Biomimetic Organic Synthesis: 1-2

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The Asp residue is therefore not likely to be activated in the same way as the corresponding Asp residue in squalene-hopene cyclase. The additional activation may not be necessary due to the greater nucleophilicity of the epoxide relative to the 2,3-alkene of squalene. However, any hydrogen bonds that are formed with Asp could increase the reaction rate.

As previously mentioned, oxidosqualene is believed to be arranged by the enzyme active site into a chair-boat-chair conformation. Analogous to D-ring formation in squalene-hopene cyclase, C-ring formation in oxidosqualene cyclase is believed to be a 5- exo Markovnikov process. Formation of tricycle 73 from substrate analog 71 supports this theory, thereby necessitating a ring expansion step at some point subsequent to cyclopentannulation Chart 1. Further evidence suggesting a 5- exo C-ring closure can be found in several additional substrate analogs which have been shown to produce tricyclic products when submitted to oxidosqualene cyclases Scheme Substrate analogue oxaoxidosqualene and products formed upon cyclization by oxidosqualene cyclase.

Albeit circumstantial as it relates to the cyclization of natural oxidosqualene, the argument has been advanced that it is unlikely that each of these diverse substrate analogs follows a cyclization pathway different from that of the natural substrate. Although methyl and hydride shifts are not observed in the cyclization from squalene to hopene, formation of the protosterol cation by oxidosqualene cyclase is followed by a series of hydride and methyl group migrations that occur to form lanosterol Scheme Support for this hypothesis can be found in the synthetic work of van Tamelen, who showed that cyclization of 5 followed by rearrangement to 86 could be accomplished using a simple nonenzymatic Lewis acid Scheme In , the structure of human oxidosqualene cyclase was solved by X-ray diffraction of crystals containing lanosterol.

This three dimensional picture compliments those of SHC solved in , , and Moreover, it provides a timely ruling to some conclusions drawn from mutagenesis studies of the past decade. In order for OSC to operate it must accommodate several functional differences: 1 epoxide activation, 2 B-ring boat conformation, 3 control of D-ring size, and 4 migrations to the final product.

The Hoffmann-LaRoche team successfully cocrystallized lanosterol 2. Figure 15 reveals the active site interactions between the oxidosqualene cyclase and its product.

Endiandric acid C

A second key difference is the assignment of Cys and Cys as hydrogen bond donors that increase the acidity of Asp X-Ray crystal structure of lanosterol-bound OSC illustrating residues necessary for activation protonation. Stabilization of the chair-boat-chair conformation of squalene, as well as the positive charge generated at the rehybridizing carbons during cyclization is achieved by residues Phe, Tyr, and Trp positioned near C6 and C10 , and Tyr98 forces C10 methyl downward to encourage B-ring boat conformation Figure Similarly, the boat conformation involving the C10 olefin is disfavored in SHC by an additional residue on this face of squalene en route to hopene in SHC.

X-Ray crystal structure of lanosterol-bound OSC illustrating residues necessary for charge stabilization during polycyclization. Stabilization of the C14 cation is achieved by the closely positioned His and Phe Figure Another fundamental difference between OSC and SHC is the lack of aromatic Trp in the former to stabilize the secondary carbenium ion necessary for hopene formation. Moreover, water is usable to access these intermediate carbenium ions due to the hydrophobic nature of the active site.

AB Research Group

His is appropriately positioned for deprotonation leading to the olefin in lanosterol, but Tyr was suggested to play a role as well through its hydrogen bond to His Enzymes and antibodies share the common amino acid building block, and so it is pertinent to wonder whether the overall structural differences might be overcome to find common function. This question has been addressed in the context of oxidosqualene cyclase activity.

In , Janda and coworkers elicited an antibody to the charged transition state analog, N -oxide 90 , and demonstrated antibody catalysis for the cationic cyclization from 87 to 88 Scheme This approach was later extended to the formation of decalin ring systems analogous to the AB ring systems of steroidal natural products.

Janda's antibody catalyzed cyclization of substrate 91 to afford decalin products. In their march toward a catalytic antibody surrogate for oxidosqualene cyclase, Janda and coworkers recently reported their studies involving epoxysqualene substrate mimics such as This represents the first demonstration that an epoxide could be used in combination with the catalytic antibody to trigger a cationic cyclization.

N -Oxide hapten 98 was synthesized from lithocholic acid and used to elicit antibody HAA The authors speculate that the antibody merely lacks the proper peptide cavity for the additional cyclizations, and that epoxysqualene cyclase functions with this distinction. What cannot be excluded is a mechanism in which the substrate binds to the surface of the antibody, and the antibody effects an enantioselective Lewis acid-catalyzed epoxide ring opening.

Cyclization of an oxidosqualene-like substrate by an antibody elicited to a steroidal hapten. The conversion of 2,3-oxidosqualene to lanosterol is a quintessential cascade reaction in that an epoxide with one stereogenic center is transformed to a tetracyclic steroid containing seven stereogenic centers.

Although a great deal has been learned about the enzymatic transformation, the degree of enzymatic assistance remains difficult to determine. S -2,3-Oxidosqualene is cyclized in some plants to primarily dammarenediol The first total synthesis of this tetracycle using a polyolefin cascade cyclization designed to mirror the biosynthetic transformation was reported by Corey in Epoxide was prepared using a regioselective, enantioselective dihydroxylation. The cascade cyclization proceeds through a chair-chair-chair transition state.

The reader should be reminded that plant oxidosqualene cyclases, which are responsible for dammarenediol biosynthesis, are the exceptions rather than the rule in that they favor a chair-chair-chair conformation during the cyclization of oxidosqualene.

Aldol condensation, stereoselective enone reduction, and homologation at C17 led to the penultimate product, which furnished the desired dammarenediol in enantioenriched form after carbamate deprotection. Scalarendial is an unusual squalene-derived natural product in that the relative syn stereochemistry of the C10 and C14 angular methyls does not follow from any precedent in either squalene or epoxysqualene cyclase.

Conversion of the acetate to bromide and treatment with iminyl silane provided the homologated acylsilane after hydrolysis. The acylsilane functionality serves as the lynchpin to a final coupling that provides an enol ether. Specifically, a sulfone is deprotonated n BuLi and added in 1,2-fashion to the acylsilane carbonyl.

There is at least partial silicon transfer to the aluminum alkoxide, necessitating treatment with aqueous hydrogen fluoride in acetonitrile. Additionally, the D-ring silylmethylene substituent is present as a mixture of epimers and required equilibration with basic methanol to converge to the equatorial diastereomer. Hence, a single tetracycle is formed with a apparent high degree of diastereoselection, save the D-ring substituent configuration.

The relative configuration dictates a chair-chair-chair-chair transition state, and again, the importance of using a C14 methyl instead of C15 as in epoxysqualene should be noted. Reduction of the lactone to the diol was followed by oxidation to the dialdehyde natural product target Similarly, epoxyketone was elaborated to epoxide for treatment with an identical series of reagents as for Scheme The adociasulfates are a family of hexaprenoid hydroquinone sulfates isolated from the sea sponge Haliclona a.

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Adocia that exhibit micromolar inhibition of motor proteins in the kinesin super family of proteins. Adociasulfates 1 and 7 are also proton pump inhibitors. Synthesis of the key geranylgeraniol intermediate commenced from bromoarene Scheme Sharpless epoxidation then provided the epoxide necessary for tetracyclization attempts. Thirteen additional steps were required to complete the total synthesis. Overman's total synthesis of the adociasulfate from an epoxysqualene-like polycyclization. Breslow speculated in that the biosynthesis of sterols from squalene might involve an oxidative free radical pathway.

Epoxysqualene was ultimately hypothesized , and confirmed as the biosynthetic intermediate, but the radical pathway has nevertheless been exploited successfully in several polycarbocyclizations. These demonstrations have established that carbenium ions are not necessary intermediates for diastereoselective carbocyclizations in the stereocontrolled formation of terpene frameworks. Breslow used a CuCl-catalyzed thermal decomposition to benzoyloxy radicals, with cupric benzoate added as the terminator.

Soon thereafter, Snider extended this methodology to include 1,3-dicarbonyl compounds. That this homolytic polycyclization is not limited to radical cation intermediates was demonstrated later by Pattenden who used an acyl radical generated from an acyl selenide and Bu 3 SnH-AIBN to effect a tetracyclization eq 9.

This strategy was more recently elaborated to a short biomimetic synthesis of a steroidal skelton. Photoinduced electron transfer then initiated the polycyclization by formation of radical cation From the ensuing cascade, eight stereogenic centers were created to form only two of the greater than possible isomers Scheme It is significant to note that the C3 hydroxy results from water in this approach, thereby providing a possible alternative biosynthetic pathway to produce epoxysqualene-derived steroids under nonoxidative conditions.

Insofar as many total syntheses based on biomimetic strategies have indeed been successful, it is important to still measure the value of mimicking biology in a case-by-case manner. And when reflecting on the success of a biomimetic strategy in total synthesis, irrational exuberance must remain in check as van Tamelen 12 stated:.

This review has identified benchmarks in the evolution of terpene biosynthesis and total synthesis. In all cases, biosynthesis inspired a key polycyclization that generated substantial complexity in a single transformation. Similarly, synthetic studies of the polycyclization led to discovery of the need to stabilize developing charge at specific carbons in the squalene backbone during cyclization. This same need was discovered much later during mutagenesis studies, indication that the cyclase had long used this tactic.

This is exactly how organic synthesis and biosynthetic studies are synergistic as each evolves in parallel with the other Figure The complexity of the protein environment, in conjunction with levels of selectivity that were considered not long ago unattainable with small molecule catalysts tempt one to believe that selectivity and catalyst complexity are directly related. However, the Yamamoto catalysts clearly lack the functional complexity, much less the steric size, but are still able to furnish polycyclic products with high selectivity.

Only further work in biomimetic catalyst development will determine whether both selectivity and efficiency can be controlled simultaneously to approximate that of an enzyme catalyst.

A Case Study in Biomimetic Total Synthesis: Polyolefin Carbocyclizations to Terpenes and Steroids

Similarly, total synthesis stands to benefit immensely from biosynthetic thinking since it often provides a basis, however tenuous and circumstantial, for taking strategic risk that promises tremendous benefit if successful. We thank Julie Pigza and Benjamin Nugent for their assistance with the preparation of this manuscript. The first draft of the latter was done by Lucy Stark, and initiated by Prof. Eric Sorensen. We extend our sincere appreciation for their priceless insight and time. Professor Johnston graduated summa cum laude from Xavier University in with a B.

Chemistry degree. His graduate work with Leo A. Evans at Harvard University, he began his independent career in at Indiana University where he is presently Associate Professor of Chemistry. His research interests include the development of new reactions and reagents, including nonconventional free radical-mediated addition reactions to azomethines, chiral protic acid catalysis, and the total synthesis of alkaloid natural products.

Ryan Yoder graduated from Indiana University in with a B. Chemistry degree Honors. He then joined the Johnston research program as a graduate student, and began work that ultimately resulted in the first definitive example of chiral proton catalysis. His interests include the development of a mechanistic understanding of these reagents, and their application to natural product synthesis.

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This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Chem Rev. Author manuscript; available in PMC Oct PMID: Ryan A. Yoder and Jeffrey N. Corresponding author. Jeffrey N.