A global and local desymmetrization approach to the synthesis of steroidal alkaloids: Stereocontrolled total synthesis of paspaline

Article abstract of DOI:10.1021/jacs.5b02631

A stereocontrolled total synthesis of the indole diterpenoid natural product paspaline is described. Key steps include a highly diastereoselective enzymatic desymmetrization, substrate-directed epoxidation, Ireland-Claisen rearrangement, and diastereotopi

Full text of DOI:10.1021/jacs.5b02631

Communication
pubs.acs.org/JACS
A Global and Local Desymmetrization Approach to the Synthesis of
Steroidal Alkaloids: Stereocontrolled Total Synthesis of Paspaline
Robert J. Sharpe and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
As part of our ongoing efforts in applying stereoselective
ABSTRACT: A stereocontrolled total synthesis of the
indole diterpenoid natural product paspaline is described.
Key steps include a highly diastereoselective enzymatic
desymmetrization, substrate-directed epoxidation, Ireland-
Claisen rearrangement, and diastereotopic group selective
C−H acetoxylation to assemble the target with excellent
stereofidelity. The route and results described herein
outline complementary conceptual disconnections in the
arena of steroid natural product synthesis.
desymmetrization methods in the synthesis of chiral small
molecules,8,9 we identified paspaline and its related structures as
exemplary targets for investigation. Paspaline’s core structure
presents a number of synthetic challenges, most notably its
three all-carbon quaternary centers (C4a, C12b, C12c).
Additionally, the 2,6-cis-tetrahydropyranyl F-ring is a unique
departure from the classical steroid structure and requires
careful synthetic planning for stereoselective assembly. These
synthetic problems have been addressed through varied
approaches since paspaline’s discovery, significantly via the
work of Smith of co-workers.10 A number of total and partial
synthetic studies of paspaline and related molecules have since
been disclosed.11 In developing our synthesis plan for paspaline,
we noted that the majority of these approaches rely on the use
of the Wieland-Miescher ketone as the key intermediate for
establishing the C4a stereocenter. While this compound
represents a classical “single stereocenter” desymmetrization,12
we envisaged that a functionalized diketone such as 2 might set
the stage for a more complex desymmetrization, simultaneously
establishing both the C4a and C14a stereocenters via a
biocatalytic diketone monoreduction (3) and introducing the
functionality required for pyran assembly. In anticipation of the
challenges associated with the late-stage creation of the C12b
quaternary center,10a we hypothesized that a diastereotopic-
group selective C−H activation on dimethyl ketone 4 or its
derivatives would establish this critical stereocenter (5). This
global and local desymmetrization approach would allow
maximum control of stereochemical environments en route
to 1.
he terpene alkaloids represent a novel subset of natural
Tproducts due to their unique biological profiles and their
departure from the archetypal steroidal motif. The veratrums,
for example, have been implicated in prostate, pancreatic, and
breast cancers and, as a result, have been investigated as
therapeutics.1 Among these, jervine and cyclopamine have
demonstrated marked inhibition of the hedgehog signaling
pathway in vitro and are currently under study in clinical trials.
The structurally distinct indole diterpenoids were first
discovered from Claviceps paspali in the 1960s with the
isolation of paspaline (1, Scheme 1);2 related compounds
including paspalinine,3 paspalicine,2 paxilline,4 JBIR-03,5 and
others have since been reported.6 Derivatives of paspalinine
have shown potent activity as potassium channel antagonists
and may be useful in the treatment of glaucoma.7 JBIR-03
exhibits anti-MRSA activity and antifungal activity against apple
Valsa canker-causing fungus, Valsa ceratosperma.5
Our synthesis commenced with establishing the key C4a−
C14a stereochemical relationship via reductive desymmetriza-
tion of diketone 6 (Scheme 2).13 In a racemic sense, the
reaction of this compound with NaBH4 resulted in highly
stereoselective monoreduction (20:1 dr), giving the opposite
diastereomer to that required. Fortunately, biocatalytic
monoreduction of 6 promoted by Saccharomyces cerevisiae
completely overrode the inherent substrate bias, providing the
desired (4aR,14aS)-relationship in 7 (paspaline numbering)
with excellent diastereo- and enantioselectivity.14,15 The
remaining ketone was then converted to its tosyl hydrazone 8
in 97% yield. The reaction of trisubstituted alkene 8 with m-
CPBA followed by PPTS led to a stereoselective epoxidation/
intramolecular etherification sequence, providing the cis-pyran
9 directly in 77% yield and >20:1 dr (15 g scale), and thence
Scheme 1. Synthesis Plan for Paspaline
Received: March 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b02631
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
investigating multiple approaches to D-ring assembly.17 In the
iteration that ultimately proved successful, α-methylation of the
dianion derived from 10 followed by in situ deprotonation,
Shapiro reaction, and trapping with (HCHO)n delivered the
desired primary allylic alcohol 11 in 64% yield, which upon
esterification, gave the isobutyrate 12. To assemble the C12c
angular methyl stereocenter, we surmised that the stereo-
chemical outcome of an Ireland-Claisen reaction of ester 12
would be strongly influenced by the axial C4a methyl group; α-
approach of the intermediate silyl ketene acetal would provide
the requisite 1,3-syn-diaxial group relationship.18 Indeed,
enolization of 12 followed by silylation, heating, and hydrolysis
gave the rearrangement product 13 in 80% yield and 6:1 dr.
This reaction was the only step in the synthesis that proceeded
with less than complete stereocontrol. Esterification and
nucleophilic methylation provided the ketone 14 in 84% yield
over two steps. Hydroboration/oxidation of 14 proceeded with
virtually complete selectivity at C4b to afford diol 15 in 74%
yield, and subsequent global oxidation and cyclocondensation
concluded D-ring assembly (16). Hydrogenation of 16 and
condensation of the ketone with O-benzyl hydroxylamine
proceeded smoothly, giving oxime 17 in 82% yield.
a
Scheme 2. Stereocontrolled Synthesis of E- and F-Rings
a
Conditions: (a) YSC-2, H2O:DMSO (10:1), 30 °C; (b) TsHNNH2,
C7H8, 70 °C; (c) m-CPBA, CH2Cl2, 0 °C, then PPTS (10 mol %), rt;
(d) TBSOTf, 2,6-lutidine, CH2Cl2, −50 °C.
the silyl ether 10 upon treatment with TBSOTf. The hydrazone
was compulsory for the success of the sequence; when the same
epoxidation was carried out on the hydroxy ketone 7, we
isolated only the uncyclized oxirane with poor diastereose-
lectivity (<2:1). At this juncture, we speculate that the
hydrazone in 8 plays a critical role in imposing a favorable
reactive conformation on the cyclohexanol, placing the C14a
hydroxyl in close proximity to the alkene during oxidation and
subsequent ring closure. This reaction represents a rare case of
a substrate-directed epoxidation in which the directing group is
five carbons from the reaction center.16
Focus then turned to local desymmetrization to create the
C12b all-carbon quaternary stereogenic center (Scheme 4).
Scheme 4. Local Desymmetrizing C−H Activation to
a
Establish C12b Angular Methyl Stereochemistry
Our next challenge was construction of the sterically
congested D-ring in 1 (Scheme 3). We presumed that
hydrazone 10 would provide a great deal of flexibility in
Scheme 3. D-Ring Construction and 1,3-Bis Angular Methyl
a
Group Installation
a
Conditions: (a) Pd(OAc)2 (15 mol %), PhI(OAc)2, AcOH:Ac2O
(1:1), 100 °C; (b) HCl, H2O:MeOH:THF:acetone (10:10:10:1), 85
°C; (c) DMP, CH2Cl2, rt.
Cognizant of the fact that the lowest-energy conformation of
17 places the C−N π-bond in plane with the equatorial methyl
group, we implemented a directed C−H activation reaction
inspired by the report of Sanford and co-workers.19,20 In the
event, the direct application of Sanford’s conditions to oxime
17 provided the desired monoacetate 18 in 79% yield as a
single diastereomer (1.6 g scale). This transformation
completed assembly of the final quaternary center, which
upon global deprotection and oxidation, gave ketoaldehyde 19
poised for synthesis completion.
From tricycle 19, there remained the challenges of
establishing the C6a methine stereocenter and C-ring
construction (Scheme 5). The needed carbon atoms were
incorporated by bis-vinylation of 19 to give diol 20,21 which,
upon ring-closing metathesis, provided allylic alcohol 21 in 71%
yield. Acid-catalyzed elimination cleanly delivered the uncon-
jugated enone 22, which participated in a highly stereoselective
catalytic hydrogenation (Pd/C), providing exclusively the
epimeric C6a methine stereocenter. This selectivity was not
altogether unexpected; catalytic hydrogenation of related
steroidal systems have been documented to proceed from the
a
Conditions: (a) nBuLi, THF, −50 °C, then MeI; nBuLi, −50 °C to rt,
then (HCHO)n; (b) isobutyric acid, DCC, DMAP (10 mol %),
CH2Cl2, rt; (c) LDA, THF, −78 °C, then TMSCl, −78 to 75 °C; (d)
TMSCHN2, MeOH:C7H8 (2:1), rt; (e) MeLi, Et2O, 0 °C to rt; (f)
BH3·THF, THF, 50 °C, then H2O2, NaOH, 0 °C to rt; (g) (COCl)2,
DMSO, CH2Cl2, −78 °C, then DIPEA, −78 to 0 °C; (h) KOH,
THF:MeOH (1:1), 0 °C to rt; (i) H2 (1 atm), Pd/C (1.5 mass equiv),
EtOAc, rt; (j) NH2OBn·HCl, NaOAc, MeOH:H2O (5:1), 85 °C.
B
DOI: 10.1021/jacs.5b02631
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 5. C-Ring Construction and Synthesis Completion
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization, and spectral data for
all compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*jsj@unc.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award No. R01
GM084927 from the National Institute of General Medical
Sciences. R.J.S. acknowledges an NSF Graduate Research
Fellowship and ACS Division of Organic Chemistry graduate
fellowship. X-ray crystallography was performed by Dr. Peter
White (UNC).
REFERENCES
■
a
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Communication
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