Asymmetric synthesis of chiral 9,10-dihydrophenanthrenes using Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols

Article abstract of DOI:10.1021/ol300770w

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel-Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydro

Full text of DOI:10.1021/ol300770w

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2350–2353
Asymmetric Synthesis of Chiral 9,10-
Dihydrophenanthrenes Using Pd-Catalyzed
Asymmetric Intramolecular FriedelÀCrafts
Allylic Alkylation of Phenols
Yuta Suzuki, Tetsuhiro Nemoto, Kazumi Kakugawa, Akinari Hamajima, and
Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana,
Chuo-ku, Chiba 260-8675, Japan
hamada@p.chiba-u.ac.jp
Received March 26, 2012
ABSTRACT
We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric
intramolecular FriedelÀCrafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene
derivatives in high yield with up to 94% ee.
Highly oxygenated 9,10-dihydrophenanthrenes are ubiq-
uitous structural motifs in biologically active natural pro-
ducts, such as cedrelins, which are cytotoxic against Sta-
phylococcus aureus (209P), Bacillus subtilis (IAM1213),
and paralycolines, which exhibit cytotoxic activity against
KB and P388 cells (Figure 1).1 In addition to the multiple
oxygen functionalities on the aromatic rings, these natural
products commonly possess an isopropenyl group at the
10-position of the 9,10-dihydrophenanthrene skeleton.
The potential for diverse biological activities, as well as
their various substitution patterns of this class of natural
products, make this structural motif an interesting syn-
thetic target. Therefore, the development of an efficient
and flexible synthetic method for multisubstituted 9,10-
dihydrophenanthrenes has attracted attention in synthetic
organic chemistry and medicinal chemistry.2
Transition-metal-catalyzed asymmetric allylic alkyla-
tionisone of the mostimportant synthetictransformations
in organic synthesis.3 Various stabilized carbon nucleo-
philes, and nitrogen, oxygen, and sulfur nucleophiles, are
applicable to this reaction process. Phenols are generally
utilized as oxygen nucleophiles in this catalytic transfor-
mation, with very few exceptions of C-allylation.4 In
contrast to the general reactivity, we recently reported that
Pd-catalyzed intramolecular allylic alkylation of para-
substituted phenol derivatives occurs on the aromatic
carbons, affording the corresponding spirocyclohexadienones
(1) (a) Ezaki, K.; Satake, M.; Kusumi, T.; Kakisawa, H. Tetrahedron
Lett. 1991, 32, 2793. (b) Monache, F. D.; Monache, G. D.; Cavalcanti,
J. F.; Pinheiro, R. M. Tetrahedron Lett. 1987, 28, 563. (c) Monache,
F. D.; Monache, G. D.; Botta, B.; Gacs-Baitz, E.; Recettori, C. C.
Heterocycles 2002, 56, 589.
(2) For recent selected examples of the synthesis of functionalized
9,10-dihydrophenanthrenes, see: (a) Pratap, R.; Ram, V. J. J. Org.
Chem. 2007, 72, 7402. (b) Zhu, C.; Shi, Y.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2008, 10, 1243. (c) Jana, R.; Chatterjee, I.; Samanta, S.; Ray, J. K.
Org. Lett. 2008, 10, 4795. (d) Saito, N.; Shiotani, K.; Kinbara, A.; Sato,
Y. Chem. Commun. 2009, 4284. (e) Sustac Roman, D.; Takahashi, Y.;
Charette, A. B. Org. Lett. 2011, 13, 3242. (f) Ueno, S.; Komiya, S.;
Tanaka, T.; Kuwano, R. Org. Lett. 2012, 14, 338.
(3) For reviews, see: (a) Trost, B. M.; Crawley, M. L. Chem. Rev.
2003, 103, 2921. (b) Lu, Z.; Ma, Z. Angew. Chem., Int. Ed. 2008, 47, 258.
(4) (a) Malkov, A. V.; Davis, S. L.; Baxendale, I. R.; Mitchell, W. L.;
ꢀ
Kocovsky, P. J. Org. Chem. 1999, 64, 2751. (b) Fernandez, I.;
Hermatschweiler, R.; Breher, F.; Pregosin, P. S.; Veiros, L. F.; Calhorda,
M. J. Angew. Chem., Int. Ed. 2006, 45, 6386. For an example of Pd-
catalyzed C-allylation of phenols via an O-allylationÀClaisen rearrange-
ment sequence, see: (c) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998,
120, 815.
(5) Nemoto, T.; Ishige, Y.; Yoshida, M.; Kohno, Y.; Kanematsu, M.;
Hamada, Y. Org. Lett. 2010, 12, 5020.
r
10.1021/ol300770w
Published on Web 04/17/2012
2012 American Chemical Society

through an ipso-FriedelÀCrafts-type reaction.5,6 This re-
action could be extended to a catalytic asymmetric pro-
cess by selecting a suitable chiral ligand. This background
led us to hypothesize that 10-isopropenyl-9,10-dihydro-
phenantherene-1-ol I, the core structure of cedrelins and
paralycolines, could be synthesized in an optically active
form using a Pd-catalyzed asymmetric intramolecular
FriedelÀCrafts allylic alkylation of m-hydroxy biaryl
compounds II, which in turn, could be prepared using
catalytic biaryl coupling reactions (Scheme 1). Herein, we
report a novel method for synthesizing 10-vinyl or 10-
isopropenyl chiral dihydrophenanthrenes using a Pd-
catalyzed asymmetric intramolecular FriedelÀCrafts
allylic alkylation of phenols.7
After oxidation of commercially available 1 using DessÀ
Martin periodinane (DMP), the obtained crude residue
was reacted with a Wittig reagent to give the northern
fragment 2 in 89% yield. On the other hand, the southern
fragment was prepared from compound 3 through a one-pot
process involving a bromineÀlithium exchange, followed
by entrapment with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,
2-dioxaborolane, and compound 4 was obtained in 75%
yield. SuzukiÀMiyaura cross-coupling8 of 2with 4proceeded
smoothly using 5 mol % of PdCl2(dppf) and K3PO4 as a
base, affording biaryl derivative 5 in 95% yield. After reduc-
tion of the ester unit with DIBAL-H (96% yield), the
obtained alcohol 6 was transformed into 7a in 95%
yield over two steps.
Scheme 2. Synthesis of a Model Substrate
Figure 1. Natural products with a 10-isopropenyl 9,10-dihydro-
phenanthren-1-ol skeleton.
Scheme 1. Synthetic Plan
The reaction conditions were optimized using 7a as the
substrate (Table 1). We first examined the reaction using
5 mol % of Pd(dba)2 and 12 mol % of PPh3 in CH2Cl2
at room temperature, which were the optimum conditions
for the previously reported Pd-catalyzed intramolecular
ipso-FriedelÀCrafts allylic alkylation of phenols. Desired
product 8a was obtained in only 12% yield but was,
however, accompanied by the formation of some oligomeric
byproduct through intermolecular allylic etherification.9
The use of other common solvents failed to improve the
yield (entries 1À4). In this reaction system, deprotonation of
the phenol occurs by the endogenous methoxide anion to
increase the nucleophilicity of the aromatic carbon, as
well as the phenol oxygen.5 Therefore, solvation of the
We first prepared a model substrate for the target
reaction based on a biaryl coupling reaction (Scheme 2).
(6) For other examples of transition-metal-catalyzed ncleophilic
dearomatization of phenols, see: (a) Wu, Q.-F.; Liu, W.-B.; Zhuo,
C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011,
50, 4455. (b) Rousseaux, S.; Garcıa-Fortanet, J.; Del Aguila Sanchez, M. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 9282.
(7) For representative examples of transition metal-catalyzed asym-
metric FriedelÀCrafts allylic alkylation of indoles or other heterocycles,
see: (a) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314. (b)
Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; UmaniÀ
Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424. (c) Cheung, H. Y.;
Yu, W.-Y.; Lam, F.-L.; Au-Yeung, T. T.-L.; Zhou, Z.; Chan, T. H.;
Chen, A. S. C. Org. Lett. 2007, 9, 4295. (d) Liu, W.-B.; He, H.; Dai,
L.-X.; You, S.-L. Org. Lett. 2008, 10, 1815. (e) Bandini, M.; Eichholzer, A.
Angew. Chem., Int. Ed. 2009, 48, 9533. (f) Wu., Q.-F.; He, H.; Liu, W.-B.;
You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418. (g) Hoshi, T.; Sasaki, K.;
Sato, S.; Ishii, Y.; Suzuki, T.; Hagiwara, H. Org. Lett. 2011, 13, 932. (h)
Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H. Org. Lett. 2011, 13,
2164. (i) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci
2012, 3, 205. (j) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed.
2012, 51, 1680.
(8) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457. (b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722.
(9) O-allylated adducts shown below were obtained as the major
byproduct in this reaction.
Org. Lett., Vol. 14, No. 9, 2012
2351

phenoxide anions by the addition of a protic solvent was
expected to prevent the undesired intermolecular O-alkyl-
ation selectively. Thus, we examined the reaction using a
protic solvent as the cosolvent. The yield was significantly
improved to 71% when the reaction was performed
in a CH2Cl2ÀMeOH mixed solvent system (entry 6). The
satisfactory results using PPh3 led us to focus on the
asymmetric version of this transformation. First, we ex-
amined the reaction using chiral monodentate phosphorus
ligands. 9-NapBN,10 MOP,11 and phosphoramidite
ligands12 like Monophos are effective chiral monodentate
phosphorus ligands in transition-metal-catalyzed allylic
substitution reactions. Trials using these chiral ligands,
however, gave unsatisfactory results (entries 10À13).
We next examined the reaction using privileged bidentate
ligands for the transition metal-catalyzed asymmetric
allylic substitution reactions. Although the reaction rarely
occurred using a PHOX-type ligand (entry 14),13 the
desired transformation proceeded smoothly when Trost
ligandswereused(entries15À17).AmongtheTrostligands
examined, (R,R)-ANDEN-phenyl Trost ligand H was
best for asymmetric induction, and chiral dihydro-
phenanthrene derivative 8a was obtained in 97% yield
and 91% ee (entry 17).14
The stereochemistry of the product 8a was determined
using X-ray analysis (Scheme 3). Reduction of the double
bond of 8a (91% ee), followed by bromination of the
phenolic ring, afforded 9 in 86% yield in two steps. After
esterification of the phenol with a p-nitrobenzoyl chloride
(99% yield), single recrystallization of the product from
hexane-ethyl acetate gave compound 10 with 99% ee.
X-ray analysis of the obtained crystal revealed that the
absolute stereochemistry of the benzylic position of 8a
was (S).15
Table 1. Optimization of the Reaction Conditions Using 7a
ligand
time yielda
eeb
(%)
entry
(mol %)
solvent
(h)
(%)
1
2
3
4
5
6
7
8
9
PPh3 (12) CH2Cl2
5
16
5
12
PPh3 (12) CH3CN
trace
11
PPh3 (12) toluene
PPh3 (12) THF
3
trace
63
PPh3 (12) THF/MeOH (4/1)
PPh3 (12) CH2Cl2/MeOH (4/1)
PPh3 (12) CH2Cl2/MeOH (1/1)
PPh3 (12) CH2Cl2/MeOH (9/1)
PPh3(12) CH2Cl2/t-BuOH (4/
1)
6
16
16
16
16
71
12
46
30
10
11
12
13
14
15
16
17
A (12)
B (12)
C (12)
D (12)
E (6)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
CH2Cl2/MeOH (4/1)
10
16
6
trace
62
À7
4
56
18
16
16
6
76
À32
trace
66
F (6)
À65
À10
91
G (6)
88
H (6)
6
97
a Isolated yield. b Determined by chiral HPLC analysis. Negative
value means the opposite enantiomer.
We next examined the scope and limitations of various
substrates under the optimized reaction conditions. All
reactions were performed using 5 mol % of Pd(dba)2 and
(10) (a) Hamada, Y.; Seto, N.; Ohmori, H.; Hatano, K. Tetrahedron
Lett. 1996, 37, 7565. (b) Hamada, Y.; Seto, N.; Takayanagi, Y.; Nakano,
T.; Hara, O. Tetrahedron Lett. 1999, 40, 7791. (c) Hamada, Y.; Saka-
guchi, K.; Hatano, K.; Hara, O. Tetrahedron Lett. 2001, 42, 1297.
(d) Hara, O.; Koshizawa, T.; Makino, K.; Kunimune, I.; Namiki, A.;
Hamada, Y. Tetrahedron 2007, 63, 6170.
(11) (a) Uozumi, Y.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 9887.
(b) For a review on the MOP ligands, see: Hayashi, T. Acc. Chem. Res.
2000, 33, 354.
Scheme 3. Determination of the Absolute Configuration of 8a
(12) For a review on the chiral phosphoramidite ligands, see:
Teichert, J. F.; Feringa, B. L. Angew. Chem., Int. Ed. 2010, 49, 2486.
(13) For a review on the PHOX ligands, see:Helmuchen, G.; Pfaltz,
A. Acc. Chem. Res. 2000, 33, 336.
(14) For recent selected examples of catalytic asymmetric reactions
using the ANDEN-phenyl Trost ligand H, see: (a) Trost, B. M.; Tsui,
H.-C.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 3534. (b) Trost,
B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744. (c) Trost, B. M.;
Frederiksen, M. U. Angew. Chem., Int. Ed. 2005, 44, 308. (d) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 2846. (e) Trost, B. M.; Xu, J. J. Am.
Chem. Soc. 2005, 127, 17180. (f) Trost, B. M.; Xu, J.; Reichle, M. J. Am.
Chem. Soc. 2007, 129, 282. (g) Trost, B. M.; Thaisrivongs, D. A. J. Am.
Chem. Soc. 2008, 130, 14092. (h) Trost, B. M.; Thaisrivongs, D. A.
J. Am. Chem. Soc. 2009, 131, 12056. (i) Trost, B. M.; Lehr, K.; Michaelis,
D. J.; Xu, J.; Buckl, A. K. J. Am. Chem. Soc. 2010, 132, 8915. (j) Trost,
B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132, 15534. (k) Trost,
B. M.; Thaisrivongs, D. A.; Hartwig, J. J. Am. Chem. Soc. 2011, 133,
€
12439. (l) Trost, B. M.; Schaffner, B.; Osipov, M.; Wilton, D. A. A.
Angew. Chem., Int. Ed. 2011, 50, 3548.
(15) See the Supporting Information for details.
2352
Org. Lett., Vol. 14, No. 9, 2012

Table 2. Scope and Limitationsa
a Reaction conditions: Pd(dba)2 (5 mol %), (R,R)-Trost ligand (6 mo l%), CH2Cl2ÀMeOH (4/1) (0.05 M). b Isolated yield. Enantiomeric excesses
were determined by chiral HPLC analysis. Absolute configuration of the reaction products other than (S)-(+)-8a was tentatively assigned based on the
sign of optical rotation. c 10% of para-substituted adduct was also obtained. d 13% of para-substituted adduct was also obtained.
6 mol % of (R,R)-Trost ligand in a CH2Cl2ÀMeOH mixed
solvent system. Similar to the case of model substrate 7a,
asymmetric intramolecular FriedelÀCrafts allylic alkyla-
tion of substrate 7b, bearing a symmetric 3,5-dihydroxy-
phenyl ring, proceeded smoothly at room temperature and
produced the corresponding products 8b in 99% yield with
90% ee (Table 2, entry 2). Substrates with a trisubstituted
olefin 7c and 7d were also applicable to this reaction. Using
(R,R)-DACH-phenyl Trost ligand F, 10-isopropenyldihy-
drophenanthrene derivatives 8c and 8d were obtained in
excellent yield with93% eeand 91% ee, respectively. When
phenol derivatives bearing asymmetric substituent pat-
terns on the southern ring, such as 7e and 7f, were used
as substrates, the FriedelÀCrafts allylic alkylation prefer-
entiallyoccurredon the ortho-position, providing 10-vinyl-
9,10-dihydrophenantherene-1-ols 8e and 8f in 85% yield
with 92% ee and 83% yield with 94% ee, respectively. In
addition, compounds 7gÀi, bearing electron-donating and
electron-withdrawing functionalities on the northern aro-
matic ring, were tolerant to this reaction, giving the corre-
sponding products 8gÀi in high yield with 87À94% ee.
In conclusion, we achieved a Pd-catalyzed asymmetric
intramolecular FriedelÀCrafts allylic alkylation of phe-
nols that provided a series of 10-vinyl- or 10-isopropenyl-
dihydrophenanthren-1-ol derivatives in high yield with
high enantiomeric excess. Application of the developed
method to asymmetric synthesis of natural products is
ongoing.
Acknowledgment. This work was supported by a
Grant-in Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology,
Japan, and the Research Foundation for Pharmaceutical
Sciences.
Supporting Information Available. Experimental pro-
cedures, compound characterization, crystallographic
information file (CIF) of 10, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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