Tandem transformations of cyclopentene α,α-dichlorocarboxamides into epoxy lactones induced by a γ-hydroxyl group; A short synthesis of the Corey epoxy lactone and its enantiomer

Article abstract of DOI:10.1016/j.tetlet.2015.10.106

The stable iminolactone 6 was obtained by NBS induced bromocyclization of carboxamide 4. Under treatment of 6 with DBU a tandem recyclization transformation occurred resulting in the formation of epoxyiminolactone 7. Bromo(iodo)cyclization of 4 in aqueous organic medium followed by treatment with base gave epoxylactone 9. Under the optimized conditions, Corey epoxylactone 1 and its enantiomer ent-1 were obtained from diastereomeric carboxamides 4 and 5 in an overall yield of 40%.

Full text of DOI:10.1016/j.tetlet.2015.10.106

Tetrahedron Letters 56 (2015) 6904–6907
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Tandem transformations of cyclopentene
a,a-dichlorocarboxamides
into epoxy lactones induced by a -hydroxyl group; a short synthesis
c
of the Corey epoxy lactone and its enantiomer
⇑
Zuleykha R. Valiullina, Vera A. Akhmetyanova, Nadezhda A. Ivanova, Mansur S. Miftakhov
Ufa Institute of Chemistry of the Russian Academy of Sciences, 450054, Prosp. Octyabrya, 71, Ufa, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The stable iminolactone 6 was obtained by NBS induced bromocyclization of carboxamide 4. Under treat-
ment of 6 with DBU a tandem recyclization transformation occurred resulting in the formation of epoxy-
iminolactone 7. Bromo(iodo)cyclization of 4 in aqueous organic medium followed by treatment with base
gave epoxylactone 9. Under the optimized conditions, Corey epoxylactone 1 and its enantiomer ent-1
were obtained from diastereomeric carboxamides 4 and 5 in an overall yield of 40%.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 15 May 2015
Revised 9 October 2015
Accepted 29 October 2015
Available online 30 October 2015
Keywords:
Halocyclization
Carboxamides
Epoxyiminolactone
Corey epoxylactone
Introduction
Herein, we report an efficient syntheses of 1 and its enantiomer
ent-1 from racemic Grieco dichlorolactone ( )À3,7 proceeding via
Vicinal tetrasubstituted cyclopentanes are of great interest for
the development of synthetic approaches to cyclopentanoids and
other natural products.1a–e Chiral epoxy lactone 1, which was
first described by Corey and Noyori, has been utilized for the
synthesis of prostaglandins.2 Later, Partridge3 and co-workers pre-
pared 1 from a 5-substituted cyclopentadiene derivative via a
rather capricious asymmetry inducing step to give (À)-Grieco lac-
tone (À)-2. Ferrier4 and co-workers also produced compound 1 via
the electrophilic tandem type cyclization of carboxamides 4 and
5.8 Carboxamides 4 and 5 were synthesized by the ring opening
of 3 with (+)-
a
-methylbenzylamine in ꢀ34% yield for each amide9
and were easily separated by column chromatography on SiO2 due
to significant differences of their Rf values (Scheme 1). The stereo-
chemistry of 4 and 5 were determined by chemical synthesis—
transformation of 4 to known compound 23 by the reductive
dechlorination with Zn–Cu in MeOH followed by treatment with
acid.
a multistep reaction sequence starting from D
-glucose. Olivo5 and
co-workers have also reported the synthesis of 1 from racemic
Grieco lactone 26 during the synthesis of the natural macrolide
auriside.
Under electrophilic cyclization conditions10 the reaction of 4
using the NBS–MeCN system proceeded smoothly, leading to imi-
noether 6 in good yield (Scheme 2). The structure of bromide 6
O
O
O
O
O
O
O
O
O
O
1
ent-1
2
( )-3
Cl
Cl
was confirmed by 1D and 2D NMR spectroscopy (Fig. 1) and mass
spectrometry. Dehydrobromination of 6 with DBU in benzene at
⇑
Corresponding author.
E-mail address: bioreg@anrb.ru (M.S. Miftakhov).
http://dx.doi.org/10.1016/j.tetlet.2015.10.106
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

Z. R. Valiullina et al. / Tetrahedron Letters 56 (2015) 6904–6907
6905
H2N
OH
OH
O
C6H6
O
O
+
+
2-pyridinol,
O
N
H
Ph
N
H
Ph
20oC, 2 days
Cl
Cl
Cl
Cl
Cl
Scheme 1.
OH
Cl
( )-3
4, 33%
5, 34%
Br
DBU, C6H6
O
NBS, CH3CN,
20 °C, 2 h, 95%
80 °C, 1 h, 76%; or
O
Ph
N
Cl
t-BuOK, THF
20 °C, 15 min, 40%
O
Cl
Cl
Cl
OH
7
O
Ph
N
6
N
Ph
H
Cl
Cl
4
X
(a) NBS, THF-H2O
20 °C, 24 h; or
O
O
+
O
(b) I2, THF-H2O,
20 °C, 24 h
O
O
HO
Cl
8
X=Br, I
Cl
Cl
Cl
9, 70% over 2 steps via (a)
DBU, C6H6
20 °C, 3 h
65% over 2 steps via (b)
Scheme 2.
H
O
H
The reaction of 4 with NBS or I2 in THF–H2O (3:1) afforded a
H
OH
H
Cl
mixture containing predominantly epoxylactone 9 with less polar
compound 8 as a minor component. After standard work up, the
reaction mixture was treated with DBU and stirred at room tem-
perature for 3 h to smoothly transform minor compound 8 into
9, with a yield of 65% over 2 steps.
H
Br
H
Cl
Exocyclic oxyiminolactones are known to be labile com-
pounds.12 Surprisingly, under anhydrous conditions, exocyclic imi-
nolactone 6 was stable to chromatography on SiO2 and additionally
survived transformation into 7. The relative stability of exocyclic
iminolactone 7 was probably caused, by the steric and electronic
effects of the gem-dichloride substituents.
N
6
Figure 1. Key NOE-interactions in compound 6.
The proposed mechanism for the formation of compound 7
most likely includes a sequence of tandem type transformations
proceeding via the generation of charged tricyclic intermediate
11 which forms as a result of intramolecular attack of the hydroxyl
anion of 10 onto the imine moiety and the consequent cleavage of
the C–O bond in 11. The SN2 type substitution of halide X in inter-
mediate 12 leads to formation of the stable epoxy lactone 7
(Scheme 3).
When the haloiminolactonization reaction of 4 was performed
in THF–H2O (Scheme 2), the initially formed bromohydrin 6 (or
corresponding iodohydrin) was transformed into 13. Elimination
of phenylethylamine (PEA) from compound 13 led to hydroxylac-
tone 14, which undergoes rearrangement into the sterically and
thermodynamically more favorable lactone 8.13 Finally, the treat-
ment of 8 with DBU in benzene gives epoxide 9 (Scheme 4). The
formation of epoxide 9 in the absence of DBU was unexpected
and an explanation is proposed as follows. Released HBr from the
formation of 6, catalyzes the hydration reaction to give 13. Rapid
fragmentation of 13 gives 14 and its cyclic tautomer 15 which
can undergo partial rearrangement to compound 8. The eliminated
PEA deprotonates the highly activated hydroxyl group of 15 and
via fragmentation of 16 yields epoxylactone 9.
Figure 2. ORTEP representation of compound 7.
reflux or t-BuOK in THF at room temperature proceeded smoothly
to give epoxyiminolactone 7 (Scheme 2). The anti configuration of
imine 7 was determined by single crystal X-ray analysis11 (Fig. 2).
It should be noted that acidic hydrolysis of iminolactone 6 under
standard conditions gave only lactone 8 (75%) while epoxylactone 9

6906
Z. R. Valiullina et al. / Tetrahedron Letters 56 (2015) 6904–6907
O-
X
O
X
X
O
DBU or
6
7
Ph
Cl
Cl
Cl
t-BuOK
N
O
O
O
Cl
Cl
Cl
N
N
Ph
Ph
10
12
11
X = Br, I
Scheme 3.
OH
X
OH
X
X
O
H3O+
NBS (or I2)
DBU
4
6
9
-PEA
O
Cl
Cl
Cl
Cl
OH
NH
O
O
HO
Cl
Cl
O
Ph
13
14
8
X=Br, I
X
O
O
X
PEA
Cl
Cl
Cl
O
O
Cl
OH
O
15
16
Scheme 4.
X
O
10% HCl-THF (1:3)
20 °C, 8 h, 75%
O
HO
OH
Cl
Br
Cl
Cl
8
X=Br
O
Cl
Ph
N
X
O
O
NBS, THF-H2O
6
+
O
20 °C, 24 h, 60%
O
O
HO
Cl
Cl
Cl
Cl
8
9
1:3
X=Br
Scheme 5.
H
O
O
O
O
Zn-Cu, NH4Cl,
MeOH, 64 °C, 2 h
Ph
O
+
O
O
O
N
O
O
O
H
Cl
Cl
Cl
Cl
Cl
7
9
13
1, 50%
Scheme 6.
H
H
was not formed. The reaction of 6 with NBS in THF–H2O led to a
mixture of 8 and 9 (1:3) in 60% yield (Scheme 5).
H
O 3
2
1a
5b
2a
5a
Thus, this sequence represents a new tandem type rearrange-
4
O
1
O
ment of
c-hydroxyiminolactones into epoxyiminolactones, of
5
H
which hydrolysis furnishes the corresponding epoxylactones. An
examination of the literature revealed only three distantly similar
types of rearrangements, only the transformations of the iminolac-
tone?lactam type.14–16
H
Cl
13
Figure 3. NOE-interactions in compound 13.

Z. R. Valiullina et al. / Tetrahedron Letters 56 (2015) 6904–6907
6907
OH
O
1. NBS, THF-H2O,
O
O
O
20 °C, 24 h
Zn-Cu, NH4Cl,
O
O
O
2. DBU, C6H6,
20 °C, 3 h
O
O
MeOH, 64 °C, 2 h
O
O
N
H
Ph
Ph
Cl
Cl
Cl
Cl
, 70%
Cl
4
5
9
1
, 60%
OH
O
1. NBS, THF-H2O,
20 °C, 24 h
O
Zn-Cu, NH4Cl,
O
2. DBU, C6H6,
20 °C, 3 h
MeOH, 64 °C, 2 h
N
H
Cl
Cl
Cl
ent-9, 70%
ent-1, 60%
Scheme 7.
The reductive dechlorination reaction of
7
using the
for quantum chemistry calculation (Ufa Institute of Chemistry),
Professor L. M. Khalilov (Institute of Petroleum Chemistry and
Catalysis, Ufa) for X-ray analysis.
Zn–Cu–NH4Cl system in MeOH was studied next. This multistage
reaction afforded the products of dechlorination and hydrolysis
of the imine moiety—compounds 9, 13, and 1 in yields of 10%,
25%, and 20%, respectively (Scheme 6). These compounds were
individually isolated by quenching the reaction mixture immedi-
ately after iminolactone 7 had been consumed. When the reaction
was not stopped prematurely, the slow consumption of intermedi-
ates 9 and 13 as well as the formation of epoxylactone 1 in 50%
yield was observed. The yield of epoxylactone 1 could be increased
to 60% upon dechlorination of the isolated dichloroderivative 9.
The structure of monochlorolactone 13 (Scheme 6) was con-
firmed by 1H and 13C NMR spectroscopy. Strong NOE interactions
between the cis-protons at C-5 and C-5a (J = 8.6 Hz) showed exo-
orientation of the chlorine substituent at C-5 (Fig. 3). Thus, after
the initial reductive removal of the more sterically available 5b-
chlorine substituent of dichlorolactone 9 the Zn-enolate formed
of the monochlorolactone can be protonated from the sterically
more accessible b-face, giving 13.
Scheme 7 summarizes the efficient transformations of carbox-
amides 4 and 5 into the target epoxylactones 1 and ent-1.
Note that the transformation of compounds 4 and 5 did not
require the purification of intermediates and only final products
were purified by column chromatography on SiO2.
In conclusion, we have described a new tandem type ‘cycliza-
tion–recyclization’ transformation of carboxamides 4 and 5. The
syntheses of the synthetically important epoxylactone 1 and its
enantiomer ent-1 have been developed from easily available car-
boxamides 4 and 5 in two stages with an overall yield of 40–42%.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
106.
References and notes
1. (a) Gimazetdinov, A. M.; Ivanova, N. A.; Miftakhov, M. S. Nat. Prod. Commun.
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7171.
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Suponitzky, K. Yu.; Miftakhov, M. S. Russ. J. Org. Chem. 2014, 50, 810.
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11. Crystal data for
7
(CCDC no. 1061971).
C15H15Cl2NO2, M = 312.18,
orthorhombic, a = 8.7768(4), b = 11.7032(5), c = 14.4305(6) Å, V = 1482.25
(11) Å3, T = 293.2 K, space group P212121 (no. 19), Z = 4, 5491 reflections
measured, 4751 unique (Rint = 0.0128) which were used in all calculations. The
final R1 was 0.0384 (I > 2sigma(I)) and wR(F2) was 0.0989 (all data).
12. Tan, C. K.; Yeung, Y-Y. Chem. Commun. 2013, 7985.
13. It was shown in a DFT approximation with polarizable continuum model
(PCM) that structure 8 is more stable than 14 (DG) on 6.3 kcal/mol.
Acknowledgments
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The authors thank Dr. A. S. Erastov for assistance with mass
spectral studies, Professor S. L. Khursan and Dr. M. Yu Ovchinnikov