Pd-catalysed C-C macrocyclisation of a simple tripeptide: Efficient total synthesis of K-13

Article abstract of DOI:10.1039/b008078k

The cyclic tripeptide K-13 has been prepared in 11 steps from commercially available starting materials (11% overall yield); the key step is the Pd-catalysed macrocyclisation of the zinc reagent prepared by selective insertion of zinc into the aliphatic C

Full text of DOI:10.1039/b008078k

Pd-catalysed C–C macrocyclisation of a simple tripeptide: efficient total
synthesis of K-13
Manuel Pe´rez-Gonza´lez and Richard F. W. Jackson*
Department of Chemistry, Bedson Building, The University of Newcastle, Newcastle upon Tyne, UK NE1 7RU.
E-mail: r.f.w.jackson@ncl.ac.uk
Received (in Liverpool, UK) 29th September 2000, Accepted 31st October 2000
First published as an Advance Article on the web 21st November 2000
The cyclic tripeptide K-13 has been prepared in 11 steps
from commercially available starting materials (11% overall
yield); the key step is the Pd-catalysed macrocyclisation of
the zinc reagent prepared by selective insertion of zinc into
the aliphatic C–I bond of the linear tripeptide 3, followed by
Pd-catalysed macrocyclisation.
therapeutic agents.3 Previous routes to these and related
compounds have relied on macrocyclisation involving classical
amide bond formation, or on formation of the biaryl ether. This
latter approach has employed oxidative phenol coupling using
thallium trinitrate, Ullmann cyclisations and the SNAr reaction.4
These approaches have the advantage that the precursors for
cyclisation are generally easy to prepare, with minimal reliance
on protecting groups.
We have already described the palladium-catalysed reaction
between aromatic iodides and the organozinc reagent derived
from a protected iodolalanine derivative.5 The reaction has
proved to be versatile and has been extended to dipeptide-
derived organozinc reagents.6 We have therefore explored
whether this reaction might be applied to the synthesis of K-13,7
in which the key macrocyclisation step is a Negishi cross-
coupling reaction of the corresponding open chain peptide 3
(Scheme 1).8 This approach has the benefit of requiring the
synthesis of relatively simple macrocyclisation precursors, and
the potential for broader application since there is no absolute
requirement for a biaryl ether in the target.
The conformation of peptides is a key parameter in determining
their biological activity. Cyclic peptides, in which the degrees
of conformational freedom are reduced, are therefore poten-
tially important targets. Some examples of natural products
falling into this class include the aminopeptidase inhibitor
OF4949-III1a and the ACE inhibitor K-13 (1).1b There is
It was expected that the crucial C–C bond formation could be
achieved after chemoselective Zn insertion into the aliphatic
C–I bond, followed by a palladium-catalyzed cross-coupling
reaction of the resulting organometallic reagent. The viability of
this type of coupling in an intermolecular sense had already
been demonstrated.9 Compound 3 could be obtained by amide
bond formation between the peptide 4 and the N-protected
biaryl ether amino acid 5, in which the hydroxy group of the
serine residue could then be transformed into an iodide.
substantial interest in the preparation of these targets,2 and
analogues of these compounds have been proposed as potential
Scheme 2 Reagents and conditions: (a) 2-fluorobenzaldehyde, K2CO3,
DMF, 70 °C, 4 d; (b) MeI, NaHCO3, DMF, rt, 16 h, 85% (two steps); (c) i,
MCPBA, NaHCO3, CHCl3, 55 °C, 16 h; ii, K2CO3 (cat), MeOH; (d)
Chloramine-T, NaI, DMF, rt, 90 min; (e) MeI, K2CO3, DMF, rt, 16 h, 71%
(three steps); (f) LiOH, THF–H2O (1+4), quantitative.
Scheme 1
DOI: 10.1039/b008078k
Chem. Commun., 2000, 2423–2424
This journal is © The Royal Society of Chemistry 2000
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condensation of compound 5 and HCl·410 gave the dipeptide 12
(94%), which was transformed into the iodide 3 (76%) using
(PhO)3PMeI in DMF.11 Treatment of iodide 3 with zinc dust in
DMF gave a solution of the organometallic intermediate 13,
which was added dropwise to a dilute solution of a catalyst
prepared from Pd2(dba)3 and P(o-Tol)3 in THF (maximum
conc. of 13, 3 3 1023 M at 60 °C, and the solution was then
stirred overnight. After extractive work up, cyclic dipeptide 2
was isolated by flash chromatography (35%). Compound 2 was
transformed into K-13 following the experimental procedure
published by Evans and Ellman7 in good overall yield (74%).
Synthetic K-13 exhibited physical and spectroscopic properties
in close agreement with those reported.12
We thank the Spanish Ministerio de Educacio´n y Cultura for
a fellowship (M. P.-G.), the EU for a Marie Curie fellowship,
HPMF-CT-1999-00050 (M. P.-G.), and Professor J. Zhu for
providing spectra of synthetic K-13 for comparison.
References
1 (a) S. Sano, K. Ikai, K. Katayama, K. Takesako, T. Nakamura, A.
Obayashi, Y. Ezure and H. Enomoto, J. Antibiot., 1986, 39, 1685; (b) T.
Yasuzawa, K. Shirahata and H. Sano, J. Antibiot., 1987, 40, 455.
2 For a review, see: A. V. Rama Rao, M. K. Gurjar, K. L. Reddy and A. S.
Rao, Chem. Rev., 1995, 95, 2135.
3 D. W. Hobbs and W. C. Still, Tetrahedron Lett., 1989, 30, 5405; A. G.
Brown, M. J. Crimmin and P. D. Edwards, J. Chem. Soc., Perkin Trans.
1, 1992, 13; D. L. Boger and D. Yohannes, Bioorg. Med. Chem. Lett.,
1993, 3, 245; A. D. Abell and M. D. Oldham, J. Org. Chem., 1997, 62,
1509. For a review, see: D. P. Fairlie, G. Abbenante and S. R. March,
Curr. Med. Chem., 1995, 2, 654.
Scheme 3 Reagents and conditions: (a) 4, EDCI, BtOH, iPr2NEt, DMF, rt,
16 h, 94%; (b) (PhO)3PMeI, DMF, rt, 20 min, 76%; (c) Zn, I2 (cat), DMF,
rt, 30 min; (d) Pd2(dba)3, (0.03 equiv.), P(o-Tol)3, (0.12 equiv.), 3 3 1023
M THF, 60 °C, 16 h, 35%; (e) i, TFA, thioanisole, CH2Cl2; ii, Ac2O,
pyridine 87%; (f) AlBr3, EtSH, CH2Cl2, 85%.
The synthesis of fragment 5 started from commercially
available N-Boc protected tyrosine 6. Thus, nucleophilic
aromatic substitution reaction between N-Boc protected tyro-
sine 6 and 2-fluorobenzaldehyde afforded the diaryl ether 7,
which was directly transformed into the corresponding methyl
ester 8 in 85% overall yield (Scheme 2). Perkin reaction on the
aromatic aldehyde 8, using MCPBA in CHCl3, followed by
treatment of the formate intermediate with a catalytic amount of
K2CO3 in MeOH, provided the phenol 9 in quantitative yield,
which was used in the next step without further purification.
This compound had already been synthesised by Jung using a
different route in 30% yield over three steps.9 At this stage, the
enantiomeric purity of compound 9 was checked by removal of
the Boc protecting group and Mosher’s amide formation using
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlor-
ide. The enantiomeric purity of 9 was found to be > 95% by 1H-
NMR spectroscopy. The use of the free carboxylic acid
derivative of tyrosine 6 in the reaction with 2-fluorobenzalde-
hyde is crucial to ensure high enantiomeric purity; use of the
corresponding methyl ester derivative afforded racemic mix-
tures under a wide variety of conditions. Compound 9 was
treated without further purification, following Jung’s condi-
tions,9 with one equivalent of Chloramine-T hydrate (sodium
salt of N-chlorotoluene-p-sulfonamide)–NaI to produce a
mixture of 5-iodo 10 and 3,5-diiodo derivatives in a 90+10 ratio.
This mixture was submitted to methylation (MeI, K2CO3,
DMF) to give 11 (71% from 8 over three steps).This procedure
allowed the synthesis of compound 11 on a multigram scale in
60% overall yield from commercially available N-Boc-tyrosine
and 2-fluorobenzaldehyde. Finally, acid 5 was obtained in
quantitative yield by saponification.
4 For a review, see: J. Zhu, Synlett, 1997, 133.
5 R. F. W. Jackson, R. J. Moore, C. S. Dexter, J. Elliott and C. E.
Mowbray, J. Org. Chem., 1998, 63, 7875. For a review see: S. Gair and
R. F. W. Jackson, Curr. Org. Chem., 1998, 2, 527.
6 M. J. Dunn and R. F. W. Jackson, Tetrahedron, 1997, 53, 13905.
7 D. A. Evans and J. A. Ellman, J. Am. Chem. Soc., 1989, 111, 1063. For
other syntheses of K-13 see: S. Nishiyama, Y. Suzuki and S. Yamamura,
Tetrahedron Lett., 1989, 30, 379; D. L. Boger and D. Yohannes, J. Org.
Chem., 1989, 54, 2498; D. L. Boger and D. Yohannes, J. Org. Chem.,
1990, 55, 6000; A. V. Rama Rao, T. K. Chakraborty, K. Laxma Redy
and A. Srinivasa Rao, Tetrahedron Lett., 1992, 33, 4799; J. W. Janetka
and D. H. Rich, J. Am. Chem. Soc., 1997, 119, 6488; A. Bigot, M. Bois-
Choussy and J. Zhu, Tetrahedron Lett., 2000, 41, 4573.
8 For an early example of a transition metal catalysed macrocyclisation by
C–C bond-formation, see: M. F. Semmelhack and L. S. Ryono, J. Am.
Chem. Soc., 1975, 97, 3873. For a review on the intramolecular Stille
reaction, see: M. A. J. Duncton and G. Pattenden, J. Chem. Soc., Perkin
Trans. 1, 1999, 1235.
9 M. E. Jung and L. S. Starkey, Tetrahedron, 1997, 53, 8815.
10 Compound 4 was prepared from the known Boc-Tyr(OMe)-Ser-OMe:
S. Lee, H. Aoyagi, Y. Shimohigashi, N. Izumiya, T. Ueno and H.
Fukami, Tetrahedron Lett., 1976, 17, 843.
11 J. P. H. Verheyden and J. G. Moffatt, J. Org. Chem., 1970, 35, 2319.
12 Synthetic K-13 (1): mp (MeOH–diethyl ether) 265–270 °C (decomp.);
lit.1b mp 260–270 °C (decomp.); [a]D = 26.6 (c 1.4, MeOH); lit.7 [a]D
= 26.5 (c 0.46, MeOH), natural1b [a]D = 23.4 (c 0.6, MeOH); 1H-
NMR (500 MHz, CD3OD) d 7.29 (dd, J 8.0, 2.0, 1 H), 7.04 (dd, J 8.5,
2.5, 1 H), 6.99–6.93 (m, 3 H), 6.80 (dd, J 8.0, 1 H), 6.73 (dd, J 8.0, 2.0,
1 H), 6.66 (dd, J 8.0, 2.5, 1 H), 6.62–6.57 (BBA, 2 H), 6.38 (d, J 2.0, 1
H), 4.48–4.40 (m, 2 H), 4.17 (t, J 5.5, 1 H), 3.17 (dd, J 15.5, 2.0, 1 H),
3.01 (dd, J 12.5, 5.5, 1 H), 2.95 (dd, J 13.0, 6.0, 1 H), 2.91 (dd, J 15.5,
9.0, 1 H), 2.85 (dd, J 13.5, 5.0, 1 H), 2.77 (t, J 12.0, H), 2.03 (s, 3 H);
13C-NMR (125.7 MHz, CD3OD) d 175.5, 172.9, 172.2, 171.5, 158.2.
157.0, 147.8, 147.5, 132.8, 132.0 (3C), 131.2, 130.7, 128.2, 125.4,
122.1, 120.8, 118.8, 117.5, 115.8 (2C), 57.3, 55.9, 54.3, 39.1, 38.7, 36.6,
22.4.
With the key intermediate 5 in hand, the synthesis of the
crucial precursor 3 proved straightforward (Scheme 3). Thus,
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