Total synthesis of (-)-kainic acid and (+)-: Allo -kainic acid through SmI2-mediated intramolecular coupling between allyl chloride and an α,β-unsaturated ester

Article abstract of DOI:10.1039/c7ob01427a

A 3,4-disubstituted pyrrolidine ring was effectively cyclized through SmI₂-mediated reductive coupling between allyl chloride and an α,β-unsaturated ester, although little has been reported about SmI₂-promoted C-C bond formation of an allyl chloride with an α,β-unsaturated ester. Selection of either the 3,4-cis- or 3,4-trans-selective cyclization can be accomplished simply by changing the additives from NiI₂ to HMPA during reductive cyclization conducted in H₂O-THF. Total synthesis of (-)-kainic acid and (+)-allo-kainic acid, which are pyrrolidine alkaloids used in neuroscience and neuropharmacology as useful molecular probes, was successfully achieved by using the stereo-complementary ring closure reactions promoted by SmI₂ for the construction of the 2,3,4-trisubsituted pyrrolidine scaffold of kainoids.

Full text of DOI:10.1039/c7ob01427a

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January 2016 Pages 1–372
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DOI: 10.1039/C7OB01427A
Organic & Biomolecular Chemistry
PAPER
Total Synthesis of (–)‐Kainic Acid and (+)‐allo‐Kainic Acid through
SmI ‐Mediated Intramolecular Coupling between Allyl Chloride
2
and an ,‐Unsaturated Ester
Received 00th January 20xx,
Accepted 00th January 20xx
Junya Suzuki, Natsumi Miyano, Shunpei Yashiro, Taiki Umezawa,* Fuyuhiko Matsuda*
DOI: 10.1039/x0xx00000x
A 3,4‐disubsituted pyrrolidine ring was effectively cyclized through SmI ‐mediated reductive coupling between the allyl
2
www.rsc.org/
chloride and an ,‐unsaturated ester, although little has been reported about SmI ‐promoted C‐C bond formation of an
2
allyl chloride with an ,unsaturated ester. Selection of either the 3,4‐cis‐ or 3,4‐trans‐selective cyclization can be
accomplished simply by changing the additives from NiI
2
to HMPA during reductive cyclization conducted in H O‐THF. Total
2
synthesis of (–)‐kainic acid and (+)‐allo‐kainic acid, which are pyrrolidine alkaloids used in neuroscience and
neuropharmacology as useful molecular probes, were successfully achieved by using the stereo‐complementary ring closure
reactions promoted by SmI for the construction of the 2,3,4‐trisubsituted pyrrolidine scaffold of kainoids.
2
Introduction
(
–)‐Kainic acid (
1), a pyrrolidine alkaloid with three
contiguous stereocenters on
a
densely functionalized
pyrrolidine ring, was isolated originally from the Japanese
marine alga Digenea simplex (Japanese name, kainin‐sou) along
with its C4‐epimer, (+)‐allo‐kainic acid (2) by Takemoto in 1953
Fig. 1 Structure of kainic acid (1) and allo‐kainic acid (2).
1,2
(
Figure 1). In 1970, Sinozaki reported that
1
induced strong
3
activation of neurons. Based on this report,
1 was found to bind
kainoids and ongoing research into the development of efficient
C‐C bond formation reactions mediated by SmI
glutamate receptors at many synapses in mammalian central
2
employing allyl
nervous systems (CNS) to induce neuronal disease and was
chlorides, a new approach to kainic acids
as shown in Scheme 1. Thus, SmI
cyclization between the allyl chloride and
1 and 2 was envisioned
4
classified as a KA type ionotropic receptor. Subsequently,
1
has
2
‐mediated reductive
‐unsaturated ester
been used in neuroscience and neuropharmacology as a useful
molecular probe. Since determination of the chemical structure,
,
moieties of
or while simultaneously installing the requisite C3‐
carboxymethyl and C4‐isopropenyl substituents of the kainoids.
Only intramolecular coupling with SmI between the allyl
bromide and ‐unsaturated ester forming the 6‐membered
carbocycle has been reported by Yamada and Nagaoka.
Evidently, little is known about the SmI ‐promoted C‐C bond
formation of the allyl chloride with the ‐unsaturated ester.
Compound was planned to be synthesized via reductive
amination of the ‐unsaturated aldehyde with the
ammonium salt derived from the commercially available
serine ester hydrochloride.
3 should assemble the pyrrolidine ring skeleton of 1
1
has attracted attention from synthetic organic chemists as a
2
synthetic target due to its intriguing biological activities and the
characteristic frameworks. More than four decades of total
2
5,6
syntheses of
1
and
2
have been reported.
) has evolved as a unique, single‐
,
Samarium(II) iodide (SmI
2
9
,10
electron reducing reagent for inducing reductive couplings to
2
7
achieve C‐C bond formation under mild conditions. Previous
,
research has demonstrated the convenient cyclization of
medium rings using intramolecular Barbier‐type allylation
3

,
4
induced by SmI
ketones. In annulation reactions, the use of the allyl chlorides
was critical to the success of ring closure. Given the interest in
2
of the allyl chlorides with aldehydes or
5
D‐
8
Recently, we have found that 3,4‐disubstituted pyrrolidines
were synthesized with high efficiency through intramolecular
coupling between the allyl chloride and
using SmI . Complementary diastereoselectivity was observed
in the SmI ‐induced cyclization reactions simply by changing the
additive from HMPA to NiI . This new type of annulation
,‐unsaturated ester
a.
Graduate School of Environmental Science, Hokkaido University, N10W5 Sapporo
2
060‐0810, Japan. E‐mail: umezawa@ees.hokudai.ac.jp,
2
fmatsuda@ees.hokudai.ac.jp
2
†
Electronic Supplementary Information (ESI) available: NOESY spectra of 8 and 13,
1
13
ROESY spectra of 17 and 18, and H and C NMR spectra for all compounds. See method has been applied with success to the total synthesis of
DOI: 10.1039/x0xx00000x
(
–)‐kainic acid (1) and (+)‐allo‐kainic acid (2).
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
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PAPER
Organic &Biomolecular Chemistry
View Article Online
Cl
CO2R3
OR2
DOI: 10.1039/C7OB01427A
CO2H
CO2H
CO2H
4
3
2
CO2H
N
N
N
1
H
3
R1
2
H
Cl
CO2R4
OR2
+
+
H3N
4
CHO
5
Scheme 1 Retrosynthetic analysis of kainic acid (1) and allo‐kainic acid (2).
Results and discussion
First, cyclization of the pyrrolidine ring was attempted
through intramolecular reductive coupling of the
unsaturated ester derived from chloroacetone ( ) (Scheme 2).
Horner‐Wadsworth‐Emmons reaction of provided the
unsaturated ester in 64% yield as a 2:1 mixture of the E‐ and
Z‐isomers. After reduction of with LiAlH , oxidation with PDC
afforded the ‐unsaturated aldehyde (mixture of the E‐ and
Z‐isomer). Curiously, reductive amination of 2‐aminoethanol
with NaBH using as a mixture of the geometric isomers
followed by Boc‐protection in a one‐pot operation gave the E‐
Scheme 2 Synthesis of the E‐

,

‐unsaturated ester
9
.
,‐
9
6
upon lowering the reaction temperature to 0 °C (entry 9).
Reaction at –78 °C did not produce any desired cyclization
products (entry 10). However, the stereochemical outcome of
6
,‐
7
1
1
7
4
2
the SmI ‐promoted reductive annulation of 9 could be switched

,

4
simply by changing the additive from HMPA (60 equiv) to NiI
2
1
2
24
(
0.3 equiv). From a synthetic point of view, the stereo‐
4
4
complementarity controlled by the additives was advantageous
because it enhanced the possibilities for divergent synthesis of
diastereoisomeric
stereochemistry about the two newly formed contiguous
stereogenic centers.
1
3,14
allyl chloride
Successive Dess‐Martin oxidation of
reaction with Bu
8
as a single geometric isomer
in 47% yield.
followed by Wittig
in 55% yield (2
products
with
complementary
15
8
n
16
3
P=CHCO
2
Et produced
9
steps).
Table 1 summarizes the results from experiments using
9.
Table 1 Optimization on cyclization of 9
a
The initial attempt involving treatment of with SmI (6 equiv)
9
2
in THF at room temperature without any additives resulted in
poor yield (entry 1). However, conducting the reaction in the
17,18
19,20
presence of HMPA (24 equiv)
and H
2
O (10 equiv)
(entry
2
) resulted in intramolecular coupling to provide the 3,4‐trans‐
pyrrolidine 11 with 3,4‐cis‐pyrrolidine 10 in a 28:72 cis:trans
HMPA
H
2
O
NiI
(equiv)
2
yield
(%) b
10:11c
ratio in 58% combined yield. The diastereomeric ratios were
entry
(equiv)
(equiv)
1
determined from H NMR spectra of the mixtures of 10 and
21
1
2
0
24
60
60
24
0
0
0
0
7
ND
1
1.
A greater diastereomeric ratio (cis:trans = 19:81) was
obtained in 56% combined yield by increasing the amount of
HMPA from 24 equiv (4 equiv to SmI ) to 60 equiv (10 equiv to
SmI ) (entry 3). Lowering the reaction temperature to –78 °C
10
10
10
0
58
56
33
34
23
56
62
50
0
28:72
19:81
18:82
50:50
33:67
83:17
83:17
72:28
2
3
0
2
4d
5
0
significantly decreased the chemical yield (33% combined yield)
with nearly the same cis/trans ratio (cis:trans = 18:82) (entry 4).
Control experiments revealed that the exclusion of additives
0
HMPA and H
and 6). Apparently, both HMPA and H
trans‐selective cyclization. Notably, the intramolecular coupling
2
O suppressed the cyclization reaction (entries 5
6
10
0
0
2
O were essential for the
7
0
0.3
0.3
0.3
0.3
8
0
10
10
10
occurred cleanly between the allyl chloride and

,
‐
unsaturated ester in the presence of a catalytic amount of NiI
2
9 e
0
2
2,23
(
0.3 equiv)
with a reversal of the diastereoselectivity (entry
1
0 d
0
7
). Thus, the cis‐pyrrolidine 11 was stereoselectively obtained in
a ratio of 83:17 (cis:trans) in 56% combined yield. Improvement
in the chemical yield was achieved by adding H O (10 equiv) in
2% combined yield without any loss in diastereoselectivity
cis:trans = 83:17) (entry 8). Obviously, NiI was indispensable
a
were used. b Combined yield after silica gel chromatography. c Ratio
6
.0 Equiv of SmI
2
2
estimated by H NMR. Reaction performed at –78 °C. e Reaction performed at 0 °C.
1
d
6
(
2
to cis‐selective cyclization. The combined yield (50%)
decreased and the product ratio changed (cis:trans = 72:28)
2
| Org. Biomol. Chem., 2017, 00, 1‐3
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Organic &Biomolecular Chemistry
PAPER
Next, the total synthesis of (–)‐kainic acid (
kainic acid
was investigated using the stereo‐ ratio (cis:trans) and in 55% combined yieldDO(eI:n1t0r.y1033)9./ACd7OdBit0io14n27oAf
complementary annulation promoted by SmI . For this purpose, O (10 equiv) improved the combined chemical yield up to 61%
the ‐unsaturated esters ‐14 and ‐14 were synthesized first without affecting the stereoselectivity (cis:trans = 31:69) (entry
as shown in Scheme 3. Synthesis started with the amine 4). Thus, the effect of the ligands on diastereoselection was
hydrochloride 12, prepared from ‐serine methyl ester investigated by screening various ligands (entries 5‐14).
hydrochloride following a known procedure. Similar to the Eventually, 2,2’‐bipyridine was found to result in preferred
preparation of (Scheme 2), the E‐allyl chloride 13 was formation of 15, which was obtained as the major diastereomer
produced as a single geometric isomer
reductive amination of 12 and subsequent Boc‐protection in a reductive reaction of
1) and (+)‐allo‐ yielded trans‐isomer 16 as the major isomer in a 3V2ie:w68ArtpicrleoOdnulicnet
(2)
2
H
2

,
E
Z
2
7
D
2
5
9
1
3,14
in 72% yield via in a cis:trans ratio of 62:38 and in 45% combined yield through
E
‐14 with NiI
2
(0.05 equiv) and 2,2’‐
O (10 equiv) to
2
8
29
one‐pot reaction. Reduction of 13 with DIBAL, Dess‐Martin bipyridine (0.2 equiv) (entry 13). Adding H
2
oxidation, and Wittig reaction, yielded
steps). ‐14 was also obtained from 13 in 69% yield (3 steps).
As shown in Table 2, SmI ‐mediated cyclization of ‐14 or
proceeded cleanly to give a mixture of the two trans‐selective cyclization of
diastereomeric pyrrolidines 15 and 16 after removal of the TBS HMPA (60 equiv) and H O (10 equiv) to afford 16 in higher
E
‐14 in 60% yield (3 the reaction medium gave better yield (51% combined yield)
but poorer diastereoselectivity (cis:trans = 58:42) (entry 14). In
addition, ring‐closure reactions of ‐14 were examined. The
‐14 occurred in the presence of
Z
2
E
Z
‐
Z
1
4
Z
2
group with TBAF. None of the other stereoisomers could be combined chemical yield (73%) and a lower cis/trans ratio
1
detected from the H NMR spectrum or chromatographic (cis:trans = 38:62) (entry 15) than those of trans‐selective
analysis using the crude product mixture. In all cases, the annulation of
products consisted of only two of the four possible (cis:trans = 45:55) were produced from
stereoisomers. Moreover, both diastereoisomers 15 and 16 had and H O (10 equiv) (entry 16). Reaction in the presence of NiI
E
‐14 (entry 2). Nearly equal amounts of 15 and 16
Z
‐14 with NiI (0.3 equiv)
2
2
2
trans‐stereochemistry at the C2‐C3 chiral centers, which is the (0.05 equiv) and 2,2’‐bipyridine (0.2 equiv) gave 15 as a major
appropriate relative configuration for total synthesis of kainoids. stereoisomer with improved chemical yield (66%) while
The preferred 2,3‐trans arrangement of the appendages may be retaining the diastereoselectivity (cis:trans = 62:38) (entry 17),
due to steric repulsion between the t‐butyldimethylsiloxy‐ as compared to the cis‐selective annulation of
E
‐14 (entry 13).
methyl group at C2 and the

,

‐unsaturated ester moiety. Addition of H
2
O (10 equiv) led to a significant loss in
1
Diastereoselectivity was estimated using H NMR analysis of the diastereoselectivity (cis:trans = 50:50, 69% combined yield)
mixtures of cyclization products 15 and 16. Pure samples of 15 (entry 18).
and 16 were obtained through separation by HPLC. Since the
C4‐epimers 15 or 16 led to (–)‐kainic acid ( ) or (+)‐allo‐kainic as the major diastereomer (cis:trans = 18:82) from cyclization of
acid ( ), respectively, stereochemistries of 15 and 16 were ‐14 with HMPA (60 equiv) and H O (10 equiv) (Table 2, entry
established unambiguously. 2). The cyclization of ‐14 in the presence of NiI (0.05 equiv)
As expected from 3,4‐trans‐selective cyclizations of (Table and 2,2’‐bipyridine (0.2 equiv) (Table 2, entry 17) furnished 3,4‐
, entries 2 and 3), reductive cyclization of ‐14 with SmI (6 cis‐pyrrolidine 15 as the major diastereomer (cis:trans = 62:38).
equiv) was performed in the presence of HMPA (24 equiv) and Finally, each alcohol 15 or 16 was subjected to 3‐step
As described above, 3,4‐trans‐pyrrolidine 16 was obtained
1
2
E
2
2
6
Z
2
9
1
E
2
2
d,26a
H
3
2
O (10 equiv) to give the 3,4‐trans‐pyrrolidine 16 along with sequence:
,4‐cis‐pyrrolidine 15 in a ratio of 28:72 (cis:trans) and in 68% LiOH, and (3) removal of Boc group with TFA to afford (–)‐kainic
combined yield (Table 2, entry 1). Increasing the amount of acid ( ) or (+)‐allo‐kainic acid ( ) in 79% or 80% yield (3 steps),
HMPA to 60 equiv increased the diastereoselectivity (cis:trans respectively (Scheme 4). Spectroscopic data ( H and C NMR,
18:82, 64% combined yield) (entry 2). In contrast to the cis‐ specific rotation) of and were identical with those reported
selective annulation of (Table 1, entries 7 and 8), cyclization from previous total syntheses.
of ‐14 in the presence of a catalytic amount of NiI (0.3 equiv)
(1) Jones oxidation, (2) hydrolysis of ester with
1
2
1
13
=
1
2
6c,26
9
E
2
Conclusions
In summary, a novel ring‐closure method for constructing
,4‐disubstituted pyrrolidines was developed using SmI
promoted reductive coupling between allyl chloride and
unsaturated ester. During the SmI ‐induced pyrrolidine
3
2
‐
,‐
2
cyclizations, switchable diastereoselectivity with regard to the
trans‐ and cis‐relationships at the C3‐C4 asymmetric centers of
the pyrrolidine could be achieved simply by changing the
2
additive from HMPA to NiI . From a synthetic point of view, such
additive‐determined stereo‐complementarity is highly
advantageous because it provides divergent syntheses of
diastereoisomeric products. Based on this new annulation
Scheme 3 Synthesis of the E‐,‐unsaturated ester 9.
procedure using SmI
2
, the total syntheses of (–)‐kainic acid (
1)
and (+)‐allo‐kainic acid (
2) were accomplished successfully. The
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Organic &Biomolecular Chemistry
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DOI: 10.1039/C7OB01427A
Table 2 Optimization of cyclizations of E‐14 and Z‐14a
c
entry
substrate
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
E‐14
Z‐14
Z‐14
Z‐14
Z‐14
HMPA (equiv)
H
2
O (equiv)
NiI
2
(equiv)
ligand b
none
none
none
none
yield (%) 15:16 d
1
2
3
4
5
6
7
8
9
24
60
0
10
10
0
0
68
64
55
61
54
41
40
50
54
38
41
43
45
51
73
56
66
69
28:72
18:82
32:68
31:69
36:64
29:71
36:64
48:52
37:63
29:71
36:64
48:52
62:38
58:42
38:62
45:55
62:38
50:50
0
0.3
0.3
0
10
0
0
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0
PPh
3
0
0
dppm
dppe
0
0
0
0
dppp
0
0
dppb
10
11
12
13
14
15
16
17
18
0
0
ethylenediamine
1,10‐phenanthroline
2,2’‐bipyridylamine
2,2’‐bipyridine
2,2’‐bipyridine
none
0
0
0
0
0
0
0
10
10
10
0
60
0
0.3
none
0
0.05
0.05
2,2’‐bipyridine
2,2’‐bipyridine
0
10
a
were used. b 0.2 Equiv of ligand was used. Combined yield after silica gel chromatography. Ratio estimated by H NMR.
c
d
1
6.0 Equiv of SmI
2
Experimental
General Methods
Tetrahydrofuran (THF), methanol (MeOH), and acetonitrile
MeCN) were purchased from Kanto Chemical Co. Inc.
Dichloromethane (CH Cl ) and triethylamine (Et N) were
. All commercially obtained reagents were
(
2
2
3
distilled from CaH
used as received.
2
Analytical TLC was carried out using pre‐coated silica gel
plates (Merck TLC silica gel 60F254). Wakogel 60N 63‐212
m
Scheme 4 Total Synthesis of 1 and 2 .
was used for column chromatography. IR spectra were recorded
1
on a JASCO FTIR‐4100 Type A spectrometer using a NaCl cell. H
longest linear sequences were 12 steps from commercially
available chloroacetone ( ). Mechanistic studies on the roles of
13
and C NMR spectra were recorded using a JNM‐EX 400 (400
MHz and 100 MHz) spectrometer. Chemical shifts are reported
6
additives in switching stereochemical course are currently
underway.
in ppm relative to CHCl
3
(

= 7.26) in CDCl
3
and 3‐(trimethylsilyl)‐
= 0.00) in D O for
propionic‐2,2,3,3‐d
4
acid sodium salt (TSP) (

2
4
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Organic &Biomolecular Chemistry
1H NMR, and CDCl
PAPER
3
(

= 77.0) and TSP (

= 0.00) in D
2
O for 13C
,‐Unsaturated Ester 9
View Article Online
DOI: 10.1039/C7OB01427A
NMR. Splitting patterns are designated as s, d, t, q, and m, To a solution of
8
2 2
(259 mg, 0.983 mmol) in CH Cl (4 mL) was
indicating singlet, doublet, triplet, quartet, and multiplet, added DMP (500 mg, 1.18 mmol) at room temperature under
respectively. Ar atmosphere. The mixture was stirred for 20 min, quenched
‐Unsaturated Ester 7. with sat. NaHCO /20% Na (1:1), and extracted with AcOEt.
Et (4.00 mL, 20.0 mmol) in The combined organic layers were washed with brine, dried

,
3
2 2 3
S O
To a solution of (EtO)
THF (100 mL) cooled at 0 C was added NaH(0.800 g, 20.0 mmol) over Na
under Ar atmosphere. After stirring at 0 C for 20 min, crude aldehyde which was directly employed in the next
2
(O)PCH
2
CO
2
o
2
SO
4
, filtered, and concentrated in vacuo to give the
o
o
chloroacetone (
6) (1.61 mL, 20.0 mmol) was added at 0 C. After reaction.
stirring at room temperature for 13 h, the mixture was To a solution of the crude aldehyde in CH
quenched with sat. NaHCO and extracted with AcOEt. The n‐Bu P=CHCO Et (1.00 M in CH Cl , 1.30 mL, 1.30 mmol) at room
combined organic layers were washed with brine, dried over temperature under Ar atmosphere. The mixture was stirred for
Na SO , filtered, and concentrated in vacuo. The residue was 16 h and the solvent was concentrated in vacuo. The residue
purified by silica gel column chromatography (hexane/AcOEt, was purified by silica gel column chromatography
0:10) to give (2.07 g, 12.8 mmol, 64%) as a 2:1 mixture of E‐ (hexane/AcOEt, 90:10) to give 12 (178 mg, 0.536 mmol, 55% for
and Z‐isomers: IR (neat) 1163, 1228, 1656, 1764, 2856, 2929, 2 steps) as a colorless oil: IR (neat) 690, 773, 883, 938, 958, 988,
956, 2985, 3630, 3651, 3678, 3691, 3712, 3736, 3753, 3855 1040, 1119, 1164, 1249, 1271, 1301, 1367, 1408, 1456, 1662,
2 2
Cl (2.5 mL) was added
3
3
2
2
2
2
4
9
7
2
–
1
1
–1 1
cm ; H NMR (400 MHz, CDCl
3
)

1.28 (3H, t, J = 7.3 Hz), 2.03 1697, 1721, 2933, 2979 cm ; H NMR (400 MHz, CDCl
3
)  1.26
(
(
1H, s), 2.23 (2H, s), 4.03 (1.33H, s), 4.16 (2H, q, J = 7.3), 4.67 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 1.73 (3H, s), 3.86‐3.96 (4H, m),
1
3
0.67H, s), 5.79 (0.33H, s), 5.96 (0.67H, s); C NMR (CDCl
3
, 100 3.97 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 5.49 (1H, bs), 5.83 (1H, d, J
1
3
MHz)
1
C

14.2, 16.7, 22.8, 42.1, 49.9, 60.1, 60.2, 119.0, 119.6, = 16.1 Hz), 6.80 (1H, d, J = 15.6 Hz); C NMR (CDCl
3
, 100 MHz)

+
51.9, 152.3, 165.6, 166.0; HRMS (EI‐TOF) m/z: M ; Calcd for 14.4, 14.5, 14.6, 28.2, 28.5, 28.6, 44.3, 44.7, 47.6, 51.5, 60.5,
7
H
11
O
2
Cl 162.0448; Found 162.0446.
60.7, 80.6, 122.2, 126.1, 144.0, 155.3, 166.3; HRMS (ESI‐
+

,
‐Unsaturated Aldehyde 4
orbitrap) m/z: [M + Na] ; Calcd for C16
H
26
O
4
NClNa 354.1448;
To a solution of
7
(2.07 g, 12.7 mmol) in Et
2
O (100 mL) cooled at Found 354.1443.
o
0
C was added LiAlH
4
(482 mg, 12.7 mmol) under Ar Preparation of THF solution of SmI
2
‐HMPA. To a slurry of Sm
o
atmosphere. The mixture was stirred at 0 C for 4 h, quenched metal powder (1.50 g, 9.98 mmol) in THF (46.3 mL) was added
with sat. Na
filtrate was concentrated in vacuo to give the crude alcohol atmosphere. The mixture was stirred for 12 h and HMPA (9.74
which was directly employed in the next reaction. mL, 56.0 mmol) was then added to the blue solution. The
To a solution of the crude alcohol in CH Cl (59 mL) was added initially blue solution turned deep purple. The resulting solution
DMP (5.94 g, 14.0 mmol) at room temperature under Ar was used directly to effect the following reductive cyclization.
atmosphere. The mixture was stirred for 20 min, quenched with Cyclization of with HMPA and H O. To a solution of (26.1 mg,
sat. NaHCO /20% Na (1:1), and extracted with Et O. The 0.0787 mmol) and H O (14.0 L, 0.787 mmol) in THF (0.80 mL)
combined organic layers were washed with brine, dried over (degassed by Freeze‐Pump‐Thaw) was added SmI ‐HMPA
Na SO , filtered, and concentrated in vacuo to give the crude (0.100 M in THF, 4.70 mL, 0.470 mmol) at room temperature in
aldehyde which was directly employed in the next reaction. one portion under Ar atmosphere. The mixture was stirred for
‐Allyl Chloride 8 a few minutes, quenched with H O, and extracted with AcOEt.
To a solution of , in The combined organic layers were washed with brine, dried
CH Cl (15 mL) was added 2‐aminoethanol (300 μL, 4.97 mmol) over Na SO , filtered, and concentrated in vacuo. The residue
(171 mg, was purified by silica gel column chromatography
2 4 2 2
SO , and filtered through a plug of celite pad. The CH I (0.450 mL, 5.60 mmol) at room temperature under Ar
2
2
9
2
9
3
2
S
2
O
3
2
2

2
2
4
4
E
2
4
, started from 965 mg (5.92 mmol) of 7
2
2
2
4
at room temperature. After stirring for 30 min, NaBH
4
o
4
.52 mmol) and MeOH (25 mL) were added at 0 C. After stirring (hexane/AcOEt, 95:5) to give 10 and 11 (13.0 mg, 0.0437 mmol,
o
at 0 C for further 30 min, Boc
NaHCO
2
O (1.10 mL, 4.93 mmol) and sat. 56%) as a mixture of diastereomers (10
:
11 = 19:81). Pure
o
3
(25 mL) were then added at 0 C. The mixture was samples of 10 and 11 were obtained through the partial
stirred at room temperature for 17 h, poured into H
extracted with AcOEt. The combined organic layers were VX‐SIL 5
washed with brine, dried over Na SO , filtered, and (98:2 gradient to 80:20 by 40 min, 3.0 mL/min)].
concentrated in vacuo. The residue was purified by silica gel 3,4‐cis‐Pyrrolidine 10
column chromatography (hexane/AcOEt, 70:30) to give (611 IR (neat) 772, 890, 1029, 1096, 1130, 1171, 1256, 1323, 1366,
mg, 2.31 mmol, 47% for 3 steps) as a pale oil: IR (neat) 688, 773, 1403, 1456, 1478, 1647, 1698, 1735, 2932, 2977, 3077 cm ; H
2
O, and purification by HPLC [SHINWA CHEMICAL INDUSTRIES, ULTRON

m, 20.0×250 mm, elution with hexane/2‐propanol

2
4
8
–
1 1
8
2
1
84, 943, 1052, 1127, 1167, 1251, 1366, 1414, 1460, 1691, 2930, NMR (400 MHz, CDCl
976, 3430 cm ; H NMR (400 MHz, CDCl , 70 C) 
3
3
)

1.25 (3H, t, J = 6.8 Hz), 1.45 (9H, s), 1.72
1.47 (9H, s), (3H, s), 2.13 (1H, dd, J = 16.6, 8.8 Hz), 2.24 (1H, dt, J = 16.6, 4.9
.79 (3H, s), 3.36 (2H, d, J = 5.4 Hz), 3.72 (2H, t, J = 5.4 Hz), 3.92 Hz), 2.73‐2.83 (2H, m), 3.22‐3.55 (4H, m), 4.12 (2H, q, J = 6.8 Hz),
–
1
1
o
13
13
(
(
2H, d, J = 6.8 Hz), 4.00 (2H, s), 5.56 (1H, t, J = 6.8 Hz); C NMR 4.66 (0.5H, s), 4.68 (0.5H, s), 4.89 (1H, s); C NMR (100 MHz,
CDCl
o
3
, 100 MHz, 70 C)

14.3, 28.5, 46.1, 50.0, 51.1, 62.1, 80.4, CDCl
3
,)

14.2, 22.54, 22.57, 28.5, 33.1, 36.0, 36.9, 46.9, 47.3,
+
1
26.6, 134.5, 158.4; HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd 47.6, 47.8, 50.7, 51.1, 60.48, 60.51, 79.3, 112.5, 112.7, 142.2,
22 3
for C12H O NClNa 286.1186; Found 286.1180.
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem., 2017,, 00, 1‐3 | 5
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 6 of 11
PAPER
Organic &Biomolecular Chemistry
1
+
3
42.4, 154.6, 154.7, 172.5, 172.8; HRMS (ESI‐orbitrap) m/z: [M After stirring for 40 min, NaBH (354 mg, 9.36 mmol) and MeOH
4
View Article Online
o
DOI: 10.1039/C7OB01427A
+
o
Na] ; Calcd for C16
H
27
O
4
NNa 320.1832; Found 320.1832.
(40 mL) were added at 0 C. After stirring at 0 C for further 30
,4‐trans‐Pyrrolidine 11
2 3
min, Boc O (2.70 mL, 11.7 mmol) and sat. NaHCO (40 mL) were
IR (neat) 772, 890, 1028, 1129, 1163, 1255, 1306, 1340, 1365, then added at 0 oC. The mixture was stirred at room
1
1
403, 1455, 1478, 1646, 1697, 1735, 2935, 2977, 3077; H NMR temperature for 21 h, poured into H
2
O, and extracted with
(
400 MHz, CDCl
3
)

1.25 (3H, t, J = 7.3 Hz), 1.45 (9H, s), 1.72 (3H, AcOEt. The combined organic layers were washed with brine,
SO , filtered, and concentrated in vacuo. The
.22 (1H, m), 3.50‐3.60 (1H, m), 3.74‐3.82 (1H, m), 4.11 (2H, q, J residue was purified by silica gel column chromatography
s), 2.14‐2.20 (1H, m), 2.41‐2.54 (3H, m), 2.92‐3.01 (1H, m), 3.17‐ dried over Na
2
4
3
=
1
5
1
1
3
7.3 Hz), 4.83 (1H, s), 4.87 (1H, s); C NMR (100 MHz, CDCl
4.1, 19.1, 28.5, 36.4, 36.6, 37.4, 38.0, 49.3, 49.8, 50.9, 51.1, steps) as a colorless oil: [
1.3, 51.9, 60.5, 79.28, 79.31, 113.6, 112.7, 142.1, 154.27, 777, 838, 914, 1076, 1116, 1166, 1253, 1366, 1457, 1700, 1747,
3
,) (hexane/AcOEt, 95:5) to give 13 (3.66 g, 8.41 mmol, 72% for 3
2
5

D 3
] +38.2 (c 1.06, CHCl ); IR (neat) 687,
+
–1
1
o
3
54.34, 172.0, 172.2; HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd 2857, 2953 cm ; H NMR (400 MHz, CDCl , 70 C)  0.07 (6H, s),
for C16
27
H O
4
NNa 320.1832; Found 320.1831.
0.90 (9H, s), 1.44 (9H, s), 1.77 (3H, s), 3.70 (3H, s), 3.91 (1H, dd,
Preparation of THF solution of SmI
powder (1.50 g, 9.98 mmol) in THF (56.0 mL) was added CH
2
. To a slurry of Sm metal J = 15.8, 6.3 Hz), 4.00 (2H, s), 4.03‐4.18 (4H, m), 5.68 (1H, t, J =
1
3
o
2
I
2
3
5.8 Hz); C NMR (100 MHz, CDCl , 70 C)  –5.50, 14.3, 18.2,
(
0.450 mL, 5.60 mmol) at room temperature under Ar 25.8, 28.4, 43.0, 45.6, 51.4, 51.7, 61.6, 62.3, 80.5, 123.4, 136.6,
+
atmosphere. The mixture was stirred for 12 h. The resulting blue 157.6, 170.4; HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd for
solution was used directly to effect the following reductive
cyclization.
C
20
H
38
O
5
NClNaSi 458.2100; Found 458.2093.
E‐,‐Unsaturated Ester E‐14
Cyclization of
9
with NiI
2
. To a solution of
9
(28.3 mg, 0.0853 To a solution of 13 (3.66 g, 8.41 mmol) in CH
(8.00 mg, 0.0256 at 0 C was added DIBAL (1.00 M in toluene, 20.0 mL, 20.0
2
Cl
2
(70 mL) cooled
o
mmol), H O (15.5 μL, 0.853 mmol), and NiI
2
2
o
mmol) in THF (0.80 mL) (degassed by Freeze‐Pump‐Thaw) was mmol) under Ar atmosphere. After stirring at 0 C for 50 min,
added SmI
temperature in one portion under Ar atmosphere. The mixture temperature for 2 h, and extracted with AcOEt. The combined
was stirred for a few minutes, quenched with H O, extracted organic layers were washed with brine, dried over Na SO
with AcOEt, washed with brine, dried over Na SO , filtered, and filtered, and concentrated in vacuo to give the crude alcohol
concentrated in vacuo. The residue was purified by silica gel which was directly employed in the next reaction.
column chromatography (hexane/AcOEt, 95:5) to give 10 and To a solution of the crude alcohol in CH Cl (40 mL) was added
(15.6 mg, 0.0525 mmol, 62%) as a mixture of diastereomers DMP (4.24 g, 10.0 mmol) at room temperature under Ar
10 11 = 83:17). atmosphere. The mixture was stirred for 20 min, quenched with
Amine Hydrochloride 12 sat. NaHCO /20% Na (1:1), and extracted with Et O. The
2
(0.100 M in THF, 5.20 mL, 0.520 mmol) at room the mixture was poured into Rochelle salt, stirred at room
2
2
4
,
2
4
2
2
1
1
(
:
3
2
S
2
O
3
2
To a solution of AcCl (4.10 mL, 57.0 mmol) in MeOH (100 mL) combined organic layers were washed with brine, dried over
o
was added
D
‐serine(2.00 g, 19.0 mmol) at 0 C. The mixture was Na
2
SO
4
, filtered, and concentrated in vacuo to give the crude
o
o
heated to 70 C, stirred at 70 C for 17 h, and concentrated in aldehyde which was directly employed in the next reaction.
vacuo to give the crude ester which was directly employed in To a solution of the crude aldehyde in CH Cl (40 mL) was added
Et (1.00 M in toluene, 10.0 mL, 10.0 mmol) at
(100 mL) were added room temperature. The mixture was stirred for 4 h and the
2
2
the next reaction.
To a solution of the crude ester in CH Cl
2 2
3 2
nBu P=CHCO
imidazole (3.89 g, 57.0 mmol) and TBSCl (4.30 g, 28.5 mmol) at solvent was concentrated in vacuo. The residue was purified by
room temperature under Ar atmosphere. The mixture was silica gel column chromatography (hexane/AcOEt, 98:2) to give
2
6
stirred for 17 h and EtOH (1.0 mL) was then added. After stirring
for 15 min, the mixture was poured into 0.20 M HCl and ‒9.79 (c 0.720, CHCl
extracted with CH Cl . The combined organic layers were 1007, 1041, 1112, 1167, 1253, 1305, 1345, 1366, 1404, 1453,
washed with brine, dried over Na SO , filtered, and 1472, 1658, 1697, 1723, 2711, 2740, 2858, 2931, 2955, 3369,
concentrated in vacuo to give 12 (7.84 g, 33.6 mmol, 59%) as a 3428 cm ; H NMR (400 MHz, CDCl
pale solid which has enough purity for further reaction: IR (neat) (9H, s), 1.29 (3H, t, J = 7.3 Hz), 1.46 (9H, s), 1.76 (3H, s), 3.75‐
E
‐14 (2.86 g, 6.01 mmol, 72 % for 3 steps) as a colorless oil: [
]
D
3
); IR (neat) 691, 777, 815, 839, 940, 980,
2
2
2
4
–
1
1
o
3
, 70 C)  0.08 (6H, s), 0.91
6
1
1
3
66, 726, 778, 838, 923, 938, 1007, 1044, 1108, 1143, 1173, 3.86 (3H, m), 3.93‐4.01 (1H, m), 3.98 (2H, s), 4.21 (2H, q, J = 7.3
220, 1256, 1337, 1362, 1389, 1437, 1464, 1471, 1598, 1681, Hz), 4.49 (1H, br), 5.58 (1H, t, J = 6.3 Hz), 5.90 (1H, dd, J = 15.8,
13
747, 2711, 2740, 2858, 2885, 2930, 2953, 3195, 3319, 3388, 1.9 Hz), 6.92 (1H, dd, J = 15.8, 4.9 Hz); C NMR (100 MHz
、
–
1
1
o
736, 3855 cm ; H NMR (400 MHz, CDCl
3
)

0.03 (3H, s), 0.04 CDCl
3
, 70 C)

–5.45, –5.39, 14.3, 18.2, 18.3, 25.9, 28.5, 44.0,
(
3H, s), 0.90 (9H, s), 3.53 (1H, t, J = 4.4 Hz), 3.72 (3H, s), 3.78 (1H, 51.3, 59.4, 60.4, 63.5, 80.4, 122.9, 123.1, 128.2, 144.5, 155.2,
1
3
+
dd, J = 9.8, 4.4 Hz), 3.89 (1H, dd, J = 9.8, 4.4 Hz); C NMR (100 166.0; HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd for
MHz, CDCl
HRMS (EI‐TOF) m/z: M ; Calcd for C10
3
)

–5.6, –5.5, 18.2, 25.7, 51.9, 56.5, 65.4, 174.4;
C
23
H
42
O
5
NClNaSi 498.2413; Found 498.2413.
+
24
H O
3
NCl 234.1520; Found
Z‐,‐Unsaturated Ester Z‐14
2
34.1521.
To a solution of 13 (107 mg, 0.248 mmol) in CH
cooled at 0 C was added DIBAL (1.00 M in toluene, 620
0.620 mmol) under Ar atmosphere. After stirring at 0 C for 50
2
Cl
2
(1.0 mL)
o
E
‐Allyl Chloride 13
L,
o
To a solution of
4
, started from 1.90 g (11.7 mmol) of
7
, in CH
2
Cl
2
(
40 mL) was added 12 (2.73 g, 11.7 mmol) at room temperature. min, the mixture was poured into Rochelle salt, stirred for 2 h
6
| Org. Biomol. Chem., 2017, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 11
Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Organic &Biomolecular Chemistry
PAPER
at room temperature, and extracted with AcOEt. The combined
organic layers were washed with brine, dried over Na SO
[

]26
D
–28.1 (c 1.03, CHCl
3
); IR (neat) 772, 895, 974, 1060, 1096,
View Article Online
DOI: 10.1039/C7OB01427A
2
4
,
1126, 1168, 1251, 1288, 1366, 1410, 1477, 1558, 1692, 1735,
–
1 1
filtered, and concentrated in vacuo to give the crude alcohol 2889, 2978, 3076, 3421 cm ; H NMR (400 MHz, CDCl
which was directly employed in the next reaction. (3H, t, J = 7.3 Hz), 1.46 (9H, s), 1.70 (3H, s), 2.20‐2.24 (2H, m),
To a solution of the crude alcohol in CH Cl (1.0 mL) was added 2.41‐2.47 (2H, m), 2.87‐2.92 (1H, m), 3.45 (2H, d, J = 6.8 Hz),
DMP (137 mg, 0.298 mmol) at room temperature under Ar 3.61‐3.82 (5H, m), 4.07‐4.19 (2H, m), 4.66 (1H, s), 4.89 (1H, s);
3
)  1.24
2
2
1
3
atmosphere. The mixture was stirred for 20 min, quenched with
3
C NMR (100 MHz, CDCl )  14.1, 22.2, 28.5, 33.3, 39.2, 45.6,
sat. NaHCO
3
/20% Na
2
S
2
O
3
(1:1), and extracted with Et
2
O. The 48.9, 51.0, 60.7, 65.1, 67.0, 80.7, 113.1, 142.0, 156.9, 172.3;
+
combined organic layers were washed with brine, dried over HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd for C17
29
H O
5
NNa
Na
aldehyde which was directly employed in the next reaction.
To a solution of (CF CH O) (O)PCH CO Et (98.8 mg, 0.298
2
SO
4
, filtered, and concentrated in vacuo to give the crude 350.1938; Found 350.1939.
3,4‐trans‐Pyrrolidine 16
2
6
D 3 D 3
[] ‒9.79 (c 0.720, CHCl [ ‒9.4 (c 1.04, CHCl )]; IR
) [lit.27a ]20
3
2
2
2
2
mmol) and 18‐crown‐6 (197 mg, 0.744 mmol) in THF (1.0 mL) (neat) 730, 1028, 1171, 1257, 1404, 1549, 1692, 1737, 2233,
o
–1 1
cooled to –78 C was added KHMDS (0.500 M in toluene, 595

L, 2921, 3430 cm ; H NMR (400 MHz, CDCl
3
)

1.25 (3H, t, J = 7.3
o
0
3
.298 mmol) under Ar atmosphere. After stirring at –78 C for Hz), 1.46 (9H, s), 1.70 (3H, s), 2.12‐2.19 (1H, m), 2.41‐2.52 (3H,
0 min, a solution of the crude aldehyde in THF (0.50 mL) was m), 3.13 (1H, t, J = 10.7 Hz), 3.60‐3.80 (5H, m), 4.09 (2H, q, J =
added. The mixture was stirred at –78 C for 20 min, warmed to 6.8 Hz), 4.85 (2H, s); C NMR (100 MHz, CDCl
o
13
3
)

14.1, 18.6, 28.4,
o
0
3
C, poured into sat. NaHCO , and extracted with AcOEt. The 36.2, 40.3, 50.5, 51.0, 60.7, 65.9, 66.4, 80.6, 114.5, 141.5, 156.5,
+
combined organic layers were washed with brine, dried over 171.9; HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd for
Na SO , filtered, and concentrated in vacuo. The residue was NNa 350.1938; Found 350.1940. Spectroscopic data
purified by silica gel column chromatography (hexane/AcOEt, were identical with those reported.
2
4
17 29 5
C H O
2
6a
9
8:2) to give
Z

‐14 (82.0 g, 0.173 mmol, 69 % for 3 steps) as a Cyclization of E‐14 with NiI
2
. A solution of
E
‐14 (72.4 mg, 0.152
2
7
colorless oil: [
]
D
‒13.7 (c 1.61, CHCl
3
); IR (neat) 778, 836, 1029, mmol), 2,2’‐bipyridyl (4.70 mg, 0.0304 mmol), and NiI
2
(2.40 mg,
1
2
0
110, 1171, 1253, 1366, 1413, 1472, 1490, 1720, 2857, 2930, 0.00760 mmol) in THF (2.0 mL) (degassed by Freeze‐Pump‐
–
1
1
o
956, 3370 cm ; H NMR (400 MHz, CDCl
3
, 70 C)

0.07 (3H, s), Thaw) was stirred for 30 min at room temperature under Ar
‐THF (0.100 M in
.08 (3H, s), 0.90 (9H, s), 1.29 (3H, t, J = 7.3 Hz), 1.46 (9H, s), 1.78 atmosphere. To the solution was added SmI
2
(
3H, s), 3.77 (1H, dd, J = 10.3, 5.4 Hz), 3.98 (2H, s), 3.92‐3.99 (3H, THF, 9.12 mL, 0.912 mmol) at room temperature in one portion.
m), 4.19 (2H, q, J = 7.3 Hz), 5.23‐5.26 (1H, m), 5.59 (1H, t, J = 5.8 The mixture was stirred for a few minutes, quenched with H O,
2
13
Hz), 5.84 (1H, dd, J = 11.4, 1.4 Hz), 6.38 (1H, br); C NMR (100 and extracted with AcOEt. The combined organic layers were
o
MHz, CDCl
3
, 70 C)

–5.40, –5.37, 14.3, 18.2, 26.0, 26.1, 28.6, washed with brine, dried over Na
2
SO
4
, filtered, and
5
1.5, 60.1, 63.6, 80.0, 121.6, 128.4, 132.7, 144.6, 155.0, 165.4; concentrated in vacuo to the give the crude pyrrolidines which
+
HRMS (ESI‐orbitrap) m/z: [M + Na] ; Calcd for C23
98.2413; Found 498.2413.
Cyclization of E‐14 with HMPA and H
74.8 mg, 0.157 mmol) and H O (28.5
mL) (degassed by Freeze‐Pump‐Thaw) was added SmI
0.100 M in THF, 9.43 mL, 0.943 mmol) at room temperature in were washed with brine, dried over Na
one portion under Ar atmosphere. The mixture was stirred for concentrated in vacuo. The residue was purified by silica gel
a few minutes, quenched with H O, and extracted with AcOEt. column chromatography (hexane/AcOEt, 80:20) to give 15 and
The combined organic layers were washed with brine, dried 16 (22.6 mg, 0.0691 mmol, 45% for 2 steps) as a mixture of
over Na SO , filtered, and concentrated in vacuo to give the diastereomers (15 16 = 62:38).
crude pyrrolidines which was directly employed in the next Cyclization of Z‐14 with NiI . A solution of
reaction. mmol), 2,2’‐bipyridyl (1.20 mg, 0.000723 mmol) and NiI
To a solution of the crude pyrrolidines in THF (2.0 mL) was mg, 0.00181 mmol) in THF (0.40 mL) (degassed by Freeze‐Pump‐
added n‐Bu NF (1.00 M in THF, 235 L, 0.235 mmol) at room Thaw) was stirred for 30 min at room temperature under Ar
temperature. The mixture was stirred for 2.5 h, quenched with atmosphere. To the solution was added SmI ‐THF (0.100 M in
NH Cl, and extracted with AcOEt. The combined organic layers THF, 2.20 mL, 0.216 mmol) at room temperature in one portion.
were washed with brine, dried over Na SO , filtered, and The mixture was stirred for a few minutes, quenched with H O,
concentrated in vacuo. The residue was purified by silica gel and extracted with AcOEt. The combined organic layers were
column chromatography (hexane/AcOEt, 80:20) to give 15 and washed with brine, dried over Na SO , filtered, and
(33.0 mg, 0.101 mmol, 64% for 2 steps) as a mixture of concentrated in vacuo to the give the crude pyrrolidines which
diastereomers (15 16 = 18:82). Pure samples of 15 and 16 were was directly employed in the next reaction.
obtained through the partial purification by HPLC [SHINWA To a solution of the crude pyrrolidines in THF (1.0 mL) was
CHEMICAL INDUSTRIES, ULTRON VX‐SIL 5 m, 20.0×250 mm, added n‐Bu NF (1.00 M in THF, 114 L, 0.114 mmol) at room
elution with hexane/2‐propanol (95:5 gradient to 60:40 by 30 temperature. The mixture was stirred for 2.5 h, quenched with
min, 3.0 mL/min)]. NH Cl, and extracted with AcOEt. The combined organic layers
,4‐cis‐Pyrrolidine 15 were washed with brine, dried over Na SO , filtered, and
H42ClO
5
NNaSi was directly employed in the next reaction.
To a solution of the crude pyrrolidines in THF (2.0 mL) was
‐14 added n‐Bu NF (1.00 M in THF, 228 L, 0.228 mmol) at room
L, 1.57 mmol) in THF (2.0 temperature. The mixture was stirred for 2.5 h, quenched with
‐HMPA NH Cl, and extracted with AcOEt. The combined organic layers
SO , filtered, and
4
2
O. To a solution of
E
4

(
2

2
4
(
2
4
2
2
4
:
2
Z
‐14 (17.2 mg, 0.0361
(0.600
2
4

2
4
2
4
2
2
4
1
6
:


4

4
3
2
4
This journal is © The Royal Society of Chemistry 20xx
Org. Biomol. Chem., 2017,, 00, 1‐3 | 7
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 8 of 11
PAPER
Organic &Biomolecular Chemistry
Cl (0.60 mL)
concentrated in vacuo. The residue was purified by silica gel To a solution of the crude dicarboxylic acid in CH
column chromatography (hexane/AcOEt, 80:20) to give 15 and was added TFA (0.30 mL) at room tempDeOrIa: t1u0r.1e0.39T/hCe7OmB0ix1t4u27reA
2
2
View Article Online
1
6
(7.80 mg, 0.0238 mmol, 66% for 2 steps) as a mixture of was stirred for 2 h and concentrated in vacuo to give crude allo‐
+
diastereomers (15
:
16 = 62:38).
kainic acid. The residue was purified by Dowex‐50 H (100‐200
Kainic Acid (1)
3
wet mesh) column chromatography (elution with 3.8% NH ) to
To a solution of 15 (20.6 mg, 0.0629 mmol) in acetone (0.60 mL) give
2
(11.3 mg, 0.0530 mmol, 80% for 3 steps) as a pale oil:
o
25
26a
20
was dropwised Jones reagent (2.50 M in H
2
O, 10 drops) at 0 C.
[
]
D
+7.96 (c 0.57, H
2
O) [lit.
[

]
D
+7.77 (c 0.18, H
2
O)]; IR
O)
o
–1
1
The mixture was stirred at 0 C for 30 min, quenched with 2‐ (neat) 900, 1397, 1635, 2972 cm ; H NMR (400 MHz, D
2

propanol, filtered through a plug of celite. The filtrate was 1.72 (3H, s), 2.47 (1H, dd, J = 15.1, 7.3 Hz), 2.60‐2.67 (1H, m),
poured H O and extracted with AcOEt. The combined organic 2.72 (1H, dd, J = 15.1, 4.9 Hz), 2.83‐2.89 (1H, m), 3.31 (1H, t, J =
layers were washed with brine, dried over Na SO , filtered, and 11.2 Hz), 3.51 (1H, dd, J = 11.2, 7.8 Hz), 3.90 (1H, d, J = 8.8 Hz),
concentrated in vacuo to give the crude carboxylic acid which 4.96 (2H, s); C NMR (100 MHz, D O)  19.2, 39.3, 43.7, 49.7,
2
2
4
1
3
2
was directly employed in the next reaction.
To a solution of the crude carboxylic acid in MeOH/H
53.0, 66.3, 116.7, 142.0, 175.0, 179.1; HRMS (ESI‐orbitrap) m/z:
–
2
O (3:1, [M ‒ H] ; Calcd for C10
H
14
O
4
N 212.0928; Found 212.0927.
o
26a,b
0
.80 mL) was added LiOH‐H
2
O (26.4 mg, 0.629 mmol) at 0 C. Spectroscopic data were identical with those reported.
The mixture was warmed to room temperature, stirred for 44 h,
quenched with 0.20 M HCl, and extracted with AcOEt. The
combined organic layers were washed with brine, dried over
Acknowledgements
2 4
Na SO , filtered, and concentrated in vacuo to give the crude
dicarboxylic acid which was directly employed in the next
reaction.
This work is supported by The NOVARTIS Foundation (Japan) for
the Promotion of Science (to T. U.).
To a solution of the crude dicarboxylic acid in CH
2 2
Cl (0.60 mL)
was added TFA (0.30 mL) at room temperature. The mixture
was stirred for 2 h and concentrated in vacuo to give crude Notes and references
+
kainic acid. The residue was purified by Dowex‐50 H (100‐200
1
S. Murakami, T. Takemoto and Z. Shimizu, J. Pharm. Soc. Jpn.
953, 73, 1026‐1029.
For the absolute stereochemistries of
H. Watase and Y. Tomiie, Nature 1958, 181, 761‐762. (b) I.
Nitta, H. Watase and Y. Tomiie, Bull. Chem. Soc. Jpn. 1958, 31
wet mesh) column chromatography (elution with 3.8% NH
give mixture including (10.6 mg) which was further purified by
HPLC [NOMURA CHEMICAL Devolsil C30‐UG‐5, 10.0×250 mm,
elution with MeOH/H O (20 : 80 gradient to 100:0 by 30 min,
(8.1 mg, 0.0380 mmol, 60% for 3 steps)
3
) to
1
1
2
1 and 2, see: (a) I. Nitta,

,
2
7
9
1
14‐725. (c) H. Watase, Bull. Chem. Soc. Jpn. 1958, 31, 932‐
2
.0 mL/min) to afford
1
40. (d) W. Oppolzer and K. Thirring, J. Am. Chem. Soc. 1982,
04, 4978‐4979.
2
5
6c
24
as a colorless oil: [
.5, H
MHz, D
dd, J = 16.1, 6.3 Hz), 2.96‐3.06 (2H, m), 3.43 (1H, t, J = 11.7 Hz),
.62 (1H, dd, J = 11.7, 7.3 Hz), 4.06 (1H, d, J = 2.9 Hz), 4.74 (1H,

]
D
–14.6 (c 0.53, H
2
O) [lit. [

]
D
–14.6 (c
–
1
1
0
2
O)]; IR (neat) 1541, 2916, 3649, 3735 cm ; H NMR (400
3
4
H. Shinozaki, and Konishi, S. Brain Res. 1970, 24, 368–371.
(a) Excitatory Amino Acids; P. R. Simon, Ed.; Thieme Medical:
New York, 1992. (b) Glutamate: Transmitter in Central
Nervous Systems; P. J. Roberts, J. Storm‐Mathesen, G. A. R.
Johnston, Eds.; Wiley: Chichester, U.K., 1981. (c) R. L. Johnson
and J. F. Koerner, J. Med. Chem. 1988, 31, 2057‐2066. (d)
Kainic Acid as a Tool in Neurobiology; E. G. McGeer, J. W.
Oleny, and P. L. McGeer, Eds.; Raven: New York, 1978.
For reviews on kainoid syntheses, see: (a) C. I. Stathakis, E. G.
Yioti and J. K. Gallos, Eur. J. Org. Chem. 2012, 4661‐4673. (b)
A. F. Persons, Tetrahedron 1996, 52, 4149‐4174.
2
O)  1.77 (3H, s), 2.22 (1H, dd, J = 16.1, 8.3 Hz), 2.33 (1H,
3
13
s), 5.03 (1H, s); C NMR (100 MHz, D
2
O)  22.5, 35.4, 41.8, 46.1,
6.7, 66.2, 113.5, 140.5, 173.9, 178.7; HRMS (ESI‐orbitrap) m/z:
M + H] ; Calcd for C10H O N 214.1074; Found 214.1075.
16 4
Spectroscopic data were identical with those reported.
4
[
+
6
c,26b
5
6
allo‐Kainic Acid (2)
To a solution of 16 (21.6 mg, 0.0660 mmol) in acetone (0.80 mL)
For selected recent total syntheses of
1 and 2, see: (a) H. W.
o
was dropwised Jones reagent (2.50 M in H
2
O, 10 drops) at 0 C.
The mixture was stirred at 0 C for 30 min, quenched with 2‐
propanol, filtered through a plug of celite. The filtrate was
O and extracted with AcOEt. The combined organic
SO , filtered, and
concentrated in vacuo to give the crude carboxylic acid which
Shi, J. L. Li, Y. M. Liu, Z. L. Du, Z. Y. Huang, N. Zhao, N. Li and J.
Yang, Tetrahedron 2016, 72, 5502‐5506. (b) M. Zhang, K.
Watanabe, M. Tsukamoto, R. Shibuya, H. Morimoto and T.
Ohshima, Chem. Eur. J. 2015, 21, 3937‐3941. (c) K. Oe, Y.
Ohfune and T. Shinada, Org. Lett. 2014, 16, 2550‐2553. (d) N.
o
poured H
2
layers were washed with brine, dried over Na
2
4
Kesava Reddy and S. Chandrasekhar, J. Org. Chem. 2013, 78
,
3355‐3360. (e) G. Arena, C. C. Chen, D. Leonori and V. K.
Aggarwal, Org. Lett. 2013, 15, 4250‐4253. (f) H.‐J. Yu, C. Shao,
Z. Cui, C.‐G. Feng and G.‐Q. Lin, Chem. Eur. J. 2012, 18, 13274‐
was directly employed in the next reaction.
To a solution of the crude carboxylic acid in MeOH/H
.80 mL) was added LiOH‐H
2
O (3:1,
1
3278. (g) A. Orellana, S. K. Pandey, S. Carret, A. E. Greene and
o
0
2
O (27.7 mg, 0.660 mmol) at 0 C.
J.‐F. Poisson, J. Org. Chem. 2012, 77, 5286‐5296. (h) K.
Kitamoto, Y. Nakayama, M. Sampei, M. Ichiki, N. Furuya, T.
Sato and N. Chida, Eur. J. Org. Chem. 2012, 4217‐4231. (i) Z.
Luo, B. Zhou and Y. Li, Org. Lett. 2012, 14, 2540‐2543. (j) P. A.
Evans and P. A. Inglesby, J. Am. Chem. Soc. 2012, 134, 3635‐
The mixture was warmed to room temperature, stirred for 42 h,
quenched with 0.20 M HCl, and extracted with AcOEt. The
combined organic layers were washed with brine, dried over
Na SO , filtered, and concentrated in vacuo to give the crude
2 4
dicarboxylic acid which was directly employed in the next
reaction.
3
638. (k) P. J. Parsons, S. P. G. Rushton, R. R. Panta, A. J.
Murray, M. P. Coles and J. Lai, Tetrahedron 2011, 67, 10267‐
1
2
0273. (l) G. Wei, J. M. Chalker and T. Cohen, J. Org. Chem.
011, 76, 7912‐7917. (m) A. Farwick, J. U. Engelhart, O.
8
| Org. Biomol. Chem., 2017, 00, 1‐3
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Org aP nl ei ac s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Organic &Biomolecular Chemistry
PAPER
Tverskoy, C. Welter, Q. A. Umlauf, F. Rominger, W. J. Kerr and
G. Helmchen, Adv. Synth. Catal. 2011, 353, 349‐370. (n) K.
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Hasegawa and D. P. Curran, Tetrahedron Lett. 19V9ie3w,A3rt4ic,le1O7n1li7ne‐
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DOI: 10.1039/C7OB01427A
Totleben, Synlett 1992, 943‐961.
Lett. 2010, 12, 5756‐5759. (o) A. Farwick and G. Helmchen, 19 The addition of H
2
O enhanced reactivity in numerous
Org. Lett. 2010, 12, 1108‐1111. (p) K. Tomooka, T. Akiyama, P.
Man and M. Suzuki, Tetrahedron Lett. 2008, 49, 6327‐6329.
reactions of SmI . See: (a) X. Just‐Baringo and D. J. Procter, Acc.
2
Chem. Res. 2015, 48, 1263‐1275 and references cited therein.
(
q) H. Sakaguchi, H. Tokuyama and T. Fukuyama, Org. Lett.
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Cohen, Org. Lett. 2007,
Tokuyama and T. Fukuyama, Org. Lett. 2007,
(b) E. Hasegawa and D. P. Curran, J. Org. Chem. 1993, 58,
2
5008‐5010.
9
, 3825‐3828. (s) H. Sakaguchi, H. 20 The wide‐ranging studies on the mechanism of SmI
2
‐mediated
O have been carried out. See: (a) X. Zhao, L.
Perrin, D. J. Procter and L. Maron, Dalton Trans. 2016, 45
9
, 1635‐1638.
reactions with H
2
7
8
For reviews on SmI
2
‐mediated C‐C bond formation reactions,
,
see: (a) M. Szostak, N. J. Fazakerley, D. Parmar and D. J.
3706‐3710. (b) M. Szostak, M. Spain and D. J. Procter, J. Am.
Chem. Soc. 2014, 136, 8459‐8466. (c) M. Szostak, S. E. Lyons,
M. Spain and D. J. Procter, Chem. Commun. 2014, 50, 8391‐
8394. (d) M. Szostak, M. Spain, K. A. Choquette, R. A. Flowers
II and D. J. Procter, J. Am. Chem. Soc. 2013, 135, 15702‐15705.
(e) D. V. Sadasivam, J. A. Teprovich Jr., D. J. Procter and R. A.
Flowers II, Org. Lett. 2010, 12, 4140‐4143. (f) D. Parmar, L. A.
Duffy, D. V. Sadasivam, H. Matsubara, P. A. Bradley and R. A.
Flowers II, Procter, D. J. J. Am. Chem. Soc. 2009, 113, 15467‐
15473. (g) A. M. Hansen, K. B. Lindsay, P. K. S. Antharjanam, J.
Karaffa, K. Daasbjerg, R. A. Flowers II and T. Skrydstrup, J. Am.
Chem. Soc. 2006, 128, 9616‐9617. See also, ref. 18c.
Procter, Chem. Rev. 2014, 114, 5959‐6039. (b) K. C. Nicolaou,
S. P. Ellery and J. S. Chen, Angew. Chem. Int. Ed. 2009, 48
,
7
140‐7165. (c) D. J. Edmonds, D. Johnston and D. J. Procter,
Chem. Rev. 2004, 104, 3371‐3404. (d) A. Krief and A. M. Laval,
Chem. Rev. 1999, 99, 745‐778. (e) G. A. Molander and C. R.
Harris, Chem. Rev. 1996, 96, 307‐338. (f) G. A. Molander,
Chem. Rev. 1992, 92, 29‐68.
(a) H. Tamiya, K. Goto and F. Matsuda, Org. Lett. 2004,
6, 545‐
5
47. (b) F. Matsuda, M. Kito, T. Sakai, N. Okada, M. Miyashita
and H. Shirahama, Tetrahedron 1999, 55, 14369‐14380. (c) F.
Matsuda, T. Sakai, N. Okada and M. Miyashita, Tetrahedron
Lett. 1998, 39, 863‐864. (d) M. Kito, T. Sakai, H. Shirahama, M. 21 Due to the presence of the rotamers with regard to the amide
1
Miyashita and F. Matsuda, Synlett 1997, 219‐220.
moieties, H NMR spectra of the Boc‐pyrrolidines 10 and 11
were too complex to estimate the stereostructures. After the
removal of the Boc groups with TFA, the 3,4‐cis‐ and 3,4‐trans‐
stereochemistries of 10 and 11 were unequivocally confirmed
by ROESY experiments on the TFA pyrrolidines 17 and 18
9
1
H. Miyaoka, A. Nishiyama, H. Nagaoka and Y. Yamada, Synlett
2
003, 717‐719.
0 Molander reported that the intramolecular conjugated
addition reactions promoted by SmI between the alkyl
iodides and the ‐unsaturated esters occurred in the
presence of catalytic amount of NiI affording the 5‐
2
†

,

derived from 10 and 11, respectively. See the ESI for details.
2
membered carbocycles. See: (a) G. A. Molander and D. J. S.
Jean, Jr. J. Org. Chem. 2002, 67, 3861‐3865. (b) G. A. Molander
and C. R. Harris, J. Org. Chem. 1997, 62, 7418‐7429.
1
1
1
1 The stereochemistries of the E‐ and Z‐isomers of
assigned by the 2D ROESY experiment on
2 P. S. Baran, C. A. Guerrero and E. J. Corey, J. Am. Chem. Soc.
003, 125, 5628–5629.
3 The E‐geometries of the allyl chloride moieties of
determined by NOESY spectra of the corresponding E‐
7 were
7
.
2
2 The beneficial effects of addition of catalytic amounts of NiI
in the SmI ‐promoted reactions have been well recognized.
2
2
2
See: (a) G. A. Molander, K. M. George and L. G. Monovich, J.
Org. Chem. 2003, 68, 9533‐9540. (b) G. A. Molander, Y. L.
Huérou and G. A. Brown, J. Org. Chem. 2001, 66, 4511‐4516.
8
and 13 was
,‐
†
unsaturated esters
4 The exclusive formation of the E‐isomer in each of the
reductive amination of with 2‐aminoethanol or 12 seem to
be due to the E/Z isomerization on the olefin part of the imine
intermediate generated form For the geometric
isomerization of the imines prepared from the
unsaturated aldehydes, see: (a) C. Arbonés, F. J. Sánchez, M.‐
P. Marco, F. Camps and A. Messeguer, Heterocycles 1990, 31
9 and E‐14. See the ESI for details.
(
c) M. Ricci, P. Blakskjær and T. Skrydstrup, J. Am. Chem. Soc.
1
2
000, 122, 12413‐12421. (d) N. Miquel, G. Doisneau and J. M.
4
Beau, Angew. Chem. Int. Ed. 2000, 39, 4111‐4114. (e) F.
Machrouhi and J. L. Namy, Tetrahedron Lett. 1999, 40, 1315‐
4
.
1
6
1
318. (f) G. A. Molander and F. Machrouhi, J. Org. Chem. 1999,
, 4119‐4123. (g) F. Machrouhi and J. L. Namy, Tetrahedron
998, 54, 11111‐11122. (h) F. Machrouhi, E. Pârlea and J. L.
,‐
4
,
Namy, Eur. J. Org. Chem. 1998, 2431‐2436. (i) F. Machrouhi, J.
L. Namy and H. B. Kagan, Tetrahedron Lett. 1997, 38, 7183‐
6
1
7‐78. (b) G.‐C. Zheng and H. Kakisawa, Bull. Chem. Soc. Jpn.
989, 62, 602‐604.
7
1
186. (j) B. Hamann, J. L. Namy and H. B. Kagan, Tetrahedron
996, 52, 14225‐14234. (k) F. Machrouhi, B. Hamann, J. L.
1
1
1
5 D. B. Dess and J. C. Martin, J. Org. Chem. 1983, 48, 4155‐4156.
6 C. Harcken and S. F. Martin, Org. Lett. 2001, , 3591‐3593.
7 Many SmI ‐induced reactions benefit from the presence of
3
Namy and H. B. Kagan, Synlett 1996, 633‐634. Also see ref 10.
3 Although the mechanistic basis for effect of NiI had been
unknown, recently, Flowers has revealed the role of catalytic
NiI in the intermolecular Barbier coupling induced by SmI
between 3‐pentanone and 1‐iodododecane. See: K. A.
Choquette, D. V. Sadasivam and R. A. Flowers II, J. Am. Chem.
Soc. 2011, 133, 10655‐10661.
2
2
2
2
HMPA. See: (a) K. Otsubo, K. Kawamura, J. Inanaga and M.
Yamaguchi, Chem. Lett. 1987, 16, 1487‐1490. (b) J. Inanaga, M.
Ishikawa, and M. Yamaguchi, Chem. Lett. 1987, 16, 1485‐1486.
2
2
(
c) K. Otsubo, J. Inanaga and M. Yamaguchi, Tetrahedron Lett.
986, 27, 5763‐6764.
8 The role of HMPA in reactions of SmI
1
1
2
is quite understood.
4 Interestingly, trans‐selective cyclization occurred when both
HMPA (60 equiv) and NiI (0.3 equiv) were used as additives
2
See: (a) K. A. Choquette, D. V. Sadasivam and R. A. Flowers, II
J. Am. Chem. Soc. 2010, 132, 17396‐17398. (b) D. V. Sadasivam,
P. K. S. Antharjanam, E. Prasad and R. A. Flowers, II J. Am.
Chem. Soc. 2008, 130, 7228‐7229. (c) R. A. Flowers, II Synlett
to afford 11 as the major isomer in lower cis/trans ratio
cis:trans = 25:75) and higher combined yield (67%) than
(
those observed for trans‐selective annulation with HMPA (60
equiv) (Table 1, entry 3).
2
008, 1427‐1439 and references cited therein. (d) R. J.
Enemærke, T. Hertz, T. Skrydstrup and K. Daasbjerg, Chem.
Eur. J. 2000, , 3747‐3754. (e) Z. Hou and Y. Wakatsuki, Bull.
2
2
5 G. Bartoli, G. D. Antonio, R. Fiocchi, S. Giuli, E. Marcantoni and
M. Marcolini, Synthesis 2009, 951‐956.
6 The 3,4‐trans‐pyrrolidine 16 has already been synthesized
during the total synthesis of (+)‐allo‐kainic acid (2) achieved
6
Chem. Soc. Jpn. 1997, 70, 149‐153. (f) Z. Hou and Y. Wakatsuki,
J. Chem. Soc., Chem. Commun. 1994, 1205‐1206. (g) E.
This journal is © The Royal Society of Chemistry 20xx
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Organic &Biomolecular Chemistry
by Benetti. All the data ( H and 13C NMR, IR, and optical
rotation) of our sample of 16 were identical with those
reported by Benetti. See: (a) A. Barco, S. Benetti and G.
Spalluto J. Org. Chem. 1992, 57, 6279‐6286. Moreover,
Hanessian accomplished the synthesis of the C4‐epimeric
pyrrolidines 19 and 20 having methyl ester group at the C3
1
View Article Online
DOI: 10.1039/C7OB01427A
side chain in the total synthesis of (–)‐kainic acid (
1
) and (+)‐
1
13
allo‐kainic acid (
2). The H and C NMR spectral data of 15
and 16 were quite similar to those of the corresponding 3,4‐
cis‐ and 3,4‐trans‐pyrrolidines 19 and 20, respectively,
described by Hanessian. See: (b) S. Hanessian and S. Ninkovic,
J. Org. Chem. 1996, 61, 5418‐5424.
2
2
7 In the NiI
2
‐catalyzed cyclization of
2
E‐14 with SmI in the
presence of H
2
O (10 equiv), no significant effect on yield and
diastereoselectivity of the 3,4‐cis‐ and 3,4‐trans‐pyrrolidines
1
5
and 16 was observed by lowering the catalyst loading from
.3 equiv to 0.05 equiv (64% combined yield, cis:trans = 29:71).
‐14 with NiI (0.05 equiv) and
,2’‐bipyridine, a decrease in amount of 2,2’‐bipyridine from
.2 equiv to 0.05 equiv caused a loss in diastereoselection
0
8 In the reductive cyclization of
2
0
E
2
between 15 and 16 (cis:trans = 50:50, 43% combined yield).
At higher ligand loading (1.0 equiv of 2,2’‐bipyridine), 15 and
1
6
were produced in better yield (54% combined yield), but
cis/trans ratio was dropped (cis:trans = 58:42).
9 Interestingly, upon treatment of the E‐ ‐unsaturated ester
with SmI in the presence of catalytic amount of NiI (0.05
2
,
9
2
2
equiv) and 2,2’‐bipyridine (0.2 equiv), the cyclization formed
the 3,4‐cis‐ and 3,4‐trans‐pyrrolidines 10 and 11 in lower
chemical yield (50% combined yield) and product ratio
(
cis:trans = 80:20) than those obtained in the cis‐selective
cyclizations of
2
9 with NiI (0.3 equiv) in the absence of 2,2’‐
bipyridine (Table 1, entries 7 and 8).
1
0 | Org. Biomol. Chem., 2017, 00, 1‐3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01427A
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