QS-21 is one of the most promising new adjuvants for immune response potentiation and dose-sparing in vaccine therapy given its exceedingly high level of potency and its favorable toxicity profile. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV-1, and malaria are among the numerous maladies targeted in more than 80 recent and ongoing vaccine therapy clinical trials involving QS-21 as a critical adjuvant component for immune response augmentation. QS-21 is a natural product immunostimulatory adjuvant, eliciting both T-cell- and antibody-mediated immune responses with microgram doses. Herein is reported the synthesis of QS-21A(api) in a highly modular strategy, applying novel glycosylation methodologies to a convergent construction of the potent saponin immunostimulant. The chemical synthesis of QS-21 offers unique opportunities to probe its mode of biological action through the preparation of otherwise unattainable nonnatural saponin analogues.
QS-21A is one of the most promising new adjuvants for immune response potentiation and dose-sparing in vaccine therapy, given its exceedingly high level of potency and its favorable toxicity profile. Melanoma, breast cancer, small cell lung cancer, prostate cancer, HIV-1, and malaria are among the numerous maladies targeted in more than 80 recent and ongoing clinical trials involving QS-21A as a critical component for immune response augmentation in microgram doses. Herein is reported the first synthesis and structure verification of QS-21Aapi, applying novel glycosylation methodologies in the convergent modular construction of this rare and potent natural product immunostimulant.
In this report, it is demonstrated that chiral vinyl aziridines can be stereospecifically ring expanded. This synthetic approach allows controlled access to chiral 2,5-cis or 2,5-trans-3-pyrroline products from starting materials with the appropriate aziridine geometry. Twenty three ring expansion examples, most of which feature a stereospecific cyclization, are presented.A cursory review of the structural motifs of the top 200 top selling drugs 1 reveals that around 90% contain at least one nitrogen atom and approximately 65% are decorated with a heterocycle. Not surprisingly, the majority of these heterocycles are nitrogenous, with pyrrolidines a commonly occurring heterocyclic scaffold. Given the success of chiral pyrrolidines as important pharmaceutical building blocks it follows that a range of practical synthetic methods are needed 2 to provide access to any targeted structural and stereochemical pyrrolidine pattern.We have chosen to tackle the challenge of developing useful pyrrolidine forming methods by revisiting the ring expansion of vinyl aziridines, first reported by Atkinson. 3 Surprisinigly, despite the potential usefulness of converting a vinylaziridine into a 3-pyrroline, there had only been a single study focused on using metal catalysts to aid the rearrangement prior to our contribution to this field. 4 Oshima and coworkers found that tosylated dieneaziridines could be ring expanded in the presence of a palladium catalyst to the 3-pyrrolines. Both the N-tosyl group and the diene moiety were reported to be essential for the success of this rearrangement. Simple non-dienic vinyl aziridines did not ring expand, furnishing instead a complex mixture of products. In our recent report, we demonstrated that this significant substrate limitation could be solved using Cu(hfacac) 2 as a catalyst. 5 The substrate scope of this new transformation, which we demonstrated for a range of tosyl (Ts) and N-phthalimide (NPhth) protected vinyl aziridines, was shown to be quite broad. In this report we expand these investigations further and focus our attention on stereospecific vinyl aziridine ring expansions and application of this new methods towards accessing chiral pyrroline products.njardars@email.arizona.edu. Supporting Information Available Full experimental details for all new compounds reported in this article including X-ray data for compounds 15d, 15j, 15l, 21d and 21f are available free of charge via the Internet at http://pubs.acs.org. In order to maximize the synthetic potential of our method for preparing chiral pyrroline products, it is essential that reliable, asymmetric, convergent, and scalable routes be available to access the requisite starting materials (chiral vinyl aziridines). 6 The union of an imine and suitably activated nucleophile quickly emerged as the optimal approach (Scheme 1). The imine based retrosynthetic analysis is highlighted for chiral pyrroline 3, which we envisioned would originate from the copper catalyzed ring expansion of a trans-or cis-vinyl aziridine (4 and ...
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