Mechanistic investigation of the domino oxy-cope/ene/claisen reaction and its application to the synthesis of desdimethyl ambliol B

Article abstract of DOI:10.1055/s-0031-1291144

We report an efficient and highly diastereoselective oxy-Cope/ene/Claisen reaction for the synthesis of decalin frameworks possessing four contiguous stereogenic centers. A detailed mechanistic investigation and its application to a short and protecting group free synthesis of desdimethyl ambliol B are presented. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291144

SPECIAL TOPIC
▌1833
special topic
Mechanistic Investigation of the Domino Oxy-Cope/Ene/Claisen Reaction and
Its Application to the Synthesis of Desdimethyl Ambliol B
Investigation of the Domino Oxy-Cope/Ene/Claisen Reaction
Louis Barriault,* Irina Denissova, Nathalie Goulet
Centre for Catalysis Research and Innovation, University of Ottawa, Department of Chemistry, 10 Marie Curie, Ottawa, Ontario,
K1N 6N5, Canada
Fax +1(613)5625170; E-mail: lbarriau@uottawa.ca
Received: 20.03.2012; Accepted: 22.03.2012
In 2002, we reported a highly diastereoselective cascade
Abstract: We report an efficient and highly diastereoselective oxy-
oxy-Cope/ene/Claisen reaction of 1,2-divinylcyclohexa-
Cope/ene/Claisen reaction for the synthesis of decalin frameworks
nol 4 to generate decalin framework 5 possessing four
possessing four contiguous stereogenic centers. A detailed mecha-
nistic investigation and its application to a short and protecting
contiguous stereogenic centers (Scheme 1, equation 1).6
group free synthesis of desdimethyl ambliol B are presented.
Upon heating at 220 °C, the alcohol 4 was converted into
ketone 6 via an oxy-Cope–tautomerization rearrange-
ment. Compound 6 is poised to undergo a transannular
carbonyl-ene reaction to give enol ether 7, which is set up
for a Claisen rearrangement on the less hindered face to
afford 5. In the light of these results, we envisaged the
syntheses of compounds 1 and 3, via a common interme-
diate 9 which could be obtained through a domino oxy-
Cope/ene/Claisen reaction of 8 (Scheme 1, equation 2).
Key words: oxy-Cope/ene/Claisen, domino, sigmatropic, diastereo-
selectivity, macrocycle
The development of efficient synthetic methods for the
rapid assembly of complex polycyclic frameworks from
simple substrates constitutes an important research en-
deavor in organic synthesis. In addition, the ever-increas-
ing need for efficient and waste-minimizing processes is
becoming more and more important, whilst the use of
domino reactions has emerged as an attractive strategy for
the generation of multiple carbon–carbon bonds.1 The ste-
reoselective formation of quaternary carbon centers is a
problem frequently encountered during the synthesis of
carbocycles.2 As examples, the bioactive molecules am-
bliol B (1),3 dysidiolide (2)4 and agelasimine A (3)5 all
bear a quaternary carbon at C-5 and a tertiary alcohol at C-
1 (Figure 1).
OH
R3
O
R3
O
HO
µwaves
R1
R2
(1)
R1 R2
70–90%
220 °C, PhMe
5
4
dr > 20:1
oxy-Cope
R2
Claisen
OH
R3
R1
O
O
ene
R1
O
R3
R2
7
O
6
O
O
OH
OH
O
OH
5
5
HO
O
OH
1
µwaves
Fg
Fg
(2)
dysidiolide (2)
ambliol B (1)
8
9
N
MeN
Scheme
1
General mechanism for the domino oxy-
N
Me
Cope/ene/Claisen reaction; Fg = functional group
N
N
To evaluate the feasibility of this approach, allyl ether 10
was heated at 220 °C for three hours. To our dismay, the
desired decalin 11 was obtained in only 27% yield along
with a mixture of two other diastereomers, 12 (44%) and
13 (11%) (Scheme 2). In an effort to rationalize the prod-
uct distribution, it was decided to investigate the ene reac-
tion and Claisen rearrangement transition states. The
transition states of the ene reaction leading to decalin 18
requires that the methyl at C-4 is oriented equatorially.
Consequently, the corresponding transition states of mac-
rocycles 14 and 15 exhibit syn-pentane and 1,3-allylic in-
teractions, respectively. On the other hand, the formation
OH
agelasimine A (3)
Figure 1 Structures of natural clerodane diterpenes
SYNTHESIS 2012, 44, 1833–1840
Advanced online publication: 01.06.2012
DOI: 10.1055/s-0031-1291144; Art ID: SS-2012-C0291-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1834
L. Barriault et al.
SPECIAL TOPIC
of decalin 19 necessitates the methyl at C-4 to be posi- The oxy-Cope rearrangement of 20a (R = H) gives 10-
tioned axially in the transition states of macrocycles 16 membered ring macrocycle A, which can undergo a ring
and 17. Finally, the Claisen rearrangement of 18 proceeds inversion to give diastereomer B (Scheme 3). After tau-
anti to the tertiary alcohol to give tricyclic 11. Owing to tomerization, a rapid equilibrium between ketone C and D
the orientation of the C-4 methyl in decalin 19, the sigma- takes place (note that when R = H, macrocycles C and D
tropic shift occurs preferentially syn to the alcohol afford- are identical to E and F). The corresponding transition
ing aldehyde 12 as the major product. The preferential state for the conversion of D→22a has the methyl orient-
formation of decalins 12 and 13 over 11 strongly suggests ed in the axial position, while the methyl is equatorial in
that: 1) the rotation barrier of the trisubstituted olefin is a the transition state for the ene reaction of C→23a. The ob-
lower energy process competing with the ene reaction, served ratio of 3.2:1 corresponds to a difference of 1.14
and 2) the chirality transfer efficacy in the domino process kcal/mol (calculated at 493 K, 220 °C) between transition
relies upon conformational preferences of the macrocyclic states C→23a and D→22a leading to 23a and 22a, re-
transition state for the ene reactions. In this article, we re- spectively. Taking into account that the AMe is 1.74
port a detailed mechanistic analysis of the domino oxy- kcal/mol (at 300 K), it can be proposed that the absolute
Cope/ene/Claisen reaction and its application toward the value for the transition state of D→22a should be higher
stereoselective synthesis of desdimethyl ambliol B.
in energy than that leading to 23a, thus explaining the ob-
served diastereoselectivity. Assuming that the ene reac-
tion is under Curtin–Hammett control, the thermal
rearrangement of 21a (R = H) should give the same ratio
of 23a (25a) and 22a (24a). Alcohol 21a was irradiated
with microwaves at 220 °C to afford 23a and 22a in a ratio
of 3.2:1 and 60% yield (Table 1, entry 2). This clearly
demonstrates that the transannular ene reaction is under
Curtin–Hammett control.
If it is assumed that the transannular ene reaction is gov-
erned by the Curtin–Hammett principle, the ratio of prod-
ucts should correspond to the relative values for the
absolute energies for the two transition states.7 It can be
proposed that the diastereoselectivity of the domino reac-
tion could be dictated using a remote chiral center located
on the macrocycle.8 To validate this approach, 1,2-divi-
nyl-1-cyclohexanols 20a–c and 21a–c, readily prepared
from 2-chloro-1-cyclohexanone, were subjected to micro- Table 1 (entry 3) revealed that replacement of R = H by
wave irradiation at 220 °C for one to three hours (Table R = Me, as in substrate 20b, led to a mixture of 22b and
1).9
23b in 77% yield in a diastereomeric ratio of 3.4:1. Inter-
estingly, the major product had the methyl at C-4 in the
axial position suggesting that the stereocenter at C-2 gov-
erned the diastereoselectivity of the reaction. When R was
changed from a hydrogen into an ethyl sulfide (Table 1,
The thermal rearrangement of 20a gave a 3.2:1 mixture of
23a and 22a in 70% yield (Table 1, entry 1). The major
compound possessed the methyl at C-4 syn to the alcohol.
The product distribution can be rationalized as follows.
OH
O
OHC
O
OH
µwaves
+
+
220 °C, PhMe
OH
OH
O
12 (44%)
13 (11%)
11 (27%)
10
Hb
O
O
Ha
Hb
Ha
4
4
O
O
H
O
Ha
O
Ha
Hb
b O
16
O
4
14 4
15
17
O
OH
O
19
OH
18
OH
OHC
O
OH
OH
12 (44%)
O
13 (11%)
11 (27%)
Scheme 2 Proposed mechanism for the domino oxy-Cope/ene/Claisen reaction
Synthesis 2012, 44, 1833–1840
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Investigation of the Domino Oxy-Cope/Ene/Claisen Reaction
1835
Table 1 Thermal Rearrangement of 1,2-Divinylcyclohexanols
Entry
Substrate
Product
Yield (dr)
OH
OH
+
+
1
70% (3.2:1)
22aOH
23a
20a
OH
2
3
4
60% (3.2:1)
77% (3.4:1)
81% (>20:1)
OH
22aOH
23a
21a
OH
OH
+
22bOH
23b
20b
EtS
OH
EtS
OH
25b
21b
OH
5
6
93% (>20:1)
64% (>20:1)
Ph
OH
OH
Ph
22c
20c
Ph
Ph
OH
25c
21c
entry 4), the diastereoselectivity of the reaction increased can be excluded when R ≠ H since its existence would pre-
from 3.2:1 (Table 1, entry 2) to 20:1 in 81% yield in favor dict the formation of decalins 22b and 23b. These results
of decalin 25b. It is important to point out that the exis- are in agreement with a high energy barrier to rotation of
tence of a rapid equilibrium between A and B (R = SEt) tetrasubstituted enols in 10-membered rings.10 Heating of
OH
R
R
OH
OH
HO
21
B
20
A
R
R
O
O
R
R
R
O
O
D
R
E
C
F
OH
OH
R
R
R
OH
OH
R
22
24
25
23
Scheme 3 Proposed mechanism of the oxy-Cope/ene/Claisen
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1833–1840

1836
L. Barriault et al.
SPECIAL TOPIC
20c (R = Ph) afforded compound 22c in 93% yield as the The synthesis began with the treatment of vinyl bromide
sole isomer (Table 1, entry 5). Subjection of 21c to micro- 30 with tert-butyllithium in diethyl ether at –100 °C fol-
wave irradiation gave decalin 25c in 64% yield as the only lowed by the addition of 29 to give chlorohydrine 31 in
detectable isomer (Table 1, entry 6).
52% yield (Scheme 5). The latter was converted into ke-
tone 32, in 32% yield, via a 1,2-shift using one equivalent
of vinylmagnesium bromide in the presence of two equiv-
alents of N,N,N′,N′-tetramethylethylenediamine in tetra-
hydrofuran at reflux temperature.12 A second alkylation
using vinylethyl sulfide gave the desired alcohol 28 in
43% yield (dr >20:1). As expected, the thermal rearrange-
ment of 28 at 200 °C provided lactol 27 in 65% yield as
the only detectable diastereomer. The relative configura-
tion of 27 was established without ambiguity by 2D NMR
spectroscopy. Reduction of the lactol moiety into the cor-
responding methyl analogue was realized using potassium
hydroxide and hydrazine hydrate, in ethyl glycol (EG) at
reflux temperature, to give decalin 33 in 85% yield. With
compound 33 in hand, the removal of the ethyl sulfinyl
group was envisaged to afford alkene 34. Frustratingly, all
our attempts to obtain alkene 34 via reduction of the C–S
bond, or aldehyde 37 through oxidation of 33 were unsuc-
cessful. Thus, we envisioned that increasing the steric
bulk toward the alkene would prevent any further over-
reduction. Decalin 33 underwent an alkene dimerization
using Grubbs II catalyst to give dimer 35 in quantitative
yield.13 Cleavage of the C–S bond using Raney nickel in
tetrahydrofuran–water produced compound 36 in 98%
yield. This was followed by a Lemieux–Johnson oxida-
tion to afford the desired aldehyde 37 in 47% yield. The
unstable aldehyde 37 was converted into furan 38 (75%
yield), which upon treatment with acetic anhydride in a
solution of dichloromethane–pyridine gave acetate 39 in
80% yield. Finally, reduction of the acetate group with el-
emental lithium in condensed ammonia at –78 °C provid-
ed desdimethyl ambliol B (26) in 93% yield.
These results confirmed that: 1) the transannular ene reac-
tion was governed by the Curtin–Hammett principle, and
2) the diastereoselectivity of the reaction could be directed
by a stereogenic center at C-2. Having determined the or-
igin of the high selectivity of the domino reaction, we next
applied this cascade process to the synthesis of a clero-
dane diterpene analogue, desdimethyl ambliol B (26)
(Scheme 4).
Our retrosynthetic analysis revealed immediately that 26
could be prepared from lactol 27. The latter could be
efficiently generated through
Cope/ene/Claisen reaction of 28 which in turn could be
rapidly assembled from commercially available 2-chloro-
cyclohexanone (29) and vinyl bromide 3011 (Scheme 4).
a
domino oxy-
O
OH
OH
O
EtS
desdimethyl ambliol B (26)
27
O
EtS
Br
Cl
+
HO
28
O
O
29
30
Scheme 4 Retrosynthetic analysis of desdimethyl ambliol B (26)
O
t-BuLi, TMEDA
H2C=CHMgBr (1 equiv)
TMEDA (2 equiv)
Br
t-BuLi, Et2O
Cl
EtS
O
–100 °C then 29
THF, reflux, 32%
HO
31
O
52%
O
Et2O, r.t., 43%
30
32
nOe
OH
H
EtS
OH
O
OH
KOH, H4N2⋅H2O
Et3N (5 equiv)
EG, 130–210 °C
85%
PhMe, 200 °C
65%
EtS
EtS
HO
O
27
33
34
28
Grubbs II
CH2Cl2, 99%
O
Br
O
OH
OH
t-BuLi,
Li, THF-NH3
–78 °C, 93%
R
OH
OsO4 (cat.), NMO
THF–H2O, 47%
O
26
R
OR
Et2O, –78 °C
75%
OH
37
35 R = SEt
36 R = H
38 R = H
Ni (Raney)
THF–H2O, 98%
Ac2O, py
CH2Cl2, 80%
39 R = Ac
Scheme 5 Synthesis of desdimethyl ambliol B (26)
Synthesis 2012, 44, 1833–1840
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Investigation of the Domino Oxy-Cope/Ene/Claisen Reaction
1837
1H NMR (300 MHz, CDCl3): δ = 4.89–4.87 (m, 1 H), 4.58 (dd,
J = 1.8 Hz, 1.8 Hz, 1 H), 2.59–2.51 (m, 1 H), 2.20–2.14 (m, 1 H),
1.98–1.91 (m, 1 H), 1.80–1.65 (m, 2 H), 1.60–1.41 (m, 5 H), 1.35–
1.06 (m, 7 H), 0.81 (d, J = 6.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 154.4 (C), 108.9 (CH2), 73.8 (C),
44.6 (CH), 39.1 (CH), 38.7 (CH2), 36.3 (CH), 35.6 (CH2), 26.2
(CH2), 24.5 (CH2), 21.9 (CH2), 19.9 (CH3), 14.8 (CH3).
In conclusion, a careful examination of the reaction mech-
anism revealed that the diastereoselectivity of the oxy-
Cope/ene/Claisen reaction was controlled by the confor-
mational preferences of the macrocycles at the transition
state for the transannular ene reaction. The effectiveness
of this domino process was confirmed via a short synthe-
sis of desdimethyl ambliol B (26) in 11 steps from vinyl
bromide 30. The application of the domino oxy-
Cope/ene/Claisen reaction in the synthesis of other natural
clerodane diterpenes is underway and will be reported in
due course.
HRMS (EI): m/z [M+] calcd for C13H22O: 194.1671; found:
194.1676.
(±)-(2S,4R,4aR,8aR)-2-Methyl-1-methylene-4-phenyldecahy-
dronaphthalen-4a-ol (22c)
Yield: 65 mg (93%); colorless oil.
IR (neat): 3555, 3083, 3060, 2931, 2894 cm–1.
All reactions were carried out under dry N2 or Ar atmospheres, in
flame-dried glassware or sealed tubes equipped with a magnetic stir
bar and a rubber septum, unless otherwise indicated. THF and Et2O
were freshly distilled from Na/benzophenone. Toluene, CH2Cl2 and
Et3N were freshly distilled from CaH2. Other commercially avail-
able reagents were used without purification, unless otherwise indi-
cated. Reactions were monitored by TLC analysis of aliquots using
aluminum and glass sheets pre-coated (0.2 mm and 0.25 mm layer
thickness, respectively) with silica gel 60 F254 (E. Merck). TLC
plates were viewed under UV light and stained with p-anisaldehyde
or phosphomolybdic acid staining solution. Flash chromatography
was carried out on Silicycle silica gel (0.35–0.75 mm, 60 Å pore
size).IR spectra were recorded on a Bomen Michaelson 100 FTIR
1H NMR (300 MHz, CDCl3): δ = 7.30–7.15 (m, 5 H), 4.89–4.87 (m,
1 H), 4.61 (dd, J = 1.9 Hz, 1.9 Hz, 1 H), 2.67 (dd, J = 3.7 Hz, 13.6
Hz, 1 H), 2.53–2.44 (m, 1 H), 2.24–2.14 (m, 2 H), 1.67–1.36 (m, 6
H), 1.29–1.11 (m, 3 H), 1.08 (d, J = 7.2 Hz, 3 H), 1.03–0.92 (m, 1
H).
13C NMR (75 MHz, CDCl3): δ = 153.9 (C), 142.6 (C), 128.3 (2
CH), 126.82 (2 CH), 126.81 (CH), 109.3 (CH2), 73.9 (C), 49.3
(CH), 45.0 (CH), 39.1 (CH), 37.2 (CH2), 36.9 (CH2), 26.2 (CH2),
24.5 (CH2), 21.7 (CH2), 19.8 (CH3).
HRMS (EI): m/z [M+] calcd for C18H24O: 256.1827; found:
256.1846.
1
spectrometer. H NMR spectra were recorded on Bruker Avance
(±)-(2S,4R,4aS,8aS)-4-(Ethylthio)-2-methyl-1-methylenedeca-
hydronaphthalen-4a-ol (25b)
Yield: 11 mg (81%); colorless oil.
IR (neat): 3524, 2931, 2854, 1644, 1449 cm–1.
1H NMR (500 MHz, C6D6): δ = 4.77 (s, 1 H), 4.69 (s, 1 H), 2.54–
2.50 (m, 1 H), 2.41–2.29 (m, 3 H), 1.93 (ddd, J = 4.0 Hz, 4.0 Hz,
13.0 Hz, 1 H), 1.84–1.79 (m, 1 H), 1.74–1.57 (m, 4 H), 1.54–1.45
(m, 3 H), 1.25 (s, 1 H), 1.13–1.08 (m, 4 H), 0.99–0.92 (m, 4 H).
300 MHz, 400 MHz and 500 MHz spectrometers; 13C NMR spectra
were recorded at 75 MHz, 100 MHz and 125 MHz. HRMS spectra
were obtained using a Kratos Analytical Concept instrument. Mi-
crowave reactions were conducted in a CEM Model ESP-1500 Plus
oven equipped with a pressure monitoring device and an EST-300
Plus fibre optic temperature probe. All experiments were performed
in a quartz tube previously washed with aqueous i-PrOH–NaOH so-
lution.
13C NMR (75 MHz, C6D6): δ = 152.6 (C), 105.8 (CH2), 74.2 (C),
55.4 (CH), 50.4 (CH), 41.6 (CH2), 38.7 (CH), 37.5 (CH2), 26.3
(CH2), 26.2 (CH2), 24.9 (CH2), 21.8 (CH2), 18.0 (CH3), 15.5 (CH3).
HRMS (EI): m/z [M+] calcd for C14H24OS: 240.1548; found:
240.1534.
Microwave-Assisted Domino Reaction; General Procedure
To a soln of divinyl cyclohexanol in toluene (0.1 M) in a quartz tube
(previously washed with aq i-propanol–NaOH soln) equipped with
a carboflonTM insert was added freshly distilled Et3N (10 equiv).
The resulting soln was deoxygenated with Ar for 0.5 h, and the tube
sealed and heated in a CEM microwave oven at 220 °C for 1 h. The
mixture was then cooled to r.t. The soln was transferred to a round-
bottom flask and concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (EtOAc–hex-
anes, 20:80) afforded the corresponding decalin.
(±)-(2S,4S,4aS,8aS)-2-Methyl-1-methylene-4-phenyldecahy-
dronaphthalen-4a-ol (25c)
Yield: 16 mg (64%); yellowish oil.
IR (neat): 3553, 3087, 3060, 2931, 2855, 1643 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.25–7.11 (m, 5 H), 4.84 (d,
J = 1.1 Hz, 1 H), 4.71 (s, 1 H), 2.37 (dd, J = 4.7 Hz, 12.1 Hz, 1 H),
1.96–1.86 (m, 1 H), 1.82–1.77 (m, 1 H), 1.68–1.39 (m, 7 H), 1.29–
1.21 (m, 1 H), 1.15–1.05 (m, 2 H), 1.01–0.91 (m, 4 H).
(±)-(2S,4aR,8aS)-2-Methyl-1-methylenedecahydronaphthalen-
4a-ol (23a) and (±)-(2S,4aS,8aR)-2-Methyl-1-methylenedecahy-
dronaphthalen-4a-ol (22a)
Yield: 21 mg (70%, mixture of 23a and 22a); colorless oil.
13C NMR (75 MHz, C6D6): δ = 153.9 (C), 142.8 (C), 128.2 (2 CH),
128.0 (2 CH), 126.6 (CH), 106.2 (CH2), 73.3 (C), 55.2 (CH), 50.6
(CH), 40.7 (CH2), 38.7 (CH), 37.1 (CH2), 26.2 (CH2), 24.8 (CH2),
21.7 (CH2), 18.3 (CH3).
HRMS (EI): m/z [M+] calcd for C18H24O: 256.1827; found:
256.1818.
IR (neat): 3549, 3479, 2933, 2859 cm–1.
1H NMR (300 MHz, CDCl3): δ (data for 23a) = 4.92 (dd, J = 1.6
Hz, 1.6 Hz, 1 H), 4.84 (br s, 1 H), 4.70 (br s, 1 H), 4.57 (dd, J = 1.9
Hz, 1.9 Hz, 1 H), 2.58 (q, J = 6.7 Hz, 1 H), 2.22 (m, 1 H), 2.03–1.20
(m, 28 H), 1.09 (d, J = 7.0 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ (mixture of 23a and 22a) = 154.7,
154.1, 108.7, 106.0, 72.4, 72.3, 50.4, 44.3, 40.3, 39.0, 38.9, 38.8,
35.0, 33.1, 29.2, 26.4, 26.3, 24.5, 24.2, 21.7, 21.6, 19.1, 18.7.
(±)-(1S,2S)-1-[(Z)-1-(Allyloxy)but-2-en-2-yl]-2-chlorocyclohex-
anol (31)
To a soln of vinyl bromide 30 (2.46 g, 12.9 mmol) in Et2O (100 mL)
was added dropwise t-BuLi (17.8 mL, 23.2 mmol, 1.3 M in pentane)
at –100 °C. After stirring for 1 h, a soln of ketone 29 (1.5 mL, 12.9
mmol) was added at –100 °C. The mixture was gradually warmed
to –60 °C and then cooled to –100 °C. H2O (100 mL) was added and
the mixture allowed to warm to r.t. The mixture was extracted with
Et2O (3 × 100 mL) and the combined organic phase dried over
HRMS (EI): m/z [M+] calcd for C12H20O: 180.1514; found:
180.1503.
(±)-(2S,4S,4aS,8aR)-2,4-Dimethyl-1-methylenedecahydronaph-
thalen-4a-ol (22b)
Yield: 34 mg (60%); colorless oil.
IR (neat): 3571, 2931, 2853, 1460 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1833–1840

1838
L. Barriault et al.
SPECIAL TOPIC
MgSO4, filtered and concentrated. The residue was purified by flash
chromatography (EtOAc–hexanes, 5:95).
13C NMR (125 MHz, C6D6): δ = 154.9 (C), 137.7 (C), 134.2 (CH),
129.9 (CH), 116.6 (CH2), 103.9 (CH2), 76.4 (C), 74.0 (CH2), 69.7
(CH2), 44.8 (CH), 40.1 (CH2), 28.3 (CH2), 26.6 (CH2), 26.1 (CH2),
21.8 (CH2), 13.6 (CH3), 12.7 (CH3).
HRMS (EI): m/z [M+] calcd for C17H28O2S: 296.1810; found:
296.1799.
Yield: 1.64 g (52%); colorless oil.
IR (neat): 3571, 3494, 2938, 1648 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.92–5.85 (m, 1 H), 5.60 (q,
J = 7.4 Hz, 1 H), 5.25 (dddd, J = 17.3 Hz, 1.7 Hz, 1.7 Hz, 1.7 Hz, 1
H), 5.16 (dddd, J = 10.4 Hz, 1.7 Hz, 1.4 Hz, 1.4 Hz, 1 H), 4.43 (dd,
J = 11.9 Hz, 4.6 Hz, 1 H), 4.23 (d, J = 11.1 Hz, 1 H), 4.02 (dddd,
J = 12.7 Hz, 5.3 Hz, 1.4 Hz, 1.4 Hz, 1 H), 3.88 (ddd, J = 12.7 Hz,
5.7 Hz, 1.4 Hz, 1 H), 3.81 (d, J = 11.1 Hz, 1 H), 3.30 (br s, 1 H), 2.07
(ddd, J = 15.9 Hz, 12.7 Hz, 3.8 Hz, 1 H), 1.96–1.92 (m, 2 H), 1.86
(d, J = 7.4 Hz, 3 H), 1.80–1.64 (m, 3 H), 1.47–1.41 (m, 1 H), 1.36–
1.25 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140.2 (C), 134.2 (CH), 127.5
(CH), 116.2 (CH2), 76.3 (C), 75.6 (CH2), 70.2 (CH2), 66.4 (CH),
37.1 (CH2), 32.1 (CH2), 26.0 (CH2), 20.1 (CH2), 14.8 (CH3).
HRMS (EI): m/z [M+] calcd for C13H21O2Cl: 244.1230; found:
244.1194.
(1S,2S,4R,4aS,8aS)-1-Allyl-4-(ethylthio)-2-methyloctahydro-
1H-4a,1-(epoxymethano)naphthalen-10-ol (27)
To a soln of 28 (14 mg, 0.046 mmol) in toluene (15 mL) was added
Et3N (0.02 mL, 0.19 mmol). The resulting soln was degassed using
Ar (30 min) and then heated at 200 °C in a sealed tube for 48 h. The
mixture was cooled to r.t. and then concentrated. The residue was
purified by flash chromatography (EtOAc–hexanes, 20:80) to give
the desired lactol.
Yield: 9 mg (65%); yellowish oil.
IR (neat): 3403, 2926, 2851, 1641 cm–1.
1H NMR (500 MHz, C6D6): δ = 5.76–5.68 (m, 1 H), 5.21–5.14 (m,
2 H), 4.88 (d, J = 3.6 Hz, 1 H), 2.64–2.52 (m, 2 H), 2.30 (d, J = 3.6
Hz, 1 H), 2.25 (dd, J = 11.6 Hz, 5.6 Hz, 1 H), 2.14 (dd, J = 15.6 Hz,
8.4 Hz, 1 H), 2.09–2.02 (m, 1 H), 1.99 (ddd, J = 12.8 Hz, 5.6 Hz,
5.2 Hz, 1 H), 1.76–1.30 (m, 6 H), 1.26 (t, J = 7.4 Hz, 3 H), 1.19 (dd,
J = 11.9 Hz, 6.3 Hz, 1 H), 1.08–0.99 (m, 2 H), 0.80 (d, J = 6.4 Hz,
3 H).
13C NMR (125 MHz, C6D6): δ = 135.7 (CH), 117.0 (CH2), 99.1
(CH), 85.4 (C), 54.6 (CH), 52.5 (C), 50.1 (CH), 38.6 (CH2), 35.7
(CH), 33.5 (CH2), 31.6 (CH2), 25.3 (CH2), 25.2 (CH2), 24.5 (CH2),
22.2 (CH2), 16.3 (CH3), 15.4 (CH3).
(±)-(E)-2-[1-(Allyloxy)but-2-en-2-yl]cyclohexanone (32)
To a soln of 31 (9.96 g, 40.7 mmol) in THF (400 mL) was added
TMEDA (18 mL, 122.1 mmol) followed by vinylmagnesium bro-
mide (51 mL, 44.8 mmol, 0.9 M in THF). The resulting mixture was
heated to reflux temperature and stirred for 2 h. The mixture was
cooled to r.t. and sat. aq NH4Cl soln (400 mL) was added. The mix-
ture was extracted with EtOAc (3 × 100 mL) and the combined or-
ganic phase dried over MgSO4, filtered and concentrated. The
residue was purified by flash chromatography (EtOAc–hexanes,
10:90) to give ketone 32.
HRMS (EI): m/z [M+] calcd for C17H28O2S: 296.1810; found:
296.1818.
Yield: 2.63 g (32%); yellowish oil.
IR (neat): 2936, 2861, 1711, 1644 cm–1.
(±)-(1R,2S,4R,4aS,8aS)-1-Allyl-4-(ethylthio)-1,2-dimethyldeca-
hydronaphthalen-4a-ol (33)
1H NMR (500 MHz, CDCl3): δ = 5.93–5.78 (m, 1 H), 5.72 (q,
J = 6.9 Hz, 1 H), 5.22 (dddd, J = 17.3 Hz, 1.7 Hz, 1.7 Hz, 1.7 Hz, 1
H), 5.12 (dddd, J = 10.4 Hz, 1.7 Hz, 1.4 Hz, 1.4 Hz, 1 H), 3.93–3.87
(m, 4 H), 3.29 (dd, J = 12.7 Hz, 5.6 Hz, 1 H), 2.37–2.23 (m, 1 H),
2.12–1.81 (m, 4 H), 1.78–1.60 (m, 2 H), 1.55 (d, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 209.7 (C), 134.9 (CH), 134.3 (C),
126.5 (CH), 116.7 (CH2), 73.6 (CH2), 70.6 (CH2), 51.2 (CH), 42.0
(CH2), 31.6 (CH2), 26.6 (CH2), 25.3 (CH2), 13.8 (CH3).
A soln of lactol 27 (310 mg, 1.04 mmol) in ethylene glycol (10 mL)
was degassed under reduced pressure for 45 min, after which hy-
drated hydrazine (0.25 mL, 5.2 mmol) was added. The soln was
heated at 130 °C for 1 h and then cooled to r.t. KOH (580 mg, 10.4
mmol) was added and the resulting mixture heated at 210 °C for 2
h. The mixture was diluted with H2O (10 mL) and extracted with
EtOAc (3 × 50 mL). The combined organic phase was washed with
brine (50 mL), dried over MgSO4, filtered and concentrated. The
residue was purified by flash chromatography (EtOAc–hexanes,
3:97) to give alkene 33.
HRMS (EI): m/z [M+ – CH2CH=CH2] calcd for C10H15O2:
167.1072; found: 167.1075.
Yield: 249 mg (85%); colorless oil.
IR (neat): 3528, 3074, 2930, 1643 cm–1.
(±)-(1R,2R)-2-[(E)-1-(Allyloxy)but-2-en-2-yl]-1-[1-(ethylthio)vi-
nyl]cyclohexanol (28)
To a soln of ethyl(vinyl)sulfane (0.62 mL, 6.1 mmol) and TMEDA
(0.92 mL, 6.1 mmol) in Et2O (10 mL) was added dropwise n-BuLi
(2.5 mL, 6.1 mmol, 2.4 M in hexanes) at 0 °C. The mixture was
warmed to r.t. and stirred for 15 min. A soln of ketone 32 (212 mg,
1 mmol) in Et2O (2 mL) was added to the reaction mixture. After
stirring for 2 h, H2O (50 mL) was added and the mixture extracted
with Et2O (3 × 100 mL). The combined organic phase was dried
over MgSO4, filtered and concentrated. The residue was purified by
flash chromatography (EtOAc–hexanes, 20:80) to give the title
product.
1H NMR (500 MHz, C6D6): δ = 5.79–5.70 (m, 1 H), 5.11 (d,
J = 10.2 Hz, 1 H), 5.04 (d, J = 17.0 Hz, 1 H), 2.34–2.28 (m, 3 H),
2.13–1.88 (m, 4 H), 1.79–1.65 (m, 4 H), 1.56–1.44 (m, 4 H), 1.16–
1.08 (m, 5 H), 0.99 (s, 3 H), 0.91–0.86 (m, 1 H), 0.83 (d, J = 6.7 Hz,
3 H).
13C NMR (125 MHz, C6D6): δ = 135.2 (CH), 117.1 (CH2), 74.1 (C),
57.0 (CH), 48.5 (CH), 41.8 (CH2), 40.0 (CH2), 39.6 (C), 37.8 (CH),
35.9 (CH2), 27.6 (CH2), 27.2 (CH2), 22.1 (CH2), 22.0 (CH2), 17.0
(CH3), 15.9 (CH3), 15.6 (CH3).
HRMS (EI): m/z [M+] calcd for C17H30OS: 282.2017; found:
282.1995.
Yield: 126 mg (43%); yellowish oil.
IR (neat): 3383, 2937, 1646 cm–1.
1H NMR (500 MHz, C6D6): δ = 5.91–5.83 (m, 1 H), 5.82 (q, J = 6.8
Hz, 1 H), 5.40 (d, J = 2.0 Hz, 1 H), 5.30 (dddd, J = 17.3 Hz, 1.7 Hz,
1.7 Hz, 1.7 Hz, 1 H), 5.12 (dddd, J = 10.5 Hz, 1.5 Hz, 1.5 Hz, 1.4
Hz, 1 H), 4.82 (s, 1 H), 4.17 (d, J = 11.7 Hz, 1 H), 3.94–3.89 (m, 1
H), 3.93 (s, 1 H), 3.62 (dddd, J = 12.9 Hz, 5.7 Hz, 1.5 Hz, 1.5 Hz, 1
H), 3.31 (dd, J = 12.6 Hz, 3.2 Hz, 1 H), 2.57–2.45 (m, 2 H), 2.29–
2.12 (m, 4 H), 1.88–1.83 (m, 1 H), 1.81 (d, J = 6.9 Hz, 3 H), 1.68–
1.62 (m, 1 H), 1.49–1.40 (m, 2 H), 1.16 (t, J = 7.5 Hz, 3 H).
(±)-(1S,2R,4S,4aR,8aR)-4-(Ethylthio)-1-{4-
[(1R,2S,4R,4aS,8aS)-4-(ethylthio)-4a-hydroxy-1,2-dimethyl-
decahydronaphthalen-1-yl]but-2-enyl}-1,2-dimethyldecahy-
dronaphthalen-4a-ol (35)
To a degassed soln of 33 (22 mg, 0.077 mol) in CH2Cl2 (2 mL) was
added Grubbs II catalyst (7 mg, 0.0077 mol) under Ar. After heating
at reflux temperature for 2 h, the soln was concentrated. The residue
was purified by flash chromatography (EtOAc–hexanes, 3:97) to
give dimer 35.
Synthesis 2012, 44, 1833–1840
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Investigation of the Domino Oxy-Cope/Ene/Claisen Reaction
1839
Yield: 21 mg (99%); white foam.
IR (neat): 3516, 2929, 2855, 1446 cm–1.
1H NMR (400 MHz, C6D6): δ = 5.45–5.43 (m, 2 H), 2.55–2.45 (m,
2 H), 2.40–2.30 (m, 4 H), 2.20–2.05 (m, 4 H), 2.00–1.85 (m, 4 H),
1.80–1.20 (m, 22 H), 1.10–1.00 (m, 6 H), 1.06 (s, 6 H), 0.93 (d,
J = 6.7 Hz, 6 H).
13C NMR (100 MHz, C6D6): δ = 129.0, 74.1, 57.1, 48.7, 40.6, 40.2,
39.9, 37.9, 35.8, 27.6, 27.4, 22.1, 22.0, 16.9, 15.9, 15.4.
HRMS (EI): m/z [M+] calcd for C32H56O2S2: 536.3722; found:
536.3713.
1H NMR (500 MHz, C6D6): δ = 7.16–7.12 (m, 2 H), 6.26–6.24 (m,
1 H), 4.59–4.57 (m, 1 H), 2.01–1.13 (m, 16 H), 1.09 and 0.82 (d,
J = 6.7 Hz, 3 H), 1.00 (s, 3 H).
13C NMR (125 MHz, C6D6): δ (diastereomer A) = 143.2 (CH),
138.1 (CH), 132.0 (C), 108.6 (CH), 71.3 (C), 63.2 (CH), 47.8 (CH),
45.1 (CH2), 42.6 (CH2), 41.4 (CH2), 39.2 (C), 37.4 (CH), 27.0
(CH2), 26.9 (CH2), 22.0 (CH2), 21.7 (CH2), 17.2 (CH3), 16.2 (CH3).
13C NMR (125 MHz, C6D6): δ (diastereomer B) = 143.2 (CH),
138.3 (CH), 131.6 (C), 108.7 (CH), 71.1 (C), 63.4 (CH), 47.3 (CH),
44.9 (CH2), 42.5 (CH2), 41.4 (CH2), 39.1 (C), 37.9 (CH), 27.0
(CH2), 26.8 (CH2), 21.9 (CH2), 21.6 (CH2), 17.4 (CH3), 16.7 (CH3).
HRMS (EI): m/z [M+] calcd for C18H28O3: 292.2038; found:
292.2064.
(±)-(1S,2R,4aS,8aR)-1-{4-[(1R,2S,4aR,8aS)-4a-Hydroxy-1,2-di-
methyldecahydronaphthalen-1-yl]but-2-enyl}-1,2-dimethyl-
decahydronaphthalen-4a-ol (36)
To a soln of Raney nickel (180 mL) in H2O (1 mL) was added a soln
of dimer 35 (9 mg, 0.017 mmol) in THF (3 mL) and the mixture
heated at reflux temperature for 18 h. The resulting suspension was
filtered through Celite then concentrated. The residue was purified
by flash chromatography (EtOAc–hexanes, 8:92) to give the title
product 36.
(±)-1-(Furan-3-yl)-2-[(1R,2S,4aR,8aS)-4a-hydroxy-1,2-dimeth-
yldecahydronaphthalen-1-yl]ethyl Acetate (39)
Ac2O (0.06 mL, 0.633 mmol) was added to a soln of 38 (11 mg,
0.038 mmol) in pyridine (0.8 mL) and CH2Cl2 (3 mL). After stirring
overnight, DMAP (10 mg, 0.082 mmol) was added and the mixture
stirred for a further 6 h. Sat. aq NH4Cl soln (6 mL) was added and
the mixture extracted with CH2Cl2 (3 × 20 mL). The combined or-
ganic phase was washed with brine (20 mL), dried over MgSO4, fil-
tered and concentrated. The residue was purified by flash
chromatography (EtOAc–hexanes, 10:90) to give acetate 39 as a
mixture of diastereomers (1:1).
Yield: 7 mg (98%); white foam.
IR (neat): 3491, 2926, 2858, 1446 cm–1.
1H NMR (400 MHz, C6D6): δ = 5.35–5.33 (m, 2 H), 2.25–2.15 (m,
2 H), 2.00–1.90 (m, 2 H), 1.80–1.60 (m, 4 H), 1.60–1.40 (m, 5 H),
1.40–1.20 (m, 21 H), 1.03 (s, 6 H), 0.98 (d, J = 6.7 Hz, 6 H).
Yield: 10 mg (80%); yellowish oil.
IR (neat): 3535, 3148, 2937, 1735 cm–1.
13C NMR (100 MHz, C6D6): δ = 129.0, 71.1, 47.4, 42.5, 41.5, 40.4,
1H NMR (400 MHz, C6D6): δ = 7.28 and 7.25 (m, 1 H), 7.01–6.99
(m, 1 H), 6.28–6.26 (m, 1 H), 6.10–6.05 (m, 1 H), 2.14 and 2.01 (dd,
J = 15.9 Hz, 8.6 Hz, 1 H), 1.82–1.69 (m, 4 H), 1.67 and 1.63 (s, 3
H), 1.60–1.12 (m, 13 H), 1.02 and 0.68 (d, J = 6.7 Hz, 3 H), 0.93 (s,
3 H).
13C NMR (100 MHz, C6D6): δ (diastereomer A) = 169.3 (C), 143.3
(CH), 140.0 (CH), 128.1 (C), 109.0 (CH), 71.1 (C), 64.8 (CH), 47.4
(CH), 42.6 (CH2), 41.9 (CH2), 41.3 (CH2), 39.3 (C), 38.0 (CH), 26.9
(CH2), 26.6 (CH2), 21.6 (CH2), 21.5 (CH2), 20.6 (CH3), 17.2 (CH3),
16.4 (CH3).
13C NMR (125 MHz, C6D6): δ (diastereomer B) = 169.3 (C), 143.3
(CH), 140.0 (CH), 128.3 (C), 109.0 (CH), 71.1 (C), 64.6 (CH), 47.8
(CH), 42.6 (CH2), 41.9 (CH2), 41.2 (CH2), 39.3 (C), 37.4 (CH), 27.3
(CH2), 26.7 (CH2), 21.8 (CH2), 21.7 (CH2), 20.9 (CH3), 17.1 (CH3),
16.0 (CH3).
39.8, 37.3, 27.2, 26.8, 21.7, 21.4, 16.9, 16.0.
(±)-2-[(1R,2S,4aR,8aS)-4a-Hydroxy-1,2-dimethyldecahydro-
naphthalen-1-yl]acetaldehyde (37)
To a soln of dimer 36 (42 mg, 0.10 mmol) in THF (2.5 mL) and H2O
(0.5 mL) was added OsO4 (4% in H2O, 0.012 mmol, 0.07 mL) and
sodium periodate (128 mg, 0.60 mmol). The mixture was stirred for
2 h then sat. aq Na2SO3 soln (5 mL) was added. After stirring for 30
min, the mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic phase was washed with brine (50 mL), dried over
MgSO4, filtered and concentrated. The residue was purified by flash
chromatography (EtOAc–hexanes, 10:90) to give the desired prod-
uct.
Yield: 21 mg (47%); colorless oil.
IR (neat): 3481, 2925, 2862, 1712 cm–1.
1H NMR (400 MHz, C6D6): δ = 9.62 (dd, J = 3.4 Hz, 3.1 Hz, 1 H),
2.15 (dd, J = 14.8 Hz, 3.4 Hz, 1 H), 2.07 (dd, J = 14.8 Hz, 3.1 Hz, 1
H), 1.74–1.62 (m, 2 H), 1.55–1.01 (m, 12 H), 0.89 (s, 3 H), 0.87 (d,
J = 6.7 Hz, 3 H).
13C NMR (100 MHz, C6D6): δ = 201.7 (CH), 70.8 (C), 50.6 (CH2),
49.1 (CH), 42.0 (CH2), 40.91 (CH2), 40.89 (C), 39.1 (CH), 26.8
(CH2), 26.5 (CH2), 21.7 (CH2), 21.4 (CH2), 16.3 (CH3), 16.2 (CH3).
HRMS (EI): m/z [M+ – C2H4O2] calcd for C18H26O2: 274.1933;
found: 274.1890.
Desdimethyl ambliol B (26)
A soln of 39 (20 mg, 0.060 mmol) in THF (3 mL) was added to a
soln of Li (10 mg) in NH3 (15 mL) at –78 °C. After stirring for 15
min, the excess Li was quenched by the addition of MeOH (5 mL)
and the mixture was warmed to r.t. After complete evaporation of
NH3, H2O (20 mL) was added and the mixture extracted with Et2O
(3 × 20 mL). The combined organic phase was washed with 10%
NaOH (20 mL) and H2O (20 mL), dried over MgSO4, filtered and
concentrated. The residue was purified by flash chromatography
(EtOAc–hexanes, 7:93) to give the title product as a mixture of
diastereomers (1:1).
HRMS (EI): m/z [M+ – C2H3O] calcd for C12H21O: 181.1592; found:
181.1600.
(±)-(1R,2S,4aR,8aS)-1-[2-(Furan-3-yl)-2-hydroxyethyl]-1,2-di-
methyldecahydronaphthalen-4a-ol (38)
To a soln of 3-bromofuran (0.02 mL, 0.126 mmol) in Et2O (4 mL)
was added t-BuLi (0.17 mL, 0.238 mmol, 1.4 M in pentane) at –
78 °C. After stirring for 2 h, sat. aq NH4Cl soln (6 mL) was added.
The mixture was extracted with EtOAc (3 × 15 mL). The combined
organic phase was washed with brine (20 mL), dried over MgSO4,
filtered and concentrated. The residue was purified by flash chro-
matography (EtOAc–hexanes, 10:90) to give furan 38 as a mixture
of diastereomers (1:1).
Yield: 15.4 mg (93%); yellowish oil.
IR (neat): 3493, 2929, 2871 cm–1.
1H NMR (500 MHz, C6D6): δ = 7.34 (s, 1 H), 7.20 (s, 1 H), 6.25 (s,
1 H), 2.31 (td, J = 13.7 Hz, 4.3 Hz, 1 H), 2.18 (td, J = 13.7 Hz, 4.3
Hz, 1 H), 1.81–1.18 (m, 16 H), 0.84 (d, J = 6.7 Hz, 3 H), 0.83 (s, 3
H).
Yield: 11 mg (75%); yellowish oil.
IR (neat): 3434, 2925, 2858, 1442 cm–1.
13C NMR (100 MHz, C6D6): δ = 142.8 (CH), 138.6 (CH), 125.8 (C),
111.1 (CH), 71.0 (C), 47.1 (CH), 42.4 (CH2), 41.4 (CH2), 38.6 (C),
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1833–1840

1840
L. Barriault et al.
SPECIAL TOPIC
37.7 (CH2), 36.9 (CH), 27.1 (CH2), 26.8 (CH2), 21.6 (CH2), 21.3
(CH2), 18.2 (CH2), 17.4 (CH3), 15.9 (CH3).
HRMS (EI): m/z [M+] calcd for C18H28O2: 276.2089; found:
120, 1615. (d) Demeke, D.; Forsyth, C. J. Org. Lett. 2000, 2,
3177. (e) Piers, E.; Caillé, S.; Chen, G. Org. Lett. 2000, 2,
2483. (f) Paczkowski, R.; Maichle-Mössmer, C.; Maier, M.
E. Org. Lett. 2000, 2, 3967. (g) Takahashi, M.; Dodo, K.;
Hashimoto, Y.; Shirai, R. Tetrahedron Lett. 2000, 41, 2111.
(h) Miyaoka, H.; Kajiwara, Y.; Yamada, Y. Tetrahedron
Lett. 2000, 41, 911. (i) Miyaoka, H.; Kajiwara, Y.; Hara, Y.;
Yamada, Y. J. Org. Chem. 2001, 66, 1429. (j) Jung, M. E.;
Nishimura, N. Org. Lett. 2001, 3, 2113. (k) Demeke, D.;
Forsyth, C. J. Tetrahedron 2002, 58, 6531.
276.2062.
Acknowledgment
We thank NSERC, Merck Frosst Canada, Boehringer Ingelheim,
the Government of Ontario (PREA) and the University of Ottawa
for generous funding. N.G. thanks NSERC (PGS-M).
(5) (a) Ohba, M.; Kawase, N.; Fujii, T. J. Am. Chem. Soc. 1996,
118, 8250. (b) Ohba, M.; Iizuka, K.; Ishibashi, H.; Fujii, T.
Tetrahedron 1997, 53, 16977.
(6) (a) Barriault, L.; Denissova, I. Org. Lett. 2002, 4, 1371.
(b) Farand, J. A.; Denissova, I.; Barriault, L. Heterocycles
2004, 62, 735.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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