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Revision as of 10:15, 11 August 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEBI').← Previous edit		Latest revision as of 11:45, 1 March 2024 edit undoAchmad Rachmani (talk | contribs)Extended confirmed users84,340 edits →Biochemistry method: Non-Latin character
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			{{cs1 config|name-list-style=vanc}}
	{{chembox		{{chembox
			| Verifiedfields = changed
	| verifiedrevid = 402706327
			| Watchedfields = changed
			| verifiedrevid = 470618015
	| ImageFile1 = tropinone.png		| ImageFile1 = tropinone.png
	| ImageFile2 = Tropinone-3D-sticks.png		| ImageFile2 = Tropinone-3D-sticks.png
	| IUPACName = 8-Methyl-8-azabicyclooctan-3-one		| IUPACName = 8-Methyl-8-azabicyclooctan-3-one
	| OtherNames = 3-Tropinone		| OtherNames = 3-Tropinone
	| Section1 = {{Chembox Identifiers		|Section1={{Chembox Identifiers
	| Abbreviations =		| Abbreviations =
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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	| StdInChIKey = QQXLDOJGLXJCSE-KNVOCYPGSA-N		| StdInChIKey = QQXLDOJGLXJCSE-KNVOCYPGSA-N
	| InChIKey1 = QQXLDOJGLXJCSE-KNVOCYPGSA-N		| InChIKey1 = QQXLDOJGLXJCSE-KNVOCYPGSA-N
	| CASNo_Ref = {{cascite|correct|cas}}		| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 532-24-1		| CASNo = 532-24-1
			| UNII_Ref = {{fdacite|correct|FDA}}
			| UNII = 2A8CC8KA5F
	| EINECS =		| EINECS =
	| PubChem = 446337		| PubChem = 446337
			| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
	| DrugBank = DB01874		| DrugBank = DB01874
	| SMILES = CN12CC1CC(=O)C2		| SMILES = CN12CC1CC(=O)C2
	| InChI =
	| RTECS =		| RTECS =
	| MeSHName =		| MeSHName =
			| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 16656		| ChEBI = 16656
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG =		| KEGG =
			}}
	| ATCCode_prefix =
			|Section2={{Chembox Properties
	| ATCCode_suffix =
	| ATC_Supplemental =}}
	| Section2 = {{Chembox Properties
	| Formula = C<sub>8</sub>H<sub>13</sub>NO		| Formula = C<sub>8</sub>H<sub>13</sub>NO
	| MolarMass = 139.195 g/mol		| MolarMass = 139.195 g/mol
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	| Density =		| Density =
	| MeltingPtC = 42.5		| MeltingPtC = 42.5
	| Melting_notes =		| MeltingPt_notes =
	| BoilingPt = (decomposes)		| BoilingPt = (decomposes)
	| Boiling_notes =		| BoilingPt_notes =
	| Solubility =		| Solubility =
	| SolubleOther =		| SolubleOther =
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	| pKa =		| pKa =
	| pKb = }}		| pKb = }}
	| Section7 = {{Chembox Hazards		|Section6={{Chembox Pharmacology
	| EUClass =		| ATCCode_prefix =
	| EUIndex =		| ATCCode_suffix =
			| ATC_Supplemental =
			}}
			|Section7={{Chembox Hazards
	| MainHazards =		| MainHazards =
			| GHSPictograms = {{GHS05}}{{GHS07}}<ref name="echa">{{cite web |title=Tropinone |url=https://echa.europa.eu/substance-information/-/substanceinfo/100.007.756 |website=Substance Information |publisher=ECHA}}</ref>
			| GHSSignalWord = Danger
			| HPhrases = {{H-phrases|302|314}}<ref name="echa" />
			| PPhrases =
	| NFPA-H = 2		| NFPA-H = 2
	| NFPA-F = 1		| NFPA-F = 1
	| NFPA-R = 0		| NFPA-R = 0
	| NFPA-O =
	| RPhrases =
	| SPhrases =
	| RSPhrases =
	| FlashPt =		| FlashPt =
	| Autoignition =		| AutoignitionPt =
	| ExploLimits =		| ExploLimits =
	| PEL = }}		| PEL =
			}}
	}}		}}
	'''Tropinone''' is an ], famously synthesised in 1917 by ] as a ] precursor to ], a scarce commodity during ].<ref>{{cite doi|10.1039/CT9171100762}}</ref><ref>{{Cite pmid|10649349}}</ref> Tropinone and the alkaloids ] and atropine all share the same ] core structure.		'''Tropinone''' is an ], famously synthesised in 1917 by ] as a ] precursor to ], a scarce commodity during ].<ref>{{Cite journal| last1 = Robinson | first1 = R.| title = LXIII. A Synthesis of Tropinone| journal = Journal of the Chemical Society, Transactions| volume = 111| pages = 762–768| year = 1917| doi = 10.1039/CT9171100762| url = https://zenodo.org/record/1429739}}</ref><ref>{{Cite journal
			| last1 = Nicolaou | first1 = K. C.
			| author-link1 = K. C. Nicolaou
			| last2 = Vourloumis | first2 = D.
			| last3 = Winssinger | first3 = N.
			| last4 = Baran | first4 = P. S.
			| author-link4 = Phil S. Baran
			| title = The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century
			| journal = Angewandte Chemie International Edition
			| volume = 39
			| issue = 1
			| pages = 44–122
			| year = 2000
			| doi = 10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L | pmid=10649349
			}}</ref> Tropinone and the alkaloids ] and atropine all share the same ] core structure. Its corresponding conjugate acid at pH 7.3 major species is known as tropiniumone.<ref></ref>
	==Synthesis==		==Synthesis==
	The first synthesis of tropinone was by ] in 1901. It started from the seemingly related ], but required many steps to introduce the nitrogen bridge; the overall ] for the synthesis path is only 0.75%.<ref name=smit>{{Cite doi|10.1039/9781847551573}}</ref> Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.<ref>{{Cite doi|10.1039/b001713m}}</ref>		The first synthesis of tropinone was by ] in 1901. It started from the seemingly related ], but required many steps to introduce the nitrogen bridge; the overall ] for the synthesis path is only 0.75%.<ref name=smit>{{Cite book| title = Organic Synthesis| year = 1998| isbn = 978-0-85404-544-0| doi = 10.1039/9781847551573| last1 = Smit| first1 = Wim A.| last2 = Smit| first2 = William A.| last3 = Bochkov| first3 = Alekseĭ Feodosʹevich| last4 = Caple| first4 = Ron}}</ref> Willstätter had previously synthesized cocaine from tropinone, in what was the first synthesis and elucidation of the structure of cocaine.<ref>{{Cite journal| last1 = Humphrey | first1 = A. J.| last2 = O'Hagan| first2 = D.| title = Tropane alkaloid biosynthesis. A century old problem unresolved| journal = ]| publisher = ]| volume = 18| pages = 494–502| year = 2001| doi = 10.1039/b001713m| pmid = 11699882 | issue = 5}}</ref>
			]
	]
			===Robinson's "double Mannich" reaction===
	The 1917 synthesis by Robinson is considered a classic in ]<ref>{{Cite doi|10.1098/rsnr.1993.0034}}</ref> due to its simplicity and biomimetic approach. Tropinone is a ], but the ]s used in its preparation are fairly simple: ], ] and ] (or even ]). The synthesis is a good example of a ] reaction or '''biogenetic-type synthesis''' because ] makes use of the same building blocks. It also demonstrates a ] in a ]. Furthermore the yield of the synthesis was 17% and with subsequent improvements exceeded 90%.<ref name=smit />
			The 1917 synthesis by Robinson is considered a classic in ]<ref>{{Cite journal| last1 = Birch | first1 = A. J.| title = Investigating a Scientific Legend: The Tropinone Synthesis of Sir Robert Robinson, F.R.S| journal = Notes and Records of the Royal Society of London| volume = 47| issue = 2| pages = 277–296| year = 1993 | jstor = 531792| doi = 10.1098/rsnr.1993.0034 | s2cid = 143267467}}</ref> due to its simplicity and biomimetic approach. Tropinone is a ], but the ]s used in its preparation are fairly simple: ], ] and ] (or even ]). The synthesis is a good example of a ] reaction or '''biogenetic-type synthesis''' because ] makes use of the same building blocks. It also demonstrates a ] in a ]. Furthermore, the yield of the synthesis was 17% and with subsequent improvements exceeded 90%.<ref name=smit />
	:]
			:]
	This reaction is described as an intramolecular "double ]" for obvious reasons. It is not unique in this regard, as others have also attempted it in piperidine synthesis.<ref>{{Cite pmid|10669562}}</ref><ref>{{Cite pmid|11425577}}</ref>
			This reaction is described as an intramolecular "double ]" for obvious reasons. It is not unique in this regard, as others have also attempted it in piperidine synthesis.<ref>{{Cite journal
			| doi = 10.1021/jm990516x
			| pmid = 10669562
			| year = 2000
			| last1 = Wang | first1 = S.
			| last2 = Sakamuri
			| last3 = Enyedy
			| last4 = Kozikowski
			| last5 = Deschaux
			| last6 = Bandyopadhyay
			| last7 = Tella
			| last8 = Zaman
			| last9 = Johnson
			| title = Discovery of a novel dopamine transporter inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone, as a potential cocaine antagonist through 3D-database pharmacophore searching. Molecular modeling, structure-activity relationships, and behavioral pharmacological studies
			| volume = 43
			| issue = 3
			| pages = 351–360
			| journal = ] | first2 = S. | first3 = I. J. | first4 = A. P. | first5 = O. | first6 = B. C. | first7 = S. R. | first8 = W. A. | first9 = K. M.
			}}</ref><ref>{{Cite journal
			| pmid = 11425577
			| year = 2001
			| last1 = Wang | first1 = S.
			| last2 = Sakamuri
			| last3 = Enyedy
			| last4 = Kozikowski
			| last5 = Zaman
			| last6 = Johnson
			| title = Molecular modeling, structure--activity relationships and functional antagonism studies of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketones as a novel class of dopamine transporter inhibitors
			| volume = 9
			| issue = 7
			| pages = 1753–1764
			| journal = Bioorganic & Medicinal Chemistry
			| doi = 10.1016/S0968-0896(01)00090-6
			}}</ref>
	In place of acetone, acetonedicarboxylic acid is known as the "]" the 1,3-dicarboxylic acid groups are so-called "]s" to facilitate the ring forming reactions. The calcium salt is there as a "]" as it is claimed that higher yields are possible if the reaction is conducted at "] ]".		In place of acetone, acetonedicarboxylic acid is known as the "]" the 1,3-dicarboxylic acid groups are so-called "]s" to facilitate the ring forming reactions. The calcium salt is there as a "]" as it is claimed that higher yields are possible if the reaction is conducted at "] ]".
	== Reaction mechanism==		=== Reaction mechanism===
	The main features apparent from the reaction sequence below are:		The main features apparent from the reaction sequence below are:
	#] of ] to ], followed by loss of water to create an ]		#] of ] to ], followed by loss of water to create an ]
	#Intramolecular addition of the imine to the second aldehyde unit and first ring closure		#] addition of the imine to the second aldehyde unit and first ring closure
	#] ] of the ] of acetone dicarboxylate		#] ] of the ] of acetone dicarboxylate
	#New enolate formation and new imine formation with loss of water for		#New enolate formation and new imine formation with loss of water for
	#Second ] mannich reaction and second ring closure		#Second intramolecular Mannich reaction and second ring closure
	#Loss of 2 carboxylic groups to tropinone		#Loss of 2 carboxylic groups to tropinone
	:]		:]
	Some authors have actually tried to retain one of the CO<sub>2</sub>H groups.<ref>{{Cite doi|10.1021/jo01362a022}}</ref>		Some authors have actually tried to retain one of the CO<sub>2</sub>H groups.<ref>{{Cite journal| last1 = Findlay | first1 = S. P.| title = Concerning 2-Carbomethoxytropinone | journal = Journal of Organic Chemistry | year = 1957 | volume = 22 | issue = 11| pages = 1385–1394| doi = 10.1021/jo01362a022}}</ref>
			CO<sub>2</sub>R-tropinone has 4 stereoisomers, although the corresponding ] alkyl ester has only a pair of enantiomers.
			===From cycloheptanone===
			] dehydrogenation (oxidation) of ] (suberone) to 2,6-cycloheptadienone followed by reaction with an amine is versatile a way of forming tropinones.<ref>{{US patent|8609690}}</ref><ref>{{cite journal | doi = 10.1021/ja012127+ | pmid = 11878978 | year = 2002 | last1 = Nicolaou | first1 = K. C. | last2 = Montagnon | first2 = T. | last3 = Baran | first3 = P. S. | last4 = Zhong | first4 = Y. L. | title = Iodine(V) reagents in organic synthesis. Part 4. O-Iodoxybenzoic acid as a chemospecific tool for single electron transfer-based oxidation processes | journal = Journal of the American Chemical Society | volume = 124 | issue = 10 | pages = 2245–58 }}</ref> The mechanism evoked is clearly delineated to be a double ] (i.e. conjugate addition).
			===Biochemistry method===
			{{empty section|date=April 2022}}
			<ref name="BedewitzJones2018">{{cite journal|last1=Bedewitz|first1=Matthew A.|last2=Jones|first2=A. Daniel|last3=D'Auria|first3=John C.|last4=Barry|first4=Cornelius S.|title=Tropinone synthesis via an atypical polyketide synthase and P450-mediated cyclization|journal=Nature Communications|volume=9|issue=1|year=2018|page=5281|issn=2041-1723|doi=10.1038/s41467-018-07671-3|pmid=30538251|pmc=6290073|bibcode=2018NatCo...9.5281B|doi-access=free}}</ref>
			===Reduction of tropinone===
			The reduction of tropinone is mediated by ]-dependent reductase enzymes, which have been characterized in multiple plant species.<ref>{{cite journal | doi = 10.1016/0031-9422(92)80247-C | title = Two tropinone reducing enzymes from Datura stramonium transformed root cultures | year = 1992 |author1=A. Portsteffen |author2=B. Draeger |author3=A. Nahrstedt | journal = Phytochemistry | volume = 31 | pages = 1135 | issue = 4| bibcode = 1992PChem..31.1135P }}</ref> These plant species all contain two types of the reductase enzymes, tropinone reductase I and tropinone reductase II. TRI produces tropine and TRII produces pseudotropine. Due to differing kinetic and pH/activity characteristics of the enzymes and by the 25-fold higher activity of TRI over TRII, the majority of the tropinone reduction is from TRI to form tropine.<ref>{{cite journal |vauthors=Boswell HD, Dräger B, McLauchlan WR |title=Specificities of the enzymes of ''N''-alkyltropane biosynthesis in Brugmansia and Datura |journal=Phytochemistry |volume=52 |issue=5 |pages=871–8 |date=November 1999 |pmid=10626376 |doi= 10.1016/S0031-9422(99)00293-9|bibcode=1999PChem..52..871B |display-authors=etal}}</ref>
			]
			== See also ==
	CO<sub>2</sub>R-tropinone has 4 stereoisomers, although the corresponding ] alkyl ester there is only a pair of enantiomers.
			* ]
			* ]
			* ] (2-CMT) an intermediate in the creation of ] ]
			*]
	== References ==		== References ==
			{{reflist|2}}
	<references />
	==External links==		== External links ==
	*		*
	*
			]
	]
	]
	]		]
	]		]
	]
	]
	]
	]