Protective Groups in Synthetic ... - University of Chicagosnyder-group.uchicago.edu/downloads/Lectures2020... · "To kill two birds with one stone" Me NC HO TBSO H Me Me NC O TBSO

Protective Groups in SyntheticOrganic Chemistry

OO

OMeMe

OPMB

XX

OTBS

Lecture Notes

Key Texts

P. J. Kocienski, Protecting Groups (2nd Edition), 1994,Georg Thieme Verlag: Stuttgart, p. 260.

P. J. Kocienski, Protecting Groups (3rd Edition), 2004,Georg Thieme: Stuttgart, p. 679.

T. W. Greene, P. G. M. Wutz, Protective Groups in Organic Synthesis (3rd Edition), 1999,John Wiley and Sons: New York, p. 779.

Key Reviews

Selective Deprotections: T. D. Nelson, R. D. Crouch, Synthesis 1996, 1065.

Protective Groups:Background and General Considerations

"Protection is a principle, not an expedient" Benjamin Disraeli, British Prime Minister, 1845

"Like death and taxes, protecting groups have becomea consecrated obstruction which we cannot elude"

Peter Kocienski, Organic Chemist

Every protecting group adds at least one, if not two steps to a synthesisThey only detract from the overall efficiency and beauty of a route, but, without them,there are certainly transformations which we would not be able to do at all.

Remember:

Protective Groups:Temporary Protection

Temporary protection involves the ideal for protecting groups when they are required:the protection step, desired reaction, and deprotection all occur in the same pot.

MeO

O

OO THF, -40 °C

MeO

O

OOLi

NPh Me

LiNPh Me

MeO

OO

HOLi

Li

aqueouswork-up

Ene Reactions in Total Synthesis:Ene/Retro-Ene Sequence to Protect Indole

P. S. Baran, C. A. Guerrero, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 5628.P. S. Baran, C. A. Guerrero, E. J. Corey, Org. Lett. 2003, 5, 1999.

NH

NAc

Me Me

CO2MeH

N

NN NMe

O

OH

NN NMe

O

O

+

N

NAc

Me Me

CO2MeH

MTAD = N-methyltriazolinedione

NHN

MeN

O

OCH2Cl2,

0 °C,1 min

150 °C,1 min

MTAD

NH

N

HN

NMeMe

OOH

H

Me Me

MTAD,CH2Cl2,

0 °C, 1 h;

Ene reaction

okaramine N

NH

N

N

NMeMe

OO

OHH

HH

Me MeN

N

N

NMeMe

OOH

H

Me Me

NHN

MeN

O

OOH

H

(70%overall

based onr.s.m.)

110 °C,30 min

1O2(O2,

methyleneblue)

RetroEne

reaction

Protective Groups:Background and General Considerations

Tactical considerations to consider for each protecting group selected in a synthesis:

It should be easily and efficiently introduced.

It should be cheap and readily available.

It should be easy to characterize and avoid the introduction of new stereogenic centers.

It should not afford so many spectroscopic signals that it hides key resonances for the substrate.

It should be stable to chromatography.

It should be stable to a wide range of reaction conditions.

It should be removed selectively and efficiently under highly specific conditions.

The by-products of deprotection shoud be easily separated from the substrate.

Protective Groups:Something to be Very Carefully Considered

O

HN N

HO

O HNO

NH

OMeOMe

MeO

O

TBSO

NH

MeO2C

O

Cl

ClOMe

OTBSO

Me

MeN Me

H

O NHDdm

HNO Boc

O

HN N

HO

O HNO

NH

OHOH

HO

O

HO

NH

HO2C

O

Cl

ClOH

OHO

Me

Me

HN Me

H

O NH2

HNO

vancomycin aglycon

(62% overall)Global deprotections

1. HF•py/py, THF, 0→25 °C, 12 h2. AlBr3, EtSH/CH2Cl2 (1:1), 25 °C, 4 h

K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2708.

Protective Groups:Orthogonal Sets of Protecting Groups

Orthogonal Set = a groups of protecting groups whose removal is accomplished in any order with reagents and conditions that do not affect protecting groups in any other orthogonal set.

O

OBz

OAcH

PvO

TESOMe

MeMe

TBDPSO

TBSO

Me

OrthogonalSet #1

OrthogonalSet #2

In practice this concept is incredibly difficult to reduce to practice, but it is a useful framework and organizing principle to think about protecting group regimes for a complex molecule synthesis.


1. Cleavage by basic solvolysis

RO

O

MeROH

OHRO

O

Me RO

ORO

O

RO

O

Cl Cl

Cl Cl ClCl

1 760 16,000 100,000krel


1. Cleavage by basic solvolysis

2. Cleavage by acidic hydrolysis

RO

O

MeROH

OHRO

O

Me RO

ORO

O

RO

O

Cl Cl

Cl Cl ClCl

1 760 16,000 100,000krel

OO OHHOH OO

RO OMeR R

Other groups easily cleaved by acid


3. Cleavage by heavy metals

S

S HgCl2 O


3. Cleavage by heavy metals

4. Cleavage by fluoride

S

S HgCl2 O

Si

MeMeMe

RO MeMeSi

MeMeMe

RO MeMe

n-Bu4NF F H2OROH

-[t-BuMe2SiF]

Strength of Si-F bond is 810 kJ/mol while Si-O bond is 530 kJ/mol

RO n-Bu4N

n-Bu4N


5. Reductive Elimination

O

RO O

Troc = trichloroethoxycarbonyl

Zn, AcOHROHCl

Cl Cl

O

RO O ZnCl

Cl Cl

HCl

Cl-

-[CO2]


5. Reductive Elimination

6. β-elimination

O

RO O

Troc = trichloroethoxycarbonyl

Zn, AcOHROHCl

Cl Cl

O

RO O ZnCl

Cl Cl

HCl

Cl-

O

R2N O

O

R2N O R2NH2-[CO2]

Fmoc = 9-fluorenylmethylcarbamate

+

-[CO2]

Mildbase


7. Hydrogenolysis

OR H2, Pd/C+ ROH O O

R R

Ph

Other examples of cleavable groups

benzyl ether


7. Hydrogenolysis

8. Oxidation

OR H2, Pd/C+ ROH O O

R R

Ph

ORDDQ or CAN,

THF/H2O+ ROH

MeO

O

OCN

CNCl

ClOxidation viaSingle-electron

transfer

O

MeO

Other examples of cleavable groups

DDQ

benzyl ether

p-methoxybenzylether


9. Dissolving Metal Reduction

ORLi/NH3,t-BuOH

+ ROHO

OROnly other protecting group

applicable to these conditions


9. Dissolving Metal Reduction

10. Transition Metal Catalysis (i.e. Allyl-based protecting groups)

ORLi/NH3,t-BuOH

+ ROHO

OR

RO

Pd,morpholine

or dimedone

Can also use (Ph3P)3RhCl and acid

ROHRO

PdL2

Only other protecting group applicable to these conditions


11. Light

NO2

OR

hν NO

O

ROH

NO2

O

O

OR

NO2

O

O

R

alcohol PG acid PG

+


11. Light

12. Enzymes

NO2

OR

hν NO

O

ROH

NO2

O

O

OR

NO2

O

O

R

alcohol PG acid PG

O

O

NHFmocO O OMeAcHN

OAcAcO

AcO

O

O

NHFmocOHAcHN

OAcAcO

AcO

O

O

NHFmocO O OMeAcHN

OHHO

HO

wheat germ lipasepapain

cysteinebuffer

+

Protective Groups:Relay Deprotection

O

SO2Ph

Me

Me

MeOMeO

MeO

Cl

Me

O

SO2Ph

Me

Me

MeOMeO

MeO

SO2Ph

Me1. NaSPh2. mCPBA

NaBH4OH

SO2Ph

Me

Me

MeOMeO

MeOH

Me

Relay deprotection: when a protecting group that is stable under most conditions is transformed chemically into a new, and more labile, protecting group.

Protective Groups:Mutual Protection

"Une pierre, deux oiseaux""Zwei Fleigen mit einer Klappe schlagen"

"To kill two birds with one stone"

Me

NCHO

TBSO

HMe

Me

NCO

TBSO

HMe

py•HBr3

pyridine

Br

O HMe

Br

OOHO

HO CO2MeOH

HO HMe

OOHO

HO CO2MeOH Zn,

AcOH(96%)

(96%)

B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131.

Protective Groups:Sometimes Not-So-Innocent Bystanders

O

O

OTs

OTs

NaCN,DMSO80 °C

O

O

OTs CN

OO

NC

Protective Groups:Sometimes Not-So-Innocent Bystanders

O

O

OTs

OTs

NaCN,DMSO80 °C

O

O

OTs CN

OO

NC

O

O Me

MeOO

O Me

MeOBr3B

O

O Me

BrO

Me

O

BBr3 Br

Hydroxyl Protecting Groups:Silyl Ethers

RO SiMe

MeMe RO Si

Et

EtEt RO Si

Me

Met-Bu RO Si

i-Pr

i-Pri-PrRO Si

Ph

Pht-Bu

trimethylsilyl(TMS)

triethylsilyl(TES)

t-butyldimethylsilyl(TBS or TBDMS)

t-butyldiphenylsilyl(TBDPS)

triisopropylsilyl(TIPS)


RO SiMe

MeMe RO Si

Et

EtEt RO Si

Me

Met-Bu RO Si

i-Pr

i-Pri-PrRO Si

Ph

Pht-Bu

trimethylsilyl(TMS)

triethylsilyl(TES)

t-butyldimethylsilyl(TBS or TBDMS)

t-butyldiphenylsilyl(TBDPS)

triisopropylsilyl(TIPS)

Relative Acid Stability1 64 20,000 700,0005,000,000

Relative Base Stability1 10 - 100 20,000 20,000 100,000

(t1/2 in 5% NaOH/MeOH)

(<1 min) (1 min) (> 24 h) (> 24 h) (> 24 h)

(t1/2 in 1% HCl/MeOH)

(<1 min) (<1 min) (<1 min) (255 min) (55 min)


Formation:

R R

OH R3SiCl,imidazole, DMF

R R

OSiR3

or R3SiOTf,2,6-lutidine,

CH2Cl2

Cleavage:

R R

OHFluoride sourceR R

OSiR3

Common Fluoride Sources

HF3HF•NEt3

HF•pyrn-Bu4NF (TBAF)/AcOH

HF•pyr/pyrn-Bu4NF (TBAF)


Selective Monosilylation of Diols is Possible:

NaH (1 eq),THF; TBSCl,

or n-BuLi (1 eq),THF; TBSCl,

HO OH HO OTBS

O

N

O

OH

TESO

MeO

MeOH

ONO

O

O

Me

Me

O OH

OTIPS

O

N

O

OTES

TESO

MeO

MeOH

ONO

O

O

Me

Me

O OH

OTIPS

TESCl,2,6-lutidine,

CH2Cl2,-78 °C(97%)

TESCl/imid and TESOTf/2,6-lutidine gave bis-silylated product

D. A. Evans, D. M. Fitch, Angew. Chem. Int. Ed. 2000, 39, 2536.


Selective Deprotection of Silyl Ethers is Also Possible:

R. A. Holton and co-workers, J. Am. Chem. Soc. 1994, 116, 1599.

O

OHO

OAcH

BzO

AcOMe

MeMe

HO

ONH

Ph

O

OH

PhO Me

Taxol

O

OBOM

OAcH

O

HOMe

MeMe

O

TBSO

Me

O

O

OBOM

OAcH

O

TESOMe

MeMe

O

TBSO

Me

O

HF•pyr, CH3CN,0 °C, 11 h

(100%)


Selective Deprotection of Silyl Ethers is Also Possible:

E. M. Carreira, J. DuBois, J. Am. Chem. Soc. 1995, 117, 8106.

OOCO2HOH

HO2CHO2C

OHO

O

OAc

Me

zaragozic acid

Me

OO

OH

OAcAcOOAc

MeOTBS

TBSO

OO

OH

OAcAcOOAc

MeOH

TBSOCl2CHCO2H

Hydroxyl Protecting Groups:Esters and Carbonates

RO

O

Me RO

O

RO

O

RO

O

RO

O

RO

ORO

ORO

O

acetate (Ac)

Cl Cl

Cl Cl ClCl

chloroacetate dichloroacetate trichloroacetate

F FF

trifluoroacetateMeMeMe

pivaloate (Pv)OMe

benzoate (Bz) p-methoxybenzoate


RO

O

Me

RO

O

RO

O

RO

O

RO

ORO

O

RO

O

acetate (Ac)

Cl

ClCl ClCl

dichloroacetatetrichloroacetateF FF

trifluoroacetate

MeMeMe

pivaloate (Pv)OMe

benzoate (Bz)p-methoxybenzoate

In general, the ease with which esters hydrolyze under basic conditions increases withthe acidity of the product acid. Sterics also can play a role (i.e. pivaloate group)

< < <

<

<<<

[most stable]

[least stable]

RO

OCl

chloroacetate

All can hydrolyze under acidic conditions, but typically only when water is present.


RO

O

OMemethyl carbonate

9-(fluorenylmethyl)carbonate (Fmoc)

allyl carbonate (Alloc)

2,2,2-trichloroacetylcarbonate (Troc)

2-(trimethylsilyl)ethyl carbonate (Teoc)

benzyl carbonate (Cbz)

RO

O

O

RO

O

O

RO

O

OCl ClCl RO

O

O

RO

O

O Me

RO

O

O SiMe3

MeMe

t-butylcarbonate (Boc)[resistant to

nucleophilic attack]

[cleaved by mild base] [cleaved with Zn/HOAc] [cleaved with fluoride][cleaved by

hydrogenolysis]

[cleaved with Pd/Nu]


General methods for the formation of esters and carbonates:

ROH +O

Cl R'

pyridine,4-DMAP O

RO R'

ROH +O

O R'

pyridine,4-DMAP O

RO R'

O

R'

ROH +O

Cl OR'pyridine O

RO OR'

B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522.


General methods for the formation of esters and carbonates:

ROH +O

Cl R'

pyridine,4-DMAP O

RO R'

ROH +O

O R'

pyridine,4-DMAP O

RO R'

O

R'

ROH +O

Cl OR'pyridine O

RO OR'

N

NMe Me4-DMAP

N

NMe Me

OR

X

Proposed acyltransfer reagent

B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522.


Tricks for selective formation of an ester from diol starting materials:

For a review, see: S. Hanessian, S. David, Tetrahedron, 1985, 41, 643.

HO OBnOH toluene,

110 °C

OBnOSn OBu Bu

AcCl,CH2Cl2

0 °CAcO OBn

OH

Bu2SnO


Tricks for selective formation of an ester from diol starting materials:

For a review, see: S. Hanessian, S. David, Tetrahedron, 1985, 41, 643.

HO OBnOH toluene,

110 °C

OBnOSn OBu Bu

AcCl,CH2Cl2

0 °CAcO OBn

OH

OMe

HOOBn

OMe

HOOH

Bu2SnO, toluene, Δ; BnBr, n-Bu4NI,

25→110 °C

The sterically least encumbered position is always protected selectively; on sugars, if both positions are secondary and sterics are roughly equal, an equatorial alcohol

will be protected selectively over an axially disposed alcohol.

Bu2SnO


A. G. Myers and co-workers, J. Am. Chem. Soc. 1998, 120, 5319.D. R. Deardorff and co-workers, Tetrahedron Lett. 1986, 27, 1255.

OMe

Me

O

O

OH

OO

MeMe

OHO

O

OCl

OMe

Me

O

O

OH

OO

MeMe

OHO

OHn-PrNH2

(83%)

Examples of selective deprotection:


A. G. Myers and co-workers, J. Am. Chem. Soc. 1998, 120, 5319.D. R. Deardorff and co-workers, Tetrahedron Lett. 1986, 27, 1255.

OMe

Me

O

O

OH

OO

MeMe

OHO

O

OCl

OMe

Me

O

O

OH

OO

MeMe

OHO

OHn-PrNH2

OAc

OAc

OH

OAc

O

OAc

acetyl-cholinesterase

(94%)(99% e.e.)

PCC

(83%)

Examples of selective deprotection:

Hydroxyl Protecting Groups:Acetals

RO OMe RO O

O

methoxymethylether (MOM)[cleaved withstrong acid]

benzyloxymethylether (BOM)[cleaved by

hydrogenation]

2,2,2-trichloroethoxymethyl ether

[cleaved with Zn]

OMep-methoxybenzyl

ether (PMBM)[cleaved with DDQ]

RO OCl ClCl

RO SMe

methylthiomethylether (MTM)

[cleaved with HgCl2or AgNO3]

RO

2-(trimethylsilyl)ethoxymethyl ether (SEM)

[cleaved with fluoride]

RO O SiMe3

OROtetrahydropyranyl

ether (THP)[cleaved with mild acid]

Hydroxyl Protecting Groups:Acetals

ORO

Formation of acetals:

ROH + R'OCH2X

i-Pr2NEtor NaH,solvent

RO OR'

ROHO

PPTS orp-TsOH

PPTS = pyridinium p-toluenesulfonate

P. A. Grieco and co-workers, J. Org. Chem. 1977, 42, 3772.

+

Hydroxyl Protecting Groups:Ethers

RO RORO

allyl ether[cleaved with

Pd/Nu]

trityl ether[cleaved bystrong acid]

p-methoxybenzylether (PMB)

[cleaved with DDQ]

RO

OMe

OO

R R

Me Me

OO

R R

benzyl ether (Bn)[cleaved by hydrogenation]

dimethyl acetonide[cleaved with acid]

benzylidene acetal[cleaved by hydrogenation]


OO

R R

Me Me

Formation of ethers

ROH + R'XNaH,

solventROR'

Exception is trityl groups; they require Ph3CCl and 4-DMAP at elevated temperatures.

O

Me Me Me Me

MeO OMeor or

OMe

Me

OHOH

R R+ H

Concept applies to any group that can be appended to a diol.Thus, to form a benzylidene acetal, one should use benzaldehyde.


What about polyols? Which cyclic ether will be formed selectively?

HOOH

Me

OHO

Me Me

p-TsOH(A:B = 5:1)

OH

Me

OO

MeMe

HOO

Me

O

MeMe

+

A B

In general, simple acetonide formation with 1,2-diols occurs in preference to 1,3-diols.Note, though, that benzylidene acetals display reverse selectivity!

D. R. Williams, S.-Y. Sit, J. Am. Chem. Soc. 1984, 106, 2949.



W. R. Roush, J. W. Coe, J. Org. Chem. 1989, 54, 915.

The case of a 1,2,3-polyol

Me

OH

OHHO

Me

OH

OO

MeMe

HO H OO

HMe

MeMe

Thermodynamic productKinetic product

In general, the more substituted acetonide is favored, especially when the substituents on the 5-membered ring are in a trans orientation; in a cis case, the

less substituted acetonide might be favored.

acetoneacid

+

1:5



W. R. Roush, J. W. Coe, J. Org. Chem. 1989, 54, 915.

The case of a 1,2,3-polyol

Me

OH

OHHO

Me

OH

OO

MeMe

HO H OO

HMe

MeMe

Thermodynamic productKinetic product

In general, the more substituted acetonide is favored, especially when the substituents on the 5-membered ring are in a trans orientation; in a cis case, the

less substituted acetonide might be favored.

OH

OH

OH

OTBSH O

O

HHO

Me Me

OTBS

OH

OOH

OTBS

H

MeMe0% 100%

acetoneacid

acetoneacid

+

+

1:5

Phenol Protecting Groups

OMe O O O

Protecting groups cleaved by base or acid are typically far more labile on phenols than a standard aliphatic alcohol. This property has important implications, as it explains why phenolic methyl ethers can be cleaved, whereas standard methyl ethers are effectively the Rock of Gibralter when it comes to

deprotection (i.e., it ain't coming off)!

OSiR3 O

O

R O

O

OR O ORacetalsphenyl carbonatesphenyl esterssilyl ethers

methyl ether[cleaved with TMSI,

BBr3, or 9-Br-9-BBN]

t-butyl ether[cleaved with

neat TFA]

benzyl ether allyl ether

Phenol Protecting Groups:Methyl Ethers

OMs

HN NHTfaO

O

HO Cl

OPiv

NH

O

OMeOMe

MeO

O

HN

MeHN

O

AlBr3,EtSH, 0 °C

OMs

HN NHTfaO

O

HO Cl

OPiv

NH

O

OHOH

HO

O

HN

MeHN

O

D. A. Evans and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2700.S. L. Schreiber and co-workers, J. Am. Chem. Soc. 1993, 115, 10378.

Phenol Protecting Groups:Methyl Ethers

MeO

MeO O

O HN OCO2Me

OMe

MeH

MeO

H

HO

HO O

O HN OCO2H

OMe

MeH

HO

H

X1 year of hard work

OMs

HN NHTfaO

O

HO Cl

OPiv

NH

O

OMeOMe

MeO

O

HN

MeHN

O

AlBr3,EtSH, 0 °C

OMs

HN NHTfaO

O

HO Cl

OPiv

NH

O

OHOH

HO

O

HN

MeHN

O

D. A. Evans and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2700.S. L. Schreiber and co-workers, J. Am. Chem. Soc. 1993, 115, 10378.

Carbonyl Protecting Groups

R R'

OMeMeO

R R'OO

R R'O O

dimethyl acetal 1,3-dioxane 1,2-dioxolane

All are formed by the action of an acid with the appropriate alcohol

Reactivity order towards forming these protecting groups:

O

= R R'

OO O O

R

R'

R'

OO

=> > > > >>RO


Rates of formation:

HO OHMe Me

HO OHHO OH

O

O

RR

O

O

RR

Rates of cleavage:

> >

>

O

O

RR

MeMe O

O

RR

Me O

O

RR

krel 50,000 5,000 1

> >>

M. Ohno and co-workers, Tetrahedron Lett. 1982, 23, 1087.


Me

O

OHO OH

p-TsOH

Me

O

O O

(95%)


Me

O

OHO OH

p-TsOH

Me

O

O O

(95%)

Me

O

Me

O

O

Me

O

O

HO OH

acid

fumaric acid (pKa = 3.03)phthalic acid (pKa = 2.89)oxalic acid (pKa = 1.23)p-TsOH (pKa < 1.0)

10070800

03020100

+


R R'

SMeMeS

R R'SS

R R'S S

dimethyl thioacetal 1,3-dithiane 1,2-dithiolaneR R'

NC OR

cyanohydrin[deprotected with Hg, NBS, IBX]


R R'

SMeMeS

R R'SS

R R'S S

dimethyl thioacetal 1,3-dithiane 1,2-dithiolaneR R'

NC OR

cyanohydrin[deprotected with Hg, NBS, IBX]

RSS

R

NC OR base

RSS

R

NC OR R'X

RSS

R

NC OR

R' R'

O Umpolung = formal reversal of thepolarity of a functional group

" "These groups turnaldehydes into nucleophiles

Special uses for these protecting groups:

or or or

Carboxylic Acid Protecting Groups

R OMe R O

O

methyl ester t-butyl ester allyl ester

OMep-methoxybenzyl ester

Me R O

benzyl ester

R

silyl ester[must be TBS, TBDPS,

or TIPS if you wantto purify by chromatography]

O O MeMe O

O

OR

O

O

R OSiR3

R'

OR

OROR

ortho ester

Amine Protecting Groups

R2N

O

OMemethyl carbamate

9-(fluorenylmethyl)carbamate (Fmoc)

allyl carbamate (Alloc)

2,2,2-trichloroacetylcarbamate (Troc)

2-(trimethylsilyl)ethyl carbamate (Teoc)

benzyl carbamate (Cbz)

R2N

O

O

R2N

O

O

R2N

O

OCl ClCl

R2N

O

OR2N

O

O Me

R2N

O

O SiMe3

MeMe

t-butylcarbamate (Boc)[resistant to

nucleophilic attack]

[cleaved by mild base] [cleaved with Zn/HOAc] [cleaved with fluoride]

[cleaved byhydrogenolysis]

[cleaved with Pd]

R2N

R2N

Protecting Groups:Putting it all Together

OTBDPS

OTESOTMS

MeNH

THPO

MeO2C

OTBDPS

MeNBoc

HO

MeO2C

O

1. Boc2O, Et3N, 4-DMAP, CH2Cl2, 25 °C2. AcOH/H2O (19:1), 80 °C

NaHCO3, DMF, 80 °C(83%)

(62% overall)OTBDPS

HOOH

MeNBoc

HO

MeO2C

p-TsCl, n-Bu2SnO,Et3N, CH2Cl2, 25 °C

OTBDPS

TsOOH

MeNBoc

HO

MeO2C

(84%)

T. Fukuyama and co-workers, J. Am. Chem. Soc. 2002, 124, 2137.

Protective Groups:Sometimes They Really Are Not Needed . . .

O

Me

O

HO

TBSO

MeO

MeO

Me

O Me

MeHO

Me

OMe

O

PMP

O

O

OMe

MeO

Me

OMe

Me OTBS

Me

OMe

O

PMP

Me

OHO

OTBS

O

O

O

Me

O

O

O

Me

OH

HO

Me

OMe

HO HO

Me

MeO

MeOHOH

Me

O Me

OMe

Me

Me

OH

O Me

MeHO

Me

OMe

swinholide A

1. O

Cl

Cl

Cl

ClEt3N, toluene,25 °C, 2.5 h;4-DMAP,80 °C, 15 h

2. HF, MeCN, 0 °C, 105 min

(42% overall)Yamaguchi

macrolactonizationand global

deprotection

With protecting group present on the other alcohol,dramatically lower yields observed

I. Paterson and co-workers, J. Am. Chem. Soc. 1994, 116, 9391.

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Protective Groups in Synthetic ... - University of Chicagosnyder-group.uchicago.edu/downloads/Lectures2020... · "To kill two birds with one stone" Me NC HO TBSO H Me Me NC O TBSO