The synthesis of five amino phosphorus derivatives, 1a-e, is described. The derivatives were incorporated into a series (18) of analogues of the 5-14 portion of angiotensinogen, in most cases at the scissile Leu-Val bond. The resultant compounds were tested in vitro for their ability to inhibit human plasma renin. Replacement of the scissile bond with the phosphinic analogue of Leu10-Val11 (1b) gave the most potent inhibitors, having IC50 = 7.5 x 10(-8) M for H-Pro-His-Pro-Phe-His-(1b)-Ile-His-Lys-OH and IC50 = 1.0 x 10(-7) M for Z-Arg-Arg-Pro-Phe-His-(1b)-Ile-His-NH2. The shorter phosphonic acid sequence Z-Pro-Phe-His-(1d) retained biological activity with an IC50 = 6.4 x 10(-6) M.
Chemical and spectroscopic studies lead to the [7,0] metacyclophane structures (2) and (3) for myricanol and myricanone, phenolic extractives from Myrica nagi. X-Ray analysis of the meta-bridged biphenyl, 16-bromomyricanol (nitromethane solvate), by the heavy-atom method, confirmed these assignments, and gave the absolute configuration of myricanol. The compound crystallises in the monoclinic space group P2, with Z = 2 in a unit cell of dimensions a = 6.02 * 0.01. b = 17.34 f 0.02, c = 11 a 2 2 f 0.02 8, and p = 98.4" f 0.2"; the structure was refined to R 0.057 for 1075 independent reflections. C.d. measurements suggest t h a t myricanol prefers t h e same conformation in solution as in the crystalline state. The biphenyl nucleus in 16-bromomyricanot is detormed by metameta-bridging. Similar strain in myricanone (3) is relieved by rearrangement with Lewis acids to the onho,rneta-bridged ketone (1 3). The natural phenols may be biogenetically related to diarylheptanoids.THE stem bark of Mypica nagi (Myricaceae) (reputed to be a fish poison) has been stated 2 to contain the rotenoid (I) among its phenolic constituents, with a t r a n s -~/ c ring fusion of unspecified absolute configuration, and a previously all assigned a C ~S -B / C junction (6aSJ12aS) with ring E attachment, if present,, isoprenoid (or degraded isoprenoid) in character. We have attempted reisolation of the claimed rotenoid, without success. t r 11 10 hexadienyl substituent in ring E. Both reported The phenolic fractions from M . nagi have instead features would be unique among natural rote no id^,^ yielded two unusual meta-bridged biphenyls, myricanol, t Professor Seshadri has informed us that the rotenoid assigne v. K*shnamoodhy, N. R. Krisnaswamy, and T. R. seshadri, ment should now be withdrawn.
Aminomethylphosphinic acid ( 7 ) , protected at nitrogen as the imine derived from benzophenone and at phosphorus as the diethylacetal and ethyl ester [i.e. (6)], undergoes facile LDA-induced alkylation. Treatment with primary alkyl halides affords, on product hydrolysis, a versatile route to phosphinic analogues of or-amino carboxylic acids. Analogues of alanine, valine, leucine, phenylalanine, tyrosine, histidine, and aspartic and glutamic acids are thus prepared; the phosphonic histidine analogue (23b) can be prepared similarly from the imine phosphonate diester (21 ). Intra-and inter-molecular dialkylation reactions provide analogues of 1 -aminocyclopropanecarboxylic acid (1 4) and 2,6diaminoheptanedioic acid (1 6). Benzyl bromide alkylation of (25a) and (30a), where the nitrogen is protected as the imine of the 2-hydroxypinan-3-one chiral auxiliary (24) or (29), is diastereospecific leading to asymmetric synthesis of either (+)-or (-)-phenylalanine analogues; this selectivity is compared to that shown by the corresponding chiral imine phosphonate (25b) and imine carboxylate (25c).In a previous paper from these laboratories,' the synthesis of a-amino phosphinic acids (1)$ was described by addition of phosphinic acid to the imine derived from an aldehyde and benzhydrylamine followed by hydrolysis (Scheme 1). It was rationalised that this class of compound would be the closest phosphorus analogue to the a-amino carboxylic acids.The previous method depends upon the availability of a suitable precursor aldehyde, and these compounds are not always readily prepared. An alternative synthetic strategy can be envisaged by alkylation of a suitably protected aminomethylphosphinic acid. This method is well known for synthesis of a-amino carboxylic acids and or-amino phosphonic and we now demonstrate that it can also be applied to synthesizing a-amino phosphinic acids (1).
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