Org. Synth. 2012, 89, 323-333 323 Published on the Web 2/10/2012

© 2012 Organic Syntheses, Inc.

Discussion Addendum for:

Diastereoselective Homologation of D-(R)-Glyceraldehyde

Acetonide Using 2-(Trimethylsilyl)thiazole: 2-O-Benzyl-3,4-

isopropylidene-D-erythrose

OCHO

OO

O

OH

N

S

2-TST

1. MeI2. NaBH43. HgCl2, H2O

62%96%

N

S Br

N

S SiMe3

2-TST

1. BuLi2. Me3SiCl

NaHBnBr

85%

84%

OO

OBn

N

SO

O

OBn

CHO

Prepared by Alessandro Dondoni*1 and Alberto Marra.

Original article: Dondoni, A.; Merino, P. Org. Synth. 1995, 72, 21–31.

Introduction

Over the last several decades, numerous heterocycles have emerged as

useful tools (precursors, reagents, chiral auxiliaries) in new methodologies

for organic synthesis.2 In that context, the five-membered heterocycle 1,3-

thiazole attained considerable popularity by virtue of its stability under a

wide range of reaction conditions, as well as its facile conversion into the

formyl group by a very efficient three-step one-pot procedure.3 The

widespread use of the thiazole ring as masked formyl group led to the

formulation of a general synthetic strategy that we have referred to as the

“Thiazole-Aldehyde Synthesis”.4 Thus, the stereoselective synthesis of a

chiral -hydroxy aldehyde (aldehydo-D-erythrose) by one-carbon chain

homologation of D-glyceraldehyde using 2-trimethylsilylthiazole (2-TST or

TMST) as a formyl anion equivalent (see scheme above) represented the

first example of diastereoselective thiazole-based synthesis reported from

our laboratory in 1986. Notably, this reaction sequence was repeated over

several consecutive cycles, with the result being that various chiral

polyhydroxylated aldehydes (aldehydo sugars) with up to eight carbon atoms

were prepared.5 Moreover, this strategy was applied also to dialdoses to

give, via elongation of the side chain, homologues with up to nine carbon

atoms.6 Thus, as 2-TST can be easily prepared by an efficient procedure (see

the original paper in this journal), or can be purchased at reasonable price

DOI:10.15227/orgsyn.089.0323

324 Org. Synth. 2012, 89, 323-333

from a number of suppliers, its use in the Thiazole-Aldehyde Synthesis over

the past 25 years became routine. Most notable is the fact that 2-TST reacts

readily with aldehydes and other C-electrophiles (acyl chlorides, pyridinium

chlorides, ketenes),7 as well as sulfenyl halides,

8 without the need of any

catalytic fluoride ion. These fluoride-free C- and S-desilylation processes

had no precedents in silicon chemistry as they proceed by a special

mechanism involving a thiazolium ylide intermediate.9

Scope of the 2-TST-Based Thiazole-Aldehyde Synthesis

The key role of 2-TST (often referred to as the Dondoni reagent)

serving as a masked formyl anion equivalent has been reviewed in a

comprehensive article3

covering the period ranging from its first synthesis10

in 1981 up to 2003. Nevertheless, some examples highlighting the role of 2-

TST in synthetic routes leading to biologically active compounds are

reported again below in Schemes 1-10 of this discussion addendum.

OO

O

O

S

N

OH

OO

O

OCHO

OBn 67%

1. BnBr, NaH2. MeOTf3. NaBH44. CuCl2, H2O

4 steps

87%

O

OAc

OAcAcO

O

OAc

OOAc

OC(O)NH2OAc

OAc

OCHO

O

O

O

ds 95%

2-TST

Scheme 1. Synthesis of the disaccharide subunit of bleomycin A2 from

aldehydo-L-xylose.11

OAllO

OH

OBzAllO

S

N

TBPSiO CHOOAll

OAll

TBPSiOOAll

OAll

OH2-TST

91%

1. MeOTf2. NaBH43. CuCl2, H2O4. Bu4NF

79%

*3 steps S

N

TBPSiOOAll

OAll

OBz

43% (ds 66%)

OAllO

O

OBzAllO

OOPMB

OBnOH

OMe

74%

2 steps

Scheme 2. Synthesis of the oligosaccharide portion of everninomicin

13,384-1 from aldehydo-L-threose.12

Org. Synth. 2012, 89, 323-333 325

OCHO

NBocO

NBoc

OH

N

SO

NBoc

OBn

CHO

ONBoc

BnO N

SOH

ONBoc

BnOCHO

OBn

2-TST

78% (ds 92%)

1. BnBr, NaH2. MeI3. NaBH44. HgCl2, H2O 2-TST

75% (ds 85%)

1. BnBr, NaH2. MeI3. NaBH44. HgCl2, H2O

55%

72%

AcOC14H29

AcHN

OAc

OAc4 steps

26%

Scheme 3. Synthesis of an acetylated phytosphingosine from N-Boc serinal

acetonide.13

CHO

NHBoc 1. 2-TST2. DMP, TsOH

62% (ds 83%)

N

S

NBoc

O

1. Me2SO42. NaBH43. NBS, H2O

CHONBoc

O

2-TST

ds >95%

43% (4 steps)

N

SNBoc

O

OH

1. BnBr, NaH2. Me2SO43. NaBH44. NBS, H2O

CHO

NBoc

O

OBn2 steps

41% (6 steps)

NBoc

O

OHN

Scheme 4. Synthesis of a protected amino diol, a building block of renin

inhibitors, from N-Boc cyclohexylalaninal.14

Ph CHO

NHBoc

OH

stepsNH

Ro 31-8959

OHN

Ph

CONHt-Bu

H

HHN

O

OCONH2

N

PhCHO

NHBoc

Ph

N

S

BocHN

OH 96%

1. MeI2. NaBH43. HgCl2, H2O

92% (ds 33%)

2-TST

BocHN

OH

N

Ph

CONHt-Bu

H

H

steps

Scheme 5. Synthesis of a hydroxyethylamine isosteric dipeptide precursor

of Saquinavir (Ro 31-8959) from N-Boc phenylalaninal (Hoffman-La Roche

method).15

326 Org. Synth. 2012, 89, 323-333

PhCHO

7 stepsN

Bocp-MeOBn

Ph

N

S

NBocp-MeOBn

OH 45%

2-TST

64% (ds 75%)

Ph CHO

NHBoc

t-BuMe2SiO

stepsBocHN

OH

N

Ph

CONHt-Bu

H

H stepsRo 31-8959

Scheme 6. Synthesis of a hydroxyethylamine isosteric dipeptide precursor

of Saquinavir (Ro 31-8959) from N-Boc,N-PMB phenylalaninal (Dondoni

method).16

PhCHO

NHBoc

Ph

N

S

BocN

O

1. 2-TST2. CH2=C(OMe)-CH3 PPTS

67% (ds 80%)

1. MeOTf2. NaBH43. CuCl2, H2O Ph CHO

BocN

O

4 steps Ph

NH2

OH

Ph

NH2

80%

75% (ds 94%)

Scheme 7. Synthesis of a chiral pseudo C2-symmetric 1,3-diamino-2-

propanol derivative from N-Boc phenylalaninal.17

Ph

N

S

BzN

O

1. 2-TST2. DMP, CSA

1. MeOTf2. NaBH43. CuCl2, H2O

Ph CHO

NHBz

66% (ds 95%)

PhCHO

BzN

O

80%

KMnO4Ph

CO2H

BzN

O90%

Scheme 8. Synthesis of N-benzoyl 3-phenylisoserine, viz the side chain of

Taxol, from N-benzoyl phenylglycinal.18

Org. Synth. 2012, 89, 323-333 327

CHOt-BuPh2SiO

O

t-BuPh2SiO

O

OH

N

S2-TST

86% (ds 100%)

5 steps

70% (ds 90%)

t-BuPh2SiO

O

CHO

O

N3

8 steps

12%HO

O

O

BocHN

O

O

NH2

O

Scheme 9. Synthesis of N-Boc and acetonide protected 5-O-carbamoyl

polyoxamic acid from chiral epoxy butanal.19

2-TST

85%(ds 100%)

CHOBocN

O

S

N

OH

1. BnBr, NaH2. MeOTf3. NaBH44. CuCl2, H2O

BocN

O

82%

CHO

OBnBocN

O

7 steps

43%

CO2HHN

NH2OH

O OH

O

OOH

AI-77-B Scheme 10. Synthesis of the amino acid side chain of the pseudopeptide

microbial agent AI-77-B from a formyl oxazolidine.20

Even with the development of new research methods, the Thiazole-

Aldehyde Synthesis based on the use of 2-TST continued to be an attractive

synthetic tool. Thus, recent applications of this chemistry that have been

carried out in our own and other laboratories are reported below.

In the context of a study on the synthesis of C-fucosides of biological

relevance, we set out to develop the syntheses of R- and S-epimeric C-

fucosyl hydroxyphenyl acetates21

(Scheme 11). These glycoconjugates were

expected to constitute the glycosidic part of new antibiotics similar to

existing natural products.22

The -L-C-fucosyl aldehyde 1, which was

prepared in our laboratory, was utilized as the starting material for the

synthesis of both epimers. The chiral alcohols 4 and 5 with R and S

configuration at quaternary carbon atoms, respectively, were produced by

using essentially the same reagents, but employing them in an inverse order.

For example, aldehyde 1 was first reacted with phenylmagnesium bromide

(PhMgBr) and the resulting mixture of diastereomeric alcohols was oxidized

to give the ketone 2. Addition of 2-lithiothiazole (2-LTT) to this ketone

328 Org. Synth. 2012, 89, 323-333

afforded the R-configured tertiary alcohol 4. For the preparation of the

alternate epimer, the sequence was initiated by the addition of 2-TST to the

aldehyde 1 and oxidation of the mixture of epimeric alcohols to ketone 3

followed by addition of PhMgBr to furnish the S-configured alcohol 5.

Having both stereoisomeric tertiary alcohols 4 and 5 in hand, their absolute

configuration was assigned from their 1H NMR spectra (NOE experiments).

Finally, both thiazolyl alcohols were readily transformed in the

corresponding aldehydes 6 and 7 by the standard thiazole-to-formyl

unmasking protocol and these aldehydes were oxidized to the representative

esters 8 and 9.

OMe

BnO

OBn

OBn

Ph

O

OMe

BnO

OBn

OBn

Ph

OHTh

( R )

OMe

BnO

OBn

OBn

Ph

OBnR

2-LTT 75%

67%

1. PhMgBr2. PCC

2

4

7 R = CHO

9 R = CO2MeI2, KOH, MeOH

70%

OMe

BnO

CHOOBn

OBn

1

OMe

BnO

OBn

OBn

Th

O

OMe

BnO

OBn

OBn

Th

OHPh

( S )

OMe

BnO

OBn

OBn

R

OHPh

99%

3

5

72%

1. 2-TST2. Ac2O DMSO

PhMgBr

1. NaH, BnBr2. MeOTf3. NaBH44. AgNO3, H2O

50%

1. MeOTf2. NaBH43. AgNO3, H2O81%

6 R = CHO

8 R = CO2Me72%

1. Jones ox.2. CH2N2

Scheme 11. Syntheses of R- and S-epimer C-fucosyl hydroxyphenyl

acetaldehydes and acetates.

Another paper on the use of 2-TST in the Thiazole-Aldehyde

Synthesis that appeared in mid-2005 was reported by Alcaide, Almendros,

and their co-workers.23

These authors developed a synthetic route leading to

azabicyclo[4.3.0]nonane (indolidizinone) amino esters from -lactams

(Scheme 12) by using -alkoxy -lactam acetaldehydes as key

intermediates. Interest in the synthesis of indolizidinone amino acids

stemmed from their behavior as conformationally restricted dipeptide

mimetics. Thus, the readily available enantiopure 4-oxoazetidine-2-

carbaldehydes 10 and 11 were transformed into the one-carbon higher

homologues via stereoselective addition of 2-TST to give the thiazole

Org. Synth. 2012, 89, 323-333 329

derivatives 12-13 and unmasking of the formyl group from the thiazole ring

(Scheme 12). In all cases, well established conditions4 for 2-TST addition to

aldehydes, as well as for thiazole cleavage, were employed resulting in the

isolation of the -alkoxy -lactam acetaldehydes 14 and 15 in good yields.

These aldehydes were transformed into the target indolizidinone amino

esters 16 and 17 via standard heterocyclic chemistry. A similar 2-TST-based

strategy was followed by the same research group for the conversion of

enantiopure cis-4-formyl-1-(3-methyl-2-butenyl)-3-methoxy- -lactam into

the corresponding higher homologue, an -silyloxylated aldehyde that

served as key intermediate for the synthesis of a mixture of diastereomeric

dihydroxycarbacephams via an intramolecular carbonyl-ene reaction.24

It

was emphasized in both instances that the addition of 2-TST to 4-

oxoazetidine 2-carbaldehydes to give the -hydroxyalkylthiazoles was not a

trivial process as the same authors had previously observed the reaction of

2-TST with N-aryl-4-formyl- -lactams to give enantiopure -alkoxy- -keto

acid derivatives via N1-C4 bond cleavage of the -lactam ring.25

1. 2-TST2. t-BuMe2SiOTf, Et3N

N

CHOMeO

RO

H H

N

MeO

RO

H H

N

S

t-BuMe2SiO

N

MeO

RO

H HCHO

t-BuMe2SiO

10 R = allyl

11 R = benzyl

12 R = allyl (69%)

13 R = benzyl (42%)

1. MeOTf2. NaBH43. AgNO3, H2O

14 R = allyl (56%)

15 R = benzyl (52%)

steps

16 R = H

17 R = methyl

N

Ht-BuMe2SiO

MeO

HN

CO2MeRO

CO2Me

Scheme 12. Synthesis of -alkoxy -lactam acetaldehydes from 4-

oxoazetidine-2-carbaldehydes en route to azabicyclo[4.3.0]nonane

(indolidizinone) amino esters.

A fourth paper on the use of 2-TST was reported in 2007 by Cateni

and co-workers in the effort to prepare a natural cerebroside from

Euphorbiaceae.26

These authors took advantage of the availability of the O-

and N-protected amino sugar 18 (L-ribo configuration) that was previously

prepared in our laboratory by 2-TST-based homologation of the Garner

aldehyde.13

Thus, the aldehydo sugar 18 was transformed into the one-

carbon higher homologue 19 by the standard 2-TST-based methodology

330 Org. Synth. 2012, 89, 323-333

(Scheme 13). Wittig reaction of this aldehydo sugar (L-allo configuration)

with a long chain alkyl phosphorane afforded under suitable conditions the

Z-olefin 20 displaying a chiral polar head and a lipophilic tail. Compound 20

was, in fact, the required C18-sphingosine, which after glycosylation and

acylation at the polar head, led to the targeted natural cerebroside.

ONBoc

BnOCHO

OBn

1. 2-TST2. BnBr, NaH3. MeI4. NaBH45. HgCl2, H2O

78%

2 steps

31%

18

ONBoc

BnO

OBn

19

CHO

OBn

HONH2

BnO

OBn

20

OBnC11H23

Scheme 13. Synthesis of a C18-sphingosine intermediate in the synthesis of a

natural cerebroside.

Conclusion

From the selected examples reported in the above schemes, it appears

that since its discovery in 1981, 2-TST has found use as a formyl anion

equivalent in various synthetic routes leading to compounds of biological

relevance. The fidelity of this reagent to react spontaneously with aldehydes

bearing a wide variety of substituents has been amply demonstrated. It has to

be mentioned, however, that the synthetic utility of 2-TST extends beyond

its use in the Thiazole-Aldehyde Synthesis, as in recent years numerous

applications of this reagent have appeared in thiazole chemistry27

and in

synthetic routes leading to thiazole-containing compounds of biological

relevance.28

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Org. Synth. 2012, 89, 323-333 333

Alessandro Dondoni was born and grew up in Ostiglia, Italy.

He received a degree (laurea) in industrial chemistry from the

University of Bologna in 1960. After postdoctoral studies at the

IIT in Chicago with Sidney I. Miller, he returned to the

University of Bologna in 1963 where he began his independent

scientific career. In 1973 he joined the University of Ferrara

and was named Professor of organic chemistry in 1975. He

retired in 2008 and at present (2012) is Senior Research

Scientist in the same University. At the beginning of his career

he was involved in studies of the kinetics and mechanism of

1,3-dipolar cycloaddition reactions and physicochemical

properties of sulfur compounds, while more recently he has

focused on the development of new synthetic methods for

heterocyclic and carbohydrate chemistry.

Alberto Marra graduated in Pharmaceutical Sciences from the

University of Pisa (Italy) and obtained his Ph.D. degree in

Organic Chemistry from the University Paris VI (France) under

the supervision of Prof. P. Sinaÿ. After a postdoctoral

fellowship at the University of Zurich (Switzerland) with Prof.

A. Vasella, he was appointed to a lectureship in Organic

Chemistry at the University of Ferrara, where he joined the

group of Prof. A. Dondoni. In 1998 he was promoted to the

position of Associate Professor at the same university. He was

Visiting Professor at the Université de Picardie (2008) and the

Université de Cergy-Pontoise (2010).