Preparation of enantiomerically pure pyridyl amino acids from serine.

Article abstract of DOI:10.1039/b308750f

A range of substituted pyridyl amino acids have been prepared by palladium catalysed cross-coupling of serine-derived organozinc reagents with differently substituted halopyridines. Following this procedure a DMAP analogue has been synthesised and used as

Full text of DOI:10.1039/b308750f

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Preparation of enantiomerically pure pyridyl amino acids from
serine
Stefania Tabanella,a Ingrid Valancogneb and Richard F. W. Jackson*a
a Department of Chemistry, Dainton Building, The University of Sheffield, Sheffield,
UK S3 7HF. E-mail: r.f.w.jackson@shef.ac.uk
b Department of Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne,
UK NE1 7RU
Received 28th July 2003, Accepted 23rd September 2003
First published as an Advance Article on the web 15th October 2003
A range of substituted pyridyl amino acids have been prepared by palladium catalysed cross-coupling of
serine-derived organozinc reagents with differently substituted halopyridines. Following this procedure a DMAP
analogue has been synthesised and used as a building block in the preparation of two related tripeptides, which
have been tested as catalysts in the kinetic resolution of trans-2-(N-acetylamino)cyclohexan-1-ol, resulting in
modest enantioselectivity.
for performing both the insertion reaction and the subsequent
Introduction
coupling.20 The organozinc reagents were prepared using com-
mercial zinc dust activated sequentially with 1,2-dibromo-
ethane and TMSCl in dry DMF,28 or with zinc activated using
iodine in the absence of solvent. The use of zinc activated with
iodine allows complete zinc reagent formation within 2 hours at
room temperature, as well as the use of smaller amounts of
solvent. Cross-coupling reactions of the zinc reagents 2 with
bromopyridine derivatives were performed using bis(triphenyl-
phosphine)palladium dichloride as catalyst, and gave the
desired pyridyl amino acid derivatives 3–9 in consistent yields
ranging from 40 to 60% (Scheme 1, Table 1).
Pyridylalanines (Fig. 1) and substituted analogues are extremely
interesting because of their use as components of bioactive
compounds and as chiral building blocks in organic synthesis.
They have been studied for several pharmaceutical appli-
cations,1,2 including use as components of anti-inflammatory3
and antitumour agents.4 There is therefore an ongoing interest
in developing good routes for the synthesis of these com-
pounds. In the last ten years, several approaches to the synthesis
of pyridylalanines have been reported, including catalytic
asymmetric hydrogenation,5 enzymatic resolution6,7 and the use
of chiral auxiliaries.8
Fig. 1
Scheme 1 Reagents and conditions: i, activated Zn; ii Pd(PPh3)2Cl2
Some time ago, we reported the synthesis of protected
2-pyridylalanine by the palladium catalysed coupling of a
serine-derived organozinc reagent with 2-bromopyridine.9 The
organozinc reagent was prepared from the corresponding
iodoalanine-derivative by treatment with a Zn/Cu couple using
ultrasonic irradiation. This approach has since been success-
fully adapted and employed by several groups for the synthesis
of other pyridylalanine derivatives,10–15 and extended to the
synthesis of related heterocyclic derivatives.16,17
(5.4 mol%), electrophile, DMF, rt.
The 2- and 4-bromopyridines are better substrates than
3-bromopyridine in this reaction. Compounds 3b, 4b and 5b
have been prepared by Walker et al.10 using the same approach
and the same trend was observed. Indeed, 2,5-dibromopyridine
gave 6, the product of coupling at the 2-position, with none of
the other compounds arising from coupling at the 5-position
detected. 2-Amino-6-bromopyridine was successfully employed
as an electrophile to give the adducts 8a and 8b. Although we
had previously demonstrated that anilines can be tolerated in
cross-coupling reactions with organozinc reagents,29 the com-
patibility with the substantially more acidic 2-aminopyridine is
noteworthy. Coupling of 2a with 2-amino-5-iodopyridine was
attempted unsuccessfully. Unfortunately, coupling in position
5, as noted previously, is less favourable than in position 2, even
with an iodide rather than a bromide. Finally, hydrolysis of the
ester moiety using LiOH6,30 in a representative number of cases
gave the corresponding carboxylic acids 10–13.
Coupling of 2,6-dibromopyridine with 1 equivalent of either
zinc reagent 2a or 2b gave the corresponding mono-coupled
products, 7a and 7b as the only products isolated, while treat-
ment of 2,6-dibromopyridine with an excess of zinc reagent 15
(derived from iodoalanine 14)31 did give the expected dicoupled
product 16 (10%), along with the mono-coupled product 17
(30%) (Scheme 2). This result suggests that bromopyridyl-
alanines might be useful as starting materials for further
palladium-catalysed coupling reactions.
Different groups have commented,11,19 in short communi-
cations, upon the reliability of the methods available for form-
ation of the organozinc reagents needed for these coupling reac-
tions, and given our recent advances in this area,20–22 we now
report, in full, the results of a systematic study of methods for
the synthesis of a range of substituted pyridylalanine deriv-
atives. In the context of a study to assess the use of pyridyl
amino acids as chiral DMAP analogues,23–26 we have considered
the synthesis of amino-substituted pyridine derivatives, to be
used as components of potentially catalytically active peptides.27
In order to allow maximum flexibility in the incorporation of
these pyridyl amino acids into peptides, we have investigated the
synthesis of both Fmoc and Boc-protected derivatives.
Results and discussion
The key findings from our work are that proper activation of
zinc is essential for efficient formation of zinc reagents from
iodoalanine derivatives, and that DMF is an excellent solvent
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Preparation of pyridylalanines
Electrophile
Zinc reagent
Product
Ar
Protecting group
Yield (%)
2-Bromopyridine
3-Bromopyridine
4-Bromopyridine
2,5-Dibromopyridine
2,5-Dibromopyridine
2,6-Dibromopyridine
2,6-Dibromopyridine
2-Amino-6-bromopyridine
2-Amino-6-bromopyridine
2-Bromo-6-pyrrolidinopyridine
2a
2a
2a
2a
2b
2a
2b
2a
2b
2bb
3aa
4a
5a
6a
6b
7a
7b
8a
8b
9b
2-Pyridyl
3-Pyridyl
4-Pyridyl
5-Bromo-2-pyridyl
5-Bromo-2-pyridyl
6-Bromo-2-pyridyl
6-Bromo-2-pyridyl
6-Amino-2-pyridyl
6-Amino-2-pyridyl
6-Pyrrolidino-2-pyridyl
Fmoc
Fmoc
Fmoc
Fmoc
Boc
Fmoc
Boc
Fmoc
Boc
Boc
57
45
57
60
45
57
52
56
40
50
a The X-ray crystal structure of this compound has been determined.18 b Iodine activation of zinc.
the reaction conditions, and that a substantial amount of
4-chloropyridine was recovered from the reaction mixture.† By
the simple expedient of adding a second equivalent of electro-
phile to the reaction, the yield of 19 could be significantly
improved (36%). The replacement of chloride was performed
by refluxing a solution of 19 in pyrrolidine, which initially gave
the amide 20, which was subsequently converted into the
4-pyrrolidinopyridine 21 on further reaction (47%). While this
compound had a substantial optical rotation, we have not been
able to determine whether any racemisation occurred in its
formation. The higher reactivity of the methyl ester function
towards pyrrolidine means that a different protecting group
regime would be required if the free amino acid corresponding
to the DMAP-analogue 21 is required.
Scheme 2 Reagents and conditions: i, activated Zn; ii Pd(PPh3)2Cl2,
2,6-dibromopyridine, DMF, rt.
Preparation of a DMAP analogue
While the 2-pyrrolidinopyridine 9b is a potential acylation cata-
lyst, it is known that introduction of substituents in the 2- and
6-positions of DMAP analogues results in a very substantial
decrease in their activity as catalysts in acylation reactions. We
therefore identified the 4-chloropyridine derivative 19 as a suit-
able precursor of a DMAP analogue. The chloropyridine 19
could, in principle, be prepared from 3-iodo-4-chloropyridine
18, although the failure of the coupling reaction between zinc
reagent 2a and 2-amino-5-iodopyridine was a cause for con-
cern. 3-Iodo-4-chloropyridine 18 was prepared using a modifi-
cation of a known procedure,32 in which the hydrochloride salt
of 4-chloropyridine was treated directly with 2 equivalents of
LDA at low temperature, followed by quenching with iodine.
This modification obviated the need to isolate volatile, easily
polymerisable 4-chloropyridine. Coupling of zinc reagent 2b
with 18 gave the desired product 19 after overnight reaction at
40 ЊC using Pd(PPh3)2Cl2 as catalyst, albeit in very poor yield
(20%) (Scheme 3). Efforts to improve the yield of this coupling
using more reactive palladium catalysts (including (tBu3P)2Pd
and the combination of 2-(tBu2P)biphenyl with Pd(OAc)2)
proved even less effective, so this is not a problem relating to the
activity of the catalyst. We established that one of the reasons
for the low yield was that the electrophile 18 was not stable to
Scheme
3
Reagents and conditions: i, Pd(PPh3)2Cl2, DMF, rt;
ii, pyrrolidine, reflux, 3 h; iii, pyrrolidine, reflux, 3 d.
Since our purpose was to use this residue as building block,
we checked the catalytic activity of 21 as a nucleophilic catalyst.
As a test reaction we chose the acetylation of 1-methylcyclo-
hexanol 22 to give 23 (Scheme 4). Acetylation of 22 occurs in
the presence of DMAP but not of pyridine.24 GC analyses after
24 hours indicated 79% conversion. As expected, compound 9b
under the same conditions only gave rise to traces of the
acetylated product.
Scheme 4 Reagents and conditions: i, Ac2O, Catalyst 21 or 9b, NEt3, rt.
† The synthesis of pyridylzinc halides by oxidative addition of active
zinc to halopyridines has been reported,41 so we suspect that this is the
cause.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
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Synthesis of catalysts for kinetic resolution
Ϫ50 ЊC. Catalyst 25 under the same conditions shown in Scheme
6 gave 100% yield and no ee. Complete conversion was also
observed by reducing the temperature to Ϫ78 ЊC. Our inter-
pretation of these data is that the DMAP residue confers too
great a catalytic activity upon the tripeptides under the condi-
tions under which they have been tested, with the result that the
catalysts show low selectivity.
In the last ten years there has been growing interest in develop-
ing asymmetric nucleophilic catalysts. A particularly relevant
approach was the tripeptidic system developed by Miller and
co-workers.33–36 Their design involves a catalytically active resi-
due, 3-imidazoylalanine, at the N-terminus. We have therefore
synthesised analogues of Miller’s catalyst, 24 and 25, in which
the N-terminal amino acid was replaced with our DMAP ana-
logue precursor 28. The tripeptide 29 was synthesised using
standard peptide solution coupling conditions, and then treat-
ment with pyrrolidine gave the desired tripeptide 24 (Scheme 5).
This strategy overcame the problem that we had not prepared
the free carboxylic acid corresponding to the DMAP amide
derivative 21. Tripeptide 25, where -proline was replaced by
-proline, was also synthesised following the same procedure.
The overall isolated yields of both 24 and 25 were each around
40%, and while there was no evidence for the presence of dia-
stereoisomers in these reactions, we cannot exclude the possibility
that some epimerisation of the compound occurred under the
conditions of the pyrrolidine displacement reaction. What is
clear, however, is that products 24 and 25 are diastereoisomeric-
ally pure, as judged by their NMR data, and that they are there-
fore also enantiomerically pure since they each contain one non-
labile stereogenic centre (in the methylbenzylamine fragment).
Conclusions
Our approach to the synthesis of pyridyl amino acids has
proved to be efficient and reliable. Cross coupling with a par-
ticularly unreactive electrophile has been investigated and the
DMAP analogue precursor 19 was obtained, albeit in modest
yield. This residue has shown very good activity as a nucleo-
philic catalyst.
Experimental
Unless otherwise stated, NMR spectra were obtained at room
temperature on either a Bruker WP200 (200 MHz), a Jeol
Lambda 500 (500 MHz) or a Bruker AMX 2–400 NMR spec-
trometer (400 MHz). Coupling constants are quoted in Hertz
and chemical shifts in ppm. 1H NMR spectra were recorded in
CDCl3 at 400 and at 500 MHz, reference TMS. 13C NMR spec-
tra were recorded in CDCl3 at 125 and 100 MHz and referenced
to TMS. Mass spectra were obtained using a micromass
Autospec M machine or a Micromass LCT. Peaks due to 79Br
and 35Cl only are recorded. Infrared spectra were measured on
a Nicolet 20 SX instrument or on a Paragon 1000. Elemental
analyses were performed using a Carlo Erba 1106 machine or a
Perkin Elmer 2400 CHN Elemental Analyser. Melting points
were determined on an Agar 600C Heating Stage used in con-
junction with a B300 Prior Laboratory Microscope. A polAAr
2001 instrument or an AA-10 from Optical Activity Ltd at
room temperature was used for obtaining [α]D readings. Optical
rotations are given in 10Ϫ1 deg cm2 gϪ1. Chiral phase HPLC was
carried out on a Beckman System Gold machine attached to a
166 detector, 127 solvent module and 507 autosampler using a
Daicel OD (0.46 cm ꢀ × 25 cm) chiral column. Chiral phase GC
was carried out on a heptakis (2,6-di-O-methyl-3-O-pentyl)-β-
cyclodextrin chiral GC column using a Perkin-Elmer 8500 gas
chromatograph, with H2 as carrier gas at 15 psi. All reaction
solvents were distilled. Petroleum ether refers to the fraction
with a boiling point from 40–60 ЊC. Dry DMF, toluene and
dichloromethane were distilled from calcium hydride. DMF
and toluene were stored over 4 Å molecular sieves. Dry THF
was distilled from potassium benzophenone ketyl. TMSCl was
distilled from and stored over poly(2-vinylpyridine). TsCl was
purified by recrystallisation from chloroform–petroleum. TLC
was performed using Merck silica gel 60 F254 aluminium
backed plates, and were visualised under UV light first, then by
using a ninhydrin solution (approx. 0.1% w/v in ethanol)
followed by warming. Flash chromatography was performed
on BDH silica gel, 0.2–0.5 mm, 30–70 mesh. All organic
extracts were dried using magnesium sulfate and concentrated
under reduced pressure by rotary evaporation. All reactions
requiring anhydrous conditions were conducted under a posi-
tive nitrogen atmosphere in oven-dried glassware using stand-
ard syringe techniques. N-(Fluorenylmethoxycarbonylamino)-
3-iodo-propionic acid t-butyl ester 14 was prepared according
to a known procedure.31 4-Bromopyridine,37 2-amino-6-bromo-
pyridine,38 and 2-bromo-6-pyrrolidinopyridine39 were prepared
by literature methods. Dipeptides 31 and 32 were prepared by
standard methods.
Scheme 5 Reagents and conditions: i, EDCI (1.1 eq.), HOBt (1.1 eq.),
31 or 32, DMF, rt; ii, pyrrolidine, reflux, 3 d.
Both 24 and 25 were tested as asymmetric catalysts in the kin-
etic resolution of racemic trans-aminoacetyl-2-cyclohexanol 26,
with formation of the acetylated product 27, since this was the
process which Miller and co-workers investigated. Catalyst 24
gave 50% yield (based on the amount of acetic anhydride) and
41% ee when used at a level of 0.5 mol% under the conditions
reported in Scheme 6. No enantiomeric excess was observed by
using 1 eq of acetic anhydride and lowering the temperature to
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-para-toluene-
sulfonatepropionic acid methyl ester
Fmoc-serine methyl ester (10 g, 29.3 mmol) was dissolved in
Scheme 6 Reagents and conditions: i, 24 (0.5 mol%), Ac2O (0.1 eq),
0 ЊC.
pyridine (100 cm3) and cooled to Ϫ5 ЊC. para-Toluenesulfonyl
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
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chloride (11.16 g, 58.58 mmol), freshly recrystallised from tolu-
ene–petroleum, was added to the solution. The reaction mix-
ture was left overnight and then poured into ice–water and the
aqueous mixture was extracted into ethyl acetate (50 cm3). The
organic layer was washed with 1 M citric acid (3 × 30 cm3),
saturated sodium bicarbonate (2 × 30 cm3), brine (30 cm3), 1 M
hydrochloric acid (2 × 20 cm3), saturated sodium bicarbonate
(2 × 20 cm3) and brine (3 × 20 cm3). The organic extracts were
finally dried, filtered, and concentrated under reduced pressure.
The compound crystallised when ether was added. The tosylate
was recrystallised from ethanol–petroleum and white crystals
were obtained (13.6 g, 27.45 mmol, 94%); mp 125–127 ЊC;
[α]D ϩ17.6 (c 1 in CH2Cl2); found C 62.7%, H 5.1, N 2.8,
C26H25NO7S requires C 62.9%, H 5.0, N 2.8; νmax (KBr disc)/
cmϪ1: 3450, 3050, 2950, 1720, 1350, 1160; δH (125 MHz, CDCl3)
7.77 (2H, d, J 7.5), 7.75 (2H, d, J 8.0), 7.59 (2H, t, J 8.0), 7.46–
7.39 (2H, m), 7.32 (2H, t, J 7.0), 7.27 (2H, d, J 8.0), 5.62 (1H, d,
J 7.5), 4.56–4.60 (1H, m), 4.44 (1H, dd, JAX 5.5, JAB 10.5), 4.37–
4.33 (2H, m), 4.27 (1H, dd, JBX 4.5, JAB 10.5), 4.18 (1H, t, J 7.5),
3.73 (3H, s), 2.36 (3H, s); δC (500 MHz, CDCl3) 168.6, 155.5,
145.2, 143.7, 143.6, 141.3, 132.2, 129.9, 128.0, 127.8, 127.1,
125.2, 120.0, 67.5, 53.3, 53.1, 46.9, 21.6; m/z (EI) 495 (Mϩ,
35%), 436 (23), 178 (100) 59 (35).
derivative (1 eq.) was dissolved in dry DMF (1.3 cm3 mmolϪ1
)
and transferred via syringe to the reaction mixture, which was
previously cooled to 0 ЊC. Monitoring the reaction by TLC,
petroleum ether–ethyl acetate, 2 : 1, typically showed complete
consumption of the starting material after 90 min.
Palladium-catalysed cross coupling procedure C:
The ice bath was removed and the electrophile (1.33 eq.)
was added to the flask, followed by bis(triphenylphosphine)-
palladium() dichloride (0.054 eq.). The reaction was heated at
different temperatures and periods depending on the electro-
phile and then allowed to cool to room temperature. The mix-
ture was diluted with ethyl acetate, washed with water and brine
and dried. Flash column chromatography on silica gel, with an
appropriate petroleum–ethyl acetate gradient, furnished the
expected protected pyridyl α-amino acid.
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(pyrid-2Ј-yl)propi-
onic acid methyl ester 3a
Coupling of zinc reagent 2a, prepared from iodide 1a (0.31 g,
0.7 mmol) using procedure A, with 2-bromopyridine (89 µl, 0.9
mmol) using procedure C, gave 3a (0.16 g, 57%) as colourless
crystals; mp 98–100 ЊC (from ethanol–petroleum); [α]D ϩ16.3
(c 1 in CH2Cl2); found C 71.8%, H 5.4, N 6.7, C24H22N2O4
requires C 71.6%, H 5.5, N 6.9; νmax (cap. film)/cmϪ1 3337, 3064,
2951, 1722, 1510, 1437, 739; δH (500 MHz, CDCl3) 8.49 (1H, d,
J 4.0), 7.71 (2H, d, J 7.5), 7.58–7.54 (3H, m), 7.35 (2H, t, J 7.5),
7.27 (2H, t, J 7.5), 7.12–7.09 (2H, m), 6.43 (1H, d, J 8.0), 4.79–
4.75 (1H, m), 4.33 (2H, dd, J 3.0, 7.5), 4.20 (1H, t, J 7.5), 3.67
(3H, s), 3.34 (1H, dd, JAX 5.0, JAB 15.0), 3.30 (1H, dd, JBX 6.0,
JAB 15.0); δC (125 MHz, CDCl3) 173.4, 158.5, 157.5, 150.6,
145.3, 142.7, 138.0, 129.0, 128.4, 126.6, 125.1, 123.3, 121.3,
68.5, 54.9, 53.7, 48.6, 40.4; m/z (EI) 402 (Mϩ, 17%), 343 (11),
238 (38), 207 (39), 196 (69), 178 (100), 165 (31).
(2R)-(N-Fluorenylmethoxycarbonylamino)-3-iodopropionic acid
methyl ester 1a
A solution of sodium iodide (8.16 g, 54.4 mmol) in acetone (25
cm3) was added dropwise to a solution of the tosylate (13.5 g,
27.2 mmol) prepared above in acetone (55 cm3), under nitrogen.
The resulting yellow solution was stirred overnight, at room
temperature. The reaction mixture was filtered and the filtrate
was concentrated under reduced pressure. The gum was taken
up with chloroform (150 cm3), washed with water (3 × 80 cm3),
sodium thiosulfate (2 × 50 cm3) and brine (2 × 50 cm3). The
organic layer was dried, filtered and concentrated under
reduced pressure to give a pale-yellow solid. The iodide 1a was
recrystallised from ethanol–petroleum ether to give white crys-
tals, (11.3 g, 92 %); mp 153–154 ЊC (from ethanol–petroleum);
[α]D ϩ5.2 (c 1 in ethyl acetate); found C 50.6%, H 3.7, N 3.0,
C19H18NO4I requires C 50.5%, H 4.0, N 3.1; νmax (KBr disc)/
cmϪ1 3316, 3053, 2944, 1736, 1691, 1537, 1278, 739; δH (500
MHz, CDCl3) 7.77 (2H, d, J 7.5), 7.62 (2H, d, J 7.5), 7.41 (2H,
t, J 7.5), 7.35–7.32 (2H, m), 5.66 (1H, d, J 7.0), 4.65–4.56 (1H,
m), 4.45–4.36 (2H, m), 4.25 (1H, t, J 7.5), 3.83 (3H, s), 3.62–
3.59 (2H, m); δC (125 MHz, CDCl3) 169.8, 155.5, 143.7, 141.1,
127.9, 127.2, 125.2, 120.2, 67.5, 54.2, 53.3, 47.2, 7.49; m/z (EI)
451 (Mϩ, 45%), 392 (35), 323 (30), 228 (27), 178 (100), 165 (80),
59 (30).
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(pyrid-3Ј-yl)-
propionic acid methyl ester 4a
Coupling of zinc reagent 2a, prepared from iodide 1a (0.31 g,
0.7 mmol) using procedure A, with 3-bromopyridine (91 µl, 0.9
mmol) using procedure C, gave 4a (0.13 g, 45%) as pale yellow
solid; mp 40–43 ЊC; [α]D ϩ20.6 (c 1 in CH2Cl2); νmax (KBr disc)/
cmϪ1 3309, 3036, 2949, 1717, 1532, 740; δH (500 MHz, CDCl3)
8.50 (1H, s), 8.38 (1H, s), 7.77 (2H, d, J 7.3), 7.57–7.53 (2H, m),
7.41–7.38 (3H, m), 7.33–7.30 (2H, m), 7.21 (1H, t, J 7.0),
5.34 (1H, d, J 7.5), 4.67 (1H, d, J 7.0), 4.45 (1H, t, J 7.0), 4.38
(1H, t, J 7.0), 4.20 (1H, t, J 7.0), 3.74 (3H, s), 3.16 (1H, dd,
JAX 6.0, JAB 14.0), 3.08 (1H, dd, JBX 5.0, JAB 14.0); δC (125
MHz, CDCl3) 171.5, 155.5, 150.4, 148.6, 143.6, 141.3, 136.8,
132.1, 128.5, 127.1, 125.0, 123.4, 120.2, 67.0, 54.5, 52.6, 47.1,
35.5; m/z (EI) 402 (Mϩ, 52%), 178 (100), 165 (12), 93 (20).
General procedure A for zinc insertion:
Zinc dust (0.27 g, 4.2 mmol, 6 eq.), was weighed into a 50 cm3
flask with side arm. The flask was heated, then evacuated and
flushed with nitrogen 3 times. Dry DMF (0.5 cm3) and 1,2-
dibromoethane (18 µl, 0.21 mmol, 0.3 eq.) were added, and the
mixture was heated on a hot water bath (90 ЊC) with vigorous
stirring for 30 min. The reaction mixture was allowed to cool to
room temperature. Trimethylsilylchloride (5 µl, 0.042 mmol,
0.06 eq.) was added to the mixture which was allowed to stir for
a further 30 min. The iodide 1a,b (0.7 mmol, 1 eq.) was dissol-
ved in dry DMF (0.9 cm3), and transferred via syringe to the
reaction mixture, which was then heated to 35 ЊC. Monitoring
the reaction by TLC, petroleum–ethyl acetate, 2 : 1, typically
showed complete consumption of starting material after 2 h.
ϩ
Acc. Mass. calcd for C24H22N2O4 requires m/z 402.1579.
Found 402.1566.
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(pyrid-4Ј-yl)-
propionic acid methyl ester 5a
Coupling of zinc reagent 2a, prepared from iodide 1a (0.31 g,
0.7 mmol) using procedure A, with 4-bromopyridine (0.15 g,
0.9 mmol) using procedure C gave 5a (0.16 g, 57%) as a white
foam; mp 54–56 ЊC; [α]D ϩ24.4 (c 1 in CH2Cl2); νmax (KBr disc)/
cmϪ1 3326, 3036, 2950, 1719, 1603, 1215, 741; δH (500 MHz,
CDCl3) 8.50 (2H, s), 7.77 (2H, d, J 7.5), 7.56 (2H, d, J 7.5), 7.41
(2H, t, J 7.5), 7.31 (2H, t, J 7.5), 7.01–7.00 (2H, m), 5.29 (1H, d,
J 7.5), 4.69 (1H, dd, JAX 6.0, JBX 5.0), 4.50 (1H, dd, J 7.0, 11.0),
4.40 (1H, dd, J 6.0, 11.0), 4.20 (1H, t, J 6.5), 3.74 (3H, s), 3.15
(1H, dd, JAX 6.0, JAB 14.0), 3.05 (1H, dd, JBX 5.0, JAB 14.0);
δC (125 MHz, CDCl3) 171.2, 155.4, 149.7, 143.7, 141.4, 132.1,
127.8, 127.0, 125.0, 124.9, 124.6, 120.0, 66.9, 54.0, 52.6, 47.2,
37.6; m/z (EI) 402 (Mϩ, 68%), 343 (12), 277 (78), 196 (92), 178
General procedure B for zinc insertion:
Zinc dust (2 eq.) was weighed into a 50 cm3 flask with side arm.
Iodine (0.03 eq.) was added. The flask was evacuated, heated
with a heat gun and flushed with nitrogen 3 times. The iodide
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
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ϩ
(100), 165 (18). Acc.Mass calcd for C24H22N2O4 requires m/z
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(6Ј-aminopyrid-
402.1579. Found 402.1564.
2Ј-yl)propionic acid methyl ester 8a
Coupling of zinc reagent 2a, prepared from iodide 1a (0.62 g,
1.4 mmol) using procedure B, with 2-amino-6-bromopyridine
(0.32 g, 1.9 mmol), using procedure C, gave 8a (0.32 g, 56%) as a
yellow solid; mp 47–49 ЊC; [α]D ϩ7.6 (c 1 in CH2Cl2); νmax (KBr
disc)/cmϪ1 3365, 3038, 2949, 1717, 1615, 1464, 1449, 1214, 759,
740; δH (500 MHz, CDCl3) 7.75 (2H, d, J 7.5), 7.57 (2H, dd,
J 7.5, 7.5), 7.37 (2H, d, J 7.5), 7.29 (2H, d, J 7.5), 6.47 (1H, d,
J 7.5), 6.37 (1H, d, J 8.0), 6.33 (1H, d, J 7.5), 4.67 (1H, dd, J 5.5,
13.0), 4.47 (2H, s), 4.35–4.33 (2H, m), 4.24 (1H, t, J 7.5), 3.74
(3H, s), 3.17 (1H, dd, JAX 6.5, JAB 14.5), 3.12 (1H, dd, JBX 5.0,
JAB 14.5) (NH obscured); δC (125 MHz, CDCl3) 172.1, 157.7,
156.0, 154.8, 144.0, 141.3, 138.6, 127.6, 127.0, 125.2, 120.0,
113.7, 106.9, 67.0, 53.4, 52.3, 47.1, 38.5; m/z (EI) 417 (Mϩ,
45%), 358 (25), 239 (40), 196 (21), 178 (100), 165 (12). Acc.
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(5Ј-bromopyrid-2Ј-
yl)propionic acid methyl ester 6a
Coupling of zinc reagent 2a (0.31 g, 0.7 mmol), prepared
from iodide 1a (0.31 g, 0.7 mmol) using procedure A, with 2,5-
dibromopyridine (0.22 g, 0.9 mmol) using procedure C, gave 6a
(0.20 g, 60%), as a yellow solid; mp 99–101 ЊC; [α]D ϩ22.5 (c 1 in
CH2Cl2); found C 60.1%, H 4.1, N 5.8, C24H21N2O4Br requires
C 59.9%, H 4.4, N 5.8; νmax (cap. film)/cmϪ1 3333, 3064, 2951,
1721, 1516, 1450, 759, 739; δH (500 MHz, CDCl3) 8.58 (1H, s),
7.76–7.73 (3H, m), 7.57 (2H, t, J 7.5), 7.40 (2H, t, J 7.5), 7.30
(2H, t, J 7.5), 7.03 (1H, d, J 8.0), 6.04 (1H, d, J 7.5), 4.78–4.74
(1H, m), 4.37 (2H, d, J 7.0), 4.22 (1H, t, J 7.0), 3.72 (3H, s), 3.34
(1H, dd, JAX 5.5, JAB 15.0), 3.29 (1H, dd, JBX 4.5, JAB 15.0);
δC (125 MHz, CDCl3) 172.1, 155.7, 155.0, 150.2, 143.9, 141.3,
139.4, 127.7, 127.0, 125.1, 125.1, 119.9, 118.6, 67.1, 53.2, 52.5,
47.2, 38.4; m/z (EI) 480 (Mϩ, 20%), 421 (12), 284, (81), 257, (32),
178 (100), 165 (62).
ϩ
Mass calcd for m/z C24H23N3O4 requires 417.1688. Found
417.1672
When the dried ethyl acetate extracts were evaporated, crys-
tals were formed which were identified as the pyridyl palladium
salt 33 by X-ray crystallography.40
(2S )-(N-tert-Butoxycarbonylamino)-3-(5Ј-bromopyrid-2Ј-yl)-
propionic acid methyl ester 6b
Coupling of zinc reagent 2b, prepared from iodide 1b (0.46 g,
1.4 mmol) using procedure A, with 2,5-dibromopyridine (0.44
g, 1.8 mmol) using procedure C, gave 6b (0.27 g, 54%) as a
yellow oil; found C 46.5%, H 5.4, N 7.5, C14H19N2O4Br requires
C 46.8%, H 5.3, N 7.8; νmax (cap. film)/cmϪ1 3369, 2977, 2953,
1746, 1714, 1501, 1366, 861, 632; δH (500 MHz, CDCl3) 8.56
(1H, s), 7.73 (1H, dd, J 8.0, 2.0), 7.06 (1H, d, J 8.0), 5.73 (1H, d,
J 8.0), 4.71–4.66 (1H, m), 3.70 (3H, s), 3.28 (1H, dd, JAX 6.0,
JAB 14.5), 3.24 (1H, dd, JBX 5.0, JAB 14.5), 1.42 (9H, s); δC (125
MHz, CDCl3) 172.1, 155.7, 155.3, 150.2, 139.0, 125.0, 118.9,
79.8, 52.7, 52.3, 38.8, 28.3; m/z (EI) 358 (Mϩ, 30%), 302 (46),
284 (55), 171 (35), 57 (100).
(2S )-(N-tert-Butyloxycarbonylamino)-3-(6Ј-aminopyrid-2Ј-yl)-
propionic acid methyl ester 8b
Coupling of zinc reagent 2b, prepared from iodide 1b (0.46 g,
1.4 mmol) using procedure A, with 2-amino-6-bromopyridine
(0.32 g, 1.9 mmol) using procedure C, gave 8b (0.16 g, 40%) as a
yellow solid; mp 90–92 ЊC; [α]D ϩ6.0 (c 1 in CH2Cl2); found C
57.0%, H 6.9, N 13.9, C14H21N3O4 requires C 56.9%, H 7.1, N
14.2; νmax (KBr disc)/cmϪ1 3462, 3358, 2976, 2960, 1745, 1682,
1517, 1504, 1464, 1440, 1243, 1226, 784; δH (500 MHz, CDCl3)
7.33–7.27 (1H, m), 6.42 (1H, dd, J 2.0, 4.0), 6.33 (1H, dd, J 2.0,
8.0), 5.91 (1H, d, J 8.0), 4.71–4.63 (2H, br s), 4.61 (1H, app q,
J 5.0), 3.68 (3H, s), 3.11 (1H, dd, JAX 5.5, JAB 14.0), 3.03 (1H,
dd, JBX 4.5, JAB 14.0), 1.42 (9H, s); δC (125 MHz, CDCl3) 172.7,
158.2, 155.5, 155.2, 138.2, 113.2, 106.7, 79.6, 53.1, 52.1, 38.9,
28.3; m/z (EI) 295 (Mϩ, 16%), 239 (18), 222 (16), 195 (50), 108
(78), 57 (100).
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(6Ј-bromopyrid-
2Ј-yl)propionic acid methyl ester 7a
Coupling of zinc reagent 2a (0.31 g, 0.7 mmol), prepared from
iodide 1a (0.31 g, 0.7 mmol) using procedure A, with 2,6-
dibromopyridine (0.22 g, 0.9 mmol) using procedure C, gave 7a
(0.19 g, 57%) as a yellow solid; mp 97–99 ЊC (from ethanol–
petroleum); [α]D ϩ32.2 (c 1 in CH2Cl2); νmax (thin film)/cmϪ1
3339, 3064, 2950, 1732, 1555, 1437, 759, 739; δH (500 MHz,
CDCl3) 7.74 (2H, d, J 7.5), 7.58 (2H, dd, J 7.5, 14.0), 7.43 (2H,
t, J 7.5), 7.38 (2H, t, J 7.5), 7.34 (1H, d, J 8.0), 7.29 (1H, app t,
J 7.5), 7.06 (1H, d, J 7.5), 5.99 (1H, d, J 8.0), 4.75–4.71 (1H, m),
4.35 (2H, d, J 7.0), 4.21 (1H, t, J 7.0), 3.75 (3H, s), 3.32–3.30
(2H, m); δC (125 MHz, CDCl3) 171.6, 158.2, 155.8, 143.8, 143.7,
138.9, 127.6, 127.0, 126.3, 125.1, 122.6, 119.9, 67.0, 53.3, 52.5,
47.0, 38.7; m/z (EI) 480 (Mϩ, 15%), 421 (23), 297 (67), 285 (63),
178 (100). Acc. Mass for m/z C24H21N2O4Br requires 480.0684.
Found 480.0673.
(2S )-(N-tert-Butoxycarbonylamino)-3-(6Ј-pyrrolidin-1Ј-yl-
pyridine)propionic acid methyl ester 9b
Coupling of zinc reagent 2b, prepared from iodide 1b (0.32 g, 1
mmol) using procedure B, with 2-bromo-6-pyrrolydinylpyridine
(0.30 g, 1.3 mmol) using procedure C, gave 9 (0.17 g, 50%) as a
yellow oil; [α]D ϩ22 (c 1, DCM); νmax (thin film)/cmϪ1 3339,
2973, 1750, 1715, 1495, 1165; δH (500 MHz, CDCl3) 7.30–7.28
(1H, m), 6.87 (1H, d, J 7.5), 6.29 (1H, d, J 7.5), 6.17 (1H, d,
J 8.5), 4.47–4.45 (1H, m), 3.55 (3H, s), 3.30–3.27 (4H, m),
3.09 (1H, dd, J 15.0, 5.0), 2.94 (1H, dd, J 15.0, 4.5), 1.84–
1.81 (4H, m), 1.31 (9H, s); δC (125 MHz, CDCl3) 172.4,
156.3, 155.6, 155.0, 137.3, 110.4, 104.4, 78.9, 52.8, 51.8, 46.3,
37.7, 28.1, 25.3; m/z (EI) 349 (Mϩ, 100%), 276 (37), 234 (89),
190 (42), 162 (60), 57 (97); m/z (ES) 350 (MHϩ, 100%);
Acc.Mass. (ES) calcd for C18H27N3O4ϩH requires m/z
350.2080. Found 350.2070.
(2S )-(N-tert-Butoxycarbonylamino)-3-(6Ј-bromopyrid-2Ј-yl)-
propionic acid methyl ester 7b
Coupling of zinc reagent 2b, prepared from iodide 1b (0.46 g,
1.4 mmol) using procedure A, with 2,6-dibromopyridine (0.44
g, 1.8 mmol) using procedure C, gave 7b (0.26 g, 52%) as pale
yellow oil; [α]D Ϫ29.7 (c 1.65 in acetone); found C 47.0%, H 5.1,
N 7.7, C14H19N2O4Br requires C 46.8%, H 5.3, N 7.8; νmax (cap
film)/cmϪ1 3365, 2978, 1746, 1715, 1502, 1166; δH (500 MHz,
CDCl3) 7.48 (1H, app t, J 8.0), 7.34 (1H, d, J 8.0), 7.12 (1H, d,
J 7.5), 5.44 (1H, d, J 7.5), 4.71–4.63 (1H, m), 3.76 (3H, s), 3.33–
3.23 (2H, m), 1.42 (9H, s); δC (125 MHz, CDCl3) 172.0, 158.5,
155.2, 141.4, 138.7, 126.2, 122.6, 79.9, 52.9, 52.4, 39.3, 28.2; m/z
(EI) 359 (MHϩ, 45%), 285 (35), 259 (55), 199 (80), 171 (55), 57
(100).
General procedure D for hydrolysis of methyl esters:
The amino acid was dissolved in THF–H2O (3 : 2) (4 cm3
mmolϪ1). Two equivalents of LiOH were added and the mixture
stirred at rt until TLC indicated complete consumption of the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
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starting material. The solvent was removed under reduced
pressure. Water was added and the solution extracted with ethyl
acetate. The aqueous layer was acidified to pH 3 with HCl
(0.1 M) and extracted with ethyl acetate. The organic layer
was dried and the solvent evaporated under reduced pressure
yielding the carboxylic acid.
(2S )-(N-tert-Butoxycarbonylamino)-3-(6Ј-pyrrolidin-1Ј-ylpyrid-
ine)propionic acid 13
According to general procedure D, 13 (0.28 g, 0.84 mmol) was
obtained from the methyl ester 9b (0.35 g, 1 mmol) as a brown
solid in 84% yield. Mp 193–195 ЊC; [α]D ϩ95 (c 1, CHCl3);
found C 59.7%, H 7.7, N 12.1, C17H25N3O4 requires C 59.9%, H
7.5, N 12.5; νmax (KBr disk)/cmϪ1 3378, 2976, 2878, 1708, 1629,
1479; δH (400 MHz, CDCl3) 7.60–7.58 (1H, m), 6.71 (1H, d,
J 7.5); 6.45 (1H, d, J 9.0), 6.05–6.03 (1H, br s), 4.25–4.23 (1H,
m), 3.65–3.50 (4H, m), 3.20–3.18 (2H, m), 2.10–2.0 (4H, m),
1.45 (9H, s) (carboxylic acid proton not observed); δC (125
MHz, CDCl3) 174.8, 155.9, 153.4, 152.7, 141.4, 111.8, 108.1,
79.8, 53.1, 48.3, 38.7, 30.1, 25.7; m/z (ES) 336 (MHϩ, 100%),
280 (50).
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(pyrid-2Ј-yl)-
propionic acid 10a
According to general procedure D, 10a (0.46 g, 1.2 mmol) was
obtained from the methyl ester 3a (0.80 g, 2 mmol), as a yellow
solid in 60% yield; mp 160–162 ЊC; [α]D ϩ71.5 (c 1 in CH2Cl2);
found C 70.9%, H 5.2, N 6.9, C23H20N2O4 requires C 71.1%, H
5.2, N 7.2; νmax (KBr disc)/cmϪ1 3323, 3036, 2886, 1733, 1698,
1544, 1443, 1260, 738; δH (500 MHz, CDCl3) 11.0–10.8 (1H, br
s), 8.57 (1H, d, J 4.5), 7.78–7.76 (3H, m), 7.61 (2H, d, J 7.5),
7.40 (2H, t, J 7.5), 7.35–7.30 (3H, m), 7.26 (1H, d, J 4.5), 6.05
(1H, d, J 6.0), 4.60–4.58 (1H, m), 4.47 (1H, dd, JAX 7.5, JAB
10.5), 4.39 (1H, dd, JBX 7.0, JAB 10.5), 4.23 (1H, app t, J 7.0),
3.49–3.45 (2H, m); δC (125 MHz, CDCl3) 175.5, 172.7, 155.6,
146.2, 143.7, 141.3, 139.3, 127.7, 127.1, 125.7, 125.1, 123.0,
119.9, 66.8, 53.2, 47.2, 38.1; m/z (EI) 297 (Mϩ Ϫ CH2-pyr, 20%),
196 (5), 178 (100), 165 (15), 94 (6).
(2ЈS )-2,6-Bis-[2Ј-(N-Fluorenylmethoxycarbonylamino)-2Ј-(tert-
butoxycarbonyl)ethyl]pyridine 16
Coupling of the zinc reagent 15, prepared from 14 (0.34 g, 0.7
mmol) using general procedure A, with 2,6-dibromopyridine
(0.11 g, 0.5 mmol) using procedure C, gave the product 16
(46 mg, 10%) as a yellow solid; mp 73–75 ЊC; [α]D ϩ23.8 (c 0.5 in
CH2Cl2); νmax (KBr disc)/cmϪ1 3341, 3003, 2976, 2932, 1724,
1520, 1222, 1154, 739; δH (500 MHz, CDCl3) 7.74 (2H, d, J 7.5),
7.67 (4H, t, J 7.0), 7.57 (4H, t, J 7.5), 7.50–7.45 (2H, m), 7.34–
7.27 (4H, m), 7.17 (1H, q, J 8.0), 7.00 (2H, d, J 8.0), 6.71 (2H, d,
J 8.5), 4.88–4.85 (2H, m), 4.22–4.13 (4H, m), 4.05 (2H, t, J 7.5),
3.38 (2H, dd, JAX 6.5, JAB 15.5), 3.27 (2H, dd, JBX 4.0, JAB 15.5),
1.38 (18H, s); δC (125 MHz, CDCl3) 171.2, 157.0, 156.5, 143.9,
141.1, 136.7, 127.7, 127.0, 125.5, 121.8, 119.8, 81.6, 67.1, 53.2,
47.0, 39.9, 28.0; m/z (EI) 809 (Mϩ, 18%), 708 (8), 631 (16), 587
(65), 486 (34), 430 (40), 178 (100), 165 (31).
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(5Ј-bromopyrid-
2Ј-yl)propionic acid 11a
According to general procedure D, 11a (0.79 g, 1.7 mmol) was
obtained, from the methyl ester 6a (0.96 g, 2 mmol), as a yellow
solid in 85% yield; mp 219–221 ЊC, found M 466.0497,
C23H19N2O4Br requires 466.0528; νmax (KBr disc)/cmϪ1 3321,
3037, 1695, 1421, 838, 757; δH (500 MHz, CDCl3) 8.65 (1H, s),
7.85 (1H, d J 8.0), 7.78 (2H, d, J 7.5), 7.59 (2H, d, J 7.5), 7.42
(2H, d, J 7.5), 7.33 (2H, t, J 7.5), 7.09 (1H, d, J 8.0), 5.97–5.90
(1H, br s), 4.62–4.56 (1H, m), 4.48 (1H, dd, J 10.5, 7.0), 4.41
(1H, dd, J 10.5, 6.5), 4.23 (1H, t, J 7.0), 3.40–3.34 (2H, m)
(carboxylic acid proton not observed); δC (125 MHz, CDCl3)
175.5, 172.7, 155.6, 146.2, 143.7, 141.3, 139.3, 127.7, 127.1,
125.7, 125.1, 123.0, 119.9, 66.8, 52.3, 47.2, 38.1; m/z (EI) 466
(Mϩ, 13%), 448 (63), 242 (25), 227 (80), 196 (17), 178 (100), 165
(80).
(2S )-(N-Fluorenylmethoxycarbonylamino)-3-(6Ј-bromopyrid-
2Ј-yl)propionic acid tert-butyl ester 17
Also obtained in the above reaction was product 17 (0.11 g,
30%); mp 49–51 ЊC; δH (500 MHz, CDCl3) 7.76 (2H, d, J 7.5),
7.60 (2H, dd, J 7.5, 11.5), 7.45 (2H, t, J 7.5), 7.39 (2H, t, J 7.5),
7.35 (1H, d, J 8.5), 7.30 (1H, t, J 7.5), 7.10 (1H, d, J 7.5), 5.95
(1H, d, J 8.0), 4.64–4.60 (1H, m), 4.35 (2H, d, J 7.0), 4.22 (1H, t,
J 7.0), 3.32 (1H, dd, JAX 5.5, JAB 14.5), 3.27 (1H, dd, JBX 5.0, JAB
14.5), 1.42 (9H, s); δC (125 MHz, CDCl3) 170.0, 158.7, 155.8,
143.8, 143.7, 141.2, 138.7, 127.6, 127.0, 126.6, 126.2, 122.7,
120.0, 82.4, 66.9, 53.7, 47.1, 39.0, 27.9.
(2S )-(N-tert-Butyloxycarbonylamino)-3-(5Ј-bromopyrid-2Ј-yl)-
propionic acid 11b
According to general procedure D, 11b (0.76, 2.2 mmol) was
obtained from the methyl ester 6b (1 g, 3 mmol), as a yellow
solid in 75% yield; mp 165–166 ЊC, [α]D Ϫ9.0 (c 1 in acetone);
found C 44.9%, H 4.9, N 7.8, C13H17N2O4Br requires C 45.2%,
H 5.0, N 8.1; νmax (KBr disc)/cmϪ1 3378, 2985, 2973, 1737, 1687,
1548, 1165, 650; δH (500 MHz, CDCl3) 8.48 (1H, s), 7.74 (1H, d,
J 7.0), 7.15 (1H, d, J 7.0), 6.02–5.98 (1H, br s), 4.48–4.45 (1H,
m), 3.29–3.27 (1H, m), 3.20–3.18 (1H, m), 1.35 (9H, s) (carb-
oxylic acid proton not observed); δC (125 MHz, CDCl3) 176.6,
156.7, 155.9, 149.5, 140.0, 125.9, 118.9, 80.0, 54.8, 38.9, 28.3; m/z
(EI) 300 (33%), 288 (30), 271 (65), 244 (80), 171 (40), 57 (100).
4-Chloro-3-iodopyridine 18
A solution of LDA (13.2 mmol) in dry THF (10 cm3) was pre-
pared as follows: to a magnetically stirred solution of dry diiso-
propylamine (1.70 cm3, 13.2 mmol) in dry THF (4 cm3) under
nitrogen at Ϫ78 ЊC, n-BuLi (4.87 cm3 of solution 2.5 M in
hexanes, 13.2 mmol) was added via syringe. This solution was
stirred at Ϫ78 ЊC for 20 min and then transferred to a suspen-
sion of 4-chloropyridine hydrochloride (1 g, 6.6 mmol) in dry
THF (2 cm3) keeping the temperature below Ϫ70 ЊC. The result-
ing lithiopyridine precipitated as a white solid in an orange
solution. The mixture was stirred for 20–30 min at Ϫ78 ЊC and
then treated over 10 min with a solution of I2 (1.67 g, 6.6
mmol) in dry THF (4 cm3) keeping the internal temperature
below Ϫ65 ЊC. The reaction mixture was allowed to warm to r.t.
over 4 h, poured into 8% aqueous sodium bisulfite (20 cm3) and
extracted with Et2O (20 cm3). The combined organic extracts
were washed with 8% aqueous sodium bisulfite (20 cm3), 5%
aqueous sodium hydrogencarbonate (20 cm3), water (20 cm3)
and brine (20 cm3), dried and concentrated to yield a dark
brown solid. Purification via chromatography (eluent: di-
chloromethane) afforded 0.97 g of 18 (61%). Mp 78–80 ЊC;
found C 25.1%, H 0.9, N 5.8, C5H3NClI requires C 25.1%, H
1.2, N 5.8; νmax (KBr disc)/cmϪ1 3300, 2000–1800, 1550–1430;
δH (500 MHz, CDCl3) 8.95 (1H, s), 8.43 (1H, d, J 5.0), 7.42 (1H,
(2S )-(N-tert-Butyloxycarbonylamino)-3-(6Ј-bromopyrid-2Ј-yl)-
propionic acid 12
According to general procedure D, 12 (0.61, 1.3 mmol) was
obtained from the methyl ester 7b (0.72 g, 1.5 mmol) as a white
solid in 87% yield; mp 156–158 ЊC; [α]D Ϫ12.0 (c 1 in acetone);
found C 44.9%, H 4.9, N 7.9, C13H17N2O4Br requires C 45.2%,
H 4.9, N 7.9; νmax (KBr disc)/cmϪ1 3330, 2980, 1725, 1686, 1518,
1166; δH (500 MHz, CDCl3) 7.58 (1H, app t, J 7.5), 7.43 (1H, d,
J 7.5), 7.27 (1H, d, J 7.5), 5.81 (1H, d, J 6.0), 4.59–4.56 (1H, m),
3.36–3.26 (2H, m), 1.44 (9H, s); δC (125 MHz, CDCl3) 173.3,
158.7, 155.6, 140.4, 140.0, 126.7, 123.1, 80.4, 52.6, 38.9, 28.3;
m/z (EI) 345 (MHϩ, 80%), 300 (40), 244 (35), 201, 199 (100), 171
(95), 57 (95).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
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d, J 6.0); δC (125 MHz, CDCl3) 158.4, 149.6, 147.9, 124.9, 98.4;
m/z (EI) 239 (Mϩ, 100%), 112 (43).
[(S )-2-((S )-2-{Methyl-1-[1-(R)-phenylethylcarbamoyl]ethyl-
carbamoyl}pyrrolidin-1-yl)-2-oxo-1-(4-pyrrolidin-1-ylpyridin-3-
ylmethyl)ethyl]carbamic acid tert-butyl ester 24
(2S )-(N-tert-Butoxycarbonylamino)-3-(4Ј-chloropyridin-3Ј-yl)-
Acid 28 (0.11 g, 0.42 mmol) and dipeptide 31 (0.11 g, 0.42
mmol) were dissolved in DMF (5 cm3) in the presence of
N-methylmorpholine (0.05 cm3, 0.42 mmol). HOBt (0.07 g, 0.42
mmol) was added and the solution was cooled to Ϫ23 ЊC. After
adding EDCl (0.08 g, 0.42 mmol) the mixture was stirred for 2 h
at Ϫ23 ЊC and for 15 h at rt. A saturated solution of NaHCO3
(10 cm3) was poured into the reaction flask and the solution was
extracted with ethyl acetate. The organic layer was washed with
water and brine and then dried over MgSO4. After evaporating
the solvent under reduced pressure, the crude product was puri-
fied via chromatography (eluent: AcOEt) to yield peptide 29
(0.12 g, 52%). Peptide 29 (0.05 g, 0.08 mmol) was dissolved in
pyrrolidine (2 cm3) and the solution was kept at reflux for
3 days. After evaporating the solvent, the residue was purified
by chromatography (eluent DCM–MeOH: 9 : 1) and the
pyrrolidinopyridine 24 (0.021 g, 40%) was obtained. [α]D ϩ2.8
(c 0.36, CHCl3); νmax (KBr)/cmϪ13436, 2925, 2953, 1683, 11652,
1639; δH (400 MHz, CDCl3) 8.10 (1H, d, J 6.0), 7.98 (1H, s);
7.40–7.10 (5H, m), 6.79–6.78 (1H, br s), 6.66 (1H, d, J 6.0), 5.25
(1H, m), 5.05 (1H, m), 4.68 (1H, m), 4.05–4.03 (1H, b), 3.70–
3.40 (6H, m), 3.12 (1H, dd, J 5.5, 14.0), 2.99 (1H, m), 2.05–1.80
(4H, m), 1.51–1.48 (4H, m), 1.43 (3H, d, J 7.0), 1.40 (6H, s),
1.35 (9H, s); δC (125 MHz, CDCl3) 173.5, 170.8, 155.0, 153.8,
150.9, 146.5, 144.2, 128.3, 126.6, 126.2, 119.9, 109.2, 80.0, 61.3,
57.4, 52.5, 50.6, 48.7, 47.2, 35.6, 28.5, 28.3, 26.4, 25.6, 25.1,
24.8, 21.9; m/z (ES) 621 (MHϩ, 48%), 500 (20), 404 (65), 403
(100), 347 (48); Acc. Mass. calcd for C34H48N6O5ϩH requires
m/z 621.3764, found 621.3760.
propionic acid methyl ester 19
Coupling of zinc reagent 2b, prepared from iodide 1b (0.2 g,
0.35 mmol) using procedure B, with 4-chloro-3-iodopyridine
was carried out using procedure C. After stirring for 16 h at
room temp., additional electrophile (0.186 g, 0.78 mmol) was
added to give a crude product, which was purified by chrom-
atography (ethyl acetate–petroleum ether: 2 : 1) to give 19 (0.067
g, 36%). [α]D ϩ11 (c 1, CHCl3); νmax (hexachlorobutadiene)/
cmϪ1 3437, 2979, 2953, 1748, 1721, 1688, 1495; δH (400 MHz,
CDCl3) 8.35–8.33 (2H, m), 7.25 (1H, d, J 5.5); 5.25 (1H, d,
J 8.0), 4.62 (1H, dd, J 14.0, 8.0), 3.71 (3H, s), 3.33 (1H, dd,
J 14.0, 5.5), 3.05 (1H, dd, J 14.0, 8.0), 1.33 (9H, s); δC (125
MHz, CDCl3) 171.8, 154.8, 155.6, 151.9, 149.1, 144.3, 130.5,
124.4, 80.0, 52.7, 52.5, 37.7, 28.1; m/z (FAB) 315 (MHϩ, 21%),
259 (12), 186 (33), 154 (100), 149 (62), 136 (72). Acc. Mass. (ES)
calcd for C14H19N2O4ClϩH requires m/z 315.1112. Found
315.1101.
[1(R)-(4-Chloropyridin-3-ylmethyl)-2-oxo-2-pyrrolidin-1-
ylethyl]carbamic acid tert-butyl ester 20
A solution of chloropyridine 19 0.24 g (0.7 mmol) in pyrroli-
dine (3 cm3) was kept at reflux for 3 h. After evaporating the
solvent, the residue was recrystallised from ethyl acetate–pet-
roleum ether to give amide 20 (0.17 g, 68%). Mp 138–142 ЊC;
[α]D Ϫ2 (c 0.5, CHCl3); found C 57.6%, H 6.8, N 11.8,
C17H24N3O3Cl requires C 57.8%, H 6.8, N 11.9; νmax (KBr disk)/
cmϪ1 3274, 2977, 1702, 1632; δH (400 MHz, CDCl3) 8.36 (1H, s),
8.35 (2H, d, J 5.5), 7.23 (1H, d, J 5.5), 5.54 (1H, d, J 9.0), 4.86–
4.84 (1H, m), 3.68–3.18 (4H, m), 3.08–2.97 (1H, dd, J 6.0, 13.5),
2.94 (1H, dd, J 8.5, 13.5), 2.01–1.88 (4H, m), 1.35 (9H, s);
δC (125 MHz, CDCl3) 169.1, 154.8, 154.8, 152.3, 149.1, 130.6,
124.2, 79.6, 50.1, 46.4, 45.9, 34.4, 28.1, 25.9, 24.0; m/z (ES) 354
(MHϩ, 100%), 298 (25).
[(S )-2-{(R)-2-[Methyl-1-(1-phenylethylcarbamoyl)ethyl-
carbamoyl]pyrrolidin-1-yl}-2-oxo-1-(4-pyrrolidin-1-ylpyridin-3-
ylmethyl)ethyl]carbamic acid tert-butyl ester 25
Acid 28 (0.11 g, 0.42 mmol) and dipeptide 32 (0.10 g, 0.45
mmol) were dissolved in 3 cm3 of DMF in the presence of
N-methylmorpholine (0.05 cm3, 0.45 mmol). HOBt (0.06 g,
0.4 mmol) was added and the solution was cooled to Ϫ23 ЊC.
After adding EDCl (0.08 g, 0.38 mmol) the mixture was stirred
for 2 h at Ϫ23 ЊC and for 15 h at rt, 10 cm3 of saturated solution
of NaHCO3 were poured into the reaction flask and the solu-
tion was extracted with ethyl acetate. The organic layer was
washed with water and brine and then dried over MgSO4. After
evaporating the solvent under reduced pressure, the crude
product was purified via chromatography (eluent: AcOEt) to
yield peptide 30 (0.09 g, 50%). Peptide 30 (0.04 g, 0.07 mmol)
was dissolved in pyrrolidine (2 cm3) and the solution was kept at
reflux for 3 days. After evaporating the solvent, the residue was
purified by chromatography (eluent DCM–MeOH: 9 : 1) and
the pyrrolidinopyridine 25 (0.02 g, 40%) was obtained. [α]D
Ϫ7.7 (c 0.26, CHCl3); mp 103–105 ЊC; νmax (KBr)/cmϪ1 3436,
2926, 1693, 1686, 1638; δH (400 MHz, CDCl3) 8.10 (1H, d,
J 6.0), 7.98 (1H, s); 7.40–7.20 (5H, m), 6.55 (1H, d, J 6.0), 5.47
(1H, d, J 8.5), 5.05–5.03 (1H, m), 4.85 (1H, m), 4.20–4.18 (1H,
b), 3.65–3.15 (6H, m), 3.12 (1H, dd, J 5.5, 14.0), 3.05–3.02 (1H,
m), 2.05–1.80 (4H, m), 1.75–1.10 (24H, m); δC (125 MHz,
CDCl3) 171.3, 169.3, 154.9, 154.1, 150.9, 146.5, 128.3, 126.2,
117.6, 109.2, 79.6, 61.4, 52.0, 50.5, 49.1, 46.5, 45.8, 43.1, 36.8,
28.2, 26.2, 25.6, 25.3, 24.2; m/z (ES) 644 (MNaϩ, 7%), 621
(MHϩ, 100), 619 (14). Acc. Mass: C34H48N6O5ϩH requires
621.3764, found 621.3756.
[2-Oxo-2-pyrrolidin-1-yl-1-(4-pyrrolidin-1-yl-pyridin-3-
ylmethyl)ethyl]carbamic acid tert-butyl ester 21
A solution of chloropyridine 19 (0.24 g, 0.7 mmol) in pyrrol-
idine (3 cm3) was kept at reflux for 3 d. After evaporating the
solvent, the residue was recrystallised from ethyl acetate–
petroleum ether to give the pyrrolidinopyridine 21 (0.12 g,
47%). Mp 153–155 ЊC; [α]D Ϫ44 (c 0.41, MeOH); found C
61.9%, H 8.3, N 13.6, C21H32N4O3 requires C 62.3%, H 8.3, N
13.9; νmax (KBr disk)/cmϪ1 3260, 2977, 1695, 1636; δH (400
MHz, CDCl3) 8.06 (1H, d, J 6.0), 7.95 (1H, s), 6.46 (1H, d,
J 6.0), 5.47 (1H, d, J 9.0), 4.55 (1H, dt, J 18.5, 9.0, 5.0), 3.50–
3.40 (8H, m), 2.99–2.97 (1H, m), 2.50–2.48 (1H, m), 2.0–1.8
(4H, m), 1.65–1.40 (4H, m), 1.35 (9H, s); δC (125 MHz, CDCl3)
169.4, 154.9, 153.5, 151.9, 147.5, 117.2, 108.8, 79.5, 52.0, 50.4,
46.1, 36.5, 36.5, 28.2, 25.7, 25.6, 23.9; m/z (ES) 389 (MHϩ,
100%), 333 (5).
(2S )-(N-tert-Butoxycarbonylamino)-3-(4Ј-chloropyridin-3Ј-yl)-
propionic acid 28
According to general procedure D, 28 (0.14 g, 0.46 mmol) was
obtained from the methyl ester 19 (0.25 g, 0.8 mmol) as a white
solid in 58% yield. Mp 146–148 ЊC; [α]D Ϫ43 (c 7.5, MeOH);
νmax (KBr disk)/cmϪ1 3430, 1732, 1684, 1458; δH (400 MHz,
DMSO) 13.8–13.6 (1H, b), 8.45 (1H, s); 7.68 (1H, d, J 5.5), 7.21
(1H, d, J 5.5), 7.26 (1H, d, J 8.0), 4.18 (1H, m), 3.21–3.18 (1H,
dd, J 5.0, 14.0), 2.95–2.91 (1H, m), 1.21 (9H, s); δC (125 MHz,
DMSO) 172.9, 155.4, 152.3, 149.1, 143.0, 131.5, 124.3, 78.2,
52.4, 31.9, 28.1; m/z (ES) 301 (MHϩ, 68%), 279 (23), 247 (17),
245 (100). Acc. Mass. calcd for C13H17ClN2O4 requires m/z
301.0940, found 301.0950.
General procedure for the determination of the catalytic activity
of pyridyl amino acid derivatives
1-Methylcyclohexanol 22 (0.228 g, 2 mmol) was dissolved in
toluene (5 cm3). Triethylamine (0.42 cm3, 3 mmol) and catalyst
(0.08 mmol) were added. Acetic anhydride (0.40 cm3, 4.2 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 5 4 – 4 2 6 1
4260

View Article Online
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was added. The mixture was stirred for 24 h, after which the
solvent was evaporated under reduced pressure. The residue
was dissolved in ethyl acetate (10 cm3) and the solution was
washed with water (10 cm3) and 1 M HCl (5 cm3). After drying,
the solvent was removed. The crude product was purified via
chromatography (eluent: petroleum ether–ethyl acetate: 1 : 1).
Two samples were taken during the reaction after 10 and 24 h
and their composition was checked by GC. GC conditions:
isotherm at 60 ЊC; retention times: starting material 22 2.52,
product 23 6.96. δH (200 MHz, CDCl3) 2.01 (3H, s), 1.65–1.40
(10H, m), identical to an authentic sample.
Kinetic resolution of trans-N-(2-hydroxycyclohexyl)acetamide
Alcohol ( )-26 (157 mg, 1 mmol) and catalyst 24 (0.0005 mmol)
were dissolved in CHCl3 (1 cm3), and toluene (9 cm3) was added
to produce a white suspension. The reaction mixture was
cooled to 0 ЊC and acetic anhydride (9.4 µl, 0.10 mmol) was
then added and the reaction was allowed to stir for 48 h at 0 ЊC.
The reaction mixture was applied directly to a silica gel column.
The product was eluted with ethyl acetate to afford acetylated
product 27 (10 mg). δH (400 MHz, CDCl3) 5.79 (1H, b), 4.60
(1H, dt, J 4.4, 10.8), 3.81–3.75 (1H, m), 1.99 (3H, s), 1.87 (3H,
s), 2.19–1.10 (8H, m); δC (125 MHz, CDCl3) 171.8, 169.6, 74.6,
52.7, 32.0, 31.0, 24.1, 24.0, 23.3, 21.1. The enantiomers were
separated by GC. Conditions: isotherm 110 ЊC; retention times
for the two enantiomers: 27.9 min, 30.0 min.
24 E. F. V. Scriven, Chem. Soc. Rev., 1983, 12, 129.
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Acknowledgements
We thank the European Union for support under the TMR
Network FMRX-CT 96–0011, and the IHP Network HPRN-
CT-2000–00014, and Professor W. Clegg and Dr L. Horsburgh
(University of Newcastle upon Tyne) for X-ray determination
of the crystal structures for compounds 3a and 33.
31 H. J. C. Deboves, C. Hunter and R. F. W. Jackson, J. Chem. Soc.,
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