Stereoselective Total Synthesis of the Dimeric Naphthoquinonopyrano-?-lactone (-)-Crisamicin A: Introducing the Dimerization Site by a Late-Stage Hartwig Borylation

Article abstract of DOI:10.1021/acs.orglett.0c01078

The first stereoselective total synthesis of the dimeric naphthoquinonopyrano-?-lactone (-)-crisamicin A was realized (13 steps, 5% overall yield). 1,4,5-Trimethoxynaphthalene, reached in five known steps, was brominated at C-3 to install a but-3-enoic ester by an ensuing Heck coupling. An asymmetric Sharpless dihydroxylation followed and gave a β-hydroxy-?-lactone with >99.9% ee. Its OH substituent and acetaldehyde established the dihydropyran ring in a completely diastereoselective oxa-Pictet-Spengler cyclization. The 2,3-fused anisole moiety allowed the C⁵-H bond under Hartwig's conditions to be borylated. This set the stage for engaging the resulting C⁵-B bond in an oxidative dimerization, which led to a binaphthohydroquinon-5-yl. The latter was advanced to synthetic crisamicin A by a double CAN oxidation (→ a binaphthoquinon-5-yl) and a double demethylation.

Full text of DOI:10.1021/acs.orglett.0c01078

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Letter
Stereoselective Total Synthesis of the Dimeric
Naphthoquinonopyrano-γ-lactone (−)-Crisamicin A: Introducing the
Dimerization Site by a Late-Stage Hartwig Borylation
Julia Kopp and Reinhard Bruckner*
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ABSTRACT: The first stereoselective total synthesis of the dimeric
naphthoquinonopyrano-γ-lactone (−)-crisamicin A was realized (13
steps, 5% overall yield). 1,4,5-Trimethoxynaphthalene, reached in five
known steps, was brominated at C-3 to install a but-3-enoic ester by an
ensuing Heck coupling. An asymmetric Sharpless dihydroxylation
followed and gave a β-hydroxy-γ-lactone with >99.9% ee. Its OH
substituent and acetaldehyde established the dihydropyran ring in a
completely diastereoselective oxa-Pictet−Spengler cyclization. The 2,3-
fused anisole moiety allowed the C5−H bond under Hartwig’s conditions
to be borylated. This set the stage for engaging the resulting C5−B bond
in an oxidative dimerization, which led to a binaphthohydroquinon-5-yl.
The latter was advanced to synthetic crisamicin A by a double CAN oxidation (→ a binaphthoquinon-5-yl) and a double
demethylation.
precursor-induced biosyntheses of (−)-crisamicin A (5) starting
aphthoquinonopyrano-γ-lactones (for examples, see
NFigure 1) have attracted attention in medicine, once from 1-13C-labeled sodium acetate and once from 2-13C-
labeled sodium acetate.13
pharmacology, and chemistry.1 They act against Gram-positive
and Gram-negative bacteria, pathogenic fungi, and yeasts and
may exhibit antiviral or anticancer activities.2 Naphthoquino-
nopyrano-γ-lactones from nature may be monomeric (e.g., 1a,3
1b,4 ent-1a5) or dimeric (e.g., 3,6 57,8). In addition, some natural
products have the structure of benzylic hydrogenolysis products
of naphthoquinonopyrano-γ-lactones, no matter whether they
are monomeric (cf. 29 vs ent-1a5) or dimeric (cf. 410 vs 36).11
In the following, we disclose the first stereoselective total
synthesis of the dimeric naphthoquinonopyrano-γ-lactone
(−)-crisamicin A7,8 (5). As a natural product, this compound
was isolated by Nelson et al.7 and Ling et al.8 It was the main
bioactive ingredient of a potpourri of compounds produced by
the soil bacterium Micromonospora purpureochromogenes subsp.
halotolerans from the Philippines.7,8 (−)-Crisamicin A is highly
soluble in DMA, DMF, and DMSO, moderately soluble in
CH3CN, EtOAc, CHCl3, AcOH, and acetone, yellow in acid and
purple in base.7 (−)-Crisamicin A is active against Gram-
positive bacteria,7 B16 melanoma cells,12 and the Herpes
simplex,12 Vaccinia,12 and Vesicular stomatitis viruses.12 The
Syntheses of monomeric naphthoquinonopyrano-γ-lactone
natural products as pure enantiomers abound. Targets, which
were reached, include kalafungin (1a)15/nanaomycin D (ent-
1a),16 frenolicin B (1b),17 arizonin B1,18 arizonin C1,19 and
griseusin A.20 The only stereoselective synthesis to date of a
naturally occurring dimeric naphthoquinonopyrano-γ-lactone
pertained to (+)-γ-actinorhodin (36). Neumeyer from our group
achieved it in 11 steps.21 A second stereoselective synthesis in
the field is due to K. Suzuki et al., who attained the related
compound (+)-actinorhodin (410) in 20 steps recently.22 From
the information in the introductory paragraph, the absence of γ-
lactone moieties23 lets compound 4 look like a hydrogenolysis
product of compound 3, though. The dimeric naphthoquino-
nopyrano-γ-lactone crisamicin A (5) was targeted four times
before the endeavor described below: Brimble’s group reached a
hexasubstituted binaphthyl in 200324 and the dimethyl ether of a
di-epi-diastereomer of 5 in 2014;25 the latter could neither be
demethylated nor isomerized.25 In 2008, Wang et al. synthesized
what must have beenwithout being addresseda 50:50
8
1
molecular formula (C32H22O127), H NMR, as well as 13C
NMR spectroscopy,13 ORD,8 and the Cotton effect8,14 in the
ORD curve revealed that (−)-crisamicin A (5) is a
naphthoquinonopyrano-γ-lactone dimer composed of two
identical subunits with the absolute configurations depicted in
Figure 1. That the dimerization site is at C-8 and C-8′ was
suggested based on a two-step derivatization8 and proved by
Received: March 24, 2020
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© XXXX American Chemical Society
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cyclization of the hydroxylactone 7;27 as often28 its steric course
was hardly predictable. (2) The hydroxylactone 7 should arise
by an asymmetric Sharpless dihydroxylation/in situ lactoniza-
tion from a trans-configurated β,γ-unsaturated ester 8.29 (3)
Such esters result from Heck couplings between a but-3-enoic
ester and an aryl halide,30 here the bromonaphthalene 9. 9 would
be made from NBS and 1,4,5-trimethoxynaphthalene44 (10).
The latter had been prepared in five steps from 1,5-
dihydroxynaphthalene (“route A”31−34 = our route) or in four
steps from 1,4-dimethoxybenzene (“route B”35−37).
We synthesized three trans-configured type-8 esters, namely, a
methyl ester (8a, 59%), benzyl ester (8b, 91%), and tert-butyl
ester (8c, 75%), by the Heck couplings30,38,39 shown in Scheme
1. They were performed at 140−145 °C in a sealed tube for 3−4
Scheme 1. Synthesis of the β,γ-Unsaturated Esters 8a−c by
Heck Couplings of the Bromonaphthalene 9 with the
a
Butenoates 12a−c
Figure 1. Naturally occurring naphthoquinonopyrano-γ-lactones (1a−
5) and three synthetic diastereomers (meso-, meso,iso-, and meso,rac-5).
mixture of rac-5 and meso-5 (for the formulas, see Figure 1).11a
In 2015, Fernandes and Mulay developed an intriguing
bidirectional approach;11b it led to what must have beenbut
was not recognized asa 50:50 mixture of the unnatural
naphthoquinonopyrano-γ-lactone dimers rac,iso-526 and meso,-
iso-526 (for the formulas, see Figure 1).11b
a
Reagents and conditions: (a) K2CO3 (1.2 equiv), acetone, rt, 20
min; MeI (1.5 equiv), 0 °C, 15 min; reflux, 4.5 h; 36% [with acetone
(22 wt %) accompanying the low-boiling product 12a; ref 41, 77%];
(b) Cl−CO2Bn (1.1 equiv), pyridine (2.4 equiv), CH2Cl2, rt, 22 h;
78% [with EtOAc (9 wt %) accompanying the low-boiling product
12b; ref 42, 67%]; (c) t-BuOAc (4.0 equiv), BF3·OEt2 (7 mol %), rt,
64 h; 46% [with t-BuOAc (10 wt %) accompanying the low-boiling
product 12c; ref 43, 80%]; (d) NBS (1.1 equiv), CCl4, rt, 8.5 h; 82%
(ref 44, 90%); (e) Pd2(dba)3 (2 mol %), t-Bu3P (8 mol %), Cy2NMe
(3.0 equiv), toluene, 140−145 °C (sealed tube), 3−4 days; for R =
Me, 59% of an 82:18 mixture of 8a/iso-8a separated from 35%
recovered 9; for R = Bn, 91% of an 84:16 mixture of 8b/iso-8b; for R
= t-Bu, 75% of an 84:16 mixture of 8c/iso-8c.40
The pivotal step in our retrosynthetic analysis of (−)-crisa-
micin A (Figure 2) is a late-stage oxidative Hartwig borylation/
days as opposed to being refluxed at ambient pressure for 2
days40 to reach the mentioned yields. The coupling products
8a−c were the major constituents of inseparable 84:16 to 82:18
mixtures with the bond-shifted isomers iso-8a−c. The but-3-
enoates 12a−c, which partook in these Heck couplings, were
prepared from but-3-enoic acid (11) by O-methylation41 (MeI/
K2CO3), BAC2 benzylation42 (ClCO2Bn, pyridine), or O-tert-
butylation43 (t-BuOAc, cat. BF3·OEt2); the less volatile the ester,
the higher its yield (78% for the benzyl ester 12b). Their partner
in the Heck couplings, the bromonaphthalene 9, stemmed from
a known bromination of 1,4,5-trimethoxynaphthalene (10),44
which, in turn, was at hand from an earlier execution21 of a
known31 five-step synthesis.
Figure 2. Retrosynthetic analysis of (−)-crisamicin A (5) with a late-
stage Hartwig borylation for creating the dimerization site.
The mixtures of deconjugated esters 8a−c and conjugated
isomers iso-8a−c were subjected to (DHQ)2PHAL-controlled
NaHCO3-buffered45 Sharpless dihydroxylations one by one
(Scheme 2). This gave the dihydroxyester (13; 65%) by
employing the tert-butyl esters 8c/iso-8c, but led to the desired
hydroxylactone 7 with >99.9% ee when starting from the methyl
esters 8a/iso-8a46 (58% yield) or from the benzyl esters 8b/iso-
8b46 (77% yield after increasing the amounts of osmium and
oxidative homocoupling tandem transformation 2 × 6 → → 5. It
held the promise of proceeding in an innovative manner from a
monomeric to a dimeric naphthoquinonopyrano-γ-lactone here.
It also entailed the hope of being useful beyond this specific
objective. The ensuing retrosynthetic simplifications are akin to
our approach to (+)-γ-actinorhodin:21 (1) The tetracyclic
building block 6 should stem from an oxa-Pictet−Spengler
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Scheme 2. Enantio- and Diastereoselective Conversion of the
Scheme 3. Regioselective Pinacolatoborylation of the
Naphthalene-Containing β,γ-Unsaturated Esters 8a−c into
Naphthohydroquinonopyrano-γ-lactone 6 (→ 14) and
Ensuing Autoxidation (→ 15; X-ray Analysis)/Oxidation/
Demethylation Sequence Leading to (−)-Crisamicin A (5)
a
the Monomeric Naphthohydroquinonopyrano-γ-lactone 6
a
a
Reagents and conditions: (a) K2OsO2(OH)4 (0.6 mol %),
(DHQ)2PHAL (1.1 mol %), K3Fe(CN)6 (3.0 equiv), K2CO3 (2.9−
3.0 equiv), NaHCO3 (2.9−3.0 equiv), MeSO2NH2 (1.0−1.1 equiv), t-
BuOH/H2O (1:1), rt, 1 day;45 58% (>99.9% ee); (b) same as (a) but
K2OsO2(OH)4 (2.0 mol %), (DHQ)2PHAL (10 mol %), 16 h;47 77%
(>99.9% ee); (c) trifluoroacetic acid (20 mol %), toluene, reflux, 35
min; 55% 7 separated from 22% of a diastereomer (1H NMR
spectroscopy proved that this lactone is trans-configured; without
knowing its absolute configuration, one cannot tell whether it formed
from 7 by a benzylic or by a homobenzylic epimerization); (d)
acetaldehyde (8 equiv), BF3·OEt2 (10 equiv), CH2Cl2, 0 °C → rt, 50
min;48 88%; (e) same as (d); 67%; (f) same as (a); 65% (>99.9% ee).
ligand47). The same hydroxylactone 7 was reached via the
dihydroxyester 13 and F3CCO2H by being refluxed in toluene
(55% yield, >99.9% ee), albeit less efficiently (36% overall from
8c/iso-8a).
a
Reagents and conditions: (a) Pinacolborane (2.7 equiv), [{Ir(μ-
OMe)COD}2] (2.5 mol %), 4,4′-di-tert-butyl-2,2′-dipyridyl (5 mol
%), THF, 80 °C, 1 day; filtration over silica;52 (b) KF (3.7 equiv),
B(OH)3 (4.6 equiv), O2 (1.0 bar), PdCl2(PPh3)2 (20 mol %), THF/
H2O (4:1), rt, 2.5 h; 46% over two steps;54 (c) (NH4)2[Ce(NO3)6]
(4.7 equiv), MeCN/H2O (2:1), rt, 20 min; 65%;56 (d) AlCl3 (12
equiv), CH2Cl2, 0 °C, 20 min; to rt, 3 h; 67%.56b
The chemistry of Scheme 2 ended with a “simple” oxa-Pictet−
Spengler cyclization, incorporating acetaldehyde in the presence
of BF3·OEt248 (7 → 6; 88% yield). In an “elaborate variant” of
that cyclization, it concurred with tert-butyl ester cleavage and
lactonization (13 → 6; 67% yield). Both procedures delivered
the naphthohydroquinonopyrano-γ-lactone 6 with perfect
3a,5trans-selectivity.49 Disconcerted by the lack of precedence
for such a pleasing outcome,28,50 we tried many other oxa-
Pictet−Spengler conditions before obtaining an inseparable
mixture of naphthohydroquinonopyrano-γ-lactone diaster-
eomers 6, 5-epi-6, and 3a-epi-6.51 The newly formed compounds
5-epi-6 and 3a-epi-6 were the 3a,5cis- and 3a,11btrans-isomer of the
desired diastereomer 6 (3a,5trans,3a,11bcis) according to 1H NMR
similarities to model compounds.48
Having met the stereochemical exigencies of our endeavor
(Scheme 2), the naphthohydroquinonopyrano-γ-lactone 6 was
dimerized in steps (a) and (b) of Scheme 3. Step (a), a Hartwig
borylation, succeeded with pinacolborane, 2.5 mol % of [{Ir(μ-
OMe)COD}2], and 5 mol % of 4,4′-di-tert-butyl-2,2′-
dipyridyl.52,53 It activated the least hindered naphthyl−H
bond of substrate 6 with perfect regioselectivity; that is, it
attacked meta relative to both the MeO group and the annulated
ring. The expected boronic ester 14 was so labile that it could not
be purified by flash chromatography but only by filtration over
silica. This measure reduced the time expenditure for the
ensuing step (b), a Pd-catalyzed autoxidative homocoupling
“under operationally simple conditions”,54 from 1 day to 2.5 h
and increased the yield of the desired binaphthyl 15in an
inseparable 77:23 mixture with Ph3POto 46% over two
steps.55 The biaryl nature of compound 15 became clear from a
C38H39O12 peak [M + H⊕] in the high-resolution mass spectrum
(ESI) and from a NOESY cross-peak, which interrelated C-7
with C-9′ (and, indistinguishably, C-7′ with C-9). We managed
to crystallize compound 15 so that its 3D structure could be
proven by the first X-ray structural analysis of a dimeric
naphthohydroquinonopyrano-γ-lactone.
Oxidizing the binaphthyl 15 (accompanied by Ph3PO) with
(NH4)2[Ce(NO3)6] delivered the naphthoquinonopyrano-γ-
lactone dimethyl ether 1656 in 65% yield (Scheme 3).
Gratifyingly, it was separable from Ph3PO by column
chromatography using pentane/acetone as an eluent.57 In
CH2Cl2, the ether functions of compound 16 were cleaved
21,58
smoothly with AlCl3
(→ 67% 559) but unselectively with
BCl358,60 (→ 5 + a structurally similar contaminant, which was
1
inseparable). The H NMR spectrum (500.10 MHz, CDCl3,
CD2Cl2) and 13C NMR spectrum (125.75 MHz, CDCl3,
CD2Cl2) of our totally synthetic (−)-crisamicin A (5) matched
their precedents from isolated (−)-crisamicin A (58,13).
In conclusion, we realized the first stereoselective total
synthesis of the dimeric naphthoquinonopyrano-γ-lactone
(−)-crisamicin A (5). Starting from 1,5-dihydroxynaphthalene
(which gave 46% of the trimethoxynaphthalene 10 in five
steps;31 not depicted in Scheme 1), it comprised 13 steps and
C
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totaled 5% yield. A key feature of our approach is that binaphthyl
formation occurred late and affected the naphthalene moiety of
compound 6, which had been unfunctionalized at the
dimerization site up to that stage (Scheme 3). This naphthalene’s
C7−H bond was activated by a regioselective Hartwig
borylation, upon which the resulting naphthylboronic pinacolate
14 was dimerized oxidatively (→ biaryl 15). Quinone formation
(→ 16) and ether cleavage (→ 5) finished our route.
It appears as if Hartwig borylation/C−C homocoupling
tandem reactions like this study’s sequence (6 → 14 → biaryl
15) have not been used previously for reaching symmetrical
condensed biaryls with functional groups.61 Nevertheless,
accesses of that kind to “all sorts of symmetrical biaryls with
functional groups” are conceivable. These might even include
symmetrical condensed heterocyclic biaryls with functional
groups (or precursors thereof), for example, a bi(quinolin-6-
yl),62 a bi(pyrido[1,2-a]pyrimidin-8-yl),63 a bi(benzothiazol-6-
yl),64 or a bi(indol-5-yl);65 none of these compounds was
synthesized by this strategy.
DEDICATION
■
Commemorating Professor Rolf Huisgen (Ludwig-Maximilians-
̈
̈
Universitat Munchen), who passed away this year shortly before
reaching his 100th birthday.
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ASSOCIATED CONTENT
■
̅
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01078.
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̈
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CCDC 1979688 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
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̅
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AUTHOR INFORMATION
■
Corresponding Author
Reinhard Bruckner − Institut fur Organische Chemie, Albert-
̈ ̈
(12) Reference 8 cites a personal communication between D. Ling and
C. P. Schaffner as the source of this statement. The latter only publishes
the activity against Gram-positive bacteria in ref 7.
̈
Ludwigs-Universitat, D-79104 Freiburg, Germany;
orcid.org/0000-0002-9028-8436;
Email: reinhard.brueckner@organik.chemie.uni-freiburg.de
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1988, 41, 1659−1667.
(14) In ref 8, the optical activity of (−)-crisamicin A (5) was only
characterized by an ORD spectrum not by explicit specific rotations.
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M. Bull. Chem. Soc. Jpn. 1985, 58, 1699−1706. (b) Tatsuta, K.;
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Author
Julia Kopp − Institut fur Organische Chemie, Albert-Ludwigs-
̈
̈
Universitat, D-79104 Freiburg, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01078
680−682. (c) Fernandes, R. A.; Bruckner, R. Synlett 2005, 1281−1285.
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The manuscript was written through contributions of both
authors.
Notes
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Hengartner, U.; Streith, J. Helv. Chim. Acta 1997, 80, 43−58. (d) Ref
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Dr. Daniel Kratzert (Institut fu
sche Chemie, Albert-Ludwigs-Universitat Freiburg) for the X-
ray crystal structure analysis.
̈
r Anorgani-
̈
D
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15e. (e) Zhang, Y.; Wang, X.; Sunkara, M.; Ye, Q.; Ponomereva, L. V.;
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the non-patent literature: Yasuda, D.; Nakajima, M.; Yuasa, A.; Obata,
R.; Takahashi, K.; Ohe, T.; Ichimura, Y.; Komatsu, M.; Yamamoto, M.;
Imamura, R.; Kojima, H.; Okabe, T.; Nagano, T.; Mashino, T. Bioorg.
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̈
2539.
(19) (a) Mahlau, M.; Fernandes, R. A.; Bru
̈
ckner, R. Eur. J. Org. Chem.
(39) Only previous Heck coupling with tert-butyl but-3-enoate (12c)
in the non-patent literature: Mackman, R. L.; Steadman, V. A.; Dean, D.
K.; Jansa, P.; Poullennec, K. G.; Appleby, T.; Austin, C.; Blakemore, C.
A.; Cai, R.; Cannizzaro, C.; Chin, G.; Chiva, J.-Y. C.; Dunbar, N. A.;
Fliri, H.; Highton, A. J.; Hui, H.; Ji, M.; Jin, H.; Karki, K.; Keats, A. J.;
Lazarides, L.; Lee, Y.-J.; Liclican, A.; Mish, M.; Murray, B.; Pettit, S. B.;
Pyun, P.; Sangi, M.; Santos, R.; Sanvoisin, J.; Schmitz, U.; Schrier, A.;
Siegel, D.; Sperandio, D.; Stepan, G.; Tian, Y.; Watt, G. M.; Yang, H.;
Schultz, B. E. J. Med. Chem. 2018, 61, 9473−9499.
2011, 4765−4772. (corrections of absolute configuration: ref 19b,
footnote 133 in ref 19c, and footnote 18b in ref 18). (b) Fernandes, R.
A.; Mulay, S. V.; Chavan, V. P. Tetrahedron: Asymmetry 2013, 24,
1548−1555. (c) Neumeyer, M.; Bru
̈
ckner, R. Eur. J. Org. Chem. 2016,
5060−5087.
(20) (a) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983, 48,
2311−2314. (b) Zhang, Y.; Ye, Q.; Wang, X.; She, Q.-B.; Thorson, J. S.
Angew. Chem. 2015, 127, 11371−11374; Angew. Chem., Int. Ed. 2015,
54, 11219−11222.
(40) Procedure from ref 18 (reflux, 2 days) modified to sealed tube,
140−145 °C, 3 days.
(21) Neumeyer, M.; Bruckner, R. Angew. Chem. 2017, 129, 3432−
̈
3437; Angew. Chem., Int. Ed. 2017, 56, 3383−3388.
́
́
(41) Esteban, G.; Lopez-Sanchez, M. A.; Martínez, E.; Plumet, J.
Tetrahedron 1998, 54, 197−212.
(22) Ninomiya, M.; Ando, Y.; Kudo, F.; Ohmori, K.; Suzuki, K. Angew.
Chem. 2019, 131, 4308−4314; Angew. Chem., Int. Ed. 2019, 58, 4264−
4270.
(42) Okamura, T.; Asano, K.; Matsubara, S. Chem. Commun. 2012, 48,
5076−5078.
(23) Such γ-lactone moieties may form diastereoselectively by
autoxidizing what paragraph 1 of this paper addresses as “benzylic
hydrogenolysis products” (e.g., compound 4) with air. (a) Ref 5:
nanaomycin A (2) → nanaomycin D (ent-1a). (b) Li, T.-T.; Ellison, R.
H. J. Am. Chem. Soc. 1978, 100, 6263−6265. (nanaomycin A (2) →
nanaomycin D (ent-1a) and kalafungin (1a). (c) Ref 15f. (d) Ref 11b.
(24) Brimble, M. A.; Lai, M. Y. H. Org. Biomol. Chem. 2003, 1, 2084−
2095.
(43) Tsai, F.-T.; Wang, Y.; Darensbourg, D. J. J. Am. Chem. Soc. 2016,
138, 4626−4633.
(44) Carreno, M. C.; García Ruano, J. L.; Sanz, G.; Toledo, M. A.;
̃
Urbano, A. J. J. Org. Chem. 1995, 60, 5328−5331.
(45) Procedure from Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K.
B. Tetrahedron Lett. 1994, 35, 3469−3472 (0 °C) modified to room
temp.
(46) Whereas the AD mix dihydroxylated the major components 8a−
c of our substrate mixtures (8c → 13) and induced two subsequent
lactone formations (8a,b → 7), the accompanying α,β-unsaturated
esters iso-8a−c remained inert. They were separated from 7 or 13 by
column chromatography.
(25) Brimble, M. A.; Hassan, N. P. S.; Naysmith, B. J.; Sperry, J. J. Org.
Chem. 2014, 79, 7169−7178.
(26) Reference 11b designates a constitutional isomer of (−)-crisa-
micin A (5), wherein the phenolic OH groups were displaced from C-
10 and C-10′ to C-7 and C-7′, respectively, as “iso-crisamicin A”.
(27) (a) Eid, C. N.; Shim, J.; Bikker, J.; Lin, M. J. Org. Chem. 2009, 74,
423−426. (b) Korwar, S.; Nguyen, T.; Ellis, K. C. Bioorg. Med. Chem.
Lett. 2014, 24, 271−274. (c) Ref 48.
(47) The standard amounts of K2OsO2(OH)4 (0.2 mol %) and ligand
(1 mol %) are occasionally surmounted in order to increase the reaction
rate (and possibly also the ee). The respective reagent mixtures were
designated “modified AD-mix” (e.g., ref 47a) or “super AD-mix” (e.g.,
refs 47b and 47c). (a) K2OsO2(OH)4 (1 mol %), (DHQ)2PHAL (5
mol %): Bennani, Y. L.; Sharpless, K. B. Tetrahedron Lett. 1993, 34,
2079−2082. (b) K2OsO2(OH)4 (1 mol %), ligand (5 mol %): Kolb, H.
C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483−
2547 (footnote 76). (c) K2OsO2(OH)4 (1 mol %), (DHQ)2PHAL (10
mol %): Nicolaou, K. C.; Yue, E. W.; La Greca, S.; Nadin, A.; Yang, Z.;
Leresche, J. E.; Tsuri, T.; Naniwa, Y.; de Riccardis, F. Chem. - Eur. J.
1995, 1, 467−494 (Table 2). The three references described
dihydroxylations at 0 °C, whereas we worked at room temp.
(28) Ref 18, p 2518, and discussion thereof.
(29) Genealogy of this tandem transformation: (a) Wang, Z. M.;
Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-Bagchi, A.; Keinan, E.
Tetrahedron Lett. 1992, 33, 6407−6410. (b) Rama Mohan, H.; Rao, A.
S. Synth. Commun. 1993, 23, 2579−2585. (c) Miyazaki, Y.; Hotta, H.;
Sato, F. Tetrahedron Lett. 1994, 35, 4389−4392. (d) Harcken, C.;
̈
Bruckner, R. Angew. Chem. 1997, 109, 2866−2868; Angew. Chem. Int.
Ed. 1997, 36, 2750−2752.
(30) Heck couplings with methyl but-3-enoate (12a): (a) Zhang, Y.;
Ye, Q.; Wang, X.; She, Q.-B.; Thorson, J. S. Angew. Chem. 2015, 127,
11371−11374; Angew. Chem., Int. Ed. 2015, 54, 11219−11222. (b) Ref
48.
(31) Route A: (1) Methylation of both hydroxy groups of 1,5-
dihydroxynaphthalene (99% yield32);33 (2) mono-Vilsmeier−Haack
reaction (93%33 or 92%32 yield); (3) mCPBA oxidation (99%33 or
92%32 yield); (4) formate methanolysis (77% yield over two steps33 or
64% yield32); (5) methylation of the hydroxy group (86% yield34); the
overall yield of compound 10 from refs 32 and 34 was 46%.
(32) Abbott, G. L.; Wu, X.; Zhao, Z.; Guo, L.; Birman, V. B.; Hasinoff,
B. B.; Dmitrienko, G. I. MedChemComm 2014, 5, 1364−1370.
(33) Hannan, R. L.; Barber, R. B.; Rapoport, H. J. Org. Chem. 1979, 44,
2153−2158.
(34) Tanoue, Y.; Terada, A.; Matsumoto, Y. Bull. Chem. Soc. Jpn. 1989,
62, 2736−2738.
(35) Route B: (1) Bromination of 1,4-dimethoxybenzene (96%
yield36); (2) aryne formation and Diels−Alder addition to furan;37 (3)
hydrolysis and dehydration;37 (4) methylation of the hydroxy group
(87% yield over three steps37); the overall yield of compound 10 was
83%.
(48) Procedure adapted from: Neumeyer, M.; Kopp, J.; Bruckner, R.
̈
Eur. J. Org. Chem. 2017, 2883−2915.
(49) The 3a,5trans-configuration of compound 6 was deduced from a
cross-peak correlating the resonances of 3a-H and 5-CH3 in a 500.10
MHz NOESY spectrum.
(50) Why diastereomer 6 arises completely 3a,5trans-selectively
remains a riddle. The structural feature, which we contemplated as
the reason for the 90:10 3a,5trans-selective formation of another
naphthohydroquinonopyrano-γ-lactone21 (not in the least because
seemingly in line with a number of related results28) is clearly absent
here. A weakness in understanding such 3a,5trans-selectivities in general
is that it is always unclear whether they are due to kinetic or
thermodynamic control. If thermodynamic control prevails, 3a,5trans-
selective naphthohydroquinonopyrano-γ-lactone formation could have
the identical reason as the well-known 3a,5cis-→ 3a,5trans-naphthoqui-
nonopyrano-γ-lactone isomerizations: the minimization of 1,3-allyl
strain in the substructure O−CC−C5−Me, which accompanies a
pseudoaxial orientation of the methyl group at C5 in a 3a,5trans-
substituted dihydropyran ring as opposed to a pseudoequatorial
orientation of the same methyl group at C5 in a 3a,5cis-substituted
dihydropyran ring. This kind of pseudoaxial orientation of the methyl
group at C5 in the 3a,5trans-substituted dihydropyran ring of the
preferred diastereomer 6 of our oxa-Pictet−Spengler product emerges
from the following analysis of its solid-state structure:
(36) Zysman-Colman, E.; Arias, K.; Siegel, J. S. Can. J. Chem. 2009, 87,
440−447.
(37) Ando, Y.; Matsumoto, T.; Suzuki, K. Synlett 2017, 28, 1040−
1045.
E
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(51) The conversion of lactone 7 into a 77:15:8 mixture of 6, 5-epi-6,
and 3a-epi-6 succeeded by treatment with acetaldehyde dimethyl acetal
(4.3 equiv) and BF3·OEt2 (10 equiv) in CF3CO2H/THF (4:1) at 70 °C
for 4 min. These diastereomers were separable by analytical but not by
preparative HPLC (detailed NMR analyses are in Supporting
Information, section 3).
(52) Procedure adapted from: (a) Hume, P.; Furkert, D. P.; Brimble,
M. A. Tetrahedron Lett. 2012, 53, 3771−3773. (b) Schunemann, K.;
̈
Furkert, D.; Connelly, S.; Fraser, J.; Sperry, J.; Brimble, M. A. Synlett
2014, 25, 556−558. (c) Young Jeong, J.; Sperry, J.; Taylor, J. A.;
Brimble, M. A. Eur. J. Med. Chem. 2014, 87, 220−227.
(53) Hartwig borylations of naphthalenes are known to tolerate
bromine substituents,52c OMe52a,b or OTBS52a groups, and a
conjugated keto function.52a The borylation of 6 → 14 of Scheme 3
occurred without touching the lactone motif.
(54) Method: Darzi, E. R.; White, B. M.; Loventhal, L. K.; Zakharov,
L. N.; Jasti, R. J. Am. Chem. Soc. 2017, 139, 3106−3114.
(55) We could separate this mixture only partially, fractioning it
through column chromatography. High-field NMR spectra of the
resulting pure product showed (1) one 1H NMR resonance fewer for
the dimer 15 than for the monomer 6 but (2) the same number of 13C
NMR resonances in 15 vs 6.
(56) Procedure adapted from: (a) Sperry, J.; Sejberg, J. J. P.; Stiemke,
F. M.; Brimble, M. A. Org. Biomol. Chem. 2009, 7, 2599−2603. (b) Ref
21.
(57) According to ref 25, oxidation of 5,5′-epi,epi-16 failed with
(NH4)2[Ce(NO3)6] or PIFA and succeeded with AgO/HNO3 (98%
crude yield), but all purification attempts degraded the product.
(58) Didemethylations of the crude diether 5-epi,5′-epi-16 with AlCl3
or with BCl3 gave complex mixtures according to ref 25.
(59) Previously,21 we synthesized (+)-γ-actinorhodin (3) by the same
kind of ether cleavage. Its extraction from the aqueous phase was
hampered by its being almost insoluble and extremely slowly soluble in
EtOAc. No such problem arose when isolating (−)-crisamicin A (5).
(60) Contrasting our finding, BCl3 in CH2Cl2 was suitable for
didemethylating what must have been a 50:50 mixture of the diethers
rac- and meso-16 to what must have been a 50:50 mixture of rac- and
meso-5 according to ref 11a.
(61) (a) Tandem transformations starting with a Hartwig borylation
but which continued differently than by an oxidative dimerization
already have a record in natural product synthesis: Yuan, C.; Liu, B. Org.
Chem. Front. 2018, 5, 106−131. (b) While our work was underway, a
tandem process of numerous aromatics was published: Pei, X.; Zhou,
G.; Li, X.; Xu, Y.; Panicker, R. C.; Srinivasan, R. Org. Biomol. Chem.
2019, 17, 5703−5707. It is akin to our tandem transformation leading
to the symmetrical condensed biaryl 15. Entitled “Sterically Controlled
C−H/C−H Homocoupling of Arenes via C−H Borylation”, this study
describes the conversion of monocyclic arenes (24 isocyclic, 6
heterocyclic) to symmetrical noncondensed biaryls by sequential
Hartwig borylations and Cu(OAc)2-catalyzed air oxidations. The
same sequence was applied to the condensed aromatic monomers
naphthalene, 6-bromoquinoline, benzofuran, and benzothiophen
(62) Ardashev, B. I.; Malina, Z. V. J. Gen. Chem. USSR 1951, 3, 1349−
1354 cited from a structure search with SciFinder.
(63) Szebenyi-Gyori, E.; Koleszar, K.; Kovacs-Mindler, V.; Hermecz,
I.; Horvath, G.; Toth, G. Magyar Keminai Folyoirat 1982, 88, 327−329
cited from a structure search with SciFinder.
(64) Found by a structure search with SciFinder (CAS registry
number: 1987263-58-0) yet without a reference.
(65) Zegkhugkh, D.; Kadzhrishvili, D. O.; Samsoniya, S. A.; Suvorov,
N. N. Chem. Heterocycl. Compd. 1990, 26, 293−295.
F
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Org. Lett. XXXX, XXX, XXX−XXX