Biomimetic Syntheses of Analogs of Hongoquercin A and B by Late-Stage Derivatization

Article abstract of DOI:10.1021/acs.joc.0c02638

The hongoquercins are tetracyclic meroterpenoid natural products with the trans-transoid decalin-dihydrobenzopyran ring system, which display a range of different bioactivities. In this study, the syntheses of a range of hongoquercins using gold-catalyzed enyne cyclization reactions and further derivatization are described. The parent enyne resorcylate precursors were synthesized biomimetically from the corresponding dioxinone keto ester via regioselective acylation, Tsuji-Trost allylic decarboxylative rearrangement, and aromatization. The dioxinone keto ester 12 was prepared in 6 steps from geraniol using allylic functionalization and alkyne synthesis.

Full text of DOI:10.1021/acs.joc.0c02638

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Biomimetic Syntheses of Analogs of Hongoquercin A and B by Late-
Stage Derivatization
Thomas Mies, Andrew J. P. White, Philip J. Parsons, and Anthony G. M. Barrett*
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ABSTRACT: The hongoquercins are tetracyclic meroterpenoid
natural products with the trans−transoid decalin-dihydrobenzopyr-
an ring system, which display a range of different bioactivities. In
this study, the syntheses of a range of hongoquercins using gold-
catalyzed enyne cyclization reactions and further derivatization are
described. The parent enyne resorcylate precursors were
synthesized biomimetically from the corresponding dioxinone
keto ester via regioselective acylation, Tsuji-Trost allylic decarbox-
ylative rearrangement, and aromatization. The dioxinone keto ester 12 was prepared in 6 steps from geraniol using allylic
functionalization and alkyne synthesis.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The retrosynthetic analysis for the hongoquercin analogs 7 is
outlined in Scheme 2. Thus, the key intermediate 8 should be
available from dienyne 9 by gold-catalyzed carbocyclization, a
process reported by Michelet, Toste, and Echavarren, among
others.6 Dienyne 9 should, in turn, be available from the
sequential C-acylation of keto-ester 12,7 palladium-catalyzed
decarboxylative allylic rearrangement8 to give diketo-dioxinone
10 and aromatization5 to produce resorcylate 9. Dienynol 13,
which should be available from geraniol (14), could then be
easily converted into the key dienynol ester 12 using ketene
generation and trapping.5,7,9
Meroterpenoids are natural products that are biosynthesized
via two different pathways, such as the polyketide pathway for
the arene moiety and the terpene pathway.1 A subgroup of the
meroterpenoids are natural products that incorporate a
sesquiterpene unit and these include the hongoquercins.
These natural products have attracted attention, not only
due to the synthetic challenges with the 4 continuous
stereocenters and highly substituted arene scaffold but also
in consequence of their biological activities that include
inhibition of methicillin-resistant Staphylococcus aureus and
vancomycin-resistant Enterococcus faecium.2 Abbanat’s pro-
posed mechanism of antibiotic action for hongoquercins (1)
and (2) involves binding and disruption of the bacterial
membrane. Hongoquercin A (1) showed higher biological
activity than hongoquercin B (2) in both studies. Previous
syntheses of the hongoquercins have used a coupling reaction
between the arene entity, such as aryl halide 4 and an allylic
functionalized decalin 3.3 The Barrett group has also reported
two syntheses of hongoquercin A and B, which employed a
dual-biomimetic polyketide and terpene polyene cyclization
strategy with either early terpene 6 or late stage terpene 5
remote functionalization (Scheme 1).4 In order to enhance the
structural diversity of analogs of the hongoquercins, we now
report the application of gold-catalyzed 1,5-enyne cyclo-
isomerization reactions and postcyclization modification to
convert dienyne-resorcylates into a small library of novel
( )-hongoquercins. The dienyne-resorcylates were in turn
synthesized using diketo-dioxinone chemistry5 with modified
terpenoid starting materials derived from geraniol.
Protection of geraniol (14) as its benzoate ester 15 (96%)10
and subsequent allylic oxidation using selenium dioxide and t-
butyl hydroperoxide (56% on 40 mmol scale)11 gave alcohol
16 which was converted into allylic bromide 17 under Appel
conditions12 (91%). Subsequent reaction of bromide 17 with
3-trimethylsilyl-1-prop-2-ynyllithium13 gave the acetylene 18,
which was desilylated using tetrabutylammonium fluoride to
give the key trans, trans-dienynol 13 (70% from bromide 17)
(Scheme 3).
Dioxinone carboxylic acid 20 activation and homologation
by DCC-mediated coupling with the Meldrum’s acid derivative
20i gave dioxane-4,6-dione keto dioxanone 19, which following
literature precedent,7 gave the highly electrophilic dioxinone
acyl ketene regioselectively upon heating at 55 °C. Trapping in
Received: November 5, 2020
Published: December 28, 2020
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Scheme 1. Known Retrosynthetic Strategies for Hongoquercin A and B
Scheme 2. Retrosynthetic Analysis
Scheme 3. Synthesis of the 1,5-Enyne Allylic Alcohol 13
situ with dienynol 13 gave the 1,5-enyne β-keto ester 12 in
good yield (87%). Subsequent magnesium chloride mediated
regioselective C-acylation, palladium(0)-catalyzed decarboxy-
lative allylic migration, and aromatization of the intermediate
diketo-dioxinone 10 gave the 1,5-enyne resorcylate 9 (47%
over 2 steps) (Scheme 4).
the partially cyclized material 21.6a Cyclization using XPhos
AuNTf2 (5 mol %) in 1,2-dichloroethane proceeded with a
6i
better overall conversion (combined yields > 80%) as well as
providing greater selectivity favoring the required pentacyclic
product 8 (Scheme 5). This is in accord with the fact that
XPhos is a sterically less demanding ligand and renders the
Au+-species more alkynophilic.14 Initial coordination of [Au]+
to the alkyne provides complex 22 which gives rise to the
Reaction of dienyne 9 with a range of gold catalysts
produced two compounds: the fully cyclized resorcylate 8 and
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Scheme 4. Synthesis of the Resorcylate Dienyne 9
Scheme 5. Dienyne Cyclization to Produce Hongoquercin Alkene 8 and Proposed Mechanism
formation of the 6-membered ring in complex 23 and the
derived tertiary carbocationis then available for classical
cationic cyclization (path a). Alternatively, as postulated by
Echavarren,6d activation of the acetylene by [Au]+ as
intermediate 22 promotes cyclization via intermediate 23
and rearrangement to the cyclopropyl-gold-carbene 25 (path
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Scheme 6. Cyclization with Dual Catalysis
Scheme 7. Dual Catalyst System for the Synthesis of Analogs of Hongoquercin A
Scheme 8. Synthesis of Unsubstituted Analogs of Hongoquercin B
b) that can undergo ring opening to produce carbocations 23
or 24, which undergo classical terpene cyclization. On the
other hand, removal of an α-proton next to the carbocation 23
or cleavage of the cyclopropyl-gold-carbene 25 gives triene 26,
which will lead to the formation of the partially cyclized
material 21 (path c). The structure of the pentacyclic product
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Scheme 9. Synthesis of Methyl-Substituted Analogs of Hongoquercin B
8 was confirmed as having the rigid trans-trans-ring stereo-
chemistry by an X-ray single crystal structure determination.
The use of other Lewis acids, among others, indium bromide
or bismuth triflate, gave the pentacyclic product 8 in inferior
yields (58%) or gave chromane 27 (26%) (Scheme 6). In
addition, upon scale up and also with lower gold-catalyst
loadings (1−4 mol %), cyclization to produce the pentacyclic
product 8 was slow and proceeded in inferior yield (16%) with
formation of the partially cyclized compounds 21 (47%) as the
major products (Scheme 6). Reactions in alternative solvents
(diethyl ether, dichloromethane, or toluene) did not improve
the efficiency of full cyclization. Such partial cyclization is a
common observation in cationic polyene cyclizations.15
Reaction of the dienyne 21 with a Lewis acid enhanced
Brønsted acid catalyst, stannic chloride with trifluoroacetic
acid,4b,15b,c also did not provide high yields of the pentacyclic
product 28 (50%) and more so as a mixture of isomers.6f
To avoid this issue of olefin isomerization, dual gold(I) and
Lewis acid catalysis was examined. Thus, reaction using XPhos
AuNTf2 (2 mol %) and indium triflate (2 mol %) gave the
pentacyclic product 8 as the major product (69−73%) with
only traces of the partially cyclized trienes 21 (Scheme 7). The
exact role of indium triflate remains unclear; however, we
speculate it helps in stabilizing intermediates 23 or 25 to favor
cyclization over elimination. To the best of our knowledge,
such a dual catalysts system has not been reported for dienyne
cyclizations.16 Subsequent hydrogenation of the pentacyclic
product 8 over palladium on carbon (80%) followed by
saponification gave resorcylic acid 30 in excellent yield (89%).
Alternatively, saponification of the pentacyclic product 8 gave
resorcylic acid 31 in good yields (81%).
chloroperbenzoic acid gave the α-epoxide 32 (86%), and its
stereochemistry was confirmed by NOE correlation exper-
iments.6g,19a Subsequent trans-diaxial ring opening with
samarium(II) iodide in dichloromethane solution gave the
iodo-alcohol 33 (98%) rather than any products derived from
reduction.18 Indeed, the same iodo-alcohol 33 (82%) was
formed when epoxide 32 was allowed to react with
samarium(II) iodide and triethylsilane. The structure and
stereochemistry of the iodo-alcohol 33 were confirmed by X-
ray crystallography. Reaction of iodo-alcohol 33 with Raney
nickel19 in ethanol gave alcohol 34 (88%). Attempts to
reductively ring open epoxide 32 using lithium aluminum
hydride17 or lithium triethyl borohydride resulted in reductive
cleavage of the dioxinone ring to produce the benzylic alcohol
41.
Oxidation of alcohol 34 with Dess-Martin Periodinane
(DMP) gave ketone 37 (87%) which was reduced with NaBH4
to the β-alcohol 38 in excellent yields (89%).20 Attempted
Mitsunobu reaction of alcohol 34 using triphenylphosphine,
di-iso-propyl azodicarboxylate, and acetic acid failed to give the
β-alcohol acetate in significant conversion.21 While this
sequence is not redox economic,22 we anticipated that the
ketone functionality may have different bioactivities compared
to the alcohol since it can only serve as an H-bond acceptor.
Saponification of dioxinone 34 with potassium hydroxide in
THF gave the desired resorcylic acid 35 in 45% yield and the
corresponding decarboxylated resorcylate 36 in 24% yield. It
was anticipated that β-alcohol 38 might react similarly; thus, to
suppress this undesired reaction, the saponification was carried
out using potassium tert-butoxide in water,23 which gave the β-
alcohol resorcylic acid 39 in 52% as the sole product.
Saponification of the ketone analog 37 was more complicated
due to anticipated self-aldol reactions with common
Further analogs of hongoquercin were synthesized from the
pentacyclic product 8 (Scheme 8). Reaction with m-
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Scheme 10. Synthesis of Azido- and Amino-Analogs of Hongoquercin B
saponification methods. Thus, reaction of 37 with lithium
diisopropylamide, in an attempt to protect the ketone as its
enolate, followed by addition of potassium trimethylsilanoate
gave lactone 40 in 24%, presumably via an anionically
accelerated retro-Diels−Alder reaction, followed by rapid
quenching of the quino-methide ketene intermediate with
acetone.
(48%)28 However, protection of azido-alcohol 49 with acetic
anhydride gave acetoxy azide 50 (63%),29 which on reaction
with trimethylphosphinein THF and aqueous sodium hydrox-
ide gave amine 51, which was directly allowed to react with
acetic anhydride, DMAP, and triethylamine to produce the
acetamido-ester 52 in 97% over 2 steps.30 Chemoselective
saponification of the acetate and dioxinone groups gave the
resorcylic acid 53 in moderate yields (48%).
The syntheses of methyl-branched hongoquercins are
described in Scheme 9. Reaction of the α-epoxide 32 with
the methylcopper magnesium bromide and boron trifluoride
etherate complex gave alcohol 43 in good yield (80%).24,25
The course of this reaction is dependent on the order of
addition. While initial preparation of the Me2CuMgBr and
boron trifluoride etherate complex and reaction gave alcohol
43 in good yield, the addition of boron trifluoride etherate to a
mixture of the epoxide and Me2CuMgBr gave both alcohol 43
and bromohydrin 42, the structure of which was determined
by X-ray crystallography. Alternative methylation protocols
including methyl Grignard, trimethyl aluminum, or the methyl
cuprate derived from the reaction of MeMgBr and CuBr·SMe2
failed to give alcohol 43 or showed incompatibility with the
dioxinone group. Bromohydrin 42 was also obtained when a
mixture of methylmagnesium bromide and magnesium
chloride was allowed to react with epoxide 32. Bromohydrin
42 was reconverted into alcohol 34 via Raney-Nickel-mediated
dehalogenation in 90% yield. Oxidation of α-alcohol 43 with
Dess Martin periodinane gave ketone 45 (89%), and
subsequent stereoselective reduction with sodium borohydride
gave the β-alcohol 46 (85%).20 Saponification of dioxinones 43
and 46 with potassium tert-butoxide in water, respectively, gave
the resorcylic acids 44 (70%) and 47 (37%), while reaction of
45 with lithium diisopropylamide followed by potassium
trimethylsilanoate gave lactone 48 (33%).
CONCLUSION
■
In conclusion, several analogs of hongoquercin A and B were
synthesized employing a late stage derivatization strategy from
the hongoquercin alkene 8. A dual bioinspired synthesis
involving polyketide aromatization and a dual gold(I)−
indium(III) catalyzed polyenye cyclization gave alkene 8
with full control of relative stereochemistry. This common
precursor 8 was converted into the analogs 29 to 53 through
late-stage functional group manipulation thereby enhancing
the structural diversity of analogs of hongoquercin antibiotics.
Further studies on the lithium diisopropylamide mediated
formation of lactones 40 and 48 are ongoing.
EXPERIMENTAL SECTION
■
G e n e r a l M e t h o d s . C H 2 C l 2 , C l C H 2 C H 2 C l ,
CH3OCH2CH2OCH3, DMF, THF, Et2O, MeOH, EtOH, and
PhMe were purified by filtration through activated alumina columns
or purchased as extra dry solvents and stored over 4 Å molecular
sieves. NEt3, HNiPr2, pyridine, and NiPr2Et were purchased as extra
dry reagents and stored over 4 Å molecular sieves. Pentane refers to
the petroleum alkane fraction boiling between 40 and 60 °C. The
concentration of n-BuLi was determined by titration against
diphenylacetic acid according to the procedure by Kofron and
Baclawski.31 2-Phenyl-1,3-dioxane-4,6-dione and 2-(2,2-dimethyl-4-
oxo-4H-1,3-dioxin-6-yl)acetic acid were prepared according to
literature procedures.7b
Reactions were carried out in cooled oven-dried (180 °C)
glassware under a nitrogen or argon atmosphere using standard
Schlenk techniques and with transfers by cannulas and syringes.
Unless stated to the contrary, reactions were carried out at room
temperature, when reaction temperatures refer to the external bath
temperature. In all cases, DrySyn heating mantels were used for
reactions at elevated temperatures. Unless stated to the contrary,
chromatography was carried out using the flash techniques of Still.32
The progress of reactions was monitored by analytical thin-layer
chromatography (TLC) on silica gel coated aluminum oxide F254
The syntheses of azido- and amino-hongoquercins are
described in Scheme 10. Ring opening of the α-epoxide 32
with sodium azide in acetic acid and DMF gave the trans-
diaxial azido-alcohol 49. The reduction of this compound to
the corresponding amino-alcohol proved problematic, and the
use of hydrogenolysis over palladium on carbon or palladium
hydroxide, with thioacetic acid, or with Raney nickel and
thioacetic acid26,27 failed to provide the corresponding amine
or acetamide. An attempted Staudinger reaction was also
unproductive and led to the recovery of the epoxide 32
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plates. Components on TLC plates were visualized under UV light or
by spraying with KMnO4 or acidic vanillin and warming. Flash
column chromatography was performed by employing silica gel 60 Å,
particle size 40−63 μm.
with distilled water (50 mL) and brine (50 mL). The organic phase
was dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (2:1 to 1:1 pentane:Et2O) gave allylic
alcohol 16 (6.07 g, 22.1 mmol, 57%) as a colorless oil: Rf 0.19
(pentane:EtOAc 4:1); IR: νmax 3417, 1715, 1269, 711 cm−1; 1H NMR
(400 MHz, CDCl3): δ 8.11−8.00 (m, 2H), 7.60−7.50 (m, 1H), 7.43
(t, J = 7.7 Hz, 2H), 5.47 (tq, J = 7.0, 1.4 Hz, 1H, H2), 5.37 (tt, J = 7.0,
1.5 Hz, 1H), 4.84 (d, J = 7.0 Hz, 2H), 3.97 (s, 2H), 2.26−2.14 (m,
2H), 2.16−2.06 (m, 2H), 1.77 (d, J = 1.2 Hz, 3H), 1.66 (d, J = 1.3
Hz, 3H), 1.43 (s, 1H); 13C{1H}-NMR (101 MHz, CDCl3): δ 166.8,
141.9, 135.4, 133.0, 130.6, 129.7, 128.5, 125.4, 119.0, 69.0, 62.0, 39.2,
25.8, 16.7, 13.8; HRMS (ESI-ToF) m/z: [M + Na]+ calcd for
(C17H22O3 + Na)+: 297.1461, found: 297.1471. Analytical data were
in good agreement with literature values.10,11 Upon repeating this
experiment on a 100 mmol scale, the yield dropped to 28% with
methyl benzoate (4.70 g, 54%) obtained after the reduction. Glyme
was shown to be an appropriate substitute for methanol in the
reduction step, giving an overall yield of 56% on a 100 mmol scale.
The experimental procedure followed the one above with SeO2 (1.10
g, 9.91 mmol, 0.10 equiv), and t-BuOOH (70 wt % in H2O, 40.2 mL,
198 mmol, 2.00 equiv) added sequentially in one portion with stirring
to benzoate 15 (25.6 g, 99.1 mmol, 1.00 equiv) in CH2Cl2 (300 mL).
Workup as above and removal of volatiles via coevaporation with
PhMe gave a crude oil, which was dissolved in 1,2-dimethoxyethane
(100 mL). To the ice-cold crude oil was added NaBH4 (900 mg, 23.8
mmol, 0.24 equiv) in several portions with stirring over 30 min.
Workup as above and chromatography (2:1 to 1:1 pentane:Et2O)
gave allylic alcohol 16 (15.0 g, 54.7 mmol, 56%) as a colorless oil.
(2E,6E)-8-Bromo-3,7-dimethylocta-2,6-dien-1-yl Benzoate (17).
CBr4 (3.14 g, 9.46 mmol, 2.00 equiv) was added in one portion with
stirring to the ice-cold allylic alcohol 16 (1.30 g, 4.73 mmol, 1.00
equiv) in Et2O (50.0 mL). PPh3 (2.48 g, 9.46 mmol, 2.00 equiv) was
added in several portions over 15 min. After stirring for 18 h, the
mixture was diluted with CH2Cl2 (20 mL) and quenched with
saturated aqueous NaHCO3 (20 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 40 mL) and the
combined organic layers were washed with brine (30 mL). The
organic phase was dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was dissolved in CH2Cl2 (5 mL),
filtered through Celite, and chromatographed (100% pentane to 4:1
pentane:Et2O) to give bromide 17 (1.44 g, 4.28 mmol, 91%) as a
colorless oil: Rf 0.61 (pentane:EtOAc 3:1); IR: νmax 1715, 1268, 1107,
1097, 711 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.11−7.98 (m, 2H),
7.61−7.50 (m, 1H), 7.49−7.39 (m, 2H), 5.63−5.53 (m, 1H), 5.47
(ddq, J = 7.1, 5.6, 1.3 Hz, 1H), 4.91−4.79 (m, 2H), 3.95 (d, J = 0.7
Hz, 2H), 2.23−2.15 (m, 2H), 2.15−2.08 (m, 2H), 1.77 (d, J = 1.3 Hz,
3H), 1.76 (q, J = 0.9 Hz, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ
166.8, 141.6, 133.0, 132.6, 130.6, 130.6, 129.7, 128.5, 119.1, 61.9,
41.8, 38.7, 26.5, 16.7, 14.8; HRMS (ESI-ToF) m/z: [M − OBz]•
calcd for (C10H16Br)•: 215.0435, found: 215.0441. Analytical data
were in good agreement with literature values.10
1H NMR and proton decoupled 13C NMR spectra were,
respectively, recorded at 400 and 101 MHz in deuterated solvents
at ambient temperature with chemical shifts reported in ppm (δ)
relative to Me4Si and referenced to the residual solvent peak (CDCl3:
1H at 7.26 ppm, 13C at 77.16 ppm; CD3OD: 1H at 3.31 and 4.87 ppm,
13C at 49.0 ppm). Assignments of the 1H NMR and 13C NMR spectra
were made by the analysis of chemical shift and coupling constant
values and as appropriate using COSY, DEPT-135, HSQC, and
HMBC. MS spectra were recorded by the Imperial College Mass
Spectrometry Service under conditions of electrospray ionization
(ESI), chemical ionization (CI), or electron ionization (EI). Infrared
spectra of solids and liquids were recorded as thin films. Melting
points were recorded on a melting point apparatus and are
uncorrected. X-ray diffraction data were recorded at the Imperial
College X-ray Crystallography Facility. Elemental microanalyses were
recorded at the University of Cambridge Microanalysis Facility.
(E)-3,7-Dimethylocta-2,6-dien-1-yl benzoate (15). A mixture of
pyridine (6.33 g, 6.48 mL, 80.0 mmol, 2.00 equiv) and DMAP (978
mg, 8.00 mmol, 0.20 equiv) was added in one portion with stirring to
geraniol (14) (6.16 g, 7.00 mL, 40.0 mmol, 1.00 equiv) in Et2O (120
mL). Subsequently, PhCOCl (6.19 g, 5.11 mL, 44.0 mmol, 1.10
equiv) was added dropwise with stirring. After 20 h, reaction was
quenched with saturated aqueous NaHCO3 (30 mL), the layers were
separated, and the organic layer was washed with saturated aqueous
NaHCO3 (2 × 40 mL), aqueous HCl (1 M; 3 × 30 mL), and brine (2
× 40 mL). The organic phase was dried (MgSO4), filtered, and
concentrated under reduced pressure. Chromatography (2:1
pentane:Et2O) gave benzoate 15 (9.23 g, 35.7 mmol, 90%) as a
colorless oil: Rf 0.65 (pentane:EtOAc 4:1); IR: νmax 1716, 1267, 1107,
710 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.08−8.03 (m, 2H),
7.58−7.53 (m, 1H), 7.43 (dd, J = 8.4, 7.0 Hz, 2H), 5.47 (tp, J = 7.0,
1.3 Hz, 1H), 5.09 (ddq, J = 8.3, 5.6, 1.5 Hz, 1H), 4.84 (dq, J = 7.1, 0.7
Hz, 2H), 2.19−2.10 (m, 2H), 2.10−2.04 (m, 2H), 1.77 (d, J = 1.7 Hz,
3H), 1.67 (d, J = 1.3 Hz, 3H), 1.61 (d, J = 1.3 Hz, 3H); 13C{1H}-
NMR (101 MHz, CDCl3): δ 166.8, 142.5, 132.9, 132.0, 130.7, 129.7,
128.4, 123.9, 118.5, 62.0, 39.7, 26.5, 25.8, 17.9, 16.7; HRMS (ESI-
ToF) m/z: [M + H]+ calcd for (C17H23O2)+: 259.1693, found:
259.1705. When the reaction was carried out on a 70 mmol scale, the
yield was 96%. On a 100 mmol scale the yield was ∼99%. The
experimental procedure followed the one above with pyridine (15.8 g,
16.2 mL, 200 mmol, 2.00 equiv) and DMAP (2.44 g, 20.0 mmol, 0.20
equiv) added in two portions with stirring to geraniol (14) (15.5 g,
17.6 mL, 100 mmol, 1.00 equiv) in Et2O (500 mL). Subsequently,
PhCOCl (15.5 g, 12.8 mL, 110 mmol, 1.10 equiv) was added
dropwise with stirring. Workup as above and chromatography (2:1
pentane:Et2O) gave benzoate 15 (25.6 g, 99.1 mmol, 99%) as a
colorless oil. Analytical data were in good agreement with reported
values.10
(2E,6E)-3,7-Dimethyl-11-(trimethylsilyl)undeca-2,6-dien-10-yn-
1-ol (18). n-BuLi (2.36 M, 8.75 mL, 20.7 mmol, 4.50 equiv) was
added dropwise with stirring to the dry ice cold 1-(trimethylsilyl)-
propyne (2.33 g, 3.07 mL, 20.7 mmol, 4.50 equiv) in THF (95.0 mL).
The resulting solution was stirred at −78 °C for 2 h, when bromide
17 (1.55 g, 4.61 mmol, 1.00 equiv) in THF (38.0 mL) was added
dropwise with stirring and allowed to warm up to 23 °C. After 16 h,
reaction was quenched with saturated aqueous NH4Cl (50 mL), and
the aqueous layer was extracted with Et2O (2 × 50 mL). The
combined organic layers were washed with distilled water (10 mL)
and brine (10 mL). The organic phase was dried (MgSO4), filtered,
and concentrated under reduced pressure. Chromatography (5:1 to
3:1 pentane:Et2O) gave a crude mixture containing silyl enynol 18 as
a yellow oil, which was used for the next step without further
purification: Rf 0.30 (pentane:EtOAc 3:1); IR: νmax 3330, 1248, 837,
(2E,6E)-8-Hydroxy-3,7-dimethylocta-2,6-dien-1-yl Benzoate (16).
SeO2 (429 mg, 3.87 mmol, 0.10 equiv) and t-BuOOH (70 wt % in
H2O, 15.7 mL, 77.4 mmol, 2.00 equiv) were added sequentially in one
portion with stirring to benzoate 15 (10.0 g, 38.7 mmol, 1.00 equiv)
in CH2Cl2 (150 mL). After 30 h, the reaction was quenched with a
saturated aqueous NaHCO3 (100 mL), the layers were separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic layers were washed with distilled water (50 mL)
and brine (100 mL). The organic phase was dried (MgSO4), filtered,
and concentrated under reduced pressure (excess of t-BuOOH was
removed by the addition and coevaporation of PhMe). The resultant
crude oil was used without further purification.
NaBH4 (350 mg, 9.28 mmol, 0.24 equiv) was added with stirring to
the ice-cold crude oil in MeOH (110 mL) in several portions over 30
min. After 2 h at 0 °C, the mixture was concentrated under reduced
pressure, the residue was dissolved in Et2O (100 mL) and quenched
with distilled water (50 mL). The aqueous layer was extracted with
Et2O (3 × 50 mL), and the combined organic layers were washed
1
759 cm−1; H NMR (400 MHz, CDCl3): δ 5.41 (tq, J = 6.9, 1.3 Hz,
1H), 5.16 (dddd, J = 6.9, 5.6, 2.6, 1.3 Hz, 1H), 4.19−4.12 (m, 2H),
2.30 (ddd, J = 7.7, 6.9, 1.1 Hz,2H), 2.21−2.16 (m, 2H), 2.16−2.08
(m, 2H), 2.07−2.00 (m, 2H), 1.68 (dd, J = 1.3, 0.7 Hz, 3H), 1.60 (q, J
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= 0.9 Hz, 3H), 1.17 (s), 0.14 (s, 9H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 139.8, 134.0, 125.2, 123.6, 107.5, 84.8, 59.6, 39.6, 38.7,
26.4, 19.4, 16.4, 16.0, 0.3; HRMS (ESI-ToF) m/z: [M − OH]+ calcd
for (C16H27Si)+: 247.1877, found: 247.1890.
equiv) was added dropwise, and, after 1 h at 0 °C, the reaction was
quenched with saturated aqueous NH4Cl (10 mL) and the pH was
adjusted to 1−2 with aqueous HCl (1 M). The organic layer was
separated, and the aqueous layer was further extracted with EtOAc (3
× 10 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
dissolved in THF (4.30 mL), and tri(2-furyl)phosphine (53.0 mg,
0.228 mmol, 0.32 equiv) and tris(dibenzylideneacetone)-
dipalladium(0) (35.0 mg, 0.0382 mmol, 0.05 equiv) were added
sequentially in one portion with stirring. After 1.5 h, cesium acetate
(413 mg, 2.15 mmol, 3.00 equiv) in 2-propanol (4.30 mL) was added
in one portion. After 1.5 h, reaction was quenched with aqueous HCl
(1 M, 15 mL), the organic layer was separated, and the aqueous layer
was further extracted with CH2Cl2 (3 × 10 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated under
reduced pressure. Chromatography (19:1 to 15:1 pentane:EtOAc)
gave resorcylate 9 (129 mg, 0.337 mmol, 47%) as a yellow-white oil
which solidified on standing.
(2E,6E)-3,7-Dimethylundeca-2,6-dien-10-yn-1-ol (13). Bu4NF (1
M in THF; 13.0 mL, 13.0 mmol, 2.82 equiv) was added dropwise
with stirring to the ice-cold crude silyl enynol 18. After 19 h, reaction
was quenched with saturated aqueous NaHCO3 (20 mL), the layers
were separated, and the aqueous layer was extracted with Et2O (2 ×
40 mL). The combined organic layers were washed with saturated
aqueous NaHCO3 (20 mL) and brine (20 mL). The organic phase
was dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (3:1 pentane:Et2O) gave dienynol 13
(838 mg, 4.36 mmol, 95%) as a yellow oil: Rf 0.26 (pentane:EtOAc
3:1); IR: νmax 3341, 1249, 1019, 839, 759 cm−1; 1H NMR (400 MHz,
CDCl3): δ 5.42 (tq, J = 6.9, 1.3 Hz, 1H), 5.18 (ddq, J = 8.3, 5.5, 1.3
Hz, 1H), 4.15 (dd, J = 7.2, 3.5 Hz, 2H), 2.31−2.25 (m, 2H), 2.23−
2.17 (m, 2H), 2.17−2.10 (m, 2H), 2.05 (dd, J = 9.2, 6.1 Hz, 2H), 1.95
(t, J = 2.6 Hz, 1H), 1.68 (d, J = 1.3 Hz, 3H), 1.61 (t, J = 1.1 Hz, 3H),
1.13 (s, 1H); 13C{1H}-NMR (101 MHz, CDCl3): δ 139.7, 133.7,
125.3, 123.6, 84.5, 68.5, 59.6, 39.5, 38.5, 26.3, 17.7, 16.4, 16.0; HRMS
(APCI) m/z: [M + H]+ calcd for (C13H21O)+: 193.1587, found:
193.1587. Major peak: m/z [M − OH]+ calcd for (C13H19)+:
175.1481, found: 175.1481. Analytical data were in good agreement
with literature values.13 For larger scale reactions (>8 mmol) the yield
was 67−72%. The experimental procedure followed the one above
with n-BuLi (2.36 M, 38.1 mL, 90 mmol, 4.50 equiv) added dropwise
with stirring to the dry ice cold 1-(trimethylsilyl)propyne (10.1 g, 13.3
mL, 90 mmol, 4.50 equiv) in THF (250 mL). After 2 h at −78 °C,
bromide 17 (6.74 g, 20.0 mmol, 1.00 equiv) in THF (80 mL) was
added dropwise with stirring. Workup as above and chromatography
(5:1 to 3:1 pentane:Et2O) afforded a crude oil. Bu4NF (1 M in THF;
56.4 mL, 56.4 mmol, 2.82 equiv) was added dropwise with stirring at
0 °C. Workup as above and chromatography (3:1 pentane:Et2O) gave
dienynol 13 (2.76 g, 14.4 mmol, 72%) as a yellow oil.
(2E,6E)-3,7-Dimethylundeca-2,6-dien-10-yn-1-yl 4-(2,2-dimeth-
yl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (12). DCC (781 mg,
3.79 mmol, 1.82 equiv) and DMAP (463 mg, 3.79 mmol, 1.82 equiv)
were sequentially added in one portion with stirring to 2-phenyl-1,3-
dioxane-4,6-dione (728 mg, 3.79 mmol, 1.82 equiv) in CH2Cl2 (32.0
mL). After 15 min, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic
acid (705 mg, 3.79 mmol, 1.82 equiv) was added in one portion. After
18 h, the mixture was cooled to 0 °C, the precipitate was filtered off,
and the solid was washed with small portions of CH2Cl2 until the
precipitate appeared colorless. The filtrate was washed with aqueous
HCl (1 M, 2 × 20 mL). The organic phase was dried (MgSO4),
filtered, and concentrated under reduced pressure. The residue was
dissolved in PhMe (8.00 mL), and dienynol 13 (400 mg, 2.08 mmol,
1.00 equiv) in PhMe (8.00 mL) was added in one portion with
stirring. The resulting pale-yellow solution was heated to 55 °C for 4
h after which the solution was concentrated. Chromatography (9:1 to
7:1 to 4:1 pentane:EtOAc) gave β-keto ester 12 (730 mg, 1.81 mmol,
87%) as orange oil: Rf 0.09 (pentane:EtOAc 4:1); IR: νmax 1724,
1638, 1389, 1375, 1272, 1202, 1016 cm−1; 1H NMR (400 MHz,
CDCl3): δ 5.36 (d, J = 0.6 Hz, 1H), 5.33 (tq, J = 7.2, 1.3 Hz, 1H),
5.15 (ddd, J = 5.4, 4.1, 2.8 Hz, 1H), 4.66 (d, J = 7.3 Hz, 2H), 3.51 (s,
2H), 3.50 (s, 2H), 2.31−2.24 (m, 2H), 2.23−2.16 (m, 2H), 2.15−
2.10 (m, 2H), 2.10−2.04 (m, 2H), 1.94 (t, J = 2.5 Hz, 1H), 1.71 (s,
9H), 1.61 (d, J = 1.3 Hz, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ
195.8, 166.5, 163.7, 160.6, 143.5, 133.9, 124.9, 117.6, 107.5, 97.3,
84.5, 68.6, 62.8, 49.3, 47.1, 39.5, 38.5, 26.2, 25.2, 17.7, 16.6, 16.0;
HRMS (ESI-ToF) m/z: [M + H]+ calcd for (C23H31O6)+: 403.2115,
found: 403.2106. Major peak m/z: [M + Na]+ calcd for
(C22H30O6Na)+: 425.1935, found: 425.1947.
Alternatively, MgCl2 (95.0 mg, 0.996 mmol, 1.00 equiv) and
pyridine (158 mg, 161 μL, 1.99 mmol, 2.00 equiv) were added
sequentially each in one portion with stirring to ice-cold β-keto ester
12 (401 mg, 0.996 mmol, 1.00 equiv) in CH2Cl2 (5.00 mL). After 15
min, AcCl (117 mg, 106 μL, 1.49 mmol, 1.50 equiv) was added
dropwise, and after 1 h at 0 °C, reaction was quenched with saturated
aqueous NH4Cl (10 mL) and the pH was adjusted to 1−2 with
aqueous HCl (1 M). The organic layer was separated, and the
aqueous layer was further extracted with EtOAc (3 × 10 mL). The
combined organic extracts were dried (MgSO4), filtered, and
concentrated under reduced pressure. The residue was dissolved in
THF (4.30 mL), and tri(2-furyl)phosphine (69.0 mg, 0.299 mmol,
0.30 equiv) and tris(dibenzylideneacetone)dipalladium(0) (46.0 mg,
0.0498 mmol, 0.05 equiv) were added sequentially in one portion
with stirring. After 1.5 h, Et3N (302 mg, 417 μL, 2.99 mmol, 3.00
equiv) was added in one portion, and, after 20 h, the reaction was
quenched with an aqueous HCl (1 M; 15 mL). The organic layer was
separated, and the aqueous layer was further extracted with CH2Cl2 (3
× 10 mL). The combined organic extracts were dried (MgSO4),
filtered, and concentrated under reduced pressure. Chromatography
(19:1 to 16:1 to 12:1 pentane:EtOAc) gave resorcylate 9 (176 mg,
0.460 mmol, 46%) as yellow-white oil, which solidified upon standing:
Rf 0.33 (pentane:EtOAc 7:3); IR: νmax 3294, 1726, 1692, 1607, 1590,
1
1451, 1409, 1388, 1376, 1295, 1275, 1209, 1166, 1107 cm−1; H
NMR (400 MHz, CDCl3): δ 6.40 (d, J = 0.9 Hz, 1H), 5.91 (s, 1H,
OH), 5.22−5.15 (m, 1H), 5.12 (tt, J = 5.6, 1.4 Hz, 1H), 3.32 (d, J =
7.3 Hz, 2H), 2.59 (d, J = 0.8 Hz, 3H), 2.29−2.21 (m, 2H), 2.21−2.15
(m, 2H), 2.15−2.09 (m, 2H), 2.06 (dt, J = 7.3, 3.1 Hz, 2H), 1.93 (t, J
= 2.5 Hz, 1H), 1.79 (d, J = 1.3 Hz, 3H), 1.69 (s, 6H), 1.59 (d, J = 1.3
Hz, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 161.0, 160.1, 156.1,
143.1, 138.6, 134.0, 125.0, 121.1, 113.8, 112.7, 105.6, 105.0, 84.5,
68.5, 39.7, 38.5, 26.3, 25.9, 22.2, 22.0, 17.7, 16.4, 16.0; HRMS (ESI-
ToF) m/z: [M + H]+ calcd for (C24H31O4)+: 383.2217, found:
383.2234. Anal. Calcd for C24H30O4: C, 75.36; H, 7.91. Found: C,
75.29; H, 7.80.
( )-2,2,5,7a,13a-Pentamethyl-7a,8,9a,12,13,13a,13b,14-octahy-
dro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (8). 2-Dicy-
clohexylphosphino-2′,4′,6′-triiso-propylbiphenylgold(I) bis-
(trifluoromethanesulfonyl)imide (28 mg, 0.029 mmol, 0.025 equiv)
was added in one portion with stirring to resorcylate 9 (444 mg, 1.16
mmol, 1.00 equiv) in CH2Cl2 (25 mL). After 30 min, In(OTf)3 (16
mg, 0.029 mmol, 0.025 equiv) was added in one portion. After 17 h,
the reaction was quenched with water (20 mL), the organic layer was
separated, and the aqueous layer was further extracted with CH2Cl2 (3
× 20 mL). The combined organic layers were washed with brine (40
mL), dried (MgSO4), and filtered. Concentration under reduced
pressure and chromatography (15:1 pentane:EtOAc) gave pentacyclic
resorcylate 8 (325 mg, 0.85 mmol, 73%) as a white solid: mp 198 °C
− 200 °C (CH2Cl2/pentane); Rf 0.61 (pentane:EtOAc 4:1); IR: νmax
1727, 1616, 1573, 1305, 1289, 1279,1208, 1167, 1129 cm−1; 1H NMR
(400 MHz, CDCl3): δ 6.34 (d, J = 0.9 Hz, 1H), 5.58 (dq, J = 10.0, 3.2
Hz, 1H), 5.38 (dq, J = 9.9, 2.1 Hz, 1H), 2.66 (dd, J = 16.8, 4.9 Hz,
8-((2E,6E)-3,7-Dimethylundeca-2,6-dien-10-yn-1-yl)-7-hydroxy-
2,2,5-trimethyl-4H-benzo[d][1,3]dioxin-4-one (9). MgCl2 (68.0 mg,
0.718 mmol, 1.00 equiv) and pyridine (114 mg, 120 μL, 1.44 mmol,
2.00 equiv) were added sequentially in one portion with stirring to
ice-cold β-keto ester 12 (289 mg, 0.718 mmol, 1.00 equiv) in CH2Cl2
(3.60 mL). After 15 min, AcCl (85.0 mg, 76.6 μL, 1.08 mmol, 1.50
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1H), 2.57 (s, 3H), 2.33−2.23 (m, 1H), 2.13 (ddq, J = 5.2, 3.9, 2.7, 1.9
Hz, 2H), 2.07 (dt, J = 12.9, 3.4 Hz, 1H), 2.03 (dt, J = 3.2, 1.6 Hz,
1H), 1.87 (dt, J = 12.8, 4.0 Hz, 1H), 1.79−1.70 (m, 1H), 1.73 (s,
3H), 1.69 (s, 3H), 1.66−1.62 (m, 1H), 1.59 (td, J = 6.5, 5.9, 3.7 Hz,
1H), 1.50−1.42 (m, 1H), 1.27 (d, J = 1.0 Hz, 3H), 1.22 (dd, J = 5.0,
4.1 Hz, 1H), 0.82 (d, J = 0.8 Hz, 3H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 161.0, 159.1, 156.2, 142.3, 129.9, 126.1, 114.6, 108.6,
104.9, 104.2, 78.9, 48.8, 46.0, 40.2, 35.2, 35.0, 26.3, 25.6, 25.2, 23.2,
22.1, 21.5, 17.0, 11.5; HRMS (ESI-ToF) m/z: [M + H]+ calcd for
(C24H31O4)+: 383.2217, found: 383.2223.
1H), 0.83 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 161.0,
159.0, 156.2, 142.2, 114.6, 108.6, 104.9, 104.1, 78.9, 49.9, 47.7, 40.2,
38.8, 36.5, 28.1, 26.8, 26.6, 26.3, 25.6, 22.1, 21.3, 21.1, 16.7, 12.2;
HRMS (APCI) m/z: [M + H]+ calcd for (C24H33O4)+: 385.2373,
found: 385.2370. Anal. Calcd for C24H32O4: C, 74.97; H, 8.39.
Found: C, 75.29; H, 8.59.
( )-11-Hydroxy-6a,9,12b-trimethyl-1,3,4,4a,5,6,6a,12,12a,12b-
decahydro-2H-benzo[a]xanthene-10-carboxylic acid (30). Aqueous
KOH (5 M; 1.0 mL, 5 mmol, 100 equiv) was added with vigorous
stirring to resorcylate 29 (20 mg, 0.052 mmol, 1.00 equiv) in THF
(1.0 mL). After 6 days at 60 °C, the mixture was diluted with H2O
(10 mL) and EtOAc (10 mL) and acidified with aqueous HCl (1 M;
10 mL). The organic layer was separated, and the aqueous layer was
further extracted with EtOAc (3 × 5 mL). The combined organic
layers were washed with brine (15 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. Chromatography (1:4:5
EtOAc:CH2Cl2:pentane) gave resorcylic acid 30 (16 mg, 0.046
mmol, 89%) as an off-white solid: m.p., 183−185 °C (CH2Cl2); Rf
0.15 (pentane:EtOAc 7:3), IR: νmax 2927, 1616, 1595, 1576, 1454,
1269, 1263, 1183, 1109, 800 cm−1; 1H NMR (400 MHz, CD3OD): δ
6.13−6.09 (m, 1H), 2.70 (dd, J = 16.9, 5.0 Hz, 1H), 2.46 (d, J = 2.9
Hz, 3H), 2.26 (ddd, J = 15.9, 13.6, 6.7 Hz, 1H), 1.97 (dt, J = 12.5, 3.2
Hz, 1H), 1.84−1.77 (m, 1H), 1.77−1.70 (m, 1H), 1.68 (d, J = 11.7
Hz, 1H), 1.60−1.56 (m, 1H), 1.55−1.50 (m, 1H), 1.47−1.41 (m,
2H), 1.40 (d, J = 2.8 Hz), 1.34−1.30 (m, 4H), 1.27−1.24 (m, 1H),
1.21 (d, J = 0.9 Hz, 3H), 1.02 (s, 1H), 0.88 (d, J = 0.8 Hz, 3H); 13C
NMR (101 MHz, CD3OD): δ 175.6, 164.5, 159.0, 141.8, 112.9,
109.0, 104.9, 79.2, 51.6, 47.8, 41.3, 40.0, 37.5, 30.8, 29.2, 27.7, 24.2,
22.4, 21.2, 17.8, 12.4; HRMS (APCI) m/z: [M + H]+ calcd for
(C21H29O4)+: 345.2060, found: 345.2068.
( )-11-Hydroxy-6a,9,12b-trimethyl-1,4a,5,6,6a,12,12a,12b-octa-
hydro-2H-benzo[a]xanthene-10-carboxylic acid (31). Aqueous
KOH (5 M; 1.5 mL, 7.5 mmol, 129 equiv) was added in one portion
with stirring to resorcylate 8 (22 mg, 0.058 mmol, 1.00 equiv) in THF
(1.5 mL). After vigorously stirring for 6 days at 60 °C, the mixture
was diluted with water (5 mL) and EtOAc (5 mL) and acidified with
aqueous HCl (1 M; 10 mL). The organic layer was separated, and the
aqueous layer was further extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (15 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure.
Chromatography (1:2:7 EtOAc:CH2Cl2:pentane) gave resorcylic
acid 31 (16 mg, 0.047 mmol, 81%) as an off-white solid: mp 158
°C − 162 °C (CH2Cl2); Rf 0.12 (pentane:EtOAc 7:3); IR: νmax 2927,
1621, 1454, 1264 cm−1; 1H NMR (400 MHz, CD3OD): δ 6.12 (dd, J
= 2.2, 0.9 Hz, 1H), 5.66−5.53 (m, 1H), 5.39 (dq, J = 9.8, 2.1 Hz, 1H),
2.80−2.67 (m, 1H), 2.46 (s, 3H), 2.39−2.26 (m, 1H), 2.14 (dq, J =
5.8, 3.2 Hz, 2H), 2.06−2.01 (m, 1H), 2.00−1.94 (m, 1H), 1.94−1.84
(m, 1H), 1.73 (ddd, J = 16.3, 8.9, 4.1 Hz, 1H), 1.68−1.59 (m, 1H),
1.59−1.54 (m, 1H), 1.54−1.44 (m, 1H), 1.35−1.31 (m, 1H), 1.26 (d,
J = 0.9 Hz, 3H), 0.85 (d, J = 0.9 Hz, 3H); 13C{1H}-NMR (101 MHz,
CD3OD): δ 164.1, 159.0, 154.3, 141.8, 131.0, 126.9, 112.9, 109.0,
105.2, 79.3, 50.4, 47.2, 41.4, 36.1, 36.0, 26.2, 24.2, 24.1, 21.7, 18.1,
11.8; HRMS (APCI) m/z: [M + H]+ calcd for (C21H27O4)+:
343.1904, found: 343.1905; also found m/z: [M + D]+ calcd for
(C21H26DO4)+: 344.1965; found: 344.1967. Anal. Calcd for
C21H26O4·0.5H2O: C, 71.77; H, 7.74. Found: C, 71.89; H, 7.49.
( )-3a,6,9,9,11b-Pentamethyl-1a,1b,3,3a,11,11a,11b,12,13,13a-
decahydro-2H,7H-[1,3]dioxino[4,5-a]oxireno[2′,3′:5,6]benzo[1,2-j]-
xanthen-7-one (32). m-CPBA (65.0 mg, 0.291 mmol, 1.05 equiv)
was added in two portions with stirring to resorcylate 8 (106 mg,
0.277 mmol, 1.00 equiv) in CH2Cl2 (3.00 mL) and saturated aqueous
NaHCO3 (0.5 M, 0.84 mL). After 3 h, further m-CPBA (18.0 mg,
83.1 μmol, 0.3 equiv) was added, and after 1.5 h, reaction was
quenched with water. The organic layer was separated, and the
aqueous layer was further extracted with CH2Cl2 (1 × 10 mL). The
combined organic layers were washed with aqueous NaOH (1 M; 15
mL), distilled water (10 mL), and brine (15 mL). The organic phase
was dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (6:1 to 4:1 pentane:EtOAc) gave epoxide
32 (95.0 mg, 0.238 mmol, 86%) as a white foam: Rf 0.18
(E)-7-Hydroxy-2,2,5-trimethyl-8-(3-methyl-5-(2-methylcyclo-
hexa-2,5-dien-1-yl)pent-2-en-1-yl)-4H-benzo[d][1,3]dioxin-4-one,
(E)-7-Hydroxy-2,2,5-trimethyl-8-(3-methyl-5-(6-methylenecyclo-
hex-2-en-1-yl)pent-2-en-1-yl)-4H-benzo[d][1,3]dioxin-4-one, and
(E)-7-Hydroxy-2,2,5-trimethyl-8-(3-methyl-5-(2-methylcyclohexa-
1,5-dien-1-yl)pent-2-en-1-yl)-4H-benzo[d][1,3]dioxin-4-one (21).
Resorcylate 9 (30.0 mg, 78.4 μmol, 1.00 equiv) in PhMe (1.00
mL) was added dropwise with stirring to 2-(dicyclohexylphosphino-
2′,4′,6′-triisopropylbiphenyl)gold(I) bis(trifluoromethanesulfonyl)-
imide (53.0 mg, 3.92 μmol, 0.05 equiv). After 17 h, the mixture
was filtered through a silica plug with CH2Cl2 (2 × 5.00 mL) and
EtOAc (1 × 5.00 mL) and the combined filtrates were concentrated
under reduced pressure. Chromatography (17:1 to 9:1 pentane:E-
tOAc) gave a mixture of the three alkenes 21 (13.0 mg, 34.0 μmol,
42%) as a yellow oil: Rf 0.23 (pentane:EtOAc 4:1); IR: νmax 3337,
1
2924, 1728, 1696, 1607, 1592, 1452, 1295, 1277, 1209 cm−1; H
NMR (400 MHz, CDCl3): δ 6.41 (d, J = 0.9 Hz, 1H), 6.37 (dd, J =
1.7, 0.9 Hz, 1H), 5.87−5.75 (m, 1H), 5.66−5.60 (m, 1H), 5.59−5.51
(m, 1H), 5.45−5.40 (m, 1H), 5.35−5.27 (m, 1H), 5.23−5.16 (m,
1H), 3.32 (d, J = 7.2 Hz, 2H), 2.77 (dd, J = 14.0, 9.5 Hz, 1H), 2.66 (t,
J = 5.3 Hz, 1H), 2.59 (t, J = 0.9 Hz, 5H), 2.56 (d, J = 0.7 Hz, 1H),
2.39−2.26 (m, 1H), 2.22−2.07 (m, 3H), 2.07−1.82 (m, 2H), 1.82−
1.80 (m, 2H), 1.79 (q, J = 1.5 Hz, 1H), 1.70 (d, J = 4.3 Hz, 3H), 1.68
(s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 161.5, 161.3, 160.1,
159.4, 144.3, 143.0, 142.4, 138.1, 137.0, 130.6, 126.0, 125.9, 124.9,
124.2, 124.1, 122.9, 122.2, 121.3, 117.9, 116.0, 113.7, 113.5, 105.0,
104.9, 49.1, 41.8, 38.6, 35.6, 33.9, 33.6, 32.1, 31.8, 31.0, 30.5, 29.8,
28.8, 26.0, 25.9, 23.4, 22.4, 22.2, 22.0, 21.4, 17.1, 16.4, 11.5; HRMS
(ESI-ToF): m/z [M − H]− calcd for (C24H29O4)−: 381.2071, found:
381.2057.
( )-2,2,5,8-Tetramethyl-8-(4-methyloct-3-en-7-yn-1-yl)-9,10-di-
hydro-4H,8H-[1,3]dioxino[4,5-f]chromen-4-one (27). The experi-
mental procedure followed that for compound 21 with 0.30 equiv of
Bi(OTf)3. Chromatography (pentane:EtOAc 15:1) gave chromane 27
(8.0 mg, 0.0209 mmol, 26%) as yellow oil: Rf 0.47 (pentane:EtOAc
3:1); IR: νmax 1728, 1574, 1282 cm−1; 1H NMR (400 MHz, CDCl3):
δ 6.36 (d, J = 2.2 Hz, 1H), 5.26−5.14 (m, 1H), 2.89 (d, J = 6.5 Hz,
1H), 2.58 (s, 4H), 2.29−2.25 (m, 2H), 2.20 (d, J = 6.9 Hz, 1H,), 2.12
(q, J = 7.5 Hz, 1H), 2.08−1.98 (m, 1H), 1.94 (dq, J = 3.9, 2.4, 1.7 Hz,
1H), 1.79 (dq, J = 23.1, 6.8 Hz, 2H), 1.70 (s, 9H), 1.61 (d, J = 1.3 Hz,
3H), 1.30 (s, 3H); HRMS (ESI-ToF) m/z: [M + H]+ calcd for
(C24H31O4)+: 383.2217, found: 383.2208.
( )-2,2,5,7a,13a-Pentamethyl-7a,8,9a,10,11,12,13,13a,13b,14-
decahydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthen-4-one (29).
Pd/C (5%, 10 mg) was added in one portion with stirring to
resorcylate 8 (25 mg, 0.063 mmol, 1.00 equiv) in MeOH (3.0 mL)
and EtOAc (1.0 mL). The black suspension was purged with H2 three
times. After 17 h stirring under H2, the mixture was filtered through
Celite and the solids rinsed with EtOAc (3 × 20 mL). The combined
organic layers were concentrated under reduced pressure. Chroma-
tography (9:1 pentane:Et2O) gave resorcylate 29 (20 mg, 0.052
mmol, 80%) as white solid: mp 162 °C − 164 °C (CH2Cl2/pentane);
Rf 0.58 (pentane:EtOAc 7:3); IR: νmax 1724, 1615, 1572, 1450, 1375,
1
1299, 1282, 1207, 1171, 1129, 901, 730 cm−1; H NMR (400 MHz,
CDCl3): δ 6.33 (d, J = 1.0 Hz, 1H), 2.61 (dd, J = 17.0, 5.1 Hz, 1H),
2.57 (s, 3H), 2.28−2.18 (m, 1H), 2.00 (dt, J = 12.5, 3.2 Hz, 1H),
1.82−1.75 (m, 1H), 1.72 (s, 3H), 1.70 (d, J = 2.1 Hz), 1.69 (s, 3H),
1.57 (d, J = 5.0 Hz, 1H), 1.53 (t, J = 4.9 Hz, 2H), 1.41 (d, J = 9.6 Hz,
1H), 1.39−1.33 (m, 2H), 1.32−1.28 (m, 2H), 1.28 (dd, J = 4.3, 3.3
Hz), 1.24 (d, J = 8.1 Hz), 1.21 (d, J = 0.9 Hz, 3H), 1.02−0.91 (m,
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(pentane:EtOAc 4:1); IR: νmax 1718, 1615, 1571, 1289, 1279, 1206,
1128, 1036, 919, 900, 727 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.32
(d, J = 0.2 Hz, 1H), 3.19 (t, J = 3.4 Hz, 1H), 2.79 (dt, J = 4.0, 0.9 Hz,
1H), 2.59 (dd, J = 17.0, 4.8 Hz, 1H), 2.56 (s, 3H), 2.27−2.10 (m,
1H), 2.16−2.09 (m, 1H), 2.06 (ddd, J = 12.8, 6.6, 2.5 Hz, 1H), 1.94−
1.88 (m, 1H) 1.87 (td, J = 5.0, 4.0, 2.3 Hz, 1H), 1.71 (d, J = 5.6 Hz,
1H), 1.71 (d, J = 0.7 Hz, 3H), 1.67 (d, J = 0.7 Hz, 3H), 1.67−1.60
(m, 1H), 1.57 (dd, J = 13.2, 3.3 Hz, 1H), 1.53−1.50 (m, 1H) 1.50 (m,
1H), 1.26 (d, J = 1.0 Hz, 3H), 1.03−0.95 (m, 1H,), 0.83 (d, J = 0.6
Hz, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 160.8, 158.8, 156.1,
142.2, 114.5, 108.2, 104.9, 104.2, 78.2, 54.8, 51.8, 47.9, 47.5, 40.0,
34.3, 31.7, 26.3, 25.5, 24.5, 22.0, 21.4, 20.8, 17.2, 12.6; HRMS (ESI-
ToF) m/z: [M + H]+ calcd for (C24H31O5)+: 399.2166, found:
399.2176.
1.77−173 (m, 1H), 1.71 (s, 3H), 1.73 (s, 1H), 1.67 (s, 3H), 1.64 (d, J
= 5.0 Hz, 1H), 1.61 (d, J = 4.7 Hz, 1H), 1.56 (dt, J = 7.9, 2.5 Hz, 1H),
1.53−1.46 (m, 2H), 1.47−1.40 (m, 1H), 1.40−1.30 (m, 2H), 1.21 (s,
3H), 0.82 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 161.0,
159.0, 156.2, 142.1, 114.6, 108.5, 104.9, 104.1, 78.7, 66.1, 49.4, 40.0,
39.4, 36.3, 35.1, 32.7, 28.4, 26.3 (2 x C), 25.5, 22.1, 21.0, 16.7, 11.1;
HRMS (ESI-ToF) m/z: [M + H]+ calcd for (C24H33O5)+: 401.2323,
found: 401.2330. Similar yields (90%) were obtained when the
bromohydrin 40 was allowed to react in this fashion.
(
) - 3 , 1 1 - D i h y d r o x y - 6 a , 9 , 1 2 b - t r i m e t h y l -
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-
carboxylic acid (35). Aqueous KOH (5 M, 1.0 mL) was added
dropwise with stirring to α-alcohol 34 (37 mg, 0.092 mmol, 1.00
equiv) in THF (1.0 mL). After vigorous stirring for 6 days at 60 °C,
the mixture was diluted with H2O (10 mL) and EtOAc (10 mL) and
acidified with aqueous HCl (1 M, 10 mL). The organic layer was
separated, and the aqueous layer was further extracted with EtOAc (3
× 5 mL). The combined organic layers were washed with brine (15
mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (1:9 to 2:8 to
3:7 EtOAc:CH2Cl2) gave resorcylic acid 35 (15 mg, 0.042 mmol,
45%) as a yellow-transparent film: Rf 0.09 (pentane:EtOAc 1:1); IR:
νmax 3478, 2928, 2862, 1621, 1578, 1452, 1262, 1175 cm−1; 1H NMR
(400 MHz, CDCl3): δ 11.92 (s, 1H, OH), 6.22 (d, J = 0.8 Hz, 1H),
4.11 (d, J = 3.3 Hz, 1H), 2.76 (dd, J = 16.8, 4.9 Hz, 1H), 2.51 (s, 3H),
2.30 (dd, J = 16.8, 13.3 Hz, 1H), 2.05−2.00 (m, 1H), 1.80 (dd, J =
13.2, 3.1 Hz, 1H), 1.77−1.74 (m, 1H), 1.72 (d, J = 6.0 Hz, 1H), 1.67
(d, J = 4.5 Hz, 1H), 1.64 (d, J = 5.7 Hz, 1H), 1.63 (d, J = 4.3 Hz, 1H),
1.60−1.46 (m, 2H), 1.41 (s, 1H), 1.38 (dd, J = 9.7, 2.7 Hz, 2H), 1.23
(d, J = 0.9 Hz, 3H), 0.84 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3):
δ 175.6, 163.9, 159.0, 141.6, 112.8, 108.2, 102.7, 78.7, 66.4, 49.7, 40.1,
39.6, 36.4, 35.1, 32.8, 28.5, 26.4, 24.3, 21.1, 17.0, 11.1; HRMS (ESI-
ToF) m/z: [M − H]− calcd for (C21H27O5)−: 359.1864, found:
359.1867.
(
)-11-Hydroxy-10-iodo-2,2,5,7a,13a-pentamethyl-
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (33). Et3SiH (48 mg, 0.066 mL, 0.42
mmol, 2.4 equiv) and SmI2 (0.1 M in THF; 3.2 mL, 0.32 mmol, 1.88
equiv) were sequentially added dropwise with stirring to strictly
deoxygenated epoxide 32 (69 mg, 0.17 mmol, 1.00 equiv) in CH2Cl2
(5.0 mL). After 20 min, the mixture was diluted with Et2O (5 mL)
and quenched with H2O (5 mL). Saturated aqueous NaHCO3 (5
mL) was added, and the organic layer was separated. The aqueous
layer was further extracted with Et2O (2 × 10 mL), and the combined
organic layers were washed with brine (15 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. Chromatography
(3:1 pentane:Et2O to 3:1 pentane:EtOAc) gave iodohydrin 33 (75
mg, 0.14 mmol, 82%) as a white solid.
Alternatively: SmI2 in THF (0.1 M; 2.3 mL, 0.23 mmol, 1.8 equiv)
was added dropwise with stirring to a strictly deoxygenated epoxide
32 (50 mg, 0.13 mmol, 1.00 equiv) in CH2Cl2 (8.0 mL). After 1 h, the
mixture was diluted with Et2O (10 mL) and quenched with H2O (10
mL). Saturated aqueous NaHCO3 (10 mL) was added, the organic
layer was separated, and the aqueous layer was further extracted with
Et2O (2 × 10 mL). The combined organic layers were washed with
brine (20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Chromatography (1:1:8 pentane:EtOAc:CH2Cl2)
gave iodohydrin 33 (65 mg, 0.12 mmol, 98%) as a white solid: m.p.:
117−120 °C (dec.) (CH2Cl2/pentane); Rf 0.21 (pentane:EtOAc
7:3); IR: νmax 3425, 1727, 1701, 1619, 1573, 1307, 1293, 1284, 1171,
1130, 1047 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.31 (s, 1H), 4.39
(q, J = 2.7 Hz, 1H), 4.26 (dt, J = 3.9, 2.1 Hz, 1H), 2.99 (s, 1H, −OH),
2.56 (d, J = 6.9 Hz, 1H), 2.54 (s, 3H), 2.34−2.28 (m, 1H), 2.28−2.23
(m, 1H), 2.07 (d, J = 10.3 Hz, 1H), 1.90−1.79 (m, 1H), 1.71 (s, 3H),
1.69 (s, 1H), 1.67 (s, 3H), 1.62 (dd, J = 5.5, 4.2 Hz, 1H), 1.61−1.59
(m, 1H), 1.58 (d, J = 3.3 Hz, 1H), 1.55 (d, J = 4.5 Hz, 1H), 1.51 (d, J
= 3.7 Hz, 1H), 1.39−1.37 (m, 1H), 1.22 (s, 3H), 1.12 (s, 3H);
13C{1H}-NMR (101 MHz, CDCl3): δ 161.2, 158.8, 156.2, 142.2,
( )-6a,9,12b-Trimethyl-1,3,4,4a,5,6,6a,12,12a,12b-decahydro-
2H-benzo[a]xanthene-3,11-diol (36). Aqueous KOH (5 M, 1.0 mL)
was added dropwise with stirring to α-alcohol 34 (37 mg, 0.092
mmol, 1.00 equiv) in THF (1.0 mL). After vigorous stirring for 6 days
at 60 °C, the mixture was diluted with H2O (10 mL) and EtOAc (10
mL) and acidified with aqueous HCl (1 M, 10 mL). The organic layer
was separated, and the aqueous layer was further extracted with
EtOAc (3 × 5 mL). The combined organic layers were washed with
brine (15 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography (1:9
to 2:8 to 3:7 EtOAc:CH2Cl2) gave phenol 36 (7.0 mg, 0.022 mmol,
24%) as a yellow-white film: Rf 0.29 (pentane:EtOAc 1:1); IR: νmax
3381, 1587, 1445, 1333, 1260, 1172, 1059, 1035, 1018, 988, 822
1
cm−1; H NMR (500 MHz, CDCl3): δ 6.24 (s, 1H), 6.17 (d, J = 1.6
Hz, 1H), 4.68 (s, 1H), 4.13−4.06 (m, 1H), 2.67 (dd, J = 16.2, 5.1 Hz,
1H), 2.37−2.29 (m, 1H), 2.20 (s, 3H), 2.00 (dt, J = 12.6, 3.3 Hz,
1H), 1.81−1.78 (m, 1H), 1.77 (dd, J = 4.4, 2.3 Hz, 1H), 1.74 (dd, J =
4.7, 3.4 Hz, 1H), 1.72−1.66 (m, 1H), 1.66−1.62 (m, 1H), 1.61−1.58
(m, 1H), 1.53−1.44 (m, 2H), 1.41 (t, J = 4.3 Hz, 1H), 1.39−1.34 (m,
2H), 1.22 (d, J = 1.0 Hz, 3H), 0.85−0.81 (m, 3H); 13C{1H}-NMR
(126 MHz, CDCl3): δ, 154.2, 153.9, 137.4, 110.4, 107.2, 106.8, 77.0,
66.4, 50.0, 40.3, 39.6, 36.3, 35.2, 32.9, 28.5, 26.4, 21.3, 21.0, 16.9,
11.1; HRMS (APCI) m/z: [M + H]+ calcd for (C20H29O3)+:
317.2111, found: 317.2102. Phenol 36 has a similar Rf value to the
starting material. Reactions might therefore be considered incomplete
due to the similarity of the Rf value. Noteworthy, while the starting α-
alcohol 34 is UV-active and stains with acidic vanillin, phenol 36 is
not strongly UV-active and only appears upon staining with acidic
vanillin.
( )-2,2,5,7a,13a-Pentamethyl-7a,8,9a,12,13,13a,13b,14-octahy-
dro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthene-4,11(10H)-dione
(37). Dess-Martin periodinane (201 mg, 0.474 mmol, 2.00 equiv) was
added with stirring in two portions over the course of 5 min to ice-
cold α-alcohol 34 (95.0 mg, 0.237 mmol, 1.00 equiv) in CH2Cl2 (5.0
mL). After 1.5 h, the mixture was concentrated and loaded onto a
column with a Celite pad. Chromatography (1:1 to 1:2
114.5, 108.0, 105.0, 104.1, 78.3, 73.1, 51.0, 42.3, 39.5, 37.3, 36.7, 31.5,
28.5, 26.3, 25.6, 23.2, 22.1, 21.0, 15.9, 14.2; HRMS (APCI) m/z: [M
+ H]+ calcd for (C24H32IO5)+: 527.1289, found: 527.1284; Anal.
Calcd for C24H31IO5: C, 54.76; H, 5.94. Found: C, 54.66; H, 5.88.
(
) - 1 1 - H y d r o x y - 2 , 2 , 5 , 7 a , 1 3 a - p e n t a m e t h y l -
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (34). Raney-Ni (50% aqueous suspen-
sion; 1.4 mL) was added portionwise with stirring to iodohydrin 33
(75 mg, 0.14 mmol, 1.00 equiv) in EtOH (7.0 mL). After heating at
reflux for 3 h, the mixture was filtered through Celite and the solids
rinsed with EtOH (20 mL). The filtrate was concentrated under
reduced pressure, and the residue dissolved in EtOAc (20 mL) and
washed with water (10 mL). The organic layer was separated, and the
aqueous layer was further extracted with EtOAc (2 × 10 mL). The
combined organic layers were dried (MgSO4), filtered, and
concentrated under reduced pressure. Chromatography (3:1 to 1:1
pentane:Et2O) gave α-alcohol 34 (50 mg, 0.12 mmol, 88%) as a white
solid: mp 97−100 °C (CH2Cl2/pentane); Rf 0.12 (pentane:EtOAc
7:3); IR: νmax 3430, 1707, 1614, 1570, 1282, 1207, 1170, 1127, 1097,
907, 727 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.32 (s, 1H), 4.07 (q,
J = 2.9 Hz, 1H), 2.61 (dd, J = 16.8, 4.9 Hz, 1H), 2.55 (s, 3H), 2.29−
2.18 (m, 1H), 2.00 (dt, J = 12.6, 3.2 Hz, 1H), 1.81−1.78 (m, 1H),
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pentane:CH2Cl2) gave ketone 37 (82.0 mg, 0.206 mmol, 87%) as a
white solid: mp 223−226 °C (dec.) (CH2Cl2/pentane); Rf 0.22
(pentane:EtOAc 7:3); IR: νmax 1709, 1615, 1572, 1451, 1299, 1279,
[4,3-i]xanthene-3,12-dione (40). n-BuLi (2.30 M, 0.140 mL, 0.326
mmol, 1.30 equiv) was added dropwise with stirring to dry ice cold
HNiPr2 (45.7 μL, 33.0 mg, 0.326 mmol, 1.30 equiv) in THF (1.5
mL). The resulting solution was stirred at −78 °C for 30 min, then
warmed up to 0 °C for 30 min, and cooled back down to −78 °C,
when ketone 37 (100 mg, 0.251 mmol, 1.00 equiv) in THF (2.5 mL)
was added dropwise with stirring. After 1 h, KOTMS (322 mg, 2.51
mmol, 10.0 equiv) was added with stirring, and the mixture was
allowed to warm up to 23 °C. After 13 h, reaction was quenched with
saturated aqueous NH4Cl (20 mL) and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine (30 mL). The organic phase was dried
(MgSO4), filtered, and concentrated under reduced pressure.
Chromatography (9:1 CH2Cl2:EtOAc) gave lactone 40 (20.0 mg,
0.0603 mmol, 24%) as a white film: Rf 0.43 (pentane:EtOAc 1:1); IR:
νmax 1652, 1631, 1584, 1388, 1357, 1297, 1267, 1222, 1168, 1100, 731
cm−1; 1H NMR (400 MHz, CDCl3): δ 11.63 (s, 1H), 6.16−6.09 (m,
1H), 2.86 (d, J = 2.4 Hz, 2H), 2.81 (dd, J = 16.8, 4.9 Hz, 1H), 2.49
(dt, J = 8.6, 2.8 Hz, 1H), 2.46−2.41 (m, 1H), 2.41−2.35 (m, 1H),
2.32 (dd, J = 15.5, 1.6 Hz, 1H), 2.27−2.21 (m, 1H), 2.21−2.14 (m,
1H), 2.10−2.03 (m, 1H), 1.83−1.70 (m, 1H), 1.71−1.65 (m, 1H),
1.65−1.57 (m, 1H), 1.51 (ddt, J = 7.3, 4.0, 2.4 Hz, 1H), 1.46 (s, 3H),
1.45 (d, J = 4.1 Hz, 5H), 1.30 (d, J = 0.9 Hz, 3H), 1.08 (s, 3H);
13C{1H}-NMR (101 MHz, CDCl3): δ 210.8, 169.8, 161.8, 159.5,
137.3, 108.5, 108.1, 100.1, 81.7, 78.4, 49.2, 46.5, 44.0, 39.7, 39.4, 38.5,
37.3, 36.0, 27.5, 27.3, 26.5, 21.0, 17.3, 11.6; HRMS (APCI) m/z: [M
+ H]+ calcd for (C24H31O5)+: 399.2166, found: 399.2162.
1
1206, 1170, 1128, 1038, 912, 899, 725 cm−1; H NMR (400 MHz,
CDCl3): δ 6.32 (s, 1H), 2.63 (dd, J = 16.7, 5.0 Hz, 1H), 2.54 (s, 3H),
2.49−2.35 (m, 2H), 2.35−2.29 (m, 1H), 2.28−2.18 (m, 2H), 2.17−
2.09 (m, 1H), 2.04 (dt, J = 12.9, 3.2 Hz, 1H), 1.74 (d, J = 5.1 Hz,
1H), 1.71 (s, 3H, H1), 1.68 (s, 1H), 1.67 (s, 3H), 1.65−1.57 (m,
1H), 1.55−1.45 (m, 2H), 1.45−1.38 (m, 1H), 1.25 (s, 3H), 1.05 (s,
3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 210.5, 160.8, 158.6,
156.1, 142.4, 114.5, 107.9, 104.9, 104.2, 78.2, 49.0, 46.3, 43.9, 39.5,
38.3, 37.2, 35.8, 26.3, 26.3, 25.5, 22.0, 20.8, 17.3, 11.5; HRMS (ESI-
ToF) m/z: [M + H]+ calcd for (C24H31O5)+: 399.2166, found:
399.2174; Anal. Calcd for C24H30O5: C, 72.34; H, 7.59. Found: C,
72.19; H, 7.52.
(
) - 1 1 - H y d r o x y - 2 , 2 , 5 , 7 a , 1 3 a - p e n t a m e t h y l -
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (38). NaBH4 (2.3 mg, 0.062 mmol, 1.30
equiv) was added in one portion with stirring to ice-cold ketone 37
(19 mg, 0.048 mmol, 1.00 equiv) in EtOH (1.0 mL). After 1 h at 0
°C, the mixture was diluted with Et2O (5.0 mL), and the reaction was
quenched with saturated aqueous NH4Cl (3.0 mL). The organic layer
was separated, and the aqueous layer was further extracted with Et2O
(3 × 5.0 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (1:1:8 EtOAc:pentane:CH2Cl2) gave β-
alcohol 38 (17 mg, 0.042 mmol, 89%) as a white foam: Rf 0.08
(pentane:EtOAc 7:3); IR: νmax 3440, 2930, 1718, 1615, 1572, 1452,
(
) - 7 - ( H y d r o x y m e t h y l ) - 3 a , 6 , 9 b - t r i m e t h y l -
1
1388, 1376, 1287, 1209, 1129, 1042, 902, 731 cm−1; H NMR (400
1a,1b,3,3a,9,9a,9b,10,11,11a-decahydro-2H-oxireno[2′,3′:3,4]-
benzo[1,2-a]xanthen-8-ol (41). LiBHEt3 in THF (1 M; 0.110 mL,
0.105 mmol, 1.05 equiv) was added dropwise with stirring to ice-cold
epoxide 32 (40.0 mg, 0.100 mmol, 1.00 equiv) in THF (1.00 mL).
After 2 h, the reaction was quenched with saturated aqueous NH4Cl
(15 mL) and the organic layer was separated, and the aqueous layer
was further extracted with EtOAc (2 × 15 mL). The combined
organic layers were washed with brine (15 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. Flash column
chromatography (4:1 pentane:Et2O) gave benzylic alcohol 41 (33.0
mg, 0.0958 mmol, 95%) as a transparent film: Rf 0.43
(pentane:EtOAc 1:1); IR: νmax 1627, 1585, 1457, 1421, 1350, 1227,
1217, 1191, 1107 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.31 (s, 1H),
4.94 (s, 2H), 3.20 (t, J = 3.5 Hz, 1H), 2.80 (d, J = 3.8 Hz, 1H), 2.75
(d, J = 5.0 Hz, 1H), 2.25 (dd, J = 16.9, 13.3 Hz, 1H), 2.13−2.09 (m,
1H), 2.09−2.04 (m, 1H), 2.03 (s, 3H), 1.97−1.90 (m, 1H), 1.89−
1.84 (m, 1H), 1.81−1.68 (m, 1H), 1.68−1.60 (m, 1H), 1.57 (d, J =
3.5 Hz, 1H), 1.53 (t, J = 3.4 Hz, 1H), 1.50 (d, J = 2.8 Hz, 1H), 1.25
(s, 3H), 0.99 (s, 1H), 0.84 (s, 3H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 152.9, 146.9, 132.3, 112.6, 111.7, 109.3, 77.4, 61.5, 55.1,
52.0, 48.4, 47.7, 40.3, 34.4, 31.8, 24.7, 21.4, 20.9, 17.7, 17.4, 12.7;
HRMS (EI) m/z: [M − OH]• calcd for (C21H27O3)•: 327.1960,
found: 327.1955.
MHz, CDCl3): δ 6.33 (d, J = 1.0 Hz, 1H), 3.65 (tt, J = 10.6, 4.8 Hz,
1H), 2.63−2.58 (m, 1H), 2.56 (s, 3H), 2.28 (dd, J = 16.8, 13.3 Hz,
1H), 2.02 (dt, J = 12.6, 3.0 Hz, 1H), 1.90−1.85 (m, 1H), 1.85−1.81
(m, 1H), 1.72 (s, 3H), 1.70 (d, J = 1.0 Hz, 1H), 1.68 (s, 3H), 1.65
(dd, J = 4.8, 2.2 Hz, 1H), 1.59−1.51 (m, 1H), 1.51−1.46 (m, 1H),
1.48−1.34 (m, 2H), 1.30 (dd, J = 11.3, 1.5 Hz, 1H), 1.27−1.23 (m,
1H), 1.22 (d, J = 0.9 Hz, 3H), 1.13−1.03 (m, 1H), 0.87 (s, 3H);
13C{1H}-NMR (101 MHz, CDCl3): δ 161.0, 158.9, 156.2, 142.3,
114.6, 108.3, 104.9, 104.2, 78.7, 71.1, 49.5, 45.3, 40.1, 37.2, 37.2, 35.8,
30.7, 26.4, 26.3, 25.6, 22.1, 21.0, 17.1, 12.3; HRMS (ESI-ToF) m/z:
[M + H]+ calcd for (C24H33O5)+: 401.2323, found: 401.2318.
(
) - 3 , 1 1 - D i h y d r o x y - 6 a , 9 , 1 2 b - t r i m e t h y l -
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-
carboxylic acid (39). H2O (0.300 mL, 16.6 mmol, 391 equiv) was
added dropwise to an ice-cold suspension of KO-tBu (162 mg, 1.44
mmol, 34.0 equiv) in Et2O (0.50 mL). After 5 min, β-alcohol 38 (17.0
mg, 0.0424 mmol, 1.00 equiv) in THF (0.4 mL) and Et2O (0.4 mL)
was added dropwise with stirring. The flask was rinsed with THF (0.4
mL) and Et2O (0.4 mL), which was added dropwise with stirring.
After 48 h, the mixture was diluted with H2O (10 mL) and EtOAc
(10 mL) and acidified with aqueous HCl (1 M, 10 mL). The organic
layer was separated, and the aqueous layer was further extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with
brine (20 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography (2:8
EtOAc:CH2Cl2) gave resorcylic acid 39 (8.00 mg, 0.0222 mmol,
52%) as a transparent-white film: Rf 0.06 (pentane:EtOAc 1:1); IR:
(
)-10-Bromo-11-hydroxy-2,2,5,7a,13a-pentamethyl-
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (42). MgCl2 (7.5 mg, 0.079 mg, 0.40
equiv) was added in one portion with stirring to epoxide 32 (77 mg,
0.19 mmol, 1.00 equiv) in THF (2.0 mL) at −78 °C, followed by the
dropwise addition of MeMgBr in Et2O (3 M; 0.070 mL, 0.20 mmol,
1.05 equiv). After gradually warming up over 24 h, the mixture was
diluted with Et2O (5 mL) and the reaction was quenched with
saturated aqueous NH4Cl (5 mL). The organic layer was separated,
and the aqueous layer was further extracted with Et2O (2 × 10 mL).
The combined organic layers were washed with distilled water (10
mL) and brine (15 mL), and the organic layer was dried (MgSO4),
filtered, and concentrated under reduced pressure. Chromatography
(6:1 to 3:1 pentane:EtOAc) gave bromohydrin 42 (46 mg, 0.096
mmol, 50%) as pale-yellow oil which solidified to a white solid: mp
120 °C (dec.) (CH2Cl2/pentane); Rf 0.23(pentane:EtOAc 7:3); IR:
νmax 3439, 1701, 1616, 1571, 1296, 1284, 1205, 1195, 1168, 1129,
1047, 910, 898, 731 cm−1; 1H NMR (400 MHz, CDCl3): δ 6.32 (d, J
= 1.0 Hz, 1H), 4.25 (q, J = 2.7 Hz, 1H), 4.14−4.09 (m, 1H), 2.58
1
νmax 3437, 2925, 2853, 1618, 1577, 1453, 1262,1034 cm−1; H NMR
(400 MHz, CD3OD): δ 6.11 (d, J = 0.8 Hz, 1H), 3.63−3.50 (m, 1H),
2.70 (dd, J = 16.9, 5.0 Hz, 1H), 2.46 (s, 3H), 2.37−2.23 (m, 1H),
1.98 (dt, J = 11.8, 3.1 Hz, 1H), 1.84 (q, J = 5.2, 4.3 Hz, 1H), 1.82−
1.77 (m, 1H), 1.78−1.64 (m, 1H), 1.61 (dtd, J = 7.4, 4.7, 2.1 Hz,
1H), 1.53−1.48 (m, 1H), 1.48−1.40 (m, 1H), 1.31−1.29 (m, 1H),
1.28−1.28 (m, 3H), 1.21 (d, J = 0.9 Hz, 3H), 1.18−1.04 (m, 1H),
0.90 (d, J = 0.7 Hz, 3H); 13C{1H}-NMR (101 MHz, CD3OD): δ
175.6, 164.5, 159.0, 141.8, 112.9, 108.9, 104.9, 79.2, 71.6, 51.1, 46.5,
41.3, 38.3, 37.9, 36.8, 31.4, 27.5, 24.2, 21.2, 18.2, 12.5; HRMS (ESI-
ToF) m/z: [M − H]− calcd for (C21H27O5)−: 359.1864, found:
359.1863.
(
) - 1 3 - H y d r o x y - 6 a , 1 0 , 1 0 , 1 4 b - t e t r a m e t h y l -
1,4,4a,5,6,6a,9,14,14a,14b-decahydro-2H,10H-benzo[a]pyrano-
1812
https://dx.doi.org/10.1021/acs.joc.0c02638
J. Org. Chem. 2021, 86, 1802−1817

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(dd, J = 5.0, 2.8 Hz, 1H), 2.55 (s, 3H), 2.34−2.26 (m, 1H), 2.26−
2.18 (m, 1H), 2.12−2.09 (m, 1H), 2.08−2.05 (m, 1H), 1.80 (d, J =
9.4 Hz, 1H), 1.75 (d, J = 12.9 Hz, 1H), 1.72 (s, 3H), 1.68 (s, 3H),
1.63 (d, J = 4.4 Hz, 1H), 1.61 (d, J = 3.2 Hz, 1H), 1.59 (dd, J = 4.8,
2.2 Hz, 1H), 1.56−1.49 (m, 1H), 1.49−1.44 (m, 1H), 1.23 (s, 3H),
1.10 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 161.1, 158.8,
156.2, 142.3, 114.6, 108.1, 105.0, 104.2, 78.4, 71.3, 57.2, 50.7, 43.3,
39.9, 36.7, 31.7, 26.3, 25.9, 25.6, 23.2, 22.1, 21.0, 16.1, 14.5; HRMS
(APCI) m/z: [M + H]+ calcd for (C24H32BrO5)+: 479.1428, found:
479.1423; Anal. Calcd for C24H31BrO5: C, 60.13; H, 6.52. Found: C,
59.98; H, 6.48.
(45). Dess-Martin periodinane (139 mg, 0.328 mmol, 2.00 equiv) was
added in two portions with stirring over 5 min to ice-cold α-alcohol
43 (68.0 mg, 0.164 mmol, 1.00 equiv) in CH2Cl2 (4.00 mL). After 1.5
h, the mixture was concentrated and loaded onto a column with a
Celite pad. Chromatography (1:1 to 1:2 pentane:CH2Cl2) gave
ketone 45 (60.0 mg, 0.145 mmol, 89%) as a white solid: mp 170−171
°C (CH2Cl2/pentane); Rf 0.26 (pentane:EtOAc 7:3); IR: νmax 1726,
1616, 1575, 1288, 1170, 1130 cm−1; 1H NMR (400 MHz, CDCl3): δ
6.39−6.31 (m, 1H), 2.70−2.63 (m, 1H) 263−2.58 (m, 1H), 2.57 (s,
3H), 2.52−2.43 (m, 1H), 2.39−2.35 (m, 1H), 2.35−2.30 (m, 1H),
2.15 (dd, J = 6.6, 3.2 Hz, 1H), 2.1 (dd, J = 7.0, 3.7 Hz, 1H), 1.89−
1.79 (m, 1H), 1.77−1.75 (m, 1H), 1.74 (s, 3H), 1.73 (d, J = 1.9 Hz,
1H), 1.69 (s, 3H), 1.67−1.58 (m, 1H), 1.52 (dd, J = 13.3, 6.0 Hz,
1H), 1.49−1.41 (m, 1H), 1.26 (d, J = 1.4 Hz, 3H), 1.15 (d, J = 7.8
Hz, 3H), 1.11 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ 215.0,
160.8, 158.5, 156.0, 142.3, 114.4, 107.7, 104.9, 104.1, 78.1, 50.1, 48.4,
48.4, 39.9, 38.3, 36.1, 34.3, 26.2, 25.5, 23.6, 22.0, 20.6, 16.6, 14.6,
13.6; HRMS (ESI-ToF) m/z: [M + H]+ calcd for (C25H33O5)+:
413.2323, found: 413.2321; Anal. Calcd for C25H32O5: C, 72.79; H,
7.82. Found: C, 72.75; H, 7.81.
(
) - 1 1 - H y d r o x y - 2 , 2 , 5 , 7 a , 1 0 , 1 3 a - h e x a m e t h y l -
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (43). MeMgBr in Et2O (3 M; 0.13 mL,
0.40 mmol, 2.4 equiv) was added dropwise with stirring to CuBr·
SMe2 (16 mg, 0.079 mmol, 0.46 equiv) in THF (1.0 mL) −78 °C.
After 1h at −78 °C, BF3·OEt2 in Et2O (46.5%; 0.20 mL) was added
dropwise with stirring. After 5 min, epoxide 32 (67 mg, 0.17 mmol,
1.00 equiv) in THF and Et2O (1:2, 6.0 mL) were added dropwise.
After 40 min at −78 °C, the mixture was diluted with Et2O (10 mL)
and poured onto an ice−water mixture (30 mL) which was acidified
with aqueous HCl (1 M; 5 mL). The organic layer was separated, and
the aqueous layer was further extracted with Et2O (3 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried
(MgSO4), filtered, and concentrated under reduced pressure.
Chromatography (3:1 to 1:1 pentane:Et2O) gave α-alcohol 43 (56
mg, 0.14 mmol, 80%) as a white solid: mp 97−100 °C (CH2Cl2/
pentane); Rf 0.17 (pentane:EtOAc 7:3); IR: 3456, 1707, 1614, 1570,
(
) - 1 1 - H y d r o x y - 2 , 2 , 5 , 7 a , 1 0 , 1 3 a - h e x a m e t h y l -
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (46). NaBH4 (2.3 mg, 0.066 mmol, 1.3
equiv) was added in one portion with stirring to ice-cold ketone 45
(21 mg, 0.051 mmol, 1.00 equiv) in EtOH (1.0 mL). After 1 h at 0
°C, the mixture was diluted with Et2O (5.0 mL) and the reaction
quenched with saturated aqueous NH4Cl (3.0 mL). The organic layer
was separated, and the aqueous layer was further extracted with Et2O
(3 × 5.0 mL). The combined organic layers were washed with brine
(10 mL), dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (1:2 pentane:Et2O) gave β-alcohol 46 (18
mg, 0.043 mmol, 85%) as a white foam: Rf 0.09 (pentane:EtOAc 7:3);
IR: νmax 3438, 1711, 1615, 1572, 1450, 1388, 1284, 1205, 1129, 1046,
1
1283, 1206, 1197, 1128, 1042, 908, 727 cm−1; H NMR (400 MHz,
CDCl3): δ 6.33 (d, J = 1.0 Hz, 1H), 3.82 (q, J = 2.6 Hz, 1H), 2.56 (s,
3H), 2.52 (d, J = 5.0 Hz, 1H), 2.28−2.19 (m, 1H), 2.07 (dt, J = 12.3,
3.1 Hz, 1H), 1.95−1.87 (m, 1H), 1.85 (ddd, J = 10.2, 4.9, 2.4 Hz,
1H), 1.82−1.76 (m, 1H), 1.72 (s, 3H), 1.68 (s, 3H), 1.67−1.63 (m,
1H), 1.63−1.59 (m, 1H), 1.58−1.56 (m, 1H), 1.59−1.52 (m, 1H),
1.46 (dd, J = 13.8, 4.2 Hz, 1H), 1.39−1.30 (m, 1H), 1.20 (d, J = 0.9
Hz, 3H), 0.93 (d, J = 7.6 Hz, 3H), 0.89 (s, 3H); 13C{1H}-NMR (101
MHz, CDCl3): δ 161.0, 158.9, 156.2, 142.1, 114.5, 108.3, 104.9,
104.0, 78.7, 71.7, 50.6, 42.6, 41.2, 40.5, 36.5, 32.3, 26.3, 25.5, 24.6,
24.3, 22.1, 20.8, 16.2, 14.8, 14.4; HRMS (ESI-ToF) m/z: [M − H]−
calcd for (C25H33O5)−: 413.2333, found: 413.2334; Anal. Calcd for
C25H34O5: C, 72.44; H, 8.27. Found: C, 72.03; H, 8.07.
1
914, 731 cm−1; H NMR (400 MHz, CDCl3): δ 6.33 (s, 1H), 3.76
(ddd, J = 9.5, 7.3, 5.6 Hz, 1H), 2.56 (s, 3H), 2.52 (dd, J = 17.5, 5.8
Hz, 1H), 2.26−2.20 (m, 1H), 2.08 (dd, J = 9.2, 2.9 Hz, 1H), 2.06−
1.98 (m, 1H), 1.82 (dt, J = 13.1, 3.5 Hz, 1H), 1.75 (s, 1H), 1.73 (s,
1H), 1.72 (s, 3H), 1.68 (s, 3H), 1.65 (dd, J = 9.3, 3.5 Hz, 2H), 1.51
(dd, J = 13.2, 5.0 Hz, 1H), 1.38 (q, J = 2.7, 1.9 Hz, 1H), 1.36 (d, J =
3.2 Hz, 1H), 1.20 (d, J = 1.1 Hz, 3H), 1.09 (dtd, J = 13.3, 8.8, 8.2, 3.4
Hz, 1H), 0.92 (s, 3H), 0.90 (s, 3H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 161.0, 158.8, 156.2, 142.3, 114.5, 108.1, 104.9, 104.1, 78.7,
73.7, 50.8, 48.9, 40.6, 40.0, 37.9, 36.1, 26.3, 25.8, 25.6, 25.1, 22.1,
20.8, 16.6, 15.5, 9.0; HRMS (ESI-ToF) m/z: [M + H]+ calcd for
(C25H35O5)+: 415.2479, found: 415.2474.
(
) - 3 , 1 1 - D i h y d r o x y - 4 , 6 a , 9 , 1 2 b - t e t r a m e t h y l -
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-
carboxylic acid (44). H2O (100 μL, 9.97 mg, 0.554 mmol, 6.95
equiv) was added dropwise to an ice-cold suspension of KO-tBu (129
mg, 1.15 mmol, 14.4 equiv) in Et2O (0.50 mL). After 5 min, α-alcohol
43 (33.0 mg, 0.0796 mmol, 1.00 equiv) in THF/Et2O (2:1, 1.0 mL)
was added dropwise with stirring. The flask was rinsed with THF (0.2
mL) and Et2O (0.2 mL), which was also added dropwise with stirring.
After 2 weeks, the mixture was diluted with H2O (10 mL) and EtOAc
(10 mL) and acidified with aqueous HCl (1 M, 5 mL). The organic
layer was separated, and the aqueous layer was further extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with
brine (15 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography (2:8
EtOAc:CH2Cl2) gave resorcylic acid 44 (21.0 mg, 0.0561 mmol,
70%) as a white foam: Rf 0.05 (pentane:EtOAc 1:1); IR: νmax 3420,
2927, 2864, 1621, 1578,1453, 1264, 1170 cm−1; 1H NMR (400 MHz,
CD3OD): δ 6.11 (s, 1H), 3.73 (q, J = 2.7 Hz, 1H), 2.64 (dd, J = 16.9,
5.0 Hz, 1H), 2.46 (s, 3H), 2.35−2.21 (m, 1H), 2.14−1.97 (m, 1H),
1.97−1.89 (m, 1H), 1.86 (ddd, J = 9.6, 4.6, 2.7 Hz, 1H), 1.81−1.76
(m, 1H), 1.76−1.73 (m, 1H), 1.72 (d, J = 9.2 Hz, 1H), 1.59 (t, J = 4.5
Hz, 1H), 1.57−1.53 (m, 1H), 1.53−1.41 (m, 2H, 1.35−1.32 (m, 1H),
1.19 (s, 3H), 0.95 (d, J = 7.9 Hz, 3H), 0.93 (s, 3H); 13C{1H}-NMR
(101 MHz, CD3OD): δ 174.9, 163.9, 158.3, 141.1, 112.2, 108.1,
10.49, 78.6, 71.9, 51.9, 43.3, 41.6, 41.2, 36.9, 33.0, 25.1, 24.1, 23.6,
20.4, 16.7, 14.5, 14.1; HRMS (ESI-ToF) m/z: [M + H]+ calcd for
(C22H31O5)+: 375.2166, found: 375.2176.
(
) - 3 , 1 1 - D i h y d r o x y - 4 , 6 a , 9 , 1 2 b - t e t r a m e t h y l -
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-
carboxylic acid (47). H2O (0.300 mL, 16.6 mmol, 382 equiv) was
added dropwise to an ice-cold suspension of KO-tBu (160 mg, 1.44
mmol, 34.0 equiv) in Et2O (0.50 mL). After 5 min, β-alcohol 46 (18.0
mg, 0.0434 mmol, 1.00 equiv) in THF (0.4 mL) and Et2O (0.4 mL)
was added dropwise with stirring. The flask was rinsed with THF (0.3
mL) and Et2O (0.3 mL), which was also added dropwise with stirring.
After 48 h, the mixture was diluted with H2O (5 mL) and EtOAc (5
mL) and acidified with aqueous HCl (1 M, 10 mL). The organic layer
was separated, and the aqueous layer was further extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed with
brine (15 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography (1:9
to 3:7 EtOAc:CH2Cl2) gave resorcylic acid 47 (6.00 mg, 0.0160
mmol, 37%) as a white film: Rf 0.07 (pentane:EtOAc 1:1); IR: νmax
1
3421 (br, s), 2922, 2852, 1651, 1622, 1456, 1264, 1045 cm−1; H
NMR (400 MHz, CD3OD): δ 6.11 (d, J = 0.9 Hz, 1H), 3.72 (dt, J =
11.6, 5.0 Hz, 1H), 2.67−2.57 (m, 1H), 2.46 (s, 3H), 2.35−2.24 (m,
1H), 2.08−2.02 (m, 1H), 2.01−1.98 (m, 1H), 1.81 (dd, J = 8.6, 4.9
Hz, 1H), 1.77 (d, J = 6.0 Hz, 1H,), 1.75−1.66 (m, 1H), 1.62 (tt, J =
9.2, 4.2 Hz, 1H), 1.49 (dd, J = 13.1, 5.0 Hz, 1H), 1.46−1.38 (m, 3H),
1.19 (d, J = 0.8 Hz, 3H), 1.18−1.07 (m, 1H), 0.94 (d, J = 0.7 Hz,
3H), 0.91 (d, J = 7.5 Hz, 3H); 13C{1H}-NMR (101 MHz, CD3OD):
δ 175.6, 164.5, 158.9, 141.8, 112.8, 108.7, 105.4, 79.2, 74.5, 52.5, 50.1,
( )-2,2,5,7a,10,13a-Hexamethyl-7a,8,9a,12,13,13a,13b,14-octa-
hydro-4H,9H-benzo[a][1,3]dioxino[5,4-j]xanthene-4,11(10H)-dione
1813
https://dx.doi.org/10.1021/acs.joc.0c02638
J. Org. Chem. 2021, 86, 1802−1817

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
41.8, 41.5, 39.0, 37.2, 33.1, 26.2, 24.2, 21.0, 17.7, 15.9, 9.5; HRMS
(ESI-ToF) m/z: [M − H]− calcd for (C22H29O5)−: 373.2020, found:
373.2010.
filtered, and concentrated under reduced pressure. Chromatography
(1:5:4 EtOAc:pentane:CH2Cl2) gave acetate 50 (65.0 mg, 0.134
mmol, 63% over 2 steps) as a yellow-white solid: mp 74−79 °C
(CH2Cl2/pentane); Rf 0.46 (pentane:EtOAc 7:3); IR: νmax 2100,
(
) - 1 3 - H y d r o x y - 4 , 6 a , 1 0 , 1 0 , 1 4 b - p e n t a m e t h y l -
1
1727, 1616, 1574, 1375, 1286, 1232, 1206, 1170, 1129 cm−1; H
1,4,4a,5,6,6a,9,14,14a,14b-decahydro-2H,10H-benzo[a]pyrano-
[4,3-i]xanthene-3,12-dione (48). n-BuLi (2.30 M, 0.0800 mL, 0.189
mmol, 1.30 equiv) was added dropwise with stirring to dry ice cold
HNiPr2 (26.5 μL, 19.0 mg, 0.189 mmol, 1.30 equiv) in THF (0.5
mL). The resulting solution was stirred at −78 °C for 30 min, then
warmed up to 0 °C for 30 min and cooled back down to −78 °C,
when ketone 45 (60.0 mg, 0.145 mmol, 1.00 equiv) in THF (1.0 mL)
was added dropwise with stirring. After 1 h, KOTMS (187 mg, 1.45
mmol, 10.0 equiv) was added with stirring and the mixture was
allowed to warm up to 23 °C. After 12 h, the reaction was quenched
with saturated aqueous NH4Cl (10 mL) and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (15 mL). The organic phase was dried
(MgSO4), filtered, and concentrated under reduced pressure.
Chromatography (9:1 CH2Cl2:EtOAc) gave lactone 48 (20.0 mg,
0.0485 mmol, 33%) as a white film: Rf 0.55 (pentane:EtOAc 1:1); IR:
νmax 1707, 1653, 1631, 1585, 1388, 1357, 1297, 1285, 1169, 1100, 732
cm−1; 1H NMR (400 MHz, CDCl3): δ 11.62 (s, 1H), 6.12 (d, J = 1.0
Hz, 1H), 2.86 (d, J = 2.5 Hz, 2H), 2.80 (dd, J = 16.8, 5.0 Hz, 1H),
2.56−2.45 (m, 1H), 2.44−2.40 (m, 1H), 2.40−2.35 (m, 1H), 2.37−
2.27 (m, 1H), 2.23−2.14 (m, 1H), 2.09 (dq, J = 13.1, 3.0 Hz, 1H),
1.84 (dq, J = 11.0, 3.5, 2.6 Hz, 1H), 1.73−1.62 (m, 1H), 1.62−1.55
(m, 1H), 1.46 (s, 3H), 1.44 (s, 3H), 1.40 (dt, J = 7.2, 3.6 Hz, 1H),
1.36 (dq, J = 5.3, 2.4 Hz, 1H), 1.33 (d, J = 2.1 Hz, 1H), 1.29 (d, J =
0.9 Hz, 3H), 1.14 (s, 3H), 1.04 (d, J = 6.6 Hz, 3H); 13C{1H}-NMR
(101 MHz, CDCl3): δ 212.3, 169.8, 161.8, 159.5, 137.3, 108.5, 108.1,
100.1, 81.7, 78.0, 53.1, 49.5, 44.7, 39.9, 39.4, 39.0, 37.2, 36.8, 27.5,
27.3, 23.3, 20.9, 17.3, 12.8, 11.8; HRMS (ESI-ToF) m/z: [M + H]+
calcd for (C25H33O5)+: 413.2323, found: 413.2325.
NMR (400 MHz, CDCl3): δ 6.32 (s, 1H), 4.98 (q, J = 2.9 Hz, 1H),
3.61 (td, J = 2.9, 1.3 Hz, 1H), 2.55 (s, 3H), 2.52 (d, J = 4.9 Hz, 1H),
2.25 (dd, J = 16.8, 13.3 Hz, 1H), 2.10 (ddd, J = 14.2, 8.4, 2.7 Hz, 1H),
2.05 (s, 3H), 1.98−1.89 (m, 1H), 1.84−1.76 (m, 1H), 1.72 (s, 1H),
1.71 (d, J = 4.4 Hz, 5H), 1.68 (d, J = 2.7 Hz, 1H), 1.66 (s, 3H), 1.61
(dd, J = 13.2, 4.8 Hz, 1H), 1.52 (dd, J = 9.2, 3.1 Hz, 1H), 1.33 (d, J =
10.2 Hz, 1H), 1.24 (s, 3H), 1.01 (s, 3H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 170.0, 160.9, 158.7, 156.2, 142.3, 114.4, 108.0, 104.9,
104.2, 78.3, 70.2, 63.9, 50.3, 44.7, 40.1, 35.8, 32.6, 26.2, 25.6, 23.9,
22.1, 21.5, 21.4, 21.1, 16.2, 13.9; HRMS (ESI-TOF) m/z: [M + H]+
calcd for (C26H34N3O5)+: 484.2442, found: 484.2444; Anal. Calcd for
C26H33N3O5: C, 64.58; H, 6.88.; N, 8.69. Found: C, 64.16; H, 6.81;
N, 8.62.
(
) - 1 0 - A m i n o - 2 , 2 , 5 , 7 a , 1 3 a - p e n t a m e t h y l - 4 - o x o -
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-11-yl acetate (51). PMe3 in THF (1 M; 0.10
mL, 0.10 mmol, 2.5 equiv) was added dropwise to acetate 50 (20 mg,
0.041 mmol, 1.00 equiv) in THF (3.0 mL) and distilled water (5.0
μL). The mixture was warmed to 35 °C after which aqueous NaOH
(2 M; 0.10 mL) was added dropwise. After 5 h at 35 °C, the mixture
was poured onto a mixture of water and EtOAc (1:1, 15 mL). The
mixture was adjusted to pH 7 with saturated aqueous NH4Cl, the
organic layer was separated, and the aqueous layer was further
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine (25 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure to give the crude amine 51
which was used without further purification in the next step: Rf 0.01
(pentane:EtOAc 7:3); IR: νmax 3430, 1727, 1618, 1573, 1282, 1129
1
cm−1; H NMR (400 MHz, CDCl3): δ 6.33 (d, J = 0.9 Hz, 1H),
(
)-10-Azido-11-hydroxy-2,2,5,7a,13a-pentamethyl-
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-4-one (49). AcOH (0.5 mL) and NaN3 (166
mg, 2.56 mmol, 12.0 equiv) were added sequentially each in one
portion to epoxide 32 (85.0 mg, 0.213 mmol, 1.00 equiv) in DMF
(3.50 mL). After 15 h at 110 °C, the mixture was poured onto an ice
water and saturated aqueous NaHCO3 mixture (1:1; 100 mL). The
mixture was diluted with EtOAc, stirred for 30 min, the organic layer
was separated, and the aqueous layer was further extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (20 mL), distilled water (20 mL), and
brine (25 mL). The organic phase was dried (MgSO4), filtered, and
concentrated under reduced pressure. Filtering through a small silica
plug with EtOAc gave the crude azide 49 which was used without
further purification in the next step: Rf 0.18 (pentane:EtOAc 4:1); IR:
νmax 3466, 2924, 2099, 1728, 1706, 1616, 1573, 1288 cm−1; 1H NMR
(400 MHz, CDCl3): δ 6.32 (s, 1H), 4.05 (q, J = 2.8 Hz, 1H), 3.58 (td,
J = 3.0, 1.4 Hz, 1H), 2.57 (s, 4H) 2.36 (s, 1H), 2.25 (dd, J = 16.8,
13.1 Hz, 1H), 2.14−2.06 (m, 1H), 2.06−2.00 (m, 1H), 1.96 (ddd, J =
14.9, 4.6, 2.2 Hz, 1H), 1.92−1.86 (m, 1H), 1.82 (dd, J = 13.0, 10.2
Hz, 1H), 1.78 (d, J = 5.3 Hz, 1H), 1.72 (s, 3H), 1.68 (s, 3H), 1.65−
1.48 (m, 3H), 1.25 (s, 3H), 1.01 (s, 3H); 13C{1H}-NMR (101 MHz,
CDCl3): δ 161.1, 158.8, 156.2, 142.2, 114.5, 108.1, 104.9, 104.1, 78.4,
67.9, 66.8, 50.2, 43.4, 40.1, 36.1, 32.0, 26.2, 25.6, 24.3, 24.0, 22.1,
21.0, 16.2, 13.7; HRMS (APCI) m/z: [M + H]+ calcd for
(C24H32N3O5)+: 442.2336, found: 442.2336.
(
) - 1 0 - A z i d o - 2 , 2 , 5 , 7 a , 1 3 a - p e n t a m e t h y l - 4 - o x o -
NMR (400 MHz, CDCl3): δ 6.34 (s, 1H), 5.49 (d, J = 9.2 Hz, 1H,
NH), 4.86 (q, J = 2.7 Hz, 1H), 4.15 (dd, J = 10.1, 3.9 Hz, 1H), 2.57
(s, 3H), 2.56 (d, J = 4.6 Hz, 1H), 2.31−2.20 (m, 1H), 2.14−2.09 (m,
1H), 2.04 (s, 3H), 2.01 (s, 3H), 1.95 (d, J = 11.0 Hz, 1H), 1.87−1.84
(m, 1H), 1.83 (d, J = 8.3 Hz, 1H), 1.78 (dd, J = 11.7, 6.2 Hz, 1H),
1.72 (s, 3H), 1.69 (d, J = 8.7 Hz, 1H), 1.67 (s, 3H), 1.66 (s, 1H), 1.58
(d, J = 3.8 Hz, 1H), 1.43−1.28 (m, 1H), 1.27 (d, J = 2.9 Hz, 1H),
1.21 (s, 3H), 1.01 (s, 3H); 13C{1H}-NMR (101 MHz, CDCl3): δ
169.8, 169.7, 160.9, 158.6, 156.2, 142.5, 114.5, 107.6, 105.0, 104.2,
78.1, 70.6, 51.6, 50.4, 43.3, 39.9, 35.8, 32.2, 26.4, 25.5, 23.8, 23.1,
7a,8,9a,10,11,12,13,13a,13b,14-decahydro-4H,9H-benzo[a][1,3]-
dioxino[5,4-j]xanthen-11-yl acetate (50). NEt3 (432 mg, 0.595 mL,
4.27 mmol, 20.0 equiv) and Ac2O (218 mg, 0.202 mL, 2.13 mmol,
10.0 equiv) were sequentially added dropwise to crude azide 49 in
CH2Cl2 (2.50 mL). DMAP (26.1 mg, 0.213 mmol, 1.00 equiv) was
added in one portion, and after 2 h, the mixture was diluted with
CH2Cl2 (5.0 mL) and the reaction quenched with saturated aqueous
NaHCO3 (20 mL). The organic layer was separated, and the aqueous
layer was further extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (25 mL), dried (MgSO4),
1814
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J. Org. Chem. 2021, 86, 1802−1817

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
22.1, 21.5, 21.4, 20.9, 16.2, 14.4; HRMS (ESI-TOF) m/z: [M + H]+
calcd for (C28H38NO7)+: 500.2643, found: 500.2635; also found: m/z
[M + CH3CN + Na]+ calcd for (C30H40N2O7 + Na)+: 563.2733,
found: 563.2762.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
)-4-Acetamido-3,11-dihydroxy-6a,9,12b-trimethyl-
Peter Haycock, Corey Fulop, and Dr. Lisa Haigh (Imperial
College London) are gratefully acknowledged for their help
with NMR and mass spectrometry, respectively. We also
extend our thanks to Nigel Howard (University of Cambridge)
for elemental microanalyses. We thank GlaxoSmithKline for a
generous endowment (to A.G.M.B.).
1,3,4,4a,5,6,6a,12,12a,12b-decahydro-2H-benzo[a]xanthene-10-
carboxylic acid (53). Aqueous KOH (2M; 2.0 mL, 4.0 mmol, 67
equiv) was added in one portion to acetamide 52 (30 mg, 0.060
mmol, 1.0 equiv) in THF (2.0 mL). After vigorously stirring at 60 °C
for 4 days, the mixture was diluted with EtOAc (5.0 mL) and distilled
water (5.0 mL) and acidified to pH 1 with aqueous HCl (1 M). The
organic layer was separated, and the aqueous layer was further
extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (15 mL), dried (MgSO4), filtered, and
concentrated under reduced pressure. Chromatography (100%
EtOAc) gave resorcylic acid 53 (12 mg, 0.028 mmol, 48%) as a
white foam: Rf 0.01 (EtOAc 100%); IR: νmax 3392, 1651, 1645, 1634,
REFERENCES
■
(1) Page, J. E.; Nagel, J. In Integrative Plant Biochemistry; Romeo, J.
T., Ed.; Recent Advances in Phytochemistry; Elsevier, 2006; pp 179−
210.
1
1622, 1576, 1456, 1418, 1262 cm−1; H NMR (400 MHz, CD3OD):
(2) (a) Roll, D. M.; Manning, J. K.; Carter, G. T. Hongoquercins A
and B, New Sesquiterpenoid Antibiotics: Isolation, Structure
Elucidation, and Antibacterial Activity. J. Antibiot. 1998, 51, 635−
639. (b) Abbanat, D. A.; Singh, M. P.; Greenstein, M. Hongoquercins,
New Antibacterial Agents from the Fungus LL-23G227: Fermentation
and Biological Activity. J. Antibiot. 1998, 51, 708−714.
(3) (a) Tsujimori, H.; Bando, M.; Mori, K. Synthesis and Absolute
Configuration of Hongoquercin A, an Antibacterial Sesquiterpene-
Substituted Orsellinic Acid Isolated as a Fungal Metabolite. Eur. J.
Org. Chem. 2000, 2000, 297−302. (b) Tsujimori, H.; Mori, K.
Synthesis and Absolute Configuration of Hongoquercin B, a
Sesquiterpene-substituted Orsellinic Acid Isolated as a Fungal
Metabolite. Biosci., Biotechnol., Biochem. 2000, 64, 1410−1415.
(c) Kurdyumov, A. V.; Hsung, R. P. An Unusual Cationic [2 + 2]
Cycloaddition in a Divergent Total Synthesis of Hongoquercin A and
Rhododaurichromanic Acid A. J. Am. Chem. Soc. 2006, 128, 6272−
6273. (d) Rosen, B. R.; Simke, L. R.; Thuy-Boun, P. S.; Dixon, D. D.;
Yu, J.-Q.; Baran, P. S. C-H Functionalization Logic Enables Synthesis
of (+)-Hongoquercin A and Related Compounds. Angew. Chem., Int.
δ 7.14 (d, J = 9.2 Hz, 1H, NH), 6.12 (d, J = 0.9 Hz, 1H), 4.09−4.01
(m, 1H), 3.75 (q, J = 2.8 Hz, 1H), 2.66 (dd, J = 16.9, 5.0 Hz, 1H),
2.51 (d, J = 2.8 Hz, 1H), 2.46 (s, 3H), 2.29 (dd, J = 16.9, 13.2 Hz,
1H), 2.03 (d, J = 9.6 Hz, 1H), 2.01 (s, 1H), 2.00 (s, 3H), 1.97−1.89
(m, 1H), 1.73 (tt, J = 11.8, 6.2 Hz, 1H), 1.63 (d, J = 24.2 Hz, 1H),
1.58 (d, J = 6.6 Hz, 1H), 1.56 (s, 2H), 1.48−1.39 (m, 1H), 1.20 (s,
3H), 1.02 (s, 3H); 13C{1H}-NMR (101 MHz, CD3OD): δ 173.2,
164.5, 158.8, 155.5, 141.8, 112.8, 109.8, 108.6, 78.8, 69.5, 55.5, 52.1,
44.5, 41.4, 36.9, 33.1, 24.9, 24.5, 24.2, 22.8, 21.0, 17.3, 14.1; HRMS
(ESI) m/z: [M + H]+ calcd for (C23H32NO6)+: 418.2224, found:
418.2218.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02638.
1H and 13C NMR spectra for compounds 8, 9, 12, 13,
15−18, 21, 27, and 29−53 and X-ray structural data for
8, 33, 42, and 45 (PDF)
́
Ed. 2013, 52, 7317−7320. (e) Fernandez, A.; Alvarez, E.; Alvarez-
Manzaneda, R.; Chahboun, R.; Alvarez-Manzaneda, E. A. A short
synthetic route towards merosesquiterpenes with a benzoxanthene
skeleton. Chem. Commun. 2014, 50, 13100−13102. (f) Dethe, D. H.;
Murhade, G. M.; Dherange, B. D.; Sau, S. K. Enantiospecific
Syntheses of Hongoquercins A and B and Chromazonarol. Eur. J. Org.
Chem. 2017, 2017, 1143−1150.
Accession Codes
CCDC 2026869−2026872 contain the supplementary crys-
tallographic 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 Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(4) (a) Barrett, T. N.; Barrett, A. G. M. Cascade Polyketide and
Polyene Cyclizations: Biomimetic Total Synthesis of Hongoquercin B.
J. Am. Chem. Soc. 2014, 136, 17013−17015. (b) Ma, T.-K.; Elliott, D.
C.; Reid, S.; White, A. J. P.; Parsons, P. J.; Barrett, A. G. M.
Meroterpenoid Synthesis via Sequential Polyketide Aromatization and
Cationic Polyene Cyclization: Total Syntheses of (+)-Hongoquercin
A and B and Related Meroterpenoids. J. Org. Chem. 2018, 83, 13276−
13286.
AUTHOR INFORMATION
■
Corresponding Author
(5) Cookson, R.; Barrett, T. N.; Barrett, A. G. M. β-Keto-dioxinones
and β,δ-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis.
Acc. Chem. Res. 2015, 48, 628−642 and citations therein,.
Anthony G. M. Barrett − Department of Chemistry, Imperial
College, Molecular Sciences Research Hub, London W12
0BZ, England; orcid.org/0000-0002-8485-215X;
Email: agmb@ic.ac.uk
(6) Selected examples for gold mediated cyclizations: (a) Toullec, P.
Y.; Blarre, T.; Michelet, V. Mimicking Polyolefin Carbocyclization
Reactions: Gold-Catalyzed Intramolecular Phenoxycyclization of 1,5-
Enynes. Org. Lett. 2009, 11, 2888−2891. (b) Sethofer, S. G.; Mayer,
T.; Toste, F. D. Gold(I)-Catalyzed Enantioselective Polycyclization
Reactions. J. Am. Chem. Soc. 2010, 132, 8276−8277. (c) Pradal, A.;
Chen, Q.; Faudot dit Bel, P.; Toullec, P. Y.; Michelet, V. Gold-
Catalyzed Cycloisomerization of Functionalized 1,5-Enynes - An
Entry to Polycyclic Framekwork. Synlett 2012, 2012, 74−79.
(d) Rong, Z.; Echavarren, A. M. Broad scope gold(I)-catalysed
polyenyne cyclizations for the formation of up to four carbon-carbon
bonds. Org. Biomol. Chem. 2017, 15, 2163−2167. (e) Imagawa, H.;
Iyenaga, T.; Nishizawa, M. Mercuric Triflate-Catalyzed Tandem
Cyclization Leading to Polycarbocycles. Org. Lett. 2005, 7, 451−453
for selected examples of other π-Lewis acid promoted cyclizations:.
Authors
Thomas Mies − Department of Chemistry, Imperial College,
Molecular Sciences Research Hub, London W12 0BZ,
England
Andrew J. P. White − Department of Chemistry, Imperial
College, Molecular Sciences Research Hub, London W12
0BZ, England; orcid.org/0000-0001-6175-1607
Philip J. Parsons − Department of Chemistry, Imperial
College, Molecular Sciences Research Hub, London W12
0BZ, England; orcid.org/0000-0002-9158-4034
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02638
́
(f) Nelsen, D. L.; Gagne, M. R. Platinum(II) Enyne Cyclo-
1815
https://dx.doi.org/10.1021/acs.joc.0c02638
J. Org. Chem. 2021, 86, 1802−1817

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
isomerization Catalysis: Intermediates and Resting States. Organo-
metallics 2009, 28, 950−952. (g) Qiu, W.-W.; Surendra, K.; Yin, L.;
Corey, E. J. Selective Formation of Six-Membered Oxa- and
Carbocycles by the In(III)-Activated Ring Closure of Acetylenic
Substrates. Org. Lett. 2011, 13, 5893−5895. (h) Surendra, K.; Qiu,
W.; Corey, E. J. A Powerful New Construction of Complex Chiral
Polycycles by an Indium(III)-Catalyzed Cationic Cascade. J. Am.
Chem. Res. 2011, 44, 603−613. (c) Wang, D.; Cai, R.; Sharma, S.;
Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang, H.; Liu, X.;
Petersen, J. L.; Shi, X. Silver Effect” in Gold(I)-Catalysis: An
Overlooked Important Factor. J. Am. Chem. Soc. 2012, 134, 9012−
9019. (d) Al-Amin, M.; Roth, K. E.; Blum, S. A. Mechanistic Studies
of Gold- and Palladium Cooperative Dual-Catalytic Cross-Coupling
Systems. ACS Catal. 2014, 4, 622−629. (e) Wang, X.; Dong, S.; Yao,
Z.; Feng, L.; Daka, P.; Wang, H.; Xu, Z. Synthesis of Spiroaminals and
Spiroketals with Bimetallic Relay Catalysis. Org. Lett. 2014, 16, 22−
25. (f) Peng, H.; Akhmedov, N. G.; Liang, Y.-F.; Jiao, N.; Shi, X.
Synergistic Gold and Iron Dual Catalysis: Preferred Radical Addition
toward Vinyl-Gold Intermediate over Alkene. J. Am. Chem. Soc. 2015,
137, 8912−8915. (g) Alyabyev, S. B.; Beletskaya, I. P. Gold as a
Catalyst. Part I. Nucleophilic addition to the triple bond. Russ. Chem.
Rev. 2017, 86, 689−749. Schafroth, M. A.; Sarlah, D.; Krautwald, S.;
Carreira, E. M. Iridium-Catalyzed Enantioselective Polyene Cycliza-
tion. J. Am. Chem. Soc. 2012, 134, 20276−20278 A noteworthy
example of dual catalysis in polyene cyclizations:.
́
Chem. Soc. 2011, 133, 9724−9726. (i) Mezailles, N.; Ricard, L.;
Gagosz, F. Phosphine Gold(I) Bis-(trifluoromethanesulfonyl)imidate
Complexes as New Highly Efficient and Air-Stable Catalysts for the
Cycloisomerization of Enynes. Org. Lett. 2005, 7, 4133−4136.
(7) (a) Elliott, D. C.; Ma, T.-K.; Selmani, A.; Cookson, R.; Parsons,
P. J.; Barrett, A. G. M. Sequential Ketene Generation from Dioxane-
4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcy-
lates. Org. Lett. 2016, 18, 1800−1803. (b) Ma, T.-K.; White, A. J. P.;
Barrett, A. G. M. Meroterpenoid total synthesis: Conversion of
geraniol and farnesol into amorphastilbol, grifolin and grifolic acid by
dioxinone-β-keto-acylation, palladium catalyzed decarboxylative allylic
rearrangement and aromatization. Tetrahedron Lett. 2017, 58, 2765−
2767.
(17) Fox, M. E.; Li, C.; Marino, J. P.; Overman, L. E.
Enantiodivergent Total Syntheses of (+)- and (−)-Scopadulcic Acid
A. J. Am. Chem. Soc. 1999, 121, 5467−5480.
(18) van de Weghe, P.; Collin, J. Ring opening reactions of epoxides
catalyzed by samarium iodide. Tetrahedron Lett. 1995, 36, 1649−
1652.
(8) Anderson, K.; Laclef, S.; Barrett, A. G. M. Mechanistic studies of
highly regioselective decarboxylative-prenyl migration reactions of
prenyloxycarbonyl-diketo-dioxinones. Tetrahedron 2014, 70, 5569−
5579.
(9) The keto-esters exist as a mixture of keto and enol tautomers.
For brevity, only the keto form is drawn.
(19) (a) Kurosawa, T.; Nomura, Y.; Mahara, R.; Yoshimura, T.;
Kimura, A.; Ikegawa, S.; Tohma, M. Synthesis of 19-Hydroxylated
Bile Acids and Identification of 3α,7α,12α,19-Tetrahydroxy-5β-
cholan-24-oic Acid in Human Neonatal Urine. Chem. Pharm. Bull.
1995, 43, 1551−1557. (b) Barrero, A. F.; Alvarez-Manzaneda, E. J.;
Chahboun, R.; Meneses, R.; Romera, J. L. Raney Nickel: An Effective
Reagent for Reductive Dehalogenation of Organic Halides. Synlett
2001, 2001, 0485−0488.
(10) Armstrong, R. J.; Weiler, L. Synthesis of ( )-trixagol by an
electrophilic cyclization of an allylsilane. Can. J. Chem. 1983, 61,
2530−2539.
(11) Rajendar, G.; Corey, E. J. A Systematic Study of Functionalized
Oxiranes as Initiating Groups for Cationic Polycyclization Reactions.
J. Am. Chem. Soc. 2015, 137, 5837−5844.
(12) Kobayashi, S.; Ando, A.; Kuroda, H.; Ejima, S.; Masuyama, A.;
Ryu, I. Rapid access to 6-bromo-5,7-dihydroxyphthalide 5-methyl
ether by a CuBr2-mediated multi-step reaction: concise total syntheses
of hericenone J and 5′-deoxohericenone C (hericene A). Tetrahedron
2011, 67, 9087−9092.
(20) (a) Dauben, W. G.; Fonken, G. J.; Noyce, D. S. The
Stereochemistry of Hydride Reductions. J. Am. Chem. Soc. 1956, 78,
2579−2582. (b) Wigfield, D. C.; Phelps, D. J. Enthalpy-Entropy
Relations in the Reduction of Hindered and Unhindered Cyclo-
hexanones by Sodium Borohydride. J. Org. Chem. 1976, 41, 2396−
2401. (c) Wigfield, D. C. Stereochemistry and mechanism of ketone
reductions by hydride reagents. Tetrahedron 1979, 35, 449−462.
(21) Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. A
Mechanistic Study of the Mitsunobu Esterification Reaction. J. Am.
Chem. Soc. 1988, 110, 6487−6491.
(13) Huang, J.; Wu, C.; Wulff, W. D. Total Synthesis of
( )-Phomactin B2 via an Intramolecular Cycloheadienone Annula-
tion of a Chromium Carbene Complex. J. Am. Chem. Soc. 2007, 129,
13366−13367.
́
(14) (a) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M.
Intramolecular [4 + 2] Cycloadditions of 1,3-Enynes or Arylalkynes
with Alkenes with Highly Reactive Cationic Phosphine Au(I)
Complexes. J. Am. Chem. Soc. 2005, 127, 6178−6179. (b) Paz
(22) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Redox Economy in
Organic Synthesis. Angew. Chem., Int. Ed. 2009, 48, 2854−2867.
(23) Gassman, P. G.; Schenk, W. N. A General Procedure for the
Base-Promoted Hydrolysis of Hindered Esters at Ambient Temper-
atures. J. Org. Chem. 1977, 42, 918−920.
Munoz, M.; Adrio, J.; Carretero, J. C.; Echavarren, A. M. Ligand
̃
Effects in Gold- and Platinum-Catalyzed Cyclization of Enynes:
Chiral Gold Complexes for Enantioselective Alkoxycyclization.
Organometallics 2005, 24, 1293−1300.
̈ ̈ ̈
(24) Glaser, F.; Brohmer, M. C.; Hurrle, T.; Nieger, M.; Brase, S.
The Diels-Alder Approach to Δ9-Tetrahydrocannabinol Derivatives.
Eur. J. Org. Chem. 2015, 2015, 1516−1524.
(15) (a) Ishihara, K.; Ishibashi, H.; Yamamoto, H. Enantioselective
Biomimetic Cyclization of Homo(polyprenyl)arenes. A New Entry to
(+)-Podpcarpa-8,11,13-triene Diterpenoids and (−)-Tetracyclic Poly-
prenoid of Sedimentary Origin. J. Am. Chem. Soc. 2001, 123, 1505−
1506. (b) Ishihara, K.; Ishibashi, H.; Yamamoto, H. Enantio- and
Diastereoselective Stepwise Cyclization of Polyprenoids Induced by
Chiral and Achiral LBAs. A new Entry to (−)-Ambrox,
(+)-Podocarpa-8,11,13-triene Diterpenoids, and (−)-Tetracyclic
Polyprenoids of Sedimentary Origin. J. Am. Chem. Soc. 2002, 124,
3647−3655. (c) Ishibashi, H.; Ishihara, K.; Yamamoto, H. A New
Artifical Cyclase for Polyprenoids: Enantioselective Total Synthesis of
(−)-Chromazonarol, (+)-8-epi-Puupehedione, and (−)-11’-Deoxy-
taondiol Methyl Ester. J. Am. Chem. Soc. 2004, 126, 11122−11123.
(16) Selected examples of dual gold-transition metal catalysis:
(a) Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A. Catalyzed
Catalysis Using Carbophilic Lewis Acid Gold and Lewis Basic
Palladium: Synthesis of Substituted Butenolides and Isocoumarins. J.
Am. Chem. Soc. 2009, 131, 18022−18023. (b) Hirner, J. J.; Shi, Y.;
Blum, S. A. Organogold Reactivity with Palladium, Nickel, and
Rhodium: Transmetalation, Cross-Coupling, and Dual Catalysis. Acc.
(25) (a) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J. A.; Nguyen, S.
L. Effects of Lewis acids on higher order, mixed cuprate couplings.
Tetrahedron Lett. 1984, 25, 5959−5962. (b) Yamamoto, Y. Selective
Synthesis by Use of Lewis Acids in the Presence of Organocopper and
Related Reagents. New Synthetic Methods (61). Angew. Chem., Int.
Ed. Engl. 1986, 25, 947−959. (c) Lipshutz, B. H.; Elsworth, E. L.;
Siahaan, T. J. The role of boron trifluoride etherate in reactions of
lower order (Gilman) organocuprates. J. Am. Chem. Soc. 1989, 111,
1351−1358.
(26) Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J.
Mechanism of Thio Acid/Azide Amidation. J. Am. Chem. Soc. 2006,
128, 5695−5702.
̈
(27) Staudinger, H.; Meyer, J. Uber neue organische Phosphorver-
bindungen III. Phosphinmethylenderivate und Phosphinimine. Helv.
Chim. Acta 1919, 2, 635−646.
(28) Willeit, A.; Muller, E. P.; Peringer, P. Umsetzung von 2-
̈
Azidoalkoholen mit Trialkylphosphiten Bildung von Aziridinen und
5
̈
̈
Amidophosphorsaureesten via Imidophosphorsaureester und 1,3,5λ -
Oxazaphospholidine. Helv. Chim. Acta 1983, 66, 2467−2480.
1816
https://dx.doi.org/10.1021/acs.joc.0c02638
J. Org. Chem. 2021, 86, 1802−1817

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(29) Gong, J.; Li, W.; Fu, P.; MacMillan, J.; De Brabander, J. K.
Isolation, Structure, and Total Synthesis of the Marine Macrolide
Mangrolide D. Org. Lett. 2019, 21, 2957−2961.
(30) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. The
Chemistry of Amine-Azide Interconversion: Catalytic Diazotransfer
and Regioselective Azide Reduction. C.-H. Wong. J. Am. Chem. Soc.
2002, 124, 10773−10778.
(31) Kofron, W. G.; Baclawski, L. M. A convenient method for
estimation of alkyllithium concentrations. J. Org. Chem. 1976, 41,
1879−1880.
(32) Still, W. C.; Kahn, M.; Mitra, A. Rapid chromatographic
technique for preparative separations with moderate resolution. J. Org.
Chem. 1978, 43, 2923−2925.
1817
https://dx.doi.org/10.1021/acs.joc.0c02638
J. Org. Chem. 2021, 86, 1802−1817