A new dirhodium(II) carboxamidate complex as a chiral Lewis acid catalyst for enantioselective hetero-Diels-Alder reactions

Article abstract of DOI:10.1002/anie.200453821

Excellent enantioselectivities (up to 99% ee) and turnover numbers (up to 48000) were attained in the hetero-Diels-Alder reaction of a diverse range of aldehydes and activated dienes catalyzed by [Rh₂(S-bptpi) ₄] (see scheme).

Full text of DOI:10.1002/anie.200453821

Angewandte
Chemie
Cycloadditions
A New Dirhodium(ii) Carboxamidate Complex as
a Chiral Lewis Acid Catalyst for Enantioselective
Hetero-Diels–Alder Reactions**
Masahiro Anada, Takuya Washio, Naoyuki Shimada,
Shinji Kitagaki, Makoto Nakajima, Motoo Shiro, and
Shunichi Hashimoto*
Over the last decade, the exceptional power of chiral
dirhodium(ii) carboxylate and carboxamidate catalysts has
been demonstrated in a diverse array of enantioselective
metal carbene transformations of diazocarbonyl com-
pounds.[1] Aside from the superiority in diazo decomposition,
a dirhodium(ii) complex with vacant coordination sites at the
[*] Dr. M. Anada, T. Washio, N. Shimada, Dr. S. Kitagaki,
Dr. M. Nakajima, Prof. Dr. S. Hashimoto
Graduate School of Pharmaceutical Sciences
Hokkaido University, Sapporo 060–0812 (Japan)
Fax: (+81)117-063-236
E-mail: hsmt@pharm.hokudai.ac.jp
Dr. M. Shiro
Rigaku Corporation
3-9-12 Matsubara, Akishima, Tokyo 196-8666 (Japan)
[**] This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) “Exploitation of Multi-Element Cyclic
Molecules” from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan. We thank Ms. H. Matsumoto, A.
Maeda, S. Oka, and M. Kiuchi of the Center for Instrumental
Analysis, Hokkaido University, for technical assistance in MS and
elemental analysis.
Supporting information for this articleis availableon theWWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 2665 –2668
DOI: 10.1002/anie.200453821
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2665

Communications
Table 1: RhII-catalyzed enantioselective HDA reactions.[a]
axial position of each octahedral rhodium center is Lewis
acidic as the molecule has a high affinity for axial ligands.[2]
Although this important feature provides a great incentive to
develop dirhodium(ii) complexes as a new class of chiral
Lewis acid catalysts, this goal has remained elusive until a
recent breakthrough by Doyle et al.[3] Doyle and co-workers
reported that use of 1 mol% of dirhodium(ii) tetrakis[4S-
methoxycarbonyl-1-(3-phenylpropanoyl)-2-oxoimidazolidi-
nate], [Rh2(4S-MPPIM)4] (1, Scheme 1), promoted hetero-
Entry RhII
5
R
T [8C] t [h]
7
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
2a 5a 4-NO2C6H4
2b 5a 4-NO2C6H4
2c 5a 4-NO2C6H4
2d 5a 4-NO2C6H4
3a 5a 4-NO2C6H4
3a 5b C6H5
23
23
23
23
23
23 32
23 48
23 18
2
2
2
2
2
7aa 95
7aa 97
7aa 92
7aa 90
7aa 91
7ab 92
7ac 83
7ad 94
6
22
29
45
94
95
96
93[d]
69
87
90
92
3a 5c 4-MeOC6H4
3a 5d 2-furyl
ꢀ
9
3a 5e PhC C
23
À20
23
À20
0.5 7ae 97
7ae 96
0.5 7ae 95
7ae 91
ꢀ
10
11
12
3a 5e PhC C
6
ꢀ
3b 5e PhC C
ꢀ
3b 5e PhC C
6
[a] All reactions were performed on a 0.3-mmol scale (0.5m) with
1.5 equivalents of diene. [b] Yields of isolated products. [c] Determined
by HPLC on a Daicel Chiralcel OD-H (see Supporting Information for
details). [d] The absolute stereochemistry was not determined.
commonly regarded as weaker Lewis acids than dirhodium(ii)
carboxylates. It is also noteworthy that 3a is even more active
than 1, which is manifested by much shorter reaction times
(2 h vs. 24 h).[3] With respect to the mechanism of the Lewis
acid catalyzed HDAreaction, two mechanistic pathways have
been proposed: either a pericyclic or a Mukaiyama aldol–
Michael pathway.[5] In the present reaction, the 1H NMR
spectrum of the crude reaction mixture obtained without the
use of TFArevealed the exclusive formation of the 2,6- cis-
dihydropyran 6aa. Furthermore, no detectable cyclization of
the Mukaiyama aldol adduct prepared independently was
observed under the present reaction conditions. These results
demonstrated that the reaction proceeds through a concerted
[4+2] mechanism in an endo mode.[6i,m,10]
The applicability of this catalytic system to a range of
aldehydes was then investigated. The use of aromatic
aldehydes, including benzaldehyde, p-anisaldehyde, and fur-
fural, afforded the corresponding dihydropyranones in similar
high yields and asymmetric induction as those found with
electron-poor p-nitrobenzaldehyde, although these reactions
required significantly longer times to reach completion
(Table 1, entries 6–8). In contrast, switching from aromatic
aldehydes to phenylpropargylaldehyde dramatically acceler-
ated the reaction, but caused a sharp drop in enantioselec-
tivity (69% ee; Table 1, entry 9). This result suggests that the
steric interaction between the acetylenic moiety and the
phthalimido group protruding toward the rhodium–aldehyde
adduct might be less severe than that with an aromatic ring
(see below). Although the reaction at À208C gave an
improved enantioselectivity (87% ee; Table 1, entry 10), we
were particularly attracted to the possibility of enhancing the
enantioselectivity by extending the phthalimido group with an
additional benzene ring, as was with the case with dirhodiu-
m(ii) carboxylate catalysts in enantioselective carbonyl ylide
cycloadditions.[11] Gratifyingly, the HDAreaction at room
temperature under the influence of the newly developed
Scheme 1. Chiral dirhodium(ii) complexes. MPPIM=4-methoxycar-
bonyl-1-(3-phenylpropanoyl)-2-oxoimidazolidinate, PTPA=N-phthaloyl-
phenylalaninate, PTA=N-phthaloylalaninate, PTV=N-phthaloylvali-
nate, PTTL=N-phthaloyl-tert-leucinate, PTPI=3-phthalimido-2-piperi-
dinonate, BPTPI=3-(benzene-fused-phthalimido)-2-piperidinonate.
Diels–Alder (HDA) reactions[4–6] between 1-methoxy-3-(tri-
methysilyloxy)-1,3-butadiene (the Danishefsky diene) and
nitro-substituted aromatic aldehydes to give, after treatment
with trifluoroacetic acid (TFA), dihydropyranones with a
maximum of 95% ee. Although an exceptionally high turn-
over number of 6200 was possible with p-nitrobenzaldehyde
(10 days, 62% yield, 80% ee), a major challenge in terms of
reaction rates, enantioselectivity, and the scope with regard to
dienes and aldehydes still remained. Herein we report that
[Rh2(S-BPTPI)4] (3b), a new dirhodium(ii) carboxamidate
complex that incorporates (S)-3-(benzene-fused-phthali-
mido)-2-piperidinonate as chiral bridging ligands, is a more
general and highly efficient catalyst for endo- and enantiose-
lective HDAreactions.
At the outset of this work, the HDA reaction between 1-
methoxy-3-(triethylsilyloxy)-1,3-butadiene (4a) and p-nitro-
benzaldehyde (5a) in dichloromethane was explored at room
temperature in the presence of 1 mol% of our dirhodium(ii)
catalysts 2a–d[7] and 3a[8] (Table 1, entries 1–5). Whereas
dirhodium(ii) carboxylate catalysts 2a–d displayed poor
enantioselectivities similar to those found by Doyle et al.,
catalysis with dirhodium(ii) tetrakis[3(S)-phthalimido-2-
piperidinoate], [Rh2(S-PTPI)4] (3a), provided dihydropyra-
none (S)-7aa[9] in 91% yield with 94% ee after desilylation
(Table 1, entry 5). Interestingly, the activity of 3a is similar to
that of 2a–d, although dirhodium(ii) carboxamidates are
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Chemie
[Rh2(S-BPTPI)4] (3b)[12] produced 7ae in 95% yield with
90% ee (Table 1, entry 11), in which a slight enhancement (up
to 92% ee) was observed at À208C without lowering the yield
(Table 1, entry 12).
(0.0075–0.002 mol%) without compromising the yield or
enantioselectivity (Table 2, entries 14–16). The turnover
numbers (as high as 48000) are probably among the highest
ever reported for Lewis acid catalyzed asymmetric reac-
tions.[14,15]
The present [Rh2(S-BPTPI)4] catalytic system allowed
considerable variations in the substitution pattern of the
activated diene and the nature of the aldehyde component
(Table 2). The applicable aldehydes include aromatic, a,b-
acetylenic, a,b-olefinic, aliphatic, and a-alkoxy deriva-
tives (Table 2, entries 1–9). The HDAreaction with 4-
methyl-substituted Danishefsky-type dienes 4c and 4d
produced 2,3-cis-dihydropyranones 7ca and 7da with
essentially complete diastereoselectivities and enantio-
selectivities in excess of 96% (Table 2, entries 10 and
11), which confirmed the preference for the endo-mode
transition state. [Rh2(S-BPTPI)4]-catalyzed reactions of
monooxygenated dienes 4e and 4 f with phenylpropar-
gylaldehyde proceeded smoothly at À208C to yield all-
cis tetrahydropyranones 8ee and 8 fe in 99% and
97% ee, respectively (Table 2, entries 12 and 13).[13] As
expected from the robustness and high activity of 3b,
selected reactions with highly reactive aldehydes pro-
ceeded smoothly with very low catalyst loadings
The stereochemical outcome of the present HDAreaction
can be rationalized based on the crystal structure of the
bis(acetonitrile) adduct of [Rh2(S-PTPI)4] (3a; Figure 1)[16]
Figure 1. Ball-and-stick (left) and schematic (right) representation of the crystal struc-
tureof 3a·(MeCN)2.
Table 2: Enantioselective HDA reactions catalyzed by 3b.
À
coupled with the formyl C H···O hydrogen-bond concept
proposed by Corey and co-workers.[17] As in the case of 3a, 3b
is considered to adopt a conformation with a C2-like
symmetry in which the benzene-fused-phthalimido groups
are aligned in a “down-down-up-up” arrangement. Conse-
quently, two stereochemical models of the rhodium catalyst–
RCHO complexes, A and B, can be presented in which a
favorable hydrogen bond between the formyl hydrogen atom
and the carboxamidate oxygen atom is allowed (Figure 2).
The approach of dienes (e.g. 4) to A in an endo mode to avoid
intrusion into the rhodium framework is preferred over the
pathway via B owing to the serious repulsion between the
incoming diene and the benzene-fused phthalimido wall in B,
which leads to the observed cycloadduct. In this context, it
should be noted that the benzene-fused-phthalimido group,
Entry
4
5
R4
T [8C] t [h] Prod. Yield [%][a] ee [%][b]
1
2
3
4
5
4a 5 f 4-MeC6H4
4a 5g 4-ClC6H4
4a 5h 4-CNC6H4
4a 5i 4-CF3C6H4
4a 5j n-C5H11C C
4a 5k (E)-PhCH=CH 23 36 7ak 86
23 24 7af
97
96[c]
95[c]
95[c]
95[c]
93[c]
96
23
23
23
À20
6
3
1
2
7ag 95
7ah 93
7ai
7aj
93
71
ꢀ
6
7
8
9
10
11
12
13
4a 5l PhCH2CH2
4a 5m BnOCH2
4b 5n MOMOCH2
4c 5a 4-NO2C6H4
4d 5a 4-NO2C6H4
23
9
7al
89
94
91
À20 18 7am 83
À20 24 7bn 86
23 18 7ca 97
23 10 7da 92
À20 20 8ee 87
93[c,d]
96[c]
97[c]
99[c]
97[c]
94
ꢀ
4e 5e PhC C
ꢀ
4 f 5e PhC C
À20 12 8 fe
81
14[e] 4a 5a 4-NO2C6H4
0
0
0
48 7aa 96[f]
72 7ah 88[h]
64 7ae 96[j]
15[g] 4a 5h 4-CNC6H4
96[c]
91
16[i]
4a 5e PhC C
ꢀ
[a] Yields of isolated products. [b] Determined by HPLC on a Daicel
Chiralcel OD-H unless otherwise stated. [c] The absolute stereochemistry
was not determined. [d] Determined by HPLC on a Daicel Chiralpak AD.
[e] Performed on a 10-mmol scale with 0.0075 mol% of 3b. [f] Turnover
number (TON)=12800. [g] Performed on
a 10-mmol scale with
0.005 mol% of 3b. [h] TON=17600. [i] Performed on a 10-mmol scale
with 0.002 mol% of 3b. [j] TON=48000. MOM=methoxymethyl.
Figure 2. Plausible stereochemical pathway.
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Communications
Kobayashi, J. Am. Chem. Soc. 2003, 125, 3793; p) Y. Huang,
A. K. Unni, A. N. Thadani, V. H. Rawal, Nature 2003, 424, 146.
[7] For enantioselective rhodium carbene transformations catalyzed
by 2a–d, see: H. Saito, H. Oishi, S. Kitagaki, S. Nakamura, M.
Anada, S. Hashimoto, Org. Lett. 2002, 4, 3887, and references
therein.
which interacts more severely with the aldehyde substituent R
than the parent phthalimido group, also greatly favors the
formation of a complex A as demonstrated by the reaction
with the sterically less demanding phenylpropargylaldehyde.
This model also explains the preference of dirhodium(ii)
carboxamidate catalysts 3a,b over the carboxylate counter-
parts 2a–d with similar C2-symmetry-like conformations[18] in
[8] S. Kitagaki, H. Matsuda, N. Watanabe, S. Hashimoto, Synlett
1997, 1171.
[9] R. F. Lowe, R. J. Stoodley, Tetrahedron Lett. 1994, 35, 6351.
[10] Y. Motoyama, Y. Koga, H. Nishiyama, Tetrahedron 2001, 57, 853.
[11] S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C. Umeda, N.
Watanabe, S. Hashimoto, J. Am. Chem. Soc. 1999, 121, 1417.
[12] For the preparation of 3b, see the Supporting Information.
[13] Ahigh order of asymmetric induction in HDAreactions
between monooxygenated 1,3-dienes and unactivated aldehydes
has been achieved only by using the Jacobsen tridentate Schiff
base CrIII complex as a chiral catalyst: A. G. Dossetter, T. F.
Jamison, E. N. Jacobsen, Angew. Chem. 1999, 111, 2549; Angew.
Chem. Int. Ed. 1999, 38, 2398.
[14] a) S. Yao, M. Johannsen, H. Audrain, R. G. Hazell, K. A.
Jørgensen, J. Am. Chem. Soc. 1998, 120, 8599, in which
0.05 mol% of catalyst was used in the HDAreaction with a
maximum of 98.4% ee; b) see reference [6l], in which
0.005 mol% of catalyst was used in the HDAreaction with
96.2% ee; c) Y, Motoyama, Y. Koga, K. Kobayashi, K. Aoki, H.
Nishiyama, Chem. Eur. J. 2002, 8, 2968, in which 0.0083 mol% of
catalyst was used in Michael reaction of a-cyanopropionates
with 81% ee; d) Y. Huang, T. Iwama, V. H. Rawal, J. Am. Chem.
Soc. 2002, 124, 5950, in which 0.05 mol% of catalyst in Diels –
Alder reaction with 98% ee; e) Y. Yuan, X. Zhang, K. Ding,
Angew. Chem. 2003, 115, 5636; Angew. Chem. Int. Ed. 2003, 42,
5478, where 0.01 mol% of catalyst was used in glyoxylate-ene
reaction with up to 97.9% ee.
[15] J. M. Ready, E. N. Jacobsen, Angew. Chem. 2002, 114, 1432;
Angew. Chem. Int. Ed. 2002, 41, 1374, in which 0.0004 mol% of
catalyst was used in hydrolytic kinetic resolution of terminal
epoxides with > 99% ee.
[16] CCDC 222738 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[17] For an overview, see: E. J. Corey, T. W. Lee, Chem. Commun.
2001, 1321.
[18] a) H. Tsutsui, M. Matsuura, K. Makino, S. Nakamura, M.
Nakajima, S. Kitagaki, S. Hashimoto, Isr. J. Chem. 2001, 41, 283;
b) K. Hikichi, S. Kitagaki, M. Anada, S. Nakamura, M.
Nakajima, M. Shiro, S. Hashimoto, Heterocycles 2003, 61, 391.
À
these reactions, in which four sets of formyl C H···O hydro-
gen-bonding interactions are possible.
In conclusion, we have demonstrated that 3b is an
exceptionally effective Lewis acid catalyst for endo and
enantioselective HDAreactions of a diverse range of
aldehydes with Danishefsky-type dienes as well as with
monooxygenated dienes, in which up to 99% ee and turnover
numbers as high as 48000 have been achieved. The catalyst is
readily synthesized, air-stable, and easily handled. The
absolute stereochemical model proposed herein will provide
a useful guide for the development of other classes of Lewis
acid catalyzed enantioselective reactions.
Received: January 21, 2004 [Z53821]
Keywords: aldehydes · asymmetric catalysis · cycloaddition ·
.
heterocycles · rhodium
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