Applications of the Horner–Wadsworth–Emmons Olefination in Modern Natural Product Synthesis

SYNTHESIS0039-78811437-210X Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart 2021, 53, 2713–2739 review 2713 en

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O O Dávid Roman 0000-0002-6223-7869 O O O 1 Maria Sauer 1 H R3 R4 R3 R O P R O P 1 2 1 R2 R O R Christine Beemelmanns* 0000-0002-9747-3423 R O O O O O 1 R1O P R2 R O P Chemical Biology of Microbe-Host Interactions, Leibniz Institute for 1 X R2 R1O N R O Natural Product Research and Infection Biology – Hans-Knöll-Institute H O O (HKI), Beutenbergstrasse 11a, 07745 Jena, Germany O O 1 [email protected] 1 2 R O P R O P R 3 3 2 2 R H R R R1O OR R1O O (E) (Z) or X O O H/R4 R2 R4/H H O O ChristineChemicaleMailCorresponding [email protected] BeemelmannsBiology of AuthorMicrobe-Host Interactions, Leibniz Institute for Natural Product Research and Infection Biology – Hans-Knöll-Institute (HKI), Beutenbergstrasse 11a, 07745 Jena, Germany 1 2 NH R O P R R1O P S R1O S 1 R O R2 Natural Product Synthesis

Received: 20.01.2021 referred to as olefination, is a fundamental reaction in Accepted after revision: 28.04.2021 organic chemistry and allows further transformations, such Published online: 28.04.2021 DOI: 10.1055/a-1493-6331; Art ID: ss-2021-z0027-r as oxidation, metathesis, or polymerization. The challenge License terms: of selectively introducing double bond motifs into poly- © 2021. The Author(s). This is an open access article published by Thieme under the functional molecules motivated organic chemists early on, terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, and gained an enormous momentum when Wittig pub- permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, lished his discovery on carbonyl olefination in 1954 (Figure transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/) 1), later called the Wittig reaction. He treated carbonyl

compounds with substituted quaternary phosphonium Abstract The Horner–Wadsworth–Emmons (HWE) reaction is one of salts in the presence of certain condensing agents and dis- the most reliable olefination reaction and can be broadly applied in organic chemistry and natural product synthesis with excellent selectivity. covered that the intermediate phosphonium ylides reacted Within the last few years HWE reaction conditions have been optimized with the carbonyl compound to form an unstable interme- and new reagents developed to overcome challenges in the total syn- diate, which then broke down to phosphine oxide and an theses of natural products. This review highlights the application of olefin.1 This epochal discovery significantly changed the di- HWE olefinations in total syntheses of structurally different natural rection of olefination chemistry. Since then, the Wittig products covering 2015 to 2020. Applied HWE reagents and reactions conditions are highlighted to support future synthetic approaches and principle of double bond formation has been thoroughly serve as guideline to find the best HWE conditions for the most compli- studied and because of its effectiveness and applicability cated natural products. has led to the development of related transformations.2 1 Introduction and Historical Background Most notably, in 1958 Horner showed that the acidity of a 2 Applications of HWE 2.1 Cyclization by HWE Reactions phosphonate correlates with its reactivity to form a stabi- 2.2.1 Formation of Medium- to Larger-Sized Rings lized phosphonate carbanion that reacts with carbonyl 2.2.2 Formation of Small- to Medium-Sized Rings compounds to yield an olefin.3 To prove his theory, he react- 2.3 Synthesis of ,-Unsaturated Carbonyl Groups ed methyldiphenylphosphine oxide with benzophenone in 2.4 Synthesis of Substituted C=C Bonds the presence of sodium amide in benzene and obtained the 2.5 Late-Stage Modifications by HWE Reactions 2.6 HWE Reactions on Solid Supports predicted products diphenylphosphinic acid and 1,1-di- 2.7 Synthesis of Poly-Conjugated C=C Bonds phenylpropene. Wadsworth and Emmons discussed the re- 2.8 HWE-Mediated Coupling of Larger Building Blocks action reported by Horner and defined its limitations in 2.9 Miscellaneous 1961.4 They found that both the Wittig and Horner reac- 3 Summary and Outlook tions share same principles but with the major difference Key words HWE reaction, olefination, C=C bond formation, phospho- that phosphonate carbanions are stabilized by electron- nate, aldehyde, alkenes, natural products withdrawing groups, which makes them more nucleophilic and less basic compared to phosphonium ylides (Figure 2). The systematic exploration of the now titled Horner– 1 Introduction and Historical Background Wadsworth–Emmons (HWE) olefination opened a wide range of new possibilities and quickly became one of the Carbon–carbon double bonds are ubiquitous in natural most intensively studied and commonly applied reactions and biologically active products and common motifs in or- for selective double bond formation. ganic building blocks. The formation of a C=C bond, often

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Leopold Horner W. Clark Still & Michael W. Rathke & Wittig reaction with Cesare Gennari Michael Nowak

stabilized phosphonate Developed new reagents, Mild HWE conditions using carbanions conditions for Z-selective LiBr or MgBr2 and Et3N reaction

Georg Wittig William S. Wadsworth & Satoru Masamune & Kaori Ando

Olefination reaction William D. Emmons William R. Roush Reported conditions with phosphonium Defined scope of Mild HWE conditions using for Z-selective alkene ylides Wittig reaction and weak bases DBU or DIPEA formation proposed mechanism

Figure 1 Historical timeline capturing the most important discovery milestones in the development of the Horner–Wadsworth–Emmons reaction

In 1983 Still and Gennari modified the HWE reaction to sociating base, such as potassium hexamethyldisilazanide obtain almost exclusively Z-selective alkenes.5,6 This trans- (KHMDS) and 18-crown-6 in THF, which allowed highly ste- formation was achieved by using electrophilic bis(trifluoro- reoselective formation of Z-unsaturated esters. In 1995, ethyl)phosphonoacetate in combination with a strong dis- Ando reported that the use of ethyl diphenylphosphono-

Biographical Sketches

Christine Beemelmanns dustrie and the Studienstiftung Leopoldina, she joined the Leib- (1981) received her diploma in des Deutschen Volkes. After niz Institute for Natural Product chemistry at the RWTH Aachen postdoctoral stays in Prof. Keis- Research and Infection Biology (Germany) in 2006. After a one- uke Suzuki’s group at the Tokyo (Jena, Germany) as junior re-

year research stay in Prof. Mikiko Institute of Technology (Tokyo, search group leader at the end Sodeoka’s group at RIKEN Japan) and Prof. Jon Clardy’s of 2013. Her research focuses (Wako-Shi, Japan) she then per- group at Harvard Medical on the isolation, characteriza- formed her Ph.D. under the su- School (USA), supported by fel- tion, and total synthesis of mi- pervision of Prof. Hans-Ulrich lowships from the German Ex- crobial signaling molecules. Reissig with a fellowship from change Service and German the Fonds der Chemischen In- National Academy of Sciences

Dávid Roman received his in the DAx Global Discovery of Microbe-Host Interactions led B.Sc. degree in chemistry Chemistry (GDC) department of by Dr Christine Beemelmanns at (2015) and M.Sc. degree in or- Novartis Institute for Biomedical the Hans-Knoll Institute in Jena ganic chemistry (2017) from research (NIBR) in Basel (Swit- (Germany). His main research University of Pavol Jozef Šafárik zerland) for a research stay. focuses on total synthesis and in Košice (Slovakia). After his Since 2018, he has been per- derivatization of natural prod- graduation in 2017, he joined forming his doctoral studies in ucts of microbial origin. the lab of Dr Andreas Lerchner the group of Chemical Biology

Maria Sauer received her B.Sc. 2019, she joined Dr. Christine in total synthesis of biologically and M.Sc. degrees in chemistry Beemelmanns’ group where she active natural products as part (2019) from Friedrich-Schiller- is currently working on method of her doctoral studies. University in Jena (Germany). In development and applications

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stabilized carbanions. This mainly includes the Julia– Kocienski olefination (methylated aryl alkyl sulfones)13 and Peterson olefination (-silyl carbanion).14 The enormous numbers of HWE reaction possibilities in addition to its functional group compatibility and selectivity resulted in its wide synthetic use, in particular in natural product synthesis. Building up on preceding reviews that discuss the mechanisms and reaction scopes of Wittig2 and HWE reactions,15 this review aims to highlight the diversity of employed HWE reagents and their applications in natural product total syntheses covering 2015 to 2020 (Scheme 1). Subsections are structured chronologically and according to the formation of macrocycles, such as small to medium rings, ,-unsaturated carbonyls, and conjugated double bonds. The applied reagents and reaction conditions of the herein described syntheses are highlighted in Table 1 and allow the reader to navigate through the diversity of HWE reactions and support identifying suitable reagents and conditions for challenging natural product syntheses.

2 Applications of HWE

2.1 Cyclization by HWE Reactions

At the being of the 1970s the HWE reaction was exam- ined a synthetic tool in the synthesis of lactones,39 lact- Figure 2 Reaction mechanism of the HWE reaction ams,40 macrocycles,41 and hetero-polycycles.42 Since then, intramolecular HWE-based cyclization reactions have be- acetate results in an almost exclusive formation of Z- come very popular in natural product total synthesis due to alkenes by using Still’s conditions [KHMDS/18-crown-6] their functional group tolerance, high yields, and selectivi- and benzyltrimethylammonium hydroxide (Triton B) as a ty.43 base.7 Shortly after the reports by Still and Gennari, Masamune 2.2.1 Formation of Medium- to Larger-Sized Rings and Roush reported in 1984 that the presence of lithium chloride leads to complexation of the phosphonate reagent, Polyfunctionalized macrocyclic natural products are which results in increased acidity and reactivity; weaker ubiquitous in nature. Their stereochemical complexity and bases like DBU or diisopropylethylamine (DIPEA) can be ring size most often confers high bioactivities, thus making used for deprotonation.8 Rathke and Nowak extended these them interesting targets for medicinal and organic chem- 44 studies in 1985 and reported that the use of LiBr or MgBr2 ists. To showcase the application of HWE reaction, we se- and triethylamine leads to a conversion of aldehydes and lected four recent literature examples. ketones with similar yields to those reactions reported with Cytochalasans are a diverse group of polyketide-derived strong bases.9 These studies triggered a cascade of explora- macrocycles of fungal origin, which are known for their tions to optimize the conditions for HWE reactions (phase broad range of biological activities.45 This includes cytotox- transfer catalyst,10 microwave irradiation, metal-promoted ic, immunomodulatory, and nematicidal properties.46 The HWEs),11 selectivity (enantioselective or diastereoselective cytochalasan family has been a popular synthetic target for transformations),12 and substrate scope. While these semi- decades47 and numerous reports describe synthetic strate- nal findings unraveled the correlation of acidity, complex- gies towards cytochalasin B,48 cytochalasin H,49 cytochala- ation, and reactivity in phosphonate-based olefination resin O,50 chaetochalasin A,51 aspochalasin B,52 and other reactions, they also stimulated the usage of other heteroatom- lated congeners of the cytochalasan family.

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A) B) O O O H O HO H O H OH H H HN O OH HN OH O O O O O OH H O O OH O O OH OH O O H 2 4 HO OH (–)-aspochalasin B propindilactone G OH 70b Trauner and co-workers (2018)53 Gui and co-workers (2020) 1 34 Deng and co-workers (2018) HO OMe (–)-marinisporolide C 3 O O 63 Dias and de Lucca (2017) asperchalasine D Deng and co-workers (2018)34 O H O H H C) O N N OH N O 5 (–)-flueggenine C 70a O O O Han and Jeon (2017) O O OH D) HO N N OH O O H HO 6 OH O (–)-lasonolide A O OH 7 Hong and co-workers (2018)33 (+)-neooxazolomycin 25 Kim and co-workers (2019) O HN CO2Me O HO OH OH OH O O

HN 10 O OH tiancimycin B O N O HO Nicolaou and co-workers (2020)16 H 8 9 militarinone D fumosorinone A 32 Schobert and co-workers (2018)28 O Sim and co-workers (2015) NH H OH E) H O O O AcO O P NMe3 O O H O O O O H 12 OAc pericoannosin A OH 11 O COOH Lindsley and co-workers (2019)80 O O 11 15 NHSO3H (–)-indoxamycin A siladenoserinol A Liang and co-workers (2019)85 Doi and co-workers (2018)119 O 17 HO Tong, Qian and co-workers (2019) O H O Cl O CHO H N O OMe OH OMe N O O H O H OCOAr OMe 16 14 13 rhizoxin D anaenamide A melleolide Fürstner and co-workers (2019)123 Luesch and co-workers (2020)31 Takasu and co-workers (2019)18

Scheme 1 Examples of some natural products synthesized using HWE reactions (highlighted red) presented herein incorporated in their total syntheses. Natural products are sorted according the outcome of the HWE reaction within their synthetic strategy for the formation of (A) macro- and medium-sized ,-unsaturated rings, (B) small rings, (C) polyconjugated C=C bonds, (D) ,-unsaturated esters and enones, and (E) coupling of larger building blocks.

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Table 1 Summary of Some HWE Reagents and Conditions Sorted According to the General Formulas Presented

HWE phosphonate reagents Conditions Products of HWE reaction Yield (%) Ratio (E/Z) Year (Section)a

O O R1O P 2 R1O OR

O O O HN CO2Me 16 P NaH, THF O 2020 EtO OMe 84 8:1 EtO –78 to 0 °C, ca 5 h OH (2.5) 17

O OH 10

O O O O TBSO N EtO P O 10 Boc O NMe EtO 3 DBU, LiCl, THF 201917 H O O O O O 77 only E P r.t., 2 h O P (2.8) H 5 O O OTIPS O O O NMe3 18 OTIPS 19

H CO2Et O O O 18 EtO P NaH, toluene 78 (2 2019 only E b EtO OEt 0 °C to r.t., 1.5 h H steps) (– ) 20 OTIPS 21

O O 19 MeO P n-BuLi, DMPU, THF 2019 TBSO 98 20:1 b MeO OMe 0 °C, 4.5 h (– ) 22 COOMe

O O 1 R O P 2 R1O R

Me O O O 20 MeO P NaH, t-BuOK, THF 20 (2 2020 only E b MeO Me –78 °C to r.t., ca. 1 h steps) (– ) O N 24 O

O O OTBS O MeO P O OTBDPS LiCl, DIPEA, MeCN O OTBDPS 202021 91 only E MeO 0 °C to r.t., 8 h (2.8) OPMB 26 27

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Table 1 (continued)

HWE phosphonate reagents Conditions Products of HWE reaction Yield (%) Ratio (E/Z) Year (Section)a

O O OTBS O OTBS EtO P O O O Ba(OH) ·8H O, THF 201822 EtO 2 2 OBn 85 only E OBn r.t., 1 h TBSO (–b)

28 29

O O LiCl, Et N, THF i-PrO2C OTBS 201623 MeO P OTBS 3 90 only E MeO 0 to 40 °C, 2.5 h (2.3) SO2Ph 30 31

O O O OTBS 24 MeO P OTBS Ba(OH)2·8H2O, THF 73 2019 only E b MeO r.t., 12.5 h (2 steps) (– ) 32 OTBDPS 33

i-Pr

i-Pr Si O i-Pr O O i- O O O O Si Pr MeO P Ba(OH) , THF/H O OH 201925 N 2 2 FmocHN N 75 only E MeO –30 °C, 16 h (2.7) HO O O O O 35 34

O O 1 R O P 3 2 R1O R R

O O O EtO P LiHMDS, HMPA, THF 201926 Bu Sn OMe 69 only E EtO OMe –78 °C to r.t., 2 h 3 (–b) 36 37

O O OTBS O EtO P n-BuLi, THF 201727 OMe 96 5.6:1 EtO OMe –78 °C to r.t., ca 1 h (–b)

36 38

O O O NaH, THF 201828 EtO P OEt 67 95% de EtO OEt 0 °C to r.t. (2.7) 39 40

O O O O LDA, THF 60 201729 MeO P OEt 5:1 OEt –78 to 0 °C, 2 h (2 steps) (2.7) MeO O 41 42

O O O O H H O EtO P n-BuLi, THF N OEt 201630 OEt 62 only E EtO r.t., 17 h H (2.7) TBSO 43 44

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Table 1 (continued)

HWE phosphonate reagents Conditions Products of HWE reaction Yield (%) Ratio (E/Z) Year (Section)a

O O R1O P 2 R1O OR R3

O O O MeO P n-BuLi, THF BocHN 202031 OMe OMe 50 6:1 MeO –78 °C, 3 h (2.4) Cl Cl 45 46

O O O EtO P NaH, THF 71 201532 OEt OEt 1.2:3 EtO 0 °C to r.t., 1 h (2 steps) (2.7) Me Me 47 48

MeO2C Me O O O F3CH2CO P 18-crown-6, KHMDS, EtO2C 74 (2 201833 OMe only Z F3CH2CO THF –78 °C, 2 h steps) (2.7) Me 49 OH 50

O O OTBS F CH CO Me 3 2 P 18-crown-6, KHMDS, 201919 OMe 90 1:20 F3CH2CO THF –78 °C, 1.5 h (–b) Me O OMe 49 51

O R1O P 2 R1O R

O KHMDS, THF 201834 EtO P 82 7:1 EtO 0 °C, 10 min OTBS (2.2.1) TBSO 52 OTBS 53

O O LDA, THF 201623 EtO P N 86 only E EtO N r.t., 12 h (2.3) 54 CHO 55

OTBS O

O N O O n-BuLi, THF 202035 EtO P SMe SMe 55 only E N –78 to 0 °C, 1.5 h (2.5) EtO TESO N 56 O

O OTES O 57

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Table 1 (continued)

HWE phosphonate reagents Conditions Products of HWE reaction Yield (%) Ratio (E/Z) Year (Section)a

O O O O O O NH 1 2 1 2 R1O P S R O P R R O P R 2 1 N 1 S R1O R R O H R O

O O O OTBS O O EtO P N LiCl, DIPEA, MeCN N O 202036 EtO O 77 only E r.t., 24 h (2.4) Bn BnO 58 59

H COSEt O O NaH, toluene O 78 201918 EtO P only E EtO SEt 0 °C, 11.5 h H (2 steps) (2.3)

60 OTIPS 61

O O NH O NH EtO P t-BuOK, THF 201637 EtO N 7 N 85 9.2:0.8 b H r.t., 5 h H (– ) 62 63

O O NH HN O EtO P S S n-BuLi, THF 201638 EtO 98 only E –78 °C, 2 h (–b)

64 65 a Section in which relevant material can be found for this synthesis. b Not discussed in following sections.

An excellent example of a ring-closing HWE reaction in fragment 53, starting from L-arabinose via a known 3-step the total synthesis of (–)-aspochalasin D (72) was described sequence to obtain hemiacetal 74.54 This was followed by a in 2018 by Trauner and co-workers (Scheme 2).53 Their Wittig reaction, TBS-protection, and the hydrogenation of strategy started with epoxy alcohol 66 that was converted the double bond to yield methyl ketone 75 in 69%. Methyl into isoindolone moiety 67 in 7 steps. Addition of dimethyl ketone 75 was directly subjected to an HWE reaction with lithiomethylphosphonate (68) yielded N-debenzoylated dienyl phosphonate 52 under strongly basic conditions to phosphonate 69. Aldehyde 70 was formed following selec- give the conjugated triene 53 in 82% yield (E/Z ~7:1).55 The tive TBS deprotection and oxidation with the Dess–Martin synthesis of lactam 77 was achieved in 8 steps from N-Boc- periodinane (DMP) of the primary alcohol. The HWE reac- L-leucine 76 via C-acylation with methyl chloroformate,56 tion using Masamune and Roush conditions (LiCl, DIPEA, selenylation, and oxidative elimination. Heating a mixture MeCN) afforded macrocycle 71 without epimerization in 3 of 53 and 77 (100 °C, neat) resulted in the formation of the steps and 46% yield.8 The synthesis of (–)-aspochalasin D Diels–Alder product 78 (E/Z 2:1). The phosphonate was in- (72) was completed by TBS deprotection using tetra- stalled by addition of dimethyl lithiomethylphosphonate to butylammonium fluoride, while acidic TBS deprotection the methyl ester 78. Deprotection and oxidation of the pri- using HF in acetonitrile yielded aspergillin PZ (73) in 89% mary alcohol yielded aldehyde 79 as a substrate for HWE yield. (–)-Aspochalasin D (72) was treated in 45% yield. macrocyclization. The 11-membered enone 72 was not Deng and co-workers accomplished the first total syn- achieved after screening different reaction conditions 9 57 58 theses of asperchalasines A, D, E, and H in 2018, which in- (KHMDS, NaH, LiBr/Et3N, K2CO3/18-crown-6 or NaOCH2CF3 ). cluded a highly diastereoselective intermolecular Diels– Only a mild Lewis acid, Zn(OTf)2, in combination with TMEDA Alder reaction and an HWE macrocyclization step to yield and triethylamine was found to promote intramolecular the monomer aspochalasin B (2) (Scheme 3).34 Their syn- HWE olefination. This was followed by TBS deprotection to thesis started with the stereospecific synthesis of triene obtain enone (–)-aspochalasin D (72) in 79% with minimal

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Naturally occurring 12, 14, or 16-membered macrolides

OH are most often of polyketide origin and have been shown to 7 steps H 60 OTBS exhibit diverse pharmacological activities. A series of new O CO2Me 14-membered macrolides, named pestalotioprolides B–H, BzN OTBS 66 O 67 were discovered from the mangrove-derived endophytic OTBS fungus Pestalotiopsis microspora by Liu, Proksch, and co- O H workers in 2016; the derivatives showed significant cyto- OTBS Li P 1. Et3N·3HF OMe toxicity against the murine lymphoma cell lines.61 The first 2. DMP OMe HN 68 total synthesis of derivatives pestalotioprolide E (83) and OTBS O O 75% P OMe OTBS pestalotioprolide F (84), with revision of its proposed struc- O 69 OMe ture, was accomplished by Goswami and co-workers (Scheme 4).62 The key step of this synthesis was the HWE H OTBS LiCl, DIPEA, MeCN reaction of 81a and 82b, which were obtained by partial hy- 46% HN H (3 steps) drogenation of Sonogashira products 80a and 80b. Oxida- OTBS O O P OMe tion of the primary alcohols yielded the corresponding O O 70 OMe aldehydes 81a and 81b that were necessary for the intra- H molecular HWE reaction.

HF, MeCN After testing different macrocyclization conditions, the 89% HN H H O O OTBS combination of LiCl/DIPEA or Ba(OH)2·8H2O were found to TBSO 71 provide macrocycles 82a and 82b in optimized 30% yield. H O HN TBAF Subsequent desilylation of 82a and 82b resulted in pestalo- O 53% O H OH tioprolide E (83) and the revised structure of pestalotiopro- H 73 aspergillin PZ lide F (84), respectively. HN Dias and de Lucca designed the first total synthesis of OH O O the 30-membered (–)-marinisporolide C (1) in 2017, which 72 OH

(–)-aspochalasin D allowed the determination of the relative and absolute con- figuration of the natural product (Scheme 5).63 Aldehyde 85 Scheme 2 Synthesis of (–)-aspochalasin D and aspergillin PZ by Traun- er and co-workers was prepared in 16 steps and elongated using Takai–Utimoto olefination with CHI3 producing vinyl iodide 86 in 82% yield.64 The free OH group in 86 was then subjected to epimerization at C18.59 The synthesis of (–)-aspochalasin B Yamaguchi esterification with 87 to afford 88 in 92%.65 (2) was completed after oxidation of the allylic alcohol in Treatment with HF·pyridine led to global TBS deprotection (–)-aspochalasin D (72) with TEMPO in 92% yield. and spiroketal formation. The remaining hydroxyl groups

O OH 52 O 3 steps KHMDS P OEt TBSO 52 OEt HO OH TBSO OTBS 82% dr = 7:1 OTBS OTBS TBSO 74 75 53

H 1. BuLi, MePO(OMe)2 2. HF·pyridine 3. DMAP neat, 100 °C O CO2Me BzN 8 steps CO Me 85% 2 O 72% (over 3 steps) OH E/Z = 2:1 OTBS N O NHBoc Bz 78 OTBS 76 77 TBSO

H 1. Zn(OTf) H H 2 TsOH, H2O Et3N, TMEDA 2. TBAF TEMPO HN HN HN O 92% 18 79% O OTBS OO OH OO OH O HO O MeO P O 2 72 79 MeO TBSO aspochalasin B aspochalasin D

Scheme 3 Total synthesis of (–)-aspochalasin D and aspochalasin B by Deng and co-workers

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OEt 2.2.2 Formation of Small- to Medium-Sized Rings OEt O P 1. Ni(OAc)2•4H2O OTBS NaBH4, H2, EDA The selective synthesis of small (3–5) and medium- O EtOH, r.t., 1 h O 90–91% OH O sized (6–13) ring systems are still a challenge in total syn- O O 2. DMP, NaHCO 66 3 * thesis. The HWE reaction has been applied in the forma- DCM R1 O P OEt 0 °C to r.t., 2 h OEt tion of many five- and six-membered ring systems as TBSO * 1 quant. shown in the following three examples. 1 R 1 OTBS 80a R = OTBS 81a R = In 2015, Brimble and co-workers employed a one-pot 80b R1 = OTBS 81b R1 = OTBS benzoyl transfer-intramolecular HWE reaction as a key step Ba(OH)2•8H2O THF/H2O in the construction of cis--hydroxycarvone-based building 0 °C to r.t., 2 h blocks, which are important intermediates in the synthesis 31% of sesterterpenoid natural products (Scheme 6).67 OH OTBS CSA, DCM/MeOH The synthesis of the key starting material allylsilane 98 0 °C to r.t., 6 h was accomplished in a 6-step synthesis from 92 and 93 via 95–96% * * a sequence of diastereoselective conjugate addition, nucleo- R1 O O R1 O O philic phosphonate addition, and the key benzoyl transfer- intramolecular HWE reaction to construct the cyclohexen- pestalotioprolide E 83 R1 = OH 82a R1 = OTBS 1 1 pestalotioprolide F 84 R = OH 82b R = OTBS one 98. Subsequent transformation into an allyl bromide allowed Barbier coupling with farnesal and subsequent Scheme 4 Synthesis of pestalotioprolide E and pestalotioprolide F deprotection of the benzoyl group yielded phorbin A (100) and its C4′-epimer 99. This synthetic approach showed that were again protected with tert-butyldimethylsilyl trifluoro- benzoyl enol ethers could serve as a masking group of methanesulfonate (TBSOTf) and afforded spiroketal 89. -ketophosphonates and allow a one-pot benzoyl transfer- Stille cross-coupling with 90 followed by oxidation of the intramolecular HWE reaction. The same protocol was also primary alcohol with TEMPO and bis(acetoxy)iodobenzene applied in the synthesis of sesterterpenoid natural prod- (BAIB) provided the necessary aldehyde 91. HWE olefina- ucts, such as phorbaketal A, which showed selective activi- tion to the macrocycle was accomplished using Masamune– ty against a range of cancer cell lines.68 Roush conditions (LiCl, DBU) in acetonitrile. After global In the same year, Hiemstra and co-workers described deprotection with HF·pyridine and HCl, (–)-marinisporolide the total synthesis of sesquiterpene lactone aquatolide C (1) was achieved in 25 steps (longest linear sequence) (107), which was isolated from Asteriscus aquaticus with 1.15% overall yield.

OTBS OTBS O O OHC I EtO P EtO OH 87 CHI3, CrCl2 TBSO TBSO dioxane, THF 87, TCBC, Et3N, DMAP, PhH

82%

OH O O O O OTBS O OH O O O O OTBS O 92% dr = 89:11 dr = 50:50 OTBS OTBS 85 86 OTBS I

1. 90, PdCl2(MeCN)2 OTBS PO(OEt) I PO(OEt)2 DMF, 98% 2 1. HF·py, THF TBSO 2. TEMPO, BAIB, DCM * O 2. TBSOTf, 2,6-lutidine, DCM * O O O O O O O 87% (over 2 steps) O O O O O O OTBS O

OTBS OTBS 88 89 O O O OTBS 1. LiCl, DBU, MeCN OH P OEt 2. HF·py, THF 4 O OH OH * OEt O 3. HCl, MeOH O O O O O O O O 15% (over 4 steps) OH OH O SnBu3 90 OTBS HO OH 91 1 (–)-marinisporolide C

Scheme 5 Final synthetic sequence within the total synthesis of (–)-marinisporolide C by Dias and de Lucca

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O O OMe

t 1. Ti(Oi-Pr)4, -BuOK O MeO t-BuLi, CuCN, Li-thiophene MeO THF, –10 °C, 4 h OMe + O

Et2O, –30 °C + 2. HC(OMe) , p-TsOH Br 76% 3 OH O O MeOH, 16 h O TMS O TMS 101 102 62% (2 steps) 103

92 93 94 1. 104, DCC O OBn DMAP, CH Cl EtPO(OEt)2 NaH, THF 2 2 3 h PO(OEt)2 PO(OEt)2 n-BuLi, THF 16 h –78 °C OBn O 1. BzCl, Et3N, DMAP 76% 2. aq HCl CH2Cl2, r.t., 88% acetone, 24 h BzO O 78% O O O 2. CSA 92% (2 steps) 106 PO(OEt)2 MeCN/MeOH/H O 105 HO 2 O (2:2:1), r.t., 52% O HO O O TMS (88% brsm) TMS 96 95 PO(OEt)2 O 11 steps HO O P OEt O (COCl) , DMSO OEt 2 1 Et N, CH Cl NaH, THF 1 O 107 104 3 2 2 BzO –78 °C to r.t. 0 °C to r.t. aquatolide OBn 4 4 53% O (over 2 steps) OBz Scheme 7 Total synthesis of aquatolide by Hiemstra and co-workers HO TMS TMS 98 97 1. NBS, THF OH OH –78 °C, 100% O O 2. Farnesal, Zn by methanolic deacetylation. Subsequent treatment of alco- NH4Cl (aq) THF, 30 °C hol 111 with methanesulfonyl chloride and triethylamine + OH OH sonication followed by TFA-induced Boc-deprotection and final basic 3. K2CO3, THF MeOH, r.t. treatment (aq K2CO3 in THF) resulted in (–)-flueggenine C (5).

100 37%:19% 99 phorbin A 2.3 Synthesis of ,-Unsaturated Carbonyl Groups Scheme 6 Synthesis of phorbin A and its C-4′ epimer by Brimble and co-workers ,-Unsaturated esters and enones are common motifs in chemical building blocks and natural products. Here, we highlight five recent natural product syntheses that re- (Scheme 7).69 The total synthesis started with a cross-aldol quired the introduction of ,-unsaturated carbonyl groups reaction of isobutyraldehyde (101) and propynal (102) fol- via HWE reactions. lowed by treatment with trimethyl orthoformate yielding acetal 103. The intramolecular HWE-based cyclization was introduced after esterification with phosphonate 104 by treatment with an excess of NaH (1.5 equiv) under diluted BocN H OH AcO (EtO) P(O)CH CO H conditions (0.02 M) to form pentenolide 106 in 76% yield. 8 steps O 2 2 2 N OH HO DCC, THF The synthesis required 11 more steps, including Crabbé ho- O Boc O 51% mologation to an allene, photochemical [2+2]-cycloaddi- N H tion, hydroboration, intramolecular Mukaiyama-type aldol 108 Boc 109 reaction to cyclize the eight-membered ring, Dess–Martin OAc EtO oxidation, and Lewis acid catalyzed cyclization of silyl enol O BocN OEt O H P NaH, THF EtO P AcO ether to yield racemic aquatolide (107) (16 steps, longest O then MeOH O linear chain) with an overall yield of 2.2%. EtO O O O Jeon and Han accomplished the first total synthesis of 52% O N H (–)-flueggenine C (5) (Scheme 8) in 2017,70a which belongs Boc 110 71 to the plant-derived securinega alkaloids family. OAc Their synthesis started with the conversion of Boc-pro- BocN O O O H D HO O tected -proline 108 in 8 steps. This included diastereo- 1. MsCl, Et3N O O O H O DCM, TFA H selective Rauhut–Currier (RC) reaction to acetylated dimer H 72 2. aq K2CO3 109. The tertiary alcohols were both esterified by slow N H N Boc THF N addition of diethylphosphonoacetic acid to 109 in the pres- 111 62% (2 steps) 5 ence of DCC affording phosphonate 110 in 51% yield. The OH (–)-flueggenine C phosphonate 110 was then converted into olefin 111 via an Scheme 8 Synthesis of (–)-flueggenine C by Jeon and Han intramolecular HWE using NaH as base that was followed

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The first example is pinolide (117), which is a member O O 73 30, LiCl, Et3N of naturally occurring decanolides isolated in 2012 and CO2i-Pr TBSO CO2i-Pr was synthesized in 2016 by Shelke and Suryavanshi THF SO2Ph 0 °C to 40 °C SO2Ph 74 (Scheme 9). The synthesis started with asymmetric 118 2.5 h, 90% 31 9 steps -aminooxylation of pentanal (112) using L-proline and ni- trosobenzene as an electrophilic oxygen source. -Anilino- H oxy aldehyde 113 was subjected to HWE olefination (LiCl O O HN TBSO P OMe and DBU) in the second step with phosphonoacetate 20 to OMe N O 30 yield -anilinooxy-,-unsaturated ester 114, which under- O PhO2S went copper-mediated N–O bond cleavage to produce sec- 119 ondary alcohol 115 in 77% yield (99% ee). Total synthesis of 1. NaH, n-BuLi pinolide 117 was accomplished in 10 additional steps. THF, 0 °C, 30 min then 1-bromobut-2-yne OAc O O 2 h, 72% O OAc O O P OMe 2. NaH, 1,3-diacetoxyacetone EtO OMe P 24 THF, 0 °C to r.t. 120

EtO OEt 76% 20 ONHPh then 20 O 1. 1 M HCl, H2O, EtOH H H LiCl, DBU 65 °C, 24 h, 80% PhNO, L-proline 1 h EtO P N 2. (COCl)2, DMSO, Et3N EtO N 112 O MeCN, –20 °C, 24 h O –78 °C to r.t., 85% 113 54 O O 54, LDA, THF OH CuSO •5H O (30 mol%) ONHPh r.t., 12 h 4 2 O OEt MeOH, 25 °C, 12 h OEt O then 1 M HCl petrol ether, 86% 121 77%; 99% ee 55 115 O (over 2 steps) 114 O

HO H 8 steps O O HO OH 7 steps N O 119 + 55 O O OPMB O H O 117 H N 116 pinolide Scheme 9 Total synthesis of pinolide by Shelke and Suryavanshi 122 (–)-nakadomarin A In the 2016 total synthesis of nakadomarin A by Scheme 10 Synthesis of (–)-nakadomarin A by Boeckman and co- Boeckman and co-workers, an HWE reaction was employed workers to construct necessary building blocks.23 Nakadomarin A belongs to the manzamine alkaloid family and was isolated Another example for the use of Masamune and Roush’s from marine sponges by Kobayashi and co-workers.75 Mem- HWE conditions for the synthesis of linear unsaturated car- bers of this compound family exhibit a broad range of bio- bonyl units in a natural product synthesis was described in activities, such as cytotoxicity, antimicrobial, antileishma- 2017 by Scheidt and co-workers.77 They reported the total nial, antimalarial, and many more.76 synthesis of four sesquiterpenoids belonging to the protoil- As shown in Scheme 10, transformation of aldehyde 118 ludane, mellolide, and marasmane families (Scheme 11). and phosphonate 30 under Masamune and Roush condi- The synthesis of these bioactive natural products was based tions (LiCl/Et3N) resulted in the formation of the ,-unsat- on an HWE olefination of aldehyde 123 with phosphonate urated ketone 31 in 90% yield.25 A second reaction sequence 124 in the presence of LiCl and DIPEA, which produced started with the dianion of phosphonate 24 being propar- enone 125 in good overall yield (70%). Intramolecular re- gylated and converted into enone 120 via an HWE olefina- ductive pinacol coupling was subsequently employed to tion with 1,3-diacetoxyacetone (55% yield over 2 steps). Af- synthesize the key intermediate cis-cyclobutanediol 126. ter deprotection and Swern oxidation the resulting furan- The total synthesis of echinocidin D (127) was accom- carbaldehyde 121 was again subjected to an HWE reaction plished by desilylation of 126 with tris(dimethylamino)sul- with iminophosphonate 54 in the presence of LDA and sub- fonium difluorotrimethylsilicate (TASF). Intermediate 126 sequent deprotection yielded 55. With both 119 and 55 was also used to synthesize isovelleral (130) (3 additional building blocks in hand, the total synthesis of (–)-nakadom- steps), amillaridin (128), and echinocidin B (129). arin A (122) was accomplished in 17 steps (longest linear sequence) with an overall yield of 3%.

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O O O O P OEt EtO P O EtO SEt OEt H H O 124 60 COSEt O EtO 124, LiCl O 60, NaH O 4 steps EtO DIPEA O 78% (2 steps) 70% H H O OTIPS OTIPS O 131 61

101 123 125 HO 1. PMe3, 69% 2. TBAF, NH4F, 91% Ar = 3. NCS, SMe2, Et3N, 87% OH OTBDPS OH 4. NaBH(OAc)3, 68% HO 5. ArCOOH, EDC·HCl HO HO HO H DMAP, 68% TASF CHO 6. Pd/C, Et3SiH, MgSO4, 88% 87% OHO Me Me Ar H O 127 126 H H COSEt COSEt echinocidin D 13 melleolide OH OH Cl MeO H OTIPS H OH OH O NaBH4, 90% O 133 135 HO O HO HO O OH LiAlH4, 78% LiAlH4, 78% HO H O OH OH H H OHO R OH OH H O 128 129 130 H H amillaridin echinocidin B isovelleral 132 OH OH melleolide F echinocidin D 134 echinocidin B 136 Scheme 11 Synthesis of isovelleral, amillaridin, and echinocidins B and D and by Scheidt and co-workers Scheme 12 Total synthesis of melleolide, melleolide F, and echinoci-

dins B and D by Takasu and co-workers

Takasu and co-workers also described the synthesis of subjected to an HWE reaction with 20 in the presence of protoilludane sesquiterpenes melleolide (13), melleolide F NaH in toluene to obtain unsaturated ester 139 in 63% yield (132), echinocidins B (136) and D (134) (Scheme 12).18 (2 steps). After reduction of ester 139 to a primary alcohol Here, an HWE reaction of ketoaldehyde 131 with phospho- and silyl-protection, the secondary alcohol was trans- nate 60 yielded ,-unsaturated thioester 61 (78% yield over formed into the respective azide 140 under Mitsunobu con- 2 steps). Subsequent intramolecular Morita–Baylis– ditions with inversion of the stereocenter. Mesylation of the Hillman reaction with trimethylphosphine yielded the cy- alcohol and intramolecular carbamate N-alkylation after clized precursor 133. cleavage of silyl group with TBAF resulted in 2,3-cis-disub- The synthesis of protoilludane by Takasu and co-work- stituted piperidine 141. Boc-deprotection and coupling of ers was accomplished by using a redox sequence including a the amine with but-3-enoic acid provided diene 142, which Corey–Kim oxidation to cyclobutanone, reduction with was subjected to ring-closing metathesis using the 2nd gen-

NaBH(OAc)3 to 135, esterification of the alcohol with orsell- eration Hoveyda–Grubbs catalyst yielding an unsaturated inic acid, and Fukuyama reduction of the thioester to obtain quinolizidinone. The total synthesis of (–)-epiquinamide melleolide (13). Reduction of the aldehyde 13 with NaBH4 (144) was completed by hydrogenation of the saturated yielded melleolide F (132). The synthesis of other natural amine 143, followed by N-acetylation and reduction of lact- products of the protoilludane family from intermediate 133 am with BH3·SMe2 complex. was also achieved. This includes echinocidin D (134) by reduction and desilylation with lithium aluminum hydride 2.4 Synthesis of Substituted C=C Bonds and echinocidin B (136) from reduction of intermediate 135 with LiAlH4. The following two examples illustrate the formation of Kongkathip and co-workers described the asymmetric substituted doubles bonds by HWE olefinations. total synthesis of (–)-epiquinamide (144) in 2019,78a which Lindsley and co-workers described the formal total syn- is a quinolizidine alkaloid isolated from the skin of an Ecua- thesis of pericoannosin A (12) in 2019 (Scheme 14),80 which dorian frog78b (Scheme 13). Quinolizidines are an important was isolated in 2015 from Periconia sp. F31 as a new PKS- group of natural products, which show a broad range of bi- NRPS hybrid metabolite with a 3-(hexahydro-1H-iso- ological activity. For the total synthesis, furanoside 137,79 chromen-3-yl)-5-isobutylpyrrolidin-2-one core structure.81 derived from D-glucose, was subjected to a Zn-mediated The new synthetic route included an HWE reaction to in- Bernet–Vasella reaction. The resulting aldehyde 138 was stall the substituted olefin and required fewer steps with

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O Zn, AcOH OH 20 OH O H O 50% NaH I O OEt 2 Steps 63% + O

BocHN O NHBoc (2 steps) NHBoc O EtO 148 n-BuLi, 91% 137 138 139 H O O OH 1. LiBH4, 81% O 2. TBDPSCl 145 146 147 EtO P 94% ee EtO OEt imidazole, 92% 3. DIAD, PPh 1. TFA 20 3 1. DIBAL-H, 80% H H N DPPA, 84% 2. but-3-enoic acid 3 2. TBSOTf Ba(OH)2·8H2O N EDCI, DMAP 1. TBAF, 70% 3 2,6-lutidine, 90% acetaldehyde OTBDPS O O

87% 2. MsCl, DMAP 81% 3. 9-BBN then NaOH (2 steps) BocN 3. NaH, 84% (2 steps) H H NHBoc H2O2, 81% H O P 141 140 4. DMP, NaHCO3, 73% 149 150 N EtO OEt 3 NH2 NHAc O O H H NH 1. Grubbs-II 1. Ac2O, NaOH H H OH 86% 99% literature N N N known 2. BH ·SMe H 2. Pd/C, H2 3 2 OTBS O O 95% 68% 144 O O H P OEt 142 143 (–)-epiquinamide H 148 OEt Scheme 13 Total synthesis of (–)-epiquinamide by Kongkathip and co- 151 12 pericoannosin A workers Scheme 14 Formal synthesis of pericoannosin A by Lindsley and co- workers improved overall yield in comparison to the total synthesis of 12 described by Lücke, Kalesse, and co-workers in 2018.82 In short, an asymmetric Diels–Alder reaction with 145 and saturated ester and its double bond geometry impacts the isoprene (146) yielded an ,-unsaturated aldehyde, which cytotoxicity. Luesch and co-workers achieved the synthesis was subjected to a Wittig reaction to give terminal alkene of anaenoic acid (154) in 9 steps that included an HWE re- 147. The corresponding -ketophosphonate 149 was ob- action to introduce the vinyl halide moiety (Scheme 15).31 tained by treatment of 147 with excess lithiated diethyl Building blocks 153a and 153b were synthesized from com- ethylphosphonate 148 in 91% yield. An HWE reaction of ac- mercially available 152 and phosphonate 45 via HWE olefi- etaldehyde with phosphonate 149 and Ba(OH)2 as base pro- nation, followed by Boc deprotection under acidic condi- duced enone 150 in 81% yield. A Felkin–Anh stereoselective tions. Final coupling of anaenoic acid (154) with a crude reduction of enone 150 with DIBAL-H afforded the second- mixture of 153a and 153b by the use of EDC, HOBt, and ary alcohol. Protection of the alcohol followed by selective DIPEA led to the E- and Z-isomers (14 and 155, respectively) hydroboration of the terminal alkene and basic oxidizing of anaenamide. work-up resulted in an alcohol, which underwent Dess– Goswami and co-workers described the first total syn- Martin oxidation to aldehyde 151. thesis and stereochemical assignment of penicitide A (163) Anaenamides A (14) and B (155) are new anticancer cy- in 2020, which is a marine secondary metabolite (Scheme anobacterial depsipeptides containing a chlorinated phar- 16).36 Penicitide A (163) was isolated from a marine red al- macophore and were isolated from a marine cyanobacteri- gal species by Wang and co-workers in 2011 and showed um derived from the Anae Island reef system in Guam in moderate cytotoxicity against pathogen Alternaria brassi- 2020.31 Their scaffold has an unusual -chlorinated ,-un- cae and human hepatocellular liver carcinoma cell lines.83

O OMe O O O Cl n-BuLi P OMe + OMe + H H3N MeO then TFA H3N Cl OMe O Cl NHBoc 153a 153b 45 152

153a and 153b O O EDC, HOBt, DIPEA O O O + O O OMe O O 53% O O Cl O O H H H O O OMe O OMe OH OMe N OMe N Cl H H O 154 14 155 anaenoic acid anaenamide A anaenamide B

Scheme 15 Total synthesis of anaenamides A and B by Luesch and co-workers

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OTBS OTBS 58, LiCl, DIPEA Dess–Martin oxidation and one carbon Wittig olefination (COCl)2, DMSO, Et3N 77% led to the first building block 161. Alkenes 161 and 162 OH quant. O 156 157 were subjected to cross olefin metathesis, hydrogenation, and deprotection to obtain penicitide A (163) in 15 linear 1. H2/Pd-C, 94% OTBS O O OTBS 2. NaHMDS, MeI, 74% steps with an overall yield of 4.3%. Their synthesis allowed a 3. LiBH4, 81% N OH O divergent synthetic approach with easy access to all possi- 158 59 Bn ble stereoisomers, which led to confirmation of the stereo-

(COCl)2, DMSO chemical assignments in penicitide A (163). Et3N, quant. OTBS 1. 58, LiCl, DIPEA, 73% OTBS 2.5 Late-Stage Modifications by HWE Reactions 2. Pd/C, H2, quant. OH 3. NaHMDS, MeI, 68% O 160 159 4. LiBH4, 82% Indoxamycins A–F were isolated in 2009 from a saline 1. DMP, NaHCO3 quant. culture of marine-derived actinomyces by Sato and co- O O

O 2. Ph3PCH3Br workers as new members of the polyketide structure P t-BuOK, 68% EtO N 84 EtO O OTBS class. The structure elucidation of indoxamycins revealed a highly congested [5.5.6] tricyclic carbon skeleton featuring Bn 58 an ,-unsaturated carboxylic acid side chain and a trisub- 161 stituted alkene. The congested core structure consists of six 1. 161, Grubbs-II 60% stereogenic centers with three quaternary carbons. This in- O O 2. H2, Pd/C triguing structure along with the remarkable biological ac- 3. PTSA O OH O tivity makes the indoxamycin family a captivating target for 58% OH (2 steps) OH total synthetic approaches. 162 163 Liang and co-workers successfully used the HWE reac- penicitide A tion in 2019 to install an ,-unsaturated ester at a late Scheme 16 Total synthesis of penicitide A by Goswami and co-workers stage in the total synthesis of (–)-indoxamycins A (11) and B (169).85 The syntheses commenced with alcohol 156, which was The synthesis of indoxamycins required the generation first subjected to Swern oxidation and the resulting alde- of 165 from (R)-carvone 164 (Scheme 17). This was done in hyde 157 transformed by an HWE olefination with phos- 10 steps including acylation under KH/dimethyl carbonate phonate 58 in the presence of LiCl and DIPEA to obtain pri- conditions, methylation of the generated potassium enolate marily E-isomer 59 in 77% yield. Alcohol 158 was obtained salt, addition of Comins’ reagent, and Pd-catalyzed reduc- after hydrogenation, Evans methylation, and reduction with tive detriflation.

LiBH4. After another Swern oxidation aldehyde 159 was HWE olefination with 166, phosphonate 167, and NaH treated again with phosphonate 58 under Masamune and followed by in situ removal of the tert-butyl group resulted Roush conditions (LiCl, DIPEA) yielding the olefin in 73%. A in the formation of (–)-indoxamycin A (11) in 92% yield. A second sequence of Evans methylation and reduction fol- similar procedure was applied for the synthesis of indoxa- lowing hydrogenation resulted in compound 160. A final mycin B (169). Reduction and oxidation were used to obtain

O O

H EtO P H H EtO Ot-Bu H 167 5 steps O O 167, NaH then TFA, 92% H H O H COOH H H O 166 11 10 steps (–)-indoxamycin A O O H H H 164 H 1. Ac2O, py, DMAP, 84% H 6 steps 2. 17, t-BuOK, 59% 165 3. Me3SnOH, 80% O OH O OH H O H O O COOH EtO P 168 EtO OMe 169 17 (–)-indoxamycin B

Scheme 17 Total synthesis of (–)-indoxamycins A and B by Liang and co-workers

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olefination of 171 with phosphonate 17 and NaH as a base provided the E- and Z-isomers of tiancimycin B (10) in 84% 1. Ac2O, DIPEA DMAP, quant. and 10% yield, respectively. 2. 3HF·Et N, 85% O HN OTES 3 O HN O Late-stage HWE olefinations were also used in the mod- O O OH 3. DMP, 89% OH ification of epothilone B analogues designed by Nicolaou 4. K2CO3, MeOH 96% and co-workers to improve their potencies and pharmacological properties as anticancer drugs (Scheme 19).35 Intro- O OH O OH duction of different heterocycle side chains to the macro- 170 171 cyclic core was achieved via HWE reactions in the presence

COOMe 17, NaH, 94%

Z O HN E/ = 8:1 of NaHMDS, n-BuLi, or NaHMDS/t-BuOK, followed by desil- O OH ylation. O EtO P COOMe 2.6 HWE Reactions on Solid Supports EtO O OH 17 10 tiancimycin B Solid phase synthesis (SPS) is mainly applied in the synthesis of longer and difficult to purify peptides and nucleo- Scheme 18 Total synthesis of tiancimycin B by Nicolaou and co-workers tides. However, this method has increasingly been used for SP-supported HWE reactions in the synthesis of other small molecules.87 Most notably, the synthesis of ,-unsaturated aldehyde 168. Next acetylation of the primary alcohol was amides,88 esters and nitriles,89 macrocycles,90 olefins,91 tri- followed by HWE reaction with phosphonate 17 to give the azolopyridazines, and peptides containing E-alkene amide product with low conversion due to steric hindrance linkages have been reported.92 Furthermore, several reports around the aldehyde. Several bases were screened (NaH, on the synthesis of Z-,-unsaturated esters,93 solvent-free n-BuLi, and t-BuOK) and t-BuOK was relatively effective in reactions,94 and crosslinking polysulfones under phase the HWE reaction giving the corresponding unsaturated transfer catalysis (PTC)95 have been published. ester in 59% yield. Simultaneous hydrolysis of the methyl Beemelmanns and co-workers reported the application ester and acetyl group removal with Me3SnOH led to of SP-based HWE reagents to prepare the vinylogous amino (–)-indoxamycin B (169). acid containing natural product barnesin A (177) (Scheme Another example for late-stage introduction of ,-un- 20),96 which was previously isolated from anaerobic bacte- saturated esters using HWE reactions was reported in 2020 by Nicolaou and co-workers in the total synthesis of tianci- 16

mycin B (10) (Scheme 18). TES-protected uncialamycin O O DIPEA, DCM O O 2-chlorotrityl then MeOH P 170 was synthesized in 2016 from hydroxyisatin in 22 chloride P OEt O OEt HO OEt 86 resin OEt steps. It was transformed to uncialamycin analogue 171 in 172 173 four steps with a newly introduced ketone moiety. HWE O O NHFmoc 173 H LiBr, DIPEA NHFmoc DCM O 175 174 O 1 R R1 EtO P R2 R1 = EtO R2 X 1. NaHMDS or HN X O O H n-BuLi or NHBoc H BocN NHBoc N NaHMDS, t-BuOK H 3 RO HO N R O 2. HF·py or HO R2 2 H R = Ph, 4-HOC6H4 O TFA O OH R3 = C H 176 O n m R1 O OR O O OH O R = TES, TBS, X = NR, CR2, O

Me O O S S S O H SMe N CF3 SMe N HO N N N Boc N N H O O S 177 HN barnesin A N N N HN NH2

Scheme 19 Synthesis of epothilone B analogues by Nicolaou and co- Scheme 20 Solid-phase based synthesis of cysteine proteases inhibitor workers barnesin A and derivatives by Beemelmanns and co-workers

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Synthesis D. Roman et al. Review rium Sulfurospirrilum barnesii as the first secondary me- O O tabolite from Epsilonproteobacteria and the first NRPS-PKS EtO P 97 1. TBAF, THF OEt hybrid molecule from this bacterial family. EtO quant. The synthesis began with loading a 2-chlorotrityl chlo- 47 2. (COCl)2, DMSO ride resin (CTC resin) with diethylphosphonoacetic acid Et3N 47, NaH, THF (172),88 which served as a linker, and phosphonate for the 71% (over 2 steps) 178 OTBS 179 O HWE reaction. Resin-bound phosphonate 173 was depro- tonated with DIPEA and subjected to an HWE reaction with 1. DIBAL-H, DCM, 90% 2. (COCl)2, DMSO, Et3N Fmoc-protected aldehyde 174 (LiBr and DIPEA) yielding sol- O 3. I2, Et2O O id-bound olefin 175, which allowed for further peptide cou- 180 97% (over 2 steps) 48 O pling steps. Subsequent global deprotection produced 14 E/Z = 1:2.3 39, NaH, THF O O lipodipeptides with micromolar to nanomolar inhibitory 80% P EtO OEt activity against different cysteine proteases. EtO 39 1. DIBAL-H, DCM, 78% 2.7 Synthesis of Poly-Conjugated C=C Bonds O 2. MnO2, DCM

40 O R1 Conjugated -bond systems allow delocalization of - electrons through alternating single and double bonds. This 1. 182, n-BuLi, THF O 72% (over 2 steps) concept was introduced by Claisen in 1926 and later named 2. MnO2, DCM, quant. 181 98 vinylogy. HWE reactions play a central role in the con- 3. p-TsOH, THF/H2O, 56% struction of vinylogous systems and polyconjugated double HO MOMO OH O OMOM bonds, especially in natural product synthesis as shown in 1 Br the following eight examples.99,100 R The polyunsaturated side chain of the alkaloids militari- N O 182 N OMOM H 8 none D (8) (Scheme 21), isolated in 2003 from Paecilomyces militarinone D

101 militaris, was accomplished by Sim and co-workers in Scheme 21 Total synthesis of militarinone D by Sim and co-workers 2015 using a sequence of HWE reactions.32 The first HWE reaction (NaH in THF) of aldehyde 179 with phosphonate 47 yielded unsaturated ester 48 in 71% yield (2 steps, E/Z O O P OEt 1:2.3). A subsequent reduction/oxidation sequence pro- R1 EtO OEt duced the aldehyde as an E/Z mixture where the Z-isomer O 39 39, NaH, THF was converted into the E-isomer 180 by treatment with cat- EtO2C 67% alytic iodine. The second HWE olefination (NaH in THF) of (95% de) 40 183 unsaturated aldehyde 180 and phosphonate 39 yielded O OH O 1. DIBAL-H, DCM 85%

triene 40 in 80% yield, which was again transformed into al- P OEt t-BuS 2. MnO2, DCM dehyde 181 in a reduction/oxidation sequence. Aldehyde OEt 92% 184 181 was added to lithiated pyridine 182 in the final se- O OH O

184, BuLi, THF

1 1 quence and the resulting allylic alcohol was oxidized to a t-BuS R R 95% ketone. This was followed by a global MOM removal to 185 181 complete the synthesis of militarinone D (8) in 5% overall 186, AgOCOCF TBSO 3 NHDMB yield. Et3N, THF 89% CO Me A structurally related NRPS-PKS based fungal-derived O OH 2 186 natural product, fumosorinone A (9),102 was isolated in TBSO DMB N R1 2017, and shown to contain a pentaene moiety attached to 1. NaOMe, MeOH, quant. 2. TFA, DCM, 30% CO2Me a pyrrolidine-2,4-dione. Due to its potent protein tyrosine 3. KF, MeOH, 60% phosphatase 1B inhibitor activity and intriguing structure, 187 O OH it was synthesized in 2018 by Schobert and co-workers (Scheme 22).28 The required aldehyde 183 was prepared HN from commercially available (S)-citronellol in 10 steps to O HO synthesize the polyunsaturated PKS side-chain, which was 9 fumosorinone A then subjected to the chain elongating HWE reaction with phosphonate 39 and NaH as base to produce elongated ole- Scheme 22 Total synthesis of fumosorinone A by Schobert and co- fin 40 in 67% yield. Ester 40 was subjected to a reduc- workers tion/oxidation sequence yielding aldehyde 181, which was

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Synthesis D. Roman et al. Review subjected to a second HWE olefination following Loscher’s 195 to give product 196. The alcohol 196 was then methyl- protocol103 giving thioester 185 in a 95% yield as a 2:3 ke- ated and the ester was hydrolyzed to carboxylic acid 197, to/enol mixture. Silver-mediated acylation with amino acid which was used for completion of the total synthesis of 186 resulted in ketoamide 187. Subsequent cyclizations fol- nannocystin Ax (188). lowed by a partial TBS deprotection with TFA and global Similarly, the HWE reaction was used by Mori and co- desilylation with KF completed the first total synthesis of workers in their total synthesis of brevisamide (203) fumosatinone A (9). (Scheme 24),30 a natural marine product isolated from di- Another application of an HWE reaction in the synthesis noflagellate containing a tetrahydropyran (THP) ring incor- of conjugated C=C bonds was described by Gerstmann and porated into a conjugated carbon chain. Kalesse in their total syntheses of nannocystin Ax (188) and The synthesis of the unsaturated side chain started from aetheramide A (189) (Scheme 23).104 Chiral aldehyde 191 [4 commercial 4-(benzyloxy)butanol, which was converted steps from benzaldehyde (190)] was subjected to an HWE into diol 198 in 10 steps. A short reaction sequence afforded reaction using phosphonate 36 and n-BuLi to yield acrylic mono-TBS deprotected alcohol 201. The primary alcohol ester 192 in 96% yield in favor of the desired E-isomer 201 was oxidized with Dess–Martin periodinane to yield (5.6:1). Ester 192 was reduced and subsequently oxidized to Lindsley’s aldehyde 202 as a precursor for the HWE reac- aldehyde 193, which was used in a vinylogous Mukaiyama tion.100a,105 The olefination of 202 was accomplished using aldol reaction with acetal 194 in the presence of catalyst the vinylogous phosphonate 43 and n-BuLi at room temperature to provide dienoate 44 in 62% yield. Ethyl ester 44 HO was subsequently reduced to the corresponding alcohol us-

OMe ing DIBAL-H. This was followed by desilylation of the sec- MeO O O ondary alcohol and final oxidation of the primary alcohol O O O N with MnO2 gave brevisamide (203). O NH NH Hong and co-workers reported an extraordinary syn- HO H N N thetic strategy towards the total synthesis of lasonolide A O O O (6) in 2018 (Scheme 25).33 This is a natural product con- Cl O OMe tains two functionalized tetrahydropyran moieties and ex- OH HO hibits high and selective cytotoxicity against cancer cells. 188 189 Cl nannocystin Ax aetheramide A

EtO Tf2O, 2,6-lutidine 4 steps OMe

P –80 °C, 0.7 h

EtO OH then OTBS O O TBSOTf O TBSO O 36 0 °C, 0.8 h BnO OH BnO OTf 190 191 O 88% O 36, n-BuLi, THF H H H H –78 °C to r.t. 198 199 96% 1. DIBAL-H, DCM E/Z = 5.6:1 H –78 °C, 92% 1. N Cbz 2. MnO2, DCM, r.t. OMe OTBS 200 DMP O DCM, r.t., 4 h H KHMDS, 18-crown-6 TBSO 192 O HO N THF, r.t., 0.5 h, 90% O 76% OTES H H 2. Pd(OH) , H 194, 195, EtCN O 2 2 O –78 °C, acidic workup 201 EtOAc, r.t., 1 h, 96% OEt 77% (2 steps)

TBSO 193 OTBS dr 3.1:1 194 43, n-BuLi, THF H r.t., 17 h 1. MeO +BF – O N 3 4 OEt proton sponge O O OH H H 62% P OEt DCM, r.t., 93% O 202 O O 2. LiOH, THF TBSO 43 MeOH, H2O 196 O 0 °C to r.t., quant. OTBS 1. DIBAL-H, DCM OEt DCM, –78 °C, 15 min, 79% H 2. TBAF, THF, r.t., 2 h, 96% N OMe EtO2C O H H O 3. MnO2, DCM, 88% O TBSO 44 HN OH 197 O N O H Ts B O N 195 O OH Ph H H H 203 O brevisamide Scheme 23 Structure of nannocystin Ax and aetheramide A and the total synthesis of a building block by Gerstmann and Kalesse Scheme 24 Synthesis of brevisamide by Mori and co-workers

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1. CSA, Me2C(OMe)2 Sia2BH, THF OH 9-BBN, THF DCM, r.t. EtO2C TBDPSO OH OH OH O TBDPSO OAc –78 °C to –30 °C TBDPSO OH –30 °C to 0 °C then TBAF, r.t. OH 80% O • then TBAOH/H2O2 then (+)-IpcBH2, –20 °C 2. TEMPO, BAIB, THF, r.t. 86% 207 then NaOH, H2O2, r.t. Z/E > 20:1 then Ph3P=CHCO2Et, r.t. 73% 206 1. 208, EtOH, reflux 204 205 81% dr 6.4/1 E/Z > 20:1 82% dr 11:1 2. 4-PhCO -TEMPO 1. 39, LiHMDS, THF HO 2 MeO2C BAIB, DCM, r.t. –78 °C to 0 °C 1. 2,6-lutidine,TBSOTf then NaOH, 60 °C, 67% E/Z = 14:1 O O DCM, r.t., 87% O 49, KHMDS 2. DMP, DCM, 0 °C, 94% 2. DIBAL-H, DCM, –78 °C THF, –78 °C EtO2C O OTBS OH 74% O Z/E = 10:1 O 50 EtO2C 210 (over 2 steps) OH EtO2C P OEt 209 OEt OTBS 39 O O F3C O P CO2Me O O O 1. 9-BBN, DME O –20 to 50 °C F3C 2. 212, LiHMDS, –75 °C 49 O then HCl, r.t. PhH, 90 °C 213 TBSO OTMS O then HF, r.t. HO2C 65% OTBS E/Z = 12:1 58% 211 (over 2 steps) HO2C OH OH OTBS O O O O O O Cl SO3H O O S BT 208 OH O O 212 TBSO OTMS 6 lasonolide A O OH

Scheme 25 Total synthetic strategy lasonolide A by Hong and co-workers

A hydroboration-oxidation sequence starting from al- stable mimetics to investigate the importance of the double lene 204 provided polyhydroxy alkane 206 in good overall bond for the activity and the mode of action in Buruli ulcer yields. The alcohol in 206 was first subjected to an oxida- pathogenesis (Scheme 26). tion-Wittig elongation sequence to produce ester 207. Acid- Their synthesis started from methyl 2-iodobenzoate ic tetrahydropyran formation was followed by the oxidation (214), which was converted into vinyl iodide 215 via Sono- to aldehyde 209 that allowed the first HWE reaction with gashira coupling with TMS-acetylene, desilylation, reduc- Still–Gennari phosphonate 49 yielding trisubstituted cis- tion of the ester, and zirconium-catalyzed carboalumina- conjugated methyl ester 50 in good yields (Z/E 10:1). Silyl- tion/iodination of the terminal alkyne moiety. After oxida- ation of the secondary alcohol in 50 proceeded smoothly tion of the primary alcohol 215 with MnO2 the resulting and DIBAL-H mediated reduction of the ester delivered al- aldehyde was subjected to an HWE reaction with triethyl dehyde 210, which was again subjected to HWE olefination phosphonoacetate (20) to yield ,-unsaturated ester 216 with a vinylogous phosphate 39 and LiHMDS as a base. (99% over 2 steps). Stille coupling of vinyl iodine 216 with Subsequent Dess–Martin oxidation of the allylic alcohol stannane 217 followed by saponification gave acid 218. Fi- provided Z-enone 211 in 94% yield. An unusual 9-BBN com- nal esterification with macrolactone 219 and desilylation plexation of free carboxylic acid allowed successful Julia yielded 220. Analogous syntheses for cyclopentene-derived olefination with sulfone 212 to give 213. Lactonization was acids 224 and 225 starting from 2-oxocyclopentane-1-car- employed to complete the total synthesis of (–)-lasonolide boxylate (221) and 1,4-bis(hydroxymethyl)cyclohexane A (6). were also reported. The synthesis of polyconjugated mycolactone mimetics The marine secondary metabolite nafuredin B (237) was by Altmann and co-workers in 2019 represents an addition isolated in 2017 from deep-sea-derived Talaromyces aculea- example for the efficient application of HWE reactions tus and Penicillium variabile together with penitalarins A–C (Scheme 26).106 Mycolactones A (227) and B (228) feature a and known nafuredin A.111 Nafuredins contain a linear skel- common 12-membered macrolactone core, which can in- eton with an unsaturated chain linked to ,-unsaturated teract with several cellular targets, such as mTor,107 Sec61 lactone and showed cytotoxicity against several cell lines in translocon,108 Wiskott–Aldrich syndrome protein,109 and the micro-molar range thus making them attractive syn- the angiotensin II receptor.110 Their synthesis targeted my- thetic targets. colactone analogues 220, 225, and 226 as configurationally

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A give the secondary alcohol 232. Subsequent oxidation to O 1. TMSCCH, Pd(PPh3)Cl2 ketone 233 and an HWE reaction (NaH) with triethyl phos- CuI, Et3N 1. MnO2 OMe 2. K2CO3, 89% (2 steps) OH 2. 20, NaH phonoacetate (20) produced the elongated unsaturated side 3. DIBAL-H, 71% 99% chain in 234 (82% yield, E/Z 6:1). The final elongation via Ju- I (2 steps) 4. ZrCp2Cl2, AlMe3, I2, 84% lia–Kocienski olefination was pursued after another reduc- 214 215 O O I tion/oxidation sequence and transformation with sulfone EtO P 113,114 HO O EtO OEt 1. 217, Pd(PPh ) 235 to obtain 236. The last three steps involved treat- 3 4 COOEt 20 CuI, CsF, 89% ment with p-toluenesulfonic acid to afford a diol, subse- 2. LiOH, 98% OTBS quent acrylation, and then ring-closing metathesis provided the desired nafuredin B (237). I 216 218 OTBS OTBS O 1. DIBAL-H, DCM, 97% OTBS 2. DMP, NaHCO3, DCM CO2Et 1. 219, 2,4,6-Cl3C6H2COCl 3. 230, KHMDS, THF, 70% DIPEA, DMAP, 97% Bu Sn 4. TBAF, THF, 98%

220 3 O 229 2. TBAF, then NH4F OTBS OTBS 37% 217 O O O N S OTBDPS OH B N 231 O COOEt N 230 O OH 1. MnO N OMe 2 Ph 4 steps 2. 20, NaH 1. DMP, NaHCO3, DCM 2. CH MgCl, THF 93% 3 O 84% (over 2 steps) (2 steps) 223 I DMP, NaHCO I 3 OH O O O 221 222 1. 217, Pd(PPh3)4 DCM HO O CuI, CsF, 74% 2. LiOH, 96% 88% O 233 O 232 OTBS O O O O 1. 20, NaH, THF, 82% Si 2. DIBAL-H, DCM, 94% P OEt

EtO OEt t O O t OTBS OTBS -Bu -Bu 224 20 1. 219, 2,4,6-Cl3C6H2COCl

DIPEA, DMAP, 97% O 2. TBAF then NH4F 1. DMP, NaHCO3, DCM, quant. OH 50% OH 2. 235, KHMDS, THF, 62% 219 234 225 O O cis-mimetics inactive 1. p-TsOH, MeOH, 78% 2. acryloyl chloride, DIPEA, 52% O 236 OH OH 3. Grubbs-II, DCM, 70% 226 O O O O trans-mimetic 220 225 S active OH N N OH N N 235 O O 237 Ph

nafuredin B

O Z: mycolactone A 227 OH OH O E: mycolactone B 228 Scheme 27 Total synthesis of nafuredin B by Goswami and co-workers Scheme 26 Synthesis of mycolactone analogues by Altmann and co- workers Separacenes A (242) and B (243) were isolated in 2013 The first total synthesis of nafuredin B (237) was ac- from a marine actinomycete115 and contain an unusual tet- complished by Goswami and co-workers (Scheme 27)112 raene moiety with a diols on both ends. Goswami and Das and was based on an elongation sequence of one HWE reac- reported the first convergent stereoselective total synthesis tion and two Julia–Kocienski olefinations. Commercially (Scheme 28) shortly afterwards in 2017.29 The synthesis available prenol was converted into unsaturated ester 229 started from D-tartaric acid which was transformed to un- using a known procedure. Ester 229 was then reduced with saturated ester 238 (see Table 1, Entry 14). A deprotec- DIBAL-H and oxidized with Dess–Martin periodinane and tion/protection and reduction/oxidation sequence yields the intermediate aldehyde was directly subjected to Julia– TBSOTf-protected aldehyde 239. They screened several con- Kocienski olefination with sulfone 230 to obtain the olefin ditions for the HWE reaction of aldehyde 239 and keto- (E/Z 4:1). The isomers were separated and the E-isomer was phosphonate 240, such as LiCl, DIPEA, THF (0%, 24 h); LiCl, treated with TBAF to produce primary alcohol 231, which DBU, THF (0%, 24 h); Cs2CO3, MeCN (60%, 5.5:1 dr, 12 h), and was again oxidized and treated with Grignard reagent to were finally able to react 239 with 240 in the presence of

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116 1. CSA, EtOH, 87% logical activities. The key substrate 244 was obtained O 2. TBSOTf, 2,6-lutidine, DCM, 95% D 3. DIBAL-H, DCM, 95% from -serine in 16 steps and reacted with dimethyl 4. IBX, EtOAc, 90% lithiomethylphosphonate to give phosphonate 246 in 82% EtO2C 238 O yield. Further modifications yielded dioxasilinane-protect- OTBS ed phosphonate 34,117 which was then reacted with alde-

240, Ba(OH)2·H2O, THF O 67% (5.5:1 dr) hyde 248 in a temperature-sensitive Ba(OH)2-mediated 239 OTBS OTBS OTBS HWE reaction to afford the partially deprotected and elon-

gated 35 in 75%. Ketone 35 was subsequently reduced to the 1. (R)-CBS, BH3·SMe2 THF, 60% corresponding alcohol and acetylated to give 249. The sec- O OTBS

241 2. TBAF, THF, 80% ond fragment, 250, was synthesized in 13 steps and cou- 1. (S)-CBS, BH ·SMe OH OH 3 2 pled with 249. This was then treated with K2CO3 and MeOH THF, 60% 2. TBAF, THF, 80% to produce globally deprotected (+)-neooxazolomycin (7). 242 OH separacene A OH OH OH OTBS 2.8 HWE-Mediated Coupling of Larger Building OMe Blocks P OMe OH 243 OH separacene B O O 240 The intramolecular HWE reaction, where one building block contains a phosphonate moiety and the other has an Scheme 28 Total synthesis of separacenes A and B by Goswami and aldehyde or ketone, has found immediate application in Das synthetic chemistry and natural product synthesis. Here, we give four recent examples.

Ba(OH)2 to yield elongated ketone 241 (80%, 5.5:1 dr, 12 h). Siladenoserinol A (15) was isolated in 2013 from a tuni- They obtained 242 and 243 by stereoselective reduction of cate collected in Indonesia,118 and found to contain a 6,8-di- ketone 241 with the Corey–Bakshi–Shibata reagent R-CBS oxabicyclo[3.2.1]octane skeleton with two long chains that and S-CBS, respectively, and global deprotection with TBAF. each contain a sulfamated serinol or glycerophosphocho- The asymmetric total synthesis of (–)-neooxazolomycin line moiety. Doi and co-workers reported the first total syn- (7) (Scheme 29) reported by Kim and co-workers is the fi- thesis of siladenoserinol A (15) in 2018 (Scheme 30).119 nal example.25 The structurally complex natural product Their synthetic strategy started with commercially avail- consists of a unique lactam-lactone structure and an unsat- able D-malic acid, which was converted into aldehyde 251 urated polyketide-based sidechain that exhibits potent bio- in 21 steps. The glycerophosphocholine moiety was intro-

(MeO)2P–Me O TMS TMS CO t-Bu 1.TBAF, THF, 80% O CO2t-Bu 245 O 2 O O O O 2. FeCl3, Et3SiH, DCM O OH N 51% MeO N 245, n-BuLi, THF MeO P N MeO P N HO MeO HO O HO 82% MeO O O 244 O O 247 O 246 R1

Si(i-Pr)2(OTf)2, 2,6-lutidine O 99% FmocHN O O O 248 i-Pr i-Pr O O O O Si i-Pr 1. L-Selectride, THF O Si i-Pr O 1 1 Ba(OH)2, 248 R OH 2. Ac O, pyridine R OH N 2 N THF/H2O MeO P N HO HO O OAc 75% (over 2 steps) O 75% MeO O O i-Pr Si O 249 O 35 O 34 i-Pr O O 1. BOPCl, Et3N, DCM N N DBU, DCM 51%

2. K2CO3, MeOH O then Amberlyst IRC-86 O O OH O 90% HO N N BzO OH H HO OH O 250 7 (+)-neooxazolomycin

Scheme 29 Total synthesis of (+)-neooxazolomycin accomplished by Kim and co-workers

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duced by an HWE reaction using the previously prepared O phosphonate 252 yielding the unsaturated ester 253 in 64% OTBS OEt yield. The Boc group was removed with HCl and sulfamate O P OEt formation finished the synthesis of siladenoserinol A (15). O O O LiCl, DBU TBSO O 86% OEt OMe 254 255 OEt AcO O O P O O + O P NMe3 O O

O O O O 11 1. [Mo(N(t-Bu)Ar)3], 67% O 2. TBAF, THF, 90% O O OAc 251 252 BocN DBU, LiBr, THF TBSO 64% O O O O O AcO O P NMe3 O O O TBSO 256 O O O 11 OAc HO OMe O O 1. HCl, 83% O O O 253 BocN 2. SO3·py, Et3N, 58% O O O HO AcO O P NMe3 OMe O O HO O O O 257 11 OAc O N O OH O O NHSO H 15 3 siladenoserinol A OMe 16 Scheme 30 Total synthesis of siladenoserinol A 15 by Doi and co- rhizoxin D workers Scheme 31 Total synthesis of rhizoxin D by Fürstner and co-workers

Tong, Qian, and co-workers described a second asymmetric synthesis of 15 in 2019 (see Table 1, formation of sired macrolactone 257. Next steps such as trans-hydro- 19).17 They also applied an HWE reaction for the construc- stannation, C-methylation, and other known procedures led tion of the ,-unsaturated ester moiety and included the to rhizoxin D (16). synthesis of siladenoserinol H, which is a structural ana- Formosalides A (261) and B (262) were isolated in 2009 logue, to test for antibacterial activity of this compound by Lu and co-workers from the dinoflagellate Prorocentrum class.120 sp. from southern Taiwan.124 These macrolides consist of Rhizoxin is a natural product produced by species of the substituted tetrahydropyran (THP), a tetrahydrofuran ring, bacterial genus Burkholderia.121 It was isolated in 1984 and and a C-14 linear unsaturated chain containing four cis- showed high in vitro cytotoxicity and in vivo antitumor ac- double bonds.125 Both compounds exhibited good cytotoxic tivity.122 Fürstner and co-workers presented their own syn- activity against human T-cell, acute leukemia cells, and hu- thetic effort in 2019 that extended earlier studies and re- man colon adenocarcinoma cells and were thus selected for sulted in a different modern strategy (Scheme 31).123 The total synthesis. synthesis was based on intermolecular HWE olefination for Mohapatra and co-workers reported a simple and effi- coupling 254 and 255 followed by macrocyclization to form cient synthesis of the C1–C16 fragment of the proposed a 16-membered ring through ring-closing alkyne meta- structure of formosalide B (262) (Scheme 32).21 The synthe- thesis. sis started from commercially available materials and was Their synthesis started from commercially available (R)- completed in 9 steps. Aldehyde 258 was prepared from pen- oct-1-en-3-ol in its optically pure form, which was convert- tane-1,5-diol in 5 steps. Both building blocks were then ed into substrate 254 in 14 steps. The second segment 255 coupled using an HWE reaction in the presence of LiCl and was prepared from crotyl alcohol in 11 steps. A straightfor- DIPEA in acetonitrile to furnish the E-isomer enone 27 in ward HWE reaction between phosphonate 254 and alde- 91% yield. Olefin 27 underwent dihydroxylation using a hyde 255 in the presence of LiCl and DBU was performed to Sharpless ligand to give diol 259 (dr 9:1). Finally, 259 was couple both segments and afforded cyclization precursor subjected to acid-mediated ketalization to form the THP 256 in 86% yield. Ring-closing alkyne metathesis was fol- ring 260 and complete the fully functional C1–C16 frag- lowed by TBAF deprotection of silyl groups and yielded de- ment of formosalide B (262).

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PMBO 268 in the presence of NaHMDS to obtain 269 in a quantita- tive yield (Z/E 3.6:1). Hydrostannylation and Stille coupling OMe O TBDPSO O P LiCl, DIPEA OMe + 91% produced pure (–)-exiguolide 271 (Z-isomer). O O 26 258 OTBS

(DHQD)2PHAL, K3Fe(CN)6 PMBO K2CO3, MeSO2NH2 O OMOM 80% TBDPSO O MOMO 263 O 27 O OTBS P MeO C OH MeO2C MeO OMe 2 PPTS, MeOH O O TBDPSO H 82% NaH, THF H O OBn O OBn O OH OTBS OPMB 68% 259 TBDPSO O TBDPSO 264 265 TBDPSO O H 1. Cu(OAc)2·H2O, BSPB H MeO PMHS, 93% OH O PMBO O 2. TMSI, DCM, 67% O H 3. BF3·OEt2, Et3SiH O OH OH 78% (dr > 20:1) OR HO O OH 260 HO O 1. LiOH, MeOH, H2O HO O 2. 2,4,6-Cl3C6H2COCl MeO2C 261 formosalide A, R = H 85% (over 2 steps) 262 formosalide B, R = Me O O 3. Bu4NF, THF, 87% O O Scheme 32 Total synthesis of the C1–C16 fragment of formosalides by 4. DMP, DCM, quant. Mohapatra and co-workers O TBDPSO 267 266 NaHMDS, 268 quant. Exiguolide (271) was isolated in 2006 from a marine Z/E = 3.6:1 sponge Geodia exigua Thiele by Ohta, Ikegami, and co-work- 126 ers. It contains a unique 20-membered macrolide core MeO2C and two tetrahydropyran rings and was shown to have in- O O 1. Bu3SnH, Pd2(dba)3 O O hibitory activity against human lung cell carcinoma, human Cy3P·HBF4, 54% 2. CuTC, NMP, 270, 75% lung adenocarcinoma cells, pancreatic cancer, and breast O O cancer cells.127 Exiguolide (271) has been a captivating tar- O O MeO C MeO2C get for synthesis due to its interesting structure and re- 2 271 269 markable biological properties. The first total synthesis of it (–)-exiguolide was accomplished in 2010 by Sasaki and Fuwa.128 Several synthetic strategies have since been developed and de- O O 129 scribed. In 2020, Ishihara and co-workers reported an P CO2Me I 130 asymmetric total synthesis of 271 (Scheme 33). The first O MeOOC 270 building block, 263, was prepared in 8 steps and the THP- 268 based fragment, 264, was prepared from propane-1,3-diol Scheme 33 Total synthesis of (–)-exiguolide by Ishihara and co-work- in 7 steps. Phosphonate 263 and aldehyde 264 were then ers subjected to an HWE reaction using NaH to give enone 265 in a 68% yield. This was then reacted with Stryke’s reagent to provide a saturated compound.131 Cleavage of MOM and 2.9 Miscellaneous Bn groups by treatment with trimethylsilyl iodide was accomplished, which was followed by silane reduction that Xu and co-workers described the first enantioselective yielded bis(tetrahydropyran) 266 as single isomer.132 Sa- total synthesis of dapholdhamine B (276) in 2019, an alka- ponification, macrolactonization, removal of the TBDPS loid with a rare aza-adamantane core skeleton (Scheme group, and subsequent oxidation of the secondary alcohol 34A).133 The critical homologation of the key building block to the corresponding aldehyde yielded compound 267. An 272 was achieved via an HWE reaction with 273 in the asymmetric HWE reaction based on Fuji’s method was em- presence of NaH to give intermediate 274, which then un- ployed to convert aldehyde 267 with chiral phosphonate derwent a one-pot acidic hydrolysis to obtain thioester 275. This was followed by basic hydrolysis to obtain dapholdhamine B (276) (21 steps).

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A O O O A O MeO P OH S S R + OMe OMe MeO R X HN HN H PG X PG O 273, NaH H X = B(OR)3, Br, I 280 281 OH PG = Cbz, Boc Z-enamine N H L = bpy O N H O H H OMe R H H R 272 N – CuL N OMe HS 274 Cu PG PG L O O O S 282 283 21 examples 47–98% 2 M HCl H aq. NaOH H B H H OH N O N O OH PO(OMe)2, Et3N N N H H H PhMe O N N P H H H H H 284 285 MeO OMe 276 275 dapholdhamine B H H N O 1. NaH, THF N O O CO Me +

B 2 2. R-CHO R n-BuLi, 273 R

N N

p-TsOH H then NaOMe 286 287 Scheme 35 Synthesis of substituted indoles (A) and bicyclic imines and N N CO2Me amines (B)

277 278 SS Another application is the synthesis of bicyclic imines H2, Pt/C N 286 and amines 287 of the hexahydroquinoxaline-2(1H)- EtO P O H one class by Wojaczyńska, Olszewski, and co-workers EtO

273 (Scheme 35B). These compounds show broad pharmacolog- 279 136 caldaphnidine O ical properties. Subsequent HWE reactions of chiral phosphonate 285 with different aldehydes in the presence Scheme 34 Total synthesis of dapholdhamine B and caldaphnidine O by Xu and co-workers of NaH resulted in a tautomeric mixture of imine 286 and enamine 287, in favor of the imine form. Additional reduc-

tion of the imine or enamine with NaBH4 led to bicyclic Xu and co-workers also reported the total synthesis of amines. alkaloid (–)-caldaphnidine O (279) in 22 steps from cyclohexane-1,3-dione (Scheme 34B).134 After the synthesis of aldehyde 277, they employed an HWE reaction with thio- 3 Summary and Outlook ketal phosphonate 273 and n-BuLi followed by acidic and basic workup to produce methyl ester 278. After diastereo- In recent decades, the HWE reaction has been an active selective hydrogenation of the alkene motif they obtained area for applications to natural product synthesis. To solve (–)-caldaphnidine O (279). increasingly challenging synthetic problems the required In a second example, Lim and Choi employed an HWE phosphonate reagents have been diversified from simple reaction for synthesis of indoles and azaindoles (Scheme phosphonates to highly activated, branched, and modified 35A).135 In detail, reaction of commercially available N-Cbz- phosphonate reagents. Here, we have summarized repre- protected phosphonoglycine trimethyl ester 280 and sub- sentative examples of functionalized reagents used in natu- stituted 2-bromobenzaldehydes afforded enamines 281, ral product synthesis reported in 2015–2020. Our compre- which were converted into indole 283 via Cu-catalyzed cy- hensive review will support future synthetic approaches clization. This method was also envisaged for the synthesis and serve as guideline to find the best HWE conditions for of thiophene- and benzothiophene-linked pyrroles, which the most complicated natural products. makes it a versatile tool in drug discovery. Conflict of Interest

The authors declare no conflict of interest.

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