Enantio- and diastereoselective hetero-Diels-Alder reactions between 2-aza-3-silyloxy-1,3-butadienes and aldehydes catalyzed by chiral dirhodium(ii) carboxamidates

Article abstract of DOI:10.1039/c2cc32876c

The first catalytic asymmetric hetero-Diels-Alder reaction between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described. With dirhodium(ii) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh₂(S-BPTPI) ₄, the cycloaddition reaction proceeded exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-4-ones in high yields with up to 98% ee.

Full text of DOI:10.1039/c2cc32876c

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COMMUNICATION
Enantio- and diastereoselective hetero-Diels–Alder reactions between
2-aza-3-silyloxy-1,3-butadienes and aldehydes catalyzed by chiral
dirhodium(II) carboxamidateswz
Yudai Watanabe, Takuya Washio, Janagiraman Krishnamurthi, Masahiro Anada* and
Shunichi Hashimoto*
Received 23rd April 2012, Accepted 17th May 2012
DOI: 10.1039/c2cc32876c
The first catalytic asymmetric hetero-Diels–Alder reaction
between 2-aza-3-silyloxy-1,3-butadienes and aldehydes is described.
With dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piper-
idinonate], Rh2(S-BPTPI)4, the cycloaddition reaction proceeded
exclusively in an endo mode to give all-cis-substituted 1,3-oxazinan-
4-ones in high yields with up to 98% ee.
that Rh2(S-BPTPI)4 (1) catalyzes the HDA reaction between
2-aza-3-silyloxy-1,3-butadienes and aldehydes to provide
1,3-oxazinan-4-ones in high yields and with high levels of
enantioselectivity (up to 98% ee).
At the outset, we explored the HDA reaction between 2-aza-
3-silyloxy-1,3-butadiene 2a and benzaldehyde (3a) (1.5 equiv.)
using 1 mol% of Rh2(S-BPTPI)4 (1). The reaction in dichloro-
methane at room temperature proceeded to completion in
24 h and gave, after desilylation with methanol according to
Ghosez’s procedure,6 cis-2,6-disubstituted 1,3-oxazinan-4-one
5a as the sole product in 95% yield with no signs of isomer-
ization (Table 1, entry 1).3h,4a,b The cis-stereochemistry of 5a
was established by the 1H NOE between C2–H and C6–H. The
enantioselectivity of this reaction was determined to be 98% ee
by HPLC analysis with a Daicel Chiralpak AD-H column.
The preferred absolute stereochemistry of 5a [[a]2D4 ꢁ39.8
The hetero-Diels–Alder (HDA) reaction of 2-aza-3-silyloxy-
1,3-butadienes, originally introduced by Ghosez et al.,1,2 with
carbonyl compounds provides a convergent and practical
route to substituted 1,3-oxazinan-4-ones, which have been
demonstrated to serve as valuable precursors for the synthesis
of 1,3-amino alcohols and b-hydroxy amide derivatives.3–5 In
this context, asymmetric HDA reaction of the corresponding
chiral 2-azadienes with a wide array of aldehydes in the
presence of a stoichiometric amount of BF3ꢀOEt2 has been
developed and extensively advanced by Panunzio et al.3,6
However, despite the great synthetic importance, a catalytic
asymmetric version of this cycloaddition reaction has not been
addressed to date, probably because an achiral catalyst suitable
for such a reaction has not been identified.7
Table 1 Enantioselective HDA reaction between 2-aza-3-siloxy-1,3-
butadines and benzaldehyde (3a) catalyzed by Rh(II) complexesa
Since the pioneering work by Doyle et al. on enantio-
selective HDA reactions of 1-methoxy-3-(trimethylsilyloxy)-
1,3-butadiene (Danishefsky’s diene) with aldehydes, chiral
dirhodium(II) carboxamidates have been widely recognized
as a new class of effective Lewis acid catalysts.8–10 In this
area, we reported that Rh2(S-BPTPI)4 (1), a dirhodium(II)
carboxamidate complex that incorporates (S)-3-(benzene-
fused-phthalimido)-2-piperidinonate as chiral bridging ligands,
is a highly efficient Lewis acid catalyst for endo- and enantio-
selective HDA reactions of a diverse range of aldehydes with
Danishefsky-type dienes and monooxygenated dienes as well
as with Rawal’s diene.11 As part of our interest in further
extension of the scope and utility of 1, we herein report
Entry
Diene
SiR3
Catalyst
t/h
Yieldb (%)
eec (%)
1
2
3
4
5
6
2a
2a
2a
2a
2b
2c
TBS
TBS
TBS
TBS
Me3Si
Et3Si
1
24
96
96
96
24
24
95
63
50
40
68
85
98
ꢁ34
ꢁ77
ꢁ70
90
6a
6b
6c
1
1
90
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
HPLC on a Daicel Chiralpak AD-H (see ESI for details).
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo,
Japan. E-mail: hsmt@pharm.hokduai.ac.jp,
anada@pharm.hokudai.ac.jp; Fax: +81 11 706 4981;
Tel: +81 11 706 3236
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc32876c
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6969–6971 6969

(c, 1.03, CHCl3) for 98% ee] was assigned as 2S,6S by its
transformation (HCl, MeOH)3a to the known methyl 3-hydroxy-
3-phenylpropanoate [[a]2D2 ꢁ51.6 (c, 0.95, CHCl3); lit.,12
[a]2D0 +46.9 (c, 1.2, CHCl3) for (R)-enantiomer]. In the present
reaction, the 1H NMR spectrum of the crude reaction mixture
obtained prior to methanolysis revealed the exclusive
formation of 2,6-cis-dihydro-1,3-oxazine 4a (SiR3 = TBS).
This result suggests that Rh2(S-BPTPI)4-catalyzed cyclo-
addition with 2-azadiene 2a proceeds through the same con-
certed [4+2] mechanism in an endo mode as those with
Danishefsky-type dienes11a and Rawal’s diene11d (vide infra).6
A survey of solvents revealed that dichloromethane was the
optimal solvent for this transformation.13 We next evaluated
the performance of chiral dirhodium(II) carboxylates,
Rh2(S-PTTL)4 (6a),14 Rh2(S-TFPTTL)4 (6b),15 and
Rh2(S-TCPTTL)4 (6c) (entries 2–4).16 Compared with the
catalysis with Rh2(S-BPTPI)4, the use of these catalysts
required significantly longer reaction times to reach comple-
tion and substantially diminished the product yields because of
competitive degradation of 2a. Although perfect endo diastereo-
selectivity was observed in every case, cycloadditions with
6a–6c brought about a reversal in enantioselection to give
(2R,6R)-cis-1,3-oxazinan-4-one ent-5a with 34–77% ee.
Clearly, Rh2(S-BPTPI)4 (1) proved to be the catalyst of choice
for the HDA reaction in terms of the rate and product yield as
well as enantioselectivity.17,18 We also examined the effect of
silicon substituents of 2-azadienes 2a–2c on enantioselectivity.
Variation in the silyl group revealed that the tert-butyl-
dimethylsilyl functionality was optimal for this process
(entries 1 vs. 5 and 6).
Table 2 Asymmetric HDA reaction between 2-aza-3-siloxy-1,3-
butadines and aldehydes 3 catalyzed by Rh2(S-BPTPI)4 (1)a
Diene Aldehyde
Product
T/1C t/h
Yieldb (%) eec (%)
R1
R2
Entry
1
2
3
4
5
6
7
8
2a H
3b 4-NO2C6H4
3c 4-CF3C6H4
3d 4-MsOC6H4
3e 4-ClC6H4
3f 4-MeC6H4
3g 3-MeC6H4
3h 3-ClC6H4
3i 4-MeOC6H4
3j C6H5CRC
3k nC5H11CRC
3l BnOCH2
3m 2-furyl
3n 2-thienyl
3o (E)-PhCHQCH 23
3p PhCH2CH2
3q nC3H7
0
23
23
23
23
23
23
30
0
0
0
23
23
12 5b 98
7 5c 96
91
94
90
94
96
92d
92
92
95
96
97
95
96
96
92d
93
91
92
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
2a H
24 5d 97
16 5e 93
48 5f 97
48 5g 84
16 5h 92
48 5i 64
3 5j 99
9
10
11
12
13
14
15
16
17
18
8 5k 94
12 5l 86
24 5m 93
48 5n 81
48 5o 88
48 5p 95
12 5q 92
10 5r 95
36 5s 89
23
23
0
2d CH3 3j C6H5CRC
2d CH3 3k nC5H11CRC
0
a
All reactions were performed on a 0.3 mmol scale (0.5 M) with
b
1.5 equivalents of 3. Yields of isolated product 5. Determined by
d
HPLC unless otherwise stated (see ESI for details). Determined by
c
HPLC after conversion to the corresponding b-hydroxy methyl ester
(see ESI for details).
With optimized conditions in hand, we then investigated the
scope of the reaction with respect to the aldehyde component
(Table 2). High yields and enantioselectivities were consis-
tently observed with aromatic aldehydes bearing a methyl
group or electron-withdrawing groups at the para or meta
position on the benzene ring (90–96% ee, entries 1–7). A high
enantioselectivity (92% ee) was maintained with electron-rich
p-anisaldehyde (3i), though a marked drop in product yield
was observed owing to the decreased reactivity of 3i (entry 8).
The use of highly reactive aldehydes such as a,b-acetylenic
aldehydes 3j,k and benzyloxyacetaldehyde (3l) afforded the
corresponding HDA adducts 5j–l in high yields and with high
levels of asymmetric induction when the reactions were con-
ducted at 0 1C (95–97% ee, entries 9–11). 2-Furfural (3m),
2-thiophenecarbaldehyde (3n), trans-cinnamaldehyde (3o) and
straight-chain aliphatic aldehydes 3p,q were also effective
dienophiles for this reaction (92–96% ee, entries 12–16). We
next explored the possibility of using 4-methyl substituted
2-azadiene 2d. Although the scope of the reaction is limited
to a,b-acetylenic aldehydes, the HDA reaction with 2d produced
all-cis 1,3-oxazinan-4-ones 5r,s as the sole products in high
yields and with high levels of enantioselectivity (91 and
92% ee, entries 16, 17). These results confirmed the exclusive
preference for a concerted HDA mechanism in an endo mode.
To illustrate the utility of the present catalytic protocol, we
conducted an asymmetric synthesis of syn-b-hydroxy-a-methyl
amide 7, the amide terminus of F-ATPase inhibitor cruentaren A
(Scheme 1).20 The HDA reaction between 2d and 2-butynal
(3r) with the use of 1 mol% of Rh2(R-BPTPI)4 (8) proceeded
uneventfully at ꢁ10 1C to give, after methanolysis, all-cis-1,3-
oxazinan-4-one 5t in 91% yield with 93% ee. Catalytic hydro-
genation of the triple bond followed by N-allylation and
hydrolysis furnished 7 as a single syn-isomer in 82% yield.
The observed sense of asymmetric induction (approach of 2
from the less hindered Si-face of the aldehyde in an endo
mode) is consistent with the proposed model for HDA reactions
catalyzed by Rh2(S-BPTPI)4,11a,b,d which contains a hydrogen
bond between the formyl hydrogen atom and the carbox-
amidate oxygen atom in the rhodium catalyst–aldehyde
complex (Fig. 1).21
In summary, we have developed the first catalytic asymmetric
HDA reaction between 2-aza-3-silyloxy-1,3-butadienes and
aldehydes. The cycloaddition reaction catalyzed by 1 mol%
of Rh2(S-BPTPI)4 proceeded exclusively in an endo mode to
give, after methanolysis, all-cis-substituted 1,3-oxazinan-4-
ones in high yields and with high levels of enantioselectivity
Scheme 1 Synthesis of syn-b-hydroxy-a-methyl amide 7.
c
6970 Chem. Commun., 2012, 48, 6969–6971
This journal is The Royal Society of Chemistry 2012

6 For a theoretical study on the BF3ꢀOEt2-promoted HDA reaction
between 2-aza-3-silyloxy-1,3-butadiene and formaldehyde, see:
A. Bongini and M. Panunzio, Eur. J. Org. Chem., 2006, 972–977.
7 Panunzio and co-workers reported that the HDA reaction between
2-aza-3-siloxydienes and aromatic aldehydes in the presence of
5 mol% of Eu(fod)3 or Yt(fod)3 (fod = 6,6,7,7,8,8,8-heptafluoro-
2,2-dimethyl-3,5-octanedionate) under microwave heating gave
1,3-oxazinan-4-ones in good yields and with modest diastereo-
selectivities. See ref. 4b.
8 (a) M. P. Doyle, I. M. Phillips and W. Hu, J. Am. Chem. Soc.,
2001, 123, 5366–5367; (b) M. P. Doyle, M. Valenzuela and
P. Huang, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5391–5395;
(c) M. Valenzuela, M. P. Doyle, C. Hedberg, W. Hu and
A. Holmstrom, Synlett, 2004, 2425–2428; (d) X. Wang, Z. Li and
M. P. Doyle, Chem. Commun., 2009, 5612–5614.
Fig. 1 Plausible stereochemical course.
9 For the [2+2]-cycloaddition reaction of (trimethylsilyl)ketene with
ethyl glyoxylate, see: R. E. Forslund, J. Cain, J. Colyer and
M. P. Doyle, Adv. Synth. Catal., 2005, 347, 87–92.
(up to 98% ee). Using this catalytic protocol, we developed a
novel approach to syn-b-hydroxy-a-methyl amide terminus of
cruentaren A. Further application of this method to catalytic
asymmetric synthesis of biologically active natural products is
currently in progress.
10 For the effective use of chiral cationic dirhodium(II,III) carbox-
amidate complexes in asymmetric Lewis acid catalysis, see:
(a) Y. Wang, J. Wolf, P. Zavalij and M. P. Doyle, Angew. Chem.,
Int. Ed., 2008, 47, 1439–1442; (b) X. Wang, C. Weigl and
M. P. Doyle, J. Am. Chem. Soc., 2011, 133, 9572–9579.
11 (a) M. Anada, T. Washio, N. Shimada, S. Kitagaki, M. Nakajima,
M. Shiro and S. Hashimoto, Angew. Chem., Int. Ed., 2004, 43,
2665–2668; (b) T. Washio, R. Yamaguchi, T. Abe, H. Nambu,
M. Anada and S. Hashimoto, Tetrahedron, 2007, 63, 12037–12046;
(c) T. Washio, H. Nambu, M. Anada and S. Hashimoto, Tetra-
hedron: Asymmetry, 2007, 18, 2606–2612; (d) Y. Watanabe,
T. Washio, N. Shimada, M. Anada and S. Hashimoto, Chem.
Commun., 2009, 7294–7296; (e) M. Anada, T. Washio,
Y. Watanabe, K. Takeda and S. Hashimoto, Eur. J. Org. Chem.,
2010, 6850–6854.
This research was supported, in part, by a Grant-in Aid for
Scientific Research on Innovative Areas ‘‘Organic Synthesis
Based on Reaction Integration’’ (No. 2105) from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan. We thank Ms. S. Oka, and M. Kiuchi of the Center
for Instrumental Analysis at Hokkaido University for technical
assistance in the MS and elemental analyses.
12 C. Xu and C. Yuan, Tetrahedron, 2005, 61, 2169–2186.
13 The product yields and enantioselectivities obtained with other
solvents are as follows: acetone, 12 h, 89% yield, 89% ee; toluene,
24 h, 86% yield, 45% ee; diethyl ether, 48 h, 87% yield, 63% ee.
14 K. Takeda, T. Oohara, M. Anada, H. Nambu and S. Hashimoto,
Angew. Chem., Int. Ed., 2010, 49, 6979–6983, and references cited
therein.
15 M. Anada, M. Tanaka, T. Washio, M. Yamawaki, T. Abe and
S. Hashimoto, Org. Lett., 2007, 9, 4559–4562, and references cited
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Notes and references
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2 For reviews on [4+2] cycloaddition using 2-azadienes, see:
(a) D. Boger and S. M. Weinreb, Hetero Diels–Alder Methodology
in Organic Chemistry, Academic Press, San Diego, 1987,
16 N. Shimada, T. Oohara, J. Krishnamurthi, H. Nambu and
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´
S. Fustero, Synlett, 1990, 129–138; (c) D. Boger, in Comprehensive
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17 The reaction between 2a and 3a at room temperature in the
presence of chiral bis(oxazoline)copper(II) complex, which has
previously been shown to be an effective catalyst for the asym-
metric Diels–Alder reaction between 2-aza-3-silyloxy-1,3-buta-
dienes and 3-(2-alkenoyl)-1,3-oxazolidin-2-ones, led to a complex
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18 The reaction of 2a with 3a at room temperature using 1 mol% of
Rh2(pfb)4 (pfb = perfluorobutyrate) went to completion in 48 h
and gave 5a as the sole product in 64% yield, while Rh(II)
complexes such as Rh2(OAc)4, Rh2(tpa)4,19 Rh2(piv)4, Rh2(oct)4
and Rh2(cap)4 (tpa = triphenylacetate, piv = pivalate, oct =
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¨
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6969–6971 6971