First asymmetric synthesis of (+)-sordidin and (-)-7-epi-sordidin, aggregation pheromones of the banana weevil cosmopolites sordidus

Article abstract of DOI:10.1002/ejoc.200500112

The asymmetric synthesis of (1S,3R,5R,7S)-(+)-sordidin and 7-epi-(1S,3R,5R,7R)-(-)-sordidin, both components of the natural male-produced aggregation pheromone of the banana weevil Cosmopolites sordidus (Germar), starting from 2,2-dimethyl-1,3-dioxan-5-one is described. Two of the stereogenic centers were generated by three α-alkylations of the corresponding RAMP-hydrazone. Diastereoselective epoxide opening as another key step of the synthesis employing the aza-enolate of 3-pentanone SAEP-hydrazone as nucleophile and subsequent acidic intramolecular acetalisation furnished the sordidin C-7 epimers in good overall yield (39%) as a 1.5:1 diastereomeric mixture. The epimers could be separated by preparative GC and thus, each of them could be obtained in high diastereomeric and enantiomeric purity (de ≥ 97%, ee ≥ 98%).

Full text of DOI:10.1002/ejoc.200500112

FULL PAPER
First Asymmetric Synthesis of (+)-Sordidin and (–)-7-epi-Sordidin,
Aggregation Pheromones of the Banana Weevil Cosmopolites sordidus
Dieter Enders,*[a] Irene Breuer,[a] and Anja Nühring[a]
Keywords: Pheromones / Asymmetric synthesis / SAMP/RAMP-Hydrazones / Quaternary stereocenters / Epoxide opening
The asymmetric synthesis of (1S,3R,5R,7S)-(+)-sordidin and
7-epi-(1S,3R,5R,7R)-(–)-sordidin, both components of the nat-
ural male-produced aggregation pheromone of the banana
weevil Cosmopolites sordidus (Germar), starting from 2,2-di-
methyl-1,3-dioxan-5-one is described. Two of the stereogenic
centers were generated by three α-alkylations of the corre-
sponding RAMP-hydrazone. Diastereoselective epoxide
opening as another key step of the synthesis employing the
aza-enolate of 3-pentanone SAEP-hydrazone as nucleophile
and subsequent acidic intramolecular acetalisation furnished
the sordidin C-7 epimers in good overall yield (39%) as a
1.5:1 diastereomeric mixture. The epimers could be sepa-
rated by preparative GC and thus, each of them could be
obtained in high diastereomeric and enantiomeric purity (de
Ն 97%, ee Ն 98%).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
We now wish to report on the first asymmetric synthesis
of (1S,3R,5R,7S)-(+)-sordidin (1), the main component of
Introduction
The banana weevil Cosmopolites sordidus (Germar) is the the pheromone and its epimer, 7-epi-(1S,3R,5R,7R)-(–)-sor-
most important world-wide insect pest of banana plants.[1] didin (7-epi-1), starting from the dioxanone RAMP-hydra-
These longlived weevils lay their eggs in the rhizome of the zone 6 as a chiral 1,3-dihydroxyacetone equivalent.
plant. The larvae hatch and then feed and tunnel in the
As is depicted in Scheme 1, our retrosynthetic analysis
rhizome of the plant, weakening it and leading to snapping led us to the dihydroxy ketone 2, which after intramolecular
of the rhizome at ground level before the bunch is ripe. The acetalisation would lead to the target pheromone. The dihy-
first evidence for a volatile male-produced pheromone was droxy ketone 2 was planned to be prepared by diastereo-
given by Budenberg et al. in 1993.[2] In 1995 Ducrot et al. selective ring opening of the epoxide 3 with either enantio-
reported the isolation and identification of the major phero- merically pure 3-pentanone SAMP- (R = H) or SAEP- (R
mone compound,[3] for which they proposed the trivial = Et) -hydrazone 4 in one of the key steps of the synthesis.
name sordidin. They also carried out the first synthesis, in- To create the desired configuration in oxirane 3, it would
cluding a Baeyer–Villiger oxidation as the key step.[4] Fur- be necessary to start from the tosyl dioxane 5, which in turn
ther syntheses were published by Ducrot,[5] Oehlschlager,[6]
Mori,[7] and Kitching.[8] Recently, Wardrop et al. reported
on the synthesis of rac-7-epi-sordidin employing a regiose-
lective rhodium(ii)-catalysed intramolecular diazocarbonyl
C–H insertion as key step.[9] Since the conversion of rac-7-
epi-sordidin to rac-sordidin has been discribed by Mori et
al., the latter synthesis also constitutes a formal synthesis
of rac-sordidin (1).[7]
To the best of our knowledge, all of these former ap-
proaches are based on the concept of ex-chiral-pool synthe-
sis or led to a racemic mixture of the title pheromones. To
date no asymmetric synthesis leading directly to the enan-
tiomerically pure major pheromone (+)-sordidin (1) has
been published.
[a] Institut für Organische Chemie, Rheinisch-Westfälische Techni-
sche Hochschule,
Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49-241-8092127
E-mail: enders@rwth-aachen.de
Scheme 1. Retrosynthetic analysis of sordidin (1).
Eur. J. Org. Chem. 2005, 2677–2683
DOI: 10.1002/ejoc.200500112
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2677

D. Enders, I. Breuer, A. Nühring
FULL PAPER
leads back to the RAMP-hydrazone 6, the starting material Cleavage of the acetonide occurred either by treatment of 5
for asymmetric alkylations using the SAMP/RAMP-hydra- with trifluoroacetic acid in a biphasic system (THF/H2O)
zone methodology.[10]
or with 3 n HCl in aqueous methanol at room temperature.
Initial attempts to employ a related iodide instead of ep- The latter conditions revealed the diol 14 bearing a second-
oxide 3 as electrophile in the final alkylation step, unfortu- ary and a tertiary alcohol function in 87% yield, slightly
nately failed.
better than the TFA conditions (84%). According to the
retrosynthetic analysis given in Scheme 1, the secondary
alcohol function had to be protected previous to the terti-
ary one. This was achieved by using 1 equiv. each of
TBSOTf and 2,6-lutidine and afforded chemoselectively
Results and Discussion
As outlined in Scheme 2, our asymmetric synthesis of the and quantitatively the alcohol 15 leaving the less reactive
key intermediate epoxide 3 started from 2,2-dimethyl-1,3- tertiary alcohol unprotected. Deprotonation of the tertiary
dioxan-5-one RAMP-hydrazone 6, available by condensa- alcohol with paraffin-free sodium hydride (4.0 equiv.) in dry
tion of (R)-1-amino-2-methoxymethylpyrrolidine (RAMP) THF afforded the oxirane 3 in 99% yield and in virtually
with the corresponding dioxanone.[11,12] Double alkylation diastereomerically pure form according to 13C NMR spec-
of hydrazone 6 with methyl iodide at the α- and αЈ-positions troscopy (de Ն 96%) without the need of further purifica-
was carried out under standard conditions for this system tion. The enantiomeric excess (ee Ն 98%) of this key inter-
(tBuLi, THF, –78 °C, 2 h, then MeI, –100 °C to room tem- mediate 3 was determined by chiral stationary phase GC
perature, 15 h) and led to the trans-dimethylated hydrazone based on the available enantiomeric oxirane ent-3, which
7 in 79% yield for two steps and excellent stereoselectivity was synthesized starting from 2,2-dimethyl-1,3-dioxan-5-
(de, ee Ն 96%).[11,13] In the next step, the quaternary ste- one SAMP-hydrazone ent-6.
reocenter bearing the desired tertiary alcohol function was
generated using benzyloxymethyl chloride (BOMCl) as the
electrophile to trap the lithiated hydrazone 7 according to
our dioxanone procedure.[14] The α-quaternary hydrazone 8
was thus obtained in very good yield (92%) and excellent
diastereomeric and enantiomeric excesses (de, ee Ն 96%,
13C NMR, GC) with the required cis relationship of the
methyl substituents at the α- and αЈ-positions as a conse-
quence of the typical relative topicity in RAMP-hydrazone
alkylations in the third step. Subsequent ozonolysis at
–78 °C occurred without epimerisation and provided the
trisubstituted dioxanone 9 in 79% yield. As it has been pre-
viously demonstrated in related substrate cases, the most
efficient reaction sequence for the removal of the oxo group
is a radical deoxygenation according to the Barton–
McCombie protocol.[15] Thus, ketone 9 was reduced with
sodium borohydride to a diastereomeric mixture of the
alcohols 10 (dr = 1:4), which were converted into the corre-
sponding xanthates 11 in excellent yield (98%, 2 steps). Re-
duction of the xanthates 11 was easily accomplished with
tributyltin hydride and a catalytic amount of AIBN in re-
fluxing toluene and furnished the dioxane 12 in 98% yield.
In the next step the benzyl protecting group of the primary
Scheme 2. Synthesis of the key intermediate 3. a) 1. tBuLi, THF,
alcohol had to be transformed into a leaving group in order
to generate, after cleavage of the acetonide, an epoxide moi-
ety at the quaternary carbon atom. This protection and
leaving group had to be stable against acidic conditions and
therefore the tosylate group was chosen. To achieve depro-
tection of the benzyl group first the benzyl ether 12 was
cleaved with calcium in liquid ammonia to the primary
–78 °C, 2. BOMCl, –100 °C to room temperature; b) O3, CH2Cl2,
–78 °C; c) NaBH4, MeOH, 0 °C; d) 1. NaH, THF, 0 °C, 2. CS2,
MeI; e) nBu3SnH, AIBN, toluene, reflux; f) Ca/NH3; g) Et3N,
DMAP, CH2Cl2, TsCl, room temperature; h) 3n HCl, H2O/MeOH,
room temperature; i) 2,6-lutidine, CH2Cl2, TBSOTf, 0 °C; j) NaH,
THF, 0 °C.
Finally, the oxirane 3 was opened by the aza-enolate of
alcohol 13 in excellent yield (97%). The standard hydrogen- 3-pentanone SAEP-hydrazone 4 in the presence of anhy-
ation protocol (Pd/C) for removal of benzyl protecting drous LiCl (6.0 equiv.) as additive according to a modified
groups did not work in this case. Furthermore, initial literature procedure for enolate oxirane ring openings.[16] In
attempts to convert the alcohol 13 directly into the corre- our case, a large excess of aza-enolate (9.2 equiv.), generated
sponding iodide using triphenylphosphane, imidazole and from 3-pentanone SAEP-hydrazone
4
and LDA
iodine, failed. Next the alcohol 13 was transformed to the (11.0 equiv.), was required to reach a complete conversion
corresponding tosylate 5 in practically quantitative yield. in this reaction. Related aza-enolates derived from 3-penta-
2678
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2677–2683

First Asymmetric Synthesis of (+)-Sordidin and (–)-7-epi-Sordidin
FULL PAPER
none SAMP-hydrazone and 3-pentanone N,N-dimethylhy- preparative GC and their NMR spectroscopic data[6] and
drazone instead of 4 did not improve the results. Thus, the optical rotation values[17] are consistent with those given in
mixture of the crude product hydrazone 16 and the excess the literature.
of hydrazone 4 was directly used in an acidic acetalisation
reaction utilizing aqueous 3 n HCl in a biphasic system
(H2O/n-pentane) and gave after column chromatography a
Experimental Section
diastereomeric mixture of sordidin (1) and 7-epi-sordidin
(7-epi-1) in 84% yield over two steps in a 1.5:1 ratio from freshly opened containers. Solvents were dried and purified
General Remarks: All reagents were of commercial quality used
by conventional methods prior to use. Tetrahydrofuran was freshly
distilled under argon from sodium/lead alloy. tBuLi (15% in n-pen-
tane) and nBuLi (1.6 n in hexane) were purchased from Merck,
Darmstadt. Diisopropylamine was distilled from CaH2 and stored
over molecular sieves. Reactions were conducted using standard
Schlenk techniques under argon. Preparative column chromatog-
raphy: Merck silica gel 60, particle size 0.040–0.063 mm (230–240
mesh). Analytical TLC: silica gel 60 F254 plates from Merck, Darm-
stadt. Optical rotation values were measured with a Perkin–Elmer
P241 polarimeter, solvents used were of Merck UVASOL quality.
Microanalyses were obtained with an Elementar Vario EL. Mass
spectra were recorded with Varian MAT 212 (EI, 70 eV, 1 mA) and
with Finnigan MAT SSQ 7000 (CI, 100 eV) spectrometers. High-
resolution MS: Finningan MAT, MAT 95. IR spectra were ob-
tained with a Perkin–Elmer FT/IR 1760 instrument. 1H and 13C
NMR spectra were recorded with Varian VXR 300, Varian Gemini
300 or Varian Inova 400 spectrometers. All measurements were per-
formed with tetramethylsilane as internal standard. The chiral aux-
iliaries RAMP [(R)-1-amino-2-(methoxymethyl)pyrrolidine] and
SAMP [(S)-1-amino-2-(methoxymethyl)pyrrolidine] were prepared
from (R)-proline or (S)-proline according to literature pro-
cedures.[18] 2,2-Dimethyl-1,3-dioxan-5-one was prepared according
to the procedure described by Hoppe et al.[19] Benzyloxymethyl
chloride was prepared according to a literature procedure.[20]
(Scheme 3).
Scheme 3. Final steps of the asymmetric synthesis of sordidin and
7-epi-sordidin. a) 1. LiCl, LDA, THF, –78 °C, 4, 1 h, then 0 °C,
10 min, 2. 3, –78 °C to room temperature, 15 h; b) 3 n HCl, H2O/
n-pentane, room temperature, 6 d.
[(4S,5E,6R)-4-(Benzyloxymethyl)-2,2,4,6-tetramethyl-1,3-dioxan-5-
ylidene][(R)-2-(methoxymethyl)pyrrolidin-1-yl]amine [(S,R,R)-8]: To
a
solution of α,αЈ-dimethylated 2,2-dimethyl-1,3-dioxan-5-one
RAMP-hydrazone (R,R,R)-7 (3.20 g, 11.8 mmol) in dry THF
(24 mL) tBuLi (12 mL, 17.8 mmol) was slowly added at –78 °C.
After stirring for 1.5 h, the reaction mixture was cooled to –100 °C,
BOMCl (2.8 g, 19.3 mmol) was added dropwise and the solution
was stirred for 1 h. Then the mixture was allowed to warm to room
temperature over a period of 15 h and quenched with a pH 7 buffer
(36 mL). The aqueous phase was extracted with Et2O (400 mL) and
the organic phase was washed with brine (20 mL). The combined
aqueous phases were extracted with Et2O (70 mL) and the com-
bined organic layers were dried (MgSO4). Removal of the solvent
under reduced pressure and purification of the residue by flash
chromatography (SiO2, Et2O/n-pentane, 1:7) afforded (S,R,R)-8 as
a colourless solid. Yield: 4.28 g (92%). de Ն 96% (13C NMR).
[α]2D6 = +40.2 (c = 1.31, CHCl3). (R,S,S)-8: [α]2D6 = –43.7 (c = 1.73,
CHCl3). Further analytical data are consistent with those reported
in the literature.[14]
Obviously, under the acidic conditions applied, both the
TBS protecting group and the hydrazone moiety were hy-
drolysed, followed by an intramolecular acetalisation to the
target pheromone in one single step. However, the dia-
stereoselectivity, which has apparently been obtained by
prior asymmetric epoxide opening of 3 with the aza-enolate
of 3-pentanone SAEP-hydrazone 4 has been affected under
the acidic conditions causing substantial C-7 epimerisation
as it has been previously observed by Mori et al.[7]
Gratifyingly, we succeeded in separating the desired sor-
didin epimers by preparative gas chromatography. As a re-
sult, both could be obtained in diasteromerically pure form
according to GC analysis (in the case of sordidin: de Ն
99%; in the case of 7-epi-sordidin: de Ն 97%) and with
high enantiomeric excess for each epimer (ee Ն 98%).
(4R,6R)-4-(Benzyloxymethyl)-2,2,4,6-tetramethyl-1,3-dioxan-5-one
[(R,R)-9]: A solution of (S,R,R)-8 (4.14 g, 10.6 mmol) in CH2Cl2
(40 mL) was ozonolyzed at –78 °C. Removal of the solvent under
reduced pressure and purification of the residue by flash
Conclusions
chromatography (Et2O/n-pentane, 1:4) afforded (R,R)-9 as
a
=
colourless oil. Yield: 2.33 g (79%). de Ն 96% (13C NMR). [α]2D6
In summary, we have described the first asymmetric syn-
thesis of the banana weevil aggregation pheromones sor-
didin and 7-epi-sordidin in 14 steps with excellent diastereo-
and enantiomeric excesses (de Ն 97%, ee Ն 98) and in 39%
overall yield, starting from 2,2-dimethyl-1,3-dioxan-5-one
+140.5 (c = 1.01, CHCl3). (S,S)-9: [α]2D6 = –131.5 (c = 1.08, CHCl3).
Further analytical data are consistent with those reported in the
literature.[14]
(4R,6R)-4-(Benzyloxymethyl)-2,2,4,6-tetramethyl-1,3-dioxan-5-ol
RAMP-hydrazone. Both diastereomers were separated by [(R,R/S,R)-10]: To a solution of (R,R)-9 (1.71 g, 6.1 mmol) in
Eur. J. Org. Chem. 2005, 2677–2683
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2679

D. Enders, I. Breuer, A. Nühring
FULL PAPER
MeOH (30 mL) was added NaBH4 (0.46 g, 12.3 mmol) at 0 °C. The
solution was stirred for 4 h. After removal of the solvent under
reduced pressure, the residue was diluted with Et2O. The organic
phase was washed with water and brine and dried (MgSO4). Re-
moval of the solvent under reduced pressure afforded (R,R/S,R)-10
as a colorless oil. Yield: 1.72 g (100%). dr = 4:1. [α]2D6 = +15.1 (c
= 1.00, CHCl3). ent-10: [α]2D6 = –15.4 (c = 1.17, CHCl3). IR (film):
(CHOC=S), 99.5 [C(CH3)CH3], 127.8 (oCPh), 127.9 (pCPh), 128.6
(mCPh), 138.6 (CPh), 217.3 (C=S) ppm. Minor isomer: [α]2D6
=
1
–12.2 (c = 1.10, CHCl3). H NMR (400 MHz, C6D6): δ = 1.39 [d,
J = 0.6 Hz, 3 H, C(CH3)CH3], 1.43 (d, J = 6.6 Hz, 3 H, CHCH3),
1.44 [d, J = 0.6 Hz, 3 H, C(CH3)CH3], 1.59 (s, 3 H, CCH3), 2.10
(s, 3 H, SCH3), 3.35 [d, J = 8.8 Hz, 1 H, C(CH3)CHHO], 3.67 [d,
J = 8.8 Hz, 1 H, C(CH3)CHHO], 4.04 (dq, J = 6.6, 4.4 Hz, 1 H,
ν = 3564 cm–1 (m), 3485 (m), 3089 (w), 3064 (w), 3029 (m), 2989 CHCH3), 4.29 (d, J = 12.1 Hz, 1 H, OCHHC6H5), 4.33 (d, J =
˜
(s), 2936 (s), 2868 (m), 1497 (m), 1454 (s), 1380 (s), 1333 (w), 1308
12.1 Hz, 1 H, OCHHC6H5), 5.80 (d, J = 4.7 Hz, 1 H, CHOC=S),
(m), 1248 (s), 1202 (s), 1169 (s), 1152 (s), 1090 (s), 1055 (s), 1005 7.08–7.30 (m, 5 H, C6H5) ppm. 13C NMR (100 MHz, C6D6): δ =
(s), 977 (s), 903 (w), 888 (w), 841 (m), 812 (m), 739 (m), 699 (m), 18.9 (CHCH3), 21.0 (CCH3), 24.9 (SCH3), 24.5, 31.14 [C(CH3)
597 (w), 540 (w). Major isomer: 1H NMR (400 MHz, C6D6): δ =
1.21 (d, J = 6.4 Hz, 3 H, CHCH3), 1.39 (s, 3 H, CCH3), 1.55 [s, 3
H, CH(OH)CCH3], 2.04 (d, J = 11.0 Hz, 1 H, OH), 3.27 [d, J =
CH3], 68.8 (CHCH3), 73.7 [C(CH3)CH2O], 74.6 (OCH2Ph), 75.4
(CCH3), 84.5 (CHOC=S), 99.5 [C(CH3)CH3], 127.9 (oCPh, pCPh),
128.5 (mCPh), 138.7 (CPh), 215.8 (C=S) ppm. MS (EI, 70 eV):
9.2 Hz, 1 H, C(CH3)CHHO], 3.33 (dd, J = 11.0, 1.5 Hz, 1 H, m/z (%) = 370 (0.5) [M+], 249 (10), 191 (15), 141 (27), 97 (5), 91
CHOH), 3.47 [d, J = 9.2 Hz, 1 H, C(CH3)CHHO], 3.98 (dq, J =
6.4, 1.5 Hz, 1 H, CH3CHCHOH), 4.19 (d, J = 12.2 Hz, 1 H,
OCHH), 4.27 (d, J = 12.2 Hz, 1H OCHH), 7.07–7.20 (m, 5 H,
C6H5) ppm. 13C NMR (100 MHz, C6D6): δ = 17.5 (CHCH3), 23.7
(CCH3), 25.5 [C(CH3)CH3], 31.7 [C(CH3)CH3], 65.1 (CHCH3),
68.6 (OCH2Ph), 73.5 [C(CH3)CH2O], 75.2 (CCH3), 77.6 (CHOH),
98.9 [C(CH3)CH3], 127.7 (mCPh), 128.5 (oCPh), 128.5 (pCPh),
(100). C18H26O4S2 (370.53): calcd. C 58.35, H 7.07; found C 57.91,
H 6.76.
(4S,6R)-4-(Benzyloxymethyl)-2,2,4,6-tetramethyl-1,3-dioxane
[(S,R)-12]: Tri-n-butyltin hydride (3.4 mL, 12.9 mmol) was dis-
solved in toluene (80 mL) in a Schlenk flask. The solution was
post-purged with argon for 10 min and was then heated to reflux.
The xanthate (R,R/S,R)-11 (1.58 g, 4.3 mmol) dissolved in toluene
(10 mL) was added dropwise by cannula over a period of 3 h. Dur-
ing the addition a satd. solution of AIBN in toluene (1.1 mL,
0.2 mL/mmol xanthate) was added dropwise by cannula and the
solution was stirred under reflux for 3 h. After complete conversion
of the starting material had been indicated by TLC, the solvent was
removed under reduced pressure. Column chromatography (silica
gel, first: Et2O/pentane, 1:20 to remove the tin by-products, second:
Et2O/n-pentane, 1:5) yielded (S,R)-12 as a colourless oil. Yield:
1.11 g (98%). de Ն 96% (13C NMR). [α]2D6 = +2.5 (c = 1.11,
1
138.4 (CPh) ppm. Minor isomer: H NMR (400 MHz, C6D6): δ =
1.39 (d, J = 6.1 Hz, 3 H, CHCH3), 1.40 (s, 3 H, CCH3), 1.45 [s, 3
H, CH(OH)CCH3], 1.47 (s, 3 H, CCH3), 2.90 (d, J = 6.1 Hz, 1 H,
OH), 3.36 [d, J = 9.2 Hz, 1 H, C(CH3)CHHO], 3.38 (dd, J = 6.1,
8.2 Hz, 1 H, CHOH), 3.76 [d, J = 9.2 Hz, 1 H, C(CH3)CHHO],
3.93 (dq, J = 8.2, 6.1 Hz, 1 H, CHCH3), 4.12 (d, J = 12.0 Hz, 1 H,
OCHH), 4.17 (d, J = 12.0 Hz, 1 H, OCHH), 7.07–7.20 (m, 5 H,
HPh) ppm. 13C NMR (100 MHz, C6D6): δ = 19.8 (CHCH3), 25.5
(CCH3), 26.4 [C(CH3)CH3], 31.2 [C(CH3)CH3], 68.4 (CHCH3),
73.7 (OCH2Ph), 75.4 [C(CH3)CH2O], 77.6 (CCH3), 77.7 (CHOH),
98.9 [C(CH3)CH3], 127.7 (mCPh), 128.5 (oCPh), 128.5 (pCPh),
138.4 (CPh) ppm. MS (EI, 70 eV): m/z (%) = 279 (3) [M+ – 1], 265
(14), 165 (11), 158 (56), 101 (37), 92 (13), 91 (100), 59 (41), 58 (12).
C16H24O4 (280.36): calcd. C 68.55, H 8.63; found C 68.38, H 8.60.
CHCl3). ent-12: [α]2D6 = –2.1 (c = 1.32, CHCl ). IR (film): ν =
˜
3
3088 cm–1 (w), 3064 (w), 3030 (m), 2975 (s), 2934 (s), 2915 (s), 2868
(s), 1497 (m), 1454 (s), 1405 (m), 1377 (s), 1315 (m), 1246 (s), 1200
(s), 1165 (s), 1146 (s), 1102 (s), 1050 (s), 1029 (m), 1009 (s), 985 (s),
970 (m), 908 (m), 876 (m), 844 (m), 737 (s), 699 (s). 1H NMR
(400 MHz, C6D6): δ = 1.10 (d, J = 6.0, 3 H, CHCH3), 1.25 [ddd,
J = 13.2, 11.0, 0.6 Hz, 1 H, CH(CH3)CHH], 1.37 [d, J = 0.6 Hz, 3
H, CCH3(CH3)], 1.40 (s, 3 H, CCH3), 1.53 [d, J = 0.6 Hz, 3 H,
C(CH3)CH3], 1.72 [dd, J = 13.5, 3.0 Hz, 1 H, CH(CH3)CHH], 3.27
[dd, J = 8.8, 0.6 Hz, 1 H, C(CH3)CHHO], 3.48 [d, J = 8.8 Hz, 1
H, C(CH3)CHHO], 3.9 (ddq, J = 3.0, 6.1, 11.0 Hz, 1 H, CHCH3),
4.30 (d, J = 12.4 Hz, 2 H, OCHHC6H5), 4.34 (d, J = 12.4 Hz,
2 H, OCHHC6H5), 7.10 (m, 1 H, CHp-arom.), 7.18 (m, 2 H,
CHm-arom.), 7.25 (m, 2 H,CHo-arom.) ppm. 13C NMR (100 MHz,
C6D6): δ = 22.5 (CHCH3), 26.2 [C(CH3)CH3], 29.0 (CCH3), 32.1
[C(CH3)CH3], 39.3 [CH(CH3)CH2], 62.0 (CHCH3), 72.8 (CCH3),
73.4 (OCH2Ph), 76.1 (CCH2O), 98.52 [C(CH3)CH3], 127.6 (oCPh),
128.1 (pCPh), 128.4 (mCPh), 128.8 (CPh) ppm. MS (EI, 70 eV):
m/z (%) = 249 (23) [M+ – CH3], 143 (69), 101 (22), 99 (15), 91
(100), 85 (38), 59 (23). C16H24O3 (264.36): calcd. C 72.60, H 9.15;
found C 72.15, H 9.50.
O-(4R,6R)-4-(Benzyloxymethyl)-2,2,4,6-tetramethyl-1,3-dioxan-5-yl
S-Methyl Dithiocarbonate [(R,R/S,R)-11]: To a solution of (R,R/
S,R)-10 (1.76 g, 6.3 mmol) in dry THF (60 mL) under argon a 60%
suspension of NaH in mineral oil (0.50 g, 12.5 mmol) was added at
0 °C. After 30 min, CS2 (1.3 mL, 21.9 mmol) was added dropwise.
Stirring was continued for additional 30 min and iodomethane
(1.2 mL, 18.8 mmol) was added. The mixture was stirred at room
temperature overnight. The suspension was hydrolysed with water
and extracted with Et2O (2×250 mL). The combined organic layers
were washed with satd. aqueous NH4Cl solution (40 mL) and brine
(40 mL), dried (MgSO4) and concentrated under reduced pressure.
Purification of the residue by column chromatography (silica gel,
Et2O/n-pentane, 1:2) afforded (R,R/S,R)-11 as a yellow oil. Yield:
2.31 g (98%). dr = 4:1. ent-11: [α]2D6 = –44.8 (c = 1.18, CHCl3). IR
(film): ν = 2988 cm–1 (m), 2937, 2864 (m), 1721 (w), 1497 (w), 1454
˜
(m), 1425 (w), 1412 (w), 1379 (s), 1316 (m), 1272 (m), 1218 (s),
1154 (s), 1064 (s), 1029 (m). Major isomer: [α]2D6 = +64.5 (c = 1.02,
[(4S,6R)-2,2,4,6-Tetramethyl-1,3-dioxan-4-yl]methanol [(S,R)-13]:
CHCl3). 1H NMR (400 MHz, C6D6): δ = 1.20 (d, J = 6.3 Hz, 3 H, Pieces of calcium (0.52 g, 20.8 mmol) were added to liquid NH3
CHCH3), 1.29 [d, J = 0.6 Hz, 3 H, C(CH3)CH3], 1.46 (s, 3 H,
(75 mL) in a three-necked flask fitted with a dry ice condenser. The
CCH3), 1.50 [d, J = 0.6 Hz, 3 H, CCH3(CH3)], 2.13 (s, 3 H, SCH3), benzyl ether (S,R)-12 (1.10 g, 4.15 mmol) dissolved in dry THF
3.33 [d, J = 9.6 Hz, 1 H, C(CH3)CHHO], 3.49 [d, J = 9.6 Hz, 1 H, (5 mL) was added at –78 °C to the stirred dark blue solution. After
C(CH3)CHHO], 4.15 [dq, J = 6.3, 2.5 Hz, 1 H, (CH3)CHCHO], 30 min, the cooling bath was removed and the solution was kept
4.29 (d, J = 12.4 Hz, 1 H, OCHHC6H5), 4.33 (d, J = 12.1 Hz, 1
under reflux (–33 °C) for 2 h. The reaction was quenched with solid
H, OCHHC6H5), 6.26 (d, J = 2.5 Hz, 1 H, CHOC=S), 7.08–7.30 NH4Cl and the NH3 was evaporated at room temperature. The
(m, 5 H, C6H5) ppm. 13C NMR (100 MHz, C6D6): δ = 17.1
(CHCH3), 18.7 (CCH3), 22.7 (SCH3), 25.9, 31.1 [C(CH3)CH3], 64.9
(CHCH3), 73.5, 75.7 [C(CH3)CH2O, OCH2Ph], 76.3 (CCH3), 79.6
residue was diluted with Et2O. The organic phase was washed with
water and brine and dried (MgSO4). Removal of the solvent under
reduced pressure afforded (S,R)-13 as a colorless oil without fur-
2680
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2677–2683

First Asymmetric Synthesis of (+)-Sordidin and (–)-7-epi-Sordidin
FULL PAPER
ther purification. Yield: 0.70 g (97%). de Ն 96% (13C NMR). Et2O) afforded (S,R)-14 as a colorless wax. Yield: 0.76 g (87%). de
[α]2D6 = –8.9 (c = 1.05, CHCl3). ent-13: [α]2D5 = +14.3 (c = 1.40,
Ն 96% (13C NMR). [α]2D6 = +12.1 (c = 1.19, CHCl3). ent-14: [α]2D6
CHCl ). IR (film): ν = 3453 cm–1 (s), 2976 (s), 2936 (s), 2882 (m),
= –13.4 (c = 1.23, CHCl ). IR (film): ν = 3378 cm–1 (m), 2972 (m),
˜
˜
3
3
1451 (m), 1378 (s), 1316 (m), 1243 (s), 1231 (s), 1199 (s), 1150 (s),
1123 (m), 1058 (s), 1039 (s), 1006 (s), 982 (s), 964 (m), 934 (w), 909
(m), 872 (w), 841 (m). H NMR (400 MHz, C6D6): δ = 1.06 (d, J
2931 (m), 1598 (m), 1495 (w), 1455 (m), 1428 (m), 1401 (m), 1358
(vs), 1308 (w), 1292 (w), 1212 (m), 1190 (vs), 1176 (vs), 1140 (s),
1098 (s), 1039 (w), 1020 (w), 980 (vs), 909 (w), 848 (s), 833 (s), 816
1
= 6.0 Hz, 3 H, CHCH3), 1.15 (dd, J = 10.7, 13.5 Hz, 1 H, (s), 787 (m), 686 (w), 668 (vs), 575 (m), 555 (s), 531 (w), 505 (w).
CHaxHeqCHCH3), 1.23 (s, 3 H, CCH3), 1.31 [s, 3 H, C(CH3)CH3], 1H NMR (400 MHz, C6D6): δ = 0.90 (d, J = 6.0 Hz, 3 H, CHCH3),
1.42 (dd, J = 3.9, 13.5 Hz, 1 H, CHaxHeqCHCH3), 1.46 [s, 3 H, 1.13 [s, 3 H, C(OH)CH3], 1.44 [m, 2 H, CH2CH(OH)CH3], 1.89 (s,
C(CH3)CH3], 2.28 (s, 1 H, CH2OH), 3.26 (dd, J = 7.4, 11.0 Hz, 1
H, CHHOH), 3.44 (dd, J = 4.4, 10.7 Hz, 1 H, CHHOH), 3.75 (ddq,
J = 3.8, 6.1, 14.3 Hz, 1 H, CHCH3) ppm. 13C NMR (100 MHz,
C6D6): δ = 22.5 (CHCH3), 25.6 [C(CH3)CH3], 28.0 (CCH3), 31.6
3 H, CCH3), 3.93 (d, J = 9.3 Hz, 1 H, CHHOTs), 3.89 [m, 1 H,
CH(OH)], 4.18 (d, J = 9.3 Hz, 1 H, CHHOTs), 6.80 (m, 2 H,
mHPh), 7.78 (m, 2 H, oHPh) ppm. 13C NMR (100 MHz, C6D6): δ
= 21.2 (PhCH3), 24.6 (CHCH3), 26.6 (CCH3), 44.8 [CH(CH3)CH2],
[C(CH3)CH3], 38.9 [CH(CH3)CH2], 62.1 (CHCH3), 68.5 [C(CH3) 65.4 (CHCH3), 71.4 (CCH3), 74.4 [C(CH3)CH2O], 128.1 (oCPh),
CH2OH], 73.2 (CCH3), 98.8 [C(CH3)CH3] ppm. MS (EI, 70 eV):
m/z (%) = 159 (33) [M+ – CH3], 143 (59), 101 (32), 99 (35), 85 (56),
81 (13), 59 (100), 57 (15), 55 (12). C9H18O3 (174.24): calcd. C 62.04,
H 10.41; found C 61.65, H 10.21.
128.8 (mCPh), 133.4 (CPhCH3), 144.5 (SO2CPh) ppm. MS (EI,
70 eV): m/z (%) = 289 (0.9) [M+], 229 (12), 155 (35), 103 (100), 92
(12), 91 (30), 85 (28), 61 (33), 59 (11), 45 (9). C13H20O5S (288.36):
calcd. C 54.15, H 6.99; found C 54.00, H 7.04.
[(4S,6R)-2,2,4,6-Tetramethyl-1,3-dioxan-4-yl]methyl Toluene-4-sul-
fonate [(S,R)-5]: To a solution of (S,R)-13 (0.89 g, 3.9 mmol) in
dry CH2Cl2 (50 mL) were added NEt3 (1.1 mL, 8.0 mmol) and a
catalytical amount of DMAP. The mixture was stirred at room tem-
perature for 1 h and TsCl (1.14 g, 6.0 mmol) was added. The re-
sulting mixture was stirred at room temperature for 20 h. After
TLC monitoring had indicated that conversion was incomplete, ad-
ditional NEt3 (0.5 mL) and TsCl (0.30 g) were added. The mixture
was stirred again for 48 h until completion of the reaction. CH2Cl2
(20 mL) and satd. aqueous NH4Cl solution (5 mL) were added.
The organic layers were washed with a satd. aqueous NH4Cl solu-
tion, water and brine and were dried with MgSO4. Column
chromatography (silica gel, Et2O/n-pentane, 1:1) gave (S,R)-5 as a
bright yellow sirup. Yield: 1.30 g (100%). de Ն 96% (13C NMR).
[α]2D6 = +18.0 (c = 1.05, CHCl3). ent-5: [α]2D6 = –19.2 (c = 1.42,
(2S,4R)-4-[(tert-Butyldimethylsilyl)oxy]-2-hydroxy-2-methylpentyl
Toluene-1-sulfonate [(S,R)-15]: A solution of (S,R)-14 (0.65 g,
2.3 mmol) in dry CH2Cl2 (20 mL) was cooled to 0 °C and 2,6-luti-
dine (0.26 mL, 2.3 mmol) was added. After stirring for 15 min,
TBSOTf (0.53 mL, 2.3 mmol) was added. The mixture was allowed
to warm to room temperature and was stirred for another 3 h until
completion of conversion was indicated by TLC monitoring. The
resulting reaction mixture was washed with water and extracted
with CH2Cl2 (3×50 mL). The combined organic layers were dried
with MgSO4 and the solvent was removed under reduced pressure.
Column chromatography (silica gel, Et2O/n-pentane, 1:2) gave
(S,R)-15 as a colorless oil. Yield: 1.30 g (100%). de Ն 96% (13C
NMR). [α]2D6 = –3.8 (c = 1.09, CHCl3). ent-15: [α]2D6 = +4.2 (c =
1.24, CHCl ). IR (film): ν = 3457 cm–1 (m), 2956 (s), 2931 (s), 2886
˜
3
(m), 2858 (s), 1599 (w), 1495 (w), 1472 (m), 1411 (m), 1368 (vs),
1292 (w), 1257 (s), 1190 (vs), 1178 (vs), 1138 (vs), 1098 (s), 1080
CHCl ). IR (film): ν = 2991 cm–1 (m), 2937 (m), 1656 (w), 1599
˜
3
(m), 1561 (w), 1543 (w), 1497 (m), 1459 (m), 1359 (s), 1309 (m),
1291 (m), 1252 (m), 1191 (s), 1179 (s), 1158 (s), 1122 (m), 1098 (m), 779 (vs), 713 (w), 686 (m), 667 (vs), 575 (m), 555 (vs), 531 (m). H
(m), 1045 (s), 1020 (w), 977 (vs), 926 (s), 890 (m), 838 (vs), 814 (s),
1
1082 (m), 1050 (m), 1009 (s), 981 (s), 964 (s), 938 (m), 909 (m), 860
NMR (400 MHz, C6D6): δ = 0.02 [s, 3 H, Si(CH3)CH3C(CH3)3],
(s), 842 (s), 819 (s), 792 (m), 766 (m), 671 (s), 632 (w), 590 (w), 558 0.05 [s, 3 H, Si(CH3)CH3C(CH3)3], 0.88 [s, 9 H, Si(CH3)2C(CH3)3],
(s), 529 (m), 516 (m). 1H NMR (400 MHz, C6D6): δ = 0.97 (d, J = 0.92 (d, J = 6.0 Hz, 3 H, CHCH3), 1.18 [s, 3 H, C(OH)CH3], 1.56
6.0 Hz,
CHHCHCH3), 1.14 (s, 3 H, CCH3), 1.21 [s, 3 H, C(CH3)CH3], 1.36 9.3 Hz, 1 H, CHHOSO2), 4.12 (m, 1 H, CHCH3), 4.22 (d, J =
[s, H, C(CH3)CH3], 1.38 (dd, 3.0, 13.7 Hz, H, 9.3 Hz, 1 H, CHHOSO2), 4.35 (s, 1 H, OH), 6.75 (m, 2 H, mHPh),
CHHCHCH3), 1.91 (s, 3 H, C6H4CH3), 3.61 (ddq, J = 3.3, 6.0, 7.78 (m, 2 H, oHPh) ppm. 13C NMR (100 MHz, C6D6): δ = –4.9,
12.1 Hz, 1 H, CHCH3), 3.88 (d, J = 9.6 Hz, 1 H, CHHOSO2), 4.07 –3.4 [Si(CH3)2], 17.8 [C(CH3)3], 21.1 (PhCH3), 25.0 (CHCH3), 25.9
3 H, CHCH3), 1.06 (dd, J = 11.0, 13.7 Hz, 1H [m, 2 H, CH2CH(OH)CH3], 1.88 (s, 3 H, CCH3), 3.90 (d, J =
3
J
=
1
(d, J = 9.6 Hz, 1 H, CHHOSO2), 6.80 (m, 2 H, CHarom.), 7.76 (m, [SiC(CH3)3], 26.6 (CCH3), 45.5 [CH(CH3)CH2], 67.6 (CHCH3),
2 H, CHarom.) ppm. 13C NMR (100 MHz, C6D6): δ = 21.1
(CH3Ph), 22.2 (CHCH3), 25.6 [C(CH3)CH3], 28.1 (CCH3), 31.7
70.8 [C(CH3)OH], 74.4 [C(CH3)CH2O], 127.9 (oCPh), 129.7
(mCPh), 133.5 (CPhCH3), 144.3 (SO2CPh) ppm. MS (EI, 70 eV):
[C(CH3)CH3], 38.3 [CH(CH3)CH2], 61.6 (CHCH3), 71.3 (CCH3), m/z (%) = 345 (3) [M+ – C(CH3)3], 301 (12), 231 (11), 230 (16), 229
73.6 [C(CH3)CH2O], 98.8 [C(CH3)CH3], 128.1 (oCPh), 129.7 (100), 217 (57), 174 (10), 173 (85), 159 (56), 155 (22), 129 (11), 119
(mCPh), 133.6 (CPhCH3), 144.4 (SO2CPh) ppm. MS (EI, 70 eV):
(29), 115 (12), 99 (15), 91 (24), 81 (14), 75 (50), 73 (21).
m/z (%) = 314 (13), 313 (92) [M+ – CH3], 157 (22), 156 (10), 155 C19H34O5SSi (402.62): calcd. C 56.68, H 8.51; found C 56.33, H
(95), 143 (100), 141 (11), 101 (34), 99 (54), 97 (26), 92 (11), 91 (55), 8.45.
85 (61), 81 (33), 65 (12), 59 (25). C16H24O5S (328.43): calcd. C
58.51, H 7.37; found C 58.86, H 7.22.
tert-Butyldimethyl[(R)-1-{[(S)-2-methyloxiran-2-yl]prop-2-yl}-
oxy]silane [(S,R)-3]: In a Schlenk flask under argon a 60% suspen-
(2S,4R)-2,4-Dihydroxy-2-methylpentyl Toluene-1-sulfonate [(S,R)-
14]: Tosylate (S,R)-5 (1.00 g, 3.0 mmol) was dissolved in methanol
(6.1 mL) at room temperature and aqueous 3 n HCl (6.07 mL⁾ was
added. After stirring for 30 min, the conversion was complete (TLC
monitoring). Then solid NaHCO3 was added until the aqueous
phase showed neutral conditions. The mixture was extracted with
Et2O (2×150 mL) and the combined organic layers were dried with
MgSO4. Removal of the solvent under reduced pressure and purifi-
cation of the crude product by column chromatography (silica gel,
sion of NaH in mineral oil (0.16 g, 4.1 mmol) was washed paraffin-
free with several portions of dry n-pentane. The residue was care-
fully dried in vacuo and the resulting colourless powder was purged
with argon. Then dry THF (40 mL) were added and the suspension
was cooled to 0 °C. The tertiary alcohol (S,R)-15 (0.41 g, 1.0 mmol)
was added dropwise and the suspension was stirred at this tempera-
ture for 2 h and then at room temperature overnight. After com-
plete conversion had been indicated by TLC monitoring, the sus-
pension was quenched with a pH 7 buffer. The aqueous layer was
Eur. J. Org. Chem. 2005, 2677–2683
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2681

D. Enders, I. Breuer, A. Nühring
FULL PAPER
extracted with Et2O and the combined organic layers were dried
with MgSO4. Removal of the solvent under reduced pressure af-
forded pure (S,R)-3 as a colourless oil. Yield: 0.23 g (99%). de Ն
in n-pentane (14.0 mL) at room temperature and aqueous 3 n HCl
(3.0 mL⁾ was added. The two-phase system was stirred until com-
plete conversion to the product had been indicated by TLC moni-
96% (13C NMR). ee Ն 98% (chiral GC, Chirasil-dex 25m, 1 bar toring (6 d). The aqueous phase was neutralized with satd. aqueous
H2). [α]2D4 = +0.3 (c = 1.21, CHCl3). ent-3: [α]2D6 = –0.3 (c = 1.89,
NaHCO3 solution, extracted with Et2O and the combined organic
layers were finally washed with a pH 7 buffer und dried with
MgSO4. The solvent was removed under reduced pressure and fur-
ther purification by column chromatography (silica gel, Et2O/n-
pentane, 1:10) gave sordidin (1) and 7-epi-sordidin (7-epi-1) as a
mixture with a ratio 1.5:1 as colourless oil. Yield: 0.23 g (84% over
two steps). The two epimers could be separated by preparative GC
CHCl ). IR (film): ν = 3038 cm–1 (w), 2932 (vs), 2858 (vs), 1467
˜
3
(s), 1379 (s), 1255 (vs), 1208 (w), 1139 (vs), 1108 (s), 1080 (s), 1056
(vs), 1003 (vs), 932 (s), 835 (vs), 808 (vs), 776 (vs), 720 (w), 658
(w), 516 (w). 1H NMR (400 MHz, C6D6): δ = 0.00, 0.02 [s, 6 H,
Si(CH3)2], 0.92 [s, 9 H, Si(CH3)2C(CH3)3], 1.04 (d, J = 6.0 Hz, 3
H, CHCH3), 1.17 (s, 3 H, CCH3), 1.45–1.51 [dd, J = 8.2, 14.0, 1 H,
CH(CH3)CHHC], 1.59 [ddd, J = 1.1, 4.4, 13.7 Hz, 1 H, CH(CH3) (Varian 1200, 2 m×2.06 mm i.d. pre-column, coverage: 20% CW-
CHHC], 2.31 (dd, J = 1.1, 5.2 Hz, 1 H, CHHO), 2.45 (d, J =
5.2 Hz, 1 H, CHHO), 3.79–3.87 (m, 1 H, CHCH3) ppm. 13C NMR
(100 MHz, C6D6): δ = –4.9, –4.3 [Si(CH3)2], 17.9 [Si(CH3)2C-
(CH3)3], 21.1 (CCH3), 24.4 (CHCH3), 25.8 [Si(CH3)2C(CH3)3], 47.1
20M, mesh 100/120, 3 m×2.06 mm i.d. main column, coverage:
20% CW-20M, mesh 60/80, steel columns, isotherm at 120 °C). IR
(CH Cl): ν = 2970 cm–1 (vs), 2934 (vs), 2878 (vs), 1458 (s), 1378
˜
3
(s), 1252 (w), 1196 (s), 1162 (m), 1136 (s), 1091 (w), 1036 (m), 1001
[CH(CH3)CH2], 54.0 [C(CH3)CH2O], 54.2 (CCH3), 66.3 (CHCH3) (m), 941 (s), 914 (w), 883 (w), 831 (w), 462 (w). (1S,3R,5R,7S)-(+)-
ppm. MS (EI, 70 eV): m/z (%) = 215 (3) [M+ – CH3], 174 (12), 173
sordidin (1): de Ն 99% (after preparative GC, according to GC
(90), 167 (10), 159 (26), 155 (23), 149 (24), 129 (73), 115 (16), 103
analysis). ee Ն 98% (based on determined ee of epoxide 3). [α]2D4
=
(28), 99 (15), 97 (12), 85 (16), 83 (11), 81 (13), 75 (100), 73 (42), 71 +25.1 (c = 0.94, Et2O); ref.[17]: [α]2D1 = +26.0 (c = 0.48, Et2O). H
1
(22), 69 (11), 57 (29), 55 (14). C12H26O2Si (230.42): calcd. C 62.55, NMR (400 MHz, C6D6): δ = 0.87 [d, J = 7.1 Hz, 3 H, CCH(CH3)],
H 11.37; found C 62.90, H 11.17.
0.93 [dd, J = 3.6, 12.6 Hz, 1 H, OCH(CH3)CHH], 0.97 [ddd, J =
1.6, 4.7, 12.4 Hz, 1 H, CCH(CH3)CHH], 1.14 [d, J = 6.1 Hz, 3 H,
OCH(CH3)CH2], 1.20 [s, 3 H, C(CH3)], 1.21 (t, J = 7.4 Hz, 3 H,
CH3CH2), 1.27 [dd, J = 12.6, 11.0 Hz, 1 H, OCH(CH3)CHH], 1.68
(dq, J = 7.4, 14.8 Hz, 1 H, CH3CHH), 1.79 [dd, J = 8.8, 12.4 Hz,
1 H, CCH(CH3)CHH], 1.88 (dq, J = 7.4, 13.7 Hz, 1 H, CH3CHH),
2.15 [m, 1 H, CCH(CH3)CH2], 3.72 [m, 1 H, OCH(CH3)CH2] ppm.
13C NMR (100 MHz, C6D6): δ = 8.4 (CH3CH2), 20.0 (CH3CHC),
22.3 (OCHCH3), 26.8 (CH3C), 27.9 (CH3CH2), 40.5 (CH3CHC),
44.2 [OCH(CH3)CH2], 45.0 [CCH(CH3)CH2C], 64.5 [OCH(CH3)
CH2], 78.3 [OC(CH3)], 108.4 (OCO) ppm. 7-epi-(1S,3R,5R,7R)-
(–)-Sordidin (7-epi-1): de Ն 97% (after preparative GC, according
to GC analysis). ee Ն 98% (based on determined ee of epoxide 3).
[α]2D4 = –6.9 (c = 1.11, Et2O). ref.[17]: [α]2D1 = –7.6 (c = 0.48, Et2O).
1H NMR (400 MHz, C6D6): δ = 0.98 [dd, J = 3.8, 12.6 Hz, 1 H,
OCH(CH3)CHH], 0.99 [d, J = 7.1, 3 H, CCH(CH3)CH2], 1.13 [d,
J = 6.0 Hz, 3 H, OCH(CH3)CH2], 1.15 (t, J = 7.5 Hz, 3 H,
CH3CH2), 1.17 [m, 1 H, CCH(CH3)CHH], 1.22 [s, 3 H, C(CH3)],
1.34 [dd, J = 12.1, 12.1 Hz, 1 H, OCH(CH3)CHH], 1.63 (dq, J =
7.4, 15.1 Hz, 1 H, CH3CHH), 1.75 [dd, J = 12.4, 13.5 Hz, 1 H,
CCH(CH3)CHH], 1.87 (dq, J = 7.4, 14.0 Hz, 1 H, CH3CHH), 2.08
[(S)-2-(1-Ethyl-1-methoxypropyl)pyrrolidin-1-yl](1-ethylpropylidene)-
amine [(S)-4]: A solution of pentan-3-one (2.80 g, 32.5 mmol) and
(2S)-(1-ethyl-1-methoxypropyl)pyrrolidine (4.66 g, 25.00 mmol) in
cyclohexane (70 mL) was refluxed for 3 h using a Dean–Stark trap.
Then the solvent was removed under reduced pressure and the
crude hydrazone was obtained as a brown oil. High-vacuum distil-
lation afforded (S)-4 as an orange oil. Yield: 5.76 g (91%); b.p.
125 °C/0.015 Torr. [α]2D7 = +366.9 (c = 1.46, CHCl3). IR (CH3Cl):
ν = 2968 cm–1 (vs), 2881 (vs), 2826 (s), 1629 (w), 1460 (s), 1376 (w),
˜
1120 (m), 1086 (s), 943 (w), 922 (w). 1H NMR (300 MHz,
C6D6): δ = 0.86–1.12 (m, 12 H, CH3CH2), 1.44–2.42 [m, 13 H,
(CH3CH2)2C=N, NCHC(CH2CH3)2, NCH2CH2, NCH2CH2CH2,
NCHcisHtrans], 2.96–3.06 (m, 1 H, NCHcisHtrans), 3.34 (s, 3 H,
OCH3), 3.75 (dd, J = 9.4, 7.2 Hz, 1 H, NCH) ppm. 13C NMR
(75 MHz, C6D6): δ = 7.9, 8.4, 10.4, 11.0 (CH3CH2), 23.8, 24.0, 24.3,
25.3, 27.3, 27.8 [(CH3CH2)2C=N, NCHC(CH2CH3)2, NCH2CH2,
NCH2CH2CH2], 49.9 (OCH3), 57.3 (NCH2), 72.0 (NCH), 79.6
[C(CH2CH3)2], 166.9 (C=N) ppm. MS (EI, 70 eV): m/z (%) = 255
(31) [M+ – 1], 254 (29), 253 (27), 225 (13), 224 (16), 223 (100), 153
(86). HRMS: calcd. 254.2358; found 254.2359.
[m, 1 H, CCH(CH3)CH2], 3.85 [m, 1 H, OCH(CH3)CH2] ppm. 13
C
(1S,3R,5R,7S)-(+)-Sordidin and 7-epi-(1S,3R,5R,7R)-(–)-Sordidin
(1 and 7-epi-1): LiCl (0.40 g, 8.8 mmol) was dehydrated in a
Schlenk flask at 120 °C in vacuo (0.1 Torr) for 20 min and sus-
pended in dry THF (14 mL). To the stirred suspension diisopro-
pylamine (2.3 mL, 16.0 mmol) was added. The suspension was co-
oled to –78 °C and nBuLi (6.4 mL, 16.0 mmol) was added by sy-
ringe using a pump. The suspension was allowed to warm to 0 °C
for 10 min, then it was cooled again to –78 °C and 3-pentanone
SAEP-hydrazone 4 (0.34 g, 13.4 mmol) diluted in dry THF (10 mL)
was added dropwise. The metalation reaction mixture was stirred
at this temperature for 1 h, then it was allowed to warm to 0 °C
for 10 min to be again cooled to –78 °C for adding the oxirane
(S,R)-3 (0.34 g, 1.46 mmol) diluted in dry THF (3 mL) through a
double-ended needle. The suspension was allowed to warm to room
temperature overnight and was quenched with a pH 7 buffer
(26 mL). The aqueous layer was extracted with Et2O, washed with
desalted water, satd. aqueous NaCl solution and the combined or-
ganic layers were dried with MgSO4. Removal of the solvent under
reduced pressure furnished the crude product 16 (plus excess of 4)
as a yellow oil, which was used in the next step without further
purification. The crude product of the former step was dissolved
NMR (100 MHz, C6D6): δ = 8.3 (CH3CH2), 12.9 (CH3CHC), 22.5
(OCHCH3), 26.7 (CH3C), 29.8 (CH3CH2), 41.6 (CH3CHC), 42.6
[OCH(CH3)CH2], 44.6 [CCH(CH3)CH2C], 65.5 [OCH(CH3)CH2],
78.3 [OC(CH3)], 107.4 (OCO) ppm. MS (EI, 70 eV): m/z (%) = 185
(0.2) [M+ + 1], 184 (4) [M+], 142 (20), 113 (27), 110 (12), 95 (100),
85 (11), 83 (29), 57 (66). HRMS: calcd. 184.1463; found 184.1463.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Graduiertenkolleg 440, Sonderforschungsbereich 380) and the
Fonds der Chemischen Industrie. We would like to thank Degussa
AG, BASF AG, Bayer AG and Wacker Chemie for donations of
chemicals. Further we would like to thank Dr. D. Belder, Max-
Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, for the
preparative GC separations.
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First Asymmetric Synthesis of (+)-Sordidin and (–)-7-epi-Sordidin
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Received February 10, 2005
Published Online: May 3, 2005
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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