An iterative catalytic route to enantiopure deoxypropionate subunits: Asymmetric conjugate addition of Grignard reagents to α,β-unsaturated thioesters

Article abstract of DOI:10.1021/ja053020f

A highly enantioselective (up to 96% ee) conjugate addition of Grignard reagents, in particular, MeMgBr, to α,β-unsaturated thioesters is provided as well as its application to a diastereo- and enantioselective iterative route to syn- and anti-1,3-dimethyl arrays and deoxypropionate subunits. The versatility of the method is illustrated in the synthesis of (-)-lardolure, a multimethyl-branched insect natural pheromone. Copyright

Full text of DOI:10.1021/ja053020f

Published on Web 06/23/2005
An Iterative Catalytic Route to Enantiopure Deoxypropionate Subunits:
Asymmetric Conjugate Addition of Grignard Reagents to r,â-Unsaturated
Thioesters
Renaud Des Mazery, Maddalena Pullez, Fernando Lo´pez, Syuzanna R. Harutyunyan,
Adriaan J. Minnaard,* and Ben L. Feringa*
Department of Organic Chemistry and Molecular Inorganic Chemistry, Stratingh Institute, UniVersity of Groningen,
Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Received May 9, 2005; E-mail: B.L.Feringa@rug.nl; A.J.Minnaard@rug.nl
Table 1. Enantioselective CA of Grignard Reagents (R3MgBr) to
The occurrence of polydeoxypropionate chains in numerous
biologically relevant compounds has stimulated the development
R,â-Unsaturated Thioesters (1)a,b
of methods for their stereocontrolled synthesis.1 Most of the reported
procedures are based on iterative chiral auxiliary strategies (i.e.,
enolate alkylations, conjugate additions, and allylic alkylations),2
although, very recently, an attractive iterative catalytic asymmetric
procedure was disclosed by Negishi and co-workers.3 Despite these
important advances, the development of simple, enantioselective
methods for the construction of these units with absolute stereo-
entry
1
R1
R2
Grignard (R3)
yield (3) (%)c
ee (%)d
control and high synthetic flexibility continues to be a particularly
desirable goal.
1
a
a
b
c
d
e
f
g
a
b
e
h
a
a
nPent
Et
Et
Me
Et
Et
Et
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
EtMgBr
90 (a)
90 (a)
93 (b)
93 (c)
92 (d)
92 (e)
94 (f)
88 (g)
89 (h)
91 (i)
87 (j)
90 (c)
93 (k)
80 (l)
96
96
96
2e
3e
4e
5e
6e
7e
8e
9
nPent
nPent
nBu
nPr
Recently, we reported a highly enantioselective conjugate
addition (CA) of Grignard reagents to R,â-unsaturated esters.4
Unfortunately, despite the scope of the method, the poor results
obtained in the 1,4-additions of the less reactive MeMgBr impeded
the development of catalytic iterative methodology for 1,3-dimethyl
arrays. To address this issue, we focus our attention on the more
reactive but equally readily accessible R,â-unsaturated thioesters.5
The reduced electron delocalization in the thioester moiety,6
compared to oxoesters, results in a higher reactivity toward CA
reactions,7,8 while the presence of the thioester in the chiral product
offers additional synthetic versatility.9 Herein, we report the
implementation of this strategy, which results in a practical method
for the addition of methyl Grignard reagents and a highly efficient
and enantioselective iterative catalytic protocol for the synthesis
of deoxypropionates.
95 (R)f
96 (R)f
92 (R)f,g
95 (R)f
95 (S)f
86
Et
BnO(CH2)3 Et
Ph
Et
Et
Me
Et
Et
Et
Et
nPent
nPent
Et
10
11
12
13
14
EtMgBr
87
85
nPrMgBr
nBuMgBr
iPrMgBr
iBuMgBr
Me
90 (S)f
25
nPent
nPent
15
a Conditions: 1 (1.0 equiv), R3MgBr (1.2 equiv), CuBr‚SMe2 (5 mol
t
%), 2 (6 mol %), in BuOMe (0.1 M), -75 °C, 2-5 h, unless otherwise
noted. b All conversions > 98% (GC-MS). c Isolated yield. d Regio- and
enantioselectivity determined by chiral GC or HPLC.11 e With 1 mol %
CuBr‚SMe2, 1.2 mol % 2. f Absolute configuration determined by correlation
with known compounds.11 g Enantiomeric excess determined on the
oxoester.4,11
Preliminary investigations involving unsaturated thioester 1a
revealed the feasibility of this approach. Indeed, the in situ prepared
complex from CuBr‚SMe2 (5 mol %) and Josiphos (2, 6 mol %)
catalyzed the 1,4-addition of MeMgBr, providing complete conver-
sion to 3a in 2 h at -75 °C (Table 1, entry 1). Importantly, these
conditions afforded an excellent enantioselectivity of 96% for this
CA.10 The scope of the new method was next investigated, and it
can be seen from Table 1 that a range of thioesters are suitable
substrates for the CA, furnishing exclusively the 1,4-addition
products 3 with excellent yields, high enantioselectivity, and
complete regioselectivity.
Particularly noteworthy, the additions of MeMgBr proceed with
equally high selectivity when the catalyst loading is reduced to only
1 mol %, providing the methylated 1,4-addition products with 92-
96% ee and isolated yields of 88-94% (entries 2-8). The CA to
substrate 1f, bearing a protected hydroxyl group, and to the aryl-
substituted unsaturated thioester 1g proceeded with excellent 95%
ee (entries 7, 8), further demonstrating the scope and potential of
the method. Only substrate 1e, bearing a smaller ethyl group at the
alkene, gave a slightly lower 92% ee (entry 6).
enantioselectivities in the range of 85-90% (entries 9-12). Bulky
Grignard reagents, such as iPrMgBr and iBuMgBr, however, gave
poor enantioselectivities under these conditions (entries 13, 14).
The drastically higher yields obtained for the methyl adducts
from R,â-unsaturated thioesters, compared to the oxoester ana-
logues,4 are most probably due to their inherent electronic properties
which are closer to those of enones (vide supra).6c However, a
possible positive effect arising from a coordination of the active
catalyst to the sulfur atom may not be ruled out.
Once the new, practical, and effective procedure for the enan-
tioselective CA of MeMgBr to unsaturated acid derivatives was
developed, an iterative method to provide access to optically active
syn- and anti-1,3-dimethyl arrays was pursued.12 The approach,
based on sequential enantioselective CAs to unsaturated thioesters,
is shown in Scheme 1. The first stereogenic center was created in
95% ee by the addition of MeMgBr to 1c, using Josiphos 2. The
resulting thioester 3c was efficiently converted in one step into the
corresponding aldehyde 4 (Et3SiH, 10 mol % Pd/C, 92% yield),13
which subsequently underwent a Wittig reaction to give the desired
Michael acceptor 5 in 88% yield. Finally, a second catalytic (1
mol %) CA using Josiphos 2 or its enantiomer ent-2 afforded with
Furthermore, other linear Grignard reagents, such as EtMgBr,
nPrMgBr, and nBuMgBr, also participate in the CA, providing
9
9966
J. AM. CHEM. SOC. 2005, 127, 9966-9967
10.1021/ja053020f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1 a
1,3-dimethyl arrays and deoxypropionate chains. The versatility of
the method is illustrated in the synthesis of (-)-lardolure, a
multimethyl-branched insect pheromone, obtained in 12 steps and
26% overall yield from commercial available (E)-hex-2-enoic acid.
Acknowledgment. Financial support from the Dutch Ministry
of Economic Affairs (EET scheme; Grants Nos. EETK-97107 and
99104) and the European Community’s 6th Framework Program
(Marie Curie IntraEuropean Fellowship to F.L.) is gratefully
acknowledged. We thank Dr. H.-U. Blaser (Solvias) for a gift of
Josiphos, and T. Tiemersma for GC and HPLC support.
a Conditions: (a) MeMgBr (1.2 equiv), 2 (1.2 mol %), CuBr‚SMe2 (1
mol %), tBuOMe, -75 °C, 2 h; (b) 10% Pd/C (5 mol %), Et3SiH, CH2Cl2,
rt, 20 min; (c) Ph3PCHCOSEt, CH2Cl2, reflux; (d) MeMgBr (1.2 equiv),
Supporting Information Available: Experimental procedures and
spectroscopic data of the reaction products (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
t
ent-2 (1.2 mol %), CuBr‚SMe2 (1 mol %), BuOMe, -75 °C, 3 h.
References
Scheme 2 a
(1) For recent synthesis of deoxypropionate-containing natural products, see
(a) Borrelidin: Hanessian, S.; Yang, Y.; Giroux, S.; Mascitti, V.; Ma, J.;
Raeppel, F. J. Am. Chem. Soc. 2003, 125, 13784-13792. (b) Ionomycin:
Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org.
Lett. 2002, 4, 1879-1882. (c) Siphonarienolone: Magnin-Lachaux, M.;
Tan, Z.; Liang, B.; Negishi, E. Org. Lett. 2004, 6, 1425-1427. (d)
Birkbeck, A. A.; Enders, D. Tetrahedron Lett. 1998, 39, 7823-7826.
(2) (a) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J.
Am. Chem. Soc. 1990, 112, 5290-5313. (b) Myers, A. G.; Yang, B. H.;
Chen, H.; Kopecky, D. J. Synlett 1997, 457-459 and references therein.
(c) Breit, B.; Herber, C. Angew. Chem., Int. Ed. 2004, 43, 3790-3792
and references therein. (d) Williams, D. R.; Nold, A. L.; Mullins, R. J. J.
Org. Chem. 2004, 69, 5374-5382. (e) See ref 1a.
(3) (a) Novak, T.; Tan, Z.; Liang, B.; Negishi, E. J. Am. Chem. Soc. 2005,
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B. L. Angew. Chem., Int. Ed. 2005, 44, 2752-2756.
a Conditions: (a-c) see Scheme 1 caption; (d) (S)-MeSOpTol, LDA,
THF, -78 °C; (e) DIBAL-H, ZnBr2, THF, -78 °C; (f) Raney-Ni, EtOH,
rt; (g) HCOOH, 65 °C.
(5) Thioesters can be efficiently obtained in one step from the corresponding
oxoesters, aldehydes, carboxylic acids, anhydrides, or acyl chlorides.11
(6) (a) Yang, W.; Drueckhammer, D. G. J. Am. Chem. Soc. 2001, 123, 11004-
11009 and references therein. (b) Cronyn, M. W.; Chang, M. P.; Wall, R.
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(7) Despite these unique properties, unsaturated thioesters have only been
scarcely used as Michael acceptors, and among the few asymmetric
examples, only two involve catalytic procedures: (a) Bandini, M.; Melloni,
A.; Tommasi, S.; Umani-Ronchi, A. HelV. Chim. Acta 2003, 86, 3753-
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1998, 120, 4043-4044.
(8) The higher acidity of the R-hydrogens of saturated thioesters is also related
to the lower electron delocalization in these acid derivatives. This feature
has been extensively exploited in thioenolate-aldol chemistry. See: (a)
Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem. Soc.
1981, 103, 3099-3111. (b) Gennari, C.; Beretta, M. G.; Bernardi, A.;
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909.
excellent yields and selectivity the 1,3-dimethyl derivatives (3R,5R)-6
(90% yield, dr 96:4) and (3S,5R)-7 (91% yield, dr 95:5). The high
diastereoselectivities obtained in this simple three-step iterative
protocol demonstrate the efficiency of the chiral catalyst to control
the configuration at the new stereocenter, independently of the
absolute configuration of the chain.14
The synthetic utility of the iterative sequence and the versatility
of â-methyl-substituted thioesters are further demonstrated in the
asymmetric total synthesis of (-)-lardolure,15 the aggregation
pheromone of the acarid mite Lardoglyphus konoi (Scheme 2).
The route starts with the enantiopure thioester 3d, obtained in
92% yield and 96% ee from the 1,4-addition of MeMgBr to 1d.
The iterative sequence shown in Scheme 2 provided the polydeoxy-
propionate derivative 9 in 52% yield over six steps from 3d.
Importantly, the second and third 1,4-addition proceed with
excellent diastereoselectivities (dr 97.5:2.5 and 98:2, respectively)
at the newly formed stereocenter, affording 9 with an overall de >
95%. For the introduction of the final stereogenic center, the
stereocontrolled reduction of enantiopure â-ketosulfoxides, a well-
established method for preparing enantiomerically pure alcohols,
was employed.16
The synthesis of the sulfinyl ketone 10 was efficiently achieved
by condensation of thioester 9 with the lithium anion of (S)-methyl-
p-tolylsulfoxide.17 Notably, the purification of 10 allowed the
increase of the diastereomeric purity above 97%. Subsequent
reduction with DIBAL-H in the presence of ZnBr2 afforded the
â-hydroxysulfoxide 11 in 86% yield and with excellent diastereo-
selectivity (dr 98.5:1.5) at the new stereocenter. Finally, desulfu-
rization of 11 followed by formylation of the resulting alcohol led
to (-)-lardolure 12 in 82% yield (two steps).18
(9) For selected recent examples demonstrating the versatility of these
functional groups, see: (a) Lalic, G.; Aloise, A. D.; Shair, M. D. J. Am.
Chem. Soc. 2003, 125, 2852-2853. (b) Wittenberg, R.; Srogl, J.; Egi,
M.; Liebeskind, L. S. Org. Lett. 2003, 5, 3033-3035 and references
therein. (c) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737-1740.
(10) For catalytic asymmetric 1,4-additions of Grignard reagents to enones,
see: (a) Feringa, B. L.; Badorrey, R.; Pen˜a, D.; Harutyunyan, S. R.;
Minnaard, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5834-5838. (b)
Lo´pez, F.; Harutyunyan, S. R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2004, 126, 12784-12785.
(11) See Supporting Information for procedures and details.
(12) For a previous four-step approach to 1,3-dimethyl arrays, see: Schuppan,
J.; Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2004, 792-793.
(13) Fukuyama, T.; Tokuyama, H. Aldrichim. Acta 2004, 37, 87-96.
(14) On the basis of the mass action law, and considering the absence of internal
asymmetric induction, a reliable ee > 99.9% for (3R,5R)-6 and (3S,5R)-7
can be predicted. See ref 3b.
(15) (a) For the stereochemistry of (-)-lardolure, see: Mori, K.; Kuwahara S.
Tetrahedron 1986, 42, 5545-5550. (b) For a previous synthesis, based
on a chiral resolution step, see: Mori, K.; Kuwahara, S. Tetrahedron 1986,
42, 5539-5544. (c) For other approaches, see: Hanaki, N.; Ishihara, K.;
Kaino, M.; Naruse, Y.; Yamamoto, H. Tetrahedron 1996, 52, 7297-7320.
(16) Carren˜o, M. C.; Garcia Ruano, J. L.; Martin, A. M.; Pedregal, C.;
Rodriguez, J. H.; Rubio, A.; Sanchez, J.; Solladie´, G. J. Org. Chem. 1990,
55, 2120-2128.
(17) To the best of our knowledge, this is the first example of the use of a
thioester for this reaction, further demonstrating their synthetic versatility.
(18) NMR properties (1H and 13C), optical rotation, and mass spectrometry
data of 12 were identical to those reported for the natural pheromone.
In summary, we have developed a highly enantioselective (up
to 96% ee) CA of Grignard reagents, in particular, MeMgBr, to
R,â-unsaturated thioesters and demonstrated its application in a
diastereo- and enantioselective iterative route to both syn- and anti-
JA053020F
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