Enantioselective total synthesis and determination of absolute configuration of vittatalactone

Article abstract of DOI:10.1021/ol901591t

The first asymmetric total synthesis of vittatalactone features the divergent synthesis of two dlastereomers to assign the absolute configuration of the natural product. Its consecutive propionate and deoxyproponate stereogenic centers are established by

Full text of DOI:10.1021/ol901591t

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4767-4769
Enantioselective Total Synthesis and
Determination of Absolute Configuration
of Vittatalactone
Yvonne Schmidt and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Freiburg Institute for AdVanced Studies
(FRIAS), Albert-Ludwigs-UniVersita¨t Freiburg, Alberstr. 21, 79104 Freiburg, Germany
bernhard.breit@chemie.uni-freiburg.de
Received July 13, 2009
ABSTRACT
The first asymmetric total synthesis of vittatalactone features the divergent synthesis of two diastereomers to assign the absolute configuration
of the natural product. Its consecutive propionate and deoxypropionate stereogenic centers are established by enantioselective o-DPPB directed
allylic substitution.
The striped cucumber beetle, Acalymma Vittatum, is a cause
of major damage to cucurbit crops in North America. To
develop an environmentally benign plant protection strategy,
recent research has focused on identifying sex pheromones
of the cucumber beetle. In this context, vittatalactone (1) has
been isolated by Morris and Francke, and its possible role
as an aggregation pheromone was determined employing
electrophysiological studies.1 Structural investigations re-
vealed the constitution of vittatalactone featuring a trideoxy-
propionate unit as well as a ꢀ-lactone derived from a
propionate unit.
From spectroscopic analysis of the Mosher ester derivative,
the absolute configuration on the ꢀ-lactone could be deduced
to be 2R,3R, but the relative configuration of the trideoxy-
propionate side chain was not determined so far. However,
after comparison of the chemical shifts of C5H2 and C7H2-
hydrogens with known trideoxypropionate diastereomers, we
presumed the methyl substituents to be all-syn configured
(Figure 1).1,2 Still, the relative configuration between the
Figure 1. Known structural features of vittatalactone.
ꢀ-lactone (i.e., propionate) and deoxypropionate subunit
remained unknown. We herein report on the total synthesis
of the two diastereomers 1a and 1b in enantiomerically pure
form, thus enabling the determination of the relative and
(2) By comparison of NMR data we found a strong splitting (0.2 and
0.3 ppm, respectively) for the chemical shift of the methylene protons, which
has been shown to be typical for the internal methylene unit of a
syn-deoxypropionate unit. In the case of the anti-configured diastereomers,
the chemical shift differences decrease. For experimental data, see: (a)
Herber, C.; Breit, B. Chem.sEur. J. 2006, 12, 6684–6691. (b) Herber, C.;
Breit, B. Eur. J. Org. Chem. 2007, 3512–3519. (c) Hanessian, S.; Yang,
Y.; Giroux, S.; Mascitti, V.; Ma, J.; Raeppel, F. J. Am. Chem. Soc. 2003,
125, 13784–13792. For a theoretical overview of conformation control, see:
(d) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39, 2054–2070, and
references cited therein.
(1) Morris, B. D.; Smyth, R. R.; Foster, S. P.; Hoffmann, M. P.; Roelofs,
W. L.; Franke, S.; Francke, W. J. Nat. Prod. 2005, 68, 26–30.
10.1021/ol901591t CCC: $40.75
Published on Web 09/30/2009
 2009 American Chemical Society

absolute configuration of vittatalactone. The synthesis em-
ploys our recently developed methodology for polyketide
construction relying on the o-DPPB-directed copper-mediated
allylic substitution, which allows for stereospecific 1,3-
chirality transfer (Scheme 1).3,4
Our synthesis started with monoprotected diol 8,5 which
is available in two steps from the corresponding Roche ester
through O-protection and hydride reduction. Alcohol 8 was
activated as its tosylate and submitted to the conditions of a
copper-catalyzed sp3-sp3-coupling reaction with i-PrMgBr
(Scheme 3) to furnish PMB ether 9 in good yield. Trans-
Scheme 1. o-DPPB-Directed Allylic Substitution with
Grignard-Derived Organocopper Reagents
Scheme 3. Synthesis of Grignard Precursor 7 and
o-DPPB-Directed Allylic Substitution
Our synthesis plan is outlined in Scheme 2. Thus, to enable
a late-stage divergency toward both diastereomers 1a and
Scheme 2. Retrosynthetic Analysis of Vittatalactone
formation of 9 toward bromide 7 was conducted as a one-
pot procedure due to the high volatility of both alcohol and
bromide. Bromide 7 was converted into the corresponding
Grignard reagent and subsequently subjected to the condi-
tions of the directed allylic substitution with the unfunction-
alized o-DPPB ester 6.3c,6 The SN2′ substitution product 10
was obtained in 86% yield with respect to ester 6 using 1.1
equiv of Grignard only. Analysis of the substitution product
by capillary GC showed a diastereomeric ratio of >99:1.
Iteration for trideoxypropionate construction began with
ozonolysis of alkene 10 and reductive workup to give the
corresponding alcohol (Scheme 4). Mukaiyama redox con-
Scheme 4. Iteration of o-DPPB-Directed Allylic Substitution
1b, we decided in favor of functionalized trideoxypropionate
3 as the common intermediate. A catalyst-controlled Sharp-
less epoxidation followed by methylcuprate epoxide ring
opening, adjustment of oxidation state, and lactone formation
would furnish both diastereomers of vittatalactone, 1a and
1b.
The common allylic alcohol 3 could be constructed
stereospecifically employing our iterative copper-mediated
o-DPPB-directed allylic substitution. The first disconnection
leads to o-DPPB-ester 4 and the Grignard reagent derived
from bromide 5 which in turn should be the coupling product
of o-DPPB-ester 6 and the Grignard reagent obtained from
bromide 7.
densation7 furnished bromide 5. Transfer into the corre-
sponding Grignard reagent occurred upon treatment with
magnesium in diethylether, and subsequent subjection to the
conditions of the directed allylic substitution with O-
functionalized o-DPPB-ester 4 furnished the allylic silyl ether
(3) (a) For a recent review, see: Schmidt, Y.; Breit, B. Chem. ReV. 2008,
108, 2928–2952. (b) Reiss, T.; Breit, B. Chem.sEur. J. 2009, 15, 6345–
6348. (c) Herber, C.; Breit, B. Angew. Chem. 2005, 117, 5401-5403;
Angew. Chem., Int. Ed. 2005, 44, 5267-5269.
(5) Walkup, R. D.; Boatman, P. D., Jr.; Kane, R. R.; Cunningham, R. T.
Tetrahedron Lett. 1991, 32, 3937–3940.
(6) Herber, C.; Breit, B. Angew. Chem. 2004, 116, 3878-3880; Angew.
Chem., Int. Ed. 2004, 43, 3790-3792.
(4) For a recent synthesis of bourgeanic acid employing this methodol-
(7) Mukaiyama, T. Angew. Chem. 1976, 88, 111-120; Angew. Chem.,
Int. Ed. 1976, 15, 94-103.
ogy, see: Reiss, T.; Breit, B. Org. Lett. 2009, 11, 3286–3289
.
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11 in excellent yield and stereoselectivity.3b Fluoride-
mediated liberation of the key allylic alcohol 3 was quantita-
tive.
Transformation of 3 toward the two diastereomeric target
structures 1a and 1b started with the catalyst-controlled
stereoselective Sharpless epoxidation employing D- and
L-diethyl-tartrate, respectively.8 Both diastereomeric epoxy-
alcohols 2a and 2b were obtained in good yields and
diastereoselectivity, even for the mismatched case toward
2b.
Both diastereomeric lactones were subjected to NMR
spectroscopic analysis. Comparison of the proton and carbon
NMR data with those of the natural material isolated by the
Francke group1 showed a perfect match for ꢀ-lactone 1b.13
Hence, 1b has the correct relative configuration of natural
vittatalactone.
However, compared with the structure analysis by the
Mosher ester method, lactone 1b is 2S,3S configured and
should therefore be the enantiomer of natural vittatalac-
tone. Thus, by synthesis of the enantiomer, the absolute
configuration of vittatalactone can be assigned to be
2R,3R,4S,6S,8S.14
In conclusion, the enantioselective total synthesis of ent-
vittatalactone 1b from Acalymma Vittatum has been ac-
complished, thus enabling the relative and the absolute
configuration of the natural product to be determined. The
successful enantioselective synthesis of the two diastereomers
1a and 1b highlights the synthetic power of our recent
methodology for deoxypropionate and propionate construc-
tion, which relies on the o-DPPB-directed allylic substitution
by Grignard-derived organocopper reagents. Thus, this
methodology complements more traditional strategies for
polyketide synthesis relying on enolate alkylation and aldol
addition reactions.15
Acknowledgment. This work was supported by the DFG,
the International Research Training Group “Catalysts and
Catalytic Reactions for Organic Synthesis” (IRTG 1038), the
Fonds der Chemischen Industrie (Fellowship to YS), and
Novartis and Wacker (Donation of Chemicals). We thank
Prof. Dr. Wittcko Francke (Univ. Hamburg) for sharing
preliminary results, as well as G. Fehrenbach and Dr. M.
Keller for analytical assistance and J. Weipert for synthetic
work (Univ. Freiburg).
The carbon skeleton of vittatalactone was completed by
addition of cyanodimethylcuprate to give the 1,3-diols 12a
and 12b, respectively, in good yield and stereoselectivity.9
At this stage, the minor diastereomers could be separated
by column chromatography. Selective oxidation of the
primary alcohol function of diol 12 toward the ꢀ-hydroxy
aldehyde was accomplished applying 4-methoxy-TEMPO/
hypochlorite.10 Pinnick oxidation then furnished the corre-
sponding ꢀ-hydroxy acid.11 Finally, ring closure with tosyl
chloride in pyridine yielded the ꢀ-lactones 1a and 1b in good
to high yields.12
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.
OL901591T
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976. (b) For a review, see: Katsuki, T. ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Heidelberg, 1999; Vol. II, pp 621-677.
(13) See Supporting Information for details.
(14) Unfortunately, we could not compare the optical rotation of 1b
with the natural product since this has neither been reported (ref 1) nor
determined.
(15) For recent reviews, see: (a) Paterson, I. Asym. Synth. 2007, 278–
282. (b) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506–
7525. (c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–947. For Evans
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Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290–5313. For a
review covering deoxypropionate synthesis, see: (e) Hanessian, S.; Giroux,
S.; Mascitti, V. Synthesis 2006, 1057–1076.
(9) Marshall, J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63,
817–823.
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124, 12806–12815. (b) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J.
Org. Chem. 1987, 52, 2559–2562.
(11) Pinnick, H. W.; Balkrishna, S. B.; Childers, W. E., Jr. Tetrahedron
1981, 37, 2091–2096.
(12) Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000–
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