Synthesis of bis-phenylalanine, a novel eight-membered cyclic dipeptide

Article abstract of DOI:10.1080/00397910701771090

Cyclic eight-membered ring lactams have been prepared which are formally analogs of Phe-Ala or Ala-Phe dipeptides joined together on their side chains. These are termed bis-phenylalanines because they are phenylalanine with respect to both of the residues

Full text of DOI:10.1080/00397910701771090

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Synthesis of bis‐Phenylalanine, A Novel
Eight‐Membered Cyclic Dipeptide
Brian V. Falcone a , Christopher J. Creighton a , Michael H. Parker a & Allen
B. Reitz a
a Johnson & Johnson Pharmaceutical Research and Development ,
Pennsylvania, USA
Published online: 28 Jan 2008.
To cite this article: Brian V. Falcone , Christopher J. Creighton , Michael H. Parker & Allen B. Reitz (2008)
Synthesis of bis‐Phenylalanine, A Novel Eight‐Membered Cyclic Dipeptide, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:3, 411-418, DOI:
10.1080/00397910701771090
To link to this article: http://dx.doi.org/10.1080/00397910701771090
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Synthetic Communicationsw, 38: 411–418, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701771090
Synthesis of bis-Phenylalanine, A Novel
Eight-Membered Cyclic Dipeptide
Brian V. Falcone, Christopher J. Creighton,
Michael H. Parker, and Allen B. Reitz
Johnson & Johnson Pharmaceutical Research and Development,
Pennsylvania, USA
Abstract: Cyclic eight-membered ring lactams have been prepared which are formally
analogs of Phe-Ala or Ala-Phe dipeptides joined together on their side chains. These
are termed bis-phenylalanines because they are phenylalanine with respect to both of
the residues in which the phenyl ring is shared between the two. The key synthetic
step was the Negishi coupling of Boc-b-I-Ala methyl ester with a suitably protected
20-I phenylalanine.
Keywords: bis-phenylalanine, hydrophobic dipeptide, Negishi coupling,
peptidomimetic
INTRODUCTION
Peptidomimetics and modified peptide derivatives can display improved
specificity of biological action and increased bioavailability, and favorably
influence other adsorption, distribution, metabolism, and excretion (ADME)
properties.[1] Peptidomimetics that possess a defined secondary structure
such as the a-helix, b-turn, or g-turn can mimic ligand–protein or protein–
protein interactions such as hormone binding, antigen recognition, and
enzymatic regulation.[2] Our interest in the area of peptidomimetics arose
from the study of ox-[Cys-Cys] 1 found in a limited number of proteins
such as the N-terminal ligand-binding domain of the nicotinic acetylcholine
Received in the USA July 17, 2007
Address correspondence to Allen B. Reitz, International Drug Discovery Institute,
109 Greenbriar Rd., Lansdale, PA 19466, USA. E-mail: areitz@i-ddi.org
411

412
B. V. Falcone et al.
receptors.[3] We have recently reported the synthesis and conformational
analysis of saturated and unsaturated eight-membered carbocyclic lactam
dipeptides 2 and 3 in which the disulfide functionality of 1 is replaced by
an olefin spacer.[4] We then sought to obtain and evaluate peptide sequences
that mimic 1 and 3 bearing benzo-ring fusion. Remarkably, cyclic bis-phenyl-
alanines such as 4 and 5 have not been previously described, although the
uncyclized bis-amino acid 6 was prepared by Porzi, Sandri, and coworkers
by hydrolysis of the corresponding diketopiperazine.[5] In addition, seven-
membered ring phenylalanine derivative 7 is a conformationally restricted
dipeptide containing a cyclized Phy-Gly moiety described by Rabi-Barakay
and Ben-Ishai.[6] We describe here the synthesis of bis-phenylalanines 4 and
5, which are expected to impart specific conformational constraints when
incorporated into longer sequences. Compounds 4 and 5 can be considered
to result from the formal cyclization of Phe-Ala or Ala-Phe. The Phe-Phe
dipeptide has recently been shown to play a critical role in initiating the aggre-
gation of a variety of proteins and peptides and is found in the pentapeptide
Leu-Val–Phe-Phe-Ala (LVFFA) implicated in the aggreation of the
b-amyloid1–42 peptide involved in Alzheimer’s disease pathology.[7] The con-
strained bis-phenylalanine derivatives we describe may be useful for the study
of peptide and protein aggregation and self-association.
RESULTS AND DISCUSSION
The synthesis of bis-phenylalanines 4 and 5 began with the conversion of the
N-Boc-protected commercially available 20-iodo-L-phenylalanine 8 to N-
Fmoc derivative 9 (Scheme 1). Negishi coupling of 9 with either L- or
D-Boc-(b-I)Ala-Ome furnished dipeptides 10 and 11, respectively.[8] The
use of the o-tolyl phosphine ligand Pd[P(o-tolyl)3]2Cl2 was essential as triphe-
nylphosphine did not promote the reaction. In addition, formation of
the zinc-iodide intermediate derived from Boc-(b-I)Ala-OMe must be
performed cold and then added to a heated mixture of the electrophile and
Pd catalyst. When the complex was added directly to the heated mixture,
b-elimination resulted in the dehydroalanine methyl ester, which underwent
a Heck reaction to give the desired product but with racemization. The Boc

bis-Phenylalanine
413
Scheme 1. (a) 4 N HCl, dioxane, quant.; (b) Fmoc-OSu, NEM, THF, 94%; (c) Zn, l2,
Boc-b-l-L-Ala-OMe, DMF, Pd[P(o-toly)3]2, 47%; (d) Zn, l2, Boc-b-l-D-Ala-OMe,
DMF, Pd[P(o-tolyl)3]2Cl2; 42%; (e) H2, Pd/C (10% dry), MeOH; (f) 4 N HCl, dioxane,
quant.; (g) HOAt, HATU, NEM, DMF; (h) 33% MeNH2/EtOH, quant.; (i) Ac2O,
PS-CH2NMe2.
and benzyl ester groups of bis-amino acids 10 and 11 were removed, which
was then followed by amide bond formation and cyclization with 1-
hydroxy-7-azabenzotriazole (HOAT) and O-(7-azabenzotriazole-1-yl)-
N,N,N0,N0-tetramethyluronium hexafluorophosphate (HATU) to provide
eight-membered ring lactams 12 and 13, respectively. The Fmoc protecting
groups on 12 and 13 were cleaved along with simultaneous amidolysis of
the ester with methyl amine. Acetylation of the free amino group then
provided model dipeptides 4 and 5.
CONCLUSIONS
The hydrophobic dipeptide bis-phenylalanines 4 and 5 have been prepared in a
modular sequence, which can be modified so as to obtain any of the possible
diastereomers. These dipeptides may prove useful as cyclic, constrained turn
elements in peptide chains or as mimics of the Phe-Phe residues that promote
aggregation.
EXPERIMENTAL
General Methods
1H NMR spectra were collected on Bruker 300-MHz NMR spectrometer
unless otherwise specified. Chemical shifts are reported relative to tetra-
methylsilane (TMS). Mass spectra were obtained with a single quadrapole

414
B. V. Falcone et al.
and fitted with an electrospray source. Reagents and solvents were purchased
from Sigma-Aldrich and used without further purification. Compound 8 was
purchased from Genzyme Pharmaceuticals (Cambridge, MA).
S-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-(2-iodo-phenyl)-
propionic Acid Benzyl Ester (9)
S-Boc-(2-iodo-phenyl)-phenylalanine benzyl ester (8, 2.84 g, 5.9 mmol) was
dissolved in 20 mL of 4 N HCl in 1,4-dioxane and stirred for 120 min. The
solvent was evaporated in vacuo, and the resulting white solid was
dissolved in 50 mL of dry THF. The flask was evacuated, filled with argon,
and then chilled to 08C. Fmoc-OSu (2.04 g, 5.9 mmol) in 50 mL of THF
was added to the solution, followed by N-ethylmorpholine (1.6 mL,
12.2 mmol). The reaction was allowed to warm to ambient temperature over
4 h, after which time the THF was removed in vacuo, and the resulting
solid was suspended in 120 mL of ethyl acetate. The organic layer was
washed twice with 60 mL of 2 N KHSO4, twice with 60 mL water, dried
(MgSO4), filtered, and condensed to a pale yellow solid. Purification was
performed using flash chromatography (1:1 heptane/ethyl acetate) to yield
1
9 as a white powder (3.33 g, 94%). H NMR (CDCl3) d 7.81 (dd, J ¼ 7.9,
1.1 Hz, 2H), 7.76 (d, J ¼ 7.5 Hz, 2H), 7.56 (m, 2H), 7.33 (m, 10H), 6.90
(td, J ¼ 7.3, 1.6 Hz, 2H), 5.36 (d, J ¼ 8.7 Hz, 1H), 5.18 (s, 2H), 4.78
(m, 1H), 4.32 (m, 2H), 4.16 (t, J ¼ 7.1 Hz, 1H), 3.34 (dd, J ¼ 14, 6.0 Hz,
1H), 3.18 (dd, J ¼ 14, 6 Hz, 1H). MS m/z (% relative intensity, ion): 604
(42, M þ Hþ), 626 (100, M þ Naþ). HR-MS: theory 604.0985, found
604.0991.
2S,2S-3-[2-(2-tert-Butoxycarbonylamino-2-methoxycarbonyl-
ethyl)-phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
propionic Acid Benzyl Ester (10)
A three-necked, 50-mL, round-bottom flask outfitted with two glass stoppers
and a hose adapter was charged with zinc (1.079 g, 16.5 mmol, 5 mol equiv.)
and iodine (78.8 mg, 0.31 mmol, 0.094 mol equiv.). The flask was evacuated,
heated for 5 min with a heat gun, cooled to room temperature, and filled with
argon three times. The flask was then chilled to 08C, and (R)-Boc-(b-I)-
alanine methyl ester (2.78 g, 8.35 mmol, 2.4 mol equiv.) in 10 mL of dry
DMF was added via syringe; the reaction was stirred for 70 min at 08C. In a
separate 50-mL flask, 9 (1.99 g, 3.3 mmol) and Pd[P(o-tolyl)3]2Cl2 (166 mg,
0.2 mmol, 0.06 mol equiv.) were dissolved in 4 mL of DMF, heated to
558C, and stirred for 5 min. The cold zinc complex solution was added
dropwise to the solution containing 9 with vigorous stirring; after addition,
the reaction was allowed to proceed for an additional 4.5 h. The reaction

bis-Phenylalanine
415
mixture was then poured into 100 mL of ethyl acetate, washed twice with
50 mL of brine, dried (MgSO4), filtered, and condensed to a brown oil. Puri-
fication was performed using flash chromatography (9:1 to 7:3 heptane–ethyl
acetate) to yield 10 (47%). 1H NMR (CDCl3) d 7.75 (d, J ¼ 7.0 Hz, 2H), 7.54
(m, 2H), 7.32 (m, 9H), 7.11 (m, 4H), 5.57 (d, J ¼ 7.7 Hz, 1H), 5.15 (s, 2H),
5.05 (d, J ¼ 8.2 Hz, 1H), 4.73 (q, J ¼ 6.9 Hz, 1H), 4.57 (q, J ¼ 6.4 Hz,
1H), 4.32 (d, J ¼ 6.5 Hz, 2H), 4.16 (t, 1H), 3.64 (s, 3H), 3.0–3.3 (m, 4H),
1.33 (s, 9H). MS m/z (% relative intensity, ion): 579 (99, M 2 Boc), 701
(100, M þ Naþ). TLC (7:3 heptane–ethyl acetate) Rf ¼ 0.21. Mp ¼ 1108C.
Anal. calcd. for C40H42N2O8: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.64;
H, 6.34; N, 4.12.
2S,2R-3-[2-(2-tert-Butoxycarbonylamino-2-methoxycarbonyl-
ethyl)-phenyl]-2-(9H-fluoren-9-ylmethoxycarbonylamino)-
propionic Acid Benzyl Ester (11)
Using 9 and (S)-Boc-(b-I)-alanine methyl ester, the procedure to prepare 10
was repeated, furnishing 11 in 50% yield. 1H NMR (CDCl3) d 7.75
(d, J ¼ 7.0 Hz, 2H), 7.54 (m, 2H), 7.32 (m, 9H), 7.11 (m, 4H), 5.61
(d, J ¼ 7.7 Hz, 1H), 5.13 (s, 2H), 5.07 (d, J ¼ 8.2 Hz, 1H), 4.70
(q, J ¼ 6.9 Hz, 1H), 4.51 (d, J ¼ 6.4 Hz, 1H), 4.32 (d, J ¼ 6.5 Hz, 2H),
4.16 (m, 1H), 3.60 (s, 3H), 3.0–3.3 (m, 4H), 1.37 (s, 9H). MS m/z (%
relative intensity, ion): 579 (99, M 2 Boc), 701 (100, M þ Naþ). TLC (7:3
heptane–ethyl acetate) Rf ¼ 0.21. Mp ¼ 1088C. Anal. calcd. for
C40H42N2O8: C, 70.78; H, 6.24; N, 4.13. Found: C, 70.74; H, 6.24; N, 4.07.
2S,5S-5-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-oxo-
1,2,3,4,5,6-hexahydrobenzo[d]azocine-2-carboxylic Acid Methyl
Ester (12)
Compound 10 (295 mg, 0.435 mmol) was dissolved in 50 mL of MeOH and
chilled to 08C under argon. Dry 10% Pd/C (331 mg) was added, and the
resulting suspension was placed on a Parr shaker at 45 psi H2. The reaction
was monitored by LC/MS, which showed complete hydrogenolysis of the
benzyl ester after 5 h. The heterogeneous mixture was filtered through
Celitew, and the MeOH was evaporated. The resulting white powder was
dissolved in 10 mL of 4 N HCl in 1,4-dioxane and stirred for 1 h, after
which the solution was evaporated to dryness. The deprotected intermediate
was then suspended in 60 mL of dry methylene chloride, and HOAt
(61.8 mg, 0.454 mmol, 1.04 mol equiv.), HATU (169 mg, 0.439 mmol,
1.01 mol equiv.), and N-ethylmorpholine (140 mL, 1.06 mmol, 2.45 mol
equiv.) were added sequentially. The resulting suspension turned a hazy
yellow, becoming clear over the course of 20 min. After 1 h, 30 mL of dry

416
B. V. Falcone et al.
DMF was added to the mixture. The solution was permitted to stir for 12 h,
after which time the solvent was removed and the solid was resuspended in
80 mL of ethyl acetate. The organic layer was washed with 10% aq.
Na2CO3 (three times), saturated aqueous NaCl, 1 N HCl (three times), and
saturated aqueous NaCl again (40 mL each); dried (MgSO4); filtered; and
condensed. Purification by flash chromatography (1:1 heptane–ethyl
acetate) furnished 12 as a white powder, which recrystallized as white
1
needles from 1:1 heptane–ethyl acetate (115 mg, 76%). H NMR (CDCl3)
d 7.78 (d, J ¼ 7.4 Hz, 2H), 7.64 (d, J ¼ 7.4 Hz, 2H), 7.31 (m, 8H), 6.99
(d, J ¼ 6.2 Hz, 1H), 6.26 (d, J ¼ 6.1 Hz, 1H), 6.17 (d, J ¼ 6.6 Hz, 1H),
4.74 (q, J ¼ 5.4 Hz, 1H), 4.58 (q, J ¼ 7.1 Hz, 1H), 4.44 (dd, J ¼ 7.0,
2.8 Hz, 2H), 4.25 (t, J ¼ 6.8, 1H), 3.89 (s, 3H), 3.54 (m, 2H), 3.10 (dd,
J ¼ 15, 6.2 Hz, 1H), 2.95 (dd, J ¼ 15, 4.9 Hz, 1H). MS m/z (% relative
intensity, ion): 471 (100, M þ Hþ), 493 (56, M þ Naþ). TLC (1:1 heptane–
ethyl acetate) Rf ¼ 0.23. Mp ¼ 201–2028C. Anal. calcd. for C28H26N2O5:
C, 71.47; H, 5.57; N, 5.95. Found: C, 71.39; H, 5.66; N, 6.00.
2R,5S-5-(9H-Fluoren-9-ylmethoxycarbonylamino)-4-oxo-
1,2,3,4,5,6-hexahydrobenzo[d]azocine-2-carboxylic Acid Methyl
Ester (13)
Using intermediate 11 the procedure to prepare 12 was repeated furnishing 13
(75%). 1H NMR (CDCl3) d 7.78 (d, J ¼ 7.4 Hz, 2H), 7.63 (d, J ¼ 7.4 Hz, 2H),
7.31 (m, 8H), 7.08 (br s, 1H), 6.00 (d, J ¼ 7.0 Hz, 1H), 5.50 (br s, 1H), 4.95 (br
s, 1H), 4.67 (m, 1H), 4.42 (dd, J ¼ 7.0, 2.8 Hz, 2H), 4.25 (dd, J ¼ 7.5, 6.8,
1H), 3.82 (s, 3H), 3.54 (m, 2H), 3.35 (d, J ¼ 5.6 Hz, 1H), 2.72 (dd, J ¼ 15,
10 Hz, 1H). MS m/z (% relative intensity, ion): 471 (100, M þ Hþ), 493
(56, M þ Naþ). TLC (1:1 heptane–ethyl acetate) Rf ¼ 0.26. Mp ¼ 215–
2178C. Anal. calcd. for C28H26N2O5: C, 71.47; H, 5.57; N, 5.95. Found: C,
71.40; H, 5.52; N, 6.03.
2S,5S-5-Acetylamino-4-oxo-1,2,3,4,5,6-hexahydro-benzo[d]azocine-
2-carboxylic Acid Methylamide (4)
Intermediate 12 (213 mg, 0.453 mmol) was dissolved in 20 mL of 33% meth-
ylamine in EtOH and stirred for 65 min. The solution was evaporated, and the
solid was suspended in 20 mL of dry methylene chloride. The suspension was
chilled to 08C, and dimethylaminomethyl polystyrene resin (500 mg) was
added, followed by acetic anhydride (100 mL, 1.06 mmol, 2.3 mol equiv.).
The reaction was allowed to stir at 08C for 3 h, after which time it was con-
centrated and redissolved in 40 mL of methylene chloride. The organic
layer was washed three times with 20 mL of heptane each and concentrated.
Purification by flash chromatography (9:1 chloroform–methanol) furnished

bis-Phenylalanine
417
the product as a white solid, which recrystallized in water to produce 4 as clear
square crystals (101 mg, 77%). 1H NMR (MeOD, 08C) d 7.20 (s, 4H), 7.08 (br
s, 1H), 5.08 (dd, J ¼ 9.1, 4.0 Hz, 1H), 4.77 (t, J ¼ 7.7 Hz, 1H), 3.60 (m, 2H),
3.07 (dd, J ¼ 15.3, 7.3 Hz, 1H), 2.86 (s, 3H), 2.83 (d, J ¼ 4.0 Hz, 1H), 2.09
(s, 3H). MS m/z (% relative intensity, ion): 290 (100, M þ Hþ), 312 (30,
M þ Naþ). Mp ¼ 236.8–239.08C. Anal. calcd. for C15H19N3O3: C, 62.27;
H, 6.62; N, 14.52. Found: C, 61.91; H, 6.67; N, 14.39.
2R,5S-5-Acetylamino-4-oxo-1,2,3,4,5,6-hexahydro-
benzo[d]azocine-2-carboxylic Acid Methylamide (5)
Using intermediate 13, the procedure to prepare 4 was repeated to furnish 5
1
(67% yield). H NMR (MeOD, 08C) d 7.20 (m, 4H), 7.08 (br s, 1H), 5.03
(t, J ¼ 9.6 Hz, 1H), 3.97 (dd, J ¼ 13, 7.7 Hz, 1H), 3.63 (dd, J ¼ 15.5, 9.1,
1H), 3.43 (m, 2H), 2.87 (s, 3H), 2.81 (dd, J ¼ 15.2, 10.7 Hz, 1H), 2.06
(s, 3H). MS m/z (% relative intensity, ion): 290 (100, M þ Hþ), 312 (30,
M þ Naþ). Mp ¼ 250.3–252.08C. Anal. calcd. for C15H19N3O3: C, 62.27;
H, 6.62; N, 14.52. Found: C, 62.19; H, 6.74; N, 14.30.
ACKNOWLEDGMENTS
We thank Victor Day of Crystalytics for the X-ray data. In addition, we thank
Ehud Gazit of the Weismann Institute and Reza Ghadiri of the Scripps
Research Institute for advice and encouragement.
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