Simple synthesis of conjugated all-(E)-polyenic aldehydes, ketones, and esters using chemoselective cross-metathesis and an iterative sequence of reactions: Application to the synthesis of navenone B

Article abstract of DOI:10.1055/s-0028-1087953

By using a very simple sequence of reactions such as allylation, acetylation, chemoselective cross-metathesis, and elimination, even and odd conjugated all-(E)-polyenes can be synthesized from very simple alkenes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087953

LETTER
803
Simple Synthesis of Conjugated All-(E)-Polyenic Aldehydes, Ketones, and
Esters Using Chemoselective Cross-Metathesis and an Iterative Sequence of
Reactions: Application to the Synthesis of Navenone B
Synthesis of
N
a
avenone
B
mir BouzBouz,*a,b Christophe Roche,a Janine Cossy*a
a
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: janine.cossy@espci.fr; E-mail: samir.bouzbouz@univ-rouen.fr
Laboratoire de Chimie Organique, UFR Médecine-Pharmacie, CNRS, 22 Boulevard Gambetta, 76183 Rouen Cedex 03, France
b
Received 15 November 2008
ing allylations, acetylations, chemoselective cross-meta-
theses,14 and domino elimination.
Abstract: By using a very simple sequence of reactions such as al-
lylation, acetylation, chemoselective cross-metathesis, and elimina-
tion, even and odd conjugated all-(E)-polyenes can be synthesized
from very simple alkenes.
Depending on the first transformation of alkenes of type
A either to an a,b-unsaturated aldehydes B (cross-meta-
Key words: polyenes, cross-metathesis, elimination, allylation, thesis) or to aldehydes of type B¢ (oxidative cleavage of
navenone B
the double bond), conjugated odd all-(E)-polyenes of type
C or conjugated even all-(E)-polyenes of type C¢ were
synthesized (Scheme 1).
Conjugated all-(E)-polyenes are present in a great variety
O
O
of natural products of biological interest such as, for ex-
ample, antibiotics1 (filipin III), immunosuppressive
agents (pseudotrienic acid),2 and anticoagulants (tetra-
fibricin)3 (Figure 1). Among the different protocols that
have been reported to synthesize conjugated all-(E)-poly-
enes, we can cite iterative Wittig–Horner reactions,4 as
well as the Corey–Schlessinger–Mills-modified Peterson
olefination,5 iterative Pd-catalyzed cross-couplings such
as Stille coupling,6 Suzuki–Miyaura coupling,7 Negishi
coupling,8 Sonogashira coupling,9 treatment of dienic
benzoates with Na/Hg,10 Julia–Lythgoe olefination,11 or
ring opening of bicyclo[4.2.0]octadiene acetate with
LiAlH4.12
CM
[O]
R1
H
R1
H
O
R1
B
A
B'
O
R2
R1
R2
R1
n
n
C
n = 2,4,6...
odd all-(E)-polyenes
C'
n = 4,6...
even all-(E)-polyenes
Scheme 1
Alkene A, which at first was chosen to produce conjugat-
ed odd and even all-(E)-polyenes of type C and C¢, was
the protected but-1-en-3-ol 1. We have to point out that
the allylation of intermediate aldehydes of type B and B¢
were achieved using either allylmagnesium chloride or
allyltrichlorosilane15 in order to obtain the corresponding
Herein, we would like to report the synthesis of conjugat-
ed odd all-(E)-polyenes of type C as well as conjugated
even all-(E)-polyenes of type C¢13 from simple alkenes of
type A by using an iterative sequence of reactions involv-
OH OH OH OH OH OH
C5H11
O
O
OH
H
N
O
HO
N
H
OH
O
O
HO
OH
OH
filipin III
pseudotrienic acid
HO2C
HO
OH OH
OH
OH
OH OH OH OH
tetrafibricin
O
H2N
OH
Figure 1
SYNLETT 2009, No. 5, pp 0803–0807
x
x.
x
x.
2
0
0
9
Advanced online publication: 25.02.2009
DOI: 10.1055/s-0028-1087953; Art ID: G36308ST
© Georg Thieme Verlag Stuttgart · New York

804
S. BouzBouz et al.
LETTER
homoallylic alcohols. Concerning the elimination step, sized 3, the latter compound was also transformed to
the reagents used were either DBU, TBAF, or BF3·OEt2. pentaene 8 by realizing a CM/allylation/acetylation/CM/
Only the reagents producing the best yields for the allyla- domino elimination sequence. Thus, after a chemoselec-
tion and the elimination are reported.
tive CM with acrolein [Ru-II (5 mol%), CH2Cl2, r.t.], a,b-
unsaturated aldehyde 6 was formed, which after an allyla-
tion (allylMgCl, Et2O, –78 °C)/acetylation sequence led
to 7 (58%). The latter compound was then converted into
8 after a chemoselective CM with ethyl acrylate followed
by an elimination step using TBAF. Another conjugated
odd all-(E)-polyene, heptaene 11, was also obtained from
the previously synthesized trienic diacetate 7. After a
chemoselective CM with acrolein in the presence of Ru-
II, followed by an allylation (allylSiCl3, DMF, 0 °C)/
acetylation sequence, 10 was isolated (70%) and then
transformed to heptaene 11 after a CM (ethyl acrylate)
followed by treatment with TBAF which induced a dom-
ino elimination (35% overall yield for the two steps)
(Scheme 2).
In order to obtain conjugated odd all-(E)-polyenes of type
C, compound 1 was transformed to the unsaturated alde-
hyde 2 by treatment with acrolein (3 equiv) under cross-
metathesis (CM) conditions [Hoveyda–Grubbs second-
generation catalyst = Ru-II (5 mol%),16 CH2Cl2, r.t., 85%
yield]. Aldehyde 2 was then converted into triene 5 in four
steps. After addition of allylmagnesium chloride (Et2O,
0 °C), the obtained homoallylic alcohol was acetylated
(Ac2O, pyridine, DMAP, CH2Cl2, 0 °C) to produce the
corresponding acetate 3 (for the two steps, 87%) which
was then transformed to conjugated triene 5 in two steps.
Due to the presence of the acetyl group, a chemoselective
CM could be performed with ethyl acrylate14 [Ru-II (5
mol%), CH2Cl2, r.t.] and this reaction resulted in the for-
mation of the nonconjugated dienic ester 417 (69% yield) Compound 3 can be considered as a cornerstone in the
which, after treatment with DBU (THF, 15 min), fur- synthesis of conjugated odd all-(E)-polyenes, as it al-
nished conjugated triene 518 in 54% yield. Having synthe-
O
acrolein
OR
OR
( )
( )
H
2
2
Ru-II, CH2Cl2
r.t., 12 h
85%
2
1
1 - allylMgCl
Et2O, 0 °C, 3 h
2 - Ac2O, DMAP
CH2Cl2–Py
R = TBDPS
87%
0 °C, 12 h
O
OAc
OAc
ethyl acrylate
OR
OR
( )
( )
EtO
2
2
Ru-II, CH2Cl2
r.t., 12 h
69%
4
3
acrolein
Ru-II, CH2Cl2
r.t., 12 h
DBU, THF
r.t., 15 min
62%
54%
O
O
OAc
OTBDPS
OR
( )
EtO
( )
H
2
2
5
6
1 - allylMgCl
Et2O, –78 °C, 1.5 h
2- Ac2O, DMAP
58%
CH2Cl2–Py, 0 °C, 4.5 h
OAc
OAc
O
1 - ethyl acrylate
OR
OH
( )
2
( )
EtO
2
Ru-II, CH2Cl2
12 h, r.t. (67%)
3
7
9
8
acrolein
2 - TBAF, THF
r.t., 12 h (70%)
80%
Ru-II, CH2Cl2
r.t., 12 h
O
OAc
NMes
MesN
OR
( )
2
H
Cl
Cl
2
Ru
1 - allylSiCl3
DMF, 0 °C
O
then r.t., 2 h (76%)
2 - Ac2O, DMAP
CH2Cl2–Py,
Ru-II
0 °C, 2 h (92%)
O
OAc
OAc
1 - ethyl acrylate
OH
OR
( )
)
(
EtO
2
5
2
Ru-II, CH2Cl2
r.t., 12 h (60%)
2
11
10
2 - TBAF, THF
r.t., 24 h (58%)
Scheme 2
Synlett 2009, No. 5, 803–807 © Thieme Stuttgart · New York

LETTER
Synthesis of Navenone B
805
lowed an easy access to triene 5, pentaene 8, and heptaene Other homoallylic alcohols than 1 can be used to prepare
11 (Scheme 2).
conjugated even all-(E)-polyenes. For example, homoal-
lylic alcohol 16 (prepared from p-methoxybenzaldehyde)
was transformed to 19 in five steps (Scheme 4). After a
CM reaction in the presence of acrolein (3 equiv) and Ru-
II (5 mol%, CH2Cl2, r.t.), homoallylic alcohol 16 was con-
verted into unsaturated aldehyde 17 (90%) which was
then treated with allylmagnesium chloride (Et2O, 0 °C)
and, the obtained diol was acetylated (DMAP, Ac2O,
CH2Cl2, r.t.) furnishing diacetate 18. This latter com-
pound was then treated with ethyl acrylate (3 equiv) in the
presence of Ru-II (5 mol%, CH2Cl2, r.t.) and the resulting
CM product 19 was transformed to tetraene 20 after a
domino elimination performed with TBAF (59% overall
yield from 18). Compound 18 was also transformed to 23
in five steps. After a CM reaction with acrolein, 21 was
isolated (61%) and this latter was transformed to 22 by ad-
dition of allyltrichlorosilane (DMF, 0 °C) and acetylation.
In order to synthesize conjugated even all-(E)-polyenes of
type C¢, aldehyde 12 was prepared by oxidative cleavage
of the double bond (OsO4 then NaIO4, t-BuOH/H2O) of
the protected but-3-en-1-ol 1. As for the synthesis of con-
jugated odd all-(E)-polyenes, the same sequence of reac-
tions was used. Thus, trichloroallylsilane was added to 12
and the resulting homoallylic alcohol was involved in a
CM reaction with acrolein (3 equiv) in the presence of Ru-
II (5 mol%, CH2Cl2, r.t.) leading to 13 (49% overall
yield). Unsaturated aldehyde 13 was then transformed to
14 in two steps (allylation with allylMgCl and acetylation,
69% overall yield) and the latter compound was involved
in a CM (ethyl acrylate)/elimination (DBU) sequence to
afford the conjugated ester 15 (54% overall yield)
(Scheme 3).
1 - allylSiCl3
O
[O]
DMF, 0 °C, 12 h
(61%)
O
OH
OR
( )
OR
( )
H
OR
2
2
( )
H
1
2
12
2 - acrolein
Ru-II, CH2Cl2
r.t., 12 h
13
1 - allylMgCl
R = TBDPS
Et2O, 0 °C, 5 h
2 - Ac2O, DMAP
CH2Cl2–Py 0 °C, 12 h
69%
(80%)
OAc
OAc
OR
O
1 - ethyl acrylate
OTBDPS
( )
( )
2
EtO
2
Ru-II, CH2Cl2
r.t., 12 h
(72%)
2
14
15
2 - DBU, THF
r.t., 12 h (75%)
Scheme 3
OH
O
OH
acrolein
Ru-II, CH2Cl2, r.t., 12 h
H
17
MeO
90%
16
MeO
1 - allylMgCl
THF, 0 °C, 1 h
2 - Ac2O, DMAP
CH2Cl2–Py, r.t., 2 h
74%
OAc
ethyl acrylate
OAc
Ru-II
OAc
OAc
O
CH2Cl2, r.t., 16 h
OEt
79%
MeO
19
18
MeO
acrolein
TBAF
THF, r.t., 24 h
75%
61%
OAc
Ru-II,
CH2Cl2, r.t., 16 h
O
OAc
O
OEt
H
MeO
20
21
MeO
1 - allylSiCl3,
DMF, 0 °C, 2 h
2 - Ac2O, DMAP
71%
CH2Cl2–Py, r.t., 2 h
1 - ethyl acrylate
O
Ru-II
OAc
OAc
CH2Cl2, r.t., 16 h
OEt
2
2
2 - TBAF
THF, r.t., 24 h
MeO
23
22
MeO
55%
Scheme 4
Synlett 2009, No. 5, 803–807 © Thieme Stuttgart · New York

806
S. BouzBouz et al.
LETTER
OAc
OAc
O
O
BF3⋅OEt2, CH2Cl2
0 °C, 30 min
H
H
48%
MeO
21
24
MeO
OH
Scheme 5
OH
O
acrolein
Ru-II, CH2Cl2, r.t., 16 h
H
90%
26
25
1 - allylMgBr, THF,
0 °C, 1 h
2 - Ac2O, DMAP
CH2Cl2–Py, r.t., 2 h
74%
OAc
OAc
O
1 - MVK
Ru-II, CH2Cl2, r.t., 16 h
2 - TBAF, THF, r.t., 24 h
51%
navenone B
27
Scheme 6
(2) Pohanka, A.; Broberg, A.; Johansson, M.; Kenne, L.;
Levenfors, J. J. Nat. Prod. 2005, 68, 1380.
(3) Kamiyama, T.; Umino, T.; Fujisaki, N.; Fujimori, K.; Satoh,
T.; Yamashita, Y.; Ohshima, S.; Watanabe, J.; Yokose, K.
J. Antibiot. 1993, 46, 1039.
(4) See, for example: (a) Maryanoff, B. E.; Reitz, A. B. Chem.
Rev. 1989, 89, 863. (b) Horner, L.; Hoffmann, H.; Wippel,
J. H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499.
(c) Wadsworth, W. S. Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733.
(5) (a) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett.
1976, 7. (b) Schlessinger, R. H.; Poss, M. A.; Richardson,
S.; Lin, P. Tetrahedron Lett. 1985, 26, 2391. (c) Desmond,
R.; Mills, S. G.; Volante, R. P.; Shinkai, I. Tetrahedron Lett.
1988, 29, 3895.
The resulting triacetate 22 (71% overall yield) was then
converted into the conjugated hexaene 23 (55% yield)
after a CM reaction realized with ethyl acrylate [Ru-II
(5 mol%), CH2Cl2, r.t.] and an elimination step performed
with TBAF (THF, r.t.) (Scheme 4).
If conjugated even all-(E)-polyenic esters, such as 15, 20,
and 23, were obtained easily when the last CM reaction
was achieved by utilizing ethyl acrylate, conjugated all-
(E)-polyenic aldehydes were also synthesized when the
last CM reaction was achieved with acrolein. Thus, com-
pound 21 was converted into 24 in 48% yield after treat-
ment with BF3·OEt2 (0 °C, CH2Cl2) (Scheme 5).
By using methyl vinyl ketone to achieve the last CM reac-
tion, conjugated all-(E)-polyenic ketones can be isolated.
This methodology was used to synthesize navenone B
which is an alarm pheromone secreted by the blind Pacific
opistobranch mollusk Navanax inermis.19,20 When under
duress, this mollusk secretes components which induce an
alarm avoidance response in other Navanax, and among
the compounds, navenone B was isolated. Navenone B
was obtained in five steps from homoallylic alcohol 25.
After a CM with acrolein, 25 was transformed into 26 and
by utilizing an allylation–acetylation sequence, 27 was
formed (74% yield) and converted into navenone B using
a chemoselective CM (involving methyl vinyl ketone)/
elimination (TBAF) sequence (51% overall yield from
27) (Scheme 6).
(6) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
New York, 1988, 167. (c) Farina, V.; Krihnamurthy, V.;
Scott, W. J. The Stille Reaction; John Wiley and Sons: New
York, 1998.
(7) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(c) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
New York, 1998, 49.
(8) Zeng, F.; Negishi, E.-I. Org. Lett. 2001, 3, 719.
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Chinchilla, R.; Nájera, C. Chem.
Rev. 2007, 107, 874.
(10) (a) Solladié, G.; Urbano, A.; Stone, G. B. Synlett 1993, 548.
(b) Solladié, G.; Colobert, F.; Kalaï, C. Tetrahedron Lett.
1993, 34, 6489. (c) Solladié, G.; Colobert, F.; Kalaï, C.
Tetrahedron Lett. 2000, 41, 4197. (d) Solladié, G.; Adamy,
M.; Colobert, F. J. Org. Chem. 1996, 61, 4369.
(11) (a) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833.
(b) Kocienski, P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc.,
Perkin Trans. 1 1978, 829. (c) Keck, G. E.; Savin, K. A.;
Weglarz, M. A. J. Org. Chem. 1995, 6, 3194.
In conclusion, by using a very simple sequence of reac-
tions mainly chemoselective CM, allylation of aldehydes,
elimination, conjugated even and odd all-(E)-polyenes
can be synthesized from very simple alkenes.
References and Notes
(d) Blakemore, R. P.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 26. (e) Kocienski, P. J. Phosphorus Sulfur
Relat. Elem. 1985, 24, 97. (f) Kelly, S. E. Comp. Org. Synth.
1991, 1, 792.
(1) (a) Rychnovsky, S. D.; Richardson, T. I. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1227. (b) Rychnovsky, S. D. Chem. Rev.
1995, 95, 2021.
Synlett 2009, No. 5, 803–807 © Thieme Stuttgart · New York

LETTER
Synthesis of Navenone B
807
(12) (a) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003,
125, 10899. (b) Boschelli, D.; Takemasa, T.; Nishitani, Y.;
Masamune, S. Tetrahedron Lett. 1985, 26, 5339.
(13) For the synthesis of compounds of type C and C¢, R¢ = H,
see: Escher, I.; Glorius, F. Aldehydes, In Science of
Synthesis, Vol 25; Brückner, R., Ed.; Thieme: Stuttgart,
2007, 711.
(14) (a) BouzBouz, S.; Cossy, J. J. Org. Chem. 2001, 3, 1451.
(b) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 6, 3469.
(15) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994, 59, 6620; and
references therein.
133.8, 131.6, 129.6, 129.1, 127.6, 124.2, 72.8, 63.1, 60.3,
37.3, 35.6, 26.8, 21.2, 19.2, 14.2. MS: m/z = 377, 241, 199,
105.
(18) Synthesis of Compound 5
To a solution of nonconjugated dienic ester 4 (147 mg, 0.30
mmol) in THF (1 mL) was added at r.t. DBU (1 mL, 6.7
mmol). The mixture was stirred for 15 min then neutralized
with sat. aq NH4Cl. The layers were separated, and the
aqueous phase was extracted with EtOAc. The combined
organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the residue by flash
chromatography (hexane/EtOAc, 95:5) afforded conjugated
triene 5 (70 mg, 54%) as a pale yellow oil. Rf = 0.61 (hexane/
EtOAc, 9:1). IR: 1710, 1619, 1257 cm–1.1H NMR (300 MHz,
CDCl3): d = 7.66 (m, 4 H), 7.41 (m, 6 H), 7.30 (dd, J = 15.5,
11.5 Hz, 1 H), 6.44 (dd, J = 15.1, 10.2 Hz, 1 H), 6.13 (dd,
J = 15.1, 11.5 Hz, 1 H), 6.09 (dd, J = 14.8, 10.2 Hz, 1 H),
5.92 (dt, J = 14.8, 6.4 Hz, 1 H), 5.85 (d, J = 15.5 Hz, 1 H),
4.13 (q, J = 7.2 Hz, 2 H), 3.69 (t, J = 6.4 Hz, 2 H), 2.39 (q,
J = 6.4 Hz, 2 H), 1.26 (t, J = 7.2 Hz, 3 H), 1.04 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 167.2, 144.7, 140.9, 136.6,
135.6, 133.8, 131.6, 129.6, 128.2, 127.6, 120.3, 63.2, 60.2,
36.3, 26.8, 19.2, 14.3. MS: m/z = 377, 227, 199, 105.
(19) Sleeper, H. L.; Fenical, W. J. Am. Chem. Soc. 1977, 99,
2367.
(16) Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.;
Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A.
Org. Biomol. Chem. 2004, 2, 8.
(17) Synthesis of Compound 4
To a solution of alkene 3 (190 mg, 0.45 mmol) in CH2Cl2
(2.3 mL) was added at r.t. ethyl acrylate (0.15 mL, 1.35
mmol) and Ru-II (14 mg, 0.023 mmol). The reaction
mixture was stirred at r.t. overnight and then concentrated in
vacuo. Purification of the residue by flash chromatography
(hexane/EtOAc, 99:1) afforded 4 (154 mg, 69%) as a yellow
oil. Rf = 0.43 (hexane/EtOAc, 9:1). IR: 1739, 1720, 1656,
1232 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.66 (m, 4 H),
7.41 (m, 6 H), 6.83 (dt, J = 15.8, 7.2 Hz, 1 H), 5.85 (dt,
J = 15.8, 1.5 Hz, 1 H), 5.76 (m, 1 H), 5.47 (dt, J = 15.5,
6.8 Hz, 1 H), 5.34 (m, 1 H), 4.18 (q, J = 6.8 Hz, 2 H), 3.69
(t, J = 6.4 Hz, 2 H), 2.49 (m, 2 H), 2.28 (q, J = 6.8 Hz, 2 H),
2.02 (s, 3 H), 1.26 (t, J = 6.8 Hz, 3 H), 1.04 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 170.1, 166.2, 143.3, 135.6,
(20) For syntheses, see: Crousse, B.; Mladenova, M.; Ducept, P.;
Alami, M.; Linstrumelle, G. Tetrahedron 1999, 55, 4353;
and references therein.
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