As seen in the jasplakinolide post earlier this week, solid-supported natural product syntheses are often conducted with a goal of generating analogs as chemical probes and for SAR studies. A review entitled “Advances in Solution and Solid-Phase Synthesis Toward the Generation of Natural Product-Like Libraries” has just been made available as a Chemical Reviews ASAP article which highlights efforts in this area. There are two major sections to the review; a) the “Solid phase synthesis of natural products and their analogs” and b) the “Solid phase synthesis of cyclic peptides as natural products and their analogs”. There are also two smaller sections on solid phase synthesis of alkaloids and oxygen rich natural products. Note that despite the title there isn’t a section entitled “Solution phase synthesis of natural products and their analogs“.
In looking over the review, there were only a handful of examples of solution phase work. Some of the epothilone work conducted by Nicolaou, for example. Also included was the total synthesis of plicamine by Ley which used solid supported reagents. Even that’s a stretch, since as the authors note they made no analogs. A library of one if you will.
While there were a few other true solution phase approaches, the majority of solution phase syntheses were fluorous based. Examples described included curicin, mappacine, murisolin, and passifloricin. The curicin analogs were conducted by Prof. Peter Wipf’s group, while the latter three natural products were all conducted by Curran et al using fluorous mixture synthesis (FMS). Since the review covers the literature up to 2006 it doesn’t mention the work on discodermolide (Curran) or radicical A (Winssinger) which has also been conducted using fluorous methods.
The curicin work by Wipf is interesting in that a double fluorous tag was used with fluorous liquid-liquid extraction (FLLE) as the purification method. The work which was conducted in the mid-90′s may actually be the first instance of solvent tuning. Although FC-72 was still being used as the fluorous phase, they used CH3CN/H2O as the organic phase. The addition of water clearly makes the organic phase more fluorophobic increasing the fluorous partition coefficients.
As noted in the jasplakinolide post, numerous advantages can be realized using fluorous methods over solid phase methods. It’s a good fit since natural products are very often highly dense in functionality requiring complex syntheses which are more amenable to fluorous techniques than solid supported techniques. Perhaps the examples shown in this review and the recent successes in DOS using fluorous methods will inspire those making natural product-like libraries to reconsider the type of phase tag used.
I was struck by two passages in the text. First, from the introduction:
“Although natural products from a variety of sources (plants, soil, sea, etc.) are very useful candidates for identifying lead compounds, the major limitation with natural products in most cases is their follow-up organic synthesis / medicinal chemistry efforts. In many cases, the availability of the natural product is not sufficient for the various desired biological assays, thereby limiting the exploration of their full potential. Developing similar relatively simple structural analogs to natural products with comparative biological responses often is a challenging and highly time-consuming undertaking.”
And the second, speaking of the Curran Group’s fluorous mixture synthesis of murisolin:
“In [fluorous mixture synthesis], only 39 chemical transformations were required as compared with 156 steps that would have been required if the analogs were synthesized individually.”
The Curran Group routinely leverages their synthetic effort with fluorous mixture synthesis, making relevant natural product analogs for structure and activity studies in the same amount of work needed to make only the natural product. Seems like the perfect answer to the problems that the authors identified in the introduction.
Yes, the FMS (fluorous mixture synthesis) is a good way to tell the absolute configuration of natural products or SAR research.