Craig M. Williams

Discovery of a Widespread Infestation of Aedes albopictus in the Torres Strait, Australia

ABSTRACT Aedes albopictus is a container-breeding Stegomyia mosquito that has dispersed widely from its origins in Southeast Asia. Because Ae. albopictus is a known dengue vector and a potential vector of a variety of arboviruses and it can tolerate cooler climates than Aedes aegypti, Australian quarantine and health authorities have strategies to detect and eliminate it from international ports. Following the detection of 42 adult Ae. albopictus in BG-Sentinel traps set on Yorke island in the Torres Strait of Australia in April 2005, extensive surveys were conducted to determine the distribution of Ae. albopictus in the Torres Strait and adjoining Cape York Peninsula. A total of 17 islands and the northern peninsula area of Cape York Peninsula were surveyed by collection of larvae and pupae from flooded containers and human bait collections of adult mosquitoes with aspirators and sweep nets. Aedes albopictus was detected on 10 islands and comprised 100% of the day-biting container-breeding mosquitoes on Yorke and Stephens Islands. No Ae. albopictus were detected in the mainland sites on Cape York. Retrospective genetic analysis of larvae collected in April 2004 and April 2005 on Yorke Island indicated that Ae. albopictus was present in low densities in 2004 and that there were 3 genetically distinct mitochondrial haplotypes on Yorke Island in April 2005. Additionally, on Yorke Island there is evidence that Ae. albopictus is displacing Aedes scutellaris.

Asymmetric [4 + 3] Cycloadditions between Vinylcarbenoids and Dienes: Application to the Total Synthesis of the Natural Product (−)-5-epi-Vibsanin E

The total synthesis of (-)-5-epi-vibsanin E (2) has been achieved in 18 steps. The synthesis combines the rhodium-catalyzed [4 + 3] cycloaddition between a vinylcarbenoid and a diene to rapidly generate the tricyclic core with an effective end game strategy to introduce the remaining side-chains. The [4 + 3] cycloaddition occurs by a cyclopropanation to form a divinylcyclopropane followed by a Cope rearrangement to form a cycloheptadiene. The quaternary stereogenic center generated in the process can be obtained with high asymmetric induction when the reaction is catalyzed by the chiral dirhodium complex, Rh(2)(S-PTAD)(4).

Synthesis of phenanthridine derivatives via photolysis.

An improved photochemical method for producing the prolifically bioactive phenanthridine system is reported. A wide variety of derivatives were obtained in two steps in yields ranging from 31 to 95%.

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.

Natural Products with Anti-Bredt and Bridgehead Double Bonds

Well over a hundred years ago, Professor Julius Bredt embarked on a career pursuing and critiquing bridged bicyclic systems that contained ring strain induced by the presence of a bridgehead olefin. These endeavors founded what we now know as Bredts rule (Bredtsche Regel). Physical, theoretical, and synthetic organic chemists have intensely studied this premise, pushing the boundaries of such systems to arrive at a better understood physical phenomenon. Mother nature has also seen fit to construct molecules containing bridgehead double bonds that encompass Bredts rule. For the first time, this topic is reviewed in a natural product context.

Copper(I)-catalyzed cycloaddition of silver acetylides and azides: Incorporation of volatile acetylenes into the triazole core

Silver acetylides and organic azides react under copper(I) catalysis to afford 1,4-disubstituted 1,2,3-triazoles. Mechanistic studies implicate a process involving transmetallation to copper acetylides prior to cycloaddition. This work demonstrates that silver acetylides serve as suitable precursors for entry into copper-mediated coupling reactions. This methodology allows the incorporation of volatile and difficult-to-handle acetylenes into the triazole core.

Structure and Absolute Stereochemistry of the Anticancer Agent EBC-23 from the Australian Rainforest

EBC-23 (2), a prostate anticancer agent, was isolated from the fruit of Cinnamomum laubatii (family Lauraceae) in the Australian tropical rainforest. Extensive NOE experiments enabled the relative stereochemistry of the proposed EBC-23 (2) structure to be determined. Total synthesis of both enantiopodes over nine linear steps, involving challenging RCM and spiroacetal cyclizations, confirmed the gross structure and relative and absolute stereochemistry.

Unexpected titanium shifts during cyclopropanation of N,N-dibenzylformamide with ligand-exchanged titanium-alkadiene complexes

A number of readily available dienes and a triene were applied to exchange the alkene ligand on the in situ generated titanium-alkene complexes which react with N,N-dialkylcarboxamides to give N,N-dialkylcyclopropylamines. The ligand-exchanged intermediates were found to give the most highly substituted alkenylcyclopropylamines (abnormal products) in good yields (47-64%), rather than the least substituted alkenylcyclopropylamine (expected products). This has been attributed to an unforeseen and unprecedented titanium migration along the ligand

Anticancer agents from the Australian tropical rainforest: Spiroacetals EBC-23, 24, 25, 72, 73, 75 and 76

EBC-23, 24, 25, 72, 73, 75 and 76 were isolated from the fruit of Cinnamomum laubatii (family Lauraceae) in the Australian tropical rainforests. EBC-23 (1) was synthesized stereoselectively, in nine linear steps in 8 % overall yield, to confirm the reported relative stereochemistry and determine the absolute stereochemistry. Key to the total synthesis was a series of Tietze-Smith linchpin reactions. The novel spiroacetal structural motif, exemplified by EBC-23 (1), was found to inhibit the growth of the androgen-independent prostate tumor cell line DU145 in the mouse model, indicating potential for the treatment of refractory solid tumors in adults.

Total synthesis of (+)-5, 14-bis-epi-Spirovibsanin A

The total synthesis of (+/-)-5,14-bis-epi-spirovibsanin A was achieved in 18 steps. Physical data obtained from (+/-)-5,14-bis-epi-spirovibsanin A lends strong support to the proposed connectivity and relative stereochemistry of spirovibsanin A.