Total asymmetric syntheses of β-hydroxy-δ-lactones via umpolung with sulfur dioxide

Article abstract of DOI:10.1021/jo102035d

Cyclic stereotriads and stereotetrads of the β-hydroxy-d-lactone type, e.g. prelactonesBandE, commonin polyketides and polypropionates, are prepared via SO2-induced oxyallylations of enoxysilanes with (1E,3Z)-1-(1-phenylethoxy) penta-1,3-dien-3-yl carboxylates. Using (Z)- or (E)-enoxysilanes both 4,5-cis- or 4,5-trans-d-lactones are obtained. Depending on the reduction method applied to the obtained aldol intermediates 5,6-trans or 5,6-cis-derivatives are formed. The d-lactones can be prepared in both their enantiomeric forms depending on the (1R)- or (1S)-configuration of the starting 1-(1-phenylethoxy)penta-1,3- dienes.

Full text of DOI:10.1021/jo102035d

pubs.acs.org/joc
Total Asymmetric Syntheses of β-Hydroxy-δ-lactones
via Umpolung with Sulfur Dioxide†
Claudia J. Exner,‡,^ Sylvain Laclef,‡,^ Florent Poli,‡ Maris Turks,§ and Pierre Vogel*,‡
‡Laboratory of Glycochemistry and Asymmetric Synthesis (LGSA), Swiss Federal Institute of
Technology Lausanne (EPFL), Batochime, CH-1015 Lausanne, Switzerland, and Faculty of Material
Science and Applied Chemistry, Riga Technical University, LV-1048 Riga, Latvia.
§
^These authors contributed equally to this work
pierre.vogel@epfl.ch.
Received October 18, 2010
Cyclic stereotriads and stereotetrads of the β-hydroxy-δ-lactone type, e.g. prelactones B and E, common in
polyketides and polypropionates, are prepared via SO2-induced oxyallylations of enoxysilanes with
(1E,3Z)-1-(1-phenylethoxy)penta-1,3-dien-3-yl carboxylates. Using (Z)- or (E)-enoxysilanes both
4,5-cis- or 4,5-trans-δ-lactones are obtained. Depending on the reduction method applied to
the obtained aldol intermediates 5,6-trans or 5,6-cis-derivatives are formed. The δ-lactones can be
prepared in both their enantiomeric forms depending on the (1R)- or (1S)-configuration of the
starting 1-(1-phenylethoxy)penta-1,3-dienes.
Introduction
structural motif in a large number of natural polyketides and
polypropionates and are intermediates in the step-by-step
biosynthesis of these compounds.6 As such, they have been
isolated from different polyketide-producing organisms.
Polyketides and polypropionates represent an important
class of natural compounds1 with broad potential for phar-
macological applications.2 Their stereochemical complexity
has stimulated intensive research toward the development of
chemical3,4 and biochemical methods5 for their total synthe-
sis. β-Hydroxy-δ-lactones like compounds 1-7 (Chart 1)
constitute, as cyclic stereotriads and stereotetrads, a common
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† Dedicated to Professor Janine Cossy, ESPCI, Paris, on the occasion of being
awarded the Grand Prix Achille LeBel.
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840 J. Org. Chem. 2011, 76, 840–845
Published on Web 01/10/2011
DOI: 10.1021/jo102035d
r
2011 American Chemical Society

Exner et al.
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CHART 1. Different δ-Lactones 1-7, Synthesized Using SO2-Chemistry
SCHEME 1. One-Pot Synthesis of R,β,γ-syn,anti- or anti,anti-Stereotriads through SO2-Induced Oxyallylation of (Z)-or (E)-Enoxysilanesa
aThe shown structures are obtained for R* = (S)-1-phenethyl.
For instance, β-hydroxy-δ-lactone prelactone B (1) has
been found in the fermentation broth of Streptomyces pro-
ducing concanamycins and bafilomycins (Chart 1),7 which
stimulated several syntheses of (þ)-(1) and its stereoisomers
using various approaches.8 Prelactone E ((-)-2), a product
of chemical degradation of concanolide derivatives,9 has
been synthesized recently by two groups applying Evans’
aldol chemistry.10,11 Using an L-proline-catalyzed aldol reaction
Barbas and co-workers obtained lactone (þ)-3 in a two-step
process with 11% ee, that could be improved by carrying out
the reaction in an ionic liquid.12,13 Lactone (-)-4, the 5-epimer of
(þ)-3, has been prepared by Cordova and co-workers from
propanal in a three-step process with an ee >99% involving
two successive L-proline- and D-proline-catalyzed aldol reac-
tions followed by MnO2-oxidation.14 Compound (-)-5 was
obtained by Hoffmann and co-workers via enantioselective
crotylboration of methacroleine followed by diastereoselective
of meso-(anti,anti)-2,4-dimethyl-1,3,5-pentanetriol.15,16 δ-Lactone
(þ)-6, the 5-epimer of (-)-5, has been obtained only through
biological synthesis applying polyketide synthase.6a Both
lactones, (-)-5 and (þ)-6, contain an R,β,γ-anti,anti-stereotriad
subunit, the most elusive to obtain.17
In this report we propose alternative syntheses of lactones
(þ)-1-(þ)-6. Our method is general and has been applied
also to the synthesis of lactone (-)-7, a yet unknown
compound.18
With the use of our SO2-reaction cascade that combines
electron-rich dienes 8 and (Z)- or (E)-enoxysilanes 10 via
SO2-Umpolung, we have developed a one-pot synthesis of
R,β,γ-syn,anti- and -anti,anti-stereotriads of types 12 and 13,
respectively (Scheme 1).19,20 The starting dienes 8 are readily
obtained from pentan-3-one, ethyl formate and inexpensive,
enantiomerically enriched (S)- or (R)-1-phenylethanol, the
source of chirality.21
hydroboration.17b Chenevert and co-workers made (-)-5 in
A hetero-Diels-Alder addition between diene 8 and SO2
followed by Lewis acid-assisted ionization gives a zwitterionic
^
a few steps with 58% overall yield via enzymatic desymmetrization
^
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K. H.; Rosenblum, M. J. Org. Chem. 1997, 62, 3344–3454. (b) Tholander, J.;
Carreira, E. M. Helv. Chim. Acta 2001, 84, 613–622. (c) Pichlmair, S.; Marques,
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Alvarez, A.; Sordo, J. A. Acc. Chem. Res. 2007, 40, 931–942. (b) Turks, M.;
Exner, C. J.; Hamel, C.; Vogel, P. Synthesis 2009, 1065–1074.
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SCHEME 2. Syntheses of Prelactones B ((þ)-1) and E ((-)-2)
SCHEME 3. Syntheses of δ-Lactones (þ)-3, (-)-4, (-)-5, and (þ)-6
842 J. Org. Chem. Vol. 76, No. 3, 2011

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SCHEME 4. Synthesis of δ-Lactone (-)-7
species 9, which undergoes an oxyallylation reaction with
alkenes 10 to silylsulfinates 11. The latter are converted
in situ into stereotriads 12 and 13, respectively, in the pres-
ence of catalytic Pd(OAc)2/PPh3, involving a highly stereo-
selective chirality transfer from the ε-center in 11 to the γ-center
in 12 respective 13 (Scheme 1).22,23
diastereoselectivities of 6:1 and 3:1, respectively.28 Treat-
ment of 24 with TiCl4 in CH2Cl2 at -78 ꢀC afforded titanium
alkoxide 26 which was reacted directly with BH3 Me2S29 to
3
give stereotetrad (þ)-27 in 90% yield. Ozonolysis of the enol
ester of (þ)-27 followed by workup with Me2S provided
lactone (þ) 3 (78%). Aqueous workup of 26 furnished
26
alcohol (-)-28. Its reduction with Me4NBH(OAc)3 gave
Results and Discussion
(þ)-29 (67%), the ozonolysis of which provided lactone
(-)-4 (78%). The same reaction sequence applied to (þ)-25
furnished stereotetrads (þ)-32 (72%) and (-)-33 (67%),
which were ozonolyzed to produce lactones (-)-5 (62%)
and (þ)-6 (73%), respectively. Structures of lactones (þ)-3,
(-)-4, (-)-5, and (þ)-6 were proven by their spectral data.
Their relative configuration was established by the vicinal
3JH,H coupling constants in the 1H NMR sprectra. Structures
of (-)-5 and (þ)-6 were also confirmed by single-crystal X-ray
diffraction studies.30 The diversity of our methodology is
demonstrated by the synthesis of four different stereotetrads,
i. e. structures (þ)-27, (þ)-29, (þ)-32, and (-)-33 (Scheme 3),
all using the same diene (R)-22 as starting material.
Our syntheses of the natural prelactones B ((þ)-1) and E
((-)-2) combine diene 1424 with (Z)-enoxysilanes 15a and
15b, respectively. The SO2-induced oxyallylation and con-
comitant desulfinylative desilylation afforded 3:1-mixtures
of R,β-syn- and R,β-anti-stereodiad 16a/17a (72% yield) and
16b/17b (55% yield), respectively (Scheme 2). These mixtures
were treated with TiCl4 in CH2Cl225 to cleave the phenethyl
ether moieties and provided 3:1 mixtures of the correspond-
ing alcohols 18a/19a (84%) and 18b/19b (95%). Reduction
of these mixtures with Me4NBH(OAc)3/AcOH26 gave 3:1
mixtures of stereotriads 20a/21a (94%) and 20b/21b (60%).
Ozonolysis of the latter, treatment with Me2S, and chroma-
tographic purification furnished (þ)-1 (83% based on 20a)
and (-)-2 (91% based on 20b).
This synthesis of (þ)-1 gives the final product in four steps
and 35% yield based on diene (S)-14 or in eight steps and
13% yield based on propionyl chloride, the starting material
of diene (S)-14.24 Prelactone E ((-)-2) was obtained in four
steps and 21% overall yield based on diene (S)-14.
The β-hydroxy-δ-lactones (þ)-3, (-)-4, (-)-5, and (þ)-6
(Scheme 3) were obtained by applying our oxyallylation cascade
to diene (þ)-22,21,27 and using (Z)-15b and (E)-enoxysilane
23. This generated the stereotriads (þ)-2427 and (þ)-2520 with
Lactone (þ)-3 was synthesized in three steps and 48%
overall yield from diene (þ)-22, and (-)-4 was obtained in
four synthetic steps and 29% overall yield based on (þ)-22.
Diastereoisomers (-)-5 and (þ)-6 were synthesized in four
and three steps with 14% and 26% overall yields, respectively,
starting from diene (þ)-22.
Lactone (-)-7 was derived in a similar way from diene
(-)-3427 and (E)-enoxysilane 35 (Scheme 4). Their SO2-mediated
condensation produced stereotriad (-)-3620 (67%, dr>10:1).
Reduction of ketone (-)-36 with Me2AlCl/Bu3SnH31 in
CH2Cl2 (workup with KF) gave stereotetrad (-)-3720 in
90% yield (dr > 10:1). FeCl3-induced SN1-debenzylation of
(-)-37 provided diol (þ)-38 (93%, dr > 10:1). Its relative
configuration was confirmed by the 1H- and 13C NMR
(22) Huang, X.; Craita, C.; Vogel, P. J. Org. Chem. 2004, 69, 4272–4275.
(23) Vogel, P.; Turks, M.; Bouchez, L.; Craita, C.; Huang, X.; Murcia,
M. C.; Fonquerne, F.; Didier, C.; Flowers, C. Pure Appl. Chem. 2008, 80,
791–805.
(24) Turks, M.; Fonquerne, F.; Vogel, P. Org. Lett. 2004, 6, 1053–1056.
(25) Turks, M.; Murcia, M. C.; Scopelliti, R.; Vogel, P. Org. Lett. 2004, 6,
3031–3034.
(26) (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560–3578. (b) Evans, D. A.; Chapman, K. T. Tetrahedron Lett.
1986, 27, 5939–5942.
(28) Compound 25 may be obtained with a better diastereomeric ratio of
5:1 using the tert-butyric ester of diene (S)-14 ((1E,3Z)-2-methyl-1-((S)-1-
phenylethoxy)penta-1,3-dien-3-yl pivalate). See also ref 20.
(29) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.;
Sambri, L. Eur. J. Org. Chem. 2001, 4679–4684.
(30) See Supporting Information.
(31) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am. Chem.
Soc. 2001, 123, 10840–10852.
(27) Turks, M.; Huang, X.; Vogel, P. Chem. Eur. J. 2005, 11, 465–476.
;
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spectra of the corresponding acetonide (þ)-39 obtained by
14.0, 10.0, 28.9, 36.0, 42.3, 73.2, 84.8, 173.9. ESI-HRMS: m/z
calcd for C10H19O3þ 187.1334, found 187.1336 [M þ Hþ].
(2Z,4R,5R,6R,7R)-5,7-Dihydroxy-4,6-dimethylnon-2-en-3-yl
2-methylpropanoate ((-)-33). One molar TiCl4 in CH2Cl2 (3 mL,
3.0 mmol) was added quickly to a stirred soln of (þ)-(1Z,2R,
3S,4S)-1-ethylidene-2,4-dimethyl-5-oxo-3-[(1R)-1-phenylethoxy]-
heptyl-2-methylpropanoate ((þ)-25) (550 mg, 1.47 mmol). After
treatment of (þ)-38 with (MeO)2CMe2 and catalytic TsOH
3
H2O (96%). It was furthermore verified by single-crystal
X-ray diffraction studies of crystalline ketone (-)-40 ob-
tained by treatment of (þ)-39 with MeLi LiBr in DME/Et2O
3
(86%).30 Ozonolysis of enol ester (þ)-38 and subsequent
treatment with Me2S provided crystalline lactone (-)-7, the
structure of which was also proven by single-crystal X-ray
diffraction studies.30
stirring at -78 ꢀC for 1 h, 1 M BH3 Me2S in CH2Cl2 (6.7 mL,
3
6.7 mmol) was added, and the mixture was stirred at -78 ꢀC for
two more hours. The reaction mixture was quenched with a sat.
aq soln of NaHCO3 (15 mL). The mixture was extracted with
EtOAc (3ꢀ10 mL). The combined organic extracts were washed
with brine (15 mL) and dried (MgSO4). Solvent evaporation
and flash chromatography on silica gel (PE/EtOAc) gave (-)-33
Conclusion
Fully substituted 4-hydroxy-δ-lactones containing up to
four continuous stereocenters can be prepared applying the
oxyallylation of enoxysilanes through SO2-Umpolung of
enantiomerically enriched (1E,3Z)-1-(1-phenylethoxy)penta-
1,3-dien-3-yl carboxylates. These stereotriads and stereotetrads
are common motifs in a large number of natural polyketides
and polypropionates. The number of synthetic steps, yields,
and availability of starting materials are comparable with
other well-accepted methods. The present methodology offers
an alternative approach and extends the toolbox of chemists
chasing cyclic polypropionate structures. We were able to obtain
lactone (þ)-6 for the first time using chemical synthesis6a
as well as the yet unknown (-)-(3R,4R,5S,6R)-4-hydroxy-
6-isopropyl-3,5-dimethyltetrahydro-2H-pyran-2-one ((-)-7).
(269 mg, 67%) as colorless oil. Rf=0.29 (PE/EtOAc, 4:1). R25
=
D
-26 (CHCl3, c=0.58). IR (film): ν (cm-1)=3438, 2970, 2935,
2876, 1746 (s), 1691, 1459, 1408, 1337, 1240, 1138, 968. 1H NMR
3
(CDCl3, 400 MHz): (ppm) = 0.93 (d, 3H, J = 7.0 Hz), 0.97
(t, 3H, 3J=7.5 Hz), 1.08 (d, 3H, 3J=6.5 Hz), 1.26 (d, 6 H, 3J=
7.0 Hz), 1.34-1.49 (m, 1H), 1.46 (d, 3H, 3J=6.5 Hz), 1.58-1.78
(m, 2H), 2.64-2.76(m, 2H), 3.19(dd, 1H, 3J=5.0Hz, 3J=7.5Hz),
3.51-3.61 (m, 1H), 5.25 (q, 1H, 3J=7.0 Hz). 13C NMR (CDCl3,
100.6 MHz): (ppm)=10.1, 10.9, 15.3, 16.6, 19.2, 19.3, 27.9, 34.3,
40.1, 44.4, 76.5, 78.5, 114.6, 149.0, 176.2. ESI-HRMS: calcd for
C15H29O4þ 273.2066, found 273.2059 [M þ Hþ].
(þ)-(2Z,4S,5S,6S,7S)-5,7-Dihydroxy-4,6,8-trimethylnon-2-en-
3-yl benzoate ((þ)-38). To a soln of (2Z,4S,5S,6S,7S)-7-hydroxy-
4,6,8-trimethyl-5-[(1S)-1-phenylethoxy]non-2-en-3-yl benzoate
((-)-37) (277 mg, 0.65 mmol) in CH2Cl2 (50 mL) was added a
solution of FeCl3 (0.2 g, 1.3 mmol) in 20 mL of CH2Cl2. The result-
ing mixture was stirred vigorously for 10 min at 25 ꢀC, and H2O was
added. The aq phase was extracted with CH2Cl2 (3ꢀ 30 mL). The
combined organic layers were washed with brine (50 mL), dried
(Na2SO4), filtered, and evaporated. Flash chromatography on silica
gel(PE/EtOAc,9:1) gave(þ)-38 (195 mg, 93%) as colorless oil. Rf=
0.48 (PE/AcOEt, 8:2). R25D =þ16 (CHCl3, c=0.22). IR (film): ν
(cm-1)=3441, 3063, 2963, 2930, 2875, 1722, 1715, 1694, 1601, 1462,
1453, 1261, 1176, 1165, 1142, 1105, 1069, 1026. 1H NMR (CDCl3,
400 MHz): (ppm)=0.88, 0.88 (2d, 6H, 3J=6.8 Hz), 1.00, 1.19 (2d,
6H, 3J=6.8 Hz), 1.53 (d, 3H, 3J=6.8 Hz), 1.79-1.90 (m, 2H), 2.91
(quint, 1H, 3J=7.4 Hz), 3.32 (dd, 1H, 3J= 7.4, 4.3 Hz), 3.50 (dd,
1H, 3J= 8.6, 3.1 Hz), 5.38 (q, 1H, 3J= 7.4 Hz), 7.51 (t, 2H, 3J=
7.4Hz),7.64(t,1H,3J=7.4 Hz), 8.13 (d, 2H, 3J=8.0Hz).13CNMR
(CDCl3, 100.6 MHz): (ppm) = 11.1, 14.7, 15.4, 16.9, 20.4, 30.2,
37.6, 44.2, 78.7, 79.7, 114.9, 128.7, 129.1, 130.2, 133.8, 149.3, 165.5.
ESI-HRMS: calcd for C19H28O4Naþ 343.1885; found 343.1895
[M þ Naþ].
Experimental Section
(þ)-(3R,4R,5S,6R)-6-Ethyl-4-hydroxy-3,5-dimethyltetrahydro-
2H-pyran-2-one ((þ)-6). O3 was bubbled into a soln of (-)-33
(12 mg, 0.037 mmol) in CH2Cl2 (2 mL) at -78 ꢀC until persistence
of the blue color. After the disappearance of (-)-33 by TLC,
Me2S (0.1 mL) was added and the mixture stirred at -78 ꢀC for
20 min. The mixture was allowed to warm to 25 ꢀC. Solvent eva-
poration and flash chromatography on silica gel (PE/EtOAc)
gave (þ)-6 (5 mg, 73%) as colorless crystals (X-ray, Supporting
Information). Rf=0.23 (PE/EtOAc, 3:2). Mp 79-81 ꢀC. R25
=
D
þ21 (CHCl3, c=0.16). IR (film): ν (cm-1)=3433, 2971, 2938,
2882, 1707 (s), 1461, 1380, 1212, 1172, 1119, 992, 974. 1H NMR
(CDCl3, 400 MHz): (ppm)=1.02 (t, 3H, 3J=7.5 Hz), 1.07 (d, 3H,
3J = 6.5 Hz), 1.33 (d, 3H, 3J = 7.0 Hz), 1.55 (ddq, 1H, 3J = 7.0,
7.5 Hz), 1.82 (ddq, 1H, 3J=3.0, 7.0, 7.5 Hz), 1.87-1.93 (m, 1H),
2.53 (dq, 1H, 3J = 3.0, 7.0 Hz), 3.84 (br s, 1H), 4.36 (ddd, 1H,
3J=3.0, 7.0, 10.5 Hz). 13C NMR (CDCl3, 100.6 MHz): δ (ppm)=
8.7, 12.9, 14.3, 26.1, 37.7, 42.6, 73.3, 82.1, 173.8. ESI-HRMS: m/z
calcd for C9H17O3þ 173.1178, found 173.1175 [M þ Hþ].
(-)-(3S,4S,5R,6S)-4-Hydroxy-6-isopropyl-3,5-dimethyltetra-
hydro-2H-pyran-2-one ((-)-7). O3 was bubbled through a soln
of (-)-38 (200 mg, 0.62 mmol) in CH2Cl2 (5 mL) at -78 ꢀC until
persistence of the blue color, then O2 was bubbled. After the
disappearance of (-)-38 by TLC, Me2S (0.25 mL) was added
and the mixture was allowed to warm to 25 ꢀC overnight. Water
(10 mL) was added and the aq phase was extracted with CH2Cl2
(3 ꢀ 10 mL). The combined organic extracts were washed with
brine (2ꢀ10 mL) and dried (Na2SO4), and the solvent was evap-
orated. Flash chromatography on silica gel (CH2Cl2/EtOAc)
gave pure (-)-7 (110 mg, 87%), that was recrystallized from
hexane (X-ray, Supporting Information). Rf=0.45 (PE/EtOAc,
7:3). Mp 92-95 ꢀC. R25D = -28 (CHCl3, c = 0.40). IR (film):
ν (cm-1)=3370, 3260, 2970, 2920, 1725, 1695, 1465, 1370, 1345,
1220, 1195, 1170, 1120, 990. 1H NMR (CDCl3, 400 MHz): (ppm)
=0.89 (d, 3H, 3J=7.1 Hz), 1.06, 1.11 (2d, 6H, 3J=7.0 Hz), 1.32
(d, 3H, 3J=7.1 Hz), 1.87 (sept, 1H, 3J=7.0 Hz), 1.95 (dq, 1H, 3J=
6.6, 10.7 Hz), 2.51 (q, 1H, 3J=7.1 Hz), 3.85 (s, 1H), 4.29 (d, 1H,
3J=10.7 Hz). 13C NMR (CDCl3, 100.6 MHz): δ (ppm)=12.7,
(þ)-(2Z,4S)-4-[(4S,5S,6S)-2,2,5-Trimethyl-6-(propan-2-yl)-
1,3-dioxan-4-yl]pent-2-en-3-yl benzoate ((þ)-39). To a soln of diol
(þ)-38 (190 mg, 0.59 mmol) in dimethoxypropane (2 mL) was
added p-TsOH H2O (5.6 mg, 0.03 mmol). The mixture was stirred
3
for 1 h at 25 ꢀC, then neutralized by adding solid NaHCO3, filtered,
and evaporated. Flash chromatography on silica gel (PE/EtOAc,
9:1) gave (þ)-39 (200 mg, 96%) as a colorless oil. R25D = þ6
(CHCl3, c = 0.30). IR (film): ν (cm-1) = 2964, 2930, 2875, 2849,
1738, 1687, 1602, 1492, 1453, 1390, 1378, 1261, 1201, 1174, 1154,
1133, 1105, 1026. 1H NMR (CDCl3, 400 MHz): (ppm)=0.72 (d,
3H, 3J=6.5 Hz), 0.88, 0.93 (2d, 6H, 3J=6.4 Hz), 1.18 (s, 3H), 1.21
3
3
(d, 3H, J = 7.1 Hz), 1.30 (s, 3H), 1.54 (d, 3H, J = 6.8 Hz),
1.80-1.90 (m, 2H), 2.68 (qd, 1H, 3J= 7.4, 1.8 Hz), 3.32 (dd, 1H,
3J=10.4, 1.8 Hz), 3.40 (dd, 1H, 3J=9.8, 2.4 Hz), 5.33 (q, 1H, 3J=
6.8 Hz), 7.48 (t, 2H, 3J=7.4 Hz), 7.58 (t, 1H, 3J=7.4 Hz), 8.13 (d,
2H, 3J=8.0 Hz). 13C NMR (CDCl3, 100.6 MHz): (ppm) =10.8,
11.4, 14.1, 15.7, 18.8, 19.8, 27.8, 29.5, 29.7, 32.6, 39.1, 76.4, 77.0,
97.3, 112.7, 128.0, 129.7, 132.6, 148.8, 163.5. ESI-HRMS: calcd for
C22H32O4Kþ 399.1938; found 399.1937 [M þ Kþ]. Anal. calcd for
C22H32O4 (360.49): C, 73.30%; H, 8.95%; O, 17.75%. Found C,
73.22%; H, 8.85%; O, 17.74%.
844 J. Org. Chem. Vol. 76, No. 3, 2011

Exner et al.
JOCArticle
(-)-(4S,5S,6S,7S)-5,7-Isopropylidendioxy-4,6,8-trimethylnona-
3-one (-)-40. Asolnof(þ)-39 (1.00 g, 2.78 mmol) in DME (15 mL)
ESI-HRMS: m/z calcd for C15H28O3Naþ 279.1936, found
279.1939 [M þ Naþ].
was added to a soln of MeLi LiBr (2.1 M in Et2O, 6.6 mL,
3
13.9 mmol) in Et2O (10 mL) at -78 ꢀC. The mixture was stirred at
-78 ꢀC for 5 h, poured into an ice-cold sat. aq soln of NH4Cl
(30 mL). The aq phase was extracted with Et2O (4ꢀ20 mL). The
organic layers were washed with brine (20 mL), dried (Na2SO4),
and evaporated. The residue was purified by recrystallization from
hexane, giving (-)-40 (615 mg, 86%) as colorless crystals. Rf =
0.52 (PE/AcOEt, 9:1). Mp=89-92 ꢀC. R25D=-20 (CHCl3, c=
0.15). IR (film): ν (cm-1) = 2975, 2959, 2938, 2875, 2841, 1693,
1458, 1412, 1378, 1358, 1346, 1249, 1198, 1164, 1152, 1130, 1101,
1048. 1H NMR (CDCl3, 400 MHz): (ppm) = 0.75, 0.80 (2d, 6H,
3J=6.7 Hz), 0.91 (d, 3H, 3J=6.9 Hz), 1.01 (t, 3H, 3J=7.1 Hz),
1.19 (d, 3H, 3J = 7.3 Hz), 1.31, 1.36 (2s, 6H), 1.44 (m, 1H), 1.85
(sept, 1H, 3J = 6.6 Hz), 2.45, 2.59 (2qd, 2H, 2J = 18.1 Hz, 3J =
7.2 Hz), 2.71 (m, 1H), 3.27 (d, 1H, 3J=10.0 Hz), 3.56 (d, 1H, 3J=
10.3 Hz). 13C NMR (CDCl3, 100.6 MHz): (ppm) =7.4, 7.6, 11.7,
13.7, 14.2, 19.1, 20.1, 27.9, 29.9, 34.1, 49.7, 76.9, 77.6, 97.8, 214.2.
Acknowledgment. This work was supported by the Swiss
National Science Foundation (Grants 200020-116212/1 and
200020_124724) and by the Roche Research Foundation.
We are grateful also to Dr. C. Mazet, University of Geneva,
Dr. L. Menin, F. Sepulveda, andM. Reyfortechnicalassistance,
and Dr. R. Scopelliti for the X-ray diffraction studies.
Supporting Information Available: Further complete experi-
mental procedures and compound characterization data for
(þ)-1, (-)-2, (þ)-3, (-)-4, (-)-5, 16a, 16b, 18a, 18b, 20a, 20b,
(þ)-27, 28, (þ)-29, (-)-31, (þ)-32, (-)-33 as well as copies of 1H
and 13C NMR spectra for all newly reported compounds. X-ray
data for (-)-5, (þ)-6, (-)-7, and (-)-40 have been deposited at
the Cambridge crystallographic database. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 845