Unexpected regioselectivity in the synthesis of pyranonaphthoquinone via the diels-alder reaction

Article abstract of DOI:10.1021/ol901902v

The unusual regioselectivity In the Diels-Alder reactions of pyranoquinone 1 with (4,4-dlmethoxybuta-1,3-dlen-2-yloxy)trimethylsilane 2 are explored by both computations and experiments. The regioselectivity Is controlled by the electrostatic interaction of the lactone ring-oxygen and the vicinal quinone oxygen on the transition structure, which can be tuned by the terminal methyl group of the butadienes.

Full text of DOI:10.1021/ol901902v

ORGANIC
LETTERS
2
009
Vol. 11, No. 20
628-4631
Unexpected Regioselectivity in the
Synthesis of Pyranonaphthoquinone via
the Diels-Alder Reaction
4
†
‡
†
†
,†
,†
Yi Cui, Hao Jiang, Zhengtao Li, Na Wu, Zhen Yang,* and Junmin Quan*
Laboratory of Chemical Genomics, Shenzhen Graduate School of Peking UniVersity,
Shenzhen 518055, China, Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education and Beijing National Laboratory for Molecular
Science (BNLMS), College of Chemistry, Peking UniVersity, Beijing 100871, China,
and Institute of Traditional Chinese Medicine and Natural Products, College of
Pharmacy, Jinan UniVersity, Guangzhou 510632, China
quanjm@szpku.edu.cn; zyang@pku.edu.cn
Received August 16, 2009
ABSTRACT
The unusual regioselectivity in the Diels-Alder reactions of pyranoquinone 1 with (4,4-dimethoxybuta-1,3-dien-2-yloxy)trimethylsilane 2 are
explored by both computations and experiments. The regioselectivity is controlled by the electrostatic interaction of the lactone ring-oxygen
and the vicinal quinone oxygen on the transition structure, which can be tuned by the terminal methyl group of the butadienes.
The Diels-Alder (DA) reaction of substituted butadiene with
pyranoquinone is the key step in the synthesis of the core
structure of the pyranonaphthoquinone family, a series of
biologically important natural products such as kalafungin,
1
frenolicin B, and crisamicin A (Figure 1).
A decade ago, Kraus and co-workers synthesized pyranon-
aphthoquinone 8 via a Diels-Alder reaction with high regi-
2
oselectivity. Based on the model, Kraus suggested that the
†
College of Chemistry, Peking University, and Shenzhen Graduate
School of Peking University.
‡
Jinan University.
(1) (a) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 1655. (b) Bergy, M. E.
J. Antibiot. 1968, 21, 454. (c) Hoeksema, H.; Krueger, W. C. J. Antibiot.
1
976, 29, 704. (d) Tsukamoto, M.; Muriika, K.; Hirayama, M.; Hirano, K.;
Figure 1. Naturally occurring pyranonaphthoquinones.
Yoshida, S.; Kojiri, K.; Suda, H. J. Antibiot. 2000, 53, 26. (e) Tatsuta, K.;
Ozeki, H.; Yamaguchi, M.; Tanaka, M.; Okui, T.; Nakata, M. J. Antibiot.
1
991, 44, 901.
2) (a) Kraus, G. A.; Li, J. J. Am. Chem. Soc. 1993, 115, 5859. (b) Kraus,
G. A.; Li, J.; Gordon, M. S.; Jensen, J. H. J. Org. Chem. 1995, 60, 2254.
3) The pyranoquinone here is the enantiomer of that used in Kraus’
experiments, which is for the convenience of discussion and does not
influence the conclusion.
(
regioselectivity was dictated by the molecular geometry and
the unequal charge distribution of the dienophile induced by
the lactone ring oxygen (Scheme 1, eq 1).
(
10.1021/ol901902v CCC: $40.75
Published on Web 09/16/2009
 2009 American Chemical Society

Scheme 1. Syntheses of Pyranoquinones 8 and 11
Figure 2. B3LYP-optimized structures of the pyranoquinone.
Distances are in angstroms. Dihedral angles are in degrees. Relative
enthalpies are in kcal/mol. The axial-like and equatorial-like
conformations are defined according to their δ
like) and |δ | < 60° (equatorial-like). The puckering of quinone is
defined according to δ and δ , the deviation from the plane.
1
; |δ | > 60° (axial-
1
1
3
4
We recently finished the total synthesis of crisamicin A
4 in Figure 1), and one of the key steps is the intermolecular
4
(
Diels-Alder reaction to construct the tetracylic core structure
in 10 (Scheme 1, eq 2); compound 10 was then converted
to its triflate 11, and its structure was confirmed by X-ray
study. Interestingly, the regioselectivity for the formation of
8
and 10 is opposite to each other with regard to the terminal
substituents, which inspired us to do further investigation
for this important reaction. Herein we report our combined
efforts of both computations and experiments for study of
this important reaction and found that the substituents on
the butadiene could tune the electrostatic interaction between
the oxygen of the lactone ring and the oxygen of the vicinal
quinone on the transition structure, leading to the unusual
regioselectivity observed in our Diels-Alder reaction.
5
Calculations were carried out with the B3LYP density
functional method as implemented in the Gaussian03 suite
6
7
of programs. The 6-31G* basis set was used for C, O, and
8
H; the Lanl2dz basis set was used for Si. All the stationary
points were confirmed by the frequency calculations.
The B3LYP-optimized pyranoquinone 1 had two distinct
structures, axial-like and equatorial-like with regard to the
conformations of the methyl group on the dihydropyran ring.
The axial-like structure was more stable than the equatorial-
(
4) Li, Z.; Gao, Y.; Tang, Y.; Dai, M.; Wang, G.; Wang, Z.; Yang, Z.
Org. Lett. 2008, 10, 3017.
5) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
(
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (c) Becke, A. D. J. Chem.
Phys. 1993, 98, 1372. (d) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.;
Frisch, M. J. J. Phys. Chem. 1994, 98, 1623. (r) Hehre, W. J.; Radom, L.;
Schleyer, P. V.; Pople, J. A. Ab initio Molecular Orbital Theory; Wiley:
New York, 1986.
Figure 3. Eight different methods for the cycloaddition of pyra-
noquinone 6 with substituted dienes 7 and 9. The syn in exo-syn-
near represents diene approaches to the quinone plane from the
same face of lactone oxygen. The near in exo-syn-near indicates
that the terminal substituents are close to the side of the lactone
oxygen and away from the site of the methyl group of pyrano-
quinone. Others are defined in a similar way.
(
6) Frisch, M. J. Gaussian 03, D.02; Gaussian, Inc.; Wallingford, CT,
2
004. See the Supporting Information for the full reference.
(
7) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
5
5
2
4, 724. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972,
4, 2257. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28,
13.
(
8) (a) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. (b) Wadt,
W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284.
Org. Lett., Vol. 11, No. 20, 2009
4629

Table 1. B3LYP Enthalpies (kcal/mol) for the Endo-Syn-near
and Endo-Syn-Far TSs of Different Substituents on the
Butadienes
a
The terminal R group of entry 4 is H. The definitions for endo-syn-
near and endo-syn-far are similar to those of other R groups.
the corresponding anti TSs by about 2 kcal/mol. The syn
preference is because that the quinone ring puckering induced
by the anti attacking causes larger repulsion with the oxygen
of lactone ring. The near TSs are ∼0.7-1.6 kcal/mol less
stable than the far TSs (Table S1, Supporting Information).
The most stable two transition states are endo-syn-near and
endo-syn-far, and their activation enthalpies are 16.6 and 15.0
kcal/mol, respectively (Figure 4). This result is in agreement
with Kraus’ experimental observations in which the far
product is dominant. The preference of the far TS is the result
of electron redistribution in TS that led to larger electrostatic
repulsion in the near TS; the repulsion between oxygen of
OTMS and the lactone oxygen might also have some
contributions.
For diene 9, the syn TSs were generally more preferred
than the anti TSs; in those syn TSs, the endo TSs were more
favorable than the exo TSs. The most stable two transition
states are endo-syn-near and endo-syn-far, the activation
enthalpies of them were 13.9 and 14.9 kcal/mol, respectively
(Figure 4). This result is in consistent with our observations
in the total synthesis of crisamicin A in which the near
product is dominant.
Figure 4. Transition structures for pyranoquinones with substituted
butadienes 7 and 9. Distances are in angstroms. Activation
enthalpies are in kcal/mol. The Mulliken charges of quinone and
lactone oxygen are shown in parentheses.
like structure by ∼3.8 kcal/mol. This result is consistent with
2b
the results of Kraus’ modeling. The equatorial-like structure
was less stable due to the stronger electrostatic repulsion
between the oxygen of lactone ring and its vicinal oxygen
of quinone and the steric effect of the axial position of the
larger lactone ring (Figure 2). On the other hand, the
puckering of the quinone ring was not obvious, which
indicates that puckering of the quinone ring at the reactant
2
b
might not contribute much to the regioselectivity.
The cycloaddition could occur via eight different methods
with regard to regiochemistry and stereochemistry, and the
detailed definitions of the different methods are also found
in Figure 3.
For the diene 7, the endo transition structures (TSs) were
more preferred than the corresponding exo TSs (Hexo-endo
about 4.7 to 5.6 kcal/mol). The syn TSs are more stable than
The regioselectivity for this multisubstituted diene-based
Diels-Alder reaction could be interpreted by the existence
of hydrogen bonding between the hydrogen of the methoxy
group in diene 9 and the oxygen of the lactone in 6, which
significantly reduces the activation energy of the near TS,
leading to the unusual regioselectivity of a Diels-Alder
4630
Org. Lett., Vol. 11, No. 20, 2009

6
to form their corresponding products 15-17, respectively.
Accordingly, the diene 7 under our reaction condition gave
results identical to those of Kraus and co-workers with the
dominant far product. However, when diene 14 was applied
to the Diels-Alder reaction, two regioisomers 16 and 17
formed, and compound 17 was the major isomer (Scheme
2
), which is in good agreement with the calculations. The
structures of 16 and 17 were confirmed by HMBC experi-
ments of their NMR study, in which the correlation between
the protons and their corresponding carbonyl were observed
(Scheme 2).
Scheme 2. Syntheses of Pyranonaphthoquinones 15-17
Figure 5. Transition structures for pyranoquinone 6 with substituted
butadiene 14.
reaction. Roles of such nontraditional hydrogen bonding as
O···H(C) interactions have been also discussed in other
9
systems.
To dissect the contributions of the substituents of butadiene
on the reaction, further calculations on butadienes with
different substituents were performed. Table 1 shows the
relative enthalpies of the endo-syn-near and endo-syn-far
TSs. Entries 1-3 indicate that 4,4-dimethoxy groups make
major a contribution to the preference of the near TS and
the 2-OTMS has just minor role. Unexpectedly, entry 4 with
a monomethoxy group favors the far TS. The main reason
is because the terminal methyl group prefers trans orientation
rather than cis orientation in the TS, but the methyl group
on the trans orientation cannot form O···H(C) interactions
and stabilize the near TS (Figure 5). It is noted that the cis
orientation of the terminal methyl group is more stable in
the isolated diene.
In summary, B3LYP calculations elucidate the origin of
the regioselectivity in intermolecular Diels-Alder reactions
of substituted butadienes with pyranoquinones, which is
controlled by the electrostatic repulsion between the lactone
ring-oxygen and the vicinal quinone oxygen on the transition
structure. Shielding of this repulsion by the substituents on
the dienes can switch the regioselectivity of Diels-Alder
reactions.
Acknowledgment. Financial support from Peking Uni-
versity Shenzhen Graduate School (grant to J.Q.), the
Shenzhen municipal “Shuang Bai Project”, and the National
Science Foundation of China (Grant Nos. 20272003,
To further verify our calculations, we have synthesized
two additional dienes 7 and 14 and carried out the Diels-Alder
reactions under the conditions for the synthesis with quinone
2
0325208, and 20832003 to Z.Y.) are gratefully acknowl-
edged.
Supporting Information Available: B3LYP Cartesian
(
9) (a) Desiraju, G. R. Acc. Chem. Res. 1996, 29, 441. (b) Corey, E. J.;
Rohde, J. J.; Fisher, A.; Azimioara, M. D. Tetrahedron Lett. 1997, 38, 33.
c) Corey, E. J.; Rohde, J. J. Tetrahedron Lett. 1997, 38, 37. (d) Acevedo,
coordinates and electronic energies of all the stationary
points. Full citation for ref 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
O.; Evanseck, J. D. Org. Lett. 2003, 5, 649. (e) Bakalova, S. M.; Santos,
A. G. J. Org. Chem. 2004, 69, 8475. (f) Gordillo, R.; Dudding, T.; Anderson,
C. D.; Houk, K. N. Org. Lett. 2007, 9, 501.
OL901902V
Org. Lett., Vol. 11, No. 20, 2009
4631