Angewandte
Communications
Chemie
no interpretable result. A 2:1 mixture of NBS and 17 in DMF
delivered an inseparable 19:38:34:9 mixture of four products.
1
According to GC-MS and H NMR analysis (300 MHz,
CDCl ), they represent monobromonaphthalene 18, two
3
unassigned dibromonaphthalenes 19 and iso-19, and tribro-
monaphthalene 20, respectively. This result is in sharp
contrast to the chemo- and regioselectivity of the dibromina-
tion of tetramethoxynaphthalene 13. Whence the difference?
The carbon–halogen bonds in aryl bromide 16a and aryl
iodide 16c exert a remote substituent effect during the
bromination of these substrates (Figure 2). We suggest that
Scheme 3. Heck coupling route to SAD substrates as employed in
Scheme 4. a) Pd(OAc) (2 mol%), P(oTol) (8 mol%), NEt , ethyl
2
3
3
2
-vinylacetate, propionitrile, reflux, 2 h; 74%. [a] Compounds 23a and
b’
g’
2
3b are mixtures of the trans,trans-configured diesters with a C =C ,
b g g’ a b
b’
C =C and a C =C ,C =C motif, respectively. [b] With Pd(OAc)
2
(
5 mol%) and P(oTol) (20 mol%) at reflux for 6 h.
3
Sharpless asymmetric dihydroxylation (SAD) of the
mixture of enoate isomers 21 and 21’ under buffered
[
47]
conditions gave 62% of b-hydroxy-g-lactone 24 with high
[
40]
enantiocontrol as predicted
b-naphthyl)ethanol moiety formed a hemiacetal with acet-
aldehyde, which underwent an oxa-Pictet–Spengler cycliza-
(99.3% ee; Scheme 4). The
(
[
39]
tion. This led to a 90:10 mixture of the naphthohydroqui-
nonopyrano-g-lactones 26 and epi-26. The former compound
was the desired one and could be purified by recrystalliza-
tion. The 90:10 diastereoselectivity of this reaction con-
trasts with the inverse 67:33 diastereoselectivity of the oxa-
[
48]
[
42]
Figure 2. A remote, yet relayed steric effect for rationalizing regiocon-
trol during the brominations of 16a to 14a (step 2 of the dibromina-
tion 13!14a) and of 16c to 14c in Scheme 3.
Pictet–Spengler cyclization of 25 and acetaldehyde to give
[
49]
epi-27 and 27. The respective substrates are very similar
because 24 represents 6’-bromo-25. A remote, but relayed
steric effect, akin to the remote halogen effects in the
naphthalene-based Wheland complexes pre-14a and pre-14c,
might cause the difference: the C6’ꢀBr bond in 24 should
[46]
this effect is steric in nature: The 2–halogen bond forces the
1
-OꢀMe and 8-OꢀMe bonds to point away from itself and
+
away from one another. If, in addition, the Cꢀ OꢀCꢀCꢀCꢀ push the methoxy groups at C5’ and C4’ closer to the
3
OꢀC moiety ortho to the sp -hybridized carbon atom in the
Wheland complex is planar for maximum resonance stabili-
zation, the 6-brominated Wheland complexes pre-14c and
pre-14a should be less sterically hindered than the respective
cyclization site (C3’) than in the bromine-free substrate 24.
[
50]
This establishes distinct neighborhoods.
We dimerized the monomeric structure 26 into a precursor
of g-actinorhodin (5), as shown in Scheme 5, top. Although
[
51]
7
-brominated isomers pre-iso-14c and pre-iso-14a. If, more-
conceptually straightforward, such dimerizations may be
[52,53]
over, the naphthalene 2-halides 16a and 16c react with NBS
in accordance with the Hammond postulate, the C6 position
should be brominated faster than the C7 position, which is
what we observed.
a challenge in practice.
Subjecting half of bromonaph-
Next, we studied monocouplings of naphthalene dibro-
mide 14a, diiodide 14b, and bromide/iodide 14c with ethyl
2
-vinylacetate (Scheme 3). Heck couplings with this olefin are
[
41]
[41b]
known. Employing Pd(OAc) /P(oTol)3
as the precata-
2
lyst, we hoped for enough delay between the desired first and
the unintended second Heck coupling of dihalides 14a–14c.
However, dibromide 14a and diiodide 14b underwent the
Heck couplings without much kinetic differentiation: The
dibromide gave 34% of the monocoupled and 11% of the
biscoupled product. Similarly, the diiodide led to 30%
monocoupling and 26% biscoupling. In contrast, subjecting
monoiodonaphthalene 14c and ethyl 2-vinylacetate to the
Heck conditions functionalized only the CꢀI bond. This
Scheme 4. Synthesis of building block 26. a) AD-mix b, NaHCO3,
MeSO NH , tBuOH/H O, RT, 2 days; 62%; b) MeCHO, BF ·OEt ,
produced a 90:10 mixture of the bromine-containing trans-
configured esters 21 (b,g-unsaturated, desired) and 21’ (a,b-
unsaturated, undesired) in 74% yield.
2
2
2
3
2
CH Cl , 08C!RT, 30 min; 88%; recrystallized from n-heptane/EtOH;
2
2
75%; c) MeCHO, BF ·OEt , CH Cl , RT, 1.5 h; 86%.
3
2
2
2
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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