Tetrahedron Letters
Short asymmetric syntheses of sphinganine [(2S,3R)-2-
aminooctadecane-1,3-diol] and its C(2)-epimer
⇑
Solange Da Silva Pinto, Stephen G. Davies , Ai M. Fletcher, Sophie K. Newton, Paul M. Roberts,
James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A short asymmetric synthesis of sphinganine [(2S,3R)-2-aminooctadecane-1,3-diol] and its C(2)-epimer is
reported. The synthesis of sphinganine employs diastereoselective aminohydroxylation of tert-butyl 2-
Received 2 October 2020
Revised 30 November 2020
Accepted 4 December 2020
Available online 29 December 2020
octadecenoate [conjugate addition of lithium (S)-N-benzyl-N-(
late oxidation with (+)-camphorsulfonyloxaziridine (CSO)] and a stereospecific rearrangement of the
resultant anti- -hydroxy-b-amino ester into the corresponding anti- -amino-b-hydroxy ester. Final
a-methylbenzyl)amide, then in situ eno-
a
a
hydrogenolysis and ester reduction completes the synthesis of the sphingoid base target. The synthesis
of the C(2)-epimer follows a similar route, incorporating a diastereoselective reduction protocol to trans-
Dedicated to Professor Stephen F. Martin in
recognition of his significant contributions
to organic chemistry.
form the anti-
a-hydroxy-b-amino ester into its syn-
a
-hydroxy-b-amino ester counterpart.
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Sphinganine
Safingol
2-Aminooctadecane-1,3-diol
Conjugate addition
Sphinganine—(2S,3R)-2-aminooctadecane-1,3-diol (Fig. 1)—is
one of the three main sphingoid bases that form the backbones
of the sphingolipids, which are essential components of eukaryotic
cells [1]. Sphingoid bases and their derivatives have been shown to
elicit growth inhibition and provoke apoptosis in a number of
tumor cells [1,2], and for example the non-natural, C(3)-epimer
of sphinganine—safingol, or (2S,3S)-2-aminooctadecane-1,3-diol
(Fig. 1)—was evaluated in a Phase I clinical trial, in combination
with cisplatin, for the treatment of advanced solid tumors [3].
The culmination of the interest in these compounds renders meth-
ods for their production of continued interest to the research com-
munity [4,5], and of particular interest are those methods which
have the potential to enable the synthesis of all of the possible
stereoisomers of 2-aminooctadecane-1,3-diol [6]. Herein we report
a short and concise asymmetric synthesis of sphinganine and its C
(2)-epimer reliant on the diastereoselective aminohydroxylation of
tert-butyl 2-octadecenoate with enantiopure lithium (S)-N-benzyl-
ization of the
elective reduction reaction sequence. The stereospecific conversion
of these epimeric -hydroxy-b-amino esters to their -amino-b-
hydroxy ester counterparts is then followed by ester reduction
and hydrogenolysis to give the targets. The ready availability of
N-benzyl-N-(a-methylbenzyl)amine in either enantiomerically
pure form renders this approach equally applicable to the prepara-
tion of the remaining two stereoisomeric forms.
a-stereocentre through an oxidation and diastereos-
a
a
The requisite epimeric
substrates for the proposed stereospecific rearrangement to the
corresponding epimeric -amino-b-hydroxy esters, were prepared
using established methodology [7–11]. ,b-Unsaturated tert-butyl
a-hydroxy-b-amino esters 2 and 4, the
a
a
ester 1 was prepared in 71% yield from hexadecanal, via a modified
Wadsworth-Emmons olefination [7]. Diastereoselective aminohy-
droxylation of 1 was achieved upon conjugate addition of lithium
(S)-N-benzyl-N-(
oxidation with (+)-camphorsulfonyloxaziridine (CSO) [8], which
gave anti- -hydroxy-b-amino ester 2 in 64% yield as a single com-
pound (>95:5 dr). The absolute (2S,3S, S)-configuration of 2 was
confidently assigned by reference to the well-established outcome
of this aminohydroxylation procedure when applied to achiral ,b-
a-methylbenzyl)amide followed by in situ enolate
N-(
camphorsulfonyloxaziridine (CSO). The anti-
ester product of this reaction can be readily transformed into the
a-methylbenzyl)amide in conjunction with the oxidant (+)-
a
a-hydroxy-b-amino
a
corresponding syn-
a-hydroxy-b-amino ester by effecting epimer-
a
unsaturated esters [8]. Oxidation of 2 under Swern conditions gave
complete conversion to ketone 3, which was reduced diastereose-
lectively using NaBH4 in MeOH at À20 °C [9,11] to give
⇑
Corresponding author.
syn-a-hydroxy-b-amino ester 4 in 96:4 dr [12], and upon
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.