Highly stereoselective and efficient synthesis of ω-heterofunctional di- and trienoic esters for Horner-Wadsworth-Emmons reaction via alkyne hydrozirconation and Pd-catalyzed alkenylation

Article abstract of DOI:10.1016/j.tetlet.2009.02.023

In situ OH metalation with ⁱBu₂AlH and hydrozirconation with HZrCp₂Cl of HOCH₂C{triple bond, long}CH, (E)-HOCH₂CH{double bond, long}CHC{triple bond, long}CH, and HOCH₂C{triple bond, long}CC

Full text of DOI:10.1016/j.tetlet.2009.02.023

Tetrahedron Letters 50 (2009) 3220–3223
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly stereoselective and efficient synthesis of
x-heterofunctional
di- and trienoic esters for Horner–Wadsworth–Emmons reaction via alkyne
hydrozirconation and Pd-catalyzed alkenylation
*
Guangwei Wang, Zhihong Huang, Ei-ichi Negishi
Herbert C. Brown Laboratories of Chemistry, Purdue University 560 Oval Drive, West Lafayette, IN 47907-2084, USA
a r t i c l e i n f o
a b s t r a c t
i
Article history:
In situ OH metalation with Bu2AlH and hydrozirconation with HZrCp2Cl of HOCH2C„CH, (E)-HOCH2
CH@CHC„CH, and HOCH2C„CCH3 followed by Pd-catalyzed alkenyl–alkenyl coupling with (E)-
BrCH@CHCO2Et and (E)-BrCH@C(Me)CO2Et using PEPPSI-IPr (7) as a catalyst provides a highly efficient
Received 15 January 2009
Revised 23 January 2009
Accepted 2 February 2009
Available online 8 February 2009
and selective (P98% all-E) route to
phosphonate esters (1c–4c) of P98% isomeric purity can be obtained via conventional bromination–
phosphonation in >80% yields. As expected, their carbonyl olefination is ca. 85–90% E-selective with alkyl
x-hydroxy di- and trienoic acid esters (1a–6a). The corresponding
Dedicated to Dr. John Birmingham (Boulder
Scientific Co. whose pioneering synthesis of
ZrCp2Cl2 with G. Wilkinson in 1954 led to
the major development of organozirconium
chemistry)
aldehydes but P98% E-selective with PhCHO and some
a
,b-unsaturated aldehydes under the conditions
used.
Ó 2009 Published by Elsevier Ltd.
Keywords:
Pd-catalyzed alkenylation
Alkyne hydrozirconation
x
-Heterofunctional di- and trienoic esters
Horner–Wadsworth–Emmons reaction
1. Introduction
allylic chiral center have been selectively and conveniently pre-
pared by Pd-catalyzed alkenylation.4 Moreover, in recent
syntheses of conjugated oligoenes5,6 (Scheme 1), it has been
shown to be attractive to efficiently and selectively prepare key
reagents for the Horner–Wadsworth–Emmons (HWE, hereafter)
olefination by Pd-catalyzed alkenylation. It then occurred to us
that little, if any, had been explored along the line of this prom-
ising and potentially useful concept.
Herein, we report highly efficient and selective syntheses of
several conjugated diene- and triene-containing HWE olefination
reagents via alkyne hydrozirconation7 and Pd-catalyzed alkenyl–
alkenyl cross-coupling.3–5,8
Regio- and stereodefined alkenes including oligoenes and
polyenes exhibit a variety of significant biological and medicinal
activities. Until a few decades ago, they were most often pre-
pared by aldol and related carbonyl olefination reactions, espe-
cially those promoted by P-, S-, and Si-functional groups.1 In
the 1970s, some fundamentally different routes to alkenes via
organometallic alkenylation, represented by stoichiometric hyd-
roboration—migratory insertion routes to conjugated dienes2
and the Pd-catalyzed alkenylation using Al, Zr, Zn, B, and other
metal countercations,3 were discovered and developed. These
organometallic alkenylation reactions usually display P98% ste-
reo- and regioselectivity, and the Pd-catalyzed alkenylation has
been developed into the alkene synthetic method of very wide
applicability. And yet, carbonyl olefination and organometallic alk-
enylation can be mutually more complementary than competi-
tive. Thus, for example, alkenes containing an asymmetric
carbon center in the allylic positions are most readily and widely
prepared by carbonyl olefination, while those containing a homo-
In view of both proven and potential synthetic values, the fol-
lowing set of several (all-E)-diene- and triene-containing HWE
olefination reagents (1c–4c) were considered (Fig. 1). For various
reasons, we opted for their syntheses via the corresponding
x-hy-
droxy (1a–4a) and -bromo (1b–4b) derivatives. For one thing,
x
these hydroxy and bromo derivatives are by themselves useful re-
agents for various other purposes as well. Our preliminary investi-
gation also indicated some unclarified complications and
difficulties in attempted early incorporation of the desired phos-
phonate groups, and this potentially more convergent route is to
be further explored later.
* Corresponding author. Tel.: +1 765 494 5301; fax: +1 765 494 0239.
E-mail address: negishi@purdue.edu (E. Negishi).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.023

G. Wang et al. / Tetrahedron Letters 50 (2009) 3220–3223
3221
(1) i) HZrCp2Cl,
ii) I2
i) HZrCp2Cl,
(2)
,
BrZn
ii) (E)-BrCH=C(Me)CONHR
OH
OH
OH
PO(OEt)2
Pd cat.
2 steps
Pd cat.
CONHR
CONHR
NH
NHR =
OMe
Corey-Schlessinger-Mills
Modified Peterson Olefination
CHO
CHO
OTBS
Pd-catalyzed
alkenylation
HWE
OTBS
CONHR
OH
HWE olefination
CSM-Peterson olefination
Scheme 1. Synthesis of (all-E)-O-methylmyxalamide D via carbonyl olefination-Pd-catalyzed alkenylation synergy (previously reported5).
respectively, from propargyl alcohol. In both cases, ethyl (E)-3-
bromoacrylate12 prepared by addition of HBr to commercially
available propiolic acid followed by esterification was used as
one of the key intermediates. Sequential treatment of propargyl
alcohol with one equiv of iBu2AlH and hydrozirconation with
Z
Z
Z
Z
Z
COY
COY
COY
COY
COY
1
2
3
6
Z
i
HZrCp2Cl, generated in situ by treating ZrCp2Cl2 with Bu2AlH in
COY
THF,7d cleanly produced a solution containing the hydrozircona-
tion product in P95% yield by 1H NMR spectroscopic analysis.
Addition of ethyl (E)-3-bromoacrylate (1.0 equiv) and 1.0 mol %
of PEPPSI-IPr (7)13 obtained from Aldrich Chemical Co. for 6 h at
23 °C provided after the standard workup and chromatography
(silica gel, 30% EtOAc in hexanes) 1a of P98% E,E in 86% yield. Con-
version of 1a to 1c via 1b proceeded uneventfully with full reten-
tion of the E configuration in 85% yield over two steps. Although
the overall efficiency and selectivity of this particular synthesis
may be roughly comparable to those of the previously developed
HWE route,7 the Pd-catalyzed alkenylation route is readily adapt-
able to the syntheses of other related compounds without major
modification of the synthetic strategy, as detailed in Schemes 2
and 3. Distinct advantages of the synthesis of 2a–c reported herein
over the previously reported one10 should be clear.
4
5
c: Y = OEt, Z = PO(OEt)2
a: Y = OEt, Z = OH. b: Y = OEt, Z = Br.
Figure 1. (all-E)-Diene- and triene-containing HWE olefination reagents (1c–4c)
and the corresponding OH (1a–6a) and Br (1b–4b) derivatives.
2. Synthesis of unbranched dienoates (1) and trienoates (2)
x
-Phosphonodienoate ester (1c) has been synthesized from a
commercially available 3:1 mixture of ethyl (E)-4-bromocrotonate
and its 2-bromo isomer in four steps in 55% overall yield via HWE
olefination.9 Both 2- and 4-bromo isomers were converted to the
desired product. Despite somewhat high cost of the starting com-
pounds, it may be considered to a reasonably satisfactory synthe-
sis, and 1c has been successfully used in the synthesis of
oligoenes, such as amphotericin B, scyphostatin, and their oligoene
fragments.9 On the other hand, a recently reported synthesis of
ethyl (all-E)-8-hydroxy-2,4,6-octatrienoate (2a) required nine
steps from (Z)-2-butene-1,4-diol (14% overall yield).10 As summa-
rized in Scheme 2 1a and 2a11 of P98% isomeric purity can be pre-
pared in 86% yield in one step and 49% yield over three steps,
3. Synthesis of methyl-branched dienoates (3, 5, and 6) and
trienoates (4)
As pointed out above, the Pd-catalyzed alkenylation route to
x-
heterofunctional di- and oligoenoic acid derivatives is conceptually
straightforward and potentially widely adaptable besides being
(1) PBr3, py.
(2) P(OEt)3
OH
OH
PO(OEt)2
(i)A (ii) B
eq. 1
CO2Et
(> 98% E, E)
CO2Et
(> 98% E, E)
86%
85% over 2 steps
1c
1a
(ii) I (2) C
(1)(i) A
62% over 2 steps
2
OH
(1) PBr3, py.
(2) P(OEt)3
OH
PO(OEt)2
(i)A (ii) B
79%
eq. 2
CO2Et
(> 98% E, E, E)
CO2Et
(> 98% E, E, E)
82% over 2 steps
(> 98% E)
2a
2c
i
iPr
A: (i) iBu2AlH (1 equiv), (ii) ZrCp2Cl2-iBu2AlH (1.2 equiv)
Pr
PEPPSI-IPr:
(7)
i
Br
B:
CO2Et
iPr
(1.0 equiv), PEPPSI-IPr (7) (1 mol%)
Pr
Cl Pd Cl
C:
(1.2 equiv), Pd(DPEPhos) Cl2 (2 mol%)
BrZn
+
N
Cl
Scheme 2. Synthesis of unbranched dienoates (1a) and trienoates (2a) and the corresponding HWE olefination reagents (1c and 2c).

3222
G. Wang et al. / Tetrahedron Letters 50 (2009) 3220–3223
efficient and highly selective (generally P98% stereoselective).
Thus, the use of ethyl (E)-b-bromomethacrylate readily prepared
by sequential treatment of inexpensive ethyl methacrylate with
Br2 and NaOH in 90% yield14 in place of ethyl (E)-bromoacrylate
provided 3a (P98% E,E) in one step in 88%, which was readily con-
verted to 3c via 3b in 86% yield over two steps with full retention
(1) PBr3, py.
(2) P(OEt)3
OH
OH
OH
PO(OEt)2
(i)A (ii) D
eq. 1
CO2Et
(> 98% E, E)
CO2Et
86% over 2 steps
88%
(> 98% E, E)
3c
3a
(1) PBr3, py.
(2) P(OEt)3
OH
PO(OEt)2
(i)A (ii) D
eq. 2
eq. 4
CO2Et
(> 98% E, E, E)
CO2Et
(> 98% E, E, E)
81%
83% over 2 steps
4a
(> 98% E)
4c
OH
OH
OH
OH
(i)E (ii) B
75%
(i)E (ii) D
eq. 3
CO2Et
(> 98% E, E)
CO2Et
73%
5a
(> 98% E, E)
6a
CO Et (1.0 equiv), PEPPSI-IPr (7) (1 mol%)
E: (i) iBu2AlH (1 equiv), (ii) HZrCp2Cl (2.0 equiv)
Br
D:
2
Scheme 3. Synthesis of methyl-branched dienoates (3, 5, and 6) and trienoates (4).
Table 1
HWE olefination of aldehydes with
x
-phosphonooligoenoic acid derivatives
LiHMDS, THF
-78 23 ºC
n = 1 or 2
PO(OEt)2 H(Me)
CO2Et
R
RCHO
+
CO2Et
R
n
n
PO(OEt)2 H(Me)
CO2Et
CO2Et
(Yield, nPurity)
Entry
RCHO
n
nPr
PO(OEt)2
nPrCHO
CO2Et
84% (E,E,E/E,E,Z = 10/1)
1
(1c)
CO2Et
PO(OEt)2
CO2Et
2
3
4
5
CH3CHO
PhCHO
PhCHO
(2c)
81% (E,E,E,E/E,E,E,Z = 8/1)
CO2Et
PO(OEt)2
Ph
CO2Et
82% (>98% all E)
(1c)
CO2Et
PO(OEt)2
Ph
CO2Et
(2c)
78% (>98% all E)
CO2Et
PO(OEt)2
O
O
TBSO
TBSO
TBSO
TBSO
(1c)
CO2Et
87% (E,E,E/E,E,Z = 10/1)
CO2Et
CO2Et
PO(OEt)2
PO(OEt)2
CO2Et
6
7
(1c)
85% (E,E,E/E,E,Z = 6/1)
O
(4c)
CO2Et
CO2Et
OTBS
OTBS
80% (>98% all E)

G. Wang et al. / Tetrahedron Letters 50 (2009) 3220–3223
3223
of stereochemistry (Eq. 1 in Scheme 3). Similarly, sequential treat-
References and notes
ment of 2-butyn-1-ol with one equiv of iBu2AlH and 2.0 equiv (not
1.2 equiv) of HZrCp2Cl followed by addition of ethyl (E)-3-bromoac-
rylate or ethyl (E)-3-bromomethacrylate and 1.0 mol % of PEPPSI-
IPr (7) gave methyl-branched dienoate 5a or 6a in 73–75% yield
with P98% isomeric purity (Eqs. 3 and 4). As in the recently
reported preparation of (E,E,E)-(EtO)2P(O)CH2(CH@CH)2CH@C(Me)
CONHR, where R is (S)-CH(Me)CH2OMe as shown in Scheme 1,5 the
corresponding Et ester 4c was readily prepared from (E)-
HOCH2CH@CHC„CH and (E)-BrCH@C(Me)CO2Et via 4a and 4b in
3 steps in 67% overall yield (Eq. 2 in Scheme 3).
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1c–4c
5. (a) Wang, G.; Huang, Z.; Negishi, E. Org. Lett. 2008, 10, 3223–3226; For an
alternate route, see: (b) Coleman, R. S.; Lu, X.; Modolo, I. J. Am. Chem. Soc. 2007,
129, 3826–3827.
Although many examples of the HWE olefination of aldehydes
6. For
a review of Pd-catalyzed synthesis of conjugated oligoenes, see: (a)
with
x
-phosphonooligoenoic acid derivatives, such as 1c,7 are
Lipshutz, B. H. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; Wiley: New York, 2002; pp 807–823. Chaptet III. 2.17.1; For Ru-
catalyzed synthesis of conjugated dienes, see: (b) Trost, B. M.; Toste, F. D.;
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known, detailed and precise description of the reaction itself prior
to fractional purification are relatively limited. With P98% pure 1c
and 2c in hand, their HWE reaction with several representative al-
kyl-, aryl-, and alkenyl-containing aldehydes were examined. The
experimental results are summarized in Table 1, and the results
obtained under the conditions used reveal the following: (1) Alkyl
aldehydes, regardless of the presence or absence of proximal
branching groups and/or free and protected OH groups, exhibited
the E-selectivity of 85–90%. Chromatographic purification (silica
gel) did provide the major all E isomers as >98% pure compounds
in 70–80% isolated yields. (2) In sharp contrast, use of PhCHO (en-
tries 3 and 4) and alkenyl-containing aldehyde (entry 7) produced
the desired products of P98% purity in good yields. However, the
corresponding reactions of crotonaldehyde and (E)-cinnamalde-
hyde under the same reaction conditions led to disappointingly
low yields of 34% and 36%, respectively. Clearly, further optimiza-
tion of the reaction parameters is needed.
7. (a) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet. Chem. 1971, 27, 373–378;
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11. Representative procedure: Ethyl (2E, 4E, 6E)-8-hydroxy-2,4,6-octatrienoate (2a
in Scheme 2). To a solution of Cp2ZrCl2 (1.75 g, 6 mmol) in THF (20 mL) cooled
to 0 °C was added slowly
a
solution of iBu2AlH (6.0 mL, 1 M in hexane,
6.0 mmol) under argon. This mixture was stirred for 30 min at 0 °C, and a
solution of O-aluminated propargyl alcohol prepared from (E)-2-penten-4-yn-
1-ol (0.41 g, 5 mmol) and iBu2AlH (5.0 mL, 1 M in hexane, 5.0 mmol) was added
at À78 °C. The mixture was stirred at 23 °C until a homogeneous solution
resulted (ca. 0.5 h) and was added to ethyl (E)-3-bromoacrylate (0.89 g,
5.0 mmol) and PEPPSI-IPr (34 mg, 0.05 mmol) in THF (10 mL). After stirring at
23 °C for 4 h, the reaction mixture was quenched with water, extracted with
ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated.
Flash chromatography (silica gel, 30% EtOAc in hexanes) gave 2a (0.72 g, 79%,
P98% isomerically pure) as light yellow wax..
Acknowledgments
We thank the National Institute of Health (GM 36792) and Pur-
due University for support of this research. We also thank Alber-
marle, NICHIA corporation, and Sigma–Aldrich for chemicals.
12. Weir, J. R.; Patel, B. A.; Heck, R. F. J. Org. Chem. 1980, 45, 4926–4931.
13. Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46,
2768–2813.
Supplementary data
14. For preparation of (E)-b-bromomethacrylic acid as well as Me and Et esters,
see: (a) Caubere, P. Bull. Soc. Chim. Fr. 1966, 144; (b) For their application in Pd-
or Ni-catalyzed alkenylation, see, for example, Refs. 3b,d–f,5.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.023.