Improved synthesis of 7,5-fused bicyclic lactams for use as peptidomimetics

Article abstract of DOI:10.1081/SCC-200051719

An improved synthesis of (3S, 7R, 10S)-methyl-2-oxo-3-N-phthaloylamino-1- azabicyclo[5.3.0]decane-10-carboxylate from L-glutamic acid and L-allylglycine is presented.

Full text of DOI:10.1081/SCC-200051719

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Improved Synthesis of 7,5‐Fused Bicyclic
Lactams for Use as Peptidomimetics
Wesly Seide a & Samuel E. Watson a
a Department of Chemistry and Biochemistry , Long Island University ,
Brooklyn, New York, USA
Published online: 21 Aug 2006.
To cite this article: Wesly Seide & Samuel E. Watson (2005) Improved Synthesis of 7,5‐Fused Bicyclic Lactams
for Use as Peptidomimetics, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:7, 995-1002, DOI: 10.1081/SCC-200051719
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Synthetic Communicationsw, 35: 995–1002, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051719
Improved Synthesis of 7,5-Fused Bicyclic
Lactams for Use as Peptidomimetics
Wesly Seide and Samuel E. Watson
Department of Chemistry and Biochemistry, Long Island University,
Brooklyn, New York, USA
Abstract: An improved synthesis of (3S, 7R, 10S)-methyl-2-oxo-3-N-phthaloylamino-
1-azabicyclo[5.3.0]decane-10-carboxylate from L-glutamic acid and L-allylglycine is
presented.
Keywords: Bicyclic lactam, beta-turn, peptidomimetic, dipeptide
There has been considerable interest in recent years in the design and synthesis
of small organic molecules that mimic portions of biologically active
peptides.[1] To this end we have been interested in the design and synthesis
of rigid scaffolds for mimicking the common type I b-turn conformation.[2]
Molecular modeling studies have indicated that the known 7,5-fused
bicyclic lactam 1[3] would be a suitable scaffold to which to append amino-
acid residues for mimicking the b-turn conformation. We herein report an
improved synthesis of this molecule utilizing a modification of the Robl
approach[3] in which the key ring-forming step is an iminium ion cycliza-
tion.[4] Using our improved methodology, gram amounts of the 7,5-bicyclic
lactam are readily available.
Our synthesis begins with commercially available L-N-carbobenzyloxy
glutamic acid 2 (Scheme 1). In one step, the a-amino and carboxyl groups
were protected as the oxazolidinone 3 using conditions reported by Itoh and
Received in the USA December 9, 2004
Address correspondence to Samuel E. Watson, Department of Chemistry and
Biochemistry, Long Island University, One University Plaza, Brooklyn, NY 11201,
USA. E-mail: swatson@liu.edu

996
W. Seide and S. E. Watson
Scheme 1.
Miller.[5] Refluxing the Cbz-protected amino acid with an excess of para-
formaldehyde and a catalytic amount of p-toluenesulfonic acid in toluene
with azeotropic removal of water provided compound 3 in excellent yield
and of sufficient purity to be used directly in the next step. The oxazolidinone
3 was transformed to the thioester 4 in 72% yield using ethane thiol in the
presence of dicyclohexyl carbodiimide and dimethylaminopyridine.[6] It was
found that column chromatography was necessary at this stage to ensure that
residual ethanethiol did not poison the palladium catalyst in the subsequent
reduction step. This was accomplished by the method of Fukuyama[7] by
stirring an excess of triethylsilane (3 equivalents) with a catalytic amount of
palladium on carbon (10 mol%) at 08C. The reaction was reliable on a
several-gram scale but all attempts to purify and fully characterize the
sensitive aldehyde 5 resulted in decomposition to a viscous, greenish oil that
remained at the baseline on TLC characterization. It was found, however,
that adding an equal volume of methanol to the crude methylene chloride
solution of 5 and a catalytic amount of PTSA provided the dimethyl acetal 6
in good yields for the two steps. Final deprotection could be accomplished
in three steps. Although there have been reports of oxazoline cleavage and
ester formation in one step,[5b] in our hands better yields were obtained by
first cleaving the oxazoline ring with 2 equivalents of sodium hydroxide in
tetrahydrofuran, followed by methylation using methyl iodide and potassium
carbonate in acetone. Catalytic hydrogenation to cleave the carbobenzyloxy
group provided the free amine 7 in 72% yield for these three steps and in
34% overall yield from the N-Cbz protected glutamic acid.
(S)-allyglycine, prepared from racemic material by the method of
Bodansky,[8] was protected as the phthalimide 9 (Scheme 2) using N-carbo-
ethoxyphthalimide as described by Funabashi.[9] This was coupled with the
dimethal acetal derivative 7 using conventional methodology[10] in a 1:1

7,5-Fused Bicyclic Lactams
997
Scheme 2.
mixture of dimethylformamide/methylene chloride to give the dipeptide 10
in good yield. Treatment of this dipeptide 10 with a catalytic amount of trifluor-
oacetic acid in refluxing 1,1,1-trichloroethane for two days gave the enamine 11
in 70% yield after chromatography on silica gel. After considerable experimen-
tation, it was found that formation of the second ring and reduction to the desired
bicyclic lactam could be efficiently accomplished in a three-step sequence. Using
conditions for the iminium ion cyclization as described by Overman,[11]
treatment of compound 11 with trifluorosulfonic acid in the presence of tetrabu-
tylammonium iodide in methylene chloride provided a mixture of iodolactams.
Treatment of this crude material with two equivalents of triethylsilane in
refluxing toluene gave an isomeric mixture of unsaturated olefins whose
proton NMR and mass spectral data is consistent with the structures 12 and
13. Catalytic hydrogenation provided the desired bicyclic lactam 1 in good
overall yields.
In conclusion, it can be said that the present methodology, a modification
of that originally outlined by Robl, provides gram quantities of the bicyclic
lactam 1 and 2, which is useful as a peptidomimetic.
EXPERIMENTAL
All NMR spectra were recorded on a 400-MHz Varian Inova spectrometer.
1H and 13C spectra are reported as chemical shift values (ppm) with

998
W. Seide and S. E. Watson
reference to TMS as the internal standard. Mass data were obtained using the
FAB technique at Washington University, Mass Spectrometry Resource.
Infrared spectra were obtained on a Nicolet Magna 760 FTIR. Optical
purity was determined by measuring the optical rotation using a Poly-
Science SR-6 model polarimeter in the indicated solvents at the given concen-
trations. Melting points were determined with a Mel-Temp II melting point
apparatus in open capillary tubes and are uncorrected.
N-Cbz-oxazolidine-propionic acid 3. N-Cbz glutamic acid 2 (12 g,
43 mmol) was dissolved in toluene (200 mL) in a flask equipped with a
Dean Stark trap for azeotropic removal of water and a reflux condenser. Para-
formaldehyde (2.1 g) and p-toluenesulfonic acid monohydrate (0.42 g,
2.2 mmol) were added and the mixture was heated at reflux for 7 h. When
the theoretical amount of water was collected, the reaction was cooled to rt,
washed with saturated sodium carbonate (125 mL), acidified to pH 2–3
with concentrated hydrochloric acid, and extracted three times with ethyl
acetate (100 mL portions). The ethyl acetate layers were combined, dried
over MgSO4, and condensed under reduced pressure to give 3 (11.98 g,
95%) as a clear oil. The product was of sufficient purity to be used directly
in the following step. Spectral data was in agreement with literature
values.[5] 1H NMR (CDCl3) d 2.0–2.28 (m, 4H), 4.38 (t, J ¼ 5.2 Hz, 1H),
5.02–5.2 (m, 3H), 5.53 (m, 1H), 7.40 (s, 5H); HRMS (m/z): 293.0884 (Mþ,
calcd. for C14H15NO6: 293.0899); anal. calcd. for C14H15NO6: C, 57.32, H,
5.16; N, 4.78. Found: C, 57.56; H, 5.03; N, 4.59.
N-Cbz-oxazolidinepropionic acid ethylthioester 4. Carboxylic acid 3
(11.32 g, 39 mmol) was dissolved in dry methylene chloride (200 mL) and
cooled to 48C under a nitrogen atmosphere, and dimethylaminopyridine
(0.46 g, 3.76 mmol) was added, followed by ethanethiol (8.55 mL,
115 mmol) and dicyclohexylcarbodiimide (9.48 g, 46 mmol). The mixture
was stirred at 48C for 2 h, warmed to rt, and stirred overnight. Filtration of
the solid urea, removal of the solvent under reduced pressure, and purification
over silica gel (elution with 40% ethyl acetate in hexanes) provided thioester 4
1
(9.46 g, 72%) as a clear oil. H NMR (CDCl3) d 1.2 (t, J ¼ 7.6 Hz, 3H), 2.2
(m, 2H), 2.36 (t, J ¼ 6.8 Hz, 2H), 2.82 (q, J ¼ 7.6 Hz, 2H), 4.34 (m, 1H),
5.16–5.28 (m, 3H), 5.49 (m, 1H), 7.38 (s, 5H). Anal. calcd. for
C16H19NO5S: C, 57.01; H, 5.68; N, 4.15. Found: C, 56.83; H, 5.46; N, 4.24.
N-Cbz-oxazolidine propionic acid dimethyl acetal 6. Ethylthioester 4
(6.39 g, 19 mmol) was dissolved in dry methylene chloride (100 mL) contai-
ning a suspension of palladium-on-carbon (10%, 100 mg) at 48C, under an
inert atmosphere. Triethylsilane (9.08 mL, 57 mmol) was added slowly
dropwise while keeping the temperature below 108C. The reaction was
allowed to warm to rt and stirred for 30 min. Then, the reaction mixture
was filtered over a small pad of celite.
To the aldehyde solution (100 mL) was added an equal volume of dry
methanol and p-toluenesulfonic acid (1 g). The mixture was heated at reflux

7,5-Fused Bicyclic Lactams
999
under an inert atmosphere for 4 h. The solvents were removed under reduced
pressure; the residue was taken up in ethyl acetate (125 mL) and washed with
water (125mL), 5% sodium bicarbonate (50mL), and water (50 mL). The
organic layer was dried over MgSO4 and condensed under reduced pressure to
give a yellow syrup that was purified on SiO2 (eluted with 40% ethyl acetate in
hexanes) to give acetal 6 (4.16 g, 68% for the two steps) as a clear syrup.
1
[a]2D2 ¼ þ73.1 (c1.0, CH2Cl2); H NMR (CDCl3) d 1.6–1.8 (m, 4H), 3.23
(s, 3H), 4.29 (br s, 2H), 5.10–5.18 (m, 2H), 5.45 (br s, 2H), 7.33 (s, 5H); IR
(neat) cm21: 1070.84, 1419.06, 1465.15, 2883.64, 2914.37, 2955.33; HRMS
(m/z): 322.1293 (Mþ 2 1, calcd. for C16H20NO6: 322.1290); LRMS: 322
(14%, M þ H-H2), 292 (12%), 248 (20%), 218 (22%), 191 (12%), 147 (18%).
(S)-2-Amino-5-formyl(dimethylacetal)pentanoic acid, methyl ester 7.
N-Cbz-oxazolidine acetal 7 (6.5 g, 20 mmol) was dissolved in THF (65 mL) at
rt. Sodium hydroxide (39 mL, 1 N) was added, the reaction mixture was stirred
for 1 h and acidified with 1 N HCl, and the THF was removed under reduced
pressure. The residue was taken up in ethyl acetate (80 mL), washed with
water, and dried over MgSO4. The solvent was removed under reduced
pressure to afford the N-Cbz-protected carboxylic acid (4.67 g, 75%) as a
clear oil. The product was not purified but was used as is in the following
1
step. H NMR (CDCl3) d 1.66–1.80 (m, 4H), 3.28 (s, 6H), 4.34 (m, 2H),
5.2 (s, 2H), 5.55 (d, J ¼ 18.4 Hz, 1H), 6.17 (br s, 1H), 7.32 (s, 5H); IR
(neat) cm21: 732.80, 999.15, 1075.96, 1234.71, 1413.37, 1454.91, 2878.52,
2914.37, 2960.46.
The carboxylic acid (6.54 g, 21 mmol) was dissolved in acetone (50 mL)
at rt, and anhydrous potassium carbonate (3.04 g, 22.05 mmol) was added,
followed by methyl iodide (5.26 mL, 105.14 mmol). The mixture was stirred
for 2 h at rt. The acetone was removed under reduced pressure. Thee
residue was taken up in ethyl acetate (50 mL), washed with water (50 mL),
dried over MgSO4, and condensed under reduced pressure to give an amber
oil, which was chromatographed on silica gel (eluting with 30% ethyl
acetate in hexanes) to give the N-Cbz protected methyl ester (5.34 g, 78%)
1
as a yellow oil. H NMR (CDCl3) d 1.6–1.8 (m, 4H), 3.25 (s, 6H), 3.68
(s, 3H), 4.34 (m, 2H), 5.05 (s, 2H), 5.4 (d, J ¼ 18.4 Hz, 1H), 7.31 (s, 5H).
The N-Cbz protected methyl ester (2.71 g, 8.31 mmol) was added to a
suspension of 10% Pd/C (50 mg) in methanol (50 mL) in a Parr pressure
bottle. The suspension was shaken under an atmosphere of hydrogen at
50 psi for 48 h. The reaction mixture was filtered through a small pad of
celite; the solvent was removed under reduced pressure to give the free
1
amine 7 (1.13 g, 71%) as a yellow oil. [a]2D2 ¼ þ45.7 (c1.2, CH3OH); H
NMR (CDCl3) d 1.5–1.8 (m, 6H), 3.28 (s, 6H), 3.4 (m, 1H), 3.68 (s, 3H), 4.4
(m, 1H). Anal. calcd. for C8H17NO4: C, 50.28; H, 8.97; N, 7.32. Found: C,
50.01; H, 9.12; N, 7.13.
N-Phthaloyl-L-allylglycine 9. L-allylglycine 8 (3.5 g, 30.4 mmol) was
added to a solution containing sodium carbonate (monohydrate, 3.96 g,

1000
W. Seide and S. E. Watson
32 mmol) dissolved in water (80 mL) at rt. When everything dissolved,
N-carboethoxyphthalimide (6.67 g, 30.4 mmol) was added and the mixture
was stirred for 5 h. The mixture was filtered and the filtrate was transferred
to a separatory funnel and washed three times with 50 mL portions of ethyl
acetate. The aqueous layer was acidified to pH 2–3 with concentrated HCl.
The aqueous layer was extracted twice with ethyl acetate (50 mL portions).
The organic layers were combined, dried with MgSO4, and condensed
under reduced pressure. Purification on SiO2 (eluting with 30% ethyl
acetate in hexanes) gave 9 (3.84 g, 55%) as a white solid; mp 49–518C;
1H NMR (CDCl3) d 2.91–3.05 (m, 2H), 4.95–5.06 (m, 3H), 5.7 (m, 1H),
7.69 (m, 2H), 7.84 (m, 2H). Anal. calcd. for C13H12NO4: C, 63.45; H, 4.92;
N, 5.69. Found: C, 63.22; H, 5.11; N, 5.73.
2-[(S)-2-N-Phthaloylamino-4-pentenoyl]amino-5-formyl(dimethylacetal)
pentanoic acid, methyl ester 10. Aminoacetal 7 (1.67 g, 15.34 mmol) and
N-phthaloyl-L-allylglycine 9 (2.40 g, 15.34 mmol) were dissolved in
CH2Cl2/DMF (1:1, 30 mL) at 48C under an inert atmosphere. Hydroxybenzo-
triazol (1.81 g, 15.34 mmol) was added, followed by N-methylmorpholine
(0.96 mL, 15.34 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimi-
dehydrochloride (1.76 g, 16 mmol). The mixture was stirred for 2 h at 48C,
warmed to rt, and stirred overnight. The reaction mixture was filtered, the
volatiles were removed under reduced pressure, and the residue was taken
up in ethyl acetate (60 mL), washed successively with 5% HCl, saturated
NaHCO3 and H2O, dried over MgSO4, and condensed to give an off-white
solid. This was purified on SiO2 (eluting with 2% CH3OH in CH2Cl2) to
give 10 (5.01 g, 80%) as a white paste that slowly solidified; mp 83–878C;
1H NMR (CDCl3) d 1.4–1.9 (m, 4H), 2.9 (m, 2H), 3.2 (s, 6H), 3.7 (s, 3H),
4.2 (s, 1H), 4.5 (m, 1H), 4.8–5.06 (m, 3H), 5.7 (m, 1H), 6.9 (d, 1H), 7.7–
7.84 (m, 4H); 13C NMR (CDCl3) d 27, 29, 34, 53.5, 54.2, 54.5, 104, 120,
124, 132, 134, 135, 168.9, 169.2, 173.4; IR (KBr) cm21: 1127.17, 1328.09,
1536.84, 1649.50, 1716.56; HRMS (m/z): 441.1653 (M þ Na, calcd. for
C21H26N2O7Na: 441.1638).
1-[(2S-Phthaloylamino-4-pentenoyl]-2,3-dehydropyrrole-2-carboxylic
aicd methyl ester 11. Dipeptide 10 (3.18 g, 7.61 mmol) was dissolved in 1,1,1-
trichloroethane (25 mL) containing 4 A8 molecular sieves. Trifluroacetic acid
(2 mL) was added, and the mixture was heated at 85 8C for 3 days. The reaction
mixture was cooled to rt, filtered, washed with water (20 mL); and 5% sodium
bicarbonate (15 mL), dried over MgSO4, and condensed under reduced pressure
to give a yellow oil that was purified on silica gel (eluting with 40% ethyl
acetate in hexanes) to give enamide 11 (1.15 g, 55%) as a white semi-solid.
1H NMR (CDCl3) d 2.5–3.06 (m, 4H), 3.72 (s, 3H), 4.78 (m, 1H), 4.94–5.07
(m, 5H), 5.7 (m, 1H), 7.69–7.79 (m, 4H); 13C NMR (CDCl3) d 28, 29, 34,
53.19, 53.53, 54.26, 54.56, 104, 120, 124, 132, 134, 135, 168.94, 169.24, 173;
IR (neat) cm21: 1203.98, 1378.09, 1552.20, 1649.50, 1716.07, 2325.46,
2361.31; HRMS (m/z): 355.1290 (Mþ þ 1, calcd. for C19H19N2O5: 355.1294);

7,5-Fused Bicyclic Lactams
1001
LRMS (m/z): 355.2 (Mþ þ 1, 42%), 228.3 (12%), 200.3 (100%), 182.3 (9%),
160.2 (6%), 128.1 (13%).
(3S, 7R, 10S)-Methyl-2-oxo-3-N-phthaloylamino-1-azabicyclo[5.3.0]-
dec-4-ene 10-carboxylate 12 and the dec-5-ene isomer 13. Enamide 11
(870 mg, 2.46 mmol) in methylene chloride (5 mL) was added slowly to
a mixture of trifluorosulfonic acid (1.43 mL), trifluorosulfonyl anhydride
(0.14 mL) and tetrabutylammonium iodide (1.09 g, 2.95 mmol) in methy-
lene chloride (10 mL) at 48C (ice bath). After the addition was complete,
the cooling bath was removed and the reaction was stirred at rt for 5 h. The
reaction mixture was washed with water and brine, dried over sodium
sulfate, and condensed under reduced pressure to give a brownish solid
(0.85 g, 2.03 mmol).
The crude material from above (0.85 g) was dissolved in toluene (10 mL)
at rt and triethylsilane (0.64 mL, 4.064 mmol) was added. The reaction
mixture was stirred at rt for 30 min and heated to 55 8C for 2 h. The reaction
mixture was cooled, diluted with ethyl acetate (10 mL), washed with water
(10 mL), dried over MgSO4, and condensed under reduced pressure to give
a yellow solid that was purified on silica gel (eluting with 40% ethyl acetate
1
in hexanes) to give a white solid (0.59 g, 1.659, 82%). mp: 55–598C; H
NMR (CDCl3) d 1.20–2.41 (m, 4H), 3.04 (m, 2H), 3.69 (s, 3H), 4.3–4.7
(m, 3H), 5.07–5.4 (m, 2H), 7.6–7.8 (m, 4H); LRMS (m/z): calcd. for
C19H19N2O5: 355.1293; found: 355.2 (Mþ þ 1, 27%).
(3S, 7R, 10S)-Methyl-2-oxo-3-N-phthaloylamino-1-azabicyclo[5.3.0]-
decane-10-carboxylate 1. The mixture of olefins 12 and 13 from above
(100 mg, 0.28 mmol) was added to a suspension of 10% Pd/C (10 mg) in
dry (5 mL) in a Parr pressure bottle. The suspension was shaken under an
atmosphere of hydrogen at 50 psi for 48 h. The reaction mixture was filtered
through a small pad of celite and condensed under reduced pressure to
give a yellow oil that was purified on silica gel (eluting with 40% ethyl
acetate in hexane) to give 1 (82 mg, 0.176 mmol, 80%) as a yellow oil.
[a]2D2 ¼ þ24.6 (c1.2, CH3Cl); 1H NMR (CDCl3) d 1.18–3.07 (m, 11H),
3.66 (s, 3H), 4.61–4.84 (m, 2H), 7.64–7.77 (m, 4H); HRMS (m/z):
357.1449 (Mþ þ 1, calcd. for C19H21N2O5: 357.1450); LRMS (m/z): 357.2
(Mþ þ 1, 100%), 331.2 (8%), 307.2 (8%), 297.2 (39%), 279.2 (12%),
269.2 (18%).
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