Protecting Groups (2Nd Edition), 1994, Georg Thieme Verlag: Stuttgart, P

Home , Ester, Protecting group, Trimethylsilyl

Protective Groups in Synthetic Organic Chemistry OTBS OPMB O Lecture Notes O Me Key Texts O Me XX 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 become a consecrated obstruction which we cannot elude" Peter Kocienski, Organic Chemist

Remember:

Every protecting group adds at least one, if not two steps to a synthesis They 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. Protective Groups: Temporary Protection

Li Li O O N Li HO Ph Me O O O THF, -40 °C OLi aqueous O MeO O MeO work-up MeO N Ph Me

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. Ene Reactions in Total Synthesis: Ene/Retro-Ene Sequence to Protect Indole O O H CO Me CH2Cl2, MeN H CO Me 2 O NH 2 0 °C, N NAc 1 min O N NAc NMe N N + NMe N N 150 °C, H O N 1 min N H Me Me O Me Me MTAD MTAD = N-methyltriazolinedione

Me N MTAD, N OH Me Me N OH CH2Cl2, O MeH Me H 110 °C, MeH 0 °C, 1 h; N 30 min N N O H O O H 1 MeN NH H O2 H O (70% H O N N H O N (O2, O overall N methylene based on blue) r.s.m.) Retro N Ene N N H Me Me reaction Me Me Ene H Me Me reaction okaramine N

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. 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 OMe Cl O O TBSO Cl OTBS H O H O H O Boc N N N N N O N Me O H H O H Me NH O NHDdm Me MeO2C OMe OMe MeO (62% overall) 1. HF•py/py, THF, 0→25 °C, 12 h Global deprotections 2. AlBr3, EtSH/CH2Cl2 (1:1), 25 °C, 4 h OH Cl O O HO Cl OH H O H O H O H N N N N N O N Me O H H O H Me NH O NH2 Me HO2C OH vancomycin aglycon OH HO 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.

TESO OBz Me Me Orthogonal Me TBSO Set #1 Me H O TBDPSO PvO OAc

Orthogonal Set #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. Protective Groups: Orthogonal Sets of Protecting Groups

1. Cleavage by basic solvolysis

O O O O O Cl Cl OH Cl RO RO ROH RO Me RO Cl RO Me Cl Cl krel 1 760 16,000 100,000 Protective Groups: Orthogonal Sets of Protecting Groups

1. Cleavage by basic solvolysis

O O O O O Cl Cl OH Cl RO RO ROH RO Me RO Cl RO Me Cl Cl krel 1 760 16,000 100,000

2. Cleavage by acidic hydrolysis

H O O O O HO OH RO OMe R R Other groups easily cleaved by acid Protective Groups: Orthogonal Sets of Protecting Groups

3. Cleavage by heavy metals

S HgCl2 O S Protective Groups: Orthogonal Sets of Protecting Groups

3. Cleavage by heavy metals

S HgCl2 O S

4. Cleavage by fluoride

Me Me Me Me Me Me n-Bu NF 4 F H2O Si Si RO n-Bu4N ROH RO Me RO Me -[t-BuMe SiF] Me Me 2 n-Bu4N Strength of Si-F bond is 810 kJ/mol while Si-O bond is 530 kJ/mol Protective Groups: Orthogonal Sets of Protecting Groups

5. Reductive Elimination Cl H O O - Cl Cl Zn, AcOH ZnCl RO O RO O ROH Cl Cl -[CO2] Cl Cl Troc = trichloroethoxycarbonyl Protective Groups: Orthogonal Sets of Protecting Groups

5. Reductive Elimination Cl H O O - Cl Cl Zn, AcOH ZnCl RO O RO O ROH Cl Cl -[CO2] Cl Cl Troc = trichloroethoxycarbonyl

6. β-elimination

O O Mild base R2N O R2N O R2NH2 + -[CO2]

Fmoc = 9-fluorenylmethyl carbamate Protective Groups: Orthogonal Sets of Protecting Groups

7. Hydrogenolysis

Ph OR H2, Pd/C + ROH O O R R benzyl ether Other examples of cleavable groups Protective Groups: Orthogonal Sets of Protecting Groups

7. Hydrogenolysis

Ph OR H2, Pd/C + ROH O O R R benzyl ether Other examples of cleavable groups

8. Oxidation

O O DDQ or CAN, Cl CN OR THF/H2O + ROH Oxidation via MeO MeO Cl CN Single-electron O p-methoxybenzyl transfer ether DDQ Protective Groups: Orthogonal Sets of Protecting Groups

9. Dissolving Metal Reduction

Li/NH3, O OR t-BuOH + ROH OR Only other protecting group applicable to these conditions Protective Groups: Orthogonal Sets of Protecting Groups

9. Dissolving Metal Reduction

Li/NH3, O OR t-BuOH + ROH OR Only other protecting group applicable to these conditions

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

Pd, morpholine RO or dimedone RO ROH PdL2

Can also use (Ph3P)3RhCl and acid Protective Groups: Orthogonal Sets of Protecting Groups

11. Light NO NO O 2 2 NO 2 N hν ROH + O OR O R OR O O O alcohol PG acid PG Protective Groups: Orthogonal Sets of Protecting Groups

11. Light NO NO O 2 2 NO 2 N hν ROH + O OR O R OR O O O alcohol PG acid PG 12. Enzymes O O O O OMe AcHN NHFmoc papain AcO cysteine wheat germ lipase buffer AcO OAc O O O O OH O O OMe AcHN AcHN NHFmoc AcO NHFmoc HO

AcO HO OAc OH Protective Groups: Relay Deprotection

SO Ph SO2Ph 2 SO2Ph Me Me Me Me Me Me 1. NaSPh NaBH Me Me 4 Me O 2. mCPBA O OH MeO MeO MeO O O OH MeO MeO MeO Me Me Me

Cl SO2Ph

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 Me py•HBr3 NC NC H pyridine H HO O Me (96%) Me TBSO TBSO Br

CO Me HO CO2Me HO 2 OH Zn, OH O O AcOH HO HO O O H (96%) H HO O Me Me Br

B. M. Trost, M. J. Krische, J. Am. Chem. Soc. 1999, 121, 6131. Protective Groups: Sometimes Not-So-Innocent Bystanders

OTs OTs CN O NaCN, O NC DMSO O O 80 °C O OTs O Protective Groups: Sometimes Not-So-Innocent Bystanders

OTs OTs CN O NaCN, O NC DMSO O O 80 °C O OTs O

Br3B BBr3 Br MeO MeO Br O O O O O

O Me O Me Me O Me Hydroxyl Protecting Groups: Silyl Ethers

Me Et Me Ph i-Pr RO Si Me RO Si Et RO Si t-Bu RO Si t-Bu RO Si i-Pr Me Et Me Ph i-Pr trimethylsilyl triethylsilyl t-butyldimethylsilyl t-butyldiphenylsilyl triisopropylsilyl (TMS) (TES) (TBS or TBDMS) (TBDPS) (TIPS) Hydroxyl Protecting Groups: Silyl Ethers

Relative Acid Stability (t1/2 in 1% HCl/MeOH) 1 64 20,000 5,000,000 700,000 (<1 min) (<1 min) (<1 min) (255 min) (55 min)

Relative Base Stability (t1/2 in 5% NaOH/MeOH) 1 10 - 100 20,000 20,000 100,000 (<1 min) (1 min) (> 24 h) (> 24 h) (> 24 h) Hydroxyl Protecting Groups: Silyl Ethers

Formation:

R SiCl, OH 3 imidazole, DMF OSiR3 R R R R or R3SiOTf, 2,6-lutidine, CH2Cl2

Cleavage:

Common Fluoride Sources

HF OSiR3 OH Fluoride source 3HF•NEt3 HF•pyr R R R R n-Bu4NF (TBAF)/AcOH HF•pyr/pyr n-Bu4NF (TBAF) Hydroxyl Protecting Groups: Silyl Ethers

Selective Monosilylation of Diols is Possible:

NaH (1 eq), THF; TBSCl, HO OH HO OTBS or n-BuLi (1 eq), THF; TBSCl,

OTIPS OTIPS

O O TESCl, O O OH N 2,6-lutidine, OTES N MeO MeO O CH2Cl2, O O Me -78 °C O Me O O TESO TESO N (97%) N OH OH O Me Me O Me Me O OH O OH

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

D. A. Evans, D. M. Fitch, Angew. Chem. Int. Ed. 2000, 39, 2536. Hydroxyl Protecting Groups: Silyl Ethers

Selective Deprotection of Silyl Ethers is Also Possible:

TESO OBOM Me Me HO OBOM Me Me Me HF•pyr, CH3CN, TBSO 0 °C, 11 h Me Me TBSO (100%) Me H O O H O O OAc O O OAc O O

O AcO OH O Ph O Me Me Me Ph N O H Me OH H O HO BzO OAc Taxol

R. A. Holton and co-workers, J. Am. Chem. Soc. 1994, 116, 1599. Hydroxyl Protecting Groups: Silyl Ethers

Selective Deprotection of Silyl Ethers is Also Possible:

AcO OAc AcO OAc OAc OAc TBSO Cl2CHCO2H TBSO O O O O Me Me OH OH OTBS OH

O O OH OAc Me HO2C O HO2C O CO H Me OH 2 zaragozic acid

E. M. Carreira, J. DuBois, J. Am. Chem. Soc. 1995, 117, 8106. Hydroxyl Protecting Groups: Esters and Carbonates

O O O O Cl Cl Cl RO Me RO RO RO Cl Cl Cl acetate (Ac) chloroacetate dichloroacetate trichloroacetate

O O O O RO F Me RO RO RO F Me F Me OMe trifluoroacetate pivaloate (Pv) benzoate (Bz) p-methoxybenzoate Hydroxyl Protecting Groups: Esters and Carbonates

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

O O O O Me RO < RO RO < < Me RO Me Me OMe pivaloate (Pv) p-methoxybenzoate benzoate (Bz) acetate (Ac) [most stable] <

O O O O

< < F Cl < Cl Cl RO RO RO RO F Cl F Cl Cl trifluoroacetate trichloroacetate dichloroacetate chloroacetate [least stable]

All can hydrolyze under acidic conditions, but typically only when water is present. Hydroxyl Protecting Groups: Esters and Carbonates

O O Me O Me RO OMe RO O Me RO O methyl carbonate t-butylcarbonate (Boc) allyl carbonate (Alloc) [resistant to [cleaved with Pd/Nu] nucleophilic attack]

O O RO O O O Cl RO O RO O SiMe3 Cl RO O Cl

9-(fluorenylmethyl) 2,2,2-trichloroacetyl 2-(trimethylsilyl) benzyl carbonate (Cbz) carbonate (Fmoc) carbonate (Troc) ethyl carbonate (Teoc) [cleaved by [cleaved by mild base] [cleaved with Zn/HOAc] [cleaved with fluoride] hydrogenolysis] Hydroxyl Protecting Groups: Esters and Carbonates

General methods for the formation of esters and carbonates:

pyridine, O 4-DMAP O ROH + Cl R' RO R'

O O pyridine, O 4-DMAP ROH + R' O R' RO R'

O pyridine O ROH + Cl OR' RO OR'

B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522. Hydroxyl Protecting Groups: Esters and Carbonates

General methods for the formation of esters and carbonates:

N pyridine, O 4-DMAP O ROH + Cl R' N RO R' Me Me 4-DMAP

O O pyridine, O 4-DMAP ROH + R' O R' RO R' R O

N X O pyridine O ROH + Cl OR' RO OR' N Me Me Proposed acyl transfer reagent

B. Neises, W. Steglich, Angew. Chem. Int. Ed. Engl. 1978, 17, 522. Hydroxyl Protecting Groups: Esters and Carbonates

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

AcCl, Bu2SnO OBn HO OBn O CH2Cl2 AcO OBn toluene, Sn O OH Bu 0 °C OH 110 °C Bu

For a review, see: S. Hanessian, S. David, Tetrahedron, 1985, 41, 643. Hydroxyl Protecting Groups: Esters and Carbonates

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

AcCl, Bu2SnO OBn HO OBn O CH2Cl2 AcO OBn toluene, Sn O OH Bu 0 °C OH 110 °C Bu

Bu2SnO, toluene, Δ; Me O BnBr, n-Bu4NI, Me O 25→110 °C HO HO OH OBn

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.

For a review, see: S. Hanessian, S. David, Tetrahedron, 1985, 41, 643. Hydroxyl Protecting Groups: Esters and Carbonates

Examples of selective deprotection: Me Me Me O Me O O O O OMe OMe Cl n-PrNH2 O O O OH (83%) Me O Me O

OH O OH O OH OH

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

Examples of selective deprotection: Me Me Me O Me O O O O OMe OMe Cl n-PrNH2 O O O OH (83%) Me O Me O

OH O OH O OH OH

OAc OH O acetyl- cholinesterase PCC (94%) (99% e.e.) OAc OAc OAc

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

RO O Cl SiMe3 RO OMe RO O RO O Cl Cl methoxymethyl benzyloxymethyl 2,2,2-trichloroethoxy 2-(trimethylsilyl) ether (MOM) ether (BOM) methyl ether ethoxymethyl ether (SEM) [cleaved with [cleaved by [cleaved with Zn] [cleaved with fluoride] strong acid] hydrogenation]

RO O RO SMe OMe RO O methylthiomethyl p-methoxybenzyl tetrahydropyranyl ether (MTM) ether (PMBM) ether (THP) [cleaved with DDQ] [cleaved with mild acid] [cleaved with HgCl2 or AgNO3] Hydroxyl Protecting Groups: Acetals

Formation of acetals:

i-Pr2NEt or NaH, solvent + ROH R'OCH2X RO OR'

PPTS or p-TsOH ROH + RO O O

PPTS = pyridinium p-toluenesulfonate

P. A. Grieco and co-workers, J. Org. Chem. 1977, 42, 3772. Hydroxyl Protecting Groups: Ethers

RO RO RO RO

OMe allyl ether trityl ether benzyl ether (Bn) p-methoxybenzyl [cleaved with [cleaved by [cleaved by hydrogenation] ether (PMB) Pd/Nu] strong acid] [cleaved with DDQ]

Me Me O O O O R R R R dimethyl acetonide benzylidene acetal [cleaved with acid] [cleaved by hydrogenation] Hydroxyl Protecting Groups: Ethers

Formation of ethers

NaH, solvent ROH + R'X ROR'

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

Me Me O MeO OMe OMe OH OH H O O or or + Me Me Me Me Me R R R R

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

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

O Me Me Me OH OH Me Me Me O OH O O HO + O HO p-TsOH Me (A:B = 5:1) Me Me 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. Hydroxyl Protecting Groups: Ethers

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

The case of a 1,2,3-polyol Me Me Me Me OH Me O acetone O Me H + HO O HO acid O H OH OH 1:5 Me Kinetic product Thermodynamic 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.

W. R. Roush, J. W. Coe, J. Org. Chem. 1989, 54, 915. Hydroxyl Protecting Groups: Ethers

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

The case of a 1,2,3-polyol Me Me Me Me OH Me O acetone O Me H + HO O HO acid O H OH OH 1:5 Me Kinetic product Thermodynamic product

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

O OMe O O

methyl ether t-butyl ether benzyl ether allyl ether [cleaved with TMSI, [cleaved with BBr3, or 9-Br-9-BBN] neat TFA]

O O

OSiR3 O R O OR O OR silyl ethers phenyl esters phenyl carbonates acetals

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)! Phenol Protecting Groups: Methyl Ethers OPiv OPiv O OMs O OMs

HO HO Cl Cl O O H H O N AlBr3, O N N NHTfa EtSH, 0 °C N NHTfa H H O HN O HN O O

MeHN OMe MeHN OH OMe OH

MeO HO

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 OPiv OPiv O OMs O OMs

HO HO Cl Cl O O H H O N AlBr3, O N N NHTfa EtSH, 0 °C N NHTfa H H O HN O HN O O

MeHN OMe MeHN OH OMe OH

MeO HO

Me H Me CO Me H MeO O HN 2 CO H O 1 year of hard work HO O HN 2 O OMe X OMe H H MeO O MeO HO O HO 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

MeO OMe O O O O R R' R R' R R' 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 O O O O O O O = > = > R > >> R' R R R' > R' Carbonyl Protecting Groups

Rates of formation:

Me Me > HO > HO OH HO OH OH

Rates of cleavage:

O O R R > R R O O

Me O Me O R Me R O R > >> R R O R O O

krel 50,000 5,000 1

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

O Me O OH Me O HO p-TsOH O (95%) O Carbonyl Protecting Groups

O Me O OH Me O HO p-TsOH O (95%) O

Me Me Me OH HO O + O O acid O O

fumaric acid (pKa = 3.03) 100 0 phthalic acid (pKa = 2.89) 70 30 oxalic acid (pKa = 1.23) 80 20 p-TsOH (pKa < 1.0) 0 100 Carbonyl Protecting Groups

MeS SMe NC OR S S S S R R' R R' R R' R R' dimethyl thioacetal 1,3-dithiane 1,2-dithiolane cyanohydrin [deprotected with Hg, NBS, IBX] Carbonyl Protecting Groups

MeS SMe NC OR S S S S R R' R R' R R' R R' dimethyl thioacetal 1,3-dithiane 1,2-dithiolane cyanohydrin [deprotected with Hg, NBS, IBX]

Special uses for these protecting groups:

NC OR base NC OR R'X S S or or or NC OR S S S S R R R R R R' R R'

These groups turn " O " Umpolung = formal reversal of the aldehydes into nucleophiles polarity of a functional group Carboxylic Acid Protecting Groups

O O Me O O Me

R OMe R O Me R O R OSiR3 methyl ester t-butyl ester allyl ester silyl ester [must be TBS, TBDPS, or TIPS if you want to purify by chromatography]

O O OR R O R O OR R' OR OMe benzyl ester p-methoxybenzyl ester ortho ester Amine Protecting Groups

O O Me O O Me R2N O R N O Me R2N OMe 2 R2N O methyl carbamate t-butylcarbamate (Boc) allyl carbamate (Alloc) benzyl carbamate (Cbz) [resistant to [cleaved with Pd] [cleaved by nucleophilic attack] hydrogenolysis]

R2N O O O R N Cl SiMe 2 R2N O 3 Cl R2N O Cl R N 9-(fluorenylmethyl) 2,2,2-trichloroacetyl 2-(trimethylsilyl) 2 carbamate (Fmoc) carbamate (Troc) ethyl carbamate (Teoc) [cleaved by mild base] [cleaved with Zn/HOAc] [cleaved with fluoride] Protecting Groups: Putting it all Together

THPO OTES HO OTMS HO 1. Boc2O, Et3N, 4-DMAP, OH CH2Cl2, 25 °C Me 2. AcOH/H O (19:1), 80 °C Me N 2 N H (62% overall) Boc MeO2C MeO C OTBDPS 2 OTBDPS

p-TsCl, n-Bu SnO, 2 (84%) Et3N, CH2Cl2, 25 °C

HO HO O TsO OH NaHCO3, DMF, 80 °C

Me (83%) Me N N Boc Boc MeO2C MeO C OTBDPS 2 OTBDPS

T. Fukuyama and co-workers, J. Am. Chem. Soc. 2002, 124, 2137. Protective Groups: Sometimes They Really Are Not Needed . . .

OMe OMe 1. Cl O Me Me Cl O Me PMP O Me Me Me Cl Cl HO HO OH O O OTBS Me Me Et N, toluene, Me Me 3 O O 25 °C, 2.5 h; Me Me 4-DMAP, OMe O HO O OMe O TBSO O 80 °C, 15 h O OH O MeO O MeO Me Me 2. HF, MeCN, O HO 0 °C, 105 min Me Me Me (42% overall) HO OH OH OTBS HO O O Me Me Yamaguchi Me Me O Me O PMP macrolactonization Me Me and global deprotection OMe O OH OMe swinholide A

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

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