Michael addition-elimination reactions of chiral enolates with ethyl 3-halopropenoates

Article abstract of DOI:10.1021/ol702632m

Key dienoic or dienal substructures of cytotoxic macrolides amphidinolide E and dictyostatin have been prepared via a Michael addition (followed by elimination of X-) of chiral enolates on β-halo derivatives of ethyl acrylate, with full retention of the i

Full text of DOI:10.1021/ol702632m

ORGANIC
LETTERS
2008
Vol. 10, No. 1
65-68
Michael Addition−Elimination Reactions
of Chiral Enolates with Ethyl
3-Halopropenoates
Jorge Esteban, Anna M. Costa, AÅ lex Go´mez, and Jaume Vilarrasa*
Departament de Qu´ımica Orga`nica, Facultat de Qu´ımica, UniVersitat de Barcelona,
AV. Diagonal 647, 08028 Barcelona, Catalonia, Spain
jVilarrasa@ub.edu
Received October 30, 2007
ABSTRACT
Key dienoic or dienal substructures of cytotoxic macrolides amphidinolide E and dictyostatin have been prepared via a Michael addition
-
(followed by elimination of X ) of chiral enolates on
â-halo derivatives of ethyl acrylate, with full retention of the initial E or Z configuration.
Evans oxazolidin-2-ones and our related thiazolidin-2-ones, as well as a fine-tuning of the reaction conditions, have been essential. Many
chiral building blocks are accessible from these adducts.
In connection with a total synthesis of amphidinolide E,1
we analyzed several strategies to reach the fragment tagged
in Scheme 1 (C1-C7).1e Similar moieties are found in other
Scheme 1. Dienal and/or Dienoate Fragments of
Amphidinolide E and Dictyostatin
interesting molecules, such as in the microtubule-stabilizing
anticancer agent dictyostatin (fragment C1-C7).2 These and
related fragments can be prepared by a suitable manipulation
of methyl (R)-3-hydroxy-2-methylpropanoate (the Roche
ester) or by a Pd-catalyzed cross-coupling of appropriate syn-
thons, but our interest in asymmetric Michael reactions3
prompted us to evaluate also the disconnections shown in
Scheme 1.
Michael additions of Ti enolates from chiral propanoyl
derivatives (Aux*COEt) to activated double bonds (such as
(1) Structure: (a) Kubota, T.; Tsuda, M.; Kobayashi, J. J. Org. Chem.
2002, 67, 1651. Total syntheses: (b) Va, P.; Roush, W. R. J. Am. Chem.
Soc. 2006, 128, 15960. (c) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.;
Woo, S. K.; Jung, S. K.; Lee, E. Angew. Chem., Int. Ed. 2006, 45, 8019.
(d) Va, P.; Roush, W. R. Tetrahedron 2007, 63, 5768 and references therein.
(e) Esteban, J. Ph.D. unpublished results.
(2) Reviews on total syntheses of dictyostatin (and other marine
macrolides): (a) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237.
H2CdCH-COOMe), to afford 1,5-difunctional synthons of
(b) Nicholas, G. M.; Phillips, A. J. Nat. Prod. Rep. 2006, 23, 79. (c) Morris,
type 1, have been reported;4 it is known that alkaline metal
J. C.; Nicholas, G. M.; Phillips, J. Nat. Prod. Rep. 2007, 24, 87.
(3) For example: (a) Mas, G.; Gonza´lez, L.; Vilarrasa, J. Tetrahedron
Lett. 2003, 44, 8805. (b) Rodr´ıguez-Escrich, C.; Olivella, A.; Urp´ı, F.;
enolates do not undergo such a reaction (Scheme 2).3,4
Vilarrasa, J. Org. Lett. 2007, 9, 989.
Conversion of C-trisubstituted enolates to compounds with
10.1021/ol702632m CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/11/2007

Scheme 2. Alkylation of Enolates via Michael Reactions
Table 1. Reaction of Various Alkaline Enolates with Ethyl
3-Iodopropenoatesa
E or Z,
yield
(%)
E/Z,
entry
Aux*
M
5a or 5b
conditions
R/Sb
4a/4b
quaternary carbons (e.g., 2 and 3), often in the presence of
chiral phase-transfer catalysts (PTC), has also been devel-
oped.5,6 While molecules of type 2 and 3 cannot epimerize,
our challenge was to obtain structures of type 4, which can
show a higher tendency to epimerize than 1 due to the higher
acidity of HR (as the deprotonation of 4 gives rise to a very
delocalized enolate); control of the double bond configuration
was also essential. Thus, proton exchanges between 4 and
the base excess or between 4 and the enolate had to be
reduced to a minimum; in principle, catalytic processes and
heating seemed counter-indicated.
We report here how we obtained enantiopure compounds
of type 4 in excellent yields by using haloacrylates (e.g., 5a
and 5b). The resulting products could be easily converted
to a plethora of C1-C5 chiral fragments.
We carried out the first trial experiments with B, Ti, and
Li enolates of the Evans most common auxiliary7 and the
ethyl ester of (E)-3-iodopropenoic acid (iodoacrylate 5a). No
reaction occurred in the first two cases, in CH2Cl2, even at
room temperature (rt). With the Li enolate and 5b in THF
at -78 °C, the reaction was too slow, while at -40 °C for
several hours, 40-60% of conversion was observed, but
unfortunately, we obtained a mixture of diastereomers (the
diastereomeric ratios, dr, were ca. 85:15 R/S and 20:80 E/Z).
This outcome was not useful but indicated that a suitable
1
2
3
4
5
6
7
8
9
Evans
Evans
Evans
Evans
Evans
Evans
Evans
Na E (5a) THF
81
78:22 >99:1
Na
K
E
E
CH2Cl2-THFc 95d >97:3d >99:1
CH2Cl2-tol
92
81
95:5 >99:1
75:25 <1:99
87:13 <1:99
88:12 <1:99
Na Z (5b) THF
Na
Na
Na
Z
Z
Z
THF, -100 °C 70
tol-THF 85
CH2Cl2-THFc 95d >97:3d
<1:99
Nagao-I Na E (5a) CH2Cl2-THF 0e
Nagao-II Na
E
E
CH2Cl2-THF 0e
CH2Cl2-THF 73 >97:3 >99:1
10 Oppolzer Na
11 Oppolzer Li Z (5b) THF, -30 °C NR
12 Oppolzer Na
13 Oppolzer K
14 ours
15 ours
Z
Z
CH2Cl2-THF 22
83:17
28:72
CH2Cl2-tol
0e
Na E (5a) CH2Cl2-THF 95d >97:3d >99:1
Na Z (5b) CH2Cl2-THF 93d >97:3d
<1:99
a The commercially available THF solution of the base (1.0-1.1 equiv,
but not more) was added at -78 °C (unless otherwise indicated), with a
syringe, to solutions of the acylated auxiliary in the solvent indicated first;
a few min later, 1.1-1.2 equiv of 5a or 5b in THF, CH2Cl2, or toluene
(tol) was added (e.g., this meant a final 9:1 CH2Cl2-THF mixture). Within
10-15 min, full conversions were noted in most cases. b Ratio R/S for the
1
major isomer (Z or E) by H NMR and HPLC. c Under these conditions,
the reaction works identically with achiral, nonsubstituted oxazolidin-2-
one. d Ratios of 97.5 ( 0.3 to 2.5 ( 0.3 were determined by HPLC,
comparing the crudes with authentic samples of the diastereomers. e De-
composition of the acylated auxiliary.
optimization could provide the desired results. Table 1 sum-
marizes the most significant results among more than 60
experiments.
It is worth noting that the use of a 9:1 CH2Cl2-THF
mixture (that is, CH2Cl2 with the small volume of THF
arising from the base solution) is key to get a full stereo-
control (entries 2 and 7); THF alone favors the exchange of
protons HR. The Evans auxiliary performed perfectly under
these conditions, with both 5a and 5b. These reactions were
scaled up with the same outcome (see Supporting Informa-
tion). On the other hand, the alkaline enolates of acylated
oxazolidine-2-thione and thiazolidine-2-thione derivatives
(see entries 8 and 9 for representative trials), related to those
developed by Nagao et al.8 in the 1980s and popularized
more recently by Crimmins et al.,9 are too unstable. The
Oppolzer camphorsultam10 failed when we allowed it to react
(4) Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry,
D.; Kato, Y. J. Org. Chem. 1991, 56, 5750.
(5) For a very recent review, see: (a) Maruoka, K.; Ooi, T. Angew.
Chem., Int. Ed. 2007, 46, 4222 (section 4). For other excellent reviews,
see: (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. (c) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033 (section 8). For very recent,
related works, see: (d) Linton, B. R.; Reutershan, M. H.; Aderman, C. M.;
Richardson, E. A.; Brownell, K. R.; Ashley, C. W.; Evans, C. A.; Miller,
S. J. Tetrahedron Lett. 2007, 48, 1993 and references therein. (e)
Hamashima, Y.; Hotta, D.; Umebayashi, N.; Tsuchiya, Y.; Suzuki, T.;
Sodeoka, M. AdV. Synth. Catal. 2005, 347, 1576 and references therein.
(6) (a) Bell, M.; Poulsen, T. B.; Jo¨rgensen, K. A. J. Org. Chem. 2007,
72, 3053. (b) Wang, X.; Kitamura, M.; Maruoka, K. J. Am. Chem. Soc.
2007, 129, 1038. (c) Poulsen, T. B.; Bernardi, L.; Bell, M.; Jo¨rgensen, K
A. Angew. Chem., Int. Ed. 2006, 45, 6551 and references therein. Pioneering
reactions with 3-haloacrylates: (d) Smith, A. B., III; Kilenyi, S. N.
Tetrahedron Lett. 1985, 26, 4419 (1,3-diketones). (e) Bruncko, M.; Crich,
D. J. Org. Chem. 1994, 59, 7921 (dioxanone enolates). (f) Ma, D.; Ma, Z.;
Jiang, J.; Yang, Z.; Zheng, C. Tetrahedron: Asymmetry 1997, 8, 889
(oxazolidin-5-ones).
(8) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J.
Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao, Y.; Kumagai, T.;
Yamada, S.; Fujita, E.; Inoue, Y.; Nagase, Y.; Aoyagi, S.; Abe, T. J. Chem.
Soc., Perkin Trans. 1 1985, 2361. (c) Nagao, Y.; Hagiwara, Y.; Kumagai,
T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem. 1986,
51, 2391.
(7) According to standard procedures. See for example: (a) Evans, D.
A.; Bartrol´ı, X.; Shi, T. L. J. Am. Chem. Soc. 1981, 103, 2127 (B enolates).
(b) Evans, D. A.; Urp´ı, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T. J.
Am. Chem. Soc. 1990, 112, 8215 (Ti enolates). (c) Evans, D. A.; Ennis, M.
D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737 (Li and Na enolates).
66
Org. Lett., Vol. 10, No. 1, 2008

with the Z isomer 5b (entries 11-13). Finally, our auxiliary11
(entries 14 and 15) was as efficient as that of the Evans
group.
In general, provided that the temperature was kept at -78
°C, the presence of 10 mol % of NaN(SiMe3)2 in excess did
not cause any epimerization at CR in CH2Cl2-THF.
To confirm the absolute configurations of 4a and 4b, a
sample of each was hydrogenated in MeOH, affording
quickly and quantitatively the same unsaturated, known
pentanedioic acid derivative (Scheme 3, top).3,4 Compound
The relevance of the halogen atom was also investigated.
Reactions of the Na enolates of the Evans auxiliary under
the optimum conditions of entries 2 and 7 of Table 1, with
the available (E)- and (Z)-3-chloropropenoate derivatives,
gave in g95% yields only one stereoisomer in each case,
with full retention of the configuration of the double bond,
and which were respectively identical to the products arising
from the (E)- and (Z)-3-iodoacrylates. We also checked the
analogous Z isomer of the ethyl 3-bromopropenoate, with
the same result. In short, the three halo derivatives can be
used with similar efficiency.
This is reasonable for a mechanism13a in which the Michael
addition is followed by the quick elimination of NaX from
the intermediate, at -78 °C. In other words, retention of
configuration at the double bond can be accounted for (see
Scheme 4) by the quick departure of the leaving group with
Scheme 3. Reactions of 4a and 4b (Aux* ) Evans Auxiliary)
Scheme 4. Plausible Mechanisms
4a, treated with Me3SiO-K+ in 1:1 CH2Cl2-THF at -40
°C for 14 h, followed by neutralization, gave 6a.12 The
equilibrium mixture shown in Scheme 3 (bottom) was
established, so that the thermodynamically more stable
compound (6a) eventually predominated.
a minimum rotation around the CHX-C(sp2) single bond13b
(the Newman projection of which is not drawn to save space).
Reaction of the Na enolate of Aux*COEt (Aux* ) Evans
auxiliary drawn in Table 1) with methyl propynoate (methyl
propargylate), a synthetic equivalent of 5a/5b, also proceeded
in good yield and >97:3 dr at CR but gave a 77:23 Z/E
mixture under our standard conditions (Scheme 4, bottom)
and similar mixtures under other conditions. Thus, the
auxiliary controls the R stereocenter, but as 23% of the more
stable E isomer is obtained rather than the anticipated Z
isomer alone (arising from a trans addition), a ketene enolate
is assumed to be the intermediate.
Standard transformations of the characteristic groups of
the adducts can provide a series of chiral fragments of
C-substituted five-carbon chains. Examples of these building
blocks are shown in Scheme 5. Removal of the chiral
auxiliary of 4a (Aux* ) Evans auxiliary shown in Table 1)
with NaBH4 in THF-H2O at rt14 gave 7a in excellent
(9) (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am. Chem. Soc.
1997, 119, 7883. (b) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2,
775. (c) Crimmins, M. T.; Caussanel, F. J. Am. Chem. Soc. 2006, 128,
3128 and references therein.
(10) (a) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. HelV. Chim. Acta
1984, 67, 1397. (b) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603. (c) Oppolzer, W.; Blagg, J.; Rodr´ıguez, I.; Whalter, E. J.
Am. Chem. Soc. 1990, 112, 27667.
(11) (a) We prepared the N-propanoyl derivative of our thiazolidin-2-
one by oxidation of the N-propanoyl-Nagao-II auxiliary with DDQ. More
details and other applications of this chiral auxiliary will be reported in a
future full paper. (b) Spectral data of the addition-elimination product 4a′
(isomer E): 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J ) 7.0 Hz, 3H), 1.34
(d, J) 6.8 Hz, 3H), 2.95 (m, 2H), 3.11 (dd, J ) 12.8 Hz, J ) 3.6 Hz, 1H),
3.35 (dd, J ) 12.8 Hz, J ) 7.2 Hz, 1H), 4.20 (m, 1H), 5.93 (dd, J ) 15.6
Hz, J ) 1.2 Hz, 1H), 7.08 (dd, J ) 15.6 Hz, J ) 7.2 Hz, 1H), 7.25-7.45
(m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 14.2, 16.9, 28.5, 37.4, 41.4,
59.7, 60.5, 122.6, 127.2, 128.9, 129.4, 136.4, 146.0, 166.1, 172.2, 172.3.
Spectral data of the adduct 4b′ (isomer Z), under the same conditions: 1H
NMR δ 1.28 (t, J ) 7.2 Hz, 3H), 1.35 (d, J ) 6.8 Hz, 3H), 2.95 (m, 2H),
3.21 (br d, J ) 13.2 Hz, 1H), 3.30-3.35 (m, 1H), 4.18 (q, J ) 7.2 Hz,
2H), 4.90 (m, 1H), 5.44 (m, 1H), 5.90 (dd, J ) 11.6 Hz, J ) 1.2 Hz, 1H),
6.37 (dd, J ) 11.6 Hz, J ) 8.6 Hz, 1H), 7.25-7.45 (m, 5H); 13C NMR δ
14.2, 16.7, 28.6, 37.4, 39.4, 60.0, 60.3, 121.2, 127.1, 128.8, 129.4, 136.5,
146.7, 165.2, 171.5, 174.2.
(12) The reactions were followed by NMR: during the first hours, an
equilibration with 4a-S was noted (2:1) but eventually only 6a was obtained.
Isomer 4b isomerized much more slowly, to yield 4a + 4a-S, but after 48
h, all the isomers had also been converted to 6a (whereas 4b-S and the Z
isomer of 6a were not detected).
(13) (a) Classical review of SN(AdN-E) mechanisms in conjugate
alkenes: Rappoport, Z. Acc. Chem. Res. 1992, 25, 474. (b) That is, before
the equilibration among the three rotamers could take place.
(14) Prassad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067.
Org. Lett., Vol. 10, No. 1, 2008
67

catalytic amount of NaH to the mixture in THF at rt
converted completely 7b into 10 within a few hours.
Moreover, when the reaction of 4b with an excess of
DIBALH at -78 °C was quenched with EtOAc, allowed to
warm up, and isolated, only 1118 and Aux*H were obtained,
in g90% yields.
Scheme 5. Conversion of 4a and 4b to Various Chiral
Fragments (Aux* ) Evans Auxiliary)
In principle, a plethora of related chiral blocks from other
alkaline enolates (not only Aux*-containing enolates) and
diversely substituted conjugate esters, nitriles, or ketones
(X-CRdCH-COOR, X-CHdCR-CN, or X2CdCH-
COR) may be accessible by similar protocols.
In summary, we have uncovered a simple procedure to
which, surprisingly, nobody had paid attention before: the
Na enolates of the N-propanoyl derivatives of the most
common auxiliary (and of our new thiazolidin-2-one auxil-
iary) react with ethyl 3-halopropenoates in 9:1 CH2Cl2-THF
at -78 °C within a few minutes, to afford excellent yields
of adduct 4a or 4b with an extraordinary stereocontrol; this
is not the case when alkyl propynoates are used instead. The
adducts can be manipulated appropriately to obtain a range
of C1-C5 chiral building blocks (chiroblocks).
Acknowledgment. Financial support from the Spanish
Ministerio de Educacio´n y Ciencia, through the grants SAF-
2002-02728 and CTQ-2006-15393, and a Ramo´n y Cajal
Research Contract to A.M.C. are acknowledged. J.E. holds
a UB studentship (Jan. 2004 to Dec. 2007) and thanks
Ph.D. student Mireia Sidera, of our department, for an
additional batch of 4a. The Generalitat de Catalunya
contributed partially by means of the grant 2001SGR065
(2001-2005, Grup de S´ıntesi Estereoselectiva d’Antibio`tics
i Antiv´ırics).
yields,15 operating under the following milder conditions:
140 mol % of NaBH4 and 110 mol % of Na2HPO4 in water
at 0 °C were added dropwise to 4a in THF at 0 °C, the bath
was removed, and stirring was continued for 2-3 h;
otherwise, the saturated hydroxyester was obtained as a
byproduct in 20-30% yields (by concomitant reduction of
the conjugate double bond). On the other hand, the reduction
of 4a with an excess of DIBALH in CH2Cl2-hexane at -78
°C afforded 8a selectively.16 Oxidation of 8a with DMP gave
the desired 9a (our true goal, as mentioned in Scheme 1), in
nearly quantitative yields.
Supporting Information Available: Experimental data
1
and copies of the H and 13C NMR spectra of the new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Reduction of 4b with NaBH4 under the above-mentioned
conditions gave a mixture of 7b and 10.17 Addition of a
OL702632M
(15) Enantiopure 7a had been obtained from D-mannitol by a sequence
that includes an epoxide opening, with AlMe3, in the last step: Miyazawa,
M.; Ishibashi, N.; Ohnuma, S.; Miyashita, M. Tetrahedron Lett. 1997, 38,
3419.
(16) We could not stop the reduction at the aldehyde stage, but to a
mixture of alcohol and aldehyde, using low amounts of DIBALH and other
solvents, as well as operating even at -100 °C.
(17) The racemic form of 10 is a known compound: (a) Dieter, R. K.;
Guo, F. Org. Lett. 2006, 8, 4779 and references therein. (b) We have
measured an [R]D value of -6.0 (c 0.60, CHCl3) for our sample.
(18) Known in its racemic form: (a) Andreana, P. R.; McLellan, J. S.;
Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875 and references therein. (b)
We have measured an [R]D value of -52.7 (c 0.80, CHCl3) for 11.
68
Org. Lett., Vol. 10, No. 1, 2008