DI- -BUTYLSILYL BIS(TRIFLUOROMETHANESULFONATE) Di-t ... · trinems from commercially available 4-acetoxy-3-[(R)-l-tert-butyldimethylsilyloxyethyl]-2-azetidinone.17 Epoxide 20 was

DI-t-BUTYLSILYL BIS(TRIFLUOROMETHANESULFONATE) 1

Di-t-butylsilyl Bis(trifluoromethane-sulfonate)

t-Bu2Si(OSO2CF3)2

[85272-31-7] C10H18F6O6S2Si (MW 440.44)InChI = 1S/C10H18F6O6S2Si/c1-7(2,3)25(8(4,5)6,21-23

(17,18)9(11,12)13)22-24(19,20)10(14,15)16/h1-6H3InChIKey = HUHKPYLEVGCJTG-UHFFFAOYSA-N

(reagent for the protection of diols)

Physical Data: bp 73–75 ◦C/0.35 mmHg; d 1.208 g cm−3.Solubility: sol most common organic solvents.Form Supplied in: liquid.Preparative Method: by the treatment of di-t-butylchlorosilane

with Trifluoromethanesulfonic Acid, followed by distillation(71% yield).1

Purification: distillation.Handling, Storage, and Precautions: moisture sensitive; reacts

with hydroxylic solvents; corrosive.

Original Commentary

Snorri T. Sigurdsson & Paul B. HopkinsUniversity of Washington, Seattle, WA, USA

Protection of Alcohols. Di-t-butylsilyl bis(trifluoromethane-sulfonate) is a reagent for the selective protection of polyhydroxycompounds. This reagent reacts with 1,2-, 1,3-, and 1,4-diols undermild conditions to give the corresponding dialkylsilylene deriva-tives in high yield (0–50 ◦C, 79–96%). Deprotection is conve-niently achieved by using aqueous Hydrofluoric Acid in acetoni-trile (eq 1).

HF (aq), MeCN, 25 °C

+

OH OH t-Bu

Si(OTf)2

t-Bu

O OSi

t-But-Bu

(1)

2,6-lutidine

CDCl3, 25 °C

88%

96%

Unlike Di-t-butyldichlorosilane, this reagent reacts with hin-dered alcohols. Even pinacol reacts to give the silylene derivative(100 ◦C, 24 h, 70%). Di-t-butylsilylene derivatives of 1,2-diols aremore reactive than those of 1,3- and 1,4-diols and undergo rapidhydrolysis (5 min) in THF/H2O at pH 10, while the 1,3- and 1,4-derivatives are unaffected at pH 4–10 (22 ◦C) for several hours.This protecting group is stable under the conditions of PDC oxida-tion of alcohols (CH2Cl2, 25 ◦C, 27 h) and tosylation of alcohols(pyridine, 25 ◦C, 27 h).

The reagent has seen limited use for the protection of alcoholsbut has been used to protect nucleosides (eq 2).2–5 The procedureconsists of sequential addition of the ditriflate and Triethylamineto the nucleoside in DMF. The choice of solvent is critical.

t-BuSi(OTf)2

t-Bu

(2)

+OHO

HO

B

X

OO

O

B

XSit-Bu

t-Bu

X = OH, H

1. DMF, rt

2. NEt3

The ribonucleosides of uracil, adenine, and guanine give theprotected derivative in 94–95% yield.2 Cytidine gives a low yieldof the desired product under these conditions. Subsequent stud-ies suggested that O2 of cytosine participates in the reaction.Addition of Trifluoromethanesulfonic Acid or Silver(I) Triflu-oromethanesulfonate at 0 ◦C prior to addition of the silylatingagent results in a 99% yield of the desired derivative.3 The deriva-tives are acid sensitive, presumably due to the proximity of the2′-hydroxy group. Acetylation, tetrahydropyranylation, meth-oxytetrahydropyranylation, and silylation of the 2′-hydroxy groupare accomplished without affecting the dialkylsilylene protectinggroup. The 2′-deoxyribonucleosides, including 2′-deoxycytidine,can also be prepared by the aforementioned procedure (yields90–99%). These cyclic silylene derivatives of nucleosides canbe deprotected conveniently using tributylamine hydrofluoride inTHF (5 min, 1 M, rt, 20 equiv).4 A one-pot procedure has been re-ported for simultaneously protecting the 2′-, 3′-, and 5′-hydroxysof a ribonucleoside, which utilizes the acid generated upon sily-lating the 3′- and 5′-hydroxys for catalyzing the formation of aTHP acetal at the 2′-position (eq 3).5

OHO

HO

A t-BuSi(OTf)2

t-BuOH

OO

O

A

OTHPSi

+

1. DMF, rt2. DHP3. NEt3

t-Bu

t-Bu

(3)

91%

Derivatization of Alcohols. Di-t-butylsilyl bis(trifluoro-methanesulfonate) has been used to derivatize hindered diols, togive derivatives such as (1), for analysis by gas chromatography–electron impact mass spectrometry.6 The major fragmentation isthat of the Si–C bonds.

(1)

OSi

O

t-But-Bu

m/z 366 (M+), 309 (M+ – Bu), 191 (B)

Reagent in Enantioselective Additions. In a study of enan-tioselective conjugate addition to cyclohexanone it was found thatthe presence of HMPA and various silyl reagents markedly in-creases the enantioselectivity (eq 4).7 Di-t-butylsilyl bis(trifluoro-methanesulfonate) gives a 67% yield and 40% ee but t-Butyldi-phenylchlorosilane gives a 97% yield and 78% ee.

2 DI-t-BUTYLSILYL BIS(TRIFLUOROMETHANESULFONATE)

t-BuSi(OTf)2

t-Bu(4)+ BuMgBr +

HMPA, THF–78 °C

O O

Buchiral catalyst

Other Substitution Reactions. An extremely hindered silylreagent, tri-t-butylsilyl trifluoromethanesulfonate, was preparedfrom di-t-butylsilyl bis(trifluoromethanesulfonate) and t-Butyl-lithium (eq 5).8 This reagent might find use in the protection ofalcohols.

t-Bu

Si(OTf)2

t-Bu(5)

t-BuSi

t-Bu

OTft-Bu

t-BuLi

–10 °C

pentane

In conjunction with the study of alkyl-substituted silyltriflates, (2) and (3) have been prepared from the correspondingalkynyllithium reagents and di-t-butylsilyl bis(trifluoro-methanesulfonate).9

Sit-Bu Pht-Bu

TfO

(2)

Si SiOTf

t-But-Bu

t-Bu

TfOt-Bu

(3)

The preparation of other derivatives of di-t-butylsilyl bis(tri-fluoromethanesulfonate) using germanium.10 and phosphorus11

nucleophiles has been reported and provides bifunctional silanessuch as (4) and (5).

t-BuSi

t-Bu

GePh3

OTf

(4)

X = –C CPh, –SiPh3, –N(TMS)2, –PHPh, –O-i-Pr, –SPh

t-BuSi

t-Bu

PPh2

X

(5)

A compound closely related to di-t-butylsilyl bis(trifluoro-methanesulfonate) is di-t-butylchlorosilyl trifluoromethane-sulfonate, which has been used to tether two structurally dif-ferent alcohol derivatives in order to effect an intramolecularDiels–Alder reaction (eq 6).12

O

SiO

H

H

CO2Et

O

SiO

H

H

CO2Et

t-But-Bu

t-But-Bu

OSi

O

t-Bu

t-Bu

CO2Et

(6)

>99:<1

160–190 °Cxylene

+

>90%

First Update

Jitendra BelaniInfinity Pharmaceuticals, Cambridge, MA, USA

In the past 10 years, there has been a dramatic increase in useof di-tert-butylsilyl bis(trifluoromethanesulfonate) as a protect-ing group for diols to provide the required orthogonality or toimpart selectivity in various reactions both in synthesis of naturalproducts and in carbohydrate and oligonucleotide syntheses.

Applications in Total Synthesis of Natural Products andDevelopment of New Methods. Paterson et al. strategically useddi-tert-butylsilyl bis(trifluoromethanesulfonate) to avoid differen-tial protection of C21 and C23 hydroxyl groups in their efforts tosynthesize the C19–C32 fragment of swinholide A (eq 7).13a Theelaboration of the fragment to the natural product was reported inthe subsequent communications13b–d and the authors were ableto remove the silylene protecting group using HF·pyridine. Theauthors have also reported similar application of di-tert-butylsilylbis(trifluoromethanesulfonate) to protect 1,3-diols in total synthe-sis of concanamycin A.14

O

OMe

OBn

OH OH

2123

O

OMe

OBn

O OSi

t-Bu t-Bu

t-Bu2Si(OTf)2, 2,6-lutidine

CH2Cl2, 20 °C, 16 h

86%

swinholide A

(7)

212332

19

(6)

(7)

The first total synthesis of concanamycin F by Toshima et al.also utilized di-tert-butylsilyl bis(trifluoromethanesulfonate) forprotection of 1,3-diols.15 The key aldol reaction between 11 and12 was best achieved using PhBCl2 and i-Pr2NEt in CH2Cl2 at−78 ◦C to provide the desired aldol 13 as the sole isomer in 84%yield. The selective deprotection of di-tert-butylsilylene was thenachieved using HF·pyridine, which resulted in concomitant for-mation of the hemiacetal 15. Removal of the diethylisopropylsilylgroup using TBAF provided concanamycin F (eq 8).


H3CCH3

OHOH

CH3

OAc

H3CCH3

OOOAcSi

t-Bu t-But-Bu2Si(OTf)2

2,6-lutidine

DMF, 0 °C, 2 h

84%

1. NaOMe, MeOH, rt

4 h, 91%

2. Dess–Martin periodinane

Py, CH2Cl2, rt, 2.5 h, 93%

H3CCH3

OO

CH3

OSi

t-Bu t-Bu(8) (9)

(10)

ODEIPS

O

CH3

DEIPSO

CH3 OCH3

OCH3

CH3

H3C

CH3

CHOH3C

CH3

OO

CH3

OSi

t-Bu t-Bu

+

PhBCl2, i-Pr2NEt, CH2Cl2 –78 °C, 1.5 h, 84%

HF–Py, THF, 0 °C

15 min, 94%

ODEIPS

ODEIPSO

CH3 OCH3

OCH3

CH3

H3C

CH3

H3C

OH

H3CCH3

OO

CH3

OSi

t-Bu t-Bu

CH3

OHOH

CH3

O

ODEIPS

O

CH3

DEIPSO

CH3 OCH3

OCH3

CH3

H3C

CH3

H3C O

ODEIPS

O

CH3

DEIPSO

CH3 OCH3

OCH3

CH3

H3C

CH3

H3C

OH

CH3

OH

CH3

CH3

OH

O

OH

O

CH3

HO

CH3 OCH3

OCH3

CH3

H3C

CH3

H3C

OH

OH

CH3

CH3

OH

TBAF, THF, rt, 2.5 h, 59%

DEIPS = SiEt2i-Pr

(16), concanamycin F

(11)

(12)

(13)

(14)

(15)

(8)

CH3

CH3


In another report, Panek and Jain used chiral allylsilane method-ology for construction of C1–C17 polypropionate fragment of ru-tamycin B and oligomycin C.16 The aldehyde partner used for thesequence consisted of a diol protected as a di-tert-butylsilylene18. The reaction proceeded in the presence of TiCl4 in excellentdiastereoselectivity and yield (eq 9).

O OSi

t-Bu t-Bu

CH3 CH3

O

H

TiCl4, CH2Cl2

–78 to –35 °CH3C

CO2Me

SiMe2Ph+

O OSi

t-Bu t-Bu

CH3 CH3

OH

CH3

CO2Me

90%

diastereoselection: >30:1 syn:anti

steps

rutamycin B

and oligomycin C

(17)(18)

(19) (9)

Di Fabio et al. reported synthesis of 3-alkoxy-substitutedtrinems from commercially available 4-acetoxy-3-[(R)-l-tert-butyldimethylsilyloxyethyl]-2-azetidinone.17 Epoxide 20 wastreated with ceric ammonium nitrate in acetonitrile to providethe intermediate nitrate ester 21 in 55% yield. Simultaneous pro-tection of the secondary alcohol and the amide was accomplishedusing di-tert-butylsilyl bis(trifluoromethanesulfonate) to providethe tricyclic β-lactam 22. Removal of the nitro group by catalytichydrogenation provided the desired secondary alcohol that wasalkylated with allyl bromide to provide 23 in quantitative yield(eq 10).17

NH

H

O

H

O

TBSO

CAN, acetonitrile

0 °C, 10 min

NH

H H

O

TBSO

OH

ONO2

t-Bu2Si(OTf)2, 2,6-lutidine

CH2Cl2, 0 °C, 12 h

55%

80% N

H H

O

TBSO

O

ONO2

Si

t-Bu t-Bu

1. H2, Pd/C, EtOAc

2. NaH, allyl bromide

TBAI, THF, rt, 12 hN

H H

O

TBSO

O

OAllyl

Si

t-Bu t-Bu

quant

(20) (21)

(22)

(10)

(23)

A successful approach to construction of the tricyclic corecommon to hamigeran terpenes was demonstrated using anintramolecular Pauson–Khand reaction.18 For an effective cy-clization, the authors report that it was necessary to tether theolefin-containing moiety to the aromatic framework to reduce its

conformational mobility using the di-tert-butylsilylene protectinggroup (eq 11).

OH OH

OH

t-Bu2Si(OTf)2, CH2Cl2pyridine, 86%

O O

OH

Sit-Bu t-Bu

O OSi

t-Bu t-Bu

HOO

Co2(CO)8, PhMe

then 70 °C, 70%

(24) (25)

(26)

(11)

Stoltz and coworkers reported a highly selective catalytic re-ductive isomerization reaction using 10% Pd/C and hydrogen inMeOH. During their explorations of the total synthesis of (+)-dragmacidin F, olefin isomerization using the carbonate 27 (eq 12)was developed.19 The authors provided evidence that the methoddoes not proceed via a stepwise reduction/elimination sequence ora π-allylpalladium intermediate. Replacement of the carbonate bya dioxasilyl linkage (29), however, did not result in isomerization,only diastereoselective reduction of the exo-olefin was observed(eq 12).19

O

O CO2Me

OTBS

Sit-Bu

t-Bu

H2, Pd/C

MeOH, 0 °C O

O CO2Me

OTBS

Sit-Bu

t-Bu

O

O CO2Me

OTBS

O HO CO2Me

OTBSH2, Pd/C

MeOH, 0 °C

94%

68%

(27) (28)

(29) (30)

(12)

Hillaert and Van Calenbergh have reported synthesis of (S)-3-(hydroxymethyl)butane-1,2,4-triol, a versatile, chiral buildingblock that can be transformed into useful compounds such as (S,S)-4-(hydroxymethyl)pyrrolidine-3-ol and oxetanocin A.20 The au-thors reported a short synthesis of the protected triol 33 from theepoxide 31 in six steps. The use of di-tert-butylsilylene as the pro-tecting group provided the desired differentiation of the hydroxylgroups, which was necessary for their successful investigation intothe stereoselective synthesis of N-homoceramides (eq 13).20


OHO OMe

O

1. TrCl, DIPEA

2. NaBH4

MeOH/THF

3. 1,3-dithiane

n-BuLi, THF, –20 °C

HOOTr

OH

S S65%

1. t-Bu2Si(OTf)2, pyr

2. Mel, CaCO3

MeCN/H2O

3. NaBH4, EtOH/THF

O OSi

OTr

t-Bu t-Bu

(S)-3-(hydroxymethyl)butane-

1,2,4-triol

HO

OH

C14H29

OH

R = –C(O)C15H31

HO

OH

C13H27

D-ribo-N-homophytoceramide

E- and Z-N-homoceramides

steps

steps

O OSi

OTr

t-Bu t-Bu

75%

(31) (32)

(33)

(33)

(34)

(35)

(13)

RHN

RHN

HO

HO

Synthesis of polypropionate marine natural product(+)-membrenone C and its 7-epi-isomer has been reportedusing a key desymmetrization technique to create five contiguouschiral centers from bicyclic precursor 36.21 The diol was protectedusing di-tert-butylsilyl bis(trifluoromethanesulfonate) and furtherelaborated into the natural product and its epimer (eq 14).21 In aseparate communication, Perkins et al. utilized di-tert-butylsilylbis(trifluoromethanesulfonate) for synthesis of a model systemen route to the polypropionate natural products auripyrones Aand B.22

BnO OBn

CH3 CH3

OHOH

CH3t-Bu2Si(OTf)2, 2,6-lutidine

CH2Cl2, 8 h, 65 °C

90%BnO OBn

CH3 CH3

OO

CH3

Sit-Bu t-Bu

CH3 CH3

OO

CH3

Sit-Bu t-Bu

O O O O

1. HF–Py, pyridine, THF

2. TFA, CH2Cl2steps

O O

CH3CH3

O O

CH3

(+)-7-epi-membrenone C

O

OO

OPMB

steps

(36) (37)

(38)

(39)(40)

(14)

Danishefsky and coworkers reported studies toward the totalsynthesis of tetrahydroisoquinoline alkaloid, ecteinascidin.23 Thesynthesis required a pentasubstituted E-ring system where theyutilized the di-tert-butylsilylene protecting group in the sequenceto prepare the amino acid 42 (eq 15). In addition to above ex-amples, protection of 1,3-diol using di-tert-butylsilyl bis(triflu-oromethanesulfonate) has been reported in the synthesis ofbrasilinolides,24 polyol fragments of ansamycin antibiotics,25

(±)-epi-stegobinone,26 24-demethylbafilomycin C1,27 pelorusideA,28, bafilomycin A1,29 premisakinolide A,30 (+)-papulacandinD,31 and other polyether natural products such as maitotoxin,32

yessotoxin,33 and gambieric acids.34

O

SiO

t-Bu

t-BuOCH3

CH3

OH

O

PMBO

BnO

OCH3

CH3

OH

NMe(Boc)

O

steps(15)

(41)

(42)

A mixed di-tert-butylsilylene has been prepared from (S)-5-hexen-2-ol and prochiral 1,4-pentadiene-3-ol for synthesis of(2S,7S)-dibutyroxynonane, the sex pheromone of Sitodiplosismosellana. The intermediate 43 was then subjected to ring closingmetathesis to provide the diene 44 in 70% yield over two steps(eq 16). Deprotection of the nine-membered silylene was achievedusing TBAF under refluxing condition in the presence of molecu-lar sieves. Reduction with H2/PtO2 and diacetylation yielded thedesired (2S,7S)-dibutyroxynonane in 22% overall yield.35


0 °C, THF, pyridine

DMAP, cool to –78 °C

(S)-5-hexen-2-ol, warm to rt

1,4-pentadien-3-ol

OO

Si

t-But-Bu

OO

Si

t-But-Bu

Grubbs' catalyst

(bis(tricyclohexylphosphine)benzylidene-

ruthenium(IV) chloride), CH2Cl2, 40 °C

70%

(over 2 steps)

1. 10 equiv TBAF, 4 Å mol sieves

reflux 18 h, 78%

2. H2, PtO2, MeOH, 83%

3. butyric anhydride

pyridine, DMAP, 85%

O

O

O

O

(2S,7S)-dibutyroxynonane

99% ee

94% de

(43)

(44)

(45)

(16)

t-Bu2Si(OTf)2

Kita and coworkers reported a novel method to prepare 2,2′-substituted biphenyl compounds using phenyliodine(III) bis(tri-fluoroacetate) (PIFA), a hypervalent iodine reagent.36 The sub-strate for the coupling was first prepared by reacting 1 equivof di-tert-butylsilyl bis(trifluoromethanesulfonate) with 2 equivof the phenol 46. Di-tert-butylsilylene 47 then underwent an in-tramolecular cyclization in the presence of BF3·OEt2 to providethe desired tricyclic compound 48. Removal of silylene ether wasaccomplished by TBAF in excellent yields. This sequence workedwell for both 2,2′-disubstituted symmetrical and unsymmetricalbiphenyls (eq 17).36

H3CO

H3CO

OH

t-Bu2Si(OTf)2, Et3N

DMF, 60 °C, 3 h

OCH3

OCH3OSi

O

t-But-Bu

H3CO

H3CO

PIFA, BF3 ·Et2O

CH2Cl2, –40 °C

OSi

O

t-Bu t-Bu

OCH3H3CO

OCH3H3CO

HO

OH

H3CO

OCH3

H3CO OCH3TBAF, THF, 2 h

98%

81%

81%

(46)

(47)

(48)

(49)

(17)

In a separate communication, Kita and coworkers also reportedan enantiodivergent synthesis of an ABCDE ring analog of the an-titumor antibiotic fredericamycin A via an intramolecular [4 + 2]cycloaddition. Late-stage oxidations were performed on the di-tert-butylsilylene for protection of phenolic hydroxyl groups. Syn-theses of both (R)- and (S)-enantiomers were reported (eq 18).37

O

SPh

O

O

Si

O

OMe

OMe

t-Bu

t-Bu

O

OH

OO

O

HO

O

OMe

5 steps

(R)

(50) (51)

(18)

In a study on copper-catalyzed enantioselective intramolec-ular aminooxygenation of alkenes, Chemler and coworkersshowed that this reaction allows synthesis of chiral indolines andpyrrolidines.38 Accordingly, the protected amino-diol 53 under-goes aminooxygenation in the presence of copper triflate, bisox-azoline ligands, and molecular oxygen to provide the desiredspirodecane 54 in 87% yield and 89% ee (eq 19).38

HO

HO NHTs

t-Bu2Si(OTf)2

2,6-lutidine

CH2Cl2, rt, 24 h

O

O NHTs

Sit-Bu

t-Bu

Cu(OTf)2

(4R,5S)-Bis-Phbox

K2CO3, TEMPO, O2

PhCF3, 120 °C, 24 h

O

O

Sit-Bu

t-Bu

NTs

ON

87%

89% ee

96%

(52) (53)

(54)

(19)

Craig and coworkers have reported stereocontrolled polyolsynthesis via C–H insertion reactions of silicon-tethered diazo-acetates.39 Menthol was treated with di-tert-butylsilyl bis(tri-fluoromethanesulfonate) and the product was condensed withethyl diazoacetate to provide the precursor 57a to the C–H in-sertion reaction (eq 20). The rhodium(II) octanoate-catalyzed de-composition of the diazoacetate 57a, however, did not provide thedesired C–H insertion product, although the reaction was success-ful with diisopropylsilyl bis(trifluoromethanesulfonate) (eq 20).


CH3

OHO

EtO

N2

1. R2Si(OTf)2 DIPEA

–78 °C, Et2O

2. menthol, DIPEA+

CH3

OSi

R

R

N2 CO2Et

CH3

Si

O R

R

CO2EtH

1–3% Rh2(oct)4

PhH, reflux

(55) (56)

(57a), R = t-Bu; 37%(57b), R = i-Pr; 78%

(58a), R = t-Bu; 0%(58b), R = i-Pr; 94%

(20)

In a study about stereoselective allylation of chiral monoperox-ides, Ahmed and Dussault focused on induction from 2-, 3-, and4-substituted monoperoxyacetals.40 It was observed that neigh-boring iodo-, alkoxy-, acetoxy-, and silyl, groups imparted usefullevels of diastereoselection in the Lewis acid-mediated allylationof monoperoxyacetals. While investigating 1,3-stereoinduction,the homoallylic alcohol 59 was ozonized and the resultant hy-droperoxy alcohol was silylated using di-tert-butylsilyl bis(triflu-oromethanesulfonate) to provide 3-sila-1,2,4-trioxepane 60.Unfortunately, the substrate provided only 5% of allylated sila-trioxepane under SnCl4-mediated allylation (eq 21).40

C7H15

OHO

O

OSit-Bu t-Bu

C7H15O

1. O3, 2-methoxyethanol

2. t-Bu2Si(OTf)2, DMF

imidazole

30%MeO

OO

OSit-Bu t-Bu

C7H15

allyltrimethylsilane

SnCl4, 0 °C

5%

(59)(60)

(61)

(21)

Applications in Carbohydrate and OligonucleotideSyntheses. In efforts to synthesize aza-C-disaccharides, Bau-dat and Vogel used a key cross-aldolization of aldehyde 62and (−)-(1S,4R,5R,6R)-6-chloro-5-(phenylseleno)-7-oxabicyclo-[2.2.1] heptan-2-one ((−)-63) to provide the product alcohol 64stereoselectively in 70% yield.41 The stereochemistry of the aldolproduct was confirmed by reduction of the ketone followed by pro-tection of the diol using di-tert-butylsilyl bis(trifluoromethanesul-fonate) providing a mixture of rotamers 65 resulting from benzylcarbamate. Treatment of this mixture with m-CPBA provided thevinyl chloride 66 that displayed typical 1H NMR vicinal couplingconstants, thus confirming the stereochemistry of exo-anti aldol(+)-64 (eq 22). A NOE experiment further confirmed the structureof (+)-66.41

N

O

O

CH3 Cbz

CHO

OBn

H3C

H3C

O

Cl

PhSe

O

1. LiN(SiMe3)2

–78 °C

2. (–)-12, THF

–95 °C

O

Cl

PhSe

O

H

CbzN

H3C

OBn

O

O

H3C

CH3

OH

H

(–)-(62)(–)-(63)

(+)-(64)

O

Cl

PhSe

O

H

CbzN

H3C

OBn

O

O

H3C

CH3

O

H

Si

t-Bu

t-Bu

1. NaBH4, THF/MeOH

2. t-Bu2Si(OTf)2, 2,6-lutidine

CHCl3, 50 °C, 14 h

89%

m-CPBA, CH2Cl2

–78 to 20 °C

OCl

H H

H HOOSi

t-Bu

t-BuR1

H

4.4 Hz

~0 Hz

10.8 Hz

CbzN

H3C

OBn

O

O

H3C

CH3

R1 =

74%

(+)-(66)

(–)-(65)

(22)

70%+


While investigating glycosyl phosphates for selective synthesisof α and β-glycosidic linkages using conformationally restrainedmannosyl phosphate 69, Seeberger and coworkers observed onlythe desired α-isomer 71 by virtue of the participating pivaloylgroup as expected (eq 23). These reactions were high yielding,fast, and completely selective.42

OHO

HO

OH

OBn

HO

OO

Si

O

t-Bu

t-Bu

OH

OBn

HO

t-Bu2Si(OTf)2, DMF

–40 °C to rt

35%

4 steps

OO

Si

O

t-Bu

t-Bu

OPiv

O

TBSO

P OPh

OPh

O

O

O

O

O

OH

O

OO

Si

O

t-Bu

t-Bu

OPiv

O

TBSO

P OPh

OPh

O

OO

Si

O

t-Bu

t-Bu

OPiv

TBSO

O

O

O

OO

O

+ TMSOTf, CH2Cl2–78 to –50 °C

(67) (68) (69)

(70)

(69)

(71)

(23)

68%

85%

O

OCH3

O

HO 1. NaOBn, BnOH, 120 °C, 83%

2. t-Bu2Si(OTf)2, pyridine, CH2Cl2 –78 to 0 °C, 74% O

OCH3

OBn

OO

Sit-Bu t-Bu 1. H2, Pd(OH)2, CH3OH, rt, 94%

2. PCC, NaOAc, CH2Cl2, rt

3. Cp2Ti(CH3)2, THF, 70 °C

71% (over 2 steps) O

OCH3

OO

Sit-Bu t-Bu

1. RuCl3·H2O, NaIO4, EtOAc

CH3CN, H2O, 0 °C

2. PhCH(OCH3)2, p-TsOH, CH2Cl2

rt to 40 °C, 60% (over 2 steps) O

OCH3

OO

Sit-Bu t-Bu

OO

Ph

1. HF, pyridine, THF, rt, 86%

2. TBDMSCl, DMF, imidazole

0 °C, 87%O

OCH3

OTBSO

OBn

1. NBS, BaCO3, CCl4, reflux

2. K2CO3, DMF, rt, 47%

(over 2 steps) O

OCH3

OHO

OH

oligosaccharides

(72)

(73)

(74)

(75)

(76)

(77)

(24)

In a study of synthesis and conformational analysis of arabino-furanosyl oligosaccharide analogs in which one ring is locked intoeither the E3 or ◦E conformation, Houseknecht and Lowary useddi-tert-butylsilyl bis(trifluoromethanesulfonate) to protect the 1,4-diol. The di-tert-butylsilylene 73 is stable under a variety of reac-tion conditions and can be easily removed under mild HF–pyridineconditions (eq 24).43


Electrophilic glycosidation of 3,5-O-(di-tert butylsilylene)-4-thioglycal 80 has been reported to exclusively provide theβ-anomer of 4′-thionucleosides irrespective of the nucleobaseemployed. The face selectivity of the approach to 1′,2′-doublebond by the incoming electrophile can be controlled by changingthe protecting group of the 3′- and 5′-hydroxyl groups. Hence,approach to the α-face using NIS or PhSeCl increased in the orderof 3′,5′-O-(di-tert-butylsilylene):DTBS > 3′,5′-O-(1,1,3,3-tetraisopropyldisilox-ane-1,3-diyl):TIPDS > 3′,5′-bis-O-(tert-butyldimethylsilyl):TBDMS (eq 25).44

S SBnBnO

BnO

1. BBr3, CH2Cl2, –70 °C, 1 h

followed by pyridine, MeOH

2. t-Bu2Si(OTf)2, DMF, imidazole

S SBnO

OSit-Bu

t-Bu

1. m-CPBA, CH2Cl2, –70 °C

2. i-Pr2NEt, xylene, reflux

57%

77%

S

O

OSit-Bu

t-Bu

S

O

OSit-Bu

t-Bu

S

O

OSit-Bu

t-Bu

B

E

base, electrophile

ACN, 0 °C, 1 h

Electrophile Base Yield (%)Entry

81a PhSeCl uracil-1-yl 88

uracil-1-yl 73NIS

81c PhSeCl thymin-1-yl 62

81d PhSeCl cytosin-1-yl 85

(78)

(79)

(80)

(80)(81a–d)

81b

(25)

Ohnishiy and Ichikawa reported a stereoselective synthesis ofa C-glycoside analog of N-Fmoc-serine β-N-acetylglucosaminide(85) using a key Ramberg–Bäcklund rearrangement.45 The di-tert-butylsilylene protecting group provided the desired stabilityunder the strongly basic conditions of the rearrangement (eq 26).

In a report on synthesis of 5′-O-DMT-N-acyl-2′-O-TBDMS-protected nucleoside precursors for phosphoramidite RNA syn-thesis, Serebryany and Beigelman used di-tert-butylsilyl bis(tri-fluoromethanesulfonate) to protect 3′- and 5′-hydroxyl functionsof a nucleoside.46 The silylated derivatives were obtained in highyields and were crystalline and easy to purify. Acylation of theN2-position of the guanosine derivative provided crystalline com-pound 89 in quantitative yield. Deprotection of the silylene 89using mild HF–pyridine followed by protection of the primary al-cohol with dimethoxytrityl chloride in pyridine gave the desiredcompound 90 in about 60% yield over five steps (eq 27).46

Synthesis of 2′-C-difluoromethylribonucleosides has been sep-arately reported where simultaneous protection of the 3- and 5-hydroxyl groups of the methyl d-ribose with di-tert-butylsilylbis(trifluoromethanesulfonate) afforded the silylene 91.47 Dess–Martin periodinane oxidation of the C-2 hydroxyl group followedby nucleophilic addition of difluoromethyl phenyl sulfone in the

presence of lithium hexamethyldisilazane converted 91 exclu-sively to sulfone 92 in 57% yield. Reduction of the sulfone usingSmI2, coupling with persilylated bases, and a sequence of depro-tection steps provided the desired 2′-C-difluoromethylribonucleo-sides (eq 28).47

O

NHAcAcO

AcO

OAc

S

BocN

O

O

NHAc

S

BocN

O

OSi

OTBSO

t-Bu

t-Bu

1. Et3N/MeOH–H2O

2. t-Bu2Si(OTf)2, 2,6-lutidine/DMF

88% (2 steps)

3. TBDMSCl, imidazole/DMF, 95%

1. m-CPBA, Na2HPO4/CH2Cl2, 77%

2. KOH/Al2O3, CBrF2CBrF2/tBuOH

50 °C, 38%

O

BocN

O

OSi

OTBSO

t-Bu

t-Bu

HNHAc

O

NHAcAcO

AcO

OAc

CO2H

NHFmoc

steps

(82)

(83)

(84)

(85)

(26)

OHO B

OHOH

O

O

B

OHOSit-Bu

t-Bu

t-Bu2Si(OTf)2

DMF

TBSCl, Im

DMF

O

O

B

OTBSOSit-Bu

t-Bu

O

O

BR

OTBSOSit-Bu

t-Bu

1. HF–Py, CH2Cl2, 0 °C

2. DMT-Cl, pyridine

ODMTO BR

OTBSOH

(CH3)2CHCOCl

CH2Cl2, pyridine

quant

BR = Gi-Bu

base (B) = G

80%

(over 2 steps)

(27)

(86)

(87)

(88)

(89)

(90)


O

O

OCH3

OHOSit-Bu

t-Bu

1. Dess–Martin periodinane

overnight, 91%

2. PhSO2CF2H, LiHMDS

THF/HMPA (10/1)

–78 °C, 2 h, 63%

O

O

OCH3

CF2SO2PhOSit-Bu

t-Bu

OH

SmI2 (4 equiv), THF/HMPA

(20:1), 0 °C, 30 min

74%

O

O

OCH3

CF2HOSit-Bu

t-Bu

OH

OHO

B

CF2HOH

OH

B = C, U

6 steps

(91)

(92)

(93)(94)

(28)

Van der Marel and coworkers reported a novel method to pre-pare pyrophosphates by coupling of a sugar phosphate and anucleoside phosphoramidite.48 Benzyl-2-acetamido-2-deoxy-α-d-glucoside 95 was first protected using di-tert-butylsilyl bis-(trifluoromethanesulfonate) to improve solubility of GlcNAcderivative. In four additional steps, the silyl ketal was convertedinto the tetrabutylammonium salt of GlcNAc-α-1-phosphate 97.Uridine phosphoramidite 98 was then coupled with GlcNAc-α-1-phosphate 97 in the presence of dicyanoimidazole. The reac-tion was monitored using 31P NMR spectroscopy. Upon com-plete disappearance of amidite 99, the mixture was treated witht-butylperoxide to provide diastereomeric cyanoethyl-protectedpyrophosphate 100. The cyanoethyl group was then removedby treatment with anhydrous DBU, followed by treatment withHF/Et3N to deprotect the di-tert-butylsilylene group, and finallyammonium hydroxide was used to hydrolyze the acetate protect-ing groups to provide UDP-N-acetylglucosamine 101 in 76% yield(eq 29).48

O

AcHN

HO

HO

OH

O

AcHN

OSi

O

HO

t-Bu

t-Bu

t-Bu2Si(OTf)2, DMF

–40 °C, 94%

OBn

OBn

5 steps O

AcHN

OSi

O

AcO

t-Bu

t-Bu

OPO3H–Bu4N

+

GlcNAc-α-1-phosphate

ON

OAcAcO

NH

O

O

O

P

O

NiPr2

CN

dicyanoimidazole

97, MeCN, rt, 30 min

ON

OAcAcO

NH

O

O

OP

O

NC

O

AcHN

OSi

O

AcO

t-Bu

t-Bu

O

P

O

O

–O

ON

OAcAcO

NH

O

O

OP

O

NC

O

AcHN

OSi

O

AcO

t-Bu

t-Bu

O

P

O

O

–O

O

t-BuOOH

rt, 30 min

1. DBU

2. HF/NEt33. NH4OH

ON

OAcAcO

NH

O

O

OP

O–

O

AcHN

HO

HO

HO

O

P

O

O

–O

O

UDP-GlcNAc

76%

(over 5 steps)

(29)

(95)

(96)

(97)

(98)(99)

(100)

(101)


Kishi and coworkers reported a protocol to improve the overallstereoselectivity of the Ireland–Claisen rearrangement for pyra-noid and furanoid glucals.49 To prepare building blocks for ma-rine natural product halichondrins, the authors reported synthesisof silylene 102 in two steps from d-galactal. Under the conditionsreported by Ireland (LHMDS, TBSCl, HMPA, THF, −78 ◦C), 102was converted to the corresponding O-silyl ketene acetal 103,which was estimated as a 7.3:1 mixture of Z-103 and E-103 asmonitored using 1H NMR analysis. Upon heating at 80 ◦C in ben-zene for 1 day, this mixture furnished the carboxylate 104 as asingle diastereomer in >85% yield, along with 102 and E-103 inca. 12% combined yield. The authors further provided experimen-tal evidence that Claisen rearrangement took place through Z-103and that the Me stereochemistry of 104 indicated that the Claisenrearrangement proceeded exclusively via the boatlike transitionstate (eq 30).49

A practical approach for the stereoselective introduction of β-arabinofuranosides has been developed by locking an arabinosyldonor in a conformation in which nucleophilic attack from the β-face is favored.50 This was achieved by using di-tert-butylsilylbis(trifluoromethanesulfonate) to protect the C-5 and C-3 hy-droxyl groups. This resulted in C-5 and O-3 in a pseudoequa-torial orientation, resulting in a perfect chair conformation ofthe protecting group. The nucleophilic attack from the α-face isdisfavored due to unfavorable steric interactions with H-2. Theglycosyl donor 107 was prepared in two convenient steps fromcommercially available thioglycoside 106. The coupling of theconformationally constrained glycosyl donor 107 with the glyco-syl acceptor 108 in the presence of the powerful thiophilic pro-moter system N-iodosuccinimide/silver triflate (NIS/AgOTf) inDCM at−30 ◦C gave disaccharide 109 with excellentβ-selectivity(β:α = 15:1) in 91% yield (eq 31).50

O

SiO

OH

HO

t-Bu

t-Bu

O

CH3

O

SiO

OH

HO

t-Bu

t-Bu

OTBS

CH3

O

SiO

OH

HO

t-Bu

t-Bu

OTBS

CH3

O

SiO

OH

H

t-Bu

t-Bu

CH3

CO2TBS

H

O

SiO

OH

H

t-Bu

t-Bu

CH3

CO2TBS

H

(E-103)

(Z-103) 85%

(102)

(104)

(105)

(30)

OSPh

OH

OH

HO

OSPh

OBn

OSi

O

t-Bu

t-Bu

1. t-Bu2Si(OTf)2, 2,6-lutidine

DMF/DCM, 0 °C, 81%

2. BnBr, NaH, THF, 79%

O

Si OOt-Bu

t-Bu

SPhBnO

O

BzOBzO

BzO

OH

OMe

O

BnO

OSi

O

t-Bu

t-Bu

O

O

BzOBzO

BzO

OMe

(107)

107

NIS/AgOTf, DCM, –30 °C

β:α = 15:1

91%

(106)

(108)

(109)

(31)

Another β-selective glycosylation was reported by Lowary andcoworkers who intended to study ligand specificity of CS-35,a monoclonal antibody that recognizes mycobacterial lipoarabi-nomannan.51 Selective glycosylation followed by two-step depro-tection of the hydroxyl groups provided the desired pentasaccha-ride 112 in 51% overall yield (eq 32). Subsequently, Crich et al.studied the importance of the activation method for the observedselectivity in glycosylation using 3,5-O-(di-tert-butylsilylene)-2-O-benzylarabinothiofuranosides as glycosyl donors for the syn-thesis of β-arabinofuranosides.52


OO

OSit-Bu

t-Bu

OBn

STol

O

O

OBn

OCH3

O

OBn

OHBnO

O

OBn

OH

O

BnO

+

1. NIS/AgOTf, DCM, –30°C, 92%

2. TBAF, THF, rt, 62%

3. H2, Pd(OH)2/C, rt, 83%

O

O

OH

OCH3

O

OH

OHO

O

OH

O

O

HO

O

OH

HOHO

O

OH

HOHO

(32)

(110) (111)

(112)

HO OH

ON

N

O

NH

NH2NHO

OO

OHOSit-Bu

t-Bu

N

N

O

NH

NH2N

OO

OHOSit-Bu

t-Bu

N

N

O

N

NH2N

S

O

O

i-Pr

i-Pr

i-Pr

OO

OCH3OSit-Bu

t-Bu

N

N

O

N

NN

S

O

O

i-Pr

i-Pr

i-Pr

NMe2

HO OCH3

ON

N

O

NH

NNHO

NMe2

t-Bu2Si(OTf)2/DMF

0 °C, 1.5 h

89%

2,4,6-triisopropylbenzenesulfonyl

chloride, Et3N, DMAP/CH2Cl2, 3 h

96%

1. N,N-dimethylformamide dimethyl

acetal/DMF, overnight, 99%

2. MeI, NaH/DMF, molecular sieve 3 Å

0 °C, 30 min, 84%

1. 2-nitrobenzaldoxime

N,N,N′,N′-tetramethyguanidine/MeCN, 1 h

2. Et3N/HF, triethylamine/THF, 1 h, 77%

(33)

(113)

(114)

(115)

(116)

(117)

A novel six-step synthesis of N2-dimethylaminomethylene-2′-O-methylguanosine has been reported.53 The synthesis utilizesdi-tert-butylsilylene protection for 3′- and 5′-hydroxyl groups.The arenesulfonylation at the O6 position of 3′-and 5′-O-protectedguanosine without 2′-O-protection was found to be completely se-lective. Compound 117 is a useful intermediate for oligonucleotideconstruction (eq 33). A similar application of di-tert-butylsilyleneprotecting group was originally reported for the synthesis of N2-isobutyryl-2′-O-methyl guanosine.54

Sabatino and Damha recently reported synthesis, characteri-zation, and properties of oxepane nucleic acids.55 These sugarphosphate oligomers have the pentofuranose ring of DNA andRNA replaced with a seven-membered sugar ring. The oxepanenucleoside monomers were prepared from the ring expansion re-action of a cyclopropanated glycal, 118, and their conversion intophosphoramidite derivatives. Properties of these oxepane nucleicacids were then compared to naturally occurring DNA (eq 34).


OO

SiO

t-Bu

t-Bu

persilylated thymidine, TMSOTf

MeCN, reflux, 12 h, 40%

OAc

O

SiO

t-Bu

t-Bu

OB

4 stepsHO

O

OB

Pi-Pr2N

CN

β:α = 10:1

(118)

(119)

(120)

(34)

Regioselective Monodeprotection. The monodeprotectionof di-tert-butylsilylene ethers prepared from substituted 1,3-pent-anediols and 2,4-hexanediols has been achieved withBF3·SMe2.56 The reaction is highly selective and providesaccess to 1,3-diols silylated at the sterically more hinderedposition. This is consistent with coordination of boron tothe sterically more accessible oxygen prior to intramoleculardelivery of fluoride. The reaction conditions for deprotectionare compatible with esters, allyl ethers, and TIPS ethers. Theresulting secondary di-tert-butylfluorosilyl ethers are stable tovarious conditions including low pH aqueous solutions andsilica gel chromatography; the di-tert-butylfluorosilyl ethers arereadily cleaved with HF–pyridine. An example is provided below(eq 35).

Ph

OH OH

THF:Me2NCHO (2:1)t-Bu2Si(OTf)2, –30 °C to rt pyridine

87%Ph

O OSi

t-Bu t-Bu

BF3·SMe2

KOAc, C3H5SiMe3

3 Å sieves, CHCl3, rt, 5.5 h

81% Ph

O OHSi

t-Bu

t-Bu

F

(121) (122)

(123)

(35)

Second Update

Samir Ghosh & Peter R. AndreanaUniversity of Toledo, Toledo, OH, USA

The choice of protecting groups is a very important, if not crucial,factor for glycal chemistry as particular reaction conditions forprotection and deprotection may impart unsatisfactory results. Forexample, acid-catalyzed installation of protecting groups can pro-duce variable quantities of rearranged products (Ferrier rearrange-ment) that are observed in the case of benzylidene acetal forma-tion. Mild conditions utilized to introduce p-methoxybenzylideneacetal are more labile, whereas siloxanylidene acetals are oftenformed in low yield or with moderate regioselectivity, especiallyin cases using d-galactal. Based on these shortcomings, a con-

venient and useful protecting group has come to light—di-tert-butylsilyl bis(trifluoromethanesulfonate) that is generally utilizedas a protecting group for diols when synthesizing natural prod-ucts, oligonucleotides, and so on. Although it has been found tobe useful, there are other venues where it can be exploited inreaction-based organic synthesis.

Hoberg57 reported the protection of diols (O-4 and O-6) of d-glucal by using the di-t-butylsilylidene group following a sim-ilar strategy reported for the protection of ribonucleoside byFurusawa.2 After glycosylation of d-glucal, the silylene groupwas removed by treatment with Bu4NF in THF (eq 36).

O

OH

HO

HO

O

OH

O

OSi

tBu

tBu

124 125

a

OO

OSi

tBu

tBu

126

OHO

HO

b

c

127

(36)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, pyr. (b) (1)Ac2O/Py; (2) TMS-allyl, TMSOTf; (c) Bu4NF, THF.

In another report, Gabrielli58 utilized the same reaction, as pub-lished by Hoberg,57 to protect diols (O-4 and O-6) of d-glucaland d-galactal. The reaction was performed under very mild con-ditions (−40 ◦C, 30 min) using di-t-butylsilyl ditriflate in DMFto produce the 4,6-O-protected D-glucals 128 from d-glucal 124and the 4,6-O-protected d-galactal 129 from 125 in 96 and 83%yield, respectively.

OHO

OSiO

tBu

tBu

128

OHO

OO

Si

tBu tBu

129

Silylidene glycals 128 and 129 are stable synthons that cansubsequently undergo a series of reactions that ultimately affordsthe expected disaccharide 138 and 140 (eq 37).


OHO

OO

Si

tBu tBu

129

134

128 OHO

OSi

OtBu

tBu

OOOSi

OtBu

tBu

O O131132

O

OOO

Si

tBu tBu

O135

O

130

133

a b c or d

a b c or d

OOBn

OBnOBn

OHO

OSiO

tBu

tBu

OH

OHO

OH

OO

Si

tBu tBu

132 OOSiO

tBu

tBu

O OS

OOSiOtBu

tBu

OSO

OOBn

OBnOBn

OHOHO

OSO

e f g

135O

OO

Si

tBu tBu

OOS

OOO

Si

tBu tBu

O

OOBn

OBnOBn

O S

f

138

e

136137

139

140

(37)

Reagents and conditions: (a) (1) NIS, H2O, CH3CN, rt, 25–45min; (2) NaHCO3, Na2S2O4, THF, rt, 3–4 h. (b) Fetizon59 reagent,benzene, reflux, 3–20 h. (c) DMSO, trifluoroacetic anhydride,CH2Cl2, −60 to −30 ◦C, 1.5 h. (d) IBX, EtOAc, 80 ◦C, 2.5–3.5 h.(e) PhtNSCl, CHCl3, pyr., rt, 15 min. (f) 3,4,6-Tri-O-benzyl-d-glucal, 60 ◦C, 22 h–3 days. (g) TBAF, DMF, rt, 1.5 h, 71%.

Recently, di-t-butylsilyl bis(trifluoromethanesulfonate) wasused by Lewis and coworkers60 for the preparation of silanederivatives by selective protection of diols in polyhydroxy com-pounds (eq 38).

OO

CO2Bn

SitBu

tBu

OHOH

CO2Bn

OO

CO2H

SitBu

tBu

141

142

143

a b

(38)

Reagents and conditions: (a) tBu2Si(OTf)2, NEt3, CH2Cl2, rt,9 h, 81%. (b) H2, Pd/C MeOH, rt, 24 h, 53%.

Pieters and coworkers61 used di-t-butylsilyl bis(trifluoro-methanesulfonate) for the protection of diols in the synthesisof derivatives for an antifungal agent named papulacandin D.Synthesis of a d-glucose moiety present in the core structure ofthe compound initiated with glycal 124, which was treated withdi-t-butylsilyl bis(trifluoromethanesulfonate) in the presence ofpyridine and DMF at −40 ◦C to afford O-4- and O-6-protectedd-glucal 125. Following four additional steps, the synthesizedsilanol building block 144 and compound 145 were subjected toa palladium-catalyzed cross-coupling reaction using Pd2(dba)3

to furnish compound 146. After several reaction transformations,compound 149 was obtained having the silane moiety intact, ulti-mately being treated with TBAHF in THF for removal. Depro-tection of the TIPS group was achieved with TBAF and onlythereafter the cyclic silyl protecting group was reinstalled to ob-tain compound 152. A variety of compounds were obtained fromcompound 152, all of which were treated with TBAHF in THFresulting in deprotection of the silane group to form compounds153–156 (eq 39).


O

OH

HO

HO

O

OH

O

OSi

tBu

tBu

124 125

O

OTIPS

O

OSi

tBu

tBu

Si OH

+

OBn

I

BnO

OPiv

O

OTIPS

O

OSi

tBu

tBu

OBnBnO

OPiv

144146

b

O

TIPSO

OSi

O

tBu

tBu

OR

147 R1 = Bn, R = H148 R1 = R = H149 R1 = R = MOM

c

d

e

150 R = TIPS, R1 = MOM151 R = OH, R1 = MOM

f

152 R = OMOM

g

153 R = sor154 R = pal155 R = lin

156 R = ret

h

aO

OTIPS

O

OSi

tBu

tBu

Si OH

144

OR1O

OR1

O

RO

HOHO

OR1

OR1O

OR1

O

HO

OSi

O

tBu

tBu

OR

ORO

OR

145

O

O

HOHO

OH

OHO

OH

R

O

(39)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, pyr. (b)Pd2(dba)3·CHCl3, NaOtBu, toluene, 50 ◦C, 6–20 h. (c) Pd/C,NaHCO3, H2, THF, rt, 1.5 h. (d) MOMCl, DIPEA, DMAP,CH2Cl2, rt, 4 d. (e) TBAHF, THF, rt, 2 d. (f) TBAF·3H2O, THF,rt, 3 d. (g) tBu2Si(OTf)2, pyr., DMF, −40 ◦C to rt, 2 h. (h) (1)RCOOH, NEt3, 2,4,6-trichlorobenzoyl chloride, toluene, rt, 1 h,DMAP, toluene, rt, 3 h; (2) TBAHF, THF, rt, 2–3 days; (3) Dowex50 × 8, MeOH, 50 ◦C, 20 h.

As a component of the synthesis of acid-sensitive biomaterialsuseful for drug delivery and degradable devices, Parrott et al.62

utilized a bifunctional silyl ether linker for the construction ofrelevant medical devices. Di-t-butylsilyl ditriflate was used for theintroduction of silyl ether linker in alkaline conditions (eq 40).

O

O

OH

O

O

OO

OSi

tBu

tBu

O

Pyridine

O Si

tBu

tBu

O SSF3C CF3

O

O

O

O

+

(40)

DCM, 0 ºC

With a strategy to synthesize a safe, effective, and acid-labileprodrug, Parrott et al.63 (eq 41) introduced bifunctional silyl etherlinkers by treating di-t-butylsilyl ditriflate or dichlorodialkyl silanewith the pendant alcohol on chemotherapeutics such as Camp-tothecin (CPT), Dasatinib (DAS), and Gemcitabine (GEM). Theasymmetric bifunctional silyl ether prodrugs were incorporatedinto nanoparticles and the combination as a whole ascertained therelease of therapeutics in active form under biological acidic con-ditions with no trace of the silyl ether modification on the drug.

Drug OHbase

RSi+

X

R

X

O

OHO

O

OO

RSi

O

R

Drug

+

R1 = Et, iPr, tBuX = Cl, OTf

X = Cl, OTf

(41)

acid


Maas and coworkers64 reported a reaction of dialkylsilyl-bis(trifluoromethanesulfonates) with equimolar amounts of di-azoacetates in the presence of a tertiary amine resulting in[(trifluoromethylsulfonyloxy)-dialkylsilyl] diazoacetates, wherenucleophilic substitution of the trifloxy group could take placewith alcohol to form alkyloxy- (or alkenyloxy-, alkinyloxy-)-dialkylsilylldiazoacetates. However, the same reagent whenreacted with 2 equiv of diazoacetates formed dialkylsilyl-bisdia-zoacetates, and with diazomethyl ketones formed the correspond-ing dialkylsilyl-bis(diazomethyl ketones), which was reported asbeing stable when the alkyl group was bulky such as the tert-butyl group. Therefore, the reagent di-t-butylsilyl-bis(trifluoro-methanesulfonates) could be useful when in a 2:1 ratio (withrespect to 2 equiv diazoacetates and 1 equiv di-t-butylsilyl-bis(tri-fluoromethanesulfonates)) for generating the desired product(eq 42).

HC

N2

COOR2

R1

2Si(OTf)2 n+ + n NEt(iPr)2

n = 1

n = 2

C

N2

COOR2

Si

R1

R1

TfO

C

N2

COOR2

Si

R1

R1

C

N2

R2OOC

R1 = Me,

iPr,

tBu R

2 = Me, Et

(42)

Massaro et al.65 utilized di-t-butylsilyl bis(trifluoromethane-sulfonate) as a promoter for a Boekelheide66-type reaction to syn-thesize pyrrolidines and piperidines from (amino-alkyl)pyridineN-oxides (eq 43). Generally, the Boekelheide reaction requiresactivation of pyridine N-oxides by electrophilic agents such asAc2O, P2O5, TsCl, or TFAA that make this reaction one of lim-ited use due to the need for protection of other functional groupsin the molecule that cannot tolerate the use of such reactive pro-moters. This reaction proceeds through the activation of the pyri-dine ring followed by a nucleophilic attack to form the Boekel-heide intermediate. This group introduced nucleophiles bonded tothe pyridine ring that undergo intramolecular cyclization to formN-heterocycles.

N NH

Bn

O

N

N

2 equiv tBu2Si(OTf)2

4 equiv TEA

N NH

Bn

OSi

tBu tBu

OSi

OH

tButBu

+

157

158

159

(43)

DCM, 2 h, rt

52% (MW: 78%)

Treatment of amino pyridine N-oxide 157 with di-t-butylsilylbis(trifluoromethanesulfonate) and triethylamine in dichloro-methane resulted in intramolecular cyclization to form pyrroli-dine 158 in 52% yield along with the compound 139 derived froma Boekelheide rearrangement66 in 30% yield. Microwave irradia-tion (50 ◦C, 250 W, 20 min) increased the product yield up to 78%.The oxophilic nature of the promoter featuring a nonnucleophiliccounterion was considered to be compatible in the presence of un-protected basic amines that lead to the participation of an aminein the intramolecular cyclization with activated pyridine N-oxide.

The analogous quinoline N-oxide, under the same reaction con-ditions, resulted in the desired cyclized product in 51% yield undernormal conditions and 75% yield when microwave irradiation wasused (eq 44).

N NH

Bn

O

N


4 equiv TEA

N (44)

DCM, 2 h, rt

MW: 75%

2-(N-Benzylpiperidine-2-yl)pyridine was synthesized in 38%yield under normal reaction conditions and in 60% yield whenmicrowave irradiation was used from a compound having onecarbon more in the alkyl chain carrying the amino group (eq 45).

N

O

HN

Bn


4 equiv TEA

N

N(45)

DCM, 2 h, rt

MW: 60%


To extend the scope of this reaction, the group investigatedintramolecular cyclization reactions at position 4 of the pyridinering. When (4-aminoalkyl)pyridine N-oxides were subjected to thesame reaction conditions, corresponding pyrrolidine and piperi-dine were obtained in 45 and 35% yield, respectively, under nor-mal reaction conditions and 62 and 48%, respectively, under mi-crowave irradiation (eq 46).

N

O


4 equiv TEANH

Bn

N

N

N

O


4 equiv TEA

N

HN

Bn

N

(46)

DCM, 2 h, rt

MW: 62%

DCM, 2 h, rt

MW: 48%

Again they investigated the effect of substituents on the lat-eral chain, for both the chemical and the stereochemical behavior(eq 47).

N

N

N

OHN

N

OHN

N

OHN

N

OHN

N

OHN

N

N

N

N

N

N

N

N

50%syn/anti = 1:3

42%syn/anti = 3:1

25%ratio ca = 3:1

38%ratio ca = 2:1

(47)

Mori and Hayashi reported67 an enantioselective synthetic ap-proach to 1,3-O-di-tert-butylsilylene-protected d- and l-erythri-tols 160 and 161 (eq 48) from d-glucose that are chiral build-ing blocks for highly symmetrical transfused polytetrahydropy-rans 162 (eq 49). Di-t-butylsilyl bis(trifluoromethanesulfonate)was used for the protection of the diols that was regarded as abetter protecting group due to the reduced acid lability of silylenerelative to an acetal.

O

O

O

PhHO

OH

HOO

OHO

HO

Ph

H

H

O

OO

SiO

PhtButBu

OH

OHO

SiO

tButBu

H

H

a b

c

OH

OH

O

OH

O

SiO

O

OHtBu

tBu

b

O

SiO

HO

HO

tBu

tBu

d

H

H

160

161

H

H

(48)

Reagents and conditions: (a) (1) NaIO4, NaHCO3; (2) NaBH4.(b) tBu2Si(OTf)2, 2,6-lutidine, DMF. (c) H2, Pd(OH)2/C, EtOAc.(d) (1) NaIO4, OsO4, MeOH, H2O; (2) NaBH4, MeOH.


OR1

OR2

O

SiO

tBu

tBu

H

H

a

OR2

O

SiO

tBu

tBu

H

H

OBn

SO2Tol

OO

SiO

tButBu

H

H

OBn

H

O

BnO SO2Tol

b

OO

SiO

tButBu

H

H

OBn

H

OH

c

d OO

SiO

tBu

tBu H

H

OH

H

OHH

162H

(49)

Reagents and conditions: (a) n-BuLi, THF, −100 ◦C. (b) (1)TsOH, MeOH; (2) MgBr2.OEt2; (3) DBU. (c) NaBH4. (d) H2,Pd(OH)2/C.

In a report aiming to examine the mechanism of T-cell help forthe production of B-cell antibodies, Besra and coworkers.68 syn-thesized a novel haptenated derivative of α-d-galactosyl ceramide169.

O

OHOH

OHO

OH2N C14H19

NH OH

OH169

4

C25H51O

To synthesize the sugar moiety present in the hapten, di-t-butylsilyl-bis(trifluoromethanesulfonate) was used for the protec-tion of O-4 and O-6 of the sugar as a cyclic silylene, which afterglycosylation was deprotected by treating with TBAF in THF(eq 50).

OSPh

OTBDPSO

OHO

OSPh

OHOH

OHO

OSPh

OO

OBzO

Si

tBu tBu

N34

OSPh

OTBDPSO

OO

N34

N3

OHC14H19

NH OBz

OBz

OtBuO

O

OO

OBzO

Si

tBu tBu

N3 C14H19

NH OBz

OBz

OtBuO

O

4

4

169

a b

c

d

163

164

165 166

167

168

e(50)

Reagents and conditions: (a) (1) DMF, NaH, (CH2)5Br2, quant;(2) NaN3, DMSO, 60 ◦C. (b) (1) TBAF, THF, quant; (2) TFA,CH2Cl2, 78%. (c) (1) tBu2Si(OTf)2, DMF, Et3N, quant; (2) BzCl,pyr. (d) p-NO2PhSCl, AgOTf, CH2Cl2, −78 ◦C, 75%. (e) (1)TBAF, THF, quant; (2) NaOMe/MeOH, 88%; (3) TFA, CH2Cl2,quant.; (4) C25H51COCl, THF/NaOAc (1:1), 71%; (5) H2, Pd,MeOH, 90%.

Painter and coworkers69 also reported the synthesis of α-d-galactosyl ceramide with the use of di-t-butylsilyl-bis(trifluoro-methanesulfonate) (eq 51).

O

OHOH

OHHO

O

OO

ORRO

Si

tBu tBu

a c

170O

171 R = H172 R = Bn

b

O

O

OO

OBnBnO

SitBu

tBu

O

173 R = H174 R = TCA

d

(51)

Reagents and conditions: (a) tBu2Si(OTf)2, DMAP, pyr. (65%).(b) NaH, BnBr, DMF (66%). (c) Ph2P2(COD)Ir+PF6

−, THF, thenAcCl, MeOH–CH2Cl2. (d) CCl3CN, DBU, CH2Cl2 (40%).


For synthesizing microcrystalline solids in which organicmolecules are bonded to each other through O–Si–O linkages,phenylacetylene nitrile molecules with an attached terminal hy-droxyl group bearing an alkoxymethyl side chain was treatedwith di-t-butylsilyl-bis(trifluoromethanesulfonate) to afford cova-lent O–Si–O bonds between adjacent phenylacetylene molecules(eq 52).70

2,6-di-t-butyl pyridine

CN

NC CN

O

CN

NC CN

O

HO

O

SitBu OH

tBu

+ Dimer (52)

tBu2Si(OTf)2, THF

Nierengarten and coworkers71 explored a regioselective syn-thesis of fullerene bis-adducts by a double or multiple Bingel72

reaction between C60 and linear or macrocyclic di-t-butylsilylene-tethered bis-malonates. The di-t-butylsilylene played a role as aprotecting group as well as a directing group. The deprotectionof silylene was achieved by treatment with HF-pyridine in THFor 20 equiv of BF3·Et2O in CH2Cl2/CH3CN and the product wasobtained in excellent yield (eqs 53 and 54).


O OOO

(CH2)n

(CH2)n

Si

O

OO

O

O O

O O

(CH2)n

O O

O O

(CH2)n O Si(tBu)2

OH

O OOO

(CH2)n

(CH2)n

O

OO

O

OH OH

a

b

c

n = 2, 3

n = 2, 3

n = 2, 3

O O

2

(53)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, pyr., rt, 12 h.(b) C60, DBU, I2, PhMe, −15 ◦C, 1 h. (c) BF3·Et2O, CH2Cl2,CH3CN, rt, 12 h.

O OOO

O

O O

O

OOO

O OH

O O

O OSi

O

RR

O

O

O

O ClCl

Cl

O O

O O

OH

OH

Cl

Cl

O

O

O O

O O

O R

O

O

Cl

Si

Cl

Cl

Cl

175 R = OH

176 R = OTs

177 R = Cl

f

g

a b

c

d

e

(54)

Reagents and conditions: (a) Meldrum’s acid, 120 ◦C, 3 h.(b) 1,3-Propanediol, EDC, DPTS, CH2Cl2, 0 ◦C to rt, 12 h. (c)tBu2Si(OTf)2, DMF, pyr., rt, 4 h. (d) C60, DBU, I2, PhMe, −15 ◦C,1 h. (e) BF3·Et2O, CH2Cl2, CH3CN, rt 12 h. (f) TsCl, pyr.,CH2Cl2, 0 ◦C to rt, 48 h. (g) n-Bu4NCl, THF, rt, 4 h.

Nierengarten and coworkers73 also illustrated the applicationof di-t-butylsilyl bis(trifluoromethanesulfonate) in C60 chemistry(eq 55).


H

OTHP

a

Si

OR

OR

tBu

tBu

R = THPR = H

b

SitBu

tBu

Si

tBu

tBu

O

O

O

O

O

O

O

O

SitBu

tBu

Si

tBu

tBu

O

O

O

O

O

O

O

O

+trans-3 (C2)

c

d

(55)

Reagents and conditions: (a) n-BuLi, THF, 0 ◦C, 1 h, thentBu2Si(OTf)2, 0 ◦C, 1 h (81%). (b) pTsOH, EtOH, rt, 12 h (78%).(c) Malonyl chloride, DMAP, CH2Cl2, rt, 12 h (9%). (d) C60,DBU, I2, PhMe, −15 ◦C, 1 h (5: 8%, 6: 18%).

Piccirilli and coworkers74 reported (eq 56) efficient methodsfor the synthesis of five C-nucleoside phosphoramidite deriva-tives (186a–186e). Starting from commercially available 2-amino-5-bromopyrimidine or 2-amino-5-bromopyridine 178, they

synthesized intermediate 179a or 179b, which reacted withtBu2Si(OTf)2 in DMF to form the corresponding cyclic silylenederivatives in good yield, thus affording regioselective protectionof the 2′-hydroxyl group as a 2′-O-TBS ether. After installing allthe suitable protecting groups, silyl ether was removed with theaid of pyridinium poly-(HF) in THF.


O

OH

O

Si OtButBu

X N

X N

NH2

Br

O

HO OH

HO

X N

NBn2

NBn2

O

OTBS

O

Si OtButBu

X N

NR2

O

OTBS

O

Si OtBu tBu

X N

N N

O

HO OTBS

RO

X N

N N

O

O OTBS

DMTO

X N

N N

PN

O CN

181 R = Bn182 R = H

a

b

c

e

d

184 R = H185 R = DMT

f

g

178

180

179

X = N (comp a) or CH (comp b)

183

186a186b

(56)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, 0 ◦C. (b)TBSCl, pyr., 1H-imidazole. (c) (NH4)2Ce(NO3)6, CH3CN:H2O(98:2), 50 ◦C. (d) DMF-DMA, MeOH. (e) HF-pyr., THF. (f)DMTCl, pyr. (g) i-Pr2NP(OCH2CH2CN)Cl, 1-methylimidazole,i-Pr2NEt, DCM.

The other synthesized nucleosides (186c–186e) usedtBu2Si(OTf)2 to protect O-3′ and O-5′ of sugar moiety.

O

O OTBS

DMTO

N

NHAc

PN

O CN

186c

POM

O

O

O OTBS

DMTO

N N

N N

PN

O CN

186d

N N

O

O OTBS

DMTO

N NH

N N

PN

O CN

186e

O

In an attempt to develop 5-hmC phosphoramidite buildingblocks using readily removable protecting groups, that is, TBDMSfor 5-hydroxymethyl group, Dai et al.75 utilized tBu2Si(OTf)2

group for the protection of O-3′ and O-5′. The initial strategystarted with the conversion of commercially available 2′-deoxyu-ridine to compound 189 followed by the regioisomer 190. Owingto the difficulty in separation of compound 189 and 190 by col-umn chromatography, the mixture was treated with di-t-butylsilylbistriflate in DMF that resulted in the protection of diol 189 toafford compound 191 leading to the separation from compound190 (eq 57).


OHO

HN

N

O

OH

O

OHO

HN

N

O

OH

O

OH

OR1O

HN

N

O

OH

O

OR2

O

O

Si OtButBu

HN

N

O

O

OTBDMS

189 R1 = H, R2 = TBDMS190 R1 = TBDMS, R2 = H

a b

c

187 188

191

(57)

Reagents and conditions: (a) (HCHO)x, Et3N,CH3CN/H2O. (b) AgNO3, TBDMS-Cl, THF/pyr. (c) tBu2Si-(OTf)2, DMF.

To increase the product yield, another strategy was followedby initiating the reaction with 6-iodo-3′, 5′-di-O-TBDMS-2′-de-oxyuridine 192 and after conducting multiple steps, the desiredphosphoramidite 201 was obtained. Within the synthetic strategy,the diol was protected as a silylene, the removal of which wasaccomplished with HF-pyridine in DMF (eq 58).

OHO

HN

N

O

OH

OO

O

Si OtButBu

HN

N

O

O

I

a b

c

I

O

O

Si OtButBu

HN

N

O

O

H

O

O

O

Si OtButBu

HN

N

O

O

OR

O

O

Si OtButBu

N

N

NHR

O

OTBDMS

ORO

N

N

NHBz

OH

O

OTBDMS

ODMTrO

N

N

NHBz

O

O

OTBDMS

PNCH2CH2CO N(i-Pr)2

195 R = H196 R = TBDMS

197 R = H198 R = Bz

d

199 R = H200 R = TrMD

h

g i

f

e

192 193

194

201

(58)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, 0 ◦C. (b)Pd2(dba)3, CHCl3/Ph3P, CO, toluene. (c) NaBH4, CeCl3, MeOH.(d) TBDMS-Cl/imidazole, DMF. (e) 1,2,4-triazole, POCl3,NH4OH/dioxane. (f) BzCl/pyr. (g) HF-pyr., THF. (h) DMTr-Cl,pyr. (i) (i-Pr)2NP(Cl)OCH2CH2CN, i-Pr2NEt, DCM.


In an effort to synthesize two xRNA (size-expanded RNA)monomer phosphoramidite derivatives (compounds 208 and 214)for their successful incorporation into synthetic oligoribonucleo-tides to examine their use as probes of positional steric sensitivityin RNAi, Kool and coworkers76 exploited di-t-butylsilyl bistri-flate for the protection of diol of rxA (size-expanded versions ofadenosine) triol 202 as well as rxU (size-expanded versions ofuridine) triol 209.77 The silylene protection ascertained the re-quired regiospecific protection of xRNA monomer for automatedoligonucleotide synthesis (eqs 59 and 60).

N

NO

HO OH

HON

N

NH2

N

N N

N

NH2

O

OR

O

Si OtButBu

N

N N

N

N

O

OTBDMS

O

Si OtButBu

N

N

NO

HO OTBDMS

HON

N

N N

N

NO

HO OTBDMS

DMTON

N

N NN

NO

O OTBDMS

DMTON

N

N N

PN

O CN

a c

e

f

d

203 R = H204 R = TBDMS

b202

205 206

207208

(59)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, 0 ◦C to rt,1 h, 85%. (b) TBDMSCI, imidazole, pyr., rt, overnight, 88%. (c)N,N-Dimethylacetamide dimethyl acetal, MeOH, rt, 90%. (d) HF-pyr., THF, 0 ◦C to rt, 15 min, 87%. (e) DMTCI, DMAP, pyr., 12h, 86%. (f) 2-Cyanoethyl N,N-diisopropylchlorophosphoramidite,1-methylimidazole, i-Pr2NEt, CH2Cl2, rt, 6 h, 87%.


O

HO OH

HO O

OR

O

Si OtButBu

NH

NH

O

O NH

NH

O

Oa

210 R = OH211 R = OTBDMS

b

c

O

HO OTBDMS

HO

NH

NH

O

O

O

HO OTBDMS

DMTO

NH

NH

O

Od

e

O

O OTBDMS

DMTO

NH

NH

O

O

PN

O CN

209

212213

214

(60)

Reagents and conditions: (a) tBu2Si(OTf)2, DMF, 0 ◦C to rt,1 h, 71%. (b) TBDMSCI, imidazole, pyr., rt, overnight, 89%. (c)HF-pyr., THF, 0 ◦C to rt, 15 min, 86%. (d) DMTCI, AgNO3, 2,6-di-t-butylpyridine, CH3CN, rt, 20 min, 82%. (e) 2-CyanoethylN,N,N′,N′-tetraisopropylphosphordiamidite, pyridinium triflu-oroacetate, CH3CN, rt, 18 h, 92%.

In the mechanistic studies of spore photoproduct lyase, via sin-gle cysteine mutation, Li’s research group78 synthesized TpTOH221 from thymine residue 215. After installation of the hydroxylgroup on the methyl moiety of the thymine, the diol 216 was pro-tected using di-t-butylsilyl bistriflate (eq 61).

OHO

N

NH

OH O

OOHO

N

NH

O

Oa

ODMTrO

N

NH

TBSO O

OO

O

Si OtButBu

N

NH

c

TBSO O

O

b

OH OH

OAc

OHO

N

NH

TBSO O

O

OAc

d

+ ODMTO

N

NH

PN

O CN

OO

N

NH

OH O

O

OH

O

O

O

OHO

N

NH

O

O

O PO O

TpTOH

215 216

217218

219220

221

(61)

Reagents and conditions: (a) (HCHO)x, Et3N, H2O. (b) (1)tBu2Si(OTf)2, DMF; (2) AgNO3, TBSCI, THF/pyr. (c) (1) HF-pyr., THF; (2) DMTrCI, pyr.; (3) Ac2O/pyr. (d) p-TsOH, MeOH.

Richichi et al.79 reported the use of di-t-butylsilyl bis(trifluoro-methanesulfonate) for the synthesis of α-O-fucosyl derivative 225(eq 62).


O

OH

HO

O

O

O

222223

SitButBu

O

SCOOMe

O

OOSi

tBu tBu

O

S

COOMe

a

O

OHOH

O

S

COOH

b

224

225

(62)

Reagents and conditions: (a) tBu2Si(OTf)2, pyr., 0 ◦C, 1 h, 62%.(b) CHCl3, 0 ◦C, 48 h, 76%.

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