Natural (5′-oxoheptene-1′E,3′E-dienyl)-5,6-dihydro-2H- pyran-2-one: Total synthesis and revision of its absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2004.01.143

The synthesis of (5′-oxoheptene-1′E,3′E-dienyl)-5,6- dihydro-2H-pyran-2-one has been performed in seven steps using four key steps: a ring-closing metathesis reaction to build up the unsaturated lactone, a Wittig reaction to control the C6-C7 (E) double bond, a cross-metathesis reaction to control the (E) double bond at C8-C9, and an enantioselective allyltitanation to control the absolute configuration at C5. Spectroscopic data (IR, MS, ¹H, and ¹³C NMR) were identical to those of the natural compound except for the optical rotation, which led us to re-assign the absolute configuration of the natural product.

Full text of DOI:10.1016/j.tetlet.2004.01.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2615–2617
Natural (50-oxoheptene-10E,30E-dienyl)-5,6-dihydro-2H-pyran-2-
one: total synthesis and revision of its absolute configuration
a
a,
b
c
Samir Bouzbouz,a,* Elsa de Lemos, Janine Cossy, Jairo Saez, Xavier Franck and
*
c,
*
ꢀ
Bruno Figadere
aLaboratoire de Chimie Organique associꢁe au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris, Cedex 05, France
bInstitute of Chemistry, Universidad de Antioquia, PO Box 1226, Medellin, Colombia
cLaboratoire de Pharmacognosie associꢁe au CNRS (BioCIS), Universitꢁe Paris-Sud, Facultꢁe de Pharmacie, rue J-B. Clꢁement,
92296 Ch^atenay-Malabry, France
Received 1 December 2003; revised 19 January 2004; accepted 28 January 2004
Abstract—The synthesis of (50-oxoheptene-10E,30E-dienyl)-5,6-dihydro-2H-pyran-2-one has been performed in seven steps using
four key steps: a ring-closing metathesis reaction to build up the unsaturated lactone, a Wittig reaction to control the C6–C7 (E)
double bond, a cross-metathesis reaction to control the (E) double bond at C8–C9, and an enantioselective allyltitanation to control
the absolute configuration at C5. Spectroscopic data (IR, MS, 1H, and 13C NMR) were identical to those of the natural compound
except for the optical rotation, which led us to re-assign the absolute configuration of the natural product.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently Saez and co-workers reported the isolation of a
new 6-substituted 5,6-dihydro-a-pyranone from Rai-
mondia cf monoica (Annonaceae), possessing leishman-
icide activity, namely (S)-(50-oxoheptene-10E,30E-
dienyl)-5,6-dihydro-2H-pyran-2-one A.1 In the same
study a known compound was also isolated: the (R)-
(50-oxoheptene-10Z,30E-dienyl)-5,6-dihydro-2H-pyran-2-
one B whose absolute configuration was determined to
be (R) by analysis of its CD spectrum.2
O
1
O
2
O
5
O
O
E
E
7
E
9
11
Z
3
4
12
O
A
B
Reported structure: C5 (S)
Revised structure : C5 (R)
Reported structure: C5 (R)
Revised structure : C5 (S)
Figure 1.
Since compound A had the opposite sign for both its
specific rotation (½aꢀ þ60:8°, c 9.2, EtOH)1 and Cotton
compound, based on the use of the highly enantio-
selective allyltitanium complex (R,R)-I6 (Scheme 1), which
produces homoallylic alcohols with the (S) configura-
tion, to verify the absolute configuration in compound A
at C5. The control of the (Z) double bond at C2–C3
would be achieved by using a ring-closing metathesis
reaction (RCM), whereas the (E) double bond at C8–C9
would be controlled by using a cross-metathesis reaction
(CM)7 between acrolein and pent-1-en-3-ol 1. The (E)
double bond at C6–C7 would be controlled by applying
a Wittig reaction to aldehyde 2 (Scheme 1).
D
effect (kmax 260 nm, De ¼ þ5:24)1 relative to those of B
(½aꢀ ꢁ48°, c 0.125, EtOH and Cotton effect: kmax
D
260 nm, De ¼ ꢁ4:7),1 the (S) absolute configuration was
proposed for the natural compound A (Fig. 1).1
Previously, the C5 substituted unsaturated lactones
present in fostriecin,3 passifloricin,4 and strictifolione5
were synthesized by using enantioselective allyltitanium
complexes to control the absolute configuration at C5.
As a similar C5-substituted unsaturated lactone is
present in compound A, we decided to synthesize this
Treatment of pent-1-en-3-ol 1 with 3 equiv of acrolein in
the presence of HoveydaÕs catalyst (3 mol %) at 25 °C in
CH2Cl2 led to aldehyde 2 in 80% yield, and with an E/Z
ratio superior to 30:1 (Scheme 2). To control the (E)
double bond at C6–C7, aldehyde 28 was treated with the
* Corresponding authors. Tel.: +33-01-46-83-55-92; fax: +33-01-46-83-
53-99; e-mail addresses: samir.bouzbouz@espci.fr (S.B.); janine.
cossy@espci.fr (J.C.); bruno.figadere@cep.u-psud.fr (B.F.)
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.143

2616
S. Bouzbouz et al. / Tetrahedron Letters 45 (2004) 2615–2617
enantioselective allyltitanium complex (R,R)-I (ether,
CM
O
Wittig
S
)78 °C). Treatment of allylic alcohol 5 with acryloyl
chloride (i-Pr2NEt, CH2Cl2 )78 °C), produced the cor-
responding ester 6 in 96% yield, which after a ring-
closing metathesis reaction, induced by GrubbsÕ catalyst
II10 (CH2Cl2, reflux 12 h), furnished lactone 7 in 23%
yield. The spectroscopic data of 7 were identical to those
of the natural product A except for the specific rotation
O
O
RCM
H
OH
CM
2
O
A
allyltitanation
Ph
Ph
(½aꢀ ꢁ 32° c 0.10, EtOH), which has the opposite sign of
O
O
Ti
O
D
O
+
the specific rotation reported for the extracted natural
compound A. We were thus forced to re-examine the
assignment of the absolute configuration of the natural
lactone A.
H
OH
O
Ph
Ph
1
(R,R)-I
Re-examination of SnatzkeÕs rules,11 modified by Bee-
cham,12 led us to re-attribute the (R) absolute configu-
ration at C5 for the natural compound A. In fact,
unsaturated six-membered lactones substituted at C5,
which show a positive Cotton effect in their CD spec-
trum, (due to the carbonyl n–pꢂ transition) have (R)
absolute configurations.11–13 The chromophoric enone
side chain (weak n–pꢂ at kmax around 310–330 nm) can
adopt different conformations but the energy difference
between these conformations is small and their contri-
butions to the Cotton effect are substantially compen-
sated.11
Scheme 1.
O
H
O
CO2Et
O
3'
+
a
b
OH
1
OH
2
EtO
O
3
4
c
OH
O
d
H
In conclusion, the synthesis of (S)-(50-oxoheptene-
O
O
5
10E,30E-dienyl)-5,6-dihydro-2H-pyran-2-one
7
was
e
accomplished in seven steps and with good enantiomeric
excess, from pent-1-en-3-ol. We also conclude that the
natural compound A has the (R) absolute configuration
at C5, implying that the natural compound B has the (S)
absolute configuration at C5.
O
O
O
O
f
O
O
6
7
N
N
PCy
Ru
3
Cl
Cl
Cl
Acknowledgements
Ru
Cl
Ph
O
PCy
3
We wish to thank the CNRS for financial support.
Hoveyda's catalyst
Grubbs' catalyst II
Scheme 2. Reagents and conditions: (a) acrolein, HoveydaÕs catalyst
(3 mol %), CH2Cl2, 25 °C, 80%; (b) Ph3PCHCO2Et, toluene, 110 °C; (c)
(i) Dibal-H, CH2Cl2, )78 °C; (ii) MnO2, CH2Cl2, rt, 15% from 2; (d)
(R,R)-I, ether, )78 °C, 4 h, 50%; (e) acryloyl chloride, i-Pr2NEt,
CH2Cl2, )78 °C, 96%; (f) GrubbsÕ catalyst II, (5 mol %), refluxing
CH2Cl2, 12 h, 23%.
References and notes
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ꢀ
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stabilized ylide ethyl (triphenylphosphoranylidene)ace-
tate, in toluene at 110 °C. Under these conditions, the
reaction was not stereoselective and the dienes 3 (E/E)
and 30 (Z/E) were obtained in a 4 to 1 ratio. These two
dienes were separated by flash chromatography on silica
gel. Aldehyde 4, which will allow the control of the C5
stereogenic center present in A, was prepared in two
steps from 3. After reduction of 3 by Dibal-H (CH2Cl2,
)78 °C), the resulting diol was directly oxidized by
MnO2 (CH2Cl2, 25 °C), and the (E)-aldehyde 4 was
isolated in an overall yield of 15% from 2. Aldehyde 4
was then transformed into the desired (S) homoallylic
alcohol 59 in 50% yield by using the chemoselective and
8. Spectroscopic data for compound 2:
1H NMR (CDCl3,) d: 9.38 (d, J ¼ 8:1 Hz, 1H); 6.60 (dd,
J ¼ 15:8 and 4.4 Hz, 1H); 6.02 (ddd, J ¼ 16:2, 8.1, and
1.5 Hz, 1H); 4.06 (q apparent, J ¼ 5:5 Hz, 1H); 3.46 (s
large, OH); 1.46–1.21 (m, 2H); 0.73 (t, J ¼ 7:4 Hz, 3H) 13
C

S. Bouzbouz et al. / Tetrahedron Letters 45 (2004) 2615–2617
2617
NMR (CDCl3, 75 MHz) d: 194.2 (d); 160.1 (d); 130.3 (d);
71.7 (d); 29.0 (t); 9.3 (q).
MS (IE) m/z (70 eV): 114 (M+,0.01); 85 (80); 57 (100).
MS (IE) m/z (70 eV): 180 (M+ꢃ, 0.2); 139 (M)C3H5, 89); 81
(22); 57 (100).
10. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
11. Snatzke, G. Angew. Chem., Int. Ed. Engl. 1968, 7, 14.
12. Beecham, A. F. Tetrahedron 1972, 28, 5543.
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9. Spectroscopic data for compound 5:
20
D
½aꢀ ꢁ 11° (c, 0.21, CHCl3).
IR (neat): 3400, 1650; 1600, 1205, 1000 cmꢁ1
.
1H NMR (CDCl3,) d: 7.08 (dd, J ¼ 15:4 and 10.3 Hz, 1H);
6.30 (dd, J ¼ 14:7 and 10.7 Hz, 1H); 6.10 (m, 2H); 5.70
(ddd, J ¼ 17:6, 13.6, and 2.6 Hz, 1H); 5.08 (m, 2H); 4.25
(m, 1H+OH); 2.55 (q, J ¼ 7:4 Hz, 2H); 2.30 (m, 2H); 1.05
(t, J ¼ 7:3 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d: 201.2
(s); 144.8 (d); 141.4 (d); 133.4 (d); 129.3 (d); 127.8 (d);
118.6 (t); 70.5 (d); 41.4 (t); 33.5 (t); 8.0 (q).