Kinetic deconjugation: A gateway to the synthesis of Xxx-Gly (E)-alkene dipeptide isosteres

Article abstract of DOI:10.1016/j.tetlet.2011.09.136

A new method for the preparation of Xxx-Gly (E)-alkene dipeptide isosteres (EADIs), using LDA deprotonation followed by 1 N HCl quench, was explored. The method, named kinetic deconjugation, enabled the synthesis of Tyr-Gly, Gly-Gly, Ser-Gly, Pro-Gly, and

Full text of DOI:10.1016/j.tetlet.2011.09.136

Tetrahedron Letters 52 (2011) 6603–6605
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Kinetic deconjugation: a gateway to the synthesis of Xxx-Gly (E)-alkene
dipeptide isosteres
Arnaud Proteau-Gagné a, Jean-François Nadon a, Sylvain Bernard a, Brigitte Guérin b, , Louis Gendron c,
⇑
⇑
,
Yves L. Dory a,
⇑
a Laboratoire de Chimie Supramoléculaire, Département de Chimie, Université de Sherbrooke, 3001 12e Av. Nord, Sherbrooke, QC, Canada J1H 5N4
b Département de Médecine Nucléaire et de Radiobiologie, Université de Sherbrooke, 3001 12e Av. Nord, Sherbrooke, QC, Canada J1H 5N4
c Département de Physiologie et Biophysique, Université de Sherbrooke, 3001 12e Av. Nord, Sherbrooke, QC, Canada J1H 5N4
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the preparation of Xxx-Gly (E)-alkene dipeptide isosteres (EADIs), using LDA deproto-
nation followed by 1 N HCl quench, was explored. The method, named kinetic deconjugation, enabled the
synthesis of Tyr-Gly, Gly-Gly, Ser-Gly, Pro-Gly, and Phe-Gly EADIs, as well as one Tyr-Gly trisubstituted
alkene dipeptide isostere (TADI). Overall, this method, based on commercially available materials, leads
to high yields, requires few synthetic steps and works on the gram scale in the synthesis of a wide variety
of EADIs.
Received 18 August 2011
Revised 22 September 2011
Accepted 29 September 2011
Available online 6 October 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
(E)-Alkene dipeptide isostere
Trisubstituted alkene dipeptide isostere
(E)-b,c-Unsaturated ester
Peptidomimetics
Lithium diisopylamine
Introduction
EADIs.4,7 We now report a novel short and efficient synthetic meth-
od to obtain Xxx-Gly EADIs.
Replacement of the amide function by an isosteric function in a
peptide sequence is a recognized way to improve ‘drug like’ prop-
erties of a peptide.1 A widely used isostere of the amide bond is the
(E)-alkene dipeptide isostere (EADI). The incorporation of an al-
kene replacing an amide bond increases hydrophobicity and enzy-
matic resistance of the peptide.2 Some of those peptidomimetics
are very potent toward their biological target.3,4 Other alkene isos-
teres of the amide have been developed such as trisubstituted al-
kene dipeptide isostere (TADI). It is reported that certain TADIs
can promote beta turns in peptidomimetics.5 Since these modifica-
tions are useful, a lot of work has been done to develop synthetic
methods to obtain those building blocks. The copper mediated
ones are still largely used and studied nowadays.6 These effective
and stereoselective methods lead to EADIs bearing two chiral cen-
ters. In counterpart, they involve many synthetic steps. Other
methods requiring fewer steps have been developed, but some lack
stereocontrol.4 In the case of a Xxx-Gly EADIs, only one chiral cen-
ter is present. This causes the use of long methods to be irrelevant,
but few shorter syntheses have been developed for Xxx-Gly
The treatment of a (E)-
by a quench using HCl at low temperature, is an already known
way to obtain the corresponding (E)-b,
-unsaturated ester.8 We
named this reaction ‘kinetic deconjugation’. Alkylation of (E)-
b-unsaturated ester was also previously reported as a useful way
to obtain EADIs with two chiral centers (Xxx-Yyy in Scheme
1).4,9,10 According to our knowledge, no one has previously re-
ported that a quench of a specific enolate with a d nitrogen atom
(Fig. 1) by means of a protic source can lead directly to a Xxx-Gly
EADI (Scheme 1). In this report, we explore the scope of this kinetic
deconjugation to form EADIs on a variety of amino acids. We also
report a synthesis to obtain a TADI.
a,b-unsaturated ester with LDA, followed
c
a,
⇑
Corresponding authors. Tel.: +1 819 564 5299.
E-mail addresses: Brigitte.Guerin2@usherbrooke.ca (B. Guérin), Louis.Gendron@
Scheme 1. Alkylation and kinetic deconjugation to obtain an EADI.
USherbrooke.ca (L. Gendron), Yves.Dory@USherbrooke.ca (Y.L. Dory).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.09.136

6604
A. Proteau-Gagné et al. / Tetrahedron Letters 52 (2011) 6603–6605
Figure 1. b,c-Unsaturated enolate bearing a d nitrogen atom.
Results
Our synthetic strategy was first applied to tyrosine to obtain a
Tyr-Gly EADI (Scheme 2). Diazomethane was added to the mixed
anhydride, which resulted from the addition of isobutyl chlorofor-
mate to Boc-Tyr(tBu)-OH, to yield the diazoketone 1.11 Wolf rear-
rangement of 111 led to the ester 2, which was then reduced to
the aldehyde.11 Addition of the suitable ylide produced the (E)-
a
,b-unsaturated ester 3. Formation of the conjugated enolate using
LDA, followed by a kinetic quench using HCl at low temperature
afforded the (E)-b,
-unsaturated ester 4.12 The methyl ester was
c
then hydrolyzed using LiOH to yield the carboxylic acid 5. This
six step synthesis was executed with an overall yield of 63%. All
reactions were done on a gram scale. Cautious measures were ta-
ken for reagents such as CH2N2, DIBAL, and LDA.
The same synthetic strategy was used with the inclusion of an
alkylation to obtain Tyr-Gly CH3-ADI (Scheme 3). The previously
obtained ester 2 (Scheme 2) was alkylated with MeI13 and the dia-
stereoisomers were separated (total yield of 87% with syn:anti ratio
Scheme 3. Synthesis of Tyr-Gly CH3-ADI.
acetic acid gave mainly the starting material. This illustrates that
the use of a strong acid like 1 N HCl solution is mandatory to
achieve a kinetic quench of the conjugated enolate. It is already
a carbon (Fig. 1) possesses the greatest electronic den-
sity in the conjugated enolate. Consequently, under kinetic condi-
of 2:1). The stereochemistry of
a carbon was assigned by compar-
ing 1H NMR with very similar reported compounds.13 The major
known that
syn diastereoisomer obtained 6 was then reduced to the aldehyde
and subsequent addition of the ylide produced the (E)-
rated ester 7. After the treatment with LDA, followed by HCl
quench, (E)-b, -unsaturated ester 8 was obtained. The (E) geome-
a,b-unsatu-
tions, the quench with a strong acid yields (E)-b,c-unsaturated
ester.14
c
To show the different uses of our method, we applied our syn-
thetic route to other amino acids. The first three steps (Arndt–
Eistert homologation, reduction with DIBAL, and Wittig reaction)
were done on phenylalanine, glycine, proline, and serine to obtain
substrates 10–14. In the case of serine, we used two different sets
of protections (see entries for substrates 11 and 14 in Table 1).
Treatment with LDA, followed by HCl quench at low temperature
try of the alkene was determined by NOESY experiments. The
methyl ester was then hydrolyzed using LiOH to yield carboxylic
acid 9. This seven step synthesis was executed with an overall yield
of 13%.
At least 3 equiv of LDA in a concentrated THF solution are re-
quired to form the conjugated enolate. Since the use of the lithium
stabilizing agent TMEDA did not increase the yield in (E) alkene 8
(Scheme 3) it was not used subsequently. The use of other quench-
ing agents to obtain (E) alkene 8 such as brine, saturated aqueous
NH4Cl solution, saturated aqueous citric acid solution, or glacial
afforded (E)-b,c-unsaturated esters in yields ranging from 27% to
66% (Table 1). For each product the (E) geometry was determined
by looking at the coupling constant of the alkene hydrogens in
1H NMR spectra. Total yields of both (E) and (Z) b,
c-unsaturated es-
ters oscillated between 46% and 71% for all reactions. Flexible side
chains (substrates 3, 10, and 11) seem to favor (E) adducts. Re-
stricted side chains as in 14 lead to more (Z) adducts (E/Z ꢀ 2/1).
The simplest and more flexible substrate 12 definitely favors the
(Z) adduct. Illustrations of this phenomenon already exist in the lit-
erature for simpler substrates.8 For all substrates in Table 1, less
than 5% of starting material could be isolated. The carbamate
hydrogen on the substrates 10–12 had no significant effect on
the yield when compared to substrates 13 and 14 devoid of this la-
bile hydrogen.
Conclusion
The high overall yield of our method in Scheme 1 illustrates the
usefulness of our method over the already existing ones to achieve
a Xxx-Gly EADI.7 Since all steps are known to be large scale com-
patible, there should be no major problem applying this synthesis
on even larger quantities.15 The Boc protected (E)-b,
c-unsaturated
acids are suitable for the solid phase peptide synthesis using Boc
methodology. Removal of the Boc protection with TFA and subse-
quent reaction of the amino group with Fmoc-Cl could provide a
protected building block suitable for the solid phase peptide
synthesis using Fmoc methodology.4
Scheme 2. Synthesis of Tyr-Gly EADI.

A. Proteau-Gagné et al. / Tetrahedron Letters 52 (2011) 6603–6605
6605
Table 1
Kinetic deconjugation of a variety of substrates
Substrate
Side chain (R)
Corresponding dipeptide
Yielda (%)
10
11
12
–CH2Ph
–CH2OTBDPS
–H
Phe-Gly
Ser-Gly
Gly-Gly
66
63
27c
13
14
–CH2CH2–
Pro-Gly
Ser-Gly
46
–C(CH3)2O–b
47c
a
b
c
Isolated (E) alkene yield.
Serine is protected with a cyclic dimethyl acetal (Garner).
43% (Z) b, -Unsaturated ester product was isolated for 12 and 24% for 14.
c
3. Tomita, K.; Oishi, S.; Ohno, H.; Peiper, S. C.; Fujii, N. J. Med. Chem. 2008, 51,
7645–7649.
4. Proteau-Gagne, A.; Bournival, V.; Rochon, K.; Dory, Y. L.; Gendron, L. ACS Chem.
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7. (a) Kranz, M.; Kessler, H. Tetrahedron Lett. 1996, 37, 5359–5362; (b) Otaka, A.;
Yukimasa, A.; Watanabe, J.; Sasaki, Y.; Oishi, S.; Tamamura, H.; Fujii, N. Chem.
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The synthetic strategy shown in Scheme 3 could be used to ob-
tain TADIs bearing other functional groups than methyl. A wide
selection of commercial electrophiles can be used in the alkylation
step. Following the same synthetic pathway, a variety of TADIs
could be obtained. The alkylation step could be carried out earlier
in the synthesis by alkylating the diazoketone. This could provide
milder conditions with the use of KHMDS instead of LDA.16
In summary, this synthetic method using kinetic deconjugation
is an efficient way to obtain Xxx-Gly EADIs. We have shown that a
few high yield steps are required to obtain gram quantities of Tyr-
Gly EADI using commercially available starting material. The meth-
od was applied on different amino acids and on the synthesis of
CH3-ADI with successful results. Although we believe this method
could lead to more complex EADIs and TADIs, further investiga-
tions are required to evaluate its full scope.
11. Shi, K.; Harrison, B. A.; Verdine, G. L. Org. Lett. 2003, 5, 633–636.
12. Kinetic deconjugation general protocol: n-BuLi (20 mL, 1.6 M in hexane,
31.2 mmol) was slowly added to DiPA (6 mL, 41.6 mmol) at À20 °C under an
Ar atmosphere, and the mixture was stirred for 30 min at À20 °C. The reaction
was cooled to a temperature of À78 °C, and anhyd THF (20 mL) was added,
Acknowledgment
This work has been supported by the Canadian Institute for
Health Sciences (CIHR) Grant No. MOP-102612 awarded to B.G.,
L.G. and Y.L.D. L.G. is the recipient of a Fonds de la Recherche en
Santé du Québec Junior 2 salary support.
then the conjugated ester
3 (4.05 g, 10.4 mmol), dissolved in anhyd THF
(100 mL), was added over a 15 min period. The reaction mixture was stirred for
30 min at À78 °C and the reaction was quenched rapidly with HCl 1 N
(120 mL). When the mixture was at rt, a saturated solution of NH4Cl was
added, then brine, and the mixture was extracted with ethyl ether
(4 Â 200 mL). The organic layers were combined, dried with MgSO4, filtered,
evaporated under reduced pressure and purified by flash chromatography on
silica gel eluting with EtOAc and hexane (from 3:17 to 1:4 to 1:3) to afford the
title compound as a yellowish oil (3.36 g, 83%).
Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.09.136.
13. Anne, C.; Blommaert, A.; Turcaud, S.; Martin, A.-S.; Meudal, H.; Roques, B. P.
Bioorg. Med. Chem. 2003, 11, 4655–4660.
14. Katzenellenbogen, J. A.; Crumrine, A. L. J. Am. Chem. Soc. 1976, 98, 4925–4935.
15. (a) Su, X.; Bhongle, N. N.; Pflum, D.; Butler, H.; Wald, S. A.; Bakale, R. P.;
Senanayake, C. H. Tetrahedron: Asymmetry 2003, 14, 3593–3600; (b) Perrault,
W. R.; Shephard, K. P.; LaPean, L. A.; Krook, M. A.; Dobrowolski, P. J.; Lyster, M.
A.; McMillan, M. W.; Knoechel, D. J.; Evenson, G. N.; Watt, W.; Pearlman, B. A.
Org. Process Res. Dev. 1997, 1, 106–116; (c) Proctor, L. D.; Warr, A. J. Org. Process
Res. Dev. 2002, 6, 884–892.
References and notes
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