N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

Since Garner’s aldehyde has several drawbacks, first of all is prone to racemization, alternative three-carbon chirons would be of great value in enantioselective syntheses of natural compounds and/or drugs. This review article summarizes applications of N-(1-phenylethyl)aziridine-2-carboxylates, -carbaldehydes and -methanols in syntheses of approved drugs and potential medications as well as of natural products mostly alkaloids but also sphingoids and ceramides and their 1- and 3-deoxy analogues and several hydroxy amino acids and their precursors. Designed strategies provided new procedures to several drugs and alternative approaches to natural products and proved efficiency of a 2-substituted N-(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary.


Introduction
The synthesis of enantiomerically pure compounds belongs to the most challenging tasks in organic chemistry for several reasons, just to mention structural studies of natural products or preparation of chiral drugs. They become available by asymmetric synthesis frequently employing chiral synthons (chirons) [1].
Another important strategy of asymmetric synthesis relies on chiral auxiliaries, i.e., a specially selected homochiral part of a starting material governing the stereoselectivity of subsequent reactions which is finally easily removed [11]. Among threecarbon chirons related to Garner's aldehyde derivatives of N-(1phenylethyl)aziridine-2-carboxylic acid 5-8 ( Figure 2) play an important role in asymmetric synthesis as they function as a chiral synthon combined with a chiral auxiliary [(R)-or (S)-1phenylethyl group].
As the closest analogues of Garner's aldehyde (3a) and other chiral α-aminoaldehydes, e.g., 4, or aziridine aldehydes 6 do not undergo epimerization during preparation as well as in further transformations conducted in the presence of basic reagents because of the high barrier to inversion at the nitrogen in the aziridine ring. The immediate starting materials, esters 5 and methyl ester 3b, are easier (one step and separation of diastereoisomers for 5 vs three steps for 3b) to prepare for the aziridine chiron while they are priced comparably. Although DIBAL-H was applied as a reagent of choice in the synthesis of Garner's aldehyde it has several drawbacks, e.g., overreduction, tricky removal of aluminum salts, a two-step easy to perform sequence (ester 5 to alcohol 7 reduction and re-oxidation to 6) was generally adapted for aziridine-2-carbaldehydes 6.
In this review we wish to focus attention on applications of 5-8 in syntheses of biologically important compounds having a 2-amino-1,3-disubstituted propane unit implanted into their structures because vicinal amino alcohol and 2-aminopropane-1,3-diol scaffolds are present in many natural products as well as compounds of commercial interest as medications.
Synthetic strategies to molecules as simple as amino alcohols to as complex as indolizine alkaloids will be discussed with a special focus on stereoselectivities of key transformations. Whenever possible biological activities of new compounds will be shown to underscore their biological potency. In a few cases mechanistic considerations will be presented to clarify the structural diversity of the products resulted from openings of the aziridine ring. This review was intended to cover the entire literature including patents on (1-phenylethyl)aziridine-2carboxylic acid and its derivatives till the beginning of 2019. The usefulness of any chiron depends on its availability and to some extent on versatility of the protective groups. In case of the 1-phenylethyl group its removal at any stage of synthesis is not limited to a catalytic hydrogenation but metal-ammonia reduction (Birch reaction) and organic acid in anisole (vide infra) can be efficiently applied. We begin with a short presentation of syntheses of aziridine-2-carboxylates, the corresponding aldehydes and 2-methanols.

Syntheses of biologically relevant compounds from N-(1-phenylethyl)aziridine-2carboxylate esters
A 2-ketoaziridine scaffold present in esters 5 and aldehydes 6 can undergo a variety of transformations. Elongation together with further functionalization are possible employing ester and aldehyde groups and the stereochemical outcome of these reactions is controlled by configurations at C2 and at the chiral auxiliary (Scheme 3). The opening of the aziridine ring is expected to occur at the less substituted carbon atom and can be executed with nucleophiles to provide 9 or even by catalytic hydrogenation to form 10. Thus, biologically important fragments like vicinal amino alcohols 11 or 2-amino-1,3-propanediols 12a [Nu = OH] can be obtained in highly enantioselective procedures preserving the absolute configuration at C2. The latter compounds are useful precursors to amino acids. Installation of halogen atoms in 9 (Nu = Cl, Br, I) allows for extending of the carbon chain.
Before we start reviewing the synthesis of biologically relevant compounds prepared via opening of the aziridine ring it should be mentioned that cyanides (2R,1'S)-and (2S,1'S)-13 prepared from the respective esters (Scheme 4) 5b appeared moderately active as immunostimulants [18].
The synthesis of amino alcohols of general formula 11 (Scheme 3) from 2-substituted N-(1-phenylethyl)aziridines 5 and 6 can be achieved by a regioselective reductive aziridine ring opening combined with functionalization of the C2 substituent and optional alkylation or arylation of the nitrogen atom [44].
Following a similar regioselective aziridine opening, a mixture of epimeric amino alcohols (2R/S,1'R)-23 was prepared in two steps from the aziridine alcohol (2R/S,1'R)-7 (Scheme 6) which was found to be an effective inhibitor of the mitotic kinesin.
In search for a sphingolipid analogue synthesis of compounds of general formula (R)-76 was undertaken (Scheme 19) [53]. The aziridine ketone (2S,1'R)-77 obtained from Weinreb amide (2S,1'R)-18 was subjected to a three-step deoxygenation (reduction, mesylation of the alcohol (2S,1'R)-78 and reduction of the mesylate) to locate the 2-phenylethyl substituent at C2. Installation of the pyrrolidine ring at C3 was achieved after opening of the aziridine ring with iodotrimethylsilane to give a protected diamine (R)-80a. Removal of the chiral auxiliary yielded the diamine (R)-80b which after acylation provided analogues (R)-76. Compound (R)-76 (R = C 9 H 19 ) appeared inactive as inhibitor of human sphingosine kinases 1 and 2.
MeBmt (2S,3R,4R,6E)-139 is a nonproteinogenic amino acid found as a constituent of the naturally occurring cyclic peptide cyclosporine currently in medical use as immunosuppressant [89]. Syntheses of MeBmt are rather challenging endeavor since these amino acids in addition to an E-configured C=C bond has three neighboring stereogenic centers. The starting aziridine aldehyde (2R,1'R)-6 already introduces the required configuration at C2 and the two other centers of chirality were created by the stereospecific crotylation with a homochiral boronate to give the aziridine alcohol (2R,1'R,2'R,1''R)-140 (Scheme 36) [90]. After O-benzylation and N-methylation the ring opening in the intermediate aziridinium ion was tried. It appeared that the best regioselectivity (87:13) was achieved with cesium acetate and the major product (2R,3R,4R,1'R)-141 was separated chromatographically. To install two lacking carbon atoms the vinyl moiety was transformed into the respective aldehyde 143 (via a primary alcohol 142) which when subjected to Julia-Kocienski reaction furnished the E-olefinic terminus. Since under these conditions the acetate function was also hydrolyzed the carboxy group was formed by oxidation of the hydroxymethyl residue. To complete the synthesis N-and O-benzylic protecting groups were removed during the Birch reaction.

Miscellaneous
FDA-approved meropenem and R-82301 belong to a class of carbapenem antibiotics containing a substituted exocyclic 3-mercaptopyrrolidine scaffold. In search for new drugs this fragment was replaced by a 5-methyl-4-mercaptopyrrolidin-2one moiety which was synthesized from aziridine esters 5 [123]. Thus, a five-carbon framework was assembled from (2S,1′S)-5b and ethyl acetate followed by reduction of an intermediary ketone which produced a diastereoisomeric pair of aziridine alcohols readily separable chromatographically. Hydrogenation of, e.g., the alcohol 242 led to the formation of the pyrrolidine-2-one (4R,5S)-243 (Scheme 60). The hydroxy for mercapto replacement was achieved in Mitsunobu reaction to produce (4S,5S)-244 after deacetylation. Three other enantiomers were prepared accordingly. Modified carbapenems, e.g., 245, were obtained by coupling of the thiol (4S,5S)-244 with the respective enolphosphate and some of them appeared as active as meropenem and R-82301 towards selected bacterial strains.

Conclusion
The current body of literature on N-(1-phenylethyl)aziridine-2carboxylate esters and their derivatives revealed their successful applications in syntheses of over a dozen of approved drugs and potential medications as well as over 40 important natural products mostly alkaloids including ephedrine and related compounds, polyhydroxy pyrrolidines, piperidines, pyrrolizidines and indolizidines but also various sphingoids and ceramides and their 1-and 3-deoxy analogues and several hydroxy amino acids and their precursors. Designed strategies provided new procedures to several drugs and alternative approaches to natural products. This was possible because three-carbon aziridine chirons 5-7 are configurationally stable, in majority of cases the openings of the aziridine ring took place at the less substituted C3 atom, either alkoxycarbonyl or hydroxymethyl but especially formyl functionalities could be further elaborated in a highly stereoselective manner while the cleavage of the chiral auxiliary could be easily accomplished with three different reagents depending on a particular stage of multi-step sequences.
Since a vicinal amino alcohol unit and various amino(dihydroxy)propyl and (diamino)hydroxypropyl combinations are crucial for biologically active compounds (2R)-or (2S)-aziridine-2-carboxylates, -carbaldehydes and -methanols appeared perfectly suited for introducing the required stereochemistry into a C*-N moiety of the target compound without fear of racemization. The next stereogenic center was best created by reductions of 2-acyl-N-(1-phenylethyl)aziridines which proceeded in almost diastereospecific manner when a NaBH 4 / ZnCl 2 mixture or ʟ-Selectride ® were used to give alcohols of opposite configurations. To install at C2 the 1,2-dihydroxyalkyl substituent of required configurations the cis-dihydroxylation of E-or Z-olefins obtained in Wittig or HWE reactions appeared a method of choice. Although Michael reaction on the respective E-or Z-acylates could introduce various nucleophiles (C, N, O), the stereoselectivity of additions in most cases was not satisfactory. Summing up, a majority of strategies relied on specific functionalization at the C2 site of starting aziridines.
Expansions of a three-carbon framework of aziridines 5-8 were also carried out starting from regioselective openings at less substituted C3 with appropriate nucleophiles combined with further functionalizations but were less common and no stereogenic center was generated. Furthermore, hydrogenolytic cleavage of the aziridine ring always occurred at C3 and allowed for the one-step introduction of the terminal methyl group. Amines also reacted preferentially at C3 leading to formation of 1,2-diamino-or 1,2-diamino-3-propyl fragments of designed stereochemistry extremely useful in the synthesis of new sphingoid and ceramide analogues for biological studies. Although hydroxylations also took place at C3, they were carried out as a two-step process (acetylation and saponification).
Openings of the aziridine ring at C2 in 2-substituted N-(1phenylethyl)aziridines were observed in a few cases and were limited to a Lewis acid-catalyzed five-membered ring closure and the aziridine ring opening sequence as well as to reactions at C2-COOEt.
Regardless of regioselectivity the aziridine ring opening in N-(1-phenylethyl)aziridines required prior activation to form respective aziridinium ions. Besides protic (AcOH, HF) and Lewis acids (aluminum chloride, boron trifluoride etherate), chlorotrimethylsilane-amine pairs, iodotrimethylsilane, phosgene and triphosgene were applied to mention frequently used. However, when bicyclic aziridinium ions are formed their further reactivity appeared to be under steric and/or electronic control and followed rules recently described [124,125].
On a few occasions only epimers of naturally occurring compounds were obtained without any comments on modification of the synthetic strategy to reach the target molecule. With a collection of reliable transformations of 2-substituted N-(1phenylethyl)aziridines in hands new applications in enantioselective syntheses of medications and natural products will appear soon and we hope this review will stimulate further research in this area.