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Protective G roups in Synthetic O rganic C hem istry
Lecture Notes Key Texts P. J. Kocienski, Protecting G roups (2nd Edition), 1994, G eorg Thiem e Verlag: Stuttgart, p. 260. P. J. Kocienski, Protecting G roups (3rd Edition), 2004, G eorg Thiem e: Stuttgart, p. 679. T. W . G reene, P. G . M . W utz, Protective G roups in O rganic Synthesis (3rd Edition), 1999, John W iley and Sons: N ew York, p. 779.

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

Protective G roups: B ackground and G eneral C onsiderations

"Protection is a principle, not an expedient" B enjam in Disraeli, B ritish Prim e M inister, 1845

"Like death and taxes, protecting groups have becom e a consecrated obstruction w hich w e cannot elude" Peter K ocienski, O rganic C hem ist

R em em ber: Every protecting group adds at least one, if not tw o steps to a synthesis They only detract from the overall efficiency and beauty of a route, but, w ithout them , there are certainly transform ations w hich w e w ould not be able to do at all.

Protective G roups: Tem porary Protection

Li O O O M eO Ph Li N Me M eO Ph N O O O Li Me Li aqueous w ork-up HO O O M eO

THF, -40 ° C

Tem porary protection involves the ideal for protecting groups w hen they are required: the protection step, desired reaction, and deprotection all occur in the sam e pot.

Protective G roups: B ackground and G eneral C onsiderations
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 m any spectroscopic signals that it hides key resonances for the substrate. It should be stable to chrom atography. It should be stable to a w ide range of reaction conditions. It should be rem oved selectively and efficiently under highly specific conditions. The by-products of deprotection shoud be easily separated from the substrate.

Protective G roups: Som ething to be Very Carefully C onsidered
OMe O TBSO H O N NH O M eO 2 C M eO OMe OMe 1. H F?py/py, TH F, 0 ? 25 ° 12 h C, 2. A lBr 3 , EtSH/C H 2 C l 2 (1:1), 25 ° , 4 h C O O O NH O HO 2 C HO OH OH
vancom ycin aglycon

O O O N H

Cl O TBS B oc O N N Me H Me Me

Cl H N

H N H O

O

N HDdm

(62% overall) G lobal deprotections

OH O HO H O N Cl H N

Cl OH O O N H

O

N H

H N H NH 2

H N

Me Me

Me

K. C . N icolaou and co-w orkers, A ngew . C hem . Int. Ed. 1998, 37, 2708.

Protective G roups: O rthogonal Sets of Protecting G roups
O rthogonal Set = a groups of protecting groups w hose rem oval is accom plished in any order w ith reagents and conditions that do not affect protecting groups in any other orthogonal set.

TESO Me O rthogonal Set #1 Me TB SO TB D PSO Me

OBz Me

H PvO

O OAc

O rthogonal Set #2

In practice this concept is incredibly difficult to reduce to practice, but it is a useful fram ew ork and organizing principle to think about protecting group regim es for a com plex m olecule synthesis.

Protective G roups: O rthogonal Sets of Protecting G roups
1. Cleavage by basic solvolysis

O RO Me

O OH ROH RO k rel 1 Me RO

O Cl RO

O Cl Cl RO

O Cl Cl Cl

760

16,000

100,000

Protective G roups: O rthogonal Sets of Protecting G roups
1. Cleavage by basic solvolysis

O RO Me

O OH ROH RO k rel 1 Me RO

O Cl RO

O Cl Cl RO

O Cl Cl Cl

760

16,000

100,000

2. Cleavage by acidic hydrolysis

H O O HO OH

O R

O RO R OMe

O ther groups easily cleaved by acid

Protective G roups: O rthogonal Sets of Protecting G roups
3. Cleavage by heavy m etals

S S

H gC l 2

O

Protective G roups: O rthogonal Sets of Protecting G roups
3. Cleavage by heavy m etals

S S

H gC l 2

O

4. C leavage by fluoride

Me Me Me RO Si Me Me

Me n-Bu 4 N F RO

Me Me Si F -[t-B uM e 2 SiF] Me Me R O n-B u 4 N H 2O ROH

n-B u 4 N Strength of Si-F bond is 810 kJ/m ol w hile Si-O bond is 530 kJ/m ol

Protective G roups: O rthogonal Sets of Protecting G roups
5. R eductive Elim ination Cl O RO O Cl Cl Cl Zn, AcO H RO O Cl O H ZnCl Cl Cl RO H -[C O 2 ]

Troc = trichloroethoxycarbonyl

Protective G roups: O rthogonal Sets of Protecting G roups
5. R eductive Elim ination Cl O RO O Cl Cl Cl Zn, AcO H RO O Cl O H ZnCl Cl Cl RO H -[C O 2 ]

Troc = trichloroethoxycarbonyl

6. ? -elim ination O O M ild base R 2N O -[C O 2 ] R 2N H 2 +

O R 2N

Fm oc = 9-fluorenylm ethyl carbam ate

Protective G roups: O rthogonal Sets of Protecting G roups
7. Hydrogenolysis Ph OR H 2 , Pd/C + ROH R benzyl ether O O R

O ther exam ples of cleavable groups

Protective G roups: O rthogonal Sets of Protecting G roups
7. Hydrogenolysis Ph OR H 2 , Pd/C + ROH R benzyl ether O O R

O ther exam ples of cleavable groups

8. O xidation O Cl + M eO ROH Cl O DDQ CN CN

OR M eO p-m ethoxybenzyl ether

D D Q or C A N, TH F/H 2 O O xidation via Single-electron transfer

O

Protective G roups: O rthogonal Sets of Protecting G roups
9. Dissolving M etal R eduction

OR

Li/N H 3 , t-BuO H + ROH

O OR O nly other protecting group applicable to these conditions

Protective G roups: O rthogonal Sets of Protecting G roups
9. Dissolving M etal R eduction

OR

Li/N H 3 , t-BuO H + ROH

O OR O nly other protecting group applicable to these conditions

10. Transition M etal C atalysis (i.e. Allyl-based protecting groups)

Pd, m orpholine or dim edone RO

RO ROH PdL 2

C an also use (Ph 3 P) 3 R hC l and acid

Protective G roups: O rthogonal Sets of Protecting G roups
11. Light O NO2 h? N RO H + O OR O O alcohol PG OR O O acid PG R NO2

NO2

Protective G roups: O rthogonal Sets of Protecting G roups
11. Light O NO2 h? N RO H + O OR 12. Enzym es O O A cH N papain cysteine buffer O O A cHN A cO A cO OAc OH N H Fm oc HO HO OH A cO AcO O Ac O A cH N O N H Fm oc w heat germ lipase O O N H Fm oc O OMe O OMe O O alcohol PG OR O O acid PG R NO2

NO2

Protective G roups: R elay D eprotection

SO 2 Ph Me Me M eO M eO Me Cl Me 1. N aSPh O O 2. m C PB A M eO M eO Me Me

SO 2 Ph Me N aB H 4 O O Me SO 2 Ph Me Me M eO M eO

SO 2 Ph Me OH OH Me

R elay deprotection: w hen a protecting group that is stable under m ost conditions is transform ed chem ically into a new , and m ore labile, protecting group.

Protective G roups: M utual Protection
"U ne pierre, deux oiseaux" "Zw ei Fleigen m it einer Klappe schlagen" "To kill tw o birds w ith one stone"

Me NC HO TB SO H Me

Me py?H B r 3 pyridine (96% ) NC O TB SO Br H Me

H O CO 2 M e HO HO O O

H O CO 2 M e OH H Me Br Zn, A cO H (96% ) HO O O O

OH H Me

B. M . Trost, M . J. K rische, J. A m . C hem . Soc. 1999, 121, 6131.

Protective G roups: Som etim es N ot-So-Innocent B ystanders

O O O Ts

O Ts

N aC N , D M SO 80 ° C

O O

O Ts

CN NC O O

Protective G roups: Som etim es N ot-So-Innocent B ystanders

O O O Ts

O Ts

N aC N , D M SO 80 ° C

O O

O Ts

CN NC O O

M eO O O

B Br 3

B r3B M eO O

Br Br O Me O Me O O Me

Me

O

H ydroxyl Protecting G roups: Silyl Ethers

Me RO Si M e Me trim ethylsilyl (TM S)

Et R O Si Et Et triethylsilyl (TES)

Me R O Si t-Bu Me t-butyldim ethylsilyl (TB S or TB D M S)

Ph R O Si t-B u Ph t-butyldiphenylsilyl (TBD PS)

i-Pr R O Si i-Pr i-Pr triisopropylsilyl (TIPS)

H ydroxyl Protecting G roups: Silyl Ethers

Me RO Si M e Me trim ethylsilyl (TM S)

Et R O Si Et Et triethylsilyl (TES)

Me R O Si t-Bu Me t-butyldim ethylsilyl (TB S or TB D M S)

Ph R O Si t-B u Ph t-butyldiphenylsilyl (TBD PS)

i-Pr R O Si i-Pr i-Pr triisopropylsilyl (TIPS)

R elative A cid Stability (t 1/2 in 1% HC l/M eO H) 1 (<1 m in) 64 (<1 m in) 20,000 (<1 m in) 5,000,000 (255 m in) 700,000 (55 m in)

R elative B ase Stability (t 1/2 in 5% N aO H /M eO H) 1 (<1 m in) 10 - 100 (1 m in) 20,000 (> 24 h) 20,000 (> 24 h) 100,000 (> 24 h)

H ydroxyl Protecting G roups: Silyl Ethers
Form ation: OH R R R 3 SiCl, im idazole, DM F or R 3 SiO Tf, 2,6-lutidine, C H 2 C l2 R O SiR 3 R

C leavage: Com m on Fluoride Sources HF 3HF?NEt 3 H F?pyr n-B u 4 N F (TB A F)/A cO H H F?pyr/pyr n-B u 4 N F (TB A F)

O SiR 3 R R

Fluoride source R

OH R

Hydroxyl Protecting G roups: Silyl Ethers
Selective M onosilylation of Diols is Possible: N aH (1 eq), THF; TBSCl, HO OH or n-BuLi (1 eq), THF; TB SCl, HO O TBS

O TIPS O OH M eO O TE SO O N Me Me O OH O Me OH O Me Me O N O O O

O TIPS

TESCl, 2,6-lutidine, C H 2 Cl 2 , -78 ° C (97% )

O TES M eO O TESO N O

N

O O

Me OH OH

TESCl/im id and TESO Tf/2,6-lutidine gave bis-silylated product

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

H ydroxyl Protecting G roups: Silyl Ethers
Selective Deprotection of Silyl Ethers is A lso Possible:

TESO Me Me TBSO O O Me

OBOM Me H F?pyr, C H 3 CN, 0 ° , 11 h C H O O OAc (100% ) TB SO

HO Me Me Me O O A cO O Me OH Me

O BO M Me

H O

O O Ac

O Ph N H

Ph

O O

Me

OH HO Taxol

Me H BzO O OAc

R . A . Holton and co-w orkers, J. A m . C hem . Soc. 1994, 116, 1599.

H ydroxyl Protecting G roups: Silyl Ethers
Selective Deprotection of Silyl Ethers is A lso Possible:

AcO TB SO O OH

O Ac

OAc C l 2 C H CO 2 H TB SO

AcO O

O Ac

O Ac

O O TB S

Me

O OH

OH

Me

O O Me H O 2C H O 2C O OH O C O 2H OH OAc

Me

zaragozic acid

E. M . C arreira, J. DuB ois, J. Am . Chem . Soc. 1995, 117, 8106.

H ydroxyl Protecting G roups: Esters and C arbonates

O RO Me RO

O Cl RO

O Cl RO Cl

O Cl Cl Cl

acetate (A c)

chloroacetate

dichloroacetate

trichloroacetate

O RO F F RO

O Me RO Me Me pivaloate (Pv)

O RO

O

F trifluoroacetate

OMe benzoate (Bz) p-m ethoxybenzoate

H ydroxyl Protecting G roups: Esters and C arbonates
In general, the ease w ith w hich esters hydrolyze under basic conditions increases w ith the acidity of the product acid. Sterics also can play a role (i.e. pivaloate group) O RO Me Me Me < RO OMe p-m ethoxybenzoate benzoate (B z) acetate (A c) O < RO O O < RO Me

pivaloate (Pv) [m ost stable]

<

O F F trifluoroacetate [least stable] RO < F RO

O Cl < Cl Cl RO

O < Cl Cl dichloroacetate RO

O Cl

trichloroacetate

chloroacetate

A ll can hydrolyze under acidic conditions, but typically only w hen w ater is present.

H ydroxyl Protecting G roups: Esters and C arbonates

O RO OMe RO

O O

Me Me Me RO

O O

m ethyl carbonate

t-butylcarbonate (B oc) [resistant to nucleophilic attack]

allyl carbonate (A lloc) [cleaved w ith Pd/N u]

O RO O RO O O Cl 9-(fluorenylm ethyl) carbonate (Fm oc) [cleaved by m ild base] Cl Cl RO O O O SiM e 3 RO O

2,2,2-trichloroacetyl carbonate (Troc) [cleaved w ith Zn/H O A c]

2-(trim ethylsilyl) benzyl carbonate (C bz) ethyl carbonate (Teoc) [cleaved by hydrogenolysis] [cleaved w ith fluoride]

Hydroxyl Protecting G roups: Esters and Carbonates
G eneral m ethods for the form ation of esters and carbonates:

O RO H + Cl R'

pyridine, 4-D M AP RO

O R'

O RO H + R' O

O R'

pyridine, 4-D M AP RO

O R'

O RO H + Cl O R'

pyridine RO

O OR'

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

Hydroxyl Protecting G roups: Esters and Carbonates
G eneral m ethods for the form ation of esters and carbonates:

N O RO H + Cl R' pyridine, 4-D M AP RO O R' N Me Me 4-DM AP

O RO H + R' O

O R'

pyridine, 4-D M AP RO

O R' R N O

O RO H + Cl O R'

pyridine RO

O OR'

X N Me Me Proposed acyl transfer reagent

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

H ydroxyl Protecting G roups: Esters and Carbonates
Tricks for selective form ation of an ester from diol starting m aterials:

HO OH

O Bn

Bu 2 SnO toluene, 110 ? C

O Sn O Bu Bu

O Bn

A cC l, C H 2 C l2 0 ?C

A cO OH

OBn

For a review , see: S. H anessian, S. D avid, Tetrahedron, 1985, 41, 643.

H ydroxyl Protecting G roups: Esters and Carbonates
Tricks for selective form ation of an ester from diol starting m aterials:

HO OH

O Bn

Bu 2 SnO toluene, 110 ? C

O Sn O Bu Bu

O Bn

A cC l, C H 2 C l2 0 ?C

A cO OH

OBn

Me HO

O

Bu 2 SnO , toluene, ? ; BnB r, n-B u 4 NI, 25 ? 110 ? C

Me HO

O

OH

O Bn

The sterically least encum bered position is alw ays protected selectively; on sugars, if both positions are secondary and sterics are roughly equal, an equatorial alcohol w ill be protected selectively over an axially disposed alcohol.

For a review , see: S. H anessian, S. D avid, Tetrahedron, 1985, 41, 643.

H ydroxyl Protecting G roups: Esters and Carbonates
Exam ples of selective deprotection: Me Me OMe Cl O Me O OH O OH O O O n-PrN H 2 (83% ) Me O OH O OH Me Me OMe O OH O

O

O

A. G . M yers and co-w orkers, J. A m . C hem . Soc. 1998, 120, 5319. D . R . D eardorff and co-w orkers, Tetrahedron Lett. 1986, 27, 1255.

H ydroxyl Protecting G roups: Esters and Carbonates
Exam ples of selective deprotection: Me Me OMe Cl O Me O OH O OH O O O n-PrN H 2 (83% ) Me O OH O OH Me Me OMe O OH O

O

O

OAc acetylcholinesterase (94% ) (99% e.e.)

OH PC C

O

OAc

O Ac

OAc

A. G . M yers and co-w orkers, J. A m . C hem . Soc. 1998, 120, 5319. D . R . D eardorff and co-w orkers, Tetrahedron Lett. 1986, 27, 1255.

H ydroxyl Protecting G roups: A cetals

RO

OMe

RO

O

RO

O Cl

Cl Cl RO O

SiM e 3

m ethoxym ethyl ether (M O M ) [cleaved w ith strong acid]

benzyloxym ethyl ether (B O M ) [cleaved by hydrogenation]

2,2,2-trichloroethoxy m ethyl ether [cleaved w ith Zn]

2-(trim ethylsilyl) ethoxym ethyl ether (SEM ) [cleaved w ith fluoride]

RO RO SM e

O OMe RO O

m ethylthiom ethyl ether (M TM ) [cleaved w ith H gC l 2 or A gN O 3 ]

p-m ethoxybenzyl ether (PM B M ) [cleaved w ith DD Q ]

tetrahydropyranyl ether (TH P) [cleaved w ith m ild acid]

Hydroxyl Protecting G roups: Acetals
Form ation of acetals:

RO H

+

i-Pr 2 NEt or NaH, solvent R'O CH 2 X RO OR'

R OH

+ O

PPTS or p-TsO H RO O

PPTS = pyridinium p-toluenesulfonate

P. A. G rieco and co-w orkers, J. O rg. C hem . 1977, 42, 3772.

H ydroxyl Protecting G roups: Ethers

RO

RO

RO

RO OMe p-m ethoxybenzyl ether (PM B) [cleaved w ith D D Q ]

allyl ether [cleaved w ith Pd/N u]

trityl ether [cleaved by strong acid]

benzyl ether (Bn) [cleaved by hydrogenation]

Me Me O R O R O O

dim ethyl acetonide [cleaved w ith acid]

R R benzylidene acetal [cleaved by hydrogenation]

H ydroxyl Protecting G roups: Ethers
Form ation of ethers NaH, solvent

ROH

+

R 'X

ROR'

Exception is trityl groups; they require Ph 3 CC l and 4-D M AP at elevated tem peratures.

Me Me O or Me Me Me Me M eO O M e or Me OMe + R OH OH R H R O O R

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

H ydroxyl Protecting G roups: Ethers
W hat about polyols? W hich cyclic ether w ill be form ed selectively?

O OH HO Me OH Me Me p-TsO H (A :B = 5:1) Me

Me O OH + Me A HO

Me Me O O

O

Me B

In general, sim ple acetonide form ation w ith 1,2-diols occurs in preference to 1,3-diols. N ote, though, that benzylidene acetals display reverse selectivity!

D. R . W illiam s, S.-Y. Sit, J. A m . C hem . Soc. 1984, 106, 2949.

H ydroxyl Protecting G roups: Ethers
W hat about polyols? W hich cyclic ether w ill be form ed selectively? The case of a 1,2,3-polyol Me Me O O OH K inetic product Me + 1:5 HO H O O H OH Me Therm odynam ic product Me Me

OH HO

Me

acetone acid

In general, the m ore substituted acetonide is favored, especially w hen the substituents on the 5-m em bered ring are in a trans orientation; in a cis case, the less substituted acetonide m ight be favored.

W . R. R oush, J. W . C oe, J. O rg. Chem . 1989, 54, 915.

H ydroxyl Protecting G roups: Ethers
W hat about polyols? W hich cyclic ether w ill be form ed selectively? The case of a 1,2,3-polyol Me Me O O OH K inetic product Me + 1:5 HO H O O H OH Me Therm odynam ic product Me Me

OH HO

Me

acetone acid

In general, the m ore substituted acetonide is favored, especially w hen the substituents on the 5-m em bered ring are in a trans orientation; in a cis case, the less substituted acetonide m ight be favored. Me OH OH O TB S OH acetone acid HO 0% W . R. R oush, J. W . C oe, J. O rg. Chem . 1989, 54, 915. H O O H O TB S + H O Me Me 100% O TB S Me OH H O

Phenol Protecting G roups

OMe m ethyl ether [cleaved w ith TM SI, B Br 3 , or 9-B r-9-B BN ]

O t-butyl ether [cleaved w ith neat TFA]

O benzyl ether

O allyl ether

O O SiR 3 silyl ethers O R O

O OR O acetals OR

phenyl esters

phenyl carbonates

Protecting groups cleaved by base or acid are typically far m ore labile on phenols than a standard aliphatic alcohol. This property has im portant im plications, as it explains w hy phenolic m ethyl ethers can be cleaved, w hereas standard m ethyl ethers are effectively the R ock of G ibralter w hen it com es to deprotection (i.e., it ain't com ing off)!

Phenol Protecting G roups: M ethyl Ethers
O Piv O HO O HN O M eH N OMe OMe M eO N H O Cl H N O O M eH N OH OH HO OMs HO A lB r 3 , EtSH, 0 ° C O HN N H O O Cl H N O O Piv OMs

NHTfa

NHTfa

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

Phenol Protecting G roups: M ethyl Ethers
O Piv O HO O HN O M eH N OMe OMe M eO Me CO 2 M e O OMe H M eO O M eO HO O HO 1 year of hard w ork HO O H HN N H O Cl H N O O M eH N OH OH HO OMs HO A lB r 3 , EtSH, 0 ° C O HN N H O O Cl H N O O Piv OMs

NHTfa

NHTfa

H M eO O HN

Me CO 2 H O OMe H

X

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

C arbonyl Protecting G roups

M eO O M e O R R' R dim ethyl acetal O R'

O R

O R'

1,3-dioxane

1,2-dioxolane

A ll are form ed by the action of an acid w ith the appropriate alcohol

R eactivity order tow ards form ing these protecting groups:

O O = R > R O R' =

O >

O > R

O > R'

O >>

O R'

Carbonyl Protecting G roups
Rates of form ation:

Me Me HO OH

>

HO

OH

>

HO

OH

R ates of cleavage: O > O R R O O

R R

R R k rel

O O

Me Me >

R R

O O 5,000

Me >>

R R

O O 1

50,000

M . O hno and co-w orkers, Tetrahedron Lett. 1982, 23, 1087.

Carbonyl Protecting G roups
O HO O p-TsO H (95% ) OH

Me

O Me

O

O

Carbonyl Protecting G roups
O HO O p-TsO H (95% ) OH

Me

O Me

O

O

Me HO O acid O fum aric acid (pK a = 3.03) phthalic acid (pK a = 2.89) oxalic acid (pK a = 1.23) p-TsO H (pK a < 1.0) OH O

Me + O O 100 70 80 0

Me

0 30 20 100

Carbonyl Protecting G roups

M eS SM e R R'

S R

S R'

S R

S R'

NC O R R R'

dim ethyl thioacetal

1,3-dithiane

1,2-dithiolane

cyanohydrin

[deprotected w ith H g, NBS, IBX]

Carbonyl Protecting G roups

M eS SM e R R'

S R

S R'

S R

S R'

NC O R R R'

dim ethyl thioacetal

1,3-dithiane

1,2-dithiolane

cyanohydrin

[deprotected w ith H g, NBS, IBX]

Special uses for these protecting groups:

NC O R S R S or R

base S R S or

NC O R R'X R S R S R'

or

NC O R R R'

These groups turn aldehydes into nucleophiles

"

O

"

Um polung = form al reversal of the polarity of a functional group

Carboxylic Acid Protecting G roups

O R OMe R

O O

Me Me Me R

O O allyl ester R

O O SiR 3

m ethyl ester

t-butyl ester

silyl ester [m ust be TBS, TBD PS, or TIPS if you w ant to purify by chrom atography]

O R O R

O O OMe R' OR OR OR

benzyl ester

p-m ethoxybenzyl ester

ortho ester

A m ine Protecting G roups

O O R 2N OMe R 2N O O Me Me Me R 2N O R 2N O benzyl carbam ate (Cbz) [cleaved by hydrogenolysis] allyl carbam ate (Alloc) [cleaved w ith Pd] O

m ethyl carbam ate

t-butylcarbam ate (Boc) [resistant to nucleophilic attack]

O R 2N O R 2N 9-(fluorenylm ethyl) carbam ate (Fm oc) [cleaved by m ild base] O O Cl Cl Cl R 2N O O SiM e 3

R 2N

2,2,2-trichloroacetyl carbam ate (Troc) [cleaved w ith Zn/HO Ac]

2-(trim ethylsilyl) ethyl carbam ate (Teoc) [cleaved w ith fluoride]

R 2N

Protecting G roups: Putting it all Together

THPO

O TES O TM S Me

HO 1. B oc 2 O , Et 3 N , 4-D M A P, C H 2 C l 2 , 25 ° C 2. A cO H /H 2 O (19:1), 80 ° C (62% overall) N B oc M eO 2 C

HO OH Me

N H M eO 2 C

O TBD PS

O TB DPS

p-TsC l, n-Bu 2 SnO , (84% ) Et 3 N , C H 2 C l 2 , 25 ° C

HO O N aH CO 3 , D M F, 80 ° C N B oc M eO 2 C Me (83% )

HO

TsO OH Me

O TBD PS

N B oc M eO 2 C

O TBD PS

T. Fukuyam a and co-w orkers, J. A m . C hem . Soc. 2002, 124, 2137.

Protective G roups: Som etim es They R eally A re Not Needed . . .
OMe OMe

1.
PM P Me O O Me OM e O HO O TBS Me Me O HO O Me Me O PM P Me Me O TBS O O TBSO Me M eO O O Me Me Cl

Cl

O Cl Cl Me OMe O OH Me Me Me HO HO O O O O Me Me O HO OH OH Me Me Me HO M eO Me O OH O Me Me

Et 3 N , toluene, 25 ° , 2.5 h; C 4-D M A P, 80 ° , 15 h C 2. H F, M eC N , 0 ° 105 m in C, Me (42% overall) Yam aguchi m acrolactonization and global deprotection

O

OH

OM e

OMe

sw inholide A W ith protecting group present on the other alcohol, dram atically low er yields observed

I. Paterson and co-w orkers, J. A m . C hem . Soc. 1994, 116, 9391.

Retrosynthetic A nalysis: G eneral Principles and B ackground

Me

Me

Retrosynthetic A nalysis: G eneral Principles and B ackground

Me H ydrogenation

Me

Me

Me

Retrosynthetic A nalysis: G eneral Principles and B ackground

Me H ydrogenation

Me

D iels-A lder reaction

Me
+

Me

Me

Me

Retrosynthetic A nalysis: G eneral Principles and B ackground

Me H ydrogenation

Me

D iels-A lder reaction

Me
+

Me

Me

Me

O lefin m etathesis

M cM urry C oupling

HWE olefination EtO O EtO P

M e Tandem W ittig reaction Me

O O Me O

Me

Me

Me

R etrosynthetic A nalysis: C ase Study #1: Epothilone A

O S HO O O OH O N

epothilone A

R etrosynthetic A nalysis: C ase Study #1: Epothilone A
Epoxidation O S HO O O OH O O OH O N HO O S N

epothilone A

epothilone C

R etrosynthetic A nalysis: C ase Study #1: Epothilone A
Epoxidation O S HO O O OH O O OH O N HO O S N O lefin m etathesis

epothilone A

epothilone C

S HO O O O TBSO N

R etrosynthetic A nalysis: C ase Study #1: Epothilone A
Epoxidation O S HO O O OH O O OH O N HO O S N O lefin m etathesis

epothilone A S N OH HO C O 2H O O TB S O HO

epothilone C

S N O O TBSO Esterification

R etrosynthetic A nalysis: C ase Study #1: Epothilone A

HO CO 2 H Aldol reaction C O 2H O O TB S S N OH O O TB S + H O

R1 O

O

R

2

CO 2 H OH

R3

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A

Me H

O OH

H Me H
12

Me O

Me

Me

elisabethin A

Me

O OH

H Me H O

Me Me

colom biasin A

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
B ase
Me H O OH Me H O OH

H Me H
12

Me O

C-12 O xidation
H Me

2

Me O H HO

Me

Me

12

Me

elisabethin A

Me

O OH

H Me H O

Me Me

C2-C12 Alkylation

colom biasin A

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
B ase
Me O OH Me H O OH Me H O OH

C 1-C 9 Cyclization
H Me H
12

1

Me O
12

Me O

C-12 O xidation
H Me

2

Me O H HO

H Me
9

Me Me

HO

Me

Me

12

Me

elisabethin A

Me

O OH

Me

O OH

D ielsAlder reaction
H Me O H

Dehydration

H Me

Me O Me

Me Me

C2-C12 Alkylation

colom biasin A

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Diels-A lder reaction
Me O OH Me O
16

OM e

Dem ethylation
H Me H O Me Me

5

Deoxygenation

HO

H

Me O Me

Me

colom biasin A

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Diels-A lder reaction
Me O OH Me O
16

OM e

Dem ethylation
H Me H O Me Me

5

Deoxygenation

HO

H

Me O Me

Me

colom biasin A

W ittig olefination
Me PP h 3 Br

Q uinone form ation

Me

OMe OMe

Me

OM e OM e

Hydroboration O xidation
TBSO
6

5

TBSO

6

H Me

Me OMe

H Me

Me
7

OMe

O

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Me OM e OM e
5 6

TBSO

H Me

Me OMe

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Me OM e OM e
5 6

Me

OMe OMe

TBSO

H Me

Me OMe O

O OMe O Me

Me

Pd-Catalyzed allylic alkylation

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Me OM e OM e
5 6

Me

OMe OMe

O -A cylation

TBSO

H Me

Me OMe O

O OMe O Me

Me

Pd-Catalyzed allylic alkylation
O Cl O

Me

Me

OMe OM e

O OM e

Me

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Me OM e OM e
5 6

Me

OMe OMe

O -A cylation

TBSO

H Me

Me OMe O

O OMe O Me

Me

Pd-Catalyzed allylic alkylation
O Cl O

Me

Me

H

O

A rom atization and OMe m ethylation
Me O

Me

OMe OM e

O

Me OM e

H

O

R etrosynthetic A nalysis: C ase Study #2: C olom biasin A
Me OM e OM e
5 6

Me

OMe OMe

O -A cylation

TBSO

H Me

Me OMe O

O OMe O Me

Me

Pd-Catalyzed allylic alkylation
O Cl O

Me

Me

O OMe

Me

H

O

A rom atization and OMe m ethylation
Me O

Me

OMe OM e

+
TBSO O Me O Me OM e H O

Asym m etric D iels-Alder reaction

Retrosynthetic A nalysis: G eneral Principles and B ackground

N O M eO N M eO Me H

O xidative lactonization
O

O N H O i-Pr

M eO N M eO Me H

aspidophytine O ne-pot cascade
O O H O O i-P r TM S NH2

N ever be afraid to add groups to your m olecule; often, the m ost im pressive synthetic schem es seek to do the non-obvious.

H

+

M eO N M eO Me

R etrosynthetic A nalysis: G eneral Principles and B ackground

OMe
8

N OH

Hoffm annLaR oche oxygenation

OMe N

OMe
8

NH OR

Alkylation
N

N

H

"Rabe" disconnection

N

( ? )-quinine

deoxyquinine

G . Stork and co-w orkers, J. A m . C hem . Soc. 2001, 123, 3239.

R etrosynthetic A nalysis: G eneral Principles and B ackground

OMe
8

N OH

Hoffm annLaR oche oxygenation

OMe N

OMe
8

NH OR

Alkylation
N

N

H

"Rabe" disconnection

N

( ? )-quinine

deoxyquinine

W ords of w isdom from R obert Ireland: A ll too often the m ost convenient w ay to a m olecule on paper belies the m ost efficient synthetic approach G . Stork and co-w orkers, J. A m . C hem . Soc. 2001, 123, 3239.

R etrosynthetic A nalysis: G eneral Principles and B ackground

OMe
8

N OH

Hoffm annLaR oche oxygenation

OMe N

OMe
8

NH OR

Alkylation
N

N

H

"Rabe" disconnection

N

( ? )-quinine

deoxyquinine

OMe OMe N OR N N N OR N

O M e Selective

hydride delivery
H
8

OR

N H

W ords of w isdom from R obert Ireland: A ll too often the m ost convenient w ay to a m olecule on paper belies the m ost efficient synthetic approach G . Stork and co-w orkers, J. A m . C hem . Soc. 2001, 123, 3239.


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