Efficient generation of ortho -quinone methide: Application to the biomimetic syntheses of (±)-schefflone and tocopherol trimers

Article abstract of DOI:10.1021/ol202641y

An efficient method using silver oxide-mediated oxidation for the synthesis of ortho-quinone methides has been developed and applied to the biomimetic syntheses of novel trimeric natural products, (±)-schefflone and tocopherol trimers. Further studies of the critical trimerization as well as substrate scope and limitations are also reported.

Full text of DOI:10.1021/ol202641y

ORGANIC
LETTERS
2012
Vol. 14, No. 1
18–21
Efficient Generation of ortho-Quinone
Methide: Application to the Biomimetic
Syntheses of (()-Schefflone and
Tocopherol Trimers
Daohong Liao,† Houhua Li,‡ and Xiaoguang Lei*,†,‡
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072,
China, and National Institute of Biological Sciences (NIBS), Beijing 102206, China
leixiaoguang@nibs.ac.cn
Received September 30, 2011
ABSTRACT
An efficient method using silver oxide-mediated oxidation for the synthesis of ortho-quinone methides has been developed and applied to the
biomimetic syntheses of novel trimeric natural products, (()-schefflone and tocopherol trimers. Further studies of the critical trimerization as well
as substrate scope and limitations are also reported.
ortho-Quinone methides (o-QMs) are a class of important
and versatile synthetic intermediates, which have been broadly
utilized in the synthesis of complex natural products1 as well as
† Tianjin University.
‡ National Institute of Biological Sciences.
(1) For selected recent total syntheses using an o-QM intermediate,
see: (a) Green, J. C.; Jiminez-Alonso, S.; Brown, E. R.; Pettus, T. R. R.
Org. Lett. 2011, 13, 5500. (b) Spence, J. T. J.; George, J. H. Org. Lett.
2011, 13, 5318. (c) Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.;
Lee, V.; Kershaw, J. A.; Thompson, A. T. Org. Lett. 2010, 12, 1676. (d)
Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; De Brabander, J. K.
J. Am. Chem. Soc. 2009, 131, 11350. (e) Batsomboon, P.; Phakhodee, W.;
Ruchirawat, S.; Ploypradith, P. J. Org. Chem. 2009, 74, 4009. (f) Lumb, J. P.;
Choong, K. C.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 9230.
(2) (a) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2011, 133,
15730. (b) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2011, 133,
5573. (c) Percivalle, C.; Rosa, A. L.; Verga, D.; Doria, F.; Mella, M.;
Palumbo, M.; Antonio, M. D.; Freccero, M. J. Org. Chem. 2011, 76,
3096. (d) Arumugam, S.; Popik, V. V. J. Am. Chem. Soc. 2009, 131,
11892.
(3) For a recent review of o-QMs, see: (a) Ferreira, S. B.; Silva, F. C.;
Pinto, A. C.; Gonzaga, D. T. G.; Ferreira, V. F. J. Heterocycl. Chem.
2009, 46, 1080. (b) Van De Water, R. W.; Pettus, T. R. R. Tetrahedron
2002, 58, 5367. For recent review of biomimetic total synthesis via o-QM
intermediate, see: (c) Jackson, S. K.; Wu, K-L; Pettus, T. R. R. In
Biomimetic Organic Synthesis; Poupon, E., Nay, B., Eds.; Wiley-VCH:
Weinheim, 2011; Chapter 19.
Figure 1. Structures of Trimeric Natural Products.
the development of new bioorthogonal “click” reactions.2
Despite that many synthetic methodologies have been devel-
oped to access them, new methods for the efficient generation
of highly reactive and functionalized o-QM intermediate
under mild condition are particularly attractive.3
r
10.1021/ol202641y
Published on Web 11/02/2011
2011 American Chemical Society

(()-Schefflone 14 and tocopherol trimers 2 and 35 are
structurally complex natural products which have the
unique spiro-chroman-type trimeric skeleton (Figure 1).
Biogenetically, these natural products could be derived
from tandem hetero-DielsꢀAlder cycloadditions of the o-
QM precursors. Although hetero-DielsꢀAlder dimeriza-
tion or trimerization of o-QM was used for the synthesis of
the spiro-chroman skeleton,6 total synthesis of the trimeric
natural products directly from the monomeric o-QM inter-
mediate has rarely been reported thus far.7 Herein, we
report the biomimetic syntheses of (()-schefflone and
tocopherol trimers through silver oxide mediated o-QM
formation. Further studies of the key trimerization as well
as substrate scope and limitations are also described.
According to the biosynthetic hypothesis,4 two tandem
[4 þ 2]-hetero-DielsꢀAlder cycloadditions of the ortho-
quinone methide intermediate 4 generated from the natu-
rally occurring monomer including hydroxyespintanol 58
or espintanol 69 may be responsible for the formation of
homotrimer 1 (Scheme 1). Initial attempts to generate the
desired o-QM 4 from hydroxyespintanol 5 under either hv
or microwave conditions proved to be unsuccessful.10
Therefore, we focused on the generation of o-QM 4 via
oxidation of espintanol 6.
We first investigated a number of oxidants. As shown in
Table 1, CAN (entry 1) and DDQ (entry 2) only afforded
the byproduct quinone 7 in high yields, while K3Fe(CN)6
(entry 3) and MnO2 (entry 4) provided the desired (()-
schefflone 1 in moderate yields. Synthetic 1 was confirmed
tobe identical tonatural schefflone by 1H and 13C NMR as
well as HRMS data.11 To improve the yield, we further
examined other oxidants. Interestingly, we found that by
treating espintanol 6 with silver oxide6,12 (entry 5) in benzene
at room temperature (16 h), we could obtain trimeric (()-
schefflone 1 and dimer 8 in 72% and 8% yields, respectively.
Further reaction screening using various Ag(I) salts (entries
6ꢀ10) revealed that Ag2O was still the better oxidant for
the efficient generation of o-QM and subsquent trimer and
dimer formations. Notably, the use of AgOAc as an
oxidant (entry 9) led to the production of acetate 9 in
40% yield, which was conceivably due to the Michael
addition of the acetate anion to o-QM 4.
Table 1. Optimization of the Oxidative Trimerization
Scheme 1. Synthetic Plan for (()-Schefflone 1
yield (%)b
reagents and
entry
conditionsa
1
7
8
9
1
2
3
CAN, MeCN, 0 °C to rt, 2 h
DDQ, MeNO2, rt, 1 h
ꢀ
98
98
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
K3Fe(CN)6, Benzene/2 M NaOH,
rt, 16 h
68
4
MnO2, Benzene, rt, 16 h
Ag2O, Benzene, rt, 16 h
AgSbF6, Benzene, rt, 24 h
AgOTf, Benzene, rt, 16 h
AgNO3, Benzene, rt, 16 h
AgOAc, Benzene, rt, 16 h
Ag2CO3, Benzene, rt, 16 h
67
72
ꢀ
13
ꢀ
ꢀ
8
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
40
ꢀ
(4) Nkunya, M. H. H.; Jonker, S. A.; de Gelder, R.; Wachira, S. W.;
Kihampaa, C. Phytochemistry 2004, 65, 399.
(5) Row, L. -C.; Ho, J. C.; Chen, C. M. J. Nat. Prod. 2007, 70, 1214.
(6) (a) Moore, R. F.; Waters, W. A. J. Chem. Soc. 1954, 243.
(b) Bolon, D. A. J . Org. Chem. 1970, 35, 715.
5
6
40
90
90
30
40
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
7
ꢀ
8
ꢀ
(7) For previous syntheses of tocopherol dimers and trimers, see:
(a) Krol, E. S.; Escalante, D. D. J.; Liebler, D. C. Lipids 2001, 36, 49.
9
ꢀ
€
(b) Schroder, H.; Netscher, T. Magn. Reson. Chem. 2001, 39, 701.
10
10
(c) Yamauchi, R.; Kato, K.; Ueno, Y. Lipids 1988, 23, 779. (d) Nelan,
D. R.; Robeson, C. D. J. Am. Chem. Soc. 1962, 84, 2963.
(8) Ichimaru, M.; Nakatani, N.; Moriyasu, M.; Nishiyama, Y.; Kato,
A.; Mathenge, S. G.; Juma, F. D.; ChaloMutiso, P. B. J. Nat. Med. 2010,
64, 75.
a K3Fe(CN)6 and MnO2 were used in 3 equiv amounts, while other
reagents were used in 1.2 equiv amounts. b Yield of isolated product.
ꢀ
(9) For isolation of espintanol, see: (a) Hocquemiller, R.; Cortes, D.;
Arango, G. J.;Myint, S. H.; Cave, A.; Angelo, A.; Munoz, V.; Fournet, A.
~
To understand the mechanism of the critical trimeriza-
tion process promoted by Ag2O, we designed and con-
ducted several expriments (Scheme 2).11 First, we used
LC-MS to monitor the trimerization, which indicated
J. Nat. Prod. 1991, 54, 445. For total syntheses of espintanol, see:
ꢀ~
ꢀ
ꢀ
(b) Zuniga, A. C.; Romero-Ortega, M.; Jose G. Avila Zarraga, J. G. A.
Synthesis 2005, 4, 527. (c) Tomooka, C. S.; Liu, H.; Moore, H. W. J. Org.
€
Chem. 1996, 61, 6009. (d)Soderberg, B. C.; Fields, S. L. Org. Prep. Proced.
Int. 1996, 28, 221. (e) Wadsworth, D. J.; Losch, S. Tetrahedron 1994, 50,
ꢀ
8673. (f) Hocquemiller, R.; Cortes, D.; Arango, G. J.; Myint, S. H.; Cave,
~
A.; Angelo, A.; Munoz, V.; Fournet, A. J. Nat. Prod. 1991, 54, 445.
(11) See Supporting Information for details.
(12) (a) Jurd, L. Tetrahedron 1977, 33, 163. (b) Jurd, L.; Roitman,
J. N. Tetrahedron 1978, 34, 57. (c) Jurd, L. Aust. J. Chem. 1978, 31, 347.
(10) (a) Bharate, S. B.; Singh, I. P. Tetrahedron Lett. 2006, 47, 7021. (b)
Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am. Chem. Soc. 2002, 124, 717. Under
Singh’s condition we only obtained the hydroxyespintanol acetate 9.
Org. Lett., Vol. 14, No. 1, 2012
19

that in the first 15 min only dimer 8 was formed, and the
reaction proceeded through the formation of trimer 1
until the ratio of dimer 8 to trimer 1 was not changed
after 22 h. Second, we applied 1H NMR experiments to
study the interconversion between dimer 8 and trimer 1.
When dimer 8 was heated (benzene-d6, 60 °C, 48 h),
trimer 1 was formed; however, thermolysis of trimer 1
(benzene-d6, 60 °C, 48 h) only led to the recovered
starting material. Finally, we conducted the trapping
experiment to confirm the existence of the highly reac-
tive o-QM intermediate 4. When excessive electron-rich
dienophile ethyl vinyl ether was added into the reaction,
chroman 10 was generated in almost quantative yield
through [4 þ 2]-hetero-DielsꢀAlder cycloaddtion.13 These
studies strongly suggest that the initial formation of dimer 8
from the highly reactive o-QM intermediate 4 is rapid and
reversible, but the second [4 þ 2]-hetero-DielsꢀAlder
cycloaddtion of dimer 8 with o-QM 4 is irreversible to “lock”
the structure and thus render trimer 1 as a major product.
Table 2. Substrate Scope and Limitations
Scheme 2. Mechanistic Studies for the Trimerization
To gain insight into the substrate scope and limitations
for the Ag2O-promoted trimerization and understand the
effect of substitution on the aromatic ring to the trimeriza-
tion process, a number of phenol substrates were evaluated
under this condition (Table 2). Oxidation of 2,6-dimethyl-
phenol 11 (entry 1) which is not substituted at the para
position to phenol exclusivelyled tothe formationofbiaryl
coupled products phenol 12 and quinone 13.14 This result
indicates that substitution at the para position to phenol is
necessary for trimerization. Therefore, we decided to further
test the para-substituted substrates. When 2,4,6-trimethyl-
phenol 14 (entry 2) bearing a methyl group at the para
position was treated with Ag2O, dimer 15 was observed as a
major product through a radical coupling process, which
also confirms that the para substitution should not have R
hydrogens.6b Next, we examined the effect of an electron-
donating group at the para position. Oxidation of 2-methyl-4-
methoxylphenol 16 (entry 3) afforded a spiroketal-type trimer
17 instead of the expected [4 þ 2]-hetero-DielsꢀAlder trimer.
This result might be rationalized by the initial formation of
a Yield of isolated product. b Reaction condition: 1.2 equiv of Ag2O,
Et2O, ꢀ78 °C to rt.
a biaryl coupled bisphenol intermediate through the more
favored radical coupling process, followed by oxidative
ketalization to furnish the spiroketal motif.15 In contrast,
oxidation of 2,4-dimethoxyl-6-methylphenol 18 (entry 4)
smoothly generated the desired trimer 19 in 58% yield.
Other related substrates 20 and 22 (entries 5 and 6)
containing a methoxyl group at the para position all
yielded the desired trimers 21 and 23, respectively. How-
ever, oxidation of substrate 22 bearing only one ortho
substitution showed a much lower yield (11%) than the
di-ortho substituted substrate 20 (92%). Finally, we studied
(13) Bolon, D. A. J . Org. Chem. 1970, 35, 3666.
(14) Kneifel, H.; Poszich-Buscher, C.; Rittich, S.; Breimaier, E.
Angew. Chem., Int. Ed. 1991, 30, 202.
(15) Bowman, D. F.; Hewgill, F. R.; Kennedy, B. R. J. Chem. Soc. C
1966, 24, 2274.
20
Org. Lett., Vol. 14, No. 1, 2012

In conclusion, an efficient method using Ag2O mediated
oxidation for the generation of ortho-quinone methide has
been developed and applied to the biomimetic total synth-
eses of (()-schefflone and tocopherol trimers. Further
experiments provided mechanistic insight into the critical
[4 þ 2]-hetero-DielsꢀAlder trimerization. Studies of sub-
strate scope and limitations also showed the substitution
effects for successful trimerization. Applications of this
methodology to produce other complex natural products
are in progress and will be reported in due course.
Scheme 3. Syntheses of Tocopherol Trimers
Acknowledgment. We thank Ms. Mingyan Zhao and Ms.
Rui Liu (NIBS) for NMR and HPLC-MS analysis and Dr.
Jiang Zhou (Peking University) for HRMS analysis. Finan-
cial support from the National High Technology Projects 863
(2008AA022317), Program for New Century Excellent Ta-
lents in University (NCET-10-0614), and NSFC (20802050,
21072150) is gratefully acknowledged.
the effect of an electron-withdrawing group at the
para postion. As shown in entry 7, the oxidation of 4-acetyl-
2,6-dimethyl phenol 24 was sluggish and led to no
reaction.
Based on the results from substrate scope and limita-
tions, we envisioned that the fully substituted tocopherol
25 should be a suitable substrate for the Ag2O-mediated
trimerization. As expected, treatment of tocopherol 25
with Ag2O in benzene smoothly afforded (ꢀ)-tocopherol
trimer 2 (36%) and (þ)-tocopherol trimer 3 (37%)
(Scheme 3). All of these synthetic samples were identical to
the previously reported natural products.11
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Note Added after ASAP Publication. This article was
published ASAP on November 2, 2011. Figure 1 and
Scheme 1 have been updated. The corrected version was
posted on November 11, 2011. Scheme 3, Figure 1,
reference 7, and the Supporting Information were re-
placed on November 29, 2011.
Org. Lett., Vol. 14, No. 1, 2012
21