Synthesis of chiral propargyl alcohols following the base-induced elimination protocol: application in the total synthesis of natural products

Uma Maheshwar Gonela *a and Jhillu S. Yadav *ab
aNatural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India. E-mail: uma.gonela@famu.edu; yadavpub@gmail.com
bSchool of Science, Indrashil University, Kadi, Gujarat, India

Received 11th November 2019 , Accepted 14th February 2020

First published on 20th February 2020


Synthesis of enantiomerically pure propargyl alcohols is one of the most important tools in organic synthesis. Base-induced elimination of β-alkoxy chlorides could offer enantiomerically pure propargyl alcohols corresponding to their precursor. This protocol has been serving organic synthesis methods for three decades and has shown its enormous utility in the synthesis of a variety of natural products and small molecules. In this review, for the first time we compile the applications of the “base-induced elimination of β-alkoxy chlorides” protocol (BIEP) in the total synthesis of natural products. Furthermore, we discuss the scope and how this protocol could be a promising tool to generate propargyl alcohols.


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Uma Maheshwar Gonela

Uma Maheshwar Gonela was born in Adilabad, India in 1987. He completed his Master of Science in Organic chemistry from Osmania University, India. In 2010, he joined Dr J. S. Yadav's group at CSIR-IICT, Hyderabad, to pursue his doctoral degree in synthetic organic chemistry. In his PhD, he worked on the total synthesis of bioactive natural products. After achieving his PhD in Chemistry from Kakatiya University in 2016, he moved to the University of Alabama, USA, for Postdoctoral research under Prof. Robin D. Rogers. From 2017, he continued his postdoctoral research in Florida A&M University with Prof. Seth Y. Ablordeppey in medicinal chemistry, as an NIH-sponsored research associate. In particular, he is working on CNS-antipsychotic drug discovery.

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Jhillu S. Yadav

Dr J. S. Yadav was born in 1950 in Azamgarh, Uttar Pradesh, India. He obtained a doctorate in 1976 in India. He was a Post-Doc at Rice University, Houston and at UW, Madison in the USA for 3.5 years. In 1981, he joined the CSIR service at the National Chemical Laboratory (NCL), Pune. Subsequently, he moved in 1986 to the Indian Institute of Chemical Technology (IICT), Hyderabad. In a research career of three decades, Dr Yadav has successfully carried out extensive basic and applied research investigations into the synthesis of complex natural products of biological relevance. He is a specialist in asymmetric synthesis aiming to create new chiral centers in complex organic molecules and their effective utilization in the synthesis of many bioactive molecules.


1. Introduction

Natural products containing chiral 3-hydroxy alkyne functionalities exhibit remarkable biological properties including having phytotoxic, anti-inflammatory, antiviral, antimicrobial, cytotoxic, and antitumor activities.1 These building blocks are widely used for the synthesis of alkaloids, prostaglandins,2 pyrethroids,3 leukotrienes,4 steroids5 and many more families of medicinal compounds. It is well known that terminal acetylenic motifs readily participate in C–C bond formation.6 Participation of these terminal and C-sp halides under homogeneous/heterogeneous catalysis leads to a great increase in their utility. Propargyl alcohols can be transformed into a variety of substrates, such as alkanes/alkenes followed by selective reduction, optically active allenes, benzylic alcohols, vinylsilanes, and hydroxyl ketones. Furthermore, the partial reduction of 3-hydroxyalkynes could offer allyl alcohols with cis or trans geometries (Scheme 1).7
image file: c9nj05626b-s1.tif
Scheme 1 General reaction outline.

Several advanced synthetic routes have been developed for the synthesis of “enantio-enriched” chiral propargyl alcohols. These can be broadly categorized as follows:

(1) Selective reduction of α-ynones,

(2) Asymmetric alkynylation of aldehydes

(3) Enzymatic kinetic resolution.

Selective reduction of α-ynones could produce chiral alkynyl carbinols with high enantioselectivity in the presence of chiral ligands and transition metals. However, to synthesize the precursor ynones, an additional step is required such as oxidation of propargyl alcohols and selective reduction associated with expensive chiral ligands (Noyori/CBS asymmetric reduction) (Fig. 1).8


image file: c9nj05626b-f1.tif
Fig. 1 Retrosynthetic approach for chiral propargyl alcohols.

Asymmetric alkynylation on aldehydes is another attractive strategy which has received a considerable amount of attention during the past decade. However, owing to its limited efficiency, selectivity and substrate scope, there is a need to address the problems encountered.9 Enzymatic kinetic resolution of racemic secondary propargyl alcohols, using enzymes such as Lipase AK, Novozym 435, is also considered as one of the key strategies which provides enantio-enriched propargyl alcohols, while the other enantiomer remains unreacted.10 Although a higher selectivity is appreciated in these cases, loss of half of the racemic substrate all the time is one of the major drawbacks.

In 1988, Yadav and co-workers developed a novel and practical method for the synthesis of optically pure propargyl alcohols from tartaric acid which is commercially available in both enantiomeric forms.11 This strategy involves the base-induced double elimination of β-alkoxy chloride to produce chiral propargyl alcohols, corresponding to their γ-alkoxide precursor. This protocol comprises the smooth conversion of mono-protected 4-methoxy ether 1 to its chloride 2 using triphenylphosphine (2 equiv.) under carbon tetrachloride refluxing conditions, which on further reaction with lithium ammonia afford the chiral acetylenic alcohol 3 in high yield.

Bifunctional chiral propargyl alcohols are useful precursors for the synthesis of a wide range of biologically active targets. Propargyl functional groups could be used for the construction of C–C bonds and as a source for allylic alcohols with cis and trans alkene geometry.7 Using the Zipper reaction, the substituted propargyl alcohols 3 (R = n-alkyl) could be transformed into terminal acetylenic diols.12

In the present review, we made an attempt to discuss the widely used “Base-induced elimination protocol” (BIEP) with various substrates and its application in the total synthesis of different classes of natural products. Synthesis of chiral propargyl alcohols following BIEP is one of the key steps for the total synthesis of various natural products. This review is broadly divided into Sections 2.1–2.4 based on the substrates used for the synthesis of chiral propargyl alcohols (Fig. 2).


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Fig. 2 Representative figure.

2. Synthetic applications

2.1. Tartrate derivatives

Yadav et al. extended this protocol for the tartrate substrate as depicted in Scheme 2. One mole of base (LiNH2) abstracts a proton from the halogen attached carbon, followed by the elimination of the β-alkoxy group to afford vinyl chloride. Another mole of base led to the formation of dianion 2a. As anticipated, the dianion could react in situ with electrophiles which affords chiral propargyl alcohol 3.
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Scheme 2 Reaction mechanism of the tartrate derivative to chiral carbinol.
2.1.1. Enprostil. Prostaglandins (PGs) are active lipid compounds, which control a multitude of important physiological processes and can exert a host of pharmacological effects. In recent decades, several therapeutically useful prostaglandin analogues have been developed.13 Numerous side effects of PGs and chemical and metabolic instability impeded their therapeutic use; consequently, the synthesis of artificial PG analogues with improved stability and fewer side effects has received great attention. Synthesis of Enprostil, an antiulcer agent, was reported by Sato et al., successfully utilizing the BIEP strategy for the ω side chain (Scheme 3).14 This synthesis started from the commercially available (+)-2,3-O-isopropylidene-l-threitol. As depicted in Scheme 3, chloro-4 upon treatment with LDA resulted in chiral propargyl 5. Silyl protected 5 was converted to vinyl-stannane 6 in the presence of AIBN. The reaction of 7 with the organocopper compound prepared from 6 afforded the bis-silyl ether of enprostil, which upon treatment with HF in THF, resulted in enprostil (61% yield).
image file: c9nj05626b-s3.tif
Scheme 3 Total synthesis of enprostil.
2.1.2. Longimicin C. Longimicin C (15), a naturally occurring annonaceous acetogenin, is endowed with a C2-symmetrical bis-THF motif and a long-carbon chain connecting its bis-THF segment with appended γ-lactone.15 The first synthesis was achieved by Yao et al.16 Considering the C2 symmetry involved in the target molecule, the synthesis of bis-THF-fragment 13 was achieved from the commercially available and inexpensive D-mannitol (Scheme 4). Chlorination of diol 9 was achieved using PPh3, K2CO3 and N,N-diisopropylethylamine in CCl4, which improved the product formation. Diol 10 was obtained by BIEP using LDA, which was further transformed into intermediate 13. Bis-THF 13 was further elaborated to longimicin C (15).
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Scheme 4 Total synthesis of longimicin C.
2.1.3. (+)-Sapinofuranone B. A decade back, while working on the production of Xenovulene A, Simpson and co-workers isolated a novel metabolite sapinofuranone B (19) from fermentation extracts.17 The synthesis of sapinofuranone B began with L (+) DET. The chloro compound 16 was subjected to BIEP for acetonide opening with LiNH2 in liquid ammonia at −30 °C, which gave the chiral propargyl alcohol 17 in 79% yield. Further transformations following Mitsunobu inversion,18 Sonogashira coupling,19 and PTSA in MeOH proceeded for the total synthesis of sapinofuranone B (19) (Scheme 5).20
image file: c9nj05626b-s5.tif
Scheme 5 Total synthesis of (+)-sapinofuranone B.
2.1.4. Ivorenolide A. Recently, immunosuppressive diacetylene motif-containing natural products Ivorenolide A (27) and B were isolated from the stem bark of Khaya ivorensis.21 In general, immunosuppressive agents are used to suppress the immune system in order to suppress the rejection of the transplanted organ.22 Ivorenolide A exhibited significant inhibition of ConA-induced T-cell proliferation and LPS-induced B-cell proliferation. Yadav et al. reported the total synthesis of the natural isomer of Ivorenolide A utilizing BIEP23 (Scheme 6). Fragment 21 was synthesised from the DET derivative. (+)DET was converted to alcohol 20, subsequently subjected to chlorination followed by BIEP to obtain 21. Another fragment was synthesized from L-ethyl lactate, which was converted to epoxy alcohol 22, and then further subjected to chlorination followed by BIEP. Fragments 21 and 24 were coupled under modified Sonogashira cross-coupling conditions. The coupled product was further reacted for the total synthesis of the natural isomer of Ivorenolide A.
image file: c9nj05626b-s6.tif
Scheme 6 Total synthesis of ivorenolide A.

2.2. Carbohydrate derivatives

The BIEP method was further used for carbohydrate derivatives. L-Chloro-l-deoxy-2,3[thin space (1/6-em)]:[thin space (1/6-em)]4,5-O-isopropylidene-DL-xylitol (29) was prepared from 28, which when treated with base (LiNH2, 6 equiv.), in liquid NH3 at −33 °C, afforded the acetylenic alcohol 30 as a single product in 92% yield (Scheme 7).24 Later, it was observed that the elimination reaction of 29 could also be carried out with LDA (5 equiv.) in THF at −78 °C in almost similar yields. This approach was conducted on various chiral chlorides which were derived from the corresponding carbohydrates, which afforded the enantiomerically pure propargyl alcohols in excellent yields.
image file: c9nj05626b-s7.tif
Scheme 7 Carbohydrate derivative to chiral carbinol.
2.2.1. (11R,12S,13S)-Trihydroxy-(9Z,15Z)-octadecadienoic acid. BIEP of β-alkoxy chlorides derived from carbohydrates was successfully utilized in the first stereo convergent synthesis of (11R,12S,13S)-trihydroxy-(9Z,15Z)-octadecadienoic acid (34) by the Yadav group.25 This trihydroxy fatty acid was isolated26 from the rice plant Fukuyuki, which was affected by rice blast disease caused by the fungus Pyricularia oryzae. The alkyne precursor 33 was synthesized from D-ribose, following BIEP and lithiated alkyl chain extension as key steps (Scheme 8). 31 was treated with Ph3P in refluxing CCl4 to afford the corresponding chloride. The chloride was subjected to LiNH2 in liquid NH3 to form the acetylenic derivative 32, and further modifications along with carbon-chain elongation and CH2N2 methylation concluded the synthesis of 34.
image file: c9nj05626b-s8.tif
Scheme 8 Total synthesis of (11R,12S,13S)-trihydroxy-(9Z,15Z)-octadecadienoic acid.
2.2.2. (10S,11R,12R)-Trihydroxyeiarsa-(5Z,8Z,14Z)-trienoic acid. Yadav's group continued work on the synthesis of various enoic acids, which resulted in the accomplishment of the synthesis of (10S,11R,12R)-trihydroxyeiarsa-(5Z,8Z,14Z)-trienoic acid27,28 (39, Scheme 9) utilizing BIEP on a carbohydrate derivative. Alcohol 35 was obtained from D-mannose using a sequence of known procedures.29 Alcohol 35 was treated with Ph3P in refluxing CCl4 to form the chloride (90%), which was then subjected to the BIEP protocol with LiNH2 in liquid NH3 to produce dianion 36. This dianion was further used for in situ C-alkylation with 37 which proved to be futile. This issue was successfully addressed with sequential alkylation via n-BuLi, CuI in THF-HMPA (3[thin space (1/6-em)]:[thin space (1/6-em)]1) followed by the dropwise addition of bromide 37 in THF (−78 °C to rt, 2 h). This was further used for the synthesis of target 39 following partial reduction and saponification.
image file: c9nj05626b-s9.tif
Scheme 9 Total synthesis of (10S, 11R, 12R)-trihydroxyeiarsa-(5Z, 8Z, 14Z)-trienoic acid.
2.2.3. Triyne carbonate L-660, 631 methyl ester (42). In 1987, the Merck Sharp–Dohme group and Schering-Plough Corporation independently reported the isolation of a novel triacetylenic dioxolane unit from the fermentation broths of Actinomycetes and Microbispora sp., respectively.30 Utilizing BIEP of β-alkoxy chloride as a key reaction, Yadav et al. described the total synthesis of triyne carbonate L-660, 631 methyl ester starting from D-glucose (inversion of the stereocenter at C5 was involved, Scheme 10). Reaction of primary alcohol 40 with Ph3P–CCl4 under reflux conditions resulted in the chloro compound. Furthermore, hydrolysis with LiOH afforded the acid. The key BIEP of the β-alkoxy chloride afforded the propargyl alcohol. Then, the free hydroxyl group was protected as p-methoxyphenyl methyl ether, which was further used for the total synthesis of triyne carbonate L-660, 631 methyl ester (42).
image file: c9nj05626b-s10.tif
Scheme 10 Total synthesis of triyne carbonate L-660, 631 methyl ester.
2.2.4. Oploxynes A and B. Oploxynes A and B were isolated from the extract of the stem of Oplopanax elatus.31 They exhibit inhibition of NO and PGE2 production with an IC50 of 1.90 ± 0.28 and 3.08 ± 0.37 mg mL−1. With the goal of assigning the absolute configuration of the natural product 47, Yadav et al. described the total synthesis of oploxynes A and B, utilizing BIEP to generate the chiral acetylenic alcohols (Scheme 11).32
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Scheme 11 Total synthesis of oploxynes A and B.

Carbohydrate-derivative alcohol 43 could be obtained from D-ribose, which was treated with Ph3P and cat. imidazole in CCl4 under reflux conditions to afford the chloride compound, which was then subjected to the BIEP reaction, which provided the chiral propargylic alcohol 44. This fragment was further coupled with bromoalkyne 45 by following the Cadiot–Chodkiewicz cross-coupling conditions33 and further progressed to the total synthesis of oploxyne A and led to a revision of the absolute configuration of oploxyne B.34

2.3. Chiral epoxide derivatives

The salient features of this strategy are the transformation of chiral 2,3-epoxyalcohol 49 into 2,3-epoxychloride 50 (using Ph3P-CCl4, under reflux conditions) followed by the treatment with LiNH2 or LDA, leading to the formation of chiral propargyl alcohol 51 in excellent yield. 49 would be obtained from Sharpless epoxidation35 of allylic alcohols (Scheme 12).
image file: c9nj05626b-s12.tif
Scheme 12 General reaction mechanism of the chiral epoxide derivative to chiral carbinol.
2.3.1. (R)-Strongylodiol A. The synthesis of (R)-strongylodiol A (55) was reported by Yadav et al. as depicted in Scheme 13.36 The BIEP strategy adopted for the total synthesis involved the coupling of the two terminal acetylenes under Cadiot–Chodkiewicz cross-coupling conditions.37 The epoxy substrate 53 was obtained from 1,10-decanediol, including a Z-selective long-chain Wittig olefination and epoxidation under Sharpless conditions. The primary alcohol was treated with Ph3P–CCl4 under reflux conditions, and the subsequent base treatment (LiNH2 in liquid NH3) smoothly afforded chiral carbinol 54 in excellent yields. The final Cu(I)-catalyzed Csp–Csp eliminative cross-coupling between 54 and 3-bromopropynol delivered the targeted (R)-strongylodiol A (55) in 85% yield.
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Scheme 13 Total synthesis of (R)-strongylodiol A.
2.3.2. Oplopandiol. An example of the BIEP strategy utilized in the total synthesis of oplopandiol by Yadav et al. is outlined in Scheme 14.38 Treatment of epoxy alcohol 56 with Ph3P/CCl4 under reflux conditions gave the chloro epoxide, and the subsequent base treatment using n-BuLi at −78 °C afforded the corresponding chiral propargyl alcohol 57. This was further transformed into 58, which was used in the synthesis of oplopandiol by attachment of the other side chain alkyne through the Cadiot–Chodkiewicz cross-coupling. Stereoselective substrate-controlled epoxidation and Lewis acid-catalyzed regio- and stereoselective epoxy-ring-opening provided the natural products 61 and 62, respectively, from the advanced intermediate 58.
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Scheme 14 Total synthesis of oplopandiol.
2.3.3. Leiocarpin C. Leiocarpin C was isolated from the seeds of Goniothalamus leiocarpus (Annonaceae),39 possessing potent cytotoxic activity against human lung carcinoma A-549 and p-388 murine leukemia cells. Yadav et al. reported the first total synthesis of leiocarpin C by utilizing BIEP (Scheme 15).40 Epoxide 63 derived from cinnamyl alcohol was converted into epoxy chloride (Ph3P/CCl4-reflux conditions), and subsequently transformed into the anticipated chiral propargyl alcohol 64 utilizing BIEP-ring opening with n-BuLi in a high yield. Regioselective ring opening of chiral epoxide 65, trans-reduction of an internal alkyne 66, and Sharpless asymmetric dihydroxylation led to the total synthesis of leiocarpin C (68). Further functional group transformations led to the synthesis of goniodiol.41
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Scheme 15 Total synthesis of leiocarpin C.
2.3.4. Synrotolide. The class of unsaturated γ-lactone rings connected with a polyoxygenated chain were found to possess excellent cytotoxic activity against human tumour cells, as well as antimicrobial and antifungal activities.42 For example, lactones such as anamarine,43 hyptolide,44 synargentolide,45 spicigerolide46 and synrotolide47 were isolated from the species of Hyptis, Syncolostemon and related genera of the family Lamiaceae possessing bioactivity. The total synthesis of (−)-synrotolide diacetate is described by Yadav et al. utilizing BIEP, a Grignard-assisted lactol opening with a terminal alkyne and a Horner–Emmons Wittig reaction as the key steps (Scheme 16).48 Epoxy alcohol 69 derived from homopropargyl alcohol was converted to chloride (Ph3P/CCl4 reflux conditions) and then treated with excess lithium in liquid ammonia to give the desired chiral carbinol 70. In situ lithiated acetylene when treated with lactol 71 (derived from D-ribose) afforded the functionalized intermediate 72. The intermediate was then reacted in a short reaction sequence to (−)-synrotolide diacetate (73).
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Scheme 16 Total synthesis of synrotolide.
2.3.5. (+)-Anamarine. The Yadav group has investigated the total synthesis of (+)-anamarine applying BIEP and cross-metathesis as pivotal steps (Scheme 17).49 Epoxy alcohol 74 was converted into propargyl alcohol 75 by a two-step process, initially converting to the chloro epoxy compound, which on elimination using n-BuLi smoothly afforded the chiral carbinol in high yield. Then, they underwent formylation, asymmetric dihydroxylation50 and chelation-controlled vinyl Grignard reaction to offer 77.51 From this intermediate 77, RCM and a few more steps were all that was required to complete the total synthesis of (+)-anamarine (78).
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Scheme 17 Total synthesis of (+)-anamarine.
2.3.6. Putaminoxin. Putaminoxin (84), a disubstituted phytotoxic nonenolide, was isolated from the culture filtrates of Phoma putaminum fungus by Evidente et al., which causes a necrotic leaf disease Erigeron annuus (annual fleabane).52 The total synthesis of putaminoxin was achieved by demonstrating the use of the previously developed BIEP strategy by Yadav's group (Scheme 18).53 Epoxy alcohol 80 with requisite stereochemistry afforded the corresponding chlorooxirane, which was further converted into propargyl alcohol 81 upon treatment under Birch reaction conditions (Li in liquid NH3, THF, –33 °C) in high yield. Further transformations including regioselective opening of terminal epoxide with terminal alkyne, partial reduction and Yamaguchi macrolactonisation54 provided putaminoxin (84) in good yields.
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Scheme 18 Total synthesis of putaminoxin.
2.3.7. (9S,12R,13S)-Pinellic acid. Pinellic acid is a novel and potentially useful oral adjuvant when used in conjunction with intranasal inoculation of influenza HA vaccines.55 All the possible isomers of pinellic acid were isolated from an oriental medicine, Pinelliae tuber. Among the all possible isomers, 9S and 13S-configured diastereomers possess a stronger activity. Yadav's group explored the synthesis of pinellic acid utilizing BIEP for the synthesis of key intermediate 86, to install the C-9 stereocentre (Scheme 19).56
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Scheme 19 Total synthesis of (9S,12R,13S)-pinellic acid.

Epoxide 85 was modified into the corresponding epoxy chloride by using Ph3P/CCl4 (under reflux conditions) and subjected to BIEP using lithium in liquid ammonia at −33 °C to afford acetylene 86 in a stereoselective fashion. Lithiated alkyne was added to aldehyde to afford 87 in an 18[thin space (1/6-em)]:[thin space (1/6-em)]2 diastereomeric ratio. This was further used in the synthesis of pinellic acid (88).

2.3.8. Attenols A and B. Chandrasekhar et al. have extended the versatility of this reaction in the total synthesis of the unique spiroketals attenols A and B.57 Attenols were isolated by Uemura and co-workers, from Chinese bivalve Pinna attenuata.58 In an early step, chlorination of chiral epoxy alcohol 89 using N-chlorosuccinimide (NCS)/Ph3P resulted in the epoxy chloride, which was further converted to chiral alkynol 90 using lithium diisopropylamide (LDA) at −40 °C in 87% yield in two steps. Further alkynylation on aldehyde 91 with lithiated alkyne provided alkynone 92. Subsequently, one-pot global deprotection followed by spiro-ketalization was achieved with pTSA in methanol, providing the desired spiroketal products attenols A (93) and B (94) in 52% and 12% yields, respectively (Scheme 20).59
image file: c9nj05626b-s20.tif
Scheme 20 Total synthesis of attenols A and B.
2.3.9. (+)-Spirolaxine methyl ether. Spirolaxine and its methyl ether possess cholesterol-lowering activities,60 along with cytotoxic activities toward endothelial cells (BMEC and HUVEC) and a variety of tumour cell lines (LoVo and HL60). Due to its fascinating potent biological activities and structural features, the total synthesis of spirolaxine methyl ether was carried out and reported.61 Yadav and co-workers successfully utilized the BIEP strategy and Alder–Rickert reaction62 in the total synthesis of (+)-spirolaxine methyl ether (Scheme 21).63 Epoxy alcohol 95 was subjected to chlorination using Ph3P in CCl4 in the presence of NaHCO3 (10 mol%) at reflux temperature, followed by BIEP to give propargyl alcohol 96 in 88% overall yield. Alkyne 96 with n-BuLi followed by the addition of methyl chloroformate gave the long-chain acetylenic ester 97. Alkyne 97 underwent an Alder–Rickert reaction with cat. N,N-Dimethylaniline in a sealed tube at 200 °C to give the aromatic precursor 98 in 45% yield. The use of N,N-dimethylaniline as an additive was critical for the success of this reaction. Julia-olefination and hydrogenation of olefin with PtO2 delivered the desired natural product 99.
image file: c9nj05626b-s21.tif
Scheme 21 Total synthesis of (+)-spirolaxine methyl ether.
2.3.10. (+)-Amphidinolide J. Amphidinolides are a family of macrolides with a unique structure and interesting biological activities;64 these macrolides are isolated from the marine dinoflagellate Amphidinium sp., a good source of novel secondary metabolites such as amphidinolides. In 1998, Williams and co-workers reported the first total synthesis of amphidinolide family macrolide Amphidinolide J (104, Scheme 22).65 They implemented the BIEP strategy brilliantly to synthesize a precursor of chiral allylic alcohol. Sharpless asymmetric epoxidation product 100 was subjected to chlorination, and subsequently, treatment with LiNH2 provided 101. syn-Hydrozirconation of alkyne 101 produced E-vinyl iodide 102, which after palladium-catalyzed Negishi coupling66 with a stable homoallylic zinc reagent resulted in 103. This was further reacted to complete the total synthesis of amphidinolide J (104).
image file: c9nj05626b-s22.tif
Scheme 22 Total synthesis of (+)-amphidinolide J.
2.3.11. Asimin. In 2002, Marshall et al. reported the modular synthesis of Annonaceous acetogenins,67 asiminocin, asimicin, asimin and bullanin,68 which are active against H-116 human colon cancer cells. For the synthesis of segment E of Asimin, BIEP was utilized. Diepoxy diol 105 was synthesized from 1,5-cyclooctadiene in four steps (Scheme 23). The corresponding chloride on treating with LDA provided the elimination product chiral dialkyne diol 106, and after further desymmetrization afforded segment E. Coupling of the butenolide terminus under Sonogashira conditions69 resulted in enyne 108 in good yields. Only a few more modifications were needed to complete the synthesis of asimin (109).
image file: c9nj05626b-s23.tif
Scheme 23 Total synthesis of asimin.
2.3.12. (+)-Gambieric acid A. The total synthesis of the complex ether structured Gambieric acid A was achieved by Sasaki in a convergent manner,70 involving the coupling of individual ABCD rings and FGHIJ rings through the Suzuki–Miyaura coupling.71 In their successful synthesis, they adopted a stepwise approach to the construction of AB rings (Scheme 24). First chlorination of 110 with Ph3P/NCS and subsequent treatment of the derived chloro-epoxide with LDA gave the desired chiral carbinol 111 in high yield. This was further converted to cis-vinyl iodide 112 (NIS/AgNO3 subsequent diimide cis-selective reduction),72 one of the partners for Suzuki–Miyaura cross-coupling with alkylborate ([PdCl2(dppf)·CH2Cl2], Ph3As, Cs2CO3, aqueous THF/DMF, 50 °C), which was further elaborated to AB rings of gambieric acid.
image file: c9nj05626b-s24.tif
Scheme 24 Total synthesis of (+)-gambieric acid A.
2.3.13. Amphidinolide T1. Yadav et al. utilized BIEP for the synthesis of Amphidinolide T1 and Amphidinin B (Scheme 25).73 They approached what they identified as the stereochemically and functionally most challenging portion of the natural product containing a trans-tetrahydrofuran with a chiral methyl created through radical cyclization. Subsequent reactions on 115, using Ph3P in CCl4 under reflux conditions, followed by BIEP using LiNH2 in liquid NH3 gave chiral carbinol 116. Further subjecting it to NBS/ethyl vinyl ether following radical cyclization (n-Bu3SnH/AIBN) provided lactoether 117 in high yield, which was further reacted to form Amphidinolide T1. Amphidinin B was synthesized in a similar manner.74
image file: c9nj05626b-s25.tif
Scheme 25 Total synthesis of amphidinolide T1.
2.3.14. (−)-Isolaurallene. Allenes have considerable applications in organic synthesis, including cycloaddition,75 cyclization,76 ionic addition,77 and cross-coupling for C–C bond formation.78 Allenes can serve as carbon nucleophiles in the synthesis of homopropargyl ethers. The stereoselective construction of allenes79 can be achieved through a highly stereo-controlled propargylic alcohol. Crimmins et al. successfully utilized BIEP for the synthesis of chiral propargyl alcohol as a precursor for the diastereoselective synthesis of allene in the total synthesis of (−)-isolaurallene (Scheme 26).80 Conversion of the epoxy alcohol 121 to the chloride set the stage for BIEP for the synthesis of the propargyl alcohol 122. The conversion of the propargylic alcohol to the sulphonate, followed by its SN2′ displacement through exposure to LiCuBr2 affords the bromoallene.81 The desired regioisomer 123 was obtained as an 8[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of isomeric bromoallenes and direct SN2 displacement. This compound was then converted into (−)-isolaurallene (124) in a straightforward manner.
image file: c9nj05626b-s26.tif
Scheme 26 Total synthesis of (−)-isolaurallene.
2.3.15. Gliomasolide E. Recently, a new 14-membered macrolide family of natural products have been isolated from a sponge-derived fungus Gliomastix sp. ZSDS1-F7-2 and the South China Sea marine sponge Phakellia fusca Thiele by Xu et al.82 Total synthesis of R and S isomers of Gliomastix led to the assignment of configuration of stereocenters at C-7 and revealed that the absolute stereochemistry of gliomasolide E should be 130 (2E,5R,7R,9R,13R).83 Hexanol was converted to epoxy alcohol, which was subjected to chlorination followed by BIEP (Scheme 27). Lithiation of the terminal acetylene followed by quenching with chiral epoxide 128 offered 129, which was further reacted to complete the total synthesis of R and S C-7 of gliomasolide E.
image file: c9nj05626b-s27.tif
Scheme 27 Total synthesis of gliomasolide E.
2.3.16. (+)-Sacrolide A. Recently, Thirupati et al. reported the total synthesis of (+)-Sacrolide A utilizing BIEP followed by transselective hydrometallation of the propargylic alcohol and acid-catalyzed Kita macrolactonization.84 The product of Sharpless asymmetric epoxidation, 132, was converted to chloride and subjected to BIEP, which resulted in chiral propargyl alcohol 133. Furthermore, nucleophilic addition of lithiated alkyne 133 to aldehyde 134 in the presence of HMPA furnished a propargyl alcohol (19[thin space (1/6-em)]:[thin space (1/6-em)]1 diastereomeric mixture by 1H-NMR analysis), this advanced intermediate further reacted for the synthesis of the desired natural product 135 (Scheme 28).
image file: c9nj05626b-s28.tif
Scheme 28 Total synthesis of (+)-sacrolide A.

2.4. Tetrahydropyran derivatives

Several methodologies have been developed to construct 1,3-diols.85 1,3-Diols are an important subunit in a number of biologically active polyketide natural products and intermediates.86 To synthesize 1,3-diols, a diastereoselective and convergent approach has been attempted via highly stereoselective Prins-cyclization followed by reductive ring opening by Yadav et al.87 Prins-cyclization of homoallylic alcohol 136 and various aldehydes, individually, afford the multisubstituted pyrans 137. Pyranyl methanol 138 was treated with TPP and NaHCO3 in refluxing CCl4 to produce chloro compounds, which upon reacting with LiNH2 or LDA underwent reductive opening, which could furnish 1-alkynyl anti-4,6-diols 139 (Scheme 29).
image file: c9nj05626b-s29.tif
Scheme 29 Tetrahydropyran derivative to chiral carbinol.
2.4.1. 7-Desmethoxyfusarentin and its methyl ether. Yadav and co-workers reported the total synthesis of 7-desmethoxyfusarentin and its methyl ether involving Prins cyclization, tetrahydropyran-ring-opening and Alder–Rickert's reactions as key steps (Scheme 30).88 Homoallylic alcohol 140 treated with butyraldehyde under Prins-cyclization conditions, in the presence of TFA, followed by trifluoroacetate hydrolysis with K2CO3 in methanol resulted in the trisubstituted tetrahydropyran 141 in 52% yield. Pyranyl methanol 142 was converted to chloride using TPP in CCl4 in the presence of a catalytic amount of NaHCO3 under reflux conditions. Furthermore, ring opening with LiNH2 gave the partially protected anti-4,6-diol of alkyne 143 in 60% yield, which was involved in the Diels–Alder reaction2 and further elaborated to 7-desmethoxyfusarentin and its methyl ether (146).89
image file: c9nj05626b-s30.tif
Scheme 30 Total synthesis of 7-desmethoxyfusarentin and its methyl ether.
2.4.2. (+)-Crocacin C. The protecting-group-free total synthesis of (+)-crocacin C was reported by Bressy, Pons and co-workers, following an enantioselective enzymatic desymmetrization of a meso-diol, a one-pot hydrostannylation/Stille coupling, and a BIEP of a THP ring as the key steps (Scheme 31).90 Pyranyl methanol was converted to the chloro compound using PPh3, imidazole and CCl4 under reflux conditions. A base-induced THP ring opening allowed the formation of alkyne 150. As reported by Bressy, using 5 equiv. of LDA at temperatures ranging from −78 to −30 °C, the corresponding alkoxyalkyne 150 was obtained as the only product in 47% yield, and 46% of the starting material was recovered, and the protonated form of the intermediate vinyl chloride was not observed. These results suggested that the elimination step from vinyl chloride intermediate A occurred faster than its formation through the ring-opening step. Further hydrostannylation91 and Stille coupling92 achieved the total synthesis of the natural product (+)-crocacin C (151). It is noteworthy that this protocol has been utilized for the synthesis of bioactive intermediates and drug-like structures.93
image file: c9nj05626b-s31.tif
Scheme 31 Total synthesis of (+)-crocacin C.

3. Conclusion

This review on the base-induced elimination of β-alkoxy chloride, which has been utilized in total synthesis reactions over the past three decades, revealed its efficiency, versatility and scope to produce chiral alkylnylcarbinols corresponding to their γ-alkoxide.

Overall, we provided our conjecture on this strategy that chiral propargyl functionality can be used for C–C bond formation as well as a source for cis and trans double bond transformations. Hence, it allows easy access to the synthesis of several long chain acetylenic chiral diols, which would offer many important and elegant applications in total synthesis.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

U. M. G thanks University Grant Commission, New Delhi, India, for financial assistance in the form of a senior research fellowship.

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