J . Org. Chem., Vol. 44, No. 14, 1979 2487
Unnatural Cyclic Amino Acids was crystallized from n-hexane and then recrystallized from n-hexane-ethyl acetate to give the heptatriene 5 (50 mg, 50%); mp 166-167 "C. Concentration of the filtrate gave starting 7 (40 mg, 40%), mp 174-175 "C, from n-hexane. Both compounds gave satisfactory mixture melting points. X-Ray S t r u c t u r e of' Photoproduct B. Colorless crystals of tricyclophotoproduct 7 !were grown from a hexane solution. The crystal selected for structure analysis was a parallelepiped with approximate dimensions 0.30 X 0.23 X 0.23 mm and was mounted on a glass fiber with silicone adhesive. Precession photographs of this crystal led to a space group assignment of P 2 J c with lattice constants of a = 1.4.813 (2) A, b = 10.717 (2) A, c = 16.827 (3) A, and p = 80.84 (21". The observed and calculated densities, assuming four molecules,of CS7Hmper unit cell volume, were 1.18 g/mL. Data were collected on a Picker FACS 1diffractometer by using the 0-28 scan technique with Zr-filtered Mo K a radiation and a takeoff angle of ,-2.5". Each of the 3774 independent data (28 5 45.77") was scanned 1.2" in 20 plus an allowance for spectral dispersion at a rate of l"/min, and backgrounds were of 20-s duration. Three standards inserted after every 100 reflections remained statistically constant. The data were reduced to a set of IF,l's by application of Lorentz and polarization corrections ( L p ) . Standard deviations were calculated according to OF = [(C' + k2B)/41F,1z(Lp)z]1/2
block-diagonalanisotropic refinementz1which produced an R value ~ F o difference ~ . of 10.7%, where R = zllFol - ~ F c ~ ~ /A~Fourier synthesis18 at this stage provided for the 30 H atoms. In order to reduce the number of varied parameters, theoretical positions of the 20 phenyl hydrogens were calculated at a distance of 0.95 8, from their respective carbons and included as fixed contributors in the subsequent cycles of refinementz1while the coordinates of the 10 hydrogens in the fused-ring system were varied. This unit-weighted refinement converged with an R value of 6.1% and R, = 6.1%, where R, = C[w(lFol- lFcl)z/~w(F,Jzll~z. Empirical weights were then calculated as described previouslyz2 and used in the final cycles of refinement, which produced R = 5.76% and R, = 5.91%.
where C and B are the counts of scan and backgrounds, respectively, and k is the riitio of scan to background counting time. Some 2897 data with F, > 2aF were taken as observed and used in final stages of refinement. Normalized structure factor amplitudes [El'swere calculated16 and the largest 400 were used in the reiterative application of the Sayre equati011.l~ Carbo11 atomic positions found from an E map1* were used in full-matrix isotropic refinement19,z@ followed by
Registry No. lb, 33593-04-3; 4, 23934-49-8; 5, 70456-57-4; 6, 70456-58-5;7,70456-59-6;9,70456-60-9;10,70456-61-0;11,70456-62-1; tetracyclone, 479-33-4; trans-1-phenyl-1-propene, 873-66-5; 1phenylpropyne, 673-32-5; cis-1-phenyl-1-propene, 766-90-5; maleic anhydride, 108-31-6;tetrachloroethylene, 127-18-4.
-(16) Program FAME by €1. Dewar and A. Stone was used. (17) Program REL by R. E. Long was used. (18) Program FORDAP by A. Zalkin was used. (19) Atomic form factors from D. T. Cromer and J. :L. Mann, Acta Crystallogr.,Sect. .4,24, 321 (1968). (20) W. R. Busing, K. D. Martin, and H. A. Levy, "OR-FLS, A Fortran
CrystallographicLeast-Squares Program", Report ORNL-TM-305,Oak Ridge National Laboratory, Oak Ridge, TN, 1962.
Acknowledgments. We are indebted to N. C. Y a n g and G. Griffin for helpful discussions and to T. Kinstle for some mass spectral data. L. J. Radonovich acknowledges the University of North Dakota for a Summer Research Professorship and the Computer Center for computer time. N. F. Woolsey acknowledges financial support of the Petroleum Research Foundation, administered by the American Chemical Society, and the University of North Dakota F a c u l t y Research Committee. The National Science Foundation provided financial assistance in purchase of the carbon-13 NMR spectrometer.
Supplementary Material Available: Tables of bond distances (Table I) and angles (Table II), atomic coordinates (Table 111), and thermal parameters (Table IV) for photoproduct 7 (6 pages). Ordering information is given on any current masthead page. (21) Program REFINE by J. J. Park was used. The function minimized was ~culF,I - lFCl2. (22) L. J. Radonovich, A. Bloom, and J. L. Hoard, J . Am. Chem. SOC., 94, 2066 (1972).
Synthetic Stud.ies in Unnatural Cyclic Amino Acids Ving J. Lee*la and R. B. Woodward*lb Department
of
Chemistry, Harvard C'niuersity, Cambridge, Massachusetts 02138 Received October 5 , 1978
The nitrosation of diethyl (3-chloropropyl)malonate with ethyl nitrite-sodium ethoxide affords ethyl 5,6dihydro-4H-l,2-oxazine-3-carboxylate (7), which was converted into 5,6-dihydro-N-methyl-4H-1,2-oxazine-3carboxamide (IO). Chloroacetylation and acetylation of 10 produce dehydro amides 11 and 12, respectively. These were converti?d into derivatives of ~~-tetrahydro-2H-1,2-oxazine-3-carboxylic acid (la).
Vast methodology exists i n t h e literature for t h e synthesis of cr-amino acids and their derivatives. However, there is a paucity of information pertaining t o the chemistry of unnat.ura1 cyclic amino acids, specifically those with a nitrogen--oxygen bond to the carboxylate function. W e were interested in an unambiguous synthesis of ~~-tetrahydro-2H-1,2-oxazine-3-carboxylic acids (la, R = H ; lb, R = OCHJ and their derivatives in connection (1) (a) Please address correspondence to Infectious Disease Research Section,Lederle Laboratories, American Cyanamid Co., Pearl River, New York 10965. (b) Department of Chemistry, Converse Laboratory, Harvard University, Cambridge, Mass. 02138.
H
12,R=H l b , R=OCH3
-
with several synthetic goals. Amino acids la,b a r e of potential utility as biochemical probes as well as synthons
0022-3263/79/1944-2487$01.00/0 0 1979 American Chemical Society
2488 J . Org. Chem., Vol. 44, No. 14, 1979 Scheme I
/
-2
/LH3 CH3NH2 C 2 H 5 0 H 70-80
c
5,R = C H 3 6. R=lCH313C
of 2-amino-5-hydroxypentanoicacids. The earlier synthesis of tetrahydro-1,2-oxazines according to King via the double alkylation of N-hydroxyurethane with 1,4-dibromoalkanes was unsuitable for the synthesis of la,b.2 Consequently we chose to functionalize 5,6-dihydro-4H-1,2-oxazine (2). Attempts at electrophilic addition of cyanide (e.g., liquid hydrogen cyanide or trimethylsilyl cyanide-anhydrous zinc iodide) to oxazine 2 were unsuccessful. Oxazine 2 was obtained in ca. 50% yield from tetrahydro-l,2-oxazine (3)3by lead tetraacetate oxidation. The corresponding N-methyloxazinium salt 4, obtained by alkylation of 2 with methyl fluorosulfonate, reacted with cyanide readily to afford ~~-tetrahydro-Xmethyl-1,2-oxazine-3-carbonitrile (5). Unfortunately, attempts to remove the N-alkyl group from either 5 or 6 were fruitless. Nitrile 6 was obtained via the Eschenmoser chloronitrone method4 by using the tert-butylnitrone from chloroacetaldehyde and ethylene, in ca. 25-28% yield (Scheme I). Alternatively, we investigated the feasibility of synthesizing ethyl 5,6-dihydro-4H-1,2-oxazine-3-carboxylate (7) and its subsequent conversion to derivatives of la,b. Diethyl (3-chloropropyl)malonate on nitrosation (0 "C) with ethyl nitrite-sodium ethoxide afforded ester 7 in 35-6570 yield (>%YO purity according to 'H NMR integration). n-Butyl nitrite or isoamyl nitrite afforded an inseparable mixture of ester 7 and starting malonate concomitant with an alkaline-extractable component 8 which was obtained in yields of
