Asymmetric synthesis of (-)-bissetone via a highly enantioselective hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tet.2013.07.048

We demonstrate a new approach for the asymmetric synthesis of bissetone. The key reaction is the highly enantioselective hetero-Diels-Alder cycloaddition of triene 3 with ethyl glyoxylate catalyzed by readily available BINOL-Ti complexes. The HDA cycloadduct 4 was then transformed in five steps into O-protected bissetone (8) and its C5-epimer in good yield.

Full text of DOI:10.1016/j.tet.2013.07.048

Tetrahedron 69 (2013) 8463e8469
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of (ꢀ)-bissetone via a highly enantioselective
hetero-DielseAlder reaction
,
,
b
,
c
Jakub Majer a, Janusz Jurczak a b, Piotr Kwiatkowski a , Livius Cotarca ,
*
Jean-Claude Caille d
a Institute of Organic Chemistry, Polish Academy of Sciences, 01-224 Warsaw, Poland
b Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
c ZaChdZambon Chemicals, Via Dovaro 2, 36045 Lonigo VI, Italy
d Ozonora Consulting, 30 rue Bernier, 49000 Angers, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We demonstrate a new approach for the asymmetric synthesis of bissetone. The key reaction is the
highly enantioselective hetero-DielseAlder cycloaddition of triene 3 with ethyl glyoxylate catalyzed by
readily available BINOLeTi complexes. The HDA cycloadduct 4 was then transformed in five steps into O-
protected bissetone (8) and its C5-epimer in good yield.
Received 12 February 2013
Received in revised form 27 June 2013
Accepted 15 July 2013
Available online 22 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Bioactive natural products
Enantioselective catalysis
Hetero-DielseAlder reaction
Tetrahydropyran-4-ones
1. Introduction
OH
O
O
O
O
OH
O
OH
OH
HO
Bissetone is one of the naturally occurring metabolites of 1,5-
anhydro-
lated from the very polar extracts of the Gorgonian soft coral
Briareum polyanthes.1 1,5-Anhydro-
-fructose is produced with the
help of -1,4-glucan lyase by the degradation of glycogen, starch or
D-fructose having an antimicrobial activity, and is iso-
O
O
D
OH
OH
a
1,5-Anhydro-
-fructose
Haliclonol
(-)-Bissetone
maltosaccharides. This compound and its derivatives and metab-
olites like bissetone, haliclonol, palythazine, isopalythazine, 1-
deoxymannojirimycin, 5-epipentenomycin I, or clavulazine are
very interesting molecules due to their pharmaceutical potential
(Fig. 1).2
Bissetone is a tetrahydro-4H-pyran-4-one functionalized in
positions 2 and 5 and containing two stereogenic centers. The
structure and relative stereochemistry of bissetone were assigned
by X-ray diffraction analysis.1 The absolute configuration was
D
Fig. 1. ‘1,5-Anhydro-D-fructose and its metabolites’.
addition of the lithium enolate of acetone to the carbonyl group of
the dihydropyranone, the (ꢀ)-BzO-protected bissetone was ob-
tained in 64% yield. Alternatively, methylallyl titanium triisoprop-
oxide could be used as an acetone synthon, although required an
additional ozonation step.
confirmed by chemical synthesis from
D
-glucose by Lichtenthaler.3
-glucose in eight steps in 37%
D-glucose was transformed into
Bissetone was obtained from
D
2. Results and discussion
overall yield (Scheme 1).3 Firstly,
a dihydropyranone intermediate with one stereogenic center. After
In this paper, we demonstrate a new approach to the synthesis
of bissetone and its stereoisomers. As a key step, our strategy in-
volved the use of an enantioselective hetero-DielseAlder reaction4
for the construction of a six-membered oxo-ring with a stereogenic
center in position 2 (Scheme 2). The second stereogenic center at C5
* Corresponding author. E-mail address: pkwiat@chem.uw.edu.pl (P.
Kwiatkowski).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.048

8464
J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
OBz
O
OLi
OH
1)
6 steps
O
D
-Glucose
O
2) hydrolysis
O
O
dihydro-
(-)-Bissetone
OBz
OH
pyranone
Scheme 1. The synthesis of (ꢀ)-bissetone from D-glucose by Lichtenthaler.
OSiR'3
O
OSiR'3
OH
4
5
1
R
O
+
R
2
O
CO2Alk
O
CO2Alk
O
OH
HDA precursor
(-)-Bissetone
R = H or Me
Scheme 2. The retrosynthetic analysis of bissetone.
with a tertiary hydroxyl group and carbonyl at C4 would be in-
troduced via Rubottom oxidation of a silyl enol ether moiety.5,6
Finally, our synthetic plan envisioned formation of an exo-cyclic
carbonyl group (acetone subunit) by ozonation (R¼Me) or Wack-
ereTsuji oxidation (R¼H)7 of the corresponding alkene moiety and
deprotection of the primary alcohol.
Initially, triene 3 for the hetero-DielseAlder reaction was pre-
pared (Scheme 3). Firstly, diethyl (2-oxopropyl)phosphonate (1)8
was alkylated with allyl bromide in the presence of K2CO3 and
a catalytic amount of tetrabutylammonium bromide. The sub-
sequent HornereWadswortheEmmons reaction was carried out in
the same flask by addition of paraformaldehyde. The reaction yield
in this step was moderate (45%) due to gem-diallylation of 1. Finally,
the TBS-protected triene 3 was obtained from ketone 2 and tert-
butyldimethylsilyl chloride in the presence of 2 equiv of ButOK in
85% yield.
in this cycloaddition reaction (Table 1). Optimization of the reaction
conditions showed that 5 mol % of [(R)-6,60-dibromo-BINOL]2Ti com-
plex in toluene16 gave the highest enantioselectivity (up to 98.5% ee,
entry 8) and good yield (73%) of the product 4. Importantly, 1 mol % of
the same catalyst in a more concentrated reaction mixture (0.4 mL of
toluene on a 1 mmol scale) led to comparable results (71% yield, 98% ee,
entry 9). Using a catalyst with an unsubstituted binaphthol gave
product 4with slightlylowerenantioselectivity (90e93% ee vs 95e98%
ee, entries 1, 2, 9, and 10). The use of (R)-BINOLeTi catalysts resulted in
formation of the (R)-enantiomer of cycloadduct 4. The observed di-
rection of the asymmetric induction is in agreement with enantiose-
lective HDA reactions of glyoxylates catalyzed by BINOLeTi complexes
reported in the literarure.10aee
In the synthesis of natural (ꢀ)-bissetone, a titanium catalyst
based on (S)-6,60-dibromo-BINOL was applied in the hetero-Diel-
seAlder reaction. In the next step, the cycloadduct 4 was reduced
1.
Br
t
OTBS
O
O
P
O
KOBu
cat. Bu4NBr
K2CO3 in DCM
TBSCl
OEt
OEt
2. paraform-
aldehyde
THF
1
45%
85%
2
3
Scheme 3. The synthesis of triene 3 for the HDA reaction.
The enantioselective hetero-DielseAlder reaction of the triene 3
and commercially available ethyl glyoxylate was used as the key
step for the construction of the oxo six-membered ring framework
(Table 1). The literature describes several catalytic systems useful in
HDA reactions of glyoxylates with non-activated9 as well as acti-
vated 1-alkoxy 1,3-dienes10 and Danishefsky-type dienes.11 Oxo-
DielseAlder reactions of 1,3-dienes with one activating group in
position 2 are rare in the literature.12 To the best of our knowledge,
HDA reactions with 2-silyloxy-3-alkyl dienes of type 3 proposed in
our retrosynthetic analysis have not been previously reported.
Among various catalytic systems, we concentrated our attention on
BINOLetitanium complexes, which have been applied successfully
in asymmetric catalysis, including hetero-DielseAlder reactions, by
Mikami,10aec,13 and Keck.14 Recently, we also demonstrated very
efficient FriedeleCrafts type reactions of activated heteroarenes
with glyoxylates in the presence of BINOLeTi catalyst.15
with LiAlH4 to the corresponding alcohol 5 in practically quanti-
tative yield and with unchanged optical purity (Scheme 4).17 The
primary alcohol 5 was protected by either trityl or benzoyl groups
(see products 6a and 6b). We expected that the larger protecting
group (i.e., Tr) at this position could increase diastereoselectivity in
the oxidation step.
Oxidation of TBS-protected enols 6a and 6b containing the allyl
substituent with meta-chloroperoxybenzoic acid (m-CPBA) under
optimized conditions, followed by desilylation with Bu4NF$3H2O,
led chemoselectively to the expected products 7a and 7b in good
yields (70e90%), but unfortunately with practically no diaster-
eoselectivity (w1:1 mixture of cis/trans) (Scheme 5).6 Other com-
monly used oxidation conditions (OsO4/NMO, Na2WO4/H2O2, t-
BuOOH, Oxone/K2CO3/cyclohexanone) failed in this reaction. We
concentrated our efforts on oxidation with m-CPBA in various sol-
vents (AcOEt, toluene, CH2Cl2, THF, MeOH, hexane, cyclohexane,
MeCN) and also with base additives (e.g., K2CO3, NaHCO3, K2HPO4,
Et3N). Unfortunately, in many cases, a mixture of products difficult
Titanium complexes generated from binaphthol and Ti(OiPr)4 using
the Keck14 method were found to be very useful asymmetric catalysts

J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
8465
Table 1
The enantioselective hetero-DielseAlder reaction
X
X
OTBS
OTBS
(R)-L1 or L2/
Ti(OiPr)4
OH
OH
+
CO2Et
1.3 equiv
O
O
CO2Et
L1 X =H; L2 X = Br
3
(R)-4
Entry
Catalyst
mol %
Solventa (mL/mmol)
Temp (ꢁC)
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
L1/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (1:1)
L2/Ti(OiPr)4 (2:1)
L2/Ti(OiPr)4 (2:1)
L1/Ti(OiPr)4 (2:1)
5%
5%
5%
5%
5%
1%
1%
5%
1%
2%
CH2Cl2 (dry) (0.8)
CH2Cl2 (dry) (0.8)
Toluene (0.8)
Toluene (0.8)
Toluene (0.8)
Toluene (0.16)
Toluene (0.16)
Toluene (2.0)
Toluene (0.4)
Toluene (1.0)
0
0
0
0
4
4
4
2.5
5
5
20
5
20
15
89
90
83
52
73
45
81
73
71
80
90
95
96.5
96
97
94
95
98.5
98
93
20
0
0/20
0/20
0/20
0
Conditions: triene 3 (1.0 mmol), ethyl glyoxylate (1.3 mmol) in toluene or CH2Cl2.
a
Use of dry toluene is not necessary for high enantioselectivity.
OTBS
LiAlH4
OTBS
O
OTBS
O
RCl, Et3N
cat. DMAP
Et2O
0 oC
CH2Cl2
O
CO2Et
10 min
OH
OR
up to 99%
(S)-4, 98% ee
(S)-5, 98% ee
96%
64%
6a R = Tr, 98% ee
6b R = Bz, 98% ee
Scheme 4.
for characterizing was observed. Finally, the best results in the
terms of yield were obtained with m-CPBA in AcOEt and toluene.
The mixture of diastereoisomers of products 7a and 7b could be
separated by careful chromatography on silica.
trityl group was easily removed from (2S,5S)-8a in the presence of
FeCl3$6H2O in dichloromethane to afford (ꢀ)-bissetone in 78%
yield. Hydrolysis of 8b under basic conditions was previously
described.3
O
O
OTBS
m-CPBA
O
O
HO
HO
.
Bu4NF 3H2O
TBSO
NaHCO3
+
THF
AcOEt
0 o
C
0 o
C
O
O
O
OR
(2S,5S)-7a, 98% ee
(2S,5S)-7b, 98% ee
dr ~ 1 : 1
OR
(2S,5R)-7a
(2S,5R)-7b
OR
OR
6a R = Tr, 98% ee
6b R = Bz, 98% ee
up to 90%
85%
(two steps)
Scheme 5. Oxidation of the silyl enol ethers 6a and 6b.
In the next step, single diastereoisomers of 7a and 7b were
oxidized under WackereTsuji conditions (O2, PdCl2, CuCl)7 to
give O-protected bissetone ((2S,5S)-8a/8b) or the corresponding
C5-epimers (2S,5R)-8a/8b with 57e85% yield (Scheme 6). Op-
tionally, mixtures of diastereoisomers 7 could be oxidized and
separated.
The structure of diastereoisomers 8a was assigned by NMR
experiments and X-ray analysis of trans-8a (Fig. 2). The structure
and absolute configuration of (2S,5S)-8b were confirmed by com-
parison to the literature data (NMR and optical rotation).3 The
3. Conclusions
A simple and efficient enantioselective approach to bissetone
and its stereoisomers has been proposed. O-Protected bissetone 8
and its 5-epimer were obtained in good overall yield (up to 65% for
R¼Tr) in six steps starting from a hetero-DielseAlder reaction. A
highly enantioselective HDA cycloaddition of 2,3-substituted diene
and glyoxylate catalyzed by easily available BINOLeTi was dem-
onstrated. Despite the efficiency of our approach, the most chal-
lenging step is still the control of diastereoselectivity in the

8466
J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
O
O
O
O
O
HO
HO
HO
10 mol% PdCl2
O
O
1 eq CuCl, O2
hydrolysis
R = Tr
DMF/H2O
O
.
FeCl3 6H2O/DCM
78%
OR
OH
OR
(2S,5S)-7a, R = Tr
(2S,5S)-7b, R = Bz
(2S,5S)-8a (62-85%)
(-)-bissetone
(2S,5S)-8b (57%)
R = Bz [ref.3]
O
O
HO
HO
10 mol% PdCl2
1 eq CuCl, O2
O
O-protected
epimer of
bissetone
DMF/H2O
O
O
OR
OR
(2S,5R)-7a, R = Tr
(2S,5R)-7b, R = Bz
(2S,5R)-8a (65%)
(2S,5R)-8b (60%)
Scheme 6. The WackereTsuji oxidation.
The enantiomeric excess (ee) of the products was determined by
high performance liquid chromatography (HPLC). HPLC analyses
were performed on a chromatograph fitted with the diode-array
detector (DAD) and Chiralpak AD-H (250ꢂ4.6 mm, 5
(250ꢂ4.6 mm, 5 m), or Chiracel OD-H (250ꢂ4.6 mm, 5
umns eluted with iso-propanol (1e20%) in hexane.
m
m), AS-H
m
mm) col-
All solvents and commercially available chemicals were used
without additional purification, unless otherwise noted. Ethyl
glyoxylate was distilled under vacuum over P2O5 before use. (R)-
and (S)-1,10-bi-2-naphthol, ethyl glyoxylate (50% solution in tolu-
ene), and Ti(OiPr)4 (97% purity) were purchased from Aldrich. (R)-
and (S)-6,60-dibromo-1,10-bi-2-naphthol (L2) were prepared
according to the procedures described in the literature.18
4.2. Experimental procedures and characterization data
4.2.1. 3-Methylenehex-5-en-2-one (2). A 150-mL round-bottomed
flask with a stir bar was charged with (2-oxopropyl)phosphonate
(10.0 g, 51 mmol)8 in CH2Cl2 (40 mL), K2CO3 (28.5 g, 4 equiv), and
5 mol % of tetrabutylammonium bromide (0.83 g). After stirring for
0.5 h at room temperature, allyl bromide (6.9 g,1.1 equiv) was added
in one portion and reaction was continued for 2 days at room tem-
perature in the dark. After this time, paraformaldehyde (1.89 g,
1.2 equiv) was added and reaction mixture was refluxed for 2 h. The
reaction mixture was cooled to room temperature and poured into
water (200 mL). The volatile product was extracted with CH2Cl2
(3ꢂ20 mL), the combined organic layers were dried over MgSO4, and
carefully evaporated in vacuo (20 ꢁC water bath). Vacuum distillation
at 70e75 ꢁC/80 mmHg with effective cooling (ca. ꢀ5 ꢁC) afforded the
title compound (2.64 g, 45%) as a colorless oil. IR (film) 3080, 2925,
1680, 1430, 1365, 1262, 1025, 918 cmꢀ1; 1H NMR (400 MHz, CDCl3)
Fig. 2. X-ray crystal structure of (ꢃ)-TrO-protected bissetone (trans-8a).
oxidation of silyl enol ether, and this issue requires more attention
in the future. Finally, stereoisomer (2S,5S)-7a was oxidized
under WackereTsuji conditions and deprotected to afford the
(ꢀ)-bissetone.
4. Experimental section
4.1. General information
All reported NMR spectra were recorded on a Varian 400, 500 or
600 using CDCl3 as solvent and (CH3)4Si as internal standard.
d
6.07 (s, 1H), 5.88e5.77 (m, 2H), 5.09e5.03 (m, 2H), 3.02 (dm,
Chemical shifts of 1H NMR and 13C NMR are reported as
d
values
J¼6.7 Hz, 2H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 199.2 (C),
relative to (CH3)4Si (
d
¼0.00) and to the central CDCl3
(
d
¼77.0), re-
147.4 (C), 135.4 (CH), 125.7(CH2), 116.7 (CH2), 34.6 (CH2), 25.8 (CH3).
spectively. Coupling constants (J) in the 1H NMR are in hertz. The
following abbreviations are used to indicate the multiplicity:
sdsinglet; dddoublet; tdtriplet; qdquartet; mdmultiplet;
dmddoublet of multiplets. High-resolution mass spectra (HRMS)
were recorded on a Mariner PE Biosystems unit using the ESI
technique. IR spectra were taken on an FT-IR PerkineElmer Spec-
trum 2000 using a film (CH2Cl2). Optical rotations were measured
on a JASCO DIP-1000 digital polarimeter. Analytical TLC was carried
out on commercial plates coated with 0.25 mm of Merck Kieselgel
60. Preparative flash silica chromatography was performed using
Merck Kieselgel 60 (230e400 mesh).
4.2.2. 2-tert-Butyldimethylsilyloxy-3-methylenehexa-1,5-diene
(3). To stirred suspension of potassium tert-butoxide (1.02 g,
9.0 mmol) in dry THF (20 mL) cooled to ꢀ78 ꢁC under argon atmo-
sphere, was added dropwise 3-methylidenehex-5-en-2-one (2)
(0.50 g, 4.5 mmol). After 10 min tert-butyldimethylchlorosilane
(1.64 g, 10 mmol) in toluene (50% solution) was introduced and
stirred for 30 min at ꢀ78 ꢁC. The reaction mixture was warmed
to ꢀ30 ꢁC and quenched by the addition of 15% aqueous NH4Cl
(10 mL). The product was extracted with Et2O (3ꢂ10 mL), the com-
bined organic layers were dried over MgSO4, evaporated in vacuo,

J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
8467
and purified by chromatography (or distillation after scale-up) to
afford 856 mg of triene 3 as a colorless oil with 85% yield. IR (film)
2957, 2930, 2859,1589,1472,1255,1159,1018, 909, 839, 780 cmꢀ1; 1H
were added Et3N (0.62 g, 6.12 mmol), triphenylmethyl chloride
(0.94 g, 3.36 mmol), and 4-dimethylaminopyridine (18 mg,
0.15 mmol). The reaction mixture was stirred under argon at-
mosphere for 24 h, and washed with an aqueous solution of
NaHCO3 (5%, 20 mL). After extraction with CH2Cl2 (3ꢂ10 mL),
combined organic phases were dried over Na2SO4, filtered, con-
centrated in vacuo, and purified by short column chromatogra-
phy using hexane/AcOEt (98:2) as an eluent. The (2S)-5-allyl-4-
tert-butyldimethylsilyloxy-2-trityloxymethyl-3,6-dihydro-2H-
pyran was isolated with 96% yield (1.54 g) and 98% ee. IR (film)
NMR (400 MHz, CDCl3)
5.14e4.99 (m, 3H), 4.54e4.50 (m, 1H), 4.36e4.33 (m, 1H), 3.00e2.95
(m, 2H), 0.98 (s, 9H), 0.18 (s, 6H); 13C NMR (100 MHz, CDCl3)
155.6
d 5.96e5.80 (m, 1H), 5.56e5.52 (m, 1H),
d
(C), 142.7 (C), 136.5 (CH), 116.0 (CH2), 113.8 (CH2), 92.9 (CH2), 37.2
(CH2), 25.8 (3ꢂ CH3), 18.3 (C), ꢀ4.7 (2ꢂ CH3).
4.2.3. (ꢀ)-(2S)-Ethyl 5-allyl-4-tert-butyldimethylsilyloxy-3,6-
dihydro-2H-pyran-2-carboxylate (4). A 5-mL round-bottomed
flask was charged with (S)-6,60-Br2BINOL (L2) (45.0 mg,
0.10 mmol), toluene (2.0 mL, 0.05 M) and capped with a septum. To
the stirred solution of the ligand, titanium tetraisopropoxide
2931, 2859, 1692, 1491, 1449, 1208, 1179, 1072, 840, 780 cmꢀ1
;
1H
NMR (500 MHz, CDCl3) 7.52e7.40 (m, 6H), 7.34e7.26 (m, 6H),
d
7.26e7.13 (m, 3H), 5.76e5.63 (m, 1H), 5.06e4.92 (m, 2H), 4.08 (s,
2H), 3.84e3.74 (m, 1H), 3.28 (dd, J¼9.5, 5.9 Hz, 1H), 3.06 (dd,
J¼9.5, 5.2 Hz, 1H), 2.83 (dd, J¼15.1, 5.8 Hz, 1H), 2.72 (dd, J¼15.1,
6.8 Hz, 1H), 2.22e1.96 (m, 2H), 0.94 (s, 9H), 0.13 (2ꢂs, 6H); 13C
(14.7 mL, 14.2 mg, 0.050 mmol, 5.0 mol %) was added via syringe
directly under the solution surface at room temperature (inert at-
mosphere is not required). The resulting dark red mixture was
stirred for 2 h at room temperature and cooled to 0 ꢁC. Ethyl
glyoxylate (0.133 g, 1.3 mmol; distilled under vacuum over P2O5
before use) was introduced and, finally, after 5 min, 2-tert-butyl-
NMR (126 MHz, CDCl3)
d 144.0 (C), 141.0 (C), 135.8 (CH), 128.7
(CH), 127.8 (CH), 126.9 (CH), 115.3 (CH2), 111.4 (C), 86.4 (C), 74.1
(CH), 67.3 (CH2), 66.4 (CH2), 33.3 (CH2), 30.6 (CH2), 25.7 (CH3),
18.1 (C), ꢀ3.5 (CH3), ꢀ3.9 (CH3); HRMS calcd for C34H42O3NaSi
[(MþNa)þ]: 549.2795; found: 549.2804; HPLC: (Chiralpak AD-H,
dimethylsilyloxy-3-methylenehexa-1,5-diene
(3)
(225
mg,
1.0 mmol) was added at 0 ꢁC. The reaction mixture was allowed to
warm slowly to 20 ꢁC and after stirring for 5 h was directly sub-
jected to flash chromatography using hexane/AcOEt (9:1) as an
eluent. Purification afforded 240 mg (73% yield) of cycloadduct 4 as
2% i-PrOH in hexane, 1.0 mL/min,
or, tR¼4.3 mindminor).
l
¼206 nm, tR¼3.9 mindmaj
4.2.6. (2S)-(5-Allyl-4-tert-butyldimethylsilyloxy-3,6-dihydro-2H-py-
ran-2-yl)methyl benzoate (6b). To a cooled (0 ꢁC) solution of crude
alcohol 5 (1.00 g, w3.5 mmol), Et3N (0.71 g, 7.0 mmol), and 4-
dimethylaminopyridine (0.042 g, 0.35 mmol) in CH2Cl2 (20 mL),
was added dropwise benzoyl chloride (0.74 g, 5.27 mmol). The
reaction mixture was allowed to warm slowly to room temperature
and after stirring for 1 day was washed with an aqueous solution of
NaHCO3 (5%, 30 mL) and extracted with CH2Cl2 (3ꢂ10 mL). The
combined organic phases were dried over Na2SO4, filtered, con-
centrated in vacuo, and purified by short column chromatography
using hexane/AcOEt (90:10) as an eluent. The (2S)-(5-allyl-4-tert-
butyldimethylsilyloxy-3,6-dihydro-2H-pyran-2-yl)methyl benzo-
ate was isolated with 63% yield (858 mg). IR (film) 2932, 2859,1719,
1692, 1451, 1379, 1211, 1177, 1111, 876, 839 cmꢀ1; 1H NMR (500 MHz,
a colorless oil with 98.5% ee (for other reaction conditions, see Table
20
1). [a
]
ꢀ153.2 (c 2.0, CHCl3); IR (film) 3408, 2956, 2931, 2858,
D
1738, 1692, 1472, 1305, 1256, 1220, 1184, 1118, 1030, 903, 840,
780 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
5.79e5.59 (m, 1H),
5.10e4.90 (m, 2H), 4.37e4.18 (m, 4H), 4.11 (d, J¼14.8 Hz, 1H), 2.83
(dd, J¼15.4, 6.5 Hz, 1H), 2.72 (dd, J¼15.4, 6.5 Hz, 1H), 2.51e2.25 (m,
2H), 1.31 (t, J¼7.1 Hz, 3H), 0.95 (sm, 9H), 0.15 (s, 3H), 0.14 (s, 3H); 13
C
NMR (126 MHz, CDCl3)
d 170.9 (C]O), 139.9 (C), 135.3 (CH), 115.6
(CH2), 111.3 (C), 73.3 (CH), 66.9 (CH2), 61.2 (CH2), 32.5 (CH2), 30.4
(CH2), 25.7 (CH3), 18.1 (C), 14.2 (CH3), ꢀ3.6 (CH3), ꢀ4.90 (CH3);
HRMS calcd for
349.1797; HPLC (Chiralpak AS-H, 1% i-PrOH in hexane, 1.0 mL/min,
C
17H30O4NaSi [(MþNa)þ]: 349.1806; found:
l¼206 nm, tR(S)-4¼4.3 mindmajor, tR(R)-4¼6.1 mindminor).
CDCl3)
d 8.10e8.04 (m, 2H), 7.59e7.52 (m, 1H), 7.48e7.41 (m, 2H),
4.2.4. (2S)-(5-Allyl-4-tert-butyldimethylsilyloxy-3,6-dihydro-2H-py-
ran-2-yl)methanol (5). To a vigorously stirred solution of the
cycloadduct 4 (1.00 g, 3.06 mmol) in dry Et2O (20 mL) cooled to
5.77e5.64 (m, 1H), 5.10e4.94 (m, 2H), 4.40 (dd, J¼11.7, 3.9 Hz, 1H),
4.36 (dd, J¼11.7, 6.5 Hz, 1H), 4.12 (s, 2H), 4.03e3.92 (m, 1H), 2.85
(dd, J¼15.1, 5.8 Hz, 1H), 2.75 (dd, J¼15.0, 6.7 Hz, 1H), 2.34e2.22 (m,
1H), 2.10e1.99 (m, 1H), 0.95 (s, 9H), 0.13 (2ꢂs, 6H); 13C NMR
0
ꢁC, a suspension of LiAlH4 (0.223 g, 6.12 mmol) in Et2O (20 mL)
was added dropwise. After 10 min, the reaction mixture was
quenched by the addition of acetone (5 mL). Longer reduction
time increases amount of impurities. After a few minutes, a satu-
rated aqueous solution of Na2SO4 (5 mL), solid Na2SO4 (0.5 g), and
AcOEt (20 mL) were added. The mixture was vigorously stirred to
give a transparent organic phase and a gray solid phase, which
was extracted with EtOAc (2ꢂ20 mL). Combined organic phases
were dried over Na2SO4, filtered, and concentrated under reduced
pressure, to give quantitatively crude primary alcohol 5 (0.87 g) as
a colorless oil. IR (film) 3591, 2931, 2859, 1691, 1377, 1206, 1179,
(126 MHz, CDCl3) d 166.5 (C), 140.3 (C), 135.5 (CH), 133.0 (CH), 130.0
(C), 129.7 (CH), 128.3 (CH), 115.5 (CH2), 111.5 (C), 72.7 (CH), 67.3
(CH2), 66.7 (CH2), 32.3 (CH2), 30.6 (CH2), 25.7 (CH3), 18.1 (C), ꢀ3.6
(CH3), ꢀ3.8 (CH3); HRMS calcd for C22H32O4NaSi [(MþNa)þ]:
411.1962; found: 411.1961.
4.2.7. Rubottom oxidation of 6a. To a suspension of silyl enol ether
6a (350 mg, 0.664 mmol) and solid NaHCO3 (111 mg, 1.32 mmol) in
AcOEt (8 mL) at 0 ꢁC was added dropwise a pre-cooled (0 ꢁC) so-
lution of m-CPBA (250 mg, 0.87 mmol, 60% of purity) in AcOEt
(8 mL). After stirring for 1 h at 0 ꢁC, the excess of m-CPBA was
decomposed by addition of a saturated aqueous solution of Na2SO3
(1 mL). The reaction mixture was washed with an aqueous solution
of NaHCO3 (5%, 20 mL) and extracted with AcOEt (3ꢂ10 mL). The
combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was dissolved in THF (10 mL),
cooled to 0 ꢁC and solution of pre-cooled (0 ꢁC) Bu4NF$3H2O
(0.314 g, 0.99 mmol) in THF (10 mL) was added. After stirring for
15 min, an aqueous solution of NaHCO3 (5%, 20 mL) was added and
product was extracted with AcOEt (3ꢂ15 mL). Combined organic
phases were dried over Na2SO4, filtered, concentrated in vacuo, and
subjected to column chromatography using hexane/AcOEt (9:1) as
an eluent. Purification afforded w55:45 mixture of isomers
1063, 997, 867, 840 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 5.76e5.63
(m, 1H), 5.06e4.93 (m, 2H), 4.09 (d, J¼0.7 Hz, 2H), 3.73e3.64 (m,
2H), 3.62e3.53 (m, 1H), 2.86 (dd, J¼15.1, 6.3 Hz, 1H), 2.70 (dd,
J¼15.0, 6.8 Hz, 1H), 2.25e2.11 (m, 2H), 1.91e1.81 (m, 1H), 0.93 (s,
9H), 0.13 (2ꢂs, 6H); 13C NMR (126 MHz, CDCl3)
d 140.7 (C), 135.6
(CH), 115.5 (CH2), 111.4 (C), 75.1 (CH), 67.2 (CH2), 65.4 (CH2), 31.6
(CH2), 30.6 (CH2), 25.7 (CH3), 18.1 (C), ꢀ3.6 (CH3), ꢀ3.9 (CH3);
HRMS calcd for
307.1699.
C
15H28O3NaSi [(MþNa)þ]: 307.1700; found:
4.2.5. (2S)-5-Allyl-4-tert-butyldimethylsilyloxy-2-trityloxymethyl-
3,6-dihydro-2H-pyran (6a). To solution of crude alcohol
(0.87 g, w3.06 mmol) in CH2Cl2 (15 mL), at room temperature
a
5

8468
J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
trans/cis-7a with 85% yield after two steps (131 mg of the first-
eluted trans-7a and 111 mg of second-eluted cis-7a).
hexane/AcOEt compared to trans-7b; [
a
]
20 þ30.5 (c 1.20, CHCl3); IR
D
(film) 3553, 2957, 1723, 1602, 1452, 1316, 1178, 1151, 1113, 1071,
926 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 8.05e7.98 (m, 2H),
4.2.7.1. (2S,5S)-5-Allyl-5-hydroxy-2-(trityloxymethyl)-tetrahy-
7.62e7.54 (m, 1H), 7.49e7.41 (m, 2H), 5.84e5.72 (m, 1H), 5.23e5.13
(m, 2H), 4.54 (dd, J¼11.9, 6.3 Hz, 1H), 4.47e4.40 (m, 1H), 4.38 (dd,
J¼11.9, 3.6 Hz, 1H), 3.94 (d, J¼12.0 Hz, 1H), 3.78 (d, J¼12.0 Hz, 1H),
3.46 (s, 1H), 2.87e2.74 (m, 2H), 2.70 (dd, J¼14.3, 7.2 Hz, 1H), 2.45
20
dropyran-4-one (trans-7a). [
a
]
ꢀ60.1 (c 1.17, CHCl3); IR (film)
D
3495, 2926, 2875, 1717, 1491, 1449, 1220, 1146, 1079, 1054,
926 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
7.44e7.37 (m, 5H), 7.36e7.18
(m, 10H), 5.84e5.69 (m, 1H), 5.19e5.10 (m, 2H), 4.21e4.12 (m, 1H),
3.84 (d, J¼11.8 Hz, 1H), 3.70 (d, J¼11.8 Hz, 1H), 3.44 (s, 1H),
3.29e3.19 (m, 2H), 2.76e2.61 (m, 3H), 2.43 (dd, J¼14.3, 7.3 Hz, 1H);
(dd, J¼14.3, 7.4 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d 207.0 (C), 166.1
(C), 133.3 (CH), 131.2 (CH), 129.7 (CH), 129.4 (C), 128.5 (CH), 119.7
(CH2), 76.7 (C), 74.9 (CH), 72.9 (CH2), 65.4 (CH2), 40.2 (CH2), 39.1
(CH2); HRMS calcd for C16H18O5Na [(MþNa)þ]: 313.1047; found:
313.1050.
13C NMR (126 MHz, CDCl3)
d 207.7 (C), 143.4 (C), 131.5 (CH), 128.6
(CH), 127.9 (CH), 127.2 (CH), 119.4 (CH2), 87.2 (C), 76.7 (C), 76.3 (CH),
73.0 (CH2), 64.9 (CH2), 40.7 (CH2), 39.2 (CH2); HRMS calcd for
C
28H28O4Na [(MþNa)þ]: 451.1880; found: 451.1902; HPLC: 98.0% ee
4.2.9. WackereTsuji oxidation: (2S,5S)-5-hydroxy-5-(2-oxopropyl)-
2-(trityloxymethyl)-tetrahydropyran-4-one (trans-8a). A 25-mL
round-bottomed flask was charged with (2S,5S)-trans-7a (122 mg,
0.284 mmol), PdCl2 (5.1 mg, 0.029 mmol), CuCl (29 mg, 0.29 mmol)
in a 7:1 mixture of DMF (5 mL) and H2O (0.72 mL). The resulting
dark-brown solution was stirred at room temperature under an
oxygen atmosphere (1 atm). After 12 h, an aqueous solution of
NaHCO3 (5%, 5 mL) was added and extracted with Et2O (10 mL) and
next with AcOEt (2ꢂ10 mL). The combined organic phases were
dried over Na2SO4, filtered, concentrated in vacuo, and purified by
column chromatography using hexane/AcOEt (8:2) as an eluent.
(Chiralpak AD-H, 3% i-PrOH in hexane, 1.0 mL/min,
tR¼7.9 mindmajor, tR¼12.5 mindminor).
l¼206 nm,
4.2.7.2. (2S,5R)-5-Allyl-5-hydroxy-2-(trityloxymethyl)-tetrahy-
dropyran-4-one (cis-7a). Isomer with lower Rf value in 7:3 hexane/
20
AcOEt compared to trans-7a; [
a]
þ14.1 (c 1.24, CHCl3); IR (film)
D
3549, 2925, 2877, 1721, 1491, 1449, 1223, 1150, 1078, 999, 925 cmꢀ1
;
1H NMR (500 MHz, CDCl3)
d
7.50e7.43 (m, 5H), 7.38e7.11 (m, 10H),
5.78e5.66 (m, 1H), 5.22e5.09 (m, 2H), 4.09 (d, J¼11.2 Hz, 1H), 3.83
(s, 1H), 3.80e3.72 (m, 1H), 3.32 (dd, J¼10.6, 3.6 Hz, 2H), 3.22 (dd,
J¼9.9, 4.5 Hz, 1H), 2.88e2.70 (m, 2H), 2.58 (dd, J¼14.3, 6.6 Hz, 1H),
The product trans-8a was isolated as a white solid with yield in the
20
2.47 (dd, J¼14.1, 2.6 Hz, 1H); 13C NMR (126 MHz, CDCl3)
d
209.6 (C),
range of 62e85%. (2S,5S)-8a: [
a]
ꢀ20.2 (c 1.2, CHCl3); IR (film)
D
143.7 (C), 131.0 (CH), 128.6 (CH), 127.9 (CH), 127.2 (CH), 119.2 (CH2),
86.7 (C), 78.7 (CH), 78.1 (C), 75.4 (CH2), 65.6 (CH2), 42.1 (CH2), 41.1
(CH2); HRMS calcd for C28H28O4Na [(MþNa)þ]: 451.1880; found:
451.1899; HPLC: 98.0% ee (Chiralpak AD-H, 3% i-PrOH in hexane,
3458, 3058, 2872, 1724, 1679, 1490, 1449, 1359, 1215, 1153, 1125,
1078, 747, 705 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
7.45e7.35 (m, 6H),
7.33e7.26 (m, 6H), 7.26e7.20 (m, 3H), 4.19 (s,1H), 4.01 (d, J¼11.2 Hz,
1H), 3.79e3.70 (m, 1H), 3.37 (d, J¼16.7 Hz, 1H), 3.27 (dd, J¼9.9,
4.3 Hz,1H), 3.24e3.16 (m, 2H), 3.12 (d, J¼16.7 Hz,1H), 2.91e2.78 (m,
J¼13.3, 11.6 Hz, 1H), 2.58 (dd, J¼13.4, 2.8 Hz, 1H), 2.19 (s, 3H); 13C
1.0 mL/min,
l¼206 nm, tR¼21.6 mindmajor, tR¼24.3 mindminor).
4.2.8. Rubottom oxidation of 6b. To a suspension of silyl enol ether
6b (370 mg, 0.952 mmol) and solid NaHCO3 (160 mg, 1.90 mmol) in
AcOEt (10 mL) at 0 ꢁC was added dropwise a pre-cooled (0 ꢁC)
solution of m-CPBA (356 mg, 1.24 mmol, 60% of purity) in AcOEt
(10 mL). After stirring for 1 h at 0 ꢁC, the excess of m-CPBA was
decomposed by addition of a saturated aqueous solution of Na2SO3
(1 mL). The reaction mixture was washed with an aqueous solution
of NaHCO3 (5%, 20 mL) and extracted with AcOEt (3ꢂ10 mL). The
combined organic phases were dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was dissolved in THF (10 mL),
cooled to 0 ꢁC and solution of pre-cooled (0 ꢁC) Bu4NF$3H2O
(0.450 g, 1.43 mmol) in THF (10 mL) was added. After stirring for
15 min, an aqueous solution of NaHCO3 (5%, 20 mL) was added and
product was extracted with AcOEt (3ꢂ15 mL). Combined organic
phases were dried over Na2SO4, filtered, concentrated in vacuo, and
subjected to column chromatography using hexane/AcOEt (9:1) as
an eluent. Purification afforded w1:1 mixture of isomers trans/cis-
7b with 90% yield after two steps (128 mg of the first-eluted trans-
7b and 122 mg of second-eluted cis-7b).
NMR (151 MHz, CDCl3) d 207.9 (C), 206.3 (C), 143.6 (C), 128.6 (CH),
127.9 (CH), 127.2 (CH), 86.8 (C), 79.6 (CH), 76.4 (CH2), 65.6 (CH2),
50.1 (CH2), 42.3 (CH2), 31.3 (CH3); HRMS calcd for C28H28O5Na
[(MþNa)þ]: 467.1829; found: 467.1852; HPLC: 98.0% ee (Chiralpak
AD-H, 5% i-PrOH in hexane, 1.0 mL/min,
tR¼18.2 mindmajor, tR¼22.2 mindminor).
l¼206 nm,
4.2.9.1. (2S,5R)-5-Hydroxy-5-(2-oxopropyl)-2-(trityloxymethyl)-
tetrahydropyran-4-one (cis-8a). Prepared according to the analo-
gous procedure for trans-8a. The product cis-8a was isolated with
65% yield. IR (film) 3425, 3058, 2925, 1719, 1491, 1448, 1412, 1362,
1221, 1177, 1093, 1076, 765, 706 cmꢀ1 1H NMR (600 MHz, CDCl3)
;
d
7.48e7.42 (m, 6H), 7.34e7.28 (m, 6H), 7.28e7.23 (m, 3H), 4.83 (s,
1H), 4.03 (d, J¼12.0 Hz, 1H), 3.92e3.85 (m, 1H), 3.51 (d, J¼12.0 Hz,
1H), 3.36 (dd, J¼9.8, 5.5 Hz, 1H), 3.20 (dd, J¼9.8, 5.1 Hz, 1H),
3.09e3.00 (m, 1H), 2.90 (d, J¼16.7 Hz, 1H), 2.54e2.39 (m, 2H), 2.30
(s, 3H); 13C NMR (151 MHz, CDCl3)
d 209.5 (C), 206.6 (C), 143.6 (C),
128.6 (CH), 127.9 (CH), 127.1 (CH), 86.8 (C), 78.4 (CH), 77.4 (C), 75.3
(CH2), 65.6 (CH2), 43.5 (CH2), 41.7 (CH2), 31.5 (CH3); HPLC: 98.0% ee
(Chiralpak AD-H, 5% i-PrOH in hexane, 1.0 mL/min,
l
¼206 nm,
4.2.8.1. ((2S,5S)-5-Allyl-5-hydroxy-4-oxo-tetrahydro-2H-pyran-
tR¼25.3 mindminor, tR¼28.5 mindmajor); LRMS calcd for
2-yl)methyl benzoate (trans-7b). [
a
]
D
20 ꢀ87.4 (c 1.14, CHCl3); IR (film)
C
28H28O5Na [(MþNa)þ]: 467.2; found: 467.2.
3497, 2959, 2863, 1721, 1452, 1177, 1148, 1111, 1044, 926 cmꢀ1
;
1H
NMR (500 MHz, CDCl3)
d
8.04e7.95 (m, 2H), 7.55e7.49 (m, 1H),
4.2.9.2. ((2S,5S)-5-Hydroxy-5-(2-oxopropyl)-4-oxo-tetrahydro-
7.45e7.35 (m, 2H), 5.72e5.57 (m, 1H), 5.15e5.01 (m, 2H), 4.47e4.30
(m, 2H), 4.04 (d, J¼11.3 Hz, 1H), 4.00e3.90 (m, 1H), 3.75 (s, 1H), 3.31
(d, J¼11.4 Hz, 1H), 2.77e2.61 (m, 2H), 2.60e2.44 (m, 2H); 13C NMR
2H-pyran-2-yl)methyl benzoate (trans-8b). Prepared according to
the analogous procedure for trans-8a. The product (2S,5S)-8b was
isolated with 57% yield. [
a
]
D
20 ꢀ31.1 (c 0.9, CHCl3) [lit.,3b
[a
]
20 ꢀ31.6 (c
D
(126 MHz, CDCl3)
d
208.4 (C), 166.1 (C), 133.4 (CH), 130.8 (CH), 129.7
1.2, CHCl3)]; IR (film) 3456, 2859, 1722, 1451, 1361, 1274, 1157, 1112,
(CH), 129.5 (C), 128.5 (CH), 119.4 (CH), 77.9 (C), 77.1 (CH), 75.2 (CH2),
65.9 (CH2), 41.6 (CH2), 41.1 (CH2); HRMS calcd for C16H18O5Na
[(MþNa)þ]: 313.1047; found: 313.1054.
1071, 713 cmꢀ1 1H NMR (600 MHz, CDCl3)
; d 8.10e8.00 (m, 2H),
7.61e7.55 (m, 1H), 7.48e7.42 (m, 2H), 4.47 (dd, J¼11.8, 3.8 Hz, 1H),
4.42 (dd, J¼11.8, 5.7 Hz, 1H), 4.20 (s, 1H), 4.03 (d, J¼11.3 Hz, 1H),
4.02e3.97 (m, 1H), 3.33 (d, J¼16.6 Hz, 1H), 3.26 (d, J¼11.3 Hz, 1H),
3.12 (d, J¼16.6 Hz, 1H), 2.88e2.81 (m, 1H), 2.72 (dd, J¼13.3, 2.8 Hz,
4.2.8.2. ((2S,5R)-5-Allyl-5-hydroxy-4-oxo-tetrahydro-2H-pyran-
2-yl)methyl benzoate (cis-7b). Isomer with lower Rf value in 7:3
1H), 2.19 (s, 3H); 13C NMR (151 MHz, CDCl3)
d 206.8 (C), 206.3 (C),

J. Majer et al. / Tetrahedron 69 (2013) 8463e8469
8469
2. Fiskesund, R.; Abeyama, K.; Yoshinaga, K.; Abe, J.; Yuan, Y.; Yu, S. Planta Med.
2010, 76, 1635e1641.
166.00 (C), 133.3 (CH), 129.6 (CH), 129.5 (C), 128.5 (CH), 78.0 (CH),
76.8 (C), 76.2 (CH2), 65.8 (CH2), 50.0 (CH2), 41.8 (CH2), 31.4 (CH3);
HRMS calcd for C16H18O6Na [(MþNa)þ]: 329.0996; found: 329.1002.
€
3. (a) Brehm, M.; Dauben, W. G.; Kohler, P.; Lichtenthaler, F. W. Angew. Chem., Int.
€
Ed. Engl. 1987, 26, 1271e1273; (b) Brehm, M.; Gockel, V. H.; Jarglis, P.; Lich-
tenthaler, F. W. Tetrahedron: Asymmetry 2008, 19, 358e373.
4. For reviews, see: (a) Pellissier, H. Tetrahedron 2009, 65, 2839e2877; (b)
Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558e3588.
5. (a) Rubottom, G. M.; Vazquez, M. A.; Pellagrina, D. R. Tetrahedron Lett. 1974, 15,
4319e4322; (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org. Chem. 1975, 40,
3427e3429; (c) Brook, A. G.; Macrae, D. M. J. Organomet. Chem. 1974, 77,
C19eC21.
6. Selected examples of applications to natural product synthesis: (a) Larson, E. R.;
Danishefsky, S. J. Am. Chem. Soc. 1982, 104, 6458e6460; (b) Danishefsky, S. J.;
Larson, E.; Askin, D.; Kato, N. J. Am. Chem. Soc. 1985, 107, 1246e1255; (c) Hrib, N.
J. Tetrahedron Lett. 1987, 28, 19e22; (d) Taber, D. F.; Christos, T. E.; Rheingold, A.
L.; Guzei, I. A. J. Am. Chem. Soc. 1999, 121, 5589e5590; (e) Thompson, C. F.;
Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482e10483; (f)
Ghosh, K. A.; Li, J. Org. Lett. 2009, 11, 4164e4167.
7. (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger, R.; Kojer,
H. Angew. Chem. 1959, 71, 176e182; (b) Clement, W. H.; Selwitz, C. M. J. Org.
Chem. 1964, 29, 241e243; (c) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth.
1984, 62, 9e13.
8. Commercially available or obtained from chloroacetone and triethyl phosphite
in the presence of stoichiometric amount of KI; 75% yield Kitamura, M.; To-
kunaga, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 2931e2932.
9. (a) Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60, 5757e5762; (b)
Graven, A.; Johannsen, M.; Jørgensen, K. A. Chem. Commun. 1996, 2373e2374;
(c) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.; Inoue, Y. J. Org. Chem.
1999, 64, 8660e8667; (d) Kwiatkowski, P.; Asztemborska, M.; Caille, J.-C.; Ju-
rczak, J. Adv. Synth. Catal. 2003, 345, 506e509.
10. (a) Terada, M.; Mikami, K.; Nakai, T. Tetrahedron Lett. 1991, 32, 935e938; (b)
Mikami, K.; Motoyama, Y.; Terada, M. J. Am. Chem. Soc. 1994, 116, 2812e2820;
(c) Motoyama, Y.; Terada, M.; Mikami, K. Synlett 1995, 967e968; (d) Christ-
mann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse, M. Angew. Chem., Int. Ed.
2000, 39, 4364e4366; (e) Quitschalle, M.; Christmann, M.; Bhatt, U.; Kalesse,
M. Tetrahedron Lett. 2001, 42, 1263e1265; (f) Kwiatkowski, P.; Asztemborska,
M.; Jurczak, J. Synlett 2004, 1755e1758; (g) Kwiatkowski, P.; Asztemborska, M.;
Jurczak, J. Tetrahedron: Asymmetry 2004, 15, 3189e3194; (h) Berkessel, A.; Vogl,
N. Eur. J. Org. Chem. 2006, 5029e5035.
11. (a) Motoyama, Y.; Mikami, K. J. Chem. Soc., Chem. Commun. 1994, 1563e1564; (b)
Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K. Tetrahedron: Asymmetry
1996, 7, 2165e2168; (c) Matsukawa, S.; Mikami, K. Tetrahedron: Asymmetry
1997, 8, 815e816; (d) Qian, C.; Wang, L. Tetrahedron Lett. 2000, 41, 2203e2206;
(e) Motoyama, Y.; Koga, Y.; Nishiyama, H. Tetrahedron 2001, 57, 853e860; (f)
Tonoi, T.; Mikami, K. Tetrahedron Lett. 2005, 46, 6355e6358.
4.2.9.3. ((2S,5R)-5-Hydroxy-5-(2-oxopropyl)-4-oxo-tetrahydro-
2H-pyran-2-yl)methyl benzoate (cis-8b). Prepared according to the
analogous procedure for trans-8a. The product (2S,5R)-8b was iso-
lated with 60% yield. IR (film) 3441, 2958,1719,1451,1362,1275,1177,
1113, 1071, 713 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
8.05 (d, J¼7.8 Hz,
2H), 7.58 (t, J¼7.4 Hz, 1H), 7.45 (t, J¼7.8 Hz, 2H), 4.99e4.86 (m, 1H),
4.48 (dd, J¼11.8, 6.3 Hz, 1H), 4.42 (dd, J¼11.8, 4.0 Hz, 1H), 4.08 (dd,
J¼11.2, 4.9 Hz, 2H), 3.53 (d, J¼12.1 Hz, 1H), 3.17 (dd, J¼13.4, 10.5 Hz,
1H), 2.90 (d, J¼16.9 Hz, 1H), 2.52 (dd, J¼13.4, 3.2 Hz, 1H), 2.44 (d,
J¼16.9 Hz, 1H), 2.29 (s, 3H); 13C NMR (151 MHz, CDCl3)
d 209.5 (C),
205.8 (C), 166.2 (C), 133.2 (CH), 129.7 (CH), 129.5 (C), 128.4 (CH), 77.4
(C), 76.8 (CH), 75.3 (CH2), 65.9 (CH2), 43.3 (CH2), 40.8 (CH2), 31.5
(CH3); LRMS calcd for C16H18O6Na [(MþNa)þ]: 329.3; found: 329.1.
4.2.10. (ꢀ)-Bissetone. To
a solution of (2S,5S)-8a (100 mg,
0.225 mmol) in CH2Cl2 (8 mL) was added solid FeCl3$6H2O (122 mg,
0.45 mmol). The mixture was stirred at room temperature, moni-
tored by TLC and after 0.5 h was directly subjected to flash chro-
matography using hexane/AcOEt (4:1)/AcOEt as an eluent.
Purification afforded 36 mg of a colorless oil (78% yield). [
a
]
20 ꢀ52.1
D
20
(c 0.5, CHCl3) [lit.,3b
CDCl3)
[
a
]
D
ꢀ69.4 (c 1.0, EtOH)]; 1H NMR (400 MHz,
d
4.19 (br s, 1H), 4.04 (d, J¼11.3 Hz, 1H), 3.80 (dd, J¼11.8,
2.8 Hz, 1H), 3.74 (dm, J¼11.7 Hz, 1H), 3.62 (dd, J¼11.8, 5.2 Hz, 1H),
3.28 (d, J¼16.5 Hz,1H), 3.26 (d, J¼11.3 Hz,1H), 3.11 (d, J¼16.5 Hz,1H),
2.87 (dd, J¼13.3,11.6 Hz,1H), 2.54 (dd, J¼13.3, 2.7 Hz,1H), 2.21 (s, 3H)
1.7 (br s,1H); 13C NMR (101 MHz, CDCl3)
d 207.6 (C]O), 206.3 (C]O),
80.6 (CH), 77.2 (C), 76.2 (CH2), 64.9 (CH2), 49.8 (CH2), 41.1 (CH2), 31.5
(CH3); LRMS calcd for C9H14O5Na [(MþNa)þ]: 225.1; found: 225.0.
Acknowledgements
12. (a) Momiyama, N.; Tabuse, H.; Terada, M. J. Am. Chem. Soc. 2009, 131,
12882e12883; (b) Li, L.-S.; Wu, Y.; Hu, Y.-J.; Xia, L.-J.; Wu, Y.-L. Tetrahedron:
Asymmetry 1998, 9, 2271e2277; (c) Hu, Y.-J.; Huang, X.-D.; Yao, Z.-J.; Wu, Y.-L. J.
Org. Chem. 1998, 63, 2456e2461.
Authors thank Zambon for the generous support.
13. (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111, 1940e1941; (b)
Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 3949e3954.
14. (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993, 115, 8467e8468;
(b) Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58
6543e6544; (c) Keck, G. E.; Li, X.; Krishnamurthy, D. J. Org. Chem. 1995, 60,
5998e5999.
15. (a) Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2011, 13, 5944e5947; (b)
Majer, J.; Kwiatkowski, P.; Jurczak, J. Org. Lett. 2009, 11, 4636e4639; (c) Majer, J.;
Kwiatkowski, P.; Jurczak, J. Org. Lett. 2008, 10, 2955e2958.
Supplementary data
Copies of 1H, 13C NMR spectra, HPLC chromatograms, and crys-
tallographic data. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.07.048.
References and notes
16. Use of dry toluene is not necessary for high enantioselectivity.
17. A typical reduction time in diethyl ether is ca. 10 min. After longer reaction time
more impurities was observed.
1. Cardellina, J. H., II; Hendrickson, R. L.; Manfredi, K. P.; Strobel, S. A.; Clardy, J.
18. Sogah, G. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1979, 101, 3035e3042.
Tetrahedron Lett. 1987, 28, 727e730.