Synthesis of (+)/(-) pentenomycins via Me2AlCl induced cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2013.03.092

An efficient approach for the synthesis of (+) pentenomycin and (-) pentenomycin from d-ribose and d-mannose, respectively, is described using Tebbe olefination of lactones 9 and 7 followed by Me₂AlCl induced disfavoured 5-(enol-endo)-exo-trig

Full text of DOI:10.1016/j.tetlet.2013.03.092

Tetrahedron Letters 54 (2013) 2845–2848
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Synthesis of (+)/(ꢀ) pentenomycins via Me AlCl induced cascade reaction
2
⇑
Bejugam Santhosh Kumar, Girija Prasad Mishra, Batchu Venkateswara Rao
Organic and Biomolecular Chemistry Division, CSIR—Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the synthesis of (+) pentenomycin and (ꢀ) pentenomycin from
D
-ribose and
Received 6 November 2012
Revised 19 March 2013
Accepted 22 March 2013
Available online 3 April 2013
D
-mannose, respectively, is described using Tebbe olefination of lactones 9 and 7 followed by Me AlCl
2
induced disfavoured 5-(enol-endo)-exo-trig cyclization.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbocyclitols
Pentenomycins
Tebbe reaction
2
Me AlCl reaction
Carbocyclitols are part structures of many interesting biologi-
The retrosynthesis for 1 and 2 (Scheme 2) was envisaged based
on our Tebbe-mediated cascade method as shown in Scheme 2.
Oxidative cleavage of the double bond followed by 1,2 elimination
of water molecule in the proposed intermediates 6 and 8 should
give pentenomycins 1 and 2. The compounds 6 and 8 in turn can
be obtained by treating the lactones 7 and 9, respectively, with
cally active compounds.1 These molecules inhibit glycosidases
and show interesting biological activity such as anti-diabetic,
2
anti-HIV, and anti-cancer. Conversion of readily available carbohy-
drates into highly oxygenated carbocycles is an attractive route
2–6
adopted by many synthetic chemists,
since this approach gives
1
4,15
the target compounds with high optical purity. Among the re-
ported methods, Ferrier rearrangement is considered as useful
transformation for the synthesis of cyclohexitols from 5-enopyr-
Tebbe reagent.
the commercially available
For the synthesis of (+) pentenomycin 2 (Scheme 3),
was converted into compound 10 in three steps using the reported
The lactones 7 and 9 can be synthesized from
-mannose and -ribose, respectively.
-ribose
D
D
D
7
anosides. Later, Sinay and co-workers also developed a methodol-
1
3f,16
ogy for the cyclohexitols from the 5-enohexopyranosides using
procedure.
Treatment of 10 with NaOH followed by chopping
afforded compound 11 in 80% yield. Refluxing
8
TIBAL. However, these methods failed to give cyclopentitols from
the diol with NaIO
4
corresponding 4-enofuranosides, since they have to undergo unfa-
compound 11 in the presence of catalytic amount of PPTS in 2-pro-
panol furnished compound 7 required for the cascade reaction in
84% yield. When compound 7 was treated with Tebbe reagent
(1.8 equiv), the expected cascade reaction did not proceed, instead,
olefination of lactone took place to give the enol ether 13 in 78%
yield. Attempts to progress the cascade reaction by adding excess
Tebbe reagent (4 equiv) at 0 °C, at rt or at reflux are unsuccessful.
vorable 5-(enol-endo)-exo-trig cyclization.9
However, recently we developed a Tebbe-mediated cascade
reaction for the synthesis of cyclopentitols 4 and 5 from five-
membered sugar lactone 3 via 5-(enol-endo)-exo-trig cyclization
(
Scheme 1), which is considered as a disfavored reaction according
1
0
to Baldwin rules. Herein we would like to present our observa-
tions while applying this cascade method for the synthesis (ꢀ)
and (+) pentenomycins 1 and 2 (Fig. 1).
In order to know whether free hydroxy group
a to the lactone
obstructs further reaction by complexing with the Tebbe reagent,
the free hydroxy group was converted into TBS protected ether
to give 12. Treatment of compound 12 with Tebbe reagent also
failed to give the desired transformation and culminated at olefin
stage giving 14. From the above experiment, it was concluded that
the quaternary center adjacent to the enol ether in 13 and 14 may
be preventing the molecule to undergo further transformation.
(
ꢀ) Pentenomycin 1 belongs to the pentenomycin group of anti-
11
biotics and was isolated by Umino et al. from Streptomyces
eurythermus, which exhibits activity against both Gram positive
and Gram negative bacteria. In view of its complex structure
and important biological activities, several synthetic approaches
for pentenomycins have been reported for racemic as well as
enantiopure forms.
12
1
3
17
At this stage, it was decided to screen various Lewis-acids
(
Table 1) for the transformation of 13 into carbocycle. Different
Lewis-acids such as BF , TiCl , SnCl in DCM and ZnCl in
ꢁOEt
were tried on 13 and none of them gave the required
product and every time decomposition occurred and we failed to
3
2
4
4
2
1
8
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
2
THF/H O
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.092

2
846
B. S. Kumar et al. / Tetrahedron Letters 54 (2013) 2845–2848
H
H
H
LA
O
LA
O
O
O
O
O
HO
O
cleavage of
methylation
O
intramolecular
aldol reaction
isopropyl
group
Tebbe reagent
O
O
O
O
O
O
O
O
3
4
-enofuranoside
HO
OH
OH
HO
methylation
HO
OH
4
Tebbe reagent
O
O
HO
HO
OH
5
Scheme 1. Tebbe-mediated cascade approach for the synthesis of cyclopentitols.
Table 1
List of Lewis-acids
O
O
Entry
Reagent (equiv)
BF (1.2)
TiCl
SnCl
ZnCl
Conditions
Yield (15)
OH
OH
OH
OH
HO
HO
1
2
3
4
5
3
ꢁOEt
2
DCM 0 °C, 30 min
DCM 0 °C–rt, 1 h
DCM 0 °C–rt, 1 h
THF/H O, 0 °C–rt, 7 h
2
DCM, ꢀ78 °C, 20 min
Decomposition
Decomposition
Decomposition
Decomposition
70% yield
1
2
(
-) pentenomycin
(+) pentenomycin
4
(1.2)
(1.2)
(1.2)
4
2
Figure 1. Structures of pentenomycins.
Me
2
AlCl (1.2)
O
O
HO
O
O
Tebbe
OH
OH
OH
OH
D-mannose
mediated
cascade
HO
OH
O
O
O
O
(
-) pentenomycin
1
6
7
O
HO
O
O
O
Tebbe
D-ribose
OH
OH
mediated
cascade
HO
(
OH
O
O
O
O
+) pentenomycin
2
8
9
Scheme 2. Retrosynthesis of compounds 1 and 2.
O
O
O
O
OH
HO
O
OH
O
O
HO
a
b
d
c
OR
R=H
2 R=TBS
O
O
O
O
O
O
7
1
0
1
11
O
O
O
e
f
O
OR
OH
OH
O
O
O
O
HO
OH
2
1
5
1
3 R=H
14 R=TBS
Scheme 3. Synthesis of (+) pentenomycin 2. Reagents and conditions: (a) (i) NaOH, H
2
O, 40 °C, 20 min, (ii) NaIO
4
, 0 °C, BaCl
2
, 30 min; 80%; (b) 2-propanol, PPTS (cat.), reflux,
AlCl (1.2 equiv), ꢀ78 °C, 20 min, 70%; (f)
8
0 °C, 1.5 h, 84%; (c) TBS-Cl, imidazole, DCM, DMAP (cat.) 1 h, 85%; (d) Tebbe reagent (1.8 equiv), THF, 0 °C, 1 h, 78%; (e) Me
2
Ò
2
Amberlyst -15 in THF/H O (2:1), 70 °C, 5 h, 75%.

B. S. Kumar et al. / Tetrahedron Letters 54 (2013) 2845–2848
2847
Ò
isolate any product in pure form. Then it was thought to use
Me AlCl for this transformation, since it is known for its
group in 22 was achieved with Amberlyst -15 in THF/H
2
O (2:1)
2
to give (ꢀ) pentenomycin 1 in 75% yield, whose analytical data
19
20
D
exceptional 1,3 chelating ability and also aluminum-mediated
transformation of vinyl acetal to tetrahydropyrans was well
established in the literature which is popularly known as the
Petasis–Ferrier rearrangement.2
were in good agreement with the reported values. {½
aꢂ
¼ ꢀ31:0
1
2,13
21
D
(c = 0.35, EtOH), lit.:
½
a
ꢂ
¼ ꢀ32:0 (c = 0.30, EtOH)}.
To further understand the mechanism, we then applied this
reaction on unsubstituted enol ether 23 (Scheme 6) where there
is no possibility of above said 1,3 chelation. For this, compound 3
0,21
When enol ether 13 was subjected to Me
2
AlCl at ꢀ78 °C in DCM,
1
0
interestingly it resulted directly in compound 15 in 70% yield.
obtained from
D
-ribose was converted into 23. When 23 was sub-
AlCl as listed in Table 1,
the required product transformation was not observed, every time
decomposition occurred. This further supports the specific reactiv-
2
D
0
13f
{
mp 61–64 °C, ½
a
ꢂ
¼ ꢀ19:0 (c = 1.0, CHCl
3
), lit.:
63–65 °C,
jected to various Lewis-acids including Me
2
2
D
0
½
a
ꢂ
¼ ꢀ21:16 (c = 1.0, CHCl
3
)}. Removal of the isopropylidene
Ò
group in 15 was achieved with Amberlyst -15 in THF/H
2
O (2:1) to
give (+) pentenomycin 2 in 75% yield, whose analytical data
2
ity of Me AlCl with 13 and 21 by 1,3 chelation which helped the
required transformation to occur.
2
0
were in good agreement with the reported values. {½
a
ꢂ
¼ þ30:8
D
3f
25
D
(
c = 0.14, EtOH), lit.:1
½
aꢂ
¼ þ30:1, (c = 0.1, EtOH)}. Again
In conclusion, we developed a Tebbe-mediated cascade method
2
3
attempts to continue the cascade reaction in the presence of Me
2
AlCl
for the synthesis of (+) and (ꢀ) pentenomycins. During this ap-
proach, we observed that the Tebbe reaction on tertiary substi-
tuted lactones 7 and 9 gave only enol ethers 13 and 21 instead of
in THF or DCM/THF along with Tebbe reagent on 13 have met with
failure.
1
0
The mechanism is depicted in Scheme 4 for the formation of
product 15. 1,3 Chelation of the alkoxyaluminum with ring oxygen
in 16 might have exerted effective activation for the opening of the
ring to give active species 17, which resulted in 18 through the
intramolecular aldol reaction via 5-(enol-endo)-exo-trig-cycliza-
tion. Further, 1,2 elimination has taken place in the same pot to
give required enone 15.
the cyclopentitols which we observed earlier. For the transforma-
tion of 13 and 21 into cyclopentenones 15 and 22 different Lewis-
acids have been studied. It was found that Me AlCl is a suitable re-
2
agent for this transformation which is taking place via 5-(enol-
endo)-exo-trig cyclization a disfavored transformation as per Bald-
2
win rules. The failure of Me AlCl condition for the conversion of
simple enol ether 23 into 24 can be attributed to the lack of inter-
nal 1,3 chelation. Further applicability of this methodology is un-
der progress.
After successfully achieving (+) pentenomycin 2, we turned our
attention to synthesize the natural (ꢀ) pentenomycin 1 (Scheme
3f,22
5
). For this, the required lactone 191
was prepared from D-man-
nose in four steps. Ring opening of 19 with NaOH followed by
chopping the diol gave compound 20 in 80% yield. Lactone 9 was
obtained by treatment of 20 with acid in 2-propanol in 84% yield.
Tebbe olefination of 9 gave the enol ether 21 in 78% yield.
O
O
O
LA
O
O
O
Tebbe
O
O
Table 1
O
O
O
O
(1 equiv.)
2
Compound 21 when subjected to Me AlCl gave the required
compound 22, whose analytical data were in good agreement with
23
24
1
2e,13e,f
11b,13a
the reported values.
{mp 63–65 °C, lit.:
)}. Removal of the isopropylidene
63–66 °C
20
½
aꢂ
¼ þ20:0 (c = 1.0, CHCl
3
Scheme 6. Study on unsubstituted enol ether.
D
Al
Al
O
Al
O
O
O
O
O
RO
intramolecular
aldol reaction
1,2 elimination
13
OH
O
O
O
O
O
O
O
O
O
O
O
16
17
15
18
R =
or H
Scheme 4. Plausible mechanism for the formation of 15.
HO
HO
O
O
HO
O
O
O
O
a
O
c
b
OH
OH
OH
O
O
O
O
O
O
19
9
O
O
d
O
O
OH
e
OH
OH
O
O
O
O
HO
OH
1
22
Scheme 5. Synthesis of (ꢀ) pentenomycin 1. Reagents and conditions: (a) (i) NaOH, H
2 4 2
O, 40 °C, 20 min. (ii) NaIO , 0 °C, BaCl , 30 min, 80%; (b) 2-propanol, PPTS (cat.), reflux,
Ò
8
0 °C, 1.5 h, 84%; (c) Tebbe reagent (1.8 equiv), THF, 0 °C, 1 h, 78%; (d) Me AlCl (1.2 equiv), ꢀ78 °C, 20 min, 70%; (e) Amberlyst -15 in THF/H O (2:1), 70 °C, 5 h, 75%.
2
2

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B. S. Kumar et al. / Tetrahedron Letters 54 (2013) 2845–2848
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