Introduction and goals

In 2015, we decided to update the knowledge on ethynylglycine synthon 1a since our latest review in 2005 (Reginato et al. 2005b). The recently published part I of this review (Benfodda et al. 2015) dealt with the preparations of this compound (and its derivatives) from Garner’s aldehyde 2a described in the literature so far (Fig. 1). The synthetic strategy adopted, the optical purity, and the preferred protection for the amino protecting group have been discussed there. The present part II of this review will be devoted to the uses of ethynylglycine synthon in synthesis that have been reported since our 2005 review (2005–2017), showing the broad range of recent synthetic applications of this polyfunctional chiral synthon.

Fig. 1
figure 1

(R)-2,2-dimethyl-3-(tert-butoxycarbonyl)-4-ethynyl-oxazolidine {ethynylglycine synthon} 1a and Garner’s aldehyde 2a

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The data that appeared after 2005 and that were not cited previously by us in our 2005 review (Reginato et al. 2005b) will be developed in this review; the previous references already cited in the 2005 review will only be cited in the paragraph headings, but the chemistry will not be developed. While writing this part II review, we noticed that a limited number of results earlier than 2005 were not developed in our 2005 review (Reginato et al. 2005b), that is why they now appear in the present review.

In neighbouring topics, it should be pointed out that Jirgensons recently published a review on the methods for the synthesis of α-ethynylglycines derivatives described since 1996 (Bolsakova and Jirgensons 2016), the precedent review being our older report on β,γ-alkynyl α-amino acids. (Meffre and Le Goffic 1996). We also published recently a comprehensive review on synthesis of α-quaternary α-ethynyl α-amino acids (Boibessot et al. 2016b).

Due to the presence of the oxazolidine ring (used especially as a synthetic precursor of α-amino acids) and of the terminal alkyne moiety, that allows several synthetic transformations, ethynylglycine synthon 1a is a useful building block for the synthesis of compounds of biological interest. The review will be organized considering the reaction type performed on the terminal alkyne (Fig. 1).

Metallation and reaction with electrophiles (Reginato et al. 1995, 1997; Meffre et al. 1996; Serrat et al. 1999; Cabarrocas et al. 2000a, b, 2001; Dondoni et al. 2001)

Electrophile is an aldehyde

Historically, this reaction was the first to be reported in the field of ethynylglycine synthon chemistry, in 1990. Because the Corey–Fuchs strategy (Benfodda et al. 2015) from aldehyde ent-2a yields to ethynylglycine synthon lithium acetylide (Li+)-ent-1a, the latter was directly trapped with paraformaldehyde to give a propargyl alcohol derivative 3 (Chung and Wasicak 1990). This compound was further functionalized to lead to an oxotremorine analogue 4. Oxotremorine 5 is the active metabolite of tremorine, a muscarinic receptor agonist (Fig. 2).

Fig. 2
figure 2

Synthesis of the oxotremorine analogue 4

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Compound 3 was also used in 2010 to obtain the allenic oxazolidine 7 via a copper-mediated ortho-(diphenylphosphanyl)benzoate (oDPPB)-directed SN2′ reaction with an excellent regioselectivity (SN2′/SN2 = 95/5) (Fig. 3) (Spangenberg et al. 2010).

Fig. 3
figure 3

Synthesis of the allenic oxazolidine 7 via SN2′ reaction

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The lithium acetylide derived from 1a was also reacted to TBDMS protected salicylaldehyde to give alcohol 8 (no yield given) which was then subjected to a one-pot acid-catalyzed nucleophilic substitution, fluoride TBDMS desilylation and exo-dig cycloisomerization to 2,3-disubstituted benzofuran 10 (Raji Reddy et al. 2012) (Fig. 4). It is worth noting that B(C6F5)3 was used as acid catalyst instead of BF3.Et2O because of the presence of acid labile acetonide group in 8.

Fig. 4
figure 4

Synthesis of the 2,3-disubstituted benzofuran 10

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The lithium acetylide derived from ent-1a was again used and converted to an alkynyl zinc reagent in the presence of excess zinc chloride, necessary to ensure a highly selective addition to aldehyde 11 in favor of the formation of the 1,2-syn alkoxide 12, followed by a ring opening of the epoxide activated by excess Lewis acid zinc chloride. α-C-(ethynylglycine)-galactoside 13 was thus obtained (Guillarme et al. 2006) (Fig. 5).

Fig. 5
figure 5

Synthesis of the α-C-(ethynylglycine)-galactoside 13

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Electrophile is a carboxylate or an isocyanate

The lithium acetylide derived from ent-1a was also condensed with methylchloroformate (inverse addition method to avoid the formation of enyne due to deprotonation and acetone elimination) to obtain alkynoate ent-14. Hydrostannylation followed by Stille cross coupling with iodo tryptophan 16 and NBoc deprotection led to the synthesis of 17. Compound 17 is a precursor to (+)-asperazine, an alkaloid with cytotoxic activity against human leukemia (14 steps from ent-1a) (Govek and Overman 2007) (Fig. 6).

Fig. 6
figure 6

Synthesis of methyl enoate 17, precursor of (+)-asperazine

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The alkynoate 14 (obtained by condensation of the lithium acetylide derived from 1a with methyl cyanoformate, Mander’s reagent) was also engaged in a cycloaddition with benzyl formhydroximate 18 to afford isoxazole 19 which is a precursor of isoxazole 20 (9 steps from 1a). Isoxazole 20 is the precursor of a tetracycline core structure (11 steps from 20) (Wzorek et al. 2012) (Fig. 7).

Fig. 7
figure 7

Synthesis of isoxazole 20, precursor of a tetracyclic core structure

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The arylamide 22, also obtained by condensation of the lithium acetylide derived from 1a with isocyanate 21, was subjected to an In-mediated radical cyclization to yield oxindole 24, a possible precursor of TMC-95A, a naturally occurring proteasome inhibitor (Yanada et al. 2005) (Fig. 8). Indeed, looking at the configuration of the starting material 1a used by the authors, and at the configuration of the stereogenic carbon 8 in TMC-95A, it seems that using (R)-1a oxindole (R)-24 would be actually obtained, which is a precursor of a diastereoisomer of TMC-95A (Fig. 8).

Fig. 8
figure 8

Synthesis of oxindole 24, precursor of TMC-95A

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Electrophile is an alkyl halide

Some time ago, our groups reported the synthesis of silylated amino acids using the ethynylglycine synthon (Meffre et al. 1996; Reginato et al. 1998, 1999). More recently, we described the synthesis of unsaturated amino acids containing an allyl silane moiety (Reginato et al. 2006), using a silylated alkyl halide as electrophile, the amino acid being obtained from the oxazolidine ring by oxidation (Fig. 9).

Fig. 9
figure 9

Synthesis of an allylsilane amino acid derivative 28

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Finally, ethynylglycine synthon rac-1a was converted to cyclic carbamate 29. The terminus of the alkyne in 29 was functionalized with trimethyl silyl and phenyl groups to give 30 and 31 which were subjected to an allenic Alder-ene reaction to give unstable triene 34 and 35 (Brummond and Yan 2008) (Fig. 10).

Fig. 10
figure 10

Synthesis of conjugated trienes 34 and 35

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Pd-catalyzed coupling reactions: Sonogashira couplings (Reginato et al. 1997; Crisp et al. 1997; Cameron and Khambay 1998)

The terminal alkyne moiety on ethynylglycine synthon 1a allows functionalization using the well-known Pd-catalyzed Sonogashira coupling reaction (Chinchilla and Nájera 2007).

Furanomycin 41 is an unusual amino acid containing a 2,5-dihydrofuran ring that presents antibiotic activity (Katagiri et al. 1967; von Nussbaum et al. 2006) (Fig. 11).

Fig. 11
figure 11

Structures of (+)-furanomycin 41 and tryprostatins A 42 and B 43

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The 2,5-dihydrofuran ring in the furanomycin analogue 40 was synthesized using a gold-catalyzed cycloisomerization of α-hydroxyallene 38 as the key step to obtain the precursor bicyclic dihydrofuran 39. α-Hydroxyallene 38 is obtained from propargyl oxirane 37 by a copper-mediated SN2′-substitution. Propargyl oxirane 37 is prepared from the corresponding enyne 36 which is obtained in turn from ethynylglycine synthon 1a by a Sonogashira coupling with 1-bromocyclooctene (Fig. 12) (Erdsack and Krause 2007).

Fig. 12
figure 12

Synthesis of furanomycin analogue 40

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Tryprostatins A (42) and B (43) are naturally occurring 2,3-disubstituted indoles that present antimitotic properties (Fig. 11) (Evidente et al. 2014).

Total synthesis of tryprostatin B (Fig. 13) starts with Sonogashira coupling of the aromatic iodide 45 on the terminal alkyne of ent-1a. After partial reduction and dehydration, ortho-alkenyl isocyanide 47 is obtained. The 2,3-disubstituted indole 49 is obtained from 47 in a one-pot process by a radical cyclisation using V70 (2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) as a radical initiator, followed by a Stille-type coupling reaction through the 2-stannyl indole intermediate 48. After protection/deprotection steps and oxidation, compound 51, key intermediate in the synthesis of tryprostatin B, is obtained. (Yamakawa et al. 2010, 2011, 2014). Tryprostatin A is obtained using the same strategy.

Fig. 13
figure 13

Synthesis of carboxylic acid 51, precursor of tryprostatine B 43

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Tryptophan analogues are interesting compounds, because they are possible indoleamine 2,3-dioxygenase (IDO) inhibitors and could have application in the treatment of inflammatory and neurodegenerative diseases (Röhrig et al. 2010). N,O-protected d-Homotryptophan 58 and its sulfur analogue 57 have been synthesized by Sonogashira coupling between 3-iodoheteroarenes and ethynylglycine synthon 1a followed by reduction of the alkyne, oxidation of the alcohol, and esterification using diazomethane (Fig. 14) (Goswami et al. 2012b). The selenohomotryptophan 59 (Fig. 14) was synthesized by the same group using the same route (Goswami et al. 2013).

Fig. 14
figure 14

Synthesis of homotryptophane derivative 58

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The same group described the synthesis of 2- and 3-indolylglycine derivatives and of their oxygen analogues using ethynylglycine synthon 1a as starting material. Indolylglycines are interesting scaffolds which are present in bis-indole alkaloids like dragmacidins and hamacanthins (Goswami et al. 2012a).

3-Indolylglycine 68 and its oxygen analogue derivative 69 (Fig. 15) were prepared starting from the internal silyl derivatives 60 and 61 in turn obtained from 1a using the literature procedure (Meffre et al. 1996). The key step is a Larock’s heteroannulation with 2-iodoaniline and 2-iodophenol derivatives, to obtain compounds 62 and 63. After desilylation and acid-catalyzed oxazolidine opening into N-Boc-protected amino alcohols 66 and 67, the N,O-protected 3-indolylglycine 68 and the oxygen analogue 69 are obtained by oxidation and esterification (Goswami et al. 2012a).

Fig. 15
figure 15

Synthesis of 3-indolylglycine 68 and oxygen analogue 69

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Unfortunately, the synthesis of the 2-substituted indole derivatives using the same strategy failed, due to the incompatibility of Boc-protecting group. For example Larock’s iodocyclization conditions (I2, CH2Cl2) proved to be problematic because of Boc-protecting group participation (nucleophilic attack). In this case, compound 71 was formed instead of expected indole derivative 72 (Fig. 16) (Goswami et al. 2012a).

Fig. 16
figure 16

Nucleophilic attack of Boc group under Larock’s iodocyclisation condition: formation of cyclic carbamate 71 instead of indole 72

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To solve this problem, ethynylglycine synthon 1a was transformed into ethynyloxazolidinone 73, through the removal of acetonide protection and reaction of the resulting amino alcohol with thionyl chloride (Fig. 17). Coupling of cyclic carbamate 73 under Sonogashira conditions gave compounds 74 and 75, which after Boc protection and carbamate opening gave N-Boc-protected amino alcohols 76 and 77, from which the N,O-protected 2-indolylglycine 78 and the oxygen analogue 79 are obtained by oxidation and esterification (Goswami et al. 2012a).

Fig. 17
figure 17

Synthesis of 2-indolylglycine derivative 78 and oxygen analogue 79

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During the synthesis of the chronic obstructive pulmonary disease (COPD) biomarker (+)-desmosine 86, a cross-linking amino acid of elastin, two of the four amino acid moieties present in the structure are introduced simultaneously using a Sonogashira cross-coupling reaction on ethynylglycine synthon ent-1a, as a first step. Another Sonogashira coupling reaction using propargylglycine derivatives 81 introduces a third amino acid moiety. Hydrogenation and usual functional group transformations led to the pyridine derivative 83, which is alkylated with the ω-iodobutylglycine derivative 84 to give N-Boc-protected desmosine 85. (+)-desmosine 86 is obtained after deprotection (Fig. 18) (Usuki et al. 2012; Yamada et al. 2015).

Fig. 18
figure 18

Synthesis of (+)-desmosine 86

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Compound 88 was prepared by Sonogashira coupling between the ethynylglycine synthon ent-1a and triflate 87 and used to prepare 8-hydroxy-3-substituted isocoumarine 89 using a gold(I)-catalyzed cyclization (Fig. 19) (Mallampudi et al. 2017).

Fig. 19
figure 19

Synthesis of isocoumarine derivative 89

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Cycloaddition reactions on the terminal alkyne (Falorni et al. 1998; Giacomelli et al. 2003)

The copper(I)-mediated reaction between nitrones and terminal alkynes (Kinugasa reaction) is a well-known method used for the β-lactam ring formation (Comas-Barceló and Harrity 2017). This reaction when applied to ethynylglycine synthon 1a leads to the formation of lactam 91 only in traces, although the same reaction conducted on D-glyceraldehyde alkyne analogue 92 led to lactam 93 in 46% yield and with a good diastereoselectivity (Fig. 20) (Stecko et al. 2009).

Fig. 20
figure 20

Synthesis of β-lactams 91 and 93

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The [3 + 2]-cycloaddition of alkynes with in situ generated difluoromethyl nitrile oxide 94 (obtained from oxime 95) leads to CF2H-isoxazoles. This reaction when applied to ethynylglycine synthon ent-1a lets to isoxazole 96, a precursor of the fluorinated isoxazole amino acid 97 (Fig. 21) (Khutorianskyi et al. 2017). Due to bioisosterism of CHF2 and OH groups, compound 97 is an analogue of ibotenic acid 98, a naturally occurring non-selective glutamate receptor agonist. (Frydenvang et al. 2010).

Fig. 21
figure 21

Synthesis of isoxazole amino acid derivative 97

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For another similar reaction, see (Falorni et al. 1998; Giacomelli et al. 2003), already cited in our previous review (Reginato et al. 2005b).

Huisgen 1,3-dipolar cycloaddition of an alkyne and an azide is a well-known access to 1,2,3-triazoles (Huisgen 1963; Totobenazara and Burke 2015). N-styryl triazole 101 was obtained from ethynylglycine synthon ent-1a by Huisgen cycloaddition with azido styrene 99 (generated in situ from cinnamic acid 100, CAN and NaN3) (Kavitha et al. 2011) (Fig. 22).

Fig. 22
figure 22

Synthesis of triazole amino acid rhizobitoxine analogue 104

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Protected triazole amino acid 104 was also synthesized by us using the Huisgen cycloaddition of alkyne 102 and azido alanine 103 derived from l-serine. Protected aminoalcohol 102 was obtained by acid-catalyzed opening of the oxazolidine ring of ethynylglycine synthon ent-1a. Invertion of the deprotection/cycloaddition sequence led to lower yields (Boibessot et al. 2016a). Compound 104 is an analogue of rhizobitoxine 105, a plant growth regulator and inhibitor of PLP-dependent enzymes cystathionine β-lyase and ACC synthase (Fig. 22) (Owens et al. 1968; Xiong and Fuhrmann 1996; Yasuta et al. 1999; Sugawara et al. 2006).

Arylglycines are an interesting class of unusual amino acids, because this moiety is present in the structures of important biologically active natural products (Mazuela et al. 2017).

These types of compounds have been prepared by Dötz benzannulation between Fischer chromium carbene complexes 106 and the alkyne functionality of the ethynylglycine synthon 1a (Fig. 23) (Pulley et al. 1999, 2005).

Fig. 23
figure 23

Synthesis of arylglycine derivatives 110

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In the key benzannulation reaction, the use of ultrasounds was found to improve yields.

The last oxidation step of arylglycinols 109 to arylglycines 110 proved to be problematic: the best results were obtained with a Dess–Martin oxidation followed by sodium chlorite oxidation using the Cbz-protecting group. The same oxidation performed on one of the Boc-protected arylglycinols proceeded in a lower yield (see, note 21 in Pulley et al. 2005).

Compounds 111 and 112 are serotoninergic chroman-based ligands with good activity (Fig. 24) (Holmberg et al. 2004, 2005). Badarau et al. synthesized compound 117, the 3-amino-7-azabenzofuran analogue of 111 and 112, starting from racemic ethynylglycine synthon 1a (Badarau et al. 2009). After ring opening, substitution of the methyl sulfonate in triazine 114 gave 115 which, through an intramolecular hetero-Diels–Alder reaction between the triazine residue and the alkyne moiety, led to compound 116. The reaction was carried out under microwave conditions using Cbz-protected alkyne 113. It is worth noting that, due to the presence of a good leaving group, the same reaction led to the formation of an oxazolidinone when performed on Boc-protected amino alcool 102 (Fig. 22) (Badarau et al. 2009).

Fig. 24
figure 24

Synthesis of a 3-amino-7-azabenzofuran derivative 117 analogue of serotoninergic ligands 111 and 112

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Finally, the cyclopropene glutamate analogue 120 was synthesized by an Rh-catalyzed cyclopropanation of ethyl diazoacetate and ethynylglycine synthon 1a as a key step. Deprotection of oxazolidine 118 and oxidation of the alcohol finally furnished amino ester 120 although in low yield (Fig. 25) (Kumar et al. 2016). Ester deprotection proved to be unsuccessful. The unstability of these derivatives is due to the presence of the cyclopropene moiety and the acidic α-proton which lead to the formation of the corresponding allene (see supporting information in the reference of the work).

Fig. 25
figure 25

Synthesis of a cyclopropene amino acid glutamate analogue derivative 120

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Addition of mixed tributylstannyl cuprate to the terminal alkyne and Stille coupling reactions (Reginato et al. 1997, 2000; Crisp et al. 1997)

Addition of stannylcuprate 121 onto ethynylglycine synthon 1a gave the vinyl copper intermediate 122. Hydrolytic work-up led to the γ-stannylated (E)-ethenyloxazolidine 123 in very good yield (Reginato et al. 1997).

Stille coupling with vinyl bromide gave diene 124. The use of palladium acetate Pd(OAc)2 and triphenylarsine AsPh3 as ligand proved to be necessary to obtain diene 130 when 2-bromopropene is used.

Trapping the intermediate vinyl copper 122 with electrophiles gave β-substituted stannyl allylamines 125, 126, and 127. Again Stille couplings led to diene 128 and triene 129 (Reginato et al. 2005a) (Fig. 26).

Fig. 26
figure 26

Synthesis of diene and triene amino acid precursors 124, 128, 129, and 130

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It is possible to obtain selectively the β-stannylated 131, the regioisomer of 123 (131/123 = 9:1), the two compounds being separated by chromatography, using hydrostannation of ethynylglycine synthon 1a (Fig. 27) (Lin and Kazmaier 2007).

Fig. 27
figure 27

Synthesis of functionalized amino alcohols and heterocycles by hydrostannation

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Compound 131 was subjected to Stille coupling reactions to afford alkenes 132 and 133. Vinylketones 132 were used for Michael additions, while alkenes 133 led to protected aminoalcohols 135 after oxazolidine cleavage (in two steps).

This strategy was also used in the same paper to obtain chiral amino heterocycles by hydrostannation and ring-closing metathesis (RCM) (Fig. 28) (Lin and Kazmaier 2007).

Fig. 28
figure 28

Synthesis of functionalized amino alcohols and heterocycles by hydrostannation

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For this purpose, dienes 137 and 138 were needed. Because acidic cleavage of the oxazolidine ring could not be performed on the stannylated oxazolidine 131 (Fig. 27), alkyne ent-102 was first obtained by acidic deprotection and hydrostannation was performed to give vinyl stannane 136 which was converted to dienes 137 and 138.

Stille coupling and ring-closing metathesis led to heterocycles 141–142 and 147–148 (Fig. 28).

Metal-catalyzed C–C bond-forming reaction to the terminal alkyne (other than Pd-catalyzed couplings)

Enantiomerically pure N-Boc-protected (R,R)-diaminosuberic acid 152 was synthesized using a copper-catalyzed dimerization of ethynylglycine synthon 1a as key step, followed by usual transformations (hydrogenation, deprotection, and oxidation). This strategy would allow a facile introduction of tritium or deuterium (Fig. 29) (Callahan et al. 2000).

Fig. 29
figure 29

Synthesis of protected diaminosuberic acid 152

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It is possible to synthesize a C-glycosyl derivative using an indium-mediated alkynylation reaction between a glycal or sugar derivative and alkynyl iodides under Barbier conditions (Ayed et al. 2010a). This reaction, when applied to alkynyliodide 153 (derived from ethynylglycine synthon 1a) and carbonyl compound 154 (derived from gluconolactone), leads to propargylic alcohol 155 in 66% yield, as a mixture of diastereoisomers (Fig. 30) (Ayed et al. 2010b).

Fig. 30
figure 30

Synthesis of C-glycosylated derivatives and the amino protecting group issue

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Unfortunately, when the same alkynyliodide 153 was treated with tri-O-acetyl-D-glucal 156, no coupling product was detected in the same reaction conditions. Instead of the C-glycosylated derivative 157, the cyclic compound 158 was formed in 91% yield because of Boc intramolecular cyclization (Fig. 30) (Ayed et al. 2010a) (see also the discussion about the amino protecting group issue in our precedent Part I report) (Benfodda et al. 2015).

Indeed, when different protecting groups in alkynyliodide 153 were used (compounds 159 and 161), the coupling products 160 and 162 (Ferrier-type rearrangement) could be formed exclusively in the α-anomeric form (Fig. 31) (Ayed et al. 2010b, a).

Fig. 31
figure 31

Synthesis of C-glycosylated derivatives and the amino protecting group issue

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Finally, propargyl hydroxylamine 164 was obtained in 75% yield by a C–C bond-forming reaction using a Lewis acid/metal amide hybrid-catalyzed reaction of ethynylglycine synthon 1a with nitrone 163 (Fig. 32) (Yamashita et al. 2014).

Fig. 32
figure 32

Synthesis of propargyl hydroxylamine derivative 164

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Miscellaneous

Ethynylglycine synthon 1a was converted to allenic carbamate 165 using the Crabbé reaction (Fig. 33) (Crabbe et al. 1985; Alcaide et al. 2013).

Fig. 33
figure 33

Synthesis of oxazinone 166

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The 6-methylene 1,3-oxazinan-2-one 166 has then been obtained using a gold-catalyzed oxycyclization of the allene 165 at room temperature (6-endo-dig oxyauration, kinetically controlled product). The same reaction conducted at high temperature led to a complex mixture (Fig. 33).

It is worth noting that the same reactions were performed (among other allenic carbamates) on the proline derivative 167. In that case, the thermodynamically favored 1,3-oxazine-2-one 170 was formed at high temperature (6-exo-dig oxyauration) (Fig. 34) (Alcaide et al. 2013).

Fig. 34
figure 34

Synthesis of oxazinones 169 and 170

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Ethynylglycine synthon 1a was converted to protected propargylamine alcohol 171 which was subjected to intramolecular Mitsunobu reaction to lead to aziridine 172. Bromoallene 174 was then synthesized from aziridine 172 via an acid-mediated ring opening reaction and bromination through mesylate 173 (Fig. 35) (Ohno et al. 2002).

Fig. 35
figure 35

Synthesis of 2-ethynyl aziridine 172, mixture of enantiomers

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Bromoallene 174 was used as a model in the course of the study of the intramolecular amination reaction of chiral bromoallenes into 2-ethynylaziridines in basic conditions (for example (R) and (S)-172 resulted from syn- and anti-SN2′ processes when bromoallene 174 was treated with LHMDS) (Fig. 35) (Ohno et al. 2002).

To circumvent the Wittig strategy to prepare alkene 175 from Garner’s aldehyde 2a (that proved to be unreliable to some authors) (Belanger et al. 2009), ethynylglycine synthon 1a was hydrogenated to alkene 175 using Lindlar catalyst. Cross-coupling metathesis using Grubbs’ catalyst II led to alkene 177. This compound is an intermediate in the synthesis of cyclic peptide 178 as a complexing agent of poly(vinyl alcohol) (PVA). This chemistry is outside the scope of this review and will not be detailed here (Fig. 36) (Belanger et al. 2009).

Fig. 36
figure 36

Synthesis of cyclic peptide 178

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Conclusion

This review shows the great potentiality of ethynylglycine synthon as a polyfunctional chiral building block available for the synthesis of biologically relevant compounds, from “simple” to more “complex” structures. The terminal alkyne moiety has been exploited in metallation and reaction with a large variety of electrophile; in metal-catalyzed coupling reactions (Pd: Sonogashira, Cu, In); in cycloaddition reactions on nitrones, nitrile oxides, azide (Huisgen reaction), Fischer chromium carbene complexes, triazines (hetero-Diels–Alder), and ethyl diazo acetate (Rh-catalyzed cyclopropenation); in additions of stannylcuprates followed by Stille coupling reactions. Most of the times, the integrity of the chirality in ethynylglycine synthon was maintained in the final compounds or used as a chiral inducer.

The well-known reactivity of the terminal alkyne together with the presence of the stable chiral aminoalcohol substructure explain the increasing use of the ethynylglycine synthon in recent years (2005–2017: 35 reports) and suggests a great future.