Preparation of the conjugated polyene chains with the 1,4-dimethyl substitution

Article abstract of DOI:10.1016/j.tetlet.2004.07.146

Allylic sulfones undergo the conjugate addition to diethyl chloroisopropylidenemalonate, followed by intramolecular cyclopropanation. DBU-promoted ring opening and subsequent desulfonation reactions of the resulting adduct produce the conjugated polyene chains with the 1,4-dimethyl substitution.

Full text of DOI:10.1016/j.tetlet.2004.07.146

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7023–7026
Preparation of the conjugated polyene chains with the
1,4-dimethyl substitution
Hye-Sun Jeon and Sangho Koo*
Department of Chemistry, Myong Ji University, Yongin, Kyunggi-Do, 449-728, Korea
Received 7 June 2004; revised 19 July 2004; accepted 30 July 2004
Abstract—Allylic sulfones undergo the conjugate addition to diethyl chloroisopropylidenemalonate, followed by intramolecular
cyclopropanation. DBU-promoted ring opening and subsequent desulfonation reactions of the resulting adduct produce the con-
jugated polyene chains with the 1,4-dimethyl substitution.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Carotenoids, which are classified as isoprenoids accord-
ing to their biogenetic origin, have the general structural
feature of the conjugated polyene chain.1 These carote-
noids are enzymatically synthesized in biological sys-
tems by the coupling reactions of isopentenyl
pyrophosphate (IPP) or dimethylallyl pyrophosphate
(DMAP),2 which gives rise to the basic repeating unit
of the C5 prenyl group (Fig. 1a). There are four different
ways of connecting the prenyl group: head–head (h–h),
head–tail (h–t), tail–head (t–h), and tail–tail (t–t)
attachments (Fig. 1b). The t–t combination generates
the 1,6-dimethyl substitution pattern, which is mainly
found in the center of carotenoid compounds such as
b-carotene, lycopene, and astaxanthin etc. The 1,5-di-
methyl substitution is the general substitution pattern
of carotenoids and retinoids, which is generated from
the t–h or the h–t combinations. The h–h combination,
producing the 1,4-dimethyl substitution, is not uncom-
mon but present in some natural products from the mar-
ine origin or from the gliding bacteria such as
immunosuppressant (ꢀ)-pateamine,3 antibiotic haliangi-
cin,4 and myxopyronin5 (Fig. 1c) as well as some
carotenoid compounds of isomethylpseudoionone, 3-
and isocrocetin.
There have been intensive synthetic efforts for (ꢀ)-pate-
amine, myxopyronin, and isomethylpseudoionone
where the installation of the 1,4-dimethyl substituted
polyene chain was the key issue. While the Stille cou-
Figure 1. (a) The prenyl group; (b) the attachment patterns of two
prenyl groups in the polyene chains and (c) some representative
natural products containing the 1,4-dimethyl substituted polyene
chain.
hydroxy-80-apo-b,w-caroten-80-al,
pling has been the main repertoire for (ꢀ)-pateamine,3
aldol condensation was used for the synthesis of myxo-
pyronin5a and isomethylpseudoionone.6
Keywords: Polyene; 1,4-Dimethyl substitution; Carotene; Prenyl
group; Sulfone.
*
We have reported the general and systematic synthetic
methods of the 1,5- and the 1,6-dimethyl substituted
Corresponding author. Tel.: +82 31 330 6185; fax: +82 31 335
7248; e-mail: sangkoo@mju.ac.kr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.146

7024
H.-S. Jeon, S. Koo / Tetrahedron Letters 45 (2004) 7023–7026
Two different coupling conditions of n-BuLi in THF
and t-BuOK in DMF were utilized for each allylic ha-
lide. The allylic coupling of 3a was observed as the ma-
jor pathway (A) for the reactive allylic bromide 4a 9 with
acyclic diester substituents to give 5 (entries 1 and 2). A
small amount of 6a, which arose from the pathway B
was also obtained in both coupling conditions. With
the less reactive allylic chloride 4b10 with acyclic diester
substituents, on the other hand, the coupling reaction of
3a followed the pathway B to give 6a11 (83% yield)
exclusively under the condition utilizing n-BuLi (entry
3). The coupling reaction of 3a and 4b under t-BuOK
was less effective since a somewhat low-yield mixture
of 5 and 6a was obtained (entry 4). It was surprising that
only the pathway B was observed for the coupling reac-
tion of 3a and the allylic bromide 4c12 with cyclic dilac-
tone substituents (entries 5 and 6). It seemed that the
unsaturated cyclic diester group activated 4c toward
the conjugate addition of 3a even in the presence of
the reactive allylic bromide moiety. The conditions using
n-BuLi were better than those using t-BuOK in provid-
ing high yields of the coupling products and good selec-
tivities between the two reaction pathways.
Figure 2. The retinoid 1 and its isomethyl derivative 2a, and the
coupling pathways of the C15 allylic sulfone 3a and the allylic halides 4
with diesters (E) in conjugation.
polyene chains, and thus completed the total syntheses
of retinoid and carotenoid compounds.7 In the synthetic
study toward the retinoic acid and its various derivatives
1, we have developed a new and efficient way of produc-
ing the polyene chain 2a, and generalized this approach
to the synthesis of the polyene chains with the 1,4-di-
methyl substitution (Fig. 2). We herein report the details
of this study.
The coupled product 6a then reacted with DBU in
benzene at the reflux temperature to give the fully conju-
gated polyene chain compound 2a13 with the 1,4-
dimethyl substitution in 92% yield. This reaction pro-
ceeded through the initial generation of carbanion at
the a carbon to the benzenesulfonyl group of 6a, fol-
lowed by the opening reaction of the cyclopropane ring
containing diester substituents to give the stabilized
carbanionic intermediate structure C. After the double
bond migration to give the structure D, the desulfona-
tion reaction via the allylic E1cb mechanism produced
all-(E)-2a (Fig. 3). This reaction was highly stereoselec-
tive to produce (E)-configurations of the carbon–carbon
double bonds.
The C15 allylic sulfone 3a has been efficiently utilized in
the synthesis of retinoid compounds by the Julia
olefination reaction with the proper C5 allylic halides.8
It was envisioned that the reaction of the C15 allylic sulf-
one 3a and the allylic halides 4 containing two electron-
withdrawing ester groups (E) might follow either the
allylic coupling pathway (route A) to give 5 or the con-
jugate addition and subsequent intramolecular cyclo-
propanation pathway (route B) to give 6a (Fig. 2),
that would generate the conjugated polyene compound
1 with the 1,5-dimethyl substitution or the conjugated
polyene compound 2a with the 1,4-dimethyl substitu-
tion, respectively, after base-promoted dehydrosulfona-
tion reaction.
The general applicability of this two-step sequence
to the synthesis of the conjugated polyene chains 2 with
the 1,4-dimethyl substitution has been tested for three
other allylic sulfones 3b–d and the allylic chloride 4b
(Fig. 4 and Table 2). The coupling condition of n-BuLi
in THF was used, in which no product derived from the
direct allylic coupling (the pathway A in Fig. 2) was ob-
tained. Comparable yields of 82% and 81% to 6a were
obtained for 6b and 6c, respectively. A somewhat lower
yield of 68% for 6d was attributed to the instability of
the allylic sulfone compound 3d containing the acyclic
conjugated triene unit. DBU-promoted dehydrosulfona-
tion reactions of 6b–d proceeded efficiently to produce
The coupling reaction of the C15 allylic sulfone 3a with
three different allylic halides 4a–c has been extensively
studied, and the results were summarized in Table 1.
Table 1. The yields and the conditions of the reactions in Figure 2
Entry
1
4
a
Condition
5 (%)
6a (%)
n-BuLi/THF
75
9
2
t-BuOK/DMF
60
8
3
4
b
c
n-BuLi/THF
––
20
83
36
t-BuOK/DMF
5
6
n-BuLi/THF
––
––
75
54
t-BuOK/DMF
Figure 3. The mechanism of the reaction from 6a to the conjugated
polyene compound 2a with the 1,4-dimethyl substitution.

H.-S. Jeon, S. Koo / Tetrahedron Letters 45 (2004) 7023–7026
7025
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1651–1658.
Figure 4. A general synthetic method of the conjugated polyene chains
with the 1,4-dimethyl substitution.
Table 2. Structures of the substrates and the yields of the reactions in
Figure 4
Entry
1
Suffix
Structure of R
6 (%)
2 (%)
a
83
92
2
3
b
c
CH3
82
81
52
62
6. (a) Boulin, B.; Arreguy-San Miguel, B.; Delmond, B.
Synth. Commun. 2003, 33, 1047–1055; (b) Climent, M. J.;
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Choi, H.; Park, M.; Kee, M.; Jeong, Y. C.; Koo, S. Angew.
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Jeong, Y. C.; Jin, J.; Baik, W.; Lee, S.; Kim, J. S.; Park,
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4
d
68
52
the conjugated polyene chains 2b–d with the 1,4-di-
methyl substitution pattern. Once again, the instability
of the acyclic conjugated triene unit in 2b–d might ex-
plain a little lower yields of 52–62%.
In conclusion, we have developed an efficient synthetic
method of the conjugated polyene chains with the 1,4-
dimethyl substitution, in which (i) the chemoselective
conjugate addition of allylic sulfones to the allylic ha-
lides with conjugated diesters followed by cyclopropana-
tion and (ii) DBU-promoted dehydrosulfonation of the
resulting b-cyclopropylidenesulfone have been demon-
strated for the first time. We have proven the generality
of this method, which can be usefully applied to the syn-
theses of various isoprenoid natural products containing
the polyene chains with the 1,4-dimethyl substitution.
9. (a) Togo, H.; Hirai, T. Synlett, 2003, 702–704; (b)
Haefliger, W.; Petrzilka, T. Helv. Chim. Acta 1966, 49,
1937–1950.
10. Lehnert, W. Tetrahedron 1973, 29, 635–638.
11. The representative experimental procedure for 6a: To a
stirred solution of the C15 allylic sulfone 3a (1.00g,
2.90mmol) in THF (30mL) at ꢀ78ꢁC under Ar atmos-
phere was added a 1.6M solution of n-BuLi (2.0mL,
3.20mmol). The mixture was stirred for 30min at that
temperature, and a solution of 4b (0.89g, 3.77mmol) in
THF (5mL) was added. The resulting mixture was stirred
at ꢀ78ꢁC for 30min and then at room temperature for
1.5h. The reaction mixture was quenched with 1M HCl
solution (50mL), extracted with ether (20mL · 3), dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by silica
gel flash chromatography to give 6a (1.30g, 2.39mmol) in
83% yield. Data for 6a: 1H NMR (300MHz, CDCl3) d
0.97 (3H, s), 0.98 (3H, s), 1.11 (3H, s), 1.26 (1H, A of ABq,
J = 5.1Hz), 1.34 (1H, B of ABq, J = 5.1Hz), 1.37 (3H, t,
J = 7.2Hz), 1.38 (3H, t, J = 7.2Hz), 1.42–1.51 (2H, m),
1.49 (3H, s), 1.57–1.66 (2H, m), 1.68 (3H, s), 2.00 (2H, br t,
J = 6.0Hz), 4.23–4.43 (4H, m), 4.97 (1H, d, J = 11.1Hz),
Acknowledgements
This work was supported by the RRC (Regional Re-
search Center) program of MOST (Ministry of Science
and Technology), KOSEF (Korea Science and Engi-
neering Foundation), and Kyunggi-Do.
References and notes
1. (a) Pommer, H. Angew. Chem. 1960, 72, 911–915; (b)
Pommer, H.; Nurrenbach, A. Pure Appl. Chem. 1975, 43,
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527–551; (c) Isler, O. Pure Appl. Chem. 1979, 51, 447–462;
(d) Widmer, E. Pure Appl. Chem. 1985, 57, 741–752; (e)
Bernhard, K.; Mayer, H. Pure Appl. Chem. 1991, 63,
35–44; (f) Paust, J. Pure Appl. Chem. 1991, 63, 45–58.
2. (a) Koskinen, A. Asymmetric Synthesis of Natural Prod-
ucts; Wiley: Chichester, 1993; pp 168–191; (b) Cane, D. E.
In Comprehensive Natural Products Chemistry; Barton, D.,
Nakanishi, K., Eds.; Elsevier: Oxford, 1999; Vol. 2, pp
1–13.
5.71 (1H, d, J = 11.1Hz), 5.97 (1H,
J = 16.2Hz), 6.04 (1H, B of ABq, J = 16.2Hz), 7.42–7.56
A of ABq,
(3H, m), 7.72–7.74 (2H, m) ppm; 13C NMR (75.5MHz,

7026
H.-S. Jeon, S. Koo / Tetrahedron Letters 45 (2004) 7023–7026
CDCl3) d 11.9, 14.0, 14.1, 17.8, 19.1, 21.5, 26.2, 28.8, 28.8,
pressure. The crude product was purified by silica gel flash
chromatography to give 2a (0.56g, 1.39mmol) in 92%
yield. Data for 2a: 1H NMR (300MHz, CDCl3) d 1.04
(6H, s), 1.30 (3H, t, J = 7.2Hz), 1.35 (3H, t, J = 7.1Hz),
1.44–1.50 (2H, m), 1.57–1.67 (2H, m), 1.73 (3H, s), 1.92
(3H, s), 2.02 (3H, s), 2.00–2.07 (2H, m), 4.25 (2H, q,
J = 7.1Hz), 4.32 (2H, q, J = 7.2Hz), 6.22 (1H, A of ABq,
J = 15.2Hz), 6.34 (1H, d, J = 12.1Hz), 6.38 (1H, B of
ABq, J = 15.2Hz), 6.91 (1H, d, J = 12.1Hz), 7.36 (1H, s)
ppm; 13C NMR (75.5MHz, CDCl3) d 12.9, 13.1, 14.0,
14.2, 19.2, 21.8, 28.9, 28.9, 33.1, 34.2, 39.6, 61.2, 61.4,
122.0, 125.3, 130.0, 130.5, 131.4, 137.4, 137.6, 138.5, 142.4,
146.5, 165.0, 167.5ppm; IR (KBr) 2930, 1732, 1716, 1567,
30.8, 32.8, 34.1, 39.4, 40.2, 61.5, 62.0, 62.2, 118.5, 128.6,
128.7, 128.9, 129.5, 133.1, 136.0, 137.2, 139.0, 142.4, 168.0,
170.5ppm; IR (KBr) 2931, 1716, 1447, 1370, 1307,
1149cmꢀ1; HRMS (FAB+) calcd for C25H37O4 401.2692,
found 401.2687.
12. Hunter, N. R.; Green, N. A.; McKinnon, D. M. Tetra-
hedron Lett. 1980, 21, 4589–4592.
13. The representative experimental procedure for 2a: The
mixture of 6a (0.80g, 1.50mmol) and DBU (1.14mL,
7.5mmol) in benzene (20mL) was heated at reflux for 4h.
The reaction mixture was then cooled to room tempera-
ture, and quenched with 1M HCl (10mL). The mixture
was extracted with ether (20mL · 3), dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
1253, 1223, 1200cmꢀ1
;
HRMS (FAB+) calcd for
C25H36O4 400.2614, found 400.2613.