270
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methallyl-Si moiety is deemed to be a protected form of F-Si. An example follows.
propriate catalyst and solvent, we could perform a highly stereospecific, chemoselective synthesis of a conjugated polyene system free from any stereoisomers. Thus, the silicon-based cross-coupling reaction may find wide application in the field of total synthesis of natural products. Research in this area is in progress in our laboratories.
quantitative (GLC)
Yasuo Hatanaka, Tamejiro Hiyama* Sagami Chemical Research Center 4-4-1 Nishiohnuma, Sagamihara Kanagawa 229, J a p a n Received November 10, 1988
83% isolated yield
In conclusion, the study reported herein has shown that fluorine substituent(s) on the silyl group of alkenylsilanes accelerate the F--promoted cross-coupling reactions of alkenylsilanes with alkenyl iodide. By choosing the ap-
Articles Synthesis of (lS,2R)and ( lS,2S)-1-Amino[2-2H]cyclopropane-l-carboxylic Acids: The Total 'H NMR Assignment of Cyclo [ACC-a-methyl-Phe] Pullachipatti K. Subramanian, Douglas M. Kalvin, Kondareddiar Ramalingam, and Ronald W. Woodard* Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Michigan, A n n Arbor, Michigan 48109-1065
Received August 3, 1988 An asymmetric synthesis of stereospecifically monodeuteriated ACC's, (1S,2R)- and (lS,2S)-l-amin0[2-~H]cyclopropane-1-carboxylicacids, is described. The reduction of methyl (Z)-2-acetamido-4-methoxybut-2-enoate with 2Hzgas in the presence of the asymmetric reduction catalysts, (Ra)-dipampand (S,S)-chiraphos,afforded, after acid hydrolysis, (2S,3R)-[2,3-2Hz]-and (2R,3S)-[2,3-'%Jhomoserine lactones, respectively. The chiral synthon by coupling bis(1actim ethers) were derived from the chiral auxiliary reagent (R)-(+)-2-methyl-3-phenylalanine with the above dideuteriated homoserine lactones by utilizing standard procedures. The cyclopropane ring systems are formed by treating each bis(1actim ethers) derivative with butyllithium. The stereochemistry of this intramolecular cyclization to form the cyclopropane ring is discussed. The desired cyclopropane derivatives are obtained by successive treatments with first 0.25 N HC1 and then heating at reflux with 6 N HCl. The proton NMR assignment has been made for all four diastereotopic hydrogens of ACC when incorporated into the as well as in the underivatized diketopiperazine ring [bis(lactimethers) derivative] {cyclo[ACC-a-methyl-Phe]J parent compound.
Introduction The various enzymatic steps in the biosynthetic pathway in which 5'-adenosyl-L-methionine (SAM) is converted to ethylene, the plant-ripening hormone, have recently been the subject of investigation in a number of laboratories.l*P (1)For examples, see the following: (a) Adama, D. 0.;Yang, S. F. Proc. Natl. Acad. Sci. U S A . 1979,76,170-174. (b) Boller, T.;Herner, R. C.; Kende, H. Planta 1979,145,293-303.(c) Yu, Y.-B.; Adams, D. 0.;Yang, S. F. Arch. Biochem. Biophys. 1979,198,28C-286. (d) Adlington, R. M.; Aplin, R. T.; Baldwin, J. E.; Rawlings, B. J.; Osborne, D. J. Chem. SOC., Chem. Commun. 1982, 1086-1087. (e) Hoffman, N. E.; Yang, S. F.; Ichihara, A.; Sakamura, S. Plant. Physiol. 1982, 70, 195-199. (f) Adlington, R. M.; Baldwin, J. E.; Rawlings, B. J. J. Chem. SOC., Chem. Commun. 1983,290-292. (g) Pirrung, M. C.; McGeehan, G. M. J. Org. Chem. 1983,48,5143-5144.(h) Pirrung, M. C. J. Am. Chem. SOC.1983, 105,7207-7209. (i) Oskouee, S.K.-; Jones, J. P.; Woodard, R. W. Biochem. Biophys. Res. Commun. 1984,121, 181-187. fi) Peiser, G. D.; Wang, N. E.; Hoffman, N. E.; Yang, S. F.; Liu, H. W.; Walsh, C. T. Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 3059-3063. (k) Baldwin, J. E.; Adlington, R. M.; Lajore, G. A.; Rawlings, B. J. J. Chem. SOC., Chem. Commun. 1985,1496-1498. (1) Pirrung, M. C.; McGeehan, G. M. Angew. Chem., Znt. Ed. Engl. 1985,24,1044-1045. (m) Ramalingam, K.; Lee, K.-M.; Woodard, R. W.; Bleecker, A. B.; Kende, H. Proc. Natl. Acad. Sci. U.S.A. 1985,82,7820-7824.(m) Wiesendanger, R.; Martinoni, B.; Boller, T.; Arigoni, D. Experientia 1986,42,207-209. (0)Pirrung, M. C. Biochemistry 1986,25,114-119.(p) Wiesendanger, R.; Martinoni, B.; Boller, T.; Arigoni, D. J. Chem. Soc., Chem. Commun. 1986,238-239.
0022-326318911954-0270$01.50/0
Our laboratory has been involved in the investigation of the stereochemistry of the enzymatic reaction in which the PLP-dependent enzyme ACC synthase converts SAM into the immediate biosynthetic precursor of ethylene, 1aminocyclopropane-1-carboxylicacid (ACC), in the ratelimiting step, the partial results of which have been recently reported by both our grouplm and the Arigoni gr0up.l" In our approach to answer2the final question remaining concerning the stereochemical mechanism of ACC synthase, namely the enzymatic events a t the a-amino acid center, it became necessary to determine the chemical shift values of (or differentiate between) all four of the hydrogen (2) After completion of thii synthesis, the Arigoni group published the results from a study involving one regiospecifically dideuteriated SAM analogue, which indicates that the Stereochemical event(s) at the a-amino acid center of SAM involve inversion of configuration (or an odd number of inversions), see ref lp. We have synthesized both [2S,3R,4SS(S)]-and [2S,3S,4R,S(S)]-3,4-*H2]SAM, incubated with them individually with ACC synthase, measured the 'H NMR of the resulting ACC's,and, based on the chemical shift values obtained from the present work and the information presented in ref 17, have determined the stereochemical outcome of the events at the a-center to involve an inversion of configuration, which is in agreement with their findings.
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J. Org. Chem., Vol. 54, No. 2, 1989 271
l-Amino[2-2H]cyclopropane-l-carboxylic Acids
atoms attached to the two prochiral methylene carbons of ACC. The most direct and reliable method for this assignment would be the preparation of ACC's that are stereospecifically labeled with deuterium via routes in which the stereochemistry of each reaction is known with certainty. Methods have been published for the synthesis of [2,2,3,3-2H4]ACC,'d,3(f)-[2,2-2H2]ACC,3cis-[2,3-'H2]ACC,'"" and (~)-tr~m-[2,3-~H~]ACC.'~~~ These synthetic routes involve either dialkylation of a Schiff-base protected glycine esterldlfshor dialkylation of ethyl isocyanoacetate with the appropriately deuteriated dibromoethane or 2bromoethyl tosylate specie^.^ The dialkylation of ethyl isocyanoacetate with 1,2-dibromoethane was originally utilized by Schollkopf in the preparation of nonlabeled ACC.* Recently, three elegant syntheses of optically active [2,2-2H2]ACChave been communicated?a.b However, to date, no methods for the synthesis of the total diastereomeric mixture of monodeuteriated ACC's or either of the enantiomeric pairs have appeared, much less the synthesis of a single optically active stereospecifically monodeuteriated ACC.6 This paper reports the synthesis of two of the four possible stereospecifically monodeuteriated ACC's (the other two are available via the same methodology) and the 'H-NMR assignment of ACC and its diketopiperazine derivative, cyclo-[(R)-2-methyl-3-phenylalanyl-1-aminocyclopropane-1-carboxylic acid] bis(1actim methyl ether) (cyclo[ACC-a-methyl-Phe]).
Results and Discussion The synthesis of (1S,2R)- and (1S,2S)-[2-2H]ACC'sdescribed in this paper may be divided into three major segments: (a) the synthesis of (2S,3R)-[2,3-2H2]-and (2R,3S)-[2,3-2H2]homoserinelactones; (b) coupling of the two homoserine lactones to (2R)-N-Boc-2-methyl-3phenylalanine hydroxysuccinimide ester followed by cyclization of the deprotected dideuteriated dipeptide lactones to the dideuteriated diketopiperazines and conversion into bis(1actim ether) derivatives; and ( c ) intramolecular cyclization of the protected dideuteriated diketopiperazines to afford the monodeuteriated spirocyclopropane dilketopiperazine derivatives, which were cleaved to give the target monodeuteriated ACC's. Previously our laboratory had prepared (2S,3R)-[3-2H]and (2S,3S)-[2,3-2H2]homoserine lactones from (2S,3R)[2,3-2H]-and (2S,3S)-[2,3-2Hz]aspartic acidse7 The necessary deuteriated aspartic acids were obtained by the method of Young8 by incubation of the appropriately E dideuteriated ammonium fumarate with the enzyme Laspartase (commercially available but relatively expensive) in HzO or by incubation of ammonium fumarate with the enzyme L-aspartase in 2Hz0. A maximum yield of 40% for the deuteriated aspartic acids was obtained by this enzymatic process. The further elaboration of these as(3) Ramalingam, K.; Kalvin, D.; Woodard, R. W. J.Labelled Compd. Radiopharm. 1984,31,833-841. (4)Schollkopf, U.;Harm, R.; Hoppe, D. Justus Liebigs Ann. Chem. 1973,611-618. (5).(a) Hill, R. K.; Prakash, S. R.; Wiesendanger, R.; Angst, W.; Martinoni, B.; Arigoni, D.; Liu, H. W.; Walsh, C. T. J. Am. Chem. SOC. 1984, 106, 795-796. (b) Subramanian, P. K.; Woodard, R. W. J. Org. Chem. 1987,52, 15-18. (6) A reviewer has kindly brought to our attention that Dr. Richard K. Hill's group a t the University of Georgia has prepared a monodeuteriated ACC in a stereospecific manner, but to the best of our knowledge this procedure has not been reported in the literature. (7) Ramalingam, K.;Woodard, R. W. J. Org. Chem. 1988, 53, 1900-1903. (8)Young, D. W.; Gani, P. J . Chem. SOC.,Perkin Trans. 1 1983, 2393-2398.
Scheme In R4 COOCH,
a H$OCHz
D \ W 8 l l l C-C R3'
NHCOCH,
1
D /
I I I I R ' L
b~,
95% pure as judged by NMR; IR ( f i i ) 1694 cm-' (C=N); 'H NMR (Me2SO-d6)6 1.18 (t,J = 7.00 Hz, 1 H, C2H~H&H2), 1.42 (s, 3 H, CHJ, 2.70,3.11 (AB, d, J = 12.72 Hz, 2 H, C&,CH2), 2.94 (m,2 H,CH2HCH2),3.63(s,3 H, OCH,), 3.65 (s, 3 H, OCH,), 6.93-7.24 (m, 5 H, C d , ) ; MS m / e 354 (M - l)', 356 (M + .')1 cyclo -[( R)-2-Methyl-3-phenylalanyl-( lS,2S)-l-amino[22H]cyclopropane-l-carboxylicacid] Bis(lactim methyl ether) (9a). To a stirred solution of compound 8a (0.18 g, 0.51 mmol) in dry THF (2 mL) at -78 "C was added a precooled solution of 1.65 N butyllithium (0.34 mL, 0.56 mmol) in hexane by syringe, and stirring was continued for 12 h at -78 "C. The solvent was removed at 40 "C (bath)/l4 Torr with a rotary evaporator, and the residual crude product was shaken with phosphate buffer solution (pH 7; 5 mL). The aqueous phase was extracted with ether (2 x 10 mL), the ether extract was dried (MgSO,), the solvent was removed in vacuo, and the residual product was purified by gravity column chromatography, eluting with hexane/ethyl acetate (955) to yield 0.1 g (72.0%) of 9a (de at C-6 50%)of 9a and 9b (31)as a colorless liquid, >97% pure as judged by NMR IR (film) 1695 cm-' (C=N); 'H NMR (CDCl,; 6 0.17 (dd, J = 4.17 Hz, 9.79 Hz, 1H, 6"-H&), 0.56 (m, 1 H, 6"-HRHS), 0.71 (m, 1H, 6'-HR), 1.52 (s, 3 H, CH,), 2.78, 3.11 (AB, d, J = 12.81 Hz, 2 H, C&,CH2), 3.62 (9, 3 H, OCH,), 3.64 ( 8 , 3 H, OCH3), 6.99-7.19 (m, 5 H, C a , ) . cyclo -[(R)-2-Methyl-3-phenylalanyl-( lS,2R)-l-amino[%2H]cyclopropane-l-carboxylic acid] Bis(1actim methyl ether) (loa). By the above procedure, compound 8b (0.3 g, 0.8 mmol) was cyclized with butyllithium (1.65 N, 0.5 mL, 0.84 mmol) in dry THF at -78 "C to give 0.15 g (65%) of bis(1actim ether) 10a (de at C-6 50%) or 10a and 10b (3:l) as a colorless liquid, >97% pure as judged by NMR IR (film) 1695 cm-' (C=N); 'H NMR (CDCI,) 6 0.17 (m, 1 H, 6"-H&), 0.56 (dd, J = 4.26 Hz, 9.87 Hz, 1 H, 6"-HRHS),1.20 (m, 1 H, 6'-Hs), 1.52 (s, 3 H, CH,), 2.78, 3.11 (AB, d, J = 12.80 Hz, 2 H, C,jH,CH2), 3.62 (s, 3 H, OCH3),3.64 (s, 3 H, OCH,), 6.98-7.20 (m, 5 H, C&f5). ( 1S,2S)-l-Amino[2-2H]cyclopropane-l-carboxylic Acid (12a). A mixture of compound 9a (de at C-6 50%) (0.1 g, 0.37 mmol) and 0.25 N hydrochloric acid (6 mL, 1.5mmol) was stirred at room temperature for 72 h and extracted with ether (2 X 10 mL), the ether extract was discharged, and the aqueous phase was evaporated in vacuo. The residual products, (1laHC1) and (2R)-2-methyl-Phe-OCH3.HCl,were refluxed in 6 N hydrochloric acid ( 5 mL) for 1 h. After the mixture was cooled to room temperature, 10 mL of water was added, and the entire solution was absorbed onto a column of Dowex 5OW-x 8 (H' form) cation exchange resin. The column was eluted with water to neutrality followed by 1N NH40H (50 mL). Concentration of the ninhydrin positive fractions of the eluate yielded a mixture of (R)-2methyl-Phe and the title amino acid. The two amino acids were separated by preparative TLC on silica gel with a 2-propanol/ ammonia/water (16:3:1) solvent system. The target amino acid (Rf = 0.26) was recrystallized from water/methanol to give 20 mg (54%) of the [2H]ACC12a (de at C-1 50%) of 12a and 12b (3:1), which melted at 228-230 "C (lit.22mp 229-231 "C for the non-
J . Org. Chem. 1989, 54, 276-279
276
methanol) (lit.= mD 229-231 "C for the nondeuteriated analome): NMR (DiO) 6 l.OL(m, 1H, ~ - H R H 1.19 ~ ) , (m, 2 H, 2-Hs, 3-HiHsj; MS, m l e 103 (MH)'.
deuteriated analogue): NMR (DzO) 6 1.04 (m, 2 H, 2-HR, 3-HRHs),1.18 (m, 1 H, 3-HRHs);MS, m l e 103 (MH)'. ( 1S,2R)-l-Amino[2-2H]cyclopropane-l-carboxylic Acid (14a). The title [2H]ACC 14a was obtained in 50% de at C-1 [or 14a and 14b (3:1)] in a manner similar to that for 12a from 0.1 g (0.37 mmol) of the compound 10a (de at C-6 50%) by hydrolysis with hydrochloric acid in 48% yield: mp 228-230 "C (water/
Acknowledgment. This work was supported by U S . Public Health Service Grant 30097. We are grateful to the USPHS and the College of Pharmacy for their contributions to the purchase of the IBM 270-MHz NMR spectrometer.
(22)Rich, D.H.; Tam, J. P. Synthesis 1978,46.
Syntheses of (15,25,35,4R)- and ( 1R ,2R,35,4R)-2,3,4-Trihydroxycyclopentane1-methanol, Carbocyclic Arabinofuranose and P-D-Ribofuranose' Analogues of a-LKin-ichi Tadano,* Ken Hakuba, Hiroshi Kimura, and Seiichiro Ogawa Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi,Kohoku-ku, Yokohama 223, Japan
Received July 12, 1988 The title compounds, two carbocyclic analogues of aldopentofuranoses, were synthesized from D-glucose. The key cyclopentane ring formation was achieved under the glycol cleavage reaction of methyl 3-0-benzyl-5,6-dideoxy-6-C-(methoxycarbonyl)-~-xylo-hepto-1,4-furanuronate, which was prepared by a seven-step sequence from D-glUCOSe. The diastereomeric mixture of dimethyl 2-acetoxy-4-(formyloxy)-3-(benzyloxy)cyclopentane-l,l-dicarboxylates was converted into the title compounds through demethoxycarbonylation, Dibal-H reduction, hydroboration of thus formed 1-cyclopentene-1-methanolfollowed by oxidative workup, and deprotection.
We reported recently the synthesis of enantiomerically pure 2,3,4,5-tetrahydroxycyclohexane-l-methanol and 2,3,4-trihydroxycyclopentane-l-methanol.zThese polyoxygenated six- and five-membered compounds can be regarded as carbocyclic analogues of carbohydrates. Access to the five-membered carbocycles opens an alternative synthetic approach toward carbocyclic nucleoside antibiotics, which have aroused much interest in recent years owing to their significant antitumor and antimicrobial a ~ t i v i t i e s . ~Our synthesis of these carbocycles relies on the intramolecular aldol cyclization of carbohydrate-derived precursors. Herein, we report syntheses of (1S,2S,3S,4R)- and (lR,2R,3S,4R)-2,3,4-trihydroxycyclopentane-1-methanol (1and 2, respectively) from D-glucose. The present syntheses are based on a similar approach reported previously.2f Compounds 1 and 2 are pseudo-aL-arabinofuranose and pseudo-P-D-ribofuranose, respectively., Glycol cleavage of 3-O-benzyl-1,2-O-isopropylidene-cuD-glucofuranose (3)5 with NaIO, and successive Knoeven(l).This work was presented at the 56th National Meeting of the Chemical Society of Japan, Tokyo, April 1-4 1988; Abstract 3XID12. (2)(a) Suami, T.; Tadano, K.; Kameda, Y.; Iimura, Y . Chem. Lett. 1984,1919;J. Carbohydr. Chem. 1987,6,231.(b) Suami, T.; Tadano, K.; Ueno, Y.;Fukabori, C. Chem. Lett. 1985,1557.(c) Tadano, K.;Ueno, Y.; Fukabori, C.; Hotta, Y.; Suami, T. Bull. Chem. SOC.Jpn. 1987,60,1727. (d) Tadano, K.; Maeda, H.; Hoahino, M.; Iimura, Y.; Suami, T. Chem. Lett. 1986,1081;J. Org. Chem. 1987,52,1946. (e) Tadano, K.;Fukabori, C.; Miyazaki, M.; Kimura, H.; Suami, T. Bull. Chem. SOC.Jpn. 1987,60, 2189. (0 Tadano, K.; Kimura, H.; Hoshino, M.; Ogawa, S.; Suami, T. Bull. Chem. SOC.Jpn. 1987,60,3673. (9)Tadano, K.;Hoshino, M.; Ogawa, S.; Suami, T. Tetrahedron Lett. 1987,28, 2741;J. Org. Chem. 1988,53, 1427. (3)Suhadolnik, R. J. Nucleoside Antibiotics; Wiley: New York, 1970; pp 236-245,and for related papers, see ref 2g. (4)Compounds 1,2,and 14-20 are considered to be carbocyclic analogues of carbohydrates, which are frequently designated as pseudosugars.
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age1 condensation of the resulting 1,5-dialdofuranose4 with dimethyl malonate in a mixture of pyridine and acetic anhydride gave a,@-unsaturateddiester 5. 1,4-Conjugate addition of hydride to 5 with NaBH, gave the saturated diester 6 in an overall yield of 41% from 3. The isopropylidene group in 6 was then hydrolyzed with aqueous HCl to give 7 as an anomeric mixture. Hydrolysis of the ester groups also occurred partly under these conditions. Unfortunately, we could not find optimal conditions for selective hydrolysis of the isopropylidene group. The glycol in 7 was cleaved with NaIO, in aqueous MeOH solution. Under the glycol cleavage conditions, the intermediate 8 cyclized spontaneously in an intramolecular aldol fashion. The resulting diastereomeric mixture of the cyclized products 9 and 9' were acetylated to give 10 and 10' in a combined yield of 30.5% from 6 (7% of 6 was also recovered at this stage). By careful chromatography on a silica gel column, pure 10 and 10' were separated in an approximately 5 to 1 ratio. The configurations of the newly introduced asymmetric carbons ((2-2) in 10 and 10' (therefore those in 9 and 9') are tentatively assigned as depicted based on 'H NMR (400 MHz) spectra analyses. H-2 of the major isomer 10 appears at 6 5.93 as a doublet with J2,3= 3.4 Hz, while that of 10' appears a t 6 6.01 as a doublet with J2,3= 4.4 Hz. These data indicate that relationship of H-2 and H-3 are trans for 10 and cis for lo', respectively.6 We did not carry out any further experiments for confirmation of the structures of 10 and 10'. The (5) Whistler, R. L.; Lake, W. C.; In Methods in Carbohydrate Chemistry; Whistler, R. L., BeMiller, J. N., Eds.; Academic Press: New York, 1972;Vol. VI, p 286. (6) For 'H NMR spectral interpretation of five-membered compounds, see: Jackman, L. M.; Sternhell, S. Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry, 2nd ed.; Pergamon Press: Oxford, 1969;p 287.
0 1989 American Chemical Society
