Boron Reagents

for Asymmetric Synthesis

Gordon J. Florence
University of St Andrews

SCI Review Meeting 2009

4th December 2009
London
 Overview

1) Hydroboration
2) Reductions
3) Aldol Reactions
4) Allylboration Reactions
5) Vinylations and Homologations
Hydroboration
 Hydroboration
The Starting Point
S
H B
H H
S H2O2,
H H2B H B H HO H
3 NaOH
R R H B H
R R R R R R
R R R R
R R R R R R
R R

“In the course of investigating the facile conversion of olefins into trialkylboranes under the
influence of the sodium borohydride-aluminum chloride reagent, we have discovered that in the
presence of organic ethers diborane adds to olefins with remarkable ease and speed at room
temperature to form the corresponding organoboranes in yields of 90-95%.”

Brown and Rao, JACS 1956, 78, 5694

JOC 1957, 22, 1136
JOC 1957, 22, 1137

“At the time many individuals expressed scepticism as to the value of devoting so much research
effort to this reaction. They took the position that hydroboration, while a clean, simple reaction,
produces only organoboranes, compounds of no known use……… We bided our time.”

Brown & Ramachandran Pure Appl. Chem, 1991, 63 307

 Hydroboration
Common Reagents Examples
Borane complexes
i) BH3•THF NHBoc
NHBoc
ii) MeOH
tBuO tBuO O
BH3•THF BH3•DMS B2H6 B
iii)
O O O
HO

OH
Christianson et al. JACS 1997, 119, 8107
Alkylboranes
HB S S
HB
2 i) cHex2BH
N N
9-BBN cHex2BH ii) H2O2, NaOH
OTBS OTBS
90%
HB H2B
2
OH
disiamylborane thexylborane
Panek et al. OL 2000, 2, 2575

Dialkyloxyboranes
O
O O HB OPMB OH
OPMB
HB HB O C10H21 B
C10H21 OH
O O
then H2O
catecholborane pinacolborane
pinBH cross-coupling precursor
Kobayashi et al. JOC 2001, 66, 5580

For a recent review, see: Buckhardt and Matos, Chem. Rev. 2006, 106, 2617
 Diastereoselective Hydroboration - Acyclic Systems
Hydroboration of trisubstituted olefins can be controlled by A(1,3) strain

OH
RL B2H6 RL
OH OH
H2O2
RM RM

RM
H
H B H Me
• A(1,3) strain minimised RM H H
Me CH2OR
• Staggered transition state RL H
H CH2OR B H
• Sterics : RL vs RM H
RL H

major minor
For detailed TS calculations and discussion, see: Houk et al. Tetrahedron 1984, 40, 2257

Representative Applications
E-olefins
Z-olefins

H2B
B2H6
CH2OBn CH2OBn then BH3 TrO OTr
O H2O2 O
OH work-up OH OH OH
TrO OTr
dr = 8 : 1 dr = 5 : 1

Kishi et al. JACS 1979, 101, 259 Still & Barrish JACS 1983, 105, 2487
 Diastereoselective Hydroboration - Acyclic Systems
Hydroboration of acyclic 1,1-disubstituted olefins controlled by A(1,2) strain

In general - Houk’s rules

RL OH BH3 RL L2BH RL OH
H2O2 H2O2
RM RM RM

H R
H R
B H clash B H
For boranes RM H RM H For dialkylboranes
H
Me
TS1 H
Me
H H
•Small reagent •Bulky reagent
RL RL
major minor
•Minimisation of •Minimisation of
A(1,2) strain H R steric interaction
favours TS1 H B H H B R between boron
A(1,2)
RM H
H TS2 RM H
H ligand and RM
Me H Me H favours TS2
RL RL
minor major

For detailed TS calculations and discussion, see: Houk et al. Tetrahedron 1984, 40, 2257
 Diastereoselective Hydroboration - Acyclic Systems
Hydroboration of acyclic 1,1-disubstituted olefins controlled by A(1,2) strain
OMe
Applications
BH3•SMe2 O O OH OH

(85%) O N O
OMe H

OH OH Bn
9-BBN OMe
diastereoselectivity
OH O 92:8
H2O2 O OH

O N O
RM = OH OMe H
OMe
Still & Barrish JACS 1983, 105, 2487 Bn
O O OH OH
9-BBN

(60%) O N O
OMe H
Bn
diastereoselectivity
> 95: 5
Lonomycin: Evans et al. JACS 1995, 117, 2487

PMBO OH OH PMBO OH OH
BH3•DMS steps 9-BBN (> 20:1 dr)
OH TESO TESO anti
H2O2 H H2O2 H
O H O H
O O OH
(> 6:1 dr) MeO MeO
syn O O
TESO TESO
TES TES

Spirangien A: Paterson et al. ACIEE 2007, 46, 6699; Chem. Comm. 2008, 6408
 Diastereoselective Hydroboration - Cyclic Systems
substituted methylenecyclohexanes
OH
BH3•THF i) LiMe2BH2 NH2OSO3H;
ii) TMSCl BMe2 NaOH, H2O NH2
tBu tBu
dr = 2.1 : 1

OH
Brown et al. JACS 1966, 88, 2870
BH3•THF
Review, see: Brown & Sinagram Pure. Appl. Chem. 1987, 59, 879
tBu tBu

dr = 1.2 : 1
H
BH3•THF BH3•DMS B
OH
tBu tBu

dr = 3.3 : 1 (+)-α-pinene (-)-Ipc2BH

OH
Brown & Zweifel JACS 1961, 83, 486
BH3•THF
tBu tBu

dr = 2.4 : 1
HO HO
OH
BH3•THF BnO O BH3•THF BnO O
tBu HO HO OH
tBu
O O

dr = 99 : 1
sole product
• Largely governed by steric interactions
• dr greater when 2-position substituent is axial
Fraser-Reid et al. JACS 1984, 106, 731
Senda et al. Tetrahedron 1977, 33, 2933
 Asymmetric Hydroboration - Brown’s Ipc reagents
H H
BH3•DMS B B BH3•DMS

(+)-α-pinene (-)-Ipc2BH (+)-Ipc2BH (-)-α-pinene

(-)-Ipc2BH OH
IpcBH2 - alleviates E-olefin limitation

i) TMEDA
>98.4% ee BH2
ii) BF3
JACS 1961, 83, 486; JACS 1964, 86, 1076; JOC 1982, 47, 5065 (-)-Ipc2BH

OH JOC 1978, 43, 4395; JOC 1982, 47, 5069

(-)-Ipc2BH

X X R (-)-IpcBH2 R

X = O, >99% ee
X = NBn, >99% ee OH
X = Cbz, 89% ee
R = H, 73% ee
OH NB: reversed sense of induction R = Me, 53% ee
(-)-Ipc2BH

X X (-)-IpcBH2

X = O, >99% ee Ph Ph OH
X = S, >99% ee
JOC 1986, 51, 4296; Heterocycles 1987, 25, 641 72% ee
JOC 1982, 47, 5074
Limitations

R •For perspective reviews, see: Pure Appl. Chem. 1991, 63, 316; Pure
14% ee 15% ee R = iPr, 32% ee Appl. Chem. 1987, 59, 879; Acc. Chem. Res. 1988, 21, 287
R = Ph, - •Highlight on asymmetric hydroboration, see: Thomas & Aggarwal
ACIEE 2009, 48, 1896
 Asymmetric Hydroboration - Masamune’s C2-symmetric borolanes
Me Me

B H H B

Me Me
(S,S) (R,R)

Advantages: Uniformly high enantioselectivities for all olefins apart from 1,1-disubstituted

OH HO
(R,R) (R,R)

97.6% ee 95.6% ee

R (R,R) R
(R,R) HO

OH

R = H, 99.5% ee 99.3% ee
R = Me, 97.6% ee

H
Selectivity rationalised by TS
R model:
B R2 • hydrogen occupies position
H R1 closest to Me group of borolane
• loss of selectivity when R = H
Largely ignored due to one disadvantage:

Reagent prepared in seven steps, including:

1. Separation of diastereomers
2. Resolution of racemic trans-borolane
Masamune et al. JACS 1985, 107, 4549
 Asymmetric Hydroboration: 10-TMS-9-BBD and 10-Ph-9-BBD
TMS Ph H
H B
B

(10R)-9-TMS-10-BBD-H (10S)-9-Ph-10-BBD-H
Ph Ph
10R-TMS OH OH
10S-Ph
B H B H
Me H H H
82% ee 32% ee H Me
Me H

Favoured H clash Me

10R-TMS OH 10S-Ph OH
10S-Ph
R R
R R

R = H, 96% ee R = H, 96% ee
R = Me, 84% ee R = Me, 74% ee
Ph

10R-TMS OH 10S-Ph OH B H
H
Ph Ph
Ph Ph RS
66% ee 78% ee
RL
TMS

B H • Good levels of enantioselectivity observed with 1,1-disubstituted olefins using

H H either reagent system
H RS
• First real solution to this longstanding hydroboration problem

RL
10S-TMS Initial disclosure: Soderquist et al. ACS Symposium Series 783, Organoboranes for Synthesis, P. V.
Ramachandran, H. C. Brown, Ed., Ch 13, pp 176-194, American Chemical Society, Washington, DC, 2000.
Soderquist et al. JACS 2008, 130, 9218
 Catalytic Hydroboration

O O
HB HB
OH O O O O

OH
0.5 mol% ClRh(PPh3)3
2h

Männig & Nöth ACIEE, 1985, 24, 878

•need to use an unreactive dialkoxyboranes
•hydroboration is achieved over ketone reduction by use of Wilkinson’s catalyst

Styrene gives reversal of selectivity

O
HB OH
O

1 mol% [Rh(COD)2]BF4
R R
Cl dppb or PPh3
Rh P selectivity >99:1
P P or
ClRh(PPh3)3
B(OR)2 Hayashi et al. Tetrahedron Asymmetry 1991, 2, 601
Burgess et al. JACS 1992, 114, 9350
Ph Cl HB(OR)2
Rh P
P solv

Catalytic cycle with Wilkinson’s catalyst

Cl
P
(RO)2B Rh
P
P Reversal of selectivity rationalised by formation of η3-Rh
H
Cl Rh complex with Ph group after insertion of Rh-H
Ph B(OR)2
P
Wilkinson’s catalyst is highly sensitive to oxygen -
Cl
(RO)2B P significant as slight variation in catalyst structure changes
Rh
P H Ph reaction outcome - much debate in early studies
Ph
Reviews, see: Beletskaya & Pelter Tetrahedron 1997, 53, 4957; Crudden & Edwards EJOC 2003, 4695
 Catalytic Hydroboration of 1,3-dienes

• Regioselective hydroboration of 1,3-diene by choice of Fe(II)-ligand

• Sequential hydroboration/crotylation

Ritter et al. JACS 2009, 131, 12915

 Asymmetric Catalytic Hydroboration

O
HB OH
O PPh2
PPh2
1 mol% [Rh(COD)2]BF4
R R
2 mol% (+)-BINAP
88-96% ee
R = Cl, Me, OMe
(+)-BINAP

Hayashi et al. JACS 1989,111, 3426

Tetrahedron Asymmetry 1991, 2, 601

Hayashi was first to report catalytic asymmetric hydroboration of styrene with high ee
To date, BINAP remains one of the best ligand systems

PCy2
Notable ligand systems
PCy2
Ph O C2-diphosphane
Ph O CF3 70-93% ee
N
O Ph Knochel et al.
P
N tBu PPh2 P O Ph N 2 ACIEE 2001, 40, 1235
O
N CF3
PPh2 PPh2 Fe

Ph O
tBu Ph
Josiphos-derivative O
QUINAP Pyphos Taddol-based phosphane-phosphite 98.5% ee
78-94% ee O Ph
90% ee 91% ee
Togni et al. P O Ph
J. M. Brown et al. Chan et al. Schmalz et al. JACS 1994, 116, 4062 N
Chem. Comm. 1993, 1673 JOC 2002, 67, 2769 Adv. Synth. Catal. 2002, 344, 868 ACIEE, 1995, 34, 931; Bn Ph
monodentate-Taddol
90-96% ee
Takacs et al.
OL 2006, 8, 3097

Reviews, see: Beletskaya & Pelter Tetrahedron 1997, 53, 4957; Crudden & Edwards EJOC 2003, 4695
 Asymmetric Catalytic Hydroboration

Mes N N Mes

CuCl
0.5 mol%

0.5 mol% NaOtBu Bpin

O
HB selectivity > 98%
Hoveyda et al.
O
JACS 2009, 131, 3160

Hoveyda has recently established the catalytic hydroboration of 1,2-disubstituted olefins

Use Cu-NHC complex and pinacolborane for regioselective hydroboration
Substrate Scope Enantioselective variant
OH
O Ph Ph
OMe OH
O S iPr
Bpin
N N 76%, 96% ee
96% yield O
iPr
iPr
OMe
Bpin OH
Bpin
7.5 mol% CuCl, 30 mol% KOtBu
B2pin2, MeOH (2 eq), THF, -50°C, 2 d 51%, 89% ee
X 80%, 98% ee
after oxidative workup
X= CH2, 97% Ph Ph
X= O, >98%
Ph
N N
O
BF4 Ph
O OMe Bpin
Bpin
76% yield X 7.5 mol% CuCl, 30 mol% KOtBu X
B2pin2, MeOH (2 eq), THF, -50°C, 2 d
X = CH2, 63%, 72% ee
X = O, 98%, 89% ee

Hoveyda et al. JACS 2009, 131, 3160

Reductions
 Reductions with Borane Reagents

O B2H6 O "B2H6" "B2H6"

CN
H OH Ph OH diglyme Ph OH Ph Ph NH2
diglyme
H. C. Brown PhD thesis, University of Chicago diborane generated in situ from NaBH4 and BF3•OEt2
Brown, Schlesinger & Burg JACS 1939, 61, 673 Brown & Rao JOC 1957, 22, 1135

Commercial Boranes

Primary Applications BH3•THF BH3•DMS B2H6 BH3•pyr BH3•NEt3 BH3•NH2tBu

Carboxylic acid reduction Reductive amination
Amide reduction enamine reduction
Oxime reduction
NH
R1
O H Ar Me Ar Me
BH3•DMS HO O BH3•pyr
HO2C O O N R N R
O N
RT 76%, >1kg
100% O O
O2N O2N R1

Hoffman-La Roche: US Patent 4112225, 1978 Parker et al. Org. Proc. Res. Dev. 2003, 7, 67

Cl Cl
MeO MeO
O
H H H2N OMe
BH3•THF
OMe
O2N NBn O2N NBn H H
reflux O i) OMe N
OMe
H H H
O 90%
ii) BH3•NH2tBu
AcOH, PhMe
Pfizer: US Patent 5256791, 1993
Draper et al. Org. Proc. Res. Dev. 1998, 2, 175

For review, see: Buckhardt & Matos Chem. Rev. 2006, 106, 2617
 Reductions with Borohydride Reagents
O
NaBH4, MeOH
H OH

Chaikin & W. C. Brown JACS 1949, 71, 122

H.C. Brown, Mead & Rao JACS 1955, 77, 6209

A selection of some commercial borohydrides and applications

NaBH4 LiBH4 LiBH(Et)3 Met-BH(sBu)3

Super Hydride Met = Li, Na, K

Met-Selectride

ketone/aldehydes + esters Hindered ketones Stereoselective reductions of ketones

acid chlorides directed ketone reductions SN2 - Ts/Ms displacement Enone reductions - 1,2 or 1,4
Amide to alcohol Lactones to lactols

O HO
O OH 7 7
O O K-Selectride, 79% O O
LiBH(Et)3 9 : 1 dr at C7
PhHN 1 5 1
PhHN NH PhHN NH
OTBS OTBS
Killigore et al. WO Appl. 0140184, 2001 Smith et al. JACS 2000, 122, 8654

NaBH3(CN) NaBH(OAc)3 Me4NBH(OAc)3

reductive amination directed ketone reductions

 Directed Reductions of β-Hydroxy Ketones
1,3-syn reduction - Narasaka-Prasad
H
Et2BOMe; H Et
OH O O NaBH4 R OH OH O
H
O B
Ph OMe THF/MeOH Et Ph OMe
O
H 1,3-syn diol, 98% ds

• Formation of intermediate boron aldolate

• Axial addition of hydride from lowest energy half-chair
• Reaction can be done in situ following boron aldol reaction
With trialkylboranes: Narasaka & Pai Tetrahedron 1984, 40, 2233
Modification with alkoxyboranes: Prasad et al. TL 1987, 28, 155

1,3-anti reduction of β-hydroxy ketones - Evans-Saksena Reduction

H
H OAc OH OH O
O+ Major
B- OMe
R1 O OAc
H
R2 1,3-anti
OH O O Me4NBH(OAc)3 Favoured
OMe

H OAc
OH OH O
R2
B- Minor
R1 O OAc OMe
H
O+ 1,3-syn
H
Disfavoured

1,3-directed reductions with NaBH4 / AcOH: Saksena & Mangiaracina TL 1983, 24, 273
Optimisation and utility in polyketide synthesis: Evans et al. JACS 1988, 110, 3560
 Asymmetric Borane Reductions
Brown’s Ipc-based Boranes
O H OH
chiral borane

OBn

B Li+ B Li+ B
H H

Alpine-Borane Alpine-Hydride NB-Enantride

Brown et al. JOC 1977, 42, 2534 Midland et al. JOC 1982, 47, 2495
20% ee 1% ee
effective for ynones (99% ee) - effective for straight chain ketones (68-79% ee)
Midland et al. JACS 1980, 102, 867
Cl
Cl Cl
B
B B

(-)-Ipc2BCl (+)-Ipc2BCl Eap2BCl

Brown et al. JACS 1988, 110, 1539 Brown et al. Pure. Appl. Chem. 1991, 63, 307

98% ee >99% ee

(+)-Ipc2BCl reduction

RL Rs RL Rs
Me H
• boron chloride reagents work by de- O
O H
hydroboration and loss of pinene
B
B Me H
Me H Cl
Cl (-)-α-pinene

For a comparative study with various classes of ketones prior to CBS, see: Brown et al. J. Org. Chem. 1987, 52, 5406
 Asymmetric Borane Reductions
Itsuno’s Reagent
O (S), BH3•THF OH O (S), BH3•THF OH R = Me, 94% ee
R = Et, 94% ee
H RL Rs RL Rs Ph R Ph R R = Pr, 96% ee
Ph
Ph

HN O O (R), BH3•THF OH
B OR
N (S), BH3•THF NH2
RL Rs R = Me, 99% ee
H RL Rs R = Bn, 95% ee
(S) Ph Ph
Itsuno's reagent
• reagent and BH3•THF mixed in situ to form diborane complex
• stoichiometric reagent system works well for ketones with defined large and small groups
• catalytic version developed by Corey (see below)
• oxime ether reduction gives reversal of facial selectivity
Itsuno et al. J. Chem. Soc. Chem. Comm. 1983, 469
J. Chem. Soc. Perkin Trans. 1, 1985, 2039
Corey’s CBS Reagent
H Ph H Ph Ph
Ph O OH Me
Ph 5-10 mol% (S)-MeCBS
R = tBu, 94% ee
N O R Me R Me R = Ph, 94% ee H N
N O 0.6-1 eq BH3•THF H B
B B B H Ph
Me Me H O
Rs
(S)-MeCBS (R)-MeCBS •Corey proposed mechanistic rationale for observed selectivity
•Optimised catalytic version of reaction RL
•Both (R)- and (S)-MeCBS commercially available
Corey et al. JACS 1987, 109, 5551

O O O OH O O
(R)-MeCBS •Utility has been demonstrated in process
N O N O chemistry - 50 kg scale
BH3•THF
F F
•Remains a go to reagent for many total synthesis
Ph Ph
97% yield, 95% de campaigns for tricky reductions
15-50 kg scale
Schering-Plough: Fu et al. TL 2003, 44, 801; Wu et al. JOC 1999, 64, 3714
Aldol Reactions
 Boron Reagents for Aldol Reactions

Focus of intense interest over last 30 or so years due to its primary utility in the synthesis of polyketide natural
products
OH O OH O

R3 R1 R3 R1 syn
O O aldol R2 R 2
+ reaction
R3 H R1
R2
OH O OH O
anti
R3 R1 R3 R1
R2 R2

1) Mukaiyama
TMS
O O LA O OH
R3
R1 H R4 R1 R4
R2 R2 R3

Lewis acid promoted (e.g. BF3•OEt2)

2) Boron-mediated
O L2BX OBL2 O OH
R3N O
R1 R1
+ R1 R3
H R3
R2 R2 R2

Formation of boron enolate and reaction with aldehyde

 Mukaiyama Aldol Reactions

TMS Mukaiyama et al.

O O TiCl4 O OH Chem. Lett. 1973, 1011
JACS 1974, 96, 7503
Ph H Ph Ph Ph
Reviews: Org. React. 1994, 46, 1

• Reaction of silyl enol ether and aldehyde in presence of Lewis acid promoter (e.g. TiCl4, BF3•OEt2)
• Proceeds via open transition state
LA R1 LA
TMS O O
O O LA O OH R2 R3 R2
R3 TMSO
R1 H R4 R1 R4 H R4 H R4
R2 R2 R3 R3
R1 OTMS

antiperiplanar synclinal
"Favoured"

Possible to control relative and absolute stereochemistry by use of:

1) Chiral silyl enol ether (limited application)
2) Chiral aldehydes
3) Chiral Lewis acid

1) Chiral silyl enol ether

TMS TMS
TBSO O BF3•OEt2 TBSO O OH TBSO O BF3•OEt2 TBSO O OH

+ anti + anti
iPrCHO iPrCHO

dr = 59 : 41 dr = 95 : 5
Evans: JACS 1995, 117, 9598 enolsilane facial selectivity = 95 : 5 enolsilane facial selectivity = 90 : 10

Reviews, see: Mahrwald, Chem. Rev. 1999, 99, 1095; Nelson, Tetrahedron: Asymmetry 1998, 9, 357
 Mukaiyama Aldol Reaction: Chiral Aldehydes
α-chiral aldehydes
F3B
TBS H
O BF3•OEt2 O Me
O O OH RL RL
Ph Ph Me Nu
R H R H
F3B O H
Nu H
R = Me, dr = 91 : 9
Favoured
R = tBu, dr = 96: 4 Anh & Eisenstein Noveau J. Chim. 1977,1, 61

• Mukaiyama aldol reactions with α-chiral aldehydes proceed with high levels of Felkin-Anh induction
• Increasing size of nucleophile leads to increased selectivity for Felkin-Anh product
β-oxygenated aldehydes
TMS F3B H H
O O OP BF3•OEt2 O OH OP
O H
H PO R PO R
F3B
H O
Nu Nu
P = PMB, dr = 92 : 8
P = TBS, dr = 80 : 20 Favoured dipole destabilization

•Mukaiyama aldol reactions with β-OPMB proceed with high levels of 1,3-anti induction (also OBn),
according to Evans’ 1,3-polar model

Merging stereochemical models

O OPMB BF3•OEt2 O OH OPMB O OH OPMB

O OPMB BF3•OEt2 O OH OPMB H TMS R R

O
H TMS R
O R Felkin anti-Felkin
R = Me, dr = 17 : 83
R R = Me, dr = 97 : 3 R = iPr, dr = 56 : 44
R = tBu, dr = 99 : 1 R = tBu, dr = 96 : 4
anti diastereomer syn diastereomer
α and β reinforcing α and β non-reinforcing Small nuceophile - 1,3-control
Large nucleophile - Felkin control

Evans et al. JACS 1996, 118, 4322; JACS 2001, 123, 10840
 Mukaiyama Aldol Reaction: Chiral Boron Lewis Acids
Yamamoto’s Chiral (Acyloxy)Boranes

OTMS O OH OTMS 20 mol% CAB O OH

20 mol% CAB
OiPr O CO2H nBu PhCHO nBu Ph PhO PhCHO PhO Ph
O
81%, 85% ee 63%, 84% ee
O
O O
OiPr B OTMS O OH OTMS O OH
20 mol% CAB
20 mol% CAB
H
CAB Et Et Ph PhO Pr PhO Pr
PhCHO OHC

94%, 94% ds, 96% ee 97%, 96% ds, 97% ee

•Yamamoto’s tartrate-derived CAB give high levels of ee

•substituted silyl enol ethers/ketene acetals give syn adduct regardless of starting geometry
Yamamoto et al. JACS 1991, 113, 1041; Synlett 1991, 439; Bull. Chem. Soc. Jpn. 1993, 66, 3483; JACS 1993, 115, 10412

Masamune’s Oxaborolidine Catalysts

Me
OTMS 20 mol% 1 O OH OTMS 20 mol% 1 O OH
O
iPr EtO PhCHO EtO Ph PhO PhCHO PhO Ph
p N O
TolO2S B 77%, 93% ee
83%, 91% ee
H
OTMS 20 mol% 1 O OH

tBuS PhCHO t
BuS Ph

94% ds, 82% ee

Masamune et al. JACS 1991, 113, 9365; TL 1992, 33, 1729

Reviews, see: Mahrwald, Chem. Rev. 1999, 99, 1095; Nelson, Tetrahedron: Asymmetry 1998, 9, 357
 Mukaiyama Aldol Reaction: Chiral Boron Lewis Acids
Corey’s Oxaborolidine Catalyst:
O
OTMS 20 mol% OXB-Bu O OH OTMS 20 mol% OXB-Bu
N O
H Ph PhCHO Ph Ph MeO PhCHO;
then TFA O Ph
p N O
TolO2S B 82%, 89% ee 100%, 82% ee
n
Bu
aldol - cyclisation: formal hetero-Diels Alder
Corey: TL 1992, 33, 6907
Derivatives and related applications

O OH OTMS 5 mol% 2 O OH
N O OTBS 20 mol% 1
H
MeO Ph PhCHO Ph Ph
N MeO iPrCHO
pTolO O
2S B 99%, 94% ee
75%, 98% ee
R vinylogous aldol reaction:
Yamamoto et al. JOC, 2000, 65, 9125
1: R = Ph, Kalesse et al. OL 2007, 9, 5637
2: R = 3,5-(CF3)2C6H3

Diels-Alder reactions Origin of facial selectivity

OTIPS OTIPS π−π interaction between

HN
R
carbonyl of aldehyde and indole
10 mol% OXB-Bu
H ring of catalyst
CHO -78 °C O
O O Nu
Cl CHO
B •Only re-face exposed for
94% ee R
nucleophile addition
Ts
Corey: JACS 1994, 116, 3611
JACS, 1991, 113, 8966; JACS 1992, 114, 8290
 Boron-mediated Aldol Reaction

Focus of intense interest over last 30 or so years due to its primary utility in the synthesis of polyketide natural
products
OH O OH O

R3 R1 R3 R1 syn
O O aldol R2 R2
+ reaction
R3 H R1
R2
OH O OH O
anti
R3 R1 R3 R1
R2 R2

General mechanism L H
X O
L B
L2B L2 B O
O L2BX O O O R3
R3N R3 H
H
R1 R1 R1 R1
R2 R2 R2 R2

L L
B
O O workup O OH

R1 R3 R1 R3
R2 R2

Stereochemical issues to consider:

1) relative stereocontrol - selective enolization
2) absolute stereocontrol - π-facial selectivity
 Why Boron?
Comparison of Group I, II and III enolates

M O
O O OH M O
O OH O OH
3 O O OH
R H 3
X X R 3 R H
X R3 R3
R3

M syn anti

Li >98 2 M syn anti

X = CMe3 MgBr >95 5
BBu2 >97 3 Li 48 52
AlEt2 50 50
X = C6H5 Li 80 20 BBu2 17 83
BBu2 >97 3

X = Et Li 80 20
BBu2 >97 3

cHex2BCl BcHex2 O
• stereocontrol with Li- and Mg-enolates optimal with Et3N O O OH
“large” X Ph H
Ph Ph Ph
• high levels of selectivity maintained with use of B-enolates O
95% anti
• B-O bond length < M-O bond length - tighter transition Ph O
B-9-BBN
state - higher levels of stereocontrol from metal centre O O OH
Ph H
9-BBN-OTf Ph Ph Ph
iPr2NEt

M O B O M C B C 98% syn

1.9-2.2 Å 1.4-1.5 Å 2.0-2.2 Å 1.5-1.6 Å In general

Boron chloride → (E)-enolate → anti aldol

Boron triflate → (Z)-enolate → syn aldol

 Controlling Enolate Geometry

L2BCl O L2BOTf

Et3N iPr NEt

R 2

cis trans
L2B O deprotonation R + TfO – L deprotonation L2B O
O – L
Me H R + B
B L
Cl L O R
R Favoured H Me Favoured
for electronic H for steric
reasons :NEt3 A H B reasons
(E)-enolate (Z)-enolate
proton activated :NEtiPr2
by cis B–Cl

trans Cl cis
L2B O deprotonation L R L2B O
O+ L deprotonation
R + B– Me
O L H B
R Disfavoured H TfO
– L Disfavoured R
Me
H
(Z)-enolate H (E)-enolate

• sterically demanding ligands (e.g. cHex) • small ligands (e.g. n-butyl, 9-BBN)
• poor leaving group (e.g. chloride) • good leaving group (e.g. triflate)
• small amine base (e.g. Et3N, Me2NEt) • bulky amine base (e.g. iPr2NEt)
 Relative Stereocontrol

H L
O OH
R1 +
M
R3 O L R1 R3
H
O
R2
R2 TS-1 1,2-syn
OBL2
R2 clash
R1 R3 L
R1 + O OH
(Z)-enolate
M
H O L
H R1 R3
O
R2
R 2 TS-2

H L
O OH
R1 +
3 M
R O L
R2 R1 R3
O
R2
H TS-3
OBL2 1,2-anti
clash
R1 R3 L
R2 R1 + O OH
M
H O L
(E)-enolate
R2 R1 R3
O
R2
H TS-4

• enolate geometry faithfully transferred by 6-membered Zimmerman-Traxler TS (for R2 ≠ H)

• rationalizes observed relative stereochemistry

• widely accepted but is this really the case?

 Relative Stereocontrol: Revised

DFT Transition state calculations - Jaguar v4.2, 6-31G** basis set, B3LYP

H H H
B O B O B O
O O O

chair chair chair

0 +0.55 +1.46

O H O H O H
B B B
O O O

Boat A Boat A Boat A

+1.30 0 0

O O O
B B B
O H O H O H

Boat B Boat B Boat B

+3.37 +0.67 +0.93

relative energies in kcal mol-1

For Z-enolborinates - boat A and B destabilized by 1,4-steric interactions between Me and ligand - Chair favoured

For E-enolborinates - chair destabilized by 1,3-diaxial repulsion (ligand ↔ enolate sidechain) - Boat A favoured

For unsubstituted enolborinate - chair disfavoured strongly (ligand ↔ enolate sidechain) - Boat A favoured

Goodman and Paton, Chem Comm 2007, 2124

 Absolute Stereocontrol in Boron Aldol Reactions

Selection of one diastereomer over an other

OBL2 OH O OH O
O
+ R2
R1 R3 R1 R3 R1
R3 H
R2 R2

L2BOTf
iPr2NEt

R1
R2

L2BCl
Et3N

OBL2
O OH O OH O
+ R1
R3 H R3 R1 R3 R1
R2
R2 R2

• Use of chiral aldehydes where R3 is a stereogenic group

• Use of auxillary control where R1 is a stereogenic group and is subsequently removed
• Use of substrate control where R1 is a stereogenic group which is retained
• Use of reagent control by using chiral boron reagents
 α-chiral aldehydes and (Z)-enolates

OML2 O
+ R2
R1 H
(Z) 23
Normal 'Felkin' Anti-Felkin
conformer conformer
R1 L R1 L H L
H H R2
M M R1
O L O L Me M
H H O L
O O H
H R2 A R2 Me O
Me Me H
Me TS-6
Me TS-5 H
gauche Favoured for R2 > Me
syn pentane

O OH O OH
R2 R2
R1 R1

Felkin product Anti-Felkin product

Minor Major

O OBBu2 O O OH
O

O N H O N

62% ds

Evans & Bartoli TL 1982, 23, 807

 α-chiral aldehydes and E-enolates

H
Me R1 L O OH
H O
B R2
Me R1
O L
H
R2
Anti-Felkin product
gauche
OBL2 O Anti-Felkin transition state
Minor
(E) R2
R1 + H

R1 H O OH
L
O
B R2
Me R1
H O L
R2
H
Felkin product
Me
Felkin transition state Major

Example: Spongistatin C15-C16 bond construct

O
H O O
HO
OAc OMe
TESO TESO
O OMe cHex2BCl OH OMe
O O
Et3N O O
O O O O
O O O AcO HO
O
O O
AcO TBSO AcO TBSO HO
OH O
OPMB OPMB
O OCH2CCl3 O OCH2CCl3 O OH
H OH
Cl OH
89%, 90% ds spongistatin 1 (altohyrtin A)

Paterson: ACIEE, 2001, 40, 4055

See also: Evans: Tetrahedron 1999, 55, 8671 (Spongistatin 2)
 Chiral Auxiliaries: Evans’ Oxazoladinones

Bu Bu
B O
O O nBu2BOTf O O
O O OH
iPr2NEt R H
O N O N O N R

iPr iPr iPr

>99 : 1 for achiral aldehydes

• The benchmark - reliable 1,2-syn aldol product via Z-enolate

• Facial bias of enolate overides any inherent selectivity of chiral aldehydes
• Auxillary readily available from parent amino acid (or Aldrich)
• Readily removed by hydrolysis, formation of Weinreb amide

Transition states

O
O
H
O N L N
QuickTime™ and a L O QuickTime™ and a
decompressor H decompressor
are needed to see this picture. B H
O B O
are needed to see this picture.
L L
O O
R R

Favoured

References
Evans et al. JACS 1981, 103, 2127; Pure Appl. Chem. 1981, 53, 1109
Calculations: Goodman and Paton, Chem Comm 2007, 2124
 Chiral Auxiliaries: Evans’ Oxazoladinones

Auxiliaries
O O O O

O NH O NH O NH O NH

iPr Bn Ph Bn

Evans et al. JACS 1981, 103, 2127; Pure Appl. Chem. 1981, 53, 1109 SuperQuat: Davies et al. Tetrahedron 2004, 60, 7553;
OBC 2004, 2, 3385

Applications

O O O O O O O O O O
Cl OBn NBn2
O N O N O N O N O N

Bn Bn Bn Bn Bn
propionate crotyl imide α-chloro glycolate-type α-amino

O O O O

H Et H H Ph H Ph

O O O O OH O O OH O O OH
O OH O OH

O N R O N Et O N O N Ph O N Ph
Cl OBn NBn2
Bn Bn Ph Bn Bn

TL 1986, 27, 4957 TL 1987, 28, 39 Tetrahedron 2004, 60, 7553

 Chiral Auxiliaries: Evans’ Oxazoladinones
Limitations - the acetate aldol
O
BBu2 O O
O O H O OH O OH

O N O N O N

iPr iPr iPr

Ratio = 52 : 48

QuickTime™ and a
decompressor QuickTime™ and a •Competing boat transition states
decompressor
are needed to see this picture. are needed to see this picture. •TS1 - iPr group occupies position pointing away from TS
•TS2 - iPr group occupies position pointing towards TS
•Energy difference between TSs is negligible
•No selectivity

Auxiliary-based Solutions
1. Introduce temporary group 2. Nagao Sn(II) acetate aldol
O
S O Sn(OTf)2 S O OH
BBu2
O O H O O OH O O OH N-Et-piperidine
RaNi O N O N R
SMe
O N O N O N O
i
SMe i
Pr Pr
iPr iPr iPr
H R
93-97% ds
98% ds
Nagao et al. Chem. Soc., Chem. Commun. 1985, 1418
Pure Appl. Chem. 1981, 53, 1109
Nagao et al. J. Org. Chem. 1986, 51, 2391.
 Chiral Auxiliaries: α-oxygenated ketones

O OR O
O O O O
RO
TBSO TBSO TBSO
OR OTBS
TBS
R = Bn R = Bn
R = Bz R = Bz

Masamune Enders Heathcock Paterson Cardo, Marco Romea

JACS 1981, 103 1566 ACIEE 1988, 27, 581 JOC 1991, 56, 2499 TL 1994, 35, 9083 & 9087 TL 1999, 40, 6845 OL 2000, 2, 2599

• Simple chiral ketones

• Use α-substituent to dictate π-facial selectivity
• Aldol products are the manipulated to excise directing group

Syn aldols
L
L O PO H H L
O B O R1 O OH
PO L2BX, R3N PO H R2 B PO
R2 O
L R2
H
1 X = OTf or Cl 1 O 1
R R R
R1 = C6H11, tBu, Me, CH2OBn Me 92-99% ds
P = TBS, TMS, Bn

• Preferential formation of (Z)-enolate due to chelation of reagent with α-alkoxy/siloxy group, independent of reagent

• Chair TS, in which alkoxy group aligned to oppose dipole of enolate oxygen and alkyl group is positioned to avoid
steric congestion
 Chiral Auxiliaries: α-oxygenated ketones
Paterson anti aldols
O
O cHex2BCl OBL2 O OH
BzO Me2NEt H R BzO
BzO
R

95-99% ds

• selective E-enolisation - α-oxygen of benzoate unable to chelate boron reagent

• high levels of selectivity for anti-anti diastereomer
• Enolate induction normally overides any other stereodifferentiating factors

Ph Ph
O H-bond

L O H O O
Me H Me H H
B L O
L O R B
Me Me
O
O R
H L
H

chair boat

• Both chair and revised boat TSs account for π-facial selectivity
• Boat TS - significantly less congested
• A13 strain minimised between Me of enolate and α-stereocentre
• Contrasteric - large OBz directed in to TSs
• Electronic effect - lone pair repulsion between n(O) enolate and Bz group minimised and
TS stabilised by H-bonding of C=O to formyl H,

Paterson et al. Tetrahedron Lett. 1994, 35, 9083 & 9087; Synthesis 1998, 639
 Chiral Auxiliaries: α-oxygenated ketones
Manipulation of α-oxygenated aldol adducts
TBSO H cHex2BCl, Et3N
+ OBz H
+ OBn
O O
O O
cHex2BCl 99%
Me2NEt >97% ds cHex2BCl 85% OBn
Et3N 90% ds
O O
B
TBSO L2
OBz
OBn EtMgBr 92%
OH O 90% ds
OH O
a) PMBTCA, H+
b) NaBH4; K2CO3 a) TBSOTf
b) SmI2 OBn
c) NaIO4
OH OH

TBSO H a) LiDBB
b) NaIO4
TBSO O
PMBO O

JACS 2001,123,9535 TL 1994, 35, 9087

OH O
• useful tool to incorporate anti-aldol motif
• complimentary to Evans syn-aldol
• products readily manipulated to remove superfluous stereodirecting group
• ketones readily available from cheap (R)- and (S)-lactate esters
• not limited to ethyl ketones

O O O O
BzO BzO BzO BzO

C6H13 OMe OP

P = Bn: TL 1994, 35, 9087

TL 1994, 35, 9083 TL 1999, 40, 393 ACIEE 2000, 39, 1308
P = PMB: Shiori et al. TL 1999, 40, 3187
 Reagent Control

Concept : Control absolute configuration by using chiral ligands on boron

OH O OH O

R3 R1 R3 R1
O O R2 R2
L*2BX, R3N
+
R1 R3 H
L* = chiral ligand
2
R
OH O OH O

R3 R1 R3 R1
R2 R2

First example - Meyers and Yamamoto JACS 1981, 103, 4278

O (-)-Ipc2BOTf O tBuCHO OH O

N iPr2NEt N i) workup tBu OMe

BH ii) H+; CH2N2
29%
(based on boron reagent)
94% ds, 79% ee
 Reagent Control: Isopinocampheyl Boron Reagents

X X
B B

(-)-Ipc2BX (+)-Ipc2BX
X = Cl or OTf X = Cl or OTf

• Most common chiral reagents for asymmetric boron aldols

• Ipc2BCl introduced by Brown for asymmetric reduction of ketones in 1985
• Reagents readily prepared from (+)- or (-)-α-pinene by hydroboration
• Ipc2BCl is commercially available from Aldrich, (+)- or (-)-DIPCl
• Ipc2BOTf prepared in situ from the corresponding Ipc2BH

Application of Ipc-reagents for aldol reactions by Paterson

O OHC
OBL*2
O OH
(-)-Ipc2BOTf

iPr2NEt

L* = (-)-Ipc 78%
98% ds, 91% ee

Paterson et al.
Tetrahedron Lett. 1986, 27, 4787; Tetrahedron 1990, 46, 4663; Pure Appl. Chem. 1992, 64,1821
 Reagent Control: Isopinocampheyl Boron Reagents

Origin of facial selectivity Me Me

R
O O
L H L H
O R O
O B B
OBL*2 H
O OH Me
H R H
Me Me Me
R
Me Me
L* = (-)-Ipc
Me Me
Si-face
FAVOURED Re-face
•Competing chair transition states
•Attack on Re-face leads to unfavourable interaction between enolate sidechain and Me of pseudoaxial Ipc ligand
•Calculations predict Si-face addition (88% ee) - consistent with experimental observations (66-93% ee)

Methyl ketones
H
L L
OHC
O H O
B B
O OBL*2 O OH R
(-)-Ipc2BOTf O O
R
iPr2NEt Me
Me
Me Me
L* = (-)-Ipc 59%, 73% ee

Me Me

•Facial selectivity is opposite Re-face Si-face

•Attributed to boat-like transition state FAVOURED
•Confirmed by calculations

Paterson et al.
Tetrahedron Lett. 1986, 27, 4787; Tetrahedron 1990, 46, 4663; Pure Appl. Chem. 1992, 64,1821
 Reagent Control: C2-symmetric borolanes
Me Ph

B OTf B Cl

Me Ph

Masamune Reetz
JACS 1986, 108, 8279 Tetrahedron Lett. 1986, 27, 4721
Pure Appl. Chem. 1988, 60, 1587 Pure Appl. Chem. 1988, 60, 1607
Me

B OTf

Me B B
OH O O OH O
O O RCHO RCHO
R SCEt3 SCEt3 R SCEt3
SCEt3 iPr2NEt SCEt3

71 - 95% yield 71 - 95% yield

syn : anti = >30 : 1 90-98% ee
H
>98% ee
R
O H
Me Me
O
B
H •Enolisation of alkylthioester gives E-enolate, exclusively
Favoured Me •Selectivity rationalised by chair transition state
SCEt3
H •Essentially perfect stereocontrol in anti-aldol products
•Comparable levels of stereocontrol are achieved in thioacetate aldol
clash reaction
H
H Me
SCEt3 • Why is this reagent overlooked?
B
R O
Me Me
O H Practicality: Advantage of high ee outweighed by the 7-step reagent
H synthesis (including diastereomer separation and a resolution)
 Reagent Control: C2-symmetric diazaborolidines
CF3 CF3 CF3 CF3
Ph Ph Ph Ph Ph Ph

Ar Ar
S N B N S F3C S N B N S CF3 F3C S N B N S CF3
O O OO O O OO O O OO
Br Br Br
(R,R)-2 (R,R)-1 (S,S)-1
Corey
JACS 1989, 111, 5493; JACS 1990, 112, 4976;
TL. 1991, 32, 2857; TL 1993, 34, 1737
thiopropionate
BL*2 Ph
O O OH O 71 - 95% yield S S Ph R3N L2B S Ph
(S,S)-1 RCHO
syn : anti = >30 : 1 O L2B O Br- O
SPh SPh R SPh >98% ee L2B
iPr2NEt
Br

diethyl ketone • enolisation of aryllthiopropionate/

O
OH O 68-91% yield diethylketone gives Z-enolates, attributed
(R,R)-2 RCHO syn : anti = >94 : 6 to dissociation of bromide following ate
R Et >95% ee
Et iPr2NEt R= Ph, Et, iPr formation
Ar = p-NO2-C6H4
• high levels of induction
thioacetate • acetate gives reverse sense of induction
O OH O 82-84% yield with high ee
(S,S)-1 RCHO 91% ee: R = Ph • t-butyl propionate enolisation gives
R SPh 83% ee: R = iPr
SPh iPr2NEt “expected” E-enolate

t-butyl-propionate All propionate diastereomers are

accessible simply by choice of starting
BL*2 ester and ligand
O (S,S)-1 O RCHO OH O 82-93% yield
syn : anti = >96 : 4
OtBu Et3N OtBu R OtBu 75-98% ee
 Substrate Control: Syn aldol reactions of α-chiral ethyl ketones
Substrate Control: Use stereogenic centre in a chiral ketone to control facial selectivity, which is then
retained in subsequent steps
Syn aldol reactions

OBL2 O OH
RCHO
RL RL
R
RM RM

RL = large group, RM = medium group

Me Me
R R
O O O OH
L H O OH H L
O O
B RL B RL
H R vs H R
RM RL
L RM L RM
H H
RL RM
FAVOURED

In general,

• reaction of α-chiral (Z)- boron enolates governed by sterics to give syn-syn adduct
• favoured TS, A(1,3) strain and steric interactions are minimised by RL pointing away
from chair TS
• also applicable to titanium aldols (TiCl4, Hunig’s base)

Evans, JACS 1991, 113, 1047

 Substrate Control: Syn aldol reactions of α-chiral ethyl ketones
Examples
O O OH
TBS
nBu2BOTf iPrCHO TBS
iPr2NEt
Enders
90% ds ACIEE 1988, 27, 581

OHC O
TBSO O TBSO O OH
9-BBNOTf steps OH O O

iPr2NEt

83%, 95% ds
ebelactone A
Paterson and Hulme JOC, 1995, 60, 3288

Comparison of metal (Z)-enolates

M M Yield (%) SS : SA
TBSO O TBSO O OH TBSO O OH
iPrCHO
TiCln 96 96 : 4
9-BBN 66 92 : 8
Li 85 17 : 76 : 7(anti)
SS SA

M TBSO O OH
TBSO O
iPrCHO

M = TiCln: 95% ds
M = 9-BBN: 92% ds Titanium: Evans JACS 1991, 113, 1047
Boron: Evans TL, 1995, 36, 9245
Lithium: McCarthy JOC 1987, 52, 4681
•configuration of β-silyloxy has limited effect on selectivity
 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
In general
OBL2 O OH
RCHO
RL RL
R
RM RM

SA
RL = large group, RM = medium group

Anti aldol with (E)-enolate under steric control gives syn-anti diastereomer

H H
R R
O O O OH
L Me O OH Me L
O O
B RL B RL
H R H R
H H
L RM L RM
RM RL
RL RM AA
SA
FAVOURED

•A(1,3) strain is minimised between α-substituent and Me group of enolate in proposed chair TSs
•large group orientated away in favoured TS (chair)
•Boat-type TS can also be envisaged - same stereochemical outcome

L
L H
B
R O OH
O
Me RL
O R
H RM
H
RM SA
RL

Evans: Tetrahedron 1992, 48, 2127; JACS 1995, 117, 6619

 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
Examples: Steric Control

TBSO O TBSO O OH TBSO O TBSO O OH

cHex2BCl iPrCHO cHex2BCl iPrCHO
Et3N Et3N
90%, 94% ds 75%, 96% ds

Evans: Tetrahedron 1992, 48, 2127

With α-chiral aldehydes

O OPMB
BL2
TBSO O H TBSO O OH OPMB

matched

L = cHex 85%, >99% ds

O OPMB
BL2
TBSO O H TBSO O OH OPMB

mismatched

L = cHex 79%, 81% ds

Evans: JACS 1995, 117, 6619

 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones

Paterson’s α-chiral ethyl ketone building blocks

BL2
PO O PO O PO O OH
cHex2BCl RCHO
Et3N R

P = Bn, PMB, DMB L = cHex AA : >95% ds

• Anti-anti diastereomer formed with high selectivity

• Proven building block for assembly of polypropionate units in natural products
• Both enantiomers readily available from commerical (R)- or (S)-Roche ester
• Does not follow steric TS model - electronic effect

OBn

H L
H Me L Me H
BnO H
+ B- -B +
R O
Me L O R
O L Me
O
H
H

Favoured Disfavoured
re-face si-face

TL 1989, 30, 7121; Pure Appl. Chem. 1992, 64,1821; JACS 1994, 116, 11287
Modeling: Tetrahedron 1993, 49, 685
 Substrate Control: Anti aldol reactions of α-chiral ethyl ketones
Applications in synthesis
Sug
O
O OTBS

H I
O
DMBO O DMBO O OH OTBS H OH
cHex2BCl
MeO O O
Et3N I
99%, 95% ds Cl
callipeltoside
OL 2003, 5, 4477
Formaldehyde aldol Pure Appl. Chem. 2008, 80, 1773

PMBO O PMBO O OH
cHex2BCl HCHO discodermolide
Et3N OL, 2003, 5, 35;
JOC 2005, 70, 150
96%, 93% ds

OMe
Propyl ketone with in-situ reduction OH O
L L Sugar
OHC OH O O
BnO O B OH
BnO O O BnO OH OH
cHex2BCl LiBH4 HO O
concanamycin A
Et3N OMe

TL 1997, 38, 4183

94%, 95% ds
ACIEE 2000, 39,1308
In situ reduction: TL 1992, 33,801; Tetrahedron 1996, 52, 811
Benzyloxymethyl-ketone

PMBO O PMBO O OH
cHex2BCl MeCHO
spongistatin 1
Et3N TL 1997, 38, 5727
OBn OBn ACIEE, 2001, 40, 4055
93%, >97% ds
 Substrate Control: Aldol reactions of α-chiral methyl ketones

BL2 H
BnO O BnO O BnO O OH
L2BCl PrCHO
Et3N Pr H
PO L
1,4-syn H O B
L = cHex: 88% ds
L = (-)-Ipc: 92% ds L
O
R'
• Boron aldol reaction of methyl ketone gives 1,4-syn adduct
• Level of selectivity can be increased by using chiral ligand system
• Sense of induction in line with analogous ethyl ketone Paterson, Goodman, Isaka, TL 1989, 30, 7121
• Rationalised by boat TS- formyl H-bond stabilises favoured TS TS Calculations: Goodman and Paton OL, 2006,8, 4299

Application OH
O MeO OMe
O OH O
ODMB
O O
H ODMB

OTES OTES
steps
O
MeO OTBS cHex2BCl, Et3N MeO OTBS H OH
MeO O O
Br Br
(89%; >95 : 5 dr) Br
dolastatin 19

OL, 2006, 8, 2131; Tetrahedron 2007, 63,5806

Pure Appl. Chem. 2008, 80, 1773
 Substrate Control - β-oxygenated methyl ketones
1,5-anti induction

BnO BnO BnO

iPrCHO
L2BCl, Et3N
5 1

TESO OP O L = c-Hex TESO OP OBL2 TESO OP O OH

or (-)-Ipc

1 : P = PMB P = PMB
2 : P = TBS P = TBS
entry ketone L dsa (yield)

1 1 c-Hex 92 (78)
2 1 (-)-Ipc 96 (71)
3 2 c-Hex 77 (80)
4 2 (-)-Ipc 95 (84)
Paterson et al. TL 1996 37, 8585

OTr OTr OTr

Bu2BOTf, iPr2NEt Ph(CH2)2CHO
5 1 R

O O O O O OBL2 O O O OH

Ph Ph Ph
R R = (CH2)2Ph
(70%, >95% ds)
H
PO L Evans et al. JOC 1997, 62, 788; JACS 2003, 125, 10893
H O B

L •High levels of 1,5-anti induction from methyl ketones with bearing β-alkoxy group
O
R' •Numerous applications in polyacetate natural products since discovery
1,5-Anti •Rationalised by boat TS - formyl H-bond and R group points away
Favoured
Goodman and Paton OL, 2006, 8, 4299
 Substrate Control: 1,6-induction - the limit of induction?

γ−methyl-(Z)-enones
RL
Me
RL
Me
H
O (c-Hex)2BCl, Et3N; H L L
6
H
B H O B
OH O 1 O L
O L
iPrCHO O
TBSO OTBS TBSO OTBS R R
99%, 81% ds chair boat

working models

dienolate in s-trans conformation

A(1,3) strain minimised
sterics control facial selectivity
Application
cHex2BCl
O Et3N O H
MeO2C
O O O
TBS
TBSO NH2
OTBS

HO O O O
MeO2C TBS
OTBS NH2

OTBS 64%, 95% ds at C5

Paterson et al. OL 2003, 5, 35; JOC, 2005, 70, 160

Allylboration Reactions
 Allylboration and Crotylboration: Introduction

General process
H L
O R3
B
R5 R4 R2 R6 O L
R3 OH R1
H R6 R5
R2B R1 R5 via
R6 R2 R4
R3 R4 R2 R1
M C B C

2.0-2.2 Å 1.5-1.6 Å

• Transfer of allyl group to an aldehyde via highly ordered cyclic TS

• Reaction proceeds via 6-membered Zimmerman-Traxler transition state
• High levels of relative stereocontrol from tight TS - short B-C bonds
• Control of absolute stereochemistry typically by using chiral boron ligands
Typical applications

Allylation O
OH
H R
R2B R

O O
Crotylation
OH OH
H R H R
R2B R R2B R

(E)-crotylborane anti-product (Z)-crotylborane syn-product

First examples reported by R. W. Hoffmann in late 70’s

Developments through 80’s - 90’s paralleled those in asymmetric aldol methodology and continue today
Resulting terminal olefin can then be elaborated or retained as a masked functionality to be revealed at a later point
Using pinacol-based reagents: Hoffmann & Zeiß ACIEE 1979, 18, 306; JOC 1981, 46, 1309
 Asymmetric Allylboration: Chiral Boronic Esters

Hoffmann - 1979

OH O
O i) MeCHO steps
O B O
Ph ii) N(CH2CH2OH)3
O
93%, 60-70% ee
ent-stegobinone

First example of asymmetric allylboration using camphor-based scaffold

Hoffmann et al. ACIEE 1978, 17, 768; TL 1979, 48, 4653

Hall redesign - 2003

OH
O 10 mol% Sc(OTf)3 OH
O B R O 10 mol% Sc(OTf)3
RCHO
O B R
Ph RCHO
up to 96% ee Ph
94 - 97% ee

OH
O 10 mol% Sc(OTf)3
O B R
RCHO
Ph
70-97% ee

• Subtle redesign of original Hoffmann system

• Movement of Ph-group and use of catalytic scandium triflate boosts ee
Hall et al. JACS 2003, 125, 10160; Synthesis 2004, 1290
 Asymmetric Allylboration: Chiral Boronic Esters

Roush’s tartrate-derived systems - 1985

iPrO2C
OH
O
iPrO2C cHexCHO
OH iPrO2C B cHex
O O
cHexCHO
iPrO2C B cHex
O 90%, 83% ee
iPrO2C
72%, 87% ee OH
O
cHexCHO
iPrO2C B cHex
O

O >99%, 91% ee
iPrO O
iPrO

iPrO O H
iPrO O
B H
O O R B
O Me O
O Me
O
Favoured R

• Practical and predictable system using tartrate ester derivatives

• available in either enantiomeric form
•Favoured transiton state minimises interaction of aldehyde and ester lone pairs
Roush et al. JACS 1985, 107, 8186; TL 1988, 29, 5579

Variations
iPrO2C iPrO2C
OH
O OH O
RCHO RCHO KH R
iPrO2C B iPrO2C B TMS R
O R O
TMS
56%, 92% ee
Z-diene >20:1
Yamamoto et al. JACS 1982, 104, 7667
Roush et al. TL 1990, 31, 7563; TL 1992, 48, 1981
Myles et al. JOC 2003, 68, 6646
 Asymmetric Allylboration: Brown’s Ipc-Reagents
Allylation
H

OH L H
BOMe BrMg B MeCHO O R
2 B
2
Me
BF3•OEt2
H
(-)-Ipc2BOMe >99% ee Me
Me

Me

Crotylation

K
OH
BOMe B MeCHO • Deprotonation of (Z)- or (E)-2-butene with
2 2
BF3•OEt2 Me Schlosser’s base at -78 °C gives respective
anion
(-)-Ipc2BOMe 99% ds, 96% ee
• Formation of reagent by addition of
Ipc2BOMe, followed by BF3•OEt2 to break-
up ate complex
BOMe K B OH
MeCHO
2 2 • Reaction with aldehydes proceeds with
Me
BF3•OEt2
high selectivities
(-)-Ipc2BOMe 99% ds, 96% ee
• Ipc2BOMe commercially available from
Aldrich in either enantiomeric form

Brown et al.
Allylation: JACS 1983, 105, 2092; JOC 1991, 56, 401
Crotlyation: JACS 1986, 108, 293; JACS 1988, 110, 1535
Full paper: JOC 1986, 51, 432
 Asymmetric Allylboration: Soderquist’s 10-TMS-9-BBD Reagents
Allylations
Ph
Ph
Me O TMS O TMS
TMS
BrMg B B OH
B RCHO
Me N MeHN OH
R
H R
96-99% ee
O TMS
air stable x-tals
B R recycled
reagent
10R H
proposed TS

• Treatment of precursor 10R with allylMgBr generates allylborane reagent in situ

• allylation of aldehyde proceeds through proposed TS
• allyl group points away from 10-TMS group
• R group of aldehyde minimises steric interaction with BBD ring system
• 10R recovered by refluxing with (S,S)-pseudoephedrine

Crotylations
TMS K TMS
OH B OH
K B
RCHO RCHO
R 10R R

>98% ds >98% ds
94-95% ee 96-99% ee
Using (S,S)-pseudoephedrine reagent recovery

Initial disclosure: Soderquist et al. ACS Symposium Series 783, Organoboranes for Synthesis, P. V. Ramachandran, H. C.
Brown, Ed., Ch 13, pp 176-194, American Chemical Society, Washington, DC, 2000.

Soderquist et al. JACS 2005, 127,8044

 Asymmetric Allylboration: Soderquist’s 10-Ph-9-BBD Reagents
Ketone Allylations
Ph

Me O O
Ph O Ph
BrMg Ph
Me N B B HO
B RL
tBu
H tBu Rs

70% yield
10R-Ph 99% ee

• 10R-Ph adopts chair-like conformation on side of Ph-group - larger chiral pocket for small group of ketone
• Allows ketone allylation- phenyl group is smaller than corresponding 10R-TMS
• 10R recovered by refluxing with (S,S)-pseudoephedrine
Soderquist et al. JACS 2005, 127,11572

Ketimine allylation
Ph
TMS
Me O N
Ph Ph TMS
BrMg Me NH2
Me N B B R Ph
R N
H R B
Me
50-82% yield
10R-Ph 60-94% ee

• 10R-Ph allylation used to prepare series of enantiomeric enriched 3° carbamines

• Powerful solution to access rare motif
• NB - sense of induction opposite to carbonyl additions
• Ketimine approaches trans to Ph group
Soderquist et al. JACS 2006, 128, 8712
 Asymmetric Allylboration: Soderquist’s Double Allylation

TMS O
Ph H
B B TMS B
B R1
B O
Ph
-78°C, 12 h R1
Ph TMS
B
10S-TMS 10S-Ph
trans-10-SS

rearrangement

BBDPh
BBDPh O Me O
OH OH H2O2, NaOH
O OBBDTMS R1
R1 = iPr, R2 = Ph, 71%, 98% ee R H
R1 = Ph, R2 = iBu, 63%, 98% ee R1 R2 R1 R2

TMS

• Hydroboration of 10S-TMS with 10S-Ph gives diboron reagent

• Ketone allylation followed by borotropic rearrangent
• Subsequent aldehyde allylation and oxidative work-up gves 1,3-diols with essentially complete ds and ee
• Variation of reagent configuration gives access to further diastereomers by design

Soderquist et al. JACS 2009, 131, 1269

 Catalytic Asymmetric Ketone Allylboration
Last decade has seen significant advances in catalytic asymmetric protocols
Aldehyde allylation dominated by use of Ti-BINOL-type catalysis with allylsilanes or allylstannanes
O
OH
H R
TMS R
Ti-BINOL
or
Tagliavini et al. Org Lett 1999,1,1061
>97% ee
Bu3Sn Maruoka et al. TL 2001, 42,1935

Ketone allylation remained a significant hurdle until 2006:

Schaus’s organocatalytic allylboration

O O OH
2 mol% S-3,3-Br2-BINOL
B
Ar Me O t-BuOH, RT Ar

>96% ee
Br
O O OH
4 mol% S-3,3-Br2-BINOL
B OH
Ph Me O t-BuOH, RT Ph OH

97% ds, 98% ee Br

O O OH
4 mol% S-3,3-Br2-BINOL S-3,3-Br2-BINOL
B
Ph Me O t-BuOH, RT Ph

96% ds, 94% ee

Schaus et al.
Shibasaki reported CuF2-DUPHOS system in 2004 (~80% ee) Original report: JACS 2006, 128, 12660
JACS 2004, 126, 8910; For review, see: Chem. Rev. 2008, 108, 2853 Optimised reaction: ACIEE, 2009, 48, 1
 Schaus’s organocatalytic allylboration
Catalytic Cycle
O O OH Br
2 mol% S-3,3-Br2-BINOL
B
Ar Me O t-BuOH, RT Ar
OH
>96% ee OH

OH O Br
HO B
Ph O S-3,3-Br2-BINOL
HO

HO
H
O O HO
H
Me B O
O O
O B
Ph O

with OiPr
HO
H B
Ph O OiPr
O O
Me B
O Schaus et al.
O Original report: JACS 2006, 128, 12660
Ph
Optimised reaction: ACIEE, 2009, 48, 1

With acyl imines

O

N Ph OiPr 15 mol% S-3,3-Ph2-BINOL NHBz

B • NB - reversal of facial selectivity
R H OiPr PhMe, RT R
• High ee’s
R= alkyl, aryl • Crotylations also very efficient
91-98% ee
Original report: JACS 2007, 129, 15398
 Substrate-directed allylborations
R. W. Hoffmann intramolecular allylations
MeO OMe
LiBF4
X X
Bpin
MeCN OH
H X=O X = O, >98% ds
X = NCO2Me X = NCO2Me, >98% ds
O
O
B
O OH
MeO OMe
>98% ds Bpin OH
LiBF4
X X
Liebigs Ann. Chem. 1993, 1185 MeCN
X=O X = O, 94% ds
X = NBoc X = NBoc, >98% ds
Liebigs Ann. Chem. 1996, 1283

OMe OMe OMe

MeO H Bpin MeO Bpin LiCH2Cl MeO Yb(OTf)3
O O O Bpin HO O
Rh(PPh3)3Cl

Matteson: Organometallics 1985, 4, 1687

Brown: JOC 1986, 51, 3150

Synthesis of medium ring ethers

N(Me)OMe

O DIBAL; s-BuLi
pinB-OiPr O HO

OTBS then pH7 OTBS OTBS

O O O
pinB
laurencin core JACS 1997, 119, 7499

For an overview, see: Hoffmann et al. ACS Symposium Series 783, Organoboranes for Synthesis, P. V. Ramachandran, H. C. Brown,
Ed., Ch 12, pp 160-175, American Chemical Society, Washington, DC, 2000
 Substrate-directed allylborations
Hall’s sequential HDA-allylation

Bpin Bpin
Jacobsen-HDA RCHO QuickTime™ and a
R decompressor
O OEt are needed to see this picture.
O OEt O OEt
OH
>99% ds, 96%ee
R = aryl, alkyl

JACS 2003, 125, 9308

Chem. Eur. J. 2006, 12, 3132
Jacobsen HDA, see: ACIEE 2002, 41, 3059

Application in Synthesis
Bpin
O
Bpin Bpin
OPMB
Jacobsen-HDA HO pinB
O O OEt
pinB
O OEt O
O OEt O OEt EDCI
OH PMBO
O
84%, 96 % ee
LDA,
TMSCl•NEt3

pinB
OPMB OPMB O OEt
H2O2, NaOH [3,3]
MeO HO O
O OEt O OEt PMBO
then CH2N2
O OH O Bpin OTMS
55%, >98% ds
• HDA-allylation with aldehyde then sets stage for B-Ireland-Claisen
• Allows hydroxyl differentiation and rapid assembly of carbon framework
palmerolide A
JACS 2009, 131, 14216
Vinylations and Homologations
 Petasis Reaction
General Scheme
R1 H OH R1
R1 O OH heat R4 transfer
N O B N R4
N B
R 2
H R 3
H R4
OH R 2
OH R2
R3 R4 R3
R1 = alkyl R3 = alkyl, COOH, aryl R4 = alkenyl, aryl,
R2 = alkyl, OH, heteroaryl
O-alkyl, NHBoc

• Formation of hemiaminal, followed by ate formation

• Transfer of alkenyl or aryl group from intermediate ate complex gives allylic/benzylic amine products
• Mechanism remains a point of discussion
TL, 1993, 34, 583; Tetrahedron 1997, 53, 16463; JACS 1997, 119, 445
Modifications
Hydroxyl-Directed
R1 R2
O R1 R2 N
1
R OH heat N R4 transfer
R3 R3
N H B R3 R4
R2 H R4 OH H
OH OH
R4 O
R1 = H, alkyl, benzyl R3 = alkyl, CH2OH R4 = alkenyl, aryl, B
OH
R2 = alkyl, benzyl heteroaryl OH >99% de

JACS 1998, 120, 11798

Cyclic N-acyliminium
OH OH HO OH
H
O OH
BF3•OEt2
N OH B N
O OAc N OAc
Cbz Cbz
6-deoxycastanospermine

Batey et al. JACS 1999, 121, 5075; TL 2000, 41, 9935

 Asymmetric Petasis Reactions
Takemoto - 2007 CF3
CF3
S
S
F3C N N
R1 R2 OH F3C N N
H H H H N
B N R1 HO
Ar OH R1 R2 O
N 10 mol% B
HO O
Ar N OPh
O N
CO2Ph
Cl OPh Ph
R2
82-96% ee
TS-concept
•Vinylation of N-acylated quinolines catalysed by isothiourea
Takemoto et al. JACS 2007, 129, 6687

Schaus - 2008

R1 Bn
O N
R1 OEt 15 mol% (S)-VAPOL
OEt OEt
N H B R2
Bn H R2 OEt 3A MS, -15 °C, PhMe Ph OH
O O
Ph OH
R1 = alkyl, benzyl R2 = aryl, alkyl 78-94% ee

• First asymmetric variant of classical Petasis reaction catalysed by chiral biphenol

• Need to use ethyl glyoxalate to achieve high ee’s (S)-VAPOL
• Tolerates range of FGs in both amine and vinyl boronate

Lou & Schaus JACS 2008, 130, 6922

 Rh-mediated 1,4-addition of Boronic Acids
Miyaura-Hayashi 1997
O Rh(acac)(CO)2 / dppb O
(3 mol%)
Ph B(OH)2
cyclohexane/ H2O ( 6 : 1)
50°C, 16h Ph
52%
Asymmetric: Miyaura-Hayashi 1998 Miyaura, Hayashi et al. Organometallics 1997, 16, 4229

O Rh(acac)(C2H4)2 / (S)-BINAP O
O Rh(acac)(C2H4)2 / (S)-BINAP O
(3 mol%)
Ph B(OH)2 (3 mol%)
B(OH)2
dioxane/ H2O ( 10 : 1)
Ph C5H13 dioxane/ H2O ( 10 : 1)
100°C, 5h C5H13
100°C, 5h
93%, 97% ee
64%, 96% ee

PPh2 • Initial report closely followed by asymmetric variant

PPh2 • Uses Rh-Binap catalyst
• Both aryl and alkenyl boronic acids can be used with generally high ee
• Remains the benchmark for other metal ligand systems
(S)-BINAP
Miyaura, Hayashi et al. JACS 1998, 120, 5579

Esters and amides

O Rh -BINAP O
(3 mol%)
X Ar B(OH)2 X •High ee’s for cyclic lactone/lactams
dioxane/ H2O ( 10 : 1) •Comparable ee’s for acyclic systems under
100°C, 5h Ar
same conditions
X = O, 97-98% ee
X = NBn, 97-98% ee

Esters: Hayashi et al. Tetrahedron: Asymmetry 1999, 10, 4047

Amides: Hayashi et al. JOC 2001, 66, 6852 For review, see: Chem. Rev. 2003, 103, 2829
 Rh-mediated 1,4-addition of Boronic Acids
Addition of organotrifluoroborates

O [Rh(cod)2][PF6] / (R)-BINAP O O [Rh(cod)2][PF6] / (R)-BINAP O

(3 mol%) BF3K (3 mol%)
BF3K
S
toluene/ H2O ( 10 : 1) toluene/ H2O ( 10 : 1)
105-110 °C C6H13 105-110 °C C6H13 S
99%, 92% ee
84%, 90% ee

• Extended to include organotrifluoroborates (easier to handle, greater stability)

• Addition of vinyl group - not possible with vinyl boronic acid

Genet et al. TL 2002, 43, 6155; EJOC 2002, 3552

Tandem 1,4-additon - alkylation/aldol reaction

O

BuLi, allylBr
BBN
O Rh(OMe)(cod)2 / (S)-BINAP O Ph
(3 mol%) 98% ee
Ph B(OH)2
toluene
80°C, 1h Ph
O OH
PrCHO H
Pr

Ph
Reaction performed under aprotic conditons using B-Ar-9-BBN 98% ee
Intermediate Rh-enolate transmetallates back to 9-BBN-enolate
Followed by direct aldol addition
Or further transmetallation with BuLi enables alkylation Hayashi et al. JOC 2003, 68, 1901

For review, see: Chem. Rev. 2003, 103, 2829

 Organocatalytic 1,4-additions of Boronic Esters
Asymmetric Alkynylation: Chong 2005
C6H13
I
(S)-3,3-I2-BINOL
O iPrO O
20 mol% OH
B C6H13
Ph R iPrO DCM Ph R OH

R = Ph, 94%, 86% ee I

R = Me, 89%, 94% ee (S)-3,3-I2-BINOL
• Asymmetric addition of alkynylboronic ester to enones
• Enone must contain aryl group to achieve high ee
• Chong proposes complete ligand exchange with catalyst- see Schaus allylation for alternative view
Wu & Chong JACS 2005, 127, 3244

Asymmetric Alkenylation: Chong 2007

C6H13 QuickTime™ and a
decompressor
are needed to see this picture.
(R)-3,3-I2-BINOL R = Ph, 93%, 97% ee
O MeO O
20 mol% R = Me, 95%, 96% ee
B
Ph R MeO C6H13 DCM Ph R R = CO2Me, 84%, 97% ee

R
(R)-3,3-I2-BINOL
O MeO O R = CH2OBn, 83%, 97% ee
20 mol%
B R = Ph, 97%, 98% ee
Ph Ph MeO R DCM Ph Ph QuickTime™ and a
decompressor
are needed to see this picture.

• Analogous alkenylation also proceeds with high ee

• Trisubstituted alkenylboronic esters can also be used
•Possible TS’s shown for (R)-3,3-I2-BINOL
Wu & Chong JACS 2007, 129, 4908
 Organocatalytic 1,4-additions of Boronic Acids
Takemoto 2009
CF3
R2
S
O OH 10 mol% thiourea* O
OH B OH F3C N N
R1 R2 OH PhMe, rt R1 H H
N

R1 = aryl R2 = aryl 91-98% ee thiourea* HO OMe

• Combination of hydrogen bonding to isothiourea

and formation of ate complex between substrate,
boronic ester and catalyst prior to intramolecular
transfer

Derivitisation of products OMe

OMe

MeO
H 1. NBS DIAD, PPh3,
O 2. tBuOK O o-NsNH2 Ph
O OH
Ph
Ph O
H

Takemoto et al. OL 2009, 11, 2425

 MacMillan’s α-vinylation of aldehydes
O O O
20 mol% 1•TFA R NMe
H KF3B H
R 2.5 eq CAN, H2O N
C6H15 C6H15
DME or Acetone, -50°C Ph H
•TFA
R = aryl, alkyl 89-95% ee
1•TFA
• Organo-SOMO catalysis -
• Applicable to range of aliphatic aldehydes with high selectivity

O O O
O NMe NMe NMe
-H2O
H N N Bn
H N
X Ph - 1e- Ph
X

X
KF3B
KF3B R
R

- 1e-
O
X H2O O O
H
NMe NMe

Bn Bn N
N
R
X X

KF3B
R R

• Single electron oxidation of intermediate enamine

• Radical cation then undergoes reaction with alkene
• Further single electron oxidation of intermediate radical
• Dicationic species then undergoes Peterson-like trans-elimination of boron trifluoride
Kim & MacMillan JACS, 2008, 130, 398
 Aggarwal’s Homologation of Boranes and Boronic Esters
OLi
O O O
LiCHCl2 O OtBu
B B B
B O
O O O
Cl Cl Cl OtBu
O
• Matteson reported the homologation of boronic esters in 1980 using LiCHCl2
• Use of chiral pinane diol ester enabled asymmetric version - though applications limited
Matteson et al. JACS, 1980, 102, 7588 & 7590

• Alternative would be to use chiral deprotonation - Aggarwal 2007

R2 BBN
or R2
s-BuLi BL2 R2
(-)-sparteine
Li O MgBr2 H2O2 R2
R2 Bpin
R R R R
R OCb O NiPr2 OCb BL2 OH
H H H H
R2 = Et, Ph
R = alkyl 90-96% ee
transmetallation with retention Li O
R3
O NiPr2
H

HO HO HO HO
R R2 R R2
H H2O2 H
Ph Ph Ph Ph
R3 R3
BL2 OH
H H
>90% ds, >96% ee
• Utilises Hoppe’s chiral deprotonation to give stabilized lithiated carbamates
• Reaction with alkyl/aryl boranes or boronates proceeds with retention
• Migration of alkyl/aryl group from B to C -
• Further iterations possible by sequential addition of lithiated carbamates/migration process
• Either enantiomer of lithiated carbamate available by use of appropriate sparteine/ sparteine surrogate

Aggarwal et al. ACIEE 2007, 46, 7491

 Aggarwal’s Homologation of Boranes and Boronic Esters

R2 BBN
or R2
s-BuLi BL2 R2
(-)-sparteine
Li MgBr2 H2O2 R2
R2 Bpin
R R R R
R OCb OCb OCb BL2 OH
H H H H
R2 = Et, Ph
R = alkyl 90-96% ee
sp3 - C-Li transmetallation with retention

• For R = alkyl: transmetallation occurs with retention- C-Li sp3 hybridised

Et
Et Bpin Bpin heat Et H2O2 Et
HO Me
Me Me Me
retention OCb Bpin OH
Ar Ar Ar Ar Et
Me Li
s-BuLi 98% ee
Me
Ar OCb OCb
Ar

Et BEt2 Me heat Me H2O2 Me Me OH

OCb Bpin OH
Ar Ar Ar
Ar Et
inversion Bpin Et Et
Et
98% ee

R
• With substituted benzylic-type carbamates - lithiated O
carbamate has more sp2 character, resulting in flatter RO B
anion - interaction with Ar group Et Li O Li O

Me Me
• For boronic ester- interaction with Li and OR group of O NiPr2 O NiPr2
Ar Ar
boronic ester delivers on same face as metal -retention
Et BEt2
• For borane- no complexation and significant electron
denisty on opposite face - inversion
Aggarwal et al. Nature 2008, 456, 778
Extras
 β-alkoxy aldehydes
For E-enolates - effect of β-oxygen is moderate, Felkin adduct predominates
BL2
O O OR O OH OR O OH OR

L = cHex
R major minor

centres reinforcing TBS 99 1

PMB 93 7
BL2
O O OR O OH OR O OH OR

L = cHex
R major minor

centres non-reinforcing TBS 94 6

PMB 74 26 Evans JACS 1995, 117, 9073
For methyl ketones - effect of β-oxygen is not so predictable
BL2
O O OR O OH OR
BL2
O O OPMB O OH OPMB Bn
H
H Bn
BL2 = 9-BBN
BL2 = 9-BBN R = PMB, 77% ds
69% ds
R = TBS, 48% ds
BL2
O O OPMB O OH OPMB
BL2
H O O OTBDPS O OH OTBDPS

BL2 = 9-BBN 77% ds H

β-OPMB dominates - 1,3-anti addition
L = cHex 89% ds
 Chiral Auxiliaries: Oppolzer’s Sultam

nBu2BOTf
iPr NEt
O 2
O O OH
N N L
Me O N
S B L R
O2 S
H R O2 H O Me
SO2
H
R > 97% ds
crystalline

Complimentary Sn-aldol

BuLi H O OH
Bu3SnCl O Me
O
N N N
R R
Me O S O
S H
O2 SO2
H R O O
Sn
Bu Bu
Bu 64-87% ds
crystalline

Oppolzer et al. JACS 1990,112, 2767

 Substrate Control: α-amino ethyl ketones

α-amino ethyl ketones

OBBu2 Bu2BOTf O cHex2BCl OB(cHex)2

Bn2N iPr2NEt Bn2N Me2NEt Bn2N

(Z)-enolate (E)-enolate

Me H
R R
O O
L H L Me
O O
B B
H H
NBn2 H
L L
H Me
Me NBn2
Control: Opposing dipoles Control: Sterics

iPrCHO iPrCHO

O OH O OH
Bn2N Bn2N

SA: 86% ds AS: 85% ds

Paterson and Mackay: TL 2001, 42, 9269

 Substrate Control - β-oxygenated methyl ketones
PO O
Origin of 1,5-anti induction
R
Comparison of Expt’l and Calculated dr
Goodman and Paton OL, 2006, 8, 4299 L2BX, R3N;
R'CHO

R H

H R
PO O OH PO O OH
PO L L OP
R R' H O B B
O H R R'

O L L O
R' R'
1,5-Anti 1,5-Syn
Favoured

methyl ketone major adduct exp. dr model system major adduct pred. dr

B(c-Hex)2 BMe2
PMBO OMe O PMBO OMe O OH OMe O OMe O OH
i) i-PrCHO 75:258 MeCHO 80:20

OTBS OTBS
B(c-Hex)2 BMe2
PMBO O PMBO O OH OBn O OBn O OH
ii) Ph(CH2)2CHO 94:065 MeCHO 97:03
(CH2)2Ph

PMP PMP Ph Ph
BBu2 BMe2
O O O O O O OH O O O O O O OH
Ph(CH2)2CHO
iii) 93:075 MeCHO 100:00
(CH2)2Ph

B(c-Hex)2 BMe2
TBSO O TBSO O OH TMSO O TMSO O OH
iv) i-PrCHO 58:423 MeCHO 66:34
 Substrate Control: Merging 1,4- and 1,5-induction

combine effects to increase selectivity

TBSO

PMBO O PMP PMP

H cHex2BCl,
(-)-Ipc2BCl OTBS O O O O O O OH
Et3N
Et3N O
MeCHO

TBSO
OTBS >95% ds
PMBO O OH
Dias et al. OL 2002, 4, 4325
83%, 95% ds
Mulzer & Burger TL 1998, 39, 803

Paterson discodermolide synthesis

cHex2BCl,
Et3N OHC
5 1
MeO2C MeO2C R 4
PO O PO OBL2 PO O OH

P = TBS, PMB 1,4-syn 1,5-anti (major) P = TBS: ACIEE, 2000, 39, 377; TL 2000, 41,
P = TBS (62%, 54% ds) 6935; JACS 2001, 123, 9535
P = PMB (73%, 95% ds) P = PMB: Florence & Paterson, unpublished
24

O 7
L2BCl, Et3N
MeO2C
H O O O
TBSO O 24
TBS
OTBS NH2 L Yield ds
MeO 1 7S
cHex 67 16
(+)-Ipc 87 84
O O O OH O O O
TBS TBS
Use chiral reagent in combination to overturn aldehyde facial selectivity OTBS NH2
 Asymmetric Allylboration: Brown’s Ipc-Reagent Diversity
Methallylation

BOMe BuLi, TMEDA B OH

RCHO
2 2
R
BF3•OEt2 • acetone aldol equivalent
(-)-Ipc2BOMe 90-96% ee
TL 1984, 25, 5111; JOC 1986, 51, 432

Isoprenylation

BH B OH
RCHO
2 2
R

(-)-Ipc2BH 89-96% ee
TL 1984, 25, 1215; JOC 1986, 51, 432

K
BOMe B OH
RCHO
2 2
R
BF3•OEt2

(-)-Ipc2BOMe 90-96% ee TL 1990, 31, 455

methoxyallylation chloroallylation
OMe Cl
OH OH
s-BuLi B RCHO LDA B RCHO
(-)-Ipc2BOMe 2 (-)-Ipc2BOMe 2
OMe R Cl R
BF3•OEt2 BF3•OEt2
OMe Cl
95-96% ee 90-99% ee

JACS 1988, 110, 1535 Hu, Jayaraman & Oehlschlager JOC 1996, 61, 7513
 Asymmetric Allylboration: Soderquist’s 10-TMS-9-BBD Reagents
R1
Anti-allenylation R1
R1

TMS TMS EtO TMS TMS

H B
LiAlH3(OEt) B B B
TMSCl R1 Li EtO BF3•OEt2
10R-TMS

10R-TMSBBD-H
O

R2 H
1
R R1

R1 = nC5H11, R2 = Pr, 73%, 98% ee 2 H2O2

R O TMS
R1 = (CH2)4Cl, R2 = Ph, 78%, 99% ee NaOH
B
OH R2

• Sequential alkyne hydroboration-insertion-allylation to give 1,2-anti-3-allenes

• Tolerates wide-range of terminal alkynes
• High levels of selectivity
• Syn variant is also comparable

syn-allenylation

TMS EtO O
H
B TMS TMS
MgBr B B Ph H
Li Ph
BF3•OEt2 then
H2O2 OH
NaOH
10S-TMSBBD-H 71%, 96% dr, 99% ee

Soderquist et al. JACS 2009, 131, 9924