Accessing brominated natural product motifs using phosphoramidite catalysis

Article abstract of DOI:10.1071/CH14539

This article describes the application of a first-generation phosphoramidite catalyst to the construction of the most commonly encountered subunits of bromine-containing natural products. The process is compared with previous efforts, and is found to be complementary to existing methods. Application of the process enables bromocarbocyclisations, bromoetherifications, and bromoallene formation using the common laboratory reagent N-bromosuccinimide.

Full text of DOI:10.1071/CH14539

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH14539
Accessing Brominated Natural Product Motifs Using
Phosphoramidite Catalysis
A
,
A B
Carl Recsei and Christopher S. P. McErlean
A
School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia.
Corresponding author. Email: christopher.mcerlean@sydney.edu.au
B
This article describes the application of a first-generation phosphoramidite catalyst to the construction of the most
commonly encountered subunits of bromine-containing natural products. The process is compared with previous efforts,
and is found to be complementary to existing methods. Application of the process enables bromocarbocyclisations,
bromoetherifications, and bromoallene formation using the common laboratory reagent N-bromosuccinimide.
Manuscript received: 1 September 2014.
Manuscript accepted: 9 October 2014.
Published online: 19 November 2014.
Introduction
[5,6]
compounds function as antifouling and antimicrobial agents.
The marine environment provides an abundance of natural
products bearing halogen atoms. With them being discovered
at a rate exceeding 100 per year, the number of characterised
In the non-natural settings of agrichemical and medicinal
research, asymmetrically halogenated compounds display a
range of beneficial properties, ranging from insecticidal to
[
1,2]
[7–9]
halogenated natural products now stands at ,5000.
The
anticancer activity.
A notable example is thyrsiferyl-23-
acetate (4), which possesses subnanomolar activity against
distribution of these metabolites is heavily skewed towards
compounds containing a single halogen atom, with mono-
brominated compounds being the most numerous. Many of
these have the bromine atom appended at an element of chirality
[
10]
P-388 cells.
With such a diverse array of potential applications, methods
for the rapid generation of these asymmetric organohalogen
containing compounds, and in particular organobromine com-
pounds, are of widespread interest. To that end, we recently
[
1,2]
(either a stereogenic centre or an axis of chirality).
representative examples are shown in Fig. 1.
Some
0
In their natural settings, asymmetrically halogenated com-
pounds play multiple roles. Many marine species (including
sponges and macroalgae) rely on chemical means to deter
predation, and halogenated secondary metabolites are often
the ‘weapon of choice’ for this purpose. For example, panacene
developed a family of N-heterocycle-flanked 1,1 -bi-2-naphthol
[
11,12]
(BINOL) phosphoramidites as nucleophilic catalysts.
Our
aim was to employ the phosphoramidite as a bromonium shuttle
that would allow us to conduct bromination reactions using the
[
13]
common laboratory reagent N-bromosuccinimide (NBS).
(
1) is accumulated in the mantle of the sea hare Aplysia
In order for any proposed catalyst to be generally applicable,
it would need to be capable of generating the architectures
observed in brominated natural products. In this article, we
detail our investigations into the scope of phosphoramidite
catalysis for the construction of important natural product
motifs.
[
3]
brasiliana because it repels sharks and predatory fish. Simi-
larly, marine organisms that compete for sunlight require
chemical defences against colonisation by other organisms.
The red alga Laurencia rigida deploys (ꢀ)-10a-bromo-9b-
hydroxy-a-chamigrene (2) to prevent colonisation by the green
[
4]
alga Chlorella fusca.
Other asymmetrically halogenated
Results and Discussion
Br
H
H
It is known that the predominant biosynthesis of asymmetrically
halogenated natural products involves reaction of cyclic bro-
monium intermediates, which are generated by the action of
HO
Br
OH
H
O
H
[14]
vanadium bromoperoxidase (VBrPO) enzymes.
An exami-
O
H
H
nation of asymmetrically brominated compounds revealed three
modes of cyclisation that are frequently involved in the bio-
genesis of these compounds.
O
H
2
Br
3
1
OH
Carbocyclisation reactions: as depicted in Fig. 2, the enzy-
matically generated cyclic bromonium intermediate can react
with a carbon nucleophile (typically an alkene) to give a
H
O
O
H OAc
O
OH
O
[15]
brominated alicyclic ring, such as is seen in luzonesin (5).
H
H
4
Bromoetherification and esterification reactions: in this
case, cyclic bromonium intermediates react with oxygen
nucleophiles – typically alcohols and epoxides, though less
Br
Fig. 1. Selected bromine-containing natural products.
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

B
C. Recsei and C. S. P. McErlean
often, carbonyl units. Fig. 3 illustrates how the bromonium
species 8 reacts with an internal epoxide to give prelaureatin
prevalence of 12 in brominated natural products – a 2013 review
identified more than 120 such compounds from a single family
[
16]
[9]
of red algae. Synthetically, the most significant advance in
(
3).
Bromoallene-forming reactions: in addition to the preceding
brominative methods to access substructure 12 has been the
introduction of bromodiethylsulfonium bromopentachloro-
modes of cyclisation, panacene (1) contains a bromoallene
moiety that is derived via bromination of an enyne system. As
depicted in Fig. 4, cyclisation of cis-laurediol (10) gives the
[
18–20]
antimonate (BDSB).
Developed by Snyder and
coworkers, BDSB is able to accomplish previously inaccessible
bromocyclisation reactions. For instance, BDSB converted
homogeranylbenzene (13) into the tricyclic compound 14, a
reaction that could not be performed efficiently using traditional
brominating reagents. In order to provide comparisons with
BDSB, we elected to study the brominative carbocyclisation of
homogeranylbenzene (13) using our phosphoramidite-catalysed
protocol.
[
17]
bromoallene-containing compound hachijojimallene (9),
[
with aromatises to give panacene (1).
3]
Any laboratory-based brominating reagent that aspires to be
widely applicable must, by necessity, be capable of mimicking
these common modes of cyclisation. We therefore attempted to
synthesise these key natural product motifs in a biomimetic
fashion employing N-heterocycle-bearing phosphoramidites as
nucleophilic catalysts.
[
20]
The synthesis of compound 13 is set down in Scheme 2.
Geraniol (15) was converted into the phosphate ester 16.
Coordination of the phosphate unit to benzylmagnesium chlo-
ride helps guide delivery of the nucleophile to the a-position to
regioselectively give (E)-homogeranylbenzene (13) in high
overall yield.
Carbocyclisation Reactions
In 2009, Snyder identified 135 natural products containing
substructure 12, the result of a carbocyclisation reaction (see
[18]
Scheme 1). This number is doubtless an underestimate of the
Our previous studies on the oxidative stability of N-hetero-
cycle-containing BINOL phosphoramidites pointed to the
advantage of employing electron-withdrawing groups on an
[
12]
Br
appended triazole ring.
Therefore, with 13 in hand, we
Br
explored the catalytic activity of the (S)-2,4,6-trichlorophenyl-
triazolyl BINOL phosphoramidite catalyst 17 (TCPT)
(Scheme 3). The outcomes of those reactions and relevant
literature precedents are presented in Table 1.
ϩ
5
6
Fig. 2. Substructure generation by carbocyclisation.
OH
H
H
ϩ
O
O
O
H
H
ϩ
Br
Br
H
Br
3
8
7
Fig. 3. Substructure generation by bromoetherification.
Br
H
Br
H
OH
H
H
H
O
H
OH
H
O
H
Br
10
O
H
O
H
OH
Br
1
9
Fig. 4. Substructure generation by bromoallene formation.
(a)
Br
Br
H
12
1
3
1
4
Scheme 1. Bromocyclisation of homogeranylbenzene (13). Reagents and conditions: (a) BDSB, MeNO
5 %.
2
, ꢀ258C, 5 min,
7

Phosphoramidite Catalysis
C
Treatment of 13 with NBS at low temperature resulted in no
reaction (entry 1). Snyder has already reported that activated
bromonium sources such as bromine and silver(I) (entry 2) and
tetrabromocyclohexadienone (TBCO) (entry 3) require polar
solvents and deliver the tricyclic compound 14 in low and
demonstrates that we were able to reduce the catalyst loading
to 2 mol-% without significantly affecting the yield. The
phosphoramidite-catalysed bromination protocol complements
existing methodologies. Although BDSB is selective for the
formation of the tricyclic system, the TCPT system is selective
for monocyclisation. Disappointingly, neither of the bromo-
cyclised products 18 or 19 was optically active.
[
20]
moderate yield respectively.
with PPh required long reaction times and was non-selective,
Similarly, activation of NBS
3
[
returning all possible products. For selective formation of 14,
20]
During this work, we did not observe formation of the
tetrasubstituted alkene 22 (Scheme 4). The absence of that
thermodynamically favourable isomer accords with the obser-
vation that the hydrogen atoms that participate in the elimination
[20]
BDSB was the superior reagent (entry 4).
adding a suspension of NBS in toluene to solution of TCPT
17) and substrate 13 at ꢀ788C resulted in rapid bromocyclisa-
tion (,1 min to completion) to give a mixture of 18 and 19 in
6 % yield (entry 6). Concerned that localised heating might be
Gratifyingly,
(
a
b
reaction (designated H and H on compound 21) are most
favourably oriented with respect to the developing carbocation.
Similarly, the absence of the tricyclic compound 14 suggests
that the ring closure does not proceed through a concerted
Stork–Eschenmoser-type cyclisation, but involves a discrete
carbocation intermediate 21. In non-polar solvents (such as
toluene), elimination to form the trisubstituted and exocyclic
alkenes 18 and 19 outcompetes the Friedel–Crafts reaction,
which would give 14. As shown in Table 1 (entry 8), when
7
affecting the rate of reaction, solid NBS was cooled with liquid
nitrogen before introduction into the reaction vessel. Rapid
dissolution of the NBS was observed and the bromocyclisation
was complete in less than 5 min. This modified procedure gave
an identical product mixture to the initial conditions. We
therefore concluded that we had not appreciably perturbed the
temperature of the system during the addition of NBS. Entry 7
(a)
(b)
OEt
OEt
OH
O
P
O
1
5
16
13
N, Et
Scheme 2. Synthesis of homogeranylbenzene (13). Reagents and conditions: (a) (EtO)
temperature (RT), 93 %; (b) BnMgCl, THF, ꢀ408C, 74 %.
2
POCl, C
5
H
5
2
O, ꢀ108C - room
Cl
O
O
Cl
P
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
TCPT
1
7
see Table 1
Br
ϩ
ϩ
Br
Br
H
1
3
1
4
18
19
Scheme 3. Bromocyclisation of homogeranylbenzene (13).
Table 1. Comparison of the bromocyclisation of homogeranylbenzene (13) with various reagents
Entry
Reagent(s)
NBS
Conditions
Solvent
Yield [%] 14/18/19
˚
1
2
3
4
5
6
7
8
ꢀ788C, 1 h, 4 A MS
ꢀ258C, 5 min
CH
2
Cl
2
0/0/0
[20]
9/,1/,1
Br
2
, AgBF
4
MeNO
2
[20]
27/,1/,1
TBCO
ꢀ788C, 10 min
CH
CH
3
CN
Cl
[20]
13/18/13
NBS, PPh
BDSB
3
ꢀ788C, 24 h then ꢀ408C, 6 h
ꢀ258C, 5 min
2
2
[
20]
MeNO
2
75/,1/,1
,1/36/40
,1/29/30
38/15/22
˚
NBS(S)-TCPT (10 mol-%)
NBS(S)-TCPT (2 mol-%)
NBS(S)-TCPT (10 mol-%)
ꢀ788C, 10 min, 4 A MS
Toluene
Toluene
˚
ꢀ788C, 10 min, 4 A MS
˚
ꢀ788C, 10 min, 4 A MS
2 2
CH Cl

D
C. Recsei and C. S. P. McErlean
increasing the polarity of the solvent from toluene to dichloro-
methane, the carbocation 21 persists and the formation of 14 is
Br
ϩ
[
21]
Br
observed.
relative stereochemistry of the newly formed carbocyclic rings
8 and 19 was ascertained by nuclear Overhauser enhancement
Finally, although the products were racemic, the
H
NOE
2
0
1
8
1
Ha
Hb
non-polar
(NOE) experiments, which demonstrated exclusive formation of
the syn isomer (Scheme 4).
solvent
ϩ
Phosphoramidite catalysis promotes the rapid bromocyclisa-
tion reaction to give an important natural product motif. Catalyst
loadings between 2 and 10 mol-% were effective. The system
showed a proclivity for monocyclisation, which is complemen-
tary to the established BDSB reagent.
Br
Hc
Br
NOE
2
1
19
polar
solvent
Bromoetherification and Bromoesterification Reactions
Structures arising from a bromoetherification reaction are
abundant in marine natural products. Two families of red algae
in particular, Rhodomelaceae and Plocamium, produce hun-
Br
Br
H
2
2
[9]
1
4
dreds of such compounds. Cyclic bromoethers ranging from
5
- to 12-membered rings have been isolated. Snyder has raised
Scheme 4. Pathway to the tetrasubstituted alkene 22.
the intriguing possibility that the medium-ring brominated
cyclic ethers are produced from smaller cyclic ethers that act
as internal nucleophiles during electrophilic brominations
t
t
O Bu
O Bu
[22,23]
(
Scheme 5).
This remarkable result implies that the key to
O
O
O
O
synthesising the members of this class of natural products with
medium-ring ethers is to synthesise the corresponding five-
membered ethers in a stereodefined fashion. Our initial goal was
to show that we could enforce selectivity in the cyclisation of
linear terpenoid precursors to give brominated tetrahydrofurans.
O
O
Br
ϩ
2
4
2
3
Bromocyclisation of (ꢀ)-Linalool
We selected (ꢀ)-linalool (27) as a substrate to explore the
reactivity of our catalytic system in promoting the bromoether-
ification of terpenoid derivatives (Scheme 6). Table 2 shows our
results along with comparative efforts by other researchers.
The use of a VBrPO-mimic (entry 1) was reported to give both
tetrahydrofuran isomers (28 and 29) along with both tetrahy-
O
O
O
O
H
H
H
O
O
[24]
dropyran isomers (30 and 31).
Butler and coworkers
employed the native enzyme, but under laboratory conditions,
this gave an intractable mixture of cyclic ethers that could not be
O
ϩ
O
H
[
25,26]
H
separated (entry 2).
during the synthesis of the thyrsiferol A (entries 3 and 4).
TBCO has been used to cyclise 27
[
Br
27,28]
Br
2
6
2
5
That reagent favoured generation of the tetrahydropyran ring
system with low levels of diastereoselectivity. Whereas NBS
was not capable of effecting the cyclisation (entry 5), in the
Scheme 5. Proposed ring-expanding biosynthesis of medium-ring
bromoethers.
Br
Br
OH
O
O
O
O
H
H
Br
Br
2
7
2
8
29
30
31
Scheme 6. Bromoetherification of linalool (27).
Table 2. Comparison of the bromoetherification of linalool (27) with various reagents
Entry
Reagent(s)
VO(L)(OEt)
Conditions
Solvent
Yield [%] 28/29/30/31
[24]
, TBHP, NaBr
1
2
3
4
5
6
3
308C, 24 h
RT, 1 h
Propylene carbonate
EtOH/buffer (30 : 70)
23/14/27/15
[
25,26]
VBrPO, NaBr, H
2
O
2
33 (composition of mixture not quantified)
[
28]
TBCO
TBCO
NBS
08C, 5 h
08C, 5 h
MeNO
MeNO
2
17 (28 þ 29)/38/26
10/7/38/24
[27]
2
˚
ꢀ788C, 10 min, 4 A MS
CH
CH
2
Cl
Cl
2
0/0/0/0
˚
NBS(S)-TCPT (10 mol-%)
ꢀ788C, 10 min, 4 A MS
2
2
67/12/0/16

Phosphoramidite Catalysis
E
presence of phosphoramidite catalyst 17, the cyclisation pro-
ceeded in high yield (entry 6). In contrast to entries 3 and 4, the
phosphoramidite-catalysed process favoured production of tet-
rahydrofuran 28. Interestingly, the tetrahydropyran 30 (the
major product from the TBCO reaction) was not observed.
As was the case for the carbocyclisations discussed above,
phosphoramidite catalysis appears to be complementary to the
established reagents. We attribute the ring-size selectivity to a
kinetic process. Five-membered ring closures are known to
occur more rapidly than the corresponding six-membered
must be as depicted in Fig. 5, with the methyl groups in a closer
spatial relationship to H-6 than the vinyl unit.
These outcomes demonstrate that the phosphoramidite-
catalysed process is a competent method for the bromoether-
ification of unprotected alcohols to give, predominantly, the
five-membered ring systems.
Cyclisation of Geranyl Acetate
The bromocyclisation of simple geraniol derivatives in
which a carbonyl unit participates as the nucleophile has
traditionally been a challenging transformation. Efforts to
induce the bromocyclisation of geranyl derivatives using com-
[
29]
ring-closing reactions.
By conducting the reaction at low
temperature, we were able to enhance the level of selectivity.
Gaining relative stereochemical information for five-
membered rings is less straightforward than the corresponding
six-membered rings. NOE data are often ambiguous, and in this
instance, the products were obtained as oils, precluding the use
of X-ray diffraction. Conventional NOE experiments revealed a
large number of through-space interactions that were not diag-
[31]
mon brominating reagents generally fail, and when success-
[32–41]
ful, the yield of such transformations is low.
the bromocyclisation of geranyl acetate 32 to give alcohol 35
For example,
was reported in 1976 by Wolinsky and Faulkner, who obtained a
2
I
0 % yield when using Br in combination with an Ag salt
2
[37]
(
Table 3, entry 1).
That result remained the state-of-the-art
[
30]
nostic of the relative stereochemistry of 28. The stereochem-
istry of the tetrahydrofuran 28 was ascertained by employing a
series of NOE experiments in which the mixing time was
steadily increased. Through-space cross-relaxation occurs in a
time-dependent fashion. At the shortest mixing times, only those
nuclei close to the irradiated atom will be capable of being
involved in the through-space spin-polarisation transfer. As the
mixing time slowly increases, nuclei at increasing distances will
be capable of becoming involved in the relaxation process and
the corresponding resonances will exhibit NOE enhancements.
This allows a time-dependent experiment to differentiate
between nuclei that are closer to the irradiated atom than those
that are further away.
[18]
until Snyder deployed BDSB 33 years later (entry 2).
Similarly, efforts to induce the cyclisation enzymatically have
also proved troublesome. Use of purified enzyme VBrPO to
[26]
effect the bromocyclisation of 32 was low-yielding (entry 3).
We therefore examined whether the bromocyclisation involving
a carbonyl unit as the nucleophile could be effected under
phosphoramidite catalysis.
Geranyl acetate (32) was synthesised according to the
[18]
published procedure.
When subjected to the action of NBS
at low temperature, no background reaction occurred (entry 4).
However, when the reaction was repeated in the presence of the
phosphoramidite catalyst (17), a 1 : 1 mixture of the racemic
alkenes 36 and 37 was obtained (entry 5).
The histogram in Fig. 5 represents the NOE enhancements
observed when H-6 is irradiated as a function of mixing time. It
clearly shows that with incremental increases in mixing time, it
is the methyl group H-8 and H-9 that show the first increase in
signal enhancement. The vinyl proton H-2 only begins to show
increased enhancement at relatively long mixing times. There-
fore, the relative stereochemistry of the tetrahydrofuran ring
The production of the alcohols 34 and 35 has previously
[1,15]
been rationalised as shown in Scheme 7.
The (developing)
carbocation from an initial carbocyclisation event is trapped by
the carbonyl oxygen to give the stabilised oxonium species 33.
Subsequent cleavage by water gives the observed products. In a
similar way, the production of 36 and 37 may result from
catalyst (or succinimide anion)-mediated elimination of 33.
However, given the facile elimination observed during the
carbocyclisation studies described above, we considered it
equally likely that the phosphoramidite-catalysed system did
not engage the acetate moiety as a nucleophile, but cyclised in a
process akin to that shown in Scheme 4. To discriminate
between these possible scenarios, we sought a related substrate
for which the engagement of a carbonyl nucleophile would
result in an irreversible cyclisation.
1.0
0.8
0.6
0.4
0.2
0
H-8
H-9
H-2
H
9
3
CH
H
2
1
2
H
O
6
H
7
8
Me
Br
Geranyl tert-butyl carbonate (38, Scheme 8) was synthesised
[
18]
following literature protocols. As carbocation capture by the
tert-butyl carbonate nucleophile is made irreversible through
subsequent fragmentation, this system would establish whether
the carbonyl moiety participated in phosphoramidite-catalysed
bromocyclisation reactions. As before, treatment of 38 with
0.2
0.4
0.6
0.8
1.0
Mixing time [s]
Fig. 5. Time-dependent NOEs of compound 28 when H-6 is irradiated.
Table 3. Comparison of the bromoetherification of geranyl acetate (32) with various reagents
Entry
Reagent(s)
Br , AgBF
Conditions
Solvent
Yield [%] 34/35/36/37
[
37]
18]
1
2
3
4
5
2
4
08C, 24 h
08C, 24 h
VBrPO, NaBr, H
MeNO
MeNO
2
10/10/0/0
17/63/0/0
[
BDSB
VBrPO
NBS
2
2
O
˚
2
EtOH/buffer (40 : 60)
0/0/,3/,3
0/0/0/0
ꢀ788C, 10 min, 4 A MS
CH
CH
2
Cl
Cl
2
˚
NBS(S)-TCPT (10 mol-%)
ꢀ788C, 10 min, 4 A MS
2
2
0/0/31/31

F
C. Recsei and C. S. P. McErlean
NBS at ꢀ788C did not induce any reaction. However, when the
alkene. Scheme 9 summarises the conclusions of Braddock and
[
42]
reaction was performed in the presence of the TCPT catalyst
(
coworkers.
When the (E)-enyne 44 cyclised, bromoallenes
17), we again observed a 1 : 1 mixture of alkene isomers 42 and
3. No trace of bicyclic products 40 and 41 were visible in the
46 and 47 were produced in a 6 : 1 ratio. Attempted cyclisation of
the pure (Z)-enyne 45 under identical conditions resulted in
decomposition. Intriguingly, cyclisation a 1 : 1.6 mixture of 44
and 45 returned a 1 : 1.5 mixture of 46 and 47 quantitatively.
This observation suggests that the mechanism is not straight-
forward and may involve coordination of a bromonium ion
between multiple unsaturated moieties.
4
1
H NMR spectrum of the crude reaction mixture. We therefore
consider it unlikely that the carbonyl moiety was participating in
the catalytic bromocyclisation.
So phosphoramidite catalysis is capable of engaging free
alcohols in the cyclisation event, but not the corresponding
carbonyl units. Once again, this reactivity pattern is comple-
mentary to the established BDSB reagent.
Br
H
Bromoallene Forming Reactions
OH
O
H
H
Bromoallenes are surprisingly common in marine natural pro-
ducts. Since the isolation of the first bromoallene-containing
4
4
4
5
46
H
[32]
natural product, panacene (1) (see Figs 1 and 4), the number
of compounds containing this functional unit has grown to at
Br
[
5]
least 40. These are predominantly isolated from red algae, and
are known to be biogenetically derived from enynes. The key
synthetic report in this area is by Braddock and coworkers, who
demonstrated that the bromoetherification of linear enynes
was stereospecific with respect to the geometry of the starting
O
H
H
OH
47
[42]
Scheme 9. Braddock’s enyne cyclisations.
carbonyl
involvement
O
ϩ
hydrolysis
O
Br
3
3
OH
OH
O
O
O
O
ϩ
Br
Br
elimination
O
O
3
4
35
3
2
no carbonyl
involvement
ϩ
O
O
Br
Br
O
O
3
6
3
7
Scheme 7. Bromocyclisation of geranyl acetate (32).
O
O
O
ϩ
O
Ϫ
O
O
tBu
ϩ
O
O
ϪH
O
Br
Br
3
8
4
0
3
9
ϩ
(a) or (b)
O
O
O
Br
ϩ
O
O
O
O
41
tBu Br
tBu
Br
O
O
4
2
43
Scheme 8. Reagents and conditions: (a) NBS, CH
dr 42 : 43 1 : 1). NR, no reaction.
2
Cl
2
ꢀ788C, NR; (b) (S)-TCPT 17 (10 mol-%), NBS, CH
2
2
Cl , ꢀ788C, 78 %
(

Phosphoramidite Catalysis
G
Given those outcomes, we initially targeted cyclisation of the
Z)-enyne 45 in order to test whether phosphoramidite catalysis
the presence of the phosphoramidite catalyst (S)-TCPT 17, we
were pleased to observe that bromoallene formation occurred
cleanly at ꢀ788C. Surprisingly, and in contrast to Braddock’s
(
could complement existing methods of bromoallene generation.
[
42]
The synthesis of 45 is depicted in Scheme 10. Protection of
4
work,
mixture.
the bromoallenes 46 and 47 were generated as a 1 : 1
[43]
-pentyn-1-ol (48) as the silyl ether and iodination gave 49. It
is known that ethynyl iodides can be reacted with diimide to give
the (Z)-configured alkene without over-reduction to the alkane,
provided that careful attention is paid to the stoichiometry and
To probe the origin of the 1 : 1 product ratio, we synthesised a
1 : 1.6 mixture of (E)-enyne 44 and (Z)-enyne 45 according to
[
42]
Braddock’s procedure.
When this mixture was subjected to
[
44]
concentration of reactants. In this instance, when two equiva-
lents of the diimide precursor tosylhydrazide were employed,
the phosphoramidite-catalysed conditions, we again observed a
1 : 1 ratio of the bromoallene products 46 and 47. There is
evidence for the coordination of Lewis bases to the halonium ion
in the transition states of certain Lewis base-promoted bromo-
[
45]
compound 49 was reduced to stereochemically pure 50
without over-reduction. Subsequent Sonogashira coupling of
the iodoalkene with trimethylsilylacetylene and double depro-
[
47]
lactonisations.
The lack of stereospecificity in this instance
[
46]
tection gave the desired (Z)-enyne 45.
When subjected to the action of NBS at low temperature, (Z)-
enyne 45 was recovered unchanged (Scheme 11). However, in
suggests that the phosphoramidite system proceeds through a
more a-bromocation-like intermediate, allowing bond rotation
and access to both diastereomers.
The phosphoramidite-catalysed bromination of enynes deli-
vers bromoallenes in high yield. The process is not stereo-
specific. In a total synthesis setting, the cyclising alcohol would
almost certainly be attached to a stereogenic centre, perhaps
allowing a diastereoselective process that is independent of the
enyne geometry. Work to that end is currently under way in our
laboratory.
(
a), (b)
TBSO
TBSO
HO
4
9
I
4
8
(c)
I
(
d), (e)
Catalyst Recovery
OH
45
50
In each of the foregoing processes, exposure of the crude mix-
ture to the air resulted in aerobic oxidation of the phosphor-
amidite catalyst 17 to give the phosphoramidate 51 (see
Scheme 12). Therefore, the preferred method for catalyst
recovery was filtration of the crude reaction mixture to remove
succinimide, followed by an extractive workup. The oxidised
Scheme 10. Reagents and conditions: (a) TBSCl, imidazole, CH
room temperature (RT), 60 h; (b) I , KOH, MeOH/H
6 h, 74 % (2 steps); (c) TsNHNH , NaOAc, THF/H O (1 : 1), D, 15 h, 86 %;
, CuI, THF/NEt
2
Cl
2
,
2
2
O (5 : 1), 08C - RT,
1
2
2
(
d) TMSCꢁCH, Pd(PPh
3
)
4
3
(1 : 1), RT, 16 h; (e) TBAF,
THF, ꢀ108C - 08C, 3 h, 91 % (2 steps).
Br
H
H
Br
OH
(b)
(a) or (b)
ϩ
44
OH
O
H
H
O
H
H
4
5
4
6
47
OH
4
5
˚
Scheme 11. Reagents and conditions: (a) NBS, CH
˚
10 mol-%), NBS, 4 A MS, CH
2
Cl
2
, 4-A molecular sieves (MS), ꢀ788C, NR; (b) (S)-TCPT 17
(
2
Cl
2
, ꢀ788C, 82 % (dr 46 : 47 1 : 1). (NR, no reaction).
CI
CI
CI
CI
CI
CI
CI
CI
CI
N
N
N
N
N
N
N
N
N
O
P
O
O
N
(a)
(b)
OH
OH
O
P
N
N
O
N
N
N
N
N
N
N
5
1
52
17
N
CI
CI
CI
CI
CI
CI
CI
CI
CI
Scheme 12. Reagents and conditions: (a) HCl (10 M in H
b) PCl , toluene, D, 16 h, then (CH NH, 08C - RT, 0.5 h, 91 %.
2 2 2
O), CH Cl /MeOH (1 : 9), room temperature (RT), 16 h, 99 %;
(
3
2 4
)

H
C. Recsei and C. S. P. McErlean
phosphoramidate 51 was substantially more polar than the
cyclisation products and was recovered chromatographically,
after elution of the desired cyclisation products. Recovery of 51
was typically 98 %. As shown in Scheme 12, cleavage of the
phosphorus(V) unit to regenerate the diol 52 was facile. The
phosphoramidite 17 was then regenerated, with no loss of
spectroscopy (COSY) 2D experiments. High-resolution mass
spectra (HRMS) were recorded on a Bruker ApexII Fourier-
transform ion cyclotron resonance mass spectrometer with a
7.0-T magnet, fitted with an off-axis analytical electrospray
ionisation (ESI) source. Column chromatography was per-
formed using Grace Davidson 40–63-mm (230–400 mesh) silica
gel using distilled solvents. Analytical thin-layer chromatogra-
phy was performed using preconditioned plates (Merck TLC
silica gel 60 F254 on aluminium) and visualised using UV light
[
11,12]
optical rotation.
Conclusion
(
254 and 365 nm) and ethanolic anisaldehyde.
This article describes our use of phosphoramidite catalysis to
construct several bromine-containing motifs that are com-
monly encountered in natural products. The reactivity of this
system was found to be complementary to the current gold-
standard reagent, BDSB. The phosphoramidite-catalysed car-
bocyclisation of homogeranylbenzene proceeded in high yield
and diastereoselectivity, and monocyclisation was highly
favoured. The bromoetherification of the unprotected tertiary
allylic alcohol, linalool, favoured formation of the tetra-
hydrofuran product. In contrast to BDSB, carbonyl units
were not nucleophilic enough to engage in cyclisation during
the phosphoramidite-catalysed process. And finally, the
phosphoramidite-catalysed bromination of enynes led to the
corresponding bromoallenes. Reaction with diastereomerically
pure linear enynes demonstrated that the process was not
stereospecific, which opens avenues for substrate-controlled
processes.
Representative Bromination Procedure
A representative protocol for the bromocyclisation reactions is
as follows: a solution of substrate (0.50 mmol, 1.0 equiv.) and
(
(
(
(
2
S)-TCPT catalyst 17 (0.05 mmol, 0.10 equiv.) in CH Cl2
˚
10 mL) was stirred (7 h) over activated 4-A molecular sieves
0.5 g). The mixture was cooled to ꢀ788C and a solution of NBS
0.50 mmol 1.0 equiv.) in CH Cl (10 mL) was added over 5 min
2
2
via syringe pump. The solution was stirred (5 min) at ꢀ788C,
then quenched via the addition of a solution of sodium sulfite
(5 % in water, 20 mL) and allowed to warm to room temperature.
The aqueous phase was extracted with CH Cl (2 ꢂ 5 mL) and
2
2
the organic extracts combined with the organic partition of the
reaction mixture and washed with water (50 mL), brine (50 mL),
dried over sodium sulfate, and concentrated. Column chroma-
tography was used to isolate the product(s).
In conclusion, phosphoramidite catalysis permits the use of
the stable and readily available brominating reagent NBS for the
synthesis of a range of brominated natural product motifs.
[
20]
(E)-3,7-Dimethylocta-2,6-dien-1-yl diethyl phosphate 16
To a mixture of geraniol (10 mL, 58 mmol, 1.0 equiv.), pyridine
19 mL, 0.23 mol, 4.1 equiv.), and diethyl ether (100 mL) at
108C was added, dropwise, diethyl chlorophosphate (10 mL,
(
ꢀ
Experimental
General Experimental
69 mmol, 1.2 equiv.) and the reaction stirred, while being
allowed to warm slowly to room temperature (16 h). The mix-
ture was cooled to 08C and quenched via addition to a solution
of sodium hydroxide (1.0 M in water, 200 mL). The resulting
mixture was extracted with ethyl acetate (3 ꢂ 100 mL) and the
combined organic extracts washed with water (2 ꢂ 100 mL),
brine (50 mL), and dried over sodium sulfate. Column chro-
matography (ether) gave the product (15.6 g, 93 %) as a col-
2980, 1275, 1101, 1035. dH
300 MHz, CDCl ) 5.33 (1H, m), 5.01 (1H, m), 4.50 (2H, dt, J
.5, 0.5), 3.99–4.07 (4H, m), 1.94–2.08 (4H, m), 1.60 (3H, s),
.60 (3H, s), 1.26 (6H, dt, J 7.1, 0.9). d (75 MHz, CDCl ) 142.3
Reagent-grade dichloromethane and triethylamine were freshly
distilled from calcium hydride. Tetrahydrofuran and methanol
TM
were collected using an Innovative Technology Inc. PureSolv
[
48]
solvent purification system. Tosyl hydrazide,
diethyl
5-tert-
[49,50]
[20]
chlorophosphate,
butyldimethylsilyloxypent-1-yne,
geranyl diethyl phosphate,
[
51]
1-iodo-5-tert-butylsi-
[52,53]
[43]
methylsilyloxypent-1-yne,
and TBCO
were synthe-
ꢀ
1
ourless oil. nmax (neat)/cm
(
7
1
sised according to literature procedures. All other solvents and
reagents were used as received from commercial sources.
Melting points were determined using a Stanford Research
Systems Optimelt automated melting point system and are
uncorrected. Infrared spectra were acquired neat on a Bruker
3
C
3
(C), 131.7 (C), 123.4 (CH), 118.8 (CH, JC–P 6.4), 63.9 (CH2,
JC–P 5.5), 63.4 (2C, CH , J 6.1), 39.3 (CH ), 26.0 (CH ), 25.5
1
2
C–P
2
2
Alpha-E attenuated total reflection (ATR) spectrometer. H and
1
C NMR spectra were recorded on a Bruker Avance DPX300
3
(CH ), 17.5 (CH ), 16.2 (CH ), 15.9 (2C, CH , J 6.5).
C–P
3
3
3
3
1
13
H frequency 300 MHz, C frequency 75 MHz) or Bruker
(
Avance DPX500 ( H frequency 500 MHz, C frequency
[
20]
1
13
(E)-(4,8-Dimethylnona-3,7-dien-1-yl)benzene 13
1
25 MHz). H chemical shifts are expressed as parts per million
1
A solution of benzyl chloride (0.230 mL, 2.00 mmol, 2.0 equiv.)
in THF (10 mL) was cooled to 08C and added over 30 min to
ground magnesium turnings (97 mg, 4.00 mmol, 4.0 equiv.),
activated with a crystal of mercury(II) chloride. The solution was
stirred at 08C (1 h), then cooled to ꢀ408C and added to a solu-
tion of 16 (290 mg, 1.00 mmol, 1.0 equiv.) in THF (2.0 mL) at
ꢀ408C. The mixture was stirred, being allowed to warm grad-
ually to room temperature (4 h). The reaction was quenched with
saturated aqueous ammonium chloride (15 mL), then extracted
with ethyl acetate/hexanes 1 : 1 (3 ꢂ 20 mL). The combined
organic extracts were washed with saturated aqueous sodium
hydrogen carbonate (20 mL), then brine (20 mL), dried over
sodium sulfate and concentrated. Column chromatography
(ethyl acetate/light petroleum 1 : 99) gave 13 (2.6 g, 74 %) as a
(
(
ppm) with residual chloroform (d 7.26) or tetramethylsilane
d 0.00) as reference and are reported as chemical shift (dH),
relative integral, multiplicity (s, singlet; br, broad; d, doublet; t,
triplet; dd, doublet of doublets; dt, doublet of triplets; m,
1
3
multiplet), and coupling constants (J) reported in Hz. C NMR
chemical shifts are expressed as parts per million (ppm) with
residual chloroform (d 77.16) as internal reference and are
reported as chemical shift (d ), multiplicity (assigned from
C
distortionless enhancement by polarisation transfer (DEPT)
experiments). NMR assignments were made on the basis of
heteronuclear single quantum coherence (HSQC), hetero-
nuclear multiple-bond correlation (HMBC), nuclear Overhauser
effect spectroscopy (NOESY), and homonuclear correlation

Phosphoramidite Catalysis
I
slightly yellow oil. R 0.76 (CH Cl /hexanes 1 : 4). n
133.9 (C), 122.3 (CH), 64.0 (CH), 63.8 (CH ), 49.1 (CH), 35.1
2
f
2
2
max
ꢀ
1
neat)/cm 3052, 2965, 1495, 1376, 1109, 835. d (300 MHz,
(
CDCl ) 7.37 (2H, dd, J 7.2, 1.8), 7.26–7.36 (3H, m), 5.32 (1H, tt,
(C), 29.9 (C, CH ), 28.6 (CH ), 21.9 (CH ), 21.3 (CH ), 16.6
3
H
2
3
3
(CH ). Compound 37: d (300MHz, CDCl ) 4.95 (1H, s), 4.66
3 H 3
3
J 7.2, 1.1), 5.24 (1H, m), 2.09–2.82 (8H, m), 1.80 (3H, s), 1.73
(3H, s), 1.68 (3H, s). d (75 MHz, CDCl ) 142.3 (C), 135.6 (C),
(1H, s), 4.50–4.37 (2H, m), 4.13 (1H, dd, J 9.9, 7.1), 2.03 (3H, s),
2.59–1.64 (3H, m), 1.23 (3H, s), 0.91 (3H, s). d (75MHz, CDCl )
C 3
C
3
1
(
31.2 (C), 128.4 (2C, CH), 128.1 (2C, CH), 125.6 (CH), 124.4
CH), 123.6 (CH), 39.7 (CH ), 36.2 (CH ), 29.9 (CH ), 26.8
171.2 (C), 144.0 (C), 110.1 (CH ), 66.1 (CH), 62.7 (CH ), 51.2
2 2
(CH), 36.3 (C), 35.3 (CH ), 29.9 (C, CH ), 28.4 (CH ), 21.2
2 2 3
2
2
2
(
CH ), 25.7 (CH ), 17.6 (CH ), 15.9 (CH ).
2
(CH ), 17.5 (CH ). m/z (EI) (relative intensity) 216 (8), 214 (9),
3 3
3
3
3
135 (100), 119 (30), 107 (40), 93 (37), 79 (10), 43 (97).
(
2-((1R*,5S*)-5-Bromo-2,6,6-trimethylcyclohex-2-en-1-yl)
(
(1R,5S)-5-Bromo-2,6,6-trimethylcyclohex-2-en-1-yl)
methyl tert-Butyl Carbonate 42 and ((1R,3S)-3-Bromo-
,2-dimethyl-6-methylenecyclohexyl)methyl tert-Butyl
ethyl)benzene 18 and (2-((1R*,3S*)-3-Bromo-2,2-dimethyl-
6
[
20]
-methylenecyclohexyl)ethyl)benzene 19
2
These compounds were synthesised using the representative
procedure in toluene. They were obtained, after column chro-
matography using CH Cl /hexanes (1 : 19), as a colourless oil
comprising a 1 : 1.1 mixture of 18 and 19 (76 %), R 0.40
(
1
(
7
(
Carbonate 43
These compounds were synthesised using the representative
procedure. They were obtained, after column chromatography
(ethyl acetate/hexanes 1 : 99), as a colourless oil comprising a
1
1
2
2
f
ꢀ
(neat)/cm 2952, 1675, 1649,
max
1
CH Cl /hexanes 1 : 9). n
2
2
: 1 mixture of 42 and 43 (65 %). R 0.70 (ethyl acetate/hexanes
f
363, 1232. Compound 18: dH (300 MHz, CDCl ) 7.26–7.33
3
2H, m), 7.16–7.23 (3H, m), 5.25 (1H, br s), 4.18 (1H, dd, J 9.0,
.2), 2.88 (1H, ddd, J 16.2, 11.0, 5.3), 1.81–2.62 (5H, m), 1.80
3H, br s), 1.67 (1H, dddd, 17.6, 13.7, 7.1, 5.0), 1.07 (3H, s), 0.90
ꢀ1
: 50). nmax (neat)/cm 2927, 1747, 1649, 1394, 1364, 1232.
Compound 42: d (300 MHz, CDCl ) 5.39 (1H, br s), 4.39–4.53
H
3
(
(
(
2H, m), 4.39 (1H, a, dd, J 11.8, 3.9), 1.64–2.63 (2H, m), 1.52
3H, s), 1.45 (9H, s) or 1.43 (9H, s), 1.24 (3H, s), 0.98 (3H, s). dC
75 MHz, CDCl ) 153.5 or 153.1 (C), 134.1 (C), 122.6 (CH),
(
1
(
3H, s). d (100 MHz, CDCl ) 142.7 (C) or 142.4 (C), 136.7 (C),
C
3
3
26.0–128.6 (3C, CH) 121.0 (CH), 65.3 (CH), 49.7 (CH), 39.1
C), 37.5 (CH ), 36.1 (CH ), 35.5 (CH ), 31.8 (CH ), 28.5
2 2 2 2
6
4.4 (CH), 63.6 (CH ), 49.4 (CH), 34.9 (C), 29.9 (CH ), 28.6
2 2
(
(
(
(
0
1
CH ), 27.8–27.9 (3C, CH ), 21.7 (CH ), 18.3 (CH ), 16.5
3 3 3 3
(CH ), 22.4 (CH ), 16.7 (CH ). Compound 19: d (300 MHz,
CDCl ) 7.26–7.33 (2H, m), 7.16–7.23 (3H, m), 5.01 (1H, s), 4.77
(
4
CDCl ) 145.7 (C), 142.7 (C) or 142.4 (C), 126.0–128.6 (3C, CH)
1
3
3
3
H
CH ). Compound 43: d (300 MHz, CDCl ) 4.99 (1H, s), 4.67
3
H
3
3
1H, s), 4.39–4.53 (2H, m), 4.17 (1H, dd, J 9.9, 7.1), 1.64–2.63
4H, m), 1.52 (3H, s), 1.45 (9H, s) or 1.43 (9H, s), 1.26 (3H, s),
.93 (3H, s). d (75 MHz, CDCl ) 153.5 or 153.1 (C), 144.3 (C),
C 3
1H, s), 4.11 (1H, dd, J 11.4, 5.7), 2.81 (1H, ddd, J 13.9, 10.3,
.5), 1.81–2.62 (7H, m), 1.13 (3H, s), 0.84 (3H, s). d (100 MHz,
C
3
09.8 (CH ), 66.4 (CH), 62.9 (CH ), 51.9 (CH), 36.1 (C), 35.3
2
2
09.2 (CH ), 67.4 (CH), 52.3 (CH), 42.0 (C), 38.1 (CH ), 37.5
2 2
(
(
(
CH ), 29.9 (CH ), 28.4 (CH ), 27.8–27.9 (3C, CH ), 18.1
2 2 3 3
(
CH ), 34.9 (CH ), 28.6 (CH ), 28.4 (CH ), 15.7 (CH ).
2 2 2 3 3
CH ), 17.7 (CH ). m/z (EI) (relative intensity) 216 (18), 214
3
3
19), 135 (100), 119 (27), 93 (23), 43 (86).
Z)-5-tert-Butyldimethylsilyloxy-1-iodopent-4-yne 49
To a solution of 48 (1.0 mL, 11 mmol, 1.0 equiv.) in DMF
(
2R,5S)-5-(2-Bromopropan-2-yl)-2-methyl-2-
[27,28]
[
43]
vinyltetrahydrofuran 28
(
This compound was synthesised using the representative pro-
cedure. It was obtained as a colourless oil (67 %). This com-
pound elutes last among the four isomers produced in the
cyclisation. A pure sample of 28 may be obtained by preparative
(
1
2
30 mL) was added tert-butyldimethylchlorosilane (2.1 g,
4 mmol, 1.3 equiv.), then imidazole (1.8 g, 26 mmol,
.5 equiv.). The mixture was stirred at room temperature (60 h),
2
4
thin-layer chromatography (ether/light petroleum 2 : 98). a
D
(neat)/
then filtered. The filtrate was diluted with hexanes (100 mL),
washed with water (3 ꢂ 100 mL), brine (100 mL), dried over
sodium sulfate and passed through a plug of silica, washing with
CH Cl /hexanes 1 : 9 (50 mL), and concentrated to give a
þ6.0 (c 1.0, CHCl ). R 0.60 (ether/hexanes 1 : 19). n
3
f
max
ꢀ
1
cm 2970, 1260, 1091, 1065, 1018, 916, 801. d (500 MHz,
H
CDCl ) 5.99 (1H, dd, J 17.4, 10.8), 5.22 (1H, dd, J 17.4, 1.4),
3
2
2
4
m), 1.75 (3H, s), 1.72 (3H, s), 1.30 (3H, s). d (125 MHz, CDCl )
.99 (1H, dd, J 1.4, 10.8), 3.99 (1H, app t, J 6.8), 1.77–2.08 (4H,
colourless oil. This colourless oil was taken up in methanol
(25 mL) and a solution of potassium hydroxide (1.5 g, 27 mmol,
2.5 equiv.) in water (7 mL) added. The mixture was cooled to
08C and stirred with protection from light while iodine (4.1 g,
C
3
1
44.0 (CH), 111.7 (CH ), 86.1 (CH), 84.0 (C), 68.4 (CH), 37.6
2
(
(
CH ), 31.6 (CH ), 29.2 (CH ) 29.0 (CH ), 25.7 (CH ). m/z
2 3 3 2 3
þ
þESI) (relative intensity) 321 (97), 319 (100), 257 (39, MNa ),
1
6 mmol, 1.5 equiv.) was added in small portions, allowing the
þ
2
C H
C H
1
55 (38, MNa ). m/z (HRMS, þESI) 255.03563, calc. for
brown colour of dissolved iodine to dissipate between portions.
The mixture was stirred for a further 16 h, while being allowed to
warm to room temperature. The reaction mixture was parti-
tioned between hexanes (100 mL) and water (100 mL). The
aqueous partition was washed with hexanes (50 mL) and the
hexane wash combined with the organic partition of the reaction
mixture, and washed with water (3 ꢂ 100 mL), brine (50 mL),
7
9
BrONa 255.03550 [M þ Na]; 257.03361, calc. for
1
0
17
17
8
1
BrONa 257.03345.
0
(
(1R*,5S*)-5-Bromo-2,6,6-trimethylcyclohex-2-en-1-yl)
methyl Acetate 36 and ((1R*,3S*)-3-Bromo-2,2-dimethyl-
[
18,26]
6
-methylenecyclohexyl)methyl Acetate 37
These compounds were synthesised using the representative
procedure. They were obtained, after column chromatography
dried over NaSO , and concentrated. Column chromatography
4
(ether/light petroleum 1 : 9) gave 49 (2.6 g, 74 %) as a slightly
ꢀ1
(ethyl acetate/hexanes 1 :49), as a colourless oil comprising a 1 : 1
mixtureof36and37(62 %). R 0.55 (ethyl acetate/hexanes 1 : 50).
yellow oil. R
2190, 1471, 1253, 1007, 835, 776. d
(2H, d, J 6.1), 2.44 (2H, t, J 7.0), 1.72 (2H, dt, J 13.9, 6.4), 0.88
(9H, s), 0.03 (3H, s). d (75 MHz, CDCl ) 94.2 (C), 61.3 (CH ),
31.4 (C), 25.9 (3C, CH ), 18.3 (CH ), 17.3 (CH
), ꢀ5.3 (2C,
CH
), ꢀ7.1 (CI).
f
0.25 (EtOAc/hexanes 1 : 50). nmax (neat)/cm
(300 MHz, CDCl ) 3.67
f
H
3
ꢀ1
nmax (neat)/cm 2952, 2925, 1754, 1395, 1232. Compound 36:
d (300 MHz, CDCl ) 5.35 (1H, br s), 4.50–4.37 (2H, m), 4.35
H
3
C
3
2
(1H, dd, J 11.8, 3.9 Hz), 2.06 (3H, s), 2.59–1.64 (3H, m), 1.49 (3H,
s), 1.21 (3H, s), 0.95 (3H, s). d (75MHz, CDCl ) 171.2 (C),
3
2
2
C
3
3

J
C. Recsei and C. S. P. McErlean
[
45]
(
Z)-5-tert-Butyldimethylsilyloxy-1-iodopent-4-ene 50
d (75 MHz, CDCl ) 145.1 (CH), 108.9 (CH), 81.9 (CH), 80.4
C 3
(C), 62.0 (CH ), 31.4 (CH ), 26.5 (CH ). m/z (ESI) (relative
intensity) 111 (39, MH ), 93 (100), 51 (34).
A solution of 49 (1.61 g, 4.96 mmol, 1.0 equiv.) in THF (5 mL)
was added to a stirred solution of tosyl hydrazide (1.85 g,
2 2 2
þ
9
3
.93 mmol, 2.0 equiv.) and sodium acetate (1.22 g, 14.9 mmol,
.0 equiv.) in water (5 mL) and the mixture heated to reflux
(
4
2R*)-2-((S*)-3-Bromopropa-1,2-dien-1-yl)tetrahydrofuran
6 and (2R*)-2-((R*)3-Bromopropa-1,2-dien-1-yl)
(
16 h) with strict exclusion of light. The reaction mixture was
poured onto a solution of ammonium chloride (5 % in water,
00 mL) and the resulting mixture extracted with ethyl acetate/
[
42]
tetrahydrofuran 47
1
A solution of 45 (205 mg, 1.86 mmol, 1.0 equiv.) and (S)-TCPT
catalyst (163 mg, 0.185 mmol, 0.10 equiv.) in CH Cl (20 mL)
was dried by stirring over 4-A molecular sieves (7 h), then
cooled to ꢀ788C and a suspension of NBS (330 mg, 1.85 mmol,
1.0 equiv.) in CH Cl (10 mL) added via syringe pump over
hexanes 1 : 9 (3 ꢂ 20 mL). The combined organic extracts were
washed with water (2 ꢂ 100 mL), brine (50 mL), dried over
sodium sulfate, and concentrated. Column chromatography
2
2
˚
(
8
ether/hexanes 1 : 200) gave 50 as a slightly yellow oil (1.39 g,
6 %). R 0.25 (ether/hexanes 1 : 200). dH (300 MHz, CDCl3)
2
2
5 min. The solution was stirred at ꢀ788C (3 h), then quenched
f
6
.17–6.23 (2H, m), 3.64 (2H, t, J 6.3), 2.21 (2H, t, J 5.5), 1.67
2H, tt, J 6.3, 5.5), 0.90 (9H, s), 0.06 (6H, s). dC (75 MHz,
with a solution of sodium sulfite (5 % w/v in H O, 10 mL) and
2
(
CDCl ) 141.1 (CH), 82.6 (CH), 62.5 (CH ), 31.5 (CH ), 31.2
allowed to warm to room temperature. The mixture was filtered,
then partitioned between water (50 mL) and ethyl acetate/hex-
anes 1 : 1 (10 mL). The aqueous partition was extracted with
ethyl acetate/hexanes 1 : 1 (2 ꢂ 10 mL) and the organic extracts
combined with the organic partition of the reaction mixture
and washed with water (2 ꢂ 100 mL), brine (100 mL), dried over
sodium sulfate, and concentrated. Column chromatography
(ether/light petroleum 1 : 9) gave a slightly yellow oil consisting
of equal proportions of 46 and 47 (288 mg, 82 %). R 0.53 (light
petroleum/ether 7 : 3). Compound 46: dH (300 MHz, CDCl3)
6
m), 3.75–3.90 (2H, m), 2.02–2.14 (1H, m), 1.87–2.00 (2H, m),
1
7
d (300 MHz, CDCl ) 6.04 (1H, dd, J 5.7 1.6), 5.40 (1H, dd, J
3
5
m), 1.87–2.00 (2H, m), 1.71–1.86 (1H, m). d (75 MHz, CDCl )
3
2
2
(
(
CH ), 26.1 (3C, CH ), 18.4 (C), ꢀ5.7 (2C, CH ). m/z (EI)
2
3
3
þ
relative intensity) 326 (MH , 1), 269 (100), 164 (15), 75 (45).
[
46]
(
Z)-Hept-4-en-6-yn-1-ol 45
To a mixture of 50 (1.39 g, 4.26 mmol, 1.00 equiv.), copper(I)
iodide (60 mg, 0.32 mmol, 0.074 equiv.) and tetra-
kistriphenylphosphinepalladium(0)
0
then trimethylsilylacetylene (1.5 mL, 11 mmol, 2.5 equiv.). The
mixture was stirred (16 h), then partitioned between water
f
(200 mg,
0.17 mmol,
.041 equiv.) in THF (10 mL) was added triethylamine (10 mL),
.03 (1H, dd, J 5.7 1.9), 5.42 (1H, dd, J 5.7 5.4), 4.52–4.56 (1H,
.71–1.86 (1H, m). d (75 MHz, CDCl ) 201.3 (C), 102.4 (C),
C 3
(100 mL) and hexanes (20 mL). The aqueous partition was
5.7 (CH), 68.3 (CH ), 31.5 (CH ), 25.5 (CH ). Compound 47:
2
2
2
extracted with hexanes (2 ꢂ 20 mL) and the organic extracts
combined with the organic partition of the reaction mixture
and washed with saturated aqueous ammonium chloride
H
.9 5.7,), 4.52–4.56 (1H, m), 3.75–3.90 (2H, m), 2.02–2.14 (1H,
C
3
(
2 ꢂ 20 mL), water (100 mL), brine (100 mL), and dried over
2
(
7
01.2 (C), 102.8 (C), 75.1 (CH), 73.9 (CH), 68.2 (CH ), 31.5
2
sodium sulfate. The solution was passed through a plug of silica,
washing with ether/hexanes: 1/9. Volatile components were
removed under vacuum to give (Z)-1-tert-butyldimethylsily-
CH ), 25.3 (CH ). m/z (EI) (relative intensity) 158 (8), 156 (7),
2
2
1 (100).
[
54]
loxy-7-trimethylsilylhept-4-en-6-yne
nmax (neat)/cm 2954, 2121, 1610, 1447, 1054. d (300 MHz,
CDCl ) 5.94 (1H, dt, J 10.9, 7.4), 5.47 (1H, dt, J 10.9, 1.5), 3.63
(2H, t, J 6.5), 2.36 (2H, ddt, J 9.9, 7.4, 1.5), 1.64 (2H, tt, J 6.5,
as a colourless oil.
Catalyst Recycling
ꢀ1
H
The yield for the installation of the phosphoramidite moiety is
[11,12]
higher than in our previous report.
3
Rather than the stan-
dardised workup employed for comparative purposes in our
study of structure–activity, here we desired simply to maximise
production of the desired phosphorus(III)-centred catalyst 17.
To this end, the crude mixture was diluted with ethyl acetate to
precipitate pyrrolidinium chloride, filtered under a flow of
nitrogen, volatile components removed under vacuum, and a
toluene solution of the residue immediately subjected to column
chromatography (WARNING: the highly exothermic adsorp-
tion on silica of this mixture can be mitigated by using a buffer
of alumina above the main silica column. Dichloromethane is
unsuitable for loading this crude mixture onto a chro-
matographic medium. Toluene is preferred.)
9
1
2
.9), 0.90 (9H, s), 0.19 (6H, s), 0.05 (3H, s). d (75 MHz, CDCl )
C 3
45.1 (CH), 109.5 (CH), 62.9 (CH ), 32.0 (CH ), 27.1 (CH ),
2
2
2
6.1 (3C, CH ), 18.5 (C), 0.2 (3C, CH ), ꢀ5.1 (2C, CH ). m/z
3
3
3
þ
(
EI) (relative intensity) 296 (MH , 2), 239 (100), 133 (89), 73
74). This bis-silylated compound was deprotected in the next
(
step without further purification.
The sample of (Z)-1-tert-butyldimethylsilyloxy-7-trimethyl-
silylhept-4-en-6-yne prepared as described above was taken up
in THF (20 mL) and cooled to ꢀ108C. A solution of tetrabuty-
lammonium fluoride (TBAF) (1.0 M in THF, 8.7 mL, 2.0 equiv.)
was added slowly and the mixture stirred (1 h), being allowed to
warm to 08C. The reaction was quenched with water (10 mL),
then partitioned between water (100 mL) and ethyl acetate/
hexanes 1 : 1 (20 mL). The aqueous partition was extracted with
ethyl acetate/hexanes 1 : 1 (2 ꢂ 20 mL) and the organic extracts
combined with the organic partition of the reaction mixture and
washed with water (100 mL), brine (100 mL), dried over sodium
sulfate, and concentrated. Column chromatography (ether/
hexanes 3 : 7) gave 45 (1.15 g, 91 %, 2 steps) as a colourless
Supplementary Material
Copies of NMR spectra of compounds 18, 19, 28, 42, 43, 46,
and 47 are available on the Journal’s website.
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