Structural diversification of the aminobicyclo[4.3.0]nonane skeleton using alkynylsilyl-derived allylic trichloroacetimidates

Article abstract of DOI:10.1039/C7OB00456G

The amino substituted bicyclo[4.3.0]nonane is a molecular scaffold found in a wide range of natural products and medicinal agents. Despite this, synthetic methods for the general preparation of this structural motif are sparse. Here we evaluate a diastere

Full text of DOI:10.1039/C7OB00456G

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Structural diversification of the
aminobicyclo[4.3.0]nonane skeleton using alkynylsilyl-
derived allylic trichloroacetimidates†
Received 00th January 20xx,
Accepted 00th January 20xx
Mohamed A. B. Mostafa, Angus E. McMillan and Andrew Sutherland*
DOI: 10.1039/x0xx00000x
The amino substituted bicyclo[4.3.0]nonane is a molecular scaffold found in a wide range of natural products and
medicinal agents. Despite this, synthetic methods for the general preparation of this structural motif are sparse.
www.rsc.org/
Here we evaluate
a
diastereoselective approach for the preparation of vinylsilyl derived
aminobicyclo[4.3.0]nonanes using a one-pot multi-bond forming process involving a Pd(II)-catalysed Overman
rearrangement, a Ru(II)-catalysed ring closing enyne metathesis reaction, followed by a hydrogen bonding
directed Diels-Alder reaction. We show that a benzyldimethylsilyl-substituted alkene analogue is amenable to
further functionalisation and the late stage generation of diverse sp3-rich, drug-like aminobicyclo[4.3.0]nonane
scaffolds with up to six stereogenic centres.
the presence of a C-7 substituent within the allylic
trichloroacetimidate substrate, allowed the use of mild
palladium(II)-catalysed conditions for the Overman
Introduction
The amino substituted bicyclo[4.3.0]nonane core is found
in various natural products,1 such as guanidine alkaloid
netamine A (1),2 the antitumour antibiotics (+)-ptilocaulin
(2)3 and kinamycin A (3),4 as well as the lycopodium
alkaloid serratinine (4) (Fig. 1).5 Amino-indanes, a
partially saturated form of the aminobicyclo[4.3.0]nonane
rearrangement step.12
Although diversity could be
introduced into the aminobicyclo[4.3.0]nonane core
during the final-stage Diels-Alder reaction, the other point
of diversity was via a Sonogashira reaction during the first
step. This required substantial effort to generate a small
library of these compounds with various R-groups. To
overcome this limitation, we decided to investigate an
alternative C-7 substituent that would be compatible with
scaffold are also found in
a
diverse range of
pharmacologically important compounds including the
monoamine transporter inhibitor (+)-indatraline (5)6 and,
rasagiline (Azilect), used for the treatment of Parkinson’s
disease.7 While there are synthetic methods for the
preparation of specific aminobicyclo[4.3.0]nonanes,8 there
are relatively few general strategies for the
stereoselective synthesis of this scaffold that is modular,
allowing late-stage structural diversification.9
With the aim of developing new strategies for the
preparation of drug-like scaffolds, we reported a one-pot,
three-step multi-bond forming process of alkyne derived
allylic alcohols that utilised an Overman rearrangement, a
ring closing enyne metathesis (RCEYM) step and a Diels-
Alder reaction for the general preparation of
aminobicyclo[4.3.0]nonanes.10 More recently the diversity
of this library was extended by using C-7 substituted
hept-2-en-6-yn-1-ols (Scheme 1a).11 As well as yielding
aminobicyclo[4.3.0]nonanes with additional functionality,
the
synthesis
of
alkyne-derived
allylic
trichloroacetimidates, allow a Pd(II)-catalysed Overman
rearrangement and be used as a functional handle for
late-stage diversification.
H
H
O
n-Pr
OH
OAc
n-Hex
n-Bu
HO
H
H
HN
NH
HN
NH
O
OAc
N2
OAc
NH
NH
Netamine A (1)
(+)-Ptilocaulin (2)
Kinamycin A (3)
Cl
OH
Cl
H
O
.HO SMe
NH
3
N
OH
MeHN.HCl
Serratinine (4)
(+)-Indatraline (5)
Rasagiline (6)
Fig. 1 Biologically active aminobicyclo[4.3.0]nonanes and amino-indanes.
This journal is © The Royal Society of Chemistry 20xx
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a) Previous work11
DOI: 10.1039/C7OB00456G
one-pot
three-step
Pd(II) Ru(II)
7
R
R
X
R
R-I, [Cu]
[Pd]
Y
then
dienophile
OH
Cl3C
H
OH
HN
O
NH
O
CCl3
b) This work
one-pot
[Si]
three-step
Pd(II) Ru(II)
R
[Si]
vinylsilane
functionalisation
Y
Y
then
dienophile
Cl3C
OH
Cl3C
H
H
NH
HN
O
NH
X
X
O
O
CCl3
Scheme 1 One-pot methods for the synthesis of aminobicyclo[4.3.0]nonanes.
We now report the use of alkynylsilyl derived allylic
trichloroacetimidates as substrates for the one-pot
multi-bond forming process and the diastereoselective
synthesis of aminobicyclo[4.3.0]nonanes bearing a
vinylsilane functional handle (Scheme 1b). We also
11 were converted to the (E)-α,β-unsaturated ethyl
esters 12 and 13 in high yields using a one-pot Swern
oxidation and Horner-Wadsworth-Emmons reaction
under
mild
Masamune-Roush
condtions.18,19
Reduction of the ester groups using DIBAL-H then
gave allylic alcohols 14 and 15 in excellent yields. The
highly efficient six-step route (90% overall yield) for the
preparation of BDMS-derived allylic alcohol 15 was
easily amenable to scale-up, allowing synthesis of
multi-gram quantities of this key substrate.
demonstrate
benzyldimethylsilyl (BDMS) analogue for the late-stage
synthesis of small library of novel, drug-like
the
synthetic
utility
of
a
a
aminobicyclo[4.3.0]nonanes with up to six stereogenic
centres.
DHP, p-TsOH
Results and discussion
CH2Cl2
The first aim of this project was the synthesis of a hept-
2-en-6-yn-1-ol bearing a C-7 silyl group. Although a
wide-range of silanes have been developed for cross-
coupling reactions,13 the BDMS group14 was chosen as
this was likely to be stable to the various steps
required for allylic alcohol synthesis and the conditions
of the one-pot process. While the vinyl-BDMS
functionality is relatively robust, it has been used in a
number of Hiyama-Denmark type couplings.15 To
probe the steric requirements of the one-pot three-step
process, the tert-butyldimethylsilyl (TBDMS) analogue
was also prepared. Initially, pent-4-yn-1-ol bearing a C-
5 TBDMS group was prepared in a one-pot operation
by silylation of both the alkyne and alcohol moieties,
followed by acid-mediated hydrolysis of the silyloxy
group (Scheme 2).16 While this allowed rapid access to
5-(tert-butyldimethylsilyl)pent-4-yn-1-ol (8), the overall
yield was only 31%. Therefore, preparation of the
corresponding BDMS analogue 11 was performed in a
stepwise fashion, with protection of the hydroxyl group
as a THP ether before silylation of the alkyne with
benzyldimethylsilyl chloride under basic conditions.17
Removal of the THP protecting group then gave 5-
(benzyldimethylsilyl)pent-4-yn-1-ol (11) in quantitative
yield over the three steps. The pent-4-yn-1-ols 8 and
0 ºC to rt
2.5 h, 100%
OH
OTHP
7
9
TBDMSCl, n-BuLi
THF, -78 ºC to rt, 18 h
then 1 M HCl, 31%
BnMe2SiCl
n-BuLi, THF
-78 ºC, 5 h
100%
[Si]
SiMe2Bn
p-TsOH
MeOH
rt, 18 h
100%
OH
OTHP
10
8 [Si] = TBDMS, 31%
11 [Si] = BDMS
(COCl)2, DMSO
Et3N, CH2Cl2 (EtO)2POCH2CO2Et
MeCN, rt, 18 h
then DBU, LiCl
-78 ºC to rt, 3 h
[Si]
OH
[Si]
DIBAL-H
Et2O
-78 ºC to rt
18 h
CO2Et
12 [Si] = TBDMS, 80%
13 [Si] = BDMS, 92%
14 [Si] = TBDMS, 92%
15 [Si] = BDMS, 98%
Scheme 2 Synthesis of alkynyl derived allylic alcohols 14 and 15.
2 | J. Name., 2012, 00, 1-3
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Having prepared the alkynylsilyl derived allylic
alcohols, conditions for an optimal one-pot synthesis of
the corresponding aminobicyclo[4.3.0]nonanes were
next explored. The TBDMS-analogue that was
designed to probe the steric limitation of the one-pot
process was initially investigated (Scheme 3). The
allylic trichloroacetimidate was formed by reaction of
14 with trichloroacetonitrile and DBU and without
purification,20 this was subjected to the one-pot three-
step process. In our previous study that evaluated C-7
substituted alkyne derived allylic alcohols for the one-
pot process, it was found that while a relatively bulky
substituent prevented coordination of the Pd(II)-
catalyst to the alkyne and facilitated an efficient
Overman rearrangement, the presence of this group
hindered the following RCEYM step.11b With the
TBDMS-derived allylic trichloroacetimidate, a similar
outcome was observed for both steps. The Pd(II)-
catalysed Overman rearrangement proceeded under
View Article Online
DOI: 10.1039/C7OB00456G
[Si]
[Si]
OH
Cl3CCN, DBU
CH2Cl2, rt, 3 h
HN
O
CCl3
14 [Si] = TBDMS
15 [Si] = BDMS
PdCl2(MeCN)2
(10 mol%)
toluene, rt, 12 h
[Si]
[Si]
Grubbs II
1,7-octadiene
90 ºC
HN
O
Cl3C
NH
CCl3
O
N-phenyl
maleimide
75 ºC
standard
trichloroacetamide after 12 hours,21 however, the
RCEYM reaction required forcing conditions.
conditions
to
give
the
allylic
[Si]
[Si]
A
combination of the use of 1,7-octadiene (an in situ
source of ethylene) to accelerate the reaction,22 high
loading of Grubbs 2nd generation catalyst (20 mol%)
and a 120 hour reaction time was required for
complete conversion to the enyne.23 Following the
hydrogen bonding directed Diels-Alder reaction with N-
phenyl maleimide, aminobicyclo[4.3.0]nonane 16 was
isolated as a single diastereomer in 19% yield over the
four steps. This relatively low yield is likely due to the
extended RCEYM step and demonstrates the steric
limitation of the one-pot process.
Application of the one-pot process using BDMS-
allylic alcohol 15 was more straightforward (Scheme
3). Again, allylic trichloroacetimidate formation and
Pd(II)-catalysed Overman rearrangement proceeded
under standard conditions. The RCEYM reaction did
require the presence of 1,7-octadiene, but needed only
7 mol% catalyst loading and was complete after 18
hours. Diels-Alder reaction with N-phenyl maleimide
then gave aminobicyclo[4.3.0]nonane 17 as a single
diastereomer in 57% yield over the four steps. As
previously reported for the Diels-Alder reaction of
trichloroacetamide derived cyclic exo-dienes, the
reaction proceeds via a hydrogen bonding controlled
endo transition state, forming the syn-products (syn
relationship of hydrogen atoms at C-3a, C-8, C-8a and
C-8b) with excellent diastereoselectivity (>20:1).10,11
Analysis of BDMS-derived aminobicyclo[4.3.0]nonane
17 using difference NOE experiments confirmed the
relative stereochemistry and that the Diels-Alder
reaction has proceeded in the same manner as other
trichloroacetamide derived cyclic exo-diene substrates
(Scheme 3).24
O
Ph
O
N
O
H
NH
O
NH
CCl3
NPh
O
O
Cl3C
16 [Si] = TBDMS, 19%
17 [Si] = BDMS, 57%
NOE enhancements for 17:
SiMe2Bn
O
H
8a 3a
8
O
N
H
Cl3C
H
H
N
H
2.3% NOE
O
Ph
2.7% NOE
2.2% NOE
Scheme 3 Synthesis of aminobicyclo[4.3.0]nonanes 16 and 17.
Having used the BDMS-group to perform a mild
Pd(II)-catalysed
Overman
rearrangement
and
efficiently access the aminobicyclo[4.3.0]nonane core,
we next wanted to demonstrate that the resulting
vinylsilane could be used for the late-stage synthesis
of a wide range of derivatives. Initially, removal of the
trialkylsilyl group to access the parent scaffold was
investigated (Scheme 4). During introduction of the
BDMS-group for cross-coupling reactions, Trost and
co-workers showed that BDMS-vinylsilanes were
stable to proto-desilylation under typical fluoride
conditions.14 This was confirmed on treatment of
vinylsilane 17 with TBAF, which showed no reaction.
Increasing the temperature or duration of the reaction
only led to decomposition. Cleavage of the C-Si bond
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was achieved under acidic conditions. While the use of
dilute hydrochloric acid solutions (2 M or 4 M) gave
only partial proto-desilylation, treatment of 17 with 6 M
hydrochloric acid at 60 °C gave 18 cleanly, in 74%
yield. The reactivity of tri-substituted alkene 18 to
oxidation was next studied. Osmium tetroxide
mediated dihydroxylation under Donohoe conditions
After some optimisation, vinyl iodide 21 was found
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to be an efficient cross-couplingDOpaI: r1t0n.1e0r39f/oCr7OSB0u0z4u5k6Gi-
Miyaura reactions. Using Pd(PPh3)4 (10 mol%) and
phenylboronic acid under typical conditions gave the
cross-coupled product 22 in 76% yield. Reaction of an
electron-rich variant, p-methoxyphenylboronic acid
also proceed smoothly, giving 23 in 53% yield. In
previous studies, we have found that the
trichloroacetamide group is prone to dechlorination
during Pd(0)-catalysed reactions.11b,29 Similarly, in the
Suzuki-Miyaura reactions to form 22 and 23, small
amounts of dichloroacetamide analogues of these
compounds were observed in the reaction mixture
(<10%). This became a more significant issue in
attempting a cross-coupling reaction with electron-
defficient p-fluorophenylboronic acid, where substantial
amounts of the reduced coupled product were also
detected (~20%). However, this by-product could be
minimised (<10%) by using a shorter reaction time,
which allowed the synthesis of 24 in 46% yield. To
expand the diversity of aminobicyclo[4.3.0]nonanes at
gave the desired diol product 19 as
a single
diastereomer in 86% yield.25 In a similar fashion,
treatment of 18 with m-CPBA proceeded with high
selectivity and the major diastereomer 20 was isolated
in 73% yield.26,27 The high selectivity for both reactions
is a consequence of the relative stereochemistry at the
C-3a, C-8, C-8a and C-8b positions of the tricyclic core
of 18. This creates a curved shape to the molecule
where reactions readily take place at the more
exposed convex face.
The final stage of this project then investigated
cross-coupling reactions of vinylsilane 17 for the late-
stage diversification of the aminobicyclo[4.3.0]nonane
core. Using standard conditions for Hiyama-Denmark
reactions with the BDMS-group,14 attempts were made
to couple 17 with various electron-rich and electron-
deficient aryl iodides. However, these reactions
showed only decomposition of vinylsilane 17. Due to
the inability of 17 to undergo cross-coupling reactions,
an alternative strategy was sought using a more
reactive vinyl functionality. Iodo-desilylation of
vinylsilane 17 was found to proceed readily with iodine
monochloride and gave vinyl iodide 21 in 88% yield
(Scheme 5).28 This was then used to explore various
palladium-catalysed cross-coupling reactions.
the C-5 position,
a
Sonogashira reaction with
phenylacetylene was also performed. For this
example, both palladium-mediated coupling and
reduction of the trichloroacetamide were found to be
rapid, leading to isolation of the dichloroacetamide-
derived enyne 25 as the major product, in 48% yield.
SiMe2Bn
Ph
PhB(OH)2
Pd(PPh3)4, Na2CO3
O
O
H
NH
O
NPh
toluene/MeOH
70 ºC, 48 h
76%
O
H
O
NH
NPh
Cl3C
O
17
Cl3C
SiMe2Bn
22
ICl, CH2Cl2
-78 °C, 88%
I
p-MeOPh
O
p-MeOPhB(OH)2
Pd(PPh3)4
O
H
NH
OH
NPh
HO
H
Na2CO3
O
O
Cl3C
O
OsO4, TMEDA
CH2Cl2
O
H
toluene/MeOH
70 ºC, 36 h
53%
NH
O
H
17
NPh
NH
NPh
O
Cl3C
O
O
-78 °C to rt
3 h, 86%
6 M HCl 60 ºC, 18 h
MeOH/THF
Cl3C
O
21
NH
74%
23
NPh
O
Ph
Pd(PPh3)2Cl2
CuI, Et3N, DMF
rt, 2 h, 48%
Cl3C
19
p-FPh
Ph
O
p-FPhB(OH)2
Pd(PPh3)4
Na2CO3
O
H
NH
NPh
O
O
Cl3C
O
H
O
H
toluene/MeOH
70 ºC, 12 h
46%
NH
18
NPh
O
m-CPBA
CH2Cl2
Cl3C
24
O
O
O
H
O
0 °C to rt
36 h, 73%
NH
NPh
NH
NPh
O
Cl2HC
O
Cl3C
25
20
Scheme 5 Synthesis and cross-coupling reactions of vinyl iodide 21.
Scheme 4 Synthesis and oxidation of aminobicyclo[4.3.0]nonane 18.
4 | J. Name., 2012, 00, 1-3
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5-(tert-Butyldimethylsilyl)pent-4-yn-1-ol (8)30
Conclusions
View Article Online
DOI: 10.1039/C7OB00456G
n-Butyllithium (0.520 mL, 1.31 mmol, 2.5 M in hexane)
was added dropwise to a solution of 4-pentyn-1-ol (7)
(0.050 g, 0.590 mmol) in tetrahydrofuran (20 mL) at
−78 °C. The reaction mixture was stirred for 0.75 h at
−78 °C. tert-Butyldimethylsilyl chloride (0.220 g, 1.48
mmol) was then added. The reaction mixture was
allowed to warm to room temperature and stirred for 18
h. A 1 M aqueous solution of hydrochloric acid (2 mL)
was then added and the mixture was stirred for 2 h.
The resulting mixture was diluted with ethyl acetate (10
mL), washed with water (2 × 15 mL) and a saturated
solution of sodium bicarbonate (15 mL). The aqueous
layers were washed with ethyl acetate (2 × 15 mL),
and the combined organic phase was washed with
brine (20 mL), dried (MgSO4), filtered and
concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/ethyl acetate, 9:1)
gave 5-(tert-butyldimethylsilyl)pent-4-yn-1-ol (8) (0.036
g, 31%) as a colourless oil. Spectroscopic data were
consistent with the literature.30 δH (400 MHz, CDCl3)
0.06 (6H, s, Si(CH3)2), 0.90 (9H, s, SiC(CH3)3), 1.75
(2H, quin., J 6.5 Hz, 2-H2), 1.99 (1H, br s, OH), 2.34
(2H, t, J 6.5 Hz, 3-H2), 3.74 (2H, t, J 6.5 Hz, 1-H2); δC
(101 MHz, CDCl3) −4.5 (2 × CH3), 16.5 (C), 16.5 (CH2),
26.1 (3 × CH3), 31.3 (CH2), 61.8 (CH2), 83.3 (C), 107.2
(C); m/z (ESI) 221 (MNa+. 100%).
In conclusion, two alkynylsilyl derived allylic
trichloroacetimidates have been prepared and
evaluated as substrates for a one-pot multi-reaction
process
aminobicyclo[4.3.0]nonanes.
for
the
preparation
While
of
novel
TBDMS-
a
derivative showed the steric limitations of this process,
a BDMS-analogue was efficiently converted to the
corresponding aminobicyclo[4.3.0]nonane in good
overall yield. The BDMS-compound was then explored
for
the
late-stage
diversification
of
the
aminobicyclo[4.3.0]nonane core. Vinylsilane 17 was
found to undergo both proto-desilylation and iodo-
silylation reactions, leading to derivatives that could
undergo a range of oxidation and cross-coupling
reactions. Overall, this study has developed a general
route to novel, sp3-rich aminobicyclo[4.3.0]nonanes
incorporating diversity at a late-stage of the synthesis.
To exemplify the strategy, the project focused on using
a single dienophile, N-phenyl maleimide during the
Diels-Alder reaction. However, as shown in previous
studies,11 we believe that other alkenes will react
readily with the BDMS-derived diene allowing further
late-stage expansion of the compounds that can be
formed via this process. Work is currently underway to
achieve this goal and explore further reactions of
BDMS-derived aminobicyclo[4.3.0]nonanes.
1-(Tetrahydropyran-2’-yloxy)-4-pentyne (9)31
To a solution of 4-pentyn-1-ol (7) (0.900 g, 10.8 mmol)
and a catalytic amount of p-toluenesulfonic acid
monohydrate (0.020 g) in dichloromethane (25 mL) at
0 °C was added 3,4-dihydro-2H-pyran (2.71 g, 32.2
mmol). The reaction mixture was allowed to warm to
room temperature and stirred for 2.5 h. Ethyl acetate
(50 mL) was then added and the solution was poured
into a solution of sodium hydrogen carbonate (100
mL). The mixture was then extracted with ethyl acetate
(3 × 50 mL). The organic layers were combined,
washed with brine (100 mL), dried (MgSO4), filtered
and concentrated in vacuo. Purification by flash
column chromatography (petroleum ether/diethyl ether,
10:1) gave 1-(tetrahydropyran-2’-yloxy)-4-pentyne (9)
(1.81 g, 100%) as a colourless oil. Spectroscopic data
were consistent with the literature.31 δH (400 MHz,
CDCl3) 1.46−1.86 (8H, m, 2-H2, 3’-H2, 4’-H2 and 5’-H2),
1.94 (1H, t, J 2.7 Hz, 5-H), 2.28−2.35 (2H, m, 3-H2),
3.45−3.55 (2H, m, 1-HH and 6’-HH), 3.80−3.91 (2H, m,
1-HH and 6’-HH), 4.60 (1H, t, J 3.3 Hz, 2’-H); δC (101
MHz, CDCl3) 15.1 (CH2), 19.2 (CH2), 25.4 (CH2), 28.6
(CH2), 30.4 (CH2), 61.7 (CH2), 65.4 (CH2), 68.5 (CH),
83.6 (C), 98.4 (CH); m/z (EI) 168 (M+. 4%), 149 (8),
125 (11), 111 (12), 84 (74), 67 (28), 49 (100).
Experimental
All reagents and starting materials were obtained from
commercial sources and used as received. All dry
solvents were purified using a PureSolv 500 MD
solvent purification system. All reactions were
performed under an atmosphere of argon unless
otherwise mentioned. Brine refers to a saturated
solution
of
sodium
chloride.
Flash
column
chromatography was performed using Fisher matrix
silica 60. Macherey-Nagel aluminium-backed plates
pre-coated with silica gel 60 (UV254) were used for
thin layer chromatography and were visualised by
staining with KMnO4. H and 13C NMR spectra were
1
recorded on a Bruker DPX 400 (1H: 400 MHz; 13C: 101
MHz) spectrometer or a Bruker 500 (1H: 500 MHz; 13C:
126 MHz) spectrometer with chemical shift values
reported in ppm relative to a residual solvent peak and
in the solvent stated. Assignment of 1H NMR signals is
based on COSY experiments. Assignment of 13C NMR
signals is based on HSQC and/or DEPT experiments.
All coupling constants, J, are quoted in Hz. Mass
spectra were obtained using
a JEOL JMS-700
spectrometer for EI and CI or a Bruker Microtof-q for
ESI. Infrared spectra were obtained neat using a
Shimadzu IRPrestige-21 spectrometer. Melting points
were determined on a Reichert platform melting point
apparatus.
5-(Benzyldimethylsilyl)-1-(tetrahydropyran-2’-
yloxy)pent-4-yne (10)32
n-Butyllithium (2.56 mL, 6.40 mmol, 2.5 M in hexane)
was slowly added to
a stirred solution of 1-
(tetrahydropyran-2’-yloxy)-4-pentyne (9) (0.980 g, 5.82
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Page 6 of 11
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Journal Name
mmol) in tetrahydrofuran (28 mL) at −78 °C. The
resulting solution was stirred at –78 °C for 0.5 h at
which time benzyldimethylsilyl chloride (1.16 mL, 6.40
mmol) was added. The resulting solution was stirred at
–78 °C for 5 h. The reaction was quenched with a
saturated solution of ammonium chloride (20 mL) and
extracted with diethyl ether (3 × 20 mL). The combined
organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Purification by flash column
chromatography (petroleum ether/diethyl ether, 8:2)
reaction mixture was stirred for 0.5 h at −78 °C and
DOI: 10.1039/C7OB00456G
then allowed to warm to room temperature and stirred
View Article Online
for a further 3 h. A solution of lithium chloride (0.750 g,
1.78 mmol), triethyl phosphonoacetate (0.354 mL, 1.78
mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (2.66
mL, 1.78 mmol) in acetonitrile (4 mL) was then
prepared and stirred for 1 h. The Swern solution was
concentrated in vacuo, then the Horner-Wadsworth-
Emmons solution was added and the reaction mixture
was stirred at room temperature overnight. The
reaction was quenched with a saturated solution of
ammonium chloride (2.5 mL) and concentrated to give
an orange residue, which was then extracted with
diethyl ether (4 × 5 mL). The organic layers were
combined, dried (MgSO4), filtered and concentrated in
vacuo. Purification by flash column chromatography
(petroleum ether/ethyl acetate, 7:3) gave ethyl (2E)-7-
(tert-butyldimethylsilyl)hept-2-en-6-ynoate (12) (0.211
g, 80%) as a colourless oil. νmax/cm−1 (neat) 2929
(CH), 2364, 1723 (C=O), 1472, 1250, 1040, 837; δH
(400 MHz, CDCl3) 0.07 (6H, s, Si(CH3)2), 0.91 (9H, s,
SiC(CH3)3), 1.28 (3H, t, J 7.1 Hz, OCH2CH3), 2.34–
2.45 (4H, m, 4-H2 and 5-H2), 4.18 (2H, q, J 7.1 Hz,
OCH2CH3), 5.88 (1H, d, J 15.7 Hz, 2-H), 6.97 (1H, dt, J
15.7, 6.6 Hz, 3-H); δC (101 MHz, CDCl3) −4.6 (2 ×
CH3), 14.2 (CH3), 16.4 (C), 18.8 (CH2), 26.0 (3 × CH3),
31.3 (CH2), 60.2 (CH2), 84.0 (C), 105.8 (C), 122.5
(CH), 146.5 (CH), 166.3 (C); m/z (ESI) 289.1590
(MNa+. C15H26NaO2Si requires 289.1594).
gave
5-(benzyldimethylsilyl)-1-(tetrahydropyran-2’-
yloxy)-4-pentyne (10) (1.84 g, 100%) as a colourless
oil. Spectroscopic data were consistent with the
literature.32 δH (400 MHz, CDCl3) 0.10 (6H, s,
Si(CH3)2), 1.47−1.87 (8H, m, 2-H2, 3’-H2, 4’-H2 and 5’-
H2), 2.18 (2H, s, SiCH2), 2.35 (2H, t, J 7.1 Hz, 3-H2),
3.42−3.54 (2H, m, 1-HH and 6’-HH), 3.79−3.91 (2H, m,
1-HH and 6’-HH), 4.60 (1H, t, J 3.3 Hz, 2’-H),
7.05−7.12 (3H, m, 3 × ArH), 7.19−7.25 (2H, m, 2 ×
ArH); δC (101 MHz, CDCl3) 0.0 (2 × CH3), 18.7 (CH2),
21.4 (CH2), 27.4 (CH2), 28.4 (CH2), 30.7 (CH2), 32.6
(CH2), 64.0 (CH2), 67.7 (CH2), 85.0 (C), 100.6 (CH),
110.2 (C), 126.2 (CH), 130.0 (2 × CH), 130.3 (2 × CH),
141.1 (C); m/z (ESI) 339 (MNa+. 100%).
5-(Benzyldimethylsilyl)pent-4-yn-1-ol (11)17
p-Toluenesulfonic acid monohydrate (0.008 g, 0.042
mmol)
was
added
to
a
solution
of
5-
(benzyldimethylsilyl)-1-(tetrahydropyran-2’-yloxy)pent-
4-yne (10) (0.085 g, 0.270 mmol) in methanol (3 mL).
The resulting solution was stirred at room temperature
for 18 h. The reaction was quenched by addition of
brine (50 mL). The aqueous layer was extracted with
ethyl acetate (3 × 50 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated
in vacuo. Purification by flash column chromatography
(petroleum ether/diethyl ether, 1:1) gave 5-
(benzyldimethylsilyl)pent-4-yn-1-ol (11) (0.065 g,
100%) as a colourless oil. Spectroscopic data were
consistent with the literature.17 δH (400 MHz, CDCl3)
0.12 (6H, s, Si(CH3)2), 1.76 (2H, quin., J 6.5 Hz, 2-H2),
1.86 (1H, s, OH), 2.19 (2H, s, SiCH2), 2.35 (2H, t, J 6.5
Hz, 3-H2), 3.72 (2H, t, J 6.5 Hz, 1-H2), 7.06–7.13 (3H,
m, 3 × ArH), 7.21–7.27 (2H, m, 2 × ArH); δC (101 MHz,
CDCl3) 0.0 (2 × CH3), 18.4 (CH2), 28.4 (CH2), 33.0
(CH2), 63.6 (CH2), 85.5 (C), 110.0 (C), 126.2 (CH),
130.0 (2 × CH), 130.3 (2 × CH), 141.1 (C); m/z (ESI)
255 (MNa+. 100%).
Ethyl
(2E)-7-(benzyldimethylsilyl)hept-2-en-6-
ynoate (13)
Ethyl
(2E)-7-(benzyldimethylsilyl)hept-2-en-6-ynoate
(13) was synthesised as described for ethyl (2E)-7-
(tert-butyldimethylsilyl)hept-2-en-6-ynoate (12) using 5-
(benzyldimethylsilyl)pent-4-yn-1-ol (11) (0.990 g, 4.28
mmol). Purification by flash column chromatography
(petroleum ether/diethyl ether, 8:2) gave ethyl (2E)-7-
(benzyldimethylsilyl)hept-2-en-6-ynoate (13) (1.19 g,
92%) as a colourless oil. νmax/cm−1 (neat) 2958 (CH),
1720 (C=O), 1656 (C=C), 1494, 1249, 1154, 1039,
833, 758; δH (400 MHz, CDCl3) 0.10 (6H, s, Si(CH3)2),
1.29 (3H, t, J 7.1 Hz, OCH2CH3), 2.18 (2H, s, SiCH2),
2.34–2.45 (4H, m, 4-H2 and 5-H2), 4.20 (2H, q, J 7.1
Hz, OCH2CH3), 5.87 (1H, dt, J 15.7, 1.4 Hz, 2-H), 6.97
(1H, dt, J 15.7, 6.6 Hz, 3-H), 7.03–7.12 (3H, m, 3 ×
ArH), 7.19–7.25 (2H, m, 2 × ArH); δC (101 MHz,
CDCl3) 0.0 (2 × CH3), 16.3 (CH3), 20.8 (CH2), 28.3
(CH2), 33.1 (CH2), 62.2 (CH2), 86.3 (C), 108.8 (C),
124.5 (CH), 126.3 (CH), 130.1 (2 × CH), 130.3 (2 ×
CH), 141.0 (C), 148.4 (CH), 168.2 (C); m/z (ESI)
323.1422 (MNa+. C18H24NaO2Si requires 323.1438).
(2E)-7-(tert-Butyldimethylsilyl)hept-2-en-6-yn-1-ol
(14)
Ethyl
(2E)-7-(tert-butyldimethylsilyl)hept-2-en-6-
ynoate (12)
Dimethyl sulfoxide (0.176 mL, 2.48 mmol) was added
to a stirred solution of oxalyl chloride (0.120 mL, 1.39
mmol) in dichloromethane (5 mL) at −78 °C. The
mixture was stirred for 0.3
h
before 5-(tert-
butyldimethylsilyl)-pent-4-yn-1-ol (8) (0.196 g, 0.990
mmol) in dichloromethane (2 mL) was slowly added.
The mixture was stirred for a further 0.3 h before
triethylamine (0.690 mL, 4.95 mmol) was added. This
Ethyl (2E)-7-(tert-butyldimethylsilyl)hept-2-en-6-ynoate
(12) (0.165 g, 0.620 mmol) was dissolved in diethyl
ether (4 mL) and cooled to −78 °C. DIBAL-H (1 M in
hexane) (1.36 mL, 1.36 mmol) was added dropwise
6 | J. Name., 2012, 00, 1-3
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ARTICLE
mL) and
and the reaction mixture was stirred at −78 °C for 3 h,
before warming to room temperature overnight. The
solution was cooled to 0 °C and quenched by the
addition of a saturated solution of Rochelle salt (2 mL)
and warmed to room temperature with vigorous stirring
for 1 h, producing a white precipitate that was filtered
through a pad of Celite® and washed with diethyl ether
(3 × 4 mL). The filtrate was then dried (MgSO4), filtered
and concentrated in vacuo. Purification by flash
dissolved
in
toluene
(6
View Article Online
bis(acetonitrile)palladium chlorideDOI(:010.0.100369/Cg7O, B000.40526G4
mmol) was then added and the reaction mixture was
stirred at room temperature for 12 h. Grubbs second
generation catalyst (0.020 g, 0.024 mmol) was added
with 1,7-octadiene (0.142 mL, 0.960 mmol) and the
reaction mixture was stirred for 60 h at 90 °C. A
second portion of Grubbs second generation catalyst
(0.020 g, 0.024 mmol) was added with 1,7-octadiene
(0.142 mL, 0.960 mmol) and the reaction mixture was
stirred for further 60 h at 90 °C. N-Phenyl maleimide
(0.062 g, 0.360 mmol) was added with hydroquinone
(0.003 g, 0.030 mmol). The reaction mixture was
stirred for 18 h at 75 °C. The reaction mixture was then
cooled and the solvent was evaporated. Flash column
chromatography (petroleum ether/ethyl acetate, 8:2)
gave (3aS*,8R*,8aS*,8bR*)-5-(tert-butyldimethylsilyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (16) (0.025 g, 19%) as a yellow oil.
νmax/cm−1 (neat) 3319 (NH), 2954 (CH), 1699 (C=O),
1517 (C=C), 1388, 1199, 827, 755; δH (400 MHz,
CDCl3) 0.08 (3H, s, SiCH3), 0.15 (3H, s, SiCH3), 0.86
(9H, s, SiC(CH3)3), 1.83 (1H, ddd, J 18.6, 12.4, 7.6 Hz,
7-HH), 2.12–2.21 (2H, m, 4-HH and 7-HH), 2.24–2.38
(1H, m, 6-HH), 2.65 (1H, dd, J 16.5, 7.6 Hz, 6-HH),
2.92–2.98 (1H, m, 8a-H), 3.01 (1H, dd, J 14.8, 1.3 Hz,
4-HH), 3.32 (1H, ddd, J 8.9, 7.2, 1.3 Hz, 3a-H), 3.40
(1H, dd, J 8.9, 6.3 Hz, 8b-H), 4.77–4.88 (1H, m, 8-H),
7.12–7.17 (2H, m, 2 × ArH), 7.37–7.50 (3H, m, 3 ×
ArH), 8.84 (1H, d, J 9.6 Hz, NH); δC (126 MHz, CDCl3)
−5.1 (CH3), −4.2 (CH3), 18.3 (C), 26.8 (3 × CH3), 30.3
(CH2), 30.5 (CH2), 31.9 (CH2), 39.3 (CH), 40.6 (CH),
43.1 (CH), 52.3 (CH), 92.9 (C), 126.4 (2 × CH), 128.8
(C), 129.0 (CH), 129.3 (2 × CH), 131.5 (C), 156.1 (C),
162.3 (C), 178.1 (C), 179.8 (C); m/z (ESI) 563.1045
(MNa+. C25H3135Cl3N2NaO3Si requires 563.1062).
(3aS*,8R*,8aS*,8bR*)-5-(Benzyldimethylsilyl)-
column
chromatography
(petroleum
ether/ethyl
acetate, 8:2) gave (2E)-7-(tert-butyldimethylsilyl)hept-
2-en-6-yn-1-ol (14) (0.128 g, 92%) as a colourless oil.
νmax/cm−1 (neat) 3332 (OH), 2929 (CH), 2174, 1472,
1250, 1007, 968, 837, 825, 774; δH (400 MHz, CDCl3)
0.07 (6H, s, Si(CH3)2), 0.92 (9H, s, SiC(CH3)3), 1.32
(1H, br s, OH), 2.23–2.39 (4H, m, 4-H2 and 5-H2), 4.09
(2H, br t, J 4.6 Hz, 1-H2), 5.66–5.78 (2H, m, 2-H and 3-
H); δC (101 MHz, CDCl3) −4.5 (2 × CH3), 16.5 (C), 19.9
(CH2), 26.0 (3 × CH3), 31.5 (CH2), 63.5 (CH2), 83.1
(C), 107.0 (C), 130.4 (CH), 130.8 (CH); m/z (ESI)
247.1479 (MNa+. C13H24NaOSi requires 247.1489).
(2E)-7-(Benzyldimethylsilyl)hept-2-en-6-yn-1-ol (15)
(2E)-7-(Benzyldimethylsilyl)hept-2-en-6-yn-1-ol
was synthesised as described for (2E)-7-(tert-
butyldimethylsilyl)hept-2-en-6-yn-1-ol (14) using ethyl
(2E)-7-(benzyldimethylsilyl)hept-2-en-6-ynoate
(1.35 g, 4.49 mmol). Purification by flash column
chromatography (petroleum ether/ethyl acetate, 9:1)
(15)
(13)
gave
(2E)-7-(benzyldimethylsilyl)hept-2-en-6-yn-1-ol
(15) (1.14 g, 98%) as a colourless oil. νmax/cm−1 (neat)
3367 (OH), 2922 (CH), 2175, 1494, 1249, 838, 762,
698; δH (500 MHz, CDCl3) 0.11 (6H, s, Si(CH3)2), 1.43
(1H, br s, OH), 2.18 (2H, s, SiCH2), 2.23–2.34 (4H, m,
4-H2 and 5-H2), 4.10 (2H, d, J 4.4 Hz, 1-H2), 5.65–5.76
(2H, m, 2-H and 3-H), 7.06–7.12 (3H, m, 3 × ArH),
7.20–7.25 (2H, m, 2 × ArH); δC (101 MHz, CDCl3) 0.0
(2 × CH3) 21.8 (CH2), 28.4 (CH2), 33.2 (CH2), 65.4
(CH2), 85.5 (C), 109.9 (C), 126.2 (CH), 130.0 (2 × CH),
130.3 (2 × CH), 132.3 (CH), 132.6 (CH), 141.1 (C); m/z
(ESI) 281.1323 (MNa+. C16H22NaOSi requires
281.1332).
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (17)
(3aS*,8R*,8aS*,8bR*)-5-(tert-Butyldimethylsilyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (16)
(3aS*,8R*,8aS*,8bR*)-5-(Benzyldimethylsilyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (17) was synthesised as described
(2E)-7-(tert-Butyldimethylsilyl)hept-2-en-6-yn-1-ol (14)
(0.054 g, 0.240 mmol) was dissolved in
dichloromethane (6 mL) and cooled to 0 °C. To the
solution 1,8-diazabicyclo[5.4.0]undec-7-ene (0.007 mL,
0.048 mmol) and trichloroacetonitrile (0.036 mL, 0.360
mmol) were added. The reaction mixture was allowed
to warm to room temperature and stirred for 3 h. The
reaction mixture was filtered through a short pad of
silica gel with diethyl ether (100 mL) and the filtrate
concentrated in vacuo to give the allylic
trichloroacetimidate, which was used without further
purification. The allylic trichloroacetimidate was
for
3aS*,8R*,8aS*,8bR*)-5-(tert-butyldimethylsilyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione
(16)
using
(2E)-7-
(benzyldimethylsilyl)hept-2-en-6-yn-1-ol (15) (0.500 g,
1.92 mmol), except that the reaction mixture was
stirred with Grubbs second generation catalyst (0.114
g, 0.134 mmol) and 1,7-octadiene (1.13 mL, 7.66
mmol) for 18 h at 90 °C before N-phenyl maleimide
(0.500 g, 2.87 mmol) was added with hydroquinone
(0.026 g, 0.24 mmol). The reaction mixture was stirred
for 12 h at 75 °C. The reaction mixture was cooled to
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ARTICLE
Journal Name
room temperature and the solvent was evaporated.
Purification by flash column chromatography
26.1 (CH2), 28.6 (CH2), 31.7 (CH2), 39.4Vie(wCAHrti)c,le O4n1li.n2e
(CH), 41.5 (CH), 52.9 (CH), 92D.9OI:(1C0.)1,0319/1C77.O1B0(0C45H6G),
126.5 (2 × CH), 129.1 (CH), 129.3 (2 × CH), 131.5 (C),
145.8 (C), 162.3 (C), 178.5 (C), 179.6 (C); m/z (CI)
427.0373 (MH+. C19H1835Cl3N2O3 requires 427.0383),
393 (65%), 359 (100), 325 (65), 311 (20), 266 (25),
174 (25), 113 (25), 71 (73).
(3aS*,5S*,5aR*,8R*,8aR*,8bR*)-5,5a-Dihydroxy-2-
phenyl-3a,4,5,5a,6,7,8a,8b-octahydro-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (19)
(petroleum
ether/diethyl
ether,
9:1)
gave
(3aS*,8R*,8aS*,8bR*)-5-(benzyldimethylsilyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (17) (0.631 g, 57%) as a yellow oil.
νmax/cm−1 (neat) 3313 (NH), 3023 (CH), 2957 (CH),
1698 (C=O), 1518 (C=C), 1389, 1198, 830, 754; δH
(500 MHz, CDCl3) 0.05 (3H, s, SiCH3), 0.09 (3H, s,
SiCH3), 1.73–1.89 (1H, m, 7-HH), 2.06–2.27 (5H, m,
SiCH2, 4-HH, 6-HH and 7-HH), 2.52 (1H, dd, J 16.5,
7.6 Hz, 6-HH), 2.90–2.96 (1H, m, 8a-H), 2.99 (1H, dd,
J 14.7, 1.6 Hz, 4-HH), 3.34 (1H, ddd, J 8.9, 6.8, 1.6 Hz,
3a-H), 3.42 (1H, dd, J 8.9, 6.5 Hz, 8b-H), 4.75–4.88
(1H, m, 8-H), 6.91–6.96 (2H, m, 2 × ArH), 7.04–7.10
(1H, m, ArH), 7.14–7.21 (4H, m, 4 × ArH), 7.38–7.50
(3H, m, 3 × ArH), 8.91 (1H, d, J 9.5 Hz, NH); δC (126
MHz, CDCl3) −3.2 (CH3), −2.6 (CH3), 25.2 (CH2), 29.4
(CH2), 29.8 (CH2), 31.9 (CH2), 39.5 (CH), 40.7 (CH),
43.1 (CH), 52.3 (CH), 92.9 (C), 124.3 (CH), 126.3 (2 ×
CH), 128.2 (2 × CH), 128.3 (2 × CH), 129.0 (C), 129.1
(CH), 129.4 (2 × CH), 131.5 (C), 139.3 (C), 155.7 (C),
162.3 (C), 178.4 (C), 179.9 (C); m/z (ESI) 597.0898
(MNa+. C28H2935Cl3N2NaO3Si requires 597.0905).
(3aS*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-Hexahydro-2-
phenyl-8-(2’,2’,2’-
(3aS*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-Hexahydro-2-
phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (18) (0.029 g, 0.068 mmol) was
dissolved in dichloromethane (2 mL) at –78 °C.
Tetramethylethylenediamine (0.011 mL, 0.075 mmol)
was added and the reaction mixture stirred for 0.1 h,
before the addition of osmium tetroxide (0.019 g, 0.075
mmol). The dark coloured solution was stirred for 1 h
at –78 °C before warming to room temperature and
then stirred for a further 2 h. The solvent was removed
in vacuo and the dark coloured solid was dissolved in
methanol (2 mL). 12 M Hydrochloric acid (0.5 mL) was
added and the reaction stirred for a further 2 h. The
solvent was removed in vacuo to afford a dark solid.
Flash
column
chromatography
19:1) gave
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (18)10
(dichloromethane/methanol,
(3aS*,5S*,5aR*,8R*,8aR*,8bR*)-5,5a-dihydroxy-2-
phenyl-3a,4,5,5a,6,7,8a,8b-octahydro-8-(2’,2’,2’-
To
a
solution
of
(3aS*,8R*,8aS*,8bR*)-5-
(benzyldimethylsilyl)-3a,4,6,7,8a,8b-hexahydro-2-
phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (19) (0.027 g, 86%) as a white
solid. Mp 168–170 °C; νmax/cm–1 (neat) 3471 (OH),
3329 (NH), 2946 (CH), 1698 (C=O), 1515 (C=C), 1386,
1175, 821, 754; δH (500 MHz, CDCl3) 1.61–1.76 (1H,
m, 6-HH), 1.85–2.03 (2H, m, 6-HH and 7-HH), 2.09
(1H, dt, J 13.5, 3.7 Hz, 4-HH), 2.18 (1H, ddd, J 13.5,
10.8, 6.7 Hz, 4-HH), 2.41–2.55 (1H, m, 7-HH), 2.70–
2.89 (2H, m, 8a-H and OH), 3.00 (1H, br s, OH), 3.22
(1H, dd, J 9.0, 7.1 Hz, 8b-H), 3.35 (1H, ddd, J 9.0, 6.7,
3.7 Hz, 3a-H), 3.62 (1H, d, J 10.8 Hz, 5-H), 5.04–5.16
(1H, m, 8-H), 7.21–7.25 (2H, m, 2 × ArH), 7.40–7.56
(3H, m, 3 × ArH), 8.56 (1H, d, J 9.5 Hz, NH); δC (126
MHz, CDCl3) 29.7 (CH2), 30.3 (CH2), 37.1 (CH2), 38.6
(CH), 39.3 (CH), 48.1 (CH), 51.9 (CH), 70.1 (CH), 81.9
(C), 92.8 (C), 126.3 (2 × CH), 129.2 (CH), 129.5 (2 ×
CH), 131.2 (C), 162.1 (C), 178.0 (C), 178.8 (C); m/z
(ESI) 483.0242 (MNa+. C19H1935Cl3N2NaO5 requires
483.0252).
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (17) (0.038 g, 0.066 mmol) in
tetrahydrofuran (1 mL) was added methanol (2 mL)
and 6 M hydrochloric acid (3 mL). The reaction mixture
was stirred at 60 °C for 18 h. A 20% solution of
aqueous sodium carbonate (6 mL) was added and the
mixture was extracted with ethyl acetate (3 × 10 mL).
The combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. Purification by flash
column
acetate,
chromatography
7:3) gave
(petroleum
(3aS*,8R*,8aS*,8bR*)-
ether/ethyl
4,6,7,8,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (18) (0.021 g, 74%) as a white
solid. Mp 174‒176 °C; νmax/cm‒1 (neat) 3304 (NH),
2955 (CH), 2924 (CH), 1695 (C=O), 1516 (C=C), 1388,
1288, 1202, 1182, 822, 750; δH (500 MHz, CDCl3) 1.81
(1H, qd, J 12.5, 7.6 Hz, 7-HH), 2.10‒2.18 (1H, m, 7-
HH), 2.19‒2.38 (2H, m, 6-HH and 4-HH), 2.47 (1H, dd,
J 16.2, 7.6 Hz, 6-HH), 2.85 (1H, ddd, J 15.1, 7.2, 1.1
Hz, 4-HH), 2.89‒2.96 (1H, m, 8a-H), 3.33 (1H, ddd, J
8.7, 7.2, 1.1 Hz, 3a-H), 3.43 (1H, dd, J 8.7, 6.4 Hz, 8b-
H), 4.80‒4.91 (1H, m, 8-H), 5.75‒5.81 (1H, m, 5-H),
7.15‒7.20 (2H, m, 2 × ArH), 7.39‒7.51 (3H, m, 3 ×
ArH), 8.95 (1H, d, J 9.2 Hz, NH); δC (126 MHz, CDCl3)
(3aS*,5S*,5aR*,8R*,8aR*,8bR*)-5,5a-Epoxy-
3a,4,5,5a,6,7,8a,8b-octahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (20)
3-Chloroperbenzoic acid (0.052 g, 0.300 mmol) was
added to a stirred solution of (3aS*,8R*,8aS*,8bR*)-
4,6,7,8,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
8 | J. Name., 2012, 00, 1-3
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Page 9 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
1,3(2H,3aH)-dione (18) (0.032 g, 0.075 mmol) in
dichloromethane (2 mL) at 0 °C. The reaction mixture
was warmed from 0 °C to room temperature over 18 h.
The mixture was then cooled to 0 °C before 3-
chloroperbenzoic acid (0.052 g, 0.300 mmol) was
added. The reaction mixture was stirred for a further 24
h at room temperature, quenched by the addition of a
saturated solution of sodium sulfite (3 mL) and
extracted with dichloromethane (2 × 3 mL). The
combined organic layers were washed with a saturated
solution of sodium hydrogen carbonate (3 × 6 mL),
water (6 mL), brine (6 mL), then dried (MgSO4), filtered
and concentrated in vacuo. Purification by flash
solid. Mp 130−132 °C; νmax/cm−1 (neat) 3309 (NH),
View Article Online
2954 (CH), 1698 (C=O), 1517 (C=DCO)I,: 1103.190139,/1C72O0B00,0845263G;
δH (400 MHz, CDCl3) 1.86 (1H, qd, J 12.3, 8.2 Hz, 7-
HH), 2.12–2.34 (2H, m, 6-HH and 7-HH), 2.46 (1H, dd,
J 16.9, 8.2 Hz, 6-HH), 2.84–2.94 (1H, m, 4-HH), 3.02–
3.08 (1H, m, 8a-H), 3.28 (1H, dd, J 15.7, 1.2 Hz, 4-
HH), 3.37 (1H, ddd, J 8.6, 6.7, 1.2 Hz, 3a-H), 3.42 (1H,
dd, J 8.6, 5.8 Hz, 8b-H), 4.86–4.99 (1H, m, 8-H), 7.16–
7.21 (2H, m, 2 × ArH), 7.41–7.53 (3H, m, 3 × ArH),
8.84 (1H, d, J 9.6 Hz, NH); δC (101 MHz, CDCl3) 30.6
(CH2), 33.6 (CH2), 39.8 (CH2), 40.6 (CH), 41.1 (CH),
44.5 (CH), 53.9 (CH), 82.0 (C), 92.8 (C), 126.5 (2 ×
CH), 129.3 (CH), 129.4 (2 × CH), 131.4 (C), 151.0 (C),
162.1 (C), 177.0 (C), 178.9 (C); m/z (ESI) 574.9151
(MNa+. C19H1635Cl3IN2NaO3 requires 574.9163).
column
chromatography
(petroleum
ether/ethyl
acetate, 7:3) gave (3aS*,5S*,5aR*,8R*,8aR*,8bR*)-
5,5a-epoxy-3a,4,5,5a,6,7,8a,8b-octahydro-2-phenyl-8-
(2’,2’,2’-
(3aS*,8R*,8aS*,8bR*)-2,5-Diphenyl-3a,4,6,7,8a,8b-
hexahydro-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (20) (0.024 g, 73%) as a light
brown solid. Mp 154–156 °C; νmax/cm−1 (neat) 3265
(NH), 2934 (CH), 1697 (C=O), 1520 (C=C), 1394,
1192, 824, 773; δH (500 MHz, CDCl3) 1.65−1.72 (1H,
m, 6-HH), 1.94−2.11 (2H, m, 6-HH and 7-HH), 2.23
(1H, dd, J 15.5, 8.5 Hz, 4-HH), 2.26−2.34 (1H, m, 7-
HH), 2.77 (1H, dd, J 15.5, 4.1 Hz, 4-HH), 2.96 (1H, dd,
J 11.2, 5.0 Hz, 8a-H), 3.05−3.12 (1H, m, 3a-H), 3.17
(1H, dd, J 9.8, 5.0 Hz, 8b-H), 3.59 (1H, d, J 4.1 Hz, 5-
H), 4.70−4.82 (1H, m, 8-H), 7.27−7.33 (2H, m, 2 ×
ArH), 7.38−7.53 (3H, m, 3 × ArH), 9.33 (1H, d, J 9.8
Hz, NH); δC (126 MHz, CDCl3) 25.6 (CH2), 29.1 (CH2),
32.8 (CH2), 38.4 (CH), 40.0 (CH), 40.5 (CH), 50.5
(CH), 56.5 (CH), 67.9 (C), 92.8 (C), 126.7 (2 × CH),
128.9 (CH), 129.3 (2 × CH), 132.3 (C), 162.5 (C),
178.9 (C), 180.3 (C); m/z (ESI) 465.0144 (MNa+.
C19H1735Cl3N2NaO4 requires 465.0146).
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (22)11b
To a solution of (3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-
hexahydro-5-iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (21) (0.019 g, 0.045 mmol) in a 5:1
mixture of toluene/methanol (3 mL) at room
temperature was added phenylboronic acid (0.008 g,
0.070 mmol), tetrakis(triphenylphosphine)palladium(0)
(0.005 g, 0.005 mmol) and sodium carbonate (0.025 g,
0.180 mmol). The reaction mixture was heated to 70
°C and stirred for 48 h. The mixture was allowed to
cool to room temperature and then concentrated in
vacuo. The residue was dissolved in ethyl acetate (5
mL), washed with water (5 mL), brine (5 mL), dried
(MgSO4), and then concentrated in vacuo. Flash
column chromatography (petroleum ether/diethyl ether,
7:3)
gave
(3aS*,8R*,8aS*,8bR*)-2,5-diphenyl-
(3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-Hexahydro-5-
iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (21)
3a,4,6,7,8a,8b-hexahydro-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (22) (0.017 g, 76%) as a yellow
solid. Mp 151–153 °C; νmax (neat) 3358 (NH), 2936
(CH), 1695 (C=O), 1517, 1498, 1387, 1154, 822 cm−1;
δH (400 MHz, CDCl3) 1.75 (1H, dq, J 12.3, 10.2 Hz, 7-
HH), 2.10–2.20 (1H, m, 7-HH), 2.53–2.66 (3H, m, 4-
HH and 6-H2), 3.12 (1H, dd, J 9.1, 5.8 Hz, 8a-H), 3.30
(1H, dd, J 15.2, 1.4 Hz, 4-HH), 3.46–3.56 (2H, m, 3a-H
and 8b-H), 4.88–5.01 (1H, m, 8-H), 7.06–7.10 (2H, m,
2 × ArH), 7.23–7.47 (8H, m, 8 × ArH), 8.96 (1H, d, J
9.6 Hz, NH); δC (126 MHz, CDCl3) 28.4 (CH2), 31.6
(CH2), 31.7 (CH2), 40.3 (CH), 41.7 (CH), 43.7 (CH),
52.9 (CH), 93.0 (C), 126.6 (2 × CH), 127.2 (CH), 127.5
(2 × CH), 128.5 (2 × CH), 129.2 (CH), 129.4 (2 × CH),
130.2 (C), 131.5 (C), 139.0 (C), 139.7 (C), 162.3 (C),
178.6 (C), 179.8 (C); m/z (ESI) 525 ([MNa]+, 100%),
481 (18), 454 (7), 413 (7), 345 (24), 323 (21), 297 (9),
236 (11), 218 (7), 196 (6); m/z (ESI) 525.0947 (MNa+.
C25H2135Cl3N2NaO3 requires 525.0510).
To
a
solution
of
(3aS*,8R*,8aS*,8bR*)-5-
(benzyldimethylsilyl)-3a,4,6,7,8a,8b-hexahydro-2-
phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (17) (0.470 g, 0.820 mmol) in
dichloromethane (10 mL) at −78 °C was added iodine
monochloride (0.057 mL, 1.14 mmol). The reaction
mixture was stirred at −78 °C for 3 h, then the excess
iodine monochloride was destroyed by adding a 10%
solution of sodium thiosulfate (20 mL) and the mixture
was extracted with dichloromethane (3 × 20 mL). The
combined organic layers were dried (MgSO4), filtered
and concentrated in vacuo. Purification by flash
column
acetate,
chromatography
8:2) gave
(petroleum
(3aS*,8R*,8aS*,8bR*)-
ether/ethyl
3a,4,6,7,8a,8b-hexahydro-5-iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (21) (0.400 g, 88%) as a white
(3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-Hexahydro-5-
(4”-methoxyphenyl)-2-phenyl-8-(2’,2’,2’-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 11
ARTICLE
Journal Name
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (23)11b
756; δH (500 MHz, CDCl3) 1.69–1.82 (1H, m, 7-HH),
DOI: 10.1039/C7OB00456G
2.12–2.20 (1H, m, 7-HH), 2.48–2.66 (3H, m, 4-HH and
View Article Online
The reaction was carried out according to the
6-H2), 3.12 (1H, dd, J 8.6, 6.6 Hz, 8a-H), 3.25 (1H, dd,
J 15.2, 1.2 Hz, 4-HH), 3.45–3.56 (2H, m, 3a-H and 8b-
H), 4.88–4.98 (1H, m, 8-H), 7.00–7.09 (4H, m, 3”-H, 5”-
H and 2 × ArH), 7.19–7.25 (2H, m, 2”-H and 6”-H),
7.37–7.48 (3H, m, 3 × ArH), 8.95 (1H, d, J 9.6 Hz, NH);
δC (126 MHz, CDCl3) 28.3 (CH2), 31.7 (CH2), 31.7
(CH2), 40.3 (CH), 41.6 (CH), 43.7 (CH), 52.8 (CH),
92.9 (C), 115.4 (2 × CH, 2JCF 21.4 Hz), 126.5 (2 × CH),
previously
described
procedure
for
3aS*,8R*,8aS*,8bR*)-2,5-diphenyl-3a,4,6,7,8a,8b-
hexahydro-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (22) using (3aS*,8R*,8aS*,8bR*)-
3a,4,6,7,8a,8b-hexahydro-5-iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (21) (0.025 g, 0.045 mmol) and 4-
methoxyphenylboronic acid (0.010 g, 0.070 mmol) and
performed at 70 °C for 36 h. Flash column
chromatography (petroleum ether/diethyl ether, 8:2)
gave (3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-hexahydro-
5-(4”-methoxyphenyl)-2-phenyl-8-(2’,2’,2’-
3
129.2 (2 × CH, JCF 8.0 Hz), 129.2 (CH), 129.4 (2 ×
4
CH), 129.4 (C), 131.4 (C), 134.9 (C, JCF 3.2 Hz),
1
139.6 (C), 161.8 (C, JCF 247.3 Hz), 162.3 (C), 178.5
(C), 179.7 (C); m/z (ESI) 543.0393 (MNa+.
C25H20F35Cl3N2NaO3 requires 543.0416).
(3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-Hexahydro-5-
(phenylethynyl)-2-phenyl-8-(2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (23) (0.013 g, 53%) as a yellow
solid. Mp 115–117 °C; νmax/cm−1 (neat) 3308 (NH),
2959 (CH), 1698 (C=O), 1512 (C=C), 1391, 1247, 823;
δH (400 MHz, CDCl3) 1.66–1.81 (1H, m, 7-HH), 2.09–
2.19 (1H, m, 7-HH), 2.52–2.62 (3H, m, 4-HH and 6-
H2), 3.10 (1H, dd, J 8.9, 6.3 Hz, 8a-H), 3.27 (1H, dd, J
15.2, 1.2 Hz, 4-HH), 3.44–3.54 (2H, m, 3a-H and 8b-
H), 3.81 (3H, s, OCH3), 4.87–4.99 (1H, m, 8-H), 6.85–
6.92 (2H, m, 3”-H and 5”-H), 7.04–7.09 (2H, m, 2 ×
ArH), 7.17–7.23 (2H, m, 2”-H and 6”-H), 7.34–7.46
(3H, m, 3 × ArH), 8.97 (1H, d, J 9.6 Hz, NH); δC (101
MHz, CDCl3) 28.3 (CH2), 31.6 (CH2), 31.7 (CH2), 40.3
(CH), 41.7 (CH), 43.7 (CH), 52.9 (CH), 55.3 (CH3),
92.9 (C), 113.8 (2 × CH), 126.5 (2 × CH), 128.7 (2 ×
CH), 129.1 (CH), 129.4 (2 × CH), 129.8 (C), 131.4 (C),
131.4 (C), 138.1 (C), 158.7 (C), 162.3 (C), 178.6 (C),
dichloromethylcarbonylamino)cyclopent[e]isoindol
e-1,3(2H,3aH)-dione (25)
To a solution of (3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-
hexahydro-5-iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (21) (0.016 g, 0.029 mmol) in N,N-
dimethylformamide (0.5 mL) were added copper iodide
(0.001
g,
0.006
mmol)
and
bis(triphenylphosphine)palladium dichloride (0.002 g,
0.003 mmol). Phenylacetylene (0.004 mL, 0.037 mmol)
was dissolved in degassed triethylamine (2 mL) and
added to the reaction mixture. The solution was briefly
heated to 60 °C and then left to stir at room
temperature for 2 h. The solution was concentrated in
vacuo and purified by flash column chromatography
(petroleum ether/ethyl acetate, 3:2) to give
(3aS*,8R*,8aS*,8bR*)-3a,4,6,7,8a,8b-hexahydro-5-
(phenylethynyl)-2-phenyl-8-(2’,2’-
179.8
(C);
m/z
(ESI)
555.0599
(MNa+.
C26H2335Cl3N2NaO4 requires 555.0616).
(3aS*,8R*,8aS*,8bR*)-5-(4”-fluorophenyl)-
3a,4,6,7,8a,8b-Hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindo
le-1,3(2H,3aH)-dione (24).
dichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (25) (0.007 g, 48%) as a colourless
oil. νmax/cm−1 (neat) 3021 (CH), 2361, 1705 (C=O),
1522 (C=C), 1393, 1215, 754; δH (400 MHz, CDCl3)
1.78‒1.92 (1H, m, 7-HH), 2.09‒2.22 (1H, m, 7-HH),
2.35‒2.57 (2H, m, 4-HH and 6-HH), 2.84 (1H, dd, J
17.6, 7.7 Hz, 6-HH), 2.99‒3.02 (1H, m, 8a-H), 3.06
(1H, dd, J 15.0, 1.3 Hz, 4-HH), 3.39 (1H, ddd, J 8.8,
7.7, 1.3 Hz, 3a-H), 3.47 (1H, dd, J 8.8, 6.3 Hz, 8b-H),
4.94 (1H, dtd, J 12.3, 9.8, 7.1 Hz, 8-H), 5.97 (1H, s,
CHCl2), 7.18‒7.23 (2H, m, 2 × ArH), 7.29‒7.34 (3H, m,
3 × ArH), 7.38‒7.53 (5H, m, 5 × ArH), 8.58 (1H, d, J
9.8 Hz, NH); δC (101 MHz, CDCl3) 28.7 (CH2), 31.0
(CH2), 31.3 (CH2), 39.4 (CH), 41.1 (CH), 42.8 (CH),
51.7 (CH), 66.6 (CH), 86.7 (C), 93.5 (C), 111.8 (C),
123.0 (C), 126.5 (2 × CH), 128.3 (2 × CH), 128.4 (CH),
129.1 (CH), 129.3 (2 × CH), 131.5 (2 × CH), 131.5 (C),
151.4 (C), 164.5 (C), 177.7 (C), 179.0 (C); m/z (ESI)
The reaction was carried out according to the
previously
described
procedure
for
3aS*,8R*,8aS*,8bR*)-2,5-diphenyl-3a,4,6,7,8a,8b-
hexahydro-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (22) using (3aS*,8R*,8aS*,8bR*)-
3a,4,6,7,8a,8b-hexahydro-5-iodo-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (21) (0.030 g, 0.054 mmol) and 4-
fluorophenylboronic acid (0.019 g, 0.135 mmol) and
performed at 70 °C for 12 h. Flash column
chromatography (petroleum ether/ethyl acetate, 9:1)
gave
(3aS*,8R*,8aS*,8bR*)-5-(4”-fluorophenyl)-
3a,4,6,7,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-
trichloromethylcarbonylamino)cyclopent[e]isoindole-
1,3(2H,3aH)-dione (24) (0.013 g, 46%) as a white
solid. Mp 124–126 °C; νmax/cm−1 (neat) 3312 (NH),
2926 (CH), 1700 (C=O), 1510 (C=C), 1500, 1391, 838,
515.0875
(MNa+.
C27H2235Cl2N2NaO3
requires
515.0900).
10 | J. Name., 2012, 00, 1-3
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Page 11 of 11
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
15 For example, see: (a) C. S. Junker, M. E. Welker and
Acknowledgements
View Article Online
C. S. Day, J. Org. Chem., 2010, 75, 8155. (b) J.
Bergueiro, J. Montenegro, F. CDaOmI:b1e0.i1r0o3,9C/C.7OSBa0á04a5n6Gd
S. López, Chem. Eur. J., 2012, 18, 4401. (c) C. S.
Junker and M. E. Welker, Tetrahedron, 2012, 68,
5341.
Financial support from the Ministry of Higher Education
and Scientific Research, Omar Al-Mukhtar University,
Libya (studentship to M.A.B.M.) and the University of
Glasgow is gratefully acknowledged.
16 B. C. Bishop, I. F. Cottrell and D. Hands, Synthesis,
1997, 1315.
17 D. Gallenkamp and A. Fürstner, J. Am. Chem. Soc.,
2011, 133, 9232.
18 R. E. Ireland and D. W. Norbeck, J. Org. Chem.,
1985, 50, 2198.
19 M. A. Blanchette, W. Choy, J. T. Davis, A. P.
Essenfeld, S. Masamune, W. R. Roush and T. Sakai,
Tetrahedron Lett., 1984, 25, 2183.
20 C. E. Anderson, L. E. Overman and M. P. Watson,
Org. Synth., 2005, 82, 134.
21 L. E. Overman and N. E. Carpenter, In Organic
Reactions; L. E. Overman, Ed.; Wiley: Hoboken, NJ,
2005, Vol. 66, 1–107 and references therein.
22 S. Fustero, P. Bello, J. Miró, A. Simón and C. del
Pozo, Chem. Eur. J., 2012, 18, 10991.
23 (a) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs,
Org. Lett., 1999, 1, 953; (b) M. S. Sanford, J. A. Love
and R. H. Grubbs, J. Am. Chem. Soc., 2001, 123,
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Notes and references
1
S. V. Bhat, B. A. Nagasampagi and M. Sivakumar, In
Chemistry of Natural Products, Springer, Berlin,
Germany, 2005.
2
(a) H. Sorek, A. Rudi, S. Gueta, F. Reyes, M. J.
Martin, M. Aknin, E. Gaydou and J. Vacelet,
Tetrahedron, 2006, 62, 8838. (b) E. Gros, A. Al-
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Frederich, M. Aknin, Y. Kashman and A. Gauvin-
Bialecki, J. Nat. Prod., 2014, 77, 818.
3
4
A. E. Walts and W. R. Roush, Tetrahedron, 1985, 41,
3463 and references therein.
(a) S. Ito, T. Matsuya, S. Omura, M. Otani and A.
Nakagawa, J. Antibiot., 1970, 23, 315. (b) S. Mithani,
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12 Mono-substituted
alkyne
derived
allylic
trichloroacetimidates are poor substrates for
a
palladium(II)-catalysed Overman rearrangement due
to binding of the catalyst to the alkyne moiety. For
these compounds,
a high temperature thermal
Overman rearrangement is required for preparation
of the allylic trichloroacetamide.
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