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Review
. 2009 Nov 27;7(4):705-53.
doi: 10.3390/md7040705.

A submarine journey: the pyrrole-imidazole alkaloids

Barbara Forte  1 , Beatrice Malgesini, Claudia Piutti, Francesca Quartieri, Alessandra Scolaro, Gianluca Papeo
Affiliations
Review

A submarine journey: the pyrrole-imidazole alkaloids

Barbara Forte et al. Mar Drugs. .

Abstract

In his most celebrated tale "The Picture of Dorian Gray", Oscar Wilde stated that "those who go beneath the surface do so at their peril". This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity--from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products.

Keywords: marine sponges; oroidin; pyrrole-imidazole alkaloids; total synthesis.

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Figures

Figure 1.
Figure 1.
PIAs complexity extremes.
Figure 2.
Figure 2.
PIAs biogenetic speculations.
Figure 3.
Figure 3.
Examples of oroidin modification towards antibiofilm inhibitors.
Figure 4.
Figure 4.
Structures of HMD and DBH.
Figure 5.
Figure 5.
Axinohydantoins.
Figure 6.
Figure 6.
Agelastatins.
Figure 7.
Figure 7.
Different synthetic routes to achieve agelastatin A total synthesis.
Figure 8.
Figure 8.
Proposal for the biogenetic origin of sceptrin (8).
Figure 9.
Figure 9.
Ageliferins.
Figure 10.
Figure 10.
Proposal for biogenetic origin for ageliferin (9).
Figure 11.
Figure 11.
Extracts composition of Agelas conifera. Reproduced with permission from Verlag Z. Naturforsch. [145].
Figure 12.
Figure 12.
Previously assigned (101a) and revised (101b) structure of palau’amine.
Figure 13.
Figure 13.
Structurally related PIAs cyclic dimers.
Figure 14.
Figure 14.
Different approaches toward intermediate A.
Figure 15.
Figure 15.
Proposed biogenesis for ageladine A (138).
Figure 16.
Figure 16.
Approaches to ageladine A (138).
Scheme 1.
Scheme 1.
Approach to oroidin and related compounds via intermediate 10.
Scheme 2.
Scheme 2.
The Al Mourabit synthesis of oroidin.
Scheme 3.
Scheme 3.
Ando’s synthesis of dispacamide A.
Scheme 4.
Scheme 4.
Synthetic approaches to (Z)-HMD (17) and (Z)-DBH (19).
Scheme 5.
Scheme 5.
Northern ring installation.
Scheme 6.
Scheme 6.
Benzoyl removal and double bond isomerization.
Scheme 7.
Scheme 7.
Racemic approaches to (±)-dibromophakellstatin 32.
Scheme 8.
Scheme 8.
Enantioselective synthesis of (−)-32.
Scheme 9.
Scheme 9.
Tandem Pd-AAA reported by Trost and Dong.
Scheme 10.
Scheme 10.
Completion of the Trost (−)-agelastatin A synthesis.
Scheme 11.
Scheme 11.
Allyl cyanate [3.3] sigmatropic rearrangment involving a [1,3] chirality transfer.
Scheme 12.
Scheme 12.
Access to key vicinal diamine 54.
Scheme 13.
Scheme 13.
Aziridination reaction used in agelastatin A synthesis.
Scheme 14.
Scheme 14.
Yoshimitsu and Tanaka’s second-generation approach to (−)-37.
Scheme 15.
Scheme 15.
Synthesis of selenide key intermediate 64.
Scheme 16.
Scheme 16.
Synthesis of all cis-substituted cyclopentene 68.
Scheme 17.
Scheme 17.
Completion of (±)-37 synthesis according to Dickson and Wardrop.
Scheme 18.
Scheme 18.
Synthesis of key compound 75.
Scheme 19.
Scheme 19.
Chida and co-workers completion of (−)-37 total synthesis.
Scheme 20.
Scheme 20.
Retrosynthetic approach to Nagelamide D (79).
Scheme 21.
Scheme 21.
Nagelamide D: Fragment Assembly and Reduction.
Scheme 22.
Scheme 22.
Completion of the synthesis of nagelamide D (79).
Scheme 23.
Scheme 23.
Baran’s total synthesis of (−)-sceptrin (8). PLE = pig liver esterase, DMT-MM = 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride.
Scheme 24.
Scheme 24.
Enantioselective synthesis of (−)-ageliferin (9) and (−)-nagelamide E (90).
Scheme 25.
Scheme 25.
Chen approach to oroidin cyclic dimers core.
Scheme 26.
Scheme 26.
IMDA approach to ageliferins and palau’amine cores.
Scheme 27.
Scheme 27.
Scheuer's proposal for biogenesis of palau'amine.
Scheme 28.
Scheme 28.
Romo’s approach to palau’amine core 107.
Scheme 29.
Scheme 29.
Overman’s synthesis of congeners 111 and 112 of epi-palau’amine.
Scheme 30.
Scheme 30.
Harran's approach to palau'amine spirocyclic core 120.
Scheme 31.
Scheme 31.
Baran synthesis of key intermediate 131.
Scheme 32.
Scheme 32.
Completion of the axinellamine A (121) and B (122) total synthesis. * 77% (H, OH=β) and 48% (H, OH= α) after optimization: 132, H2O, TFA 10% (v:v), r.t155
Scheme 33.
Scheme 33.
Synthesis of 125 and 126.
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