High 1,5-anti stereoinduction in boron-mediated aldol reactions of methyl ketones

Article abstract of DOI:10.1021/ol026968c

(equationpresented) We report herein a very efficient and synthetically useful 1,4-anti-1,5-anti boron-mediated aldol reaction of a chiral α-methyl-β-alkoxy methyl ketone with achiral aldehydes. * Fax: +55-019-3788-3023. ? This paper is dedicated to the B

Full text of DOI:10.1021/ol026968c

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4325-4327
High 1,5-Anti Stereoinduction in
Boron-Mediated Aldol Reactions of
Methyl Ketones†
,‡
Luiz C. Dias,* Rosana Z. Bau´,‡ Ma´rcio A. de Sousa,‡ and
J. Zukerman-Schpector§
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP,
C.P. 6154 13083-970, Campinas, SP, Brazil, and Departamento de Qu´ımica,
UFSCar, C.P. 676, 13565-905, Sa˜o Carlos, SP, Brazil
ldias@iqm.unicamp.br
Received September 26, 2002
ABSTRACT
We report herein a very efficient and synthetically useful 1,4-anti-1,5-anti boron-mediated aldol reaction of a chiral r-methyl-â-alkoxy methyl
ketone with achiral aldehydes.
The use of enolborinates derived from R-methyl and R-meth-
yl-â-alkoxy methyl ketones for asymmetric aldol reactions
generally gives low levels of stereoselectivities when com-
pared with the high selectivities observed with boron enolates
of the ethyl ketones.1,2 Usually, reagent control using chiral
ligands on boron is required to obtain useful levels of
asymmetric induction in the addition of boron enolates of
R-methyl methyl ketones to achiral aldehydes, particularly
the use of (+)- and (-)-diisopinocampheyboron chlorides
(Ipc2BCl), as described by Paterson et al.3-5
Our approach began with the known acyloxazolidinone
1, which was most conveniently prepared by acylation of
the corresponding (S)-oxazolidinone (Scheme 1).6 Asym-
Scheme 1
We report here that high levels of substrate-based, 1,5-
stereocontrol can be achieved in the boron-mediated aldol
reactions of R-methyl-â-alkoxy methyl ketones by the proper
choice of protecting groups.
* Fax: +55-019-3788-3023.
† This paper is dedicated to the Brazilian Chemical Society (SBQ).
‡ Universidade Estadual de Campinas.
metric aldol addition of the boron enolate derived from
oxazolidinone 1 with inexpensive methacrolein 2c gave the
aldol adduct 3 as a crystalline solid (mp 57-59 °C) in 89%
yield and >95:5 diastereoselectivity (Scheme 1).7 Exchange
of the oxazolidinone auxiliary in syn-aldol 3 with N,O-
§ UFSCar.
(1) For a review on asymmetric aldol reactions using boron enolates,
see: Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(2) (a) Paterson, I.; Goodman, J. M. Tetrahedron Lett. 1989, 30, 997.
(b) Paterson, I.; Florence, G. J. Tetrahedron Lett. 2000, 41, 6935.
10.1021/ol026968c CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/02/2002

dimethylhydroxylamine generated the Weinreb amide, whose
purification was facilitated by isolation of the recyclable
oxazolidinone chiral auxiliary (92%) by efficient crystal-
lization from the reaction mixture.8 Protection of the OH-
function as its TBS ether, followed by selective hydrobora-
tion with 9-BBN in THF, cleanly provided the primary
alcohol 4 (>95:5 diastereoselection) in 83% yield over the
two-step sequence, together with small amounts of lactone
5 (∼5%).9
Scheme 4
After a two-step sequence involving protection of the
primary alcohol functionality in 4 with PMB-acetimidate
in the presence of catalytic amounts of CSA, followed by
reaction with methyllithium at 0 °C, methyl ketone 6 was
isolated in 89% overall yield (Scheme 2). Amide 4 was
52:48 mixture of 1,4-syn and 1,4-anti aldol adducts 8e and
9e, respectively, in 79% yield.4
We next examined the use of methyl ketone 7. As shown
in Scheme 4 and Table 1, these boron-mediated aldol
Table 1. Aldol Reactions of Methyl Ketone 7 with RCHO
2a-e
Scheme 2
(c-Hex)2BCl
entry
aldehyde (R)
anti:syna
yield (%)b
1
2
3
4
5
2a , Me
2b, Pr
2c, C(Me)dCH2
2d , Ph
2e, m-C6H4OBn
>95:05
>95:05
>95:05
>95:05
>95:05
89
77
75
77
82
i
1
a Ratio determined by H and 13C NMR analyses of the diastereomeric
mixture of adducts. b Isolated yields after SiO2 flash chromatography.
reactions were found to proceed with an unexpectedly high
degree of remote stereoinduction (1,5-anti:1,5-syn > 95:5).10
In all cases, the major 1,5-anti adduct 10a-e, corresponding
to re-face attack on the aldehyde, was obtained with good
selectivities using (c-Hex)2BCl.
The 1,5-anti induction obtained in these boron-mediated
aldol reactions did not vary significantly with the size of
the aldehyde R group, and high levels of stereocontrol were
observed even with acetaldehyde (entry 1). These results
indicate that the nature of the protecting groups is critical in
determining the level of induction and that a cyclic protection
of the 1,3-diol proved to be essential for high levels of aldol
stereocontrol.
smoothly converted to methyl ketone 7 after treatment with
TBAF in THF and protection of the 1,3-diol as a p-
methoxybenzylidene acetal followed by reaction with me-
thyllithium at 0 °C (89% overall yeld).
Initially, the aldol reaction of methyl ketone 6, containing
both TBS- and PMB- protected hydroxyl groups, with
aldehyde 2e was explored using (c-Hex)2BCl/Et3N in Et2O
for enolization (Scheme 3). As expected, the use of the boron
Scheme 3
The use of n-Bu2BOTf led to similar results in terms of
diastereoselectivites, although the yields were lower when
compared to the same reactions with (c-Hex)2BCl.
(4) For studies on the synthesis of bafilomycin A using aldol reactions
of methyl ketones, see: Roush, W. R.; Bannister, T. D.; Wendt, M. D.;
Jablonowski, J. A.; Scheidt, K. A. J. Org. Chem. 2002, 67, 4275.
(5) For diastereoselective aldol reactions of chiral methyl ketone tri-
chorosilyl enolates under base catalysis, see: Denmark, S. E.; Fujimori, S.
Synlett 2001, 1024.
(6) (a) Evans, D. A.; Gage, J. R. Org. Synth. 1989, 68, 83.
(7) (a) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099. (b) Evans, D. A.; Vogel, E.; Nelson, J. V. J. Am.
Chem. Soc. 1979, 101, 6120.
(8) Levin, J. I.; Turos, E.; Weinreb, S. Synth. Commun. 1982, 12, 989.
(9) Formation of this lactone is in accordance with the results of Smith
et al. and Day et al.: (a) Smith, A. B., III; Beauchamp, T. J.; LaMarche,
M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 2000, 122, 8654. (b) Day, B. W.; Kangani, C. O.; Avor,
K. S. Tetrahedron: Asymmetry 2002, 13, 1161.
enolate formed from methyl ketone 6 showed only modest
1,4-stereoinduction upon addition to aldehyde 2e to give a
(3) An exception is the aldol reaction of â-alkoxy methyl ketones, which
proceeds with high 1,5-stereoinduction under substrate control: (a) Evans,
D. A.; Coleman, P. J.; Coˆte´, B. J. Org. Chem. 1997, 62, 788. (b) Evans, D.
A.; Trotter, B. W.; Coleman, P. J.; Coˆte´, B.; Dias, L. C.; Rajapakse, H. A.;
Tyler, A. N. Tetrahedron 1999, 29, 8671. (c) Paterson, I.; Collett, L. A.
Tetrahedron Lett. 2001, 42, 1187. (d) Paterson, I.; Gibson, K. R.; Oballa,
R. M. Tetrahedron Lett. 1996, 37, 8585. (e) Tanimoto, N.; Gerritz, S. W.;
Sawabe, A.; Noda, T.; Filla, S. A.; Masamune, S. Angew Chem. Int. Ed.
Engl. 1994, 33, 673.
(10) Arefolov, A.; Panek. J. S. Org. Lett. 2002, 4, 2397.
4326
Org. Lett., Vol. 4, No. 24, 2002

The relative stereochemistry for aldol adduct 10a (R )
Me) was confirmed by a single-crystal X-ray structure
determination, as shown in Figure 1.
Scheme 5
also that dipole organization is critical to chirality transfer,
and the â-alkoxy substituent is oriented anti to the enolate
C-O bond. Approach of the aldehyde re-face from the less
hindered face of the boron enolate provides the observed
1,4-anti-1,5-anti product.
As this work was in progress, Panek and Arefolov
published an example of a similar methyl ketone aldol
reaction mediated by n-Bu2BOTf leading to the correspond-
ing 1,4-syn-1,5-anti product.10
On the basis of our results and those described by Arefolov
and Panek, we believe that the R-stereocenter plays a
secondary role in these methyl ketone aldol reactions, with
the â-alkoxy substituent being responsible for the enolate
facial bias in these aldol processes.
Depending on the relative stereochemistry of the R-methyl-
â-alkoxy methyl ketone used, both 1,4-syn and 1,4-anti aldol
adducts could be obtained without the need to use a chiral
auxiliary.
Figure 1.
We reported here that high levels of substrate-based, 1,5-
stereocontrol can be achieved in the boron-mediated aldol
reactions of methyl ketones by the proper choice of protecting
groups. These stereoselective aldol reactions should prove
to be valuable in polyketide synthesis, and further studies
are underway to explore their generality and origin.14
Although both chairlike and boatlike transition structures
must be considered in any transiton-state analysis of methyl
ketone aldol reactions, we believe that the origin of the high
1,5-anti selectivity can be explained by the preferred transi-
tion state A (Scheme 5), which minimizes A(1,3) allylic
strain in the boron enolate.11-13 The enolate R-stereocenter
adopts a more favorable rotamer with the methyl group
eclipsing the enolate double bond. A boatlike arrangement
is proposed, as it avoids steric interactions between the chiral
residue of the enolate, the R group in the aldehyde, and a
bulky ligand (L ) c-Hex) in the chair structure. We believe
Acknowledgment. We are grateful to FAPESP (Funda-
c¸a˜o de Amparo a Pesquisa do Estado de Sa˜o Paulo) and
CNPq (Conselho Nacional de Desenvolvimento Cient´ıfico
e Tecnolo´gico) for financial support. We thank also Prof.
Carol H. Collins for helpful suggestions about English
grammar and style.
(11) For the use of an NMR method for assigning the relative stereo-
chemistry of â-hydroxy ketones, deriving from aldol reactions of methyl
ketones with chiral aldehydes, see: Roush, W. R.; Bannister, T. D.; Wendt,
M. D.; VanNieuwenhze, M. S.; Gustin, D. J.; Dilley, G. J.; Lane, G. C.;
Scheidt, K. A.; Smith, W. J., III. J. Org. Chem. 2002, 67, 4284.
(12) Several computational studies indicate that chairlike and boatlike
transiton states in methyl ketone aldol reactions are relatively close in
energy: (a) Li, Y.; Paddow-Row, M. N.; Houk, K. N. J. Org. Chem. 1990,
55, 1535. (b) Bernardi, F.; Robb, M. A.; Suzzi-Vall, G.; Tagliavini, E.;
Trombin, C.; Umani-Ronchi, A. J. Org. Chem. 1991, 56, 6472.
(13) (a) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24. (b)
Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
Supporting Information Available: Spectroscopic data
for compounds 3, 4, 6, 7, and 10a-e and crystallographic
data for aldol adduct 10a. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL026968C
(14) New compounds and the isolatable intermediates gave satisfactory
1H and 13C NMR, IR, HRMS, and analytical data. Yields refer to
chromatographically and spectroscopically homogeneous materials.
Org. Lett., Vol. 4, No. 24, 2002
4327