was purified by FC (SiO2, pentane/AcOEt, 4:1) to
afford 12a as a yellowish oil (248 mg, 88%). [h]2D1=
−12.9 (c=2.94, CHCl3). IR (CHCl3): 3015s, 2937s,
1651s, 1477m, 1437m, 1317w. 1H NMR (500 MHz,
CDCl3, 50°C): 1.45–1.57 (m, 4H); 1.69 (dt, J=9, 3,
1H); 1.81–1.88 (m, 2H); 1.89–1.99 (m, 2H); 3.19 (s, 3H);
3.66 (s, 3H); 3.87–3.89 (m, 1H); 7.22–7.26 (m, 3H);
7.56–7.59 (m, 2H). 13C NMR (125 MHz, CDCl3): 16.6
(d); 18.4 (t); 20.6 (d); 20.7 (t); 23.4 (d); 29.4 (t); 32.8 (q);
35.4 (d); 61.2 (q); 127.0 (d); 128.9 (d); 130.4 (s); 134.0
+
’
+
’
(d); 20.2 (d); 20.3 (t); 22.5 (t); 24.6 (d); 31.9 (t); 32.9 (q);
(d); 171.8 (s). MS: 339 (M , 3), 337 (M , 1%), 334 (7),
183 (12), 182 (96), 178 (5), 177 (52), 160 (5), 159 (9), 158
(27), 157 (28), 156 (15), 155 (19), 154 (14), 153 (8), 152
(19), 151 (13), 150 (10), 123 (8), 122 (13), 121 (100), 117
(5), 116 (6), 95 (13), 94 (19), 93 (46), 92 (8), 91 (45), 88
(5), 81 (18), 80 (7), 79 (35), 78 (44), 77 (71), 74 (5), 73
(6), 69 (5), 68 (6), 67 (11), 66 (13), 65 (26), 62 (5), 60
(12), 59 (6), 58 (24), 57 (75), 56 (9), 55 (39), 53 (18), 52
(5), 51 (22), 50 (8). HRMS: 339.0750 and 337.0731
+
+
’
61.1 (q); 66.6 (d); 172.9 (s). MS: 199 (M , 1), 182 (20),
142 (9), 140 (7), 139 (72), 121 (21), 111 (10), 97 (6), 96
(5), 95 (16), 94 (11), 93 (85), 91 (16), 84 (6), 83 (12), 82
(8), 81 (23), 79 (20), 77 (21), 73 (5), 69 (9), 68 (10), 67
(32), 66 (10), 65 (9), 62 (5), 61 (100), 60 (7), 58 (12), 57
(11), 56 (7), 55 (55), 54 (7), 53 (33), 51 (7), 46 (10), 45
+
’
(7). HRMS: 199.1230 (C10H17O3N , calcd 199.1208).
78
+
80
’
3.2.3.
(1S,2S,6R,7R)-N,N-Diethyl-2-hydroxybicyclo-
(C16H21O2N Se , calcd 337.0730 and C16H21O2N Se
’
[4.1.0]heptane-7-carboxamide 11b. A solution of Et2NH
(660 mg, 9.06 mmol) in dichloroethane (DCE, 2.0 mL)
was added slowly, at 0°C to a suspension of AlCl3 (630
mg, 4.72 mmol) in DCE (2.0 mL). After stirring the
mixture for 30 min the cooling was stopped, and a
solution of 9 (500 mg, 3.62 mmol) in DCE (1.0 mL)
was added at once to the homogeneous solution. The
mixture was stirred at rt for 1.5 h, and a white precipi-
tate separated. H2O (5.0 mL) was added, the layers
were separated, and the aqueous layer was extracted
with CH2Cl2 (3×100 mL). The combined organic phases
were washed with 1 M HCl (50 mL) and H2O, then
dried (MgSO4) and evaporated. Flash chromatography
of the residue (SiO2, pentane/AcOEt, 1:1) afforded 11b
as a colorless solid (745 mg, 97%), mp 58–60°C. [h]2D1=
−117.3 (c=1.29, CHCl3). IR (CHCl3): 3352mbr, 2999m,
, calcd 339.0738).
3.2.5.
(1S,2R,6R,7R-N,N-Diethyl-2-phenylseleno-bi-
cyclo[4.1.0]heptane-7-carboxamide 12b. The procedure
described for reaction of 11a was applied to 11b (1.60
g) and afforded 12b as a yellow oil (2.17 g, 82%).
[h]2D1=−26.7 (c=0.95, CHCl3). IR (CHCl3): 3021m,
1
2400w, 1622w, 1522s, 1206s, 928w, 748s. H NMR (500
MHz, CDCl3): 1.10 (t, J=7.1, 3H); 1.14 (t, J=7.1, 3H);
1.20–1.29 (m, 1H); 1.36–1.42 (m, 1H); 1.43–1.59 (m,
4H); 1.71–1.81 (m, 2H); 1.83–1.91 (m, 1H); 3.29–3.45
(m, 4H); 3.95–3.99 (m, 1H); 7.25–7.28 (m, 3H); 7.58–
7.61 (m, 2H). 13C NMR (125 MHz, CDCl3): 13.2 (q);
14.0 (q); 15.1 (d); 19.5 (t); 20.4 (t); 21.4 (d); 22.2 (d);
29.1 (t); 36.3 (d); 39.2 (t); 41.5 (t); 127.0 (d); 128.9 (d);
+
’
130.3 (s); 133.9 (d); 169.2 (s). SM: 351 (M , 4), 349
1
+
’
1610s, 1484m, 1447m, 1265m, 1148w, 725w. H NMR
(M , 2), 195 (20), 194 (100), 166 (12), 157 (5), 154 (6),
(500 MHz, CDCl3): 0.71–0.79 (m, 1H); 0.87–0.97 (m,
1H); 0.99–1.06 (m, 1H); 1.07 (t, J=7.1, 3H); 1.14 (t,
J=7.2, 3H); 1.33–1.39 (m, 1H); 1.44–1.57 (m, 2H); 1.67
(dd, J=9.5, 8.9, 1H); 1.81–1.90 (m, 2H); 3.08 (dq,
J=6.9, 6.9, 1H); 3.25 (dq, J=7.2, 7.2, 1H); 3.59 (dq,
J=7.2, 6.9, 1H); 3.67 (dq, J=7.2, 6.9, 1H); 4.00–4.08
(m, 1H); 5.27 (d, J=11.3, 1H). 13C NMR (125 MHz,
CDCl3): 13.2 (q); 13.8 (q); 19.0 (d); 20.0 (t); 20.1 (d);
121 (15), 100 (69), 95 (5), 93 (13), 91 (11), 81 (7), 79
(15), 78 (8), 77 (19), 74 (9), 72 (56), 67 (5), 66 (5), 65 (6),
58 (7), 55 (9), 53 (6), 52 (8). HRMS: 349.1113 and
78
+
’
351.1086 (C18H25ON Se , calcd 349.1109 and
80
+
’
C18H25ON Se , calcd 351.1101).
3.2.6. (1S,6R,7R)-N-Methoxy-N-methylbicyclo[4.1.0]-
hept-2-ene-7-carboxamide 13a. To a solution of 12a (85
mg, 0.25 mmol) and pyridine (0.040 mL) in CH2Cl2 (1.2
mL) was added 30% aqueous H2O2 (0.057 mL) and the
mixture was stirred at rt for 10 min. THF (0.2 mL) was
added, and stirring was continued for 30 min until all
of 12a was consumed. After addition of Et2O (3.0 mL)
the mixture was washed with 10% Na2S2O4 (3.0 mL)
followed by H2O (2.0 mL), dried (Na2SO4), and evapo-
22.6 (t); 25.1(d); 31.8 (t); 39.9 (t); 42.3 (t); 66.7 (d);
+
’
170.1(s). MS: 211 (M , 10), 196 (8), 194 (7), 193 (27),
192 (12), 178 (5), 168 (23), 167 (31), 155 (5), 154 (47),
152 (25), 140 (5), 139 (9), 126 (13), 124 (5), 121 (10), 115
(35), 101 (5), 100 (86), 97 (5), 95 (9), 94 (7), 93 (20), 91
(10), 86 (6), 83 (7), 82 (6), 81 (24), 80 (5), 79 (12), 77
(11), 74 (15), 73 (15), 72 (86), 71 (6), 70 (7), 69 (7), 68

P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
555
rated. The residue was purified by FC (SiO2, pentane/
AcOEt 1:1) to give 13a as a colorless liquid (32 mg,
71%). [h]2D1=+124.2 (c=1.20, CHCl3). IR (CHCl3):
3016s, 2935w, 1650s, 1437m, 1213s. 1H NMR (500
MHz, CDCl3, 50°C): 1.59–1.69 (m, 2H); 1.83–1.90 (m,
1H); 1.97–2.06 (m, 3H); 2.17–2.23 (m, 1H); 3.18 (s, 3H);
3.71 (s, 3H); 5.70 (dt, J=10.1, 4.1, 1H); 5.83–5.87 (m,
1H). 13C NMR (125 MHz, CDCl3): 15.8 (d); 16.5 (t);
77), 192 (25), 178 (23), 164 (16), 151 (15), 124 (7), 124
(12), 121 (25), 118 (6), 115 (8), 102 (7), 100 (82), 94 (18),
93 (36), 92 (20), 91 (73), 85 (15), 84 (6), 83 (9), 82 (13),
80 (9), 79 (34), 78 (15), 77 (55), 74 (13), 72 (9), 72 (100),
68 (16), 68 (11), 66 (12), 65 (25), 58 (26), 56 (25), 55
(15), 53 (21), 52 (9), 51 (14). HRMS: 193.1461
+
’
(C12H19ON , calcd 193.1467).
16.9 (d); 21.9 (t); 25.9 (d); 33.1 (q); 60.9 (q); 122.1 (d);
3.2.9. (1S,6R,7R)-Bicyclo[4.1.0]hept-2-ene-7-carboxylic
acid 15. The amide 13a (20 mg, 0.11 mmol) was heated
under reflux with KOH (31 mg, 0.55 mmol) in H2O (1.0
mL) for 4 h. The mixture was cooled to rt, then
extracted with CH2Cl2 (3.0 mL). The aqueous layer was
acidified with 1 M HCl and extracted with AcOEt
(5×10 mL). The organic layer was dried (MgSO4) and
evaporated to afford 15 as a colorless solid (14 mg,
92%), mp 83–85°C (from MeOH). [h]2D1=+359.8 (c=
0.57, CHCl3). IR (CHCl3): 2933m, 1702s, 1441m,
1228m, 1115w, 896m, 705s. 1H NMR (500 MHz,
CDCl3): 1.59–1.65 (m, 1H); 1.72 (dt, J=8.5, 3.7, 1H);
1.79 (dd, J=8.9, 8.2, 1H); 1.83–1.90 (m, 1H); 1.92–2.01
(m, 3H); 5.66–5.71 (m, 1H); 5.77–5.82 (m, 1H). 13C
NMR (125 MHz, CDCl3): 15.7 (t); 17.4 (d); 17.9 (d);
+
’
128.2 (d); 171.2 (s). MS: 181 (M , 17), 150 (25), 121
(31), 120 (6), 103 (15), 94 (12), 93 (100), 92 (11), 91 (74),
89 (6), 81 (6), 79 (36), 78 (13), 77 (70), 73 (7), 67 (6), 66
(5), 65 (21), 63 (5), 61 (11), 58 (18), 55 (36), 53 (12), 52
+
’
(6), 51 (11). HRMS: 181.1098 (C10H15O2N , calcd
181.1103).
3.2.7. (1S,6R,7R)-N,N-Diethyl-bicyclo[4.1.0]hept-2-ene-
7-carboxamide 13b. To a solution of 12b (115 mg, 3.28
mmol) and pyridine (0.5 mL) in CH2Cl2 (15 mL) was
added rapidly 30% H2O2 (0.75 mL) at rt after stirring
the mixture for 5 min. THF (2.5 mL) was added, and
stirring was continued for 30 min, when all of 12b had
reacted. Et2O (35 mL) was added, and the solution was
washed with 10% Na2S2O4 (10 mL) and H2O (10 mL),
then dried (Na2SO4) and evaporated. FC of the residue
(SiO2, pentane/AcOEt, 1:1) gave 13b as a colorless oil
(49 mg, 77%). [h]D21=+48.8 (c=0.66, CHCl3). IR
(CHCl3): 3001m, 1623s, 1435m, 1263w, 1140w, 776m.
1H NMR (500 MHz, CDCl3): 1.06 (t, J=7.1, 3H); 1.17
(t, J=7.1, 3H); 1.58–1.62 (m, 2H); 1.75 (dd, J=9.1, 8.2,
1H); 1.78–1.97 (m, 3H); 2.17–2.24 (m, 1H); 3.24 (dq,
J=6.9, 6.9, 1H); 3.39–3.49 (m, 2H); 3.58 (dq, J=7.2,
7.2, 1H); 5.63–5.68 (m, 1H); 5.90–5.95 (m, 1H). 13C
NMR (125 MHz, CDCl3): 12.8 (q); 13.9 (q); 15.1 (d);
21.6 (t); 26.6 (d); 120.5 (d); 130.2 (d); 176.5 (s). MS: 138
+
’
(M , 48), 123 (5), 120 (10), 110 (9), 97 (18), 95 (6), 94
(9), 93 (100), 92 (26), 91 (86), 84 (13), 79 (44), 78 (23),
77 (76), 70 (5), 69 (6), 68 (5), 67 (11), 66 (35), 65 (27),
63 (9), 60 (40), 57 (9), 55 (12), 53 (17), 52(8), 51 (19), 50
+
’
(7), 45 (10). HRMS: 138.0685 (C8H10O2 , calcd
138.0681). (35), 65 (27), 63 (9), 60 (40), 57 (9), 55 (12),
53 (17), 52(8), 51 (19), 50 (7), 45 (10). HRMS: 138.0685
+
’
(C8H10O2 , calcd 138.0681).
3.2.10. (1S,6R,7R)-Bicyclo[4.1.0]hept-2-ene-7-carbonyl
azide 8. To 15 (96 mg, 0.70 mmol) in toluene (7 mL)
was added Et3N (0.39 mL, 2.78 mmol) and
(PhO)2PON3 (0.30 mL, 1.39 mmol) at 0°C. After stir-
ring for 30 min at rt, the mixture was cooled to 0°C,
and satd NaHCO3 (2.0 mL) and Et2O (4.0 mL) were
added. The aqueous layer was separated and extracted
with Et2O (3×8 mL), the organic layer was dried
(MgSO4) and evaporated. Flash chromatography of the
residue (SiO2, pentane/AcOEt, 4:1) gave 8 ( 84 mg,
76%) as light-yellow oil. [h]2D1=+89.6 (c=0.317,
CHCl3). IR (CHCl3): 3024w, 2150m, 1689s, 1660s,
17.0 (t); 17.2 (d); 21.9 (t); 27.3 (d); 39.1 (t); 41.7 (t);
+
’
123.0 (d); 127.1 (d); 169.4 (s). MS: 194 (10), 193 (M ,
67), 192 (21), 178 (21), 164 (6), 152 (5), 126 (7), 124 (5),
121 (21), 120 (15), 119 (6), 115 (6), 101 (6), 100 (81), 94
(8), 93 (31), 92 (20), 91 (71), 87 (5), 86 (10), 84 (6), 82
(9), 81 (10), 80 (9), 79 (31), 78 (14), 77 (53), 74 (13), 73
(6), 72 (100), 70 (6), 68 (6), 67 (9), 66 (12), 65 (26), 63
(6), 58 (26), 56 (15), 55 (25), 54 (6), 53 (21), 52 (9), 51
+
’
(14). HRMS: 193.1461 (C12H19ON , calcd 193.1467).
3.2.8. (1S,6R,7S)-N,N-Diethyl-bicyclo[4.1.0]hept-2-ene-
7-carboxamide 14. To the diethylamide 13b (40 mg, 0.21
mmol) in THF (2.0 mL) was added, successively H2O
(7.5 mL, 0.41 mol) and tert-BuOK (186 mmol, 1.66
mmol). The mixture was stirred vigorously at rt for 2 h.
It was acidified to pH 2–3, and was then extracted with
AcOEt (3×10 mL). The combined organic phases were
washed with H2O (10 mL) and satd NaCl (10 mL),
dried (Na2SO4) and evaporated. Purification of the
residue by FC (SiO2, pentane/AcOEt, 1:1) yielded 14 as
a colorless oil (37 mg, 92%). [h]2D1=+140.1 (c=2.03,
CHCl3). IR (CHCl3): 3006m, 1633s, 1445m, 1264w,
1
1220s, 740m. H NMR (500 MHz, CDCl3): 1.79 (dq,
J=7.9, 2.8, 1H); 1.85 (dd, J=8.5, 8.5, 1H); 1.91–1.99
(m, 2H); 2.01–2.06 (m, 1H); 2.07–2.12 (m, 2H); 5.69–
5.73 (m, 1H); 5.91–5.96 (m, 1H). 13C NMR (125 MHz,
CDCl3): 15.4 (t); 19.5 (d); 20.5 (d); 21.5 (t); 29.5 (d);
+
’
119.7 (d); 130.9 (d); 176.8 (s). MS: 163 (M , 1), 135
(26), 134 (39), 121 (15), 120 (38), 118 (7), 116 (5), 108
(7), 107 (62), 106 (41), 93 (27), 92 (41), 91 (84), 90 (9);
81 (5); 80 (31); 79 (100), 78 (24); 77 (66); 67 (9); 66 (15);
65 (31); 64 (5); 63 (12); 62 (5), 56 (7); 55 (9), 54 (12); 53
(27); 52 (51); 51 (36), 50 (17). HRMS: 163.0745
1
+
’
1135w, 757m. H NMR (500 MHz, CDCl3): 1.11 (t,
(C8H9O2N3 , calcd 163.0743).
J=7.1, 3H); 1.21 (t, J=7.1, 3H); 1.61–1.69 (m, 1H);
1.71–1.80 (m, 2H); 1.88–1.97 (m, 2H); 2.00–2.05 (m,
1H); 3.30–3.45 (m, 4H); 5.51–5.57 (m, 1H); 5.99–6.03
(m, 1H). 13C NMR (125 MHz, CDCl3): 13.3 (q); 14.9
3.2.11. (1S,4S,5R)- and (1S,4R,5R)-4-Butoxy-3-aza-
bicyclo[3.2.2]non-6-en-2-one 18. The azide 8 (80 mg,
0.49 mmol) and n-butanol (36 mg, 0.49 mmol) in
toluene (6.0 mL) was heated under reflux for 15 min.
The mixture was rapidly cooled with an ice-bath. The
(q); 17.6 (t); 20.0 (d); 20.9 (t); 23.0 (d); 24.1 (d); 40.8 (t);
+
’
42.1 (t); 124.5 (d); 126.7 (d); 171.1 (s). MS: 193 (M ,

556
P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
solvent was evaporated in vacuo and the residue was
purified by FC (SiO2, pentane/AcOEt, 1:1) to afford 18
(71 mg, 65%) as a 60:40 mixture of diastereomers as a
semi-solid, yellowish oil. IR (CHCl3): 3390w, 2960m,
1675s, 1450m, 1080m, 970w. 1H NMR (500 MHz,
CDCl3): 0.91 (t, J=7.4, 3H); 0.93 (t, J=7.3, 3H);
1.32–1.45 (m, 4H); 1.52–1.62 (m, 4H); 1.69–1.95 (m,
5H); 2.05–2.23 (m, 2H); 2.32–2.41 (m, 1H); 2.74–2.79
(m, 1H); 3.0–3.08 (m, 1H); 3.19–3.25 (m, 2H); 3.37–3.43
(m, 1H); 3.48–3.54 (m, 1H); 3.65 (dd, J=6.6, 6.6, 1H);
4.47–4.50 (m, 1H); 4.52–4.54 (m, 1H); 5.65 (s large,
1H); 5.83 (s large, 1H); 6.16–6.34 (m, 3H). 13C NMR
(125 MHz, CDCl3): 13.7 (q); 19.2 (t); 19.3 (t); 20.7 (t);
23.9 (t); 24.3 (t); 24.7 (t); 31.7 (t); 31.8 (t); 35.9 (d); 36.0
(d); 43.4 (d); 43.5 (d); 67.5 (t); 67.6 (t); 86.3 (d); 88.6 (d);
The residue was purified by flash chromatography
(SiO2, pentane/AcOEt, 4:1) to yield 19 as a colorless oil
(187 mg, 81%). [h]D21=+143 (c=0.98, CHCl3). IR
1
(CHCl3): 2932m, 1721w, 1685s, 1129w, 702m. H NMR
(500 MHz, CDCl3): 1.65–1.77 (m, 2H); 1.78–1.85 (m,
1H); 1.91–2.02 (m, 2H); 2.03–2.10 (m, 1H); 2.19–2.27
(m, 1H); 5.73–5.78 (m, 1H); 5.89–5.94 (m, 1H); 9.23 (d,
J=7.1, 1H). 13C NMR (125 MHz, CDCl3): 16.8 (t);
19.7 (d); 22.6 (d); 22.8 (t); 34.9 (d); 122.3 (d); 127.7 (d);
+
’
203.3 (d). MS: 122 (M , 16), 104 (8), 103 (5), 93 (16),
92 (9), 91 (35), 80 (9), 79 (43), 78 (100), 77 (50), 66 (6),
65 (11), 53 (6), 52 (5), 51 (10). HRMS: 122.0731
+
’
(C8H10O , calcd 122.0732).
3.3.2. (Z/E)-(1S,6R,7R)-[2-(2-Bicyclo[4.1.0]hept-2-en-7-
yl-vinyloxy)-ethyl]trimethylsilane 20a and 20b. A solu-
tion of KHMDS in toluene (5.8 mL, c=0.5 M, 2.89
mmol) was added dropwise to 2-(trimethylsilyl)-
ethoxymethylenetriphenylphosphonium chloride (1.35
mg, 3.14 mmol) suspended in Et2O (9.0 mL) at 0°C.
The solution was stirred for 4–5 min at this tempera-
ture, after which the aldehyde 19 (187 mg, 1.53 mmol)
in Et2O (4.0 mL) was added. After stirring for 30 min
at 0°C, then 1 h at rt, the mixture was hydrolyzed with
satd NH4Cl (10 mL). The aqueous layer was extracted
with Et2O (3×20 mL), the organic phase was dried
(MgSO4) and evaporated. The residue was purified by
flash chromatography (SiO2, pentane/AcOEt, 9:1) to
afford an unseparable 55:45 Z/E mixture of olefins 20
(214 mg, 60%). The pure (Z)-isomer 20a was isolated
by flash chromatography (see below) after partial rear-
rangement of the Z/E mixture at 100°C. Data: [h]2D1=+
78.1 (c=2.66, CHCl3) for 94% e.e. IR (CHCl3): 2925m,
1654m, 1367m, 1075s, 862m. 1H NMR (500 MHz,
CDCl3): 0.02 (s, 9H); 0.97–1.01 (m, 2H); 1.38–1.43 (m,
1H); 1.48–1.52 (m, 1H); 1.66–1.81 (m, 3H); 1.97–2.04
(m, 2H); 3.80–3.85 (m, 2H); 4.11 (dd, J=9.15, 6.3, 1H);
5.64–5.68 (m, 1H); 5.82–5.86 (m, 1H); 6.04 (dd, J=6.3,
0.95, 1H). 13C NMR (125 MHz, CDCl3): −1.39 (q); 15.1
129.6 (d); 130.3 (d); 131.0 (d); 132.4 (d); 173.4 (s); 174.2
+
’
(s). MS: 209 (M , 1), 151 (5), 149 (23), 125 (6), 123 (6),
122 (5), 121 (5), 119 (8), 113 (5), 112 (5), 111 (10), 110
(9), 109 (36), 108 (8), 107 (5), 105 (13), 99 (6), 97 (14),
96 (10), 95 (23), 94 (8), 93 (7), 92 (8), 91 (21), 85 (18),
84 (12), 83 (21), 82 (11), 81 (39), 80 (100), 79 (80), 78
(11), 77 (28), 73 (7), 72 (7), 71 (37), 70 (12), 69 (26), 68
(24), 67 (18), 66 (8), 65 (9), 59 (6), 57 (51), 56 (79), 55
(46), 54 (8), 53 (18), 52 (11), 51 (17), 50 (9), 46 (8).
+
’
SM-HR: 209.14150 (C12H19O2N , calcd 209.14158).
3.2.12. (1S,5R)-3-Aza-bicyclo[3.2.2]non-6-en-2-one 7. To
a solution of 18 (56 mg, 0.27 mmol and Et3SiH (98 mg,
0.84 mmol) in CH2Cl2 (3.0 mL) was added CF3COOH
(0.2 mL) dropwise at rt. After the addition, the solution
was stirred for 15 min, and then poured on a mixture of
ice and satd NaHCO3. The aqueous layer was extracted
with CH2Cl2 (3×12 mL) and the organic phase was
washed with satd NaCl (6.0 mL), dried (Na2SO4) and
evaporated. Treatment of the residue with pentane (0.5
mL) afforded colorless crystals of 7 (28 mg, 76%), mp
127–130°C (from hexane). [h]2D1=−234.5 (c=0.81,
CHCl3) for 88% e.e. (HPLC: Chiracel OD-H; n-hexane:
i-propanol=10/1; 0.5 mL/min; T1: 21.8 min (major
enantiomer), T2: 36.5 min GC: 85% e.e. (b-dex 120 to
130°; T1: 60.5 min (major enantiomer), T2: 74.9 min).
IR (CHCl3): 3630w, 3019w, 1651s, 1430w, 756s. 1H
NMR (500 MHz, CDCl3): 1.68–1.77 (m, 2H); 1.84–1.90
(m, 1H); 2.15–2.21 (m, 1H); 2.56–2.62 (m, 1H); 3.03–
3.07 (m, 1H); 3.24–3.27 (m, 2H); 5.40 (s large, 1H);
6.17–6.24 (m, 2H). 13C NMR (125 MHz, CDCl3): 24.4
(d); 16.9 (t); 17.7 (d); 18.5 (t); 20.9 (d); 22.8 (t); 69.7 (t);
+
’
102.5 (d); 124.9 (d); 125.9 (d); 146.1 (d). MS: 236 (M ,
0.5), 208 (15), 129 (5), 118 (15), 117 (18), 113 (11), 92
(7), 91 (7), 75 (12), 74 (11), 73 (100), 45 (6). HR-MS:
+
’
208.12990 (C14H24OSi –C2H4, calcd 208.12834).
1
Data for E-20: H NMR (500 MHz, CDCl3): 0.03 (s,
(t); 25.6 (t); 31.3 (d); 43.1 (d); 49.5 (t); 131.0 (d); 132.4
9H); 0.92–0.98 (m, 2H); 1.38–1.43 (m, 1H); 1.48–1.52
(m, 1H); 1.61 (q, J=8.3, 1H); 1.66–1.80 (m, 2H);
1.97–2.04 (m, 2H); 3.73 (dt, J= 7.9, 1, 2H); 4.56 (dd,
J=12.6, 8.15 (1H); 5.66–5.71 (m, 1H); 5.85–5.91 (m,
1H); 6.35 (d, J=13, 1H). 13C NMR (125 MHz, CDCl3):
−1.41 (q); 14.5 (d); 16.6 (t); 17.1 (d); 17.8 (t); 22.8 (t);
23.2 (d); 66.9 (t); 100.6 (d); 124.8 (d); 125.9 (d); 147.0
(d).
+
’
(d); 174.3 (s). MS: 137 (M , 16), 95 (7), 94 (22), 93 (9),
92(5), 91 (9), 81 (9), 80 (35), 79 (100), 78 (11), 77 (29),
69 (45), 66 (10), 65 (7), 57 (8), 55 (5), 54 (5), 53 (12),
52(8), 51 (40), 50 (19), 45 (58). HRMS: 137.0837
+
’
(C8H11ON , calcd 137.0841).
3.3. Synthesis of (1S,5R)-bicyclo[3.2.2]nona-3,6-dien-2-
one 22
3.3.1. (1S,6R,7R)-Bicyclo[4.1.0]hept-2-ene-7-carboxalde-
hyde 19. DIBAL-H (1 M in THF, 3.80 mL, 3.78 mmol)
was added dropwise to 13a (343 mg, 3.78 mmol) in
THF (23 mL) at −78°C. After stirring for 3 h at −78°C
the solution was hydrolyzed with satd NH4Cl. The
aqueous phase was extracted with Et2O (3×20 mL) and
the organic phase was dried (Na2SO4) and evaporated.
3.3.3.(1S,2R,5R)-[2-(Bicyclo[3.2.2]nona-3,6-dien-2-yloxy)-
ethyl]-trimethyl-silane 21a. The Z/E mixture of 20a and
20b (90 mg, 0.38 mmol) in anhydrous CCl4 (2.0 mL)
was heated to 100°C for 3 h. The solvent was evapo-
rated, and the residue was purified by flash chromatog-
raphy (SiO2, pentane/CH2Cl2, 9:1), then pentane
(AcOEt, 9:1) to afford 21a (36 mg, 40%). The Z-isomer

P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
557
20a (46 mg; 51%) was recovered, characterized and
transformed to 21a upon heating to 190°C for 7 h in a
sealed tube to afford 21a in 49% yield (with respect to
20a). Total yield with respect to 20a and 20b 65%.
Data: [h]2D1=+82.9 (c=0.625, CHCl3). IR (CHCl3):
2920w, 1630m, 1357m, 1080s, 834w. 1H NMR (500
MHz, CDCl3): 0.01 (s, 9H); 0.92–0.97 (m, 2H); 1.55–
1.64 (m, 2H); 1.77–1.88 (m, 2H); 2.71–2.77 (m, 1H);
2.98–3.04 (m, 1H); 3.55 (q, J=8.5, 1H); 3.65 (q, J=8.6,
1H); 3.66–3.69 (m, 1H); 5.43 (ddd, J=11.1, 4, 3.5, 1H);
5.90 (dd, J=8.1, 7.3, 1H); 6.14 (ddd, J=9.8, 8.3, 1.3,
1H); 6.46 (dd, J=8.3, 7.8, 1H). 13C NMR (125 MHz,
CDCl3): −1.39 (q); 18.6 (t); 21.1 (t); 27.8 (t); 33.0 (d);
(3.0 mL) and extracted with Et2O (5×10 mL). The
organic layer was washed with saturated NaCl (3.0
mL), dried (MgSO4, and evaporated. The residue was
purified by flash chromatography (SiO2, pentane/
AcOEt, 9:1) to afford 21c (25 mg, 89%).
3.3.5. (1S,5R)-Bicyclo[3.2.2]nona-3,6-dien-2-one 22. To
a solution of 21b (20 mg, 0.15 mmol) in anhydrous
DMF (1.0 mL) was added PDC (138 mg, 0.37 mmol).
The mixture was stirred for 1 h at rt then diluted with
H2O (5.0 mL) and extracted with Et2O (5×10 mL). The
combined organic layers were washed with satd NaCl,
dried (Na2SO4) and evaporated. The residue was
purified by flash chromatography (SiO2, pentane/
AcOEt, 9:1) to afford the ketone 22 as a colorless oil
(17 mg, 86%). [h]2D1=−99.8 (c=0.50, CHCl3) for 94%
e.e. (HPLC, Chiracel OD-H, hexane/2-propanol, 25:1,
0.5 mL/min, T1: 13.3 min (major enantiomer), T2: 15.1
min). IR (CHCl3): 3001w, 1660s, 1218w, 1160w, 794m,
35.6 (d); 65.9 (t); 78.6 (d); 127.6 (d); 128.5 (d); 135.5 (d);
+
’
139.2 (d). MS: 236 (M , 1), 208 (9), 119 (7), 118 (14),
117 (16), 92 (7), 91 (14), 75 (11), 74 (9), 73 (100).
+
’
HR-MS: 236.16000 (C14H24OSi , calcd 236.15964).
3.3.4. (1S,2S,5R)-Bicyclo[3.2.2]nona-3,6-dien-2-ol 21b
and
(1S,2S,5R)-2-ethoxybicyclo[3.2.2]nona-3,6-diene
1
21c. Method A: The silyl ether 21a (50 mg, 0.21 mmol)
and tetra-n-butylammonium fluoride (165 mg, 0.63
mmol) in HMPA (1.5 mL) was stirred at 100°C for 12
674s. H NMR (500 MHz, CDCl3): 1.68–1.76 (m, 1H);
1.81–1.87 (m, 1H); 1.91–1.99 (m, 2H); 3.31–3.36 (m,
1H); 3.48–3.53 (m, 1H); 5.75 (dd, J=11, 2, 1H); 6.04
(dd, J=7.9, 7.9, 1H); 6.51 (dd, J=7.9, 7.9, 1H); 6.7.04
(dd, J=11, 8.6, 1H). 13C NMR (125 MHz, CDCl3):
,
h in the presence of 4 A molecular sieves. The mixture
was treated with H2O (5 mL) and the aqueous layer
was extracted with Et2O (5×10 mL). The residue
obtained after drying (MgSO4) and evaporation was
purified by flash chromatography (SiO2, pentane/
AcOEt, 9:1) to afford the alcohol 21b (8.0 mg, 28%)
and the ethyl ether 21c (22 mg, 64%).
21.2 (t); 26.9 (t); 37.0 (d); 52.3 (d); 126.6 (d); 129.9 (d);
+
’
138.6 (d); 153.4 (d); 198.6 (s). MS: 134 (M , 35%), 133
(17), 119 (5), 116 (9), 115 (7), 106 (11), 105 (40), 103 (9),
93 (6), 92 (62), 91 (100), 80 (14), 79 (62), 78 (90), 77
(44), 66 (7), 65 (16), 63 (5), 57 (8), 56 (5), 55 (22), 53
+
’
(14), 52 (22), 51 (21). HRMS: 134.07474 (C9H10O ,
Data for 21b: colorless oil. [h]2D1=+39.0 (c=0.96,
CHCl3) for 94% e.e. IR: (CHCl3): 3550wbr, 2990s,
1550w, 1221s, 990w, 790s. 1H NMR (500 MHz,
CDCl3): 1.55–1.65 (m, 2H); 1.80–1.89 (m, 2H); 2.71–
2.76 (m, 1H); 2.94–3.00 (m, 1H); 3.95–4.00 (m, 1H);
5.38–5.42 (m, 1H); 5.87–5.91 (m, 1H); 6.09–6.13 (m,
1H); 6.52–6.57 (m, 1H). 13C NMR (125 MHz, CDCl3).
calcd 134.07317).
3.3.6. (1S,2S,5R)-Bicyclo[3.2.2]nona-3,6-dien-2yl [(1S)-
3-oxo-4,7,7-trimethyl-2-oxybicyclo[2.2.1]heptene-1]-car-
boxylate 23. (−)-Camphanic acid chloride (56 mg, 0.26
mmol) was added at 0°C to 21b (27 mg, 0.20 mmol) in
dry pyridine (2.0 mL). After 2 h of stirring at rt, the
solvent was evaporated under reduced pressure, and the
residue was purified by flash chromatography (SiO2,
pentane/AcOEt, 9:1) to afford 23 as a colorless solid
(52 mg, 83%), mp 107–109°C (from hexane/CH2Cl2),
[h]2D1=+125.9 (c=0.49, CHCl3). IR (CHCl3): 2948w,
1780s, 1730s, 1450w, 1261m, 1170w, 1112m, 1055s,
20.7 (t); 27.2 (t); 33.3 (d); 39.1 (d); 71.5 (d); 127.8 (d);
+
’
129.7 (d); 135.7 (d); 141.8 (d). MS: 136 (M , 7%), 117
(4), 107 (4), 100 (23), 91 (4), 79 (4). HRMS: 136.08700
+
’
(C9H12O , calcd 136.08882).
Data for 21c: colorless oil, [h]2D1=+10.9 (c=0.4, CHCl3)
for 94% e.e. IR (CHCl3): 3017w, 1212m, 748m, 668w.
1H NMR (500 MHz, CDCl3): 1.18 (t, J=6.95, 3H);
1.55–1.61 (m, 2H); 1.75–1.86 (m, 2H); 2.69–2.74 (m,
1H); 2.98–3.04 (m, 1H); 3.49 (dq, J=7, 9.1, 1H); 3.60–
3.68 (m, 2H); 5.38–5.42 (m, 1H); 5.88 (dd, J=7.5, 8.2,
1H); 6.10–6.15 (m, 1H); 6.44 (dd, J=7.9, 8.2, 1H). 13C
NMR (125 MHz, CDCl3), 15.8 (q); 21.0 (t); 27.8 (t);
1
913m. H NMR (500 MHz, CDCl3): 0.93 (s, 3H); 1.02
(s, 3H); 1.08 (s, 3H); 1.55–1.75 (m, 3H); 1.80–1.90 (m,
3H); 1.95–2.05 (m, 1H); 2.33–2.41 (m, 1H); 2.78–2.84
(m, 1H); 2.93–2.99 (m, 1H); 5.29–5.35 (m, 2H); 5.86
(dd, J=7.9, 7.9, 1H); 6.24 (dd, J=9.5, 8.5, 1H); 6.45
(dd, J=7.9, 7.9, 1H). 13C NMR (125 MHz, CDCl3): 9.7
(q); 16.7 (q); 16.9 (q); 20.8 (t); 27.2 (t); 29.0 (t); 30.4 (t);
32.9 (d); 35.9 (d); 54.0 (s); 54.7 (s); 74.2 (d); 91.2 (s);
33.1 (d); 35.5 (d); 64.2 (t); 78.9 (d); 127.6 (d); 128.4 (d);
+
’
135.8 (d); 139.3 (d). MS: 165 (10), 164 (M , 80), 139
(10), 136 (15); 135 (42), 120 (22), 118 (73), 117 (81), 110
(10), 107 (31), 103 (19), 92 (58), 91 (100), 95 (18), 80
124.7 (d); 127.8 (d); 138.4 (d); 139.8 (d); 166.7 (s); 178.2
(s) MS: 316 (M , 6%), 182 (7); 180 (8); 179 (7), 171 (6);
+
’
(70), 78 (28), 67 (18), 65 (16), 57 (52), 55 (25). HR-MS:
167 (11); 165 (5); 164 (8); 155 (8); 153 (7); 149 (15); 139
(6); 137 (10); 136 (24); 135 (24); 125 (30); 124 (31); 121
(5); 119 (22); 118 (71); 117 (22); 116 (5); 111 (8); 110 (5);
109 (42); 108 (7); 107 (15); 97 (40); 96 (7); 95 (9); 93
(13); 92 (14); 91 (69); 85 (7); 84 (9); 83 (100); 82 (11); 81
(10); 79 (13); 78 (5); 77 (7), 71 (10); 70 (6); 69 (19); 68
+
’
164.12053 (C11H16O , calcd 164.12012).
Method B: A solution of the silyl ether 21a (50 mg, 0.21
mmol) in anhydrous HMPA (1.0 mL) was added to a
mixture of CsF (510 mg, 3.36 mmol) in anhydrous
HMPA (0.5 mL). The mixture was stirred at 140°C for
30 h. After cooling, the mixture was poured into H2O
(5); 67 (17); 65 (14); 57 (25); 56 (10); 55 (71); 53 (6); 45
+
’
(19). HRMS: 316.16971 (C19H24O4 , calcd 316.16746).

558
P. Mu¨ller et al. / Tetrahedron: Asymmetry 13 (2002) 551–558
Hudlicky, T.; Fan, R.; Reed, J. F.; Gadamasetti, K. G.
3.4. X-Ray crystal structure of 23
Org. React. 1992, 41, 1–133.
C19H24O4; Mr=316.4; v=0.09 mm−1, dx=1.267 g cm−3,
monoclinic, P21, Z=2, a=6.7858(6), b=10.6555(10),
c=11.4752(13) A, i=91.865(12)°, V=829.3(1) A ; cell
dimensions and intensities were measured at 200 K on
a Stoe IPDS diffractometer. Full-matrix least-squares
refinement based on F using weight of 1/(|2(Fo)+
0.0002(Fo )) gave final values R=ꢀR=0.029 and S=
1.50(4) for 252 variables and 2081 contributing
reflections.
6. (a) Doering, W.v. E.; Goldstein, M. Tetrahedron 1959, 5,
53–69; (b) Sasaki, T.; Eguchi, G. D.; Ohno, M. J. Org.
Chem. 1972, 37, 466–469; (c) Paquette, L. A.; Ewing, G.
D. J. Am. Chem. Soc. 1978, 100, 2908–2909; (d) Vogel, E.
Angew. Chem. 1962, 74, 829–839; (e) Vogel, E. Angew.
Chem., Int. Ed. Engl. 1963, 2, 1–11.
3
,
,
2
7. Imogai, H.; Bernardinelli, G.; Gra¨nicher, C.; Moran, M.;
Rossier, J.-C.; Mu¨ller, P. Helv. Chim. Acta 1998, 81,
1754–1764.
8. (a) Doyle, M. P.; Protopopova, M.; Mu¨ller, P.; Ene, D.;
Shapiro, E. A. J. Am. Chem. Soc. 1994, 116, 8492–8498;
(b) Protopopova, M. N.; Doyle, M. P.; Mu¨ller, P.; Ene,
D. J. Am. Chem. Soc. 1992, 114, 2755–2757.
9. Mu¨ller, P.; Imogai, H. Helv. Chim. Acta 1999, 82, 315–
322.
Crystallographic data (excluding structure factors) for
23 have been deposited at the Cambridge Crystallo-
graphic Data Base as supplementary material, publica-
tion number CCDC 179658. Copies of the data can be
obtained free of charge on application to the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: Int. +44
(1223) 336-033; e-mail: deposit@ccdc.cam.ac.uk).
10. Mu¨ller, P.; Toujas, J.-L.; Bernardinelli, G. Helv. Chim.
Acta 2000, 83, 1525–1534.
11. Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D.
A.; Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem.
Soc. 1995, 117, 11021–11022.
Acknowledgements
12. Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.;
Yang, C. I.; Miertschin, C. S.; Winchester, W. R. Recl.
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S. J. Org. Chem. 2000, 65, 1305–1318.
14. Knollmu¨ller, M.; Ferenic, M.; Ga¨rtner, P.; Merater, K.;
Noe, C. R. Tetrahedron: Asymmetry 1998, 9, 4009–4010.
15. Clive, D. L. S.; Daigneault, S. J. Org. Chem. 1991, 56,
3801–3814.
This work was supported by The Swiss National Sci-
ence Foundation (Grant Nos. 20-52581.97 and 2027-
048156) and the European Commission for Science,
Research and Development (COST Action D12). The
authors are indebted to Ms. M. Marot for technical
assistance, to A. Pinto and J.-P. Saulnier for the NMR
spectra and to Ms. D. Klink for the mass spectra.
16. (a) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Tetrahedron Lett. 1977, 1977–1980; (b) Ninomiya, K.;
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