Synthesis of an eight-membered cyclic pseudo-dipeptide using ring closing metathesis

Article abstract of DOI:10.1021/ol015530u

matrix presented Ring closing metathesis of diallylglycine 6 provided cyclic Z-olefin 7 in 80% yield. The reaction was promoted by substitution of the amide nitrogen with the 2,4-dimethoxybenzyl group allowing for the required cis diallylglycine amide rot

Full text of DOI:10.1021/ol015530u

ORGANIC
LETTERS
2
001
Vol. 3, No. 6
93-895
Synthesis of an Eight-Membered Cyclic
Pseudo-Dipeptide Using Ring Closing
Metathesis
8
Christopher J. Creighton and Allen B. Reitz*
The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads,
Spring House, PennsylVania 19477
areitz@prius.jnj.com
Received January 8, 2001
ABSTRACT
Ring closing metathesis of diallylglycine 6 provided cyclic Z-olefin 7 in 80% yield. The reaction was promoted by substitution of the amide
nitrogen with the 2,4-dimethoxybenzyl group allowing for the required cis diallylglycine amide rotamer. Removal of the protecting groups
provided cyclic dipeptide 2, a constrained scaffold useful in peptidomimetic research.
Cyclic, constrained peptide derivatives are useful tools for
understanding the structure and function of biologically
relevant molecules. The most common unit used to form
cyclic peptides and proteins is cystine, which provides a
bridging tether that can directly influence biological activity
and physical properties. The oxidized cyclic Cys-Cys
dipeptide 1 is an eight-membered ring disulfide that is found
only infrequently in nature.
conformational changes involving 1 are proposed to be the
primary switch for ligand-mediated modulation of nAChR
1
2
activity. An oxidized Cys-Cys eight-membered ring is
3
found in the catalytic domain of mercuric ion reductase and
4
,5
in the bicyclic peptide malformin. The oxidized Cys-Cys
motif has also been incorporated into short peptides such as
6
7
somatostatin and kemptide.
Peptidomimetics in which the disulfide functionality of
cystine has been replaced by two carbon atoms have been
prepared in order to increase the chemical stability of a
Disulfide 1 is of interest because it is conserved in all
known nicotinic acetylcholine receptors (nAChRs), and
(
1) For examples on the use of peptididomimetic scaffolds, see: (a)
(2) Avizonis, D. Z.; Farr-Jones, S.; Kosen, P. A.; Basus, V. J. J. Am.
Chem. Soc. 1996, 118, 13031.
(3) Schiering, N.; Kabsch, W.; Moore, M. J.; Destefano, M. D.; Walsh,
C. T.; Pai, E. F. Nature 1991, 352, 168-171.
(4) Bodanszky, M.; Stahl, G. L. Proc. Natl. Acad. Sci. U.S.A. 2000, 71,
2791.
Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug DiscoVery
Volume 1: Principles and Practice, 5th ed.; Wolff, M. E., Ed.; John Wiley
Sons: 1995; Vol. 1, pp 833-838. (b) Hanessian, S.; McNaughton-Smith,
G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854.
c) Sawyer, T. K. In Stucture-Based Drug Design: Targets, Techniques
&
(
and DeVelopments; Veerapandian, P., Ed.; Marcel Dekker: New York, 1997;
Vol. 1, pp 559-634. (d) Creighton, C. J.; Zapf, C. W.; Bu, J. H.; Goodman,
M. Org. Lett. 1999, 1, 1407-1409. (e) Hruby, V. J.; Hill, P. S. In
Conformational Analysis of Medium-Sized Heterocycles; Glass, R. S., Ed.;
VCH: New York, 1988; pp 217-60. (f) Ripka, A. S.; Rich, D. H. Curr.
Opin. Chem. 1998, 441-452.
(5) Malformin contains cyclic (D) Cys-(D) Cys.
(6) Brady, S. F.; William J. Paleveda, J.; Arison, B. H.; Saperstein, R.;
Brady, E. J.; Raynor, K.; Reisine, T.; Veber, D. F.; Freidinger, R. M.
Tetrahedron 1993, 49, 3449-3466.
(7) Prorok, M.; Lawrence, D. S. J. Am. Chem. Soc. 1990, 112, 8626-
8627.
1
0.1021/ol015530u CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/01/2001

8
variety of important compounds. Carbon mimics of 1 such
as 2 and 3 have not been specifically evaluated, although
one research group attempted to prepare them.
Scheme 1a
9
Very recently, the synthesis of a protected variant of 3
was described in 12 chemical steps starting from a derivative
1
0
of L-serine. In this letter we report the synthesis of 2 and
via a sequence of reactions using Grubbs ring closing
metathesis (RCM) as the key synthetic step. Eight-membered
3
1
1
ring dipeptides such as 2 and 3 may be useful scaffolds in
peptidomimetic research and for studies involving amide self-
association.12
Ruthenium-based ring closing metathesis has been used
1
3,14
extensively for the preparation of macrocyclic alkenes.
a
9
,15
(a) 2,4-Dimethoxybenzaldehyde, NaBH(OAc) , >95%. (b) Boc-
3
Peptidic dienes have also been used as substrates.
allylglycine-OH, HATU, HOAT, NEM, 75%. (c) Grubbs catalyst,
reflux in DCM, 60 h, 80%. (d) (1) LiOH, MeOH/H O, quant; (2)
0% TFA in DCM, 3 h; (3) 1 N HCl and lyophilize, 78%. (e) Pd/
C, H , quant.
However, Boc-(S)-allylgly-(S)-allylgly-OPh was found to not
be suitable for RCM, which was attributed to a high
preference for the trans amide bond rotamer that was
2
1
2
9
incapable of intramolecular reaction. We have overcome
this difficulty by using transient alkylation16 on the amide
nitrogen allowing for the cis amide rotamer to participate in
the reaction (see Scheme 1). (S)-Allylglycine methyl ester
in solution. N-Substitution of a secondary amide to induce
a conformational change is an established strategy to improve
17
(4) was subjected to reductive amination with 2,4-dimethoxy-
the yields of certain intramolecular reactions. Ring closing
metathesis of 6 provided protected olefin 7 in 80% yield.18
The olefin geometry of 7 was assigned as cis on the basis of
the coupling constant of the olefinic protons (10.6 Hz). The
methyl ester of 7 was then hydrolyzed with LiOH, and the
benzaldehyde to afford derivative 5. Amide bond formation
with Boc-(S)-allylglycine using HATU gave compound 6.
N-Substituted dipeptide 6 is an excellent substrate for ring
closing metathesis because there is a significant amount of
19
the cis amide rotamer in which the alkenes can react
Boc and dimethoxybenzyl groups were removed with TFA
1
20
intramolecularly. Indeed, inspection of the H NMR (CDCl
3
)
to afford 2. Alkene 2 was then subjected to hydrogenolysis
spectrum of 6 revealed a 3:2 mixture of amide bond rotamers
to yield saturated derivative 3.
(
8) (a) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J. Org.
(17) For a recent example, see: Chao, W.; Weinreb, S. M. Tetrahedron
Lett. 2000, 41, 9199. Also while this paper was under peer review Vo-
Thanh et al. reported an analogous strategy for the synthesis of medium
sized lactams via RCM. See Vo-Thanh, G.; Boucard, V.; Sauriat-Dorizon,
H.; Guibe, F. Synlett 2001, 1, 37-40.
Chem. 1980, 45, 3078. (b) Veber, D. F.; Strachan, R. G.; Bergstrand, S. J.;
Holly, F. W.; Homnick, C. F.; Hirschmann, R.; Torchiana, M. L.; Saperstein,
R. J. Am. Chem. Soc. 1976, 98, 2367. (c) Jost, K.; Rudinger, J. J. Collect.
Czech. Chem. Commun. 1967, 32, 1229. (d) Rudinger, J.; Jost, K.
Experientia 1964, 20, 570.
(18) Experimental procedure for the ring closing metathesis of 6 to
give 7. Compound 6 (3.0 g, 6.25 mmol) was dissolved in methylene chloride
(200 mL) and added to a 5-L round-bottom flask equipped with a condenser
containing methylene chloride (1800 mL). Grubbs catalyst (benzylidene
bis(tricyclohexylphosphine)dichlororuthenium) (0.514, 0.625 mmol) was
added in one aliquot, and the reaction was heated to reflux for 60 h under
a stream of dry nitrogen. Upon complete formation of compound 7 (as
determined by LCMS and TLC) the solvent was removed by rotary
evaporator, and the crude product was purified by flash chromatography
(3:1 hexanes/ethyl acetate) to provide a clear, light brown oil (2.25 g, 80%
yield): 1H NMR (300 MHz, CDCl3, δ) 7.09 (d, 1H, J ) 8 Hz); 6.40 (m,
2 H); 6.20 (d, 1H, J ) 5 Hz); 5.72 (m, 1H); 5.45 (m, 1 H); 4.95 (m, 2H);
4.60 (d, 1H, J ) 15 Hz); 4.28 (d, 1 H, J ) 15 Hz); 3.80 (s, 3H); 3.80 (s,
3H); 3.44 (s, 3 H); 3.00 (m, 1H); 2.70 (m, 2H); 2.35 (ddd, 1 H, J ) 16, 8,
3 Hz); 1.45 (s, 9H). Anal. Calcd for C23H32N2O7: C, 61.59; H, 7.19; N,
6.25. Found: C, 61.82; H, 7.20; N, 5.96.
(
9) Williams, R. M.; Liu, J. J. Org. Chem. 1998, 63, 2130.
(10) Derrer, S.; Davies, J. E.; Holmes, A. B. J. Chem. Soc., Perkin Trans.
1
2000, 2043.
11) Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A J. Am. Chem. Soc.
998, 4334-4344.
12) Nadin, A.; Derrer, S.; McGeary, R. P.; Goodman, J. M.; Raithby,
P. R.; Holmes, A. B. J. Am. Chem. Soc. 1995, 117, 9768.
13) Recent reviews: (a) F u¨ rstner, A. Angew. Chem., Int. Ed. 2000, 39,
012. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c) Schuster,
(
1
(
(
3
M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Grubbs,
R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(14) Second generation imidazole/imidazoline Grubbs catalysts: (a)
Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153. (b) Briot, A.; Bujard,
M.; Gouverneur, V.; Nolan, S. P.; Mioskowski, C. Org. Lett. 2000, 2, 1517.
(
9
c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
53. (d) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674.
15) (a) Reichwein, J. F.; Liskamp, R. M. J. Eur. J. Org. Chem. 2000,
(19) Green, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons: New York, 1999; p 640.
1
(
(20) Characterization of compound 2‚HCl‚H2O: H NMR (300 MHz,
2
2
1
335. (b) Reichwein, J. F.; Versluis, C.; Liskamp, R. M. J. J. Org. Chem.
000, 65, 6187. (c) Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem.
998, 63, 2133. (d) Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am.
CDCl3, δ) 5.8 (m, 2H); 4.9 (m, 1H); 4.7 (dd, 1H, J ) 8, 3 Hz); 3.25 (m,
1 H); 3.05 (m, 1H); 2.55 (m, 1 H); 2.37 (ddd, 1 H, J ) 17, 8, 4 Hz). [R]D
) 43.2 (c 1.0, water). Mp > 240 °C. Anal. Calcd: C, 40.26; H, 6.33; N,
11.74; Cl, 14.85; KF H2O, 7.56. Found: C, 40.33; H, 6.26; N, 11.69; Cl,
14.86; KF H2O, 7.44.
Chem. Soc. 1996, 118, 9606.
16) Rich, D. H.; Tam, J. P. Tetrahedron Lett. 1977, 749-750.
(
894
Org. Lett., Vol. 3, No. 6, 2001

The method described here for the preparation of 3
involves six chemical steps and an overall yield of 60%.
Although we could have used a variety of amide substituents,
the 2,4-dimethoxybenzyl group has the advantage of being
peptide chains replacing the oxidized, cyclic Cys-Cys is
expected to provide stable and potentially useful peptido-
mimetic derivatives.
Acknowledgment. We thank Gregory C. Leo, Alexey
Dyatkin, and Charles H. Reynolds of our laboratories for
helpful discussions and insight. We also thank Prof. Dan Rich
a model system for the extension of this approach to solid
phase using a dialkoxy benzaldehyde resin.21
Ring closing metathesis is a versatile reaction that has now
been applied to the formation of an eight-membered ring
alkene starting from a substrate bearing adjacent allylglycine
residues. We obtained olefin 7, a valuable synthon for further
elaboration,22 and we will report on the use of 7 and 2 for
that purpose in the future. Incorporation of 2 and 3 into
(University of Wisconsin, Madison) for useful advice.
Supporting Information Available: NMR data for
compounds 2, 3, 6, and 7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL015530U
(
21) Polymer-supported ring closing metathesis: Sch u¨ rer, S. C.; Gessler,
S.; Buschmann, N.; Blechert, S. Angew. Chem., Int. Ed. 2000, 39, 3898
and references therein.
(22) For a notable example, see: White, J. D.; Hrnciar, P. J. Org. Chem.
2000, 65, 9129-9142.
Org. Lett., Vol. 3, No. 6, 2001
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