Interactivity box illustrating the mechanism in Figure 2

  1. The initial step involves attack by the phosphorus on either of the two sulfur atoms of ETP 7; sulfur β via TS1 or sulfur α via TS1 (iso). The former (TS1) has a calculated barrier ΔG298 of 19.6 relative to 7 while the later (TS1 (iso)) has a higher barrier of 27.7 kcal/mol because of hindrance from the methyl groups; only the former corresponds to a viable room temperature reaction. The products of this initial step are Int1 or Int1(iso) and are respectively 14.6 and 16.1 kcal/mol higher in free energy than 7.
  2. The second step via (TS2) (or TS2 (iso)) corresponds to elimination of triphenylphosphine sulfide from Int1 to create the zwitterionic intermediate Int2. The barrier for elimination of Ph3S from Int1 is very small; ΔG298 2.2 (TS2) or 4.8 (TS2 (iso)) relative to Int1 or 16.7 (TS2) or 21.0 (TS2 (iso)) kcal/mol relative to 7. These energies are lower than those for TS1 and hence this second step is not rate determining. Int2 itself is computed 4.5 kcal/mol lower than Int1 and Int2(iso) is 3.4 kcal/mol lower than Int1(iso). This regiochemical outcome is consistent with the experimental work of Ottenheijm et al through trapping of a key intermediate Int2 with a methanol nucleophile.


  1. The mechanism now bifurcates into two pathways involving either retention of configuration or racemisation. The retentive pathways involve re-closure of the zwitterion to reform the sulfur bridge, with barriers of 10.6 (TS3) or 15.3 (TS3 (iso)). Once again, these are significantly lower in energy than TS1. This suggests that for product retention, attack by triphenylphosphine (TS1) is rate determining, with the remainder of the pathway being energetically downhill.
  2. We identified a number of higher energy fates for Int2/Int2(iso). TS4 corresponds to an elimination to form a C=S double bond, with N-C bond migration to give Int3. This can undergo further ring opening to give an intermediate Int4 that can in principle atropisomerise. Such a process would result in racemisation of the original carbon stereogenic centres. Alternatively, TS4(iso) corresponds to formation of a C=S double bond with diketopiperazine ring opening. Bond rotation and ring closure would also result in racemization of the original carbon stereogenic centres in Int3(iso). The barriers to these racemization processes are 35.3 (TS4) or 30.9 (TS4(iso)) kcal/mol, significantly higher than the rate limiting step on the pathway to retention of configuration.
  3. The energy profiles of these reaction sequences strongly suggest that desulfurization of ETP 7 occurs with retention of configuration rather than racemization. It is difficult to envisage a mechanistic pathway (not involving entropically disfavoured intervention of other molecules such as solvent) that could result in highly stereospecific inversion of both stereogenic centres, as claimed by Ottenheijm and co-workers.

Click on the links above to load the geometry and animation of the transition state normal mode. Right-click in the display are to select specific normal vibrational modes. Full details on any calculation can be obtained from a digital repository by following the resolvers: TS1 10042/to-13699, TS1 (iso) 10042/to-13247, Int1 10042/24695, Int1(iso) 10042/24698, TS2 10042/to-13795, TS2 (iso) 10042/to-13603, Int2 10042/to-13896, Int2(iso) 10042/24702, TS3 10042/to-13894, TS3 (iso) 10042/to-13568, Int3 10042/to-13902, Int3(iso) 10042/to-13909, TS4 10042/to-13570, TS4 (iso) 10042/to-13893.