Steroidal sapogenin-derived chirons: underdeveloped building blocks with methyl-branched chiral centers

Abstract

Three kinds of chiral lactones with methyl-branched stereocenters were obtained on large scale based on H₂O₂-mediated oxidative degradation of steroidal sapogenins. These chiral lactones are valuable chirons for the total synthesis of bioactive compounds containing methyl-branched chiral centers. This review comprehensively summarizes the synthetic application of the steroidal sapogenin-derived chiral lactones in insect pheromones, complex natural products and pharmaceuticals, with a particular focus on the chirality transfer from chiral lactones to the corresponding motifs of target molecules. We hope these underdeveloped chirons can act as a complement to commonly used methyl-branched chirons such as citronellol and Roche ester, and meet more synthetic applications in the future.

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Ran Gao

Ran Gao is currently a lecturer at Huaibei Normal University. He completed his undergraduate at Southwest University in 2013, followed by a Ph.D. from Shanghai Institute of Organic Chemistry, CAS, in 2018. Then Dr Gao joined the faculty at Huaibei Normal University in 2019. His research is focused on the efficient synthesis of steroid and terpenoid natural products from inexpensive, readily available starting materials.

Cheng-Yu He

Cheng-Yu He is currently an associate professor at China West Normal University. He obtained his B.E. degree from Southwest Minzu University in 2011. He obtained his Master's degree from Shanghai Institute of Organic Chemistry (SIOC) in 2016 under Prof. Wei-Sheng Tian, and three years later, he obtained his Ph.D. degree from SIOC under Prof. Guo-Qiang Lin. He joined China West Normal University in July 2019, and during 2023–2024, he joined in Prof. V. K. Aggarwal's laboratory and worked there as a research associate. His current research interests include asymmetric synthesis, resource chemistry and diazo chemistry.

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1. Introduction

Methyl-branched chiral centers are extensively found in different kinds of bioactive compounds, including terpenes, polyketides, macrolides, peptides, and their hybrids (Fig. 1, top). The installation of a methyl group in drug candidates sometimes leads to a sharp improvement in biological activity (Fig. 1, bottom), referred to as “magic methyl” effects.¹ The absolute configuration of the methyl-branched stereocenter in such compounds affects their biological activity significantly, posing great significance for the enantioselective construction of methyl-branched stereocenters. In synthetic chemistry, the methyl-branched chiral centers could be installed by catalytic asymmetric synthesis, chiral substrate/auxiliary-controlled synthesis, dynamic kinetic resolution and chiron approach. Among them, employing trustworthy and economic chirons as the building blocks for the total synthesis of bioactive compounds containing methyl-branched chiral centers is extremely appealing, especially when the products need to be produced on large scale. In addition, by using the chiron strategy, the condition optimization process to get high stereoselectivity could be completely avoided, which is generally tricky and challenging in non-chiron strategies. The commonly used methyl-branched chirons are citronellol, linalool, and Roche ester, and their synthetic application has tremendously enriched the chiron strategy. Despite the advances achieved by the well-known chiral building blocks, new methyl-branched chirons featuring high optically purity and low cost are always welcome.

Fig. 1 Representative bioactive compounds with methyl-branched stereocenters and the magic methyl effect.

Resource chemistry is basically a subclass of synthetic chemistry that features the rational use of resource compounds.² Prof. Tian proposed this concept in the 1990s, and the core of resource chemistry is to identify and make full use of resource compounds, those readily accessible substances produced in large scale and with low price. There is no doubt that the practice of resource chemistry benefits the environment and productivity. However, it might be challenging to figure out the potential applications of a certain resource compound, because the resource chemistry generally needs to consider the whole molecule instead of functional groups, which is best exemplified by the semisynthesis of taxol from baccatin III.³

Prof. Tian carried out the concept of resource chemistry in steroidal sapogenins, a research area with great significance for the pharmaceutical industry but also with several primary issues to be resolved. One of the problems in the steroidal industry from the very beginning is the environmental pollution and irrational usage of steroidal resources.

Diosgenin, tigogenin, and hecogenin are the most commonly used sapogenins in the steroidal industry, and generally, they need to be degraded for further usage. For a long time, Marker oxidative degradation⁴ of steroidal sapogenins has been the only available degradation protocol and promoted the production of steroidal pharmaceuticals significantly. However, with the development of society and the economy, the related environmental issues of this protocol became more and more severe. Specifically, high temperature and large quantities of chromium trioxide are needed in Marker degradation, and therefore, a large amount of hazardous chromium is produced inevitably (Scheme 1A). Besides, the methyl-branched side chain (the shadowed part) in steroidal sapogenin was hard to recover and discharged as organic waste.

Scheme 1 Two degradation methods for steroids.

To eliminate the environmental pollution and make full use of steroidal sapogenins as much as possible, Tian et al. independently developed an environment-friendly degradation method for steroidal sapogenin, the hydrogen peroxide degradation strategy.⁵ Take tigogenin 1 for example (Scheme 1B): on one hand, pseudo-tigogenin diacetate 5 could be oxidatively degraded into the corresponding allopregnanolone acetate 6, (R)-4-methyl-δ-valerolactone (R)-8 and (R,R)-4-methyl-2-hydroxy-δ-valerolactone 7 using commercially available 30% H₂O₂ as the oxidant instead of CrO₃ used in Marker degradation (path A); on the other hand, tigogenin can be directly oxidatively degraded into pregnanetriol 10 and (R)-4-methyl-δ-valerolactone (R)-8 using peracid as the oxidant that is generated in situ from 30% H₂O₂ and formic acid (path B). Alternatively, adding catalytic amounts of iodine or iodide can change the regioselectivity to give the abnormal Baeyer–Villiger oxidation products, steroidal α-methyl-γ-lactone 11 and (R)-3-methyl-γ-butyrolactone (R)-9 (path C). It is worth mentioning that with the degradation of sarsasapogenin according to the same protocol, the enantiomers (S)-4-methyl-δ-valerolactone and (S)-3-methyl-γ-butyrolactone could be obtained as well.

The newly established degradation procedure for steroidal sapogenins is not only green but also provides opportunities to make 100% utilization of the steroidal resource from an atom level. The steroid core is a valuable starting material applied to synthesize steroid drugs and natural products,^6–8 which however is not the theme of this paper; the steroid side-chain containing a methyl-branched chiral center was transformed into three kinds of lactones with considerable application in organic synthesis.

Chiral lactones constitute the structural core of numerous natural products and also serve as important building blocks.^9–15 For enantioenriched 3-methyl-γ-butyrolactones and 4-methyl-δ-valerolactones, they can be obtained by other methods, although the efficiency and cost-effectiveness might be inferior compared with the degradation strategy. The representative strategies are shown in Scheme 2. For enantioenriched 3-methyl-γ-butyrolactones (Scheme 2A), they could be prepared by the chiron strategy developed by Mori¹⁶ and Simeone,¹⁷ in which (S)-9 is furnished in six steps from (R)-Roche ester and (R)-9 is obtained in three steps from chiral building block (R)-13. In two of the routes, hypertoxic sodium cyanide needs to be used to extend carbon chain. Alternatively, (R)-9 and (S)-9 can also be prepared from achiral starting materials 15 and 17 developed by Noyori¹⁸ and Helmchen,¹⁹ in which the key methyl-branched chiral center is established by transition metal-catalyzed asymmetric hydrogenation of alkenes.

Scheme 2 The representative protocols to construct enantioenriched 3-methyl-γ-butyrolactone and 4-methyl-δ-valerolactone.

The enantioenriched 4-methyl-δ-valerolactones (Scheme 2B) were prepared predominantly by applying chiron strategy. The (S)-8 could be constructed from (S)-Roche ester in five steps following the procedure of Nakada.²⁰ Meanwhile, it can also be generated from chiral ketone 20 in just one step,²¹ although the starting material (R)-3-methylcyclopentanone generally shows limited accessibility and high price. As for (R)-8, it could be prepared from (−)-menthone according to the procedure of Ishmuratov.²²

The chiral lactones [(R)-4-methyl-δ-valerolactone, (R,R)-4-methyl-2-hydroxy-δ-valerolactone, and (R)-3-methyl-γ-butyrolactone] obtained from H₂O₂ degradation method showed excellent enantiomeric purity (about 97.7% ee) and could be used directly (easy to polymerize) or converted into methyl-branched difunctional synthons with higher stability (Scheme 3A). A batch of C6 and C5 chirons containing varied functional groups could be prepared from these chiral lactones within limited steps.²³ Compared to the commercially available difunctional chirons with a methyl-branched chiral center (Scheme 3B), such as (R)-Roche ester, (R)-linalool, (S)-citronellal and (1S,2R,5S)-isopulegol, the synthons obtained from H₂O₂ degradation of steroidal sapogenins feature the following characteristics. First, these chiral blocks were recovered from what was taken as wastes, giving a low economic burden. Second, the distance between the methyl-branched chiral center and existing functional groups in these synthons could be in a 1,4-, 1,3- and 1,2-position relationship, providing tremendous opportunities for their synthetic application. Finally, the functional groups existing in these synthons exhibit considerable diversity, including carbonyl, hydroxy, alkenyl, alkynyl, halogen and pseudo-halogen etc.

Scheme 3 Commercially available difunctional chirons with methyl-branched chiral centers and the related ones derived from steroidal sapogenins.²⁴

Chiral lactones can be readily transformed into a variety of linear difunctional synthons, which could be applied as building blocks to install methyl-branched bioactive compounds, such as insect pheromones, pharmaceuticals, and complex natural products. Careful retrosynthetic analysis and rational cleavage of bonds based on these methyl-branched synthons generally make the total synthesis much more efficient. In the present review, we summarize the synthetic utilization of the three kinds of chiral lactones [(R)-4-methyl-δ-valerolactone, (R,R)-4-methyl-2-hydroxy-δ-valerolactone, and (R)-3-methyl-γ-butyrolactone] reported in the literature and try to show their potential in constructing complex molecules with methyl-branched chiral centers. This review mainly covers works where chiral lactones came from the degradation of steroidal sapogenins, and the references highlighted herein are categorized by the types of lactones, following a chronological order.

2. Synthetic application of enantioenriched 4-methyl-δ-valerolactone

Optically pure 4-methyl-δ-valerolactone can be prepared by steroidal sapogenin degradation on large scale. Due to the facile access and structural advantages, (R)-4-methyl-δ-valerolactone has found its position as a privileged chiron in the field of organic synthesis since the early twenty-first century.

In 2005, Ma and co-workers reported the first total synthesis of halipeptin A, a potent anti-inflammatory and highly methylated cyclic depsipeptide.^25,26 In their retrosynthetic plan, this molecule is divided into part A and B via macrocyclization and peptide formation strategies, in which part A could be assembled from (R)-4-methyl-δ-valerolactone (Scheme 4).

Scheme 4 Retrosynthetic plan of halipeptin A based on steroidal sapogenin-derived chiral lactone.

Transesterification of chiral lactone (R)-8 with methanolic sodium methoxide followed by protection of the hydroxy group provided the difunctional product 22 (Scheme 5). Reduction of the ester group with DIBAL-H at extremely low temperature gave the opportunity to install the second chiral center by asymmetric allylboration based on the protocol of Brown and Racherla²⁷ to deliver a homoallylic alcohol, which was then converted into product 23 by treatment with sodium hydride and methyl iodide. To establish the third chiral center, the CH₂OTBS group needs to be transformed into aldehyde as well, which was readily accomplished by a deprotection-hydrogenation-Swern oxidation procedure to give 24. Then, they built the β-hydroxy-α,α-dimethyl ester motif by a chiral borane-mediated aldol reaction.²⁸ Specifically, treatment of the mixture of aldehyde 24 and 1-(trimethylsiloxy)-1-methoxy-2-methyl-1-propene 26 with borane 25 at −78 °C produced methyl ester 27 in 95% yield as a single isomer. Further allylation of 27 followed by esterification gave the desired intermediate part A.

Scheme 5 The application of steroidal sapogenin-derived chiron in the synthesis of halipeptin A.

In 2007, Tian and co-workers reported a total synthesis of the sex pheromones of pine sawflies, a widely distributed insect of coniferous forests, from (R)-4-methyl-δ-valerolactone (Scheme 6).^29,30 By the treatment of HBr/MeOH, lactone (R)-8 was converted into bromoester 30, which reacted with heptylmagnesium bromide under a Li₂CuCl₄/NMP system to afford product 31. After LiAlH₄ reduction and Swern oxidation, the resulting aldehyde 32 was reacted with chiral reagent 33 to give product 34 diastereoselectively. The terminal methyl-branched chiral center in 36 was established by the addition reaction of lithium dimethylcuprate to the oxidative product of 35. Deprotection of 36 followed by sulfonate formation and NaBH₄ reduction afforded product 37, which further proceeded with desilylation and Mitsunobu reaction to give the target compounds 38 and 39. Alternatively, the authors also disclosed a shorter synthetic route of the sex pheromones of pine sawflies from the same starting material.³¹ In the new route, compound 31 was transformed into the corresponding organocuprate that then reacted with (2S,3S)-2,3-dimethyloxirane prepared from L-tartaric acid to give the key alcohol 42 efficiently.

Scheme 6 The application of steroidal sapogenin-derived chiron in the synthesis of sex pheromones of pine sawflies.

(R,R)-2,6,10-Trimethylundecan-1-ol is an important side chain found in many bioactive compounds, such as chlorophyll A, vitamin E, vitamin K, and phytol, thus making it of great significance to elaborate a practical access to this compound. In 2007, Tian and co-workers reported an effective synthesis of (R,R)-2,6,10-trimethylundecan-1-ol from (R)-4-methyl-δ-valerolactone (Scheme 7).³² The difunctional synthon 43 was prepared via a two-step procedure from chiral lactone (R)-8 on a large scale. Bromoether 44 was synthesized from ester 43 via LiAlH₄ reduction and bromination. The cross-coupling reaction between 44 and isopropylmagnesium bromide proceeded in 93% yield under a Li₂CuCl₄/NMP catalytic system. After deprotection and Swern oxidation, compound 45 was transformed into aldehyde 46. Notably, the application of i-Pr₂NEt instead of Et₃N in Swern oxidation was the key to avoid undesired racemization of the methyl-branched stereocenter in 45. The cross-coupling between 46 and 43 underwent smoothly by treating with LDA to provide β-hydroxyl ester 47 in 80% yield. Jones oxidation of 47 followed by alkaline decarboxylation in LiOH/H₂O/THF under reflux provided the key intermediate 48. After a four-step procedure (reduction of ketone, installation of methanesulfonyl, reductive cleavage of C–O bond, and deprotection of MOM), the target compound (R,R)-2,6,10-trimethylundecan-1-ol was obtained from 48 in high yield. Alternatively, the target molecule can also be prepared directly from 48 under a Clemmensen reduction condition, albeit with a little bit racemization of the product.

Scheme 7 The application of steroidal sapogenin-derived chirons in the synthesis of (R,R)-2,6,10-trimethylundecan-1-ol.

(S)-Hydroprene is an insect growth regulator with high juvenile hormone activity for troublesome dipteran pests, such as mosquitoes, flies and tabanus, and thus plays an important role in animal husbandry. In 2012, Tian and co-workers reported a concise synthesis of (S)-hydroprene from chiral synthon 30 (Scheme 8).³³ Treating bromoester 30 with isoamylMgBr under a Li₂CuCl₄/NMP catalytic system yielded the coupling product 50 in 86% yield. After sequential reduction and Swern oxidation, the aldehyde 51 was afforded, which reacted with triphenylphosphite and bromine to generate the gem-dibromide 52 in high yield. Elimination of two molecules of HBr under a KH/1,3-diaminopropane system gave terminal alkyne 53 in nearly quantitative yield. Hydroboration of terminal alkyne with Br₂BH·SMe₂ followed by hydrolysis afforded the (E)-alkenylboronic acid 54. The cross-coupling reaction between 54 and 56 prepared from 55 proceeded stereospecifically to give (S)-hydroprene in high yield.

Scheme 8 The application of steroidal sapogenin-derived chiron in the synthesis of (S)-hydroprene.

Many chemical odorants used in perfumery and flavor industries feature a methyl-branched side chain, which make steroidal sapogenin-derived chiral lactones the ideal starting material for their total synthesis. In 2015, Tian and co-workers reported a concise synthesis of (R)-muscone, the king of fragrances, from (R)-5-bromo-4-methylpentanoate in eight steps and 32% overall yield (Scheme 9).³⁴ The starting material 30 was converted into the corresponding ether 58 smoothly by treating with LiAlH₄ and MOMCl. Treatment of 58 with Li/Na generated the anionic nucleophile in situ that reacted with Weinreb amide 60 derived from 59. After sequential deprotection, Swern oxidation, and Wittig olefination, compound 62, the precursor of the ring-closing reaction, was provided in high yield. The macrocyclic product (R)-muscone was constructed effectively via Grubbs 1^st-catalyed ring-closing metathesis (RCM) reaction followed by hydrogenation of the C=C bond.

Scheme 9 The application of steroidal sapogenin-derived chiron in the synthesis of (R)-muscone.

(R,R)-3,9-dimethyldodecanal is a sex pheromone produced by the banded cucumber beetle, Diabrotica balteata LeConte, which is harmful to a variety of vegetables. In 2015, Tian and co-workers accomplished the total synthesis of this compound in 20% overall yield from (R)-4-methyl-δ-valerolactone (Scheme 10).³⁵ The methyl-branched difunctional compound 63 was generated from lactone (R)-8 in 68% yield. After the carboxyl group in 63 was reduced into hydroxyl group, the compound 64 was transformed into the hydroxyl-protected iodide 66 and the chain-extended aldehyde 68, respectively. The coupling reaction between 68 and 66 proceeded smoothly via nucleophilic addition to afford 69 in 95% yield. The hydroxyl group in 69 was removed through sequential sulfonate-formation and reductive cleavage of the C–O bond to give product 70, which features two distinguished hydroxyl-protective groups. The OBn moiety was transformed into a masked aldehyde group via a three-step procedure to give 71. Then, the MOM group was removed under acidic conditions to give compound 72, which further transformed into 73 via reductive cleavage of the C–O bond and unmasking of acyl. Finally, the target product (R,R)-3,9-dimethyldodecanal was obtained in high yield via HWE reaction and Pd/C hydrogenation.

Scheme 10 The application of steroidal sapogenin-derived chiron in the synthesis of the sex pheromone of the banded cucumber beetle.

Aggregation pheromones are of great importance for pest control because they can lure both sexes of insects within the same species to a certain spot. Tribolium castaneum, T. confusum, T. freeman, and T. madens are insects found worldwide that are considered grain storage pests, and they share a common aggregation pheromone, tribolure, the composition of which was identified as a 4 : 1 mixture of (4R,8R/S)-80 and (4S,8R/S)-80.³⁶ Namely, only the configuration of C4 in 4,8-dimethyldecanal needs to be controlled in its synthesis, and the tribolure will be prepared exactly by mixing (4R,8R/S)-80 and (4S,8R/S)-80 together in a 4 : 1 ratio (Scheme 11A). In 2015, Tian and co-workers reported a concise synthesis of tribolure from (R)-4-methyl-δ-valerolactone (Scheme 11B), in which the (4R,8R/S)-80 was obtained in 30% yield over eight steps, and the counterpart (4S,8R/S)-80 was constructed in four steps in 67% overall yield from the same starting material.³⁷ Specifically, treating chiral lactone (R)-8 with dimethoxymethane under acidic conditions, followed by LiAlH₄ reduction, led to the linear alcohol 75. The application of cross-coupling reaction between iodide and Grignard reagent twice enabled chain extension at both ends of compound 76. The (4R,8R/S)-80 was formed in high yield as an inseparable mixture through ozonation of the allyl moiety. On the other hand, treatment of chiral lactone (R)-8 with HBr/HOAc followed by methanol gave the bromoester 30 in 83% yield, which reacted with 3-methylpentylmagnesium bromide 81 to provide the aliphatic ester 82. Reduction of 82 followed by TEMPO oxidation gave (4S,8R/S)-80 as an inseparable mixture in excellent yield. This is an elegant example to show the high efficiency and superiority of the chirons obtained from the saponin industry in synthesizing chiral methyl-branched pheromones.

Scheme 11 The application of steroidal sapogenin-derived chiron in the synthesis of aggregation pheromone.

In 2020, Chen and co-workers reported an efficient asymmetric synthesis of oxacyclododecindione-type macrolactones, 4-dechloro-14-deoxy-oxacyclododecindione 91 and 14-deoxy-oxacylododecindione 90, from steroidal sapogenin-derived lactone (S)-8 (Scheme 12).³⁸ These two natural compounds were isolated from the imperfect fungus Exserohilum rostratum by Opatz and Erkel and exhibited potent anti-inflammatory and anti-fibrotic activities. The total synthesis commenced from the reduction of (S)-8 with DIBAL-H, furnishing the corresponding lactol 83, which reacted with ylide 84 to give alkene 85 in 82% yield. To construct the second methyl-branched chiral center, the strategy of Ti-catalyzed diastereoselective methylation of aldehyde³⁹ was applied, and the product (6S,7S,E)-87 was obtained in 94% yield with >95 : 5 dr. It is worth mentioning that using the mismatched (S,S)-TADDOL–Ti complex as the catalyst afforded an inseparable 7R/S-87 mixture with 76 : 24 dr. Although the configuration of C7 was opposite that of the target molecules, it could be converted by the subsequent Mitsunobu reaction. After intramolecular Friedel–Crafts acylation and deprotection, the synthesis of 4-dechloro-14-deoxy-oxacyclododecindione 90 was achieved. The 14-deoxy-oxacylododecindione 91 could be obtained smoothly after further chlorination with N-chlorosuccinimide. This work represents a good example of the synthetic application of (S)-4-methyl-δ-valerolactone and installation of a new chiral center adjacent the existing methyl-branched stereogenic center.

Scheme 12 The application of steroidal sapogenin-derived chiron in the synthesis of oxacyclododecindione-type macrolactones.

Recently, Li and co-workers reported a new group of minor plant sesterterpenoids, gracilisoid A–E, from a Lamiaceae ethnomedicinal plant, Eurysolen gracilis.⁴⁰ These compounds showed significant immunosuppressive activity without obvious cytotoxicity. For their total synthesis, gracilisoid A was taken as the key precursor for gracilisoids B–E that feature two types of highly functionalized bicyclo[3.2.0]heptane carbon skeletons (Scheme 13). In the retrosynthetic plan of gracilisoid A, the target molecule could be constructed from key intermediate 101 by applying the strategies of furan formation and alkene oxidation. The furyl ketone moiety in 101 could be facilely established from intermediate 99, which is in turn afforded through a ring-opening reaction of epoxide 98. The compound 98 is then disconnected into to two fragments via Julia–Kocienski olefination, one of which could be prepared from (S)-citronellal and the other could be derived from chiral lactone (R)-4-methyl-δ-valerolactone.

Scheme 13 The structures of gracilisoids A–E and the retrosynthetic plan of gracilisoid A.

The chiral starting material 92 was prepared from diosgenin over two steps by applying a degradation strategy, and it was transformed into 94 via Mitsunobu reaction and ester reduction (Scheme 14). After thioether oxidation and hydroxy protection, sulfone 95, one of the coupling partners of Julia–Kocienski olefination, was afforded on decagram scale and in high overall yield. For the counterpart of Julia–Kocienski olefination, aldehyde 97 was prepared in 3 : 1 dr from (S)-citronellal via an asymmetric cyclization developed by MacMillan followed by Shi's asymmetric epoxidation. The coupling reaction between diastereomeric mixture 97 and sulfone 95 proceeded smoothly to give alkene 98 in 86% yield with a E/Z ratio of >20 : 1. Treating 98 with the bulky Lewis acid (C₆F₅)₃B triggered a cascade epoxide ring-opening to deliver aldehyde 99. The 4-methylfuran-derived organolithium species reacted with 99, followed by TPAP/NMO oxidation, providing an efficient access to ketone 101. At this stage, the C6-diastereoisomers (3 : 1 ratio) of 101 became separable by flash column chromatography, and the minor isomer 6-α-Me-101 could be converted into the thermodynamically more stable 6-β-Me-101 in 78% yield by treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). After a series of transformations involving alkene oxidation and furan installation, gracilisoid A was obtained, which was further used to prepare other sesterterpenoids.

Scheme 14 The application of steroidal sapogenin-derived chiron in the synthesis of gracilisoid A.

3. Synthetic application of (R,R)-4-methyl-2-hydroxy-δ-valerolactone

(R,R)-4-Methyl-2-hydroxy-δ-valerolactone could be prepared on a large scale from steroidal sapogenin degradation and has been engaged in organic synthesis over the last decade. In contrast with (R)-4-methyl-δ-valerolactone, (R,R)-4-methyl-2-hydroxy-δ-valerolactone shows some unique transformations because of the existence of the α-hydroxy group.

Sacubitril is a neprilysin inhibitor developed by G. M. Ksander et al. in the early 1990s,⁴¹ and its combination with valsartan presents an important medication, Entresto, for heart failure. In 2016, Tian and co-workers reported a multigram-scale synthesis of sacubitril from the chiral methyl-branched synthon 102, which could be prepared from steroidal sapogenin-derived chiral lactone 7 via alcoholysis, hydroxy protection and ester reduction.⁴² As depicted in Scheme 15, the authors envisioned that the R-stereogenic center next to the ester group in sacubitril could be constructed by inheriting from the chiral starting material, and the other S-stereogenic center adjacent to amide should be installed by chirality-inversion via S_N2-type reaction. After much experiments, the authors identified the optimal conditions for the preparation of epoxide 104 via intermediate 103 by treating 102 with C₄F₉SO₂F/DBU in DCM at 0 °C, in which the relatively lower reactivity of C₄F₉SO₂F benefited the regioselectivity in the first step. The 1,1′-biphenyl motif was introduced in high yield by the nucleophilic reaction of (1,1′-biphenyl)-4-ylmagnesium bromide with epoxide catalyzed by CuBr·Me₂S to give product 106. The chirality inversion in compound 106 was achieved in 92% yield by a two-step procedure involving mesylation and azide installation to give azido compound 107. After establishment of the carboxylic ester, the next issue is to install the amide moiety. However, under conventional Pd/C hydrogenation conditions, the lactam 109 was generated exclusively from 108; in contrast, performing the azide reduction under Staudinger conditions (with triphenylphosphine) followed by adding succinic anhydride led to sacubitril in 76% yield. All the stereogenic centers in sacubitril came from chiron 102 (one inherited and the other one inverted), and almost all the transformations involved in the total synthesis were multigram scale. This is an elegant example to show the high efficiency of chirons derived from steroidal sapogenins in preparing valuable chiral methyl-branched bioactive compounds in a practical way.⁴³

Scheme 15 The application of steroidal sapogenin-derived chiron in the synthesis of sacubitril.

Apratoxin E, a secondary metabolite of apratoxins, which was isolated from Lyngbya bouillonii collected in Guam, contains a unique peptide–polyketide hybrid. In 2016, Luesch and Zhang accomplished the first total synthesis of apratoxin E and its C30-epimer, correcting the absolute configuration of C30 from 30S to 30R.⁴⁴ In their synthetic route, the chiral C37-methyl motif came from (−)-citronella. In 2017, Wei and co-workers reported another total synthesis of apratoxin E, as well as three analogues (30-epi-Apratoxin E and two Oxoapratoxin E).⁴⁵ In their retrosynthetic plan for apratoxin E, this molecule was disconnected into tripeptide 117 and thiazoline chain 116 by peptide formation strategy (Scheme 16). Compound 116 could be disconnected by cross-metathesis, in which the steroidal sapogenin-derived (R,R)-4-methyl-2-hydroxy-δ-valerolactone can be utilized to install the C37–methyl chirality in the key fragment 115.

Scheme 16 Retrosynthetic plan of apratoxin E based on steroidal sapogenin-derived chiral lactone.

Treatment of (R,R)-4-methyl-2-hydroxy-δ-valerolactone with benzyl chloride and NaOH in toluene under reflux led to the selective benzylation product that further reacted with MeOH under acidic conditions to afford product 111 (Scheme 17). To install the tertiary butyl motif, the α-hydroxy ester 111 was transformed into an aldehyde by periodate oxidation of diol followed by nucleophilic addition of tert-butylmagnesium chloride. Then, chirality next to the hydroxyl group in 112 was reconstructed by Dess–Martin oxidation followed by CBS reduction to give product 113. Protection of the secondary alcohol with TBS, followed by hydrogenation-deprotection, generated the desired alcohol 114. Iodination of 114, followed by a copper-catalyzed cross-coupling reaction with vinylmagnesium bromide, led to the key fragment 115 in high yield.

Scheme 17 The application of steroidal sapogenin-derived chiron in the synthesis of apratoxin E.

Rupestonic acid was isolated from Artemisia rupestris L, a well-known traditional Chinese medicinal plant (yizhihao in Chinese), in Xinjiang in 1988, demonstrating its potential use in detoxification, antibacterials, etc. However, its absolute structure was ambiguous for a long time. To shed light on the discrepancy of the absolute structure of natural rupestonic acid, in 2017, Wei and co-workers accomplished a total synthesis of the proposed rupestonic acid.⁴⁶ In their retrosynthetic plan (Scheme 18), compound 130 was taken as a key intermediate, in which the five-membered ring could be constructed by intramolecular aldol condensation from 131. The seven-membered ring in 131 can be installed via ring-closing metathesis from 128, in which one of the two terminal C=C bonds could be formed through Peterson olefination. The linear intermediate 126 can be obtained by SmI₂-mediated coupling reaction of iodide (R,R)-125 with aldehyde 124. The methyl-branched chiral center in fragment 124 could be inherited from steroidal sapogenin-derived (R,R)-4-methyl-2-hydroxy-δ-valerolactone.

Scheme 18 Retrosynthetic plan of rupestonic acid based on steroidal sapogenin-derived chiral lactone.

The chiral pool 7 was converted into the linear chiral acid 118 according to the known procedure in 41% overall yield (Scheme 19).^45,47 To establish the second chiral center, auxiliary oxazolidinone 119 was introduced, followed by asymmetric allylation, leading to product 120 in 63% yield with very high diastereoselectivity. After removal of the chiral auxiliary and protection of hydroxy, the terminal alkene motif in 121 was oxidized sequentially by K₂OsO₄ and NaIO₄ to afford an aldehyde that reacted with ethylmagnesium bromide to give the chain-extended product 122. After protection–deprotection procedure and subsequential oxidation, the key intermediate 124 was generated in 84% yield. Then, the key coupling reaction between aldehyde 124 and iodide (R,R)-125 was performed by treating SmI₂ in the presence of hexamethylphosphoric triamide (HMPA), leading to the product (3R)-126 in 52% yield. After protection of hydroxy and selective deprotection, (6R)-127 was obtained. Another terminal vinyl group in (5R)-128 was installed by Peterson olefination. After a series of transformations afterwards, the initially proposed rupestonic acid (5S,8S,8aS)-129 was obtained. However, to the authors’ surprise, the analytical data of this compound was not consistent with those reported for rupestonic acid. To investigate this problem, the authors synthesized (5R,8S,8aS)-129, a diastereomer of the initially proposed rupestonic acid, following a similar synthetic route by taking (S,S)-125 as the coupling partner. The data for the newly synthesized compound were in excellent agreement with those reported for isolated pechueloic acid and the originally proposed natural rupestonic acid, proving that the absolute structure of natural rupestonic acid isolated from the traditional Chinese medicinal plant (yizhihao) in Xinjiang in 1988 was the same as the pechueloic acid isolated from Decachaeta scabrella in 1987.

Scheme 19 The application of steroidal sapogenin-derived chiron in the synthesis of rupestonic acid.

In 2018, Du and co-workers disclosed a total synthesis of the sex pheromone of the tea tussock moth based on the chiral pool strategy (Scheme 20).⁴⁸ Selective benzylation of (R,R)-4-methyl-2-hydroxy-δ-valerolactone under alkaline conditions followed by esterification afforded the linear product 132 in high yield. It was revealed that the hydroxyl-branched chiral center was partially epimerized under basic benzylation conditions. However, the epimerization did not affect the whole synthesis of the target compound, as the α-hydroxy ester motif was converted into an aldehyde group via diol oxidation. Then, Julia–Kocienski coupling was performed between the chiral aldehyde 133 and 5-(isobutylsulfonyl)-1-phenyl-1H-tetrazole 134, affording the alkene 135. Under Pd/C hydrogenation conditions, hydrogenation of the C=C double bond and removal of the benzyl group were achieved in one pot to afford the chiral alcohol 136. To extend the carbon chain, compound 136 was converted into the sulfone reagent 137, followed by m-CPBA oxidation and a second Julia coupling to give the corresponding alkene product 140 with an E/Z ratio of 2 : 1. The target molecule 141 was formed in 96% yield under Pt/C catalytic hydrogenation from 140. Worth mentioning is that racemization of the allylic chiral center (highlighted by red) in 140 took place when the hydrogenation reaction was performed in a Pd/C catalytic system, and this deleterious propensity could be prevented under a Pt/C or diimide hydrogenation condition.⁴⁹

Scheme 20 The application of steroidal sapogenin-derived chiron in the synthesis of the sex pheromone of tea tussock moth.

(S)-14-Methyl-1-octadecene is the sex pheromone of the peach leafminer moth, a destructive pest for peach orchards. It was revealed that the S-isomer is bioactive and could be used in pest control by disrupting the moth's mating process, while the R-isomer is almost inactive.⁵⁰ In 2021, He and co-workers disclosed a total synthesis of (S)-14-methyl-1-octadecene from (R,R)-4-methyl-2-hydroxy-δ-valerolactone (Scheme 21).⁵¹ By applying a sequential benzylation and periodate oxidation, (R)-4-(benzyloxy)-3-methylbutanal 142 could be prepared from chiral lactone 7. Then, sequential Wittig olefination and hydrogenation enabled carbon chain extension to afford product 145. After Dess–Martin oxidation of 145, the second round of Wittig olefination with propyl ylide provided alkene 146 as a Z/E mixture. To install the terminal alkenyl group, the alcohol 147 was transformed into bromide followed by treatment with the bulky base t-BuOK, leading to the desired product (S)-14-methyl-1-octadecene in good yield.

Scheme 21 The application of steroidal sapogenin-derived chiron in the synthesis of the sex pheromone of the peach leafminer moth.

4. The synthetic application of (R)-3-methyl-γ-butyrolactone

(R)-3-Methyl-γ-butyrolactone can also be prepared from steroidal sapogenin degradation via a formal abnormal Baeyer–Villiger rearrangement. However, compared to (R)-4-methyl-δ-valerolactone and (R,R)-4-methyl-2-hydroxy-δ-valerolactone, the synthetic application of (R)-3-methyl-γ-butyrolactone is extremely rare.

5,9-Dimethylpentadecane was reported as the major component of the female sex pheromone of the coffee leaf miner moth, Leucoptera coffeella. Among its stereoisomers, (5S,9R)-5,9-dimethylpentadecane was verified to show the highest activity. In 2008, Mori reported a concise total synthesis of (5S,9R)-5,9-dimethylpentadecane, in which the two methyl-branched chiral centers were derived from (R)-3-methyl-γ-butyrolactone⁵² and (S)-citronellal, respectively (Scheme 22).⁵³ Reduction of chiral lactone (R)-9 with DIBAL-H gave lactol 148 in 92% yield. Compound 148 was treated with Wittig reagent prepared from n-butyltriphenylphosphonium iodide and n-butyllithium, affording the linear product 149. Hydrogenation of 149 followed by tosylate formation gave product 151, which was converted into the corresponding iodide by treating with NaI in DMF. The coupling reaction between two chiral fragments was accomplished by nucleophilic addition of lithium reagent derived from 152 to (S)-citronellal in 83% yield. The resulting hydroxy group was eliminated via a sequential sulfonylation-reduction procedure to give product 154. The aldehyde 155 was generated by epoxidation of 154 with m-CPBA, followed by epoxide oxidation with periodic acid dihydrate. The target molecule 156 was furnished by sequential Wittig olefination and Pt-catalyzed hydrogenation in high yield.

Scheme 22 The application of (R)-3-methyl-γ-butyrolactone in the synthesis of the female sex pheromone of the coffee leaf miner moth.

In 2013, Perlmutter and co-workers reported a one-pot transformation of chiral lactones based on nucleophilic alkylation followed by modified Clemmensen reduction.⁵⁴ They found that treating chiral lactones with 1.1 equiv. of organolithiums under low temperature gave the monoadducts in good yields; the in situ generated keto-alcohol salts can undergo deoxygenation effectively in the conditions of 10 equiv. of TMSCl and Zn dust to afford the chiral alcohols (Scheme 23). This one-pot procedure enriched the synthetic transformation of chiral lactones. Five-, six- and seven-membered lactones proceeded smoothly for this reaction, and several chiral isoprenoid derivatives have been synthesized based on this protocol. For example, this one-pot methodology enabled the efficient synthesis of (S)-9-methylnonadecane, the major component of the sex pheromone of female moths and larvae of the cotton leafworm, Alabama argillacea. Specifically, when (R)-3-methyl-γ-butyrolactone was applied for the one-pot transformation, compound 157 was formed in 76% yield. Tosylation of 157 followed by a Cu-catalyzed substitution reaction with n-heptMgBr gave the (S)-9-methylnonadecane in 73% yield in two steps.

Scheme 23 The one-pot transformation of chiral lactones and its synthetic application in the synthesis of the sex pheromone of female moths and larvae of cotton leafworm.

5. Conclusions

This review summarized the synthetic applications of steroidal sapogenin-derived chirons, a neglected but versatile building block containing methyl-branched chiral centers. Following the Tian oxidative degradation method of steroidal sapogenins, three kinds of chiral lactones, (R)-4-methyl-δ-valerolactone, (R,R)-4-methyl-2-hydroxy-δ-valerolactone, and (R)-3-methyl-γ-butyrolactone, were prepared on a large scale, which could be further converted into a series of chiral methyl-branched difunctional synthons. As shown in this review article, these synthons could be applied in the total synthesis of methyl-branched bioactive compounds efficiently. Despite the advancements in this domain, the facile availability and great synthetic potential of the steroidal sapogenin-derived chirons is yet to be known by more chemists. Especially, the synthetic application of (R)-3-methyl-γ-butyrolactone is rarely observed. Compared to the general methyl-branched chirons, the steroidal sapogenin-derived ones show structural diversification, thus providing more opportunities for synthetic application. We believe that these chiral lactones can act as an important complement to commonly used methyl-branched chirons such as citronellol and Roche ester. Meanwhile, based on the transformation of lactone or ester group,^55–57 more novel methyl-branched building blocks with versatile difunctional groups could be developed from the steroidal sapogenin-derived lactones, which could better serve the synthesis of biologically active compounds.

Data availability

No primary research results, software or code have been included, and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (No. 22201234), Key Laboratories of Fine Chemicals and Surfactants in Sichuan Provincial Universities, Natural Science Research Project of Anhui Educational Committee (2022AH050409), Independent Research Project of Key Laboratory of Green and Precise Synthetic Chemistry and Applications (Huaibei Normal University), Ministry of Education (KLGPSCA202309) for financial support.

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Footnote

† These authors contributed equally to this work.

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