50 Years of Zweifel Olefination: A Transition-Metal-Free Coupling

Dedicated to Professor Herbert Mayr on the occasion of his 70^th birthday

Abstract

The Zweifel olefination is a powerful method for the stereoselective synthesis of alkenes. The reaction proceeds in the absence of a transition-metal catalyst, instead taking place by iodination of vinyl boronate complexes. Pioneering studies into this reaction were reported in 1967 and this short review summarizes developments in the field over the past 50 years. An account of how the Zweifel olefination was modified to enable the coupling of robust and air-stable boronic esters is presented followed by a summary of current state of the art developments in the field, including stereodivergent olefination and alkynylation. Finally, selected applications of the Zweifel olefination in target-oriented synthesis are reviewed.

1 Introduction

2.1 Zweifel Olefination of Vinyl Boranes

2.2 Zweifel Olefination of Vinyl Borinic Esters

2.3 Extension to Boronic Esters

3.1 Introduction of an Unsubstituted Vinyl Group

3.2 Coupling of α-Substituted Vinyl Partners

3.3 Syn Elimination

4 Zweifel Olefination in Natural Product Synthesis

5 Conclusions and Outlook

Key words

Zweifel olefination - coupling - boronic esters - alkenes - transition­-metal-free - enantiospecific

1

Introduction

The stereocontrolled synthesis of alkenes is a topic that has attracted a great deal of attention owing to the prevalence of this motif in natural products, pharmaceutical agents and materials.[1] Of the many olefination methods that exist, the Suzuki–Miyaura coupling represents a highly convergent method to assemble alkenes (Scheme [1, a]).[2] However, although the coupling of vinyl halides with primary and sp² boronates takes place effectively, the coupling of secondary and tertiary (chiral) boronates remains problematic.[3] Furthermore, the high cost and toxicity of the palladium complexes required to catalyze these processes also detract from the appeal of this methodology.[4]

Varinder K. Aggarwal(right) studied chemistry at Cambridge University and received his Ph.D. in 1986 under the guidance of Dr Stuart Warren­. After postdoctoral studies (1986–1988) under Professor Gilbert Stork, Columbia University, he returned to the UK as a Lecturer at Bath University. In 1991, he moved to Sheffield University, where he was promoted to Professor in 1997. In 2000, he moved to Bristol University where he holds the Chair in Synthetic Chemistry. He was elected Fellow of the Royal Society in 2012.
Roly J. Armstrong (left) graduated with an MSci in Natural Sciences from Pembroke College, Cambridge (2011) spending his final year working in the laboratory of Professor Steven Ley. He subsequently moved to Merton College, Oxford to carry out a DPhil under the supervision of Professor Martin Smith (2011–2015) working on asymmetric counterion-directed catalysis. In October 2015, he joined the group of Professor Varinder Aggarwal at the University of Bristol as a postdoctoral research associate.

The Zweifel olefination represents a powerful alternative to the Suzuki–Miyaura reaction, enabling the coupling of vinyl metals with enantioenriched secondary and tertiary boronic esters with complete enantiospecificity (Scheme [1, b]).[5] The reaction is mediated by iodine and base and proceeds with no requirement for a transition-metal catalyst. This process is based upon pioneering studies reported in 1967 by Zweifel and co-workers on the iodination of vinyl boranes. This short review summarizes the key contributions made over the last 50 years that have enabled this transformation to evolve into an efficient and atom-economical method for the coupling of boronic esters. Recent contributions to the field are described including the development of Grignard-based vinylation, stereodivergent olefination and alkynylation processes. Finally, selected examples of Zweifel olefination in target-oriented synthesis are reviewed to highlight the utility of this methodology.

Scheme 1 Olefination of boronic esters

2.1

Zweifel Olefination of Vinyl Boranes

In 1967, Zweifel and co-workers reported that vinyl boranes­ 1, obtained by hydroboration of the corresponding alkynes, could be treated with sodium hydroxide and iodine­, resulting in the formation of alkene products 2 (Scheme [2]).[6] Intriguingly, although the intermediate vinyl boranes were formed with high E-selectivity, after addition of iodine, Z-alkenes were produced. A reaction with a dia­stereomerically pure secondary borane afforded the coupled product, 2d, as a single anti diastereoisomer, indicating that the process proceeds with retention of configuration.[7] Mechanistically, this reaction is thought to proceed by activation of the π bond with iodine along with complexation of sodium hydroxide to form a zwitterionic iodonium intermediate 3. This species is poised to undergo a stereospecific 1,2-metalate rearrangement resulting in the formation of a β-iodoborinic acid 4. In the presence of sodium hydroxide, this intermediate then undergoes anti elimination to afford the resulting Z-alkene product.[8]

Scheme 2 Zweifel olefination: iodination of vinyl boranes

Because vinyl borane intermediates could only be accessed by hydroboration of alkynes, the iodine-mediated Zweifel coupling was initially limited to the synthesis of Z-alkenes.[9] However, Zweifel and co-workers subsequently reported an elegant strategy for the complementary synthesis of E-alkenes (Scheme [3]).[10] This transformation was achieved by reacting dialkyl vinyl borane 5 with cyanogen bromide under base-free conditions. Following stereospecific bromination, a boranecarbonitrile intermediate 8, was formed, a species that was sufficiently electrophilic to undergo syn elimination. A variety of boranes underwent this transformation, forming alkenes 6a–c in high yields and with very high levels of E-selectivity. Chiral non-racemic boranes could be transformed with complete stereospecificity.

Scheme 3 Synthesis of E-alkenes using cyanogen bromide

A related syn elimination process was reported by Levy and co-workers (Scheme [4]).[11] In this case, a vinyl lithium reagent was prepared by lithium–halogen exchange and then combined with a symmetrical trialkylborane resulting in formation of boronate complex 9. Treatment of this intermediate with iodine resulted in stereospecific iodination to produce β-iodoborane 10. The enhanced electrophilicity of this species (compared to β-iodoborinic acids such as 4) enabled a syn elimination to occur, generating the corresponding trisubstituted alkene 11 with high levels of stereocontrol. Although the substrate scope of the process is wide, the method was limited to the use of symmetrical trialkyl boranes.

Scheme 4 Olefination of symmetrical trialkylboranes

Scheme 5 Alkynylation of boranes

Brown and co-workers demonstrated that the Zweifel olefination can also be applied to the synthesis of alkynes (Scheme [5]).[12] In this case, monosubstituted alkynes were deprotonated to form lithium acetylides, which were reacted with trialkylboranes to form alkynylboronate complexes 12. Addition of iodine triggered a 1,2-metallate rearrangement to generate β-iodoboranes 13, which spontaneously underwent elimination to form alkyne products. This process represents a convenient alternative to the alkylation of lithium acetylides with alkyl halides and has been successfully employed in total synthesis.[13]

2.2

Zweifel Olefination of Vinyl Borinic Esters

Scheme 6 Diene synthesis by Zweifel olefination of boranes or borinic esters

The transformations described in the previous section suffer from an inherent limitation in that only one of the alkyl groups present in the borane starting materials is incorporated into the alkene product. This is particularly wasteful when the borane is challenging to access or expensive. One solution to this problem would be to employ a mixed borane in which one (or two) of the boron-bound groups demonstrates a low migratory aptitude (e.g., thexyl).[14] However, in practice, determining which group will migrate has proved to be non-trivial and highly substrate-dependent. For example, Zweifel and co-workers showed that treatment of divinylalkylborane 15 (obtained by double hydroboration of 1-hexyne with thexylborane) with iodine resulted in competitive migration of both the sp² and thexyl groups leading to a mixture of the desired product 16 along with 17 (Scheme [6]).[15] They overcame this problem by treating the intermediate divinylalkylborane 15 with trimethylamine oxide, resulting in selective oxidation of the B–C_thexyl bond to afford borinic ester 18. Due to the low migratory aptitude of an alkoxy ligand on boron,[16] addition of iodine and sodium hydroxide now led to selective formation of Z,E-diene 16. Although this allowed control over which group migrated, the method was limited to the synthesis of symmetrical dienes.

A more general approach to the iodination of vinyl borinic esters was later reported by Brown and co-workers (Scheme [7]).[17] In this case, non-symmetrical vinyl borinic esters 20 were obtained by hydroboration of alkynes with alkylbromoboranes followed by methanolysis of the resulting bromoborane intermediates 19. Addition of sodium methoxide­ and iodine led to alkene products 21a–d in good yields and very high levels of Z-selectivity.

Scheme 7 Synthesis of Z-alkenes from vinyl borinic esters

2.3

Extension to Boronic Esters

Although the use of borinic esters significantly expanded the potential of the Zweifel olefination, there were still significant problems with this approach, most notably associated with the high air sensitivity of the borane starting materials. In contrast to boranes, boronic esters are air- and moisture-stable materials which can be readily prepared via a wide range of methods.[18] Evans and Matteson independently recognized the potential of boronic esters as substrates for Zweifel olefination communicating independent studies almost simultaneously.[19] [20]

Matteson’s coupling process began with the synthesis of a vinyl boronate complex 23 by addition of an organolithium reagent to a vinyl boronic ester 22 (Scheme [8]).[19] This intermediate was treated with iodine and sodium hydroxide, resulting in iodination followed by 1,2-metallate rearrangement to form a β-iodoboronic ester which underwent anti elimination to form the corresponding Z-alkene. This reaction could be carried out with alkyl or aryl lithium reagents and the coupled products 24a and 24b were formed in moderate to good yields.

Scheme 8 Zweifel olefination of vinyl boronic esters

Evans and co-workers’ strategy also began with formation of a vinyl boronate complex (Scheme [9]).[20] In contrast to Matteson’s approach, this intermediate was accessed by reacting E-vinyl lithium reagent 26a (prepared by lithium–halogen exchange) with secondary alkyl boronic ester 25. Treatment of the resulting vinyl boronate complex 27a with iodine and sodium methoxide resulted in formation of alkene 28a in 75 % yield (>96:4 Z/E). When a Z-vinyl lithium precursor 26b was employed, alkene 28b was obtained in 58 % yield with very high E-selectivity. The flexibility derived from the ability to form identical vinyl boronate complexes by either reacting a vinyl boronic ester with an organolithium or a vinyl lithium with a boronic ester is a particularly appealing feature of the Zweifel olefination.

Scheme 9 Zweifel olefination of vinyl lithiums with boronic esters

Brown and co-workers subsequently extended this methodology to enable the synthesis of trisubstituted alkenes (Scheme [10]).[17c] [21] By reacting various trisubstituted vinyl boronic esters (29) with organolithium nucleophiles, a range of products was prepared in good to excellent yields. Notably, heteroaromatic groups could be introduced (in 31b) and alkyl Grignard reagents could be used in place of organolithium reagents (in 31d).

Scheme 10 Zweifel olefination of trisubstituted vinyl boronic esters

The methods shown in Schemes 8–10 represented a significant advance upon the early work on the Zweifel olefination of boranes and borinic esters. However, at the time the potential of the method was not fully realized owing to the paucity of methods available for the preparation of boronic esters. Consequently, only a handful of studies involving Zweifel olefination were published over the following three decades.[22] In recent years, the huge increase in methods available for the enantioselective synthesis of boronic esters has led to a renaissance in chemistry based upon the Zweifel olefination. Several new studies into the process have been reported along with elegant reports employing Zweifel olefination in total synthesis. These results are described in the following sections.

3.1

Introduction of an Unsubstituted Vinyl Group

The introduction of a vinyl group into a target molecule is commonly required in synthesis owing to the prevalence of this motif in natural products and as a valuable handle for further functionalization. The first report describing the introduction of an unsubstituted vinyl group by Zweifel olefination was published by Aggarwal and co-workers in their stereocontrolled synthesis of (+)-faranal (Scheme [11]).[23] In this process, vinyl lithium was prepared in situ from tetravinyltin by tin–lithium exchange and was then reacted with enantioenriched secondary boronic ester 32. The resulting vinyl boronate complex was treated with iodine and sodium methoxide, thus promoting 1,2-metallate rearrangement and elimination affording alkene 33. This key intermediate was directly subjected to hydroboration and oxidation to provide alcohol 34 in 69 % yield with very high diastereoselectivity. Oxidation with PCC completed the synthesis of (+)-faranal in 76 % yield.

Scheme 11 Introduction of an unsubstituted vinyl group with vinyl lithium: stereoselective synthesis of (+)-faranal; R = (CH₂)₂CHCMeEt; pin = pinacolato

It was subsequently shown that the vinyl lithium approach could be also be applied to the enantiospecific coupling of trialkyl tertiary boronic esters (Scheme [12, a])[24] and benzylic tertiary boronic esters[25] (Scheme [12, b]). It is noteworthy that in these cases despite the sterically congested nature of the boronic ester starting materials, the coupled products were obtained in excellent yields. The double vinylation of primary–tertiary 1,2-bis(boronic esters) has also been achieved using this approach (Scheme [12, c]).[26] Using four equivalents of vinyl lithium, diene 37 was obtained in 77 % yield.

Scheme 12 Applications of Zweifel olefination with vinyl lithium (prepared from tetravinyltin); PMP = p-methoxyphenyl; e.s. = enantiospecificity

Vinylation under Zweifel conditions represents a powerful strategy for the synthesis of alkenes. However, the necessity of preparing vinyl lithium in situ from the corresponding toxic stannane or volatile vinyl bromide detracts from the appeal of the process. In contrast, stable THF solutions of vinylmagnesium chloride or bromide are commercially available.[27] Aggarwal and co-workers have studied the Zweifel olefination of tertiary boronic ester 38 with vinylmagnesium bromide in THF.[25] Monitoring the reaction by ¹¹B NMR spectroscopy revealed that with one equivalent of vinylmagnesium bromide, the expected vinyl boronate complex 39 was not observed and instead a mixture of unreacted boronic ester 38 and trivinyl boronate complex 40 was formed (Scheme [13]). The latter species originates from over-addition of vinylmagnesium bromide promoted by the high Lewis acidity of the Mg²⁺ counterion. Upon addition of an excess of vinylmagnesium bromide (4 eq.), trivinyl boronate complex 40 was obtained exclusively, and after addition of I₂ followed by NaOMe, the coupled product 41a was obtained in good yield. These conditions were successfully applied to the synthesis of a series of benzylic tertiary substrates 41a–d. The reaction is ineffective at forming very hindered alkenes such as 36, although this product could be synthesized efficiently with vinyl lithium.

Scheme 13 Zweifel olefination of tertiary boronic esters with vinylmagnesium bromide in THF

Scheme 14 Zweifel olefination of boronic esters with vinylmagnesium chloride in THF/DMSO; R = (CH₂)₂PMP

Very recently, an improved procedure for coupling unhindered boronic esters with vinylmagnesium chloride has been reported (Scheme [14]).[28] As with tertiary boronic esters, it was observed that addition of vinylmagnesium chloride to a THF solution of secondary boronic ester 42 resulted in over-addition to form trivinyl boronate complex 44. However, if the reaction was carried out in a 1:1 THF/DMSO mixture,[29] over-addition was completely suppressed and only mono-vinyl boronate complex 43 was obtained. After addition of iodine and sodium methoxide, the coupled product 45a was obtained in 89 % yield. This process proceeds effectively with a range of primary, secondary and aromatic boronic esters. Notably, the use of the mild Grignard reagent allows chemoselective coupling to occur in the presence of reactive functional groups such as carbamates (in 45b) and ethyl esters (in 45d). Although good yields of product were obtained with unhindered tertiary boronic esters (in 45e), in general, the Zweifel vinylation of tertiary boronic esters is best achieved either with four equivalents of vinylmagnesium halide in THF or with vinyl lithium.

In summary, there are currently three methods available to introduce an unsubstituted vinyl group by Zweifel olefination (Scheme [15]). For aromatic, primary and unhindered secondary boronic esters, the desired boronate complex can be formed efficiently using 1.2 equivalents of vinylmagnesium halide in 1:1 THF/DMSO. For the majority of tertiary boronic esters it is recommended to employ four equivalents of vinylmagnesium halide in THF (to form the trivinyl boronate complex), although with extremely hindered tertiary boronic esters, the best results are obtained with vinyl lithium.

Scheme 15 Summary of the best methods for boronate complex formation for the Zweifel vinylation of various boronic esters; R = alkyl group

3.2

Coupling of α-Substituted Vinyl Partners

In addition to the synthesis of alkyl-substituted alkenes, the Zweifel olefination has also been applied to the coupling of vinyl partners α-substituted with a heteroatom. The coupling of lithiated ethyl vinyl ether 46 (readily prepared by deprotonation of ethoxyethene with ^t BuLi) with a tertiary boronic ester proceeded smoothly to provide enol ether 47, which was hydrolyzed under mild conditions to form 48 (Scheme [16, a]).[25] [30] This process represents a novel method for the conversion of boronic esters into ketones. This methodology has also been extended to the enantiospecific synthesis of vinyl sulfides (Scheme [16, b]).[28]

Scheme 16 Synthesis of ketones and vinyl sulfides by Zweifel olefination

A related strategy for the alkynylation of boronic esters has recently been reported by Aggarwal and co-workers (Scheme [17]).[31] In contrast to the successful alkynylation reactions of trialkyl boranes discussed previously (Scheme [5]),[12] [13] boronic esters undergo reversible boronate complex formation with lithium acetylides. This means that addition of electrophiles does not result in coupling, but instead leads to direct trapping of the acetylide and recovery of the boronic ester. A solution to this problem was developed in which vinyl bromides or carbamates were lithiated at the α-position with LDA and then reacted with boronic esters in a Zweifel olefination. Treatment of the resulting vinyl bromides or carbamates with base (TBAF for bromides and ^t BuLi or LDA for carbamates) triggered elimination to form the corresponding alkynes 50. Coupling of a wide range of secondary and tertiary boronic esters was achieved in excellent yields with complete enantiospecificity.

In 2014, an interesting intramolecular variant of the Zweifel olefination for the construction of four-membered ring products was reported (Scheme [18]).[32] In this process, 51, which possesses both a boronic ester and a vinyl bromide, was treated with tert-butyllithium resulting in chemoselective lithium–halogen exchange followed by spontaneous cyclization to form cyclic vinyl boronate complex 52. Upon treatment with iodine and methanol this species underwent stereospecific ring contraction to provide β-iodo­boronic ester 53. Elimination of this intermediate gave exocyclic alkene 54 in 63 % yield. It is particularly noteworthy that this challenging Zweifel olefination occurs in good yield despite the highly strained nature of the exomethylene cyclobutene product.

Scheme 17 Alkynylation of enantioenriched boronic esters; Cb = C(O)N ⁱ Pr₂

Scheme 18 Construction of an exomethylene cyclobutene by an intramolecular Zweifel olefination; Ar = 2-MeO-4-MeC₆H₃

3.3

Syn Elimination

Aggarwal and co-workers have reported a method for the synthesis of allylsilanes through a lithiation–borylation­–Zweifel olefination strategy (Scheme [19]).[33] In this process, silaboronate 56 was homologated with configurationally stable lithium carbenoids 55 to provide α-silylboronic esters 57, which were then subjected to Zweifel olefination to obtain allylsilane products 58. Notably, it was necessary to carry out the Zweifel olefination without sodium methoxide owing to the instability of the allylsilane products under basic conditions. The substrate scope of the process was wide and a range of allylsilanes was prepared in high yields and with excellent levels of enantioselectivity. Interestingly, with a hindered α-silylboronic ester, E-crotylsilane 58d was obtained as a single geometrical isomer, but Z-crotylsilane 58c was formed in slightly reduced selectivity (95:5 Z/E).

Scheme 19 Synthesis of allyl- and crotylsilanes via a lithiation–borylation–Zweifel olefination strategy; Si = SiPhMe₂; (–)-sp = (–)-sparteine

To rationalize the reduced selectivity observed in the formation of Z-crotylsilane 58c, it was postulated that as the boronic ester becomes more hindered, the transition state for anti elimination becomes disfavored due to a steric clash between the bulky R¹ and R² substituents (Scheme [20]). This allows the usually less favorable syn elimination pathway to compete, resulting in the formation of small amounts of the E-isomer.

Scheme 20 Rationalization for reduced Z/E selectivity with bulky boronic­ esters

Similar behavior has been observed in the Zweifel olefination of hindered secondary boronic esters with alkenyllithiums (Scheme [21]).[34] As the boronic ester becomes more sterically encumbered (for example, benzylic or β-branched), increasing formation of the E-isomer was observed, up to 90:10 Z/E in the case of menthol-derived alkene 60c.

Scheme 21 Reduced Z/E selectivity with bulky boronic esters

In these cases, Aggarwal and co-workers have shown that iodine can be replaced with PhSeCl resulting in the formation of β-selenoboronic esters (Scheme [22]).[35] Because the selenide is a poorer leaving group than the corresponding iodide, treatment of these intermediates with sodium methoxide led exclusively to anti elimination providing the coupled products 60a–c as a single Z-isomer in all cases.[34]

Scheme 22 Highly Z-selective olefination of sterically hindered boronic esters

Scheme 23 Stereodivergent olefination of boronic esters

It was also demonstrated that β-selenoboronic esters (obtained by selenation of vinyl boronate complexes) could be directly treated with m-CPBA resulting in chemoselective oxidation of the selenide to give the corresponding selenoxide (Scheme [23, a]).[34] A novel syn elimination then occurred in which the selenoxide oxygen atom attacked a boron atom instead of a hydrogen atom, providing E-alkenes with high selectivity. In conjunction with the Zweifel olefination (or its PhSeCl-mediated analogue) this represents a stereodivergent method where either isomer of a coupled product can be obtained from a single isomer of vinyl bromide starting material (Scheme [23, b]). The substrate scope of both processes is broad and a range of di- and trisubstituted alkenes was prepared including 61c which represents the C9–C17 fragment of the natural product discodermolide.

In some cases, the ability to carry out syn elimination of β-iodoboronic esters is also desirable. For example, very recently Aggarwal and co-workers reported a coupling of cyclic vinyl lithium reagents with boronic esters (Scheme [24]).[28] In this case, the cyclic β-iodoboronic ester intermediates 63 cannot undergo bond rotation and therefore must undergo a challenging syn elimination. It was found that this elimination could be promoted by adding an excess of sodium methoxide (up to 20 eq.). Using this methodology, a range of five- and six-membered cycloalkene products 64 were prepared in high yields and with complete stereospecificity, including glycal 64b and abiraterone derivatives such as 64c.

Scheme 24 Synthesis of cycloalkenes via a challenging syn elimination

Since the pioneering studies on Zweifel olefination reported by Evans and Matteson, the method has been significantly developed such that a wide range of functionalized alkene products can now be obtained. The final section of this short review showcases selected examples where Zweifel olefination has been used in complex molecule synthesis.[36]

4

Zweifel Olefination in Natural Product Synthesis

Aggarwal and co-workers recently reported an 11-step total synthesis of the alkaloid (–)-stemaphylline employing a tandem lithiation–borylation–Zweifel olefination strategy (Scheme [25]).[37] Pyrrolidine-derived boronic ester 65 was homologated with a lithium carbenoid to afford boronic ester 66 in 58 % yield and 96:4 d.r. A subsequent Zweifel olefination with vinyl lithium (synthesized in situ from tetra­vinyltin) gave alkene 67 in 71 % yield. Notably, these two steps could be combined into a one-pot operation, directly providing 67 in 70 % yield. The alkene was later employed in a ring-closing-metathesis–reduction sequence to form the core 5-7 ring system of (–)-stemaphylline.

Scheme 25 Stereocontrolled synthesis of (–)-stemaphylline; Si = TBDPS; TIB = 2,4,6-triisoproylbenzoyl

A recent formal synthesis of the complex terpenoid natural product solanoeclepin A has been reported by Hiemstra and co-workers (Scheme [26]).[38] A key step in this synthesis was the vinylation of the bridgehead tertiary boronic ester in 68. Formation of the trivinyl boronate complex with excess vinylmagnesium bromide in THF followed by addition of iodine and sodium methoxide produced alkene 69, which was employed without purification in a subsequent sequence of oxidative cleavage and Horner–Wadsworth–Emmons olefination to form 70 in a yield of 67 % over four steps.

Scheme 26 Formal synthesis of solanoeclepin A

Scheme 27 Enantioselective synthesis of debromohamigeran E

Morken and Blaisdell have reported an elegant stereoselective synthesis of debromohamigeran E that employs a Zweifel coupling of an α-substituted vinyl lithium (Scheme [27]).[39] Cyclopentyl boronic ester 72 was prepared from 1,2-bis(boronic ester) 71 in 42% yield by a highly selective hydroxy-directed Suzuki–Miyaura coupling. This intermediate was then subjected to Zweifel coupling with isopropenyllithium (synthesized by Li–Br exchange) to form 73 in 93 % yield. Completion of the synthesis of debromohamigeran E required four further steps including hydrogenation of the alkene to an isopropyl group.

A short enantioselective total synthesis tatanan A was reported by Aggarwal and co-workers, which employs a stereospecific alkynylation reaction (Scheme [28]).[40] Boronic ester 74 (synthesized by a diastereoselective Matteson homologation) was subjected to Zweifel olefination with lithiated vinyl carbamate. Treatment of the resulting vinyl carbamate 75 with LDA resulted in elimination to form alkyne 76 in 97 % yield with complete diastereospecificity. This alkyne was converted into the trisubstituted alkene of tatanan A in two further steps.

Scheme 28 Total synthesis of tatanan A; Ar = 2,4,5-trimethoxyphenyl; d.s. = diastereospecifity

A collaborative study on the synthesis of ladderane natural products was recently published by the groups of Boxer, Gonzalez-Martinez and Burns (Scheme [29]).[41] A key intermediate in these studies was the unusual lipid tail [5]-ladderanoic acid. This compound was prepared from meso-alkene 77 by a sequence involving copper-catalyzed desymmetrizing hydroboration (95 % yield, 90 % ee) followed by Zweifel olefination with vinyl lithium reagent 79 (3:1 E/Z). It was found that carrying out the Zweifel olefination with N-bromosuccinimide rather than iodine was critical to achieve efficient coupling. Following silyl deprotection, the coupled product 80 was obtained in 88 % yield as an inconsequential mixture of Z/E isomers. Hydrogenation of the alkene followed by Jones oxidation of the primary alcohol completed the first catalytic enantioselective synthesis of [5]-ladderanoic acid.

Scheme 29 Zweifel olefination in the synthesis of [5]-ladderanoic acid

Negishi and co-workers have employed a Zweifel olefination in the synthesis of the side chain of (+)-scyphostatin (Scheme [30]).[42] In this case, a boronate complex was formed between vinyl boronic ester 81 (prepared in 7 steps from allyl alcohol) and methyllithium. After addition of iodine and NaOH followed by silyl deprotection, trisubstituted alkene 82 was obtained in 76 % yield. The very high stereoselectivity obtained in this reaction (>98:2 E/Z) is particularly noteworthy and represents a significant improvement upon previous synthetic approaches toward this fragment.

Scheme 30 Construction of the side chain of (+)-scyphostatin

Hoveyda and co-workers have employed a similar strategy to synthesize the antitumor agent herboxidiene (Scheme [31]).[43] In this case, Z-vinyl boronic ester 83 was prepared as a single stereoisomer by a Cu-catalyzed borylation–allylic substitution reaction. Boronic ester 83 was then converted into trisubstituted alkene 84 in a Zweifel olefination with methyllithium. The resulting alkene was obtained as a single E-isomer in 70 % yield and could be converted into herboxidiene in five steps.

Scheme 31 Total synthesis of herboxidiene; BOM = benzyloxymethyl

A stereocontrolled synthesis of (–)-filiformin has been reported by Aggarwal and co-workers involving an intramolecular Zweifel olefination (Scheme [32]).[32] Intermediate 85 (synthesized in high stereoselectivity by lithiation–borylation­) was converted into cyclic boronate complex 86 by in situ lithium–halogen exchange. Addition of iodine and methanol brought about the desired ring contraction to provide exocyclic alkene 87 in 97 % yield. Deprotection of the phenolic ether followed by acid-promoted cyclization and bromination completed the synthesis of (–)-filiformin.

Scheme 32 Synthesis of (–)-filiformin via an intramolecular Zweifel olefination

5

Conclusions and Outlook

Fifty years have passed since the first report by Zweifel and co-workers on the iodine-mediated olefination of vinyl boranes. Since then, this process has evolved into a robust and practical method for the enantiospecific coupling of boronic esters with vinyl metals. Recent contributions have significantly expanded the generality of the process, enabling the efficient coupling of a wide range of different alkenyl partners and allowing increasingly precise control over the stereochemical outcome of the transformation. Rapid progress in enantioselective boronic ester synthesis combined with the extensive applications of chiral alkenes bode well for the continued development and application of the Zweifel olefination in synthesis.

Acknowledgment

We are grateful to Dr Eddie Myers and Dr Adam Noble for helpful discussions and suggestions during the preparation of this manuscript.

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• 9 For the synthesis of trisubstituted alkenes, see: Brown HC. Basavaiah D. Kulkarni SU. J. Org. Chem. 1982; 47: 171
• 10 Zweifel G. Fisher RP. Snow JT. Whitney CC. J. Am. Chem. Soc. 1972; 94: 6560
• 11 LaLima NJ. Levy AB. J. Org. Chem. 1978; 43: 1279
• 12 Suzuki A. Miyaura N. Abiko S. Itoh M. Brown HC. Sinclair JA. Midland MM. J. Am. Chem. Soc. 1973; 95: 3080

For selected examples of alkynylation of boranes and borinic esters, see:
• 13a Negishi E. Lew G. Yoshida T. J. Chem. Soc., Chem. Commun. 1973; 22: 874
• 13b Suzuki A. Miyaura N. Abiko S. Itoh M. Midland MM. Sinclair JA. Brown HC. J. Org. Chem. 1986; 51: 4507
• 13c Naruse M. Utimoto K. Nozaki H. Tetrahedron 1974; 30: 2159
• 13d Naruse M. Utimoto K. Nozaki H. Tetrahedron Lett. 1973; 14: 2741
• 13e Pelter A. Drake RA. Tetrahedron Lett. 1988; 29: 4181
• 13f Sikorski JA. Bhat NG. Cole TE. Wang KK. Brown HC. J. Org. Chem. 1986; 51: 4521
• 13g Canterbury DP. Micalizio GC. J. Am. Chem. Soc. 2010; 132: 7602
• 14a Aggarwal VK. Fang GY. Ginesta X. Howells DM. Zaja M. Pure Appl. Chem. 2006; 78: 215
• 14b Slayden SW. J. Org. Chem. 1981; 46: 2311
• 14c Slayden SW. J. Org. Chem. 1982; 47: 2753
• 15 Zweifel G. Polston NL. Whitney CC. J. Am. Chem. Soc. 1968; 90: 6243
• 16a Tripathy PB. Matteson DS. Synthesis 1990; 200
• 16b Elliott MC. Smith K. Jones DH. Hussain A. Saleh BA. J. Org. Chem. 2013; 78: 3057
• 17a Brown HC. Basavaiah D. J. Org. Chem. 1982; 47: 3806
• 17b Brown HC. Basavaiah D. J. Org. Chem. 1982; 47: 5407
• 17c Brown HC. Basavaiah D. Kulkarni SU. Bhat NG. Prasad JV. N. V. J. Org. Chem. 1988; 53: 239
• 18a For a review see: Collins BS. L. Wilson CM. Myers EL. Aggarwal VK. Angew. Chem. Int. Ed. 2017; DOI: in press; 10.1002/anie.201701963.

For selected recent examples, see:
• 18b Schmidt J. Choi J. Liu AT. Slusarczyk M. Fu GC. Science 2016; 354: 1265
• 18c Zhang L. Lovinger GJ. Edelstein EK. Szymaniak AA. Chierchia MP. Morken JP. Science 2016; 351: 70
• 18d Li C. Wang J. Barton LM. Yu S. Tian M. Peters DS. Kumar M. Yu AW. Johnson KA. Chatterjee AK. Yan M. Baran PS. Science 2017; DOI: in press; 10.1126/science.aam7355.
• 19a Matteson DS. Jesthi PK. J. Organomet. Chem. 1976; 110: 25
• 19b Matteson had previously described this work in a review article: Matteson DS. Synthesis 1975; 147
• 20a Evans DA. Thomas RC. Walker JA. Tetrahedron Lett. 1976; 17: 1427
• 20b Evans DA. Crawford TC. Thomas RC. Walker JA. J. Org. Chem. 1976; 41: 3947
• 21 Brown HC. Bhat NG. J. Org. Chem. 1988; 53: 6009

For selected applications of Zweifel reactions of boranes and borinic esters, see:
• 22a Abatjoglou AG. Portoghese PS. Tetrahedron Lett. 1976; 17: 1457
• 22b Kulkarni UU. Basavaiah D. Brown HC. J. Organomet. Chem. 1982; 225: C1
• 22c Basavaiah D. Brown HC. J. Org. Chem. 1982; 47: 1792
• 22d Mikhailov BM. Gurskii ME. Pershin DG. J. Organomet. Chem. 1983; 246: 19
• 22e Hyuga S. Takinami S. Hara S. Suzuki A. Tetrahedron Lett. 1986; 27: 977
• 22f Benmaarouf-Khallaayoun Z. Baboulene M. Speziale V. Lattes A. J. Organomet. Chem. 1986; 306: 283
• 22g Wang KK. Dhumrongvaraporn S. Tetrahedron Lett. 1987; 28: 1007
• 22h Ichikawa J. Sonoda T. Kobayashi H. Tetrahedron Lett. 1989; 30: 6379
• 22i Hoshi M. Masuda Y. Arase A. J. Chem. Soc., Perkin Trans. 1 1990; 12: 3237
• 22j Brown HC. Iyer RR. Mahindroo VK. Bhat NG. Tetrahedron: Asymmetry 1991; 2: 277
• 22k Brown HC. Mandal AK. J. Org. Chem. 1992; 57: 4970
• 22l Periasamy M. Bhanu Prasad A. Suseela Y. Tetrahedron 1995; 51: 2743
• 22m Yang DY. Huang X. J. Organomet. Chem. 1996; 523: 139
• 22n Hoshi M. Tanaka H. Shirakawa K. Arase A. Chem. Commun. 1999; 627
• 22o Smith K. Balakit AA. El-Hiti GA. Tetrahedron 2012; 68: 7834
• 23 Dutheuil G. Webster MP. Worthington PA. Aggarwal VK. Angew. Chem. Int. Ed. 2009; 48: 6317
• 24 Pulis AP. Blair DJ. Torres E. Aggarwal VK. J. Am. Chem. Soc. 2013; 135: 16054
• 25a Sonawane RP. Jheengut V. Rabalakos C. Larouche-Gauthier R. Scott HK. Aggarwal VK. Angew. Chem. Int. Ed. 2011; 50: 3760
• 25b Shimizu M. Angew. Chem. Int. Ed. 2011; 50: 5998
• 26 Blair DJ. Tanini D. Bateman JM. Scott HK. Myers EL. Aggarwal VK. Chem. Sci. 2017; 8: 2898
• 27 Linstrumelle G. Alami M. Vinylmagnesium Bromide. In e-EROS Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons; Chichester: 2001
• 28 Armstrong RJ. Niwetmarin W. Aggarwal VK. Org. Lett. 2017; 19: 2762

For related use of DMSO to promote boronate complex formation with vinyl Grignard reagents, see:
• 29a Lovinger GJ. Aparece MD. Morken JP. J. Am. Chem. Soc. 2017; 139: 3153
• 29b Edelstein EK. Namirembe S. Morken JP. J. Am. Chem. Soc. 2017; 139: 5027
• 30 For a related example involving trialkylboranes, see: Levy AB. Schwartz SJ. Wilson N. Christie B. J. Organomet. Chem. 1978; 156: 123
• 31 Wang Y. Noble A. Myers EL. Aggarwal VK. Angew. Chem. Int. Ed. 2016; 55: 4270
• 32 Blair DJ. Fletcher CJ. Wheelhouse KM. P. Aggarwal VK. Angew. Chem. Int. Ed. 2014; 53: 5552
• 33a Aggarwal VK. Binanzer M. de Ceglie MC. Gallanti M. Glasspoole BW. Kendrick SJ. F. Sonawane RP. Vázquez-Romero A. Webster MP. Org. Lett. 2011; 13: 1490

For related examples see:
• 33b Bhat NG. Lai WC. Carroll MB. Tetrahedron Lett. 2007; 48: 4267
• 33c Meng F. Jang H. Hoveyda AH. Chem. Eur. J. 2013; 19: 3204
• 34 Armstrong RJ. García-Ruiz C. Myers EL. Aggarwal VK. Angew. Chem. Int. Ed. 2017; 56: 786
• 35 Armstrong RJ. Sandford C. García-Ruiz C. Aggarwal VK. Chem. Commun. 2017; 53: 4922

For other examples of Zweifel olefination in synthesis, see:
• 36a Man H.-W. Hiscox WC. Matteson DS. Org. Lett. 1999; 1: 379
• 36b Fletcher CJ. Blair DJ. Wheelhouse KM. P. Aggarwal VK. Tetrahedron 2012; 68: 7598
• 36c Shoba VM. Thacker NC. Bochat AJ. Takacs JM. Angew. Chem. Int. Ed. 2016; 55: 1465
• 36d Casoni G. Myers EL. Aggarwal VK. Synthesis 2016; 48: 3241
• 36e Chakrabarty S. Takacs JM. J. Am. Chem. Soc. 2017; 139: 6066
• 37 Varela A. Garve LK. B. Leonori D. Aggarwal VK. Angew. Chem. Int. Ed. 2017; 56: 2127
• 38 Kleinnijenhuis RA. Timmer BJ. J. Lutteke G. Smits JM. M. de Gelder R. van Maarseveen JH. Hiemstra H. Chem. Eur. J. 2016; 22: 1266
• 39 Blaisdell TP. Morken JP. J. Am. Chem. Soc. 2015; 137: 8712
• 40 Noble A. Roesner S. Aggarwal VK. Angew. Chem. Int. Ed. 2016; 55: 15920
• 41 Mercer JA. M. Cohen CM. Shuken SR. Wagner AM. Smith MW. Moss FR. Smith MD. Vahala R. Gonzalez-Martinez A. Boxer SG. Burns NZ. J. Am. Chem. Soc. 2016; 138: 15845
• 42 Xu S. Lee C.-T. Rao H. Negishi E. Adv. Synth. Catal. 2011; 353: 2981
• 43 Meng F. McGrath KP. Hoveyda AH. Nature 2014; 513: 367