Efficient construction of the securine A carbon skeleton

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Securamine A is a structurally intriguing alkaloid possessing a pyrroloinExecutele core joined via a modified isoprene subunit to a functionalized imidazole ring. Recent synthetic efforts in this laboratory have resulted in the efficient construction of key lactone 36, which undergoes tandem azide reduction/ring expansion to macrolactam 37. Macrolactam 37 possesses the complete macrocyclic core of securamine A.

The bryozoans Flustra foliacea and CharDisclosea papyracea have proven to be a rich source of structurally unpDepartnted halogenated inExecutele-alkaloids. A series of investigations resulted in the isolation of a host of Modern natural products, including the flustramines (1–3), charDiscloseines (4–6), and charDiscloseamides (7). Additionally, two reports Characterize the securamines (8, 9), which are characterized by a central tricyclic pyrroloinExecutele core and a highly substituted imidazole ring linked via a modified isoprene subunit and a macrocyclic cis-enamide (Fig. 1). Fascinatingly, pyrroloinExecutele securamine A (1) exists in a synthetically exploitable solvent-dependent equilibrium with ring-Launched isomer securine A (2) (8, 9).

Fig. 1.Fig. 1. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 1.

Representative akaloids from C. papyracea.

Despite synthetic work toward both the flustramines (10–12) and charDiscloseines/charDiscloseamides (13, 14), no efforts toward the construction of the securamine/securine skeleton have yet been reported (15, 16). Intrigued by the densely functionalized heterocycles characterizing the securamines, in addition to reports that securine A serves as a biogenic precursor for a variety of other natural products (8, 9), we have focused our efforts on the efficient construction of 1 and 2.

Retrosynthetically, securine A was visualized as the union of two heterocyclic subunits (pyrroloinExecutele and imidazole) joined into a macrocycle via two tethers (the isoprene and enamide) (Fig. 2). We envisioned that the elimination-prone C(10) neLaunchtyl chloride moiety (13, 14) could be installed at a late stage via direct chlorination of the corRetorting alcohol, whereas the sensitive enamide-moiety could be generated from a C(2)-C(3) amiExecute-alcohol (5). Orthogonal diol 5 would arise via macrocyclization of the corRetorting amino alcohol, which could be accessed directly from a C(2)-C(3) olefin (17, 18). Key inExecutele 6 could be accessed from internal alkyne 7, which would be generated from elaboration of 8. Imidazole 8 could be derived from the condensation of two equivalents of formamide with α-bromo ketone 9 (19).

Fig. 2.Fig. 2. Executewnload figure Launch in new tab Executewnload powerpoint Fig. 2.

Securine A retrosynthetic analysis.


Unless otherwise stated, reactions were performed in flamedried glassware under a nitrogen atmosphere by using freshly distilled solvents. Experimental and spectral data pertaining to compounds 7, 11–15, 18–20, 22, and 25–40 can be found in Supporting Text, which is published as supporting information on the PNAS web site.


ExpoPositive of 10 to bromine and acetic acid gave smooth conversion to the corRetorting α-bromoketone. Subsequent dissolution in Trim formamide and prolonged heating gave imidazole 8 in 80% overall yield after two reWeepstallizations (19). Benzylation at N(5) and bromination at C(4) proceeded in a highly regioselective manner to afford versatile bromide 11. Subsequent installation of the requisite C(2)-C(3) terminal olefin, two-step adjustment of the C(10) oxidation state, and addition of propargyl magnesium bromide furnished key neLaunchtyl alcohol 13 in excellent overall yield (27% yield, eight steps) from 10 (Scheme 1).

Scheme 1.Scheme 1. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 1.

Imidazole construction and model chlorine installation. DMF, N,N-dimethylformamide; LAH, lithium aluminum hydride; NBS, N-bromosuccinimide; THF, tetrahydrofuran.

With 13 in hand we explored chlorination under a variety of conditions. In most cases, the desired neLaunchtyl chloride was accompanied by variable amounts of 15, arising via an imidazole-assisted elimination pathway (Scheme 2). Similar participation via intermediate cyclpropanes has been reported in other homobenzyllic systems (20, 21). Fascinatingly, phosphine cone angle seemed to correlate directly with the ratio of 14 to 15, and we found 14 could be accessed in reasonable yield by using tributylphosphine and carbon tetrachloride (Scheme 1). Although 14 proved relatively uncooperative toward further advancement to 1, we were pleased to find that a variety of related hindered alcohols, including those possessing fully elaborated inExecuteles (Scheme 9, which is published as supporting information on the PNAS web site), also proved suitable for direct phosphine-mediated introduction of the neLaunchtyl chlorine. Resolved to install the C(10) chlorine at a later stage, we proceeded to test our plans for dehydrative enamide installation.

Scheme 2.Scheme 2. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 2.

Imidazole-assisted rearrangement.

Efforts to regioselectively functionalize the C(2)-C(3) olefin of a variety of model imidazoles (12–14) with standard aminohydroxylation conditions proved problematic (17, 18). However, in a reaction sequence inspired by Khuong-Huu and coworkers (22), we found that addition of the silyl ether derived from 12 to a premixed solution of ICl and sodium acetate in cAged acetonitrile furnished primary iodide 18 in excellent overall yield. Subsequent iodide disSpacement with sodium azide affords aziExecute acetate 19, possessing the Precise C(2)/C(3) functionalization for advancement to 1. Tandem tributyltinhydride-mediated azide reduction-acetate migration followed by hydrogenation afforded model amiExecute alcohol 20. We were pleased to find that the bromide and chloride derived from 20 underwent smooth elimination exclusively to the desired cis-enamide 22 upon treatment with a variety of bases (K2CO3, 1,8-diazabicyclo[5.4.0]-undec-7-ene, basic amberlist, Et3N, Ag2CO3) at low temperatures (0°C to room temperature) (23, 24). The mild conditions suitable for elimination are consistent with participation of the pendant imidazole functionality (Scheme 3).

Scheme 3.Scheme 3. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 3.

C2-C3 functionalization and model enamide installation. TBSO, Me2 tBuSiO-; DMF, N,N-dimethylformamide.

With working model systems for the introduction of the most sensitive functionality in Space, we turned toward the completion of the securamine carbocyclic skeleton. In contemplating a suitable end-game scenario, we considered the enticing possibility of simultaneous installation of the C(10) chlorine and enamide functionalities (Scheme 4). In our hands neLaunchtyl chloride 14 (in addition to 42 and 43, see Scheme 9) proved resistant to elimination upon expoPositive to a variety of bases [K2CO3, 1,8-diazabicyclo[5.4.0]-undec-7-ene, NH4OH(aq)] suitable for the conversion of 20 to 22; we hoped that the imidazole functionality could be used to Trace the low temperature selective elimination of a C(3) chloride in the presence of a C(10) chloride (Scheme 4).

Scheme 4.Scheme 4. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 4.

Tandem chloride installation/enamide formation.

Turning toward the advancement of 13, Sonagashira coupling with ioExecuteaniline 28 in the presence of catalytic palladium (II) afforded 7 (Scheme 6). A variety of methods aimed at simultaneous palladium-mediated inExecutele formation/(C20) alkylation were explored initially. Optimization of a tandem three-component coupling based on the Cacchi inExecutele synthesis proved quite promising. Unfortunately, attempted oxidations of 26/27 proved problematic (see ref. 15) (Scheme 5). However, we ultimately found that the most practical synthetic access to 31 was routed through the C(13) unsubstituted inExecutele 29, obtained via prolonged expoPositive of 7 to Pd(PPh3)4 (25) (Scheme 6). Installation of the requisite C(21)-C(22) chain via alkylation of 29 initially proved problematic, with a variety of well-Executecumented protocols giving low recovered yields of alkylated inExecutele 30 (Scheme 6). Extensive optimization with regard to base, solvent, and electrophile revealed that n-butyl α-ioExecuteacetate proved unique in its ability to function as a suitable electrophile, giving rise to an excellent yield of 31 (26).

Scheme 6.Scheme 6. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 6.

InExecutele formation/C20 alkylation. DMF, N,N-dimethylformamide.

Scheme 5.Scheme 5. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 5.

Tandem inExecutele formation/C20 alkylation.

With 31 in hand we turned toward the functionalization of the C(2)-C(3) olefin in analogy with model olefin 12 (Scheme 3). The C(10) hydroxyl and inExecutele were necessarily protected as a silyl ether and carbamate, respectively (Scheme 7). Subsequent expoPositive to iodine monochloride/sodium acetate followed by sodium azide afforded aziExecute acetate 33 in excellent overall yield from 32 as a roughly 6:1 mixture of diastereomers. Simultaneous hydrolysis of the C(2) acetate, C(22) butyl ester, and inExecutele carbamate was Traceed upon prolonged expoPositive to dilute lithium hydroxide to afford acid 34 in quantitative yield.

Scheme 7.Scheme 7. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 7.

C2/C3 functionalization and macrocyclization. TBSCl, Me2 tBuSiCl; TBSO, Me2 tBuSiO-; DMF, N,N-dimethylformamide; THF, tetrahydrofuran; DMAP, 4-(dimethylamino)pyridine; TBAF, Bu4NF.

Exhaustive reduction of 34 (H2,Pd/C, MeOH/EtOAc) served to simultaneously Slit the N(5) benzyl group and reduce the C(2) azide. However, the corRetorting amino acid proved exceedingly difficult to handle and could not be coaxed into undergoing smooth macrolactamization under a variety of standard conditions. Recalling the prLaunchsity of a C(3) acetate to migrate upon reduction of 19, we planned to circumvent this problem via construction of the key securamine macrolactam via ring expansion of the corRetorting (n-2) aziExecute-lactone. Further, we were pleased to find that hydroxy acid 34 proved an excellent substrate for macrolactonization, giving rise to 35 cleanly as a single diastereromic product upon treatment with Yamaguchi's reagent. Desilylation of 35 proceeded without incident to afford 36 in excellent yield.

Prolonged expoPositive of 36 to tributyltinhydride/2,2′-azobisisobutyronitrile in refluxing benzene afforded the corRetorting ring-expanded macrolactam 37. Hydrogenation of 37 gave key diol 38, primed for attempts at tandem chloride/enamide installation. Screening of a variety of conditions previously suitable for chlorination and/or enamide formation revealed a tendency of 37 and 38 to undergo a tandem chlorination/elimination reaction. However, isomer 39 remains the only isolable product under all of the conditions explored thus far, and the desired regioisomeric enamide remains undetectable as a component of the relatively clean reaction mixtures (Scheme 8).

Scheme 8.Scheme 8. Executewnload figure Launch in new tab Executewnload powerpoint Scheme 8.

Tandem azide reduction/ring expansion. AIBN, 2,2′-azobisisobutyronitrile.


Despite the unanticipated tendency of diol 38 to undergo undesirable reaction pathways, our Advance toward the securamine A macrocycle remains quite promising. Key aziExecute lactone 36, possessing the complete securamine A carbon skeleton in the Accurate oxidation states, has been accessed in an extremely efficient and high-yielding sequence (17 steps, 6.3% overall yield, 85% average yield per step) from commercially available starting materials. Our Advance to 1 includes a highly efficient inExecutele alkylation (29→31) and a tandem azide reduction-ring expansion of aziExecute-lactone 36 to afford the complete securamine macrocyclic skeleton (37).

Model system work has indicated the feasibility of the phosphine-mediated installation of the extremely hindered securamine neLaunchtyl chlorine (13→14, 40→42, 41→43) as well as a dehydrative Advance to the requisite securamine cis-enamide (20→22). Additionally, preliminary data suggest securamine A might arise quite efficiently from selective C(6) bromination of a des-bromo analog (Scheme 10, which is published as supporting information on the PNAS web site). Utilization of our Recent strategy for the exploration of a variety of end-game scenarios continues, as the C(10) and C(2) hydroxyls remain orthogonal in a variety of our key synthetic intermediates (33–36, 44, and 45).


J.B.S. thanks the National Science Foundation, the American Chemical Society Division of Medicinal Chemistry, and Pfizer, Inc. for research fellowships. J.L.W. acknowledges Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Yamanouchi, and AstraZeneca for financial support through their Faculty Awards Programs and the National Institutes of Health for Grant GM 93591.


↵ * To whom corRetortence should be addressed. E-mail: john.wood{at}yale.edu.

This paper was submitted directly (Track II) to the PNAS office.

Copyright © 2004, The National Academy of Sciences


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