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Author: Subject: Total synthesis of mushroom alcohol
kavu
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[*] posted on 5-7-2012 at 15:42
Total synthesis of mushroom alcohol


1-Octen-3-ol, also known as mushroom alcohol for it's odor, is an extremely potent olfactory attractant for many insects. The compound is found in several plants and fungi, but also in the sweat of humans and animals. [1] Synthesis of the bioactive racemate is as simple as reacting hexanal with vinylmagnesium bromide. Nothing that dried glassware and some argon balloons can't handle :)


Fig 1. Planned route

A reasonable way to hexanal is PCC oxidation of 1-hexanol. This method has been used in the literature to synthesize deuterated aliphatic aldehydes for a multitude of purposes. [2,3] Another method commonly used, though not in my reach, is to reduce methyl hexanoate with DIBAL-H. [4] The Vogel procedure with a combustion tube filled with copper/chromium oxide catalyst seems to be a bit overkill for these purposes. [5]

Vinylmagnesium bromide is a bit tougher task. At the moment it seems that it's easiest just to purchase it as THF solution.

As soon as I get the 1-hexanol, I'll be posting on how the synthesis is working out.

[1] J. Biol. Chem., Vol 276, No. 10, 7150-7155, 2001
[2] J. Org. Chem., Vol. 49, No. 9, 1511-1517, 1984
[3] J. Org. Chem., Vol. 54, No. 23, 5522-5527, 1989
[4] Org. Lett., Vol 6, No 3., 349-352, 2004
[5] Vogel's textbook of practical organic chemistry, 5th edition, Longman Scientific & Technical, London, p. 589

[Edited on 6-7-2012 by kavu]
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chemrox
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[*] posted on 5-7-2012 at 21:21


What is the issue with making vinyl Mg-Br/ether ?



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kavu
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[*] posted on 6-7-2012 at 00:30


Vinyl halides tend to be gaseous at room temperature, this combined with the carcinogenicity is putting me off.
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Lithium
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[*] posted on 13-7-2012 at 22:31


can't wait for a write up!



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DDTea
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[*] posted on 20-7-2012 at 20:49


Looks like a workable route. Something to consider: PCC is toxic and carcinogenic. It has fallen out of favor for this very reason. If you have access to the reagents, have you considered using a Swern oxidation?

Alternatively, have you considered the Grignard reaction between n-pentyl magnesium bromide and acrolein. Acrolein can be generated in the lab from glycerin (dirt cheap) and potassium bisulfate (http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv1... ).

[Edited on 7-21-12 by DDTea]




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kavu
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[*] posted on 21-7-2012 at 02:07


Byproducts of Swern oxidation are so smelly that without a fume hood I'm not very keen on trying it out. I would also have to purchase DMSO and oxalyl chloride for the project. Otherwise it would be a good and less toxic alternative. I chose PCC as the materials are readily available and synthesis is to be carried out in mmol scale.

I also gave a thought to the acrolein route, but the prep is rather complex. Might be worth trying in microscale, though. Thanks for the feedback!
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kavu
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[*] posted on 21-7-2012 at 14:48


Preparation of PCC

Nothing much to say, pretty generic synthetic procedure. Chromium(IV) is toxic so take care. Chromium trioxide is allowed to react with HCl to form chlorochromic acid. Addition of pyridine to this solution will lead to formation of pyridinium chlorochromate [1]:
HCl + CrO3 → ClCrO3H
ClCrO3H + Py → [ClCrO3]⁻ [Py-H]⁺

PCC has been known for a long time, but it's use as an organic oxidation reagent was published in 1975 by Corey and Suggs [1,2]. Hence it's other name: Corey-Suggs -reagent. This article described how PCC dissolved in DCM oxidized alcohols in good yields [2]. PCC is a handy reagent, it's stable in room temperature and easily prepared from cheap materials. It's downsides are rather toxic nature of Cr(IV) and high acidity [1]. Acidity problem can be solved by adding a buffering base, such as NaOAc, to the reaction mixture [1]. PCC oxidations tend to leave tarry residues of reduced chromium compounds. Purification is usually done by filtering through a celite pad. Modern way to overcome this problem is to impregnate PCC on alumina [1]. The following synthetic procedure is generic [3].

Chromium trioxide (3,00 g; 30 mmol) was dissolved in 6 ml of 6M hydrochloric acid in a 50 ml RBF. To the stirred red solution pyridine (2,43 mL; 30 mmol) was added dropwise keeping the temperature below 40°C. After addition the mixture was cooled in an ice bath and PCC precipitated out. PCC was filtered and dried in vacuum for an hour. Bright orange powder, 5.34 g (82 %).

Fig 1. Pyridine being slowly added to the stirred CrO3 solution

Fig 2. PCC has a bright orange colour, common to hexavalent chromium

Fig 3. Product in vacuum line

[1] Oxidation of Alcohols to Aldehydes and Ketones, 1st edition, G. Tojo, M. Fernandez, 2006, Springer Science & Business Media, Inc., p. 46-51
[2] E. J. Corey, J. W. Suggs, Tetrahedron Lett., 1975, 16, 2647-2650
[3] Organic experiments, 7th edition, L. F. Fieser, K. L. Williamson, 1992, D. C. Heath and Company, p. 256

[Edited on 21-7-2012 by kavu]
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