Dipeptide unit

Substitution of a dipeptide unit by a cychc dipeptide derivative within a peptide chain can induce certain conformational restraints that may alter the biological response via changing receptor selectivity. A facile procedure for synthesis of pyrazinone ring-containing opioid mimetics [21] has been elaborated, based on the cycHzation of readily available dipep-tidyl chloromethyl ketones [22] (Scheme 6). This method affords 2(IH)-pyrazinone derivatives containing substituents with desired functional groups at positions 3 and 6 in high yield. 

Scheme 2 Antibiotics related to penicillin. Note that in sulfazecin, 8, the dipeptide unit contains D-glutamate and D-alanine...

A further modification is a single (3-lactam ring as found in the mon-obactams. Characteristically, there is a sulfonate residue (derived from sulfate) on the nitrogen atom. An example is sulfazecin 8 from Pseudomonas acidophila and P. mesoacidophila. This material also contains a dipeptide unit of D-glutamate and D-alanine (Scheme 2). Pharmaceutical chemists have synthesized many variations on the (3-lactam structure and have devised semisynthetic processes. The resulting materials are not natural products and are beyond the scope of this article. 

A. Otaka, E. Mitsuyama, J. Watanabe, H. Watanabe, N. Fujii, Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units. Biopolymers 76 (2004) 140-149. 

It may be worthy to note that 2-(aminoalkyl)oxazole-4-carboxyhc elements are masked Xaa-Ser/Thr dipeptide units and, thus, may also serve in particular cases to enhance the synthetic potential, since after acid hydrolysis both amide bonds are released restoring Xaa-Ser/Thr (Scheme 39). 

Good stereoselectivity is observed in the synthesis of 3,4-dihydroisocoumarins from the oxazoline 49 and the protected leucinal 50 (Scheme 29). Further reaction with an azetidinone introduces a dipeptide unit at C-3 <99JCS(P1)1083>. 

Both the size of the preceding amino acid in the dipeptide X-Pro, and that of groups in the COOR residue are able to influence (730MR547 79MI6) their conformer ratio. The conformational characteristic found for the dipeptide Gly-Pro, with the glycine amino acid bonded to a bulky residue, are close to those of poly (Gly-Pro), suggesting (77MI7) that the conformational behavior of one polymer is related to local properties of dipeptide units. 

The energy barrier for internal rotation in dipeptides is generally high (89.6 kJ mor in L-hystidyl-L-proline) (82MI6) but decreases when the dipeptide unit is introduced in internal positions of a longer sequence. This is seen (82MI6), for example, in the octapeptide angiotensin II, in which the L-hystidyl-L-prolyl unit is in position 6 or 7, and the interconversion rate becomes 70 times faster than in the isolated dipeptide. 

As a key feature of the TASP approach, the template is designed to direct and reinforce the folding of the covalently attached secondary structure elements in the predetermined tertiary structures (Scheme 1), e.g. a four a-helical bundle. The major purpose of artificial turn-inducing mimics is to constrain, when incorporated at the appropriate location, the peptide chain into a semi-rigid, defined, spatial arrangement. 39 8-(Aminomethyl)-5,6,7,8-tetrahydro-2-naphthoic acid (Amhn) is designed to substitute for the central dipeptide unit of a reverse turn and is prepared in a five-step procedure starting from commercially available 4-phen-ylbutanoic acid 40 (Scheme 3). 

The synthetic approach involves three key features (1) linkage to the solid support through the side-chain L-asparaginyl residue at position 12, (2) on-support cyclization between the a-carboxy of the Asn12 residue and the side-chain amino group of the Lys6 moiety, and (3) addition of the 1,2-modified dipeptide unit in a single step (Scheme 1). 

The key step of the approach to 45 is the ring opening of /V-Boc p-lactam 43 with ammonia, Scheme 17. The synthesis starts from the 4-carboxy azetidin-2-one 41, which is a p-hydroxy aspartic acid form possessing the p-carboxyl group and the a-amino moiety simultaneously protected. The dipeptide unit 42 is obtained in 95% overall yield after activation of the a-carboxy group with cyanuric fluoride and... 

Given these requirements, it is obvious that the P-tetralin based N- and C-caps could not be used as position-independent templates. While the P-tetralin amino acid and the dipeptide units are compatible with a position-independent template design, the biphenyl ether linker unit clearly was not. In N- and C-caps, the linker unit forms a side chain (P-tetralin) to backbone constraint (either to the C-terminal carboxylate or the N-terminal amine), and only one attachment site for a peptide... 

Conformational maps show values of phi and psi that fall into two regions the first region contains points that are always allowable and the second region contains points that are sometimes allowed. As shown in Figure 2.11, all points within the inner lines are always allowed and those within the outer solid lines are sometimes allowed. Hence the entropy (or rotational freedom of a peptide) is obtained from the area surrounded by the solid lines on a conformational map (Figure 2.11) and is proportional to the number of allowable conformations of a dipeptide unit. Please note a flexible chain with a lot of rotational freedom is easier to stretch than a rigid chain. We define the flexibility of a polypeptide as the natural logarithm of the number of allowable conformations,, times Boltzmann s constant (Equation (2.1)). 

The dipeptide unit was the subject of much of this early work. It is the structural unit of which proteins are built and is shown in Figure 2. In a sense it is the "ethane" of the theoretical biophysicist. In the early work it was reasoned that the energy to stretch bonds and to distort angles is very large, relative to conformational variations, so these internal coordinates could be maintained at their equilibrium values. Furthermore the peptide bond... 

LiBr-(Ala-Gly) 2H20 (lithium atom is bonded to two carboxyl oxygens of one dipeptide unit, one carbonyl oxygen of another, and a water molecule) U—O 1.91 113... 

Brennan TM, Hendrick ME. Branched amides of L-aspartyl-D-amino acid dipeptides. United States Patent No. 4,411,925 25 Oct, 1983. 

Carbene addition to an E/Z mixture of vinyl ether 21, followed by solvolysis of the resultant cyclopropane 22 afforded (Z)-a-fluoroenal 23 (Scheme 10.6) [16]. (Z)-a-Fluo-roenal 23 was used for the preparation of Substance P analogues containing a Phe- F[(Z)-CF=CH]-Gly dipeptide unit as described next. 

---