Friday, May 04, 2007

Tethered aminohydroxylations Donohoe stylie

Back in 2002 I started on a project where we considered using the Sharpless asymmetric aminohydroxylation (AA) as a key step. However, the anticipation of major regioselectivity issues and the success we experienced using the Sharpless asymmetric dihydroxylation meant we abandoned this approach entirely. However, I clearly remember sitting at my desk drawing a tethered version of the AA reaction where the amine was attached to an allylic alcohol as a carbamate. I'm sure that hundreds of other guys where drawing similar stuff and scratching their heads, however, Timothy Donohoe, from Oxford University decided to put the pencil down and get some students to get on with it. I completely missed the first paper that came out in 2001 in Chem. Commun. (DOI: 10.1039/b107253f) and only picked up on what they were doing when they published a paper on their TA work in JACS in 2002 (DOI: 10.1021/ja0276117). Ever since I have been following the Donohoe groups progress closely. The reason that I'm posting this now is because they finally nailed the reaction down in a recent Org. Lett. paper (DOI:10.1021/ol070430v). Anyway, let's get down to business. Firstly, it's important to realise that the TA reaction isn't asymmetric. It is however, a stereospecific, stereo-, regio- and chemoselective process. In other words if you start with optically active substrates you are laughing. Here's the condensed version of the story so far:

(1) Donohoe et al., Chem Comm, 2001, pp 2078-2079 (DOI: 10.1039/b107253f)
TA of acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 41 to 61%. Here's a really nice example with a diene:

(2) Donohoe et al., JACS, 2002, pp 12934-12935 (DOI: 10.1021/ja0276117)
TA of cyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 50 to 83%. Works for 6,7 and 8-membered rings but only 5-membered rings with exocyclic double bonds undergo aminohydroxylation. Here's another nice example making a protected amino-sugar:

(3) Donohoe et al., Org. Lett., 2004, pp 2583-2585 (DOI: 10.1021/ol049136i)
TA of chiral acyclic, allylic carbamates using tert-butyl hypochlorite as the reoxidant with 4 mol% osmium. Yields ranging from 57 to 74% with excellent syn-selectivity. Some very impressive examples of TA reactions in this paper, for example:

(4) Donohoe et al., JACS, 2006, pp 2514-2515 (DOI: 10.1021/ja057389g)

Finally, they manage to get rid of hypochlorite and NaOH by attaching a mesitylsulfonyl substituent to the carbamate nitrogen. As a consequence catalyst loading can go down to 1%, yields have improved (69-83%) and homo-allylic carbamates have become viable systems. Check this homo-allylic TA out:Nice stuff innit and it gets better.

(5) Donohoe et al., Org. Lett., 2007, pp. 1725-1728 (DOI: : 10.1021/ol070430v)
And finally the climax. This is the final, and very recent paper, from the Oxford lab. Previously some of the TAs just didn't work (with the mesitylsulfonyl N-substituent) for no apparent reason. So they screen a bunch of different N-leaving groups and discover that things take off big time when pentafluorobenzoyl is attached to the carbamate. Catalyst loading is now permanently down to 1 mol%, yields are up (71-98%) also for difficult homo-allylic substrates, and it works for both cyclic and acyclic systems. Here's a nice homo-allyic example:

So it took about 6 years to develop this methodology to the point where I believe it will start finding wide spread use in synthesis. I'm itching to try one of these for myself and I'm desperately looking for an excuse. If anyone has tried running some of these Donohoe TAs I would very much like to hear any comments - is it really as good as it looks on paper? D!


Anonymous said...

I'm a big fan of Donohoe's work - very elegant

Daniel Sejer said...

Wooooo-hooooo, finally a comment. I was wondering if anyone read the more serious stuff. D!