Synthesis of (-)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition-Rearrangement and Cross-electrophile Coupling

Article abstract of DOI:10.1021/acs.orglett.7b01513

An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp³-Csp² cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product.

Full text of DOI:10.1021/acs.orglett.7b01513

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Synthesis of (−)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide
Cycloaddition−Rearrangement and Cross-electrophile Coupling
Younes Fegheh-Hassanpour, Tanzeel Arif,† Herman O. Sintim,§ Hamad H. Al Mamari,‡
and David M. Hodgson*
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom
S
* Supporting Information
ABSTRACT: An asymmetric synthesis of (−)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the
following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation−hydrolysis to
provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide
formation−cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and
(3) stereoretentive Ni-catalyzed Csp3−Csp2 cross-electrophile coupling between tricarboxylate core and unsaturated side chain
to complete the natural product.
the C-1 position of the 2,8-dioxabicyclo[3.2.1]octane core 3.
haracterized by a 2,8-dioxabicyclo[3.2.1]octane core
Cadorned with hydroxyl and carboxylic acid functionality Following cycloaddition and rearrangement, it was anticipated
this strategy would then allow convergent and flexible side-
chain introduction through Csp3−Csp2 cross-coupling12 with a
suitable alkene partner 4. The carbonyl ylide precursor,
diazoketone 8, could, in principle, be accessed following our
earlier racemic approach involving aldol reaction between a
diazoacetate and an α-ketoester; however, the only known
asymmetric variant is not viable with enolizable α−ketoesters.13
On consideration of alternatives, we conceived a new strategy
that would simultaneously generate the ylidic carbonyl
progenitor and diazo functionality, involving chemoselective
ozonolysis of an unsaturated hydrazone 9. We viewed the
corresponding unsaturated ketone precursor 10 as potentially
being available, as a single enantiomer, through a novel use of
R,R-tartrate 11 “contra-steric”14 alkylation chemistry originally
described by Seebach.15 Although Seebach reported that the
limited stability of the lithium enolate of tartrate acetonide 11
restricted feasible alkylation to reactive (methyl, allylic,
benzylic) halides (∼85:15 drs),15 we have found that n-alkyl
iodides can be successfully induced to react under prolonged
reaction times at low temperature and with improved
(essentially complete) diastereoselectivity (eg, n-PrI, 66%
yield). For the current synthesis (Scheme 2), homoallylic
iodide 15 was prepared in three steps from isoprenol (12) by
addition of paraformaldehyde to the corresponding dianion,16
monobenzylation17 of the resulting symmetrical diol 13, and
iodination of benzyl ether 14. Reaction of iodide 15 with
(1, Scheme 1), the zaragozic acids/squalestatins have been the
focus of considerable interest ever since reports of their
isolation appeared in the early 1990s.1 Potent mammalian
squalene synthase inhibition originally propelled these natural
products into the limelight as lead structures for cholesterol-
lowering therapeutics.2 More recent studies include potential
application for retinal degenerative disorders,3 new antima-
larials,4 activity against hepatitis C,5 and antitumor agents.6 The
biological activity combined with their structural challenges and
novelty have made them compelling targets for synthetic
studies, and many inventive strategies have been investigated
resulting in several full, partial, and model syntheses of
members of the zaragozic acid/squalestatin family.7 Our
approach has focused on construction of the core 3 of 6,7-
dideoxysqualestatin H5 (2)8 from a diazoketone 8 using
Rh(II)-catalyzed tandem carbon ylide formation and cyclo-
addition with a glyoxylate (8 → 7 → 5), followed by acid-
catalyzed transketalization (Scheme 1). While so far only
demonstrated on a racemic model system bearing a methyl
group at C-1 (CH2X = H),9 we considered the complexity-
inducing pericyclic transformation10 attractive for further
development as it delivers the correct stereochemistry at the
desired triacid oxidation level. In the present work, we report
the advancement of this chemistry to a synthesis of (−)-6,7-
dideoxysqualestatin H5 (2).11
Successful translation of our earlier observations to a
synthesis of (−)-6,7-dideoxysqualestatin H5 (2) first required
asymmetric access to a carbonyl ylide precursor 8, containing
functionality (X) to subsequently install the full side-chain at
Received: May 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01513
Org. Lett. XXXX, XXX, XXX−XXX

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lithiated tartrate acetonide resulted in the isolation of
diastereomerically pure alkylated tartrate 16 in 78% yield.
Conversion of the alkylated tartrate 16 to the unsaturated
ketone 18 was achieved by oxidation of the lithium enolate of
the alkylated tartrate 16 using MoOPH18 followed by acid-
catalyzed elimination of acetone from the resulting hydrox-
yacetonide 17 and tertiary alcohol silylation.
Scheme 1. Retrosynthetic Analysis of 2
With a new and asymmetric route to the β-oxy-α-ketoester
motif established, conversion of the hydrazone 19, derived from
unsaturated ketone 18, to the carbon ylide precursor,
diazoketone 20, could be studied. Revealing the diazo
functionality prior to double-bond manipulation was antici-
pated to be problematic since a structurally related (but
simpler) unsaturated α-diazoester has been observed to
undergo spontaneous intramolecular dipolar cycloaddition to
give a 1-pyrazoline.19 Also, under ozonolysis conditions,
hydrazones are known to transform to ketones,20 but the rate
of this currently undesired process is expected to be reduced by
proximal electron deficiency20a (in the present case by the
presence of the ester and Ts groups). In the event, ozonolysis
of unsaturated hydrazone 19 in the presence of Sudan red 7B as
an end-point indicator21 followed by addition of Et3N cleanly
produced diazoketone 20 (80% yield);22 here, the Et3N
functions as a base in two processes: facilitating anionic
cycloreversion of the intermediate ozonide to the ketone (and
triethylammonium formate)23 and in the Bamford−Stevens
reaction.24
Rh2(OAc)4-catalyzed tandem carbon ylide formation cyclo-
addition of diazoketone 20 with methyl glyoxylate followed the
Scheme 2. Synthesis of (−)-6,7-Dideoxysqualestatin H5 (2)
B
DOI: 10.1021/acs.orglett.7b01513
Org. Lett. XXXX, XXX, XXX−XXX

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desired regio- and stereochemical induction for squalestatin
synthesis, as anticipated from our previous model study.9
Cycloadduct 21 was isolated in 75% yield; minor isomeric
cycloadducts may have also formed in the reaction but could
not be isolated. The structure of cycloadduct 21 was confirmed
following debenzylation by X-ray crystallographic analysis of
the resulting primary alcohol 22.25 The stereochemical
outcome of the cycloaddition can be rationalized by the
glyoxylate preferentially undergoing reaction on the less-
hindered face (opposite the silyloxy group) of the carbonyl
ylide 7 (Scheme 1) and orientating exo (with respect to the
ylide-containing ring) to minimize interactions with the out-of-
plane (β-) ester group. Acid-catalyzed transketalization (best
carried out after debenzylation) with concomitant desilylation
gave a 60:40 ratio of unrearranged and rearranged cores (23
and 24, respectively). In the model system (Scheme 1, CH2X =
H), the rearranged core was favored (34:66).9 These results
indicate the equilibrium position is sensitive to variation in the
C-1 chain. Nevertheless, the unrearranged diol 23 could be
separated and resubmitted to the reaction conditions, and after
two cycles, the desired diol 24 was obtained in 68% overall
yield.
The E-alkenyl iodide bearing side chain 4 required for
attachment to the core was prepared from R-α-benzyl
propionaldehyde26 in three steps involving Corey−Fuchs
homologation to the alkyne 6 and hydrozirconation−
iodination27 (Scheme 1).25 In preparation for cross-coupling,
the primary alcohol of diol 24 was activated as the iodide 25;
however, iodide 25 (and the corresponding bromide) displayed
unexpected thermal instability on moving to 40 °C or above
which, along with the pre-existing functionality on the core,
significantly limited the cross-coupling protocols that could
potentially be investigated.12 After a lack of success with some
more traditional approaches,28 we were attracted to recent
methodological developments in reductive cross-electrophile
coupling29 where prior generation of one of the partners as a
carbon nucleophile is redundant. In particular, we focused on
the Ni-catalyzed technology pioneered by Weix30 due to the
chemistry showing promise for reasonable stereoretention with
an internal E-alkenyl halide being tolerant of ester functionality
and, in the most recent report,30c operating at ambient
temperature. Under optimized conditions (solvent, ratio of
reactants, concentration, and additives were examined on
model systems),25 a 1:1 mixture of hydroxy iodide 25 and
alkenyl iodide 4 in DMF (0.8 M) gave alkene 26 in 66% yield
with complete stereoretention. Desilylation using TBAF was
accompanied by hydrolysis31 of the C-3 ester to give the
known8c diester 27 in 67% yield. Finally, hydrolysis of the
remaining more-hindered esters using anhydrous KOH32 gave
(−)-6,7-dideoxysqualestatin H5 2 possessing spectral data in
complete agreement with that previously reported.8
showcases the power of the latter pericyclic process to deliver
high levels of stereocontrol from functional group rich
precursors. Finally, a late-stage ester and alcohol functional
group-tolerant Ni-catalyzed Mn-mediated Csp3−Csp2 cross-
electrophile coupling involving equimolar quantities of the
halide partners and occurring at room temperature with
geometrical integrity at the internal alkenyl halide demonstrates
the utility of this emerging technology in complex natural
product synthesis.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01513.
Detailed experimental procedures, spectral data and X-
ray crystallographic data (PDF)
X-ray data for compound 22 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.hodgson@chem.ox.ac.uk.
ORCID
Herman O. Sintim: 0000-0002-2280-9359
David M. Hodgson: 0000-0001-7201-9841
Present Addresses
†(T.A.) Ferrier Research Institute, Victoria University of
Wellington 6012, New Zealand.
§(H.O.S.) Department of Chemistry, Purdue University, West
Lafayette, IN 47907−2112.
‡(H.H.A.M.) Department of Chemistry, Sultan Qaboos
University, Muscat 123, Oman.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC, the Higher Education Commission of
Pakistan, the University of Oxford, and the Sultanate of Oman
for studentship support (to Y.F.H., T.A., H.O.S., and H.H.A.M.,
respectively), Dr. John Jolliffe (Oxford) for crystal structure
determination and Dr. Paolo Ricci (Oxford) for assistance with
HPLC purification.
REFERENCES
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DOI: 10.1021/acs.orglett.7b01513
Org. Lett. XXXX, XXX, XXX−XXX