Enantioselective Ullmann ether couplings: Syntheses of (-)- myricatomentogenin, (-)-jugcathanin, (+)-galeon, and (+)-pterocarine

Article abstract of DOI:10.1021/ol402096k

The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the diarylether heptanoid natural products (-)-myricatomentogenin, (-)-jugcathanin, (+)-galeon, and (+)-pterocarine.

Full text of DOI:10.1021/ol402096k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Ullmann Ether Couplings:
Syntheses of (ꢀ)-Myricatomentogenin,
(ꢀ)-Jugcathanin, (þ)-Galeon, and
(þ)-Pterocarine
M. Quamar Salih and Christopher M. Beaudry*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis,
Oregon 97331, United States
christopher.beaudry@oregonstate.edu
Received July 24, 2013
ABSTRACT
The first enantioselective Ullmann cross-coupling reactions to prepare diaryl ethers are reported. The reactions were used to prepare the
diarylether heptanoid natural products (ꢀ)-myricatomentogenin, (ꢀ)-jugcathanin, (þ)-galeon, and (þ)-pterocarine.
The Ullmann ether coupling1 is a versatile reaction that
is used to prepare diarylethers and other types of ethers
that cannot be accessed by the Williamson2 method. Classic
Ullmann conditions require high temperatures and stoichio-
metric copper reagents and often proceed in modest yields.
However, modern improvements to this reaction have
increased the reactivity as well as chemical yields and
lowered reaction temperatures.3 Such improvements to
the Ullmann coupling use ligands to accelerate the reaction
and improve the efficiency of the Cu catalyst.4 Many of the
ligands that accelerate the Ullmann reaction happen to be
chiral, although, they are often used in racemic form
because the product diarylethers are usually achiral.5
We hypothesized that use of nonracemic ligands in the
presence of Cu salts would render the Ullmann reaction
enantioselective, and we decided to evaluate such condi-
tions in the syntheses of the conformationally chiral cyclo-
phane natural products (ꢀ)-myricatomentogenin, (ꢀ)-
jugcathanin, (þ)-galeon, and (þ)-pterocarine (Figure 1).
To the best of our knowledge, there are no examples of an
enantioselective Ullmann ether synthesis. However, de-
symmetrization reactions forming CꢀN bonds were recently
reported.6 Moreover, enantioselective Ullmann couplings
could find applications in reagent-controlled syntheses of
atropodiasteromeric ether substructures in molecules such as
vancomycin.7 Finally, substituted diarylethers can be chiral
depending on their substitution pattern, and an enantioselec-
tive Ullmann reaction would find application in the syntheses
of such molecules.8
(1) Ullmann, F.; Sponagel, P. Ber. 1905, 38, 2211–2212.
(2) Williamson, W. Liebigs Ann. Chem. 1851, 77, 37–49.
(3) For reviews, see: (a) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2008, 47, 3096–3099. (b) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400–5449.
(4) For recent examples, see: (a) Fagan, P. J.; Hauptman, E.;
Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043–5051.
(b) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973–976. (c) Wang, D.; Ding, K. Chem. Commun. 2009, 1891–
1893. (d) Lv, X.; Bao, W. J. Org. Chem. 2007, 72, 3863–3867. (e) Niu, J.;
Zhou, H.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2008, 73, 7814–7817.
(5) (a) Ouali, A.; Taillefer, M.; Spindler, J.-F.; Jutand, A. Organomet.
2007, 26, 65–74. (b) Wang, Z.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008,
2540–2546. (c) Thakur, K. G.; Sekar, G. Chem. Commun. 2011, 47,
6692–6694. (d) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008, 221–
224.
Diarylether heptanoids (DAEHs)9 are a class of natural
productsisolatedfrom woody plantsthatarecharacterized
by an oxa[1.7]metaparacyclophane architecture. Members
(6) (a) Zhou, F.; Guo, J.; Liu, J.; Ding, K.; Yu, S.; Cai, Q. J. Am.
Chem. Soc. 2012, 134, 14326–14329. (b) Cai, Q.; Zhou, F. Synlett 2013,
408–411.
(7) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S. Chem.
Rev. 1995, 95, 2135.
(8) Betson, M. S.; Clayden, J.; Worrall, C. P.; Peace, S. Angew.
Chem., Int. Ed. 2006, 45, 5803–5807.
r
10.1021/ol402096k
XXXX American Chemical Society

Figure 1. Chiral diarylether heptanoids lacking stereocenters.
Scheme 1. Racemic Synthesis of Chiral Diarylether Heptanoids
Lacking Stereocenters
of this natural product family have broad biological
activities including leishmanicidal,10 anti-inflammation,11
and anticancer activities.12 The DAEHs have attracted
interest from synthetic chemists.12b,13
Our interest in the DAEHs arises from their chiral
properties.14 Recently, we showed that of the 16 DAEHs
Figure 2. Evaluation of binapthol-type ligands in the Ullmann
coupling of 7. Yield based on recovered starting material.
Isolated yield (average of three trials).
a
b
(9) (a) Zhu, J.; Islas-Gonzalez, G.; Bois-Choussy, M. Org. Prep.
Proc. Int. 2000, 32, 505–546. (b) Claeson, P.; Tuchinda, P.; Reutrakul, V.
J. Indian Chem. Soc. 1994, 71, 509–521.
(10) Takahashi, M.; Fuchino, H.; Sekita, S.; Satake, M. Phytother.
Res. 2004, 18, 573–578.
(11) Singh, S. B.; Jayasuriya, H.; Zink, D. L.; Polishook, J. D.;
Dombrowski, A. W.; Zweerink, H. Tetrahedron Lett. 2004, 45, 7605–
7608.
(12) (a) Ishida, J.; Kozuka, M.; Tokuda, H.; Nishino, H.; Nagumo,
S.; Lee, K.-H.; Nagai, M. Bioorg. Med. Chem. 2002, 10, 3361–3365. (b)
Bryant, V. C.; Kumar, G. D. K.; Nyong, A. M.; Natarajan, A. Bioorg.
Med. Chem. Lett. 2012, 22, 245–248. (c) Jin, W. Y.; Cai, X. F.; Na, M. K.;
Lee, J. J.; Bae, K. H. Biol. Pharm. Bull. 2007, 30, 810–813. (d) Akihisa,
T.; Takeda, A.; Akazawa, H.; Kikuchi, T.; Yokokawa, S.; Ukiya, M.;
Fukatsu, M.; Watanabe, K. Chem. Biodivers. 2012, 9, 1475–1489.
that do not possess a stereocenter, 4 DAEHs are chiral:
(ꢀ)-myricatomentogenin,15 (ꢀ)-jugcathanin,16 (þ)-galeon,15,17
and (þ)-pterocarine.18 These chiral DAEHs all possess the
same pR19 absolute configuration (Figure 1).14a Our synthe-
ses of the racemic DAEHs involves an intramolecular
Ullmann ether coupling of bromophenols 1, 2, and 3 to
(15) Morihara, M.; Sakurai, N.; Inoue, T.; Kawai, K.-i.; Nagai, M.
Chem. Pharm Bull. 1997, 45, 820–823.
€
ꢀ
ꢀ
ꢀ
(13) (a) Keseru, G. M.; Dienes, Z.; Nogradi, M.; Kajtar-Peredy, M.
(16) (a) Li, Y.-X.; Ruan, H.-L.; Zhou, X.-F.; Zhang, Y.-H.; Pi, H.-F.;
Wu, J.-Z. Chem. Res. Chin. Univ. 2008, 24, 427–429. (b) Liu, J.-X.; Di,
D.-L.; Wei, X.-N.; Han, Y. Planta Med. 2008, 74, 754–759.
(17) Malterud, K. E.; Anthonsen, T.; Hjortas, J. Tetrahedron Lett.
1976, 17, 3069–3072.
(18) Liu, H. B.; Cui, C. B.; Cai, B.; Gu, Q. Q.; Zhang, D. Y.; Zhao,
Q. C.; Guan, H. S. Chin. Chem. Lett. 2005, 16, 215–218.
(19) For review of the stereochemical descriptors pR and pS, see:
Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds: Wiley-Interscience: New York, 1994; pp 1121ꢀ1122.
J. Org. Chem. 1993, 58, 6725–6728. (b) Kumar, G. D. K.; Natarajan, A.
Tetrahedron Lett. 2008, 49, 2103–2105. (c) Vermes, B.; Keseru, G. M.;
^
ꢀ
ꢀ
ꢀ
ꢀ
Mezey-Vandor, G.; Nogradi, M.; Toth, G. Tetrahedron 1993, 49, 4893–
4900. (d) Islas Gonzalez, G.; Zhu, J. J. Org. Chem. 1999, 64, 914–924. (e)
Jeong, B.-S.; Wang, Q.; Son, J.-K.; Jahng, Y. Eur. J. Org. Chem. 2007,
1338–1344.
(14) (a) Salih, M. Q.; Beaudry, C. M. Org. Lett. 2012, 14, 4026–4029.
(b) Zhu, Z.-Q.; Salih, M. Q.; Fynn, E.; Bain, A. D.; Beaudry, C. M.
J. Org. Chem. 2013, 78, 2881–2896. (c) Zhu, Z.-Q.; Beaudry, C. M.
J. Org. Chem. 2013, 78, 3336–3341.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of (þ)-Galeon and (þ)-Pterocarine
yield
(%)a
erb
Cu source
Cul
base
solvent
(pR:pS)
Diamines including N,N-dimethylcyclohexyldiamine
have been used to accelerate Cu-catalyzed cross-coupling
reactions.21 However, use of diamines did not lead to appre-
ciable amounts of the desired product. Similarly, Taillefer has
used a chiral Schiff base ligand to increase the rate of the
Ullmann reaction.5a A moderate yield of the product was
observed when Schiff base ligands were used; however, the
enantioselectivity was low. Other privelidged ligand classes
that have been used in carbonꢀheteroatom bond formations
were evaluated including chiral phosphines,22 bisoxazo-
lines,23 salen,24 and Trost ligands,25 but yields of the coupl-
ing were low and the product was not appreciably
enantioenriched.
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
DMF
16
12
0
53:47
54:46
ꢀ
Cul
Cul
Cul
Cul
Cul
Cul
NMP
EtOAc
THF
18
7
60:40
61:39
ꢀ
TBME
dioxane
0
41
68:32
Cu(OTf)2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
18
12
5
57:43
58:42
54:46
61:39
62:38
58:42
CuBr DMS
3
CuTC
Cu(MeCN)4BF4
13
26
10
Cu(OTf) PhMe
3
Cu(TMEDA)CI2
Gratifyingly, we found that use of N-methyl proline in the
reaction did lead to increased product yield and encouraging
levels of enantioselectivity (Figure 2).26 Proline and a variety
of analogs were then investigated in the reaction. Variation
in the N-alkyl group, ring size, and the carboxylic acid func-
tionality did not markedly improve the yield or enantios-
electivity of the reaction. Use of dipeptides or other N,
N-dimethyl amino acids did not improve the selectivity.
We then selected N-methylproline as the preferred ligand
and investigated the other reaction variables (Table 1).
Variation of the solvent did not improve the yield or selectiv-
ity compared with our standard conditions, nor did variation
of the Cu source. Finally, we surveyed a variety of inorganic
and organic bases in the Ullmann coupling and found that
use of K3PO4 gave the product with a higher enantiomeric
ratio without a significant decrease in chemical yield.
Dimethyl cyclophane 8 was recrystallized to obtain
material that was enantioenriched (92:8 er). It was then
converted to a 1:1 mixture of (þ)-galeon and (þ)-pterocarine
without any measurable loss in enantiopurity (Scheme 2).
Diisopropyl-substituted bromophenol 9 was prepared
following the same general strategy used for 7. Cyclization
using the optimized conditions gave 10 in moderate yield
and enantioselectivity (Scheme 3). Cyclophane 10 could be
further purified by recrystallization to give material that
was enantioenriched (82:18 er). Treatment of 10 with BCl3
Cul
Cul
Cul
Cul
Cul
Cul
2,6-lutidine
DBU
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
0
ꢀ
0
ꢀ
K2CO3
18
0
64:36
ꢀ
NaOH
NaHCO3
K3PO4
0
ꢀ
39
72:28
a Isolated yield. b Determined by HPLC.
give chiral cyclophanes 4, 5, and 6, respectively (Scheme 1).
Such reactions convert an achiral starting material to a
chiral product, employ a metal catalyst, and are ligand
accelerated. These factors suggest the Ullmann ether synth-
esis could be rendered enantioselective.
Ullmann substrate 7 was prepared using conditions
developed in our previous galeon synthesis, and we knew
from previous studies that the cyclophane product 8 was a
common intermediate for a galeon and pterocarine synthe-
sis (Figure 2).20 The intramolecular coupling was evalu-
ated using enantiopure ligands known to accelerate the
Ullmann reaction and some other privileged ligand struc-
tures. Note that racemization of the chiral DAEHs (and
alkylated congeners) does not occur at the temperature of
the Ullmann cyclization.14a
BINOL-type ligands have been used in Cu-catalyzed
cross-coupling reactions.5b,6 We found that use of such
ligands in the coupling gave some of the cyclophane
product with modest enantioselectivities (Figure 2). Per-
haps unsurprisingly, the chemical yields were low, because
a significant amount of the phenolic ligand coupled with
the bromide functionality of 7.
(22) Pratap, R.; Parrish, D.; Gunda, P.; Venkataraman, D.; Lakshman,
M. K. J. Am. Chem. Soc. 2009, 131, 12240–12249.
(23) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J. Am. Chem. Soc. 1991, 113, 726–728.
(24) Li, Z.; Conser, K. A.; Jacobsen, E. N. J. Am. Chem. Soc. 1993,
115, 5326–5327.
(25) Trost, B. M. Acc. Chem. Res. 1996, 29, 355–364.
(26) Ma, D.; Cai, Q. Synlett 2004, 128–130.
(27) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979,
2593–2598.
(20) Unpublished results.
(21) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 7421–7428. (b) Strieter, E. R.; Blackmond, D. G.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4120–4121.
Org. Lett., Vol. XX, No. XX, XXXX
C

deprotection of 11 gave (ꢀ)-jugcathanin with no loss in
enantiomeric ratio.
Scheme 3. Synthesis of (ꢀ)-Myricatomentogenin and
(ꢀ)-Jugcathanin
In summary, we found that the use of nonracemic
ligands render the Ullmann ether synthesis enantioselec-
tive. To the best of our knowledge, this is the first example
of an enantioselective Ullmann ether coupling. In a survey
of a variety of ligands known to accelerate the Ullmann
reaction, N-methyl proline was the best ligand in terms of
chemical yield and enantioselectivity. The nonracemic
cyclophane product could be enriched by recrystallization,
and the enantioenriched material was used in the first
enantioselective synthesis of (ꢀ)-myricatomentogenin,
(ꢀ)-jugcathanin, (þ)-galeon, and (þ)-pterocarine.
Acknowledgment. Financial support from Oregon State
University.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data, depiction of 1H and 13C
NMR spectra for all new compounds. Chiral HPLC
traces for chiral DAEHs. This material is available free
of charge via the Internet at http://pubs.acs.org.
gave a 1:1 mixture of (ꢀ)-myricatomentogenin and the
product of removal of the more accessible isopropyl ether
(11) in nearly quantitative yield and no loss in
enantioenrichment.27 Methylation and subsequent
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX