Facile total synthesis of gymnoconjugatin A and B

Article abstract of DOI:10.1016/j.tetlet.2013.04.110

A facile total synthesis of the microbial natural products gymnoconjugatin A and B, isolated from soil microbe of Gymnoascus reessii has been accomplished using inexpensive raw materials, furfural and trans-methyl crotonate using Horner-Wadsworth-Emmons (HWE) and Wittig reactions.

Full text of DOI:10.1016/j.tetlet.2013.04.110

Tetrahedron Letters 54 (2013) 3624–3626
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Tetrahedron Letters
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Facile total synthesis of gymnoconjugatin A and B
a
a
b
Ramakrishna Samala a,b, Balaram Patro a, , Manas K. Basu , N. S. Kameswara Rao , K. Mukkanti
⇑
a Medicinal Chemistry Division, GVK Biosciences Pvt Ltd, 28A, IDA, Nacharam, Hyderabad 500076, India
b Chemistry Division, IST, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile total synthesis of the microbial natural products gymnoconjugatin A and B, isolated from soil
microbe of Gymnoascus reessii has been accomplished using inexpensive raw materials, furfural and
trans-methyl crotonate using Horner–Wadsworth–Emmons (HWE) and Wittig reactions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 November 2012
Revised 22 April 2013
Accepted 26 April 2013
Available online 10 May 2013
Keywords:
Gymnoconjugatin
Horner–Wadsworth–Emmons olefination
Weinreb amide
Tetraene
Pyrone
Gymnoconjugatin A (1) and B (2) were isolated from the soil
microbe of Gymnoascus reessii along with several known
polyenyl-pyrroles including auxarconjugatin A (3) isorumbrin
(4) (Fig. 1). The first total synthesis of 1 and 2 reported by
Coleman and Walczak1 was based on a linchpin coupling strategy
using a boron/tin hetero-bis-metallated butadiene, Stille, and
Suzuki–Miyaura couplings. Off late, Fang et al.2 reported the
synthesis of 3 and 4 using similar synthetic strategy. Despite
sharing close structural homology, the biological studies carried
out by the fore said groups have established the importance of
3-chloropyrrole moiety in eliciting biological activity. To gain
further insights, it is essential to develop a robust synthetic route
where-in different heterocyclic groups can be easily substituted
in place of furan and pyrrole. Such a study may provide a
molecular rationale for future therapeutic interventions in
carcinogenesis.1,2 We now report the stereocontrolled synthesis
of 1 and 2 without using tin and palladium chemistry from fairly
inexpensive starting materials.
The synthesis of gymnoconjugatin A and B was thought to ret-
rosynthetically originate from the b-diketo ester 6 and 7 via base-
mediated cyclization. It was proposed to construct the b-diketo es-
ter by coupling dianion 10 with compounds 8 and 9 which in turn
could be prepared from dienoate 11 in four steps from furfural
(Scheme 1).
Our synthesis instigated with the conversion of methyl croto-
nate to the known phosphonate 133 using Arbuzov reaction, while
the conjugated phosphorus ylide 174 was synthesized in three
steps from methyl crotonate involving bromination, formation of
R
O
O
O
Gymnoconjugatin A (1) R = Me
Gymnoconjugatin B (2) R = H
O
2-Steps
R
O
O
O
OH
O
6:
R = Me
7: R = H
3-Steps
R
O
O
1
OR
O
O
8: R = Me; R1= Et
9: R = H; R1 = Me
O
10
3-Steps
O
O
O
O
1-Step
11
O
12
⇑
Corresponding author. Tel.: +91 40 66281666; fax: +91 40 66281505.
E-mail address: balaram.patro@gvkbio.com (B. Patro).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.110

R. Samala et al. / Tetrahedron Letters 54 (2013) 3624–3626
3625
Table 1
R
Optimization of the HWE reaction conditionsa
O
O
O
O
O
O
O
EtO
O
P
O
O
EtO
O
O
13
11
1
Gymnoconjugatin A ( ): R = Me
Gymnoconjugatin B (2): R = H
Entry
Base
Solvent
Temp (°C)
Time (h)
Yieldb (%)
Cl
1
2
3
4
5
6
7
8
9
10
NaH
NaH
NaH
LDA
n-BuLi
NaH
LiOH-MS
LiCl, DBU
K2CO3, DBU
THF
0–rt
0–rt
0–rt
À78–40
À78–40
0–rt
Reflux
rt
1
1
1
1.5
1.5
1
18
5
32
81
18
30
25
31
36
26
28
21
DMF
DME
THF
THF
CH3CN
THF
CH3CN
CH3CN
DMF
R
O
N
H
O
O
Auxarconjugatin A (3): R = H
12E-isorumbrin (4: R = Me
rt
rt
5
3
t-BuOK
a
Reaction conditions: Furfural (1 equiv), Phosphonate 13 (1.2 equiv).
Isolated yields of pure trans-dienoate 11.
b
O
O
Cl
O
these conditions afforded the expected dienoate 118 as a mixture
of cis and trans isomers in poor yields. To overcome this problem,
we examined a number of alternative conditions and found that
sodium hydride in DMF condition worked exceptionally well with
phosphonate 13. Treatment of 13 with 1.5 equiv of sodium hydride
in dry DMF under high dilution (20 volumes), followed by the addi-
tion of furfural afforded exclusively trans-dienoate 11 in 81% yield
(Scheme 2; Table 1, entry 2). The geometry was confirmed by
1D-NOESY analysis and coupling constants.
Reduction of 11 with LiAlH4 in diethyl ether furnished alcohol
149, which was oxidized with Dess–Martin periodinane to provide
aldehyde 15.10 Contrary to our expectation, aldehyde 15 when sub-
jected to Horner–Wadsworth–Emmons (HWE) olefination with
phosphonate 13 afforded the tetraene ester 911 in low yields.
However, decent yield was obtained by coupling 15 with stable
N
H
Rumbrin (5)
Figure 1. Structures of Gymnoascus reessii natural products.
Wittig salt and then ylide. The phosphorus ylide 165 was derived
from commercially available ethyl tiglate via allylic bromination
followed by a Wittig reaction (Scheme 2).
The base-catalyzed Horner–Wadsworth–Emmons olefination of
aldehydes and ketones with trialkyl phosphonocrotonates has
been commonly used6 for the preparation of 2,4-dienoates. A vari-
ety of bases including, NaH, n-BuLi, LDA, LiOH-4Å molecular sieves
in THF, DBU7 in CH3CN have been frequently employed. However,
O
O
EtO
P
OMe
EtO
13
a
b
O
c
OH
O
O
O
O
O
O
R
12
O
11
15
14
O
(Ph)3P
OR1
R
d
R
e
OR1
f
OH
1
O
16
: R = Me; R = Et
O
17: R = H; R1 = Me
O
18
19
8: R = Me; R1= Et
: R = H; R = Me
: R = Me
O
1
: R = H
9
R
O
N
R
g
h
O
O
O
20
21
O
O
6
7
: R = Me
: R = Me
: R = H
O
OH
O
: R = H
R
R
OH
O
i
O
O
O
22: R = Me
23: R = H
Gymnoconjugatin A (1): R = Me
Gymnoconjugatin B (2): R = H
O
O
Scheme 2. Synthesis of gymnoconjugatin A and B. Reagents and conditions: (a) NaH, DMF, 0 °C–rt, 1 h, 81%; (b) LiAlH4, diethyl ether, 5–10 °C–rt, 1 h, 95%; (c) Dess–Martin
periodane, CH2Cl2, 0 °C–rt, 2 h, 82%; (d) compound 16 or 17, MeOH, 0 °C–rt, 1 h, 48% (8), 54% (9); (e) LiOH, MeOH, THF, H2O, rt, 5 h, 90% (18), 91% (19); (f) EDCl, HOBt, Et3N,
N(OMe) MeÁHCl, CH2Cl2; 0 °C–rt, overnight, 62% (20), 65% (21); (g) sodium salt of ethyl 2-methylacetoacetate, n-BuLi, THF, À10–0 °C, 40 min, 58% (6), 60% (7); (h) DBU,
toluene, reflux, 2 h, 70% (22), 68% (23); (i) Me2SO4, K2CO3, DMSO, rt, 2 h, 65% (1), 68% (2).

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R. Samala et al. / Tetrahedron Letters 54 (2013) 3624–3626
phosphorus ylide 17 in methanol at room temperature. The same
sequence was applied for the synthesis of trans-tetraene ester 8
by reacting aldehyde 15 with phosphorus ylide 16 in 48% yield.
The trans-tetraene esters (8, 9) were hydrolyzed to trans-tetraene
acids (18, 19)12 using lithium hydroxide in a mixture of THF,
MeOH, and H2O [4:1:1] in good yields.
References and notes
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aldehydes14, and imidazolyl amides15 of simple substrates are well
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jugatin A (1) and B (2) (Scheme 2). The analytical data of synthet-
ically accomplished gymnoconjugatin A and B were in agreement
with the reported data.
In conclusion, we have developed an efficient protocol for the
synthesis of gymnoconjugatin A and B. Unlike the earlier reported
synthesis, where metal catalysts were used, the present route is
economical. The present synthetic route developed with a view
to support future structure–activity relationship studies for syn-
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Acknowledgments
We sincerely thank GVK Biosciences Private Limited for finan-
cial support and encouragement. We are thankful to Dr. Rajesh
Bagepalli Madhu for helpful discussion. Also, we acknowledge
the support extended by the analytical department throughout this
study.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.
110.