New strategies for the synthesis and functionalization of tetrahydroxanthones

Article abstract of DOI:10.1016/j.tet.2015.10.051

Two strategies for the functionalization of simple tetrahydroxanthones (THX) on either of the carbocyclic rings are reported. By application of palladium catalysis, concomitant assembly of this heterocyclic scaffold with controlled introduction of substituents on the aromatic ring at C-5, C-6 or C-7 can be achieved. Variation in the nature of the added carbon fragment (aryl, alkenyl and alkynyl) is explored through use of different cross-coupling partners. Separately, functionalization at C-4 of the saturated carbocyclic ring is demonstrated through use of the extended enolate derived from 1-hydroxytetrahydroxanthone.

Full text of DOI:10.1016/j.tet.2015.10.051

Tetrahedron 71 (2015) 9433e9438
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New strategies for the synthesis and functionalization of
tetrahydroxanthones
,
Penelope A. Turner a, Samiullah a b, Joanna V. Geden a, Alexander White a,
,
Guy J. Clarkson a, Michael Shipman a
*
a Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
b Department of Chemistry, University of Balochistan, Suryab Road, Quetta, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 August 2015
Received in revised form 3 October 2015
Accepted 16 October 2015
Available online 19 October 2015
Two strategies for the functionalization of simple tetrahydroxanthones (THX) on either of the carbocyclic
rings are reported. By application of palladium catalysis, concomitant assembly of this heterocyclic
scaffold with controlled introduction of substituents on the aromatic ring at C-5, C-6 or C-7 can be
achieved. Variation in the nature of the added carbon fragment (aryl, alkenyl and alkynyl) is explored
through use of different cross-coupling partners. Separately, functionalization at C-4 of the saturated
carbocyclic ring is demonstrated through use of the extended enolate derived from 1-
hydroxytetrahydroxanthone.
Keywords:
Palladium catalysis
Tetrahydroxanthone
Cross-coupling
Extended enolate
Dihydroxylation
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Polycyclic xanthones are an important family of natural prod-
ucts that are based upon a highly oxygenated hexacyclic frame-
work.1 Based on the oxidation state of the xanthone nucleus, this
compound class can be subdivided into fully aromatic-, tetrahydro-
and hexahydro-derivatives. Of these, the most synthetically chal-
lenging are the tetrahydroxanthone (THX) derivatives due to their
increased complexity and potential to aromatize to xanthones by
dehydration. Important examples include kigamicin
simaomicin
A
(1),2
(2),3 kibdelone A (3),4 isokibdelone C (4)5 and albo-
a
fungin (5),6 which all possess potent bioactivity (Fig. 1). These and
other THX natural products show variation in the level of oxidation
in the saturated xanthone ring, the relative stereochemistry of the
appended alcohol and ether substituents, and how the THX is fused
to the remaining rings of the polycyclic xanthone skeleton.
As a consequence of their important biological activities, there is
much current interest in the synthesis of THX based natural
products and simplified analogues with which to probe structure-
activity relationships. For example, Porco and co-workers have
recently completed elegant total syntheses of (þ)-kibdelone A7 and
(þ)-kibdelone C8 among others9 whilst Ready has reported efficient
* Corresponding author. Tel.: þ44 24765 23186; e-mail address: m.shipman@
warwick.ac.uk (M. Shipman).
Fig. 1. Tetrahydroxanthone containing natural products.
http://dx.doi.org/10.1016/j.tet.2015.10.051
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

9434
P.A. Turner et al. / Tetrahedron 71 (2015) 9433e9438
syntheses of (ꢀ)-kibdelone C10 and (ꢀ)-simaomicin a 11
.
Other
always essential for the CeO bond construction.16 However, the
reaction times are longer and the reactions less clean without it.
To extend the scope of this chemistry still further, we examined
if Pd-catalyzed Heck and Sonogashira cross-couplings could be
combined with THX assembly. These reactions were performed
under our standard conditions, without further optimization. Two
illustrative systems were explored (Scheme 3). Reaction of dibro-
mide 915 with styrene yielded C-7 substituted THX 10 by way of
a Heck coupling (Scheme 3). Similarly, treatment of dichloride 7b
with 4-ethynylanisole provided C-6 substituted THX 11 in excellent
yield by way of a Sonogashira reaction.
groups have devised routes to functionalized THXs related to such
natural products.12e16 In our laboratory, a mild method for the
synthesis of 7-arylated THX derivatives by concomitant CeO and
CeC bond construction has been developed (Scheme 1). To date,
this simple yet powerful methodology has enabled us to identify
the minimum anti-austerity pharmacophore of the kigamicins,15
and make glycosylated derivatives for study.16
Scheme 1. Previous work towards 7-substituted THXs.
In this article, we extend our investigations to a range of func-
tionalized THXs beyond C-7 substitution, which has the potential to
provide analogues with which to reveal insights into the biology of
other polycyclic xanthone natural products. Specifically, we explore
the feasibility of accessing derivatives functionalized on either
carbocyclic ring of the THX. Two strategies are explored that are
highly complementary and allow access to a range of simple de-
rivatives. To make compounds substituted on the aromatic ring,
further development of our Pd catalyzed methodology is explored.
Additionally, the feasibility of making di- and tri-hydroxylated
derivatives by controlled hydroxylation of the saturated ring of
the THX is examined, through the use of extended enolates of this
heterocycle nucleus.
Scheme 3. THX assembly combined with Heck and Sonogashira couplings.
2.2. Use of extended enolates derived from THX nucleus
2. Results and discussion
Complex THX natural products such as 1e5 possess a variety of
hydroxylation patterns within the saturated six-membered ring,
and the role of these alcohol and ether substituents on bioactivity is
poorly understood (Fig. 1). Consequently, strategies for the as-
sembly of hydroxylated THXs are of much interest.13,16 Since all
these natural products contain a hydroxyl group at C-1, a poten-
tially simple and direct approach for the introduction of diol and
triol motifs would be to generate and exploit the extended enolate
derived from 1-hydroxy-tetrahydroxanthone.
2.1. Assembly of functionalized THXs using Pd catalysis
Building on the initial findings depicted in Scheme 1, we set out
to ascertain if this chemistry could be extended to different sub-
stitution patterns, by location of the second halogen at other sites
on the benzene ring, and to other types of cross-coupling reactions.
First, we examined if we could make THXs bearing substituents at
C-5 and C-6, mapping over, for example, the structures of iso-
kibdelone C (4) and albofungin (5), respectively (Fig. 1). Thus, cy-
clohexanone (6) was C-acylated with the appropriate acid chlorides
to give 7a,b in good yield which, in CDCl3, exist exclusively in the
enol form (Scheme 2). Treatment of these substrates with phenyl-
boronic acid under our optimized conditions smoothly provided
8a,b by way of concomitant CeO and CeC bond formation. Clearly,
the SuzukieMiyaura reactions work well with aryl chlorides under
these conditions. While the transition metal is essential for the
cross-coupling, we should stress that in recent work directed to-
wards glycosylated THXs, we have noted that Pd catalysis is not
To explore this idea, we began with an examination of the
enolate chemistry of (ꢁ)-12a17 (Scheme 4). Generation of the po-
tassium enolate from 12a was readily achieved by deprotonation
with 2.1 equiv of potassium tert-butoxide in THF at low tempera-
ture. Quenching of the presumed dianion intermediate 13 with
PhSeCl provided selenide 14 as a mixture of diastereomers through
selective functionalization at C-4. The use of the unprotected hy-
droxyl group at C-1 proved critical to success. Using 12b or 12c, in
which the hydroxyl group was protected as the TBS or PMB ether,
respectively, led only to recovery of starting materials upon addi-
tion of PhSeCl.18 Moreover, no improvements were seen using LDA
as base with 12b. Selenide 14, as a mixture of diastereomers, was
converted to the corresponding PMB ether which was further
transformed into dihydroxanthone 15 by oxidation to the selen-
oxide and syn-elimination. Despite concerns that this material
might be prone to elimination to the aromatic xanthone, it proved
reasonably stable. syn-Dihydroxylation of olefin 15 under Upjohn
conditions gave diol 16 as a single diastereomer in 53% yield.
Quantities of xanthone (20%) were isolated alongside this diol as
a result of elimination of PMBOH under the reaction conditions. To
our surprise, 16 has all the ring substituents on the same face, as
a result of dihydroxylation from the seemingly more hindered face
of the olefin. To confirm our assignments, the structures of both
alkene 15 and diol 16 were established by single crystal XRD
(Scheme 4 and Supplementary data).19 It is known that hydroxyl
groups can direct dihydroxylation of allylic and homoallylic
Scheme 2. Synthesis of THXs substituted at C-5 and C-6.

P.A. Turner et al. / Tetrahedron 71 (2015) 9433e9438
9435
cyclohexenols to all-syn products by means of hydrogen bonding
with the osmate ester.20 Here, we observe what we believe to be
the first example of a PMB ether influencing the stereochemical
course of dihydroxylations in a similar manner.
Scheme 6. Direct hydroxylation of extended enolate of (R)-12a.
3. Conclusion
Two complementary methods for the synthesis of substituted
tetrahydroxanthones have been established. By application of
palladium catalysis, both assembly of the heterocyclic scaffold and
controlled introduction of groups on the aromatic ring at C-5, C-6
or C-7 has been achieved in good yields. Through use of a boronic
acid, an alkene or an alkyne as the coupling partner, a variety of
different carbon substituents can be introduced. Additionally, we
have shown that extended enolates of 1-hydroxy THX 12a can be
made using potassium tert-butoxide, and used to introduce sub-
stituents at C-4 of the saturated ring. For example, enantiopure
1,4-dihydroxylated THXs 20 and 21 were prepared by hydroxyl-
ation of the enolate derived from R-12a. These products overlay
the THX nucleus of albofungin (5) and simaomicin
a (2), re-
spectively suggesting that this methodology may be useful in the
development of SAR for these natural products. Although the ef-
ficiency and selectivity of this hydroxylation process is modest,
these limitations are off-set, in part, by the brevity and simplicity
of the chemistry. Additionally, we have shown that differentially
protected 1,3,4-trihydroxylated THX 16 can be accessed in four
steps in a stereocontrolled manner using the same extended
enolate through introduction of an arylselenide substituent. In-
terestingly, we observed a syn-selective dihydroxylation of dihy-
droxanthone 15, providing access to simplified analogues of the
important polyhydroxylated THX, kigamicin A (1). Ongoing studies
are focused on the use of such methodology for the development
of SAR within these and related families of natural products.
Scheme 4. Use of an extended enolate to make 1,3,4-trihydroxylated 16.
To further extend the utility of this methodology, we sought to
access 12a as a single enantiomer. This was achieved by asymmetric
transfer hydrogenation of 17 using Noyori’s RuCl(p-cymene)[(R,R)-
Ts-DPEN] catalyst (18) in the presence of triethylamine and formic
acid (Scheme 5).21 This provided R-12a in good yield as a result of
chemoselective reduction, and in excellent enantiopurity as de-
termined by chiral HPLC analysis (Scheme 5 and Supplementary
data). The R-configuration of 12a was supported by analysis using
the Mosher method,22 and is in accordance with the predictions
based on the model for similar reductions with 18.21
4. Experimental section
4.1. General information
Anhydrous solvents were purchased in Sure/SealÔ bottles from
SigmaeAldrich. All other solvents and reagents were used as re-
ceived or purified by standard protocols. Petroleum ether refers to
the fraction of petroleum ether having a boiling point between 40
and 60 ꢂC. All experiments were performed under an inert atmo-
sphere (N2) and moisture sensitive reactions were conducted in
oven- or flame-dried glassware. Flash chromatography was carried
out using Matrex silica 60. Thin layer chromatography was per-
formed on pre-coated aluminium-backed plates and developed
using UV fluorescence (254 nm) and/or potassium permanganate,
followed by heating. Infrared spectra were recorded neat using
a PerkinElmer Spectrum One FT-IR spectrometer with internal
calibration. 1H and 13C NMR spectra were recorded at 300 MHz and
75 MHz, respectively on a Bruker DPX-300; at 400 MHz and
100 MHz, respectively on a Bruker DPX-400; and at 500 MHz and
125 MHz, respectively on a Bruker AV-500 spectrometer. High
resolution mass spectra were obtained on a Bruker MicroTOF in-
strument. Melting points were recorded on a Gallenkamp MPD350
apparatus.
Scheme 5. Enantiocontrolled synthesis of (R)-12a.
Using R-12a, direct hydroxylation of the extended enolate at C-4
is possible. Generation of the dianion from (R)-12a as described
previously, and subsequent quenching with the Davies oxazir-
idine23 19 provided the diols as a 1:1 mixture of cis and trans iso-
mers. Further bisacetylation of this mixture provided the readily
separable diacetates (R,S)-20 and (R,R)-21 (Scheme 6). To confirm
the site of hydroxylation, and verify the relative and absolute ste-
reochemistry of (R,S)-20, its structure was determined by single
crystal XRD (see Supplementary data).19

9436
P.A. Turner et al. / Tetrahedron 71 (2015) 9433e9438
4.2. (2,3-Dichloro-phenyl)-(2-hydroxy-cyclohex-1-enyl)meth-
anone (7a)
163.9 (C), 152.8 (C), 136.3 (C), 133.9 (CH), 131.1 (C), 129.5 (CH), 128.3
(CH), 127.8 (CH), 125.2 (CH), 124.4 (CH), 123.6 (C), 118.3 (C), 28.1
(CH2), 21.9 (CH2), 21.7 (CH2), 21.0 (CH2); MS (ESþ) m/z 277 [MHþ];
HRMS (ESþ) calcd for C19H16NaO2 [MNaþ]: 299.1043; found:
299.1041.
Diisopropylamine (2.7 mL, 19.3 mmol) in THF (10 mL) was
cooled to ꢀ78 ꢂC and n-BuLi (2.5 M in hexane, 7.6 mL, 19.1 mmol)
was added. The solution was stirred for 5 min before adding cy-
clohexanone (2.0 mL, 19.3 mmol). The solution was stirred at
ꢀ78 ꢂC for 1 h before addition of 2,3-dichlorobenzoyl chloride
(1.3 mL, 9.30 mmol). The solution was then allowed to warm to
room temperature and stirred at room temperature for 18 h. HCl
(2 M, 15 mL) was added and the product was extracted with EtOAc
(3ꢃ50 mL) then the combined organic layers dried (MgSO4). Re-
moval of the solvent and purification by column chromatography
(35% EtOAc in petroleum ether) gave 7a as a white solid (2.12 g,
84%). Mp 101e102 ꢂC; IR (film) 2935, 1557, 1410, 1316, 1153, 900,
4.5. 6-Phenyl-1,2,3,4-tetrahydro-xanthen-9-one (8b)
To 7b (100 mg, 0.37 mmol) in dioxane (1 mL) were added
Pd2(dba)3 (8 mg, 0.009 mmol), XPhos (11 mg, 0.02 mmol), Cs2CO3
(264 mg, 0.81 mmol) and phenylboronic acid (135 mg, 1.11 mmol).
The mixture was heated to reflux for 2.5 h. After cooling to room
temperature, the mixture was filtered through CeliteÒ washing
with CH2Cl2 (5ꢃ10 mL). The filtrate was dried (MgSO4), filtered and
the solvent removed in vacuo. Column chromatography (10% EtOAc
in petroleum ether) gave 8b as a white solid (81 mg, 79%). Mp
795 cmꢀ1
; dH (400 MHz, CDCl3) 15.70 (1H, s, enol), 7.50 (1H, dd,
J¼1.5, 7.8 Hz, ArH), 7.27 (1H, t, J¼7.8 Hz, ArH), 7.13 (1H, dd, J¼1.5,
7.8 Hz, ArH), 2.48 (2H, t, J¼6.5 Hz, CH2), 2.05 (2H, br s, CH2),
1.78e1.70 (2H, m, CH2), 1.64e1.57 (2H, m, CH2); dC (100 MHz, CDCl3)
191.5 (C), 187.3 (C), 139.3 (C), 133.6 (C), 130.9 (CH), 128.7 (C), 127.8
(CH), 125.6 (CH), 107.7 (C), 32.0 (CH2), 24.3 (CH2), 22.8 (CH2), 21.5
(CH2); MS (ESþ) m/z 271 [MHþ, 35Cl, 35Cl], 273 [MHþ, 35Cl, 37Cl], 275
[MHþ, 37Cl, 37Cl]; HRMS (ESþ) calcd for C13H12Cl2NaO2 [MNaþ, 35Cl,
35Cl]: 293.0107; found 293.0106.
143e144 ꢂC; IR (film) 2932, 1636, 1612, 1424, 1152, 754 cmꢀ1
; dH
(400 MHz, CDCl3) 8.24 (1H, d, J¼7.2 Hz, ArH), 7.65 (2H, dd, J¼1.5,
7.2 Hz, ArH), 7.59 (2H, dd, J¼1.5, 7.2 Hz, ArH), 7.48 (2H, dt, J¼1.5,
7.2 Hz, ArH), 7.42 (1H, m, ArH), 2.72e2.66 (2H, m, CH2), 2.64e2.58
(2H, m, CH2), 1.94e1.84 (2H, m, CH2), 1.82e1.74 (2H, m, CH2); dC
(100 MHz, CDCl3) 177.6 (C), 164.0 (C), 156.3 (C), 146.0 (C), 139.4 (C),
129.0 (CH), 128.5 (CH), 127.4 (CH), 126.2 (CH), 123.5 (CH), 122.0 (C),
118.6 (C), 115.6 (CH), 28.2 (CH2), 21.9 (CH2), 21.7 (CH2), 21.1 (CH2);
MS (ESþ) m/z 277 [MHþ]; HRMS (ESþ) calcd for C19H16NaO2
[MNaþ]: 299.1043; found: 299.1044.
4.3. (2,4-Dichloro-phenyl)-(2-hydroxy-cyclohex-1-enyl)meth-
anone (7b)
4.6. 7-Styryl-1,2,3,4-tetrahydro-xanthen-9-one (10)
Diisopropylamine (2.7 mL, 19.3 mmol) in THF (10 mL) was
cooled to ꢀ78 ꢂC and n-BuLi (2.5 M in hexane, 7.6 mL, 19.0 mmol)
was added. The solution was stirred for 5 min before cyclohexanone
(2.0 mL, 19.3 mmol) was added. The solution was stirred at ꢀ78 ꢂC
for 1 h before addition of 2,4-dichlorobenzoyl chloride (1.3 mL,
9.27 mmol). The solution was then allowed to warm to room
temperature and stirred at room temperature for 18 h. HCl (2 M,
15 mL) was added and the product was extracted with EtOAc
(3ꢃ50 mL) then the combined organic layers dried (MgSO4). Re-
moval of the solvent and purification by column chromatography
(35% CH2Cl2 in petroleum ether) gave 7b as an oil which solidified
on standing. Trituration with Et2O and filtration gave the title
compound as a white solid (2.02 g, 81%). Mp 62e63 ꢂC; IR (film)
To 9 (100 mg, 0.28 mmol) dissolved in dioxane (1 mL) was added
Pd2(dba)3 (6 mg, 0.007 mmol), XPhos (8 mg, 0.02 mmol), Cs2CO3
(199 mg, 0.61 mmol) and styrene (0.16 mL, 1.39 mmol) The mixture
was heated to reflux for 2.5 h. After cooling to room temperature,
the mixture was filtered through CeliteÒ washing with CH2Cl2
(5ꢃ10 mL). The filtrate was dried (MgSO4), filtered and the solvent
removed in vacuo. Column chromatography (10% EtOAc in petro-
leum ether) gave 10 as a white solid (39 mg, 46%). Mp 140e142 ꢂC;
IR (film) 2941, 1627, 1605, 1438, 813, 747, 687, 564 cmꢀ1
; dH
(300 MHz, CDCl3) 8.28 (1H, d, J¼2.3 Hz, ArH), 7.77 (1H, dd, J¼2.3,
8.8 Hz, ArH), 7.53 (2H, d, J¼7.2 Hz, ArH), 7.41e7.34 (3H, m, ArH),
7.31e7.25 (1H, m, ArH), 7.16 (2H, s, HC]CH), 2.71e2.56 (4H, m,
CH2), 1.93e1.72 (4H, m, CH2); dC (100 MHz, CDCl3) 177.6 (C), 163.8
(C), 155.3 (C), 137.0 (C), 133.9 (C), 130.8 (CH), 129.6 (CH), 128.8 (CH),
127.9 (CH), 127.1 (CH), 126.6 (CH), 123.3 (CH), 118.5 (C), 118.1 (CH),
28.2 (CH2), 21.9 (CH2), 21.7 (CH2), 21.1 (CH2); MS (ESþ) m/z 305
[MHþ]; HRMS (ESþ) calcd for C21H18NaO2 [MNaþ]: 325.1199; found:
325.1197.
2951, 1584, 1409, 1100, 822, 781 cmꢀ1
; dH (400 MHz, CDCl3) 15.80
(1H, s, enol), 7.44 (1H, d, J¼2.0 Hz, ArH), 7.31 (1H, dd, J¼2.0, 8.1 Hz,
ArH), 7.18 (1H, d, J¼8.1 Hz, ArH), 2.47 (2H, t, J¼6.5 Hz, CH2), 2.06
(2H, t, J¼6.2 Hz, CH2), 1.78e1.69 (2H, m, CH2), 1.65e1.56 (2H, m,
CH2); dC (100 MHz, CDCl3) 190.5 (C), 188.0 (C), 135.6 (C), 131.3 (C),
129.6 (CH), 128.6 (CH), 127.3 (CH), 107.9 (C), 32.2 (CH2), 24.4 (CH2),
22.8 (CH2), 21.6 (CH2); MS (ESþ) m/z 271 [MHþ, 35Cl, 35Cl], 273
[MHþ, 35Cl, 37Cl], 275 [MHþ, 37Cl, 37Cl]; HRMS (ESþ) calcd for
4.7. 6-(4-Methoxy-phenylethynyl)-1,2,3,4-tetrahydroxanthen-
9-one (11)
C
13H12Cl2NaO2 [MNaþ, 35Cl, 35Cl]: 293.0107; found 293.0108.
4.4. 5-Phenyl-1,2,3,4-tetrahydroxanthen-9-one (8a)
To 7b (100 mg, 0.37 mmol) dissolved in dioxane (1 mL) was
added Pd2(dba)3 (8 mg, 0.009 mmol), XPhos (11 mg, 0.02 mmol),
Cs2CO3 (264 mg, 0.81 mmol) and 4-methoxyphenylacetylene
(0.06 mL, 0.48 mmol). The mixture was heated to reflux for 2.5 h.
After cooling to room temperature, the mixture was filtered
through CeliteÒ washing with CH2Cl2 (5ꢃ10 mL). The filtrate was
dried (MgSO4), filtered and the solvent removed in vacuo. Column
chromatography (10% EtOAc in petroleum ether) gave 11 as a yel-
low solid (100 mg, 82%). Mp 139e140 ꢂC; IR (film) 2938, 2209, 1624,
To 7a (100 mg, 0.37 mmol) in dioxane (1 mL) were added
Pd2(dba)3 (8 mg, 0.009 mmol), XPhos (11 mg, 0.02 mmol), Cs2CO3
(264 mg, 0.81 mmol) and phenylboronic acid (135 mg, 1.11 mmol).
The mixture was heated to reflux for 2.5 h. After cooling to room
temperature, the mixture was filtered through CeliteÒ washing
with CH2Cl2 (5ꢃ10 mL). The filtrate was dried (MgSO4), filtered and
the solvent removed in vacuo. Column chromatography (10% EtOAc
in petroleum ether) gave 8a as an off-white solid (86 mg, 84%). Mp
1614, 1603, 1251, 1151, 831 cmꢀ1
; dH (300 MHz, CDCl3) 8.13 (1H, d,
152 ꢂC; IR (film) 2939, 1624, 1425, 1409, 1156, 758, 698 cmꢀ1
;
dH
J¼8.3 Hz, ArH), 7.52e7.46 (3H, m, ArH), 7.43 (1H, dd, J¼1.3, 8.3 Hz,
ArH), 6.89 (2H, d, J¼8.7 Hz, ArH), 3.83 (3H, s, OCH3), 2.69e2.61 (2H,
m, CH2), 2.61e2.53 (2H, m, CH2), 1.92e1.81 (2H, m, CH2), 1.80e1.70
(2H, m, CH2); dC (100 MHz, CDCl3) 177.1 (C), 164.0 (C), 160.2 (C),
155.6 (C), 133.3 (CH), 128.4 (C), 127.4 (CH), 125.7 (CH), 122.3 (C),
(400 MHz, CDCl3) 8.22 (1H, dd, J¼1.7, 7.9 Hz, ArH), 7.65 (1H, dd,
J¼1.7, 7.9 Hz, ArH), 7.58 (2H, d, J¼7.9 Hz, ArH), 7.50e7.45 (2H, m,
ArH), 7.44e7.38 (2H, m, ArH), 2.64e2.57 (4H, m, CH2), 1.89e1.81
(2H, m, CH2), 1.80e1.73 (2H, m, CH2); dC (100 MHz, CDCl3) 177.8 (C),

P.A. Turner et al. / Tetrahedron 71 (2015) 9433e9438
9437
120.2 (CH), 118.7 (C), 114.5 (C), 114.2 (CH), 92.9 (C), 87.1 (C), 55.3
(CH3), 28.1 (CH2), 21.9 (CH2), 21.6 (CH2), 21.0 (CH2); MS (ESþ) m/z
331 [MHþ]; HRMS (ESþ) calcd for C22H18NaO3 [MNaþ]: 353.1148;
found: 353.1145.
brine (3ꢃ15 mL), dried over MgSO4 and the solvent removed in
vacuo. Column chromatography (25% EtOAc in petroleum ether)
gave 1-(4-methoxybenzyloxy)-1,2,3,4-tetrahydro-4-(phenylselanyl)
xanthen-9-one (3.00 g, 6.10 mmol), which was used directly in the
next step. To this material in DCM (25 mL) at ꢀ15 ꢂC was added
mCPBA (77%, 1.48 g, 6.60 mmol) over 2 min. The mixture was
allowed to warm to room temperature and stirred until TLC in-
dicated complete consumption of the starting material (ca. 2 h). The
mixture was diluted with H2O (20 mL) and extracted with DCM
(3ꢃ15 mL). The combined organic extracts were washed with sat-
urated sodium thiosulfate solution (20 mL), brine (15 mL) then
dried (MgSO4), filtered and concentrated in vacuo. Trituration with
petroleum ether provided a white solid (810 mg, 30% over two
4.8. (R)-1,2,3,4-Tetrahydro-1-hydroxyxanthen-9-one (12a)
A solution of (R,R)-Ts-DPEN (62 mg, 0.1 mmol) in 5:2 HCO2
-
H:Et3N (5.0 mL) was stirred at room temperature for 30 min. 17
(2.07 g, 9.66 mmol) was added followed by anhydrous DCM
(10 mL), and the reaction mixture was stirred at room temperature
for 16 h. The reaction mixture was partitioned between DCM
(100 mL) and H2O (100 mL), the layers were separated, and the
aqueous layer was extracted with DCM (2ꢃ100 mL). The combined
organic extracts were dried (MgSO4), filtered and concentrated in
vacuo. The residue was purified by chromatography (33% EtOAc in
petroleum ether) to give (R)-12a as a cream solid (1.99 g, 95%). HPLC
steps). IR (film) 2836, 1609, 1426, 1245, 1026, 760 cmꢀ1
; dH
(400 MHz CDCl3) 8.26 (1H, dd, J¼1.6, 8.0 Hz, ArH), 7.68e7.63 (1H, m,
ArH), 7.47e7.38 (2H, m, ArH), 7.31e7.26 (2H, m, ArH), 6.83 (2H, d,
J¼8.6 Hz, ArH), 6.64e6.58 (1H, m, CH]), 6.42 (1H, dd, J¼3.0, 9.9 Hz,
CH]), 5.11 (1H, d, J¼6.1 Hz, CHOPMB), 4.63 (1H, d, J¼11.4 Hz, CH2),
4.55 (1H, d, J¼11.4 Hz, CH2), 3.77 (3H, s, OCH3), 2.89 (1H, dd, J¼5.8,
19.3 Hz, CH2), 2.58e2.48 (1H, m, CH2); dC (125 MHz) 176.9 (C), 160.8
(C), 159.0 (C), 155.4 (C), 139.1 (CH), 133.4 (CH), 131.0 (C), 129.5 (CH),
125.9 (CH), 125.0 (CH), 124.6 (C), 120.9 (CH), 118.0 (CH), 114.1 (C),
113.6 (CH), 70.9 (CH2O), 65.6 (CHO), 55.2 (OCH3), 31.1 (CH2); MS
(ESþ) m/z¼357 ([MþNa]þ); HRMS (ESþ): calcd for C21H18O4Na
[MþNaþ]: 357.1097; found 357.1095.
i
analysis using a Daicel Chiralcel OD column (9:1 hexane: PrOH,
1 mL/min, 25 ꢂC) showed the major enantiomer at 10.4 min (99.8%)
and the minor enantiomer at 12.9 min (0.2%), ee>99%; [
a
]
30 ꢀ117.5
D
(c 0.20, CHCl3). Mp 105e106 ꢂC; IR (film) 2949, 1626, 1461, 1245,
1163, 1073, 848 cmꢀ1
;
dH (500 MHz, CDCl3) 8.19 (1H, dd, J¼1.6,
8.0 Hz, ArH), 7.68e7.64 (1H, m, ArH), 7.44e7.37 (2H, m, ArH), 5.07
(1H, t, J¼5.4 Hz, CHOH), 4.20 (1H, s, OH), 2.80e2.61 (2H, m, CH2),
2.12e1.98 (2H, m, CH2), 1.98e1.78 (2H, m, CH2); dC (125 MHz) 179.0
(C), 166.0 (C), 156.0 (C), 133.7 (CH), 125.5 (CH), 124.9 (CH), 123.4 (C),
120.1 (C), 117.8 (CH), 63.9 (CH), 30.2 (CH2), 29.6 (CH2), 18.0 (CH2);
MS (ESþ) m/z 239 ([MþNa]þ); HRMS (ESþ): calcd for C13H12O3Na
[MþNaþ]: 239.0679; found: 239.0678.
4.11. (1R*,3S*,4S*)-1-(4-Methoxybenzyloxy)-1,2,3,4-
tetrahydro-3,4-dihydroxyxanthene-9-one (16)
To a stirred solution of 15 (1.20 g, 3.61 mmol) in a mixture of
4.9. (1R*, 4S*)- and (1R*, 4R*)-1,2,3,4-Tetrahydro-1-hydroxy-4-
acetone (6 mL), H2O (6 mL) and tBuOH (2.4 mL) at room tempera-
(phenylselanyl)-xanthen-9-one (14)
ture was added N-methylmorpholine-N-oxide monohydrate
t
(583 mg, 4.33 mmol) and OsO4 (20
mL, 0.02 g/mL in BuOH). The
To a solution of 12a (1.00 g, 4.62 mmol) in THF (25 mL) at
ꢀ78 ꢂC was added KOtBu (1.10 g, 9.80 mmol) in two portions over
10 min. The reaction mixture was allowed to warm up to 10 ꢂC, and
stirred for 1 h. To the dark red solution was added phenylselenyl
chloride (1.06 g, 5.53 mmol) then the mixture warmed to room
temperature and stirred for a further 2 h. The reaction was
quenched by addition of saturated NH4Cl solution (5 mL) then
diluted with H2O (15 mL). The mixture was extracted with ethyl
acetate (3ꢃ30 mL), washed with brine (3ꢃ15 mL), dried (MgSO4)
and the solvent removed in vacuo. Column chromatography (15%
EtOAc in petroleum ether) gave 14 (1.37 g, 80%) as a yellow oil
which could be partially separated by further chromatography. IR
reaction mixture was stirred for 48 h, and then treated with sodium
metabisulfite (820 mg, 4.31 mmol). The reaction mixture was stir-
red for 1 h then extracted with EtOAc (3ꢃ30 mL). The combined
organic extracts were washed with 1 M HCl (20 mL), H2O
(3ꢃ30 mL), brine (3ꢃ15 mL), dried over MgSO4, filtered and the
solvent removed in vacuo. Column chromatography (40% EtOAc in
petroleum ether) gave 16 (648 mg, 53%) as a yellow solid. Mp
129e131 ꢂC; IR (film) 2967, 1608, 1462, 1248, 1095, 755 cmꢀ1
; dH
(300 MHz CDCl3) 8.22 (1H, dd, J¼1.7, 8.0 Hz, ArH), 7.72e7.66 (1H, m,
ArH), 7.57 (1H, dd, J¼0.8, 8.4 Hz), 7.45e7.38 (1H, m, ArH), 7.34e7.26
(2H, m, ArH), 6.89e6.83 (2H, m, ArH), 5.13e5.08 (1H, m, CHOPMB),
4.76 (1H, d, J¼10.7 Hz, CH2O), 4.72 (1H, d, J¼10.7 Hz, CH2O), 4.65
(1H, d, J¼9.0 Hz, OH), 4.58e4.50 (1H, m, CHOH), 4.35e4.26 (1H, m,
CHOH), 3.78 (3H, s, OCH3), 3.48 (1H, d, J¼10.1 Hz, OH), 2.67e2.58
(1H, m, CH2), 1.91e1.81 (1H, m, CH2); dC (125 MHz) 176.8 (C), 162.9
(C), 159.5 (C), 156.4 (C), 134.1 (CH), 129.9 (CH), 129.6 (C), 125.9 (CH),
125.3 (CH), 123.5 (C), 118.3 (CH), 118.2 (C), 113.9 (CH), 73.1 (CH2),
69.1 (CH), 68.9 (CH), 67.8 (CH), 55.3 (OCH3), 30.8 (CH2); MS (ESþ) m/
z 391 ([MþNa]þ); HRMS (ESþ): calcd for C21H20O6Na [MþNaþ]:
391.1152; found: 391.1155.
(film) 3456, 2918, 1620, 1463, 1223, 1044, 759 cmꢀ1
; dH (300 MHz
CDCl3) 8.17e8.10 (1H, m, ArH), 7.67e7.55 and 7.40e7.11 (8H, m,
ArH), 5.06e4.99 (1H, m, CHOH), 4.40e4.33 (1H, m, CHSePh),
4.04e3.56 (1H, br s, OH), 2.79e2.45 and 2.21e1.73 (4H, m, 2ꢃCH2);
dC (75 MHz) 178.6 (C), 178.3 (C), 167.5 (C), 166.8 (C), 155.4 (C), 154.9
(C), 136.2 (C), 136.1 (C), 133.4 (CH), 133.2 (CH), 130.0 (CH), 129.6
(CH), 128.5 (CH), 128.0 (CH), 126.2 (CH), 126.1 (CH), 125.1 (CH),
124.9 (CH), 124.6 (CH), 124.4 (CH), 122.6 (C), 122.5 (C), 121.7 (C),
119.6 (C), 117.2 (CH), 117.2 (CH), 63.9 (CH), 63.3 (CH), 39.4 (CH), 39.2
(CH), 26.4 (CH2), 26.1 (CH2), 25.3 (CH2), 25.2 (CH2); MS (ESþ) m/z
395 ([MþNa]þ); HRMS (ESþ): calcd for C19H16O3SeNa [MþNa]þ:
395.0158; found: 395.0173.
4.12. R,S- and R,R-1,2,3,4-Tetrahydro-1,4-diacetoxyxanthen-9-
one (20, 21)
To a solution of 12a (100 mg, 0.46 mmol) in THF (5 mL) at ꢀ78 ꢂC
was added KOtBu (111 mg, 0.99 mmol) in two portions over 10 min.
The mixture was allowed to warm to 10 ꢂC, and stirred for 1 h. To
the dark red solution was added 19 (240 mg, 0.92 mmol) and the
mixture warmed to room temperature and stirred for a further 2 h.
The reaction was quenched by addition of saturated NH4Cl solution
(2 mL) and extracted with ethyl acetate (3ꢃ5 mL). The combined
organic layers were washed with brine (3ꢃ5 mL), dried (MgSO4)
and concentrated in vacuo to give a colourless oil, which was
4.10. 1-(4-Methoxybenzyloxy)-1,2-Dihydroxanthen-9-one (15)
To a solution of 14 (3.00 g, 8.08 mmol) in Et2O (30 mL) was
added p-methoxybenzyl trichloroacetimidate (1.75 mL, 8.42 mmol)
and a few drops of triflic acid. The dark red reaction mixture was
stirred for 3 h. The mixture was poured into H2O (20 mL), the or-
ganic layer separated then the aqueous layer was extracted with
Et2O (3ꢃ15 mL). The combined organic extracts were washed with

9438
P.A. Turner et al. / Tetrahedron 71 (2015) 9433e9438
further purified by column chromatography (2% MeOH in DCM). To
the resulting diols (40 mg, 0.17 mmol) in pyridine (5 mL) was added
acetic anhydride (0.16 mL, 1.69 mmol) and catalytic 4-dimethyla-
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.10.051.
minopyridine (2 mg,16 mmol). The resulting solution was stirred for
24 h and then H2O (10 mL) was added. The mixture was extracted
with EtOAc (3ꢃ10 mL) and the combined organic extracts were
washed with 0.5 M HCl (3ꢃ10 mL), H2O (3ꢃ10 mL), saturated
NaHCO3 solution (3ꢃ10 mL) and brine (3ꢃ15 mL). The organic
phase was dried (MgSO4), filtered and concentrated in vacuo. Col-
umn chromatography (40% Et2O in petroleum ether) gave (1R,4R)-
References and notes
1. Winter, D. K.; Sloman, D. L.; Porco, J. A., Jr. Nat. Prod. Rep. 2013, 30, 382.
2. (a) Kunimoto, S.; Someno, T.; Yamazaki, Y.; Lu, J.; Esumi, H. J. Antibiot. 2003, 56,
1012; (b) Someno, T.; Kunimoto, S.; Nakamura, H.; Naganawa, H.; Ikeda, D. J.
Antibiot. 2005, 58, 56; (c) Masuda, T.; Ohba, S.; Kawada, M.; Osono, M.; Ikeda,
D.; Esumi, H.; Kunimoto, S. J. Antibiot. 2006, 59, 209.
3. (a) Lee, T. M.; Carter, G. T.; Borders, D. B. J. Chem. Soc., Chem. Commun. 1989,
1771; (b) Carter, G. T.; Goodman, J. J.; Torrey, M. J.; Borders, D. B.; Gould, S. J. J.
Org. Chem. 1989, 54, 4321; (c) Koizumi, Y.; Tomoda, H.; Kumagai, A.; Zhou, X.-P.;
Koyota, S.; Sugiyama, T. Cancer Sci. 2009, 100, 322.
4. Ratnayake, R.; Lacey, E.; Tennant, S.; Gill, J. H.; Capon, R. J. Chem.dEur. J. 2007,
13, 1610.
5. Ratnayake, R.; Lacey, E.; Tennant, S.; Gill, J. H.; Capon, R. J. Org. Lett. 2006, 8,
5267.
6. (a) Gurevich, A. I.; Karapetyan, M. G.; Kolosov, M. N.; Omelchenko, K.; Ono-
prienko, V. V.; Petrenko, G. I.; Popravko, S. A. Tetrahedron Lett. 1972, 18, 1751; (b)
Onoprienko, V. V.; Kozmin, Y. P.; Kolosov, M. N. Bioorg. Khim. 1978, 4, 1418.
7. Winter, D. A.; Endoma-Arias, M. A.; Hudlicky, T.; Beutler, J. A.; Porco, J. A., Jr. J.
Org. Chem. 2013, 78, 7617.
8. Sloman, D. L.; Bacon, J. W.; Porco, J. A., Jr. J. Am. Chem. Soc. 2011, 133, 9952.
9. Qin, T.; Skraba-Joiner, S. L.; Khalil, Z. G.; Johnson, R. P.; Capon, R. J.; Porco, J. A., Jr.
Nat. Chem. 2015, 7, 234.
21 (25 mg, 17% over two steps) as a white solid. [
CHCl3); mp 154e155 ꢂC; IR (film) 2928, 1744, 1652, 1212, 1040,
727 cmꢀ1
dH (400 MHz, CDCl3) 8.16 (1H, d, J¼8.2 Hz, ArH),
a
]D þ94.0 (c 0.40,
;
7.68e7.63 (1H, m, ArH), 7.42e7.36 (2H, m, ArH), 7.26e7.25 (1H, s,
CHO), 5.96e5.89 (1H, m, CHO), 2.22 (3H, s, CH3), 2.23e2.04 and
1.98e1.85 (4H, m, 2ꢃCH2), 2.06 (3H, s, CH3); dC (100 MHz) 176.2 (C),
170.2 (C), 170.1 (C), 162.4 (C), 155.8 (C), 134.1 (CH), 125.9 (CH), 125.4
(CH), 123.5 (C), 118.4 (C), 118.1 (CH), 67.2 (CH), 63.3 (CH), 25.4 (CH2),
24.0 (CH2), 21.1 (CH3), 21.0 (CH3); MS (ESþ) m/z 389 ([MþNa]þ);
HRMS (ESþ): calcd for C17H16O6Na [MþNaþ]: 339.0841; found:
339.0839; and (1R,4S)-20 (27 mg, 19% over two steps) as a white
solid. [
a]
ꢀ13.3 (c 0.30, CHCl3); mp 147e148 ꢂC; IR (film) 2937,
D
1742, 1648, 1468, 1220, 1017, 756 cmꢀ1
; dH (400 MHz CDCl3) 8.16
(1H, dd, J¼1.4, 8.0 Hz, ArH), 7.71e7.65 (1H, m, ArH), 7.47e7.37 (2H,
m, ArH), 7.26 (1H, s, CHO), 5.90e5.86 (1H, m, CHO), 2.30e1.96 (4H,
m, 2ꢃ CH2), 2.14 (3H, s, CH3), 2.04 (3H, s, CH3); dC (100 MHz) 176.3
(C), 170.1 (C), 169.9 (C), 162.3 (C), 155.9 (C), 134.2 (CH), 126.0 (CH),
125.4 (CH), 123.7 (C), 118.8 (C), 118.2 (CH), 66.1 (CH), 63.0 (CH), 23.9
(CH2), 23.1 (CH2), 21.1 (CH3), 21.1 (CH3); MS (ESþ) m/z 389
([MþNa]þ); HRMS (ESþ): calcd for C17H16O6Na [MþNaþ]: 339.0841;
found: 339.0839.
10. Butler, J. R.; Wang, C.; Bian, J.; Ready, J. M. J. Am. Chem. Soc. 2011, 133, 9956.
11. Wang, Y.; Wang, C.; Butler, J. R.; Ready, J. M. Angew. Chem., Int. Ed. 2013, 52,
10796.
12. Xiao, Z.; Cai, S.; Shi, Y.; Yang, B.; Gao, S. Chem. Commun. 2014, 5254.
13. Castillo-Contreras, E. B.; Dake, G. R. Org. Lett. 2014, 16, 1642.
14. Wen, S.-S.; Wang, J.; Luo, Y.-M.; Yang, H. Tetrahedron 2014, 70, 9314.
15. Turner, P. A.; Griffin, E. M.; Whatmore, J. L.; Shipman, M. Org. Lett. 2011, 13, 1056.
16. Turner, P. A.; Samiullah; Whatmore, J. L.; Shipman, M. Tetrahedron Lett. 2013, 54,
6538.
17. Meister, A. C.; Encinas, A.; Sahin, H.; Singer, E. M. C.; Nising, C. F.; Nieger, M.;
€
Brase, S. Eur. J. Org. Chem. 2014, 4861.
18. In the case of 12b, quantities of 12a were isolated alongside recovered starting
material.
19. Crystallographic data (including structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre.
CCDC numbers: CCDC 1413972(15); CCDC 1413973 (16) and CCDC 1413974 (20).
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
20. Donohoe, T. J.; Bataille, C. J. R.; Innocenti, P. Org. React. 2012, 76, 1 See also, Cha,
J. K.; Kim N.-S. Chem. Rev. 1995, 95, 1761.
21. Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
Acknowledgements
We acknowledge the University of Balochistan and Cancer Re-
search UK (C1252/A9196) for financial support of this work. The X-
ray crystallographic analyses were performed using an Oxford
Diffraction Gemini XRD system obtained through the Science City
Advanced Materials project: Creating and Characterisation Next
Generation Advanced Materials, with support from Advantage
West Midlands.
22. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512 See also, Hoye, T. R.;
Jeffrey, C. S.; Shao, F. Nature Protocols, 2007, 2, 2451.
23. Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.