A multigram synthesis of the C29-C51 subunit of altohyrtin C (spongistatin 2) has been accomplished. Union of this intermediate with the C1-C28 fragment and further elaboration furnished the natural product. Completion of the C29-C51 subunit began with the aldol coupling of the boron enolate derived from methyl ketone 8 and aldehyde 9. Acid-catalyzed deprotection/cyclization of the resulting diastereomeric mixture of addition products was conducted in a single operation to afford the E-ring of altohyrtin C. The diastereomer obtained through cyclization of the unwanted aldol product was subjected to an oxidation/reduction sequence to rectify the C35 stereocenter. The C45-C48 segment of the eventual triene side chain was introduced by addition of a functionalized Grignard reagent derived from (R)-glycidol to a C44 alclehyde. Palladium-mediated deoxygenation of the resulting allylic alcohol was followed by adjustment of protecting groups to provide reactivity suitable for the later stages of the synthesis. The diene functionality comprising the remainder of the C44-C51 side chain was constructed by addition of an allylzinc reagent to the unmasked C48 aldehyde and subsequent dehydration of the resulting alcohol. Completion of the synthesis of the C29-C51 subunit was achieved through conversion of the protected C29 alcohol into a primary iodide. The synthesis of the C29-C51 iodide required 44 steps with a longest linear sequence of 33 steps. From commercially available tri-O-acetyl-D-glucal, the overall yield was 6.8%, and 2 g of the iodide was prepared. The C29-C51 primary iodide was amenable to phosphonium salt formation, and the ensuing Wittig coupling with a C1-C28 intermediate provided a fully functionalized, protected seco-acid. Selective deprotection of the required silicon groups afforded an intermediate appropriate for macrolactonization, and, finally, global deprotection furnished altohyrtin C (spongistatin 2). This synthetic approach required 113 steps with a longest linear sequence of 37 steps starting from either tri-O-Lacetyl-D-glucal or (S)-malic acid.