A new strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: a key precursor of Ipomoeassin family of compounds and C1–C15 domain of halichondrins

Article abstract of DOI:10.1016/j.tetlet.2016.07.059

A highly efficient synthesis of (S)-1-(furan-2-yl)pent-4-en-1-ol, known to be an initial precursor of Ipomoeassin family of compounds and C1–C15 domain of halichondrins has been achieved via a sequence involving the use of Weinreb amide formation followed by Weinreb ketone synthesis and finally CBS (Corey–Bakshi–Shibata) reduction. Detailed study on improvement of each step is described. The title compound was converted to a potential cytotoxic agent for further pharmacological studies.

Full text of DOI:10.1016/j.tetlet.2016.07.059

Accepted Manuscript
A new strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: A key precursor
of Ipomoeassin family of compounds and C1-C15 domain of halichondrins
Subba Rao Jammula, Venkateswara Rao Anna, Sudhakar Tatina, Thalishetti
Krishna, B. Yogi Sreenivas, Manojit Pal
PII:
S0040-4039(16)30905-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.059
TETL 47921
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 June 2016
15 July 2016
16 July 2016
Please cite this article as: Jammula, S.R., Anna, V.R., Tatina, S., Krishna, T., Yogi Sreenivas, B., Pal, M., A new
strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: A key precursor of Ipomoeassin family of compounds and
C1-C15 domain of halichondrins, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.059
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A new strategy for accessing (S)-1-(furan-2-
yl)pent-4-en-1-ol: a key precursor of
Ipomoeassin family of compounds and C1-
C15 domain of halichondrins
Leave this area blank for abstract info.
Subba Rao Jammula, Venkateswara Rao Anna, Sudhakar Tatina, Thalishetti Krishna, B. Yogi Sreenivas and
Manojit Pal*
Weinreb
ketone
synthesis
Weinreb
amide
O
O
CBS
reduction
O
O
Overall yield
75% (present method)
~42% (reported method)
formation
O
OH
O
O
Me
89%
98.8% ee
N
HO
92%
92%
OMe
Grubbs catalysts
(second generation)
OH
O
70%
CO2Me
cytotoxic agent

1
Tetrahedron Letters
A new strategy for accessing (S)-1-(furan-2-yl)pent-4-en-1-ol: a key precursor of
Ipomoeassin family of compounds and C1-C15 domain of halichondrins
Subba Rao Jammula,a,b Venkateswara Rao Anna,b Sudhakar Tatina,a Thalishetti Krishna,a B. Yogi
Sreenivas,c and Manojit Palc,*
a Custom Pharmaceutical Services, Dr. Reddys Laboratories Limited, Bollaram Road, Miyapur, Hyderabad 500 049, India.
b Department of Chemistry, Koneru Lakshmaiah University (KLU), Green Fields, Vaddeswaram, Guntur District, 522502, Andhra Pradesh, India.
cDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly efficient synthesis of (S)-1-(furan-2-yl)pent-4-en-1-ol, known to be an initial precursor
of Ipomoeassin family of compounds and C1-C15 domain of halichondrins has been achieved
via a sequence involving the use of Weinreb amide formation followed by Weinreb ketone
synthesis and finally CBS (Corey-Bakshi-Shibata) reduction. Detailed study on improvement of
each step is described. The title compound was converted to a potential cytotoxic agent for
further pharmacological studies.
Available online
Keywords:
Ipomoeassin
Halichondrins
Furan
2009 Elsevier Ltd. All rights reserved.
Cytotoxicity
MCR
Ipomoeassin family of resin glycosides isolated from the
morning glory Ipomoea squamosa (collected from the Suriname
rain forest)1,2 are known to posses interesting cytotoxic
properties. Due to their unique structural features and cytotoxic
activities synthesis of this class of compounds attracted particular
attention.3,4 The reported synthesis of some of the members of
this family involved the preparation of an intermediate i.e. (S)-1-
(furan-2-yl)pent-4-en-1-ol (C) from furan-2-carbaldehyde (A) via
B leading to the key precursor D (Scheme 1).3 Notably, the
compound C has also been explored for the synthesis of C1-C15
domain of halichondrins5 (a class of polyether macrolides isolated
from the marine sponge Halichondria okadai that showed
unusual antitumor activities) and palmerolide A6 (a 20-membered
macrocyclic polyketide that showed potent and selective
cytotoxicity activities). While the sequence shown in Scheme 1 is
an useful method for the preparation of C the methodology
especially the second step (Sharpless resolution) however suffers
from some limitations such as isolation of desired enantiomer C
in moderate yield (~ 47%), and requirement of low temperature (-
20 ºC).3-5 Thus there was a need for the development of
alternative and high yielding method for the preparation of C.
This prompted us to adopt a different strategy for accessing C
from furan-2-carboxylic acid (E) which is based on the use of
Weinreb amide formation as a key step followed by Weinreb
Ti (OiPr)4, DIPT
O
Br
Mg, THF
O
tBuOOH, DCM, -20°C
O
O
47%
OH
H
82-89%
OH
A
Grignard reaction
O
B
C
Sharpless resolution
VO (acac)2
Ipomoeassin family of
compounds
or
C1-C15 domain of
halichondrins
tBuOOH, DCM
O
71-73%
Achmatowicz
oxidation
D
OH
Scheme 1. Reported synthesis of intermediate C3 and its
further uses.
Weinreb
ketone
synthesis
Weinreb
amide
formation
O
O
CBS
reduction
O
O
O
OH
O
O
Me
89%
98.8% ee
(92%)
(92%)
N
HO
OMe
C
E
Scheme 2. An alternative strategy for the synthesis of C
(figure in the parentheses represents isolated yield of
respective product after performing the actual reaction, see
infra for details).
----------------
* Corresponding author: Tel.: +91 40 6657; fax: +91 40 6657 1581
E-mail address: manojitpal@rediffmail.com (M. Pal)
ketone synthesis and finally CBS (Corey-Bakshi-Shibata)
reduction (Scheme 2). We were particularly interested in
avoiding the resolution step of previously reported method that

2
Tetrahedron Letters
decreased the yield of desired stereoisomer significantly. Herein
better than other bases when used in THF (Entry 5, Table 1).
Moreover, being cheaper than DBU (that was used in the
previously reported method)14 the use of Et3N is advantageous.
Additinally, in contrast to earlier method the amine was used
directly as its hydrochloride salt in the present case. While the
duration of the reaction was 60 min the decrease in reaction time
decreased the yield of 2a (Entry 6, Table 1). Overall, the
condition of Entry 5 of Table 1 was identified as the best one and
used for further study.
we report our results and potential of this strategy that includes
assessing the generality and scope of each steps involved. To the
best of our knowledge exploration of a same or similar approach
for accessing C has not been reported earlier.
Since the formation of a Weinreb amide was the first step of
our pre-designed approach (Scheme 2) hence establishing a
suitable and efficient condition for this amide formation was the
key challenge initially. Weinreb amides7 are well known
precursors for a range of compounds including carbonyl
derivatives, alkynes, heterocycles, natural products etc.
Generally, these amides are prepared via the treatment of N,O-
dimethylhydroxylamine with an activated carboxylic acid
derivative. A variety of peptide coupling reagents has been used
for this purpose that includes BOP,8 DCC,9 DCC/HOBt,10
CBr4/PPh3,11 EDC/HOBt,12 and CDMT.13 However, a recent
report on the use of commercially available T3P (1-
propanephosphonic acid cyclic anhydride) and DBU to obtain
Weinreb amides14 prompted us to adopt a similar strategy in our
case. While this methodology mainly focused on the use of N-
protected amino/peptide acids only we anticipated that the
conditions used in these reactions might be effective for other
class of acids too. Moreover, the use of T3P has several
advantages including milder reaction conditions, wide functional
group tolerance, high product yields and less toxicity. Formation
of water soluble byproducts and their easy separation from the
main products is another advantage associated with the use of
T3P. Nevertheless, we performed an optimization study to
establish the best reaction condition suitable for the preparation
of Weinreb amides from non-amino/peptide acids. Accordingly,
the reaction of thiophene-2-carboxylic acid (1a) with N,O-
dimethylhydroxylamine hydrochloride in the presence of T3P
was performed under various conditions and results are
summarized in Table 1. A number of bases e.g. Et3N
(triethylamine), DIPEA and DBU were examined in this reaction.
For each base at least four solvents e.g. THF, EtOAc, MeCN and
toluene were tested. It is evident from Table 1 that Et3N was
To examine the applicability of this methodology to other
non-amino/peptide acids a wide range of carboxylic acids were
employed under the optimized reaction conditions (Table 2, see
ESI). These acids may carry a group like heteroaryl (entry 1 and
2, Table 2), aryl (entries 3-8 and 11-13, Table 2), cycloalkyl
(entry 14 and 17, Table 2), alkenyl (entry 10, Table 2) or cyclic
ether moiety (entry 9, Table 2). Indeed, appropriately protected
amino acids were also employed in this reaction (entry 15, 16 and
Table 2: Synthesis of Weinreb amides (2) in the presence of
T3P and triethylamine a
O
O
(MeO)MeNH.HCl
R
OMe
R
N
OH
T3P, Et3N
THF, rt
Me
1
2
Entry Carboxylic acid (1);
Product
(2)
Time
(min)
Yieldb (%)
R =
1
1a; 2-Thienyl
2a
2b
2c
2d
2e
2f
60
96
92
90
84
84
86
98
90
86
87
92
92
92
80
2
1b; Furan-2-yl
1c; p-ClCH2C6H4
1d; o-IC6H4
80
3
60
4
120
60
5
1e; p-NO2(o-Cl)C6H3
1f; o-MeCOC6H4
1g; Ph
6
120
120
110
60
7
2g
2h
2i
Table 1: Effect of reaction conditions on formation of
Weinreb amide 2a.a
8
1h; o-PrOC6H4
1i; Tetrahydrofuran-2-yl
1j; PhCH=CH-
1k; p-MeOC6H4
1l; p-(p-ClC6H4)C6H4
1m; p-FC6H4
9
O
O
(MeO)MeNH.HCl
S
10
11
12
13
14
2j
90
S
OMe
N
2k
2l
60
OH
T3P, base
solvent
Me
70
1a
2a
2m
2n
80
Entry
Catalyst
Solvent
Temp (°C)/
Time (min)
Yield (%)b
1n; Cyclohex-3-enyl
HO
110
1
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
THF
120
120
120
120
60
68
70
70
28
96
73
82
86
90
78
84
15
16
Bn2N
2o
2p
60
92
89
1o;
2
EtOAc
CH3CN
Toluene
THF
3
240
tBuO
4
FMOC
NH
1p;
5
O
6
Et3N
THF
40
2q
2r
180
120
88
86
17
18
O
7
Et3N
EtOAc
CH3CN
THF
60
8
Et3N
60
1q;
1r;
9
DBU
65
H
N
SPh
zbc
10
11
DBU
EtOAc
CH3CN
70
DBU
70
aThe reaction was performed by using 1a (8.9 mmol),
(MeO)MeNH.HCl (13.3 mmol), T3P (50% in EtOAc, 10.6 mL,
17.7 mmol), and a base (22.2 mmol) in a solvent (15 mL) at room
temp (25 ºC) under nitrogen.
aThe reaction was performed by using 1 (8.9 mmol),
(MeO)MeNH.HCl (13.3 mmol), T3P (50% in EtOAc, 10.6 mL,
17.7 mmol), and Et3N (22.2 mmol) in THF (15 mL) at room temp
(25 ºC) under nitrogen.
bIsolated yield.
b Isolated yield.

3
18, Table 2). The reaction proceeded well in all these cases
affording desired Weinreb amides (2) in good to high yields. All
the amides synthesized were characterized by spectral (NMR, IR
and HRMS) data. For example, an IR absorption at 1621 cm-1
and a 13C NMR signal at 162.2 ppm observed in case of
compound 2a indicated the presence of an amidic carbonyl
group. Moreover two singlets appeared at δ 3.78 and 3.37 in the
1HNMR spectra and at 61.5 and 33.0 ppm in the 13CNMR spectra
of the same compound were due to the -OMe and -NMe groups,
respectively.
these results and therefore decided to focus on the next step of
our strategy (Scheme 2). Accordingly, the ketone 3a and 3b were
reduced to the corresponding alcohol 4a and 4b respectively
under the condition of CBS (Corey-Bakshi-Shibata) reduction17
(Scheme 3 and 4). In general the alcohols were obtained in high
yields with good enantiomeric excess (ee > 98%) as indicated by
20
results of chiral HPLC. The specific optical rotation (SOR []D
= -6.6º, see ESI) of 4a was found to be identical with the reported
value.3 Thus we were able to prepare 4a avoiding the resolution
step of previously reported method thereby improving the yield
of desired stereoisomer [overall yield 75% (Scheme 2) vs ~42%
of reported method (Scheme 1)].
To follow our strategy (Scheme 2) and expand the further
synthetic potential of the present Weinreb amide synthesis we
performed Weinreb ketone synthesis7a,15 using selected amides
including 2b (Table 3). Thus amide 2b was treated with but-3-
enyl magnesium bromide (a Grignard reagent) when the desired
ketone 3a was isolated in excellent yield (entry 1, Table 3).
Similarly amides 2h, 2k, 2l and 2m were treated with ethyl
magnesium bromide individually under the same reaction
conditions. The reaction proceeded well to afford the
corresponding ketone (3b-e) in good to high yield (entries 2-5,
Table 3).16 The spectral data of all these compounds e.g. an IR
absorption in the range 1655-1675 cm-1 and a 13C signal in the
range 175-200 cm-1 confirmed the presence of a ketone carbonyl
group. Moreover, the disappearance of signals for -NMe and -
Ph
H
Ph
O
OH
N
O
B
O
O
Borane-DMS-Complex
THF, 0oC, 45 min
4a
89% yield
98.8% ee
3a
Scheme 3. Reduction of 3a under CBS reduction conditions.
Ph
H
Ph
OH
1
OMe group of amide moiety in the H and 13CNMR spectra
O
O
N
B
clearly indicated chemical transformation of –CONMeOMe
moiety during the reaction. Nevertheless, we were delighted with
O
Borane-DMS-Complex
THF, 0oC, 65 min
O
Table 3. Preparation of ketones (3) via Weinreb ketone
synthesis using amides 2b, 2h, 2k, 2l and 2m.a
4b
82% yield
99.2% ee
3b
Scheme 4. Reduction of 3b under CBS reduction conditions.
O
O
R'MgBr
Having prepared the compound 4a (or C, Scheme 1 and 2)
successfully following our new strategy we then performed the
formal synthesis of compound D [(S)-2-(but-3-enyl)-6-hydroxy-
2H-pyran-3(6H)-one, Scheme 1] using VO(acac)2 (2 mol%) and
R
OMe
R
N
R'
Dry THF
0-5°C
Me
3
2
Entry Amide (2)
Ketone (3)
Time Yieldb
(min) (%)
tBuOOH
in dichloromethane according to the reported
procedure.3,5 The D was isolated in 76% yield confirming that the
strategy presented here could be an useful alternative towards the
synthesis of Ipomoeassin family of compounds or construction of
C1-C15 domain of the halichondrins.
80
92c
O
O
1
2
Me
N
3a
MeO
2b
120
76d
Recently,
6-(furan-2-yl)-6-hydroperoxyhex-2-enoic
acid
O
O
framework has been explored as potential cytotoxic agents
against three cancer cell lines e.g. MDA-MB-231 (breast), A-549
(lung), and HT29 (colon).18 Prompted by this report we converted
the compound 4a to a structurally similar 6-(furan-2-yl)-6-
hydroxyhex-2-enoic acid derivative (5) using the Grubbs olefin
metathesis19 as shown in Scheme 5. Thus the compound 4a was
treated with methyl acrylate in the presence of Grubbs catalysts
(second generation) in dichloromethane at room temperature
when the desired product 5 was isolated in 70% yield. Notably,
the compound 6 seemed to be formed due to the intermolecular
cyclization of compound 5 was also isolated as a minor product
in this reaction. We were delighted to isolate the product 5 as this
compound not only may attract attention due to its potential
pharmacological interest but also may serve as a precursor for
other target compounds.
OMe
N
Et
OPr
Me
OPr
3b
2h
60
89d
O
O
Me
Et
N
3
4
OMe
MeO
3c
MeO
2k
75
80
88d
94d
O
O
p-ClC6H4
Me
N
Et
3d
OMe
p-ClC6H4
2l
O
O
Me
N
Et
5
OH
OMe
OH
MesN
NMes
PCy3
F
F
3e
O
O
CO2Me
5 (Major); 70%
2m
Cl
Cl
Ru
aReactions were performed using amide 2 (3.3 mmol), alkyl
magnesium bromide (1.0 M in THF, 9.8 mL, 10 mmol), in dry
THF (10 mL) under argon atmosphere at 0-5°C.
+
4a
+
Ph
O
O
CO2Me
CO2Me
DCM, rt, 10h
6 (Minor)
bIsolated yield.
Scheme 5. Preparation of compound 5 via Grubbs olefin
metathesis.
cBut-3-enyl magnesium bromide was used as the Grignard
reagent.
dEthyl magnesium bromidewas used as the Grignard reagent.

4
Tetrahedron Letters
The compound 5 was tested at 3, 10 and 30 µM against the
Supplementary data
breast adenocarcinoma cells MCF-7 using the sulphorhodamine
B (SRB) assay20a,b with gemcitabine20c (10 µM) as a reference
compound. The compound 5 showed dose dependent inhibition
(i.e. ~ 40, 60 and 90% at 3, 10 and 30 µM) of MCF-7 cells when
gemcitabine showed ~ 50% inhibition at 10 µM (Fig. 1). Thus
compound 5 deserves further attention as a potential anticancer
agent. Nevertheless, synthesis of other analogues of compound 5
is currently underway upon completion of which all these
compounds will be evaluated for their potential pharmacological
activities.
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
References and notes
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In conclusion, a practical and efficient synthesis of (S)-1-
(furan-2-yl)pent-4-en-1-ol has been achieved in 75% overall
yield (better than ~ 42% overall yield of the previously reported
method). The synthesis involved the use of Weinreb amide
formation followed by Weinreb ketone synthesis and finally CBS
(Corey-Bakshi-Shibata) reduction of the resulting ketone. The
methodology does not require resolution of enantiomers. To
expand the generality and scope of each steps involved a variety
of Weinreb amides were prepared mostly from non-
amino/peptide acids using the cheaper and improved optimized
conditions. Some of these amides were converted to the
corresponding ketones two of which were taken forward for CBS
reduction. The furan precursor synthesized was converted to the
next intermediate i.e. (S)-2-(but-3-enyl)-6-hydroxy-2H-pyran-
15. For applications of Weinreb ketone synthesis, see: (a) Paek, S.-M.;
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Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc.
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M.; Tosini, S.; Skehan, P.; Scudiero, D. A.; Monks, A.; Boyd, M.
R. J. Natl. Cancer Inst. 1990, 82, 1113; (b) Skehan, P.; Storeng,
R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.
T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst.
1990, 82, 1107; c) Chu, E.; DeVita, V.T. Physicians' Cancer
Chemotherapy Drug Manual, Jones & Bartlett, 2007.
3(6H)-one and
a 6-(furan-2-yl)-6-hydroxyhex-2-enoic acid
derivative of potential pharmacological interest. Overall, the
current methodology not only presents a better alternative
towards the synthesis of Ipomoeassin family of compounds or
construction of C1-C15 domain of halichondrins but also may
find applications in synthesizing small molecules for Chemical
Biology / Med Chem purpose.
Acknowledgements
The authors thank Dr. Vilas Dahanukar, Dr. H. Rammohan
and Shiva Kumar K. B. of Dr. Reddy’s Laboratories Limited for
useful discussions and the Analytical Department of Dr. Reddy’s
Laboratories Limited for spectra. The authors thank Dr. Mohd
Ashraf Ashfaq for SRB assay.
.

5
Highlights
 A practical synthesis of (S)-1-(furan-2-yl)pent-4-en-1-ol has been achieved.
 The methodology does not require resolution of enantiomers.
 The overall yield (i.e. 75%) is better than that (i.e. ~ 42%) of earlier method.
 The title compound was converted to a promising cytotoxic agent.