Total Synthesis of (-)-Nemorosone and (+)-Secohyperforin

Article abstract of DOI:10.1021/acs.orglett.5b01121

A general strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols is described in which a scalable, Lewis acid catalyzed epoxide-opening cascade cyclization is used to furnish common intermediate 4. The utility of this approach is exemplified by the total syntheses of both ent-nemorosone and (+)-secohyperforin, which were each accomplished in four steps from this intermediate.

Full text of DOI:10.1021/acs.orglett.5b01121

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Nemorosone and (+)-Secohyperforin
Brian A. Sparling, James K. Tucker, David C. Moebius, and Matthew D. Shair*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02139, United States
S Supporting Information
*
ABSTRACT: A general strategy for the synthesis of polycyclic
polyprenylated acylphloroglucinols is described in which a scalable,
Lewis acid catalyzed epoxide-opening cascade cyclization is used to
furnish common intermediate 4. The utility of this approach is
exemplified by the total syntheses of both ent-nemorosone and
(
+)-secohyperforin, which were each accomplished in four steps
from this intermediate.
he polycyclic polyprenylated acylphloroglucinols (PPAPs)
In order to obviate this unwanted side effect while
maintaining potency, we have begun a program to probe the
SAR of hyperforin. We deliberately incorporated elements of
modularity into our hyperforin synthesis strategy to facilitate
access to diverse hyperforin analogues. As part of this program,
we targeted the total synthesis of several other naturally
occurring PPAPs. While hyperforin has been extensively
studied, no other PPAP has been probed for antidepressant
T
are a burgeoning class of phytochemical natural products,
1
of which there are currently over 260 members. PPAPs are
isolated from medicinal plants used in many traditional and
ethnopharmaceutical therapies and display antibacterial, anti-
oxidant, anti-inflammatory, and antiproliferative effects as well
as activity against neurological disorders. From a structural
point of view, PPAPs contain a densely substituted, highly
oxygenated bicyclo[3.3.1]nonane core. Owing to their wide
ranging biological activity as well as their structural complexity,
PPAPs have garnered significant attention from the chemical
6
activity. Herein, we describe the first total synthesis of
secohyperforin as well as the first enantioselective synthesis of
7
nemorosone.
2
community leading to several total syntheses.
Nemorosone (2) has been isolated from five species of Clusia
Recently, we reported the enantioselective total synthesis of
throughout Brazil, Venezuela, and Cuba as well as from the
3
the PPAP hyperforin (1, Figure 1). Hyperforin is considered
8
propola of Cuban honeybees. Several studies have demon-
strated that nemorosone is cytotoxic toward a variety of cancer
9
cell lines. This activity may be in part due to epigenetic effects;
nemorosone interacts with p300 histone acetyltransferase and
10
alters cancer cell gene expression. This PPAP also displayed
mild antileishmanial, antitrypanosomal, and antiviral effects as
well as dose-dependent activity against the molting of Rhodnius
11
prolixus, an insect vector of Chagas disease. Interestingly,
nemorosone demonstrated activity against Paenibacillus larvae
8
c
and Paenibacillus alvei, two honeybee pathogens. Antioxidant
8h
activity was observed in a DPPH assay.
Unlike nemorosone, very little is known about secohyperfor-
in (3). This PPAP was isolated in small quantities from
Hypericum performatum in Yerevan, Armenia and was
characterized using flow techniques (i.e., LC−MS and LC−
Figure 1. Structures of hyperforin, nemorosone, and seco-hyperforin.
12
NMR).
Our retrosynthesis strategy for nemorosone and secohyper-
forin is found in Scheme 1a. We postulated that both natural
products could be accessed from a common intermediate, 4.
This intermediate would be the expected product generated
from sequential allylic oxidation and Keck allylation of 5, which
to be the active component of St. John’s wort (SJW), a
medicinal herb widely used in the treatment of depression.
While hyperforin-enriched SJW extracts have proven efficacy
4
and tolerability in numerous clinical studies, hyperforin
potently activates pregnane X receptor (PXR), upregulating
xenobiotic metabolism and subsequently causing significant
drug−drug interactions, which has limited its utility as a
Received: April 16, 2015
5
depression therapeutic option.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01121
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
3
Scheme 1. (a) Retrosynthesis of Nemorosone (2) and
Secohyperforin (3) and (b) Transition-State Analysis of the
Key Cyclization
nonaqueous workup protocol developed by Sharpless
involving P(OMe) -facilitated in situ derivitization to the
corresponding water-insoluble mesylate 11 in 85% ee.
3
1
4
Bromination of this unstable intermediate provided 8 in 51%
yield over two steps.
Coupling of epoxy bromide 8 with cyclohexadiene 7 afforded
cyclization precursor 6. While cyclization using TMSOTf
accessed 12, we wished to preclude the formation of a cyclic
ketal. An analogous cyclic ketal utilized in our total synthesis of
hyperforin required the use of Me BBr for cleavage; this
2
pyrophoric reagent was difficult to implement on larger scale
reactions and provided inconsistent yields.
The results of screening a panel of Lewis and Brønsted acids
with 6 for the selective conversion to the bicyclo[3.3.1]nonane
products 13 and 14 are shown in Table 1. A variety of products
were obtained throughout these studies. Aside from ketal 12,
exposure of TMSOTf also produced a mixture of 15 and 16
(
entry 1). The reaction of 6 with PPTS in MeOH selectively
afforded tertiary methyl ether 17 (entry 2), the product of
epoxide-opening methanolysis followed by ketalization of the
Table 1. Reactions of Various Acids with 6
would be generated via a diastereoselective, Lewis acid-
mediated epoxide-opening cyclization of 6. Finally, this
cyclohexadiene would be made from the regioselective
alkylation of 7 with (bromomethyl)oxirane 8.
In the key transformation, the two diastereotopic enol ethers
flanking the prostereogenic C5 quaternary center of 6 would be
differentiated through a preferred chairlike transition state TS-1
over its diastereomeric transition state TS-2, which must adopt
a boatlike conformation bearing two unfavorable eclipsing
interactions (Scheme 1b). Therefore, 5 was predicted to be
favored over 9, and in a single operation, the shared bicyclic
core of both 2 and 3 would be generated bearing three key
stereocenters. A similar cyclization was implemented during our
3
total synthesis of hyperforin.
We began our studies by focusing on the synthesis of (R)-
(
bromomethyl)oxirane 8 from prenol (10, Scheme 2). The
enantioselective Sharpless epoxidation of 10 was problematic
owing to the significant water solubility of epoxyprenol. A
Scheme 2. Synthesis of (R)-(Bromomethyl)oxirane 8 and
Formation of Ketal 12 from 6
B
DOI: 10.1021/acs.orglett.5b01121
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Organic Letters
Letter
Scheme 3. Synthesis of Common Intermediate 4 from 14 and Conversion to (−)-Nemorosone (2) and (+)-Secohyperforin (3)
resulting secondary carbinol with one of the methyl enol ethers.
Exposure to HCl in MeOH afforded a mixture of 17 and ketal
epimer 18 (entry 3). We observed chloride 19 selectively when
Et AlCl was employed (entry 4). The reaction of 6 to Me BBr
Nemorosone synthesized herein was found to be opposite in
18
optical rotation sign compared to naturally isolated material.
This was further confirmed through optical rotation analysis of
19
nemorosone O-methyl ether. No optical rotation data has
been published for secohyperforin.
2
2
or Et AlI afforded bromide 20 and iodide 21, respectively
2
In summary, we have rapidly implemented our hyperforin
synthesis strategy toward two other PPAP natural products,
secohyperforin and nemorosone. Continued efforts in our
laboratory will allow us to access many other hyperforin
mimetics using this chemistry, and we will begin testing these
analogues for antidepressant activity as well as other bioactivity.
(
entries 5 and 6).
We also investigated the use of other trialkylsilyl triflates.
TESOTf produced a mixture of 12, 15, and 16 (entry 7), very
similar to TMSOTf. In contrast, hemiketal 22 was isolated
upon exposure of 6 to TBSOTf (entry 8). If pyridine was used
instead of 2,6-lutidine, no reaction was observed at −78 °C, but
upon warming to rt, we isolated both ketone 13 and triketone
ASSOCIATED CONTENT
Supporting Information
■
2
3 (entry 9). While this was an extremely promising result that
*
S
would allow us to circumvent Me BBr-mediated ketal
2
Experimental procedures, spectroscopic data, and H and 13C
NMR spectra. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01121.
1
hydrolysis, the yield was mediocre. Gratifyingly, warming a
solution of 6, TIPSOTf, and 2,6-lutidine from −78 °C to rt
afforded a very high yield of 14 as a single product. This
reaction was both reproducible and scalable. We hypothesized
that the increased steric demand of larger trialkylsilyl groups
prevented cyclic ketal formation.
Allylic oxidation of 14 was a very challenging transformation
given the steric environment around the desired site of
reactivity and the presence of other, more accessible allylic
sites (Scheme 3). Exposure of 14 to Pearlman’s catalyst and
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shair@chemistry.harvard.edu.
Notes
The authors declare no competing financial interest.
1
5
TBHP afforded a mixture of unstable allylic peroxide 24 and
the desired β-methoxyenone 25. DBU facilitated the isohypsic
fragmentation of peroxide 24 to 25. Stepwise desilylation and
thionocarbonylation of 25 produced radical cyclization
precursor 26, and Keck allylation afforded 27. After vinyl
silylation to give 28, olefin cross-metathesis with 2-methyl-2-
butene mediated by Hoveyda−Grubbs second-generation
ACKNOWLEDGMENTS
■
We acknowledge financial support from Chemiderm, Inc.
B.A.S. acknowledges a NSF Predoctoral Fellowship and an
AstraZeneca Graduate Research Fellowship in Organic
Chemistry. We thank Benjamin C. Milgram (Harvard
University) for experimental assistance.
1
6
catalyst yielded 4.
Both nemorosone and secohyperforin were synthesized in
four steps from 4. First, bridgehead acylation with benzoyl and
isobutyryl chlorides followed by desilylation afforded 29 and
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