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Article

Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

by
Dzmitry M. Zubrytski
1,
Gábor Zoltán Elek
2,
Margus Lopp
2 and
Dzmitry G. Kananovich
2,*
1
Department of Organic Chemistry, Belarusian State University, Leningradskaya 14, 220050 Minsk, Belarus
2
Department of Chemistry and Biotechnology, School of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(1), 140; https://doi.org/10.3390/molecules26010140
Submission received: 9 December 2020 / Revised: 24 December 2020 / Accepted: 26 December 2020 / Published: 30 December 2020
(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Organic Synthesis)
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Abstract

:
Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates in aprotic solvents (dichloromethane, chloroform, toluene) produces mixed anhydrides. The fragmentation reaction is especially facile with phenyliodine(III) reagents bearing electron-withdrawing carboxylate ligands (trifluoroacetyl, 2,4,6-trichlorobenzoyl, 3-nitrobenzoyl), and affords 95−98% yields of the corresponding mixed anhydride products. The latter can be straightforwardly applied for the acylation of various nitrogen, oxygen and sulfur-centered nucleophiles (primary and secondary amines, hydroxylamines, primary alcohols, phenols, thiols). Intramolecular acylation yielding macrocyclic lactones can also be performed. The developed transformation has bolstered the synthetic utility of cyclopropanols as pluripotent intermediates in diversity-oriented synthesis of bioactive natural products and their synthetic congeners. For example, it was successfully applied for the last-stage modification of a cyclic peptide to produce a precursor of a known histone deacetylase inhibitor.

Graphical Abstract

1. Introduction

Currently, hydroxy-substituted cyclopropanes (cyclopropanols) are widely used in organic synthesis as versatile C3-building blocks [1,2,3,4,5], with a rapidly growing number of novel applications [6,7]. The remarkable progress in the field has been largely driven by the two following reasons. First, the hydroxy-substituted cyclopropanes are readily available compounds [8], which can be prepared by a number of high-yielding methods, including titanium-catalyzed cyclopropanation of carboxylic esters with Grignard reagents (the Kulinkovich reaction) [9,10], cyclopropanations with zinc carbenoids [11,12], 1,3-cyclization reactions [13,14] and via transformations of different cyclopropane precursors [15,16,17,18,19]. Second, the internal ring strain and the presence of electron-donating hydroxyl group facilitate ring-opening reactions of cyclopropanols under mild conditions, well tolerated by other functionalities. Typically, these reactions occur upon treatment with electrophilic reagents and proceed via homo- or heterolytic fission of the electron-rich carbon−carbon bonds adjacent to oxygen, affording β-functionalized ketones [20,21,22].
However, in the reactions of cyclopropanols 1 with lead(IV) acetate [23,24] and phenyliodine(III) dicarboxylates [25,26] the initially produced β-functionalized ketone intermediates (e.g., A, Scheme 1) easily undergo Grob-type fragmentation, which is triggered by the nucleophilic attack of a solvent R′OH on the carbonyl group of A. The reaction cascade results in a fast (typically, within few minutes) oxidative fragmentation of 1 via the cleavage of both carbon−carbon bonds adjacent to oxygen and produces carboxylic acid (or ester) and alkene. Importantly, the fragmentation step requires anti-periplanar arrangement of the cleaved C−C and C−I bonds in intermediate B and occurs in a stereospecific fashion, with the stereochemistry of starting cyclopropanol fully preserved in the double bond of olefin product [24,25].
Oxidative ring scissoring of cyclopropanols with phenyliodine(III) diacetate (PIDA) or more reactive bis(trifluoroacetate) (PIFA) has been frequently utilized in total synthesis of natural products (selected examples are presented in Scheme 1). Intramolecular ring cleavage of bicyclic cyclopropanols is especially powerful since it allows installation of both ester function and a stereodefined double bond in a single preparative step [13,27]. For example, Kirihara and co-workers utilized oxidative fragmentation as the key step in the short synthesis of an alkaloid (−)-pinidine [28,29], while our group reported synthesis of natural macrolactone (+)-recifeiolide via the ring opening-macrolactonization cascade in an aprotic solvent [30]. On the other hand, cyclopropanol moiety can be considered as a convenient “protecting group” for carboxylate functionality, readily installed by Kulinkovich reaction with ethylmagnesium bromide [31,32,33,34,35,36]. The “deprotection” is performed by oxidative cleavage with PIDA and produces ethylene gas as the side product. The fragmentation reaction is generally high-yielding, compatible with densely functionalized substrates, and therefore can be rendered at the last steps, as Kulinkovich’s synthesis of epothilone D exemplifies [37,38].
Recently, we proposed the use of cyclopropanol moiety as pluripotent functional group for the diversity-oriented synthesis of bioactive compounds, which was validated by the efficient preparation of several histone deacetylase inhibitory cyclopeptides from the single cyclopropane-containing precursor [39]. The last-step ring opening in the latter required an expedient and high yielding protocol to generate a range of different carboxylic acid derivatives. Although the oxidation with hypervalent iodine reagents could provide access to esters and carboxylic acids, the similar route had not been previously applied for the preparation of other carboxylic acid derivatives, such as amides and hydroxamic acids, known as powerful histone deacetylase inhibitors [40,41,42,43]. Taking into account that amide bond is frequently occurs in pharmaceuticals [44,45] and therefore novel methods of amide synthesis currently attract a great deal of attention [46,47,48], one-pot preparation of amides from cyclopropanols was highly desired to bolster the performance of cyclopropanol moiety as pluripotent functionality suitable for the generation of bioactive molecular libraries.
In 2014, we noticed that oxidation of cyclopropanols with PIFA in CH2Cl2 affords mixed anhydrides of trifluoroacetic acid (TFA) as by-products [30], a plausible result of nucleophilic attack of TFA on the carbonyl group of A (Scheme 1), which occurs in the absence of large excess of a competitive nucleophile. Generation of mixed anhydride as intermediate in the oxidation reaction with PIDA in acetic acid was also evidenced by Momose and co-workers in 1995 [25]. However, the scope and limitations of the oxidative fragmentation leading to mixed anhydrides have remained unexamined and its synthetic potential has stayed untapped. We surmised that generation of mixed anhydrides as activated derivatives of carboxylic acids would offer a suitable solution to render the desired amide products upon the reaction with amines [49]. Here we report the general strategy for one-pot preparation of various carboxylic acid derivatives from cyclopropanols by oxidative fragmentation with phenyliodine(III) dicarboxylates via the intermediate formation of mixed anhydrides.

2. Results and Discussion

2.1. Generation of Mixed Anhydrides via Ring Scissoring of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates

At the outset, the reactions of cyclopropanol 1a (Scheme 2) with phenyliodine(III) reagents 2a–e, bearing various carboxylate ligands, have been monitored by 1H-NMR spectroscopy (Table 1) in order to establish the best reaction conditions furnishing the desired mixed anhydride products 3 in high yields.
Oxidative fragmentation of 1a with PIDA (2a) in a nucleophilic solvent (CD3OD) resulted in a rapid formation of the corresponding methyl ester 4 in 93% yield (Table 1, Entry 1). On the other hand, performing the same oxidation reaction in inert solvent (CDCl3) in the presence of benzylamine as external nucleophile, completely inhibited the oxidation of cyclopropanol 1a and did not produce the corresponding N-benzylamide product (Entry 2). This result evidences that nucleophilic amines are incompatible with the oxidation step and therefore must be added only after its completion. Without the amine additive, the reaction between 1a and PIDA in CDCl3 slowly generated the corresponding mixed anhydride 3a, which was produced in 50% yield after 10 h reaction time (Entry 3). The structure of 3a was confirmed by 13C-NMR and HMBC correlation spectra, showing two distinct signals of carbonyl groups in 3a at δC 168.7 and 166.5 ppm (see the Supplementary Materials), while HRMS analysis of the crude reaction mixture revealed a mass peak with m/z = 215.0670, expected for a 3a-derived molecular ion C11H12O3Na+. Although rather high (~90%) conversion of the starting materials was observed after 10 h reaction time, the modest 50% yield of anhydride 3a was attained due to the generation of several oxidation side products, e.g., β-acyloxyketone 5a (R = Me) [50].
As it was shown before by Momose and co-workers [51], catalytic amounts of triflic acid can greatly enhance the rate of oxidation, probably because of the generation of highly reactive iodonium triflates in situ [52,53,54] (Brønsted acid activation of carbonyl group in γ-keto iodonium intermediate A can also contribute to the rate acceleration effect). In our hands, addition of TfOH (1 mol%) tremendously accelerated the oxidation rate in CDCl3 (Entry 4). The reaction was completed less than in 5 min and yield of anhydride 3a was also noticeably improved (up to 90%). The only side product was ester 6 (10% yield), a plausible outcome of acylation of 1a with 3a in the presence of TfOH catalyst.
The use of more reactive PIFA reagent (2b) also resulted in fast (7 min) oxidation reaction, rendering the corresponding mixed TFA anhydride 3b in high 95% yield with only trace amount of by-products (Entry 5). In contrast, the reaction with sterically hindered pivalate reagent 2c was found to be extremely sluggish and produced a complex mixture of oxidation products after 24 h, even in the presence of TfOH catalyst (Entries 6 and 7).
Next, we attempted to generate mixed anhydrides of aromatic carboxylic acid, by using hypervalent iodine oxidants 2d and 2e, derivatives of benzoic and 2,4,6-trichlorobenzoic acids respectively. While the oxidation reaction with 2d was rather slow and low-yielding (Entry 8), enhancing the electrophilic character of the phenyliodine(III) reagent by introducing more electron-deficient 2,4,6-trichlorobenzoate ligand was highly beneficial. Thus, the oxidative fragmentation of cyclopropanol 1a with reagent 2e was completed within 2 h (entry 9), producing the corresponding mixed anhydride in 98% yield and only trace amount of β-acyloxyketone side product 5e. The structure of mixed anhydride 3e was firmly confirmed by 13C-NMR and HMBC correlation spectra and supported by HRMS data (see the Supplementary Materials). The oxidation reaction can be further accelerated with Brønsted acid catalysts with the rate enhancement order TfOH>MsOH>TFA, corresponding to increasing acid strength (Entries 10–12). On the other hand, the Brønsted acid additives reduced yield of 3e due to competitive acylation of cyclopropanol 1a. Interestingly, replacement of CDCl3 solvent with toluene also notably accelerated the oxidation reaction (Entry 13 vs. 9), however resulted in slightly less clean reaction mixture (90% yield of 3e). In contrast to dicarboxylates 2, benziodoxole reagent 7 did not oxidize 1a even in a nucleophilic solvent (methanol). Commonly, the reactions of benziodoxole-type reagents with cyclopropanols follow the radical mechanistic pathway [55,56] and require transition metal catalyst to trigger the ring opening [57,58,59].
As it can be clearly seen from the results presented in Table 1, the oxidation rate increases with an increase of electrophilic character of hypervalent iodine reagent 2 (e.g., 2d vs. 2e, Entries 8 and 9), which can be adjusted by altering the carboxylate substituents. To confirm that, we examined the reactivity difference of four phenyliodine(III) dicarboxylates, derivatives of benzoic (2d), 3-fluorobenzoic (2f), 3-nitrobenzoic (2g) and 2,4,6-trichlorobenzoic (2e) acids. These hypervalent iodine compounds were prepared in high yields from the corresponding benzoic acids and commercially available PIDA reagent via replacement of acetate ligands in the latter, performed in chlorobenzene [60,61] or diethyl carbonate as a sustainable replacement solvent (see the Experimental Section).
The oxidation reactions with PhI(OCOAr)2 reagents were carried out under the pseudo-first-order reaction conditions with excess of cyclopropanol 1a (10 equiv., 0.2 M in CDCl3). Progress of the reactions was followed by 1H-NMR spectroscopy and pseudo-first-order rate constants have been determined (Figure 1a). As expected, the rate constants increased in order 2e > 2g > 2f > 2d following the increased electron-withdrawing character of the respective carboxylate ligands, a conclusion also supported by the corresponding linear free energy relationship (Figure 1b), showing a correlation between logk values and pKa values of the corresponding benzoic acids [62], a parameter strongly dependent on phenyl ring electron density.
To summarize, electrophilic and reactive oxidants like PIFA (2b) or 2,4,6-trichlorobenzoic reagent 2e are required for clean and fast generation of mixed anhydrides. The reactivity of phenyliodine(III) dicarboxylates in this reaction can be enhanced by installation of electron-deficient carboxylate ligands or by addition of strong Brønsted acid catalyst (e.g., TfOH).

2.2. Application of Mixed Anhydrides for Acylation of N-, O-, S-Nucleophiles and in Macrolactonizations

Mixed anhydrides contain two distinct reactive carbonyl groups, with the direction of nucleophilic attack and therefore selectivity of amide product formation governed by steric and/or electronic factors. Therefore, at the next stage, we evaluated suitability of several mixed anhydrides, produced by oxidation of cyclopropanol 1b, for preparation of a model N-benzyl amide 8 (Table 2).
According to 1H-NMR monitoring, oxidation of cyclopropanol 1b occurred faster than for 1a. After completion of the oxidation step (TLC control) the reaction mixtures were quenched with excess (3 equiv.) of benzylamine. N-Benzylnonanamide (8) was isolated by column chromatography on silica gel (Table 2). As expected, the reaction with PIDA (2a, Entry 1) afforded low 22% yield of amide 8, due to the lack of acylation selectivity (44% of N-benzylacetamide was formed) and formation of oxidation by-products (8-oxoundecyl acetate was isolated in 12% yield). On the other hand, mixed anhydrides of aromatic carboxylic acids, generated with reagents 2h, 2e, 2i and 2g, cleanly produced the required N-benzylamide 8 in high 88−95% yields (Entries 2−5). As in the case of cyclopropanol 1a described above, the reaction rate increased with the increased electron-withdrawing character of a carboxylate ligand, with the fastest oxidation reaction (<14 min) observed for 2,4-dinitrobenzoyloxy reagent 2i (Entry 4). On the contrary, oxidations with reagents 2k and 2j failed to render high yield of amide 8 due to the low solubility of these reagents in CH2Cl2 or chloroform and therefore slow oxidation rates (Entries 6 and 7). Reagents 2e and 2g were found to be the most suitable for practical applications, in terms of both amide product yields and the reaction times (Entries 3 and 5).
Having the most optimal conditions in hand, we performed one-pot synthesis of several amide products 8–19 (Scheme 3) by utilizing mixed anhydrides derived from reagents 2g, 2e and a number of cyclopropanols 1a-f. After generation of the corresponding mixing anhydrides, the reaction mixtures were treated with excess (3 equiv.) of amine coupling partner (for BnNH2, Et2NH, morpholine) or with 1–2 equiv. of the corresponding amine in the presence of a base (3 equiv., Et3N, DIPEA or N-methylimidazole, see the Experimental Section). For the reactions with O-benzylhydroxylamine, a solution of mixed anhydride was added dropwise to excess of BnONH2 (10 equiv.) to avoid double acylation of the latter.
Following the general reaction protocol (see the Experimental Section), both primary N-benzyl amides 11, 8 and secondary amide 9 were obtained in high 90−95% yields from cyclopropanols 1b and 1a. Weinreb amides 10, 12 and N-benzyl hydroxamic acid 13 were also prepared in satisfactory yields from the same starting materials. The amidation reactions performed via generation of more sterically hindered mixed anhydrides, containing secondary alkyl substituents, were also successful, for both primary (14) and secondary (15) amide products. Hydroxy-substituted amide 16 was flawlessly prepared in 81% yield by the selective acylation of amino group in 1-amino-2-methylpropan-2-ol, since tertiary alcohols were found to be totally unreactive (see below). No column chromatography was required for the isolation of crystalline products 14–15 (see the Experimental Section). Aromatic and low-nucleophilic ethyl 4-aminobenzoate also afforded high 84% yield of amide 17 in the presence of N-methylimidazole (NMI) as a base [63]. Intramolecular oxidative fragmentation of bicyclic hydroxycyclopropane 1f with reagent 2e afforded amide with stereodefined trans-double bond 18 after quenching with benzylamine. The most important, a cyclopeptide scaffold tolerated the developed one-pot oxidation-amidation protocol, to produce N-benzyl-protected hydroxamic acid 19 in 75% yield. Compound 19 is known as immediate precursor of the corresponding hydroxamic acid Ky-2, a powerful histone deacetylase (HDAC) inhibitor and a potent anticancer agent [40,41,64]. This achievement illustrates the suitability of the developed protocol for the synthesis of bioactive amides and was previously employed by us, along with several other ring-opening reactions, to generate a number of HDAC inhibitors from the single cyclopropanol precursor according to diversity-oriented synthesis paradigm [39].
Besides preparation of amides, oxygen and sulfur-centered nucleophiles can also be employed to furnish the corresponding esters and thioester (Scheme 3). The two-step approach is advantageous for easily oxidizing nucleophilic partners (e.g., phenols, thiols), which are incompatible with hypervalent iodine compounds or are impractical to be used as solvents in a classical Momose reaction protocol. Thus, benzyl ester 20 was obtained in 92% yield by acylation of benzyl alcohol in the presence of Et3N. Acylation of phenol and pentafluorophenol can also be performed, to afford the corresponding ester products 22 and 23. Ester 22 can also be prepared without a basic additive, upon the reaction of mixed TFA anhydride with phenol [65]. Thioester 24 was obtained in 64% yield by acylation of the corresponding thiol. The only limitation was the reaction with tert-butyl alcohol, which did not afford the expected ester 21. This restriction, on the other hand, allowed to preform high-yielding synthesis of amide 16. As it was shown by Momose and co-workers, preparation of esters from tertiary alcohols can be achieved in the presence of TfOH catalyst [51].
Synthesis of macrocyclic lactones from ω-hydroxycarboxylic (seco) acids represent one of the most prominent applications of mixed anhydrides in organic synthesis [66,67]. Thus, the venerable Yamaguchi esterification protocol relies on generation of mixed anhydrides with 2,4,6-trichlorobenzoic acid [68], while in the Shiina macrolactonizations the use of 4-trifluoromethylbenzoic [69] and 2-methyl-6-nitrobenzoic [70] anhydrides have been manifested. Importantly, macrolactonization of seco acid-derived anhydrides can also be promoted by Lewis acid catalysts [71,72,73,74] thus avoiding organic bases, what prompted us to investigate the direct conversion of ω-hydroxyalkyl substituted cyclopropanols 1g and 1h into the corresponding macrolactones 25a,b upon treatment with phenyliodine(III) reagents 2e and 2h (Table 3).
At the outset (Entry 1), we examined scandium triflate-mediated intramolecular cyclization of the mixed anhydride, derived from cyclopropanol 1g and 3-nitrobenzoic reagent 2g, under the conditions developed by Yamamoto and co-workers [71]. Unfortunately, cyclopropanol ring opening product 27 was obtained instead of expected 11-membered macrolactone 25a. To our delight, simple exchange of the solvent system from acetonitrile/THF to CH2Cl2/acetonitrile (Entry 2) allowed to perform the desired oxidative fragmentation-macrolactonization reaction. Addition of small amount of acetonitrile as co-solvent (ca. 1 mL per 150 mL of CH2Cl2) was only necessary to solubilize Sc(OTf)3 catalyst, which mediated intramolecular cyclization of intermediate 3-nitrobenzoic mixed anhydride [71] and furnished 25a in 62% isolated yield, along with 14% of cyclic diolide side product 26a. The macrocyclizations were performed with a diluted solution of 2g or 2e (ca. 0.005 M).
The analogous transformation performed with cyclopropanol 1h afforded larger 13-membered macrocyclic lactone 25b in 82% yield (Entry 3), although proceeded significantly slower and required 189 h reaction time, including slow 21 h addition of 1h and subsequent refluxing of the reaction mixture for ca. 7 days. Aqueous work-up before the indicated time resulted in reduced yields of 25b and delivered considerable amounts of 12-hydroxydodecanoic acid. The reaction outcome can be further improved with 2,4,6-trichlorobenzoic reagent 2e (Entry 4) or with the use or hafnium(IV) triflate catalyst (Entry 5) [73,74].
Finally, we tested the performance Sc(OTf)3-catalyzed macrolactonization in tandem with intramolecular ring scissoring of bicyclic cyclopropanol 1i with reagent 2e (Scheme 4). Unfortunately in this case macrolactonization was less successful, affording the corresponding 13-membered macrocycle 28 with endocyclic trans-double bond in low 30% yield due to formation of several non-cyclic and diolide side-products. Nevertheless, yield of macrocycle 28 was almost twice higher than obtained previously by the reaction of 1i with PIFA [30].

3. Experimental Section

3.1. General Experimental Methods

Solvents were used as obtained from commercial sources without any further purification or dried if required over 4 Å molecular sieves. Chemicals (including phenyliodine(III) reagents 2a, 2b) were purchased from Sigma-Aldrich (St. Louis, MO, USA), Fluorochem (London, UK) and Alfa Aesar (Ward Hill, Mass, USA) and used as received unless other indicated. Bis(tert-butylcarbonyloxy)iodobenzene 2c was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). Commercial samples of scandium and hafnium triflates were dehydrated prior to use by heating under reduced pressure (>1 torr). Cyclopropanols 1a-d have been prepared by Kulinkovich cyclopropanation of the corresponding esters or lactones [9]. Preparation of cyclopropanols 1g and 1h is described in the Supplementary Materials. Peptide cyclopropanol 1e and bicyclic cyclopropanols 1f and 1i have been prepared by following the published protocols [30,39]. Silica gel 40–100 μm was used for column chromatography; silica gel 60F254 plates were used for TLC. 1H-NMR (400 and 500 MHz), 13C-NMR (100.6 and 125 MHz) spectra were recorded on Avance spectrometers (Bruker, Billerica, Mass, USA). Chemical shifts are given in δ value with CHCl3 (δ = 7.26 ppm) and CDCl3 (δ = 77.16 ppm) as internal standards for 1H-NMR and 13C-NMR spectra. FT-IR spectra were recorded on a Bruker Tensor 27 FT or a Bruker Vertex 70 spectrometers. HRMS data was obtained on a HPLC/Q-TOF G6540A Mass Spectrometer (Agilent, Santa Clara, CA, USA) using AJS ESI method in positive ion detection modes or a LTQ Orbitrap Discovery spectrometer (Thermo Fisher Scientific, Waltham, Mass, USA) using electrospray ionization (ESI). Melting points were determined with a SMP40 apparatus (Stuart, Staffordshire, UK).

3.2. Typical Procedure for Preparation of PhI(O2CAr)2 Reagents [for Ar = 2,4,6-trichlorophenyl, 2e]

A 250 mL round-bottom flask was charged with (diacetoxyiodo)benzene (3.22 g, 10 mmol) and 2,4,6-trichlorobenzoic acid (4,51 g, 20 mmol). Anhydrous diethyl carbonate (50 mL) was added and the solids were dissolved via stirring and gentle heating with a heat gun. The obtained clear solution was stirred at room temperature for 2 h (during this stage, white precipitate could start to form). The solvent was evaporated under reduced pressure. The remained solid or oily residue was triturated with cyclohexane, filtered, washed with cyclohexane (2 × 10 mL) and dried under reduced pressure to afford the title compound (6.19 g, 95% yield) as white or slightly yellowish crystals. The obtained material is pure enough to be used as obtained. If required, purification can be performed by recrystallization from ethyl acetate/cyclohexane. (Bis(2,4,6-trichlorobenzoyloxy)iodo)benzene 2e: white crystalline solid, m.p. 159 °C (ethyl acetate/cyclohexane). IR (KBr), cm−1 1659, 1580, 1572, 1120, 557. 1H-NMR (400 MHz, CDCl3) δ = 8.26 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.27 (s, 4H). 13C-NMR (100.6 MHz, CDCl3) δ = 168.2, 135.7, 135.6, 132.7, 132.4, 131.4, 128.1, 123.0. HRMS (ESI) m/z calcd for C20H9Cl6IO4Na+ [M+Na]+ 672.7569 (monoisotopic), 674.7541 (most abundant), found [M+Na]+ 672.7555 (monoisotopic), 674.7531 (most abundant).
(Bis(3-nitrobenzoyloxy)iodo)benzene (2g): white crystalline solid, m.p. 150–151 °C (dichloromethane/petroleum ether). IR (KBr), cm−1 1657, 1625, 1615, 1524, 1348, 721, 430. 1H-NMR (400 MHz, CDCl3) δ = 8.71 (t, J = 1.9 Hz, 2H), 8.36 (ddd, J = 8.3, 1.9, 1.1 Hz, 2H), 8.32–8.20 (m, 4H), 7.78–7.67 (m, 1H), 7.66–7.56 (m, 4H). 13C-NMR (100.6 MHz, CDCl3) δ = 169.1, 148.2, 136.0, 135.2, 132.6, 131.8, 131.6, 129.6, 127.2, 125.2, 122.3.
(Bis(benzoyloxy)iodo)benzene (2d): white crystalline solid. 1H-NMR (400 MHz, CDCl3) δ = 8.27–8.21 (m, 2H), 7.96–7.90 (m, 4H), 7.66–7.60 (m, 1H), 7.59–7.46 (m, 4H), 7.41–7.34 (m, 4H). 13C-NMR (100.6 MHz, CDCl3) δ = 171.5, 135.0, 132.6, 131.8, 131.1, 130.3, 130.2, 128.3, 122.5. NMR data correspond to those published previously [75].
(Bis(3-fluorobenzoyloxy)iodo)benzene (2f): white crystalline solid. 1H-NMR (400 MHz, CDCl3) δ = 8.27–8.20 (m, 2H), 7.74–7.70 (m, 2H), 7.69–7.62 (m, 1H), 7.62–7.51 (m, 4H), 7.35 (td, J = 8.0, 5.5 Hz, 2H), 7.19 (tdd, J = 8.0, 2.7, 1.1 Hz, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 170.2 (d, JCF = 2.8 Hz), 162.5 (d, JCF = 246.9 Hz), 135.0, 132.4 (d, JCF = 7.2 Hz), 132.1, 131.3, 129.9 (d, JCF = 7.7 Hz), 126.0 (d, JCF = 3.0 Hz), 122.4, 119.7 (d, JCF = 21.4 Hz), 117.1 (d, JCF = 22.7 Hz).
Other phenyliodine(III) dicarboxylates 2h-k were prepared analogously in chlorobenzene as solvent on a 1–2 mmol scale following published procedures [60,61], and used as obtained without any purification.

3.3. General Procedure for Generation of Mixed Anhydrides from Cyclopropanols and Reagent 2e

A solution of cyclopropanol 1 (0.5 mmol) in anhydrous CHCl3 or CH2Cl2 (3 mL) was added to the stirred solution of phenyliodine(III) reagent 2e (327 mg, 0.5 mmol, 1.0 equiv.) in anhydrous CHCl3 or CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature. TLC analysis or 1H-NMR monitoring (in CDCl3) showed full consumption of the starting cyclopropanol 1 after 2 h. The reaction with reagent 2g was carried out in the same manner. The obtained solution of a mixed anhydride was quenched with a corresponding nucleophile as described below, affording compounds 8–24.

3.3.1. N-Benzylnonanamide (8)

Benzylamine (160 mg, 1.5 mmol, 3 equiv.) was added to the solution of mixed anhydride, generated from 1-octylcyclopropan-1-ol 1b and reagent 2g in CH2Cl2. Stirring was continued overnight (12 h). The reaction was quenched with 10% HCl solution, then extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (117 mg, 95% yield). IR (CCl4) cm−1 3453, 3331, 3089, 3068, 3032, 1682, 1532, 1505. 1H-NMR (400 MHz, CDCl3) δ = 7.38–7.22 (m, 5H), 5.69 (br.s, 1H), 4.45 (d, J = 5.6 Hz, 2H), 2.21 (t, J = 7.5 Hz, 2H), 1.66 (quint., J = 7.5 Hz, 2H), 1.38–1.18 (m, 10H), 0.88 (t, J = 6.8 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.5, 138.5, 128.7, 127.8, 127.5, 43.7, 36.8, 31.9, 29.4, 29.2, 25.9, 22.7, 14.1. NMR data correspond to those published previously [76].

3.3.2. N,N-Diethylnonanamide (9)

Diethylamine (110 mg, 1.5 mmol, 3 equiv.) was added to the solution of mixed anhydride, generated from cyclopropanol 1b and reagent 2g in CH2Cl2. Stirring was continued overnight (12 h) at room temperature, then refluxed for 2 h. The reaction was quenched with 10% HCl solution, then extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (96 mg, 90% yield). IR (liquid film) cm−1 1643. 1H-NMR (500 MHz, CDCl3) δ = 3.36 (q, J = 7.1 Hz, 2H), 3.29 (q, J = 7.1 Hz, 2H), 2.27 (t, J = 7.8 Hz, 2H), 1.71–1.53 (m, 2H), 1.38–1.20 (m, 10H), 1.16 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 6.7 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ = 172.7, 42.1, 40.2, 33.3, 32.0, 29.7, 29.6, 29.3, 25.7, 22.8, 14.5, 14.2, 13.2. NMR data correspond to those published previously [77].

3.3.3. N-Methoxy-N-methylnonanamide (10)

A solution of N-methoxy-N-methylamine was prepared by mixing of N,O-dimethylhydroxylamine hydrochloride (98 mg, 1 mmol, 2 equiv.) and triethylamine (404 mg, 4 mmol, 8 equiv.) in anhydrous CH2Cl2 (5 mL) and CH3CN (3 mL). The obtained solution was added to the solution of mixed anhydride, generated from cyclopropanol 1b and reagent 2g in CH2Cl2. Stirring was continued overnight (12 h) at room temperature, then refluxed for 2 h. The reaction was quenched with 10% HCl solution, then extracted with CH2Cl2 (3 × 8 mL). The combined organic layers were washed successively with saturated NaHCO3, NaCl, dried (Na2SO4) and filtered. After evaporation of the solvents, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (82 mg, 82% yield). IR (liquid film) cm−1 1671. 1H-NMR (500 MHz, CDCl3) δ = 3.67 (s, 3H), 3.16 (s, 3H), 2.39 (t, J = 7.4 Hz, 2H), 1.66–1.55 (m, 2H), 1.37–1.17 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ = 175.0, 61.3, 32.0, 32.0, 29.8, 29.6, 29.5, 29.3, 24.8, 22.8, 14.2. NMR data correspond to those published previously [78].

3.3.4. N-Benzyl-3-phenylpropanamide (11)

Benzylamine (80 mg, 0.75 mmol, 1.5 equiv.) and triethylamine (152 mg, 1.5 mmol, 3 equiv.) were added to the solution of mixed anhydride, generated from 1-phenethylcyclopropan-1-ol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 10% HCl solution, then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). White crystalline solid (108 mg, 90% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.33–7.25 (m, 5H), 7.25–7.18 (m, 3H), 7.17–7.12 (m, 2H), 5.59 (br.s, 1H), 4.40 (d, J = 5.7 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.52 (t, J = 7.6 Hz, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 172.0, 140.9, 138.3, 128.8, 128.7, 128.6, 127.9, 127.6, 126.4, 43.7, 38.7, 31.9. NMR data correspond to those published previously [79].

3.3.5. N-Methoxy-N-methyl-3-phenylpropanamide (12)

N,O-Dimethylhydroxylamine hydrochloride (73 mg, 0.75 mmol, 1.5 equiv.) and triethylamine (152 mg, 1.5 mmol, 3 equiv.) were added to the reaction mixture containing the mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 10% HCl solution, then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (85 mg, 88% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.37–7.13 (m, 5H), 3.58 (s, 3H), 3.17 (s, 3H), 2.96 (t, J = 7.9 Hz, 2H), 2.74 (t, J = 7.9 Hz, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.8, 141.3, 128.5, 128.5, 126.1, 61.2, 33.8, 32.2, 30.7. NMR data correspond to those published previously [80].

3.3.6. N-(Benzyloxy)-3-phenylpropanamide (13)

The reaction mixture containing the mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3, was slowly added dropwise (within an hour) to the excess of O-benzylhydroxylamine BnONH2 (615 mg, 5.0 mmol, 10 equiv.) in anhydrous CHCl3 (3.5 mL). Stirring was continued overnight (10 h). After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). White crystalline solid (91 mg, 71% yield). 1H-NMR (400 MHz, CD3OD) δ = 7.41–7.23 (m, 7H), 7.23–7.15 (m, 3H), 4.71 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H). Note: signal of the amide NH proton was not observed due to proton exchange with the solvent. 13C-NMR (100.6 MHz, CD3OD) δ = 171.8, 141.7, 136.9, 130.3, 129.6, 129.5, 129.5, 129.4, 127.3, 79.0, 35.6, 32.4. NMR data correspond to those published previously [81].

3.3.7. N-Benzylcyclohexanecarboxamide (14)

A solution of benzylamine (160 mg, 1.5 mmol, 3 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from 1-cyclohexylcyclopropan-1-ol 1c and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The organic phase was washed with 2M aq. HCl (2 mL), water (2 mL), sat. aq. NaCl (1 mL) and organic solvent was evaporated under reduced pressure. To remove 2,4,6-trichlorobenzoic acid, the residue was treated with 2M aq. KOH (2 mL), then extracted with CH2Cl2 (3 × 2 mL) and dried (MgSO4). The solvent was evaporated and the obtained residue was triturated with hexane, filtered and washed with hexane to afford the title compound as white crystalline solid (84 mg, 77% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.37–7.28 (m, 2H), 7.31–7.22 (m, 3H), 5.78 (br.s, 1H), 4.43 (d, J = 5.6 Hz, 2H), 2.11 (tt, J = 11.8, 3.5 Hz, 1H), 1.93–1.84 (m, 2H), 1.84–1.70 (m, 2H), 1.70–1.61 (m, 1H), 1.59–1.39 (m, 2H), 1.34–1.13 (m, 3H). 13C-NMR (100.6 MHz, CDCl3) δ = 176.0, 138.7, 128.8, 127.8, 127.6, 45.7, 43.5, 29.9, 25.9. HRMS (ESI) m/z calcd for C14H20NO+ [M+H]+ 218.1539, found 218.1541. NMR data correspond to those published previously [82].

3.3.8. tert-Butyl 4-(morpholine-4-carbonyl)piperidine-1-carboxylate (15)

A solution of morpholine (130 mg, 1.5 mmol, 3 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from the tert-butyl 4-(1-hydroxycyclopropyl)piperidine-1-carboxylate 1d and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The organic phase was washed with 2M aq. HCl (2 mL), water (2 mL), sat. aq. NaCl (1 mL) and the organic solvent was evaporated under reduced pressure. To remove 2,4,6-trichlorobenzoic acid, the residue was treated with 2M aq. KOH (2 mL), then extracted with CH2Cl2 (3 × 2 mL) and dried (MgSO4). The solvent was evaporated and the obtained residue was triturated with hexane, filtered and washed with hexane to afford the title compound as white crystalline solid (122 mg, 82% yield). 1H-NMR (400 MHz, CDCl3) δ = 4.14 (br.s, 2H), 3.73–3.64 (m, 4H), 3.64–3.56 (m, 2H), 3.55–3.44 (m, 2H), 2.85–2.65 (m, 2H), 2.64–2.53 (m, 1H), 1.83–1.58 (m, 4H), 1.44 (s, 9H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.2, 154.8, 79.7, 67.1, 66.9, 46.1, 43.3, 42.2, 38.4, 28.6, 28.5. HRMS (ESI) m/z calcd for C15H26N2O4Na+ [M+Na]+ 321.1785, found 321.1783.

3.3.9. N-(2-Hydroxy-2-methylpropyl)-3-phenylpropanamide (16)

A solution of DIPEA (194 mg, 1.5 mmol, 3 equiv.) and 1-amino-2-methylpropan-2-ol (45 mg, 0.5 mmol, 1.0 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The organic phase was washed with 2M aq. HCl (2 mL), water (2 mL), sat. aq. NaCl (1 mL) and the organic solvent was evaporated under reduced pressure. To remove 2,4,6-trichlorobenzoic acid, the residue was treated with 2M aq. KOH (1 mL), then extracted with CH2Cl2 (3 × 2 mL) and dried (Na2SO4). Solvents were evaporated and the obtained residue was triturated with hexane, filtered and washed with hexane to afford the title compound as white crystalline solid (90 mg, 81% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.32–7.23 (m, 2H), 7.24–7.15 (m, 3H), 5.85 (br.s, 1H), 3.21 (d, J = 6.0 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.53 (t, J = 7.6 Hz, 2H), 2.35 (br.s, 1H), 1.13 (s, 6H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.2, 140.8, 128.7, 128.5, 126.5, 70.9, 50.4, 38.6, 31.9, 27.3. HRMS (ESI) m/z calcd for C13H20NO2+ [M+H]+ 222.1489, found 222.1484. NMR data correspond to those published previously [83].

3.3.10. Ethyl 4-(3-phenylpropanamido)benzoate (17)

A solution of N-methylimidazole (123 mg, 1.5 mmol, 3 equiv.) and ethyl 4-aminobenzoate (83 mg, 0.5 mmol, 1.0 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 2M aq. HCl (2 mL), then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). White crystalline solid (125 mg, 84% yield). 1H-NMR (400 MHz, CDCl3) δ = 8.00–7.95 (m, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.35–7.27 (m, 3H), 7.25–7.19 (m, 3H), 4.35 (q, J = 7.1 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) δ = 170.7, 166.3, 142.0, 140.5, 130.9, 128.8, 128.5, 126.6, 126.1, 118.9, 61.0, 39.7, 31.5, 14.5. HRMS (ESI) m/z calcd for C18H20NO3+ [M+H]+ 298.1438, found 298.1437.

3.3.11. (E)-N-Benzyl-12-(benzyloxy)dodec-6-enamide (18)

Benzylamine (160 mg, 1.5 mmol, 3 equiv.) was added to the solution of mixed anhydride, generated from exo-7-(5-(benzyloxy)pentyl)bicyclo[4.1.0]heptan-1-ol (1f) and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 10% HCl solution, then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (Na2SO4) and filtered. After evaporation of the solvent, the white product (118 mg, 60%) was isolated by silica gel column chromatography (PE/EtOAc). IR (CCl4) cm−1 3453, 3090, 3068, 3032, 1683. 1H-NMR (400 MHz, CDCl3) δ = 7.39–7.23 (m, 10H), 5.71 (br.s, 1H), 5.45–5.30 (m, 2H), 4.49 (s, 2H), 4.44 (d, J = 5.6 Hz, 2H), 3.45 (t, J = 6.6 Hz, 2H), 2.25–2.14 (m, 2H), 2.07–1.92 (m, 4H), 1.73–1.53 (m, 6H), 1.46–1.29 (m, 4H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.0, 138.9, 138.6, 130.9, 130.0, 128.9, 128.5, 128.0, 127.8, 127.7, 127.6, 73.0, 70.6, 43.8, 36.8, 32.6, 32.4, 29.8, 29.5, 29.4, 25.9, 25.4. Found: C, 79.29; H, 8.95%. C26H35NO2 requires C, 79.35; H, 8.96%.

3.3.12. 6-((3S,9S,14aR)-9-Benzyl-6,6-dimethyl-1,4,7,10-tetraoxotetradecahydropyrrolo[1,2-a][1,4,7,10]tetraazacyclododecin-3-yl)-N-(benzyloxy)hexanamide (cyclopeptide 19)

Preparation of this compound and its characterization has been described by us previously [39].

3.3.13. Benzyl nonanoate (20)

Benzyl alcohol (54 mg, 0.5 mmol, 1.0 equiv.) and DMAP (122 mg, 1.0 mmol, 2.0 equiv.) were added to the solution of mixed anhydride, generated from cyclopropanol 1b and reagent 2g in CH2Cl2. Stirring was continued overnight (12 h). The reaction was quenched with 10% HCl solution, then extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried (Na2SO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (114 mg, 92% yield). IR (liquid film) cm−1 3091, 3067, 3035, 1739. 1H-NMR (400 MHz, CDCl3) δ = 7.50–7.28 (m, 5H), 5.12 (s, 2H), 2.36 (t, J = 7.5 Hz, 2H), 1.65 (quint., J = 7.5 Hz, 2H), 1.40–1.20 (m, 10H), 0.89 (t, J = 6.9 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) δ = 173.8, 136.3, 128.7, 128.3, 66.2, 34.5, 31.9, 29.3, 29.3, 29.2, 25.1, 22.8, 14.2.

3.3.14. Phenyl 3-phenylpropanoate (22)

Method A: A solution of DIPEA (194 mg, 1.5 mmol, 3 equiv.) and phenol (52 mg, 0.55 mmol, 1.1 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 2M aq. HCl (2 mL), then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (86 mg, 76% yield).
Method B [65]: A solution of phenol (47 mg, 0.5 mmol, 1.0 equiv.) in CHCl3 (0.5 mL) was added to the solution of mixed TFA anhydride, generated from cyclopropanol 1a and reagent 2b (PIFA) in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with sat. aq. NaHCO3 solution, then extracted with CHCl3 (3 × 3 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (79 mg, 70% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.37–7.28 (m, 4H), 7.27–7.17 (m, 4H), 7.01–6.99 (m, 1H), 6.99–6.97 (m, 1H), 3.06 (t, J = 7.7 Hz, 2H), 2.90–2.84 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 171.5, 150.8, 140.3, 129.5, 128.7, 128.5, 126.6, 125.9, 121.7, 36.1, 31.1. HRMS (ESI) m/z calcd for C15H14O2Na+ [M+Na]+ 249.0886, found 249.0888. NMR data correspond to those published previously [84].

3.3.15. Pentafluorophenyl 3-phenylpropanoate (23)

A solution of DIPEA (194 mg, 1.5 mmol, 3 equiv.) and pentafluorophenol (101 mg, 0.55 mmol, 1.1 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 2M aq. HCl (2 mL), then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (137 mg, 87% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.37–7.31 (m, 2H), 7.28–7.23 (m, 3H), 3.15–3.05 (m, 2H), 3.03–2.97 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 168.9, 139.4, 128.9, 128.4, 126.9, 35.1, 30.8. Note: the signals of carbon atoms from the C6F5 fragment has been accumulated with low S/N ratio due to coupling on fluorine atoms, and therefore cannot be reliably described. HRMS (ESI) m/z calcd for C15H9F5O2Na+ [M+Na]+ 339.0415, found 339.0420.

3.3.16. S-(4-Methoxybenzyl) 3-phenylpropanethioate (24)

A solution of DIPEA (194 mg, 1.5 mmol, 3 equiv.) and (4-methoxyphenyl)methanethiol (85 mg, 0.55 mmol, 1.1 equiv.) in CHCl3 (1 mL) was added to the solution of mixed anhydride, generated from cyclopropanol 1a and reagent 2e in CHCl3. Stirring was continued overnight (12 h). The reaction was quenched with 2M aq. HCl (2 mL), then extracted with CHCl3 (3 × 5 mL). The combined organic layers were dried (MgSO4) and filtered. After evaporation of the solvent, the product was isolated by silica gel column chromatography (PE/EtOAc). Colorless oil (92 mg, 64% yield). 1H-NMR (400 MHz, CDCl3) δ = 7.32–7.25 (m, 2H), 7.25–7.14 (m, 5H), 6.86–6.80 (m, 2H), 4.09 (s, 2H), 3.79 (s, 3H), 3.04–2.95 (m, 2H), 2.91–2.84 (m, 2H). 13C-NMR (100.6 MHz, CDCl3) δ = 198.5, 159.3, 140.5, 130.4, 130.0, 129.0, 128.8, 126.8, 114.5, 55.8, 45.7, 33.2, 31.9. HRMS (ESI) m/z calcd for C17H18O2SNa+ [M+Na]+ 309.0920, found 309.0915.

3.4. General Procedure for the Synthesis of Macrolactones 25a,b

To a solution of reagent 2e (430 mg, 0.66 mmol, 2 equiv.) in anhydrous CH2Cl2 (140 mL, 0.005 M) a solution of scandium(III) triflate (32 mg, 0.066 mmol, 0.2 equiv.) in anhydrous CH3CN (0.7 mL) was added dropwise with stirring under inert (argon) atmosphere. To the resulting mixture a solution of 1-(11-hydroxyundecyl)cyclopropan-1-ol 1h (75 mg, 0.33 mmol) in anhydrous CH2Cl2 (9 mL) was added dropwise over 19 h under reflux conditions and stirring. Upon completion of the addition, the mixture was refluxed for 7 days, cooled to room temperature, and treated with saturated aqueous NaHCO3 solution (30 mL) until pH~8. The aqueous phase was separated and extracted with diethyl ether (2 × 30 mL). The combined organic extracts were washed with brine (2 × 15 mL) and dried with Na2SO4. After evaporation of solvents under reduced pressure and purification of the residue by silica gel column chromatography (eluent: PE, then PE/EtOAc), oxacyclotridecan-2-one 25b (59 mg, 91% yield) and 1,14-dioxacyclohexacosane-2,15-dione 26b (5 mg, 8% yield) were obtained.
Analogously oxacycloundecan-2-one 25a (35 mg, 62% yield) and 1,12-dioxacyclodocosane-2,13-dione 26a (8 mg, 14% yield) were obtained from 1-(9-hydroxynonyl)cyclopropan-1-ol 1g with reagent 2g. The reactions were carried out for a total of 17 h (addition of substrate during 11 h following with heating of the reaction mixture under reflux conditions during 6 h).

3.4.1. Oxacycloundecan-2-one (25a)

Colorless oil. IR (liquid film) cm−1 1731. 1H-NMR (400 MHz, CDCl3) δ = 4.20–4.14 (m, 2H), 2.36–2.31 (m, 2H), 1.79–1.67 (m, 4H), 1.56–1.47 (m, 2H), 1.47–1.22 (m, 8H). 13C-NMR (100.6 MHz, CDCl3) δ = 174.3, 64.9, 35.4, 26.4, 25.6, 25.5, 24.9, 24.3, 22.7, 21.6. HRMS (ESI) calcd for C10H19O2+ [M+H]+ 171.1380, found 171.1392. NMR data correspond to those published previously [85].

3.4.2. Oxacyclotridecan-2-one (25b)

Colorless oil. IR (liquid film) cm−1 1734. 1H-NMR (400 MHz, CDCl3) δ = 4.18–4.12 (m, 2H), 2.39–2.32 (m, 2H), 1.74–1.59 (m, 4H), 1.47–1.27 (m, 14H). 13C-NMR (100.6 MHz, CDCl3) δ = 174.3, 64.7, 34.8, 27.6, 26.8, 26.6, 25.6, 25.6, 25.2, 24.7, 24.4. HRMS (ESI) calcd for C12H23O2+ [M+H]+ 199.1693, found 199.1690. NMR data correspond to those published previously [86].

3.5. Preparation of (E)-oxacyclotridec-7-en-2-one (28)

To a solution of reagent 2e (181 mg, 0.277 mmol, 1.08 equiv.) in anhydrous CH2Cl2 (61 mL, 0.005 M) a solution of scandium(III) triflate (25 mg, 0.051 mmol, 0.2 equiv.) in anhydrous CH3CN (0.3 mL) was added dropwise with stirring under inert (argon) atmosphere. To the resulting mixture a solution of exo-7-(5-hydroxypentyl)bicyclo[4.1.0]heptan-1-ol (1i, 51 mg, 0.258 mmol, 1.0 equiv.) in anhydrous CH2Cl2 (9 mL) was added dropwise over 19 h under reflux conditions and stirring under inert atmosphere. Upon completion of the addition, the mixture was refluxed for 26 h, cooled to room temperature, and treated with saturated aqueous NaHCO3 solution (35 mL) until pH~8. The aqueous phase was separated and extracted with CHCl3 (2 × 15 mL). The combined organic extracts were washed with brine (1 × 10 mL) and dried with MgSO4. After evaporation of solvents under reduced pressure, the product was isolated by silica gel column chromatography (eluent: PE, then PE/EtOAc). Colorless oil (15 mg, 30% yield). Isolated product was contaminated with about 13% of inseparable by column chromatography impurity, likely diolide. IR (CCl4) cm−1 1741, 1580, 976. 1H-NMR (500 MHz, CDCl3) δ = 5.47–5.38 (m, 1H), 5.29–5.20 (m, 1H), 4.11 (t, J = 5.0 Hz, 2H), 2.30–2.24 (m, 2H), 2.06–1.99 (m, 2H), 1.98–1.92 (m, 2H), 1.73–1.65 (m, 2H), 1.56–1.49 (m, 2H), 1.49–1.37 (m, 6H). 13C-NMR (125 MHz, CDCl3) δ = 173.7, 132.4, 130.5, 63.3, 35.4, 31.0, 30.7, 29.2, 27.1, 25.9, 23.2, 22.2.

4. Conclusions

In conclusion, we have demonstrated that cyclopropanols can serve as useful precursors of versatile mixed anhydrides, which can be generated by oxidative fragmentation of the cyclopropane ring with phenyliodine(III) dicarboxylates in inert solvents, such as chloroform or dichloromethane. The reaction is especially facile and affords high 95–98% yields of the corresponding mixed anhydrides with phenyliodine(III) dicarboxylates bearing electron-withdrawing carboxylate ligands, e.g., trifluoroacetate, 3-nitro- or 2,4,6-trichlorobenzoate. Mixed anhydrides generated by this approach are suitable to perform the most common acylation reactions, delivering a range of amides, thioester, esters, 11- and 13-membered macrocyclic lactones in good to excellent yields. The reaction conditions are mild and suitable for the last-stage installation of amide functionality into the peptide scaffold. The developed protocol can be used in step-economical syntheses of natural products based on cyclopropanol-ring cleavage strategies, along with generation of molecular libraries from the single cyclopropanol precursor in the framework of diversity-oriented synthesis paradigm. Furthermore, in view of general importance of acyl-transfer reactions from mixed anhydrides [49,87,88], the new method of their generation could serve as a beneficial supplement to the existing approaches.

Supplementary Materials

Additional experimental protocols, characterization of mixed anhydrides 3a and 3e, characterization of by-products, preparation of cyclopropanols 1g and 1h, copies of 1H and 13C-NMR spectra.

Author Contributions

D.M.Z. and G.Z.E. conducted the experimental part, characterization of new compounds; D.M.Z. developed the method for preparation and synthetic use of mixed anhydrides; D.M.Z. and D.G.K. prepared the original draft; M.L. and G.Z.E. reviewed and edited the draft; M.L. and D.G.K. supervised the project and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Tallinn University of Technology (TalTech, Grant No. B58), Centre of Excellence in Molecular Cell Engineering (Grant 2014–2020.4.01.15–0013) and Estonian Ministry of Education and Research (Grant IUT19-32). The work has been partially supported by ASTRA “TUT Institutional Development Program for 2016-2022” Graduate School of Functional Materials and Technologies (2014-2020.4.01.16-0032).

Data Availability Statement

The data presented in this study are available in the article and supplementary material.

Acknowledgments

We would like to thank Ivar Järving and Tatsiana Shalima (Tallinn University of Technology, TalTech) for their help with HRMS measurements. Marina Kudrjašova (TalTech) is acknowledged for the assistance with NMR acquisitions.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 26 00140 sch001 550
Scheme 1. Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates and its applications in total synthesis. Outline of the current work.
Scheme 1. Oxidative fragmentation of tertiary cyclopropanols with phenyliodine(III) dicarboxylates and its applications in total synthesis. Outline of the current work.
Molecules 26 00140 sch001
Molecules 26 00140 sch002 550
Scheme 2. Generation of mixed anhydrides by oxidative fragmentation of cyclopropanol 1a.
Scheme 2. Generation of mixed anhydrides by oxidative fragmentation of cyclopropanol 1a.
Molecules 26 00140 sch002
Molecules 26 00140 g001 550
Figure 1. (a) Kinetic plot for the reaction of PhI(OCOAr)2 reagents 2d (Ar = phenyl), 2f (3-fluorophenyl), 2g (3-nitrophenyl) and 2e (2,4,6-trichlorophenyl) with excess of cyclopropanol 1a (10 equiv.) in CDCl3 at 295 K and the corresponding pseudo-first-order rate constants. Initial concentration of 2 [A]0 = 0.02 M; (b) Relationship between the logarithm of rate constants and pKa values of the corresponding substituted benzoic acids ArCO2H.
Figure 1. (a) Kinetic plot for the reaction of PhI(OCOAr)2 reagents 2d (Ar = phenyl), 2f (3-fluorophenyl), 2g (3-nitrophenyl) and 2e (2,4,6-trichlorophenyl) with excess of cyclopropanol 1a (10 equiv.) in CDCl3 at 295 K and the corresponding pseudo-first-order rate constants. Initial concentration of 2 [A]0 = 0.02 M; (b) Relationship between the logarithm of rate constants and pKa values of the corresponding substituted benzoic acids ArCO2H.
Molecules 26 00140 g001
Molecules 26 00140 sch003 550
Scheme 3. Acylation of N, O and S-nucleophiles with mixed anhydrides generated from cyclopropanols 1a-f and phenyliodine(III) dicarboxylates. Unless noted otherwise, the reactions were run with 2,4,6-trichlorobenzoyloxy reagent 2e in 0.5 mmol scale. Yields of isolated products are given (see Experimental Section for the details). NMR inspection of the several crude reaction mixtures evidenced quantitative formation of the corresponding amide products. Notes: a The reaction was performed with 3-nitrobenzoyloxy reagent 2g. b With N-methylimidazole (NMI) as a base. c Nonanoic acid was obtained after aqueous work-up. d Oxidation was carried out with PIFA (2b), acylation of PhOH was performed in the absence of a base.
Scheme 3. Acylation of N, O and S-nucleophiles with mixed anhydrides generated from cyclopropanols 1a-f and phenyliodine(III) dicarboxylates. Unless noted otherwise, the reactions were run with 2,4,6-trichlorobenzoyloxy reagent 2e in 0.5 mmol scale. Yields of isolated products are given (see Experimental Section for the details). NMR inspection of the several crude reaction mixtures evidenced quantitative formation of the corresponding amide products. Notes: a The reaction was performed with 3-nitrobenzoyloxy reagent 2g. b With N-methylimidazole (NMI) as a base. c Nonanoic acid was obtained after aqueous work-up. d Oxidation was carried out with PIFA (2b), acylation of PhOH was performed in the absence of a base.
Molecules 26 00140 sch003
Molecules 26 00140 sch004 550
Scheme 4. Synthesis of trans-alkenolide 28 via intramolecular ring scissoring-macrocyclization of bicyclic cyclopropanol 1i.
Scheme 4. Synthesis of trans-alkenolide 28 via intramolecular ring scissoring-macrocyclization of bicyclic cyclopropanol 1i.
Molecules 26 00140 sch004
Table
Table 1. Oxidation fragmentation of cyclopropanol 1a with phenyliodine(III) reagents. a
Table 1. Oxidation fragmentation of cyclopropanol 1a with phenyliodine(III) reagents. a
EntryReagent SolventAdditive or CatalystReaction Time, Min bMain ProductYield % cYield of 5, % c
12aCD3OD–<15493–
22aCDCl3BnNH2 (3 equiv.)300no reaction
32aCDCl3–600 d3a5012
42aCDCl3TfOH (1 mol%)<53a9010 e
52bCDCl3–73b95Trace f
62cCDCl3–1500– g– g– g
72cCDCl3TfOH (1 mol%)1500– g– g– g
82dCDCl3–500 d3d468
92eCDCl3–1003e982
102eCDCl3TfOH (1 mol%)<53e7030 e
112eCDCl3MsOH (1 mol%)303e954 e
122eCDCl3CF3CO2H (1 mol%)903e945 e
132etoluene-d8–<153e904
147CD3ODor CDCl3–1500no reaction
a Reactions were run in NMR tubes with approx. 0.0375 mmol of 1a and 2a–d in 0.75 mL of the respective solvent (0.05 M). Progress was monitored by 1H-NMR spectroscopy. b Time required for full conversion of 1a. c Yields determined by 1H- NMR. d Time required for ~90% conversion of 1a, full conversion was achieved within 24 h. e Yield of 6. f 1-Phenylpentan-3-one was formed in ~4% yield. g Not determined, complex mixture of products.
Table
Table 2. Acylation of benzylamine with mixed anhydrides generated from 1-octylcyclopropanol 1b and phenyliodine(III) dicarboxylates 2a-k.a.
Table 2. Acylation of benzylamine with mixed anhydrides generated from 1-octylcyclopropanol 1b and phenyliodine(III) dicarboxylates 2a-k.a.
Molecules 26 00140 i001
EntryReagent 2a-kRTime, min bYield of 8, % c
12aMe12022 e,d
22h Molecules 26 00140 i0029591
32e Molecules 26 00140 i0033094
42i Molecules 26 00140 i004<1488
52g Molecules 26 00140 i0059095
62j Molecules 26 00140 i006– f58
72k Molecules 26 00140 i007– f– f
a Preparative reaction were run with 1 mmol of 1b and 1.07 mmol of 2a-k in CH2Cl2. After the full consumption of cyclopropanol 1b (TLC control), benzylamine (3 mmol, 3 equiv.) was added. b The reaction progress was monitored by 1H-NMR in CDCl3 as a separate experiment (~0.03 M 1b). c Yield of isolated product. d After the aqueous work-up, 8-oxoundecyl acetate by-product was isolated in 12% yield. e N-Benzylacetamide was formed as major product in 44% yield. f Not determined due to low solubility of 2k and 2j and slow reaction rates.
Table
Table 3. Intramolecular O-acylation: synthesis of macrolactones 25a,b.
Table 3. Intramolecular O-acylation: synthesis of macrolactones 25a,b.
Molecules 26 00140 i008
EntrySubstrate Reagent CatalystSolventTime, hYield of 25, % aYield of 26, % a
11g (n = 9)2gSc(OTf)3CH3CN/THF200 b0
2 2gSc(OTf)3CH2Cl2/CH3CN c176214
31h (n = 11)2gSc(OTf)3CH2Cl2/CH3CN1898210
4 2eSc(OTf)3CH2Cl2/CH3CN187918
5 2gHf(OTf)4CH2Cl2/CH3CN17893>7
a Yields of isolated products. b 12-Hydroxydodecan-3-one 27 was isolated in 81% yield. c Acetonitrile was used as a solubilizing additive for Sc(OTf)3, ca. 1 mL per 150 mL of CH2Cl2.
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Zubrytski, D.M.; Elek, G.Z.; Lopp, M.; Kananovich, D.G. Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates. Molecules 2021, 26, 140. https://doi.org/10.3390/molecules26010140

AMA Style

Zubrytski DM, Elek GZ, Lopp M, Kananovich DG. Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates. Molecules. 2021; 26(1):140. https://doi.org/10.3390/molecules26010140

Chicago/Turabian Style

Zubrytski, Dzmitry M., Gábor Zoltán Elek, Margus Lopp, and Dzmitry G. Kananovich. 2021. "Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates" Molecules 26, no. 1: 140. https://doi.org/10.3390/molecules26010140

APA Style

Zubrytski, D. M., Elek, G. Z., Lopp, M., & Kananovich, D. G. (2021). Generation of Mixed Anhydrides via Oxidative Fragmentation of Tertiary Cyclopropanols with Phenyliodine(III) Dicarboxylates. Molecules, 26(1), 140. https://doi.org/10.3390/molecules26010140

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