A convergent approach for the synthesis of fluorinated sphingosine analogues

Abstract

An improved route to a fluorinated analogue of sphingosine has been developed starting from Garner's aldehyde with two cross-metathesis couplings and an electrophilic fluorodesilylation as the key steps. This approach eliminates the problem of double bond transposition encountered with strategies relying on the nucleophilic fluorinating reagent DAST and supplies the target compound as well as a fluorinated intermediate amenable to functional variations at three sites.

Synthesis of Enantiomerically Enriched Amino Sulfide Building Blocks from Acyclic Chiral Amino Allylsilanes

“…As far as amino allylsilanes are concerned, we have shown that they can react smoothly with electrophiles such as 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor) to give structurally diverse fluorinated amines in high yield but in a roughly 1:1 diastereomeric mixture (Scheme ). This was in agreement with previous findings, as electrophilic fluorodesilylation of chiral acyclic allylsilanes has been reported as a high-yielding process, albeit with a poor level of diastereocontrol. , Likewise, we deemed that β-sulfenyl amines could be obtained by electrophilic sulfodesilylation of allylsilanes, and to prove this, the reactivity of phthalimidesulfenyl chloride with our substrates was tested.…”

“…This was in agreement with previous findings, as electrophilic fluorodesilylation of chiral acyclic allylsilanes has been reported as a high-yielding process, albeit with a poor level of diastereocontrol. 32,33 Likewise, we deemed that β-sulfenyl amines could be obtained by electrophilic sulfodesilylation of allylsilanes, and to prove this, the reactivity of phthalimidesulfenyl chloride with our substrates was tested.…”

Diastereodivergent Hydroxyfluorination of Cyclic and Acyclic Allylic Amines: Synthesis of 4-Deoxy-4-fluorophytosphingosines

“…Around 30–40% of agrochemicals and 20% of pharmaceuticals on the market in 2006 contained at least one fluorine atom, as did 10 of the leading 30 blockbuster drugs by sale in the USA in 2008 . Although much attention has been lavished on the beneficial effects that fluorine can confer on rationally designed molecules, there has also been considerable activity in the preparation and biological evaluation of fluorinated analogues of naturally occurring amino compounds, including α- and β-amino acids, aminosugars, iminosugars, amino- and diaminocyclitols, and sphingoid bases and ceramides . To meet the ever-increasing demand for stereodefined, fluorinated organic compounds, a number of nucleophilic and electrophilic fluorination methods have been developed, including asymmetric protocols .…”

Generating Stereodiversity: Diastereoselective Fluorination and Highly Diastereoselective Epimerization of α-Amino Acid Building Blocks

“…Deoxofluorination with DAST α to the stereogenic center of a 2,2-dimethyloxazolidine moiety has been reported, but only one diastereoisomer could be synthesized via this route . Alternatively, a 1:1 diastereoisomeric mixture of fluorinated product was synthesized by desilylation–fluorination of an allylsilane derivative …”

“…8 Alternatively, a 1:1 diastereoisomeric mixture of fluorinated product was synthesized by desilylation−fluorination of an allylsilane derivative. 9 We initially focused on a 1,3-benzothiazol-2-yl sulfone, N-Boc-protected (R)-4-((benzo [d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyloxazolidine. Synthesis commenced from either (R)-Garner aldehyde or from D-serine (Scheme 1, also see the Supporting Information (SI)), to give the common intermediate (S)-4-(hydroxymethyl)-2,2-dimethyloxazolidine.…”