An efficient one-pot asymmetric synthesis of biaryl compounds via Diels-Alder/retro-Diels-alder cascade reactions

Article abstract of DOI:10.1021/ol063013b

(Chemical Equation Presented) A single-step chirality transfer method for the synthesis of axially chiral biaryl compounds by construction of the second aromatic ring via a Diels-Alder/retro-Diels Alder cascade reaction is reported. This methodology shoul

Full text of DOI:10.1021/ol063013b

ORGANIC
LETTERS
2007
Vol. 9, No. 5
805-808
An Efficient One-Pot Asymmetric
Synthesis of Biaryl Compounds via
Diels−Alder/Retro-Diels−Alder Cascade
Reactions
Yongxiang Liu, Kui Lu, Mingji Dai,† Kai Wang, Wanqing Wu, Jiahua Chen,*
Junmin Quan,* and Zhen Yang*
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education and Beijing National Laboratory for Molecular Science (BNLMS),
College of Chemistry, Laboratory of Chemical Genomics, Shenzhen Graduate School,
and the State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Science, Peking UniVersity, Beijing 100871, China
zyang@pku.edu.cn
Received December 13, 2006
ABSTRACT
A single-step chirality transfer method for the synthesis of axially chiral biaryl compounds by construction of the second aromatic ring via
a Diels Alder/retro-Diels Alder cascade reaction is reported. This methodology should find broad application in the synthesis of natural
−
−
products and asymmetric catalysts.
Axially chiral compounds are of great importance because
of their decisive roles in governing the pharmacological
properties of bioactive molecules1 and controlling the cata-
lytic outcomes in ligand-mediated asymmetric synthesis.2
Various synthetic methods have been exploited to make
chiral biaryls,3 which can be strategically divided into three
categories: (a) resolution or desymmetrization of stereochem-
icially undefined biaryls,4 (b) direct atroposelective biaryl
coupling,5 and (c) atroposelective biaryl synthesis by con-
struction of the second aromatic ring.6
(1) (a) Nicolaou, K. C.; Boddy, C. N. C.; Bra´se, S.; Winssinger, N.
Angew. Chem., Int. Ed. 1999, 38, 2096. (b) Bringmann, G.; Menche, D.;
Bezabih, M.; Abegaz, B. M.; Kaminsky, R. Planta Med. 1999, 65, 757. (c)
Hubbard, B. K.; Walsh, C. T. Angew. Chem., Int. Ed. 2003, 42, 730. (d)
Kuroda, M.; Mimaki, Y.; Sakagami, H.; Sashida, Y. J. Nat. Prod. 2003,
66, 894. (e) Mutanyatta, J.; Bezabih, M.; Abegaz, B. M.; Dreyer, M.; Brun,
R.; Kocher, N.; Bringmann, G. Tetrahedron 2005, 61, 8475.
(2) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; VCH:
Weinheim, 2000. (b) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23,
345. (c) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809.
† Current address: Department of Chemistry, Columbia University, New
York, NY.
10.1021/ol063013b CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/01/2007

The third category has emerged recently and generally
needs multiple steps to achieve chirality transfer. Recently,
syntheses of biaryl skeleton-based natural products and
ligands via Diels-Alder reaction have grown rapidly.7
However, no asymmetric version has been reported so far.
Herein, we wish to communicate a single-step chirality
transfer method for the synthesis of axially chiral biaryl
compounds by construction of the second aromatic ring Via
Diels-Alder/retro-Diels-Alder cascade reactions,8 which
should find broad application in the synthesis of natural
products and asymmetric catalysts.
from the chiral diene A to axial biaryl compound E. The
key point in driving the conversion of C/D to E/F is the
aromatization by fragmentation to give conjugated diene G
instead of an alkyne (see later computational discussions).
It is worthwhile to mention that, in addition to the facile
aromatization, the existing isopropenyl group at C3 of
substrate A might provide an intrinsic instability in the
bicyclic intermediate C, which would drive the retro-Diels-
Alder reaction to the formation of G, rather than the reverse
Diels-Alder reaction to starting materials A and B.
With the above in mind, we synthesized electron-rich
dienes9 1a-i from (R)-(-)-carvone (see the Supporting Infor-
mation) and reacted them with dimethyl diacetylenedicar-
boxylate (DMAD) under microwave (MW) conditions to get
the corresponding biaryl compounds listed in Table 1.
As shown in Scheme 1, the bicyclic intermediates C and
D could be derived from cycloaddition of chiral diene A
Scheme 1. Formation of Axially Chiral Biaryl Molecules via
the Diels-Alder/retro-Diels-Alder Cascade Reactions
Table 1. Asymmetric Synthesis of Biaryl Compoundsa
and dienophile B. With regard to the regiochemistry being
controlled largely by the nature of electron-rich oxygenated
diene9 A and electron-deficient dienophile B, we envisioned
that intermediate C would be formed predominately, in light
of there being less steric interactions between Ha and Hb,
Hc than those between R1 and Hb, Hc in intermediate D.
We also envisaged that, once formed, intermediate C
would undergo a facile retro-Diels-Alder reaction, consider-
ing its congested nature, to give the axially chiral biaryl E
and 2-methyl-1,3-butadiene G, realizing the chirality transfer
(3) For representative reviews, see: (a) Kamikawa, K.; Uemura, M.
Synlett 2000, 938. (b) Lloyd-Williams, P.; Giralt, E. Chem. Soc. ReV. 2001,
30, 145. (c) Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615.
(d) Baudoin, O. Eur. J. Org. Chem. 2005, 4223. (e) Bringmann, G.; Price
Mortimer, A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M.
Angew. Chem., Int. Ed. 2005, 44, 5384.
(4) (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495. (b) Harada, T.; Tuyet, T.
M. T.; Oku, A. Org. Lett. 2000, 2, 1319. (c) Ku, Y. Y.; Grieme, T.; Raje,
P.; Sharma, P.; King, S. A.; Morton, H. E. J. Am. Chem. Soc. 2002, 124,
4282. (d) Bringmann, G.; Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.;
Kamikawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31. (e)
Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003, 68, 9517.
(5) (a) Miyano, S.; Tobita, M.; Hashimoto, H. Bull. Chem. Soc. Jpn.
1981, 54, 3522. (b) Wilson, J. M.; Cram, D. J. J. Am. Chem. Soc. 1982,
104, 881. (c) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F. J. Am.
Chem. Soc. 1993, 115, 9276. (d) Uemura, M.; Kamikawa, K. J. Chem. Soc.
Chem. Commun. 1994, 2697. (e) Yin, J.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 12051. (f) Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett.
2001, 3, 1137. (g) Meyers, A. I.; Nelson, T. D.; Moorlag, H.; Rawson, D.
J.; Meier, A. Tetrahedron 2004, 60, 4459.
a Reagents and conditions: Reactions were run in a sealed tube with
diene (1.0 mmol) and DMAD (2.0 mL) using a Biotage initiator microwave
synthesizer under the conditions described in the Supporting Information.
b Isolated yield. c Chiral HPLC. d Recrystallized yield in parentheses.
Accordingly, all reactions went to completion within 5 min
under MW irradiation at 140 °C to give products 2a-2i in a
range of 65-84% yields with modest ee values (64-74%),
806
Org. Lett., Vol. 9, No. 5, 2007

except entry 9, in which only 16% ee was obtained.
Prolonged reaction times did not improve the yields in all
cases.
to formation of biaryls with Ra and Sa configurations,
respectively. The computed free energy of activation for the
Diels-Alder cycloaddition (TS1) is about 10 kcal/mol higher
than TS2 for the retro-Diels-Alder reaction which re-
leases the 2-methyl-1,3-butadiene, indicating that the first
step is rate-determining. Calculations indicate that, in both
reactions of entries 4 and 9, TS1 (Ra) is ca. 2 kcal/mol
higher than TS1 (Sa), suggesting that formation of intermedi-
ate with Sa configuration is favored in the first step. How-
ever, before going forward to the final product, the Sa
configuration intermediate would shift to more stable Ra
configuration due to relatively lower transition barrier. This
is consistent with our early analysis. Therefore, formation
of biaryls with Ra configuration is dominant. This preference
of TS1 (Sa) over TS1 (Ra) is due to the steric repulsion
between R1 and the dienophile in TS1 for the Ra pathway,
as shown in Figure 2. The fact that Int (Ra) is more stable
than Int(Sa) can be understood by the early analysis of
Scheme 1.
We then carried out the reactions at 80 °C, for 1 h, which
gave relatively lower yields (56-80%) as compared with
those obtained at 140 °C. However, the atroposelectivity
improved (64-80% ee) at the lower temperature, especially
in the case of entry 9, for which the ee value increased from
16% to 71%. We speculated that the lower atroposelectivity
at the higher temperature might be caused by biaryl rotation.
In order to clarify the observation, product 2i with 71%
ee was heated at 140 °C for 10 min under MW irraditation;
as expected, the ee value of 2i dropped to ca. 3%, indicating
that biaryl compound 2i, with a methoxy group at its ortho
position, easily rotated to cause the racemization.
To understand the outcome of enantioselectivity in the
present cascade reactions, DFT calculations (B3LYP/
6-31G)10 were performed to elucidate the mechanistic details
of reactions in entries 4 and 9 (Figure 1).
Figure 2. Computed transition-state structures of Ra and Sa
pathways for the Diels-Alder cycloaddition step of entry 9
(distances in Å). The steric interaction between the substituent R1
and the dienophile is indicated by the double arrows.
Rotation of biaryls leads to racemization, which would
reduce enantioselectivity. Therefore, it is critical to know
the rotation barrier for the products. For the small substituent,
R1 ) MeO, the calculated barrier between Ra and Sa products
is 32.8 kcal/mol, which is close to that of TS1; therefore,
the rotation/racemization would occur at high temperature,
as observed in our experiment. For the large substituent, R1
) Cl, the calculated rotation barrier between Ra and Sa
Figure 1. Mechanistic elucidation. The schematic free energy
profile and the transition state structures and intermediates for the
Diels-Alder/retro-Diels-Alder cascade reactions of entries 4 and
9. The inset is the transition barrier for the interconversion between
the intermediates.
(7) (a) Reed, J. A.; Schilling, C. L.; Tarvin, R. F.; Rettig, T. A.; Stille,
J. K. J. Org. Chem. 1969, 34, 2188. (b) McDonald, E.; Suksamrarn, A.;
Wylie, R. D. J. Chem. Soc. Perkin Trans. 1 1979, 1893. (c) Boger, D. L.;
Panek, J. S. J. Am. Chem. Soc. 1985, 107, 5745. (d) Sain, B.; Sandhu, J. S.
J. Org. Chem. 1990, 55, 2545. (e) D’Auria, M. Tetrahedron Lett. 1995,
36, 6567. (f) BalR´zo´, L.; KR´das, I.; To˜ke, L. Tetrahedron Lett. 2000, 41,
7583. (g) Hilt, G.; Smolko, K. I. Synthesis 2002, 686. (h) Baran, P. S.;
Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908. (i) Ashburn, B. O.; Carter,
R. G. Angew. Chem., Int. Ed. 2006, 45, 6737.
(8) (a) Alder, K.; Rickert, H. F. Ann. 1936, 524, 180. (b) Rubottom, G.
M.; Krueger, D. S. Tetrahedron Lett. 1977, 18, 611. (c) Yang, Z.-Q.;
Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602. (d) Yang, Z.-Q.;
Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 7881.
We speculated that each reaction in Figure 1 has two
competitive pathways, labeled as Ra and Sa pathways, leading
(6) (a) Bao, J.; Wulff, W. D.; Fumo, M. J.; Grant, E. B.; Heller, D. P.;
Whitcomb, M. C.; Yeung, S.-M. J. Am. Chem. Soc. 1996, 118, 2166. (b)
Hattori, T.; Date, M.; Sakurai, K.; Morohashi, N.; Kosugi, H.; Miyano, S.
Tetrahedron Lett. 2001, 42, 8035. (c) Vorogushin, A. V.; Wulff, W. D.;
Hansen, H.-J. J. Am. Chem. Soc. 2002, 124, 6512. (d) Gutnov, A.; Heller,
B.; Fischer, C.; Drexler, H.-J.; Spannenberg, A.; Sundermann, B.; Sunder-
mann, C. Angew. Chem., Int. Ed. 2004, 43, 3795. (e) Nishii, Y.; Wakasugi,
K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358. (f) Shibata,
T.; Fujimoto, T.; Yokota, K.; Takagi, K. J. Am. Chem. Soc. 2004, 126,
8382.
(9) (a) Kahn, S. D.; Pau, C. F.; Overman, L. E.; Hehre, W. J. J. Am.
Chem. Soc. 1986, 108, 7381. (b) Danishefsky, S. Tetrahedron 1997, 53,
8689.
Org. Lett., Vol. 9, No. 5, 2007
807

products is 39.4 kcal/mol, about 7 kcal/mol higher than TS1,
so the final product is stable, even at 140 °C. Therefore, the
substituent R1 not only exerts its influence on the pathway
for the Diels-Alder/retro-Diels-Alder cascade reactions, but
also on the stability of the final product.
In conclusion, we have demonstrated a direct and atro-
poisomer-selective synthesis of axially chiral birayl com-
pounds based on the MW-assisted Diels-Alder/retro-Diels-
Alder reactions, and applied it to synthesize a series of biaryl
compounds with good yields and moderate ee. Currently,
we are working on growing crystals for X-ray studies of their
absolute stereochemistry and on improving efficiency and
the asymmetric induction of the reactions by evaluating the
steric and electronic effects of substituents of our dienes.
(10) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma,
K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.;
Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.;
Pople, J. A. Gaussian 03; Revision B.05 ed. Gaussian, Inc: Pittsburgh,
PA, 2003.
Acknowledgment. This work is supported by grants from
the National Science Foundation of China (20325208,
20225318, and 20521202).
Supporting Information Available: Experimental (in-
cluding spectra) and calculation (including coordinates)
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL063013B
808
Org. Lett., Vol. 9, No. 5, 2007