Andrei I. Savchenko

Mono- and Disubstituted N,N-Dialkylcyclopropylamines from Dialkylformamides via Ligand-Exchanged Titanium–Alkene Complexes†

Dibenzylformamide was treated with cyclohexylmagnesium bromide in the presence of either titanium tetraisopropoxide or methyltitanium triisopropoxide and a variety of cyclic and acyclic alkenes and alkadienes to give new mono- and disubstituted as well as bicyclic dialkylcyclopropylamines (Tables 1–3, 2, 3) in yields ranging from 18 to 90 % (in most cases around 55 %). 3-Benzyl-6-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane (10 a) and the orthogonally bisprotected 3-tert-butoxycarbonyl-6-(N,N-dibenzyl)-3-azabicyclo[3.1.0]hexane (10 d) as well as the analogous 6-(N,N-dibenzylamino)bicyclo[3.1.0]hexane (12) were obtained as pure exo diastereomers in particularly high yields (87, 90, and 88 %, respectively) from N-benzylpyrroline (15 a), N-Boc-pyrroline (15 d; Boc=tert-butyloxycarbonyl) and cyclopentene (19). 1,3-Butadiene (52) and substituted 1,3-butadienes were also aminocyclopropanated quite well to give 2-ethenylcyclopropylamines in good yields (51–64 %). Except for alkenyl- and aryl-substituted compounds, N,N-dibenzylcyclopropylamines can be debenzylated by catalytic hydrogenation to the primary cyclopropylamines as demonstrated for 10 a and 10 d to yield the fully deprotected 10 e (93 %) and mono-Boc-protected 10 f (98 %), respectively. The latter are interesting templates for combinatorial syntheses of libraries of small molecules with a well defined distance of 4.3 A between two nitrogen atoms.

Isolation and confirmation of the proposed cleistanthol biogentic link from Croton insularis.

The proposed cleistanthol biosynthetic intermediate en route to spruceanol, and other related family members, was isolated for the first time from Croton insularis, confirming the Jacobs-Reynolds hypothesis. Anticancer evaluation of the new isolates and their aerial oxidation products is also reported.

Cyclopropylamines from N,N-dialkylcarboxamides and Grignard reagents in the presence of titanium tetraisopropoxide or methyltitanium triisopropoxide.

Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl- and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,N-dicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.

EBC-316, 325-327, and 345: new pimarane diterpenes from Croton insularis found in the Australian rainforest

Five new pimarane and related-type diterpenes (i.e. EBC-316, 325–327, and 345 (10–15)), together with two known pimaranes (EBC-221 (8) and EBC-346 (9)), were isolated from the stems of Croton insularis, found in the Australian rainforest. All pimarane diterpenes disclosed herein are suggested to be biogenetically related to the same keto-Jacobs–Reynolds intermediate 2, via ring A and C oxidation. Anticancer activities of compounds 11–13 are reported.

Unprecedented 1,14-seco-crotofolanes from Croton insularis: oxidative cleavage of crotofolin C by a putative homo-Baeyer-Villiger rearrangement.

EBC-162 isolated from Croton insularis, obtained from the northern rainforest of Australia, was structurally affirmed as crotofolin C (4). Novel oxidative degradation products, EBC-233 and EBC-300, which are the first crotofolane endoperoxides, were also isolated. Both endoperoxides were found to be stable intermediates, which are proposed to undergo an unprecedented homo-Baeyer-Villiger biosynthetic rearrangement to give a new class of 1,14-seco-crotofolane diterpenes. Prolonged storage of all isolates assisted in authenticating their natural product status. Anticancer activities of reported compounds are presented.

The First Casbane Hydroperoxides EBC‐304 and EBC‐320 from the Australian Rainforest.

Investigation of the Australian rainforest plant Croton insularis led to isolation of the first casbane hydroperoxide diterpenes EBC-304 and EBC-320. Extensive DFT and electronic circular dichroism (ECD) calculations in combination with 2D NMR spectroscopy determined the absolute configurations. EBC-304 and EBC-320 both display significant cytotoxicity.

EBC-318 and 339: bicyclo[10.2.1]alkanes from Croton insularis

Two new crotinsulidanes EBC-318 and EBC-339 were isolated from the Australian rain forest plant Croton insularis. Both compounds are characterised by a bicyclo[10.2.1]alkane skeleton, one of which contains a bridgehead double bond. Cancer cell line cytotoxicity and biosynthetic considerations are presented.

Furofuran lignans from the Simpson Desert species Eremophila macdonnellii

The Eremophila plant family, which occurs in the arid zones of Australia, have witnessed extensive investigation, mostly inspired by Aboriginal traditional medicine. A wide and varied biological and phytochemical profile has been reported for over 18 individual species of Australian Eremophila, although E. macdonnellii from the Simpson Desert has not yet been investigated. Isolation and elucidation of one new and six known furofuran lignans are reported. The new lignan, epimethoxypiperitol, displayed moderate anti-cancer activity against the breast cancer cell line (MCF-7).

An improved preparation of phorbol from croton oil

Background: Croton oil is the only commercial source of the diterpenoid phorbol (1a), the starting material for the semi-synthesis of various diesters extensively used in biomedical research to investigate cell function and to evaluate in vivo anti-inflammatory activity. While efficient chemoselective esterification protocols have been developed for phorbol, its isolation from croton oil is technically complicated, and involves extensive manipulation of very toxic materials like the oil or its native diterpenoid fraction. Results: The preparation of a crude non-irritant phorboid mixture from croton oil was telescoped to only five operational steps, and phorbol could then be purified by gravity column chromatography and crystallization. Evidence is provided that two distinct phorboid chemotypes of croton oil exist, differing in the relative proportion of type-A and type-B esters and showing different stability to deacylation. Conclusion: The isolation of phorbol from croton oil is dangerous because of the toxic properties of the oil, poorly reproducible because of differences in its phorboid profile, and time-consuming because of the capricious final crystallization step. A solution for these issues is provided, suggesting that the poor-reproducibility of croton oil-based anti-inflammatory assays are the result of poor quality and/or inconsistent composition of croton oil.