The tethered aminohydroxylation (TA) of cyclic allylic carbamates

Article abstract of DOI:10.1021/ja0276117

The tethered aminohydroxylation of cyclic allylic carbamates is described using catalytic amounts of potassium osmate. The mechanism of reaction involves formation of an imido-osmium complex which adds intramolecularly to alkenes with complete control of

Full text of DOI:10.1021/ja0276117

Published on Web 10/10/2002
The Tethered Aminohydroxylation (TA) of Cyclic Allylic Carbamates
Timothy J. Donohoe,* Peter D. Johnson, Andrew Cowley,† and Martine Keenan‡
Dyson Perrins Laboratory, South Parks Road, Oxford, OX1 3QY, UK and Eli Lilly and Company Ltd.,
Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK
Received July 9, 2002
Scheme 1. Tethered Hydroxyamination of Allylic Carbamates
The Sharpless aminohydroxylation reaction has recently emerged
as a powerful method of preparing vicinal amino alcohols from
alkenes using osmium catalysts.1 Using a carbamate as the source
of nitrogen and (basic) tert-butyl hypochlorite as the oxidant, good
yields of amino alcohol products can be obtained in the presence
of catalytic amounts of potassium osmate (K2OsO2(OH)4).2
One of the complications with this methodology is a lack of
regiochemistry when some unsymmetrical alkenes are oxidized;3
in response to this issue we tethered the source of nitrogen
(carbamate) to an achiral allylic alcohol and discovered a method
of controlling completely the regiochemistry of the product (1 f
2, Scheme 1).4
Scheme 2 a
This work describes our efforts to control not only the regiose-
lectivity but also the stereoselectivity of hydroxyamination reactions.
Although the basic hydroxyamination reaction is stereospecific,
there are currently no good strategies for the stereoselective
hydroxyamination of chiral substrates. With this goal in mind,
oxidation of a carbamate such as 3 (Scheme 1) should lead to a
single regio- and stereoisomer. This outcome would represent a
significant increase in the degree of control possible during the
oxidation of allylic alcohol substrates.5
To test our hypothesis, we prepared a range of carbamates from
five- and six-membered cyclic allylic alcohols (Cl3CCONdCdO
then K2CO3 (aq), 78-99%). These derivatives were then subjected
to hydroxyamination, Scheme 2.
As the results show, there is one incompatibility in the tethered
aminohydroxylation of five-membered rings, with only exocyclic
alkenes being viable substrates; we believe this is because of undue
strain in the azaglycolate osmate ester that would be formed from
5, vide infra. However, the TA reaction on six-membered rings
proved to be versatile and completely stereoselective; entries 5 and
6 show that 3-aminosugars can be prepared easily from alkene
precursors.
In general, the yields for the TA rection are good, especially
when one considers the amount of recovered starting material, which
can easily be recycled through the oxidation regime.
During development of the reaction conditions, we examined
the role of various amines as promoters for the TA of compound
(+)-10, Table 1. The presence of an amine is beneficial to the rate,
with Sharpless’ catalysts and i-Pr2NEt giving the highest yields.6
Surprisingly, quinuclidine is not good at accelerating the reaction,
and we suspect that it is destroyed by one of the chlorinating agents
present in solution. Importantly, there was no significant difference
in rate (or yield) for oxidation using (DHQ)2PHAL and its
pseudoenantiomer (DHQD)2PHAL; this points to a role for the
chiral ligand that does not include stereochemical induction and
fits well with our observations using achiral allylic carbamates.4
a (i) K2OsO2(OH)4 (4 mol %), t-BuOCl (1 equiv), NaOH (0.9 equiv),
amine (5 mol %), PrOH, H2O. (a) EtNiPr2. (b) (DHQ)2PHAL. (c) Yield
after one recycle.
* Corresponding author. E-mail: timothy.donohoe@chem.ox.ac.uk.
† Author for correspondence regarding the crystal structure.
‡ Lilly Research Centre.
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J. AM. CHEM. SOC. 2002, 124, 12934-12935
10.1021/ja0276117 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Oxidation of 10 f 11 (Recovered Starting Material)
azaglycolate osmate ester C (Os(VI)) which is oxidized and
hydrolyzed in situ (second cycle not withstanding).
entry
additive
time
yield %
We present two pieces of experimental evidence in support of
this hypothesis: (1) repetition of the TA reaction using optimum
conditions, but no potassium osmate, gave no cyclized products,
(2) the osmate ester C could be intercepted by the addition of
TMEDA to the reaction mixture to give D (no water was present
here to avoid hydrolysis of C).
1
2
3
4
5
6
7
(DHQ)2PHAL (5%)
(DHQD)2PHAL (5%)
i-Pr2NEt (5%)
i-Pr2NEt (100%)
quinuclidine (5%)
quinuclidine (100%)
none
2.3 h
2.5 h
2.5 h
-
55 (25)
46 (29)
48 (29)
45 (17)
35 (40)
6 (74)
>7 h
-
5.5 h
43 (37)
Previously, we have used diamines to improve the hydrogen-
bonding ability of OsO4;8 one consequence of this combination is
the extra stability that TMEDA confers to the osmate ester, making
them difficult to hydrolyze during the reaction.9 Thus, we were
able to obtain an X-ray crystal structure of complex D,10 and its
structure fits exactly with our predictions. In a separate step,
intermediate D could be hydrolyzed (aq Na2SO3) to alcohol 9.
To conclude, we have shown the utility of the tethered amino-
hydroxylation reaction toward cyclic substrates. The regio- and
stereoselective synthesis of all syn amino-diol motifs in protected
form is now straightforward, and this methodology will prove its
utility in synthesis. Moreover, we have probed the reaction
mechanism and obtained an X-ray crystal structure of an azagly-
colate osmate ester. This rare example provides key information
about the nature of one of the many intermediates in aminohy-
droxylation reactions.
Scheme 3 a
a (i) K2OsO2(OH)4 (4 mol %), t-BuOCl (1 equiv), NaOH (0.9 equiv),
(DHQ)2PHAL (5 mol %), PrOH, H2O. (a) Yield after one recycle.
Acknowledgment. We thank the EPSRC and Lilly for financial
support of this project and Novartis and Pfizer for unrestricted
funding.
Supporting Information Available: Representative experimental
procedures and spectroscopic data for all new compounds, plus proof
of stereochemistry and X-ray data for compound D (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews see: O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326; Kolb
H. C.; Sharpless, K. B. In Transition Metals For Organic Synthesis; Beller,
M., Bolm, C., Eds.; Wiley: New York, 1998, 2, pp 243; Reiser, O. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1309.
(2) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207; Li,
G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 2813.
(3) For examples see: Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3,
401; Morgan, A. J.; Masse, C. E.; Panek, J. S. Org. Lett. 1999, 1, 1949;
Han, H.; Cho, C.-W.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565; Tao, B.;
Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 2507.
(4) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M. Chem. Commun.
2001, 2078.
(5) Sellier, O.; Van de Weghe, P.; le Nouen, D.; Strehler, C.; Eustache, J.
Tetrahedron Lett. 1999, 40, 853; Pringle, W.; Sharpless, K. B. Tetrahedron
Lett. 1999, 40, 5151.
Figure 1.
Naturally, we examined the recovered starting material from
oxidation of racemic substrates, and they had a specific rotation of
zero, which rules out a kinetic resolution.
(6) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem. 1999,
Next, we examined the tethered aminohydroxylation reaction on
both seven- and eight-membered rings and found that the oxidation
worked well, giving predominantly the all syn isomer with the
seven-membered ring and the anti isomer (g10:1 dr) with the eight,7
Scheme 3.
In terms of mechanism, we suggest that in situ chlorination and
deprotonation of the allylic carbamate gives a species A (a nitrene
equivalent) that is capable of oxidizing potassium osmate (Os(VI))
to the osmium tetroxide analogue B (Os(VIII), Figure 1). Addition
to the alkene (amine accelerated as in dihydroxylation?) gives
64, 9613.
(7) For related diastereoselectivty in the directed oxidation of seven- and eight-
membered rings see: Itoh, T.; Kaneda, K.; Teranishi, S. J. Chem. Soc.,
Chem. Commun. 1976, 421; DuBois, J.; Espino, C. G. Angew. Chem.,
Int. Ed. 2001, 40, 598.
(8) Donohoe, T. J.; Moore, P. R.; Waring, M. J.; Newcombe, N. J. Tetrahedron
Lett. 1997, 38, 5027.
(9) Donohoe, T. J.; Blades, K.; Moore, P. R.; Winter, J. J. G.; Helliwell M.;
Stemp, G. J. Org. Chem. 1999, 64, 2980.
(10) Griffith, W. P.; McManus, N. T.; Skapski, A. C.; Nielson, A. J. Inorg.
Chim. Acta 1985, 103, L5.
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