Enantioselective total synthesis of the unnatural and the natural stereoisomers of vittatalactone

Article abstract of DOI:10.1021/jo100383u

(Figure presented) 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

Full text of DOI:10.1021/jo100383u

pubs.acs.org/joc
Enantioselective Total Synthesis of the Unnatural and the Natural
Stereoisomers of Vittatalactone
Yvonne Schmidt, Konrad Lehr, Ulrich Breuninger, Gabriel Brand, Tomislav Reiss, 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 March 4, 2010
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, we developed
the asymmetric total synthesis of the aggregation pheromone of A. vittatum, Vittatalactone, to
determine its absolute configuration and to further examine the pheromone response in field
studies. The synthesis features an enzyme-catalyzed approach toward the deoxypropionate
structural motif. A preformed organocopper reagent could then be coupled in an enantioselec-
tive o-DPPB-directed allylic substitution with a functionalized o-DPPB-ester. By means of
this efficient transformation, Vittatalactone could be obtained following a highly convergent
synthetic process.
Introduction
for sustainable plant protection is high, since classical use of
insecticides can be extremely expensive and additionally impacts
pollinators and natural enemies.
It has been found by Smyth and Hoffmann that feeding by
“male pioneers” results in a pheromone signal produced by the
males, which attracts conspecifics.3 This aggregation behavior or
concentrated feeding is a key component for the development of
a bacterial wilt epidemic.4 The composition of the pheromone
mixture secreted by the feeding male beetles was first analyzed by
Morris and Francke, who discovered the main component to be
Vegetable crops are an important commodity in the United
States. The Northeastern states, in particular, have a high
proportion of their vegetable crop industry invested in cucurbit
crops, including squash, melons, cucumbers, and pumpkins.1
The main insect pest of these cucurbit crops is the striped
cucumber beetle, Acalymma vittatum, which also serves as the
vector for Erwinia tracheiphila, a bacterium that causes a lethal
wilt disease in cucurbits.2 On this background, the demand
(1) Cavanagh, A.; Hazzard, R.; Adler, L. S.; Boucher, J. J. Econ. Entomol.
2009, 102, 1101–1107.
(2) (a) Garcia-Salazar, C. G.; Gildow, F. E.; Fleischer, S. J.; Cox-Foster,
D.; Lukezic, F. L. Environ. Entomol. 2000, 29, 542–550. (b) Garcia-Salazar,
C. G.; Gildow, F. E.; Fleischer, S. J.; Cox-Foster, D.; Lukezic, F. L. Can.
Entomol. 2000, 132, 1–13.
(3) (a) Smyth, R.; Hoffmann, M. P. Physiol. Entomol. 2002, 27, 325–242.
(b) Smyth, R.; Hoffmann, M. P. J. Insect Behav. 2003, 16, 347–359.
(4) (a) Brust, G. E. Environ. Entomol. 1997, 26, 580–584. (b) Fleischer,
S. J.; deMackiewicz, D.; Gildow, F. E.; Lukezic, F. L. Environ. Entomol.
1999, 28, 470–476.
4424 J. Org. Chem. 2010, 75, 4424–4433
Published on Web 06/09/2010
DOI: 10.1021/jo100383u
r
2010 American Chemical Society

Schmidt et al.
JOCArticle
CHART 1. Structures of Vittatalactone (1), 10-Norvittatalac-
tone (2), and Ebelactone A (3)
SCHEME 1. Synthesis Plan for Diastereomeric β-Lactones 1a
and 1b
Vittatalactone (1), accompanied by a minor compound, 10-
Norvittatalactone (2).5 With 5 stereogenic centers, both
β-lactones represent very complex structures among physio-
logically active insect volatiles.
Recently, we reported on the total synthesis of the enantio-
mer of Vittatalactone based on an iterative allylic substitution
concept.6 By means of the enantiomer synthesis, we were able to
elucidate the absolute configuration of the natural product. We
herein describe in full detail the evolution of our total synthesis,
the determination of the absolute configuration of Vittatalac-
tone through total synthesis of two eventual diastereomers, and
finally a new and more convergent as well as scalable synthesis
of the natural enantiomer of Vittatalactone (1).
Target Structure Assignment. The structure published by
the Francke group did not include the stereogenic informa-
tion on the methyl branched side chain (Chart 1). By NMR
analysis of the Mosher ester derivative of the corresponding
hydroxy acid, they assigned the stereocenters at C2 and C3 of
(1) to be (2R,3R).5 Unknown at this point was the relative
configuration of the alcohol at C3 and the methyl group on
C4, while Morris and Francke referred to the close structural
relationship of 1 to Ebelactone A (3), isolated from a strain of
Streptomyces, which is an inhibitor of esterases, lipases, and
N-formylmethionine aminopeptidases.7 This lactone exhi-
bits an anti-relationship between C3 and C4 and results from
polyketide biosynthesis, involving propionate-derived sub-
units, which also seems likely for Vittatalactone (1).8
In addition to the findings of Morris and Francke, we
compared the NMR shifts of the methylene protons at C5
and C7 with the NMR data obtained for other deoxypro-
pionate derived compounds, and this examination resulted
in the presumption of an all-syn configuration referring to
the methyl groups.6,9 On this background, we chose the syn-
and anti-lactones 1a and 1b (Scheme 1), respectively, as our
target structures. This is a promising choice, since it would
enable us to derive both possible diastereomers of the natural
product from an enantioselective Sharpless epoxidation of a
common intermediate, allylic alcohol 5. Hence, such a
divergent approach would then allow us to determine the
absolute configuration of Vittatalactone.
Results and Discussion
First Generation Retrosynthetic Approach. The lactones 1a
and 1b would be accessible from the epoxides 4a and 4b,
respectively, by regioselective ring opening with a methyl
copper reagent (Scheme 1). We then targeted the allylic alco-
hol 5 as the common intermediate for the epoxide synthesis.
This polyketide structure could be assembled via the iterative
o-diphenylphosphinobenzoic acid (o-DPPB) directed allylic
substitution method developed in our group.10 We have suc-
cessfully demonstrated this principle in several syntheses,6,11
(5) 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.
(6) Schmidt, Y.; Breit, B. Org. Lett. 2009, 11, 4767–4769.
(7) (a) Umezawa, H.; Aoyagi, T.; Uotani, K.; Hamada, M.; Takeuchi, T.;
Takahashi, S. J. Antibiot. 1980, 33, 1594–1596. (b) Uotani, K.; Naganawa,
H.; Kondo, S.; Aoyagi, T.; Umezawa, H. J. Antibiot. 1982, 35, 1495–1499.
(c) Nonaka, Y.; Ohtaki, H.; Ohtsuka, E.; Kocha, T.; Fukuda, T.; Takeuchi,
T.; Aoyagi, T. J. Enzyme Inhib. 1995, 10, 57–63.
(8) (a) Uotani, K.; Naganawa, H.; Aoyagi, T.; Umezawa, H. J. Antibiot.
1982, 35, 1670–1674. For a thorough overview on polyketide biosynthesis,
see: Hertweck, C. Angew. Chem., Int. Ed. 2009, 48, 4699–4716.
(9) 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-deoxypro-
pionate unit. In case of the anti-configured diastereomers the chemical shift
differences decrease. For experimental data, see: (a) Herber, C.; Breit, B.
Chem.;Eur. 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) Schmidt, Y.; Breit, B.
Org. Lett. 2010, 12, 2218-2221, and references cited therein.
(10) (a) For a recent review, see: Schmidt, Y.; Breit, B. Chem. Rev. 2008,
108, 2928–2952. (b) Reiss, T.; Breit, B. Chem.;Eur. J. 2009, 15, 6345–6348.
(c) Herber, C.; Breit, B. Angew. Chem. 2004, 116, 3878-3880; Angew. Chem.,
Int. Ed. 2004, 43, 3790-3792. (d) Herber, C.; Breit, B. Chem.;Eur. J. 2006, 12,
6684–6691.
(11) (a) Reiss, T.; Breit, B. Org. Lett. 2009, 11, 3286–3289. (b) Rein, C.;
Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew. Chem., Int. Ed. 2007,
46, 8670–8673. (c) Herber, C.; Breit, B. Angew. Chem., Int. Ed. 2005, 44,
5267–5269. (d) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512–3519.
J. Org. Chem. Vol. 75, No. 13, 2010 4425

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SCHEME 2. Synthesis of Grignard Precursors 13 and 14
SCHEME 3. Alternative Syntheses of Grignard Precursor 14
and Vittatalactone provided another challenging test case to
explore the generality of this concept. Thus, the common inter-
mediate 5 could stem from a directed allylic substitution of
functionalized o-DPPB-ester 6 and dideoxypropionyl organo-
metallic reagent 7. This step could set the third tertiary stereo-
genic center of the trideoxypropionate unit and would simul-
taneously introduce the allylic alcohol functionality.
tosylate 12 and submitted to the conditions of a copper-cata-
lyzed sp3-sp3 cross-coupling reaction with isopropylmagnesium
bromide (Scheme 2) to furnish PMB-ether 13 in good yield.14,15
The preparation of the suitable Grignard precursors, bromide 14
and iodide 15, was performed as a one-pot procedure because of
the high volatility of the intermediate alcohol and the bromide
and iodide, respectively.
The dideoxypropionyl organometallic reagent 7 in turn could
be derived from a second directed allylic substitution employing
the deoxypropionate building block 8 and the organometallic
reagent 9. This first tertiary stereogenic center may again be
generated on performing an allylic substitution on o-DPPB-
ester 8 with an isobutyl Grignard reagent. Alternatively, it may
stem from the commercially available Roche ester 10.12
Synthesis of (-)-Vittatalactone and Structure Elucidation.
Preliminary Study on Allylic Substitution and Synthesis of
Dideoxypropionyl Bromide (-)-19. Our synthesis started with
monoprotected diol 11,13 which is available in two steps from the
Roche ester 10 through alcohol protection and hydride reduc-
tion of the ester functionality. Alcohol 11 was activated as the
Additionally, alternative synthetic approaches based on
methodology developed in this group toward bromide 14 were
studied. Thus, subjection of allylic o-DPPB-ester 8 to the con-
ditions of the copper-mediated allylic substitution with isobutyl
magnesium bromide furnished the corresponding syn-SN20
product (Scheme 3).10d Subsequent ozonolysis followed by a
reductive workup and bromination gave bromide 14 in overall
good yields. Two alternative syntheses of 14 rely on the zinc-
catalyzed enantiospecific sp3-sp3 coupling developed re-
cently in our group.16 Thus, starting from D-lactic acid derived
triflate 16, bromide 14 was accessible in three steps. Notably,
the yield in the zinc-catalyzed coupling step with isobutyl
SCHEME 4. First Allylic Substitution Study towards Alkene 15
(12) (a) Goodhue, C. T.; Schaeffer, J. R. Biotechnol. Bioeng. 1971, 13,
203–214. (b) Ohta, H.; Tetsukawa, H.; Noto, N. J. Org. Chem. 1982, 47,
2400–2404. (c) Molinari, F.; Gandolfi, R.; Villa, R.; Urban, E.; Kiener, A.
Tetrahedron: Asymmetry. 2003, 14, 2041–2043.
(13) We received the alcohol 10 as a generous gift from Novartis; for
synthesis of 10, see: Walkup, R. D.; Boatman, P. D., Jr.; Kane, R. R.;
Cunningham, R. T. Tetrahedron Lett. 1991, 32, 3937–3940.
(14) Fouquet, C.; Schlosser, M. Angew. Chem. 1974, 86, 50-51; Angew.
Chem., Int. Ed. Engl. 1974, 13, 82-83.
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SCHEME 5. Directed Allylic Substitution and Iteration to Grignard Precursor (-)-19
SCHEME 6. Enantioselective Synthesis of o-DPPB-esters (R)-(þ)-6 and (S)-(-)-6
magnesium chloride was essentially quantitative. Alternatively,
one may start from triflate 17, which is readily available
through diazotization of L-leucine. Coupling with methyl
magnesium chloride, LiAlH4 reduction, and bromination pro-
vided a third efficient pathway toward bromide 14.
which was directly used in the o-DPPB-directed allylic substitu-
tion with unfunctionalized o-DPPB-ester 8 to furnish dideox-
ypropionate 18 in excellent diastereoselectivity (>99:1) and
yield (86% based on the ester, Scheme 5). To incorporate the
third propionate unit, we initiated the next iteration, which
began with ozonolysis of alkene 18 and a reductive workup
to furnish the corresponding alcohol. Mukaiyama redox
condensation provided bromide (þ)-19.17
Directed allylic substitution using the o-DPPB-ester 810c,d
as coupling partner was examined first with the iodide 15,
according to the procedure used in the synthesis of 4,6,8,10,
16,18-hexamethyldocosane (Scheme 4).11c,d Thus, iodine-
lithium exchange was effected upon treatment of iodide 15 in
diethyl ether with 2 equiv of tert-butyllithium at -100 °C. The
thus-obtained organolithium species was transmetalated to
magnesium upon warming to room temperature with magne-
sium dibromide etherate. The resulting Grignard reagent was
subjected to the conditions of the directed allylic substitution
with 1 equiv of o-DPPB-ester 8 to furnish the SN20 substitution
product 18 in good yield and diastereoselectivity.
Although this procedure works quite well on a small (1-2
mmol) reaction scale, it has limitations on larger scale. Thus, the
use of pyrophoric tert-butyllithium in large quantities is un-
desirable, as is the requirement of the extreme low temperature
conditions of -100 °C. To allow for a more convenient and
scalable allylic substitution process, we looked at the direct
Grignard synthesis starting from bromide 14. Indeed, the bro-
mide 14 (1.1 equiv) was reduced with magnesium (turnings,
etched three times with dibromoethane and thoroughly washed
with diethylether) to the corresponding Grignard reagent,
Enantioselective Preparation of o-DPPB-esters (R)- and
(S)-6. For installation of the third methyl-branched tertiary ster-
eogenic center with concomitant assembly of the allylic alcohol in
5, we required access to oxygen-functionalized o-DPPB-esters 6.
Thus, crotonaldehyde was treated with HCN in the presence of
an (R)-oxynitrilase readily obtained from grinding and scouring
of bitter almonds,18 which gave the (R)-cyanohydrin with high
levels of enantioselectivity (>96% ee).19 Subjecting the cyanohy-
drin to the conditions of a Pinner reaction furnished the ethyl
ester 20 (Scheme 6).20 The reduction with lithium aluminum
hydride led to diol 21, and subsequent silylation furnished the
silylether 22 on a multigram scale.21 Applying the standard Ste-
glich esterification protocol22 with o-diphenylphosphanylbenzoic
(17) Mukaiyama, T. Angew. Chem. 1976 88, 111-120; Angew. Chem.,
Int. Ed. 1976, 15, 94-103.
(18) (a) Rosenthaler, L. Biochem. Z. 1908, 14, 238–253. (b) Becker, W.;
Benthin, U.; Eschenhof, E.; Pfeil, E. Biochem. Z. 1963, 337, 156–166.
(19) Effenberger, F.;Gaupp, S. Tetrahedron: Asymmetry 1999, 10, 1765–1775.
(20) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1878, 11, 1475–1487.
(21) Warmerdam, E. G. J. C.;vanden Nieuwendijk, A. M. C. H.;Brussee, J.;
Kruse, C. G.; van der Gen, A. Tetrahedron: Asymmetry 1996, 7, 2539–2550.
€
€
(15) Tamura, M.; Kochi, J. Synthesis 1971, 303–305.
(16) Studte, C.; Breit, B. Angew. Chem., Int. Ed. 2008, 47, 5451–5455.
(22) Hofle, G.; Steglich, W.; Vorbruggen, H. Angew. Chem. 197890,
602-615; Angew. Chem., Int. Ed. Engl. 1978, 17, 569-583.
J. Org. Chem. Vol. 75, No. 13, 2010 4427

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SCHEME 7. o-DPPB-Directed Allylic Substitution towards Allylic Alcohol (-)-5
SCHEME 8. Final Steps towards Diastereomeric β-Lactones 1a and (-)-1b
acid (o-DPPBA)23 provided o-DPPB-ester (R)-(þ)-6 quantita-
tively. Crystallization of this product improved the enantiopurity
to greater than 99% ee. To obtain the requested (S)-enantiomer
of 6 one could apply a corresponding (S)-oxynitrilase. However,
such enzymes are far more difficult to access.24 Hence, we looked
at a Mitsunobu inversion protocol, which ideally would use
o-DPPBA itself as the nucleophile.25 Since o-DPPBA is both a
carboxylic acid and a phosphine, we expected this to be a
nontrivial reaction because the reagent triphenylphosphine as
well as o-DPPBA may react with the azodicarboxylate electro-
phile. Interestingly, we observed a clean Mitsunobu reaction of
the allylic alcohol 22 with o-DPPBA to furnish the corres-
ponding (S)-(-)-enantiomer of o-DPPB-ester 6 in good yield
(81%). After recrystallization (S)-(-)-6 was obtained in >99%
enantiopurity.
diastereomers of Vittatalactone. Thus, bromide (þ)-19 was
transformed into the corresponding Grignard reagent upon
treatment with magnesium in diethylether26 and, subjected to
the conditions of the o-DPPB-directed allylic substitution with
the oxygen-functionalized o-DPPB-ester (S)-(-)-6, furnished the
allyl silyl ether 23 in excellent yield and diastereoselectivity
(Scheme 7).27 Noteworthy, only 1.05 equiv of the valuable
bromide (þ)-19 was necessary to achieve full conversion in the
directed allylic substitution, which renders this reaction a valu-
able tool in enantioselective carbon skeleton construction and
even suitable for use as a fragment coupling in the course of a
convergent total synthesis.11b Finally, fluoride-mediated desilyla-
tion of 23 liberated the key allylic alcohol (-)-5 quantitatively.
Transformation of allylic alcohol (-)-5 toward the two
diastereomeric target structures 1a and 1b commenced with
the catalyst-controlled stereoselective Sharpless epoxidation
employing D- and L-diethyltartrate, respectively (Scheme 8).28
Both diastereomeric epoxy alcohols 4a and (-)-4b were
obtained in good yields and diastereoselectivities.
Final Steps toward β-Lactones 1a and 1b. With the bromide
(þ)-19 and o-DPPB-ester (S)-(-)-6 in hand, we could approach
the construction of the central allylic alcohol intermediate 5
in our divergent synthesis strategy toward both eventual
(23) (a) Hoots, J. E.; Rauchfuss, T. B.; Wrobleski, D. A. Inorg. Synth.
1982, 21, 175–180. (b) Kemme, S. T.; Schmidt, Y.; Gr€unanger, C. U.; Laungani,
A. C.; Breit, B. Synthesis 2010, 1924-1928. (c) o-DPPBA is commercially
available on a multigram scale from SinoMax Solutions Co., Ltd., Beijing, China;
http://www.sinomaxchem.com.
(26) Careful cleaning of the used Mg powder is essential for this trans-
formation; see also ref 6.
(27) Reiss, T.; Breit, B. Chem.;Eur. J. 2009, 15, 6345–6348.
(28) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976.
(b) For a review, see: Katsuki, T. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol.
II, pp 621-677.
(24) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555–1564.
(25) Mitsunobu, O. Synthesis 1981, 1–28.
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FIGURE 1. Comparison of NMR spectra of natural Vittatalactone (black),5 β-lactone (-)-1b (red), and β-lactone 1a (blue, dr 92:8).
SCHEME 9. Improved Retrosynthesis of Vittatalactone
SCHEME 10. Alternative Synthesis of Grignard Precursor
(-)-19
secondary alcohol renders it a rather difficult synthetic opera-
tion.31 Pinnick oxidation then completed the oxidation step to
furnish the respective β-hydroxy acids.32 The final ring closure
was initiated with tosyl chloride in pyridine to give desired
β-lactones 1a and (-)-1b in good to high yields.33
Structure Elucidation of Vittatalactone. Both diastereo-
meric lactones 1a and (-)-1b were subjected to NMR spectro-
scopic analysis. Comparison of the proton and carbon NMR
data with those of the natural material isolated by the Francke
group showed a complete match for β-lactone (-)-1b (Figure 1).5
Hence, (-)-1b possesses the correct relative configuration of
the natural product, whereas compared with the Mosher
ester structure analysis of Francke et al., β-lactone (-)-1b is
(2S,3S)-configured and should therefore be the enantiomer
of natural vittatalactone.
The carbon skeleton of vittatalactone was completed by
addition of cyanodimethylcuprate to give the 1,3-diols 24a
and (þ)-24b, respectively, in good yield.29 At this stage, the
minor diastereomer of (þ)-24b (being 24a) could be separated
by column chromatography to provide (þ)-24b in a diastereo-
meric ratio of >98:2. A highly selective oxidation of the primary
alcohol of the 1,3-diols 24 toward the corresponding β-hydroxy
aldehydes was accomplished applying 4-methoxy-TEMPO/hy-
pochlorite in good yields,30 even though the proximity of the
Second Generation Synthesis of Natural (þ)-Vittatalac-
tone. With the knowledge of the correct absolute configura-
tion of Vittatalactone, we decided to prepare the natural
(29) Marshall, J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63, 817–823.
(30) (a) Hu, T.; Takanaka, N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124,
12806–12815. (b) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org.
Chem. 1987, 52, 2559–2562.
(31) Miyazawa, T.; Endo, T. J. Org. Chem. 1985, 50, 3930–3931. Inokuchi,
T.; Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462–466. For
an overview, see: de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
1996, 1153–1174.
(32) Pinnick, H. W.; Balkrishna, S. B.; Childers, W. E., Jr. Tetrahedron
1981, 37, 2091–2096.
(33) Adam, W.; Baeza, J.; Liu, J.-C. J. Am. Chem. Soc. 1972, 94, 2000–2006.
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SCHEME 11. Completion of Vittatalactone ((þ)-1b) Synthesis
stereoisomer by way of a modified and more convergent syn-
thetic strategy that would allow for the synthesis of enough
material for biological studies. Thus, a commercially avail-
able starting material for the bromide 19 is the meso-anhy-
dride 25 (Scheme 9). Enzymatic desymmetrization of the
corresponding meso-diol is well-known.34
absolute configuration of Vittatalactone ((þ)-1b) from Aca-
lymma vittatum. With the development of a more convergent
and practical second generation synthesis we could prepare
over 50 mg of the natural stereoisomer in 11 steps for the
longest linear sequence and a total yield of 18%.
The successful enantioselective synthesis of the two unnatural
diastereomers 1a and (-)-1b as well as the natural isomer (þ)-1b
highlights the synthetic power of the directed allylic substitution
for deoxypropionate and propionate construction.
Now, the door is open for extensive biological studies to see
whetherthispheromonecanindeedbecomeanenvironmentally
friendly and efficient tool for a cucurbit plant protection
strategy in the future.
Thus, following the protocol developed by Mori et al.,
commercially available meso-anhydride 25 was reduced with
lithium aluminum hydride to the corresponding meso-diol
(Scheme 10). Subsequent desymmetrization with lipase AK
and vinylacetate furnished the monoacetate 26 in high enan-
tiomeric purity (97% ee)35 in 80% yield. The hydroxy group
was activated as a tosylate 27 and subjected to the conditions
of a copper-catalyzed sp3-sp3 cross-coupling reaction em-
ploying an excess of isopropyl magnesium bromide. The
resulting alcohol 28 was converted to the bromide (-)-19 via
Mukaiyama redox condensation.16 Thus, with this route
starting from commercially available meso-anhydride 24,
the desired dideoxypropionyl bromide (-)-19 was readily
available in large scale in four steps and 62% overall yield
employing only one chromatographic purification.
The final steps toward natural Vittatalactone were straight-
forward according to the enantiomer synthesis (Scheme 11).
Allylic substitution with o-DPPB-ester (R)-(þ)-6 and deprotec-
tion afforded the allylic alcohol (þ)-5 with complete diastereos-
electivity. We also tried to further enhance the stereoselectivity
by using the diisopropyltartrate instead of diethyltartrate at
-20 °C.36 However, the stereoselectivity for the formation of
epoxide (þ)-4b could not be raised beyond a diastereomeric
ratio of 90:10.
Experimental Section
(R,E)-5,7-Dimethyloct-3-ene. (R,E)-Hex-4-en-3-yl 2-(diphenyl-
phosphino)benzoate (8) (402 mg, 1.02 mol, 1.00 equiv, 98% ee) and
copper(I) bromide dimethyl sulfide complex (105 mg, 0.510 mmol,
0.500 equiv) were suspended in diethyl ether (20 mL). A solution
of isopropyl magnesium bromide in diethyl ether (about 1.0 M,
3.6 mL, 1.2 equiv) was added over 1.5 h at room temperature with a
syringe pump. The reaction mixture was stirred for another 1 h until
full conversion was observed by TLC. The reaction mixture was
directly transferred on a silica gel plug and rinsed with pentane. The
resulting solution was washed with aqueous sodium hydroxide
(0.25 M, 50 mL) and washed with saturated aqueous sodium hy-
drogen carbonate (20 mL). Because of the high volatility of the
product, it was used in the next step without further concentration
or purification. Rf = 0.82 (pentane).
(R)-2,4-Dimethylpentan-1-ol. The solution of (R,E)-5,7-di-
methyloct-3-ene in diethyl ether/pentane (about 100 mL) was cooled
to -78 °C. Then ozone was bubbled through the solution until a
blue color persisted. Immediately afterward nitrogen was purged
through the solution until the blue color disappeared. Remaining at
-78 °C, sodium borohydrate (1.1 g, 30 mmol, 30 equiv) was added
in portions. The reaction mixture was allowed to warm to room
temperature overnight. The suspension was quenched with water
(30 mL) and stirred vigorously for 2 h. The phases were separated,
and the aqueous phase was extracted with diethyl ether (4 ꢀ 30 mL).
The combined organic phases were dried over sodium sulfate and
concentrated in vacuo. Purification by flash chromatography
(pentane/diethyl ether 1:1, φ 2 cm, length 16 cm, fraction size 6 mL,
fractions 12-18) to obtain the title compound as a volatile colorless
liquid (89 mg, 76% over two steps from 8). Rf = 0.63 (diethyl ether);
Subsequently, the oxidation level of Vittatalactone was
adjusted employing the selective two-step oxidation protocol
developed in the first generation approach, to give the
hydroxy acid 29 without any trace of overoxidation to the
β-keto acid. Final ring closure to the natural product was
accomplished with tosyl chloride in pyridine to furnish
natural Vittatalactone ((þ)-1b) in good yield.
Conclusion
Through total synthesis and comparison of NMR data
of synthetic and natural material we could elucidate the
[R]24 = þ10.6° (c 0.7, CHCl3, 98% ee); to determine the ee the
(34) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493–502.
(35) The enantiomeric excess was determined after tosylation to 25.
(36) (a) Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin,
V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Synthesis 1983, 589–
604. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
D
alcohol was converted into the corresponding benzoyl ester ((R)-2,4-
dimethylpentyl benzoate): HPLC Diacel Chiralpak AD-3 column,
heptane/isopropanol 400:1, flow rate =1.0 mL/min, 20 °C,
detection at 227 nm, t1=4.05 min (major), t2=4.72 min (minor).
4430 J. Org. Chem. Vol. 75, No. 13, 2010

Schmidt et al.
JOCArticle
The NMR-spectroscopic analysis is consistent with literature
data.7
reaction or for analytical purposes purified by flash chromatogra-
phy (diethyl ether, φ 5 cm, length 16 cm, fraction size 40 mL,
fractions 9-16) to obtain the clean title compound as a colorless oil
(R)-2,4-Dimethylpentan-1-ol. Lithium aluminum hydride (33 mg,
0.86 mmol, 2.0 equiv) was suspended in diethyl ether (5 mL) and
cooled to -20 °C. Then a solution of (R)-tert-butyl 2,4-dimethyl-
pentanoate (80 mg, 0.43 mmol, 1.00 equiv) in diethyl ether (5 mL)
was added during 10 min. The reaction mixture was allowed to
warm to room temperature overnight. It was cooled back to 0 °C,
quenched with saturated aqueous sodium sulfate (0.4 mL), and
dried over sodium sulfate. Purification by flash chromatography
(pentane/diethyl ether 1:1, φ 2 cm, length 16 cm, fraction size 7 mL,
fractions 9-15) to obtain the title compound as a colorless liquid
(48 mg, 96%). The NMR-spectroscopic analysis is consistent with
literature data.7
(2.09 g, 79%). Rf = 0.42 (cyclohexane/ethyl acetate 1:1); [R]24
=
D
1
þ11.42 (c 1.05, CHCl3); H NMR (400 MHz, CDCl3, TMS as
internal standard) δ (ppm) 0.95 (d, J=6.7 Hz, 3 H), 0.96 (d, J=6.7
Hz, 3 H), 1.00 (ddd, J=13.8, 7.7, 7.1 Hz, 1 H), 1.45 (ddd, J=13.7,
7.1, 6.6 Hz, 1 H), 1.52 (br s, 1 H), 1.74 (ddqdd, J = 7.7, 7.1, 6.7, 6.6,
5.5 Hz, 1 H), 1.90 (ddqdd, J=7.1, 6.8, 6.7, 6.6, 5.4 Hz, 1 H), 2.06 (s, 3
H), 3.41 (dd, J=10.3, 6.6, 1 H), 3.50 (dd, J=10.3, 6.6, 1 H), 3.85 (dd,
J=10.8, 6.8, Hz, 1 H), 3.97 (dd, J = 10.8, 5.4 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 17.2, 17.8, 20.9, 30.0, 33.0, 37.3, 68.0,
69.2, 171.3. These spectroscopic data are in agreement with those
reported.39
(2S,4R)-2,4-Dimethyl-5-(tosyloxy)pentyl Acetate (27). A so-
lution of (2S,4R)-5-hydroxy-2,4-dimethylpentyl acetate (26)
(1.70 g, 9.76 mmol, 1.00 equiv) in dry pyridine (30 mL) was
cooled to 0 °C. Then p-toluenesulfonyl chloride (2.79 g, 14.6
mmol, 1.50 equiv) was added stepwise. The reaction mixture was
allowed to warm to room temperature overnight. It was quenched
by the addition of water (50 mL), followed by extraction with
diethyl ether (3 ꢀ 40 mL). The organic layers were combined and
washed with saturated aqueous copper(II) sulfate solution (2 ꢀ
60 mL), saturated aqueous sodium hydrogen carbonate (30 mL),
and brine (30 mL). The solution was dried over sodium sulfate and
concentrated in vacuo. This crude product was either directly used
in the next step or for analytical purposes purified by flash chro-
matography (cyclohexane/ethyl acetate 1:1, φ 5 cm, length 18 cm,
fraction size 40 mL, fractions 7-10) to obtain the title compound
as a colorless oil (3.10 g, 97%, 97% ee). Rf = 0.52 (cyclohexane/
ethyl acetate 1:1); [R]24D = þ1.61 (c 1.24, CHCl3; 97% ee); HPLC
Chiralcel OJ-H column, heptane/ethanol 75:25, flow rate = 0.8
mL/min, 23 °C, detection at 230 nm, t1 = 15.37 min (major), t2 =
20.83 min (minor); 1H NMR (400 MHz, CDCl3, TMS as internal
standard) δ (ppm) 0.90 (d, J = 6.7 Hz, 3 H), 0.92 (d, J=6.7 Hz,
3 H), 1.00 (ddd, J = 13.9, 7.4, 7.4 Hz, 1 H), 1.39 (ddd, J=13.8, 6.9,
6.9, Hz, 1 H), 1.79 (dqddd, J = 7.4, 6.8, 6.8, 6.8, 6.8 Hz, 1 H), 1.89
(qdddd, J=6.7, 6.7, 6.7, 6.2, 5.4 Hz, 1 H), 2.04 (s, 3 H), 2.45 (s,
3 H), 3.79 (dd, J=10.8, 6.5 Hz, 1 H), 3.80 (dd, J=9.5, 6.2Hz, 1 H),
3.87 (dd, J=10.7, 5.4 Hz, 1 H), 3.88 (dd, J=10.6, 5.3 Hz, 1 H),
7.33-7.37 (m, 2 H), 7.76-7.81 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 17.1, 17.4, 20.9, 21.6, 29.8, 30.3, 36.9, 68.8, 74.7,
127.8 (2 C), 129.8 (2 C), 133.1, 144.7, 171.1. These spectroscopic
data are in agreement with those reported.40
(R)-1-Bromo-2,4-dimethylpentane (14). A solution of (R)-2,4-
dimethylpentan-1-ol (10 mg, 86 μmol, 1.00 equiv) in dichloro-
methane (1 mL) was cooled to 0 °C. Triphenylphosphine (33 mg,
130 μmol, 1.50 equiv) was added and the mixture was stirred until it
turned into a homogeneous clear solution. N-bromosuccinimide
(23 mg, 130 μmol, 1.50 equiv) was added at 0 °C. The reaction
mixture was allowed to warm to room temperature overnight. The
dark reaction mixture was directly purified by filtration through a
pad of silica gel (φ 1 cm, length 2 cm) and rinsed with pentane. The
title compound was obtained as a colorless liquid (13.8 mg, 90%,
contained pentane). Rf = 0.78 (pentane); [R]24D = þ6.2 (c 0.98,
1
CHCl3, 98% ee); H NMR (400 MHz, CDCl3, TMS as internal
standard) δ (ppm) 0.90 (d, J=6.4 Hz, 3 H), 0.92 (d, J=6.6 Hz, 3H),
1.02 (d, J=6.6 Hz, 3 H), 1.12 (ddd, J=13.6, 8.2, 6.4 Hz, 1 H), 1.22-
1.38 (m, 1 H), 1.67 (dqqd, J = 7.6, 6.6, 6.6, 6.5 Hz, 1 H), 1.89 (m, 1
H), 3.32 (dd, J=9.7, 6.3 Hz, 1 H), 3.42 (dd, J=9.7 Hz, 4.6 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 19.0, 23.2, 25.4, 27.0, 33.0,
42.0, 44.4. These spectroscopic data are in agreement with those
reported.37
(2R,4S)-2,4-Dimethylpentane-1,5-diol. A suspension of (3R,5S)-
3,5-dimethyldihydro-2H-pyran-2,6(3H)-dione (25) (100 mmol,
14.3 g, 1.00 equiv) in diethyl ether (300 mL) was cooled to 0 °C.
Lithium aluminum hydride (200 mmol, 7.59 g, 2.00 equiv) was
added in portions under vigorous stirring over 1 h. The suspension
was allowed to warm to room temperature overnight. The reaction
mixture was cooled again to 0 °C, and water (8 mL), aqueous sodi-
um hydroxide solution (15%, 8 mL), diethyl ether (100 mL), and
water (24 mL) were added successively. The reaction mixture was
stirred until it turned from gray to white (about 2 h) and dried over
sodium sulfate. The solvent was removed in vacuo to obtain the title
compound as a colorless, viscous, and hygroscopic oil (13.0 g,
98%). Rf = 0.28 (ethyl acetate); 1H NMR (400 MHz, CDCl3, TMS
as internal standard) δ (ppm) 0.94 (ddd, J=14.2, 7.1, 7.1 Hz, 1 H)
0.95 (d, J= 6.7 Hz, 6 H), 1.53 (ddd, J = 13.7, 6.8, 6.8 Hz, 1 H), 1.74
(ddqdd, J = 7.0, 6.8, 6.7, 5.7, 5.7, 2 H), 1.87 (br s, 2 H), 3.48 (d, J =
5.7 Hz, 4 H); 13C NMR (100 MHz, CDCl3) δ(ppm) 17.6 (2 C), 33.1
(2 C), 37.0, 67.9 (2 C). These spectroscopic data are in agreement
with those reported.38
(2S,4R)-5-Hydroxy-2,4-dimethylpentyl Acetate (26). A solu-
tion of (2R,4S)-2,4-dimethyl-pentane-1,5-diol (2.00 g, 15.1 mmol,
1.00 equiv) in tetrahydrofuran (20 mL) was cooled to 0 °C. At
this temperature Amano Lipase AK (110 mg) and vinyl acetate
(2.10 mL, 1.95 g, 22.7 mmol, 1.50 equiv) were added. The reaction
mixture was stirred for 30 min at 0 °C and 7 h at 5 °C. The enzyme
was removed by suction filtration through Celite and washed with
diethyl ether (40 mL). The homogeneous filtrate was concentrated
in vacuo. This crude product was either directly used in the next
(2S,4S)-2,4,6-Trimethylheptan-1-ol (28). Lithium chloride (42
mg, 1.0 mmol, 0.60 equiv) and copper(II) chloride (68 mg, 0.50
mmol, 0.30 equiv) were flame-dried in a flask and dissolved in
tetrahydrofuran (10 mL) to obtain an orange solution of lithium
tetrachlorocuprate(II) (0.1 M in tetrahydrofuran).
A solution of (2S,4R)-2,4-dimethyl-5-(tosyloxy)pentyl acet-
ate (27) (1.01 g, 3.07 mmol, 1.00 equiv) in tetrahydrofuran (20 mL)
was cooled to -78 °C. The lithium tetrachlorocuprate(II) solution
(0.1 M in tetrahydrofuran, 10 mL, 1.0 mmol, 0.30 equiv) was added
via syringe. After 10 min an isopropylmagnesium bromide solution
(1.0 M in tetrahydrofuran, 15.4 mL, 15.4 mmol, 5.00 equiv) was
added via cannula. The reaction mixture was allowed to warm to
room temperature overnight. The reaction mixture was then cooled
to 0 °C, and lithium aluminum hydride (117 mg, 3.07 mmol, 1.00
equiv) was added. It was again allowed to warm to room tempera-
ture overnight. The reaction mixture was cooled to 0 °C and
quenched by the addition of saturated ammonium chloride solution
(50 mL). Tetrahydrofuran was removed in vacuo. The residue was
taken up in diethyl ether (50 mL). The phases were separated, and
the aqueous phase was extracted with diethyl ether (4 ꢀ 50 mL). If
€
(37) Tang, R.; Webster, F. X.; Muller-Schwarze, D. J. Chem. Ecol. 1995,
21, 1745.
(38) Ley, S. V.; Tackett, M. N.; Maddess, M. L.; Anderson, J. C.;
Brennan, P. E.; Cappi, M. W.; Heer, J. P.; Helgen, C.; Kori, M.; Kouklovsky,
ꢀ
C.; Marsden, S. P.; Norman, J.; Osborn, D. P.; Palomero, M. A.; Pavey,
(39) Fujita, K.; Mori, K. Eur. J. Org. Chem. 2001, 493.
(40) van Summeren, R. P.; Reijmer, S. J. W.; Feringa, B. L.; Minnaard,
A. J. Chem. Commun. 2005, 1387.
J. B. J.; Pinel, C.; Robinson, L. A.; Schnaubelt, J.; Scott, J. S.; Spilling, C. D.;
Watanabe, H.; Wesson, K. E.; Willis, M. C. Chem.;Eur. J. 2009, 15, 2874.
J. Org. Chem. Vol. 75, No. 13, 2010 4431

Schmidt et al.
JOCArticle
no good phase separation was observed, some sodium potassium
tartrate was added. The combined organic phases were washed with
brine (30 mL), dried over sodium sulfate, and concentrated in
vacuo. Purification by flash chromatography (petroleum ether/
diethyl ether 1:1, φ4 cm, length 20 cm, fraction size 25 mL, fractions
22-28) or short path distillation (10 mbar, 120-130 °C oil bath
temperature) to obtain the title compound as a colorless oil (88 mg,
80%). Rf = 0.18 (cyclohexane/ethyl acetate 9:1); [R]24D=-16.3 (c
1.03, CHCl3); 1H NMR (400 MHz, CDCl3, TMS as internal
standard) δ (ppm) 0.84 (d, J=6.5 Hz, 3 H), 0.86 (d, J=6.6 Hz, 3
H), 0.87 (d, J = 6.6 Hz, 3 H), 0.92 (d, J = 6.7 Hz, 3 H), 0.89-0.99
(m, 2 H), 1.11 (ddd, J=13.7, 8.9, 5.0 Hz, 1 H), 1.27 (ddd, J=13.6,
6.8, 6.8 Hz, 1 H), 1.49 (br s, 1 H), 1.50-1.79 (m, 3 H), 3.37 (dd, J=
10.5, 6.8 Hz, 1 H), 3.53 (dd, J=10.5, 5.2 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 17.3, 20.5, 22.0, 23.7, 25.2, 27.7, 33.0, 41.6,
46.5, 68.4. These spectroscopic data are in agreement with those
reported.41
(2S,4S)-1-Bromo-2,4,6-trimethylheptane ((-)-19). A solution
of (2S,4S)-2,4,6-trimethylheptan-1-ol (28) (800 mg, 5.05 mmol,
1.00 equiv) in dichloromethane (10 mL) was cooled to 0 °C.
Triphenylphosphine (1.99 g, 7.60 mmol, 1.50 equiv) was added at
once, and the mixture was stirred until it became a homogeneous
solution. N-Bromosuccinimide (1.35 g, 7.60 mmol, 1.50 equiv) was
added in portions over 15 min at 0 °C. The reaction mixture was
allowed to warm to room temperature overnight. The dark reaction
mixture was concentrated in vacuo, purified by filtration through a
pad of silica gel (φ5 cm, length 10 cm), and rinsed with pentane. The
title compound was obtained as a colorless liquid (1.06 g, 96%) by
removal of the solvent. Rf = 0.78 (pentane); [R]24D=-2.16 (c 1.25,
CHCl3); 1H NMR (400 MHz, CDCl3, TMS as internal standard) δ
(ppm) 0.85 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.6 Hz, 3 H), 0.88 (d,
J= 6.6 Hz, 3 H), 0.93-1.13 (m, 3 H), 1.01 (d, J= 6.6 Hz, 3 H), 1.37
(ddd, J= 13.6, 6.9, 6.7 Hz, 1 H), 1.48-1.61 (m, 1 H), 1.60-1.71 (m,
1 H), 1.83-1.96 (m, 1 H), 3.31 (dd, J = 9.8, 6.3 Hz, 1 H), 3.41 (dd,
J = 9.8, 6.3 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 19.5,
20.2, 22.2, 23.5, 25.2, 27.7, 32.4, 41.7, 43.0, 46.7. These spectroscopic
data are in agreement with the reported data of the enantiomeric
compound.42
tert-Butyldiphenyl((4S,6S,8S,E)-4,6,8,10-tetramethylundec-
2-enyloxy)silane ((þ)-23). Magnesium powder (330 mg, 14 mmol,
5.0 equiv) was suspended in diethyl ether (5 mL) and etched with
dibromoethane (0.1 mL). Then the solvent was removed via syringe
from the suspension. The etching process was repeated three times.
Diethyl ether (5 mL) and one drop of dibromoethane were added
(about 20 μL) to the remaining magnesium powder. Then (2S,4S)-
1-bromo-2,4,6-trimethylheptane ((-)-19) (600 mg, 2.71 mmol, 1.20
equiv) was added over 20 min and stirred for 30 min at room
temperature. A syringe was charged with the Grignard suspension.
A separate flask was charged with copper(I) bromide dimethyl
sulfide complex (232 mg, 1.13 mmol, 0.500 equiv), (R,E)-1-(tert-bu-
tyldiphenylsilyloxy)pent-3-en-2-yl 2-(diphenyl-phosphino)benzoate
((R)-(þ)-6) (1.42 g, 2.26 mmol, 1.00 equiv), and diethyl ether (50
mL). The Grignard suspension was added via a syringe pump over
1.25 h and stirred for another 1.5 h. The reaction mixture was con-
centrated in vacuo. Purification by flash chromatography (petro-
leum ether, φ 5 cm, length 19 cm, fraction size 45 mL, fractions
6-12) to obtain the title compound as a colorless oil (0.99 g, 80%, dr
> 95:5 by NMR). Rf = 0.25 (petroleum ether); [R]24D=þ3.00 (c
1.10, CHCl3); 1H NMR (400 MHz, CDCl3, TMS as internal
standard) δ (ppm) 0.79 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 6.5 Hz,
3 H), 0.85 (d, J = 6.5 Hz, 6 H), 0.96 (d, J = 6.7 Hz, 3 H), 0.81-0.98
(m, 3 H), 1.05 (s, 9 H), 1.08-1.31 (m, 3 H), 1.42-1.72 (m, 3 H),
2.17-2.29 (m, 1 H), 4.15-4.17 (m, 2 H), 5.44-5.56 (m, 2 H),
7.34-7.44 (m, 6 H), 7.65-7.71 (m, 4 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 19.2, 20.2, 20.3, 21.7, 22.1, 23.6, 25.2, 26.9 (3 C),
27.4, 27.5, 33.9, 44.4, 46.1, 46.8, 64.7, 127.1, 127.6 (2 C), 129.5 (4 C),
134.0 (2 C), 135.6 (4 C), 136.9. These spectroscopic data are in
agreement with the reported data of the enantiomeric compound.25
(4S,6S,8S,E)-4,6,8,10-Tetramethylundec-2-en-1-ol ((þ)-5).
To a solution of tert-butyldiphenyl((4S,6S,8S,E)-4,6,8,10-tetra-
methylundec-2-enyloxy)silane ((þ)-23) (200 mg, 430 μmol, 1.00
equiv) in tetrahydrofuran (3 mL) was added tetrabutylammo-
nium fluoride trihydrate (407 mg, 1.30 mmol, 3.00 equiv) at
room temperature. After 4.5 h TLC showed complete conver-
sion. The reaction mixture was concentrated in vacuo. Purifica-
tion by flash chromatography (petroleum ether/tert-butyl
methyl ether, φ 3 cm, length 17 cm, fraction size 25 mL, fractions
21-27) to obtain the title compound as a colorless oil (96 mg,
98%). Rf = 0.15 (petroleum ether/ethyl acetate 9:1); [R]24
=
D
1
þ9.89 (c 2.81, CHCl3); H NMR (400 MHz, CDCl3, TMS as
internal standard) δ (ppm) 0.80 (d, J = 6.5 Hz, 3 H), 0.83 (d, J=
6.5 Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H),
0.98 (d, J=6.69 Hz, 3 H), 0.85-1.01 (m, 3 H), 1.04-1.19 (m, 2
H), 1.28 (ddd, J = 13.9, 9.5, 4.6 Hz, 1 H), 1.34 (br s, 1 H),
1.46-1.59 (m, 2 H), 1.60-1.69 (m, 1 H), 2.20-2.32 (m, 1 H),
4.08-4.11 (m, 2 H), 5.51 (dddd, J=15.4, 7.9, 1.1, 1.1 Hz, 1 H),
5.61 (dddd, J=15.4, 5.6, 5.6, 0.6 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 20.3, 20.3, 21.5, 22.1, 23.6, 25.2, 27.5, 27.5, 34.0,
44.3, 46.0, 46.8, 63.9, 127.3, 139.1. These spectroscopic data are
in agreement with the reported data of the enantiomeric com-
pound.25
((2R,3R)-3-((2S,4S,6S)-4,6,8-Trimethylnonan-2-yl)oxiran-2-
yl)methanol ((þ)-4b). tert-Butyl hydroperoxide (about 4 M in
decane, 0.25 mL, about 4 equiv) was diluted with dichloro-
˚
methane (0.75 mL) and dried over 4 A ground molecular sieves
for 2 h. A Schlenk flask was charged with titanium tetraisoprop-
oxide (20 μL, 68 μmol, 0.25 equiv) and dichloromethane (2 mL)
˚
and dried over 4 A ground molecular sieves for 1.5 h. (4S,6S,8S,
E)-4,6,8,10-Tetramethylundec-2-en-1-ol ((þ)-5) (60.0 mg, 0.275
mmol, 1.00 equiv) was dissolved in dichloromethane (1 mL) and
˚
dried over 4 A ground molecular sieves for 30 min. The titanium
tetraisopropoxide was cooled to -20 °C and stirred for another
30 min. Then D-(-)-diisopropyltartrate (17 μL, 81 μmol, 0.30
equiv) was added. After 30 min the solution of the allyl alcohol
was added slowly over 10 min. Directly afterward the tert-butyl
hydroperoxide solution was added, and the reaction mixture
was stirred overnight at -20 °C (about 20 h, TLC shows full
conversion).
The reaction mixture was quenched at -20 °C by addition of a
solution containing iron(II) sulfate heptahydrate (3.3g), citricacid
(1.1 g), and water (10 mL). The mixture was stirred vigorously and
allowed to warm to room temperature for 30 min, followed by
extraction with diethyl ether (3 ꢀ 8 mL) and drying over sodium
sulfate. Purification by flash chromatography (petroleum ether/
diethyl ether 8:2, φ 2 cm, length 20 cm, fraction size 10 mL, frac-
tions 26-31) to obtain the title compound as a colorlessoil (54 mg,
83%, dr 90:10 determined by 1H NMR). Rf = 0.18 (cyclohexane/
ethyl acetate 8:2); [R]24D = þ16.27 (c 8.05, CHCl3); 1H NMR (400
MHz, CDCl3, TMS as internal standard) δ (ppm) 0.82 (d, J = 6.5
Hz, 3 H), 0.84 (d, J=6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.87
(d, J=6.6 Hz, 3 H), 0.84-0.97 (m, 2 H), 1.02 (d, J = 6.6 Hz, 3 H),
1.02-1.18 (m, 3 H), 1.36 (ddd, J=13.7, 8.6, 5.2 Hz, 1 H), 1.44-
1.51 (m, 1 H), 1.51-1.69 (m, 3 H), 1.72 (br s, 1 H), 2.68 (dd, J =
7.7, 2.4 Hz, 1 H), 2.99 (ddd, J= 4.5, 2.5, 2.5 Hz, 1 H), 3.61 (dd, J=
12.5, 3.7 Hz, 1 H), 3.92 (dd, J=12.5, 2.1 Hz, 1 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 18.0, 20.4, 20.6, 22.0, 23.7, 25.2, 27.4, 27.5,
32.9, 41.5, 45.8, 46.6, 58.5, 60.6, 61.8. These spectroscopic data are
in agreement with the reported data of the enantiomeric com-
pound.25
(2S,3R,4S,6S,8S)-2,4,6,8,10-Pentamethylundecane-1,3-diol
((-)-24b). Copper(I) cyanide (223 mg, 2.49 mmol, 3.00 equiv)
was suspended in diethyl ether (10 mL) and cooled to -78 °C. A
solution of methyl lithium (about 1.5 M in diethyl ether, 5 mL, 6
(41) Stahl, M.; Schopfer, U. J. Chem. Soc., Perkin Trans. 2 1997, 905.
(42) Schmidt, Y.; Breit, B. Org. Lett. 2009, 11, 4767.
4432 J. Org. Chem. Vol. 75, No. 13, 2010

Schmidt et al.
JOCArticle
equiv) was slowly added. The solution was stirred for 20 min at
-78 °C. Then((2R,3R)-3-((2S,4S,6S)-4,6,8-trimethylnonan-2-yl)-
oxiran-2-yl)methanol ((þ)-4b) (dr 90:10, 201 mg, 0.829 mmol, 1.00
equiv) dissolved in diethyl ether (5 mL) was added slowly. The
solution was stirred for 1 h at -78 °C and allowed to warm to
room temperature overnight. The reaction was cooled down to
0 °C, quenched with saturated ammonium chloride solution (20
mL), and stirred vigorously for 10 min. Then aqueous ammonia
solution (about 25%, 5 mL) was added, and the mixture was
stirred until the aqueous phase turned into a light blue (about
5-20 min). The phases were separated, and the aqueous phase was
extracted with ethyl acetate (4 ꢀ 25 mL). The combined organic
phases were dried over sodium sulfate and concentrated in vacuo.
Purification by flash chromatography (petroleum ether/diethyl
ether 1:1, φ 4 cm, length 18 cm, fraction size 30 mL, fractions 30-
42) to obtain the title compound as a colorless oil (209 mg, 97%,
major diastereomer 189 mg). Rf=0.52 (diethyl ether, major dias-
acid, φ 1 cm, length 18 cm, fraction size 4 mL, fractions 21-27)
to obtain the title compound as a viscous oil (6.5 mg, 78%). Rf =
1
0.26 (ethyl acetate); [R]24D=-8.00 (c 0.85, CHCl3); H NMR
(400 MHz, CDCl3, TMS as internal standard) δ (ppm) 0.83 (d,
J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3
H), 0.88 (d, J = 6.7 Hz, 6 H), 0.88-0.96 (m, 2 H), 1.00 (ddd, J =
13.7, 8.0, 6.8 Hz, 1 H), 1.10 (ddd, J = 13.7, 9.0, 4.9 Hz, 1 H),
1.13-1.19 (m, 1 H), 1.19 (d, J = 7.2 Hz, 3 H), 1.45 (ddd, J =
13.7, 7.6, 6.1 Hz, 1 H), 1.52-1.70 (m, 3 H), 1.77 (qdddd, J = 6.7,
6.5, 6.5, 6.5, 3.0 Hz, 1 H), 2.67 (dq, J = 8.6, 7.1 Hz, 1 H), 3.66
(dd, J = 8.7, 3.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ (ppm)
13.0, 14.0, 20.5, 20.6, 22.0, 23.8, 25.2, 27.0, 27.6, 31.5, 41.3, 43.3,
45.8, 46.5, 74.9, 181.0. These spectroscopic data are in agree-
ment with the reported data of the enantiomeric compound.25
(þ)-Vittatalactone ((þ)-1b). A solution of (2R,3R,4S,6S,8S)-
3-hydroxy-2,4,6,8,10-pentamethylundecanoic acid (29) (39.9
mg, 0.146 mmol, 1.00 equiv) in dry pyridine (0.4 mL) was cooled
to 0 °C. p-Toluenesulfonyl chloride (57 mg, 0.29 mmol, 2.0 equiv)
was added at once. The solution was allowed to warm to room
temperature and stirred overnight. After TLC showed complete
consumption of starting material (about 12 h) the reaction mixture
was diluted with diethyl ether (10 mL) and water (10 mL). The
phases were separated, and the aqueous phase was extracted with
diethyl ether (3ꢀ10 mL). The combined organic phases were washed
with saturated aqueous sodium hydrogen carbonate (5 mL), dried
over sodium sulfate, and concentrated in vacuo (200 mbar, 40 °C).
Purification by flash chromatography (pentane/diethyl ether 9:1, φ2
cm, length 16 cm, fraction size 5 mL, fractions 10-18) to obtain the
title compound as a volatile colorless liquid (28.3 mg, 76%). Rf =
0.33 (pentane/diethyl ether 9:1); [R]24D = þ1.2 (c 1.29, CH2Cl2); 1H
NMR (400 MHz, CDCl3, TMS as internal standard) δ (ppm) 0.84
(d, J= 6.6 Hz, 6 H), 0.88 (d, J=6.6Hz, 3H), 0.90(d, J=6.6Hz, 3
H), 0.86-0.94 (m, 2 H), 1.02 (d, J = 6.6 Hz, 3 H), 0.97-1.05 (m, 1
H), 1.10 (ddd, J = 13.6, 9.3, 4.5 Hz, 1 H), 1.16-1.34 (m, 2 H), 1.39
(d, J=7.5 Hz, 3 H), 1.50-1.70 (m, 3 H), 1.87 (ddqd, J = 8.4, 8.4,
6.5, 5.0 Hz, 1 H), 3.25 (qd, J = 7.5, 4.1 Hz, 1 H), 3.87 (dd, J = 8.2,
4.1Hz, 1H);13C NMR (100 MHz, CDCl3) δ(ppm) 12.9, 15.8, 20.8,
21.0, 21.8, 23.9, 25.2, 27.3, 27.7, 34.8, 39.8, 45.2, 46.0, 48.9, 83.8,
172.0. These spectroscopic data are in agreement with the reported
data of the enantiomeric compound.25
teromer); Rf = 0.47 (diethyl ether, minor diasteromer); [R]24
=
D
-4.48 (c 0.87, CHCl3); 1H NMR (400 MHz, CDCl3, TMS
as internal standard) δ (ppm) 0.82 (d, J = 6.9 Hz, 3 H), 0.84
(d, J=6.7 Hz, 3 H), 0.84 (d, J=6.5 Hz, 3 H), 0.85 (d, J=6.8 Hz, 3
H), 0.86 (d, J=6.8 Hz, 3 H), 0.88 (d, J=6.6 Hz, 3 H), 0.84-0.96
(m, 2 H), 0.99 (ddd, J=13.6, 8.0, 6.8 Hz, 1 H), 1.11 (ddd, J=13.7,
9.0, 4.9 Hz, 1 H), 1.18 (ddd, J=13.5, 7.2, 6.3 Hz, 1 H), 1.37 (ddd,
J = 13.7, 7.8, 6.0 Hz, 1 H), 1.52-1.70 (m, 3 H), 1.73-1.84 (m, 1
H), 1.83-1.95 (m, 1 H), 2.38 (br s, 2 H), 3.47 (dd, J=9.1, 2.5 Hz,
1 H), 3.67 (dd, J=10.7, 7.8 Hz, 1 H), 3.73 (dd, J=10.7, 3.8 Hz, 1
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 12.9, 13.5, 20.5, 20.6,
22.0, 23.8, 25.2, 27.0, 27.6, 32.0, 37.5, 41.4, 45.9, 46.5, 69.0, 79.5.
These spectroscopic data are in agreement with the reported
data of the enantiomeric compound.10
(2R,3R,4S,6S,8S)-3-Hydroxy-2,4,6,8,10-pentamethylundeca-
noic Acid (29). To a solution of (2S,3R,4S,6S,8S)-2,4,6,8,10-
pentamethylundecane-1,3-diol ((-)-24b) (8.0 mg, 31 μmol, 1.0
equiv) in dichloromethane (4 mL) were added saturated sodium
hydrogen carbonate solution (20 mL) and sodium bromide
(about 4 mg). The suspension was cooled to 0 °C. At this
temperature 2,2,6,6-tetramethylpiperidine-1-oxyl free radical
(about 4 mg) and after 5 min aqueous sodium hypochlorite
(0.01 M, 4.0 mL) were added. After 25 min of stirring at 0 °C,
TLC showed complete conversion. At 0 °C the reaction was
quenched with saturated sodium thiosulfate solution (25 mL)
and allowed to warm to room temperature. The reaction
mixture was extracted with ethyl acetate (5 ꢀ 8 mL), dried over
sodium sulfate, and concentrated in vacuo. The crude aldehyde
((2R,3R,4S,6S,8S)-3-hydroxy-2,4,6,8,10-
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 Y.S.), the
Stiftung der Deutschen Wirtschaft (fellowship to K.L.),
Novartis, and Wacker (Donation of Chemicals). We thank
Prof. Dr. Wittcko Francke for sharing preliminary results, as
well as G. Fehrenbach and Dr. M. Keller for analytical
assistance and J. Weipert for synthetic work.
pentamethylundecanal) (Rf = 0.79 (diethyl ether)) was used in
the next step without any further purification.
Preparation of the Stock Solution. tert-Butanol (1.6 mL),
2-methyl-2-butene (purity 80%, 0.7 mL), sodium chlorite (28 mg),
sodium dihydrogen phosphate (23 mg), and water (1.2 mL) were
stirred vigorously in a small test tube for 10 min.
The freshly prepared stock solution was added to the alde-
hyde and stirred at room temperature for 3.5 h. Subsequently,
the reaction mixture was diluted with water (8 mL) and ex-
tracted with ethyl acetate (5 ꢀ 8 mL). Purification by flash
chromatography (cyclohexane/ethyl acetate 1:1 with 1% acidic
Supporting Information Available: Starting materials pre-
pared by literature procedures and 1H and 13C NMR spectra of
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 13, 2010 4433