Unusual magnesium chloride catalyzed non-evans anti-aldol reactions of an enolizable L-threose derivative

Article abstract of DOI:10.1002/ejoc.200700854

The magnesium chloride catalyzed anti-aldol reaction of phenyl acetate derived oxazolidinones proceeds readily with enolizable L-threose derivative 8 to provide anti-aldol adducts in high yields and with very high diastereoselectivities. The reaction is a

Full text of DOI:10.1002/ejoc.200700854

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700854
Unusual Magnesium Chloride Catalyzed Non-Evans anti-Aldol Reactions of an
Enolizable -Threose Derivative
L
James McNulty,*[a] Jerald J. Nair,[a] Marcin Sliwinski,[a] Laura E. Harrington,[a] and
Siyaram Pandey[b]
Keywords: Aldol reactions / Synthetic methods / Diastereoselectivity / Natural products
The magnesium chloride catalyzed anti-aldol reaction of
phenyl acetate derived oxazolidinones proceeds readily with
allows access to stereochemically defined fragments appli-
cable to the synthesis of alkaloid and phenylpropanoid deriv-
atives.
enolizable
L-threose derivative 8 to provide anti-aldol ad-
ducts in high yields and with very high diastereoselectivities.
The reaction is also efficient with aromatic aldehydes and
provides slightly lower diastereoselectivities. This extension
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
ity (Scheme 1).[7] This potentially valuable anti-aldol route
was shown to be restricted to nonenolizable aldehydes un-
der these conditions.
Introduction
The directed aldol reaction is widely recognized as one of
the most powerful carbon–carbon bond forming reactions
available for the regio-, diastereo-, and enantioselective con-
struction of complex intermediates.[1] Despite recent ad-
vances in organocatalytic routes to asymmetric aldol reac-
tions,[2] auxiliary-based approaches remain steadfast as a
principle means to achieve high yields of aldol adducts with
reliably high stereocontrol. Of these, the Evans’ oxazolidin-
ones and their sulfur analogs are most reliable in stereocon-
trolled syn-aldol reactions,[3] whereas the Abiko–Masamune
norephedrine-based auxiliary is perhaps the most depend-
able route to anti-aldol adducts.[4] In general, syn-aldol ad-
ducts are readily accessed through a variety of methods,
whereas efforts to achieve enantioselective anti-aldol reac-
tions are still actively sought.[5]
Most auxiliary-based aldol reactions require the stoi-
chiometric addition of a metal salt (B, Ti, Si, etc.) to form
the required enolate derivative.[1] Recently, Evans and co-
workers reported the first examples of metal-catalyzed aldol
reactions by using both standard[6a] oxazolidinone 1a and
thiazolidine thione[6b] 1b based auxiliaries. The addition of
a magnesium halide (0.1–0.2 equiv.) to a 0.5  ethyl acetate
(EtOAc) solution of the auxiliary (1.0 equiv.) and aldehyde
(1.2 equiv.) in the presence of triethylamine (TEA) and tri-
methylsilyl chloride (TMSCl) yielded non-Evans 2 and Ev-
ans anti-aldol adducts 3 in high yield and with high selectiv-
Scheme 1. Magnesium halide catalyzed anti-aldol reactions.
We have been engaged in an on-going project to identify
and probe the anticancer pharmacophore contained within
the pancratistatin series of Amarillidaceae alkaloids exem-
plified by pancratistatin and its 7-deoxy analog
4
(Scheme 2).[8,9] These compounds initiate apoptosis selec-
tively in various human tumor cell lines through a mecha-
nism currently being elucidated in our laboratories.[8] Re-
cent work[9] has established that the minimum structural
requirements for potent anticancer activity consist of a
2,3,4-triol-functionalized ring-C[9a] moderated significantly
through inclusion of a β-benzyloxy substituent at position
C1,[9b] as depicted in 5 (Scheme 2). In part, we were at-
tracted to an Evans–Ivanoff strategy as a potential means
of introducing two key stereocenters that might allow for
further elaboration to both 4 and 5.
[a] Department of Chemistry, McMaster University,
1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada
Fax: +1-905-522-2509
E-mail: jmcnult@mcmaster.ca
[b] Department of Chemistry, University of Windsor,
Windsor, Ontario N9B 3P4, Canada
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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J. McNulty, J. J. Nair, M. Sliwinski, L. E. Harrington, S. Pandey
SHORT COMMUNICATION
Scheme 2. Retrosynthetic analysis of 7-deoxypancratistatin 4.
The Ivanoff reaction of magnesium carboxylate derived auxiliary to give diol 13, followed by a subsequent reaction
enolates (magnesium ketene acetals) has previously been with benzaldehyde/dimethylacetal (BDMA) to yield crystal-
documented to favor anti-aldol reactions through induced line benzylidene 14. X-ray structural determination of 14
stereoselectivity, most likely as a consequence of (E)-enolate confirmed the relative and absolute stereochemistry as
geometry.[10] Surprisingly, few reports involving the use of shown (Figure 1).
phenyl acetate derived auxiliaries have previously been
The selective formation (95:5) of stereochemically proven
documented in aldol chemistry,[11] despite obvious applica- anti-aldol adduct 9 is of interest, as it indicates that the
bility in the alkaloid field through elaboration of derived facial selectivity of the auxiliary has an over-riding influ-
chiral β-arylethylamine derivatives. Hence, despite the re- ence on the stereochemical outcome of this reaction and
port that enolizable aldehydes are not general participants any Felkin–Anh bias on the part of the aldehyde is over-
in Evans MgX2-catalyzed crossed-aldol-type processes, the come. Minor adduct 10 from this reaction appeared to be
combination of the Ivanoff reactivity in conjunction with the Evans anti adduct through NMR spectroscopic analy-
these potential applications prompted us to investigate this sis. Reductive removal of the auxiliary from 10 and its reac-
reaction as a means of accessing stereochemically defined tion with BDMA as above provided diastereomeric benzyl-
fragments of relevance to both alkaloid and phenylpro- idene 15 (Scheme 3).
panoid[4b] synthesis.
In order to asses the degree of match/mismatch in the
forgoing aldol reaction, the reaction of ent-7 with 8 was
investigated under the same conditions. This reaction
(Scheme 4) also proceeded efficiently to give non-Evans anti
Results and Discussion
In our retrosynthetic analysis (Scheme 2), a non-Evans adduct 11 as a single stereoisomer in near quantitative
anti-aldol reaction of methylenedioxy functionalized phenyl yield, and possible anti-aldol 12 was not detected in the
acetate derived auxiliary 7 with -threose chiron 8 (derived reaction mixture. Major adduct 11 was treated as before to
from -tartaric acid) would generate adduct 6, which is suit- give diol 16 and then converted into benzylidene 15, which
ably functionalized for elaboration to 4 and 5. Previous re- was identical to that obtained from the minor adduct in
ports on nucleophilic addition to this and related aldehydes the first series. The small mismatch in the former reaction
indicate that the wrong stereochemistry would be attained confirms that the auxiliary contributes the over-riding stere-
through intrinsic diastereoselectivity, and the results ex- odirecting effect on the reaction and that stereoelectronic
plained are in accord with the Felkin–Anh model.[12] In this effects on the part of the aldehyde play only a minor role
communication we report the remarkable success of the re- in diastereoselection.
quired anti-selective aldol reaction catalyzed by magnesium
halides and demonstrate the overriding stereochemical di- is the efficiency of the reaction conducted under these con-
recting effect of the auxiliary. ditions with an enolizable aldehyde. We readily confirmed
The most surprising issue in the foregoing aldol reactions
The overall aldol strategy is outlined in Scheme 3. The that enolizable aliphatic aldehydes suffer from low conver-
necessary phenyl acetate auxiliary 7 was prepared by using sion as noted by Evans et al.[6a] In fact, acetonide-protected
standard methods as shown. The aldol addition of 7 to - -glyceraldehyde 17 (Scheme 5) was the only other aldehyde
tartaric acid derived threose derivative 8 proceeded under identified that provided reasonable yield of adduct under
Evans’ conditions to yield adducts 9 and 10 in a ratio of these conditions.[13] Slow addition of this aldehyde to ent-7
95:5 and to our surprise in 98% isolated yield. The reaction as before provided 18 in 20% yield as the product of the
was repeated on numerous occasions without incident and non-Evans anti-aldol reaction (90:10 ratio of 18 to Evans
was conducted on a 10.0-g scale. The aldol adducts were anti diastereomer). In this reaction, aldehyde 17 was fully
readily separable by silica gel chromatography. The stereo- consumed and significant portions of imide ent-7 remained,
chemistry of adduct 9 was proven to be the expected non- which indicated that enol ether formation or homo-aldol
Evans’ anti diastereomer through reductive removal of the condensation of 17 was an issue.
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Unusual MgCl2-Catalyzed Non-Evans anti-Aldol Reactions
Scheme 3. Slight mismatched anti-aldol reaction.
with steric crowding around the α-hydrogen, which would
be expected to lower the rate of enolization relative to that
of aldolization.
The overall results can be explained empirically through
changes in the relative rates of these two competitive pro-
cesses as a result of the contributing conformational and
electronic effects. The model shown in Figure 2 depicts al-
dehyde 8 in its presumed most reactive conformation, incor-
porating modified Cornforth[14a] (dipole moment minimi-
zation on α-alkoxy[14c,14d] aldehydes) and open-chain[14b]
(i.e. nonchelation) elements. It is readily apparent that one
of the methyl groups of the acetonide is in spatial proximity
to the α-hydrogen. This is also the case for aldehyde 17.
Furthermore, in aldehyde 8, the α-hydrogen is further
shielded through an almost syn-periplanar relationship to
the very bulky C3 to C4 CH2-OTBS (bold) substituent.
Thus, as the expected (Z)-magnesium enolate[11d] of 7 or
ent-7 approaches the carbonyl in these sterically α-con-
gested aldehydes, aldolization may effectively compete with
α-deprotonation in these specific cases. The high yields of
aldol product and minor match/mismatch results reported
in the reaction of 7 and ent-7 with 8 indicates aldolization
to be the preferred mode of reactivity of 8 irrespective of
Si or Re approach of the nucleophile on the aldehyde as
controlled by the auxiliary.[6]
Figure 1. X-ray structure of 14.
Conformational analysis of the successful aldehyde parti-
cipants, 8 and 17, revealed that the enhanced aldol reactiv-
ity may be attributed to electronic effects in conjunction
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J. McNulty, J. J. Nair, M. Sliwinski, L. E. Harrington, S. Pandey
SHORT COMMUNICATION
Scheme 4. Matched anti-aldol reaction.
tion. In this regard, we were also driven to investigate the
use of phenyl acetate derivative ent-7 and propanoyl deriva-
tive 19 as a potential asymmetric entry to phenylpropanoids
and related derivatives.[4b] As shown in Scheme 6, the reac-
tion of ent-7 with benzaldehyde or anisaldehyde proceeded
readily under the standard conditions to give adducts 20a,b
and 21a,b in good yields but slightly lower diastereoselectiv-
ities. Major adduct 20a was proven to be non-Evans anti
though single-crystal X-ray structural determination (Fig-
ure 3).[15]
Scheme 5. anti-Aldol reaction of 2,3-acetonide-protected glyceral-
dehyde.
Scheme 6. anti-Aldol reactions with aromatic aldehydes.
In contrast, the reactions of aliphatic imide 19 with aro-
matic aldehydes (benzaldehyde and anisaldehyde, Scheme 6)
proceeded in high yields and with high diastereoselectivities,
similar to the benzyl oxazolidinones,[6a] to provide anti-al-
dols 22 and 23. Again, the major product proved to be non-
Evans anti diastereomer 23 as depicted in Figure 4 (X-ray).
These results show that in addition to yield, the diastereo-
Figure 2. Newman projection of aldehyde 8.
The successful phenyl acetate derived adducts and deriv- selectivity also depends considerably on both the structure
atives 9, 11, 13, 14, 15, and 16 should prove to be of value of the aldehyde and the nature of the donor group on the
in natural product synthesis as described in the introduc- part of the auxiliary.
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Unusual MgCl2-Catalyzed Non-Evans anti-Aldol Reactions
[2] a) A. Berkessel, H. Groger in Asymmetric Organocatalysis:
From Biomimetic Concepts to Applications in Asymmetric Syn-
thesis, Wiley-VCH, Weinheim, 2005; b) B. List in Modern Aldol
Reactions, Wiley-VCH, Weinheim, 2004, vol. 1, ch. 4.
[3] D. A. Evans, J. A. Bartoli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129.
[4] a) A. Abiko, Acc. Chem. Res. 2004, 37, 387–395; b) A. Abiko,
J. F. Liu, S. Masamune, J. Am. Chem. Soc. 1997, 119, 2586–
2587.
[5] S. Fanjul, A. N. Hulme, J. W. White, Org. Lett. 2006, 8, 4219–
4222.
[6] a) D. A. Evans, J. S. Tedrow, J. T. Shaw, C. W. Downey, J. Am.
Chem. Soc. 2002, 124, 392–393; b) D. A. Evans, C. W. Downey,
J. T. Shaw, J. S. Tedrow, Org. Lett. 2002, 4, 1127–1130. For re-
lated syn-selective aldol reactions, see: c) M. T. Crimmins, B. W.
King, E. A. Tabet, K. Chaudhary, J. Org. Chem. 2001, 66, 894–
902; d) D. A. Evans, C. W. Downey, J. L. Hubbs, J. Am. Chem.
Soc. 2003, 125, 8706–8707.
[7] Magnesium halide catalyzed Mukaiyama-type anti-selective al-
dol reactions have previously been reported, see: a) E. J. Corey,
W. Li, G. A. Reichard, J. Am. Chem. Soc. 1998, 120, 2330–
2336; b) W. Li, X. Zhang, Org. Lett. 2002, 4, 3485–3488.
[8] a) A. M. McLachlan, N. Kekre, J. McNulty, S. Pandey,
Apoptosis 2005, 10, 619–630; b) S. Pandey, N. Kekre, J.
McNulty, J. Naderi, Cancer Chemother. Pharmacol. 2005, 56,
29–38; c) S. Pandey, N. Kekre, J. McNulty, J. Naderi, Art. Cells,
Blood Sub. & Biotechnol. 2005, 33, 279–295.
Figure 3. X-ray structure of 20a.
[9] a) J. McNulty, V. Larichev, S. Pandey, Bioorg. Med. Chem. Lett.
2005, 15, 5315–5318; b) G. R. Pettit, N. Melody, D. L. Herald,
J. Nat. Prod. 2004, 67, 322–327; c) U. Rinner, T. Hudlicky,
Synlett 2005, 365–387.
[10] a) D. Ivanoff, A. Spassoff, Bull. Soc. Chim. Fr. 1931, 49, 371–
375; b) M. Braun in Modern Aldol Reactions, Wiley-VCH,
Weinheim, 2004, vol. 1, ch. 1.
[11] For select reports on phenyl acetate derived auxiliaries, see: a)
M. P. Gore, J. C. Vederas, J. Org. Chem. 1986, 51, 3700–3704;
b) M. Prashad, H. Y. Kim, D. Har, O. Repic, T. J. Blacklock,
Tetrahedron Lett. 1998, 39, 9369–9372; c) S. J. Wittenberger,
M. A. McLaughlin, Tetrahedron Lett. 1999, 40, 7175–7178; d)
S. D. Bull, S. G. Davies, M. S. Key, R. L. Nicholson, E. D. Sa-
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Figure 4. X-ray structure of 23.
Conclusions
[12] a) A. Chattopadhyay, B. Dhotare, Tetrahedron: Asymmetry
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c) T. Wong, P. D. Wilson, S. Woo, A. G. Fallis, Tetrahedron
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Yomada, F. Tabusa, Tetrahedron 1990, 46, 265–276; e) J.
Mulzer, A. Angermann, Tetrahedron Lett. 1983, 24, 2843–2846.
[13] See ref.[6a] footnote 13. A series of aliphatic and α-substituted
aldehydes (such as 2-benzyloxyacetaldehyde, Garner aldehyde)
did not provide any identifiable crossed-aldol adduct. The use
of other solvents (EtOAc, THF, DCM, PhMe), bases, silylating
agents TMSCl, TMSOTf, (TMS)2O, etc.], metal salts [MgCl2,
MgBr2, MgI2, Mg(OTf)2, Yb(OTf)3, etc.], modifications to the
order of reagent addition or slow addition of aldehyde, and so
on also failed to promote the reaction in other cases.
[14] a) J. W. Cornforth, R. H. Cornforth, K. K. Matthew, J. Chem.
Soc. 1959, 112–127; b) D. J. Cram, D. R. Wilson, J. Am. Chem.
Soc. 1963, 85, 1245–1249; c) D. A. Evans, S. J. Siska, V. J. Cee,
Angew. Chem. Int. Ed. 2003, 42, 1761–1765; d) V. J. Cee, C. J.
Cramer, D. A. Evans, J. Am. Chem. Soc. 2006, 128, 2920–2930.
[15] CCDC-654288 (for 14), -654286 (for 20a), and -654287 (for 23)
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallography Data Centre via www.ccdc.cam.
ac.uk/data_requestcif.html.
The magnesium halide catalyzed non-Evans anti-aldol
reaction of phenyl acetate derived oxazolidinones was ex-
tended to aromatic aldehydes and conformationally re-
strained aldehydes having hindered α-hydrogen atoms. Ap-
plication of this successful anti-aldol process towards the
synthesis of anticancer alkaloids and phenylpropanoids is
now in progress. Further work to explore the reactivity of
aldehydes such as 8 in this reaction with achiral enolates
under nonchelation conditions is also underway.
Supporting Information (see footnote on the first page of this arti-
cle): Full procedures and spectroscopic data, selected ORTEP and
packing diagrams.
Acknowledgments
We thank NSERC and the Lotte and John Hecht Memorial Foun-
dation for financial support.
[1] R. Mahrwald (Ed.), Modern Aldol Reactions, Wiley-VCH,
Weinheim, 2004, vols. 1, 2.
Received: September 11, 2007
Published Online: October 16, 2007
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