Tetrahedron Letters
A new and versatile synthesis of 3-substituted oxetan-3-yl methyl
alcohols
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Scott Boyd , Christopher D. Davies
AstraZeneca R&D, Oncology IMED, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a novel route for the efficient synthesis of pharmaceutically significant 3-substituted
oxetan-3-yl methyl alcohols starting from readily available malonates. The synthesis harnesses the diver-
sity of malonate chemistry and allows access to a range of oxetanes, which exemplifies the versatility of
this procedure.
Received 1 April 2014
Revised 19 May 2014
Accepted 5 June 2014
Available online 12 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Oxetane
Malonate
Cyclisation
Drug discovery
Medicinal chemistry
Oxetanes are important functional groups for drug discovery1–3
and since Carreira’s pioneering work in 2006,2 and subsequent
publications,3 interest in oxetanes has been revitalised. Their judi-
cious incorporation into a molecule allows the medicinal chemist
the potential to improve metabolic stability whilst maintaining
or reducing lipophilicity.3 The ring oxygen can act as a hydrogen
bond acceptor which can lead to increase in potency.4 They have
been used as replacements for gem-dimethyl, isopropyl, carbonyl,
methylene and tert-butyl groups in drug development projects.3,5
Herein we disclose the preparation of two previously unreported
3-substituted oxetan-3-yl methyl alcohols, which were required
as part of a drug discovery project at AstraZeneca. The synthetic
route we have developed is flexible and versatile and has been
used to make an array of 3,3-disubstituted oxetanes.
The initial required intermediate was (3-methoxyoxetan-3-
yl)methanol (5). Its synthesis had not been previously reported,
therefore a new route was designed (Scheme 1) which used readily
available dimethyl 2-methoxymalonate (1) as a starting material.
The first step was the base-mediated reaction of this malonate with
formaldehyde to give the primary alcohol in 98% yield. This was
protected using TBDPSCl to give dimethyl 2-[(tert-butyldiphenylsi-
lyloxy)methyl]-2-methoxymalonate (2) in 84% yield. The silyl pro-
tecting group was selected to ease the handling and isolation
during subsequent steps. Reduction of the diester with lithium alu-
minium hydride was unsuccessful, however, reduction with lithium
SiPh2tBu
O
SiPh2tBu
O
O O
O
O
i, ii
iii
HO
OH
O
O
O
O
O
O
O
3
1
2
iv
O
O
v
O
O
O
OH
SiPh2tBu
5
4
Scheme 1. Reagents and conditions: (i) H2CO, NaHCO3, EtOH, H2O, 98%; (ii)
TBDPSCl, imidazole, DMF, 84%; (iii) LiBH4, THF, 80%; (iv) n-BuLi, TsCl, THF, then n-
BuLi, 70%; (v) TBAF, THF, 82%.
borohydride proceeded smoothly to give 2-{[tert-butyl(diphenyl)
silyl]oxymethyl}-2-methoxypropane-1,3-diol (3) in 80% yield.
Attempts to cyclise the diol to the desired oxetane failed when
NaH and mesyl chloride were used. However, deprotonation with
n-BuLi, treatment with tosyl chloride to give the mono tosylated
product and then a second deprotonation with n-BuLi resulted in
the intramolecular displacement of the tosyl group, via a 4-exo-tet
cyclisation, which gave the silyl protected oxetane 4 in 70% yield.6
Deprotection with TBAF gave the target oxetane 5 in 82% yield.
Further analogues were subsequently prepared. To achieve this
we synthesised a benzyl protected oxetane 11 (Scheme 2). Diazo
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Corresponding author. Tel.: +44 (0)1625516128.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.