Peptide modification through site-selective residue interconversion: application of the rhodium-catalysed 1,4-addition of aryl siloxanes and boronates

Article abstract of DOI:10.1016/j.tet.2008.07.067

The site-selective interconversion of serine and cysteine residues of di- and tripeptides into phenylalanine derivatives, bearing a range of functionalities, has been achieved in high yield and selectivity through the common dehydroalanine intermediate. T

Full text of DOI:10.1016/j.tet.2008.07.067

Tetrahedron 64 (2008) 9528–9539
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Tetrahedron
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Peptide modification through site-selective residue interconversion: application
of the rhodium-catalysed 1,4-addition of aryl siloxanes and boronates
,
Christopher J. Chapman a, Jonathan D. Hargrave a, Gerwyn Bish b, Christopher G. Frost a
*
a Chemistry Department, University of Bath, Claverton Down, Bath BA1 7AY, UK
b Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2008
Received in revised form 1 July 2008
Accepted 17 July 2008
Available online 23 July 2008
The site-selective interconversion of serine and cysteine residues of di- and tripeptides into phenylala-
nine derivatives, bearing a range of functionalities, has been achieved in high yield and selectivity
through the common dehydroalanine intermediate. Through the application and development of the
rhodium-catalysed 1,4-addition to a,b-dehydroamino acid moieties with organometallic nucleophiles,
a variety of peptides have been successfully modified to contain unnatural amino acid residues in pre-
designated residue positions.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
show that the diastereoselectivity can be switched through the
application of chiral rhodium complexes.
Proteins and peptides are fundamental in life with an extensive
array of functions born of the multitude of possible structures.
Consisting of common fragments the primary, secondary and
tertiary structures formed through intra- and inter-molecular
interactions provide innumerable variations of structure and re-
sultant activity in biological systems. However, the serial nature of
synthetic peptide synthesis leads to the perpetual problem of long
synthetic routes when investigating residue effects through ana-
logue synthesis. Whilst the ability to modify individual residues of
peptides and complex molecules selectively and reliably leads to
a number of exciting possibilities in chemical biology and synthetic
strategies. Currently, the majority of methods applied to the
modification of biological systems are based on biochemical
techniques,1 however, examples of modifications achieved through
small molecule (chemical) reactivity is increasing.2,3
2. Results and discussion
The preparation of an array of unnatural phenylalanine residues
within a preformed peptide allows for the rapid variation of
complex biomolecules and the possibility to explore residue effects
quickly through shrewd alteration at individual sites. To this end,
we envisaged the combination of the, previously described trans-
formation of serine or cysteine residues to dehydroalanine together
with the rhodium-catalysed conjugate addition reactio, would
provide a simple and efficient technique to introduce variation to
complex molecules (Scheme 1).
The dehydroalanine (DAla) residue itself is of significant interest
in protein chemistry due to the rigid nature of the conjugate system
and the associated effects imparted on the peptide chain.9 Syn-
thetic routes to dehydroamino acid containing peptides include
a variety of approaches. The elimination of water from serine is
a well established route with the activation of the hydroxyl group
enabling elimination by various reagents including: carbodiimide/
copper(I) chloride,10 dichloroacetyl chloride/triethylamine,11 tosyl
The rhodium-catalysed 1,4-addition of aryl boronates to
a,b-
unsaturated carbonyl derivatives has developed in recent years
from Miyaura4 and Hayashi’s5 primary publications to a highly
selective and synthetically robust method for the formation of b-
aryl ketones and their related structures.6 Previously, ourselves and
others have reported the rhodium-catalysed 1,4-conjugate addition
anhydride/1,4-diazabicyclo[2.2.2]octane
(DABCO),12
triphenyl
of aryl boronates7 and siloxanes8 to
a-substituted activated alkenes
phosphine/diethyl azodicarboxylate (DEAD),13 Boc-anhydride/4-
(N,N-dimethylamino)pyridine (DMAP),14 O-Cbz or O-Eoc/potas-
sium carbonate,15 and exchange to form the selenoether with
diphenyl diselenide followed by oxidation and elimination though
thermolysis.16 Similarly, cysteine thioethers can be oxidised and
eliminated through thermolysis in the presence of 1,8-dia-
zabicyclo[5.4.0]undec-7-ene (DBU) or sodium hydroxide.17 Re-
cently, Davis and co-workers have successfully modified a peptide
and dehydroalanine (DAla) derivatives. Within this article, we
highlight catalytic methodology facilitating the elaboration of
peptides and pseudo-peptide fragments through site-selective
modification of common natural amino acid residues. Moreover, we
* Corresponding author. Tel.: þ44 (0) 1225 386142; fax: þ44 (0) 1225 386231.
E-mail address: c.g.frost@bath.ac.uk (C.G. Frost).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.067

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9529
OH
O
O
H
N
H
N
N
H
R1
O
R2
Ar
O
Rhodium-catalysed
1,4-addition
O
O
O
O
H
N
H
N
H
N
H
N
Elimination
N
H
N
H
R1
O
R2
R1
R2
SH
O
O
O
H
N
H
N
N
H
R1
R
2
Scheme 1. Proposed route for site-selective modification of peptides though selective residue elimination and sequential rhodium-catalysed 1,4-addition.
through the application of the O-mesitylenesulfonylhydroxylamine
(MSH) mediated conversion of cysteine to dehydroalanine subunits
under mild aqueous conditions.18
Our initial investigations focused on the dipeptide Boc-Val-
DALa-OMe 1 with the D-alanine portion present as the acrylate
ester, prepared in 91% yield from Boc-Val-Ser-OMe though the
application of 1-ethyl-3-(30-dimethylaminopropyl)carbodiimide
(EDCI)/CuCl. In comparison with our previously described work on
methyl 2-acetamidoacrylate,7c exchange of the N-acetyl group for
Boc-valine produced no detrimental effect concerning the re-
activity of the substrate. However, unlike with Ac-DAla-OMe, ap-
plication of a (Rac)-BINAP derived catalyst provided the minimal
natural selectivity of 8% de in preference to the formation of the
unnatural D
-phenylalanine (Table 1, entry 3).19 Application of chiral
Table 1
Ligand effects on the rhodium-catalysed 1,4-addition with phenyboronic acida
Elaboration of the method with a variety of organometallic
nucleophiles proved successful (Table 2). However, only low dia-
stereoselectivities could be achieved using BINAP as the chiral li-
gand. Both aryl siloxanes and boronic acids were efficiently coupled
to provide an assortment of functionalised phenylalanine de-
rivatives. Of note, 4-formylphenyl boronic acid was successfully
coupled to afford the corresponding aldehyde functionalised pep-
tide in 33% isolated yield. The low yield of this reaction, when
Entry
Catalyst
Ligand
Conv. (d.e.)c (%)
1
2
3
4
5
6
7
8
9
[Rh(acac)(C2H4)2]
[Rh(acac)(C2H4)2]
[Rh(acac)(C2H4)2]
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
[RhCl(C2H4)2]2
(R)-BINAP 3
(S)-BINAP
(Rac)-BINAP
(S)-BINAP
(S,S)-Chiraphos 8
(R,R,R)-1
(R,R)-Norphos 4
(R,R)-DUPHOS 7
(R)-3,5-Xylyl-BINAP 5
100 (39 R)
100 (23 S)
100 (8 R)
83b (29 S)
33 (NR)
Table 2
82b (22 S)
97 (37 S)
21 (NR)
Additions to Boc-Val-DAla-OMe
89 (40 R)
a
Conditions: [Rh] (3 mol % Rh), ligand (1.1 equiv to Rh), PhB(OH)2 (4 equiv), NaF
(3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h.
b
Isolated yield.
c
Diastereoselectivity calculated from proton NMR spectroscopy, configuration of
new stereocentre of the major diastereomer.
Entry
Conditionsa
Organometallic
Yield (d.e.)b (%)
1
2
3
4
5
6
7
8
A
A
A
A
A
B
B
B
B
B
B
4-Cl-PhB(OH)2
4-Ac-PhB(OH)2
1-Naphthyl-PhB(OH)2
3-Br-PhB(OH)2
4-CHO-PhB(OH)2
PhSi(OMe)3
4-OMe-PhSi(OMe)3
4-CF3-PhSi(OMe)3
4-Me-PhSi(OMe)3
4-Cl-PhSi(OMe)3
2,3,4,5,6-F-PhSi(OMe)3
86 (39 R)
86 (37 R)
62 (21 R)
86 (33 R)
33 (34 R)
68 (<1)
85 (ND)
61 (22 S)
66 (2 S)
53 (12 S)
0 (0)
BINAP catalysts provided marginal enhancements in selectivity
with (R)-BINAP affording the matched pair with 39% de (
lectivity) and (S)-BINAP the mis-matched pair with 23% de (
selectivity). Disappointingly, the application of variety of
D
-(R)-se-
L-(S)-
a
bisphosphine ligands provided no significant enhancement in
selectivity including diphosphite ligand (R,R,R)-6, which had pre-
viously afforded up to 72% ee when applied to the addition of
boronic acids to methyl 2-acetamidoacrylate.7c The rhodium source
used in the reaction had little effect on the reactivity and selectivity
of the reaction with the presence of sodium fluoride having
a greater effect reducing the undesired side reactions and providing
cleaner products.
9
10
11
a
Conditions: (A) [RhCl(C2H4)2]2 (1.5 mol %), (R)-BINAP (3.3 mol %), ArB(OH)2
(3 equiv), NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h; (B) [Rh(COD)2][BF4]
(3 mol %), ArSi(OMe)3 (2 equiv), dioxane/H2O 10:1, 110 ꢀC, 24 h.
b
Diastereoselectivity calculated from proton NMR spectroscopy, configuration of
new stereocentre of the major diastereomer.

9530
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
compared to previous studies,7b was attributed to the dimerisation
of the boronic acid to itself via the rhodium-catalysed 1,2-addition
to the aldehyde, a reaction, which is hindered in the absence of
organic solvent. Whilst addition of phenylsiloxane provided no
natural selectivity, the more electron deficient 4-trifluorophenyl
and 4-chlorophenyl siloxanes afforded 22% and 12% diaster-
eoselectivity, respectively. Intriguingly, a reversal in natural selec-
tivity from R to S is also observed possibly as a result of the
coordination orientation during the all important protonation step.
However, throughout our previous studies, we have observed no
switch in selectivity.8b
Table 3
Additions to dipeptides 9–11
Entry
Substrate
Conditionsa
Organometallic
Yield (d.e.)b
%
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
A
B
B
B
C
C
C
C
C
D
D
D
D
D
D
PhB(OH)2
66 (23 R)
43 (20 S)
65 (22 S)
33 (38 S)
80 (<1)
60 (<1)
81 (4 S)
76 (15 S)
78 (<1)
86 (<1)
65 (<1)
57 (<1)
65 (<1)
68 (<1)
50 (<1)
3-NO2-PhB(OH)2
4-Ac-PhB(OH)2
4-CHO-PhB(OH)2
PhSi(OMe)3
4-Cl-PhSi(OMe)3
2-Me-PhSi(OMe)3
9-phenanthrene-Si(OMe)3
4-OMe-PhSi(OMe)3
4-CN-PhB(OH)2
4-OMe-PhB(OH)2
4-Cl-PhB(OH)2
9
9
10
11
12
13
14
15
10
10
10
11
11
11
Variation of the N-terminal amino acid was also possible and
provided equivalent reactivity. The three tripeptides Boc-Phe-
OMe 9, Boc-Tyr- Ala-OMe 10 and Boc-Trp- Ala-OMe 11 were
prepared from the corresponding serine precursors. Dehydration
was performed using EDCI and Cu(I) Cl with the Boc-Phe- Ala-OMe
DAla-
4-CN-PhB(OH)2
4-Cl-PhB(OH)2
4-F-PhB(OH)2
D
D
D
a
Conditions: (A) [RhCl(C2H4)2]2 (3 mol %), (R,R,R)-6 (6.6 mol %), PhB(OH)2
(4 equiv), NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h; (B) [RhCl(C2H4)2]2
(1.5 mol %), (R)-BINAP (3.3 mol %), ArB(OH)2 (3 equiv), NaF (3 equiv), dioxane/H2O
10:1, 100 ꢀC, 20 h; (C) [Rh(COD)2][BF4] (3 mol %), ArSi(OMe)3 (2 equiv), dioxane/H2O
10:1, 110 ꢀC, 24 h; (D) Rh(acac)(C2H4)2 (6 mol %), (Rac)-BINAP (6.6 mol %), ArB(OH)2
(4 equiv), NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h.
dipeptide isolated in >75% yield. The presence of the phenolic OH
of tyrosine proved problematic, however, with yields decreasing to
around 45%. A comparable loss of reactivity was observed with
tryptophan providing average yields of 55%.
b
Calculated from proton NMR spectroscopy, configuration of new stereocentre of
the major diastereomer.
to a dehydroalanine fragment encased in a tripeptide or poly-
peptide. To this end, we investigated the addition to tripeptide
substrates with an a,b-unsaturated amide. These substrates provide
a number of interesting facets including an expected drop in
reactivity of the acrylate and steric effects provided on either side of
the acrylate.
Dehydration of Boc-Phe-Ser-Gly-OMe with EDCI and CuCl
afforded the desired
DAla containing peptide 15 in 82%. However,
as with the dipeptide series where tyrosine or tryptophan residues
were adjacent to the serine, problems were encountered during
dehydration with little product isolated. Further attempts at
progressing via O-acetyl serine with elimination under basic con-
ditions also failed to provide significant quantities of the desired
peptide. Pleasingly, application of oxidative elimination of cysteine
However, the reactivity of the rhodium-catalysed addition to
these substrates was comparable to those with Boc-Val-DAla-OMe
with a range of siloxanes and boronic acids coupled in 33–86% yield
(Table 3). The proximity of the phenol and indole groups to the
reactive centre affected the selectivity with little or no natural
ethers allowed for the preparation of Boc-Trp-
67% yield over three steps.
DAla-Tyr-OMe 16 in
diastereoselectivity observed for the addition to Boc-Trp-
DAla-OMe
and Boc-Tyr- Ala-OMe (Table 3, entries 10–15).
D
Further to these dipeptides, we also synthesised Boc-Val-
Cys(SMe)-Ser-OMe 12 with a view to investigate the resilience of
the methodology to the presence of a thioether, which would also
allow for the subsequent elimination through oxidation to sulfox-
ide. Pleasingly, the serine residue can be dehydrated with CuCl and
EDCI to provide the dehydroalanine containing peptide Boc-Val-
Cys-DAla-OMe 13 in 83% yield, and the 1,4-addition can be per-
formed albeit in low yield and selectivity with 4-tert-butylphenyl
boronic acid, 30% and 23%, respectively (Scheme 2). The ability to
perform the selective elimination and 1,4-addition provides a
viable route to the sequential modification of a peptide chain or
complex organic molecule at a late stage of the synthesis.
Initial additions to the simple tripeptide Boc-Phe-DAla-Gly-OEt
15 with phenyl boronic acid provided a pleasing level of reactivity,
with the Rh(acac)(C2H4)2/Rac-BINAP catalyst providing 85% isola-
ted yield. Cyclooctadiene based rhodium catalysts, [Rh(COD)2][BF4],
[RhCl(COD)]2, [Rh(OH)(COD)]2, provided significantly lower yields
Whilst the addition to a dehydroalanine ester as a dipeptide is
noteworthy, the greater challenge would be the selective addition
Scheme 2. Chemoselective modification of tripeptide 12. (i) EDCI, Cu(I) Cl, CH2Cl2, rt, 18 h; (ii) [RhCl(C2H4)2]2 (3 mol %), (S)-BINAP (6.6 mol %), 4-t-Bu-PhB(OH)2 (4 equiv), NaF
(3 equiv), dioxane/H2O (10:1), 100 ꢀC, 20 h.

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9531
compared to the bisphosphine/Rh(ethylene) based systems
Rh(acac)(C2H4)2 and [RhCl(C2H4)2]2 in the reaction. Disappoint-
ingly, addition of phenylsiloxanes could not be achieved with
L
-phenylalanine being formed. Application of the chiral BINAP
complexes provided more promising results with (S)-BINAP pro-
viding a 45% yield of solely the -phenylalanine addition product,
whilst (R)-BINAP provided a 50% yield of the -phenylalanine
adduct together with an 8% yield of the unnatural -isomer also
D
these
a,
b-unsaturated amide substrates. Whilst no natural selec-
L
tivity was observed in the addition of phenyl boronic acid with
Rac-BINAP based catalysts, additions performed with 4-fluoro-
phenylboronic acid provided a selectivity of 8% de. In similar
fashion to the dipeptide substrates, the use of chiral BINAP com-
plexes provided marginal selectivity with (R)-BINAP yielding a 28%
de and (S)-BINAP 44% de. Significantly, the reversal in ligand
selectivity should be highlighted from that obtained with the
D
isolated by flash column chromatography. Similarly, the addition of
three further boronic acids with (R)-BINAP based catalysts provided
single isomers of the products in 32–68% isolated yield as single
diastereoisomers (Table 5). These results further confirm this
methodology as a plausible method for the late stage modification
of peptides and complex organic molecules.
Boc-Val-DAla-OMe system with in this case (S)-BINAP rather than
Table 5
(R)-BINAP providing the matched pair and the higher diaster-
Additions to the lower portion of Urotensin agonist substrate 18
eoselectivity. The presence of a chiral centre on either side of the
dehydroalanine residue affords only
product (Table 4).
a single diastereomeric
Table 4
Additions to tripeptides 15 and 16
Conditionsa
Organometallic
Yield (d.e.)b
%
Entry
Conditionsa
Boronic acid
Yield (%)
Entry
Substrate
1
2
3
4
5
6
7
(R)-A
(R)-B
(S)-A
(Rac)-A
(R)-B
(R)-B
(R)–B
PhB(OH)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
1-NaphthylB(OH)2
2-NaphthylB(OH)2
3,5-di(F)-PhB(OH)2
50 L(S)þ8 D(R)
31 L(S)
45 D(R)
1
2
3
4
5
6
7
8
15
15
15
15
15
15
15
15
16
16
16
(Rac)-A
(R)-A
(S)-B
(Rac)-A
C
(Rac)-A
(Rac)-A
(Rac)-A
(Rac)-A
(Rac)-A
(Rac)-A
PhB(OH)2
85
4-F-PhB(OH)2
4-F-PhB(OH)2
4-F-PhB(OH)2
PhSi(OMe)3
4-Cl-PhB(OH)2
3-NO2-PhB(OH)2
4-Br-PhB(OH)2
4-F-PhB(OH)2
4-CN-PhB(OH)2
3,5-di-CF3-PhB(OH)2
61c (28 ꢂ)
82c (44 þ)
79 (8 þ)
0
82
43
34 (19% d.e. L(S))
56 L(S)b
68 L(S)b
32 L(S)b
35
a
Conditions: (A) [RhCl(C2H4)2]2 (3 mol %), BINAP (6.6 mol %), PhB(OH)2 (4 equiv),
NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h; (B) [Rh(acac)(C2H4)2]2 (1.5 mol %),
BINAP (3.3 mol %), ArB(OH)2 (3 equiv), NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h.
9
10
11
54 (>99 þ)
14 (>99 þ)
38 (>99)
b
Assigned by comparison of proton NMR spectroscopy and selectivity in other
a
reactions.
Conditions: (A) Rh(acac)(C2H4)2 (6 mol %), BINAP (6.6 mol %), ArB(OH)2
(4 equiv), NaF (3 equiv), dioxane/H2O 10:1, 100 ꢀC, 20 h; (B) [RhCl(C2H4)2]2
(1.5 mol %), BINAP (3.3 mol %), ArB(OH)2 (3 equiv), NaF (3 equiv), dioxane/H2O 10:1,
100 ꢀC, 20 h; (C) [Rh(COD)2][BF4] (3 mol %), ArSi(OMe)3 (2 equiv), dioxane/H2O 10:1,
110 ꢀC, 24 h.
3. Conclusion
b
Calculated from proton NMR spectroscopy, configuration of new stereocentre of
Inconclusion, wehaveselectivelymodified peptidesatdesignated
residues through an efficient process enabling the incorporation of
diversity both quickly and with high diastereoselectivity. The prep-
aration of a common intermediate, which can be modified, from
a range of different primary residues enables the highly selective
alteration of complex molecules. We have shown that this method-
ology can be applied to a range of peptide substrates with high
selectivity and yield, enabling the rapid interjection of an array of
chemical variation in a molecule from a common beginning. Efforts
are ongoing to further appreciate the mechanism and understanding
of the chirality inducing protonation phase.
the major diastereomer.
To further explore the scope of this result and the limits of the
methodology, we investigated its application as an efficient pro-
cedure to synthesise analogues of the urotensin receptor agonists
recently described by Hirschmann and co-workers (Scheme 3).20
We elected to investigate the lower portion as a viable test sub-
strate, in which to modify the
easily imagine the preparation of a
b
-naphthylalanine residue. One can
Ala residue from which mul-
D
tiple analogues can be prepared to investigate interactions with the
binding pocket of the urotensin. Synthesis of the lower half of the
cyclic hexapeptide was performed by standard peptide coupling
techniques to provide the tripeptide Boc-Lys(Cbz)-Ser-Ala-OMe 19,
which was subsequently dehydrated at the serine residue in 89%
yield to afford the dehydroalanine containing tripeptide 18.
Preliminary studies looking at the addition of phenyl boronic acid
proved fruitful with Rac-BINAP providing the desired product in
34% yield and a natural selectivity of 19% de in preference to the
4. Experimental
4.1. General procedure for the rhodium-catalysed 1,4-
addition of aryl boronic acids to
DAla containing peptides
An oven dried flask was charged with peptide (0.2 mmol),
Rh(acac)(C2H4)2 (6 mol %, 1.2ꢁ10ꢂ5 mol), Rac-BINAP (6.6 mol %,
Scheme 3. Urotensin agonist 17 provides a worthy test substrate for the application of the residue selective modification of proteins. (i) CuCl, EDCI, DCM, 18 h.

9532
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
1.3ꢁ10ꢂ5 mol), ArB(OH)2 (4 equiv 0.8 mmol) and dioxane (2 mL),
evacuated and backfilled with argon and stirred at room temper-
ature for 10 min. Water (0.2 mL) was added and the mixture heated
at 100 ꢀC for 20 h. After cooling to room temperature, the resulting
mixture was diluted with ethyl acetate (5 mL) and extracted with
water (10 mL). The aqueous wash was back extracted with ethyl
acetate (2ꢁ5 mL) and the combined organics washed with satu-
rated NaHCO3 solution (10 mL), brine (10 mL), dried over MgSO4
and evaporated in vacuo. The residue was purified by column
chromatography to afford the desired compound.
(minor) and 17.5; HRMS (ESIþ) calcd for C20H30N2NaO5: 401.2041
[MþNa]þ, found: 401.2052 [MþNa]þ.
4.3.3. Boc-Val-Phe(4-Cl)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-DAla-OMe (150 mg, 0.5 mmol)
was reacted with 4-chlorobenzene boronic acid (235 mg,
1.5 mmol). The title compound was obtained as a mixture of
diastereomers in 86% yield (177 mg) as an off white solid. Mp 121–
123 ꢀC; IR (film, cmꢂ1
) n 4215, 3429, 3332, 3019, 2970, 2934, 2875,
2401, 1742, 1668, 1494, 1447, 1436, 1410, 1392, 1368, 1218, 1173,
4.2. General procedure for the rhodium-catalysed 1,4-
1093, 1016, 928, 869, 841, 758, 668; 1H NMR (CDCl3, 300 MHz)
addition of organosiloxanes to
D
Ala containing peptides
d
7.25 (2H, dd, J¼2.1, 8.7), 7.05 (2H, dd, J¼2.1, 8.7), 6.50 and 6.38 (1H,
d, J¼7.8), 5.01–4.83 (2H, m), 4.00–3.95 and 3.87 (1H, m and dd,
J¼6.3, 8.4), 3.72 (3H, s), 3.17–3.02 (2H, m), 2.21–2.04 (1H, m), 1.45
and 1.44 (9H, s), 0.90–0.80 (6H, m); 13C NMR (CDCl3, 75.5 MHz)
An oven dried carousel tube was charged with [Rh(COD)2][BF4]
(3 mol %) and the corresponding peptide (0.25 mmol) in anhydrous
dioxane (2 mL) under an atmosphere of nitrogen, followed by the
appropriate siloxane (0.5 mmol, 2 equiv) and water (0.2 mL). The
resulting solution was heated to reflux for 24 h at 110 ꢀC and
allowed to cool to room temperature. Solvents were removed
under reduced pressure, the residue re-dissolved in ethyl acetate
(20 mL) and washed with water (20 mL), saturated NaHCO3 solu-
tion (20 mL) and brine (20 mL). The organic extract was dried over
MgSO4 and concentrated in vacuo to afford the crude product,
which was further purified by flash chromatography to afford the
desired compound.
d
171.9 and 171.8, 171.67 (minor) and 171.65, 156.18, 134.57 and
134.53 (minor), 133.42, 130.96 (minor) and 130.89, 129.11 and
129.08, 80.69, 60.04, 53.31 (minor) and 53.17, 52.81 and 52.80
(minor), 37.72 and 37.69 (minor), 31.02 (minor) and 30.77, 28.61,
19.66 and 19.56 (minor), 17.46 and 17.44 (minor); HRMS (ESIþ)
calcd for C20H29ClN2NaO5: 435.1663 [MþNa]þ, found: 435.1661
[MþNa]þ.
4.3.4. Boc-Val-Phe(4-Ac)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-DAla-OMe (150 mg, 0.5 mmol)
4.3. Dipeptides
was reacted with 4-acetylbenzene boronic acid (246 mg,
01.5 mmol). The title compound was obtained as a mixture of di-
astereomers in 86%ꢂy1ield (181 mg) as a colourless solid. Mp 123–
4.3.1. Boc-Val-DAla-OMe (1)
An oven dried flask was charged with Boc-Val-Ser-OMe (3.31 g,
10.4 mmol) dissolved in degassed dichloromethane (80 mL) under
an atmosphere of nitrogen, copper(I) chloride (309 mg, 3.12 mmol)
and EDCI (2.19 g, 11.4 mmol) were subsequently added and the
resultant suspension stirred for 18 h at ambient temperature. The
solution was washed with two portions of water (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure.
Purification by flash column chromatography (petroleum ether/
126 ꢀC; IR (film, cm
) n 3340, 3008, 2967, 2934, 2875, 1744, 1652,
1608, 1520, 1436, 1415, 1392, 1366, 1269, 1175, 1120, 1043, 1018, 958,
928, 870, 850, 822, 755, 666, 596; 1H NMR (CDCl3, 300 MHz)
d
7.86
(2H, d, J¼8.4), 7.21 (2H, d, J¼8.4), 6.61 and 6.49 (1H, d, J¼7.5), 5.03–
4.85 (2H, m), 3.98–3.85 (1H, m), 3.70 (3H, s), 3.21 and 3.20 (1H, dd,
J¼5.7, 14.1), 3.12 and 3.11 (1H, dd, J¼5.7, 14.1), 2.56 and 2.55 (3H, s),
2.17–2.03 (1H, m), 1.43 and 1.41 (9H, s), 0.92–0.83 (4H, m), 0.79
(2H, d, J¼6.9); 13C NMR (CDCl3, 75.5 MHz)
d 198.0 and 197.9 (mi-
ethyl acetate 5:1) gave the title compound as a colourless foam in
91% yield (2.85 g). [
nor), 171.81, 171.75 (minor) and 171.71, 156.1, 141.84 and 141.79
(minor), 136.3, 129.85 (minor) and 129.80, 129.0, 80.4, 60.3 (minor)
and 60.0, 53.23 (minor) and 53.11, 52.79 and 52.77 (minor), 38.3,
31.0 and 30.8, 28.58, 26.9, 19.6 and 19.5 (minor), 17.5; HRMS (ESIþ)
calcd for C22H32N2NaO6: 443.2158 [MþNa]þ, found: 443.2152
[MþNa]þ.
20
a]
ꢂ23.19 (c 0.69, CHCl3); IR (film, cmꢂ1
) n
D
3281, 3045, 2956, 2254, 1824, 1743, 1667, 1536, 1437, 1389, 1364,
1297, 1247, 1155, 1043, 1018, 992, 909, 882, 867, 800, 718; 1H NMR
(CDCl3, 300 MHz)
d
8.23 (1H, s), 6.60 (1H, s), 5.89 (1H, d, J¼1.5), 5.12
(1H, d, J¼8.1), 4.06 (1H, m), 3.83 (3H, s), 2.19 (1H, app octet, J¼6.9),
1.43 (9H, s), 0.97 (3H, d, J¼6.9), 0.91 (3H, d, J¼6.9); 13C NMR (CDCl3,
75.5 MHz)
d
171.0, 164.6, 156.1, 130.9, 109.6, 80.4, 60.9, 53.3, 31.1,
4.3.5. Boc-Val-1-Nal-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-DAla-OMe (150 mg, 0.5 mmol)
28.6, 19.6, 17.8; HRMS (ESIþ) calcd for C14H24N2NaO5: 323.1583
[MþNa]þ, found: 323.1585 [MþNa]þ.
was reacted with 1-naphthyl boronic acid (258 mg, 1.5 mmol). The
title compound was obtained as a mixture of diastereomers in 62%
4.3.2. Boc-Val-Phe-OMe (2)
In accordance with the representative procedure for 1,4-addi-
yield (132 mg) as a colourless solid. Mp 119–122 ꢀC; IR (film, cmꢂ1
)
tions with boronic acids, Boc-Val-
D
Ala-OMe (60 mg, 0.2 mmol) was
n
3431, 3018, 2969, 2091, 1740, 1665, 1501, 1456, 1438, 1392, 1368,
reacted with phenyl boronic acid (97.5 mg, 0.8 mmol). The title
compound was obtained as a mixture of diastereomers in 83% yield
1283, 1216, 1163, 1018, 927, 757; 1H NMR (CDCl3, 300 MHz)
d
8.13
and 8.12 (1H, d, J¼8.4), 7.85 (1H, d, J¼8.1), 7.76 (1H, d, J¼8.1), 7.59–
7.46 (2H, m), 7.38 (1H, app t, J¼8.7), 7.27 (1H, app t, J¼6.3), 6.84 and
6.72 (1H, d, J¼7.8), 5.16 (1H, app t, J¼9.0), 5.01 (1H, app q, J¼7.5),
4.03–3.94 (1H, m), 3.60 and 3.59 (3H, s), 3.57–3.52 (2H, m), 1.46 and
(63 mg) as a colourless solid. Mp 93–96 ꢀC; IR (film, cmꢂ1
)
n
3422,
2968, 1742, 1654, 1551, 1498, 1456, 1391, 1367, 1298, 1169, 1106,
1044, 1017, 911, 872, 839, 697; 1H NMR (CDCl3, 300 MHz)
7.3–7.2
d
(3H, m), 7.11 (2H, dd, J¼1.7, 7.8), 6.57 and 6.45 (1H, d, J¼7.8), 5.2–5.0
(1H, m), 4.9–4.8 (1H, m), 4.0–3.9 (1H, m), 3.70 (3H, s), 3.13 (1H, dd,
J¼5.4, 13.8), 3.05 (1H, d, J¼6.9, 14.1), 2.1–2.0 (1H, m), 1.44 and 1.43
(9H, s), 0.91 (1H, d, J¼6.9), 0.86 (3H, app d, J¼6.9), 0.78 (2H, d,
1.44 (9H, s), 0.94–0.75 (6H, m); 13C NMR (CDCl3, 75.5 MHz)
d 172.5
(minor) and 172.3, 171.8 and 171.7 (minor), 156.1 and 156.0 (minor),
134.12 and 134.10 (minor), 132.5, 132.3 (minor) and 132.2, 129.1,
128.20 and 128.19 (minor), 127.7, 126.7 and 126.6 (minor), 126.0,
125.50 (minor) and 125.45, 123.7 (minor) and 123.6, 80.0, 60.0
(minor) and 59.8, 53.4 (minor) and 53.3, 52.5 and 52.4 (minor), 35.8
and 35.6 (minor), 31.2 (minor) and 31.1, 19.42 and 19.38 (minor),
17.86 (minor) and 17.52; HRMS (ESIþ) calcd for C24H33N2O5:
429.2389 [MþH]þ, found: 429.2374 [MþH]þ.
J¼6.9); 13C NMR (CDCl3, 75.5 MHz)
d 172.5 and 172.0 (minor), 171.6,
156.1 and 156.0 (minor), 136.1 and 136.0 (minor), 129.5 (minor) and
129.4, 128.91 and 128.89 (minor), 127.4, 80.2, 60.1 (minor) and 59.9,
53.4 (minor) and 53.3, 52.63 and 52.59 (minor), 38.3 and 38.2
(minor), 31.2 (minor) and 31.0, 28.6, 19.5 and 19.4 (minor), 18.0

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9533
4.3.6. Boc-Val-Phe(3-Br)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-
(CDCl3, cmꢂ1
1368, 1325, 1299, 1216, 1165, 1125, 1067, 1018, 757, 666; 1H NMR
(CDCl3, 300 MHz)
6.43 (1H, d, J¼7.8), 4.98–4.78 (2H, m), 3.84–3.78 and 4.00–3.86 (1H,
m), 3.65 (3H, s), 3.16 (1H, dd, J¼5.6, 13.9), 3.04 (1H, dd, J¼6.4, 13.9),
1.94–2.20 (1H, m), 1.37 and 1.34 (9H, s), 0.96–0.70 (6H, m); 13C NMR
) n 3430, 3018, 2967, 1740, 1685, 1656, 1521, 1438, 1392,
D
Ala-OMe (150 mg, 0.5 mmol)
d
7.47 (2H, d, J¼7.9), 7.18 (2H, d, J¼7.9), 6.54 and
was reacted with 3-bromobenzene boronic acid (301 mg,
1.5 mmol). The title compound was obtained as a mixture of
diastereomers in 86% yield (196 mg) as a colourless foam. IR (film,
cmꢂ1
)
n
3344, 2962, 2872, 1734, 1688, 1649, 1552, 1521, 1476, 1435,
1390, 1366, 1349, 1299, 1245, 1177, 1121, 1073, 1044, 1020, 851, 818,
697; 1H NMR (CDCl3, 300 MHz)
(CDCl3, 75.5 MHz) d 171.8 and 171.8, 171.8 and 171.7, 156.1, 140.4,
129.6, 125.9, 122.7, 80.4, 60.5 and 60.1, 53.2 and 53.1, 52.8 and 52.8,
38.1, 30.5, 28.6, 19.7 and 19.6; 19F NMR (CDCl3, 376.4 MHz) ꢂ62.48
and ꢂ62.54; HRMS (ESIþ) calcd for C21H29F3N2O5: 447.2029
[MþH]þ, found: 447.2106 [MþH]þ.
d
7.35 (1H, dt, J¼7.8, 1.5), 7.28 (1H,
s), 7.14 (1H, app t, J¼7.8), 7.06 (1H, dt, J¼7.8, 1.5), 6.66 and 6.60 (1H,
d, J¼7.5), 5.08 (1H, d, J¼8.7), 4.90–4.81 (1H, m), 4.01–3.89 (1H, m),
3.71 (3H, s), 3.11 (1H, dd, J¼13.8, 5.7), 3.00 (1H, dd, J¼13.8, 8.1),
2.15–2.02 (1H, m), 1.44 and 1.42 (9H, s), 0.93–0.80 (6H, m); 13C NMR
4.3.10. Boc-Val-Phe(4-Me)-OMe
(CDCl3, 75.5 MHz)
d
171.9, 171.8 and 171.7 (minor), 156.1, 138.6 and
In accordance with the representative procedure for 1,4-addi-
138.5 (minor), 132.64 and 132.63 (minor), 130.5, 130.41 and 130.40
(minor), 128.2 (minor) and 128.1, 122.85 and 122.82 (minor), 80.2,
60.4 (minor) and 59.9, 53.4 (minor) and 53.3, 52.8 and 52.7 (minor),
37.9, 31.1 and 30.0 (minor), 28.6, 19.6 and 19.5 (minor), 18.1 (minor)
and 17.5; HRMS (ESIþ) calcd for C20H30BrN2O5: 457.1338 [MþH]þ,
found: 457.1329 [MþH]þ.
tions with siloxanes, Boc-Val-
reacted with triethoxy(p-tolyl)silane (193
compound was isolated as a mixture of diasteromers as a colourless
oil (98 mg, 66%). Mp 92–94 ꢀC; IR (CDCl3, cmꢂ1
3312, 3053, 2963,
D
Ala-OMe (75 mg, 0.25 mmol) was
mL, 0.75 mmol). The title
)
n
2929, 2873, 2251, 1745, 1702, 1656, 1542, 1515, 1458, 1435, 1390,
1366, 1291, 1248, 1176, 1119, 1043, 1017, 910, 880, 731, 647; 1H NMR
(CDCl3, 300 MHz)
d
7.08 (2H, d, J¼7.9), 6.99 (2H, d, J¼7.9), 6.40 and
4.3.7. Boc-Val-Phe(4-CHO)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-DAla-OMe (150 mg, 0.5 mmol)
6.28 (1H, d, J¼7.9), 5.08–4.90 (1H, m), 4.84 (1H, app dq, J¼7.9, 6.0),
4.00–3.85 (1H, m), 3.71 (3H, s), 3.14–2.99 (2H, m), 2.30 (3H, s), 2.16–
2.01 (1H, m), 1.44 and 1.43 (9H, s) 0.93–0.8 (6H, m); 13C NMR
was reacted with 4-formylbenzene boronic acid (225 mg,
1.5 mmol). The title compound was obtained as a mixture of
diastereomers in 33% yield (45 mg) as an off white foam. IR (film,
(CDCl3, 75.5 MHz) d 172.2 and 172.1, 171.6 and 171.5, 156.1, 137.1,
132.9,130.2,129.7 and 129.4, 80.2, 60.2 and 60.0, 53.5 and 53.4, 52.9
and 52.6, 37.9, 31.2 and 31.0, 28.6, 21.8 and 21.4, 21.2; HRMS (ESIþ)
calcd for C21H32N2NaO5: 415.2209 [MþNa]þ, found: 415.2224
[MþNa]þ.
cmꢂ1
)
n
3425, 3316, 3019, 2968, 2934, 2875, 1743, 1702, 1670, 1610,
1578, 1507, 1455, 1438, 1420, 1392, 1368, 1216, 1171, 1118, 1043, 1019,
851, 759, 668; 1H NMR (CDCl3, 300 MHz)
9.94 and 9.93 (1H, s),
d
7.78 (2H, d, J¼8.1), 7.30 (2H, d, J¼8.1), 6.74 and 6.64 (1H, d, J¼4.8),
5.09–5.03 (1H, m), 4.92–4.87 (1H, m), 3.99–3.86 (1H, m), 3.702 and
3.699 (3H, s), 3.23 (1H, dd, J¼5.7, 13.8), 3.13 and 3.12 (1H, dd, J¼6.9,
4.3.11. Boc-Phe-DAla-OMe (9)
An oven dried flask was charged with Boc-Phe-Ser-OMe (1.80 g,
4.91 mmol) dissolved in degassed dichloromethane (60 mL) under
an atmosphere of nitrogen, copper(I) chloride (145 mg, 1.47 mmol)
and EDCI (1.04 g, 5.40 mmol) were subsequently added and the
resultant suspension stirred for 18 h at ambient temperature. The
solution was washed with two portions of water (20 mL), dried
over MgSO4, filtered and concentrated under reduced pressure.
Purification by flash column chromatography (petroleum ether/
13.8), 2.15–2.02 (1H, m),1.43 and 1.41 (9H, s), 0.91–0.77 (6H, m); 13
C
NMR (CDCl3, 75.5 MHz)
d 192.13 (minor) and 192.08, 171.9 (minor)
and 171.84, 171.77 and 171.6 (minor), 156.2 and 156.1 (minor),
143.54 and 143.47 (minor), 135.63 and 135.61 (minor), 130.27,
130.25, 80.3, 60.3 (minor) and 60.0, 53.2 (minor) and 53.1, 52.79
and 52.77 (minor), 38.5, 31.0 (minor) and 30.8, 28.6, 19.6 and 19.5
(minor), 18.3 (minor) and 17.5; HRMS (ESIþ) calcd for C21H31N2O6:
407.2182 [MþH]þ, found: 407.2159 [MþH]þ.
ethyl acetate 5:1) gave the title compound as a colourless foam in
20
77% yield (1.32 g). [
a]
ꢂ17.58 (c 0.46, CHCl3); mp 94–96 ꢀC; IR
D
(CDCl3, cmꢂ1
) n 3362, 3019, 2088, 1748, 1687, 1527, 1443, 1392, 1368,
4.3.8. Boc-Val-Phe(4-OMe)-OMe
1326, 1252, 1221, 1172, 1057, 1030, 988, 746, 702, 668; 1H NMR
(CDCl3, 300 MHz) 8.22 (1H, br s), 7.34–7.18 (5H, m), 6.62 (1H, s),
In accordance with the representative procedure for 1,4-
d
additions with siloxanes, Boc-Val-
was reacted with triethoxy(4-methoxyphenyl)silane (196
D
Ala-OMe (75 mg, 0.25 mmol)
5.90 (1H, d, J¼1.5), 5.11 (1H, br d, J¼7.2), 4.55–4.39 (1H, br m), 3.80
mL,
(3H, s), 3.16 (1H, dd, J¼6.6, 14.1), 3.13–3.04 (1H, m), 1.42 (9H, s); 13
C
0.75 mmol). The title compound was isolated as a mixture of
diasteromers as a colourless solid (87 mg, 85%). Mp 98–99 ꢀC; IR
NMR (CDCl3, 75.5 MHz) d 170.6, 164.3, 155.6, 136.6, 130.9, 129.5,
129.0, 127.3, 109.6, 80.7, 56.8, 53.2, 38.4, 28.5; HRMS (ESIþ) calcd for
(CDCl3, cmꢂ1
)
n
3054, 2964, 2935, 2874, 2838, 2253, 1743, 1706,
1664, 1612, 1513, 1465, 1437, 1367, 1265, 1250, 1178, 1117, 1036, 909,
840, 733; 1H NMR (CDCl3, 300 MHz)
C
18H24N2NaO5: 371.1583 [MþNa]þ, found: 371.1569 [MþNa]þ.
d
7.01 (2H, d, J¼8.6), 6.80 (2H,
4.3.12. Boc-Phe-Phe-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-OMe (70 mg, 0.2 mmol)
d, J¼8.6), 6.49 and 6.37 (1H, d, J¼7.9), 5.12–4.96 (1H, m), 4.86–4.77
(1H, m), 4.00–3.85 (1H, m), 3.76 and 3.75 (3H, s), 3.69 (3H, s), 3.05–
3.01 (2H, m), 2.17–2.03 (1H, m), 1.43 and 1.41 (9H, s), 0.96–0.84 (6H,
was reacted with phenyl boronic acid (98 mg, 0.8 mmol). The title
compound was obtained as a mixture of diastereomers in 66% yield
m); 13C NMR (CDCl3, 75.5 MHz)
d 172.3 and 172.1, 171.6 and 171.5,
159.1, 156.1, 130.6 and 130.5, 128.0 and 127.9, 114.4 and 114.4, 80.3,
60.2 and 60.0, 55.5 and 55.5, 53.6 and 53.5, 52.9 and 52.8, 37.5 and
37.4, 31.3 and 31.1, 28.6, 19.6 and 19.5; HRMS (ESIþ) calcd for
(55 mg) as a colourless solid. Mp 108–110 ꢀC; IR (film, cmꢂ1
) n 3312,
3088, 3065, 3030, 3008, 2980, 2953, 2932, 2864, 1950, 174, 1660,
1498, 1455, 1438, 1392, 1367, 1251, 1218, 1171, 1116, 1080, 1049, 1023,
C
21H32N2NaO6: 401.2158 [MþNa]þ, found: 431.2145 [MþNa]þ.
918, 887, 856, 817, 756, 700, 666; 1H NMR (CDCl3, 300 MHz)
d 7.32–
7.15 (8H, m), 7.02–6.94 (2H, m), 6.48 and 6.37 (1H, d, J¼7.5), 4.98–
5.05 (1H, m), 4.88–4.76 (1H, m), 4.42–4.32 (1H, m), 3.67 (3H, s),
3.12–2.94 (4H, m), 1.41 and 1.39 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
4.3.9. Boc-Val-Phe(4-CF3)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with siloxanes, Boc-Val-DAla-OMe (75 mg, 0.25 mmol) was
d 171.8 (minor) and 171.6, 171.2 and 171.1 (minor), 155.6, 136.9 and
reacted with triethoxy(4-(trifluoromethyl)phenyl)silane (210 mg,
0.75 mmol). The title compound was isolated as a mixture of dia-
steromers as a colourless solid (68 mg, 61%). Mp 122–124 ꢀC; IR
136.8 (minor), 135.95 and 135.87 (minor), 129.64 and 129.63 (mi-
nor), 129.50 and 129.45 (minor), 128.9 (minor) and 128.8, 127.42
(minor) and 127.37, 127.2, 80.4, 53.6, 53.4, 52.5, 38.7, 38.3 and 38.2

9534
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
(minor), 28.5; HRMS (ESIþ) calcd for C24H31N2O5: 427.2233
2933, 1740, 1651, 1614, 1583, 1512, 1475, 1418, 1491, 1378, 1313, 1257,
1227, 1175, 1111, 1033, 931; 1H NMR (250 MHz, CDCl3)
7.30–7.05
[MþH]þ, found: 427.2219 [MþH]þ.
d
(7H, m), 6.82 (2H, dd, J¼6.8), 6.35 and 6.25 (1H, d, J¼7.8), 4.9–4.65
(2H, m), 4.45–4.40 and 4.28–2.20 (1H, m), 3.61 and 3.60 (3H, s), 3.1–
2.8 (4H, m), 1.34 and 1.31 (9H, s); 13C NMR (75.5 MHz, CDCl3) 170.2
and 170.1, 169.9 and 169.8, 154.3, 135.5 and 135.4, 133.1 and 133.0,
132.1 and 132.0,129.6 and 129.5,128.34 and 128.31,127.7 and 127.6,
126.04 and 125.99, 79.4, 52.1 and 51.9, 51.5 and 51.4, 47.1 and 46.9,
37.2 and 31.1, 36.3 and 36.2, 27.2; HRMS (ESIþ) calcd for
4.3.13. Boc-Phe-Phe(3-NO2)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-OMe (174 mg, 0.5 mmol)
was reacted with 3-nitrobenzene boronic acid (250 mg, 1.5 mmol).
The title compound was obtained as a mixture of diastereomers in
43% yield (101 mg) as an off white solid. Mp 95–99 ꢀC; IR (film,
cmꢂ1
)
n
3316, 3065, 3028, 3009, 2979, 2956, 2932, 2868, 1746, 1671,
C
24H29N2NaO5Cl: 483.1663 [MþNa]þ, found: 483.1646 [MþNa]þ.
1531,1455,1438, 1392,1367,1352,1317,1252,1219,1170, 1082,1054,
1028, 988, 920, 885, 855, 820, 756, 700, 667; 1H NMR (CDCl3,
4.3.17. Boc-Phe-Phe(2-Me)-OMe
300 MHz)
d
8.08 (1H, dm, J¼7.5), 7.91–7.89 (1H, m), 7.40 (1H, app t,
In accordance with the representative procedure for 1,4-addi-
tions with siloxanes, Boc-Phe-DAla-OMe (87 mg, 0.25 mmol) was
reacted with triethoxy(o-tolyl)silane (127 mg, 0.5 mmol). The title
compound was obtained as a mixture of diastereomers in 81% yield
J¼7.8), 7.3–7.1 (6H, m), 6.63 and 6.53 (1H, d, J¼7.5), 4.92 (1H, d,
J¼8.1), 4.9–4.8 (1H, m), 4.4–4.3 (1H, m), 3.79 and 3.70 (3H, s), 3.3–
2.9 (4H, m) 1.38 and 1.36 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
d
171.49 (minor) and 171.45, 171.1, 155.7, 148.54 and 148.53 (minor),
(90 mg) as a colourless oil. IR (film, cmꢂ1
)
n
3054, 2984, 1741, 1712,
1678, 1497, 1255, 1438, 1368, 1211, 1167, 1049; 1H NMR (300 MHz,
CDCl3) 7.35–7.05 (8H, m), 7.00–6.89 (1H, m), 6.55 and 6.40 (1H, dd,
J¼7.6), 5.10–5.05 (1H, m), 4.75 (1H, m), 4.40–4.30 (1H, m), 3.64 (3H,
s), 2.88–3.14 (4H, m), 2.32 and 2.31 (3H, s), 1.41 and 1.39 (9H, s); 13
138.3 (minor) and 138.2, 136.8 and 136.7 (minor), 135.92 (minor)
and 135.86, 129.79 and 129.75 (minor), 129.7 (minor) and 129.6,
129.0, 127.4, 124.5 (minor) and 124.4, 122.5, 80.8, 56.1, 53.4 (minor)
and 53.3, 52.9, 38.3, 37.9, 28.6 (minor) and 28.5; HRMS (ESIþ) calcd
for C24H29N3NaO7: 494.1903 [MþNa]þ, found: 494.1899 [MþNa]þ.
d
C
NMR (75.5 MHz, CDCl3) 172.5, 172.2, 171.2, 137.0, 136.9, 134.4, 131.0,
130.1, 130.1, 129.7, 129.7, 129.0, 127.6, 127.3, 126.4, 80.5, 60.8, 52.8,
38.7, 36.3, 36.1, 28.6, 21.4, 19.7, 19.6, 14.6; HRMS (CIþ) calcd for
4.3.14. Boc-Phe-Phe(4-Ac)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-OMe (174 mg, 0.5 mmol)
C
25H33N2O5: 441.2384 [MþH]þ, found: 441.2385 [MþH]þ.
was reacted with 4-acetylbenzene boronic acid (246 mg, 1.5 mmol).
The title compound was obtained as a mixture of diastereomers in
4.3.18. Boc-Phe-Anthtra-OMe
In accordance with the representative procedure for 1,4-addi-
tions with siloxanes, Boc-Phe-
65% yield (152 mg) as a colourless foam. IR (film, cmꢂ1
)
n
4064,
D
Ala-OMe (87 mg, 0.25 mmol) was
(170 mg,
3672, 3303, 3063, 3029, 3807, 2979, 2964, 2932, 2866, 1744, 1682,
1608, 1521,1455, 1438,1415,1392,1366,1269,1219,1170, 1121,1079,
1048, 1019, 959, 888, 853, 823, 755, 700, 666, 597; 1H NMR (CDCl3,
reacted with triethoxy(phenanthren-10-yl)silane
0.5 mmol). The title compound was obtained as a mixture of di-
astereomers in 76% ꢂy1ield (100 mg) as a colourless solid. Mp 199–
) n 3320, 1744, 1659, 1523, 1497, 1455, 1391,
300 MHz)
d
7.83 and 7.52 (2H, d, J¼8.1), 7.32–7.05 (7H, m), 6.68 and
201 ꢀC; IR (film, cm
6.56 (1H, d, J¼7.5), 5.08 (1H, d, J¼8.1), 4.90–4.89 (1H, m), 4.44–4.34
1357, 1213, 1123, 1022, 856; 1H NMR (300 MHz, CDCl3)
d 8.64–8.63
(1H, m), 3.67 (3H, s), 3.19–2.94 (4H, m), 2.564 and 2.559 (3H, s), 1.40
(1H, m, Ar), 8.60–8.56 (1H, d, J¼8.1), 8.10–8.04 (1H, m), 7.72–7.70
(1H, m), 7.63–7.40 (4H, m), 7.41–7.34 (1H, d, J¼15.2), 7.00–7.18 (5H,
m), 6.42 and 6.30 (1H, dd, J¼7.4), 4.9 (2H, m), 4.28 (1H, m), 3.42 (3H,
s), 3.41–3.30 (2H, m), 2.90 (2H, m), 1.28 (9H, s); 13C NMR (75.5 MHz,
CDCl3) 172.4, 172.1, 171.4, 136.8, 131.7, 131.2, 131.2, 131.1, 131.1, 130.8,
130.5, 129.7, 129.6, 129.0, 128.9, 128.6, 127.4, 127.3, 127.2, 127.0,
124.5, 124.4, 123.7, 122.9, 79.1, 53.3, 53.3, 52.6, 36.4, 28.6, 14.1;
HRMS (ESIþ) calcd for C32H35N2O5: 527.2540 [MþH]þ, found:
527.2542 [MþH]þ.
and 1.38 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
d 197.92 (minor) and
197.87, 171.5, 171.33 and 171.29 (minor), 155.6, 141.7 (minor) and
141.6, 136.8 and 136.7 (minor), 136.21 and 136.20 (minor), 129.6,
128.9,128.84 and 128.79 (minor),127.2, 80.5, 56.0, 53.3 (minor) and
53.1, 52.6, 38.4 and 38.2 (minor) and 38.1, 28.5, 26.8; HRMS (ESIþ)
calcd for C26H33N2O6: 469.2339 [MþH]þ, found: 469.2340 [MþH]þ.
4.3.15. Boc-Phe-Phe(4-CHO)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-
D
Ala-OMe (174 mg, 0.5 mmol)
4.3.19. Boc-Phe-Phe(4-OMe)-OMe
was reacted with 4-formylbenzene boronic acid (225 mg,
1.5 mmol). The title compound was obtained as a mixture of
diastereomers in 33% yield (76 mg) as a colourless foam. IR (film,
In accordance with the representative procedure for 1,4-addi-
tions with siloxanes, Boc-Phe-
reacted with triethoxy(4-methoxyphenyl)silane
0.75 mmol). The title compound was obtained as a mixture of di-
astereomers in 78% yield (90 mg) as a colourless oil. IR (film, cmꢂ1
3315, 2978, 2934, 1743, 1659, 1613, 1584, 1513, 1455, 1441, 1391,
1367, 1301, 1249, 1216, 1173, 1118, 1032, 911, 838, 789, 732, 700, 647;
1H NMR (300 MHz, CDCl3)
7.26–7.08 (5H, m), 6.85–6.65 (4H, m),
D
Ala-OMe (87 mg, 0.25 mmol) was
(148 mg,
cmꢂ1
)
n
3316, 3063, 3031, 2978, 2931, 2860, 2738, 2361, 1746, 1698,
1608, 1577, 1529, 1454, 1437, 1392, 1367, 1274, 1252, 1171, 1118, 1052,
1025, 986, 887, 852, 751, 700, 646; 1H NMR (CDCl3, 300 MHz)
9.95
)
d
n
(1H, s), 7.75 and 7.74 (2H, d, J¼8.1), 7.36–7.10 (7H, m), 6.61 and 6.50
(1H, d, J¼7.5), 5.99 (1H, d, J¼8.4), 4.91–4.81 (1H, m), 4.39–4.30 (1H,
m), 3.672 and 3.668 (3H, s), 3.21–2.95 (4H, m), 1.40 and 1.37 (9H, s);
d
6.27 and 6.17 (1H, d, J¼7.5), 4.86–4.80 (1H, m), 4.75–4.65 (1H, m),
4.45–4.20 (1H, m), 3.70 and 3.69 (3H, s), 3.60 (3H, s), 3.04–2.88 (4H,
m), 1.34 and 1.31 (9H, s); 13C NMR (75.5 MHz, CDCl3) 171.9 and
171.8, 171.1 and 171.0, 159.1 and 159.0, 155.9, 137.0 and 136.9, 130.6
and 130.5, 129.7 and 129.7, 129.0, 127.9 and 127.8, 127.3, 114.4 and
114.3, 80.6, 55.5, 53.8 and 53.5, 52.8 and 52.6, 48.3, 38.7, 37.4 and
37.4, 28.6; HRMS (ESIþ) calcd for C25H32N2NaO6: 479.2158
[MþNa]þ, found: 479.2158 [MþNa]þ.
13C NMR (CDCl3, 75.5 MHz)
d 192.12 (minor) and 192.09, 171.43,
171.38, 155.7, 143.3 (minor) and 143.2, 136.8 and 136.7 (minor),
135.6, 130.2, 129.6, 129.0, 127.3, 80.7, 56.0, 53.3 (minor) and 53.1,
52.7, 38.43, 38.37, 28.5; HRMS (ESIþ) calcd for C25H31N2O6:
455.2182 [MþH]þ, found: 455.2172 [MþH]þ.
4.3.16. Boc-Phe-Phe(4-Cl)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with siloxanes, Boc-Phe-
DAla-OMe (87 mg, 0.25 mmol) was
4.3.20. Boc-Tyr-DAla-OMe (10)
reacted with triethoxy(4-chlorophenyl)silane (185 mg, 0.75 mmol).
The title compound was obtained as a mixture of diastereomers in
To an oven dried flask were added Boc-Tyr-Ser-OMe (0.28 g,
0.73 mmol) in degassed dichloromethane (10 mL), copper(I) chlo-
ride (22 mg, 0.22 mmol) and EDCI (154 mg, 0.80 mmol, 1.1 equiv),
60% yield (69 mg) as a colourless oil. IR (film, cmꢂ1
) n 3331, 2987,

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9535
the flask was sealed and the solution stirred under an atmosphere
(CDCl3, 75.5 MHz)
d
171.8, 171.7, 171.6, 155.9, 155.7, 134.5, 134.4,
of nitrogen for 18 h at ambient temperature. The solution was di-
luted with dichloromethane (5 mL) and washed with two portions
of water (10 mL), dried over MgSO4, filtered and concentrated un-
der reduced pressure. Purification by flash column chromatography
133.5, 133.4, 131.0, 130.9, 130.8, 129.2, 129.1, 128.1, 116.0, 81.0, 53.8,
53.5, 52.8, 37.8, 37.7, 37.6, 28.6; HRMS (ESIþ) calcd for
C
24H30ClN2O6: 477.1787 [MþH]þ, found: 477.1788 [MþH]þ.
(ethyl acetate/petroleum ether 1:5) gave the title compound as
4.3.24. Boc-Trp-DAla-OMe (11)
20
a colourless solid (119 mg, 45%). [
a
]
ꢂ10.6 (c 0.47, CH2Cl2); mp
To an oven dried flask were added Boc-Trp-Ser-OMe (0.50 g,
1.23 mmol) in degassed dichloromethane (10 mL), copper(I) chlo-
ride (37 mg, 0.3 mmol) and EDCI (260 mg,1.35 mmol,1.1 equiv), the
flask was sealed and the solution stirred under an atmosphere of
nitrogen for 18 h at ambient temperature. The solution was diluted
with dichloromethane (5 mL) and washed with two portions of
water (10 mL), dried over MgSO4, filtered and concentrated under
reduced pressure. Purification by flash column chromatography
D
128–130 ꢀC; IR (KBr) 3415 (br), 3218 (br), 3015, 2929, 1736, 1687,
1665, 1634, 1593, 1544, 1515, 1479, 1440, 1400, 1368, 1269, 1199,
1163 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d 8.04 (1H, br s), 6.98 (2H, d,
J¼8.1), 6.69 (2H, d, J¼8.1), 6.60 (1H, s), 6.10–5.90 (1H, br s), 5.82 (1H,
br s), 4.92 (1H, br s), 4.15–4.02 (1H, m), 3.73 (3H, s), 2.99–2.94 (2H,
m), 1.35 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
d 170.8, 164.4, 155.9,
130.9, 130.7, 128.1, 116.1, 116.0, 109.9, 81.1, 57.1, 53.4, 49.7, 28.6; MS
(ESIþ) m/z 265.2 [MþH]þ; HRMS (ESIþ) calcd for C18H25N2O6:
365.1707 [MþH]þ, found: 365.1706 [MþH]þ.
(ethyl acetate/petroleum ether 1:5) gave the title compound as
20
a colourless solid (260 mg, 55%). Mps–[
a]
ꢂ35.8 (c 2.4, CH2Cl2);
D
mp 78–80 ꢀC; IR (KBr) 3371 (br), 3067, 2977, 2931, 2852, 1710, 1682,
1636, 1517, 1439, 1328, 1250, 1166, 1098, 1054, 1010, 961, 906,
4.3.21. Boc-Tyr-Phe(4-CN)-OMe
In accordance with the representative procedure for 1,4-addi-
742 cmꢂ1; 1H NMR (CDCl3, 400 MHz)
d 8.23 (1H, br s), 8.06 (1H, br
tions with boronic acids, Boc-Tyr-
D
Ala-OMe (55 mg, 0.15 mmol)
s), 7.53 (1H, d, J¼9.0), 7.26 (1H, d, J¼9.0), 7.11 (1H, t, J¼6.9), 7.05 (1H,
t, J¼6.9), 6.95 (1H, br s), 6.52 (1H, br s), 5.78 (1H, br s), 5.07 (1H, br
s), 4.45 (1H, br s), 3.64 (3H, s), 3.24–3.13 (2H, m), 1.32 (9H, s); 13C
was reacted with 4-cyanobenzene boronic acid (87 mg, 0.6 mmol,
4 equiv) in the presence of sodium fluoride (19 mg, 0.45 mmol). The
title compound was obtained as a mixture of diastereoisomers in
NMR (CDCl3, 75.5 MHz)
d 171.2, 164.3, 155.9, 136.7, 131.1, 127.8,
86% yield (60 mg) as an off white foam. IR (film, cmꢂ1
)
n
3408 (br),
3020, 2983, 2231, 1742, 1666, 1614, 1516, 1443, 1368,1217, 1171, 1119,
1052, 1022, 850, 826, 756, 669; 1H NMR (CDCl3, 300 MHz)
7.53
123.6, 122.7, 120.2, 119.1, 111.6, 110.6, 109.7, 80.9, 56.4, 53.2, 49.6,
28.6; MS (ESIþ) m/z 388.2 [MþH]þ; HRMS (ESIþ) calcd for
d
C
20H26N3O5: 388.1867 [MþH]þ; found: 388.1870 [MþH]þ.
(1H, d, J¼8.3), 7.51 (1H, d, J¼8.1), 7.13 (1H, d, J¼8.3), 7.05 (1H, d,
J¼8.1), 7.02 (2H, app d, J¼8.4), 6.74 (1H, d, J¼8.4), 6.72 (1H, d, J¼8.4),
6.55 and 6.37 (1H, d, J¼6.3 and 7.8), 5.6–5.3 (1H, br s, OH), 4.99–4.73
(2H, m), 4.33–4.21 (1H, m), 3.69 and 3.68 (3H, s), 3.20–2.86 (4H, m),
1.42 and 1.40 (9H, s); 13C NMR (CDCl3, 75.5 MHz, mixture of
4.3.25. Boc-Trp-Phe(4-CN)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Trp-DAla-OMe (58 mg, 0.15 mmol)
was reacted with 4-cyanobenzene boronic acid (89 mg, 0.6 mmol,
4 equiv). The title compound was obtained as a mixture of di-
astereomers in 65% yield (48 mg) as an off white foam. IR (film,
diastereoisomers)
d 171.71 and 171.67, 171.4 and 171.2, 155.9, 155.5,
141.9 and 141.8, 132.72 and 132.67, 130.86 and 130.83, 130.54 and
130.45, 129.1, 128.3, 127.8, 119.2, 116.0, 111.4, 81.1, 53.4, 53.2, 53.0,
38.4 and 38.3, 37.7, 28.6; HRMS (ESIꢂ) calcd for C25H28N3O6:
466.1978 [MꢂH]ꢂ, found: 466.1977 [MꢂH]ꢂ.
cmꢂ1
)
n
3409 (br), 3018, 2928, 2856, 1680, 1612,1514, 1457, 1442,
1368, 1249, 1216, 1165, 1119, 1093, 1026, 855, 757, 669; 1H NMR
(CDCl3, 300 MHz, mixture of diastereoisomers) 8.35 (1H, br s),
d
7.63 (1H, app t, J¼8.7), 7.36 (3H, app d, J¼8.4), 7.23–7.16 (1H, m),
7.15–7.09 (1H, m), 7.02 (1H, dd, J¼10.5, 2.0), 6.89 (2H, d, J¼8.1), 6.43
and 6.32 (1H, d, J¼7.2), 5.00–5.18 (1H, m), 4.84–4.67 (1H, m), 4.52–
4.36 (1H, m), 6.60 and 3.59 (3H, s), 3.07–3.38 (2H, m), 2.84–3.06
(2H, m),1.43 and 1.39 (9H, s); 13C NMR (CDCl3, 75.5 MHz, mixture of
4.3.22. Boc-Tyr-Phe(4-OMe)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Tyr-DAla-OMe (73 mg, 0.2 mmol) was
reacted with 4-methoxybenzene boronic acid (122 mg, 0.8 mmol,
4 equiv). The title compound was obtained as a mixture of di-
astereomers in 65% yield (79 mg) as an off white foam. IR (film,
diastereoisomers)
d 171.86 and 171.81, 171.13 and 170.98, 155.8,
141.69 and 141.60,136.62 and 136.56,132.46 and 132.38, 130.30 and
130.27, 127.71 and 127.63, 123.6, 123.4, 122.72 and 122.68, 120.16
and 120.12, 119.21 and 119.12, 119.01 and 118.99, 111.62 and 111.58,
111.21 and 111.17, 110.7, 80.7, 53.2, 53.0, 52.7, 38.21, 38.15, 28.58 and
28.56; HRMS (ESIþ) calcd for C27H31N4O5: 491.2294 [MþH]þ,
found: 491.2285 [MþH]þ.
cmꢂ1
650; 1H NMR (CDCl3, 300 MHz)
)
n
3413 (br), 2254,1655,1516,1446, 1368,1249,1166, 908, 733,
7.05–6.82 (1H, br s), 6.99–6.85
d
(4H, m), 6.78–6.70 (4H, m), 6.51 and 6.38 (1H, d, J¼7.2), 5.11–5.01
(1H, m), 4.80–4.69 (1H, m), 4.42–4.23 (1H, m), 3.75 and 3.74 (3H, s),
3.66 and 3.65 (3H, s), 3.01–2.87 (4H, m), 1.40 and 1.39 (9H, s); 13C
NMR (CDCl3, 75.5 MHz, mixture of diastereoisomers)
d 172.1, 171.7,
159.1, 155.9, 130.8, 130.63 and 130.56, 129.83, 127.9 and 127.8, 116.1,
114.5 and 114.4, 80.7, 55.6, 53.9, 53.7,52.7, 37.9, 37.47 and 37.36,
28.7; HRMS (ESIþ) calcd for C25H33N2O7: 473.2288 [MþH]þ, found:
473.2280 [MþH]þ.
4.3.26. Boc-Trp-Phe(4-Cl)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Trp-DAla-OMe (58 mg, 0.15 mmol)
was reacted with 4-chlorobenzene boronic acid (70 mg, 0.45 mmol,
3 equiv). The title compound was obtained as a mixture of di-
astereomers in 68% yield (51 mg) as an off white foam. IR (film,
4.3.23. Boc-Tyr-Phe(4-Cl)-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Tyr-DAla-OMe (55 mg, 0.15 mmol)
cmꢂ1
)
n
3416 (br), 3019, 1742, 1671, 1492, 1458, 1438, 1368, 1216,
1167, 1093, 1016, 842, 757, 669; 1H NMR (CDCl3, 300 MHz, mixture
of diastereoisomers)
8.24 (1H, br s), 7.64 (1H, app t, J¼8.4), 7.36
was reacted with 4-chlorobenzene boronic acid (70 mg, 0.45 mmol,
3 equiv). The title compound was obtained as a mixture of di-
astereomers in 57% yield (41 mg) as an off white foam. IR (film,
d
(1H, dm, J¼7.8), 7.21 (1H, tm, J¼7.2), 7.14 (1H, dm, J¼7.2), 7.12–7.05
(2H, m), 7.00 and 6.97 (1H, d, J¼2.4), 6.71 (2H, app dd, J¼5.4, 8.4),
6.33 and 6.26 (1H, d, J¼7.5), 5.20–5.00 (1H, m), 4.81–4.66 (1H, m),
4.52–4.38 (1H, m), 3.60 (3H, s), 3.33–3.21 (1H, m), 3.23 and 3.12
(1H, dd, J¼7.2, 14.4), 2.95–2.83 (1H, m), 2.89 and 2.78 (1H, dd, J¼5.7,
13.8 and m), 1.43 and 1.40 (9H, s); 13C NMR (CDCl3, 75.5 MHz) 171.6,
171.5, 171.3, 171.2, 136.4, 136.3, 134.3, 134.1, 133.1, 133.0, 130.6, 130.6,
128.8,128.7,127.6,123.4,123.2,122.5,120.0,119.9,119.0,119.0,111.4,
cmꢂ1
)
n
4214, 3419 (br), 3020, 2983, 2401, 1742, 1665, 1615, 1516,
1493, 1445, 1369, 1216, 1166, 1093, 1017, 929, 756, 669; 1H NMR
(CDCl3, 300 MHz) 1.32 and 1.34 (9H, s), 2.78–3.00 (4H, m), 3.58
d
and 3.59 (3H, s), 4.11–4.32 (1H, m), 4.64–4.77 (1H, m), 4.91–5.06
(1H, m), 6.38 and 6.54 (1H, d, J¼7.5), 6.64 (2H, dd, J¼2.1, 8.7), 6.68
(1H, br s), 6.78–6.92 (4H, m), 7.12 (2H, dd, J¼1.5, 8.4); 13C NMR

9536
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
111.4, 80.4, 55.3, 53.2, 53.0, 52.4, 37.3, 37.2, 28.4; HRMS (ESIþ) calcd
34.4 (minor), 31.6, 31.1 and 30.9 (minor), 28.6, 19.64 (minor) and
19.61, 17.9 and 17.8 (minor), 16.0 and 15.9 (minor); HRMS (ESIþ)
calcd for C28H46N3O6S: 552.3107 [MþH]þ, found: 552.3111 [MþH]þ.
for C26H31O5N3Cl: 500.1947 [MþH]þ, found: 500.1946 [MþH]þ.
4.3.27. Boc-Trp-Phe(4-F)-OMe
In accordance with the representative procedure for 1,4-addi-
4.5. Tripeptides
tions with boronic acids, Boc-Trp-DAla-OMe (58 mg, 0.15 mmol)
was reacted with 4-fluorobenzene boronic acid (84 mg, 0.6 mmol,
4 equiv). The title compound was obtained as a mixture of di-
astereomers in 50% yield (36 mg) as an off white foam. IR (film,
4.5.1. Boc-Phe-DAla-Gly-OEt (15)
An oven dried flask was charged with Boc-Phe-Ser-Gly-OMe
(2.00 g, 4.57 mmol) dissolved in degassed dichloromethane
(40 mL) under an atmosphere of nitrogen. Copper(I) chloride
(136 mg, 1.37 mmol) and EDCI (964 mg, 5.03 mmol) were added
and the resultant suspension stirred for 18 h at ambient tempera-
ture. The solution was washed with three portions of water (15 mL),
dried over MgSO4, filtered and concentrated under reduced pres-
sure. Purification by flash column chromatography (petroleum
ether/ethyl acetate 1:1) gave the title compound as an off white
solid in 82% yield (1.57 g). Mp 134–137 ꢀC; 1H NMR (CDCl3,
cmꢂ1
)
n
3414 (br), 3018, 2968, 1742, 1672, 1602, 1510, 1458, 1439,
1368, 1216, 1160, 1093, 1047, 1016, 927, 846, 755, 668; 1H NMR
(CDCl3, 300 MHz)
d
8.14 (1H, br s), 7.65 (1H, app t, J¼6.6), 7.36 (1H,
d, J¼8.1), 7.21 (1H, app tdd, J¼7.2, 3.0, 1.2), 7.13 (1H, app tdd, J¼7.2,
1.8, 1.2), 7.04 and 7.00 (1H, d, J¼2.1), 6.84–6.71 (4H, m), 6.28 and
6.21 (1H, d, J¼7.8), 5.15–5.00 (1H, m), 4.78–4.65 (1H, m), 4.49–4.38
(1H, m), 3.61 (3H, s), 3.37–3.06 (2H, m), 2.93–2.85 (1H, m), 2.76 and
2.90 (1H, dd, J¼5.4, 13.8), 1.43 and 1.40 (9H, s); 13C NMR (CDCl3,
75.5 MHz, mixture of diastereoisomers)
d
171.7 and 171.58, 171.56
300 MHz)
d
8.49 (1H, br s), 7.32–7.16 (5H, m), 6.84 (1H, app t, J¼4.8),
and 171.5, 163.9, 155.72 and 155.70, 136.59 and 136.55, 131.60 and
131.56 (d, J¼7.6), 131.98 and 130.95 (d, J¼7.6), 127.8, 123.6, 123.3,
122.7, 120.21 and 120.19, 119.3 and 19.2, 115.71 and 115.60 (d,
J¼21.9), 111.6 and 111.5, 111.0, 80.6, 53.5, 53.3, 52.6, 37.4, 37.3, 28.6;
6.48 (1H, s), 538 (1H, s), 5.04 (1H, d, J¼7.2), 4.49–4.43 (1H, m), 4.23
(2H, q, J¼7.2), 4.06 (2H, app t, J¼4.8), 3.16 (1H, dd, J¼13.8, 6.0), 3.06–
2.99 (1H, m), 1.38 (9H, s), 1.29 (3H, t, J¼7.2); 13C NMR (CDCl3,
75.5 MHz)
d 170.8, 169.9, 164.0, 155.7, 136.5, 133.7, 129.5, 129.0,
19F NMR (CDCl3, 376.5 MHz)
C
d
ꢂ115.84; HRMS (ESIþ) calcd for
127.3, 103.5, 80.7, 62.1, 56.7, 42.1, 38.6, 28.5, 14.4; HRMS (ESIþ) calcd
for C21H29N3NaO6: 442.1949 [MþNa]þ; found: 442.1948 [MþNa]þ.
Anal. Calcd for C 60.13, H 6.97, N 10.02; found C 60.2, H 7.05, N
9.96%.
26H31FN3O5: 484.2248 [MþH]þ, found: 484.2247 [MþH]þ.
4.4. Difunctionalised peptides
4.4.1. Boc-Val-Cys(Me)- Ala-OMe (13)
D
4.5.2. Boc-Phe-Phe-Gly-OEt
An oven dried flask was charged with Boc-Val-Cys(Me)-Ser-
OMe (349 mg, 0.8 mmol) dissolved in degassed dichloromethane
(10 mL) under an atmosphere of nitrogen. Copper(I) chloride
(24 mg, 0.24 mmol) and EDCI (169 mg, 0.88 mmol) were added and
the resultant suspension stirred for 18 h at ambient temperature.
The solution was diluted with dichloromethane (10 mL) and
washed with two portions of water (10 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. Purification by
flash column chromatography (Petroleum ether/ethyl acetate 1:1)
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-Gly-OEt (105 mg,
0.25 mmol) was reacted with benzene boronic acid (121 mg,
1.0 mmol). The title compound was obtained as a mixture of di-
astereomers in 85% yield (105 mg) as a colourless foam. IR (film,
cmꢂ1
)
n
3418, 2090, 1751, 1645, 1554, 1497, 1455, 1392, 1368, 1250,
1194, 1029, 700; 1H NMR (CDCl3, 300 MHz)
d
7.33–7.20 (6H, m),
7.17–7.08 (3H, m), 7.00 (1H, d, J¼6.0), 6.96 and 6.59 (1H, br s), 6.46
and 6.40 (1H, d, J¼5.4), 5.14 and 4.92 (1H, d, J¼6.3), 4.79–4.70 (1H,
m), 4.30 and 4.14 (1H, m), 4.18 and 4.16 (2H, q, J¼7.4), 4.02 and 3.96
(1H, dd, J¼18.0, 5.4), 3.81 and 3.80 (1H, dd, J¼18.0, 5.4), 3.14–2.80
(4H, m), 1.36 and 1.35 (9H, s), 1.27 and 1.25 (3H, t, J¼7.4); 13C NMR
gave the title compound as a colourless foam in 83% yield (371 mg).
20
[
a]
ꢂ9.6 (c 0.73, CHCl3); IR (film, cmꢂ1
) n 3682, 3297, 3019, 2968,
D
2932, 2875, 2401, 1743, 1662, 1504, 1449, 1392, 1368, 1295, 1216,
1168, 1043, 1016, 967, 928, 909, 868, 850, 755, 669; 1H NMR (CDCl3,
(CDCl3, 75.5 MHz)
d 171.8 and 171.6 (minor), 171.3 and 171.2
300 MHz)
d
8.71 (1H, s), 7.09 (1H, d, J¼8.7), 6.56 (1H, s), 5.91 (1H, d,
(minor), 169.8 and 169.6, 156.1, 136.8, 136.7 and 136.6 (minor),
129.8, 129.70, 129.67, 129.2, 129.1, 129.0, 127.5, 127.40 and 127.37
(minor), 81.0 (minor) and 80.8, 61.77 and 61.75 (minor), 57.0 and
56.4 (minor), 54.2, 41.7, 38.4, 38.0 and 37.7 (minor), 28.62 and
28.59, 14.53 and 14.52; HRMS (ESIþ) calcd for C27H36N3O6:
498.2599 [MþH]þ; found: 498.2595 [MþH]þ. Anal. calcd for C
65.17, H 7.09, N 8.44; found C 64.7, H 7.04, N 8.23%.
J¼1.5), 5.20 (1H, d, J¼10.5), 4.69 (1H, dd, J¼7.2, 8.4), 4.06–3.99 (1H,
m), 3.83 (3H, s), 2.98–2.79 (2H, m), 2.22–2.09 (1H, m), 2.14 (3H, s),
1.42 (9H, s), 0.96 (3H, d, J¼8.1), 0.90 (3H, d, J¼8.1); 13C NMR (CDCl3,
75.5 MHz)
d 172.4, 169.2, 164.3, 156.2, 131.1, 110.3, 80.4, 53.7, 53.3,
36.1, 31.0, 28.6, 19.6, 17.9, 16.2; HRMS (ESIþ) calcd for C18H32N3O6S:
418.2012 [MþH]þ, found: 418.1991 [MþH]þ.
4.4.2. Boc-Val-Cys(Me)-Phe(4-t-Bu)-OMe (14)
4.5.3. Boc-Phe-Phe(4-F)-Gly-OEt
In accordance with the representative procedure for 1,4-addi-
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Val-Cys(Me)-
D
Ala-OMe (167 mg,
tions with boronic acids, Boc-Phe-DAla-Gly-OEt (63 mg,
0.4 mmol) was reacted with 4-tert-butylbenzene boronic acid
(341 mg, 1.9 mmol). The title compound was obtained as a mixture
of diastereomers in 30% yield (66 mg) as a colourless foam. 1H NMR
0.15 mmol) was reacted with 4-fluorobenzene boronic acid (84 mg,
0.6 mmol). The title compound was obtained as a mixture of di-
astereomers in 79%ꢂy1ield (61 mg) as a colourless solid. Mp 137–
(CDCl3, 300 MHz)
d
7.32–7.27 (2H, m), 7.08–6.99 (3H, m), 6.92 and
140 ꢀC; IR (film, cm
) n 3446, 2991, 2092, 1755, 1645, 1560, 1510,
6.91 (1H, d, J¼7.5), 5.05–5.02 (1H, m), 4.79 (1H, dt, J¼7.5, 6), 4.58–
4.46 (1H, m), 3.99–3.91 (1H, m), 3.71 and 3.69 (3H, s), 3.18–3.00
(2H, m), 2.92–2.83 (1H, m), 2.79–2.59 (1H, m), 2.20–2.10 (1H, m),
1485, 1392, 1271, 1192, 1122, 1061, 1029, 827, 700; 1H NMR (CDCl3,
300 MHz) 7.35–7.25 (3H, m), 7.18–7.14 (2H, m), 7.07–7.02 (1H, m),
d
6.97–6.87 (3H, m), 7.05 and 6.58 (1H, br s), 6.46 and 6.38 (1H, d,
J¼8.4), 5.12 and 4.93 (1H, d, J¼6.9), 4.73 and 4.70 (1H, q, J¼6.6), 4.30
and 4.16 (1H, q, J¼6.6), 4.18 and 4.17 (2H, q, J¼7.2), 4.02 and 3.96
(1H, dd, J¼18, 6.0), 3.84 and 3.78 (1H, app t, J¼6.0), 3.12–2.77 (4H,
m), 1.37 and 1.36 (9H, s), 1.27 and 1.26 (3H, t, J¼7.2); 13C NMR
2.09 (3H, s), 1.44 (9H, s), 1.29 and 1.28 (9H, s), 0.95–0.87 (6H, m); 13
C
NMR (CDCl3, 75.5 MHz)
d 171.97 (minor) and 171.89, 171.80 and
171.77 (minor), 170.2 and 170.1 (minor), 156.4 and 156.2 (minor),
150.4 and 150.3 (minor),133.0 (minor) and 132.8,129.3 (minor) and
129.2, 125.9 and 125.8 (minor), 80.6 (minor) and 80.5, 60.5 (minor)
and 60.3, 54.0 and 53.7 (minor), 52.7 and 52.6 (minor), 52.1 and
51.9 (minor), 37.5 (minor) and 37.4, 36.4 and 36.3 (minor), 34.8 and
(CDCl3, 75.5 MHz)
d 171.7 and 171.5 (minor), 171.0 and 170.9 (mi-
nor), 169.7 and 169.6, 162.5 (d, J¼245), 156.1, 136.7 (minor) and
136.6, 132.2 (q, J¼3), 131.3 (q, J¼5), 129.7, 129.2, 129.1, 127.6, 115.98

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9537
(minor) and 115.97, 115.70 (minor) and 115.69, 81.1 (minor) and
81.0, 61.8, 57.3, 56.5, 54.0, 41.7, 38.2, 37.1, 36.7, 28.60 and 28.56,
14.53 (minor) and 14.51; HRMS (ESIþ) calcd for C27H34FN3O6:
516.2504 [MþH]þ, found: 516.2502 [MþH]þ.
130.2 and 130.1 (minor), 128.3, 127.8 (minor) and 127.7, 126.2, 79.8
(minor) and 79.6, 60.4, 55.8 and 55.0, 52.4, 40.4, 37.0, 35.7 and 35.6,
27.22 (minor) and 27.18,13.14; HRMS (ESIþ) calcd for C27H35BrN3O6:
576.1704 [MþH]þ, found: 576.1703 [MþH]þ.
4.5.4. Boc-Phe-Phe(4-Cl)-Gly-OEt
4.5.7. Preparation of Boc-Trp-DAla-Tyr-OMe (16)
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-
D
Ala-Gly-OEt (63 mg,
4.5.7.1. Mixture of Boc-Trp-Cys(SOBzl)-Tyr-OMe and Boc-Trp-Cys-
(SO2Bzl)-Tyr-OMe. The thioether of Boc-Trp-Cys(SBzl)-Tyr-OMe
was oxidised as described in the literature.17a Sodium metaper-
iodate (1.47 g, 6.88 mmol, 2.2 equiv) was dissolved in water (50 mL)
and cooled in an ice bath. Boc-Trp-Cys(Bzl)-Tyr-OMe (2.11 g,
3.13 mmol) was dissolved in dioxane (100 mL) and added dropwise
to the oxidant. The reaction mixture was stirred on ice for 2 h and at
40 ꢀC for 6 h, then concentrated to w50 mL, water (50 mL) was
added and the product extracted into DCM (3ꢁ50 mL). The com-
bined organics were washed with water (50 mL), brine (50 mL),
dried (MgSO4) and concentrated in vacuo to give a colourless glass,
which was progressed to the next step without further purification.
MS (ESIꢂ) m/z 705.3 and 689.3 [MꢂH]ꢂ sulfone and sulfoxide,
respectively.
0.15 mmol) was reacted with 4-chlorobenzene boronic acid (93 mg,
0.6 mmol). The title compound was obtained as a mixture of
diastereomers in 85% yield (105 mg) as a colourless solid. Mp 163–
166 ꢀC; IR (film, cmꢂ1
)
n
2361, 1756, 1708, 1645, 1562, 1555, 1475,
1409, 1290, 1193, 1091, 1016, 978, 889, 841; 1H NMR (CDCl3,
300 MHz)
d
7.23–7.17 (3H, m), 7.14–7.06 (4H, m), 6.94 (1H, d, J¼8.4),
6.84 (1H, d, J¼7.2), 7.05 and 6.58 (1H, m), 6.68 and 6.39 (1H, d,
J¼7.2), 5.01 and 4.92 (1H, d, J¼7.2), 4.67 (1H, app pentet, J¼6.9), 4.24
and 4.12 (1H, q, J¼6.9), 4.11 and 4.08 (2H, q, J¼6.9), 3.93 and 3.88
(1H, dd, J¼16.8, 5.7), 3.77 and 3.71 (1H, app t, J¼5.7), 3.00–2.71 (4H,
m),1.29 and 1.28 (9H, s),1.20 and 1.18 (3H, t, J¼7.2); 13C NMR (CDCl3,
75.5 MHz) d 170.5 and 170.2 (minor), 169.7 and 169.6 (minor), 168.3
and 168.2, 154.7, 135.3 (minor) and 135.2, 133.7 (minor) and 133.6,
131.9 and 131.8 (minor), 129.8 (minor) and 129.7, 128.3, 127.8 (mi-
nor) and 127.7, 126.1, 79.7 (minor) and 79.5, 60.4, 55.7 and 55.0,
52.5, 40.3, 36.9, 35.9 and 35.6, 27.20 (minor) and 27.17, 13.12 (mi-
nor) and 13.10; HRMS (ESIþ) calcd for C27H35ClN3O6: 532.2209
[MþH]þ, found: 532.2204 [MþH]þ.
4.5.7.2. Boc-Trp-DAla-Tyr-OH. Boc-Trp-Cys(SOBzl)-Tyr-OMe (2 g,
2.83 mmol), was dissolved in methanol (120 mL) and cooled on an
ice–salt bath. Aqueous NaOH (1 M, 14 mL, 5 equiv) was added
dropwise and the reaction mixture allowed to warm to room
temperature over 2 h. The reaction mixture was concentrated in
vacuo to approx 3 mL, acidified to pH 4 with 2 M KHSO4 and the
product extracted into DCM (3ꢁ50 mL), washed with water
(100 mL) and brine (50 mL), dried (MgSO4) and concentrated to
dryness to afford the title compound as a gummy foam. 1H NMR
4.5.5. Boc-Phe-Phe(3-NO2)-Gly-OEt
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-Gly-OEt (63 mg,
0.15 mmol) was reacted with 3-nitrobenzene boronic acid (100 mg,
0.6 mmol). The title compound was obtained as a mixture of
diastereomers in 43% yield (35 mg) as a colourless solid. Mp 142–
(DMSO-d6, 250 MHz)
d
12.81 (1H, br s), 10.84 (1H, d, J¼1.8), 9.23
(1H, s), 9.11 (1H, s), 8.68 (1H, d, J¼8.3), 7.58 (1H, d, J¼7.8), 7.34 (1H,
d, J¼8.0), 7.28 (1H, d, J¼8.0), 7.15 (1H, d, J¼1.8), 7.12–6.94 (4H, m),
6.67 (2H, d, J¼8.5), 6.29 (1H, s), 5.59 (1H, s), 4.49–4.36 (1H, m),
4.32–4.19 (1H, m), 3.24–2.84 (4H, m), 1.30 (9H, s); HRMS (ESIꢂ)
calcd for C28H31N4O7: 535.2198 [MꢂH]ꢂ; found 535.2207 [MꢂH]ꢂ.
144 ꢀC; IR (film, cmꢂ1
)
n
3432, 2983, 2930, 2861, 2361, 2093, 1750,
1704, 1646, 1531, 1498, 1454, 1352, 1251, 1195, 1167, 1122, 1023, 700;
1H NMR (CDCl3, 300 MHz)
8.01–7.97 (1H, m), 7.88 (1H, br s), 7.43
d
and 7.33 (1H, m), 7.38–7.32 (1H, m), 7.23–7.15 (4H, m), 7.10–7.04
(2H, m), 6.77–6.68 (1H, m), 5.13–4.96 (1H, d, J¼6.9), 4.80–4.72 (1H,
m), 4.25–4.15 (1H, m), 4.10 and 4.08 (2H, q, J¼6.9), 3.97–3.73 (2H,
m), 3.18–2.80 (4H, m), 1.27 (9H, s), 1.20 and 1.18 (3H, t, J¼6.9); 13C
4.5.7.3. Boc-Trp-
(250 mg, 2.97 mmol, 1.1 equiv) in anhydrous DMF (10 mL) were
added Boc-Trp- Ala-Tyr-OH (1.45 g, 2.7 mmol) and methyl iodide
(186
L, 2.97 mmol). This mixture was stirred at 25 ꢀC for 20 h.
DAla-Tyr-OMe (16). To a suspension of NaHCO3
NMR (CDCl3, 75.5 MHz)
d
172.2 and 171.9 (minor), 170.8 and 170.6
D
(minor), 169.8 (minor) and 169.7, 156.1, 148.7 and 148.6 (minor),
138.92 (minor) and 138.89,137.1, 136.7 (minor) and 136.6,136.2 and
136.1 (minor), 129.9 and 129.8 (minor), 129.7, 129.63 and 129.60
(minor), 129.2, 129.1 and 129.0 (minor), 127.50 and 127.48 (minor),
127.35, 124.8 and 124.7 (minor), 122.5 and 122.4 (minor), 81.1
(minor) and 80.9, 61.93 and 61.91 (minor), 57.0 and 56.5 (minor),
53.8 and 53.7 (minor), 41.7, 38.8 and 38.3, 37.8 and 37.5, 28.58
(minor) and 28.56, 14.51 and 14.49 (minor); HRMS (ESIþ) calcd for
m
Distilled water was added and the product extracted with ethyl
acetate (3ꢁ20 mL). The combined organic phases were washed
with distilled water, dried over MgSO4 and concentrated in vacuo to
the crude product, which was purified by flash chromatography
(ethyl acetate/petroleum ether 1:1) to afford the titled compound
as an off white solid (930 mg, 67% over three steps).21 Mp 205 ꢀC;
20
[a
]
þ9.38 (c 0.21, CH2Cl2); IR (film, cmꢂ1
) n 4214, 3362 (br), 3019,
D
C
27H35N4O8: 543.2449 [MþH]þ, found: 543.2451 [MþH]þ.
2980, 2933, 2856, 2401, 1887, 1738, 1694, 1633, 1616, 1515, 1455,
1369, 1216, 1171, 1109, 1060, 1022, 988, 963, 892, 843, 755, 699, 668;
4.5.6. Boc-Phe-Phe(4-Br)-Gly-OEt
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Phe-DAla-Gly-OEt (63 mg,
1H (CDCl3, 300 MHz)
d
8.31 (1H, s), 8.30 (1H, s), 7.57 (1H, d, J¼7.8),
7.32 (1H, d, J¼8.1), 7.16 (1H, dt, J¼0.9, 7.8), 7.08 (1H, dt, J¼0.9, 8.1),
6.96 (1H, d, J¼1.8), 6.88 (2H, AB d, J¼8.4), 6.74 (2H, AB d, J¼8.4), 6.54
(1H, d, J¼7.8), 6.40 (1H, br s), 6.35 (1H, s), 5.19 (1H, s), 5.16 (1H, s),
4.76 (1H, dt, J¼5.7, 7.4), 4.51 (1H, br s), 3.73 (3H, s), 3.33–3.19 (2H,
0.15 mmol) was reacted with 4-bromobenzene boronic acid
(120 mg, 0.6 mmol). The title compound was obtained as a mixture
of diastereomers in 35% yield (30 mg) as a colourless solid. Mp 159–
m), 3.06 (1H, dd, J¼5.7,14.1), 2.98 (1H, dd, J¼6,14.1),1.40 (9H, s); 13
C
161 ꢀC; 1H NMR (CDCl3, 300 MHz)
d
7.37–7.26 (5H, m), 7.17–7.13
(CDCl3, 75.5 MHz) d 172.1, 171.4, 163.4, 155.9, 155.8, 136.6, 133.8,
(2H, m), 7.02 and 6.58 (1H, m), 6.94 (1H, d, J¼8.4), 6.84 (1H, d,
J¼7.8), 6.39 and 6.28 (1H, d, J¼8.4), 5.08 and 4.90 (1H, d, J¼6.3), 4.73
and 4.70 (1H, q, J¼6.6), 4.28 and 4.14 (1H, q, J¼6.9), 4.18 and 4.16
(2H, q, J¼7.2), 4.00 and 3.95 (1H, dd, J¼18, 5.7), 3.83 and 3.77 (1H,
dd, J¼7.2, 5.7), 3.10 and 2.76 (1H, m), 3.09–2.85 (3H, m), 1.36 and
1.35 (9H, s), 1.27 and 1.25 (3H, t, J¼7.2); 13C NMR (CDCl3, 75.5 MHz)
130.7, 127.8, 127.2, 123.5, 122.6, 120.0, 119.0, 116.1, 111.6, 110.3, 103.8,
80.9, 56.5, 54.1, 52.9, 37.2, 37.1, 28.6; HRMS (ESIþ) calcd for
C
29H34N4NaO7: 573.2325 [MþNa]þ, found: 573.2309 [MþNa]þ.
4.5.8. Boc-Trp-Phe(4-F)-Tyr-OMe
In accordance with the representative procedure for 1,4-addi-
d
170.4 and 170.1 (minor), 169.6 and 169.5 (minor), 168.2 and 168.1,
tions with boronic acids, Boc-Trp-
DAla-Tyr-OMe (110 mg, 0.2 mmol)
154.8, 135.3 (minor) and 135.1, 134.13 (minor) and 134.06, 130.7,
was reacted with 4-fluorobenzene boronic acid (122 mg,

9538
C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
0.8 mmol, 4 equiv) in the presence of sodium fluoride (25 mg,
(petroleum ether/ethyl acetate 1:1) gave the title compound as
20
0.6 mmol, 3 equiv). The title compound was obtained in 54% yield
a colourless foam in 89% yield (1.88 g). [
(film, cmꢂ1
3435, 3019, 2083, 1696, 1653, 1512, 1455, 1368, 1223,
1167, 1054, 772, 733, 668; 1H NMR (CDCl3, 300 MHz)
8.61 (1H, s),
a
]
D
ꢂ5.5 (c 1.3, CHCl3); IR
20
(70 mg) as an off white solid. Mp 92–94 ꢀC; [
a
]
D
þ6.8 (c 0.15,
) n
CH2Cl2); IR (film, cmꢂ1
)
n
4214, 3390 (br), 3020, 2982, 2932, 2854,
d
2401, 1893, 1737, 1664, 1615, 1512, 1439, 1369, 1216, 1172, 1114, 1054,
1015, 929, 844, 757, 669, 621, 575, 538; 1H NMR (CDCl3, 300 MHz)
8.28 (1H, s), 7.62 (1H, d, J¼7.8), 7.35 (1H, d, J¼7.8), 7.22–7.06 (2H, m),
6.85 (1H, d, J¼2.1), 6.9–6.66 (8H, m), 6.29 (1H, d, J¼8.1), 6.20 (1H, d,
J¼8.1), 5.06 (1H, d, J¼7.8), 4.66 (1H, dt, J¼6.9, 6.0), 4.53–4.34 (2H, m),
3.70 (3H, s), 3.14–2.96 (3H, m), 2.83–2.73 (3H, m), 1.40 (9H. s); 13C
NMR (CDCl3, 75.5 MHz) 172.1, 172.0, 170.3, 155.7, 152.0, 136.6, 132.2
and 132.1, 131.2 (d, J¼8.0), 130.7, 127.7 and 127.6, 124.1, 123.7 and
123.6, 122.9, 120.3, 119.2, 116.2, 115.7 (d, J¼21.9), 111.7, 110.6, 81.1,
54.1, 53.8, 52.9, 52.8, 37.3, 37.2, 30.1, 28.7; 19F NMR (CDCl3,
7.33–7.30 (5H, m), 7.02 (1H, d, J¼6.0), 6.43 (1H, s), 5.36 (1H, s), 5.32
(1H, d, J¼7.5), 5.07 (2H, s), 5.02 (1H, m), 4.59 (1H, app pentet, J¼7.2),
4.21–4.18 (1H, m), 3.75 (3H, s), 3.16 (2H, q, J¼6.0), 1.84–1.76 (1H, m),
1.69–1.38 (5H, m), 1.44 (3H, s), 1.41 (9H, s); 13C NMR (CDCl3,
75.5 MHz)
d 173.9, 172.0, 163.9, 157.0, 156.3, 137.0, 134.1, 128.8,
128.4, 103.91, 80.5, 66.9, 55.6, 53.0, 49.0, 40.8, 32.2, 29.7, 28.7, 23.0,
18.0; HRMS (ESIþ) calcd for C26H38N4NaO8: 557.2587 [MþNa]þ,
found: 557.2553 [MþNa]þ.
4.6.2. Boc-Lys(Cbz)-
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)- Ala-Ala-OMe (107 mg,
L-Phe-Ala-OMe
376.5 MHz)
d
ꢂ115.80; HRMS (ESIþ) calcd for C35H39FN4NaO7:
669.2700 [MþNa]þ, found: 669.2699 [MþNa]þ.
D
0.2 mmol) was reacted with benzene boronic acid (98 mg,
4.5.9. Boc-Trp-Phe(4-CN)-Tyr-OMe
0.8 mmol) and (R)-BINAP. The title compound was isolated as
In accordance with the representative procedure for 1,4-addi-
a single diastereomer in 50% yield (61 mg) as a colourless glass.
20
tions with boronic acids, Boc-Trp-DAla-Tyr-OMe (110 mg,
[a
]
ꢂ21.2 (c 0.33, CHCl3); mp 126–129 ꢀC; IR (film, cmꢂ1
)
n
3434,
D
0.2 mmol) was reacted with 4-cyanobenzene boronic acid
(122 mg, 0.8 mmol, 4 equiv) in the presence of sodium fluoride
2094, 1652, 1511, 1162, 806; 1H NMR (CDCl3, 300 MHz)
d 7.37–7.18
(10H, m), 6.67 (2H, d, J¼7.8), 5.22 (1H, br s), 5.10 (2H, s), 5.08–5.03
(1H, m), 4.70 (1H, dt, J¼7.8, 6.6), 4.48 (1H, app pent, J¼7.2), 4.05–
3.98 (1H, m), 3.69 (3H, s), 3.19–3.02 (4H, m), 1.80–1.70 (1H, m),
1.64–1.40 (3H, m), 1.40 (9H, s), 1.32 (3H, d, J¼7.2), 1.33–1.25 (2H, m);
(25 mg, 0.6 mmol, 3 equiv). The title compound was obtained in
20
14% yield (14 mg) as an off white foam. [
IR (film, cmꢂ1
733, 650; 1H NMR (CDCl3, 300 MHz)
a
]
þ6.8 (c 0.15, CH2Cl2);
D
)
n
3413 (br), 2254, 1655, 1516, 1368, 1249, 1175, 908,
8.32 (1H, s), 7.58 (1H, d,
d
13C NMR (CDCl3, 75.5 MHz)
d 173.1, 172.4, 170.7, 157.1, 156.2, 137.0,
J¼7.8), 7.40–7.13 (5H, m), 6.98–6.67 (8H, m), 6.65–6.28 (1H, br s),
6.14 (1H, d, J¼7.2), 5.13 (1H, d, J¼4.5), 4.69–4.60 (2H, m), 4.27 (1H, q,
J¼6.9), 3.69 (3H, s), 3.19–3.12 (2H, m), 3.00–2.82 (3H, m), 2.55 (1H,
136.7, 129.7, 128.9, 128.8, 128.5, 128.4, 127.3, 80.5, 67.0, 55.1, 54.3,
52.7, 48.5, 40.5, 38.3, 31.9, 29.8, 28.6, 22.6, 18.3; HRMS (ESIþ) calcd
for C32H44N4NaO8: 635.3057 [MþNa]þ, found: 635.3035 [MþNa]þ.
dd, J¼13.8, 6.9), 1.39 (9H, s); 13C NMR (CDCl3, 75.5 MHz)
d 172.6,
172.2, 170.1, 155.7, 155.6, 141.9, 136.6, 132.6, 130.7, 130.6, 127.8, 127.7,
123.7, 122.9, 120.4, 119.2, 119.0, 116.1, 111.9, 111.1, 110.3, 80.2, 56.4,
54.1, 53.5, 52.8, 37.4, 37.2, 30.1, 28.7; HRMS (ESIþ) calcd for
4.6.3. Boc-Lys(Cbz)-
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)- Ala-Ala-OMe (107 mg,
D-Phe-Ala-OMe
D
C
36H39N5NaO7: 676.2747 [MþNa]þ, found 676.2740 [MþNa]þ.
0.2 mmol) was reacted with benzene boronic acid (98 mg,
0.8 mmol) and (S)-BINAP. The title compound was isolated as
4.5.10. Boc-Trp-Phe(3,5-di-CF3)-OMe
a single diastereomer in 45% yield (55 mg) as a colourless glass.
20
In accordance with the representative procedure for 1,4-addi-
[a
]
þ11.8 (c 0.085, CHCl3); IR (film, cmꢂ1
) n 3423, 3018, 2088,1700,
D
tions with boronic acids, Boc-Trp-DAla-Tyr-OMe (110 mg, 0.2 mmol)
1669, 1517, 1455, 1368, 1225, 1208, 1165, 1057, 1028, 925, 853, 778,
was reacted with 3,5-bis-trifluoromethylbenzene boronic acid
(206 mg, 0.8 mmol, 4 equiv) in the presence of sodium fluoride
(25 mg, 0.6 mmol, 3 equiv). The title compound was obtained in 38%
741, 699, 668; 1H NMR (CDCl3, 300 MHz)
d 7.36–7.19 (10H, m), 6.86
(1H, d, J¼8.1), 6.80 (1H, d, J¼8.1), 5.18 (1H, d, J¼6.9), 5.09 (2H, s),
4.96–4.93 (1H, m), 4.74 (1H, app q, J¼7.5), 4.50 (1H, app pent,
J¼7.2), 3.94 (1H, dt, J¼6.3, 7.2), 3.69 (3H, s), 3.19–3.01 (4H, m), 1.70–
1.10 (6H, m), 1.40 (9H, s), 1.28 (3H, d, J¼7.2); 13C NMR (CDCl3,
yield (59 mg) as an off white foam. IR (film, cmꢂ1
)
n
4214, 3411 (br),
3020, 1651, 1516, 1440, 1379, 1280, 1216, 1177, 1138, 1013, 902, 757,
707, 682, 668; 1H NMR (CDCl3, 300 MHz)
8.31 (1H, d, J¼0.9), 7.68
d
75.5 MHz) d 173.5,172.6,170.7,156.9,156.1, 137.0,136.9,129.7, 129.0,
(1H, s), 7.61 (1H, d, J¼7.8), 7.41 (2H, s), 7.33 (1H, d, J¼8.1), 7.20–7.06
(2H, m), 6.94 (1H, d, J¼2.1), 6.77 (2H, d, J¼8.4), 6.8–6.5 (1H, br s), 6.68
(1H, d, J¼8.4), 6.46–6.30 (2H, m), 5.02 (1H, d, 7.5), 4.68–4.57 (2H, m),
4.36 (1H, dd, J¼14.4, 6.6), 3.69 (3H, s), 3.25 (1H, dd, J¼5.4, 14.4), 3.11
(1H, dd, J¼6.9,14.4), 3.01–2.77 (4H, m),1.37 (9H, s); 13C NMR (CDCl3,
75.5 MHz) 172.4, 171.9, 169.4, 156.1, 155.7, 139.1, 136.7, 132.1, 131.7,
131.2, 130.7, 130.1, 127.6, 127.4, 125.4,123.5, 122.9, 121.8, 121.3, 120.2,
119.3, 116.2, 111.8, 110.4, 81.3, 55.7, 53.8, 53.7, 52.8, 37.6, 37.2, 30.1,
128.9, 128.6, 128.5, 127.3, 80.5, 67.0, 55.1, 54.4, 52.8, 48.4, 40.7, 38.2,
31.9, 29.7, 28.6, 22.6, 18.1; HRMS (ESIþ) calcd for C32H44N4NaO8:
635.3057 [MþNa]þ, found: 635.3035 [MþNa]þ.
4.6.4. Boc-Lys(Cbz)-Phe(3,5-di-F)-Ala-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)-DAla-Ala-OMe (107 mg,
0.2 mmol) was reacted with 3,5-difluorobenzene boronic acid
(126 mg, 0.8 mmol) and (R)-BINAP. The title compound was iso-
28.5; 19F NMR (CDCl3, 376.5 MHz)
d
ꢂ62.92; HRMS (ESIþ) calcd for
[MþH]þ C37H39F6N4O7: 765.2723, found: 765.2716[MþH]þ.
lated as a single diastereomer in 32% yield (42 mg) as a colourless
20
glass. [
a
]
ꢂ17.8 (c 0.51, CHCl3); IR (film, cmꢂ1
) n 4213, 3419, 3019,
D
4.6. Synthesis of urotensin receptor agonist fragments
2100, 1660, 1518, 1222, 1208, 1164, 1119, 786, 732, 668; 1H NMR
(CDCl3, 300 MHz)
d 7.37–7.31 (5H, m), 6.81–6.63 (5H, m), 5.31 (1H,
4.6.1. Boc-Lys(Cbz)-
D
Ala-Ala-OMe (18)
d, J¼6.6), 5.10 (2H, s), 5.08–5.01 (1H, m), 4.72 (1H, dt, J¼6.9, 7.8),
4.50 (1H, pent, J¼7.2), 4.05–3.98 (1H, m), 3.72 (3H, s), 3.22–3.13 (2H,
m), 3.09–3.06 (2H, m), 1.81–1.72 (1H, m), 1.65–1.58 (1H, m), 1.50–
1.31 (4H, m), 1.41 (9H, s), 1.35 (3H, d, J¼7.2); 13C NMR (CDCl3,
An oven dried flask was charged with Boc-Lys(Cbz)-Ser-Ala-
OMe (3.31 g, 10.4 mmol) dissolved in degassed dichloromethane
(40 mL) under an atmosphere of nitrogen. Copper(I) chloride
(117 mg, 1.18 mmol) and EDCI (831 mg, 4.33 mmol) were sub-
sequently added and the resultant suspension stirred for 18 h at
ambient temperature. The solution was washed with two portions
of water (15 mL), dried over MgSO4, filtered and concentrated un-
der reduced pressure. Purification by flash column chromatography
75.5 MHz)
d
173.1, 172.5, 170.0, 164.9 (d, J¼12.8), 161.7 (d, J¼12.8),
157.2, 140.8 (d, J¼9.1), 136.9, 128.9, 128.5, 112.8, 112.5, 102.9 (t,
J¼25.1), 80.8, 67.0, 55.2, 53.8, 52.8, 48.6, 40.3, 37.9, 31.4, 29.8, 28.6,
22.5, 18.3; HRMS (ESIþ) calcd for C32H43F2N4O8: 649.3049 [MþH]þ,
found: 649.3042 [MþH]þ.

C.J. Chapman et al. / Tetrahedron 64 (2008) 9528–9539
9539
4.6.5. Boc-Lys(Cbz)-1-Nal-Ala-OMe
EPSRC Mass Spectrometry Service at the University of Wales
Swansea are thanked for valuable assistance.
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)-DAla-Ala-OMe (107 mg,
0.2 mmol) was reacted with 1-naphthyl boronic acid (138 mg,
0.8 mmol) and (R)-BINAP. The title compound was isolated as
References and notes
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a single diastereomer in 56% yield (75 mg) as a colourless glass.
20
[
a]
ꢂ31.58 (c 0.19, CHCl3); IR (film, cmꢂ1
) n 4211, 3414, 3011, 2085,
D
1701, 1654, 1499, 1454, 1368, 1242, 1163, 1057, 1027, 926, 802; 1H
3. (a) Dibowski, H.; Schmidtchen, F. P. Angew. Chem., Int. Ed. 1998, 37, 476–478; (b)
Bong, D. T.; Ghadiri, M. R. Org. Lett. 2001, 3, 2509–2511; (c) Joshi, N. S.; Whi-
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5. Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc.
1998, 120, 5579–5580.
NMR (CDCl3, 300 MHz)
d
8.20 (1H, d, J¼8.4), 7.85 (1H, dd, J¼1.2, 8.1),
7.75 (1H, dd, J¼2.1, 7.2), 7.59–7.46 (2H, m), 7.38–7.30 (7H, m), 6.81
(1H, d, J¼7.2), 6.35 (1H, d, J¼7.2), 5.17–5.13 (1H, m), 5.09 (2H, s), 4.99
(1H, t, J¼6.0), 4.80 (1H, dt, J¼7.2, 7.5), 4.38 (1H, pent, J¼7.2), 4.05–
3.99 (1H, m), 3.63 (3H, s), 3.61–3.46 (2H,m), 3.15 (2H, q, J¼6.3),
1.80–1.42 (4H, m), 1.39 (9H, s), 1.24 (3H, d, J¼7.2), 1.24–1.15 (2H, m);
13C NMR (CDCl3, 75.5 MHz)
d
172.7, 172.2, 170.5, 157.0, 156.2, 136.9,
134.2, 132.9, 132.3, 129.2, 128.8, 128.4, 128.2, 126.9, 126.2, 125.7,
124.0, 80.6, 67.0, 55.1, 54.3, 52.7, 48.6, 40.4, 35.5, 31.7, 29.8, 28.6,
22.4, 18.3; HRMS (ESIþ) calcd for C36H47N4O8: 663.3394 [MþH]þ,
found: 663.3363 [MþH]þ.
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2024; (e) Navarre, L.; Darses, S.; Genet, J.-P. Angew. Chem., Int. Ed. 2004, 43, 719–
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4.6.6. Boc-Lys(Cbz)-2-Nal-Ala-OMe
In accordance with the representative procedure for 1,4-addi-
tions with boronic acids, Boc-Lys(Cbz)-DAla-Ala-OMe (107 mg,
0.2 mmol) was reacted with 2-naphthyl boronic acid (138 mg,
0.8 mmol) and (R)-BINAP. The title compound was isolated as
a single diastereomer in 68% yield (90 mg) as a colourless glass.
20
[
a]
ꢂ15.56 (c 0.45, CHCl3); IR (film, cmꢂ1
) n 4214, 3418, 3018,
D
9. (a) Bonauer, C.; Walenzyk, T.; Ko¨nig, B. Synthesis 2006, 1, 1–20; (b) Burrage, S.;
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2399, 2096, 1693, 1667, 1515, 1455, 1438, 1368, 1226, 1206, 1162,
1027, 929, 794, 721, 665, 629; 1H NMR (CDCl3, 300 MHz)
d 7.79–7.74
(3H, m), 7.61 (1H, s), 7.45–7.42 (2H, m), 7.38–7.33 (6H, m), 6.73–6.68
(2H, m), 5.28 (1H, br s), 5.11 (1H, d, J¼18.6), 5.08 (1H, d, J¼18.6), 4.92
(1H, t, J¼6.0), 4.81 (1H, dt, J¼6.6, 7.8), 3.98 (1H, m), 3.60 (3H, s),
3.35–3.19 (2H, m), 3.11–3.02 (2H, m), 1.75–1.64 (1H, m), 1.60–1.49
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(1H, m), 1.38–1.10 (16H, m); 13C NMR (CDCl3; 75.5 MHz)
d 172.9,
172.2, 170.6, 157.1, 136.9, 134.2, 133.8, 132.8, 128.9, 128.7, 128.5,
128.4, 128.0, 127.7, 126.5, 126.0, 80.6, 67.0, 55.3, 54.1, 52.6, 48.6, 40.1,
38.3, 31.3, 29.7, 28.5, 22.2, 18.3; HRMS (ESIþ) calcd for C36H47N4O8:
663.3394 [MþH]þ, found: 663.3359 [MþH]þ.
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Acknowledgements
19. No Selectivity was observed in previous studies investigating the addition of
boronic acids to dehydroalanine, see Refs. 7a,c.
20. Foister, S.; Taylor, L. L.; Feng, J.-J.; Chen, W.-L.; Lin, A.; Cheng, F.-C.; Smith, A. B.,
III; Hirschmann, R. Org. Lett. 2006, 8, 1799–1802.
The authors would like to thank the EPSRC (DTA) and Pfizer
Limited (CASE award) for funding (to J.D.H.). Dr. Anneke Lubben
(Mass Spectrometry Service at the University of Bath) and the
21. Jung, M.; Starkey, L. S. Tetrahedron 1997, 53, 8815–8824.