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Homologation and Alkylation of Boronic Esters and Boranes by1,2-Metallate Rearrangement of Boron Ate Complexes

Citation for published version:Thomas, SP, French, RM, Jheengut, V & Aggarwal, VK 2009, 'Homologation and Alkylation of BoronicEsters 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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https://doi.org/10.1002/tcr.20168

https://doi.org/10.1002/tcr.20168


© 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.24

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

STEPHEN P. THOMAS, ROSALIND M. FRENCH, VISHAL JHEENGUT, VARINDER K. AGGARWALSchool 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 ste-reochemistry. 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

The Chemical Record, Vol. 9, 24–39 (2009)

T H E C H E M I C A L

R E C O R D

� Correspondence to: Varinder K. Aggarwal; email: [email protected]

Introduction

Organoboranes and boronic esters are very useful synthetic intermediates as they can be converted into a broad range of functional groups, often with complete stereospecifi city.1 These transformations are usually initiated by nucleophilic addition to the electrophilic boron atom followed by 1,2-migration. Among all the metals and semimetals, boron seems to possess a unique ability to orchestrate these processes cleanly and with 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-

pheylborane by H. C. Brown in 1961 provided the fi rst non-enzymatic asymmetric synthesis that resulted in truly practical levels of enantioselection.2 In the early 1980s Matteson reported a complementary route to chiral boronic esters.3 In fact, the discoveries by Matteson that very high diastereoselectivities could be achieved in: (i) reactions of (dichloromethyl)lithium with boronic esters, and (ii) reactions of Grignard reagents

H o m o l o g a t i o n o f B o r o n i c E s t e r s

25© 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

� 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. �

with (α-haloalkyl)boronic esters opened up a whole new fi eld in organoboron chemistry.4

In Matteson’s approach, a chiral auxiliary is embedded in the diol moiety of the boronic ester and subsequent transfor-mations are controlled by its architecture (substrate control; Scheme 1). An alternative approach uses a chiral reagent to construct a related chiral ate complex that subsequently evolves into the chiral boronic ester following 1,2-metallate rearrange-ment (reagent control; Scheme 1). These two approaches are discussed in this review.

Homologation–Alkylation of Chiral Boronic Esters: Substrate Control

Reaction of an enantiopure boronic ester 1 with (dichloromethyl)lithium forms (dichloromethyl)borate complex 2. In the presence of zinc chloride, borate 2 rearranges via transition structure (TS) 3 leading to a single α-chloroboronic ester 5 with a high diastereomeric purity, often >99 : 1 dr (Scheme 2). It has been proposed that in the preferred TS 3 zinc chloride promotes and directs the

� 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. �

R1 B

OR*

OR*

B

OR*

OR*R1

ClB

OR*

OR*R1

Cl

R2

R2 B

OR

OR

R1 LG

M

B

OR

ORR1

LG

R2

B

OR*

OR*R1

R2

LiCHCl2

∗ ∗

∗

∗

∗

Substrate control

Reagent control

1,2-Metallate rearragement

LG = leaving group

R2M

-MCl

-LiCl

-MLGM

M

Scheme 1. Complementary routes to homochiral organoboranes involving 1,2-metallate rearrangement.

© 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

T H E C H E M I C A L R E C O R D

26

migration of R1 by complexation to the less hindered oxygen atom of the boronic ester while simultaneously assisting the departure of a chloride ion.3c It is also believed that this TS is further stabilized by an interaction between the chloride of zinc

chloride (which becomes more nucleophilic in the TS) and the C-H bond (which becomes more electrophilic in the TS as the chloride leaves).5 No such interaction can occur in the migra-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. �

Cl

H

Cl

B O

O

R

R

Zn

Cl

Cl

R1

Cl

Cl

H

B O

O

R

R

Zn

Cl

Cl

R1

Favoured

4

Disfavoured

BR1 OBO

R

R

R1

Cl

Cl

H

THF, − °C

B

Cl

ZnCl2

r.t.

B

R2

R1

LiCHCl2

R1

21

58

3

O

O

O

O

O

O R

R

R

R

R

R

OBO

R

R

R1

Cl

Cl

HZnCl2

Cl

H

R1

BO

O

R

R

M

X

X

R2

6

OBO

R

R

R2

Cl

R1

H

OBO

R

R

R2

Cl

R1

HMX2

7

3

7

Scheme 2. Matteson homologation–alkylation sequence.



disfavored (TS 4). Indeed, Midland has calculated that there is a 12.6 kcal mol−1 difference between the two TSs.6

Reaction of the α-haloboronic ester with a Grignard or organolithium reagent gives intermediate borate 6 that is analogous to intermediate borate 2. However, in this case the reaction is stereospecifi c as the migrating group has to align anti-periplanar to the leaving group (TS 7, Scheme 2). Never-theless, it is rather fortuitous that with this particular diaste-reoisomer the features required for the smooth 1,2-metallate rearrangement (chelation of the metal to the less hindered oxygen, binding of the leaving group to the metal and the stabilizing interaction between the halide and the C-H bond) are all still present. However, this is not always the case (see further discussion).

A number of signifi cant observations have been made by Matteson4c over the course of his investigations that are sum-marized in the following.

1. Boronate complexes do not rearrange at low tempera-ture (e.g., −78°C). This prevents multiple insertions of (dihalomethyl)lithium as any excess reagent decomposes before the homologated boronic ester has been formed.

2. The electrophilic nature of the boron atom results in an effi cient ate-complex formation. This inhibits side reactions such as β-elimination.

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 sequester free chloride, thus inhibiting the slow epimeriza-tion of the product by free chloride.

4. Boronic esters bearing β-halides, or other weakly basic func-tions, are not stable with respect to elimination of the halide and the boronic ester group.

5. C2-symmetric boronic esters, for example, 1, are generally more stereoselective than boronic esters derived from pinanediol as they lead to the same diastereomeric ate complex when starting from the α-(dichloromethyl)boronic ester and reacting with an organometallic reagent as when starting from the corresponding boronic ester and reacting with (dichloromethyl)lithium (Scheme 3). In contrast, pinanediol boronic esters give different diaste-reomeric ate complexes that show very different levels of stereocontrol in the subsequent migration. In order to achieve good diastereoselectivity the migrating group must be present on the pinanediol boronic ester before the addition of (dichloromethly)lithium. In contrast, poor levels of stereocontrol are observed when pinanediol (dichloromethyl)boronate is reacted with an organometallic species.7

6. Alkoxy groups (OBn, OPMB, OCPh3) and nitrides are well tolerated at both α- and β-positions in sequential homolo-gations. Halide, carbonyl, thioether, and cyano substituents

are compatible, but there must be at least two carbons between the functional group and the boron centre other-wise β-elimination results.

7. Suitably protected α-amino boronic esters and α-azido boronic esters are tolerated under certain reaction conditions.

8. A wide range of nucleophiles, including RMgX, RLi, RO−, RS−, R2N−, N3

−, and LiCH2CN, have been shown to undergo stereospecifi c 1,2-metallate rearrangement.

Applications of Matteson-Type Homologation–Alkylation in Synthesis

Matteson has elegantly demonstrated the potential of this homologation/alkylation methodology in the synthesis of numerous natural products. This is illustrated in the concise synthesis of japonilure 14, a Japanese beetle pheromone.8 Reaction of boronic ester 10 with (dichloromethyl)lithium gave the (α-chloro)boronic ester 11 as a single diastereoisomer. Subsequent treatment with lithiated alkyne 12 gave, after 1,2-metallate rearrangement, boronic ester 13 that was readily converted to Japonilure 14 (Scheme 4).

Matteson further applied the homologation/alkylation methodology to the fi rst total synthesis of the epimerically labile pheromone (2S,3R,1’R)-stegobinone 20 (Scheme 5).9 The two key synthetic components—aldehyde 18 and alcohol 19—used in this synthesis were prepared from a common boronic ester 17. Reaction of ethyl boronic ester 15 with (dichloromethyl)lithium followed by alkylation with sodium benzoxide gave the substituted boronic ester 16 that was converted into the common boronic ester 17 through a similar sequence. This was then subjected to a further (dichloromethyl)lithium homologation, and either oxidation to give aldehyde 18 or methyl magnesium chloride alkylation and oxidation to give alcohol 19.

BR

1

O

O

R

R

BCl2HCO

O

R

R

BO

O

R

R

R

3

R BO

OH

BO

OH

R

BO

OH

RB

O

OH

LiCHCl2

LiCHCl2 RLi

RLi

BO

OH

BO

OH

R

R

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Cl

Highdr

Lowdr

Scheme 3. Effect of order of addition of reagents to different boronic esters.



28

Hoffmann has completed a number of natural product syntheses (e.g., erythronylide) using the Matteson-type homol-ogation/alkylation methodogy to prepare chiral allylic boronic ester 21.10 Reaction of this boronic ester with chiral/achiral aldehydes usually proceeds with very high levels of stereocon-

trol. Even the mismatched case shown in Scheme 6 gave good levels of stereoselctivity.

O

B O

tBuCO2

Cy

CyHO

HOO

B O

tBuCO2

Cy

Cy

LiCHCl2

ZnCl2

OB

O

Cy Cy

Cl

LiC8H17

OB

O

Cy Cy

C8H17

O

O

C8H17

Japonilure

019

11 13

14

94%

79% 97%

tBuCO2H

H

H

1. H2O2

2. H2, Lindlar cat.

tBuCO2

12

Scheme 4. Synthesis of Japonilure.

1. LiCHCl2, ZnCl2O

BO

Cy

Cy

1. LiCHCl2, ZnCl2

2. NaOBn

O

BO

Cy

Cy

BnO

O

BO

Cy

Cy

Me

BnO

2. H2O2, NaOHH

BnO

Me

O

1. LiCHCl2, ZnCl2

OH

2 CH3MgCl

2. CH3MgCl

Me

Me

BnO

O

Me

O

O

(2S,3R,1'R)-Stegobinone

3. H2O2, NaOH

19

1817

20

1615

1. LiCHCl2, ZnCl2

Scheme 5. Synthesis of the two key intermediates used in the fi rst total synthesis of (2S,3R,1′R)-stegobinone.

OH

O

BO

Cy

Cy1. LiCH3, ZnCl2

2.Cl

ClLi

O

BO

Cy

Cy

21

O1.

2. PMBCl3. OsO4

4. NaIO4

PMBO O PMBO OHPMBO

80 : 16

21

Scheme 6. Synthesis and application of allyl boronates generated by Matterson homologation.

Armstrong has shown that the high levels of stereoselectiv-ity observed for the homologation/alkylation reaction of pinanediol-derived boronic esters can be used to great effect in 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 alcohol 22 with excellent stereocontrol over the three con-tiguous stereocentres (Scheme 7).

Davoli et al. used multiple Matteson-type homologation–alkylation reactions in the synthesis of (−)-microcarpalide 25.12 Using two boronic esters derived from the opposite enantio-mers of pinanediol, successive (dichloromethyl)lithium homol-ogations and 1,2-metallate rearrangements of both carbon and oxygen nucleophiles were used for the synthesis of intermediates 23 and 24 with excellent diastereoselectivity (Scheme 8).

Different diastereoisomers of a compound can usually be prepared by simply altering the order of addition of the com-ponent reagents as demonstrated in the synthesis of the phero-mone 33 of the elm bark tree beetle Scolytus multistriatus and an epimer 29. They were synthesized via diastereomeric inter-mediates 27 and 31 (Scheme 9).13 It should be noted that obtaining the different alcohol stereochemistries at C-3 in 29 and 33 required the (R,R) and (S,S) boronic ester diol stereochemistries, respectively. However, to obtain the (S)-stereochemistry at C-4 in both 27 and 31 required both a different addition sequence of nucleophiles and different enantiomeric chiral diols.

Limitations of the Matteson-type Homologation–Alkylation

Although a powerful transformation, Matteson’s homologation–alkylation sequence suffers from a number of



minor drawbacks. Occasionally, diastereomeric ate complexes do not behave in the same way. For example, although ate complex 34 uneventfully evolved to the homologated boronic ester 36, its diastereoisomer 37 did not. In this case, instead of the standard C-migration, contra-thermodynamic O-migration occurred to give borinic ester 41 (Scheme 10).13 Evidently, the TS required for C-migration 38, which suffers from both a loss of the stabilizing interaction between the halide and C-H bond, and steric clash between the benzyl group and the magnesium halide substituent, must be strongly 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 displacement, and halide–CH interaction) but now has the oxygen antiperiplanar to the departing chloride and so this group migrates instead.

Although it is often possible to obtain opposite stereoiso-mers simply by changing the order of addition of reagents (see Scheme 9), occasionally this is not possible and a three-step sequence to invert (by exchange) the boronic ester diol stereochemistry is required. In the synthesis of mono-protected diol 48, an epimer of the diol used in the total syn-thesis of stegobinone (see Scheme 5), the (R,R)-diol 44 is required to “control” the stereochemistry of the ether stereo-genic centre of 45 and the (S,S)-diol ent-44 is needed for the subsequent homol ogation and methylation of boronic ester 46 (Scheme 11).14 Therefore, iterative homologation sequences may sometimes require additional steps to change the stereochemistry of the diol of the boronic ester prior to homologation.

Although highly successful for the synthesis of second-ary alcohols,4f,h 1,2-metallate rearrangement of boron-ate complexes have had limited success for the synthesis of tertiary alcohols as variable levels of selectivity were obtained and even the sense of asymmetric induction was unpredictable.15

Me BO

OH

BO

OH

1.LiCHCl2, ZnCl2

2. MgBrMe

1.LiCHCl2, ZnCl2

2. LiOPMBB

O

OH

PMBO

Me1.LiCHCl2, ZnCl2

2. MgBr OTBS

BO

OH

PMBO

Me

TBSO

1.LiCHCl2, ZnCl2

2. NaHB(OMe)3

3. H2O2, NaOH

OTBS

Me

PMBO

OH

22

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

n-C6H13 BO

O

LiCHCl2

64%

BO

On-C6H13

Cl

1. LiOBn, 70%

2. LiCHCl2, 61%

B

O

On-C6H13

Cl

BnO

1. AllylMgBr, 74%

2. H2O2, NaOH, 90%

OHn-C6H13

BnO

BO

O

2. LiOBn

44% (2 steps)

OBn

CO2tBu

2. VinylMgBr

44% (2 steps) CO2tBuBnO

1. H2O2, NaOH, 89%

2. NaH, BnBr, 48%

CO2H

BnO

BnO

BO

OB

O

O

+

3. TFA, CH2Cl2, 100%

OO

OH

OH

n-C6H13

OH

(−)-Microcarpalide

23

2425

1. LiCHCl2

1. LiCHCl2

CO2tBu

Scheme 8. Synthesis of (−)-microcarpolide.



30

Homologation–Alkylation of Boronic Esters and Boranes using Chiral Carbanions: Reagent Control

In the previous section we discussed the use of boronic esters derived from chiral diols and their subsequent homologation with achiral organometallic reagents. In that section, newly formed stereogenic centers were controlled by the diol archi-tecture (substrate control). The following section describes the reactions between chiral carbanions bearing potential leaving

groups with achiral boronic esters (reagent control). In this case, chirality is embedded in the reagent and so is comple-mentary to the Matteson approach described earlier.

Chiral Carbanions Derived from Sulfur Ylides

Ylides represent a class of carbanions with leaving groups attached directly to the carbanion. In reactions of boranes with different ylides (sulfur-, nitrogen-, and phosphorus ylides),

B

O

OB

O

O

CH3

B

O

O

CH3

CH3

OH

CH3

H3CB

O

OB

O

O

CH3

CH3

OH

CH3

B

O

O

CH3

1. (i) LiCHCl2 (ii) ZnCl2

2. H3CMgBr


2. EtMgBr



2. EtMgBr

H2O2, NaOH

26

30

2827 29

3231 33

2. nPrMgBr

34

34

(R,R)

(S,S)

H2O2, NaOH

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

PhB

Cl

O

O

B

O

O

Ph

H

MeMgBr

MeMgBr

MeMgBr

34 36

37

41

35

38

40

O BO

R

R

Me

Cl

BnH

Mg

ClH

Bn

BO

OMg

X

X

Me

Cl

Bn

H

BO

O

Mg

X

X

Me

X

X

ClBn

H

BO

OMg

X

X

Me

PhB

Cl

O

O

PhB

Me

O

O

PhB

Me

O

O

Me

39

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



sulfur ylides were found to behave optimally as they possessed the best balance of stability and leaving group ability.16 Furthermore, such reactions could be easily rendered asym-metric using chiral sulfonium salts such as 49 that had been previously developed for asymmetric epoxidation, aziridina-tion, and cyclopropanation reactions.17 Thus, reaction of an aryl-stabilized sulfur ylide, generated in situ by deprotonation of sulfonium salt 49, with triaryl, or trialkyl boranes gave the homologated boranes that were oxidized to the corresponding alcohols and amines 50 in high yield and high ee.18 The major enantiomer is formed from the favored conformation of the ylide 51 reacting on the less hindered face (Scheme 12).

The synthesis of the enantioenriched alcohol 52 and amine 54, intermediates in the synthesis of the anti-infl ammatory agents neobenodine 53 and cetirizine 55, respectively, demonstrated the potential of this methodology (Scheme 13).17

However, reactions with 9-BBN derivatives 57 gave mixed results (Table 1).19 Whereas aryl, alkenyl, and secondary alkyl borane derivatives resulted in exclusive migration of the desired boron substituent, hexynyl and cyclopropyl groups resulted in exclusive migration of the boracycle and primary alkyl groups gave mixtures of both. The main factors responsible for the outcome of the reaction are the conformations of the different intermediate ate complexes and the barriers to interconversion between them (Scheme 14).

The reactions of alkenyl 9-BBN derivatives with sulfur ylides provided a unique asymmetric route to α,γ-substituted

allylic boranes—compounds that had not been prepared previ-ously due to their high lability (Scheme 15).20 Reaction of the ylide derived from sulfonium salt 56 with vinylboranes at −100°C followed by the addition of benzaldehyde at the same temperature, and subsequent warming to room temperature gave the homoallylic alcohol 61 in 96% yield as a single anti-diastereoisomer with a high Z selectivity (Procedure A, Scheme 15). Using this protocol, the aldehyde trapped the allylic borane as it was formed, thus not allowing time for isomeriza-tion to occur. The high lability of these allylic boranes has also been exploited. If the intermediate allyl borane 60 was allowed to warm to 0°C, isomerization occurred to give the thermody-namically more stable allylic borane 62 that could be trapped with benzaldehyde at −78°C to give the isomeric alcohol 63 in high yield and with similarly high diastereoselectivity (Procedure B, Scheme 15).

These mentioned processes were rendered asymmetric by the use of the enantiopure sulfonium salt 49.20 In all cases, essentially complete enantio- and diastereoselectivity was observed, with a very high Z selectivity (Table 2). The chiral sulfi de was also re-isolated routinely in greater than 90% yield. With less electron-rich vinyl groups (entries 3–5), yields were lower due to competing migration of the boracycle.

Procedure B was also applied to the same range of vinyl boranes and chiral sulfonium salt 49 (Table 3). Again,

OB

OCy

Cy

Me

OBn

(97%, >20:1 dr )

1. NaOH (HOCH2)3C-R

2. H+

43

OB

OCy

Cy

Me1. LiCHCl2

2. LiOBn

42R = NH(CH2)3SO3

-

HOB

HO Me

OBn

OH

OH

Cy

Cy

+

44 4577%

HO OH

Cy Cy

OB

OCy

Cy

Me

OBn

(59%, >20:1 dr )

46

ent-44

B

OBnO

OCy

Cy

(79%, >20:1 dr )

2. MeMgBr

1. LiCHCl2OBnOH

4847

Scheme 11. Stereocontrol through change of boronic ester stereochemistry.

S

O

Ph

H

Et3B

Ph Et

BEt2S Ph

HBEt3

S

O

H

Ph

Et3B

Ph Et

BEt2S H

PhBEt3

ΔE = 4.37 kcal/mol

O

O

HH

51major

product

S

O

+ BR3Ph R

OH/NH2

BF4

(i) 1.2 eq. LiHMDS°C

0594

(ii) BR3

(iii) H2O2, NaOH or NH2OSO3H

68-73% Yield

95-97% ee

Scheme 12. Reactions of chiral sulfur ylides with organoboranes.



32

essentially complete enantio- and anti-diastereoselectivity was 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 observed complete selectivity in the allyl borane isomeriza-tion when following procedure B is consistent with a highly stereoselective, intramolecular 1,3-borotropic rearrangement process. The preferred isomer results from the minimization of A1,3 strain21 in the conformations required for the borotropic rearrangement to occur.

This work was applied to the synthesis of (+)-iso-agatharesinol 66.17 The key ylide addition, 1,2-metallate rearrangement, and trapping with the aldehyde occurred in 72% yield and with >99% ee giving (+)-iso-agatharesinol pre-cursor (+)-65 (Scheme 16). This allowed the unambiguous assignment of the relative and absolute stereochemistry of the natural product.

Ph

OMe2N

Ph

OH

Ph

NH2

Cl

N

RN

neobenodine63% yield, 96% ee

Cl

S

OMe

BF4

S

OCl

BF4

1. (i) LiHMDS (ii) BPh3

2. H2O2, NaOH

3525

1. (i) LiHMDS (ii) BPh3

2. BEt3, Me2S.BH3

3. H2NOSO3H

cetirizine

5545

Ph

63% yield, 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.

S

BF4

Ph R

OH

HO

Ph

1. LiHMDS, − °C

2. − °C to r.t.

3. H2O2, NaOH

+

OH

Ph H+

B

R

8565 9575

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% Trace6 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 or boracycle in boronate complexes derived from sulfur ylides.



Table 2. Asymmetric synthesis of homoallylic alcohols.

S

O

Ph

BF4

PhCHO

Ph

Ph

OH

R

1. LiN(SiMe3)2 − °C THF, CH2Cl2, 30 min

2. − °C

49 61

− °C

B

R

Ph R

B

60

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

1 nBu 79 15 : 1 >95 : 5 >992 Me 81 40 : 1 >95 : 5 >993 H 61 >40 : 1 >95 : 5 >994 TMSOCH2 61 >40 : 1 >95 : 5 >995 AcOCH2CH2 72 >40 : 1 >95 : 5 >99

S

Ph

BF4

B

nBu

Ph nBu

Ph nBu

B

Ph

Ph

OH

nBu

Ph

OH

Ph nBu

PhCHO, − °C

1. LiN(SiMe3)2, CH2Cl2,

2. − °C

PhCHO, − °C

96% yield,

79% yield,

Procedure A

Procedure B

°C

B

0665

3626

61

− °C, 2 h

Z:E = 16:1

anti:syn >25:1,

Z:E = 10:1

anti:syn >25:1,

B = 9-BBN

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

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

Ph

OH

Ph R

Ph R

−78 °C

3. 0 °C

B

S

O

Ph

BF4

PhCHO

1. LiN(SiMe3)2

−78 °CTHF, CH2Cl2,30 min

2. −100 °C

49 63

B

R

62

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

1 nBu 81 10 : 1 >95 : 5 >992 Me 76 30 : 1 >95 : 5 >993 TMSOCH2 49 >30 : 1 >95 : 5 >994 AcOCH2CH2 56 13 : 1 >95 : 5 >99



34

The reactions of sulfur ylides with boranes are limited to aryl substituents: alkyl- and silyl-substituted ylides give low enantioselectivity. In the case of the latter ylides, it was found that ate complex formation was reversible and the migration step was now the selectivity-determining step (Scheme 17).22

benoids.24 However, in contrast to reaction with organomag-nesium reagents they found that sulfoxide ligand exchange with alkyl lithium reagents gave a lithium carbenoid that underwent chain extension of catechol and neopentyl glycol boronic esters with considerably higher levels of stereochemical control (Scheme 18).25

S

O

Ar1

BF4

3. TBSOCH2CHO

OTBS

Ar1

OH

Ar2

OH

OH

OH OH

1. LiHMDS, THF-CH2Cl2,−78 °C, 30 min

2. −100 °C

1. LiBH4

2. TBAF

72%, >99% ee

81% Ar1 = p-PivOC6H4

B

Ar2

(+)-666

(+)-66564

Ar2 = p-TBSOC6H4

Scheme 16. Synthesis of (+)-iso-agatharesinol.

(i) LiHMDS, THF, −78 °C

Me3Si Bu

OHS

O

SiMe3

OTf

(ii) H2O2, NaOH

Bu3B

20% ee

Scheme 17. Lithiation-borylation reaction of trimethylsilyl-stabilized sulfur ylides.

S

Ph

Cl

O

p-Tol

e.e. >98%

M

Ph

Cl

R1-B

O

O

R1

Ph

OH

RLi = 67-86% yield, 82-96% ee

B(neo)

BnH

Cl

R1

NaOH

H2O2

THF,−78 °C

−78 °C

EtMgBr = 9-56% yield, 59-82% ee

nBuLiorEtMgCl

M = Li or MgCl R1 = Ph, nBu,

Ph(CH2)2, c-hex

B(neo)

R1

BnH

OH

R1

BnH

Scheme 18. Homologation of boronic esters with lithiated alkyl chlorides.

A signifi cant limitation of the sulfur ylide reactions is that the outcome with nonsymmetrical boranes is highly dependent on the substituents on boron. A potential solution to this problem is to use boronic esters. Unfortunately, boronic esters do not react with sulfur ylides. They are much less electrophilic and the barrier to migration is considerably higher.19,23 With relatively stable anions like aryl-stabilized sulfur ylides, addi-tion may occur but the high barrier to migration results in reversibility in the ate complex formation and ultimately decomposition of the ylide.19 To carry out reagent-controlled additions and subsequent 1,2-metallate rearrangements with boronic esters requires a less stable carbanion that possesses a good enough leaving group.

Chiral Carbanions of Lithiated Alkyl Chlorides

Blakemore et al. have developed the homologation of boronic esters using enantioenriched Hoffmann-type magnesium car-

The process mentioned earlier showed good substrate scope in the range of boronic esters that could be employed (primary or secondary aliphatic; pinacol or neopentyl glycol) leading to secondary alcohols in 82–96% ee. The scope in terms of the chiral organometallic was more limited: although primary aliphatic substrates worked well (Bn, Et, i-Bu, BnCH2), secondary (i-Pr, 0% yield) and methyl (23% yield, 60% ee) were less effective.26

This work was extended to iterative stereospecifi c reagent-controlled homologations. Alkyllithium-effected sulfoxide ligand exchange using t-BuLi in toluene of enantioenriched α-chloroalkyl sulfoxide 68, prepared by chlorination of sulfox-ide 67, gave the enantioenriched lithiated carbanion 69 that was reacted with boronic ester 70 to give the homologated boronic ester 71. One carbon chain extension followed by treatment with the organolithium 69 then gave alcohol 72, after oxidation, as an 79 : 21 mixture of diastereoisomers in which the major isomer was formed with >99 : 1 er. This protocol was then used to prepare all four diastereoisomers of alcohol 72 from boronic ester 70 by sequential reaction with the required enantiomer of carbanion 69/ent-69, (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 together the enantiomeric ratio of the desired product is enhanced but at the expense of formation of diastereomeric by-products. This occurs through a statistical amplifi cation process fi rst reported by Horeau.27



ArS

O

Cl

Bn

Cl

BnLi Bn

Bn

Bn

OH

Cl

BnBBn

OO(pin)B Bn

Bn

Bn B(pin)

69

38% Yield

ArS Bn

ONCSK2CO3 tBuLi

67 68 (R,R)-72

2. 692 eq.

1. LiCH2Cl

71

70

99:1 er, 79:21 dr

3. H2O2

Bn B(pin)

70

2. LiCH2Cl

1. 69 or ent-69

4. H2O2

3. 69 or ent-69

Bn

Bn

Bn

OH

(R,S)-72

Bn

Bn

Bn

OH

(S,S)-72

Bn

Bn

Bn

OH

(S,R)-72

or or

97:3 er,

81:19 dr

99:1 er,

76:24 dr

99:1 er,

80:20 dr

Chiral Carbanions of Lithiated Carbamates

An alternative to lithiated chlorides are the more stable lithi-ated carbamates. Hoppe et al. have shown that borate ester 75, derived from the corresponding carbamate 73 by asymmetric lithiation and borylation, reacted with Grignard reagents to give, after oxidation, secondary alcohols 78 in good yield and high ee.28 This showed that the carbamate group was a good enough leaving group in the 1,2-metallate rearrangement of boronic ester ate complexes 76, although it was probably facilitated by the magnesium bromide present in the reaction (Scheme 20).

This type of reaction was recently applied by Kocienski in the synthesis of (S)-(−)-N-acetylcolchinol 85 (Scheme 21).29 Along with the stepwise reaction (Scheme 21, path A), Kocien-ski also showed that a chiral lithiated carbamate could react directly with B-aryl-pinacol boronic ester 82 (Scheme 21, path B). However, to achieve rearrangement required exchange of solvent, addition of magnesium bromide, and heating to 80°C. Notably, this direct reaction of boronic ester 82 with lithiated carbamate 80 gave alcohol 84 in higher yield and excellent enantiomeric ratio.

Direct reaction of Lithiated Carbamates with Boronic Esters and Boranes

Aggarwal et al. have shown that the direct reaction of lithiated carbamates with boranes and boronic esters shows considerable scope and therefore potential for synthesis (Table 4). In all cases high enantioselectivities were observed (er 95 : 5–98 : 2).30,31

A number of points worthy of note:

1. In contrast to the reactions of sulfur ylides with 9-BBN derivatives, reaction with lithiated carbamates resulted in clean migration of the boron substituent rather than the boracycle in all cases. This is highly unusual32 and has only previously been observed with halide leaving groups, sug-gesting that the carbamate should also be considered as a small substituent in these types of reaction.

2. In the case of B-Ph-9-BBN, higher er was obtained in the presence of magnesium bromide (entries 4 vs. 5, Table 4), whereas in other cases involving aliphatic groups magne-sium bromide was not found to be necessary. It is believed that magnesium bromide sequesters the diamine ligand preventing it from binding to the borane. Binding of the diamine to benzylic boranes results in an erosion in er.

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

O

H HNN

Li

HR1

O

O

NiPr2

NiPr2

O sBuLi(−)-sparteine

1. B(OiPr)3

Et2O, −78 °C

2. pinacol, p-TsOHMgSO4, CH2Cl2

B

H

R1

O

O

NiPr2

OO

(90%, e.r. >98:2)

R2MgBr, −78 °C

R2

H

R1

OH

warm

50-70% yield, er 98:2

R2 = Pr, iPr, tBu, c-Hex

R1 = (CH2)2Ph

Ph

B

HR1

OCb

(90%, er >98:2)

OO

R2

R2

H

R1

Bpin

H2O2OCb = C(O)NiPr2

THF, r.t.

Et2O, −78 °C

73 74

75

77 78

76

Scheme 20. Hoppe-type alkylation of boronic esters by carbamate lithiation/borylation and subsequent nucleophile triggered 1,2-metallate rearrangement.



36

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

O NiPr2

OLi

H

R1

N N

R1 OCb

H H 1. R2B(R3)2

Et2O, −78 °C(−)-sparteine

1. warm

OCb

B(R3)2

H

R1

R2

B(R3)2

R2

H

R1

OH

R2

H

R1

2. Lewis Acid

86 74 87 89

2. H2O2

86

sBuLi

Entry R1 R2 (R3)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 7 Me2C¨CH(CH2)2 Et Et2 — 90 97 : 3 8 Ph 9BBN MgBr2 71 95 : 5 9 Et Pinacol MgBr2 75 97 : 310 Ph Pinacol MgBr2 73 98 : 211 TBSO(CH2)2C(Me)2 Et Et2 — 67 95 : 512 CH2 Ph 9BBN MgBr2 65 97 : 313 Ph Pinacol MgBr2 64 98 : 214 iPr Ph 9BBN MgBr2 68 96 : 415 Ph Pinacol MgBr2 70 98 : 216 Me Ph Pinacol MgBr2 70 97 : 3

OCb

MeO

MeO

OMe

Li

sBuLi (1.2 eq),

O

BO

OiPr

MgBr

OTBS

Et2O, r.t.

OCbMeO

MeO

OMe

OO

OTBS

H2O2, K2CO3, H2O, r.t.

MeO

MeO

OMe

OH

OTBSNH

OHO

MeO

MeO

MeO

A 51% yield (over 2 steps)

94:6 er85

(S)-(−)-N-Acetylcolchinol

Et2O, −78 °C

(−)-sparteine (1.2 eq),

−78 °C

B(Pin)

OTBS Et2O, r.t.,

A

B

A

B 65% yield

98:2 er

i. ii. MgBr2, (1.2 eq), −78 °C

iii. 80 °C

79 80

82

84

83

B

OCb

OOB

Scheme 21. Synthesis of (S)-(−)-N-acetylcolchinol.



3. 1,2-Metallate rearrangement of ate complexes is much slower in the case of boronic esters compared to boranes and required magnesium bromide in diethyl ether at refl ux in the former case whereas the ate complexes derived from boranes began to rearrange at −40°C without further additives.

4. A broad range of alkyl carbamates including methyl, primary, and branched secondary alkyl chains can be employed together with a broad range of aryl and alkyl boranes and boronic esters. The methodology therefore shows considerable substrate scope.

5. Reactions of lithiated carbamates with both the boranes and boronic esters occurred with retention of confi guration (74Æ87, Table 4). This is probably because the non-stabilized anion is sp3 hybridized and as such there is little electron density opposite the metal.

Extension of this methodology to iterative homologations was demonstrated by the synthesis of all four stereoisomers of 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 of boronic ester 94 with lithiated carbamate 95a gave, after oxidative work-up, alcohol 96 as a 96 : 4 mixture of diastereo-isomers and with an enantiomeric ratio of >98 : 2 for the major diastereomer. The diastereomeric alcohol 97 was prepared by reaction of boronic ester 94 with the enantiomer of lithiated carbamate 95b, prepared using O’Brien’s sparteine surrogate (+)-9133,34 in place of (−)-sparteine 90, in similarly high dia-stereo- (94 : 6 dr) and enantioselectivities (er >98 : 2; Scheme 22). The absence of matched/mismatched pairs indicates that

the chiral lithiated carbamate is effectively blind to the stereo-chemistry of the chiral boronic ester. Thus, the outcome of the reaction is completely controlled by the chiral reagent and is not infl uenced by the inherent chirality of the substrate. The enantiomeric pair to alcohols 96 and 97 were obtained with similar diastereo- and enantioselectivities using the same pro-tocol but from the enantiomer of boronic ester ent-94, which was obtained using O’Brien’s sparteine surrogate (+)-91 in the fi rst homologation (Scheme 22). As was the case in the iterative homologations of Blakemore et al. (Scheme 19),26 statistical enhancement of enantiomeric excess27 further increases the enantiopurity of alcohols 96 and 97.

The asymmetric lithiation-borylation and 1,2-metallate rearrangement has also been applied to N-linked benzylic and cyclic carbamates (Scheme 23).35 However, the poorer leaving-group ability of the N-linked carbamate limited the scope of the methodology to boranes and even then a strong Lewis acid (TMSOTf) was required to trigger the 1,2-metallate rearrangement.

Conclusions and Future Outlook

The asymmetric homologation of boronic esters is a powerful method for the stereocontrolled synthesis of substituted carbon chains. It can be conducted using either substrate or reagent control. In the substrate-controlled process the key step involves the addition of (dichloromethyl)lithium to a chiral diol-derived boronic ester and subsequent 1,2-metallate rearrangement. This rearrangement is highly diastereoselective when con-ducted in the presence of zinc chloride. The (α-chloro)boronic

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



38

ester that is formed is subsequently reacted with a Grignard reagent, or other nucleophile, to give a secondary alkyl boronic ester stereospecifi cally. The reactions show considerable scope and have been applied in synthesis. It is especially suited to the synthesis of α-amido boronic esters, a class of protease inhibitors now used on the clinic, where it has been utilized on considerable scale.36 Considering the practicality of the process it is somewhat surprising that the methodology has not been employed more widely. It is not clear whether this is because of reports that occasionally the intermediate ate 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.

In the reagent-controlled processes, chiral sulfur ylides have been found to react with boranes giving homologated products with high ee but reactions are limited to aryl-stabilized ylides. A further limitation is that sulfur ylides only react with boranes. Nevertheless, reactions with alkenyl 9-BBN derivatives provide a unique entry to α,γ-substituted allylic boranes that are important intermediates in stereoselective synthesis. α-Chloroalkyllithiums are considerably more reac-tive and less stable than sulfur ylides and consequently react with boronic esters. They can be used iteratively but suffer from somewhat limited scope in the nature of the alkyl group that can be used (not methyl or β-branched). The reagents with the greatest scope are Hoppe’s lithiated carbamates: a broad range of alkyl carbamates can react with a range of alkyl and aryl boranes and boronic esters. As chiral carbanions are derived from simple primary alcohols, access to these chiral reagents is especially facile. Furthermore, they can be used iteratively thus allowing carbon chains to be grown interspersed with substitu-

ents of specifi c stereochemistry. They therefore offer the great-est versatility and fl exibility in the homologation of boranes and boronic esters.

I am indebted to my dedicated team of coworkers who have contributed practically and intellectually to the development of our research programme. V. K. Aggarwal thanks the Royal Society for a Wolfson Research Merit Award and the EPSRC for a Senior Research Fellowship. We also thank EPSRC and Merck for generous research support.

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NBoc

ArN

BocAr

BR3

R

Ar BR2

R

Ar OH

(i) nBuLi,(−)-sparteine,−78 °C TMSOTf H2O2, NaOH

(ii) BR3 25 °C

62-83% Yield

92:8 to 95:5 er

N

Boc

HNR

N OH

R

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BocBoc

OHBoc

1. (i) sBuLi, (−)-sparteine(ii) R3B, TMSOTf, −78 °C

2. NaOH, H2O2, 25 °C

R = Et, 58% Yield, 95:5 er

R = nBu, 59% Yield, 92:8 er

1. (i) sBuLi, (−)-sparteine(ii) R3B, TMSOTf, −78 °C

2. NaOH, H2O2, 25 °C

R = Et, 67% Yield, 97:3 er

R = nBu, 64% Yield, 96:4 erH

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



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