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Chemistry Forums for Students => Organic Chemistry Forum => Topic started by: Rutherford on December 28, 2015, 11:28:21 AM

Title: Synthesis using protecting groups
Post by: Rutherford on December 28, 2015, 11:28:21 AM
How to achieve the attached transformation. I thought about protecting O(1) with TIPSCl then O(3) and O(4) with acetone and finally O(2) with TBSCl. Deprotection of O(5) with PBr3 shouldn't destroy the other groups (or maybe it will???). O(3) and O(4) could be deprotected under mildly acidic conditions, but I don't see how to methylate only O(4) and not O(3). Any hints?
Title: Re: Synthesis using protecting groups
Post by: phth on December 29, 2015, 02:17:13 AM
look more closely and draw the chair.  I think acetonation of C2, C3 will happen.  up-up is an axial-equitorial conformation.  You will get the down-up ring
Title: Re: Synthesis using protecting groups
Post by: Rutherford on December 29, 2015, 08:43:18 AM
How do you mean that an up-down ring will be obtained from an up-up relationship of OH groups?
Title: Re: Synthesis using protecting groups
Post by: phth on December 29, 2015, 05:19:55 PM
(https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fi.imgur.com%2FknLOVry.png&hash=05d1d07b65be5908d0fac11c62595d5e7eb02815)I don't think this is a trick question, and sorry if I was not clear b4.  the acetonation is favored to the hydroxyls that sit in the equitorial positions. The axial equitorial 2,3-acetonation is the kinetic product.  It puts more strain on the α-anomer allignment, takes the 6-ring out of the chair conformation destabilizing the system.  ofc it depends on solvent, but the desired ring formation will happen under the equilibration conditions.  There are only 3 hydroxyls availible when the α,6 hydroxyl positions are protected, so you will get a mixture, but it is controllable.  example provided: (https://www.chemicalforums.com/proxy.php?request=http%3A%2F%2Fi.imgur.com%2FA4sdydC.png&hash=9dae70502ce6c0ca7ccf2c3cd71490e25284c365)
Title: Re: Synthesis using protecting groups
Post by: Rutherford on December 30, 2015, 01:14:15 PM
I've read in Modern Organic Synthesis by Zweifel that trans OH groups on rings don't form five membered cyclic acetals that easily, while cis do. Seems like it's a mistake. Do you have any reference or any book recommendation, as I would like to explore this further (protecting groups in carbohydrate chemistry).
Title: Re: Synthesis using protecting groups
Post by: Dan on December 30, 2015, 03:40:04 PM
Quote from: Rutherford on December 30, 2015, 01:14:15 PM
I've read in Modern Organic Synthesis by Zweifel that trans OH groups on rings don't form five membered cyclic acetals that easily, while cis do. Seems like it's a mistake. Do you have any reference or any book recommendation, as I would like to explore this further (protecting groups in carbohydrate chemistry).

Your book is correct, phth is mistaken on this one. Mannopyranosides preferentially form the 5-membered cis-fused ketal with acetone or 2,2-dimethoxypropane, this is well documented in the literature. As you have numbered your original compound, this would be the 3/4 position. Note however that in carbohydrate nomenclature position 1 of an aldose is the anomeric centre (and the primary alcohol is position 6). Acetonation of methyl D-mannopyranoside gives methyl 2,3-O-isopropylidene-D-mannopyranoside in high yield, this one:

COC1O[C@H](CO)[C@@H](O)[C@@H]2OC(C)(C)O[C@H]12

As for books, I will have a look in my collection when I get home from holidays and recommend one or two (PM me if I forget). They're general carbohydrate chemistry texts and I can't remember which ones cover protection in the most depth.

This one is very useful, but expensive: http://eu.wiley.com/WileyCDA/WileyTitle/productCd-0471133396.html

I need to see if I still have my copy of it.
Title: Re: Synthesis using protecting groups
Post by: Rutherford on December 31, 2015, 04:46:15 AM
Thanks Dan for clarifying this. Any thoughts about the initial problem?
Title: Re: Synthesis using protecting groups
Post by: Dan on December 31, 2015, 05:06:04 AM
Quote from: Rutherford on December 31, 2015, 04:46:15 AM
Thanks Dan for clarifying this. Any thoughts about the initial problem?

This should give you some ideas: http://onlinelibrary.wiley.com/doi/10.1002/anie.199422721/abstract
Title: Re: Synthesis using protecting groups
Post by: Rutherford on December 31, 2015, 06:42:29 AM
I cannot access it.
Title: Re: Synthesis using protecting groups
Post by: Dan on December 31, 2015, 11:01:42 AM
Also:

http://onlinelibrary.wiley.com/doi/10.1002/anie.199422901/abstract
http://pubs.rsc.org/en/content/articlelanding/2008/cs/b717902b

I'm struggling to find free pages...

Edit: Try this (https://www.researchgate.net/publication/51422362_ChemInform_Abstract_The_Conformational_Rigidity_of_Butane-12-diacetals_as_a_Powerful_Synthetic_Tool).
Title: Re: Synthesis using protecting groups
Post by: Rutherford on December 31, 2015, 03:19:20 PM
So the usage of dispiroacetals will selectively protect O2 and O3 leaving O4 unprotected and ready to participate in methylation?
Title: Re: Synthesis using protecting groups
Post by: Rutherford on January 01, 2016, 08:17:58 AM
2,2,3,3-tetramethoxybutane (TMB) can be used, too to afford butane 2,3-bisacetal. The O(2) and O(3) atoms are selectively protected in excellent yield.
Title: Re: Synthesis using protecting groups
Post by: Dan on January 01, 2016, 08:53:35 AM
Yes, I would start with BDA (butane diacetal) protection. How do you proceed from there?
Title: Re: Synthesis using protecting groups
Post by: Rutherford on January 01, 2016, 09:02:21 AM
Deprotection of O5 with PBr3 and subsequent methylation would give smaller than 50% yield I guess (statistical formation of products).

The alternative: Protect O4 with PMB (MPM) group, then deprotect O5 with BBr3, then protect O5 with Bn group. Deprotect O4 with DDQ, methylate with NaH/MeI and finally deprotect O5 using hydrogenation. All these steps combined would probably give an ever lower yield than the first approach.
Title: Re: Synthesis using protecting groups
Post by: Dan on January 01, 2016, 09:14:27 AM
PBr3 will generate HBr and cleave the BDA group. Remember, O5 (your numbering) is part of an acetal (as is the BDA group) so you can remove them both at the same time in the presence of an ether.

How are you dealing with O1 (your numbering)?
Title: Re: Synthesis using protecting groups
Post by: Rutherford on January 01, 2016, 10:22:40 AM
TBS group for O1.

Not sure how to deprotect O5, leaving other groups intact.
Title: Re: Synthesis using protecting groups
Post by: Dan on January 01, 2016, 05:43:39 PM
Quote from: Rutherford on January 01, 2016, 10:22:40 AM
Not sure how to deprotect O5, leaving other groups intact.

Why do you need the other groups to stay intact?
Title: Re: Synthesis using protecting groups
Post by: Rutherford on January 02, 2016, 06:37:21 AM
On methylation they will also react.
Title: Re: Synthesis using protecting groups
Post by: Dan on January 02, 2016, 07:39:40 AM
You can demethylate the O5 acetal in the presence of a methyl ether at O4 (your numbering).

The most straightforward strategy I see is to protect O1-3 (O5 is already protected as an acetal), methylate O4, then remove all protecting groups.
Title: Re: Synthesis using protecting groups
Post by: Rutherford on January 02, 2016, 08:32:15 AM
Ah, okay, I understood now.