Efficient acyclic stereocontrol using the tethered aminohydroxylation reaction

Article abstract of DOI:10.1021/ol049136i

(Matrix Presented) The tethered aminohydroxylation (TA) of acyclic allylic carbamates has been achieved in a stereospecific and stereoselective manner. Unusually high levels of stereocontrol were observed in the oxidation of 1,1-disubstituted substrates.

Full text of DOI:10.1021/ol049136i

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2583-2585
Efficient Acyclic Stereocontrol Using the
Tethered Aminohydroxylation Reaction
,†
Timothy J. Donohoe,* Peter D. Johnson,† Richard J. Pye,† and Martine Keenan‡
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K., and Eli Lilly and Company, Ltd.,
Lilly Research Centre, Erl Wood Manor, Sunninghill Road,
Windlesham, Surrey GU20 6PH, U.K.
timothy.donohoe@chem.ox.ac.uk
Received May 12, 2004
ABSTRACT
The tethered aminohydroxylation (TA) of acyclic allylic carbamates has been achieved in a stereospecific and stereoselective manner. Unusually
high levels of stereocontrol were observed in the oxidation of 1,1-disubstituted substrates.
The widespread occurrence of amino alcohols in biologically
active molecules and natural products1 has led to the need
for simple, efficient, and reliable methodology for the
introduction of such functional groups. The pioneering
asymmetric aminohydroxylation (AA) reaction developed by
Sharpless is a powerful method for the stereospecific
preparation of vicinal amino alcohols using catalytic potas-
sium osmate in the presence of a nitrogen source (typically
a carbamate) and tert-butyl hypochlorite as the oxidant.2
Despite its utility, the variability of regiocontrol during the
oxidation of several unsymmetrical olefins within the AA
remains a problem. Other workers have addressed this issue
by manipulating the steric and electronic properties of various
alkenes in an attempt to bias the aminohydroxylation
reaction, but without finding a general solution.3-5 Our
method for achieving reliable regiocontrol during amino-
hydroxylation involves tethering the carbamate nitrogen
source to the substrate, which, in the presence of tert-butyl
hypochlorite and catalytic potassium osmate, constitutes an
intramolecular AA reaction (described as the tethered ami-
nohydroxylation, TA).6 Investigation of the TA reaction on
achiral allylic carbamates confirmed that this novel approach
gave total regioselectivity (Scheme 1)7 and an extension to
cyclic allylic alcohol systems proved successful; the reaction
proved to be both regio- and stereoselective.8
This paper describes our efforts to apply the TA reaction
to flexible, chiral, acyclic substrates. In this case, achieving
acyclic stereoselectivity would provide us with a powerful
and novel method of preparing linear amino diols with fixed
and predictable stereochemistry. Consequently, a series of
cis and trans acyclic allylic carbamates were prepared from
their respective alcohols and duly subjected to the TA
conditions. As Scheme 2 illustrates, the reaction proceeded
smoothly to furnish protected amino alcohols with complete
regiocontrol and with excellent syn stereoselectivity. In all
† University of Oxford.
‡ Eli Lilly and Company, Ltd.
(1) Bergmeier S. C. Tetrahedron 2000, 56, 2561.
(2) For representative references, see: Chang, H.-T.; Li G.; Sharpless,
K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 2813. Brunko, M.; Schlingloff,
G.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 1483. Rubins,
A. E.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 2637. For a
recent review on the AA reaction, see: Bodkin, J. A.; McLeod, M. D. J.
Chem. Soc., Perkin Trans. 1 2002, 24, 2733.
(6) Donohoe, T. J.; Johnson, P. D.; Pye, R. J. Org. Biomol. Chem. 2003,
1, 2025.
(3) Angelaud, R.; Landais, Y. Tetrahedron Lett. 1997, 38, 1407.
(4) Cho, C.-W.; Han, H.; Janda, K. D. Chem. Eur. J. 1999, 5, 1565.
(5) Masse, C. E.; Morgan, A. J.; Panek, J. S. Org. Lett. 1999, 1, 1949.
Tao, B.; Schlingloff, G.; Sharpless, K. B. Tetrahedron Lett. 1998, 39, 2507.
(7) Donohoe, T. J.; Helliwell, M.; Johnson, P. D.; Keenan, M. Chem.
Commun. 2001, 2078.
(8) Donohoe, T. J.; Cowley, A.; Johnson, P. D.; Keenan, M. J. Am. Chem.
Soc. 2002, 124, 12934.
10.1021/ol049136i CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/01/2004

Syn-selective stereocontrol within 1,1-disubstituted acyclic
alkene substrates is rare11 because of the competing influence
of A[1,2] over A[1,3] strain. Three 1,1-di or 1,1,2-trisubstituted
allylic carbamates were synthesized in order to assess the
degree of stereocontrol that could be induced using the TA
reaction. Reaction of 11, 13, and 15 under standard TA
conditions furnished three oxidized products with nearly
complete syn stereoselectivity (entries a-c, Scheme 3). The
Scheme 1
Scheme 3a
examples, good yields, mass recovery, and functional group
tolerance were found. It is of note that cis-substituted allylic
carbamates (entries d and e) gave nearly total stereocontrol
in comparison to their trans counterparts.9 The stereochem-
ical outcome of the reactions in Scheme 2 was proven by
X-ray crystallography on compounds 6, 8, and 10 with the
stereochemistry of compound 2 identified by symmetry
properties10 and 4 by analogy. These results show that (i)
the addition of nitrogen and oxygen was suprafacial (ste-
reospecific) and (ii) the reaction was syn selective (stereo-
selective) in each case.
Scheme 2a
a Conditions: (i) K2Os(OH)4O2 (4 mol %), t-BuOCl (1.0 equiv),
NaOH (0.92 equiv), EtN-i-Pr2 (5 mol %), n-PrOH/H2O (1:1). (a)
Recovered starting material in parentheses. (b) All ratios calculated
1
by H NMR spectroscopy on the crude reaction mixture.
stereochemistry of 12, 14, and 16 was confirmed in each
case by X-ray analysis. The yields for the reactions were
good, and the overall mass recovery was excellent. This is
a remarkable and useful set of results demonstrating that the
factors controlling the stereoselectivity of the TA reaction
are not unduly affected by the presence of a geminal
substitutent on the alkene.
The synthesis of a set of structurally more complex acyclic
carbamates was undertaken so that we might probe not only
the stereo- and regiocontrol of the TA but also the chemo-
selectivity. Aminohydroxylation of 176 and 19 proved to be
an efficient, stereospecific, and stereoselective reaction which
was also totally regio- and chemoselective. Analysis of the
product by 1H NMR spectroscopy revealed formation of only
(9) Ratios of >10:1 mean that we could not detect the other diastereo-
isomer in the NMR spectra of the products.
(10) The stereochemistry of 2 was deduced by hydrolysis of the
oxazolidinone ring and conversion of the stereoisomers to their respective
triacetates which were separable. Symmetry properties then allowed
assignment of the syn and anti products.
(11) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. See also: Adam, W.; Mitchell, C. M.; Saha-Mo¨ller, C. R. J. Org.
Chem. 1999, 64, 3699. Donohoe, T. J.; Waring, M. J.; Newcombe, N. J.
Tetrahedron Lett. 1999, 40, 6881. Evans, D. A.; Fu, G. C.; Hoveyda, A. H.
J. Am. Chem. Soc. 1988, 110, 6917.
a Conditions: (i) K2Os(OH)4O2 (4 mol %), t-BuOCl (1.0 equiv),
NaOH (0.92 equiv), EtN-i-Pr2 (5 mol %), n-PrOH/H2O (1:1). (a)
Recovered starting material in parentheses. (b) All ratios calculated
1
by H NMR spectroscopy on the crude reaction mixture.
2584
Org. Lett., Vol. 6, No. 15, 2004

the kinetically favored five-membered oxazolidine ring in
both instances (Scheme 4). The preference for syn stereo-
such a linear arrangement is present during the TA reaction
(Figure 1). The nitrogen and oxygen then overlap with the
π-orbitals of the alkene, with deformation of the linear (C-
NdOs) arrangement occurring as the reaction proceeds to
furnish an azaglycolate osmate ester.8 A consequence of
starting with a linear osmium-nitrogen-carbon bond is that
the initial dihedral angle (ϑ) required to give good orbital
overlap between the oxidant and alkene must be large.
Therefore, only two reactive conformations need be consid-
ered, which lead to the syn or anti product respectively
(Figure 1).
Scheme 4a
Assuming the presence of a linear osmium-nitrogen-
carbon arrangement and the subsequently large angle (ϑ)
required for a successful reaction to occur, the factors which
will govern the reactivity of these conformations, and hence
the outcome of the TA reaction, can now be considered.
Primarily, there will be A[1,3] strain between the Rcis group
and the allylic substituent in the inside position. Clearly, this
is minimized in A (H inside, leading to syn) versus B (R
inside, leading to anti). This factor also predicts greater syn
selectivity when the Rcis group is not hydrogen.
a Conditions: (i) K2Os(OH)4O2 (4 mol %), t-BuOCl (1.0 equiv),
NaOH (0.92 equiv), EtNi-Pr2 (5 mol %), n-PrOH:H2O (1:1). (a)
Recovered starting material in parentheses. (b) All ratios calculated
1
by H NMR spectroscopy on the crude reaction mixture.
Second, we suggest that any A[1,2] strain between R1 and
R2 is relatively unimportant and the level of A[1,2] strain is
approximately equivalent in both reactive conformations
(because of the large angle (ϑ) in the transition state). Finally,
the presence of a large group in the inside allylic position
(see R2 in B) may also hinder approach of the active osmium
species to the alkene and slow the rate of oxidation via this
conformation.
Therefore, inspection of our results indicates that reaction
via conformation A (which leads to the syn product) is
preferred. There is also greater syn selectivity during the
oxidation of cis- versus trans-carbamates, as predicted by
the model. The unusually high levels of syn selectivity
observed in the 1,1-disubstituted series is (with A[1,2] strain
similar in both conformations) also explained by our model.
In conclusion, we report a successful application of the
stereoselective TA reaction to chiral acyclic systems. The
reaction displays excellent levels of syn stereoselectivity
while providing complete control over the regio- and
chemoselectivity of the oxidation. The high level of stereo-
control displayed in the 1,1-disubstituted systems is particu-
larly exciting. A simple mechanistic model has been proposed
which rationalizes the stereochemical outcome of the reac-
tion. We believe these developments to the TA reaction will
allow this methodology to find a wider application in an
important area of organic synthesis.
chemistry in 18 was proven by derivization to a previously
reported compound,12 while the stereochemistry of 20 was
assigned by analogy with the previous examples.
To rationalize these results, a model was proposed which
supports the syn selectivity observed during the reaction. The
key step is intramolecular addition of the RNdOsdO
fragment across the alkene, which could lead to syn or anti
relative stereochemistry (Figure 1).
Figure 1. Transition states which rationalize the syn selectivity
observed during the TA reaction.
It has been shown by X-ray crystallography that related
transition-metal complexes form linear metal-nitrogen-
carbon arrangements (with the metal forming a double bond
to an acyl-substituted nitrogen).13 We suggest, therefore, that
Acknowledgment. We thank the EPSRC and Eli Lilly
for funding this project. Pfizer, Novartis, AstraZeneca, and
Merck are thanked for generous unrestricted funding.
Supporting Information Available: Experimental pro-
cedures and analytical and spectroscopic characterization of
all starting materials and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) The stereochemistry of TA product 18 was deduced by base cleavage
of the oxazolidinone ring and conversion of the stereoisomers to their
respective triacetates. Hydrogenation of the double bond formed a common
intermediate from previous studies.7
(13) Thomas, S.; Lim, P. J.; Gable, R. W.; Young, C. G. Inorg. Chem.
1998, 37, 590.
OL049136I
Org. Lett., Vol. 6, No. 15, 2004
2585