Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

Abstract

Esters of crotonic acid were brominated on a multigramme scale using a free radical procedure. A phase transfer catalysed fluorination transformed these species to the 4-fluorobut-2E-enoates reproducibly and at scale (48-53%, ca. 300 mmol). Asymmetric dihydroxylation reactions were then used to transform the butenoate, ultimately into all four diastereoisomers of a versatile fluorinated C4 building block at high enantiomeric-enrichment. The (DHQ)2AQN and (DHQD)2AQN ligands described by Sharpless were the most effective. The development and optimisation of a new and facile method for the determination of ee is also described; (19)F{(1)H} spectra recorded in d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers.

Keywords: asymmetric; dihydroxylation; ee determination; fluorination; fluorosugars; organo-fluorine.

Scheme 1

Key steps from the synthesis of 6-fluoro-D-olivose (6) from D-glucose (1).

Scheme 2

De novo asymmetric syntheses of 6-deoxy-6-fluorohexoses [13].

Scheme 3

Fluorobutenoate building block 14, and related species 16 and 19 from the literature [–16].

Scheme 4

Fluorobutenoate building blocks 25 and 26 prepared from crotonic acid.

Figure 1

Side product 27 isolated from attempted fluorination.

Figure 2

The ligand panel used in the asymmetric dihydroxylation studies. The bold oxygen shows the point of attachment; individual ligands are represented by combinations of components, for example (DHQD)₂ PHAL, present in AD-mix β.

Scheme 5

Typical AD procedure; see Table 1 for outcomes.

Scheme 6

Conversion of enantiomerically-enriched diols to dibenzoates for HPLC analysis.

Figure 3

Diisopropyl L-tartrate (30) used as a chiral modifier for NMR determination of ee.

Figure 4

Partial ¹⁹F{¹H} NMR spectra (376 MHz, L-(+)-DIPT/CDCl₃, 300 K) spectra of (a) racemate 28c, (b) diol 28b and (c) 28a under standard acquisition parameters revealing the partial enantiomer overlap.

Figure 5

Partial ¹⁹F{¹H} NMR (400 MHz, L-(+)-DIPT/CDCl₃, 300 K) spectra of 28b and 28a using optimised conditions: SW 40; AQ = 0.8; O1P −230; d1 = 5; 32 or 64 scans.

Scheme 7

Applying cyclic sulfate methodology to gain access to anti-diastereoisomers (transformations were developed from racemic diol 28c, but are shown for diol 28b only).

Scheme 8

Protecting and chain extending the educts of asymmetric dihydroxylation.