A convenient new route to enantiopure 3-hydroxy-5-oxo esters and 5,6-dihydropyran-2-ones: intricacies of the trithioorthoester protecting group

Article abstract of DOI:10.1016/j.tetlet.2009.12.058

3-Hydroxy-5-oxo esters are useful precursors to biologically active compounds. An expedient three-step synthesis of 3-hydroxy-5-oxo esters based on dithiane anion chemistry is presented along with the transformation of the 3-hydroxy-5-oxo esters into 5,6-dihydropyran-2-ones.

Full text of DOI:10.1016/j.tetlet.2009.12.058

Tetrahedron Letters 51 (2010) 1158–1160
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Tetrahedron Letters
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A convenient new route to enantiopure 3-hydroxy-5-oxo esters
and 5,6-dihydropyran-2-ones: intricacies of the trithioorthoester
protecting group
*
Rebecca L. Grange, Craig M. Williams
School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, 4072 Queensland, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Hydroxy-5-oxo esters are useful precursors to biologically active compounds. An expedient three-step
synthesis of 3-hydroxy-5-oxo esters based on dithiane anion chemistry is presented along with the trans-
formation of the 3-hydroxy-5-oxo esters into 5,6-dihydropyran-2-ones.
Received 15 October 2009
Revised 3 December 2009
Accepted 11 December 2009
Available online 16 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
O
Enantiopure 3-hydroxy-5-oxo esters 1 are key intermediates for
active pharmaceuticals such as HMG-CoA reductase inhibitors
[statins, e.g., Mevastatin (2)1], which are a top-selling family of
cholesterol-lowering drugs.2 Furthermore, enantiopure esters 1
are potential precursors to the 5,6-dihydropyran-2-one motif that
appears in numerous biologically active natural products [e.g., (+)-
passifloricin A (3)] (Fig. 1).3
HO
O
O
O
O
O
OH
O
O
OH
OH
H
*
1
R
OR'
During the course of our own work, we required an enantiopure
3-hydroxy-5-oxo ester motif. We were surprised when a compre-
hensive literature search revealed that firstly, only a limited num-
ber of methods for accessing this popular moiety in enantiopure
form exist, and secondly, these methods are not overly attractive.
Contrary to our expectations for a seemingly simple motif, many
existing protocols seem to be quite lengthy. For example, a com-
mon4 non-enzymatic approach to HMG-CoA reductase inhibitors
involves a Wittig, or a Horner–Wadsworth–Emmons reaction in
addition to at least three steps to synthesise the ylide 4 or phos-
phonate ester 5 (Fig. 2).5 Other methods for preparing enantiopure
3-hydroxy-5-oxo esters rely on enzymes to introduce chirality at
C3.6 Blandin7 accessed a 3-hydroxy-5-oxo ester through asymmet-
ric hydrogenation of a 3,5-dioxo ester, and although this method-
ology is highly promising, the maximum ee achieved to date is
75%. Moreover, autoclave equipment, which is not always available
in a synthetic organic chemistry laboratory, was required to gener-
ate this result. Accordingly, new methods to assemble rapidly
enantiopure 3-hydroxy-5-oxo esters 1 using standard techniques,
and readily available enantiopure starting materials, could be of
some benefit.
HO
2
C14H29
3
Figure 1.
O
OTBS
O
O
OTBS
Ph3P
CO2Me
(MeO)2P
CO2Me
*
*
4
5
Figure 2.
relay chemistry11) that we,12 and others13 have utilised in the syn-
thesis of complex natural products. Hence, we wondered whether
this powerful methodology could be further extended to encom-
pass enantiopure 3-hydroxy-5-oxo esters 1. This Letter describes
the successful extension of such chemistry to this goal.
More specifically, we envisaged a concise synthesis, featuring
the reaction of a dithiane anion with an epoxide linked to the
tris(methylthio) masked ester group14 which culminates in a glo-
bal deprotection step. The chemistry was initially developed using
racemic epichlorohydrin but enantiopure epichlorohydrin was
used in the later work. Both (S)- and (R)-epichlorohydrin are
commercially available. The key epoxy trithioorthoester 6 was
prepared in good yield by reacting epichlorohydrin (7) with
The ring opening of epoxides by dithiane anions, followed by
thioketal deprotection, is a well known strategy for constructing
enantiopure b-hydroxy ketones.8 This transformation forms the
cornerstone of the Tietze9–Smith10 linchpin reaction (i.e., anion
* Corresponding author. Tel.: +61 7 33653530; fax: +61 7 33654299.
E-mail address: c.williams3@uq.edu.au (C.M. Williams).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.058

R. L. Grange, C. M. Williams / Tetrahedron Letters 51 (2010) 1158–1160
1159
S
S
O
i) nBuLi
SMe
Cl
ii)
TMS
i) nBuLi
O
SMe
Li
MeS
MeS
7
10
ii)
SMe
MeS
43%
70%
53%
O
SMe
6
MeS
iii) HMPA
iv) nBuI
8
i) nBuLi
SMe
6
ii)
iii) HMPA
SMe
O
MeS
MeS
OR
S
SMe
MeS
MeS
OTMS S
6
S
S
MeS
S
S
nBu
SMe
Bun
13a R = H
13b R = TMS
SMe
H
11
9
THF
MeOH
H2O
Hg(ClO4)2
CaCO3
i) tBuLi,
HMPA
ii) nBuI
47%
O
OH
O
MeO
Bun
14
MeS
MeS
OTMS S
MeOBEt2
NaBH4
THF
MeOH
S
Bun
H
12
O
O
OH OH
O
p-TsOH
nBu
MeO
Bun
toluene
reflux
30% (3 steps)
16
15
Scheme 1.
tris(methylthio)methyllithium (8) (Scheme 1).15,16 Epoxide 6 failed
to react with the anion of 2-butyl-1,3-dithiane (9) but did engage
with the lithio derivative of TMS-dithiane 10 to afford, after Brook
rearrangement, adduct 11. When compound 11 was treated with
tBuLi and nBuI, lithium–sulfur exchange rather than dithiane
deprotonation occurred, affording the masked ketoaldehyde 12 in-
stead of the desired 3-hydroxy-5-oxo ester precursor 13b. Lith-
ium–sulfur exchange is well precedented,17 but to the best of our
knowledge, this is the first example of lithium–sulfur exchange
in a molecule bearing an acidic dithiane proton.
i) nBuLi
ii)
SMe
O
MeS
SMe
MeS
MeS
OH
S
6
S
S
52%
S
SMe
Ph
Ph
18
17
i) Hg(ClO4)2, CaCO3
ii) MeOBEt2, NaBH4
iii) p-TsOH
38%
(3 steps)
The problem of competition between lithium–sulfur exchange
and dithiane deprotonation was ultimately solved using Smith’s
three-component linchpin protocol18 and compound 13b was ac-
cessed from TMS-dithiane 10, epoxide 6 and 1-iodobutane, in
one step, in 53% yield (Scheme 1). Simultaneous removal of all
three protecting groups with HgCl2/HgO15a afforded the target 3-
hydroxy-5-oxo ester 14 in 49% yield. Global deprotection could
also be realised with Hg(ClO4)2.19 To demonstrate the utility of this
dithiane-based approach to 3-hydroxy-5-oxo esters, compound 14
was further elaborated to the 5,6-dihydropyran-2-one 15. Syn
selective reduction20 of 14 furnished diol 16 and treatment with
catalytic p-TsOH effected lactonisation and dehydration to give lac-
tone 15 in 30% yield from dithiane 13b (Scheme 1).21
O
O
Ph
19
Scheme 2.
many previously reported non-enzymatic methods. In addition,
competition between trithioorthoester lithium–sulfur exchange
and dithiane anion generation has been revealed for the first time.
Acknowledgement
Attention turned to making the methodology applicable to 5-
aryl-3-hydroxy-5-oxo esters. Pleasingly, the anion of 2-phenyl-
1,3-dithiane (17) opened epoxide 6 to provide alcohol 18 in mod-
erate yield (Scheme 2), albeit unoptimised. Alcohol 18 was
smoothly converted into lactone 19 in the same manner as de-
scribed for the n-butyl derivative (i.e., 15). Lactone 19 was obtained
in good overall yield (38% over three steps)22 and in 94% ee23 (the
commercially available (R)-epichlorohydrin used had an ee of 98%
and 98% is a typical de20 for a diethylmethoxyborane-mediated
reduction).
The University of Queensland is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.058.
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1160
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