Enantioselective synthesis of allylic alcohols via an oxazaborolidinium ion catalyzed diels-alder/retro-diels-alder sequence

Article abstract of DOI:10.1021/ol902280d

A triflimide-activated oxazaborolidine catalyst successfully promoted the asymmetric Diels-Alder reaction of 9-methylanthracene with methacrolein in high regio- and enantioselectivity. The cycloadduct obtained was subsequently used as a chiral template to

Full text of DOI:10.1021/ol902280d

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5358-5361
Enantioselective Synthesis of Allylic
Alcohols via an Oxazaborolidinium Ion
Catalyzed Diels-Alder/Retro-Diels-
Alder Sequence
Simon Jones* and Damien Valette
Department of Chemistry, UniVersity of Sheffield, Dainton Building, Brook Hill,
Sheffield S3 7HF, U.K.
simon.jones@sheffield.ac.uk
Received October 2, 2009
ABSTRACT
A triflimide-activated oxazaborolidine catalyst successfully promoted the asymmetric Diels-Alder reaction of 9-methylanthracene with
methacrolein in high regio- and enantioselectivity. The cycloadduct obtained was subsequently used as a chiral template to access secondary
and tertiary allylic alcohols in good to high enantiomeric excess via a cycloreversion by flash vacuum pyrolysis.
Chiral allylic alcohols are versatile synthetic intermediates
and may be accessed by numerous routes, including selective
1,2-reduction of R,ꢀ-unsaturated carbonyl compounds,1
kinetic resolution,2 and enantioselective addition of vinyl
groups to aldehydes.3-5 Although the latter methodology
allows the formation of a wide range of secondary alcohols,
only a few asymmetric catalytic systems have been optimized
to promote efficient vinyl addition to ketones.6 In this paper,
we report a new strategy to access secondary allylic alcohols
in high enantioselectivity and quaternary centers in excellent
yield.
Research from our group7 and others8 has previously
demonstrated the efficiency of a Diels-Alder/retro-Diels-
(5) (a) dem Bussche-Hu¨nnelfeld, J. L.; Seebach, D. Tetrahedron 1992,
48, 5719–5730. (b) Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1
1994, 1257–1258. (c) Saito, S.; Kano, T.; Hatanaka, K.; Yamamoto, H. J.
Org. Chem. 1997, 62, 5651–5656. (d) Tomita, D.; Wada, R.; Kanai, M.;
Shibasaki, S. J. Am. Chem. Soc. 2005, 127, 4138–4139. (e) Sato, I.; Asakura,
N.; Iwashita, T. Tetrahedron: Asymmetry 2007, 18, 2638–2642.
(6) (a) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538–6539.
(b) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 8355–8361.
(7) (a) Jones, S.; Atherton, J. C. C. Tetrahedron: Asymmetry 2001, 12,
1117–1119. (b) Atherton, J. C. C.; Jones, S. Tetrahedron Lett. 2001, 42,
8239–8241. (c) Atherton, J. C. C.; Jones, S. J. Chem. Soc., Perkin Trans.
1 2002, 2166–2173. (d) Jones, S.; Bawa, R. A. Tetrahedron 2004, 60, 2765–
2770. (e) Adams, H.; Jones, S.; Ojea-Jimenez, I. Org. Biomol. Chem. 2006,
4, 2296–2303. (f) Adams, H.; Bawa, R. A.; Jones, S. Org. Biol. Chem.
2006, 4, 4206–4213. (g) Adams, H.; Bawa, R. A.; McMillan, K. G.; Jones,
S. Tetrahedron: Asymmetry 2007, 18, 1003–1012.
(1) For examples, see: (a) Noyori, R.; Tomino, I.; Nishizawa, M. J. Am.
Chem. Soc. 1979, 101, 5843–5844. (b) Ohkuma, T.; Ooka, H.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 10417–10418. (c) Corey, E. J.;
Bakashi, R. K.; Shibata, S.; Chen, C. P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926. (d) Brown, H. C.; Srebnik, M.; Ramachandran, P. V.
J. Org. Chem. 1989, 54, 4504–5844.
(2) For examples, see: (a) Martin, V. S.; Woodard, S. S.; Katsuki, T.;
Yamada, Y.; Ikeda, M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103,
6237–6240. (b) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113,
6129–6139. (c) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc.
1997, 119, 1492–1493.
(3) For reviews, see: (a) Soai, K.; Niwa, S. Chem. ReV. 1992, 92, 833–
856. (b) Pu, L.; Yu, H.-B. Chem. ReV. 2001, 101, 757–824
.
(4) (a) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988, 29, 5645–
5648. (b) Oppolzer, W.; Radinov, R. N. HelV. Chim. Acta 1992, 75, 170–
173. (c) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002,
124, 12225–12231. (d) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003,
(8) (a) Corbett, M. S.; Liu, X.; Sanyal, A.; Snyder, J. K. Tetrahedron
Lett. 2003, 44, 931–935. (b) Burgess, K. L.; Lajkiewicz, N. J.; Sanyal, A.;
Yan, W.; Snyder, J. K. Org. Lett. 2005, 7, 31–34. (c) Sanyal, A.; Yuan, Q.;
Snyder, J. K. Tetrahedron Lett. 2005, 46, 2475–2478.
125, 10677–10683
.
10.1021/ol902280d CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

Table 1. Evaluation of a Suitable Catalytic Systema
entry
concn of diene (M)
temp (°C)
catalyst loading (mol %)
activator
convb (%)
4:5b
ee of 4 (%)
ee of 5c (%)
1
2
3
4
5
6
7
8
9
0.25
0.5
0.5
-78
-78
-78 to rt
rt
-78
rt
-78
-78
-78
30
10
10
10
30
30
30
30
30
0
8
94
100
100
100
100
100
57
AlBr3
AlBr3
AlBr3
Tf2NH
Tf2NH
TfOH
BF3.Et2O
TiCl4
96:4
97:3
92:8
92:8
99:1
97:3
93:7
39c
19c
90c
84c
13d
15c
70d
64
56
83
87
0.5
0.25
0.25
0.25
0.25
0.25
a Reactions performed in the presence of 5 equiv of dienophile under a nitrogen atmosphere. b Based on comparison of ratios of integrals of appropriate
signals in the 1H NMR spectrum of the crude reaction mixture. c Enantioselectivity was determined by reduction to the primary alcohol (NaBH4) and
chiral-phase HPLC analysis using a Daicel Chiralpak AD as a stationary phase. d Enantioselectivity was determined by reduction to the primary alcohol
(NaBH4) and chiral-phase HPLC analysis using a Phenomenex Lux column as a stationary phase.
Alder sequence based on a chiral-substituted anthracene tem-
plate to generate small-molecule building blocks in high
enantioselectivity. However, a drawback of this strategy remains
the preparation of the parent chiral auxiliary via asymmetric
synthesis. The use of substoichiomeric amounts of a chiral
catalyst would make this chemistry significantly more appealing.
Achiral anthracenes, such as anthrone, together with appropriate
catalysts have been employed in the past,9 including the use of
a chiral oxazaborolidine catalyst, delivering the N-methylma-
leimide cycloadduct in 60% ee.10 Given the recent interest in
the development of oxazaborolidium catalysts,11,12 we became
interested in developing this latter approach using 9-methy-
lanthracene as a diene, since this is more reactive than the
anthrone counterpart. Herein, we report the first catalytic
Diels-Alder cycloaddition of 9-methylanthracene using
Corey’s cationic oxazaborolidine.
Our study commenced with the evaluation of a suitable
activator for the oxazaborolidine precursor 3 in the
Diels-Alder reaction of 9-methylanthracene with methac-
rolein (Table 1). Initial investigations were carried out with
aluminum bromide as a Lewis acid activator. Using the
procedure developed by Corey et al.,13 the reaction proceeded
with low conversion at -78 °C (entry 2). Pleasingly, we
found that full conversion could be achieved when the
reaction was warmed to room temperature (entries 3 and 4);
however, the enantioselectivity dropped from 39 to 19% ee.
Thus, we investigated the use of triflimide activation,
previously reported to confer beneficial effects on the catalyst
stability with no loss of potency.14 Full conversion was
observed irrespective of the reaction temperature in high
enantioselectivity (entries 5 and 6).15 A nonseparable mixture
of regioisomers (ratio 92:8) was obtained in favor of
cycloadduct 4 (determined by comparison of 1H NMR data
and independent synthesis). During our investigations, it
emerged that any modification of reaction conditions as well
as the catalyst loading resulted in a loss of both conversion
and enantioselectivity. Among the other potential activators
examined, TfOH, BF3·Et2O, and TiCl4 gave less promising
results (entries 7 to 9). The efficiency of the catalyst was
also demonstrated compared to the racemic synthesis of the
cycloadduct under thermal conditions which required about
5 days to complete in 78% yield.
With the major cycloadduct 4 in hand, addition of various
Grignard reagents in toluene at room temperature was performed
(Scheme 1). Alcohols 6 were obtained in moderate to good
yields. However, the diastereoselectivity of the reaction was
not fully controlled, presumably since free rotation of the
carbon-carbon bond bearing the carbonyl group presented
different prochiral faces amenable to nucleophilic addition.16
Neither the use of a Lewis acid nor the use of lower reaction
temperature improved the diastereoselectivity. Nevertheless, we
found that the dr could be increased by further purification of
the crude reaction mixture (up to 98:2, entry 1). It should be
noted that attempts to functionalize cycloadduct 6 with i-propyl
or tert-butyl groups resulted in the ꢀ-hydride elimination of the
Grignard reagent and isolation of the reduced product.
(9) (a) Riant, O.; Kagan, H. B. Tetrahedron Lett. 1989, 30, 7403–7406.
(b) Riant, O.; Kagan, H. B.; Ricard, L. Tetrahedron 1994, 50, 4543–4554.
(c) Uemae, K.; Masuda, S.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1
2001, 1002–1006. (d) Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.;
Xu, J.; Tan, C.-H. J. Am. Chem. Soc. 2006, 128, 13692–13693.
(10) Burgess, K. L.; Corbett, M. S.; Eugenio, P.; Lajkiewicz, N. J.; Liu,
X.; Sanyal, A.; Yan, W.; Yuan, Q.; Snyder, J. K. Bioorg. Med. Chem. 2005,
13, 5299–5309.
(11) For reviews, see: (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41,
1650–1667. (b) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2–20
.
Org. Lett., Vol. 11, No. 22, 2009
5359

dr within 2 h (entry 1), while addition of the ethynyl and
vinyl groups required a longer reaction time to achieve
completion with a poor dr (entries 2 and 3).
Scheme 1. Formation of Secondary Alcohols
Cycloadducts 6 and 8 were then subjected to flash vacuum
pyrolysis. Secondary allylic alcohols were isolated in excel-
lent yields and high ee without any further purification (Table
2). Furthermore, the enantioselectivity of each product was
Table 2. Generation of Allylic Alcohols via Retro-Diels-Alder
Reactiona
a Values for dr were based on comparison of ratios of integrals of
appropriate signals of the major regioisomer in the 1H NMR spectrum.
b Purification by column chromatography. c Purification by recrystallization.
Attempts to add EtMgBr (entry 2) also led to reduction but
in this case provided a 60:40 ratio in favor of cycloadduct 6b,
which was isolated in 42% yield by silica gel chromatography.
Considering the valuable interest in making quaternary
stereogenic centers, we then focused on investigating the
possibility of forming enantiomerically enriched tertiary
allylic alcohols. Since cycloadduct 6c was amenable to
purification to remove the unwanted diastereoisomer, it was
selected to carry out such transformations. Dess-Martin
oxidation provided ketone 7 in 80% yield, and subsequent
addition of Grignard reagents afforded cycloadducts 8
(Scheme 2). However, in contrast to the aldehyde, addition
of Grignard reagents to the ketone resulted in a low
diastereoselectivty; cycloadduct 8a was obtained in a 78:22
a Cycloadducts were subjected to FVP (0.01 mmHg; see the Supporting
Information for further details). b Values for ee determined by chiral-phase
GC analysis using a Supelco fused silica capillary column as a stationary
phase (see the Supporting Information for further details). c The ee was
higher than expected due to several recrystallizations of the starting material.
in accordance with the dr of the cycloadducts before the
retro-Diels-Alder process. Unfortunately, alcohol 6e could
not be isolated as it underwent a retro-ene reaction and
methacrolein was isolated as a result (Scheme 3). The
Scheme 2. Formation of Tertiary Alcohols
Scheme 3
absolute stereochemistry of the allylic alcohol from the retro-
Diels-Alder reaction of 6a was established by comparison
of its optical rotation with that reported in the literature and
extended to the other secondary alcohols by analogy.17
The retro-Diels-Alder reaction of cycloadduct 8a afforded
a valuable tertiary alcohol in 52% ee (Table 2, entry 7).18
a Reaction was performed using 3 equiv of Grignard reagent. b Reaction
was performed using 11 equiv of Grignard reagent. c Values for dr were
based on comparison of ratios of integrals of appropriate signals of the
1
major regioisomer in the H NMR spectrum.
5360
Org. Lett., Vol. 11, No. 22, 2009

In summary, we have developed an asymmetric catalytic
system for the Diels-Alder reaction of 9-methylan-
thracene with methacrolein. The utility of such a trans-
formation was illustrated by the synthesis of secondary
and tertiary allylic alcohols, both with good yield and
enantioselectivity. Work is now underway to expand the
range of substrates available.
(12) (a) Futatsugi, K.; Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44,
1484–1487. (b) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2007,
129, 9536–9537. (c) Balskus, E. P.; Jacobsen, E. N. Science 2007, 317,
1736–1740.
Acknowledgment. We thank the EPSRC for funding.
(13) Liu, D.; Canales, E.; Corey, E. J. J. Am. Chem. Soc. 2007, 129,
1498–1499.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388–6390.
(15) We found that the enantioselectivity of the reaction was highly
dependent on the quality of bis(trifluoromethanesulfonyl)imide. Ideally, a
0.2 M solution in CH2Cl2 was freshly prepared under an argon atmosphere
in a glovebox (see the Supporting Information for further details).
(16) Due to this, the absolute configurations of cycloadducts 6 and 8
remain unknown.
OL902280D
(17) Hayashi, M.; Kaneko, T.; Oguni, N. J. Chem. Soc., Perkin Trans.
1 1991, 25–28.
(18) The absolute configuration of the tertiary alcohols remains
unknown.
Org. Lett., Vol. 11, No. 22, 2009
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