Synthesis of furan derivatives of cyclic β-amino acid cispentacin via intramolecular nitrile oxide cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2012.05.126

Two furan derivatives of cispentacin have been synthesized starting from a d-mannitol derived conjugated nitroolefin through intramolecular nitrile oxide cycloaddition (INOC) as a key step.

Full text of DOI:10.1016/j.tetlet.2012.05.126

Tetrahedron Letters 53 (2012) 4283–4287
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Synthesis of furan derivatives of cyclic b-amino acid cispentacin via
intramolecular nitrile oxide cycloaddition
⇑
Ranjan Kumar Basak, Suresh Dharuman, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two furan derivatives of cispentacin have been synthesized starting from a D-mannitol derived conju-
Received 5 April 2012
Revised 26 May 2012
Accepted 27 May 2012
Available online 7 June 2012
gated nitroolefin through intramolecular nitrile oxide cycloaddition (INOC) as a key step.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cispentacin
Cyclic b-amino acids
Furan
Intramolecular nitrile oxide olefin
cycloaddition reaction
Immense importance of the chemistry and biological signifi-
cance of b-amino acids has been well recognized1 by organic and
medicinal chemists over the past few years. This stems from the
fact that b-amino acids are (i) part of some biologically important
natural products2 such as taxol which possesses anticancer proper-
ties; cispentacin an antifungal antibiotic, etc. and (ii) useful start-
ing materials for the synthesis of b-lactams,3 a class of useful
antibiotics.
To enhance the therapeutic effectiveness of cispentacin, there
have been several synthetic efforts2 to prepare analogues, of which
two of them PLD-118 3 and BAY 9379 4 (Fig. 2) are under clinical
trials. Apart from naturally occurring b-amino acids, synthetically
made ones such as Sitagliptin phosphate 58a and LBM4152g 6 too
have found use in pharmaceuticals. Because of the biological
importance of cispentacin a number of methods are reported in
the literature of its synthesis and its analogues.9a The analogues in-
clude various heterocyclic molecules,9b norbornene derivatives7f,g
and cyclobutane derivatives.9c
Apart from this, since the natural system is primarily made up
of a-amino acids and is devoid of metabolizing b-amino acids, ef-
forts have been made4 to synthesize peptides and proteins derived
from b-amino acids leading to metabolically stabler proteins and
peptides. The b-amino acids exhibit the striking ability of attaining
Our continued interest10 in employing derivatives of
D-mannitol
to synthesize biologically important chiral molecules including
some glycosidase inhibitors and amino acids, led us to explore
the potential of intramolecular nitrile oxide addition11 using man-
nitol derived conjugated nitroolefin and its Michael adduct12 with
allyl alcohol (Scheme 1).
secondary structures far more efficiently than
a-amino acids due
to which the term ‘foldamers’ has been coined for them.5 As a re-
sult, the predictable folding pattern exhibited by b-amino acids6
has been used in biomechanistic investigation.7 At the same time
numerous methodologies have been developed2 to prepare chiral
b-amino acids.
In this regard, the nitroolefin 8 was readily derived from D-man-
nitol based cyclohexylidene protected aldehyde.13 This aldehyde
was subjected to the Henry reaction with nitromethane to yield
an inseparable mixture of diastereomeric nitro alcohol 714 which
upon treatment with methanesulfonyl chloride in the presence of
Cispentacin viz. (1R,2S)-2-amino cyclopentanoic acid (ACPC) 1
(Fig. 1) shows potent antifungal activity against Candida albicans
which causes deadly disease in mice. An analogue of cispentacin
viz. ethyl trans-2-(dimethylamino)-1-phenyl-3-cyclohexene-1-
carboxylate hydrochloride (Tilidine8) 2, obtained in free form from
opium, possesses analgesic properties and is used in relieving
moderate to severe pain.
NH2
NMe2
CO2Et
Ph
COOH
1
2
⇑
Corresponding author.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
Figure 1. Structures of cispentacin 1 and tilidine 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.126

4284
R. K. Basak et al. / Tetrahedron Letters 53 (2012) 4283–4287
NH2
analysis of the crude reaction mixture. For this purpose, 1H–1H
NH2
COOH
COSY spectra of pure 9a and 9b were recorded to ascertain the
chemical shifts of C-3 protons which were found to be d 4.67,
4.53 for 9a and d 4.57, 4.48 for 9b as doublet of doublets. The inte-
gration values of these protons were compared in the 1H NMR
spectrum of the crude mixture to determine this ratio.14 The use
of THF as a solvent led to somewhat poorer yield of the Michael
adduct (ꢀ56%). On the other hand, use of allyl alcohol as a solvent
and reactant along with nitroolefin 8 having been dissolved in min-
imum amount of dry CH2Cl2 gave an improved yield of the Michael
adducts (ꢀ64%). The configurations of the major and minor prod-
ucts were assigned based on comparisons of the data as reported
by Hassner and co-workers.12
COOH
3
4
F
F
NH2
O
N
N
N
H3PO4 H2O
F
N
CF3
5
The major Michael adduct 9a upon treatment with phenyl iso-
cyanate at room temperature under inert conditions yielded an
inseparable mixture of isoxazolines 10 (Scheme 3). The mixture
of diastereomers was subjected to LiAlH4 reduction followed by
selective amine protection as benzyloxycarbamate. Chromato-
graphic separation led to the isolation of the major carbamate 11
in 59%. The minor isomer, however, could not be procured in pure
form.
O
N
H
N
OH
N
N
OHC
O
F
O
6
Figure 2. Synthetic analogues of cispentacin.
The major amino alcohol 11 was oxidized to the corresponding
carboxylic acid16 with TEMPO followed by esterification with
diazomethane yielding 12 (Scheme 4). The protected b-amino ester
was subjected to the acid catalysed deprotection to the free diol 13
followed by oxidative cleavage to aldehyde and subsequent so-
dium borohydride mediated reduction to furnish 5-hydroxymethyl
furan b-amino ester 14.
triethylamine, using the McMurry conditions,15 furnished the
nitroolefin 8 in 86% yield14 (Scheme 2). O-allylation of 8 could be
realized using NaH and allyl alcohol yielding allylated products
9a and 9b in 42% and 22% yields respectively. The ratio of
compounds 9a and 9b was found to be 4:1 based on 1H NMR
NHCbz
CO2Me
O
NHCbz
O
N
O
H
HO
O
O
OH
O
O
O
14
11
10
1,3-cycloaddition
O
O
O
NO2
O
NO2
O
8
9
Scheme 1. Retrosynthetic analysis.
iii) MsCl (2 eq.)
i) ref. 13
O
O
D-mannitol
O
ii) CH3NO2, Et3N (cat.),
0 oC-rt, 9 h, 79%
Et3N (2.2 eq.),
CH2Cl2 dry,
-30 oC, 15 mins,
86%
O
NO2
NO2
OH
8
7
1
O
Allyl alcohol
O
+
2''
NO2
O
O
NaH (1.2 eq),
CH2Cl2, 0 oC,
1 h, 64%
1''
4
NO2
2
3
O
O
1'
2'
9a
9b
3'
Scheme 2. Synthesis of nitroolefin 8 and its Michael adducts 9a and 9b.

R. K. Basak et al. / Tetrahedron Letters 53 (2012) 4283–4287
4285
i) LiAlH4, THF, rt, 6 h
Phenyl isocyanate
O
N
O
H
9a
H
O
NHCbz
Et3N, C6H6,
72 h, rt, 70%
O
ii) CbzCl, NaHCO3,
EtOAc : H2O (9 : 1),
rt, 2 h, 79%
H
O
OH
O
O
10
Scheme 3. Intramolecular cycloaddition and LiAlH4 reduction.
11 = 59%
characterized as its acetate 18. 18 The structure of this bicyclic mol-
ecule was established based on spectral characteristics including
2D-COSY and NOE experiments. Thus, in NOE experiment, irradia-
tion of the signal at d 3.73 corresponding to H-4a led to enhance-
ment (2.5%) of the signal at d 2.81 corresponding to H-7 and vice
versa. This suggests that the protons H-4a and H-7 are cis oriented
to each other. Irradiation of the signal at d 5.10 corresponding to H-
4 led to enhancement (7.8%) of the signal at d 6.11 corresponding
to N–H and this proves that H-4 proton is closely oriented to N–
H proton. In addition, one of the two H-9 protons appearing at d
3.31 also gets enhanced during the irradiation of H-4a suggesting
that H-4 is indeed axially oriented. Further, irradiation at d 5.10
corresponding to H-4 did not show any enhancement of H-7a pro-
ton, again supporting the fact that H-4 proton is axially oriented
and thus the protons H-4 and H-7a are trans to each other.
It is likely that the reaction proceeds through two different
types of conformations of nitrile oxides viz. I and II (Scheme 6).
The cycloaddition takes place preferentially through conformation
I leading to III whose reduction must be proceeding via a cis-bicy-
clic intermediate IV that eventually gives the observed major prod-
uct 11 which has been isolated in pure form. On the other hand,
conformer II may lead to a less stable intermediate V via cycload-
dition to eventually give the amino alcohol VII, a product that was
not obtained in pure form.
i)TEMPO, NaOCl,
KBr, Bu4NBr, brine
NaHCO3 sat sol.,
O
NHCbz
1N HCl, MeOH
H
11
O
oC, 1 h, 72%
COOMe
0
oC - rt, 2 h, 87%
0
ii) Et2O, CH2N2, 0 oC,
15 min, 76%
O
12
over 2steps
i) NaIO4,
MeCN : H2O,
(1.4 :1), 0 oC,
30 min, 89%
NHCbz
H
CO2Me
O
HO
NHCbz
H
HO
CO2Me
HO
ii) NaBH4, MeOH,
0 oC - rt, 1 h,
85%
O
14
13
Scheme 4. Conversion into the target cispentacin derivatives.
The stereochemistry of the newly generated chiral centres in 14
was established by NOE experiments after converting the ester into
a bicyclic molecule 18 (Scheme 5). Thus, the hydroxyl group in
compound 11 was protected as a p-nitrobenzoyl ester and then
the cyclohexylidene protected diol was freed upon treatment with
HCl in methanol yielding the amino diol 16 in 82% yield. The
primary hydroxyl group was protected as a trityl ether followed
by treatment with NaH in order to effect cyclization17 which led
to the corresponding bicyclic carbamate derivative which was
In summary, we have synthesized a new route to furan based b-
amino acids with 2-hydroxymethyl as well as 1,2-dihydroxyethyl
side chains, through INOC reaction, which are furan derived
cispentacin analogues.
NHCbz
NHCbz
O
O
PNBCl/Et3N
1 M HCl/MeOH
rt, 3 h, 82 %
H
H
O
O
OPNB
OH
DCM, rt, 5 h, 87 %
O
O
15
11
PNBCl: p-nitrobenzoyl chloride
HO
NHCbz
HO
NHCbz
H
H
HO
(i) NaH/THF
TrCl/Py
TrO
OPNB
OPNB
rt, 18 h, 88 %
(ii) Ac2O/ Et3N, DCM
62 % over 2 steps
O
O
16
17
1.4%
O
H
OTr
H
H
9
H
H
4a
NH
O
OTr
O
O
4
O
TrO
H
O
1N
7a H
2
O
N
H
OAc
6
O
H
O
AcO
H
18
7
AcO
18
Scheme 5. Synthetic sequence for stereochemistry proof and NOE correlations for 18.

4286
R. K. Basak et al. / Tetrahedron Letters 53 (2012) 4283–4287
H
H
H
R
H
O
H
R
O
H
O
O
R
LiAlH4
R
O
O
OH
H
N
H
N
H
N
NH2
H
O
III
I
H
IV
11 (Major)
OH
O
O
R
HN
O
NH2
R
O
LiAlH4
O
O
R
R
H
O
H
H
H
H
N
H
N
H
H
H
H
VII
II
V
VI
Scheme 6. Proposed intermediates for cycloaddition and reduction with LiAlH4.
1505–1513; (g) Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.; Jones, W.; Malik, K.
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Acknowledgments
We thank the Department of Science and Technology, New Del-
hi, for J.C. Bose National Fellowship (JCB/SR/S2/JCB-26/2010) to
Y.D.V. and the Council of Scientific and Industrial Research, New
Delhi, for financial support [Grant No. 01(2298)/09/EMR-II].
R.K.B. and S.D. thank the Council of Scientific Industrial Research,
New Delhi, for Senior Research Fellowships.
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Supplementary data
Supplementary data associated with this article can be found, in
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18. Experimental data of selected compounds: Benzyl (2S,3R,4R)-4-(hydroxymethyl)-
2-((R)-1,4-dioxaspiro[4.5]decan-2-yl)tetrahydro-furan-3-ylcarbamate (11): To an
ice cooled solution of LiAlH4 (160 mg, 4.2 mmol) in dry Et2O (6 mL) was added
isoxazoline 10 (1 gm, 3.95 mmol) dissolved in dry Et2O (8 mL) over a period of
15 min and the reaction was allowed to attain room temperature and stirred
for 6 h. The reaction mixture was cooled to 0 °C and quenched by adding a
mixture of 9:1 EtOAc/H2O (5 mL) and filtered over celite pad. Organic solvent
was removed under reduced pressure. The crude product was dissolved in a
mixture of 9:1 EtOAc/H2O (5 mL) followed by the addition of NaHCO3 (340 mg,
4.05 mmol) and benzyloxycarbonyl chloride (0.5 mL) at room temperature and
allowed to stir at this temperature for 2 h. Ten mL of H2O was added to the
reaction mixture and extracted with EtOAc (3 ꢁ 20 mL) and dried over
anhydrous Na2SO4. Purification over silica gel column chromatography with
30–50% EtOAc/hexane gave 11 as a colourless viscous oil in 903 mg (59%)
yield; Rf: 0.3 in 40% EtOAc/hexane; ½a D28
ꢂ
= +14 (c = 1.2, CH2Cl2); 1H NMR (CDCl3,
500 MHz) d 1.33–1.41 (m, 2H), 1.53–1.59 (m, 8H), 2.65–2.72 (m, 1H), 3.18 (br,
OH), 3.50 (t, J = 8.9 Hz, 1H), 3.57–3.63 (m, 2H), 3.68 (dd, J = 7.2, 3.1 Hz, 1H),
3.86 (dd, J = 8.3, 5.2 Hz, 1H), 3.97–4.02 (m, 2H), 4.05–4.08 (m, 1H), 4.37–4.40
(m,1H), 5.12 (d, J = 12.0 Hz, 1H), 5.15 (d, J = 12.0 Hz, 1H), 5.32 (d, J = 7.9 Hz,
NH), 7.32–7.88 (m, 5H); 13C NMR (CDCl3, 125 MHz) d: 23.7, 23.9, 25.0, 34.6,
36.4, 44.7, 54.9, 59.2, 66.4, 67.3, 68.6, 75.6, 85.4, 110.3, 128.2, 128.3, 128.6,
135.9, 157.1; IR (neat, cmꢃ1): 3383, 2923, 1708; HRMS (ESI) m/z calcd for
C
21H30NO6 [M+H]+ 392.2073, found 392.2074.
(3S,4R,5S)-methyl 4-(benzyloxycarbonylamino)-5-(hydroxymethyl)tetrahydrofuran-
3-carboxylate (14): To an ice cooled solution of diol 13 (100 mg, 0.29 mmol) in
MeCN (2 mL) and H2O (1.2 mL) was added NaIO4 (70 mg, 0.32 mmol) and the
reaction mixture was allowed to stir at same temperature for 30 min. The
reaction mixture was filtered through celite pad, organic solvent was removed
under reduced pressure followed by addition of 10 mL of H2O and extraction
with EtOAc (3 [ 10 mL), washed with brine and dried over anhydrous Na2SO4.
The crude product was cooled to 0 °C in MeOH (2 mL) and was added NaBH4
(5.3 mg, 0.14 mmol) and stirred at same temperature for 1 h. The reaction
mixture was quenched with saturated solution of NH4Cl at 0 °C followed by
removal of organic solvent under reduced pressure and extraction with EtOAc
(3 [ 10 mL) after adding 10 mL H2O. Purification over silica gel column
chromatography with 60% EtOAc/hexane gave 14 as a colourless viscous oil

R. K. Basak et al. / Tetrahedron Letters 53 (2012) 4283–4287
4287
in 31 mg (40%) yield (overall 2 steps); Rf: 0.35 in EtOAc; ½a D28
ꢂ
= +42.3 (c = 1.5,
followed by the addition of Et3N (0.011 ml) and Ac2O (0.0098 ml) at 0 °C and
allowed to stir at room temperature for 2 h. Ten mL of H2O was added to the
reaction mixture and extracted with CH2Cl2 (3 [ 20 mL) and dried over
anhydrous Na2SO4. Purification over silica gel column chromatography with
30–50% EtOAc/hexane gave 18 as a colourless viscous oil in 21 mg (62%) yield
CH2Cl2); 1H NMR (CDCl3, 400 MHz) d: 2.57–2.61 (m, 1H), 3.61–3.75 (m, 7H),
4.06 (dd, J = 8.9, 7.8 Hz, 1H), 4.22–4.28 (m, 1H), 5.12 (br s, 2H), 5.76 (d,
J = 8.1 Hz, NH), 7.33–7.40 (m, 5H); 13C NMR (CDCl3, 125 MHz) d: 43.5, 54.4,
60.4, 63.3, 67.4, 69.0, 84.8, 128.4, 128.5, 128.7, 136.1, 157.3, 171.4; IR (cmꢃ1):
3355, 2924, 1711; HRMS (ESI) m/z calcd for C15H20NO6 [M+H]+ 310.1291, found
310.1297.
(overall 2 steps); Rf: 0.3 in 30% EtOAc/hexane; ½a D28
ꢂ
= ꢃ12 (c = 0.25, CH2Cl2); 1
H
NMR (CDCl3, 400 MHz) d 2.16 (s, 3H, OAc), 2.81 (m,1H, H-7), 3.31 (dd, 1H,
J = 5.5, 10.7 Hz, H-9), 3.45 (dd, J = 2.4, 10.4 Hz, 1H, H-90), 3.73 (dd, J = 2.5,
8.5 Hz, 1H, H-4a), 3.87–3.95 (m, 3H, H-4, H-6, H-60), 4.10 (dd, J = 2.4, 11.6 Hz,
1H, H-8), 4.29 (dd, J = 2.0, 11.6 Hz, 1H, H-80), 5.10–5.12 (m, 1H, H-4), 6.11 (s,
NH), 7.23–7.43 (m, 15H, Aromatic); 13C NMR (CDCl3, 125 MHz) d: 21.0, 36.2,
54.8, 63.0, 64.9, 68.1, 70.7, 81.0, 86.8, 127.1-143.5 (m, Ar-C) 154.3, 171.1; IR
(neat, cmꢃ1): 2925, 1713, 1372; HRMS (ESI) m/z calcd for C29H29NO6Na
[M+Na]+ 510.1893, found 510.1891.
((4R,4aS,7S,7aR)-2-oxo-4-(trityloxymethyl)hexahydro-1H-furo[3,2-d][1,3]oxazin-
7-yl)methyl acetate (18): To an ice cooled solution of NaH (3.4 mg, 0.085 mmol)
in dry THF (1 mL) was added 17 (50 mg, 0.071 mmol) dissolved in dry THF
(1 mL) over a period of 15 min and the reaction was allowed to attain room
temperature and stirred for 0.5 h. The reaction mixture was cooled to 0 °C,
quenched by adding saturated NH4Cl solution and extracted with EtOAc
(3 ꢁ 10 mL). Organic solvent was removed under reduced pressure and dried
over anhydrous Na2SO4. The crude product was dissolved in dry CH2Cl2 (1 mL)