Todd:Pictet-Spengler to PZQ - Revision history

Matthew Todd: /* Supporting Information */ added ugi isocyanide scheme to SI

Matthew Todd — Thu, 13 Sep 2012 17:14:02 GMT

Supporting Information: added ugi isocyanide scheme to SI

←Older revision		Revision as of 17:14, 13 September 2012
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	Synthesis of 7b: MW32-3 (93%)		Synthesis of 7b: MW32-3 (93%)
	''(What about &c and d by this route?)''		''(What about &c and d by this route?)''
		+
		+	Synthesis of Ugi Isocyanides
		+	[[Image:Isocyanide.png\|thumb\|center\|450px\| '''Scheme X''': Formation of Isocyanides 6e and 6f.]]

	Synthesis/Acquisition of Candidate Catalysts		Synthesis/Acquisition of Candidate Catalysts

Matthew Todd: /* 1. Preparation of Cyclization Precursors */ rewriting ugi sm preps

Matthew Todd — Thu, 13 Sep 2012 17:13:12 GMT

1. Preparation of Cyclization Precursors: rewriting ugi sm preps

←Older revision		Revision as of 17:13, 13 September 2012
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	The conventional stepwise synthesis successfully gave the cyclisation precursors ''(need method summary and description of yields)'' (See Supporting Information).		The conventional stepwise synthesis successfully gave the cyclisation precursors ''(need method summary and description of yields)'' (See Supporting Information).

-	Synthesis of these materials ''via'' Ugi multicomponent coupling was also successful and more convenient ''(~~need summary of results~~)''. Details may be found in the Supporting Information.	+	Synthesis of these materials ''via'' Ugi multicomponent coupling was also successful and more convenient. Synthesis of the isocyanides '''6e''' ([http://www.ourexperiment.org/racemic_pzq/1564/Preparation_of_2phenylethyl_isocyanide__alternative_route__MW343.html MW34-3]) and '''6f''' ([http://www.ourexperiment.org/racemic_pzq/3915/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR42.html MNR4-2]) was achieved ''via'' the Ugi formamide route from the corresponding amines following Doemling's 2-step procedure.[[http://onlinelibrary.wiley.com/doi/10.1002/anie.197205301/abstract Ugi, Angew Int, 1972],[http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009115333A1&KC=A1&FT=D&date=20090924&DB=EPODOC&locale=en_ep Doemling PCT Int, 2009]] Attempts to use a Hoffman-type procedure did give the desired product ([http://www.ourexperiment.org/racemic_pzq/309/Preparation_of_2Phenylethyl_isocyanide_MW341.html MW34-1])in one step using chloroform as the source of C<sup>l</sup>, but this approach proved less efficient, especially on scale up ([http://www.ourexperiment.org/racemic_pzq/338/Scaleup__Preparation_of_2Phenylethyl_isocyanide_MW342.html MW34-2]). Details may be found in the Supporting Information.<br>

-	''~~1b. i) Synthesis of the isocyanides''<br>~~	+	''(need completion of summary of results here)''.
-	Isocyanides [http://www.ourexperiment.org/racemic_pzq/1564/Preparation_of_2phenylethyl_isocyanide__alternative_route__MW343.html MW34-3] and [http://www.ourexperiment.org/racemic_pzq/3915/Preparation_of_234Dimethoxyphenylethyl_isocyanide_MNR42.html MNR4-2] were prepared via the Ugi formamide route from the corresponding amines following Doemlings 2-step procedure.[[http://onlinelibrary.wiley.com/doi/10.1002/anie.197205301/abstract Ugi, Angew Int, 1972],[http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009115333A1&KC=A1&FT=D&date=20090924&DB=EPODOC&locale=en_ep Doemling PCT Int, 2009]] Attempts to use a Hoffman type procedure produced the desired product (~~[http://www.ourexperiment.org/racemic_pzq/309/Preparation_of_2Phenylethyl_isocyanide_MW341.html MW34-1])in one step using chloroform as the source~~ of ~~Cl, but this proved less efficient especially on scale up ([http://www.ourexperiment.org/racemic_pzq/338/Scaleup__Preparation_of_2Phenylethyl_isocyanide_MW342.html MW34-2]~~)~~.<br>~~	+
-		+
-	*Care should be taken in the handling of the isocyanides as they have a strong odour with an unpleasant metallic taste<br>	+
-		+
-	~~[[Image:Isocyanide.png\|thumb\|center\|450px\| '''Scheme: Formation of isocyanides MW34-4 and MNR4-2'~~''.]]	+

	''1b. ii) Ugi: Multicomponent Couplings''		''1b. ii) Ugi: Multicomponent Couplings''

Matthew Todd: /* Supporting Information */ moved sm synth to SI

Matthew Todd — Thu, 13 Sep 2012 17:04:55 GMT

Supporting Information: moved sm synth to SI

←Older revision		Revision as of 17:04, 13 September 2012
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	==Supporting Information==		==Supporting Information==
		+
		+
		+	'''Synthesis of cylisation precursors using conventional stepwise approach'''
		+	[[Image:Stepwise_MW.png\|thumb\|center\|650px\| '''Scheme: Stepwise Formation of Pictet-Spengler Starting Materials''']]
		+	Synthesis of 3e: MW???
		+	Synthesis of 3f: MW9-3-79
		+	Synthesis of 4e: MW7-2-27
		+	Synthesis of 4f: MW14-3-79 (74%)
		+	Synthesis of 7a: MW29-4 (98%)
		+	Synthesis of 7b: MW32-3 (93%)
		+	''(What about &c and d by this route?)''

	Synthesis/Acquisition of Candidate Catalysts		Synthesis/Acquisition of Candidate Catalysts

Matthew Todd: /* Results */ reworking the synthesis of starting materials

Matthew Todd — Thu, 13 Sep 2012 17:04:03 GMT

Results: reworking the synthesis of starting materials

←Older revision		Revision as of 17:04, 13 September 2012
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	===1. Preparation of Cyclization Precursors===		===1. Preparation of Cyclization Precursors===

-	The peptide acetal precursors '''7a-d''' ~~to the PS reaction could~~ be made using a [http://www.thesynapticleap.org/node/288 traditional stepwise approach][[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim, Tet, 1998], [http://www.springerlink.com/content/55122gr811h23370/?MUD=MP Min, Arch. Pharm. Res., 1998]] or an Ugi 3-component coupling [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem.Eur.J. 2010]] (Scheme 1). These were then shown to undergo PS reactions in the presence of excess acid, to give PZQ and its three analogs as racemates. Investigations of chiral acids were then undertaken collaboratively in a search for an effective catalyst system for optimization.<br>	+	The peptide acetal precursors to the PS reaction ('''7a-d''') can be made using a [http://www.thesynapticleap.org/node/288 traditional stepwise approach][[http://www.sciencedirect.com/science/article/pii/S0040402098004013 Kim Tet, 1998], [http://www.springerlink.com/content/55122gr811h23370/?MUD=MP Min Arch. Pharm. Res., 1998]] or an Ugi 3-component coupling [[http://onlinelibrary.wiley.com/doi/10.1002/chem.201002046/abstract Doemling Chem. Eur. J. 2010]] (Scheme 1).<br>

-	'''1a. ~~Conventional Stepwise Synthesis'''~~	+	The conventional stepwise synthesis successfully gave the cyclisation precursors ''(need method summary and description of yields)'' (See Supporting Information).

-	~~[[Image:Stepwise_MW.png\|thumb\|center\|650px\| '''Scheme: Formation~~ of ~~Pictet-Spengler starting~~ materials''']]	+	Synthesis of these materials ''via'' Ugi multicomponent coupling was also successful and more convenient ''(need summary of results)''. Details may be found in the Supporting Information.
-		+
-	'''~~1b. Synthesis via Ugi Multicomponent Coupling'~~''	+

	''1b. i) Synthesis of the isocyanides''<br>		''1b. i) Synthesis of the isocyanides''<br>
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	Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[[http://pubs.acs.org/doi/abs/10.1021/om00105a047 Nishiyama, Organometallics, 1989]] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 % of [http://www.ourexperiment.org/racemic_pzq/4755/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB16.html KAB1-6] and 87% for [http://www.ourexperiment.org/racemic_pzq/4684/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB815.html KAB8-15] with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion (see experiments [http://www.ourexperiment.org/racemic_pzq/3757/The_metal_triflate_catalysed_PictetSpengler_to_give_racemic_PZQ_KAB39__KAB310.html KAB3-9 and KAB3-10]). A negative control was also carried out using AgCl (table entry 6, [http://www.ourexperiment.org/racemic_pzq/4510/AgCl_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB813.html KAB8-13]). This confirmed that the metal alone was not catalysing the cyclisation.		Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[[http://pubs.acs.org/doi/abs/10.1021/om00105a047 Nishiyama, Organometallics, 1989]] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 % of [http://www.ourexperiment.org/racemic_pzq/4755/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB16.html KAB1-6] and 87% for [http://www.ourexperiment.org/racemic_pzq/4684/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB815.html KAB8-15] with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion (see experiments [http://www.ourexperiment.org/racemic_pzq/3757/The_metal_triflate_catalysed_PictetSpengler_to_give_racemic_PZQ_KAB39__KAB310.html KAB3-9 and KAB3-10]). A negative control was also carried out using AgCl (table entry 6, [http://www.ourexperiment.org/racemic_pzq/4510/AgCl_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB813.html KAB8-13]). This confirmed that the metal alone was not catalysing the cyclisation.
	[[Image:Table03.PNG\|thumb\|center\|700px]]		[[Image:Table03.PNG\|thumb\|center\|700px]]
-
-

	==Experimental Protocols for Catalyst Screening==		==Experimental Protocols for Catalyst Screening==

Matthew Todd: /* Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions */

Matthew Todd — Thu, 13 Sep 2012 16:51:33 GMT

Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions

←Older revision		Revision as of 16:51, 13 September 2012
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	==Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions==		==Literature: Examples of Catalytic, Enantioselective Pictet-Spengler Reactions==

-	There is only currently [http://en.wikipedia.org/wiki/Pictet%E2%80%93Spengler_reaction a brief account of PS reactions on Wikipedia], and no page for the asymmetric version of the reaction. A review on [[Todd:Catalytic%2C_Asymmetric_Pictet-Spengler_Reaction \| The Catalytic, Asymmetric Pictet-Spengler Reaction]]is currently being assembled .<br>	+	There is only currently [http://en.wikipedia.org/wiki/Pictet%E2%80%93Spengler_reaction a brief account of PS reactions on Wikipedia], and no page for the asymmetric version of the reaction. A review on [[Todd:Catalytic%2C_Asymmetric_Pictet-Spengler_Reaction \| The Catalytic, Asymmetric Pictet-Spengler Reaction]]is currently being assembled.<br>

	==Results==		==Results==

Murray N Robertson: /* Experimental Protocols for Catalyst Screening */

Murray N Robertson — Sun, 17 Jun 2012 04:31:03 GMT

Experimental Protocols for Catalyst Screening

←Older revision		Revision as of 04:31, 17 June 2012
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	[http://www.ourexperiment.org/data/files/3274/IMG_1283.jpeg MNR8 reaction to KAB1-2 TLC (60% EtOAc:Hex)] Starting material Rf = 0.2, Product Rf = 0.1, Enamide Rf = 0.33		[http://www.ourexperiment.org/data/files/3274/IMG_1283.jpeg MNR8 reaction to KAB1-2 TLC (60% EtOAc:Hex)] Starting material Rf = 0.2, Product Rf = 0.1, Enamide Rf = 0.33
	<br><br>		<br><br>
-	[http://openwetware.org/images/e/e1/HPLC_kab1_25EtOH_05ml.pdf Chiral HPLC trace of KAB1 using 25% EtOH in hexane + 0.2% TEA.]	+	[http://openwetware.org/images/e/e1/HPLC_kab1_25EtOH_05ml.pdf Chiral HPLC trace of KAB1 using 25% EtOH in hexane + 0.2% TEA.] using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min
	<br><br>		<br><br>
	2-benzoyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one ('''KAB8-16''')		2-benzoyl-9,10-dimethoxy-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(11bH)-one ('''KAB8-16''')
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	[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33		[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33
	<br><br>		<br><br>
-	[http://openwetware.org/images/a/a3/HPLC_kab8.pdf Chiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.]	+	[http://openwetware.org/images/a/a3/HPLC_kab8.pdf Chiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.] using a CHIRALCEL OD-H column and a flow rate of 0.5 mL/min

	==Outlook==		==Outlook==

Matthew Todd: /* Experimental Protocols for Catalyst Screening */

Matthew Todd — Tue, 12 Jun 2012 12:58:49 GMT

Experimental Protocols for Catalyst Screening

←Older revision		Revision as of 12:58, 12 June 2012
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	[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33		[http://www.ourexperiment.org/data/files/3556/IMG_1410.jpg MNR10 reaction to KAB8-16 TLC (60% EtOAc:Hex)] Starting material Rf = 0.23, Product Rf = 0.15, Enamide Rf = 0.33
	<br><br>		<br><br>
-	[http://openwetware.org/images/a/a3/HPLC_kab8.~~pdfChiral~~ HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.]	+	[http://openwetware.org/images/a/a3/HPLC_kab8.pdf Chiral HPLC trace of KAB8 using 25% EtOH in hexane + 0.2% TEA.]

	==Outlook==		==Outlook==

Murray N Robertson: /* Summary */

Murray N Robertson — Thu, 17 May 2012 07:53:45 GMT

Summary

←Older revision		Revision as of 07:53, 17 May 2012
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	[[Image:Table03.PNG\|thumb\|center\|700px]]		[[Image:Table03.PNG\|thumb\|center\|700px]]

-	~~==Summary==~~

-	~~Results:~~
-	~~Use of catalytic vs stoich achiral acid? Results.~~
-	~~Use of chiral acids. Little reaction. What is the evidence for any hemiaminals? Starting material – lots in unactivated. Messy NMR, so some reaction.~~
-
-	~~Discussion of range of acidity – what we have tried compared to what not.~~

	==Experimental Protocols for Catalyst Screening==		==Experimental Protocols for Catalyst Screening==

Murray N Robertson: /* 2. Racemic Cyclizations */

Murray N Robertson — Thu, 17 May 2012 07:28:55 GMT

2. Racemic Cyclizations

←Older revision		Revision as of 07:28, 17 May 2012
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	[[Image:Table02.PNG\|thumb\|center\|600px]]		[[Image:Table02.PNG\|thumb\|center\|600px]]
-	Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[~~REF~~] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 and 87% ~~yields~~ with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion.	+	Continuing on, metal triflates were then studied with the potential of employing bisoxazoline ligands (BOX ligands) to generate chiral catalysts.[[http://pubs.acs.org/doi/abs/10.1021/om00105a047 Nishiyama, Organometallics, 1989]] Copper and silver triflate were investigated with the silver triflate being more extensively screened. Again as for the previous examples, electron rich systems (MNR8 and MNR10) cyclised and the desired products were isolated in 78 % of [http://www.ourexperiment.org/racemic_pzq/4755/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_PZQ_analogue_KAB16.html KAB1-6] and 87% for [http://www.ourexperiment.org/racemic_pzq/4684/AgOTf_catalysed_PS_reaction_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB815.html KAB8-15] with a catalyst loading of 10%. No further attempts at this stage were taken to reduce the catalyst loading any further. Also, as before, increasing the catalyst loading did not help to push KAB5-2 and MW51-1 to completion (see experiments [http://www.ourexperiment.org/racemic_pzq/3757/The_metal_triflate_catalysed_PictetSpengler_to_give_racemic_PZQ_KAB39__KAB310.html KAB3-9 and KAB3-10]). A negative control was also carried out using AgCl (table entry 6, [http://www.ourexperiment.org/racemic_pzq/4510/AgCl_catalysed_PS_to_give_the_dimethoxy_Nbenzoyl_PZQ_analogue_KAB813.html KAB8-13]). This confirmed that the metal alone was not catalysing the cyclisation.
	[[Image:Table03.PNG\|thumb\|center\|700px]]		[[Image:Table03.PNG\|thumb\|center\|700px]]
-
-
-
-
-
-
-
-
-
-	~~Relevant Literature~~
-
-	* [http://pubs.acs.org/doi/abs/10.1021/jo0524775 Youn 2006 JOC]

	==Summary==		==Summary==

Murray N Robertson: /* 2. Racemic Cyclizations */

Murray N Robertson — Thu, 17 May 2012 06:54:36 GMT

2. Racemic Cyclizations

←Older revision		Revision as of 06:54, 17 May 2012
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	[[Image:MW56.png\|thumb\|center\|500px]]		[[Image:MW56.png\|thumb\|center\|500px]]

-	Moving on triflic acid (TfOH) was screened as a catalyst for the Pictet-Spengler reaction using the four Ugi products from above. At a catalyst loading of 5 mol %, the desired product for the two electron rich systems ([http://www.ourexperiment.org/racemic_pzq/5642/Preparation_of_the_dimethoxy_Ugiintermediate_MNR85.html MNR8-5], [http://www.ourexperiment.org/racemic_pzq/4011/Preparation_of_the_dimethoxy_Ugiintermediate_MNR102.html MNR10-2]) was isolated in excellent yields of 91 for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB1-5]and 96% for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB8-14]. Unfortunately, as with the previous examples, complete cyclisation was not observed for the other two examples ([http://www.ourexperiment.org/racemic_pzq/2696/Stoichiometric_acidmediated_PictetSpengler_of_MW294_to_give_racemic_PZQ_KAB31_and_KAB32.html KAB3-2] and [http://www.ourexperiment.org/racemic_pzq/4441/TfOH_catalysed_PS_reaction_to_give_the_Nbenzoyl_PZQ_analogue_KAB73.html KAB7-3])and intermediate enediamide was isolated as the major product. Increasing catalyst loading did not help to push these reactions to completion [http://www.ourexperiment.org/racemic_pzq/4127/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB312_to_KAB316.html KAB3-12].	+	Moving on triflic acid (TfOH) was screened as a catalyst for the Pictet-Spengler reaction using the four Ugi products from above. At a catalyst loading of 5 mol %, the desired product for the two electron rich systems ([http://www.ourexperiment.org/racemic_pzq/5642/Preparation_of_the_dimethoxy_Ugiintermediate_MNR85.html MNR8-5], [http://www.ourexperiment.org/racemic_pzq/4011/Preparation_of_the_dimethoxy_Ugiintermediate_MNR102.html MNR10-2]) was isolated in excellent yields of 91 for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB1-5]and 96% for [http://www.ourexperiment.org/racemic_pzq/4520/TfOH_catalysed_PS_reactions_to_give_the_dimethoxy_PZQ_analogues_KAB814__KAB15.html KAB8-14]. Unfortunately, as with the previous examples, complete cyclisation was not observed for the other two examples ([http://www.ourexperiment.org/racemic_pzq/2696/Stoichiometric_acidmediated_PictetSpengler_of_MW294_to_give_racemic_PZQ_KAB31_and_KAB32.html KAB3-2] and [http://www.ourexperiment.org/racemic_pzq/4441/TfOH_catalysed_PS_reaction_to_give_the_Nbenzoyl_PZQ_analogue_KAB73.html KAB7-3])and intermediate enediamide was isolated as the major product. Increasing catalyst loading did not help to push these reactions to completion ([http://www.ourexperiment.org/racemic_pzq/4127/TfOH_catalysed_PS_reaction_to_give_PZQ_KAB312_to_KAB316.html KAB3-12]).

	[[Image:KAB_cats_TfOH.png\|thumb\|center\|500px]]		[[Image:KAB_cats_TfOH.png\|thumb\|center\|500px]]