Synthesis of orthogonally protected biaryl amino acid derivatives

Article abstract of DOI:10.1039/b609360d

The efficient and direct synthesis of protected biaryl amino acids, including dityrosine (50% overall yield over 3 steps), by Negishi cross-coupling of the serine-derived organozinc reagent 4 with iodo- and di-iodobiaryls, is reported. An improved, althou

Full text of DOI:10.1039/b609360d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of orthogonally protected biaryl amino acid derivatives
Eduardo Moreno, Luca Antonio Nolasco, Lorenzo Caggiano* and Richard F. W. Jackson*
Received 3rd July 2006, Accepted 8th August 2006
First published as an Advance Article on the web 23rd August 2006
DOI: 10.1039/b609360d
The efficient and direct synthesis of protected biaryl amino acids, including dityrosine (50% overall
yield over 3 steps), by Negishi cross-coupling of the serine-derived organozinc reagent 4 with iodo- and
di-iodobiaryls, is reported. An improved, although still not perfect, diiodination of 2,2ꢀ-biphenol has
been achieved using NMe3BnICl2–ZnCl2. Protection of phenolic hydroxyl groups as acetates, rather
than benzyl ethers, is required for efficient cross-coupling, and evidence for acetyl migration has been
observed during debenzylation of a substituted 2-acetoxy-2ꢀ-benzyloxybiaryl. Aromatic C–I to C–Cl
conversion has been detected as a minor reaction pathway in the palladium-catalyzed coupling of aryl
iodide 3b with organozinc reagent 4.
In particular, the formation of biphenol amino acid derivatives
Introduction
by the crosslinking of tyrosyl residues on the cell membrane of the
sea urchin egg generates a hard fertilisation envelope (HFE), which
serves to protect the embryo from disruptive agents, physical forces
and polyspermy.14,15 Similarly, the oocyst cell wall of apicomplexan
parasites in their infective form is hardened by the formation of
dityrosine cross-links between proteins encapsulating the oocyst,
and protects it from the environment.16
The presence of dityrosine in several proteins is also related
to non-specific oxidative damage upon exposure to a variety
of agents,17 including oxygen free-radical species,18 hydrogen
peroxide,19 nitrogen dioxide20 and related species21 and ultraviolet
(UV) irradiation.22 The non-specific formation of tyrosine cross-
links has been implicated in several human diseases which
include neurodegenerative disorders such as Parkinson’s23,24 and
Alzheimer’s diseases,25 atherosclerosis,26 diabetes,27 cystic fibrosis28
and the formation of cataractous lens in humans.29 During some of
these investigations, the urinary levels of dityrosine had been used
as a non-invasive biological marker to examine protein oxidative
stress in vivo,26,27 since these levels can be easily monitored due to
the amino acid 2 possessing an intense 420-nm fluorescence.17,30
Cross-linked biphenol amino acid derivatives have also been
implicated as playing an important role in the oxidative damage of
proteins, through the formation of the tyrosyl radical,31 and that
such damaged proteins mediate signals for degradation.32
Previous syntheses of dityrosine derivatives have either re-
lied on oxidative dimerisation of tyrosine, or on methods in-
volving Pd-catalyzed coupling reactions. The enzyme-catalyzed
preparation of dityrosine from L-tyrosine using horseradish
peroxidase has been reported,33,34 as well as non-enzymatic
oxidative methods using acidic aqueous potassium bromate,35
or VOF3 with N-benzyloxycarbonyl-L-tyrosine methyl ester.36
Yamamura and co-workers reported electrolytic phenolic ox-
idation of a 3,5-diiodotyrosine derivative as the key-step in
the synthesis of dityrosine, albeit in low overall yield.37 Lygo
reported a catalytic asymmetric phase transfer alkylation of
a glycine-derived imine to install the amino-acid fragments
of dityrosine in one high-yielding step.38 Alternative strategies
which employ palladium catalyzed cross-coupling reactions to
generate the biaryl link have also been reported. Achab has
Biaryl amino acids are present in a variety of natural products,
from relatively simple amino acids to complex macrocycles, many
of which display a range of biological activities.1 Of particular
interest is the 2,2ꢀ-biphenol amino acid 1, a structural motif
commonly found in nature, which in certain circumstances can
exhibit atropisomerism.2 2,2ꢀ-Biphenol derivatives have also found
many applications in asymmetric catalysis, for example as the
backbone of phosphoramidite ligands which have been used to
effect a variety of enantioselective transformations.3
Dityrosine 24 occurs naturally and is a member of a larger fam-
ily which contains, amongst others, isodityrosine,5,6 trityrosine,4
isotrityrosine,7 pulcherosine8 and di-isodityrosine.9 The formation
of dityrosine was initially reported by Gross and Sizer by the
oxidation of tyrosine with aqueous hydrogen peroxide and perox-
idase, resulting in dimerisation by formation of the biaryl bond.10
Andersen then identified the cross-links of resilin, a rubber-like
protein present in some of the elastic ligaments of arthropods,
as dityrosine and trityrosine.4 Subsequently, LaBella reported the
presence of dityrosine in mammalian collagen11 and vertebrate
elastin,12 and suggested that the cross-linking of this amino acid
was partially responsible for their structural properties. Dityrosine
formation was also subsequently shown to be induced by oxidation
of a variety of nonstructural proteins.13
Department of Chemistry, Dainton Building, University of Sheffield, Brook
Hill, Sheffield, UK S3 7HF. E-mail: r.f.w.jackson@shef.ac.uk
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reported that a Stille biaryl-coupling between 3-iodo and 3-
stannyl tyrosine derivatives can be achieved in moderate yields,39
while a Miyaura borylation–Suzuki intermolecular cross-coupling
approach has been successfully used by van Vranken40 and
Hutton.41,42
observed in the 1H NMR spectrum might be the result of
diastereoisomers resulting from atropisomerism. However, 1H
NMR studies in CDCl3 (at 62 ◦C), and especially in DMSO (at 27
and 107 ◦C), which showed exactly the same ratio of signals in each
case, instead strongly suggested the presence of two constitutional
isomers. Structural assignment was supported by chemical trans-
formations which afforded either the free biphenol derivative 1d or
the diacetylated compound 1e as single compounds (Scheme 2).
In addition, compounds 1d and 1e each exhibited a single set
of signals in the 1H NMR spectrum. Since neither of these
compounds exhibited atropisomerism, it seemed reasonable to
deduce that neither would the phenol 1b. Debenzylation which
resulted in acyl migration has been previously reported, although
in this case intramolecular transfer occurred between nitrogen
substituents.50
Results and discussion
Our approach to the synthesis of the protected biphenol amino
acid 1 and dityrosine 2 employs the Negishi cross-coupling
reaction of an appropriate iodobiaryl 3 with the organozinc
iodide 4.43,44 We have previously employed a related strategy in
an intramolecular fashion for the synthesis of the macrocyclic
tripeptide K13,45 and intermolecularly in the synthesis of a non-
natural, macrocyclic potential protease inhibitor.46
The synthesis of the aromatic iodide coupling partner 3a used
commercially available 2,2ꢀ-biphenol, which already has the biaryl
linkage installed (Scheme 1). Mono-benzylation of 2,2ꢀ-biphenol
was achieved efficiently (95% yield), using the conditions originally
reported for an analogous transformation of 1,1ꢀ-bi-2-naphthol
by Oda.47 Regioselective mono-iodination was subsequently ac-
complished in high yield, following the procedure reported by
Harrowven for a similar substrate,48 based on earlier work,49 and
subsequent acetylation gave the protected iodobiphenol derivative
3a (88% over two steps). Coupling of the amino acid-derived
organozinc iodide 4 with the differentially protected iodobiphenol
derivative 3a furnished the desired mono-coupled product 1a in
62% isolated yield (Scheme 1).
Scheme 2
Treatment of 2,2ꢀ-biphenol with KOtBu and an excess of benzyl
bromide gave the corresponding 2,2ꢀ-dibenzyl–biphenol derivative
5 in 92% yield. When the protected biphenol 5 was subjected to
the conditions for iodination reported by Kajigaeshi,51 the desired
diiodinated protected biphenol 3b was obtained in 75% isolated
yield (Scheme 3).
Scheme 1
The differentially protected 2,2ꢀ-biphenol 1a appeared to be a
potentially useful intermediate for further elaboration. Deben-
zylation, however, gave an inseparable 60 : 40 mixture of two
1
compounds (as determined by H NMR), which were ultimately
identified as the expected phenol 1b, and the product of acetyl
transfer 1c. Initially, it was suspected that the two sets of signals
Scheme 3
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Use of 2,2ꢀ-biphenol as a substrate for this reaction gave the
corresponding unprotected diiodide derivative 3c in 82% yield.
Upon close inspection of the mass spectrum, it was apparent
that the isolated material was an approximately 10 : 1 mixture
of the diiodide 3c and the corresponding mono-iodinated, mono-
chlorinated product 5-chloro-5ꢀ-iodo-2,2ꢀ-biphenol 3cꢀ, as sug-
gested by the relative intensities of the respective molecular ions.
Efforts to separate the compounds by column chromatography
proved unsuccessful. No competing chlorinated product was
observed in the formation of the dibenzyl diiodide 3b, presumably
due to the less reactive nature of the dibenzyl ether precursor
5. It is noteworthy that, although diiodination of 2,2ꢀ-biphenol
with NMe3BnICl2–ZnCl251 was not completely clean, giving small
amounts of 3cꢀ, previous attempts to effect controlled iodination
using a variety of iodination procedures gave complicated mixtures
of mono- and poly-iodinated phenols, which proved difficult to
separate and purify, an observation also made by Harrowven
during attempted mono-iodination.48 Treatment of the diiodide
3c with acetic anhydride gave the acetylated derivative 3d in 95%
yield, again as a 10 : 1 mixture with the 5-chloro-5ꢀ-iodo derivative
3dꢀ (Scheme 3). The composition of this mixture was again
determined by the relative intensities of the two corresponding
molecular ions (EI+) and, in this case, also by the elemental
analysis of the product mixture. The self-consistent results that
were obtained from each method validated the earlier assessment
of the 3c : 3cꢀ ratio.
due to the increased acidity of the biphenolic derivative 3c arising
from a co-operative effect of hydrogen-bonding interactions
between the OH substituents (PhOH pKa = 10.0, 2,2ꢀ-biphenol
pKa1 = 7.6 in water).53–55
The dibenzyl (3b) and diacetyl (3d) protected biphenol deriva-
tives reacted under palladium catalysis with the organozinc
reagent 4 to afford the expected bis-coupled products 2a
and 2b, respectively, together with varying amounts of the
mono-coupled (6 and 7) and the homo-coupled (8) products
(Scheme 4 and Table 1). Use of an excess of zinc reagent 4
resulted in a satisfactory overall yield (65%) of the desired pro-
duct 2b.
The initial products of mono-coupling are the species 6a and
7a, which possess an iodine substituent at the 5ꢀ position, and can
then each, therefore, undergo a second cross-coupling reaction to
afford the protected dityrosine derivative 2a and 2b, respectively.
Compounds 6c and 1e, may arise from insertion of excess zinc,
present in the reaction mixture, into the aromatic C–I bond,
followed by protonation. Alternatively, compounds 6c and 1e
could arise from initial insertion of zinc into one of the carbon–
iodine bonds of 3b or 3d, respectively, prior to cross-coupling with
the zinc reagent 4. In an effort to minimise this side reaction,
the solution of organozinc reagent 4 was transferred into a
separate flask containing the electrophile. Although this allowed
the isolation of the mono-coupled product 7a (Table 1, entry 4) it
did not prevent the formation of the reduced by-product 1e when
a large excess of the organozinc reagent 4 was employed (Table 1,
entry 5). The mass balance in all these reactions suggested that,
in the absence of an excess of the zinc reagent 4 (Table 1, entries
2 and 4), a substantial amount of the diiodide 3d was consumed
by non-productive side reactions. The crude NMR spectra did
Previous studies established that 4-iodophenol, possessing an
unprotected phenolic OH group, is compatible with the Negishi
cross-coupling reaction of the organozinc iodide 4.52 Attempted
cross-coupling reaction of the unprotected biphenol derivative 3c,
however, resulted in substantial amounts of alanine, presumably
Scheme 4
Table 1 Palladium catalyzed double cross-coupling reactions
Entry
Equivalents of reagent 4
Diiodide
Products (%)a
1
2
2.4
1.2
2.1
1.2
4.0
3b
3d
3d
3d
3d
2a, 22
2b, 36
2b, 50
2b, 19
2b, 65
6a + 6b, 14b
6c, 19
1e, 15
1e, 15
7a, 25
1e, 16
7b, 4
7b, 4
7b, —d
7b, 5
3
4c
5c
a Yields are calculated with respect to diiodide derivative 3, isolated after column chromatography. In all cases the homo-coupled product 8 was obtained
in 4–8% isolated yield. b A 4 : 1 ratio of 6a to 6b was observed by ES+. c The solution of organozinc iodide 4 was added to a separate flask containing the
diiodo biphenol derivative 3d. d Not isolated.
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contain evidence of additional aromatic by-products, but no other
compounds were isolated.
red spectra were recorded on a Perkin Elmer Paragon 100 FTIR
spectrophotometer (tmax in cm−1) with KBr disks.
A small amount of the mono-coupled product 7b, which
contains a chloro substituent at the 5ꢀ position, was observed in
entries 2, 3 and 5 (Table 1). This is not unexpected, since the
diacetate derivative 3d was accompanied by the corresponding 5ꢀ-
chloro-5-iodo derivative 3dꢀ, which underwent a single selective
cross coupling reaction at the 5-iodo position. It is interesting
to note that a mixture of 6a and 6b was also obtained with
the dibenzyl protected derivative 3b, even though the starting
material was devoid of any chlorinated biphenol (Table 1, entry
1). Compound 6b could arise by a palladium-catalyzed aromatic
Finkelstein reaction, in which the necessary chloride anions are
produced during the zinc activation process (which uses Me3SiCl);
aromatic Finkelstein reactions have been previously reported using
both copper56 and nickel catalysts,57 and an analogous fortuitous
observation resulted in the discovery of the copper-catalyzed
process.56 Further experiments to investigate this preliminary
observation of a palladium-catalyzed halide exchange appear
warranted.
Thin layer chromatography (TLC) was performed on precoated
plates (Merck aluminium sheets silica 60 F254, art. no. 5554).
Visualisation of compounds was achieved by illumination under
ultraviolet light (254 nm) or using an appropriate staining reagent.
Flash column chromatography was performed on silica gel 60
(Merck 9385).
General procedure 1: iodination of aromatic ethers using
benzyltrimethylammonium dichloroiodate and zinc chloride
Following the method described by Kajigaeshi,51 benzyltrimethy-
lammonium dichloroiodate (2.2 eq.) and excess anhydrous ZnCl2
was added to a stirred solution of the 1,1ꢀ-biarylphenol derivate (1
eq.) in acetic acid. The mixture was stirred at room temperature
for 16 h. Water (20 ml) and aqueous NaHSO3 (10% w/v solution,
20 ml) was added to the reaction mixture. The aqueous fraction
was extracted with diethyl ether (3 × 50 ml), the organic fractions
collected, dried over MgSO4 and the solvent removed under
reduced pressure to afford the crude product which was purified
by silica gel column chromatography.
Conclusions
General procedure 2: zinc-activation and insertion into C–I bond
using Me3SiCl as the activating agent
In summary, the expedient synthesis of a range of enantiomerically
pure, novel biphenol amino acid derivatives is reported, which
could find application in asymmetric catalysis and as useful
synthetic intermediates. The synthesis of orthogonally protected
dityrosine derivative 2b (50% yield over 3 steps from commercially
available materials) is also reported, in which the key step is a
palladium catalyzed double cross-coupling reaction of the amino
acid-derived organozinc reagent 4 and the diiodide 3d.
Chlorotrimethylsilane (100–150 ll) was added to a rapidly stirred
suspension of zinc powder (5–6 eq.) in dry DMF (2–3 ml) and the
resulting mixture stirred for 15 min at room temperature under a
nitrogen atmosphere. The suspension was allowed to settle, and
the supernatant was removed by syringe and discarded. The zinc
powder was washed with fresh dry DMF (3 × 1 ml) and the
supernatant removed each time and discarded. Finally the powder
was dried using a heating gun under reduced pressure. Once at
room temperature, dry DMF (1 ml mmol−1 of iodo-alanine) was
added to the zinc powder and the iodo-alanine derivative Boc–I–
Ala–OMe (1.2 to 4 eq.) was added in one portion to the rapidly
stirred suspension under nitrogen. An exotherm was typically
observed during the zinc insertion process, which was controlled
with the aid of a water bath at room temperature. The zinc
insertion can be monitored by TLC (80% Et2O–petroleum ether).
Aryl iodide (1 eq.), Pd2(dba)3 (3 mol%) and P(o-Tol)3 (12 mol%)
were added to the stirred suspension at room temperature and
the mixture stirred overnight. The suspension was filtered through
silica gel, eluted with ethyl acetate and the solvent removed under
reduced pressure to afford the crude reaction mixture which was
purified by column chromatography.
Experimental
All moisture/air sensitive reactions were conducted under a
positive pressure of nitrogen in flame dried or oven dried glassware.
All reagents used were purchased from commercial sources or
prepared and purified according to literature procedure. Dry
˚
DMF was distilled from calcium hydride and stored over 4 A
molecular sieves. Dry dichloromethane was distilled from calcium
hydride. Dry THF was distilled from potassium benzophenone
ketyl. Petroleum ether refers to the fraction with a boiling point
between 40–60 ◦C.
Nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker AC-250, Bruker AMX2–400 or a Bruker DRX-500
NMR spectrometer at room temperature. Chemical shifts were
measured relative to residual solvent and are expressed in parts
per million (d). Coupling constants (J) are given in Hertz and
the measured values are rounded to one decimal place. High-
resolution mass spectra were recorded using a MicroMass LCT
operating in electrospray (ES) mode or a MicroMass Prospec
operating in either electro impact (EI) or chemical ionisation (CI)
mode. Chemical analyses were performed using a Perkin Elmer
2400 CHN elemental analyser. Optical rotations were measured
on a Perkin Elmer 241 automatic polarimeter at k 589 nm (Na,
D-line) with a path length of 1 dm at the stated temperature
and concentrations. The concentration is given in g per 100 ml
and the optical rotations are quoted in 10−1 deg cm2 g−1. Infra-
General procedure 3: zinc-activation and insertion into C–I bond
using Me3SiCl as the activating agent
The general procedure 2 was followed, except that after zinc
insertion, the stirred suspension was allowed to settle, and the
solution transferred to a second flask which contained a stirred
mixture of the aryl iodide (1 eq.), Pd2(dba)3 (3 mol%) and P(o-Tol)3
(12 mol%) at room temperature under a nitrogen atmosphere,
and was stirred overnight. The suspension was filtered through
silica gel, eluted with ethyl acetate and the solvent removed under
reduced pressure to afford the crude reaction mixture which was
purified by column chromatography.
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2ꢀ-Benzyloxybiphenyl-2-ol
ether) gave the iodophenol derivative 3a (540 mg, 98%) as a viscous
yellow oil tmax(film)/cm−1 3050, 2995, 1761 and 1182; dH (400 MHz;
CDCl3) 1.99 (3 H, s, OAc), 5.06 (2 H, s, CH2Ph), 6.93 (1 H, d, J
8.5, Ar), 6.98–7.03 (2 H, m, Ar), 7.20 (1 H, dd, J 7.5 and 2.0, Ar),
7.27–7.34 (6 H, m, Ar), 7.68 (1 H, dd, J 8.5, J 2.0, Ar) and 7.74
(1 H, d, J 2.0, Ar); dC (100 MHz; CDCl3) 20.7, 70.5, 89.7, 113.2,
120.9, 124.4, 125.7, 126.9, 127.6, 128.4, 129.5, 130.9, 134.0, 136.9,
137.2, 140.3, 148.4, 155.5 and 168.9; m/z (EI) 444 (M+, 12%), 402
(M+–Ac, 12) and 91 (100) (found M+ 444.0205. C21H17O3I requires
444.0222).
Using the conditions originally reported for an analogous trans-
formation by Oda,47 a solution of benzyl bromide (1.91 ml,
16.2 mmol) in dry THF (75 ml) was added dropwise to a stirred
suspension of 2,2ꢀ-biphenol (3.00 g, 16.1 mmol) and KOtBu (1.81 g,
16.2 mmol) in dry THF (300 ml) over a period of 10 min at room
temperature, under an atmosphere of nitrogen. The suspension
was heated at reflux for 14 h and the reaction was cooled to room
temperature and concentrated under reduced pressure. The brown
residue was partitioned between CH2Cl2 and a saturated aqueous
solution of Na2CO3. The organic layer was separated, washed with
brine and dried over MgSO4. The solvent was evaporated under
reduced pressure to give a brown solid (4.44 g), which was purified
by crystallization from methanol–water to give the benzyl mono-
protected biphenol (4.22 g, 95%) as yellow crystals. Mp 97–98 ◦C
(methanol–water). (Found: C, 82.7; H, 5.6. C19H16O2 requires C,
82.6; H, 5.8%); tmax(film)/cm−1 3380, 3062, 1209; dH (400 MHz;
CDCl3) 5.12 (2 H, s, CH2Ph), 6.33 (1 H, s, OH), 7.02 (2 H, br t, J
8.2, Ar), 7.11 (1 H, br d, J 9.0, Ar), 7.15 (1 H, br d, J 9.0, Ar) and
7.26–7.38 (9 H, m, Ar); dC (100 MHz; CDCl3) 71.7, 114.3, 117.4,
120.9, 122.7, 126.3, 127.2, 128.0, 128.1, 128.5, 129.2 (×2), 131.2,
132.6, 135.9, 153.6 and 154.7; m/z (EI) 276 (M+, 60%), 91 (100)
(found M+ 276.1149. C19H16O2 requires 276.1150).
(2S)-tert-Butoxycarbonylamino-3-(2-acetoxy-2ꢀ-
benzyloxybiphenyl-5-yl)propionic acid methyl ester (1a)
Using general procedure 2, compound 3a (1.0 g, 2.25 mmol),
Zn (0.88 g, 13.5 mmol), Boc–I–Ala–OMe (0.89 g, 2.70 mmol),
Pd2(dba)3 (62 mg, 0.067 mmol) and P(o-Tol)3 (82 mg, 0.27 mmol)
in dry DMF (2.70 ml) gave, after purification by column chro-
matography (20% EtOAc–petroleum ether), the biaryl amino
acid 1a (726 mg, 62%) as an oil. [a]2D2 +32.7 (c 1.2 in CHCl3);
tmax(film)/cm−1 3372, 2964, 2924, 1759, 1744, 1713, 1500, 1444,
1362, 1220, 1189, 1011 and 751; dH (500 MHz; CDCl3) 1.39 (9 H, s,
(CH3)3C), 1.97 (3 H, s, OAc), 3.08–3.11 (2 H, m, b), 3.64 (3 H, s,
OMe), 4.58 (1 H, dd, J 13.9 and 6.2, a), 5.00 (1 H, br s, NH),
5.03 (2 H, s, CH2Ph), 6.95 (1 H, d J 8.2, Ar), 6.98 (1 H, td, J
7.5 and 0.9, Ar), 7.09 (1 H, d, J 9.0, Ar), 7.11–7.16 (2 H, m, Ar),
7.17 (1 H, dd J 7.5 and 1.8, Ar) and 7.23–7.30 (6 H, m, Ar);
dC (125 MHz; CDCl3) 20.7, 28.2(×3), 37.6, 52.2, 54.3, 70.5, 79.9,
113.3, 120.9, 122.4, 126.8(×2), 127.0, 127.5, 128.3(×2), 129.1(×2),
131.2, 131.8, 132.5, 133.4, 137.2, 147.5, 155.1, 155.7, 169.2 and
172.2; m/z (ES) 542 (MNa+, 50%) and 420 (100) (found MNa+
542.2162. C30H33NO7Na requires 542.2155).
2ꢀ-Benzyloxy-5-iodobiphenyl-2-ol
Following the procedure originally described by Edgar,49 an aque-
ous solution of NaOCl (4% available chlorine, 6.4 g, 3.6 mmol)
was slowly added over a period of 30 min to a stirred solution of
2ꢀ-benzyloxybiphenyl-2-ol (500 mg, 1.81 mmol), NaOH (72 mg,
1.8 mmol) and NaI (270 mg, 1.8 mmol) in methanol (5 ml) in
an ice bath. When the reaction was judged complete by TLC, a
saturated aqueous solution of Na2S2O3 (5 ml) was added, followed
by 1 M HCl until pH 6–7 was achieved. The mixture was extracted
with EtOAc (3 × 20 ml) and the organic phases combined and
washed with water, brine and dried over MgSO4. The solvent
was evaporated under reduced pressure, and purification by
column chromatography (8% EtOAc–petroleum ether) gave 2ꢀ-
benzyloxy-5-iodobiphenyl-2-ol (653 mg, 90%) as a pale yellow oil.
m(film)/cm−1 3340, 2960, 2920 and 1215; dH (400 MHz; CDCl3)
5.12 (2 H, s, CH2Ph), 6.34 (1 H, s, OH), 6.79 (1 H, d, J 9.0, Ar),
7.09–7.16 (2 H, m, Ar), 7.24–7.28 (2 H, m, Ar), 7.29–7.34 (4 H,
m, Ar), 7.35–7.40 (1 H, m, Ar) and 7.52–7.57 (2 H, m, Ar); dC
(100 MHz; CDCl3) 71.8, 82.9, 114.3, 119.7, 122.8, 126.5, 127.3,
128.4, 128.6, 128.8, 129.8, 132.3, 135.6, 137.8, 139.5, 153.7 and
154.5; m/z (ES) 401 ((M–H)−, 30%) (found (M–H)− 401.0029.
C19H14O2I requires 401.0039).
(2S)-tert-Butoxycarbonylamino-3-(2-acetoxybiphen-2ꢀ-ol-5-yl)-
propionic acid methyl ester (1b) and (2S)-tert-butoxycarbonyl-
amino-3-(2ꢀ-acetoxybiphen-2-ol-5-yl)propionic acid methyl
ester (1c)
A degassed suspension of the amino acid 1a (0.5 g, 0.96 mmol) in
ethyl acetate (30 ml), Pd/C (10% on carbon, 50 mg) and 3 drops
of acetic acid, under an atmosphere of hydrogen gas (balloon),
was vigorously stirred until the reaction was judged complete by
R
TLC analysis. The reaction mixture was filtered through Celiteꢀ
and concentrated under reduced pressure. The crude mixture
was purified by column chromatography (20% EtOAc–petroleum
ether) to give isomeric phenols 1b and 1c (314 mg, 76% yield) as a
mixture. tmax(film)/cm−1 3361, 2954, 2924, 1749, 1708, 1505, 1362,
1260, 1194, 1164, 1021 and 802; dH (500 MHz; CDCl3) (X : Y ratio
40 : 60) 1.34 (9 H, s, (CH3)3C, Y), 1.39 (9 H, s, (CH3)3C, X), 1.98 (3
H, s, OAc, Y), 2.02 (3 H, s, OAc, X), 2.91 (1 H, dd, J 13.7 and 7.5,
b, Y), 2.95 (1 H, dd, J 13.9 and 5.6, b, X), 3.03 (1 H, dd, J 13.9 and
5.7, b, X), 3.16 (1 H, dd, J 13.7 and 4.2, b, Y), 3.65 (3 H, s, OMe,
X), 3.67 (3 H, s, OMe, Y), 4.48–4.53 (1 H, m, a, X), 4.56–4.64 (1 H,
m, a, Y), 5.06 (1 H, br s, NH, X), 5.19 (1 H, br s, NH, Y), 6.83–6.67
(1 H, m, Ar, Y), 6.89 (1 H, t, J 7.5, Ar, Y), 6.92–6.99 (1 H, m, Ar, X
and Y), 7.05–7.09 (1 H, m, Ar, X and Y), 7.11–7.24 (2 H, m, Ar, Y),
7.11–7.24 (3 H, m, Ar, X), 7.26–7.33 (1 H, m, Ar, X and Y) and 7.38
(1 H, t, J 7.8, Ar, X); dC (125 MHz; CDCl3) (ratio 40 : 60) 20.5, 28.1,
37.1, 38.1, 52.1, 52.4, 54.3, 54.5, 79.8, 80.0, 116.2, 116.3, 119.6,
2-Acetoxy-2ꢀ-benzyloxy-5-iodobiphenyl (3a)
An excess of Ac2O (2 ml) was added dropwise to a stirred
solution of 2ꢀ-benzyloxy-5-iodobiphenyl-2-ol (500 mg, 1.24 mmol)
in pyridine (3 ml) and was left to stir overnight. EtOAc (20 ml) and
water (30 ml) were added and the mixture separated. The aqueous
phase was extracted with EtOAc (20 ml) and the combined organic
phases were washed with 1 M HCl (30 ml), saturated aqueous
NaHCO3 (30 ml), water and brine. The organic layer was dried
over MgSO4 and the solvent evaporated under reduced pressure.
Purification by column chromatography (30% Et2O–petroleum
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122.7, 122.8, 123.4, 124.0, 126.4, 127.4, 129.2, 129.4, 130.1, 130.2,
131.5, 131.6, 132.7, 134.3, 147.5, 148.5, 152.2, 153.3, 155.0, 169.7,
172.1 and 172.2; m/z (ES) 881 (M2Na+, 30%) and 452 (MNa+,
100) (found MNa+ 452.1692. C23H27NO7Na requires 452.1685).
8.03 mmol) was added dropwise to a stirred solution of 2,2ꢀ-
biphenol (0.50 g, 2.68 mmol) and KOtBu (0.66 g, 5.90 mmol)
in THF (30 ml) at room temperature, under an atmosphere of
nitrogen. The stirred suspension was heated at reflux for 14 h
and the reaction was then cooled to room temperature and
concentrated under reduced pressure. The brown residue was
partitioned between CH2Cl2 and a saturated aqueous solution of
Na2CO3. The organic layer was separated, washed with brine and
dried over MgSO4. The solvent was evaporated under reduced
pressure to give, without the need for further purification, the
dibenzyl protected biphenol58 5 (0.90 g, 92%) as a white solid. Mp
(2S)-tert-Butoxycarbonylamino-3-(2,2ꢀ-biphenol-5-yl)propionic
acid methyl ester (1d)
K2CO3 (0.50 g, 3.62 mmol) was added to a stirred solution of the
mixture of phenols 1b and 1c (0.53 g, 1.23 mmol) in methanol
(20 ml) at room temperature. The reaction was stirred overnight at
this temperature and quenched by the addition of EtOAc (20 ml)
and water (30 ml). The layers were separated and the aqueous
phase extracted with EtOAc (20 ml). The organic phases were
combined and washed with 1 M HCl (30 ml), saturated aqueous
NaHCO3 (30 ml), water and brine. The organic layer was dried
over MgSO4 and the solvent removed under reduced pressure.
Purification by column chromatography (40% EtOAc–petroleum
ether) gave the biphenol 1d (433 mg, 91% yield) as a viscous oil.
[a]D22 +34.6 (c 1.0 in CHCl3); tmax(film)/cm−1 3343, 2972, 2918, 1738,
1679, 1503, 1489, 1362, 1226 and 1163; dH (500 MHz; CDCl3) 1.37
(9 H, s, (CH3)3C), 2.93 (1 H, dd, J 13.9 and 6.7, b), 3.07 (1 H,
dd, J 13.9 and 5.3, b), 3.79 (3 H, s, OMe), 4.51–4.58 (1 H, m, a),
5.19 (1 H, d, J 8.2, NH) and 6.96–7.27 (9 H, m, Ar and ArOH);
dC (125 MHz; CDCl3) 28.2(×3), 37.5, 52.4, 54.6, 80.5, 116.9(×2),
121.1, 124.8, 125.2, 128.3, 129.3, 130.0, 131.3, 132.4, 152.1, 153.0,
155.4 and 172.6; m/z (ES) 410 (MNa+, 50%) and 288 (100) (found
MNa+ 410.1566. C21H25NO6Na requires 410.1580).
◦
100–102 C; tmax(film)/cm−1 3065, 3016, 2919, 2852, 1592, 1500,
1481, 1442, 1263, 1224, 1021, 749 and 696; dH (250 MHz; CDCl3)
5.07 (4 H, s, CH2Ph), 7.03 (2 H, dd, J 8.2 and 0.9, Ar), 7.11 (2 H,
td, J 7.3 and 0.9, Ar), 7.26 (8 H, br s, Ar) and 7.32–7.44 (6 H, m,
Ar); dC (62.5 MHz; CDCl3) 70.2, 113.0, 120.8, 126.6, 127.4, 128.3,
+
128.5, 128.6, 131.7, 137.6 and 156.3; m/z (CI) 384 (M + NH4 ,
8%), 367 (MH+, 10), 289, 275, 216, 199, 108 and 91 (100).
2,2ꢀ-Dibenzyloxy-5,5ꢀ-diiodobiphenyl (3b)
Following general procedure 1, dibenzyl protected biphenol 5
(0.40 g, 1.09 mmol), benzyltrimethylammonium dichloroiodate
(0.836 g, 2.40 mmol) and ZnCl2 (1.6 g, 11.7 mmol) in acetic acid
(24 ml) gave, after purification by column chromatography (10%
EtOAc–petroleum ether), the diiodo dibenzyl biphenol derivative
3b (506 mg, 75%) as a white solid. Mp 144–146 ◦C; tmax(film)/cm−1
3025, 2916, 2847, 1494, 1450, 1252, 1242, 1144, 1005, 798, 733 and
694; dH (250 MHz; CDCl3) 4.98 (4 H, s, CH2Ph), 6.73 (2 H, d, J 8.2,
Ar), 7.16–7.30 (10 H, m, Ar), 7.55 (2 H, dd, J 8.2 and 2.1, Ar) and
7.58 (2 H, s, Ar); dC (62.5 MHz; CDCl3) 70.3, 82.9, 115.0, 126.6,
127.7, 128.5, 129.3, 136.7, 137.6, 139.8 and 156.0; m/z (ES) 641
(MNa+, 100%) and 515 (34) (found MNa+ 640.9457. C26H20O2I2Na
requires 640.9451).
(2S)-tert-Butoxycarbonylamino-3-(2,2ꢀ-diacetoxybiphenyl-5-yl)-
propionic acid methyl ester (1e)
An excess of Ac2O (2 ml) was added dropwise to a stirred solution
of the mixture of phenols 1b and 1c (0.5 g, 1.16 mmol) in pyridine
(3 ml) at room temperature. The reaction was stirred overnight at
this temperature and quenched by the addition of EtOAc (20 ml)
and water (30 ml). The layers were separated and the aqueous
phase extracted with EtOAc (20 ml). The organic phases were
combined and washed with 1 M HCl (30 ml), saturated aqueous
NaHCO3 (30 ml), water and brine. The organic layer was dried
over MgSO4 and the solvent removed under reduced pressure.
Purification by column chromatography (20% EtOAc–petroleum
ether) gave the diacetate 1e (519 mg, 95%) [a]2D2 +33.6 (c 0.5 in
CHCl3); tmax(film)/cm−1 3372, 2964, 2913, 1764, 1708, 1499, 1367,
1194, 1011, 914 and 756; dH (400 MHz; CDCl3) 1.41 (9 H, s,
(CH3)3C), 2.03 (3 H, s, OAc), 2.05 (3 H, s, OAc), 3.06 (1 H, dd,
J 13.9 and 5.9, b), 3.14 (1 H, dd, J 13.9 and 5.8, b), 3.71 (3 H, s,
OMe), 4.55–4.63 (1 H, m, a), 5.05 (1 H, d, J 7.9, NH), 7.04 (1 H,
br s, Ar), 7.08 (1 H, d, J 8.2, Ar), 7.13 (1 H, d, J 7.6, Ar), 7.14–7.17
(1 H, m, Ar), 7.24–7.30 (2 H, m, Ar) and 7.39 (1 H, ddd, J 7.9,
6.7 and 2.3, Ar); dC (125 MHz; CDCl3) 20.7(×2), 28.3(×3), 37.6,
52.3, 54.3, 80.0, 122.5, 122.6, 125.9, 129.0, 129.7, 130.3, 130.5,
131.1, 132.2, 133.7, 147.1, 148.0, 155.0, 169.3(×2) and 172.1; m/z
(ES) 494 (MNa+, 100%) and 372 (30) (found MNa+ 494.1782.
C25H29NO8Na requires 494.1791).
5,5ꢀ-Diiodo-2,2ꢀ-biphenol (3c) with ∼10% 5-chloro-5ꢀ-iodo-2,2ꢀ-
biphenol (3cꢀ)
Following general procedure 1, 2,2ꢀ-biphenol (0.40 g, 2.15 mmol),
benzyltrimethylammonium dichloroiodate (1.64 g, 4.71 mmol)
and ZnCl2 (1.6 g, 11.7 mmol) in acetic acid (24 ml) gave, after
purification by column chromatography (20% EtOAc–petroleum
ether), diiodo biphenol 3c (0.772 g, 82%), contaminated with
∼10% 5-chloro-5ꢀ-iodo-2,2ꢀ-biphenol 3cꢀ. tmax(film)/cm−1 3155
(br), 1474, 1382, 1222, 1180, 1111, 1015 and 877; dH (250 MHz;
CD3OD) 5.12 (2 H, br s, OH), 6.73 (2 H, d, J 8.5, Ar) and 7.45–7.57
(4 H, m, Ar); dC (62.5 MHz; CD3OD) 80.6, 117.9, 127.1, 137.2,
139.3 and 153.9; m/z (EI) 438 (M+(3c), 100%) and 346 (M+(3cꢀ),
10%) (found M+ 437.862264. C12H8O2I2 requires 437.861384).
2,2ꢀ-Acetoxy-5,5ꢀ-diiodobiphenyl (3d) with ∼10% 2,2ꢀ-acetoxy-5-
chloro-5ꢀ-iodobiphenyl (3dꢀ)
Acetic anhydride (2.0 ml, 21 mmol) was added dropwise to a
stirred solution of the diiodo biphenol 3c (0.50 g, 1.14 mmol) in
pyridine (3 ml), and the solution allowed to stir for 16 h. EtOAc
(20 ml) and water (30 ml) were added to the reaction mixture.
The layers were partitioned, separated and the aqueous phase
washed with EtOAc (20 ml). The combined organic fractions
were washed with 1 M HCl (30 ml), saturated aqueous NaHCO3
2,2ꢀ-Dibenzyloxybiphenyl (5)
Modifying the conditions originally reported by Oda for mono-
benzylation of a binaphthol derivative,47 benzyl bromide (0.96 ml,
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(30 ml), water and brine. The organic fraction was dried over
MgSO4 and the solvent evaporated under reduced pressure to
give, after purification by column chromatography (30% EtOAc–
petroleum ether), the diacetate protected biphenol derivative
3d (566 mg, 95%), contaminated with ∼10% 2,2ꢀ-acetoxy-5-
chloro-5ꢀ-iodobiphenyl (3dꢀ) as a white solid. Mp 119–123 ◦C;
tmax(film)/cm−1 3508, 3327, 3064, 2919, 2847, 1762, 1490, 1468,
1368, 1205, 1182, 1114, 1019 and 906; dH (250 MHz; CDCl3) 2.06
(6 H, s, OAc), 6.92 (2 H, d, J 8.5, Ar), 7.62 (2 H, d, J 2.1, Ar) and
7.70 (2 H, dd, J 8.5 and 2.1, Ar); dC (62.5 MHz; CDCl3) 20.7, 89.9,
124.7, 131.2, 138.3, 139.6, 147.9 and 168.8; m/z (EI) 522 (M+(3d),
21%), 430 (M+(3dꢀ), 2); m/z (ES) 545 (MNa+(3d), 100%) (found
MNa+ 544.8714. C16H12O4I2Na requires 544.8723).
bonyl-ethyl]biphenyl-5-yl}propionic acid methyl ester (2a) (68 mg,
22%) as an oil [a]D22 +37.2 (c 2.0 in CHCl3); tmax(film)/cm−1 3367,
2974, 2916, 1745, 1712, 1497, 1362, 1249, 1220, 1166 and 1016;
dH (500 MHz; CDCl3) 1.39 (18 H, s, (CH3)3C), 3.05 (4 H, d, J
5.8, b), 3.65 (6 H, s, OMe), 4.53–4.58 (2 H, m, a), 4.97 (4 H, s,
CH2Ph), 5.01 (2 H, br s, NH), 6.88 (2 H, d, J 8.2, Ar), 7.02–
7.07 (4 H, m, Ar), 7.10–7.19 (4 H, m, Ar) and 7.20–7.28 (6 H,
m, Ar); dC (125 MHz; CDCl3) 28.2(×3), 37.5, 52.1, 54.5, 70.3,
79.8, 130.0, 126.5(×2), 127.3, 127.9, 128.3(×2), 128.5, 129.2,
132.3, 137.4, 155.1, 155.3 and 172.5; m/z (ES) 791.6 (MNa+,
100%) and 769.6 (MH+, 45) (found MH+ 769.3699. C44H53N2O10
requires 769.3700), and the homo-coupled compound (2S,5S)-
2,5-bis-tert-butoxycarbonylaminohexane-1,6-dioic acid dimethyl
ester (8) (31 mg, 8%) as an oil tmax(film)/cm−1 3361, 2968, 2925,
1742, 1712, 1515, 1362, 1249, 1161 and 1057; dH (500 MHz; CDCl3)
1.42 (18 H, s, (CH3)3C), 1.57–1.68 (2 H, m, b), 1.84–1.93 (2 H, m,
b), 3.72 (6 H, s, OMe), 4.26–4.35 (2 H, m, a) and 5.03 (2 H, d, J
7.8, NH); dC (125 MHz; CDCl3) 28.2, 28.8, 52.4, 52.9, 80.0, 155.3
and 172.8; m/z (ES) 427 (MNa+, 100%) and 405 (MH+, 40) (found
MH+ 405.2221. C18H33N2O8 requires 405.2237).
Table 1, entry 1
Following
general
procedure
2,
2,2ꢀ-dibenzyloxy-5,5ꢀ-
diiodobiphenyl 3b (250 mg, 0.40 mmol), Zn (320 mg, 4.89 mmol),
Boc–I–Ala–OMe (320 mg, 0.97 mmol), Pd2(dba)3 (11 mg,
0.012 mmol) and P(o-Tol)3 (15 mg, 0.048 mmol) in dry DMF
(0.97 ml) gave, after purification by column chromatography
(gradient 10–20% EtOAc–petroleum ether), the mono-coupled
products 6a, 6b and 6c as a mixture, and the bis- and homo-
coupled products 2a and 8 also as a mixture. Compounds 6a and
6b were separated from 6c by column chromatography (2% Et2O–
petroleum ether) to give (2S)-tert-butoxycarbonylamino-3-(2,2ꢀ-
dibenzyloxy-5ꢀ-iodobiphenyl-5-yl)propionic acid methyl ester
(6a) and (2S)-tert-butoxycarbonylamino-3-(2,2ꢀ-dibenzyloxy-5ꢀ-
chloro-biphenyl-5-yl)propionic acid methyl ester (6b) as a 80 : 20
mixture (37 mg, 14%) as an oil dH (500 MHz; CDCl3) 1.40 (9 H, s,
(CH3)3C), 3.00–3.10 (2 H, m, b), 3.66 (3 H, s, OMe), 4.51–4.58
(1 H, m, a), 4.95 (2 H, s, CH2Ph), 4.97 (2 H, s, CH2Ph), 4.99 (1
H, br s, NH), 6.69 (1 H, d, J 8.6, Ar), 6.88 (1 H, d, J 8.5, Ar),
7.00–7.07 (3 H, m, Ar), 7.12–7.26 (9 H, m, Ar), 7.53 (1 H, dd,
J 8.6 and 2.3, Ar) and 7.56 (1 H, d, J 2.3, Ar); dC (125 MHz;
CDCl3) 28.3, 37.4, 52.1, 54.5, 70.2, 70.3, 79.9, 82.9, 112.8, 115.1,
126.5, 126.6, 127.0, 127.4, 127.5, 128.0(×2), 128.3(×2), 126.6,
130.9, 132.3, 136.9(×2), 137.2, 139.8, 155.2, 156.1 and 172.4; m/z
(ES) 716 (MNa+ (6a), 100%) and 624 (MNa+ (6b), 30%) (found
MNa+ (6a) 716.1461. C35H36NIO6Na requires 716.1485) and
(found MNa+ (6b) 624.2133. C35H36NClO6Na requires 624.2129),
and (2S)-tert-butoxycarbonylamino-3-(2,2ꢀ-dibenzyloxybiphenyl-
5-yl)propionic acid methyl ester (6c) (43.5 mg, 19%) as an oil. [a]D22
+46.5 (c 0.4 in CHCl3); tmax(film)/cm−1 3423, 2915, 2849, 1739,
1711, 1495, 1448, 1363, 1222, 1161, 1016 and 734; dH (500 MHz;
CDCl3) 1.40 (9 H, s, (CH3)3C), 3.02–3.11 (2 H, m, b), 3.66 (3 H, s,
OMe), 4.54–4.58 (1 H, m, a), 4.97 (1 H, br s, NH), 4.98 (2 H, s,
CH2Ph), 5.00 (2 H, s, CH2Ph), 6.89 (1 H, d, J 8.2, Ar), 6.96 (1 H,
br d, J 7.8, Ar), 7.00–7.08 (4 H, m, Ar), 7.14–7.19 (3 H, m, Ar),
7.19–7.23 (5 H, m, Ar) and 7.28–7.30 (3 H, m, Ar); dC (125 MHz;
CDCl3) 28.3(×3), 37.4, 52.1, 54.5, 70.2(×2), 79.8, 112.9, 120.7,
126.5(×3), 126.6(×3), 127.3, 127.8(×2), 128.4(×4), 128.6, 128.7,
128.8, 129.1, 131.4, 132.5, 137.5, 155.4(×2), 156.2 and 172.5; m/z
(ES) 590 (MNa+, 50%) and 534 (100) (found MNa+ 590.2545.
C35H37NO6Na requires 590.2519).
Table 1, entry 2
Following general procedure 2, diiodo diacetate biphenol deriva-
tive 3d (250 mg, 0.48 mmol), Zn (187 mg, 2.86 mmol), Boc–I–
Ala–OMe (188 mg, 0.57 mmol), Pd2(dba)3 (13 mg, 0.014 mmol)
and P(o-Tol)3 (17 mg, 0.057 mmol) in dry DMF (0.57 ml)
gave, after purification by column chromatography (gradient
20–30% EtOAc–petroleum ether), the mono-coupled products
1e, 7b and the homo-coupled product 8 as a mixture, and
the bis-coupled product (2S)-tert-butoxycarbonylamino-3-{2,2ꢀ-
diacetoxy-5ꢀ -[(2S)-tert-butoxycarbonylamino-2-methoxycarbo-
nylethyl]biphenyl-5-yl}propionic acid methyl ester (2b) (116 mg,
36%) as an oil [a]D22 +46.5 (c 1.0 in CHCl3); tmax (film)/cm−1 3370,
2979, 2928, 1760, 1749, 1708, 1500, 1365, 1195, 1165, 1055, 1012
and 910; dH (500 MHz; CDCl3) 1.40 (18 H, s, (CH3)3C), 2.02 (6 H,
s, OAc), 3.03 (2 H, dd, J 13.8 and 6.2, b), 3.11 (2 H, dd, J 13.8 and
5.5, b), 3.69 (6 H, s, OMe), 4.54–4.59 (2 H, m, a), 5.05 (2 H, br d, J
7.5, NH), 7.00 (2 H, br s, Ar), 7.05 (2 H, d, J 8.2, Ar) and 7.15 (2 H,
br d, J 8.2, Ar); dC (125 MHz; CDCl3) 14.1, 28.2(×3), 37.6, 52.3,
54.3, 80.0, 122.5, 129.8, 130.3, 132.0, 133.8, 147.1, 155.1, 169.3
and 172.1; m/z (ES) 695 (MNa+, 1%), 673 (MH+, 18) and 517
(100) (found MNa+ 695.2761. C34H44N2O12Na requires 695.2792).
The mixture of compounds 1e, 7b and 8 was separated by a sec-
ond chromatography column (8% Et2O–petroleum ether), which
gave the mono-coupled product (2S)-tert-butoxycarbonylamino-
3-(2,2ꢀ-diacetoxy-5ꢀ-chloro-biphenyl-5-yl)propionic acid methyl
ester (7b) (9.5 mg, 4%) as an oil [a]2D2 +53.7 (c 0.9 in CHCl3);
tmax(film)/cm−1 3375, 2980, 2923, 1759, 1711, 1499, 1364, 1191,
1042, 1008, 907 and 734; dH (500 MHz; CDCl3) 1.41 (9 H, s,
(CH3)3C), 2.03 (3 H, s, OAc), 2.05 (3 H, s, OAc), 3.05 (1 H, dd,
J 13.9 and 6.0, b), 3.14 (1 H, dd, J 13.9 and 6.0, b), 3.71 (3 H, s,
OMe), 4.55–4.61 (1 H, m, a), 5.04 (1 H, d, J 7.8, NH), 7.02 (1 H,
d, J 1.8, Ar), 7.07 (1 H, d, J 8.6, Ar), 7.08 (1 H, d, J 8.4, Ar),
7.16 (1 H, dd, J 8.4 and 1.8, Ar), 7.26 (1 H, d, J 2.6, Ar) and
7.34 (1 H, dd, J 8.6 and 2.6, Ar); dC (125 MHz; CDCl3) 20.6, 20.7,
28.3(×3), 37.6, 52.4, 54.3, 80.1, 122.7, 123.8, 128.9, 129.1, 130.2,
130.9, 131.2, 131.9, 134.0(×2), 146.6, 146.9, 155.0, 169.1(×2) and
172.0; m/z (ES) 528 (MNa+, 90%), 506 (MH+, 34) and 406 (100)
The mixture of compounds 2a and 8 was separated by a second
chromatography column (8% Et2O–petroleum ether), which gave
the bis-coupled product (2S)-tert-butoxycarbonylamino-3-{2,2ꢀ-
dibenzyloxy-5ꢀ -[(2S)-tert-butoxycarbonylamino-2-methoxycar-
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(found MNa+ 528.1388. C25H28NO8ClNa requires 528.1401), the
mono-coupled product 1e (34 mg, 15%) and the homo-coupled
product 8 (9 mg, 4%) as oils, all spectroscopically consistent with
the data already reported.
3 C. Monti, C. Gennari, U. Piarulli, J. G. de Vries, A. H. M. de Vries and
L. Lefort, Chem.–Eur. J., 2005, 11, 6701 and references therein.
4 S. O. Andersen, Biochim. Biophys. Acta, 1964, 93, 213.
5 S. C. Fry, Biochem. J., 1982, 204, 449.
6 S. C. Fry, Methods Enzymol., 1984, 107, 388.
7 D. Fujimoto, K. Horiuchi and M. Hirama, Biochem. Biophys. Res.
Commun., 1981, 99, 637.
8 J. D. Brady, I. H. Sadler and S. C. Fry, Phytochemistry, 1998, 47,
349.
9 J. D. Brady, I. H. Sadler and S. C. Fry, Biochem. J., 1996, 315, 323.
10 A. J. Gross and I. W. Sizer, J. Biol. Chem., 1959, 234, 1611.
11 F. S. LaBella, P. Waykole and G. Queen, Biochem. Biophys. Res.
Commun., 1968, 30, 333.
12 F. S. LaBella, F. W. Keeley, S. Vivian and D. P. Thornhill, Biochem.
Biophys. Res. Commun., 1967, 26, 748.
13 R. Aeschbach, R. Amado` and H. Neukom, Biochim. Biophys. Acta,
1976, 439, 292.
14 T. Deits, M. Farrance, E. S. Kay, L. Medill, E. E. Turner, P. J. Weidman
and B. M. Shapiro, J. Biol. Chem., 1984, 259, 13525.
15 K. Nomura, N. Suzuki and S. Matsumoto, Biochemistry, 1990, 29,
4525.
Table 1, entry 4
2S-tert-Butoxycarbonylamino-3-(2,2ꢀ-diacetoxy-5ꢀ-iodobiphenyl-
5-yl)propionic acid methyl ester (7a).
A pure sample of
compound 7a was obtained following general procedure 3, with
diiodo diacetate biphenol derivative 3d (250 mg, 0.48 mmol), Zn
(187 mg, 2.86 mmol), Boc–I–Ala–OMe (188 mg, 0.57 mmol),
Pd2(dba)3 (13 mg, 0.014 mmol) and P(o-Tol)3 (17 mg, 0.057 mmol)
in dry DMF (0.57 ml) which gave, after purification by column
chromatography (gradient 20–30% EtOAc–petroleum ether), the
mono-coupled product 7a (72 mg, 25%) as an oil [a]2D2 +33.1
(c 0.7 in CHCl3); tmax(film)/cm−1 3377, 2969, 2919, 1760, 1711,
1494, 1478, 1365, 1195, 1007 and 912; dH (500 MHz; CDCl3) 1.41
(9 H, s, (CH3)3C), 2.03 (3 H, s, OAc), 2.06 (3 H, s, OAc), 3.05
(1 H, dd, J 13.9 and 6.0, b), 3.14 (1 H, dd, J 13.9 and 5.5, b), 3.71
(3 H, s, OMe), 4.55–4.61 (1 H, m, a), 5.04 (1 H, br d, J 8.1, NH),
6.89 (1 H, d, J 8.6, Ar), 7.01 (1 H, br s, Ar), 7.08 (1 H, d, J 8.2,
Ar), 7.16 (1 H, br d, J 8.2, Ar), 7.59 (1 H, d, J 2.2, Ar) and 7.68
(1 H, dd, J 8.6 and 2.2, Ar); dC (125 MHz; CDCl3) 20.6, 20.7,
28.3(×3), 37.6, 52.3, 54.3, 80.1, 89.8, 122.7, 124.5, 128.9, 130.2,
131.9, 132.7, 134.0, 137.9, 139.7, 146.9, 148.0, 155.0, 168.9, 169.1
and 172.0; m/z (ES) 620 (MNa+, 100%) (found MNa+ 620.0742.
C25H28NO8INa requires 620.0757). The bis-coupled product 2b
(61 mg, 19%) and the homo-coupled product 8 (15 mg, 6%) were
also obtained as oils and spectroscopically consistent with the
data already reported.
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Table 1, entry 5
Following general procedure 3, diiodo diacetate biphenol deriva-
tive 3d (250 mg, 0.48 mmol), Zn (0.62 g, 9.48 mmol), Boc–I–Ala–
OMe (0.62 g, 1.91 mmol), Pd2(dba)3 (13 mg, 0.014 mmol) and
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We thank Dr R. J. Butlin and Dr P. D. Kemmitt (Astra Zeneca,
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partial funding of a studentship (Luca Nolasco) and the European
Commission for the award of a Marie Curie Fellowship (to
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referee for a helpful review.
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