Stereospecific functionalizations and transformations of secondary and tertiary boronic esters

The formation of highly enantioenriched boronic esters through both stoichiometric and catalytic methods has received much attention over the past decade. Accordingly, the transformations of the boronic ester moiety into other functional groups is of considerable interest in synthesis. Specifically, transformations which retain the high enantioenrichment of the starting boronic ester, either through a stereoretentive or a stereoinvertive pathway, lead to the formation of new C–C, C–O, C–N, C–X, or C–H bonds at stereogenic centres. This feature article summarises the current state of the art in stereo-specific transformations of both secondary and tertiary boronic esters into other functionalities and groups, whilst considering critically the transformations that are currently unattainable and would represent future advances to the field.


Introduction
Organoboron compounds are of significant utility in asymmetric synthesis.Accompanied with a large expansion in routes to obtain enantioenriched organoboron compounds, their subsequent transformations into a range of functional groups provide access to a broad array of diverse molecules with high enantioselectivity.
Asymmetric hydroboration, reported in 1961 by H. C. Brown, 1 heralded the birth of modern asymmetric synthesis because, for the first time, it was shown that small molecules (Ipc 2 BH) were capable of providing high levels of enantioselectivity, levels that had previously been the sole preserve of enzymes.Stereospecific oxidation of the chiral alkylboranes (R 3 B) formed through hydroboration gave enantioenriched alcohols.Subsequently, further stereospecific transformations of the alkylboranes were elucidated, enabling the C-B bond to be converted into a wide range of other functional groups. 2owever, despite the range of reactions that can be carried out using alkylboranes, their synthetic utility is tempered by their air and moisture sensitivity.Changing the organoborane into a boronic ester (RB[OR 0 ] 2 ) enables easier purification, especially in the case of boronic acid pinacol esters (RBpin). 3This characteristic facilitates the use of boronic esters in synthesis and as a tool to create new bonds.Perhaps most notably, the Suzuki-Miyaura reaction has been applied extensively because of operational simplicity and the range of arylboronic esters and acids that are commercially available. 4his journal is © The Royal Society of Chemistry 2017 As a tool for chiral synthesis, the development of novel methods to obtain enantioenriched alkylboronic esters has received much attention over the past decade.Methods to introduce the boronic ester moiety into organic compounds with high levels of asymmetric induction include both stoichiometric methods (such as homologation 5 and lithiation-borylation 6 ) and catalytic methods (such as hydroboration, 7 conjugate addition 8 and diboration 9 ).Having established routes to the synthesis of these molecules, attention has also turned to their manipulation and subsequent stereospecific transformations into a wide range of functional groups, 10 in a similar vein to the range of transformations open to alkylboranes.
In this feature article, we review the range of stereospecific transformations that are currently available to secondary and tertiary boronic esters, operating through either a stereoretentive or a stereoinvertive pathway (i.e.not a radical pathway).The transformations covered (Fig. 1) include oxidations (C-O bond formation), conversions of boron to other heteroatoms (C-N, C-X), protodeboronation (C-H), as well as the formation of new C-C bonds (resulting from homologations, olefinations, alkynylations and coupling reactions).These transformations have been selected for their applicability to any general alkylboronic ester, and so reactions that are dependent on the presence of specific functional groups (such as allylic boronic esters, or coupling reactions activated by neighbouring directing groups), except for benzylic boronic esters, have been omitted.With this review, we aim to showcase the work that we, and others, have conducted to expand the synthetic utility of enantioenriched boronic esters, whilst also identifying transformations that remain elusive and would represent significant future advances to the field.

Oxidation of boronic esters to alcohols
The stereospecific oxidation of boronic esters to the corresponding alcohol is the most versatile and widely used functionalization reaction of boronic esters.Building upon the oxidation of organoboranes through the use of basic hydrogen peroxide, developed by Brown and co-workers in 1961, 11 the reaction of an enantioenriched boronic ester under these conditions affords the alcohol with complete retention of configuration.Addition of the peroxide anion to the empty p-orbital of the boron atom forms boronate complex 1 (Scheme 1).The boronate complex then undergoes a 1,2-metallate rearrangement -migration of the C-B s-bond onto the adjacent oxygen atom, with loss of hydroxide.The nature of this 1,2-metallate rearrangement step is such that the stereoconfiguration of the carbon initially attached to boron is retained, a feature that is common to many of the stereospecific transformations discussed throughout this review.Finally, hydrolysis cleaves the O-B bond to afford alcohol 3. The oxidation of a boronic ester is slower than for analogous boranes owing to donation of the oxygen lone pairs into the empty p-orbital of boron, an attribute that decreases the electrophilicity of the boron.Although numerous synthetic routes are available to produce primary and secondary alcohols, the formation of stereodefined tertiary alcohols is significantly less developed.We found that oxidation can also be applied to tertiary boronic esters (Scheme 2), 12 which can be prepared by lithiation-borylation (see Section 4.3).During the course of our studies on the oxidation of tertiary boronic esters, we have found that it is sometimes advantageous to add dibutylhydroxytoluene (BHT) to prevent the formation of peroxy radicals, and ethylenediaminetetraacetic acid (EDTA) to minimize the decomposition of hydrogen peroxide by trace metals. 12,13urthermore, we find that THF is an ideal solvent for improving miscibility with the aqueous phase.
As a milder alternative to the hydrogen peroxide conditions, sodium perborate effects the oxidation with higher functionalgroup tolerance. 14For example, Fontani et al. reported that the oxidation of diastereomerically pure cyclopropylboronic acid pinacol ester 8 with hydrogen peroxide led to a poor conversion along with the formation of ring-opened carbonyl compounds. 15Conversely, the oxidation with sodium perborate was found to afford the desired alcohol 9 in 81% yield (Scheme 3).Furthermore, sodium perborate is also often the reagent of choice for oxidations where the boron moiety is situated b to an electron-withdrawing group (such as a sulfone or a carbonyl group). 16Household bleach (aq.NaOCl) has also been used to oxidise a tertiary b-keto boronic ester with complete retention of configuration. 17

Amination of boronic esters
Although trialkylboranes can be readily converted into the corresponding amines by reaction with reagents such as chloramine 18 or alkyl azides, 19 the reduced Lewis acidity of boronic esters prevents reactivity with these weakly Lewis basic reagents due to ineffective association.To facilitate the stereospecific amination of boronic acid glycol esters 10, Brown and co-workers (Scheme 4a) reported the initial conversion into the more Lewis acidic borinic ester 11 with methyllithium and subsequent amination by using hydroxylamine-O-sulfonic acid (NH 2 OSO 3 H). 20eeking a direct stereospecific amination protocol for alkylboronic acid pinacol esters, Morken and co-workers 21 (Scheme 4b) proposed increasing the nucleophilicity of the amination reagent by using lithiated alkoxy amines.Reaction of enantioenriched boronic ester 13 with 3.0 equivalents of methoxyamine and n-butyllithium, followed by Boc protection, was found to afford Boc-protected amine 14 in 84% yield.This transformation was found to proceed with complete retention of stereoconfiguration for secondary boronic esters, an outcome that is consistent with a 1,2-metallate rearrangement involving migration of the C-B s-bond onto the nitrogen atom with loss of methoxide.However, these conditions were not amenable for the amination of tertiary alkylboronic esters.
Although a method for the direct amination of tertiary boronic esters has yet to be reported, we sought to provide the desired tertiary amines by first converting the boronic ester 15 into the trifluoroborate salt 16 (Scheme 4c), 22 which can be achieved in essentially quantitative yields using KHF 2 in MeOH. 23Pleasingly, we found that a modification of Matteson's amination conditions for trifluoroborate salts, 24 using SiCl 4 to form the alkyldichloroborane 25 and then reaction with an alkylazide, 19b led to the corresponding amine 17 through a retentive pathway without loss in stereochemical integrity.The reaction can occur intramolecularly to obtain piperidines (19), and we subsequently discovered that the methodology can also be applied to non-benzylic tertiary boronic esters. 26

Boronate complexes as chiral organometallic-type reagents
In addition to the functionalization of boronic esters via the stereospecific migration of the C-B bond, we envisaged that This journal is © The Royal Society of Chemistry 2017 enantioenriched boronic esters could serve as precursors to chiral organometallic-type nucleophilic reagents. 27We proposed that the boronic ester could be activated by addition of an electron-rich aryllithium to form a nucleophilic boronate complex.The complex is configurationally stable and should thus confer the chirality of the starting material into the desired functionalized compound.
Upon addition of p-MeOC 6 H 4 Li 21 to boronic ester 20 (Scheme 5a), 28 followed by reaction with I 2 as the electrophile, the desired C-I bond was formed in 80% yield and 97% es.It was determined that the reaction is invertive at the stereogenic carbon (a polar, S E 2inv pathway).However, high enantiospecificity was not observed when using diisopropyl azodicarboxylate (DIAD) as the electrophile: hydrazine 25 was formed in 82% yield and only 13% es (Scheme 5b).We postulated that the low enantiospecificity resulted from a competing single-electron transfer (SET) pathway (Fig. 2), a mechanism that is supported by radical-clock experiments.Nonetheless, the SET pathway could be reduced by adjusting the electronics of the aryllithium used to form the boronate complex; by using the electron-deficient aryllithium 24, the enantiospecificity of the reaction was found to increase to 66%.
With the optimal nucleophilic boronate complex in hand, we were able to functionalize the C-B bond of enantioenriched secondary boronic esters with a range of different heteroatom electrophiles with up to complete stereoinversion -enabling iodination, chlorination, bromination, as well as the formation of C-N bonds.C-O bonds can also be formed using this stereoinvertive method, thus being complementary to the standard oxidation conditions which are stereoretentive (see Section 2.1).For example, reaction of the boronate complex with 2,2,6,6tetramethylpiperidine-1-oxoammonium tetrafluoroborate (26)  and subsequent N-O bond cleavage affords the corresponding alcohol 27 in 64% yield and 70% es (Scheme 5c).The reaction was found to be applicable to both benzylic and non-benzylic substrates, with the former exhibiting both enhanced reactivity and enantiospecificity.These reactions are related to the halogenation of boronate complexes derived from chiral boranes which also occurred with inversion. 29he range of heteroatoms that can be introduced using a boronate complex was further expanded to include fluorine, 30 providing access to enantioenriched alkylfluorides (Scheme 5d).Boronate complex 29 was formed by reacting boronic ester 28 with phenyllithium, and was then reacted with Selectfluor II (30) in acetonitrile, resulting in the formation of alkylfluoride 31 in 72% yield, but only 80% es.We discovered that the addition of styrene as a cheap and readily-available additive enhanced the enantiospecificity, enabling the product to be formed in 83% yield and complete enantiospecificity.Interestingly, the use of styrene led to no measurable decrease in yield in the reaction, suggesting that it was not merely acting as a radical trap for the SET pathway.Instead, we proposed that a fast radical propagation mechanism is inhibited by styrene, which acts as a radical scavenger (Fig. 3), thus allowing the desired S E 2inv pathway to dominate.In order to determine the range of electrophiles that might be suitable for reactions with boronate complexes, we sought to determine the nucleophilicity parameter (N) of the complexes to compare with other nucleophiles. 31In collaboration with Mayr and co-workers, we discovered that the aryl group has a significant effect on reactivity: the boronate complex derived from phenyllithium is 100 times more reactive than that derived from 3,5-(CF 3 ) 2 C 6 H 3 Li (24). 32Furthermore, the order of the nucleophilicity parameter follows the trend: secondary benzylic 4 primary alkyl 4 primary benzylic 4 secondary alkyl.With these relative levels of reactivity known, we aim to explore other electrophiles that should participate in this S E 2inv pathway (see also Section 4.5).

Protodeboronation of tertiary benzylic boronic esters
The stereospecific conversion of the C-B bond of a tertiary boronic ester into a C-H bond represents an efficient synthesis of tertiary alkyl stereogenic centres, including 1,1-diarylalkanes.Tertiary boranes are known to undergo protodeboronation by using propionic acid as the reagent of choice, 33 owing to strong B-O bond formation driving the reaction.We discovered that this reagent is not efficient for the protodeboronation of tertiary benzylic boronic esters, 34 leading to slow conversion predominantly towards elimination products.We reasoned that the reaction could be facilitated if the driving force was changed to the formation of stronger B-F bonds.Consequently, we found that the addition of CsF and H 2 O in dioxane at 30 1C leads to the protodeboronation of diarylalkyl boronic ester 32 in 91% yield and 99% es (Scheme 6a), via a stereoretentive pathway.The methodology also provides access to enantioenriched deuterated tertiary alkanes by simply substituting the H 2 O with D 2 O.
In contrast with diarylalkyl boronic esters, aryldialkyl boronic esters were found to be significantly more difficult to protodeboronate.Nevertheless, using the more reactive TBAFÁ3H 2 O enabled the protodeboronation of 35 in 99% yield and 99% es when conducted in n-pentane (Scheme 6b).Notably, the protodeboronation conditions require activated substrates, such as a benzylic (or allylic 35 ) boronic ester.However, our research group found that non-benzylic boronic esters could undergo protodeboronation by employing oxidative conditions, leading to homolytic cleavage of the C-B bond, 36 the resulting C-H bond being formed without stereospecificity owing to the radical nature of the intermediates.
The TBAFÁ3H 2 O reaction is believed to occur via a hydrogenbonded boronate complex, which delivers the proton to the same side as the boron atom (Scheme 7).In more polar solvents, solvation of the water molecules is proposed to cause a competing invertive pathway and subsequent erosion in enantiospecificity.
This protodeboronation strategy provides ready access to enantioenriched alkanes that are otherwise difficult to access, since the newly formed stereogenic centre can be placed distal to other functional groups.Indeed, we have applied the methodology to the synthesis of a wide range of biologically and therapeutically active molecules (Fig. 4). 34,37 Carbon-carbon bond formation

One-carbon homologations
The homologation of an enantioenriched boronic ester 38 by a one-carbon unit allows facile chain extension whilst retaining the valuable boronic ester group for future functionalization.The simplest such homologation is the insertion of a methylene (CH 2 ) unit into the C-B bond, a reaction that was initially reported by Sadhu and Matteson in 1985. 39In their seminal work, it was found that addition of n-butyllithium to a mixture of boronic ester 37 and iodochloromethane in THF at À78 1C affords the homologated boronic ester 39 in 95% yield, a transformation that proceeds through a stereoretentive 1,2-metallate rearrangement (Scheme 8a).Initially, iodine-lithium exchange forms LiCH 2 Cl, which adds to the empty boron p-orbital to form boronate complex 38, thus triggering the 1,2-metallate rearrangement with Scheme 6 Protodeboronation of tertiary dibenzylic and monobenzylic boronic esters.
Scheme 7 Proposed mechanism for the stereoretentive protodeboronation of tertiary benzylic boronic esters.When we investigated the homologation of tertiary boronic esters, 26,42 we discovered that the use of bromochloromethane led to competitive oxygen migration, forming borinic ester 42 (Scheme 8b).However, through analysis of conformation 43, we reasoned that using bromide as a bulkier and less-polar leaving group would disfavour oxygen migration; indeed, when using in situ formed bromomethyllithium, the carbonmigration product 41, which was subsequently oxidized to the alcohol, was formed in 83% yield and with complete stereoretention.
Computational studies on the effect of sterics in this migration conducted by Elliott et al. have shown that the energy difference between the barriers to carbon-and oxygenmigrations are significantly reduced for sterically bulky tertiary boronic esters, and that decomplexation and/or undesired reactions of the boronate complex can take place in these cases. 43Consequently, greater yields were found by decreasing steric hindrance around the boron atom through replacing the pinacol ligand with propane-1,3-diol.
Manipulation of the oxidation state of the carbon atom introduced from the organolithium allows access to alternative homologated functional groups.Using LiCHCl 2 (derived from the deprotonation of CH 2 Cl 2 ) provides access to the homologated aldehyde 45 44 after oxidation of the intermediate a-chloroboronic ester 44 (Scheme 9a). 45For a tertiary boronic ester, we have found the homologation reaction to proceed in 68% yield with complete stereoretention (Scheme 9b). 42andrick et al. have subsequently applied this homologation on a decagram scale to install a quaternary stereogenic centre in their synthesis of 5-lipoxygenase-activating protein (FLAP) inhibitor 50 (Scheme 9c). 46r the homologation to the corresponding carboxylic acid, Crudden and co-workers found the direct homologation to be challenging, 44 but can be achieved via a two-step procedure involving oxidation of the a-chloroboronic ester 44 with NaClO 2 (Scheme 9a).This two-step strategy had previously been applied by Matteson and Beedle to oxidise a-azido boronic esters into the corresponding carboxylic acids in their synthesis of enantioenriched a-amino acids. 47As an alternative route, we have also applied a two-step procedure involving oxidation of the homologated alcohol with pyridinium dichromate. 48

Three-carbon homologations
As an alternative to one-carbon homologation processes where the 1,2-metallate rearrangement proceeds by an S N 2-type displacement of a leaving group (see Section 4.1), an S N 2 0 -type process can be achieved by using a vinylboronate complex with an allylic leaving group, thereby introducing a three-carbon motif and forming an allylic organoboron compound.This process works well for boranes, 49 and the homologation was applied to achiral tertiary boronic esters by Smith et al. 50When our research group applied this technique, homologation of enantioenriched tertiary boronic ester 51 with (3-chloroprop-1-en-1-yl)-lithium 52 afforded, after oxidation, allylic alcohol 53 in 68% yield and 100% es, albeit in 1 : 1 dr (Scheme 10a). 26To obtain higher diastereoselectivity, we have found an S N 2-type displacement of chloride to be preferential since the configurationally labile organolithium is then able to undergo a dynamic kinetic resolution.In this case, the homologation of 15 with 1-chloroallyllithium 54 afforded the allylic boronic ester 55 in 73% yield, 100% es and 24 : 1 dr (Scheme 10b). 42e envisaged that if we could identify a method for promoting a 1,3-borotropic rearrangement of the products, we would have access to terminal allylic boronic esters for further functionalization. 48owever, this posed two challenges: firstly, the homologation of a chiral secondary boronic ester by using 1-chloro-allyllithium leads to a mixture of under-and over-homologated products; secondly, allylic pinacol boronic ester products are stable to 1,3-borotropic rearrangements, unlike their propylene glycol analogues.50b, 51 Consequently, to address the first challenge, we adopted a two-step, one-pot protocol involving a one-carbon Matteson homologation followed by in situ treatment with vinyl magnesium bromide (Scheme 10c). 48Next, to facilitate the 1,3-rearrangement, we discovered that palladium catalysis in the presence of base and B 2 pin 2 gave access to a Bpin-bound p-allyl-Pd II complex 60 (Fig. 5) which, upon reductive elimination, affords the desired product with excellent E selectivity.The three-carbon homologation of secondary boronic ester 13 was found to afford 57 in 61% yield (over 2 steps), E/Z 495 : 5 and 100% es (Scheme 10c).To demonstrate the synthetic utility of the three-carbon homologation, we applied our methodology to the synthesis of a fragment of (+)-jasplakinolide.

Lithiation-borylation homologations
Owing to the stereospecific nature of the 1,2-metallate rearrangement, there is the opportunity to create two or more configurationally well-defined contiguous stereocentres with high fidelity through a stereoselective homologation.We have realised this through the application of our lithiationborylation methodology, 6,12,13d,52 in which a configurationally stable carbenoid, possessing a suitable leaving group, is added to a boronic ester to ultimately form a new carbon-carbon bond at a stereogenic centre.Lithiated carbamate 63 can be formed by the deprotonation of the parent carbamate using secbutyllithium in the presence of (À)-sparteine (Scheme 11a). 53he addition of enantioenriched boronic ester 62 leads to the formation of boronate complex 64 which, following 1,2-metallate rearrangement and oxidation of the boronic ester, affords alcohol 66 in 82% yield, with 498 : 2 er and 96 : 4 dr.52a Simply changing the enantiomer of sparteine (or using O'Brien's (+)-sparteine surrogate 54 ) during the lithiation gives access to the other diastereomer of the product (70).We have subsequently applied this methodology to install two contiguous stereocentres in the synthesis of a range of natural products.37a,55 Scheme 10 Three-carbon homologations of enantioenriched boronic esters, and the palladium-catalyzed 1,3-borotropic shift.R = CH 2 CH 2 Ph.A modified method can be used to incorporate quaternary stereocentres.Application of the standard method, described above, to the homologation of tertiary boronic ester 15 (99 : 1 er) with lithiated carbamate 63 (98 : 2 er), gives alcohol 72 with a surprisingly low dr (88 : 12; Scheme 11b). 56It was discovered that epimerization had occurred at the quaternary stereogenic centre derived from the boronic ester.Consequently, the origin of minor diastereomer 78 was proposed to result from fragmentation of the sterically crowded boronate complex, forming a new organolithium (75) which can racemize and recombine with boronic ester 76 (Scheme 11c).To suppress this racemization pathway, the procedure was adapted as follows: firstly, adding allyl bromide after formation of boronate complex 74 traps any subsequently formed fragmentation anion 75; secondly, using diamine-free conditions (73 obtained by tin-lithium exchange from the corresponding stannane) minimises steric hindrance of the lithiated carbamate, thus enabling boronate complex formation.Application of these conditions affords alcohol 72 in 73% yield, 499 : 1 er and 98 : 2 dr (Scheme 11b).
Extending these conditions further to the synthesis of contiguous quaternary-quaternary stereogenic centres was found to be even more challenging, with no 1,2-metallate rearrangement observed upon the addition of a tertiary boronic ester to a lithiated secondary carbamate. 57However, the reaction does proceed with mixed borane 80 (derived from in situ addition of MeMgBr to neopentyl glycol boronic ester 79) to afford, after oxidation, alcohol 82 in 70% yield, 499 : 1 er and 98 : 2 dr (Scheme 12).Notably, these mixed boranes complex with the benzylic lithium carbenoids with inversion of configuration at the carbenoid carbon atom. 12In addition to oxidation, amination of the borane intermediate using chloramine also worked well.
Using lithiation-borylation methodology, we have been able to develop a route to multiple contiguous stereocentres through an assembly-line process, without the requirement for multiple purifications.Nine iterative homologations, starting from boronic ester 83 and using lithiated benzoate ester 84 as the carbenoid (the OTIB group acts as a better leaving group when compared to OCb 52b ), afforded boronic ester 85 in 58% yield with only two aqueous work-up steps and one purification (Scheme 13a). 58The all-anti isomer was found to adopt an irregular conformation, but by varying the enantiomer of 84 during the assembly-line process, the all-syn (86) and alternating syn-anti (87) isomers could be obtained, molecules that were found to adopt helical and linear conformations respectively.Assembly-line synthesis has also been applied using combinations of different types of homologation reactions.For example, incorporating sequential lithiation-borylation and Matteson homologation steps (see Section 4.1) followed by Morken's amination protocol (see Section 2.2) afforded 89 in 52% yield (Scheme 13b), an intermediate in the synthesis of (+)-kalkitoxin (90). 59Sequential homologations were also utilised in the synthesis of (+)-hydroxyphthioceranic acid (92) from boronic ester 91 in 12.4% overall yield (Scheme 13c).

Olefinations and alkynylations
The selective formation of a single alkene isomer from a borane starting material was first reported by Zweifel and co-workers in 1967. 60In their seminal study, it was found that the addition of iodine to alkenyldialkylborane 93 (formed by hydroboration across an alkyne) results in the formation of iodonium ion 94, which, upon migration of an alkyl substituent of the boron, is opened to afford b-iodo-organoborane 95 (Scheme 14a).Deboronoiodination of this intermediate (usually facilitated by hydroxide or methoxide as a base) leads to cis-alkene 96.
The reaction was subsequently expanded to the coupling of a boronic ester (98) with a vinyllithium (97) by Evans and co-workers (Scheme 14b). 61Owing to the stereospecific nature of the 1,2-metallate rearrangement, the reaction can be used to couple enantioenriched boronic esters with olefinic functional groups without loss of stereochemical integrity.
Our research group has shown that upon subjection of tertiary benzylic boronic esters to Zweifel olefination conditions, vinylmagnesium bromide adds not once but three times to the boronic ester, to form boronate complex 101 (Scheme 15a). 42The addition of four equivalents of vinylmagnesium bromide leads to complete conversion to this boronate complex, which, upon addition of iodine and NaOMe/MeOH, affords the olefination product 102 in 79% yield and 100% es.
In further studies within our group, we have identified that Zweifel olefination conditions can be applied to the homologation of a boronic ester to the corresponding methyl ketone using ethoxy vinyllithium (Scheme 15b). 26,42We have also applied this versatile reaction in synthesis -propenylation of 104 affords compound 105 as an intermediate in the synthesis of (À)-aplysin 106 (Scheme 15c), 62 and an intramolecular Zweifel reaction of compound 107 was used in the synthesis of (À)-filiformin 109 (Scheme 15d). 56e deboronoiodination of intermediate 95 occurs through an anti elimination process and gives access to the cis alkene.We reasoned that access to the alternative trans isomer would be facilitated through a syn elimination step. 63Replacing iodine with PhSeCl as the electrophile, followed by chemoselective oxidation of the b-selenoboronate intermediate 111 to the corresponding selenoxide 112, initiates syn elimination of selenium and boron (Scheme 16a).This protocol allowed the coupling of vinyllithium 114 (derived by lithium-halogen exchange from the parent vinylbromide) with boronic ester 28 to afford trans alkene 115 in 74% yield, 498 : 2 E/Z selectivity and 100% es (Scheme 16b). 64Taken in combination with the Zweifel cis olefination, the two procedures provide stereodivergent access to either alkene isomer. 65xtension of olefination techniques to alkynylation is more challenging.The reaction of a metallated alkyne with a boronic ester is reversible, 66 and, consequently, addition of iodine affords an iodoalkyne rather than the desired p-electrophilic activation of the alkynyl boronate.However, our group has shown that suitably functionalized alkenes, which can be coupled to boronic esters by using the Zweifel olefination, can give an alkyne through a subsequent 1,2-elimination. 67eprotonation of vinylbromide by LDA and addition to enantioenriched secondary alkylboronic ester 116, followed by the addition of iodine in methanol, was found to afford 1,1-bromoalkyl-alkene 117 (Scheme 17a).A solution of crude vinyl bromide 117 was then treated with TBAF to achieve elimination and afford the desired alkyne 118 in 81% overall yield and complete enantiospecificity.
For the alkynylation of tertiary boronic esters, we found that vinyl carbamate is a superior reagent, with the intermediate carbamoylalkylalkene 119 easily undergoing elimination by using tert-butyllithium to afford alkyne 120 in 84% yield and 100% es (Scheme 17b).Secondary benzylic boronic esters also undergo alkynylation by using vinyl carbamate, but the stoichiometry of the tert-butyllithium must be carefully controlled to prevent deprotonation at the benzylic carbon centre and a concomitant reduction in enantiospecificity.

Addition to aldehydes and iminium ions
During our studies into the reactivity of boronic esters, we observed that benzylic boronic esters react with aldehydes in the presence of CsF, albeit with only 43% es. 68Switching to a benzylic trifluoroborate salt 121 (obtained from the parent boronic ester in excellent yields and stereospecificity) 23 and using a catalytic amount of [{RhCl(cod)} 2 ] enabled the addition to aldehyde 122 to be conducted in 86% yield and 100% es, through a stereoretentive pathway (Scheme 18a).The retention of configuration was explained by invoking rhodium acting as a Lewis acid to simultaneously coordinate both the aldehyde and boron compound and facilitate carbon-carbon bond formation (Fig. 6).Both secondary and tertiary benzylic trifluoroborate salts participate in this reaction, and TEMPO-mediated oxidation of the products led to the corresponding ketone 124 without stereoerosion.Yun and co-workers extended this methodology to form g-butyrolactones 127, using KHF 2 as an additive to enable the reaction of benzylic boronic esters, albeit with moderate diastereocontrol (Scheme 18b). 69n addition to the reaction of trifluoroborate salts, our group has also shown that boronate complexes (see Section 2.3) react with iminium ions to form C-C bonds without loss of stereochemical integrity.Reaction of boronate 128 with commercially available Eschenmoser's salt 129 gives tertiary amine 130 in 64% yield and 94% es (Scheme 18c). 28Benzylic boronate complexes also react with cyclic iminium ions -the addition of boronate 128 to pyridine 131 (activated using Troc-Cl) affords dihydropyridine 132 in 83% yield, 96 : 4 dr and 100% es (Scheme 18d). 70Activated quinolines and dihydroisoquinolines can also be used as electrophiles.

sp 2 -sp 3 coupling reactions
The formation of key C-C bonds by cross-coupling reactions, such as the Suzuki-Miyaura reaction, is one of the most established methods in modern synthesis. 4,71However, the  Suzuki-Miyaura reaction is largely limited to the formation of sp 2 -sp 2 bonds, owing to problems of slow transmetalation and competing b-hydride elimination when extended to coupling of sp 3 carbon centres. 72Specifically, b-hydride elimination and subsequent hydropalladation leads to racemization of stereogenic centres and loss of stereochemical information.Accordingly, significant research has focussed on the coupling of sp 3 organometallic nucleophiles within recent years. 73he first general stereospecific coupling of an enantioenriched secondary benzylic boronic ester was achieved by Crudden and co-workers in 2009; 74 using [Pd 2 (dba) 3 ]/PPh 3 as the catalyst, boronic ester ent-13 was coupled in a stereoretentive manner with aryl iodide 133 in 62% yield and 91% es (Scheme 19a).Crucially, the use of Ag 2 O as the base, which increases the rate of the transmetalation step, was found to be critical to obtaining high yields and high levels of enantiospecificity. 75Crudden and co-workers have further extended their methodology to enable the coupling of dibenzylic boronic esters; in this case, neopentyl glycol boronic ester 135 was coupled to give triarylmethane 136 in high yield and enantiospecificity (Scheme 19b). 76Liao and co-workers found that although dibenzylic boronic esters coupled with retention of configuration, the corresponding trifluoroborates coupled with inversion of configuration (Scheme 19c). 77he first report of an enantiospecific Suzuki-Miyaura coupling of an unactivated dialkylboron compound was reported by Biscoe and co-workers in 2014. 78Stereoinvertive coupling of enantioenriched trifluoroborate salt 140 with chlorobenzene 141 was achieved using preformed P t Bu 3 -ligated palladium precatalyst 142, 79 affording 143 in 64% yield and 94% es (Scheme 19d).The bulky, electron-rich phosphine ligand is used to suppress b-hydride elimination and subsequent isomerization, as reported by the groups of Dreher and Molander. 80s a consequence of the difficulties associated with transitionmetal-mediated sp 2 -sp 3 coupling reactions, particularly the inability to couple tertiary boronic esters under current protocols, we reasoned that the desired C-C bond could be formed using an alternative transition-metal-free route.In our approach, we proposed that activation of the aromatic ring of boronate complex 144 by an electrophile (in an analogous fashion to the activation of the alkene in a Zweifel reaction; see Section 4.4) would facilitate the desired 1,2-metallate rearrangement (Fig. 7). 81Upon nucleophilic attack at the boron centre, the compound would re-aromatize with the elimination of the electrophile, affording the desired coupled product 146 in a stereoretentive fashion.
We initially tested this reaction manifold on the coupling of 2-lithiofuran (formed by deprotonation of furan by n-butyllithium) with enantioenriched boronic ester ent-20 (Scheme 20a).81a,b Following formation of boronate complex 147, addition of N-bromosuccinimide as the electrophile facilitates the desired coupling in 91% yield and 100% es.Significantly, the procedure  This journal is © The Royal Society of Chemistry 2017 can be applied to tertiary boronic esters (Scheme 20b), which are not good substrates for the alternative transition-metalmediated coupling reactions discussed above.The reaction was also found to be applicable to coupling six-membered aromatics: the reaction of lithiated meta-methoxybenzene with boronic ester ent-20 gave the coupled product in 72% yield and 100% es (Scheme 20c).It was found that an electron-donating group at the meta position of the aromatic ring was essential to prevent reaction of the boronate complex with the electrophile at the sp 3 carbon-boron bond (cf.Section 2.3).
The scope of this coupling reaction has been extended to include N-heteroaromatic compounds. 82Reminiscent of the reactions involving the addition of nucleophilic boronate complexes to activated cyclic iminium ions (see Section 4.5), 70 we proposed that activation of the nitrogen atom of boronate complex 153, through acylation with Troc-Cl, would facilitate 1,2-metallate rearrangement (Scheme 20d).Oxidation of the resulting boronic ester facilitated rearomatization to afford coupled product 154 in 84% yield and with complete retention of configuration.
In a further extension to this methodology, we reasoned that using a carbon-based electrophile would afford intermediate 145 (Fig. 7), but this intermediate would not be susceptible to elimination.Oxidation of the boronic ester and subsequent rearomatization would instead yield a three-component coupling product.To test this strategy, 83 we applied electrophilic trifluoromethylation to obtain 2,5-disubstituted furans containing a key CF 3 group.For example, trifluoromethylation of boronate complex 155, through the addition of Umemoto's reagent, afforded intermediate 156, which could be oxidised using iodine to give the three-component coupled product 157 in 72% yield and 100% es (Scheme 21a).Tertiary boronic esters could also be used, but the oxidation step was found to be more challenging: only one diastereomer of 160 could be oxidised to the threecomponent coupled product 159 under the reaction conditions (Scheme 21b).Mechanistic studies determined that the reaction proceeds through a radical propagation cycle; the trifluoromethyl radical was observed by EPR spectroscopy using a spin trapping experiment.

Conclusions and outlook
The capability of boronic esters to undergo stereospecific transformations facilitates access to a wide range of enantioenriched building blocks for synthesis.Consequently, new asymmetric methods to create chiral boronic esters represent an efficient route towards diverse functionality.These two research areas are currently developing synergistically to form a major pillar in modern asymmetric synthesis. 26,42,84or the main part, the stereospecificity of these reactions results from a 1,2-metallate rearrangement of a boronate complex, in which the carbon-boron s-bond migrates with retention of configuration.This 1,2-metallate rearrangement has been manipulated to enable a range of new bond-forming reactions, most notably, oxidation, amination, homologation, olefination, alkynylation and arylation reactions.However, in some cases new reactivity pathways for boronic esters have been uncovered: the reaction of nucleophilic boronate complexes with electrophiles, a transformation that occurs with inversion of configuration; complexation to water molecules in protodeboronation; boron-palladium transmetalation without significant b-hydride elimination.
Broad though these methods are, access to certain functional groups remains elusive.Considering homologation reactions, if the desired nucleophile for attacking the boronic ester is too stabilised, it simply decomplexes from the boron centre rather than undergo 1,2-migration.This reluctance to form stable boronate complexes has thwarted some attempts at developing novel functionalization reactions of boronic esters, such as direct alkynylation by using alkynyl anions (see Section 4.4).We anticipate that new strategies to circumvent these problems will provide access to new functionalities, notable current remaining challenges being stereospecific transformations to thiols, nitriles, carboxylic acids, nitro compounds, trifluoromethyl groups, and phosphorus functional groups.
Finally, the stereospecific coupling of secondary and tertiary boronic esters to aromatic groups is a field that has received considerable interest over the last decade, owing to the synthetic utility of the products.Some progress has been made, but further developments to expand its generality are still required.One significant transformation that remains to be achieved is a general traceless sp 3 -sp 3 coupling reaction between an enantioenriched boronic ester and a suitable coupling partner (such as an alkyl halide).The development of such a method would further extend the broad array of transformations available to enantioenriched boronic esters and would be a major step forward for the field of asymmetric synthesis.

Fig. 1
Fig. 1 Summary of stereospecific functional group transformations of secondary and tertiary boronic esters.

Fig. 3
Fig. 3 Undesired radical pathways for the fluorination of boronate complexes, leading to the formation of racemic product, unless prevented by styrene.

Fig. 4
Fig.4Examples of biologically and therapeutically active molecules synthesised using a protodeboronation step to introduce the displayed hydrogen(s) enantiospecifically.

Scheme 14
Scheme 14 Early examples of the Zweifel olefination reaction applied to boranes and boronic esters.