L-Proline-derived ligands to mimic the '2-His-1-carboxylate' triad of the non-haem iron oxidase active site

Article abstract of DOI:10.1016/j.tet.2012.02.031

Non-haem iron(II) oxidases (NHIOs) catalyse a variety of oxidative transformations in biology. The iron-binding environment of the NHIO active site typically incorporates a '2-His-1-carboxylate' facial triad of amino acid side-chains, a motif that has emerged as a defining feature of the enzyme family. Towards the goal of biomimetic, iron-mediated C-H activation we have synthesized a series of peptidomimetic ligands from l-proline. By coupling l-proline to 2,6-bis(bromomethyl)pyridine, 2-(bromomethyl)-6-((tert- butyldimethylsilyloxy)methyl)pyridine and picolinic acid, we have generated several new ligand architectures designed to complex with iron(II) and mimic the NHIO active site. The resulting iron complexes promote modest levels of alkene dihydroxylation and allylic oxidation using hydrogen peroxide as oxidant.

Full text of DOI:10.1016/j.tet.2012.02.031

Tetrahedron 68 (2012) 3231e3236
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
L
-Proline-derived ligands to mimic the ‘2-His-1-carboxylate’ triad of the
non-haem iron oxidase active site
1
*
Victoria J. Dungan, Shwo Mun Wong, Sarah M. Barry , Peter J. Rutledge
School of Chemistry F11, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Non-haem iron(II) oxidases (NHIOs) catalyse a variety of oxidative transformations in biology. The iron-
binding environment of the NHIO active site typically incorporates a ‘2-His-1-carboxylate’ facial triad of
amino acid side-chains, a motif that has emerged as a defining feature of the enzyme family. Towards the
goal of biomimetic, iron-mediated CeH activation we have synthesized a series of peptidomimetic li-
Received 4 November 2011
Received in revised form 28 January 2012
Accepted 13 February 2012
Available online 22 February 2012
gands from L-proline. By coupling L-proline to 2,6-bis(bromomethyl)pyridine, 2-(bromomethyl)-6-((tert-
butyldimethylsilyloxy)methyl)pyridine and picolinic acid, we have generated several new ligand archi-
tectures designed to complex with iron(II) and mimic the NHIO active site. The resulting iron complexes
promote modest levels of alkene dihydroxylation and allylic oxidation using hydrogen peroxide as
oxidant.
Keywords:
Amino acids
Biomimetic chemistry
Bioorganic chemistry
Non-haem iron enzymes
Oxidation
Ó 2012 Elsevier Ltd. All rights reserved.
Synthesis
1. Introduction
Nature has long served as an inspiration for the design of new
oxidation catalysts.1e9 Non-haem iron oxidases (NHIOs) are
amongst the most effective catalysts of biological oxidation re-
actions, promoting an array of oxidative chemistry in vivo including
hydroxylation, epoxidation, dihydroxylation, desaturation, cyclisa-
tion and ring opening reactions.10e18 The iron-binding environment
of the NHIO active site is highly conserved across the family, with
the metal characteristically bound by a ‘2-His-1-carboxylate triad’
of amino acid side-chains 1 (two histidine residues, plus an as-
partate or glutamate, (Fig. 1)).19,20
Fig. 1. The generalized non-haem iron(II) oxidase (NHIO) active site 1, and the ligand
architectures we have previously constructed to mimic NHIO structure and function:
‘2N,2O’ systems 234 and ‘3N,1O’ systems 3.35 (X¼solvent or substrate-derived ligand;
R¼Et or Ph).
This metal binding environment is highly conserved, but NHIOs
activate dioxygen using a variety of mechanisms and cosubstrate
transfer between an NADH or NADPH cofactor and the oxygenase
subunit.24 Isopenicillin N synthase (IPNS) mediates substrate oxida-
tion without direct involvement of additional cosubstrates or
cofactors, however ascorbate is required for optimum enzyme
activity.25
Various small-molecule mimics of NHIO structure and function
have been reported.4,5,18,26e29 Some of these systems have proved
veryeffective catalysts foralkenedihydroxyation and CeH activation;
amongst the most efficient are tris(2-pyridylmethyl)amine (TPA),
N,N0-bis(2-pyridylmethyl)-N,N0-dimethyl-1,2-cyclo-hexanediamine
(BPMCN), 2-({2-[1-(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-
1-yl}methyl)pyridine (PDP or BPBP), 1,1,1-tris{2-[N2-(1,1,3,3-tetra-
methylguanidino)]ethyl}amine (TMG3tren), 20,20-(2,20-(methyl-
azanediyl)bis(ethane-1,2-diyl))bis(1,1,3,3-tetramethylguanidine)
(TMG2dien) and related polyamine ligands.5,26,27,29e32
strategies.4,5,10 Many NHIOs use an
a-ketoacid cosubstrate (e.g., a-
ketoglutarate), which undergoes oxidative decarboxylation alongside
oxidation of the primary substrate,21 while 1-aminocyclopropane-1-
carboxylate oxidase (ACCO, the ‘ethylene forming enzyme’) uses
ascorbate and carbon dioxide.22 The sub-family of pterin-dependent
hydroxylases use tetrahydrobiopterin as a two-electron-donating
cofactor23 and the Rieske dioxygenases are multicomponent en-
zymes that include a reductase component to mediate electron
* Corresponding author. Tel.: þ61 2 93515020; fax: þ61 2 93513329; e-mail
address: peter.rutledge@sydney.edu.au (P.J. Rutledge).
1
Present address: Department of Chemistry, University of Warwick, Coventry,
CV4 7AL, UK.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.031

3232
V.J. Dungan et al. / Tetrahedron 68 (2012) 3231e3236
Fig. 2. The new proline-derived ligands 4e7 reported in this paper, and the related system 9 recently reported as a ligand in biomimetic catechol oxidation.39
We have recently reported several new tetradentate ligands
designed to mimic the NHIO active site: ‘two-nitrogen-two-oxygen’
methyl ester 10 in the presence of DIPEA, giving 15 in good yield
(78%). Removal of the silyl ether with TBAF in THF afforded alcohol
16 in high yield (85%). To complete the synthesis of 5, the methyl
ester was cleaved under basic conditions to furnish the lithium
salt 5-Li in excellent yield (95%).
ligands
2 and related ‘three-nitrogen-one-oxygen’ systems 3
(Fig. 1).33e35 These ligands combine with iron(II) acetate and hy-
drogen peroxide to convert a range of simple alkenes to diol
products, though only in low yield as allylic oxidation via radical
pathways competes.36
To access ligand 6, we had envisaged that the secondary amine
arm would be introduced by conversion of alcohol 16 to the cor-
In this paper we report four new ligands 4 to 7 (Fig. 2), which
responding bromide and substitution with (S)-(ꢀ)-
a-methyl-
combine the substituted pyridine scaffold with
L-proline to mimic
benzylamine, in an analogous manner to that previously
employed to prepare ligands 2 and 3.34,35 However all attempts to
brominate 16 with triphenylphosphine and carbon tetrabromide41
at various temperatures between ꢀ78 ꢁC and room temperature
were unsuccessful. Mass spectra of the resulting reaction mix-
tures suggested formation of polymeric species, presumably via
intermolecular reaction between the nucleophilic pyridine and
the benzylic bromide: simple 2-bromomethylpyridines are known
to dimerise to afford the dipyrido[1,2-a:10,20-d]pyrazinium ring
system.42,43 It is an interesting contrast that the structurally re-
lated bromide 14 is a stable, isolable compound;33 presumably the
bulk of the (tert-butyldimethylsilyloxy)methyl side-chain is key to
avoiding dimerisation in that case.
the NHIO metal binding motif. It was envisaged that using the cyclic
amino acid would increase the rigidity of the system and enhance
the binding affinity of these ligands for iron, thus increasing the
stability of the resulting iron(II) complexes and suppressing com-
peting radical pathways.
Klein Gebbink and co-workers have previously reported the
synthesis and coordination behaviour of 8 (the dimethyl ester of 4)
and two prolinol-based analogues prepared by reducing the esters,
and demonstrated that the iron(II) complexes of such systems can
catalyse the oxidation of alkenes and sulphides.37,38 The related
system 9 was recently employed in complex with iron and 3,5-di-
tert-butylcatechol as a functional model for extradiol-cleaving cat-
echol dioxygenase, another member of the NHIO enzyme family.39
The ligands 4e7 reported herein have been designed to explore
the potential of proline-derived architectures to bind and activate
iron(II) for oxidative catalysis, using a series of ligands which in-
corporate a range of different O- and N-donor groups.
To complete the synthesis of 6, an alternative route was de-
veloped using reductive amination. Oxidation of alcohol 16 under
Swern conditions gave the aldehyde 17 in moderate yield (49%).44
Reductive amination using (S)-(ꢀ)-
a-methylbenzylamine and so-
dium triacetoxyborohydride delivered the amine 18 in moderate
yield (50%).45 Ester cleavage was again effected using lithium hy-
droxide to generate the lithium salt 6-Li in excellent yield (90%).
2. Results and discussion
2.1. Synthesis of bis-proline ligand 4
2.3. Synthesis of the amide-linked ligand 7
L
-Proline methyl ester 10 and 2,6-bis(bromomethyl)pyridine 11
were prepared from -proline 12 and 2,6-pyridinedimethanol 13,
respectively, by adapting standard methods.40,41 To prepare the bis-
proline ligand 4 (Scheme 1), -proline methyl ester 10 and dibro-
The amide 7 has been reported previously, as a substrate for 1,3-
dipolar cycloaddition reactions with 2-chloroacrylonitirile46 and as
a mechanistic probe in kinetic assays of swine kidney prolidase.47
However in neither case is its synthesis clearly described nor full
characterization data presented so these details are included
herein. Picolinic acid 19 was converted to the acid chloride, which
L
L
mide 11 were first coupled using sodium methoxide in refluxing
methanol as reported by Klein Gebbink and co-workers.37 This
procedure returned only moderate yields (up to 51%) in our hands,
while substituting the alkoxide for an amine base (N,N-diisopro-
pylethylamine, DIPEA) improved the yield of 8 to 70%. Ester
cleavage was achieved using lithium hydroxide to give the di-
lithium salt of the desired ligand (4-Li2) in excellent yield (98%).
was coupled in situ to -proline methyl ester 10 in the presence of
L
excess triethylamine to give amide 20 (Scheme 3). Deprotection
using lithium hydroxide gave the ligand 7 in excellent yield (98%).
NMR data for compound 20 indicate that rotation about the
amide bond is restricted: all peaks in the 1H NMR and 13C NMR
spectra are duplicated (see Supplementary data). Hindered rotation
about the NeC(O) bond of amides is well documented,48,49 arising
due to delocalisation of the nitrogen lone pair, which affords an
amide bond partial double bond character. In the case of 20 the two
isomers are well resolved at room temperature, present in a ca. 1:1
ratio. Variable temperature NMR experiments (Supplementary
data) confirmed that the signals coalesce as the temperature in-
creases (as the increased energy in the system increases rotation
about the amide bond).
Scheme 1. Synthesis of ligand 4; i. 10 (2 equiv), DIPEA, MeOH, reflux, 16 h, 70%; ii. 1 M
LiOH(aq), MeOH, reflux, 3 h, 98%.
2.2. Synthesis of mono-proline ligands 5 and 6
2.4. Iron(II) mediated oxidations
2-(Bromomethyl)-6-((tert-butyldimethylsilyloxy)methyl)pyri-
dine 14 was prepared from 2,6-pyridinedimethanol 13 as pre-
viously reported.33 Towards both ligands 5 and 6 (Scheme 2), the
Oxidative turnover experiments were carried out to test the
efficacy of amines 4e7 as ligands for biomimetic iron-mediated
dihydroxylation of alkene substrates. Iron complexes were
protected monobromide 14 was coupled with 1 equiv of L-proline

V.J. Dungan et al. / Tetrahedron 68 (2012) 3231e3236
3233
Scheme 2. Synthesis of ligands 5 and 6; i. 10, DIPEA, MeOH, reflux, 16 h, 78%; ii. TBAF, THF, rt, 1.5 h, 85%; iii. 1 M LiOH(aq), MeOH, reflux, 3 h, 95%; iv. (COCl)2, DMSO, DCM, ꢀ78 ꢁC,
49%; v. NaBH(OAc)3, (S)-(ꢀ)-
a-methylbenzylamine, DCE, rt, 1.5 h, 50%; vi. 1 M LiOH(aq), MeOH, reflux, 3 h, 90%.
dominant pathway; with 6 and 7 these products are formed at
similar levels to diol 22. However the overall levels of oxidative
turnover are low.
To test the scope of this iron-mediated dihydroxylation reaction,
ligand4 wasusedinturnoverexperimentswithasmallsetofaliphatic
alkenes (Table 2). Diol products were observed for all substrates.
The most promising results were seen with the terminal alkenes
1-heptene (TN¼0.7) and 1-octene (TN¼0.9), results that are closer to
the catalytic reactivity sought. Allylic oxidation products akin to 23
and 24 were also observed from these substrates but not quantified.
Scheme 3. Synthesis of ligand 7; i SOCl2, reflux, 16 h; then 10, TEA, DCM, rt, 16 h, 53%,
over two steps; 1 M LiOH(aq), THF, reflux, 16 h, 98%.
prepared in situ by mixing equimolar amounts of each ligand (4e6
as their lithium salts; 7 as the zwitterion) with iron(II) acetate in
methanol, and used directly in oxidation reactions with cyclo-
hexene 21 and hydrogen peroxide (Scheme 4).34,35
Table 2
Oxidation of other alkene substrates by iron complex of ligand 4a,b
Entry
Substrate
Product
Yieldc,d
1
2
3
4
5
Cyclohexene
Cyclopentene
Cyclooctene
1-Heptene
1-Octene
cis-1,2-Cyclohexanediol
cis-1,2-Cyclopentanediol
cis-1,2-Cyclooctanediol
1,2-Heptanediol
4.0
1.3
0.5
7.0
9.0
Under these conditions, all four ligands 4e7 promote dihy-
droxylation of cyclohexene 21 to cis-cyclohexane-1,2-diol 22
(Table 1). This reaction is not seen in the absence of ligand (Table 1,
entry 5). The bis-proline ligand 4 is the most effective of these
systems at promoting the dihydroxylation reaction: a turnover
number (TN) of 0.40 is observed for this ligand (TN¼amount of
1,2-Octanediol
a
Catalyst prepared in situ from ligand and iron(II) acetate in methanol.
b
Initial ratio catalyst/H2O2/substrate 1:10:1000. See Experimental section for
more details.
product formed in mmol/amount Fe complex in mmol). This corre-
c
Percentage yield relative to H2O2, the limiting reagent. Turnover numbers (
product produced per mol catalyst) can be derived by dividing these percentage
yields by 10. Percentage conversion of alkene¼percentage yield/100.
mmol
sponds to a 4.0% yield relative to the limiting reagent (hydrogen
peroxide) and 0.04% conversion of the alkene substrate. The alcohol
ligand 5 affords the diol at TN¼0.20, half the level seen with the bis-
carboxylate ligand 4, while the benzylamine-derived ligand 6 and
amide 7 return even lower levels of dihydroxylation (TN¼0.09 and
0.02, respectively). Allylic oxidation products 23 and 24 are also
observed with all four ligands; with 4 and 5, allylic oxidation is the
m
d
Alcohol and enone products equivalent to 23 and 24 were observed but not
quantified.
2.5. Conclusions
Towards the goal of biomimetic CeH oxidation, we have pre-
pared a series of ligands derived from
iron-binding environment at the NHIO active site. The pentadentate
bis-proline ligand 4 was prepared bycoupling -proline methyl ester
L-proline, which mimic the
L
10 and 2,6-bis(bromomethyl)pyridine 11; tetradentate mono-
proline ligands 5 and 6 were made by uniting the proline portion
with mono-protected/mono-brominated 2,6-pyridinedimethanol
derivative 14; bidentate amide 7 was generated by coupling proline
ester 10 and picolinic acid 19.
Combining ligands 4e7 with iron(II)acetate and H2O2 achieves
the iron-mediated dihydroxylation of a variety of alkene substrates,
but only in low yields and turnover numbers. Competing reactions
give allylic alcohol and enone products via traditional Fenton or
Fenton-type pathways (in which uncomplexed iron or iron-ligand
species generate hydroxyl radicals from hydrogen peroxide).36
Further work is needed to determine the mechanisms occurring
with these systems, in particular spectroscopic characterization
of putative high-valent iron intermediates, kinetic studies and
oxygen-labelling experiments.
Scheme 4. Potential products from the iron-mediated oxidation of cyclohexene 21:
Path A is the desired biomimetic dihydroxylation reaction mediated by the iron
complex FeeL to give cis-cyclohexane-1,2-diol 22, while Path B shows competing
Fenton-type reactivity to alcohol 23 and ketone 24. FeeL¼iron complex of ligand 4, 5,
6 or 7.
Table 1
Oxidation of cyclohexene by iron complexes of ligands 4e7
Entry
Liganda,b
22c,d
23c,d
24c,d
1
2
3
4
5
6
7
d
4.0
2.0
0.9
0.2
0.0
6.0
7.0
0.1
0.1
3.0
42.0
22.0
Tracef
0.2
4
5e
8.0
a
Catalyst prepared in situ from ligand and iron(II) acetate in methanol.
3. Experimental
b
Initial ratio catalyst/H2O2/substrate 1:10:1000. See Experimental section for
more details.
c
Percentage yield relative to H2O2, the limiting reagent. Turnover number (
mmol
3.1. General experimental
product produced per mol catalyst) can be derived by dividing these percentage
m
yields by 10. Percentage conversion of alkene¼percentage yield/100.
Solvents were purified as follows and distilled under nitrogen
immediately before use: dichloromethane (DCM) refluxed over
calcium hydride; methanol refluxed with magnesium turnings and
iodine; tetrahydrofuran (THF) refluxed over sodium metal and
d
Values shown are the averages of three repetitions except for reactions with 6,
which show the average of two repetitions.
e
Control experiment using only iron(II) acetate and H2O2 (i.e., no ligand).
Yield <0.05% observed.
f

3234
V.J. Dungan et al. / Tetrahedron 68 (2012) 3231e3236
benzophenone ketyl radical. Alkene substrates were distilled from
calcium hydride and stored over 4 A molecular sieves. Solvents
were degassed when required using the freeze/thaw method in
three cycles. Thin layer chromatography (TLC) was carried out on
removed in vacuo to yield the product as a yellow solid (0.940 g,
98%); mp 210e215 ꢁC; ½a D20
ꢀ27.5 (c 1, MeOH); nmax (thin film NaCl):
ꢃ
ꢀ
3321 (s, br), 2950 (w, CeH (aromatic), str.), 2850 (w, CeH (alkyl),
str.), 1589 (s), 1303 (w, CeO str.); dH (400 MHz, CD3OD): 1.74e1.83
(2H, m), 1.90e1.98 (2H, m), 2.01e2.12 (2H, m), 2.17e2.26 (2H, m),
2.35e2.41 (2H, m), 3.08e3.13 (2H, m), 3.25e3.29 (2H, m), 3.65 (2H,
d, J¼15.5 Hz), 3.96 (2H, d, J¼15.5 Hz), 7.11 (2H, d, J¼7.5 Hz), 7.77 (1H,
t, J¼7.5 Hz); dC (100 MHz, CD3OD): 24.0, 30.3, 54.2, 60.0, 69.9, 119.6,
138.3, 159.0, 182.6; m/z (ESꢀ) 338 (100%, [MꢀLi]ꢀ); HRMS:
C17H21N3LiOꢀ4 ([MꢀLi]ꢀ) requires 338.1692, found 338.1698.
aluminium-backed plates, pre-coated with Merck silica gel 60 F254
.
TLC plates were visualised under an ultraviolet lamp and/or by
staining with either ninhydrin solution (0.3% w/v in 97:3 n-BuOH/
AcOH) or phosphomolybdic acid (0.01% phosphomolybdic acid,
0.001% ceric sulfate, H2O/H2SO4/EtOH 20:1:40) followed by heat-
ing. Retention factors are quoted to the nearest 0.05. Flash chro-
matography was carried out using Ajax Finechem silica gel
230e400 mesh. Melting points were recorded on a GallenKamp
melting point apparatus. Optical rotations were measured on
a Perkin Elmer model 341 Polarimeter with a sodium lamp at
589 nm in a 1.0 or 0.5 dm cell at the concentration (g/100 mL) and
temperature indicated. Infrared spectra were measured on a Shi-
madzu Bio-Rad 8400S using a sodium chloride cell; absorbances
are quoted in wavenumbers (cmꢀ1) and recorded as strong (s),
medium (m), weak (w) and broad (br). NMR spectra were recorded
on Bruker DPX 200, DPX 300 and DPX 400 spectrometers; chemical
shifts are reported in parts per million (ppm) from tetramethylsi-
lane (TMS) and referenced to TMS or the appropriate residual sol-
vent peak. 1H NMR data are quoted as the signal (ppm), relative
integral, multiplicity (singlet s, doublet d, triplet t, quartet q, double
doublet dd, multiplet m) and coupling constant J (quoted in hertz to
the nearest 0.5 Hz). Low resolution mass spectra were recorded on
a Finnigan LCQ MS Detector (ESI); major peaks are recorded as mass
to charge (m/z) followed by the height of the peak as a percentage
of the base peak and assignment. High resolution mass spectra
were recorded on a Bruker Apex II FTICR mass spectrometer. GC
analyses were performed on a HewlettePackard 5890 Series II gas
chromatograph fitted with an HP-1ms column (30 mꢂ0.25 mm ID,
3.4. Methyl (1S)-((6-((tert-butyldimethylsilyloxy)methyl)
pyridine-2-yl)methyl) pyrrolidine-2-carboxylate 15
To
a
solution of
L-proline methyl ester hydrochloride
10-HCl (2.37 g, 14.3 mmol) in MeOH (30 mL), DIPEA (5.00 mL,
28.7 mmol) was added and the solution stirred at room temperature
for 15 min. A solution of the bromide 14 (3.02 g, 9.56 mmol) in MeOH
(30 mL) was added and the reaction mixture was stirred at reflux
overnight. The solvent was removed in vacuo and DCM (50 mL) was
added. The mixture was washed with H2O (2ꢂ60 mL), saturated
brine (60 mL), dried over MgSO4 and concentrated in vacuo to
provide a brown oil (3.21 g). The compound was purified by column
chromatography (5:1 EtOAc/hexane) to give the title compound 15
as a viscous brown oil (2.72 g, 78%); Rf 0.5 (EtOAc/hexane 5:1); ½a D20
ꢃ
ꢀ42.0 (c 1, MeOH); nmax (neat NaCl): 2927 (s, CeH (aromatic), str.),
2854 (s, CeH (alkyl), str.),1747 (s, C]O, str.),1591 (s, C]C (aromatic),
str.); dH (400 MHz, CDCl3); 0.08 (6H, s), 0.92 (9H, s), 1.72e1.97 (3H,
m), 2.06e2.16 (1H, m), 2.46e2.52 (1H, m), 3.03e3.09 (1H, m),
3.35e3.42 (1H, m), 3.61 (3H, s), 3.72 (1H, apparent d, J¼13.5 Hz), 3.96
(1H, apparent d, J¼13.5 Hz), 4.78 (2H, s), 7.30 (1H, d, J¼7.0 Hz), 7.34
(1H, d, J¼7.5 Hz), 7.63 (1H, t, J¼7.5 Hz); dC (100 MHz, CDCl3): ꢀ5.3,
18.4, 23.3, 26.0, 29.4, 51.7, 53.6, 60.2, 65.3, 66.1, 118.2, 121.4, 137.0,
157.6, 160.7, 174.5; m/z (ESþ): 365 (100%, [MH]þ); HRMS:
C19H33N2SiOþ3 ([MHþ]) requires 365.2260, found 365.2250.
0.25 mm; S/N US2469051H) equipped with a split/splitless capillary
inlet and flame ionisation detector (FID) and controlled using
ChemStation software.
3.2. Dimethyl (2S,20S)-1,10-(pyridine-2,6-diylbis(methylene))
3.5. Methyl (1S)-((6-(hydroxymethyl)pyridine-2-yl)methyl)
bis(pyrrolidine-2,1-diyl)diformate 8
pyrrolidine-2-carboxylate 16
To a flask containing
L
-proline methyl ester hydrochloride salt
A solution of 15 (0.430 g, 1.20 mmol) in THF (10 mL) was cooled
to 0 ꢁC and a solution of tetrabutylammonium fluoride (1 M solu-
tion in THF, 2.36 mL, 2.40 mmol) was added dropwise via syringe.
The solution was stirred at room temperature for 90 min. The re-
action was poured onto water (10 mL) and the aqueous phase was
extracted with DCM (3ꢂ10 mL). The organic phases were com-
bined, washed with saturated brine (10 mL) and dried over MgSO4.
The solvent was removed in vacuo to give a crude brown oil, which
was purified by column chromatography (10:1 DCM/MeOH) to af-
ford alcohol 16 as an orange oil (0.250 g, 85%); Rf 0.6 (5:1 DCM/
10-HCl (3.29 g, 20.0 mmol) in MeOH (40 mL), DIPEA (7.21 mL,
41.4 mmol) was added slowly and the mixture was stirred at room
temperature for 15 min. A solution of 2,6-dibromomethylpyridine
11 (1.00 g, 4.00 mmol) in MeOH (20 mL) was added to the re-
action via cannula, and the mixture was heated at reflux overnight.
The solvent was removed in vacuo, and then DCM (50 mL) was
added. The mixture was washed with water (50 mL), saturated
brine (50 mL), dried over MgSO4 and concentrated in vacuo to give
a brown oil. The product was purified by column chromatography
(EtOAc/MeOH 9:1) to give the title compound 8 as a yellow oil
MeOH); ½a 2D0
ꢀ70.0 (c 1, MeOH); nmax (neat NaCl): 3371 (br, OeH,
ꢃ
(1.00 g, 70%); Rf 0.45 (EtOAc/MeOH 9:1); ½a D20
ꢃ
ꢀ83.8 (c 1, CHCl3); dH
str.), 2940 (m, CeH (aromatic), str.), 1728 (br, C]O, str.),1600 (s, C]
C (aromatic), str.); dH (400 MHz, CDCl3); 1.72e1.73 (1H, m),
1.80e1.97 (2H, m), 2.08e2.16 (1H, m), 2.46e2.52 (1H, m), 3.06e3.11
(1H, m), 3.35e3.39 (1H, m), 3.62 (3H, s), 3.77 (1H, d, J¼13.5 Hz),
3.98 (1H, d, J¼13.5 Hz), 4.69 (2H, s), 7.10 (1H, d, J¼7.5 Hz), 7.30 (1H,
d, J¼7.5 Hz), 7.61 (1H, t, J¼7.5 Hz); dC (100 MHz, CDCl3): 23.3, 29.5,
51.9, 53.7, 59.9, 64.1, 65.3, 118.9, 122.0, 137.2, 157.7, 158.4, 174.7; m/z
(ESþ): 251 (100%, [MH]þ), 273 (97%, [MþNa]þ); HRMS: C13H19N2O3þ
([MHþ]) requires 251.1396, found 251.1387.
(400 MHz, CD3OD): 1.83e1.98 (6H, m), 2.15e2.24 (2H, m),
2.53e2.60 (2H, m), 3.05e3.10 (2H, m), 3.43e3.47 (2H, m), 3.66 (6H,
s), 3.80 (2H, apparent d, J¼13.5 Hz), 4.00 (2H, apparent d,
J¼13.5 Hz), 7.43 (2H, d, J¼7.5 Hz), 7.77 (1H, t, J¼7.5 Hz); dC
(100 MHz, CD3OD): 25.1, 31.2, 53.2, 55.3, 61.5, 67.1, 124.2, 139.5,
160.0, 176.9; m/z (ESþ): 362 (62%, [MH]þ), 384 (100%, [MþNa]þ);
HRMS: C19H27N3NaOþ4 ([MþNa]þ) requires 384.1894, found
384.1886. These data match those previously reported.37
3.3. Lithium (2S,20S)-1,10-(pyridine-2,6-diylbis(methylene))
3.6. Lithium (S)-1-((6-(hydroxymethyl)pyridine-2-yl)methyl)
bis(pyrrolidine-2,1,diyl)diformate 4-Li2
pyrrolidine-3-carboxylate 5-Li
Aqueous lithium hydroxide solution (1 M, 5.54 mL, 5.50 mmol)
was added to a solution of 8 (1.00 g, 2.80 mmol) in MeOH (10 mL).
The resulting mixture was stirred at reflux for 3 h. The solvent was
Aqueous lithium hydroxide solution (1 M, 0.690 mL,
0.690 mmol) was added to a solution of 16 (172 mg, 0.690 mmol) in
MeOH (1 mL). The resulting mixture was stirred at reflux for 3 h.

V.J. Dungan et al. / Tetrahedron 68 (2012) 3231e3236
3235
The solvent was removed in vacuo to give a pale yellow solid
3.9. Lithium (1S)-1((6-((1S)-1-phenylethylamino)pyridine-2-
yl)methyl)pyrrolidine-2-carboxylate 6-Li
(159 mg, 95%); mp 133e138 ꢁC; ½a D20
ꢃ
ꢀ70.4 (c 1.6, MeOH/H2O 1:1);
nmax (neat NaCl): 3333 (br, OeH, str.), 2968 (m, CeH (aromatic),
str.), 2831 (m, CeH (alkyl), str.), 1593 (s), 1304 (m, CeO, str.); dH
(400 MHz, CDCl3); 1.79e1.97 (3H, m), 2.17e2.27 (1H, m), 2.34e2.41
(1H, m), 3.01e3.06 (1H, m), 3.12e3.16 (1H, m), 3.61 (1H, d,
J¼14.0 Hz), 4.11 (1H, d, J¼14.0 Hz), 4.76 (2H, s), 7.38 (1H, d,
J¼7.5 Hz), 7.41 (1H, d, J¼7.5 Hz), 7.80 (1H, t, J¼7.5 Hz); dC (100 MHz,
CDCl3): 23.0, 30.9, 53.5, 60.2, 63.7, 69.5, 118.9, 121.3, 137.8, 160.6,
162.4, 183.3; m/z (ESꢀ): 235 (26%, [MꢀLi]ꢀ); HRMS: C12H15N2O3ꢀ
([MꢀLi]ꢀ) requires 235.1088, found 235.1079.
Aqueous lithium hydroxide solution (2.00 M, 0.050 mL,
0.100 mmol) was added to a solution of 18 (35.0 mg, 0.100 mmol) in
MeOH (2 mL). The resulting mixture was stirred at reflux for 3 h.
The solvent was removed in vacuo to give the title compound as
a yellow oil (31.0 mg, 90%); nmax (neat NaCl): 3333 (s, br), 2968 (w,
CeH (aromatic), str.), 1595 (s), 1303 (w, CeO, str.); ½a D20
ꢀ62.58 (c
ꢃ
1.63, CH2Cl2); dH (400 MHz, CD3OD): 1.35 (3H, d, J¼6.5 Hz),
1.68e1.88 (3H, m), 2.09e2.16 (1H, m), 2.19e2.25 (1H, m), 2.85e2.90
(1H, m), 3.04e3.08 (1H, m), 3.47 (1H, d, J¼14.0 Hz), 3.64 (2H, d,
J¼4.0 Hz), 3.67e3.72 (1H, q), 4.06 (1H, d, J¼14.0 Hz), 7.09 (1H, d,
J¼7.5 Hz), 7.15e7.21 (1H, m), 7.24e7.30 (5H, m), 7.63 (1H, t,
J¼7.5 Hz); dC (100 MHz, CD3OD): 24.1, 24.2, 31.0, 53.2, 54.5, 58.9,
63.7, 70.6, 122.9, 123.0, 128.0, 128.3, 129.7, 139.0, 145.8, 160.0, 160.1,
182.3; m/z (ESꢀ) 339 (100%, [MꢀH]ꢀ); HRMS: C20H24N3O2ꢀ
([MꢀLiꢀ]) requires 338.1874, found 338.1871.
3.7. Methyl (1S)-((6-formylpyridin-2-yl)methyl)pyrrolidine-2-
carboxylate 17
A solution of oxalyl chloride (70.0
mL, 0.800 mmol) in DCM
(2.0 mL) was cooled to ꢀ78 ꢁC and added dropwise to dimethyl
sulfoxide (113 mL, 1.60 mmol). The resulting suspension was stirred
at ꢀ78 ꢁC for 10 min, then a solution of the alcohol 16 (100 mg,
0.400 mmol) in DCM (2.0 mL) was added via cannula over 5 min.
The mixture was stirred at ꢀ78 ꢁC for 45 min before DIPEA
(0.560 mL, 3.20 mmol) was then added quickly. The slurry that
formed was warmed to 0 ꢁC and stirred for a further 30 min. The
reaction mixture was poured onto water (10 mL) and extracted
with DCM (3ꢂ10 mL). The organic phases were combined, washed
with saturated brine (10 mL) and dried (MgSO4). The solvent was
removed in vacuo to give a brown oil, which was purified by col-
umn chromatography (3:1 EtOAc/hexane). Two compounds were
isolated: recovered starting material 16 (21.0 mg, 21%) and the
desired aldehyde 17 as a brown oil (49.0 mg, 49%); Rf 0.43 (5:95
3.10. Methyl (1S)-picolinoylpyrrolidine-2-carboxylate 20
Thionyl chloride (20.0 mL, 0.300 mol) was added to picolinic
acid 19 (2.00 g, 16.0 mmol) and the suspension was refluxed for 4 h
resulting in an orange solution. This solution was concentrated in
vacuo to give the acid chloride as an orange solid. The solid was
dissolved in dry DCM (50 mL) under a nitrogen atmosphere and
cooled to 0 ꢁC. Triethylamine was added to a suspension of
L-proline
methyl ester 10 (2.07 g, 16.0 mmol) in DCM (50 mL), prompting
immediate precipitation. The suspension was cooled to 0 ꢁC before
the acid chloride solution was added via cannula. The reaction
mixture became deep purple and was stirred at 0 ꢁC for 15 min,
then at room temperature for 16 h. The reaction mixture was
washed with saturated ammonium chloride solution (30 mL) and
the aqueous phase extracted with DCM (3ꢂ20 mL). The combined
organic layers were washed with brine (15 mL) and dried (MgSO4),
then concentrated in vacuo to give an orange oil. This was purified
by column chromatography (13:7 hexane/ethyl acetate) to give the
title compound 20 as a yellow oil (1.97 g, 53%) as a mixture of cis
MeOH/CH2Cl2); ½a D20
ꢀ55.11 (c 1.35, CH2Cl2); IR (in CH2Cl2 solution)
ꢃ
2953e2827 (w, CeH and CeN, str.), 1740e1713 (s, C]O, str.) cmꢀ1
;
dH (CDCl3, 200 MHz); 1.83e2.22 (4H, m), 2.54e2.63 (1H, m),
3.08e3.13 (1H, m), 3.43e3.50 (1H, m), 3.67 (3H, s), 3.88 (1H, d,
J¼14.0 Hz), 4.15 (1H, d, J¼14.0 Hz), 7.72e7.79 (2H, m), 7.84 (1H, t,
J¼2.0 Hz), 10.06 (1H, s); dC (CD3OD, 75.5 MHz); 23.6, 29.7, 52.1, 53.9,
60.1, 65.6, 120.5, 128.0, 137.6, 152.5, 160.5, 174.8, 194.0; m/z (ESþ)
249 (100%, [MH]þ); HRMS: C13H17N2O3þ ([MHþ]) requires 249.1234,
found 249.1230.
and trans amide isomers; Rf 0.5 (ethyl acetate); ½a D20
ꢀ48.9 (c 0.65,
ꢃ
CHCl3); nmax (CHCl3 solution, cmꢀ1): 2997 (s, CeH, str.), 2954 (m,
CeH, str.),1730 (s, C]O, str.),1625 (s, C]O, str.),1587 (w, C]C, str.),
1568 (m, C]C, str.), 1477 (m), 1446 (s), 1406 (s), 1363 (w), 1286 (w),
1172 (m); dH (200 MHz, CDCl3): major atropisomer: 1.83e2.27 (4H,
m), 3.55 (3H, s), 3.74e4.41 (2H, m), 5.06 (1H, dd, J¼8.5, 3.0 Hz),
7.21e7.67 (1H, m), 7.71 (1H, t, J¼8.0 Hz), 7.96 (1H, d, J¼8.0 Hz), 8.51
(1H, d, J¼4.5 Hz); minor atropisomer: 1.83e2.27 (4H, m), 3.64 (3H,
s), 3.74e4.41 (2H, m), 4.60 (1H, dd, J¼8.0, 4.0 Hz), 7.21e7.67 (1H, m),
7.71 (1H, t, J¼8.0 Hz), 7.82 (1H, d, J¼8.0 Hz), 8.38 (1H, d, J¼4.5 Hz);
dC (50 MHz, CDCl3): 11.8, 13.3, 21.0, 24.5, 47.3, 48.7, 51.0, 51.2, 59.1,
60.6, 123.1, 123.4, 123.6, 124.1, 135.8, 135.9, 146.9, 147.3, 151.8, 152.4,
164.5, 165.3, 171.7, 172.5; m/z (ESþ): 257 (100%, [MþNa]þ); HRMS:
C12H14N2NaOþ3 ([MþNa]þ) requires 257.0897, found 257.0899.
3.8. Methyl (1S)-((6-(((1S)-phenylethylamino)methyl)pyridin-
2-yl)methyl)pyrrolidine-2-carboxylate 18
The aldehyde 17 (49.0 mg, 0.200 mmol) and (S)-(ꢀ)-
a-meth-
ylbenzylamine (25.0 L, 0.200 mmol), were dissolved in
m
dichloroethane (1.00 mL) and treated with sodium triacetox-
yborohydride (58.0 mg, 0.300 mmol). The reaction mixture was
stirred under a nitrogen atmosphere at room temperature for
1.5 h. The reaction mixture was poured onto saturated NaHCO3
(10 mL), and the product was washed with brine and dried
(MgSO4) to give a crude yellow oil, which was purified by column
chromatography (DCM/MeOH/Et3N, 94:5:1) to give the title
compound as a yellow oil (48.0 mg, 50%); Rf 0.25 (DCM/MeOH/
3.11. (1S)-Picolinoylpyrrolidine-2-carboxylic acid 7
Et3N, 97:2:1); ½a D20
ꢃ
ꢀ52.20 (c 2.00, CH2Cl2); IR (in CH2Cl2 solution)
The methyl ester 20 (80.0 mg, 0.340 mmol) was dissolved in
a minimum volume of THF (1.00 mL) and aqueous lithium hy-
droxide (1.00 M, 0.340 mL, 0.340 mmol) was added. The solution
was heated at reflux for 16 h. After cooling to room temperature,
the solution was acidified to pH 5 with 1 M HCl then reduced in
vacuo. The resulting residue was triturated with chloroform, and
the chloroform solution filtered and concentrated in vacuo to give
3059 (s, NeH, str.), 2966e2814 (s, CeH and CeN, str.), 1740 (s, C]
O, str.), 1452 (s, CeO bnd.) cmꢀ1
; dH (400 MHz, CDCl3); 1.54 (3H, d,
J¼6.0 Hz), 1.81e2.20 (4H, m), 2.55e2.59 (1H, m), 3.11e3.15 (1H,
m), 3.42e3.46 (1H, m), 3.67 (3H, s), 3.82 (1H, q, J¼10.0 Hz), 3.94
(1H, d, J¼6.0 Hz), 3.96 (1H, d, J¼6.0 Hz), 4.03 (1H, d, J¼13.5 Hz),
4.04 (1H, d, J¼13.5 Hz), 7.09e7.12 (1H, m), 7.27e7.44 (6H, m), 7.60
(1H, t, J¼7.5 Hz); dC (100 MHz, CD3OD): 23.3, 23.5, 29.5, 51.9, 53.7,
58.3, 59.9, 63.9, 65.3, 118.8, 120.9, 122.0, 127.2, 127.6, 128.4, 128.7,
137.2, 158.2, 174.8; m/z (ESþ) 354 (100%, [MH]þ); HRMS:
C21H28N3Oþ2 ([MHþ]) requires 354.2176, found 354.2166.
the title compound 7 as a pale yellow oil (75.0 mg, 98%); ½a D20
ꢀ83.0
ꢃ
(c 0.6, MeOH); mp: 41e44 ꢁC; nmax (NaCl, cmꢀ1): 3375 (s, br, OeH,
str.),1612 (s, C]O, str.), 1568 (s, C]O, str.), 1485 (m), 1452 (m), 1423
(m), 1402 (m); dH (200 MHz, CD3OD): major atropisomer: 1.71e2.24

3236
V.J. Dungan et al. / Tetrahedron 68 (2012) 3231e3236
3. Bensaude-Vincent, B.; Arribart, H.; Bouligand, Y.; Sanchez, C. New J. Chem. 2002,
26, 1e5.
4. Bugg, T. D. H. Tetrahedron 2003, 59, 7075e7101.
5. Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L. Chem. Rev. 2004, 104, 939e986.
6. Bautz, J.; Comba, P.; de Laorden, C. L.; Menzel, M.; Rajaraman, G. Angew. Chem.,
Int. Ed. 2007, 46, 8067e8070.
(4H, m), 3.52e3.78 (2H, m), 4.69 (1H, dd, J¼8.5, 3.5 Hz), 7.27e7.60
(1H, m), 7.61e7.87 (2H, m), 8.42e8.50 (1H, m); minor atropisomer:
1.71e2.24 (4H, m), 3.52e3.78 (2H, m), 4.41 (1H, dd, J¼8.5, 4.0 Hz),
7.27e7.60 (1H, m), 7.61e7.87 (2H, m), 8.42e8.50 (1H, m); dC
(50 MHz, CD3OD): 24.0, 26.6, 31.5, 49.2, 51.2, 64.4 65.5, 125.1, 125.4,
126.4, 126.7, 138.8, 139.1, 149.5, 149.9, 156.1, 168.7, 169.7, 179.8; m/z
(ESꢀ): 219 (100%, [MꢀH]ꢀ); HRMS: C11H11N2O3ꢀ ([MꢀH]ꢀ) requires
219.0775, found 219.0778.
7. Nam, W. Acc. Chem. Res. 2007, 40, 465e465.
8. Piera, J.; Backvall, J. E. Angew. Chem., Int. Ed. 2008, 47, 3506e3523.
9. Murahashi, S. I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490e1501.
10. Que, L.; Ho, R. Y. N. Chem. Rev. 1996, 96, 2607e2624.
11. Burzlaff, N. I.; Rutledge, P. J.; Clifton, I. J.; Hensgens, C. M. H.; Pickford, M.;
Adlington, R. M.; Roach, P. L.; Baldwin, J. E. Nature 1999, 401, 721e724.
12. Ogle, J. M.; Clifton, I. J.; Rutledge, P. J.; Elkins, J. M.; Burzlaff, N. I.; Adlington, R.
M.; Roach, P. L.; Baldwin, J. E. Chem. Biol. 2001, 8, 1231e1237.
13. Neidig, M. L.; Solomon, E. I. Chem. Commun. 2005, 5843e5863.
14. Abu-Omar, M. M.; Loaiza, A.; Hontzeas, N. Chem. Rev. 2005, 105, 2227e2252.
15. Elkins, J. M.; Rutledge, P. J.; Burzlaff, N. I.; Clifton, I. J.; Adlington, R. M.; Roach, P.
L.; Baldwin, J. E. Org. Biomol. Chem. 2003, 1, 1455e1460.
16. Decker, A.; Solomon, E. I. Curr. Opin. Chem. Biol. 2005, 9, 152e163.
17. Daruzzaman, A.; Clifton, I. J.; Adlington, R. M.; Baldwin, J. E.; Rutledge, P. J.
ChemBioChem 2006, 7, 351e358.
3.12. Oxidative turnover reactions
Iron(II) acetate (12.0 mg, 0.070 mmol) was dissolved in
degassed, dry methanol (1.20 mL) and an aliquot of this solution
(0.200 mL) was added to a solution of ligand (4.00 mg, 0.010 mmol)
in methanol (0.200 mL) under argon to give a yellow solution. The
reaction was stirred for 1 h at room temperature under an atmo-
sphere of argon, after which time it was diluted with methanol
(10 mL) and the alkene substrate (10.00 mmol) was added. Hy-
18. Bruijnincx, P. C. A.; van Koten, G.; Gebbink, R. Chem. Soc. Rev. 2008, 37,
2716e2744.
19. Hegg, E. L.; Que, L. Eur. J. Biochem. 1997, 250, 625e629.
20. Que, L. Nat. Struct. Biol. 2000, 7, 182e184.
21. Hausinger, R. P. Crit. Rev. Biochem. Mol. Biol. 2004, 39, 21e68.
22. McRae, D. G.; Coker, J. A.; Legge, R. L.; Thomson, J. E. Plant Physiol. 1983, 73,
784e790.
23. Kappock, T. J.; Caradonna, J. P. Chem. Rev. 1996, 96, 2659e2756.
24. Boyd, D. R.; Bugg, T. D. H. Org. Biomol. Chem. 2006, 4, 181e192.
25. Perry, D.; Abraham, E. P.; Baldwin, J. E. Biochem. J. 1988, 255, 345e351.
26. Oldenburg, P. D.; Shteinman, A. A.; Que, L. J. Am. Chem. Soc. 2005, 127,
15672e15673.
27. Chen, M. S.; White, M. C. Science 2007, 318, 783e787.
28. Que, L. Acc. Chem. Res. 2007, 40, 493e500.
drogen peroxide (30% solution in water, 13.0 mL, 0.100 mmol) in
methanol (1.00 mL) was added over 30 min via syringe pump. The
reaction was stirred at room temperature under argon for 16 h
before the solution was concentrated in vacuo and diluted with
ethyl acetate, then passed through a short silica column. The in-
ternal standard decane was added, and reaction mixtures were
analysed by gas chromatography (GC). Products were identified
unambiguously by comparison and spiking with authentic samples.
29. Suzuki, K.; Oldenburg, P. D.; Que, L. Angew. Chem., Int. Ed. 2008, 47, 1887e1889.
30. Costas, M.; Tipton, A. K.; Chen, K.; Jo, D.-H.; Que, L. J. Am. Chem. Soc. 2001, 123,
6722e6723.
Acknowledgements
€
31. England, J.; Martinho, M.; Farquhar, E. R.; Frisch, J. R.; Bominaar, E. L.; Munck, E.;
We would like to thank Dr. Fatiah Issa and Dr. Elizabeth Barrett
for advice and assistance with synthesis and turnover experiments,
Dr. Ian Luck, Dr. Kelvin Picker and Dr. Keith Fisher for technical
assistance with NMR, HPLC/GC and mass spectrometry re-
spectively. This work was supported by the Irish Research Council
for Science, Engineering and Technology (IRCSET) via an Embark
Award to SMB, and by the University of Sydney.
Que, L. Angew. Chem., Int. Ed. 2009, 48, 3622e3626.
32. England, J. ,; Guo, Y.; Van Heuvelen, K. M.; Cranswick, M. A.; Rhode, G. T.;
€
Bominaar, E. L.; Munck, E.; Que, L. J. Am. Chem. Soc. 2011, 133, 11880e11883.
33. Krall, J. A.; Rutledge, P. J.; Baldwin, J. E. Tetrahedron 2005, 61, 137e143.
34. Barry, S. M.; Rutledge, P. J. Synlett 2008, 2172e2174.
35. Dungan, V. J.; Ortin, Y.; Mueller-Bunz, H.; Rutledge, P. J. Org. Biomol. Chem. 2010,
8, 1666e1673.
36. Fenton, H. J. H. J. Chem. Soc., Trans. 1894, 65, 899.
37. Gosiewska, S.; Cornelissen, J. J. L. M.; Lutz, M.; Spek, A. L.; van Koten, G.; Geb-
bink, R. J. M. K. Inorg. Chem. 2006, 45, 4214e4227.
38. Gosiewska, S.; Lutz, M.; Spek, A. L.; Gebbink, R. J. M. K. Inorg. Chim. Acta 2007,
360, 405e417.
Supplementary data
39. Paria, S.; Halder, P.; Paine, T. K. Inorg. Chem. 2010, 49, 4518e4523.
40. McMullen, T. C. J. Am. Chem. Soc. 1916, 38, 1228e1230.
41. Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801e811.
42. Sorm, F.; Sedivy, L. Collect. Czech. Chem. Commun. 1948, 13, 289.
43. Bryce, M. R.; Eaves, J. G.; Parker, D.; Howard, J. A. K.; Johnson, O. J. Chem. Soc.,
Perkin Trans. 2 1985, 433e436.
44. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651e1660.
45. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J.
Org. Chem. 1996, 61, 3849e3862.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.02.031. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
46. Fabre, J. L.; Farge, D.; James, C.; Lave, D. Tetrahedron Lett. 1985, 26, 5447e5450.
47. Mock, W. L.; Liu, Y. J. Biol. Chem. 1995, 270, 18437e18446.
48. Phillips, W. D. J. Chem. Phys. 1955, 23, 1363e1364.
1. Barton, D. H. R. Chem. Soc. Rev. 1996, 25, 237e239.
2. Gamez, P.; Aubel, P. G.; Driessen, W. L.; Reedijk, J. Chem. Soc. Rev. 2001, 30,
376e385.
49. Kessler, H. Angew. Chem., Int. Ed. Engl. 1970, 9, 219e235.