Approach for expanding triterpenoid complexity via divergent Norrish-Yang photocyclization

Article abstract of DOI:10.1021/jo400275p

Triterpenoids comprise a very diverse family of polycyclic molecules that is well-known to possess a myriad of medicinal properties. Therefore, triterpenoids constitute an attractive target for medicinal chemistry and diversity-oriented synthesis. Photochemical transformations provide a promising tool for the rapid, green, and inexpensive generation of skeletal diversity in the construction of natural product-like libraries. With this in mind, we have developed a diversity-oriented strategy, whereby the parent triterpenoids bryonolic acid and lanosterol are converted to the pseudosymmetrical polyketones by sequential allylic oxidation and oxidative cleavage of the bridging double bond at the B/C ring fusion. The resultant polyketones were hypothesized to undergo divergent Norrish-Yang cyclization to produce unique 6/4/8-fused triterpenoid analogues. The subtle differences between parent triterpenoids led to dramatically different spatial arrangements of reactive functionalities. This finding was rationalized through conformational analysis to explain unanticipated photoinduced pinacolization, as well as the regio- and stereochemical outcome of the desired Norrish-Yang cyclization.

Full text of DOI:10.1021/jo400275p

Article
pubs.acs.org/joc
Approach for Expanding Triterpenoid Complexity via Divergent
Norrish-Yang Photocyclization
Vasily A. Ignatenko and Gregory P. Tochtrop*
Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, United States
S
* Supporting Information
ABSTRACT: Triterpenoids comprise a very diverse family of
polycyclic molecules that is well-known to possess a myriad of
medicinal properties. Therefore, triterpenoids constitute an
attractive target for medicinal chemistry and diversity-oriented
synthesis. Photochemical transformations provide a promising
tool for the rapid, green, and inexpensive generation of skeletal
diversity in the construction of natural product-like libraries.
With this in mind, we have developed a diversity-oriented
strategy, whereby the parent triterpenoids bryonolic acid and
lanosterol are converted to the pseudosymmetrical polyketones
by sequential allylic oxidation and oxidative cleavage of the
bridging double bond at the B/C ring fusion. The resultant
polyketones were hypothesized to undergo divergent Norrish-
Yang cyclization to produce unique 6/4/8-fused triterpenoid analogues. The subtle differences between parent triterpenoids led
to dramatically different spatial arrangements of reactive functionalities. This finding was rationalized through conformational
analysis to explain unanticipated photoinduced pinacolization, as well as the regio- and stereochemical outcome of the desired
Norrish-Yang cyclization.
Considerable efforts in drug discovery have focused on the
isolation and structural elucidation of novel triterpenoid
molecules from the plant sources.11−13 Moreover, semi-
synthetic triterpenoids, created by further manipulation of the
exterior functional groups, have been shown to enhance the
potency of their natural precursors.14−16 In this regard, the
increase in structural complexity of triterpenoid-like molecules
through alteration of their carbocyclic core skeleton can be
viewed as a promising tool to study the chemical biology and
medicinal chemistry of this natural product family.17,18
The use of photochemical transformations for the target-
oriented synthesis of complex natural products has proven to
be an effective approach.19,20 The advantages of these reactions
are the green and low-cost nature of the reagent, as well as the
fact that such transformations allow for the rapid construction
of strained systems that otherwise would be very difficult to
synthesize. However, the use of light as a reagent in diversity-
oriented synthesis is limited.21,22 In relation to natural products,
a single report by the group of de la Torre23 describes an
elegant application of a [2 + 2] cycloaddition and Paterno-
Buchi reaction to the synthesis of diverse polycyclic terpene-like
structures from readily available sesquiterpene Sclareolide.
We set out to apply Norrish-Yang photocyclization24,25
(Figure 2a) to the synthesis of triterpenoid analogues with
unique 6/4/8-fused ring systems. The Norrish-Yang reaction
INTRODUCTION
■
Triterpenoids are a broad and structurally diverse class of
natural products primarily derived from the plant kingdom.1
The triterpenoid family consists of nearly 30 000 members with
over 200 unique carbocyclic skeletons.2,3 Consequently,
triterpenoids are known to have a wide array of biological
activities, including antifungal,4 anti-inflammatory,5 anti-
cancer,6,7 as well as antiviral8 and antibacterial properties.9
This remarkable molecular and medicinal diversity among
triterpenoids is achieved through the variety of squalene and
oxidosqualene cyclases that catalyze these reactions,10 as well as
through further modification of the carbon skeletons by minor
rearrangements including homologation, cleavage, and degra-
dation (Figure 1).
Received: February 5, 2013
Figure 1. Selected members of the triterpenoid family.
© XXXX American Chemical Society
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1). When this rationale was taken into account, a solution of
tetraketone 1 in dry deoxygenated C6D6 was irradiated in a
Table 1. Norrish-Yang Reactivity of Tetraketone 1
isolated yield of product
(%)
entry
λmax (nm)
time (min)
3
4
1
2
3
4
254
300
350
45
90
33
63
30
56
10
13
5
Figure 2. (a) General mechanism of Norrish-Yang type II photo-
cyclization. (b) Formation of 4/8-fused carbocycle from 1,2-cyclo-
decanone. (c) Structures and carbon numbering of bryonolic acid and
lanosterol.
135
45
a
300
<1
a
Reaction was carried out in the presence of 1.0 equiv of
benzophenone.
was chosen because it allows for (1) selective C−C bond
formation from unactivated sp3-hybridized C−H bonds of
saturated hydrocarbons; and (2) formation of particular 4/8-
fused carbocycles from cyclodecanone substrates26,27 (Figure
2b). Additionally, the 1,2-diketone moiety is known to be an
excitable chromophore that can undergo Yang cyclization as
opposed to the Norrish type II fragmentation.28−33
The application of Yang cyclization to the construction of
additional four-membered rings in steroids has been reviewed
by Kamernitskii et al.34 The diversity-oriented strategy35,36
which we have envisioned is different from earlier approaches in
that the reactive keto groups are strategically positioned within
a parent triterpenoid core structure by sequential oxidation
reactions. This is followed by the generation of a new ring
fusion via regioselective photocyclization.
Here, we report the successful application of this strategy to a
pentacyclic triterpenoid, bryonolic acid, and a tetracyclic
triterpenoid, lanosterol (Figure 2c). These molecules were
chosen due to the unsaturation at the B/C ring fusion, which
allowed for the formation of the desired cyclodecane-1,2-diones
by the allylic oxidation and subsequent oxidative cleavage
reactions. The resultant ketones were systematically studied for
structural elements dictating the regio- and stereoselectivity of
the following Norrish-Yang reaction.
quartz cuvette with 254 nm UV light until complete
consumption of the starting material was detected by TLC
(45 min, Table 1, entry 1). Further investigation of the reaction
mixture showed the formation of two products, which were
separable by column chromatography on silica.
The study of the NMR spectra of the major reaction product
revealed an AX system of two doublets at 3.40 and 2.75 ppm (J
= 12 Hz) attached to isolated methylene carbon at 41.2 ppm.
These protons correlate, as observed by HMBC, with two
carbonyl carbons (C-7, δC 210.0; C-8, δC 211.5), as well as with
four quaternary carbons (C-4, δC 43.8; C-5, δC 56.9; C-10, δC
62.3; C-11, δC 92.2). These correlations allowed the assignment
of the AX system to position 6 of the cyclobutanol 3 and ruled
out structure 2, in which H-6 could only be correlated to one
carbonyl carbon by HMBC spectroscopy. Further investigation
of the structure of cyclobutanol 3 disclosed an AX system of
two doublets at 2.25 and 1.73 ppm (J = 18 Hz), attached to
another isolated methylene carbon C-12 (δC 42.4). In the
HMBC spectrum, H-12 showed cross-peaks with one carbonyl
carbon (C-9, δC 218.9), as well as one methine carbon (C-18,
δC 47.0), one methyl carbon (C-27, δC 19.0), and four
quaternary carbons (C-5, C-11, C-13, δC 40.6; C-14, δC 55.4).
Consequently, the NMR and the HRMS data were consistent
with the proposed structural framework of cyclobutanol 3
(Figure 3).
The routine NMR spectra of the minor reaction product
were inconsistent with a structure of a product of Yang
cyclization of tetraketone 1. Specifically, examination of 13C
NMR spectrum revealed the signals of two carbonyl carbons
(C-8, δC 212.6; C-9, δC 212.4), as well as three quaternary
carbons (C-5, δC 90.6; C-7, δC 90.3; C-11, δC 77.3) in the
region downfield from 50 ppm. Extensive 2D NMR experi-
ments allowed us to propose structure 4 for the minor product
of the reaction. Especially useful were the cross-peaks shown by
two doublets at 2.69 and 1.88 ppm (H-6, J = 14 Hz), attached
RESULTS AND DISCUSSION
■
Tetraketone 1 was prepared according to our previously
published method18 from doubly protected bryonolic acid in
two steps by oxidation of the Δ8,9 double bond with
ruthenium tetroxide under Sharpless conditions. Early analysis
of the bichromophoric structure of tetraketone 1 revealed that
the “bowsprit” hydrogen H-5 is in γ-position to the keto groups
at C-8 and C-11. Thus, photoexcitation of the C-8 carbonyl
bond could lead to the formation of cyclobutanol 2 via pathway
b, and concurrently, photoexcitation of C-11 carbonyl would
result in the formation of cyclobutanol 3 via pathway a (Table
B
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Figure 3. Key HMBC (1H to 13C) and COSY correlations of
cyclobutanol 3.
Figure 5. Mechanistic considerations for the formation of 3 and 4.
to an isolated methylene carbon C-6 (δC 39.8). In the HMBC
spectrum, H-6 correlated to C-5, C-7, C-8, as well as C-10 (δC
48.7) and C-11. Additionally, the correlations of two doublets
at 2.20 and 1.97 ppm (H-12) in the HMBC spectrum
supported the elucidation of the carbon framework of structure
4 by showing the cross-peaks with C-7, C-9, C-11, as well as C-
13 (δC 40.4), C-14 (δC 52.5), C-18 (δC 44.3), and C-27 (δC
22.3) (Figure 4). The structural assignment was also supported
by HRMS data.
with the C-7 carbonyl leading to a C-5,O-7-centered biradical,
which presumably can experience intermolecular H-exchange,
followed by a ring closure to form bridged structure 4 (Figure
5).
The mechanistic rationale of the reaction is in complete
agreement with the observed stereochemistry of the products 3
and 4, as determined by NOE correlation spectroscopy (Figure
6), demonstrating memory of chirality effect, whereby the chiral
information of the tetraketone 1 is retained by the
conformation of the biradical intermediate.44−47
In the NOESY spectrum of cyclobutanol 3, Hβ-6 correlates
with H-25 and H-24 while Hα-6 correlates with H-23 and H-27,
and the NOE interactions of Hβ-12 with H-25 and H-26
determine α-facial orientation of the hydroxyl group at C-11. In
the case of the bridged structure 4, Hα-6 correlates with H-24
and H-27 while Hβ-6 correlates with H-25, as well as with the
C7−OH hydroxyl group, which, in turn, shows an interaction
with H-26. This provided evidence for the β-facial orientation
of this hydroxyl group.
In an effort to force Yang cyclization into the alternative
direction to form cyclobutanol 6, we took triketone 5 as a
substrate for the photoreaction. The synthesis of triketone 5 by
direct oxidation of doubly protected bryonolic acid with
ruthenium tetroxide under Sharpless conditions was previously
reported by our group.18 The structure of triketone 5 preserves
the main structural features of tetraketone 1 but lacks the keto
group at C-11 (Table 2).
Figure 4. Key HMBC (1H to 13C) and COSY correlations of structure
4.
After elucidation of the structures of the reaction products,
the yields of cyclobutanol 3 and the minor product of the
photolysis 4 were found to be 33 and 10%, respectively (Table
1, entry 1). The changing of the light sources did not lead to
substantial difference in product distribution; however, the
highest combined yield of 3 and 4 was achieved with a 300 nm
UV lamp (76%, Table 1, entry 2). It is noteworthy that no
products of the type II photofragmentation were observed in
any reactions performed.
To gain insight into the regio- and, more importantly,
stereochemical outcome of the Yang cyclization of tetraketone
1, we next examined a plausible mechanism for the process. It
has been determined by the Scheffer group37−39 that, in order
for a ketone to undergo successful Norrish type II hydrogen
abstraction reaction, the distance between the oxygen of the
carbonyl and the γ-H has to be less than the sum of van der
Waals radii for the H and O (2.72 Å). Using B3LYP/6-
311G(d,p) calculated geometry of tetraketone 1, we
determined that only the C-11 keto group met this requirement
(d1 = 2.29 Å, Figure 5), while the carbonyl at C-8 exceeded the
suggested distance (d2 = 2.95 Å). Consequently, irradiation of
tetraketone 1 led exclusively to the formation of 1(C-5),4(C-
11)-hydroxy biradical, which is geometrically predisposed to
cyclize into cis-cyclobutanol 3. The intermediate hydroxy
biradical can concurrently undergo photopinacolization40−43
The computed distance between H-5 and the oxygen of the
C-8 carbonyl of triketone 5 is 2.56 Å, suggesting the high
possibility of the desired transformation. In addition, the 1(C-
7),2(C-8)-dione system becomes the major chromophore of
the polyketone. Accordingly, irradiation of triketone 5 with 254
nm UV light for 72 h yielded a single reaction product (6%
isolated yield, Table 2, entry 1). However, the structure of the
product of the photolysis of triketone 5 was formulated as 7 on
the basis of a thorough NMR investigation (Figure 7).
The 13C NMR spectrum of 7 showed the presence of one
carbonyl carbon C-8 (δC 212.9), as well as newly formed
quaternary carbons C-7 (δC 87.3) and C-9 (δC 78.9), and a
methylene carbon C-26 (δC 72.6) in the fingerprint region.
This observation alone excludes structure 6, which would be
expected to have two signals of the ketone groups in the 13C
1
spectrum. The H NMR of 7 exhibited a pair of doublets at
4.29 and 4.04 ppm (J = 10 Hz), corresponding to a methylene
carbon C-26 (δC 72.6). In the HMBC spectrum, H-26 showed
cross-peaks with C-7, C-8, C-13 (δC 39.7), C-14 (δC 53.9), and
a methylene carbon C-15 (δC 25.6). Structural assignment was
completed by further analysis of cross-peaks shown by H-5, H-
11, and H-25 (Figure 7), as well as HRMS data.
C
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Figure 6. Key NOESY correlations of compounds 3 and 4.
Table 2. Norrish-Yang Reactivity of Triketone 5
Figure 8. Mechanistic considerations for the formation of 7.
The changing of the light source did not significantly
improve the efficiency of this reaction; however, almost
complete conversion of the starting material was achieved by
the use of benzophenone in combination with a 300 nm UV
light (Table 2, entry 4). Low efficiency and long reaction times
of the photolyses of triketone 5 are caused, perhaps, by the
known reversibility of light-induced pinacolization and hydro-
gen-transfer processes.
The relative stereochemistry of 7 was confirmed by NOESY
spectroscopy, which showed enhancements between the
hydroxyl group at C-9 with Hβ-26, H-25, and Hβ-12. Hβ-12
in turn showed correlations with H-18 and Hβ-26, while Hα-26
showed a cross-peak with Hβ-16 (Figure 9). These NOESY
data have determined the β-facial environment of the newly
formed rings B and C.
a
a
entry λmax (nm) time (h) yield of 7 (% brsm) conversion of 5 (%)
1
2
3
4
5
254
300
72
72
72
72
72
12
57
69
15
350
n/r
0
b
c
300
39
>99
72
b
254
18
a
b
Dermined by 1H NMR. Reaction was carried out in the presence of
1.0 equiv of benzophenone. Isolated yield.
c
Figure 7. Key HMBC (1H to 13C) and COSY correlations of structure
7.
Figure 9. Key NOESY correlations of compound 7.
The formation of structure 7 was not anticipated.
Presumably, the initial photoexcitation of the C-7 keto group
is followed by a new carbon−carbon bond formation via
pinacol-type coupling reaction with the C-9 carbonyl. The
resulting oxygen-centered biradical intermediate, formation of
which is commonly associated with the photochemical cleavage
of cyclic peroxides,48−50 undergoes abstraction of ε-hydrogen
H-26 by the oxygen of the C-9 carbonyl (d2 = 2.31 Å), followed
by a radical cyclization process to form a furan ring (Figure 8).
Having established the reactivity patterns of the polyketones
derived from bryonolic acid, we then turned our attention to
the tetracyclic triterpenoid lanosterol. We have previously
found that the subtle structural differences between bryonolic
acid and lanosterol led to dramatic differences in the aldol
reactivity of the polyketones derived from these molecules.18 In
this regard, we set out to predict using conformational analysis
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and further confirm the possibility of the formation of the
alternative product of Yang cyclization via pathway b from
lanosterol-derived polyketones 14 and 17.
The oxidation chemistry leading to tetraketone 14 was next
investigated. After initial protection of the hydroxyl group at C-
3 of lanosterol 8 to generate acetate 9, the Δ24,25 double bond
of lanosterol acetate 9 was selectively oxidized according to the
method developed by Reshetova et al.51 The use of KMnO4
and NaIO4 in aqueous tert-BuOH at 60 °C to rt for 15 h,
followed by treatment of the resultant carboxylic acids with
freshly prepared diazomethane in dry THF for 30 min, gave the
desired methyl ester 10 in 65% yield, accompanied by α,β-
unsaturated ketones 11 and 12 and enedione 13 in 9, 7, and 4%
yield, respectively. It is noteworthy that the formation of α,β-
unsaturated ketone 12 was not observed by Reshetova et al.
The ester 10 was further oxidized with KMnO4 and 18-crown-6
in aqueous DCM at rt to furnish enedione 13 in 78% yield after
24 h. Finally, tetraketone 14 was prepared from enedione 13 by
catalytic oxidation with ruthenium tetroxide under Sharpless
conditions.52 The use of RuCl3 with NaIO4 as a stoichiometric
reoxidant in the mixture of CCl4, acetonitrile, and water gave
the desired product 14 in 87% yield after 15 h (Scheme 1).
1
Figure 10. Variable-temperature H NMR study of tetraketone 14.
all peaks broaden, and at temperatures at and above 80 °C, the
doubled peaks merge and only time-average resonances are
observed. We argue that the coalescence of the doubled peaks
at higher temperatures confirms that tetraketone 14 exists as an
equilibrium mixture of two conformational isomers. Lowering
the temperature to −30 °C does not lead to any difference in
the line shapes, indicating that the conformational equilibrium
has reached the slow exchange rate.
Scheme 1. Sequential Oxidation of Δ24,25 and Δ8,9 of
Lanosterol Acetate 9
On the basis of the empirical calculations using the torsional
angles in the 10-membered ring, Marsaioli and co-workers
suggested the structures of the four possible conformers of the
lanosterol-derived cyclodecatetraone (Figure 11). More accu-
A literature search revealed that Marsaioli and co-workers
have previously studied the aldol reactivity of a similar
tetraketone derived from 24,25-dihydrolanosterol.53,54 On the
1
basis of the analysis of H and 13C NMR spectra, the authors
have suggested that the tetraketone existed as a mixture of two
conformational isomers. Rigorous verification of this suggestion
was critical to our analysis and prediction of photochemical
behavior of the tetraketone 14. Therefore, we conducted a
variable-temperature NMR study of tetraketone 14, which
indeed was isolated as a mixture of two products (ca. 2.5:1 at
303.15 K), inseparable by various chromatographic means
(Figure 10).
Figure 11. Structures of the possible conformers of tetraketone 14.
rate energy minimization calculations59 of the tetraketone 14 at
the B3LYP/6-311G(d,p) level of theory disclosed that the
lowest energy conformers CCC (chair−chair−chair) and TB
(twist-boat)-1 are almost isoenergetic. Therefore, the energy
difference of 0.44 kcal/mol between CCC and TB-1 would
correspond well to the equilibrium mixture of two conformers
in ca. 2.1:1 ratio at 303.15 K. The assignment of the structures
of conformers CCC and TB-1 was further supported by
comparison of the experimental J values for H-5 of both
conformers with the J values predicted using the dihedral angles
of −114° (TB-1, H5H6α), 128° (TB-1, H5H6β), −73° (CCC,
H5H6α), and 168° (CCC, H5H6β), which were determined with
1H signals were assigned by the analysis of COSY, HMQC,
1
and HMBC spectra of tetraketone 14. H NMR experiments
carried out in toluene-d8 at 0 °C revealed that the H-3 signal
exists as a doublet of doublets at 4.82 ppm (J1 = 11.4 Hz, J2 =
4.2 Hz) and a doublet of doublets at 4.60 ppm (J1 = 11.4 Hz, J2
= 3.6 Hz); H-12 splits into two doublets at 3.54 ppm (J = 13.2
Hz) and 3.48 ppm (J = 13.8 Hz); H-26 shows two singlets at
3.42 and 3.40 ppm, while H-5 appears as a doublet of doublets
at 3.21 ppm (J1 = J2 = 3.6 Hz) and a doublet of doublets at 3.03
ppm (J1 = 15.6 Hz, J2 = 9.6 Hz). With increasing temperature,
E
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the GaussView 3.09 program. Unfortunately, NOESY experi-
ments did not provide definitive evidence as to the structures of
the conformers.
unambiguously after comprehensive analysis of 2D NMR
experiments and HRMS data (see Supporting Information). It
is noteworthy that no other products were observed during the
photolysis.
Our attention was then turned toward the oxidation reaction
leading to triketone 17 (Scheme 2). In due course, when
Next, we examined the photochemical reactivity of the
bichromophoric structure 14. Analysis of the less populated
conformational isomer CCC (Figure 11) revealed that the
“bowsprit” γ-hydrogen H-5 is anti-periplanar with C-8 and C-
11 keto groups. Disfavorable orientation of reactive function-
alities led to a conclusion that CCC must be unreactive in the
desired Norrish-Yang photocyclization. On the contrary,
examination of the more populated conformer TB-1 revealed
that H-5 is antiperiplanar with the π-bond of C-8 carbonyl, but
syn-periplanar with the C-11 keto group (Figure 12). Thus,
Scheme 2. Oxidation of Δ8,9 of α,β-Unsaturated Ketone 11
Figure 12. Mechanistic considerations for the formation of cyclo-
butanol 15.
treated with our modified ruthenium conditions, α,β-unsatu-
rated ketone 11 underwent competing cleavage of the Δ8,9
double bond to give the desired triketone 17 and regioselective
allylic oxidation at C-11 to furnish enedione 13, which was
further oxidized in the course of the reaction to yield
tetraketone 14 as a minor reaction product. It is noteworthy
that the dominating formation of aldol adduct 18 proved to be
unavoidable during column chromatography of the crude
reaction mixture on silica.
Conformational analysis of triketone 17 revealed that, despite
the fact that the keto group at C-8 is in γ-position to H-5, the
C-8 carbonyl is anti-periplanar with the C-5−H bond (Figure
13). This observation led to a conclusion that, analogously with
favorable spatial position of H-5 and the C-11 carbonyl allowed
for the prediction of regiospecific formation of the 1(C-5),4(C-
11)-hydroxy biradical, which would be structurally biased to
cyclize into cis-cyclobutanol 15 via pathway a. In addition, the
distance between H-5 and the oxygen of the C-8 carbonyl of
TB-1 was determined to be 2.27 Å, increasing the likelihood of
the desired reaction. Concomitantly, disfavorable spatial
arrangement of H-5 and C8O should exclude the formation
of cyclobutanol 16 via pathway b (Table 3).
Table 3. Norrish-Yang Reactivity of Tetraketone 14
Figure 13. Mechanistic considerations for the formation of product
20.
entry λmax (nm) time (h) yield of 15 (%) conversion of 14 (%)
the CCC conformer of tetraketone 14, a prediction can be
made that triketone 17 must be unreactive in the desired
Norrish-Yang photocyclization and cyclobutanol 19 cannot be
formed. However, the possibility of transannular photo-
pinacolization remains plausible for triketone 17. By direct
comparison with triketone 5, the excitation of the carbonyl at
C-7 can be followed by the formation of oxygen-centered
biradical. On the basis of the argument of closer spatial
proximity, ε-hydrogen H-30 may then be abstracted by the
oxygen of the C-9 carbonyl (Figure 13, d2 = 2.42 Å), followed
by the formation of a furan ring with the oxygen of C-7
carbonyl.
As a result, irradiation of the solution of triketone 17 in dry
deoxygenated C6D6 in a quartz cuvette with 254 nm UV light
for 24 h led to the exclusive formation of furan 20 in 18%
isolated yield (41% conversion, Table 4, entry 1), and no other
products of the reaction were observed. The change of the λmax
alone did not enhance the efficiency of the reaction; however,
1
2
3
4
254
20
12
6
48
100
100
60
300
27
a
b
254
72
a
300
3
66
100
a
Reaction was carried out in the presence of 1.0 equiv of
b
benzophenone. Yield of 15 is based on the recovered 14.
In complete agreement with this rationale, irradiation of the
solution of tetraketone 14 in dry deoxygenated C6D6 in a
quartz cuvette with 254 nm UV light led to the formation of the
sole product 15 in 48% yield after complete consumption of the
starting material in 20 h. The change of the light source to a
300 nm UV lamp led to a shorter reaction time; however,
cyclobutanol 15 was isolated in only 27% yield. The addition of
1.0 equiv of benzophenone significantly improved the efficiency
of the reaction, affording the highest yield of cyclobutanol 15
(66%, Table 3, entry 4). The structure of 15 was elucidated
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Table 4. Photoreactivity of Triketone 17
EXPERIMENTAL SECTION
■
(2R,4aS,6aS,9aS,11S,13aS,16aS,16bR)-Methyl-11-acetoxy-
2,4a,6a,10,10,13a,16a-heptamethyl-7,8,14,15-tetraoxodocosa-
hydrobenzo[6,7]cyclodeca[1,2-a]naphthalene-2-carboxylate
(1). Tetraketone 1 was prepared from bryonolic acid in four steps by a
previously published method18 (74 mg, 14% overall yield). Identity of
1 was confirmed by 1H and 13C NMR. Purity of 1 was determined by
1H NMR, TLC, and mp. Physical and spectroscopic data were found
to match literature18 data.
General Procedure for Photolyses of Polyketones 1, 5, 14,
and 17. A solution of a specified polyketone (20 mg) in dry C6D6 (0.6
mL) in a 4 mL rectangular quartz cuvette (0.1 cm × 0.1 cm × 0.4 cm)
was deoxygenated by purging with dry argon gas for 15 min while
stirring. When specified, benzophenone (1.0 equiv) was added to the
reaction mixture. A cuvette was then sealed with a Teflon stopper and
placed in the middle of a chamber photoreactor (10 cm distance from
the light source), equipped with six UV lamps (8 W each, specified
λmax) and a cooling fan. Solutions were irradiated at rt for a specified
amount of time, until specified polyketone was consumed or
decomposition was observed, as determined by either TLC or 1H
NMR. After removal of the solvent in vacuo, photoproducts 3, 4, 7, 15,
and 20 were isolated by column chromatography on silica with
specified ethyl acetate−hexanes mixtures.
Preparation of 3 and 4. Table 1 (entry 1). Following the general
procedure for photolyses, the use of tetraketone 1 (0.035 mmol) and
254 nm UV light for 45 min gave 3 (7 mg, 33%) and 4 (2 mg, 10%).
Table 1 (entry 2). Following the general procedure for photolyses,
the use of tetraketone 1 (0.035 mmol) and 300 nm UV light for 90
min gave 3 (12.5 mg, 63%) and 4 (2.6 mg, 13%).
entry λmax (nm) time (h) yield of 20 (% brsm) conversion of 17 (%)
1
2
3
4
254
24
24
24
24
44
19
31
39
41
69
82
55
300
a
300
a
254
a
Reaction was carried out in the presence of 1.0 equiv of
benzophenone.
the use of 1.0 equiv of benzophenone with 300 nm UV light
yielded photoproduct 20 in 25% isolated yield (82%
conversion, Table 4, entry 3). The structure of furan 20 was
confirmed after extensive 2D NMR study and by HRMS data
(see Supporting Information).
Table 1 (entry 3). Following the general procedure for photolyses,
the use of tetraketone 1 (0.035 mmol) and 350 nm UV light for 135
min gave 3 (6 mg, 30%) and 4 (1 mg, 5%).
Table 1 (entry 4). Following the general procedure for photolyses,
the use of tetraketone 1 (0.035 mmol), benzophenone (6.4 mg, 0.035
mmol), and 300 nm UV light for 45 min gave 3 (11.2 mg, 56%) and 4
(0.1 mg, <1%).
CONCLUSION
■
Here we have devised and successfully executed a DOS
strategy, whereby the substrates for divergent Norrish-Yang
photocyclization were prepared from parent triterpenoids,
bryonolic acid and lanosterol, by sequential allylic oxidation
and oxidative cleavage reactions. Irradiation of bryonolic acid-
derived tetraketone 1 brought a new 6/6/6-fused structural
type 4 to the resultant chemical library of triterpenoid
analogues by virtue of an unanticipated photopinacolization.
The unexpected structure 4 was accompanied by the expected
formation of 6/4/8-fused product of Yang cyclization 3 via
pathway a. The use of bryonolic acid-derived triketone 5 to
force Yang cyclization into pathway b led to predominant
pinacol-type coupling reaction to give 6/5/7-fused structure 7,
despite the desirable arrangement of the bowsprit H-5 and the
keto group at C-8. The subtle differences between the parent
triterpenoids resulted in completely different conformational
preferences of the polyketones and, concomitantly, completely
different spatial orientations of the reactive functionalities.
Consequently, Norrish-Yang photocyclization of lanosterol-
derived polyketones 14 and 17 via pathway b was proven to be
unfeasible, but the pinacol-type coupling reaction of triketone
17 was proven to be predictable. Thus, under our irradiation
conditions, tetraketone 14 formed a single photocycloadduct
15 via pathway a, while triketone 17 yielded the anticipated
product of photopinacolization 20.
(2aS,5R,6aR,6bS,7aR,8aS,11S,12aR,15aS)-Methyl-11-ace-
toxy-7a-hydroxy-2a,5,6b,8a,12,12,15a-heptamethyl-8,14,15-
trioxoicosahydro-1H-benzo[1′,4′]cyclobuta[1′,2′:6,7]cyclo-
octa[1,2-a]naphthalene-5-carboxylate (3). Transparent oil. Rf =
0.37 (EA/hex = 3/7). 1H NMR (600 MHz, CDCl3, δ): 5.70 (dd, J1 =
J2 = 9 Hz, 1H), 3.60 (s, 3H), 3.40 (d, J = 12.6 Hz, 1H), 3.10 (br s,
1H), 2.75 (d, J = 12.6 Hz, 1H), 2.35 (d, J = 16.2 Hz, 1H), 2.25 (d, J =
18 Hz, 1H), 2.17 (ddd, J1 = J2 = 14.4 Hz, J3 = 4.2 Hz, 1H), 2.02 (s,
3H), 1.73 (d, J = 18 Hz, 1H), 1.35 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H),
1.16 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 1.02 (s, 3H), 0.95 (m, 1H).
13C NMR (150 MHz, CDCl3, δ): 218.9 (CO), 211.5 (CO), 210.0
(CO), 178.7 (CO), 170.4 (CO), 92.2 (COH), 72.4 (CH), 62.3 (C),
56.9 (C), 55.4 (C), 52.4 (CH3), 47.0 (CH), 43.8 (C), 42.4 (CH2),
41.2 (CH2), 40.7 (C), 40.6 (C), 35.4 (CH2), 33.4 (CH2), 32.8 (CH3),
32.7 (C), 31.22 (CH3), 31.20 (CH2), 29.8 (CH2), 29.1 (CH2), 24.5
(CH2), 23.2 (CH2), 22.4 (CH3), 21.8 (CH3), 21.6 (CH3), 21.3 (CH3),
19.0 (CH3), 17.2 (CH3). HRMS (ESI) m/z calcd for C33H48O8Na+
[M + Na]+ 595.3247, found 595.3236.
(2R,4aS,6aS,7aS,8aR,10S,12aS,13aR,14aS,14bR)-Methyl-10-
acetoxy-7a-hydroxy-2,4a,6a,9,9,12a,14a-heptamethyl-7,13-
dioxoicosahydro-8a,13a-epoxybenzo[a]tetracene-2-carboxy-
1
late (4). Transparent oil. Rf = 0.32 (EA/hex = 3/7). H NMR (600
MHz, CDCl3, δ): 4.81 (dd, J1 = 10.8 Hz, J2 = 4.8 Hz, 1H), 3.61 (s,
3H), 2.69 (d, J = 14.4 Hz, 1H), 2.36 (d, 15 Hz, 1H), 2.05 (s, 3H), 1.31
(s, 3H), 1.29 (s, 3H), 1.19 (s, 3H), 1.07 (s, 3H), 1.00 (s, 3H), 0.92 (s,
3H), 0.77 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 212.6 (CO),
212.4 (CO), 178.6 (CO), 170.6 (CO), 90.6 (C), 90.3 (C), 77.3 (C),
76.5 (CH), 52.7 (C), 51.6 (CH3), 48.7 (C), 44.3 (CH), 40.4 (C), 40.4
(C), 39.8 (CH2), 38.5 (C), 35.4 (CH2), 33.9 (CH2), 32.5 (CH3), 31.5
(CH3), 31.3 (C), 31.1 (CH2), 30.7 (CH2), 29.91 (CH2), 29.87 (CH2),
24.2 (CH2), 23.1 (CH2), 22.3 (CH3), 21.4 (CH3), 20.8 (CH3), 19.4
(CH3), 18.5 (CH3), 17.7 (CH3). HRMS (ESI) m/z calcd for
C33H48O8Na+ [M + Na]+ 595.32414, found 595.32423.
We would argue that these findings constitute a general
approach, whereby the identification of substrate-dictated
conformational preferences of similar substrates will allow for
a reliable prediction of the outcome of Norrish-Yang type II
photocyclization, as well as the feasibility of transannular
photoinduced pinacol-type coupling reaction. Moreover, we
hope that this study will inspire the development of the
divergent strategies for the synthesis of polycyclic compounds
from other natural product families to screen against different
biological targets.
G
dx.doi.org/10.1021/jo400275p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(2R,4aS,6aS,9aS,11S,13aS,16aS,16bR)-Methyl-11-acetoxy-
2,4a,6a,10,10,13a,16a-heptamethyl-7,8,14-trioxodocosa-
hydrobenzo[6,7]cyclodeca[1,2-a]naphthalene-2-carboxylate
(5). Triketone 5 was prepared from bryonolic acid in three steps by a
previously published method18 (184 mg, 23% overall yield). Identity of
The reaction mixture was stirred at 50 °C overnight, after which time
pyridine was removed at reduced pressure and the crude mixture was
taken up in DCM. The organic layer was washed successively with
dilute HCl, saturated solution of sodium bicarbonate, and brine. It was
subsequently dried over Na2SO4 and the solvent removed in vacuo.
The crude product was purified by column chromatography to give 9
(60% in the mixture with 24,25-dihydrolanosterol acetate) as a white
solid (9.7 g, 88%). Rf = 0.55 (EA/hex = 10/90). Identity and purity of
9 were confirmed by 1H and 13C NMR. Spectroscopic data were found
to match literature55 data.
1
5 was confirmed by H and 13C NMR and HRMS. Purity of 5 was
1
determined by H NMR, TLC, and mp. Physical and spectroscopic
data were found to match literature18 data.
Preparation of 7. Table 2 (entry 1). Following the general
procedure for photolyses, the use of triketone 5 (0.036 mmol) and 254
nm UV light for 72 h yielded an inseparable mixture (10 mg) of 7 (1.4
Preparation of 10−13. Using a modified literature protocol,51
lanosterol acetate 9 (10 g, 60% in the mixture with 24,25-
dihydrolanosterol acetate, 12.8 mmol) was dissolved in 1 L of tert-
BuOH at 60 °C, followed by the addition of K2CO3 (10g, 72.4 mmol).
Meanwhile, a solution of KMnO4 (1.42 g, 9 mmol) and NaIO4 (24.1 g,
0.113 mol) in 800 mL of H2O was heated to 60 °C and subsequently
added to the resulting suspension in one portion. The flask was
removed from heat, and the reaction mixture was allowed to cool to rt
and stirred at rt overnight, at which time the reaction was interrupted
by the addition of saturated solution of sodium thiosulfate until
complete discoloration was observed (about 250 mL). After the
organic layer was separated and the solvent removed in vacuo, the
crude residue was acidified with dilute HCl and extracted with DCM.
The organic layer was washed successively with water and brine. It was
subsequently dried over Na2SO4 and the solvent removed in vacuo.
The crude mixture of products was separated by gradient elution
column chromatography on silica with ethyl acetate−hexanes mixtures.
The use of hexanes as an eluting solvent yielded pure 24,25-
dihydrolanosterol acetate as a white solid (3.36 g, 84%). Rf = 0.75
(EA/hex = 20/80). Mp: 118−120 °C (lit.56 mp 120−121 °C). Elution
with progressively more polar combinations of eluting solvent,
followed by the use of ethyl acetate as an eluting solvent, gave a
crude mixture (6.5 g) of carboxylic acids. In a round-bottom flask open
to atmosphere, the mixture of carboxylic acids (6.5 g) was dissolved in
50 mL of freshly distilled THF. Freshly prepared diazomethane in
diethyl ether (15 mmol) was added dropwise to the resulting solution
by a pipet, and the reaction mixture was stirred at rt until full
conversion was detected by TLC (approximately 30 min). The
reaction was quenched by dropwise addition of glacial acetic acid until
the yellow color of the solution disappeared. The solvent was removed
in vacuo, and the crude mixture of products was separated by careful
column chromatography on silica to yield 10 as a white solid (3.9 g,
65%), 11 as a white solid (610 mg, 9%), 12 as a white solid (420 mg,
7%), and 13 as a yellow solid (270 mg, 4%).
1
mg, 12% brsm, determined by H NMR) and unreacted 5 (8.6 mg,
1
57% conversion, determined by H NMR). Rf = 0.4 (EA/hex = 3/7).
Table 2 (entry 2). Following the general procedure for photolyses,
the use of triketone 5 (0.036 mmol) and 300 nm UV light for 72 h
yielded an inseparable mixture (8.3 mg) of 7 (2.1 mg, 15% brsm,
1
determined by H NMR) and unreacted 5 (6.2 mg, 69% conversion,
1
determined by H NMR). Rf = 0.4 (EA/hex = 3/7).
Table 2 (entry 3). Following the general procedure for photolyses,
the use of triketone 5 (0.036 mmol) and 350 nm UV light for 72 h
yielded unreacted 5 (20 mg, 0% conversion). Rf = 0.4 (EA/hex = 3/7).
Table 2 (entry 4). Following the general procedure for photolyses,
the use of triketone 5 (0.036 mmol), benzophenone (6.5 mg, 0.036
mmol), and 300 nm UV light for 72 h yielded 7 (7.8 mg, 39%). Rf =
0.4 (EA/hex = 3/7).
Table 2 (entry 5). Following the general procedure for photolyses,
the use of triketone 5 (0.036 mmol), benzophenone (6.5 mg, 0.036
mmol), and 254 nm UV light for 72 h yielded an inseparable mixture
1
(8.2 mg) of 7 (2.5 mg, 18% brsm, determined by H NMR) and
1
unreacted 5 (5.7 mg, 72% conversion, determined by H NMR). Rf =
0.4 (EA/hex = 3/7).
(2R,4aS,6aS,8aS,9aS,11S,13aS,13bR,15aS,15bR)-Methyl-11-
acetoxy-13b-hydroxy-2,4a,10,10,13a,15a-hexamethyl-16-
oxoicosahydro-6a,8a-methanoindeno[2,1-b]naphtho[1,2-f ]-
oxocine-2-carboxylate (7). Analytically pure 7 was obtained by the
following procedure. A round-bottom flask open to atmosphere was
charged with basic alumina (365 mg, 3.58 mmol), followed by the
addition of DCM (0.5 mL). A mixture (20 mg), containing 5 (17.2
mg, 0.031 mmol) and 7 (2.8 mg, 5 μmol) as determined by 1H NMR,
was dissolved in DCM (0.5 mL) and subsequently added to the
resulting suspension. The flask was sealed with a glass stopper and
vigorously stirred at rt overnight, at which time the suspension was
filtered over a fine sinter funnel and washed successively with ethyl
acetate. After removal of the solvent in vacuo, the column
chromatography on silica yielded 7 as a transparent oil (2 mg, 71%
1
recovery). Rf = 0.38 (EA/hex = 25/75). H NMR (600 MHz, CDCl3,
(R)-Methyl-4-((3S,5R,10S,13R,14R,17R)-3-acetoxy-
4,4,10,13,14-pentamethyl-2,3,4,5,6,7,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-
pentanoate (10). Mp: 174−177 °C (lit.51 mp 226−227 °C, lit.57 mp
174−176 °C). Rf = 0.58 (EA/hex = 20/80). Identity and purity of 10
were confirmed by 1H and 13C NMR, HRMS, and TLC. Spectroscopic
δ): 4.51 (dd, J1 = 11.4 Hz, J2 = 4.2 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H),
4.04 (d, J = 9.6 Hz, 1H), 3.64 (s, 3H), 3.07 (br s, 1H), 2.05 (s, 3H),
1.19 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H),
0.85 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 212.9 (CO), 179.3
(CO), 171.1 (CO), 87.3 (C), 80.5 (CH), 78.9 (C), 72.6 (CH2), 53.9
(C), 52.0 (CH3), 48.3 (CH), 47.4 (C), 46.7 (CH), 40.7 (C), 39.7 (C),
37.3 (C), 36.8 (CH2), 34.0 (CH2), 33.5 (CH2), 32.2 (CH2), 31.8 (C),
31.3 (CH3), 30.96 (CH2), 30.90 (CH3), 29.3 (CH2), 29.2 (CH2), 29.1
(CH3), 29.0 (CH2), 25.6 (CH2), 25.3 (CH2), 21.4 (CH3), 17.5 (CH3),
17.2 (CH3), 16.6 (CH3). HRMS (ESI) m/z calcd for C33H50O7Na+
[M + Na]+ 581.34488, found 581.34503. The starting material 5
reacted with basic alumina to give the corresponding product of aldol
addition. This product of aldol addition retained on silica during
column chromatography due to the presence of the hydroxyl group
and was not isolated. The synthesis, purification, and structural analysis
of the product of aldol addition of 5 were previously studied by our
group.18
(3S,5R,10S,13R,14R,17R)-4,4,10,13,14-Pentamethyl-17-((R)-
6-methylhept-5-en-2-yl)-2,3,4,5,6,7,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate
(9). In a round-bottom flask, lanosterol 8 (10g, 23.4 mmol; 60% in
the mixture with 24,25-dihydrolanosterol, purchased from various
commercial sources) and DMAP (143 mg, 1.17 mmol) were dissolved
in 47 mL of dry pyridine. Acetic anhydride (7.18 g, 70.3 mmol, 6.6
mL) was added to the resulting solution by a quick syringe transfer.
data did not duplicate literature51 data. H NMR (400 MHz, CDCl3,
1
δ): 4.50 (dd, J1 = 11.6 Hz, J2 = 4.4 Hz, 1H), 3.66 (s, 3H), 2.37 (m,
1H), 2.22 (m, 1H), 2.05 (s, 3H), 1.00 (s, 3H), 0.89 (d, J = 6 Hz, 3H),
0.88 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H), 0.68 (s, 3H). 13C NMR (150
MHz, CDCl3, δ): 174.9, 171.1, 134.6, 134.4, 81.1, 51.6, 50.6, 50.4,
50.0, 44.7, 38.0, 37.0, 36.2, 35.4, 31.41, 31.39, 31.1, 30.9, 28.2, 28.1,
26.5, 24.4, 24.3, 21.5, 21.1, 19.3, 18.4, 18.3, 16.7, 15.9. HRMS (ESI)
m/z calcd for C30H48O4Na+ [M + Na]+ 495.34448, found 495.34456.
(R)-Methyl-4-((3S,5R,10S,13R,14R,17R)-3-acetoxy-
4,4,10,13,14-pentamethyl-7-oxo-2,3,4,5,6,7,10,11,12,-
13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoate (11). Mp: 200−203 °C (lit.51 mp
255−258 °C). Rf = 0.28 (EA/hex = 20/80). Rf = 0.39 (EA/hex = 25/
1
75). Identity of 11 was confirmed by H and 13C NMR and HRMS.
Purity of 11 was determined by 1H NMR and TLC. 1H NMR data did
not duplicate literature51 data. 13C NMR data were not reported in
1
chemical literature. H NMR (600 MHz, CDCl3, δ): 4.52 (dd, J1 =
11.6 Hz, J2 = 4.4 Hz, 1H), 3.66 (s, 3H), 2.06 (s, 3H), 1.18 (s, 3H),
0.95 (s, 3H), 0.91 (m, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.65 (s, 3H).
13C NMR (150 MHz, CDCl3, δ): 198.8 (CO), 174.8 (CO), 171.0
H
dx.doi.org/10.1021/jo400275p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(CO), 164.7 (C), 139.1 (C), 79.7 (CH), 51.6 (CH3), 50.0 (CH), 48.9
(CH), 47.9 (C), 45.1 (C), 39.8 (C), 37.9 (C), 36.6 (CH2), 36.1 (CH),
34.6 (CH2), 32.1 (CH2), 31.4 (CH2), 31.4 (CH2), 30.2 (CH2), 28.8
(CH2), 27.5 (CH3), 25.1 (CH3), 24.0 (CH2), 23.8 (CH2), 21.4 (CH3),
18.6 (CH3), 18.5 (CH3), 16.5 (CH3), 15.9 (CH3). HRMS (ESI) m/z
1.01 (s, 3H), 0.98 (s, 3H), 0.75 (s, 3H), 0.71 (d, J = 6.6 Hz, 3H), 0.64
(s, 3H). Minor conformer: 4.60 (dd, J1 = 11.4 Hz, J2 = 3.6 Hz, 1H),
3.48 (d, J = 13.8 Hz, 1H), 3.40 (s, 3H), 3.03 (dd, J1 = 15.6 Hz, J2 = 9.6
Hz, 1H), 1.65 (s, 3H), 1.42 (s, 3H), 1.30 (s, 3H), 0.87 (s, 3H), 0.77
(d, J = 6.6 Hz, 3H), 0.63 (s, 3H). 13C NMR (150 MHz, toluene-d8,
273.15 K, δ) major conformer: 208.7, 206.1, 205.1, 203.2, 173.7, 169.8,
79.6, 62.3, 55.1, 53.1, 51.5, 49.7, 48.2, 44.3, 38.9, 37.6, 36.3, 33.8, 31.7,
31.61, 31.59, 30.9, 28.6, 24.3, 23.9, 20.3, 20.2, 19.6, 17.9, 16.5. Minor
conformer: 207.3, 207.1, 202.6, 201.3, 173.3, 169.2, 78.7, 60.6, 52.3,
50.98, 50.0, 49.4, 46.9, 41.4, 38.7, 35.6, 35.2, 34.8, 34.5, 30.7, 27.3,
24.4, 22.7, 19.64, 18.9, 17.8, 17.0, 16.2. HRMS (ESI) m/z calcd for
C30H44O8Na+ [M + Na]+ 555.29284, found 555.29296.
Preparation of 15. Table 3 (entry 1). Following the general
procedure for photolyses, the use of tetraketone 14 (0.0375 mmol)
and 254 nm UV light for 20 h yielded 15 (9.6 mg, 48%).
Table 3 (entry 2). Following the general procedure for photolyses,
the use of tetraketone 14 (0.0375 mmol) and 300 nm UV light for 12
h yielded 15 (5.3 mg, 27%).
Table 3 (entry 3). Following the general procedure for photolyses,
the use of tetraketone 14 (0.0375 mmol), benzophenone (6.8 mg,
0.0375 mmol), and 254 nm UV light for 6 h yielded unreacted 14 (8.1
mg, 60% conversion) and 15 (8.6 mg, 72% brsm).
Table 3 (entry 4). Following the general procedure for photolyses,
the use of tetraketone 14 (0.0375 mmol), benzophenone (6.8 mg,
0.0375 mmol), and 300 nm UV light for 3 h yielded 15 (13.1 mg,
66%).
(R)-Methyl-4-((1aS,4S,5aR,8aR,11R,11aR,12aR)-4-acetoxy-
12a-hydroxy-1a,5,5,8a,11a-pentamethyl-1,7,8-trioxo-
hexadecahydrobenzo[1,4]cyclobuta[1,2-a]cyclopenta[d][8]-
annulen-11-yl)pentanoate (15). Transparent oil. Rf = 0.25 (EA/
hex = 25/75). 1H NMR (400 MHz, CDCl3, δ): 5.65 (m, 1H), 3.69 (s,
3H), 2.90 (d, J = 13.9 Hz, 1H), 2.83 (br s, 1H), 2.60 (d, J = 13.9 Hz,
1H), 2.07 (s, 3H), 1.37 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 1.16 (s,
3H), 1.10 (d, J = 6.7 Hz, 3H), 0.93 (s, 3H). 13C NMR (150 MHz,
CDCl3, δ): 213.3 (CO), 210.0 (CO), 209.5 (CO), 174.3 (CO), 171.3
(CO), 94.9 (C), 78.7 (CH), 63.4 (C), 59.5 (C), 56.2 (C), 53.9 (CH),
51.8 (CH3), 47.8 (C), 43.1 (CH2), 40.9 (CH2), 40.0 (C), 35.6 (CH2),
34.2 (CH), 31.9 (CH2), 30.9 (CH2), 29.3 (CH2), 23.0 (CH2), 22.7
(CH2), 21.6 (CH3), 21.4 (CH3), 20.5 (CH3), 20.3 (CH3), 19.8 (CH3),
19.5 (CH3), 17.7 (CH3). HRMS (ESI) m/z calcd for C30H44O8Na+
[M + Na]+ 555.2934, found 555.2933.
+
calcd for C30H47O5 [M + H]+ 487.34180, found 487.34188.
(R)-Methyl-4-((3S,5R,10S,13R,14R,17R)-3-acetoxy-
4,4,10,13,14-pentamethyl-11-oxo-2,3,4,5,6,7,10,11,12,-
13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]-
phenanthren-17-yl)pentanoate (12). Mp: 144−147 °C (lit.57 mp
145−149 °C). Rf = 0.33 (EA/hex = 20/80). Rf = 0.42 (EA/hex = 25/
1
75). Identity of 12 was confirmed by H and 13C NMR and HRMS.
Purity of 12 was determined by 1H NMR, TLC, and mp.
Spectroscopic data for 12 were not previously reported. 1H NMR
(600 MHz, CDCl3, δ): 4.49 (dd, J1 = 10.2 Hz, J2 = 6 Hz, 1H), 3.65 (s,
3H), 2.99 (ddd, J1 = 13.8 Hz, J2 = J3 = 3.6 Hz, 1H), 2.64 (d, J = 16.2
Hz, 1H), 2.44 (d, J = 16.2 Hz, 1H), 2.03 (s, 3H), 1.13 (s, 3H), 1.10 (s,
3H), 0.88 (s, 3H), 0.88 (s, 3H), 0.85 (d, J = 6.6 Hz, 3H), 0.80 (s, 3H).
13C NMR (150 MHz, CDCl3, δ): 199.1 (CO), 174.6 (CO), 171.1
(CO), 164.2 (C), 139.5 (C), 80.7 (CH), 52.0 (CH), 51.9 (CH2), 51.7
(CH3), 51.6 (C), 50.1 (CH), 47.4 (C), 38.0 (C), 37.6 (C), 35.8 (CH),
34.1 (CH2), 31.2 (CH2), 31.0 (CH2), 31.0 (CH2), 29.9 (CH2), 28.4
(CH3), 27.0 (CH2), 25.9 (CH3), 24.3 (CH2), 21.4 (CH3), 19.1 (CH3),
18.1 (CH3), 17.3 (CH2), 16.9 (CH3), 16.8 (CH3). HRMS (ESI) m/z
+
calcd for C30H47O5 [M + H]+ 487.3423, found 487.3426.
(R)-Methyl-4-((3S,5R,10S,13R,14R,17R)-3-acetoxy-
4 , 4 , 1 0 , 1 3 , 1 4 - p e n t a m e t h y l - 7 , 1 1 - d i o x o -
2,3,4,5,6,7,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo-
penta[a]phenanthren-17-yl)pentanoate (13). A 100 mL round-
bottom flask open to atmosphere was charged with KMnO4 (2.67 g,
16.92 mmol) and 18-crown-6 (4.47 g, 16.92 mmol), followed by the
addition of 33.9 mL of water. A solution of 10 (1.6 g, 3.385 mmol) in
33.9 mL of DCM was then added to the resulting suspension by a
quick syringe transfer. The flask was sealed with a glass stopper, and
the reaction mixture was vigorously stirred at rt for 24 h, at which time
the mixture was filtered over a fine sinter funnel and washed with
DCM. Layers were separated, and the aqueous layer was extracted with
DCM. The organic layer was dried over Na2SO4 and the solvent
removed in vacuo. The crude product was purified by column
chromatography on silica to give 13 as a yellow solid (1.32 g, 78%).
Mp: 142−145 °C (lit.51 mp 178−179 °C, lit.58 mp 141−143 °C). Rf =
0.25 (EA/hex = 20/80). Rf = 0.37 (EA/hex = 25/75). Identity of 13
1
was confirmed by H and 13C NMR and HRMS. Purity of 13 was
Preparation of 17 and 18. In a 100 mL single-neck round-
bottom flask, RuCl3 (30 mg, 0.144 mmol) was added in one portion to
a solution of NaIO4 (646 mg, 3.02 mmol) in 22 mL of H2O, and the
resulting suspension was stirred open to atmosphere for 15 min,
followed by the addition of 14.5 mL of acetonitrile. The solution of 11
(350 mg, 0.719 mmol) in 14.5 mL of CCl4 was then added dropwise
to the reaction mixture by a syringe pump. The flask was sealed with a
glass stopper, and the resulting biphasic mixture was vigorously stirred
for 6 h, at which time 3 mL of ethanol was added to the solution. The
layers were separated, and the aqueous layer was extracted with DCM.
The organic layer was dried over Na2SO4, concentrated under vacuum,
and the crude mixture of products was further separated by column
chromatography on silica to yield tetraketone 14 as a yellow solid (24
mg, 6%), Rf = 0.39 (EA/hex = 25/75), triketone 17 as a yellow oil
(103 mg, 28%), and aldol adduct 18 as a white solid (238 mg, 64%).
(R)-Methyl 4-((1R,3aR,6aS,8S,10aS,13aR)-8-acetoxy-
3a,7,7,10a,13a-pentamethyl-4,5,11-trioxohexadecahydro-1H-
benzo[a]cyclopenta[f ][10]annulen-1-yl)pentanoate (17). Rf =
0.26 (EA/hex = 25/75). 1H NMR (400 MHz, CDCl3, δ): 4.66 (dd, J1
= 11.6 Hz, J2 = 4.4 Hz, 1H), 3.67 (s, 3H), 2.81 (dd, J1 = 16.4 Hz, J2 =
7.6 Hz, 1H), 2.06 (s, 3H), 1.37 (s, 3H), 1.30 (s, 3H), 0.98 (s, 3H),
0.96 (d, J = 6.8 Hz, 3H), 0.90 (s, 3H), 0.79 (s, 3H). 13C NMR (150
MHz, CDCl3, δ): 214.0, 209.2, 203.2, 174.4, 170.7, 79.4, 59.0, 53.4,
53.1, 52.2, 51.7, 50.4, 39.2, 36.2, 35.5, 34.3, 33.8, 33.2, 31.7, 30.8, 28.0,
26.1, 25.1, 23.4, 21.3, 20.3, 19.4, 17.7, 17.3, 16.8. HRMS (ESI) m/z
1
determined by H NMR, TLC, and mp. 13C NMR data was found to
51,58
match literature51 data. H NMR data did not duplicate literature
1
data. 1H NMR (400 MHz, CDCl3, δ): 4.51 (dd, J1 = 11.2 Hz, J2 = 5.2
Hz, 1H), 3.65 (s, 3H), 2.88 (ddd, J1 = 13.6 Hz, J2 = J3 = 3.6 Hz, 1H),
2.75 (d, J = 16 Hz, 1H), 2.58 (d, J = 16 Hz, 1H), 2.04 (s, 3H), 1.31 (s,
3H), 1.15 (s, 3H), 0.94 (s, 3H), 0.88 (s, 3H), 0.87 (d, J = 5.2 Hz, 3H),
0.78 (s, 3H). HRMS (ESI) m/z calcd for C30H45O6 [M + H]+
+
501.32107, found 501.32111.
(R)-Methyl-4-((1R,3aR,6aS,8S,10aS,13aR)-8-acetoxy-
3a,7,7,10a,13a-pentamethyl-4,5,11,12-tetraoxohexadeca-
hydro-1H-benzo[a]cyclopenta[f ][10]annulen-1-yl)pentanoate
(14). Using modified literature protocol,54 RuCl3 (62 mg, 0.299
mmol) was added in one portion to the solution of NaIO4 (539 mg,
2.52 mmol) in 18 mL of water, and the resulting suspension was
stirred open to atmosphere for 15 min, followed by the addition of 12
mL of acetonitrile. The solution of 13 (300 mg, 0.599 mmol) in 12 mL
of CCl4 was then added to the reaction mixture by a quick syringe
transfer. The flask was sealed with a glass stopper, and the resulting
biphasic mixture was vigorously stirred at rt for 15 h, at which time the
reaction was interrupted by the addition of 5 mL of ethanol. The layers
were separated, and the aqueous layer was extracted with DCM. The
organic layer was dried over Na2SO4 and the solvent removed in
vacuo. The crude product was purified by column chromatography on
silica to give 14 as a yellow solid (278 mg, 87%). Mp: 140−143 °C. Rf
= 0.39 (EA/hex = 25/75). 1H NMR (600 MHz, toluene-d8, 273.15 K,
δ) major conformer: 4.82 (dd, J1 = 11.4 Hz, J2 = 4.2 Hz, 1H), 3.54 (d, J
= 13.2 Hz, 1H), 3.42 (s, 3H), 3.21 (dd, J1 = J2 = 3.6 Hz, 1H), 2.69
(ddd, J1 = J2 = 12.6 Hz, J3 = 6.6 Hz, 1H), 1.67 (s, 3H), 1.34 (s, 3H),
+
calcd for C30H47O7 [M + H]+ 519.33163, found 519.33173.
(R)-Methyl-4-((1R,3aR,4aR,5aS,7S,9aS,10aR,11aR)-7-acetoxy-
4a-hydroxy-3a,6,6,9a,11a-pentamethyl-4,10-dioxohexadeca-
hydro-1H-cyclopenta[b]anthracen-1-yl)pentanoate (18). Mp:
I
dx.doi.org/10.1021/jo400275p | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
260−264 °C. Rf = 0.15 (EA/hex = 25/75). H NMR (600 MHz,
CDCl3, δ): 4.48 (dd, J1 = 11.4 Hz, J2 = 4.6 Hz, 1H), 3.65 (s, 3H), 3.10
(dd, J1 = 12.4 Hz, J2 = 2.6 Hz, 1H), 2.13 (d, J = 13.3 Hz, 1H), 2.04 (s,
3H), 1.28 (s, 3H), 1.12 (s, 3H), 0.99 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H),
0.88 (s, 3H), 0.68 (s, 3H). 13C NMR (150 MHz, CDCl3, δ): 211.8
(CO), 211.6 (CO), 174.6 (CO), 171.0 (CO), 80.0 (CH), 79.2 (C),
59.3 (C), 51.7 (CH3), 50.2 (CH), 49.5 (CH), 47.9 (C), 47.3 (C), 45.5
(CH), 38.5 (C), 35.3 (CH), 31.2 (CH2), 31.1 (CH2), 30.7 (CH2),
29.3 (CH2), 28.9 (CH2), 28.4 (CH2), 28.1 (CH3), 26.9 (CH2), 23.6
(CH2), 22.8 (CH3), 21.3 (CH3), 19.5 (CH3), 18.7 (CH3), 18.6 (CH3),
17.3 (CH3). HRMS (ESI) m/z calcd for C30H46O7Na+ [M + Na]+
541.31357, found 541.31373.
Reuter Foundation, and Landon Foundation INNOVATOR
award from AACR to G.P.T.
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4.7 Hz, 1H), 4.26 (d, J = 9.3 Hz, 1H), 3.80 (d, J = 9.3 Hz, 1H), 3.66 (s,
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AUTHOR INFORMATION
Corresponding Author
*E-mail: tochtrop@case.edu.
Notes
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ACKNOWLEDGMENTS
This work was supported by grants from the National Cancer
Institute CA157735 and CA132168, NSF Grant MCB-084480,
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K
dx.doi.org/10.1021/jo400275p | J. Org. Chem. XXXX, XXX, XXX−XXX