Synthesis of dihydroplakortin, 6-epi-dihydroplakortin, and their C10-desethyl analogues

Article abstract of DOI:10.1021/jo1001559

(Figure Presented) The first synthesis of the marine endoperoxide 9,10-dihydroplakortin, of its C10-desethyl analogue, and of their corresponding C6 epimers is described. Stereogenic centers at C4 and at the lateral chain have been stereoselectively synthesized through Evans' chiral auxiliary chemistry. Moreover, the reported synthesis features a one-pot three-step hydroperoxysilylation/cyclization reaction for the construction of the endoperoxide ring system. Homologation of the aldehyde resulting from diol cleavage through a Wittig-based strategy gave access to the ester-containing lateral chain at C3.

Full text of DOI:10.1021/jo1001559

pubs.acs.org/joc
Synthesis of Dihydroplakortin, 6-epi-Dihydroplakortin, and
Their C10-Desethyl Analogues
Sandra Gemma,†,‡ Emanuele Gabellieri,†,‡ Salvatore Sanna Coccone,†,‡
Francesc Martı †,‡ Orazio Taglialatela-Scafati,§,‡ Ettore Novellino,^,‡
´
,
Giuseppe Campiani,*,†,‡ and Stefania Butini†,‡
†Dipartimento Farmaco Chimico Tecnologico (DFCT), ‡European Research Centre for Drug Discovery and
Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy, §Dipartimento di
Chimica delle Sostanze Naturali (DCSN), and ^Dipartimento di Chimica Farmaceutica e Tossicologica
(DCFT), Universitaꢀ di Napoli Federico II, via D. Montesano 49, 80131 Napoli, Italy
campiani@unisi.it
Received February 1, 2010
The first synthesis of the marine endoperoxide 9,10-dihydroplakortin, of its C10-desethyl analogue,
and of their corresponding C6 epimers is described. Stereogenic centers at C4 and at the lateral
chain have been stereoselectively synthesized through Evans’ chiral auxiliary chemistry. Moreover,
the reported synthesis features a one-pot three-step hydroperoxysilylation/cyclization reaction
for the construction of the endoperoxide ring system. Homologation of the aldehyde resulting
from diol cleavage through a Wittig-based strategy gave access to the ester-containing lateral
chain at C3.
Introduction
compounds endowed with pharmacological activity9,10 and in
the field of peroxide antimalarials2 prompted us to develop a
versatile synthetic strategy to the natural product 1. Several 1,2-
dioxane-containing endoperoxides such as peroxyplakoric
acids, Yingzhaosu A, Yingzhaosu C, and various plakortides
and plakortolides have been isolated and structurally charac-
terized so far, and a few syntheses have also been reported.11-16
In general, the low stability of the O-O bond makes installa-
tion and functionalization a challenging task.11,17 Reported
procedures for the synthesis of 1,2-dioxanes involve [4 þ 2]
9,10-Dihydroplakortin (1, Figure 1) is a polyketide iso-
lated from the Caribbean sponge Plakortis simplex.1-3 It
belongs to a group of peroxide-containing natural products
that have increasingly attracted the attention of medicinal
chemists for their biological activities against malaria and
various cancers.4-8 Our interest in the total synthesis of natural
(1) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O.; Ianaro, A. Tetra-
hedron 1999, 55, 7045–7056.
(2) Fattorusso, C.; Campiani, G.; Catalanotti, B.; Persico, M.; Basilico,
N.; Parapini, S.; Taramelli, D.; Campagnuolo, C.; Fattorusso, E.; Romano,
A.; Taglialatela-Scafati, O. J. Med. Chem. 2006, 49, 7088–7094.
(3) Fattorusso, E.; Parapini, S.; Campagnuolo, C.; Basilico, N.;
Taglialatela-Scafati, O.; Taramelli, D. J. Antimicrob. Chemother. 2002, 50,
883–888.
(4) Efferth, T. Drug Resist. Updates 2005, 8, 85–97.
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(10) Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.; Saxena, A.;
Doctor, B. P. J. Am. Chem. Soc. 1996, 118, 11357–11362.
(11) McCullough, K. J.; Nojima, M. Curr. Org. Chem. 2001, 5, 601–
636.
(12) Kawanishi, M.; Kotoku, N.; Itagaki, S.; Horii, T.; Kobayashi, M.
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(13) Murakami, N.; Kawanishi, M.; Itagaki, S.; Horii, T.; Kobayashi, M.
Tetrahedron Lett. 2001, 42, 7281–7285.
(14) Xu, X. X.; Zhu, J.; Huang, D. Z.; Zhou, W. S. Tetrahedron Lett.
1991, 32, 5785–5788.
(8) Dembitsky, V. M.; Gloriozova, T. A.; Poroikov, V. V. Mini Rev. Med.
Chem. 2007, 7, 571–589.
(9) Hashimoto, M.; Liu, Y.; Fang, K.; Li, H. Y.; Campiani, G.; Nakanishi,
K. Bioorg. Med. Chem. 1999, 7, 1181–1194.
(15) Xu, X. X.; Dong, H. Q. J. Org. Chem. 1995, 60, 3039–3044.
(16) Fattorusso, E.; Taglialatela-Scafati, O. Mar. Drugs 2009, 7, 130–152.
(17) Dussault, P. H.; Lee, H. J.; Niu, Q. J. J. Org. Chem. 1995, 60, 784–
785.
DOI: 10.1021/jo1001559
r
Published on Web 03/03/2010
J. Org. Chem. 2010, 75, 2333–2340 2333
2010 American Chemical Society

Gemma et al.
SCHEME 2. Synthesis of Intermediates 9 and 15a
JOCArticle
FIGURE 1. Molecular structures of 9,10-dihydroplakortin 1, C10-
desethyldihydroplakortin 3, and their C6-epimers 2 and 4.
SCHEME 1. Retrosynthetic Analysis for 9,10-Dihydroplakor-
tin 1
aReaction conditions: (a) i. NaHMDS, THF, -78 ꢀC, 1 h; ii. EtI, -40
ꢀC, 16 h, 78% yield, dr 99%; (b) LiBH4, EtOH, Et2O, 0 ꢀC, 3 h, 80%
yield; (c) PCC, silica gel, DCM, 25 ꢀC, 16 h, 100% yield; (d) (carbethoxy-
ethylidene)triphenylphosphorane, DCM, 25 ꢀC, 16 h, 84% yield, E/Z
20:1; (e) triethyl-2-phosphonopropionate, NaH, THF, -30 ꢀC, 4 h, 53%
yield, E/Z 1:2; (f) triethyl-2-phosphonopropionate, NaH, THF, 25 ꢀC,
3 h, 92% yield, E/Z 1:3.
Regioselective hydroperoxysilylation reaction21 followed
by ring closure on a pre-existing epoxide was recognized as
a suitable strategy for constructing the 1,2-dioxane scaffold of
(6S)-5 and (6R)-6.15,22 A challenging step for the synthesis of 1
is the assembly of the ester moiety at C3. Indeed, starting from
diols 5 and 6, one approach could be the synthesis of the ester
group of 1 through oxidation of the primary alcohol to the
corresponding carboxylic acid, after deoxygenation of the
secondary alcohol. However, this latter procedure would
involve the use of hydrides or radical-forming reagents,23
both not compatible with the peroxide functionality. This
problem could be bypassed by oxidative cleavage of the 1,2-
diol of 5 and 6 followed by aldehyde homologation through
the synthesis of a key vinylether intermediate. 1,5-Diene 7,
necessary for the preparation of (6S)-5 and (6R)-6, could be
derived by the allyl iodide 8, first introducing the ethyl chain
applying Evans’ chiral auxiliary chemistry and then generat-
ing the allylic double bond through the appropriate olefina-
tion protocol. Iodide 8 could be prepared starting from R,β-
unsaturated ester 9.
Following our retrosynthetic approach, ester 9 was pre-
pared as described in Scheme 2. Reaction of the sodium
enolate derived by oxazolidinone 10 with ethyl iodide af-
forded the corresponding R-alkylated product 11.24,25
Reductive cleavage of the chiral auxiliary, accomplished
by using a mixture of lithium borohydride and ethanol as the
reducing system,26 afforded alcohol 12 that was smoothly
oxidized to aldehyde 13 with pyridinium chlorochromate
(PCC) adsorbed on silica gel. Different oxidizing reagents
cycloadditions of oxygen to 1,3-dienes18 or intramolecular
cyclization reactions of hydroperoxides with appropriate side
chains.12,13,18-20 A drawback of these methods is the lack of
stereochemical control at the newly formed stereogenic centers.
One exception is the use of the peroxide as nucleophile for the
intramolecular attack on epoxides, which has been exploited
for the synthesis of Yingzhaousu C.15 In this framework, the
main challenge for the synthesis of 9,10-dihydroplakortin 1 is
the presence of three stereogenic centers at the six-membered
endoperoxide skeleton, two of them flaking the labile peroxide
bond, and one of them (C6) being a quaternary carbon. Here
we report the first total synthesis of 1 and of its simplified
analogue 3. The synthesis of epimers at C6 of both 1 and 3 (2
and 4, respectively) was also accomplished.
Results and Discussion
The retrosynthetic logic that directed the preparation of
compounds 1-4 is illustrated in Scheme 1 for dihydropla-
kortin 1. We decided to build up the 1,2-dioxane-based
system of intermediates (6S)-5 and (6R)-6 in the latest steps
of the synthetic procedure. The need of minimizing chemical
operations after ring peroxide formation was dictated by the
poor stability of the 1,2-dioxane system during functional
group elaboration.
(21) O’Neill, P. M.; Hindley, S.; Pugh, M. D.; Davies, J.; Bray, P. G.;
Park, B. K.; Kapu, D. S.; Ward, S. A.; Stocks, P. A. Tetrahedron Lett. 2003,
44, 8135–8138.
(22) Gemma, S.; Marti, F.; Gabellieri, E.; Campiani, G.; Novellino, E.;
Butini, S. Tetrahedron Lett. 2009, 50, 5719–5722.
(23) Hudlicky, M. C. Reductions in Organic Chemistry, 2nd ed.; American
Chemical Society: Washington, DC, 1996.
(18) Yao, G.; Steliou, K. Org. Lett. 2002, 4, 485–488.
(19) Harris, J. R.; Waetzig, S. R.; Woerpel, K. A. Org. Lett. 2009, 11,
3290–3293.
(20) Tokuyasu, T.; Kunikawa, S.; McCullough, K. J.; Masuyama, A.;
Nojima, M. J. Org. Chem. 2005, 70, 251–260.
(24) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737–1739.
(25) Furuta, K.; Ashibe, K.; Shirahashi, H.; Fujita, N.; Yamashita, H.;
Yamada, N.; Kuwano, E. J. Pestic. Sci. 2007, 32, 99–105.
(26) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000–4005.
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JOCArticle
SCHEME 3. Synthesis of Intermediates 8, 17 and 7, 22a
The alkylation of the sodium enolate of 1829 with 8 or 17
afforded the corresponding carboxamides 19a,b in 63% and
73% yield, respectively. Cleavage of the chiral auxiliary to
give alcohols 20a,b was performed as described above.
Exposure of alcohols 20a,b to Dess-Martin periodinane
cleanly furnished the desired aldehyde intermediates (while
PCC adsorbed on silica gel resulted into racemization of the
neighboring chiral center), which were immediately sub-
mitted to the Wadsworth-Emmons olefination protocol.
Olefins 21a,b presented the E-configuration at the newly
installed double bond (Z-isomer not detectable at NMR).
Finally, the 2E-allylic alcohols 7 and 22 were obtained by
DIBAL-promoted reduction of the corresponding R,β-un-
saturated esters.
In the next steps of the synthesis (Scheme 4), intermediates
7 and 22 were submitted to the asymmetric Sharpless epox-
idation performed at -30 ꢀC.
The resulting epoxides were converted into the corre-
sponding acetates 23a,b by treatment with acetic anhydride
and pyridine. Regioselective hydroperoxysilylation reaction
at the quaternary olefinic carbon was accomplished by using
cobalt(II) bis[2,2,6,6-tetramethylheptane-3,5-dienoate] as
the catalyst, in the presence of oxygen and triethylsilane.21
A similar approach to an endoperoxide system was reported
by Dong and co-workers for the synthesis of Yingzhaosu C.
The authors used a three steps procedure to synthesize the
key Yingzhaosu C 1,2-dioxane intermediate.15 Here we
successfully applied a one-pot three-step synthesis to inter-
mediates 24a,b. After filtration over a short pad of silica gel
for removing the catalyst, crude 24a,b were hydrolyzed to
obtain the corresponding diols. The epimeric mixtures of
diols thus obtained were readily separated by column chro-
matography affording compounds (6S)-5, (6R)-6, (6S)-25,
and (6R)-26 as pure isomers in 36-45% overall yield from
24a,b. With the endoperoxides in our hand, construction of
the ester at C3 was accomplished by using a Wittig-based
strategy. Accordingly, oxidative cleavage of the 1,2-diols to
the corresponding aldehydes 27a,b and 28a,b was accom-
plished by treatment with sodium periodate in a 1:3 mixture
of water and acetonitrile. These latter aldehydes were im-
mediately exposed to the Wittig reagent prepared from
(methoxymethyl)triphenylphosphonium chloride and so-
dium bis(trimethylsilyl)amide. Excess of Wittig reagent and
triphenylphosphine oxide were partially removed by preci-
pitation from methyl-tert-butylether. The mixtures of eno-
lethers 29a and 29b and the mixture of enolethers 30a and 30b
were treated with 6 N HCl in acetone. The corresponding
aldehydes were oxidized to carboxylic acids using a catalytic
amount of ruthenium chloride in the presence of sodium
periodate. Completion of the synthetic scheme was realized
by diazomethane-promoted esterification of the crude car-
boxylic acid intermediates affording methyl esters 1-4.
Physical and spectroscopic properties of 1 are identical to
those of an authentic sample of 9,10-dihydroplakortin.1
aReagents and conditions: (a) DIBAL, DCM, -78 ꢀC, 1.5 h; 16a, 99%
yield, 16b, 99% yield, E/Z 2:7; (b) PPh3, imidazole, I2, 1:3 MeCN/Et2O,
0 ꢀC, 1.5 h; 8, 65% yield, 17, 95% yield, E/Z 2:3; (c) i. 18, NaHMDS,
THF, -78 ꢀC, 1.5 h; ii. 8 (or 17), THF, -35 ꢀC, 5 h; 19a, 65% yield, dr
99%; 19b, 72% yield, E/Z 2:3, dr 99%; (d) LiBH4, EtOH, Et2O, 0 ꢀC, 3 h;
20a, 63%, 20b, 73% yield, E/Z 1:1; (e) i. Dess-Martin periodinane,
DCM, 0 ꢀC, 4 h; ii. NaH, triethylphosphonoacetate, THF, 0 ꢀC, 2 h; 21a,
88% yield, 21b, 78% yield, E/Z 1:1; (f) DIBAL, DCM, -78 ꢀC, 1.5 h; 7,
95%, 22, 98% yield.
such as PCC alone, 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) and sodium hypochlorite,27 or Dess-Martin
periodinane either caused racemization of 13 or resulted in
poor yields. Wadsworth-Emmons olefination of the crude
aldehyde 13 with triethyl-2-phosphonopropionate and so-
dium hydride was performed at -30 ꢀC to avoid racemiza-
tion of the labile stereocenter and furnished the desired
product 9 in 53% yield as a 1:2 E/Z isomer mixture. In order
to improve the yield of 9, aldehyde 13 was exposed to
(carbethoxyethylidene)triphenylphosphorane in dichloro-
methane at 25 ꢀC, providing 9 in 84% yield as a 20:1 E/Z
isomer mixture. The synthesis of ester 15 (key intermediate to
dihydroplakortin analogues 3 and 4, Figure 1) was realized
by using the Wadsworth-Emmons olefination protocol,
starting from commercially available aldehyde 14.
Scheme 3 outlines the synthesis of key 9,10-dihydropla-
kortin intermediates 8 and 7 along with intermediates 17 and
22 necessary for the synthesis of simplified analogues 3 and 4
(Figure 1). Iodides 8 and 17 (Scheme 3) were obtained by a
DIBAL-mediated reduction of 9 or 15 to alcohols 16a,b
followed by treatment with I2 in the presence of triphenyl-
phosphine and imidazole.28
Conclusions
The synthetic methodology detailed herein led to the
synthesis of the natural product 9,10-dihydroplakortin.
The availability of this compound from natural sources is
highly limited, also compared to the parent compound
plakortin (0.1% of the sponge extract). Moreover, the
(27) Portonovo, P.; Liang, B.; Joullie, M. M. Tetrahedron: Asymmetry
1999, 10, 1451–1455.
(28) Carter, R. G.; Weldon, D. J. Org. Lett. 2000, 2, 3913–3916.
(29) Jacobsen, J. R.; Keatinge-Clay, A. T.; Cane, D. E.; Khosla, C.
Bioorg. Med. Chem. 1998, 6, 1171–1177.
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SCHEME 4. Synthesis Completion to Derivatives 1-4a
aReagents and conditions: (a) 4 A MS, Ti(OiPr)4, D(-)DIPT, t-BuOOH, DCM, -25 ꢀC, 48 h, (b) Ac2O, Pyr, DMAP, DCM, 0 ꢀC, 3 h; 23a, 65% over two
steps, dr 99%; 23b, 52% yield, over two steps; dr 97%, E/Z 1:1, (c) i. Co(thd)2, Et3SiH, O2, 1,2-DCE, 25 ꢀC, 5 h; ii. Amberlyst, DCM, 25 ꢀC, 18 h; (d) K2CO3,
MeOH, 3 h, 0 ꢀC; 5, 42%, 6, 36%, 25, 45%, 26, 38% yield; (e) NaIO4, 3:2MeCN/H2O, 25 ꢀC, 1 h; (f) i. (MeOCH2)PPh3þCl-, NaHMDS, -78 f0ꢀC;(g) i. 6N
HCl, acetone, 25 ꢀC, 0.5 h; ii. RuCl3, NaIO4, 1:3 H2O/MeCN, 25 ꢀC, 1 h; iii. CH2N2, Et2O, 25 ꢀC, 0.5 h; 1, 24%, 2, 35%, 3, 32%, 4, 18% yield.
versatile synthetic approach here described paves the way to
the preparation of a number of simplified plakortin analo-
gues, differing both for the structure of the alkyl/aryl side
chains and for the configuration at the stereogenic centers
with the scope to improve the pharmacodynamic profile of
the natural product. In vitro antimalarial evaluation of
compounds 2-4 is currently ongoing and will be reported
in due course.
pentane) to afford 12 (0.35 g, 80%) as a colorless liquid. Spectro-
scopic and analytical data for (S)-12 are identical to those reported
in the literature.30 [R]20 = þ3.3 (c 4.1, CHCl3); lit.30 [R]20
=
D
D
þ3.3 (c 5.3, CHCl3); HRMS (ESI) calcd for C8H18ONa (M þ
Na)þ 153.1250, found 153.1254
(S)-2-Ethylhexanal (13). To a suspension of pyridinium chlor-
ochromate (11.2 g, 52.0 mmol) and silica gel (10.8 g) in dichlor-
omethane (120 mL), cooled to 0 ꢀC, was added alcohol 12 (5.6 g,
43.0 mmol) in one portion, and the reaction mixture was stirred
at 25 ꢀC for 16 h. The suspended solid was filtered off, and the
filtrate was concentrated to give aldehyde 13 in quantitative
yield as a colorless oil. The crude aldehyde was used in the
subsequent step without further purification. Spectroscopic and
analytical data for (S)-13 are identical to those reported in the
Experimental Procedure
(4S,20S)-4-Benzyl-3-(20-ethylhexanoyl)oxazolidin-2-one (11).
A solution of 10 (2.5 g, 8.9 mmol) in THF (10 mL) was added
dropwise over 30 min to a solution of sodium bis(trimethylsilyl)-
amide (1.0 M solution in THF, 13.4 mL, 13.4 mmol) in dry THF
(20 mL) cooled to -78 ꢀC. After 1 h, ethyl iodide (1.1 mL, 13.4
mmol) was added dropwise, and the resulting mixture was
allowed to warm to -40 ꢀC and was stirred at the same tem-
perature for 16 h. The reaction was quenched by addition of a
saturated solution of ammonium chloride at -30 ꢀC, followed
by evaporation of the solvent. The aqueous phase was extracted
with chloroform, the organic extracts were dried over sodium
sulfate, and the solvent was removed. The residue was purified
by flash chromatography (1:5 diethyl ether/petroleum ether
40-60 ꢀC) to afford 11 as a colorless oil (2.4 g, 78%, dr 99%).
TLC Rf 0.45 (1:1 ethyl acetate/n-hexane); 1H NMR (300 MHz,
CDCl3) δ 7.36-7.22 (m, 5H), 4.74-4.67 (m, 1H), 4.15 (m, 2H),
3.76-3.69 (m, 1H), 3.34 (dd, J = 2.6, 13.2 Hz, 1H), 2.71 (dd, J =
10.3, 13.2 Hz, 1H), 1.81-1.44 (m, 4H), 1.29 (m, 4H), 0.96 (t, J =
7.3 Hz, 3H), 0.89 ppm (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 177.1, 153.4, 135.7, 129.6, 129.2, 127.5, 66.1, 55.7,
44.3, 38.3, 31.4, 29.8, 25.7, 23.0, 14.2, 11.7; MS (ESI) (m/z) 326
(M þ Na)þ. HRMS (ESI) calcd for C18H25NO3Na (M þ Na)þ
326.1727, found 326.1728.
literature.31 [R]20 = þ4.5 (c 3.4, CHCl3); lit.31 [R]20D= þ4.6
D
(c = 0.3, CHCl3); HRMS (ESI) calcd for C8H16ONa (M þ Na)þ
151.1093, found 151.1096.
(S,Z)-4-Ethyl-2-methyloct-2-enoic Acid Ethyl Ester ((Z)-9)
and (S,E)-4-Ethyl-2-methyloct-2-enoic Acid Ethyl Ester ((E)-9).
Procedure 1. To a suspension of sodium hydride (1.9 g, 47.1
mmol) in dry THF (120 mL), cooled to 0 ꢀC, was added triethyl-
2-phosphonopropionate (10.0 mL, 47.1 mmol) dropwise. After
1 h, the reaction mixture was cooled to -30 ꢀC, and a solution
of aldehyde 13 (5.5 g, 43.0 mmol) was added dropwise. After 3 h
the reaction mixture was quenched with a saturated solution of
ammonium chloride, the volatiles were evaporated, and the
aqueous phase was extracted with chloroform. The organic ex-
tracts were dried over sodium sulfate, and the solvent was eva-
porated. The crude product was purified by flash chromatogra-
phy (1:10 ethyl acetate/n-hexane) to afford ester 9 as a 1:2 mixture
of E and Z isomers (5.3 g, 53%). Procedure 2. A mixture of crude
aldehyde 13 (0.51 g, 3.9 mmol) and (carbethoxyethylidene)-
triphenylphosphorane (1.6 g, 4.3 mmol) was stirred overnight
at 25 ꢀC and then concentrated. The residue was purified by
column chromatography (1:50 diethyl ether/petroleum ether) to
afford afford ester 9 as a 20:1 mixture of E and Z isomers (1.0 g,
84%). (Z)-9: colorless oil; Rf 0.44 (1:50 ethyl acetate/n-hexane);
[R]20D = -2.3 (c 0.34, CHCl3); 1H NMR (300 MHz, CDCl3) δ
5.57 (d, J = 10.5 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 2.93 (m, 1H),
1.91 (s, 3H), 1.47-1.39 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H),
1.24-1.08 (m, 6H), 0.88-0.80 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.7, 147.4, 127.4, 60.1, 40.4, 35.1, 29.7, 28.5, 23.1,
(S)-2-Ethylhexan-1-ol (12). To a mixture of 11 (1.0 g, 3.4 mmol)
and ethanol (210 μL, 3.7 mmol) in dry diethylether (11 mL), cooled
to 0 ꢀC was added dropwise a 2 M solution of lithium borohydride
in THF (2.0 mL, 4.0 mmol). The resulting mixture was stirred at
0 ꢀC for 3 h and quenched by adding a 1 N solution of sodium
hydroxide. The organic phase was washed with water and dried
over sodium sulfate, and the solvent was removed. The crude
product was purified by flash chromatography (1:1 diethylether/
(30) Baczko, K.; Larpent, C. J. Chem. Soc., Perkin Trans. 2 2000,
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521–526.
4000–4005.
2336 J. Org. Chem. Vol. 75, No. 7, 2010

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JOCArticle
21.1, 14.5, 14.2, 11.9; MS (ESI) (m/z) 326 (M þ Na)þ. HRMS
(ESI) calcd for C13H24O2Na (M þ Na)þ 235.1669, found
235.1670. (E)-9: colorless oil; [R]20D = -2.5 (c 0.16, CHCl3); Rf
0.36 (1:50 ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ
6.47 (d, J = 10.5 Hz, 1H), 4.17 (q, J = 7.0 Hz, 2H), 2.25-2.19 (m,
1H),1.82 (s, 3H), 1.46-1.39 (m, 2H), 1.31-1.16 (m, 9H),
0.87-0.79 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 168.6,
147.5, 127.7, 60.6, 40.8, 34.9, 29.9, 28.3, 23.1, 14.5, 14.3, 13.1,
12.1; MS (ESI) (m/z) 235 (M þ Na)þ. HRMS (ESI) calcd for
C13H24O2Na (M þ Na)þ 235.1669, found 235.1669.
mixture of diethyl ether/n-hexane (390 mL) was added, and the
resulting precipitate was filtered off. The filtrate was concen-
trated under vacuum, and the crude product was purified by
flash chromatography (1:100 ethyl acetate/n-hexane) to afford 8
(6.3 g, 86%) as a pale yellow oil containing trace impurities
of the Z isomer. Rf 0.90 (1:20 diethyl ether/petroleum ether 40-
60 ꢀC); [R]20 = -2.6 (c 0.8, in CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 5.07 (d, J = 10.3 Hz, 1H), 3.92 (s, 2H), 2.19-2.07 (m,
1H), 1.87 (s, 3H), 1.54-1.32 (m, 2H), 1.30-1.13 (m, 6H),
0.90-0.82 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 136.1,
132.1, 40.8, 35.0, 29.9, 28.3, 23.2, 22.7, 14.3, 12.2, 8.2; MS
(ESI) (m/z) 303 (M þ Na)þ. HRMS (ESI) calcd for C11H21INa
(M þ Na)þ 303.0580, found 303.0579.
(Z)-4-Ethyl-2-methylhex-2-enoic Acid Ethyl Ester ((Z)-15)
and (E)-4-Ethyl-2-methylhex-2-enoic Acid Ethyl Ester ((E)-15).
Starting from the commercially available aldehyde 14 and
following the procedure described for the synthesis of 9
(procedure 1), the title compound was obtained in 92% yield
and as a 3:1 mixture of Z and E isomers. (Z)-15: colorless oil;
TLC Rf 0.79 (1:10 ethyl acetate/n-hexane); 1H NMR (300 MHz,
CDCl3) δ 5.49 (d, J = 10.6 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H),
2.83-2.77 (m, 1H), 1.85 (s, 3H), 1.43-1.32 (m, 2H), 1.25-1.10 (m,
5H), 0.77 (t, J = 7.3 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ
168.5, 147.0, 127.7, 60.0, 42.0, 28.1, 21.0, 14.4, 11.8; MS (ESI) (m/z)
207 (M þ Na)þ. HRMS (ESI) calcd for C11H20O2Na (M þ Na)þ
207.1356, found 207.1351. (E)-15: colorless oil; TLC Rf 0.74 (1:10
(Z)-4-Ethyl-1-iodo-2-methylhex-2-ene and (E)-4-Ethyl-1-io-
do-2-methylhex-2-ene (17). The title compound was obtained
from 16b in 95% yield and as a 3:2 mixture of Z/E isomers as
described for the synthesis of 8. Rf 0.80 (1:50 ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 5.39 (d, 1H, J = 10.0
Hz), 5.07 (d, 1H, J = 10.3 Hz), 3.97 (s, 2H), 3.93 (s, 2H), 2.17-
1.98 (m, 2H), 1.87 (s, 3H), 1.78 (s, 3H), 1.53-1.38 (m, 4H),
1.23-1.11 (m, 4H), 0.90-0.80 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ 135.7, 135.4, 133.3, 132.5, 42.5, 42.2, 31.8, 28.2, 27.9,
22.9, 22.6, 17.4, 16.2, 14.3, 12.2, 11.9; MS (ESI) (m/z) 275 (M þ
Na)þ. HRMS (ESI) calcd for C9H17INa (M þ Na)þ 275.0267,
found 275.0270.
1
ethyl acetate/n-hexane); H NMR (300 MHz, CDCl3) δ 6.45 (d,
J= 10.5 Hz, 1H), 4.15 (q, J= 7.0 Hz, 2H), 2.21-2.13 (m, 1H), 1.80
(s, 3H), 1.51-1.40 (m, 2H),1.30-1.19 (m, 5H), 0.80 (t, J = 7.3 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 168.5, 147.0, 128.0, 60.5, 42.5,
27.9, 14.5, 13.1, 12.0; MS (ESI) (m/z) 207 (M þ Na)þ. HRMS(ESI)
calcd for C11H20O2Na (M þ Na)þ 207.1356, found 207.1355.
(S,E)-4-Ethyl-2-methyloct-2-en-1-ol (16a). To a solution of 9
(5.3 g, 25 mmol) in dry dichloromethane (120 mL), cooled to
-78 ꢀC, was added dropwise a 1 M solution of diisobutylalu-
minum hydride (50 mL, 50 mmol) within 30 min. After 1 h, the
reaction mixture was quenched with a saturated solution of ammo-
nium chloride, and the mixture was allowed to warm to 25 ꢀC. The
white precipitate was filtered off, the layers were separated, and the
aqueous phase was extracted with dichloromethane. The com-
bined organic extracts were dried over sodium sulfate, and the
solvent was removed. The residue was purified by flash chroma-
tography (1:10 ethyl acetate/n-hexane) to afford 16a (4.2 g, 99%)
as a 16:1 mixture of Eand Zisomers. [R]20D =-2.4 (c 2.1, CHCl3);
(S)-4-Benzyl-3-[(2R,6S,Z)-2,6-diethyl-4-methyldec-4-enoyl]-
oxazolidin-2-one (19a). To a mixture of sodium bis(trimethyl-
silyl)amide (1.0 M in THF, 24.3 mL, 24.3 mmol) and THF (60
mL), cooled to -78 ꢀC, was added dropwise a solution of 1829
(6.0 g, 24.3 mmol) in THF (20 mL) within 30 min. After 1 h, a
solution of 8 (6.2 g, 22.1 mmol) in THF (20 mL) was added
dropwise within 30 min. The reaction mixture was allowed to
warm to -35 ꢀC, and was stirred at the same temperature for 5 h.
A saturated solution of ammonium chloride was added to the
reaction mixture, which was subsequently allowed to warm to
25 ꢀC. The volatiles were removed, and the aqueous phase was
extracted with diethyl ether. The organic extracts were dried
over sodium sulfate, and the solvent was removed. The residue
was purified by flash chromatography (1:6 diethylether/n-
hexane) to afford 19a (5.7 g, 65%, dr 99%) as a colorless thick
oil. [R]20D = þ51.0 (c 0.38, CHCl3); Rf 0.58 (1:4 ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 7.37-7.21 (m, 5H), 4.92
(d, J = 10.0 Hz, 1H), 4.71-4.64 (m, 1H), 4.20-4.12 (m, 2H),
4.00-3.94 (m, 1H), 3.34 (dd, J = 3.1, 13.3 Hz, 1H), 2.64 (dd, J =
10.3, 13.2 Hz, 1H), 2.52 (dd, J = 6.7, 13.8 Hz, 1H), 2.17-2.10
(m, 2H), 1.66 (s, 3H), 1.60-1.51 (m, 1H), 1.43-1.09 (m, 9H),
0.91 (t, J = 7.3 Hz, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.80 (t, J = 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.8, 153.4, 135.8,
133.2, 132.0, 129.6, 129.2, 127.5, 66.1, 55.8, 42.7, 42.5, 39.8, 38.3,
35.6, 30.0, 29.0, 24.8, 23.1, 16.6, 14.4, 12.2, 11.9; MS (ESI) (m/z)
422 (M þ Na)þ HRMS (ESI) calcd for C25H37NO3Na (M þ
Na)þ 422.2666, found 422.2664.
1
Rf 0.17 (1:6 diethyl ether/petroleum ether 40-60 ꢀC); H NMR
(300 MHz, CDCl3, signals reported for the major isomer only) δ
4.96 (d, 1H, J = 10.3 Hz), 4.11 (s, 2H), 2.19-2.10 (m, 1H), 1.82 (s,
3H), 1.47-1.28 (m, 2H), 1.26-1.11 (m, 7H), 0.87 (t, J = 6.5 Hz,
3H), 0.81 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, signals
reported for the major isomer only) δ 134.3, 134.2, 62.4, 39.7, 35.6,
30.0, 28.9, 23.1, 21.6, 14.3, 12.2; MS (ESI) (m/z) 193 (M þ Na)þ.
HRMS (ESI) calcd for C11H22ONa (M þ Na)þ 193.1563, found
193.1563.
(Z)-4-Ethyl-2-methylhex-2-en-1-ol and (E)-4-Ethyl-2-methyl-
hex-2-en-1-ol (16b). The title compound was obtained from 15 in
99% yield and as a 7:2 mixture of Z/E isomers as described for
(S)-4-Benzyl-3-[(R,Z)-2,6-diethyl-4-methyloct-4-enoyl]oxa-
zolidin-2-one (19b). The title compound was obtained from 18
and 17 in 72% yield (99% dr) and as a 2:3 mixture of E/Z
isomers as described for the synthesis of 19a. Rf 0.39 (1:10 ethyl
1
the synthesis of 16a. Rf 0.35 (1:20 ethyl acetate/n-hexane); H
NMR (300 MHz, CDCl3, signals reported for the major isomer
only) δ 4.90 (d, J = 10.0 Hz, 1H), 4.11 (s, 2H), 2.10-2.03 (m,
1H), 1.82 (s, 3H), 1.47-1.09 (m, 5H), 0.81 (t, J = 7.4 Hz, 6H);
13C NMR (100 MHz, CDCl3, signals reported for the major
isomer only) δ 134.6, 133.8, 62.4, 41.4, 28.6, 21.6, 12.2; MS (ESI)
(m/z) 165 (M þ Na)þ. HRMS (ESI) calcd for C9H18ONa (M þ
Na)þ 165.1250, found 165.1254.
(S,E)-4-Ethyl-1-iodo-2-methyloct-2-ene (8). A mixture of tri-
phenylphosphine (20.2 g, 77.0 mmol) and imidazole (5.7 g, 84.6
mmol) in 1:3 acetonitrile/diethyl ether (140 mL) was cooled to
0 ꢀC, and afterward iodine (10.5 g, 77 mmol) was added in two
portions. The resulting mixture was stirred at 0 ꢀC for 1 h, when
a yellow precipitate was formed. Alcohol 16a (4.4 g, 25.6 mmol)
was subsequently added and stirred at 0 ꢀC for 30 min. A 1:6
1
acetate/n-hexane); H NMR (300 MHz, CDCl3) δ 7.36-7.20
(m, 10H), 4.95 (d, J = 10.0 Hz, 1H), 4.87 (d, J = 9.7 Hz, 1H),
4.67-4.61 (m, 2H), 4.19-4.11 (m, 4H), 4.03-3.94 (m, 2H),
3.48-3.24 (m, 2H), 2.82-2.74 (m, 2H), 2.48 (dd, J = 6.7, 13.2
Hz, 1H), 2.35-2.30 (m, 1H), 2.15-2.00 (m, 4H), 1.72 (s, 3H),
1.62 (s, 3H), 1.56 (bs, 1H), 1.45-1.28 (m, 4H þ 3H), 1.20-1.06
(m, 10H), 0.87-0.76 (m, 12H); 13C NMR (100 MHz, CDCl3) δ
177.5, 177.4, 135.6, 135.5, 133.7, 132.9, 132.3, 131.8, 129.7,
129.6, 129.2, 129.1, 127.5, 66.2, 55.7, 55.6, 44.0, 41.6, 40.9,
38.1, 36.1, 35.8, 28.7, 28.6 (2C), 23.4, 17.0, 16.8, 16.6, 12.1,
12.0, 11.9; MS (ESI) (m/z) 394 (M þ Na)þ. HRMS (ESI) calcd
for C23H33NO3Na (M þ Na)þ 394.2353, found 394.2352.
J. Org. Chem. Vol. 75, No. 7, 2010 2337

Gemma et al.
JOCArticle
(2R,6S,E)-2,6-Diethyl-4-methyldec-4-en-1-ol (20a). The title
compound was obtained from 19a in 63% yield as described for
the synthesis of 12. Rf 0.72 (1:1 diethyl ether/ petroleum ether
40-60 ꢀC); [R]20D = þ8.8 (c 0.57, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 4.87 (d, J = 10.8 Hz, 1H), 3.56 (d, J = 7.2 Hz, 2H),
2.12-2.04 (m, 1H), 2.01 (d, J = 8.0 Hz, 2H), 1.68-1.59 (m, 1H),
1.61 (s, 3H), 1.56-1.09 (m, 11H), 0.91 (t, J = 7.3 Hz, 3H),
0.86-0.79 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 133.7, 132.5,
65.8, 42.5, 40.0, 39.8, 35.7, 29.9, 29.0, 23.9, 23.1, 16.7, 14.4, 12.2,
11.4; MS (ESI) (m/z) 249 (M þ Na)þ. HRMS (ESI) calcd for
C15H30ONa (M þ Na)þ 249.2189, found 249.2186.
11.9; MS (ESI) (m/z) 289 (M þ Na)þ. HRMS (ESI) calcd for
C17H30O2Na (M þ Na)þ 289.2138, found 289.2136.
(2E,4R,6Z,8S)-4,8-Diethyl-6-methyldodeca-2,6-dien-1-ol (7).
To a solution of 21a (2.7 g, 9.2 mmol) in dry dichloromethane
(30 mL), cooled to -78 ꢀC was added dropwise a 1 M solution of
diisobutylaluminum hydride (18.4 mL, 18.4 mmol) within 30 min.
After 1 h, to the reaction mixture was added a saturated solu-
tion of ammonium chloride, and the mixture was allowed to
warm to 25 ꢀC. The white precipitate was filtered off, the layers
were separated, and the aqueous phase was extracted with
dichloromethane. The combined organic extracts were dried
over sodium sulfate, and the solvent was removed. The crude
product was purified by flash chromatography (1:5 ethyl acet-
ate/n-hexane) to afford 7 (2.2 g, 95%) as a colorless oil. Rf 0.52
(1:2 ethyl acetate/n-hexane); [R]20D = þ26.9 (c 0.16, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 5.58 (dt, J = 5.9, 15.2 Hz, 1H), 5.41
(dd, J = 8.2, 15.2 Hz, 1H), 4.84 (d, J = 10.0 Hz, 1H), 4.05 (d,
J = 5.9 Hz, 2H), 2.15-1.94 (m, 4H), 1.65 (s, 3H), 1.50-1.03 (m,
11H), 0.91-0.75 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 137.5,
133.1, 132.5, 128.9, 64.1, 42.7, 39.4, 38.0, 35.8, 30.0, 29.0, 27.6,
24.1, 23.3, 14.4, 12.1, 12.0; MS (ESI) (m/z) 275 (M þ Na)þ.
HRMS (ESI) calcd for C17H32ONa (M þ Na)þ 275.2345, found
275.2341.
(R,Z)-2,6-Diethyl-4-methyloct-4-en-1-ol and (R,E)-2,6-Dieth-
yl-4-methyloct-4-en-1-ol (20b). The title compound was ob-
tained from 19b in 73% yield as a 1:1 mixture of E/Z isomers
as described for the synthesis of 12. Rf 0.40 (1:4 ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 4.92 (d, J = 10.0 Hz,
1H), 4.87 (d, J = 9.7 Hz, 1H), 3.56-3.52 (m, 4H), 2.12-1.95 (m,
6H), 1.72 (s, 3H), 1.69-1.63 (m, 2H), 1.61 (s, 3H), 1.45-1.31 (m,
10H), 1.21-1.09 (m, 4H), 0.95-0.89 (m, 6H), 0.86-0.79 (m,
12H); 13C NMR (100 MHz, CDCl3) δ 134.1, 133.8, 132.6, 132.1,
65.9, 65.8, 42.5, 41.6, 40.9, 40.5, 40.0, 34.5, 28.7, 28.62, 24.0,
23.9, 23.8, 16.7, 12.2, 12.1, 12.0, 11.9, 11.6, 11.4; MS (ESI) (m/z)
221 (M þ Na)þ. HRMS (ESI) calcd for C13H26ONa (M þ Na)þ
221.1876, found 221.1872.
(2E,4R,6Z,8S)-4,8-Diethyl-6-methyldodeca-2,6-dienoic Acid
Ethyl Ester (21a). A mixture of alcohol 20a (2.6 g, 11.5 mmol)
and Dess-Martin periodinane (7.3 g, 17.2 mmol) in dicholor-
omethane (60 mL) was stirred at 0 ꢀC for 4 h. The cold organic
phase was washed with a saturated solution of sodium dithio-
nite and a saturated solution of sodium bicarbonate. The
organic phase was dried over sodium sulfate, and the solvent
was removed. The crude aldehyde thus obtained was imme-
diately used in the next step. Accordingly, to an ice-cold
suspension of sodium hydride (430 mg, 10.7 mmol) in THF
(20 mL) was added triethylphosphonoacetate (2.1 mL, 10.7
mmol) dropwise. The suspension was stirred for 1 h, and to the
clear solution formed was added a solution of above aldehyde
in THF (20 mL). The reaction mixture was stirred at 0 ꢀC for 1
h, and afterward a saturated solution of ammonium chloride
was added. The volatiles were removed, and the aqueous
phase was extracted with chloroform. The organic extracts
were washed with brine and dried over sodium sulfate, and the
solvent was removed. The residue was purified by flash
chromatography (1:20 diethyl ether/n-hexane) to afford 21a
(2.3 g, 88%) as a colorless oil. Rf 0.90 (1:10 ethyl acetate/n-
hexane); [R]20D = þ68.2 (c 0.44, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 6.65 (dd, J = 8.9, 15.7 Hz, 1H), 5.67 (d, J = 15.7 Hz,
1H), 4.72 (d, J = 10.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 2.21-
2.09 (m, 1H), 2.06-1.91 (m, 3H), 1.47 (s, 3H), 1.45-1.30 (m,
1H), 1.28-0.97 (m, 12H), 0.79 (t, J = 7.3 Hz, 6H), 0.69 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 153.4,
133.0, 132.1, 121.2, 60.3, 45.3, 42.6, 39.8, 35.8, 31.2, 29.0,
27.0, 23.1, 16.7, 14.5, 14.4, 12.0, 11.9; MS (ESI) (m/z) 317
(M þ Na)þ. HRMS (ESI) calcd for C19H34O2Na (M þ Na)þ
317.2451, found 317.2456.
(R,2E,6Z)-4,8-Diethyl-6-methyldeca-2,6-dien-1-ol ((6Z)-22)
and (R,2E,6E)-4,8-Diethyl-6-methyldeca-2,6-dien-1-ol ((6E)-
22). The title compound was obtained from 21b in 98% yield
as a 1:1 mixture of E/Z isomers as described for the synthesis of
1
7. Rf 0.45 (1:3 ethyl acetate/n-hexane); H NMR (300 MHz,
CDCl3) δ 5.61-5.50 (m, 2H), 5.43-5.35 (m, 2H), 4.83 (d, J =
10.0 Hz, 1H), 4.74 (d, J = 10.0 Hz, 1H), 4.05-4.03 (m, 4H),
2.11-1.92 (m, 8H), 1.66 (s, 3H), 1.65 (bs, 2H), 1.53 (s, 3H),
1.46-1.30 (m, 6H), 1.24-1.03 (m, 6H), 0.86-0.75 (m, 18H); 13
C
NMR (100 MHz, CDCl3) δ 137.4, 137.3, 133.4, 132.1, 131.9,
128.9, 64.0, 46.0, 42.6, 42.2, 41.6, 40.9, 28.8, 28.7 (2C), 27.6, 27.5,
26.1, 16.8, 12.1, 12.0, 11.8; MS (ESI) (m/z) 247 (M þ Na)þ.
HRMS (ESI) calcd for C15H28ONa (M þ Na)þ 247.2032, found
247.2033.
(2R,3R,4R,8S,Z)-4,8-Diethyl-6-methyl-2,3-epoxydodec-6-ene-
1-yl Acetate (23a). A mixture of 4 A molecular sieves (3.7 g),
titanium(IV) isopropoxide (1.3 mL, 4.3 mmol), and D-(-)-
diisopropyl tartrate (1.3 mL, 6.2 mmol) in dichloromethane
(55 mL) was cooled to -25 ꢀC and allowed to stir for 1 h.
Subsequently, a solution of 7 (2.2 g, 8.7 mmol) in dichloro-
methane (10 mL) was added, followed by addition of tert-butyl
hydroperoxide (5.5 M in nonane, 3.2 mL, 17.5 mmol). The
reaction mixture was stirred at -25 ꢀC for 48 h, and afterward a
1 M solution of sodium hydroxide was carefully added. The
layers were separated, and the organic phase was washed with
1 m sodium hydroxide and water. The organic layer was dried
over sodium sulfate, and the solvent was removed. The residue
was purified by flash chromatography (1:7 ethyl acetate/petro-
leum ether 40-60 ꢀC) to afford (2R,3R,4R,8S,Z)-4,8-diethyl-6-
methyl-2,3-epoxydodec-6-ene-1-ol (1.5 g, 65%, dr 99%) as a
thick colorless oil. [R]20D = þ15.1 (c 0.007, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 4.93 (d, J = 10.0 Hz, 1H), 3.92 (dd, J =
2.5, 12.4 Hz, 1H), 3.63 (dd, J = 4.1, 12.6 Hz, 1H), 2.99-2.96 (m,
1H), 2.72 (d, J = 2.3, 7.9 Hz, 1H), 2.16 (d, J = 7.0 Hz, 2H),
2.13-2.07 (m, 1H), 1.68 (s, 3H), 1.56 (bs, 1H), 1.48-1.08 (m,
11H), 0.91 (t, J = 7.3 Hz, 3H), 0.88-0.79 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 133.1, 132.4, 61.9, 59.8, 58.5, 41.1, 39.4,
35.7, 35.4, 29.8, 29.0, 24.2, 23.9, 23.3, 14.4, 12.3, 12.1; MS (ESI)
(m/z) 291 (M þ Na)þ. HRMS (ESI) calcd for C17H32O2Na (M þ
Na)þ 291.2295, found 291.2297. A mixture of the above com-
pound (0.15 g, 0.57 mmol), pyridine (0.30 mL, 3.7 mmol), acetic
anhydride (0.17 mL, 1.8 mmol), and a catalytic amount of N,N-
dimethylaminopyridine in dichloromethane (40 mL) was stirred
at 0 ꢀC for 3 h. The organic phase was washed with a saturated
solution of sodium bicarbonate, with 1 N hydrochloric acid, and
(R,2E,6Z)-4,8-Diethyl-6-methyldeca-2,6-dienoic Acid Ethyl
Ester ((6Z)-21b) and (R,2E,6E)-4,8-Diethyl-6-methyldeca-2,6-
dienoic Acid Ethyl Ester ((6E)-21b). The title compound was
obtained from 20b in 78% yield as a 1:1 mixture of E/Z isomers
as described for the synthesis of 21a. Rf 0.85 (1:10 ethyl acetate/
n-hexane); 1H NMR (300 MHz, CDCl3) δ 6.76-6.66 (m, 2H),
5.76 (d, J = 15.5 Hz, 1H), 5.75 (d, J = 15.6 Hz, 1H), 4.87 (d, J =
10.0 Hz, 1H), 4.78 (d, J = 9.7 Hz, 1H), 4.05 (q, J = 7.0 Hz, 4H),
2.27-1.98 (m, 8H), 1.65 (s, 3H), 1.53 (s, 3H), 1.53-1.42 (m, 2H),
1.38-1.23 (m, 12H), 1.95-1.02 (m, 4H), 0.87-0.72 (m, 18H);
13C NMR (100 MHz, CDCl3) δ 166.8, 153.4, 153.1, 132.8, 132.7,
132.4, 121.2, 60.3, 60.2, 45.3, 43.0, 42.6, 41.6, 41.0, 37.4, 28.8,
28.7, 28.6, 28.5, 27.2, 27.0, 24.0, 16.7, 14.5, 12.1 (2C), 12.0 (2C),
2338 J. Org. Chem. Vol. 75, No. 7, 2010

Gemma et al.
JOCArticle
with brine. The organic extracts were dried over sodium sulfate,
and the solvent was removed. The residue was purified by flash
chromathography (1:20 ethyl acetate/n-hexane) to afford 23a
(0.17 g, 99%) as a colorless oil. Rf 0.79 (1:2 diethyl ether/petro-
was added to the reaction mixture, the volatiles were removed,
and the aqueous phase was washed with chloroform. Com-
pounds (6S)-5 and (6R)-6 were separated by flash chroma-
tography (1:5 ethyl acetate/n-hexane). (6S)-5 (41 mg, 42%):
[R]20 = þ57.5 (c 0.006, CHCl3); Rf 0.15 (1:4 ethyl acetate/n-
leum ether 40-60 ꢀC); [R]20 = þ28.0 (c 0.14, CHCl3); 1H
D
D
1
hexane); H NMR (300 MHz, CDCl3) δ 4.10-4.04 (m, 1H),
NMR (300 MHz, CDCl3) δ 4.84 (d, J = 9.7 Hz, 1H), 4.34 (dd,
J = 3.5, 12.3 Hz, 1H), 3.94 (dd, J = 6.5, 12.3 Hz, 1H), 3.05-3.01
(m, 1H), 2.64 (dd, J = 2.3, 7.6 Hz, 1H), 2.25 (dd, J = 4.7, 13.2
Hz, 1H), 2.13-2.06 (m, 1H), 2.08 (s, 3H), 2.00 (dd, J = 8.5, 14.0
Hz, 1H), 1.56 (s, 3H), 1.45-1.06 (m, 11H), 0.91 (t, J = 7.3 Hz,
3H), 0.88-0.79 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
171.0, 132.9, 132.2, 65.1, 60.3, 55.2, 42.9, 40.4, 39.8, 35.7, 29.9,
29.0, 23.6, 23.1, 21.0, 16.7, 14.4, 12.1, 11.9; MS (ESI) (m/z) 333
(M þ Na)þ. HRMS (ESI) calcd for C19H34O3Na (M þ Na)þ
333.2400, found 333.2400.
3.96-3.83 (m, 3H), 2.50 (bs, 2H), 2.27-2.03 (m, 1H), 1.60-1.39
(m, 4H), 1.36 (s, 3H), 1.33-1.20 (m, 11H), 0.95 (t, J = 7.3 Hz,
3H), 0.88 (t, J = 6.9 Hz, 3H), 0.81 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 82.7, 81.9, 69.7, 64.9, 45.6, 36.2, 35.3, 34.7,
34.2, 29.1, 27.5, 24.8, 23.3, 21.5, 14.3, 12.1, 10.7; MS (ESI) (m/z)
325 (M þ Na)þ. HRMS (ESI) calcd for C17H34O4Na (M þ Na)þ
325.2349, found 325.2351. (6R)-6 (35 mg, 36%): [R]20D = þ92.6
(c 0.05, CHCl3); Rf 0.10 (1:4 ethyl acetate/n-hexane); 1H NMR
(300 MHz, CDCl3) δ 4.04 (bs, 1H), 3.95-3.72 (m, 3H), 2.66 (bs,
1H), 2.46 (bs, 1H), 2.21-2.13 (m, 1H), 1.76 (dd, J = 3.5, 11.4
Hz; 1H), 1.68 (dd, J = 4.4, 13.8 Hz, 1H), 1.62-1.40 (m, 3H),
1.39-1.18 (m, 10H), 1.11 (s, 3H), 0.95 (t, J = 7.3 Hz, 3H),
0.90-0.82 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 82.7, 81.6,
69.7, 65.0, 39.3, 36.4, 35.1, 34.9, 34.0, 28.8, 27.6, 25.4, 24.4, 23.3,
14.4, 12.1, 11.0; MS (ESI) (m/z) 325 (M þ Na)þ. HRMS (ESI)
calcd for C17H34O4Na (M þ Na)þ 325.2349, found 325.2354.
(R)-1-((3S,4R,6S)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-di-
oxan-3-yl]ethane-1,2-diol (25) and (R)-1-[(3S,4R,6R)-4-Ethyl-
6-(2-ethylbutyl)-6-methyl-1,2-dioxan-3-yl]ethane-1,2-diol (26).
The title compounds were obtained from 24b in 45% and 38%
(2R,3R,4R,Z)-4,8-Diethyl-6-methyl-2,3-epoxydec-6-ene-1-yl
Acetate ((6Z)-23b) and (2R,3R,4R,E)-4,8-Diethyl-6-methyl-2,3-
epoxydec-6-ene-1-yl Acetate ((6E)-23b). The title compound was
obtained from 22 in 52% yield as a 1:1 mixture of E/Z isomers as
described for the synthesis of 23a. (2R,3R,4R,Z)-4,8-Diethyl-6-
methyl-2,3-epoxydec-6-ene-1-ol and (2R,3R,4R,E)-4,8-diethyl-
6-methyl-2,3-epoxydec-6-ene-1-ol (dr 97%): 1H NMR (300
MHz, CDCl3) δ 4.88 (d, J=10.0 Hz, 1H), 4.79 (d, J=9.7 Hz,
1H), 3.84 (d, J = 11.5 Hz, 2H), 3.55-3.43 (m, 2H), 2.98-2.94
(m, 4H), 2.72-2.59 (m, 2H), 2.26-2.12 (m, 4H), 2.04-1.92 (m,
4H), 1.65 (s, 3H), 1.53 (s, 3H), 1.45-1.26 (m, 8H), 1.24-1.06 (m,
4H), 0.87 (t, J = 7.3 Hz, 6H), 0.80-0.64 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 132.8, 132.7, 132.6, 132.4, 62.1, 62.0, 59.9,
59.7, 58.9, 43.0, 41.6, 41.0, 40.9, 40.4, 35.3, 28.8, 28.7, 28.6, 28.5,
24.0, 23.9, 23.6, 16.7, 12.3, 12.2, 12.0, 11.9; MS (ESI) (m/z) 263
(M þ Na)þ. HRMS (ESI) calcd for C15H28O2Na (M þ Na)þ
263.1982, found 263.1987. (Z)-23b and (E)-23b: Rf 0.83 (1:5
diethyl ether/petroleum ether 40-60 ꢀC); 1H NMR (300 MHz,
CDCl3) δ 4.84 (d, J = 10.0 Hz, 1H), 4.76 (d, J = 9.4 Hz, 1H),
4.27 (dd, J = 3.2, 12.3 Hz, 2H), 3.86 (dd, J = 6.3, 12.3 Hz, 2H),
3.00-2.94 (m, 2H), 2.58-2.53 (m, 2H), 2.19-2.07 (m, 4H), 2.00
(s, 6H), 1.99-1.90 (m, 2H), 1.60 (s, 3H), 1.49 (s, 3H), 1.48-1.01
(m, 16H), 0.84 (t, J = 7.3 Hz, 6H), 0.76-0.71 (m, 12H); 13C
NMR (100 MHz, CDCl3) δ 166.5, 132.7, 132.6, 132.5, 132.4,
65.0, 64.8, 60.3, 60.2, 55.3, 55.2, 42.9, 41.6, 41.0, 40.3, 35.2, 28.7,
28.6, 24.0, 23.8, 23.6, 20.8, 16.6, 12.1 (2C), 12.0 (2C), 11.9, 11.8;
MS (ESI) (m/z) 263 (M þ Na)þ. HRMS (ESI) calcd for
C17H30O3Na (M þ Na)þ 305.2087, found 305.2090.
yield, respectively as white low melting solids. (6S)-25: [R]20
=
D
1
þ142 (c 0.33, CHCl3); Rf 0.22 (1:3 ethyl acetate/n-hexane); H
NMR (500 MHz, CDCl3) δ 4.03 (m, 1H, H-2), 3.89 (dd, J = 5.0,
7.0 Hz, 1H, H-3), 3.84 (m, 2H, H-1), 2.63 (bs, 2H, OH), 2.20 (m,
1H, H-4), 1.61 (m, 1H, H-8), 1.56 (m, 1H, H-14a), 1.42 (over-
lapped, 5H, H-5a, H2-9, H2-11), 1.35 (s, 3H, H-13), 1.36 (m, 1H,
H-5b), 1.25 (m, 1H, H-14b), 1.22 (2H, m, H-7), 0.94 (t, J = 7.3
Hz, 3H, H-15), 0.79 (t, J = 7.3 Hz, 6H, H-10, H-12); 13C NMR
(125 MHz, CDCl3) δ 82.7 (C-6), 81.9 (C-3), 69.7 (C-2), 64.9 (C-1),
45.1 (C-7), 36.4 (C-8), 35.9 (C-5), 35.3 (C-4), 27.3 (C-9), 27.0
(C-11), 24.8 (C-14), 21.5 (C-13), 12.1 (C-15), 11.1 (C-10), 10.8
(C-12); MS (ESI) (m/z) 297 (M þ Na)þ. HRMS (ESI) calcd for
C15H30O4Na (M þ Na)þ 297.2036, found 297.2040. (6R)-26:
[R]20 = þ150 (c 0.30, CHCl3); Rf 0.15 (1:3 ethyl acetate/n-
D
hexane); 1H NMR (500 MHz, CDCl3) δ 4.04 (bs, 1H, H-2), 3.92
(dd, J = 5.0, 7.0 Hz, 1H, H-3), 3.85 (m, 2H, H-1), 2.58 (bs, 1H,
OH), 2.39 (bs, 1H, OH), 2.20 (m, 1H, H-4), 1.82 (dd, J = 4.2, 14.4
Hz, 1H, H-8), 1.68 (dd, J = 4.7, 13.8 Hz, 1H, H-5a), 1.59 (m, 1H,
H-14a), 1.50-1.37 (m, 3H, H-9a, H-11a, H-5b), 1.31-1.22 (m,
5H, H2-7, H-9b, H-11b,H-14b), 1.11 (s, 3H, H-13), 0.95 (t, J =
7.4 Hz, 3H, H-15), 0.85 (t, J = 7.4 Hz, 6H, H-10, H-12); 13C
NMR (125 MHz, CDCl3) δ 82.7 (C-6), 81.6(C-3), 69.7(C-2), 65.0
(C-1), 38.8 (C-7), 36.6 (C-5), 36.3 (C-8), 35.1 (C-4), 27.1 (C-9),
26.5 (C-11), 25.4 (C-14), 21.4 (C-13), 12.1 (C-15), 11.1 (C-10),
10.8 (C-12); MS (ESI) (m/z) 297 (M þ Na)þ. HRMS (ESI) calcd
for C15H30O4Na (M þ Na)þ 297.2036, found 297.2033.
(2R)-2-{(3S,4R)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-dio-
xan-3-yl}-2-hydroxyethyl Acetate (24a). To a solution of 23a
(0.17 g, 0.55 mmol) and Co(thd)2 (0.14 g, 0.33 mmol) in 1,2-
dichloroethane (9.0 mL), stirred under an oxygen atmosphere,
was added triethylsilane (0.18 mL, 1.2 mmol), together with a
drop of tert-butylhydroperoxide (catalytic, 5.5 M in nonane).
The resulting green mixture was stirred at 25 ꢀC for 5 h, until
consumption of the starting material. Amberlyst-15 (20 mg) was
subsequently added, and the resulting mixture was stirred at
25 ꢀC for 18 h. After evaporation of the solvent, the cyclization
product 24a was separated from the catalyst by filtering through
a short pad of silica gel affording an inseparable mixture of C6-
epimers (0.11 g, 57%) and a byproduct probably resulting from
the reduction of the peroxide bond to the corresponding tetra-
hydrofuran derivative MS (ESI) (m/z) 367 (M þ Na)þ.
(3S,4R,6S)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-diox-
ane-3-carbaldehyde (27a). A solution of (6S)-5 (45 mg, 0.15
mmol) and sodium periodate (36 mg, 0.16 mmol) in a 3:2
mixture of acetonitrile and water (2.0 mL) was stirred at 25 ꢀC
for 1 h. After this time, the resulting white precipitate was
filtered off, the volatiles were removed, and the aqueous phase
was extracted with dichloromethane. The organic extracts were
dried over sodium sulfate, and the solvent was removed. The
crude aldehyde 27a (40 mg, 99%) was immediately reacted in the
next step. 1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 4.25 (d,
1H, J = 5.3 Hz), 2.27-2.21 (m, 1H), 1.73-1.61 (m, 1H), 1.57-
1.48 (m, 3H), 1.45-1.38 (m, 1H), 1.43 (s, 3H), 1.35-1.22 (m,
10H), 0.96 (t, 3H, J = 7.4 Hz), 0.88 (t, 3H, J = 6.9 Hz), 0.81 (t,
3H, J = 7.3 Hz); MS (ESI) (m/z) 293 (M þ Na)þ.
(2R)-2-[(3S,4R)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-diox-
an-3-yl]-2-hydroxyethyl Acetate (24b). The title compound was
obtained from 23b in 62% yield as a mixture C6-epimers as
described for the synthesis of 24a. MS (ESI) (m/z) 339 (M þ
Na)þ.
(R)-1-{(3S,4R,6S)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-
dioxan-3-yl}ethane-1,2-diol (5) and (R)-1-{(3S,4R,6S)-4-Ethyl-
6-[(R)-2-ethylhexyl]-6-methyl-1,2-dioxan-3-yl}ethane-1,2-diol (6).
A mixture of 24a (0.11 g, 0.32 mmol) and potassium carbonate
(2.2 mg) in methanol (5 mL) was stirred ad 0 ꢀC for 3 h. Water
(3S,4R,6S)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-dioxane-3-
carbaldehyde (27b). The title compound was obtained from
J. Org. Chem. Vol. 75, No. 7, 2010 2339

Gemma et al.
JOCArticle
1
(6S)-25 in quantitative yield as described for the synthesis of
(6S)-27a. 1H NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 4.25 (d,
J = 5.3 Hz, 1H), 2.25-2.18 (m, 1H), 1.72-1.62 (m, 1H), 1.56-
1.44 (m, 2H), 1.42 (s, 3H), 1.38-1.19 (m, 7H), 0.95 (t, J=7.4 Hz,
3H), 0.80 (t, J = 7.2 Hz, 6H); MS (ESI) (m/z) 265 (M þ Na)þ.
(3S,4R,6R)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-diox-
ane-3-carbaldehyde (28a). The title compound was obtained
from (6R)-6 in quantitative yield as described for the synthesis
of (6S)-27a. 1H NMR (300 MHz, CDCl3) δ 10.03 (s, 1H), 4.26
(d, J = 5.3 Hz, 1H), 2.27-2.14 (m, 1H), 1.94 (dd, J = 4.8, 14.5
Hz, 1H), 1.72-1.62 (m, 2H), 1.55-1.20 (m, 12H), 1.10 (s, 3H),
0.95 (t, J = 7.4 Hz, 3H), 0.90-0.84 (m, 6H); MS (ESI) (m/z) 293
(M þ Na)þ.
(1:40 diethyl ether/n-hexane); H NMR (300 MHz, CDCl3) δ
4.53-4.47 (m, 1H, H-3), 3.71 (s, 3H, COOMe), 3.02 (dd, J =
9.4, 15.8 Hz, 1H, H-2a), 2.38 (dd, J = 3.7, 15.7 Hz, 1H, H-2b),
2.20-2.10 (m, 1H, H-4), 1.84 (dd, J = 4.5, 14.5 Hz, 1H, 7a),
1.64-1.56 (m, 1H, 5a), 1.48-1.14 (m, 13H), 1.12 (s, 3H,),
0.94-0.80 (m, 9H); 13C NMR (100 MHz, CDCl3) δ172.4 (C-
1), 81.1 (C-6), 78.7 (C-3), 52.0 (C-18), 38.2 (C-7), 36.0 (C-5), 34.6
(C-4), 34.5 (C-8), 33.8 (C-9), 31.2 (C-2), 28.5 (C-10), 27.2 (C-13),
27.3 (C-15), 25.0 (C-16), 22.4 (C-11), 14.1 (C-12), 10.3 (C-17),
10.1 (C-14); MS (ESI) (m/z) 337 (M þ Na)þ. HRMS (ESI) calcd
for C18H34O4Na (M þ Na)þ 337.2349, found 337.2346.
2-((3R,4R,6S)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-dioxan-
3-yl]acetic Acid Methyl Ester (3). The title compound was ob-
tained from (6S)-27b in 32% yield as described for the synthesis
(3S,4R,6R)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-dioxane-3-
carbaldehyde (28b). The title compound was obtained from
(6R)-26 in quantitative yield as described for the synthesis of
(6S)-27a. MS (ESI) (m/z) 265 (M þ Na)þ.
of (6S)-1. [R]20 = þ194 (c 0.01, CHCl3); Rf 0.25 (1:30 ethyl
D
1
acetate/n-hexane); H NMR (500 MHz, CDCl3) δ 4.53-4.47
(m, 1H, H-3), 3.71 (s, 3H, COOMe), 3.00 (dd, J = 9.4, 15.5 Hz,
1H, H-2a), 2.37 (dd, J = 3.5, 15.5 Hz, 1H, H-2b), 2.21 (m, 1H,
H-4), 1.45 (dd, J = 4.7, 13.5 Hz, 1H, H-5a), 1.37 (s, 3H, H-13),
1.36 (overlapped,1H, H-14a), 1.35 (overlapped, 1H, H-8), 1.30
(m, 3H, H2-7, H-14b), 1.24 (m, 2H, H-9a, H-11a), 1.20 (over-
lapped,1H, H-5b), 1.16 (overlapped, 2H, H-9b, H-11b), 0.91 (t,
2-{(3R,4R,6S)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-dio-
xan-3-yl}acetic Acid Methyl Ester (1). To a suspension of me-
thoxymethyl(triphenyl)phosphonium chloride (48.0 mg, 0.14
mmol) in dry THF (2.0 mL), cooled to -78 ꢀC, was added
sodium bis(trimethylsily)amide (1.0 M solution in THF, 130 μL,
0.13 mmol) dropwise, and the resulting red solution was stirred
at 0 ꢀC for 1 h. The Wittig reagent prepared was cooled to -78
ꢀC, and a solution of aldehyde (6S)-27a (20 mg, 0.07 mmol) in
THF (1.0 mL) was added dropwise. The reaction mixture was
allowed to warm to 0 ꢀC over 1 h and then was quenched by
addition of methy-tert-butylether. The white precipitate was
filtered off, and the filtrate was concentrated. The crude product
was dissolved in acetone (2.0 mL) containing 100 μL of 6 N
hydrochloric acid and stirred for 30 min. Afterward the solution
was neutralized by addition of a saturated solution of sodium
bicarbonate, the volatiles were removed, and the aqueous phase
was extracted with dichloromethane. The organic extracts were
dried over sodium sulfate and concentrated. The crude aldehyde
(11 mg, 0.04 mmol) was dissolved in acetonitrile (0.5 mL) and
added to a solution of sodium periodate (34.0 mg, 0.16 mmol)
and ruthenium(III) chloride (catalytic amount) in 1:3 water/
acetonitrile (1.0 mL). The reaction mixture was stirred at 25 ꢀC
for 1 h; afterward diethyl ether (5 mL) was added, and the dark
precipitate was filtered off. The filtrate was dried over sodium
sulfate and concentrated. The crude carboxylic acid was dis-
solved in diethyl ether, and a freshly prepared solution of
diazomethane was added until disappearance of the carboxylic
acid as monitored by TLC (1:5 ethyl acetate/n-hexane). The
solvent was finally removed, and the residue was purified by
flash chromatography to afford (6S)-1 (5.3 mg, 24%) as a
colorless oil. Analytical and spectral data are identical to those
reported in the literature.1 [R]20D = þ32 (c 0.001, CHCl3); lit.1
þ49 (c 0.002, CHCl3); MS (ESI) (m/z) 337 (M þ Na)þ. HRMS
(ESI) calcd for C18H34O4Na (M þ Na)þ 337.2349, found
337.2350.
J = 7.3 Hz, 3H, H-10), 0.84 (t, J = 7.3 Hz, 6H, H-12, H-15); 13
C
NMR (125 MHz, CDCl3) δ 172.4 (C-1), 81.5 (C-6), 78.8 (C-3),
52.0 (COOMe), 45.1 (C-7), 35.8 (C-5), 35.6 (C-4), 35.1 (C-8),
31.6 (C-2), 27.3 (C-14), 25.3 (C-9, C-11), 21.6 (C-13), 11.3 (C-
15), 11.1 (C-10), 10.8 (C-12); MS (ESI) (m/z) 309 (M þ Na)þ.
HRMS (ESI) calcd for C16H30O4Na (M þ Na)þ 309.2036,
found 309.2037.
2-[(3R,4R,6R)-4-Ethyl-6-(2-ethylbutyl)-6-methyl-1,2-dioxan-
3-yl]acetic Acid Methyl Ester (4). The title compound was ob-
tained from (6R)-28b in 18% yield as described for the synthesis
of (6S)-1. [R]20 = þ180 (c 0.02, CHCl3); Rf 0.25 (1:30 ethyl
D
acetate/n-hexane); 1H NMR (500 MHz, CDCl3) δ 4.52 (m, 1H,
H-3), 3.71 (s, 3H, COOMe), 3.05 (dd, J = 9.4, 15.5 Hz, 1H, H-
2a), 2.40 (dd, J = 3.5, 15.5 Hz, 1H, H-2b), 2.19 (m, 1H, H-4),
1.91 (dd, J = 4.2, 14.2 Hz, 1H, H-8), 1.62 (dd, J = 4.7, 13.5 Hz,
1H, H-5a), 1.49 (m, 2H, H-9a, H-11a), 1.35 (overlapped, 2H, H-
9b, H-11b), 1.28 (overlapped,1H, H-5b), 1.22 (m, 3H, H2-7, H-
14a), 1.18 (overlapped,1H, H-14b), 1.12 (s, 3H, H-13), 0.91 (t,
J = 7.3 Hz, 3H, H-15), 0.84 (t, J = 7.3 Hz, 6H, H-10, H-12); 13
C
NMR (125 MHz, CDCl3) δ 172.5 (C-1), 81.2 (C-6), 78.8 (C-3),
52.1 (COOMe), 38.4 (C-7), 36.4 (C-5), 36.3 (C-8), 35.1 (C-4),
31.6 (C-2), 27.1 (C-9, C-11), 25.3 (C-14), 21.6 (C-13), 11.3 (C-
15), 11.1 (C-10), 10.8 (C-12); MS (ESI) (m/z) 309 (M þ Na)þ.
HRMS (ESI) calcd for C16H30O4Na (M þ Na)þ 309.2036,
found 309.2031.
Acknowledgment. We gratefully acknowledge financial
support from EU Commission, Antimal-LSHP-CT-2005-
18834 and from MPS (grant 29815)
2-{(3R,4R,6R)-4-Ethyl-6-[(S)-2-ethylhexyl]-6-methyl-1,2-dio-
xan-3-yl}acetic Acid Methyl Ester (2). The title compound
was obtained from (6R)-28a in 35% yield as described for
the synthesis of (6S)-1. [R]20D = þ143 (c 0.001, CHCl3) Rf 0.24
Supporting Information Available: General experimental
methods and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
2340 J. Org. Chem. Vol. 75, No. 7, 2010