A Stereoselective Synthesis of the Bromopyrrole Natural Product, (–)-Agelastatin A

Agelastatin A and its congeners are a structurally intriguing class of bromopyrrole-based natural products comprised of a densely functionalized cyclopentane core adorned with four contiguous nitrogen substituent groups (Figure 1).[1] Agelastatin A and B were first isolated in 1993 from the Coral Sea marine sponge Agelas dendromorpha.[2] Subsequently, agelastatin C and D were identified in extracts from the Australian sponge Cymbastela sp.[3] The unique structural features of these compounds together with their powerful cytotoxic activities against certain human cancer cell lines have fueled efforts aimed at their de novo synthesis.[4,5] To date, seven completed syntheses of agelastatin A have appeared, each presenting a decidedly different strategy for assembly of the natural product.[6,7] For our purpose, structures such as agelastatin A serve to inspire the development of new catalytic methods for oxidative C–N bond formation. In this report, we detail an 11-step synthesis of this natural product made possible with the advent of a highly selective and efficient intramolecular olefin aziridination method.[8,9] The unique heterocyclic intermediate generated in this sequence is easily manipulated through two selective nucleophilic ring-opening reactions to afford the substituted cyclopentane core of the target. The finished work offers a flexible and highly efficient preparation of (–)-agelastatin A, easily amenable to analogue design.[10]

Figure 1.

The agelastatin family of natural products.

Recent work from our lab and others has demonstrated that homoallyl and bis-homoallyl sulfamate esters react under oxidative conditions to furnish unique bicyclic aziridine derivatives (Figure 2).[8,11,12] This process generally affords high levels of diastereocontrol with both cyclic and acyclic starting materials. The products can be smoothly converted to polyfunctionalized amine derivatives through sequential, regioselective ring opening. For the purpose of assembling (–)-agelastatin A, an attractive plan emerged that would capitalize on such a sequence of steps to establish the trans-substituted vicinal diamine unit embedded at C4 and C8 (Figure 3). Prior to initiating these investigations, we had little sense if a substrate such as 3 would undergo chemoselective oxidation to generate the unusual tricyclic structure 2 and whether such a product would be isolable. Selectivity in the subsequent aziridine displacement reaction presented an additional concern. This plan, however, could be quickly assessed due to the ready availability of sulfamate 3.

Figure 2.

Rh-catalyzed aziridination: a versatile method for assembling polyfunctionalized amines.

Figure 3.

Retrosynthetic analysis of (–)-agelastatin A.

Optically enriched lactam 4 is prepared on industrial scale and may be obtained in either antipode at a relatively inexpensive cost (Figure 4).[13] In two high yielding transformations, this material can be converted to alcohol 5, also an item of commerce. Sulfamoylation of 5 following a standard protocol that involves in situ generation of ClSO₂NH₂ is then easily accomplished.[14]

Figure 4.

Homoallylic sulfamate synthesis from commercial lactam.

Exposure of sulfamate 6 to a dimeric Rh(II) catalyst, 1.1 equiv of PhI(OAc)₂, and MgO, affords aziridine 7 as a single diastereomer in 95% yield (Figure 5). Less than 1% of the 5-membered ring product of allylic C–H insertion is obtained in this transformation. By capitalizing on our recently developed Rh₂(esp)₂ catalyst, loadings as low as 0.06 mol% (>1500 turnovers) can be used, thus enabling the reaction to be easily and inexpensively scaled.[15] The novel tricylic structure is quite stable and can be isolated in pure form following chromatography on silica gel. When treated with NaN₃ in aqueous isopropanol, regioselective attack at C4 (agelastatin numbering) proceeds at ambient temperature to yield predominantly the bridging [1,2,3]-oxathiazepane-2,2-dioxide 8 (C4/C8 regioselectivity = 9:1).[16,17] This versatile intermediate incorporates three of the four stereogenic carbamine centers found in the natural product, all differentially masked. Accordingly, this aziridination/ring opening reaction sequence should offer ready access to several derivative forms of agelastatin.

Figure 5.

Catalytic aziridination and regioselective ring-opening affords the desired oxathiazepane heterocycle 8. Rh₂(esp)₂ = Rh₂(α,α,α’,α’-1,3-benzenediproprionate)₂.

To forward the synthetic plan, a series of maneuvers was needed that would ultimately enable a single carbon excision and introduction of the C5 ketone (see Figure 3). Six- and seven-membered ring cyclic sulfamates possess intrinsic reactivity as electrophilies, which can be modulated as a result of N-functionalization.[14b,18] Taking advantage of this property, oxathiazepane 8 was first treated with diethyl pyrocarbonate to furnish the N-acylated species 9; subsequent introduction of NaSePh (prepared in a separate reaction vessel) displaces the oxathiazepane C–O bond to afford in a single operation selenide 10 (Figure 6). Access to this product in just 4 steps from 5 underscores the effectiveness of our aziridination process for the rapid assembly of stereochemically complex, orthogonally protected polyamine intermediates.

Figure 6.

Oxathiazepane 8 activation and ring opening.

Oxidation of selenide 10 and elimination of the transient selenoxide was intended to furnish the C5 exo-methylene product 11 (Figure 7). Such a reaction does occur, however, the resulting allylic azide undergoes facile [3,3]-sigmatropic rearrangement to afford cyclopentene 12.[19] As it was not possible to prevent this isomerization process, a decision was made to postpone exo-methylene introduction until the latter steps of the synthesis. Accordingly, we opted to fashion first the requisite pyrrole unit from 10 (Figure 8). Removal of the Boc-group with CF₃CO₂H precedes an efficient Paal-Knorr condensation, which employs tricarbonyl 13 and mild acid catalysis to forge the heterocycle.[20,21] The desired pyrrole 14 is generated in 85% yield over this two-step sequence.

Figure 7.

Rearrangement of allylic azide 11 necessitates strategic modification.

Figure 8.

Paal-Knorr condensation installs pyrrole unit.

To complete the agelastatin synthesis, azide 14 is reduced chemoselectively under Staudinger conditions (Me₃P, THF/H₂O, Scheme 1). Once reduction is complete, MeNCO is added to the reaction flask to produce urea 15. This compound is easily purified by normal-phase silica gel chromatography in spite of the presence of the polar N-methyl urea moiety. Exposure of 15 to m-CPBA induces selenide to selenoxide conversion and subsequent elimination to afford alkene 16. While attempts to cleave the C5 exo-methylene unit under ozonolytic conditions gave only intractable mixtures of products, successful installation of the C5 carbonyl was realized using a combination of 2.5 mol% OsO₄ and NaIO₄. Once the C5-ketone is exposed, addition of the urea is highly favored and the product is isolated exclusively as hemi-aminal 17.

Scheme 1.

a) Me₃P, THF/H₂O; then MeNCO, 81%; b) m-CPBA, DCE, 0 °C; then Et₃N, 80 °C, 89%; c) 2.5 mol % OsO₄, NaIO₄, THF/H₂O, 45 °C, 81%; d) KO^tBu, ^tAmOH, 45 °C, 77%; e) NBS, THF/MeOH, 0→25 °C, 75%. m-CPBA = meta-chloroperbenzoic acid, NBS = N-bromosuccinimide.

The stability of the hemi-aminal in 17 obviates protection as the N,O-acetal. As such, assembly of the final target can be accomplished by first exposing 17 to KO^tBu in t-amyl alcohol (Scheme 1).[22] This protocol generates the desired six-membered lactam with concomitant cleavage of the ethyl carbamate. Having intercepted the penultimate intermediate formed in prior syntheses of agelastatin A, a literature procedure using N-bromosuccinimde smoothly and selectively brominates the pyrrole unit and gives the natural product as a white, crystalline solid.[6e] This material matches reported spectral and optical rotation data in all respects.[2,6e] Starting from commercial 5, the 11-step sequence has been executed in a single pass to prepare >200 mg of the natural product (15% overall yield).

An efficient, easily scaled, and flexible route to (–)-agelstatin A has been made possible following the development and application of a selective Rh-catalyzed aziridination method. With the aid of Rh₂(esp)₂, this reaction is made to proceed in high yield at negligible catalyst loadings. The resulting tricyclic product 7 represents a unique heterocyclic structure that is efficiently transformed into a differentially protected cyclopentyltriamine. New protocols for manipulating the intermediate oxathiazepane and for crafting the pyrrole lactam also distill from this work. Overall, the preparation of agelastatin A is illustrative of the manner in which modern oxidative methods for C–N bond formation can alter the retrosynthetic logic of complex chemical synthesis.[23]