1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

Abstract

This review covers the synthetic applications of 1,4-dithianes, as well as derivatives thereof at various oxidation states. The selected examples show how the specific heterocyclic reactivity can be harnessed for the controlled synthesis of carbon-carbon bonds. The reactivity is compared to and put into context with more common synthetic building blocks, such as 1,3-dithianes and (hetero)aromatic building blocks. 1,4-Dithianes have as yet not been investigated to the same extent as their well-known 1,3-dithiane counterparts, but they do offer attractive transformations that can find good use in the assembly of a wide array of complex molecular architectures, ranging from lipids and carbohydrates to various carbocyclic scaffolds. This versatility arises from the possibility to chemoselectively cleave or reduce the sulfur-heterocycle to reveal a versatile C2-synthon.

Keywords: 1,4-dithianes; 1,4-dithiins; 2,3-dihydro-1,4-dithiins; heterocycles; target synthesis.

Scheme 1

1,3-Dithianes as useful synthetic building blocks: a) general synthetic utility (in Corey–Seebach-type reactions) [–6] and b) recent applications in the total synthesis of complex target products (original attachment place of 1,3-dithiane ‘scaffolding’ groups shown with dashed purple lines) [–11].

Scheme 2

Metalation of other saturated heterocycles is often problematic due to β-elimination [–17].

Scheme 3

Thianes as synthetic building blocks in the construction of complex molecules [18].

Figure 1

a) 1,4-Dithiane-type building blocks that can serve as C2-synthons and b) examples of complex target structures that have been prepared using 1,4-dithiane-type building blocks (see review, original attachment place of 1,4-dithiane ‘scaffolding’ groups shown with dashed purple lines), for references, see text of following chapters.

Scheme 4

Synthetic availability of 1,4-dithiane-type building blocks.

Scheme 5

Dithiins and dihydrodithiins as pseudoaryl groups [–39].

Scheme 6

Metalation of other saturated heterocycles is often problematic due to β-elimination [–42].

Figure 2

Reactive conformations leading to β-fragmentation for lithiated 1,4-dithianes and 1,4-dithiin.

Scheme 7

Mild metalation of 1,4-dithiins affords stable heteroaryl-magnesium and heteroaryl-zinc-like reagents that can be used in coupling reactions at higher temperatures [–44].

Scheme 8

Dithiin-based dienophiles and their use in synthesis [,–54].

Scheme 9

Dithiin-based dienes and their use in synthesis [–57].

Scheme 10

Stereoselective 5,6-dihydro-1,4-dithiin-based synthesis of cis-olefins [42,58].

Scheme 11

Addition to aldehydes and applications in stereoselective synthesis.

Figure 3

Applications in the total synthesis of complex target products with original attachment place of 1,4-dithiane ‘scaffolding’ groups shown with dashed purple lines, references indicated with structures.

Scheme 12

Direct C–H functionalization methods for 1,4-dithianes [–83].

Scheme 13

Known cycloaddition reactivity modes of allyl cations [–100].

Scheme 14

Cycloadditions of 1,4-dithiane-fused allyl cations derived from dihydrodithiin-methanol 90 [–107].

Scheme 15

Dearomative [3 + 2] cycloadditions of unprotected indoles with 1,4-dithiane-fused allyl alcohol 90 [30].

Scheme 16

Comparison of reactivity of dithiin-fused allyl alcohols and similar non-cyclic sulfur-substituted allyl alcohols.

Scheme 17

Applications of dihydrodithiins in the rapid assembly of polycyclic terpenoid scaffolds [–109].

Scheme 18

Dihydrodithiin-mediated allyl cation and vinyl carbene cycloadditions via a gold(I)-catalyzed 1,2-sulfur-migration.

Scheme 19

Activation mode of ethynyldithiolanes towards gold-coordinated 1,4-dithiane-fused allyl cation and vinyl carbenoid reagents.

Scheme 20

Desulfurization problems.

Scheme 21

oxidative decoration strategies for 1,4-dithiane scaffolds.