Iterative synthesis of (Oligo)deoxypropionates via zinc-catalyzed enantiospecific sp3-sp3cross-coupling

Article abstract of DOI:10.1021/ol901944b

This group's recently reported mild zinc-catalyzed enantlospeclflc sp ³-sp³ cross-coupling of lactic acid tert-butylester triflate with Grignard reagents was now applied to an iterative approach in the synthesis of a series of all fo

Full text of DOI:10.1021/ol901944b

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4668-4670
Iterative Synthesis of
(Oligo)deoxypropionates via
Zinc-Catalyzed Enantiospecific sp3-sp3
Cross-Coupling
Gabriel J. Brand, Christopher Studte, and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Freiburg Institute for AdVanced Studies
(FRIAS), Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21,
79104 Freiburg, Germany
bernhard.breit@chemie.uni-freiburg.de
Received August 21, 2009
ABSTRACT
This group’s recently reported mild zinc-catalyzed enantiospecific sp3-sp3 cross-coupling of lactic acid tert-butylester triflate with Grignard
reagents was now applied to an iterative approach in the synthesis of a series of all four possible diastereomers of the shown trideoxypropionate.
Oligodeoxypropionate structures are a common motif in a large number of biologically relevant natural products of polyketide origin thus
making our approach a versatile tool in their synthesis.
(Oligo)deoxypropionate structures are common motifs in a
large number of biologically relevant natural products of
polyketide origin.1 Several iterative methods2 have been
reported on their synthesis to date. Most strategies rely on
asymmetric induction resulting from either chiral auxiliaries
(e.g., the alkylation of enolates,3 amide enolates,4 or aza-
enolates5) or resident chirality as in the case of the conjugate
addition disclosed by Hanessian6 or the allylic alkylation
developed in our own group.7 In the past few years, iterative
catalytic asymmetric approaches reported by Negishi8 and
Feringa9 have further advanced this field.
However, the development of simple and highly flexible
procedures to access deoxypropionate units with complete
control of their relative and absolute configuration still
remains a challenging task.
Recently, we have reported a new method that allows for
(1) Ionomycin: Liu, W.-C.; Smith-Slusarchyk, D.; Astle, G.; Trejo,
W. H.; Brown, W. E.; Meyers, E. J. J. Antibiot. 1978, 31, 815. Borrelidin:
Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch. Biochem. 1949, 22,
476.
the mild zinc-catalyzed enantiospecific sp3-sp3-coupling of
(6) Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel,
F. J. Am. Chem. Soc. 2003, 125, 13784.
(2) For a good review on iterative deoxypropionate synthesis, see:
Hanessian, S.; Giroux, S.; Mascitti, V. Synthesis 2006, 7, 1057.
(3) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R.
J. Am. Chem. Soc. 1990, 112, 5290.
(7) Breit, B.; Herber, C. Angew. Chem. 2004, 116, 3878. Breit, B.;
Herber, C. Angew. Chem. 2005, 117, 5401.
(8) Novak, T.; Tan, Z.; Liang, B.; Negishi, E.-I. J. Am. Chem. Soc. 2005,
127, 2838.
(4) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett 1997,
457.
(9) Des Mazery, R.; Pullez, M.; Lo´pez, F.; Harutyunyan, S. R.; Minnaard,
A. J.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 9966.
(5) Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823.
10.1021/ol901944b CCC: $40.75
Published on Web 09/17/2009
 2009 American Chemical Society

a great variety of Grignard reagents with different R-hydroxy
ester triflates derived from the chiral pool.10 Starting from
enantiopure lactic acid tert-butyl ester triflate affords chiral
R-methyl-substituted esters with complete inversion of
configuration (Scheme 1).
relying simply on readily available lactic acid. Their sub-
sequent conversion to highly functionalized (e.g., biscar-
boxylic acid) substrates is also shown.
The synthesis of trideoxypropionates (Scheme 2) started
with a coupling reaction of phenylethyl Grignard (3) to lactic
acid tert-butyl ester triflate (L- or D-1) in the presence of a
catalytic amount of ZnCl2 affording products (S)-2 and (R)-2
in high yield (up to 87%) as single enantiomers as determined
by chiral HPLC. This reaction set the first deoxypropionate
unit. We chose the phenyl moiety as a “masked” carboxylic
acid, which at a later stage of the synthesis can easily be
transformed by using oxidizing conditions.11
Scheme 1.
Zn-Catalyzed sp3-sp3 Cross-Coupling
Iteration for dideoxypropionate construction began with
the reduction of the esters 2 with LAH yielding the
corresponding alcohols (up to 95%) which were transformed
by a Mukaiyama redox condensation12 to the corresponding
chlorides (up to 92%). From these, the Grignard reagents
(S)-4 and (R)-4 were generated and coupled once again under
the above-mentioned conditions with L-1 and D-1, respec-
tively. This afforded in excellent yield diastereoisomers syn-6
In an extension of this versatile method, we report herein
on a new practical strategy for the iterative synthesis of
(oligo)deoxypropionates. This approach allowed us to syn-
thesize all four possible diastereoisomers of trideoxypropi-
onates without the need of any chiral auxiliary or ligand,
Scheme 2
.
Enantioselective Iterative Synthesis of Di- and Trideoxypropionates on the Basis of a Zinc-Catalyzed sp3-sp3
Cross-Couplinga
a Reagents and general conditions: (1) LAH, Et2O, 0 °C, 30 min; (2) Cl3CCN, PPh3, DCM, 0 °C to rt, 3 h; (3) Mg, THF, reflux 3 h; 1, ZnCl2 (0.10 equiv),
THF, 0 °C, overnight. All ee and de determined by HPLC.
Org. Lett., Vol. 11, No. 20, 2009
4669

and anti-6 (87%, up to 10 mmol scale) as well as the
enantiomers (not shown). All ee and de were determined by
chiral HPLC to be >99%. Now the above-mentioned reduc-
tion/chlorination/Grignard formation procedure could be
repeated to construct syn-7 and anti-7 which were coupled
again to either L-1 or D-1 giving rise to all four diastereoi-
somers 8-11 of trideoxypropionates in excellent yield (up
to 92%, de > 99%).
To further demonstrate the power of our synthesis we
derivatized the trideoxypropionate 9 by converting the phenyl
moiety via oxidative cleavage with RuCl3/NaIO4 to the
carboxylic acid11 giving rise to highly substituted monoprotected
biscarboxylic acid 12 in good yield (72%) (Scheme 3).
a third Grignard reagent to give a triorganozincate species
(R3ZnMgCl). Calculations suggest that this molecule has a
trigonal planar structure14 in which the hybridization state
of the zinc-carbon bond has changed from sp to sp2. The
higher degree of p character now polarizes the electron
density in the bond toward the carbon atom resulting in an
increased nucleophilicity of the alkyl substituents. This in
turn facilitates an SN2 substitution of the triflate by the alkyl
group. Furthermore, experimental data suggest a coordination
of the magnesium ion to the triflate to occur and to be
essential since triorganozincates generated from organolith-
ium reagents do not lead to the desired product.10 Therefore,
the combination of transmetalation and Lewis acid activation
through magnesium ions seems to be the key to this highly
efficient coupling.
In summary, we have demonstrated that our recently
developed mild zinc-catalyzed enantiospecific sp3-sp3-
coupling of Grignard reagents with R-hydroxy ester triflates
is a very powerful method in the synthesis of (oligo)deox-
ypropionate structures. Enantiopure lactic acid tert-butyl ester
triflate, easily accessible from the chiral pool, has proven to
be a practical building block that allowed us to synthesize
all four diastereoisomers with perfect stereocontrol in very
high yield. Subsequent conversion of the phenyl moiety to
a carboxylic acid led to highly functionalized (oligo)deox-
ypropionate units, making this versatile methodology a
valuable and efficient tool in organic synthesis.
Scheme 3
.
Functionalization of the Phenyl Moiety to a
Carboxylic Acid
Acknowledgment. This work was supported by the DFG,
the International Research Training Group “Catalysts and
Catalytic Reactions for Organic Synthesis” (IRTG 1038), the
Fo¨rderinitiative “Zusammenspiel von molekularen Konfor-
mationen und biologischer Funktion” of the Volkswagen-
Stiftung, Novartis and Wacker (donation of chemicals). We
thank E. Schall, J. Wehrstedt, and S. Mundinger for synthetic
work as well as Dr. M. Keller and G. Fehrenbach (all at the
University of Freiburg) for analytical assistance.
Dideoxypropionate syn-6 was subjected to the same procedure
furnishing substrate 5 (71%).
As a plausible reaction mechanism for our mild coupling
reaction we postulate the following catalytic cycle13 shown
in Figure 1. In an initial step the addition of Grignard reagent
RMgCl to the zinc chloride generates a neutral, linear
diorganozinc species (R2Zn). This compound then reacts with
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901944B
(10) Studte, C.; Breit, B. Angew. Chem. 2008, 120, 5531. Studte, C.;
Breit, B. Angew. Chem., Int. Ed. 2008, 47, 5451.
(11) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
(12) Mukaiyama, T. Angew. Chem. 1976, 88, 111. Mukaiyama, T.
Angew. Chem., Int. Ed. 1976, 15, 94.
(13) Derived from the postulated mechanism for the Zn-catalyzed 1,2-
addition of Grignard reagents on carbonyl groups: Hatano, M.; Suzuki, S.;
Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.
(14) (a) Uchiyama, M.; Nakamura, S.; Ohwada, T.; Nakamura, M.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 10897. (b) Uchiyama, M.;
Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934.
Figure 1. Postulated catalytic cycle.
4670
Org. Lett., Vol. 11, No. 20, 2009