Highly enantioselective hetero-Diels-Alder reactions between Rawal's diene and aldehydes catalyzed by chiral dirhodium(ii) carboxamidates

Article abstract of DOI:10.1039/b919535a

The first example of a chiral Lewis acid-catalyzed enantioselective hetero-Diels-Alder (HDA) reaction between 1-dimethylamino-3-silyloxy-1,3- butadiene (Rawal's diene) and aldehydes is described. The cycloaddition reaction under the influence of 1 mol% of

Full text of DOI:10.1039/b919535a

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly enantioselective hetero-Diels–Alder reactions between Rawal’s
diene and aldehydes catalyzed by chiral dirhodium(II) carboxamidateswz
Yudai Watanabe, Takuya Washio, Naoyuki Shimada, Masahiro Anada and
Shunichi Hashimoto*
Received (in College Park, MD, USA) 18th September 2009, Accepted 5th October 2009
First published as an Advance Article on the web 15th October 2009
DOI: 10.1039/b919535a
The first example of a chiral Lewis acid-catalyzed enantioselective
hetero-Diels–Alder (HDA) reaction between 1-dimethylamino-
3-silyloxy-1,3-butadiene (Rawal’s diene) and aldehydes is
described. The cycloaddition reaction under the influence of 1
mol% of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-
piperidinonate], Rh2(S-BPTPI)4, proceeded cleanly and gave,
after treatment with acetyl chloride, the corresponding dihydro-
pyranones in up to 99% ee.
dienes as well as with monooxygenated dienes.8,9 As part of
our interest in further extending the scope and utility of 1a
in Lewis acid catalysis, we have successfully incorporated
1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal’s diene, 2)
into the Rh2(S-BPTPI)4-catalyzed enantioselective HDA
reaction as described herein.
Rawal’s diene (2) is known to display significantly higher
reactivity than Danishefsky’s diene in the Diels–Alder
reaction.10 In 2003, Rawal and co-workers reported the first
enantioselective HDA reaction between 2 and aldehydes
catalyzed by a,a,a0,a0-tetra(1-naphthyl)-1,3-dioxolan-4,5-
dimethanol (1-naphthyl-TADDOL) through hydrogen bond-
based activation (20 mol% catalyst, toluene, ꢀ40 1C for 24 h
or ꢀ78 1C for 48 h), which gave, upon acetyl chloride-
mediated removal of the TBS and the dimethylamino groups,
the corresponding dihydropyranones in good overall yields
with up to 98% ee.11 Since their pioneering work, various
chiral hydrogen bonding organocatalysts have been developed
for the catalysis of this cycloaddition reaction.12–15 However,
to the best of our knowledge, a chiral Lewis acid-catalyzed
enantioselective HDA reaction between Rawal’s diene (2) and
aldehydes has not been reported to date,16 probably due to the
high sensitivity of 2 to moisture in the presence of common
Lewis acids as well as their deactivation by the Lewis basic
dimethylamino group.10,17
The enantioselective hetero-Diels–Alder (HDA) reaction
between electron-rich dienes and aldehydes represents one of
the most straightforward methods for the construction of
optically active six-membered oxygen-containing heterocycles.1
Since the first report on the topic by Danishefsky and
co-workers,2 the development of a catalytic enantioselective
version of this type of reaction using various chiral Lewis acids
has been the subject of intensive investigations in the field of
asymmetric synthesis.3,4
In recent years, Doyle and co-workers demonstrated that
chiral dirhodium(II) carboxamidates function as effective
Lewis acid catalysts for enantioselective HDA reactions of
1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky’s
diene) with aldehydes5 and the [2 + 2]-cycloaddition reaction
of (trimethylsilyl)ketene with ethyl glyoxylate.6,7 In this
context, we disclosed that Rh2(S-BPTPI)4 (1a), a dirhodium(II)
carboxamidate complex which incorporates (S)-3-(benzene-
fused-phthalimido)-2-piperidinonates as bridging ligands
(Fig. 1), is a highly efficient catalyst for endo- and enantio-
selective HDA reactions of aldehydes with Danishefsky-type
At the outset of this work, we explored the HDA reaction of
2 with benzaldehyde (3a) using 1 mol% of Rh2(S-BPTPI)4
(1a). The reaction in dichloromethane proceeded smoothly at
0 1C to completion in less than 0.1 h and, after treatment
with acetyl chloride at ꢀ78 1C according to the Rawal
protocol,11a,18 gave 2-phenyl-2,3-dihydro-4H-pyran-4-one
(5a) in 70% yield (Table 1, entry 1). The enantioselectivity
of this reaction was determined to be 95% ee by HPLC
analysis with Daicel Chiralcel OD-H. The absolute stereo-
chemistry of 5a [[a]2D4 +103 (c 1.27, CHCl3)] was assigned as S
by comparing the sign of optical rotation [lit.,2c [a]D23 ꢀ96.3
(c 0.87, CHCl3) for (R)-5a]. In the present reaction, the 1H
NMR spectrum of the crude reaction mixture obtained
without the use of acetyl chloride revealed the exclusive
formation of the 2,6-cis-dihydropyran 4a. Furthermore, no
detectable cyclization of the Mukaiyama aldol adduct18
prepared independently was observed under the present
reaction conditions.z These results demonstrated that the
Rh2(S-BPTPI)4-catalyzed cycloaddition with Rawal’s diene
(2) proceeds through the same concerted [4 + 2] mechanism
in an endo mode as that with Danishefsky-type dienes8a
(vide infra). Lowering the temperature improved both product
Fig. 1 Chiral dirhodium(II) complexes.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo,
Japan. E-mail: hsmt@pharm.hokduai.ac.jp; Fax: +81 11 706 4981;
Tel: +81 11 706 3236
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme 2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experi-
mental details and spectroscopic data of the products. See DOI:
10.1039/b919535a
ꢁc
This journal is The Royal Society of Chemistry 2009
7294 | Chem. Commun., 2009, 7294–7296

Table 1 Enantioselective HDA reaction between Rawal’s diene (2)
and benzaldehyde (3a) catalyzed by dirhodium(II) complexesa
Table 2 Enantioselective HDA reaction between Rawal’s diene (2)
and aldehydes 3 catalyzed by Rh2(S-BPTPI)4 (1a)a
Aldehydes
R
Product
Yield ee
Yield ee
Solvent T/1C Time/h (%)b (%)c
Entry Rh(II) catalyst
(%)b (%)c
Entry
T/1C Time/h
1
2
3
4
5
6
7
8
9
Rh2(S-BPTPI)4 (1a) CH2Cl2
0
Rh2(S-BPTPI)4 (1a) CH2Cl2 ꢀ20
Rh2(S-BPTPI)4 (1a) CH2Cl2 ꢀ40
0.1
0.5
2
70
75
83
75
68
68
47
82
53
95
97
98
96
94
80
89
97
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
3b 4-MeC6H4
3c 3-MeC6H4
3d 4-MeOC6H4
3e 4-TBDMSOC6H4
3f 3-MeOC6H4
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
2
2
6
6
6
6
5b 77
98
95
99
98
96
96
90
97
95
94
87d
96
91
93
97
99
97
98
95
90
5c 79
5d 84
5e 73
5f 76
5g 73
5h 75
5i 71
5j 93
5k 78
5l 72
5m 71
5n 80
5o 80
5p 75
5q 93
5r 80
5s 74
5t 71
5u 73
Rh2(S-BPTPI)4 (1a) CH2Cl2 ꢀ78 24
Rh2(S-BPTPI)4 (1a) Acetone ꢀ40
Rh2(S-BPTPI)4 (1a) Toluene ꢀ40
1
8
3g 3,4-(OCH2O)C6H3 ꢀ40
Rh2(S-BPTPI)4 (1a) Et2O
ꢀ40 12
3h 3,5-(MeO)2C6H3
3i 4-ClC6H4
ꢀ40
ꢀ60
ꢀ78
ꢀ90
6
2
0.1
2
0.5
2
0.1
8
6
0.1
0.5
2
Rh2(S-PTPI)4 (1b) CH2Cl2 ꢀ40
Rh2(S-PTTL)4 (1c) CH2Cl2
6
24
0
3j 4-CF3C6H4
3k 4-NO2C6H4
a
All reactions were performed on a 0.3 mmol scale (0.5 M) with
b
1.5 equivalents of 3a. Yields of isolated product 5a. Determined by
c
3l TBDPSOCH2CRC ꢀ90
HPLC on a Daicel Chiralcel OD-H (see ESI for details).
3m 2-Naphthyl
3n 2-Furyl
ꢀ20
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ20
3o 2-Thienyl
3p (E)-PhCHQCH
3q PhCH2CH2
3r nC5H11
yield and enantioselectivity, though ꢀ40 1C was found to be
the temperature limit (entries 2–4). A survey of solvents at ꢀ40 1C
revealed that dichloromethane was the optimal solvent for this
transformation to produce 5a in 83% yield and 98% ee
3s TBDMSOCH2CH2 ꢀ40
3t cC6H11
3u 1-Adamantylmethyl
0
0
6
24
(entry 3). Acetone exhibited
a high enantioselectivity
a
All reactions were performed on a 0.3 mmol scale (0.5 M) with 1.5
(94% ee) comparable to that found with dichloromethane,
but product yield was markedly reduced (entry 5). Toluene
and diethyl ether were found to be less effective in terms of
reaction rate and product yield as well as enantioselectivity
(entries 6 and 7). Using dichloromethane as the solvent, we
next evaluated the performance of other chiral dirhodium(II)
complexes. The parent catalyst, Rh2(S-PTPI)4 (1b),8a,19 was
also effective for achieving a similar high yield and asymmetric
induction as those obtained with 1a, but catalysis with 1b
required significantly longer reaction times to reach comple-
tion (entry 8). Interestingly, Rh2(S-PTTL)4 (1c),20 a typical
representative of our dirhodium(II) carboxylate complexes,
which displayed a similar catalytic activity to that of 1a
in HDA reactions between Danishefsky-type diene and
aldehydes,8a did not accelerate the reaction even at 0 1C and
provided 5a in 53% yield with 6% ee (entry 9),21 suggesting the
unique ability of our dirhodium(II) carboxamidate complexes.
With an optimal set of reaction conditions in hand, we then
investigated the scope of the reaction with respect to the
aldehyde component (Table 2). Good yields and high to
excellent enantioselectivities were consistently obtained at
ꢀ40 1C with aromatic aldehydes bearing electron-donating
groups at the para or meta positions on the benzene ring
(90–99% ee, entries 1–7). The use of electron-poor aromatic
aldehydes 3i–3k or a,b-acetylenic aldehyde 3l afforded the
corresponding dihydropyranones 5i–5l in similar good yields
and high enantioselectivities, although these reactions required
rather low temperatures (ꢀ60 to ꢀ90 1C) to prevent
background reactions (entries 8–11). 2-Napthaldehyde (3m),
furfural (3n), 2-thiophenecarbaldehyde (3o), and trans-
cinnamaldehyde (3p) were also effective dienophiles for this
reaction (91–97% ee, entries 12–15).
b
equivalents of 3. Yields of isolated product 5. Determined by
c
d
HPLC unless otherwise stated (see ESI for details). Determined by
HPLC after reduction with NaBH4–CeCl3 (see ESI for details).
Aside from straight-chain aliphatic aldehydes 3q–3s
(95–99% ee, entries 16–18), good yields and high enantio-
selectivities were obtained with sterically hindered cyclohexane-
carbaldehyde (3t) and 1-adamantylacetaldehyde (3u) (95%
and 90% ee, entries 19 and 20). It is noteworthy that aliphatic
aldehydes 3r–3u were less effective as dienophiles in the
Rh2(S-BPTPI)4-catalyzed HDA reaction using a Danishefsky-
type diene.22
The stereochemical outcome of the present HDA reaction
can be rationalized on the basis of the absolute stereochemical
model we previously proposed,8a which contains a hydrogen
bond between the formyl hydrogen atom and the carboxamidate
oxygen atom23 in rhodium catalyst–aldehyde complexes
(Fig. 2). The approach of Rawal’s diene (2) from the less
Fig. 2 Plausible stereochemical course.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 7294–7296 | 7295

hindered Si-face of the aldehyde in an endo mode to avoid
intrusion into the rhodium framework leads to the observed
cycloadduct. The substantial difference in reaction times between
catalyses with Rh2(S-BPTPI)4 (1a) and Rh2(S-PTPI)4 (1b)
suggests that catalyst turnover, rather than cycloaddition, is
the rate-determining step in this reaction; the sterically more
demanding benzene-fused phthalimido group in 1a would facilitate
decomplexation of the cycloadduct and catalyst turnover.
7 Very recently, Doyle and co-workers reported the effective use of
chiral cationic dirhodium(II,III) carboxamidate complexes in
enantioselective 1,3-dipolar cycloaddition reactions between
nitrones and a,b-unsaturated aldehydes, see: Y. Wang, J. Wolf,
P. Zavalij and M. P. Doyle, Angew. Chem., Int. Ed., 2008, 47, 1439.
8 (a) M. Anada, T. Washio, N. Shimada, S. Kitagaki, M. Nakajima,
M. Shiro and S. Hashimoto, Angew. Chem., Int. Ed., 2004, 43,
2665; see also: (b) A. Boyer, G. E. Veitch, E. Beckmann and
S. V. Ley, Angew. Chem., Int. Ed., 2009, 48, 1317.
9 (a) T. Washio, R. Yamaguchi, T. Abe, H. Nambu, M. Anada and
S. Hashimoto, Tetrahedron, 2007, 63, 12037; (b) T. Washio,
H. Nambu, M. Anada and S. Hashimoto, Tetrahedron: Asymmetry,
2007, 18, 2606.
10 (a) S. A. Kozmin and V. H. Rawal, J. Org. Chem., 1997, 62, 5252;
(b) S. A. Kozmin, J. M. Janey and V. H. Rawal, J. Org. Chem.,
1999, 64, 3039; (c) S. A. Kozmin, M. T. Green and V. H. Rawal,
J. Org. Chem., 1999, 64, 8045.
11 (a) Y. Huang, A. K. Unni, A. N. Thadani and V. H. Rawal,
Nature, 2003, 424, 146; (b) A. N. Thadani, A. R. Stankovic and
V. H. Rawal, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5846.
12 For reviews, see: (a) P. M. Pihko, Angew. Chem., Int. Ed., 2004, 43,
2062; (b) H. Yamamoto and K. Futatsugi, Angew. Chem., Int. Ed.,
2005, 44, 1924; (c) M. S. Taylor and E. N. Jacobsen, Angew.
Chem., Int. Ed., 2006, 45, 1520.
13 (a) A. K. Unni, N. Takenaka, H. Yamamoto and V. H. Rawal,
J. Am. Chem. Soc., 2005, 127, 1336; (b) S. Rajaram and
M. S. Sigman, Org. Lett., 2005, 7, 5473; (c) A. Friberg,
C. Olsson, F. Ek, U. Berg and T. Frejd, Tetrahedron: Asymmetry,
2007, 18, 885; (d) K. H. Jensen and M. S. Sigman, Angew. Chem.,
Int. Ed., 2007, 46, 4748.
14 For theoretical studies on the 1-naphthyl-TADDOL-catalyzed
enantioselective HDA reaction between Rawal’s diene and
aldehydes, see: (a) D. J. Harriman and G. Deslongchamps,
J. Mol. Model., 2006, 12, 793; (b) R. Gordillo, T. Dudding,
C. D. Anderson and K. N. Houk, Org. Lett., 2007, 9, 501;
(c) C. D. Anderson, T. Dudding, R. Gordillo and K. N. Houk,
Org. Lett., 2008, 10, 2749.
In summary, we have developed an enantioselective HDA
reaction between Rawal’s diene and a diverse range of
aldehydes catalyzed by 1 mol% of Rh2(S-BPTPI)4 to give,
after treatment with acetyl chloride, dihydropyranone derivatives
in good yields and with excellent enantioselectivities. This
represents the first example of a chiral Lewis acid-catalyzed
HDA reaction between Rawal’s diene and aldehydes. Efforts
to extend the scope of this process to other substrates such as
nitrogen-containing heterodienes are currently underway.
This research was supported in part by a Grant-in-Aid for
Scientific Research from the Japan Society of the Promotion
of Science (JSPS). We thank Ms S. Oka, and M. Kiuchi of the
Center for Instrumental Analysis at Hokkaido University for
mass measurements and elemental analysis.
Notes and references
1 For reviews on enantioselective HDA reactions, see: (a) K. A.
Jørgensen, in Cycloaddition Reactions in Organic Synthesis,
ed. S. Kobayashi and K. A. Jørgensen, Wiley-VCH, Weinheim,
2002, ch. 4.A; (b) V. Gouverneur and M. Reiter, Chem.–Eur. J.,
2005, 11, 5806; (c) L. Lin, X. Liu and X. Feng, Synlett, 2007, 2147;
(d) K. Ding, Chem. Commun., 2008, 909; (e) H. Pellissier,
Tetrahedron, 2009, 65, 2839.
2 (a) M. Bednarski, C. Maring and S. Danishefsky, Tetrahedron
Lett., 1983, 24, 3451; (b) M. Bednarski and S. Danishefsky, J. Am.
Chem. Soc., 1983, 105, 6968; (c) M. Bednarski and S. Danishefsky,
J. Am. Chem. Soc., 1986, 108, 7060.
15 For enantioselective HDA reactions of aldehydes with Danishefsky’s
diene or Brassad’s diene promoted by hydrogen bonding organo-
catalysts, see: (a) H. Du, D. Zhao and K. Ding, Chem.–Eur. J.,
2004, 10, 5964; (b) X. Zhang, H. Du, Z. Wang, Y.-D. Wu and
K. Ding, J. Org. Chem., 2006, 71, 2862.
3 For recent examples of asymmetric HDA reactions between
Danishefsky-type dienes and aldehydes catalyzed by chiral Lewis
acids, see: (a) A. Berkessel and N. Vogl, Eur. J. Org. Chem., 2006,
5029; (b) K. Seki, M. Ueno and S. Kobayashi, Org. Biomol. Chem.,
2007, 5, 1347; (c) A. Landa, B. Richter, R. L. Johansen,
A. Minkkila and K. A. Jørgensen, J. Org. Chem., 2007, 72, 240;
(d) Z. Yu, X. Liu, Z. Dong, M. Xie and X. Feng, Angew. Chem.,
Int. Ed., 2008, 47, 1308; (e) X.-B. Yang, J. Feng, J. Zhang,
N. Wang, L. Wang, J.-L. Liu and X.-Q. Yu, Org. Lett., 2008,
10, 1299; (f) H. Du, X. Zhang, Z. Wang, H. Bao, T. You and
K. Ding, Eur. J. Org. Chem., 2008, 2248; (g) S. Eno, H. Egami,
T. Uchida and T. Katsuki, Chem. Lett., 2008, 37, 632;
(h) W. Cha"adaj, P. Kwiatkowski and J. Jurczak, Tetrahedron
Lett., 2008, 49, 6810.
16 Jørgensen and co-workers reported that the HDA reaction
between Rawal’s diene and methyl pyruvate using 10 mol%
Cu(OTf)2-bis(oxazoline) led to a racemic mixture of cycloadduct
(product yield not given), see: S. Yao, M. Johannsen, H. Audrain,
R. G. Hazell and K. A. Jørgensen, J. Am. Chem. Soc., 1998, 120,
8599.
17 Rawal and co-workers reported that the enantioselective
Diels–Alder reaction of 1-(N-alkyl-N-alkoxycarbonylamino)-3-
siloxy-1,3-butadienes with a-substituted acroleins catalyzed by
Jacobsen’s chiral Cr(III)-salen complex afforded cycloadducts in high
yields with up to 97% ee, see: (a) Y. Huang, T. Iwama and
V. H. Rawal, J. Am. Chem. Soc., 2000, 122, 7843; (b) S. A. Kozmin,
T. Iwama, Y. Huang and V. H. Rawal, J. Am. Chem. Soc., 2002, 124,
4628.
4 For examples of asymmetric HDA reactions of Brassard’s diene
with aldehydes catalyzed by chiral Lewis acids, see: (a) A. Togni,
Organometallics, 1990, 9, 3106; (b) Q. Fan, L. Lin, J. Liu,
Y. Huang, X. Feng and G. Zhang, Org. Lett., 2004, 6, 2185;
(c) J. D. Winkler and K. Oh, Org. Lett., 2005, 7, 2421; (d) Q. Fan,
L. Lin, J. Liu, Y. Huang and X. Feng, Eur. J. Org. Chem., 2005,
3542; (e) L. Lin, Z. Chen, X. Yang, X. Liu and X. Feng, Org. Lett.,
2008, 10, 1311.
5 (a) M. P. Doyle, I. M. Phillips and W. Hu, J. Am. Chem. Soc.,
2001, 123, 5366; (b) M. P. Doyle, M. Valenzuela and P. Huang,
Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5391; (c) M. Valenzuela,
M. P. Doyle, C. Hedberg, W. Hu and A. Holmstrom, Synlett,
2004, 2425; (d) X. Wang, Z. Li and M. P. Doyle, Chem. Commun.,
2009, 5612.
18 Y. Huang and V. H. Rawal, Org. Lett., 2000, 2, 3321.
19 S. Kitagaki, H. Matsuda, N. Watanabe and S. Hashimoto, Synlett,
1997, 1171.
20 K. Minami, H. Saito, H. Tsutsui, H. Nambu, M. Anada and
S. Hashimoto, Adv. Synth. Catal., 2005, 347, 1483 and references
cited therein.
21 The HDA reaction between 2 and 3a in CH2Cl2 at 0 1C in the
absence of Rh(II) complex went to completion in 24 h to afford
(ꢂ)-5a in 83% yield after treatment with acetyl chloride.
22 The Rh2(S-BPTPI)4-catalyzed HDA reaction using a Danishefsky-
type diene in CH2Cl2 gave the following results: (a) 3r, 23 1C, 36 h,
75% yield, 89% ee; (b) 3s, 23 1C, 48 h, 70% yield, 83% ee; (c) 3t,
reflux, 24 h, 52% yield, 89% ee; (d) 3u, reflux, 48 h, 31% yield,
50% ee.
6 R. E. Forslund, J. Cain, J. Colyer and M. P. Doyle, Adv. Synth.
Catal., 2005, 347, 87.
23 For an overview, see: E. J. Corey and T. W. Lee, Chem. Commun.,
2001, 1321.
ꢁc
This journal is The Royal Society of Chemistry 2009
7296 | Chem. Commun., 2009, 7294–7296