Concise Formal Synthesis of the Pseudopterosins via Anionic Oxy-Cope/Transannular Michael Addition Cascade

Article abstract of DOI:10.1021/acs.orglett.0c00486

An anionic oxy-Cope/transannular Michael addition cascade converts a spirocyclic architecture - readily available by Diels-Alder cycloaddition - into the hydrophenalene carbon skeleton of the pseudopterosin aglycones. Oxidation of the resulting cyclohexen

Full text of DOI:10.1021/acs.orglett.0c00486

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Letter
Concise Formal Synthesis of the Pseudopterosins via Anionic Oxy-
Cope/Transannular Michael Addition Cascade
Vincenzo Ramella, Philipp C. Roosen, and Christopher D. Vanderwal*
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ABSTRACT: An anionic oxy-Cope/transannular Michael addition
cascade converts a spirocyclic architecturereadily available by Diels−
Alder cycloadditioninto the hydrophenalene carbon skeleton of the
pseudopterosin aglycones. Oxidation of the resulting cyclohexenone ring
to the phenol that is characteristic of the targets completes a short formal
synthesis.
he pseudopterosin family of diterpenoid glycosides
includes over 30 members.1,2 Their diversity arises from
only three stereoisomeric aglycons and the identity of the sugar
attached via the C9 or C10 phenolic oxygen (Figure 1). These
pseudopterosins is a key component in Resilience, Estee
Lauder’s cosmetic skin care product.11
T
The pseudopterosins have been targeted by many synthetic
chemists over the past 30 years, resulting in a large body of
work on their total synthesis and the preparation of their
aglycons, starting with the first synthesis of pseudopterosin A
by Broka in 1988.12 As clearly articulated by Sherburn in the
2015 report of his group’s outstanding synthesis,13 all of the
syntheses that preceded theirs were based on “structure-goal
strategies”.14 These syntheses start from commercially available
terpene or aromatic building blocks that overlap with a portion
of the tricyclic scaffold; the target is synthesized by sequential
chain elongations and ring closures.2 On the other hand, the
synthesis by Sherburn13 and a later one by Luo15 are
transformation-based, focusing on the Diels−Alder reaction
and the Cope rearrangement, respectively. These approaches
allow for a quick increase in molecular complexity, in both
cases ultimately arriving at the target aglycons in fewer than a
dozen steps. In this communication, we report a formal
synthesis of the pseudopterosins that starts from the chiral-
pool precursor pulegone, but whose carbocyclic ring is not
featured in the final product.
Our research group has been involved in the synthesis of
isocyanoterpenes for several years.16−19 One of our early, but
unsuccessful, approaches to the flagship member 7,20-
diisocyanoadociane (DICA, 5) was predicated on the cascade
reaction shown in Scheme 1A.16 This anionic oxy-Cope/
transannular Michael addition sequence was reported by
Swaminathan and co-workers, who indicated that this reaction
type provided the all-trans, all-chair arrangement of hydro-
phenalene-type products (6 to 7).20,21 During our efforts to
Figure 1. Structures of pseudopterosin A and the three stereoisomeric
pseudopterosin aglycons.
secondary metabolites have been of significant interest to the
scientific community since the initial discovery of pseudopter-
osins A−D in 1986,3 due in part to their structures and
especially to their wide range of biological activities. Members
of the pseudopterosin family show anticancer,4 antimalarial,5
antibacterial,5 and anti-inflammatory6 properties. For example,
pseudopterosin A (1) is a significantly more potent anti-
inflammatory and analgesic agent than the clinically used
indomethacin.3,6 These natural products are still under active
investigation, and recent studies have found new anticancer7,8
and neuroprotective properties,9,10 while an extract containing
Received: February 6, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00486
© XXXX American Chemical Society
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demonstrate the feasibility of this approach with a short
formal synthesis of the pseudopterosins starting from
commercially available 3-methylcyclohexanone, which can
also be made in one step from pulegone.
Scheme 1. (A) Anionic Oxy-Cope/Transannular Michael
Addition Cascade as Initially Reported by Swaminathan20
and the Revised Structure; (B) Strategic Application of the
Cascade Reaction for a Formal Synthesis of the
Pseudopterosins
Scheme 2 describes the conversion of 3-methylcyclohex-
anone to the late-stage pseudopterosin aglycon intermediate 9
in only seven steps. Aldol condensation of 12 with
acetaldehyde under carefully optimized conditions25 provides
13, the dienophile for the subsequent Diels−Alder reaction.
SnCl4-catalyzed cycloaddition with 2-triethylsilyloxybutadiene
forms the spirocyclic products in high yields, favoring the
desired diasteromer 15 (2:1 dr). Significant attempts were
made to bias the diastereoselectivity further; while it was
possible to increase the 15:14 ratio with the application of
chiral Lewis acids, the efficiency of these reactions was low.
Fortunately, the diastereomers can easily be separated at this
stage. Oxidation of the desired silyl enol ether to enone 16
proceeds smoothly. Attempts to selectively add propynyl
organometallic reagents to the ketone over the enone were
unsuccessful, so the enone was transiently protected as its
cross-conjugated silyl enol ether. Propynylmagnesium bromide
then adds cleanly to provide 11 with a diastereoselectivity of
5.8:1 (major isomer shown, minor isomer characterized by X-
ray crystallography) after the silyl enol ether is removed in the
workup.26 In our previous efforts toward DICA, we showed
that both diastereomers at the alcohol undergo the oxy-Cope
rearrangement to give the same product,16 and that proved
true in this case as well.
With propargylic alcohol 11 in hand, we investigated the
critical anionic oxy-Cope/transannular Michael cascade. Initial
attempts to effect a one-pot transformation of 11 to tricyclic
products via the full cascade resulted in decomposition.
Therefore, we examined a stepwise version of the process
(Scheme 3). Anionic oxy-Cope rearrangement of the
diastereomeric mixture of alcohols 11 induced with KH at
low temperature gives the bicyclo[7.3.1] system 19 in nearly
quantitative yield as a single diastereomer.27 Investigation of
the double-bond isomerization and transannular Michael
addition steps eventually led to clean isomerization using
DBU in carefully degassed THF to give 20, which
unfortunately has the undesired configuration at C4. Without
careful removal of oxygen, oxygenated products such as 21 and
22 were observed during attempted transannular bond
formation; they presumably arise in part from strain-induced
apply this interesting spiro-to-fused scaffold interchange to
DICA, we noted that the relative configuration was not as
originally reported, and we offered a stereochemical revision of
the product of this otherwise highly productive rearrangement
to diastereomer 8.16,22
While of no service to a synthesis of DICA, we noted that
the hydrophenalene scaffold that results from the Swaminathan
rearrangement is well-represented in other terpenoid natural
products and considered featuring this chemistry in an
approach to the pseudopterosins (Scheme 1B). Phenol 9 and
its enantiomer are known precursors of the pseudopterosin
aglycons.23 9 can be generated by oxidation of cyclohexenone
10,24 which is the projected product of the anionic oxy-Cope/
transannular Michael addition cascade of spirocyclic yne/
enone 11. The attractiveness of this route rests in the rapid
access to spirocycle 11. In this communication, we
Scheme 2. Formal Synthesis of the Pseudopterosins
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Scheme 3. Results of Attempted Stepwise Protocols for the
Anionic Oxy-Cope/Transannular Michael Process
Scheme 4. Reactivity of Diels−Alder Side Product 14
which bears the desired C3/C4 vicinal relationship. Oxidation
of 24 affords phenol 25. In principle, the C7 stereogenic center
might be equilibrated to the natural pseudopterosin config-
uration via o-quinone methide intermediates, though we have
not investigated this possibility by experiment.
In conclusion, we have developed a concise formal synthesis
of the pseudopterosins using a transformation-based approach.
We have demonstrated that the key anionic oxy-Cope/
transannular Michael cascade can be both efficient and
remarkably selective and therefore might prove useful in the
stereocontrolled synthesis of other polycyclic natural products.
Although selectivity in the key step was not quite in our favor,
the related case of substrate 23 is highly efficient and perfectly
stereoselective. These results frame the need for further
investigations into the impact of the structural features and
reaction conditions on the diastereoselectivity of this cascade
rearrangement. Overall, as a result of the rapid synthesis of the
spirocyclic cascade precursor and the efficiency of the key step,
our synthesis competes favorably with much of the work on
the pseudopterosins that has gone before.
reactivity of the various conjugate base forms of 19. Treatment
of 20 with methanolic base led to efficient transannular ring
closure to give 17; however, this product retains the undesired
configuration at C4.28,29 Adapting the knowledge gained from
the stepwise rearrangement studies, we were able to induce
formation of the desired compound 18 in a one-pot process by
treating alcohol 11 with potassium methoxide at 85 °C in
DMF for a short time (Scheme 2). This procedure affords the
desired tricyclic core in good yield, slightly favoring the
undesired diastereomer (17 again) at C4 (1:1.5 dr). Further
attempts to bias the selectivity toward the desired stereoisomer
were unsuccessful; however, the reaction is noteworthy for
forming only two diastereomers of a possible 16.30 The cascade
reaction is subject to fluctuations in the isolated product yield
because competitive decomposition of the products occurs
under the reaction conditions. Finally, oxidation of the enone
to the phenol completes a very brief formal synthesis of the
pseudopterosins.24 This approach shortens the synthesis of
phenol 9 to eight steps (from 13 steps by Corey31).
Conversion of the phenol to the pseudopterosin aglycon can
be achieved in seven further steps, and therefore, a total
synthesis using this approach would be only slightly longer
than those reported by Sherburn13 and Luo.15
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00486.
Experimental protocols for the preparation of, and
characterization data for, all new compounds (PDF)
Accession Codes
CCDC 1982473−1982478 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
We also investigated the reactivity of 14, the minor
diastereomeric product of the Diels−Alder reaction (Scheme
4). Addition of propynylmagnesium bromide followed by IBX
oxidation provided the cascade precursor 23.32 In contrast to
the reaction of the desired diastereomer 11, the one-pot
anionic oxy-Cope/transannular Michael cascade of 23
proceeds quickly and in nearly quantitative yield at 0 °C,
giving a single diastereomer of tricyclic cascade product 24,
AUTHOR INFORMATION
■
Corresponding Author
Christopher D. Vanderwal − Department of Chemistry and
Department of Pharmaceutical Sciences, University of
California, Irvine, California 92697-2025, United States;
orcid.org/0000-0001-7218-4521; Email: cdv@uci.edu
C
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Authors
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(16) Roosen, P. C.; Vanderwal, C. D. Investigations into an Anionic
Oxy-Cope/Transannular Conjugate Addition Approach to 7,20-
Diisocyanoadociane. Org. Lett. 2014, 16, 4368−4371.
Vincenzo Ramella − Department of Chemistry, University of
California, Irvine, California 92697-2025, United States
Philipp C. Roosen − Department of Chemistry, University of
California, Irvine, California 92697-2025, United States
(17) Daub, M. E.; Prudhomme, J.; Le Roch, K.; Vanderwal, C. D.
Synthesis and Potent Antimalarial Activity of Kalihinol B. J. Am.
Chem. Soc. 2015, 137, 4912−4915.
(18) Roosen, P. C.; Vanderwal, C. D. A Formal Enantiospecific
Synthesis of 7,20-Diisocyanoadociane. Angew. Chem., Int. Ed. 2016,
55, 7180−7183.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00486
(19) Karns, A. S.; Ellis, B. D.; Roosen, P. C.; Chahine, Z.; Le Roch,
K. G.; Vanderwal, C. D. Concise Synthesis of the Antiplasmodial
Isocyanoterpene 7,20-Diisocyanoadociane. Angew. Chem., Int. Ed.
2019, 58, 13749−13752.
Notes
The authors declare no competing financial interest.
(20) Rao, C. S. S.; Kumar, G.; Rajagopalan, K.; Swaminathan, S.
Base Catalysed Rearrangement of a Spiro Oxy-Cope System and
Related Studies: A New Entry into Perhydrophenalene and
Perhydroacenaphthylene Systems. Tetrahedron 1982, 38, 2195−2199.
(21) Ravikumar, V. T.; Rajagopalan, K.; Swaminathan, S. Anionic
Oxycope Rearrangements in Acetylenic Spiro Systems. Tetrahedron
Lett. 1985, 26, 6137−6138.
ACKNOWLEDGMENTS
■
This work was funded by a DFG fellowship (RA 3139/1-1; 1-2
to V.R.) and the NIH (AI-138139 to C.D.V.). We thank Dr.
Joe Ziller for expert assistance with X-ray crystallographic
structure determination.
(22) Although 8 was the major diastereomer of this reaction, a
minor stereoisomer was also observed, but no evidence of 7 was seen.
(23) Corey, E. J.; Carpino, P. Enantiospecific Total Synthesis of
Pseudopterosins A and E. J. Am. Chem. Soc. 1989, 111, 5472−5474.
(24) Yadav, J. S.; Bhasker, E. V.; Srihari, P. Synthesis of a key
intermediate for the total synthesis of pseudopteroxazole. Tetrahedron
2010, 66, 1997−2004. The conditions described in this paper (I2,
MeOH, reflux) generate the anisole. Inspired by these conditions, we
changed the solvent from MeOH to MeNO2 to provide the phenol.
(25) See the Supporting Information for details.
(26) The more direct CeCl3-mediated addition of Grignard reagent
to 15 was successful, although after oxidation with IBX, the overall
yield of this two-step protocol is significantly lower. Intriguingly, in
that situation the diastereoselectivity for the 1,2-addition switches,
favoring the other diastereomer than that formed via the three-step
sequence shown.
(27) Although we and the Swaminathan group always characterized
this transformation as an anionic oxy-Cope rearrangement, it could
also be formulated as a vinylogous retro-aldol/Michael addition
cascade. For examples of this type of reactivity, see: (a) Shanmugam,
P.; Devan, B.; Srinivasan, R.; Rajagopalan, K. Studies in
bromoacetylenic oxy-Cope rearrangement: Synthesis of functionalised
medium-size, bicyclic and angularly fused tricyclic compounds.
Tetrahedron 1997, 53, 12637−12650. (b) Thornton, P. D.;
Cameron, T. S.; Burnell, D. J. Vinylogous anionic processes in the
formation and interconversion of tetracyclic ring systems. Org. Biomol.
Chem. 2011, 9, 3447−3456.
(28) The relative configuration of 17 could not be ascertained;
however, the configuration at C4 was determined by structural
analysis of its oxidation product to a phenol that was epimeric to 9 at
C4.
(29) Of course, the transannular Michael addition of 20 could
equally be characterized as a 6π-electrocyclic ring closure.
(30) In principle, the undesired diastereomer 17 could be salvaged
for a synthesis of the target molecules. Oxidation to the phenol and
epimerization of C4, which is activated by the o-ketone, could provide
the desired relative configuration. Initial attempts to do so were
unsuccessful, likely because deprotonation of the phenol greatly
reduces the acidity of the C4 proton.
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