Eco-Sustainable Catalytic System for Green Oxidation of Spirostanic Alcohols Using Hypervalent Iodine (III) Tempo-4-n-Acetoxyamine System

Abstract

The oxidation of the 3β-hydroxy group in the steroidal substrates obtained from naturally occurring sources, i.e., solanaceae steroidal sapogenins, is an important process in the preparation of ecdysteroid analogs. The need for selective green oxidation methodologies for steroidal alcohols (spirostenols, diosgenine, and derivatives) avoid the use of toxic Cr (VI) derivatives, without the isomerization of the double bond at 5,6 position and also without the oxidative cleavage of the spirocetal moiety is of great methodological significance. Herein, we report the oxidation of spirostanic steroidal alcohols to their carbonyl analogs using hypervalent iodine (III)/TEMPO-4-N-acetoxyamine system. The present method is simple, eco-sustainable, efficient, and high-yielding process for the oxidative transformation of secondary steroidal alcohols without any over-oxidation, isomerization of the double bond, or oxidative cleavage of spirocetalic fragment in different substrates. Therefore, this method does not involve toxic heavy metals and is expected to have wide utility in the oxidation process of these compounds.

1. Introduction

Green or Eco-sustainable Chemistry is a unique, philosophically, methodologically, pedagogically, and experimentally new discipline of chemistry where the convergency of conceptual series: Structure-related Properties-Functionality-Scalability and Environmental Responsibility demonstrates the versatility and applicability of these concepts in a dynamical evolution and design of new experimental tools, techniques, technologies, and in a more advanced structural way of thinking [1]. It is helpful to chemistry and chemical engineers in the field of research, at laboratory scale, and industrial application in real-time, mainly focusing on the development and production of more eco-friendly and efficient processes and products, including scientific-technical and engineering services, which may also have great financial and strategic benefits.

Green chemistry is, generally, based on the 12 principles, which constitute the conceptual and methodological foundation of sustainable development from the point of view of environmentally benign applied chemistry, which were proposed by Anastas and Warner [2] and developed intensively by Sheldon [3, 4] and Lancaster [5]. The principles comprise theoretical and experimental instructions to implement the green chemical eidos related to new chemical products, new unconventional synthesis, new sources of raw materials and energy, and new processes that have been extensively described in classical today’s references [6, 7, 8, 9, 10, 11, 12, 13].

Within this frame of reference, it should be noted that 12 basic principles of green or sustainable chemical engineering have also been described [14].

Steroids constitute one of the oldest known molecular systems and have been discovered in all living systems, forming structural, compositional, and functional parts of biomembranes, defensive secretions and pheromones, and complex neurochemical and hormonal information systems [15], defining, in many points, the molecular evolutionary capacity and metabolic efficiency of living organisms [16]. In this context, several naturally occurring and synthetic steroids are important therapeutic options for a wide range of pathologies. Among them can be considered sex and corticosteroid hormones, bile acids, vitamin D derivatives, and cardiotonic steroids, which have shown unique therapeutic value for the treatment of human diseases.

Oxidation of organic substrates is one of the most important processes on an industrial and laboratory scale [17], where the application of catalytic conditions (heterogeneous or homogeneous) defines the selectivity and yield of the process [18]. One of the most important reaction in organic synthesis and industrial organic chemistry is the oxidation of alcohols (I and II) to their carbonyl derivatives (aldehydes and ketones). This transformation of functionalities, from alcohol to carbonyls, via heterogeneous or homogeneous catalysis or not, using conventional procedures or not, constitutes one of the fundamental synthetic organic reactions of applied green eco-sustainable chemistry in the fundamental fields of technological development for minimizing environmental impact, in such as pharma, agrochemistry, petrochemistry, and fine chemistry [19].

Naturally occurring steroidal derivatives, such as spirostannic alcohols, are characterized by a hydroxyl group in position 3β- in the A-ring of the cyclopentane-perhydro phenanthrene nucleus, being typical secondary alcohol, and, taking into account this consideration, most common oxidative transformation in steroid chemistry is probably the oxidation of alcohol functionality into carbonyl group [20].

A large number of oxidizing agents have been described to transform the 3β-hydroxy group into a ketone group, minimizing collateral reactions depending on the specific synthetic objectives and reaction conditions; among these, the following can be highlighted: Cr₂O₇²⁻ (dichromate), CrO₃/pyridine (Collins’s reagent), Pyridinium chlorochromate (PCC), Pyridinium dichromate (PDC, Cornforth reagent), Dess–Martin periodinane, Dimethylsulfoxide (DMSO)/oxalyl chloride (Swern oxidation), CrO₃/H₂SO₄/acetone (Jones oxidation), Aluminum isopropoxide/acetone (Oppenauer oxidation) [21, 22]. It should be noted that other catalytic oxidative procedures have been developed, which employ molecular oxygen, biphasic catalysis, osmium and ruthenium salts, permanganate salts impregnated on zeolitic or alumosilicate supports, organic hydroperoxides, etc. [23, 24].

In recent years an interesting increase in the application of hypervalent iodine compounds in synthetic organic chemistry has been observed. Several compounds have been recognized as useful reagents with considerable synthetic applicability [25]. Hypervalent iodine derivatives are now commonly used in organic synthesis as efficient multipurpose reagents with very low toxicity and minimal environmental problems after their utilization. The discovery of eco-sustainable catalysis via hypervalent iodine compounds and its application in micro- and meso-scale synthetic chemistry is an important achievement that has also allowed the use of green chemistry concepts [26]. In the last decade Iodo (V), Iodo (VI) reagents have been used for efficient conversion of alcohols to carbonyl compounds [27].

The oxidation of 3-cholesteryl benzoate to the corresponding 4-ketone derivative in 67% yield has been described [28], and authors reported the utilization of Iodoxybenzene (PhIO₂) and a catalytic amount of 2,2′-dipyridyldiselenide as a very mild and efficient catalytic system.

In this setting, and considering the main objective of the communication, should be highlighted that the reagent PhI(OAc)₂ in the presence of alcohol/alkali mixtures -KOH-MeOH is equivalent to PhIO-KOH-MeOH; however, PhI(OAc)₂ (BAIB) is commercially available whilst PhIO is not. Consequently, the reagent (Diacetoxyiodo)benzene, [PhI(OAc)₂], is most widely used in synthetic processes, including in green chemistry protocols. This reagent has been employed in the synthesis of the steroidal dihydroxyacetone side chain with satisfactory yields [29, 30].

Recently N-oxoammonium salts, more specifically, 2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) derivatives have been described and used as a useful reagent for the oxidation of alcohols [31]. These have been used stoichiometrically either in isolated form or generated in situ via acid catalyzed dismutation [32]. In order to increase the efficiency and yield of the oxidation process, different reagents and techniques have been considered for use in conjunction with oxoammonium salts such as m-CPBA [33], N-chloro succinimide, electrooxidations [34, 35, 36]; impregnation on solid support [37].

However, in spite of these relatively new mild selective oxidants, the oxidation of a hydroxy functionality in the steroidal core is a major challenge in organic synthesis particularly by employing eco-friendly oxidizing catalysts [38, 39].

Considering the aforementioned explanations, the main objective of the work is to evaluate the possibility of using the Hypervalent Iodine (III) Tempo-4-n-Acetoxyamine system in the oxidation processes of steroidal alcohols (spirostanols) in eco-sustainable green chemistry conditions.

2. Results and discussion

Brassinosteroid and ecdysteroid spirostanic oxo-analogs bearing different side-chain have shown remarkable plant growth and metamorphosis promoting activities [40]. The synthesis and study of the biological activity of spirostanic compounds with characteristic functionalities of some natural brassino- and ecdy-steroids at different rings have been reported, including some oxidative protocols for selectively oxidation of 3β-hydroxy group in the A-ring into a ketone group [41, 42].

The catalytic oxidation of 3β, 6α, 6β; 12β-hydroxy groups in steroidal substrates obtained from naturally occurring sources, (i.e., solanaceae steroidal sapogenins and phytosterol mixture isolated from sugarcane), is an important process in the preparation of ecdysteroid analogs [43, 44], blatellanosides [45], cytotoxins [46], pharmaceutical molecular templates and potential plant growth promoters [47]. The need for selective oxidation methodologies for steroidal alcohols (spirostenols, diosgenin, solasodine, hecogenin, and some polyhydroxy derivatives) without the oxidation-isomerization of the double bond at Δ^5,6 position and also without the oxidative cleavage of the spirocetal moiety has remained unexplored.

Herein, we wish to report the oxidation of spirostanic steroidal alcohols to their carbonyl analogs using hypervalent iodine (III)/TEMPO-4-N-acetoxyamine system (Figure 1).

Figure 1.

Oxidation of spirostanic steroidal alcohols using hypervalent iodine (III)/ Tempo-4-N-Acetoxyamine system.

This oxidation reaction has been investigated for a large array of steroids derivatives generated from diosgenin using standard procedures and having 3β-hydroxy functionality. It is worthwhile to note, that other functionalities such as double bonds, acetoxy, and tertiary α-hydroxy groups, and spiro segments in the steroidal structure do not get affected by employing this method; the results are described in Figure 2. It is remarkable to note that solasodine (3, Figure 2) after oxidation using that catalytic system yields carbonyl derivative only without any collateral reaction in the NH functionality. The probable mechanism for this oxidation process is similar to the pathway earlier described in the literature and depicted in Figure 3 [34, 48, 49, 50, 51]. It appears that the role of the hypervalent iodine compound (BAIB) is to regenerate the TEMPO-4-N-acetoxyamine in the catalytic cycle. Furthermore, it is observed that in the absence of this TEMPO derivative the oxidation process does not take place. This methodology has also been extended to some non-steroidal substrates like 2-methyl-2-ene pentanol and n-heptanol for obtaining their corresponding carbonyl analogs, thus exhibiting the generality of this procedure.

Figure 2.

Oxidation of spirostanic alcohols. The reported yields refer to isolated, chromatographically pure, or recrystallized carbonyl derivatives. All proposed structures have been confirmed by FTIR and ¹H/¹³CNMR analysis.

Figure 3.

Proposed mechanism for the oxidation of alcohols by BAIB/TEMPO-4-N-acetoxyamine.

In the case of model reactions, obtaining (25R)-Spirost-5α-hydroxy-3,6-dione (4, Figure 2) to corroborate the conversion of the hydroxy functional group in position 3 to its carbonyl derivative (ketone), the chemical shift values (ppm) were used. In the starting substrate ((25R)-Spirost-3β,5α-dihydroxy-6-one) a typical signal (¹H-NMR) is observed at C3-H (3.93 ppm, 1H, H-3); and the ¹³C signal at carbon 3 (67.2 ppm) are related to the presence of a hydroxyl substituent at this position C-3.

During the oxidation process using the hypervalent iodine (III)/TEMPO-4-N-acetoxyamine system yields the keto derivative at C-3.

In the ¹H nmr spectrum, a variation in the magnitude of the chemical shift values (ppm) is observed. In C-3 the signal (3.93 ppm, 1H, H-3, 67.2 ppm, C-OH) disappears and a new signal in ¹³C nmr spectrum at C-3 (210.36 ppm) is observed. This variation of the magnitude of the signal towards lower fields (from 67.2 ppm to 210.2 ppm) corroborates the oxidation of the OH- in C-3 to a carbonyl derivative (ketone). The spectra are represented in Figures 4–6.

Figure 4.

1H-NMR spectrum of starting substrate ((25R)-spirost-3β,5α-dihydroxy-6-one). The typical signal of nonoxidized OH-is observed at C3-H (3.93 ppm, 1H, H-3).

Figure 5.

¹³C-NMR spectrum of starting substrate ((25R)-spirost-3β,5α-dihydroxy-6-one). The typical signal of non-oxidized C3-OH-is observed at C3 in 67.2 ppm.

Figure 6.

¹³C-NMR spectrum of obtained keto-spirosteroid (25R)-spirost-5α-hydroxy-3,6-dione (4, Figure 2). The typical signal of oxidized C3-OH-is observed at C3 in 210.36 ppm.

It should be noted that the use of this catalytic system, hypervalent iodine (III)/TEMPO-4-N-acetoxyamine, does not generate any dehydration product, as observed when conventional oxidants are used, and, also, it is not detected deformation of minor derivative 4-en-3,6-dione.

3. Experimental section

All chemicals and solvents were obtained from commercial sources and used without further purification. ¹H-NMR/¹³C-NMR (Brucker AC-250 instrument, Germany, at 25°C, using tetramethyl silane as internal reference; magnitude in ppm); FTIR (Philips Analytical FTIR PU-9600, KBr) was used to identify the compounds. Melting points were determined on VEEGO digital automatic melting points apparatus and are uncorrected.

3.1 General procedure for the oxidation of spirostanic steroidal alcohols to their carbonyl analogs

In a typical procedure, a solution of steroidal alcohol (1 mmol) in dichloromethane (3 mL), BAIB (1.1 mmol) and TEMPO-4-N-acetoxyamine (0.1 mmol) is added and stirred for 4 h at room temperature. On completion of the reaction as indicated by Thin Layer Chromatography (ethyl acetate-hexane, 3:7, v/v; vanillin in perchloric acid 50%), the reaction mixture is quenched with 10% sodium thiosulphate solution (2x10 mL) and is extracted with CH₂Cl₂. The organic layer is washed with sodium bicarbonate and brine solution, dried over anhydrous sodium sulfate, and concentrated under a vacuum to give the crude product. This is purified by column chromatography (SiO₂, CHCl₃-EtOAc, 2:8 v/v) to afford the pure product.

3.2 Model reaction II: (25R)-Spirost-5α-hydroxy-3,6-dione

(87%), mp. 283°C (methanol). FTIR (KBr): ν max 3345 (ν OH), 2953 (ν CH), 1713 (ν C=O), 1456 and 1376 (δ CH), 1057 (ν C-O), 980 and 899 (spiroketal); ¹H-NMR (δ, ppm): 2.10/1.86 (m, 2H, H-1), 2.40 (m, 2H, H-2), 2.78/2.25 (m, 2H, H-4), 2.96/2.34 (m, 2H, H-7), 1.99 (m, 1H, H-8), 1.90 (m, 1H, H-9), 1.50 (m, 2H, H-11), 1.81/1.31 (m, 2H, H-12), 1.46 (m, 1H, H-14), 1.99/1.32 (m, 2H, H-15), 4.47 (m, 1H, H-16), 1.85 (m, 1H, H-17), 0.83 (s, 3H, CH3–18), 1.04 (s, 3H, CH3–19), 1.90 (m, 1H, H-20), 1.01 (d, 3H, CH3–21), 1.69 (m, 2H, H-23), 1.50 (m, 2H, H-24), 1.66 (m, 1H, H-25), 3.5/3.38 (m, 2H, H-26), 0.82 (d, 3H, CH3–27). ¹³C-NMR (δ, ppm): 31.8 (C-1), 37.3 (C-2), 210.2 (C-3), 41.9 (C-4), 82.7 (C-5), 210.4 (C-6), 44.8 (C-7), 36.8 (C-8), 44.7 (C-9), 43.1 (C-10), 21.3 (C-11), 39.5 (C-12), 41.0 (C-13), 56.0 (C-14), 31.6 (C-15), 80.4 (C-16), 62.0 (C-17), 16.4 (C-18), 13.9 (C-19), 41.6 (C-20), 14.5 (C-21), 109.3 (C-22), 31.3 (C-23), 28.8 (C-24), 30.3 (C-25), 66.9 (C-26), 17.1 (C-27) (4, Figure 2).

4. Conclusions

It is necessary to highlight some important aspects:

• Simple procedure does not require special laboratory conditions such as extra-dry solvents, inert atmosphere, or additional treatment of the generated derivatives.

• The catalytic system is easily recovered from the reaction mixture by simple filtration.

• The yield of carbonyl derivatives exceeds 75%.

• The described process can be applied in undergraduate and graduate courses of implementation of catalytic processes in organic synthesis.

• This catalytic oxidation system, hypervalent iodine (III)/TEMPO-4-N-acetoxyamine, is applied for the first time to spirostane derivatives obtained from diosgenin for the generation of carbonyl compounds widely used as plant growth promoters and metamorphosis control in insects.

In conclusion, the present method, using hypervalent iodine (III)/Tempo-4-N-Acetoxyamine system, is a simple, efficient, convenient, and high yielding (>75%) process for the oxidative transformation of 3β-secondary steroidal alcohols without any over oxidation, isomerization of the double bond or oxidative cleavage of spirocetalic fragment in different substrates. Therefore, this method does not involve toxic heavy metals and is expected to have wide utility in the oxidation process of these compounds in eco-sustainable conditions.

Research programs related to the optimization of these catalytic oxidation processes under heterogeneous conditions using condensed pyroclastic flow, molecular oxygen, and non-conventional energy sources (microwave, infrared, and ultrasound technologies) are currently being developed.

Acknowledgments

The authors greatly acknowledge the technical, logistic, and administrative support from the Technical University of Esmeraldas “Luis Vargas Torres”, Republic of Ecuador, during 2020-2021. One of the authors (JET) thanks Prof. J. Bobbitt (University of Connecticut, School of Liberal Arts, USA) for his generosity in donating oxoammonium salts and literature, and Indian Institute of Chemical Technology (IICT-Hyderabad, Dr. Yadav S. and Dr. Ahmed Kamal) for its kindness in welcoming him as a postdoctoral fellow.

Conflict of interest

The authors declare no conflict of interest.