Cycloalkenyl halide substitution reactions of enantiopure arene cis-tetrahydrodiols with boron, nitrogen and phosphorus nucleophiles

Article abstract of DOI:10.1002/adsc.201100273

Enantiopure arene cis-tetrahydrodiols of bromobenzene and iodobenzene have been obtained in good yields, from chemoselective hydrogenation (rhodium-graphite) of the corresponding cis-dihydrodiol metabolites. Palladium-catalysed substitution of the halogen, by hydrogen, boron, nitrogen and phosphorus nucleophiles, in the acetonide derivatives, has yielded highly functionalised products for application in synthesis with potential as scaffolds for chiral ligands. Copyright

Full text of DOI:10.1002/adsc.201100273

FULL PAPERS
DOI: 10.1002/adsc.201100273
Cycloalkenyl Halide Substitution Reactions of Enantiopure
Arene cis-Tetrahydrodiols with Boron, Nitrogen and Phosphorus
Nucleophiles
D. R. Boyd,a,* N. D. Sharma,a M. Kaik,a,c M. Bell,a,c M. V. Berberian,a,b
P. B. A. McIntyre,a B. Kelly,c C. Hardacre,a,b P. J. Stevenson,a,* and C. C. R. Allend
a
School of Chemistry and Chemical Engineering, Queenꢀs University, Belfast BT9 5AG, U.K.
Fax : (+44)-28-9097-4687; e-mail: dr.boyd@qub.ac.uk or p.stevenson@qub.ac.uk
CenTACat, Queenꢀs University, Belfast BT9 5 AG, U.K.
Celtic Catalysis Ltd., Nova Centre, Belfield Innovation Park, Dublin 4, Ireland
School of Biological Sciences, Queenꢀs University, Belfast BT9 5AG, U.K.
b
c
d
Received: April 12, 2011; Published online: August 30, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100273.
Abstract: Enantiopure arene cis-tetrahydrodiols of yielded highly functionalised products for application
bromobenzene and iodobenzene have been obtained in synthesis with potential as scaffolds for chiral li-
in good yields, from chemoselective hydrogenation gands.
(rhodium-graphite) of the corresponding cis-dihydro-
diol metabolites. Palladium-catalysed substitution of
the halogen, by hydrogen, boron, nitrogen and phos- Keywords: catalytic hydrogenation; chemoenzymatic
phorus nucleophiles, in the acetonide derivatives, has synthesis; cis-dihydrodiols; cis-tetrahydrodiols
Introduction
nols, which, in turn, catalyse further decomposition.
To minimise decomposition, cis-dihydrodiols 1b–e
A wide range of benzene substrates can be efficiently must be stored below 08C. This instability presents
dihydroxylated to yield cis-dihydrodiol bioproducts, problems for storage and safe transportation. Regio-
for example, 1a–e, using toluene dioxygenase (TDO)- selective hydrogenation of the unsubstituted alkene
expressing mutant strains of the bacterium Pseudomo- bond of cis-dihydrodiol metabolites of mono-substi-
nas putida, e.g., UV4 or 39/D, and E. coli recombi- tuted benzenes, e.g., 1b–e, can, in principle, give very
nant strains, e.g., JM109
(pKST11), as biocatalyst sources (Scheme 1).[1]
These multi-functionalised cis-dihydrodiols have
ACHTUNGTREN(NUGN pDTG601) or JM109-
ACHTUNGTRENNUNG
great potential as chiral intermediates in organic syn-
thesis. One of the advantages of this biocatalytic pro-
cess is that single biotransformations can be readily
scaled up to produce large quantities (multi-grams to
kilograms) of enantiopure cis-dihydrodiols 1 (e.g.,
R=F, Cl, Br, I). Although, a small number of cis-di-
hydrodiols 1 has been extensively used in the synthe-
sis of natural products,[2–4] to date, their full potential
in the synthesis of chiral ligands has not been realised.
The current feasibility study has been carried out in
this context.
While mono-halogenated cis-dihydrodiols 1b–e,
(Scheme 1) have added to the pool of chiral precur-
sors available for synthesis, they are often unstable at
Scheme 1. Reagents and conditions: (i) P. putida UV4/O2
(R=1a–e); (ii) Rh/graphite, H2, MeOH, (R=1b–e); (iii) 2,2-
dimethoxypropane, acetone, PTSA, (R=1d, 1e); (iv) H2,
room temperature, readily dehydrating to form phe- Pd/C, Et3N, MeOH (R =1e).
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stable cis-tetrahydrodiol adducts 2b–e.[5–9] The adducts Results and Discussion
still contain the original two chiral centres and much
of the original functionality and have the advantage The initial phase of the study involved a systematic
of being stable at room temperature. In practice, se- search for optimal conditions for the regioselective
lective alkene reduction of cis-dihydrodiols 1a–e gave catalytic hydrogenation of halo-substituted dienes 1b–
a mixture of products depending on the nature of sub- e (Scheme 1). Optimal partial hydrogenation condi-
stituent R and the conditions used. In addition to the tions were established, by monitoring (GC-MS analy-
reduction of the 5,6-alkene bond, the other metal-cat- sis) the reaction mixture obtained on stirring a metha-
alysed side reactions include oxidation to a catechol, nol solution (50 mL) of cis-dihydrodiol 1b–e (250 mg)
hydrogenolysis and loss of water to form a phenol. in the presence of 5 wt% Rh-graphite catalyst (25 mg)
Even in the absence of hydrogen, 10% Pd-C catalyses under a hydrogen atmosphere (1.4 bar) in a stirred
a concomitant oxidation and reduction of cis-dihydro- tank reactor. Under these conditions (Rh/cis-dihydro-
diols 1 (R=F, Me, t-Bu, CN, CF3) to catechols and diol ratio 0.005), the partial hydrogenations of the cis-
tetrahydrodiols 2 in 30–45% yields.[10]
dihydrodiols 1b and 1c were found to be complete
Recently we published[11] our results on the partial within 15 min; the reaction rate was much slower
and exhaustive hydrogenation of a range of dienes 1, (120 min) for the partial hydrogenation of bromo de-
employing
a variety of heterogeneous catalysts. rivative 1d. Optimal conditions for hydrogenation of
Rh/graphite, in methanol as solvent, was found to be iodo cis-dihydrodiol 1e to cis-tetrahydrodiol 2e in
the catalyst of choice. Its use significantly reduced the methanol required a higher pressure of hydrogen
formation of phenol and catechol by-products. Halo- (8 bar), and elevated catalyst loading (Rh/cis-dihydro-
genated cis-dihydrodiols 1b–e, (Scheme 1), were diol ratio 0.015). Employing these conditions, low
found to be more challenging substrates for selective levels of aromatisation and hydrogenolysis by-prod-
alkene reduction, as in addition to the usual aromati- ucts were observed and cis-tetrahydrodiol 2e was ob-
sation side reaction, hydrogenolysis of the carbon-hal- tained in isolated yields of up to 90%. The partial hy-
ogen bond was also observed. Thus, the reduced yield drogenations of cis-dihydrodiols 1b–e, under these
of cis-tetrahydrodiols 2d and 2e made the otherwise stated optimal conditions, have been carried out up to
synthetically versatile bromo- and iodo-cis-dihydro- a 5-g scale. However, appropriate equipment and cat-
diol derivatives, 1d and 1e, less attractive chiral pre- alyst recycling should, in principle, readily produce
cursors.[6–9] In this context, earlier studies[6,9] showed much larger quantities of diols 2b–e. These results
that partial catalytic hydrogenation of cis-dihydrodiols show vast improvements in terms of: (i) the reduced
1c and 1d using Rh/Al2O3 catalyst in THF or EtOH rhodium catalyst to substrate ratio and (ii) isolated
solvent resulted in good yields (85%) of adducts 2c, yields of the useful and stable bromo and iodo cis-tet-
2d with minimal evidence of hydrogenolysis of the rahydrodiols 2d and 2e.
carbon-halogen bond or aromatisation occurring.
Cycloalkenyl bromides and iodides are versatile
However, when these reaction conditions were ap- functionalities and can be manipulated to introduce a
plied to, arguably the most useful, cis-dihydrodiol 1e, range of additional atoms or groups into the molecule
yields of adduct 2e never exceeded[9] 55% and purifi- by transition metal-catalysed substitution reactions.
cation of the crude reaction mixture proved to be cis-Tetrahydrodiols 2c–e have been used as synthetic
quite difficult. The main impurities found in the mix- precursors for arene oxide[6] and trans-dihydrodiol[6]
ture resulted from the significant degree of aromatisa- mammalian metabolites and fungal bioproducts (e.g.,
tion, hydrogenolysis and total hydrogenation reac- cladospolide).[13] Substitutions of the bromine atom in
tions. An alternative non-catalytic approach to the compound 3d by an alkyl group[8] or a tributyltin
partial reduction of cis-dihydrodiols 1, using dimide group[14] are among the relatively few reported exam-
was developed by Hudlicky et al.[12] This methodology ples of halide group substitution in cis-tetrahydrodiol
was successfully applied to a range of mono-substitut- derivatives. Recently, Banwell,[3] Hudlicky[4] and Gon-
ed benzene cis-dihydrodiols 1, with reported yields in zalez[15] have demonstrated that cycloalkenyl bro-
the range 60–95%. The major objectives of the cur- mides derived from 1d readily undergo Suzuki–
rent study were: (i) to develop a robust scalable cata- Miyaura cross-coupling reactions with arylboronic
lytic method for the synthesis of the versatile cis-tet- acids and potassium alkynyltrifluoroborates. These
rahydrodiols 2d and 2e and (ii) to substitute the cyclo- coupling reactions were used in the synthesis of ama-
alkenyl bromine or iodine atoms in these compounds biline, lycorine, nobilisitine A, narciclasine, pancratis-
with boron, nitrogen and phosphorus atoms, as initial tatin analogues and conduritol alkyne conjugates. Cy-
steps leading to the development of a much wider cloalkenyl halides 2d and 2e, available in good yields
range of cis-tetrahydrodiols 2 and derivatives with po- from our improved reduction procedure, were also
tential as chiral ligands.
subjected to a series of metal-catalysed substitution
reactions, to evaluate their synthetic potential.
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Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis-Tetrahydrodiols
Initially, replacement of the halogen atom with hy- kenyl bromides (or iodides) containing additional
drogen (hydrogenolysis) was investigated for cycloal- functional groups. Preliminary experiments, during
kenyl halides 2d and 2e. Treatment of cycloalkenyl the synthesis of cycloalkenylboronic ester derivatives
iodide 2e in methanol with hydrogen (1 bar), in the of acetonides 3d and 3e, involved halogen-lithium ex-
presence of a 5% Pd/C catalyst and a trace of triethyl- change followed by trapping the cycloalkenyllithium
amine, gave the enantiopure benzene cis-tetrahydro- with triisopropyl borate. However, this approach
diol derivative 2a ([a]D: ꢀ109, MeOH, 76%, proved to be unreliable, and the yields were generally
Scheme 1). This method provides an alternative route less than 35%. Using this procedure, for the boryla-
for the synthesis of (1S,2R)-cis-1,2-cyclohex-3-enediol tion reactions of aryl halides, poor reproducibility was
2a. The opposite enantiomer (>98% ee) of compound reported by other researchers, particularly, when the
2a was isolated in relatively low yield (<15%), from organolithium intermediate was unstable.[18] Our ef-
a mixture of bioproducts, resulting from a TDO-cata- forts were then focused on the palladium-catalysed
lysed biotransformation (P. putida UV4) of 1,3-cyclo- substitution of the cycloalkenyl bromide with boron
hexadiene[16] (Scheme 1). Surprisingly cycloalkenyl nucleophiles, as first described by Murata for the syn-
bromide 2d, under the same reaction conditions (H2, thesis of arylboronic acids[19] and later by Murata and
Pd/C, triethylamine), gave achiral cis-1,2-dihydroxycy- Ishiyama for the synthesis of alkenylboronic acids[20]
clohexane as the sole reaction product.
(Scheme 2).
Treatment of cis-tetrahydrodiols 2d and 2e with 2,2-
Attempts, using bis(pinacolato)diborane as borylat-
dimethoxypropane gave the corresponding acetonides ing agent, gave the desired pinacol boronic ester 4
3d and 3e. The halogen atoms in compounds 3d and 69% along with 15–20% of the unreacted cycloalken-
3e can be effectively replaced with boron, nitrogen yl bromide precursor 3d; the reaction could not be
and phosphorus nucleophiles, under mild conditions driven to completion. The alternative reagent, pina-
using palladium catalysis, to give a new range of ver- colborane, was found to be a more robust and cheap-
satile chiral intermediates (Scheme 2, Scheme 3, er borylating agent. It gave the required cycloalkenyl-
Scheme 4 and Scheme 5). Although similar transfor- boronic ester 4 as the sole product in 80% yield. The
mations have been extensively studied for aryl bro- 13C NMR spectrum of cycloalkenylboronic ester 4
mides,[17] there still remains a great deal of work to be shows a distinctive boron-substituted broad cycloal-
carried out on the substitution reactions of cycloal- kenyl signal (d=129.8) of very low intensity, due to a
Scheme 2. Reagents and conditions: (i) pinacolborane, Et3N, PdCl
PhOK, PdCl2A(Ph3P)2 , Ph3P, toluene, 508C, 69%; (ii) PdCl2A(Ph3P)2, THF, H2O, KOAc, Et3N, 80 8C, bromobenzene, 2-, 3- or 4-
bromopyridine, 65–85% or with 6,6’-dibromo-2,2’-dipyridine, 28–53%.
2ACHTUNGTREN(NGNU dppf), dioxane, 808C, 80%; or bis(pinacolato)diborane,
C
CHTUNGTRENNUNG
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Scheme 3. Reagents and conditions: (i) 2-bromopropene, PdCl2ACHTNUTRGNE(UNG dppf), THF, H2O, KOAc, Et3N, 80 8C, 67%; (ii) TFA, water,
THF, 408C, 12 h, 85%; (iii) P. putida UV4/O2; (iv) Strain S107B1/O2; (v) Pd/C, H2.
large quadrupolar effect of the boron atom. This styrene to yield cis-dihydrodiol 1m and a subsequent
effect was observed[21] in the 13C NMR spectra of cy- chemoselective biocatalytic hydrogenation of the 5,6-
cloalkenylboranes and provides a reliable indicator of alkene bond. Recently, we have also observed similar
the presence of a boron atom in compound 4. As an- consecutive bio-oxidation/reduction reactions with
ticipated, cycloalkenylboronic ester 4 underwent effi- meta-subsituted phenols, (Scheme 3). The m-phenols
cient Suzuki–Miyaura cross-coupling[22] with bromo- undergo cis-dihydroxylation to yield cyclohexenone-
benzene, 2-bromo-, 3-bromo- and 4-bromopyridines, cis-diol metabolites and further reduction of the keto
to give the corresponding cross-coupled products 3f–i group to form a new family of arene cis-tetrahydro-
with yields in the range 68–85%, (Scheme 2). This triol
method of synthesising cis-tetrahydrodiols 3g–i pro- (Scheme 3).[26]
vides an attractive alternative to use of the TDO-cata- The relative stereochemistry of the bioproduct 2m
(cis-cyclohexenetriol)
metabolites
6
1
lysed cis-dihydroxylation (P. putida UV4) of 2-, 3- and was earlier correctly assigned by H NMR spectrosco-
4-phenylpyridines to form the corresponding cis-dihy- py but the absolute stereochemistry of the two chiral
drodiols 1g–i (yield <5%) and their subsequent par- centres was not determined.[25] Attempts to synthesise
tial hydrogenations. Biphenyl dioxygenase (BPDO), cis-tetrahydrodiol 2m by selective catalytic hydroge-
present in a mutant strain (B8/36) of Sphingomonas nation of cis-dihydrodiol metabolite 1m of known ab-
yanoikuyae,[23] gave a better yield (31% to 59%) of solute stereochemistry[27] gave in our hands an insepa-
the biaryl cis-dihydrodiols 1g–i.
rable mixture of products, including diene 2m
The sequence in Scheme 2 provides an alternative (Scheme 3). As an alternative approach, chemoenzy-
route to acetonide 3j (R=Et) which has recently matic synthesis via cyclic boronate 4 was then tested.
been used in the synthesis of a series of 2,2’-bipyri- Chiral boronate 4 underwent efficient Suzuki–Miyura
dines, e.g., 3l (R=Et), for use as potential chiral li- cross-coupling with the volatile sterically hindered 2-
gands.[24] The method was also successfully applied to bromopropene, to yield the conjugated diene 3m in
the coupling of 2,2’-dibromo-2,2’-dipyridine with two 67% yield (Scheme 3). Deprotection of the acetonide
molecules of cycloalkenylboronic ester 4 to furnish group furnished cis-tetrahydrodiol 2m with an [a]D:
the corresponding chiral bipyridine 3l (R=Me, 28% ꢀ101 (c 0.3, MeOH). This compares well with the re-
yield) along with monosubstituted derivative 3k (53% ported[25] value, [a]D: ꢀ105 (c 0.8, MeOH), and hence
yield) which could be recycled. Thus, an attractive confirms that the metabolite 2m resulting from
convergent route to a range of potential chiral ligands enzyme-catalysed cis-dihydroxylation/hydrogenation
3l has been developed. Compound 3k can be used to of a-methylstyrene was enantiopure and of the
synthesise unsymmetrical derivatives.
(1S,2R) absolute configuration. This is another exam-
Omori et al. isolated[25] a novel cis-tetrahydrodiol ple of synthesis via the cyclic boronate 4 which is
metabolite 2m of a-methylstyrene, usisng an unidenti- much better than using cis-dihydrodiol precursors
fied bacterial strain, S107B1, (Scheme 3). This bio- (1m!2m).
transformation was somewhat unusual; it appeared to
The Suzuki–Miyaura cross-coupling reaction of cy-
involve an endocyclic cis-dihydroxylation of a-methyl- cloalkenylboronate 4 was found to be remarkably tol-
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Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis-Tetrahydrodiols
Scheme 4. Reagents and conditions: (i) 3d, PdCl
tone, PTSA, 75%; (iii) S. yaniokuyae B8/36/O2.
2ACHTUNGTRNEN(NUG Ph3P)2, THF, H2O, KOAc, Et3N, 80 8C, 83%; (ii) 2,2-dimethoxypropane, ace-
erant of steric hindrance; it efficiently coupled with raphy. Acetonide 10 is a configurationally stable form
cycloalkenyl bromide 3d to give the C2 symmetrical of the stereochemically labile diol 11[37] which is a
diene 7 in 83% yield (Scheme 4). In our laboratories, keto-tautomer of cis-tetrahydrophenol 12. Conversion
we had carried out the chemoenzymatic synthesis of of cycloalkenyl bromides to ketones by hydrolysis is
this type of compound using two separate biotransfor- often done under harsh reaction conditions.[38] The
mations.[28] In the first enzymatic step, biphenyl was above experiment gives a mild method for carrying
metabolised to give diol 1f, which was then converted out this conversion on acid-sensitive substrates. Fur-
into acetonide 3f’. This decreased its hydrophilicity, thermore, while the N-substituted cis-dihydrodiol 1o
and thus rendered it more susceptible to a second bio- has recently been isolated as a metabolite of N-phe-
catalytic dihydroxylation of the intact aromatic ring. nylpyrrole using TDO,[23] to date, it has not been pos-
The resulting acetonide diol 8 was converted into di- sible to isolate a cis-dihydrodiol metabolite from ani-
acetonide 9.[28] In our opinion, the cross-coupling line or N-alkyl-substituted anilines. Thus the synthesis
methodology (4!7) has advantages over the linear of chiral enamine derivatives, e.g., 3n, from the corre-
sequence (2f!3f!8!9!7) involving two BPDO- sponding cis-tetrahydrodiol precursor, via partial hy-
catalysed biotransformations.
drogenation of the corresponding cis-dihydrodiols,
Due to the pioneering work of Buchwald and Hart- e.g., 1n, was not an option.
wig[29] the Pd-catalysed substitution of an aryl halide,
Chiral phosphine ligands are employed in many
with a nitrogen nucleophile, has become a standard catalytic asymmetric transformations, often producing
reaction routinely used in organic synthesis. Similar products with high ee values. However, these ligands
reactions using copper catalysts are also gaining are generally difficult to prepare, requiring multistep
prominence[30] but the corresponding reactions with syntheses with air-sensitive intermediates.[39] As the
cycloalkenyl halides[31–33] or triflates,[34] or trifluorobo- next stage of our programme of utilising enantiopure
rate salts[35] have not been as widely studied, possibly, cis-tetrahydrodiols 2, to devise new synthetic routes
because the reaction products are not as stable as in to chiral ligands,[24,40] our efforts were directed to-
the aromatic series. Substitution of the bromine atom wards the synthesis of chiral phosphines. It is well
in compound 3d by a nitrogen atom (secondary known that arylphosphines couple with aryl halides
amine) has the potential to give an enamine. e.g., 3n, under metal catalysis,[41] usually palladium,[42,43]
which can be reacted further with electrophiles or hy- nickel[44] and more recently copper.[45] Examples of
drolysed to the ketone (Scheme 5).
phosphorus coupling to cycloalkenyl bromides[46] and
Employing Verkadeꢀs general procedure[31] cycloal- triflates[34] are rarer and have only recently been prop-
kenyl bromide 3d, on reaction with piperidine, yielded erly explored.[47]
the known enantiopure ketone 10 via the transient
Diphenylphosphine efficiently coupled to the chiral
enamine intermediate 3n,[36] during an attempted pu- cycloalkenyl bromide 3d (Scheme 5), under palladium
rification of the reaction product by flash chromatog- catalysis using the DPPF ligand.[33,43] To simplify pu-
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Scheme 5. Reagents and conditions: (i) Pd2ACHTUNGRTNE(UNG dba)3, NaOPh, piperidine, TTPU, toluene 808C; (ii) SiO2, 57% two steps; (iii) Pd2
ACHTUNGTRENNUNG(dba)3, Cs2CO3, Ph2PH, DPPF, toluene, 808C; (iv) 30% H2O2, 84% two steps; (v) LiOOH, toluene, 808C, 78%.
rification, the cycloalkenyl phosphine was character- ily prepared by a TDO-catalysed biotransformation
ised as the phosphine oxide 13, by using an oxidative of the corresponding halobenzene substrates and that
work-up. Further chirality and functionality was intro- efficient chemoselective catalytic hydrogenation can
duced into cycloalkenyl phosphine oxide 13 through be achieved in good yield (85–90%) without signifi-
epoxidation with lithium hydroperoxide[48] to give a cant aromatisation or hydrogenolysis occurring, (ii)
very stable single diastereoisomeric epoxide 14 (78% the cycloalkenyl halides can be efficiently substituted
yield). The relative stereochemistry at the new chiral directly with hydrogen, boron, nitrogen and phospho-
centres was readily determined from the vicinal rus nucleophiles. The novel cyclic boronate 4 under-
proton and phosphorus coupling constants (15.2 and goes subsequent cross-coupling reactions to give
5.2 Hz), confirming that the phosphorus atom was in enantiopure products in good yields, e.g., compounds
an axial position.[49] In compounds 13 and 14 the two 3f–m and 7 of synthetic value, for natural product and
phenyl groups attached to phosphorus are diastereo- chiral ligand syntheses.
topic, the proton and carbon NMR spectra of both
depicted a complex pattern of signals, but this, allied
to the phosphorus coupling, provided convincing evi-
dence of their structural assignments.
Experimental Section
The examples of substitution reactions of cycloal-
kenyl bromide 3d mentioned above have been used
to demonstrate the synthetic value of the cis-tetrahy-
drodiols; the corresponding cycloalkenyl iodide 3e
Melting points were determined using a Kofler hot-stage ap-
paratus and are uncorrected. H NMR spectra were record-
ed using 300 MHz (Bruker DPX 300) and at 500 MHz
(Bruker DRX 500) NMR spectrometers, in CDCl3 solvent
1
was also found to undergo similar reactions. This unless stated otherwise. Chemical shifts are given in parts
per million (d) downfield from tetramethylsilane as internal
standard and coupling constants are given in Hertz. Spectra
splitting patterns are designated as s singlet, d doublet, t
triplet, q quartet, m multiplet and br broad. Mass spectra
were recorded using a Double Focusing Triple Sector VG
Auto Spec, and accurate molecular masses were determined
by the peak matching method using perfluorokerosene as
standard reference and were accurate to within ꢁ0.006
a.m.u. Analytical TLC was carried out on Merck Kielselgel
60254 plates and the spots visualised using a Hanovia Chro-
study, which contains representative examples of the
cycloalkenyl bromide/iodide substitution reactions, is
now being extended to the synthesis of a wider range
of products with potential as chiral ligands.
Conclusions
It has been demonstrated that: (i) highly functional-
ised chiral cycloalkenyl halides 3d and 3e can be read- matolite UV lamp. Flash chromatography and preparative
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Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis-Tetrahydrodiols
layer chromatography (PLC) was performed using Merck
Kieselgel 60 (230–400 mesh) and PF254/366 respectively. cis-
Dihydrodiols 1 (R=F, Cl, Br or I) and authentic samples of
the corresponding cis-tetrahydrodiols 2 (R=F, Cl, Br or I)
were available from earlier studies.[9]
J=8.6 Hz), 106.06 (d, J=14.3 Hz), 157.09 (d, J=256.5 Hz);
LR-MS (EI): m/z=132 (M+, 7%), 113 ( 17), 95 (16), 88
(100), 69 (21), 41 (50). (1S,2S)-1,2-Dihydroxy-3-chlorocyclo-
hex-3-ene (2c), (1S,2S)-1,2-dihydroxy-3-bromocyclohex-3-
ene (2d) and (1S,2S)-1,2-dihydroxy-3-iodocyclohex-3-ene
(2e) were found to have identical physical properties and
spectroscopic characteristics to those reported earlier.[9]
The initial parallel screening of the hydrogenation reac-
tions was performed in a Baskerville multi-cell autoclave re-
actor containing a 10ꢂ10 mL vessel system capable of hy-
drogen pressures up to 100 bar and temperatures up to
2008C. Six different heterogeneous catalysts (5 wt% Pd, Pt,
Ir, Ru, Rh and Pd-Pt [1:1] on graphite) were employed to
determine the relationship between catalyst properties and
performance in hydrogenation of cis-dihydrodiols 1. All cat-
alysts were obtained from Johnson Matthey. Catalysis was
preformed in protic (water, methanol) and aprotic (toluene,
tetrahydrofuran) solvents. Optimal reaction conditions for
the partial hydrogenation of monohalogenated cis-dihydro-
diols 1 (R=F, Cl, Br, I) were determined in a Hazard Eval-
uation Laboratory (HEL) stirred tank reactor. The reactor
was first heated to 258C, and the system was purged with
hydrogen. After that the hydrogen pressure was introduced
as required and the stirrer set at 1400 rpm. These parame-
ters were maintained throughout the experiment. Under
these conditions the reactions were under kinetic control.
All the reactions were performed in duplicate and the re-
sults averaged. Typical conditions were: 250 mg of cis-dihy-
drodiol, 25 mg of 5 wt% Rh/G, in methanol (50 mL), 1.4 bar
of H2 pressure at 258C. The minimum times for completion
of the partial hydrogenation under these conditions (0.005=
Rh/substrate) for cis-dihydrodiols 1 were (R=F, 10 min),
(R=Cl, 15 min) and (R=Br, 120 min). The partial hydroge-
nation of cis-dihydrodiol 1 (R=I) required the use of a
higher pressure of hydrogen (8 bar) and an increased cata-
lyst loading (0.015=Rh/substrate and was complete after
21 min. Employing these conditions yields of up to 90% of
cis-tetrahydrodiols 2 (R=F, Cl, Br or I) were obtained.
AHCTUNGTREG(NNNU 1S,2S)-1,2-Isopropylidenedioxy-3-bromocyclohex-3-
ene (3d)
To a solution of (1S,2S)-1,2-dihydroxy-3-bromocyclohex-3-
ene 2d (5.00 g, 26.0 mmol) in a mixture of acetone (15 mL)
and 2,2-dimethoxypropene (10 mL) was added p-toluenesul-
fonic acid (25 mg, 0.13 mmol). After stirring the mixture at
room temperature overnight, most of the solvent was re-
moved under reduced pressure, water (20 mL) was added,
and the reaction mixture extracted with Et2O (2ꢂ50 mL).
The Et2O extract was washed with water (20 mL), dried
(Na2SO4) and concentrated. Purification of the concentrate
by flash chromatography (EtOAc-hexane, 1:4) gave com-
pound 3d as a white crystalline solid; yield: 5.37 g (89%);
m.p. 418C (Et2O); [a]D: +80.7 (c 0.8, CHCl3); HR-MS:
m/z=216.9864, calcd. for C8H10O279Br (MꢀMe)+: 216.9867;
1H NMR (500 MHz, CDCl3): d =1.41 (3H, s, Me), 1.45 (3H,
s, Me), 1.80–1.83 (1H, m, 5-H), 2.03–2.07 (2H, m, 5-H, 6-H),
2.27–2.33 (1H, m, 6-H), 4.41 (1H, m, 1-H), 4.50 (1H, d, J=
5.3 Hz, 2-H), 6.23 (1H, dd, J=5.7, 2.5 Hz, 4-H); 13C NMR
(125 MHz, CDCl3): d=21.45, 23.41, 25.51, 26.64, 73.26,
75.56, 108.31, 121.34, 131.21; LR-MS (EI): m/z=219
(M+ꢀMe, 81Br, 38%), 217 (40), 159 (36), 157 (34), 43 (100).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Method A: A mixture of cycloalkenyl bromide 3d (466 mg,
2 mmol), palladium dichlorobistriphenylphosphine (42 mg,
0.06 mmol), triphenylphosphine (32 mg, 0.12 mmol), bis(pi-
nacolato)diborane (558 mg, 2.20 mmol) and sodium phenox-
ide (348 mg, 3.0 mmol) in toluene (20 mL), under nitrogen
was heated at 508C for 10 h in a Schlenk tube. After addi-
tion of water (10 mL) to the reaction mixture it was extract-
ed with EtOAc, the extract washed with brine, dried
(Na2SO4) and concentrated. Column chromatography
(EtOAc-hexane, 1:4) of the concentrate gave a mixture of
compound 4 (yield: 387 mg, 69%) and unreacted cycloalken-
yl bromide 3d.
ACHTUNGTRENNUNG(1S,2R)-1,2-Dihydroxycyclohex-3-ene (2a)
A solution of cis-diol 2e (250 mg, 1.04 mmol) in methanol
(10 mL) containing triethylamine (300 mL, 2.16 mmol) was
magnetically stirred in the presence of 5% Pd/C (25 mg),
under a hydrogen atmosphere (1 atm), at room temperature.
The progress of the reaction was monitored by TLC
(EtOAc-hexane, 1:1). When nearly all of cis-diol 2e had
been consumed (ca: 3 h), the reaction was terminated by fil-
tering off the catalyst. The filtrate was concentrated and the
residue purified by preparative layer chromatography (PLC)
(EtOAc-hexane, 1:1) to give cis-diol 2a as a colourless oil;
yield: 92 mg (76%); [a]D: ꢀ109 (c 1.1, CHCl3). The spectro-
scopic data of cis-diol 2a were in agreement with the litera-
ture data.[27]
Method B:
(466 mg, 2 mmol), PdCl
amine (0.82 mL) and pinacolborane (0.44 mL) in dry diox-
A
mixture of cycloalkenyl bromide 3d
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
ane (10 mL) was heated at 808C for 12 h, under nitrogen, in
a Schlenk tube. The solvent was then removed under re-
duced pressure, water (40 mL) was added and the reaction
mixture extracted with EtOAc (3ꢂ50 mL). The combined
organic extract was dried (Na2SO4) and concentrated. PLC
purification of the concentrate (EtOAc-hexane, 1:4) gave
compound 4 as a clear oil; yield: 448 mg (80%); [a]D: +66.5
(c 1.0, CHCl3); HR-MS: m/z=280.1876, calcd. for
ACHTUNGTRENNUNG(1S,2S)-1,2-Dihydroxy-3-fluorocyclohex-3-ene (2b)
White crystalline solid; m.p. 101–1038C (from CHCl3/
hexane); [a]D: ꢀ79 (c 1.34, MeOH); anal. found: C 54.3, H
1
6.8; C6H9O2F requires: C 54.5, H 6.9%; H NMR (500 MHz,
CDCl3): d =1.74 (2H, m, 6-H, 6’-H), 2.06 (1H, m, H-5),
2.21 (1H, m, 5’-H), 3.88 (1H, m, 1-H), 4.27 (1H, m, 2-H),
5.41 (1H, m, 4-H); 13C NMR (100 MHz): d=19.68 (d, J=
7.9 Hz), 25.45 (d, J=1.8 Hz), 66.41 (d, J=23.9 Hz), 68.65 (d,
1
C15H25BO4 (M+): 280.1872; H NMR (300 MHz, CDCl3): d
=1.29 (12H, s), 1.36 (3H, s), 1.62–1.68 (1H, m), 1.83–2.11
(1H, m), 2.32–2.42 (1H, m), 4.27–4.34 (1H, m), 4.64 (1H, d,
Adv. Synth. Catal. 2011, 353, 2455 – 2465
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2461

D. R. Boyd et al.
FULL PAPERS
J=5.3 Hz), 6.73 (1H, t, J=3.8 Hz); 13C NMR (75 MHz,
CDCl3): d=21.99, 25.25 (t), 27.21, 28.22, 72.94, 83.66,
108.55, 129.77, 145.74; LR-MS (EI): m/z=281 (15%), 280
(100), 279 (30).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Employing general procedure 2 with 3-bromopyridine com-
pound 3h was obtained as an oil, yield: 68%; [a]D: +74 (c
1.6, CHCl3); HR-MS: m/z=231.1291, calcd. for C14H17NO2
General Procedure 1 for Suzuki–Miyaura Reactions
(M+): 231.1259; H NMR (500 MHz, CDCl3): d =1.41 (3H,
1
s), 1.42 (3H, s), 1.78–1.90 (1H, m), 2.06–2.11 (1H, m), 2.23–
2.36 (1H, m), 2.48–2.52 (1H, m), 4.41–4.50 (1H, m), 4.87
(1H, d, J=5.6 Hz), 6.37 (t, J=4.4 Hz), 7.23–7.26 (1H, m)
7.84 (1H, dt, 8.0, 2.0), 8.50 (1H, dd, J=4.9, 1.7 Hz), 8.77
(1H, d, J=2.3 Hz); 13C NMR (125 MHz, CDCl3): d=22.16,
25.83, 26.59, 28.43, 72.90, 74.12, 109.42, 123.48, 130.51,
133.87, 136.01, 148.08, 148.0; LR-MS (EI): m/z=232 (20%),
231 (100), 230.9 (50).
A solution of 2,2-dimethyl-7-(4,4,5,5-tetramethyl-[1,3,2]diox-
aborolan-2-yl)-3a,4,5,7a-tetrahydrobenzoACTHUNRTGNEUNG[1,3] dioxole (4,
420 mg, 2.00 mmol), palladium dichloro-bis-triphenylphos-
phine (56 mg, 0.079 mmol), potassium acetate (300 mg,
3.0 mmol), triethylamine (1.2 mL, 1.5 mmol) and cycloalken-
yl or aromatic bromide (2.5 mmol) in THF/water (6:1,
7 mL) was heated at 808C for 12 h. Water (10 mL) was
added to the reaction mixture and it was extracted with
EtOAc (3ꢂ25 mL), the extract washed with brine, dried
(Na2SO4) and concentrated. PLC of the concentrate
(EtOAc-hexane, 1:4) gave the cycloalkenyl/aromatic substi-
tuted product.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Following general procedure 2 with 4-bromopyridine gave
compound 3i as an oil, yield: 76%; [a]D: +36 (c 0.5,
CHCl3); HR-MS (ES), m/z=232.1334, calcd. for C14H18NO2
(M+H)+: 232.1338; 1H NMR (500 MHz, CDCl3): d =1.39
(3H, s), 1.44 (3H, s), 1.72–1.84 (1H, m), 1.86–1.97 (1H, m),
2.0–2.21 (1H, m), 2.32–2.46 (1H, m), 4.45–4.47 (1H, m),
4.91 (1H, d, J=5.9 Hz), 6.58 (1H, t, J=4.4 Hz), 7.46 (1H, d,
J=6.0 Hz), 8.59 (1H, d, J=5.2 Hz); 13C NMR (125 MHz,
CDCl3): d=21.99, 25.47, 26.53, 28.22, 71.93, 73.67, 109.56,
120.99, 132.43, 134.16, 147.62, 150.23; LR-MS (EI): m/z=
232 (20%), 231 (100).
General Procedure 2 for Suzuki–Miyaura Cross-
Coupling of Pyridines
A solution of bromopyridine (316 mg, 2 mmol), PdCl2ACTHNUTRGNE(NUG dppf)
(80 mg, 0.11 mmol), triethylamine (0.82 mL, 5.8 mmol), po-
tassium acetate (213 mg, 2.2 mmol) and pinacolborane 4
(0.49 g, 3.8 mmol) in a mixture of THF and water (4:1,
10 mL) was heated at 808C for 12 h under nitrogen in a
Schlenk tube. After working up the reaction mixture, as de-
scribed for procedure 1, the crude product obtained was pu-
rified by PLC (EtOAc-hexane, 1:4).
6-Bromo-6’-[(3aR,7aS)-2,2-dimethyl-3a,6,7,7a-tetra-
ACHTUNGTRENNUNG
hydrobenzo[d]
ACHTUNGTRENUN[NG 1,3]dioxol-4-yl]-2,2’-bipyridine (3k)
ACHTUNGTRENNUNG
and 6,6’-Bis[(3aR,7aS)-2,2-dimethyl-3a,6,7,7a-
AHCTUNGTRENNUNG
Following general procedure 1, compound 3f was obtained,
as a solid, yield: 85%; m.p. 68–708C; [a]D +62 (c 1, CHCl3);
HR-MS: m/z=230.1303, calcd. for C15H18O2 (M+): 230.1307;
1H NMR (300 MHz, CDCl3): d =1.34 (3H, s), 1.35 (3H, s),
1.70–1.83 (1H, m), 1.96–2.23 (1H, m), 2.0–2.21 (1H, m),
2.42–2.48 (1H, m), 4.33–4.35 (1H, m), 4.85 (1H, d, J=
5.4 Hz), 6.23 (1H, t, J=4.4 Hz), 7.17 (1H, t, J=7.4 Hz), 7.25
(2H, t, J=7.7 Hz), 7.44 (2H, d, J=6.7 Hz); 13C NMR
(75 MHz, CDCl3): d=22.14, 26.36, 27.0, 28.28, 73.07, 72.80,
108.64, 126.43, 127.58, 129.12, 136.03, 140.26; LR-MS (EI):
m/z=31 (20%), 230 (100).
tetrahydrobenzo[d]ACTHNUTRGNE[NUG 1,3]dioxol-4-yl]-2,2’-bipyridine
(3l)
Using general procedure 2 with 6,6-dibromo-2,2’-bipyridyl
(0.5 equiv.) gave a mixture of compounds 3k and 3l which
was separated by PLC (EtOAc-hexane, 1:4).
Compound 3k: oil, yield: 28%; [a]D: +45, (c 1.0, CHCl3);
HR-MS (ES): m/z= =461.2444, calcd. for C14H18NO2 (M+
H)+: 461.2440; 1H NMR (300 MHz, CDCl3): d=1.43 (6H,
s), 1.49 (6H, s), 1.83–2.03 (4H, m), 2.17–2.30 (2H, m), 2.42–
2.55 (2H, m), 4.47 (2H, ddd, J=6.41, 6.41, 3.90 Hz), 5.25
(2H, d, J=5.7 Hz), 7.17 (2H, t, J=4.3 Hz), 7.55 (2H, d, J=
7.9 Hz), 7.78 (2H, t, J=7.9 Hz), 8.39 (2H, d, J=7.7 Hz)
13C NMR (100 MHz): d=20.82, 24.66, 25.33, 26.96, 70.69,
72.60, 107.34, 118.18, 119.02, 130.96, 134.06, 136.20, 154.24,
154.30; LR-MS (EI): m/z=460 (2%), 445 (4), 402 (85), 344
(100), 315 (65).
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Following general procedure 2 with 2-bromopyridine com-
pound 3g was prepared, as a solid, yield: 82%; m.p. 98–
1088C; [a]D: +70.4 (c 1.0, CHCl3); HR-MS: m/z=231.1251,
calcd. for C14H17NO2 (M+): 231.1259; 1H NMR (500 MHz,
CDCl3): d =1.31 (3H, s), 1.37 (3H, s), 1.70–1.74 (1H, m),
1.85–1.89 (1H, m), 2.0–2.16 (1H, m), 2.32–2.46 (1H, m),
4.38–4.42 (1H, m), 5.09 (1H, d, J=5.5 Hz), 6.84 (1H, t, J=
4.4 Hz), 7.09 (1H, td, J=4.8, 1.0 Hz), 7.46 (1H, d, J=
7.8 Hz), 7.58 (1H, td, J=7.8, 2.0 Hz), 8.52 (1H, d, J=
4.8 Hz); 13C NMR (125 MHz, CDCl3): d=22.06, 26.18,
26.97, 28.56, 72.51, 74.26, 108.85, 120.9, 122.65, 132.65,
136.94, 149.48, 157.56; LR-MS (EI): m/z=232 (30%), 231
(100).
Compound 3l: light yellow oil, yield: 53%; [a]D: +28.8 (c
0.66, CHCl3); HR-MS (ES): m/z=387.0708, calcd. for
1
C14H18NO2 [M+]: 387.0708; H NMR (400 MHz, CDCl3): d=
1.35 (3H, s, CH3), 1.41 (3H, s, CH3), 1.81 (1H, m, 7’-H),
1.91 (1H, dddd, J=13.3, 6.6, 6.6, 5.1 Hz, 7-H), 2.16 (1H,
ddddd, J=14.7, 8.6, 5.1, 5.1 2.1 Hz, 6’-H), 2.41 (1H, m, H-6),
4.4 (1H, ddd, J=5.7, 5.7, 2.9 Hz, H-7a), 5.17 (1H, dt, J=5.7,
1.4 Hz, H-3a), 7.05 (1H, dd, J=4.8, 4.1 Hz, 5-H), 7.39 (1H,
dd, J=7.7, 1.0 Hz), 7.50 (1H, dd, J=7.9, 0.9 Hz), 7.57 (1H,
t, J=7.8 Hz), 7.71(1H, t, J=8.0 Hz), 8.20 (1H, dd, J=7.8,
1.0 Hz), 8.40 (1H, dd, J=7.7, 1.0 Hz): 13C NMR (125 MHz,
2462
asc.wiley-vch.de
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 2455 – 2465

Cycloalkenyl Halide Substitution Reactions of Enantiopure Arene cis-Tetrahydrodiols
CDCl3): d=21.89, 25.74, 26.46, 28.07, 71.73, 73.65, 108.53,
119.61, 119.82, 120.87, 127.82, 132.41, 135.11, 137.64, 139.04,
141.43, 153.39, 155.78, 157.73. LR-MS: (ES): m/z=797
[(2M+Na)+, 20%], 409 [(M+Na)+, 60], 387 [(M+H)+,
100], 331 (70).
(1H, m), 4.22 (1H, d, J=5.4 Hz), 2.41–2.47 (1H, m), 2.13–
2.27 (2H, m), 1.84–1.93 (3H, m), 1.38 (3H, s), 1.33 (3H, s).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
Applying general procedure 1 with 2-bromopropene com-
pound 3m was obtained as an oil; yield: 67%; [a]D: +74 (c
0.8, CHCl3); HR-MS: m/z=194.1305, calcd. for C12H18O2
(4.17 g, 12.8 mmol) and DPPF (80.2 mg, 0.38 mmol) were
added to a Schlenk tube containing a magnetic stirring bar.
Toluene (40 mL) and diphenylphosphine (1.03 mL,
6.7 mmol) were added and the resulting mixture heated with
stirring at 808C for 44 h. After cooling the reaction mixture
to ambient temperature, aqueous hydrogen peroxide solu-
tion (30%, 50 mL) was added. The mixture was diluted with
water (100 mL) and then extracted with CH2Cl2 (2ꢂ50 mL).
The combined organic extract was concentrated and the res-
idue purified by flash chromatography (EtOAc-hexane, 1:1)
to give compound 13 as a colourless oil, yield: 1.9 g (83%);
[a]D: +29 (c 1.0, CH2Cl2); HR-MS (ES): m/z=355.1463,
calcd. for C21H24O3P (M+H)+: 355.1457; 1H NMR
(300 MHz, CDCl3): d =7.64–7.68 (4H, m), 7.35–7.46 (6H,
m), 6.80 (1H, dt, J=18.7, 4.1 Hz), 4.54 (1H, t, J=5.3 Hz),
4.24 (1H, dd, J=10.0, 4.5 Hz), 2.34 (1H, ddd, J=17.2, 8.0,
3.9 Hz), 2.17–1.99 (1H, m), 1.73–1.87 (2H, m), 1.17 (3H, s),
1.14 (3H, s); 13C NMR (75 MHz, CDCl3): d =146.3 (d, J=
7.0 Hz), 131.8 (d, J=101.5 Hz), 131.2 (d, J=10.2 Hz), 131.1
(d, J=9.9 Hz), 130.7 (d, J=2.5 Hz), 130.7 (d, J=2.3 Hz),
130.6 (d, J=99.3 Hz), 130.0 (d, J=103.4 Hz), 127.2 (d, J=
12.2 Hz, 2C), 107.6, 72.0 (d, J=8.1 Hz), 69.0 (d, J=7.7 Hz),
26.4, 24.6, 24.5, 21.4 (d, J=13.3 Hz); 31P NMR (121.5 MHz,
CDCl3): d=30.57.
1
(M+): 194.1307; H NMR (300 MHz, CDCl3): d =5.98 (1H,
t, J=4.4 Hz), 5.20 (1H, s), 4.95 (1H, s), 4.69 (1H, d, J=
5.7 Hz), 4.23 (1H, dt, J=5.5, 0.9 Hz), 2.28–2.19 (1H, m),
2.05–1.98 (1H, m), 1.84 (3H, s), 1.73- 1.63 (2H, m), 1.35
(6H, s); 13C NMR (75 MHz, CDCl3): d =22.16, 23.42, 26.36,
27.28, 28.56, 73.01, 74.02, 108.62, 142.24, 145.38; LR-MS
(EI) m/z=194 (7%), 194 (100), 171 (5).
ACHTUNGTRENNUNG(1S,2R)-3-Isopropenylcyclohex-3-ene-1,2-diol (2m)
A
mixture of acetonide 3m (58 mg, 0.3 mmol), THF
(1.2 mL), TFA (0.15 mL) and water (0.3 mL) was heated at
408C until the starting material had reacted completely (12
h). The crude product obtained after removal of the solvents
was purified by PLC (EtOAc-hexane, 1:1) to give diol 2m as
an oil, yield: 39 mg (85%); [a]D: ꢀ101 (c 0.3, MeOH), lit.[25]
1
[a]D: ꢀ105 (c 0.8, MeOH); H NMR (300 MHz, CDCl3): d=
5.89 (1H, dd, J=4.7, 3.20 Hz), 5.20 (1H, s), 4.95 (1H, s),
4.43 (1H, d, J=2.6 Hz), 3.79–3.62 (1H, m), 2.27–2.26 (2H,
m), 1.84 (3H, s), 1.71–1.58 (2H, m).
(3aR,3’aR,7aS,7’aS)-2,2,2’,2’-Tetramethyl-3a,6,7,7a,3’a,
6’,7’,7’a-octahydroACTHUNGTREN[UNNG 4,4’]biAHCTNURTGEG{NNUN benzoACHTNUGRTEN[NUGN 1,3]dioxolyl} (7)
(1aS,3aS,6aS,6bR)-6b-(Diphenylphosphinoyl)-5,5-
dimethylhexahydro-1,4,6-trioxacyclopropa[e]indene
(14)
Using general procedure 1 with cycloalkenyl bromide 3d,
gave compound 7 as a white solid; yield: 83%; m.p. 89–
928C; [a]D: +30 (c 1.2, CHCl3); HR-MS: m/z=306.1831,
calcd. for C18H26O4 (M+): 306.1856; 1H NMR (500 MHz,
CDCl3): d=1.33 (6H, s), 1.34 (6H, s), 1.66–1.94 (4H, m),
1.96–2.12 (2H, m), 2.21–2.43 (2H, m) 4.35–4.37 (2H, m),
4.75 (2H, d, J=5.8 Hz), 6.28 (2H, t, J=4.2 Hz); 13C NMR
(125 MHz, CDCl3): d=22.35, 26.26, 27.07, 28.69, 71.93,
74.22, 108.69, 128.09, 134.96; LR-MS (EI): m/z=306
(100%), 279 (30).
Lithium tert-butyl peroxide (0.05M solution in toluene,
314 mL, 0.15 mmol) was added to a solution of (3aS,7aS)-7-
(diphenylphosphinoyl)-2,2-dimethyl-3a,4,5,7a-tetrahydro-
ACHUTNGRENbNUG enzoCAHTUNGTRNE[NUGN 1,3]dioxole 13 (35.4 mg, 0.1 mmol) in toluene (1 mL)
at 08C. The cooling was removed and the reaction mixture
stirred at ambient temperature for 16 h. Water (30 mL) was
added and the mixture extracted with CH2Cl2 (2ꢂ20 mL).
The combined extract was concentrated and the residue pu-
rified by flash chromatography (EtOAc-hexane, 1:1) to give
compound 14 as a gum, yield: 28.9 mg (78%); [a]D: +20 (c
1.0, CH2Cl2); HR-MS: m/z=393.1247, calcd. for
C21H23NaO4P (M+Na)+: 393.1232; 1H NMR (300 MHz,
CDCl3): d =7.98 (2H, dd, J=11.8, 8.0 Hz), 7.77 (2H, dd,
J=11.3, 8.1 Hz), 7.36–7.48 (6H, m), 4.85 (1H, dd, J=7.1,
3.7 Hz), 3.96 (1H, dd, J=15.2, 7.3 Hz), 2.96 (1H, dd, J=5.2,
2.2 Hz), 2.07–1.89 (2H, m), 1.74–1.56 (2H, m), 1.35 (3H, s),
1.11 (3H, s). 13C NMR (75 MHz, CDCl3): d=131.2 (d, J=
2.5 Hz), 131.1 (d, J=2.4 Hz), 131.0 (d, J=8.9 Hz), 130.9 (d,
J=9.7 Hz), 129.9 (d, J=101.5 Hz), 127.4 (d, J=102.6 Hz),
127.3 (d, J=12.0 Hz), 127.1 (d, J=12.2 Hz), 107.1, 71.4 (d,
J=8.2 Hz), 68.3 (d, J=11.4 Hz), 55.7 (d, J=105.8 Hz), 55.2,
26.2, 24.0, 21.8, 19.6. 31P NMR (121.5 MHz, CDCl3): d=
30.11.
A
ACHTUNGTREN[NGNU 1,3]dioxol-4-
A stirred mixture of (1S,2S)-1,2-isopropylidenedioxy-3-bro-
mocyclohex-3-ene 3d (186 mg, 0.80 mmol), Pd2A(dba)3
CTHUNGTRENNUNG
(3.6 mg, 8 mmol), sodium tert-butoxide (176 mg, 1.12 mmol),
TTPU (16 mmol, 5.4 mL) and piperidine (0.88 mmol,
86.4 mL) in toluene (8 mL) was heated at 808C for 18 h in a
Schlenk tube. The solvent was removed under vacuum and
the residue purified by flash chromatography (EtOAc-
hexane, 2:1!EtOAc) to furnish the title compound 10 as a
clear oil, yield: 77 mg (57%). The spectroscopic data of
compound 10 were in good agreement with the literature
data.[36] [a]D: + 58.4 (c 0.51, CHCl3), lit[36] [a]D (ent): ꢀ63.2
1
(c 1.0, CHCl3); H NMR (300 MHz, CDCl3): d =4.54–4.56
Adv. Synth. Catal. 2011, 353, 2455 – 2465
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asc.wiley-vch.de
2463

D. R. Boyd et al.
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Acknowledgements
Financial assistance was provided by an EU Marie Curie
Host Fellowship for Transfer of Knowledge, NOVACAT,
Project No. 29846 (MK and MB) and postgraduate student-
ships funded by CenTACat (VB) and DEL (PBAM).
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