Our retrosynthetic strategy for the southern portion of azaspiracid disconnected FGHI ring system 6 at the C34−35 linkage to yield aldehyde 7 and allyl silane 8 (Scheme 1). To establish the correct stereochemistry at C34, this key coupling would need to proceed via a Cram-chelated intermediate with aldehyde 7. The allyl silane portion would be available from the known Myers alkylation product 9.[5] The aldehyde 7 should be accessible from the Andrus aldol adduct 10, which in turn could be constructed from the sultam 11 and the chloride 12.

The synthesis of the allyl silane 8 is shown in Scheme 2. The Myers alkylation adduct 9 was prepared in four steps from the commercially available oxazolidinone 13.[5] Treatment of 9 with methyllithium yielded the methyl ketone 14. Next, conversion of 14 into the enol triflate followed by palladium-catalyzed coupling gave the allyl silane 15. Removal of the benzyl ether was accomplished by using sodium naphthalenide. Finally, Mitsunobu reaction gave the phthalimide 8.

Synthesis of the aldehyde fragment 7[6] was accomplished in eight steps (Scheme 3). After monobenzylation of the commercially available dichloride 16, cuprate addition to the known sultam 11, under similar conditions described by Paquette and Boulet,[7] led to generation of the stereocenter at C30 with excellent diastereoselectivity (d.r. > 20:1). Direct reduction of the product to the aldehyde 18 followed by boron-mediated aldol reaction with the Andrus dioxanone (19)[8] resulted in the adduct 10 again with excellent selectivity (d.r. > 10:1). Ring opening of the lactone 10 to its methyl ester 20 followed by CAN oxidative cleavage provided the diol 21. The key [3.2.1] bicyclic ketal moiety could be constructed through ozonolysis of 21 with DMS workup, which induced spontaneous C28-ketal formation. This ketalization process could be driven to completion by the addition of Amberlyst-15. Finally, reduction with DIBAL-H proceeded cleanly to give the aldehyde 7. The stereochemistry of aldehyde 7 was conclusively established through X-ray crystal structure assignment of the 2,4-dinitrohydrazone derivative 22.[9]

With the two major subunits in hand, we shifted our focus to their combination (Scheme 4). Treatment of a precooled solution of aldehyde 7 with Lewis acids (TiCl₄ or SnCl₄) followed by the addition of allyl silane 8 provided the coupled material as a single diastereomer at C34. We had hypothesized that chelating Lewis acids such as titanium or tin would proceed via the intermediate 23 to give the desired stereo-chemical outcome (24). We were surprised to find, upon conversion of the intermediate into its Mosher ester 27,[10] that the C34 stereochemistry was in fact that of the undesired isomer. Further support for this assignment can be found in the fact that treatment of 7 with BF₃·Et₂O (a Lewis acid incapable of proceeding via intermediate 23) also gave alcohol 26, again as a single diastereomer. Despite our considerable efforts, we were unable to devise a viable route to invert the stereochemistry at C34.

It would appear from our efforts that the encumbered nature of alcohol 26 made it impossible to properly install the C34 stereogenic center. On the basis of this setback, we chose to revise our approach (Scheme 5). Starting from the known PMB-protected ester 28,[11] DIBAL-H reduction, iodination, and Myers alkylation gave 30. Conversion of 30 into the methyl ketone followed by DDQ deprotection and two-step azide incorporation gave 32.

For the aldehyde component 34, selective protection at C32 was required. Triisopropylsilylation of aldol adduct 10 did yield the corresponding silyl ether; however, methanolysis of the lactone proved unsuccessful. Fortunately, treatment of 20 with TIPSOTf and 2,6-lutidine at low temperature gave selectively the C32-OTIPS product 33. None of the corresponding benzyl OTIPS ether was observed. Finally, deprotection with CAN, protection with TMS, and reduction produced the aldehyde 34.

Next, our efforts returned to the combination of the subunits 32 and 34 (Scheme 6). Aldol reaction of ketone 32 and aldehyde 34 gave the coupled adduct 35 in excellent yield as a single diastereomer. On the basis of precedent from us and others,[2e,3e,g] we suspected that the C34 stereochemistry was once again incorrect. Fortunately, after removal of the TMS group at C33 and mixed ketal formation at C36, we were able to cleanly invert the C34 stereochemistry using Martin's modified Mitsunobu conditions.[12] Staudinger reduction of the azide followed by Teoc protection and cyclization[2e] using Yb(OTf)₃ gave the HI ring system in 38. The desired stereochemistry at C34 was confirmed through modified Mosher ester analysis.[10] Treatment of 38 with TBAF in THF induced selective removal of the TIPS (C32) and PNB (C34) protecting groups in the presence of the Teoc moiety. With only alkene cleavage at C28 and [3.3.1] bicyclic ketal formation remaining, we believed that the completion of the FGHI ring system was within reach. We were surprised to find that despite considerable experimentation, we consistently observed degradation of the material during ozonolysis. Small amounts of a minor product could be isolated for which the spectral data was supportive of furan structure 42, which presumably formed via the enol ether intermediate 41.

Thwarted by the unexpected furan formation, we reexamined the ordering of cyclization events (Scheme 7). Starting from the C34 inversion product 37, C28 alkene dihydroxylation and cleavage yielded the ketone 43. Removal of the TIPS ether at C32 as well as the p-nitrobenzoate group at C34 with TBAF yielded the diol 44. While non-alcoholic solvents proved problematic in the formation of the [3.3.1] bicyclic structure, use of methanol as a solvent cleanly led to formation of the desired FGH ring system of 45. The use of a hydrogen-bonding solvent moderates the acidity of the system, thereby preventing formation of the destructive C35−36 enol ether. Finally, azide reduction and Teoc protection provided compound 46.

With the FGH rings now in place, the final challenge remaining was the formation of the azaspiro HI ring system (Scheme 8). Initial attempts to form C36 azaspiroketal using acidic media (e.g. CSA, MeOH) led to extensive decomposition. Interestingly, treatment of 46 with Yb(OTf)₃[2e,3e,g,p] in PhMe led to rapid formation (30 min, room temperature) of a single new product 47. Careful analysis by 2D NMR spectroscopy revealed that 47 possessed the undesired stereochemistry at C36. Use of extended reaction times led to formation of a second compound, compound 6; however, decomposition was a competitive pathway under these conditions. Fortunately, use of an alternate solvent (THF) at room temperature led to the desired C36 spiroaminal 6 as the major product (74% yield, 6/47 4:3 ratio). The minor product 47 could be recycled by resubmission to identical reaction conditions to generate the same thermodynamic 4:3 ratio. As we have previously demonstrated in our synthesis of the C1–C26 northern portion of azaspiracid-1 (1),[1h] we are able to control the stereochemical outcome during ketalization through the proper choice of conditions. We did find the formation of the unwanted spiroaminal 47 as the kinetic product to be surprising, as the anomerically stabilized axial orientation is typically kinetically favored as a result of a presumed lower transition-state energy. We attribute this unusual behavior to a severe steric interaction between the NTeoc group and the fused GH ring system.