Sequential transhalogenation and Heck reaction for efficient access to dioxo-tetrasubstituted 2,4 E,E-dienes: synthesis of segment C1-C6 of apoptolidin

Article abstract of DOI:10.1016/j.tetlet.2006.07.058

Efficient access to dioxo-tetrasubstituted 2,4 E,E-dienes is developed in three steps from commercially available starting materials via sequential transhalogenation and Heck reaction, which provides potentially useful synthons for the synthesis of a tetrasubstituted conjugated diene structure in complex molecules. Thereby, segment C1-C6 of apoptolidin is synthesized.

Full text of DOI:10.1016/j.tetlet.2006.07.058

Tetrahedron Letters 47 (2006) 6839–6842
Sequential transhalogenation and Heck reaction for efficient
access to dioxo-tetrasubstituted 2,4 E,E-dienes: synthesis
of segment C1–C6 of apoptolidin
Xiaojin Li*, and Xingzhong Zengà
Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN 47907, USA
Received 1 May 2006; revised 11 July 2006; accepted 14 July 2006
Available online 4 August 2006
Abstract—Efficient access to dioxo-tetrasubstituted 2,4 E,E-dienes is developed in three steps from commercially available starting
materials via sequential transhalogenation and Heck reaction, which provides potentially useful synthons for the synthesis of a
tetrasubstituted conjugated diene structure in complex molecules. Thereby, segment C1–C6 of apoptolidin is synthesized.
Ó 2006 Elsevier Ltd. All rights reserved.
Potential anticancer agents, apoptolidin (1)1 and FD-
891 (2)2 as well as apoptosis inducer mycolactone B
(3)3 all have a common tetrasubstituted conjugated
E,E-diene structure (Fig. 1), which can be envisioned
as derived from dioxo-tetrasubstituted 2,4 E,E-dienes.
The impressive biological activities and structural nov-
elty as well as complexity have promoted a number of
synthetic studies towards total syntheses of these natu-
rally occurring products, and synthetic strategies associ-
ated with these complex molecules, especially for
OH
O
HO
6
7
HO
O
O
O
Wittig
O
MeO
Wittig
OH
OH
1 O
O20
OH
FD-891 (2)
Apoptolidin (1)
OH
OMe
OH
MeO
HO
O
OMe
O
O
OH
O
OH OH
Wittig
OH
Wittig
O
OMe
O
O
HO
OH
O
O
OH OH
Mycolactone B (3)
Figure 1.
*
Corresponding author. Tel.: +1 301 846 1661; fax: +1 301 846 5946; e-mail: lix@ncifcrf.gov
Present address: National Cancer Institute at Frederick, National Institutes of Health, PO Box B, Bldg 538, Frederick, MD 21702, USA.
à Present address: Chemical Development, R&D 6630A, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.058

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X. Li, X. Zeng / Tetrahedron Letters 47 (2006) 6839–6842
constructing the diene structure, continue to be of great
interest.4–7
acrylate 6 (Scheme 1)9 and substituted vinyl ketone 11
(Table 1) have been used in the Heck reactions,8,10 our
initial study of direct coupling between 6 and 11 under
the standard Heck reaction condition generated the
dioxo-tetrasubstituted dienone 13 in only 18% yield
along with unidentified by-products.11
Aside from one of Nicolaou’s approaches to the tetra-
substituted diene in the total synthesis of 1,4 other con-
structions of the diene structure of 1,4,5 26 and 37 all
feature double Wittig-type homologations (Fig. 1).
Herein, we report a new approach to the diene structure
by developing efficient access to dioxo-tetrasubstituted
2,4 E,E-dienes (Table 1, 13–16) as synthons. The di-
oxo-tetrasubstituted 2,4 E,E-dienes are synthesized in
three steps from commercially available starting materi-
als via sequential transhalogenation and Heck reaction,
and the synthesis of segment C1–C6 of apoptolidin is
illustrated.
In order to improve the yield of this coupling product,
the more reactive E-vinyl iodide 7 (Scheme 1) was effi-
ciently prepared. According to the literature,12 7 has
been synthesized in 44% from diethyl methyl malonate
in three operations. In this study, an efficient and high
yielding route to the exclusive formation of 7 was devel-
oped by
a sequential bromination–elimination of
dimethyl acrylate 4, followed by the transhalogenation
without the need of column chromatography or distilla-
tion after workup (Scheme 1, Eq. 1). This synthesis was
facilitated by CuI-mediated transhalogenation13 of vinyl
bromide 6 in DMF in high yield (84%) as well as by
using DBU as the base in the elimination step to give
a quantitative yield. Interestingly, under the same
sequential reaction conditions, though elimination of
methyl tert-butyl acrylate 5 delivered vinyl bromide 8
in quantitative yield, the transhalogenation of 8 only
gave the carboxylic acid 912a (78%) instead of the desired
E-vinyl iodide 10 (Scheme 1, Eq. 2). Employing HMPA
at 120 °C with the reduced reagent set (1.7 equiv CuI/
According to the literature,8a tetrasubstituted 2,4 E,
E-dienedioic acid and their derivatives (Table 1, assum-
ing R1 = H or Me and R2 = OH or OMe) have been
synthesized via Heck reaction of the corresponding
(E)-3-bromo-2-methyl acrylic acid or the methyl ester
with (E)-3-methyl acrylic acid or the methyl ester,
whereas a free aldehyde reactant did not give identifiable
products in the reaction. To the best of our knowledge,
synthesis of potentially useful tetrasubstituted E,E-
dienones (Table 1, 13 and 14) or E,E-dienals (Table 1,
15 and 16) has not been reported. While b-bromometh-
O
O
(1)
OMe
1c. 5 eq CuI/15 eq KI
solvent, 140 oC, 5 h
I
Br
OMe
R1 = Me
7
6
Diglyme
HMPA
DMF
60%
80%
84%
O
1a. 1.0 eq Br2
CCl4, rt, 2 h
OR1
1b. 1.5 eq DBU
O
CCl4 rt, 5 h
quantitative
1c. 5 eq CuI/15 eq KI
DMF, 140 oC, 5 h
78%
4
5
(2)
I
OH
R1: Me tBu
O
R1 = tBu
9
Br
OtBu
O
(3)
1c. 1.7 eq CuI/5.0 eq KI
HMPA, 120 oC, 5 h
88%
8
I
OtBu
10
Scheme 1. Synthesis of vinyl iodides 7 and 10.
Table 1. Overman modified Heck reaction of iodides 7 and 10a
O
O
O
R2
Conditions
OR1
R2
+
I
OR1
CH3CN, 65 o
C
O
11
12
7
10
13
14
15
16
tBu
H
R1: Me
tBu R2: Me
H
R1: Me tBu
R2: Me Me
Me
H
Entry
SM
Reaction conditions
Pdt
Yield (%)
1
2
3
4
7
2.0 equiv 11, 5% Pd(OAc)2, 1.5 equiv Ag2CO3, 1 h
2.0 equiv 11, 5% Pd(OAc)2, 1.5 equiv Ag2CO3, 1 h
4.0 equiv 12, 10% Pd(OAc)2, 2.5 equiv Ag2CO3, 8 h
2.0 equiv 12, 5% Pd(OAc)2, 1.5 equiv Ag2CO3, 1 h
13
14
15
16
79
75
65
72
10
7
10
a All were isolated yields by silica gel column chromatography, 11 was distilled before use, and 12 was directly used as purchased.

X. Li, X. Zeng / Tetrahedron Letters 47 (2006) 6839–6842
6841
Me
6
RO
PMBO
SO2Pg
MeOCO2
7
1
O
OTBS
OH
OPg
O
O
20
t-BuO
OMe
MeO
19
17EE
,
EZ or ET
18EE, EZ or ET
Scheme 2. Retrosynthesis of aglycones 18.
O
O
10% CeCl3/2.0 eq NaBH4
MeOH, rt, 1 h
OtBu
OtBu
OH
O
20
14
O
20% DMAP/5.0 eq MeOCOCl/ 5.0 eq Py
CH2Cl2, 0 oC to rt, 3 h
OtBu
MeOCO2
19
96%
Scheme 3. Synthesis of segment C1–C6 (19).
5.0 equiv KI) completely avoided the ester cleavage, and
E-vinyl iodide 10 was exclusively formed in 88% yield
(Scheme 1, Eq. 3). It should be noted that the reduced
reagent set was also applicable for the synthesis of vinyl
iodide 7.
of the dienoic acid 21 confirmed the E,E-configura-
tion,20 which was consistent with stereospecificity of
the Heck reaction.8
In summary, the efficient accessibility for dioxo-tetrasub-
stituted 2,4 E,E-dienes (Scheme 1 and Table 1) and
proven amenability of the dioxo functional groups
(Scheme 3 and Ref. 20) features a new strategy for
constructing tetrasubstituted conjugated dienes in
complex compounds.
With vinyl iodide 7, it was found that the coupling of
vinyl ketone 11 under Overman modified Heck reaction
conditions14 gave 79% yield of E,E-dienone 13 exclu-
sively, where with vinyl iodide 10 the good yield (75%)
for E,E-dienone 14 was also obtained (Table 1, entries
1 and 2). Extension of the coupling reactions to 2-buten-
al 12, a free aldehyde, was found to work fairly well to
deliver E, E-dienals 15 (65%) and 16 (72%), respectively
(Table 1, entries 3 and 4).
Acknowledgments
We are grateful to Professor Philip L. Fuchs for his
guidance during the research and the preparation of this
manuscript. We acknowledge Arlene Rothwell and Karl
Wood for mass spectral data.
Our approach to the synthesis of apoptolidin (Fig. 1, 1)
is designed to probe the relationship between ring con-
formation and antineoplastic activity.4,15 Retrosynthesis
envisions that the aglycone 18EE, EZ or ET will arise
from a union of segments C7–C20 (17) and C1–C6
(19) by Ramberg–Ba¨cklund reaction16 with a final ring
closure by Yamaguchi macrolactonization,17 or perhaps
via the alternative order (Scheme 2).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.058.
Recently, we reported a new three-operation conjunctive
strategy towards regio/stereoselective synthesis of 17EE,
EZ and ET.18 In the current study, a concise and effi-
cient preparation of segment 19 is achieved from die-
none 14 in two steps (Scheme 3). The regiospecific
ketone reduction of 14 was achieved exclusively under
Luche reduction condition19 to give the pure dienol 20
in quantitative yield without the need of column chro-
matography. Methoxycarboxylation of 20 with methyl
chloroformate under reflux in methylene chloride deliv-
ered segment C1–C6 (19) of apoptolidin in 96% yield
(Scheme 3). In addition, X-ray crystallographic analysis
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O
5.0 eq NaOH
Na2EDTA
Yamaguchi's condition*
65%
OH
13
14
H2O/t-BuOH (10/1)
0 oC, 30 min
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CH2Cl2, reflux, 3 h, 76%
O
21
11. Study to improve the yield can be found in the Supple-
mentary data.
* a) 1.0 eq 2,4,6-trichlorobenzoyl chloride, THF, rt, 40 min
b) 2.0 eq t-BuOH, 2.0 eq DMAP, toluene, rt, 4 h