Conversion of 3-O-substituted 1,2-dibromoalkanes into 2-bromo-1-alkenes by the selective elimination: Its application to total synthesis of 12-oxygenated tremetones

Article abstract of DOI:10.1246/cl.2004.1084

2-Bromo-1-alkenes were efficiently synthesized in good yields by the regioselective HBr-elimination reaction of 3-aryloxy- or 3-acyloxy-1,2- dibromoalkanes. Total synthesis of several oxygenated tremetones has been accomplished by using the 2-bromo-1-alkene derivative produced by this elimination reaction.

Full text of DOI:10.1246/cl.2004.1084

1
084
Chemistry Letters Vol.33, No.9 (2004)
Conversion of 3-O-Substituted 1,2-Dibromoalkanes
into 2-Bromo-1-alkenes by the Selective Elimination:
Its Application to Total Synthesis of 12-Oxygenated Tremetones
ꢀ
Tadaaki Ohgiya and Shigeru Nishiyama
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522
(Received June 9, 2004; CL-040658)
2
-Bromo-1-alkenes were efficiently synthesized in good
Table 1. Synthesis of 2-bromo-1-alkenes from 1,2-dibromides
yields by the regioselective HBr-elimination reaction of 3-ary-
loxy- or 3-acyloxy-1,2-dibromoalkanes. Total synthesis of sev-
eral oxygenated tremetones has been accomplished by using
the 2-bromo-1-alkene derivative produced by this elimination
reaction.
Ratioc
2 and 3 )
Entry
1,2-Dibroalkane (1) Methoda Temp / °C 2-Broalkene (2)
Yield / %b
d
(
1
2
3
4
5
6
1a
Br
A
B
C
A
C
A
60
60
60
60
60
60
Br
2a + 3a: 96
17 : 1
20 : 1
26 : 1
1a Br
O
O
2a + 3a: 96
2a + 3a: 98
2b + 3b: 60
2b + 3b: 96
2c + 3c: 67
1a
1b
1b
1c
X
X
d
1a : X = NO2
1b : X = OMe
1c : X = Cl
2a : X=NO2
2b : X=OMe
2c : X=Cl
10 : 1
18 : 1
12 : 1
7
8
1d
1d
B
C
80
80
2d + 3d: 92
2d + 3d: 97
40 : 1
1
2
tant functional groups for preparation of vinyl lithium and vinyl
-Bromo-1-alkenes have been recognized as one of impor-
2
Br
Br
Br
>99 : 1
O
O
1d
2d
3
Grignard reagents, coupling partners in a wide range of transi-
3
9e 1e
60
60
2e + 2f + 3e: 97 40 : 1
(2e:2f = 60:1)
Br
Br
C
C
Br
,4
tion metal-mediated coupling reactions, substrates of radical
n-Pr
n-Pr
O
O
5
6
reaction, and precursors of ꢀ-haloketones. Synthesis of 2-bro-
mo-1-alkenes has been achieved by the bromo-boration of termi-
nal alkynes with 9-bromo-9-borabicyclo[3.3.1]nonane (9-Br-9-
BBN)1 or regioselective addition of hydrogen bromide to al-
Br
Br
n-Pr
1e
NO2
NO2
2e
NO2
1
0e 1f
Br
2f + 2g + 3e: 99 40 : 1
(2e:2f = 1:60)
O
n-Pr
O
a
1f
2f
NO2
kyne systems.1
b,1c
In our synthetic investigation of biologically
11
1g
Br R1
A
A
60
60
Br R1
2g + 3g: 94
2h + 3h: 98
40 : 1
75 : 1
active compounds, we unexpectedly found that the selective
elimination of 3-aryloxy- or 3-acyloxy-1,2-dibromoalkanes 1
provided the corresponding alkenyl bromide 2 (major product)
and 3 (minor product). We disclose herein the investigation of
the novel synthesis of 2-bromo-1-alkenes, and its application
to natural products synthesis.
12 1h
Br
R2
R2
OCOAr
g : R1 = H, R2 = Me
Ar = 4-NO2-Ph
OCOAr
1
2g : R1 = H, R2 = Me
Ar = 4-NO2-Ph
1
h : R1 = R2 = Me
Ar = 4-NO2-Ph
2h : R1 = R2 = Me
Ar = 4-NO2-Ph
13 1i
Br
O
C
60
Br
O
O
2i + 3i: 76
1.5 : 1
Br
O
Conversion of 3-aryloxy-1,2-dibromoalkanes 1a–1f includ-
ing the benzofuran-type compound 1d into the corresponding 3-
aryloxy-2-bromo-1-alkenes 2a–2f was investigated (Table 1).
Elimination reaction of 1a–1f, synthesized by bromination of
1i
Br
2i
Br
aMethod A; 2 equiv. of NaOAc in DMF, Method B; 2 equiv. of
NaOPiv in DMF, Method C; 1.05 equiv. of DBU in DMF.
Yield of a mixture of 2 and 3. Ratio of 2 and 3 was determined
by H NMR. Starting material was recovered (13%). Racemic
compound was used.
b
c
7
1
d
e
the corresponding olefin, provided 2a–2f under basic conditions
such as DBU, NaOAc, and NaOPiv in DMF. Characteristically,
this method required no extra-dry conditions, as well as expen-
sive reagents. Regioselectivity and yields of the reaction were
regulated by the electron-withdrawing effect of O-functional
groups at the C-3 position of 1 (Entries 1–6). Interestingly, when
using weak bases, such as NaOAc and NaOPiv, the desired elim-
inations preferentially proceeded in good yields, rather than usu-
al substitution reactions of the alkyl bromide into the corre-
sponding acylates. Upon comparison of bases used, good
regioselectivity was obtained in the order of DBU > NaOPiv
Br
Br
Br
R
R
Br
R
+
OPh or OAcyl
OPh or OAcyl
OPh or OAcyl
1
2
3
the dibromoalkane chain, effects of which were lowered by in-
sertion of a methylene group (Entry 13). Thus, the merit of our
method are as follows; (i) in contrast to precedented method,
which employed terminal acetylide precursors, our approach
with the bromo-alkene intermediate would provide an entirely
different synthetic pathway, for instance, production of 2d via
a terminal acetylene would need long steps more than our meth-
od, (ii) our method required no extra-dry conditions, as well as
expensive reagents (NaOAc and DBU), (iii) our method is appli-
cable to synthesis of bromoalkenes even at internal position, as
depicted in Entries 9, 10.
>
NaOAc. Even 1d, carrying a dihydrobenzofuran, underwent
the desired HBr-elimination selectively to produce 2d in good
yield (Entries 7, 8). In the case of 3-O-substituted-1-alkyl-1,2-di-
bromoalkane derivatives 1e and 1f, both of the syn- and anti-di-
bromides underwent the regioselective elimination to provide
the corresponding alkenes, 2e and 2f (Entries 9, 10). The 1,3-ac-
yl migration by the attack of acyloxy group to the vicinal dibro-
mide was not observed in 3-acyloxy-1,2-dibromoalkanes 1g and
7
In the next stage, the bromoalkene derivative 2d produced
by our effective elimination reaction, was utilized to the total
synthesis of several (ꢁ)-12-oxygenated tremetones. Tremetone
1h (Entries 11, 12). On the other hand, regioselectivity and
yield of the reaction were decreased in the dibromoalkane 1i
carrying the electron-withdrawing group at the C-4 position of
7
8
(ꢂ)-4 is the principal toxic ketone of white snakeroot (Eupato-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.9 (2004)
1085
rium urticaefolium) extensively growing in damp area of the
central United States. In addition, several tremetone derivatives,
possessing the (R)- and (S)-stereoisomers, were isolated from
O
b
d
O
R
O
R
O
O
OMe
9
–12
2d: R=Br
O
natural source (Figure 1).
tyl-2,3-dihydrobenzofuran-2-yl)propenoate (5) was isolated by
For instance, methyl (þ)-2-(5-ace-
9: R=CH:CH2
1d: R=CHBrCH2Br
5
c
e
d
a
8 : R=COOMe
0: R=CH2OH
1
9
O
OR
Hildebrand et al. from the roots of Microglossa pyrifolia, which
is used as a traditional medicine both in Africa and in tropical
7
: R=Ac
f
6: R=H
Asia. The first total synthesis of (ꢁ)-6 was achieved by the Nickl
reaction,13 followed by selenium-oxidation (5–16%).14 (ꢂ)-6,
Scheme 2. Reagent and conditions: a. Pyr.-HBr3, DMF, rt
ꢃ
(
95%). b. DBU, DMF, 80 C (97%). c. CO, 10 mol %
ꢃ
(
ꢂ)-7, and (ꢁ)-7 were synthesized by using diverse synthetic ap-
PdCl2(Ph3P)2, Cs2CO3, MeOH-PhMe-THF, 60 C (62%). d.
10a,14,15
proaches.
Although (þ)-5 is an ingredient of esteemed
ꢃ
ꢃ
Ac2O, SnCl4, (CH2C1)2, 0 C. (91%). e. DIBAL-H, THF, 0 C
99%). f. NH3, MeOH, rt (99%).
traditional medicine, its biological activity have been uncovered,
probably owing to insufficient supplying from natural source. In
spite of biological expectation, synthesis of 5 to supply sufficient
amounts, has not been reported to our knowledge. Additionally,
(
tion reactions. Natural tremetone derivatives 5, 6, and 7 were
successfully synthesized in racemic forms by employing our
2-bromo-1-alkene derivative.
(
ꢂ)-6 was observed to possess inhibitory activity against myelo-
10b
peroxidase. With such motivation, total synthesis of 5, 6, and
in their racemic forms using our regioselective elimination re-
action was started.
References and Notes
7
1
a) S. Hara, H. Dojo, S. Takinami, and A. Suzuki, Tetrahedron
Lett., 24, 731 (1983). b) R. K. Boeckman, Jr. and D. M. Blum,
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O
O
O
4
4
4
7
1980, 805. d) Related synthesis. See: A. E. Kalaidzhyan, S. G.
O
Akopyan, and K. A. Kurginyan, Arm. Khim. Zh., 39, 237 (1986).
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2
12
2
2
12
6
6
6
O
12 OMe
2
O
O
OR
7
7
(
2003).
2
2
S: (+)-5
RS: (+)-5
2
2
R: (-)-4
RS: (+)-4
R = H, 2R: (-)-6
R = H, 2RS: (+)-6
R = Ac, 2R: (-)-7
3
4
P. Knochel and S. A. Rao, J. Am. Chem. Soc., 112, 6146 (1990).
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(
2003). c) J. Uenishi and M. Ohmi, Heterocycles, 61, 365 (2003).
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Figure 1. Structure of tremetone and 12-oxygenated treme-
tones.
5
6
7
4
M. P. VanBrunt, R. O. Ambenge, and S. M. Weinreb, J. Org.
Chem., 68, 3323 (2003).
The olefin compounds for providing 1a–1h by bromination are
already known. See: 1a and 1b, E. Vowinkel, Ber., 95, 2997
(1962); 1c, F. M. Sonnenberg, J. Org. Chem., 35, 3166 (1970);
(+)-5, 6, 7
COOMe
Br
O
O
8
2d
1d, Ref 13; 1e and 1f, C. Goux, M. Massacret, P. Lhoste, and
D. Sinou, Organometallics, 14, 4585 (1995); 1g, B. Stefane,
M. Kocevar, and S. Polanc, Tetrahedron Lett., 40, 4429
O
Br
Br
O
(
1999); 1h, G. F. Hennion and S. O. Barrett, J. Am. Chem.
9
1d
Soc., 79, 2146 (1957); 1e and 1f were synthesized by trans-addi-
tion of Br2 with Pyr.-HBr3 from corresponding (E)-olefin and
Scheme 1. Retrosynthesis of 12-oxygenated-tremetones.
In our retrosynthetic analysis (Scheme 1), 5, 6, and 7 would
(
Z)-olefin, respectively. 4-O-Substituted-1,2-dibromoalkane de-
rivative 1i was produced from homoallylalcohol by acylation
and following bromination.
be constructed from the ꢀ,ꢁ-unsaturated ester 8, which would be
produced from bromoalkene 2d by using the Pd-catalyzed car-
bonyl insertion. The bromoalkene system of 2d would be pro-
duced from 9 through intermediate 1d. Synthesis of the oxygen-
ated tremetones 5, 6, and 7 commenced with bromination of 9 to
give dibromide 1d in 95% yield (Scheme 2). The vicinal dibro-
mide possessing a aryloxy group at the adjacent position was re-
gioselectively eliminated with DBU to yield the key 2-bromo-1-
alkene derivative 2d in 97% yield (2d:3d = >99:1). The Pd-cat-
alyzed carbonyl insertion of 2d led to methyl ester 8 in 62%
yield, followed by acetylation afforded 5 in 91% yield. In addi-
tion, the ꢀ,ꢁ-unsaturated ester 8 was converted into allyl alcohol
8
9
W. A. Bonner, J. I. DeGraw, Jr., D. M. Bowen, and V. R. Shah,
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M. Giner, and J.-L. Rios, Eur. J. Pharmacol., 460, 219 (2003).
(
1
0b
1
1 Although Rios et al. indicated the (S)-configuration of 6, we
confirmed by private communication that the absolute stereo-
chemistry of 6, isolated from Helichrysum italicum, was not de-
termined. We guessed that Rios et al. utilized (ꢂ)-6, since
H. italicum is the same genus as H. stoechs, which produced
(ꢂ)-6.
1
1
1
2 J. Ito, F.-R. Chang, H.-K. Wang, Y. K. Park, M. Ikegaki, N.
Kilgore, and K.-H. Lee, J. Nat. Prod., 64, 1278 (2001).
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10 in 99% yield, and the following acetylation, afforded 7 in
91% yield. Finally, hydrolysis of 7 led to 6 in 99% yield. All
of the synthetic 5, 6, and 7 were identical to the natural products
39, 169 (1983).
1
0,11,13
under the full range of spectroscopic data.
4 Y. Kawase, S. Yamaguchi, S. Kondo, and K. Shimokawa, Chem.
Lett., 1978, 253.
In conclusion, synthesis of 2-bromo-1-alkene systems has
been accomplished in good yields from 3-aryloxy- or 3-acy-
loxy-1,2-dibromoalkane derivatives 1 by regioselective elimina-
15 R. C. Larock, N. Berrios-Pena, and K. Narayanan, J. Org. Chem.,
55, 3447 (1990).
Published on the web (Advance View) July 26, 2004; DOI 10.1246/cl.2004.1084