Synthetic process for preparation of macrocyclic C1-keto analogs of Halichondrin B and intermediates useful therein including intermediates containing-SO2-(p-tolyl) groups

The compound of formula 1:

• wherein
• R1 and R2 each independently is H, a silyl group, an acyl group, a sulfonyl group or an alkoxycarbonyl group;
• or one of R1 and R2 is absent and the other R1 or R2 together with the nitrogen atom to which it is attached form an azide;
• R3 is H or an alcohol protecting group;
• or
• R3 and one of R1 and R2 together form —C(═O)—, —C(═O)—C(═O)— or —C(R14)(R15)—, wherein R14 and R15 each independently is H or a hydrocarbon, the hydrocarbon optionally having one or more heteroatoms;
• R4 is H, C1-3 alkyl or C1-3 haloalkyl or an alcohol protecting group;
• R5 is —SO2(p-tolyl), wherein p-tolyl is —(C6H4)—CH3, with the —CH3 at the para-position;
• R6 is OR16, wherein R16 is H or an alcohol protecting group;
• R7 and R7′ together form a ═O or a protected geminal diol, or one of R7 and R7′ is H and the other is a leaving group or a functional group that can be converted into a leaving group;
• or
• R6 and one of R7 and R7′ together form —O—, and the other R7 or R7′ is H;
• R8 is —C(═O)R17 or —CH2OR18, wherein
• R17 is H or OR19, wherein R19 is H or a hydrocarbon, the hydrocarbon optionally having one or more heteroatoms;
• R18 is H or an alcohol protecting group;
• R9 is a halide or a sulfonate;
• or
• R8 and R9 together form —C(═O)— or —CH(OR20)—, wherein R20 is H or an alcohol protecting group;
• R10, R11 and R12 each independently is H or an alcohol protecting group;
• is a single or double bond;
• and
• R13 is ═O or —OR21, wherein R21 is H or an alcohol protecting group.