[formula: see text] A mild and reliable one-pot protocol for the elaboration of sterically demanding carboxylic acids into alpha-diazoketones via acyl mesylates has been developed. Aside from delineating the reaction parameters which render this strategy quite general for hindered carboxylic acids, we have directly proven the existence of the fleeting acyl mesylate group as the reactive species in these reactions and shed light onto the differing mechanisms which are operative in the activation of hindered and simple carboxylic acids with methanesulfonyl chloride.

Efficient catalytic asymmetric prop-2-ynylation of achiral aldehydes with allenyltributylstannane promoted by a BINOL-Ti IV complex (10 mol%) is achieved with high enantioselectivity by the use of Et 2 BSPr i .

In the preceding communication [1] we described our findings from two unique strategies aimed at the total synthesis of the CP molecules 1 and 2. [2,3] The current retrosynthetic analysis (Scheme 1) is predicated on the basic strategic Scheme 1. Final retrosynthetic analysis of the CP molecules 1 and 2. TBS tert-butyldimethylsilyl, TES triethylsilyl.considerations and chemistry reported earlier from these laboratories. [1, 4,8] In addition, extensive model studies, whose disclosure will have to await the full account of this work, led us to conclude that a plan that targeted CP-263,114 (1) first would be most prudent. The virtues of such a scheme would include a decreased reliance on protecting group chemistry, greater stability and ease of handling intermediates with the pyran motif, [5] and a rare opportunity to attempt the rather daring challenge of converting the seemingly robust CP-263,114 (1) into its hydrated counterpart CP-225,917 (2). Indoline amide 14 was targeted as an ideal precursor for the CP molecules by virtue of its facile accessibility from 3[1] and because of the relative ease with which this special amide can be hydrolyzed in a two-step procedure. [6] Thus, sequential treatment of 3 with aqueous TFA/CH 2 Cl 2 to remove both silicon groups followed by exposure to CH 3 SO 3 H [2] in dry CHCl 3 led to pyranlactol 4 (Scheme 2; see Table 1 for selected physical data). A key observation was made during the selective oxidation of diol 4 to aldehyde 5. When diol 4 was oxidized with DMP [7] in CH 2 Cl 2 at ambient temperature the aldehyde lactol 5 was isolated as the major product along with significant quantities of lactone 6 (5:6 approximate ratio 2:1, 85 % combined yield). The fact that DMP was sufficient to effect this transformation, which was normally only possible using TEMPO, [1,8] indicated to us that not only was the lactolpyran behaving as a normal lactol but also that it would be plausible to employ the simple DMP protocol to reach the amide 14 (see below). Over the course of this work we have taken notice of the ability to fine-tune the reactivity of DMP by mere solvent alteration. Thus, the undesired, yet highly informative, lactonealdehyde 6 could essentially be eliminated (5:6 approximate ratio b 20:1, 90 % combined yield) by carrying out the oxidation in benzene at 25 8C.The lactol 5 was shielded from the ensuing homologation procedure (potential ring closure) by protection as the TBSether 7 (TBSOTf, 2,6-lutidine, 85 % yield). NaClO 2 oxidation of 7 proceeded smoothly to produce acid 8 in 90 % yield. The intimidating task of converting the sterically congested (neopentyl, concave face) carboxylic acid 8 into diazoketone 10 was easily accomplished via the acyl mesylate 9 (prepared in situ with MsCl/ Et 3 N at 0 8C) with excess CH 2 N 2 at 0 8C.[1] The diazoketone so obtained was immediately dissolved in DMF:H 2 O (2:1) and heated to 120 8C in the presence of excess Ag 2 O for one minute to generate the homologated acid 11 in 35 % overall yield from 8. Combining carboxylic acid 11 and i...