Syntheses of 6-8-5 tricyclic ring systems by carbonylative [2+2+1] cycloaddition of bis(allene)s

Article abstract of DOI:10.1016/j.tet.2012.12.014

The synthetic route for the construction of the 6-8-5 tricyclic carbon frameworks has been developed. The [RhCl(CO)dppp]₂-catalyzed intramolecular Pauson-Khand-type reaction of the bis(allene)s, derived from dimedone, provided the corresponding

Full text of DOI:10.1016/j.tet.2012.12.014

Tetrahedron 69 (2013) 1509e1515
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Syntheses of 6-8-5 tricyclic ring systems by carbonylative [2þ2þ1]
cycloaddition of bis(allene)s
*
M.T. Soraya Shafawati, Fuyuhiko Inagaki, Takamasa Kawamura, Chisato Mukai
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthetic route for the construction of the 6-8-5 tricyclic carbon frameworks has been developed.
The [RhCl(CO)dppp]2-catalyzed intramolecular PausoneKhand-type reaction of the bis(allene)s, derived
from dimedone, provided the corresponding bicyclo[6.3.0] skeleton in one operation.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 23 November 2012
Received in revised form 5 December 2012
Accepted 5 December 2012
Available online 12 December 2012
Keywords:
Bis(allene)s
Rhodium
[2þ2þ1] Cycloaddition
Medium-sized ring formation
1. Introduction
SO2Ph
n
PhO2S
Rh-catalyzed
O
We have recently been involved in the investigation of the Rh(I)-
catalyzed intramolecular PausoneKhand-type reaction (PKTR) be-
PKTR
n=1,2
R
n
R
1
2
tween allene and the p-component aiming at the development of an
SO2Ph
SO2Ph
efficient procedure for the construction of bicyclo[m.3.0] com-
pounds (m¼4e6). Thus, the efficient construction of both the bicyclo
[4.3.0] and bicyclo[5.3.0] frameworks 2 from the alleneealkyne and
alleneealkene species 1 could be achieved (Scheme 1).1,2 Further-
more, it is noteworthy that the PKTR of the bis(allene)s 3 emerged as
a powerful tool for constructing the larger-sized bicyclo[6.3.0]
undecadienone skeletons 4.1g,h It was, however, not the case for the
alleneealkyne and alleneealkene species 1 in which the corre-
sponding bicyclo[6.3.0] skeletons werehardly formed in satisfactory
yields.
Both the ophiobolin and fusicoccin families have the common
5-8-5 tricyclic core skeletons as exemplified by fusicoauritone
and ophiobolin A (Fig. 1).3 These natural products show a wide
variety of potentially useful physiological activities, such as an
anti-tumor activity and anti-parasitic activity.4 Because of their
unique and challenging structures, several total syntheses as
well as synthetic studies on the formation of the core tricyclic
systems have been reported.5e7 In spite of many efforts to con-
struct the medium-sized ring system including the eight-
membered ring, it is still a challenging task.8 We envisioned
that the newly developed Rh(I)-catalyzed PKTR of bis(allene)s1g,h
Rh-catalyzed
PKTR
O
SO2Ph
SO2Ph
3
4
Scheme 1. Rh(I)-catalyzed intramolecular PKTR of allene and
p-component.
leading to the bicyclo[6.3.0] derivative would provide an alter-
native route for the preparation of the core tricyclic carbon
framework (5-8-5 ring system) of the ophiobolin and fusicoccin
families.
The simple retrosynthetic analysis for the construction of the 5-
8-5 tricyclic ring systems 8 is shown in Scheme 2. Bis(propargyl
alcohol) derivatives 6 would be derived from the cycloalkane-1,3-
H
H
R
O
HOC
H
HO
O
O
H
OH
ophiobolin A
fusicoccane (R = H)
ophiobolane (R = (CH2)2 Pr)
fusicoauritone
i
* Corresponding author. E-mail address: mukai@p.kanazawa-u.ac.jp (C. Mukai).
Fig. 1. Natural products possessing dicyclopenta[a,d]cyclooctane ring systems.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.014

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M.T.S. Shafawati et al. / Tetrahedron 69 (2013) 1509e1515
dione 5 by the conventional carbonecarbon forming reactions.
Various types of bis(allene)s 7 (R¼H, CO2Me, SO2Ph, P(O)(OEt)2 etc.)
should be obtained from 6 by the transformation reaction of the
propargyl alcohols into allenes. Based on the previous results, the
Rh(I)-catalyzed PKTR of bis(allene)s 7 would be expected to pro-
duce the corresponding bicyclo[6.3.0] derivatives 8. In this study as
a preliminary examination, we focused on the preparation of the 6-
8-5 ring system 8 (n¼2) instead of the 5-8-5 ring system 8 (n¼1)
from the commercially available and inexpensive dimedone (9) to
confirm the feasibility of our plan.
overall yield. Hydroxymethylation of the alkyne 13 using EtMgBr
and (HCHO)n afforded 14 in 65% yield, however, the Sonogashira
coupling reaction of which with the propargyl alcohol under several
conditions did not furnish the diyne derivative 15 at all. We tenta-
tively assumed that the bulky silyloxy functionality of 14 might
cause the trouble encountered for introduction of the alkyne moi-
ety. Thus, the less bulkier methoxy group was chosen as an alter-
native functional group. Acetylation of the primary alcohol of 14
(99% yield) was followed by desilylationwith TBAF to afford the allyl
alcohol derivative 16 in 65% yield. Exposure of 16 to MeI and Ag2O
effected methylation to produce the corresponding methoxy de-
rivative, deacetylation of which was carried out by methoxide to
provide 17 in 85% yield. The vinyl triflate 17 was treated with
propargyl alcohol under the typical Sonogashira conditions to afford
the desired bis(propargyl alcohol) derivative 18 in 75%. The diol
derivative 18 was then converted into the bis(phenylsulfonylallene)
19 in 33% overall yield via the successive phenylsulfenyl ester for-
mation, [2,3]-sigmatropic rearrangement and oxidation.1g
R
R
OH
OH
O
Z
O
O
O
Y
Z
Y
Z
Y
Z
n
n
n
R
8
R
7
n
5
6
O
With the required bis(phenylsulfonylallene) 19 in hand, several
reaction conditions of the PKTR were examined. The treatment of
19 with 20 mol % [RhCl(CO)dppp]2 in toluene at 120 ꢀC under an
atmosphere of CO gave an intractable complex mixture (Table 1,
entry 1). Increasing the CO pressure to 5 atm did not affect the
reaction and the complex mixture was again observed (entry 2).
On the contrary, decreasing the CO pressure (under an atmosphere
consisting of 0.05 atm of CO and 0.95 atm of Ar)1j,10 produced an
18% yield of the desired tricyclic compound 20 (entry 3). A similar
result (18%) was obtained when the loading amount of the catalyst
was reduced to 10 mol % (entry 4). The formation of 20 could be
rationalized by the initial formation of 2000, followed by the formal
1,3-hydrogen shift. An alternative 1,3-hydrogen shift from 2000
would lead to the 200. The exclusive formation of 20 might reflect
the fact that its structure is more stable than that of 200 pre-
sumably due to the fully conjugated triene functionality of the
former. The distance between the C12-stereogenic center and the
newly created C8-one is too far to control each other’s
dimedone (9)
Scheme 2. Synthetic plan for tricyclic systems.
2. Results and discussion
The known allylated dimedone 10,9 easily derived from dime-
done (9), was treated with triflic anhydride to form the vinyl triflate
in 85% yield, which was reduced with NaBH4 to give the corre-
sponding alcohol 11 in 91% yield (Scheme 3). The allylic alcohol
moiety of 11 was protected with the TBS group, and the terminal
alkene was exposed to a hydroborationeoxidation protocol with
disiamylborane and hydrogen peroxide to afford the primary alco-
hol 12 in 85% overall yield. The one-carbon homologation of the
primary alcohol 12 was achieved by consecutive oxidation with IBX
and treatment with OhiraeBestmann reagent to produce 13 in a 64%
OH
1, Tf2O, CH2Cl2
1) IBX, DMSO
O
HO
-78 C, 0.5 h
85%
1, TBSCl, Imid.
TBSO
rt, 3.5 h
ref. 9
DMF, rt, overnight
O
OTf
OTf
9
2) Ohira-Bestmann
MeOH, K2CO3
rt, overnight
2, NaBH4
2, Sia2BH, THF
rt, 0.5 h then
30% H2O2 aq.
3M NaOH, rt, 1 h
CeCl3 7H2O
MeOH, rt
10
11
12
64% for 2 steps
0.5 h, 91%
85% for 2 steps
1) MeI, Ag2O
4Å MS, Et2O
reflux, overnight
89%
OH
OAc
1) Ac2O, DMAP
(HCHO)n
EtMgBr
Et3N, CH2Cl2
rt, 1 h, 99%
TBSO
TBSO
C
HO
OTf
OTf
14
OTf
16
THF, 50
2) TBAF, AcOH
THF, 0 C to rt
5 h, 65%
2) K2CO3, MeOH
rt, 10 min, 85%
overnight
65%
13
OH
OH
OH
TBSO
OH
15
SO2Ph
SO2Ph
1) PhSCl, Et3N
OH
OH
OH
THF, -78
2 h
C
PdCl2(PPh3)2
CuI, Et3N
MeO
MeO
MeO
2) mCPBA
CH2Cl2, 0
1 h
DMSO, rt
overnight
75%
OTf
C
17
33% for 2 steps
18
19
Scheme 3. Preparation of bis(phenylsulfonylallene)s 19.

M.T.S. Shafawati et al. / Tetrahedron 69 (2013) 1509e1515
1511
Table 1
Rh(I)-catalyzed PKTR of 19
yield, which was successively treated with benzenesulfenyl chlo-
ride and mCPBA to produce the bis(allene) derivative 24 possessing
phosphonate and sulfonyl groups on the bis(allene) moiety in 62%
yield. The PKTR of 24 with 20 mol % [RhCl(CO)dppp]2 under the
previously used CO/Ar atmosphere (0.05/0.95 atm) proceeded well
to afford the corresponding 6-8-5 membered compound 25 in 65%
yield.
SO2Ph
SO2Ph
SO2Ph
SO2Ph
[RhCl(CO)dppp]2
8
O
O
O
MeO
MeO
MeO
MeO
toluene, reflux
gas
12
SO2Ph
SO2Ph
SO2Ph
19
20
20'
entry
gas
Rh(I) (mol%)
time (h) results
3. Conclusions
1
2
3
4
20
20
20
10
2
2
1
1
-
-
CO (1 atm)
CO (5 atm)
CO/Ar (0.05/0.95 atm)
CO/Ar (0.05/0.95 atm)
20 (18%)
20 (18%)
In summary, we have successfully developed
a synthetic
SO2Ph
method for the construction of the 6-8-5 tricyclic ring systems by
the Rh(I)-catalyzed intramolecular PKTR of bis(allene) species that
were derived from the commercially available dimedone. Applica-
tion of the procedure described here to the synthesis of the 5-8-5
tricyclic ring system, a core carbon framework of the ophiobolin
and fusicoccin families, is currently in progress.
20"
stereochemistry. Thus, it is thought that the tricyclic product 20
consisted of two stereoisomers because of the two stereogenic
centers (C8- and C12-positions), although the TLC behavior as well
as their spectral data indicate that this product seems to be
a single stereoisomer.
We could synthesize the desired 6-8-5 tricyclic compound 20,
but the chemical yield was far from being satisfactory. In addition,
we encountered the puzzling stereochemical problem during the
conversion of 19 into 20. It is obvious that the methoxy group on
the cyclohexene ring of the substrate 19 caused the issue. There-
fore, we changed methoxy functionality to a ketone functionality.
The secondary alcohol of 16 was oxidized with IBX to furnish the
ketone in 86% yield, which was then exposed to the Sonogashira
coupling conditions with propargyl alcohol to afford the diyne
derivative 21a in 89% yield (Scheme 4). The resulting diyne com-
4. Experimental
4.1. General
Melting point is uncorrected. IR spectra were measured in CHCl3.
1H NMR spectra were measured in CDCl3. CHCl3 (7.26 ppm) for silyl
compounds and tetramethylsilane (0.00 ppm) for compounds
without a silyl group were used as internal standards. 13C NMR
spectra were measured in CDCl3 (77.0 ppm) as an internal standard.
All reactions were carried out under a nitrogen atmosphere unless
otherwise stated. Silica gel (silica gel 60, 230e400 mesh) was used
for chromatography. Organic extracts were dried over anhydrous
Scheme 4. Preparation of tricyclic derivative 25.
pound was deacylated under basic conditions to produce the cor-
responding bis(propargyl alcohol) 21b in 62% yield. In order to
improve the chemical yield in the PKTR of the bis(allene) com-
pound, we tried to introduce several types of functionalities, such
as the H,11 Me,1j CO2Me,1j and SO2Ph groups, on the bis(allene)
moiety (R2 and R3 positions) of 22 from the common bis(propargyl
alcohol) derivative 21b, but the bis(allene)s having different
functional groups could not be obtained. Upon exposure to diethyl
chlorophosphite, the propargyl alcohol moiety of 21a was con-
verted to the allenyl diethyl phosphonate in 40% yield.12 The
resulting allene derivative was converted into the alcohol 23 in 62%
Na2SO4. 2-Allyl-5,5-dimethylcyclohexane-1,3-dione (2) is a known
compound.9
4.2. 2-Allyl-3-hydroxy-5,5-dimethylcyclohex-1-enyl tri-
fluoromethanesulfonate (11)
To a solution of 10 (2.4 g, 13 mmol) and Hunig’s base (4.6 mL,
27 mmol) in CH2Cl2 (65 mL) was slowly added Tf2O (2.7 mL,
16 mmol) at ꢁ78 ꢀC. After stirring for 0.5 h, the reaction was
quenched with water, extracted with CH2Cl2. The extract was
washed with water, brine, dried, and concentrated to dryness. The

1512
M.T.S. Shafawati et al. / Tetrahedron 69 (2013) 1509e1515
residue was passed through a short pad of silica gel with hexane/
AcOEt (2:1) to afford a vinyl triflate derivative (3.4 g, 85%) as a yellow
oil. IR 3028, 1686, 1663, 1420, 1246, 1229, 1207, 1138 cmꢁ1; 1H NMR
hexane/AcOEt (10:1) to afford 13 (1.7 g, 64% from 12) as a yellow oil.
IR 3308, 1248, 1225, 1207, 1140 cmꢁ1; 1H NMR
4.45e4.41 (m, 1H),
2.57e2.47 (m, 2H), 2.38e2.29 (m, 3H), 2.06 (d, 1H, J¼16.9 Hz), 1.94
(t, 2H, J¼2.7 Hz), 1.71e1.67 (m, 1H), 1.44 (dd, 1H, J¼13.1, 8.2 Hz), 1.05
(s, 3H), 0.98 (s, 3H), 0.90 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H). 13C NMR
d
d
5.73 (ddt, 1H, J¼16.8, 10.0, 6.2 Hz), 5.07 (d, 1H, J¼16.8 Hz), 5.03 (d,
1H, J¼10.0 Hz), 3.11 (d, 2H, J¼6.2 Hz), 2.63 (s, 2H), 2.35 (s, 2H),1.11 (s,
6H); 13C NMR
d
196.8,160.8,132.9,128.8,118.2 (q, JCF¼320 Hz),116.9,
d
145.2, 130.0, 118.3 (q, J¼320 Hz), 83.0, 68.9, 68.1, 44.8, 41.3, 31.4,
50.7, 42.3, 32.8, 27.9, 27.4; DARTMS m/z 313 (Mþþ1, 64); DARTHRMS
calcd for C12H16F3O4S 313.0721, found 313.0715. To a solution of the
vinyl triflate (2.4 g, 7.7 mmol) and CeCl3$7H2O (3.4 g, 9.2 mmol) in
MeOH (19 mL) was added NaBH4 (580 mg, 15 mmol) at room tem-
perature. After stirring for 1 h, the reaction mixture was quenched
with aqueous NH4Cl, extracted with AcOEt. The extract was washed
with water, brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane/AcOEt (6:1) to afford 11 (3.7 g,
91%) as a colorless oil. IR 3589, 3421, 1691, 1637, 1412, 1248, 1225,
30.2, 26.5, 25.8, 25.3, 18.0, 16.9, ꢁ3.9, ꢁ4.9; FABMS m/z 441 (Mþþ1,
32.2); FABHRMS m/z calcd for C14H32F3O4SSi 441.1743, found
441.1727.
4.5. 3-(tert-Butyldimethylsilyloxy)-2-(5-hydroxypent-3-ynyl)-
5,5-dimethylcyclohex-1-enyl trifluoromethanesulfonate (14)
To a solution of 13 (758 mg, 1.65 mmol) in THF (9 mL) was added
EtMgBr (1.5 M, 5.0 mL, 6.6 mmol) at 0 ꢀC. After stirring for 2 h at
50 ꢀC, paraformaldehyde (149 mg) was added to the reaction
mixture, and the mixture was further stirred overnight at the room
temperature. Then the reaction was quenched with aqueous NH4Cl,
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
matographed with hexane/AcOEt (4:1) to afford 14 (473 mg, 65%) as
1207, 1138 cmꢁ1; 1H NMR
d
5.86e5.76 (m, 1H), 5.19 (dd, 1H, J¼17.0,
1.4 Hz), 5.12 (dd, 1H, J¼10.1, 1.4 Hz) 4.37e4.34 (m, 1H), 3.16 (dd, 1H,
J¼14.6, 6.0 Hz), 3.07 (dd, 1H, J¼14.6, 7.8 Hz), 2.33 (d, 1H, J¼16.5 Hz),
2.07 (d,1H, J¼16.5 Hz),1.83 (ddd, 2H, J¼13.3, 6.0,1.4 Hz),1.44 (dd,1H,
J¼13.3, 8.7 Hz), 1.08 (s, 3H), 0.97 (s, 3H). 13C NMR
d 144.6, 134.0,
129.2,118.3 (q, J¼320 Hz),117.6, 67.1, 44.4, 41.4, 31.5, 30.6, 30.1, 26.4;
EIMS m/z 314 (Mþ, 2.8); EIHRMS calcd for C12H17F3O4S 314.0800;
found 314.0795.
a yellow oil. IR 3608, 3421, 1409, 1248, 1225, 1207, 1140 cmꢁ1
NMR
;
1H
d
4.42e4.40 (m, 1H), 4.19 (t, 2H, J¼2.1 Hz), 2.54e2.46 (m, 2H),
4.3. 3-(tert-Butyldimethylsilyloxy)-2-(3-hydroxypropyl)-5,5-
dimethylcyclohex-1-enyl trifluoromethanesulfonate (12)
2.40e2.38 (m, 2H), 2.30 (d, 1H, J¼16.8 Hz), 2.08 (d, 1H, J¼16.8 Hz),
1.71 (s, 1H), 1.68 (ddd, 1H, J¼13.1, 5.8, 1.0 Hz), 1.44 (dd, 1H, J¼13.1,
8.2 Hz), 1.05 (s, 3H), 0.99 (s, 3H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s,
To a solution of 11 (2.0 g, 6.4 mmol) and imidazole (2.2 g,
32 mmol) in DMF (21 mL) was added TBSCl (2.9 g, 19 mmol) at 0 ꢀC.
After warming to room temperature, the mixture was stirred
overnight. Then the mixture was quenched with aqueous NH4Cl,
extracted with AcOEt. The extract was washed with brine, dried,
and concentrated to dryness. The residue was passed through
a short pad of silica gel with hexane/AcOEt (20:1) to afford the
crude vinyl triflate. To a solution of the crude vinyl triflate in THF
(62 mL) was added (Sia)2BH (0.50 M in THF, 24 mL,12 mmol) at 0 ꢀC.
After stirring for 30 min at room temperature, the reaction mixture
were added H2O2 (18 mL) and 3 M NaOH (18 mL) at 0 ꢀC. The
mixture was further stirred for 1 h at room temperature, then
extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was chro-
matographed with hexane/AcOEt (4:1) to afford 12 (2.4 g, 85% from
11) as a colorless oil. IR 3626, 3441, 1693, 1463, 1248, 1225, 1207,
3H). 13C NMR
d
145.2, 130.0, 118.2 (q, J¼320 Hz), 84.7, 79.3, 67.8,
51.3, 44.8, 41.2, 31.4, 30.2, 26.3, 25.7, 25.2, 18.0, 16.9, ꢁ3.9, ꢁ4.9.
DARTMS m/z 471 (Mþþ1, 4.0); DARTHRMS calcd for C20H34F3O5SSi
471.1848, found 471.1836.
4.6. 5-[6-Hydroxy-4,4-dimethyl-2-(trifluoromethylsulfonyloxy)
cyclohex-1-enyl]pent-2-ynyl acetate (16)
To a solution of 14 (344 mg, 0.732 mmol) in CH2Cl2 (7 mL) were
added Ac2O (0.20 mL, 3.2 mmol), DMAP (26 mg, 0.22 mmol), and
Et3N (0.20 mL, 1.4 mmol) at 0 ꢀC. After stirring for 1 h at room
temperature, the reaction was quenched with water, extracted with
CH2Cl2. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
hexane/AcOEt (8:1) to afford the acetate derivative (369 mg, 99%) as
a yellowoil. IR 2237,1738,1410,1248,1227,1207,1140 cmꢁ1; 1H NMR
1140 cmꢁ1
;
1H NMR
d
4.39e4.36 (m, 1H), 3.64 (t, 2H, J¼6.4 Hz),
2.40e2.25 (m, 3H), 2.04 (d, 1H, J¼16.9 Hz), 1.78e1.65 (m, 3H), 1.46
d
4.62 (s, 2H), 4.42e4.39 (m, 1H), 2.49 (t, 2H, J¼7.3 Hz), 2.40 (t, 2H,
(dd, 1H, J¼13.3, 7.8 Hz), 1.05 (s, 3H), 0.97 (s, 3H), 0.89 (s, 9H), 0.11 (s,
J¼7.3 Hz), 2.30 (d, 1H, J¼16.8 Hz), 2.07e2.04 (m, 4H), 1.68 (dd, 1H,
J¼12.7, 5.8 Hz), 1.44 (dd, 1H, J¼12.7, 8.2 Hz), 1.05 (s, 3H), 0.98 (s, 3H),
3H), 0.10 (s, 3H). 13C NMR
d
144.5, 131.5, 117.2 (q, J¼320 Hz), 67.9,
62.6, 44.8, 41.2, 31.3, 30.6, 30.0, 26.8, 25.8, 22.8, 18.0, ꢁ4.0, ꢁ4.9;
DARTMS m/z 447 (Mþþ1, 7.0); DARTHRMS calcd for C18H34F3O5SSi
447.1848, found 447.1855.
0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H). 13C NMR
d 170.3, 145.3, 129.9,
118.2 (q, J¼326 Hz), 85.9, 74.8, 68.0, 52.7, 44.8, 41.2, 31.4, 30.3, 26.3,
25.7, 25.0, 20.7, 18.0, 17.1, ꢁ3.9, ꢁ4.9. DARTMS m/z 513 (Mþþ1, 1.3);
DARTHRMS calcd for C22H36F3O6SSi 513.1954, found 513.1964. To
a solution of the acetate derivative (343 mg, 0.669 mmol) in THF
(7 mL) was added TBAF (1.0 M in THF, 0.80 mL, 0.80 mmol, neu-
tralized with AcOH) at 0 ꢀC. After stirring for 5 h at room temper-
ature, the reaction was quenched with aqueous NH4Cl, extracted
with AcOEt. The extract was washed with water and brine, dried,
and concentrated to dryness. The residue was chromatographed
with hexane/AcOEt (3:1) to afford 16 (175 mg, 65%) as a yellow oil. IR
3587, 3529, 1732, 1375, 1411, 1248, 1225, 1140 cmꢁ1. 1H NMR 4.62 (t,
2H, J¼2.1 Hz), 4.45e4.43 (m, 1H), 2.65e2.61 (m, 1H), 2.56e2.50 (m,
2H), 2.47e2.41 (m, 1H), 2.35e2.31 (m, 1H), 2.07e2.05 (m, 4H), 1.87
(ddd,1H, J¼13.1, 5.8,1.7 Hz),1.41 (dd,1H, J¼13.1, 8.9 Hz),1.08 (s, 3H),
4.4. 3-(tert-Butyldimethylsilyloxy)-2-(but-3-ynyl)-5,5-
dimethylcyclohex-1-enyl trifluoromethanesulfonate (13)
To a solution of 12 (2.0 g, 6.0 mmol) in DMSO (60 mL) was added
IBX (3.4 g, 12 mmol) at room temperature. After stirring for 3.5 h at
the same temperature, the reaction was quenched by addition of
saturated aqueous Na2S2O3 and saturated aqueous NaHCO3. Then
the mixture was extracted with Et2O, washed with water and brine,
dried, and concentrated to dryness to afford the crude aldehyde. To
a solution of the crude aldehyde and OhiraeBestmann reagent
(960 mg, 5.0 mmol) in MeOH (70 mL) was added K2CO3 (1.2 g,
8.3 mmol) at room temperature. After stirring overnight, the
mixture was quenched with saturated aqueous NaHCO3, extracted
with Et2O. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
1.00 (s, 3H). 13C NMR
75.1, 66.7, 52.6, 44.7, 41.3, 31.4, 30.4, 25.7, 24.6, 20.7,16.8. FABMS m/z
421 (Mþþ1, 79.1); FABHRMS m/z calcd for C16H21F3O6SNa 421.0909,
found 421.0907.
d
170.5, 145.2, 123.0, 118.1 (q, J¼320 Hz), 86.2,

M.T.S. Shafawati et al. / Tetrahedron 69 (2013) 1509e1515
1513
4.7. 2-(5-Hydroxypent-3-ynyl)-3-methoxy-5,5-
dimethylcyclohex-1-enyl trifluoromethanesulfonate (17)
was washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed with CH2Cl2/hexane/
AcOEt (4:1:1) to afford 19 (189 mg, 33%) as a yellow oil. IR 1967,
MeI (0.50 mL, 4.5 mmol) was added to a mixture of Ag2O (1.6 g,
1936, 1373, 1150 cmꢁ1; 1H NMR
d 7.88e7.82 (m, 4H), 7.64e7.58 (m,
ꢀ
6.7 mmol), 4 A molecular sieve (400 mg) and 16 (256 mg,
2H), 7.55e7.53 (m, 2H), 7.51e7.48 (m, 2H) 5.31 (t, 2H, J¼3.4 Hz), 5.19
(s, 2H), 3.68e3.66 (m, 1H), 3.18 (s, 3H), 2.22e2.15 (m, 2H),
2.13e2.04 (m, 2H), 1.96 (d, 1H, J¼17.2 Hz), 1.87 (td, 1H, J¼12.7,
5.2 Hz), 1.71 (ddd, 1H, J¼12.7, 5.8, 1.7 Hz), 1.35 (1H, dd, J¼12.7,
0.643 mmol) in Et2O (7 mL). After stirring overnight at 50 ꢀC, the
precipitates were filtered through a pad of Celite. The solvent of
filtrate was removed in vacuo and the residue was chromato-
graphed with hexane/AcOEt (4:1) to afford the methoxy compound
(227 mg, 89%) as a yellow oil. IR 1740, 1412, 1246, 1227, 1207,
8.6 Hz), 0.94 (s, 3H), 0.86 (s, 3H); 13C NMR
d 207.5, 207.4, 140.2,
140.1,139.4,133.6,133.4,129.0,128.9,128.3,128.0,125.1,113.7,113.4,
84.5, 82.1, 75.9, 56.1, 44.2, 39.5, 30.3, 30.1, 28.6, 26.3, 24.9; DARTMS
m/z 525 (Mþþ1, 26); DARTHRMS calcd for C29H33O5S2 525.1769,
found 525.1766.
1142 cmꢁ1; 1H NMR
d
4.63 (t, 2H, J¼2.1 Hz), 4.03e4.00 (m, 1H), 3.34
(s, 3H), 2.60e2.56 (m, 1H), 2.48e2.41 (m, 3H), 2.33e2.29 (m, 1H),
2.08e2.05 (m, 4H), 1.79 (ddd, 1H, J¼13.0, 5.8, 1.7 Hz), 1.43 (dd, 1H,
J¼13.0, 8.6 Hz), 1.07 (s, 3H), 0.99 (s, 3H). 13C NMR
d 170.3, 145.9,
128.5, 118.3 (q, J¼320 Hz), 86.1, 75.2, 74.9, 56.1, 52.7, 41.4, 39.1, 31.4,
30.2, 26.2, 25.0, 20.7, 16.9. FABMS m/z 413 (Mþþ1, 12); FABHRMS m/
z calcd for C17H24F3O6S 413.1246, found 413.1241. To a solution of
the methoxy compound (11 mg, 2.9ꢂ10ꢁ2 mmol) in MeOH (0.5 mL)
was added K2CO3 (4 mg, 0.03 mmol). After stirring for 10 min, the
mixture was quenched with water and extracted with AcOEt. The
extract was washed with brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane/AcOEt (1:2) to af-
ford 17 (9.5 mg, 85%) as a yellow oil. IR 3607, 3445, 1693, 1410, 1246,
4.10. General procedure for rhodium(I)-catalyzed carbon-
ylative [2D2D1] cycloaddition
To a solution of the bis(allene) (0.1 mmol) in toluene (1 mL) was
added 10 or 20 mol % of [RhCl(CO)dppp]2. The reaction mixture was
heated at reflux under an atmosphere consisting of 0.05 atm of CO
and 0.95 atm of Ar until the complete disappearance of the starting
material (monitored by TLC). Toluene was evaporated off, and the
residual oil was chromatographed with hexane/AcOEt or CH2Cl2/
AcOEt to afford the cyclized product. The chemical yields are
summarized in Table 1 and Scheme 4.
1227, 1205, 1140 cmꢁ1; 1H NMR
d 4.20e4.19 (m, 2H), 4.04e4.00 (m,
1H), 3.35 (s, 3H), 2.60 (dt, 1H, J¼13.1, 7.2 Hz), 2.49e2.41 (m, 3H),
2.30 (dt, 1H, J¼16.9, 2.3 Hz), 2.07 (d, 1H, J¼16.9 Hz), 1.83e1.78 (m,
1H), 1.44 (dd, 1H, J¼13.3, 8.7 Hz), 1.07 (s, 3H), 1.01 (s, 3H); 13C NMR
4.11. 12-Methoxy-14,14-dimethyl-2,8-bis(phenylsulfonyl)tri-
cyclo[9.4.0.03,7]pentadeca-1(11),2,6-trien-5-one (20)
d
145.8, 128.6, 118.2 (q, J¼320 Hz), 84.8, 79.4, 75.0, 56.1, 51.2, 41.3,
39.1, 31.3, 30.2, 26.1, 25.2, 16.7; DARTMS m/z 371 (Mþþ1, 29);
DARTHRMS calcd for C15H22F3O5S 371.1140, found 371.1137.
Compound 20 was a yellow oil. IR 1716, 1308, 1150 cmꢁ1 1H
;
NMR 7.80e7.78 (m, 4H), 7.69 (t, 1H, J¼7.3 Hz), 7.63e7.49 (m, 5H),
7.14 (s, 1H), 4.24 (dd, 1H, J¼11.9, 3.7 Hz), 3.56e3.50 (m, 2H), 3.40 (d,
1H, J¼22.0 Hz), 3.09 (s, 3H), 2.91 (d, 1H, J¼17.9 Hz), 2.60 (dd, 1H,
J¼12.8, 3.7 Hz), 2.40e2.31 (m, 1H), 2.11e1.98 (m, 2H), 1.84 (d, 1H,
J¼17.9 Hz),1.66e1.62 (m, 1H),1.32e1.25 (m, 1H),1.05 (s, 3H), 0.88 (s,
4.8. 5-[2-(3-Hydroxyprop-1-ynyl)-6-methoxy-4,4-
dimethylcyclohex-1-enyl]pent-2-yn-1-ol (18)
To a solution of PdCl2(PPh3)2 (63 mg, 9.0ꢂ10ꢁ2 mmol), CuI
(37 mg, 0.20 mmol) and 17 (480 mg, 1.3 mmol) in dry DMSO (8 mL)
were added propargyl alcohol (0.20 mL, 3.9 mmol) and triethyl-
amine (0.60 mL, 3.9 mmol). After stirring overnight at room tem-
perature, the mixture was quenched with aqueous NH4Cl and
extracted with Et2O. The extract was washed with water and brine,
dried, and concentrated to dryness. The residue was chromato-
graphed with hexaneeAcOEt (1:1) to afford 18 (269 mg, 75%) as
3H). 13C NMR
d 201.0, 160.9, 144.7, 140.3, 139.8, 138.9, 137.9, 137.4,
134.5, 133.8, 130.7, 129.5, 129.2, 128.8, 127.4, 73.2, 62.8, 55.2, 43.4,
40.0, 38.1, 31.4, 30.2, 27.9, 27.0, 24.3; DARTMS m/z 553 (Mþþ1, 56);
DARTHRMS calcd for C30H33O6S2 553.1719, found 553.1716. Regio-
chemistry of 20 was determined by HMQC and HMBC.
4.12. 5-[2-(3-Hydroxyprop-1-ynyl)-4,4-dimethyl-6-
oxocyclohex-1-enyl]pent-2-ynyl acetate (21a)
a yellow oil. IR 3605, 3448 cmꢁ1; 1H NMR
d 4.42 (s, 2H), 4.22 (t, 2H,
J¼1.8 Hz), 3.88e3.85 (m, 1H), 3.33 (s, 3H), 2.71e2.57 (m, 2H),
2.49e2.33 (m, 2H), 2.09 (d, 1H, J¼16.9 Hz), 1.90 (d, 1H, J¼16.9 Hz),
1.76 (ddd, 1H, J¼12.8, 6.4, 1.8 Hz), 1.40 (dd, 1H, J¼12.8, 8.7 Hz), 0.98
To a solution of 16 (235 mg, 0.590 mmol) in DMSO (6 mL) was
added IBX (500 mg, 1.8 mmol) at room temperature. After stirring
for 5.5 h, the reaction was quenched with saturated aqueous
Na2S2O3 and saturated aqueous NaHCO3, extracted with AcOEt. The
extract was washed with water and brine, dried, and concentrated
to dryness. The residue was chromatographed with hexane/AcOEt
(4:1) to afford the ketone derivative (205 mg, 86%) as a yellow oil. IR
(s, 3H), 0.91 (s, 3H); 13C NMR
d 142.5, 118.3, 90.9, 86.4, 85.5, 78.8,
75.7, 56.1, 51.6, 51.4, 44.0, 39.6, 30.5, 30.2, 30.1, 26.1, 17.8; DARTMS
m/z 277 (Mþþ1, 9); DARTHRMS calcd for C17H25O3 277.1804, found
277.1793.
4.9. 3-Methoxy-5,5,-dimethyl-2-(3-phenylsulfonylpenta-3,4-
dienyl)-1-(1-phenylsulfonylpropa-1,2-dienyl)cyclohex-1-ene
(19)
1736, 1686, 1420, 1246, 1227, 1138 cmꢁ1
J¼2.1 Hz), 2.62 (s, 2H), 2.54 (t, 2H, J¼7.2 Hz), 2.39e2.37 (m, 2H), 2.32
(s, 2H), 2.03 (s, 3H), 1.10 (s, 6H). 13C NMR
197.1, 170.1, 161.5, 128.5,
; d 4.56 (t, 2H,
1H NMR
d
118.2 (q, J¼320 Hz), 85.3, 75.2, 52.5, 50.6, 42.3, 32.7, 27.7, 22.4,
To a solution of 18 (300 mg, 1.09 mmol) in THF (16 mL) were
added Et3N (1.4 mL, 9.8 mmol) and PhSCl (0.97 mL, 8.7 mmol) in
THF (4 mL) at ꢁ78 ꢀC. After stirring for 2 h at the same temperature,
the reaction was quenched with water, extracted with AcOEt. The
extract was washed with water and brine, dried, and concentrated
to dryness. The residue was passed through a short pad of silica gel
with hexane/AcOEt (10:1) to afford the crude sulfoxide. To a solu-
tion of the crude sulfoxide in CH2Cl2 (1 mL) was added a mCPBA
(400 mg, 2.34 mmol) at 0 ꢀC. After stirring for 1 h at the same
temperature, the reaction was quenched with aqueous Na2S2O3 and
saturated aqueous NaHCO3, and extracted with AcOEt. The extract
20.6, 17.3. DARTMS m/z 397 (Mþþ1, 100); DARTHRMS calcd
for C16H20F3O6S 397.0933, found 397.0921. To
a solution of
PdCl2(PPh3)2 (18 mg, 0.030 mmol), CuI (11 mg, 0.060 mmol) and the
ketone derivative (146 mg, 0.40 mmol) in dry DMSO (3 mL) were
added propargyl alcohol (0.10 mL, 1.9 mmol) and Et3N (0.30 mL,
1.9 mmol). After stirring for 2 h at room temperature, the reaction
was quenched with aqueous NH4Cl, extracted with Et2O. The ex-
tract was washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed with hexane/AcOEt
(1:1) to afford 21a (108 mg, 89%) as a yellow oil. IR 3607, 3447, 1734,
1663 cmꢁ1. 1H NMR
d
4.62 (t, 2H, J¼2.1 Hz), 4.47 (s, 2H), 2.67 (t, 2H,

1514
M.T.S. Shafawati et al. / Tetrahedron 69 (2013) 1509e1515
J¼7.1 Hz), 2.59 (br s, 1H), 2.37e2.34 (m, 4H), 2.27 (s, 2H), 2.07 (s,
3H),1.01 (s, 6H). 13C NMR
198.1,170.7, 140.0, 136.7, 101.0, 86.7, 84.0,
4.15. 2-Diethoxyphosphinyl-14,14-dimethyl-8-phenylsulfonyl-
tricyclo[9.4.0.03,7]pentadeca-1(11),2,6-triene-5,12-dione (25)
d
74.7, 52.7, 51.42, 51.35, 44.8, 33.3, 27.9, 26.7, 20.8, 17.9. DARTMS m/z
303 (Mþþ1, 100); DARTHRMS calcd for C18H23O4 303.1596, found
303.1587.
Compound 25 was brown crystals; mp 169e171 ꢀC (CH2Cl2);
IR 1708, 1670, 1323, 1310, 1263, 1238, 1153, 1024 cmꢁ1 1H NMR
;
7.83e7.81 (m, 2H), 7.70e7.66 (t, 1H, J¼7.3 Hz), 7.56e7.53 (m, 2H),
7.27 (s, 1H), 4.16e4.02 (m, 5H), 3.86 (dd, 1H, J¼22.0, 2.7 Hz), 3.25
(dd, 1H, J¼22.0, 3.2 Hz), 3.22 (dd, 1H, J¼18.3, 4.1 Hz), 2.96e2.92
(m, 1H), 2.30 (d, 1H, J¼15.6 Hz), 2.20e2.00 (m, 5H), 1.35 (t, 3H,
J¼6.9 Hz), 1.31 (t, 3H, J¼6.9 Hz), 1.10 (s, 3H), 0.86 (s, 3H). 13C NMR
4.13. Diethyl 1-[2-(5-hydroxypent-3-ynyl)-5,5-dimethyl-3-
oxocyclohex-1-enyl]propa-1,2-dienylphosphonate (23)
To a solution of 21a (39 mg, 0.13 mmol) in THF (1.5 mL) were
added Et3N (0.050 mL, 0.26 mmol) and diethyl chlorophosphite
(30 mL, 0.20 mmol) at ꢁ78 ꢀC. After stirring for 30 min at the same
temperature, the reaction mixture was warmed to room tempera-
ture and then heated at reflux for 9 h. The reaction mixture was
quenched by addition of saturated aqueous NaHCO3, extracted with
AcOEt. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
DCM/AcOEt (1:1) to afford the phosphonyl allene (22 mg, 40%) as
d
201.5, 196.8, 160.7 (d, J¼28.9 Hz), 150.7 (d, J¼7.2 Hz), 150.6 (d,
J¼11.6 Hz), 138.9, 137.3, 134.5, 134.0 (d, J¼14.5 Hz), 129.4, 128.8,
127.8 (d, J¼176.3 Hz), 63.3, 62.7 (t, J¼4.3 Hz), 50.8, 44.0, 41.4 (d,
J¼4.3 Hz), 32.9, 29.8 (d, J¼8.7 Hz), 27.2, 22.3, 16.4 (d, J¼5.8 Hz),
16.3 (d, J¼8.7 Hz), 14.1 (d, J¼11.6 Hz); DARTMS m/z 533 (Mþþ1,
27); DARTHRMS calcd for C27H34O7PS 533.1763, found 533.1755.
Regiochemistry of 25 was determined by HMQC and HMBC.
a yellow oil. IR 1960, 1931, 1738, 1668, 1265, 1024 cmꢁ1
;
1H NMR
Acknowledgements
d
5.14 (s, 1H), 5.11 (s, 1H), 4.61 (s, 2H), 4.20e4.07 (m, 4H), 2.56 (t, 2H,
J¼7.8 Hz), 2.47e2.46 (m, 2H), 2.31e2.26 (m, 4H), 2.06 (s, 3H),1.32 (t,
6H, J¼7.0 Hz),1.01 (s, 6H). 13C NMR
210.2 (d, J¼3.8 Hz),198.7,170.3,
d
This work was supported in part by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, for which we are thankful. M.T.S.S. thanks
the Ministry of Higher Education, Malaysia, for the postgraduate
scholarship.
147.2 (d, J¼3.8 Hz), 135.7 (d, J¼8.6 Hz), 96.7, 94.8, 87.1, 74.3, 63.0 (d,
J¼6.7 Hz), 52.8, 51.3, 45.0, 33.1, 27.9, 26.3 (d, J¼1.9 Hz), 20.8, 18.1 (d,
J¼1.9 Hz), 16.2 (d, J¼6.2 Hz). DARTMS m/z 423 (Mþþ1, 100);
DARTHRMS calcd for C22H32O6P 423.1937, found 423.1940. To a so-
lution of the phosphonyl allene (16 mg, 4.0ꢂ10ꢁ2 mmol) in MeOH
(0.5 mL) was added K2CO3 (7 mg, 0.04 mmol). After stirring for
5 min, the mixture was quenched with water, extracted with AcOEt.
The extract was washed with brine, dried, and concentrated to
dryness. The residue was chromatographed with hexane/AcOEt
(1:2) to afford 23 (9.5 mg, 62%) as a colorless oil. IR 3597, 3398,
References and notes
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1755e1758; (b) Mukai, C.; Nomura, I.; Kitagaki, S. J. Org. Chem. 2003, 68,
1376e1385; (c) Mukai, C.; Inagaki, F.; Yoshida, T.; Kitagaki, S. Tetrahedron Lett.
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404e409.
2222, 1960, 1929, 1711, 1666, 1265, 1024 cmꢁ1. 1H NMR
d 5.11 (s, 1H),
5.07 (s, 1H), 4.18e4.08 (m, 6H), 2.53 (t, 2H, J¼7.3 Hz), 2.46e2.45 (m,
2H), 2.35e2.31 (m, 2H), 2.26 (s, 2H), 1.32 (t, 6H, J¼7.8 Hz), 1.02 (s,
6H). 13C NMR
d
210.2 (d, J¼2.9 Hz), 198.9, 147.4 (d, J¼3.8 Hz), 135.6
(d, J¼8.6 Hz), 96.6, 94.7, 84.9, 79.6, 63.0 (d, J¼6.7 Hz), 51.4, 50.9,
44.9, 33.0, 27.8, 26.0 (d, J¼1.9 Hz), 17.8 (d, J¼2.9 Hz), 16.1 (d,
J¼6.7 Hz). DARTMS m/z 381 (Mþþ1, 100); DARTHRMS calcd for
C20H30O5P 381.1831, found 381.1829.
2. (a) Geis, O.; Schmalz, H. G. Angew. Chem., Int. Ed. 1998, 37, 911e914; (b)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263e3283; (c) Mukai, C.;
Sonobe, H.; Kim, J. S.; Hanaoka, M. J. Org. Chem. 2000, 65, 6654e6659; (d)
Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800e1810; (e)
4.14. Diethyl 1-[5,5-dimethyl-3-oxo-2-(3-phenylsulfonylpenta-
3,4-dienyl)cyclohex-1-enyl]propa-1,2-dienylphosphonate (24)
~
ꢁ
ꢁ
Blanco-Urgoiti, J.; Anorbe, L.; Perez-Serrano, L.; Domínguez, G.; Perez-Castells, J.
~
Chem. Soc. Rev. 2004, 33, 32e42; (f) Bonaga, L. V. R.; Krafft, M. E. Tetrahedron
2004, 60, 9795e9833; (g) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328e2336;
To a solution of 23 (22 mg, 6.0ꢂ10ꢁ2 mmol) in THF (0.5 mL) were
added Et3N (50 mL, 0.36 mmol) and PhSCl (50 mL, 0.36 mmol) in
THF at ꢁ78 ꢀC. After stirring for 6 h at the same temperature, the
reaction was quenched with water, extracted with AcOEt. The ex-
tract was washed with water and brine, dried, and concentrated to
dryness. The residue was passed through a short pad of silica gel
with hexane/AcOEt (1:5) to afford the crude sulfoxide. To a solution
of the crude sulfoxide in CH2Cl2 (1 mL) was added mCPBA (21 mg,
0.12 mmol) at 0 ꢀC. After stirring for 1 h at the same temperature,
the reaction was quenched with saturated aqueous NaHCO3 and
saturated aqueous Na2S2O3, extracted with CH2Cl2. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with CH2Cl2/AcOEt (2:1) to af-
ford 24 (19 mg, 62%) as a yellow oil. IR 1963, 1934, 1668, 1620, 1308,
(h) Lee, H.-W.; Kwong, F.-K. Eur. J. Org. Chem. 2010, 789e811.
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A. 2007, 104, 3084e3088; (e) Leeuwen, I. J. D. V. V.; Kortekaas-Thijssen, C.;
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5. Total synthesis of ophiobolin families: (a) Rowley, M.; Tsukamoto, M.; Kishi, Y. J.
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6. Total synthesis of fusicoccane families: (a) Srikrishna, A.; Nagaraju, G. Synlett
2012, 123e127; (b) Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P.
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Tetrahedron 1996, 52, 3921e3932.
1265, 1145, 1024 cmꢁ1 1H NMR
. d 7.85e7.84 (m, 2H), 7.58 (t, 1H,
J¼7.6 Hz), 7.50 (m, 2H), 5.36 (t, 2H, J¼3.4 Hz), 5.05 (s, 1H), 5.03 (s,
1H), 4.15e4.05 (m, 4H), 2.45e2.41 (m, 4H), 2.25e2.22 (m, 4H), 1.32
(t, 6H, J¼7.0 Hz), 1.01 (s, 6H). 13C NMR 209.9, 207.7, 198.6, 147.5 (d,
J¼2.9 Hz), 140.2, 135.7 (d, J¼10.1 Hz), 133.3, 129.0, 127.9, 113.2, 96.0,
94.7, 84.5, 62.9 (d, J¼7.2 Hz), 51.3, 44.8, 33.1, 29.5, 27.8, 25.5 (d,
J¼2.9 Hz), 25.4, 16.2 (d, J¼7.2 Hz). DARTMS m/z 505 (Mþþ1, 100);
DARTHRMS calcd for C26H34O6PS 505.1814, found 505.1815.
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