Homologation and Alkylation of Boronic Esters and Boranes by 1,2-Metallate Rearrangement of Boron Ate Complexes', Chemical Record, Vol

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Homologation and Alkylation of Boronic Esters and Boranes by

1,2-Metallate Rearrangement of Boron Ate Complexes

Citation for published version: Thomas, SP, French, RM, Jheengut, V & Aggarwal, VK 2009, 'Homologation and Alkylation of Boronic Esters and Boranes by 1,2-Metallate Rearrangement of Boron Ate Complexes', Chemical record, vol. 9, no. 1, pp. 24-39. https://doi.org/10.1002/tcr.20168

Digital Object Identifier (DOI): 10.1002/tcr.20168

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Download date: 06. Oct. 2021 Homologation and Alkylation of Boronic THE CHEMICAL Esters and Boranes by 1,2-Metallate RECORD Rearrangement of Boron Ate Complexes

STEPHEN P. THOMAS, ROSALIND M. FRENCH, VISHAL JHEENGUT, VARINDER K. AGGARWAL School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK

Received 6 August 2008; Accepted 1 December 2008

ABSTRACT: Organoboranes and boronic esters readily undergo nucleophilic addition, and if the nucleophile also bears an α-leaving group, 1,2-metallate rearrangement of the ate complex results. Through such a process a carbon chain can be extended, usually with high stereocontrol and this is the focus of this review. A chiral boronic ester (substrate control) can be used for stereocontrolled

homologations with (dichloromethyl)lithium in the presence of ZnCl2. Subsequent alkylation by an organometallic reagent also occurs with high levels of stereocontrol. Chiral lithiated carbanions (reagent control) can also be used for the reaction sequence with achiral boronic esters and boranes. Aryl-stabilized sulfur ylide derived chiral carbanions can be homologated with a range of boranes including vinyl boranes in good yield and high diastereo- and enantioselectivity. Lithiated alkyl chlorides react with boronic esters, again with high stereocontrol, but both sets of reactions are limited in scope. Chiral lithiated carbamates show the greatest substrate scope and react with both boronic esters and boranes with excellent enantioselectivity. Furthermore, iterative homologation with chiral lithiated carbamates allows carbon chains to be “grown” with control over relative and absolute stereochemistry. The factors responsible for stereocontrol are discussed. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 24–39; 2009: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20168

Key words: homologation; boronic ester; 1,2-metallate rearrangement; lithiated carbamates; sulfur ylides; chiral carbanions

Introduction Organoboranes and boronic esters are very useful synthetic pheylborane by H. C. Brown in 1961 provided the fi rst non- intermediates as they can be converted into a broad range of enzymatic asymmetric synthesis that resulted in truly practical functional groups, often with complete stereospecifi city.1 These levels of enantioselection.2 In the early 1980s Matteson reported transformations are usually initiated by nucleophilic addition a complementary route to chiral boronic esters.3 In fact, the to the electrophilic boron atom followed by 1,2-migration. discoveries by Matteson that very high diastereoselectivities Among all the metals and semimetals, boron seems to possess could be achieved in: (i) reactions of (dichloromethyl)lithium a unique ability to orchestrate these processes cleanly and with with boronic esters, and (ii) reactions of Grignard reagents high stereochemical fi delity. Another attractive feature is that chiral boron reagents are easily accessible in high enantiopurity. Indeed, the hydroboration of alkenes using (−)-diisopinocam- ᭤ Correspondence to: Varinder K. Aggarwal; email: [email protected]

LiCHCl2 OR* -LiCl Cl OR* R2M Cl OR* 1 ∗ ∗ R B B B OR* M 1 -MCl OR* Substrate R1 OR* R R2 control R2 OR* 1,2-Metallate B rearragement ∗ M R1 OR* ∗ OR R1 LG LG OR 2 ∗ -MLG R B B OR M OR Reagent R1 R2 control LG = leaving group

Scheme 1. Complementary routes to homochiral organoboranes involving 1,2-metallate rearrangement. with (α-haloalkyl)boronic esters opened up a whole new ﬁ eld Homologation–Alkylation of Chiral Boronic in organoboron chemistry.4 Esters: Substrate Control In Matteson’s approach, a chiral auxiliary is embedded in the diol moiety of the boronic ester and subsequent transfor- Reaction of an enantiopure boronic ester 1 with mations are controlled by its architecture (substrate control; (dichloromethyl)lithium forms (dichloromethyl)borate Scheme 1). An alternative approach uses a chiral reagent to complex 2. In the presence of zinc chloride, borate 2 construct a related chiral ate complex that subsequently evolves rearranges via transition structure (TS) 3 leading to a single into the chiral boronic ester following 1,2-metallate rearrange- α-chloroboronic ester 5 with a high diastereomeric purity, ment (reagent control; Scheme 1). These two approaches are often >99 : 1 dr (Scheme 2). It has been proposed that in discussed in this review. the preferred TS 3 zinc chloride promotes and directs the

᭤ Stephen P. Thomas was born in Toronto, Canada, in 1981 and moved to the United Kingdom in 1991. He received his MChem from Cardiff University (2003) under the supervision of Dr Nicholas Tomkinson and then moved to Cambridge University for his Ph.D. (2007) working with Dr Stuart Warren. After postdoctoral work with Professor Andreas Pfaltz (2007–2008) at the University of Basel, Switzerland, he returned to a lectureship at the University of Bristol. ᭿

᭤ Rosalind M. French was born in Taplow, England. She received her M.Sc degree from Oxford University in 2006 under the supervision of Dr. Veronique Gouverneur. In 2006 she commenced her Ph.D. studies in the group of Prof. Varinder K. Aggarwal at Bristol University, and is currently working on the lithiation/borylation reactions of secondary benzyl carbamates. ᭿

Cl Cl Cl Cl ZnCl2 R R H Zn Zn O R H LiCHCl2 O R ZnCl2 O O Cl O 1 Cl O Cl O R Cl Cl R Cl R R B B B B B O THF, − °C r.t. O O R 1 1 H 1 Cl R R R R R R1 Cl H 1 2 3 3 4 Favoured Disfavoured

X Cl R Cl MX2 R Cl O H H M R1 O R 1 O R O B R 1 O R X B O R B O Cl B 1 O B R 2 R R 2 R O R R 2 H O R R R R2 R1 5 6 7 7 8

Scheme 2. Matteson homologation–alkylation sequence. migration of R1 by complexation to the less hindered oxygen chloride (which becomes more nucleophilic in the TS) and the atom of the boronic ester while simultaneously assisting the C-H bond (which becomes more electrophilic in the TS as the departure of a chloride ion.3c It is also believed that this TS is chloride leaves).5 No such interaction can occur in the migra- further stabilized by an interaction between the chloride of zinc tion of the other diastereotopic chloride that is consequently

᭤ Dr. Vishal Jheengut was born in Nouvelle France, Mauritius, in 1977. He received his B.Sc in chemistry at the University of Mauritius in 2001 and Ph.D. in synthetic organic chemistry in 2007 at the University of Saskatchewan, Canada, under the supervision of Professor Dale E. Ward. During his Ph.D., he worked on the development of new aldol strategies using thiopyran scaffolds and the synthesis of polypropionates. He joined the laboratory of Professor Varinder K. Aggarwal at the University of Bristol, UK in 2007 as postdoctoral researcher where he is currently working on the synthesis of all carbon quaternary centres using chiral carbenoids and their application to natural products. ᭿

᭤ Varinder K. Aggarwal was born in Kalianpur in North India in 1961 and emigrated to the United Kingdom in 1963. He received his B.A. (1983) and Ph.D. (1986) from Cambridge University, the latter under the guidance of Dr Stuart Warren. He was subsequently awarded a Harkness fellowship to carry out postdoctoral work with Professor Gilbert Stork at Columbia University, NY (1986–1988). He returned to a lectureship at Bath University and in 1991 moved to Sheffi eld University, where in 1997 he was promoted to Professor of Organic Chemistry. In 2000, he moved to the University of Bristol to take up the Chair of Synthetic Chemistry. He is the recipient of the AstraZeneca Award, Pfi zer Award, GlaxoWelcome Award, Novartis Lectureship, RSC Hickinbottom Fellowship, Nuffi eld Fellowship, RSC Corday Morgan Medal and the Leibigs Lectureship, Liebigs Lecturship (Germany), 1999/2000 (inaugural), RSC Green Chemistry Award 2004, Zeneca Senior Academic Award 2004, RSC Reaction Mechanism Award 2004, Royal Society Wolfson Merit Award 2006, RSC/GDCh-Alexander Todd-Hans Krebs Lectureship 2007, RSC Tilden Lecturer awarded 2007, and an EPSRC Senior Research Fellowship 2007. ᭿

disfavored (TS 4). Indeed, Midland has calculated that there Cl O R O R O R −1 6 LiCHCl2 RLi is a 12.6 kcal mol difference between the two TSs. R B Cl B Cl HC B R 2 Reaction of the α-haloboronic ester with a Grignard or O R O R O R organolithium reagent gives intermediate borate 6 that is 1 3 analogous to intermediate borate 2. However, in this case the reaction is stereospecifi c as the migrating group has to align H Cl H High H Cl anti-periplanar to the leaving group (TS 7, Scheme 2). Never- O LiCHCl2 O dr O RB Cl B B theless, it is rather fortuitous that with this particular diaste- O R O R O reoisomer the features required for the smooth 1,2-metallate rearrangement (chelation of the metal to the less hindered H H H Low Cl O Cl O O oxygen, binding of the leaving group to the metal and the RLi R dr B B B Cl R O stabilizing interaction between the halide and the C-H bond) Cl O O are all still present. However, this is not always the case (see Cl further discussion). Scheme 3. Effect of order of addition of reagents to different boronic A number of signifi cant observations have been made by esters. Matteson4c over the course of his investigations that are sum- marized in the following. are compatible, but there must be at least two carbons between the functional group and the boron centre other- 1. Boronate complexes do not rearrange at low tempera- wise β-elimination results. ture (e.g., −78°C). This prevents multiple insertions of 7. Suitably protected α-amino boronic esters and α-azido (dihalomethyl)lithium as any excess reagent decomposes boronic esters are tolerated under certain reaction before the homologated boronic ester has been formed. conditions. 2. The electrophilic nature of the boron atom results in an 8. A wide range of nucleophiles, including RMgX, RLi, RO−, − − − effi cient ate-complex formation. This inhibits side reactions RS , R2N , N3 , and LiCH2CN, have been shown to such as β-elimination. undergo stereospecifi c 1,2-metallate rearrangement. 3. As well as zinc, lithium cation has been shown to accelerate the rate of 1,2-metallate rearrangement but with lower stereoselectivity. This might be because zinc chloride can Applications of Matteson-Type Homologation– sequester free chloride, thus inhibiting the slow epimeriza- Alkylation in Synthesis tion of the product by free chloride. 4. Boronic esters bearing β-halides, or other weakly basic func- Matteson has elegantly demonstrated the potential of this tions, are not stable with respect to elimination of the halide homologation/alkylation methodology in the synthesis of and the boronic ester group. numerous natural products. This is illustrated in the concise 8 5. C2-symmetric boronic esters, for example, 1, are generally synthesis of japonilure 14, a Japanese beetle pheromone. more stereoselective than boronic esters derived from Reaction of boronic ester 10 with (dichloromethyl)lithium pinanediol as they lead to the same diastereomeric ate gave the (α-chloro)boronic ester 11 as a single diastereoisomer. complex when starting from the α-(dichloromethyl)boronic Subsequent treatment with lithiated alkyne 12 gave, after 1,2- ester and reacting with an organometallic reagent as metallate rearrangement, boronic ester 13 that was readily when starting from the corresponding boronic ester and converted to Japonilure 14 (Scheme 4). reacting with (dichloromethyl)lithium (Scheme 3). In Matteson further applied the homologation/alkylation contrast, pinanediol boronic esters give different diaste- methodology to the fi rst total synthesis of the epimerically reomeric ate complexes that show very different levels labile pheromone (2S,3R,1’R)-stegobinone 20 (Scheme 5).9 of stereocontrol in the subsequent migration. In order The two key synthetic components—aldehyde 18 and alcohol to achieve good diastereoselectivity the migrating group 19—used in this synthesis were prepared from a common must be present on the pinanediol boronic ester before boronic ester 17. Reaction of ethyl boronic ester 15 with the addition of (dichloromethly)lithium. In contrast, poor (dichloromethyl)lithium followed by alkylation with sodium levels of stereocontrol are observed when pinanediol benzoxide gave the substituted boronic ester 16 that was (dichloromethyl)boronate is reacted with an organometallic converted into the common boronic ester 17 through a species.7 similar sequence. This was then subjected to a further

6. Alkoxy groups (OBn, OPMB, OCPh3) and nitrides are well (dichloromethyl)lithium homologation, and either oxidation tolerated at both α- and β-positions in sequential homolo- to give aldehyde 18 or methyl magnesium chloride alkylation gations. Halide, carbonyl, thioether, and cyano substituents and oxidation to give alcohol 19.

HO Cy trol. Even the mismatched case shown in Scheme 6 gave good Cy levels of stereoselctivity. HO Cy LiCHCl2 tBuCO O t O 2 BuCO2 Cy B ZnCl2 O B O O Cy Cy 1. O O 1. LiCH3, ZnCl2 94% Cl B Cy B Cy O O 9 10 2. Li 2. PMBCl Cl 3. OsO4 4. NaIO Cy Cy 21 4 Cy Cy C8H17 Li O O PMBO O PMBO OH PMBO OH O O 12 B B 21 t t BuCO2 BuCO2 Cl H H C8H17 80 : 16 79% 97% 11 Scheme 6. Synthesis and application of allyl boronates generated by 13 Matterson homologation. O

1. H2O2 O Japonilure Armstrong has shown that the high levels of stereoselectiv- 2. H , Lindlar cat. 2 14 ity observed for the homologation/alkylation reaction of H C8H17 pinanediol-derived boronic esters can be used to great effect in Scheme 4. Synthesis of Japonilure. the synthesis of the C10¶C21 fragment of tautomycin, a serine/ threonine phosphatase inhibitor.11 Four sequential Matteson- type homologation/alkylation sequences were used to prepare Cy Cy 1. LiCHCl2, 1. LiCHCl2, alcohol 22 with excellent stereocontrol over the three con- O ZnCl2 O ZnCl2 tiguous stereocentres (Scheme 7). B Cy B Cy O 2. NaOBn O 2 CH3MgCl Davoli et al. used multiple Matteson-type homologation– BnO alkylation reactions in the synthesis of (−)-microcarpalide 25.12 15 16 Using two boronic esters derived from the opposite enantio- mers of pinanediol, successive (dichloromethyl)lithium homol- Cy ogations and 1,2-metallate rearrangements of both carbon BnO O 1. LiCHCl2, BnO O ZnCl B Cy 2 and oxygen nucleophiles were used for the synthesis of O H 2. H2O2, NaOH intermediates 23 and 24 with excellent diastereoselectivity Me Me (Scheme 8). 17 18 Different diastereoisomers of a compound can usually be prepared by simply altering the order of addition of the com-

1. LiCHCl2, ZnCl2 O ponent reagents as demonstrated in the synthesis of the phero- 2. CH3MgCl mone 33 of the elm bark tree beetle Scolytus multistriatus and O 3. H2O2, NaOH an epimer 29. They were synthesized via diastereomeric inter- O mediates 27 and 31 (Scheme 9).13 It should be noted that Me Me obtaining the different alcohol stereochemistries at C-3 in OH 20 29 and 33 required the (R,R) and (S,S) boronic ester diol (2S,3R,1'R)-Stegobinone BnO Me stereochemistries, respectively. However, to obtain the (S)- 19 stereochemistry at C-4 in both 27 and 31 required both a different addition sequence of nucleophiles and different Scheme 5. Synthesis of the two key intermediates used in the ﬁ rst total synthesis of (2S,3R,1′R)-stegobinone. enantiomeric chiral diols.

Hoffmann has completed a number of natural product Limitations of the Matteson-type syntheses (e.g., erythronylide) using the Matteson-type homol- Homologation–Alkylation ogation/alkylation methodogy to prepare chiral allylic boronic ester 21.10 Reaction of this boronic ester with chiral/achiral Although a powerful transformation, Matteson’s aldehydes usually proceeds with very high levels of stereocon- homologation–alkylation sequence suffers from a number of

H H H O O Me O 1.LiCHCl2, ZnCl2 1.LiCHCl2, ZnCl2 1.LiCHCl2, ZnCl2 Me B B B O 2. MgBr O 2. LiOPMB O 2. MgBr OTBS Me PMBO

H PMBO PMBO O 1.LiCHCl2, ZnCl2 B OTBS O 2. NaHB(OMe)3 Me Me 3. H2O2, NaOH OH 22 TBSO

Scheme 7. Synthesis of the C10¶C21 fragment of tautomycin.

O n -C6H13 B minor drawbacks. Occasionally, diastereomeric ate complexes O do not behave in the same way. For example, although ate complex 34 uneventfully evolved to the homologated boronic LiCHCl2 ester 36, its diastereoisomer 37 did not. In this case, instead of 64% the standard C-migration, contra-thermodynamic O-migration Cl occurred to give borinic ester 41 (Scheme 10).13 Evidently, n n -C6H13 O -C6H13 O 1. LiOBn, 70% B the TS required for C-migration 38, which suffers from B BnO O both a loss of the stabilizing interaction between the halide Cl O 2. LiCHCl2, 61% and C-H bond, and steric clash between the benzyl group

1. AllylMgBr, 74% and the magnesium halide substituent, must be strongly

2. H2O2, NaOH, 90% disfavored. In contrast, TS 40 maintains all the features found in TS 35 (magnesium positioned on the less hindered oxygen atom of the diol, magnesium-activated halide 23 OH displacement, and halide–CH interaction) but now has the n-C H OH 6 13 OH oxygen antiperiplanar to the departing chloride and so this BnO group migrates instead. n-C H 6 13 O + O Although it is often possible to obtain opposite stereoiso- OH BnO mers simply by changing the order of addition of reagents 25 24 (see Scheme 9), occasionally this is not possible and a three- (−)-Microcarpalide BnO step sequence to invert (by exchange) the boronic ester

CO2H diol stereochemistry is required. In the synthesis of mono- protected diol 48, an epimer of the diol used in the total syn- 1. H2O2, NaOH, 89% 2. NaH, BnBr, 48% thesis of stegobinone (see Scheme 5), the (R,R)-diol 44 is 3. TFA, CH2Cl2, 100% required to “control” the stereochemistry of the ether stereogenic centre of 45 and the (S,S)-diol ent-44 is needed for the OBn O subsequent homol ogation and methylation of boronic ester 46 O 1. LiCHCl2 B B 14 2. VinylMgBr (Scheme 11). Therefore, iterative homologation sequences O O t 44% (2 steps) t may sometimes require additional steps to change the CO2 Bu BnO CO2 Bu stereochemistry of the diol of the boronic ester prior to 1. LiCHCl 2 homologation. 2. LiOBn 44% (2 steps) Although highly successful for the synthesis of secondary alcohols,4f,h 1,2-metallate rearrangement of boron-ate O complexes have had limited success for the synthesis of B tertiary alcohols as variable levels of selectivity were O t CO2 Bu obtained and even the sense of asymmetric induction was Scheme 8. Synthesis of (−)-microcarpolide. unpredictable.15

CH CH 3 1. (i) LiCHCl2 3 1. (i) LiCHCl2 OH O (ii) ZnCl O (ii) ZnCl O H O , NaOH B 2 B 2 B 2 2 4 3 2. H CMgBr O 3 O 2. EtMgBr CH3 O CH3 (R,R)

26 27 28 29

CH3 CH3 1. (i) LiCHCl2 1. (i) LiCHCl2 OH H3C O O O B (ii) ZnCl2 B (ii) ZnCl2 B H2O2, NaOH 4 3 O 2. nPrMgBr O 2. EtMgBr CH3 O CH (S,S) 3

30 31 32 33

Scheme 9. Variation in the sequence of reagent addition in a Matteson-type homologation–alkylation to give different diastereoisomers of the product.

X Mg MeMgBr O X O Cl O B O B H B O Ph O Ph Me Cl Bn Me 34 35 36

X Mg MeMgBr O X O Cl O B O B Bn B O Ph O Ph Me Cl H Me

37 38 39

MeMgBr

X X Mg O Me Mg Cl X B X H H Cl O O Ph R Bn O O B B H O Bn R Me Me

40 41

Scheme 10. Example of different outcome from reaction of diastereomeric (α-chloro)boronic esters with Grignard reagents.

Homologation–Alkylation of Boronic Esters groups with achiral boronic esters (reagent control). In this and Boranes using Chiral Carbanions: case, chirality is embedded in the reagent and so is comple- Reagent Control mentary to the Matteson approach described earlier. In the previous section we discussed the use of boronic esters derived from chiral diols and their subsequent homologation Chiral Carbanions Derived from Sulfur Ylides with achiral organometallic reagents. In that section, newly formed stereogenic centers were controlled by the diol archi- Ylides represent a class of carbanions with leaving groups tecture (substrate control). The following section describes the attached directly to the carbanion. In reactions of boranes with reactions between chiral carbanions bearing potential leaving different ylides (sulfur-, nitrogen-, and phosphorus ylides),

1. NaOH Cy O Cy O Me BF4 1. LiCHCl2 (HOCH ) C-R B Me B 2 3 (i) 1.2 eq. LiHMDS S OH/NH2 O 2. LiOBn O OBn 2. H+ °C Cy Cy + BR3 (ii) BR3 Ph R 42 43 O - (iii) H2O2, NaOH (97%, >20:1 dr ) R = NH(CH2)3SO3 49 or NH2OSO3H 50 68-73% Yield Cy Cy 95-97% ee

HO OH Cy OH HO Me ent-44 Cy O Me H H + BEt3 B B BEt HO OBn S Ph Et3B S Ph 2 Cy OH Cy O OBn Ph Et O O 44 45 46 major 77% (59%, >20:1 dr ) 51 product

Cy OH OBn ΔE = 4.37 kcal/mol 1. LiCHCl2 O OBn Cy B 2. MeMgBr O H H Ph Ph 47 48 BEt3 BEt (79%, >20:1 dr ) S H Et3B S H 2 Ph Et Scheme 11. Stereocontrol through change of boronic ester stereochemistry. O O

sulfur ylides were found to behave optimally as they possessed Scheme 12. Reactions of chiral sulfur ylides with organoboranes. the best balance of stability and leaving group ability.16 Furthermore, such reactions could be easily rendered asymmetric using chiral sulfonium salts such as 49 that had been allylic boranes—compounds that had not been prepared previ- previously developed for asymmetric epoxidation, aziridina- ously due to their high lability (Scheme 15).20 Reaction of the tion, and cyclopropanation reactions.17 Thus, reaction of an aryl- ylide derived from sulfonium salt 56 with vinylboranes at stabilized sulfur ylide, generated in situ by deprotonation of −100°C followed by the addition of benzaldehyde at the same sulfonium salt 49, with triaryl, or trialkyl boranes gave the temperature, and subsequent warming to room temperature homologated boranes that were oxidized to the corresponding gave the homoallylic alcohol 61 in 96% yield as a single anti- alcohols and amines 50 in high yield and high ee.18 The major diastereoisomer with a high Z selectivity (Procedure A, Scheme enantiomer is formed from the favored conformation of the 15). Using this protocol, the aldehyde trapped the allylic ylide 51 reacting on the less hindered face (Scheme 12). borane as it was formed, thus not allowing time for isomeriza- The synthesis of the enantioenriched alcohol 52 tion to occur. The high lability of these allylic boranes has also and amine 54, intermediates in the synthesis of the anti- been exploited. If the intermediate allyl borane 60 was allowed inﬂ ammatory agents neobenodine 53 and cetirizine 55, to warm to 0°C, isomerization occurred to give the thermody- respectively, demonstrated the potential of this methodology namically more stable allylic borane 62 that could be trapped (Scheme 13).17 with benzaldehyde at −78°C to give the isomeric alcohol However, reactions with 9-BBN derivatives 57 gave mixed 63 in high yield and with similarly high diastereoselectivity results (Table 1).19 Whereas aryl, alkenyl, and secondary alkyl (Procedure B, Scheme 15). borane derivatives resulted in exclusive migration of the desired These mentioned processes were rendered asymmetric boron substituent, hexynyl and cyclopropyl groups resulted in by the use of the enantiopure sulfonium salt 49.20 In all cases, exclusive migration of the boracycle and primary alkyl groups essentially complete enantio- and diastereoselectivity was gave mixtures of both. The main factors responsible for the observed, with a very high Z selectivity (Table 2). The chiral outcome of the reaction are the conformations of the different sulﬁ de was also re-isolated routinely in greater than 90% yield. intermediate ate complexes and the barriers to interconversion With less electron-rich vinyl groups (entries 3–5), yields were between them (Scheme 14). lower due to competing migration of the boracycle. The reactions of alkenyl 9-BBN derivatives with sulfur Procedure B was also applied to the same range of ylides provided a unique asymmetric route to α,γ-substituted vinyl boranes and chiral sulfonium salt 49 (Table 3). Again,

BF4 1. (i) LiHMDS Me2N S OH O (ii) BPh3 Me Ph Ph O 2. H2O2, NaOH

52 53 63% yield, neobenodine 96% ee

BF R 4 N S 1. (i) LiHMDS NH2 (ii) BPh 3 N Cl Ph O . 2. BEt3, Me2S BH3 Cl Ph 3. H2NOSO3H Cl 54 55 63% yield, cetirizine 96% ee

Scheme 13. Application of ylide methodology to the synthesis of pharmaceuticals containing diaryl methanols and diaryl methylamines.

Table 1. Outcome of the 1,2-metallate rearrangement ate complexes resulting from the 9-BBN derivatives.

R OH BF4 1. LiHMDS, B − °C OH S + Ph + Ph 2. − °C H Ph R to r.t. HO 3. H O , 596 57 2 2 58 5 NaOH

Entry R Yield 58 Yield 59

1 Hexyl 56% 41% 2 Allyl 51% 39% 3 Benzyl 51% 35% 4 i-Pr Trace 77% 5 Cyclopropyl 89% Trace 6 Ph Trace 94% 7 1-Hexenyl Trace 21% 8 1-Hexynyl 92% Trace

Scheme 14. Origin of the selectivity in the migration of the boron substituent essentially complete enantio- and anti-diastereoselectivity was or boracycle in boronate complexes derived from sulfur ylides. observed with a high Z selectivity. As procedures A and B share common borate intermediates, the competing migration of the boracycle previously observed with less electron-rich vinyl boranes led to lower yields again (Table 3, entries 3, 4). The This work was applied to the synthesis of (+)- observed complete selectivity in the allyl borane isomeriza- iso-agatharesinol 66.17 The key ylide addition, 1,2-metallate tion when following procedure B is consistent with a highly rearrangement, and trapping with the aldehyde occurred in stereoselective, intramolecular 1,3-borotropic rearrangement 72% yield and with >99% ee giving (+)-iso-agatharesinol pre- process. The preferred isomer results from the minimization of cursor (+)-65 (Scheme 16). This allowed the unambiguous A1,3 strain21 in the conformations required for the borotropic assignment of the relative and absolute stereochemistry of the rearrangement to occur. natural product.

BF4 1. LiN(SiMe ) , CH Cl , Ph nBu Procedure A 3 2 2 2 OH − °C, 2 h PhCHO, − °C 96% yield, S B Ph anti:syn >25:1, Ph 2. − °C Ph nBu Z:E = 16:1 nBu B 56 60 61

°C

B = 9-BBN Ph nBu Procedure B OH 79% yield, PhCHO, − °C B Ph anti:syn >25:1, Ph nBu Z:E = 10:1

62 63

Scheme 15. Synthesis of isomeric homoallylic alcohols by lithiation-borylation reaction of sulfur ylides.

Table 2. Asymmetric synthesis of homoallylic alcohols. 1. LiN(SiMe ) BF 3 2 4 − °C THF, CH Cl , Ph R S Ph 2 2 PhCHO OH 30 min B − °C Ph O − 2. °C Ph R R B 49 60 61

Entry R Yield 61 (%) Z : E Anti : syn ee (%)

1 nBu 79 15 : 1 >95 : 5 >99 2 Me 81 40 : 1 >95 : 5 >99 3H 61 >40 : 1 >95 : 5 >99

4 TMSOCH2 61 >40 : 1 >95 : 5 >99

5 AcOCH2CH2 72 >40 : 1 >95 : 5 >99

Table 3. Synthesis of homoallylic alcohols with 1,3-transposition of allylic borane.

BF4 1. LiN(SiMe3)2 − 78 °C Ph R S Ph THF, CH2Cl2, OH 30 min PhCHO B Ph O 2. −100 °C −78 °C R Ph R B 49 3. 0 °C 62 63

Entry R Yield 63 (%) Z : E Anti : syn ee (%)

1 nBu 81 10 : 1 >95 : 5 >99 2 Me 76 30 : 1 >95 : 5 >99

3 TMSOCH2 49 >30 : 1 >95 : 5 >99

4 AcOCH2CH2 56 13 : 1 >95 : 5 >99

24 BF4 benoids. However, in contrast to reaction with organomag- OH Ar1 S 1. LiHMDS, THF-CH2Cl2, nesium reagents they found that sulfoxide ligand exchange −78 °C, 30 min OTBS with alkyl lithium reagents gave a lithium carbenoid that O 2. −100 °C Ar1 Ar2 underwent chain extension of catechol and neopentyl glycol Ar2 boronic esters with considerably higher levels of stereochemical B control (Scheme 18).25 64 (+)-665 3. TBSOCH2CHO 72%, >99% ee

OH nBuLi O 1 or R -B 1 OH O Ph Ph R 1. LiBH4 EtMgCl O B(neo) S M p-Tol 2. TBAF (+)-666 THF, −78 °C Bn Cl Cl H 81% 1 Cl −78 °C Ar = p-PivOC6H4 e.e. >98% M = Li or MgCl R1 =Ph,nBu, 2 Ar = p-TBSOC6H4 OH OH Ph(CH2)2, c-hex Scheme 16. Synthesis of (+)-iso-agatharesinol. R1 R1 Ph NaOH R1 Bn B(neo) Bn OH H H O H The reactions of sulfur ylides with boranes are limited to 2 2 OH aryl substituents: alkyl- and silyl-substituted ylides give low RLi = 67-86% yield, 82-96% ee enantioselectivity. In the case of the latter ylides, it was EtMgBr = 9-56% yield, 59-82% ee found that ate complex formation was reversible and the Scheme 18. Homologation of boronic esters with lithiated alkyl chlorides. migration step was now the selectivity-determining step (Scheme 17).22

OTf The process mentioned earlier showed good substrate scope in the range of boronic esters that could be employed S SiMe3 OH (i) LiHMDS, THF, −78 °C (primary or secondary aliphatic; pinacol or neopentyl glycol) Bu3B O Me3Si Bu (ii) H2O2,NaOH leading to secondary alcohols in 82–96% ee. The scope in 20% ee terms of the chiral organometallic was more limited: although

primary aliphatic substrates worked well (Bn, Et, i-Bu, BnCH2), Scheme 17. Lithiation-borylation reaction of trimethylsilyl-stabilized sulfur secondary (i-Pr, 0% yield) and methyl (23% yield, 60% ee) ylides. were less effective.26 This work was extended to iterative stereospecifi c reagent- A signifi cant limitation of the sulfur ylide reactions is that controlled homologations. Alkyllithium-effected sulfoxide the outcome with nonsymmetrical boranes is highly dependent ligand exchange using t-BuLi in toluene of enantioenriched on the substituents on boron. A potential solution to this α-chloroalkyl sulfoxide 68, prepared by chlorination of sulfox- problem is to use boronic esters. Unfortunately, boronic esters ide 67, gave the enantioenriched lithiated carbanion 69 that do not react with sulfur ylides. They are much less electrophilic was reacted with boronic ester 70 to give the homologated and the barrier to migration is considerably higher.19,23 With boronic ester 71. One carbon chain extension followed by relatively stable anions like aryl-stabilized sulfur ylides, addi- treatment with the organolithium 69 then gave alcohol 72, tion may occur but the high barrier to migration results in after oxidation, as an 79 : 21 mixture of diastereoisomers reversibility in the ate complex formation and ultimately in which the major isomer was formed with >99 : 1 er. This decomposition of the ylide.19 To carry out reagent-controlled protocol was then used to prepare all four diastereoisomers additions and subsequent 1,2-metallate rearrangements with of alcohol 72 from boronic ester 70 by sequential reaction boronic esters requires a less stable carbanion that possesses a with the required enantiomer of carbanion 69/ent-69, good enough leaving group. (dichloromethyl)lithium, and carbanion 69/ent-69 followed by oxidative work-up (Scheme 19).26 It should be noted that when enantiomerically enriched components are coupled Chiral Carbanions of Lithiated Alkyl Chlorides together the enantiomeric ratio of the desired product is enhanced but at the expense of formation of diastereomeric Blakemore et al. have developed the homologation of boronic by-products. This occurs through a statistical amplifi cation esters using enantioenriched Hoffmann-type magnesium car- process fi rst reported by Horeau.27

Bn B(pin) NCS O Bn Bn O K2CO3 tBuLi Li Bn 70 (pin)B Bn 1. LiCH2Cl S Bn O O S Bn Ar B Bn Ar 2eq. Cl Bn 2. 69 OH Cl Bn Bn Cl 3. H2O2 67 68 69 71 (R,R)-72 38% Yield 1. 69 or ent-69 99:1 er, 79:21 dr Bn Bn Bn Bn Bn Bn 2. LiCH2Cl Bn B(pin) OH orOH or OH 3. 69 or ent-69 Bn Bn Bn 4. H2O2 70 (R,S)-72 (S,S)-72 (S,R)-72 97:3 er, 99:1 er, 99:1 er, 81:19 dr 76:24 dr 80:20 dr

Scheme 19. Iterative boronic ester homologation with lithiated alkyl chlorides.

Chiral Carbanions of Lithiated Carbamates This type of reaction was recently applied by Kocienski in the synthesis of (S)-(−)-N-acetylcolchinol 85 (Scheme 21).29 An alternative to lithiated chlorides are the more stable lithi- Along with the stepwise reaction (Scheme 21, path A), Kocien- ated carbamates. Hoppe et al. have shown that borate ester 75, ski also showed that a chiral lithiated carbamate could react derived from the corresponding carbamate 73 by asymmetric directly with B-aryl-pinacol boronic ester 82 (Scheme 21, path lithiation and borylation, reacted with Grignard reagents to B). However, to achieve rearrangement required exchange of give, after oxidation, secondary alcohols 78 in good yield and solvent, addition of magnesium bromide, and heating to 80°C. 28 high ee. This showed that the carbamate group was a good Notably, this direct reaction of boronic ester 82 with lithiated enough leaving group in the 1,2-metallate rearrangement carbamate 80 gave alcohol 84 in higher yield and excellent of boronic ester ate complexes 76, although it was probably enantiomeric ratio. facilitated by the magnesium bromide present in the reaction (Scheme 20). Direct reaction of Lithiated Carbamates with Boronic Esters and Boranes sBuLi H H O (−)-sparteine N N Aggarwal et al. have shown that the direct reaction of i Ph O N Pr2 − lithiated carbamates with boranes and boronic esters shows Et2O, 78 °C Li O R1 considerable scope and therefore potential for synthesis i H O N Pr2 (Table 4). In all cases high enantioselectivities were observed 73 74 (er 95 : 5–98 : 2).30,31 A number of points worthy of note:

i 1. B(O Pr)3 O O 2 1. In contrast to the reactions of sulfur ylides with 9-BBN Et O, −78 °C O B O R2MgBr, −78 °C R B O 2 1 R 1 derivatives, reaction with lithiated carbamates resulted in 2. pinacol, p-TsOH i R H O N Pr2 H OCb clean migration of the boron substituent rather than the MgSO4,CH2Cl2 32 75 76 boracycle in all cases. This is highly unusual and has only (90%, e.r. >98:2) (90%, er >98:2) previously been observed with halide leaving groups, sug- gesting that the carbamate should also be considered as a

2 2 1 small substituent in these types of reaction. R R R =(CH2)2Ph warm 1 H O 1 R 2 2 R i 2. In the case of B-Ph-9-BBN, higher er was obtained in the OCb = C(O)N Pr2 H Bpin THF, r.t. H OH R2 =Pr,iPr, tBu, c-Hex presence of magnesium bromide (entries 4 vs. 5, Table 4), 77 78 whereas in other cases involving aliphatic groups magne- 50-70% yield, er 98:2 sium bromide was not found to be necessary. It is believed that magnesium bromide sequesters the diamine ligand Scheme 20. Hoppe-type alkylation of boronic esters by carbamate lithiation/borylation and subsequent nucleophile triggered 1,2-metallate preventing it from binding to the borane. Binding of the rearrangement. diamine to benzylic boranes results in an erosion in er.

MgBr

O sBuLi (1.2 eq), B OiPr O O (−)-sparteine (1.2 eq), O OTBS B MeO − Li − O O OCb Et2O, 78 °C 78 °C B Et2O, r.t. MeO

MeO OCb A A OCb MeO OMe 79 80 OMe 83 OTBS

B(Pin) − i. ii. MgBr2,(1.2eq), 78 °C 82 iii. 80 °C

OTBS Et2O, r.t.,

MeO OH MeO MeO H O ,KCO ,H O, r.t. A 51% yield (over 2 steps) 2 2 2 3 2 − 94:6 er (S)-( )-N-Acetylcolchinol MeO MeO 85 B 65% yield OMe OTBS 98:2 er NH 84 O HO Scheme 21. Synthesis of (S)-(−)-N-acetylcolchinol.

Table 4. Direct reaction of boronic ester with enantioenriched lithiated carbamates.

R2 N N 2 3 3 2 2 H H sBuLi 1. R B(R )2 B(R )2 R 1. warm R R1 R1 R1 R1 OCb − Li O 3 Et2O, 78 °C 2. Lewis Acid OCb H B(R )2 2. H2O2 OH − R1 H H ( )-sparteine i H O N Pr2 86 74 87 86 89

1 2 3 Entry R R (R )2 Lewis acid Yield 89 (%) er

1 Ph(CH2)2 Et Et2 — 91 98 : 2 2 nHex 9BBN — 90 98 : 2 3 iPr 9BBN — 81 98 : 2 4 Ph 9BBN — 85 88 : 12

5 Ph 9BBN MgBr2 94 97 : 3

6 Et Pinacol MgBr2 90 98 : 2

7Me2C¨CH(CH2)2 Et Et2 — 90 97 : 3

8 Ph 9BBN MgBr2 71 95 : 5

9 Et Pinacol MgBr2 75 97 : 3

10 Ph Pinacol MgBr2 73 98 : 2

11 TBSO(CH2)2C(Me)2 Et Et2 — 67 95 : 5

12 CH2 Ph 9BBN MgBr2 65 97 : 3

13 Ph Pinacol MgBr2 64 98 : 2

14 iPr Ph 9BBN MgBr2 68 96 : 4

15 Ph Pinacol MgBr2 70 98 : 2

16 Me Ph Pinacol MgBr2 70 97 : 3

Scheme 22. Synthesis of all four stereoisomers of alcohols 96 and 97.

3. 1,2-Metallate rearrangement of ate complexes is much the chiral lithiated carbamate is effectively blind to the stereo- slower in the case of boronic esters compared to boranes chemistry of the chiral boronic ester. Thus, the outcome of the and required magnesium bromide in diethyl ether at refl ux reaction is completely controlled by the chiral reagent and is in the former case whereas the ate complexes derived not infl uenced by the inherent chirality of the substrate. The from boranes began to rearrange at −40°C without further enantiomeric pair to alcohols 96 and 97 were obtained with additives. similar diastereo- and enantioselectivities using the same pro- 4. A broad range of alkyl carbamates including methyl, tocol but from the enantiomer of boronic ester ent-94, which primary, and branched secondary alkyl chains can be was obtained using O’Brien’s sparteine surrogate (+)-91 in the employed together with a broad range of aryl and alkyl fi rst homologation (Scheme 22). As was the case in the iterative boranes and boronic esters. The methodology therefore homologations of Blakemore et al. (Scheme 19),26 statistical shows considerable substrate scope. enhancement of enantiomeric excess27 further increases the 5. Reactions of lithiated carbamates with both the boranes enantiopurity of alcohols 96 and 97. and boronic esters occurred with retention of confi guration The asymmetric lithiation-borylation and 1,2-metallate (74Æ87, Table 4). This is probably because the non- rearrangement has also been applied to N-linked benzylic and stabilized anion is sp3 hybridized and as such there is little cyclic carbamates (Scheme 23).35 However, the poorer leaving- electron density opposite the metal. group ability of the N-linked carbamate limited the scope of the methodology to boranes and even then a strong Lewis Extension of this methodology to iterative homologations acid (TMSOTf) was required to trigger the 1,2-metallate was demonstrated by the synthesis of all four stereoisomers of rearrangement. alcohols 96/97 (Scheme 22). Lithiation of carbamate 92 in the presence of (−)-sparteine and trapping with EtB(pinacol) gave boronic ester 94 in 78% yield and 98 : 2 er. Reaction Conclusions and Future Outlook of boronic ester 94 with lithiated carbamate 95a gave, after oxidative work-up, alcohol 96 as a 96 : 4 mixture of diastereo- The asymmetric homologation of boronic esters is a powerful isomers and with an enantiomeric ratio of >98 : 2 for the major method for the stereocontrolled synthesis of substituted carbon diastereomer. The diastereomeric alcohol 97 was prepared by chains. It can be conducted using either substrate or reagent reaction of boronic ester 94 with the enantiomer of lithiated control. In the substrate-controlled process the key step involves carbamate 95b, prepared using O’Brien’s sparteine surrogate the addition of (dichloromethyl)lithium to a chiral diol-derived (+)-9133,34 in place of (−)-sparteine 90, in similarly high dia- boronic ester and subsequent 1,2-metallate rearrangement. stereo- (94 : 6 dr) and enantioselectivities (er >98 : 2; Scheme This rearrangement is highly diastereoselective when con- 22). The absence of matched/mismatched pairs indicates that ducted in the presence of zinc chloride. The (α-chloro)boronic

(i) nBuLi, BR Boc − 3 Ar N ( )-sparteine, − Boc R 78 °C Ar N TMSOTf H2O2,NaOH R 62-83% Yield 92:8 to 95:5 er (ii) BR3 25 °C Ar BR2 Ar OH

1. (i) sBuLi, (−)-sparteine (ii) R B, TMSOTf, −78 °C R R = Et, 58% Yield, 95:5 er 3 HN N Boc OH R=nBu, 59% Yield, 92:8 er Boc 2. NaOH, H2O2,25°C

1. (i) sBuLi, (−)-sparteine − R (ii) R3B, TMSOTf, 78 °C R = Et, 67% Yield, 97:3 er N H OH R=nBu, 64% Yield, 96:4 er 2. NaOH, H2O2,25°C N Boc Boc

Scheme 23. Secondary alcohol synthesis by lithiation–borylation of benzylic N-linked carbamates.

ester that is formed is subsequently reacted with a Grignard ents of specifi c stereochemistry. They therefore offer the great- reagent, or other nucleophile, to give a secondary alkyl boronic est versatility and fl exibility in the homologation of boranes ester stereospecifi cally. The reactions show considerable scope and boronic esters. and have been applied in synthesis. It is especially suited to the synthesis of α-amido boronic esters, a class of protease I am indebted to my dedicated team of coworkers who have inhibitors now used on the clinic, where it has been utilized contributed practically and intellectually to the development on considerable scale.36 Considering the practicality of the of our research programme. V. K. Aggarwal thanks the Royal process it is somewhat surprising that the methodology has Society for a Wolfson Research Merit Award and the EPSRC not been employed more widely. It is not clear whether this for a Senior Research Fellowship. We also thank EPSRC and is because of reports that occasionally the intermediate ate Merck for generous research support. complex undergoes O-migration instead of C-migration or because specifi c stereoisomers could only be made through a rather diffi cult and lengthy exchange of diol ligands. REFERENCES In the reagent-controlled processes, chiral sulfur ylides [1] (a) Brown, H. C.; Singaram, B. Pure Appl Chem 1987, 59, have been found to react with boranes giving homologated 879; (b) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; products with high ee but reactions are limited to aryl- Academic Press: New York, 1988; (c) Kaufmann, D. E.; stabilized ylides. A further limitation is that sulfur ylides only Matteson, D. S., Eds. Science of Synthesis: Vol. 6, Boron react with boranes. Nevertheless, reactions with alkenyl 9-BBN Compounds; Georg Thieme Verlag: Stuttgart-New York, derivatives provide a unique entry to α,γ-substituted allylic 2004; (d) Matteson, D. S. Stereodirected Synthesis with boranes that are important intermediates in stereoselective Organoboranes; Springer: New York, 1995, pp. 162–220; synthesis. α-Chloroalkyllithiums are considerably more reac- (e) Crudden, C. M.; Edwards, D. Eur J Org Chem 2003, tive and less stable than sulfur ylides and consequently react 2003, 4695–4712; (f) Hall D. G. In Boronic Acids. Hall, D. with boronic esters. They can be used iteratively but suffer G., Ed. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, from somewhat limited scope in the nature of the alkyl group Germany, 2005, pp. 1–85. that can be used (not methyl or β-branched). The reagents with [2] (a) Brown, H. C.; Zweifel, G. J Am Chem Soc 1961, 83, 486; (b) Zweifel, G.; Brown, H. C. J Am Chem Soc 1964, 86, the greatest scope are Hoppe’s lithiated carbamates: a broad 4393. range of alkyl carbamates can react with a range of alkyl and [3] (a) Matteson, D. S.; Ray, R. J Am Chem Soc 1980, 102, aryl boranes and boronic esters. As chiral carbanions are derived 7590–7591; (b) Matteson, D. S.; Ray, R.; Rocks, R. R.; Tsai, from simple primary alcohols, access to these chiral reagents is D. J. S. Organometallics 1983, 2, 1536–1543. (c) Matteson, especially facile. Furthermore, they can be used iteratively thus D. S.; Sadhu, K. M. J Am Chem Soc 1983, 105, allowing carbon chains to be grown interspersed with substitu- 2077–2078.

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