Total synthesis of (±)-pentenomycin

Article abstract of DOI:10.1016/j.tetlet.2006.05.156

A concise stereoselective route to (±)-pentenomycin 1 in 33% overall yield starting from the readily accessible Diels-Alder adduct 4 is reported. The key reaction involves decarbonylation of β-methoxy-α,β-unsaturated aldehyde 8 obtained from β-hydroxy-dimethylketal 6.

Full text of DOI:10.1016/j.tetlet.2006.05.156

Tetrahedron Letters 47 (2006± 5251–5253
Total synthesis of (± ±)-entenoꢀyꢁin
*
Faiz Ahmed Khan and Bhimsen Rout
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 21 April 2006; revised 15 May 2006; accepted 24 May 2006
Available online 12 June 2006
Abstraꢁt—A concise stereoselective route to (± ±)pentenomycin 1 in 33% overall yield starting from the readily accessible Diels–
Alder adduct 4 is reported. The key reaction involves decarbonylation of b)methoxy)a,b)unsaturated aldehyde 8 obtained from
b)hydroxy)dimethylketal 6.
Ó 2006 Elsevier Ltd. All rights reserved.
1
Ever since the isolation of pentenomycin I 1, usually re)
ferred to as pentenomycin, belonging to the biologically
active family of closely related polyhydroxylated cyclo)
pentenoid antibiotic natural products was reported, sev)
O
O
O
HO
or
HO
1
OH
OH
O
5
4
O
OH
OH
pentenomycin
O
2
–4
eral total syntheses have appeared in the literature.
O
OH
Pentenomycin exhibits moderate activity against
Gram)positive and Gram)negative bacteria. The pres)
ence of a cyclopentenone moiety in pentenomycins at)
tracted considerable attention due to its occurrence in
a diverse range of biologically potent natural products
and a multitude of structurally complex pharmacologi)
1
2a
2b
MeO
Br
OMe
Br
MeO
OMe
CO Me
2
2
cally important agents. The synthetic approaches to
O
3
pentenomycin can be categorized as racemic and enan)
Br
Br
O
O
Br
O
O
4
,5
tiopure syntheses. The latter can be further classified
as (i± those involving carbohydrate)based starting mate)
O
O
4
3
4
5
rials and (ii± asymmetric synthesis.
Sꢁheꢀe 1. Retrosynthetic strategy for pentenomycin.
Recently, we reported a short and stereoselective synthe)
sis of 2)hydroxymethyl)4)deoxypentenomycin and 2)
hydroxymethylpentenomycin derivatives. Our strategy
6
ing material was offset by the difficulty encountered in
its removal in 2 through an originally planned oxida)
tion–decarboxylation protocol, perhaps due to the sensi)
tivity of the enone moiety in these systems. We now
report an elegant solution to this problem that led us
to accomplish the total synthesis of the title compound
in high overall yield.
was based on the establishment of the C)5 tertiary center
as well as the C)4 stereocenter at an early stage in a ste)
reoselective manner as depicted in Scheme 1. Hydroxy)
methyl functional group addition to pentenomycin 1 at
C)2 allowed us to simplify the target to the bridged)lac)
tone 3, which is easily available from the Diels–Alder
7
adduct 4 via the methods developed in our laboratory.
Our initial efforts toward the one)carbon scission of 2 to
obtain 1 met with failure. We then took recourse to the
intermediate 5, which had furnished 2 upon treatment
Indeed the 2)hydroxymethylpentenomycin derivatives 2
were synthesized in 38% overall yield from 4. The
advantage gained by the functional group addition at
C)2 that facilitated realization of 4 as a convenient start)
6
with Amberlyst)15 in acetone, and protected the vicinal
diol to obtain the bis)acetonide derivative 6 (Scheme 2±.
Oxidation of the hydroxymethyl moiety using RuCl3–
NaIO4 furnished the carboxylic acid derivative 7
in 70% yield. We anticipated that under hydrolytic
*
0
Corresponding author. Tel.: +91 512 2597864; e)mail: faiz@iitk.ac.in
040)4039/$ ) see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.156

5252
F. A. Khan, B. Rout / Tetrahedron Letters 47 (2006) 5251–5253
MeO
O
OMe
MeO
OMe
groups of the b)ketal under acidic reaction conditions.
Aldehyde 8 was subjected to Wilkinson’s rhodium com)
OH 2,2-dimethoxypropane HO
O
HO
plex [RhCl(PPh ± ] in toluene at 100 °C to afford the
OH
O
O
3 3
8
o
corresponding decarbonylated product 9 in 81% yield.
SnCl .2H O, 20
C
2
2
O
O
36 h, 80%
With the acquisition of one)carbon scission product 9,
the stage was set for the final step where hydrolysis of
the enol ether and two acetonide moieties with concur)
rent elimination of the C)3 hydroxy group would lead
to pentenomycin. Hydrolysis was carried out initially
employing Amberlyst)15 in moist acetone which fur)
nished 10, still possessing one acetonide group that
was now located between the C)4,5 hydroxyl groups.
Subjecting 10 to 90% aqueous TFA furnished (± ±)pent)
enomycin in quantitative yield. Alternatively, treatment
of 9 with 90% aqueous TFA directly led to (± ±)penteno)
5
6
RuCl .3H O, NaIO
3
2
4
MeCN-CCl -H O
4
2
0 oC, 1 h, 70%
MeO
OMe
O
HO C
2
O
O
O
OH
9
0% aq. TFA
OH
OH
O
rt, 12 h
(
±)-1
7
9
mycin in 94% yield (Scheme 3±.
Sꢁheꢀe 2.
Having achieved the synthesis of pentenomycin via a
strategy based on decarbonylation of aldehyde 8, we
next focused our attention on bridged)lactone interme)
diate 11. This compound was obtained by tributyltin hy)
conditions, in addition to the events described during
the hydrolysis of 5 (deprotection of the dimethyl acetal
followed by elimination of the hydroxy functionality
6
6
with reorganization of the acetonide protection±, decar)
dride mediated hydrodebromination of 3 in high yield.
boxylation would also takes place giving pentenomycin.
Unfortunately, a complex mixture of products was
observed when 7 was treated with 90% aqueous TFA
We had reported previously, in a related system, that the
methyl ester moiety, rather than the lactone which is
generally considered more reactive, is reduced chemose)
(
Scheme 2±.
lectively by NaBH
4
in THF to the corresponding alco)
hol. When bridged)lactone 11 was treated with
2.5 equiv of NaBH in THF at room temperature, the
7
We modified the strategy for the one)carbon scission
and subjected the bis)acetonide derivative 6 to PCC
oxidation (Scheme 3±. To our surprise, b)methoxy)a,b)
unsaturated aldehyde 8 was obtained in 80% yield.
The formation of this unexpected product may be ac)
counted for via the elimination of one of the methoxy
4
reaction was sluggish and furnished 85% of the corre)
sponding alcohol 12 in 7 days (Table 1±. This could per)
haps be attributed to the steric congestion due to the
presence of an a)endo)hydroxyl carrying acetonide pro)
tection. Heating the reaction to reflux gave a complex
mixture. In order to reduce the reaction time and to im)
prove the yield of 12, the use of solvents, such as MeOH,
diglyme, and dioxane, were investigated (Table 1±. The
optimum result was obtained with 1.5 equiv of NaBH4
in dioxane at 85 °C. The reaction was complete in 1 h,
giving 95% of 12 (Table 1, entry 5±.
O
OMe
MeO
O
OMe
HO
H
O
O
O
O
PCC, CH Cl
2 2
O
rt, 17 h, 80%
O
O
A close inspection of alcohol 12 revealed that not only
the C)5 tertiary center, but also the C)2 substituent were
in the correct oxidation state to allow one)carbon scis)
sion via decarboxylation under hydrolytic conditions.
Therefore, we thought that subjecting 12 to acidic
hydrolysis might directly lead to pentenomycin via di)
methyl ketal hydrolysis (C)1±, decarboxylation (C)2±,
and hydroxy group (C)3± elimination in one)pot. With
this in mind, 12 was treated with 90% aqueous TFA at
room temperature for 6 h, followed by acetylation of
the crude reaction mixture after removal of TFA under
vacuum. The product obtained was characterized as tri)
acetate 13 (Scheme 4±. To our delight, when the temper)
ature for the hydrolysis step was raised to 70 °C and the
reaction was allowed to stir for 36 h, 38% of pentenomy)
6
8
RhCl(PPh ) , toluene
3
3
1
00 oC, 3 h, 81%
OMe
O
Amberlyst-15
Acetone, rt
O
OH
O
O
3
0 min, 84%
O
O
O
10
9
0% TFA/H O
0 oC-rt, 4 h
quantitative yield
9
2
O
9
cin triacetate 14 along with 11% of 13 and 5% of diac)
9
0% TFA/H O
2
etate 15 were obtained. Although the yield of
pentenomycin triacetate 14 obtained in this way was
low and fluctuated due to the sensitivity of the enone
moiety under the harsh reaction conditions, it is remark)
able that 12 could indeed furnish the target molecule in a
one)pot operation.
0 oC-rt, 40 h, 94%
OH
OH
OH
(
±)-1
Sꢁheꢀe 3.

F. A. Khan, B. Rout / Tetrahedron Letters 47 (2006) 5251–5253
5253
Table 1. NaBH
4
reduction of 11
MeO
OMe
MeO
OMe
CO Me
2
O
H
NaBH4
OH
5
O
H
O
O
O
O
O
O
11
12
Entry
Solvent
Temp
Time
Equiv of NaBH
4
Isolated yield (%±
1
2
3
4
5
THF
THF
MeOH
Diglyme
Dioxane
rt
7 d
1 h
3 h
4 h
1 h
2.5
2.0
2.0
1.5
1.5
85
Reflux
Reflux
90 °C
85 °C
Intractable mixture
56
72
95
MeO
O
OMe
Chemicals, Inc., Tokyo, Japan, for a generous gift of
vinylene carbonate.
MeO
O
OMe
OH
1
) 90% TFA, rt, 6 h
OAc
o
H
O
O
2) Ac O, py, 0 C-rt
2
Referenꢁes and notes
H
OAc
OAc
O
14 h, 66%
O
1
2
13
1
. (a± Umino, K.; Furumai, T.; Matsuzawa, N.; Awataguchi,
Y.; Ito, Y.; Okuda, T. J. Antibiot. 1973, 26, 506–512; (b±
Umino, K.; Takeda, N.; Ito, Y.; Okuda, T. Chem. Pharm.
Bull. 1974, 22, 1233–1238.
o
1
2
) 90% TFA, 70 C, 36 h
o
) Ac O, py, 0 C-rt, 14 h
2
O
MeO
OMe
2. Gibson, S. E.; Lewis, S. E.; Mainolfi, N. J. Organomet.
Chem. 2004, 689, 3873–3890.
OH
3
. (a± Smith, A. B., III; Branca, S. J.; Pilla, N. N.; Guaciaro,
M. A. J. Org. Chem. 1982, 47, 1855–1869, and references
therein; (b± Verlaak, J. M. J.; Klunder, A. J. H.;
Zwanenburg, B. Tetrahedron Lett. 1982, 23, 5463–5466;
O
OAc
+
13
+
OAc
O
H
OAc
OAc
OAc
±)-14 38%
(
11%
15 5%
(
c± Elliott, J. D.; Hetmanski, M.; Palfreyman, M. N.;
Purcell, N.; Stoodley, R. J. Tetrahedron Lett. 1983, 24, 965–
68; (d± Hetmanski, M.; Purcell, N.; Stoodley, R. J.;
Palfreyman, M. N. J. Chem. Soc., Perkin Trans. 1 1984,
089–2096; (e± Pohmakotr, M.; Popuang, S. Tetrahedron
Sꢁheꢀe 4.
9
2
In conclusion, we have demonstrated a concise stereose)
lective route to (± ±)pentenomycin in 49% overall yield
starting from 5, which in turn was obtained from the
readily accessible Diels–Alder adduct 4 in 68% overall
yield. An interesting observation during the PCC oxida)
tion of b)hydroxy)dimethylketal 6 leading to b)meth)
oxy)a,b)unsaturated aldehyde 8 was reported. A highly
efficient chemoselective reduction of the ester moiety in
lactone 11, followed by a one)pot transformation of
the resulting alcohol 12 to (± ±)pentenomycin triacetate
Lett. 1991, 32, 275–278.
4
. (a± Verheyden, J. P. H.; Richardson, A. C.; Bhatt, R. S.;
Grant, B. D.; Fitch, W. L.; Moffatt, J. G. Pure Appl. Chem.
1
978, 50, 1363–1383; (b± Achab, S.; Cosson, J. P.; Das, B.
C. J. Chem. Soc., Chem. Commun. 1984, 1040–1041; (c±
Seepersaud, M.; Al)Abed, Y. Tetrahedron Lett. 2000, 41,
4
291–4293; (d± Gallos, J. K.; Damianou, K. C.; Dellios, C.
C. Tetrahedron Lett. 2001, 42, 5769–5771; (e± Venkata
Ramana, G.; Venkateswara Rao, B. Tetrahedron Lett.
2003, 44, 5103–5105.
5
6
. (a± Sugahara, T.; Ogasawara, K. Synlett 1999, 419–420; (b±
Rivero, M. R.; De la Rosa, J. C.; Carretero, J. C. J. Am.
Chem. Soc. 2003, 125, 14992–14993.
1
4, was also reported.
. Khan, F. A.; Dash, J.; Rout, B. Tetrahedron Lett. 2004, 45,
Aꢁknowledgeꢀents
9
285–9288.
7
8
9
. Khan, F. A.; Dash, J. J. Org. Chem. 2003, 68, 4556–4559.
. Ohno, K.; Tsuji, J. J. Am. Chem. Soc. 1968, 90, 99–107.
Financial support from the Department of Science and
Technology (DST±, New Delhi, is gratefully acknowl)
edged. F.A.K. acknowledges the DST for a Swarnajay)
anti Fellowship. We thank Mr. T. Ogino of Mitsui Fine
1
13
. The spectral data ( H and C± of both (± ±)pentenomycin 1
and (± ±)pentenomycin triacetate 14 were in agreement with
1
the reported values.