Highly enantioselective Diels Alder reactions of Danishefsky type dienes with electron-deficient alkenes catalyzed by Yb(III)-BINAMIDE complexes

Article abstract of DOI:10.1021/ja804430n

1-Methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky-s diene) is recognized as a synthetically useful diene due to its high reactivity in the Diels-Alder reaction with electron-deficient alkenes to give oxygen-functionalyzed cyclohexenes and substituted cyclohexenones, which are important building blocks for the total synthesis of natural products. However, the development of catalytic enantioselective versions of Diels-Alder reactions using Danishefsky type dienes with electron-deficient alkenes has been difficult because of the instability of the dienes under Lewis acidic conditions. Only highly reactive C=O and C=N double bonds are employed in a hetero-Diels-Alder reaction which proceeds under catalysis of chiral Lewis acids. We have developed a new chiral ligand, BINAMIDE, which is easily prepared from 1,1′-binaphtyl-2,2′-diamine by acylation. The highly diastereo- and enantioselective Diels-Alder reaction of Danishefsky type dienes with electron-deficient alkenes in the presence of an Yb(III)-BINAMIDE complex has been developed. The reaction proceeded in an exoselective mode and gave chiral highly functionalized cyclohexene derivatives in good yields. Copyright

Full text of DOI:10.1021/ja804430n

Published on Web 08/30/2008
Highly Enantioselective Diels-Alder Reactions of Danishefsky Type Dienes
with Electron-Deficient Alkenes Catalyzed by Yb(III)-BINAMIDE Complexes
Yukinori Sudo, Daisuke Shirasaki, Shinji Harada, and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received June 17, 2008; E-mail: nishida@p.chiba-u.ac.jp
1-Methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky’s diene)
1a was first introduced to organic synthesis by Danishefsky and
Kitahara in 19741 and is recognized as a synthetically useful diene
due to its high reactivity in the Diels-Alder (DA) reaction with
electron-deficient alkenes to give oxygen-functionalyzed cyclo-
hexenes.2 Upon treatment with acids, the cycloadducts can be
converted to substituted cyclohexenones, which are important
building blocks for the total synthesis of natural products.3,4
However, the development of catalytic enantioselective versions
of DA reactions through the use of Danishefsky type dienes with
electron-deficient alkenes has been difficult because of the instability
of the dienes under Lewis acidic conditions.5-7 Inokuchi et al.
recently reported that lanthanide salts were effective catalysts for
the DA reaction with Danishefsky’s dienes.8 Based on their results,
we surmised that chiral Yb(III)-BINAMIDE complexes, which are
Figure 1. Asymmetric Diels-Alder reaction of Danishefsky type dienes
catalyzed by an Yb(III)-BINAMIDE complex.
prepared from Yb(OTf)3, BINAMIDE, and amines,9 may be
effective catalysts for enantioselective DA reactions (Figure 1). We
report here the highly diastereo- and enantioselective DA reaction
Scheme 1a, b
of Danishefsky type dienes with electron-deficient alkenes in the
presence of an Yb(III)-BINAMIDE complex.
We first investigated the asymmetric DA reaction of TBSoxy-
diene 1b with dienophile 2a (Scheme 1). In the presence of 10
mol% of the Yb(III)-BINAMIDE complex, prepared from
Yb(OTf)3, BINAMIDE 3b, and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), a mixture of dienophile 2a and diene 1b (3 equiv) was
stirred at 0 °C for 4 h to give cycloadduct 4a as a single
diastereomer quantitatively. The product was assigned to be an exo
a Chiral Yb complex [Yb(OTf)3/3b/DBU ) 1:1.2:2.4], 10 mol%, CH2Cl2,
0 °C, 4 h (98%). b TFA/ClCH2CH2Cl (1:50), 60 °C, 0.5 h (quant, 91% ee).
adduct based on the results of an extensive NMR study and X-ray
analysis after chemical conversion.10,11 This diastereoselectivity is
in sharp contrast to the original reaction with acrylate and also to
Rawal’s asymmetric DA reaction using 1-amino-3-siloxybutadienes
catalyzed by Cr(III)-salen complexes, in which endo adducts are
exclusively obtained.7 Acid treatment of 4a gave substituted
cyclohexenone 5a quantitatively. The enantiomeric excess of 5a
was determined to be 91% ee by HPLC analysis.12
Table 1. Ligand Effect on Asymmetric Diels-Alder Reaction of
Danishefsky Type Diene
catalyst
(mol%)
1b
(equiv)
time
(h)
5aa
(%)
eeb
(%)
entry
ligand
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3g
3h
10
10
10
10
10
10
10
10
5
3
3
3
3
3
3
2
2
2
2
24
4
4
4
4
24
4
4
5
24
84
98
90
quant
quant
48
93
quant
94
63
91
84
87
89
2
92
94
94
85
The effects of ligand modification on the DA reaction are
summarized in Table 1. 4-Bromobenzoyl ligand 3b showed higher
reactivity and selectivity than unsubstituted benzoyl-type ligand 3a
(entry 1 vs 2). Ligands with electron-withdrawing groups at the
3-positions of the benzoyl moiety (3c-e) gave better results, and
the enantiomeric excess was improved to 89% ee (entries 3-5).
On the other hand, 2-bromobenzoyl ligand 3f gave an almost
racemic product (entry 6). Among the ligands tested, BINAMIDE
ligands possessing two electron-withdrawing groups at the 3- and
5-positions of the benzene ring (3g and 3h) gave excellent
selectivities (up to 94% ee), even with a smaller amount of the
diene (entries 7 and 8). Furthermore, in the case of 3,5-difluo-
robenzoyl ligand 3g, both the reactivity and selectivity were
maintained even when catalyst loading was decreased to 5 mol%
(entry 9).
5
89
a Yields of products after purification. b Determined by HPLC analysis.
Under these optimized conditions, asymmetric DA reactions by
a combination of dienophiles 2a-i with Danishefsky type dienes
1a-c were tested. The results are summarized in Table 2. We first
examined the effect of the size of the substituents R on the
dienophiles (entries 2-8). In the reaction of acryloyl imide (R )
H), enantioselectivity was lowered and diene 1c, which has a large
9
12588 J. AM. CHEM. SOC. 2008, 130, 12588–12589
10.1021/ja804430n CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope and Limitations of Asymmetric Diels-Alder
In summary, we have developed a highly diastereo- and
enantioselective DA reaction of Danishefsky type dienes with
electron-deficient alkenes catalyzed by Yb(III)-BINAMIDE com-
plexes. The reaction gives a variety of chiral cyclohexenes and
cyclohexenones. Apparent (+)-nonlinear effects between asym-
metric induction and the enantiomeric composition of BINAMIDE
3g may suggest the possible formation of a reservoir of nonreactive
aggregates.14 Further studies to elucidate the precise catalyst
structure and to apply this reaction to the synthesis of biologically
active compounds are in progress.15
Reaction Using Danishefsky Type Diene
temp
(°C)
time
(h)
producta
(%)
eeb
(%)
entry
dienophile
diene (Si)
1c
2
3
4
5
6
7
8
9
2a (R ) Me)
2b (R ) H)
1b (TBS)
1b (TBS)
1a (TMS)
1c (TIPS) -20
1b (TBS)
1b (TBS)
1a (TMS) rt
1a (TMS) rt
1b (TBS)
0
0
0
5
4
3
3
6
26
5
27
24
4
5a (94) 94
5b (91) 45
5b (89) 41
5b (93) 71
5c (93) 97
5d (43) 56
5d (88) 87
5e (29) 56
5f (79) 88
5g (96) 94
5h (97) 89
5i (93) 92
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
2b (R ) H)
2b (R ) H)
2c (R ) n-Pr)
2d (R ) iBu)
2d (R ) iBu)
2e (R ) iPr)
2f (R ) ClCH2)
rt
rt
1
Supporting Information Available: Experimental details and H
and 13C NMR spectra of new compounds. This material is available
free of charge via the Internet at http//pubs.acs.org.
0
rt
0
0
10
11
12d
2g (R ) Ph(CH2)2) 1b (TBS)
2h (R ) BnOCH2)
2i (R ) MeO2C)
1b (TBS)
1a (TMS)
24
2
References
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Kettschau, K. Top. Curr. Chem. 1997, 189, 1.
a Yields of products after purification. b Determined by HPLC
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Scheme 2a, b, c, d, e
(4) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004, 43,
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(b) Akullian, L. C.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
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Int. Ed. 1998, 37, 979. (b) Yao, S.; Johannsen, M.; Hazell, R. G.; Jøgensen,
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(7) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2000, 122, 7843.
(8) (a) Inokuchi, T.; Okano, M.; Miyamoto, T.; Madon, H. B.; Takagi, M.
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(10) Determined by X-ray analysis of compound 7. See Supporting Information.
(11) When the reaction was carried out in the presence of 25 mol% of an achiral
Yb(OTf)3-iPr2NEt complex, the exo adduct 4a was obtained exclusively
in 63% yield. Thus, the exo selectivity should originate from substrate
control. Even when the reaction was carried out at 100 °C without any
catalyst, a mixture of diastereoisomers was obtained (exo/endo ) 3:2). The
presence of an oxazolidinone unit in the structure of dienophiles is essential
for high enantiomeric induction. Results obtained using other chiral ligands
with Yb(OTf)3 are shown in the Supporting Information.
a F3C(F2C)3SO2F, n-Bu4NSiPh3F2, CH2Cl2, 0 °C (83%). b Pd(PPh3)2Cl2
(5 mol%), PPh3 (5 mol%), formic acid, Et3N, DMF, 65 °C (7: 88%).
c Pd(PPh3)4 (2.5 mol%), PhB(OH)2, aq. Na2CO3, DME, reflux (8: 86%).
d Pd(PPh3)2Cl2 (5 mol%), CuI (5 mol%), Et3N, phenylacetylene, DMF, rt
(9: 99%). e Pd(PPh3)2Cl2 (5 mol%), methyl acrylate, Et3N, DMF, 70 °C
(10: 71%).
TIPS group, gave the best result (entry 4). In contrast, when the
substituent was large (R ) iBu), diene 1a which has a small TMS
group, gave the best result (entry 7). The steric interactions between
the substituent of the dienophile and the silyloxy group of the diene
might be the reason for these results. However, sterically hindered
isopropyl-substituted dienophile 2e gave a poor result even when
diene 1a was used (entry 8). A variety of functional groups on the
dienophiles 2f-g (halogen, aromatic ring, ether, and ester) were
tolerable and gave the desired cyclohexenones with good to
excellent enantiomeric excesses (88-94% ee, entries 9-12).
The enantiomeric excess of cycloadduct 4a was enriched from
91% ee to 99% ee by single recrystallization from n-hexane. Next,
we turned our attention to the conversion of 4a to the nonafluo-
robutanesulfonate (nonaflate) 6, which is a useful intermediate for
various coupling reactions (Scheme 2). The fluorine-catalyzed
nonafluorobutanesulfonylation13 of 4a produced the corresponding
nonaflate 6 in 83% yield. We then used 6 for various Pd-catalyzed
couplings(Suzukicoupling,Sonogashiracoupling,andMizoroki-Heck
reaction) and obtained desired products 8-10 in yields of 71-99%.
Moreover, the nonaflate 6 could be reduced to alkene 7 by Pd-
catalyzed hydrogenolysis.
(12) The absolute stereochemistry of 5b was determined to be 4S by comparison
of the specific rotation of (S)-4-(hydroxymethyl)cyclohex-2-enone (11) with
the reported value (ref 7). The absolute stereochemistries of 5a and 5c-i
were estimated to be 4S by analogy to 5b. See Supporting Information for
details.
(13) Lyapkalo, I. M.; Webel, M.; Reiꢀig, H.-U. Eur. J. Org. Chem. 2002, 67,
1015.
(14) See Sopporting Information Girard, C.; Kagan, H. B. Angew. Chem., Int.
Ed. 1998, 37, 2922.
(15) Recently, an asymmetric Diels-Alder reaction using a Danishefsky type
diene has been reported: Ward, D. E.; Shen, J. Org. Lett. 2007, 9, 2843.
JA804430N
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