discussion addendum for: diastereoselective homologation ... · discussion addendum for:...
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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).