Asymmetric bromine-lithium exchange: Application toward the synthesis of natural product

Article abstract of DOI:10.1021/ol4021157

Asymmetric bromine-lithium exchange has been successfully employed to synthesize bicoumarin chiral building blocks of (+)-isokotanin A and (-)-kotanin in good yields and with an excellent level of enantioselectivity. This is the first reported example of formal syntheses, using this direct methodology, leading to the single (M)-atropoisomer of (+)-isokotanin A and (-)-kotanin building blocks, without any resolution step.

Full text of DOI:10.1021/ol4021157

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric BromineꢀLithium
Exchange: Application toward the
Synthesis of Natural Product
ꢀ ꢀ ꢀ
Julien Graff, Thibaut Debande, Jezabel Praz, Laure Guenee, and Alexandre Alexakis*
Department of Organic Chemistry and Laboratory of Crystallography,
University of Geneva, Quai Ernest Ansermet 30, Geneva 4, CH-1211 Switzerland
Alexandre.alexakis@unige.ch
Received July 26, 2013
ABSTRACT
Asymmetric bromineꢀlithium exchange has been successfully employed to synthesize bicoumarin chiral building blocks of (þ)-isokotanin A and
(ꢀ)-kotanin in good yields and with an excellent level of enantioselectivity. This is the first reported example of formal syntheses, using this direct
methodology, leading to the single (M)-atropoisomer of (þ)-isokotanin A and (ꢀ)-kotanin building blocks, without any resolution step.
The formation of axially chiral compounds is still a topic
of interest, particularly when a chiral stoichiometric aux-
iliary should be avoided.1 The asymmetric lithiumꢀhalo-
gen exchange provides a highly valuable and innovative
synthetic method for building axial chirality.2 These first
reports deal with the improvement of the methodology,
but none of which report on a direct application toward
natural product synthesis. In fact, axial chirality is present
in a wide range of biologically active natural products.3
One of the most famous examples of this is glycopeptide
vancomycin isolated for the first time in 1953 by the
pharmaceutical company Eli Lilly, from a soil bacterium
Amycolatopsis orientalis4 that possesses important anti-
biotic activities. Axial chirality is also present in several
other natural product families:3 phenylanthraquinones
((þ)-knipholone3ꢀ5), perylenequinones (pleichrome3ꢀ6),
lignans ((þ)-schizandrin3ꢀ7), and bicoumarins (desertorin
C, isokotanin A, and kotanin)3ꢀ8 to name a few. However,
there are scarcely any strategies in natural product synthesis
that report the successful introduction of axial chirality:3ꢀ9
for example, intermolecular atropodiastereoselective biaryl
€
(5) (a) Bringmann, G.; Menche, D.; Kraus, J.; Muhlbacher, J.; Peters,
K.; Peters, E.-M.; Brun, R.; Bezabih, M.; Abegaz, B. M. J. Org. Chem.
2002, 67, 5595–5610. (b) Bringmann, G.; Menche, D. Angew. Chem., Int.
Ed. 2001, 40, 1687–1690. (c) Groh, M.; Meidlinger, D.; Bringmann, G.;
Speicher, A. Org. Lett. 2012, 14, 4548–4551.
(6) Broka, C. A. Tetrahedron Lett. 1991, 32 (7), 859–862.
(7) Tanaka, M.; Mukaiyama, C.; Mitsuhashi, H.; Maruno, M.;
(1) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.;
Garner, J.; Breunig, M. Angew. Chem., Int. Ed. 2005, 44, 5384–5427.
(2) (a) Fan, C.-A.; Ferber, B.; Kagan, H. B.; Lafon, O.; Lesot, P.
Tetrahedron: Asymmetry 2008, 19, 2666–2677. (b) Perron, Q.; Praz, J.;
Alexakis, A. Tetrahedron: Asymmetry 2009, 20, 1004–1007. (c) Perron,
Q.; Alexakis, A. Adv. Synth. Catal. 2010, 352, 2611–2620. (d) Praz, J.;
Guenee, L.; Aziz, S.; Berkessel, A.; Alexakis, A. Adv. Synth. Catal. 2012,
354, 1780–1790.
(3) Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M.
Chem. Rev. 2011, 111, 563–639 and references cited therein.
(4) McCormick, M. H.; Stark, W. M.; Pittenger, G. E.; Pittenger,
R. C.; McGuire, J. M. Antibiot. Annu. 1955, 56, 606.
Wakamatsu, T. J. Org. Chem. 1995, 60, 4339–4352.
ꢀ ꢀ
(8) (a) Bringmann, G.; Hinrichs, J.; Henschel, P.; Kraus, J.; Peters,
K.; Peters, E.-M. Eur. J. Org. Chem. 2002, 1096–1106. (b) Hussain, H.;
Hussain, J.; Al-Harrasi, A.; Krohn, K. Tetrahedron 2012, 68, 2553–2578.
€
€
(c) Huttel, W.; Nieger, M.; Muller, M. Synthesis 2003, 12, 1803–1808.
(9) Kozolwski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev.
2009, 38, 3193–3207.
r
10.1021/ol4021157
XXXX American Chemical Society

coupling with a chiral auxiliary (e.g., oxazoline by Meyers3ꢀ10),
intramolecular atropodiastereoselective oxidative coupling
(e.g., with copper, by Lipshutz11), dynamic kinetic resolution
of nonconfigurationally stable biaryls by atroposelective
lactone cleavage,3ꢀ8a and atropoenantioselective oxidative
homocoupling (e.g., with copper by Kozlowski3,9ꢀ12). In our
study, we selected the bicoumarin scaffold to apply our direct
asymmetric bromineꢀlithium exchange strategy following
the formal synthesis of (þ)-isokotanin A and (ꢀ)-kotanin
chiral building blocks.
Scheme 1. Path A of 2,20,6,60-Tetrabromo-4,40-dimethoxy-1,10-
biphenyl 6 Synthesis
Optically pure isokotanin A, isolated from Aspergillus
alliaceus,13 was synthesized for the first time by Lin and
Zhong14 via an intermolecular atropodiastereoselective
biaryl coupling.10a Considering the synthetic pathway
toward isokotanin A, we identified 2,20,6,60-tetrabromo-
4,40-dimethoxy-1,10-biphenyl 6 as the starting point for the
preparation of key-intermediate 13 (see Scheme 3). The
easier way to 6 was to apply the standard coupling
conditions2b,c to 1,3-dibromo-5-methoxybenzene. How-
ever, no desired product was isolated, probably due to
the ortho-directional character of the methoxy group dur-
ing the metalationstep.15 Therefore, weexplored two other
chemical pathways to synthesize 2,20,6,60-tetrabromo-4,40-
dimethoxy-1,10-biphenyl 6. Path A (Scheme 1) started with
the commercially available 1,3,5-tribromobenzene 1, with
which a BrꢀLi exchange, in a mixture of THF/toluene at
ꢀ78 °C, was performed, to introduce the TMS function-
ality of compound16 2, in 92% yield. Then, we carried out
an oxidative coupling, of the intermediate cyanocuprate,
to generate biaryls. This step, already well studied in our
laboratory,2b,c,17 was employed to give the desired com-
pound 3 in 22% yield. Next, we treated compound 3 with
iodine monochloride in dichloromethane at 0 °C to gen-
erate the desired 2,20,6,60-tetrabromo-4,40-diiodo-1,10-bi-
phenyl 4 in 97% yield. Then, in a one-pot three-step
sequence, BrꢀLi exchange was performed in THF, at
ꢀ78 °C, and then quenched with fluorodimethoxyborane
diethyl ether, followed by an in situ oxidation with hydro-
gen peroxide/NaOH 2 M solution, which led to the desired
product 5 in 52% yield. Finally a methylation reaction in
THF at rt gave the key intermediate 2,20,6,60-tetrabromo-
4,40-dimethoxy-1,10-biphenyl 6 in 80% yield.
straightforward synthesis of the key intermediate 2,20,6,60-
tetrabromo-4,40-dimethoxy-1,10-biphenyl 6 according to
Scheme 2. An aromatic nucleophilic disubstitution18 on
the 2,20,4,40,6,60-hexabromo-1,10-biphenyl2c 7 was per-
formed, in the presence of anhydrous sodium methoxide
powder in a mixture of DMSO/MeOH at reflux, affording
the compound of interest 6 in 70% yield. It is noteworthy
that only the 4 and 40 bromides were substituted. Withpath
B in hand (Scheme 2, overall yield of 43% after 2 steps), we
were now able to run the synthesis on a gram scale and
optimize the last two steps.
Scheme 2. Path B of 2,20,6,60-Tetrabromo-4,40-dimethoxy-1,10-
biphenyl 6 Synthesis
Next, we needed to achieve the introduction of axial
chirality by asymmetric BrꢀLi exchange (Table 1). There-
fore, we screened diamine ligands L1 to L419 and diether
ligands L5 to L8 (synthesized according to the procedure
described by Hall et al.20), under standard conditions2c as
previously developed in our laboratory.
According to the modest overall yield obtained with
path A (8.2% after 5 steps), we redesigned a much more
The best result was obtained with Tomioka’s diether
ligand L8 (entry 8, Table 1) which has already demon-
strated its efficiency2c,21 with organolithium reagents. It
allowed us to generate a promising enantiomeric excess of
(10) (a) Nelson, T. D.; Meyers, A. I. J. Org. Chem. 1994, 59, 2655–
2658. (b) Nelson, T. D.; Meyers, A. I. J. Org. Chem. 1994, 59, 2577–2580.
(c) Meyers, A. I.; Willemsen, J. J. Tetrahedron 1998, 54, 10493–10511.
(11) Lipshutz, B. H.; Kayser, F.; Liu, Z.-P. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1842–1844 and references cited therein.
(12) (a) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozolwski,
M. C. J. Org. Chem. 2003, 68, 5500–5511. (b) Li, X.; Yang, J.; Kozolwski,
M. C. Org. Lett. 2001, 3, 1137–1140.
(18) Diemer, V.; Leroux, F. R.; Colobert, F. Eur. J. Org. Chem. 2011,
327–340.
(13) Laakso, J. A.; Narske, E. D.; Gloer, J. B.; Wicklow, D. T.;
Dowd, P. F. J. Nat. Prod. 1994, 57, 128.
(14) Lin, G.-Q.; Zhong, M. Tetrahedron Lett. 1996, 37, 3015–
3018.
(19) (a) Alexakis, A.; Aujard, I.; Kanger, T.; Mangeney, P. Organic
Syntheses, Coll. Vol. 10, p 312 ; Vol. 76, p 23. (b) Cuvinot, D.; Mangeney,
P.; Alexakis, A.; Normant, J.-F. J. Org. Chem. 1989, 54, 2420–2425.
(20) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem. Soc. 2008, 130,
8481–8490.
ꢀ
(15) (a) Dabrowski, M.; Kubicka, J.; Lulinski, S.; Serwatowski, J.
Tetrahedron Lett. 2005, 46, 4175–4178. (b) Snieckus, V. Chem. Rev.
1990, 90, 879–933.
(21) (a) Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1989,
111, 8266–8268. (b) Inoue, I.; Shindo, M.; Koga, K.; Tomioka, K.
Tetrahedron 1994, 50, 4429–4438. (c) Mizuno, M.; Kanai, M.; Iiada, A.;
Tomioka, K. Tetrahedron 1997, 53, 10699–10708. (d) Inoue, I.; Shindo,
M.; Koga, K.; Kanai, M.; Tomioka, K. Tetrahedron: Asymmetry 1995,
6, 2527–2533.
€
(16) (a) Bo, Z.; Schluter, A. D. J. Org. Chem. 2002, 67, 5327–5332. (b)
Rehm, J. D. D.;Ziemer, B.;Szeimies, G.Eur. J. Org. Chem. 1999, 2079–2085.
(17) Leroux, F. R.; Simon, R.; Nicod, N. Lett. Org. Chem 2006, 3,
948–954.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Screening of Chiral Ligands for the Asymmetric BrꢀLi
Table 2. Optimization of the Dimethoxylation Reaction
Exchange
CuX
entrya (equiv)
NaOMe
source
t
conv 11:12 yield
solvent (°C) [%] ratioa
[%]
1c
2d
3e
4f
5f
6f
7f
CuCl2
(0.8)
CuI
solid
solid
solid
DMF 120 100 0:100
nd
DMSO/ 190 100 12:88
MeOH
nd
nd
nd
nd
nd
63
(2)
CuBr
(2)
DMF/
MeOH
DMF
120 100 0:100
CuBr
(2)
sol. in
MeOHb
sol. in
MeOHb
sol. in
MeOHb
120 100 25:75
CuBr
(0.2)
CuBr
(1)
DMF
DMF
120 20
100:0
L*
conv
[%]
yield
[%]
ee
entrya
(0.5 equiv)
[%]b
120 100 69:31
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
100
100
100
100
100
100
100
100
88
60
82
84
82
84
93
84
44
50
54
64
22
40
33
68
CuBr
(0.6)
sol. in DMF
MeOHb
120 >95 100:0
a Reaction conditions: At rt, the substrate (0.1 mmol, 1 equiv) was
dissolved in the appropriate reaction solvent (0.25 M). Then, sodium
methoxide (1.4 mmol, 14 equiv) was added. The reaction mixture was heated
to the corresponding temperature and the Cu salt was added. Conversion to
the desired product was confirmed by 1H NMR. b Sol. in MeOH for a 5.4 M
solution of sodium methoxide in MeOH. c Reactions were carried for 5 h at
120 °C. d Reaction was carried for 192 h at 190 °C. e Reaction was carried for
17 h at 120 °C. f Reactions were carried for 120 h at 120 °C.
a Reaction conditions: At ꢀ78 °C, the (R,R) ligand L* (0.5 equiv) was
dissolved in 2 mL of dry toluene. Then, the organolithium reagent
(n-BuLi 1.6 M in hexanes, 4 equiv) was added at ꢀ78 °C before the substrate
(0.11 mmol, 1 equiv) previously dissolved in 1 mL of dry toluene. The
reaction mixture was then stirred at ꢀ78 °C for 2 h. It was finally
quenched by methyl iodide (5 equiv) previously mixed in 1 mL of dry
THF and warmed-up to rt for 1 h. Full conversion and the desired
product were confirmed by 1H NMR. b Determined by SFC analysis
using a chiral stationary phase.
allowed, after 120 h at 120 °C, full conversion and isolation
of 63% of the desired product 11. By applying the conditions
described in entry 7, Table 2 to the (M)-intermediate 8, we
reached, after a shorter reaction time (48 h instead of 120 h),
full conversion, with a 42% yield and 72% ee for the target
molecule 13 (Scheme 3). It is important to note that no
erosion of the enantiomeric excess was observed during this
transformation. Finally, a single recrystallization step in a
1:1 mixture of pentane/ether afforded enantiomerically pure
13 (ee >99.9%, see X-ray in Supporting Information,23) in
decent overall yield (6.4%).
One atroposelective synthesis of (ꢀ)-kotanin, isolated
from Aspergillus clavatus,24 has been reported so far by Lin
and Zhong.25 The authors reported an intramolecular
atropodiastereoselective oxidative coupling11 in order to
build the biaryl skeleton. Considering this synthetic path-
way to (ꢀ)-kotanin, we identified 2,20,6,60-tetrabromo-
4,40-dimethyl-1,10-biphenyl 15 as a substrate of choice to
apply the asymmetric BrꢀLi exchange to an early stage of
68% with an isolated yield of 84% for compound 8. Finally,
a dimethoxylation step catalyzed by copper22 was required
to yield the target molecule 13. The optimization process
was performed on a racemic mixture of 2,20-dibromo-6,60-
dimethyl-1,10-biphenyl 10,2c obtained in high isolated yield
(97%) from a racemic bromineꢀlithium exchange on
2,20,6,60-tetrabromo-1,10-biphenyl 9,2b,c followed by an elec-
trophilic quench with methyl iodide.2c The copper and
sodium methoxide sources, solvent, temperature, and reac-
tion time were investigated (Table 2) to achieve full conver-
sion and avoid formation of the side product 12.
Using CuCl2, CuI, and CuBr with sodium methoxide
powder, in DMF, DMSO/MeOH, or DMF/MeOH, gave
disappointing results. Full conversion was obtained, but
almost only the side product 12 was detected (entries 1 to 3,
Table 2). Switching to a 5.4 M sodium methoxide solution
in MeOH and reducing the copper(I) bromide catalyst
loading from 2 to 0.6 equiv in DMF (entry 7, Table 2)
(23) CCDC-953058 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
€
(24) (a) Buchi, G.; Klaubrt, D. H.; Schank, R. C.; Weinreb, S. M.;
Wogan, G. N. J. Org. Chem. 1971, 36, 1143–1147. (b) For the first
€
racemic synthesis of kotanin, see: Buchi, G.; Luk, K. C.; Kobbe, B.;
(22) (a) Haalten, H. L.; van Koten, G.; Grove, D. M.; Kuilman, T.;
Piekstra, O. G.; Hulshof, L. A.; Sheldon, R. A Tetrahedron 1989, 45 (17),
5565–5578. (b) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993,
34 (6), 1007–1010.
Townsend, J. M. J. Org. Chem. 1977, 42, 244–246.
(25) Lin, G.-Q.; Zhong, M. Tetrahedron: Asymmetry 1997, 9, 1369–
1372.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Optimized Dimethoxylation Conditions
Scheme 4. (ꢀ)-Kotanin Chiral Building Block Proposed
Chemical Pathway
Table 3. Asymmetric BrꢀLi Exchange Screening Conditions
L* (0.5
conv
[%]
yield
[%]
ee
[%]b
entrya
equiv)
overall yield and 64% ee. A second double BrꢀLi exchange
in THF at ꢀ78 °C, with t-BuLi, afforded the corresponding
bis-aldehyde 18 in 87% yield and 64% ee. It is important to
note that no erosion of the enantiomeric excess was ob-
served during the second double BrꢀLi exchange. That
proves the optical stability of tetrasubstituted biaryls. Fi-
nally a BaeyerꢀVilliger/hydrolysis process26 led to the
target compound 19, in 73% yield and 64% ee. After two
recrystallizations, in a 1:1 mixture of hexane/ethylacetate,
the (ꢀ)-kotanin chiral building block 19 was obtained in
81% ee and good overall yield (12.9%).
In conclusion, two key chiral building blocks for the
synthesis of (þ)-isokotanin A and (ꢀ)-kotanin have been
successfully prepared in good yields. High levels of enan-
tioselectivity were reached for these building blocks with-
out any resolution step. The asymmetric BrꢀLi exchange
methodology proved to be highly useful in natural product
synthesis in order to install axial chirality. Further applica-
tions of this methodology are already ongoing in our
laboratory.
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
100
100
100
100
100
100
100
100
72
84
74
93
46
63
87
76
54
38
46
64
8
36
20
50
a Reaction conditions: At ꢀ78 °C, the (R,R) ligand L* (0.5 equiv) was
dissolved in 2 mL of dry toluene. Then, the organolithium reagent (n-
BuLi 1.6 M in hexanes, 4 equiv) was added at ꢀ78 °C before the substrate
(0.12 mmol, 1 equiv) previously dissolved in 1 mL of dry toluene. The
reaction mixture was then stirred at ꢀ78 °C for 2 h. It was finally
quenched by DMF (5 equiv) and warmed up to rt for 1 h. Full conversion
to the desired product was confirmed by 1H NMR. b Determined by SFC
analysis using a chiral stationary phase.
the synthesis. Therefore, we screened the same diamine
ligands L1 to L419 and diether ligands L5 to L820 as shown
in Table 1, under standard conditions.2c For this task, we
simply quenched the intermediate dilithium species with
DMF to form the corresponding dialdehyde 16 (Table 3).
With the best ligand L4 in hand, we proposed the
chemical path detailed in Scheme 4. We began with an
oxidative coupling of cyanocuprate2b,c,17 of the commer-
cially available starting material 1,3-dibromo-5-methylben-
zene 14 to give the desired 2,20,6,60-tetrabromo-4,40-
dimethyl-1,10-biphenyl 15 compound in 56% yield. We then
proceeded with a one-pot three-step sequence, via the
asymmetric BrꢀLi exchange in toluene at ꢀ78 °C, and sub-
sequent quenching using fluorodimethoxyborane diethyl
ether, by an in situ oxidation with hydrogen peroxide/
NaOH 2 M solution. The crude product was then
methylated in THF at rt to give compound 17 in 51%
Acknowledgment. The authors thank the Swiss Na-
tional Research Foundation (Grant No. 200020-126663)
and COST action CM0905 (SER Contract No. C11.0108)
for financial support. The authors also warmly thank Dr.
ꢀ ꢀ
Frederic Leroux (CNRS, ECPM Strasbourg) and Dr.
Matthieu Tissot (Cambridge University) for fruitful dis-
cussions and Dr. Beth Ashbridge (Memorial Sloan-Kettering
Cancer Center) for correction of the manuscript.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, and chiral separations for all
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(26) Lanfranchi, D. A.; Hanquet, G. J. Org. Chem. 2006, 71, 4854–
4861.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX