Total synthesis of (+/-)-diospongin A via Prins reaction

Article abstract of DOI:10.1016/j.tet.2007.05.089

A straightforward synthesis of (+/-)-diospongin A starting from benzaldehyde is described. A Prins cyclization reaction to control the relative configuration of the three stereogenic centers and a Mitsunobu inversion represent the key steps of the approac

Full text of DOI:10.1016/j.tet.2007.05.089

Tetrahedron 63 (2007) 7874–7878
Total synthesis of (D/L)-diospongin A via Prins reaction
Marie-Aude Hiebel,a,b,c Beatrice Pelotiera,b,c and Olivier Pivaa,b,c,
*
ꢀ
a
´
´
ICBMS, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires, Equipe CheOPS; CNRS, UMR 5246,
43 boulevard du 11 novembre 1918, Villeurbanne, F-69622, France
b
´
Universite de Lyon, Lyon, F-69622, France
Universite Lyon 1, Lyon, F-69622, France
c
´
Received 26 April 2007; revised 21 May 2007; accepted 22 May 2007
Available online 26 May 2007
Abstract—A straightforward synthesis of (+/ꢀ)-diospongin A starting from benzaldehyde is described. A Prins cyclization reaction to
control the relative configuration of the three stereogenic centers and a Mitsunobu inversion represent the key steps of the approach.
Ó 2007 Elsevier Ltd. All rights reserved.
O
OH
1. Introduction
MeO
HO
OMe
OH
Diarylheptanoids are a family of biologically active natural
products isolated from Asian herbs or plants.1–3 A well-
known representative found in Alpinia officinarum Chinese
medicinal herb is curcumin, which has various biological
properties such as anticancer,4 anti-inflammatory,5 and anti-
oxidative6 activities (Fig. 1). The structure of diarylhepta-
noids is either linear or cyclic like in diarylether 1, which
was found to show antileishmanial activity.7
curcumin
HO
MeO
HO
O
1
Figure 1. Linear and cyclic diarylheptanoids.
Among cyclic diarylheptanoids, some compounds present a
tetrahydropyran ring in their structure. In particular, the caly-
xin natural products isolated from Alpinia blepharocalyx
seeds show interesting cytotoxic activities (Fig. 2). The syn-
thesis of several compounds of this family was reported
using a strategy based on a Prins cyclization to form the core
2,4,6-cis-trisubstituted tetrahydropyran.8,9 A new family of
diarylheptanoids, diospongins, recently isolated from the
rhizomes of Dioscorea spongiosa exhibit promising inhibi-
tory activities on bone resorption and could be used for the
treatment of osteoporosis, a skeletal disease.10
rearrangement.13a,14–18 Various parameters like the nature
of the Lewis acid,19–22 the solvent23,24 or the source of heat-
ing,25 have a profound impact on the efficiency of the reac-
tion in terms of chemical yields and selectivities.
OMe
O
HO
OH
OH
Tetrahydropyran is a very common subunit found in numer-
ous natural products. Different strategies have already been
designed to have a rapid access to these structures.11 Among
them, cyclizations of oxocarbenium ions and especially the
Prins reaction have been extensively considered.12,13 Suit-
able conditions are now at the disposal of organic chemists
to avoid epimerization of the center directly linked to the
oxygen atom, which could occur via an oxonia Cope
O
HO
OH
calyxin L
OH
S
O
S
R
O
Keywords: Diarylheptanoid; Tetrahydropyran; Diospongin A; Prins
cyclization.
* Corresponding author. Tel./fax: +33 478 448631; e-mail: olivier.piva@
univ-lyon1.fr
diospongin A
Figure 2. Tetrahydropyranyl diarylheptanoids.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.089

M.-A. Hiebel et al. / Tetrahedron 63 (2007) 7874–7878
7875
Due to the interesting antiosteoporotic activity of diospon-
gins, syntheses of these natural products have been recently
reported.26–29 In particular, diospongin Awas obtained either
via a stereoselective reduction of the oxocarbenium derived
from the corresponding lactol27 or via an intramolecular
oxy-Michael addition from the linear diarylheptanoid pre-
cursor obtained by cross metathesis27,29 to form the tetrahy-
dropyran ring. The rapid access to analogs of thisbiologically
active natural product could lead to more active derivatives.
In this purpose, the Prins reaction seemed to us a very power-
ful method to apply to the synthesis of diospongin A as it
allows both the control of the three stereogenic centers on
the tetrahydropyran ring and the rapid variation of the sub-
strates, in particular the aldehyde counterpart and the nucleo-
phile introduced in C4-position.
homoallylic alcohol 7 and benzaldehyde led to tetrahydro-
pyran 8 as the sole diastereoisomers, which was directly
saponified into the corresponding alcohol 9, an epimer of
diospongin A, in 83% yield over the two steps. To the best of
our knowledge, this is the first example of an acid-mediated
Prins cyclization using a b-hydroxyketone. The reaction
proceeded in high yield and the potentially competing elim-
ination to an enone was not observed.
In order to invert in 9 the stereocenter bearing the hydroxyl
group, a method described by Mukaiyama was first tested.31
For compatibility reason with the ketone moiety, we had to
slightly modify the procedure and used sodium hydride as
base to assure the deprotonation of the alcohol. Instead of
the expected p-methoxyphenylester, a nonpolar structurewas
isolated in 44% yield and identified as the corresponding
chloride 10 (Scheme 3). This side reaction, which occurred
with a total inversion of the sterocenter can be easily
explained by a competitive attack of chloride ions on the ac-
tivated intermediate alkoxyphosphine. The Mitsunobu reac-
tion was next considered.32–35 The reaction was carried out
with p-nitrobenzoic acid and delivered the corresponding
ester, which was further saponified into (+/ꢀ)-diospongin A.
2. Results and discussion
Our strategy for the synthesis of (+/ꢀ)-diospongin A de-
picted on Scheme 1 is thus based on the formation of the
2,4,6-cis-trisubstituted tetrahydropyran ring via a Prins re-
action carried out between benzaldehyde and homoallylic
alcohol 7. A final inversion step is then required to invert
the C4-hydroxyl group.
OH
Cl
a,b
O
O
OH
OH
O
Ph
O
Ph
c,d
Ph
O
O
Ph
Mitsunobu
O
O
9
10
Ph
O
Ph
Ph
Ph
OH
O
diospongin A
Prins
O
(+/-)-diospongin A
+
Ph
O
HO
Ph
Scheme 3. Reagents and conditions: (a) NaH, 7, THF, 0 ꢁC then diphenyl-
phosphine chloride, 0 ꢁC to rt; (b) 2,6-dimethylbenzoquinone, p-anisic acid,
CH2Cl2, reflux (44% over two steps); (c) PPh3, DEAD, p-nitrobenzoic acid,
CH2Cl2, rt; (d) NaOH, MeOH, THF, H2O (71%, over 2 steps).
Scheme 1. Retrosynthetic analysis of diospongin A.
The homoallylic alcohol 7 was prepared from benzaldehyde
in a straightforward sequence involving two allylation reac-
tions and a selective oxidation of the benzylic alcohol 6
(Scheme 2). The TFA-promoted Prins reaction30 between
3. Conclusion
In conclusion, we have achieved the total synthesis of (+/ꢀ)-
diospongin A in 23% overall yield. A Prins reaction using an
unsaturated b-hydroxyketone represents the key step to build
the 2,4,6-cis-trisubstituted tetrahydropyran ring with a total
diastereocontrol. This convergent route could allow a rapid
access to diarylheptanoid analogs, in particular by variation
of the aromatic aldehydes or the nucleophile used in the
Prins reaction.
O
OH
OTBS
c
b
a
Ph
Ph
Ph
d
Ph
2
3
OTBS
CHO
TBSO
Ph
OH
OH OH
e
Ph
4
6
5
OR
O
OH
g
O
f
4. Experimental
4.1. General
Ph
Ph
h
O
Ph
7
(R = COCF3)
(R = H)
8
9
1H, 13C, DEPT NMR spectra were recorded on a Bruker AM
€
Scheme 2. Reagents and conditions: (a) allylmagnesium bromide, Et2O,
0 ꢁC to rt, 100%; (b) TBDMSCl, imidazole, DMF, rt, 84%; (c) O3,
CH2Cl2, ꢀ60 ꢁC then PPh3, ꢀ60 ꢁC to rt, 87%; (d) allylmagnesium bro-
mide, Et2O, 0 ꢁC to rt, 92%; (e) TBAF, THF, rt, 97%; (f) MnO2, CH2Cl2,
reflux, 61%; (g) benzaldehyde, TFA, CH2Cl2, rt; (h) NaOH, MeOH, 83%
(over two steps).
300 MHz NMR spectrometer, which provided all necessary
data for the full assignment of each compound. Chemicals
shifts were reported in parts per million. High resolution
mass spectrometry (HRMS) analyses were conducted using
a ThermoFinigan-MAT 95 XL instrument. IR spectra were

7876
M.-A. Hiebel et al. / Tetrahedron 63 (2007) 7874–7878
measured on a Perkin–Elmer Spectrum One FTIR spectro-
meter. Melting points were measured on a B-540 B€uchi
apparatus. TLC analyses were performed on plates (layer
thickness 0.25 mm) and were visualized with UV light,
phosphomolybdic acid or p-anisaldehyde solution. Column
chromatography was performed on silica gel (40–63 mm)
using ethyl acetate (EtOAc) and hexanes as eluants. When
appropriate, solvents and reagents were dried by distillation
over appropriate drying agent prior to use. Diethyl ether and
tetrahydrofuran were distilled from Na/benzophenone and
used fresh. Dichloromethane was distilled from CaH2.
bromide solution was added to a solution of aldehyde 4
(600 mg, 2.27 mmol) in dry ether (23 mL) at 0 ꢁC. The ice
bath was then removed and the reaction followed by TLC.
The reaction mixture was quenched with a saturated aqueous
ammonium chloride solution and the aqueous phase ex-
tracted with ethyl acetate (3ꢂ20 mL). The combined organic
layers were washed with brine (3ꢂ50 mL), dried with mag-
nesium sulfate, and concentrated under reduced pressure.
The 50:50 syn/anti mixture of diastereoisomers 5, were
isolated by flash-chromatography with EtOAc/hexanes 2:98
as eluent (colorless oil, 3.74 g, 25.3 mmol, 92%). Diastereo-
1
isomer syn: H NMR (300 MHz, CDCl3) d ꢀ0.25 (s, 3H),
4.1.1. 4-(tert-Butyldimethylsilyloxy)-4-phenylbut-1-ene
(3). To a solution of 1-phenylbut-3-en-1-ol (1.48 g,
10 mmol) in 35 mL of dimethylformamide were added
imidazole (1.02 g, 15 mmol) and tert-butyldimethylsilyl-
chloride (1.808 g, 12 mmol) at rt. Upon completion, the
reaction mixture was quenched with water (20 mL) and di-
chloromethane (20 mL) was added. The aqueous phase
was extracted with dichloromethane (2ꢂ20 mL). The com-
bined organic layers were washed with an aqueous saturated
ammonium chloride solution (3ꢂ40 mL), dried over MgSO4
and concentrated in vacuo. A flash-chromatography (EtOAc/
hexanes, 5:95 as eluent) afforded 3 as a colorless oil (2.20 g,
ꢀ0.04 (s, 3H), 0.89 (s, 9H), 1.72–1.92 (m, 2H), 2.17–2.29
(m, 2H), 3.48 (br s, 1H), 3.83–3.90 (m, 1H), 4.87
(dd, J¼9.42, 4.0 Hz, 1H), 5.04–5.10 (m, 2H), 5.82
(ddt, J¼17.9, 10.7, 7.0 Hz, 1H), 7.26–7.30 (m, 5H); 13C
NMR (75 MHz, CDCl3) d ꢀ4.8, ꢀ4.1, 18.3, 26.1 (3C),
42.3, 46.8, 70.8, 76.7, 117.8, 126.3 (2C), 127.8, 128.6
(2C), 135.0, 145.0; IR (neat) 3088, 3065, 3032, 2956, 2930,
2888, 2858, 2721, 1728, 1604, 1494, 1472, 1463, 1455,
1406, 1362, 1307, 1290, 1257, 1217, 1097, 1028, 1005, 978,
939, 914, 838, 778, 701 cmꢀ1; Rf¼0.25 (EtOAc/hexanes,
1
5:95). Diastereoisomer anti: H NMR (300 MHz, CDCl3)
d 0.11 (s, 3H), ꢀ0.07 (s, 3H), 0.90 (s, 9H), 1.79–1.83 (m,
2H), 2.16–2.21 (m, 2H), 3.09 (br s, 1H), 3.78–3.87 (m, 1H),
5.02–5.09 (m, 3H), 5.82 (ddt, J¼14.1, 9.7, 7.2 Hz, 1H),
7.26–7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) d ꢀ4.9,
ꢀ4.4, 18.5, 26.1 (3C), 42.5, 46.0, 67.7, 73.7, 117.7, 126.0
(2C), 127.4, 128.5 (2C), 135.2, 144.6; IR (neat) 3088,
3065, 3032, 2956, 2930, 2888, 2858, 2721, 1728, 1604,
1494, 1472, 1463, 1455, 1406, 1362, 1307, 1290, 1257,
1217, 1097, 1028, 1005, 978, 939, 914, 838, 778,
701 cmꢀ1; Rf¼0.20 (EtOAc/hexanes, 5:95).
1
8.4 mmol, 84%). H NMR (300 MHz, CDCl3) d ꢀ0.12 (s,
3H), 0.04 (s, 3H), 0.89 (s, 9H), 2.38 (dt, JAB¼13.9 Hz,
J¼5.3 Hz, 1H), 2.47 (dt, JAB¼13.9 Hz, J¼7.2 Hz, 1H),
4.69 (dd, J¼7.2, 5.3 Hz, 1H), 4.99–5.05 (m, 2H), 5.72–
5.86 (m, 1H), 7.29–7.31 (m, 5H); 13C NMR (75 MHz,
CDCl3) d ꢀ4.6, ꢀ4.3, 18.6, 26.2, 45.9, 75.4, 117.2, 126.2,
127.3, 128.3, 135.6, 145.5. IR (neat) 3078, 2957, 2930,
2896, 2858, 1642, 1493, 1472, 1463, 1454, 1362, 1257,
1089, 1069, 1006, 914, 836, 776, 700 cmꢀ1; Rf¼0.90
(EtOAc/hexanes, 5:95).
4.1.4. 1-Phenylhex-5-en-1,3-diol (6). To a solution of alco-
hol 5 (798 mg, 2.9 mmol) in tetrahydrofuran (30 mL) was
added a solution of TBAF (1 N in tetrahydrofuran, 4.3 mL).
After 2 h stirring at rt, the reaction mixture was concentrated
under reduced pressure and purified by column chromato-
graphy eluting with EtOAc/hexanes 20:80 to afford diol 6
as a 50:50 syn/anti mixture of diastereosiomers, which were
4.1.2. 3-(tert-Butyldimethylsilyloxy)-3-phenylpropanal-
dehyde (4). A solution of compound 3 (1.59 g, 6.05 mmol)
in dichloromethane (60 mL) was cooled to ꢀ60 ꢁC under
nitrogen. Ozone was then bubbled through the solution until
it became blue. The mixture was then flushed with nitrogen
and triphenylphosphine (1.74 g, 6.7 mmol) was added. The
solution was allowed to warm up to rt and after 3 h, methyl
iodide (300 mL, 6.7 mmol) was added. After overnight stir-
ring, the mixturewas filtered and concentrated under reduced
pressure. The residue was purified by column chromato-
graphy eluting with EtOAc/hexanes 5:95 to afford 4 as a col-
1
not separated (colorless oil, 537 mg, 2.80 mmol, 97%). H
NMR (300 MHz, CDCl3) d 1.69–1.79 (m, 2H), 2.13–2.18
(m, 2H), 3.65 (br s, 2H), 3.78–3.89 (m, 1H), 4.79 (dd,
J¼8.1, 5.1 Hz, 1H, isomer 1), 4.92 (dd, J¼8.1, 3.8 Hz, 1H,
isomer 2), 5.00–5.05 (m, 2H), 5.70 (ddt, J¼17.0, 9.6,
7.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) [two diastereoiso-
mers] d 42.1, 42.6, 44.3, 44.8, 68.2, 71.5, 71.8, 75.1, 118.2,
118.3, 125.8 (2C), 126.0 (2C), 127.4, 127.8, 128.6 (2C),
128.7 (2C), 134.4, 134.8, 144.6, 144.8. IR (neat) 3692–
3120, 3071, 3027, 2978, 2914, 1641, 1492, 1454, 1328,
1202, 1084, 1062, 996, 916, 759, 701 cmꢀ1; Rf¼0.30
(EtOAc/hexanes, 30:70).
1
orless oil (1.40 g, 5.29 mmol, 87%). H NMR (300 MHz,
CDCl3) d ꢀ0.14 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 2.85–
2.66 (m, 1H), 2.85 (ddd, JAB¼15.6 Hz, J¼8.1, 2.6 Hz, 1H),
5.22 (dd, J¼8.1, 4.0 Hz, 1H), 7.33–7.35 (m, 5H), 9.78–
9.80 (m, 1H); 13C NMR (75 MHz, CDCl3) d ꢀ4.8, ꢀ4.3,
18.4, 26.0 (3C), 53.3, 71.0, 126.0 (2C), 127.9, 128.8 (2C),
144.1, 201.7. IR (neat) 3078, 2957, 2930, 2896, 2858,
1642, 1493, 1472, 1463, 1454, 1362, 1257, 1089, 1069,
1006, 914, 836, 776, 700 cmꢀ1; Rf¼0.30 (EtOAc/hexanes,
5:95).
4.1.5. 3-Hydroxy-1-phenylhex-5-en-1-one (7). To a solu-
tion of 1-phenylhex-5-en-1,3-diol 6 (192 mg, 1 mmol) in
CH2Cl2 (20 mL) was added MnO2 (860 mg, 10 mmol). After
stirring for 3 h under reflux, the reaction mixture was filtered
over Celite and the residue washed with CH2Cl2 (100 mL).
The filtrate was concentrated in vacuo and purified by flash
column chromatography (EtOAc/hexanes, 15:85) to give
4.1.3. 1-(tert-Butyldimethylsilyloxy)-1-phenylhex-5-en-
3-ol (5). In a round bottom flask equipped with a reflux
condenser and a dropping funnel was placed magnesium
(381 mg, 15.9 mmol) and a catalytic amount of iodide. A
solution of allylbromide (990 mL, 11.4 mmol) in dry ether
(12 mL) was then added dropwise. The allylmagnesium
1
7 as a yellow oil (115 mg, 0.61 mmol, 61%). H NMR
(300 MHz, CDCl3) d 1.64 (br s, 1H), 2.37 (qd, J¼5.8,

M.-A. Hiebel et al. / Tetrahedron 63 (2007) 7874–7878
7877
1.1 Hz, 2H), 3.06 (dd, J¼17.7, 8.7 Hz, 1H), 3.20 (dd, J¼17.7,
3.2 Hz, 1H), 4.27–4.35 (m, 1H), 5.13–5.20 (m, 2H), 5.89
(ddt, J¼17.1, 10.2, 7.1 Hz, 1H), 7.45–7.61 (m, 3H), 7.94–
7.97 (m, 2H); 13C NMR (75 MHz, CDCl3) d 41.2, 44.5,
67.5, 118.2, 128.4 (2C), 129.0 (2C), 133.8, 134.6, 137.0,
200.9. IR (neat) 3436, 3077, 2923, 1682, 1600, 1449,
1210 cmꢀ1; Rf¼0.60 (EtOAc/hexanes, 30:70).
7.20 (br s, 5H), 7.38 (dd, J¼7.7, 7.1 Hz, 2H), 7.49 (dd,
J¼7.5, 7.1 Hz, 1H), 7.91 (dd, J¼7.1, 1.1 Hz 2H); 13C NMR
(75 MHz, CDCl3) d 38.9, 41.1, 44.9, 56.6, 69.4, 73.9, 126.1
(2C), 127.8, 128.6 (2C), 128.7(2C), 128.9 (2C), 133.5, 137.5,
142.1, 198.1. IR (KBr) 2958, 2908, 1586, 1255, 1057,
800 cmꢀ1. Rf¼0.50 (EtOAc/hexanes, 20:80); mp¼78.8–
81.2 ꢁC; HRMS (CI) calcd for C19H19O2Cl (M+H+)
315.1152, found 315.1154.
4.1.6. 2-(4-Hydroxy-6-phenyl-tetrahydropyran-2-yl)-
1-phenyl-ethanone (9). Trifluoroacetic acid (1.9 mL,
24.8 mmol) was added to a solution of homoallylic alcohol 6
(115 mg, 0.60 mmol) and benzaldehyde (140 mL, 1.4 mmol)
in dry CH2Cl2 (6 mL) under nitrogen. The reaction was fol-
lowed by TLC and upon completion the reaction mixture
was quenched with an aqueous saturated sodium hydrogen
carbonate solution (12 mL) and the pH was adjusted to >7
by addition of triethylamine. The aqueous phase was ex-
tracted with CH2Cl2 (3ꢂ15 mL) and the combined organic
layers were dried over MgSO4, filtered off, and concentrated
under reduced pressure. The resulting crude trifluoroacetate
8 was then dissolved in MeOH (6 mL) and stirred with so-
dium hydroxide (150 mg, 3.75 mmol) overnight. MeOH was
then removed under reduced pressure and water (20 mL) was
added. The mixture was extracted with CH2Cl2 (3ꢂ20 mL)
and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The product was then
purified by flash column chromatography (EtOAc/hexanes,
40:60) to afford 9 as an orange solid (148 mg, 0.5 mmol)
4.1.8. (D/L)-Diospongin A. To a stirred mixture of alcohol
9
(75 mg, 0.25 mmol), triphenylphosphine (100 mg,
0.38 mmol), and p-nitrobenzoic acid (64 mg, 0.38 mmol)
in toluene (5 mL) at rt was dropwise added diethylazodi-
carboxylate (60 mL, 0.38 mmol). After 5 min, the orange
solution became homogenous and three new additions of
reagents were necessary to obtain completion. Silica (1 g)
was then added and the mixture concentrated under reduced
pressure to give a solid residue, which was rapidly purified
by flash column chromatography (eluant: EtOAc/hexanes,
2:98). The fractions containing the intermediate ester were
collected, concentrated and, diluted in MeOH (9 mL), THF
(4.5 mL), and water (4.5 mL). Sodium hydroxide (160 mg,
4 mmol) was added to the mixture, which was stirred at rt,
overnight. After removal of the organic solvents, the result-
ing aqueous phase was extracted with CH2Cl2 (3ꢂ10 mL).
The combined organic layers were dried over MgSO4 and af-
ter filtration, concentrated under vacuo. The crude product
was purified by flash column chromatography (EtOAc/
hexanes, 30:70) to yield (+/ꢀ)-diospongin A (53 mg,
0.18 mmol) as a white solid in 71% yield over two steps.
1H NMR (300 MHz, CDCl3) d 1.64–1.81 (m, 2H), 1.94–
1.99 (m, 2H), 2.08 (br s, 1H), 3.08 (dd, JAB¼16.0 Hz,
J¼6.8 Hz, 1H), 3.43 (dd, JAB¼16.0 Hz, J¼5.6 Hz, 1H),
4.37 (t, J¼2.6 Hz, 1H), 4.62–4.70 (m, 1H), 4.94 (dd,
J¼11.7, 1.5 Hz, 1H), 7.23–7.31 (m, 5H), 7.45 (dd, J¼7.9,
7.2 Hz, 2H), 7.48–7.56 (m, 1H), 7.99 (dd, J¼8.6, 1.5 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 38.7, 40.3, 45.5, 64.9,
69.4, 74.1, 126.1 (2C), 127.5, 128.5 (2C), 128.6 (2C),
128.8 (2C), 133.4, 137.5, 143.0, 198.8. IR (KBr) 3467,
3056, 2921, 1683, 1449, 1211, 1058, 700 cmꢀ1. Rf¼0.35
(EtOAc/hexanes, 40:60); mp¼83.4–84.0 ꢁC.
1
in 83% yield over two steps. H NMR (300 MHz, CDCl3)
d 1.36 (q, J¼11.6 Hz, 1H), 1.51 (q, J¼11.5 Hz, 1H), 1.60
(br s, 1H), 2.22 (dd, J¼12.1, 4.5 Hz, 2H), 3.10 (dd,
JAB¼16.4 Hz, J¼6.4 Hz, 1H), 3.48 (dd, JAB¼16.4 Hz,
J¼6.0 Hz, 1H), 4.05 (tt, J¼10.9, 4.7 Hz, 1H), 4.16–4.23
(m, 1H), 4.43 (dd, J¼11.3, 1.1 Hz, 1H), 7.28–7.31 (m, 5H),
7.43–7.54 (m, 3H), 7.96–7.99 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 41.2, 42.8, 45.2, 68.5, 72.9, 77.9, 126.2 (2C),
127.8, 128.6 (4C), 128.9 (2C), 133.5, 137.5, 142.1, 198.4.
IR (KBr) 3402, 2947, 2914, 1683, 1449, 1063 cmꢀ1. Rf¼
0.30 (EtOAc/hexanes, 40:60); mp¼82.4–86.8 ꢁC; HRMS
(ESI) calcd for C19H20O3Na (M+Na+) 319.1310, found
319.1311.
4.1.7. 2-(4-Chloro-6-phenyl-tetrahydropyran-2-yl)-1-
phenyl-ethanone (10). To a stirred solution of alcohol 9
(49 mg, 0.17 mmol) in dry THF (700 mL) was added sodium
hydride (60% in oil, 7 mg, 0.17 mmol) at 0 ꢁC under nitro-
gen. The ice bath was removed and the reaction mixture
stirred at rt for 1 h. Chlorodiphenylphosphine (30 mL,
0.17 mmol) was then added at 0 ꢁC. The resulting mixture
was stirred for 1 h at rt and the solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2
(200 mL) and 2,6-dimethylbenzoquinone (24 mg, 0.17 mmol)
and p-anisic acid (25 mg, 0.17 mmol) were added at once
under nitrogen. The reaction was followed by TLC and
quenched with water (1 mL). The aqueous layer was ex-
tracted with CH2Cl2 (3ꢂ5 mL) and the organic phases were
dried over MgSO4, filtered off, and concentrated. The residue
was purified by flash column chromatography (EtOAc/hex-
anes, 7:93) to afford 10 (23 mg, 0.07 mmol) as a white solid
in 43% yield. 1H NMR (300 MHz, CDCl3) d 1.79–1.95 (m,
2H), 2.05–2.13 (m, 2H), 2.99 (dd, JAB¼15.9 Hz, J¼6.2 Hz,
1H), 3.33 (dd, JAB¼15.9 Hz, J¼6.2 Hz, 1H), 4.60 (t, J¼
3.0 Hz, 1H), 4.64–4.70 (m, 1H), 4.92 (d, J¼11.1 Hz, 1H),
Acknowledgements
This work was partly supported by European Union FP6 In-
tegrated Project No 503467.
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