1,2-Dibromoalkanes into alkynes by elimination reaction under DBU conditions and their application to total synthesis of sapinofuranone B

Article abstract of DOI:10.1016/j.tetlet.2006.04.075

Treatment of 1,2-dibromoalkanes with DBU effected an elimination reaction, leading to the alkynes. Oxygen substitution at the C3 position plays a critical role to abstract protons by inductive effects. By the application of this protocol, a total synthesi

Full text of DOI:10.1016/j.tetlet.2006.04.075

Tetrahedron Letters 47 (2006) 4133–4136
1,2-Dibromoalkanes into alkynes by elimination reaction
under DBU conditions and their application
to total synthesis of sapinofuranone B
Noriki Kutsumura, Tadashi Yokoyama, Tadaaki Ohgiya and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 21 March 2006; revised 11 April 2006; accepted 14 April 2006
Abstract—Treatment of 1,2-dibromoalkanes with DBU effected an elimination reaction, leading to the alkynes. Oxygen substitution
at the C3 position plays a critical role to abstract protons by inductive effects. By the application of this protocol, a total synthesis of
sapinofuranone B 4 was accomplished.
Ó 2006 Elsevier Ltd. All rights reserved.
Br
In the previous papers, we investigated a facile synthesis
of 2-bromo-1-alkenes carrying electron-withdrawing
groups under the DBU conditions, which enabled the
total synthesis of such natural products as 12-oxygen-
ated-tremetones, tuliparin B, and tanikolide.1 This elim-
ination reaction might result from the inductive effects
of the oxygen substituents, which induce high acidity
of a hydrogen at the neighboring position, leading to
the desired HBr abstraction. In addition, acidity
enhancement of hydrogen at C1 was also observed
during our extensive investigation.1a
Br
Base
Br
R2
R2
OR1
3
R2
OR1
+
DMF, 80 °C
1
OR1
1
2
3
Scheme 1. Elimination reaction of 1,2-dibromoalkanes.
to conventional methods mentioned above, we describe
herein our own DBU approach towards alkyne synthe-
sis, and its application toward c-lactone natural prod-
ucts synthesis (Fig. 1).
This observation indicated a new prospective synthesis
of alkynes from 1,2-dibromoalkanes under the DBU
conditions (Scheme 1). Alkynes are one of the important
functional groups in organic syntheses, which are emp-
loyed as precursors of cis- and trans-1-iodo-1-alkenes,2
2-iodo-1-alkenes,3 metalated alkenes,2f and alkynes,4 as
well as substrates of organometal-conducted coupling
reactions.5 HBr elimination reactions of 1,1-dibromo-
1-alkenes,6 and 1,2-dibromoalkanes using LiHMDS,
NaNH2, etc.,7 as well as coupling of aldehydes with
phosphonium diazomethanes8 have been reported as
synthetic methodologies of terminal alkynes. In addition
Elimination reaction of 1,2-dibromoalkanes carrying
oxygen substituents at the C3 positions was undertaken
by employing DBU as a base (Table 1).
General procedure (entry 3): To a solution of 1a (186 mg,
0.5 mmol) in DMF (9.2 mL) was added 5 equiv of DBU
at 0 °C; the mixture was stirred at 80 °C for 16 h. The
reaction mixture was diluted with a 2:1 mixture of hex-
ane and EtOAc, washed with 1 M aq HCl, H2O, and
brine. The organic layer was dried (Na2SO4), and con-
centrated in vacuo. The residue was purified by silica
gel column chromatography to yield 2a (89 mg, 92%).
Keywords: Elimination; Alkyne synthesis; 1,2-Dibromo-3-oxygenated
alkanes; Sapinofuranone B.
In contrast to the production of alkene 3a by 2 or
3 equiv mol of DBU (entries 1 and 2), reaction with
5 equiv mol of the base (entry 3) produced the desired
*
Corresponding author. Tel./fax: +81 45 566 1717; e-mail:
nisiyama@chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.075

4134
N. Kutsumura et al. / Tetrahedron Letters 47 (2006) 4133–4136
Br
Br
O
O
O
Br
R2
R2
R2
R1
R1
R1
3a : R1=NO2, R2=H
3b : R1=Br, R2=H
3c : R1=OMe, R2=H
3d : R1=OH, R2=H
3f : R1=NO2, R2=n-C5H11
2a : R1=NO2, R2=H
2b : R1=Br, R2=H
2c : R1=OMe, R2=H
2d : R1=OH, R2=H
2f : R1=NO2, R2=n-C5H11
1a : R1=NO2, R2=H
1b : R1=Br, R2=H
1c : R1=OMe, R2=H
1d : R1=OTf, R2=H
1e : R1=OH, R2=H
1f : R1=NO2, R2=n-C5H11
n-Pr
Br
R1 R2
O
R1
O
O
n-Pr
R2
Br
O2N
O2N
O2N
2g
O
1g : R1=H, R2=Br
1h : R1=Br, R2=H
3g : R1=n-Pr, R2=H
3h : R1=H, R2=n-Pr
O
O
O
O
O
Br
Br
Br
O2N
O2N
O2N
2i
3i
1i
Br
Br
F3C
F3C
F3C
Br
O
O
O
3j
2j
1j
O
O
O
O
Br
O
O
Br
Br
OPMB
3k
OPMB
2k
OPMB
1k
Figure 1.
Table 1. Synthesis of 1-alkynes from 1,2-dibromoalkanes in DMF
(80 °C)
produced 2-bromo-1-alkenes in the previous investiga-
tion,1a even 7 equiv mol of the salt provided ca. 1:8 mix-
ture of 2a and 3a. In comparison with the oxygen
substituent at the C3 position, higher electron-withdraw-
ing groups provided the corresponding alkynes in higher
yields (entries 3, 5, and 6). Compound 1d, possessing
a TfO group, was converted with abstraction of the
sulfonyl group to alkyne 2d in 92% yield. Removal of
the sulfonyl ester might take place after the construction
of the alkyne moiety, because there was no acquisition of
2d, but the corresponding alkene 3d was obtained in
moderate yield, from the phenolic dibromide 1e. Upon
introduction of an alkyl substituent at the C3 position
(1f), the corresponding alkyne 2f was obtained in lower
yield than the intact substrate (1a), owing to the
inductive effect of the alkyl group, which interfered in
the electron-withdrawing effect of the oxygen function
to lower the acidity of protons at the C1 and C2 positions
(entry 9). When the internal dibromides, such as
syn-1g and anti-1h were treated with DBU, 1g quantita-
tively afforded the corresponding alkyne 2g, in contrast
to 1h producing the bromo olefin 3h (entries 10 and
11). While a combination of a methyl and an acyloxy
group (1i) provided alkyne 2i in low yield (entry 12), lac-
tone 1k carrying an additional oxygen substituent gave
alkyne 2k as the sole product in good yield (entry 14).
Entry Substrates Bases
(equiv)
Yields (%)
1-Alkynes 2-Bromo1-alkenes
1a
2
1a
1a
1a
1a
1b
1c
1d
1e
1f
DBU (2)
DBU (3)
DBU (5)
2a (—)
2a (trace) 3a (46)
2a (92)
3a (100)
3
3a (—)
3a (83)
3b (10)
3c (—)
3d (—)
3d (52)
3f (12)
3g (—)
3h (94)
3i (—)
3j (30)
3k (—)
4b
5
NaOPiv (7) 2a (10)
DBU (5)
DBU (5)
DBU (6)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
DBU (5)
2b (42)
2c (68)
2d (92)
2e (—)
2f (71)
2g (95)
2g (—)
2i (29)
2j (45)
2k (73)
6
7
8
9
10c
11c
12
13
14d
1g
1h
1i
1j
1k
a 60 °C 1.5 h.
b 12 h.
c Racemic compound was used. Relative structure was shown.
d 85 h.
alkyne 2a in 92% yield as the sole product. This observa-
tion indicated that 2a is produced by a stepwise elimina-
tion through 3a. Upon using NaOPiv, which successfully

N. Kutsumura et al. / Tetrahedron Letters 47 (2006) 4133–4136
4135
The two electron-withdrawing groups enhanced the
desired alkyne synthesis, whereas considerable amounts
of alkene 3j were obtained in the case of the benzyl-
oxy group (1j) even carrying a CF3 group (entry 13).
quantitative yield, which was submitted to bromination
with Py–HBr3 to yield dibromide 1k, as a diastereomeric
mixture in 93% yield (Scheme 3), which was converted
as depicted in Table 1 to 2k under the DBU conditions.
Introduction of iodine into the terminal alkyne moiety12
in 2k gave 7 in 80% yield, which was submitted to the
diimide reduction2c,d with NBSH (o-nitrophenylsulfon-
ylhydrazide),13 leading to the cis-iodoalkene 8 in quanti-
tative yield. The Suzuki–Miyaura coupling14 of 8 with
E-1-propeneboronic acid provided 9 in 87% yield, which
upon deprotection of a p-methoxybenzyl group with
DDQ gave the expected 4 in 89% yield,15 spectroscopic
data of which was identical with that reported. In this
synthesis, the two asymmetric centers were introduced
by the Sharpless dihydroxylation protocol,16 which will
enable a synthesis of its enantiomeric form.
With the observation mentioned above, the alkyne-
synthesis protocol was applied to the total synthesis of
phytotoxic sapinofuranone B 4, isolated from Saphaer-
opsis sapinea.9 Until now, its enantiomer, isolated from
Acremonium strictum, has been synthesized by two
groups.10 As can be seen in the retrosynthetic analysis
(Scheme 2), 4 might be produced by conversion of the
alkyne moiety of 2k to the corresponding diene. Sub-
strate 1k of the elimination would be obtained by suc-
cessive p-methoxybenzylation and bromination of allyl
alcohol 5.11
Along this line, synthesis of 4 was commenced with
p-methoxybenzylation of 5 to give the PMB ether 6 in
In conclusion, our elimination reaction methodology of
3-O-substituted 1,2-dibromoalkanes proposed a new
O
O
O
O
O
Br
O
Br
OPMB
OPMB
1k
OH
2k
O
4: Sapinofuranone B
O
OH
6
5
OH
Scheme 2. Retrosynthetic analysis of sapinofuranone B 4.
O
O
2 steps
O
b
O
Br
OH
Br
OPMB
OR
5: R=H
1k
a
6: R=PMB
O
O
c
e
O
R
O
OR1 R2
8: R1=PMB, R2=I
9: R1=PMB, R2=E-CH=CHMe
OPMB
2k: R = H
7: R=I
d
f
g
4: R1=H, R2=E-CH=CHMe
Scheme 3. Reagents and conditions: (a) p-methoxybenzyl trichloroacetimidate, TfOH/Et2O (100%); (b) Py–HBr3/CH2Cl2 (93%); (c) DBU (5 equiv)/
DMF, 80 °C (73%); (d) NIS, AgNO3/acetone (80%); (e) NBSH, Et3N/THF-iPrOH (100%); (f) PdCl2(dppf), E-1-propeneboronic acid, CsF/PhMe
(87%); and (g) DDQ/CH2Cl2–H2O (89%).

4136
N. Kutsumura et al. / Tetrahedron Letters 47 (2006) 4133–4136
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This work was supported by Grant-in-Aid for the 21st
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