Cyclisation of bisphosphonate substituted enynes

Article abstract of DOI:10.1016/j.tet.2009.07.007

A new synthetic route to the bisphosphonate enyne tetraethyl hept-1-yn-6-en-4,4-diylbisphosphonate has been developed and the enyne has been used successfully in a range of transition metal-catalysed cyclisations that give structurally varied products. Th

Full text of DOI:10.1016/j.tet.2009.07.007

Tetrahedron 65 (2009) 7498–7503
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Tetrahedron
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Cyclisation of bisphosphonate substituted enynes
*
Susan E. Gibson , Peter R. Haycock, Ayako Miyazaki
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic route to the bisphosphonate enyne tetraethyl hept-1-yn-6-en-4,4-diylbisphosphonate
has been developed and the enyne has been used successfully in a range of transition metal-catalysed
cyclisations that give structurally varied products. The motifs generated via such reactions provide new
scaffolds for constructing bisphosphonic acids, an important class of therapeutic agents. NMR experi-
ments indicate that the introduction of phosphonate substitutents onto cyclisation substrates provides
a promising new approach to studying metal-catalysed cyclisations.
Received 3 February 2009
Received in revised form 25 June 2009
Accepted 2 July 2009
Available online 8 July 2009
Keywords:
Cyclisation
Enyne
Ó 2009 Elsevier Ltd. All rights reserved.
NMR
Phosphonate synthesis
1. Introduction
5 mol% Pd(OAc)2
EtO2C
10 mol% PPh3
Enynes undergo many transition metal-catalysed cyclisation
reactions leading to a diverse array of molecular structures. The
transformation of a relatively simple substrate into a more complex
product under catalytic conditions without the generation of
byproducts means that reactions of this type fulfil many of the
demanding criteria now expected in organic chemistry. As a result
there has been much interest in the cyclisation of 1,6-enynes in
recent years, not only in cycloisomerisation reactions,1 exemplified
by the seminal observation that palladium catalyses the conversion
of enyne 1a to diene 2,2 but also in reactions that couple the 1,6-
enyne with a second component such as (i) an external alkene in
the enyne diene–ene metathesis reaction between 1a and styrene
to give 3,3 or the cyclisation, rearrangement and cyclopropanation
sequence that converts 1b and styrene to 4,4 or (ii) an external al-
kyne as exemplified by the [2þ2þ2] cyclisation that takes place
between 1b and dimethyl acetylenedicarboxylate to give 55
(Scheme 1).
EtO2C
(78%)
2
10 mol% Grubbs II
EtO2C
EtO2C
PhCH=CH2
(87%)
Ph
3
RO2C
RO2C
1a R = Et
1b R = Me
MeO2C
5 mol%
AuCl[P(OAr)3]/AgSbF6
MeO2C
PhCH=CH2
(67%)
Ph
4
A spectacular range of catalysts have been used to cyclise
enynes: for example cycloisomerisations catalysed by Pd, Ru, Rh, Ir,
Pt, Au, Hg, Ti, Zr, Cr, Fe, Co, Ni, Cu, Ag, Ga and In species have all been
reported.1 In contrast, the substrates used to probe enyne cyclisa-
tions are more limited in nature. Enynes based on malonates such
as 1a, sulfonamides such as 6, or ether 7 (Fig. 1), account for the
substrates used in the vast majority of enyne cyclisations examined
to date. Occasional use has been made of the bis-sulfone 8.6
10 mol% ClRh(PPh3)3
20 mol% AgOTf
CO2Me
CO2Me
MeO2C
MeO2C
MeO2C CO2Me
(85%)
5
Scheme 1. Typical cyclisations of 1,6-enynes.
To the best of our knowledge a bisphosphonate substrate has
been used for only one type of cyclisation, the palladium-catalysed
cycloisomerisation of 9 to 10 (Scheme 2).7 A cycloisomerisation of
* Corresponding author. Tel.: þ44 207 594 1140; fax: þ44 207 594 5804.
E-mail address: s.gibson@imperial.ac.uk (S.E. Gibson).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.007

S.E. Gibson et al. / Tetrahedron 65 (2009) 7498–7503
7499
(EtO)2(O)P
EtO2C
EtO2C
Ph(O)2S
LDA
(EtO)2(O)P
TsN
O
ClP(O)(OEt)2
(100%)
P(O)(OEt)2
Ph(O)2S
14
1a
6
7
8
a)LDA
b) BrCH2C CSiMe3
(42%)
Figure 1. Typical substrates for cyclisation reactions.
(EtO)2(O)P
(EtO)2(O)P
5 mol% Pd(PPh3)4
(EtO)2(O)P
(EtO)2(O)P
AcOH
(90%)
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
nBu4NF.3H2O
(98%)
9
10
SiMe3
Scheme 2. The palladium-catalysed cycloisomerisation of bisphosphonate enyne 9.
9
15
this type has been elegantly applied in the synthesis of conforma-
tionally restricted cyclic farnesyl analogues.8
Scheme 3. A new synthesis of the bisphosphonate enyne 9.
The paucity of examples of the use of bisphosphonate substrates
such as 9 in cyclisation studies is somewhat surprising in view of (i)
the potential biological activity and therapeutic applications of the
novel bisphosphonic acid derivatives that could be accessed from
the cyclic products, given that the methylenebisphosphonic acid
unit is an excellent chelator and many of its derivatives are either in
clinical use (e.g., 11,9 zoledronic acid, Fig. 2) or under investigation
(e.g., 12,10 1311) for the treatment of diseases characterised by ab-
normal calcium metabolism, particularly abnormal bone metabo-
lism; and (ii) the potential use of a phosphorus labelled substrate
for monitoring and probing cyclisation reactions by 31P NMR
spectroscopy, particularly as many of the cyclisations studied are
based on phosphane-containing catalysts.
competition between monoalkylation and dialkylation.12] The re-
quired propargyl substituent was subsequently introduced as its
trimethylsilyl derivative to give the novel enyne 15 in satisfactory
yield, given the steric demands of creating a quaternary centre
flanked by two phosphonate esters. Removal of the trimethylsilyl
group using tetrabutylammonium fluoride proceeded smoothly to
give the desired bisphosphonate enyne 9. Overall the sequence
proved straightforward to execute and was used to make multi-
gram quantities of 9.
In order to ascertain whether or not enyne 9 was a suitable
substrate for enyne cyclisations in general, several new cyclisations
of the bisphosphonate substrate were examined (Scheme 4). These
were selected on the basis that they employed a range of different
catalysts and reaction conditions, and that they generated a struc-
turally varied array of products. Initially a platinum-catalysed iso-
merisation that had been developed on the malonate-based enyne
1a13 was investigated and this was found to proceed in excellent
yield (100%) to generate the novel bisphosphonate diene 16. Cyc-
lisations that proceed with concomitant hydrogenation14 or
hydrosilylation15 were examined next. These gave the novel
bisphosphonate alkene 17 and the novel silylated bisphosphonate
alkene 18 in 78% and 67% yield, respectively. Finally, cyclisation
accompanied by carbonylation (the catalytic Pauson–Khand
OH
(HO)2(O)P
(HO)2(O)P
11
N
N
(HO)2(O)P
(HO)2(O)P
12
H
N
(HO)2(O)P
(HO)2(O)P
13
(EtO)2(O)P
Figure 2. Bisphosphonic acid derivatives in clinical use (11), or under investigation
(12, 13), for the treatment of diseases characterised by abnormal calcium metabolism.
4 mol% PtCl2
toluene
(EtO)2(O)P
(100%)
In light of the above, we report here a new straightforward
synthesis of the bisphosphonate substrate 9, examples of its use in
several types of cyclisation leading to structurally diverse and novel
bisphosphonates, and 31P NMR experiments that demonstrate the
potential of substrate 9 for use in the monitoring of 1,6-enyne
cyclisations.
16
5 mol% Pd(OAc)2
(EtO)2(O)P
(EtO)2(O)P
10 mol% PPh3
HCO2H
toluene
(78%)
17
(EtO)2(O)P
(EtO)2(O)P
2. Results and discussion
9
The bisphosphonate enyne 9 has previously been prepared by
derivatisation of tetraethyl methylenebisphosphonate with first
propargyl bromide and then allyl bromide.7 In our hands, however,
the first step of this synthesis gave a mixture of starting material,
desired product and bis-propargylated material, which proved very
difficult to separate by either column chromatography or distilla-
tion. We thus devised the following new approach to enyne 9.
Reaction of diethyl but-3-enyl-1-phosphonate with lithium diiso-
propylamide (LDA) followed by diethyl chlorophosphate gave
bisphosphonate 14 in quantitative yield according to a literature
procedure (Scheme 3).12 [It is of note that attempts to synthesise 14
by allylation of tetraethyl methylenebisphosphonate have been
reported to give a modest yield (28%), which was attributed to
(EtO)2(O)P
3 mol% Rh4(CO)12
SiMe2Ph
Me2PhSiH
hexane
(EtO)2(O)P
(67%)
18
(EtO)2(O)P
(EtO)2(O)P
7.5 mol% Co2(CO)8
O
CO
DME
(59%)
19
Scheme 4. Cyclisations of bisphosphonate enyne 9.

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S.E. Gibson et al. / Tetrahedron 65 (2009) 7498–7503
7 mol% [Ir(cod)Cl]
14 mol% dppf
example, the phosphonates of enyne 9 appeared as a singlet at
24.2 in its 31P NMR spectrum in CDCl3. On cyclisation to 18, this
was replaced by two doublets at 27.5 and 29.7, reflecting the
diastereotopicity imparted by the chiral centre in 18. Thus the re-
action conditions for the cyclisation of 9 to 18 were very rapidly
optimised by recording the 31P NMR spectrum of the crude product
mixture. It also proved possible to readily observe isomeric mix-
tures. For example, the presence of the two geometric isomers of
2 (EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
(EtO)2(O)P
d
SiMe3
toluene
d
SiMe3
(68%)
20 (E:Z, 1:1.1)
15
Scheme 5. Iridium-catalysed cycloisomerisation of silyl-substituted enyne 15.
reaction), which has been studied and applied extensively on the
malonate substrates 1, the sulfonamide substrate 6 and the ether
substrate 7,16 was examined for the first time on the bisphospho-
nate substrate 9, leading to the isolation of the novel cyclo-
pentenone 19 in 59% yield.
diene 20 was clearly indicated by two singlets at
d 25.8 and 26.6 in
the 31P NMR spectrum (CDCl3) of the crude product mixture
obtained from the iridium-catalysed cycloisomerisation17 of the
silyl-substituted enyne 15 (singlet at
d 24.4, CDCl3) (Scheme 5).
During the course of our study of the cyclisation chemistry of
bisphosphonate enyne 9, it became apparent that the presence of
the phosphonate substituents facilitated reaction optimisation. For
More significantly, the concept of replacing the malonate, sul-
fonamide or ether linkages commonly used in cyclisation reactions
with methylenebisphosphonate linkages promises to provide
a useful tool with which to study the reaction profile of cyclisations.
The cyclisations of enyne 9 to products 10 and 16–19 were all
conducted in an NMR tube and monitored by 31P NMR spectros-
copy. In all cases the conversion of starting material 9 into product
was clearly observed (the chemical shifts for enyne 9 and products
10 and 16–19 in the given reaction solvent are provided in Table 1.)
Moreover, in some cases, reaction intermediates were observed.
In one example, close examination of the spectra obtained on
monitoring the platinum-catalysed conversion of enyne 9 (singlet
Table 1
The 31P NMR chemical shifts (
d
) of enyne 9 and cyclisation products 10 and 16–19 in
the solvents used to monitor the cyclisations
Chemical shift (
d
) of enyne
Product P
Chemical shift (d) of product Solvent
9 in reaction mixture
P in reaction mixture
25.7
24.0
23.7
10
16
17
28.1
26.4
AcOH
Toluene
Toluene
26.7 (d, J¼16.5 Hz), 27.3
(d, J¼16.5 Hz)
28.4 (d, J¼18 Hz),
29.3 (d, J¼18 Hz)
26.0 (d, J¼12.5 Hz),
27.3 (d, J¼12.5 Hz)
at
d
¼24.0) into diene 16 (singlet at
d
¼26.4) by 31P NMR spectros-
25.7
24.6
18
19
Hexane
DME
copy revealed the appearance and disappearance during the course
Figure 4. The palladium-catalysed cycloreduction of enyne 9 (singlet at
17 (doublets at ¼26.8) via diene 10
¼26.7 and 27.3) and a byproduct (singlet at
(singlet at
¼26.0).
d
¼23.7) into
Figure 3. The platinum-catalysed cyclisation of enyne 9 (
via an intermediate containing a chiral centre (pair of doublets at
d
¼24.0) into diene 16 (
d
¼26.4)
d
d
d
¼24.9 and 25.1).
d

S.E. Gibson et al. / Tetrahedron 65 (2009) 7498–7503
7501
of the reaction of a well-defined pair of doublets at
d
¼24.9 (J¼8 Hz)
Imperial College London. Elemental analyses were performed by
the London Metropolitan University microanalytical service.
and 25.1 (J¼8 Hz) (Fig. 3). At present it is only possible to say with
any certainty that the species that gives rise to these signals con-
tains an element of chirality, and further studies are required to
identify its structure. Nevertheless it is interesting to contrast these
observations with attempts to detect intermediates of the corre-
sponding cyclisation of the malonate equivalent of enyne 9 (i.e., 1a)
by 1H NMR spectroscopy. Treatment of 1a with a stoichiometric
amount of platinum chloride at 25, 40 and 80 ꢀC and monitoring by
1H NMR spectroscopy led in all cases to the observation of only
resonances associated with starting material and product.18
In a second example, the palladium-catalysed cycloreduction of
enyne 9 into methylene cyclopentane 17 was monitored and ob-
4.1.1. Tetraethyl but-3-enyl-1,1-bisphosphonate 1412
n-Butyllithium (8.9 mL, 2.50 M in hexane, 22.3 mmol) was
added to a solution of diisopropylamine (2.9 mL, 20.6 mmol) in THF
(12 mL) at ꢁ78 ꢀC. Diethyl but-3-enyl-1-phosphonate (2.0 mL,
10.5 mmol) and diethyl chlorophosphate (1.9 mL, 13.3 mmol) were
added at ꢁ78 ꢀC. After 1.5 h, the reaction mixture was allowed to
warm to room temperature and poured into cooled distilled water
(20 mL). After extraction with CH2Cl2 (4ꢂ50 mL), the combined
organic layers were washed with saturated aqueous NaCl solution
(20 mL) and dried over Na2SO4. Evaporation of the solvent under
vacuum yielded 14 (3.43 g, quant.) as a yellow oil, pure enough to
be used in the synthesis of enyne 15. Rf¼0.36 (SiO2; hexane/acetone
served to proceed via the rapid conversion of 9 (singlet at
into an intermediate indicated by a singlet at
d¼23.7)
d
¼26.0 (Fig. 4). Con-
version of 9 into the intermediate was complete after 30 min, after
1:1); 1H NMR (400 MHz):
d
¼1.37 (t, 3J(H,H)¼7 Hz, 12H, OCH2
which the intermediate was relatively slowly converted into
CH3ꢂ4), 2.41 (tt, 2J(H,P)¼24 Hz, 3J(H,H)¼6 Hz, 1H, PCH), 2.66–2.78
(m, 2H, CH2CH]CH2), 4.17–4.24 (m, 8H, OCH2CH3ꢂ4), 5.07 (dd,
3J(H,H)¼8 Hz, 2J(H,H)¼1 Hz, 1H, CH2CH]CH2 (Z)), 5.16 (dd,
3J(H,H)¼16 Hz, 2J(H,H)¼1 Hz, 1H, CH2CH]CH2 (E)), 5.99 ppm (ddt,
3J(H,H)¼16, 8, 4 Hz, 1H, CH2CH]CH2); 13C NMR (100 MHz):
product 17, characterised by the pair of doublets at
and a byproduct indicated by a singlet at
¼26.8. It was proposed
that the intermediate at
¼26.0 was a symmetrical product of
d¼26.7 and 27.3,
d
d
a rapid cyclisation process, probably the diene 10, and that the
slower second step was the reduction of diene 10 to the less sym-
metrical product 17. Indeed halting a laboratory reaction after
40 min rather then allowing it to run for 2.5 h led to the isolation of
diene 10 in 70% yield. This hypothesis is consistent with a mecha-
nism proposed for this type of cycloreduction process based on
examining the results from a range of substrates, reaction condi-
tions and the isolation of key intermediates.14
d
¼16.37, 16.43 (2ꢂd, 3J(C,P)¼2 Hz, P(O)(OCH2CH3)2), 29.9 (t,
2J(C,P)¼5 Hz, PCHCH2CH]CH2), 37.1 (t, 1J(C,P)¼133 Hz, PCH), 62.5,
62.6 (2ꢂd, 2J(C,P)¼6.5 Hz, P(O)(OCH2CH3)2), 116.6 (s, CH]CH2),
135.9 ppm (t, 3J(C,P)¼7 Hz, PCHCH2CH]CH2); 31P NMR (162 MHz):
d
¼23.1 ppm (s); IR (neat):
n
¼1641 (m, C]C), 1248 (s, P]O),
1027 cmꢁ1 (s, P–O–C); MS (CI): m/z (%): 674 (100) [2MþNHþ4 ], 657
(25) [2MþHþ], 346 (73) [MþNHþ4 ], 329 (69) [MþHþ], 191 (9)
[MþHþꢁP(O)(OCH2CH3)2].
3. Conclusion
4.1.2. Tetraethyl 1-trimethylsilylhept-1-yn-6-en-4,4-
We have developed a new and effective approach to enyne 9 and
demonstrated that it is a suitable substrate for a range of cyclisa-
tions using differing catalysts and reaction conditions, and giving
structurally varied products. The motifs generated via such re-
actions provide new scaffolds for constructing bisphosphonic acids,
an important class of therapeutic agents. NMR experiments on the
cyclisations have been carried out from which it is apparent that
the introduction of phosphonate substituents onto cyclisation
substrates is a promising tool for studying metal-catalysed cycli-
sations, and indeed cyclisations in general.
diylbisphosphonate 15
To a solution of 14 (9.50 g, 28.9 mmol) in THF (40 mL) was added
LDA (18.0 mL, 2.0 M in THF/n-heptane, 36.2 mmol) at ꢁ78 ꢀC. The
reaction mixture was stirred at ꢁ78 ꢀC for 1 h. 3-(Trimethylsilyl)-
propargyl bromide (6.5 mL, 39.9 mmol) was added dropwise to the
stirred reaction mixture at ꢁ78 ꢀC. After 16 h, the reaction mixture
was allowed to warm to room temperature and poured into cooled
distilled water (60 mL). After extraction with CH2Cl2 (4ꢂ150 mL),
the combined organic layers were washed with saturated aqueous
NaCl solution (60 mL) and dried over Na2SO4. The solvent was re-
moved in vacuo to give a brown oil. Purification by flash column
chromatography (SiO2; hexane/acetone 4:1 to 3:1) afforded 15
(5.29 g, 42%) as a yellow oil. Rf¼0.51 (SiO2; hexane/acetone 3:2); 1H
4. Experimental
4.1. General
NMR (400 MHz):
d
¼0.18 (s, 9H, Si(CH3)3), 1.36 (t, 3J(H,H)¼7 Hz, 12H,
OCH2CH3ꢂ4), 2.77–2.83 (m, 2H, CH2CH]CH2), 2.90 (t,
3J(H,P)¼15 Hz, 2H, CH2C^CSi), 4.18–4.26 (m, 8H, OCH2CH3ꢂ4), 5.15
(dd, 3J(H,H)¼10 Hz, 2J(H,H)¼2 Hz, 1H, CH2CH]CH2 (Z)), 5.22 (dd,
3J(H,H)¼17 Hz, 2J(H,H)¼2 Hz, 1H, CH2CH]CH2 (E)), 5.99 ppm (ddt,
All reactions and manipulations involving organometallic
compounds were performed under an inert atmosphere of dry
nitrogen, using standard vacuum line and Schlenk techniques.19
1,2-Dimethoxyethane, hexane, tetrahydrofuran and toluene were
distilled over sodium benzophenone ketyl and used immediately.
Dichloromethane was distilled over calcium hydride. All other
chemicals were used as purchased from commercial sources. The
concentration of n-butyllithium was determined by titration
against diphenylacetic acid in tetrahydrofuran.20 Thin layer chro-
matography (TLC) was performed on Merck silica gel glass plates 60
(F254), using UV light (254 nm) and/or iodine as visualising agents
and/or vanillin or potassium permanganate and heat as developing
agents. Flash column chromatography was performed using BDH
3J(H,H)¼17, 10, 7 Hz, 1H, CH2CH]CH2); 13C NMR (100 MHz):
¼0.0
d
(s, Si(CH3)3), 16.47, 16.50 (2ꢂd, 3J(C,P)¼2 Hz, P(O)(OCH2CH3)2),
22.2 (t, 2J(C,P)¼4 Hz, PCCH2C^CSi), 35.1 (t, 2J(C,P)¼4 Hz,
PCCH2CH]CH2), 44.8 (t, 1J(C,P)¼132.5 Hz, PCP), 62.8, 62.9 (2ꢂd,
2J(C,P)¼3.5 Hz, P(O)(OCH2CH3)2), 88.0 (s, C^CSi), 101.8 (t,
3J(C,P)¼10.5 Hz, PCCH2C^CSi), 118.6 (s, CH]CH2), 133.2 ppm (t,
3J(C,P)¼8 Hz, PCCH2CH]CH2); 31P NMR (162 MHz):
¼24.4 ppm (s);
d
IR (neat):
n
¼2181 (s, C^C), 1640 (m, C]C), 1250 (s, P]O, Si–C),
1026 cmꢁ1 (s, P–O–C); MS (CI): m/z (%): 456 (7) [MþNHþ4 ], 439 (100)
[MþHþ], 301 (22) [MþHþꢁP(O)(OCH2CH3)2]; elemental analysis
calcd (%) for C18H36O6SiP2: C 49.30, H 8.27; found: C 49.28, H 8.26.
silica gel (particle size 33–70 mm). IR spectra were recorded on
a Perkin Elmer Spectrum RX FT-IR spectrometer. NMR spectra were
recorded at room temperature on Bruker DRX 400, AV 400 or AV
500 instruments in CDCl3 unless otherwise stated. J values are
reported in hertz and chemical shifts in parts per million. Mass
spectra were recorded on Micromass Platform II and Micromass
AutoSpec-Q instruments by the mass spectrometry service at
4.1.3. Tetraethyl hept-1-yn-6-en-4,4-diylbisphosphonate 97
Enyne 15 (4.00 g, 9.13 mmol) was added to a solution of tetra-
butylammonium fluoride trihydrate (0.80 g, 3.04 mmol) in THF
(50 mL) at room temperature. After 2 h, the reaction mixture was
poured into cooled distilled water (50 mL). After extraction with

7502
S.E. Gibson et al. / Tetrahedron 65 (2009) 7498–7503
CH2Cl2 (4ꢂ150 mL), the combined organic layers were washed with
saturated aqueous NaCl solution (50 mL) and dried over Na2SO4.
The solvent was removed in vacuo to give a brown oil. Purification
by flash column chromatography (SiO2; hexane/acetone 3:2)
afforded 9 (3.26 g, 98%) as a yellow oil. Rf¼0.41 (SiO2; hexane/ac-
4.1.6. Tetraethyl 3,4-dimethylenecyclopentane-1,1-
bisphosphonate 107
The reaction described in Section 4.1.5 was repeated under
identical conditions exceptthat the reactionwas halted after40 min.
Work-up and column chromatography (SiO2; hexane/acetone 7:3 to
3:2) afforded diene 10 as a yellow oil (0.153 g, 70%). Rf¼0.35 (SiO2;
etone 1:1); 1H NMR (400 MHz):
d
¼1.36 (t, 3J(H,H)¼7 Hz, 12H,
OCH2CH3ꢂ4), 2.10 (t, 4J(H,H)¼2.5 Hz, 1H, C^CH), 2.78–2.90 (m, 4H,
CH2CH]CH2, CH2C^CH), 4.23 (dt, 3J(H,P)¼15 Hz, 3J(H,H)¼7 Hz, 8H,
OCH2CH3ꢂ4), 5.16 (d, 3J(H,H)¼10 Hz, 1H, CH2CH]CH2 (Z)), 5.24 (d,
3J(H,H)¼17 Hz, 1H, CH2CH]CH2 (E)), 6.01 ppm (ddt, 3J(H,H)¼17, 10,
hexane/acetone 3:2); 1H NMR (400 MHz):
d
¼1.31 (t, 3J(H,H)¼7 Hz,
12H, OCH2CH3ꢂ4), 3.10 (tt, 3J(H,P)¼17 Hz, 4J(H,H)¼2 Hz, 4H,
CH2C]Cꢂ2), 4.12–4.20 (m, 8H, OCH2CH3ꢂ4), 4.90 (t, 4J(H,H)¼2 Hz,
2H, C]CHHꢂ2), 5.36 ppm (t, 4J(H,H)¼2 Hz, 2H, C]CHHꢂ2); 13C
7 Hz, 1H, CH2CH]CH2); 13C NMR (100 MHz):
d
¼16.4 (m,
NMR (100 MHz):
d
¼16.3–16.4 (m, P(O)(OCH2CH3)2), 37.7 (t,
P(O)(OCH2CH3)2), 20.9 (t, 2J(C,P)¼3.5 Hz, PCCH2C^CH), 35.0 (t,
2J(C,P)¼4.5 Hz, PCHCH2CH]CH2), 44.8 (t, 1J(C,P)¼132.5 Hz, PCP),
62.9 (m, P(O)(OCH2CH3)2), 71.6 (s, C^CH), 79.3 (t, 3J(C,P)¼11.5 Hz,
PCCH2C^CH), 118.8 (s, CH]CH2), 133.0 ppm (t, 3J(C,P)¼7.5 Hz,
2J(C,P)¼4 Hz, CH2C]C), 43.5 (t, 1J(C,P)¼138 Hz, PCP), 62.8–62.9 (m,
P(O)(OCH2CH3)2), 104.4 (s, C]CH2), 145.7 ppm (t, 3J(C,P)¼4.5 Hz,
CH2C]CH2); 31P NMR (162 MHz):
d¼26.6 ppm (s); IR (neat): ¼1623
n
(w, C]C), 1248 (s, P]O), 1017 cmꢁ1 (s, P–O–C); MS (ESI): m/z (%):
755 (32) [2MþNaþ], 389 (100) [MþNaþ], 367 (53) [MþHþ].
PCCH2CH]CH2); 31P NMR (162 MHz):
n
d
¼24.2 ppm (s); IR (neat):
¼2118 (w, C^C), 1640 (m, C]C), 1247 (s, P]O), 1024 cmꢁ1 (s, P–
O–C); MS (CI): m/z (%): 384 (68) [MþNHþ4 ], 367 (100) [MþHþ].
4.1.7. Tetraethyl 1-(1-(Z)-dimethylphenylsilylmethylidene)-2-
methylcyclopentandiyl-4,4-bisphosphonate 18
4.1.4. Tetraethyl 1-vinylcyclopent-1-endiyl-4,4-bisphosphonate 16
Platinum(II) chloride (5.9 mg, 4 mol %) was added to a solution
of enyne 9 (0.20 g, 0.55 mmol) in anhydrous toluene (3 mL). The
reaction mixture was stirred at 80 ꢀC for 3 h under an atmosphere
of nitrogen. After the reaction was complete, the solvent was re-
moved in vacuo. The residue was filtered through neutral alumina
eluting with acetone to afford 16 (0.20 g, quant.) as a yellow oil.
Dodecacarbonyltetrarhodium(0) (13.5 mg, 3 mol %) was placed
in a Schlenk tube and dissolved in anhydrous CO saturated hexane
(1 mL). Dimethylphenylsilane (93 mL, 0.6 mmol) was added via
a syringe. The reaction mixture was stirred at room temperature
under an atmosphere of CO for 5 min. The reaction mixture was
then added via cannula into a solution of enyne 9 (0.22 g, 0.6 mmol)
and dimethylphenylsilane (93 mL, 0.6 mmol) in anhydrous CO sat-
Rf¼0.25 (SiO2; hexane/acetone 3:2); 1H NMR (400 MHz):
d¼1.308,
urated hexane (0.5 mL) without stirring. After stirring for 20 min,
the reaction mixture was concentrated in vacuo to give a brown
residue. Purification by flash column chromatography (SiO2; hex-
ane/acetone 4:1 to 3:1) afforded 18 (0.20 g, 67%) as a yellow oil.
1.314 (2ꢂt, 3J(H,H)¼7 Hz, 12H, OCH2CH3ꢂ4), 3.05–3.14 (m, 4H,
CH2C]CH, CH2CH]C), 4.14–4.22 (m, 8H, OCH2CH3ꢂ4), 5.07 (d,
3J(H,H)¼17.5 Hz, 1H, C]CCH]CH2 (E)), 5.09 (d, 3J(H,H)¼10.5 Hz,
1H, C]CCH]CH2 (Z)), 5.58 (m, 1H, CH2CH]C), 6.50 ppm (dd,
Rf¼0.37 (SiO2; hexane/acetone 3:2); 1H NMR (500 MHz):
¼0.36,
d
3J(H,H)¼17.5, 10.5 Hz, 1H, CCH]CH2); 13C NMR (CDCl3):
d
¼16.5 (m,
0.37 (2ꢂs, 6H, Si(CH3)2), 1.03 (d, 3J(H,H)¼7 Hz, 3H, CHCH3), 1.286,
1.293 (2ꢂt, 3J(H,H)¼7 Hz, 6H, OCH2CH3ꢂ2), 1.33 (t, 3J(H,H)¼7 Hz,
6H, OCH2CH3ꢂ2), 1.94–2.06 (m, 1H, PCCH2CH), 2.54–2.64 (m, 1H,
PCCH2CH), 2.77–2.87 (m, 2H, PCCH2CHCH3, PCCH2C]C), 3.22–3.36
(m, 1H, PCCH2C]C), 4.05–4.23 (m, 8H, OCH2CH3ꢂ4), 5.45 (s, 1H,
C]CHSi), 7.32–7.35 (m, 3H, CArHꢂ3), 7.52–7.55 ppm (m, 2H,
P(O)(OCH2CH3)2), 36.5, 38.2 (2ꢂt, 2J(C,P)¼3 Hz, PCCH2ꢂ2), 43.4 (t,
1J(C,P)¼110 Hz, PCP), 62.9 (m, P(O)(OCH2CH3)2), 115.0 (s, CH]CH2),
127.4 (t, 3J(C,P)¼3 Hz, PCCH2CH]C), 132.3 (s, CCH]CH2),
140.2 ppm (t, 3J(C,P)¼3 Hz, PCCH2C]CH); 31P NMR (162 MHz):
d¼26.8 ppm (s); IR (neat):
n¼1647 (m, C]C), 1244 (s, P]O),
1043 cmꢁ1 (s, P–O–C); MS (CI): m/z (%): 384 (53) [MþNHþ4 ], 367
(100) [MþHþ]; elemental analysis calcd (%) for C15H28O6P2: C 49.18,
H 7.70; found: C 49.07, H 7.70.
C
ArHꢂ2); 13C NMR (125 MHz):
¼ ꢁ0.98, ꢁ0.90 (2ꢂs, Si(CH3)2),
d
16.4, 16.6 (2ꢂd, 3J(C,P)¼6 Hz, P(O)(OCH2CH3)2), 23.0 (s, CHCH3),
37.0 (d, 3J(C,P)¼4 Hz, PCCH2CHCH3), 38.3 (t, 2J(C,P)¼3.5 Hz,
PCCH2CH), 41.4 (br s, PCCH2C]C), 44.5 (t, 1J(C,P)¼137 Hz, PCP),
62.5–62.8 (m, P(O)(OCH2CH3)2), 116.6 (s, C]CHSi), 127.7 (s, CArH),
128.8 (s, CArH), 133.7 (s, CArH), 139.7 (s, CArSi), 166.0 ppm (d,
4.1.5. Tetraethyl 1-methylene-2-methylcyclopentandiyl-4,4-
bisphosphonate 17
To a mixture of triphenylphosphine (15.7 mg, 10 mol %) and
palladium(II) acetate (6.7 mg, 5 mol %) was added a solution of
enyne 9 (0.22 g, 0.6 mmol) in anhydrous toluene (1.5 mL). The
yellow suspension was stirred for 10 min under a nitrogen atmo-
3J(C,P)¼10 Hz, PCCH2C]CH); 31P NMR (202 MHz):
d
¼27.5 (d,
2J(P,P)¼16 Hz), 27.7 ppm (d, 2J(P,P)¼16 Hz); IR (neat):
n
¼1629 (s,
C]C), 1247 (s, P]O, Si–C), 1023 cmꢁ1 (s, P–O–C); MS (ESI): m/z (%):
525 (100) [MþNaþ], 503 (21) [MþHþ]; elemental analysis calcd (%)
for C23H40O6P2Si: C 54.96, H 8.02; found: C 54.89, H 8.00.
sphere and then treated with formic acid (57 mL, 1.5 mmol) via
a gastight syringe. The reaction mixture was stirred for 2.5 h at
60 ꢀC in a preheated oil bath. The reaction was allowed to cool to
room temperature and concentrated in vacuo. Purification by flash
column chromatography (SiO2; hexane/acetone 7:3 to 3:2) afforded
17 as a yellow oil (0.17 g, 78%). Rf¼0.35 (SiO2; hexane/acetone 3:2);
4.1.8. Tetraethyl 7-oxobicyclo[3.3.0]oct-1-(8)-enediyl-3,3-
bisphosphonate 19
Freshly sublimed octacarbonyldicobalt(0) (14.0 mg, 7.5 mol %)
was placed in a Schlenk tube and dissolved in anhydrous CO satu-
rated DME (5.5 mL). The reaction mixture was stirred at room tem-
perature, under an atmosphere of CO for 15 min. Enyne 9 (0.20 g,
0.55 mmol) was dissolved in anhydrous CO saturated DME (1.5 mL)
and added to the reaction mixture via cannula. The reaction mixture
was stirred at 75 ꢀC for 5 h. The reaction was allowed to cool to room
temperature before being filtered through CeliteÒ and then concen-
trated in vacuo to give a brown residue. Purification by flash column
chromatography (SiO2; acetone/hexane 4:1 to 9:1) afforded 19
(0.13 g, 59%) as a yellow oil. Rf¼0.36 (SiO2; acetone/hexane 9:1); 1H
1H NMR (400 MHz):
d
¼1.10 (d, 3J(H,H)¼6.5 Hz, 3H, CHCH3), 1.31–
1.38 (m, 12H, OCH2CH3ꢂ4), 1.71–1.95 (m, 1H, CH2CH), 2.46–2.57 (m,
1H, CH2CH), 2.75 (br m, 1H, CH2CHCH3), 2.88–3.09 (m, 2H,
CH2C]C), 4.14–4.28 (m, 8H, OCH2CH3ꢂ4), 4.76 (s, 1H, C]CH2),
4.87 ppm (s, 1H, C]CH2); 13C NMR (100 MHz):
d
¼16.4–16.5 (m,
P(O)(OCH2CH3)2), 17.0 (s, CHCH3), 37.29 (m, CH2CH), 37.35 (m,
CH2C]CH2), 38.7 (m, CH2CH), 43.2 (t, 1J(C,P)¼137.5 Hz, PCP), 62.5–
63.0 (m, P(O)(OCH2CH3)2), 104.3 (s, C]CH2), 153.8 ppm (t,
3J(C,P)¼4.5 Hz, CH2C]CH2); 31P NMR (162 MHz):
d
¼27.3 (d,
2J(P,P)¼13.5 Hz), 27.9 ppm (d, 2J(P,P)¼13.5 Hz); IR (neat):
n
¼1658
NMR (500 MHz):
d
¼1.291, 1.303 (2ꢂt, 3J(H,H)¼7 Hz, 6H,
(m, C]C), 1244 (s, P]O), 1032 cmꢁ1 (s, P–O–C); MS (ESI): m/z (%):
391 (100) [MþNaþ], 369 (32) [MþHþ]; elemental analysis calcd (%)
for C15H30O6P2: C 48.91, H 8.21; found: C 49.00, H 8.14.
OCH2CH3ꢂ2), 1.36 (t, 3J(H,H)¼7 Hz, 6H, OCH2CH3ꢂ2), 1.82 (dddd,
2J(H,H)¼24.5 Hz,
3J(H,H)¼21 Hz,
3J(H,P)¼13,
11.5 Hz,
1H,
PCCH2CHCH2), 2.10 (dd, 2J(H,H)¼18 Hz, 3J(H,H)¼3 Hz, 1H,

S.E. Gibson et al. / Tetrahedron 65 (2009) 7498–7503
7503
CHCH2C]O), 2.64 (dd, 2J(H,H)¼18 Hz, 3J(H,H)¼6 Hz, 1H,
CHCH2C]O), 2.67–2.75 (m, 1H, PCCH2CHCH2), 3.09–3.26 (m, 2H,
PCCH2C]C), 3.31 (m,1H, CH2CHCH2), 4.11–4.30 (m, 8H, OCH2CH3ꢂ4),
syringed into a WILMAD screw cap (with a PTFE/silicone septum)
NMR tube under nitrogen. The NMR tube was introduced into the
NMR probe, which had been preheated to 80 ꢀC and a 31P NMR
experiment was performed collecting a spectrum at set time
intervals.
5.80 ppm (s, 1H, CH2C]CHC]O); 13C NMR (100 MHz):
d¼16.3–16.5
(m, P(O)(OCH2CH3)2), 32.3 (t, 2J(C,P)¼4 Hz, PCCH2C]C), 35.3 (t,
2J(C,P)¼4.5 Hz, PCCH2CHCH2), 42.6 (s, CHCH2C]O), 44.3 (d,
3J(C,P)¼7 Hz, PCCH2CHCH2), 46.5 (t, 1J(C,P)¼138 Hz, PCP), 62.77,
62.84 (2ꢂd, 2J(C,P)¼1.5 Hz, P(O)(OCH2CH3)2), 125.2 (s, C]CHC]O),
185.3 (t, 3J(C,P)¼4.5 Hz, PCCH2C]CH), 210.0 ppm (s, C]O); 31P NMR
4.1.11. Examination of the Pd(OAc)2 catalysed cycloreduction of 9 to
31
17 by P NMR spectroscopy at 60 ꢀC
Triphenylphosphine (7.9 mg, 10 mol %), palladium(II) acetate
(3.4 mg, 5 mol %) and enyne 9 (110 mg, 0.3 mmol) were dissolved in
anhydrous toluene (1 mL) and stirred at room temperature for
(162 MHz):
(neat):
d
¼26.7 (d, 2J(P,P)¼11 Hz), 27.9 ppm (d, 2J(P,P)¼11 Hz); IR
n
¼1713 (s, C]O), 1634 (s, C]C), 1246 (s, P]O), 1024 cmꢁ1 (s,
P–O–C); MS (CI): m/z (%): 412 (83) [MþNHþ4 ], 395 (100) [MþHþ];
elemental analysis calcd (%) for C16H28O7P2: C 48.73, H 7.16; found: C
48.65, H 7.16.
10 min. Formic acid (28 mL, 0.75 mmol) was added to the yellow
reaction mixture and stirred at room temperature for 10 min. The
resulting solution was syringed into a WILMAD screw cap (with
a PTFE/silicone septum) NMR tube under nitrogen. The NMR tube
was introduced into the NMR probe, which had been preheated to
60 ꢀC and a 31P NMR experiment was performed collecting a spec-
trum at set time intervals.
4.1.9. Tetraethyl 1-methylene-2-(1-trimethylsilylmethylidene)-
cyclopentandiyl-4,4-bisphosphonate 20
Chloro-1,5-cyclooctadiene iridium dimer (23.5 mg, 7 mol %) and
1,10-bis(diphenylphosphino)ferrocene (38.8 mg, 14 mol %) were
dissolved in anhydrous toluene (3 mL) under a nitrogen atmo-
sphere. A solution of TMS enyne 15 (0.22 g, 0.5 mmol) in anhydrous
toluene (3 mL) was added. The reaction mixture was stirred under
reflux for 24 h. The reaction was allowed to cool to room temper-
ature before being concentrated in vacuo to give a brown residue.
Immediate purification by flash column chromatography (SiO2;
hexane/acetone 4:1 to 3:2) afforded 20 as a yellow oil (0.15 g, 68%)
identified as a mixture of isomers (E/Z ratio 1:1.1). Rf¼0.47 (SiO2;
References and notes
1. For a review of cycloisomerisations of 1,n-enynes, see: Michelet, V.; Toullec,
ˆ
P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315.
2. Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988, 44, 4967–4972.
3. Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439–3442.
4. (a) Evans, P. A.; Sawyer, J. R.; Lai, K. W.; Huffman, J. C. Chem. Commun. 2005,
3971–3973; (b) Evans, P. A.; Lai, K. W.; Sawyer, J. R. J. Am. Chem. Soc. 2005, 127,
12466–12467.
5. Lo´ pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.; Nieto-Oberhuber, C.; Echavarren,
A. M. Angew. Chem., Int. Ed. 2006, 45, 6029–6032.
6. See, for example, (a) Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 9421–9438;
(b) Fernandez-Rivas, C.; Me´ndes, M.; Echavarren, A. M. J. Am. Chem. Soc. 2000,
hexane/acetone 3:2); 1H NMR (400 MHz):
d
¼0.12, 0.15 (2ꢂs, 9H,
Si(CH3)3), 1.29–1.33 (m, 12H, OCH2CH3ꢂ4), 2.64–3.14 (m, 4H,
CH2ꢂ2), 4.12–4.22 (m, 8H, OCH2CH3ꢂ4), 4.89, 4.92ꢂ2, 5.36 (4ꢂs,
2H, C]CH2), 5.94, 6.41 ppm (2ꢂs, 1H, C]CHSi); 13C NMR
ˆ
122, 1221–1222; (c) Toullec, P.-Y.; Genin, E.; Leseurre, L.; Genet, J.-P.; Michelet,
V. Angew. Chem., Int. Ed. 2006, 45, 7427–7430.
7. Li, C.; Yuan, C. Heteroat. Chem. 1993, 4, 517–520.
8. Fairlamb, I. J. S.; Pike, A. C.; Ribrioux, S. P. C. P. Tetrahedron Lett. 2002, 43, 5327–
5331.
9. (a) Green, J. R. J. Organomet. Chem. 2005, 690, 2439–2448; (b) Rodan, G. A.;
Martin, T. J. Science 2000, 289, 1508–1514.
(100 MHz):
d
¼ ꢁ2.4, ꢁ0.6 (2ꢂs, 3C, Si(CH3)3), 16.4 (br s,
P(O)(OCH2CH3)2), 27.8, 31.2, 36.9, 37.4 (m, CH2ꢂ2), 41.2 (t,
1J(C,P)¼132.5 Hz, PCP), 43.6 (t, 1J(C,P)¼138.0 Hz, PCP), 62.6–62.8
(m, P(O)(OCH2CH3)2), 104.3, 112.9 (2ꢂs, C]CH2), 117.7, 135.7 (2ꢂs,
C]CHSi), 137.8 (t, 3J(C,P)¼4.5 Hz, CH2C]CHSi), 138.8 (t,
3J(C,P)¼7 Hz, CH2C]CHSi), 147.1 (t, 3J(C,P)¼4.5 Hz, CH2C]CH2),
153.2 ppm (t, 3J(C,P)¼4.5 Hz, CH2C]CH2); 31P NMR (162 MHz):
10. Dudakovic, A.; Wiemer, A. J.; Lamb, K. M.; Vonnahme, L. A.; Dietz, S. E.; Hohl, R.
J. J. Pharmacol. Exp. Ther. 2008, 324, 1028–1036.
11. Ebetino, F. H.; Boeckman, R. K.; Song, X. Patent WO 2008/076417 A1.
12. Dufau, C.; Sturtz, G. Phosphorus, Sulfur Silicon Relat. Elem. 1992, 69, 93–102.
13. Furstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863–11869.
14. Oh, C. H.; Jung, H. H.; Sung, H. R.; Kim, J. D. Tetrahedron 2001, 57, 1723–1729.
15. Ojima, I.; Vu, A. T.; Lee, S.-Y.; McCullagh, J. V.; Moralee, A. C.; Fujiwara, M.;
Hoang, T. H. J. Am. Chem. Soc. 2002, 124, 9164–9174.
d
¼25.8 (s), 26.6 ppm (s); IR (neat): ¼1674 (m, C]C), 1247 (s, P]O,
n
Si–C), 1026 cmꢁ1 (s, P–O–C); MS (ESI): m/z (%): 439 (100) [MþHþ];
elemental analysis calcd (%) for C18H36O6P2Si: C 49.30, H 8.27;
found: C 49.26, H 8.20.
16. (a) Shibata, T. Adv. Synth. Catal. 2006, 348, 2328–2336; (b) Gibson, S. E.; Ste-
venazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800–1810.
17. Kezuka, S.; Okada, T.; Niou, E.; Takeuchi, R. Org. Lett. 2005, 7, 1711–1714.
18. Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996, 15,
901–903.
19. Shriver, D. F.; Drezdzon, M. A. The Manipulation of Air Sensitive Compounds;
Wiley: Chichester, UK, 1986.
4.1.10. Examination of the PtCl2 catalysed cyclisation of 9 to 16 by
31P NMR spectroscopy at 80 ꢀC
Platinum(II) chloride (3 mg, 4 mol %) and enyne 9 (100 mg,
0.27 mmol) were dissolved in anhydrous toluene (2 mL) and
20. Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879–1880.