A Complementary Process to Pauson-Khand-Type Annulation Reactions for the Construction of Fully Substituted Cyclopentenones

Article abstract of DOI:10.1021/acs.orglett.8b03922

A complementary process to the Pauson-Khand annulation is described that is well suited to forging densely substituted/oxygenated cyclopentenone products (including fully substituted variants). The reaction is thought to proceed through a sequence of meta

Full text of DOI:10.1021/acs.orglett.8b03922

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Complementary Process to Pauson−Khand-Type Annulation
Reactions for the Construction of Fully Substituted
Cyclopentenones
Adam B. Millham, Matthew J. Kier, Robert M. Leon, Rajdip Karmakar, Zachary D. Stempel,
and Glenn C. Micalizio*
Department of Chemistry, Dartmouth College, Burke Laboratory, Hanover, New Hampshire 03755, United States
S
* Supporting Information
ABSTRACT: A complementary process to the Pauson−Khand
annulation is described that is well suited to forging densely
substituted/oxygenated cyclopentenone products (including fully sub-
stituted variants). The reaction is thought to proceed through a sequence
of metallacycle-mediated bond-forming events that engages an internal
alkyne and a β-keto ester in an annulation process that forges two C−C
bonds. A variant of this annulation process has also been established that
delivers deoxygenated cyclopentenones that lack the allylic tertiary alcohol.
arbocyclic systems bearing dense patterns of oxygenation
present lingering challenges for efficient chemical syn-
C
thesis.1 While diverse polycyclic systems can be forged with a
great variety of available ring-forming processes, even the most
powerful of modern methods are not well equipped to
simultaneously establish numerous and/or contiguous fully
substituted sp3 centers (quaternary centers and tertiary
alcohols) within the newly formed ring. This widely
appreciated characteristic of available methods has resulted
in the conception of synthesis strategies to highly substituted
and oxygenated carbocycles that proceed in two distinct
phases, where ring formation is strategically decoupled from
the challenge of establishing densely substituted and/or highly
oxygenated motifs.1d Despite impressive innovations that
enable hydrocarbon functionalization after ring formation,2
carbocyclic systems that contain numerous/contiguous fully
substituted sp3 carbons remain quite difficult to prepare. Of the
many annulation processes routinely employed in target-
oriented synthesis campaigns, Pauson−Khand and Pauson−
Khand-like reactions3 stand out as particularly powerful for
establishing cyclopentenones, especially when conducted in an
intramolecular fashion (Figure 1A). Despite the great history
of successfully harnessing the power of such annulation
processes in complex molecule synthesis,4 this class of
reactions is most effective with sparsely substituted alkenes
(Figure 1B).3 Here, we describe a mode of reactivity that can
be employed for the formation of densely substituted
cyclopentenones that are not directly accessible with
Pauson−Khand-type reactions, enabling direct formation of
fully substituted five-membered ring-containing products
(Figure 1C).
Figure 1. Introduction.
this annulation process in studies targeting a total synthesis of
ryanodol.6 This previous success served as a foundation to the
As illustrated in Figure 2A, we have recently described a
metallacycle-mediated annulation reaction that proceeds
through intramolecular reaction of an alkyne with a β-
diketone5 and have been investigating the potential value of
Received: December 8, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03922
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Approach to cyclopentenone synthesis by intramolecular
metallacycle-mediated coupling of an alkyne to a β-keto ester.
current investigations that are based on the recognition that a
related process may be quite useful for generating densely
substituted cyclopentenones that are not accessible with
Pauson−Khand-like annulation reactions. Proceeding through
unique bond-forming events (Figure 2B), it was anticipated
that formation of a metallacyclopropene7 (A) would be
followed by intramolecular reaction with the proximal ketone
to generate an oxametallacyclopentene intermediate (B).
Subsequent engagement of the metal−carbon σ-bond of this
intermediate in an intramolecular addition reaction to the
tethered ester could result in formation of a bridged polycylic
metal alkoxide (C), the rearrangement and hydrolysis of which
would deliver a fully substituted and oxygenated cyclo-
pentenone product.
Investigations began as illustrated in eqs 1−3 of Figure 3 and
demonstrate that the planned annulation process was feasible.
These initial experiments revealed that treatment of simple
unsaturated β-keto ester substrates with the combination of
Ti(O-i-Pr)4 (2 equiv) and c-C5H9MgCl (4 equiv) results in
formation of the expected cyclopentenone product in good
yield (up to 77%),8 noting that the nature of the ester has
some impact on efficiency of the process. Perhaps not
surprisingly, the t-Bu ester 3 was less effective in the annulation
reaction, delivering the product 4 in a depressed yield of 50%;
it is believed that this decreased efficiency is due primarily to
steric effects imposed by the t-Bu substituent. Moving on,
minor modification of the quaternary center between the two
reactive carbonyls had little impact on the efficiency of the
process. As depicted in eqs 4 and 5, substrates 5 and 7 were
smoothly converted to the tricyclic products 6 and 8 in 71 and
83% yield, respectively.
Figure 3. Intramolecular annulation reactions between alkynes and β-
keto esters: initial exploration.
which only modest quantities of the expected products could
be obtained (45, 42, and 37%, respectively).
Disappointingly, the effectiveness of this organometallic
transformation was also negatively impacted by tether length
(eq 9). It is certainly appreciated that tether length plays an
important role in the efficiency and viability of all intra-
molecular Pauson−Khand-like reactions, and it is indeed
typical that substrates with tethers that result in the formation
of a five-membered ring are most effective in a great variety of
intramolecular reactions.9 While it was understood that
strategic substitution of the tether in 15 may certainly result
The substitution on the alkynyl carbon distal to the β-keto
ester appeared to have a significant impact on efficiency of the
annulation process. Moving from substrates that contain a
methyl group at this position to others that contain a phenyl
(eq 6), substituted allyl (eq 7), and trimethylsilyl substituent
(eq 8), all resulted in more complex reaction mixtures from
B
DOI: 10.1021/acs.orglett.8b03922
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Organic Letters
Letter
in enhanced efficiency for cyclization due to the impact of
conformation on rate of cyclization (i.e., Thorpe−Ingold
effect),10 attention was directed to other concerns regarding
the potential utility of this new annulation reaction in
stereoselective synthesis.11
process are rather resistant to otherwise straightforward
functional group manipulations. That said, redox manipu-
lations that engage the alkene of the enone were straightfor-
ward and provided a means to generate additional stereo-
defined carbocyclic systems. As illustrated in Figure 5, directed
As illustrated in Figure 3B, the annulation process can be
conducted in a highly diastereoselective manner. Notably, with
a substrate containing an α-chiral center (17), the annulation
process proceeds with exquisite levels of stereoselection. Here,
the bicyclic product 18 was isolated in 62% yield and with
≥20:1 dr. When the stereocenter is relocated to the β-position
(symmetrically disposed about the alkyne and the ketone), as
in 19 (eq 11), the annulation reaction also proceeds with
acceptable efficiency (68%), albeit without observable levels of
diastereoselection. In more conformationally constrained
systems (i.e., 21 and 23, eqs 12 and 13), the annulation also
proceeds to deliver fused tricyclic products 22 and 24 as single
isomers.12
While these latter annulation reactions proceeded in a
manner that indicates the great stereocontrol possible in this
new carbocycle-forming reaction, the diminished efficiencies
(43% and 40%, respectively) were concerning. As illustrated in
Figure 4, additional studies have revealed that the initial
Figure 5. Some stereoselective transformations of the cyclopentenone
products.
epoxidation, conjugate reduction, and heterogeneous hydro-
genation were all effective for stereoselectively generating the
bicyclic cyclopentanones 27, 28, and 30 (in all cases, no
evidence was found for the production of stereoisomeric
products).
In conclusion, we report a general annulation process for the
synthesis of densely functionalized and highly oxygenated
carbocycles that proceeds through the union of alkynes with β-
keto esters. The reactions that have emerged through these
studies are complementary to classic carbocycle-forming
processes in organic chemistry, delivering products not readily
available from Pauson−Khand and Pauson−Khand-like
annulation reactions. The reactivity realized is thought to
proceed through a metallacycle-centered reaction cascade that
engages each metal−carbon bond of a metallacyclopropene in
reactions with two different carbonyl systems. In addition to
establishing the basic coupling process and reporting
preliminary scope substitution (ester and alkyne) and tether
length, our studies have also shed light on structural features
that lead to stereoselection and led to the discovery of a
competing reaction process that results in the formation of
deoxygenated products. While complex, and certainly appear-
ing to be sensitive to substrate structure, we look forward to
exploring key features of this annulation reaction in ongoing
methods development projects and target-oriented synthesis
campaigns.
Figure 4. Products of the annulation are not stable under the reaction
conditions; modified reaction conditions realize sequential cyclization
and deoxygenation.
products of this metallacycle-mediated annulation process are
not stable to the reaction conditions. For example, treatment of
the tricyclic enone 22 with the combination of Ti(O-i-Pr)4 and
c-C5H9MgCl resulted in a relatively clean conversion to the
deoxygenated product 25. As such, competing rates of initial
cyclization and subsequent deoxygenation can complicate
efforts to utilize this annulation process in diverse molecular
environments. If the deoxygenated product is desired, it is
possible to conduct a tandem annulation/deoxygenation with
synthetically useful efficiency. As illustrated in eqs 15 and 16,
the β-keto ester substrates 2 and 21 are converted directly to
the deoxygenated bi- and tricyclic products 26 and 25 in 47%
and 43% yield, simply by employing additional quantities of
Ti(O-i-Pr)4 (∼4 equiv) and Grignard reagent (∼8 equiv).
While providing direct access to densely substituted
cyclopentenones not readily available from other annulation
methods, it was discovered that the products of this annulation
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.8b03922.
Experimental procedures and tabulated spectroscopic
data for new compounds including the preparation of
each substrate for the Ti-mediated annulation reactions
described (PDF)
C
DOI: 10.1021/acs.orglett.8b03922
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) A variety of Grignard reagents are known to be useful for
converting Ti(O-i-Pr)4 to a reactive organometallic intermediate in
the context of metallacycle-mediated bond-forming processes. The
choice to employ c-C5H9MgCl instead of i-PrMgCl (see ref5) here is
viewed at this point in time as being arbitrary.
(9) For example, see: Bird, R.; Knipe, A. C.; Stirling, C. J. M. J.
Chem. Soc., Perkin Trans. 2 1973, 1215−1220.
(10) (a) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc.,
Trans. 1915, 107, 1080−1106. (b) Jung, M. E.; Piizzi, G. Chem. Rev.
2005, 105, 1735−1766.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: glenn.c.micalizio@dartmouth.edu.
ORCID
Glenn C. Micalizio: 0000-0002-3408-5570
Notes
The authors declare no competing financial interest.
(11) Substrates explored for this annulation uniformly contained a
quaternary center between the two ketones due to anticipated
problems associated with competitive enolization under the reaction
conditions. Attempts to employ an α-monosubstituted β-keto imide
were unsuccessful. For an interesting selective enolization of such a β-
keto imide, see: Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V.
J.; Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866−868.
(12) Switching the nature of the ethereal solvent used for these
annulation reactions was not found to have a significant impact on
efficiency (Et2O vs THF). In addition, the competing process of
deoxygenation, as seen in Figure 4, represents an ever-present obstacle
for optimization of the annulation reaction to deliver tertiary alcohol-
containing products due to what appears to be substrate-dependent
variable rates of reaction for the subsequent deoxygenation. Over the
course of our initial study, benefits were sometimes observed by
minor modification of the reaction conditions or experimental setup
(see the Supporting Information for experimental details).
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support of this work by
the National Institutes of Health NIGMS (GM124004).
REFERENCES
■
(1) (a) Wender, P. A. Nat. Prod. Rep. 2014, 31, 433−440.
(b) Ishihara, Y.; Baran, P. S. Synlett 2010, 2010, 1733−1745.
(c) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed.
2009, 48, 2854−2867. (d) Chen, K.; Baran, P. S. Nature 2009, 459,
824−828.
(2) For recent reviews, see: (a) Hartwig, J. F. J. Am. Chem. Soc. 2016,
138, 2−24. (b) Qiu, Y.; Gao, S. Nat. Prod. Rep. 2016, 33, 562−581.
(c) Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421−1451.
(d) Chen, D. Y.-K.; Youn, S. W. Chem. - Eur. J. 2012, 18, 9452−9474.
(e) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976−
1991.
(3) (a) Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263−
3283. (b) Schore, N. E. Org. React. 1991, 40, 1−90. For examples
with more substituted enyne substrates, see: (c) Knudsen, M. J.;
Schore, N. E. J. Org. Chem. 1984, 49, 5025−5026. (d) Schore, N. E.;
Knudsen, J. J. Org. Chem. 1987, 52, 569−580. (e) Schore, N. E.;
Rowley, E. G. J. Am. Chem. Soc. 1988, 110, 5224−5225. (f) Rowley, E.
G.; Schore, N. E. J. Org. Chem. 1992, 57, 6853−6861. (g) Stolle, A.;
Becker, H.; Salaun, J.; de Meijere, A. Tetrahedron Lett. 1994, 35,
̈
́
3517−3520. (h) Tormo, J.; Verdaguer, X.; Moyano, A.; Pericas, M.
A.; Riera, A. Tetrahedron 1996, 52, 14021−14040. (i) Tormo, J.;
́
Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1997, 62, 4851−
4856. (j) Ishizaki, M.; Iwahara, K.; Kyoumura, K.; Hoshino, O. Synlett
1999, 1999, 587−589. (k) Kerr, W. J.; McLaughlin, M.; Morrison, A.
J.; Pauson, P. L. Org. Lett. 2001, 3, 2945−2948. (l) Ishizaki, M.;
Iwahara, K.; Niimi, Y.; Satoh, H.; Hoshino, O. Tetrahedron 2001, 57,
2729−2738. (m) Son, S. U.; Park, K. H.; chung, Y. K. J. Am. Chem.
Soc. 2002, 124, 6838−6839. (n) de Meijere, A.; Becker, H.; Stolle, A.;
̈
Kozhushkov, S. I.; Bes, M. T.; Salaun, J.; Noltemeyer, M. Chem. - Eur.
J. 2005, 11, 2471−2482.
(4) (a) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber, S. L.
J. Am. Chem. Soc. 1997, 119, 4353−4363. (b) Chuang, K. V.; Xu, C.;
Reisman, S. E. Science 2016, 353, 912−915. (c) Jørgensen, L.;
McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S.
Science 2013, 341, 878−882.
(5) Kier, M. J.; Leon, R. M.; O’Rourke, N. F.; Rheingold, A. L.;
Micalizio, G. C. J. Am. Chem. Soc. 2017, 139, 12374−12377.
(6) Du, K.; Kier, M. J.; Rheingold, A. L.; Micalizio, G. C. Org. Lett.
2018, 20, 6457−6461.
(7) For reviews of Ti(O-i-Pr)4-based metallacycle-mediated coupling
chemistry, see: (a) Wolan, A.; Six, Y. Tetrahedron 2010, 66, 15−61.
(b) Kulinkovich, O. G.; de Meijere, A. Chem. Rev. 2000, 100, 2789−
2834. (c) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835−2886. (d) Reichard, H. A.; McLaughlin, M.; Chen, M. Z.;
Micalizio, G. C. Eur. J. Org. Chem. 2010, 2010, 391−409. (e) Reichard,
H. A.; Micalizio, G. C. Chem. Sci. 2011, 2, 573−589. (f) Micalizio, G.
C. Early Transition Metal Mediated Reductive Coupling Reactions. In
Molander, G. A., Knochel, P., Eds. Comprehensive Organic Synthesis,
2nd ed.; Elsevier: Oxford, 2014; Vol. 5, pp 1660−1737. For a review
of the use of metallacycle-mediated cross-coupling in natural product
synthesis, see: (g) O’Rourke, N. F.; Kier, M. J.; Micalizio, G. C.
Tetrahedron 2016, 72, 7093−7123.
D
DOI: 10.1021/acs.orglett.8b03922
Org. Lett. XXXX, XXX, XXX−XXX