Enantioselective Total Synthesis of Cannogenol-3-O-α- l -rhamnoside via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions

Article abstract of DOI:10.1021/acs.orglett.7b03513

A concise and scalable enantioselective total synthesis of the natural cardenolides cannogenol and cannogenol-3-O-α-l-rhamnoside has been achieved in 18 linear steps. The synthesis features a Cu(II)-catalyzed enantioselective and diastereoselective Michae

Full text of DOI:10.1021/acs.orglett.7b03513

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Total Synthesis of Cannogenol-3‑O‑α‑L‑rhamnoside
via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular
Aldol Cyclization Reactions
Bijay Bhattarai and Pavel Nagorny*
Chemistry Department, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A concise and scalable enantioselective total synthesis of the natural cardenolides cannogenol and cannogenol-3-
O-α-L-rhamnoside has been achieved in 18 linear steps. The synthesis features a Cu(II)-catalyzed enantioselective and
diastereoselective Michael reaction/tandem aldol cyclization and a one-pot reduction/transposition, which resulted in a rapid (6
linear steps) assembly of a functionalized intermediate containing C19 oxygenation that could be elaborated to cardenolide
cannogenol. In addition, a strategy for achieving regio- and stereoselective glycosylation at the C3 position of synthetic
cannogenol was developed and applied to the preparation of cannogenol-3-O-α-L-rhamnoside.
ardiotonic steroids represent alarge andimportant familyof
these studies, anewapproach thatwas basedondiastereoselective
Cnatural steroids that exhibit a wide spectrum of biological Michael reaction/intramolecular aldolcyclization ofthefunction-
alized β-ketoester 7 and enone 8 was developed.5c The resultant
annulated product could be rapidly advanced to the fully
functionalized steroidal core 9. This steroidal intermediate was
subsequently elaborated to the natural cardenolides 19-hydroxy-
sarmentogeninandthetrewianinaglyconebearingoxygenationat
the C3, C11, C14, and C19 positions. These results suggest that
Cu(II)-catalyzed Michael addition/Aldol cascade represents a
powerful and straightforward method for achieving fast and
selective syntheses of cardiotonic steroids with various oxidation
patterns. To further demonstrate the generality and utility of this
approach, our group targeted steroids possessing the C19
hydroxylation, but lacking the C11 hydroxyl group. This
oxidation pattern is commonly found in various cardenolides
including cannogenol (2), corotoxigenin, securigenol, pachyge-
nin, and strophanthidin derivatives and their bufadienolide
counterparts such as 19-hydroxybufalin (3). It should be noted
that applying the previously developed synthetic approaches4 to
such steroids (including our diastereoselective approach5b
depicted in Figure 1B) would require incorporating a strategy
for selective removal of the C11 alcohol in the presence of the C3,
C14, C17, and C19 oxygenation as well as other functionalities.
This task might be operationally challenging and would result in a
significant increase in the overall number of steps. To circumvent
activities. The majority of these compounds are potent Na+/K+
ATPase inhibitors, afeature that makes them of great value for the
treatment of various heart-associated diseases.1 Cardiotonic
steroids are secreted endogenously and used for the regulation
of essential life processes such as renal sodium pressure, sodium
transport, arterial pressure, cell growth differentiation, apoptosis,
fibrosis, immunity, carbohydrate metabolism, and various central
nervous functions.2 The unique biological properties often
coupled with challenging structural features prompted numerous
semisynthetic and synthetic efforts toward the preparation of
variouscardiotonicsteroidsandtheiranalogs.3 Thesestudieshave
resulted in many creative solutions that have enabled medicinal
chemistry studies on many natural cardiotonic steroids and their
analogs. These advances, however, are difficult to translate into
the synthesis of highly oxygenated cardiotonic steroids, in
particular, those carrying O atoms at the C1, C11, C12, and
C19positions. Notsurprisingly, manyof thesechallenging targets
have only been synthesized in the past decade.4
Our group has long-standing interests in developing concise
synthetic approaches to cardiotonic steroids.5 Recently, we
described a concise approach to the cardenolide core that is based
on sequential enantioselective Cu(II)-catalyzed Michael/intra-
molecular aldol cyclization reactions (Figure 1B).5a This strategy
enabled rapid enantioselective formation of cardiotonic steroid
skeleta (i.e., 6) featuring the oxidized C14 and C19 positions, but
lacking the required oxygenation at the C3 position. Based on
Received: November 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03513
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Organic Letters
Letter
glycoside cannogenol-3-O-α-L-rhamnoside (1),7 an effective
nanomolar growth inhibitor of several cancer cell lines.6a,8 Our
studies commenced with generating sufficient quantities of
known precursors 5 and 7 (Scheme 1). Thus, β-ketoester 7 was
Scheme 1. Synthesis of Intermediate 11
prepared in three steps from 3-ethoxy-2-cyclohexenone (120 g
scale) and enone 5 was synthesized in two steps from 2-methyl-
1,3-cyclopentanedione (60 g scale). These substrates were
subjected to asymmetric Michael reaction5a using a 2,2′-
(cyclopropane-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole) ligand
complexed with Cu(SbF6)2 as the catalyst (10 mol %) under neat
conditions.9 Gratifyingly, this transformation proceeded effi-
ciently, and Michael adduct 12 was consistently generated on 7.2
g scale in 92% yield, >20:1 dr, and 92% ee. This compound was
then subjected to aldolization with p-TSA, which resulted in
steroid 10 with an unnatural α-C13/C14 configuration (57%,
>20:1 dr, 14 g scale). Our prior studies on a related system
containing C11 oxygenation5c indicated that such unnatural
steroids could be epimerized under basic conditions to form the
more stable natural β-configuration at the C13 and C14
stereocenters. Indeed, subjecting 10 to NaHMDS resulted in
formation of the desired diastereomer 14 through the
intermediacy of retro-aldol product 13 (64%, >20:1 dr; 7.3 g
scale). Intermediate 14 was then treated with DIBAL-H (3 g
scale), which led to 15, which was stable at room temperature for
up to 2 h. The tetraol 15 was not isolated, but rather the excess of
DIBAL-H was quenched, and the crude mixture was heated at
reflux in formic acid and 8:2 water/THF to accomplish
transposition/vinyl chloride hydrolysis to produce a mixture of
C17 epimers in 71% yield, 8:1 dr. This mixture was purified by
SiO2 column chromatography toafford α-C17 diastereomer 11 in
63% yield. This transformation allowed us to remove the
unwanted oxygenation at C7 and introduced important oxygen-
ation at C3 in a single step to set the proper steroidal framework
mimickingthe naturalproduct. Thus, thekeyintermediate 11was
synthesized in 6 linear steps (9 overall steps) from commercially
available building blocks in 17% overall yield and 92% ee.
Figure 1. Prior and current synthetic approaches.
these problems, we pursued a more direct approach that is based
on our enantioselective Cu(II)-catalyzed Michael reaction/
aldolization of 7 and 5 resulting in steroid 10 (Figure 1C). This
is the first example of using this strategy in the synthesis of natural
cardenolides, and the formation of 10 is accomplished on
decagram scale with excellent overall yield and selectivities.
Steroid 10 was then subjected to an epimerization/reductive
transposition sequence to provide intermediate 11 lacking the
C11 oxygenation. This expedient synthesis of 11 was
accomplished in only 6 linear steps, 17% yield, and 92% ee on a
3 g scale. This key intermediate may be converted to various C19
oxygenated cardiotonic steroids, which was demonstrated by
synthesizing cannogenol (2), a natural cardenolide with
anticancer properties.6 Finally, this manuscript describes a
strategy to accomplish a regioselective introduction of sugar at
the less reactive C3 position of 2 to provide natural cardiac
With the key intermediate 11 in hand, we turned our attention
to installation of the stereocenter at C5 and the butenolide ring at
C17. Steroid 11 was subjected to hydrogenation with Pd/C in the
B
DOI: 10.1021/acs.orglett.7b03513
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Letter
presence of 1% potassium hydroxide in methanol (Scheme 2).
This C19 alcohol-directed hydrogenation resulted in the
Δ16-olefin, and global removal of the silyl protecting groups. The
TMS protection of the C14 tertiary alcohol was required to
achieve a steric bias for the subsequent hydrogenation to give
exclusive β-C17, and the attempts to accomplish this protection
prior to the Stille coupling reaction resulted in poor yields of the
cross-coupled product.
Scheme 2. Synthesis of Intermediate 17 and Confirmation of
Its Absolute and Relative Configuration
Next, we investigated the possibility of adopting this route to
the synthesis of cannogenol-3-O-α-L-rhamnoside (1). Our initial
studies commenced with attempts to accomplish C3-selective
glycosylation of triol 16 as a model substrate (Scheme 4).
Scheme 4. Initial Glycosylation Studies
exclusive formation of the β-C5 center. The subsequent global
oxidation of the crude material using Dess-Martin periodinane
(DMP) followed by the selective reduction of the C19 aldehyde
and C3 ketone in the presence of the C17 ketone by a bulky K-
selectride yielded 16 in 62% yield over three steps after a single
purification at the end of the third step. The iodination of 16
under Barton’s protocol10 produced vinyl iodide 17 in 77% yield.
Compound 17 was benzoylated to provide monobenzoate 18b
(90% yield) along with the crystalline bis-benzoate 18a in 8%
yield, the absolute and the relative configuration of which was
confirmed by X-ray crystallographic analysis.
Attempts to glycosylate 16 with trichloroacetimidate 22 available
in three steps from L-rhamnose4b,c,11 resulted in the equimolar
mixture of products 23 and 24 formed in ∼70% conversion. This
result indicated that the C19 hydroxyl is more reactive than the
secondary C3 alcohol.
Anticipating similar reactivity trends for cannogenol (2), our
following efforts were focused on selectively protecting the C19
position of 2 (Scheme 5). Due to its higher reactivity, the C19
hydroxyl could be selectively protected as a p-bromobenzoate
(27) or an acetate (28). These derivatives were glycosylated with
trichloroacetimidate 22 using TMSOTf as a promoter to afford
protected α-glycosides 27 (36% yield) and 28 (56% yield). These
glycosylated steroids were subjected to ester deprotection under
basic conditions; however, this step represented a significant
challenge. The use of various basic conditions for ester hydrolysis
(i.e., Na2CO3, K2CO3, NaOMe, LiOH, or NH3) resulted in the
deprotection of the benzoyl esters on the rhamnose moiety.
However, the deprotection of the C19 ester was slow and
proceeded with the formation of multiple side products due to
concomitant opening and isomerization of butenolide. To
address this problem, more labile C19 methoxyacetate 29 was
prepared in 99% yield. This compound was subjected to TfOH-
catalyzed glycosylation with 22, which resulted in α-rhamnoside
30 in 81% yield (>20:1 dr). Compound 30 was subjected to
ammonia (50% solution in methanol) to provide the desired
As the conditions for the deprotection of the C19 benzoate
were not compatible with the butenolide functionality, 17 was
subjectedtoTBSprotection(Scheme3)resultinginintermediate
19 in 74% yield.
Scheme 3. Synthesis of Cannogenol from 17
cannogenol-3-O-α-L-rhamnoside (1) in 69% yield. The 1H, 13
C
Thisprotectionwasnecessary, asthedirectStillecouplingof17
and 20 was sluggish and resulted in lower yields. In contrast, the
Stille coupling of 19 and commercially available stannylated
butenolide 20 proceeded efficiently and resulted in steroid 21 in
82% yield. This product was elaborated to cannogenol (2) via a
three-step sequence in 69% yield.4f,h This sequence involved
TMS protection of the C14 tertiary alcohol, hydrogenation of the
NMR data and optical rotation data ([α]D20 = −10.8, c = 0.147 in
MeOH, reported7 [α]D = − 15.5, c = 0.55 in MeOH) of the
20
synthetic 1 were in good agreement with the corresponding data
obtained for the natural sample of 1.6a,7,8
In conclusion, a new asymmetric approach to cardenolides
carrying the C19 oxygenation has been developed and applied to
the synthesis of the natural products cannogenol (2) and
C
DOI: 10.1021/acs.orglett.7b03513
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Letter
Scheme 5. Synthesis of Cannogenol-3-O-α-L-rhamnoside (1)
from Cannogenol (2)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nagorny@umich.edu.
ORCID
Bijay Bhattarai: 0000-0001-6972-1998
Pavel Nagorny: 0000-0002-7043-984X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by the NIH (R01GM111476). We
thank Dr. Hem Khatri (University of Michigan), Ayesha Patel
(University of Michigan), Dr. Nathan Cichowicz (University of
Michigan), and Zachary Fejedelem (University of Michigan) for
the help in the initial stage of these studies.
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cannogenol-3-O-α-L-rhamnoside (1) possessing anticancer
activity. This approach features 3 g scale enantioselective
synthesis of the functionalized cardenolide core in 6 linear
steps, 17% yield, and 92% ee involving an enantioselective
Michael/tandem Aldol addition sequence established by our
group earlier. This key intermediate could be elaborated to
cardenolide cannogenol (2) in 9 steps, 20% yield. Cannogenol
(2) contains multiple hydroxyl functionalities, and a strategy for
the selective introduction of sugar moieties at the C3 position of 2
was developed and successfully applied to the formation of
cannogenol-3-O-α-L-rhamnoside (1). The herein described
strategies will expedite medicinal chemistry studies on C19-
hydroxylated cardenolides related to cannogenol, and the
exploration of 1, 2, and related analogs is the subject of ongoing
investigation by our group.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b03513.
1
Experimental procedures, H and 13C NMR spectra of
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H.-B.; Cui, J.-R.; Shang, M.-Y.; Cai, S.-Q. J. Nat. Prod. 2007, 70, 1429.
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compounds (PDF)
Accession Codes
CCDC 1585371 contains the supplementary crystallographic
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, UK; fax: +44 1223 336033.
D
DOI: 10.1021/acs.orglett.7b03513
Org. Lett. XXXX, XXX, XXX−XXX