A convenient synthetic route to macrocyclic cis-3-phenylproline derivatives as mimics of Sandostatin

Article abstract of DOI:10.1055/s-1999-2578

Enantiomerically pure 14- and 20-membered cyclic proline derivatives 2a- d were conveniently prepared from cis-3-phenylproline using macrolactonisation or macrolactamisation reactions.

Full text of DOI:10.1055/s-1999-2578

LETTER
189
A Convenient Synthetic Route To Macrocyclic cis-3-Phenylproline Derivatives
as Mimics of Sandostatin
Dominique Damour, Gilles Doerflinger, Guy Pantel, Richard Labaudinière, Jean-Pierre Leconte, Serge Sablé, Marc
Vuilhorgne, Serge Mignani*
Rhône-Poulenc Rorer SA, Centre de Recherche de Vitry-Alfortville, 13 Quai Jules Guesde-BP 14, 94403, Vitry-sur-Seine Cedex, France
Fax 33 (1) 55 71 80 63; E-mail: serge.mignani@rp-rorer.fr
Received 24 November 1998
Herein we describe a convenient synthesis of the ambi-
Abstract: Enantiomerically pure 14- and 20-membered cyclic pro-
scalemic compounds 2a-d5 from readily accessible cis-3-
line derivatives 2a-d were conveniently prepared from cis-3-phe-
phenylproline 9 (Schemes 2 and 3).6 Our strategy from 9
nylproline using macrolactonisation or macrolactamisation
is based on the following three points: (i) introduction of
the L-lysine chain, (ii) introduction of the phenylalanine
residue bearing on the nitrogen atom the adequate spacer,
and (iii) cyclisation reaction.
reactions.
Key words: 3-phenylprolines, cyclic prolines, macrocyclisation,
lactonisation, lactamisation
The proline derivative 9 was synthesised in a four-step se-
quence through the known compound 6 (~2/1 mixture of
cis/trans stereisomers determined by n.O.e experiments at
300 MHz in DMSO ) which was easily prepared via a lit-
erature route7 starting from the condensation of trans-cin-
namaldehyde 3 and diethyl acetamidomalonate in 52%
overall yield (Scheme 2). Selective saponification of 6
(0.5N NaOH) afforded separation into cis-3-phenylpro-
line methyl ester 7 and trans-3-phenylproline 8 in 61%
and 29% yields respectively. At that step, further n.O.e
experiments were performed to confirm the already estab-
lished cis/trans stereochemistry. As previously reported,7
the steric bulk both in the N-Boc group and the 3-phenyl
substituent contributes to reduce the rate of saponification
of the cis-isomer versus the trans-isomer. Finally, simul-
taneous N-Boc deprotection and hydrolysis of 7 with 6N
HCl in acetic acid gave pure cis-phenylproline 9 in 98%
yield.
One of the major objectives of medicinal chemistry is to
derive more metabolically stable molecules from the in-
formation provided by natural peptides. It is well known
that macrocyclic peptides play an important role in many
biological processes and have served as starting points for
the discovery of new drugs, mainly involving peptido-
mimicry of their bioactive conformation.1 As an extension
of our work on the synthesis of non-peptide mimics of
Somatostatin/Sandostatin based on the 3-arylproline de-
rivative 1,2 we required analogues 2a-d wherein the car-
bon atoms a1 and a2 are linked by a tether. From the 3D
structures of low-energy conformations of Sandostatin ,2
and those of derivatives previously described,3 we con-
cluded that one of the most appropriate places to introduce
the accurate conformational constraint would be between
the a1 and a2-carbon of 2 (Scheme 1). Using a molecular
modelling approach,4 various spacers were screened in or-
der to optimise distances and torsional angles. Finally, the
macrocyclic cis-3-phenylproline derivatives 2a-d were
chosen as a new class of potential mimics of Sandostatin
(Scheme 1).
Scheme 1
Synlett 1999, No. 2, 189–192 ISSN 0936-5214 © Thieme Stuttgart · New York

190
D. Damour et al.
LETTER
With 9 in hand, we turned our attention to the synthesis of Lactamizations of 18a-c were performed using either a
N-Boc derivative 10 which was the starting material for small excess (1.1-1.4 eq.) of PyCl/I12 or an equal amount
the preparation of the L-lysine derivatives 11 and 12 of BOP13 in presence of an excess of DMAP or TEA (3-
(Scheme 3). Thus, facile N-Boc protection of 9 was 15 eq.). Lactonisation of 18d was carried out using PyCl/
achieved using (Boc)2O under standard reaction condi- I (1.1 eq.) in presence of DMAP (6 eq.). These macrocy-
tions affording 10 in 87% yield. Condensation of 10 in the clisation reactions were performed under high dilution
presence of HOBt8 and EDCI with the N-benzyloxycarbo- conditions ([substrate] = ~8 10-3 M) in MeCN (18b,c) or
nyl-L-lysine methyl ester9 followed by chromatographic CH2Cl2 (18a,d) as solvent, to furnish the 14- and 20-mem-
purification on silica gel gave pure cis-isomer: 11 (form bered cyclic proline derivatives 19a-d in 18-37% yields
A) and 12 (form B) in non optimised 35% and 46% yields, after flash chromatographic purification on silica gel.
respectively. N-Deprotection of 11 and 12 using a mixture
The target compounds 2a-c14,15 were obtained after re-
of trifluoroacetic acid and chloroform (~1/5 v/v) gave 13
and 14 in 93% and 72% yields respectively. Coupling re-
moval the CBz group of 19a-c by action of Pd/C in pres-
ence of cyclohexene in 47% to 87% yields. Under the
same deprotection reaction conditions, hydrogenolysis of
action of 13 with the spacer molecule L-phenylalanine de-
rivatives 15a-c10 and 14 with 15d11 was carried out using
19d afforded 2d in 60-65% as determined by NMR.
either HOBt/EDCI or PyBROP or BOP in the presence of
In conclusion, this flexible synthetic route provides the
preparation of 14- and 20-membered cyclic proline deriv-
atives in a rapid and efficient manner.
a base such as DIEA or TEA. Then, pure coupling prod-
ucts 16a-d were obtained in moderate to good yields (38-
89%). Treatment of 16a-d with 1N NaOH afforded the
carboxylic derivatives 17a-c and 18d in moderate to good
yields (56-100%). N-Boc deprotection of 17a-c was per-
formed using trifluoroacetic acid under standard reaction
conditions giving trifluoroacetate salts 18a-c in good
yields (73-94%).
Acknowledgement
We wish to thank the analytical team for analysis assistance, and M.
Hurel for technical assistance.
Synlett 1999, No. 2, 189–192 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Synthetic Route To Macrocyclic cis-3-Phenylproline Derivatives
191
(8) Abbreviation used are the follows: PyBROP, bromotripyrro-
linophosphonium hexafluorophosphate; DIEA, diisopropyl-
ethylamine; PyCl/I, N-methyl-2-chloropyridinium iodide
(Mukaiyama reagent); HOBt, 1-hydroxybenzotriazole; EDCI,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimine hydrochlo-
ride.
(9) Sakaitani, M., Ohfune, Y., J. Org. Chem., 1990, 55, 870.
(10) a) The spacer compound 15a (white solid, mp 255°C, Rf 0.64
nButanol/H2O/AcOH 4/1/1) was synthesised by the condensa-
tion of (4-aminobutyl)carbamic acid 1,1-dimethylethyl ester
(Muller, D.; Zeltser, I.; Bitan, G.; Gilon C. J. Org. Chem.,
1997, 62, 411) with (R)-2-bromo-3-phenylpropionic acid
(Fournie-Zaluski, M-C.; Coulaud, A.; Bouboutou, R.; Chail-
let, P.; Devin, J.; Walsman, G.; Costentin, J.; Roques, B. P. J.
Med. Chem., 1985, 28, 1158) in 48% yield (CH2Cl2, rt., 4
days).
References and Notes
(1) For an excellent review, see : Fairlie, E. J.; Abbenante, G.;
March, D. Curr. Med. Chem., 1995, 2, 654 and references ci-
ted therein.
(2) Previous works in this field, see : Damour, D.; Barreau, M.;
Blanchard, J-C.; Burgevin, M-C.; Doble, A.; Herman, F.;
Pantel, G.; James-Surcouf, E.; Vuilhorgne, M.; Mignani, S.,
Poitou, L., Le Merrer, Y., Depezay, J-C. Bioorg. Med. Chem.
Lett., 1996, 6, 1667; Damour, D.; Barreau, M.; Blanchard, J-
C.; Burgevin, M-C.; Doble, A.; Labaudinière R ; Pantel, G.;
Mignani, S., Chem.Lett., 1998, 943. Damour, D.; Barreau, M.;
Blanchard, J-C.; Burgevin, M-C.; Doble, A.; Pantel, G.;
Labaudinière, R.; Mignani, S. Bioorg. Med. Chem., submitted
for publication .
(3) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.;
Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shake-
speare, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B.;
Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale,
W.; Freidinger, R. M.; Cascieri, M. R.; Strader, C.D. J. Am.
Chem. Soc., 1993, 115, 12550; Papageorgiou, C.; Haltiner, R.;
Bruns C.; Petcher, T. Bioorg. Med. Chem. Lett., 1992, 2, 135;
Papageorgiou, C.; Borer, X. Bioorg. Med. Chem. Lett., 1996,
6, 267; Goodman, M.; Zhang, J. Chemtracts-Organic Chemi-
stry, 1997, 10, 629 and references cited therein.
(4) Molecular dynamics simulations and other computational pro-
cedures were performed with the Discover and Insight II pak-
kage ( MSI, 10065 Barnes Canyon Rd, San Diego, CA 92121,
USA) and in-house tools.
(5) All new compounds synthesised herein gave satisfactory ana-
lytical and spectroscopic data (1H-NMR , IR , MS , Elemental
Analyses); see footnote (14) as an example for 2b.
(6) a) The macrocyclisation of 18a affording 19a is given hereaf-
ter as representative experimental procedure using PyCl/I as
coupling reagent. To a stirred solution of 18a (21 g, 2.3
mmol), DMAP (2.6 g, 21.3 mmol), and CH2Cl2 (300 ml) was
added in small portions PyCl/I (0.8 g, 3.1 mmol) and the resul-
ting mixture stirred for 1h at room temperature and then reflu-
xed for 3h under nitrogen atmosphere. After completion
(monitored by TLC), the reaction mixture was allowed to cool
to room temperature and diluted with water (150 ml). The or-
ganic phase was dried with MgSO4, filtered and evaporated.
The resulting crude compound was purified by flash chroma-
tography on silica gel (eluant: CH2Cl2/MeOH mixture 95/5 to
give 0.57 g of 19a (37 %) as a white solid.
b) The spacer compound 15b (yellow solid, mp 202°C, Rf 0.66
CH2Cl2/MeOH 95/5) was prepared by condensation of (3-
aminobenzyl)-carbamic acid tert-butyl ester (Bock, M. G.; Di-
pardo, R. M.; Evans, B. E.; Rittle, K. E.; Whitter, W. L.;
Garsky, V. M.; Gilbert, K. F.; Leighton, J. L.; Carson, K. L.;
Mellin, E. C.; Veber, D. F.; Chang, R. S. L.; Lotti, V. J.; Freed-
man, S. B.; Smith, A. J.; Patel, S.; Anderson, P. S.; Freidinger,
R. M. J. Med. Chem., 1993, 36, 4276) with 3-phenyl-2-trifluo-
romethanesulfonyloxypropionic acid methyl ester (Effenber-
ger, F.; Burkard, U.; Willfahrt, J. Liebigs Ann. Chem, 1986,
314) followed by hydrolysis (1N NaOH, THF, rt, 12 h) in 78%
overall yield.
c) The spacer compound 15c (cream solid, mp 135°C, Rf 0.13
CH2Cl2/MeOH 90/10) was prepared by the condensation of
2(2-Boc-amino-ethyl)naphth-7-yl-3-propionic acid (Sarabu,
R., Lovey, K., Madison, V. S., Fry, D. C., Greeley, D. N.,
Cook, C. M., Olson, G. L., Tetrahedron, 1993, 49, 3629) with
L-phenyl alanine methyl ester (BOP, THF, DIEA, MeCN, rt.,
12 h) followed by action of 1N NaOH (EtOH, 40°C, 2 h) in
89% overall yield.
(11) The spacer 15d (cream solid, mp 130°C, Rf 0.40 nButanol/
H2O/AcOH 4/1/1) was prepared by action of (S)-2-(hydroxy-
butylamino)-3-phenylpropionic acid with acetyl chloride/
conc.HCl in THF (rt., 12h) in 49% overall yield. The (S)-2-
(hydroxybutylamino)-3-phenylpropionic acid was prepared
by the condensation of (R)-2-bromo-3-phenylpropionic acid
(see ref. 9a) with 4-hydroxy-butylamine (CH2Cl2, 48h, rt.) in
48% overall yield.
(12) For representative examples of macrocyclisation using PyCl/I
(Mukaiyama reagent), see: Mukaiyama, T, Angew. Chem. Int.
Ed. Engl., 1979, 18, 707; Hamada, T., Zenkoh, T., Sato, H.,
Yonemitsu, O, Tetrahedron Lett., 1991, 32, 1649; Rico, I.,
Halvorsen, K., Dubrule, C., Lattes, A., J. Org. Chem., 1994,
59, 415 and references cited therein.
(13) For representative examples of macrocyclisation using BOP,
see: Hale, K. J., Cai, J., Williams, G., Synlett, 1998, 2, 149;
Shin, C-G., Okumura, K., Shigekuni, M., Nakamura, Y.,
Chem. Lett., 1998, 2, 139; Dudash, J., Jiang, J., Scott, C. M.,
Joullié, M. M., Syn. Comm., 1993, 23, 349 and references ci-
ted therein.
b) The macrocyclisation of 18b affording 19b is given here-
after as representative experimental procedure using BOP as
coupling reagent. To solution of 18b (5.1g, 5.5 mmol) and
MeCN (1l) was added in small portion BOP (2.4g, 5.5 mmol)
at 0°C under nitrogen atmosphere. Then, a solution of TEA
(2.4 g, 3.2 ml, 23.2 mmol) in MeCN (100 ml) was added drop-
wise at the same temperature. The reaction mixture was allo-
wed to stir for a further 1 h at 0°C, and then was stirred at room
temperature for 3 h. After completion (monitored by TLC),
the solvent was evaporated to dryness under reduced pressure
and the residue washed with water (200 ml). Then, TEA was
added until basic pH and the solution was extracted with
EtOAc (2 x 100 ml). The combined organic phase was con-
centrated in vacuo, and the resulting yellow oil purified by
flash chromatography on silica gel (eluant: EtOAc/MeOH
mixture 99/1) to give 1.9g of crude 19b which was purified by
preparative HPLC (Porasil /Waters) eluting with: CH2Cl2/
MeOH mixture 98/2 to afford pure 19b (1.15g, 30%) as a whi-
te solid.
(14) 2a: cream solid, mp 242°C, aD20 = +6 (MeOH, C = 0.5); 2b:
white solid, mp 109°C, aD20 = +6.2 (MeOH, C = 0.5);
2b(2HCl.H2O): white solid mp 15°C; 2c: cream solid, mp
148°C, aD20 = +66 (MeOH, C = 0.5); 2d: grey solid, mp 112°C
(hygroscopic).
(15) The NMR, IR and MS data and elemental analyses of 2b are
given hereafter as representative data: NMR (DMSO,
500MHz , 343 K) : 8.3 (1H) d , J=7 , H2 ; 8 (2H) bs , terminal
NH2 ; 7.2 to 7.4 (12H) complex m , phenyls , H5 and H8 ; 7.1
(1H) t , J=8, H2’’; 6.95 (1H) bd , J=8 , H3’’; 6.7 (1H) bd, J=8
, H1’’; 6.5 (1H) bs ,H7; 5 (1H) d , J=8 , H15; 4.45 (1H) dd ,
(7) Chung, J. Y. L., Wasicak, J. T., Arnold, W. A. , May, C. S.,
Nadzan, A. M., Holladay, M. W. J. Org. Chem., 1990, 55, 270
and references cited therein.
Synlett 1999, No. 2, 189–192 ISSN 0936-5214 © Thieme Stuttgart · New York

192
D. Damour et al.
LETTER
J=15 and 10 , H6 ; 4.3 (1H) t , J=7 , H9; 3.85 (2H) m , H6 and
H12; 3.7 (1H) m , H3; 3.35 (1H) m , H14; 3.25 (1H) m , H12;
3.20 (2H) m , CH2 benzyl; 2.8 (1H) m , H13; 2.65 (2H) m ,
H1’; 2.1 (1H) m , H13 ; 1.55 (1H) m , H2’; 1.4 (3H) m , H2’
and H4’; 1 (1H) m , H3’; 0.9 (1H) m, H3’. Assignments have
been secured thanks to 2D spectroscopies (COSY and HM-
QC) while the cis stereochemistry of the proline ring has been
confirmed by 2D (Tm = 250 ms) and 1D nOe experiments. MS
(DCI, NH3) : m/z 554 MH+ (100%); IR (KBr) cm-1: 3425 (NH
+
amide); 3000- 2250 (NH3 ); 1650 (CO amide); 1450 (NH ami-
de). 2b(2HCl,H2O) : Anal. Calcd for C33H39N5O3.2HCl.H2O :
C, 63.25 ; H,6.59 ; Cl,11.32 ; N, 11.18. Found : C, 63.4; H,
7.2 ; Cl, 11.1 ; N, 11.3.
(16) Silica gel 60 (0.063-0.2 mm), Merck.
Synlett 1999, No. 2, 189–192 ISSN 0936-5214 © Thieme Stuttgart · New York