Homologation of chiral boronic esters
and application to 1,3-polyols synthesis
Literature Seminar #1
B4 Yuta Kasamoto1

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary

2

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary3Homologation
Homologation: Method for one carbon elongation
Lithiation and borylation process○Excellent stereocontrol○Utilized in iterative reaction

https://www.chm.bris.ac.uk/org/aggarwal/research.php#li-b4Matteson reaction
Reaction discovery of Matteson homologation

Cl3COnBu
B
OnBu
Br

R-MgBru
OnB
OnBu
B
R
Br

Et2O/THF Cl3C
=1 :1
1,2-metalate migration

Cl3COnBu
B
OnBu
R

D. S. Matteson, et al. J. Am. Chem. Soc. 1963, 85, 2599.

α-Chlorol alkyl lithium reagents for homologation
Li
Cl
R O
O
Cl
B
Cl
R B
O
THF
O
Cl
-100℃ to 25℃

RClO
B
O

1,2-metalate migration
D. S. Matteson, et al. J. Am. Chem. Soc. 1980, 102, 7588.
5

Matteson reaction
Homologation of boronic acid pinacol esters with high level of diastereoselectivity

OR B
O

R1

LiCHCl2ZnCl2

R1

ChiralClClO
B
R O

R1
R1ClR

ClHOB
2RO

R1
R1

1,2-metalate migration

R1O

R1

Chiral

1,2-metalate migration
R2-MgBr

B

O

R
R2

B

O

R1

O

R1

ChiralD. S. Matteson, et al. J. Am. Chem. Soc. 1980, 102, 7590.
6

Matteson reaction
The reason for high stereocontrol✔ 2→5: ZnCl2 promotes the migration of R1 by interaction.
→α-chloroboronic ester 5: High level of diastereroselectiyity✔ 7→8: Migration group and leaving group: anti-periplanar→Homologation product 8: High level of diastereroselectiyity
V. K. Aggarwal, et al. Chemical Record. 2009, 9, 24.
7

Matteson reaction
Problems

C-migration

Desired homologation
O-migration

Thermodynamic pathway
V. K. Aggarwal, et al. Chemical Record. 2009, 9, 24.
8Matteson reaction
Problems•

To obtain opposite stereoisomers, 3 steps are required for changing ofboronic ester stereochemistry.
CyCyCy
CyO
B
OOH

Cy

3 steps

MeOBn

HO＋BOHHOBnOOBO

Cy
79%, >20:1 drMeOBnCyOH

CyOHCyO
BOMeOBnCy
59%, >20:1 dr

V. K. Aggarwal, et al. Chemical Record. 2009, 9, 24.
9Hoppe’s approach
Hoppe’s approach : Alternative homologation of boronic esters
Chiral ligand

ROCb

BuLi(-)-sparteine
Lithiation

LiROCbB(OiPr)3
then pinacol

O

Borylation

R

Chiral
R1-MgBr

O O
R1 B
R OCb

B

OOCb
Chiral
R1R

Bpin
Chiral

1,2-metalate migration✔This lithiated carbamates homologates boronic ester with high stereocontrol.
V. K. Aggarwal, et al. Acc. Chem. Res. 2014, 47, 3174.
10Aggarwal’s approach
Aggarwal’s approach : Improve Hoppe’s homologation of boronic esters
Good point
Hoppe’s approach: 2 steps per one homologation
B(OiPr)3

LiR

OCbthen pinacol

Bpin
R

R1

R1-MgBr

OCb

R

Bpin

Aggarwal’s approach: 1 step per one homologation
R1-Bpin

LiROCb

R1R

Bpin
V. K. Aggarwal, et al. Chemical Record. 2009, 9, 24.
11Aggarwal’s approach
Good point•

Stereocontrol of the homologated product
Matteson’s reaction: Substrate control
OR*

R1 B

LiCHCl2OR*Cl

*
R1OR*

B
OR*

R 2M

OR** BR1 OR*

R2Aggarwal’s approach: Reagent control
M
OR
R2 BOR*R1 LG

R2OR
* B
R1 OR

Aggarwal’s approach are easy to obtain the opposite stereoisomers.
V. K. Aggarwal, et al. Chemical Record. 2009, 9, 24.
12

Short summary
Homologation of boronic esters with high stereocontrol was developedin various ways.

V. K. Aggarwal, et al. Acc. Chem. Res. 2014, 47, 3174.
13

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary

14

Aggarwal’s iterative homologation
Aggarwal developed iterative homologation process.

V. K. Aggarwal, et al. Nature 2014, 513, 183.
15

Aggarwal’s iterative homologation
Challenges•

Full stereocontrol to obtain pure product.
→Improving e.r. of the reagent (lithiated carbamates)

V. K. Aggarwal, et al. Nature 2014, 513, 183.
16

Aggarwal’s iterative homologation
Challenges•Control of reactivity (over reaction)→It was solved by temperature control during reaction.

V. K. Aggarwal, et al. Nature 2014, 513, 183.
17

Aggarwal’s iterative homologation
Apply to iterative reaction○ One pot
○ High stereocontrol
V. K. Aggarwal, et al. Nature 2014, 513, 183.
18

Aggarwal’s iterative homologation
Similarly, alternative stereoisomer of boronic ester could be obtained.

V. K. Aggarwal, et al. Nature 2014, 513, 183.
19

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary20

Using silyl groups for iterative homologation
Aggarwal applied their iterative homologation to 1,3-polyol synthesis.

Previous work

This work
Apply to 1,3-polyols synthesis✔ Masking the hydroxy group as a silyl groupV. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
21

Using silyl groups for iterative homologation
The reason of using organosilyl lithiated reagents for iterative homologation

homologation✖Undesired reaction could happen by application of Aggarwal’s homologation.
→✔Masking the hydroxy group as a silyl groups

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
22

Using silyl groups for iterative homologation
Identifying a suitable organosilyl lithiated reagent for the homologation•

Direct application of conventional Aggarwal’s homologation
LiRTMS

R1R1-Bpin
OCbLiR OCbchiral

R1-Bpin

RBpin

TMS

R1RBpinracemic

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
23

Using silyl groups for iterative homologation
Identifying a suitable organosilyl lithiated reagent for the homologation•

Chen’s lithiated benzyl silane bearing chiral pyrrolidinomethyl○High yield and d.e.
Apply to the homologation○High yield and d.r.
V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
24

Using silyl groups for iterative homologation•Improve Chen’s lithiated benzyl silane bearing chiral pyrrolidinomethyl
OMe
N LiSiOMe
N LiOTIB

SiCl

Small and better leaving ability○Broader substrate scope

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.

25

Using silyl groups for iterative homologation
Substrate scope

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
26

Using silyl groups for iterative homologation
Subsequent homologation
OMe
Li
Bn

TIBO HMeSi
Bpin

N LiMe2Si
Bn

N
Bpin

OMe

SiCl

Coordination
61%, >95:5 d.r.

Bn

SiSiBpin
N. D.

Prevent of the homologation✔Need to remove amino group of the organosilyl lithiated reagents

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
27

Using silyl groups for iterative homologation
Using photoredox catalysis for removing amino group from the product

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
28

Using silyl groups for iterative homologation
Subsequent homologation
After photoredox cleavage (removing amino group),
the subsequent homologation reaction could proceed.

○Good yield and d. r.
V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
29

Using silyl groups for iterative homologation
1,3-polyol motif synthesis

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
30

Using silyl groups for iterative homologation
Triol with four different stereoisomer could be obtained.

V. K. Aggarwal, et al. Nat. Chem. 2017,
31 9, 896.

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary

32

Iterative diboration and homologation
Second approach to 1,3-polyols synthesis
Iterative diboration and homologation○High stereocontrol○Fewer steps per homologation
V. K. Aggarwal, et al. Nat. Chem. 2023, 15, 248.

33

Iterative diboration and homologation
Diboration of terminal alkene○High yield○High enantioselectivity○Broader substrate scope

J. P. Morken, et al. J. Am. Chem. Soc. 2013, 135, 11222.
34

Iterative diboration and homologation
HomologationProblems of Aggarwal’s lithiated reagents・Only the methyl substituted
precursors were crystalline
・Me3SnCl had toxic

New lithiated reagents: α-sulfinylbutenyl benzoate
・Easy to prepare with high e.e.
・Little toxic

V. K. Aggarwal, et al. J. Am. Chem. Soc. 2017, 139, 11877.
35

Iterative diboration and homologation
Homologation
Application of α-sulfinylbutenyl benzoate generated by MgCl
※Li carbenoid: reacting with both boronic esters

V. K. Aggarwal, et al. J. Am. Chem. Soc. 2017, 139,11877.
36

Iterative diboration and homologation
Diboration and Homologation process

Diboration
RBpin
Bpin

Homologation

R
99.2: 0.8 e. r.

Bp

Diboration

in in
Bp Bp
R60%, >99:1 d. r.

in pin pin
BB
Bpin

RBp

Homologationin pin pin pin
BB
BR

86%, 98:2 d. r.

57%, 98:2 d. r.

Diboration: Pt(dba)3, ligand, B2pin2, THF, 60 ℃, 16 h
Homologation:O
p-tol S

i-PrMgCl-LiCl, DCE

OTIB-35 ℃, 1 h then 85 ℃, 1-3 hV. K. Aggarwal, et al. Nat. Chem. 2023, 15, 248.
37

Iterative diboration and homologation
All 8 diastereomer can be formed.

V. K. Aggarwal, et al. Nat. Chem. 2023, 15,248.
38

Iterative diboration and homologation
Total synthesis of bahamaolide A

V. K. Aggarwal, et al. Nat. Chem. 2023, 15, 248.
39

Contents
1. Introduction: Homologation
1-1. Matteson reaction
1-2. Hoppe’s approach
1-3. Aggarwal’s approach2.

Contents: Iterative homologation and application to 1,3-polyols synthesis
2-1. Aggarwal’s iterative homologation
2-2. Using silyl group for iterative homologation (1,3-polyols synthesis)
2-3. Iterative diboration and homologation (1,3-polyols synthesis)

3. Summary40

Summary
Matteson’s reaction: Homologation of chiral boronic esters
OR*R1 B
OR*LiCHCl2

OR** B
R1 OR*ClR 2M

OR** B
R1 OR*

R2

Aggarwal’s approach
M

R2 OR*
OR
1* B
RLG
R2 B
1
OROR Reagents control R

Iteration

Carbon elongation
application to 1,3-polyol etc

High stereocontrol

41

Appendix

42

Chiral boronic ester
Chiral boronic eater: Significant utility in asymmetric synthesis•Various ranges of stereospecific transformations into functional groups•

Easy to purify (especially; boronic acid pinacol esters)

V. K. Aggarwal, et al. Chem. Commun. 2017, 53, 5481.
43Chiral base(-)-Sparteine

D. Hoppe, et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2282
44

Aggarwal’s approach
Aggarwal’s approach : Improve Hoppe’s homologation of boronic esters✔Improved leaving groups (OTIB)→In fewer times under reflux without the need for Lewis acid(MgBr2).
V. K. Aggarwal, et al. Acc. Chem. Res. 2014, 47, 453174.

Aggarwal’s approach
Aggarwal’s improvementV. K. Aggarwal, et al. Acc. Chem. Res. 2014, 47, 3174.
46

Aggarwal’s approach
Application
They applied this approach to synthesis of natural products.
※ (+)-faranal challenges: Its carbon chain containing adjacent methyl groups→only 6 steps.

V. K. Aggarwal, et al. Acc. Chem. Res. 2014, 47, 3174.
47

Aggarwal’s iterative homologation
Decomposition of lithiated carbenoid

V. K. Aggarwal, et al. Nature 2014, 513, 183.
48

1,3-polyols
1,3-polyols are common structure in polyketides.
MeOMeMeOH OH OH

OH OH
CO2HNHMe Me MeOH

PhHN

OO

HOH
MeMe Me Me

FAtorvastain(+)-Zincophorin
HO HO HO HO HOMeOHMeOHOO

MeMeRoxaticin

Polyketides are top-selling of small molecule drugs and have strong drug activity.
→1,3-polyols synthesis is important.
A. M. P. Koskinen, et al. Chem. Soc. Rev. 2005, 34, 677.
49

1,3-polyols
Conventional 1,3-polyols synthesis
Aldol reaction and allylation✖Require protection and deprotection→Take multiple steps for carbon unit elongation and much waste.
V. K. Aggarwal, et al. Nat. Chem. 2023, 15, 248.

50

Using silyl groups for iterative homologation
Identifying a suitable organosilyl lithiated reagent for the homologation•

Blackmore’s silylmethyllithium carbenoid bearing chiral ligand(chiral ligand: isopropyl-substituted bis(oxazoline)(BOX)ligand)✖ Moderate e. e. & yields
V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
51

Using silyl groups for iterative homologation
Generating Chen’s lithiated benzyl silane bearing chiral pyrrolidinomethyl

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
52

Using silyl groups for iterative homologation
lithiation-borylation homologation didn’t proceedwith the more hindered boronic ester under the same conditions.
→Additives Mg(ClO4)2 in CF3CH2OH promote the reaction.

V. K. Aggarwal, et al. Nat. Chem. 2017, 9, 896.
53

Using silyl groups for iterative homologation

V. K. Aggarwal, et al. Org. Lett. 2017, 19, 10, 2762

54

Iterative diboration and homologation
Diboration of terminal alkene

J. P. Morken, et al. J. Am. Chem. Soc. 2013, 135, 11222.

55

Iterative diboration and homologation
Preparation of α-sulfinylbutenyl benzoate

V. K. Aggarwal, et al. Nat. Chem. 2023, 15, 248.
56