Total Synthesis of Salimabromide: A Tetracyclic Polyketide from a Marine Myxobacterium

Article abstract of DOI:10.1021/jacs.8b06228

Salimabromide is an antibiotic polyketide that was previously isolated from the obligate marine myxobacterium Enhygromyxa salina, and its densely functionalized and conformationally rigid tetracyclic framework is unprecedented in nature. Herein we report the first chemical synthesis of the target structure by employing a series of well-orchestrated, robust transformations, highlighted by an acid-promoted, powerful Wagner-Meerwein rearrangement/Friedel-Crafts cyclization sequence to forge the two adjacent quaternary carbon centers embedded in the tetrahydronaphthalene. A high-yielding ketiminium mediated [2+2]-cycloaddition was also utilized for the simultaneous construction of the remaining three stereocenters.

Full text of DOI:10.1021/jacs.8b06228

Subscriber access provided by Kaohsiung Medical University
Communication
Total Synthesis of Salimabromide, a Tetracyclic
Polyketide from a Marine Myxobacterium
Matthias Schmid, Adriana Grossmann, Klaus Wurst, and Thomas Magauer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b06228 • Publication Date (Web): 28 Jun 2018
Downloaded from http://pubs.acs.org on June 28, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Total Synthesis of Salimabromide, a Tetracyclic Polyketide from a
Marine Myxobacterium
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Matthias Schmid,†,‡ Adriana S. Grossmann,† Klaus Wurst§ and Thomas Magauer*,‡
†Department of Chemistry, Ludwig-Maximilians-University Munich, Butenandtstrasse 5-13, 81377, Munich, Germany, ‡In-
stitute of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80–82, 6020 Innsbruck,
Austria. §Institute of General, Inorganic & Theoretical Chemistry, University of Innsbruck, Innrain 80–82, 6020 Innsbruck,
Austria.
Supporting Information Placeholder
ABSTRACT: Salimabromide is an antibiotic polyketide that was
previously isolated from the obligate marine myxobacterium
Enhygromyxa salina, and its densely functionalized and conforma-
tionally rigid tetracyclic framework is unprecedented in nature.
Herein we report the first chemical synthesis of the target structure
by employing a series of well-orchestrated, robust transformations,
highlighted by an acid-promoted, powerful Wagner–Meerwein re-
arrangement/Friedel–Crafts cyclization sequence to forge the two
adjacent quaternary carbon centers embedded in the tetrahy-
dronaphthalene. A high-yielding ketiminium mediated [2+2]-cy-
cloaddition was also utilized for the simultaneous construction of
the remaining three stereocenters.
substituted and synthetically challenging seven-mem-
bered carbocycle.5 The conformational flexibility of this
subunit is further reduced by fusion to a five-membered
lactone.
Scheme 1. a) Structural diversity produced by marine myx-
obacteria and b) key retrosynthetic bond disconnections for
salimabromide (1).
a)
H
O
Me
12 Me
H
Br
Me
13
OMe
O
O
H
11 O
H
15
1
Br
Myxobacteria of terrestrial origin produce an abun-
dance of structurally complex secondary metabolites with
notable biological activities. Prominent examples include
epothilone, corallopyronin and soraphen.1 Marine myxo-
bacteria, on the other hand, have eluded their cultivation
and isolation on many occasions and constitute a largely
unexplored treasure trove of bioactive molecules.2 Hali-
angincin (2), which was reported in seminal work by Fu-
dou in 2001,3 represents the first natural product isolated
from a strictly marine myxobacterium (Scheme 1a). Fol-
lowing this early report, only a handful of new marine
myxobacterium molecules have appeared in the litera-
ture,2 and in 2013, König disclosed the isolation of sal-
imabromide (1) in minute quantities (0.5 mg from 64 L of
culture) from the obligate marine bacterium
Enhygromxya salina.4 Although a broad biological
screening campaign was impossible at this stage, 1 was
shown to possess inhibitory activity against Arthrobacter
cristallopoietes (16 µg mL−1).
MeO
OMe
O
salimabromide (1)
[2013, antibiotic]
haliangicin (2)
[2001, antifungal]
OH
OH
Me
Me
H
O
O
O
O
H
salimyxin (3)
[2013, antibiotic]
enhygrolide A (4)
[2013, antibiotic]
b)
12
Me
H
sequential
keteniminium
H
13
1
15
oxidation
[2+2]-cycloaddition
O
H
H
H
11
[Bayer–Villiger oxidation]
[Allylic oxidation]
H
[Selective bromination]
5
From a structural point of view, salimabromide (1) con-
tains an unprecedented tetracyclic ring-architecture that
contains four consecutive stereocenters, one of which is
quaternary. Additionally, the brominated tetrahydronaph-
thalene core is bridged at C12 and C15 to form a highly
Me
Me
Wagner–Meerwein
Friedel–Crafts
N
O
O
MeO
(±)-6
7
ACS Paragon Plus Environment

Journal of the American Chemical Society
The structure for 1 was exclusively deduced from exten- 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, 0.1ꢀM),
Page 2 of 6
a
strong hydrogen-bond donor and weak nucleophile,11 as
the solvent of choice and concentrated sulfuric acid as the
optimal catalyst (10 mol%). Under these conditions, the
para-product 12 was formed with very good regioselec-
tivity (12:13 = 8:1). The remainder of the mass balance
corresponds to a complex mixture of byproducts.12 Simi-
lar results were obtained when the reaction was conducted
in a hexameric resorcinarene capsule.13 In agreement with
related Lewis-acid catalyzed semi-pinacol and Wagner–
Meerwein rearrangements,14 a high level of stereoselec-
tivity should be possible for the initial rearrangement
step. Evidence was obtained when a solution of enantio-
merically enriched 7 (82% ee) in dichloromethane was
exposed to titanium(IV) chloride at –78 °C. Under these
conditions, an enantiomeric excess of 70% was obtained
for 12 (see Supporting Information for details). This re-
sult provides an opportunity to access 1 in an asymmetric
fashion.
1
2
3
4
5
6
7
8
sive NMR measurements. While this only confirmed the
connectivity, the absolute stereochemistry was deter-
mined by comparison of calculated and measured CD
spectra.
Despite considerable progress of the Menche group,5
no total synthesis of salimabromide (1) has been accom-
plished to date. In light of these considerations, we set out
to develop a practical synthetic route to enable rapid ac-
cess to 1 and fully synthetic derivatives thereof. Herein
we describe a streamlined synthesis of 1 employing a se-
ries of robust chemical transformations. The successful
realization of this route allowed us to produce 1.9 g of a
highly advanced intermediate in a single batch from
which salimabromide (1) was prepared in only three
steps.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Our retrosynthetic bond disconnections were guided by
our desire to rapidly generate molecular complexity and
to install the individual stereocenters via a minimum
number of synthetic operations (Scheme 1b). We planned
to first install the pivotal C12 quaternary carbon center
and utilize this handle for the subsequent one-step con-
struction of the stereotriad along C11, C13 and C15. For
this purpose and in analogy to the logic of two-phase ter-
pene (bio)synthesis,6 salimabromide (1) was first reduced
to tetracycle 5. This intermediate was designed to elimi-
nate steric hindrance and cross-reactivity of the bromine
substituents en route to the tetracyclic carbon framework
of 1. Compound 5 contains the retron for a powerful keti-
minium mediated [2+2]-cycloaddition7 to produce the
simplified dihydronaphthalene 6. Further C–C bond dis-
connections involving truncation of the sidechain and a
retro-Friedel–Crafts cyclization/Wagner–Meerwein8 re-
arrangement sequence provided epoxide 7.
Scheme 2. Synthesis of the tetrahydronaphthalene frame-
work via consecutive Wagner–Meerwein rearrangement
and Friedel-Crafts cyclization.
a) Ba(OH)2
O
MeO
MeO
O
H
O
10
8
9
O
b) H2, Pd/C
(76–82%)
c) NaH, Me3SI
MeO
11
[32 g]
Me
12
OH
OH
MeO
(±)-12
MeO
(41%)
d) H2SO4,
HFIP
Me
We commenced our synthesis with the Claisen–
Schmidt condensation of commercially available 3-meth-
oxybenzaldehyde 8 with pinacolone 9 (Scheme 2). While
slow reactions (48 h) and moderate yields (48%) were ob-
served for standard bases such as sodium or potassium
hydroxide, the use of activated barium hydroxide
[Ba(OH)2·H2O, C-200]9 led to rapid consumption of the
reactants and clean conversion to the condensation prod-
uct 10. On large scale, 10 was best obtained by simple
filtration of the reaction mixture using a pad of Celite®
and evaporation of excess ethanol and pinacolone 9. The
following heterogeneous hydrogenation (1 atm H2, Pd/C,
EtOAc) was conducted on large-scale and reproducibly
provided 11 in good yield (76–83% over two steps, 32 g).
Exposure of 11 to standard Corey–Chaykovsky condi-
tions (NaDMSO, Me3SI, 0 to 23 °C)10 effected clean con-
version to epoxide 7. With 7 in hand, we investigated the
crucial rearrangement-cyclization sequence. We found
that exposure of 7 to hexanes/sulfuric acid or dichloro-
methane/titanium(IV) chloride was low-yielding for 12
(~30%) and afforded substantial amounts of the undesired
ortho-product 13 (~10%). Further screening revealed
O
Me
MeO
7
(5%)
(±)-13
aReagents and conditions: (a) [Ba(OH)2·H2O, C-200], pinacolone
9, EtOH, 78 °C; (b) Pd/C, H2, EtOAc, 23 °C, 76–82% over two
steps; (c) NaH, DMSO, 70 °C, then Me3SI, 0 to 23 °C; (d) H2SO4,
HFIP, 23 °C, 41% for 12, 5% for 13 over two steps.
Having successfully installed the crucial C12 quater-
nary stereocenter in only four steps, we turned our atten-
tion to the remaining functionalization of 12 (Scheme 3).
To begin, the primary alcohol was protected as its tert-
butyldiphenylsilyl (TBDPS) ether, and styrene 14 was
then formed via exposure to 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ, 2 equiv).15 The use of sub-
stochiometric amounts of DDQ (30 mol%) in combina-
tion with manganese(IV) oxide (6 equiv) or alternative
oxidation agents such as chloranil, Pd/C or electrochemi-
cal methods (4 V, chloranil, Pt/Pt, 0.1 M LiClO4, MeCN)
were ineffective.
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
Scheme 3. Total synthesis of salimabromide.a
1
2
3
4
5
c) LiPPh2
d) PhNTf2
e) ZnEt2, Pd(dppf)Cl2
f) TBAF
a) TBDPSCl
b) DDQ
Me
Me
Me
12
OH
OTBDPS
OTBDPS
(91%)
(99%)
(91%)
MeO
MeO
TfO
6
12
14
15
7
8
9
g) DMP
O
h)
EtO
17
N
PPh3Br
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
i) pyrrolidine
j) Tf2O,
(89%)
N
OH
O
(81%)
ꢀ
OTf
16
6
18
N
Me
Me
disfavored
O
N
19
20
Me
Me
Me
k) SeO2
H
H
13
11
13
favored
(47%, over
five cycles)
11
O
H
O
H
N
H
1
OH
22
1
H
H
21
5
[1.9 g]
[250 mg]
[X-ray]
Me
Me
Br
Me
l) t-BuCHO, Cu(OAc)2,
m) AgTFA,
Br2
H
O2, then DMP
H
O
H
+
O
O
H
11H
H
O
11 O
(79%, 23:24 = 1:3.2)
(50%)
1
1
Br
O
O
O
H
H
H
O
23
(minor)
24
(major)
1
[50 mg]
[X-ray]
aReagents and conditions: (a) TBDPSCl, imidazole, DMAP, DMF, 23°C; (b) DDQ, dioxane, 93 °C, 91% over two steps; (c) LiPPh2, THF,
60 °C; (d) PhNTf2, NEt3, THF, 23 °C, 99% over two steps; (e) ZnEt2, Pd(dppf)Cl2, dioxane, 70 °C, 92%; (f) TBAF, THF, 23 °C, 99%; (g)
DMP, K2CO3, CH2Cl2, 0 °C to 23 °C, 96%; (h) NaHMDS, 17, THF, –78 °C to 23 °C, 85%; (i) pyrrolidine, 100 °C, 99%; (j) Tf2O, 2,4,6-
collidine, ClCH2CH2Cl, 80 °C, 89%; (k) SeO2, SiO2, dioxane, 120 °C, 47% over five cycles; (l) t-BuCHO, Cu(OAc)2, O2 (1 atm),
ClCH2CH2Cl, 23 °C, then DMP, NaHCO3, CH2Cl2, 79%, 23:24 = 1:3.2; (m) AgTFA, Br2, CF3COOH, 50%.
The TBDPS group was crucial for the stability of the
silyl ether under the reaction conditions, and the presence
of the electron-donating methoxy substituent was benefi-
cial for the oxidation.16
to the Hendrickson–McMurray reagent (PhNTf2)19 to af-
ford 15 in quantitative yield. Standard Negishi cross-cou-
pling (Pd(dppf)Cl2, ZnEt2, dioxane, 70 °C)20 enabled
clean installation of the missing ethyl substituent (92%),
and cleavage of the silyl ether (TBAF, THF, 23 °C) gave
alcohol 16 (99%). The remaining carbon-chain was intro-
duced in a three-step sequence beginning with the oxida-
tion of 16 using Dess–Martin periodinane21 (96%), fol-
lowed by a high-yielding, Z-selective Wittig olefination
and amide formation (pyrrolidine, 100 °C) to provide 6
(85%).
For the installation of the missing ethyl substituent, we
initially investigated the direct coupling of 14 using
nickel (e.g. Ni(acac)2, EtMgBr, MgI2, PhMe, 100 °C;
Ni(cod)2, EtMgI, MgI2, PhMe, 100 °C).17 Since our sub-
strate proved to be remarkably unreactive under these
conditions, we decided to replace the methoxy substituent
with a more reactive triflate. For the removal of the me-
thyl ether, freshly prepared lithium diphenylphosphide
(Ph2PH, n-BuLi),17 was found to be optimal. The free
phenol was then converted to the triflate upon exposure
With robust access to the dihydronaphthalene 6, we
proceeded to investigate the key-step of our synthesis: a
ketiminium ion mediated [2+2]-cycloaddition7 to con-
struct the seven-membered carbocycle and complete the
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
tetracyclic carbon framework. Under optimized condi-
matched those reported for the natural compound. Addi-
tionally, the structure of 1 was unambiguously validated
by single-crystal X-ray diffraction analysis.
1
2
3
4
5
6
7
8
tions, a solution of amide 6 and sym-collidine (1.2 equiv)
in dichloroethane was slowly added to a refluxing solu-
tion of freshly distilled trifluoromethanesulfonic anhy-
dride (1.2 equiv) in dichloroethane (0.1 M). The cycload-
dition produced the tetracycle 5 with almost perfect regio-
and diastereoselectivity in excellent yield (89%, 1.9 g).
The exact mechanism, concerted (synchronous/asynchro-
nous) or stepwise, has been a matter of debate for many
decades.7 Depending on the substitution pattern on both
the alkene and the ketiminium salt, either of the two path-
ways might be operational.22 The greater resonance stabi-
lization of the benzylic cation 21 versus 19 was envi-
sioned to govern the regioselectivity favoring formation
of 5.
In summary, we have completed the first total synthesis
of salimabromide, a unique tetracyclic polyketide. The
highlights of the developed route are: 1) A powerful Wag-
ner–Meerwein rearrangement/Friedel–Crafts cyclization
sequence to forge the tetrahydronaphthalene skeleton and
2) a high-yielding ketiminium mediated (2+2)-cycloaddi-
tion to set the remaining three stereocenters. The overall
sequence benefits from a series of practical transfor-
mations that can be also conducted on large scale. The
robustness of the developed synthesis is evident from the
fact that more than 1.9 g of a highly advanced intermedi-
ate were prepared in a single batch.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having installed the crucial stereocenters, we were
poised to tackle the remaining challenges: regioselective
oxidation of the carbon-framework and bromination of
the arene subunit. When 5 (500 mg) was treated with se-
lenium dioxide (dioxane, 120 °C, 6 h) in the presence of
silicon dioxide (>230 mesh) to prevent agglomeration,
the diastereomerically pure allylic alcohol 22 was formed
together with unreacted 5. Extended reaction times were
detrimental as overoxidation and decomposition started
to prevail. Subjection of recovered 5 (76%) to the reaction
conditions enabled us to prepare 250 mg of 22 after five
cycles (47%, ~15% for the first cycle).23 Subsequent Bae-
yer–Villiger oxidation using standard conditions (m-
CPBA, NaHCO3, CH2Cl2) gave two regioisomeric lac-
tones, which were directly oxidized (DMP, NaHCO3,
CH2Cl2) to afford 23 and 24 in a ratio of 1.4:1 in 84%
combined yield. Separation of 23 and 24 was readily ac-
complished by flash column chromatography. To improve
this undesired outcome, further optimization of the oxi-
dant was performed. Interestingly, exposure of 22 to t-Bu-
CHO (5ꢀequiv) in the presence of molecular oxygen (1
atm) and copper(II) acetate (1 equiv) gave 24 as the major
product (79%, 23:24 = 1:3.2).24 The directing effect of the
free hydroxy group was crucial as the corresponding me-
thyl ether led to lower regioselectivity (1:1.1) only
slightly favoring the desired regioisomer (compare 24). It
is also noteworthy that replacement of t-BuCHO with m-
CPBA in the Baeyer–Villiger step under otherwise iden-
tical conditions was even less efficient and only poor re-
gioselectivity (23:24 = 1.2:1) was obtained. For the intro-
duction of the missing bromine substituents, 24 was ex-
posed to a panel of brominating agents (e.g. Br2, CHCl3;
NBS, HOAc; BnMe3NBr3, ZnBr2, HOAc). Under these
conditions, formation of 1 was only observed in trace
amounts if at all. Finally, we found that treating a solution
of 24 in trifluoroacetic acid (0.1 M) with silver(I) tri-
fluoroacetate (3 equiv) and elemental bromine (3 equiv)
enabled the desired bromination (50%) and thus com-
pleted the synthesis of salimabromide (1, 50 mg).25 The
analytical data for 1 (1H-NMR, 13C-NMR, HRMS) fully
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at http://pubs.acs.org.
Experimental details and spectroscopic data (PDF)
X-ray crystallographic data for 1, 5, 23 and 24 (CIF)
AUTHOR INFORMATION
Corresponding Author
thomas.magauer@uibk.ac.at
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
T.M. acknowledges the European Research Council under the Eu-
ropean Union's Horizon 2020 research and innovation program
(grant agreement No 714049) and the Center for Molecular Biosci-
ences (CMBI). M.S. gratefully acknowledges financial support
from the German National Academic Foundation. We thank Dr.
Kevin Mellem (Revolution Medicines) for helpful discussions,
Prof. Albrecht Berkessel (University of Cologne) for a screen of
epoxidation catalysts and Prof. Konrad Tiefenbacher (University of
Basel/ETH) for the screen of supramolecular catalysts.
REFERENCES
(1) Hermann, J.; Fayad, A. A.; Müller, R. Nat. Prod. Rep. 2017, 34,
135.
(2) (a) Dávila-Céspedes, A.; Hufendiek, P.; Crüsemann, M.; Schä-
berle, T. F.; König, G. M. Beilstein J. Org. Chem. 2016, 12, 969.
(b) Felder, S.; Kehraus, S.; Neu, E.; Bierbaum, G.; Schäberle, T.
F.; König, G. M. ChemBioChem 2013, 14, 1363.
(3) Fudou, R.; Iizuka, T.; Sato, S.; Ando, T.; Shimba, N.; Yamanaka,
S.; J. Antibiotics, 2001, 54, 153.
(4) Felder, S.; Dreisigacker, S.; Kehraus, S.; Neu, E.; Bierbaum, G.;
Wrigth, P. R.; Menche, D.; Schäberle, T. F.; König, G. M. Chem.
Eur. J. 2013, 19, 9319.
(5) Schmalzbauer, B.; Menche, D. Org. Lett. 2015, 17, 2956.
(6) Chen, K.; Baran, P. S. Nature 2009, 459, 824.
(7) (a) Snider, B. B. Chem. Rev. 1988, 88, 793. (b) Madelaine, C.; Va-
lerio, V.; Maulide, N. Chem. Asian J. 2011, 6, 2224.
(8) (a) Knölker, H.-J.; Baum, E.; Graf, R.; Jones, P. G.; Spieß, O. An-
gew. Chem. Int. Ed. 1999, 38, 2583. (b) Khalaf, A. A.; Albar, H.
A.; El-Fouty, K. O. Ind. J. Chem. 2010, 49B, 203.
(9) Sinisterra, J. V.; Garcia-Raso, A. Synthesis 1984, 502.
(10) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(11) Bégué, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004, 1, 18.
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(12) The mixture of byproducts could not be separated, however, care-
(19) (a) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 46,
4607. (b) Mc Murry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24,
979.
(20) (a) Hayashi, T.; Konishi, M.; Kobori, Y., Kumada, M.; Higuchi,
T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158. (b) Negishi, E.
Acc. Chem. Res. 1982, 15, 340.
(21) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(22) Ding, W. J.; Fang, D.-C. J. Org. Chem. 2001, 66, 6673.
(23) For an alternative Schönecker C–H oxidation, see Supplementary
Information and See, Y. Y.; Hermann, A. T.; Aihara, Y.; Baran, P.
S. J. Am. Chem. Soc. 2015, 137, 13776.
ful analysis of the 1H NMR revealed minor traces of the Meinwald
rearrangement product (Meinwald, J.; Labana, S. S.; Chadha, M.
S. J. Am. Chem. Soc. 1963, 85, 582). An indane, resulting from the
direct Friedel-Crafts reaction, was not detected.
1
2
3
4
5
6
7
(13) Zhang, Q.; Tiefenbacher, K. J. Am. Chem. Soc. 2013, 135, 16213.
(14) (a) Cram, D. J.; J. Am. Chem. Soc. 1949, 71, 3863. (b) Suzuki, K.;
Katayama, E.; Tsuchihashi, G. Tetrahedron Lett. 1984, 25, 1817.
(c) Maruoka, K.; Hasegawa, M.; Yamamoto, H. J. Am. Chem. Soc.
1986, 108, 3827. (d) Matsubara, S.; Yamamoto, H.; Oshima, K.
Angew. Chem. Int. Ed. 2002, 41, 2837.
8
9
(15) Trost, B. M. J. Am. Chem. Soc. 1967, 89, 1847.
(16) Replacement of the methoxy with a triflate group gave low yields
in the subsequent oxidation.
(24) (a) Bolm, C.; Schlingloff, G.; Weickhardt, K. Tetrahedron Lett.
1993, 34, 3405. (b) Bolm, C.; Schlingloff, G.; Weickhardt, K. Tet-
rahedron Lett. 1993, 34, 3405.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) Tobisu, M.; Takahira, T.; Morioka, T.; Chatani, N. J. Am. Chem.
Soc. 2016, 138, 6711.
(18) (a) Mann, F. G.; Pragnell, M. J. J. Chem. Soc. 1965, 4120. (b) Ire-
land, R. E.; Welch, S. J. Am. Chem. Soc. 1970, 92, 7232.
(25) (a) Haszeldine, R. N. J. Chem. Soc. 1951, 584. (b) Haszeldine, R.
N.; Sharpe, A. G. J. Chem. Soc. 1952, 993.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
Br
Me
H
1
2
3
4
5
6
7
ꢀSeven C–C Bond formations
O
O
H
MeO
Br
O
ꢀSelective Oxidations
H
O
salimabromide
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6
ACS Paragon Plus Environment