Stereocontrolled Semisyntheses of Elliptone and 12aβ-Hydroxyelliptone

Article abstract of DOI:10.1021/acs.jnatprod.7b00527

Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aβ-hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal, elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer-Villiger oxidation, and acid-catalyzed elimination sequence. Elaboration of elliptone to 12aβ-hydroxyelliptone was achieved via a diastereoselective chromium-mediated étard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods in terms of safety, scalability, and yield, while the first synthesis of 12aβ-hydroxyelliptone is also described.

Full text of DOI:10.1021/acs.jnatprod.7b00527

Article
pubs.acs.org/jnp
Cite This: J. Nat. Prod. XXXX, XXX, XXX-XXX
Stereocontrolled Semisyntheses of Elliptone and 12aβ-
Hydroxyelliptone
David A. Russell, Winston J. S. Fong, David G. Twigg, Hannah F. Sore, and David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
S
* Supporting Information
ABSTRACT: Operationally simple, stereocontrolled semisyntheses of the anticancer rotenoids elliptone and 12aβ-
hydroxyelliptone, isolated from Derris elliptica and Derris trifoliata, respectively, are described. Inspired by the work of Singhal,
elliptone was prepared from rotenone via a dihydroxylation-oxidative cleavage, chemoselective Baeyer−Villiger oxidation, and
acid-catalyzed elimination sequence. Elaboration of elliptone to 12aβ-hydroxyelliptone was achieved via a diastereoselective
́
chromium-mediated Etard-like hydroxylation. The semisynthesis of elliptone constitutes an improvement over previous methods
in terms of safety, scalability, and yield, while the first synthesis of 12aβ-hydroxyelliptone is also described.
First isolated from Derris elliptica by Harper in 1939,5
atural rotenoids form the bioactive constituents of many
Ntraditional plant preparations used for crop protection
increase in the number of rotenoids being investigated as
2004,6 12aβ-hydroxyelliptone (6) (Figure 1) was found,
potential anticancer agents.3,4 The most abundant and well-
elliptone (5) (Figure 1) represents one of the many natural
and fishing in tropical parts of the world.1,2 As powerful
inhibitors of mitochondrial respiration, there has been a steady
rotenoids whose biological activity remains, in our view,
underexplored.4a,6 Isolated from Derris trifoliata by Ito in
alongside elliptone (5), to possess cancer chemopreventive
characterized members of the rotenoid family, rotenone (1),
properties comparable to those of β-carotene; however, despite
these promising results, no further biological studies have been
reported to date.6
rotenolone (2), deguelin (3), and tephrosin (4) (Figure 1),
have been shown to be nanomolar-active inhibitors of
mitochondrial Complex I, and we suggest this finding may
explain their well-documented anticancer activities.3,4
As part of an extensive investigation into the chemistry and
biochemistry of the natural rotenoids underway in our
laboratory, we sought efficient, operationally simple semi-
synthetic routes to elliptone (5) and 12aβ-hydroxyelliptone (6)
from inexpensive rotenone (1). Our preference for semisyn-
thesis over total synthesis originated from a desire to obtain
enantiomerically pure rotenoids in the shortest and most
scalable of sequences possible.
Previous efforts toward elliptone (5) have been restricted to
a lengthy total synthesis of the racemic form, reported by
Fukami in 1965,7 and two semisyntheses of the natural
enantiomer from derivatives of rotenone (1), described by
Anzeveno and Singhal in 1979 and 1982, respectively.8,9 In
contrast, no synthesis of 12a-hydroxyelliptone (6) has been
reported to date.
Figure 1. Structures of the rotenoids rotenone (1), rotenolone (2),
deguelin (3), tephrosin (4), elliptone (5), and 12aβ-hydroxyelliptone
(6).
Received: June 19, 2017
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.7b00527
J. Nat. Prod. XXXX, XXX, XXX−XXX

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Article
Scheme 1. Comparison of the Semisyntheses of Elliptone (6) Reported by Anzeveno8a and Singhal9a and Our Proposed
Hydroxylation of Elliptone (5) to 12aβ-Hydroxyelliptone (6)
Dihydroxylation of rotenone (1) with 0.4 mol % OsO4 in the
presence of excess citric acid11 provided the diastereoisomeric
vic-diols (11) of amorphigenol in an excellent yield of 92%.
Next, the oxidative cleavage of the vic-diols (11) with aqueous
periodic acid provided the corresponding rotenone 6′-
norketone (10) in an overall yield of 72% over two steps
(Scheme 2). Importantly, both the dihydroxylation and
oxidative cleavage reactions could be carried out on a
multigram scale without any notable decrease in yield.
The subsequent chemoselective Baeyer−Villiger reaction of
the norketone 10 was more challenging. The use of traditional
oxidants such as meta-chloroperoxybenzoic acid,9a peracetic
acid, and trifluoroperacetic acid proved unproductive with
reactions suffering variously from incomplete conversion of the
norketone 10 or the formation of complex mixtures of
unidentifiable polar byproducts. More encouraging results
were obtained using Oxone,12 the potassium peroxymonosul-
fate-containing triple salt, which afforded the mono-oxygenated
lactol acetate (9) as the only identifiable product. Variations in
the amount of Oxone employed, the reaction temperature, and
the inclusion of either weakly acidic or basic additives were next
to be investigated with a view to improving both the yield and
rate of the reaction. Ultimately, however, lactol acetate (9)
could only be isolated in modest yields of 35−38% upon
treatment of the norketone 10 with 8.0 equiv of Oxone under
neutral conditions. Complete consumption of the substrate was
RESULTS AND DISCUSSION
■
In evaluating the two reported semisyntheses of elliptone (5) it
was noted that the Anzeveno route suffered from a low overall
yield,8a involved the use of many hazardous reagents and
solvents, and proceeded via an intermediate lactol, 7 (Scheme
1), accessed via an oxidative cleavage of rot-2′-enonic acid
(8),8b that proved particularly susceptible to degradation in our
hands. Additionally, the preparation of lactol 7 required a high
(7.5 mol %) loading of highly toxic and expensive osmium
tetroxide catalyst.8a The Singhal route seemed to be more
appealing, proceeding via the stable lactol acetate 9 (Scheme 1)
accessed by chemoselective Baeyer−Villiger oxidation of the
known norketone 10.9 However, this short publication lacked
experimental conditions, procedures, and characterization data,
and we were unable to successfully recreate the key Baeyer−
Villiger chemistry using the reported meta-chloroperoxybenzoic
acid (see also below).9a
Inspired by the chemistry of Singhal,9a an alternative
preparation of the lactol acetate (9) from rotenone (1) was
sought, anticipating that formal elimination of the acetoxy
group under acidic conditions would indeed deliver elliptone
(5) in a concise manner. Building upon the success of the
previous semisynthesis of tephrosin (4),10 we reasoned that
́
chromium-mediated Etard-like hydroxylation of elliptone (5)
would provide 12aβ-hydroxyelliptone (6) as a single diaster-
eoisomer (Scheme 1).
B
DOI: 10.1021/acs.jnatprod.7b00527
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a
Scheme 2
EXPERIMENTAL SECTION
General Experimental Procedures. Melting points for crystal-
line compounds were obtained using a Buchi melting point B-545
■
̈
melting point apparatus. Optical rotations were recorded on an Anton-
Paar MCP 100 polarimeter. [α]D values are reported in 10−1 deg cm2
g−1 at 598 nm; concentration (c) is given in g (100 mL)−1. Infrared
spectra were recorded on a PerkinElmer Spectrum One spectrometer.
1H and 13C NMR spectra were recorded on a Bruker Avance 500 Cryo
Ultrashield (500 MHz) spectrometer. Low-resolution mass spectra
(LRMS) were recorded using an LCMS system (Agilent series LC
with an ESCi Multi-Mode Ionization Waters ZQ spectrometer using
MassLynx 4.1 software). High-resolution mass spectra (HRMS) were
recorded using a Micromass Q-TOF. Thin-layer chromatography
retention factors (Rf) are quoted to the nearest 0.05. Flash column
chromatography was carried out according to the method of Still.14
Yields refer to chromatographically and spectroscopically pure
compounds, for which full analytical data are given. (6aS,12aS,5′R)-
Rotenone (1) (95% purity) was purchased from Molekula Fine
Chemicals as an off-white amorphous solid and was crystallized from
EtOH (×3) to give colorless plates [mp 162−163 °C (lit. 163 °C)].13
All other solvents and reagents were used as obtained from
commercial sources.
The (trivial) nomenclature and numbering systems used for the
assignments in this article are well established in this natural product
family.1c,d,13 See also Figure 2.
a
Reagents and conditions: (a) OsO4 (0.4 mol %), NMO, citric acid,
acetone−H2O (4:1), rt, 22 h, 92%; (b) H5IO6, H2O, rt, 4.5 h, 78%; (c)
Oxone, MeCN−H2O (10:1), rt, 28 h, 35%; (d) PTSA, toluene, 80 °C,
1.5 h, 76%; (e) K2Cr2O7, HOAc: H2O (2:1), 60 °C, 0.5 h then rt, 18 h,
63%.
Figure 2. Representative atom-numbering schemes for rotenone (1)
and lactol acetate (9), from which all products in this study derive.
observed after 28 h by LCMS and analysis by TLC complicated
by the highly similar retention factors of starting material and
product. Although low yielding the reaction could readily be
performed on larger scales, providing sufficient material for the
elimination step.
(6aS,12aS,5′R,6′R)- and (6aS,12aS,5′R,6′S)-Amorphigenol
(11). A solution of OsO4 (420 μL, 0.041 mmol, 2.5 wt % in t-
BuOH) was added in one portion to a solution of (6aS,12aS,5′R)-
rotenone (1) (4.00 g, 10.2 mmol), N-methylmorpholine-N-oxide (1.43
g, 12.2 mmol), and citric acid (7.80 g, 40.6 mmol) in acetone (160
mL) and H2O (40 mL). The mixture was stirred at room temperature
for 22 h. EtOAc (200 mL) was added followed by a saturated aqueous
Na2SO3 solution (200 mL), and the two phases were mixed vigorously
for 0.5 h. The organic layer was separated, washed with H2O (3 × 200
mL) and brine (200 mL), dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The crude pale yellow solid was crystallized
from MeOH−H2O (approximately 1:1) to afford a 55:45 unassigned
diastereoisomeric mixture of (6aS,12aS,5′R,6′S)- and
(6aS,12aS,5′R,6′R)-amorphigenol (11) as white needles (3.98 g,
Treatment of lactol acetate (9) with para-toluenesulfonic
acid in toluene at 80 °C proceeded smoothly to afford elliptone
(5) in 76% yield.9a Pleasingly, the Etard-like hydroxylation of
́
elliptone (5) with K2Cr2O7 in aqueous HOAc afforded 12aβ-
hydroxyelliptone (6) in 63% yield as a single diastereoisomer.
The stereochemical outcome of this reaction may be attributed
to the pericyclic ene and [2,3] sigmatropic rearrangement steps
of the Etard reaction,10 in conjunction with the “butterfly wing”
́
architecture of the substrate.
In conclusion, we have developed operationally simple four-
and five-step semisyntheses of elliptone (5) and 12aβ-
hydroxyelliptone (6) from rotenone (1). Also described is
the preparation of elliptone (5), improving upon the methods
of Anzeveno8 and Singhal9 in terms of scalability and yield.
Dihydroxylation of rotenone (1) followed by oxidative cleavage
provided norketone 10, which was susceptible to chemo-
selective Baeyer−Villiger oxidation with excess Oxone to afford
lactol acetate (9).9 Acid-catalyzed elimination according to
Singhal’s procedure afforded elliptone (5).9 A highly diaster-
92%): mp 181−184 °C; Rf 0.05 (n-hexane−EtOAc; 1:1); [α]20 −89
D
(c 0.1 in CHCl3); νmax (neat)/cm−1 3600−3200br, 1668m (C
O)ketone, 1604m, 1515m, 1348m, 1317m, 1287m, 1214m, 1201m,
1181m, 1058m, 1009m, 909m, 816m; NMR data for the major
diastereoisomer δH (500 MHz, CDCl3) 1.21 [3H, s, C(8′)H3], 2.29
[1H, dd, J 10.0, 5.0 Hz, C(7′)HH′OH], 2.40 [1H, s, C(6′)OH], 3.18
[1H, app d, J 12.0 Hz, C(4′)HH′], 3.18 [1H, app d, J 12.0, Hz,
C(4′)HH′], 3.52 [1H, ddd, J 14.0, 10.0, 5.0 Hz, C(7′)HH′OH], 3.73
[1H, ddd, J 14.0, 10.0, 5.0 Hz, C(7′)HH′OH], 3.76 [3H, s, C(2′)H3],
3.81 [3H, s, C(3′)H3], 3.84 [1H, d, J 4.5 Hz, C(12a)H], 4.18 [1H, app
d, J 15.0 Hz, C(6)HH′], 4.61 [1H, dd, J 15.0, 3.5 Hz, C(6)HH′], 4.86
[1H, app t, J 12.0 Hz, C(5′)H], 4.93 [1H, ddd, J 4.5, 3.5, 1.0 Hz,
C(6a)H], 6.45 [1H, s, C(4)H], 6.47 [1H, d, J 11.0 Hz, C(10)H], 6.75
[1H, s, C(1)H], 7.82 [1H, d, J 11.0 Hz, C(11)H]; δC (125 MHz,
CDCl3) 19.3 [C(8′)H3], 27.0 [C(4′)H2], 44.6 [C(12a)H], 55.9
[C(3′)H3], 56.3 [C(2′)H3], 66.2 [C(6)H2], 66.8 [C(7′)H2], 72.2
́
eoselective Etard-like hydroxylation of elliptone (5) gave 12aβ-
hydroxyelliptone (6), the mechanistic details of which we have
discussed previously.10 With the desired natural products in
hand biological investigations are ongoing, and the results will
be reported in due course.
C
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[C(6a)H], 73.4 [C(6′)], 87.3 [C(5′)H], 100.9 [C(4)H], 104.6
[C(10)H], 104.7 [C(13)], 110.3 [C(1)H], 113.4 [C(8)], 113.5
[C(11a)], 129.9 [C(11)H], 143.9 [C(2)], 147.4 [C(4a)], 149.5
[C(3)], 157.9 [C(7a)], 166.9 [C(9)], 189.0 [C(12)]; NMR data for
the minor diastereoisomer δH (500 MHz, CDCl3) 1.17 [3H, s, C(8′)
H3], 2.09 [1H, dd, J 10.0, 5.0 Hz, C(7′)HH′OH], 2.55 [1H, s,
C(6′)OH], 3.16 [1H, dd, J 19.5, 12.0 Hz, C(4′)HH′], 3.23 [1H, dd, J
19.5, 12.0 Hz, C(4′)HH′], 3.56 [1H, ddd, J 14.0, 10.0, 5.0 Hz, C(7′)
HH′OH], 3.76 [3H, s, C(2′)H3], 3.80 [1H, ddd, J 14.0, 10.0, 5.0 Hz,
C(7′)HH′OH], 3.81 [3H, s, C(3′)H3], 3.85 [1H, d, J 4.5 Hz, C(12a)
H], 4.18 [1H, app d, J 15.0 Hz, C(6)HH′], 4.62 [1H, dd, J 15.0, 4.0
Hz, C(6)HH′], 4.86 [1H, app t, J 12.0 Hz, C(5′)H], 4.93 [1H, ddd, J
4.5, 3.5, 1.0 Hz, C(6a)H], 6.45 [1H, s, C(4)H], 6.47 [1H, d, J 11.0 Hz,
C(10)H], 6.75 [1H, s, C(1)H], 7.83 [1H, d, J 11.0 Hz, C(11)H]; δC
(125 MHz, CDCl3) 19.7 [C(8′)H3], 27.3 [C(4′)H2], 44.6 [C(12a)H],
55.9 [C(3′)H3], 56.3 [C(2′)H3], 66.2 [C(6)H2], 68.6 [C(7′)H2], 72.2
[C(6a)H], 72.9 [C(6′)], 90.0 [C(5′)H], 100.9 [C(4)H], 104.6
[C(10)H], 104.8 [C(13)], 110.3 [C(1)H], 113.3 [C(8)], 113.7
[C(11a)], 129.9 [C(11)H], 143.9 [C(2)], 147.4 [C(4a)], 149.5
[C(3)], 157.9 [C(7a)], 166.6 [C(9)], 189.0 [C(12)]; LRMS m/z
found 429.2, C23H25O8 [M + H]+ requires 429.2; HRMS m/z found
451.1354, C23H24O8Na [M + Na]+ requires 451.1363.
[1H, s, C(4)H], 6.60 [1H, d, J 8.5 Hz, C(10)H], 6.73 [1H, s, C(1)H],
6.84 [1H, dd, J 8.5, 1.5 Hz, C(5′)H], 7.88 [1H, d, J 8.5 Hz, C(11)H];
δC (125 MHz, CDCl3) 21.0 [C(8′)H3], 32.7 [C(4′)H2], 44.7
[C(12a)H], 55.9 [C(3′)H3], 56.3 [C(2′)H3], 66.2 [C(6)H2], 72.5
[C(6a)H], 99.4 [C(5′)H], 100.9 [C(4)H], 104.4 [C(13)], 105.4
[C(10)H], 110.2 [C(1)H], 111.1 [C(8)], 114.4 [C(11a)], 130.1
[C(11)H], 143.9 [C(2)], 147.4 [C(4a)], 149.6 [C(3)], 157.8 [C(7a)],
165.0 [C(9)], 169.6 [C(7′)], 189.1 [C(12)]; LRMS m/z found 413.1,
C22H21O8 [M + H]+ requires 413.1; HRMS m/z found 413.1249,
C22H21O8 [M + H]+ requires 413.1236.
(6aS,12aS)-Elliptone (5). para-Toluenesulfonic acid monohydrate
(36.9 mg, 0.194 mmol) was added to a solution of lactol acetate (9)
(400 mg, 0.971 mmol) in dry toluene (40.0 mL) under an atmosphere
of nitrogen. The mixture was heated at 80 °C for 1.5 h, cooled to room
temperature, and diluted with EtOAc (40 mL). Saturated aqueous
NaHCO3 solution (20 mL) was added, and the two phases were mixed
vigorously for 0.5 h. The organic layer was separated, washed with
H2O (20 mL) and brine (20 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude off-white solid was
purified by flash column chromatography (n-hexane−EtOAc, 2:1) to
afford (6aS,12aS)-elliptone (5) as a white amorphous solid (259 mg,
(6aS,12aS,5′R)-Rotenone-6′-norketone (10). A diastereomeric
mixture of (6aS,12aS,5′R,6′R)- and (6aS,12aS,5′R,6′S)-amorphigenol
(11) (2.00 g, 4.67 mmol) was added in one portion to a solution of
periodic acid (4.26 g, 18.7 mmol) in H2O (200 mL). The suspension
was stirred vigorously at room temperature for 4.5 h before it was
extracted with EtOAc (4 × 80 mL). The combined organic extracts
were washed with brine (100 mL), dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude off-white solid was
crystallized from MeOH to afford (6aS,12aS,5′R)-rotenone-6′-
norketone (10) as white needles (1.44 g, 78%): mp 194−196 °C
76%): Rf 0.25 (n-hexane−EtOAc, 2:1); [α]20 +46 (c 0.1 in CHCl3);
D
νmax (neat)/cm−1 1679m (CO)ketone, 1613m, 1596w, 1514m,
1464m, 1388m, 1333m, 1214m, 1193m, 1090m, 913m, 820m; δH
(500 MHz, CDCl3) 3.75 [3H, s, C(2′)H3], 3.79 [3H, s, C(3′)H3], 3.94
[1H, d, J 4.0 Hz, C(12a)H], 4.24 [1H, d, J 12.0 Hz, C(6′)HH′], 4.72
[1 H, dd, J 12.0, 3.0 Hz, C(6)HH′], 5.08 [1H, ddd, J 4.0, 3.0, 1.0 Hz,
C(6a)H], 6.46 [1H, s, C(4)H], 6.76 [1H, s, C(1)H], 6.92 [1H, d, J 2.5
Hz, C(5′)H], 7.14 [1H, d, J 8.5 Hz, C(10)H], 7.56 [1H, d, J 2.5 Hz,
C(4′)H], 7.89 [1H, d, J 8.5 Hz, C(11)H]; δC (125 MHz, CDCl3) 44.7
[C(12a)H], 55.9 [C(3′)H3], 56.3 [C(2′)H3], 66.2 [C(6)H2], 72.9
[C(6a)H], 101.0 [C(4)H], 104.5 [C(13)], 104.9 [C(5′)H], 106.7
[C(10)H], 110.3 [C(1)H], 113.6 [C(8)], 117.2 [C(11a)], 124.0
[C(11)H], 143.9 [C(2)], 145.0 [C(4′)H], 147.4 [C(4a)], 149.6
[C(3)], 156.0 [C(7a)], 160.3 [C(9)], 189.9 [C(12)]; LRMS m/z
found 353.1, C20H17O6 [M + H]+ requires 353.1; HRMS m/z found
375.0826, C20H16O6Na [M + Na]+ requires 375.0839.
(lit. mp 198−199 °C);9b Rf 0.20 (n-hexane−EtOAc; 1:1); [α]20 −60
D
(c 0.1 in CHCl3) (no lit. value); νmax (neat)/cm−1 2910w, 1714 (C
O)ketone, 1681 (CO)ketone, 1607m, 1514m, 1457m, 1349m, 1305m,
1254m, 1238m, 1215m, 1196m, 1145m, 1092m, 1005m, 910m, 818m;
δH (500 MHz, CDCl3) 2.30 [3H, s, C(8′)H3], 3.33 [1H, dd, J 16.0,
10.0 Hz, C(4′)HH′], 3.36 [1H, dd, J 16.0, 10.0 Hz, C(4′)HH′], 3.76
[3H, s, C(2′)H3], 3.81 [3H, s, C(3′)H3], 3.86 [1H, d, J 4.0 Hz, C(12a)
H], 4.18 [1H, d, J 12.0 Hz, C(6)HH′], 4.61 [1H, dd, J 12.0, 3.0 Hz,
C(6)HH′], 4.93 [1H, dd, J 4.0, 3.0 Hz, C(6a)H], 5.13 [1H, m, C(5′)
H], 6.45 [1H, s, C(4)H], 6.58 [1H, d, J 8.5 Hz, C(10)H], 6.74 [1H, s,
C(1)H], 7.87 [1H, d, J 8.5 Hz, C(11)H]; δC (125 MHz, CDCl3) 26.3
[C(8′)H3], 29.3 [C(4′)H2], 44.6 [C(12a)H], 55.9 [C(3′)H3], 56.3
[C(2′)H3], 66.2 [C(6)H2], 72.4 [C(6a)H], 87.3 [C(5′)H], 100.9
[C(4)H], 104.5 [C(13)], 105.0 [C(10)H], 110.3 [C(1)H], 111.9
[C(8)], 114.0 [C(11a], 130.3 [C(11)H], 143.9 [C(2)], 147.4 [C(4a)],
149.6 [C(3)], 157.9 [C(7a)], 166.3 [C(9)], 188.9 [C(12)], 206.7
[C(6′)]; LRMS m/z found 397.1, C22H21O7 [M + H]+ requires 397.1;
HRMS m/z found 397.1295, C22H21O7 [M + H]+ requires 397.1287.
Lactol Acetate (9). Oxone (6.21 g, 20.2 mmol) was added in one
portion to a solution of (6aS,12aS,5′R)-rotenone-6′-norketone (10)
(1.00 g, 2.53 mmol) in MeCN (60.0 mL) and H2O (6.0 mL). The
mixture was stirred at room temperature for 28 h. Saturated aqueous
NaHCO3 solution (100 mL) was added followed by EtOAc (100 mL),
and the two phases were mixed vigorously for 0.5 h. The organic layer
was separated, washed with brine (100 mL), dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. The crude pale yellow
solid was purified by flash column chromatography (n-hexane−EtOAc,
3:1) to afford lactol acetate (9) as a white amorphous solid, which
crystallized from MeOH as white needles (360 mg, 35%): mp 193−
194 °C (no lit. value);9a Rf 0.20 (n-hexane−EtOAc, 2:1) (after two
elutions); [α]20D −294 (c 0.1 in CHCl3) (no lit. value);9a νmax (neat)/
cm−1 2935w, 1754m (CO)ester, 1670m (CO)ketone, 1601m,
1510m, 1458m, 1346m, 1251m, 1214m, 1192m, 1171m, 1050m,
913m, 816m; δH (500 MHz, CDCl3) 2.10 [3H, s, C(9′)H3], 3.12 [1H,
dd, J 10.5, 1.5 Hz, C(4′)HH′], 3.39 [1H, dd, J 10.5, 8.5 Hz,
C(4′)HH′], 3.76 [3H, s, C(2′)H3], 3.79 [3H, s, C(3′)H3], 3.87 [1H,
d, J 4.0 Hz, C(12a)H], 4.18 [1H, d, J 12.0 Hz, C(6)HH′], 4.62 [1H,
dd, J 12.0, 3.0 Hz, C(6)HH′], 4.97 [1H, app t, J 4.0 Hz, C(6a)H], 6.44
(6aR,12aR)-12aβ-Hydroxyelliptone (6). A solution of K2Cr2O7
(79.0 mg, 0.269 mmol, 0.94 equiv) in H2O (1.0 mL) was added
dropwise over a period of 2 min to a solution of (6aS,12aS)-elliptone
(5) (100 mg, 0.284 mmol) and HOAc (2.0 mL) at 60 °C. The mixture
was stirred at 60 °C for 30 min, cooled to room temperature, and
stirred for an additional 18 h. H2O (20 mL) was added to the dark-
green mixture, and the resulting suspension was stirred vigorously for
30 min while an off-white precipitate formed, which was collected by
filtration, washed with H2O (10 mL), and dried in vacuo overnight.
The crude precipitate was purified by flash column chromatography
(n-hexane−EtOAc, 2:1) to afford (6aR,12aR)-12aβ-hydroxyelliptone
(6) as a white amorphous solid (66.0 mg, 63%): Rf 0.15 (n-hexane−
EtOAc, 2:1); [α]20 −5 (c 0.1 in CHCl3); νmax (neat)/cm−1 3600−
D
3300br, 2970w, 1739 (CO)ketone, 1680w, 1613m, 1509m, 1464m,
1366m, 1216m, 1203m, 1080m, 1025m, 813m, 743m; δH (500 MHz,
CDCl3) 3.72 [3H, s, C(2′)H3], 3.80 [3H, s, C(3′)H3], 4.47 [1H, s,
C(6a)H], 4.56 [1H, d, J 12.0 Hz, C(6)HH′], 4.73 [1H, d, J 12.0 Hz,
C(6)HH′], 4.75 [1H, s, C(12a)OH], 6.49 [1H, s, C(4)H], 6.55 [1H,
s, C(1)H], 6.91 [1H, d, J 2.5 Hz, C(5′)H], 7.17 [1H, d, J 8.5 Hz,
C(10)H], 7.57 [1H, d, J 2.5 Hz, C(4′)H], 7.88 [1H, d, J 8.5 Hz, C(10)
H]; δC (125 MHz, CDCl3) 55.9 [C(3′)H3], 56.4 [C(2′)H3], 63.8
[C(6)H2], 67.7 [C(12a)OH], 76.7 [C(6a)H], 101.1 [C(4)H], 104.8
[C(5′)H], 107.1 [C(10)H], 108.4 [C(13)], 109.2 [C(1)H], 112.0
[C(11a)], 117.3 [C(8)], 123.9 [C(11)H], 144.0 [C(2)], 145.1
[C(4′)H], 148.4 [C(4a)], 151.2 [C(3)], 155.8 [C(7a)], 160.6 [C(9)],
192.2 [C(12)]; LRMS m/z found 351.1, C20H17O7 [M + H]+ requires
351.1; HRMS m/z found 391.0800, C20H16O7Na [M + Na]+ requires
391.0793.
D
DOI: 10.1021/acs.jnatprod.7b00527
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
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For related work on the preparation of rot-2′-enonic acid from
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2580.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.7b00527.
■
S
1H and 13C NMR spectra for compounds 1, 5, 6, 9, 10,
and 11 (PDF)
(9) (a) Singhal, A. K.; Sharma, R. P.; Baruah, V.; Herz, W. Chem. Ind.
1982, 540. For related work on the preparation of rotenone-6′-
norketone from rotenone see also (b) Bhandari, P.; Crombie, L.;
Kilbee, G. W.; Pegg, S. J.; Proudfoot, G.; Rossiter, J.; Sanders, M.;
Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1992, 851−863.
(10) Russell, D. A.; Freudenreich, J. J.; Ciardiello, J. J.; Sore, H. F.;
Spring, D. R. Org. Biomol. Chem. 2017, 15, 1593−1596.
(11) Dupau, P.; Epple, R.; Thomas, A. A.; Fokin, V. V.; Sharpless, K.
B. Adv. Synth. Catal. 2002, 344, 421−433.
AUTHOR INFORMATION
Corresponding Author
*E-mail: spring@ch.cam.ac.uk.
ORCID
David R. Spring: 0000-0001-7355-2824
Notes
The authors declare no competing financial interest.
■
(12) (a) Hussain, H.; Green, I. R.; Ahmed, I. Chem. Rev. 2013, 113,
3329−3371. For a report concerning the use of Oxone in affecting
ACKNOWLEDGMENTS
■
Baeyer−Villiger oxidations see: (b) Poladura, B.; Martínez-Castaneda,
̃
This research was supported by the EPSRC, BBSRC, MRC,
Wellcome Trust, and ERC (FP7/2007-2013; 279337/DOS).
D.A.R. thanks Cancer Research UK for funding. W.J.S.F. thanks
A*STAR Singapore for funding. D.G.T. thanks AstraZeneca for
funding. D.R.S. acknowledges support from a Royal Society
Wolfson Research Merit award.
A.; Rodríguez-Solla, H.; Llavona, R.; Concellon
Lett. 2013, 15, 2810−2813.
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, C.; del Amo, V. Org.
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DOI: 10.1021/acs.jnatprod.7b00527
J. Nat. Prod. XXXX, XXX, XXX−XXX