Multicomponent Couplings

Chemfiles Volume 6 Article 5

2-Silyl-1,3-dithianes

Dithianes are valuable tools in organic synthesis, particularly in their use as acyl anion equivalents in C–C bond construction (Scheme 26). Since their introduction over forty years ago in the pioneering work of Corey and Seebach,1 dithiane chemistry has matured substantially. Contemporary reactions have evolved to the extent that multicomponent couplings are possible, yielding advanced, optically active and heteroatom-rich intermediates. Much of the progress in this field can be attributed to the recent work of Amos B. Smith III (University of Pennsylvania) in the field of 2-silyl-1,3-dithiane multicomponent linchpin couplings for use in complex molecule synthesis.


Scheme 26.

For example, one-pot, three-component couplings have been performed using the combination of 2-TBS-1,3-dithiane and tandem alkylation by two unique epoxide electrophiles to give extraordinarily advanced synthetic intermediates (Scheme 27).2 Treatment of the metallated 2-silyl-1,3-dithianes with an epoxide generates an intermediate alkoxide anion. Addition of HMPA to the reaction results in a solvent-controlled Brook rearrangement, with simultaneous migration of the nucleophilic site back to the dithiane carbon. This species is then positioned to react with a second epoxide electrophile. Importantly, the final location of the silyl protecting group can be orchestrated simply by altering the order of epoxide additions. This methodology has been used in the syntheses of several complex natural product intermediates.3


Scheme 27.

The use of optically-active epichlorohydrin as the second electrophile results in the formation of a terminal epoxide by nucleophilic attack at the epoxide carbon followed by Sn2 displacement of chloride (Scheme 28). Vinyl epoxides have also been reported to be active electrophiles, with nucleophilic addition occurring at the vinyl terminus.4


Scheme 28.

Smith and co-workers used a modified methodology to prepare a C2-symmetric masked polyol fragment that could be converted to the Schreiber’s trisacetonide subtarget5 in the syntheses of mycoticins (Scheme 29).6 In this instance, a five-component linchpin coupling tactic was used that relied on the use of a bisepoxide for the second electrophile.


Scheme 29.

The total syntheses of the neotropical frog-derived alkaloids, (–)-indolizidine 223AB and alkaloid (–)-205B relied on the controlled addition of silylated dithiane nucleophiles to aziridines (Scheme 30).7


Scheme 30.

Finally, the Smith group has broadened the multicomponent linchpin coupling protocol to involve the concept of anion relay chemistry (ARC), in which a nucleophilic site is relayed between two distinct dithiane units (Scheme 31). A variety of masked 1,3,5-oxygenated systems were prepared in good yield using this methodology.8


Scheme 31.

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References

  1. Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. 1965, 4, 1075.
  2. (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925. (b) Smith, A. B., III et al. J. Am. Chem. Soc. 2003, 125, 14435.
  3. For an example, see: Smith, A. B., III et al. Org. Lett. 2002, 4, 783.
  4. Smith, A. B., III et al. Org. Lett. 2003, 5, 2751.
  5. Poss, C. S. et al. J. Am. Chem. Soc. 1993, 115, 3360
  6. Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001.
  7. (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2005, 7, 3247. (b) Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547.
  8. Smith, A. B., III; Xian, M. J. Am. Chem. Soc. 2006, 128, 66.

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