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. 2022 Jan 4;7(2):2002–2014. doi: 10.1021/acsomega.1c05468

Polyhydroxylated Cyclopentane β-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides

Fernando Fernández †, Alberto G Fernández †, Rosalino Balo †, Víctor M Sánchez-Pedregal ‡, Miriam Royo §,∥, Raquel G Soengas ⊥, Ramón J Estévez †,‡, Juan C Estévez †,‡,*
PMCID: PMC8772316  PMID: 35071888

Abstract

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A stereoselective synthesis of polyhydroxylated cyclopentane β-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic β-amino acids into peptides is also reported.

Introduction

The enantioselective synthesis of β-amino acids has received great attention in recent times,1−5 mainly because peptidomimetics6 based on these amino acids may overcome the pharmacological limitations of natural peptides.7−10 They are more resistant than α-peptides to protease and peptidase degradation,11−13 and their conformational properties and stability facilitate their interaction with receptors and enzymes, which usually results in improved activity and no side effects.14 More recently, α,β-peptides have evidenced promising applications in material sciences, mainly as nanomaterials.15

Among the many β-amino acids that have been studied, cyclopentane-based β-amino acids are particularly attractive building blocks because their peptides exhibit specific folding properties. For instance, their homo-oligomers show a high propensity to fold in well-defined secondary structures in short peptide sequences, a structural property that often gives them enhanced biostability and activity.16,17 Thus, oligomers that contain at least four units of trans-2-aminocyclopentanecarboxylic acids (trans-ACPC) adopt a stable 12-helix with topological dimensions similar to those of the α-helix in α-peptides,18−20 while their cis-homo-oligomers adopt β-sheet secondary structures.21 Homo-oligomers with alternating heterochiral cis-ACPC sequences form a 10/12 helix, while those with alternating heterochiral trans-ACPC tend to attain a polar-strand secondary structure in solution.22 In contrast with their homo-oligomers, we demonstrated that short peptides based on alternating trans-ACPC and trans-2-aminocyclohexane adopt a 14-helix fold in aqueous SDS solution but not in organic solvents.23 Moreover, cis-ACPC can satisfactorily replace prolines as inducers of β-turns in α-peptides.24,25 Controlled self-assembly of helical homo-oligomers of trans-ACPC in the presence of surfactant gives rise to 3D nanostructures of different shapes.26,27 Accordingly, cyclopentane β-amino acids proved to be ideal candidates for the stabilization of conformations in peptides.

The development of methodologies for the stereo- and regioselective synthesis of polysubstituted cyclopentane rings continues to be a challenge in synthetic chemistry.28−31 A specific goal of this significant area of research is to increase the limited number of known polyhydroxylated cyclopentane β-amino acids3,32,33 that would enable access to a larger variety of hydro- or liposoluble cyclopentane-based β-peptides. This latter goal can be achieved by protection or deprotection of the hydroxyl substituents in polyhydroxylated cyclopentane rings. In addition, it is feasible that these substituents on the cyclopentane rings could result in novel folding properties in β-peptides, which is a matter of evident interest in materials chemistry. Furthermore, polyhydroxylated cyclopentane β-amino acids have potential as clinical drugs33,34 and biological tools.14,35 Also, other molecules containing the polyhydroxylated cyclopentane ring, like some 4-amino-5-(hydroxymethyl)-1,2,3-cyclopentanetriols, have been described as potent glycosidase inhibitors.36−38

The first reported polyhydroxylated cyclopentane β-amino acid was the trans-2-aminocyclopentanecarboxylic acid derivative 3a, which was obtained in our laboratory by a novel approach involving the key stereocontrolled cyclization of d-glucose nitrosugar derivative 1 to bicyclolactone 2 (Scheme 1).39,40 Amino acid 3a was converted into its derivative 3b, which is suitably functionalized for incorporation into peptides.40 Applications of this approach to l-idose nitrosugar derivative 4 provided the first polyhydroxylated cis-2-aminocyclopentanecarboxylic acid 6 (Scheme 1).41 Nevertheless, this strategy turned out unsuitable for preparing peptides based on these β-amino acids due to the low global yields achieved for 3a (12% yield, seven steps), 3b (8% yield, 10 steps), and 6 (15% yield, seven steps). Furthermore, the scope of this synthetic strategy is relatively limited because it can provide direct access to only eight polyhydroxylated cyclopentane β-amino acids, i.e., only those arising from the eight hexoses that meet the stereochemical requirements for the key intramolecular alkylation leading to bicyclic lactones like 2 or 5 (i.e., d-glucose, d-idose, d-allose, d-talose, l-glucose, l-idose, l-allose and l-talose).42

Scheme 1. First Syntheses of Polyhydroxylated Cyclopentane β-Amino Acids.

Scheme 1

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Here, we report a more general and efficient method for the stereocontrolled synthesis of polyhydroxylated cyclopentane β-amino acids from hexoses. This approach is, in principle, of general application to all hexoses and, in consequence, should give access to a larger variety of relative configurations of these β-amino acids. Starting from a conveniently protected hexose, the strategy involves the ring-closing metathesis (RCM)43 reaction of a richly functionalized diene intermediate A leading to cyclopentenol B (Scheme 2), which is then transformed into cyclopentene carboxylic acid derivative C, followed by an aza-Michael amination44 of the α,β-unsaturated carboxylic moiety to give the target highly functionalized β-amino acid D.

Scheme 2. Outline of the Synthesis of Functionalized Cyclopentane β-Amino Acids from Hexoses.

Scheme 2

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P: protecting group.

In order to demonstrate the generality of the method, we synthesized protected polyhydroxylated cyclopentane β-amino acids starting from two hexoses (d-mannose and d-galactose) that cannot give access to them using the previous strategy via nitrosugars. Specifically, starting from d-galactose, we synthesized the derived cyclopentane β-amino acid with two alternative protecting group schemes suitable for the incorporation into peptides. In one case, we observed an unwanted elimination reaction when trying to couple these β-amino acids into peptides as already described in a previous work.40 Finally, we devised an alternative and more general procedure for the successful incorporation of this type of amino acids into peptides.45

Results and Discussion

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 12

In order to demonstrate the feasibility of this strategy with hexoses other than those suitable for the already described intramolecular nitronate cyclization strategy, we synthesized polyhydroxylated cyclopentane β-amino acid derivative 12 from d-mannose (Scheme 3). Selective protection of the primary hydroxyl group of d-mannose derivative 7a(46) with TBDPS and oxidation of its C5 free hydroxyl group with Dess–Martin reactive gave ketone 8. When 8 was submitted to Wittig reaction conditions, a double olefination occurs, one at the ketone group and the other one at the anomeric position, which spontaneously deacetylated in the basic medium of the reaction to give the expected diolefin 9a. Its free hydroxyl group was methylated, and then its silylether was deprotected to give diolefin 9c, which is suitably protected for the RCM reaction.

Scheme 3. Synthesis of Polyhydroxylated Cyclopentane β-Amino acid Derivative 12.

Scheme 3

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Conditions: (i) TBDPSCl, imidazole, CH2Cl2, rt., 15 min. 98%. (ii) Dess–Martin, CH2Cl2, rt., 2 h, 88%. (iii) n-BuLi, Ph3PCH3Br, THF, −78 °C to rt., 2 h, 83%. (iv) NaH, MeI, THF, 0 °C to rt., 4 h, 95%. (v) TBAF, THF, rt., 2 h, 85%. (vi) Grubbs 1st, CH2Cl2, rt., 24 h, 90%. (vii) a: TEMPO, BAIB, NBu4I, CH2Cl2/H2O, rt., 2 h. b: NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, tBuOH/H2O, rt., 1 h. (viii) NaHCO3, MeI, DMF, rt., 12 h, 85% (from 10). (ix) NH2Bn, DMF, rt., 48 h, 91%.

Cyclopentenol 10 was formed in 90% yield from 9c under standard RCM reaction conditions using the first-generation Grubbs catalyst. Then, oxidation of the primary hydroxyl group of 10 gave cyclopentenecarboxylic acid 11a. Reaction of 11a with NaHCO3 and MeI furnished its methyl ester derivative 11b in 85% yield for the last three steps. Finally, treatment of 11b with benzylamine resulted in the expected stereoselective aza-Michael addition on the conjugated double bond, which provided compound 12 in 91% yield. The total yield for the transformation of 7a to 12 was 40% (nine steps). This yield is much higher than that of the similar β-amino acid derivative 3b synthesized from d-glucose by the nitrosugar strategy (8% yield, nine steps).40

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19a

The satisfactory results of our strategy for the transformation of d-mannose into β-amino acid 12 prompted us to apply it to other hexoses, like the transformation of d-galactose into β-amino acid 19a (Scheme 4). The key reaction to build the cyclopentane ring of 19a was the RCM reaction of diolefin 16b, which was prepared from the known d-galactose derivative 13a.47 Olefination of the hemiacetal of 13a followed by the oxidation of the hydroxyl group of 14a gave ketone 15a, which was subjected to a second olefination step to give diolefin 16a (Scheme 4). Removal of the silylether group at the C1 of 16a by treatment with TBAF gave the desired key diolefin 16b. According to our synthetic plan, standard RCM reaction conditions, using the second-generation Grubbs catalyst, gave the expected cyclopentenol 17a in 89% yield. Oxidation of this compound with TEMPO gave cyclopentenecarboxylic acid 18a through the spontaneous oxidation of the intermediate aldehyde. Reaction of acid 18a with NaHCO3 and MeI furnished its methyl ester derivative 18b in 97% yield for the three last steps. The stereoselective aza-Michael addition to the double bond of 18a was performed with p-methoxybenzylamine (PMBNH2), instead of benzylamine (Scheme 3), to enable the selective deprotection of the amino group of 19a in the presence of the OBn substituents. The total yield of the transformation of 13a into 19a was 34% for the eight steps.

Scheme 4. Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19a.

Scheme 4

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Conditions: (i) n-BuLi, Ph3PCH3Br, THF, −78 °C to rt., 12 h, 80%. (ii) Dess–Martin, CH2Cl2, rt., 2 h, 82%. (iii) n-BuLi, Ph3PCH3Br, THF, −78 °C to rt., 12 h, 85%. (iv) TBAF, THF, rt., 1 h, 87%, (v) Grubbs 2nd, toluene, reflux, 24 h, 89%. (vi) a: TEMPO, BAIB, NBu4I, CH2Cl2/H2O, rt., 2 h. b: NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene. (vii) NaHCO3, MeI, DMF, rt., 12 h, 97% (from 17a). (viii) PMBNH2, DMF, rt., 24 h, 80%.

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19b

Next, we devised a different protection pattern for the same hexose that led to the β-amino acid derivative 19b (Scheme 5), which has its cis hydroxy substituents protected with an isopropylidene substituent. This alternative protecting scheme would open the possibility of selective deprotection of chosen hydroxyl groups. Furthermore, this substitution pattern allows us to compare the efficacy of this synthetic strategy with the one previously reported by us, which had led to the enantiomer (except for the protection of the N atom, Bn or Cbz) of 19b through a modification of the intramolecular nitronate cyclization strategy.48

Scheme 5. Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19b.

Scheme 5

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Conditions: (i) NaH, MeI, THF, 0 °C to rt., 4 h, 93%. (ii) NH4HCO2, Pd/C, MeOH, rt., 12 h, 86%. (iii) n-BuLi, Ph3PCH3Br, THF, −78 °C to rt., 12 h, 80%. (iv) Dess–Martin, CH2Cl2, rt., 24 h, 81%. (v) n-BuLi, Ph3PCH3Br, THF, −78 °C to rt., 2 h, 93%. (vi) TBAF, THF, rt., 1 h, 82%. (vii) Grubbs 1st, CH2Cl2, rt., 24 h, 92%. (viii) a: TEMPO, BAIB, NBu4I, CH2Cl2/H2O, rt., 2 h. b: NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene. (ix) NaHCO3, MeI, DMF, rt., 12 h, 82% (from 18c). (x) NH2Bn, DMF, rt., 24 h, 80%.

Accordingly, reaction of d-galactose derivative 13b(49) with methyl iodide gave its O-methylated derivative 13c, which was then converted into the anomeric mixture 13d and then into the key diene 16d, via compounds 14b, 15b, and 16c (Scheme 5), following the protocol leading to its analog 16b (Scheme 4). Next, diene 16d was subjected to standard RCM reaction conditions to yield the desired cyclopentenol 17b in 92% yield. In contrast to cyclization of diene 16b, this reaction was effective using the first-generation Grubbs catalyst, probably because the steric hindrance is now lower. Compound 17b was next converted into cyclopentene carboxylic acid 18c and then into its ester 18d. The stereoselective aza-Michael addition of BnNH2 led to the cyclopentane β-amino acid derivative 19b. This synthesis is noticeably more efficient (24% yield from 13b to 19b, 10 steps) than the previously described synthesis of the enantiomer (except for the protection of the N atom, Bn or Cbz) of 19b from its nitrosugar precursor 1 (8% yield, nine steps).48

It is worth comparing the yields of the two critical steps (ring-closing metathesis and aza-Michael addition) in the above-described synthetic sequences (Schemes 3 to 5). Although all these yields are reasonably high (80–92%), an attempt to justify the differences can be done. Regarding the RCM reaction, the more reactive second-generation Grubbs catalyst was needed for the transformation 16b → 17a (Scheme 4), i.e., with the galactose derivative with its hydroxyls protected with benzyl groups. The reason cannot be the configuration of the starting hexose as the mannose 9c (Scheme 3) and galactose 16d (Scheme 5) derivatives, which have less bulky protecting groups, reacted equally well with the less reactive first-generation Grubbs catalyst. It is unclear if the ultimate reason is the steric hindrance of the relatively bulky benzyl groups of 16b or if it is a consequence of the restrained conformational flexibility of intermediates 9c and 16d due to the protection of their cis-diols as cyclic acetonides; perhaps this might place the double bonds in a position more favorable for the reaction with the less reactive first-generation Grubbs catalyst.

Regarding the aza-Michael step, the yields are similar for the transformations of the galactose derivatives 18b → 19a (80%; Scheme 4) and 18d → 19b (80%; Scheme 5), while the yield of the mannose derivatives 11b → 12 reaches 91% (Scheme 3). The amine approximates the double bond from the side opposite to the C3 −OR substituent in all cases. That face of the double bond is more hindered in the galactose derivatives (Schemes 4 and 5) than in the mannose derivative (Scheme 3), and this could explain the difference in yield.

Synthesis of Tripeptide 21

Next, to demonstrate the usefulness of the orthogonally protected polyhydroxylated cyclopentane β-amino acids synthesized, we studied the feasibility of their incorporation into short peptide chains by peptide coupling reactions (Schemes 6 and 7). With this purpose, removal of the PMB-protecting group of 19a with CAN gave the free amine intermediate 19c, which was directly reacted with (Boc)2O to furnish the orthogonally protected β-amino acid ester 19d in 75% yield in the two steps (Scheme 6). Hydrolysis of the methoxycarbonyl group of compound 19d under mild basic conditions was followed by treatment of the resulting carboxylic acid 19e with HATU as activating reagent and then with glycine hydrochloride. Dipeptide 20a was isolated in 60% yield (two steps). The N-Boc group was easily cleaved with TFA, and the resulting amine 20b was reacted with Boc-Gly-OH upon activation with HATU. This furnished tripeptide 21 in 25% yield from 19a (six steps).

Scheme 6. Incorporation of Polysubstituted Cyclopentane β-Amino Acid 19a into Peptide 21.

Scheme 6

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Conditions: (i) CAN, CH3CN/H2O, 0 °C to rt., 6 h, (ii) (Boc)2O, NaHCO3, rt., 18 h, 75% (from 19a), (iii) Ba(OH)2·8 H2O, THF/H2O, rt., 1 h. (iv) HCl·HGly-OMe, HATU, DIEA, CH2Cl2, rt., 14 h 60% (from 19d). (v) TFA, THF, rt., 1 h. (vi) Boc-Gly-OH, HATU, DIEA CH2Cl2, rt., 10 h, 55% (from 20a).

Scheme 7. Protocol for the Incorporation of Polysubstituted Cyclopentane β-Amino Acid 19b into Peptide 24.

Scheme 7

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Conditions: (i) HO(CH2)2SiMe3, DMAP, DCC, CH2Cl2, rt., 12 h, 77%. (ii) BnNH2, DMF, rt., 60 h, 69%. (iii) TBAF, THF, rt., 24 h. (iv) 22a, PyBOP, HOBt, DIEA, DMF, 43% (two steps). (v) H2, Pd(OH)2/C 20%, MeOH, overnight. (vi) 22b, PyBOP, HOBt, DIEA, DMF, 59% (two steps).

Synthesis of Pentapeptide 24

Incorporation of 19b into peptides is more problematic, as hydrolysis of its methyl ester in basic conditions is usually accompanied by the beta elimination of the −OR substituent contiguous to the carboxymethyl alpha position as we previously reported for two analogs of the enantiomer of 19b.40 The solution we devised here involves protecting the carboxylic acid group as trimethylsilylethyl ester (18e; Scheme 7) instead of the methyl ester 18d shown in Scheme 5. This choice of protecting group is made on intermediate 18c prior to the aza-Michael addition. So, starting from carboxylic acid 18c, esterification with trimethylsilylethanol provided the expected cyclopentenecarboxylic acid ester 18e,50 which furnished β-amino acid derivative 19f when subjected to the aza-Michael addition using benzylamine as the nucleophile. Hydrolysis of this ester 19f under mild basic conditions with TBAF resulted in carboxylic acid 19g, which was efficiently transformed into tripeptide 23a by direct coupling with dipeptide 22a.51 Removal of the N-benzyl-protecting group of 23a, by catalytic hydrogenation, provided its free amino derivative 23b, which gave pentapeptide 24 when reacted with dipeptide 22b under the stated coupling conditions. The overall yield from 18c was 14% (six steps).

In conclusion, we present here a promising approach to the stereocontrolled synthesis of highly complex cyclopentane β-amino acids. This method is more general and efficient than the previously reported alternative from nitrosugars as it could be extended, in principle, to the pool of hexoses. To demonstrate the generality of the method, we applied it to two different hexoses (d-mannose and d-galactose) and with two alternative protecting patterns in the case of d-galactose. This allowed us to synthesize, in the gram scale, three new β-amino acids (12, 19a, and 19b), which are orthogonally protected for their incorporation into peptides. This method opens up opportunities for a new access to 4-amino-5-(hydroxymethyl)-1,2,3-cyclopentanetriols (potent glycosidase inhibitors) by reduction of the methoxycarbonyl group to hydroxymethyl. Furthermore, we have demonstrated how to incorporate these β-amino acids into peptide chains using classical procedures. In the case of those amino acids that present problems by classical methods, we have also developed an alternative procedure for their incorporation into peptides. The availability of more richly functionalized cyclopentane β-amino acids, like the ones shown here, would expand the opportunities of designing a larger variety of hydro- or liposoluble β-peptides. We continue working in the synthesis of monomers and peptides containing hydroxylated groups as well as studying their potential applications in biological chemistry, new materials, and catalysis. As preliminary studies, our immediate plans are directed toward the synthesis of amphiphilic β-peptides of this nature as potential ice recrystallization inhibitors and gelling agents, which are two issues of great present interest.

Experimental Section

General Information

All nonaqueous reactions were carried out under a positive atmosphere of argon in flame-dried glassware unless otherwise stated. Air- and moisture-sensitive liquid reagents were added by dry syringe or cannula. Anhydrous tetrahydrofuran (THF) was freshly distilled from sodium/benzophenone under argon, and all other solvents and reagents were used as obtained from commercial sources without further purification unless stated. Flash chromatography was performed using 60 Merck 230–400 mesh (flash, 0.04–0.063) silica. Thin-layer chromatography (tlc) was carried out on aluminium-backed sheets coated with 60 GF254 silica. Plates were developed using a spray of 0.2% w/v cerium(IV) sulfate and 5% ammonium molybdate in 2 M sulfuric acid or in 5% w/v ninhydrin in methanol. 1H and 13C NMR spectra were recorded on Bruker DPX 250 (250 MHz for 1H and 62.5 MHz for 13C) and Varian Mercury 300 (300 MHz for 1H and 75 MHz for 13C) spectrometers at room temperature unless otherwise stated. All chemical shifts are quoted on the δ scale using residual solvent as internal standard; s, d, t, q, m, and br designate singlet, doublet, triplet, quadruplet, multiplet, and broad, respectively. Coupling constants (J) are measured in Hz. Mass spectra were recorded on a Micromass VG-Autospec spectrometer [by chemical ionization (NH3, CI) or electrospray techniques, as stated]. Infrared spectra were recorded on a FT-IR Mattson Cygnus-100 spectrometer. Only the characteristic peaks are quoted (in units of cm–1); st, m, and br designate strong, medium, and broad, respectively. All the spectra were measured in KBr unless stated. Optical rotations were measured on a Jasco DIP-370 polarimeter with a path length of 0.5 dm and in a Na (589 nm) lamp. Concentrations are given in g/100 mL. Elemental analyses were carried out on a Carlo Erba EA 1108 analyzer.

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 12

(3aS,4R,6R,6aS)-6-((R)-2-((tert-Butyldiphenylsilyl)oxy)-1-hydroxyethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl Acetate (7b)

A solution of imidazole (7.04 g, 103.33 mmol), TBDPSCl (12.7 mL, 49.6 mmol), and compound 7a (10.84 g, 41.33 mmol) in CH2Cl2 (83 mL) was stirred at rt. for 15 min and then washed with water (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. Solid residue was purified by flash column chromatography (EtOAc/hexane 1:3) and provided 7b (20.28 g, 40.51 mmol, 98% yield) as a white solid. Mp 88–89 °C (CH2Cl2/hexane). [α]D22 = +19.1 (c 1.9, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.06 (s, 9H), 1.35 (s, 3H), 1.46 (s, 3H), 2.02 (s, 3H), 2.78 (br, 1H), 3.85–3.89 (m, 2H), 4.00–4.10 (m, 1H), 4.19 (dd, 1H, J4,5 = 8.2, J4,3 = 3.3 Hz), 4.70 (d, 1H, J2,3 = 5.8 Hz), 4.94 (dd, 1H, J3,2 = 5.8 Hz, J3,4 = 3.3 Hz), 6.17 (s, 1H), 7.35–7.47 (m, 6H), 7.63–7.70 (m, 4H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 18.8, 20.4, 24.4, 25.6, 26.3, 64.7, 68.8, 79.3, 80.2, 84.3, 100.1, 112.4, 127.3, 129.3, 132.4, 132.6, 135.0, 168.8. IR (NaCl, cm–1): ν 3593 (br, OH), 1746 (st, C=O), 1111 (st, Si-O-C). MS (CI, m/z, %): 501 (8, [M + H]+), 484 (60), 444 (100). Anal. calc. for C27H36O7Si: C, 64.77; H, 7.25. Found: C, 64.67; H, 7.33.

(3aS,4R,6S,6aR)-6-(2-((tert-Butyldiphenylsilyl)oxy)acetyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl Acetate (8)

A solution of compound 7b (11.27 g, 22.51 mmol) in CH2Cl2 (106 mL) was stirred with Dess–Martin periodinane (12.41 g, 29.26 mmol) for 2 h at room temperature. The mixture was quenched with saturated aq. Na2S2O3 (50 mL) and extracted with Et2O (50 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/hexane 1:4) and provided compound 8 (9.88 g, 19.81 mmol, 88%) as a white solid. Mp 55–56 °C (CH2Cl2/hexane). [α]D21 = −3.5 (c 1.6, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.10 (s, 9H), 1.25 (s, 3H), 1.27 (s, 3H), 2.06 (s, 3H), 4.47 (s, 2H), 4.68 (d, 1H, J2,3 = 5.8 Hz), 4.85 (d, 1H, J4,3 = 4.1 Hz), 5.20 (dd, 1H, J3,2 = 5.8 Hz, J3,4 = 4.1 Hz), 6.22 (s, 1H), 7.34–7.44 (m, 6H), 7.65–7.70 (m, 4H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 18.9, 20.5, 24.2, 25.3, 26.4, 68.6, 80.0, 83.8, 85.5, 100.0, 113.1, 127.4, 127.5, 129.5, 129.6, 132.1, 132.2, 135.1, 135.2, 168, 202.0. IR (NaCl, cm–1): ν 1745 (st, C=O), 1113 (st, Si-O-C). MS (CI, m/z, %): 499 (15, [M + H]+), 484 (27), 440 (100). Anal. calc. for C27H34O7Si: C, 65.04; H, 6.87. Found: C, 65.21; H, 7.08.

(R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-1-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (9a)

A suspension of Ph3PCH3Br (1.48 g, 4.15 mmol) in dry THF (5 mL) was cooled to −78 °C under argon, n-BuLi (1.5 mL, 3.82 mmol, 2.5 M solution in hexane) was added dropwise, and the mixture was stirred at −78 °C for 30 min and at 0 °C for 30 min. A solution of 8 (0.76 g, 1.66 mmol) in THF (5 mL) was added dropwise to the resulting ylide at −78 °C, and the new reaction mixture was allowed to warm up to room temperature and then heated under reflux for 12 h. The mixture was quenched with saturated aq. NH4Cl (10 mL) and extracted with Et2O (20 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc/hexane 1:12) to afford compound 9a (0.64 g, 1.42 mmol, 85%) as a yellowish oil. [α]D20 = −16.1 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.05 (s, 9H), 1.37 (s, 3H), 1.52 (s, 3H), 2.52 (d, 1H, JOH,3 = 6.6 Hz), 4.17 (dd, 1H, J3,OH = 6.6 Hz, J3,4 = 4.4 Hz), 4.27 (br, 2H), 4.31 (dd, 1H, J4,5 = 6.9 Hz, J4,3 = 4.4 Hz), 4.57 (dd, 1H, J5,6 = 7.7 Hz, J5,4 = 6.9 Hz), 5.21 (dd, 1H, J7a,6 = 10.1 Hz, J7a,7b = 1.4 Hz), 5.24 (d, 1H, J1a,1b = 1.7 Hz), 5.28 (dd, 1H, J7b,6 = 17.3 Hz, J7b,7a = 1.4 Hz), 5.31 (d, 1H, J1b,1a = 1.7 Hz), 6.00 (ddd, 1H, J6,7b = 17.3 Hz, J6,7a = 10.1 Hz, J6,5 = 7.7 Hz), 7.36–7.44 (m, 6H), 7.65–7.70 (m, 4H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 19.0, 24.7, 26.6, 27.0, 64.7, 70.4, 78.7, 78.9, 108.4, 112.7, 118.9, 127.5, 129.6, 133.0, 133.9, 135.3, 146.5. IR (NaCl, cm–1): ν 3514 (br, OH), 1112 (st, Si-O-C). MS (CI, m/z, %): 453 (5, [M + H]+), 379 (20), 198 (100). Anal. calc. for C27H36O4Si: C, 71.64; H, 8.02. Found: C, 71.29; H, 8.14.

tert-Butyl((2-((R)-((4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)(methoxy)methyl)allyl)oxy)-diphenylsilane (9b)

Sodium hydride (0.36 g, 9.05 mmol, 60%) was added in small portions over a 0 °C cooled solution of 9a (2.73 g, 6.03 mmol) in 24 mL of dry THF. Once the hydrogen bubbles ceased, methyl iodide (0.71 mL, 11.46 mmol) was added, and the reaction was stirred at room temperature for 4 h. Water (20 mL) was then added, and the mixture was extracted with EtOAc (20 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and evaporated in vacuo to give compound 9b (2.67 g, 5.73 mmol, 95%) as a pure colorless oil. [α]D20 = −18.6 (c 1.1, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.00 (s, 9H), 1.31 (s, 3H), 1.47 (s, 3H), 3.30 (s, 3H), 3.83 (d, 1H, J3,4 = 4.3 Hz), 4.28–4.30 (m, 2H), 4.35 (dd, 1H, J4,5 = 6.0 Hz, J4,3 = 4.3 Hz), 4.63 (dd, 1H, J5,6 = 7.7 Hz, J5,4 = 6.0 Hz), 5.18 (dd, 1H, J7a,6 = 10.5 Hz, J7a,7b = 1.6 Hz), 5.22 (d, 1H, J1a,1b = 1.4 Hz), 5.26 (dd, 1H, J7b,6 = 17.1 Hz, J7b,7a = 1.6 Hz), 5.32 (d, 1H, J1b,1a = 1.4 Hz), 5.97 (ddd, 1H, J6,7b = 17.1 Hz, J6,7a = 10.5 Hz, J6,5 = 7.2 Hz), 7.37–7.46 (m, 6H), 7.59–7.63 (m, 4H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 19.2, 25.0, 26.5, 27.4, 54.7, 65.1, 70.0, 79.0, 80.4, 108.1, 112.4, 119.7, 127.9, 129.3, 132.5, 133.3, 134.7, 146.7. IR (NaCl, cm–1): ν 1115 (st, Si-O-C). MS (CI, m/z, %): 467 (25, [M + H]+), 436 (88), 410 (100). Anal. calc. for C28H38O4Si: C, 72.06; H, 8.21. Found: C, 71.96; H, 8.15.

2-((R)-((4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)(methoxy)-methyl)prop-2-en-1-ol (9c)

Compound 9b (1.66 g, 3.56 mmol) was dissolved in THF (10.7 mL) and stirred with TBAF (4.3 mL, 4.3 mmol, 1 M solution in THF) at room temperature for 2 h. The reaction mixture was treated with saturated aq. NH4Cl (25 mL) and extracted with Et2O (25 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated to dryness. The crude product was subjected to flash column chromatography (EtOAc/hexane 1:4) to afford compound 9c (0.69 g, 3.02 mmol, 85%) as a yellowish oil. [α]D19 = −27.3 (c 1.4, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.40 (s, 3H), 1.56 (s, 3H), 2.85 (br, 1H), 3.24 (s, 3H), 3.64 (d, 1H, J3,4 = 4.1 Hz), 4.08 (d, 1H, J1a,1b = 13.0 Hz), 4.20 (d, 1H, J1b,1a = 13.0 Hz), 4.27 (dd, 1H, J4,5 = 6.8 Hz, J4,3 = 4.1 Hz), 4.60 (dd, 1H, J5,6 = 8.2 Hz, J5,4 = 6.8 Hz), 5.13 (d, 1H, J2’a,2’b = 1.4 Hz), 5.29 (dd, 1H, J7b,6 = 17.3 Hz, J7b,7a = 1.7 Hz), 5.34 (dd, 1H, J7a,6 = 10.2 Hz, J7a,7b = 1.7 Hz), 5.36 (d, 1H, J2’b,2’a = 1.4 Hz,), 5.96 (ddd, 1H, J6,7b = 17.3 Hz, J6,7a = 10.2 Hz, J6,5 = 8.2 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.6, 26.3, 54.8, 60.8, 78.2, 78.7, 81.1, 107.9, 115.1, 117.9, 133.5, 143.9. IR (NaCl, cm–1): ν 3462 (br, OH). MS (CI, m/z, %): 229 (13, [M + H]+), 171 (12), 166 (100). Anal. calc. for C12H20O4: C, 63.14; H, 8.83. Found: C, 62.85; H, 8.67.

((3aR,4R,6aR)-4-Methoxy-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-5-yl)methanol (10)

Grubbs first-generation catalyst (0.12 g, 0.15 mmol) was added to a deoxygenated solution of compound 9c (0.69 g, 3.02 mmol) in Cl2CH2 (91 mL), and the mixture was refluxed under argon for 24 h. Then, the mixture was concentrated to dryness under reduced pressure, and the crude product was purified by flash column chromatography (EtOAc/hexane 1:1) to provide compound 10 (0.55 g, 2.72 mmol, 90%) as a yellow oil. [α]D18 = +31.7 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.38 (s, 3H), 1.43 (s, 3H), 2.15 (br, 1H), 3.50 (s, 3H), 4.36 (d, 1H, J1’a,1’b = 13.7 Hz), 4.38 (d, 1H, J1’b,1’a = 13.7 H), 4.39 (s, 1H), 4.61 (d, 1H, J4,3 = 5.8 Hz), 5.20 (d, 1H, J3,4 = 5.8 Hz), 5.91 (s, 1H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.8, 26.5, 56.5, 58.7, 82.4, 82.6, 89.0, 110.9, 127.3, 146.4. IR (NaCl, cm–1): ν 3448 (br, OH). MS (CI, m/z, %): 201 (12, [M + H]+), 158 (15), 127 (100). Anal. calc. for C10H16O4: C, 59.98; H, 8.05. Found: C, 59.73; H, 8.21.

Methyl (3aR,4R,6aR)-4-methoxy-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate (11b)

To a solution of compound 10 (0.55 g, 2.72 mmol) in CH2Cl2/H2O (19 mL, 3:1), NBu4I (0.05 g, 0.14 mmol), TEMPO (0.09 g, 0.54 mmol), and DAIB (2.19 g, 6.81 mmol) were added. The mixture was stirred at room temperature for 2 h, quenched with saturated aq. Na2S2O3 (35 mL), and extracted with EtOAc (30 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. The crude product was dissolved in tBuOH (13.6 mL) and 2-methyl-2-butene (2,02 mL, 19.05 mmol), and a solution containing NaClO2 (0.40 g, 3.54 mmol, 80%) and NaH2PO4·H2O (0.55 g, 3.54 mmol) in water (13.6 mL) was added. The mixture was stirred at room temperature for 1 h, quenched with 10% aq. HCl (20 mL), and extracted with EtOAc (20 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. To a solution of the resulting carboxylic acid in dry DMF (13.6 mL), NaHCO3 (0.43 g, 5.17 mmol) and MeI (0.42 mL, 6.81 mmol) were added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with NH4Cl (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. Flash column chromatography of the crude (EtOAc/hexane 1:4) furnished compound 11b (0.53 g, 2.31 mmol, 85% yield from 10) as a colorless oil. [α]D18 = −16.1 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.36 (s, 3H), 1.38 (s, 3H), 3.51 (s, 3H), 3.80 (s, 3H), 4.54 (d, 1H, J5,4 = 1.6 Hz), 4.61 (d, 1H, J3,4 = 5.2 Hz), 5.43 (dd, 1H, J4,3 = 5.2 Hz, J4, = 1.6 Hz), 6.80 (s, 1H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 25.1, 26.7, 51.2, 57.4, 81.9, 82.8, 86.9, 111.2, 136.4, 144.0, 163.0. IR (NaCl, cm–1): ν 1726 (st, C=O). MS (CI, m/z, %): 229 (7, [M + H]+), 197 (8), 186 (100). Anal. calc. for C11H16O5: C, 57.89; H, 7.07. Found: C, 57.73; H, 7.01.

Methyl (3aR,4S,5S,6R,6aS)-4-(benzylamino)-6-methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-5-carboxylate (12)

Benzylamine (0.72 mL, 6.60 mmol) was added over a solution of compound 11b (1.26 g, 5.50 mmol) in dry DMF (16.5 mL), and the resulting solution was stirred at room temperature for 48 h. The reaction mixture was then poured into a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and evaporated in vacuo. The resulting residue was submitted to flash column chromatography (EtOAc/hexane 1:3), to give compound 12 (1.67 g, 4.98 mmol, 91% yield) as a pale yellow oil. [α]D17 = −56.8 (c 1.8, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.31 (s, 3H), 1.47 (s, 3H), 1.92 (br, 1H), 2.86 (dd, 1H, J1,2 = 8.8 Hz, J1,5 = 7.9 Hz), 3.41 (s, 3H), 3.43 (dd, 1H, J2,1 = 8.8 Hz, J2,3 = 2.7 Hz), 3.72 (s, 3H), 3.77 (d, 1H, JH,H′ = 13.0 Hz), 3.91 (d, 1H, JH,H′ = 13.0 Hz), 4.06 (dd, 1H, J5,1 = 7.9 Hz, J5,4 = 2.5 Hz), 4.47–4.55 (m, 2H), 7.24–7.35 (m, 5H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.5, 26.3, 51.2, 51.6, 54.3, 57.1, 64.3, 83.2, 84.4, 86.1, 112.4, 126.5, 127.7, 127.9, 139.5, 171.8. IR (NaCl, cm–1): ν 3325 (br, NH), 1737 (st, C=O). MS (CI, m/z, %): 336 (100, [M + H]+), 304 (22), 262 (27). Anal. calc. for C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C, 64.17; H, 7.53; N, 4.04.

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19a

(2R,3S,4R,5S)-3,4,5-Tris(benzyloxy)-1-(tert-butyldimethylsilyloxy)hept-6-ene-2-ol (14a)

A suspension of Ph3PCH3Br (7.99 g, 22.36 mmol) in dry THF (37.3 mL) was cooled to −78 °C under argon, and n-BuLi (14 mL, 22.36 mmol, 1.6 M solution in hexane) was added dropwise. The mixture was stirred at −78 °C for 30 min and at 0 °C for 30 min. A solution of 13a (4.21 g, 7.45 mmol) in THF (37.3 mL) was added dropwise to the resulting ylide at −78 °C, and the new reaction mixture was allowed to warm up to room temperature and then heated under reflux for 12 h. The mixture was quenched with saturated aq. NH4Cl (50 mL) and extracted with Et2O (100 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/hexane 1:9) to afford compound 14a (3.36 g, 5.96 mmol, 80% yield) as a yellowish oil. [α]D20 = −2.1 (c 1.7, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.02 (s, 6 H), 0.88 (s, 9 H); 3.06 (d, 1 H, J = 4.9 Hz), 3.56–3.62 (m, 2 H), 3.79–3.97 (m, 3 H), 4.08 (dd, 1 H, J = 7.9 Hz, J = 4.9 Hz), 4.35 (d, 1 H, J = 11.8 Hz); 4.43 (d, 1 H, J = 11.5 Hz); 4.50 (d, 1 H, J = 11.5 Hz); 4.65 (d, 1 H, J = 11.8 Hz), 4.76 (br, 2 H), 5.30 (dd, 1 H, J = 17.5, 1.6 Hz), 5.35 (dd, 1H, J = 10.5, 1.6 Hz), 5.84 (ddd, 1 H, J = 17.6, 10.4, 7.9 Hz), 7.22–7.38 (m, 15 H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.5, −5.4, 18.1, 25.8, 63.3, 70.2, 71.2, 73.2, 75.2, 75.7, 80.9, 82.3, 119.1, 127.4, 127.5, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 135.5, 138.1, 138.2, 138.3. MS (CI, m/z, %): 563 (18, [M + H]+); 456 (23); 91 (100). IR (NaCl, cm–1): ν 3492 (br, OH), 1104 (st, Si-O-C). Anal. Calc. for C34H46O5Si: C 72.56; H 8.24. Found: C 72.49; H 8.49.

(3R,4R,5S)-3,4,5-Tris(benzyloxy)-1-((tert-butyldimethylsilyl)oxy)hept-6-en-2-one (15a)

After compound 14a (1.86 g, 3.31 mmol) was subjected to the procedure for the preparation of 8, flash column chromatography of the crude reaction product (EtOAc/hexane 1:15) provided compound 15a (1.52 g, 2.72 mmol, 82% yield) as a yellowish oil. [α]D21 = +20.7 (c 1.9, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ – 0.03 (s, 3H), 0.00 (s, 3H), 0.87 (s, 9H), 3.87 (dd, 1H, J = 6.3, 4.4 Hz), 4.12 (dd, 1H, J = 7.1, 6.3 Hz), 4.22 (d, 1H, J = 4.4 Hz), 4.38 (d, 1H, J = 11.8 sHz), 4.45 (d, 2H, J = 10.2 Hz), 4.46 (br, 2H), 4.60 (d, 1H, J = 11.0 Hz), 4.62 (d, 1H, J = 11.8 Hz), 4.75 (d, 1H, J = 11.0 Hz), 5.35 (dd, 1H, J = 17.3, 1.7 Hz), 5.40 (dd, 1H, J = 10.5, 1.7 Hz), 5.84 (ddd, 1H, J = 17.3, 10.5, 7.1 Hz), 7.21–7.38 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.8, −5.6, 18.1, 25.6, 68.9, 70.4, 72.2, 74.7, 80.5, 81.4, 82.6, 119.2, 127.2, 127.3, 127.5, 127.6, 127.8, 127.9, 128.0, 128.1, 134.9, 136.9, 137.8, 138.0, 208.0. MS (CI, m/z, %): 561 (85, [M + H]+); 454 (100), 91 (90). IR (NaCl, cm–1): ν 1735 (st, C=O), 1091 (st, Si-O-C). Anal. Calc. for C34H44O5Si: C 72.82; H 7.91. Found: C 72.66; H 8.03.

(3S,4R,5S)-3,4,5-Tris(benzyloxy)-1-(tert-butyldimethylsilyloxy)-2-methylenhept-6-ene (16a)

A suspension of Ph3PCH3Br (4.01 g, 11.23 mmol) in dry THF (11.2 mL) was cooled to −78 °C under argon, and n-BuLi (6.8 mL, 10.86 mmol, 1.6 M solution in hexane) was added dropwise. The mixture was stirred at −78 °C for 30 min and at 0 °C for 30 min. A solution of compound 15a (2.10 g, 3.75 mmol) in THF (11.2 mL) was added dropwise to the ylide at −78 °C. The reaction mixture was allowed to warm up to room temperature and was stirred for 2 h. The mixture was quenched with saturated aq. NH4Cl (25 mL) and extracted with Et2O (50 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated in vacuo. Flash column chromatography of the crude product (EtOAc/hexane 1:19) afforded compound 16a (1.78 g, 3.18 mmol, 85% yield) as a yellowish oil. [α]D20 = +19.3 (c 1.4, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.02 (s, 3H), 0.03 (s, 3H), 0.91 (s, 9H), 3.59 (dd, 1H, J = 7.6, 3.8 Hz), 4.10 (d, 1H, J = 11.0 Hz), 4.12 (dd, 1H, J = 7.8, 7.6 Hz), 4.13 (d, 1H, J = 12.1 Hz), 4.25 (br, 2H), 4.32 (d, 1H, J = 12.1 Hz), 4.45 (d, 1H, J = 11.3 Hz), 4.57 (d, 1H, J = 11.0 Hz), 4.60 (d, 1H, J = 3.8 Hz), 4.63 (d, 1H, J = 11.3 Hz), 5.25 (dd, 1H, J = 17.6, 1.9 Hz), 5.28 (d, 1H, J = 1.9 Hz), 5.32 (dd, 1H, J = 10.4, 1.9 Hz), 5.48 (d, 1H, J = 1.9 Hz), 5.89 (ddd, 1H, J = 17.6, 10.4, 7.7 Hz), 7.16–7.36 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.5, 18.2, 25.9, 63.4, 70.0, 70.4, 74.9, 79.2, 80.1, 83.7, 113.4, 118.2, 127.3, 127.4, 127.6, 127.9, 128.0, 128.1, 136.1, 138.2, 138.3, 138.4, 146.4. MS (CI, m/z, %): 559 (15, [M + H]+); 468 (66); 91 (100). IR (NaCl, cm–1): ν 1099 (st, Si-O-C). Anal. calc. for C35H46O4Si: C 75.23; H 8.30. Found: C 75.37; H 8.20.

(3S,4R,5S)-3,4,5-Tris(benzyloxy)-2-methylenhept-6-ene-1-ol (16b)

Compound 16a (1.78 g, 3.18 mmol) was dissolved in THF (15.9 mL) and stirred with TBAF (3.8 mL, 3.8 mmol, 1 M solution in THF) at room temperature for 1 h. The reaction mixture was treated with saturated aq. NH4Cl (25 mL) and extracted with Et2O (25 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated to dryness. The crude product was subjected to flash column chromatography (EtOAc/hexane 1:4) to afford compound 16b (1.23 g, 2.77 mmol, 87% yield) as a yellowish oil. [α]D19 = +26.8 (c 1.3, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 2.85 (dd, 1H, J = 7.4, 5.2 Hz), 2.72 (t, 1H, J = 5.8 Hz), 4.04 (dd, 1H, J = 7.9, 7.4 Hz), 4.10–4.22 (m, 3H), 4.15 (d, 1H, J = 11.5 Hz), 4.34 (d, 1H, J = 12.1 Hz), 4.45 (d, 1H, J = 11.5 Hz), 4.62 (d, 1H, J = 12.1 Hz), 4.69 (d, 1H, J = 11.0 Hz), 4.76 (d, 1H, J = 11.0 Hz), 5.22 (dd, 1H, J = 17.3, 1.9 Hz), 5.29 (d, 1H, J = 1.9 Hz), 5.35 (dd, 1H, J = 10.4, 1.9 Hz), 5.38 (d, 1H, J = 1.9 Hz), 5.84 (ddd, 1H, J = 17.3, 10.4, 7.9 Hz), 7.20–7.34 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 62.6, 69.7, 70.2, 75.1, 79.9, 80.3, 83.4, 116.4, 118.5, 127.1, 127.3, 127.6, 127.8, 127.9, 128.0, 135.3, 137.7, 137.8, 138.0, 145.4. MS (CI, m/z, %): 445 (54, [M + H]+); 231 (64); 91 (100). IR (NaCl, cm–1): ν 3450 (br, OH). Anal. calc. for C29H32O4: C 78.35; H 7.26. Found: C 78.53; H 7.50.

(3S,4R,5S)-1-Hydroxymethyl-3,4,5-tris(benzyloxy)cyclopent-1-ene (17a)

Grubbs second-generation catalyst (0.12 g, 0.14 mmol) was added to a deoxygenated solution of compound 16b (1.23 g, 2.77 mmol) in toluene (83 mL), and the mixture was refluxed under argon for 24 h. The reaction mixture was concentrated to dryness under a vacuum. The crude product was purified by flash column chromatography (EtOAc/hexane 1:2) to provide compound 17a (1.03 g, 2.46 mmol, 89% yield) as a yellow oil. [α]D19 = +19.5 (c 1.7, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.70 (br, 1H); 4.03 (dd, 1H, J = 5.8, 4.1 Hz), 4.16 (d, 1H, J = 14.5 Hz), 4.25 (d, 1H, J = 14.5 Hz), 4.53 (d, 1H, J = 11.3 Hz), 4.63 (d, 1H, J = 11.3 Hz), 4.64 (d, 1H, J = 10.4 Hz), 4.67 (d, 1H, J = 11.8 Hz), 4.68 (d, 1H, J = 10.4 Hz), 4.71 (d, 1H, J = 5.8 Hz), 4.74 (d, 1H, J = 11.8 Hz), 4.77 (dd, 1H, J = 4.1, 1.4 Hz), 5.94 (d, 1H, J = 1.4 Hz), 7.28–7.40 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 59.7, 71.0, 71.4, 71.9, 78.7, 83.8, 86.0, 125.1, 127.4, 127.5, 127.6, 127.8, 128.0, 128.1, 137.8, 137.9, 138.1, 146.7. MS (CI, m/z, %): 417 (4, [M + H]+); 400 (63); 91 (100). IR (NaCl, cm–1): ν 3301 (br, NH), 1757 (st, C=O). Anal. calc. for C27H28O4: C 77.86; H 6.78. Found: C 77.70; H 6.92.

Methyl (3S,4R,5S)-3,4,5-tris(benzyloxy)cyclopent-1-ene-1-carboxylate (18b)

Compound 17a (1.03 g, 2.46 mmol) was subjected to the procedure for the preparation of compound 11b. Compound 18b (1.06 g, 2.39 mmol, 97% yield from 17a, two steps) was obtained as a colorless oil after flash column chromatography (EtOAc/hexane 1:6). [α]D20 = +17.3 (c 1.2, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 3.72 (s, 3H), 3.98 (dd, 1H, J = 5.8, 4.3 Hz), 4.56 (d, 1H, J = 11.8 Hz), 4.64–4.80 (m, 6H), 4.98 (d, 1H, J = 5.8 Hz), 7.02 (d, 1H, J = 1.4 Hz), 7.28–7.40 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 57.5, 71.9, 72.1, 72.3, 76.5, 84.9, 85.3, 127.4, 127.5, 127.6, 128.0, 128.1, 128.2, 128.3, 135.8, 137.6, 138.1, 147.5, 168.5. MS (CI, m/z, %): 445 (17, [M + H]+); 430 (76); 91 (100). IR (NaCl, cm–1): ν 1733 (st, C=O). Anal. calc. for C28H28O5: C 75.66; H 6.35. Found: C 75.45; H 6.32.

Methyl (1R,2S,3S,4S,5R)-2,3,4-tris(benzyloxy)-5-((4-methoxybenzyl)amino)cyclopentane-1-carboxylate (19a)

Compound 18b (1.06 g, 2.39 mmol) was dissolved in dry DMF (7.2 mL) and stirred with PMBNH2 (0.37 mL, 2.86 mmol) at room temperature under argon for 24 h. The reaction mixture was diluted with NH4Cl (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (EtOAc/hexane 1:4) to afford compound 19a (1.11 g, 1.91 mmol, 80% yield) as a yellowish oil. [α]D22 = +27.5 (c 1.8, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.87 (br, 1H), 2.87 (dd, 1H, J = 5.5, 3.3 Hz), 3.32 (dd, 1H, J = 9.0, 7.3 Hz), 3.41 (s, 3H), 3.43 (dd, 1H, J = 9.0, 7.1 Hz), 3.55 (dd, 1H, J = 7.3, 5.5 Hz), 3.66 (dd, 1H, J = 7.1, 3.3 Hz), 3.72 (s, 3H), 3.76 (d, 1H, J = 13.0 Hz), 3.78 (d, 1H, J = 13.0 Hz), 4.03–4.26 (m, 6H), 6.85–6.90 (m, 2H), 7.20–7.36 (m, 17H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 51.6, 51.9, 53.9, 57.5, 63.6, 72.1, 72.3, 73.3, 80.0, 80.9, 85.9, 113.0, 126.3, 126.5, 126.6, 126.9, 127.0, 127.1, 127.2, 130.4, 131.8, 137.4, 137.7, 138.3, 146.6, 173.7. MS (CI, m/z, %): 582 (42, [M + H]+); 551 (27); 91 (100). IR (NaCl, cm–1): ν 3351 (br, NH), 1751 (st, C=O). Anal. calc. for C36H39NO6: C 74.33; H 6.76; N 2.41; found: C 74.12; H 6.52; N 2.21.

Synthesis of Polyhydroxylated Cyclopentane β-Amino Acid Derivative 19b

(((3aS,4R,6R,7R,7aS)-6-(Benzyloxy)-7-methoxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-4-yl)methoxy)(tert-butyl)dimethylsilane (13c)

After compound 13b (2.10 g, 4.93 mmol) was subjected to the procedure for the preparation of 9b, compound 13c (2.01 g, 4.59 mmol, 93%) was obtained as a pure colorless oil. [α]D20 = −14.5 (c 1.7, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.10 (s, 6H), 0.91 (s, 9H), 1.34 (s, 3H), 1.54 (s, 3H), 3.24 (dd, 1H, J = 8.0, 7.1 Hz), 3.60 (s, 3H), 3.74 (ddd, 1H, J = 7.1, 5.5, 1.9 Hz), 3.87 (dd, 1H, J = 10.1, 5.5 Hz), 3.93 (dd, 1H, J = 10.1, 7.1 Hz), 4.03 (dd, 1H, J = 7.1, 5.4 Hz), 4.17 (dd, 1H, J = 5.4, 1.9 Hz), 4.28 (d, 1H, J = 8.0 Hz), 4.65 (d, 1H, J = 11.8 Hz), 4.92 (d, 1H, J = 11.8 Hz), 7.29–7.39 (m, 5H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.7, −5.5, 18.0, 25.6, 26.0, 27.9, 60.0, 61.9, 70.0, 73.0, 73.2, 78.8, 82.3, 101.0, 109.4, 127.5, 127.7, 128.1, 137.0. MS (CI, m/z, %): 439 (11, [M + H]+); 332 (24); 91 (100). IR (NaCl, cm–1): ν 1101 (st, Si-O-C). Anal. calc. for C23H38O6Si: C, 62.98; H, 8.73. Found: C, 62.77; H, 8.55.

(3aS,4R,6R,7R,7aS)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-7-methoxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol and (3aS,4R,6S,7R,7aS)-4-(((tert-butyldimethylsilyl)oxy)methyl)-7-methoxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-ol (13d)

Pd/C (0.64 g, 10%) and NH4HCO2 (4.58 g, 72.54 mmol) were added sequentially over a deoxygenated solution of 13c (3.18 g, 7.25 mmol) in MeOH (51 mL), and the resulting suspension was refluxed for 12 h. The reaction was then filtered through Celite and washed with MeOH, and the solution was concentrated to dryness under a vacuum. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL); the organic layer was dried (anhydrous Na2SO4) and filtered, and the solvent was removed under a vacuum. The obtained residue was submitted to flash column chromatography (EtOAc/hexane 1:2) to give compounds 13d (2.17 g, 6.24 mmol, 86%) as a yellow oil. Proportion 2:1 (d.e. 33%). 1H NMR (250 MHz, CDCl3, ppm): δ 0.08 (s, 12H), 0.89 (s, 9H), 0.90 (s, 9H), 1.35 (s, 6H), 1.51 (s, 3H), 1.54 (s, 3H), 3.19–3.24 (m, 1H), 3.36–3.43(m, 2H), 3.54 (s, 3H), 3.58 (s, 3H), 3.75–3.87 (m, 5H), 4.11–4.28 (m, 5H), 4.33–4.39 (m, 1H), 4.65–4.69 (m, 1H), 5.25–5.29 (m, 1H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 6.0, −5.9, −5.8, 17.8, 17.9, 25.4, 25.5, 25.6, 25.7, 27.5, 27.6, 58.0, 59.3, 61.5, 61.8, 67.2, 72.3, 72.5, 72.6, 74.6, 78.2, 79.1, 82.9, 89.9, 95.7, 108.4, 109.1. MS (CI, m/z, %): 349 (36, [M + H]+); 332 (63); 275 (100). IR (NaCl, cm–1): ν 3421 (br, OH); 1105 (st, Si-O-C). Anal. Calc. for C16H32O6Si: C, 55.14; H, 9.26. Found: C, 55.27; H, 9.33.

(R)-2-((tert-Butyldimethylsilyl)oxy)-1-((4S,5R)-5-((S)-1-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-ol (14b)

Starting from the mixture 13d (2.16 g, 6.24 mmol) and following the same procedure as per compound 14a, compound 14b was obtained (1.73 g, 4.99 mmol, 80%) as a pale yellow oil after flash column chromatography (EtOAc/hexane 1:7). [α]D20 = −8.6 (c 1.2, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.07 (s, 6H), 0.89 (s, 9H), 1.38 (s, 3H), 1.55 (s, 3H), 3.22 (d, 1H, J = 4.1 Hz), 3.34 (s, 3H), 3.60–3.75 (m, 3H), 3.93 (dd, 1H, J = 8.5, 3.6 Hz), 4.19 (d, 1H, J = 10.4 Hz), 4.23 (d, 1H, J = 10.4 Hz), 5.39 (dd, 1H, J = 16.7, 1.6 Hz), 5.41 (dd, 1H, J = 11.3, 1.6 Hz), 5.83 (ddd, 1H, J = 16.7, 11.3, 8.5 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.8, −5.7, 17.9, 24.7, 25.5, 25.9, 55.5, 63.5, 69.3, 75.1, 78.8, 80.4, 107.9, 119.9, 134.3. MS (CI, m/z, %): 347 (96, [M + H]+); 316 (87); 259 (100). IR (NaCl, cm–1): ν 3480 (br, OH); 1119 (st, Si-O-C). Anal. calc. for C17H34O5Si: C, 58.92; H, 9.89. Found: C, 59.08; H, 10.18.

2-((tert-Butyldimethylsilyl)oxy)-1-((4R,5R)-5-((S)-1-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethan-1-one (15b)

After compound 14b (1.73 g, 4.99 mmol) was subjected to the procedure for the preparation of 15a, flash column chromatography of the crude reaction product (EtOAc/hexane 1:9) provided compound 15b (1.39 g, 4.04 mmol, 81%) as a pale yellow oil. [α]D20 = +91.4 (c 1.1, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.08 (s, 3H), 0.11 (s, 3H), 0.93 (s, 9H), 1.33 (s, 3H), 1.58 (s, 3H), 3.06 (s, 3H), 3.58 (dd, 1H, J = 8.5, 1.6 Hz), 4.42 (dd, 1H, J = 8.2, 1.6 Hz), 4.45 (d, 1H, J = 18.7 Hz), 4.52 (d, 1H, J = 8.2 Hz), 4.76 (d, 1H, J = 18.7 Hz), 5.28 (dd, 1H, J = 17.3, 1.6 Hz), 5.33 (dd, 1H, J = 10.4, 1.6 Hz), 5.85 (ddd, 1H, J = 17.3, 10.4, 8.5 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.7, −5.4, 18.2, 23.9, 25.7, 26.0, 55.7, 67.9, 78.9, 79.5, 81.7, 109.9, 119.2, 134.2, 206.8. MS (CI, m/z, %): 345 (6, [M + H]+); 314 (27); 288 (100). IR (NaCl, cm–1): ν 1750 (st, C=O); 1100 (st, Si-O-C). Anal. calc. for C17H32O5Si: C, 59.27; H, 9.36. Found: C, 59.10; H, 9.47.

tert-Butyl((2-((4S,5R)-5-((S)-1-methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)allyl)oxy)dimethylsilane (16c)

When the procedure for the preparation of compound 16a was applied to compound 15b (1.39 g, 4.04 mmol) and the solid residue from the reaction mixture was subjected to flash column chromatography (EtOAc/hexane 1:19), compound 16c was isolated (1.29 g, 3.77 mmol, 93%) as a pale yellow oil. [α]D20 = +32.6 (c 1.6, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 0.08 (s, 6H); 0.92 (s, 9H), 1.38 (s, 3H), 1.54 (s, 3H), 3.23 (s, 3H), 3.56 (dd, 1H, J = 7.4, 6.0 Hz), 4.16 (dd, 1H, J = 6.6, 6.0 Hz), 4.20 (m, 2H), 4.63 (d, 1H, J = 6.6 Hz), 5.24 (dd, 1H, J = 17.3, 1.9 Hz), 5.26 (d, 1H, J = 1.6 Hz), 5.30 (dd, 1H, J = 10.7, 1.9 Hz), 5.31 (d, 1H, J = 1.6 Hz), 5.69 (ddd, 1H, J = 17.3, 10.7, 7.4 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ – 5.8, −5.7, 18.0, 24.8, 25.6, 26.1, 55.7, 63.9, 77.9, 80.2, 80.5, 107.9, 111.9, 118.7, 134.6, 144.2. MS (CI, m/z, %): 343 (11, [M + H]+); 312 (49); 255 (100). IR (NaCl, cm–1): ν 1252 (st, Si-O-C). Anal. calc. for C18H34O4Si: C, 63.11; H, 10.00. Found: C, 62.90; H, 10.05.

2-((4S,5R)-5-((S)-1-Methoxyallyl)-2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol (16d)

Starting from compound 16c (1.29 g, 3.77 mmol) and following the same procedure as per compound 16b, compound 16d was obtained (0.71 g, 3.09 mmol, 82%) as a pale yellow oil after flash column chromatography (EtOAc/hexane 1:4). [α]D20 = +66.6 (c 1.6, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.39 (s, 3H), 1.57 (s, 3H), 2.65 (br, 1H), 3.23 (s, 3H), 3.60 (dd, 1H, J = 7.9, 5.2 Hz), 4.19 (br, 2H), 4.29 (dd, 1H, J = 6.9, 5.2 Hz), 4.76 (d, 1H, J = 6.9 Hz), 5.21 (dd, 1H, J = 17.3, 1.9 Hz), 5.24 (d, 1H, J = 1.6 Hz), 5.33 (dd, 1H, J = 10.4, 1.9 Hz), 5.36 (d, 1H, J2’b,2’a = 1.6 Hz, H-2’b), 5.79 (ddd, 1H, J6,7b = 17.3 Hz, J6,7a = 10.4 Hz, J = 7.9 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.3, 25.8, 55.4, 63.2, 77.7, 79.6, 80.4, 107.8, 112.6, 119.1, 133.9, 144.7. MS (CI, m/z, %): 229 (6, [M + H]+); 186 (19); 166 (100). IR (NaCl, cm–1): ν 3400 (br, OH). Anal. calc. for C12H20O4: C, 63.14; H, 8.83. Found: C, 63.29; H, 9.05.

((3aR,4S,6aS)-4-Methoxy-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-6-yl)methanol (17b)

When compound 16d (2.37 g, 10.37 mmol) was submitted to the same procedure as per compound 10, compound 17b (1.91 g, 9.54 mmol, 92%) was obtained after flash column chromatography (EtOAc/hexane 1:1) as a yellow oil. [α]D20 = +31.7 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.36 (s, 3H), 1.41 (s, 3H), 2.16 (br, 1H), 3.43 (s, 3H), 4.25–4.40 (m, 3H), 4.58 (d, 1H, J = 6.0 Hz), 5.18 (dd, 1H, J = 6.0, 0.8 Hz), 5.78 (d, 1H, J = 1.4 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.9, 26.4, 56.0, 58.5, 82.4, 82.6, 88.4, 111.1, 124.3, 148.8. MS (CI, m/z, %): 201 (20, [M + H]+); 158 (18); 127 (100). IR (NaCl, cm–1): ν 3448 (br, OH). Anal. calc. for C10H16O4: C, 59.98; H, 8.05. Found: C, 59.93; H, 7.85.

Methyl (3aR,4S,6aS)-4-methoxy-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carboxylate (18d)

When compound 17b (1.91 g, 9.54 mmol) was subjected to the procedure for the preparation of compound 11b, compound 18d (1.79 g, 7.83 mmol, 82%) was obtained as a colorless oil after flash column chromatography (EtOAc/hexane 1:4). [α]D20 = +26.7 (c 1.2, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.39 (s, 3H), 1.43 (s, 3H), 3.46 (s, 3H), 3.82 (s, 3H), 4.40–4.43 (m, 1H), 4.63 (d, 1H, J = 6.0 Hz), 5.43 (dd, 1H, J = 6.0, 1.6 Hz), 6.77 (d, 1H, J = 1.4 Hz). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.4, 26.2, 51.0, 56.3, 81.6, 82.6, 88.4, 111.5, 138.3, 141.3, 163.1. MS (CI, m/z, %): 229 (6, [M + H]+); 197 (100); 186 (9). IR (NaCl, cm–1): ν 1728 (st, C=O). Anal. calc. for C11H16O5: C, 57.89; H, 7.07. Found: C, 57.78; H, 7.19.

Methyl (3aS,4R,5R,6S,6aS)-5-(benzylamino)-6-methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate (19b)

Starting from compound 18d (1.79 g, 7.86 mmol) and following the same procedure as for the preparation of compound 12, compound 19b (2.10 g, 6.26 mmol, 80% yield) was obtained as a yellowish oil after flash column chromatography (EtOAc/hexane 1:3). [α]D20 = +44.6 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.31 (s, 3H), 1.49 (s, 3H), 2.58 (d, 1H, J = 3.6 Hz), 2.92 (dd, 1H, J = 9.3 5.5 Hz), 3.41 (s, 3H), 3.44 (ddd, 1H, J = 9.3, 7.4, 3.6 Hz), 3.66 (dd, 1H, J = 7.4, 3.3 Hz), 3.71 (s, 3H), 3.78 (d, 1H, J = 13.2 Hz), 3.84 (d, 1H, J = 13.2 Hz), 4.43 (dd, 1H, J = 7.1, 3.3 Hz), 4.83 (dd, 1H, J = 7.1, 5.5 Hz), 7.24–7.34 (m, 5H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 24.0, 26.4, 50.8, 51.5, 53.1, 56.9, 64.2, 79.0, 82.4, 89.2, 111.7, 126.4, 127.6, 127.8, 139.5, 172.3. MS (CI, m/z, %): 336 (83, [M + H]+); 304 (12); 262 (100). IR (NaCl, cm–1): ν 3339 (br, NH); 1733 (st, C=O). Anal. calc. for C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C, 64.18; H, 7.39; N, 4.00.

Synthesis of Tripeptide 21

Methyl (1R,2S,3S,4S,5R) -2,3,4-Tris-(benzyloxy)-5-tert-((butoxycarbonyl)amino)cyclopentane-1-carboxylate (19d)

CAN (4.19 g, 7.64 mmol) was added to a solution of compound 19a (1.11 g, 1.91 mmol) in CH3CN/H2O (95.5 mL, 4:1) at 0 °C. The mixture was allowed to warm up to room temperature and stirred for 6 h. The mixture was quenched with saturated aq. Na2S2O3 (a few drops) and concentrated in vacuo. The crude product was dissolved in dioxane (38.2 mL) and treated with (Boc)2O (2.08 g, 9.55 mmol) and saturated aq. NaHCO3 until basic pH was reached. The mixture was stirred at room temperature for 18 h, diluted with 10% aq. HCl (50 mL), and extracted with EtOAc (100 mL). The organic layer was dried (anhydrous Na2SO4) and concentrated to dryness under reduced pressure. The crude product was purified by flash column chromatography (EtOAc/hexane 1:4) to give compound 19d (0.80 g, 1.43 mmol, 75% yield) as a yellowish oil. [α]D23 = +37.0 (c 1.6, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.41 (s, 9H), 3.16 (dd, 1H, J = 6.0, 4.1 Hz), 3.28 (dd, 1H, J = 7.8, 5.6 Hz), 3.72 (s, 3H), 3.80 (dd, 1H, J = 7.8, 7.1 Hz), 3.98 (dd, 1H, J = 5.6, 4.1 Hz), 4.18 (dd, 1H, J = 7.1, 6.0 Hz), 4.30–4.60 (m, 6H), 5.44 (br, 1H), 7.28–7.38 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 29.0, 52.4, 54.2, 54.7, 72.0, 72.4, 72.7, 74.7, 80.0, 83.3, 84.8, 127.1, 127.2, 127.3, 127.4, 128.1, 128.2, 128.3, 137.0, 137.2, 138.7, 155.3, 174.2. MS (CI, m/z, %): 562 (12, [M + H]+); 505 (49); 91 (100). IR (NaCl, cm–1): ν 3348 (br, NH), 1751 (st, C=O). Anal. calc. for C33H39NO7: C, 70.57; H, 7.00; N, 2.49. Found: C, 70.37; H, 6.92; N, 2.62.

Dipeptide 20a

Ba(OH)2·8H2O (1.34 g, 4.26 mmol) was added to a solution of compound 19d (0.80 g, 1.42 mmol) in a 1:2 THF/H2O mixture (15 mL). The reaction was stirred at rt. for 1 h and then neutralized with 50WX4-50 DOWEX resin, which was then filtered off and washed with MeOH. The solvent was removed under vacuum on a rotary evaporator. A solution of the resulting solid residue, HATU (0.57 g, 1.70 mmol), and DIEA (0.72 mL, 4.26 mmol) in dry CH2Cl2 (10 mL) was stirred at rt. for 15 min. HCl-Gly-OMe (0.20 g, 1.56 mmol) was then added, and the stirring was continued for 14 h. CH2Cl2 (15 mL) was added, the mixture was washed with 10% aq. HCl (15 mL), and the organic layer was dried (anhydrous Na2SO4) and concentrated to dryness under a vacuum. Column chromatography of the solid residue (EtOAc/hexane 1:1) led to the isolation of dipeptide 20a (0.33 g, 0.53 mmol, 60% overall yield from compound 19d) as a colorless oil. [α]D21 = +68.2 (c 1.5, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.37 (s, 9H), 3.18 (dd, 1H, J = 5.8, 4.0 Hz), 3.27 (dd, 1H, J3 = 7.8, 5.6 Hz), 3.61 (s, 3H), 3.77–3.96 (m, 2H), 4.03 (s, 2H), 4.13 (dd, 1H, J = 7.0, 5.8 Hz), 4.28–4.48 (m, 6H), 5.67 (br, 1H), 6.91 (br, 1H), 7.28–7.41 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 29.3, 39.7, 52.6, 54.2, 55.0, 72.2, 72.5, 73.6, 74.7, 80.7, 83.4, 85.4, 127.4, 128.3, 128.5, 128.6, 137.4, 137.7, 138.7, 157.3, 169.3, 172.5. MS (CI, m/z, %): 619 (56, [M + H]+); 588 (64); 91 (100). Anal. calc. for C35H42N2O8: C, 67.94; H, 6.84; N, 4.53. Found: C, 68.12; H, 7.01; N, 4.29.

Tripeptide 21

TFA (2 mL) in THF (5 mL) was added to a solution of compound 20a (0.33 g, 0.53 mmol), and the mixture was stirred at rt. for 1 h. The solvent was then coevaporated with toluene (3 × 2 mL) under a vacuum in a rotary evaporator. HATU (0.21 g, 0.64 mmol) and DIEA (0.27 mL, 1.59 mmol) were added to a solution of Boc-Gly-OH (0.10 g, 0.58 mmol) in dry CH2Cl2 (5 mL), and the mixture was stirred at rt. for 15 m. A solution of the crude amine from the previous transformation in CH2Cl2 (10 mL) was added, and the resulting mixture was stirred at rt. for 10 h. The reaction mixture was washed with 10% aq HCl (20 mL), and the organic layer was dried (anhydrous Na2SO4), filtered, and concentrated to dryness under a vacuum. Column chromatography of the solid residue (EtOAc) provided pure tripeptide 21 (0.20 g, 0.30 mmol, 55% overall yield from compound 20a) as a colorless oil. [α]D18 = +21.7 (c 1.1, CHCl3). 1H NMR (250 MHz, CDCl3, ppm): δ 1.37 (s, 9H), 3.12–3.14 (m, 1H), 3.20 (dd, 1H, J = 7.4, 5.1 Hz), 3.66 (s, 3H), 3.79–3.91 (m, 2H), 4.03–4.09 (m, 4H), 4.31–4.43 (m, 6H), 4.55 (br, 1H), 5.55 (br, 1H), 6.93 (br, 1H), 6.96 (br, 1H), 7.27–7.39 (m, 15H). 13C{1H} NMR (62.5 MHz, CDCl3, ppm): δ 29.0, 40.0, 42.5, 52.8, 55.3, 56.3, 72.0, 72.2, 72.6, 75.0, 81.1, 84.7, 85.3, 127.9, 128.5, 128.7, 128.9, 138.3, 138.6, 139.0, 156.9, 166.0, 169.8, 172.2. MS (CI, m/z, %): 676 (18); 569 (64); 91 (100). Anal. Calc. for C37H45N3O9: C, 65.76; H, 6.71; N, 6.22. Found: C, 65.59; H, 6.49; N, 5.98.

Synthesis of Pentapeptide 24

2-(Trimethylsilyl)ethyl (3aR,4S,6aS)-4-methoxy-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxole-6-carboxylate (18e)

A solution of DCC (0.12 g, 0.56 mmol) in CH2Cl2 (2.2 mL) was added to a solution carboxylic acid 18c (0.11 g, 0.51 mmol), 2-(trimethylsilyl)ethanol (15 μL, 1.02 mmol), and DMAP (6 mg, 0.05 mmol) in CH2Cl2 (2.2 mL), and the mixture was stirred at rt. for 12 h. Water (10 mL) was then added, and the resulting mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with aq. saturated solution of NaHCO3 (20 mL) and brine (20 mL), dried (anhydrous Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexane 1:7) to obtain ester 18e (0.13 g, 77%) as a clear oil. [α]D22 = +34.5 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz, ppm): δ 0.05 (s, 9H, 3× CH3), 0.88–1.19 (m, 2H, CH2Si), 1.37 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.45 (s, 3H, OMe), 4.21–4.38 (m, 2H, CH2O) , 4.40 (td, 1H, J = 2.1, 1.0 Hz, H-4), 4.61 (dt, 1H, J = 6.0, 1.0 Hz, H-3a), 5.42 (dd, 1H, J = 6.0, 1.8 Hz, H-6a), 6.71 (dd, 1H, J = 2.1, 0.8 Hz, H-5). 13C{1H} NMR (CDCl3, 75 MHz, ppm): δ – 1.4, 17.4, 25.4, 27.2, 57.5, 63.4, 82.6, 83.4, 89.3, 112.6, 141.4, 145.7, 163.9. IR (NaCl, cm–1): ν 1720 (st, C=O). HRMS (ESI+): calc. for C15H26O5Si (M + Na)+ 337.1442, found 337.1447.

2-(Trimethylsilyl)ethyl (3aS,4R,5R,6S,6aS)-5-(benzylamino)-6-methoxy-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate (19f)

Benzylamine (18 μL, 0.16 mmol) was added to a solution of ester 18e (42 mg, 0.134 mmol) in DMF (0.4 mL), and the resulting mixture was stirred at rt. for 60 h when the solvents were removed under reduced pressure. The resulting residue was taken up in EtOAc (10 mL), washed with water (3 × 5 mL), dried (anhydrous Na2SO4), and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexane 1:3), to obtain compound 19f (39 mg, 69%) as a clear oil. [α]D22 = −5.4 (c 3.4, CHCl3). 1H NMR (CDCl3, 300 MHz, ppm): δ 0.04 (s, 9H, 3× CH3), 0.99 (ddd, 2H, J = 9.1, 7.1, 1.0 Hz, CH2-Si), 1.30 (s, 3H, CH3), 1.48 (s, 3H, CH3), 1.92 (s, 1H, NH), 2.88 (dd, 1H, J = 9.1, 5.3 Hz, H-4), 3.37–3.47 (m, 4H, OMe + H-5), 3.65 (dd, 1H, J = 7.2, 3.3 Hz, H-6), 3.82 (d, 2H, J = 2.5 Hz, CH2Bn), 4.19 (ddd, 2H, J = 9.2, 7.1, 1.0 Hz, CH2-O), 4.42 (dd, 1H, J = 7.3, 3.3 Hz, H-6a), 4.84 (dd, 1H, J = 7.3, 5.3 Hz, H-3a), 7.18–7.37 (m, 5H, 5× H-Ar). 13C{1H} NMR (CDCl3, 75 MHz, ppm): δ −1.4, 17.5, 24.8, 27.1, 51.7, 54.1, 57.7, 63.6, 65.1, 79.8, 83.2, 90.1, 112.5, 127.1, 128.3, 128.5, 140.2, 172.9. IR (NaCl, cm–1): ν 3350 (br, NH); 1726 (st, C=O). HRMS (ESI+) m/z (M + H)+ calc. for C22H36O5Si 422.2357. Found 422.2360.

Tripeptide 23a

A 1 M solution of TBAF in THF (0.17 mL) was added to a solution of amino acid ester 19f (65 mg, 0.154 mmol) in THF (3 mL), and the resulting mixture was stirred at rt. for 24 h. The reaction mixture was diluted with aq. saturated solution of NH4Cl (5 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were dried (anhydrous Na2SO4) and filtered, and the solvent was evaporated under reduced pressure. The resulting crude of 19g was dissolved in dry DMF (4 mL), and then PyBOP (104 mg, 0.200 mmol) and HOBt.H2O (31 mg, 0.200 mmol) were added. After 10 min at rt., ACPC dimer 22a (54 mg, 0.185 mmol) and DIEA (110 μL, 0.616 mmol) were added, and the reaction mixture was stirred overnight at rt. The reaction was then diluted with CH2Cl2 (20 mL) and washed with 1 M HCl (20 mL), aq. saturated solution of NaHCO3 (20 mL), and brine (20 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc) to yield compound 23a (37 mg, 43%) as a white solid. [α]D22 = +29.1 (c 2.0, CHCl3). 1H NMR (CDCl3, 300 MHz, ppm): δ 1.22–1.45 (m, 4H, CH3 + CH2), 1.51 (s, 3H, CH3), 1.53–1.79 (m, 5H, 2× CH2 + CH2), 1.83–2.27 (m, 7H, 3× CH2 + NH), 2.47 (dd, 1H, J = 8.4, 4.5 Hz, CH-CO), 2.56–2.68 (m, 2H, 2× CH-CO), 3.22 (dd, 1H, J = 11.9, 8.6 Hz, CH-N), 3.47 (s, 3H, OMe), 3.59–3.71 (m, 4H, OMe + CH-N), 3.83 (d, 1H, J = 13.9 Hz, CH2Bn), 3.96 (d, J = 12.9 Hz, 1H, CH2Bn), 4.11 (t, J = 6.3 Hz, 1H, CH-N), 4.30–4.41 (m, 2H, 2× CH-O), 4.79 (t, 1H, J = 7.1 Hz, CH-O), 7.30 (td, 5H, J = 9.6, 8.6, 3.6 Hz, 5× H-Ar), 7.65 (d, 1H, J = 6.3 Hz, NH), 7.92 (d, 1H, J = 7.1 Hz, NH). 13C{1H} NMR (CDCl3, 75 MHz, ppm): δ 23.1, 24.8, 24.9, 27.2, 27.3, 28.4, 32.8, 33.3, 50.4, 50.7, 52.0, 52.4, 53.2, 54.9, 56.1, 57.8, 63.8, 77.4, 82.0, 90.4 (CH), 113.1, 127.6, 128.3, 128.7, 139.3, 172.5, 173.3, 175.6. IR (NaCl, cm–1): ν 3287 (br, NH); 1732, 1643 (st, C=O). HRMS (ESI+) m/z (M + H)+ calc. for C30H44N3O7 558.3174. Found 558.3174.

Pentapeptide 24

20% Pd(OH)2/C (12 mg) was added over a deoxygenated solution of compound 23a (23 mg, 0.041 mmol) in methanol (4 mL), and the resulting suspension was deoxygenated again and stirred overnight under a hydrogen atmosphere (P = 1 atm). The reaction was filtered through Celite and washed with methanol, and the filtrate was evaporated to dryness under a vacuum to give chromatographically pure 23b. PyBOP (28 mg, 0.054 mmol), HOBt (8 mg, 0.054 mmol), and DIEA (0.28 mL, 1.59 mmol) were added over a solution of ACPC dimer 22b (20 mg, 0.054 mmol) in dry DMF (1 mL). After 5 min stirring, a solution of the crude of 23b in dry DMF (1 mL) was added to the other solution, and the reaction mixture was stirred at rt. overnight. Then, the reaction mixture was diluted with CH2Cl2 (10 mL) and washed with 1 M HCl (10 mL), aq. saturated solution of NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried (anhydrous Na2SO4), filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (EtOAc/hexane 4:1) to obtain pentamer 24 (20 mg, 59%) as a white solid. [α]D22 = +47.7 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz, ppm): δ 1.27 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.55–1.81 (m, 12H, CH2), 1.90–2.17 (m, 13H, CH2 + CH-CO), 2.38–2.49 (m, 1H, CH-CO), 2.62 (dd, J = 9.5, 4.1 Hz, 2H, CH-CO), 2.89–3.04 (m, 1H, CH-CO), 3.45 (s, 3H, OMe), 3.66 (s, 3H, OMe), 3.85 (dd, J = 9.8, 5.4 Hz, 1H, CH-N), 4.08–4.22 (m, 3H, CH-N + CH-O), 4.33 (q, J = 9.1, 8.6 Hz, 2H, CH-N), 4.41–4.51 (m, 2H, CH-O), 5.00 (dd, J = 7.2, 4.3 Hz, 1H, CH-O), 5.12 (dd, J = 12.3, 16.7 Hz, 2H, CH2-Ar), 5.89 (d, J = 7.9 Hz, 1H, NH), 6.47 (d, J = 8.4 Hz, 1H, NH), 7.36 (s, 5H, CH2-Ar), 7.69 (d, J = 8.1 Hz, 1H, NH), 8.13–8.48 (m, 2H, NH). 13C{1H} NMR (CDCl3, 75 MHz, ppm): δ 23.6, 24.1, 24.4, 25.4, 25.5, 27.6, 28.3, 28.9, 29.0, 29.8, 32.5, 33.6, 33.9, 50.2, 51.8, 51.9, 53.1, 53.5, 54.7, 55.0, 55.6, 55.7, 57.7, 57.9, 58.0, 67.0, 78.9, 82.5, 89.4, 112.5, 127.9, 128.4, 128.8, 136.4, 156.8, 171.2, 174.3, 174.6, 175.1, 176.6. IR (ATR, cm–1): ν 3289 (NH), 3037 (NH), 1699 (C=O), 1645 (C=O), 1555 (C=O). HRMS (ESI+) m/z (M + Na)+ calc. for C43H61N5NaO11 846.4260. Found 846.4262.

Acknowledgments

This work has received financial support from the European Union (European Regional Development Fund - ERDF), the Spanish Ministerio de Economía y Competitividad (SAF2014-60138-R), the CIBER BBN (CB/06/01/0074), the Xunta de Galicia (Centro Singular de Investigación de Galicia accreditation 2019–2022, ED431G 2019/03; and grants ED431C 2018/30 and ED431C 2018/04), the Generalitat de Catalunya (2017-SGR-1439), and the Galchimia S.A. (Spain). R.B. and F.F. thank the Ministerio de Educación, Cultura y Deporte and the Ministerio de Educación y Ciencia, respectively, for FPU fellowships.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c05468.

  • Copies of 1H, 13C{1H}, and DEPT-135 NMR spectra for compounds 7b, 8, 9a, 9b, 9c, 10, 11b, 12, 13c, 13d, 14a, 14b, 15a, 15b, 16a, 16b, 16c, 16d, 17a, 17b, 18b, 18d, 18e, 19a, 19b, 19d, 19f, 20a, 21, 23a, and 24 (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao1c05468_si_001.pdf (12.7MB, pdf)

References

  1. Enantioselective Synthesis of Beta-Amino Acids, 2nd ed.; Juaristi E.; Soloshonok V. A., Eds.; Wiley: Hoboken, N.J, 2005. [Google Scholar]
  2. Weiner B.; Szymański W.; Janssen D. B.; Minnaard A. J.; Feringa B. L. Recent Advances in the Catalytic Asymmetric Synthesis of β-Amino Acids. Chem. Soc. Rev. 2010, 39, 1656. 10.1039/b919599h. [DOI] [PubMed] [Google Scholar]
  3. Kiss L.; Fülöp F. Synthesis of Carbocyclic and Heterocyclic β-Aminocarboxylic Acids. Chem. Rev. 2014, 114, 1116–1169. 10.1021/cr300454h. [DOI] [PubMed] [Google Scholar]
  4. Grygorenko O. O. Bicyclic β-Amino Acids. Tetrahedron 2015, 71, 5169–5216. 10.1016/j.tet.2015.05.069. [DOI] [Google Scholar]
  5. Ashfaq M.; Tabassum R.; Ahmad M. M.; Hassan N. A.; Oku H.; Rivera G. Enantioselective Synthesis of β-Amino Acids: A Review. Med. Chem. 2015, 5, 295–309. 10.4172/2161-0444.1000278. [DOI] [Google Scholar]
  6. Gellman S. H. Foldamers: A Manifesto. Acc. Chem. Res. 1998, 31, 173–180. 10.1021/ar960298r. [DOI] [Google Scholar]
  7. Guichard G.β-Peptides, γ-Peptides and Isosteric Backbones: New Scaffolds with Controlled Shapes for Mimicking Protein Secondary Structure Elements. In Pseudo-Peptides in Drug Development; Nielsen P. E., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, FRG, 2005; pp. 33–120, 10.1002/3527601902.ch2. [DOI] [Google Scholar]
  8. Aguilar M.-I.; Purcell A. W.; Devi R.; Lew R.; Rossjohn J.; Smith A. I.; Perlmutter P. β-Amino Acid-Containing Hybrid Peptides—New Opportunities in Peptidomimetics. Org. Biomol. Chem. 2007, 5, 2884. 10.1039/b708507a. [DOI] [PubMed] [Google Scholar]
  9. Seebach D.; Gardiner J. β-Peptidic Peptidomimetics. Acc. Chem. Res. 2008, 41, 1366–1375. 10.1021/ar700263g. [DOI] [PubMed] [Google Scholar]
  10. Chand P.; Kotian P. L.; Dehghani A.; El-Kattan Y.; Lin T.-H.; Hutchison T. L.; Babu Y. S.; Bantia S.; Elliott A. J.; Montgomery J. A. Systematic Structure-Based Design and Stereoselective Synthesis of Novel Multisubstituted Cyclopentane Derivatives with Potent Antiinfluenza Activity. J. Med. Chem. 2001, 44, 4379–4392. 10.1021/jm010277p. [DOI] [PubMed] [Google Scholar]
  11. Hook D. F.; Bindschädler P.; Mahajan Y. R.; Šebesta R.; Kast P.; Seebach D. The Proteolytic Stability of ‘Designed’ β-Peptides Containing α-Peptide-Bond Mimics and of Mixed α,β-Peptides: Application to the Construction of MHC-Binding Peptides. Chem. Biodiversity 2005, 2, 591–632. 10.1002/cbdv.200590039. [DOI] [PubMed] [Google Scholar]
  12. Heck T.; Limbach M.; Geueke B.; Zacharias M.; Gardiner J.; Kohler H.-P. E.; Seebach D. Enzymatic Degradation of β- and Mixed α,β-Oligopeptides. Chem. Biodiversity 2006, 3, 1325–1348. 10.1002/cbdv.200690136. [DOI] [PubMed] [Google Scholar]
  13. Katoh T.; Sengoku T.; Hirata K.; Ogata K.; Suga H. Ribosomal Synthesis and de Novo Discovery of Bioactive Foldamer Peptides Containing Cyclic β-Amino Acids. Nat. Chem. 2020, 12, 1081–1088. 10.1038/s41557-020-0525-1. [DOI] [PubMed] [Google Scholar]
  14. Gentilucci L.; De Marco R.; Cerisoli L. Chemical Modifications Designed to Improve Peptide Stability: Incorporation of Non-Natural Amino Acids, Pseudo-Peptide Bonds, and Cyclization. Curr. Pharm. Des. 2010, 16, 3185–3203. 10.2174/138161210793292555. [DOI] [PubMed] [Google Scholar]
  15. Gopalan R. D.; Del Borgo M. P.; Mechler A. I.; Perlmutter P.; Aguilar M.-I. Geometrically Precise Building Blocks: The Self-Assembly of β-Peptides. Chem. Biol. 2015, 22, 1417–1423. 10.1016/j.chembiol.2015.10.005. [DOI] [PubMed] [Google Scholar]
  16. Fülöp F. The Chemistry of 2-Aminocycloalkanecarboxylic Acids. Chem. Rev. 2001, 101, 2181–2204. 10.1021/cr000456z. [DOI] [PubMed] [Google Scholar]
  17. Miller J.; Nguyen S. The Enantioselective Synthesis of Conformationally Constrained Cyclic β-Amino Acids. Mini-Rev. Org. Chem. 2005, 2, 39–45. 10.2174/1570193052774117. [DOI] [Google Scholar]
  18. Appella D. H.; Christianson L. A.; Karle I. L.; Powell D. R.; Gellman S. H. β-Peptide Foldamers: Robust Helix Formation in a New Family of β-Amino Acid Oligomers. J. Am. Chem. Soc. 1996, 118, 13071–13072. 10.1021/ja963290l. [DOI] [Google Scholar]
  19. Benedek G.; Palkó M.; Wéber E.; Martinek T. A.; Forró E.; Fülöp F. Efficient Synthesis of Hydroxy-Substituted Cispentacin Derivatives: Synthesis of Hydroxy-Substituted Cispentacin Derivatives. Eur. J. Org. Chem. 2008, 2008, 3724–3730. 10.1002/ejoc.200800345. [DOI] [Google Scholar]
  20. Abraham E.; Claridge T. D. W.; Davies S. G.; Odell B.; Roberts P. M.; Russell A. J.; Smith A. D.; Smith L. J.; Storr H. R.; Sweet M. J.; Thompson A. L.; Thomson J. E.; Tranter G. E.; Watkin D. J. A Systematic Study of the Solid State and Solution Phase Conformational Preferences of β-Peptides Derived from C(3)-Alkyl Substituted Transpentacin Derivatives. Tetrahedron: Asymmetry 2011, 22, 69–100. 10.1016/j.tetasy.2010.12.007. [DOI] [Google Scholar]
  21. Martinek T. A.; Tóth G. K.; Vass E.; Hollósi M.; Fülöp F. Cis-2-Aminocyclopentanecarboxylic Acid Oligomers Adopt a Sheetlike Structure: Switch from Helix to Nonpolar Strand. Angew. Chem., Int. Ed Engl. 2002, 41, 1718–1721. . [DOI] [PubMed] [Google Scholar]
  22. Martinek T. A.; Mándity I. M.; Fülöp L.; Tóth G. K.; Vass E.; Hollósi M.; Forró E.; Fülöp F. Effects of the Alternating Backbone Configuration on the Secondary Structure and Self-Assembly of β-Peptides. J. Am. Chem. Soc. 2006, 128, 13539–13544. 10.1021/ja063890c. [DOI] [PubMed] [Google Scholar]
  23. Sussman F.; Sánchez-Pedregal V. M.; Estévez J. C.; Balo R.; Jiménez-Barbero J.; Ardá A.; Gimeno A.; Royo M.; Villaverde M. C.; Estévez R. J. Environmental Effects Determine the Structure of Potential β-Amino Acid Based Foldamers. Chem. – Eur. J. 2018, 24, 10625–10629. 10.1002/chem.201801953. [DOI] [PubMed] [Google Scholar]
  24. Wang Y.; Xing Y.; Liu X.; Ji H.; Kai M.; Chen Z.; Yu J.; Zhao D.; Ren H.; Wang R. A New Class of Highly Potent and Selective Endomorphin-1 Analogues Containing α-Methylene-β-Aminopropanoic Acids (Map). J. Med. Chem. 2012, 55, 6224–6236. 10.1021/jm300664y. [DOI] [PubMed] [Google Scholar]
  25. Keresztes A.; Szűcs M.; Borics A.; Kövér K. E.; Forró E.; Fülöp F.; Tömböly C.; Péter A.; Páhi A.; Fábián G.; Murányi M.; Tóth G. New Endomorphin Analogues Containing Alicyclic β-Amino Acids: Influence on Bioactive Conformation and Pharmacological Profile. J. Med. Chem. 2008, 51, 4270–4279. 10.1021/jm800223t. [DOI] [PubMed] [Google Scholar]
  26. Kwon S.; Jeon A.; Yoo S. H.; Chung I. S.; Lee H.-S. Unprecedented Molecular Architectures by the Controlled Self-Assembly of a β-Peptide Foldamer. Angew. Chem., Int. Ed. 2010, 49, 8232–8236. 10.1002/anie.201003302. [DOI] [PubMed] [Google Scholar]
  27. Gong J.; Eom T.; Lee W.; Roy A.; Kwon S.; Kim H.; Lee H.-S. Self-Assembly of a Β-Peptide Foldamer: The Role of the Surfactant in Three-Dimensional Shape Selection. ChemPlusChem 2019, 84, 481–487. 10.1002/cplu.201900027. [DOI] [PubMed] [Google Scholar]
  28. Hubbard R. D.; Miller B. L. Regioselective and Diastereoselective Synthesis of Highly Substituted Cyclopentanes. Tetrahedron 2003, 59, 8143–8152. 10.1016/j.tet.2003.08.053. [DOI] [Google Scholar]
  29. Heasley B. Stereocontrolled Preparation of Fully Substituted Cyclopentanes: Relevance to Total Synthesis. Eur. J. Org. Chem. 2009, 2009, 1477–1489. 10.1002/ejoc.200801229. [DOI] [Google Scholar]
  30. Parr B. T.; Davies H. M. L. Highly Stereoselective Synthesis of Cyclopentanes Bearing Four Stereocentres by a Rhodium Carbene-Initiated Domino Sequence. Nat. Commun. 2014, 5, 4455. 10.1038/ncomms5455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tan B.; Chua P. J.; Zeng X.; Lu M.; Zhong G. A Highly Diastereo- and Enantioselective Synthesis of Multisubstituted Cyclopentanes with Four Chiral Carbons by the Organocatalytic Domino Michael–Henry Reaction. Org. Lett. 2008, 10, 3489–3492. 10.1021/ol801273x. [DOI] [PubMed] [Google Scholar]
  32. Risseeuw M.; Overhand M.; Fleet G. W. J.; Simone M. I. A Compendium of Cyclic Sugar Amino Acids and Their Carbocyclic and Heterocyclic Nitrogen Analogues. Amino Acids 2013, 45, 613–689. 10.1007/s00726-013-1521-1. [DOI] [PubMed] [Google Scholar]
  33. Kiss L.; Mándity I. M.; Fülöp F. Highly Functionalized Cyclic β-Amino Acid Moieties as Promising Scaffolds in Peptide Research and Drug Design. Amino Acids 2017, 49, 1441–1455. 10.1007/s00726-017-2439-9. [DOI] [PubMed] [Google Scholar]
  34. Martínez R. F.; Jenkinson S. F.; Nakagawa S.; Kato A.; Wormald M. R.; Fleet G. W. J.; Hollinshead J.; Nash R. J. Isolation from Stevia Rebaudiana of DMDP Acetic Acid, a Novel Iminosugar Amino Acid: Synthesis and Glycosidase Inhibition Profile of Glycine and β-Alanine Pyrrolidine Amino Acids. Amino Acids 2019, 51, 991–998. 10.1007/s00726-019-02730-5. [DOI] [PubMed] [Google Scholar]
  35. Soengas R.; Lorca M.; Pampín B.; Sánchez-Pedregal V. M.; Estévez R. J.; Estévez J. C. New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-Trihydroxycyclopen-Tane-1-Carboxylic Acid: Synthesis and Structural Study. Molecules 2020, 25, 2574. 10.3390/molecules25112574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Gu X.; Gupta V.; Yang Y.; Zhu J.-Y.; Carlson E. J.; Kingsley C.; Tash J. S.; Schönbrunn E.; Hawkinson J.; Georg G. I. Structure-Activity Studies of N -Butyl-1-Deoxynojirimycin ( N B-DNJ) Analogues: Discovery of Potent and Selective Aminocyclopentitol Inhibitors of GBA1 and GBA2. ChemMedChem 2017, 12, 1977–1984. 10.1002/cmdc.201700558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schalli M.; Tysoe C.; Fischer R.; Pabst B. M.; Thonhofer M.; Paschke E.; Rappitsch T.; Stütz A. E.; Tschernutter M.; Windischhofer W.; Withers S. G. N-Substituted 5-Amino-1-Hydroxymethyl-Cyclopentanetriols: A New Family of Activity Promotors for a G M1 -Gangliosidosis Related Human Lysosomal β-Galactosidase Mutant. Carbohydr. Res. 2017, 443-444, 15–22. 10.1016/j.carres.2017.03.009. [DOI] [PubMed] [Google Scholar]
  38. Schalli M.; Weber P.; Tysoe C.; Pabst B. M.; Thonhofer M.; Paschke E.; Stütz A. E.; Tschernutter M.; Windischhofer W.; Withers S. G. A New Type of Pharmacological Chaperone for G M1 -Gangliosidosis Related Human Lysosomal β-Galactosidase: N -Substituted 5-Amino-1-Hydroxymethyl-Cyclopentanetriols. Bioorg. Med. Chem. Lett. 2017, 27, 3431–3435. 10.1016/j.bmcl.2017.05.086. [DOI] [PubMed] [Google Scholar]
  39. Soengas R. G.; Estévez J. C.; Estévez R. J. Stereocontrolled Transformation of Nitrohexofuranoses into Cyclopentylamines via 2-Oxabicyclo[2.2.1]Heptanes: Incorporation of Polyhydroxylated Carbocyclic β-Amino Acids into Peptides. Org. Lett. 2003, 5, 1423–1425. 10.1021/ol034127f. [DOI] [PubMed] [Google Scholar]
  40. Fernández F.; Pampín B.; González M. A.; Estévez J. C.; Estévez R. J. Stereocontrolled Transformation of Nitrohexofuranoses into Cyclopentylamines via 2-Oxabicyclo[2.2.1]Heptanes. Part VI: Synthesis and Incorporation of the Novel Polyhydroxylated 5-Aminocyclopent-1-Enecarboxylic Acids into Peptides. Tetrahedron: Asymmetry 2010, 21, 2021–2026. 10.1016/j.tetasy.2010.05.052. [DOI] [Google Scholar]
  41. Soengas R. G.; Pampín M. B.; Estévez J. C.; Estévez R. J. Stereocontrolled Transformation of Nitrohexofuranoses into Cyclopentylamines via 2-Oxabicyclo[2.2.1]Heptanes. Part 2: Synthesis of (1S,2R,3S,4S,5R)-3,4,5-Trihydroxy-2-Aminocyclopentanecarboxylic Acid. Tetrahedron: Asymmetry 2005, 16, 205–211. 10.1016/j.tetasy.2004.11.034. [DOI] [Google Scholar]
  42. Soengas R. G.; Estévez A. M.; Estévez J. C.; Estévez R. J. An Overview on the Synthesis of Furanoid and Pyranoid Sugar α- and β-Amino Acids and Related Aminocycloalkanecarboxylic Acids from Carbohydrates. C. R. Chim. 2011, 14, 313–326. 10.1016/j.crci.2010.11.003. [DOI] [Google Scholar]
  43. Vougioukalakis G. C.; Grubbs R. H. Ruthenium-Based Heterocyclic Carbene-Coordinated Olefin Metathesis Catalysts. Chem. Rev. 2010, 110, 1746–1787. 10.1021/cr9002424. [DOI] [PubMed] [Google Scholar]
  44. Perlmutter P.; Tabone M. A Simple Route to .Alpha.-Substituted-.Beta.-Amino Ester Precursors of Carbapenem Antibiotics. J. Org. Chem. 1995, 60, 6515–6522. 10.1021/jo00125a043. [DOI] [Google Scholar]
  45. An initial version of this work was deposited in ChemRxiv on August 02, 2021, reference:; Fernández F.; Fernández A. G.; Balo R.; Sánchez-Pedregal V. M.; Royo M.; Soengas R. G.; Estévez R. J.; Estévez J. C.. Polyhydroxylated Cyclopentane β-Amino Acids Derived from D-Mannose and D-Galactose: Synthesis and Protocol for Incorporation into Peptides. chemRxiv 2021, 10.33774/chemrxiv-2021-kk47l-v3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ichiyanagi T.; Sakamoto N.; Ochi K.; Yamasaki R. A Chemical Synthesis of 3-Deoxy-D- Manno −2-Octulosonic Acid from D-Mannose. J. Carbohydr. Chem. 2009, 28, 53–63. 10.1080/07328300802650303. [DOI] [Google Scholar]
  47. Shiozaki M.; Tashiro T.; Koshino H.; Shigeura T.; Watarai H.; Taniguchi M.; Mori K. Synthesis and Biological Activity of Hydroxylated Analogues of KRN7000 (α-Galactosylceramide). Carbohydr. Res. 2013, 370, 46–66. 10.1016/j.carres.2013.01.010. [DOI] [PubMed] [Google Scholar]
  48. Fernández F.; Estévez A. M.; Estévez J. C.; Estévez R. J. Stereocontrolled Transformation of Nitrohexofuranoses into Cyclopentylamines via 2-Oxabicyclo[2.2.1]Heptanes. IV: Synthesis of Enantiopure Methyl (1S,2R,3R,4R,5S)-5-Benzyloxycarbonylamino-2,3-Isopropylidenedioxy-4-Methoxycyclopentanecarboxylate. Tetrahedron: Asymmetry 2009, 20, 892–896. 10.1016/j.tetasy.2009.03.004. [DOI] [Google Scholar]
  49. Lehtilä R. L.; Lehtilä J. O.; Roslund M. U.; Leino R. Selectively Protected Galactose Derivatives for the Synthesis of Branched Oligosaccharides. Tetrahedron 2004, 60, 3653–3661. 10.1016/j.tet.2004.02.054. [DOI] [Google Scholar]
  50. Gerlach H. 2-(Trimethylsilyl)äthylester als Carboxylschutzgruppe; Anwendung bei der Synthese des (−)-(S)-Curvularins. Helv. Chim. Acta 1977, 60, 3039–3044. 10.1002/hlca.19770600856. [DOI] [Google Scholar]
  51. Wright K.; Wakselman M.; Mazaleyrat J.-P.; Franco L.; Toffoletti A.; Formaggio F.; Toniolo C. Synthesis and Conformational Characterisation of Hexameric β-Peptide Foldamers by Using Double POAC Spin Labelling and cw-EPR. Chem. – Eur. J. 2010, 16, 11160–11166. 10.1002/chem.201000821. [DOI] [PubMed] [Google Scholar]

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