The polycyclic guanidine alkaloids (e.g., 17) are a large family of marine natural products that have proven to be popular synthetic targets (prior syntheses noted in parentheses) over the years due to their unusual structures and antiproliferative or antiviral activities.  We recently developed a robust and convergent strategy to access isolates containing a syn-tricyclic guanidine residue, as discussed below.

As illustrated below for the synthesis of (+)-batzelladine B (2), our synthetic planning called for preparation of the target from the vessel and anchor precursors 8 and 9, respectively.  The vessel fragment was envisioned to derive from nucleophilic ring-opening–rearrangement of a suitable tropanone precursor (e.g., 10).  The latter is readily-accessible by a formal [4+3] cycloaddition between the donor–acceptor carbenoid precursor 12 and the electron-deficient pyrrole 11 (Reddy and Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312), followed by electrophilic alkynylation.  The anchor fragment was prepared from the β-aminoacid 13, which was accessed via diastereoselective addition of the pyrrolyl acetate 15 to the sulfinimine 14.

We developed a robust two-step protocol to prepare the N-amidinyl pyrole 11 from 3-pyrroline (16).  Extensive optimization of the formal [4+3] cycloaddition ultimately led to identification of the pantalactonyl ester 12 as the optimal carbenoid precursor; using this component and dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate] as catalyst (0.5–1.0 mol%), the cycloadduct 17 was obtained in 87–91% yield as a single detectable diastereomer.  Following reduction of the pyrroline ring and electrophilic alkynylation, an aldol–retro-aldol–isomerization–aza-Michael cascade was developed to provide, after hydrogenolysis of the β-keto ester, the bicyclic guanidine 19 in 49% yield.  Saponification of the chiral auxiliary provided the vessel precursor 8 in 75% yield.

The anchor fragment was synthesized by first implementing a highly diastereoselective Mannich addition (Tang and Ellman J. Org. Chem. 2002, 67, 7819) between the sulfinyl imine 14 and the pyrrolyl acetate 15.  Construction of the bicyclic guanidine residue, introduction of the guanidinyl ester, and anti-Markovnikov reductive hydration of the terminal alkyne then provided 9.

The synthesis of (+)-batzelladine B (2) was completed by EDC coupling of the vessel and anchor fragments, to provide the penultimate intermediate 26 (75%).  In a final and carefully-optimized cascade sequence, 10 discrete transformations were executed in one flask to provide the target 2 in 41% isolated yield.

Our vessel synthesis is, in essence, a three component coupling reaction.  By varying the electrophilic alkynylation reagent and the nucleophile in the addition–ring-opening rearrangement, other alkaloids may be accessible.  We are also investigating methods to epimerize the [4+3] cycloadducts to obtain targets bearing the 1,3-anti stereorelationship.