Total synthesis of (+)-roxaticin via C-C bond forming transfer hydrogenation: A departure from stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles in polyketide construction

Article abstract of DOI:10.1021/ja1082798

A total synthesis of the oxo-polyene macrolide (+)-roxaticin is achieved in 20 steps from 1,3-propanediol. In this approach, 9 of 10 C-C bonds formed in the longest linear sequence are made via metal catalysis, including 7 C-C bonds formed by iridium cata

Full text of DOI:10.1021/ja1082798

Published on Web 10/20/2010
Total Synthesis of (+)-Roxaticin via C-C Bond Forming Transfer
Hydrogenation: A Departure from Stoichiometric Chiral Reagents, Auxiliaries,
and Premetalated Nucleophiles in Polyketide Construction
Soo Bong Han, Abbas Hassan, In Su Kim, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received September 13, 2010; E-mail: mkrische@mail.utexas.edu
Scheme 1. Representative Oxo-polyene Macrolides and
Retrosynthetic Analysis of (+)-Roxaticina
Abstract: A total synthesis of the oxo-polyene macrolide (+)-
roxaticin is achieved in 20 steps from 1,3-propanediol. In this
approach, 9 of 10 C-C bonds formed in the longest linear
sequence are made via metal catalysis, including 7 C-C bonds
formed by iridium catalyzed alcohol C-C coupling. Notably, the
present synthesis, which represents the most concise preparation
of any oxo-polyene macrolide reported to date, is achieved in
the absence of chiral reagents and chiral auxiliaries with minimal
use of premetalated C-nucleophiles.
Polyketide natural products represent a broad class of secondary
metabolites used extensively in human medicine.1,2 Approximately
20% of the top-selling small molecule drugs are polyketides,2,3 and
it is estimated that polyketides are five times more likely to possess
drug activity compared to other natural product families.3 As
investigations into polyketide biosynthesis4 and chemical biology
continue to uncover important biochemical pathways and novel
therapeutic targets, the design of synthetic5 and bioengineered6
methods for polyketide construction remains at the forefront of
research.
a See Supporting Information for a graphical summary of prior syntheses.
Double C-allylation of 1,3-propanediol was accomplished as
previously described using the ortho-cyclometalated iridium C,O-
benzoate generated in situ from [Ir(cod)Cl]2, (R)-Cl,MeO-BIPHEP,
4-chloro-3-nitrobenzoic acid, and allyl acetate (eq 1).11c,d The C2-
symmetric product of double allylation 1 is obtained in 70% yield
and >99% ee, as the minor enantiomer of the monoadduct is
converted to the meso-diastereomer of 1.13,14 On a larger scale (20
mmol), to mitigate cost, double allylation reactions were conducted
using the corresponding (R)-BINAP complex, which provides 1 in
51% yield with equivalent levels of absolute stereocontrol.
The complex issues of stereoselectivity posed by polyketides are
most often addressed through the use of chiral auxiliaries, chiral
reagents, and premetalated nucleophiles.5 Although such methods
are highly effective, their use often mandates multistage preacti-
vation and excessive byproduct generation. Inspired by the atom
economy of catalytic hydrogenation, we have developed a broad
family of enantioselective “C-C bond forming hydrogenations,”7
which provide an alternative to stoichiometric organometallic
reagents in certain carbonyl and imine additions. Here, we showcase
the utility of this methodology in a total synthesis of the oxo-polyene
macrolide (+)-roxaticin.8,9d-h,10
Our approach takes advantage of carbonyl allylation7f,11a-d and
crotylation7f,11e protocols recently developed in our laboratory, wherein
primary alcohol dehydrogenation concurrently triggers aldehyde
formation and reductive generation of allyliridium nucleophiles,
enabling asymmetric carbonyl allylation and crotylation directly from
the alcohol oxidation level. Iterative two-directional carbonyl allylation
of 1,3-diols11c,d,12 was envisioned to deliver the requisite C2-symmetric
1,3-polyol substructure spanning C14-C28. Elaboration of the pro-
tected 1,3-polyol 3 to (+)-roxaticin requires differential elongation of
the homotopic diol termini, which is potentially achieved Via sequential
dehydration-cross-metathesis at C28 and direct carbonyl crotylation
from the alcohol oxidation level at C14. Installation of the oxo-
pentaene fragment takes advantage of a sequence involving cross-
metathesis-Horner-Wadsworth-Emmons olefination. Subsequent
macrocyclization and global deprotection would deliver (+)-roxaticin
(Scheme 1).
Conversion of 1 to the acetonide followed by ozonolysis of the
olefinic termini provides the homologous diol 2, constituting “one
iteration” of two-directional carbonyl allylation from the alcohol
oxidation level. In principle, subsequent iterations of two-directional
carbonyl allylation could be performed from the diol or dialdehyde
oxidation level. However, the ꢀ-alkoxy aldehydes were found to
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10.1021/ja1082798  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 15559–15561 15559

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of the Oxo-polyene Macrolide (+)-Roxaticin via C-C Bond Forming Transfer Hydrogenationa
a Yields are of material isolated by silica gel chromatography and represent the average of two runs. Enantiomeric excess of 1 was determined by chiral
stationary phase HPLC analysis. See Supporting Information for preparation of homoallylic ether A and other experimental details.
be quite unstable, whereas diol intermediates, such as 2, are highly
tractable and may be stored for long periods of time under ambient
conditions without decomposition. Therefore, in subsequent itera-
tions of two-directional carbonyl allylation, ozonolysis reactions
were quenched with NaBH4 to furnish the homologous diols.15 In
the following two double allylation reactions, complete levels of
catalyst-directed diastereoselectivity were observed, providing rapid
access to the acetonide-protected C2-symmetric 1,3-polyol 3 as a
single diastereomer. Thus, tris-acetonide 3, which possesses six
stereocenters, is prepared in only nine steps from 1,3-propanediol
(Scheme 2).
of 7d, which lacks a C14 hydroxyl protecting group, was unsuc-
cessful.
Differential elongation of the diol termini of tris-acetonide 3
begins with Grieco’s two-step method for primary alcohol dehydra-
tion.16 Because the diol termini of 3 are homotopic, the product
appears as a component of a statistical mixture. The resulting allylic
ether was exposed to the previously prepared homoallylic ether A17
in the presence of the second generation Hoveyda-Grubbs catalyst
to furnish the product of cross-metathesis 5 in 53% yield with
complete (E)-selectivity, as determined by 1H NMR.18 Direct
carbonyl crotylation from the alcohol oxidation level at C14 using
the preformed iridium C,O-benzoate complex (S)-II (eq 2) delivers
the desired adduct 6a in 85% yield with 14:1 anti-diastereoselec-
tivity.
Elaboration of hydroxy enal 7c to (+)-roxaticin was accomplished
as follows. Exposure of 7c to the previously reported Horner-
Wadsworth-Emmons reagent, EtO2C(CHdCH)3CH2PO(OEt)2,20 de-
livered the polyunsaturated ester in 61% yield. This transformation,
which involves LHMDS mediated lithium enolate generation, repre-
sents the sole use of a premetalated C-nucleophile in the longest linear
sequence. Ester hydrolysis followed by Yamaguchi lactonization21 and
global deprotection, as practiced in prior syntheses by Mori9e-g and
Evans,9h delivers (+)-roxaticin in 31% yield over the three-step
sequence. The last step of the longest linear sequence, which involves
hydrolysis of three acetonide moieties and a TES-ether, was particularly
daunting, as in Evan’s synthesis9h acetonide protecting groups could
not be removed and were abandoned for cyclopentylidene ketals, which
are hydrolytically more labile. Hence, in the present macrolactoniza-
tion-global deprotection sequence, it is possible that even higher
efficiencies would be observed were cyclopentylidene ketals employed
as protecting groups.
In summary, in this initial application of our “C-C bond forming
hydrogenation” methodology, (+)-roxaticin is prepared from 1,3-
propane diol in 20 steps (longest linear sequence), with a total
number of 29 manipulations. Notably, 9 of 10 C-C bonds formed
in the longest linear sequence are made via metal catalysis (7
hydrogen-mediated C-C couplings, 2 cross-metatheses) in pro-
cesses that exploit “native functionality” (alcohols, olefins). This
With homoallylic alcohol 6a in hand, installation of the polyene
substructure was undertaken. The unprotected homoallylic alcohol
6a was subjected to cross-metathesis with acrolein to deliver the
corresponding enal 7a in 68% yield with complete (E)-selectivity,
19
1
as determined by H NMR. Subsequent protection of the C14
alcohol to provide the triethylsilyl (TES) ether 7b was followed
by oxidative removal of the para-methoxybenzyl ether to furnish
hydroxy enal 7c. This specific sequence of functional group
interconversions was essential as the TES-ether 6b does not
participate in cross-metathesis, presumably due to the sterically
demanding environment at the homoallylic olefin. Additionally,
selective protection of the C14 and C30 diol 6c was not possible
under a variety of conditions. Finally, attempted macrolactonization
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C O M M U N I C A T I O N S
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approach circumvents additional manipulations associated with the
use of non-native functional groups or substructures to mediate bond
construction, as evident in the use of chiral auxiliaries, and
minimizes (re)functionalizations, especially redox manipulations.
Indeed, as demonstrated in carbonyl additions from the alcohol
oxidation level, as in the conversion of 5 to 6a, the union of
oxidation-construction events allows one to bypass discrete alcohol
oxidation while gaining access to more tractable synthetic inter-
mediates in the form of alcohols. These features are in line with
longstanding ideals of synthetic efficiency.22,23
Acknowledgment. Acknowledgment is made to the Robert A.
Welch Foundation (F-0038), the NIH-NIGMS (RO1-GM069445),
the American Chemical Society Green Chemistry Institute Phar-
maceutical Roundtable, and the University of Texas at Austin,
Center for Green Chemistry and Catalysis. Dr. Yasunori Ino, Dr.
Wataru Kuriyama, and Dr. Taichiro Touge of Takasago are thanked
for the generous donation of SEGPHOS. The Higher Education
Commission of Pakistan is acknowledged for graduate student
fellowship support (A.H.). The Korea Research Foundation (KRF-
2007-356-E00037) is acknowledged for postdoctoral fellowship
support (I.S.K.).
Supporting Information Available: Detailed experimental proce-
dures, spectral data for new compounds, including scanned images of
1H and 13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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