Organometallic Compounds

Dr. Ajay Kumar Das Associate Professor Department of Chemistry MLT College Saharsa ajaykumardas518@gmail.com 9431863881

Li H

B

Cr

Organometallic Reagents in Synthesis

Organometallic and other C-C bond forming reactions in some representative syntheses: Li = lithium reagent, Mg = Grignard reagent, Cu = organocopper reagent, P = Wittig reagent, Li/P Na/P K/P Horner-Wadsworth-Emmons, Pd/Sn = Stille coupling, Pd/Zn = Negishi coupling, Li/Si = Peterson olefination, Zr/Al = Tebbe reagent, B = organoboron reagent, R = Radical addition/cyclization.

Isoamijiol (14-deoxy)Majetich, G.; Song, J. S.; Ringold, C.; Nemeth, G. A.

Tetrahedron Lett. 1990, 31, 2239

Ruguluvasines A and BLiras, S.; Lynch, C. L.; Fryer, A. M.; Vu, B. T.; Martin, S. F.

J. Am. Chem. Soc 2001, 123, 5918.

H R OH O

LiLi

Si Cu R = Radical

Pd/Sn OSi

NHMe

K

HN

Shahamin KLebsack, A. D.; Overman, L. E.; Valentkovitch, R. J.

J. Am. Chem. Soc. 2001, 123, 4851.O

AcOH

OLi

Cationic cyclization olefinLi OAc

PironetinDias, L. C.; Oliveira, L. G.; Sousa, M. A.

Org. Lett. 2003, 5, 265

OLi

OMe OH OLi P/Na

LI

Cu H LiB B

Penostatin A (Deoxy)Snider, B. B.; Liu, T.

J. Org. Chem. 2000, 65, 8490-8498.

MorphineTaber, D. F.; Neubert, T. B.; Rheingold, A. L.

J. Am. Chem. Soc. 2002, 124, 12416P/Li

O

H Diels Alder (hetero)N

HLi K

LI

H PO

K OOH

P/Li Li C7H15Carbene

Okinellin BSchmitz, W. D.; Messerschmidt, N. B.

OH

LaurenyneOverman, L. E.; Thompson, A. S. J. Am. Chem. Soc.

O

J. Org. Chem. 1998, 63, 2058

HLi Li Pd/Zn

Zr/AlO

O

1988, 110, 2248

Cationiccyclization olefin

Li

O

ClK/P

K

Li/Si

MgSi

OH

HirsuteneD. P. Curran, D. M. Rakiewicz

J. Am. Chem. Soc., 1985, 107, 1448.

DysidiolideMadnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.;

Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1615.

Li

R HR

LiR = Radical cyclization

OLi

Cu

Cu

Pd•

Li

LI

H53%

H Claisen OOH

OH

1 11

2 1 1

3

2

3

2

B BO

B B Li

2

1

1

3

2 13

H

Li

t

Tedanolide (13-deoxy)Smith, A. B.; Adams, C. M.; Barbosa, S. A. L.; Degnan, A. P. J. Am. Chem. Soc 2003, 125, 350

Li Li

P LiP

S S+ PPh3

+ PPh3

S

LiS Li

OH

BrP

Br

OO

OTIPS

HP

+ PPh3

CO2Me P

P

P

2 2

O OMe O

O

1 3 3

OH O O

P

LiOH

Li

Li

OMe OPMB

Li

S S

L

O O B-Enolate O O B-Enolate CO2iPr

O N O NO

BO

CO2iPr

B Ph B Ph B

Organometallic Reactions in Partial Synthesis of Spongistatin 1Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675 CO2iPr

Major disconnections B(Ipc)2B(Ipc)2 (Mg)

OB O

CO2iPr

OHO O OBn

Li

S

BnO

TESO

S

H

OO

H Li

PhSO2

S

OTES

S

Cl

Li

H

Li

HOHO

Li

O

OHO

OH

AcO

Li

O

B

O

B

B

H

H

OLi

Li(Cu)

HO

HO

Li

H

OLi

O

Li

Li

Li

BOAc

OMe

O PhSO2

Li

Li

LI

OTBSOH

Li

SS

Li

Spongistatin 1

Li SiMe2 BuLi

PhSO2 OTESPhSO2

OTBSS S S S

OPMB

:

+

_ _ _ _

_+

_ _ _ _ _

_+

_ _ _

_+

+ _

Classes of Nucleophilic Organometallic Reagents

C M

C M

C M

C M

+ Strong Carbanion, M Weak Lewis Acid

R Li, R Na, R K, (R MgX)

Weak Carbanion, M Lewis Acid

R B, R Al, R Zn, R Ti, R-SiX3, (R MgX)

Weak Carbanion, M Non-Lewis Acidic

R Si, R Sn, R Hg, various ate complexes

Weak Carbanion, M Lewis Base

R2Cu , Pd°

High nucleophilicity

Stereochemical controlNucleophilic catalysisCyclic transition states

Regiochemical controlIsomerically stable

Unusual Reactivity patternsHigh selectivity towards electrophiles

Balancing the Reactivity of Nucleophile and Electrophile

N + E N E

O O

H +X R R

+ HX

Activate the nucleophile:O O

Li +Me2N R R

BuLi

Br

Activate the electrophile:

H +O +

R

O

R+ HCl

AlCl3O

Cl R

Assemble on a transition metal (mildly activate both E and N):

SnMe3 +

O

Cl RPd(0)

O

R+ Me3SnCl

:

-

t

-

O O O

Preparation of Organolithium Reagents1. Reduction of carbon-X bonds with lithium metal

R-X + 2Li° R-Li + LiX MeLi PhLi n-Bu-Li t-BuLi s-Bu-Li

X = Cl, Br, I, SPh

2. Metalation (Li/H exchange)

R-H + R'Li R-Li + R'-H

3. Lithium-metalloid exchange (Li/M)

R-M + R'Li R-Li + R'M

M = Br, I, SnBu 3, HgCl, SePh, TePh

4. Addition of RLi to C-C multiple bonds.

Li

OMe

Li O

RO Li

PhLi

BnOBnO

O OS

LiBn

O O

H

R-C≡C-Li

Li

RR'Li

R

Li

R'Ph

Li

RPhSO2

Li

R

5. Metalation of N-sulfonylhydrazones (Shapiro)

N NHSO2Ar 2 n-BuLiLi

Effect of Substituents on Carbanion StabilityGas Phase Acidity (kcal/mol)

Type: CH2 -X pKa of H-CH2-X Typical Metalating Agents (CH3)2CH: 10

Destabilizing (compared to H)* >60 None available -CH3

CH3CH2: CH3: 0 416.6

Very Weak** 50-60 sec-BuLi, n-BuLi/TMEDAn-BuLi/ BuOK

-OR -NR2 -SiR3 H2

H C=CH: -10

Weak*** 40-50 n-BuLi, sec-BuLi, LiTMP

SR PR2 SeR BR2

CH=CH2 -C≡C-R -Halogen -Ph

Intermediate 30-40 LDA, n-BuLi, KHO O O

CN-

O N-R NR2

OO

S S Se P

Ph:

ClCH2:MeSCH2:

Me3SiCH2:

H2C-CH-CH2: Me2PCH2:

PhCH2:

HC≡C:

Cl2CH: (Me2P)2CH:

-20

-30

-40

-50

H: NH2:

HO:

Me3Si:

CH3O:

F:

R R R R RStrong 20-30 KO-t-Bu, NaH, LDA

(Ph)3C:

-60CH3S:

O O

R OR

+S

R

R'

+PR3

KH, LiN(TMS)3

- H -70

HS:

Me3Sn:

SO2CF3

Very Strong

-NO2+

-N ≡N

10-20 NaOH, KO-t-Bu, DBU -80Brauman J. Am. Chem. Soc.

1995, 117, 4908.

***

***

Alkyl groups are invariably kinetically deactivating.

These types are not usually prepared by metalation, but by other techniques (Li/Sn, Li/Halg exchange, reduction of halogen or SR).

Need two of these (X-CH2-X') for easy metalation with LDA.

The aromatic anions (6e π system) show a level of stabilization far above that of normal conjugated systems

Effect of Substituents on Carbanion StabilityK

1. HybridizationIn almost all areas of organometallic chemistry the primary subdivision of reactivity types is by the hybridization of the

C-M carbon atom (methyl/alkyl, vinyl/aryl, alkynyl). A key second subdivision is the presence of conjugating substituents (allyl/allenyl/propargyl/benzyl).

The fractional s-character of the C-H bonds has a major effect on the kinetic and thermodynamic acidity of the carbon acid. Only s-orbitals have electron density at the nucleus, and a lone pair with high fractional s character has its electron density closer to the nucleus, and is hence stabilized. This can be easily seen in the gas-phase acidity of the prototypical C-H types, ethane, ethylene and acetylene, as well as for cyclopropane, where the hybridization of the C-H bond is similar to that in ethylene.

CH3-CH3 CH2=CH2 HC≡CH

ΔH°acid (kcal/mol) 420 411 406 375

These effects are also clearly evident in solution, with terminal acetylenes and highly strained hydrocarbons easily metalated by strong bases.

Li

n-BuLi

JACS-72-7735

2. Inductive EffectsElectron-withdrawing substituents will inductively stabilize negative charge on nearby carbons. These effects are

complex, since electronegative substituents interact with carbanions in other ways as well (e.g. O and F substituents have lone pairs, which tend to destabilize adjacent carbanion centers).

O OS

PhH

O OS

PhCH3

O OS

PhOMe

O OS

PhF

O OS

Ph

+NMe3

H H H H H

pKa (DMSO) 29.0 31.0 30.7 28.5 19.4

3. Conjugation - π DelocalizationDelocalization of negative charge, especially onto electronegative atoms, provides potent stabilizations of carbanionic

centers. Since almost all conjugating substituents are also more electronegative than H or CH 3, there is usually a significant inductive contribution to the stabilization.

O O NCH4 CH3 H H C H

t-BuO

pKa (DMSO) ~55 43 26.5 30.3 31.3

A special case is the aromatic stabilization of cyclopentadienide and related indenide and fluorenide anions (Huckel 4n + 2 π electron rule) .

pKa (DMSO) 18.0 20.1 22.6 30.1

ΔH°acid (kcal/mol) 356.1 373.9

H

K 4. Second and Third Row Element Effects ("d-orbital" effects)All measures of acidity show that there is an unusual level of carbanion stabilization for all second row elements (Cl,

S, P, Si, as well as higher elements) when these are bonded to a carbanion center.

Kinetic acidityIsotopic exchangeKNH2/NH3

CH3

0.41

300

0.25

0.45

S

6

CH3 10

330

24

6

O

0.25

0.25CH3

500

1

CH3N

0.07

CH3 0.013

14

0.2

Ph

OX

X Me

pKa (DMSO) 24.4

OMe OPh SPh SePh

22.9 21.1 17.1 18.6

Bordwell J. Org. Chem. 1976, 41, 1885

Gas phase acidity

ΔH°acid (kcal/mol)FCH3 MeOCH3 Me-CH3 409 407 420.1

ClCH3 MeSCH3 Me3SiCH3

ΔH°acid (kcal/mol) 395.6 393.2 390.9

ΔΔH°acid 13.4 13.8 19.2

The origin of this stabilization has several components. Classical overlap of the lone pair with the empty d-orbitals is at best a minor contributor, since the d-orbitals are too diffuse and too high in energy. For the electronegative elements(Cl and S) there is an inductive component. For those bearing substituents (SR, PR of σ-hyperconjugation (delocalization of charge into X-R σ* orbitals).

2, SiR3) there is a major contribution

R

S

d-orbital interaction

nσ*

R

S C

Negative hyperconjugation

A factor comparable in size to σ-hyperconjugation is the σ bond strength effect. There is a size difference between the 3p orbitals of the S and 2p orbitals in the C-H compound. In the carbanion the C orbital increases in size, resulting in a stronger sigma bond. In an oxygen-substituted system the orbital mismatch is in the opposite direction (the p orbital at oxygen is smaller than that at carbon, and this size difference is excacerbated in the carbanion). Superimposed on these effects are possible lone pair effects (Cl, S, P).

R H R R H RS C S C O C O C

R H R R H R

σ bond is stronger in S-substituted carbanions because of better orbital size match (negative charge increases size of C-S orbital)

5. Lone Pair Effects

σ bond is weaker in O-substituted carbanion because of poorer orbital size match

For the first row elements N, O, F, and perhaps also for higher elements, the presence of lone pairs has a strong destabilizing effect on a directly bonded carbanion center. This has several effects on carbanion structure: there are substantial rotational barriers around the C-X bond and the carbanion center is usually more pyramidalized.

7

7

3

1

1

7

1

1

1

1

3

3

3

1

5

4

3

1

2

6

2

2

2

5 1

1

1

Gas Phase Acidities

δΔH°acid (kcal/mol) 10 ΔH°acid (kcal/mol)

CH3-CH3 (420.1)2

Me2CH2 (419.4)2 420

CH4 (416.6)1

Me3CH (413.1)20

FCH3 (409)3

H2

H

HC=CH2

(408)

(407) -10

410

CH3OCH3 (407)3PhCH2CH2-H (406)7

ClCH3 (395.6)3

Ph-H (400.7)4

-20

400 H2 (400.4)

NH3 (399.6)

1

1

MeSCH3 (393.2)3

H2

Me3SiCH3 (390.9)

C=CH-CH3 (387.2)

3

1F2CH2 (389)7

CH2C(O)-H (387)

H

7

-30

390 HO-H (390.8)1

Me2PCH3 (384) PhCH3 (379.0)

CH3SOCH3 (372.7) N≡CCH3 (369)

CH3COCH3 (368.8) CH3SO2CH3 (366.6)

PhCOCH3 (363.2) O2NCH3 (358.7)

Cl2CH2 (374.1) (Me3Si)2CH2 (373)

(Me2P)2CH2 (370) Ph2CH2 (364.5)

(CH2=CH)2 CH2 (359.7)

1(356.1)

(386.9)F

F3CH (377)

HC≡C-H (375.4)

(Ph)3C-H

3Cl3C-H (356.7)

-40

-50

-60

380

370

360

MeO-H (380.6)

MeOO-H (374.6)

F-H (371.5)PH3 (370.4)

PhNH2 (367.1) HN

(360.7)

MeS-H (356.9)

2

6

1

1

1

1

2

Me3Si-H (383)

HOO-H (376.5)

SiH4 (372.8)

Me3Ge-H (361.5)

GeH4 (359)

NC-H (353.1)1

CF3COCH3 (347.1)5

(348.5)5 -70

350 PhO-H (351.4)HS-H (351.2)

1

2

Me3Sn-H (349)2

EtCO2

(CH3CO)2CH2 (342.6)

PhCO2

FCH2CO2

ClCH2CO2

H (345.2)

H (337.7)H (335.6)H (333.6)

5

5

5

5

-80

340 PhS-H (338.9)HSe-H (338.7)

Cl-H (333.3)(N≡C)2CH2 (331.7) 5

330

F2CHCO2H (328.4)5

-90

Br-H (323.6)1

1. Bartmess J. Am. Chem. Soc. 1979, 101, 6046 2. Braumann, J. Am. Chem. Soc. 1995, 117, 4905 3203. Braumann J. Am. Chem. Soc. 1998, 120, 29194. Tetrahedron Lett. 1997, 0, 85195. Kebarle J. Am. Chem. Soc. 1976, 98, 3399 (add 3-4?)

-100I-H (314.3)1

6. Ellison7. Squires J. Am. Chem. Soc. 1990, 112, 2517 310

t

Li Reagents by Metalation

Metalations by Organolithium Compounds,Mallan, J. M.; Bebb, R. L. Chem. Rev. 1969, 69, 693.

Allylic and Benzylic Carbanions Substituted by Heteroatoms,Biellmann, J. F.; Ducep, J. -B. Org. React . 1982, 27, 1.

Polar Allyl Type Organometallics as Key Intermediates in Regio- and Stereocontrolled Reactions: Conformational Mobilities and Preferences,

Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49, 10175. Silylallyl Anions in Organic Synthesis: A Study in Regio- and Stereoselectivity,

Chan, T.H.; Wang, D. Chem. Rev. 1995, 95, 1279-92.Delocalized Carbanions in Synthesis,

Barry, C. E. III, Bates, R. B.; Beavers, W. A.; Camou, F. A.; Gordon, B. III; Hsu, H. F. J.; Mills, N. S. Synlett 1991, 207.Regioselectivity of the Reactions of Heteroatom-Stabilized Allyl Anions with Electrophiles,

Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99, 665-722.Heteroatom-Faciliated Lithiations,

H. W. Gschwend and H. R. Rodriguez Org. React. 1979, 26, 1.Lateral Lithiation Reactions Promoted by Heteroatomic Substituents,

Clark, R. D.; Jahangir, A. Org. React. 1995, 47, 1-314. α-Heteroatom Substituted 1-Alkenyllithium Reagents: Carbanions and Carbenoids for C-C Bond Formation,

Braun, M. Angew. Chem. Int. Ed. Engl. 1998, 37, 430-51. Lewis Acid Complexation of Tertiary Amines and Related Compounds: A Strategy for α-Deprotonation and Stereocontrol,

Kessar, S.V.; Singh, P. Chem. Rev. 1997, 97, 721-38.Dipole Stabilized Carbanions,

P. Beak Chem. Rev. 1978, 78, 275.Stereo and Regiocontrol by Complex Induced Proximity Effects-Organolithium Compounds,

P. Beak, A. I. Meyers Acc. Chem. Res. 1986, 356.

Organolithium Reagents Usually Prepared by Metalation

O O

S LiPh Ph

O

S Li NC Li (EtO)

O

2P Li LiO

OLi

R2N

OLi

NR

Li

Li

O Li PhS Li Li R LiSPh R Li

OR R' H

OCH3

Li

CH2NMe2

Li

CONR2

LiS

LiO

Li N

Li

N

O

N

O Bu

Li

LiPhSe PhS RO PhS Li PhS OMe

S S

Li Li Li LiLi Li

i

t

[1]

[4]

[5]

[2]

[3]

Selected Metalation AgentsA variety of metalation agents are used to deprotonate C-H acidic compounds. For materials with pK values above ca 37only alkyllithium reagents are effective. For more acidic protons these may also work, but various lithium amides(especially LiN Pr2) are often faster and give cleaner products.

Organolithium Reagents

n-BuLi n-Butyllithium in solvents like ether or THF, sometimes with activating cosolvents like TMEDA, PMDTA,or HMPA is by far the most extensively utilized metalation agent. Alkyllithiums fail to metalate most carbonyl compounds because of competing addition to the carbonyl group, and some heteroatom substituted compounds of the 3rd, 4th and 5th period (e.g, I, Se, Te, Sn) where attack at the heteroatom can interfere (Li/I, Li/Se, Li/Te, Li/Sn exchange).

n-BuLi/KO Bu This combination, sometimes referred to as the Schlosser-Lochmann base or LIKOR base, is perhapsthe most powerful metalating combination available. The active reagent is believed to be a complex of butylpotassium. Some electrophiles are incompatible with the metalating agent, and conversion of the organometallic to an intermediate Sn compound may be required, for subsequent Li/Sn exchange to prepare the lithium reagent under milder conditions.

s-BuLi sec-Butyllithium is usually more active than n-BuLi and sometimes will successfully perform metalationsnot possible with the other alkyllithiums.

t-BuLi tert-Butyllithium . A more aggressive base than either n-BuLi or s-BuLi, t-BuLi can perform metalations notpossible with these. It is more dangerous to handle (e.g., its solutions inflame spontaneously in air) and more expensive. Steric effects may be a problem, but can also result in different selectivity.

Mesityllithium. A special purpose hindered organolithium base with very low propensity to add toLi

Lithium Amides

N Li

carbonyl compounds. Used for deprotonations of relatively acidic compunds (pKa < 40) where the presence of amines (if lithium amides would normally be used) is deleterious, where exceptional steric selectivity is desired, or where carbonyl addition or reduction is a problem with alkyllithium bases.

Lithium diisopropylamide (LDA, pKa 36). Prepared by reaction of nBuLi with HNiPr2. This is the cheapest and most convenient base for deprotonations of compounds whose pKa is less than 36, including all carbonyl compounds, alkyl sulfoxides, sulfones, and some aromatic compounds. Hindered and certain heterosubstituted ketones are sometimes reduced. In this case use LiTMP or LiN(SiMe 3)2. The amine is volatile and can be removed even from enolate solutions by distillation. LDA can be prepared from Li .

N Li

Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP, pK a 37). This is the most potent and least nucleophilic of the amide bases. It is kinetically faster than LDA, and will smoothly do many deprotonations not possible with LDA. Interference by the amine (e.g. in acylations) is minimal because of high steric hindrance. Disadvantage: the amine precursor is expensive. CAUTION: The reaction between n-BuLi and the amine is slow at -78 °C and is best done at 0°C.

Si

SiN Li

Lithium Bis(trimethylsilyl)amide (aka Hexamethyldisilazide) (LiN(SiMe3 )2, LiHMDS). A considerably weaker (pKa ca 30) base than the dialkylamides above. Used where a delicate touch is needed (e.g. for enolate alkylation when halide is part of the molecule ) and where hydride reduction occurs with LNiPr2. LiN(SiMe3 )2 will give the thermodynamic enolate under appropriate conditions. Several more hindered analogs (such as (PhMe2 Si)2NLi) have found some uses in stereoselective deprotonations

1. a) C. Kowalski, S. Creary, A. J. Rollin and M. C. Burke J. Org. Chem. 1978, 43, 2602. (b) M. T. Reetz Ann. N1980, 1471.

2. (a) M. W. Rathke J. Am. Chem. Soc. 1970, 92, 3222. (b) "Structure of Lithium Hexamethyldisilazide (LiHMDS): Spectroscopic Study of Ethereal Solvation in the Slow-Exchange Limit," Lucht, B. L.; Collum, D. B. J. Am. Chem. Soc. 1994, 116, 6009-6010.

3. S. Danishefsky, K. Vaughan, R. C. Gadwood, K. Tsuzuki J. Am. Chem. Soc. 1980, 102, 4262; 1981, 103, 4136. 4. M. W. Rathke and R. Kow J. Am. Chem. Soc. 1972, 94, 6854. R. A. Olofson and C. M. Dougherty J. Am. Chem.

Soc. 1973, 95, 582.5. I. E. Kopka, Z. A. Fataftah, M. W. Rathke J. Org. Chem. 1987, 52, 448.

DM

SO

H2O

NEt3H-C≡N

CH NO

Acidity of Conjugate Bases and SubstratesReich

Chem 547

Bases(pKa of Conjugate Acid)

Substrates(pKa)

56.0

54.0

52.0

50.0

48.0

46.0

44.0

MeLi

PhLi

n-BuLi, t-BuLi 56.0

54.0

52.0

50.0

48.0

46.0

44.0

CH4

CH2=CH2

CH3Ph42.0

40.0

38.0

36.0

34.0

32.0

30.0

28.0

26.0

LiTMP

Li NLiN(i-Pr)2

KH (?)O

NaNH2 NaCH2-S-CH3

Ph3CLiLiN(SiMe3 )2

42.0

40.0

38.0

36.0

34.0

32.0

30.0

28.0

26.0

HCPh3

CH2(SPh)2

CH3-SO2Ph

CH3C≡N

24.0pKa pKa

22.0

20.0 KO-t-Bu

NaOMe18.0

24.0

22.0

20.0

18.0

CH3-CO2Et H-C≡C-Ph

O+CH3

-PPh3

16.0

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0

NaOH

DBU/DBN

NaOPhNa2CO3

NaOAc NNH2Ph

Pyridine

OH2

N

N

DBU

16.0

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0

O O

RO OR

O O

H-S-Ph

CH2(NO2)2

OH

CH2(C≡N)2

H-S-CH3

3 2 H-O-Ph

i

i

Metalated SulfonesSultone Chemistry

D. W. Roberts, D. L. Williams, Tetrahedron 1987, 43, 1027.The Chemistry of Vinyl Sulfones,

Simpkins, N. S. Tetrahedron 1990, 46, 6951.The Use of Sulfonyl 1,3-Dienes in Organic Synthesis,

Baeckvall, J.-E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev. 1998, 98, 2291-312.Recent Progress on Rearrangements of Sulfones,

Braverman, S.; Cherkinsky, M.; Raj, P. 1999, 22, 49-84.Desulfonylation Reactions: Recent Developments,

Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547-658.The Chemistry of Acetylenic and Allenic Sulfones.

Back, T. G. Tetrahedron 2001, 57, 5263-301.Stereoselective and Enantioselective Synthesis of Five-Membered Rings via Conjugate Additions of Allylsulfone Carbanions,

Hassner, A.; Ghera, E.; Yechezkel, T.; Kleiman, V.; Balasubramanian, T.; Ostercamp, D. Pure. Appl. Chem. 2000, 72, 1671-83.

Preparation. Sulfones are easily prepared by a variety of synthetic procedures:

Oxidation of sulfides and sulfoxidesNucleophilic substitution of halides and tosylates by sodium arenesulfinateConjugate addition of sodium arenesulfinate to α,β-unsaturated carbonyl compoundsAlkylation of lithiosulfonesConjugate addition to vinyl and alkynyl sulfonesCycloaddition of SO2 to dienes

R

RX

PhSM

PhSM

PhSO2M

R

R

S

Ox

S

Ph

Ph

1. base2. RCH2X

PhS

O O

SO2S

O

O

PhS

O ORM

O OBuLi

orLiN Pr2

R

Li

PhS

O O

Metalation . All types of sulfones (1°, 2°, 3°, allyl, vinyl) which have σ-hydrogens metalate easily with n-BuLi or LiN Pr2, and the anions show good nucleophilicity. Commonly used electrophiles are alkyl halides and tosylates, epoxides, aldehydes, ketones and esters.

Subsequent Transformations. The products of reaction of metalated sulfones with electrophiles can be used in various ways: Reductive elimination of β-oxy and β-halo sulfones (Julia olefination)Oxidation of β-oxy sulfones to β-keto sulfones and desulfonylation to ketonesReductive desulfonylation with Al/HgMetalation/oxidation to form ketonesIf cleavage of the C-S bond gives a stabilized cation, some sulfones can behave as C-electrophilesβ-Elimination to give olefins if β-hydrogens are acidic

PhS O

TBSO

Li 2

OTES OPiv

Metalated Sulfone ReactionsH R'

HO R'

R

1. Ac2O2. Na/Hg

H

Julia[red]

R

[Alkyl anion]

R

Li

PhS

O O

R'CHOR

HO R'

PhS

O O

[oxid]R

O R'

PhS

O O

[red]

R

O R'

R

Julia II

R'X

R'

PhS

O O

BuLi; CH2IiPrMgCl

R'

2,

[red]

1. [base]2. [oxid]

R'

R

[Alkyl anion]

R'

1. Ac2O2. base

R

Heathcock JOC 95-1120

R'R'

[base]

PhS R

O O [Alkynyl anion]

Otera JACS 84-3670

R RO

[Acyl anion]

Synthetic Uses of Lithiosulfones - Coupling by alkylation of sulfonesCoupling using a-Lithio-sulfone Alkylation - alkyl sulfones can be reductively cleaved: Synthesis of Aplyronines: Yamada, et al. J. Org. Chem. 1996, 61, 5326

I1. THF/HMPA

TBSO OTES OPiv

+MeO

OBn 2. Na/Hg

MeOOBn

Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675

OTBS OTBS OTBS

MeOTBSO

OH

HO

OBnMeO

TBSO

OH

HO

OBn

BuLi; CH2IiPrMgCl

2,

MeOTBSO

OH

HO

OBn

I OTBS

OBn BuLi, HMPA

PhSO2OTBS

OBn

OTBS

OBn

OPMB

O PhSO2 1. PhSO2CH2Li

THF, HMPA2. TBSOTf OPMB

OTBS OPMB

OTBS

OPMB

OTBS

Spongistatin 1

Synthetic Uses of Lithiosulfones - The Julia Olefin SynthesisCoupling using Julia Olefination . The original Julia reaction involved a reductive elimination of a β-acetoxy sulfone, formed by addition of a metalated sulfone to an aldehyde or ketone.

H PhSO2PhSO2 PhSO2

Ac2O Na / Hg

O+

LiOH OAc

Synthesis of Aplyronine: Yamada, et al. J. Org. Chem. 1996, 61, 5326

OMe

TBSO OR' OPiv PhSO2 OTES OTES OR O

+

OMe

Li1. Rx

2. Ac2O, DMAP 3. Na/Hg, HaHPO 4

LIN

MeOH

TBSO OR' OPiv

O

OMe

R = CH2OCH2-C6H3(OMe)2-3,4 OMe OTES OTES OR O

R' = CH2OCH2-C6H4OMe-4 MeO

Aplyronines

Aplyronine AO OMe

HO O ONMe2

O

MeO

OMe O OHNMe2

O OAc Me

NCHO

Acyl AnionsA Compilation of References on Formyl and Acyl Anion Synthons,

Hase,T.A.; Koskimies, J.K. Aldrichim. Acta 1981, 14, 73; 1982, 15, 35.New Formyl Anion and Cation Equivalents,

Dondoni, A.; Colombo, L. Adv. Use of Synthons in Org. Chem. Vol. 1 , Jai Press, 1993. Acylvinyl and Vinylogous Synthons.

Chinchilla, R.; Najera, C. Chem. Rev. 2000, 100, 1891-928.The acyl anion equivalents most widely used are:

O

Li

= S S

R Li

O O CN

R Li

O

Li

Metalated Dithianes: Protected Cyanohydrins Metalated Enol EthersSeebach, JOC 75-231 Stork, JACS 74-5272 Baldwin, JACS 74-7125

Metalated Dithianes:Synthetic Uses of the 1,3-Dithiane Grouping from 1977-1988,

P. C. B. Page, M. B. van Niel, J. C. Prodger Tetrahedron 1989, 45, 7643.Ketene Dithioacetals in Organic Synthesis: Recent Developments,

M. Kolb Synthesis 1990, 171.Synthesis of Heterocycles from Ketene Dithioacetals,

Yokoyama, M.; Togo, H.; Kondo, S. Sulfur Reports, 1990, 10, 23.New Synthetic Applications of the Dithioacetal Functionality,

Luh, T.Y. Acc. Chem. Res. 1991, 24, 257.The Development and Application of 1,3-Dithiane 1-Oxide Derivatives as Chiral Auxiliaries and Asymmetric Building Blocks for Organic Synthesis. A Review,

Allin, S. M.; Page, P. C. B. Org. Prep. Proc. Int. 1998, 30, 145-76.The Role of 1,3-Dithianes in Natural Product Synthesis,

Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-212.Evolution of Dithiane-Based Strategies for the Construction of Architecturally Complex Natural Products,

Smith, A. B. III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.

Metalation of Cyanohydrins: Reactions of Acyl Anion Equivalent Derived from Cyanohydrins, Protected Cyanohydrins, and α-Dialkylamino Nitriles,

Albright, J.O. Tetrahedron 1983, 39, 3207.Cyanohydrins in Nature and the Laboratory: Biology, Preparations, and Synthetic Applications,

Gregory, R. J. H. Chem. Rev. 1999, 99, 3649-82.

Metalated Vinyl Ethers Generation and Reactivity of α-Metalated Vinyl Ethers.

Friesen, R. W. JCS Perk. I 2001, 1969-2001.

t

t

Metalated Dithianes

Hispidospermidine: Frontier, A. J.; Raghavan, S.; Danishevsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151. 00-14

S S

H

H

S S

1, nBuLi

2.

Br

SiMe3

S S

H

S S

SiMe3

CAN, acetone

O

O

H

SiMe3

NaOH

OL

[Dithiane alkylation]

Monicillin I : Garbachio, R. M.; Stachel, S. J.; Baeschln, D. K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903 01-19

O OO

O OO

O OO

HOCl

S

HO

S S

HO

OL

OTBDMSS

Li α/γ 6/1 OTBDMS OHMonocillin 1

Silyl Dithiane as a LynchpinSpongistatin: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675

S Sn-BuLi; TBS-Cl

S S

1. tBuLi

2.BnO

OTBSO BnO

TBSO TBSO S S OH OO

Spongistatin 1

BuMe2Si3.

OO

O HMPA

S S HMPA S S

tBuMe2Si Li

LiO R tBuMe2SiO R

Mycoticin A: Smith, A. B. et al Org. Lett. 1999, 1, 2001.

S S

BuMe2Si Li

O1. BnO

O O2.

HMPA

TBSO OH OH OTBSS S S S

BnO OBn

59%

Mycoticin AN

Roflamycoin: Rychnovsky, S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058 97-07

BnO OL

O1. Li O

Bn BnO OH

OH

BnO O

O BuLi, DMPUS

O

O 2.

S

SLi

SnBu3 S

S

SnBu3

S

S

SnBu3 O

O

Br

O

OS

Roflamycoin Br

Br

Recutive desulfurization of DithianeOkinellin B : Schmitz, W. D.; Messerschmidt, N. B. J. Org. Chem. 1998, 63, 2058.

t-BuLi

S

Li

S I OBnS

H

SOBn

O

O

Br

S SOBn

W-2 RaneyNickel

LIN

O O

OOBn

O

Okinellin B OH

2

t

t

t

t

t t

t

sLi

Et O, -78 °C

O OO Bu O Bu

N

t

Metalation α to NitrogenMetalation and Electrophilic Substitution of Amine Derivatives Adjacent to Nitrogen: α-Metallo Amine Synthetic Equivalents,

SteG

P. Beak, W. J. Zadjel, D. B. Reitz Chem. Rev. 1984, 84, 471.New Metalation and Synthetic Applications of Isonitriles,

Ito, Y. Pure & Appl. Chem. 1990, 62, 583.Metalation of Isocyanides,

Ito, Y. Synlett 1990, 245.Generation and Reactions of sp -Carbanionic Centers in the Vicinity of Heterocyclic Nitrogen Atoms,

Rewcatle, G. W.; Katritzky, A. R. Adv. Heterocyclic Chem. 1993, 56, 157.Benzotriazole-stabilized Carbanions: Generation, Reactivity, and Synthetic Utility,

Katritzky, A. R.; Yang, Z.; Cundy, D. J. Aldrichimica Acta, 1994, 27, 31-8. The Generation and Reactions of Non-Stabilized α-Aminocarbanions,

Katritzky, A. R.; Qi, M. Tetrahedron 1998, 54, 2647-68.

Amide MetalationsLi O

OBu

N Ph N O N-nitroso

BuO NLi

H NLi

compounds canalso be metalated

Beak JOC 93-1109 Meyers TL 84-939 Gawley JOC 89-3002sBuLi, TMEDA BuLi, THF nBuLi, THF

ether

RSynthesis of Solenopsin: Reding, Buchwald J. Org. Chem. 1998, 63, 6344.

1. s-BuLi, TMEDA TFA

HBuO N

OLi

N C11H23 2. Me 2SO4 Me N C11H23 Me N C11H23

O OBu O O BuH

Solenopsin R

BuON

O

Li

Chiral Organolithium Reagents - Asymmetric Metalation. Hoppe, Hintze, Tebben Angew. Chem. Int Ed. 1990, 29, 1422, 1424.

OsBuLi, Sparteine

O LiCO2

CO2H

O N O R 5h, -78 °C O N O R HO R>95% ee

The carbamate group is strongly activating - good coordination to Li The organolithium reagents are configurationally stable at -78 °C Derivatizations occur with retention of configuration, unless R = Ph.

Kerrick, Beak J. Am. Chem. Soc. 1991, 113, 9708.

BuLi, Sparteine N N

2

t t

This is an asymmetric deprotonation.

CH3I CH3

O O Bu76% yield, 95%ee

H

N

H

N

HH

Sparteine

Aromatic ortho MetalationsDirected Lithiation of Aromatic Tertiary Amides: An Evolving Synthetic Methodology for Polysubstituted Aromatics,

P. Beak and V. Snieckus Acc. Chem. Res. 1982, 15, 306.Heteroatom Directed Aromatic Lithiation,

N. S. Narasimhan, R. S. Mali Top. Curr. Chem. 1987, 138, 63.The Directed Ortho Metalation Reaction. Methodology, Applications, Synthetic Links, and a Non-aromatic Ramification,

V. Snieckus, Pure Appl. Chem. 1990, 62, 2047.Directed Ortho Metalation. Tertiary Amide and O-Carbamate Directors in Synthetic Strategies for Polysubstituted Aromatics,

Snieckus, V. Chem. Rev. 1990, 90, 879.Combined Directed Ortho Metalation-Cross Coupling Stategies. Design for Natural Product Synthesis,

Snieckus, V. Pure App. Chem. 1994, 66, 2155-8.Chelation Control in Metalation Reactions

Slocum, D. W.; Jennings, C. A. J. Org. Chem., 1976, 41, 3653.

N NN

Lin-BuLi n-BuLiEt2O TMEDA

LiEt2O

OCH3OCH3 OCH3

ortho-Metalation of Aromatic Amides - Synthesis of ERYTHROLACCIN Mills, R. J.; Snieckus, V. Tetrahedron Lett. 1984, 25, 479, 483.

NEt2 NEt2 Me NEt2

84-2

MeO

O 1. s-BuLi, TMEDA

2. Me3SiCl

O

MeO SiMe3

1. n-BuLi

2. MeI

O

MeO SiMe3

OMe OMe OMe

CsF

RCHO

Br2

Me O OMe MeO

OMe Me NEt2

1. Zn, NaOH

2. TFAA O1. n-BuLi

OMe2.

O

MeO OMe 3. CrO3 MeO OMe MeO Br

OMe O OMe H C OMe OMe

ERYTHROLACCINO

Note the use of N,N-diethyl amide, N,N-dimethyl amide is too reactive

Ortho-Metalation Directed by α-Amino AlkoxideCl

Comins D. L.; Brown, J. D. J. Org. Chem., 1984, 49, 1078. (CHO)N

O H

Cl

N1. Li N

2. n-BuLi, -78°C

O- N

Li

Cl

N

1. CH3I

2. H2O

O H

CH3

Cl

LiD. L. Comins

TL., 1989, 30, 4337.

Li

MeO N (CHO) JOC, 1990, 55, 69

t

N

Me Si 4. I3 2

t

Ortho Metalation of Heterocycles

Heteroatom Directed Aromatic Lithiation. Reactions for the Synthesis of Condensed Heterocyclic Compounds, N.S. Narasimhan, R.S. Mali, Top, Curr. Chem. 1987, 138, 63.

Directed ortho-Metalation of Pyridines,Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, L. Adv. Heterocycl. Chem. 1991, 52, 187.

Metalation and Metal-Assisted Bond Formation in π-Electron Deficient Heterocycles,Undheim, K.; Benneche, T. Act. Chem. Scand. 1993, 47, 102.

Syntheses of Heterocyclic Compounds Involving Aromatic Lithiation Reactions in the Key Step,Narasimhan,N. S.; Mali, R. S. Synthesis 1983, 957.

Synthesis and reactions of lithiated Isoxazoles,Iddon, B. Heterocycles 1994, 37, 1263.

Synthesis and reactions of lithiated Oxazoles,Iddon, B. Heterocycles 1994 37, 1321.

Synthesis and Reactions of Lithiated Pyrazoles,Grimmett, M. R.; Iddon, B. Heterocycles, 1994, 37, 2087.

Synthesis and Reactions of Lithiated Imidazoles,Iddon, B.; Ngochindo, R. I. Heterocycles, 1994, 38, 2487.

Synthesis and Reactions of Lithiated Isothiazoles and Thiazoles,Iddon, B. Heterocycles 1995, 41, 533.

Metalation of Diazines,Turck, A.; Plé, N.; Quéguiner, G. Heterocycles, 1994, 37, 2149.

Synthesis and Reactions of Lithiated Triazoles, Tetrazoles, Oxadiazoles, and Thiadiazoles,Grimmett, M. R.; Iddon, B. Heterocycles, 1995, 41, 1525-74.

The Directed Ortho Metalation Cross-Coupling Symbiosis in Heteroaromatic Synthesis,Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999, 36, 1453-68.

Synthesis of Substituted Quinazolin-4(3H)-ones and Quinazolines via Directed Lithiation.El-Hiti, G. A. Heterocycles 2000, 53, 1839-68.

Metallation of Pyridines, Quinolines and Carbolines.Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4059-90.

Metalation of Pyrimidines, Pyrazines, Pyridazines and Benzodiazines.Turck, A.; Ple, N.; Mongin, F.; Queguiner, G. Tetrahedron 2001, 57, 4489-505.

Metalation of Pyridines - Synthesis of CamptothecinComins, Baevsky, Hong J. Am. Chem. Soc. 1992, 114, 10971; Fand, Xie, Lowery J. Org. Chem. 1994, 59, 6142;Curran, Ko, Josien Angew. Chem., Int. Ed. Engl. 1995, 34, 2683.

OMe 1. BuLi O OMe O

2. Me2N N HN H

3. n-BuLiMe3Si I

49% A

BN

O

N OC D E

Et OHO

Camptothecin

MeO MeOO MeO N

N 1. BuLi NLi 2. Me2N N H

NNMe

OLi 3. n-BuLi

Me3Si Me3Si Me3Si

MeO N MeO NOMe O

NNMe

OLi 4. I2 NNMe

OLiH2O N H

Me3Si Li Me3Si IMe3Si

49%

I

1. LDA OH PBr3 Br

N Cl 2. CH2ON Cl N Br

Log

k 2(P

hnM

+ A

rLi)

THF,

0 °C

+

- + - + - +

+

The Lithium-Metalloid ExchangeThe Halogen-Metal Interconversion Reaction with organolithium Compounds.

Jones, R. B.; Gilman, H. Org. React. 1951, 6, 339.Aromatic Organolithium Reagents Bearing Electrophilic Groups. Preparation by Halogen-Lithium Exchange,

Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300. Synthetic Methods using α-Heterosubstituted Organometallics,

A. Krief Tetrahedron 1980, 36, 2531.The Mechanism of the Lithium Halogen Interchange Reaction - A Review of the Literature,

Bailey, W.F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.Selenium Stabilized Carbanions,

H. J. Reich in "Organoselenium Chemistry," D. Liotta, Ed. Wiley, 1987.Selenium-Stabilized Carbanions,

Ponthieux, S.; Paulmier, C. Top. Curr. Chem. 2000, 208, 113-42.Preparation and some Applications of Functionalized Organo-Lithium Compounds in Organic Synthesis,

Barluenga, J. Pure & Appl. Chem. 1990, 62, 595.Nucleophilic Perfluoroalkylation Using Perfluoroalkyllithiums,

Uno, H.; Suzukib, H. Synlett 1993, 91-6.Polyfluorovinyl Lithium Reagents and Their Use in Synthesis.

Coe, P. L. J. Fluor. Chem. 1999, 100, 45-52.A number of the heavy main-group elements (I, Br, Te, Se, Sn and others) undergo transmetallation reactions. The second row elements Cl, S, P, Si can only be used in exceptional circumstances.

Bu M + R-Li

BuLi + M

R

Bu M

R- Li

R' This reaction is an equilibration: the lithium cation attacks the R group in the ate complex which carries the most charge

R' R'ate

complexBu M

R

+ R'-Li

(i.e., the one that best stabilizes negative charge).

The reactions of the more commonly used metalloids (I, Br, Sn, Hg) are characteristically very fast, allowing lithium reagents to be prepared at low temperatures under mild conditions (Reich, Green, Phillips, Borst, Reich Phosphorus Sulfur 1992, 67, 83).

I > Te > Sn > Br > Se >> Cl, S, P, Si, Ge

M + Lik2

Li + M

8

6

4

Te I Ate complexes have been spectroscopically characterized as intermediates in these exchanges (Reich, Green, Phillips J. Am. Chem. Soc. 1991, 113, 1414; Reich, Gudmundsson, Dykstra J. Am. Chem. Soc. 1992, 114, 7937; Reich, Phillips J. Am. Chem. Soc. 1986,108, 2102).

2

0Sn

BiSb

-2

-4Pb

As

SeBr

I Li Te Li Se LiCH3

CH3

Li

Sn CH3

-6

-8GeSi

PS Cl

6 7 Period 8 9

t

Pro Fastest of all Li/M exchanges Works with primary iodide Exchange can be made irreversible (t-BuLi) Often BuLi is best transmetalating reagent

Con Products are reactive alkylating agents Expensive, usually have to prepare Usually fails with 2° or 3° halides

Pro Cheapest Often commercially available Stable enough to survive reactions Best for vinyl and aryl bromides

Con Fairly slow Side reactions such as α- and β-metalation Products may be reactive alkylating agents Doesn't work with most alkyl bromides

t

t

t

t

t

tTHF

The Li/I Exchange

Synthesis of Bafilomycin: K. Toshima Tetrahedron Lett. 1996, 37, 1069.OMe OMe OMe

In-BuLi

LiBu3SnCl

Bu3Sn

O O O O O O

The Li/I exchange is several orders of magnitude faster than the Li/Br exchange, and so ist much less susceptible to side reactions. Selective reactions to be performed (Evans J. Am. Chem. Soc. 2000, 122, 10035).

I Li

Br

2 BuLi, Et2O -105 °C

Br>20/1 selectivity infavor of Li/I exchange

OMe OMePrimary allkyl iodides usually work, but primary bromides rarely do. McGarvey J. Org. Chem. 1995, 60, 778.

1. 2 BuLi OH

BnO O O I 2.

H

O

O OBnO O O O O

BuLi with RBr or RI is essentially irreversible -BuX is destroyed byexcess BuLi

Several coupling methods were tried, includingLi-sulfone and Li-dithiane. This one worked best.

The Li/Br Exchange

The Li/Br exchange is slow enough that side reactions such as α- and β-metalation can compete (Meyers, J. Org. Chem. 1985, 50, 4872). This is generally not a problem with the Li/I, Li/Sn and Li/Te exchanges.

Br OEt n-BuLi Br OEt 1. PhCHO Li OEt1. MeI

OEt2. BuLiLi OEt

Li/H Li/BrOEt

Ph OLi 2. H+ Ph O

Amide bases such as LDA or LiTMP are poor transmetalating reagents, and will often perform deprotonations even when a halide is present (Schlosser Helv. Chim. Acta 1977, 60, 2085). In both cases below, the Li/Br exchange is fast enough that BuLi does not perform a Li/H exchange to make the more stable lithium reagent.

Br Br Li

LiN(iPr)2 n-BuLi

O LiO O

Takano Tetrahedron Lett. 1985, 26, 1659

S S S

OLi

S LiN(iPr)2O S n-BuLi

O S

O Br O Br O Li

Pro Modestly stable compounds Reasonable methods for preparation Not a leaving group - can have in β-position Not much likelihood of α and β-metalation Especially widely used for vinyllithiums R4Sn compounds relatively inert NMR active nucleus

Con Neurotoxins Expensive - must prepare Contamination of products with R4Sn Cannot be made irreversible Sensitive to steric effects

Pro Easy to prepare Special purpose - α-lithioSe, S

Con Not commercially available Too slow for general aplication Toxic

Pro Very fast Perhaps most general of all metalloids Even secondary systems work

Con Difficult to prepare Not commercially available Somewhat air and light sensitive

o

OHPhCHO

OH

The Li/Sn Exchange

D. Seyferth, S. C. Vick, J.Organomet. Chem. 1978, 144, 1.

Bu3SnSnBu3

n-BuLiBu3Sn

Li

This reagent is the synthetic equivalent of1,2-dilithioethylene.

" LiLi

"

α-Aminoalkyllithium reagents cannot usually be prepared by the metal-halogen exchange, and the Li/Sn exchange is the best method. D. J. Peterson, J. Am. Chem. Soc. 1971, 93, 4027.

Ph

MeN-CH2-SnBu3

n-BuLi

0 C

Ph

MeN-CH2-Li

α-Alkoxy lithium reagents are also very commonly prepared by Li/Sn exchange. The α-alkoxy tin compounds are easily prepared by reaction of R3SnLi with aldehydes or ketones, or with α-haloethers. N. Meyer, D. Seebach, Chem. Ber. 1980, 113, 1290.

2n-BuLiBu3Sn-CH2-OH Li-CH2-OLi Ph

hexane

The Li/Se Exchange

Tetrahedron Lett. 1987, 28, 1337. J. Lucchetti, A. Krief, Tetrahedron Lett. 1981, 22, 1623.SeMe

SeMe

SeMe

TBSOn-BuLi

TBSO

H H

TBSO

The Li/Te Exchange

Br TBSO

Reich, H. J.; Medina, M. A.; Bowe, M. D. J. Am. Chem. Soc. 1992, 114, 11003-11004.

Ph

Ph

TePh

H

s-BuLi, -78°Ph

Ph

Li

HPh

Ph

H

Lis-BuLi, -78°

Ph

Ph

H

TePh

Me2S2 Me 2S2

SMe H

Ph

PhH

Ph

PhSMe

t

Functionalized Organolithium Reagents Prepared by Li/M Exchange M. P. Cooke, Jr. J. Org Chem. 1993, 58, 2910; 1984, 49, 1144.

O I O

MeO n-BuLi

-78°C

95%

MeO

IFlann, Overman J. Am. Chem. Soc. 1987, 109, 6115.

H

EtO2

BrCO2Et

N OMeH

C OMe

s-BuLi

THF, -78°CN

EtO2CH

O

OMe

OMe

O

N

OH

HO

StreptazolinTaxol Synthesis: G. Stork et al J. Am. Chem. Soc. 1998, 120, 1337

Me3Sn

O O

BuLi, -100 °CLi

O O

TBSO

TBSOH

O

TBSO

TBSOOH O O

Taxol (partial)

In situ Trapping of an IsocyanateB. M. Trost, S. R. Pulley, J. Am. Chem. Soc. 1995, 117, 10143 (Pancristitatin synthesis)

OTES OTES

TESO O TESO OUse of 2 equiv. of t-BuLi in the

O O 2 BuLi, Et2O,O O metal-halogen exchange results in

an essentially irreversible process

O

MeO

BrN

CO

-78 °C O

MeO O

NH

(t-BuLi + t-BuBr → t-BuH + Me2C=CH2)

In Situ trapping of ArLi Reagents - Mesityllithium as Transmetallating agentKondo Org. Lett. 2001, 3, 13 O

I O Li HO O

O

N OMeO N OMe

Ar =

:

+

+

Chem 547Reich

The Bamford-Stevens and Shapiro Reactions Lithioalkenes from Arylsulphonylhydrazones,

Chamberlin, A. R.; Bloom, S. H. Org. React . 1990, 39, 1. Recent Applications of the Shapiro Reaction,

A. G. M. Barrett, Acc. Chem. Res. 1983, 16, 55.

N

H

N

Na

NaH N ArAr N SS Bamford-Stevens O OO O

2 BuLi LiShapiro ΔLi N Ar

N S

Δ-ArSO2Na

-N2

N

Li

N

N

N +

Li [H ]

Carbeneproducts

H

O O

Vinyllithium Reagents from TosylhydrazonesChamberlin, A. R.; Stemke, J. E.; Bond, F. T. JOC, 1979, 43, 147. This is a modification of the Shapiro olefin synthesis to allow efficient trapping of the organolithium intermediates. Tosylhydrazones and their decomposition products (p-toluenesulfinates) can behave as proton sources. The solution is to use 2,4,6-triisopropylphenylsulfonylhydrazones (trisyl hydrazones).

N

H

NS

2 n-BuLi LiN

Li

NS

Δ Li+

LiOS

Ar+ N2

O O

O Li

O O Stable at -65 °C

O

O Li

C6H13

O Li

C6H13

Li

O Li+

9:1

Vinyllithium Reagents from TosylhydrazonesBarrett, A. G. M.; Adlington, R. M. Chem. Comm., 1979, 1122; Acc. Chem. Res. 1983, 16, 55

Li

LiN

NSO2Ar O

-65 °C OLi NN

Li

SO2Ar

1. n-BuLi, -3 °C 2. CO2

3. H3O

61%O

O

Δ550°

83%

O

O

LiO Li

Martin, S. F. J. Org. Chem., 1992, 57, 2523.

NNHSO2Ar

OTBS1. 2 n-BuLi

2.H

OTBSOH

O

M

+

- +

- +

- + - +

"Softer" Organometallic Reagents

Pros and cons of Using non-Alkali Metal Organometallic Reagents

AdvantagesPrepare and use functionalized reagents

Less basic reaction conditions

Wider range of solvents may be used (even protic) Presence of β-leaving groups may be tolerated Better stereochemical and regiochemical control Different reactivity patterns

Chiral reagents easier to work with

Compatibilty with electrophilic catalysts

In situ reactions (Barbier processes)

Wider range of synthetic methods to prepare R-M

Disadvantages

Usually much more expensive (R-Li → R-M) Some elements are quite toxic, disposal problems Separation from the M-debris can be problematic Usually much less reactive than RLi or RMgX Narrower range of R groups are nucleophilic

Some Things We Would Like to be Able to do with Carbon Nucleophiles

1. Functionalized Reagents:E O O

MIntramolecular

MXβ-Leaving

M

Acyl Anion

( ) nHomoenolate

groups

2. Control Allylic and Propargylic Regioselectivity in Donor and Acceptor.

-M+

O

E

R M R

E

O

or

or

R

E

OH

3. Control Diastereoselectivity in Donor and Acceptor.

OR M

OH

R or

R

OH

O OH OH

R H + MR or R

4. Control Enantioselectivity in Donor and Acceptor.

Ph

O

O

R M

+ M

HO R

Ph

R*

orR OH

PhHO

R or

Ph

HO

NR

R

R M RHN R

Phor

R NHR

Ph

X

5. Control Side Reactions.• Enolization vs. nucleophilic addition.• Substitution vs. elimination.• Selectivity among functional groups.

X X

-

-

+- + + + +

ChemReic

Boron in Organic Synthesis

Essential Chemical Properties of Organoboron Compounds

1. Lewis Acidic Oxophilic Metal. Many boron reagents provide for simultaneous activation of acceptor and donor portions of substrate, e.g., in conjugate addition reactions:

O1. PhSe B R

OH O

H2O2 R

OH O

2. RCHOPhSe

2. Boron hydrides can serve as both electrophilic and nucleophilic H donor. Borohydrides have powerful nucleophilic properties, boranes are weak electrophiles.

RB H

R-B H

R RR

3. Carbanion donor: Enol, allyl and propargyl boranes will transfer the group on boron to suitable electrophiles. Other types show little tendency to behave as carbanion sources.

O

O

BO

O

B OB

OB

4. Transmetalation of organoboron compounds to organocopper and organopalladium (Suzuki coupling) provides a powerful method for C-C bond formation (Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457).

OR' OR'

Br R2B C5H11C5H11

Pd(PPh3)4

R'O R'O

5. Organic groups on anionic boron readily migrate to electrophilic sites on adjacent atoms:

R

B-Y-X

RB Y

X

BY

R Y = O, N, S, C, etc. X = leaving group

R-B Y+

BY

R

R-

B ERB +

EB

R

E = H , PhSe , R3Sn , epoxide, carbonylE

E

Organoboron Reviews

Organoborates in New Synthetic Reactions,Suzuki, A. Acc. Chem. Res. 1982, 15, 178; Top. in Current Chem. 1983, 112.

Carbon-Carbon Formation Involving Boron Reagents,A. Pelter Chem. Soc. Rev. 1982, 11, 191.

Formation of Carbon-Carbon and Carbon-Heteroatom Bonds via Organoboranes and Organoborates,E.-I. Negishi, M. J. Idacavage Org. React. 1985, 33, 1.

Organoboron Compounds in Organic Synthesis,R. M. Mikhailov, Harwood Academic, 1984.

Reactions of Group 13 Alkyls with Dioxygen and Elemental Chalcogens: from Carelessness to Chemistry,Barron, A. R. Chem. Soc. Rev. 1993, 22, 93.

Stereodirected Synthesis with Organoboranes,Trost, B.M. Ed., Springer: Berlin, Germany, 1995.

Contemporary Boron Chemistry,Davidson, M.; Hughes, A. K.; Marder, T. B.; Wade, K. Royal Society of Chemistry: Cambridge, U.K., 2000. Rhodium-

Catalyzed Asymmetric 1,4-Addition of Organoboronic Acids and Their Derivatives to Electron Deficient Olefins.Hayashi, T. Synlett 2001, 879-87.

"Organoboranes as a Source of Radicals."Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415-34.

Pure Enantiomers via Chiral Organoboranes,H. C. Brown, B. Singram Accounts Chem. Res. 1988, 21, 287.

Boronic Esters in Stereodirected Synthesis,D. S. Matteson Tetrahedron 1989, 45, 1859.

Recent Advances in Asymmetric Synthesis with Boronic Esters,Matteson, D. S. Pure & Appl. Chem. 1991, 63, 339.

Stereodirected Synthesis with Organoboranes,D. S. Matteson, Springer, 1995.

Asymmetric Syntheses via Chiral Organoboranes Based on α-Pinene,by Brown, H.C. Adv. in Asymm. Synth. Vol. 1, Hassner, A., Ed. JAI: Greenwich, CT, 1995.

α-Halo Boronic Esters in Asymmetric Synthesis,Matteson, D. S. Tetrahedron 1998, 54, 10555-607.

Vinyl Boranes:Synthetic Applications of Vinylic Organoboranes,

H. C. Brown and J. B. Campbell, Jr. Aldrichim. Acta 1981, 14, 3.Haloboration of 1-Alkynes and Its Synthetic Application [Vinyl Boranes],

Suzuki, A. Rev. Heteroatom Chem. 1997, 17, 271-314.

Recent Developments in the Chemistry of Amine- and Phosphine-Boranes,Carboni, B.; Monnier, L. Tetrahedron 1999, 55, 1197-248.

Useful Synthetic Transformations Via Organoboranes. 1. Amination Reactions,Carboni, B.; Vaultier, M. Bull. Soc. Chim. Fr. 1995, 132, 1003-8.

-

R

-

OB

Cy

Migration of Groups from Boron to Carbon - α Leaving Groups

R

BY-X

R-

B YR X

BY

R Y = O, N, S, C, etc. X = leaving group

Oxidation of Boranes

R

BR R

O-OH

R

R-B

R

OOH

R

RB O

R

Reaction with α-X Organolithium Reagents . Hoffman, Stiasny Tetrahedron Lett. 1995, 36, 4595.

TBSO Br

Brn-BuLi

-110 °C

TBSO Br

Li

O

BO

TBSO Br

BO - O

3:1 dr

TBSO OHMe

+ -3N-O

TBSOO -

BO

Serricornin - Boronic Ester Homologation Matteson, D. S.; Singh, R. P. J. Org. Chem. 1998, 63, 4467

98-04

Cy

O

BO

LiCHCl2

ZnCl2

Cl

B

O

O

Cy

Cy

MgBr O

BO

Cy Cy

CyLiCH2Cl B

O

1. LiCHCl22. MeMgCl

O

Cy

Cy

Cy

O OH1. H2O2

2. OsO4, NaIO4

OB

O1. LiCHCl2

2. EtMgCl

O

BO

Cy

Serricornin

Cl Cl Cy- Cl

HMe O H

Me

BO

O

Cy

Cy

ClH

MeB

O

O

Cy

Cy

• The process is repeatable, adding one chiral center at a time. • The diastereoselectivity is very high.

Allyl-Metal Species

Structure and DynamicsM

M

Structure Metals E / Z Isomerization rate

Ionic, contact or separated ion pairs:

+M

Li, Na, K Slow

Covalent, but rapidly equilibrating: Mg, Al, Zn, Hg, B, Ti, Cr M M

Covalent, slow equilibration: Sn, Ge, Si

M M

Transition metal π-complexes Pd, Pt, Ni, Co, Mo

Fast

ΔG = 10 - 25 kcal/mole

Slow

ΔG > 25 kcal/mole

Depends on rate of σ-allyl to π-allyl interconversion

M(L)n

M(L)n

Allyl-Metal Species: Reactivity

The reactivity decreases as C M bond becomes more covalent.

Lithium reagents are aggressive nucleophiles, react with weak electrophiles such as alkyl halides. Grignard reagents react well with carbonyl compounds.Allyl silanes react only with good electrophiles such as carbonium ions or halogens.

Allylic rearrangement also causes cis-trans isomerization of double bonds.

If covalently bound, the stable structure has the metal on the less-substituted side of the allyl system. For such systems, reactions usually occur at the site remote from the metal (S E2').Lewis-Acidic metals (Mg, B) usually react by a cyclic "Zimmerman-Traxler" type of transition state. For extensive comparative studies of crotyl-M species see:

Yamamoto, J. Orgmet Chem., 1985, 284, C45.Martin, J. Org. Chem., 1989, 54, 6129.

Transition metal allyl π-complexes can show either nucleophilic or electrophilic reactivity,depending on the metal and ligands.

Some Uses of Allyl AdductsOH Functionalized

OH sec-alkyl

1. H-BR'2 R

R

+

M OH2. [O]

[O]OH H

OEquivalent of aldolcondensation

O R [H2] R

OH

R

Stereocontrol for netaddition of sec-alkyl

log

k

+

- -

Reactions of Allylsilanes with ElectrophilesFleming, I.; Langley, J. A. J. Chem. Soc. Perk. Trans 1, 1981, 26, 1421.

Me3Si SiMe 2Ph

H SiMe2Ph

Me3Si SiMe 2Ph

H Me3Si + SiMe2Ph

Me3Si

41

Both starting allyl silanes give the same product ratio.

Reactivity of π-Nucleophiles with Carbenium ionsBartl, Steenken. Mayr, J. Am. Chem. Soc. 1991, 113, 7710; Mayr. Kempf, Ofial Acc. Chem. Res. 2003, 36, 66

H

Cl

hν + HSiMe3

H

11

Reactivity towards (MeC6H4 in acetonitrile at 20 °C

)2+CH

10

10.3 RS , X OSiMe3 OMe

2.7 : 1

9 8.8 OSiMe3SnBu3

8.3 OMe8.3 OEt

OSiMe3 OEt

8

7

7.7

6.6

6.1

EtOH

OH2

7.6

6.8

6.3

OMe

OEt SnPh3

SiMe3

Bu

1 : 0.19

1 : 7216

SiMe3

6SiMe3 SiMe3 OEt

51 : 15

4

3

2

SiCl3

SiMe SiMe3

1 : 37

O O

3

1 : 4.8

1

Allyl SilanesAratani, M. Tetrahedron Lett., 1982, 23, 3921.

OCO2PNBCO2 PNB OCO2PNB

ClSiR3 CO2PNB

ON AgBF4

69% ON

CO2CH3 CH3O2C

G.Majetich, C.Ringold, Heterocycles, 1987, 25, 271.

SiMe3

EtAlCl2

O94%

O O

Overman, L. E. JACS, 1991, 113, 5378.PERFORENONE

1. (Siamyl)2BH

2. LiTMPR2B 1. Me3SiCl

2. HOAcLi SiMe3

OO

H

HO H

CHOSiMe3

BF3 OEt2

73%

OO

H

HO H OH

Cram

Epoxide Cyclization of Allyl Silane - Phorbol Synthesis Pettersson, Frejd Chem. Commun. 1993, 1823.

OMe3SiO

O

OMe3SiO OH

TBSO OBF3 OEt2 TBSO O Phorbol

H

SiMe3

Efficient termination of cationic cyclization

Akuammicine Synthesis by Propargylsilane Cyclization Bonjoch, Sole, Garcia-Rubio, Bosch J. Am. Chem. Soc. 1997, 119, 7230

NSiMe3

BF3 OEt3 ArN

1. LDA; N≡CCO2MeN

Ar 2. H2, Pd

OAr = o-NO2C6H4

ON

H CO2MeAkuammicine

Synthesis of Steroids by Propargylsilane Cationic Cyclization Schmidt, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122.

80-7

SiMe3 SiMe3

EtO

EtO Cl

Li HEtO

EtO

1. NaNH2

2. Me3SiCH2Cl EtO

1. HCl, H2O

2. CH=C(CH3)MgBr

EtO HO

SiMe3

1.

O OH PPh3

SiMe3

CH3-C(OEt)3

EtCO2H, 130 °C [Claisen - Johnsom]

SiMe3

O OO O

1. LiAlH4

1. HCl, H2O 2. NaOH3. MeLi

O O

2. PhLi[Wittig - trans]

SiMe3

H O2. CrO3 EtO O

O

H 1. O3; ZnH

CF3CO2H H H 2. NaOH H H

OH58%

O

4-Androstene-3,17-dione

SiMe3+

SiMe3

+

+

Stereochemistry of Allyl-M Carbonyl Reactions

B

H

O R

H

Me

SnBu3

H MeR H

O

Y. Yamamoto, JOMC 1985, 284, C45Martin, JOC, 1989, 54, 6129 Roush, JOC, 1990, 55, 4109. Keck, JOC, 1994, 59, 7889.

Cyclic - Metal is coordinated to carbonyl group.Acyclic - Metal is not coordinated to carbonyl group.Configuration of product is determined by configuration of double bond. Reaction is Stereospecific.

Configuration of product is more or less independent of double bond configuration. Reaction may be highly Stereoselective.

Stereochemistry of Crotyl Stannane Addition to Aldehydes Yamamoto, Yatagai, Naruta, Maruyama J. Am. Chem. Soc., 1980, 102, 7109. Keck, Savin, Cressman, Abbott J. Org. Chem. 1994, 59, 7889.

SnBu3 + RO

H

BF3 OEt2

CH2Cl2 R

OH

+ R

OH

E : Z syn : anti

SnBu3 R = Ph 90 : 10 42.8 : 1 (85%)

E R = cHex 90 : 10 14.9 : 1 (88%)

Z

SnBu3 12 : 88R = PhR = cHex 12 : 88

4.2 : 11.41 : 1

(80%)(82%)

Yamamoto explanation: antiperiplanar transition state. Keck explanation: Synclinal transition states.Focus on interaction between R and CH3

(place these anti to each other)

SnBu3

groups Focus on interactions between the BF3 group and the allyl stannane, as well as on secondary orbital interactions which favor synclinal transition states.

SnBu3

HR H

OBF3

CH3 HR H

OBF3

syn

CH3

F3B+O

H

H

R CH3 F3B

HO

H

syn

R CH3

Stereochemistry of the Allyl Tin Reaction with Aldehydes - Intramolecular Case. Denmark, S. E.; Weber, E. J. J. Am. Chem. Soc. 1984, 106, 7970.

OHC H OH HO H

+

SnBu3

Et2O BF3 87 : 13

CF3CO2H 99 : 1

SnBu3 O HO

H

HH

SnBu3

.

Synthesis of AvermectinDanishefsky, S.J.; et. al. J. Am. Chem. Soc., 1989, 111, 2967.

O

O t-Bu Ph3SiPvO Me

t-Bu

t-Bu

O

O

O

OH

O

CH3

BF3 Et2O

HOMe O

PvO

OMe

OH H

OMe

Me Me2CuLi

PvO

OH H

Me

HH Me

H SiPh3O H

O HMe H

cis-silane SiPh3

3/1 to 5/1 trans-silane1/3

Reaction is stereospecific, to some extent.

OMe O Me

HO O

Me

O OHO

OH

OMe

Me

OH

Me

Me

Me

AVERMECTIN A1a

Me

Me

B B

Me

Crotyl Borane Addition to Aldehydes - Zimmerman-Traxler Type Transition States Hoffmann, R. W. Ang. Chem. Int. Ed., 1982, 21, 255.

KCl-B(NMe 2)2

B(NMe2)2

HO

HO

O

B O

MeMe OH

O B

O

O R

H

H O B

O

O R

H

H R

Me+OH

cis-Olefin syn (erythro)

trans-Olefin anti (threo)

Allyl Borane Equilibration: The Curtin-Hammett Principle Wang, Gu, Liu J. Am. Chem. Soc. 1990, 112, 4425.

R

Mesyn (erythro)

syn/anti = 97/3

Interconversion among the isomers is faster than reaction of the major isomer with the aldehyde.

Me3Si

Me3Si B B B

Me3Si

THF 25% 75% <2%All reactions occur from

this isomer.H H H

Me3

R OSi H

R OMe3Si Me Me3Si

R OB

Me Me

A BH

NaOHMe H

H2SO4

R RR = n-C5H11

R R

A; NaOH 94 1 4 1

A; H2SO4 1 90 3 6

B; NaOH 0 0 98 2

B; H2SO4 0 0 8 92

In the Peterson Olefination, treatment of the β-hydroxy silane with NaOH gives a syn elimination, whereas H2SO4 gives an anti elimination.

Electrophilic Allylboranes will even add to Olefins.Singleton Org. Lett. 1999, 1, 485.

1. BBr2OH ( )

Sn4

BBr3 BBr2

0 °C, hexane

2. NaOH, H2O2To get high yields olefin needs to be somewhat activated - norbornene, styrene, 1,1-dialkylethylenes, cyclohexadiene and

90% cyclopentadiene all work. 1-Nonene gives only 33% yield.

B

Chiral Allyl and Crotylboronate ReagentsAllylborane - stereoselectivity poorer than for crotylboranes: Smith, A. B. et al Tetrahedron Lett. 1997, 38, 8667, 8761, 8675

OH

BPSOCHO 1. Ipc2B-Allyl 2.

NaOH, H2O 2

BPSO92/8 er

)2 B

Ipc2B-Allyl

CrotylboronatesRoush, W. R.; Palkowitz, A. D. J. Am. Chem. Soc., 1987, 109, 953; 1990, 112, 6339.

O CO2iPr OH

TBDPSO H +O

BO

CO2iPr-78 °C

88% dsRO

mismatched

75% 1. Et3SiCl, Et3N, DMF 2. O3, MeOH; Me2S

Et3SiO OH CO2iPr Et3SiO O

RO98% ds

O

BO

CO2iPr+

RO H

matched

H CO2iPr

O

H

AcO

O

O O

+CO2iPr

OCO2

O

OMe

OMe

91% ds

iPr

HO AcO O O

C-19 to C29 of Rifamycin S

OMe

OMe

R O

H

R O

B

O

B

O

O

CO2iPr

CO2iPr

CO2iPr

Transition state model

CrotylboronatesSynthesis of Rutamycin B: White et al. J. Org. Chem. 2001, 66, 5217

O

TBDPSO H +O

BO

CO2iPr

CO2iPr

9 : 1

80% dsmatched

RO

OH

RO

TBSO O

H +O

BO

CO2iPr

CO2iPr>98 : 2

>96% dsmatched

RO

TBSO OH

+

+

NN

B

H

N

Allenylboronic Ester: Synthesis of (-)-IpsenolN. Ikeda, A. Arai, H. Yamamoto, J. Am. Chem. Soc., 1986, 108, 483.

86-2

Br

1. Mg(Hg)

2. B(OMe)

3. H2O

3

B(OH)2

HO CO2RB

O

O

CO2R

CO2R

HO CO2R

CHO

CH2=CHBr 1. 9-BBN-Br

HO

(-)-Ipsenol

Pd(PPh3)4

H , MeOHTHPO Br 2. HOAc

3. H2O2, NaOH 4. DHP,H

HO78%, >99% ee

Allenyl and Propargyl BoranesCorey, Yu, Lee J. Am. Chem. Soc. 1990, 112, 878.

TolSO 2

Ph

NB

Ph

SO2Tol 23 °C

H

SnBu3

TolSO 2

Ph

NB

Ph

SO2Tol

PhCHO

-78 °C, 2.5 h

Ph

OH

H

Br >99% ee, 74%

SO2TolN

O

N

SO2

R

SnPh

23 °C

3TolSO 2

Ph

NB

Ph

SO2Tol

H

PhCHO

-78 °C, 2.5 h

Ph

OH98% ee, 79%

H 1. Bu3SnCl2. Reflux, MeOH

H Ph Ph Ph Ph

MgBr 78%"propargylmagnesium bromide"

SnBu3 TolSO 2 NH H

N SO2TolBBr3

TolSO 2N

B

Br

N SO2Tol

H

MgBr

Allenyl Borane

Ph3SnCl, Et2O

71%SnPh3

Trost, Doherty J. Am. Chem. Soc. 2000, 122, 3801.

O H Ph PhHO

+ TolSO 2N

BN

SO2Tol Roseophilin

H

Allenyl StannanesRousch, et al. J. Am. Chem. Soc. 2002, 124, 6981

OMe

TESO OTBS O

H

Bu3Sn5 equiv. SiMe 3

TESO OTBS OH SiMe3

Bifilomycin

BuSnCl3, -40 °C 85%

OMe20:1 ds (4:1 with 1.2 equiv) Kinetic

resolution

BF3 should not be able to chelate - monodentate Lewis acid

+

Chelation and Felkin-Anh Controlled Additions of Allyl Stannanes to Aldehydes Keck, Boden, Tetrahedron Lett. 1984, 25, 265.

OBn

O

HSnBu3

MgBr2, CH2Cl2

-23 °C

OBn

+OH

85% >250:1

OBn

OH

OSiMe2tBuH

SnBu3 OSiMe2tBu OSiMe2tBu

O 2 BF3 OEt2

CH2Cl2, -78 °COH

+

83%OH

threo (syn) 5:95 erythro (anti)

MgBr2

OOBn +O

BF3

H H attackthreo

attack H H

OSiMe2tBu erythro

Chelation control Felkin-Anh control (Cram)

Stereochemistry of the Allyl FragmentHayashi, Konishi, Ito, Kumada, J. Am. Chem. Soc. 1982, 104, 4662, 4963.

Br + Me3Si MgBr Cat* PdSiMe3

Ph 85% ee

Ph HOH E

CH3

O

H

HR H

Ph

SiMe3

Me3CCOH, TiCl 4 t-Bu

99/1 syn

PhCH3

PhH

SiMe3

HO

CH3Ph

CH3t-Bu Ph

O CH3Ph

OH 86% ee H 87% ee H

O

53% ee

O O TiCl4 Me3CCl, TiCl4 CH3CCl, AlCl3

Stereochemistry of the Allenyl Fragment Buckle, Fleming, Tetrahedron Lett. 1993, 34, 2383.

Me

Me3Si98% ee

MeH

+

Cl

TiCl4, -78°

30% CH3

H

Product ofanti addition

Me

Me

3Si

H TiClnO

iPr

MeH

99:1

Me

Me

3Si

MeH + H

O

TiCl4, -78°

89%OH

+

OH

HiPr

OH

CH3 H

95:5