Enantioselective total synthesis and biological evaluation of (+)-kibdelone A and a tetrahydroxanthone analogue

Article abstract of DOI:10.1021/jo401169z

The total synthesis of kibdelone A has been accomplished via In(III)-catalyzed arylation of a heterocyclic quinone monoketal and iodine-mediated oxidative photochemical electrocyclization for construction of the ABCD ring moiety. Enzymatic dihydroxylation of methyl 2-halobenzoate substrates was employed for synthesis of activated 2-halo-cyclohexene F-ring fragments. A one pot oxa-Michael/Friedel-Crafts process allowed access to the first simplified DEF ring analogues of the kibdelones.

Full text of DOI:10.1021/jo401169z

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Article
Enantioselective Total Synthesis and Biological Evaluation
of (+)-Kibdelone A and a Tetrahydroxanthone Analogue
Dana K. Winter, Mary Ann Endoma-Arias, Tomas Hudlicky, John Albert Beutler, and John A. Porco
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401169z • Publication Date (Web): 08 Jul 2013
Downloaded from http://pubs.acs.org on July 9, 2013
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Enantioselective Total Synthesis and Biological
Evaluation of (+)-Kibdelone A and a
Tetrahydroxanthone Analogue
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Dana K. Winter,† Mary Ann Endoma‐Arias,‡ Tomas Hudlicky,‡ John A.
Beutler,§ and John A. Porco, Jr*,†
† Department of Chemistry, Center for Chemical Methodology and Library Development
(CMLD‐BU), Boston University, 590 Commonwealth Avenue, Boston, MA, 02215, USA.
‡ Department of Chemistry and Centre of Biotechnology, Brock University, 500 Glenridge
Ave., St. Catharines, ON, L2S 3A1, Canada.
§ Molecular Targets Laboratory, National Cancer Institute, Frederick, MD, 21702, USA
Department of Chemistry and Center for Chemical Methodology and Library Development
(CMLD‐BU), Boston University, Boston, Massachusetts 02215
* Email: porco@bu.edu
Abstract:
The total synthesis of kibdelone A has been accomplished using In(III)‐catalyzed arylation of a
heterocyclic quinone monoketal and iodine‐mediated oxidative photochemical
electrocyclization for construction of the ABCD ring moiety. Enzymatic dihydroxylation of
methyl 2‐halobenzoate substrates was employed for synthesis of activated 2‐halo‐cyclohexene
F‐ring fragments. A one pot oxa‐Michael‐Friedel‐Crafts process allowed access to the first
simplified analogues of the kibdelones
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INTRODUCTION
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In the last decade, the polycyclic xanthone natural products have attracted significant attention from the scientific
community due to the potential of several members of the family, including kibdelones A‐C (1, 3‐4, Figure 1)1, as
antiproliferative agents. Although, the exact mode of action of these natural products has yet to be determined, it is
likely that their potent anticancer activity may be related to the presence of the C‐7 substituted tetrahydroxanthone
pharmacophore (Figure 1 highlighted in red).2 In particular, kibdelones A‐C (1, 3‐4) are active at low nanomolar
concentrations against tumor cell lines while the congener isokibdelone A (2) was found to be 10 to 200 fold less
potent.3 Both natural products possess a common ABCD core and diverge in their respective connectivity of the E/F
rings (cf. 1 and 2, Figure 1) and therefore substitution of the tetrahydroxanthone core.
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Figure 1. Structures of isolated polycyclic xanthone natural products
Recently, we reported an approach to (+)‐kibdelone C (4) utilizing Pt(IV)‐mediated arylation of a quinone
monoketal to construct the ABCD ring system which was then further reacted with a chiral, non‐racemic
iodocyclohexene carboxylate EF ring synthon via site selective oxa‐Michael reaction followed by Friedel‐Crafts
cyclization to construct the hexacyclic core.4 Although our synthesis established one of the first routes to a non‐fully‐
aromatic polycyclic xanthone,5 there was still room for improved synthetic access to this family of natural products to
enable mode of action studies. In this paper, we report the total synthesis of kibdelone A employing In(III)‐catalyzed
arylation of a heterocyclic quinone monoketal for construction of the ABCD ring system. Enzymatic dihydroxylation of
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methyl 2‐halobenzoate substrates was also successfully employed for synthesis of activated halo‐cyclohexene F‐ring
fragments.
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RESULTS AND DISCUSSION
Kibdelone A (1)3 is known to be stable upon exposure to air or standing in solution in contrast to kibdelones B (3)
and C (4) which have been shown to interconvert in alcoholic solvents to an equilibrium mixture of kibdelones
A/B/C. Learning from our previous synthetic endeavors,4 we wished to access the more stable congener kibdelone A
1 using a one pot oxa‐Michael/ Friedel‐Crafts cyclization between phenanthrenetriol 5 and activated halocyclohexene
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ester synthon
6 to form the structurally challenging tetrahydroxanthone pharmacophore (Figure 2).
Figure 2. Retrosynthetic analysis for kibdelone A (1)
Activated chiral F‐ring synthon 6 may be accessed via microbial dihydroxylation of methyl 2‐halobenzoate 11
followed by acetonide formation and Markovnikov hydration of diol 8.6 As an initial synthetic approach, we
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envisioned that ABCD core structure 5 could be accessed utilizing a metal‐mediated Friedel‐Crafts/ hydroarylation
cascade between quinone monoketal 9 and aryl alkyne 10.
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We first studied the possibility for phenanthrene formation a metal‐mediated Friedel‐Crafts/ hydroarylation
cascade of model quinone monoketal 12 and the commercially available aryl alkyne, 1‐ethynyl‐3,5‐
dimethoxybenzene 13 (Scheme 1).7 This study revealed that formation of biaryl 14 and hydroarylation to
phenanthrene 15 could be achieved using PtBr4 in a one or two pot process and that highly ionizing solvents such as
1,1,1,3,3,3‐hexafluroisopropanol (HFIP)8 and 2,2,2‐trifluoroethanol (TFE) were critical for the biaryl formation;<30%
yield of 14 and longer reaction times (12h) were observed in the absence of fluorinated solvents. Other metals such
as InCl3 and AuCl3 were found to catalyze the initial biaryl formation in high yield but further hydroarylation was not
observed.
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Scheme 1. Model studies for phenanthrene formation
In order to evaluate the Friedel‐Crafts/ hydroarylation cascade on the natural product system, alkyne 10 was
synthesized in two steps from bromide 16. Under optimized reaction conditions, we were able to construct alkynyl
biaryl 7 in 62% yield by treatment of quinone monoketal 94a with aryl alkyne 10 using a catalytic amount of AuCl3 in
HFIP/DCE (10:1). However, further hydroarylation to the desired product 5 was not observed in any one or two pot
processes attempted. Metals known to catalyze alkyne hydroarylation9 with electron rich, neutral or poor systems
including PtBr4, PtCl2, PtCl2(PhCN)2/AgSbF6, Au(PPh3)Cl/AgSbF6, AuCl3, Fe(OTf)3, FeCl3, InCl3, In(OTf)3, Sc(OTf)3, RuCl3,
RhCl3, ZrCl4, Bi(OTf)3, and GaCl3 were evaluated but afforded only the starting material (7) or the derived methyl
ketone (18). Furthermore, metals known to generate metal vinylidenes10 including [RuCl2(CO)3]2,
RuClCp(PPh3)2NH4PF6, W(CO5)·THF and Mo(CO)6 and W(CO)6 were also evaluated but failed to generate the desired
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Scheme 2. First approach to the ABCD fragment of kibdelone A and isokibdelone A via a Friedel‐
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Crafts/hydroarylation cascade
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phenanthrene ring system via hydroarylation. We believe that the hydration of the alkyne was promoted by the B
ring phenol rather than by water in the reaction. The latter was demonstrated by pretreatment of biaryl 7 to form the
corresponding metal phenolate complexes (Ti(iOPr)4, toluene; B(OMe)3, benzene, reflux) and submitting these
intermediates to hydroarylation conditions (InCl3, toluene, 100 °C), which did not afford ketone product 18. The
difference in reactivity between model substrate 14 and biaryl 7 to proceed in further hydroarylation may be
explained in part by the net electron withdrawing properties of the quinolinone ring of 7 relative to biaryl alkyne 14.
Scheme 3. Second‐generation approach to ABCD triol 5 via oxidative photochemical electrocyclization
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As an alternative route, we considered access to the ABCD ring system through oxidative photochemical cyclization
utilizing biaryl styrene 20 employed in our (+)‐kibdelone C synthesis (Scheme 3). Treatment of quinone monoketal 9
with styrene 19 and InCl3 (15 mol%) in 1:1 CH3CN/HFIP led to the production of biaryl 20 in 70 % yield. The current
In(III) conditions provide an alternative and robust catalyst system to the previously reported Pt(IV) methodology.4a
With biaryl 20 in hand, we evaluated construction of the C‐ring of the ABCD core of kibdelone A (Table 1).
Historically, air and iodine have been used as oxidants in photochemical, oxidative electrocyclization of stilbenes en
route to various natural product systems.11 For example, both the Kelly12 and Mehta13 groups employed oxidative
photochemical cyclization in ambient air to construct the C‐ring of cervinomycin A2, although in both cases low yields
were observed. Initial photochemical cyclization of substrate 20 with oxidants including oxygen and PIDA were
unsuccessful. However catalytic iodine gave the desired product 21 in 38% yield (entry 3, Table 1).
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Table 1. Oxidative photochemical cyclization
Entry
1
Oxidant
O2
Solvent
Additive
None
Yielda
0%
Cyclohexane
PIDA
2
Cyclohexane
None
0%
(1.2 equiv.)
3
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5
6
7
I2 (0.1 equiv.)
I2 (0.5 equiv.)
I2 (1.0 equiv.)
I2 (1.1 equiv.)
I2 (1.1 equiv.)
Cyclohexane
Cyclohexane
Cyclohexane
Toluene
None
None
38%
20%
10%
73%
70%
None
THF (20 equiv.)
Solvent
THF
[a] Isolated yield of phenanthrene 21.
In an attempt to optimize the photochemical cyclization, we increased the amount of iodine which instead was
found to decrease yield (entries 4‐5, Table 1), likely because of product degradation by the generated hydrogen
iodide.11 Use of tetrahydrofuran as HI scavenger11a (entry 6, Table 1) was found to be effective and yielded the desired
ABCD ring system (21) in 73% yield. Use of THF as solvent14 (entry 7) was also found to give similar yields and
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enable more concentrated reaction conditions. The TBDPS protecting group of the ABCD ring system 21 was then
removed with TBAF to afford the desired phenanthrene triol 54a in 86% yield (Scheme 3).
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Our next goal was to establish whether the one pot oxa‐Michael/Friedel‐Crafts cyclization (Figure 2) between
phenanthrenetriol 5 and activated halocyclohexene ester synthon 6 was a viable route to access the challenging
tetrahydroxanthone core of kibdelone A (1). Such a route was attempted to circumvent use of an acid and heat
sensitive vinylogous carbonate intermediate as employed in our (+)‐kibdelone C4b synthesis. Furthermore, use of an
activated ester (cf. Figure 2, 6, R= H, CF3) was deemed beneficial for the oxa‐Michael reaction by lowering the LUMO
of the Michael acceptor15 and for providing a more active leaving group for Friedel‐Crafts acylation.
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For this study, the activated chiral F‐ring synthons4 (25‐27, Scheme 4) were synthesized from diols 8a/8b
obtained by microbial dihydroxylation of methyl 2‐halobenzoate substrates (11a‐b) with toluene dioxygenase
overexpressed in E. coli JM109 (pDTG601A).16 Dihydroxylation of methyl 2‐halobenzoate 11a‐b by whole‐cell
fermentation with E. coli JM 109 (pDTG601A) afforded a mixture of the corresponding diols 22a‐b and the desired
diols 8a‐b in a 4:1 mixture if the halogen was iodine and in an improved ratio of 1:3.5 if the halogen was bromine.
Scheme 4. Synthesis of activated F‐ring ester intermediates by microbial dihydroxylation
Selectivity for diol formation can be explained by Boyd’s rule17 which stipulates that the larger group directs the
enzymatic dihydroxylation. In the case where X is iodine (11a), the halogen and not the methyl ester directs the
enzymatic process and therefore provides the desired diol (8a) as the minor product.6 Furthermore, the orientation
of the benzoate during docking of the active site of the enzyme can also be influenced by the positive charge (δ+) of
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iodine.6b This is not the case when X is bromine (11b) and therefore better ratios for the desired diol (8b) are
observed. The desired diols 8a‐b were then protected as acetonides followed by Markovnikov hydration6a using
Co(acac)2 to afford the methyl‐ester F‐ring synthons 23 and 24 in just three steps.
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Methyl esters (23‐24) were subsequently transformed to the activated F‐ring synthons (25‐27) through a
saponification/DCC coupling sequence with the corresponding fluorinated alcohols. A one pot oxa‐Michael/Friedel‐
Crafts procedure was then attempted with the known monomethoxy phloroglucinol 2818 (Scheme 5). To our delight,
careful optimization utilizing the highly activated HFIP ester 26 led to the finding that tetrahydroxanthone formation
under basic conditions was possible in a one pot process allowing us to avoid isolation of the acid and heat sensitive
vinylogous carbonate (29). In addition, the oxa‐Michael reaction proceeded in a site selective manner at room
temperature, while the Friedel‐Crafts cyclization required heating to 60 °C in the presence of K3PO4 to yield
tetrahydroxanthone 30 in 41% yield. The requirement of base for the Friedel‐Crafts cyclization was supported by the
isolation of vinylogous carbonate 29 and its subsequent thermolysis in DMF (60 °C) which proved to be unfruitful.
Scheme 5. One pot oxa‐Michael/intramolecular Friedel‐Crafts cyclization for tetrahydroxanthone formation
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OH
I
MeO
OH
OH
O
O
F3C
OH
O
O
O
O
26
HO
CF3
O
O
K3PO4 (3 equiv.) DMF
F3C
O
r.t., 18h then 60 °C for 18h
OMe
28
CF3
29
OH
OH
OH
O
HO
O
HO
(41%)
3M HCl
OH
O
THF, 50 °C
33%
OMe O
31
O
OMe O
30
Both one and two pot processes were also attempted with trifluoroethyl ester 25 but were found to be lower
yielding for both the oxa‐Michael and the Friedel‐Crafts steps. Final deprotection of 30 was done under standard
acetonide deprotection conditions to afford the simplified kibdelone tetrahydroxanthone analogue2 31. The low yield
for this transformation may be explained by the propensity of the chiral ring of the tetrahydroxanthone to eliminate
water and rearomatize once deprotected.5b
We next evaluated use of the new activated F‐ring synthons with the ABCD ring core triol of kibdelone A (5, Scheme
6). We found that iodo HFIP ester 26 displayed improved reactivity in the oxa‐Michael fragment coupling with the
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ABCD ring core in comparison with our first generation F‐ring methyl‐ester (23) synthon although a one pot process
for tetrahydroxanthone formation was not observed. For example, treatment of 5 with 26 using K3PO4 in DMA at
room temperature cleanly afforded adduct 34 in 61% yield while reaction of methyl ester 23 under previously
developed conditions for (+)‐kibdelone C (DMSO, 60 °C)4b with methyl ester synthon 23 showed no reactivity. Both
trifluoro and HFIP intermediates (25‐27) proved to be quite reactive at room temperature using polar solvents with
few differences observed between iodo and bromo derivatives. Further Friedel‐Crafts cyclization was attempted
using a one or two pot process with the natural product precursors (33‐34) under thermal, Lewis acid‐catalyzed, and
N‐methylimidazole‐promoted conditions but in
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Scheme 6. Completion of the synthesis of kibdelone A (1)
OH
Cl
O
OMe
Cl
O
OMe
X
Me
Me
O
R
N
OMe
O
N
OMe
OH
+
Me
Me
O
O
O
HO
HO
HO
HO
5
O
O
23, 25-27
R
OH
32 R = CH3
33 R = CH2CF3
34 R = CH(CF3)2
K3PO4 (3 equiv.)
O
Entry
F ring
Conditions
Yield
1
2
3
4
5
6
23 (R=CH3, X=I)
DMSO, 60 °C 0%
O
25 (R=CH2CF3, X=I)
25 (R=CH2CF3, X=I)
25 (R=CH2CF3, X=I)
26 (R=CH(CF3)2, X=I) DMA, r.t.
27 (R=CH(CF3)2, X=Br) DMA, r.t.
CH3CN, r.t.
DMSO, r.t.
DMF, r.t.
12%
24%
56%
61%
53%
1) THF, 0.5M KOH, r.t., 20h
2) cyanuric chloride, pyridine,
DCE, 75 °C, 24h
52% (2 steps) when R = CHCF3
42% (2 steps) when R= CH2CF3
3) 3N HCl, THF, 40 °C, 76%
Cl OMe
Me
CAN (2.1 equiv.)
CH3CN: H2O
N
OMe
O
Me
kibdelone A (1)
O
HO
HO
0 °C to r.t., 56%
OH
O
35
HO
OH
these cases only starting material, aromatized F‐ring, or retro‐Michael products were observed. Accordingly,
cyclization was performed using a two‐step sequence via saponification/cyanuric chloride activation of vinylogous
carbonates 33‐34 in 52% and 42% yield over two steps, respectively. A three step process passing isolation of the
vinylogous carbonate from 5 and 25 or 26 was attempted but was found to be less effective (22 and 29% yields,
respectively). Final deprotection of the acetonide moiety of the F‐ring and oxidation of the B‐ring using CAN in
water/CH3CN afforded kibdelone A (1) in good yield. A careful study of the pH of the final CAN oxidation revealed that
acidic conditions such as AcOH in CH3CN or CAN impregnated on silica in CH2Cl2 which were successful for the
synthesis of (+)‐kibelone C4b were unfavorable due to increased propensity for oxidation of the D ring.
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Kibdelone A methyl ether 35 and simplified analogues (30, 31, Scheme 5) were submitted to the NCI 60 cell‐line
panel for evaluation of the relevance of C‐7 substituted tetrahydroxanthone pharmacophore to the anticancer activity
of these natural products. Kibdelone A (1) had been previously tested as the natural product. Compound 35 (OMe‐
kibdelone A) was approximately equipotent with 1 with a mean GI50 value of 3.2 nM. Simplified analogues 30 and 31,
however, were found to be inactive at 10 µM. Coupled with the inactivity of tetracycle 5 and weak activity of C19‐C20
saturated tetracyclic analogues 36 and 37 (Figure 3), both with a mean GI50 of 4.5 µM,4a it appears at this stage that
the complete hexacyclic scaffold of the kibdelones may be required for optimum cell growth inhibition.
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Figure 3. ABCD ring fragments of kibdelone and isokibdelone submitted to NCI 60‐cell line screening.4a
Cl
O
OH
Cl
O
O
Me
Me
N
OMe
Me
N
OMe
OH
Me
O
O
H
HO
OH
HO
36
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CONCLUSION
We have developed a new sequence for the construction of the ABCD rings systems of both kibdelone A and
isokibdelone A using In(III)‐catalyzed arylation of a heterocyclic quinone monoketal followed by iodine‐mediated
oxidative photochemical electrocyclization. Construction of the tetrahydroxanthone ring system for both kibdelone A
and a simplified analogue has been accomplished utilizing trifluoro‐ and HFIP‐ester activated iodo‐cyclohexene
derivatives formed from methyl 2‐halobenzoates by enzymatic dihydroxylation. A one‐pot oxa‐Michael/Friedel‐Crafts
cyclization cascade process for tetrahydroxanthone formation was possible with simple phenols but was not viable
with a kibdelone A ABCD ring fragment. Further studies on the synthesis of the kibdelones and analogues as well as
additional biological studies are currently in progress and will be reported in due course.
EXPERIMENTAL SECTION
General Methods. 1H NMR spectra were recorded at 400, 500, or 600 MHz at ambient temperature with CDCl3
as the solvent unless otherwise stated. 13C NMR spectra were recorded at 100.0, 125.00, or 151 MHz at ambient
temperature with complete proton decoupling using CDCl3 as the solvent unless otherwise stated. Infrared spectra
were recorded on a FT‐IR spectrophotometer. High‐resolution mass spectra (HRMS) was carried out by electronic
impact (EI) using a Q‐TOF mass spectrometer. Analytical thin layer chromatography was performed on 0.25 mm
silica gel 60‐F plates. Flash chromatography was performed using 200‐400 mesh silica gel. Melting points were
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recorded on a Mel‐temp apparatus. HPLC grade tetrahydrofuran, methylene chloride, diethyl ether, toluene,
acetonitrile, and benzene were purchased and dried by passing through a PURE SOLV® solvent purification system.
Photochemistry experiments were performed using a Hanovia 450 W medium pressure mercury lamp housed in
quartz immersion cooler with a system circulator. Analytical LC‐MS was performed on a UPLC (Ultra Performance
Liquid Chromatography) with a Binary solvent manager, SQ mass spectrometer, PhotoDiode Array detector, and
ELSD (Evaporative Light Scattering Detector). An Acquity UPLC BEH C18 1.7 μm column was used for analytical
UPLC‐MS. Preparative HPLC separations were carried out on a Personal Purification System using a C18 column.
Optical rotations were determined on an automatic digital polarimeter.
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2'‐Ethynyl‐4',5,6'‐trimethoxy‐[1,1'‐biphenyl]‐2‐ol (14). PtBr4 (7.8 mg, 0.015 mmol) was added to a stirred
solution of quinone monoketal 1219 (47 mg, 0.30 mmol) and 1‐ethynyl‐3,5‐dimethoxybenzene 13 (148 mg, 0.915
mmol) in CH2Cl2 (0.27 mL) /HFIP (3.1 mL) at 0 °C for 1h. The reaction mixture was concentrated under reduced
pressure to a brown oil. The oil was purified on flash silica column using 0 to 50% EtOAc in hexanes to yield
compound 14 as a yellow solid (60 mg, 69% yield). Mp 110‐114 °C; 1H NMR (400 MHz, CDCl3)  (ppm) 6.94 (d, 1H, J=
8.8 Hz), 6.85 (dd, 1H, J= 8.8, 3.2 Hz), 6.82 (dd, 1H, J= 3.2 Hz), 6.80 (d, 1H, J= 2.4 Hz), 6.60 (d, 1H, J= 2.4 Hz), 4.82 (s, 1H),
3.86 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.98 (s, 1H). 13C NMR (100 MHz, CDCl3)  (ppm) 160.2, 157.7, 153.0, 147.5,
124.4, 123.7, 121.5, 117.0, 116.9, 115.1, 109.6, 100.6, 82.1, 80.7, 56.1, 55.7, 55.6. IR (film); νmax: 3462 (br), 3279,
2940, 2838, 1596, 1464, 1152, 1037. HRMS: m/z calcd. for C17H17O4 (MH)+: 285.1127, found 285.1126.
1,5,7‐Trimethoxyphenanthren‐4‐ol (15). Method from biaryl 14: PtBr4 (1.0 mg, 0.0019 mmol) was added to a
stirred solution of biaryl 14 (10 mg, 0.035 mmol) in dichloroethane (3 mL) at room temperature. The resulting
mixture was then stirred at this temperature for 18h. The reaction mixture was concentrated under reduced pressure
to a brown oil. The oil was taken up in CH2Cl2 and purified on a flash silica column using 0 to 25% EtOAc/hexanes to
afford compound 15 as a bright orange oil (6.8 mg, 68% yield).
Method from quinone monoketal 12: PtBr4 (5.5 mg, 0.011 mmol) was added to a solution of quinone monoketal 1219
(330 mg, 2.14 mmol) and 1‐ethynyl‐3,5‐dimethoxybenzene 13 (104 mg, 0.638 mmol) in CH2Cl2 (1 mL) /HFIP (1.7
mL) at 0 °C. The resulting solution was allowed to stir at room temperature for 2h and was then heated under reflux
for 12h. The solution was concentrated under reduced pressure to afford a brown oil which was purified on a flash
silica column using a 0 to 25% EtOAc in hexanes to yield compound 15 as a bright orange oil (18.1 mg, 30% yield). 1H
NMR (400 MHz, CDCl3)  (ppm) 9.11 (s, 1H), 8.21 (d, 1H, J= 9.2 Hz), 7.54 (d, 1H, J= 9.2 Hz), 7.15 (d, 1H, J= 9.0 Hz), 7.01
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(d, 1H, J= 2.5 Hz), 7.00 (d, 1H, J= 9.0 Hz), 6.85 (d, 1H, J= 2.5 Hz), 4.06 (s, 3H), 3,99 (s, 3H), 3.97 (s, 3H). 13C NMR (100
MHz, CDCl3)  (ppm) 158.3, 155.5, 149.2, 147.6, 136.2, 125.7, 124.1, 122.4, 119.8, 115.6, 114.4, 107.6, 103.5, 101.7,
58.2, 56.4, 55.6. IR (film); νmax: 3301 (br), 3004, 2939, 2833, 1611, 1420, 1265, 1095, 740. HRMS: m/z calcd. for
C17H17O4 (MH)+: 285.1127, found 285.1128
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3‐((tert‐Butyldiphenylsilyl)oxy)‐4‐methoxy‐5‐((trimethylsilyl)ethynyl)phenol (17). A solution of bromide 164a
(3.38g, 7.40 mmol) and trimethyl (tributylstannyl)ethynyl)silane20 (8.27 mL, 22.2 mmol) in toluene (125 mL) was
degassed for 5 min. Pd(PPh3)4 (0.651 g, 0.563 mmol) was added and the solution was heated at reflux for 22h. Water
(300 mL) was added to the reaction mixture and the product extracted with EtOAc (3 X 300 mL). The organics were
combined, washed with brine, dried over Na2SO4, filtered, and concentrated to a brown oil. The oil was then purified
on a flash silica column (0 to 10% EtOAc in hexanes) to afford compound 17 as a light orange oil/ foam (2.89 g, 82%
yield). 1H NMR (400 MHz, CDCl3)  (ppm) 7.73‐7.71 (m, 4H), 7.44‐7.35 (m, 6H), 6.39 (d, 1H, J= 3.8 Hz), 6.01 (d, 1H, J=
3.8 Hz), 4.35 (s, 1H), 3.88 (s, 3H), 1.11 (s, 9H), 0.25 (s, 9H). 13C NMR (100 MHz, CDCl3)  (ppm) 152.0, 149.2, 146.5,
135.5, 132.4, 130.1, 127.9, 118.2, 111.8, 109.5, 100.9, 98.5, 60.9, 26.5, 19.6, ‐0.04. IR (film); νmax: 3550‐3200, 2958,
2896, 1592, 1461, 1426, 1062, 843. HRMS: m/z calcd. for C28H35O3Si2 (MH)+: 475.2125, found 475.2112
3‐((tert‐Butyldiphenylsilyl)oxy)‐5‐ethynyl‐4‐methoxyphenol (10). Silver nitrate (8.4 mg, 0.0493 mmol), H2O
(0.53 µL, 0.0294 mmol) and pyridine (1.6 µL, 0.0197 mmol) were added to a stirring solution of 17 (234 mg, 0.493
mmol) in acetone (5 mL) and the mixture was heated in the dark at 40 °C for 43h. The resulting solution was
concentrated under reduced pressure, diluted with EtOAc (50 mL) and washed with brine (25 mL). The aqueous
phase was extracted twice more with EtOAc (50 mL). The organics were combined and dried over Na2SO4, filtered
and concentrated to a light brown oil. The oil was purified on flash silica column using 10% EtOAc in hexanes to
afford compound 10 as a beige foam (184 mg, 93% yield). 1H NMR (500 MHz, CDCl3)  (ppm) 7.74‐7.72 (m, 4H), 7.45‐
7.36 (m, 6H), 6.43 (d, 1H, J= 2.8Hz), 6.03 (d, 1H, J= 2.8Hz), 4.41 (br s, 1H), 3.91 (s, 3H), 3.22 (s, 1H), 1.13 (s, 9H). 13
C
NMR (100 MHz, CDCl3)  (ppm) 150.9, 149.3, 146.9, 135.5, 132.3, 130.1, 127.9, 117.2, 111.9, 109.7, 80.9, 79.6, 61.2,
26.4, 19.5. IR (film); νmax: 3301 (broad), 3075, 3015, 2961, 2933, 2859, 1572, 1461, 1429, 1218, 751. HRMS: m/z
calcd. for C25H27O3Si (MH)+: 403.1729, found 403.1721.
TBDPS Biaryl alkyne 7. AuCl3 (5.4 mg, 0.0176 mmol) was added to a stirring solution of quinone monoketal 94a
(55.0 mg, 0.180 mmol) and phenol 10 in HFIP (7.6 mL)/DCE (0.8 mL). The resulting solution was degassed for 15 min
and was then heated at 70 °C for 39h. The resulting solution was then concentrated under reduced pressure to afford
a brown oil. The oil was purified on a flash silica column using 0 to 20% EtOAc in hexanes to yield 7 as an orange oil
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(75 mg, 62% yield). H NMR (500 MHz, CDCl3)  (ppm) 14.86 (s, 1H), 7.80‐7.76 (m, 4H), 7.53 (s, 1H), 7.44‐7.38 (m,
6H), 6.58 (s, 1H), 6.34 (s, 1H), 3.98 (s, 3H), 3.87 (s, 3H), 3.64 (s, 3H), 3.20 (s, 1H), 2.97‐2.94 (m, 2H), 1.69‐1.65 (m, 2H),
1.15 (s, 9H), 1.10 (t, 3H, J= 7.5 Hz). 13C NMR (100 MHz, CDCl3)  (ppm) 165.6, 151.3, 150.4, 149.3, 148.3, 146.3, 140.9,
135.6, 135.5, 132.4, 132.1, 130.1, 130.1, 127.9, 127.9, 126.4, 125.5, 120.8, 120.8, 116.8, 112.2, 111.1, 110.5, 84.3, 79.5,
61.1, 58.5, 32.6, 31.9, 26.5, 20.8, 19.6, 14.1. IR (film); νmax: 3301 (broad), 3017, 2961, 2933, 2860, 1573, 1461, 1428,
1219, 753. HRMS: m/z calcd. for C39H40ClNO6SiNa (M+Na)+: 704.2211, found 704.2198.
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Biaryl methyl ketone 18. InCl3 (0.47 mg, 0.00212 mmol) was added to a stirring solution of biaryl alkyne 7 (14.5 mg,
0.0213 mmol) in toluene (1.5 mL). The resulting mixture was stirred for 30 min at room temperature and
subsequently heated at 80 °C for 1.5h then at 100 °C for 16h. The solution was concentrated under reduced pressure
to afford a brown oil which was purified on a flash silica column (0 to 20% EtOAc in hexanes) to afford compound 18
as a light yellow foam (12.3 mg, 83%). 1H NMR (400 MHz, CDCl3)  (ppm) 14.60 (s, 1H), 7.80‐7.74 (m, 4H), 7.46‐7.38
(m, 6H), 7.09 (s, 1H), 6.29 (s, 1H), 6.15 (s, 1H), 3.92 (s, 3H), 3.81 (s, 3H), 3.65 (s, 3H), 2.98‐2.93 (m, 2H), 2.15 (s, 3H),
1.72‐1.63 (m, 2H), 1.14 (s, 9H), 1.10 (t, 3H, J= 9.2 Hz). 13C NMR (100 MHz, CDCl3)  (ppm) 204.1, 165.4, 151.4, 150.3,
149.6, 146.7, 141.1, 141.0, 138.1, 135.5, 135.5, 132.1, 132.1, 130.1, 130.1, 127.9, 127.9, 125.3, 124.2, 119.8, 114.0,
111.2, 110.8, 110.5, 62.4, 58.1, 32.6, 32.2, 32.0, 26.6, 20.8, 19.5, 14.1. IR (film); νmax: 3004, 2959, 2932, 2860, 1700,
1630, 1572, 1460, 1428, 1237, 1220, 753. HRMS: m/z calcd. for C39H43ClNO7Si (MH)+: 700.2497, found 700.2478
Biaryl styrene 20. InCl3 (54.0 mg, 0.244 mmol) was added to a stirring solution of quinone monoketal 94a (0.508 g,
1.63 mmol) and styrene 194a (16.3 mmol) in a 1:1 HFIP (50 mL)/ CH3CN (50 mL) previously degassed with argon for
30 min. Then reaction mixture was then heated at 80 °C for 45h. The solution was allowed to cool to room
temperature and was then concentrated to afford a brown foam. The foam was purified on a flash silica column using
0 to 20% EtOAc in hexanes to afford compound 204a as an orange foam (0.783 g, 70% yield).
Phenanthrene 21. Biaryl styrene 20 (111 mg, 0.162 mmol) in THF (32 mL) was placed in a Pyrex tube and degassed
for 15 min. I2 (46.0 mg, 0.180 mmol ) was added to the mixture and the reaction was stirred for 5 min. The resulting
solution was irradiated with Hanovia mercury lamp (hot water changed every hour) for 5h. The solution was
quenched with a saturated solution of sodium thiosulfate (25 mL) and extracted into EtOAc (3X 50 mL). The organics
were then dried over Na2SO4, filtered, and concentrated to afford a yellow brown oil. The oil was purified on a flash
silica column using 0 to 30% EtOAc in hexanes to afford compound 214a as a bright yellow solid.
For toluene/THF preparation (Table 1, Entry 6): Biaryl styrene 20 (199 mg, 0.291 mmol) was separated into 2
Pyrex tubes and then dissolved in toluene (55 mL each tube) and degassed for 30 min. THF (0.25 mL, 6.2 mmol) and
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I2 (41 mg each, 82 mg total, 0.32 mmol) were added and the reaction stirred for 5 min. The resulting solution was
irradiated with Hanovia mercury lamp (hot water changed every hour) for 6h. The reaction mixture was then
dissolved with toluene, washed with an aqueous saturated sodium thiosulfate solution (50 mL) and dried over
Na2SO4, filtered, and concentrated to afford a brown yellow oil. The oil was purified on flash silica column using a 0 to
20% EtOAc in hexanes solvent system to yield 214a as a bright yellow solid.
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Phenanthrene 5. TBAF (0.25 mL, 1.0M, 0.25 mmol) was added to a stirring solution of phenanthrene 21 (144 mg,
0.211 mmol) in THF (7 mL) at 0°C. The resulting solution was stirred for 1.5h at this temperature. A saturated
aqueous ammonium chloride solution was then added and the reaction mixture was extracted with EtOAc (2X 25 mL).
The organics were then dried over Na2SO4, filtered, and concentrated to a yellow oil. The oil was purified on flash
silica column using 0 to 20% EtOAc in CH2Cl2 as solvent to afford compound 54a as a bright yellow solid.
(3S,4S)‐Methyl 3,4‐dihydroxy‐2‐iodocyclohexa‐1,5‐dienecarboxylate (22a), (5S, 6R)‐methyl 5,6‐dihydroxy‐2‐
iodocyclohexa‐1,3‐dienecarboxylate (8a). In a 12‐L fermentation culture of grown E. coli JM109 (pDTG601) cells
was added 15 g of methyl 2‐iodobenzoate (11a) in 1 g portions over 3 h.16c At the end of addition, the cells were
separated from the broth by centrifugation at 7000 rpm for 20 min. The cell‐free broth was extracted three times
with a total of 8 L of base‐washed. Evaporation of the EtOAc extract afforded 3.5 g of diols 22a and 8a, in a 4:1 ratio,
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as determined by H NMR analysis. These diols were separated by column chromatography on water deactivated
silica gel (10% w/w) using 3:2 EtOAc/hexanes as eluent to afford 2.4 g of 22a (8.1 mmol, 14.3% yield), as a yellow oil
and 0.6 g of 8a (2.0 mmol, 3.5% yield). Attempts to completely remove the solvent from 8a resulted in aromatization
and thus the material was taken on directly to the next step. The amount of 8a used in the acetonide formation was
estimated from the amount of 22a recovered using the 4:1 ratio obtained previously.
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(3S,4S)‐Methyl 3,4‐dihydroxy‐2‐iodocyclohexa‐1,5‐dienecarboxylate (22a) H NMR (600 MHz, CDCl3) δ (ppm)
6.19 (d, 1H, J = 9.8 Hz), 6.11 (dd,1H, J = 9.8, 3.8 Hz), 4.42 (m, 1H), 4.36 (t, 1H, J = 6.6 Hz), 3.83 (s, 3H), 3.12 (br d, 1H, J =
7.6 Hz), 2.59 (br d, 1H, J = 7.2 Hz). 13C NMR (151 MHz, CDCl3) δ (ppm) 166.0, 134.3, 129.3, 123.9, 111.2, 75.88, 67.2,
52.4. IR (film) 3346, 2950, 2919, 1722, 1553, 1435, 1250 cm‐1. MS (EI) m/z (%) [M]+: 296 (12), 278 (83), 264 (38),
247 (90), 231 (31), 137 (100), 109 (95), 92 (43), 81 (89), 63 (35), 59 (38), 53 (62). HRMS: m/z calcd. for C8H9IO4:
295.9546, found: 295.9538. [α]D20 +50 (c 1.7, CH2Cl2).
(3aR,7aS)‐Methyl 5‐iodo‐2,2‐dimethyl‐3a,7a‐dihydrobenzo[d][1,3]dioxole‐4‐carboxylate 38).
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A catalytic amount of p‐TsOH was added to a stirred solution of diol 8a (20 mg, 0.07 mmol) and dimethoxypropane
(1 mL) in CH2Cl2 (1 mL). The reaction was monitored by TLC analysis (1:1 EtOAc/hexanes). After consumption of
starting material, the reaction mixture was diluted with CH2Cl2 (10 mL), washed with 1.0 M NaOH (1 mL), and dried
over anhydrous MgSO4. The filtrate was concentrated in vacuo and further purified by column chromatography on
silica gel (1:1 EtOAc/hexanes) to afford acetonide 38 as an oil (20 mg, 88%). 1H NMR (300 MHz, CDCl3) δ (ppm) 6.52
(d, 1H, J = 9.9 Hz), 5.79 (dd,1H, J = 9.9, 3.6 Hz), 4.98 (d, 1H, J = 8.1 Hz), 4.78 (dd, 1H, J = 8.1, 3.6 Hz), 3.87 (s, 3H), 1.43 (s,
3H), 1.40 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 166.4, 135.3, 131.5, 130.3, 106.6, 101.2, 71.5, 70.7, 52.3, 26.7, 25.4.
IR (film) 3437, 2987, 1715, 1631, 1241, 1040 cm‐1. MS (EI) m/z (%): 335 (20), 279 (32), 278 (46), 247 (40), 246 (15),
152 (34). HRMS: m/z calcd. for for C11H13IO4: 335.9864, found: 335.9859. [α]D20 +71 (c 2.0, CH2Cl2).
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(3aR,6S,7aS)‐Methyl‐6‐hydroxy‐5‐iodo‐2,2‐dimethyl‐3a,6,7,7a‐tetrahydrobenzo[d][1,3]dioxole‐4‐carboxylate
(23). To a stirred solution of acetonide 38 (20 mg, 0.06 mmol) in isopropanol (1 mL) was added cobalt
acetylacetonate (3 mg, 0.01 mmol). The resulting solution was evacuated/refilled with oxygen gas three times and
was stirred under an atmosphere of oxygen at 75 °C for 1 h. The mixture was allowed to cool to room temperature,
the solvent was removed in vacuo, and the crude residue purified by chromatography on silica gel using mixture of
hexane/EtOAc (2:1) as eluant to afford alcohol 23 as a white solid (13 mg, 62% yield), whose physical and
spectroscopic properties were identical to those previously published.4b Mp = 62‐64 °C. 1H NMR (300 MHz, CDCl3) δ
(ppm) 4.86 (dd, 1H, J = 5.1, 1.8 Hz), 4.54 (m, 1H), 4.40 (m, 1H), 3.88 (s, 3H), 2.64 (dt, 1H, J = 14.4, 4.8 Hz), 2.46 (d, 1H, J
= 4.8 Hz), 1.90 (m, 1H) 1.39 (s, 3H), 1.38 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 167.0, 137.9, 115.2, 109.8, 74.1, 71.9, 68.3,
52.5, 33.1, 27.5, 26.4. [α]D20 +170 (c 0.25, CHCl3).
(5S, 6R)‐Methyl 5,6‐dihydroxy‐2‐bromocyclohexa‐1,3‐dienecarboxylate (8b), and (3S,4S)‐methyl 3,4‐
dihydroxy‐2‐iodocyclohexa‐1,5‐dienecarboxylate (22b). Similarly, when 15 g of methyl 2‐bromobenzoate 11b
was used as substrate, 4.0 g of diols 22b and 8b in a 1:3.5 ratio was obtained. These diols were separated by column
chromatography on water deactivated silica gel (10% w/w) using 3:2 EtOAc/hexanes as eluent to afford 2.8 g of 22b,
as a yellow oil and 0.8 g of 8b which is unstable and hence converted directly to the acetonide. The amount of 8b
used in the acetonide formation was estimated from the amount of 22b recovered using the 1:3.5 ratio obtained
previously.
(5S,6R)‐Methyl 2‐bromo‐5,6‐dihydroxycyclohexa‐1,3‐dienecarboxylate (8b).
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Mp 106‐109 °C 1H NMR (600 MHz, CDCl3) δ (ppm) 6.17 (dd, 1H, J = 10.0, 2.5 Hz), 6.04 (ddd, 1H, J = 10.0, 2.5, 1.3 Hz),
4.57 (m, 1H), 4.49 (m, 1H), 3.85 (s, 3H), 3.00 (br d, 1H, J = 7.9 Hz), 2.97 (br s, 1H). 13C NMR (151 MHz, CDCl3) δ (ppm)
166.6, 137.5, 130.0, 128.0, 127.3, 68.4, 68.1, 52.3. IR (KBr) 3402, 1703, 1437, 1314, 1234, 1048 cm‐1. MS (EI) m/z (%):
248 (9), 218 (38), 216 (47), 190 (82), 189 (53), 188 (85), 187 (48), 109 (71), 108 (31), 81 (100), 65 (79), 59 (45), 53
(54). HRMS: m/z calcd. for C8H9BrO4: 247.9684; found: 247.9679. [α]D20 = +29 (c 1.0, CH2Cl2).
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(3aR,7aS)‐Methyl 5‐bromo‐2,2‐dimethyl‐3a,7a‐dihydrobenzo[d][1,3]dioxole‐4‐carboxylate (39).
1H NMR (300 MHz, CDCl3) δ (ppm) 6.17 (d, J= 0.72 Hz, 1H), 5.94 (dd, 1H, J= 9.87, 3.36 Hz), 4.99 (d, 1H, J= 8.04 Hz),
4.75 (m, 1H), 3.82 (s, 3H), 1.38 (s, 3H), 1.35 (s, 3H). 13C NMR (75 MHz, CDCl3) δ (ppm) 165.8, 131.3, 129.9, 125.8,
125.7, 106.5, 72.1, 70.6, 52.2, 26.7, 25.2. IR (film) ν 2988, 2951, 1725, 1639, 1582, 1434 cm‐1; MS (EI) m/z (%): 275
(24), 273 (25), 233 (41), 231 (45), 201 (28), 199 (28), 108 (33). HRMS: m/z calcd. for C11H13BrO4: 287.9997, found:
287.9994. [α]D20 +286 (c 1.1, CH2Cl2 ).
(3aR,6S,7aS)‐Methyl‐5‐bromo‐6‐hydroxy‐2,2‐dimethyl‐3a,6,7,7a‐tetrahydrobenzo[d][1,3]dioxole‐4‐
carboxylate (24). To a stirred solution of acetonide 39 (50 mg, 0.17 mmol) (derived from diol 8b) in isopropanol (2
mL) was added cobalt acetylacetonate (6 mg, 0.02 mmol). The resulting solution was evacuated/refilled with oxygen
three times and was stirred under an atmosphere of oxygen at 75 °C for 1 h. The mixture was allowed to cool to room
temperature, the solvent was removed in vacuo, and the crude residue purified by chromatography on silica gel using
mixture of hexanes/EtOAc (2:1) as eluant to afford alcohol 24 as a viscous oil (37 mg, 70% yield). 1H NMR (300 MHz,
CDCl3)  (ppm) 4.89 (dd, 1H, J=1.8, 5.1 Hz), 4.51 (m, 1H), 4.48 (m, 1H), 3.87 (s, 3H), 2.66 (m, 1H), 1.86‐1.94 (m, 2H),
1.39 (s, 3H), 1.38 (s, 3H). 13C NMR (75 MHz, CDCl3)  (ppm) 162.2, 132.9, 131.8, 109.8, 74.4, 71.7, 66.5, 52.4, 33.2, 27.6,
26.3. IR (film); νmax: 3432 (br), 2987, 2935, 1727, 1643, 1239, 1039, 731. HRMS: m/z calcd. for C10H12BrO5 (M‐CH3):
290.9868, found 290.9881 (4.4 ppm).
Iodocyclohexene acetonide trifluorocarboxylate 25. 0.5 M KOH (4.1 mL) was added to a stirring solution of
methyl ester 23 (229 mg, 0.647 mmol) in MeOH (2.2 mL) at room temperature. The resulting solution was stirred for
20h. The solution was then acidified to pH 2 using a 0.5M HCl solution and extracted into EtOAc (3X 50 mL). The
organics were then dried over Na2SO4, filtered and concentrated to a yellow oil. DMAP (11.2 mg, 0.097 mmol) and
2,2,2‐trifluoroethanol (0.24 mL, 3.30 mmol) were added to a stirring solution of the crude oil in dichloromethane (13
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ml). The resulting solution was cooled to 0 °C and DCC (147 mg, 0.712 mmol) was added. The reaction mixture was
slowly allowed to warm up to rt and continued to stir for 40h. The reaction mixture was then filtered through Celite®
and concentrated under reduced pressure to yield an orange oil. The solid was purified on a flash silica column using
0 to 15% EtOAc in CH2Cl2 to yield 25 as light yellow oil (0.423 g, 60%) 1H NMR (400 MHz, CDCl3)  (ppm) 4.68 (dq, 1H,
J = 12.7, 8.4 Hz), 4.60‐4.49 (m, 1H), 4.43 ‐4.34 (m, 2H), 2.66 (dt, 1H, J= 14.3, 4.8 Hz), 2.45 (d, 1H, J= 4.8 Hz), 1.91 (ddd,
1H, J= 14.2, 9.5, 2.5 Hz), 1.36 (s, 6H). 13C NMR (100 MHz, CDCl3)  (ppm) 164.9, 136.9, 122.8 (J= 221 Hz), 116.8, 110.0,
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74.0, 72.0, 68.3, 60.99 (J= 30 Hz), 32.9, 27.3, 26.3. F (ppm) ‐73.2. IR (film); νmax: 3565‐3339, 2986, 2936, 2874,
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1744, 1285, 1226, 1167, 1073. HRMS: m/z calcd. for C12H13F3IO4 (MH+‐H2O): 405.9889, found 405.9894 α]D
=
+47 °(c= 0.1, CHCl3).
Iodocyclohexene acetonide hexafluoro‐carboxylate 26. A 0.5 M aqueous KOH solution (3.9 mL) was added to a
stirring solution of methyl ester 23 (191 mg, 0.321 mmol) in MeOH (1.8 mL) at room temperature. The resulting
solution was stirred for 2h. The solution was then acidified to pH 2 using a 0.5M HCl solution and extracted into
EtOAc (3X 50 mL). The organics were then dried over Na2SO4, filtered and concentrated to a light yellow oil. DMAP
(6.6 mg, 0.054 mmol) and hexafluoroisopropanol (0.29 mL, 2.8 mmol) were added to a stirring solution of the crude
oil in dichloromethane (11 mL). The resulting solution was cooled to 0 °C and DCC (122 mg, 0.592 mmol) was added.
The reaction mixture was slowly allowed to warm up to rt and continued to stir for 14h. The reaction mixture was
then filtered through Celite® and concentrated under reduced pressure to yield a white solid. The solid was purified
on a flash silica column using a 0 to 10% EtOAc in CH2Cl2 solvent system to yield 26 as a yellow oil (0.184 g, 70%). 1H
NMR (500 MHz, CDCl3) δ (ppm) 5.81 (hept, 1H, J = 6.0 Hz), 4.75 (dd, 1H, J = 5.1, 1.8 Hz), 4.48 (td,1H, J = 4.6, 2.4 Hz),
4.34 (dtd,1H, J = 10.1, 5.1, 1.8 Hz), 2.62 (dt, 1H, J = 14.5, 5.1 Hz), 2.45 (br s, 1H), 1.87 (ddd, 1H, J = 14.5, 9.6, 2.4 Hz),
1.28 (s, 3H), 1.27 (s, 3H). 13C NMR (100 MHz, CDCl3)  (ppm) 163.3, 136.1, 120.3 (q, J= 225 Hz), 118.3, 110.2, 74.0,
72.0, 68.3, 67.0 (sept, J= 28 Hz), 32.7, 27.3, 26.3. 19 F (ppm) ‐72.1, ‐72.9. IR (film); νmax: 2995, 1762, 1383, 1224, 1110,
1074. [α]D23= +134 °(c= 0.1, CHCl3).
Bromocyclohexene acetonide hexafluoro‐carboxylate 27. A 0.5 M aqueous KOH solution (1.2 mL) was added to a
stirring solution of methyl ester 24 (48 mg, 0.157 mmol) in THF (1.5 mL) at room temperature. The resulting solution
was stirred for 20h. The solution was then acidified to pH 2 using 0.5M HCl and extracted into EtOAc (3X 50 mL). The
organics were then dried over Na2SO4, filtered, and concentrated to a light yellow oil. DMAP (2.9 mg, 0.024 mmol) and
hexafluoroisopropanol (0.08 mL, 0.80 mmol) were added to a stirring solution of the crude oil in CH2Cl2 (3.6 mL). The
resulting solution was cooled to 0 °C and DCC (39 mg, 0.19 mmol) was added. The reaction mixture was slowly
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allowed to warm up to rt and continued to stir for 14h. The reaction mixture was then filtered through Celite® and
finally concentrated under reduced pressure to yield a white solid. The solid was purified on a flash silica column
using a 0 to 20% EtOAc in hexanes solvent system to yield 27 as a clear oil (41 mg, 60%). 1H NMR (500 MHz, CDCl3) δ
(ppm) 5.87 (hept, 1H, J = 6.0 Hz), 4.87 (dd, 1H, J = 5.0, 1.9 Hz), 4.53 (td, 1H, J = 4.6, 2.4 Hz), 4.49 (dq, 1H, J = 6.2, 3.9, 2.4
Hz), 2.82 (d, 1H, J = 4.1 Hz), 2.69 (ddd, 1H, J = 14.4, 5.6, 4.2 Hz), 1.93 (ddd, 1H, J = 14.4, 9.5, 2.5 Hz), 1.34 (s, 3H), 1.33
(s, 3H). 13C NMR (100 MHz)  (ppm) 162.7, 136.0, 129.9, 120.3 (q, J= 223 Hz), 110.2, 76.7, 74.2, 71.7, 66.5, 66.9 (quint,
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J= 28 Hz), 32.8, 27.3, 26.2. F (ppm) ‐72.4, ‐73.0. IR (film); νmax: 2993, 2937, 2856, 1763, 1238, 1196, 111, 1076.
[α]D23= +95 °(c= 0.1, CHCl3).
(3aS,5S,11bR)‐5,8‐Dihydroxy‐10‐methoxy‐2,2‐dimethyl‐3a,4,5,11b‐tetrahydro‐11H‐[1,3]dioxolo[4,5‐
a]xanthen‐11‐one (30). DMA (1.0 mL, previously freeze pumped thawed) was added to a purged flask with argon
containing monomethoxy phloroglucinol 2818 (5.6 mg, 0.040 mmol), HFIP ester 26 (9.7 mg, 0.020 mmol), and K3PO4
(12.6 mg, 0.059 mmol). The solution was stirred at room temperature for 18h. The reaction mixture was then heated
at 60 °C for 18h. The solution was dissolved in EtOAc (10 mL) and an aqueous saturated solution of NH4Cl was added.
The resulting mixture was concentrated under reduced pressure (genevac) and redissolved in EtOAc, filtered through
cotton and concentrated under reduced pressure to a light brown oil. The oil was purified by column chromatography
(30% EtOAc in CH2Cl2 to 100% EtOAc then 5 to 15% MeOH in EtOAc) to yield 30 as a white foam (2.7 mg, 41%). 1H
NMR (500 MHz, CD3OD) δ (ppm) 6.47 (d, 1H, J = 2.1 Hz), 6.40 (d, 1H, J = 2.2 Hz), 5.32 (dd,1H, J = 6.0, 0.8 Hz), 4.73 (dd,
1H, J = 9.0, 5.0 Hz), 4.64 (td, 1H, J = 5.5, 3.1 Hz), 3.89 (s, 3H), 2.45 (dt, 1H, J = 13.8, 5.1 Hz), 1.95 (ddd, 1H, J = 13.8, 9.0,
3.3 Hz), 1.42 (s, 3H), 1.31 (s, 3H).13C NMR (100 MHz, CD3OD) δ (ppm)179.8, 163.6, 163.4, 161.2, 159.5, 115.8, 108.3,
107.0, 96.1, 94.9, 70.9, 69.4, 62.2, 55.0, 34.3, 26.4, 24.4. IR (film); νmax: 2925, 1625, 1580, 1500, 1467, 1331, 1203,
1078. HRMS: m/z calcd. for C17H19O7 (MH)+: 335.1131, found 335.1121 [α]D23= +4 °(c= 0.05, MeOH).
(1R,2S,4S)‐1,2,4,6‐Tetrahydroxy‐8‐methoxy‐1,2,3,4‐tetrahydro‐9H‐xanthen‐9‐one (31). 0.37 mL of an aqueous
3N HCl solution was added to a stirring solution of tetrahydroxanthone 30 (3.4 mg, 0.010 mmol) in THF (1.9 mL). The
resulting mixture was degassed for 15 min and heated at 50 °C for 30 min. The reaction mixture was allowed to cool
to room temperature and diluted with EtOAc (5 mL), washed with brine, dried over Na2SO4, filtered, and concentrated
to a brownish white solid. The solid was purified by preparative HPLC using a 2 to 90% CH3CN/water gradient to
afford 31 as a clear/whitish oil (1.0 mg, 33%). 1H NMR (500 MHz, CD3OD) δ (ppm) 6.36 (d, 1H, J = 2.1 Hz), 6.34 (d, 1H,
J = 2.1 Hz), 4.90 (d, 1H, J = 3.6 Hz), 4.66 (dd, 1H, J = 4.9, 2.7 Hz), 4.07 (dt, 1H, J = 11.7, 3.5 Hz), 3.88 (s, 3H), 2.34 (td, 1H,
J = 12.7, 4.9 Hz), 1.93 (d, 1H, J = 13.5 Hz). 13C NMR (100 MHz, CD3OD) δ (ppm) 177.0, 161.4, 161.2, 161.2, 159.9, 118.0,
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102.0, 96.7, 95.3, 65.3, 64.9, 62.9, 54.9, 33.3. IR (film); νmax: 3600‐3100 (br), 1653, 1614, 1434, 1204, 1092, 1040.
[α]D23= +42 °(c= 0.1, MeOH).
Vinylogous carbonate 33. Phenanthrene 54a (7.1 mg, 0.046 mmol) was dissolved in DMF (1.0 mL) and added to an
argon purged flask containing trifluoroethylester 25 (6.8 mg, 0.016 mmol) and K3PO4 (9.3 mg, 0.044 mmol) and the
solution was stirred at rt for 30h. The reaction mixture was then dissolved in EtOAc (5 mL), cooled to 0 °C, acidified
with 0.5 N KHSO4, and extracted with EtOAc (3 x 5 mL). The organics were combined, dried over Na2SO4, filtered, and
concentrated to a brown oil. The oil was purified on a flash silica column (0‐20% EtOAc in CH2Cl2) to yield 33 as a
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yellow foam (6.6 mg, 56%). H NMR (500 MHz, CDCl3) δ (ppm) 17.95 (s, 1H), 10.11 (s, 1H), 8.20 (d, 1H, J = 9.5 Hz),
8.13 (d, 1H, J = 9.5 Hz), 7.10 (s, 1H), 5.18 (dd, 1H, J = 5.5, 0.9 Hz), 4.72‐4.61 (m, 2H), 4.61‐4.51 (m, 1H), 4.47‐4.44 (m,
1H), 4.00 (s, 3H), 3.91 (s, 3H), 3.75 (s, 3H), 3.18 (d, 1H, J = 3.1 Hz), 3.08‐3.01 (m, 2H), 2.28 (ddd, 1H, J = 13.9, 7.4, 4.9
Hz), 2.05‐1.98 (m, 1H), 1.76 (dq, 2H, J = 15.2, 7.4 Hz), 1.53 (s, 3H), 1.43 (s, 3H), 1.16 (t, 3H, J = 7.3 Hz). 13C NMR (100
MHz, CDCl3) δ (ppm) 166.8, 164.1, 162.7, 154.2, 152.9, 146.2, 142.7, 140.4, 138.8, 133.1, 128.4, 125.1, 124.5 (d, J= 79
Hz), 123.2, 121.2, 117.7, 117.2, 111.1, 110.4, 110.2, 109.5, 107.0, 72.7, 70.7, 63.9, 62.9, 62.8, 60.2 (q, J= 29 Hz), 33.9,
32.5, 32.1, 28.1, 26.1, 21.0, 14.1. 19 F (ppm) ‐73.6. IR (film); νmax: 2970, 2936, 2874, 2856, 1739, 1588, 1411, 12283,
1163, 1003. HRMS: m/z calcd. for C35H36ClF3NO11 (MH)+: 738.19299, found 738.1898. [α]D23= ‐34 °(c= 0.1, CHCl3).
Vinylogous carbonate 34. HFIP ester 26 (44 mg, 0.090 mmol) was dissolved in DMA (4 mL) and added to a stirring
solution of phenanthrene 5 (44 mg, 0.100 mmol) and K3PO4 (57 mg, 0.27 mmol) in DMA (3 mL) at rt. And stirred for
39h. The solution was then dissolved in EtOAc (15 mL) and a saturated solution of ammonium chloride (5 mL) was
added. The resulting solution was extracted with EtOAc (3X 15 mL). The organics were combined, dried over Na2SO4,
filtered, and concentrated under reduced pressure to afford a yellow oil foam. The foam was purified on a flash silica
column (0 to 25% EtOAc in CH2Cl2) to yield 34 as a bright yellow oil (44 mg, 61%). 1H NMR (500 MHz, CDCl3) δ (ppm)
17.98 (s, 1H), 10.14 (s, 1H), 8.18 (d, 1H, J = 9.5 Hz), 8.14 (d, 1H, J = 9.5 Hz), 7.08 (s, 1H), 5.94 (p, 1H, J = 6.1 Hz), 5.16 (d,
1H, J = 5.5 Hz), 4.59 (dt, 1H, J = 8.5, 4.5 Hz), 4.52‐4.43 (m, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.75 (s, 3H), 3.20 (s, 1H), 3.09‐
3.02 (m, 2H), 2.25 (ddd, 1H, J = 15.5, 7.5, 4.9 Hz), 2.03 (ddd, 1H, J = 14.0, 6.5, 3.9 Hz), 1.76 (h, 2H, J = 7.3 Hz), 1.52 (s,
3H), 1.42 (s, 3H), 1.16 (t, 3H, J = 7.3 Hz).13C NMR (100 MHz, CDCl3) δ (ppm) 166.7, 165.0, 162.4, 154.2, 153.0, 148.3,
145.8, 142.7, 140.4, 138.6, 133.1, 128.4, 125.0, 123.2, 121.3, 117.6, 117.4, 110.2, 109.7, 108.0 (d, J= 216 Hz), 72.4,
70.6, 66.5 (quint, J= 27 Hz), 63.8, 63.0, 62.8, 33.3, 32.5, 32.1, 28.0, 26.0, 21.0, 14.1. 19 F (ppm) ‐73.0. IR (film); νmax:
3018, 2964, 1744, 1588, 1263, 1210, 1169, 1001. HRMS: m/z calcd. for C36H35ClF6NO11(MH)+: 806.1803, found
806.1808. [α]D23= ‐74 °(c= 0.1, CHCl3).
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Tetrahydroxanthone (40).
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A solution of 0.5 M KOH (0.70 mL) was added to a stirring solution of vinyloguous carbonate 34 (35 mg, 0.043 mmol)
in THF (2.6 mL) at 0°C. The reaction mixture was allowed to stir for 2.5 h. The solution was then dissolved with EtOAc
(20 mL), acidified to pH=2 using a 0.5 M KHSO4 solution and the phases separated. The aqueous layer was extracted
with EtOAc (2 X 20 mL) and the organics were combined, dried over Na2SO4, filtered and concentrated to a
yellow/brown oil. The oil (28 mg, 0.043 mmol) was resuspended in 1,2‐dichloroethane (3.4 mL). Pyridine (17 μL,
0.21 mmol) and cyanuric chloride (8.3 mg, 0.045 mmol) were added to the reaction mixture. The solution was
allowed to stir at rt for 30 min then the reaction mixture was stirred at 75 °C for 15h. The reaction mixture was
allowed to cool to rt, quenched with ice and diluted with 5 mL of cold 1.0 N HCl and 10 mL CH2Cl2. The combined
organics were filtered through Celite,® dried over sodium sulfate, filtered, and concentrated to an orange oil/solid.
Purification on preparative HPLC using a 5 to 90% CH3CN in H2O gradient afforded 40 as an orange solid (14.3 mg,
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52%, 2 steps). Mp 90‐94 °C. H NMR (500 MHz, CDCl3) δ (ppm) 14.96 (s, 1H), 13.88 (s, 1H), 8.15 (d, 1H, J = 9.4 Hz),
8.06 (d, 1H, J = 9.4 Hz), 5.44 (d, 1H, J = 6.0 Hz), 5.05 (dd, 1H, J = 9.9, 5.2 Hz), 4.77‐4.68 (m, 1H), 4.06 (s, 3H), 3.90 (s,
3H), 3.69 (s, 3H), 3.06‐2.98 (m, 2H), 2.73 (dt, 1H, J = 14.0, 4.8 Hz), 2.10‐1.98 (m, 2H), 1.72 (h, 2H, J = 7.4 Hz), 1.47 (s,
3H), 1.37 (s, 3H), 1.13 (t, 3H, J = 7.3 Hz).13C NMR (100 MHz, CDCl3) δ (ppm) 182.9, 166.3, 165.1, 157.4, 156.0, 145.3,
141.2, 140.5, 133.4, 132.0, 132.0, 124.8, 124.1, 123.1, 116.0, 114.5, 113.9, 109.2, 109.0, 107.9, 70.7, 69.2, 63.9, 63.0,
62.7, 34.3, 32.5, 31.6, 29.7, 27.5, 25.4, 21.0, 14.0. IR (film); νmax: 3009, 2960, 2932, 2872, 1624, 1581, 1474, 1444,
1263, 1218, 1014. HRMS: m/z calcd. for C33H33ClNO10 (MH)+: 638.1783, found 638.1791. [α]D23= +210 °(c= 0.1, CHCl3).
Tetrahydroxanthone (35). 0.83 mL of an aqueous 3N HCl solution was added to a stirring solution of
tetrahydroxanthone 40 (14.3 mg, 0.0224 mmol) in tetrahydrofuran (4.2 mL). The resulting mixture was degassed for
15 min and was heated at 50 °C for 1.5h. The reaction mixture was allowed to cool to rt, diluted with EtOAc (10 mL),
washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to an orange solid. The solid was purified by
preparative HPLC (5 to 90% CH3CN in water) to yield 35 as a bright orange oil/solid (9.6 mg, 72%). Mp 165‐175 °C.
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1H NMR (400 MHz, DMSO‐d6) δ (ppm) 15.04 (s, 1H), 14.07 (s, 1H), 8.12 (d, 1H, J = 9.4 Hz), 8.09 (d, 1H, J = 9.4 Hz), 6.04
(d, 1H, J = 6.3 Hz), 4.99 (d, 1H, J = 5.0 Hz), 4.75 (d, 1H, J = 6.2 Hz), 4.73‐4.69 (m, 1H), 4.03 (s, 3H), 3.96 (ddd, 1H, J =
12.2, 6.4, 3.3 Hz), 3.84 (s, 3H), 3.67 (s, 3H), 3.07‐2.99 (m, 2H), 2.34‐2.24 (m, 1H), 1.81 (d, 1H, J = 12.7 Hz), 1.70 (q, 3H, J
= 7.7 Hz), 1.09 (t, 3H, J = 7.3 Hz).13C NMR (100 MHz, DMSO‐d6) δ (ppm) 183.7, 166.1, 165.9, 157.0, 155.4, 145.8, 142.1,
141.0, 133.6, 131.7, 131.5, 125.0, 124.2, 123.9, 118.0, 115.4, 112.8, 108.4, 107.9, 107.5, 65.7, 64.6, 64.1, 62.7, 62.0,
34.3, 32.3, 32.3, 20.8, 14.3. IR (film); νmax: 3022, 2984, 2929, 2850, 1643, 1583, 1474, 1443, 1260, 1050, 1023.
HRMS: m/z calcd. for C30H29ClNO10 (MH)+: 598.1480, found 598.1481.[α]D23= +74 °(c= 0.1, CHCl3).
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Kibdelone A (1). A solution of ceric ammonium nitrate (9.2 mg, 0.017 mmol ) in 1:1 H2O/MeCN (1.8 mL) was added
dropwise to a solution of tetrahydroxanthone 35 (4.8 mg, 0.0080 mmol) in acetonitrile (2.5 mL) at 0 °C. The solution
was stirred for 6.5h while slowly warming to room temperature.. (Note reaction must be monitored by UPLC
analysis). The reaction mixture was then diluted with EtOAc (5 mL) and filtered through Celite®. The Celite® pad was
washed with EtOAc (5 mL) and the resulting filtrate was washed with H2O. The layers were separated and the
aqueous layer was extracted twice with EtOAc (2 x 5 mL). The organics were combined, dried over Na2SO4, filtered,
and concentrated to afford an orange brown solid. The solid was purified by preparative HPLC (5 to 90% CH3CN in
H2O) to yield kibdelone A as a bright orange solid (2.5 mg, 54% yield, 66% yield brsm). 1H NMR (500 MHz, DMSO‐d6)
δ (ppm) 14.29 (s, 1H), 8.41 (d, 1H, J = 9.0 Hz), 8.14 (d, 1H, J = 9.0 Hz), 6.10 (d, 1H, J = 6.4 Hz), 5.08 (d, 1H, J = 5.1 Hz),
4.79 (d, 1H, J = 6.2 Hz), 4.76‐4.68 (m, 2H), 4.03 (s, 3H), 3.95 (ddd, 1H, J = 12.8, 6.6, 3.4 Hz), 3.68 (s, 3H), 3.07‐2.96 (m,
2H), 2.27 (ddd, 1H, J = 12.9, 4.7 , 4.7 Hz), 1.79 (br d, 1H, J = 13.3 Hz), 1.65 (h, 2H, J = 7.3 Hz), 1.06 (t, 3H, J = 7.3 Hz). 13
C
NMR (100 MHz, DMSO‐d6) δ (ppm) 183.5, 181.2, 180.7, 166.2, 156.5, 156.3, 156.2, 145.3, 138.6, 137.5, 133.5, 133.1,
131.3, 125.7, 124.2, 120.8, 116.9, 113.1, 106.8, 105.5, 65.0, 63.9, 62.0, 61.2, 33.6, 33.1, 32.9, 19.5, 13.7. IR (film); νmax:
3688 (br), 2959, 2919, 2850, 1695, 1613, 1514, 1436, 1272, 1059, 756. HRMS: m/z calcd. for C29H25ClNO10 (MH)+:
582.1167, found 582.1174.[α]D23= +192 °(c= 0.1, CHCl3).
ACKNOWLEDGMENT
Financial support from the National Institutes of Health (RO1 CA137270), the Natural Sciences and Engineering
Research Council of Canada (NSERC), (Idea to Innovation and Discovery Grants), the Canada Research Chair Program,
the Canada Foundation for Innovation (CFI), TDC Research, Inc., TDC Research Foundation, Brock University, the
Intramural Research Program of the NIH, National Cancer Institute‐ Center for Cancer Research, and FQRNT (Fonds
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de Recherche Nature et Technologies du Québec) is gratefully acknowledged. We thank Drs. David L. Sloman (Merck)
and Pieter Bos (Boston University) for helpful discussions and Prof. Rob Capon (University of Queensland) and Dr.
Ernest Lacy (Microbial Screening Technologies) for providing spectra and samples of kibdelone A.
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Supporting Information Available Copies of 1H and 13C NMR spectra of all new compounds and NCI 60 data. This material
is available free of charge via the Internet at http://pubs.acs.org.
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