Toward the Total Synthesis of Ryanodol via Oxidative Alkyne-1,3-Diketone Annulation: Construction of a Ryanoid Tetracycle

Article abstract of DOI:10.1021/acs.orglett.8b02767

A synthetic strategy conceived with the intent of establishing a novel approach to the de novo construction of ryanoids is described that is based on a recently developed metallacycle-mediated intramolecular oxidative alkyne-1,3-diketone coupling reaction. In short, a one-pot annulation/oxidation sequence is shown to be capable of establishing a densely oxygenated polycyclic intermediate that could be converted to a composition of matter that contains the ABCD tetracyclic ring system present in the ryanoid family of natural products.

Full text of DOI:10.1021/acs.orglett.8b02767

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Toward the Total Synthesis of Ryanodol via Oxidative Alkyne−1,3-
Diketone Annulation: Construction of a Ryanoid Tetracycle
Kang Du,†,§ Matthew J. Kier,†,§ Arnold L. Rheingold,‡ and Glenn C. Micalizio*,†
†Department of Chemistry, Dartmouth College, Burke Laboratory, Hanover, New Hampshire 03755, United States
‡Department of Chemistry, University of CaliforniaSan Diego, La Jolla, California 92093, United States
S
* Supporting Information
ABSTRACT: A synthetic strategy conceived with the intent
of establishing a novel approach to the de novo construction of
ryanoids is described that is based on a recently developed
metallacycle-mediated intramolecular oxidative alkyne−1,3-
diketone coupling reaction. In short, a one-pot annulation/
oxidation sequence is shown to be capable of establishing a
densely oxygenated polycyclic intermediate that could be
converted to a composition of matter that contains the ABCD
tetracyclic ring system present in the ryanoid family of natural products.
yanodol (Figure 1A) has a rich history in organic
product: (1) Deslongchamps’ early success hinged on strategic
Rchemistry and biology. This natural diterpene from the use of Diels−Alder chemistry, Baeyer−Villiger oxidation, and
an interesting oxidative cleavage/transannular aldol cascade
South American plant Ryana speciosa Vahl was originally
notably, these efforts nurtured the group’s great interest in
understanding the role that stereoelectronic effects play in
organic chemistry,8 (2) Inoue’s creative design employed a C2-
symmetric fused tricycle, radical allylation, Pd-catalyzed olefin
isomerization, and ring-closing metathesis, while (3) Reisman’s
stunningly step-economical strategy featured an interesting Rh-
catalyzed Pauson−Khand reaction and a SeO2-mediated
polyoxidation process.
identified as the hydrolysis product of ryanodine, a compound
that alters the function of an intracellular calcium channel
known as the ryanodine receptor, and a natural product that
has been used as a tool to understand the role that intracellular
Ca2+ channels play in biology.1 Over the past two decades,
structure−activity relationships associated with ryanodine,
ryanodol, and synthetic esters of ryanodol/ryanodine have
led to the conclusion that a wide variety of ryanoids have
diverse and potent effects on Ca2+ channels in vivo, despite the
wide range of binding affinities reported for them.1a From a
chemical standpoint, ryanodine and ryanodol first stood as
complex problems for structure elucidation due, in part, to the
great number of fully substituted carbon atoms in their
complex polycyclic skeletons. After years of investigation,2
Wiesner reported the structure of ryanodine in 1967,3 arrived
at by a study that was later described by Pierre Deslongchamps
as “one of the most brilliant accomplishments in structure
elucidation using chemical degradation.”4a Soon after Wies-
ner’s report, an X-ray crystal structure of the p-bromobenzoate
of ryanodol was reported that supported Wiesner’s proposal
and clarified the stereochemistry at C3.4b
The intricate structure of ryanodol has presented a
significant challenge for chemical synthesis. It has a caged
pentacyclic skeleton that includes 11 stereogenic centers, all of
which are contiguous. More daunting is the fact that eight
contiguous stereocenters have fully substituted carbon atoms
(including two quaternary centers). There have only been
three reported total syntheses of ryanodol, the first appearing
from Deslongchamps nearly 40 years ago5 and two additional
recent reports from Inoue6 and Reisman.7 In all cases, these
triumphs in organic chemistry featured unique strategies to
address the challenging carbocyclic structure of the natural
Our interest in ryanodol, and ryanoids more broadly, is
driven by our desire to explore fundamentally novel
approaches to the assembly of densely oxygenated carbocyclic
systems. Paying close attention to the central five-membered
ring of the ryanoids (ring B; Figure 1A), we have embraced
this highly subsituted domain as pressure for both the
development of a new carbocycle-forming annulation reaction,
as well as the central structural element that will guide our
strategy to the incredibly complex carbocyclic structures of the
natural product family. As illustrated in Figure 1B, we have
recently developed an oxidative annulation reaction that
proceeds by intramolecular addition of an alkyne to a 1,3-
diketone, the quenching of which with t-BuOOH results in
complex polyoxygenated carbocyclic systems (1 → 2).9 The
means by which we imagined use of this reaction in an
approach to the synthesis of ryanoids is depicted in Figure 1C.
With an intermediate lactone akin to I in hand, the oxidative
annulation reaction was anticipated to be capable of delivering
product II, and hydrolysis of this intermediate was reasoned
capable of delivering the bicyclic carboxylic acid III that could
serve as an intermediate en route to the tricyclic product IV
Received: August 29, 2018
© XXXX American Chemical Society
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and subsequent oxidation and cyclization (NBS, NaHCO3,
NaOAc, THF/H2O).11 Oxidation to the lactone (CrO3,
H2SO4)12 followed by reduction of the enone (Zn, AcOH)
furnished the intermediate 5 in 59% overall yield. With this
species in hand, it was anticipated that site-selective
deprotonation of the ketone could be accomplished with
LDA, and that subsequent acylation with an unsaturated
activated ester or acid chloride (6) would deliver the 1,3-
diketone product 7. Unfortunately, while seemingly straightfor-
ward, all efforts to accomplish this transformation were met
with failure.
Hypothesizing that the lactone carbonyl may be the
structural feature that thwarted these initial attempts, we
moved forward with an approach that would allow for the
desired formation of a 1,3-diketone in the absence of this
structural motif. As illustrated, lactol 4 was selectively
protected as its corresponding TBS-ether (TBSOTf, 2,6-
lutidine), and subsequent conjugate reduction with CuI/LAH
delivered a 2:1 mixture of isomeric products favoring isomer
9.13 After purification, ketone 9 was advanced to a suitable
aunnulation substrate (12) by initial acylation of an
intermediate lithium enolate with the acyl cyanide 10, and
subsequent diastereoselective methylation (KHMDS, MeI,
THF).
With the stereodefined alkynyl 1,3-diketone in hand, efforts
were then directed toward achieving the desired oxidative
annulation reaction. As depicted in Figure 3A, initial
exploration pursued these two transformations in sequence.
Exposure of 12 to the combination of Ti(Oi-Pr)4 and i-
PrMgCl in THF (−78 to −20 °C), followed by an aqueous
quench, led to formation of the highly oxygenated and
stereodefined product 13 in 56% yield. Notably, no evidence
was found for the production of a stereoisomeric product in
this transformation. Polyol 13 was then advanced to the
stereodefined epoxide 14 with high selectivity in 66% yield by
treatment with VO(acac)2 and t-BuOOH.14
Figure 1. Introduction.
Alternatively, a one-pot oxidative annulation was inves-
tigated for the direct conversion of 12 to 14. Exposure of 12 to
Ti(Oi-Pr)4 and i-PrMgCl, followed by quenching with t-
BuOOH, delivered the highly oxygenated and stereodefined
product 14 in 43% yield. An empirical model for this oxidative
annulation reaction is illustrated in Figure 3B and features
through regioselective opening of the fully substituted epoxide.
Here, we describe our initial studies aimed at realizing such a
sequence of chemical transformations.
As illustrated in Figure 2, the unsaturated aldehyde 310 was
converted to the lactol 4 by initial reaction with 2-lithio-furan,
Figure 2. Assembly of a substrate for study of the oxidative annulation.
B
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proposed initial formation of a metallacyclopropene (A)
followed by stereoselective intramolecular addition to the
proximal ketone to generate an oxametallacyclopentene
intermediate (B). Driven by the loss of a σTi−C bond and
formation of a σTi−O bond, this intermediate is thought to
participate in a second stereoselective intramolecular C−C
bond-forming event to deliver a carbocyclic product containing
a dioxametallacyclohexane (C). Finally, by embracing the
inherent reactivity of metal alkoxides in hydroxyl-directed
epoxidation chemistry, simply adding t-BuOOH results in
directed oxidation and production of the fully functionalized
product 14 as a single stereoisomer. The structure of 14 was
confirmed by removal of the PMB ether with DDQ, to deliver
the polyol 15 which produced a suitable crystal for X-ray
diffraction (Figure 3A).
Next, Grieco elimination,15 followed by desilylation (TBAF,
THF) and oxidation of the hemiacetal with TPAP, NMO16
delivered the lactone intermediate 16 in 83% yield over three
steps (Figure 4A). A two-step process consisting of treatment
with NaOH in DME/H2O, followed by ring-closing metathesis
with the Hoveyda−Grubbs second generation catalyst,17 then
delivered a 1:3 mixture of the tetracyclic products 17 and 18 in
71% overall yield.6 This molecular transformation presumably
begins by lactone hydrolysis followed by regioselective epoxide
opening in a stereoelectronically favored 6-exo manner. While
both electrophilic sites of the epoxide may participate in a 6-
exo ring opening process,18 two factors may play a significant
role in controlling the regioselectivity for this reaction: (1)
nucleophilic addition at C12 would result in a highly strained
trans-fused bicyclo[3.3.0]octane motif,19 and (2) the C11
position is activated by the neighboring alkene.20 While those
not familiar with previous studies to prepare ryanadol may be
disappointed by the observation that both 17 and 18 are
produced in this two-step process, the propensity for the
bridging lactone to participate in translactonization chemistry
between the C11 and C3 hydroxy groups is well understood.5
That said, isomers 17 and 18 proved to be inseparable in our
hands, defining a reality that thwarted our early attempts at
characterization of the products of this two-step process.
To secure our understanding of the structures of 17 and 18,
a molecular transformation was sought that would convert this
Figure 3. Metallacycle-mediated diketone−alkyne annulation.
Figure 4. Advancing a product of oxidative diketone−alkyne annulation to a tetracyclic ABCD system of anhydroryanodol.
C
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Author Contributions
product mixture to a single molecular entity suitable for
characterization. While reduction of the lactones to the
corresponding primary alcohol was viewed as a simple means
to accompolish this, we opted to avoid such a transformation,
as the polyol product was anticipated to have an undesirable
solubility profile. Alternatively, we directed our attention to
oxidation chemistry as a means to achieve our goal. As
illustrated in Figure 4B, we were delighted to discover that
exposing the 3:1 mixture of lactone isomers to the Dess-Martin
periodinane resulted in an exceptionally efficient trans-
formation. While it was hoped that it may be possible to
selectively oxidize the C3 alcohol of 17 to the corresponding
ketone, and establish an equilibrium such that 18 would be first
converted to 17 and then oxidized to 20, this oxidation
procedure instead furnished the bridged polycyclic product 19
in 99% yield. This product presumably derives from oxidative
cleavage of the C4−C12 syn diol, followed by hemiketal
formation between the C3 secondary alcohol and the resulting
C12 ketone. The exceptional efficiency of this transformation
indicates that isomerization of the lactone (from the C3
secondary alcohol to the C11 tertiary alcohol) must be
occurring under the reaction conditions.
Overall, we report a new approach to the assembly of the
carbocyclic skeleton of ryanoids by application of a recently
developed oxidative alkyne−1,3-diketone annulation reaction.
The emerging strategy demonstrates that a functionalized
heterocyclic diketone is a suitable substrate for this oxidative
annulation reaction, and that additional π-unsaturation is
tolerated (i.e., a 1,1-disubstituted alkene) in the organometallic
transformation. Further, these investigations also highlight the
value of a polyoxygenated intermediate like 14 as an
intermediate in the synthesis of the ryanoid skeleton, as site-
selective intramolecular epoxide opening preferentially occurs
at C11 rather than C12. Remaining challenges in this
developing approach to the ryanoids include the additional
substitution required in ring A (at C1 and C2), as well as
selective hydration of the C-ring alkene. Studies to address
these challenges are underway.
§K.D. and M.J.K. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge financial support from the National
Institutes of Health (GM124004).
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: glenn.c.micalizio@dartmouth.edu.
ORCID
Kang Du: 0000-0001-6778-4733
Glenn C. Micalizio: 0000-0002-3408-5570
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