Divergent Total Syntheses of Rhodomyrtosones A and B

Article abstract of DOI:10.1021/acs.joc.5b01570

Herein, we report total syntheses of the tetramethyldihydroxanthene natural product rhodomyrtosone B and the related bis-furan β-triketone natural product rhodomyrtosone A. Nickel-(II)-catalyzed 1,4-conjugate addition of an α-alkylidene-β-dicarbonyl subst

Full text of DOI:10.1021/acs.joc.5b01570

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Article
Divergent Total Syntheses of Rhodomyrtosones A and B
Anais Gervais, Kiel E. Lazarski, and John A. Porco
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01570 • Publication Date (Web): 09 Sep 2015
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Divergent Total Syntheses of Rhodomyrtosones A and B
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Anais Gervais, Kiel E. Lazarski, and John A. Porco, Jr.*
Department of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590
Commonwealth Avenue, Boston, MA, 02215, USA.
*
E-mail: porco@bu.edu
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Abstract: Herein, we report total syntheses of the tetramethyldihydroxanthene natural product
rhodomyrtosone B and the related bis-furan β-triketone natural product rhodomyrtosone A. Nickel-
(
II)-catalyzed 1,4-conjugate addition of an α-alkylidene-β-dicarbonyl substrate was developed to
access the congener rhodomyrtosone B and oxygenation of the same monoalkylidene derivative
followed by cyclization was employed to obtain the bis-furan natural product rhodomyrtosone A.
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INTRODUCTION
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Rhodomyrtone A (1) and its isomer rhodomyrtosone
B (2) are derived from the plant Rhodomyrtus Tomentosa
Figure 1. Rhodomyrtone A and Related Natural Products
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4
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1
,2
found in Thailand (Figure 1). These natural products
present interesting synthetic challenges due to the
presence of a highly oxygenated β-triketone moiety fused
to an acylphloroglucinol which is present in both isomers.
In rhodomyrtone A (1), the ether linkage is para to the
acyl group, while in rhodomyrtosone B (2) it is ortho.
Rhodomyrtosone A (3) was also isolated from the
Rhodomyrtus genus and possesses an intriguing bis-furan
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2, 3
acylphloroglucinol core. Recently, the related natural
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5
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product watsonianone B (4) was isolated from the plant
4
Corymbia watsonia. Rhodomyrtone A 1 and rhodomyrtosone B (2) were found to be potent antibiotics against gram
positive bacteria including Staphylococcus Aureus, methicillin-resistant Staphylococcus Aureus (MRSA), and several
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Streptococcus strains (MIC = 4 and 16 µg/mL, respectively). Watsonianone B (4) possesses anti-malarial properties by
inhibiting the growth of chloroquine sensitive (3D7) and resistant (Dd2) strains of Plasmodium falciparum displaying IC50
4
values of 0.44 and 0.29 μM, respectively. Accordingly, these interesting structures and highly relevant biological activities
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make rhodomyrtosones A (3) and B (2) appealing synthetic targets. The Maier laboratory recently achieved syntheses of
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1
7
compounds 1 and 2 adopting a similar strategy developed by Jauch and coworkers for the synthesis of myrtucommulone A.
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In this paper, we report a strategy involving nickel (II)-catalyzed 1,4-conjugate addition to an α-alkylidene-β-dicarbonyl
substrate to selectively access rhodomyrtosone B (2) and oxygenation of the same monoalkylidene derivative to obtain the
bis-furan congener rhodomyrtosone A (3).
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Figure 2. Retrosynthetic Analyses for Rhodomyrtone A and Rhodomyrtosone A
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RESULTS AND DISCUSSION
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In our retrosynthetic analysis, we envisioned that rhodomyrtone A (1), rhodomyrtosone B (2), and rhodomyrtosone (3)
could be synthesized from a common starting material in a divergent manner (Figure 2). Selective dehydrative cyclizations
of intermediate 5 could be used to access both rhodomyrtone A (1) and rhodomyrtosone B (2). Intermediate 5 may arise from
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8
conjugate addition of the known acylphloroglucinol 7 to monoalkylidene 6. In accordance with the proposed biosynthesis
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2
for rhodomyrtosone A, natural product 3 may be obtained from acylphloroglucinol 7 and endoperoxide 8 after bis-furan
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formation. Endoperoxide 8 may arise from [4+2] cycloaddition of oxygen with a dienol intermediate that may be obtained
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via photoenolization of monoalkylidene 6 (Figure 2).
Our synthetic efforts began with the synthesis of monoalkylidene reaction partner 6 (Scheme 1). Treatment of syncarpic
Scheme 1. Synthesis of a Monoalkylidene Reaction Partner
1
1
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17
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19
6
o
acid 10, isovaleraldehyde, and pyrrolidine (diethyl ether, 0 C) afforded the Mannich product 9 (90 %). Acid-mediated
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2
elimination of 9 cleanly afforded monoalkylidene 6 (75% yield). We next examined a range of catalysts for 1,4-conjugate
2
2
1
0
addition of acylphloroglucinol 7 to enone 6. A reaction conducted without catalyst provided a 9 % yield of the Michael
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25
adduct 5 along with a significant amount of the endoperoxide byproduct 8 (stereochemistry unassigned) (Table 1, entry 1).
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The latter compound may be derived from [4+2] cycloaddition between the dienol tautomer of 6 and triplet oxygen (Table 1,
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11,12,13
entry 1) (vide infra).
In the presence of YbCl or FeCl , a moderate amount of 5 was isolated, albeit in low selectivity
3 3
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3
3
(
Table 1, entries 2 and 3). Rare-earth metal triflate catalysts were also investigated; however, these reactions resulted in low
1
0a
yields and selectivity (Table 1, entries 4-6). We also investigated metal perchlorate salts, which have previously been used
1
4
3
in 1,4-conjugate additions. Cu(ClO ) , Mg(ClO ) , and Zn(ClO ) did not result in significant amounts of adduct 5 (Table
4 2 4 2 4 2
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3
1, entries 7-9). Additionally, it was found that Pd (II) catalysis was not effective for this transformation (Table 1, entry 10).
Ni(ClO ) proved to be an effective catalyst, affording a 4.6:1 ratio of compounds 5:8 in 74 % isolated yield (Table 1, entry
4 2
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1
1
1). Using a 5:1 mixture of CH Cl and acetic acid as solvent led to an increased yield of the desired adduct 5 (Table 1, entry
2 2
2). Moreover, thorough degassing of solvent eliminated the production of endoperoxide 8 (Table 1, entry 13) and provided
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4
adduct 5 in 90 % yield. A control screen using the same catalysts as listed in Table 1 with degassed CH Cl was also
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conducted. Although degassing the solvent alleviated the formation of 8, the isolated yields remained low (Table 1, entries 2,
-8) except when Ni(ClO ) 6H O was employed as catalyst. Based on the results highlighted in Table 1, Ni(ClO ) 6H O
6
4
2
2
4 2
2
1
5
4
was identified as a promising catalyst for conjugate addition.
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Table 1. Evaluation of the Conjugate Addition under Lewis Acidic Conditions
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1
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15
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17
1
1
20
2
2
2
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2
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3
[
a]
[c]
[b]
Entry
1
Lewis-acid
no catalyst
5:8
5 (%)
1:2.7
1.15:1
1.3:1
1:3.3
1:2.4
1:1.7
1:4.3
N/A
9
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3
4
5
6
7
8
9
YbCl
FeCl
3
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17
6
3
Yb(OTf)
Gd(OTf)
3
3
Lu(OTf)
Cu(ClO
Mg(ClO
Zn(ClO
PdCl (PhCN)
3
)
4 2
)
2
0
4
)
2
N/A
0
4
1
0
2
2
N/A
19
1
1
1
2
Ni(ClO
Ni(ClO
mol%)
4
4
)
)
2
•6H
.•6H
2
O
4.6:1
2.8:1
74
80
O (7
2
2
3
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CH Cl :AcOH (6:1)
2
2
[
d]
1
3
Ni(ClO
4
)
2
.•6H
2
O (7
1:0
90
mol%) CH Cl :AcOH
2
2
(6:1)
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4
[
a]
[b]
Reactions conducted with monoalkylidene 6 (1 equiv) and acylphloroglucinol 7 (1.5 equiv) in 1 mL of CH Cl . Yields
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2
[
c]
reported after isolation by silica gel column chromatography. Compound 8 was the only byproduct observed after complete
consumption of starting materials. Ratio was determined after isolating both products. Solvents were thoroughly degassed
using the freeze-pump-thaw method.
[
d]
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4
1
Upon characterization by H NMR analysis in CDCl , we observed that the adduct 5 existed as a mixture of two
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atropisomers in a 2.4:1 ratio at room temperature. The tight hydrogen bond network existing within the structure may hinder
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6
free rotation generating two rotational conformers in equilibrium at room temperature (Figure 3). Variable temperature
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NMR studies were performed to determine the coalescence temperature for 5 which was found to be 60 °C which
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17
corresponds to a rotational barrier of 15 kcal/mol. A single X-ray crystal structure analysis of compound 5 was obtained
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which further highlights the strong internal hydrogen bond network between the acylphloroglucinol and vinylogous acid
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segments (Figure 3).
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We anticipated that adduct 5 could be
utilized to achieve dehydrative
cyclizations to afford natural products 1
and (vida supra). Under acidic
Figure 3. X-Ray Crystal Structure of Adduct 5
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conditions, we observed exclusive
formation of rhodomyrtosone B 2 via
dehydrative cyclization of the phenol
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19
6
ortho to the acyl group (Scheme 2). After
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Scheme 2. Dehydrative Cyclization of 5 to Rhodomyrtosone B (2)
considerable optimization, it was found
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24
that treatment of
stabilizing
5 in the carbocation-
protic
solvent
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2
1
8
hexafluoroisopropanol (HFIP)
with added
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o
trifluoroacetic acid (60 C, 12 h) afforded
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rhodomyrtosone B (2) in 42 % yield (Scheme
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3
). Our proposed mechanism for selective dehydrative cyclization leading to rhodomyrtosone B (2) is shown in Scheme 3.
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Protonation of vinylogous acid 5 leads to the vinyl oxocarbenium intermediate 11 which may exist in equilibrium with its
atropisomer 12. We believe that hydrogen bonding between the ortho-phenol and the ketone within the acyl substituent
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9
renders the ortho-phenol more nucleophilic by increasing the electron density of the phenolic oxygen. Cyclization of 12 to
hemiacetal 13 followed by dehydration affords rhodomyrtosone B (2). Hemiacetal 13 is likely a relevant intermediate in the
proposed mechanism as this structural motif exists in closely related natural products including myrtucommulone D (14)
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2
0,21
(Scheme 4).
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Scheme 3. Model for Selective Formation of 2
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In line with recent literature describing asymmetric annulations between quinone methides and cyclic 1,3-
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22,23
dicarbonyls,
we also explored an alternative three-component coupling approach toward the synthesis of rhodomyrtosone
B (2) (Scheme 4). We found that treatment of a mixture of acylphloroglucinol 7, dimethyl acetal 15, and syncarpic acid 10
with 20 mol% of scandium(III) triflate and camphorsulfonic acid (CSA) in refluxing isopropanol generated the natural
product 2 in a single step. While the reaction still proceeds if only a Lewis acid or a Brønsted acid was used, a modest
increase in yield was observed by using both in a cooperative manner. A plausible reaction mechanism is proposed in
Scheme 5. Acylphloroglucinol 7 first condenses with dimethyl acetal 15 derived from isovaleraldehyde to generate the
benzyl methyl ether 16. In the presence of acid and heat, the methyl ether may be extruded to produce quinone methides 17 /
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1
8. We believe quinone methide 18, likely activated by complexation with Sc(OTf) is a more relevant tautomeric form as its
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increased conjugation affords greater stability relative to 17. Quinone methide 18 then engages with vinylogous ester 19
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24
(
derived from the condensation of syncarpic acid 10 and isopropanol) thereby forming the tricyclic acetal 20 which
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5
subsequently loses isopropanol to afford 2. It is possible that the annulations proceeds via cycloaddition; however, literature
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6,27
reports on quinone methide annulations also propose stepwise mechanisms.
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Scheme 4. Quinone Methide Annulation Strategy towards 2
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19
Scheme 5. Proposed Mechanism for Formation of 2 via Quinone Methides 17/18
20
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Alternatively, we considered that syncarpic acid (10) may be acting as the relevant nucleophile and may condense with
the oxocarbenium to form monoalkylidene 6, similar to our previous approach (cf. Table 1). Using the reaction conditions
shown in Scheme 4, we tested this possibility by running two control experiments: one without the acylphloroglucinol 7 and
one without syncarpic acid (10) (Scheme 6). We found that in the absence of 7, syncarpic acid (10) was quickly converted to
vinylogous ester 19, but minimal condensation was observed. On the other hand, in the absence of syncarpic acid (10),
acylphloroglucinol 7 completely reacted with dimethyl acetal 15 to form the quinone methide (cf. 17 in Scheme 5). The
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quinone methide was subsequently reduced in the presence of Lewis acid and isopropanol, cleanly affording the alkylated
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5
phenol 21 which could be isolated in excellent yield. The latter reaction conditions represent a promising and mild reductive
transformation for alkylation of electron-rich arenes. These control experiments strongly support a mechanism for the 3-
component coupling (cf. Scheme 4) in which quinone methide formation precedes the annulation step.
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Scheme 6. Control Experiments Probing the Mechanism of the Three-Component Coupling
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19
20
2
2
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24
After successfully synthesizing rhodomyrtosone B (2), we next turned our attention to the synthesis of rhodomyrtosone
A (3). Specifically, we wished to prepare endoperoxide 8 as the penultimate intermediate in the synthesis of 3 (Scheme 7).
2
6
2
This was achieved using flow photochemistry employing monoalkylidene 6 using oxygen-saturated methanol as solvent to
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2
2
7
provide a 50% yield of endoperoxide 8 as a mixture of diastereomers. The stereochemistry of endoperoxide 8 was not
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assigned due to its labile nature and as its configuration was inconsequential for the subsequent cyclization step.
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o
Endoperoxide 8 and acylphloroglucinol 7 were subsequently thermolyzed in acetic acid (100 C) which afforded the bis-
3
3
furan rhodomyrtosone
A
(3) in 60
%
yield.
A
proposed mechanism for the acid-mediated
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formation of 3 is shown in Scheme 8. Treatment of peroxy acetal 8 with acid promotes the formation of the endocyclic
3
37
3
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28
peroxycarbenium ion 24 via protonated intermediate 23. Interception of the putative peroxocarbenium intermediate 23 with
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acylphloroglucinol 7 may generate endoperoxide adduct 25. The peroxide may then undergo a Kornblum–DeLaMare -type
4
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4
opening to 1,4-diketone 26 which can further cyclize to bis-furan 3 under acidic conditions. It should be noted that the
reaction sequence may also formally be reversed in which endocyclic peroxide cleavage may occur prior to nucleophilic
addition of the acylphloroglucinol.
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Scheme 7. Synthesis of Rhodomyrtosone A (3) via Endoperoxide 8
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1
12
13
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15
16
17
18
19
20
2
2
23
24
Scheme 8. Proposed Mechanism for the Formation of Rhodomyrtosone A
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26
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31
3
3
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4
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CONCLUSION
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5
5
In summary, we have developed a Ni (II)-mediated 1,4-addition of acylphloroglucinols to a syncarpic acid-derived
alkylidene as a Michael acceptor to access the natural product rhodomyrtosone B after selective dehydrative cyclization. A
three-component coupling strategy using a quinone methide intermediate was also found to be effective. In addition,
oxygenation of a dienol derived from the same alkylidene scaffold permitted access to an endoperoxide intermediate which
was utilized in a short synthesis of the bis-furan natural product rhodomytosone A. Further studies on the synthesis and
biological properties of rhodomyrtone A and related molecules are currently in progress and will be reported in due course.
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EXPERIMENTAL SECTION
1
General Methods. H NMR spectra were recorded at either at 400 MHz or 500 MHz (as noted) at ambient temperature
1
3
with CDCl as the solvent unless otherwise stated. C NMR spectra were recorded either at 100.0 MHz or 125.0 MHz (as
3
1
noted) at ambient temperature with complete proton decoupling using CDCl as the solvent unless otherwise stated. Infrared
3
1
1
13
14
15
spectra were recorded on a FT-IR spectrophotometer. High-resolution mass spectra (HRMS) was carried out by electron
impact (EI) using a Q-TOF mass spectrometer. Melting points were recorded on a Mel-temp apparatus. Analytical thin layer
chromatography was performed using 0.25 mm silica gel 60-F plates. Preparative TLC was conducted with glass backed
16
17
18
1
000 μm silica gel 60-F plates. Flash chromatography was performed using 200-400 mesh silica gel. Photochemistry
19
20
2
2
23
24
25
26
experiments were performed using a Hanovia 450 W medium pressure mercury lamp housed in quartz immersion cooler
with a system circulator. Analytical LC-MS was performed on a UPLC (Ultra Performance Liquid Chromatography) with a
Binary solvent manager, SQ mass spectrometer, PhotoDiode Array detector, and ELSD (Evaporative Light Scattering
Detector). An Acquity UPLC BEH C18 1.7 μm column was used for analytical UPLC-MS. Yields refer to
chromatographically and spectroscopically pure materials, unless otherwise stated. All reactions were carried out in flame-
27
28
29
3
0
31,32
dried glassware under an argon atmosphere unless otherwise noted. Syncarpic acid (10) and acylphloroglucinol 7
were
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31
prepared using literature procedures.
3
3
34
5
-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(pyrrolidin-1-yl)butyl)cyclohex-4-ene-1,3-dione (9): To a flask was added
35
36
o
syncarpic acid 10, (500 mg, 3 mmol, 1 equiv) and anhydrous diethyl ether (45 mL). The resulting solution was cooled to 0 C
37
38
and pyrrolidine (275 L, 3.29 mmol, 1.2 equiv) was added dropwise followed by the addition of isovaleraldehyde (370 L,
3
40
o
3
.43 mmol, 1.25 equiv). The solution became slightly cloudy. The reaction was stirred at 0 C until a white precipitate was
41
42
formed (about 30 min). The white solid was filtered and washed with cold ether and dried in vacuo to yield 9 as a white
4
4
4
powder (800 mg, 90 %). R : 0.44 hexanes:EtOAc:MeOH (1:1:0.1) Mp: 165-168 °C (diethyl ether), IR (thin film): 2974.01,
f
-
1
1
1698.89, 1583.04, 1470.19, 1455.19, 1410.05, 1366.04, 1296.99, 1215.98 cm , H NMR (CDCl , 500 MHz): δ 4.43 (d,
3
46
4
J=9.9 Hz, 1 H); 3.66-3.51 (ddd, J=2.70, 5.98, 10.44, 1H); 3.07 – 2.88 (m, 1 H); 2.89 – 2.71 (m, 1H); 2.23 – 2.08 (m, 1H);
48
4
1
3
2.08 – 1.86 (m, 5H); 1.53 – 1.34 (m, 2H); 1.34 – 1.22 ( m,12 H); 0.96 – 0.87 (m, 4 H); 0.87 – 0.75 (m, 3H) C NMR
50
5
+
(
CDCl , 125.67 MHz): δ 216.9, 98.7, 69.4, 54.1, 48.9, 32., 25.3, 24.5, 22.6, 20.4, 17.5 ppm HRMS-ESI (m/z): [M+H]
3
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53
calculated for C H NO , 322.2382; found, 322.2384
1
9
32
3
5
5
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2
,2,4,4-Tetramethyl-6-(3-methylbutylidene)cyclohexane-1,3,5-trione (6): To a flask was added adduct 9 (200 mg, 0.62
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mmol) then methylene chloride was added (15 mL, 0.04 M). A 1M solution of hydrochloric acid in water was prepared and
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saturated with ammonium chloride. This solution was added to the reaction mixture. The mixture was vigorously stirred at
room temperature for 1h. The organic layer was washed with saturated brine (3 x) and the organic fractions were dried over
anhydrous sodium sulfate. Solvents were concentrated in vacuo to yield compound 6 (116 mg, 75 %) as a pale yellow oil. Rf
: 0.6 hexanes:EtOAc (3:1), IR (thin film): 2965.63, 1695.43, 1606.38, 1465.51, 1383.58,1296.07, 1215.98. 1132.50,
1
1
-
1 1
1
039.52 cm , H NMR (CDCl , 500 MHz): δ 7.52 (t, J = 7.6 Hz, 1H), 2.61 (t, J = 7.3 Hz, 2H), 1.89 (ddt, J = 13.5, 10.8, 6.8
3
12
13
1
3
Hz, 1H), 1.31 – 1.23 (m, 12 H); 0.97 (d, J = 6.7 Hz, 6H) C NMR (CDCl , 125.67 MHz): δ 208.9, 199.5, 196.4, 159.1,
3
1
15
16
17
+
1
2
33.1, 58.5, 57.9, 38.9, 35.6, 28.7, 22.5, 22.3, 21.9, HRMS-ESI (m/z): [M+H] calculated for C H O , 251.1647; found,
1
5
23
3
51.1647
18
19
20
5
-Hydroxy-2,2,6,6-tetramethyl-4-(3-methyl-1-(2,4,6-trihydroxy-3-(3-methylbutanoyl)phenyl)butyl)cyclohex-4-ene-1,3-
2
2
23
24
dione (5): The dichloromethane and acetic acid used in this reaction were degassed three times using the freeze-pump-thaw
method. To the acyl phloroglucinol 7 (25 mg, 0.12 mmol, 1.5 equiv) was added Ni(ClO ) .6H O (2.9 mg, 0.0080 mmol, 0.1
4
2
2
2
equiv) and methylene chloride (2 mL) at room temperature under argon followed by addition of 4Å MS (20 mg). Next, a
26
2
solution of monoalkylidene 6 (20 mg, 0.08 mmol. 1 equiv) in dichloromethane (1 mL) was added to the reaction mixture
28
29
o
followed by acetic acid (0.5 mL). The reaction was stirred at room temperature for 5 h and heated to 40 C for 12 h. The
30
31
o
reaction was quenched with water and a solution of 1M KHSO at 0 C until reaching a pH ≈ 2. The reaction mixture was
4
3
3
extracted with CH Cl and washed with saturated brine. Organic fractions were gathered and dried over anhydrous sodium
2
2
34
35
36
37
sulfate. Solvents were evaporated in vacuo yielding a yellow oil. Column chromatography purification on silica gel with a
gradient of CH Cl : MeOH (90:1 to 20:1) provided 29 mg (0.06 mmol) of compound 5 in 80% yield. Mp: 51-54 °C
2
2
38
39
4
(
hexanes, MeOH), IR (thin film): 2958.19, 2872.19, 1716.58, 1622.77, 1594.68, 1467.34, 1383.88, 1367.29, 1300.61,
-
1 1
1215.23, 1118.62, 754.18 cm , H NMR (CDCl , 500 MHz): δ 0.83 (q, J= 5 Hz, 6H), 0.97 (d, J= 5 Hz, 6H), 1.23 (s, 3H),
3
41
4
1.31 (d, J= 5 Hz, 3H), 1.36 (d, J=5 Hz, 3H), 1.42 (broad m, 1H), 1.47 (s, 3H), 1.75 (m, J= 10 Hz, 1H), 2.06 (m, J= 10 Hz,
4
4
1
H), 2.25 (m, J=10Hz, 1H), 2.95 (d, J= 5Hz, 2H), 4.34 (t, J= 10 Hz, 1H), 5.86 (s, 2/3H) and 5.92 (s, 1/3H), 10.28 (s, 2/3H)
45
46
1
3
and 10.55 (s, 1/3H); 11.15 (s, 1/3H) and 11.57 (s, 2/3H), C NMR (CDCl , 125.67 MHz): δ 22.5, 22.8, 23.1, 24.5, 25.5,
3
47
48
2
6.4, 27.1, 28.2, 29.6, 29.9, 38.4, 48.9, 52.4, 55.3, 98.2, 109.5, 114.9, 158.6, 176.8, 203.4, 206.4, 212.5, HRMS-ESI (m/z):
4
50
+
[
M+H] calculated for C H O , 461.2539; found, 461.2534.
2
6
37
7
51
52
53
5
5
56
57
Rhodomyrtosone B (2) from compound 5: To a solution of compound 5 (20 mg, 0.043 mmol, 1 equiv) in
hexafluoroisopropanol (0.2 mL) was added trifluoroacetic acid (0.05 mL, 14 equiv.) at room temperature. The reaction was
stirred at 60°C for 12h. Then, the reaction was diluted with water and saturated brine and the mixture was extracted with
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ethyl acetate (3 x 1 mL). The organic fractions were dried over anhydrous sodium sulfate and solvents were evaporated in
vacuo to yield a yellow solid. Purification using column chromatography on silica gel with a hexane:acetone gradient (12:1
to 4:1) provided 8 mg (0.018 mmol) of rhodomyrtosone B 2 (42% yield). R : 0.4 hexanes : acetone (3:1), Mp: 58-62 °C IR
f
(thin film): 3359.86, 2959.21, 2925.37, 2869.81, 1719.44, 1656.43, 1625.75, 1597.94, 1504.38, 1469.46, 1431.80, 1388.20,
1
1
12
13
1
15
16
17
-
1 1
1
4
3
2
2
368.12, 1255.28, 1161.24, 1121.96, 1041.55, 1015.89 cm , H NMR (CDCl , 500 MHz): δ 13.46 (s, OH), 6.26 (s, OH),
3
.30 (t, J = 6.1 Hz, 1H), 3.24 – 2.89 (m, 2H), 2.36 (dd, J = 13.2, 6.6 Hz, 1H), 1.64 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.39 (s,
13
H), 1.39 – 1.31 (m, 4H), 1.02 (dd, J = 14.3, 6.6 Hz, 6H), 0.87 (dd, J = 8.5, 6.4 Hz, 6H), C NMR (CDCl , 125.67 MHz): δ
3
11.7, 203.9, 198.3, 167.2, 164.2, 159.5, 153.1, 114.5, 105.9, 105.5, 100.2, 56.1, 53.4, 47.2, 46.9, 25.3, 25.0, 24.7, 24.7,
+
18
19
4.5, 24.4, 24.2, 23.4, 23.1, 22.9, 22.6, HRMS-ESI (m/z): [M+H] calculated for C H O 443.2434; found, 443.2427
2
6
35
6
20
2
2
23
24
25
26
27
28
29
30
31
3
3
34
35
Rhodomyrtosone B (2) (three-component reaction): Acylphloroglucinol 7 (25 mg, 0.119 mmol), dimethyl acetal 15 (16
mg, 0.119 mmol), and syncarpic acid 10 (22 mg, 0.119 mmol) were suspended in dry isopropanol (1 mL). Camphorsulfonic
acid (6 mg, 0.2 equiv.) was added followed by the addition of scandium (III) triflate (12 mg, 0.2 equiv.). The mixture was
heated to 80°C for 6 h and was then cooled to room temperature. The reaction was quenched with saturated sodium
bicarbonate solution (3 mL) and diluted with ethyl acetate (5 mL). The organic phase was removed and the aqueous phase
was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine and dried over sodium
sulfate before being concentrated under vacuum. The resulting crude oil was then purified by silica gel chromatography
eluting with 10% ethyl acetate in hexanes to provide compound 2 (23 mg, 42% yield).
36
37
38
5
-Isopropoxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione (19): Syncarpic acid 10 (22 mg, 0.119 mmol) and dimethyl
39
40
41
42
4
4
45
46
acetal 15 (16 mg, 0.119 mmol) were suspended in dry isopropanol (1 mL). Camphorsulfonic acid (6 mg, 0.2 equiv.) was
added followed by the addition of scandium (III) triflate (12 mg, 0.2 equiv.). The solution was then heated to 80°C for 12 h.
The reaction mixture was then cooled to room temperature and quenched with sodium bicarbonate solution (3 mL) and
diluted with ethyl acetate (5 mL). The organic phase was removed and the aqueous phase was extracted with ethyl acetate (3
x 5 mL). The combined organic layers were washed with brine and dried over sodium sulfate before being concentrated
under vacuum. The crude oil was purified by silica gel chromatography yielding compound 19 as a clear liquid (12 mg, 44%
47
48
49
50
51
-
1
yield). IR (thin film): 2980.8, 2928.6, 1714.6, 1653.8, 1604.1, 1471.0, 1378.2, 1236.1, 1178.4, 1106.4,1042.7, 926.3 cm ;
5
53
1
13
H NMR (CDCl , 500 MHz): δ 5.41(s, 1H), 4.47(sep, J = 6.1 Hz, 1H), 1.34-1.26 (m, 18H); C NMR (CDCl , 100 MHz):
3
3
5
5
+
δ 213.4, 199.3, 176.4, 99.6, 71.3, 55.0, 48.0, 24.9, 24.2, 21.1 ; HRMS-ESI (m/z): [M+H] calculated for C H O ; 225.1485
1
3
21
3
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found, 225.1483
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18
19
20
3
-Methyl-1-(2,4,6-trihydroxy-3-isopentylphenyl)butan-1-one (21): Acylphloroglucinol 7 (25 mg, 0.119 mmol) and
dimethyl acetal 15 (16 mg, 0.119 mmol) were suspended in dry isopropanol (1 mL). Camphorsulfonic acid (6 mg, 0.2 equiv.)
was added followed by the addition of scandium (III) triflate (12 mg, 0.2 equiv.). The mixture was heated to 80°C for 6 h and
was then cooled to room temperature. The reaction was then quenched with saturated sodium bicarbonate solution (3 mL)
and diluted with ethyl acetate (5 mL). The organic phase was removed and the aqueous phase was extracted with ethyl
acetate (3 x 5 mL). The combined organic layers were washed with brine and dried over sodium sulfate before being
concentrated under vacuum. The resulting crude oil was then purified on silica using 10% ethyl acetate in hexanes to provide
compound 21, which was a white oil (32 mg, 95% yield). IR(thin film): 2955.8, 2560 (br), 1609.4, 1579.8, 1522.9, 1301.6,
-
1 1
1
214.9, 1094.9 cm ; H NMR (MeOD, 500 MHz): δ 5.90 (s, 1H), 2.94 (d, J = 6.8 Hz, 2H), 2.56 – 2.49 (m, 2H), 2.24 (dt, J
1
3
=
13.4, 6.7 Hz, 1H), 1.57 (dt, J = 13.2, 6.6 Hz, 1 H), 1.40 – 1.32 (m, 2H), 0.97 (dd, J = 12.2, 6.6 Hz, 13 H); C NMR
2
2
(MeOD, 100 MHz): δ 207.9, 166.0, 164.6, 162.1, 110.0, 106.3, 95.7, 54.7, 40.2, 30.3, 27.7, 24.1, 24.0, 22.0 ; HRMS-ESI
23
2
+
(
m/z): [M+H] calculated for C H O ; 281.1747 found, 281.1759
16 25
4
25
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2
28
29
30
31
3
3
8a-Hydroxy-3-isopropyl-6,6,8,8-tetramethyl-8,8a-dihydrobenzo[c][1,2]dioxine-5,7(3H,6H)-dione (8): A 0.01M solution
of alkylidene 6 (80 mg, 0.32 mmol) was prepared in 32 mL of methanol in a flamed dried flask under argon at room
temperature. A balloon of oxygen was bubbled through the solution for 30 minutes. The reaction flask with a balloon of
oxygen bubbling through was connected to the flow setup. This setup employed Idex Health Science PFA
34
35
(perfluoroalkoxyalkane) tubing (ID 0.062 in, OD 0.125 in, 500 psi max pressure) looped tightly around the Hanovia lamp
36
37
38
39
40
41
42
4
4
45
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which was then placed in a chiller. The reactor was 1.614 meters in length and the total volume was 3.1 mL. A recirculating
chiller maintained the flow reactor at -10 °C and a fan insured proper air circulation in the photobox to maintain the overall
temperature of the reaction mixture in the system at 23 °C. The optimal flow rate determined and used was 0.5 mL/min.
After the entire solution was consumed, the system was flushed with an additional 5 mL of methanol and the receiving flask
was replaced by a waste container. Irradiation was stopped and the entire flow setup was flushed with benzene. The solution
contained in the receiving flask was collected and the solvent was evaporated. Purification using column chromatography
over silica gel using a gradient of hexanes:acetone (20:1 to 10:1) provided 45 mg (50%) of endoperoxides 8 as a 1:1 mixture
diasteromers (stereochemistry unassigned).
51
5
53
o
Diastereomer 1: Rf : 0.67 hexanes:EtOAc (2:1), Mp: 115-120 C (CH Cl , MeOH), IR (thin film): 3408.97, 2975.64,
2
2
5
5
1
1
726.15, 1690.59, 1633.86, 1469.19, 1377.38, 1286.22, 1216.22, 1159.82.11, 1100.16 cm-1, H NMR (500 MHz,
56
57
Chloroform-d) δ 7.29 (d, J = 1.6 Hz, 1H), 4.74 (dd, J = 5.9, 1.6 Hz, 1H), 3.51 (s, 1H), 2.03 (dt, J = 13.4, 6.8 Hz, 1H), 1.38 (d,
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J = 8.1 Hz, 7H), 1.31 (s, 3H), 1.06 (dd, J = 6.8, 1.4 Hz, 7H), 1.03 (s, 3H). C NMR (126 MHz, cdcl3) δ 210.5, 197.5, 137.9,
1
34.3, 97.9, 83.5, 54.9, 51.7, 30.5, 26.6, 24.1, 20.7, 18.2, 17.9, 15.1., HRMS-ESI (m/z): [M+H]+ calculated for C H O ,
15 23 5
283.1545; found, 265.1440 [M+H-H O]+
2
Diastereomer 2: Rf : 0.38 hexanes:acetone (2:1), IR (thin film): 3000.50, 2933.43, 2872.53, 1693.60, 1638.03, 1470.98,
1
1
1
1
375.00, 1262.55, 1187.51, 1131.25, 1100.01 cm-1, H NMR (500 MHz, Chloroform-d): δ 7.43 (d, J = 4.1 Hz, 1H), 4.13
12
13
(dd, J = 8.3, 4.1 Hz, 1H), 3.62 (s, 1H), 2.19 – 2.09 (m, 1H), 1.43 (s, 3H), 1.39 (d, J = 5.4 Hz, 6H), 1.33 (d, J = 3.4 Hz, 3H),
1
15
16
17
13
0
2
.97 (d, J = 6.7 Hz, 6H), C NMR (126 MHz, cdcl3): δ 207.1, 197.9, 137.9, 97.6, 85.0, 32.2, 31.1, 30.1, 29.9, 26.8, 24.2,
1.1, 20.0, 19.2, 15.3., HRMS-ESI (m/z): [M+H]+ calculated for C H O , 283.1545; found, 283.1547
1
5
23
5
18
19
20
2
2
23
24
25
26
Rhodomyrtosone A (3): A solution of endoperoxides 8 (1:1 mixture of diastereomers) (6 mg, 0.021 mmol) in acetic acid 1
mL was transfered in a sealed tube and heated at 100 °C for 12 h. Then the reaction mixture was diluted with water and
quenched with a saturated sodium bicarbonate solution. The pH was kept slightly acidic. The reaction mixture was extracted
with ethyl acetate (3 x 5 mL) and the organic fractions were gathered and dried over anhydrous sodium sulfate. The solvents
were evaporated in vacuo to yield a dark yellow oil. Purification by column chromatography over silica gel provided 6 mg
27
28
2
(
60 %) of 3 as a pale yellow gum. R : 0.7 hexanes:EtOAc 1:1, IR (thin film): 2960.88, 2930.37, 2873.99, 1720.40, 1649.79,
f
30
31
-
1 1
1
22.93, 1469.93, 1420.62, 1384.14, 1305.44, 1215.98, 1171.78, 1052.58, 921.63 cm , H NMR (500 MHz, CDCl ): δ 13.27
3
3
3
(s, 1H), 9.79 (s, 1H), 6.11 (s, 1H), 4.49 (s, 1H), 2.96 (dd, J = 14.7, 6.6 Hz, 1H), 2.76 (dd, J = 14.7, 7.2 Hz, 1H), 2.40 (d, J =
34
35
3
37
38
39
6
.8 Hz, 1H), 2.17(m, J=6.6 Hz, 1H) 1.52 (s, 3H), 1.42 (d, J = 5.3 Hz, 6H), 1.34 (s, 3H), 1.10 (dd, J = 11.8, 6.8 Hz, 6H), 1.00
13
(dd, J = 10.8, 6.7 Hz, 6H), C NMR (126 MHz, CDCl ): δ 211.3, 203.8, 198.5, 179.8, 166.8, 159.9, 159.8, 129.5, 113.3,
3
+
1
04.3, 101.8, 99.7, 55.3, 51.69, 45.8, 45.1, 35.5, 26.1, 24.5, 24.3, 23.3, 22.9, 22.9, 15.9, 15.9. HRMS-ESI (m/z): [M+H]
40
calculated for C H O ; 457.2226 found, 457.2218
2
6
32
7
41
42
4
1
13
Supporting Information Available Copies of H and C NMR spectra for all new compounds, and X-ray crystal data
4
45
for compound 5 (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.
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ACKNOWLEDGMENT
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5
Financial support from the National Institutes of Health (R01-GM073855, J. A. P., Jr.) is gratefully acknowledged.
Research at the Center for Molecular Discovery (BU-CMD) is supported by NIH grant GM-111625. We thank Prof. Ramesh
Jasti (University of Oregon), Prof. Aaron Beeler (Boston University), Prof. Stephane Roche (Florida Atlantic University),
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Dr. Stephen Scully (Bind Therapeutics), and Dr. Andrew Little (Vanderbilt University) for helpful and stimulating
discussions and Dr. Jeffrey Bacon (Boston University) for X-ray crystal structure analysis.
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REFERENCES
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(
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2
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5
(14) Dalpozzo, R.; Bartroli, G.; Sambri, L. Melchiorre, P. Chem. Rev. 2010, 110, 3501–3551.
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(
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Wada, E. J. Am. Chem. Soc. 1999, 121, 8675-8676. (b) Zhuang, W.; Hazell, R. G.; Jorgensen, K. A. Chem. Comm.
001, 14, 1240-1241. (c) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett. 2005, 7, 979-981.
2
(
16) Appendino, G.; Bianchi, F.; Minassi, A.; Sterner, O.; Ballero, M.; Gibbons, S. J. Nat. Prod. 2002, 65, 334-338.
17) Please see the Supporting Information for details.
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(
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1
(18) Richard, J. P.; Toteva, M. M.; Amyes, T. L. Org. Lett., 2001, 3, 2225-2228.
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(19) (a) Gal, J-F.; Geribaldi, S.; Pfister-Guillouzou, G.; Morris, D. G. J. Chem. Soc. Perkin Trans 2. 1985, 103-104; (b)
Anderson, V. E., Ruszczycky, M.W.; Harris, M. E. Chem. Rev. 2006, 106, 3236-3251.
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(
(
(
(
(
(
20) Carroll, A. R.; Lamb, J.; Moni, R.; Guymer, G. P.; Forster, P. I.; Quinn, R. J. J. Nat. Prod. 2008, 71, 1564–1568.
21) Lee, C-K. Tetrahedron Lett. 1999, 40, 7255-7259.
22) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.; Schneider, C. Angew. Chem. Int. Ed. 2014, 53, 7923-7927.
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