A Diels-Alder-based total synthesis of (-)-kainic acid

Article abstract of DOI:10.1021/jo300608g

An efficient synthesis of (-)-kainic acid, through a high-pressure-promoted Diels-Alder cycloaddition of a vinylogous malonate derived from 4-hydroxyproline, is described. The bicyclic adduct could be converted into the natural product with complete stereocontrol.

Full text of DOI:10.1021/jo300608g

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Article
A Diels-Alder Based Total Synthesis of (–)-Kainic Acid
Arturo Orellana, Sushil Kumar Pandey, Sébastien Carret, Andrew Elliot Greene, and Jean-François Poisson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300608g • Publication Date (Web): 02 May 2012
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A Diels-Alder Based Total Synthesis of (–)-Kainic Acid
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Arturo Orellana, Sushil K. Pandey, Sébastien Carret, Andrew E. Greene, and Jean-François Poisson*
Département de Chimie Moléculaire (SERCO)
CNRS, UMR-5250, ICMG FR-2607,
Université Joseph Fourier
BP-53, 38041 Grenoble Cedex 9, France
RECEIVED DATE
CORRESPONDING AUTHOR FOOTNOTE: Tel: +33 4 76 63 59 86. Fax: + 33 4 76 51 44 94. E-mail:
jean-francois.poisson@ujf-grenoble.fr
Table of Contents Graphic
OSiR3
OSiR3
R1
CO2H
R3
R1
R3
H
R2
CO2H
(–)-Kainic acid
N
!, or 15 Kbar
N
H
R2
N
Boc
Boc
R1 = CHO, CO2Me
R2 = CH2OR, CO2R
R3 = OMe, NMe2
rd > 95:5
ABSTRACT.
An efficient and stereo- and regiooselective synthesis of (–)-kainic acid, through a high-pressure promoted
Diels-Alder cycloaddition of a trisubstituted vinylogous malonate derived from 4-hydroxyproline, is
described. The bicylic adduct could be converted to the natural product with complete stereocontrol.
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KEYWORDS. (–)-kainic acid, total synthesis, Asymmetric, Diels-Alder, high pressure
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Introduction
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(–)-Kainic acid (1) is a naturally occurring pyrrolidine with functionalized substituents at C2, C3, and C-4
in a trans-cis relationship. Isolated from Digenea simplex in the early fifties,1 it was originally used in
anthelmintic and insecticide preparations. It is now recognized to be an exceptionally potent glutamate
receptor agonist and has become an important tool of biologists for the study of serious neuronal disorders,
such as Alzheimer’s disease and epilepsy.2 In 1999, the discontinuance of its commercial extraction from the
above alga created concern as to future supply,3 but this halt in production proved to be only temporary.4 The
supply concern did, however, serve to focus the attention of synthetic chemists on this deceptively simple
natural product. Since 2000, there have been numerous total syntheses of this natural product and many
related methodological studies.5 From this effort, it is evident that the apparent simplicity of the natural
product, a pyrrolidine with just three stereogenic centers, belies the difficulty of its synthesis: most syntheses
to date require a considerable number of steps.
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CO2H
4 3
CO2H
2
N
H
(–)-Kainic Acid (1)
FIGURE 1. (–)-Kainic Acid
We have published two total syntheses of (–)-kainic acid from inexpensive trans-4-hydroxy-L-proline (2,
eq 1), surprisingly the first ones to use this amino acid, which possesses both a structure and absolute
stereochemistry seemingly ideal for accessing this target.6 The first synthesis relied on a crucial, selective
alkylation of a 4-oxo proline derivative and a cuprate-mediate isopropenylation,5hh whereas the second made
effective use of a Diels-Alder reaction, particularly attractive for setting the natural C2-C3-C4 stereochemical
relationship in a straightforward manner.5oo The latter synthesis showcased the use of high pressure (15 kbar)
to overcome the typical resistance of a trisubstituted olefin to enter into the [4+2] cycloaddition. Although it
is well-known that high pressure can promote the Diels-Alder reaction in cases of unfavorable diene-
dienophile combinations,7 thereby allowing milder reaction conditions, it has, surprisingly, been scarcely
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used in the context of total synthesis.5oo,8 Herein we provide a full account of our Diels-Alder approach to (–)-
3
4
kainic acid.
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OSiR¢3
HO
R
X
II
CO2H
CO2Me
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N
H
N
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Boc
2
I
O
OSiMe3
H
CO2H
CO2H
Me
R
H
H
N
H
CO2Me
CO2Me
N
N
Boc
Boc
(–)-Kainic acid (1)
IV
III
Figure 2. Synthetic strategy
Results and Discussion
First approach
A Diels-Alder approach with dehydroproline I seemed particularly attractive (Fig. 2). The functional group
at C-2 could be expected to induce effectively the desired face selection to the cycloaddition, which most
likely would ultimately lead to the correct stereochemistry of the C3-C4 appendages. The main concern was
the reactivity of this type of dienophile. In many, if not most, of the relative few reported examples of [4+2]
cycloaddition of trisubstituted olefins,9,10,11,12 there is "double activation" as in, for example, α-carbalkoxy
enones. Furthermore, only rarely has the trisubstutituted double bond been incorporated in a five-membered
ring (all successful examples have required that one of the substituents be an activating group).11,12,13
Since pyrroline derivative I, R= CO2R’ or CHO, would potentially be chemically and configurationally
fragile (vinylogous malonate derivatives), the feasibility of the [4+2] cycloaddition and much of the
envisioned subsequent chemistry for the synthesis of kainic acid was first studied with the corresponding C-2
TIPS-protected hydroxymethyl derivatives (Scheme 1). The preparation of the cycloaddition “model”
substrates 7 and 8 began by conversion of hydroxyproline 2 into the hydroxymethyl derivative 3 through Boc
protection and sodium borohydride reduction of the isobutyl mixed anhydride (70% overall).14 The newly
formed primary hydroxyl was next selectively protected with a triisopropylsilyl group to afford in 70% yield
silyl ether 4, which was then subjected to TPAP oxidation15 to give cleanly pyrrolidinone 5. The
corresponding enol triflate 6, formed best from 5 with sodium hexamethyldisilazide and N-phenyl triflimide,
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was converted into unsaturated ester 7 by standard methoxycarbonylation (87%, 2 steps). The corresponding
aldehyde 8, the second potential dienophile we wished to examine, could be secured in 72% yield from ester
7 by using Dibal-H, followed by oxidation with Ley's reagent (TPAP).
7
8
9
Scheme 1. Synthesis of the dienophiles
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HO
HO
1. Boc2O
2. i-BuOCOCl
TIPSCl
70%
CO2H
3. NaBH4
70%
N
Boc
N
H
OH
3
2
HO
O
TPAP
NMO
95%
NaHMDS;
PhNTf2
N
Boc
N
Boc
OTIPS
OTIPS
OTIPS
4
5
MeO2C
TfO
1. Dibal-H
Pd°, CO
MeOH
2. TPAP;
NMO
N
Boc
N
Boc
OTIPS
87%
(2 steps)
7
72%
6
OHC
N
Boc
OTIPS
8
The trisubstituted α,β-unsaturated ester 7 and aldehyde 8 showed similar behavior toward electron-rich
dienes. No cycloaddition took place thermally with either olefin in the presence of Danishefsky’s diene, with
only decomposition products and/or recovery of the olefin resulting. In contrast, the more reactive Rawal
diene provided the corresponding cycloadduct with each olefin (Scheme 2). As expected, ester 7 was found
to be the less reactive of the two, requiring 110 °C (refluxing toluene) for 15 h for complete reaction;
aldehyde 8, in contrast, was completely transformed after 16 h in chloroform at ambient temperature.
The endo:exo ratios of the dimethylamino group in the cycloadducts were, interestingly, nearly identical
(ca. 3:1). More importantly, hydrolysis of the cycloadducts 9 and 10 provided only diastereomers 11 and 12.
Thus, the cycloadditions were completely face selective, with the stereochemical outcome governed by the
silyloxymethyl group, which totally shields the β-face of the molecules. Although both cycloadditions were
highly efficient (ca. 90%), the hydrolysis of the cycloadducts 9 and 10 to give enones 11 and 12, respectively,
proceeded at best in only moderate yields, despite considerable effort toward improvement. A reluctant
elimination of the pseudoequatorial dimethylamino group in the exo isomers 9 and 10 was undoubtedly at
least part of the problem.
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Scheme 2. Diels-Alder cycloadditions
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9
OTBS
R
O
Me2N
R
H
Rawal's diene
O
Toluene, !
N
Boc
N
Boc
OTIPS
OTIPS
or THF, rt
endo : exo = 3:1
7: R = OMe
8: R = H
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9: R = OMe
10: R = H
LiOH;
NEt3, tol
11:
O
O
30%
(from 7)
O
HCl (1M)
H
H
R
N
Boc
N
Boc
OTIPS
12: KOH/THF
31%
(from 8)
OTIPS
rd > 98:2
13
11: R = OMe
12: R = H
O
DBU
92%
H
H
N
Boc
OTIPS
14
Having served their dual purpose of activating the olefin and controlling the regioselectivity of the
cycloadditions, the angular functional groups now needed to be excised. The vinylogous β-keto ester 11 on
saponification, followed by decarboxylation of the resultant acid with triethylamine in refluxing toluene,
provided enone 13 (30%, 3 steps). The same enone was formed from the vinylogous β-keto aldehyde 12 by
decarbonylation with potassium hydroxide (31%, 3 steps). In both cases the double bond, surprisingly,
suffered translocation to the non-conjugated, ring-junction position; however, fortunately, conjugation could
be easily restored with DBU to give the desired enone 14.
The possibility that a trans ring fusion resulted from this DBU-induced transformation was an obvious
concern that needed to be addressed. Catalytic hydrogenation of enone 14 afforded ketone 15, which was
converted into its derivative 16 (originally prepared for eventual X-ray crystallographic determination) for
NOE measurments (Scheme 3). A significant NOE could be observed between the two ring-junction protons
and, also, across the ring as shown. Enone 14 was thus cis-fused.16
Scheme 3. Determination of the relative stereochemistry of enone 14
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O
O
O
1. TFA
2. TsCl
3. TBAF
Noe
H
H2
H
H
4. PNBCl
DMAP
H
H
H
Pd/C
95%
N
N
Boc
N
Boc
48%
OPNB
Ts
16
OTIPS
OTIPS
14
15
9
With compound 14 in hand, we were unduly confident of success. The addition of higher-order dimethyl
cuprate to unsaturated ketone 14 led to compound 17 in excellent yield, however the closely precedented17
Baeyer-Villiger oxidation, followed by methanolysis of the unseparable lactones, led, quite unexpectedly, to a
nearly equimolar mixture of hydroxy esters 18 and 19 (Scheme 4). We, nevertheless, continued the synthesis
by conversion of the mixture into the corresponding mesylate esters. Phenylselenide displacement of the
mesylates then provided seleno esters 20 and 21, which on oxidation/elimination afforded a mixture of the
potential kainic acid precursor 22 and its isomer 23.18
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Scheme 4. End of the first route
O
O
1. Me2CuCNLi2
TMSCl
H
H
H
H
2. HCl (1M)
89%
N
Boc
N
Boc
OTIPS
OTIPS
14
17
OH
CO2Me
OH
CO2Me
+
1. mCPBA
2. MeONa
81%
H
H
H
H
N
Boc
N
Boc
OTIPS
1.1 : 1
OTIPS
18
19
SePh
CO2Me
SePh
1. MsCl
CO2Me
2. PhSeNa
+
H
H
H
H
90%
N
Boc
N
Boc
OTIPS
OTIPS
21
20
CO2Me
CO2Me
1. H2O2
93%
+
H
H
H
N
Boc
N
Boc
OTIPS
OTIPS
23
22
While at this stage we had essentially completed a Diels-Alder based approach to natural kainic acid,19 we
were not in the least pleased with its efficiency and decided to seek an alternative route. Nonetheless, the
work had been instructive: The Diels-Alder reaction had indeed proven useful for the purpose of regio- and
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stereocontrolling the introduction of the C-3 and C-4 functionalized appendages, but there were too many
transformations needed to prepare the dienophiles. The early acid reduction and hydroxyl protection added
significantly to these initial steps and would also ultimately require deprotection and oxidation to regenerate
the function, thus making the entire synthetic endeavor less than elegant. This required change. The
unexpectedly poor regioselectivity in the Baeyer-Villiger oxidation, obviously, also needed to be addressed
and a more selective alternative developed. Finally, the introduction of the double bond of the isopropenyl
group had to be achieved more directly.
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Second approach
Mindful of the possibility of facile racemization, we nonetheless undertook a study of the behavior of
diester I, R=CO2Me (Fig 1), in the Diels-Alder reaction. The preparation of this diester from hydroxyproline
2 began with esterification (thionyl chloride in MeOH), followed by Boc protection of the secondary amine,
to give methyl ester 2420 (Scheme 5). Oxidation of the hydroxyl group was best effected with PCC; other
reagents, such as TPAP/NMO, IBX, and Dess-Martin periodinane, proved considerably less amenable to
scale up. The enol triflate 2520 was then regioselectively formed by using sodium hexamethyldisilazide and
PhNTf2. While 25 could not be directly transformed efficiently under palladium catalysis to the
corresponding aldehyde I, R = CHO, because of competing reduction to I, R = H, both the related acid 26 and
ester 27 could be secured in high yield through palladium-catalyzed reactions. It was quickly discovered,
however, that stored acid 26 had a much greater configurational stability than did the ester 27, which
racemized at room temperature (20% ee after 10 days at 20 °C);21 hence, ester 27 was prepared from the acid
with diazomethane just prior to use.
Scheme 5. Synthesis of diester 27
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HO
HO
1) SOCl2
MeOH
1) PCC
CO2Me
2) NaHMDS;
PhNTf2
CO2H
2) Boc2O
Et3N
4
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N
N
H
2
Boc
24
72%
93%
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9
RO2C
TfO
CO
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Pd(PPh3)4
THF/H2O
CO2Me
CO2Me
N
N
Boc
Boc
94%
25
26 : R = H
27 : R = Me
CH2N2
94%
In refluxing toluene, ester 27 reacted to some extent (57% conversion after 82 h) with Danishefsky’s diene
(28) but, after hydrolysis, enone 30 was formed in just 22% yield and, even more discouragingly, in only
24% enantiomeric excess (Scheme 6). With the more reactive Rawal diene (29), the cycloaddition was
indeed much faster (100% conversion after 6 h), but the hydrolysis was problematic, and enone 30 could be
isolated in only less than 10% yield and again with a very low enantiomeric excess (10%). Attempted Lewis
acid activation (Et2AlCl, CuOTf, AlBr3/AlMe3) of the cycloaddition of ester 27 with diene 29, unfortunately,
led merely to decomposition products.
Scheme 6. Thermal [4+2] cycloaddition with diester 27
1. 28, Tol, !"
2. KHSO4, THF
O
MeO2C
22% (24% ee)
CO2Me
N
H
MeO2C
Boc
27
(94% ee)
CO2Me
N
1. 29, Tol, !"
Boc
30
2. TBAF, THF
10% (10% ee)
OTBDMS
OSiMe3
Me2N
MeO
28
29
Seeking an alternative that might permit milder reaction conditions, we turned our attention to high
pressure. This technique seemed particularly appropriate in present context: high pressure could be expected
to lead to high conversion at lower temperatures and at lower temperatures, and, these milder conditions
could reduce the degree of racemization of the vinyligous malonate. Indeed, ester 27 in the presence of
Rawal’s diene underwent complete reaction at room temperature under 15 kbar in just 52 h; however,
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hydrolysis produced enone 30 in only 27% yield and 54% ee, considerably better than previously obtained,
but nevertheless not synthetically useful (Scheme 7). In view of this problem, Rawal’s diene was replaced
with Danishefsky’s in the hope that it might provide an overall improvement.
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Scheme 7. High pressure [4+2] cycloaddition with diester 27
OTBS
O
MeO2C
29
Me2N
TBAF
THF
CO2Me
H
H
MeO2C
MeO2C
N
CH2Cl2
15 kbar
Boc
CO2Me
CO2Me
N
N
27
(94% ee)
Boc
Boc
27%
(54% ee)
30
With Danishesfsky’s diene, the cycloaddition reached 96% conversion at room temperature under 15 kbar
after 82 h (Scheme 8). The cycloadduct 31, obtained as a 3:1 mixture of endo:exo isomers, could be
converted into a mixture of enone 30 and ketone 32 by treatment with KHSO4. The latter could be efficiently
converted into the former by treatment with DBU in hot toluene. Thus, high pressure did once again provide
the desired gain in reactivity; however, we were both disappointed and puzzled to discover that the enone was
essentially racemic! Danishefsky’s diene had been purified by rapid distillation, but still contained traces of
triethylamine (by 1H NMR). In the belief that this very small amount of triethylamine could be at the origin of
the problem, the diene was redistilled, but this time in the presence of trichlorophenol to remove the last
traces of the triethylamine contamination. To our satisfaction, with this purified diene, enone 30 could now
be secured in both excellent yield (80%) and high enantiomeric excess (90%)22.
Scheme 8. High-pressure cycloaddition using Danishefsky diene
DBU, Tol
81%
OTMS
H
O
O
MeO2C
MeO
KHSO4 aq MeO
28
+
H
MeO2C
H
MeO2C
MeO2C
THF
CO2Me
CH2Cl2
15 kbar
N
CO2Me
CO2Me
CO2Me
N
N
N
Boc
27
Boc
Boc
32 (23%)
Boc
(94% ee)
31
30 (62%)
3:1 / endo:exo
(ee = 90%)
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The enormous impact of a minor amount of triethylamine on resulting enantiomeric excess of the product
was completely unexpected. An experiment was therefore conducted with diester 27 in a 5% solution of
triethylamine in dichloromethane at room temperature under atmospheric pressure. After 3 h, the
enantiomeric excess of the starting diester dropped to 56% (HPLC) and after 17 h, racemization was total
(Fig 3, green curve). The result of the same experiment, but under under high pressure, was quite striking in
comparison: complete racemization after just 5 min (Fig 3, red curve). To the best of our knowledge, this is
the first example of a base-catalyze high pressure-accelerated racemization, a phenomenon that would seem
to warrent further study.
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MeO2C
MeO2C
NEt3 (5mol%)
CO2Me
CH2Cl2
CO2Me
N
N
Boc
27
(94% ee)
Boc
27
HP (15 Kbar)
atm P
100
90
80
70
60
50
40
30
20
10
0
ee %
0
5
10
15
20
Time (h)
Figure 3. Pressure dependence of racemization rate of diester 27
With enone 30 now available in high yield and enantiopurity, the synthesis was continued with the removal
of the angular methoxycarbonyl group (Scheme 9). This was efficiently accomplished in 2 stages: first,
hydrolysis with lithium hydroxide to afford the crystalline diacid 33, which, conveniently, could be
recrystallized to give an upgraded ee of better than 99%.23 Next, base-induced monodecarboxylation of this
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vinylogous β-keto acid and exposure of the product to diazomethane produced ketone 34, which, as now
3
4
5
6
7
8
9
expected, was non-conjugated. The desired conjugated enone could, however, once again be regenerated
with DBU in essentially quantitative yield.24 A cis ring fusion in enone 35 was assumed, based on both
analogy with our earlier results with enone 14 and simple computational studies that indicated the cis isomer
to be ca. 6.5 kcal more stable than the trans;25 this assumption was ultimately shown to be correct through the
successful conversion of 35 into kainic acid.
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Scheme 9. Decarbomethoxylation of 30
O
O
O
O
LiOH
recryst.
80%
1. Py, !
2. CH2N2
83%
DBU
87%
HO2C
H
H
H
H
MeO2C
H
CO2H
CO2Me
CO2Me
CO2Me
N
N
N
N
Boc
33 (ee> 99%)
Boc
Boc
Boc
34
35
30
In an attempt to overcome the problem of poor regioselectivity of the previous Baeyer-Villiger reaction, the
possibility of effecting an oxidative cleavage of the enol ether obtained through cuprate 1,4-addition/TMSCl
trapping was examined next (Scheme 10). Dimethyl cyanocuprate addition to 35 in the presence of
trimethylsilyl chloride served, as planned, to both introduce the final skeletal carbon of kainic acid and
generate the enol ether, affording 36. This unstable product was directly ozonized at low temperature to give,
after dimethyl sulfide reduction, the expected aldehyde acid, which on brief exposure to diazomethane
smoothly provided diester aldehyde 37.26 The overall yield for the 3 steps was 70%. The problem of
regioselectivity resolved, the final challenge was to find an effective means to form the isopropenyl motif
from the aldehydic appendage. Rather than reduce the formyl to an hydroxyl group and apply the previous
sequence,27 we opted to try to effect reduction of the corresponding enol triflate, a potentially more direct but
surprisingly unprecedented transformation. After some experimentation,28 it was found that aldehyde 37
could be converted into the enol triflate with KHMDS and the Comins triflimide reagent.29 Palladium-
catalyzed silane reduction of the crude triflate then afforded diester 38 in 60% overall yield.30 (–)-Kainic acid
was easily obtained from this diester in 75% yield by saponification (LiOH), followed by amine deprotection
(TFA). The synthetically derived natural product (mp 241-243 °C, [a]20D –14.3 (c 0.16, H2O)) was found to
be identical with a commercial sample of the naturally derived material (mp 241-243 °C, [a]20D –13.9 (c 0.16,
H2O)).
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Scheme 10. Completion of the synthesis of kainic acid
3
4
5
6
O
OSiMe3
H
1) O3, !116 °C;
DMS
CO2Me
CO2Me
Me2CuCNLi2
TMSCl
35
H
H
7
2) CH2N2
CO2Me
N
8
9
N
70%
(3 Steps)
Boc
37
Boc
36
10
11
12
13
14
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19
20
21
22
23
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60
1) KHMDS;
Comins Triflimide
CO2Me
CO2Me
CO2H
CO2H
1) LiOH
2) TFA
75%
2) Et3SiH
Pd(PPh3)4
N
N
H
60%
Boc
38
(–)-Kainic acid (1)
Conclusion
Natural kainic acid has been prepared with nearly total stereocontrol and approximately 10% overall yield
(19 steps). The key features of the synthesis include: a high pressure-promoted Diels-Alder reaction of a
sensitive vinylogous malonate that proceeds with a high degree of enantioretention and permits, ultimately,
diastereoselective introduction of the C3 and C4 substituents of kainic acid; an efficient procedure to cleave
regioselectively a bicyclic intermediate and thereby generate appropriately functionalized side chains; a direct
method for converting a formyl into a methylene group. Finally, an intriguing effect of pressure on the rate
of racemization of a vinylogous malonate has been observed.
Experimental Section
General information. Reactions were carried out under argon in oven-dried glassware. Standard inert
atmosphere techniques were used in handling all air and moisture sensitive reagents. Dry THF and diethyl
ether were obtained by filtration over activated molecular sieves and dry CH2Cl2 by filtration through
activated aluminum oxide. Thin-layer chromatography was performed on (0.2 mm) silica sheets, which were
visualized with ultraviolet light and by heating the plate after treatment, generally with phosphomolybdic acid
in ethanol. Silica gel (0.040-0.063 mm) was employed for flash column chromatography. A Fourier transform
1
13
infrared spectrometer was used to record IR spectra. H NMR and C NMR spectra were recorded on either
300, 400, or 500 MHz apparatus. All shifts for 1H spectra were referenced to the residual solvent peak and are
reported in ppm. When ambiguous, proton and carbon assignments were established through COSY, HMQC,
and/or DEPT experiments. Mass spectra were recorded by using either DCI (ammonia/isobutane 63/37), EI,
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or ESI techniques. HRMS were recorded on an Orbitrap apparatus (ESI). Microanalyses were performed by
an in-house microanalysis service.
5
6
7
8
9
(2S,4R)-tert-Butyl 4-Hydroxy-2-(((triisopropylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (4). A solution
of diol 314 (20.1 g, 92.5 mmol) and a catalytic amount of DMAP (2.26 g, 18.6 mmol) in CH2Cl2 (200 mL) and
triethylamine (14.2 mL, 105.1 mmol) at 0 °C was treated dropwise with TIPSCl (21.8 mL, 101.8 mmol). The
reaction mixture was allowed to warm to room temperature and stirred overnight. Water was then added and
the organic layer separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layers
were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated and the crude product
was purified by column chromatography on silica gel (50:50 EtOAc-pentane) to afford 24.3 g (70%) of
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alcohol 4 as a colorless liquid: [α]20 –58.6 (c 0.42, CHCl3); IR (film) 2944, 2866, 1697, 1673, 1462, 1366,
D
1
1256, 1168, 1121, 1014, 882 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 4.50 (br s, 1H), 4.17-3.92 (m,
2H), 3.86-3.37 (m, 3H), 2.35-2.20 (m, 1H), 2.09-1.86 (m, 1H), 1.84-1.62 (m, 1H), 1.47 (s, 9H), 1.14-0.94 (m,
13
21H); C NMR (75 MHz, CDCl3) δ 154.8, 154.6, 79.5, 79.1, 70.0, 69.2, 64.4, 63.2, 57.6, 57.5, 55.5, 55.1,
37.0, 36.2, 28.5, 17.98, 17.9, 11.9; MS (DCI, NH3/isobutane) m/z 373, 318 (100%), 274; Anal. Calcd. for
C19H39NO4Si: C, 61.08; H, 10.52; N, 3.75. Found: C, 61.42; H, 10.53; N, 3.92.
(S)-tert-Butyl 4-Oxo-2-(((triisopropylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (5). To a stirred solution
of alcohol 4 (11.7 g, 31.3 mmol) in CH2Cl2 (100 mL) at 0 °C was added 4 Å molecular sieves (30.0 g) and
tetra-N-propylammonium perruthenate (0.545 g, 5 Mol %), followed by 4-methylmorpholine N-oxide (5.5 g,
46.9 mmol). The reaction mixture was stirred overnight and then filtered through silica gel with ethyl acetate
and the filtrate was concentrated by rotary evaporation under reduced pressure. The residue was purified by
silica gel column chromatography (40:60 EtOAc-pentane) to yield 11.1 g (95%) of ketone 5 as a colorless
liquid: [α]20 –7.4 (c 0.38, CHCl3); IR (film) 2944, 2865, 1716, 1698, 1682, 1463, 1397, 1365, 1253, 1159,
D
1
1118, 882 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 4.50-3.62 (m, 5H), 2.83-2.63 (m, 1H), 2.60-2.46
(m, 1H), 1.49 (s, 9H), 1.16-0.95 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 210.8, 153.8, 80.2, 66.0, 65.5, 55.9,
55.4, 54.2, 53.6, 40.7, 40.2, 28.5, 17.9, 11.8; MS (DCI, NH3/isobutane) m/z 371, 316 (100%), 272. Anal.
Calcd. for C19H37NO4Si: C, 61.41; H, 10.04; N, 3.77. Found: C, 61.68; H, 10.05; N, 3.82.
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(S)-tert-Butyl
4-(((Trifluoromethyl)sulfonyl)oxy)-2-(((triisopropylsilyl)oxy)methyl)-2,5-dihydro-1H-
3
4
5
6
7
8
9
pyrrole-1-carboxylate (6). To a stirred solution of NaHMDS (1.0 M in THF, 41.7 mL, 41.7 mmol) in THF
(30 mL) at –78 °C was added slowly a solution of ketone 5 (10.3 g, 27.7 mmol) in THF (25 mL). The
reaction mixture was stirred for 30 min and then treated with a solution of PhNTF2 (12.9 g, 36.1 mmol) in
THF (25 mL) over 15 min. This mixture was stirred for an additional 1.5 h at –78 °C, warmed to 0 °C and
quenched by slow addition of water (25 mL). The aqueous phase was extracted with Et2O and the combined
organic layers were washed with brine and dried over Na2SO4. Evaporation of the solvent under reduced
pressure and filtration of the residue through a short pad of silica gel (15:85 EtOAc-pentane) afforded the
sensitive triflate 6 (13.5 g), a small portion of which was further purified (silica gel, 15:85 EtOAc-
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35
36
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60
pentane) for analysis: [α]20 –94.6 (c 0.74, CHCl3); IR (film) 2944, 2867, 1711, 1698, 1672, 1431, 1402,
D
1217, 1140, 1108, 883 cm-1; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 5.76 and 5.72 (2 s, 1H), 4.61-4.50 (m,
13
1H), 4.40-4.05 (m, 2H), 4.04-3.82 and 3.78-3.67 (2 m, 2H), 1.49 (s, 9H), 1.20-0.94 (m, 21H); C NMR (75
MHz, CDCl3) δ 153.4, 153.3, 143.6, 143.1, 124.8, 120.6, 116.3, 115.3, 115.2, 112.1, 80.6, 80.3, 64.5, 63.5,
63.0, 51.0, 50.7, 28.3, 17.7, 11.8; MS (DCI, NH3/isobutane) m/z 503, 448 (100%), 404. Anal. Calcd. for
C20H36F3NO6SSi: C, 47.69; H, 7.20; N, 2.78. Found: C, 47.56; H, 7.27; N, 2.54.
(S)-1-tert-Butyl 3-Methyl 5-(((triisopropylsilyl)oxy)methyl)-1H-pyrrole-1,3(2H,5H)-dicarboxylate (7). A
stirred solution of the above triflate 6 (13.5 g, ca. 26.8 mmol) in MeOH (100 mL) at ambient temperature was
treated with Pd(OAc)2 (0.6 g, 2.7 mmol), PPh3 (1.4 g, 5.3 mmol), and N,N-diisopropylethylamine (7.0 mL,
40.2 mmol). CO gas was bubbled through the solution for 20 min, after which time a positive pressure of CO
was maintained for 1 h. Additional CO was then bubbled through the solution for 5 min and the reaction
mixture was stirred for another 2 h, keeping a positive pressure of CO. The solvent was removed under
vacuum and the residue was taken up in water and Et2O. The ether layer was separated and the aqueous layer
was extracted with ether. The combined ether layers were washed with brine, dried over Na2SO4 and filtered,
and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (30:70 EtOAc-pentane) to afford 10.0 g (87%, two steps) of ester 7 as a colorless liquid :
[α]20D –152.7 (c 0.44, CHCl3); IR (film) 2942, 2866, 1728, 1702, 1651, 1463, 1438, 1400, 1282, 1234, 1170,
1122, 1068, 882 cm-1; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 6.80 and 6.75 (2 s, 1H), 4.78-4.57 (m, 1H),
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4.48-4.29 (m, 1H), 4.22 and 4.17 (2 dd, J = 5.6, 2.0 Hz, 1H), 4.15-3.88 and 3.75-3.67 (2 m, 2H), 3.77 (s, 1H),
1.48 (s, 9H), 1.17-0.95 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 163.2, 153.7, 153.6, 139.7, 131.8, 79.8, 79.5,
5
6
7
8
9
66.7, 66.4, 64.4, 63.1, 52.9, 52.7, 51.5, 28.3, 17.7, 11.8; MS (DCI, NH3/isobutane) m/z 413, 358 (100%), 314;
Anal. Calcd. for C21H39NO5Si: C, 60.98; H, 9.50; N, 3.39. Found: C, 61.09; H, 9.84; N, 3.44.
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(S)-tert-Butyl 4-Formyl-2-(((triisopropylsilyl)oxy)methyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8). A
solution of ester 7 (10.0 g, 24.2 mmol) in toluene (100 mL) at –78 °C was treated slowly with DIBAL-H (1.5
M in toluene, 35.5 mL, 53.3 mmol). The reaction mixture was stirred for 2 h, quenched by the addition of
Na2SO4.10H2O and filtered with CH2Cl2. The filtrate was concentrated and the crude product was filtered
over silica gel with EtOAc to yield the crude alcohol (9.35 g), which was directly used for the next step. A
small portion was purified (silica gel, 50:50 Et2O-pentane) for analysis : [α]20 –133.1 (c 1.5, CHCl3); IR
D
1
(film) 3444, 2939, 2861, 1702, 1684, 1659, 1460, 1407, 1364, 1258, 1176, 1116, 881 cm-1; H NMR (300
MHz, CDCl3, 2 rotamers) δ 5.78 and 5.73 (2 s, 1H), 4.61 and 4.50 (2 br s, 1H), 4.32-4.16 (m, 3H), 4.10-3.85
(2 m, 3H), 1.49 (s, 9H), 1.15-0.93 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 154.3, 154.1, 139.9, 123.2, 79.7,
79.3, 65.9, 65.8, 65.0, 63.5, 59.7, 59.6, 54.2, 53.9, 53.4, 28.5, 17.9, 11.9; MS (DCI, NH3/isobutane) m/z 486,
330 (100%), 286. Anal. Calcd. for C20H39NO4Si: C, 62.29; H, 10.19; N, 3.63. Found: C, 62.21; H, 9.90; N,
3.51. To a stirred solution of the above alcohol (9.33 g, ca. 24.2 mmol) in CH2Cl2 (100 mL) at 0 °C was
added 4 Å molecular sieves (20 g) and tetra-N-propylammonium perruthenate (425 mg, 1.2 mmol), followed
by 4-methylmorpholine N-oxide (4.26 g, 36.4 mmol). The reaction mixture was stirred overnight and then
filtered through silica gel with ethyl acetate. The filtrate was concentrated by rotary evaporation under
reduced pressure and the residue was purified by silica gel column chromatography (30:70 Et2O-pentane) to
give 6.70 g, (72%, 2 steps) of aldehyde 8 as a colorless oil : [α]20 –173.8 (c 0.35, CHCl3); IR (film) 2942,
D
1
2866, 1703, 1698, 1687, 1397, 1366, 1161, 1114 cm-1; H NMR (CDCl3, 300 MHz, 2 rotamers) δ
9.76 (s, 1Η), 6.84 (s, 1Η), 4.83 and 4.73 (2 br s, 1H), 4.50-4.30 (m, 1H), 4.52 and 4.20 (dd, J = 5.4, 2.0 Hz,
13
1H), 4.13-4.00 and 3.81-3.74 (2 m, 2H), 1.49 (s, 9H), 1.16-0.90 (m, 21H); C NMR (75 MHz, CDCl3) δ
187.3, 187.1, 153.8, 153.6, 146.8, 146.6, 142.3, 142.1, 80.1, 79.8, 66.9, 66.6, 64.4, 63.1, 51.2, 51.0, 28.4,
17.8, 11.8; MS (DCI, NH3/isobutane) m/z 484, 328 (100%), 284. HRMS (LTQ-Orbitrap, ESI) Calcd. for
C20H37NO4NaSi: 406.23841. Found: 406.23877.
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(3S,3aS)-tert-Butyl
5-Oxo-3-(((triisopropylsilyl)oxy)methyl)-3a,4,5,6-tetrahydro-1H-isoindole-2(3H)-
3
4
5
6
7
8
9
carboxylate (13). Procedure A: A solution of ester 7 (0.019 g, 0.046 mmol) and Rawal’s diene (0.045 mL,
0.187 mmol) in toluene (2.0 mL) was refluxed for 15 h, after which the solvent was removed and the residue
was dissolved in THF (2.0 mL). The solution was cooled to 0 °C and slowly treated with 1M HCl (1.0 mL).
The reaction mixture was stirred for 1.5 h and water was then added. The aqueous layer was extracted with
AcOEt and the combined organic layers were washed with aq. NaHCO3 and brine, dried over Na2SO4, and
concentrated to afford 0.0086 g of crude enone 11. A 0.0077-g sample of crude enone 11 in THF (2.0 mL)
was treated with 1N LiOH (1.0 mL) for 1 h. Et2O (5 mL) was added and the organic phase was washed with
water. The combined aqueous phases were acidified to pH 2 with HCl and extracted with AcOEt. The
combined organic phases were washed with water and brine, dried over Na2SO4, and concentrated to give
0.0069 g of crude acid. A solution of a 0.0051-g sample of the crude material and NEt3 (0.03 mL) in toluene
(0.5 mL) was warmed to 80 °C for 3 h. The volatiles were then removed under reduced pressure and the
crude product was purified by silica gel column chromatography (25:75 Et2O-pentane) to afford 0.0037 g
(30%, 4 steps) of enone 13 as a colorless oil. Procedure B: A solution of aldehyde 8 (4.49 g, 11.72 mmol)
and Rawal’s diene (3.97 mL, 15.32 mmol) in THF (10 mL) at ambient temperature was stirred for 24 h, after
which the solvent was removed and the residue was dissolved in Et2O (20 mL). The solution was cooled to 0
°C and slowly treated with 1M HCl (15.0 mL). The reaction mixture was stirred for 1.5 h and then water was
added. The aqueous layer was extracted with Et2O and the combined organic layers were washed with aq.
NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude material dissolved in Et2O (150 mL) was
then stirred with 1 M KOH (6.0 mL) for 3 h under argon. The mixture was acidified with NaHSO4 and
extracted with Et2O. The combined organic layers were washed with water, dried over Na2SO4, and
concentrated and the crude product was purified by silica gel column chromatography (25:75 Et2O-pentane)
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41
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47
48
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50
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60
to afford 1.54 g (31%, 3 steps) of enone 13 as a colorless oil: [α]20 +9.6 (c 0.36, CHCl3); IR (film) 2939,
D
1
2861, 1691, 1460, 1389, 1361, 1254, 1165, 1116, 881 cm-1; H NMR (CDCl3, 300 MHz, 2 rotamers) δ
5.70 (s, 1Η), 4.38-4.06 (m, 2H), 4.03-3.76 (m, 2H), 3.65 (br s, 1H), 3.32-3.18 (m, 1H), 3.02-2.73 (m, 3H),
13
2.34 and 2.30 (2 d, J = 12.3 Hz, 1H), 1.48 (s, 9H), 1.18-0.96 (m, 21H); C NMR (75 MHz, CDCl3) δ
209.0, 154.0, 139.2, 114.7, 79.7, 65.2, 64.3, 62.7, 51.1, 43.8, 41.9, 40.2, 38.6, 28.4, 17.9, 11.9; MS (DCI,
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NH3/isobutane) m/z 424, 368 (100%), 324; Anal. Calcd. for C23H41NO4Si: C, 65.20; H, 9.75; N, 3.31.
Found: C, 64.93; H, 9.87; N, 3.32.
5
6
7
(1S,3aR,7aS)-tert-Butyl
6-Oxo-1-(((triisopropylsilyl)oxy)methyl)-3,3a,7,7a-tetrahydro-1H-isoindole-
8
9
2(6H)-carboxylate (14). A solution of enone 13 (0.84 g, 1.98 mmol) and DBU (0.29 mL, 1.97 mmol) in
CH2Cl2 (5 mL) was stirred for 24 h. Water was then added and the reaction mixture was extracted with ether.
The combined organic layers were washed with aq. KHSO4., aq. NaHCO3, and brine, dried over Na2SO4, and
concentrated. The crude product was purified by silica gel column chromatography (30:70 Et2O-pentane) to
give 0.77 g (92%) of 14 as colorless liquid : [α]20D –115.3 (c 0.97, CHCl3); IR (film) 2943, 2866, 1681, 1462,
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1403, 1367, 1264, 1170, 1120, 908 cm-1; 1H NMR (CDCl3, 300 MHz, 2 rotamers) δ 6.82−6.72 (m, 1Η), 6.05
(d, J = 9.9 Hz, 1H), 4.10-4.02 and 3.85-3.44 (m, 5H), 3.20-2.96 (m, 2H), 2.65-2.43 (m, 2H), 1.48 (s, 9H),
13
1.15-0.97 (m, 21H); C NMR (75 MHz, CDCl3) δ 197.8, 197.7, 154.2,154.0, 149.4, 148.9,130.7, 130.5,
80.0, 79.6,63.4, 63.3,62.9, 62.3, 51.5, 51.3, 40.3, 39.2, 38.6, 37.5, 37.1, 28.5, 18.0, 11.9; MS(DCI,
NH3/isobutane) m/z 424, 368 (100%), 324; Anal. Calcd. for C23H41NO4Si: C, 65.20; H, 9.75; N, 3.31.
Found: C, 64.99; H, 9.56; N, 3.29.
((1S,3aR,7aS)-6-Oxo-2-tosyloctahydro-1H-isoindol-1-yl)methyl 4-Nitrobenzoate (16). A mixture of
enone 14 (62 mg, 0.146 mmol) and 10% Pd/C (15 mg, 0.015 mmol) in EtOAc (2 mL) was stirred under H2 (1
bar) for 3 h. The reaction mixture was then filtered over Celite, the celite plug washed with ether, and the
filtrate concentrated to afford ketone 15 (59 mg, 95%) of sufficient purity to be used directly in the next step.
1H NMR (CDCl3, 400 MHz, 2 rotamers) δ 3.97 (br s, 0.35H), 3.75-3.70 (m, 1.65H), 3.55-3.40 (m, 3H), 2.81
(br s, 0.65H), 2.58 (br s, 1.35H), 2.47-2.24 (m, 3H), 2.05-2.00 (m, 1H), 1.89-1.80 (m, 1H), 1.44 (s, 9H), 1.05-
13
0.95 (m, 21H); C NMR (100 MHz, CDCl3) δ 211.3, 154.8, 79.9, 64.2, 63.1, 62.3, 50.8, 49.9, 42.4, 42.1,
41.2, 37.9, 34.9, 34.0, 28.6, 26.3, 18.0, 12.0 ; MS(ESI) m/z 448 (M+Na)+, 426 (M+H)+; HRMS (LTQ-
Orbitrap, ESI) Calcd. for C23H43NO4SiNa : 448.28536; Found : 448.28513. A solution of ketone 15 (58 mg,
ca 0.13 mmol) in CH2Cl2 (2 mL) was treated with trifluoroacetic acid (0.25 mL, 3.3 mmol) at room
temperature. After stirring for 3 h, the reaction mixture was concentrated under reduced pressure to yield the
crude ammonium trifluoroacetate. This material was dissolved in MeOH (3 mL) at room temperature and
treated with NEt3 (0.76 mL, 5.4 mmol) and TsCl (30 mg, 0.15 mmol). The reaction mixture was stirred for 12
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h and quenched with water. The aqueous phase was extracted with EtOAc and the combined organic phases
were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude tosylate was
treated with TBAF (1M/THF, 0.41 mL, 0.41 mmol) and stirred for 2 h. The reaction mixture was
concentrated and the residue purified by flash chromatography on silica gel (EtOAc/pentane, 50/50 to 80/20)
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to provided 28 mg (64 %, 3 steps) of alcohol 16´: IR (film) 3502, 2926, 2879, 1709, 1323, 1152 cm-1; H
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NMR (CDCl3, 300 MHz) δ 7.73 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 3.85 (dd, = 11.8, 4.1 Hz, 1H),
3.71-3.64 (m, 2H), 3.24-3.17 (m, 2H), 2.61-2.53 (m, 3H), 2.44 (s, 3H), 2.24-2.05 (m, 3H), 1.85-1.78 (m, 1H),
1.65 (dd, J = 14.9, 7.3 Hz, 1H), 1.34-1.25 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 209.3, 144.3, 133.4, 129.9,
127.4, 66.4, 63.9, 52.6, 42.1, 40.3, 37.5, 34.7, 25.1, 21.5 ; MS(ESI) m/z 346 (M+Na)+, 324 (M+H)+ ; HRMS
(LTQ-Orbitrap, ESI) Calcd. for C16H21NO4SNa : 346.10835; Found: 346.10814. A solution of alcohol 16´
(11 mg, 0.034 mmol), pyridine (0.005 mL, 0.068 mmol), and DMAP (4 mg, 0.034 mmol) in CH2Cl2 (2 mL)
was treated at room temperature with p-nitrobenzoyl chloride (9.5 mg, 0.051 mmol). After stirring for 12 h,
the reaction mixture was quenched with HCl (1N). The aqueous phase was extracted with EtOAc and the
combined organic phase were washed with HCl (1N), water, and brine, dried over Na2SO4, filtered and
concentrated. The residue was purified by flash chromatography on silica gel (EtOAc/pentane, 4/6 to 6/4) to
provided 12 mg (75%) of ester 16 : IR (film) 2925, 2854, 1719, 1270, 1526, 1159 cm-1; 1H NMR (CDCl3, 300
MHz) δ 8.30-8.28 (m, 2H), 8.19-8.16 (m, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.56 (dd, J
= 4.6, 11.5 Hz, 1H), 4.49 (dd, J = 7.0, 11.5 Hz, 1H), 3.72-3.68 (m, 1H), 3.65 (dd, J = 7.3, 9.9 Hz, 1H), 3.33
(dd, J = 8.6, 9.7 Hz, 1H), 2.71-2.65 (m, 1H), 2.58-2.51 (m, 1H), 2.41 (s, 3H), 2.21-2.15 (m, 3H), 1.98-1.91
13
(m, 1H), 1.73-1.68 (m, 1H), 1.56 (dd, J = 10.2, 14.6 Hz, 1H); C NMR (75 MHz, CDCl3) δ 208.8, 164.3,
150.7, 144.3, 134.9, 134.0, 130.8, 129.9, 127.4, 123.6, 66.0, 63.6, 50.9, 42.7, 40.7, 36.9, 34.6, 24.6, 21.6;
MS(ESI) m/z 473 (M+H)+, 495 (M+Na)+; HRMS (LTQ-Orbitrap, ESI) Calcd. for C23H24N2NaO7S :
495,12019; Found: 495.11900.
(1S,3aR,7aS)-tert-Butyl
4-Methyl-6-oxo-1-(((triisopropylsilyl)oxy)methyl)hexahydro-1H-isoindole-
2(3H)-carboxylate (17). Methyllithium (1.6 M in ether, 5.2 mL, 8.32 mmol) was added to a suspension of
°
CuCN (0.374 g, 4.17 mmol) in THF (5 mL) at –78 C. The solution was stirred for 30 min and allowed to
warm to 0 °C. A solution of enone 14 (0.82 g, 1.94 mmol) and TMSCl (1.07 mL, 8.43 mmol) in THF (8 mL)
was then added dropwise to the above solution at –78 °C. The resulting mixture was stirred for 3 h and
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quenched with sat. aq. NH4Cl, before being allowed to warm to room temperature. The layers were separated
and the aqueous layer was extracted with ether. The combined organic layers were washed with sat. aq.
NH4Cl and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was then
dissolved in THF (15 mL) and stirred overnight with 1N HCl (5 mL). The solution was extracted with ether
and the combined organic layers were washed with sat. aq. NaHCO3 and brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (25:75
Et2O-pentane) provided 0.76 g (89%) of ketone 17 : [α]20D –10.0 (c 0.42, CHCl3); IR (film) 2944, 2865, 1716,
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1698, 1694, 1682, 1463, 1397, 1365, 1253, 1159, 1118, 882 cm-1; 1H NMR (CDCl3, 300 MHz, 2 rotamers) δ
4.10−3.32 (m, 5Η), 2.93-2.80 (m, 1H), 2.50-2.27 (m, 3H), 2.26-2.14 (m, 1H), 2.10 and 2.06 (2 d, J = 9.9 Hz,
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1H), 1.98-1.86 (m, 1H), 1.46 (s, 9H), 1.14-0.94 (m, 24H); C NMR (75 MHz, CDCl3) δ 210.8, 154.5, 79.5,
79.2, 63.3, 63.0, 62.0, 50.3, 49.7, 46.0, 42.8, 42.5, 42.0, 41.6, 40.9, 39.6, 32.4, 28.4, 21.0, 17.9, 11.8;
MS(DCI, NH3/isobutane) m/z 440 (M + H)+, 384 (100%), 340; HRMS (LTQ-Orbitrap, ESI) Calcd. for
C24H45NO4SiNa : 462.30101; Found: 462.30147.
(2S,3S,4S)-tert-Butyl
4-(1-Hydroxypropan-2-yl)-3-(2-methoxy-2-oxoethyl)-2-(((triisopropylsilyl)oxy)-
methyl)pyrrolidine-1-carboxylate (18). To a solution of ketone 17 (762 mg, 1.73 mmol) in CH2Cl2 (15 mL)
was added m-CPBA (77% purity, 777 mg, 3.47 mmol) and the solution was stirred for 72 h at room
temperature. Sodium sulfite was added and the mixture was extracted with Et2O. The combined organic
phases were washed with NaHCO3, dried over Na2SO4, filtered and evaporated under reduced pressure.
Purification of the residue by flash chromatography afforded 698 mg (88%) of a 1.1 :1 mixture of inseparable
isomeric lactones. A solution of the lactones (649 mg, 1.42 mmol) in THF (15 mL) at –78 °C was treated
with a freshly prepared solution of NaOMe (2.9 M in MeOH, 1 mL, 2.9 mmol). After stirring for 1 h, the
reaction mixture was quenched with aqueous NH4Cl and the aqueous phase extracted with Et2O. The
combined organic phases were washed with brine and dried over Na2SO4, and the volatiles were removed
under reduced pressure. Purification of the residue by flash chromatography (60:40 Et2O-pentane) provided
642 mg (92%) of the regioisomeric esters 18 and 19. A small amount of pure 18, obtained in a column
fraction, was used for analysis : [α]20D –42.4 (c 0.33, CHCl3); IR (film) 3053, 2944, 2866, 1731, 1681, 1403,
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1366, 1265, 1171, 1120, 1084, 1022, 895 cm-1; H NMR (CDCl3, 300 MHz, 2 rotamers) δ 4.02-3.94, 3.80-
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3.56 and 3.54-3.32 (3 m, 7H), 3.67 (s, 3H), 3.10-2.93 (m, 1H), 2.79-2.66 (m, 1H), 2.60-2.32 (m, 2H), 2.24-
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2.10 (m, 1H), 1.70-1.56 (m, 1H), 1.44 (s, 9H), 1.15-0.97 (m, 21H), 0.94 (d, J = 6.4 Hz, 3H); C NMR (75
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MHz, CDCl3) δ 173.2, 154.5, 154.3, 79.5, 79.1, 66.47, 66.40, 64.9, 64.7, 63.7, 51.6, 49.3, 48.9, 41.9, 40.9,
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38.9, 38.4, 34.6, 33.2, 33.1, 28.4, 17.9, 17.8, 15.9, 15.8 11.8; MS(DCI, NH3/isobutane) m/z 487, 432, 400,
388 (100%), 356, 200; Anal. Calcd. for C25H49NO6Si: C, 61.57; H, 10.13; N, 2.88. Found: C, 61.56; H,
10.13; N, 2.71.
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(2S,3S,4S)-tert-Butyl 3-(2-Methoxy-2-oxoethyl)-4-(1-(phenylselanyl)propan-2-yl)-2-(((triisopropylsilyl)-
oxy)methyl)pyrrolidine-1-carboxylate (20) and (2S,3S,4R)-tert-Butyl 4-(4-Methoxy-4-oxobutan-2-yl)-3-
((phenylselanyl)methyl)-2-(((triisopropylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (21). A solution of
esters 18 and 19 (376 mg, 0.77 mmol) and triethylamine (0.322 mL, 2.3 mmol) in THF (10 mL) at room
temperature was treated with methanesulfonyl chloride (0.119 mL, 1.54 mmol) and stirred for 20 h. Water
was then added and the organic phase extracted with Et2O. The combined organic phases were washed with
KHSO4, NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. To a
solution of the residue and PhSeSePh (240 mg, 1.54 mmol) in MeOH (12 mL) was added NaBH4 (60 mg, 3.1
mmol) and the solution was heated to 70 °C for 2 h. The reaction mixture was allowed to cool, water was
added, and the organic phases was extracted with Et2O. The combined organic phases were washed with
brine, dried over Na2SO4, and concentrated under reduced pressure. Purification of the residue by flash
chromatography (30:70 Et2O-pentane) provided 435 mg (90%) of an inseparable 1.1 :1 mixture of the
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selenides 20 and 21 :IR (film) 3053, 2943, 2865, 1737, 1691, 1477, 1462, 1400, 1265, 1173, 1121 cm-1; H
NMR (300 MHz, CDCl3) δ 7.57-7.54 (m, 2H), 7.29-7.25 (m, 3H), 3.98 (dd, J = 10.0, 4.2 Hz, 0.45H), 3.78-
3.69 (m, 1.55H), 3.67 and 3.66 (2 s, 3H), 3.61-3.56 (m, 1H), 3.52-3.44 (m, 1H), 3.12 and 3.09 (2 br s, 1H),
2.99 and 2.88 (2 t, J = 10.7 Hz, 1H), 2.76-69 (m, 1H), 2.67-2.53 (m, 1.45H), 2.50-2.40 (m, 0.55H), 2.06-1.95
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(m, 2H), 1.63-1.50 (m, 1H), 1.46 (s, 9H), 1.13-1.05 (m, 24H); C NMR (75 MHz, CDCl3) δ 172.9, 154.3,
154.1, 133.4, 130.0, 128.9, 127.1, 127.0, 79.4, 78.9, 64.7, 64.4, 63.7, 51.4, 49.3, 48.9, 44.9, 43.8, 38.7, 38.2,
34.5, 34.4, 33.0, 32.5, 32.3, 28.3, 18.6, 18.5, 17.9, 17.8, 11.75 ; MS(ESI) m/z 650.3 (M+Na)+, 628.4 (M+H)+;
HRMS (LTQ-Orbitrap, ESI) Calcd. for C31H53NO5SeSiNa: 650.27504; Found:650.27528.
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(2S,3S,4S)-tert-Butyl
3-(2-Methoxy-2-oxoethyl)-4-(prop-1-en-2-yl)-2-(((triisopropylsilyl)oxy)methyl)-
pyrrolidine-1-carboxylate (22) and (2S,4R)-tert-Butyl 4-(4-Methoxy-4-oxobutan-2-yl)-3-methylene-2-
(((triisopropylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (23). A solution of selenides 20 and 21 (415 mg,
0.66 mmol) and triethylamine (0.277 mL, 2.0 mmol) in THF (10 mL) was treated with H2O2 (8.8 M in water,
0.30 mL, 2.6 mmol) and heated at 65 °C for 4 h. The reaction mixture was allowed to cool, water was added,
and the aqueous phase was extracted with Et2O. The combined organic phases were washed with aqueous
KHSO4, NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
Purification of the residue by flash chromatography provided 155 mg (50%) of 22 and 135 mg (43 %) of 23.
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Data for 22 : H NMR (300 MHz, CDCl3, 2 rotamers) δ 4.82 and 4.81 (2 s, 1H), 4.51 and 4.57 (2 s, 1H),
3.99 (dd, J = 10.0, 3.9 Hz, 0.45 H), 3.77-3.67 (m, 1.55H), 3.59 and 3.58 (2 s, 3H), 3.52 (br s, 1H), 3.38-3.25
(m, 2H), 3.28 (app q, J = 9.8 Hz, 0.45H), 3.18 (app q, J = 7.5 Hz, 0.55H), 2.82 -2.76 (m, 1H), 2.20-2.02 (m,
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2H), 1.65 (s, 3H), 1.38 (s, 9H), 1.00-0.95 (m, 21H); C NMR (75 MHz, CDCl3, 2 rotamers) 173.2, 142.6,
142.0, 112.3, 111.9, 79.6, 79.2, 64.2, 63.7, 52.5, 48.1, 47.5, 45.7, 44.8, 39.6, 38.8, 33.6, 28.5, 22.5, 18.0, 11.9;
MS(ESI) m/z 492.4 (M+Na)+, 470.4 (M+H)+; HRMS (LTQ-Orbitrap, ESI) Calcd. for C25H47NO5SiNa:
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492.31157; Found: 492.31152. Data for 23 : H NMR (CDCl3, 300 MHz) δ 5.08 (br s, 1H), 4.94 (br s 1H),
4.25-4.05 (m, 1.4H), 3.85-3.65 (m, 1.6H), 3.60 (s, 3H), 3.40-3.25 (m, 2H), 2.72 (br s, 1H), 2.35-2.05 (m, 3H),
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1.38 (s, 9H), 1.00-0.95 (m, 21H), 0.81 (d, J = 6.5 Hz, 3H); C NMR (75 MHz, CDCl3, 2 rotamers) 173.2,
154.0, 150.6, 150.1, 112.3, 111.8, 107.5, 107.1, 79.5, 79.2, 65.8, 65.2, 64.2, 63.7, 63.3, 51.5, 51.4, 48.1, 47.6,
47.0, 46.5, 45.7, 44.8, 40.0, 39.6, 38.8, 33.6, 32.4, 28.5, 22.5, 18.1, 17.9, 14.5, 12.2, 11.9, 11.6; MS(ESI) m/z
492.4 (M+Na)+, 470.4 (M+H)+. HRMS (LTQ-Orbitrap, ESI) calcd. for C25H47NO5SiNa: 492.31157. Found :
492.31078.
(S)-1-tert-Butyl 2-Methyl 4-(Trifluoromethylsulfonyloxy)-2H-pyrrole-1,2(5H)-dicarboxylate (25)20. To a
stirred solution of NaHMDS (1.0 M in THF, 33.9 mL, 33.9 mmol) in THF (20 mL) at –78 °C was added
slowly the ketone20 derived from 24 (7.50 g, 30.8 mmol) in THF (15 mL). The reaction mixture was stirred
for 30 min and then treated over 15 min with a solution of PhNTf2 (12.12 g, 33.9 mmol) in THF (25 mL).
The resulting mixture was stirred for 1.5 h at –78 °C, allowed to warm to 0 °C, and then quenched by the
addition of water (25 mL). The mixture was extracted with ether, and the organic layer was washed with
brine and dried over Na2SO4. Evaporation of the solvent under reduced pressure and purification of the
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residue on silica gel (15:85 EtOAc-pentane) afforded 9.85 g (85%) of triflate 2520: [α]20 –125.2 (c 1.1,
D
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CHCl3); IR (film) 1762, 1720, 1637, 1213, 1140, 1119, 1000 cm-1; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ
5.74-5.72 and 5.69-5.67 (2 m, 1H), 5.05-5.03 and 5.00-4.97 (2 m, 1H), 4.39-4.25 (m, 2H), 3.75 (s, 3H), 1.46
and 1.41 (2 s, 9H); 13C NMR (75 MHz, CDCl3, 2 rotamers) δ 169.5, 169.2, 153.1, 152.5, 146.2, 145.7, (124.8,
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120.5, 116.3, 112.0) CF3, 111,3, 111.1, 81.4, 81.3, 63.6, 63.1, 52.7, 52.5, 50.3, 50.0, 28.2, 28.1; MS (ESI+)
m/z 398 (M + Na+), 321, 307 (100%); HRMS (LTQ-Orbitrap, ESI) Calcd. for C12H16F3NO7SNa: 398.0497.
Found 398.0492 (M+Na+).
(S)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (26). To a
solution of triflate 25 (11.88 g, 31.65 mmol) in 8:2 THF-H2O (80 mL) at 20 °C was added (PPh3)4Pd (0.915 g,
0.79 mmol), and CO was then bubbled through the solution using a needle attached to a CO-filled balloon for
20 min. A slightly positive pressure of CO was maintained for 1 h, after which CO was again bubbled for 5
min through the solution, which was then stirred for another 2 h under positive pressure of CO. After
replacing the CO with argon, water was added and the mixture was extracted with ether, and the organic layer
was extracted with aqueous NaHCO3. This basic aqueous phase was acidified to pH 2 with 2 N HCl and then
extracted with ether, which was washed with brine, dried over Na2SO4, and concentrated to afford 8.05 g
(94%) of acid ester 26 as a white solid: mp 110-112 °C; [α]20D –202.5 (c 0.7, CHCl3); IR (film) 1737, 1720,
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1632, 1175, 1087, 996 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 8.51 (br s, 1H), 6.68-6.66 and 6.63-
6.61 (2 m, 1H), 5.23-5.19 and 5.12-5.08 (2 m, 1H), 4.41-4.34 (m, 2H), 3.72 (s, 3H), 1.44 and 1.38 (2 s, 9H);
13C NMR (75 MHz, CDCl3, 2 rotamers) δ 169.3, 169.0, 165.6, 165.5, 153.8, 153.2, 135.6, 135.4, 134.7,
134.6, 81.1, 67.3, 66.9, 52.7, 52.6, 52.2, 51.9, 28.2, 28.1; MS (DCI, NH3/isobutane) m/z 270 (100%), 224,
133. Anal. Calcd. for C12H17NO6: C, 53.13; H, 6.32; N, 5.16. Found: C, 52.79; H, 6.18; N, 5.20.
(S)-1-tert-Butyl 2,4-Dimethyl 1H-Pyrrole-1,2,4(2H,5H)-tricarboxylate (27). To a solution of the above
acid ester 26 (6.26 g, 23.1 mmol) in ether (60 mL) at 0 °C was added ethereal diazomethane (ca. 0.3 M, 88
mL, 26 mmol). After 15 min, the solvent was removed under reduced pressure and the crude product was
purified by chromatography on silica gel (25:75 EtOAc-pentane) to afford 6.20 g (94%) of diester 27 as a
white solid: mp 41-43 °C; [α]20D –214.2 (c 0.6, CHCl3); IR (film) 1762, 1730, 1709, 1245, 1168, 1091, 1003
cm-1; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 6.64-6.61 and 6.60-6.57 (2 m, 1H), 5.21-5.17 and 5.13-5.09
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(2 m, 1H), 4.45-4.37 (m, 2H), 3.78 (s, 3H), 3.76 and 3.75 (2 s, 3H), 1.48 and 1.43 (2 s, 9H); C NMR (75
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67.0, 66.7, 52.4, 52.3, 52.2, 52.0, 51.82, 51.80, 28.1, 28.0; MS (ESI+) m/z 292 (M + Li+), 239 (100%). Anal.
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Calcd. for C13H19NO6: C, 54.73; H, 6.71; N, 4.91. Found: C, 54.84; H, 6.82; N, 4.87.
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(1S)-2-tert-Butyl 1,3a-Dimethyl 6-Oxo-3,3a-dihydro-1H-isoindole-1,2,3a(6H,7H,7aH)-tricarboxylate
(30). A solution of diester 27 (4.72 g, 16.6 mmol) and Danishefsky’s diene (4.84 mL, 24.9 mmol, distilled
under reduced pressure in the presence of a slight excess of trichlorophenol relative to the remaining
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triethylamine, estimated by H NMR) in dichloromethane (0.5 mL) was placed in a teflon ampoule, which
was then closed (completely filled, no air bubbles). The ampoule was then subjected to a pressure of 15 kbar
for 72 h. After this time the pressure was released and the reaction mixture was added to THF (25 mL) and
saturated aqueous KHSO4 (20 mL). After being stirred for 30 minutes, the mixture was extracted with ether,
and the organic layer was washed with brine and dried over Na2SO4. Evaporation of the solvent under
reduced pressure and purification of the residue by chromatography on silica gel (35:65 EtOAc-pentane)
afforded 1.46 g (23%) of the intermediate β-methoxy ketone 32 and 3.63 g (62%) of the desired enone diester
(30). The former was converted in 81% yield to the latter on refluxing in toluene in the presence of a
catalytic amount of DBU (0.05 mL, 0.3 mmol) for 7 h. Enone diester 30 (90% ee by HPLC)22: [α]20D –6.6 (c
1
1.2, CHCl3); IR (film) 1755, 1735, 1701, 1681, 1158, 1128, 1074, 1020 cm-1; H NMR (300 MHz, CDCl3, 2
rotamers) δ 6.74-6.67 (m, 1H), 6.16 (d, J = 10.0 Hz, 1H), 4.02-3.77 (m, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.28-
3.23 (m, 1H), 2.88 and 2.82 (2 d, J = 5.4 Hz, 1H), 2.71-2.61 (m, 1H), 1.44 and 1.37 (2 s, 9H); 13C NMR (75
MHz, CDCl3, 2 rotamers) δ 194.6, 194.3, 171.6, 171.3, 169.6, 169.5, 153.1, 152.6, 146.2, 145.8, 131.9, 131.7,
80.6, 62.4, 62.2, 55.5, 55.1, 52.9, 52.8, 52.2, 52.0, 51.8, 51.0, 44.6, 43.7, 35.5, 28.0, 27.8; MS (ESI+) m/z 376
(M + Na+, 100%), 354 (MH+). Anal. Calcd. for C17H23NO7: C, 57.78; H, 6.56; N, 3.96. Found: C, 57.41; H,
6.57; N, 3.86.
(1S)-2-(tert-Butoxycarbonyl)-6-oxo-2,3,3a,6,7,7a-hexahydro-1H-isoindole-1,3a-dicarboxylic Acid (33).
A solution of enone diester 30 (3.10 g, 8.78 mmol) in THF (30 mL) was treated with LiOH (2 N, 20 mL) and
the reaction mixture was stirred for 1.5 h, whereupon water and ether were added. The separated aqueous
layer was treated with 2 N HCl to pH 2 and then extracted with ether and EtOAc. These organic extracts
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were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to provide
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2.80 g (98%) of enone diacid 33. Recrystallization of this material from hot hexane-EtOAc afforded with
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82% recovery the enantiopure (ee >99%)23 enone diacid 33: mp 116-117 °C (dec); [α]20 –21.7 (c 0.5,
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CHCl3); IR (film) 1737, 1719, 1683, 1675, 1650, 1242, 1162 cm-1; 1H NMR (300 MHz, CD3OD, 2 rotamers)
δ 6.93 (app.dd, J = 1.8, 10.2 Hz, 1H), 6.20 (d, J = 10.2 Hz, 1H), 4.00-3.83 (m, 3H), 3.30-3.24 (m, 1H), 2.98
and 2.96 (2 d, J = 17.7 Hz, 1H), 2.71 and 2.66 (2 dd, J = 2.3, 17.7 Hz, 1H), 1.49 and 1.43 (2 s, 9H); 13C NMR
(75 MHz, CD3OD) δ 198.3, 175.7, 175.3, 173.0, 156.2, 155.9, 150.2, 150.1, 133.3, 133.2, 83.2, 83.0, 65.1,
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64.7, 57.9, 57.4, 54.4, 53.7, 47.2, 46.5, 37.7, 37.6, 29.5, 29.3; MS (DCI, NH3/isobutane) m/z 325 (100%),
214, 180; HRMS (LTQ-Orbitrap, ESI) Calcd. for C15H19NO7Na: 348.1059. Found 348.1054 (M+Na+).
(1S)-2-tert-Butyl 1-Methyl 6-Oxo-5,6,7,7a-tetrahydro-1H-isoindole-1,2(3H)-dicarboxylate (34). To enone
diacid 33 (0.932 g, 2.86 mmol) in toluene (10 mL) was added dry pyridine (1.20 mL, 14.8 mmol). The
reaction mixture was refluxed for 2.5 h and then cooled to 0 °C and acidified with 2 N HCl to pH 2. The
mixture was extracted with ether, and the organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give 0.782 g of crude enone acid. An analytical sample was obtained
from a comparable sample by chromatography on silica gel (80:20:0.5 EtOAc-pentane-AcOH): mp 136 °C
(dec); [α]20D +53.4 (c 0.5, CHCl3); IR (film) 3468, 1730, 1719, 1707, 1683, 1253, 1169, 1028 cm-1; 1H NMR
(300 MHz, CDCl3, 2 rotamers) δ 9.24 (br s, 1H), 5.76 (br s, 1H), 4.23-3.98 (m, 3H), 3.20 (br s, 1H), 3.01-2.76
(m, 3H), 2.47-2.27 (m, 1H), 1.46 and 1.42 (2 s, 9H); 13C NMR (75 MHz, CDCl3, 2 rotamers) δ 207.1, 176.7,
174.8, 153.5, 137.1, 136.4, 116.5, 81.4, 65.4, 50.4, 49.9, 43.8, 42.8, 42.6, 38.4, 28.1; MS (ESI+) m/z 304 (M +
Na+, 100%), 272, 248, 226. Anal. Calcd. for C14H19NO5: C, 59.78; H, 6.81; N, 4.98. Found: C, 59.53; H,
6.76; N, 4.99. A solution of crude enone acid (0.782 g) in ether (10 mL) at 0 °C was treated with ethereal
CH2N2 (ca. 0.3 M, 10 mL). After 20 min, the solvent was removed under reduced pressure and the crude
product was purified by chromatography on silica gel (40:60 EtOAc-pentane) to give 0.700 g (83%, 2 steps)
of enone ester 34: mp 67-69 °C; [α]20D +57.0 (c 0.5, CHCl3); IR (film) 1750, 1740, 1719, 1709, 1685, 1160,
1022, 998 cm-1; 1H NMR (300 MHz, CDCl3, 2 rotamers) δ 5.75 (br s, 1H), 4.22-4.12 (m, 2H), 4.05-3.95 (m,
1H), 3.75 (s, 3H), 3.14-2.75 (m, 4H), 2.43 and 2.38 (2 d, J = 12.0, 12.3 Hz, 1H), 1.45 and 1.41 (2 s, 9H); 13C
NMR (75 MHz, CDCl3, 2 rotamers) δ 206.7, 171.9, 171.6, 153.0, 152.9, 136.5, 116.2, 116.1, 80.4, 65.4, 65.0,
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52.0, 50.0, 49.7, 43.6, 42.8, 42.6, 38.2, 28.0; MS (ESI+) m/z 318 (M + Na+, 100%). Anal. Calcd. for
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C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C, 60.70; H, 7.18; N, 4.59.
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(1S,3aR,7aS)-2-tert-Butyl 1-Methyl 6-Oxo-3,3a,7,7a-tetrahydro-1H-isoindole-1,2(6H)-dicarboxylate
(35). A solution of enone ester 34 (0.700 g, 2.37 mmol) and DBU (0.050 mL, 0.33 mmol) in CH2Cl2 (5.0
mL) at 20 °C under argon was stirred for 4 h, whereupon at 0 °C 2 N HCl was added to pH 2. The mixture
was extracted with CH2Cl2, and the organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (60:40
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EtOAc-pentane) afforded 0.607 g (87%) of enone ester 35: [α]20 –116.1 (c 0.5, CHCl3); IR (film) 1755,
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1686, 1675, 1122, 1025, 859 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 6.77 and 6.74 (2 dd, J = 4.3,
10.2 Hz, 1H), 6.13-6.07 (m, 1H), 4.09 and 3.96 (2 d, J = 5.1, 6.6 Hz, 1H), 3.90-3.80 (m, 1H), 3.75 (s, 3H),
3.66, 3.33 and 3.54-3.47 (2 dd + m, J = 3.8, 10.7 Hz, 1H), 3.20-3.08 (m, 1H), 2.97-2.85 (m, 1H), 2.65 (d, J =
13
5.3 Hz, 2H), 1.46 and 1.39 (2 s, 9H); C NMR (75 MHz, CDCl3, 2 rotamers) δ 195.2, 171.8, 171.4, 153.2,
152.6, 148.5, 147.8, 130.0, 129.9, 79.6, 62.2, 62.1, 51.6, 51.5, 50.7, 42.0, 41.2, 37.1, 37.0, 36.8, 36.6, 27.6,
27.5; MS (ESI+) m/z 302 (M + Li+, 100%), 246. Anal. Calcd. for C15H21NO5: C, 61.00; H, 7.17; N, 4.74.
Found: C, 60.76; H, 7.29; N, 4.59.
(2R,3S,4S)-1-tert-Butyl 2-Methyl 3-(2-Methoxy-2-oxoethyl)-4-(1-(trifluoromethylsulfonyloxy)prop-1-en-
2-yl)pyrrolidine-1,2-dicarboxylate (37'). An argon-flushed flask was charged with CuCN (0.495 g, 5.53
mmol) and THF (10 mL) was added. The flask was cooled to –78 °C and MeLi (1.6 M in ether, 6.9 mL, 11.0
mmol) was added slowly. Stirring was continued for 30 min at –78 °C and then a mixture of enone ester 35
(0.544 g, 1.84 mmol) and TMSCl (1.42 mL, 11.11 mmol) in THF (6 mL) was added. After 45 min at –78 °C,
the reaction mixture was quenched by the addition of an aqueous solution of NH4Cl–NH4OH. The mixture
was extracted with ether, and the organic layer was washed with brine and dried over Na2SO4. The solvent
was removed under reduced pressure to give the crude enol ether (0.683 g), which was used directly for the
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next reaction. Enol ether 36: H NMR (300 MHz, CDCl3, 2 rotamers) δ 4.75-4.70 (m, 1H), 4.02 and 3.89 (2
d, J = 5.8, 7.6 Hz, 1H), 3.74 and 3.73 (2 s, 3H), 3.85-3.52 (m, 1H), 3.44-3.37 and 3.27-3.22 (2 m, 1H), 2.58
and 2.48 (2 m, 1H), 2.32-2.21 (m, 1H), 2.16-1.80 (m, 3H), 1.45 and 1.39 (2 s, 9H), 1.01 (d, J = 6.6 Hz, 3H),
0.19 and 0.18 (2 s, 9H). A stream of O3 in O2 was bubbled through a solution of 0.675 g of the above crude
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enol ether in CH2Cl2-MeOH (3:1, 10 mL) at –116 °C. When the blue color persisted (ca. 10 min), dimethyl
sulfide (1.5 mL) was added and reaction mixture was allowed to warm to 20 °C and was stirrred for 2 h. The
solvents were then removed under reduced pressure and the residue was taken up in ether, and the organic
layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give
the the crude aldehyde acid (0.712 g), which was used directly for the next step. A solution of the above
crude aldehyde acid (0.712 g) in ether (10 mL) was cooled to 0 °C and treated with ethereal CH2N2 (ca. 0.3
M, 8.3 mL). After 15 min, the solvent was removed under reduced pressure and the crude product was
purified by chromatography on silica gel (40:60 EtOAc-pentane) to afford 0.453 g (70%, 3 steps) of unstable
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aldehyde ester 37: IR (film) 1740, 1697, 1206, 1167, 1002, 898 cm-1; H NMR (300 MHz, CDCl3, 2
rotamers) δ 9.56 (br s, 1H), 4.22-4.12 (m, 1H), 3.87-3.63 (m, 2H), 3.74 (s, 3H), 3.69 (s, 3H), 3.37-3.30 and
3.16-3.04 (2 m, 1H), 2.97-2.87 and 2.72-2.58 (2 m, 1H), 2.50-2.18 (m, 3H), 1.45 and 1.39 (2 s, 9H), 1.13 (d, J
= 7.1 Hz, 3 H). To a stirred solution of KHMDS (0.065 g, 0.33 mmol) in THF (3 mL) at –78 °C was added
aldehyde ester 37 (0.053 g, 0.15 mmol) in THF (2 mL). After 15 min, the reaction mixture was treated with a
solution of 2-[N,N-bis-(trifluoromethylsulfonyl)amino]-5-chloropyridine (0.128 g, 0.33 mmol) in THF (3
mL), stirred for 1.5 h, and then allowed to warm to 0 °C. An aqueous solution of NH4Cl–NH4OH was added
and the mixture was extracted with ether, and the organic layer was washed with brine and dried over
Na2SO4. The solvent was removed under reduced pressure to yield the crude product, which was purified by
chromatography on silica gel (15:85 EtOAc-pentane) to afford the 0.046 g (63%) of enol triflate 37´ and
0.005 g of the starting aldehyde ester. Enol triflate 37´: [α]20 –37.8 (c 1.1, CHCl3); IR (film) 3100, 1751,
D
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1730, 1704, 1686, 1140, 1057, 1018 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 6.49, 6.36 (2 s, 1H),
4.00-3.90 (m, 1H), 3.76-3.55 (m, 9H), 3.13-2.87 (m, 1H), 2.58-2.27 (m, 2H), 1.71 and 1.61 (2 d, J = 1.5 Hz,
3H), 1.45 and 1.39 (2 s, 9H); 13C NMR (75 MHz, CDCl3, 2 rotamers) δ 172.2, 172.0, 171.6, 171.1, 153.6,
153.0, 132.6, 132.5, 125.6, 125.5, (124.8, 120.6, 116.3, 112.1) CF3, 80.76, 80.71, 63.5, 63.4, 63.14, 63.0,
52.42, 52.37, 52.26, 52.20, 51.92, 51.89, 48.7, 48.3, 43.0, 42.9, 42.13, 42.10, 38.7, 37.8, 33.2, 33.1, 32.9,
32.8, 28.3 28.1; MS (ESI+) m/z 496 (M + Li+, 100%), 344; HRMS (LTQ-Orbitrap, ESI) Calcd. for
C18H26F3NO9SNa: 512.1178. Found 512.1173 (M+Na+).
(2S,3S,4S)-1-tert-Butyl
2-Methyl
3-(2-Methoxy-2-oxoethyl)-4-(prop-1-en-2-yl)pyrrolidine-1,2-
dicarboxylate (38). A mixture of enol triflate 37´ (0.105 g, 0.21 mmol), LiCl (0.027 g, 0.64 mmol),
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(PPh3)4Pd (0.050 g, 0.04 mmol), and triethylsilane (0.075 g, 0.64 mmol) in DMF (3.0 mL) was stirred at 55
°C for 2 h, whereupon it was allowed to cool to 20 °C and ether and water were added. The mixture was
extracted with ether, and the organic layer was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by chromatography on silica gel (15:85 EtOAc-pentane) to give
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0.070 g (96%) of olefin 38: [α]20 –20.0 (c 0.7, CHCl3); IR (film) 3085, 1737, 1701, 1206, 1169, 1130,
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1007, 898 cm-1; H NMR (300 MHz, CDCl3, 2 rotamers) δ 4.91 and 4.69 (2 s, 2H), 4.16 and 4.06 (2 d, J =
3.3, 3.8 Hz, 1H), 3.79-3.62 (m, 7H), 3.52-3.38 (m, 1H), 3.07-2.97 and 2.89-2.79 (2 m, 2H), 2.40-2.21 (m,
13
2H), 1.69 (s, 3H), 1.46 and 1.40 (2 s, 9H); C NMR (75 MHz, CDCl3, 2 rotamers) δ 172.6, 172.4, 172.3,
172.2, 153.7, 153.6, 141.3, 141.2, 113.3, 113.1 80.2, 63.9, 63.6, 52.2, 52.1, 51.7, 47.8, 47.5, 45.9, 45.2, 41.8,
40.9, 32.9, 28.3 28.1, 22.2, 22.1; MS (ESI+) m/z 348 (M + Li+, 100%), 303, 261; HRMS (LTQ-Orbitrap, ESI)
Calcd. for C17H27NO6Na: 364.1736. Found 364.1731 (M+Na+).
(2S,3S,4S)-3-(Carboxymethyl)-4-(prop-1-en-2-yl)pyrrolidine-2-carboxylic Acid (Kainic Acid) (1).
A
solution of olefin 38 (0.0360 g, 0.105 mmol) in THF (1.5 mL) at 0 °C was treated with 2 N LiOH (15 mL)
and then stirred for 10 h at 20 °C. The reaction mixture was acidified with 2 N HCl to pH 3 and extracted
with ethyl acetate, which was dried over Na2SO4 and concentrated. Dichloromethane (2 mL) and TFA (0.106
mL, 1.43 mmol) were added to the residue, and the resulting reaction mixture was stirred for 10 h. After
removal of the solvent, the crude product was purified on Dowex-50 (WX8-200, H+ form), eluting with
NH4OH (0.1-0.5 N), to afford 0.0206 g of slightly impure kainic acid. Recrystallization of this material from
MeOH-H2O provided the analytical sample (0.0168 g, 75%): mp 241-243 °C; [α]20D –14.3 (c 0.16, H2O); 1H
NMR (300 MHz, D2O) δ 5.11 (s, 1H), 4.82 (s, 1H), 4.15 (d, J= 3.1 Hz, 1H), 3.70 (dd, J= 11.7, 7.4 Hz, 1H)
3.50 (dd, J= 11.7, 10.5 Hz, 1H), 3.18-3.03 (m, 2H), 2.45 (dd, J= 15.6, 6.4 Hz, 1H), 2.34 (dd, J= 15.6 8.2 Hz,
13
1H), 1.83 (s, 3H); C NMR (75 MHz, D2O) δ 179.8, 174.0, 140.6, 113.3, 66.2, 46.7, 46.2, 42.1, 36.2, 22.5.
This material was spectroscopically and chromatographically indistinguishable from a commercial sample of
the natural product.
Acknowledgement.
We thank the CNRS and the French Ministry of Research for financial support (UMR 5250). A
Chateaubriand fellowship (to A. O.) from the French Ministry of Research is gratefully acknowledged.
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Supporting Information.
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1H and 13C NMR spectra for all new compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
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References.
1 Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953, 73, 1026-1028. (–)-Kainic acid has also
been isolated from Centrocerus clavulatum (Impellizzeri, G.; Mangiafico, G.; Oriente, G.; Piattelli, M.;
Sciuto, S.; Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D. Phytochemistry 1975, 14, 1549-1557) and from
Alsidum helmithocorton (Balansard, G.; Pellegrini, M.; Cavalli, C.; Timon-David, P. Ann. Pharm. Fr. 1983,
41, 77-86).
2 Since the beginning of 2006, over 300 papers have been published on the use of kanic acid for the study of
various neuronal disorders.
3 Shortage of Kainic Acid Hampers Neuroscience Research. Chem. Eng. News 2000, 78 (1), 14-15.
4 Producers Strive to Bring Kainic Acid Back on the Market. Chem. Eng. News 2000, 78 (10), 31.
5 For selected references, see: (a) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978. (b) Cooper,
J.; Knight, D. W.; Gallagher, P. T. J. Chem Soc., Chem. Commun. 1987, 1220. (c) Takano, S.; Sugihara, T.;
Satoh, S.; Ogasawara, K. J. Am. Chem. Soc. 1988, 110, 6467. (d) Takano, S.; Iwabuchi, Y.; Ogasawara, K. J.
Chem Soc., Chem. Commun. 1988, 1204. (e) Yoo, S.-E.; Lee, S.-H.; Yi, K.-Y.; Jeong, N. Tetrahedron Lett.
1990, 31, 6877. (f) Baldwin, J. E.; Monoley, M. G.; Parsons, A. F. Tetrahedron 1990, 46, 7263. (g) Barco,
A.; Benetti, S.; Pollini, G. P.; Spalluto, G.; Zanirato, V. J. Chem Soc., Chem. Commun. 1991, 390. (h) Barco,
A.; Benetti, S.; Spalluto, G. ; Casolari, A. ; Pollini, G. P. ; Zanirato, V. J. Org. Chem. 1992, 57, 6279. (i)
Cooper, J.; Knight, D. W.; Gallagher, P. T. J. Chem Soc., Perkin Trans.1 1992, 553. (j) Takano, S.; Inomata,
K.; Ogasawara, K. J. Chem Soc., Chem. Commun. 1992, 169. (k) Yoo., S.-E.; Lee, S.-H.; Jeong, N.; Cho, I.
Tetrahedron Lett. 1993, 34, 3435. (l) Hatakeyama, S.; Sugawara, K.; Takano, S. J. Chem Soc., Chem.
Commun. 1993, 125. (m) Monn, J. A.; Valli, M. J. J. Org. Chem. 1994, 59, 2773. (n) Yoo, S.-E.; Lee, S. H. J.
Org. Chem. 1994, 59, 6968. (o) Hanessian, S.; Ninkovic, S. J. Org. Chem. 1996, 61, 5418. (p) Miyata, O.;
Ozawa, Y.; Ninomiya, I.; Naito, T. Synlett 1997, 275. (q) Nakada, Y.; Sugahara, T.; Ogasawara, K.
Tetrahedron Lett. 1997, 38, 857. (r) Bachi, M. D.; Melman, A. J. Org. Chem. 1997, 62, 1896. (s) Bachi, M.
D.; Melman, A. Pure Appl. Chem. 1998, 70, 259. (t) Cossy, J.; Cases, M.; Pardo, D. G. Synlett 1998, 507. (u)
Rubio, A.; Ezquerra, J.; Escribano, A., Remuiñán, M. J. ; Vaquero ; J. J. Tetrahedron Lett. 1998, 39, 2171.
(v) Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139. (w) Cossy, J.; Cases, M.; Pardo,
D. G. Tetrahedron 1999, 55, 6153. (x) Campbell, A. D.; Taylor, R. J. K.; Raynham, T. M. Chem Commun.
1999, 245. (y) Nakagawa, H.; Sugahara, T.; Ogasawara, K. Org. Lett. 2000, 2, 3181. (z) Miyata, O.; Ozawa,
Y.; Ninomiya, I.; Naito, T. Tetrahedron 2000, 56, 6199. (aa) Campbell, A. D.; Raynham, T. M.; Taylor, R. J.
K. J. Chem. Soc., Perkin Trans. 1 2000, 3194. (bb) Hirasawa, H.; Taniguchi, T.; Ogasawara, K. Tetrahedron
Lett. 2001, 42, 7587. (cc) Xia, Qian; Ganem, B. Org. Lett. 2001, 3, 485. (dd) Clayden, J.; Menet, C. J.;
Tchabanenko, K. Tetrahedron 2002, 58, 4727. (ee) Clayden, J.; Menet, C. J.; Mansfield, D. J. Chem
Commun. 2002, 38. (ff) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 1467. (gg) Martinez, M. M.; Hoppe, D.
Org. Lett. 2004, 6, 3743. (hh) Poisson, J.-F.; Orellana, A.; Greene, A. E. J. Org. Chem. 2005, 70, 10860. (ii)
Anderson, J. C.; O’Loughlin, J. M. A.; Tornos, J. A. Org. Biomol. Chem. 2005, 3, 2741. (jj) Martínez, M.
M.; Hoppe, D. Eur. J. Org. Chem. 2005, 1427. (kk) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127,
4763. (ll) Scott, M. E.; Lautens, E. Org. Lett. 2005, 7, 3045. (mm) Morita, Y.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2005, 7, 4337. (nn) Hodgson, D. M.; Hachisu, S.; Andrews, M. D. Org. Lett. 2005, 7, 815. (oo)
Pandey, S. K.; Orellana, A.; Greene, A. E.; Poisson, J.-F. Org. Lett. 2006, 8, 5665. (pp) Thuong, M. B. T.;
Sottocornola, S.; Prestat, G.; Broggini, G.; Madec, D.; Poli, G. Synlett 2007, 1521. (qq) Sakaguchi, H.;
Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 9, 1635. (rr) Chalker, J. M.; Yang, A.; Deng, K.; Cohen, T.
Org. Lett. 2007, 9, 3825. (ss) Jung, Y. C.; Yoon, C. H.; Turos, E.; Yoo, K. S.; Jung, K. W. J. Org. Chem.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2007, 72, 10114. (tt) Tomooka, K.; Akiyama, T.; Man, P.; Suzuki, M. Tetrahedron Lett. 2008, 49, 6327. (uu)
Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2008, 10, 1711. (vv) Farwick, A.; Helmchen, G. Org.
Lett. 2010, 12, 1108. (ww) Kitamoto, K.; Sampei, M.; Nakayama, Y.; Sato, T.; Chida, N. Org. Lett. 2010, 12,
5756. (xx) Takita, S.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2011, 13, 2068. (yy) Lemière, G.;
Sedehizadeh, S.; Toueg, J.; Fleary-Roberts, N.; Clayden, J. Chem. Commun. 2011, 47, 3745. (zz) Lowe, M.
A.; Ostovar, M.; Ferrini, S.; Chen, C. C.; Lawrence, P. G.; Fontana, F.; Calabrese, A. A.; Aggarwal, V. K.
Angew. Chem., Int. Ed. 2011, 50, 6370. (aaa) Wei G., Chalker J. M.; Cohen T. J. Org. Chem. 2011, 76, 7912
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
29
30
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60
6 trans-4-Hydroxy-L-proline, however, has been employed for the synthesis of congeners. See: Remuzon, P.
Tetrahedron 1996, 52, 13803-13835.
7
For reviews on high-pressure Diels-Alder reaction, see: (a) Jenner, G. Tetrahedron 1997, 53, 2669–2695.
(b) Jenner, G. J. Phys. Org. Chem. 2002, 15, 1–13. (c) Matsumoto, K.; Hamana, H.; Iida, H. Helv. Chim. Acta
2005, 88, 2033–2234. See also : (d) High Pressure Chemistry ; van Eldik, R., Kläner, F.-G., Eds.; John Wiley
& Sons, Ltd.: Weinheim, 2002.
8 (a) Dauben, W. G.; Kessel, C. R.; Takemura, K. H. J. Am. Chem. Soc. 1980, 102, 6893. (b) Banwell, M. G. ;
Edwards, A. J. ; Harfoot, G. J. ; Jolliffe, K. A. J. Chem. Soc., Perkin Trans. 1 2002, 2439 (c) Kienzler, M. A.;
Suseno, S.; Trauner, D. J. Am. Chem. Soc. 2008, 130, 8604–8605. (d) Waalboer, D. C. J.; Schaapman, M. C.;
van Delft, F. L.; Rutjes, F. P. J. T. Angew. Chem., Int. Ed. 2008, 47, 6576-6578. (e) Ballerini, E.; Minuti, L.;
Piermatti, O.; Pizzo, F. J. Org. Chem. 2009, 74, 4311–4317. (f) Suzuki T.; Kobayashi S. Org. Lett. 2010, 12,
2920-2923.
9 Six-membered ring dienophiles: (a) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem. Soc.
1979, 101, 6996-7000. (b) Jankowski, C. K.; LeClair, G.; Bélanger, J. M. R.; Paré, J. R. J.; VanCalsteren, M.-
R. Can. J. Chem. 2001, 79, 1906-1909. (c) Boger, D. L.; Patel, M. Tetrahedron Letters 1986, 27, 683-686. (d)
Grieco, P. A.; Lis, R.; Zelle, R. E.; Finn, J. J. Am. Chem. Soc. 1986, 108, 5908-5919. (e) O'Connor, P. D.;
Mander, L. N.; McLachlan, M. M. W. Org. Lett. 2004, 6, 703-706. Acyclic dienophiles: (f) Paczkowski, R.;
Maichle-Mössmer, C.; Maier, M. E. Org. Lett. 2000, 2, 3967-3969.
10
Formyl activation with cyclopentadiene: (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
1561-1562. (b) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998, 120,
6920-6930. (c) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 9992-9993. (d) Sprott, K.
T.; Corey, E. J. Org. Lett. 2003, 5, 2465-2467. (e) Davies, H. M. L.; Dai, X. J. Am. Chem. Soc. 2004, 126,
2692-2693. Formyl activation with Rawal’s diene: (f) Huang, Y.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc.
2000, 122, 7843-7844. Formyl activation of furanoside-type dienophiles: (g) Rehnberg, N.; Sundin, A.;
Magnusson, G. J. Org. Chem. 1990, 55, 5477-5483. (h) Ponten, F.; Magnusson, G. J. Org. Chem. 1997, 62,
7978-7983. Formyl activation of indole dienophiles:(i) Chataigner, I.; Hess, E.; Toupet, L.; Piettre, S. R. Org.
Lett. 2001, 3, 515-518. (j) Chretien, A.; Chataigner, I.; L'Hélias, N.; Piettre, S. R. J.Org. Chem. 2003, 68,
7990-8002.
11 Carbalkoxy activation: (a) Strunz, G. M.; Bethell, R.; Dumas, M. T.; Boyonoski, N. Can. J.Chem. 1997, 75,
742-753. (b) Martin, C.; Mailliet, P.; Maddaluno, J. J.Org. Chem. 2001, 66, 3797-3805. (c) Pichon, N.;
Harrison-Marchand, A.;Mailliet, P.; Maddaluno, J. J. Org. Chem. 2004, 69, 7220-7227
12 Keto activation: (a) Reddy, T. J.; Rawal, V. H. Org. Lett. 2000, 2, 2711-2712. (b) Jung, M. E.; Davidov P.
Angew. Chem., Int. Ed. 2002, 41, 4125-4128. (c) Jung, M. E.; Ho, D.; Chu, H. V. Org. Lett. 2005, 7, 1649-
1651.
13
It should be noted that the unactivated pyrroline derivative I, R=H, was totally unreactive on heating in a
sealed tube or under high pressure in the presence of a variety of potential cycloaddition partners. For a
successful example with a monoactivated pyrroline derivative, see ref 26.
14
Del Valle J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923-3931; This compound is also commercially
available.
15 Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
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