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SYNTHESIS OF ENDO-12-AMINOTRICYCLO[6.3.2.02,7]TRIDECA-2(7),3,5-TRIENE-12-EXO-CARBOXYLIC ACID: A NOVEL,CONFORMATIONALLY RESTRICTED PHENYLALANINEANALOGUEPeter A. Crooks a & Jyothi Matheru aa College of Pharmacy , University of Kentucky , Lexington, KY, 40536-0082, U.S.A.Published online: 23 Aug 2006.

To cite this article: Peter A. Crooks & Jyothi Matheru (2002) SYNTHESIS OF ENDO-12-AMINOTRICYCLO[6.3.2.02,7]TRIDECA-2(7),3,5-TRIENE-12-EXO-CARBOXYLIC ACID: A NOVEL, CONFORMATIONALLY RESTRICTEDPHENYLALANINE ANALOGUE, Synthetic Communications: An International Journal for Rapid Communication of SyntheticOrganic Chemistry, 32:24, 3813-3819, DOI: 10.1081/SCC-120015400

To link to this article: http://dx.doi.org/10.1081/SCC-120015400

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©2002 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

SYNTHESIS OF ENDO-12-

AMINOTRICYCLO[6.3.2.02,7]TRIDECA-

2(7),3,5-TRIENE-12-EXO-CARBOXYLIC

ACID: A NOVEL, CONFORMATIONALLY

RESTRICTED PHENYLALANINE

ANALOGUE

Peter A. Crooks* and Jyothi Matheru

College of Pharmacy, University of Kentucky,Lexington, KY 40536-0082, USA

ABSTRACT

A seven step synthesis of the conformationally restricted phe-nylalanine analogue 9 from cycloheptadiene (1) is described.

Key Words: Amino acid; Phenylalanine analogue; Confor-mationally restricted

Previous reports from our laboratory have focused on the synthesis ofa variety of rigid, conformationally restricted phenylalanine analogues, andtheir incorporation into enkephalin peptides in place of phenylalanine.[1–4]

These studies have provided useful structural probes for examiningthe importance of the molecular conformation of the phenylalanine

SYNTHETIC COMMUNICATIONSVol. 32, No. 24, pp. 3813–3819, 2002

3813

DOI: 10.1081/SCC-120015400 0039-7911 (Print); 1532-2432 (Online)Copyright & 2002 by Marcel Dekker, Inc. www.dekker.com

*Corresponding author. E-mail: pcrooks@uky.edu

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moiety for biological activity and for opiate receptor recognition. Wenow report on the synthesis of the novel, conformationally restrictedphenylalanine analogue: endo-12-aminotricyclo-[6.3.2.02,7]trideca-2(7),3,5-triene-12-exo-carboxylic acid.

The synthetic route employed for the synthesis of amino acid 9 isillustrated in Sch. 1, and utilizes readily available cyclo-1,3-heptadiene[1]

as a starting material. The key intermediate, tricyclo[6.3.2.02,7]trideca-2(7),3,5,12-tetraene (5), was prepared from a modification of previouslyreported methodologies. Adduct 3 was obtained from the Diels-Alderreaction of cyclo-1,3-heptadiene (1) with 1,4-benzoquinone (2), followedby selective reduction with diisobutyl aluminum hydride, to afford theexo-diene-diol 4.[5] Treatment of 4 with phosphorous oxychloride in

Scheme 1. Synthesis of endo-12-aminotricyclo[6.3.2.02,7]trideca-2(7),3,5-triene-12-exo-carboxylic acid.

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pyridine resulted in aromatization to afford 5,[6] which was isolated in 63%yield after distillation of the crude product. Reaction of 5 withformic acid under reflux afforded a 2 : 1 exo : endo mixture of formic acidtricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-yl esters (6), which was thenoxidized with chromic acid to afford the ketone 7. Treatment of 7 withammonium carbonate and potassium cyanide, afforded exclusively theendo C-12,N-10-spirohydantoin stereoisomer 8. Under Bucherer conditions,it has been shown that the exo C-12,N-10 isomer is not formed in reactionsof this type,[2] since the exo-face of the 12-imino intermediate formed in theBucherer reaction is more favorable to attack by cyanide ion. The aminoacid 9 was obtained in 61% yield from acid hydrolysis of spirohydantoin 8

with concentrated HCl in a pressure tube at 145�C for 17 h.

EXPERIMENTAL

1H and 13CNMR spectra were determined using a Varian 300MHzNMR. All spectra were referenced and chemical shifts determined usingtetramethylsilane (TMS) as the internal standard. Melting points weredetermined on a Fisher-Johns visual melting point apparatus, and areuncorrected. Infrared spectra (IR) were obtained using a Bio-RadExcalibur infrared spectrophotometer. MALDI (matrix-assisted laser deso-rption ionization) experiments were carried out on a Kratos KOMPACTSEQ. The mass spectroscopy (MS) experiments were performed at the uni-versity of Kentucky Mass Spectroscopy Laboratory, Lexington, KY.Elemental analyses were conducted by Atlantic Microlabs (Norcross,GA), using automated combustion tube analysis.

Tricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-dione (3)

1,4-Benzoquinone (2) (11.3 g, 0.1046mol) and dichloromethane(188mL) were placed in a flask equipped with a nitrogen atmosphere andmagnetic stirrer. Boron trifluoride–ether (5.6mL) was added to the stirred,cooled (�20�C) solution followed by addition of cycloheptadiene (1)(10 g, 0.206mol) dropwise over 15min. After the completion of the dieneaddition, the mixture was stirred for a further 15min at �20�C under nitro-gen. The cooling bath was then removed, and the mixture was stirred for anadditional 30min. The dark brown-colored mixture was poured intoice-cold potassium hydroxide solution (180mL, 30% w/v) and the mixturestirred vigorosly for 10min. The reaction flask was rinsed with diethyl ether(�180mL) and the washing was added to the aqueous alkali mixture.

PHENYLALANINE ANALOGUE 3815

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After filtration through Celite�, the organic layer was separated,dried over anhydrous potassium carbonate and evaporated to givetricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-dione (3), as a yellowish–browncrystalline product; m.p. 81–82�C [Lit.[5] 81–82�C]. The reaction yield was63%. 1HNMR � (CDCl3): 1.56–1.82 (6H, m, C9, C10, C11 protons);3.04–3.16 (2H, m, C1, and C8 protons); 3.22–3.30 (2H, m, C2, and C7protons); 6.02–6.15 (2H, m, C12, and C13 protons); 6.60–6.70 (2H, m,C4, and C5 protons) ppm. 13CNMR � (CDCl3): 23.00 (C10-CH2); 29.60(C9- and C11-CH2); 37.20 (C1- and C8-CH); 51.00 (C2- and C7-CH); 133.00(C12- and C13-CH); 141.80 (C4- and C5-CH); 200.20 (CO) ppm.

Tricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-diol (4)

A solution of tricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-dione (3) (18.9 g,0.093mol) in toluene (�2L) was cooled to 10�C in an ice-bath anddiisobutyl aluminum hydride (1M in hexane) (232.5mL) was added veryslowly over 15min. After the addition was complete, the solution was stirredfor an additional 1 h at room temperature. Ice-cold potassium hydroxidesolution (500mL, 30% w/v) was added slowly to the reaction mixture. Theresulting solution was then vigorosly stirred for an additional 10min. Theaqueous layer was extracted with diethyl ether (5� 30mL). The combinedorganic layers were dried over anhydrous calcium chloride, and evaporatedto yield the product, tricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-diol (4); m.p.130–133�C [Lit.[5] 131–133�C] (yield 69%). 1HNMR � (CDCl3): 1.50–1.90(6H, m, C9, C10, and C11 protons); 2.30–2.35 (2H, m, C1, and C8 protons);2.40–2.50 (2H, m, C2, and C7 protons); 2.75–2.85 (2H, m, C3, and C6protons); 4.10–4.20 (2H, m, OH protons); 6.20–6.40 (2H, m, C12, andC13 protons); 6.30–6.36, 6.46–6.50 (2H, 2�m, C4, and C5 protons) ppm.13CNMR � (CDCl3): 24.00 (C10-CH2); 29.50 (C9- and C11-CH2); 35.50(C1- and C8-CH); 44.00 (C2- and C7-CH); 67.40 (C3- and C6-CH);133.70 (C12- and C13-CH); 136.40 (C4- and C5-CH) ppm.

Tricyclo[6.3.2.02,7]trideca-2(7),3,5,12-tetraene (5)

A solution of tricyclo[6.3.2.02,7]trideca-4,12-diene-3,6-diol (4) (14.77 g,0.071mol) in anhydrous pyridine (90mL) was cooled in an ice-water bath.Phosphorous oxychloride (15mL) was added dropwise to this cold reactionmixture, and the solution was then allowed to stand at room temperaturefor three days. The reaction mixture was then warmed in a steam bath for1 h, the solution was then cooled to ambient temperature, and cold water

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(50mL) was added. The reaction mixture was extracted with hexane(5� 15mL). The combined hexane layers were sequentially washed withwater (3� 30mL), 15% v/v aqueous HCl (3� 30mL), and finally water(3� 30mL). The organic layer was then dried over anhydrous calciumchloride and evaporated to yield an oily residue, which was distilled atreduced pressure (0.08mm Hg) to obtain tricyclo[6.3.2.02,7]trideca-2(7)3,5,12-tetraene (5) as a thick oil which slowly crystallized; m.p.97–99�C [Lit.[6] 95–100�C] (63% yield). 1HNMR � (CDCl3): 1.30–1.70(6H, m, C9, C10, and C11 protons); 3.35–3.45 (2H, m, C1, and C8 protons);6.40–6.44 (2H, d of d, C12, and C13 protons); 7.10–7.14 (4H, m, aromaticprotons) ppm. 13CNMR � (CDCl3): 23.00 (C10-CH2); 26.40 (C9- and C11-CH2); 40.41 (C1- and C8-CH); 125.00 (C12- and C13-CH); 126.50, 134.50(aromatic CH); 140.11 (C2- and C-7 quaternary C) ppm.

Formic Acid Tricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-yl Ester (6)

Tricyclo[6.3.2.02,7]trideca-2(7),3,5,12-tetraene (5) (6.85 g, 0.040mol)was dissolved in 99% (v/v) formic acid (7mL) and the mixture refluxed for4 h. The reaction mixture was then cooled and water (10mL) was added. Theresulting mixture was extracted with diethyl ether (3� 20mL) and the etherlayer was washed with water (3� 25mL), followed by saturated sodiumbicarbonate solution (3� 25mL), and finally water (3� 25mL). The organiclayer was then dried over anhydrous magnesium sulfate, filtered andthe solvent evaporated to yield a hygroscopic, semi-solid product consistingof a 2 : 1 mixture of the 12-endo and 12-exo isomers of formic acid tri-cyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-yl ester (6). The yield was 58%.1HNMR � (CDCl3): 1.05–2.40 (8H, m, C9, C10, C11, and C13 protons);2.60–2.70, 2.72–3.20 (2H, 2�m, C1, and C8 protons); 3.65–3.80 (1H, C12proton); 6.80–7.20 (4H, aromatic protons) ppm. 13CNMR � (CDCl3): 30.60and 30.80, 31.80 and 32.40, 32.80 and 33.00, 33.20 and 34.00 (C13-, C9-, C10-,and C11-CH2); 31.20 and 35.80, 36.00 and 36.50 (C1- and C8-CH); 45.00 and45.20 (C12-CH); 122.40 and 122.60, 124.40 and 124.50, 125.80 and 126.00,128.80 and 129.00 (aromatic CH); 137.90 and 139.60, 143.00 and 146.01(aromatic quaternary C); 162.60 and 162.40 (CO) ppm; accurate mass216.1141; theoretical mass for C14H16O2: 216.1150.

Tricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-one (7)

The endo/exo mixture of formic acid tricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-yl ester (6) (5 g, 0.023mol) was dissolved in acetone (25mL) and the

PHENYLALANINE ANALOGUE 3817

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solution placed in a flask fitted with a dropping funnel containing freshlyprepared 8N chromic acid solution (14mL) [prepared by dissolvingchromium trioxide (2 g) 8mL ice-cold water, followed by addition of1.7mL of conc. sulfuric acid and diluting to 14mL with water]. The oxidantwas added very carefully to the reaction mixture while maintaining thetemperature at 18–25�C. After the addition of 13.5mL of the oxidant, thesolution turned brown. An additional 0.5mL of the oxidant was then addedto the reaction mixture, which was allowed to stir overnight.

The excess oxidant was then decomposed by the addition of solidsodium bisulfite. The acetone layer was then decanted off from the resultinggreen sludge, washed with saturated potassium carbonate solution, anddried over anhydrous potassium carbonate. The hygroscopic semi-solidproduct of tricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-one (7) was sub-sequently obtained as an oil by evaporation of the solvent. The yield was33%. 1HNMR � (CDCl3): 1.05–2.01 (8H, m, C9, C10, C11, and C13protons); 2.20–2.30 (1H, m, C1 proton); 2.80–3.20 (1H, m C8 proton),6.80–7.40 (m, 4H, aromatic protons) ppm. 13CNMR � (CDCl3): 31.0132.80, 33.00, 35.50 (C13-, C9-, C10-, and C11-CH2); 37.50, 45.00 (C1- andC8-CH); 123.01, 124.50, 125.50, 128.80 (aromatic CH); 140.00, 143.00(aromatic quaternary C); 203.01 (CO) ppm. Anal. calcd. for C13H14O: C,83.83; H, 7.58. Found: C, 83.68; H, 7.40%.

Spiro(imidazoline-50,12-tricyclo[6.3.2.02,7

]trideca-2(7),3,5-trien)-

20,40-dione (8)

To a solution of tricyclo[6.3.2.02,7]trideca-2(7),3,5-trien-12-one (7)(2.4 g, 0.0129mol) in 50% aqueous ethanol (16mL), was added a solutionof ammonium carbonate (4.68 g, 0.029mol in 16mL of 50% aqueous etha-nol). The reaction mixture was then refluxed at 55–60�C on an oil bath. Asolution of potassium cyanide (0.752 g, 0.016mol in 16mL water) wasslowly added dropwise to the refluxing mixture over 15min. The solutionwas further allowed to reflux at 55–60�C overnight. The reaction mixturewas then cooled, and the product, spiro(imidazoline-12,20-tricy-clo[6.3.2.02,7]trideca-2(7),3,5-trien)-20,40-dione (8), m.p.>250�C, crystallizedout as a yellow solid. The reaction yield was 45%. 1HNMR � (CDCl3):1.80–2.00 (C9, C10, C11, and C13 protons); 2.02–2.30, 2.80–3.01 (2H,2�m, C1, and C8 protons); 6.80–7.20 (4H, m, aromatic protons) ppm.13CNMR � (DMSO-d6): 17.50, 29.00, 30.20, 32.40 (C10-, C9-, C11-, andC13-CH2); 34.20, 42.20 (C1- and C8-CH); 58.80 (C12 quaternary-C);125.00, 126.50, 128.50, 134.00 (aromatic-CH); 145.50, 147.40 (quaternaryaromatic-C); 155.80 (C40-CO); 178.00 (C20-CO) ppm. Anal. calcd. for

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C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C, 70.41; H, 6.52; N,10.67%.

Endo-12-aminotricyclo[6.3.2.02,7]trideca-2(7),3,5-triene-12-exo-

carboxylic Acid (9)

A solution of spiro(imidazoline-12,20-tricyclo[6.3.2.02,7]trideca-2(7),3,5-triene)-20,40-dione (8) (0.03 g, 0.0001mol) in conc. HCl (5mL) wasplaced in a pressure tube, which was tightly sealed with a teflon screw cap.The tube was then placed in an oil-bath and maintained at 145�C for 17 h.The reaction mixture was then cooled, basified to pH 6 with aqueous 4NNaOH solution, and the solvent evaporated to low volume under pressure(0.05mm Hg). After standing overnight at 4�C, crystals of endo-12-amino-tricyclo[6.3.2.02,7]trideca-2(7),3,5-triene-12-exo-carboxylic acid (9) weredeposited, m.p. 222�C (D). The reaction yield was 61%. The productafforded a positive ninhydrin reaction. 1HNMR � (methanol-d4):1.20–2.20 (8H, m, C9, C10, C11, and C13 protons); 3.00–3.20 (1H, m, C1proton); 3.60–3.80 (1H, m, C8 proton); 7.01–7.40 (4H, m, aromaticprotons). Anal. calcd. for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found:C, 72.53; H, 7.65 N, 6.31%.

REFERENCES

1. Horn, E.J.; Layton, W.J.; Smith, S.L.; Crooks, P.A. Chem. Ind. (Lond.)1986, 615–616.

2. Layton, W.J.; Smith, S.S.; Crooks, P.A.; Deeks, T.; Waigh, R.D.J. Chem. Soc. Perk. Trans. I 1984, 1283–1287.

3. Deeks, T.; Crooks, P.A.; Waigh, R.D. J. Medicin. Chem. 1983, 26,762–765.

4. Deeks, T.; Crooks, P.A.; Waigh, R.D. J. Pharm. Sci. 1984, 73, 457–460.5. Craze, G.; Watt, I. J. Chem. Soc. Perk. Trans. II 1981, 175–184.6. Schmid, G.H.; Rabai, J. Synthesis 1988, 332–333.

Received in the USA December 7, 2001

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