Syntheses of (+)-30-epi-, (-)-6-epi-, (±)-6,30-epi-13,14-Didehydroxyisogarcinol and (±)-6,30-epi-Garcimultiflorone A Utilizing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations

Article abstract of DOI:10.1021/jacs.6b09727

The first syntheses of 13,14-didehydroxyisogarcinol (6) and garcimultiflorone A (5) stereoisomers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastereoselective cationic oxycyclizations enabled asymmetric syntheses of (-)-6-epi-6 and (+)-30-epi-6. A similar strategy enabled production of the meso-dervied isomers (±)-6,30-epi-6 and (±)-6,30-epi-5. Finally, a convenient strategy for gram scale synthesis was developed utilizing diastereomer separation at a later stage in the synthesis that minimized the number of necessary synthetic operations to access all possible stereoisomers.

Full text of DOI:10.1021/jacs.6b09727

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Article
Syntheses of (+)-30-epi-, (-)-6-epi-, (+/-)-6,30-epi-13,14-
Didehydroxyisogarcinol and (+/-)-6,30-epi¬-Garcimultiflorone A
Utilizing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations
Jonathan H. Boyce, Vincent Eschenbrenner-Lux, and John A. Porco
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 16 Oct 2016
Downloaded from http://pubs.acs.org on October 16, 2016
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Journal of the American Chemical Society
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Syntheses
of
(+)-30-epi-,
(-)-6-epi-,
(+/-)-6,30-epi-13,14-
Didehydroxyisogarcinol and (+/-)-6,30-epi-Garcimultiflorone A Utiliz-
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ing Highly Diastereoselective, Lewis Acid-Controlled Cyclizations
Jonathan H. Boyce, Vincent Eschenbrenner-Lux, and John A. Porco, Jr.*
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth
Ave, Boston MA 02215
Supporting Information Placeholder
ABSTRACT: The first syntheses of 13,14-didehydroxyisogarcinol (6) and garcimultiflorone A (5) stereoiso-
mers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastere-
oselective cationic oxycyclizations enabled asymmetric syntheses of (-)-6-epi-6 and (+)-30-epi-6. A similar
strategy enabled production of the meso-dervied isomers (+/-)-6,30-epi-6 and (+/-)-6,30-epi-5. Finally, a
convenient strategy for gram scale synthesis was developed by enabling diastereomer separation at a later
stage in the synthesis which minimized the number of necessary synthetic operations to access all possible
stereoisomers.
1. INTRODUCTION
this class. Although studies have reported the im-
portance of 13,14-hydroxyls with regard to
For the past 15 years, the synthetic and biological
isogarcinol’s histone acetyltransferase (HAT) inhibi-
tion and radical-scavenging abilities,2a,6,8c,8d,11e bio-
communities have been interested in polyprenylat-
ed polycyclic acylphloroglucinols (PPAPs) as natu-
ral product targets and starting points for SAR stud-
ies due to their diverse bioactivity profiles (Figure
1A). Not surprisingly, with minor structural differ-
ences leading to significant variation in bioactivity,
PPAP natural products and their analogs are con-
sidered high priority targets for isolation, chemical
synthesis, and biological studies.1,2 The natural
products isogarcinol (1) and garcinol (2) have
gained significant attention in recent years and are
lead compounds for several clinical indications.3,4
The importance of synthesizing diverse analogs of
both garcinol and isogarcinol to probe their biologi-
cal activities was recently emphasized.5,6
logical data on analogs that lack the hydroxyl func-
tionalities (e.g. 5 and 6) are limited.7 Given that we
were able to procure natural products 5 and 6 from
the isolation team led by Chen and co-workers,7
our goal was to develop a strategy for accessing
non-natural diastereomers of 5 and/or 6 for further
biological studies (Figure 1B).
We were intrigued by the marked similarity of
13,14-didehydroxyisogarcinol (6) to isogarcinol (1),
a compound which has activity in numerous thera-
peutic indications including leukemia,8a,i colon can-
cer,8b,i HIV,8c,d brain tumors (medulloblastoma),8e
antioxidant,8f antimicrobial,8f transplantation rejec-
tion and autoimmune diseases,8g,h,l collagen-
induced and rheumatoid arthritis,8j breast cancer,8k
Isogarcinol’s
dehydroxy
isomer
13,14-
and Parkinson’s disease.8m
Interestingly,
didehydroxyisogarcinol (6) and the type A variant
garcimultiflorone A (5) were isolated in 2009 from
the fruits of Garcinia multiflora in South China and
were reported to possess anti-inflammatory activity
by inhibiting superoxide and elastase enzymes re-
leased from human neutrophils (Figure 1A).7 Apart
from this single report, however, no additional in-
formation on the biological activities of natural
products 5 and 6 exist further emphasizing the
need for an efficient and scalable synthetic route to
isogarcinol (1) is also available for human con-
sumption in mangosteen drinks and capsules as a
remedy for arthritis.9 Only one total synthesis of 1
has been reported since its isolation in 1980, an
elegant strategy accomplished in 15-steps by
Pleitker and coworkers.10,11a The compound has
been isolated from numerous sources,11 and a
large scale extraction procedure was developed for
its procurement.11g
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13,14-
Figure
1.
Representative
PPAP
Natural
Products
and
Diastereomers
of
1
2
Didehydroxyisogarcinol and Garcimultiflorone A Obtained in This Work.
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5
6
7
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11
12
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Stereoisomers of 5 and 6 have not yet been iso-
lated in nature which further emphasizes the need
for a synthetic platform to access such candidates
(Figure 1B),8i,23 especially given the diverse bioac-
tivities of isogarcinol’s closely related congeners,
specifically garcinol (2),11a cycloxanthochymol,12b,d
30-epi-cambogin A (3),12a,c,f,h and 7-epi-isogarcinol
(4).12b,d,e,g Herein, we describe asymmetric synthe-
ses of (+)-30-epi-6 and (-)-6-epi-6 in six steps from
commercially available phloroglucinol 12 utilizing a
Lewis acid-dependent diastereoselective oxycy-
clization (Figure 2). Using a similar strategy, we
also demonstrate the syntheses of meso-derived
isomers (+/-)-6,30-epi-6 and (+/-)-6,30-epi-5 (c.f.
Scheme 2B). Finally, a convenient strategy for
large scale synthesis of these enantiopure and ra-
cemic stereoisomers is demonstrated.
Figure 2. Retrosynthetic Analysis of (-)-6-epi-6
and (+)-30-epi-6.
Retrosynthetic analysis of enantiopure isomers
(-)-6-epi-6 and (+)-30-epi-6 from commercially
available phloroglucinol 12 is shown in Figure 2.
Isomers (-)-6-epi-6 and (+)-30-epi-6 may be de-
rived from cross metathesis and cationic cyclization
of precursors (-)-7 and (+)-21, respectively. Vinylic
allylation of the unsubstituted precursors (-)-8 and
(+)-13 should enable access to respective pyra-
nodienones (-)-7 and (+)-21. We envisioned that
diastereoselective, cationic oxycyclization mediated
through Lewis-acid chelation of (+)-(S,S)-9A may
furnish (-)-8 and/or (+)-13 in reasonable diastere-
oselectivity.
Regioselective bis-alkylation of
acylphloroglucinol 10 using the triflate derived from
alcohol (-)-(R)-11 may provide dearomatized ad-
duct (+)-(S,S)-9A.13
Finally, our laboratory has
previously shown that compound 10 is conveniently
2
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commercially available Figure 3. Symmetry of Meso Isomers 9B and 9C
derived
from
the
1
2
monomethylphloroglucinol 12 via Friedel-Crafts
Represented by 3D Models.
acylation.13
3
4
5
2. RESULTS AND DISCUSSION
6
7
8
9
At the outset of our investigation, racemic alco-
hol (+/-)-11 was prepared in the same manner pre-
viously described by our group in a single step from
commercially available starting materials.13 Pleas-
ingly, triflation of (+/-)-11 was followed by regiose-
lective bis-alkylation of acylphloroglucinol 10 in the
presence of LiHMDS providing the dearomatized
enols (+/-)-9A, (meso)-9B, and (meso)-9C in 53 %
yield (Scheme 1). The (R) and (S) alkyl substitu-
ents of (meso)-9B and (meso)-9C create a mirror
plane of symmetry in each structure rendering
them achiral/meso (Figure 3). Alternatively, com-
pound (+)-(S,S)-9A could be produced as a single,
enantiopure diastereomer via bis-alkylation of
acylphloroglucinol 10 utilizing the enantioenriched
triflate derived from alcohol (-)-(R)-11 (Scheme 1).
A multigram scale synthesis of alcohol (-)-(R)-11
was achieved from a modified and
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improved 3-step protocol.14 Due to their tendency
to form calcium salts on silica gel,13 enol (+)-(S,S)-
9A and racemic variants (+/-)-9A, (meso)-9B, and
(meso)-9C were conveniently purified by potassium
salt formation without the need for column chroma-
tography.14 The structure of (meso)-9C was con-
firmed by X-ray crystal structure analysis.14
We next evaluated the possibility for diastere-
oselective oxycyclization of (+)-(S,S)-9A to provide
the enantiopure pyranodienones (-)-8 and (+)-13
(Table 1). The diastereoselectivity in this case
would result if the two 1,1-disubstituted alkenes of
(+)-(S,S)-9A are protonated at different rates.
A
Scheme 1. Regioselective bis-Alkylation of
number of acidic conditions were evaluated for cy-
clization including HCl in CH2Cl2 which provided (-)-
8 and (+)-13 in 1:1.1 d.r. (Table 1, entry 1). After
considerable experimentation, we discovered that
binary acid combinations15 of LiBr with either chiral
or achiral phosphoric acids provided high yields of
(-)-18 and (+)-13 in roughly 1:2 d.r. in favor of (+)-
13 (Table 1, entries 2 – 8). In the absence of LiBr,
the reaction did not proceed as the acidity of the
phosphoric acid was presumably enhanced
through lithium coordination (Table 1, entry 10).
Since both chiral (14 – 17) and achiral phosphoric
acids (18 – 19) provided similar outcomes with LiBr
(Table 1, entries 2-8), we anticipated that the ob-
served diastereoselectivity may be the result of
Lewis acid coordination to enol (+)-(S,S)-9A which
was supported by the fact that LiBr alone favored
(+)-13 in 1:1.6 d.r. (Table 1, entry 11).
Acylphloroglucinol
10:
Racemic
and
Enantioenriched Variants.
Since it is known that Lewis acid coordination to
Brønsted acid restricts the orientational flexibility of
the proton,16,17 metal coordination to the β-keto
enol functionality of (+)-(S,S)-9A may restrict the
orientation of its enol proton in addition to making it
more acidic and prone to react with the proximal
1,1-disubstituted olefin.16 Indeed, we discovered
that stronger Lewis acids (e.g. SbCl5 and SnCl4)
improved the overall diastereoselectivity. For ex-
ample, evaluation of the Lewis acid-assisted
Brønsted acid
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Table 1. Diastereoselective Oxycyclization and
Chelation Studies.
After screening an array of Lewis acids with var-
1
2
3
4
5
6
7
8
iations in size and coordination ability along with
different phosphoric acid promoters, optimized
conditions for diastereoselective cyclization to (-)-8
or (+)-13 were identified (Table 2). The combina-
tion of SnCl4 with the inexpensive, achiral diphe-
nylphosphoric acid 18 ($3.18/gram) required lower
reaction times and provided a cost-effective ap-
proach for the production of (-)-8 (47 %, 10:1 d.r.,
Table 2, entry 4). Interestingly, the opposite selec-
tivity for cyclization was highly favored only in the
case of BF3-OEt2 and p-TsOH which provided (+)-
13 in 42 % yield and 1:5 d.r. (Table 2, entry 6).
9
10
11
12
13
14
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17
18
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Brønsted
Acid
HCla
Lewis
Acid
d.r.
It has been reported that SnCl4 and BF3-OEt2
can bind in a bidentate fashion to β-keto enol sub-
strates resulting in the formation of hexacoordinate
Sn- and tetrahedral BF2-complexes.16a,20,21 We hy-
pothesized that the observed diastereoselectivity
may be governed by an intramolecular protonation
event following complex formation wherein the
proximal olefin approach is perpendicular to the
acidic enol proton.16a,17e As SnCl4 alone provided
(-)-8 in 7:1 d.r. and 36 % yield (Table 1, entry 12),
we simplified our transition state analysis by exam-
ining bidentate complexes without Brønsted acid
ligand (Figures 4A and B). Indeed, analysis of
transition states indicated that complex SnCl4-9A-
TS1 appears to favor cyclization to (-)-8 by an en-
ergy difference of 5.3
Entry
1
Conditions
Yield
25%b
(8:13)b
-10 °C to r.t.,
72h
1:1.1
none
19
LiBr
(10 equiv)
0 oC, 48 h
2
3
99%
79%
1:1.8
(10 equiv)
18
(5 equiv)
LiBr
(5 equiv)
1:1.8
1:2
r.t., 1.5 h
(R)-14
(10 equiv)
LiBr
(10 equiv)
4
5
6
91%
91%
89%
0 °C, 48 h
0 °C, 48 h
r.t., 48 h
(S)-14
(10 equiv)
LiBr
(10 equiv)
1:3
(R)-15
(5 equiv)
LiBr
(5 equiv)
1:2.2
(S)-15
(5 equiv)
LiBr
(5 equiv)
7
8
86%
99%
1:1.8
1:1.5
r.t., 48 h
(S)-16
(10 equiv)
LiBr
(10 equiv)
0 °C, 48 h
(S)-17
(1 equiv)
SbCl5
(1 equiv)
-78 oC, 2 h
9
18%
9:1
(S)-14
(5 equiv)
-5 to 10 °C,
48 h
10
11
0%
none
1:1.6
none
Table 2.
Optimized Lewis/Brønsted Acid
Combinations
Cyclization.
for
Diastereoselective
LiBr
(10 equiv)
none
none
19%
r.t., 5 d
SnCl4
(2 equiv)
-78 to -20 °C,
48 h
12
36%
7:1
13c
58%
1:1.1
(+/-)-14
(2 equiv)
SnCl4
(1 equiv)
-78 to 50 °C,
36 h
32%d
pTsOH
(10 equiv)
BF3OEt2
(79 equiv)
-78 to -5 °C,
1 h
14
1:2
(57%
brsm)
Brønsted
Lewis
Acid
d.r.
Entry
Acid
Conditions
Yield
68 %
(8:13)b
a CH2Cl2/4M HCl in dioxane (1:1). b Determined by 1H NMR analysis of
the crude reaction mixture. c SnCl4 saturated with (+/-)-14 prior to addition
of substrate (+)-(S,S)-9A. d 54 % starting material also recovered.
(S)-14
(2 equiv)
SnCl4
(2 equiv)
-78 to -30 °C,
6 d
1
14:1
(R)-14
(2 equiv)
SnCl4
(2 equiv)
-78 to -30 °C,
6 d
2
9 %
1:0
(LBA) system developed by Corey and cowork-
ers,19 SbCl5 with 2,2’- dichloro-(S)-BINOL (S)-17 in
CH2Cl2 at -78 oC, led to the production of (-)-8 in 18
% yield and 9:1 d.r. (Table 1, entry 9).
(+/-)-14
SnCl4
3a
52 %
14:1
-78 to -20 °C,
17 h
(2 equiv)
(2 equiv)
18
SnCl4
-78 to 0 °C,
19 h
4
47 %
99 %
10:1
The effect of chelation on diastereoselectivity
was also evaluated by saturating the open coordi-
nation sites on SnCl4 with (+/-)-14 to generate the
corresponding LBA and prevent substrate chela-
tion.14,18 In this case, reaction was not observed
until the temperature reached 50 oC providing clean
formation of products (-)-8 and (+)-13 in 58 % yield
and 1:1.1 d.r (Table 1, entry 13).
(2 equiv)
(2 equiv)
18
InCl3
(10 equiv)
5
5.4:1
r.t., 1 h
(10 equiv)
-15 to -5 °C,
2 h;
-40 to -5 °C,
2 h
BF3OEt
(79 equiv)
pTsOH
(10 equiv)
42 %
6
1:5
a Substrate (+/-)-9A was used. b Determined by 1H NMR analysis.
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Figure 4A. Relative Transition State Energies for Intramolecular Protonation of SnCl4-9A.
1
2
G298° kcal/mol
(gas phase)
3
4
5
6
B3LYP/LACV3P
Jaguar Version 9.2
7
8
9
10
11
12
13
14
15
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20
21
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SnCl4-9A-TS2
SnCl4-9A-TS1
+17.3
+12.0
0.00
-1.8
SnCl4-(+)-13 (minor)
SnCl4-9A
-6.3
SnCl4-(-)-8 (major)
Figure 4B. Relative Transition State Energies for Intramolecular Protonation of BF2-9A.
G298° kcal/mol
(gas phase)
B3LYP/LACV3P
Jaguar Version 9.2
BF -9A-TS1
2
BF -9A-TS2
+13.6
2
+9.8
0.00
-2.6
BF -9A
-5.4
2
BF -(+)-13 (major)
2
BF -(-)-8 (minor)
2
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Scheme 2. Asymmetric Syntheses of (-)-6-epi-6 and (+)-30-epi-6 and Racemic Syntheses of (+/-)-6,30-
epi-6 and (+/-)-6,30-epi-5.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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35
36
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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60
kcal/mol in comparison with transition state SnCl4-
9A-TS2 leading to (+)-13 (Figure 4A). This dis-
crimination may be explained in part by improved
stabilization of SnCl4-9A-TS1 via coordination of
two chlorine ligands to the acidic enol proton and
to the emerging carbocation.14,17a,24 In contrast,
complex BF2-9A-TS2 favors the formation of (+)-
13 by an energy difference of 3.8 kcal/mol relative
to BF2-9A-TS1 leading to (-)-8 which correlates
with our experimental results (Figure 4B). To the
best of our knowledge, this represents the first
example of a SnCl4- or BF3-OEt2-phosphoric acid
LBA system and the first Lewis acid-controlled
diastereoselective oxycyclization of dearomatized
acylphloroglucinols.
yield with use of LiBr and diphenyl phosphate
(Scheme 2B). Vinylic allylation of
pyranodienones (-)-8, (+)-13, 23, and 26
proceeded smoothly utilizing lithium 2-
thienylcyanocuprate to provide the cyclization
precursors (-)-7, (+)-21, 24, and 27 respectively in
good yields (Schemes 2A and 2B).22
In our efforts to cyclize compound (-)-7 to the
PPAP core (-)-20, we observed undesired
conversion to product 25 in dry TFA. However,
we discovered that isomerization could be
completely avoided in the presence of water
allowing for efficient cyclization to cycloadduct (-)-
20 with 1:1 H2O/TFA (Scheme 2A). Compound
o
24 seamlessly cyclized at 60 C after 1.5 h in dry
With optimized methods for accessing either (-
)-8 or (+)-13 from (+)-(S,S)-9A (Scheme 2A),
oxycyclization of meso-9B and meso-9C was also
achieved in short reaction times and reasonable
TFA to its respective [3.3.1]-bicyclic core 25 in
good yield (Scheme 2B).
The relative
stereochemical assignments of compound 25
were determined by detailed NOE studies and
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impeded by undesired steric interactions in the
were later confirmed by X-ray crystal structure
analysis (Scheme 3B).14
transition state analogous to those noted in
Figure 5. Surprisingly, we discovered that 1:1 H-
2O/TFA induced unexpected cyclization at C2 of
compound 27 cleanly furnishing type A PPAP core
28 in 79 % yield (Scheme 2B). As one possibility,
the cyclization of 27 may proceed through a
cationic rearrangement wherein acid-induced
pyran opening leads to cyclization at C2 and a
1
2
3
4
5
6
7
8
The cyclization of compound (+)-21 to (+)-22
proved more challenging which may be due to
unfavorable steric interactions shown in transition
state 29 (Figure 5). The axially-oriented allyl
group at C6 likely experiences destabilizing
interactions with the proximal benzoyl or
cyclohexadienone
functionalities
disfavoring
9
formal
1,3-shift25
followed
by
an
cyclization to product (+)-22.13 In contrast, the C6
allyl group in transition state 30 is equatorially
oriented and avoids steric influences that would
deter cyclization to desired stereoisomer 25.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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60
oxycyclization/demethylation
sequence.
Pleasingly, olefin metathesis proceeded efficiently
for all stereoisomers providing type B PPAPs (-)-
6-epi-6, (+)-30-epi-6, (+/-)-6,30-epi-6, and type A
PPAP (+/-)-6,30-epi-5 in excellent yields
(Schemes 2A and 2B).
Figure 5. Comparison of Transition State
Models for Cyclization to (+)-22 and 25.
Finally, a convenient strategy for large scale
production of all stereoisomers was developed by
enabling diastereomer separation at a later stage
in the synthesis which minimized the number of
necessary synthetic operations (Scheme 3).
A
scalable strategy for the synthesis of enantiopure
bicyclo[3.3.1]nonanes (-)-20 and (+)-22 is
demonstrated in Scheme 3A.
Gram scale
oxycyclization of enol (+)-(S,S)-9A with LiBr and
diphenyl phosphate 18 provided (-)-8 and (+)-13
in 79 % yield (1:1.8 d.r. as determined by 1H NMR
analysis). Furthermore, phosphoric acid 18 could
be recovered after work-up.14 Vinylic allylation
served as the most convenient stage for
diastereomer
separation
where
column
chromatography was sufficient to provide ample
quantities of products (+)-21 and (-)-7 for
subsequent cyclization.
After considerable experimentation, we
discovered that the formation of the C-cyclization
adduct (+)-22 could only be achieved in the
presence of water, where 1 % H2O/TFA provided
an optimized yield of 14 % (Scheme 2A) along
with 69 % of byproduct (+)-31 (cf. Scheme 3A).
The relative stereochemical assignment of
compound 22 was determined by X-ray crystal
structure analysis (Scheme 3A).14 Formation of
the undesired O-cyclization product (+)-31 may
result from hydrolysis of methyl enol ether (+)-21
in H2O/TFA as further increasing the water
content provided higher yields of byproduct (+)-
31. It is also notable that compound (+)-21 did
not cyclize in dry TFA even after stirring for 24 h at
room temperature. Furthermore, in the presence
of 1:1 H2O/TFA, exclusive formation of (+)-31 was
observed.
A convenient strategy for gram scale synthesis
of racemic stereoisomers 20, 22, 25, and 28 is
shown in Scheme 3B. In comparison, their
synthesis would require a total of 13 steps (4
steps for each isomer) by the strategy presented
in Schemes 1 and 2. Hence, our modified gram
scale sequence in Scheme 3B accomplishes the
same goal in 9 fewer steps providing a superior
alternative for the synthesis of (+/-)-6-epi-6, (+/-)-
30-epi-6, (+/-)-6,30-epi-6, and (+/-)-6-epi-5. To
produce modest yields of each diastereomer in
the final cyclization step of Scheme 3B, it was
necessary to use 10 % H2O/TFA as 1 % H2O/TFA
would improve the yield of stereoisomer 22 but
minimize formation of 28 (Scheme 3B).
Moreover, substantially raising the water content
employing 1:1 H2O/TFA as solvent would prevent
synthesis of product 22 and maximize formation
Pyranodienone 27, shown in Scheme 2B,
proved unsuitable for cyclization to its
corresponding type B PPAP core which was likely
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Scheme 3. Scalable Strategy for Production of (-)-20 and (+)-22 and Gram Scale Synthesis of
Racemic Stereoisomers 20, 22, 25, and 28 in a Single Synthetic Sequence.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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of the type A PPAP core 28. This gram scale
strategy demonstrated that all stereoisomers 20,
22, 25, and 28 could be achieved in only 4
synthetic operations from acylphloroglucinol 10 in
a timeframe of 72 h (Scheme 3B).14 It should be
noted that compounds 20 and 25 were isolated as
a mixture by column chromatography and could
be further separated for characterization and bio-
logical evaluation by preparative TLC.14
stereomer of garcimultiflorone A (5) were synthe-
sized for the first time by an efficient six step
strategy from the commercially available
phloroglucinol 12 using regioselective bis-
alkylation, Lewis acid-controlled oxycyclization,
and cationic C-cyclization as key steps. Type B
stereoisomers (-)-6-epi-6, (+)-30-epi-6, and (+/-)-
6,30-epi-6 were obtained in up to 22 %, 2 %, and
16 % respective overall yields from acylphloroglu-
cinol 10. Notably, our synthesis also provided the
type A PPAP (+/-)-6,30-epi-garcimultiflorone A
((+/-)-6,30-epi-5) in 8.4 % overall yield from 10.
Moreover, diastereoselective oxycyclization of (+)-
(S,S)-9A utilized novel SnCl4 and BF3-OEt2 LBA
systems to induce stereoselective, intramolecular
3. CONCLUSION
In conclusion, all non-natural diastereomers of
13,14-didehydroxyisogarcinol (6) and one dia-
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Journal of the American Chemical Society
(3) (a) Majeed, M. US 2008/0207952 A1. 2008. (b) Taito, N.;
protonation resulting in selective formation of ei-
Atsushi, I. WO 2011/158806 A1. 2011. (c) Nishino, T.;
Wang, C.; Mochizuki-Kashio, M.; Osawa, M.; Nakauchi,
H.; Iwama, A. PLoS ONE. 2011, 6, e24298. (d) Majeed,
M. US 2012/0178801 A1. 2012.
1
2
3
4
5
6
7
8
ther pyranodienone (-)-8 or (+)-13. Finally, a
gram scale strategy was developed to allow for
production of ample quantities of each isomer in a
single synthetic sequence which minimized step
count and purification events. Notably, a synthesis
of bicyclo[3.3.1]nonanes (-)-20 and (+)-22 was
achieved without the need for preparative TLC
and the production of stereoisomers 20, 22, 25,
and 28 could be accomplished in only 4 synthetic
operations from acylphloroglucinol 10. Further
studies on the chemistry and biology of garcimulti-
florone A (5), 13,14-didehydroxyisogarcinol (6),
and their stereoisomers are in progress and will
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
characterization data for all new compounds described
herein, including CIF files for compounds (meso)-9C, (+)-
22, and 25. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
John A. Porco, Jr. (porco@bu.edu)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the National Institutes of Health (R01 GM-
073855 and R35 GM118173), and the Deutsche For-
schungsgemeinschaft (postdoctoral fellowship to V. E.-L.)
for research support, Dr. Jeffrey Bacon (Boston Universi-
ty) for X-ray crystal structure analyses, and Dr. Norman
Lee (Boston University) for high-resolution mass spec-
trometry data. Work at the BU-CMD was supported by the
National Institutes of Health (NIH) (R24GM111625). We
thank Lin-Yang Cheng and Professor Dr. Jih-Jung Chen
for providing natural product samples of 5 and 6. We also
thank Mr. Xiaowei Wu, Drs. Adam Scharf and Paul Ralifo
(Boston University) and Dr. Neil Lajkiewicz (Incyte Phar-
maceuticals) for helpful discussions.
(9) Xie, Z.; Sintara, M.; Chang, T.; Ou, B. Food Sci. Nutr.
2015, 3, 342.
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