Highly enantioselective hetero-diels-alder reaction of 1,3-bis(silyloxy)-1, 3-dienes with aldehydes catalyzed by chiral disulfonimide

Article abstract of DOI:10.1002/anie.201204262

Bulking up with F: The title reaction proceeds using 1 mol % of the new perfluoroisopropyl chiral disulfonimide catalyst 1 to deliver several 2,6-disubstituted and 2,5,6-trisubstituted dihydropyrones in good yields and with excellent enantiomeric ratios. The utility of this methodology is illustrated with the first enantioselective synthesis of a potent aromatase inhibitor. Copyright

Full text of DOI:10.1002/anie.201204262

Angewandte
Chemie
DOI: 10.1002/anie.201204262
Asymmetric Catalysis
Highly Enantioselective Hetero-Diels–Alder Reaction of 1,3-Bis-
(silyloxy)-1,3-dienes with Aldehydes Catalyzed by Chiral
Disulfonimide**
Joyram Guin, Constantinos Rabalakos, and Benjamin List*
Originating from observation by Danishefsky et al. that
hetero-Diels–Alder (HDA) reactions of 1-methoxy-3-(trime-
thylsilyloxy)butadiene (Danishefskyꢀs diene) with aldehydes
are accelerated by Lewis acids [Eq. (1); TMS = trimethyl-
mechanistically related HDA reactions of 1,3-bis(silyloxy)-
1,3-dienes, which surprisingly have previously been utilized
only in non-asymmetric catalysis.[10–12] Our interest in this
particular transformation was further stimulated by speculat-
ing that the lack of established catalytic asymmetric HDA
reactions might stem from a competing silylium-catalyzed
background reaction.[13] We had previously shown that
silyl],[1] asymmetric variants became extensively studied and
utilized in the synthesis of enantioenriched six-membered
oxygen-containing heterocycles.[2] Indeed, several efficient
metal-based chiral Lewis acids have been developed for this
reaction.[3] Recently, Rawal and co-workers introduced
a metal-free, hydrogen-bonding catalyst for asymmetric
HDA reactions of 1-dimethylamino-3-tert-butyldimethylsilyl-
oxy-1,3-butadiene (Rawalꢀs diene) with aldehydes [Eq. (1),
TBS = tert-butyldimethylsilyl].[4] Despite all this progress
however, the present catalytic systems for asymmetric HDA
reactions are largely limited to the originally introduced
dienes, and substituted and functionalized dienes have proven
to be highly challenging substrates.[3c,e,g,5] As a consequence,
only few catalytic asymmetric syntheses of 2,6-disubstituted
dihydropyrones have been reported and the catalytic enan-
tioselective synthesis of 2,5,6-trisubstituted dihydropyrones is
entirely unknown.[6,7] Herein, we report a highly enantiose-
lective HDA reaction of aldehydes with substituted 1,3-
bis(silyloxy)-1,3-dienes catalyzed by a novel, highly fluori-
nated, chiral disulfonimide [Eq. (2)].
disulfonimide-based catalysis offers an efficient solution to
this problem in Mukaiyama aldolizations.
To explore the principal utility of our DSI catalysts in
HDA reactions, we initially studied our previously used chiral
disulfonimide catalyst 1 in the reaction of 2-naphthaldehyde
with the commercially available diene 3. These experiments
showed that the product 4 could indeed be obtained in the
presence of 5 mol% of catalyst 1 at À788C in Et2O in good
yield and reasonable enantioselectivity (Table 1, entry 1). We
reasoned that improving the steric and electronic properties
of the catalyst by incorporating large perfluorinated substitu-
Table 1: Catalyst identification and reaction optimization.
Recently our group has introduced chiral disulfonimides
(DSI) as effective catalysts of asymmetric Mukaiyama and
vinylogous Mukaiyama aldol reactions with aldehydes.[8,9] We
hypothesized that such a catalyst could also promote the
[*] Dr. J. Guin, Dr. C. Rabalakos, Prof. Dr. B. List
Max-Planck-Institut fꢀr Kohlenforschung
Entry[a]
Cat. (mol%)
3 (equiv)
t [d]
Yield [%][b]
e.r.[c]
1
2
3
1 (5.0)
2 (5.0)
2 (1.0)
2 (0.5)
2 (1.0)
1.5
1.5
2.0
2.0
2.0
0.5
0.5
3.0
4.0
4.0
77
83
89
60
89
87:13
96:4
96:4
97:3
97:3
Kaiser Wilhelm-Platz 1, 45470 Mꢀlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[**] We gratefully acknowledge generous financial support from the Max
Planck Society, the European Research Council (Advanced grant
“High Performance Lewis Acid Organocatalysis, HIPOCAT” to B.L.),
and the Alexander von Humboldt Foundation (fellowships for J.G.
and C.R.).
4
5[d]
[a] Reaction conditions: 0.125 mmol of aldehyde and 0.25 mmol of diene
were stirred in the presence of catalyst in Et2O [0.16m] at À788C.
[b] Yield of isolated product. [c] Determined by HPLC analysis on a chiral
stationary phase. [d] 0.12m. TFA=trifluoroacetic acid.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204262.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 2: Diene scope.
ents at the 3,5-positions of the 3,3’-aryl moieties in the
disulfonimide backbone could have a beneficial effect on the
enantioselectivity and at the same time may also enhance the
catalytic activity. To test our hypothesis, we synthesized the
new disulfonimide 2 in which the CF3 groups have been
replaced by the larger perfluoroisopropyl substituent (for the
synthesis of catalyst 2 see the Supporting Information). As
hoped, the newly synthesized catalyst 2 was found to be
significantly more enantioselective than 1. With 5 mol% of 2,
the desired product was obtained in good yield and with an
enantiomeric ratio of 96:4 (Table 1, entry 2). Importantly, the
catalyst loading could be reduced to only 1 mol% without
diminishing the reaction efficiency, but also requiring
a slightly higher diene concentration and longer reaction
time (Table 1, entry 3). A small improvement on the enantio-
selectivity was further noticed upon lowering the amount of
catalyst to 0.5 mol%, but then full conversion of the aldehyde
could not be achieved (Table 1, entry 4). The best reaction
outcome was obtained upon using 1 mol% of 2 at a 0.12m
substrate concentration (Table 1, entry 5).
Entry[a]
Diene[b]
Product
Yield
[%][c]
e.r.[d]
1
91
56
97
95
75
87
88
96:4
96:4
99:1
99:1
98:2
98:2
96:4
2[e]
3
4
After establishing the optimal reaction conditions with
the diene 3, we began exploring the scope of this trans-
formation with various densely substituted 1,3-bis(silyloxy)-
1,3-dienes. Importantly, these dienes are readily synthesized
in one step by the reaction of commercially available and
inexpensive 1,3-diketones with TMSOTf and Et3N or with
LDA and TMSCl.[10c,11,12] Dienes were obtained as a E/Z
mixture and used as such. We were pleased to find that linear
1,3-bis(silyloxy)-1,3-dienes 5–11 underwent smooth reaction
with 2-naphthaldehyde in the presence of 1 mol% of 2.
Essentially all dienes delivered the corresponding products in
good to excellent enantiomeric ratio (Table 2). The nature of
the diene substituents has a significant influence on the
chemical reactivity and the enantioselectivity. Substantial
improvement of the enantioselectivity was realized by
increasing the steric bias of the diene (Table 2, entries 1–3),
that is, when dienes 5–7 were employed with 2-naphthalde-
hyde under the optimized reaction conditions, the corre-
sponding 2,6-disubstituted dihydropyrones 15–17 were
obtained in good yields and enantioselectivity. The tetrasub-
stituted dienes 8–11 were particularly useful and all of them
provided the corresponding 2,5,6-trisubstituted dihydropyr-
ones 18–21 in good yields with excellent enantioselectivity
(Table 2, entries 4–7). It is noteworthy to mention that the
catalytic enantioselective synthesis of products 18–21 has not
been achieved previously. Furthermore, the diene 12, bearing
a terminal substituent, could also be utilized, thus furnishing
product 22 with two contiguous stereocenters in good yield
with moderate diastereoselectivity and good enantioselectiv-
ity (Table 2, entry 8).
5
6
7
86:14 (trans),
7:93 (cis)
8[f]
93
64
9[g]
97:3
10
95
>99:1
[a] Reaction conditions: 0.125 mmol of aldehyde, 0.25 mmol of diene,
and 1 mol% of catalyst 2 were stirred in Et2O [0.12m] for 4 days at
À788C. [b] Used as E/Z mixture. [c] Yield of isolated product. [d]
Determined by HPLC analysis on a chiral stationary phase. [e] At À308C,
5 d. [f] At À508C, a 2:1 diastereomeric ratio was determined by 1H NMR
analysis of the crude reaction mixture. [g] At À158C, 5 d. Ar=2-naphthyl.
We further expanded the utility of the asymmetric
catalytic HDA reaction towards the synthesis of enantioen-
riched polycyclic skeletons by making use, for the first time, of
the so-called inner-outer-ring 1,3-bis(silyloxy)-1,3-dienes 13
and 14.[11] The diene 13 was found to be somewhat less
reactive, and the reaction proceeded only at À158C, thus
furnishing the bicyclic product 23 in reasonable yield with
excellent enantioselectivity (Table 2, entry 9), while 14, the
benzene-fused analogue of 13, proved to be more reactive and
provided the tricyclic dihydropyrone 24 with even higher
enantioselectivity and yield (Table 2, entry 10). The absolute
configuration of compound 21 was determined to be R by
single-crystal X-ray structure analysis (see the Supporting
Information).
Encouraged by our exploration of the diene scope, we
next investigated the utility of various aldehydes. The dienes
3, 7, and 8 were used in this study (Table 3). The diene 3
reacted with 6-methoxy-2-naphthaldehyde and meta-substi-
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 3: Aldehyde scope.[a,b,c]
with 7 and 8 in equal efficiency (40 and 41, respectively). A
conjugated aromatic aldehyde and a heteroaromatic aldehyde
could also be used as substrates (42 and 43, respectively).
Unfortunately, aliphatic aldehydes were found to be
extremely challenging substrates in our HDA reaction and
low chemical yields and only moderate enantioselectivity of
the desired products were obtained (44–46).
Absolute configurations of R were also determined for the
compounds 27 and 34 by comparing the sign of the optical
rotation with that of the literature data[14] and single-crystal
X-ray structure analysis, respectively (see the Supporting
Information).
To demonstrate the utility of our methodology, we have
developed the first asymmetric route to the 3’-hydroxy-
substituted 7,8-benzoflavanone 49, a potent aromatase inhib-
itor (Scheme 1). The compound 49 exhibits higher aromatase
Scheme 1. Synthesis of aromatase inhibitor 49. DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone.
[a] Reaction conditions: 0.125 mmol of aldehydes, 0.25 mmol of diene,
and 1 mol% of catalyst 2 were stirred in Et2O [0.12m] at À788C for
4 days. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] À608C. [e] À108C, 10 d.
inhibitory activity than aminogluthetimide, which is the first
nonsteroidal aromatase inhibitor used clinically in the treat-
ment of breast cancer.[15] Treating 3-benzyloxybenzaldehyde
with 14 under optimized reaction conditions gave ketone 47 in
excellent yield and enantioselectivity on a 1 mmol scale. The
resulting dihydropyrone 47 was easily aromatized to the
corresponding 7,8-benzoflavanone 48 upon DDQ oxidation.
After the sequential treatment of compound 48 with H2/Pd-C
and MnO2 (to reoxidize the obtained benzylic alcohol), the
desired benzoflavanone 49 was obtained in good overall yield
and without erosion of enantiopurity.
Toward elucidation of the mechanism of our disulfon-
imide-catalyzed HDA reaction, we could isolate an inter-
mediate in the reaction of 7 with 2-naphthaldehyde. This
compound was shown to be the trimethylsilyloxy 1,3-diketone
50, which easily cyclized to the corresponding HDA product
17 upon treatment with TFA, and only with a slight deteri-
oration of enantiomeric ratio [Eq. (3)]. This observation
suggests that our HDA reaction proceeds through
a Mukaiyama aldol pathway [path B, Eq. (3)], which is in
agreement with the widely accepted mechanism of other
(though not all)[3o] Lewis acid catalyzed HDA reactions of
Danishefskyꢀs diene with aldehydes.[3t,16]
tuted benzaldehydes with very good enantioselectivity and
reasonable yields (25–27). The diene 7 was found to be more
effective and versatile in our catalytic HDA reaction.
Comparing the results of the reactions of 3 and 7 with 2-
naphthaldehyde and m-tolualdehyde clearly demonstrated
the superiority of 7 over 3 under our reaction conditions
(compare: Table 1, entry 5 with Table 2, entry 3, and com-
pound 27 with 36 in Table 3). With 7, benzaldehyde and para-
substituted benzaldehydes delivered the corresponding prod-
ucts 28 and 29–35 in good yields (83–96%) and enantiose-
lectivity (e.r. = 91:9–98:2). Electron-deficient aldehydes such
as p-fluoro- or p-chlorobenzaldehyde gave slightly lower
enantioselectivity (33 and 34, respectively). Even stronger
electron-withdrawing aldehydes such as p-nitrobenzaldehyde
turned out to be unreactive under our reaction conditions.
The meta-substituted benzaldehydes underwent product for-
mation with uniformly good yields and enantioselectivity (36–
39). 3,5-Dimethoxybenzaldehyde underwent the reaction
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[3] a) L. Lin, Y. Kuang, X. Liu, X. Feng, Org. Lett. 2011, 13, 3868 –
3871; b) S. Mie˛sowicz, W. Chaładaj, J. Jurczak, Synlett 2010,
1421 – 1425; c) X.-B. Yang, J. Feng, J. Zhang, N. Wang, J.-L. Liu,
X.-Q. Yu, Org. Lett. 2008, 10, 1299 – 1302; d) A. Berkessel, E.
Ertꢁrk, C. Laporte, Adv. Synth. Catal. 2006, 348, 223 – 228; e) M.
Anada, T. Washio, N. Shimada, S. Kitagaki, M. Nakajima, M.
Shiro, S. Hashimoto, Angew. Chem. 2004, 116, 2719 – 2722;
Angew. Chem. Int. Ed. 2004, 43, 2665 – 2668; f) Y. Yuan, J. Long,
J. Sun, K. Ding, Chem. Eur. J. 2002, 8, 5033 – 5042; g) Y.
Yamashita, S. Saito, H. Ishitani, S. Kobayashi, Org. Lett. 2002, 4,
1221 – 1223; h) S. Kii, T. Hashimoto, K. Maruoka, Synlett 2002,
0931 – 0932; i) Y. Z. Huang, X. M. Feng, B. Wang, G. L. Zhang,
Y. Z. Jiang, Synlett 2002, 2122 – 2124; j) H. Du, J. Long, J. Hu, X.
Li, K. Ding, Org. Lett. 2002, 4, 4349 – 4352; k) J. Long, J. Hu, X.
Shen, B. Ji, K. Ding, J. Am. Chem. Soc. 2002, 124, 10 – 11; l) M. P.
Doyle, I. M. Phillips, W. Hu, J. Am. Chem. Soc. 2001, 123, 5366 –
5367; m) K. Aikawa, R. Irie, T. Katsuki, Tetrahedron 2001, 57,
845 – 851; n) K. B. Simonsen, N. Svenstrup, M. Roberson, K. A.
Jørgensen, Chem. Eur. J. 2000, 6, 123 – 128; o) A. G. Dossetter,
T. F. Jamison, E. N. Jacobsen, Angew. Chem. 1999, 111, 2549 –
2552; Angew. Chem. Int. Ed. 1999, 38, 2398 – 2400; p) S. E.
Schaus, J. Brꢂnalt, E. N. Jacobsen, J. Org. Chem. 1998, 63, 403 –
405; q) G. E. Keck, X.-Y. Li, D. Krishnamurthy, J. Org. Chem.
1995, 60, 5998 – 5999; r) K. Maruoka, T. Itoh, T. Shirasaka, H.
Yamamoto, J. Am. Chem. Soc. 1988, 110, 310 – 312; s) M.
Bednarski, C. Maring, S. Danishefsky, Tetrahedron Lett. 1983,
24, 3451 – 3454; t) M. Bednarski, S. Danishefsky, J. Am. Chem.
Soc. 1983, 105, 3716 – 3717.
[4] a) A. K. Unni, N. Takenaka, H. Yamamoto, V. H. Rawal, J. Am.
Chem. Soc. 2005, 127, 1336 – 1337; b) Y. Huang, A. K. Unni,
A. N. Thadani, V. H. Rawal, Nature 2003, 424, 146 – 146.
[5] a) Z. Yu, X. Liu, Z. Dong, M. Xie, X. Feng, Angew. Chem. 2008,
120, 1328 – 1331; Angew. Chem. Int. Ed. 2008, 47, 1308 – 1311;
b) J.-K. Wang, Y.-X. Zong, H.-G. An, G.-Q. Xue, D.-Q. Wu, Y.-S.
Wang, Tetrahedron Lett. 2005, 46, 3797 – 3799; c) B. Gao, Z. Fu,
Z. Yu, L. Yu, Y. Huang, X. Feng, Tetrahedron 2005, 61, 5822 –
5830; d) M. Valenzuela, M. P. Doyle, C. Hedberg, W. Hu, A.
Holmstrom, Synlett 2004, 2425 – 2428; e) Z. Y. Fu, B. Gao, Z. P.
Yu, L. Yu, Y. Z. Huanga, X. M. Feng, G. L. Zhang, Synlett 2004,
1772 – 1775; f) Y. Yamashita, S. Saito, H. Ishitani, S. Kobayashi,
J. Am. Chem. Soc. 2003, 125, 3793 – 3798.
In summary, we have presented an efficient catalytic
enantioselective HDA reaction of Danishefskyꢀs diene, as
well as the challenging linear- and inner-outer-ring 1,3-
bis(silyloxy)-1,3-dienes, with aldehydes catalyzed by a novel
chiral disulfonimide. Several previously inaccessible highly
enantioenriched 2,6-disubstituted and 2,5,6-trisubstituted
dihydropyrones have been synthesized. Polycyclic dihydro-
pyrones can be easily modified (e.g. by aromatization), thus
giving access to enantioenriched biologically active benzo-
flavanone derivatives. Moreover, a wide range of aldehydes
can be used as substrates. A Mukaiyama aldol reaction
mechanism has been established by isolating the correspond-
ing intermediate. Our new highly fluorinated disulfonimide
catalyst represents a significant improvement over the
originally reported catalyst and further strengthens the
potential of disulfonimide catalysis. Additional studies aim
at identifying a suitable catalyst for using aliphatic aldehydes
and ketones, and the application of our methodology in the
synthesis of enantioenriched natural products and bio-active
materials.
[6] a) L. Lin, X. Liu, X. Feng, Synlett 2007, 2147 – 2157; b) W. Yang,
D. Shang, Y. Liu, Y. Du, X. Feng, J. Org. Chem. 2005, 70, 8533 –
8537; c) C. Baker-Glenn, N. Hodnett, M. Reiter, S. Ropp, R.
Ancliff, V. Gouverneur, J. Am. Chem. Soc. 2005, 127, 1481 –
1486; d) A. Togni, Organometallics 1990, 9, 3106.
[7] For the non catalytic stereocontrolled syntheses of polysubsti-
tuted pyrans, see: W. Oppolzer, I. Rodriguez, Helv. Chim. Acta
1993, 76, 1282 – 1291.
[8] a) L. Ratjen, P. Garcꢃa-Garcꢃa, F. Lay, M. E. Beck, B. List,
Angew. Chem. 2011, 123, 780 – 784; Angew. Chem. Int. Ed. 2011,
50, 754 – 758; b) P. Garcꢃa-Garcꢃa, F. Lay, P. Garcꢃa-Garcꢃa, C.
Rabalakos, B. List, Angew. Chem. 2009, 121, 4427 – 4430; Angew.
Chem. Int. Ed. 2009, 48, 4363 – 4366.
[9] Also see: a) M. Barbero, S. Cadamuro, S. Dughera, G. Ghigo,
Org. Biomol. Chem. 2012, 10, 4058 – 4068; b) L.-Y. Chen, H. He,
W.-H. Chan, A. W. M. Lee, J. Org. Chem. 2011, 76, 7141 – 7147;
c) A. Berkessel, P. Christ, N. Leconte, J.-M. Neudçrfl, M.
Schꢄfer, Eur. J. Org. Chem. 2010, 5165 – 5170; d) M. Treskow,
J. Neudçrfl, R. Giernoth, Eur. J. Org. Chem. 2009, 3693 – 3697.
[10] a) M. Nawaz, M. Sher, P. Langer, Synlett 2010, 2383 – 2391; b) O.
Tsuge, S. Kanemasa, H. Sakoh, E. Wada, Bull. Chem. Soc. Jpn.
1984, 57, 3234 – 3241; c) S. Danishefsky, D. F. Harvey, G.
Quallich, B. J. Uang, J. Org. Chem. 1984, 49, 392 – 393; d) C.
Brisson, P. Brassard, J. Org. Chem. 1981, 46, 1810 – 1814; e) T.
Ibuka, Y. Mori, Y. Inubushi, Tetrahedron Lett. 1976, 17, 3169 –
3172.
Received: June 1, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · cycloaddition · disulfonimide ·
.
heterocycles · organocatalysis
[1] S. Danishefsky, J. F. Kerwin, S. Kobayashi, J. Am. Chem. Soc.
1982, 104, 358 – 360.
[2] For some reviews on the hetero Diels–Alder reaction, see: a) H.
Pellissier, Tetrahedron 2012, 68, 2197 – 2232; b) H. Pellissier,
Tetrahedron 2009, 65, 2839 – 2877; c) K. A. Jørgensen, Eur. J.
Org. Chem. 2004, 2093 – 2102; d) K. Maruoka in Catalysis in
Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New
York, 2000, Chap. 8A, pp. 467 – 492; e) K. A. Jørgensen, Angew.
Chem. 2000, 112, 3702 – 3733; Angew. Chem. Int. Ed. 2000, 39,
3558 – 3588; f) A. Ooi, K. Maruoka, Comprehensive Asymmetric
Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 1237 – 1254; g) R. Noyori in Asym-
metric Catalysis in Organic Synthesis, Wiley, New York, 1994;
h) H. B. Kagan, O. Riant, Chem. Rev. 1992, 92, 1007 – 1019;
i) S. J. Danishefsky, M. P. DeNinno, Angew. Chem. 1987, 99, 15 –
23; Angew. Chem. Int. Ed. Engl. 1987, 26, 15 – 23.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[11] For the utilization of inner-outer-ring dienes in Diels–Alder
reactions, see: a) B. Alcaide, R. M. de Murga, C. Pardo, C.
Rodrꢃguez-Ranera, Tetrahedron Lett. 2004, 45, 7255 – 7259; b) J.
Pꢅrez Sestelo, M. del Mar Real, L. A. Sarandeses, J. Org. Chem.
2001, 66, 1395 – 1402; c) J. Pꢅrez Sestelo, M. M. Real, A.
MouriÇo, L. A. Sarandeses, Tetrahedron Lett. 1999, 40, 985 – 988.
[12] For the pioneering use of such dienes in asymmetric vinylogous
aldol reactions, see: S. E. Denmark, J. R. Heemstra, J. Org.
Chem. 2007, 72, 5668 – 5688.
Hollis, B. Bosnich, J. Am. Chem. Soc. 1995, 117, 4570 – 4581;
c) E. M. Carreira, R. A. Singer, Tetrahedron Lett. 1994, 35,
4323 – 4326.
[14] J. D. White, S. Shaw, Org. Lett. 2011, 13, 2488 – 2491.
[15] a) S. Yahiaoui, C. Pouget, J. Buxeraud, A. J. Chulia, C. Fagnꢆre,
Eur. J. Med. Chem. 2011, 46, 2541 – 2545; b) S. Yahiaoui, C.
Fagnere, C. Pouget, J. Buxeraud, A.-J. Chulia, Bioorg. Med.
Chem. 2008, 16, 1474 – 1480.
[16] S. Danishefsky, E. Larson, D. Askin, N. Kato, J. Am. Chem. Soc.
1985, 107, 1246 – 1255.
[13] a) C.-T. Chen, S.-D. Chao, K.-C. Yen, C.-H. Chen, I.-C. Chou, S.-
W. Hon, J. Am. Chem. Soc. 1997, 119, 11341 – 11342; b) T. K.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
J. Guin, C. Rabalakos,
B. List*
&&&& — &&&&
Highly Enantioselective Hetero-Diels–
Alder Reaction of 1,3-Bis(silyloxy)-1,3-
dienes with Aldehydes Catalyzed by Chiral
Disulfonimide
Bulking up with F: The title reaction
proceeds using 1 mol% of the new per-
fluoroisopropyl chiral disulfonimide
catalyst 1 to deliver several 2,6-disubsti-
tuted and 2,5,6-trisubstituted dihydro-
pyrones in good yields and with excellent
enantiomeric ratios. The utility of this
methodology is illustrated with the first
enantioselective synthesis of a potent
aromatase inhibitor.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!