Highly enantioselective [4 + 2] cycloaddition reactions catalyzed by a chiral N-methyl-oxazaborolidinium cation

Article abstract of DOI:10.1021/ol8011502

(Chemical Equation Presented) The reaction of lithium aryl borohydrides with salts of β-amino alcohols provides a new route for the synthesis of oxazaborolidines. This method also leads to the first synthesis of hitherto elusive N-methyl oxazaborolidine c

Full text of DOI:10.1021/ol8011502

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3271-3273
Highly Enantioselective [4 + 2]
Cycloaddition Reactions Catalyzed by a
Chiral N-Methyl-oxazaborolidinium
Cation
Eda Canales and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received May 21, 2008
ABSTRACT
The reaction of lithium aryl borohydrides with salts of ꢀ-amino alcohols provides a new route for the synthesis of oxazaborolidines. This
method also leads to the first synthesis of hitherto elusive N-methyl oxazaborolidine cations, specifically the cationic proline derivative 3.
Compound 3 is a strong chiral Lewis acid which is very effective for catalysis of [4 + 2]-cycloaddition reactions in good yield and with high
enantioselectivity. Several diverse examples illustrate the scope of these catalytic reactions.
Oxazaborolidines derived from (S)- or (R)-proline, of general
formula 1, have proved to be exceptionally useful reagents
in catalytic enantioselective synthesis. They have been
applied successfully to the highly selective reduction of many
prochiral ketones in conjunction with various H-containing
boranes.1,2 In addition, cationic reagents of formula 2,
generated by the attachment of an electrophilic group to
nitrogen, are very effective and potent chiral Lewis acids
that promote Diels-Alder reactions,3 [2 + 2]-cycloadditions4
and [3 + 2]-cycloadditions,5 and Mukaiyama-Michael
reactions.6 These cationic catalysts can be generated by the
protonation of nitrogen using a very strong protic acid
(CF3SO3H or (CF3SO2)2NH), but not by weaker acids. Lewis
acid activation of 1 by AlBr3 also leads to valuable
electrophilic chiral catalysts of type 2 (Figure 1).3j Surpris-
ingly, other strong Lewis acids did not give useful catalysts
when combined with 1.
(1) For a review, see: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed.
1998, 37, 1986–2012
.
(2) For a recent application, see: (a) Yeung, Y.-Y.; Chein, R.-J.; Corey,
E. J. J. Am. Chem. Soc. 2007, 129, 10346–10347. See also: (b) Hu, Q.-Y.;
Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708–13713
.
(3) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002,
124, 3808–3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 9992–9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388–6390. (d) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 4800–4802. (e) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org.
Lett. 2003, 5, 3979–3982. (f) Snyder, S. A.; Corey, E. J. J. Am. Chem. Soc.
2006, 128, 740–742. (g) Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006,
128, 1346–1352. (h) Yeung, Y.-Y.; Hong, S.; Corey, E. J. J. Am. Chem.
Soc. 2006, 128, 6310–6311. (i) Zhou, G.; Corey, E. J. J. Am. Chem. Soc.
2005, 127, 11958–11959. (j) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem.
Soc. 2007, 129, 1498–1499.
Figure 1. Oxazaborolidine catalysts 1 and 2.
In addition, attempts during the early phase of the work
in these laboratories to generate cationic catalysts of type 2,
X ) CH3, did not meet with success because of the very
(4) Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129, 12686–12687.
10.1021/ol8011502 CCC: $40.75
Published on Web 06/27/2008
2008 American Chemical Society

low nucleophilicity of oxazaborolidines. Specifically, at-
adducts in high yield and enantiomeric purity with catalysts
2, X ) H, and 2, X ) AlBr3. In each of the five test reactions,
closely comparable results were obtained (see Table 1), and
the same enantiomer predominated.
tempts to methylate 1 using MeOSO2CF3 and Me3O+ BF4
-
did not lead to the formation of 2, X) CH3. Further, this
cation was not produced when N-methyl-1,1-diphenyl-
pyrrolidinomethanol or the corresponding bistrimethylsilyl
ether were treated with PhBBr2 or PhB(OSO2CF3)2.
In this account, we report the first successful synthesis of
2, X ) CH3, and the application of this cationic catalyst to
enantioselective [4 + 2]-cycloaddition reactions. In addition,
we provide a comparison of this catalyst with 2, X ) H,
and 2, X ) AlBr3 in a number of test cases.
Table 1. Enantioselective Diels-Alder Reaction of
Cyclopentadiene and Various Dienophiles Using Catalyst 3
Specifically, we have prepared the cationic methyl-
coordinated catalyst 3 in situ from the N-methyl-1,1-
diphenylpyrrolidinomethanol triflimide salt (4) by the two-
step sequence: (1) reaction of 4 with 1 equiv of lithium
o-tolyl-borohydride7 in CH2Cl2 at 0 °C for 1 h and (2)
treatment of the resulting cyclic borohydride 5 with 0.9 equiv
of (CF3SO2)2NH at -78 °C for 0.5 h (Scheme 1). Confirma-
Scheme 1. Preparation of Catalyst 3
a Each reaction was carried out at 0.25 M in CH2Cl2 with respect to the
dienophile, and 10 mol % of catalyst 3. b Reaction carried out at 0.20 M.
tion of the structure of 3 was obtained by 1H and 11B NMR
analysis8 and by its catalytic action as a chiral Lewis acid
which generally parallels that of the cationic complexes 2,
X ) H or X ) AlBr3. Clearly, the formation of the highly
reactive 3 from the stable dipolar ion 5 is driven by the
formation of the very stable molecule H2 byproduct. We have
not attempted to isolate the highly electrophilic, reactive, and
moisture sensitive catalyst 3. In all our work, it was generated
and used in situ in CH2Cl2 or toluene.
We then carried out a study to compare directly catalyst
3 with catalyst 2, X ) AlBr3. The results of these experi-
ments with various dienes and dienophiles are summarized
in Table 2. It can be seen from these data that catalyst 3
was generally at least equally effective as 2, X) AlBr3, and
in two of the six examples considerably more so. These
studies show that catalyst 3 is worth considering as an
alternative to 2, X ) H, or 2, X ) AlBr3, and may be more
useful in those cases where the proton or AlBr3-activated
oxazaborolidine is not satisfactory.
The effectiveness of catalyst 3 was evaluated using the
reaction of cyclopentadiene with a variety of dienophiles that
had been found in previous research to produce Diels-Alder
The absolute configuration of the Diels-Alder adducts 11,
12, and 15,2b obtained with (S)-catalyst 3, corresponds to
those resulting from the use of the triflimide activated catalyst
2, X ) H, as determined by comparison of optical rotation
and HPLC analysis using a chiral column.3d The absolute
configuration of 13 was determined by crystallization from
i-PrOH and X-ray diffraction analysis.9 The absolute con-
figuration of 14 was assigned by analogy with the other cases.
(5) Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 11958–11959.
(6) Liu, D.; Hong, S.; Corey, E. J. J. Am. Chem. Soc. 2006, 128, 8160–
8161.
(7) The lithium o-tolylborohydride was prepared using a modification
of H. C. Brown’s procedure: Singaram, B.; Cole, T. E.; Brown, H. C.
Organometallics 1984, 3, 774–777.
(8) For example, the o-tolyl methyl peak was shifted downfield to (δ)
2.78 in 3 from 2.63 in 1 which is comparable to 2, X ) AlBr3 (2.81). The
pyrrolidine methine proton was shifted to 4.95 in 3 from 4.54 in 1 which
is comparable to 2, X ) AlBr3 (5.26). The N-Me peak was shifted to 2.54
in 3 from 2.46 in 5. The 11B NMR shows a shift from (δ) +7.7 for 5 to
+34 for 3.
(9) See Supporting Information.
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Org. Lett., Vol. 10, No. 15, 2008

Table 2. Comparative Studies of [4 + 2]-Cycloaddition
Reactions Catalyzed by 3 and 2, X ) AlBr3
Scheme 2. Short Synthesis of Estrone Using Catalyst 3
demonstrates another short and simple enantioselective route
to estrone and illustrates one successful practical application
of catalyst 3.
The successful generation of 3, after numerous failed
attempts, opens the way for the synthesis and evaluation of
numerous other chiral catalysts. Specifically, the reaction of
the amino alcohol salt 4 and Li-o-tolBH3 exemplifies a new
method for the formation of oxazaborolidine and related BN
heterocycles, which should be very useful for the synthesis
of chiral Lewis acids. Studies of such structures and new
applications of 3 and its analogues are underway. We believe
that the catalyst 3 is well suited for both laboratory and
larger-scale use. The chiral amino alcohol corresponding to
4 is readily recovered from Diels-Alder reactions for reuse.
a Catalyst loading at 20 mol %. b Catalyst loading at 4 mol %. c Catalyst
loading at 10 mol %. d Prepared using the R-enantiomer of 3. e After a
single recrystallization.
Acknowledgment. E.C. is the recipient of a Pfizer
postdoctoral fellowship and gratefully acknowledges Prof.
Bakthan Singaram (UC Santa Cruz) for information on the
preparation of lithium o-tolylborohydride (see Supporting
Information).
The adduct 1610 (Table 2) was transformed into the estrone
precursors 17 and 18 as shown in Scheme 2. We have
recently described a one-flask process for the conversion of
18 into estrone methyl ether.2 The sequence shown here
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as selected
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) For comparison, the triflimide cationic catalyst 2, X ) H, afforded
16 in 85% yield and 78% ee.
OL8011502
Org. Lett., Vol. 10, No. 15, 2008
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