Anti-selective glycolate aldol additions with an oxapyrone boron enolate

Article abstract of DOI:10.1021/ol0002166

The boron enolate of pyrone 2 undergoes asymmetric aldol reactions with aldehydes to give protected anti 1,2-diols 3. The pyrone is readily available from trans stilbene using asymmetric dihydroxylation. Yields for the aldol reaction range from 62 to 92%

Full text of DOI:10.1021/ol0002166

ORGANIC
LETTERS
2000
Vol. 2, No. 19
3035-3037
Anti-Selective Glycolate Aldol Additions
with an Oxapyrone Boron Enolate
Merritt B. Andrus,* B. B. V. Soma Sekhar, Erik L. Meredith, and N. Kent Dalley
Department of Chemistry and Biochemistry, C100 BNSN, Brigham Young UniVersity,
ProVo, Utah 84602
mbandrus@chemdept.byu.edu
Received August 3, 2000
ABSTRACT
The boron enolate of pyrone 2 undergoes asymmetric aldol reactions with aldehydes to give protected anti 1,2-diols 3. The pyrone is readily
available from trans stilbene using asymmetric dihydroxylation. Yields for the aldol reaction range from 62 to 92% and the selectivities from
6:1 to >20:1 for the anti isomers. Protection and hydrogenolysis of the products can be used to remove the pyrone, giving differentially
protected diol intermediates 12 that are amenable to multistep synthesis.
Aldol reactions are often key steps in the synthesis of
complex polyketide, isoprenoid, and carbohydrate natural
products. Of the variations, a general approach to the anti-
selective oxaacetate or glycolate aldol reaction, a useful
process for the generation of contiguous differentially
protected diols, is lacking. A new approach to this problem
is the aldol reaction of the homochiral diphenyloxapyrone
now disclosed. Problems arise with known auxiliaries in that
the E-enolate geometry, needed in the closed transition state
to give the anti-product, is not favored.1 Others are limited
in use to only R-alkoxyaldehydes.1g In open arrangements
as with silyl enolates, the syn-product is produced by either
the E- or Z-enolate geometry.2 Recent methods,3 especially
the norephedrine boron enolate of Masamune,3a provide high
anti-selectivity in propionate versions, yet their application
to the anti glycolate reaction have not been established.4
Chiral boron ketone enolates are particularly useful to access
either syn or anti products.5 Known asymmetric Mukaiyama
anti-glycolate reactions are limited by the amount of ligand
needed and type of aldehyde used.6 Thioglycolate boron
enolates, requiring 2 equiv of a menthone-derived ligand,
also react with high selectivity.7 Recently an erythrulose
enolate of limited applicability was shown to give anti
products.8 Alternative approaches include osmium-catalyzed
asymmetric dihydroxylation (AD) which works very well
(2) (a) Gennari, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, Chapter 2.4.
(b) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996,
118, 5814. (c) Hattori, K.; Yamamoto, H. J. Org. Chem. 1993, 58, 5301.
(3) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997,
119, 2586. (b) Ghosh, Arun, K.; Onishi, M. J. Am. Chem. Soc. 1996, 118,
2527. (c) Paterson, I.; Wren, S. P. J. Chem. Soc., Chem. Commun. 1993,
1790. (d) Gennari, C.; Moresca, D.; Vieth, S.; Vulpetti, A. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1618. (e) Meyers, A. G.; Widdowson, K. L. J. Am.
Chem. Soc. 1990, 112, 9672. (f) Corey, E. J.; Kim, S. S. J. Am. Chem. Soc.
1990, 112, 4976. (g) Gennari, C.; Bernardi, A.; Colombo, L.; Scolastico,
C. J. Am. Chem. Soc. 1985, 107, 5812. (h) Meyers, A. I.; Yamamoto, Y.
Tetrahedron 1984, 40, 2309.
(4) Glycolate versions of the norephendrine Masamune auxiliary give
syn aldol products: Andrus, M. B.; Turner, T. M. Unpublished results.
(5) (a) Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58, 4182. (b)
Cameron, J. C.; Paterson, I. Org. React. 1997, 51, 1. (c) Paterson, I.; Wallace,
D. J.; Cowden, C. J. Synthesis 1998, 639.
(6) (a) Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994, 35, 3329.
(b) Kobayashi, S.; Hayashi, T. J. Org. Chem. 1995, 60, 1098.
(7) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53, 5909.
(1) Syn versions: (a) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem.
Soc. 1988, 110, 2506. (b) Ku, T. W.; Kondrad, K. H.; Gleason, J. G. J.
Org. Chem. 1989, 54, 3487. (c) Andrus, M. B.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 10420. Anti: (d) Danda, H.; Hansen, M. M.;
Heathcock, C. H. J. Org. Chem. 1990, 55, 173. Anti glycolate: (e) Evans,
D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem.
Soc. 1990, 112, 7001. (f) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim,
A. S. J. Org. Chem. 1992, 57, 1961. (g) Evans, D. A.; Weber, A. E. J. Am.
Chem. Soc. 1986, 108, 6757. (h) Saika, H.; Fruh, T.; Iwasaki, G.; Koizumi,
S.; Mori, I.; Hayakawa, K. Bioorg. Med. Chem. Lett. 1993, 3, 2129. (i) Li,
Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.; Odom, J. D.; Silks, L. A., III
J. Am. Chem. Soc. 2000, 122, 386. Diastereoselective Ti glycolate: (j)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Borgia, A. L. J. Org. Chem. 1992,
57, 6339.
10.1021/ol0002166 CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/22/2000

for syn diols from E olefins but is not useful for applications
with Z-alkenes leading to anti diols.9 Allylmetals are
generally limited to Z-γ-alkoxy reagents that give syn
products.10 A notable exception, which requires stoichio-
metric BINAL reduction, is the very useful indium-mediated
allyltin additions of Marshall.11
R,R enantiomeric anti aldol product can be readily accessed.
Boron reagents and bases were screened to arrive at the
optimal conditions of dicyclohexylboron triflate15 and tri-
ethylamine at -78 °C in methylene chloride with 2, followed
by addition of isobutyraldehyde (1.2 equiv, Table 1).16 After
While cyclic enolates12 have the distinct advantage of
being constrained to the E-conformation, only a few have
been used in glycolate aldol reactions.12a,b None have been
used to give differentially protected products due to depro-
tection problems. With cyclic glycolates, the E-geometry in
the chair Zimmerman-Traxler transition arrangement pro-
vides the anti adduct (eq 1). We now report a general anti-
Table 1
selective glycolate aldol reaction using enantiopure 5,6-
diphenyl-4-oxa-2-pyrone, which is readily available using
the Sharpless AD reaction, reacts with a broad range of
aldehydes, and allows for the convenient attachment of
protecting groups and further elaborations.
S,S-Diol 1 from trans-stilbene was obtained using catalytic
asymmetric dihydroxylation using AD-mix-R in 85% yield,
98% ee.13 Reaction with di-n-butyltin oxide in refluxing
benzene, followed by treatment with tert-butyl bromoacetate
and trifluoroacetic acid, gave 2 (Scheme 1).14 Either enan-
holding the reaction at that temperature for 2 h and quenching
with buffer, methanol, and peroxide followed by standard
aqueous workup and chromatography, the desired product 3
was obtained in pure form in 86% yield. The stereochemistry
of 3 was confirmed by X-ray crystallography to be the S,S,S,S
isomer as shown.17 The minor isomer 4 was shown to be
the S,S,R,R anti diastereomer.18 Di-n-butylboron triflate gave
lower yields and selectivity. The lithium enolate from LDA
and the titanium enolates were also found to be less effective.
Scheme 1
Various aldehydes were reacted in high yields, 70-90%
in high to good selectivity, >20:1 to 6:1, using the optimal
conditions (Table 2). Straight chain and branched aldehydes
gave the best results, providing anti products in high yield
and selectivity. Propionaldehyde reacted in 92% yield with
essentially complete selectivity. Branching at the â-position
lead to lower 8:1 selectivity with isovaleraldehyde. Aromatic
and unsaturated substrates gave products in lower yields and
selectivities. With isovaleraldehyde and benzaldehyde, small
amounts of syn products (<1-2%) were also detected.
1-Naphthaldehyde gave 4:1 anti selectivity together with a
significant amount of syn products. Reaction of D-glyceral-
tiomeric form of 2 is available in two steps from stilbene by
using AD-mix-R or AD-mix-â. Thus, either the S,S or the
(8) Carda, M.; Falomir, E.; Murga, J.; Castillo, E.; Gonzalez, F.; Marco,
J. A. Tetrahedron Lett. 1999, 40, 6845.
(9) (a) Wang, L.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7568.
(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 4, 2483.
(10) Syn selective: (a) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett.
1980, 4883. (b) Wuts, P. G. M.; Bigelow, S. S.; J. Chem. Soc., Chem.
Commun. 1984, 736. (c) Roush, W. R.; Michaelides, M. R. Tetrahedron
Lett. 1986, 27, 3353. (d) Keck, G. E.; Abbott, D. E.; Wiley: M. R.
Tetrahedron Lett. 1987, 28, 139. (e) Koreeda, M.; Tanaka, Y. Tetrahedron
Lett. 1987, 28, 143. (f) Brown, H. C.; Jadhav, K. P.; Bhat, K. S. J. Am.
Chem. Soc. 1988, 110, 1535. (g) Marshall, J. A.; Gung, W. Y. Tetrahedron
Lett. 1989, 30, 2183. Anti undifferentiated diols from silylallylboranates:
(h) Roush, W. R.; Grover, P. T.; Lin, X. Tetrahedron Lett. 1990, 31, 7563.
(11) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920.
(12) (a) Seebach, D.; Naef, R. HelV. Chim. Acta 1981, 64, 2704. (b)
Pearson, W. H.; Cheng, M.-C. J. Org. Chem. 1987, 52, 3176. (c) Greiner,
A.; Ortholand, J.-Y. Tetrahedron Lett. 1990, 31, 2135. (d) Reno, D. S.;
Lotz, B. T.; Miller, M. J. Tetrahedron Lett. 1990, 31, 827. (e) Majewski,
M.; Gleave, D. M.; Nowak, P. Can. J. Chem. 1995, 73, 1616. (f) Fairbanks,
A. J.; Sinay, P. Tetrahedron Lett. 1995, 36, 893. (g) Comins, D. L.; Kuethe,
J. T.; Hong, H.; Lakner, F. J. J. Am. Chem. Soc. 1999, 121, 2651. (h) Chang,
J.-W.; Jang, D.-P.; Uang, B.-J.; Liao, F.-L.; Wang, S.-L. Org. Lett. 1999,
1, 2061.
(13) Sharpless, K. B.; Amberg, W.; Bennami, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang Z. Xu, D.; Zhang,
X. J. Org. Chem. 1992, 57, 2768.
(14) (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71. (b) David,
S.; Thieffry, A.; Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1981, 1796.
(15) (a) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993,
58, 147. (b) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J. Org.
Chem. 1992, 57, 499.
(16) Paterson, I.; Wallace, D.; Cowden, C. Synthesis 1998, 639.
(17) X-ray data: for 3 (R ) i-Pr): monoclinic space group P21, a )
12.167(3), b ) 5.8264(13), and c ) 13.674(4) Å, â ) 112.742(14)°, V )
893.9, Z ) 2, independent data 1726 (Rint ) 0.0388) R1 ) 0.0500 [I >
2σ(I)]. For 3 (R ) Ph), monoclinic space group P21, a ) 9.7140(1a), b )
9.316(2), and c ) 10.9660(10) Å, â ) 106.193(8)°, V ) 953.0, Z ) 2,
independent data 2297 (Rint ) 0.0146) R1 ) 0.0424 [I > 2σ(I)] (see
Supporting Information).
(18) 1H NMR coupling constants: anti JR,â ) 4-6 Hz, JR,OH ) 3-6
Hz; syn JR,â ) 2 Hz, JR,OH ) 6-9 Hz.
3036
Org. Lett., Vol. 2, No. 19, 2000

Scheme 2
Table 2
Interestingly, if the C6-phenyl is removed as in 8,22 the
selectivity drops to 3:2 for the anti isomers together with
10% syn isomers reacted with isobutyraldehyde. With pyrone
2, the selectivity with this aldehyde was much higher at
11:1, giving only anti products.
The aldol products can be conveniently elaborated into
differentially protected 1,2-diol substrates suitable for mul-
tistep applications by first protecting the secondary alcohol
in 3 as a silyl ether or as a methyl ether (Scheme 3). The
Scheme 3
dehyde acetonide with S,S-2 gave only 6:1 selectivity
together with 30% syn products. In contrast, R,R-2 prepared
using AD-mix-â, gave very high 16:1 selectivity for the anti
products with no syn isomer observed with -glyceraldehyde
acetonide. In all other cases only the two anti isomers were
found.
benzyl ester-ether pyrone is removed by hydrogenolysis
with 10% Pd/C in ethyl acetate to give the protected hydroxy
acid 12 and diphenylethane which is easily removed.
Alternatively, 3 can be deprotected directly to the pure diol
acid 11 in one step. Multistep applications to access
differentially protected anti diol products and further refine-
ments to the pyrone substrate will be disclosed shortly.
The transition state appears to be the Zimmerman-Traxler
arrangement19 with boron acting as a Lewis acid for the
aldehyde and the enolate locked in the E-configuration (eq
1). An open arrangement cannot be ruled out at this time in
that excess boron triflate may directly active the aldehyde.20
Yet, 1 equiv of boron triflate gives a slow reaction with low
yields with good anti selectivity. In addition, excess triethyl-
amine serves to complex the boron triflate, lowering its
ability to directly coordinate the aldehyde, unlike diisopro-
pylethylamine. Thus, a closed arrangement is most likely
with the aldehyde reacting away from the C5-phenyl to give
the observed S,S,S,S stereochemistry. Approach of the
aldehyde to the same face bearing the C5-phenyl gives the
minor S,S,R,R anti isomer. As the size of the aldehyde
increases, more syn products arise presumably through a twist
boat arrangement. With larger aryl groups, as with di-o-tolyl
521 made in an analogous fashion to that of 2, the selectivity
for the reaction is not significantly changed (Scheme 2).
Acknowledgment. We wish to thank the National
Institutes of Health (GM57275) and the Brigham Young
University Cancer Center for funding and Dr. Bruce Jackson
for mass spectrometry.
Supporting Information Available: Experimental de-
tails, analytical, NMR, and X-ray data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0002166
(21) Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.; Redhouse, A.
D.; Challard, S. R. J. Chem. Soc., Perkin Trans. 1 1995, 2293.
(22) (5S)-5-Phenyl[1, 4]dioxan-2-one 8 was prepared in five steps and
33% overall yield from (S)-mandelic acid as follows: LAH reduction of
(S)-mandelic acid (Mosher, H. S.; Dale, J. A. J. Org. Chem. 1970, 35, 4002)
gave (S)-phenylethylene glycol. Selective protection of the 1° alcohol as
the TBDPS ether was followed by alkylation of the 2° alcohol by treatment
with NaH and tert-butyl bromoacetate. Deprotection using TBAF and
treatment with catalytic TFA provided 8.
(19) (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920. (b) Fenzl, W.; Koster, R. J. Liebigs Ann. Chem. 1975, 1322. (c)
Masamune, S. Aldrichimica Acta 1978, 11, 23.
(20) (a) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.
1990, 55, 173. (b) Raimundo, B. C.; Heathcock, C. H. Synlett 1990, 1213.
Org. Lett., Vol. 2, No. 19, 2000
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