Loline alkaloids are saturated pyrrolizidines with an oxygen bridge between carbon atoms C-2 and C-7 and an amino group on C-1. They are bioprotective alkaloids produced by Epichloë and Neotyphodium species, mutualistic fungal endophytes that are symbiotic with cool-season grasses. The sequence of bond formation in loline alkaloid biosynthesis was determined by synthesizing deuterated forms of potential intermediates and feeding them to cultures of the endophyte Neotyphodium uncinatum. These cultures incorporated deuterium from labeled N-(3-amino-3-carboxypropyl)proline and exo-1-aminopyrrolizidine into N-formylloline. The first result suggests that N-(3-amino-3-carboxypropyl)proline is the first committed intermediate in loline biosynthesis, and the second result demonstrates that the pyrrolizidine rings form before the ether bridge. The incorporation of these two compounds into lolines and the lack of incorporation of several related compounds clarify the order of bond formation in loline alkaloid biosynthesis.

Derivatives of the title structure bearing one or two heteroatoms adjacent to the spirocyclic carbons have been reacted principally with N-phenylmaleimide and N-methyltriazolinedione. The distributions of [4 + 21 cycloadducts have been quantified and, where mixtures have resulted, the stereoisomeric adducts have been isolated in a pure state following chromatographic separation. The stereochemical assignments follow principally from NOE measurements and X-ray crystallographic determinations. A relative reactivity ordering was established for the triazolinedione cycloadditions since this dienophile reacted with all of the available dienes. The stereoselectivities observed for these reactions suggested the intermediacy of aziridinium imide intermediates, and calculations of the AM1 type were carried out in order to examine the steric, electronic, and electrostatic properties of the reactants. Our analysis shows that electrostatic effects dominate in the syn dioxa system, whereas steric factors must be accorded proper consideration when accounting for the n-facial selectivity exhibited by the oxdthia and dithia compounds.

The regioselectivity of the oxidative coupling of the enolate anion of (LR)-(+)-verbenone (97% ee) has been examined with CuCl2 and FeCls as catalysts. With Cu(II), selective formation of the y,y-product is observed. An increase in temperature above -40 °C results in further oxidation of the intra-ring ethano bridge to a trans double bond, provided that excess LDA has been added. In the presence of Fe(III), the coupling is partially diverted to the a,y-product, which has proven amenable to direct conversion to that C2-symmetric "dimer" having the carbonyl groups in a para relationship. The second C2 "dimer" featuring meta orientation of the ketone functionalities has been conveniently prepared from the trienedione or its derived diol by thermal or photochemical transcis equilibration, thermal 6jt electrocyclization with concurrent aromatization, and PCC oxidation. Some potential applications of this conformationally rigid benzenoid system to enantioselective synthesis are outlined.The formation of 1,4-diketones by the oxidative coupling of enolate anions with cupric and ferric ions2 has served as an important synthetic tool for 2 decades. The process has serviced several synthetic objectives in both its intermolecular2-5 and intramolecular3 4567-6-8 modes. Perhaps most notable is the ability of these transition metal salts to effect cyclopropane construction as in l.8 In our view, the intermolecular variant should represent a powerful first step in the construction of structurally complex polycyclic ring systems starting with inexpensive, commercially available materials. Optically active ,/3-unsaturated ketones hold particular fascination. ch3 LDA (2.2 equiv); FeCI3, DMF,' -78 °C CH3 1This paper presents a detailed account of our initial studies involving (LR)-(+)-verbenone (2), which is readily available in high optical purity.9 Little precedent exists with which to gauge the potential response of 2 to f Atomic coordinates for the structure have been deposited with the Cambridge Crystallographic Data Centre. The coordinates can be obtained, on request, from the Director,

An unprecedented high barrier to ring inversion [Eq. (1)] prevents 1 from engaging in bifacial complexation with lithium ions. The X-ray crystal structure analysis of this hexaspiro compound corroborates the adoption of a cyclohexane chair with all six C-O bonds projected equatorially (1-eq).

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