Stereoselective synthesis of conjugated trienols from allylic alcohols and 1-iodo-1,3-dienes

Article abstract of DOI:10.1021/ol302719e

The stereoselective synthesis of conjugated trienes has been achieved from allylic alcohols and 1-iodo-1,3-dienes using Pd(OAc)₂/AgOAc.

Full text of DOI:10.1021/ol302719e

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereoselective Synthesis of Conjugated
Trienols from Allylic Alcohols and
1‑Iodo-1,3-dienes
ꢀ
Damien Brandt, Veronique Bellosta, and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received October 2, 2012
ABSTRACT
The stereoselective synthesis of conjugated trienes has been achieved from allylic alcohols and 1-iodo-1,3-dienes using Pd(OAc)2/AgOAc.
Conjugated trienes are present in a great variety of bio-
logically active polyenic natural products such as macro-
lides with antitumor, antifungal, or antibiotic properties.1
For example, trienic units are present in ansatrienine
A2 (antitumor), manumycin A3 (antifungal, antibacterial,
and antitumor agent against leukemia stem cells), and
rapamycin4 (antibacterial and immunosuppressive agent).
Furthermore, trienes are present in retinoids,5 in eicosa-
noids such as leukotriene B4,6 an antitumor agent, and in
π-conjugated materials7 (Figure 1).
Due to the importance of trienic units, new synthetic
methods toward these building blocks are of importance.
The existing approaches toward functionalized substituted
(1) Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002, 999–
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59–62. (b) Sugita, M.; Natori, Y.; Sueda, N.; Furihata, K.; Seto, H.;
Otake, N. J. Antibiot. 1982, 35, 1474–1479.
Figure 1. Examples of biologically active natural products con-
taining conjugated trienol moieties.
(3) (a) Sattler, I.; Thiericke, R.; Zeeck, A. Nat. Prod. Rep. 1998, 15,
221–240. (b) Alcaraz, L.; Macdonald, G.; Ragot, J.; Lewis, N. J.; Taylor,
R. J. K. Tetrahedron 1999, 55, 3707–3716.
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1990.
trienes, such as the Wittig8 and the HornerꢀWadsworthꢀ
Emmons9 olefinations, are not step and/or atom econom-
ical processes, as the reagents have to be used in stoichio-
metric amounts. In addition, the conditions are not mild
(8) For a review, see: Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989,
89, 863–927.
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253. (b) Kelly, S. E. In Comprehensive Organic Synthesis; Pergamon:
Oxford, 1991; pp 729ꢀ817.
r
10.1021/ol302719e
XXXX American Chemical Society

enough to be functional group tolerant. Pericyclic or
biomimetic approaches to trienes can be used as well.10,11
In addition, syntheses of π-conjugated systems through
CꢀC bond formation, catalyzed by a transition metal such
as palladium,12 gold,13 or nickel,14 have been realized
(Scheme 1).
of but-2-en-3-ol (2a). The synthesis of 1-halogeno-1,3-dienes
was realized in three steps from acetylenic derivatives 4.
After hydrozirconationꢀiodation (Cp2ZrCl2, DIBAL-H,
NIS, THF),16 the corresponding (E)-vinyl iodides 5 were
obtained and coupled with vinylboronate 6 under Heck
conditions [Pd(OAc)2, P(o-Tol)3, AgOAc, DMF, 50 °C] to
produce 7.17 The obtained conjugated dienyl boronates 7
were then treated with NIS or NBS under basic conditions
(NaOMe, THF) to furnish the desired (E,E)-1-iodo-1,3-
dienes 1 and (E,E)-1-bromo-1,3-dienes 8 respectively in
good to excellent yields (47ꢀ92%) (Scheme 3).18
Scheme 1. Synthesis of Trienic Units
Scheme 3. Preparation of 1-Halogeno-1,3-dienes
Herein, we would like to report a chemo-, regio-, and
stereoselective method for the construction of conjugated
trienols from 1-iodo-1,3-dienes 1 and nonprotected allylic
alcohols 2 under Heck conditions15 (Scheme 2).
At first, 1-iodo-1,3-diene 1a was examined. When this
diene was treated under Heck conditions [Pd(OAc)2
(10 mol %), AgOAc (1.1 equiv)] in DMF at 45 °C for 15 h
in the presence of but-3-en-2-ol (2a) (3 equiv), the coupling
product 3a was obtained in 72% yield (Table 1, entry 1).
The use of 2 equiv of alcohol 2a gave a similar result
(Table 1, entry 2). It is worth pointing out that it was also
possible to reduce the quantity of palladium acetate to
5 mol % to produce 3a with an identical yield (Table 1,
entry 3). However, when the quantity of alcohol 2a was
reduced to 1.2 equiv, only traces of the coupling product 3a
were observed (Table 1, entry 4). The best conditions
appeared to be the use of 2 equiv of the allylic alcohol,
5 mol % of Pd(OAc)2, and 1.1 equiv of AgOAc (Table 1,
entry 3).
Benzyl-, p-methoxybenzyl-, and tert-butyldiphenylsilyl
ethersweretoleratedaswellasprotectedamines, as1-iodo-
1,3-dienes 1aꢀ1d were transformed to conjugated (E,E,E)-
trienols 3aꢀ3d in good yields (54%ꢀ72%) (Table 2).
It is worth noting that the reaction of but-3-en-2-ol (2a)
with 1-bromo-1,3-diene 8 under the previously developed
conditions [2 equiv of 2a, 5 mol % of Pd(OAc)2, and 1.1
equiv of AgOAc in DMF at 45 °C] did not lead to triene 3b
and that 1-bromo-1,3-diene 8 was recovered (Scheme 4)
indicating that the conditions used were chemoselective.
Scheme 2. General Scheme
We initiated our investigation with (E,E)-1-iodo-1,3-
dienes 1 and (E,E)-1-bromo-1,3-diene 8 in the presence
ꢀ
(10) Vogel, P.; Turks, M.; Bouchez, L.; Markovic, D.; Varela-
ꢀ
ꢀ
Alvarez, A.; Sordo, J. A. Acc. Chem. Res. 2007, 40, 931–942.
(11) (a) Leblanc, Y.; Fitzsimmons, B. J.; Zamboni, R.; Rokach, J.
J. Org. Chem. 1988, 53, 265–267. (b) Hudlicky, T.; Frazier, J. O.; Seoane,
G.; Tiedje, M.; Seoane, A.; Kwart, L. D.; Beal, C. J. Am. Chem. Soc.
1986, 108, 3755–3762. (c) BouzBouz, S.; Cossy, J. Org. Lett. 2004, 6,
3469–3472.
(12) For selected examples, see: Stille coupling: (a) Crombie, L.;
Horsham, M. A.; Jarrett, S. R. M. J. Chem. Soc., Perkin Trans. 1 1991,
1511–1524. (b) Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.;
Chakraborty, T. K.; Minowa, N.; Koide, K. Chem.;Eur. J. 1995, 1,
318–333. (c) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer,
J. L.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1995, 117,
5407–5408. Sonogashira coupling: (d) Avignon-Tropis, M.; Berjeaud,
ꢀ
J. M.; Pougny, J. R.; Frechard-Ortuno, I.; Guillerm, D.; Linstrumelle,
G. J. Org. Chem. 1992, 57, 651–654. Suzuki coupling: (e) Torrado, A.;
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Iglesias, B.; Lopez, S.; de Lera, A. R. Tetrahedron 1995, 51, 2435–2454.
(f) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc. 2004, 126, 10313–
10318. (g) Fuwa, H.; Sasaki, M. Org. Lett. 2010, 12, 584–587. Hiyama
coupling: (h) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127,
8971–8973.
(13) Hadfield, M. S.; Lee, A.-L. Chem. Commun. 2011, 47, 1333–
1335.
(14) Horie, H.; Kurahashi, T.; Matsubara, S. Chem. Commun. 2010,
46, 7229–7231.
(15) (a) Jeffery, T. J. Chem. Soc., Chem. Commun. 1991, 324–325. (b)
Jeffery, T. Tetrahedron Lett. 1993, 34, 1133–1136.
(16) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675–3678.
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3928. (b) Lightfoot, A. P.; Maw, G.; Thirsk, C.; Twiddle, S. J. R.;
Whiting, A. Tetrahedron Lett. 2003, 44, 7645–7648.
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Chem. 2011, 9, 1876–1886.
B
Org. Lett., Vol. XX, No. XX, XXXX

can be synthesized using optically active allylic alcohols.
Thus, 3n was formed in 65% yield with an enantiomeric
excess superior to 92%19 when (S)-2d (ee = 99%) was
involved in the coupling reaction with 1a (Table 3, entry 10).
With alcohol 2k, in which a disubstituted double bond is
present, two trienols 3o and 3o0 were formed, in a 55/45
ratio in favor of the conjugated triene 3o, with a moderate
yield of 38% (Table 3, entry 11). It is worth noting that all
the coupling products 3eꢀ3o were obtained as pure
(E,E,E)-trienols.
Table 1. Optimization of Allylic Alcohol and Palladium Quantitya
Pd(OAc)2
(mol %)
yield in
3a (%)b
entry
2a (equiv)
In addition, the coupling reaction between 1-iodo-1,3-
dienes and allylic alcohols is stereoselective. Thus, when
1-iodo-1,3-diene 12 [(Z,E)/(E,E) = 93/7], prepared in two
steps from olefin 9 (Scheme 5), was reacted with allylic
alcohols 2a and 2g, under the previous conditions, 13a and
13b were obtained in 66% and 51% yield respectively in an
(E,Z,E)/(E,E,E) ratio of 90/10 (Scheme 5).
1
2
3
4
3
10
10
5
72
2
69
2
69
1.2
5
traces
a All experiments were performed with 1.1 equiv of AgOAc.
b Isolated yield.
In considering the retention of configuration in trienol
3n, we can suppose that the Hb β-hydrogen elimination is
Table 2. Protecting Group Tolerancea
Scheme 5. Coupling with (E,Z)-Trienols
yield
entry
1
X
3
in 3b
1
2
3
4
1a
1b
1c
1d
BnO
3a
3b
3c
3d
69%
54%
59%
58%
TBDPSO
PMBO
Boc(Ts)N
a All reaction were performed with 2 equiv of 2a, 5 mol % of
Pd(OAc)2, and 1.1 equiv of AgOAc. b Isolated yield.
Scheme 4
Scheme 6. Proposed Mechanism
A diversity of allylic alcohols of type 2 were involved in
the coupling reaction with 1-iodo-1,3-dienes 1a and 1b.
The results are reported in Table 3. Prop-2-en-1-ol (2b)
(Table 3, entry 1) as well as secondary alcohols such as
2cꢀ2d(Table 3, entries 2 and 3), 1-phenylprop-2-en-1-ol 2e
(Table 3, entry 4), sterically hindered alcohols such as
2fꢀ2h (Table 3, entries 5 to 7), and tertiary alcohol 2i
(Table 3, entry 8) led to the corresponding trienols 3eꢀ3l in
good yields. When monoprotected diol 2j was involved in
the coupling reaction with 1b, trienol3m was formed in 46%
yield (Table 3, entry 9). In addition, optically active trienols
(19) Enantiomeric excess was determined by 1H NMR spectroscopy
by addition of Eu(hfc)3 to the NMR tube. No traces of the other
enantiomer were observed.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Comparison of Different Allylic Alcohols
not proceeding. Intermediate A is probably formed in
which a coordination of palladium with the hydroxy
group is occurring, preventing the β-hydrogen elimina-
tion of Hb, as a syn-relationship between Pd and H is
required for palladium hydride elimination. In contrast,
the palladium hydride elimination can occur with Ha
(Scheme 6).
alcohols in good yields by using the Pd(OAc)2/AgOAc
system.
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have demonstrated that (E,E,E)-
trienols and (E,Z,E)-trienols can be obtained from allylic
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX