Studies Targeting Ryanodol Result in an Annulation Reaction for the Synthesis of a Variety of Fused Carbocycles

Article abstract of DOI:10.1021/acs.orglett.9b02278

An annulation reaction is described to access a range of polycyclic and highly oxygenated carbocycles. First developed in an approach to the synthesis of ryanodol, metallacycle-mediated annulative diketone-alkyne coupling defines a framework for realization of new retrosynthetic relationships for complex molecule synthesis. In addition to demonstrating this reaction in the context of forging distinct carbocyclic systems, including those featuring a seven-membered ring, the choice of quenching reagent leads to unique reaction outcomes.

Full text of DOI:10.1021/acs.orglett.9b02278

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Studies Targeting Ryanodol Result in an Annulation Reaction for the
Synthesis of a Variety of Fused Carbocycles
†
‡
,†
Rajdip Karmakar, 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: An annulation reaction is described to access a
range of polycyclic and highly oxygenated carbocycles. First
developed in an approach to the synthesis of ryanodol,
metallacycle-mediated annulative diketone−alkyne coupling
defines a framework for realization of new retrosynthetic
relationships for complex molecule synthesis. In addition to
demonstrating this reaction in the context of forging distinct
carbocyclic systems, including those featuring a seven-
membered ring, the choice of quenching reagent leads to unique reaction outcomes.
atural product total synthesis is widely appreciated to
serve as an enduring platform for the development of
mediated and hydroxyl-directed alkene epoxidation. While this
N
reaction for forging a stereodefined and densely oxygenated
bicyclo[3.3.0]octane plays a central role in ongoing studies
aimed at completing a total synthesis of ryanodol, general
aspects of this annulation process have become of great current
interest due to this reaction’s potential value in addressing a
organic chemistry. The complex structures associated with
scores of molecules from Mother Nature provide stimuli for
the invention of synthesis strategies and stereoselective
reactions, while the frequently encountered unexpected
reactivity of unique synthetic intermediates prepared in such
pursuits is a never-ending source of challenges to push
6
variety of fused polycyclic systems, including those possessing
medium-sized rings. Here it is revealed that alkyne−diketone
annulation reactions are effective at generating a wide variety
of fused carbocyclic systems beyond that originally targeted in
the context of our program focused on the synthesis of
ryanodol (Figure 1C). Notably, cyclization reactions in this
class are shown to be capable of delivering a variety of complex
carbocyclic systems by way of five-, six-, and even seven-
membered ring-forming processes, where a 1,5-diketone is
embraced as a reactive loci in intramolecular reactions with a
1
invention within the field. Highly oxygenated carbocycles are
compelling modern targets for natural product total synthesis
owing to the combined challenges associated with generating
complex polycyclic systems while addressing required sites of
heteroatom substitution. Ryanodol (1; Figure 1A) is a
particularly compelling target in this regard due not only to
its unique polycyclic skeleton and high degree of oxygenation
3
but also because of the great number of fully substituted sp
7
carbon atoms resident in its pentacyclic skeleton (i.e.,
pendant alkyne. These studies also reveal that this class of
2
annulation reaction typically proceeds with exquisite levels of
stereoselectivity, and varied quenching techniques provide a
means to subtly alter product structure and establish yet
additional novel retrosynthetic relationships of value in
stereoselective synthesis.
Our study began by examining a potential annulation
process for the establishment of a seven-membered ring by
engaging an alkyne in intramolecular metallacycle-mediated
coupling with a 1,5-diketone. As illustrated in eq 1 of Figure
quaternary centers and tertiary alcohols). Our recent efforts
3
to accomplish a total synthesis of this natural product were
driven by a desire to invent an annulation method capable of
forging the central bicyclo[3.3.0]octane (the “AB” ring system;
4
Figure 1A), the “B”-ring of which does not contain a single
3
hydrogen atom (it has five fully substituted and stereogenic sp
5
carbon atoms). The reaction technology that has emerged to
address this synthetic challenge is summarized in Figure 1A
and allows for the conversion of 2 to 3 by way of a metal-
centered oxidative alkyne−diketone coupling reaction. An
empirical model that is consistent with our experimental
observations is depicted in Figure 1B and features initial
formation of a metallacyclopropene (A) and intramolecular
stereoselective addition to the proximal ketone to generate the
oxametallacyclopentene B, followed by a second stereoselective
C−C bond-forming process to yield the intermediate C.
Oxidative quenching of this reaction with t-BuOOH is then
thought to deliver the observed product 3 by titanium-
2
A, exposure of 5 to the combination of Ti(Oi-Pr) and c-
4
C H MgCl results in ring formation, and termination of the
5
9
process by the addition of aq NaHCO3 delivers the
hydrazulene 6 in 48% yield, as what appears as a single
stereoisomer. Moving beyond simple diastereoselection
associated with cyclization of an achiral substrate, eqs 2 and
Received: July 2, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02278
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Annulation reaction suitable for a wide variety of fused
polyclic carbocycles, including those bearing medium-sized rings.
3
demonstrate that this seven-membered ring-forming reaction
can proceed in a highly stereoselective manner with the chiral
stereodefined substrate 7. Here, protic quenching of the
reaction delivers the ene-1,4-diol 8, while termination of the
8
reaction with t-BuOOH delivers the epoxydiol product 9. In
both cases, no evidence could be found for the production of
stereoisomeric products. Notably, the highly oxygenated seven-
membered ring generated here (9) possesses four contiguous
3
fully substituted sp carbon atoms, all bearing oxygenation on a
single face of the tricyclic system. As represented in the
empirical model depicted in Figure 1B for the preparation of
the tricyclic heterocycle 3, it is believed that this stereoselective
hydrazulene-forming reaction proceeds by initial C−C bond
formation to generate an intermediate cis-fused hydrindane
core, with stereoselection for the second C−C bond-forming
event being dictated by the stereochemistry of the tertiary
metal alkoxide intermediate (e.g., B → C; Figure 1B).
4
A previous study provided a glimpse that this class of
alkyne−diketone annulation reactions is compatible with 1,4-
diketone-containing substrates, defining a new approach to the
synthesis of oxygenated hydrindanes. For example, as reported
previously and illustrated in eq 4 of Figure 2B, oxidative
Figure 2. Alkyne−diketone annulation reactions to forge 5-, 6-, and 7-
membered rings. Typical annulation reactions are conducted with the
combination of Ti(O-i-Pr)4 and c-C H MgCl. (a) Quench with
5
9
annulation of 10 delivers the cis-fused oxygenated hydrindane
NaHCO (half satd aq). (b) t-BuOOH is added for the oxidative
3
4
1
1 in 49% isolated yield. Here, we demonstrate that this six-
quench. (c) 5 was used as a 1:1 mixture of diastereomers. (d) Quench
with aq HCl (1 N). *Structures of these compounds are supported by
X-ray diffraction.
membered ring-forming process is also highly effective with
stereodefined substrates and can be used to generate complex
B
DOI: 10.1021/acs.orglett.9b02278
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
fused tricyclic carbocycles with ease. For example, as depicted
in eqs 5 and 6, annulation reactions of the 1,4-diketone-
containing substrate 12 deliver either the ene-1,4-diol system
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02278.
13 or the highly oxygenated variant 14 when termination of
the reaction is conducted with t-BuOOH.
Next, the cyclopentanone-containing system 15 was ex-
plored as a substrate for this annulation process, with the goal
of accessing a distinct fused tricyclic system. Unfortunately, the
synthesis employed for this substrate was not stereoselective,
and attempts to separate the isomeric substrates were met with
failure. Nevertheless, using 15 as a 1:1 mixture of stereo-
isomers as a substrate for the oxidative annulation reaction
resulted in the tricyclic system 16 as a single stereoisomer. The
yield for this reaction (38%) appears to reflect engagement of
only the 2,5-cis isomer of 15 in the cyclization process.
With momentum being gained for the value of metallacycle-
mediated alkyne−diketone annulation as an entry to a wide
range of stereodefined carbocyclic systems, we redirected
attention toward the intramolecular reactions of alkynes with
Procedures and spectroscopic data, accompanied by
additional examples of the annulation reaction (PDF)
Accession Codes
CCDC 1903020−1903021, 1903032−1903034, 1903083,
903097, and 1905540 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
AUTHOR INFORMATION
Corresponding Author
■
*
1
,3-diketonesthe reaction process that is currently playing a
E-mail: glenn.c.micalizio@dartmouth.edu.
ORCID
central role in our studies toward a total synthesis of ryanodol.
As illustrated in eq 8, this process has previously been shown
Glenn C. Micalizio: 0000-0002-3408-5570
Notes
to be effective with chiral diketone-containing substrates like
4
1
7 (eq 8; Figure 2C), providing an entry to complex tricyclic
systems. It is revealed here that this type of cyclization
alkyne−1,3-diketone) can deliver structurally distinct poly-
cyclic oxygenated products through an acid-mediated quench.
As depicted in eq 9, Ti-mediated annulation of 17, followed by
quenching with 1 N HCl delivers the rearranged product 19,
now possessing a vicinal diol at the union of the fused
bicyclo[3.3.0]octene motif of the tricyclic system.
Finally, a limitation associated with stereoselectivity in these
cyclization reactions has been observed. Attempts to employ
alkyne−1,3-diketone coupling with a cycloheptanone-based
substrate revealed that stereoselection can be negatively
impacted by the nature of the cyclic ketone substrate. As
illustrated in eq 10, oxidative annulation of 20 proceeds with
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
The authors acknowledge financial support from the National
Institutes of Health (GM124004).
■
REFERENCES
■
(1) For recent reviews of natural product synthesis, see:
(a) Nicolaou, K. C.; Sorensen, E. J.; Winssinger, N. The Art and
Science of Organic and Natural Products Synthesis. J. Chem. Educ.
1
998, 75, 1225−1258. (b) Nicolaou, K. C.; Vourloumis, D.;
Winssinger, N.; Baran, P. S. The Art and Science of Total Synthesis
at the Dawn of the Twenty-First Century. Angew. Chem., Int. Ed.
2000, 39, 44−122. (c) Nicolaou, K. C.; Hale, C. R. H.; Nilewski, C.;
7
1% yield and delivers a 1:1 mixture of the tricylic products 21
Ioannidou, H. A. Constructing molecular complexity and diversity:
total synthesis of natural products of biological and medicinal
importance. Chem. Soc. Rev. 2012, 41, 5185−5238. (d) Hoffmann, R.
W. Natural Product Synthesis: Changes over Time. Angew. Chem., Int.
Ed. 2013, 52, 123−130. (e) Mulzer, J. Trying to rationalize total
synthesis. Nat. Prod. Rep. 2014, 31, 595−603. (f) Kuttruff, C. A.;
Eastgate, M. D.; Baran, P. S. Natural product synthesis in the age of
scalability. Nat. Prod. Rep. 2014, 31, 419−432. (g) Zweig, J. E.; Kim,
D. E.; Newhouse, T. R. Methods Utilizing First-Row Transition
Metals in Natural Product Total Synthesis. Chem. Rev. 2017, 117,
11680−11752. (h) Hui, C.; Chen, F.; Pu, F.; Xu, J. Innovation in
protecting-group-free natural product synthesis. Nat. Rev. Chem. 2019,
and 22. It appears that the dampened diastereoselectivity of
this annulation reaction is due to a lack of stereoselectivity in
the initial C−C bond-forming event that establishes the first
9
hydrazulene intermediate (cis- or trans-fused). The remaining
stereocenters formed from the second C−C bond-forming
event, as well as the directed epoxidation, appear to be tightly
controlled by the stereochemistry of the initially formed
tertiary metal alkoxide.
Overall, we report that metallacycle-mediated alkyne−
diketone coupling chemistry can be wielded to provide
convenient and stereoselective access to a variety of fused
tricyclic carbocycles, including those that contain oxygenated
seven-membered rings. Valuable features of the annulation
processes include (1) very high levels of stereoselectivity, (2)
common sets of reaction conditions for annulation processes
that forge 5-, 6-, and 7-membered rings, (3) utility of the
process to access a wide variety of stereoedefined and highly
oxygenated polycyclic systems, and (4) flexibility associated
with the quenching of these processes (simple protic, acid, or
oxidative). These combined features are rare among methods
for the synthesis of stereodefined carbocycles, and efforts are
ongoing to explore the value of these processes in target- and
function-oriented synthesis.
3
(
, 85−107.
2) (a) Bidasee, K. R.; Besch, H. R. Structure-Function Relationships
among Ryanodine Derivatives. Pyridyl Ryanodine Definitively
Separates Activation Potency from High Affinity. J. Biol. Chem.
1
998, 273, 12176−12186. (b) McPherson, P. S.; Campbell, K. P. The
2+
Ryanodine Receptor/Ca Release Channel. J. Biol. Chem. 1993, 268,
2
+
13765−13768. (c) Meissner, G. Ryanodine Receptor/Ca Release
Channels and Their Regulation by Endogenous Effectors. Annu. Rev.
Physiol. 1994, 56, 485−508. (d) Fill, M.; Copello, J. A. Physiol. Rev.
2
002, 82, 893−922. (e) McCauley, M. D.; Wehrens, X. H. T.
Targeting Ryanodine Receptors for Anti-Arrhythmic Therapy. Acta
Pharmacol. Sin. 2011, 32, 749−757. (f) Jenden, D. J.; Fairhurst, A. S.
The Pharmacology of Ryanodine. Pharmacol. Rev. 1969, 21, 1−25.
(g) Waterhouse, A. L.; Pessah, I. N.; Francini, A. O.; Casida, J. E.
Structural Aspects of Ryanodine Action and Selectivity. J. Med. Chem.
C
DOI: 10.1021/acs.orglett.9b02278
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
987, 30, 710−716. (h) Wiesner, K. The Structure, Stereochemistry
and Absolute Configuration of Anhydroryanodine. Pure Appl. Chem.
963, 7, 285−296. (i) Wiesner, K.; Valenta, Z.; Findlay, J. A. The
Structure of Ryanodine. Tetrahedron Lett. 1967, 8, 221−225.
j) Srivastava, S. N.; Przybylska, M. The Molecular Structure of
Ryanodol-p-Bromo Benzyl Ether. Can. J. Chem. 1968, 46, 795−797.
3) Du, K.; Kier, M. J.; Rheingold, A. L.; Micalizio, G. C. Toward the
F. D. Asymmetric Synthesis of Medium-Sized Rings by Intramolecular
Au(I)-Catalyzed Cyclopropanation. J. Am. Chem. Soc. 2009, 131,
2056−2057. (e) Illuminati, G.; Mandolini, L. Ring Closure Reactions
of Bifunctional Chain Molecules. Acc. Chem. Res. 1981, 14, 95−102.
(8) For a review of substrate-directable chemical reactions, including
metal-mediated hydroxyl-directed epoxidation, see: Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Substrate-Directable Chemical Reactions.
Chem. Rev. 1993, 93, 1307−1370.
1
(
(
Total Synthesis of Ryanodol via Oxidative Alkyne−1,3-Diketone
Annulation: Construction of a Ryanoid Tetracycle. Org. Lett. 2018,
(9) Sugimura, T.; Futagawa, T.; Tai, A. Synthetic Approach for
(+)-Africanol. Chem. Lett. 1990, 19, 2295−2298.
2
(
0, 6457−6461.
4) Kier, M. J.; Leon, R. M.; O’Rourke, N. F.; Rheingold, A. L.;
Micalizio, G. C. Synthesis of Highly Oxygenated Carbocycles by
Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl
Systems. J. Am. Chem. Soc. 2017, 139, 12374−12377.
(5) For examples of efforts targeting the total synthesis of ryanodol,
see: (a) Deslongchamps, P. Synthetic Studies Towards Ryanodine.
Pure Appl. Chem. 1977, 49, 1329−1359. (b) Belanger, A.; Berney, D.
́
J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.;
Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.; MacLachlan,
F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau, C.;
Saintlaurent, L.; Saintonge, R.; Soucy, P.; Ruest, L.; Deslongchamps,
P. Total Synthesis of Ryanodol. Can. J. Chem. 1979, 57, 3348−3354.
(c) Deslongchamps, P.; Belanger, A.; Berney, D. J. F.; Borschberg, H.
́
J.; Brousseau, R.; Doutheau, A.; Durand, R.; Katayama, H.; Lapalme,
R.; Leturc, D. M.; Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.;
Marazza, F.; Martino, R.; Moreau, C.; Ruest, L.; Saintlaurent, L.;
Saintonge, R.; Soucy, P. The Total Synthesis of (+)-Ryanodol. Part I.
General Strategy and Search for a Convenient Diene for the
Construction of a Key Tricyclic Intermediate. Can. J. Chem. 1990,
6
8, 115−126. (d) Deslongchamps, P.; Belanger, A.; Berney, D. J. F.;
́
Borschberg, H. J.; Brousseau, R.; Doutheau, A.; Durand, R.;
Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.;
MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.;
Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The
Total Synthesis of (+)-Ryanodol. Part II. Model Studies for Rings B
and C of (+)-Anhydroryanodol. Preparation of a Key Pentacyclic
Intermediate. Can. J. Chem. 1990, 68, 127−152. (e) Deslongchamps,
P.; Belanger, A.; Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.;
́
Doutheau, A.; Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.;
Liao, C.-C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino,
R.; Moreau, C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P.
The Total Synthesis of (+)-Ryanodol. Part III. Preparation of
(
+)-Anhydroryanodol from a Key Pentacyclic Intermediate. Can. J.
Chem. 1990, 68, 153−185. (f) Deslongchamps, P.; Belanger, A.;
́
Berney, D. J. F.; Borschberg, H. J.; Brousseau, R.; Doutheau, A.;
Durand, R.; Katayama, H.; Lapalme, R.; Leturc, D. M.; Liao, C.-C.;
MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.; Martino, R.; Moreau,
C.; Ruest, L.; Saintlaurent, L.; Saintonge, R.; Soucy, P. The Total
Synthesis of (+)-Ryanodol. Part IV. Preparation of (+)-Ryanodol
from (+)-Anhydroryanodol. Can. J. Chem. 1990, 68, 186−192.
(
g) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe,
D.; Inoue, M. Total Synthesis of Ryanodol. J. Am. Chem. Soc. 2014,
36, 5916−5919. (h) Masuda, K.; Koshimizu, M.; Nagatomo, M.;
Inoue, M. Asymmetric Total Synthesis of (+)-Ryanodol and
+)-Ryanodine. Chem. - Eur. J. 2016, 22, 230−236. (i) Chuang, K.
1
(
V.; Xu, C.; Reisman, S. E. A 15-Step Synthesis of (+)-Ryanodol.
Science 2016, 353, 912−915. (j) Xu, C.; Han, A.; Virgil, S. C.;
Reisman, S. E. Chemical Synthesis of (+)-Ryanodine and (+)-20-
Deoxyspiganthine. ACS Cent. Sci. 2017, 3, 278−282.
(6) Millham, A. B.; Kier, M. J.; Leon, R. M.; Karmakar, R.; Stempel,
Z. D.; Micalizio, G. C. A Complementary Process to Pauson−Khand-
Type Annulation Reactions for the Construction of Fully Substituted
Cyclopentenones. Org. Lett. 2019, 21, 567−570.
(7) For manuscripts that discuss strategies and methods for the
synthesis of medium-sized rings, see: (a) Molander, G. A. Diverse
Methods for Medium Ring Synthesis. Acc. Chem. Res. 1998, 31, 603−
609. (b) Yet, L. Metal-Mediated Synthesis of Medium-Sized Rings.
Chem. Rev. 2000, 100, 2963−3007. (c) Maier, M. E. Angew. Chem.,
Int. Ed. 2000, 39, 2073−2077. (d) Watson, I. D. G.; Ritter, S.; Toste,
D
DOI: 10.1021/acs.orglett.9b02278
Org. Lett. XXXX, XXX, XXX−XXX