Synthesis and Properties of 2′-Deoxy-1′,2′-seco-D-ribosyl (5′ → 3′)oligonucleotides (= 1′,2′-seco-DNA) containing adenine and thymine

Some 2′-deoxy-1′,2′-seco-D-ribosyl (5′→3′)oligonucleotides (= 1′,2′-seco-DNA), differing from natural DNA only by a bond scission between the centers C(1′) and C(2′), were synthesized and studied in order to compare their structure properties and pairing behavior with those of corresponding natural DNA and homo-DNA oligonucleotides (2′,3′-dideoxy-β-D-glucopyranosyl oligonucleotides). Starting from (?)-D-tartaric acid, 2′-deoxy-1′,2′-secoadenosine derivative 9a and 1′,2′-secothymidine ( 9b ) were obtained in pure crystalline form. Using the phosphoramidite variant of the phosphite-triester method, a dinucleotide monophosphate 1′,2′-seco-d(T₂) was synthesized in solution, while oligonucleotides 1′,2′-seco-d[(AT)₆], 1′,2′-seco-d(A₁₀) and 1′,2′-seco-d(T₁₀) were prepared on solid phase with either automated or manual techniques. Results of UV- and CD-spectroscopic as well as gel-electrophoretic studies indicated that neither adenine-thymine base pairing (as observed in natural DNA and homo-DNA), nor the adenine-adenine base pairing (as observed in homo-DNA) was effective in 1′,2′-seco-DNA, Furthermore, hybrid pairing was observed neither between 1′.2′-seco-DNA and natural DNA nor between 1′,2′-seco-DNA and homo-DNA.     

Energetic Derivatives of 4, 4′,5, 5′‐Tetranitro‐2, 2′‐bisimidazole (TNBI)

4, 4′,5, 5′‐Tetranitro‐2, 2′‐bisimidazole (TNBI) was synthesized by nitration of bisimidazole (BI) and recrystallized from acetone to form a crystalline acetone adduct. Its ammonium salt ( 1 ) was obtained by the reaction with gaseous ammonia. In order to explore new explosives or propellants several energetic nitrogen‐rich 2:1 salts such as the hydroxylammonium ( 3 ), guanidinium ( 4 ), aminoguanidinium ( 5 ), diaminoguanidinium ( 6 ) and triaminoguanidinium 7 4, 4′,5, 5′‐tetranitro‐2, 2′‐bisimidazolate were prepared by facile metathesis reactions. In addition, methylated 1, 1′‐dimethyl‐4, 4′,5, 5′‐tetranitro‐2, 2′‐bisimidazole (Me₂TNBI, 8 ) was synthesized by the reaction of 2 and dimethyl sulfate. Metal salts of TNBI can also be easily synthesized by using the corresponding metal bases. This was proven by the synthesis of pyrotechnically relevant dipotassium 4, 4′,5, 5′‐tetranitro‐2, 2′‐bisimidazolate ( 2 ), which is a brilliant burning component e.g. in near‐infrared flares. All compounds were characterized by single crystal X‐ray diffraction, NMR and vibrational spectroscopy, elemental analysis and DSC. The sensitivities were determined by BAM methods (drophammer and friction tester). The heats of formation were calculated using CBS‐4M electronic enthalpies and the atomization method. With these values and mostly the X‐ray densities different detonation parameters were computed by the EXPLO5 computer code. Due to the great thermal stability and calculated energetic properties, especially guanidinium salt 4 could be served as a HNS replacement.     

Synthesis,Crystal Structure and Hydrolysis of a Novel Anhydrogalactosucrose: 2′‐Methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside

A novel anhydrogalactosucrose derivative 2′‐methoxyl‐O‐1′,4′:3′,6′‐dianhydro‐β‐D‐fructofuranosyl 3,6‐anhydro‐4‐chloro‐4‐deoxy‐α‐D‐galactopyranoside ( 4 ) was prepared from 3,6:1′,4′:3′,6′‐trianhydro‐4‐chloro‐4‐deoxy‐galactosucrose ( 3 ) via a facile method and characterized by ¹H NMR, ¹³C NMR and 2D NMR spectra. The single crystal X‐ray diffraction analysis shows that the title molecule forms a two thee‐dimensional network structure by two kinds of hydrogen bond interactions [O(2) H(2)···O(7), O(5) H(5)···O(8)]. Its stability was investigated by acid hydrolysis reaction treated with sulfuric acid, together with the formation of 1,6‐Di‐O‐methoxy‐4‐chloro‐4‐deoxy‐β‐D‐galactopyranose ( 5 ) and 2,2‐Di‐C‐methoxy‐1,4:3,6‐dianhydromannitol ( 6 ). According to the result, the relative stability of the ether bonds in the structure is in the order: C(1) O C(5)≈C(3′) O C(6′)≈C(1′) O C(4′)>C(3) O C(6)≈C(1) O C(2′)>C(2′) O C(5′).     

Reactions of 2,2′,5′,2′-terfuran

Formylation of 2,2′,5′,2′-terfuran ( 1 ) with N-methylformanilide and phosphorus oxychloride gave 5-formyl-2,2′,5′,2′-terfuran ( 2 ) and 5,5′-diformyl-2,2′5′,2′-terfuran ( 3 ). Reduction of 2 and 3 afforded 5-hydroxymethyl-2,2′,5′,2′-terfuran ( 4 ) and 5,5′ dihydroxymethyl-2,2′,5′,2′-terfuran ( 5 ), respectively. Terfuran 1 reacted with phenylmagnesium bromide to give 5-(phenylhydroxymethyl)-2,2′,5′,2′-terfuran ( 6 ), and was carbonated to 5-carboxy 2,2′,5′,2′-terfuran ( 7 ) and 5,5′-dicarboxy-2,2′,5′,2′-terfuran ( 8 ). Bromination of 1 with N-bromosuccinimide gave 5,5′-dibromo 2,2′,5′,2′-terfuran ( 9 ).     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

Synthesis of spiro[3,4‐diaryl‐4,5‐dihydroisoxazole‐5,2′‐1′,2′,3′,4‐tetrahydro‐1′‐naphthalenone]

Synthesis of a series of novel spiro[3,4‐diaryl‐4,5‐dihydroisoxazole‐5,2′‐1′,2′,3′,4′‐tetrahydro‐1′‐naphthalenone] has been described by the regioselective cycloaddition of nitrile oxides with 2‐arylmethylene‐1,2,3,4‐tetrahydro‐1‐naphthalenone. © 2001 John Wiley & Sons, Inc. Heteroatom Chem 12:463–467, 2001     

Syntheses and Reactions of 1′,2′-Unsaturated 2′,3′-Seconucleoside Analogues

The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18 , respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H–C(1′) in comparison to H? C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5–7 by nucleophilic substitution. ZnBr₂ in dry CH₂Cl₂ was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→ 19 ), nucleophilic displacement of the tosyl group by azide (→ 20 ), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21 . The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine ( 22 ) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).     

Synthesis,structure and some reactions of 4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]‐quinazolines]

2′‐Substituted 5′,6′,7′,8′‐tetrahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 3a‐d were synthesized by condensation of 3‐substituted 5‐amino‐1,2,4‐triazoles 1a‐d with 2‐cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2′‐substituted cis‐4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 4a‐d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X‐ray analysis of 6 and 11b . The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1‐b]quinazolines.     

Enzymatic Synthesis of 7′,5′‐Bicyclo‐DNA Oligonucleotides

The selection of artificial genetic polymers with tailor‐made properties for their application in synthetic biology requires the exploration of new nucleosidic scaffolds that can be used in selection experiments. Herein, we describe the synthesis of a bicyclo‐DNA triphosphate (i.e., 7′,5′‐bc‐TTP) and show its potential to serve for the generation of new xenonucleic acids (XNAs) based on this scaffold. 7′,5′‐bc‐TTP is a good substrate for Therminator DNA polymerase, and up to seven modified units can be incorporated into a growing DNA chain. In addition, this scaffold sustains XNA‐dependent DNA synthesis and potentially also XNA‐dependent XNA synthesis. However, DNA‐dependent XNA synthesis on longer templates is hampered by competitive misincorporation of deoxyadenosine triphosphate (dATP) caused by the slow rate of incorporation of 7′,5′‐bc‐TTP.     

Synthetic approaches to 4,8‐dimethyl‐5′‐(N‐pyridiniummethyl)‐ 4′,5′‐dihydropsoralens and 4,8‐dimethyl‐5′‐ (N‐aminomethyl)‐ 4′,5′‐dihydropsoralens

New synthetic approaches to 4,8‐dimethyl‐5′‐(N‐pyridiniummethyl)‐4′,5′‐dihydropsoralens and 4,8‐dimemyl‐5′‐(N‐aminomethyl)‐4′,5′‐dihydropsoralens are described. The 5′‐halomethyl‐4′,5′‐dihydro‐psoralen precursors are formed by electrophilic ring closures of 4,8‐dimethyl‐6‐allyl‐7‐hydroxycoumarin. The ring‐closure reactions may also be applied to the synthesis of 5′‐halomethyl‐4‐methyl‐4′,5′‐dihydroangelicins. The compounds are potential therapeutic agents for improved psoralen ultraviolet A radiation treatment.     

Regio‐ and stereospecific assembly of dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidines] from simple precursors using a one‐pot procedure: synthesis,spectroscopic and structural characterization,and a proposed mechanism of formation

The synthesis and characterization of three new dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine] compounds are reported, together with the crystal structures of two of them. (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐Chlorophenyl)‐1‐hexyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₈H₃₀ClN₃O₂S₂, (I), (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐1‐benzyl‐5‐methyl‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₃₀H₂₆ClN₃O₂S₂, (II), and (3RS,1′SR,2′SR,7a′SR)‐2′‐(4‐chlorophenyl)‐5‐fluoro‐2′′‐sulfanylidene‐5′,6′,7′,7a′‐tetrahydro‐2′H‐dispiro[indoline‐3,3′‐pyrrolizine‐1′,5′′‐thiazolidine]‐2,4′′‐dione, C₂₂H₁₇ClFN₃O₂S₂, (III), were each isolated as a single regioisomer using a one‐pot reaction involving l ‐proline, a substituted isatin and (Z)‐5‐(4‐chlorobenzylidene)‐2‐sulfanylidenethiazolidin‐4‐one [5‐(4‐chlorobenzylidene)rhodanine]. The compositions of (I)–(III) were established by elemental analysis, complemented by high‐resolution mass spectrometry in the case of (I); their constitutions, including the definition of the regiochemistry, were established using NMR spectroscopy, and the relative configurations at the four stereogenic centres were established using single‐crystal X‐ray structure analysis. A possible reaction mechanism for the formation of (I)–(III) is proposed, based on the detailed stereochemistry. The molecules of (I) are linked into simple chains by a single N—H…N hydrogen bond, those of (II) are linked into a chain of rings by a combination of N—H…O and C—H…S=C hydrogen bonds, and those of (III) are linked into sheets by a combination of N—H…N and N—H…S=C hydrogen bonds.     

New heterocyclic derivatives of 1′- and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones

The preparation of 1′-and 3′-amino-5′,6′,7′,8′-tetrahydro-2′-acetonaphthones (IIIa and IIIb) is described, by reduction of the low temperature nitration products of 5′,6′,7′,8′-tetrahydro-2′-acetonaphtone (I). The structures of the nitro isomers (IIa and IIb), and the reduction products, IIIa and IIIb, were elucidated spectroscopically. By known reactions, a series of new heterocyclic compounds prepared from the o-aminoketones, IIIa and IIIb, resulted in two series of new heterocyclic compounds.     

Functionalization of 2″‐C‐(Piperazinomethyl)‐2′,3′‐BcNA (Bicyclic Nucleic Acids) with Pyren‐1‐ylcarbonyl Units

Herein, we describe the incorporation of 2″‐C‐(piperazinomethyl)‐2′,3′‐BcNA (Bicyclic Nucleic Acids) into oligonucleotides via phosphoramidite chemistry and their subsequent solid‐phase functionalization with pyren‐1‐ylcarbonyl units after oligonucleotide synthesis. Thermal denaturation measurements showed that one modification led to increased thermal stability of the resulting duplex, and that two modifications could be incorporated in close proximity without decreasing the duplex stability (compared to the duplex stability of unmodified RNA). Fluorescence studies of the modified duplexes revealed that the structure and intensity of the fluorescence spectra were largely sequence‐dependent. Furthermore, molecular‐modeling studies showed that the pyrene moieties are placed in the major groove, and that the configuration at C(2″) is important for the thermal stability of the duplex.     

Highly Soluble and Green Indigo Dyes: 4,4′,7,7′‐Tetraalkoxy‐5,5′‐diaminoindigotins

Two new types of 4,4′,7,7′‐tetraalkoxyindigotins, 1a – f and 2a – f along with the new N‐substituted indigotins 4e – f , were synthesized from dinitrobenzaldehydes 5a – f , which were prepared from 2‐hydroxy‐5‐methoxybenzaldehyde ( 7 ) via dialkoxybenzaldehydes 6a – f (Scheme). The new dialkoxyindigotin 3g was obtained from dialkoxybenzaldehyde 6g via nitrobenzaldehyde 8g . The 1,4‐dialkoxy‐2,3‐dinitrobenzenes 9 were isolated as by‐products. The 4,4′,7,7′‐tetraalkoxy‐5,5′‐diaminoindigotins 1 are soluble in organic solvents, and their solutions are green, which is highly uncommon for indigotins and is primarily caused by electronic effects of substituents, steric effects playing a minor role. The indigotins 1 produce a strong red shift of the longest‐wavelength absorption and negative solvatochromism indicating the predominance of polar resonance structures in the ground state. Tautomeric structures were excluded. These indigotins are valuable compounds for technical applications, for synthetic purposes, and for analytical studies. SANS (Small‐angle neutron scattering) experiments showed that certain 4,4′,7,7′‐tetraalkoxy‐5,5′‐diaminoindigotins 1 form rod‐like aggregates in solution. The similarly substituted 4,4′,7,7′‐tetraalkoxy‐5,5′‐dinitroindigotins 2 are far less soluble. They produce red monoanions (preferably dimers) and bluish‐purple dianions in organic solvents.     

First synthesis of novel pentaheterocyclic ring system of 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole

Reaction of 1‐amino‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (1) with dimethylformamide‐dimethylacetal (DMF‐DMA) gave 1 ‐[N,N‐(dimethylaminomethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (2). Compounds (1) reacted with triethylorthoformate yielding 1‐[N‐(ethoxymethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (3). 3‐Amino‐4‐imino‐5‐aryl‐6‐cyanopyrimido[5′,4′:5,6]pyrido[1,2‐α] benzimidazole (4) was synthesized via condensation of either (2) or (3) with hydrazine hydrate. Reactions of (4) with acetic anhydride, ethyl chloroformate or aryl isothiocyanate yielded the respective derivative of the new ring system namely 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole (5–7).     

Four cyclo­alkane­spiro‐4′‐imidazolidine‐2′,5′‐dithiones

The crystal structures of four cyclo­alkane­spiro‐4′‐imidazolidine‐2′,5′‐dithiones, namely cyclo­pentane­spiro‐4′‐imidazolidine‐2′,5′‐dithione {systematic name: 1,3‐diaza­spiro­[4.4]­nonane‐2,4‐dithione}, C₇H₁₀N₂S₂, cyclo­hexane­spiro‐4′‐imidazolidine‐2′,5′‐dithione {systematic name: 1,3‐diaza­spiro­[4.5]decane‐2,4‐dithione}, C₈H₁₂N₂S₂, cyclo­heptane­spiro‐4′‐imidazolidine‐2′,5′‐dithione {systematic name: 1,3‐diaza­spiro­[4.6]undecane‐2,4‐dithione}, C₉H₁₄N₂S₂, and cyclo­octane­spiro‐4′‐imidazolidine‐2′,5′‐dithione {systematic name: 1,3‐di­aza­spiro­[4.7]dodecane‐2,4‐dithione}, C₁₀H₁₆N₂S₂, have been determined. The three‐dimensional packing in all of the structures is based on closely similar chains, in which hydantoin moieties are linked through N—H⋯S hydrogen bonding. The size of the cyclo­alkane moiety influences the degree of its deformation. In the cyclo­octane compound, the cyclo­octane ring assumes both boat–chair and boat–boat conformations.     

Four N7‐alkoxybenzyl‐substituted 4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐diones: hydrogen‐bonded supramolecular structures in zero,one, two or three dimensions

3‐tert‐Butyl‐7‐(4‐methoxybenzyl)‐4′,4′‐dimethyl‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₁H₃₇N₃O₃, (I), 3‐tert‐butyl‐7‐(2,3‐dimethoxybenzyl)‐4′,4′‐dimethyl‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₂H₃₉N₃O₄, (II), 3‐tert‐butyl‐4′,4′‐dimethyl‐7‐(3,4‐methylenedioxybenzyl)‐1‐phenyl‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione, C₃₁H₃₅N₃O₄, (III), and 3‐tert‐butyl‐4′,4′‐dimethyl‐1‐phenyl‐7‐(3,4,5‐trimethoxybenzyl)‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐b]pyridine‐5‐spiro‐1′‐cyclohexane‐2′,6′‐dione ethanol 0.67‐solvate, C₃₃H₄₁N₃O₅·0.67C₂H₆O, (IV), all contain reduced pyridine rings having half‐chair conformations. The molecules of (I) and (II) are linked into centrosymmetric dimers and simple chains, respectively, by C—H...O hydrogen bonds, augmented only in (I) by a C—H...π hydrogen bond. The molecules of (III) are linked by a combination of C—H...O and C—H...π hydrogen bonds into a chain of edge‐fused centrosymmetric rings, further linked by weak hydrogen bonds into supramolecular arrays in two or three dimensions. The heterocyclic molecules in (IV) are linked by two independent C—H...O hydrogen bonds into sheets, from which the partial‐occupancy ethanol molecules are pendent. The significance of this study lies in its finding of a very wide range of supramolecular aggregation modes dependent on rather modest changes in the peripheral substituents remote from the main hydrogen‐bond acceptor sites.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.