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Total synthesis of bryostatins


The bryostatins, e.g. 1, are a group of complex marine macrolides which have potent antineoplasic activity, e.g. against the U.S. National Cancer Institute murine P 388 Iymphocytic leukemia, and which are now in phase 2 clinical trials.' They represent challenging target for natural product synthesis. To date one total synthesis has been reported, and several approaches to fragments have been described. 2 We have been interested in these compounds for several years, and devised a stereoselective approach to the 4-(methoxycarbonylmethylene)tetrahydropyranyl fragment C(10)-C(16) using free radical chemistry. 3 We now would like to apply our recently developed allyltin chemistry to natural product synthesis, and the bryostatins present an ideal target for this purpose. We would like complete a synthesis of the C( 1 )-C( 16) fragment 2 of the bryostatins using our allyltin chemistry, and them complete a synthesis of a bryostatin. During the course of this work we will extend the scope of our allyltin chemistry, with the stereoselective synthesis of saturated O-heterocycles, 1,3,5 polyols, and heavily oxidised aliphatic compounds being of specific interest. Improved acces to the allyltin reagents will also investigated. Alternatively the allylstannane reagent may be incorporated into a more advanced intermediate ultimately 4, which via the three step route (reaction with tosylosyacetaldehyde, epoxide formation, O-deprotection -cyclisation) will give 5 which is an advanced intermediate for a synthesis of the "upper fragment" 2. The C(l)-C(9) bryostatins is effectively a 1,3,5-triol derivative, and we are interested in applying our 1 ,S-induction chemistry to control the stereochemistry of this fragment. A synthesis of the required anti- l ,3,5-triol is described next: the tin(IV) halide mediated couplyng of the a (alkoxyallyl)stannane with a 3-alkoxypropanal is expected to give the l,5-syn-product.4 Stereoselective epoxidation, after protecting group exchange, using the cooperative effects of the allylic hydroxy group and the remote alkoxy group will give a epoxide. Regioselective reduction, directed by the hydroxyl group, will then lead to a diol, and protection followed by a Mitsunobu inversion will give a alcohol which has the required stereochemistry at C(3), C(5), and C(7) (bryostatins numbering). Chain extensionof this could be used to prepare the synthetic equivalent of the stannane 4, or the triol sequence could be applied to a more complex starting material. This approach to the stereoselective synthesis of anti,syn-triol derivatives, and related stereoisomers of 1,3,5 polyols will be of interest beyond bryostatin synthesis.
The essence of our approach to the lower fragment 3 is the Pd catalysed coupling of a vinyl bromide and an enol acetate which in situ is converted into the corresponding stannous enolate. Model studies for this reaction have been successful with the product 8 having being obtained in greater than 70% yield5. (This compares favourably with the lit epoxide opening using a vinyllithium reagent, for effecting this coupling which gives a yield of less than 30%). Having prepared a triol derivative and converted it into a complex stannane, the equivalent of 4, the synthesis of a fragment corresponding to the"upper hemisphere" of abryostatin will beattempted. Theexocyclic estermay be introduced usingasymmetri Madsworth-Emmons-Horner methodology. After release of the aldehyde at C(16), coupling with the sulphone 3 will be carried out, and lactonisation followed by deprotrection should lead to the completion of a synthesis of a bryostatin. This is a substantial project which be one of the major themes of our work over the next few years. This programme will involvr both the development of new methodology, and the application of this methodology to achieve a total synthesis of a complex an mportant natural product. Some of the Phase 2 clinical trials using bryostatins are being carried out in the Christie Hospital in Manchester. We are cooperating with the group at the Christie involved with these trials and our synthetic intermediates will be evaluated for biological activity by the Christie group.
1. G. R. Petit et al, Tetrahedron, 1985, 42, 985; A. Mc Gown, personal communication. 2. M. Kageyama, T. Tamura, M. H. Nantz, J. C. Roberts, P. Somfrai and S. Masamune, J. Am. Chem. Soc., 1990,112, 7408 3. S. P. Munt and E. J. Thomas, J. C. S. Chem. Commun., 1989, 480. 4. R. Maguire and E. J. Thomas, J. Chem. Soc., Perkin Trans., 1995, 2477 and 1487.
5. J. Gracia and E. J. Thomas, unpublished observations.


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