J.Org. Chem., Vol. 41, No. 13, 1976
Ring Opening of Aziridine Phosphonates Table 11. Squared Correlation Matrix for Variables Pertaining t o Equation 3 MR-L MR-S ir-MR-L MR-L MR-S ir-MR-L ir-MR-S
1.00
ir-MR-S
1-1
1-2
0.00 0.00 0.00 0.00 1.00
0.03 0.01 0.02 0.02 0.02 1.00
0.06
0.29
0.04
1.00
0.07
0.50 0.48 1.00
1.00
1-1 1-2
site in chymotrypsin is not typically hydrophobic is supported by the analysis of Dickerson and Geis.26 The “hydrophobic” pocket in chymotrypsin is circumscribed by the following two peptide sequences: Gly A l a Ser Gly V a l Ser Ser Cys M e t
184 185 186 187 188 189 190 191 192 Ilu V a l Ser Trp Gly Ser Ser Thr Cys Ser Thr Ser Thr Pro Gly V a l
212 213 214 21 5 216 217 218 219 220 221 222 223 224 225 226 227 The vast majority of these residues are hydrophilic, not hydrophobic; thus, correlation with MR can be used t o characterize nonhydrophobic enzyme space as ir can be used for hydrophobic space.27 Equation 3 does establish the fact t h a t it is possible to construct QSAR for stereoisomers by taking into account the type of space into which substituents fall. We believe t h a t the approach used in formulating eq 3 should be generally applicable t o problems involving stereoisomers. Registry No.-a-N-Nicotinyl-L-4-nitrophenylalaninee t h y l ester, 58816-65-2; L-4 -nitrophenylalanine, 949-99-5; L-4-nitrophenylalanine e t h y l ester HC1, 58816-66-3;L-4-nitrophenylalanine e t h y l ester, 34276-53-4;nxcotinyl azide, 4013-72-3;a-N-nicotinyl-~-4-nitrophenylalaninamide, 58816-67-4; a-N-nicotinyl-L-alanine e t h y l ester, 58816-68-5; e t h y l alaninate, 3082-75-5; a - N - n i c o t i n y l alaninamide,
2273
53503-62-1; a-N-benzoyl-4-nitrophenylalanine e t h y l ester, 5881669-6;a-N-benzoyl-4-aminophenylalanine e t h y l ester, 58816-70-9; a-N-benzoyl-~-4-methanesulfonylamidophenylalaninamide, 58816-71-0; methanesulfonyl chloride, 124-63-0. R e f e r e n c e s a n d Notes (1) (a) This investigation was supported by Public Health Service Research Grant CA-11110 from the National Cancer Institute and the Sankyo Co. of Tokyo, Japan; (b) Visiting Scientist from the Sankyo Co. (2) C. Hansch, Acc. Chem. Res., 2, 232 (1969). (3) C. Hansch and E. Coats, J. Pharm. Sci., 59, 731 1970). (4) C. Hansch, J. Org. Chem., 37, 92 (1972). (5) R. N. Smith and C. Hansch, Biochemistry, 12, 4924 (1973). (6) R. N. Smith, C. Hansch, and T. Poindexter, Physiol. Chem. Phys., 6, 323 (1974). (7) J. J. Bechet, A. Dupaix, and C. Roucous, Biochemistry, 12, 2566 (1973). (8) J. Fastrez and A. R. Fersht, Biochemistry, 12, 1067 (1973). (9) V. N. Doroska, S.D. Varfolomeyer, N. F. Kazanskaya, A. A. Klyosov, and K. Martinek, FEBS Lett., 23, 122 (1972). 10) V. Pliska and T. Earth, Collect.Czech. Chem. Commun., 35, 1576 (1970). 11) C. Hansch, K. H. Kim, and R. H. Sarma, J. Am. Chem. Soc.,95,6447 (1973). 12) J. M. Vandenbelt, C. Hansch, and C. Church, J. Med. Chem., 15,787 (1972). 13) C. Silipo and C. Hansch, J. Am. Chem. SOC.,97,6849 (1975). 14) C. Hansch and D. Calef, J. Org. Chem., 41, 1240 (1976). 15) M.Yoshimoto and C. Hansch, J. Med. Chem., 19, 71 (1976). 16) (a) C. H. Hamilton, C. Niemann, and G. S.Hammond, Proc. Natl. Acad. Sci. U.S.A.,55,664 (1966); (b) G. Hein and C. Niemann, ibid., 47, 1341 (1961); (c) D. T. Manning and C. Niemann, J. Am. Chem. SOC.,80, 1478 (1958); (d) R. J. Foster and C. Niemann, ibid., 77,3370 (1955); (e) R. J. Foster, H. J. Shine, and C. Niemann, ibid., 77, 2378 (1955); (f) H. T. Huang and C. Niemann, ibid., 74, 101 (1952). (17) L. Pauling and D. Pressman, J. Am. Chem. SOC.,67, 1003 (1945). (18) D. Agin, L. Hersh. and D. Holtzman, Roc. Natl. Acad. Sci. U.S.A.,53, 952 (1965). (19) F. Franks in “Water”, Vol. IV, F. Franks, Ed., Plenum Press, New York, N.Y., 1975, Chapter I. (20) G. E. Hein and C. Niemann, J. Am. Chem. Soc., 84, 4495 (1962). (21) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, and E. J. Lien, J. Med. Chem., 16, 1207 (1973). (22) A. N. Kurtz and C. Niemann, Biochemistry, 1, 238 (1962). (23) H. Neurath and B. S. Hartley, J. Cell. Comp. Physiol., Suppl. 7, 54, 179 (1959). (24) B. Zeiner and M. L. Bender, J. Am. Chem. SOC.,86, 3669 (1964). (25) T. A. Steitz, R. Henderson, and D. M. Blow, J. Mol. Biol., 46, 337 (1969). (26) R. E. Dickerson and I. Geis “Proteins”, Harper and Row, New York, N.Y., 1969, pp 84-85. (27) C. Hansch and D. F. Calef, J. Org. Chem., 41, 1240 (1976).
Ring Opening of Aziridine Phosphonates. Correlation of Structure, Nuclear Magnetic Resonance Spectra, and Reactivityla Alfred Hassner* and James E. Galle Department of Chemistry, State University of New York at Binghamton,lb Binghamton, New York 13901 Receiued April 1,1975 T h e r i n g opening o f several d i m e t h y l N-aziridinylphosphonates3 w i t h Clz a n d HC1 was studied. T h e reaction was f o u n d t o b e stereospecific a n d in m o s t cases regiospecific. Conformational preferences in these compounds could b e correlated w i t h 1,3P-H ( P N C C H ) coupling constants a n d w i t h reactivity in r i n g opening.
The importance of aziridines as well as their N-phosphorylated derivatives in biological systems is well documented.2 It is generally assumed t h a t the cytotoxic behavior of such compounds is due to their ability to undergo ring opening by nucleophilic sites of enzymes. The ring opening of unsubstituted aziridine phosphonates of type 1 to 2 with electrophilic reagents (E+X-) including 0
t
BN-W OR), 1
E’X-
E
X-
O
I t CH,-CH,-N-P(OR)~ 2
carboxylic acids, chlorine, and alkyl halides has been investigated by Russian chemists.3a Related N,N- dialkylaminoaziridinyl phosphoric amides react similarly.3b In this study we are reporting on the chlorination of several ring substituted aziridine phosphonates 3 in an effort to determine the factors which influence the stereochemistry, regiochemistry, and the rate of ring opening. R e s u l t s a n d Stereochemistry. The reaction of dimethyl N-aziridinylphosphonates 3a-i with chlorine in CCl4 solution a t 0-5 “C leads t o dimethyl N-chloro-N-(P-chloroethy1)phosphoramidates 4a-i in high yield. These N-chloro compounds cannot be purified effectively, but are reduced
2274 J. Org. Chem., Vol. 41, No. 13,1976
Hassner and Galle
O+P(OCH,)z I
3a-i
4a-i
a, R , = C,H,; R,= R, = R, b, R, = C6H,; R, = CH,; R, = R,= H c,. R, = C,H,; R, = CH,;
=
RL. ClGC-C--
/?:
R,,‘
R ’a 5a-i
H
0
t
- --”P(OCH,)p
R,= R, = R,
= H; R, = C(CH,), g, R, = R, = R, = CH,; R, = H h, R, = R, = CH,; R, = R, = H i, R, = R, = CH,; R, = R, = H
f,
R, = R, = H
d, R, = R, = CH,; R, = R, = H e, R,= R, = CH,; R, = R, = H
with NaHS03 in methanol* and the dimethyl N-(0-chloroethy1)phosphoramidates 5a-i characterized by elemental analysis, spectra, and chemical conversions. Ring opening of the aziridine derivatives 3 with 1equiv of HCl in ether produces the identical phosphoramidates 5. If an excess of HC1 is employed cleavage of 5 takes place and the corresponding @-chloroethylaminehydrochlorides 6 are isolateda4 1 equiv HCI
3-5
R;’ The stereochemical identity of 5 and 6 provides proof t h a t t h e ring opening of 3 occurred in a stereospecific manner. Thus, 3b (trans) produces only t h e erythro diastereomer 5b, whereas the cis isomer 3c leads exclusively t o the threo product 5c. Proof of trans ring opening is provided by the hydrolysis of 5d and 5e t o the known erythro and threo @chloroethylamine hydrochlorides 6d and 6e, respectively. Regiochemistry. The spectral properties of the products 4 and 5 (Table I) indicate t h a t ring opening of the aziridine phosphonates 3 occurs in a regioselective manner. In most cases attack by the nucleophile takes place a t the most highly substituted carbon atom. Exceptions are the aziridines 3g and 3h, which give mixtures of products in the reaction with chlorine (3h also gives a mixture with HCl), and 3f, in which ring opening occurred in the opposite regiochemical sense. The mass spectra of 5 showed base peaks resulting from cleavage a t o N, confirming t h e regiochemical assignment.6 5
R,-C=NH-P(OCH,),
I
R?
5.
0
Mechanism. The following mechanism is most plausible. Attack of electrophilic chlorine on the nitrogen electron pair leads t o intermediate 8 which is opened from the back side by chloride ion (stereospecific trans ring opening). For most of the aziridines studied there are two possible configurational intermediates, Sa and 8b. Of these, 8b should be highly favored since chlorine is expected t o have a much smaller steric requirement than the phosphonate group. For the same reason t h e phosphonate is expected t o occupy the least hindered configuration in 3. Since it is reasonable t o assume t h a t inversion about the nitrogen is rapid in phosphorylated aziridines 3,6 the relative proportion of 8a and 8b will depend on the free energies of the transition states leading t o their formation. The results indicate that the chlorine molecule prefers
\
\
R
R
R
8b
8a
t o approach the aziridine ring from the most hindered side forming t h e more stable isomer 8b. Hence, the aziridine is chlorinated from its most stable conformation. I t follows t h a t if the aziridine has bulky cis groups as in 3c or 3f it chlorinates more slowly since the chlorine must enter cis t o these groups. This was borne out experimentally. The relative rate of chlorination of 3a:3b:3c was 460:17:1.3f was also chlorinated very slowly. Conformations and Long-Range P-H Coupling. Information on the conformational preferences in simple phosphorylated aziridines 3 may be obtained frrom their NMR spectra7 (Table 11). Their basic NMR features have been discussed elsewhere.6 I n addition, we have noticed for the C-CHs groups in 3 long-range 31P-1H coupling which depends values on certain stereochemical features. For instance, JPH of 0.6 Hz were observed for aziridine phosphonates in which the phosphorus function is expected t o be cis or trans t o the methyl groups with equal facility (as in 3d, 3h, and 3j). These were verified by 31P decoupling.* Aziridines which have two cis groups (as in 3c, 3e, and 31) show larger couplings, generally 1.2-1.6 Hz. This may be rationalized in terms of a conforma.~ tional preference leading t o the well-known “W” e f f e ~ tThe phosphorus and one hydrogen on the methyl group can be in a “W” conformation only when they are on opposite sides of the ring as shown in 9. This prerequisite is met when the methyl is found on the more substituted side of the aziridine ring causing the phosphorus to be trans t o it. Attempts to find a correlation for the ring protons failed. A related compound, N-azetidinyltriphenylphosphonium iodide (lo), prepared
+.
+
8
n
9 ,CHz-N CH CHp-I
