All-catalytic, efficient, and asymmetric synthesis of α,ω- diheterofunctional reduced polypropionates via "one-pot" Zr-catalyzed asymmetric carboalumination - Pd-catalyzed cross-coupling tandem process

Article abstract of DOI:10.1021/ja043534z

A highly efficient method for the synthesis of stereochemically pure (≥99% ee and >50/1 dr) α,ω-diheterofunctional reduced polypropionates has been developed. The essential features of the method are represented by the conversion of inexpensive styrene in

Full text of DOI:10.1021/ja043534z

Published on Web 02/11/2005
All-Catalytic, Efficient, and Asymmetric Synthesis of r,ω-Diheterofunctional
Reduced Polypropionates via “One-Pot” Zr-Catalyzed Asymmetric
Carboalumination-Pd-Catalyzed Cross-Coupling Tandem Process
Tibor Novak, Ze Tan, Bo Liang, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907
Received October 25, 2004; E-mail: negishi@purdue.edu
Scheme 1 a
We report herein a highly efficient method for the synthesis of
stereoisomerically pure (g99% ee and >50/1 dr) R,ω-dihetero-
functional reduced polypropionates, the essential features of which
are represented by the conversion of inexpensive (<$1/mol) styrene
into 2-methyl-4-phenyl-1-pentanol1 (1) in 50% yield over two steps
from styrene via Zr-catalyzed asymmetric carboalumination2,3
(ZACA reaction) and Pd-catalyzed vinylation of the in situ
generated isoalkylalanes4 promoted by Zn(OTf)2 (Scheme 1). Since
oxidation of the first ZACA reaction with O2 gave 2-phenyl-1-
propanol of 89% ee by HPLC analysis of the urethane obtained by
treating the alcohol with 1-R-naphthylethyl isocyanate, the diaster-
eomeric ratio (dr) of 7.0/1 observed by 13C NMR spectroscopy for
1, before purification, indicated that the enantioface selectivity in
the second ZACA reaction was 92% and that 1 should be 99% ee.
The undesired diastereomers of 1 could be separated by ordinary
column chromatography. For synthetic applications of 1, however,
diastereomeric separation may be more efficiently and profitably
performed after the conversion of the phenyl group into COOH
and OH (vide infra).
a ZACA ) Me3Al (2-5 equiv), MAO (e0.1 equiv), or H2O (1 equiv),
3-5 mol % (+)- or (-)-(NMI)2ZrCl2 for (+) or (-)-ZACA, respectively,
CH2Cl2. Pd-cat. vinylation ) (a) evaporation of volatiles, (b) Zn(OTf)2 (1-
1.5 equiv), DMF, 70 °C, (c) 3% Pd(DPEphos)Cl2, 6% DIBAL-H,
BrCHdCH2 (5-6 equiv).
Scheme 2
To demonstrate the feasibility of using terminally phenyl-
substituted methyl-branched alcohols as intermediates for the
synthesis of R,ω-diheterofunctional polypropionates, a 7/1 diaster-
eomeric mixture of 1 was acetylated first in quantitative yield and
iBu2AlH (DIBAL-H) in a 1:2 molar ratio as a catalyst system,
and (iii) DMF as a solvent was critically important (Scheme 2).
The ZACA reaction of 1-octene proceeded in 75% ee (Mosher ester
analysis10 of 2-methyl-1-octanol). After Pd-catalyzed vinylation at
elevated temperature (120 °C used), the product was oxidatively
cleaved11 to produce 3-methylnonanoic acid. Analysis by HPLC
of the amide obtained by treating the acid with (S)-1-(R-naphthyl)-
ethylamine, NCP(O)(OEt)2, Et3N, and DMF12 indicated the car-
boxylic acid to be 75% ee. Thus, no racemization took place under
the conditions of the Pd-catalyzed vinylation.
Ionomycin13 (4) and borrelidin14 (5) are representative examples
of natural products containing reduced polypropionate moieties that
have been synthesized via R,ω-diheterofunctional tri- and tetra-
methyl-branched intermediates, respectively. Although reported
syntheses appear satisfactory, all require at least in some steps the
stoichiometric amounts or even excesses of enantiometrically pure
starting materials and/or chiral auxiliaries. To demonstrate the
feasibility of constructing some of the key intermediates employed
in the previous syntheses in an “all-catalytic” manner, 613 was
chosen for the synthesis of ionomycin (Scheme 3). For the synthesis
of borrelidin (5), 7a used by Kuwajima and Omura14d and 7b used
by Theodorakis14c were chosen (Scheme 4).
5
then subjected to Ru-catalyzed oxidation with NaIO4 to give
5-acetoxy-2,4-dimethylpentanoic acid (2) in 75% yield over two
steps. Hydrolysis of a 7/1 diastereomeric mixture of 2 with
methanolic K2CO3 followed by acidification with 2 N HCl produced
36 as a 7/1 diastereomeric mixture in quantitative yield. Thus,
conversion of 1 to 3 via 2 proceeded without epimerization.
Comparison of the 1H and 13C NMR spectral data with the reported
values in conjunction with the previously established absolute
stereochemistry for the first ZACA reaction2a,3 has firmly established
that the major stereoisomers of 1-3 are the expected (2S,4S)
isomers, as shown in Scheme 1. Similarly, a syn isomer of 1, i.e.,
(2S,4R)-1, was prepared in 47% yield over two steps as a 4.6/1
diastereomeric mixture by using (+)-(NMI)2ZrCl27 for both ZACA
reaction steps. It is noteworthy that the diastereomeric ratio is higher
for the formation of the anti isomer of 1, i.e., (2S,4S)-1 (dr ) 7.0/
1), than that of the syn isomer of 1, i.e., (2S,4R)-1 (dr ) 4.6/1).8 In
all previous cases, where 1-alkenes containing chiral alkyl groups
were subjected to the ZACA reaction, there was either a minor
preference for the formation of the syn isomers or essentially no
internal asymmetric induction.2e-g
The high efficiency in the conversation of styrene into 1 is also
critically dependent on the development of a satisfactory Pd-
catalyzed vinylation of the in situ generated isoalkyldimethylalanes
without oxidation to alcohols and/or conversion to iodides, the latter
of which is to be subsequently lithiated with the use of 2 equiv of
tBuLi before generation of alkylzinc derivatives to be vinylated.
In the synthesis of 6 shown in Scheme 3, the most sluggish first
ZACA reaction was promoted by the use of 5 equiv of Me3Al and
in situ generation of MAO by addition of 1 equiv of H2O.3 For the
other cases, 2 equiv of Me3Al were sufficient, and 0.1 equiv of
MAO was used as a promoter only in the third step. Crude 8 thus
obtained in 39% yield over three steps was a mixture of the desired
isomer and the three major diastereomers containing minor amounts
9
The use of (i) Zn(OTf)2 as an additive, (ii) Pd(DPEphos)Cl2 and
9
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J. AM. CHEM. SOC. 2005, 127, 2838-2839
10.1021/ja043534z CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
recovery) by chromatography (silica gel, 5/95 EtOAc-hexanes).
Thus, pure 11 was prepared in 10% yield over seven steps and
two chromatographic operations. Protection of 11 with dihydropyran
and TsOH followed by ester hydrolysis with methanolic K2CO3
t
gave 7a,13d while protection of 11 with BuPh2SiCl followed by
deacetylation provided 7b (99% ee by NMR analysis of the Mosher
esters).13c
In summary, an efficient all-catalytic asymmetric protocol for
the synthesis of R,ω-diheterofunctional reduced polypropionates
represented by 6 and 7 (dr g50/1) has been developed perhaps for
the first time. Although there is room for further improvements,
the protocol presented herein promises to make the synthesis of
R,ω-diheterofunctional reduced polypropionates more efficient and
satisfactory.
a See Scheme 1 for the ZACA and Pd-catalyzed vinylation conditions.
Acknowledgment. This paper is dedicated to Professor Amos
B. Smith on the occasion of his 60th birthday. We thank the
National Institutes of Health (GM 36792), the National Science
Foundation (CHE-0309613), and Purdue University for financial
support. We also thank Prof. E. A. Theodorakis for spectral data
of 7b.
Scheme 4 a
Supporting Information Available: Detailed experimental pro-
cedures and compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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