Editing Aconitine (section)

==Biosynthesis and total synthesis of related alkaloids==
Aconitine is biosynthesized by the [[monkshood]] plant via the [[terpenoid]] biosynthesis pathway (MEP chloroplast pathway).<ref>{{cite web | last1 = Viberti | first1 = Fabrizio | last2 = Raveggi | first2 = Elisa | name-list-style = vanc |title= Aconitine: How Poisonous, How Harmful? |url=http://flipper.diff.org/app/items/6692|website=flipper e nuvola|access-date=26 April 2017}}</ref> Approximately 700 naturally occurring C19-diterpenoid alkaloids have been isolated and identified, but the biosynthesis of only a few of these alkaloids are well understood.<ref name="pmid19275222">{{cite journal | vauthors = Zhao PJ, Gao S, Fan LM, Nie JL, He HP, Zeng Y, Shen YM, Hao XJ | title = Approach to the biosynthesis of atisine-type diterpenoid alkaloids | journal = Journal of Natural Products | volume = 72 | issue = 4 | pages = 645–9 | date = April 2009 | pmid = 19275222 | doi = 10.1021/np800657j | bibcode = 2009JNAtP..72..645Z }}</ref>

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory.  In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its [[total synthesis]].  The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that makes up its core and the elaborate collection of oxygenated functional groups at its periphery.  A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically.  In 1971, the Weisner group discovered the [[total synthesis]] of talatisamine (a C19-norditerpenoid).<ref name="Wiesner_1974">{{cite journal | vauthors = Wiesner K, Tsai TY, Huber K, Bolton SE, Vlahov R | title=Total synthesis of talatisamine, a delphinine type alkaloid|journal=Journal of the American Chemical Society|date=July 1974|volume=96|issue=15|pages=4990–4992|doi=10.1021/ja00822a048| bibcode=1974JAChS..96.4990W}}</ref> In the subsequent years, they also discovered the [[Total synthesis|total syntheses]] of other C19-norditerpenoids, such as chasmanine,<ref name="Wiesner_1978">{{cite journal | vauthors = Wiesner K, Tsai TY, Nambiar KP |title=A new stereospecific total synthesis of chasmanine and 13-desoxydelphonine|journal=Canadian Journal of Chemistry|date=15 May 1978|volume=56|issue=10|pages=1451–1454|doi=10.1139/v78-237|doi-access=free}}</ref> and 13-deoxydelphonine.<ref name="Wiesner_1979">{{cite journal | vauthors = Wiesner K |title=Total synthesis of delphinine-type alkaloids by simple, fourth generation methods|journal=Pure and Applied Chemistry|date=1 January 1979|volume=51|issue=4|pages=689–703|doi=10.1351/pac197951040689|doi-access=free}}</ref>

[[File:Wiesner Syntheses Schematic.jpg|thumb|Schematic for the Wiesner Syntheses of Napelline. Deoxydelphonine and Talatisamine]]

The total synthesis of napelline ('''Scheme a''') begins with [[aldehyde]] '''100'''.<ref name="Wiesner_1974"/> In a 7 step process, the A-ring of napelline is formed ('''104'''). It takes another 10 steps to form the [[lactone]] ring in the pentacyclic structure of napelline ('''106'''). An additional 9 steps creates the enone-aldehyde '''107'''. Heating in methanol with potassium hydroxide causes an [[aldol condensation]] to close the sixth and final ring in napelline ('''14'''). Oxidation then gives rise to diketone '''108''' which was converted to (±)-napelline ('''14''') in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone ('''Scheme c''').<ref name="Wiesner_1978"/> The first step of this synthesis is the generation of a conjugated [[enone|dienone]] '''112''' from '''111''' in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce '''113'''. In 11 steps, this compound is converted to [[ketal]] 114. The addition of heat, DMSO and o-xylene rearranges this ketol ('''115'''), and after 5 more steps (±)-13-desoxydelphinone ('''15''') is formed.

Lastly, talatisamine ('''Scheme d''') is synthesized from diene '''116''' and nitrile '''117'''.<ref name="Wiesner_1979"/> The first step is to form tricycle '''118'''  in 16 steps. After another 6 steps, this compound is converted to [[enone]] '''120'''. Subsequently, this allene is added to produce [[Adduct|photoadduct]] '''121'''. This adduct group is cleaved and rearrangement gives rise to the compound '''122'''. In 7 steps, this compound forms '''123''', which is then rearranged, in a similar manner to compound '''114''', to form the aconitine-like skeleton in '''124'''. A racemic relay synthesis is completed to produce talatisamine ('''13''').

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine<ref>{{cite journal | vauthors = Peese KM, Gin DY | title = Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels-Alder cycloadditions | journal = Journal of the American Chemical Society | volume = 128 | issue = 27 | pages = 8734–5 | date = July 2006 | pmid = 16819859 | pmc = 2610465 | doi = 10.1021/ja0625430 }}</ref> and neofinaconitine.<ref>{{cite journal | vauthors = Shi Y, Wilmot JT, Nordstrøm LU, Tan DS, Gin DY | title = Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine | language = EN | journal = Journal of the American Chemical Society | volume = 135 | issue = 38 | pages = 14313–20 | date = September 2013 | pmid = 24040959 | pmc = 3883312 | doi = 10.1021/ja4064958 | bibcode = 2013JAChS.13514313S }}</ref>