Highly α-selective hydrolysis of α,β-epoxyalcohols using tetrabutylammonium fluoride

Article abstract of DOI:10.1021/ol1015306

We report a simple method for the highly regio- and stereoselective hydrolysis of α,β-epoxyalcohols. Treatment of enantiopure epoxyalcohols derived from Sharpless epoxidation with TBAF/H₂O resulted in exclusive ring opening at the normally disfavored α-position, providing access to arabino- or lyxo-configured triols with full preservation of stereochemical purity. The method was applied in syntheses of 5-deoxy-l-arabinose (26) and a family of bicyclic acetals based on the insect pheromone hydroxybrevicomin (4).

Full text of DOI:10.1021/ol1015306

ORGANIC
LETTERS
2010
Vol. 12, No. 18
3986-3989
Highly r-Selective Hydrolysis of
r,ꢀ-Epoxyalcohols using
Tetrabutylammonium Fluoride
Purba Mukerjee,† Mohammed Abid, and Frank C. Schroeder*
Boyce Thompson Institute and Department of Chemistry and Chemical Biology,
Cornell UniVersity, Ithaca, New York 14853
schroeder@cornell.edu
Received July 3, 2010
ABSTRACT
We report a simple method for the highly regio- and stereoselective hydrolysis of r,ꢀ-epoxyalcohols. Treatment of enantiopure epoxyalcohols
derived from Sharpless epoxidation with TBAF/H2O resulted in exclusive ring opening at the normally disfavored r-position, providing access
to arabino- or lyxo-configured triols with full preservation of stereochemical purity. The method was applied in syntheses of 5-deoxy-L-
arabinose (26) and a family of bicyclic acetals based on the insect pheromone hydroxybrevicomin (4).
Arrays of three or more consecutive hydroxylated chiral
centers are a common structural feature of natural products
from diverse sources, including polyketides (e.g., aspicilin
(1),1 erythromycin A (2),2 or FK506 (3)3), products of fatty
acid metabolism (e.g., hydroxybrevicomin (4)4), and carbo-
hydrate derivatives. A variety of approaches are available
for the synthesis of these polyol moieties, for example,
asymmetric dihydroxylation,5 carbohydrate-based methods,6
or the hydrolysis of chiral epoxides.7 However, with the
exception of carbohydrate-based approaches, the diastereo-
† Current address: University of Wisconsin.
(1) (a) Sinha, S. C.; Keinan, E. J. Org. Chem. 1997, 62, 377, and
references therein. (b) Banwell, M. G.; McRae, K. J. Org. Lett. 2000, 2,
3583. (c) Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123.
(2) (a) Pal, S. Tetrahedron 2006, 62, 3171. (b) Evans, D. A.; Kim, A. S.
Tetrahedron Lett. 1997, 38, 53.
(3) (a) Nakatsuka, M.; Ragan, J. A.; Sammakia, T.; Smith, D. B.;
Figure 1. Natural products including or derived from D- or
Uehling, D. E.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 5583. (b)
Ireland, R. E.; Gleason, J. L.; Gegnas, L. D.; Highsmith, T. K. J. Org.
Chem. 1996, 61, 6856. (c) Ireland, R. E.; Liu, L.; Roper, T. D.; Gleason,
J. L. Tetrahedron 1997, 53, 13257.
L-arabino-configured triols.
(4) (a) Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood, D. L.;
Browne, L. E. Science 1968, 159, 889. (b) Francke, F.; Schroeder, F.;
Philipp, P.; Meyer, H.; Sinnwell, V.; Gries, G. Bioorg. Med. Chem. 1996,
4, 363.
meric purity of the resulting triols is often relatively low.
Because R,ꢀ-epoxyalcohols can be obtained in very high
stereoselectivity Via Sharpless epoxidation/kinetic resolution,8
their use for the preparation of polyol motifs is particularly
attractive, and methods of varying selectivity have been
(5) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) Guzman-Perez, A.; Corey, E. J. Tetrahedron Lett.
1997, 38, 5941.
10.1021/ol1015306  2010 American Chemical Society
Published on Web 08/19/2010

described for epoxide ring opening at the ꢀ-position.7,9 Here
we report a simple method for the highly selective hydrolysis
of R,ꢀ-epoxyalcohols at the usually disfavored R-position,
providing direct access to arabino- or lyxo-configured triols
of very high diastereomeric purity.
Scheme 1. Synthesis of Hydroxybrevicomin 4 via
Stereoselective Hydrolysis of Epoxyalcohol 9
We started investigating methods for the stereoselective
preparation of triols as part of our efforts toward synthesis
of a library of bicyclic acetals representing cryptic ketodiols
and -triols, which play important roles as pheromones in
insects and mammals.10
Previous syntheses of the bicyclic acetal hydroxybrevi-
comin (4) relied on preparation of the corresponding triol
Via hydrolysis of chiral epoxyalcohols.4b,11 Francke et al.
based their approach on Sharpless epoxidation and harnessed
its powerful kinetic resolution for generating the required
epoxyalcohols in up to 99.5% de.4b However, subsequent
hydrolysis of the epoxide led to considerable loss of
stereochemical purity. Using a similar approach, we inves-
tigated a variety of conditions to improve regioselectivity
of the hydrolysis of chiral epoxyalcohols such as 9, which
was prepared as described previously (Scheme 1).4b
Consistent with previous examples,7,9 treatment of ep-
oxyalcohol 9 with acids or bases in a variety of solvents
resulted in mixtures of the corresponding (6,7-syn,6,8-anti)-
and (6,7-anti,6,8-syn)-triols 10 (Scheme 1). For example,
treatment of 9 with KOH in water, HF in CH3CN, or HCl,
H2SO4, or TsOH in water resulted in formation of (6R,7R,8R)-
10 and (6R,7S,8S)-10 in ratios of about 70:30 to 90:10. Upon
isolation, these mixtures of ketotriols rapidly cyclized to yield
mixtures of two stereoisomers of the bicyclic acetal 4
(Scheme 1). Relative configurations were determined using
NOESY spectra.
of solvent, temperature, and reagent combinations revealed
that treatment of the epoxyalcohols 8 or 9 with 3 equiv of
TBAF in the presence of small amounts of acetonitrile and
water at 35-40 °C produced optimal results. Under these
conditions, reaction of silylated epoxyalcohol 8 or unsilylated
9 directly yielded bicyclic acetal (1R,1′R,5′R,7′R)-4 (derived
from cyclization of initially formed ketotriol (6R,7R,8R)-
10) without any detectable loss of diastereomeric purity
(Figure 2). The in situ formation of bicyclic acetals 4 from
the initially produced ketotriols 10 enabled fast and unam-
biguous assessment of the regioselectivity of the epoxide
hydrolysis process, because the bicyclic acetals’ configuration
could be assigned easily via analysis of NOESY NMR
spectra.
Using THF, ether, dichloromethane, or chloroform instead
of acetonitrile or increasing the amount of water in the
reaction mixture starkly increased reaction times and reduced
stereoselectivity. Additionally, a high concentration of TBAF
(∼60% by weight) in the reaction mixture was necessary to
maintain high stereoselectivity.
To demonstrate general utility of the method, we applied
these conditions to a variety of diastereomerically pure
epoxyalcohols. Representative examples are shown in Scheme
2, all of which were prepared Via Sharpless kinetic resolution
followed by Sharpless epoxidation. In order to investigate
whether anchimeric assistance of the carbonyl in 9 played a
role for the stereoselectivity of epoxide opening, we also
included epoxyalcohols 20, 22, and 24, which lack additional
oxygenation. In all cases, TBAF-promoted hydrolysis se-
lectively produced the corresponding arabino- or lyxo-
configured triols, of which those featuring 4-oxopentyl or
Serendipitously, it was noted that deprotection of the TBS-
ether in 8 using TBAF in acetonitrile occasionally produced
small amounts of an unexpectedly nonpolar byproduct. Upon
isolation, this byproduct was identified as (1R,1′R,5′R,7′R)-4
of very high diastereomeric purity. This observation sug-
gested that the desilylation conditions induced slow but
highly regioselective R-hydrolysis of the desilylated epoxy-
alcohol 9.
Therefore, we investigated whether TBAF could be used
to convert epoxyalcohols into the corresponding triols
without loss of diastereomeric purity. Screening of a variety
(6) (a) Oikawa, Y.; Nishi, T.; Yonemitsu, O. Tetrahedron Lett. 1983,
24, 3635. (b) Oikawa, Y.; Nishi, T.; Yonemitsu, O. J. Chem. Soc., Perkin
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(7) (a) Roush, W. R.; Brown, R. J. J. Org. Chem. 1982, 47, 1371. (b)
Roush, W. R.; Brown, R. J.; DiMare, M. J. Org. Chem. 1983, 48, 5083. (c)
Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696. (d)
Rengasamy, R.; Curtis-Long, M. J.; Seo, W. D.; Jeong, I, -Y.; Park, K. H.
J. Org. Chem. 2008, 73, 2898.
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(9) (a) Pepito, A, S.; Dittmer, D. C. J. Org. Chem. 1994, 59, 4311. (b)
Honda, T.; Ohta, M.; Mizutani, H. J. Chem. Soc., Perkin Trans 1 1999, 1,
23.
(10) (a) Francke, W.; Schulz, S. Pheromones. In ComprehensiVe Natural
Product Chemistry; Barton, D. H. R., Nakanishi, K., Eds.; Elsevier:
Amsterdam, 1999; Vol. 8, pp 197-261. (b) Rasmussen, L. E. L.;
Greenwood, D. R. Chem. Senses 2003, 28, 433.
(11) Astashko, D. A.; Kulinkovich, O. G.; Tyvorskii, V. I. Russ. J. Org.
Chem. 2006, 42, 719
.
Org. Lett., Vol. 12, No. 18, 2010
3987

1
Figure 2. NMR spectroscopic analysis of TBAF-promoted epoxyalcohol hydrolysis (600 MHz, acetone-d6). (A) H NMR spectrum
of epoxyalcohol (6R,7S,8R)-8 (green signals), containing about 3% of the (6R,7R,8S)-diastereomer (red signals). To illustrate sample
purity, 13C-satellites (intensity 0.5% of the parent signals) are marked blue. (B) 1H NMR spectrum of a 4:1 mixture of (1R,1′R,5′R,7′R)-4
(green) and its (1S,1′R,5′R,7′S)-diastereomer (red signals), along with smaller amounts of other cyclization products, obtained from
1
(6R,7S,8R)-8 via treatment with H2SO4. (C) H NMR spectrum of a 97:3 mixture of 6,8-dioxabicyclo[3.2.1]octanes obtained from
1
(6R,7S,8R)-8 via treatment with TBAF. (D) H NMR spectrum of (6R,7R,8R)-11 (green signals), containing 0.5% or less of the
(6R,7S,8S)-diastereomer (red signals). (E) 1H NMR spectrum of (1R,1′R,5′R,7′R)-12 (green signals) derived from treatment of
(6R,7R,8R)-11. 13C-satellites (blue arrows, intensity 0.5% of parent signal) are clearly visible, whereas signals of other diastereomers
are too small to be discerned.
5-oxohexyl substituents quickly cyclized forming bicyclic
acetals. NMR spectroscopic analysis of the reaction products
confirmed full preservation of diastereomeric purity of the
employed epoxyalcohols. Isolated yields varied between 65%
Scheme 2. TBAF-Promoted Hydrolysis of a Variety of
Epoxyalcohols and Synthesis of 5-Deoxy-L-arabinose
and 87%, in addition to 0-20% of recovered starting
materials.
These results show that TBAF-promoted hydrolysis of
epoxyalcohols is effective for a wide range of substrates,
for example, tolerating the presence of unprotected
carbonyl groups. The applicability toward double bond
or phenyl-substituted epoxyalcohols such as 13 or 24
allows introduction of additional oxygenation proximal
to the triol, providing access to uncommon carbohydrate
derivatives. A simple example is 5-deoxy-L-arabinose (26),
an intermediate in several published syntheses of biopterin
derivatives.12 As shown in Scheme 2, TBAF-promoted
hydrolysis of epoxyalcohol 24 allowed preparation of
5-deoxy-L-arabinose of high diastereomeric purity (>99%
de for the mixture of anomers) in five straightforward
steps.
In conclusion, our method enables preparation of arabino-
or lyxo-configured consecutive triols of very high diastere-
omeric purity Via diastereoselective R-hydrolysis of the
appropriate epoxyalcohols. The method’s simplicity and mild
3988
Org. Lett., Vol. 12, No. 18, 2010

small amounts of triol (<20% conversion after 24 h), which
was found to be of low diastereomeric purity. As could be
expected, treatment of epoxyalcohols with the much less
basic tetrabutylammonium chloride or perchlorate did not
effect any epoxide opening. On the basis of other recent
examples for solvent-dependent changes in regioselectivity
of epoxide opening,13 it seems possible that specific hydrogen-
bonding interactions facilitate R-attack in water-limited
TBAF/CH3CN/H2O mixtures. We are currently exploring the
utility of this method for opening epoxides with nucleophiles
other than hydroxyl or water.
Scheme 3. Ring Opening of R,ꢀ-Epoxyalcohols Using TBAF
Compared to Other Methods7,9
Acknowledgment. This work was supported in part by
the National Institutes of Health (GM079571). We thank Jo´n
T. Njar{arson and Joshua C. Judkins (Cornell) for helpful
suggestions.
conditions suggest broad applicability, and it effectively
complements methods that facilitate ring opening in the
ꢀ-position of epoxyalcohols (Scheme 3).7,9
Supporting Information Available: Complete experi-
mental details along with spectroscopic data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Given that for R,ꢀ-epoxyalcohols nucleophilic attack at
the ꢀ-position is generally much preferred,7,9 the selectivity
for R-attack in the presence of TBAF is striking. Interest-
ingly, this unusual reactivity seems to be specific to the
fluoride salt, as attempts to substitute TBAF with the
similarly basic tetrabutylammonium hydroxide were not
successful. Treatment of epoxyalcohols with tetrabutylam-
monium hydroxide in acetonitrile at 40 °C produced only
OL1015306
(12) Fernandez, A. -M.; Duhamel, L. J. Org. Chem. 1996, 61, 8698.
(13) Jamison, T. F.; Vilotijevic, I. Science 2007, 317, 1189.
Org. Lett., Vol. 12, No. 18, 2010
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