Highly stereoselective intermolecular oxy-michael addition reaction to α,β-unsaturated malonate esters

Article abstract of DOI:10.1021/ol049820x

The highly diastereoselective oxy-Michael addition of the "naked" anion of (6S)-methyl δ lactol to alkylidiene-, arylidene-, and heteroarylidene-malonate derivatives leading to the direct formation of THP*-protected β-hydroxy ester derivatives is describe

Full text of DOI:10.1021/ol049820x

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1357-1360
Highly Stereoselective Intermolecular
Oxy-Michael Addition Reaction to
r,â-Unsaturated Malonate Esters
David J. Buchanan, Darren J. Dixon,* and Felix A. Hernandez-Juan
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB2 1EW, U.K.
djd26@cam.ac.uk
Received January 30, 2004
ABSTRACT
The highly diastereoselective oxy-Michael addition of the “naked” anion of (6S)-methyl δ lactol to alkylidiene-, arylidene-, and heteroarylidene-
malonate derivatives leading to the direct formation of THP*-protected â-hydroxy ester derivatives is described. Subsequent acid-mediated
deprotection affords the enantioenriched aldol products in quantitative yields.
The stereoselective addition of oxygen-centered nucleophiles
to Michael acceptors has received little attention over the
years despite the potential utility of the protected hydroxyl
products in synthesis.1 Our group2 and others3 have been
involved in the development of such chiral water equivalents
for addition to highly reactive nitro olefin acceptors4 and to
this end the highly diastereoselective oxy-Michael addition
of the “naked” anions of enantiopure δ lactols has been
described. Although useful for the asymmetric synthesis of
1,2-amino alcohols, we believed an extension of this
chemistry to incorporate other Michael acceptors, while
maintaining reaction efficiency and diastereoselectivity,
would expand significantly the utility and scope of the
reaction.
Herein, we wish to describe work leading to the first highly
diastereoselective oxy-Michael reaction of a chiral water
equivalent to alkylidene-, arylidene-, and hetereoarylidiene-
malonate Michael acceptors.5,6 Our initial studies focused
on the attempted addition of the “naked” alkoxide of
6-methyl δ lactol 1 to R,â-unsaturated esters and lactones.
However, all attempts to make an oxygen-carbon bond
failed, and either starting material was returned unreacted
or the alkoxide facilitated the dimerization of the Michael
acceptor.7
(1) Reviews: (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K. In
ComprehensiVe Natural Products Chemistry; Barton, D. H. R., Nakunisha,
K., Meth-Chon, O., Eds.; Pergamon: Oxford, UK, 1999; Vol. 4. p 25. (b)
Staunton, J.; Wilkinson, B. Top. Curr. Chem. 1998, 195, 49.
It was clear that further activation of the Michael acceptor
was required for successful oxygen-carbon bond formation.
(2) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew.
Chem., Int. Ed. 2003, 35, 4241-4244. (b) Buchanan, D. J.; Dixon, D. J.;
Scott, M. S.; Laine´, D. I. Tetrahedron: Asymmetry 2004, 15, 195-197.
(3) (a) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Angew. Chem.,
Int. Ed. 1996, 35, 2388-2390. (b) Enders, D.; Haertwig, A.; Raabe, G.;
Runsink, J. Eur. J. Org. Chem. 1998, 1771-1792. (c) Enders, D.; Haertwig,
A.; Runsink, J. Eur. J. Org. Chem. 1998, 1793-1801.
(4) For diastereoselective/nonenantioselective additions to nitro olefin
acceptors, see: (a) Dumez, E.; Faure, R.; Dulce`re, J.-P. Eur. J. Org. Chem.
2001, 2577-2588. (b) Yakura, T.; Tsuda, T.; Matsumura, Y.; Yamada, S.;
Ikeda, M. Synlett 1996, 985-986.
(5) For nonenantioselective additions of oxygen-centered nucleophiles
to benzylidene(or alkylidene)malonates and related Michael acceptors,
see: (a) Cavicchioli, M.; Marat, X.; Monteiro, N.; Hartmann, B.; Balme,
G. Tetrahedron Lett. 2002, 43, 2609-2611. (b) Marat, X.; Monteiro, N.;
Balme, G. Synlett 1997, 845-847. (c) Monteiro, N.; Balme, G. J. Org.
Chem. 2000, 65, 3223-3226.
(6) For asymmetric diastereoselective substrate-controlled additions of
achiral oxygen-centered nucleophiles, see, for example: Paquette, L. A.;
Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am. Chem. Soc. 2000, 122,
2742-2748.
10.1021/ol049820x CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/06/2004

Accordingly, alkylidenemalonate acceptor8 2 was chosen as
a test substrate. The initial conditions adopted were identical
to those previously established for the additions to â-sub-
stituted nitro olefin acceptors. Thus, deprotonation of the
epimeric mixture of (6S)-methyl δ lactol 1 with KHMDS in
THF at -78 °C and addition of 18-crown-6 (1.0 equiv)
generated the “naked” chiral lactol alkoxide nucleophile.
Addition of 2 (0.67 equiv) to this mixture for 1 h and
quenching with acetic acid (2.0 equiv) at -78 °C afforded,
after aqueous workup, the crude oxy-Michael adduct 3 in a
pleasing >94% diastereomeric excess (de). Purification by
flash column chromatography afforded 3 in an excellent 80%
yield. The relative stereochemistry of the major diastereo-
meric product was unambiguously determined by single-
crystal X-ray diffraction on the bis hydroxymethyl product
4, obtained by lithium aluminum hydride reduction of 3
(Scheme 1).
Scheme 2. Stereoselective Oxy-Michael Addition of the
“Naked” Anion of 1 to a Range of Malonate-Derived Acceptorsa
a Key: (a) KHMDS (1.0 equiv), 18-crown-6 (1.0 equiv), -78
°C, THF then R1CHC(CO2R2)2 (0.67 equiv); (b) AcOH (2.0 equiv).
ester types. While diastereoselectivities remained high, some
erosion in yield (entries 5 and 14) was witnessed with a linear
hexyl group at the â-position. This was due to a competing
γ-deprotonation pathway, as deconjugated products were
clearly visible in the crude reaction mixtures. When the
â-substituent was an isopropyl group, slightly lowered
reaction diastereoselectivities were noted and the selectivity
Scheme 1. Stereoselective Oxy-Michael Addition of the
“Naked” Anion of 1 to Dimethyl Malonate Derived Acceptor 2a
Table 1. Scope of the Stereoselective Oxy-Michael Addition
of 1 to Malonate-Derived Acceptors
a Key: (a) KHMDS (1.0 equiv), 18-crown-6 (1.0 equiv), -78
°C, THF then 2 (0.67 equiv) for 1 h; (b) AcOH (2.0 equiv); (c)
LiAlH4, Et2O, 0 °C.
Having identified alkylidene malonate 2 as a suitably
reactive substrate, the scope of the oxy-Michael addition to
a range of alkylidene-, arylidene-, and heteroarylidene-
malonate derivatives was probed. Malonate acceptors were
chosen in which the ester substituent was varied from methyl
to ethyl and benzyl and the â-substituent varied between
alkyl, branched alkyl, aromatic, and heteroaromatic groups.
The conditions for the oxy-Michael reaction were as
described above for the test substrate, and the results are
detailed below (Scheme 2, Table 1).
With aromatic and heteroaromatic â-substituents, the
reaction diastereoselectivities were uniformly excellent (g96%
de in all cases), and the yields were good for all malonate
(7) For an interesting (nonenantioselective) synthesis of tetrahydrofurans
using an oxy-Michael/Michael cyclization strategy, see: Greatrex, B. W.;
Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2003, 68,
4239-4246.
(8) Readily synthesized by condensation, see: Trost, B. M.; Higuchi,
R. I. J. Am. Chem. Soc. 1996, 118, 10094-10105.
1
a Measured by analysis of the 400, 500, or 600 MHz H NMR spectra
of the crude reaction product.
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Org. Lett., Vol. 6, No. 9, 2004

was somewhat dependent on the ester group. Thus, for the
dimethyl ester case (entry 4), a reaction de of 94% was
observed; with the dibenzyl ester a de of 93% was recorded
(entry 8) and with the diethyl ester (entry 13) the de was
91%. In all three cases, however, the reaction yields were
good to excellent.
When a single diastereoisomeric product of the oxy-
Michael reaction was subjected to the “unselective” reaction
conditions, no change in the diastereomeric ratio was
observed. Thus, by adding 1.5 equiv of KHMDS to 12 (>98
de) in the presence of 0.5 equiv of lactol in THF at -78 °C
and quenching after 1 h, the starting material 12 was returned
unchanged (Scheme 4).
The relative stereochemistry of the major oxy-Michael
adduct 13 from addition to the acceptor derived from
2-furaldehyde and diethyl malonate was unambiguously
determined by single-crystal X-ray diffraction. In view of
the known stereochemistry of 4, and the correlation with the
stereochemical outcomes found in the additions to â-sub-
stituted nitro olefin acceptors, we have assigned the stereo-
chemistries of all of the other major adducts in Table 1 by
analogy.
Scheme 4. Proof of the Irreversibility of the “Unselective”
Oxy-Michael Addition of the Potassium Salt of 1a
The presence of the crown ether in all of the above
reactions was critical for high stereoselectivity and the short
reaction times. When the reactions were performed without
this sequestering agent, the observed selectivities dropped
to between 1:1 and 3:1, and the reaction rates were
dramatically reduced.9
a Key: (a) 1 (0.5 equiv), THF, -78 °C, KHMDS (1.5 equiv),
30 min, then AcOH (3.0 equiv).
For example, subjecting the Michael acceptor 18, derived
from thiophene 2-carboxaldehyde and diethyl malonate, to
1.5 equiv of the potassium salt of 6-methyl δ lactol (in the
absence of 18-crown-6) in THF at -78 °C for 20 min gave
the oxy-Michael adducts 12 and 19 in a ratio of 1.6:1 at 6%
conversion. A repeat of the same reaction but allowing for
an extended reaction time of 4 h provided 12 and 19 in a
ratio of 2.6:1 at 61% conversion. However, when the same
reaction was repeated, but with 18-crown-6 (1 equiv relative
to the alkoxide) added after 4 h, and the reaction continued
for a further 60 min before quenching, 12 and 19 were
produced in the improved ratio of 4.7:1 at 99% conversion
(Scheme 3).
These experiments indicate that either with or without 18-
crown-6, the oxy-Michael reactions of the potassium salt of
6-methyl δ lactol to malonate derived Michael acceptors are
irreversible at -78 °C. The sequestering of the potassium
counterion with 18-crown-6 leads to a substantial rate
enhancement and improved diastereoselectivity at the â-cen-
ter.
As well as inducing excellent levels of stereocontrol in
its addition to the electron poor alkenes, the naked lactol
anion allows access to enantiomerically enriched products
not previously accessible by other methods. Thus, treatment
of Michael adducts 5, 7, 10, and 13 with polymer-supported
sulfonic acid resin in methanol at room temperature leads
to quantitative THP* removal. The epimeric THP* methyl
ether side products (24) are volatile, and thus, after simple
filtration and evaporation, essentially pure, enantiomerically
enriched â-hydroxy malonate ester products 20-23 are
afforded in quantitative yield. The enantiomeric excess of
the thiophene derivative was measured as >98% ee by chiral
HPLC and confirmed that no racemization was occurring in
the deprotection step. Interestingly, any attempt at purifica-
tion of these product materials by chromatographic methods
led to extensive decomposition, thus highlighting the unique-
ness of our approach (Scheme 5, Table 2).
Scheme 3. Probing the Dependence of Reaction
Diastereoselectivity and Conversion on Time and 18-Crown-6
Additivea
Scheme 5. Acid-Mediated Deprotection of Oxy-Michael
Adductsa
a Key: (a) 1, KHMDS (1.0 equiv), 30 min, then 18 (0.67 equiv),
20 min, then AcOH (2.0 equiv); (b) 1, KHMDS (1.0 equiv), 30
min, then 18 (0.67 equiv), 4 h, then AcOH (2.0 equiv); (c) 1,
KHMDS (1.0 equiv), 30 min, then 18 (0.67 equiv), 4 h, then 18-
crown-6 (1.0 equiv), 1 h, then AcOH (2.0 equiv).
a Key: (a) MP-TsOH II, MeOH, rt.
Org. Lett., Vol. 6, No. 9, 2004
1359

In summary, the naked anion of enantiopure 6-methyl δ
lactol undergoes highly diastereoselective oxy-Michael ad-
ditions to a range of alkylidiene-, arylidene-, and het-
eroarylidenemalonate esters. The reactions occur under
kinetic control in THF at -78 °C and provide a comple-
mentary but direct asymmetric route to protected â-hydroxy
ester products. The synthetic utility of these products as well
as the origins of the high stereocontrol observed in the
reactions will be reported in due course.
Table 2. Results of Acid-Mediated Methanolysis Reactions
Acknowledgment. We gratefully acknowledge Glaxo-
SmithKline (to D.J.B.), EPSRC (to F.A.H.-J.), EPSRC
National Mass Spectrometry Service Centre, Swansea, and
Prof. S. V. Ley.
a ee determined by chiral HPLC using a Chiralcel AD column. b ee
assigned by analogy to that of 20 (entry 1) and with the de of the starting
material.
Supporting Information Available: Experimental pro-
cedures and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
The deprotected products 20-23, the esters 3, 5-17, and
the diol 4 (or derivatives thereof) should find a number of
uses in natural product synthesis and in the study of
asymmetric reaction pathways utilizing malonic acid derived
nucleophiles.
OL049820X
(9) The “unselective” reaction is routinely carried out to identify the 1H
NMR resonances of the minor diastereoisomer originating from the
â-stereocenter of the cis-THP* adducts in the “selective” reaction.
1360
Org. Lett., Vol. 6, No. 9, 2004