Asymmetric synthesis of (+)-altholactone: A styryllactone isolated from various goniothalamus species

Article abstract of DOI:10.1002/chem.200701647

The asymmetric total synthesis of (+)-altholactone (1), a member of the styryllactone family of natural products displaying cytotoxic and antitumor activities, is described. Key steps include a RAMP-hydrazone a-alkylation (RAMP = (R)-1-amino-2-methoxymethylpyrrolidine) of 2,2-dimethyl-1,3-dioxan-5-one, a boron-mediated aldol reaction, a six- to five-membered ring acetonide shuffling, an oxidative 1,5-diol to δ-lactone conversion and a stereoselective ring-closure to generate the annulated tetrahydrofuran moiety with inversion of configuration.

Full text of DOI:10.1002/chem.200701647

DOI: 10.1002/chem.200701647
Asymmetric Synthesis of (+)-Altholactone: A Styryllactone Isolatedfrom
Various Goniothalamus Species
Dieter Enders* and Julien Barbion[a]
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Abstract: The asymmetric total synthesis of (+)-altholactone (1),a member of the
styryllactone family of natural products displaying cytotoxic and antitumor activi-
ties,is described. Key steps include a RAMP-hydrazone a-alkylation (RAMP=
(R)-1-amino-2-methoxymethylpyrrolidine) of 2,2-dimethyl-1,3-dioxan-5-one,
boron-mediated aldol reaction,a six- to five-membered ring acetonide shuffling,
an oxidative 1,5-diol to d-lactone conversion and a stereoselective ring-closure to
generate the annulated tetrahydrofuran moiety with inversion of configuration.
Keywords:
altholactone · asymmetric synthesis ·
hydrazones · natural products
aldol
reaction
·
a
Introduction
Trees and shrubs of the genus Goniothalamus growing in
South East Asia have long been known as a source of di-
verse secondary metabolites such as the styryllactones.
Many of these natural products show outstanding ranges of
biological activities and have been used in folk medicine.
(+)-Altholactone (1,Figure 1),a tetrahydrofurano-2-pyrone
of the styryllactone family of natural products,has been iso-
lated from an unnamed Polyalthia (Annonaceae) species[1]
and also from various members of the Goniothalamus
family.[2] This class of natural products shares a common 5,6-
dihydro-2H-pyran-2-one[3] structural unit,other members of
the group including acetoxygoniothalamine,goniodiol ( 2),
and goniotriol (3).[4] (+)-Altholactone (1) is known to be cy-
totoxic in vitro and shows in vivo antitumor activity.[2,5]
Because of the intriguing structures of the styryllactone
family and their broad range of important biological activi-
ties,many synthetic methods to synthesise this core struc-
ture have been employed.[6] Most syntheses are based on the
chiral pool concept,employing enantiopure starting materi-
Figure 1. Typical natural products of the styryllactone family.
als such as carbohydrates,[7] glyceraldehyde,[8] hydroxy
acids,[9] and amino acids.[10] Asymmetric syntheses[11] and
chemoenzymatic approaches[12] are rather rare.
Results andDiscussion
In continuation of our efforts to develop efficient asymmet-
ric syntheses of natural products and biologically active
compounds[13] based on 2,2-dimethyl-1,3-dioxan-5-one
(4)[14,15] by the SAMP/RAMP hydrazone methodology,[16] we
now wish to report a new and efficient asymmetric synthesis
of (+)-altholactone (1). As is depicted in Scheme 1,this tet-
rahydrofurano-2-pyrone structure can retrosynthetically be
traced back to the dioxanone 4,benzaldehyde and a protect-
ed 3-bromopropanol.
The commercially available and easy to prepare dioxa-
none 4 was first converted into the corresponding RAMP-
hydrazone 5 (Scheme 2) in 90% yield by treatment with the
chiral hydrazine auxiliary (R)-1-amino-2-methoxymethylpyr-
rolidine (RAMP). After metallation with tert-butyllithium
[a] Prof. Dr. D. Enders,Dr. J. Barbion
Institute of Organic Chemistry,RWTH Aachen
Landoltweg 1,52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: Enders@RWTH-Aachen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
2842
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Chem. Eur. J. 2008, 14,2842 – 2849

FULL PAPER
and benzaldehyde,we switched to the boron-mediated aldol
variant,[20] which afforded the desired anti-aldol 7 in 68%
yield and with excellent diastereoselectivity (de > 98%) as
1
determined by H and 13C NMR spectroscopy. As had been
hoped,the relative configuration between C-6 and C-4 (see
altholactone numbering) also turned out to be anti,as was
easily determined by 13C NMR[21] from the acetonide methyl
group chemical shifts (d=23.5 and 23.6 ppm). Gratifyingly,
our strategy to control the relative and absolute configura-
tions of the remaining stereocentres diastereoselectively
through the first one created with the highly reliable SAMP/
RAMP-hydrazone methodology had worked out.
Scheme 1. Retrosynthetic analysis of (+)-altholactone (1).
Because of the sensitivity of the aldol addition product 7
and in order to achieve a high diastereoselectivity in the
subsequent reduction step,it was necessary to protect the
hydroxy group as the corresponding tert-butyldimethylsilyl
(TBS) ether 8 under standard conditions (90% yield). Selec-
tive reduction of the ketone function with L-selectride af-
forded the alcohol 9 in 88% yield and with an excellent dia-
stereoselectivity of de >96%,as determined by 1H NMR
and 13C NMR spectroscopy,in favour of the anti relative
configuration with respect to centre C-7 (Scheme 2).
In our synthetic strategy we had to discriminate between
the several secondary alcohol groups in a specific way in-
cluding an acetonide shuffling. Thus,benzylation of alcohol
9 yielded the corresponding dibenzyl ether 10 in 90% yield,
and subsequent removal of the TBS protecting group with
tetra-n-butylammonium fluoride (TBAF) gave the alcohol
11 (Scheme 3) in 95% yield. Treatment of the alcohol aceto-
nide 11 under equilibrating acidic conditions furnished a
readily separable mixture of the five-membered ring acetal
acetonide 12 and starting material. The acetonide 12 was
protected as the corresponding TBS ether 13 in 99% yield,
whereas acetonide 11 was recycled. Simultaneous double de-
benzylation of 13 under standard hydrogenolysis conditions
over 10% palladium on carbon provided a 99% yield of the
diol 14 (Scheme 3),which was used in an oxidation/in situ
cyclisation sequence with 2-iodoxybenzoic acid (IBX)[22] to
afford the corresponding lactol. This was oxidised to the d-
lactone 15 (Scheme 4) with tetra-n-propylammonium per-
ruthenate (TPAP)/N-methylmorpholine N-oxide (NMO)[23]
in 77% yield over two steps. A exploratory attempt to reach
lactone 15 in one step from diol 14 with use of TPAP/NMO
had initially been envisaged,but the reaction gave the corre-
sponding aldehyde without any observed cyclisation.
Scheme 2. a) RAMP,benzene,reflux (90%); b) 1) tBuLi,THF, ꢀ788C;
2) Br
A
steps); d) Cy2BCl,Et 3N,Et 2O, ꢀ788C,then H 2O2,MeOH,pH 7 buffer,
RT (68%); e) TBSOTf,26,-lutidine,CH 2Cl2,RT (90%); f) L-selectride,
THF, ꢀ788C (88%); g) BnBr,KH,THF,RT (90%). Tf =trifluorometha-
nesulfonyl.
and trapping of the aza-enolate with 3-benzyloxy-1-bromo-
propane at low temperature,the resulting a-alkylated hydra-
zone was hydrolysed[17] with a saturated aqueous solution of
oxalic acid. The alkylated dioxanone 6 was obtained after
purification by flash chromatography in 82% yield over the
two steps and with an excellent enantiomeric excess (ee) of
>98% as determined by chiral stationary phase GC.
We had next envisaged the use of our organocatalytic
C3+Cn biomimetic strategy[18] for carbohydrate synthesis in a
proline-catalysed anti-selective aldol reaction to form 7
from the dioxanone 4.[19] Because no satisfying results in
terms of yield and stereoselectivity could be obtained in this
special case of an organocatalytic aldol reaction between 6
Abstract in German: Die asymmetrische Totalsynthese von
(+)-Altholacton (1), einem Mitglied der Styryllacton-Familie
von Naturstoffen mit cytotoxischen und antitumor-Aktivität-
en, wird beschrieben. Unter den Schlüsselschritten sind eine
RAMP-Hydrazon-a-Alkylierung (RAMP=(R)-1-Amino-2-
methoxymethylpyrrolidin) von 2,2-Dimethyl-1,3-dioxan-5-on,
eine Bor-unterstützte Aldol-Reaktion, eine Sechs- zu Fünfring
Acetonid-Verschiebung, eine oxidative 1,5-Diol zu d-Lacton-
Überführung und ein stereoselektiver Ringschluß zur Gener-
ierung der annulierten Tetrahydrofuran-Gruppierung unter
Inversion der Konfiguration.
Scheme 3. a) TBAF,THF,RT (95%); b) 1. p-TsOH (cat.),acetone,RT.
2. 0.25 equiv 2,2-DMP, PPTS (cat.) [12 (36%), 11 (59%)]; c) TBSOTf,
2,6-lutidine, CH2Cl2,RT (99%); d) H 2,10% Pd/C,EtOAc,RT (99%).
TsOH=p-toluenesulfonic
acid.
2,2-DMP=2,2-dimethoxypropane.
PPTS=pyridinium p-toluenesulfonate.
Chem. Eur. J. 2008, 14,2842 – 2849
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
2843

D. Enders and J. Barbion
The introduction of the a,b-double bond into the d-lac-
tone 15 was achieved through an a-selenylation/elimination
sequence[24] with PhSeCl and H2O2,which provided 16 in
86% yield over two steps (calculated on the recovered start-
ing material).
tosyl group in 18 should give rise to (+)-goniotriol (3) and
(+)-goniodiol (2),respectively. These reactions are currently
under investigation in our laboratories.
In order to construct the tetrahydrofuran ring of the
target molecule through a ring-closure,the TBS protecting
group was removed with tetrabutylammonium fluoride in
74% yield to afford the alcohol 17,which was transformed
into the corresponding tosylate 18 in 95% yield. Removal of
the acetonide protecting group under acidic conditions with
Amberlyst 15[25] and simultaneous ring-closure with com-
plete inversion of configuration led to the target molecule
(+)-altholactone (1) in 93% yield (Scheme 4).
Experimental Section
Solvents were purified and dried prior to use. Tetrahydrofuran (THF)
and diethyl ether were freshly distilled over sodium and under argon. Di-
chloromethane,dimethyl sulfoxide (DMSO) and triethylamine were dis-
tilled over calcium hydride and stored under argon. Acetone was distilled
over P4O10 and stored under argon. Methanol was distilled over magnesi-
um. Diethyl ether,pentane and ethyl acetate were distilled over KOH,
CaH2 and K2CO3,respectively,prior to use. Analytical glass-backed TLC
plates (silica gel 60 F254) and silica gel (60,40–63 mm) were purchased
from Merck,Darmstadt. Reagents of commercial quality were used from
freshly opened containers unless otherwise stated. Optical rotations were
measured on a Perkin–Elmer P241 polarimeter and with solvents of
Merck UVASOL quality. Microanalyses were performed with a Heraeus
CHN-O-RAPID,Vario EL elemental analyser. 1H and 13C NMR spectra
were obtained on Varian VXR 300,Gemini 300 (both 300 and 75 MHz),
Varian Inova 400 (400 MHz and 100 MHz) or Varian Unity 500 (500 and
125 MHz) instruments with TMS as the internal standard. IR spectra
were recorded on a Perkin–Elmer 1760 FT/IR spectrometer. Mass spec-
troscopic analyses were obtained on a Varian MAT 212 (EI,70 eV,
1 mA) and a Finnigan MAT SSQ 7000 (CI,100 eV) instrument (relative
intensities are reported in brackets). High-resolution mass spectra were
recorded on a Finnigan MAT 95 machine. Melting points were measured
with a Büchi 510 apparatus and are uncorrected. 13C NMR spectra of all
compounds for which only HRMS data are given below are shown in the
Supporting Information (compounds 7, 12, 14, 16, 17, 18 and 1).
Scheme 4. a) IBX (2.2 equiv),DMSO,RT; b) TPAP (5 mol%)/NMO
(1.5 equiv),CH 2Cl2,RT (77% over two steps); c) LDA,PhSeCl,THF,
ꢀ788C; d) 30% H2O2,CH 2Cl2, 08C [16 (60%) and 15 (31%) over two
(R)-(ꢀ)-1-(2,2-Dimethyl-1,3-dioxan-5-ylidenamino)-2-methoxymethylpyr-
rolidine (5): In a flask fitted with a Dean–Stark trap and a reflux con-
denser,dioxanone 4 (8.45 g,64.93 mmol,1.0 equiv) and ( R)-1-amino-2-
methoxymethylpyrrolidine (8.48 g,65.14 mmol,1.0 equiv) in benzene
(80 mL) were heated at reflux for 20 h. After the system had cooled,
Et2O (200 mL) was added and the mixture was washed with H2O (2”
10 mL). The organic layer was dried (MgSO4),and the solvent was re-
moved under reduced pressure. The crude hydrazone was purified by dis-
tillation under reduced pressure to give RAMP-hydrazone 5 as a yellow
oil (14.16 g,90%). B.p. 106–109 8C (1 mbar); [a]2D3 =ꢀ230.0 (neat) and
ꢀ307.74 (c=1,CHCl 3); 1H NMR (300 MHz,CDCl 3): d=4.21–4.58 (m,
4H; CH2CN),3.35 (s,3H; OC H3),3.04–3.46 (m,4H; NC HH,NC H,
steps]; e) TBAF,THF,RT (74%); f) TsCl,DMAP,CH
2Cl2,RT (95%);
g) Amberlyst 15,MeOH,RT (93%). DMAP =4-(dimethylamino)pyri-
dine.
Conclusion
In summary,an efficient highly diastereo- and enantioselec-
tive synthesis of (+)-altholactone (1) in eighteen steps and
13.7% overall yield from the commercially available starting
dioxanone 4 has been achieved. The first key step of the
asymmetric synthesis is a RAMP-hydrazone a-alkylation of
the dihydroxy acetone C3-building block 4,which generates
the first stereocentre with virtually complete asymmetric in-
duction (ee > 98%),subsequently allowing the remaining
three stereogenic centres to be diastereoselectively con-
trolled. This was accomplished by a boron-mediated anti-se-
lective aldol reaction,a ketone reduction with L-selectride,
and a tetrahydrofuran ring-closure with complete inversion
of configuration under acidic conditions. Our new route to
the styryllactone family is flexible in terms both of stereose-
lectivity and of structural variations for further bioactivity
screening. For instance,the enantiomer ( ꢀ)-altholactone
should be available simply by replacing the chiral auxiliary
RAMP by its enantiomer SAMP in the first key step of the
synthesis,and the aldehyde component of the aldol reaction
may be varied. In addition,a Mitsunobu inversion of our in-
termediate alcohol 17 and a hydride displacement of the
CH2OCH3),2.50 (q, 3J
NCHCHHCH2),1.80–1.89 (m,2H; NCH 2CHH,NCHCH HCH2),1.60–
1.71 (m,1H; NCH 2CHH),1.43 [s,3H; C (CH3)],1.40 ppm (s,3H; C-
(CH3)); 13C NMR (75 MHz,CDCl ): d=160.0 (CN),99.9 [ C
(CH3)2],75.4
(CH2OCH3),66.6 (N CH),62.6 ( CH2CN),60.3 ( CH2CN),59.2 (O CH3),
55.4 (NCH2),26.7 (NHCH CH2CH2),24.5 [C (CH3)],23.2 [C (CH3)],
G
G
22.7 ppm (NCH2CH2); IR (film): n˜ =2982,2937,2874,1451,1376,1221,
1150,1094,1068,836 cm ꢀ1; MS (100 eV,CI): m/z (%): 243 (100) [M+H]+,
242 (19),211 (8)
[
M+HꢀCH3OH]+,197 (19),185 (52)
[
M+Hꢀ
(CH3)2CO]+; elemental analysis (%) calcd for C12H22N2O3 (242.31): C
59.48,H 9.15,N 11.56; found: C 59.47,H 9.36,N 11.34.
(R)-(+)-4-(3-Benzyloxypropyl)-2,2-dimethyl-1,3-dioxan-5-one (6): A dry,
argon-flushed 500 mL Schlenk round-bottomed flask containing a mag-
netic stirring bar was charged with RAMP-hydrazone
5 (4.88 g,
20.14 mmol,1.0 equiv) and anhydrous THF (80 mL). tBuLi (14.9 mL,
15% in n-pentane,22.15 mmol,1.1 equiv) was then added dropwise at
ꢀ788C. After stirring for 2 h at this temperature,the mixture was cooled
to ꢀ1008C and 1-benzyloxy-3-bromopropane (5.55 g,22.15 mmol,
1.1 equiv) in anhydrous THF (4 mL) was slowly added. After further stir-
ring for 2 h at ꢀ1008C,the mixture was allowed to warm up to room
temperature over 15 h. The mixture was quenched with buffer solution
(pH 7,4 mL) and then diluted with Et 2O (80 mL). The organic layer was
washed with buffer solution (pH 7,20 mL) and brine (2”20 mL). The
combined organic layers were dried (MgSO4) and concentrated under re-
2844
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2008, 14,2842 – 2849

Asymmetric Synthesis of (+)-Altholactone
FULL PAPER
duced pressure. A solution of the resulting crude hydrazone in Et2O
(100 mL) was vigorously stirred at room temperature with a saturated
aqueous solution of oxalic acid (80 mL) for 20 h. The aqueous layer was
separated and extracted with Et2O,and the organic extracts were com-
bined,washed with brine (40 mL),dried (MgSO 4) and concentrated
under reduced pressure. The crude product was purified by flash chroma-
tography (silica gel,PE/Et 2O 80:20) to afford the alkylated product 6
(4.60 g,82% over two steps) as a colourless liquid. [ a]2D3 =+150.96 (c=1,
The stirring was continued for 3–4 h at room temperature (TLC monitor-
ing),after which the reaction was quenched with aqueous NH Cl solution
4
(10 mL). The mixture was poured into aqueous NH4Cl solution (20 mL)
and extracted with CH2Cl2 (30 mL). The aqueous phase was diluted with
H2O (20 mL) and extracted with CH2Cl2 (2”10 mL). The combined or-
ganic layers were dried (MgSO4),filtered and concentrated under re-
duced pressure to give the crude product as a colourless syrup. Purifica-
tion by flash chromatography on silica gel (PE/Et2O 90:10) gave the
CHCl3); ee=98% (CSP-GC,Lipodex G,25 m”0.25 mm);
(300 MHz,CDCl 3): d=7.25–7.34 (m,5H; Ar- H),4.50 (s,2H; C H2Ph),
4.24 (ddd, 3J(H,H)=8.4,4.2,1.5 Hz,1H; C HCH2),4.24 [dd, 3J
(H,H)=
(H,H)=17.1 Hz,1H;
(H,H)=6.4,1.2 Hz,2H; C H2OCH2),1.93–2.03
1H NMR
TBS-protected product 8 (463 mg,90%) as a colourless oil. [ a]D23
+65.76 (c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=7.41–7.52 (m,
10H; Ar-H),5.28 [d, 3J
(H,H)=3.3 Hz,1H; PhC H(OSi)],4.65 (s,2H;
CH2Ph),4.56 [dd, 3J
(H,H)=3.3,1.1 Hz,1H; C(O)C HCH(OSi)],4.13
(ddd, 3J(H,H)=8.2,4.1,1.1 Hz,1H; C HCH2),3.62 (t, 3J
(H,H)=6.3 Hz,
2H; CH2OCH2),2.00–2.09 (m,1H; CHC HH),1.77–1.94 (m,2H;
CH2CH2CH2),1.64–1.75 (m,1H; CHCH H),1.54 [s,3H; C (CH3)],1.52 [s,
3H; C(CH3)],1.06 [s,9H; SiC (CH3)3],0.26 [s,3H; Si
(CH3)], ꢀ0.09 ppm
[s,3H; Si
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=207.7 [C(O)],140.3,
138.5 (Ar-C),128.3,127.6,127.6,127.5,127.3 (Ar- CH),101.0 [ C(CH3)2],
79.1 [C(O)CHCH(OSi)],74.1 [2C; CHCH2,Ph CH(OSi)],72.9
(OCH2Ph),69.9 (CH 2CH2CH2),25.7 [SiC (CH3)3],25.4 (CH 2CH2CH2),
25.0 (CHCH2),24.2 [C (CH3)],23.9 [C (CH3)],18.2 [Si C
(CH3)3], ꢀ5.0,
(CH3)2]; IR (film): n˜ =3746,3673,2985,2932,2857,2362,
=
A
N
A
ACHTREUNG
17.1,1.5 Hz,1H; C(O)C
HHO],3.97 [d,
3J
G
A
ACHTREUNG
C(O)CHHO],3.49 (td, 3J
N
A
ACHTREUNG
(m,1H; CHC HH),1.68–1.83 (m,2H; CH 2CH2CH2),1.57–1.65 (m,1H;
CHCHH),1.42 ppm [s,6H; C
(CH3)2]; 13C NMR (75 MHz,CDCl 3): d=
209.6 [C(O)],138.5 (Ar- C),128.4,127.7,127.6 (Ar- CH),100.8 [ C(CH3)2],
74.4 (CH),72.9 (O CH2Ph),69.9 [C(O) CH2O],66.6 (CH 2CH2CH2),25.4
(CHCH2),25.3 (CH 2CH2CH2),24.0 [C (CH3)],23.6 ppm [C (CH3)]; IR
=O),1453,1376,
T
ACHTREUNG
U
A
N
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
(film): n˜ =3030,2987,2936,2860,2361,2335,1746 (C
A
ACHTREUNG
ꢀ1
1225,1176,1104,740,700 cm
(C6H5); MS (100 eV,CI): m/z (%): 279
ACHTREUNG
(2.6) [M+H]+,261 (20) [ M+HꢀH2O]+,221 (66) [ M+Hꢀ
A
A
N
ACHTREUNG
203 (71) [M+HꢀH2Oꢀ
(CH3)2CO]+,171 (69),129 (10),113 (41),91 (100)
ꢀ4.8 ppm [Si
ACHTREUNG
[C7H7]+,71 (14); elemental analysis (%) calcd for C 16H22O4 (278.34): C
69.04,H 7.97; found: C 68.81,H 7.96.
2336,1747 (C =O),1652,1559,1541,1456,1376,1252,1225,1171,1101,
1070,838,779,738,700 (C 6H5),669 cm ꢀ1; MS (100 eV,CI): m/z (%): 499
(3.0) [M+H]+,481 (4) [ M+HꢀH2O]+,441 (1) [ M+Hꢀ
A
A
N
(10),383 (9),367 (16),309 (9),277 (7),222 (20),221 (100),91 (4) [C
7H7
dimethyl-1,3-dioxan-5-one (7): Et3N (1.7 mL,12.09 mmol,1.7 equiv) was
added by syringe at ꢀ788C to a stirred solution of dicyclohexylboryl
chloride (10.7 mL,10.67 mmol,1.5 equiv) in Et 2O (70 mL),followed
]; elemental analysis (%) calcd for C29H42O5Si (498.73): C 69.84,H 8.49;
found: C 69.89,H 8.56.
10 min later by slow addition of
a
solution of ketone
6
(1.98 g,
ACHTREUNG
7.11 mmol,1.0 equiv) in Et 2O (15 mL). Stirring was continued for an ad-
ditional 30 min at ꢀ788C,after which the mixture was allowed to warm
to 08C and stirred for 1 h. The resulting suspension was cooled to
ꢀ788C,after which a solution of freshly distilled benzaldehyde (1.1 mL,
ACHTREUNG
in THF,5.2 mL,5.20 mmol,1.5 equiv) was added dropwise at ꢀ788C to a
stirred solution of the TBS-protected aldol adduct 8 (1.73 g,3.47 mmol,
1.0 equiv) in absolute THF (35 mL). The stirring was continued for 5 h at
this temperature,after which the reaction was quenched with aqueous
NH4Cl solution (20 mL). The mixture was poured into aqueous NH4Cl
solution (30 mL) and extracted with Et2O (30 mL). The aqueous portion
was diluted with H2O (30 mL) and extracted with Et2O (3”20 mL). The
combined organic layers were dried (MgSO4),filtered and concentrated
under reduced pressure to afford the crude product as a yellow liquid.
Purification by flash chromatography on silica gel (PE/Et2O 80:20) gave
alcohol 9 (1.53 g,88%) as a colourless oil. [ a]2D3 =ꢀ73.20 (c=1,CHCl 3);
1H NMR (500 MHz,CDCl 3): d=7.56–7.70 (m,10H; Ar-C H),5.26 [d,
10.67 mmol,1.5 equiv) in Et O (20 mL) was added dropwise. Stirring was
2
continued for 1 h at ꢀ788C,after which the flask was sealed and placed
in a freezer (ꢀ248C) for 20 h. The mixture was quenched with phosphate
buffer (pH 7,140 mL) and extracted with Et 2O (280 mL). The combined
organic extracts were concentrated under reduced pressure,and the resi-
due was dissolved in a mixture of phosphate buffer (pH 7) and MeOH
(1:1,86 mL) and cooled to 0 8C,after which aqueous hydrogen peroxide
(H2O2,30% in H 2O,22.0 mL) was added dropwise. The mixture was
stirred at room temperature for 2 h,poured into phosphate buffer (pH 7,
140 mL) and extracted with CH2Cl2 (560 mL). The combined organic ex-
tracts were dried (Na2SO4),filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography (silica
gel,PE/Et 2O 70:30) to afford aldol 7 (1.86 g,68%) as a pale yellow oil.
[a]2D3 =+76.02 (c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=7.23–7.37
3J
3J
G
ACHTREUNG
N
U
ACHTREUNG
6.9 Hz,2H; C H2OCH2),3.99 (d, 3J
ACHTREUNG
3J
A
ACHTREUNG
(m,10H; Ar- H),4.86 [d, 3J
(H,H)=1.6 Hz,2H; H2Ph),4.29 [dd,
C(O)CHCH(OH)],4.09 (ddd, 3J
(H,H)=8.2,4.1,1.4 Hz,1H; C HCH2),
3.76 (s,1H; O H),3.43 (td, 3J
(H,H)=6.3,1.6 Hz,2H; C H2OCH2),1.87–
G
N
ACHTREUNG
A
C
A
N
A
ACHTREUNG
AHCTREUNG
E
N
ACHTREUNG
1.97 (m,1H; CHC HH),1.66–1.75 (m,2H; CH 2CH2CH2),1.56–1.65 (m,
1H; CHCHH),1.30 (s,3H; C H3),1.21 ppm (s,3H; C H3); 13C NMR
(100 MHz,CDCl 3): d=212.1 [C(O)],139.2,138.2 (Ar- C),128.1,127.7,
ACHTREUNG
ACHTREUNG
G
G
ACHTREUNG
127.7,127.4,127.3,127.0 (Ar- CH),101.2 [ C
74.1 (CHCH2),72.7 (O CH2Ph),72.6 [C(O) CHCH(OH)],69.6
(CH2CH2CH2),25.5 (CH CH2),25.2 (CH 2CH2CH2),23.6 [C (CH3)],
23.5 ppm [C(CH3)]; IR (film): n˜ =3474 (br,OH),3031,2986,2930,2861,
2360,1737 (C =O),1497,1453,1378,1226,1171,1104,900,747,700 cm
C
ACHTREUNG
1067,996,838,780,736,699 (C
6H5),669 cm ꢀ1; MS (100 eV,CI): m/z (%):
E
501 (4.8) [M+H]+,409 (11)
[
M+HꢀC7H8]+,367 (11),351 (28)
[M+HꢀC7H8ꢀ
(CH3)2CO]+,312 (10),311 (56),294 (20),293 (100),221
(C6H5); MS (100 eV,CI):
(41),207 (10),203 (49),191 (28),181 (12),179 (25),91 (20) [C
7H7]+,71
[M+HꢀH2O]+,309 (22) [ M+HꢀH2Oꢀ
(CH3)2CO]+,305 (13),261 (26),
(18); elemental analysis (%) calcd for C29H44O5Si (500.74): C 69.56,H
8.86; found: C 69.31,H 9.17.
61 (18); HRMS: m/z: calcd for C20H22O4 [Mꢀ
A
AHCTREUNG
found: 326.1518.
A
ACHTREUNG
A
of the alcohol 9 (695 mg,1.39 mmol,1.0 equiv) in absolute THF (10 mL)
was added dropwise at 08C to a stirred solution of potassium hydride
(30% in mineral oil,557 mg,4.16 mmol,3.0 equiv),previously washed
with distilled cyclohexane,in THF (4 mL). Stirring at this temperature
was continued for 30 min,after which freshly distilled benzyl bromide
ACHTREUNG
3.10 mmol,3.0 equiv) was added at 0 8C to a stirred solution of the hy-
droxy ketone 7 (397 mg,1.03 mmol,1.0 equiv) in CH 2Cl2 (10 mL),fol-
lowed by dropwise addition of TBSOTf (360 mL,1.5 mmol,1.55 equiv).
Chem. Eur. J. 2008, 14,2842 – 2849
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
2845

(660 mL,5.55 mmol,4.0 equiv) was added dropwise. The stirring was con-
tinued overnight at room temperature,after which the reaction was
quenched with H2O (30 mL). The mixture was poured into H2O (20 mL)
and extracted with Et2O (50 mL). The aqueous portion was extracted
with Et2O (3”20 mL). The combined organic layers were washed with
brine (20 mL),dried (MgSO 4),filtered and concentrated under reduced
pressure to give the crude product as a yellow liquid. Purification by
flash chromatography on silica gel (PE/Et2O 90:10) gave the benzyl-pro-
tected product 10 (738 mg,90%) as a colourless oil. [ a]2D2 =ꢀ1.65 (c=1,
CHCl3); 1H NMR (400 MHz,CDCl 3): d=7.42–7.62 (m,15H; Ar-C H),
ACHTREUNG
D. Enders and J. Barbion
5.11 [d, 3J
1H; CHOCHHPh),4.83 (d, 3J
(s,2H; CH 2OCH2Ph),4.11 [dd, 3J
3.98 (dd, 3J(H,H)=5.0,3.3 Hz,1H; C HCH2),3.96 (dd, 3J
2.2 Hz,1H; CHC HOCH2Ph),3.64 (t, 3J
(H,H)=6.3 Hz,2H; C H2OCH2),
1.95–2.02 (m,1H; CH 2CHHCH2),1.77–1.87 (m,3H; CH 2CHHCH2,
CHCH2),1.45 [s,3H; C (CH3)],1.08 [s,3H; C (CH3)],1.05 [s,9H; SiC-
(CH3)3],0.18 [s,3H; Si
(CH3)], ꢀ0.25 ppm [s,3H; Si
(CH3)]; 13C NMR
(100 MHz,CDCl 3): d=142.8,139.0,138.6 (Ar- C),128.3,128.2,128.1,
128.0,127.9,127.7,127.6,127.5,127.4,127.4,127.4 (Ar- CH),100.7 [ C-
(CH3)2],80.7 ( CHCH2),74.8 [ CHCH(OSi)],73.9 ( CHOCH2Ph),72.9
(CH2OCH2Ph),72.7 (CHO CH2Ph),72.4 [ CH(OSi)],70.0 ( CH2OCH2),
31.8 (CHCH2),26.1 (CH CH2CH2),26.1 [SiC (CH3)3],25.0 [C (CH3)],23.6
(CH3)2]; IR (film): n˜ =
A
G
A
AHCTREUNG
A
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
7.15–7.28 (m,15H; Ar-C H),5.17 (d, 3J
(dd, 3J
(H,H)=6.9,4.1 Hz,1H; C HCHPh),4.42 (s,2H; CH 2OCH2Ph),
4.24 (d, 3J 3J
(H,H)=11.3 Hz,1H; CHOC HHPh),3.85 (d, (H,H)=
11.3 Hz,1H; CHOCH HPh),3.44 (dd, (H,H)=5.7,4.1 Hz,1H;
3J
CHCH2),3.39 (td, 3J
(H,H)=5.4,1.9 Hz,2H; C H2OCH2Ph),2.96 (t,
3J(H,H)=4.1 Hz,1H; C HOCH2Ph),2.77 (d, 3J
(H,H)=6.4 Hz,1H; O H),
1.65–1.72 (m,1H; CH 2CHHCH2),1.59 [s,3H; C (CH3)],1.45–1.54 (m,
2H; CHCHH,CH 2CHHCH2),1.40–1.43 (m,1H; CHCH H),1.40 ppm [s,
3H; C
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=138.6,138.3,137.7 (Ar-
C),128.4,128.2,128.1,127.7,127.7,127.6,127.5,127.3,127.1 (Ar- CH),
109.2 [C(CH3)2],79.4 (C HOCH2Ph),79.3 (PhCHC H),79.2 (PhC H),73.0
(CH2OCH2Ph),72.1 (CHO CH2Ph),70.9 ( CHCH2),70.3 ( CH2OCH2),
30.4 (CH2CH2CH2),26.7 [C (CH3)],26.5 (CH CH2),25.4 ppm [C (CH3)];
(H,H)=6.9 Hz,1H; PhC H),4.58
A
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
AHCTREUNG
A
ACHTREUNG
2
[C
A
G
ACHTREUNG
AHCTREUNG
3031,2988,2930,2857,1456,1372,1249,1222,1093,1030,839,758,
699 cmꢀ1 (C6H5); MS (100 eV,CI): m/z (%): 591 (5.0) [M+H]+,575 (11),
AHCTREUNG
533 (7) [M+Hꢀ
[
M+Hꢀ
(CH3)2COꢀH2O]+,459 (10),425 (15) [ M+Hꢀ
A
ACHTREUNG
409 (14),407 (11),402 (12),401 (42),383 (36),367 (13),351 (24),319
(12),317 (13),301 (13),297 (35),295 (11),294 (17),293 (69),277 (21),
251 (29),249 (11),233 (12),222 (20),221 (100),215 (11),203 (14),191
IR (film): n˜ =3428 (br,OH),3061,3031,2928,2863,1495,1454,1374,
ꢀ1
1248,1217,1094,880,741,701 cm
(C6H5); MS (100 eV,CI): m/z (%):
477 (1.0) [M+H]+,459 (2) [ M+HꢀH2O]+,420 (30),419 (100) [ M+Hꢀ
(34),181 (33),173 (13),161 (14),91 (52) [C
(CH3)2CO]+,383 (5),311 (16),309 (12),299 (25),293 (38) [
M+Hꢀ
analysis (%) calcd for C36H50O5Si (590.86): C 73.18,H 8.53; found: C
73.39,H 8.72.
(CH3)2COꢀPhCH2OHꢀH2O]+,203 (23),192 (13),191 (99),181 (44),179
(50) [M+Hꢀ2H2Oꢀ
(CH3)2COꢀ2PhCH2OH]+,119 (24),107 (14),101
A
(21),91 (78) [C 7H7]+,71 (43); HRMS:
m/z: calcd for C19H22O3
ACHTREUNG
ACHTREUNG
[MꢀC11H14O2]: 298.1569; found: 298.1570.
fluoride (TBAF,1.0 m in THF,7.1 mL,7.11 mmol,2.0 equiv) was added
dropwise at 08C to a stirred solution of 10 (2.10 g,3.55 mmol,1.0 equiv)
in absolute THF (40 mL). Stirring was continued at room temperature
A
2,2-dimethyl-5-phenyl-1,3-dioxolan-4-yl]-pentane
(13):
2,6-Lutidine
(120 mL,1.03 mmol,3.0 equiv) was added at 0 8C to a stirred solution of
alcohol 12 (163 mg,0.34 mmol,1.0 equiv) in CH 2Cl2 (5 mL),followed by
slow addition of TBSOTf (120 mL,0.51 mmol,1.5 equiv). The stirring was
continued for 2 h at room temperature,after which the reaction was
quenched with aqueous NH4Cl solution (10 mL). The mixture was
poured into aqueous NH4Cl solution (10 mL) and extracted with CH2Cl2
(20 mL). The aqueous portion was extracted with CH2Cl2 (2”10 mL),
and the combined organic extracts were dried (MgSO4),filtered and con-
centrated under reduced pressure to give the crude product as a colour-
less syrup. Purification by flash chromatography on silica gel (PE/Et2O
80:20) gave the TBS-protected product 13 (200 mg,99%) as a colourless
oil. [a]2D2 =ꢀ 276.26 (c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=
overnight,after which the reaction was quenched with H O (30 mL). The
mixture was poured into H2O (20 mL) and diluted with Et2O (20 mL).
The aqueous phase was extracted with Et2O (3”20 mL),and the com-
2
bined organic layers were washed with brine (30 mL),dried (Na SO4),fil-
2
tered and concentrated under reduced pressure to give the crude product
as a pale brown syrup. Purification by flash chromatography on silica gel
(PE/Et2O 70:30) gave the alcohol 11 (1.60 g,95%) as a colourless oil.
[a]2D3 =ꢀ9.78 (c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=7.20–7.37
(m,15H; Ar-C H),4.90 [dd, 3J
ACHTREUNG
(d, 3J
A
ACHTREUNG
AHCTREUNG
7.45–7.62 (m,15H; Ar-C H),5.34 (d, 3J
ACHTREUNG
AHCTREUNG
3
A
ACHTREUNG
(d, J
G
ACHTREUNG
1H; PhCHCH),4.73 (s,2H; CH 2OCH2Ph),4.37 (d, 3J
1H; CHOCHHPh),3.77 (dd, 3J
(td, 3J
AHCTREUNG
AHCTREUNG
AHCTREUNG
ACHTREUNG
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
[
C
A
(
[
A
ACHTREUNG
AHCTREUNG
AHCTREUNG
ACHTREUNG
ACHTREUNG
1375,1220,1170,1093,910,736,700 (C
6H5),616,513 cm ꢀ1; MS (100 eV,
A
G
ACHTREUNG
CI): m/z (%): 477 (1.0) [M+H]+,459 (2) [ M+HꢀH2O]+,420 (29),419
AHCTREUNG
(CH3)2CO]+,383 (5),
ꢀ1
(100) [M+Hꢀ
G
1458,1372,1253,1215,1101,880,836,754,700 cm
(C6H5); MS (100 eV,
(CH3)2CO]+,499 (3),
CI): m/z (%): 591 (1.0) [M+H]+,533 (21) [ M+Hꢀ
ACHTREUNG
311 (11),294 (9),293 (41),205 (18),203 (15),191 (26),181 (14),149 (11),
91 (19) [C7H7]+; elemental analysis (%) calcd for C30H36O5 (476.60): C
75.60,H 7.61; found: C 75.53,H 8.03.
426 (12),425 (33) [ M+Hꢀ
(CH3)2COꢀPhCH2OH]+,414 (15),413 (47),
N
409 (11),401 (13),367 (21),307 (15),294 (25),293 (100),265 (11),216
2846
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
Chem. Eur. J. 2008, 14,2842 – 2849

Asymmetric Synthesis of (+)-Altholactone
FULL PAPER
(13),215 (74),187 (15),181 (12),91 (26) [C 7H7]+; elemental analysis (%)
calcd for C36H50O5Si (590.86): C 73.18,H 8.53; found: C 72.81,H 8.92.
ACHTREUNG
A
phenyl-1,3-dioxolan-4-yl]pentane-1,5-diol (14): A solution of compound
13 (200 mg,0.34 mmol,1.0 equiv) and palladium on carbon (10%,20 mg)
in EtOAc (5 mL) was stirred overnight at room temperature under hy-
drogen. The reaction mixture was filtered through a short pad of Celite,
with elution with EtOAc,and the filtrate was concentrated under re-
duced pressure to give the crude product as a colourless syrup. Purifica-
tion by flash chromatography on silica gel (PE/EtOAc 50:50) gave the
debenzylated diol 14 (138 mg,99%) as a colourless oil. [ a]2D2 =ꢀ171.80
(c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=7.35–7.47 (m,5H; Ar-
CH),5.32 (d, 3J
3.5 Hz,1H; PhCHC H),3.59 [t, 3J
(dd, 3J(H,H)=6.4,3.7 Hz,1H; C HCH2),3.27 [dd, 3J
1H; CH(OH)],2.27 [s,2H; 2”O H],1.75 [s,3H; C (CH3)],1.66–1.73 (m,
1H; CHCHH),1.57 [s,3H; C (CH3)],1.47–1.54 (m,3H; CH 2CH2CH2,
CHCHH),0.94 [s,9H; SiC (CH3)3],0.02 [s,3H; Si (CH3)],0.00 ppm [s,
3H; Si
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=137.8 (Ar-C),128.4,
128.1,127.0 (Ar- CH),108.5 (CH3)2],79.0 (Ph CH),77.5
[PhCHCHCH(OH)],71.4 ( CHCH2),71.3 [ CH(OH)],62.8 [ CH2(OH)],
28.5 (CHCH2),27.3 (CH CH2CH2),26.6 [C (CH3)],25.8 [SiC (CH3)3],24.4
(CH3)2]; IR (film): n˜ =
C
(H,H)=7.4,
AHCTREUNG
U
ACHTREUNG
The crude a-selenylated product (189 mg) was dissolved in CH2Cl2
(2 mL),and pyridine (30 mL,2.2 equiv) was added at 0 8C,followed by a
solution of 30% H2O2/H2O (1:1, v/v,400 mL,1.52 mmol,10.0 equiv). The
stirring was continued for 30 minutes at this temperature,after which the
reaction mixture was poured into H2O (20 mL) and CH2Cl2 (20 mL). The
reaction mixture was washed with H2O (20 mL) and brine (10 mL),and
the organic phase was dried (Na2SO4),filtered and concentrated under
reduced pressure to give the crude product as a brown syrup. Purification
by flash chromatography on silica gel (PE/Et2O 80:20) gave the unsatu-
rated lactone 16 (37 mg,60%) as a pale yellow solid,together with re-
maining starting material (19 mg,31%). M.p. 113 8C; [a]2D3 =ꢀ98.41 (c=
1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=7.25–7.50 (m,5H; Ar-C H),
AHCTREUNG
AHCTREUNG
G
ACHTREUNG
ACHTREUNG
[
C
ACHTREUNG
G
ACHTREUNG
2
[C
G
(CH3)3], ꢀ4.9, ꢀ4.5 ppm [Si
ACHTREUNG
3434 (br,OH),2936,2861,1464,1378,1256,1215,1164,1100,1050,887,
ꢀ1
837,758,701 cm
(C6H5); MS (100 eV,CI): m/z (%): 411 (1.0) [M+H]+,
353 (2) [M+Hꢀ
C
A
6.57 [dd, 3J
9.9,2.2 Hz,1H; C(O)C H],5.44 (d, 3J
[td, 3J (OSi)],4.47 (d, 3J
(H,H)=9.9,1.9 Hz,1H; C
PhCHCHCHO),3.55 [dd, 3J
(H,H)=9.9,0.8 Hz,1H; C HOC(O)],1.67 [s,
3H; C(CH3)],1.49 [s,3H; C (CH3)],0.90 [s,9H; SiC (CH3)3],0.16 [s,3H;
Si(CH3)],0.12 ppm [s,3H; Si
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=
161.9 [C(O)],149.6 [C(O)CH =CH],135.3 (Ar- C),128.0,127.7,126.6 (Ar-
CH),119.2 [C(O) CH],109.7 [ C(CH3)2],79.7 [ CHOC(O)],78.8 (Ph CH),
75.3 (PhCHCHCHO),63.7 CHCH=CH),26.3 [C (CH3)],25.6 [SiC-
(CH3)3],25.5 [C (CH3)],17.9 [Si C (CH3)2]; IR
(CH3)3], ꢀ5.1, ꢀ4.6 ppm [Si
(KBr): n˜ =3017,2933,2859,1739 (C =O),1465,1376,1254,1218,1163,
A
N
H
215 (100),203 (50),175 (20),91 (3) [C 7H7]+,71 (14); HRMS: m/z: calcd
for C21H35O5Si [MꢀCH3]: 395.2254; found: 395.2253.
AHCTREUNG
A
H
A
ACHTREUNG
AHCTREUNG
(5R,6S)-(ꢀ)-5-(tert-Butyldimethylsilyloxy)-6-[(4R,5R)-2,2-dimethyl-5-
A
N
ACHTREUNG
phenyl-1,3-dioxolan-4-yl]tetrahydropyran-2-one (15): A solution of diol
14 (825 mg,2.01 mmol,1.0 equiv) in DMSO (15 mL) was added dropwise
at room temperature to a stirred solution of o-iodoxybenzoic acid (IBX,
1.24 g,4.42 mmol,2.2 equiv) in freshly distilled DMSO (5 mL). The stir-
ring at this temperature was continued for 3 h,after which the reaction
was quenched with H2O (20 mL) at 08C. The reaction mixture was fil-
tered through a short pad of Celite,and the solids were washed with
Et2O. The aqueous phase was extracted with Et2O (3”20 mL). The com-
A
ACHTREUNG
AHCTREUNG
(
ACHTREUNG
A
G
A
ACHTREUNG
1106,1061,1008,974,917,871,839,757,701 (C
6H5),666 cm ꢀ1; MS
(100 eV,CI): m/z (%): 405 (53) [M+H]+,348 (26),347 (100) [ M+Hꢀ
bined organic layers were washed with brine (20 mL),dried (Na SO4),fil-
2
(CH3)2CO]+,331 (5) [ M+Hꢀ(CH3)2COꢀH2O]+,289 (11),215 (8),97
G
tered and concentrated under reduced pressure to give the crude product
as a colourless syrup.
(9),91 (1) [C 7H7]+; HRMS: m/z: calcd for C21H29O5Si [MꢀCH3]:
389.1784; found: 389.1784.
Tetrapropylammonium perruthenate (TPAP,36 mg,0.10 mmol,5 mol%)
was then added in one portion at room temperature under argon to a
stirred mixture of the crude lactol (1.08 g), N-methylmorpholine-N-oxide
(NMO,364 mg,3.01 mmol,1.5 equiv) and powdered molecular sieves
(4 Š,1.01 g,0.5 g per mmol lactol) in CH 2Cl2 (4 mL). Upon completion
(20 minutes) the reaction mixture was filtered through a short pad of
silica,which was washed with EtOAc,and the filtrate was concentrated
under reduced pressure to give the crude product as a colourless syrup.
Purification by flash chromatography on silica gel (PE/Et2O 70:30) gave
lactone 15 (625 mg,77% over two steps) as a colourless solid. M.p. 107–
1088C; [a]2D3 =ꢀ111.81 (c=1,CHCl 3); 1H NMR (400 MHz,CDCl 3): d=
A
droxy-5,6-dihydropyran-2-one (17): Tetra-n-butylammonium fluoride
(TBAF,1.0 m in THF,1.4 mL,1.44 mmol,2.0 equiv) was added dropwise
at 08C to a solution of compound 16 (290 mg,0.72 mmol,1.0 equiv) in
absolute THF (7 mL). Stirring at room temperature was continued for
1 h,after which the reaction was quenched with H 2O (10 mL). The mix-
ture was poured into H2O (10 mL),and the aqueous layer was extracted
with EtOAc (3”10 mL). The combined organic layers were washed with
brine (10 mL),dried (Na 2SO4),filtered and concentrated under reduced
pressure to give the crude product as a yellow syrup. Purification by flash
chromatography on silica gel (PE/EtOAc 50:50) gave alcohol 17 (153 mg,
74%) as a colourless solid. M.p. 1648C; [a]2D3 =ꢀ106.34 (c=1,CHCl 3);
1H NMR (400 MHz,CDCl 3): d=7.28–7.52 (m,5H; Ar-C H),6.68 [dd,
7.27–7.48 (m,5H; Ar-C H),5.42 (d, 3J
ACHTREUNG
3
(d, J
A
ACHTREUNG
1H; CHCH2),3.52 [d, 3J
3J
1.67 (dd, J
[s, 3H; C(CH3)],0.83 [s,9H; SiC
[s, 3H; Si
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=170.1 [C(O)],135.6
(Ar-C),128.1,127.8,126.6 (Ar- CH),109.6 [ C(CH3)2],80.1 [ CHOC(O)],
79.1 (PhCH),76.7 (PhCH CHCHO),65.6 ( CHCH2),26.9 (CH CH2),26.9
[CH2CH2C(O)],26.2 [C (CH3)],25.6 [SiC (CH3)3],25.2 [C (CH3)],17.8
[SiC (CH3)2]; IR (KBr): n˜ =2945,2361,2338,
ACHTREUNG
3J
1H; C(O)CH],5.47 (d,
3J(H,H)=7.3,1.1 Hz,1H; PhCHC HCHO),4.54 [ddd, 3J
2.0 Hz,1H; C H(OH)],3.68 [dd, 3J
(H,H)=9.3,1.1 Hz,1H; C HOC(O)],
2.05 (d, 3J
(H,H)=7.1 Hz,1H; O H),1.67 [s,3H; C (CH3)],1.51 ppm [s,
3H;
(CH3)]; 13C NMR (100 MHz,CDCl 3): d=161.9 [C(O)],148.2
[C(O)CH=CH],135.3 (Ar- C),128.3,128.1,126.9 (Ar- CH),120.3
[C(O)CH],110.1 (CH3)2],79.6 CHOC(O)],79.1 (Ph CH),76.0
(PhCHCHCHO),63.2 ( CHCH=CH),26.3 [C (CH3)],25.5 ppm [C (CH3)];
A
N
ACHTREUNG
3
AHCTREUNG
N
G
A
ACHTREUNG
A
N
ACHTREUNG
AHCTREUNG
ACHTREUNG
A
ACHTREUNG
AHCTREUNG
C
ACHTREUNG
A
N
ACHTREUNG
[
C
A
[
A
ACHTREUNG
A
ACHTREUNG
1726 (C=O),1462,1379,1256,1213,1170,1086,1015,919,840,780,699
(C6H5),538 cm ꢀ1; MS (100 eV,CI): m/z (%): 407 (28) [M+H]+,391 (11),
IR (KBr): n˜ =3852,3744,3678,3621,3463 (br,OH),2361,1708 (C
=O),
350 (24),349 (100) [ M+Hꢀ
1646,1548,1460,1378,1227,1084,970,904,808,743,673 (C
6H5),
(21),221 (13),217 (19); elemental analysis (%) calcd for C 22H34O5Si
(406.59): C 64.99,H 8.43; found: C 64.92,H 8.71.
559 cmꢀ1; MS (100 eV,CI): m/z (%): 291 (39) [M+H]+,275 (24),234
(13),233 (100)
[
M+Hꢀ
A
[
M+Hꢀ
Chem. Eur. J. 2008, 14,2842 – 2849
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
2847

D. Enders and J. Barbion
(CH3)2COꢀH2O]+,149 (10),148 (14),97 (10),91 (6) [C
7H7+]; HRMS:
Blµzquez,A. Bermejo,M. C. Zafra-Polo,D. Cortes,
Anal. 1999, 10,161–170.
[3] For a review of 5,6-dihydro-2H-pyran-2-ones,see: M. T. Davies-Co-
leman,D. E. A. Rivett,in Progress in the Chemistry of Organic Nat-
ural Products, Vol. 55 (Eds.: W. Herz,H. Grisebach,G. W. Kirby,
Ch. Tamm),Springer,New York, 1989,pp. 1–35.
Phytochem.
m/z: calcd for C15H15O5 [MꢀCH3]: 275.0919; found: 275.0920.
ACHTREUNG
(46 mg,0.24 mmol,1.5 equiv) were added at room temperature to a
stirred solution of alcohol 17 (47 mg,0.16 mmol,1.0 equiv) in CH 2Cl2
(2 mL). Stirring at this temperature was continued for 3 h. The organic
phase was washed with H2O (10 mL) and brine (10 mL),and the aqueous
layer was extracted with CH2Cl2 (3”10 mL). The combined organic
layers were dried (Na2SO4) and concentrated under reduced pressure to
give the crude product as a brown syrup. Purification by flash chromatog-
raphy on silica gel (PE/EtOAc 70:30) gave tosylate 18 (68 mg,95%) as
colourless crystals. M.p. 50–518C; [a]2D3 =ꢀ88.90 (c=1,CHCl 3); 1H NMR
[4] a) A. D. Argoudelis,J. F. Zieserl, Tetrahedron Lett. 1966, 7,1969–
1973; b) F. B. Ahmad,W. A. Tukol,S. Omar,A. M. Sharif,
chemistry 1991, 30,2430–2431; c) X.-P. Fang,J. E. Anderson,C.-J.
Chang,J. L. McLaughlin,P. E. Fanwick, J. Nat. Prod. 1991, 54,
Phyto-
1034–1043; d) K. Yasui,Y. Tamura,T. Nakatani,K. Kawada,M.
Ohtani, J. Org. Chem. 1995, 60,7567–7574; e) A. Bermejo,M. A.
Blµzquez,K. S. Rao,D. Cortes, Phytochem. Anal. 1999, 10,127–131.
[5] For recent reviews on the bioactivity of styryllactones,see: a) A. de
Fatima,L. V. Modolo,L. S. Conegero,R. A. Pilli,C. V. Ferreira,
L. K. Kohn,J. E. de Carvalho, Curr. Med. Chem. 2006, 13,3371–
3384; b) H. B. Mereyala,M. Joe, Curr. Med. Chem. Anti-Cancer
Agents 2001, 1,293–300.
[6] Recent Reviews: a) M. Mondon,J.-P. Gesson, Curr. Org. Synth.
2006, 3,41–75; b) J. M. Harris,M. Li,J. G. Scott,G. A. OꢁDoherty,
in Strategies and Tactics in Organic Synthesis, Vol. 5 (Ed.: M. Har-
mata),Elsevier,Amsterdam, 2004,pp. 221.
(400 MHz,CDCl ): d=7.79 (m,2H; Ar-C H),7.28–7.44 (m,7H; Ar-C H),
3
6.59 [dd, 3J
(H,H)=9.9,2.7 Hz,1H; C(O)CH =CH],5.89 [dd, 3J
ACHTREUNG
9.9,1.6 Hz,1H; C(O)C H],5.32 (d, 3J
[ddd, 3J
(H,H)=8.2,2.7,1.6 Hz,1H;
7.4 Hz,1H; PhCHC HCHO),3.81 [d, 3J
ACHTREUNG
A
C
H
G
ACHTREUNG
AHCTREUNG
2.49 (s,3H; CH 3),1.55 [s,3H; C
C
ACHTREUNG
[7] Selected references: a) V. K. Yadav,D. Agrawal, Chem. Commun
CH),122.8 [C(O) CH],110.1 [ C
75.9 (PhCHCHCHO),70.6 ( CHCH=CH),26.0 [C
21.8 ppm (CH3); IR (KBr): n˜ =3853,3744,3670,3620,3417,2925,2354,
ACHTREUNG
´
´
2007,5232–5234; b) V. Popsavin,G. Benedekovic ,B. Srec o,M. Pop-
G
ACHTREUNG
´
´
savin,J. Francuz,V. Kojic ,G. Bogdanovic , Org. Lett. 2007, 9,4235–
4238; c) M. Babjak,P. Kapitµn,T. Gracza, Tetrahedron 2005, 61,
1708 (C=O),1548,1250,1105,1022,820,758,679 (C
(100 eV,CI): m/z (%): 233 (10),232 (33) [ M+Hꢀ
6H5),564 cm ꢀ1; MS
A
2471–2479; d) M. Babjak,P. Kapitµn,T. Gracza, Tetrahedron Lett.
2002, 43,6983–6985; e) A. Hiratate,H. Kiyota,T. Noshita,R. Take-
uchi,T. Oritani, J. Pept. Sci. 2001, 26,366–370; f) T. K. M. Shing,
H.-C. Tsui,Z.-H. Zhou, J. Org. Chem. 1995, 60,3121–3130;
g) T. K. M. Shing,J. G. Gillhouley, Tetrahedron 1994, 50,8685–8698;
h) Y. Ueno,K.-I. Tadano,S. Ogawa,J. L. McLaughlin,A. Alkofahi,
Bull. Chem. Soc. Jpn. 1989, 62,2328–2337; i) S. H. Kang,W. J. Kim,
Tetrahedron Lett. 1989, 30,5915–5918; j) J.-P. Gesson,J.-C. Jacquesy,
M. Mondon, Tetrahedron 1989, 45,2627–2640; k) J. G. Gillhouley,
T. K. M. Shing, J. Chem. Soc. Chem. Commun. 1988,976–977; l) K.-
I. Tadano,Y. Ueno,S. Ogawa, Chem. Lett. 1988,111–114; m) J.-P.
(17),172 (40),155 (11),136 (10),126 (11),108 (14),107 (57),105 (34),97
(100),96 (14),95 (28),91 (59) [C 7H7]+,79 (29),77 (30),68 (13),65 (11).
(1R,6S,8R,9R)-(+)-9-Hydroxy-8-phenyl-2,7-dioxabicyclo[4.3.0]non-4-en-
G
3-one [(+)-altholactone] (1): Amberlyst 15 (128 mg,200% in weight)
was added at room temperature to a stirred solution of acetonide 18
(64 mg,0.14 mmol,1.0 equiv) in MeOH (2 mL). Stirring was continued
for 2 h,and subsequently the reaction mixture was filtered through a
short pad of Celite,and the solids were washed with MeOH. The filtrate
was concentrated under reduced pressure to give the crude product as a
yellow syrup. Purification by flash chromatography on silica gel (Et2O)
gave (+)-altholactone (1,31 mg,93%) as a colourless solid. M.p. 114 8C
(lit.:[2a] 1108C); [a]2D5 =+104.10 (c=1,CHCl 3),[ a]2D5 =+177.46 (c=0.5,
EtOH) (lit.:[1,2a] [a]2D0 =+188,[ a]2D5 =+184.7,c =0.5,EtOH); 1H NMR
Gesson,J.-C. Jacquesy,M. Mondon,
Tetrahedron Lett. 1987, 28,
3945–3948; n) J.-P. Gesson,J.-C. Jacquesy,M. Mondon, Tetrahedron
Lett. 1987, 28,3949–3952.
(400 MHz,CDCl 3): d=7.27–7.36 (m,5H; Ar-C H),7.00 [dd, 3J
9.9,4.9 Hz,1H; C(O)CH =CH],6.21 [d, 3J
(H,H)=9.9 Hz,1H; C(O)C H],
4.92 [dd, 3J HOC(O)],4.74 (d, 3J
(H,H)=5.2,2.2 Hz,1H; (H,H)=
5.8 Hz,1H; PhC H),4.63 (t, 3J
(H,H)=5.2 Hz,1H; C HCH=CH),4.44 [dd,
3J(H,H)=5.8,2.2 Hz,1H; C H(OH)],2.55 ppm (s,1H; OH); 13C NMR
N
[8] a) M. Tsubuki,K. Kanai,T. Honda, Synlett 1993,653–655; b) M.
Tsubuki,K. Kanai,H. Nagase,T. Honda,
2493–2514.
Tetrahedron 1999, 55,
AHCTREUNG
U
C
[9] Selected references: a) K. R. Prasad,S. L. Gholap, Tetrahedron Lett.
2007, 48,4679–4682; b) K. R. Prasad,S. L. Gholap, J. Org. Chem.
2008, 73,2–11; c) J. P. Surivet,J. M. Vatele, Tetrahedron 1999, 55,
13011–13028; d) P. Somfai, Tetrahedron 1994, 50,11315–11320.
[10] P. R. Rodrigues Meira,A. Venturini Moro,C. R. Duarte Correia,
Synthesis 2007,2279–2286.
AHCTREUNG
ACHTREUNG
(100 MHz,CDCl ): d=161.3 [C(O)],140.3 [C(O)CH =CH],137.9 (Ar- C),
3
128.5,128.2,125.9 (Ar- CH),123.4 [C(O) CH],86.4 [ CHOC(O)],85.9
(PhCH),83.5 [ CH(OH)],68.1 ppm ( CHCH=CH); IR (KBr): n˜ =3438
(OH),2926,2859,2279,1724 (C
1378,1259,1088,816,759,706 cm
=O, a,b-unsaturated d-lactone),1456,
ꢀ1
[11] a) C. Mukai,S. Hirai,I. J. Kim,M. Hanaoka, Tetrahedron Lett. 1996,
(C6H5); MS (100 eV,CI): m/z (%):
233 (100) [M+H]+,215 (10) [ M+HꢀH2O]+,137 (2),127 (4),119 (5),109
(7),107 (5) [ M+HꢀH2OꢀPhCH2OH]+,97 (16),91 (8) [C 7H7]+,79 (1);
HRMS: m/z: calcd for C13H12O4 [M]: 232.0735; found: 232.0733.
37,5389–5392; b) C. Mukai,S. Hirai,M. Hanaoka,
J. Org. Chem.
1997, 62,6619–6626; c) J. M. Harris,G. A. OꢁDoherty, Tetrahedron
2001, 57,5161–5171; d) J. S. Yadav,G. Rajaiah,A. K. Raju, Tetrahe-
dron Lett. 2003, 44,5831–5833; e) J. S. Yadav,A. K. Raju,P. P. Rao,
G. Rajaiah, Tetrahedron: Asymmetry 2005, 16,3283–3290 and ref.
cit. therein.
Acknowledgements
[12] A. Job,M. Wolberg,M. Müller,D. Enders, Synlett 2001,1796–1798.
[13] For some selected examples,see: a) D. Enders,U. Jegelka, Tetrahe-
dron Lett. 1993, 34,2453–2456; b) D. Enders,O. F. Prokopenko,
Liebigs Ann. Chem. 1995,1185–1191; c) D. Enders,D. Whitehouse,
J. Runsink, Chem. Eur. J. 1995, 1,382–388; d) D. Enders,T. Hun-
dertmark, Eur. J. Org. Chem. 1999,751–756; e) D. Enders,J. L. Vi-
cario,A. Job,M. Wolberg,M. Müller, Chem. Eur. J. 2002, 8,4272–
4284; f) D. Enders,A. Lenzen, Synlett 2003,2185–2187; g) D.
This work was supported by the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft (Graduiertenkolleg 440—“Methods in
Asymmetric Synthesis”). We thank BASF AG,Degussa AG,Bayer AG
and Wacker Chemie for the donation of chemicals.
Enders,A. Lenzen,M. Müller,
Synthesis 2004,1486–1496; h) D.
[1] J. W. Loder,R. H. Nearn, Heterocycles 1977, 7,113–118.
[2] a) A. E. El-Zayat,N. R. Ferrigni,T. G. McCloud,A. T. McKenzie,
S. R. Byrn,J. M. Cassady,C.-J. Chang,J. L. McLaughlin, Tetrahedron
Lett. 1985, 26,955–956; b) S. H. Goh,V. C. Chung,C. K. Sha,
T. C. W. Mak, Phytochemistry 1990, 29,1704–1706; c) M. A.
Enders,A. Müller-Hüwen, Eur. J. Org. Chem. 2004,1732–1739;
i) D. Enders,I. Breuer,G. Raabe, Synthesis 2005,3517–3530; j) D.
Enders,A. Hieronymi,A. Ridder, Synlett 2005,2391–2393; k) D.
Enders,I. Breuer,E. Drosdow,
Synthesis 2005,3239–3244; l) D.
2848
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Chem. Eur. J. 2008, 14,2842 – 2849

Asymmetric Synthesis of (+)-Altholactone
FULL PAPER
Enders,M. Vrettou, Synthesis 2006,2155–2158; m) D. Enders,C.
Grondal,M. Vrettou, Synthesis 2006,3597–3604; n) D. Enders,E.
Peiffer,R. Raabe, Synthesis 2007,1021–1026; See also: o) M. Ma-
jewski,P. Nowak, J. Org. Chem. 2000, 65,5152–5160; p) M. Majew-
ski,P. Nowak, Tetrahedron: Asymmetry 1998, 9,2611–2617.
Org. Chem. 2006, 71,3822–3828; m) I. Ibrahem,W. Zou,J. Casas,
H. Sundꢃn,A. Cꢂrdova, Tetrahedron 2006, 62,357–364; n) I. Ibra-
hem,W. Zou,Y. Ku,A. Cꢂrdova, Adv. Synth. Catal. 2006, 348,211–
222; o) M. Majewski,I. Niewczas,N. Palyam, Synlett 2006,2387–
2390; p) Y. Hayashi,S. Aratane,T. Itch,T. Okano,T. Sumiya,M.
Shoji, Chem. Commun. 2007,957–959; for recent reviews see: q) M.
Markert,R. Mahrwald, Chem. Eur. J. 2008, 14,40–48; r) U. Kazmai-
er, Angew. Chem. 2005, 117,2224–2226; Angew. Chem. Int. Ed.
2005, 44,2186–2188.
[14] a) D. Enders,B. Bockstiegel, Synthesis 1989,493–496; b) D. Enders,
M. Voith,S. J. Ince, Synthesis 2002,1775–1779.
[15] a) D. Hoppe,H. Schmincke,H.-W. Kleemann, Tetrahedron 1989, 45,
687–694; b) H. Vorbrüggen, Acta Chem. Scand. 1982,420.
[16] a) D. Enders,H. Eichenauer, Angew. Chem. 1976, 88,579–581;
Angew. Chem. Int. Ed. Engl. 1976, 15,549–551; b) D. Enders,H. Ei-
chenauer, Tetrahedron Lett. 1977, 18,191–194; c) D. Enders,H. Ei-
chenauer, Angew. Chem. 1979, 91,425–427; Angew. Chem. Int. Ed.
Engl. 1979, 18,397–399; d) D. Enders,H. Eichenauer, Chem. Ber.
1979, 112,2933–2960; Recent review: e) A. Job,C. F. Janeck,W.
Bettray,R. Peters,D. Enders, Tetrahedron 2002, 58,2253–2329.
[17] Review on the various hydrazone cleavage methods: D. Enders,L.
Wortmann,R. Peters, Acc. Chem. Res. 2000, 33,157–169.
[18] a) C. Grondal,D. Enders, Adv. Synth. Catal. 2007, 349,694–702;
b) C. Grondal,D. Enders, Tetrahedron 2006, 62,329–337; c) C.
Grondal,D. Enders, Synlett 2006,3507–3509; d) D. Enders,J. Pale-
cek,C. Grondal, Chem. Commun. 2006,655–657; e) D. Enders,M.
Vrettou, Synthesis 2006,2155–2158; f) D. Enders,C. Grondal,M.
Vrettou, Synthesis 2006,3597–3604; g) D. Enders,C. Grondal,M.
Vrettou,G. Raabe, Angew. Chem. 2005, 117,4147–4151; Angew.
Chem. Int. Ed. 2005, 44,4079–4083; h) D. Enders,C. Grondal,
Angew. Chem. 2005, 117,1235–1238; Angew. Chem. Int. Ed. 2005,
44,1210–1212; for selected examples of other groups,see: i) B.
Westermann,C. Neuhaus, Angew. Chem. 2005, 117,4145–4147;
Angew. Chem. Int. Ed. 2005, 44. 4077–4079; j) J. T. Suri,D. B. Ram-
achary,C. F. Barbas, III, Org. Lett. 2005, 7,1383–1385; k) I. Ibra-
hem,A. Cꢂrdova, Tetrahedron Lett. 2005, 46,3363–3367; l) J. T.
[19] For a recent review,see: D. Enders,M. Voith,A. Lenzen,
Angew.
Chem. 2005, 117,1330–1351; Angew. Chem. Int. Ed. 2005, 44,1304–
1325.
[20] a) B. Bockstiegel,Dissertation,RWTH Aachen (Germany),
b) D. Enders,O. F. Prokopenko,G. Raabe,J. Runsink,
1988;
Synthesis
1996,1095–1100; c) D. Enders,S. J. Ince, Synthesis 2002,619–624;
d) D. Enders,S. J. Ince,M. Bonnekessel,J. Runsink,G. Raabe,
lett 2002,962–966.
Syn-
[21] a) D. A. Evans,D. L. Rieger,J. R. Gage, Tetrahedron Lett. 1990, 31,
7099–7100; b) S. D. Rychnowsky,B. Rogers,G. Yang, J. Org. Chem.
1993, 58,3511–3515.
[22] a) D. B. Dess,J. C. Martin, J. Org. Chem. 1983, 48,4155–4156; b) M.
Frigerio,M. Santagostino,S. Sputore, J. Org. Chem. 1999, 64,4537–
4538.
[23] a) W. P. Griffith,S. V. Ley,G. P. Whitcombe,A. D. White,
J. Chem.
Soc. Chem. Commun. 1987,1625–1627; b) W. P. Griffith,S. V. Ley,
Aldrichimica Acta 1990, 23,13–19; c) S. V. Ley,J. Norman,W. P.
Griffith,S. P. Mardsen, Synthesis 1994,639–666.
[24] H. J. Reich,J. M. Renga,I. L. Reich, J. Am. Chem. Soc. 1975, 97,
5434–5447.
[25] J. G. Solsona,P. Romea,F. Urpi, Org. Lett. 2003, 5,4681–4684.
Received: October 18,2007
Suri,S. Mitsumori,K. Albertshofer,E. Tanaka,C. F. Barbas, III,
J.
Published online: January 24,2008
Chem. Eur. J. 2008, 14,2842 – 2849
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
2849