A unified strategy for kainoid synthesis

Job/Unit: O42452

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Date: 18-06-14 18:24:55

Pages: 15

FULL PAPER

DOI: 10.1002/ejoc.201402452

A Unified Strategy for Kainoid Synthesis

Masaya Fujii,^[a,b]Satoshi Yokoshima,^[a]and Tohru Fukuyama*^[a]

Keywords: Synthesis design / Total synthesis / Natural products / Alkaloids / Cyclization / Rearrangement

A unified strategy for kainoid synthesis was developed. The

key features of the strategy involve a Claisen–Ireland re-

arrangement to construct the contiguous stereogenic centers

and a palladium-catalyzed formation of the pyrrolidine ring

with complete stereoselectivity. The present protocol has en-

abled rapid access to a wide range of kainoids with diverse

types of substituents (alkenyl, aryl, and alkyl groups) at the

4-position of the pyrrolidie ring, starting from the common

intermediate and appropriate acetic acid derivatives. To test

the generality of the strategy, we have accomplished the syn-

theses of kainic acid, o-methoxyphenyl derivative (MFPA),

and a novel cyclopropyl derivative (CPKA), using 3-meth-

ylbut-3-enoic acid, 2-(2-methoxyphenyl)acetic acid, and 2-

cyclopropylacetic acid, respectively.

Introduction

The kainoids (1) are 2,3,4-trisubstituted pyrrolidine de-

rivatives that contain a glutamic acid moiety and various

substituents at the 4-position of the pyrrolidine ring (Fig-

ure 1).^[1]Kainic acid (2), the parent member of the kainoids,

was first isolated in 1953 from the Japanese marine alga

Digenea simplex.^[2]Since then, 2 has been found in another

alga (Centrocerus clavulatum) and a moss (Alsidium hel-

minthocorton).^[3]As well as showing potent anthelmintic

properties,^[4]2 acts as an excitatory amino-acid-receptor ag-

onist, and it is widely used as a tool in neuropharmacology

to stimulate nerve cells and mimic disease states, such as

epilepsy,^[5]Alzheimer’s disease, and Huntington’s chorea.^[6]

Other natural kainoids, domoic acid^[7]and isodomoic ac-

ids,^[8]isolated from another Japanese alga Chondria armata,

as well as acromelic acids A and B, isolated from the Japan-

ese mushroom Clitocybe acromelalga,^[9]also show potent

neuroexcitatory activities. It has been reported that domoic

acid (3) and acromelic acid A (5) are approximately 10 and

100 times more potent than kainic acid, respectively.^[10]

variety of unnatural kainoids have also been synthesized in

A

Figure 1. Structures of kainoids.

attempts to find new neuroexcitatory agents.^[11]For exam- tures.^[12–14]To date, more than 50 syntheses of kainic acid,

ple, Shirahama and co-workers prepared the o-meth- and several syntheses of domoic acid,^[15]the isodomoic ac-

oxyphenyl derivative MFPA (6), which is more potent than ids,^[16]and the acromelic acids,^[9a,17]have been reported.

natural kainoids.^[11i,11j]

These synthetic approaches, and also those directed at un-

Synthetic routes to the kainoids have been extensively natural analogs,^[18]are specifically designed to synthesize

explored, not only as a result of their importance in the the respective target kainoid. To the best of our knowledge,

field of neuroscience, but also due to their unique struc- there seems to be no versatile route that can prepare any

type of kainoids, including alkenyl (e.g., kainic acid, domoic

[a] Graduate School of Pharmaceutical Sciences, Nagoya

acid), aryl (e.g., acromelic acids, MFPA), and alkyl analogs.

University,

A unified synthetic strategy for a variety of kainoids would

effectively provide new analogs with potential neuroexcita-

tory activities. In this paper, we disclose syntheses of kainic

acid (2), MFPA (6), and a new cyclopropyl analog of kainic

acid (CPKA, 7) by means of a unified strategy, featuring a

Claisen–Ireland rearrangement^[19]and a palladium-medi-

ated pyrrolidine-ring formation.

Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan

E-mail: fukuyama@ps.nagoya-u.ac.jp

www.ps.nagoya-u.ac.jp/lab_pages/natural_products/

index-e.html

[b] Graduate School of Pharmaceutical Sciences, University of

Tokyo,

7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402452.

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M. Fujii, S. Yokoshima, T. Fukuyama

FULL PAPER

Our synthesis commenced with the preparation of the

common synthetic intermediate, allylic alcohol 20

(Scheme 2). According to a known procedure,^[20]l-tartaric

acid (14) was converted into diol 15. Selective protection of

one of the hydroxy groups in 15 and iodination of the re-

sulting alcohol (i.e., 16) gave iodide 17. Reduction of the

vicinal iodohydrin moiety in 17 with zinc in refluxing eth-

anol gave olefin 18 in good yield. Homologation of 18 by a

cross-metathesis reaction with olefin 19 gave the desired all-

ylic alcohol (i.e., 20).^[21]

Results and Discussion

Our retrosynthetic analysis is shown in Scheme 1. We en-

visioned that the pyrrolidine ring could be effectively

formed by palladium-catalyzed cyclization of allylic alcohol

9. The amino group in 9 could be introduced using the

carboxylic acid moiety in 10. To control the contiguous

stereogenic centers in 10, which correspond to those at the

3- and 4-positions of the pyrrolidine ring, we decided to use

the Claisen–Ireland rearrangement of chiral allylic ester 11.

Condensation of 2-substituted acetic acid 12 and allylic

alcohol 13 could give 11. According to this strategy, selec-

tion of appropriate acetic acid derivatives could introduce

a variety of substituents at the 4-position of the kainoid

products (R in 1).

Scheme 2. Synthesis of common synthetic intermediate 20; Bn =

benzyl, MOM = methoxymethyl.

With the key intermediate in hand, we aimed at synthe-

sizing kainic acid through the crucial Claisen–Ireland re-

arrangement (Scheme 3). After condensation of 20 with 3-

methylbut-3-enoic acid (21),^[22]the resulting ester (i.e., 22)

Scheme 1. Retrosynthetic analysis.

Scheme 3. Synthesis of kainic acid; Boc = tert-butoxycarbonyl, DCC = N,NЈ-dicyclohexylcarbodiimide, DMAP = 4-(dimethylamino)-

pyridine, LHMDS = lithium hexamethyldisilazide, TMS = trimethylsilyl.

2

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A Unified Strategy for Kainoid Synthesis

was treated with LHMDS in the presence of TMSCl at mized, whereas steric repulsion exists between the allylic

–78 °C to form (E)-silyl enolate 23, which, upon warming alcohol moiety and the alkyl chains in transition state B.

to –20 °C, underwent a [3,3]-sigmatropic rearrangement via

a chair-like transition state to give 24 in 91% yield, with a dative cleavage of the vinyl group (Scheme 5). However, oxi-

high diastereoselectivity (38:1).^[23]

dation of 29 with OsO₄or ozone resulted in the preferential

Completion of the synthesis of kainic acid required oxi-

It is noteworthy that the Claisen–Ireland rearrangement oxidation of the isopropenyl group. This preference in the

of the corresponding 3-methylcrotonate (i.e., 30) produced oxidation could be utilized for protection of the isopropenyl

32, a diastereomer of 24, as a major product (Scheme 4). group. Upon treatment with iodine, 29 underwent iodoeth-

This was attributed to the formation of (Z)-silyl enolate 31 erification with concomitant cleavage of the benzyl group

from 3-methylcrotonate,^[24]followed by

a

subsequent to give 33 as a mixture of diastereomers. Ozonolysis of 33

[3,3]-sigmatropic rearrangement via a chair-like transition proceeded smoothly, and after reduction with sodium

state.

borohydride, alcohol 34 was obtained in excellent yield. Re-

ductive cleavage of the cyclic ether by treatment with zinc

gave diol 35, which was then subjected to Jones oxidation

to give dicarboxylic acid 36. Finally, alkaline hydrolysis of

the methyl carbamate moiety gave kainic acid (2).

Scheme 4. Claisen–Ireland rearrangement using 3-methylcrotonate.

Next, we focused on the construction of the pyrrolidine

ring. The carboxylic acid in 24 was converted into the pri-

mary amine (in 26) by first forming primary amide 25 via

a mixed anhydride,^[25]followed by reduction with AlH₃.

Protection of the amine in 26 and subsequent cleavage of

the MOM group gave 28. Upon treatment with PdCl₂-

(MeCN)₂(0.5 mol-%) in THF at 0 °C,^[26]28 underwent ex-

ceptionally facile cyclization to give 29 stereoselectively.

NOESY experiments on 29 indicated that the product had

all the required stereochemistry for the synthesis of kainic

acid.

Scheme 5. Completion of the synthesis.

The stereoselective formation of 29 can be explained in

terms of transition state geometries (Figure 2). In the cycli-

zation step, the π-bond in the allylic alcohol and the lone

pair on the nitrogen atom in the carbamate must overlap

sufficiently. With this restriction, there are two plausible

transition states: A and B. Transition state A, which leads

to the formation of 29, is more energetically favorable be-

cause it has a conformation where the A^1,3-strain is mini-

Having established a synthetic route to kainic acid, we

next attempted to synthesize an unnatural kainoid, MFPA

(6), in order to verify the general applicability of our strat-

egy. In this synthesis, 2-(2-methoxylphenyl)acetic acid (37a),

instead of 3-methylbut-3-enoic acid (21), was used as the

coupling partner (Scheme 6). The condensation reaction be-

tween 20 and 37a gave 38a in 95% yield. The crucial

Claisen–Ireland rearrangement, introduction of the amine

moiety, and palladium-catalyzed formation of the pyrrol-

idine ring proceeded uneventfully to give 44a in good yield.

Ozonolysis of the vinyl group in 44a followed by reduction

with NaBH₄gave 45a. Cleavage of the benzyl ether by hy-

drogenolysis gave diol 46a, which could be converted into

MFPA (6) by Jones oxidation and alkaline hydrolysis. The

established transformations were also successfully used for

the synthesis of a new cyclopropyl analog of kainic acid

(CPKA, 7),^[27]starting from 2-cyclopropylacetic acid (37b)

as the coupling partner.

Figure 2. Rationale for the stereoselective cyclization.

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M. Fujii, S. Yokoshima, T. Fukuyama

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Scheme 6. Synthesis of analogs of kainic acid.

reported in ppm. The center line of the triplet at δ = 77.16 ppm for

deuteriochloroform was used as an internal standard. Spectra in

D₂O were calibrated using the signal at δ = 30.9 ppm for acetone.

Conclusions

In summary, syntheses of kainic acid (2), MFPA (6), and

CPKA (7) have been accomplished from a common inter- Infrared (IR) spectra were recorded with a JASCO FTIR-410 Fou-

rier Transform Infrared Spectrophotometer, and the data are re-

ported in wavenumbers (cm^–1). High-resolution mass spectra

(HRMS) were obtained with a JEOL JMS-T100LP AccuTOF LC-

plus instrument using either the positive electrospray ionization

(ESI) method or the positive direct analysis in real time (DART)

ionization method, with PEG as the internal standard. Optical ro-

tations were measured with a JASCO P-2200 Digital Polarimeter

at room temperature, using the sodium D line. Melting points

(m.p.) were determined with a Yanaco Micro Melting Point Appa-

ratus. Analytical thin-layer chromatography (TLC) was carried out

on Merck analytical plates, 0.25 mm thick, precoated with silica gel

60 F₂₅₄. Preparative TLC separations were carried out on Merck

analytical plates (0.25 or 0.50 mm thick) precoated with silica gel

60 F₂₅₄. Reverse-phase preparative TLC separations were carried

out on Merck analytical plates precoated with silica gel 60 RP-18

F₂₅₄S. Flash chromatography separations were carried out on

Kanto Chemicals Silica Gel 60 (spherical, 40–100 mesh). Reverse-

phase chromatography separations were carried out on Kanto

Chemicals Silica Gel 120 RP-18 (spherical, 40–50 μm particle size).

Reagents were commercial grade and were used without any purifi-

cation. Anhydrous tetrahydrofuran, diethyl ether, toluene, and

dichloromethane were purchased from Kanto Chemicals Co., Inc.,

mediate 20 by means of a unified strategy featuring a

Claisen–Ireland rearrangement to construct the contiguous

stereogenic centers and palladium-catalyzed formation of

the pyrrolidine ring with complete stereoselectivity. This

strategy can be used for the synthesis of a wide range of

kainoids with diverse types of substituents at the 4-position

of the pyrrolidine ring. Further application of this unified

strategy to the synthesis of more complex kainoids is cur-

rently underway in our laboratories.

Experimental Section

General Remarks: Nuclear magnetic resonance [¹H NMR

(400 MHz) and ¹³C NMR (100 MHz)] spectra were determined

with a JEOL-ECS400 instrument unless otherwise noted. Chemical

shifts for ¹H NMR spectra are reported in parts per million (ppm)

downfield from tetramethylsilane and coupling constants are given

in Hertz (Hz). Tetramethylsilane and/or residual solvents were used

as internal standards. The following abbreviations are used for spin

multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m =

multiplet, br = broad. Chemical shifts for ¹³C NMR spectra are

4

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A Unified Strategy for Kainoid Synthesis

and were purified using a Glass Contour Solvent System. Anhy-

drous benzene and N,N-dimethylformamide were purchased from

Kanto Chemicals Co., Inc. and stored over activated MS (4Å). An-

hydrous methanol, ethanol, and acetonitrile were also purchased

from Kanto Chemicals Co., Inc. and stored over activated MS

(3Å). All reactions sensitive to oxygen or moisture were carried out

under an argon atmosphere.

stirred for an additional 1.5 h at reflux, then it was cooled to room

temperature. The resulting mixture was filtered through a Celite

pad, and the filter cake was rinsed with methanol. The organic

solvent was removed under reduced pressure, and the residue was

diluted with brine and saturated aqueous NH₄Cl. The aqueous

mixture was extracted with diethyl ether (5ϫ), and the combined

organic extracts were dried with anhydrous sodium sulfate, filtered,

and evaporated under reduced pressure. The crude product was

purified by distillation (92 to 94 °C, 25 Torr) to give 18 (6.83 g,

{(4S,5S)-5-[(Methoxymethoxy)methyl]-2,2-dimethyl-1,3-dioxolan-4-

yl}methanol (16): NaH (60% in mineral oil; 2.74 g, 68.5 mmol) was

added to a solution of [(4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-di-

yl]dimethanol^[20](15; 10.1 g, 62.3 mmol) in tetrahydrofuran

(250 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C, then

MOMCl (5.20 mL, 68.5 mmol) was added dropwise. The mixture

was stirred for an additional 2.5 h at 0 °C, then it was quenched

with saturated aqueous NH₄Cl. The organic solvent was removed

under reduced pressure, and the aqueous mixture was extracted

with ethyl acetate (3 ϫ). The combined organic extracts were

washed with brine, dried with anhydrous sodium sulfate, filtered,

and evaporated under reduced pressure. The crude product was

purified by silica gel column chromatography (ethyl acetate/hexane,

1:3 to 3:2) to give 16 (9.46 g, 73.6%) as a colorless oil. [α]²_D³= +1.26

86.0%) as a colorless oil. [α]²_D⁵= 6.1 (c = 1.00, CHCl₃). IR (film):

1

ν = 3443, 2946, 2888, 2826, 1644, 1442, 1037, 927 cm^–1. H NMR

˜

(400 MHz, CDCl₃, 25 °C): δ = 5.86 (ddd, J = 17.3, 10.5, 5.5 Hz, 1

H), 5.39 (ddd, J = 17.3, 1.5, 1.5 Hz, 1 H), 5.22 (ddd, J = 10.5, 1.5,

1.5 Hz, 1 H), 4.69 (d, J = 6.7 Hz, 1 H), 4.67 (d, J = 6.7 Hz, 1 H),

4.35–4.29 (m, 1 H), 3.68 (dd, J = 10.5, 3.2 Hz, 1 H), 3.48 (dd, J =

10.5, 7.3 Hz, 1 H), 3.40 (s, 3 H), 2.72 (d, J = 4.1 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 136.8 (CH), 116.5 (CH₂),

97.1 (CH₂), 72.8 (CH₂), 71.7 (CH), 55.6 (CH₃) ppm. HRMS

(DART⁺): calcd. for C₆H₁₃O₃[M + H]⁺133.0865; found 133.0859.

(R,E)-6-(Benzyloxy)-1-(methoxymethoxy)hex-3-en-2-ol (20):

Grubbs catalyst 2^ndgeneration (64.2 mg, 0.0756 mmol) was added

to a solution of (R)-1-(methoxymethoxy)but-3-en-2-ol (18; 1.00 g,

7.57 mmol) and [(but-3-en-1-yloxy)methyl]benzene^[28](19; 6.14 g,

37.8 mmol) in toluene (50 mL) at 0 °C. The mixture was stirred for

15 min, then further Grubbs catalyst (64.2 mg, 0.0756 mmol) was

added. The reaction mixture was gradually warmed to room tem-

perature over 1 h, where it was stirred for another 2 h. Then, ad-

ditional [(but-3-en-1-yloxy)methyl]benzene (1.23 g, 7.57 mmol) and

Grubbs catalyst (64.2 mg, 0.0756 mmol) were added at room tem-

perature. The mixture was stirred for an additional 9 h, then the

reaction was quenched with dimethyl sulfoxide (200 μL), and the

mixture was stirred for 12 h. Activated carbon (400 mg) was added,

and the mixture was stirred for 2 h. The resulting mixture was fil-

tered through a Celite pad, and the filter cake was rinsed with

dichloromethane. The organic solvent was removed under reduced

pressure, and the residue was purified by silica gel column

chromatography (ethyl acetate/hexane, 1:2) to give 20 (1.32 g,

65.5%) as a pale yellow oil. [α]²_D⁵= –9.4 (c = 1.00, CHCl₃). IR

(c = 1.00, CHCl ). IR (film): ν = 3477, 2987, 2935, 2886, 2826,

˜

3

1456, 1372, 1215, 1153, 1041, 919, 847, 802 cm^{–1 1}H NMR

.

(400 MHz, CDCl₃, 25 °C): δ = 4.67 (s, 2 H), 4.08 (ddd, J = 8.3,

5.5, 5.0 Hz, 1 H), 3.95 (ddd, J = 8.3, 4.1, 4.1 Hz, 1 H), 3.85–3.78

(m, 1 H), 3.73–3.65 (m, 1 H), 3.70 (dd, J = 10.5, 5.5 Hz, 1 H), 3.66

(dd, J = 10.5, 5.0 Hz, 1 H), 3.38 (s, 3 H), 2.30 (m, 1 H), 1.44 (s, 3

H), 1.43 (s, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

109.6 (C), 96.8 (CH₂), 79.3 (CH), 76.4 (CH), 67.9 (CH₂), 62.4

(CH₂), 55.5 (CH₃), 27.1 (CH₃), 27.1 (CH₃) ppm. HRMS (DART⁺):

calcd. for C₉H₁₉O₅[M + H]⁺207.1233; found 207.1225.

(4R,5S)-4-(Iodomethyl)-5-[(methoxymethoxy)methyl]-2,2-dimethyl-

1,3-dioxolane (17): Imidazole (9.37 g, 138 mmol), Ph₃P (15.6 g,

59.6 mmol) and iodine (14.0 g, 55.0 mmol) were added to a solu-

tion of {(4S,5S)-5-[(methoxymethoxy)methyl]-2,2-dimethyl-1,3-di-

oxolan-4-yl}methanol (16; 9.46 g, 45.9 mmol) in dichloroethane

(200 mL) at 0 °C. The mixture was stirred for 10 min, then it was

warmed to 70 °C. After 5 h, the reaction mixture was cooled to

0 °C and quenched with saturated aqueous Na₂S₂O₃. The mixture

was extracted with dichloromethane (3ϫ), and the combined or-

ganic extracts were washed with saturated aqueous Na₂S₂O₃, satu-

rated aqueous NH₄Cl, and brine. The resulting organic layer was

dried with anhydrous sodium sulfate, filtered, and evaporated un-

der reduced pressure. The crude product was purified by silica gel

column chromatography (ethyl acetate/hexane, 1:9 to 1:4) to give

17 (12.8 g, 88.3%) as a colorless oil. [α]²_D⁴= –17.1 (c = 1.00, CHCl₃).

(film): ν = 3451, 2933, 2863, 1454, 1362, 1111, 1036 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃, 25 °C): δ = 7.38–7.26 (m, 5 H), 5.82 (dt, J =

15.0, 7.3 Hz, 1 H), 5.55 (dd, J = 15.0, 7.0 Hz, 1 H), 4.68 (d, J =

6.4 Hz, 1 H), 4.66 (d, J = 6.4 Hz, 1 H), 4.51 (s, 2 H), 4.31–4.25 (m,

1 H), 3.62 (dd, J = 10.5, 3.2 Hz, 1 H), 3.52 (t, J = 6.9 Hz, 1 H),

3.44 (dd, J = 10.5, 7.8 Hz, 1 H), 3.39 (s, 3 H), 2.63 (d, J = 3.2 Hz,

1 H), 2.38 (dt, J = 7.3, 6.9 Hz, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 138.5 (C), 130.3 (CH), 129.9 (CH), 128.5 (CH),

127.8 (CH), 127.7 (CH), 97.1 (CH₂), 73.0 (CH₂), 73.0 (CH₂), 71.5

(CH), 69.7 (CH₂), 55.5 (CH₃), 32.9 (CH₂) ppm. HRMS (ESI⁺):

calcd. for C₁₅H₂₃O₄[M + H]⁺289.1416; found 289.1408.

IR (film): ν = 2987, 2934, 2886, 2823, 1455, 1380, 1371, 1239, 1215,

˜

1151, 1111, 1040 cm^–1. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ =

4.67 (s, 2 H), 3.98 (ddd, J = 7.3, 5.5, 4.5 Hz, 1 H), 3.89 (ddd, J =

7.3, 5.5, 5.5 Hz, 1 H), 3.75 (dd, J = 10.5, 4.5 Hz, 1 H), 3.70 (dd, J

= 10.5, 5.5 Hz, 1 H), 3.39 (s, 3 H), 3.35 (dd, J = 10.5, 5.5 Hz, 1

H), 3.31 (dd, J = 10.5, 5.5 Hz, 1 H), 1.48 (s, 3 H), 1.43 (s, 3 H)

ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 110.0 (C), 96.8

(CH₂), 80.3 (CH), 77.5 (CH), 68.1 (CH₂), 55.5 (CH₃), 27.5 (CH₃),

27.4 (CH₃), 6.3 (CH₂) ppm. HRMS (DART⁺): calcd. for C₉H₁₈IO₅

[M + H]⁺317.0250; found 317.0263.

(R,E)-6-(Benzyloxy)-1-(methoxymethoxy)hex-3-en-2-yl 3-Meth-

ylbut-3-enoate (22): 3-Methylbut-3-enoic acid^[22a](21; 1.34 g,

13.4 mmol), N,NЈ-dicyclohexylcarbodiimide (2.44 g, 11.8 mmol),

and 4-(dimethylamino)pyridine (289 mg, 2.37 mmol) were added to

a solution of (R,E)-6-(benzyloxy)-1-(methoxymethoxy)hex-3-en-2-

ol (20; 2.10 g, 7.88 mmol) in dichloromethane (80 mL) at 0 °C. The

mixture was stirred for 40 min, then further N,NЈ-dicyclohexylcar-

bodiimide (1.12 g, 5.43 mmol) and 3-methylbut-3-enoic acid

(1.00 g, 9.99 mmol) were added. The mixture was stirred for an

additional 4.5 h at 0 °C, then it was quenched with saturated aque-

ous NH₄Cl. The resulting suspension was filtered through a Celite

pad, and the filter cake was rinsed with dichloromethane. The fil-

trate was extracted with dichloromethane (4ϫ), and the combined

organic extracts were washed with saturated aqueous NaHCO₃,

(R)-1-(Methoxymethoxy)but-3-en-2-ol (18): Dibromoethane

(1.00 mL, 11.6 mmol) and TMSCl (650 μL, 5.15 mmol) were added

to a suspension of zinc (39.29 g, 601 mmol) in ethanol (400 mL).

The mixture was stirred at reflux for 10 min, then (4R,5S)-4-(iodo-

methyl)-5-[(methoxymethoxy)methyl]-2,2-dimethyl-1,3-dioxolane

(17; 19.0 g, 60.1 mmol) was added dropwise. The mixture was

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saturated aqueous NH₄Cl, and brine. The resulting organic phase

was dried with anhydrous sodium sulfate, filtered, and evaporated

under reduced pressure. The crude product was purified by silica

gel column chromatography (ethyl acetate/hexane, 1:9 to 1:3) to

give 22 (2.36 g, 85.9%) as a colorless oil. [α]²_D⁵= –121 (c = 0.50,

(ethyl acetate/hexane, 1:1 to 1:0) to give 25 (1.83 g, 95.5%) as a

pale yellow oil. [α]²_D⁶= +62.7 (c = 0.50, CHCl ). IR (film): ν =

˜

3

3330, 3196, 2934, 1669, 1454, 1375, 1211, 1150, 1102, 1030, 974,

1

920 cm^–1. H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.47–7.25 (m,

5 H), 5.57 (br. s, 1 H), 5.52 (dt, J = 15.4, 6.0 Hz, 1 H), 5.35 (dd, J

= 15.4, 9.4 Hz, 1 H), 5.28 (br. s, 1 H), 4.87 (s, 1 H), 4.86 (m, 1 H),

4.58 (d, J = 6.4 Hz, 1 H), 4.56 (d, J = 6.4 Hz, 1 H), 4.51 (d, J =

11.7 Hz, 1 H), 4.44 (d, J = 11.7 Hz, 1 H), 3.97 (d, J = 6.0 Hz, 2

H), 3.53–3.43 (m, 2 H), 3.34 (s, 3 H), 2.86 (d, J = 10.6 Hz, 1 H),

2.77 (dddd, J = 10.6, 10.2, 9.4, 3.0 Hz, 1 H), 1.98–1.89 (m, 1 H),

1.69 (s, 3 H), 1.54–1.44 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 174.4 (C), 143.2 (C), 138.6 (C), 134.3 (CH),

128.4 (CH), 127.9 (CH), 127.9 (CH), 127.6 (CH), 115.1 (CH₂), 95.0

CHCl ). IR (film): ν = 2932, 1739, 1651, 1454, 1243, 1152, 1112,

˜

3

1030, 968 cm^–1. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.38–7.26

(m, 5 H), 5.84 (dt, J = 15.1, 6.8 Hz, 1 H), 5.54 (dd, J = 15.1, 6.9 Hz,

1 H), 5.45 (dt, J = 6.9, 5.0 Hz, 1 H), 4.90 (s, 1 H), 4.85 (s, 1 H),

4.63 (d, J = 6.9 Hz, 1 H), 4.61 (d, J = 6.9 Hz, 1 H), 4.50 (s, 2 H),

3.62 (d, J = 5.0 Hz, 2 H), 3.50 (t, J = 6.7 Hz, 2 H), 3.34 (s, 3 H),

3.06 (s, 2 H), 2.37 (dt, J = 6.7, 6.8 Hz, 2 H), 1.80 (s, 3 H) ppm. ¹³

NMR (100 MHz, CDCl₃, 25 °C): δ = 170.6 (C), 138.6 (C), 138.5

C

(C), 132.2 (CH), 128.5 (CH), 127.7 (CH), 127.7 (CH), 126.8 (CH), (CH₂), 72.9 (CH₂), 68.1 (CH₂), 67.3 (CH₂), 59.6 (CH), 55.2 (CH₃),

114.8 (CH₂), 96.5 (CH₂), 73.4 (CH), 73.0 (CH₂), 69.5 (CH₂), 69.0 39.1 (CH), 33.1 (CH₂), 19.7 (CH₃) ppm. HRMS (ESI⁺): calcd. for

(CH₂), 55.4 (CH₃), 43.8 (CH₂), 32.9 (CH₂), 22.5 (CH₃) ppm.

HRMS (ESI⁺): calcd. for C₂₀H₂₈NaO₅[M + Na]⁺371.1834; found

371.1842.

C₂₀H₂₉NaNO₄[M + Na]⁺370.1994; found 370.1995.

Methyl {(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-

(prop-1-en-2-yl)hex-4-en-1-yl}carbamate (27): Aluminium chloride

(3.97 g, 29.8 mmol) was added to a stirred suspension of lithium

aluminium hydride (3.40 g, 89.6 mmol) in diethyl ether (150 mL) at

0 °C, and the suspension was stirred for 30 min. The supernatant

solution was added to a stirred solution of (2S,3R,E)-3-[2-(benz-

yloxy)ethyl]-6-(methoxymethoxy)-2-(prop-1-en-2-yl)hex-4-enamide

(25; 1.00 g, 2.88 mmol) in tetrahydrofuran (25 mL) at 0 °C. The

solution was stirred for 12 h, then the reaction was quenched with

Rochelle salt (30% aqueous solution), and the mixture was stirred

for 12 h. The mixture was then extracted with the mixed solvent

(methanol/dichloromethane, 1:9; 4ϫ), and the combined organic

extracts were washed with Rochelle salt (30% aqueous solution)

and brine. The resulting organic phase was dried with anhydrous

sodium sulfate, filtered, and evaporated under reduced pressure to

give a crude primary amine.

(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-(prop-1-en-

2-yl)hex-4-enoic Acid (24): (R,E)-6-(Benzyloxy)-1-(methoxymeth-

oxy)hex-3-en-2-yl 3-methylbut-3-enoate (22; 2.26 g, 6.49 mmol) was

dissolved in diethyl ether (100 mL) and the solution was cooled to

–78 °C. Lithium bis(trimethylsilyl)amide (1.17 m in tetra-

hydrofuran; 11.1 mL, 13.0 mmol) was added over 10 min, and then

chlorotrimethylsilane (1.64 mL, 13.0 mmol) was added dropwise.

The mixture was stirred for 15 min, then it was warmed to –20 °C.

The mixture was stirred for an additional 2.5 h, then it was

quenched with saturated aqueous NH₄Cl. The mixture was ex-

tracted with ethyl acetate (4ϫ), and the combined organic extracts

were washed with brine. The resulting organic phase was dried with

anhydrous sodium sulfate, filtered, and evaporated under reduced

pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 2:3, then methanol/dichlo-

romethane, 1:9) to give 24 (2.05 g, 90.7%) as a pale yellow oil. This

The crude amine was dissolved in dichloromethane (40 mL) and

triethylamine (803 μL, 5.78 mmol) and methyl chloroformate

(287 μL, 3.74 mmol) were added at 0 °C. The mixture was stirred

for 2 h, then it was quenched with water and HCl (3 m aqueous).

The mixture was extracted with dichloromethane (3ϫ), and the

combined organic extracts were washed with brine. The resulting

organic phase was dried with anhydrous sodium sulfate, filtered,

and evaporated under reduced pressure. The crude product was

purified by silica gel column chromatography (ethyl acetate/hexane,

material was obtained as a 38:1 mixture of diastereomers. [α]²_D⁵

+47.4 (c = 0.50, CHCl ). IR (film): ν = 2938, 1731, 1705, 1644,

=

˜

3

1454, 1376, 1213, 1150, 1102, 1029, 975, 903 cm^{–1 1}H NMR

.

(400 MHz, CDCl₃, 25 °C): δ = 7.36–7.25 (m, 5 H), 5.52 (dt, J =

15.4, 6.0 Hz, 1 H), 5.31 (dd, J = 15.4, 9.6 Hz, 1 H), 4.93 (s, 1 H),

4.91 (s, 1 H), 4.58 (d, J = 6.4 Hz, 1 H), 4.56 (d, J = 6.4 Hz, 1 H),

4.51 (d, J = 11.9 Hz, 1 H), 4.44 (d, J = 11.9 Hz, 1 H), 3.97 (d, J =

5.9 Hz, 2 H), 3.52–3.41 (m, 2 H), 3.34 (s, 3 H), 3.03 (d, J = 10.6 Hz,

1 H), 2.74 (dddd, J = 10.6, 10.2, 9.6, 3.0 Hz, 1 H), 1.94–1.85 (m, 1

H), 1.72 (s, 3 H), 1.56–1.45 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 180.0 (C), 141.0 (C), 138.4 (C), 133.5 (CH),

128.4 (CH), 128.4 (CH), 127.9 (CH), 127.7 (CH), 116.2 (CH₂), 95.0

(CH₂), 72.9 (CH₂), 67.9 (CH₂), 67.2 (CH₂), 58.5 (CH), 55.3 (CH₃),

39.7 (CH), 32.9 (CH₂), 20.0 (CH₃) ppm. HRMS (ESI⁺): calcd. for

C₂₀H₂₈NaO₅[M + Na]⁺371.1834; found 371.1818.

1:4 to 2:3) to give 27 (747 mg, 66.2%) as a colorless oil. [α]²_D⁶

=

–41.3 (c = 0.50, CHCl ). IR (film): ν = 3346, 2945, 2882, 1726,

˜

3

1644, 1531, 1454, 1375, 1254, 1150, 1102, 1031, 976, 921 cm^–1. H

1

NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.26 (m, 5 H), 5.47 (dt,

J = 15.3, 5.5 Hz, 1 H), 5.39 (dd, J = 15.3, 8.5 Hz, 1 H), 4.89 (s, 1

H), 4.73 (s, 1 H), 4.62 (m, 1 H), 4.59 (d, J = 7.1 Hz, 1 H), 4.57 (d,

J = 7.1 Hz, 1 H), 4.49 (d, J = 12.2 Hz, 1 H), 4.43 (d, J = 12.2 Hz,

1 H), 3.97 (d, J = 5.5 Hz, 2 H), 3.64 (s, 3 H), 3.52–3.43 (m, 2 H),

3.43–3.36 (m, 1 H), 3.36 (s, 3 H), 3.06–2.96 (m, 1 H), 2.35–2.24 (m,

1 H), 2.24–2.13 (m, 1 H), 1.96–1.86 (m, 1 H), 1.62 (s, 3 H), 1.50–

1.40 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 156.8

(C), 143.9 (C), 138.5 (C), 134.7 (CH), 128.3 (CH), 127.7 (CH),

127.6 (CH), 127.5 (CH), 114.8 (CH₂), 95.0 (CH₂), 72.9 (CH₂), 67.9

(CH₂), 67.3 (CH₂), 55.1 (CH₃), 51.9 (CH₃), 51.3 (CH), 41.1 (CH₂),

40.3 (CH), 32.2 (CH₂), 19.9 (CH₃) ppm. HRMS (ESI⁺): calcd. for

C₂₂H₃₃NaNO₅[M + Na]⁺414.2256; found 414.2257.

(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-(prop-1-en-

2-yl)hex-4-enamide (25):^[25]Di-tert-butyl dicarbonate (2.40 g,

11.0 mmol) and pyridine (574 μL, 7.15 mmol) were added to a solu-

tion of (2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-

(prop-1-en-2-yl)hex-4-enoic acid (24; 1.92 g, 5.51 mmol) in ethyl

acetate (19 mL) at room temperature. The mixture was stirred for

3 h, then aqueous ammonia (14 m solution; 983 μL, 13.8 mmol)

was added. The mixture was stirred for an additional 2 h, then it

was quenched with HCl (1 m aqueous), then neutralized with satu-

rated aqueous NaHCO₃. The mixture was extracted with ethyl acet-

ate (5ϫ), and the combined organic extracts were washed with

brine. The resulting organic phase was dried with anhydrous so-

dium sulfate, filtered, and evaporated under reduced pressure. The

crude product was purified by silica gel column chromatography

Methyl {(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-hydroxy-2-(prop-1-en-

2-yl)hex-4-en-1-yl}carbamate (28): A solution of hydrogen chloride

in methanol (5–10 %; 10 mL) was added to a flask containing

methyl {(2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-

(prop-1-en-2-yl)hex-4-en-1-yl}carbamate (27; 747 mg, 1.91 mmol)

6

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A Unified Strategy for Kainoid Synthesis

at 0 °C. The mixture was stirred for 10 min, then it was warmed to

room temperature. The mixture was stirred for an additional 9 h,

then it was cooled to 0 °C, and quenched with saturated aqueous

NaHCO₃. The mixture was extracted with ethyl acetate (3ϫ), and

the combined organic extracts were washed with brine. The re-

sulting organic phase was dried with anhydrous sodium sulfate, fil-

tered, and evaporated under reduced pressure. The crude product

was purified by silica gel column chromatography (ethyl acetate/

(ethyl acetate/hexane, 3:10) to give 33 (191 mg, 99.6%) as a pale

yellow oil. This material was obtained as a mixture of two dia-

stereomers. [α]²_D⁶= 46.1 (c = 0.50, CHCl ). IR (film): ν = 2979,

˜

3

2949, 2888, 1701, 1451, 1385, 1083 cm^–1

.

¹H NMR (400 MHz,

CDCl₃, 25 °C; this material was observed as a mixture of two rota-

mers for each diastereomer): δ = 5.83–5.70 (m, 1 H), 5.18–5.02 (m,

2 H), 4.20–4.16 [m, (1/2)1 H], 4.09–4.04 [m, (1/2)1 H], 3.82–3.41

[m, 2 H + (1/2)1 H], 3.72 [s, (1/2)3 H], 3.68 [s, (1/2)3 H], 3.27 [dd,

hexane, 1:2 to 1:0) to give 28 (608 mg, 91.7%) as a pale yellow oil. J = 11.0, 2.3 Hz, (1/2)1 H], 3.17 [dd, J = 10.1, 6.9 Hz, (1/2)1 H],

[α]²_D⁶= –46.2 (c = 0.50, CHCl ). IR (film): ν = 3423, 3342, 2942,

3.07 [dd, J = 10.1, 9.6 Hz, (1/2)1 H], 2.47–2.27 (m, 1 H), 2.22–2.06

(m, 1 H), 1.61–1.45 (m, 2 H), 1.49 [s, (1/2)2 H], 1.41 [s, (1/4)3 H],

1.41 [s, (1/4)3 H], 1.26 [s, (1/2)2 H], 1.22 [s, (1/4)3 H], 1.21 [s, (1/4)

3 H] ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C; this material was

observed as a mixture of two rotamers for each diastereomer): δ =

˜

3

2864, 1704, 1538, 1454, 1366, 1260, 1097, 979, 897 cm^–1. H NMR

1

(400 MHz, CDCl₃, 25 °C): δ = 7.37–7.25 (m, 5 H), 5.55 (dt, J =

15.2, 5.4 Hz, 1 H), 5.39 (dd, J = 15.2, 9.2 Hz, 1 H), 4.89 (s, 1 H),

4.72 (s, 1 H), 4.64 (m, 1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.43 (d, J

= 11.9 Hz, 1 H), 4.03 (m, 2 H), 3.64 (s, 3 H), 3.55–3.35 (m, 3 H), 156.0 (C), 156.0 (C), 155.8 (C), 155.8 (C), 136.8 (CH), 136.7 (CH),

3.05–2.95 (m, 1 H), 2.34–2.24 (m, 1 H), 2.22–2.14 (m, 1 H), 1.95–

1.85 (m, 1 H), 1.63 (s, 3 H), 1.49–1.38 (m, 1 H), 1.28 (m, 1 H) ppm.

136.2 (CH), 136.2 (CH), 115.1 (CH₂), 115.1 (CH₂), 114.8 (CH₂),

114.8 (CH₂), 71.7 (2 C), 70.6 (2 C), 66.0 (CH), 65.8 (CH), 65.7

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 156.9 (C), 143.9 (C), (CH), 65.5 (CH), 61.2 (CH₂), 61.1 (CH₂), 59.9 (CH₂), 59.8 (CH₂),

138.4 (C), 132.6 (CH), 130.9 (CH), 128.3 (CH), 127.7 (CH), 127.5

52.5 (2 CH₃), 52.5 (2 CH₃), 46.4 (CH₂), 46.0 (CH₂), 44.6 (CH₂),

(CH), 114.6 (CH₂), 72.8 (CH₂), 67.9 (CH₂), 63.0 (CH₂), 52.0 (CH₃), 44.2 (CH₂), 40.5 (CH), 39.5 (CH), 39.5 (CH), 38.8 (CH), 38.7 (CH),

51.2 (CH), 41.1 (CH₂), 39.9 (CH), 31.9 (CH₂), 20.3 (CH₃) ppm. 38.5 (CH), 37.8 (CH), 37.7 (CH), 26.3 (2 CH₃), 26.1 (CH₂), 26.0

HRMS (ESI⁺): calcd. for C₂₀H₂₉NaNO₄[M + Na]⁺370.1994; (CH₂), 25.4 (CH₂), 25.3 (CH₂), 23.1 (CH₃), 23.1 (CH₃), 15.8 (CH₂),

found 370.1990.

15.7 (CH₂), 15.0 (CH₂), 14.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for

C₁₃H₂₀INaNO₃[M + Na]⁺388.0386; found 388.0376.

Methyl (2R,3S,4S)-3-[2-(Benzyloxy)ethyl]-4-(prop-1-en-2-yl)-2-vin-

ylpyrrolidine-1-carboxylate (29): Bis(acetonitrile)dichloropalladi-

Methyl (1S,3aR,7aS)-1-(Hydroxymethyl)-4-(iodomethyl)-4-methyl-

um(II) (1.90 mg, 7.34 μmol) was added to a solution of methyl hexahydropyrano[3,4-c]pyrrole-2(3H)-carboxylate (34): Dichloro-

{(2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-hydroxy-2-(prop-1-en-2-yl)hex-

4-en-1-yl}carbamate (28; 510 mg, 1.47 mmol) in tetrahydrofuran

(10 mL) at 0 °C. The mixture was stirred for 2 h, then it was

quenched with water. The mixture was extracted with ethyl acetate

(3ϫ), and the combined organic extracts were washed with water

and brine. The resulting organic phase was dried with anhydrous

sodium sulfate, filtered, and evaporated under reduced pressure.

The crude product was purified by silica gel column chromatog-

raphy (ethyl acetate/hexane, 1:4) to give 29 (466 mg, 96.4%) as a

methane saturated with ozone was added to a solution of methyl

(1R,3aR,7aS)-4-(iodomethyl)-4-methyl-1-vinylhexahydropyrano-

[3,4-c]pyrrole-2(3H)-carboxylate (33; 119 mg, 0.326 mmol, a mix-

ture of two diasteromers) in methanol (2 mL) at –78 °C. After TLC

indicated the complete consumption of starting material, argon was

passed through the reaction mixture, and then sodium borohydride

(123 mg, 3.26 mmol) was added. Then, the resulting suspension

was warmed to 0 °C, and stirred for an additional 30 min. The

reaction mixture was quenched with saturated aqueous NH₄Cl.

The mixture was extracted with ethyl acetate (3ϫ), and the com-

colorless oil. [α]²_D³= –33.8 (c = 0.50, CHCl ). IR (film): ν = 3084,

˜

3

2949, 2861, 1704, 1644, 1450, 1382, 1194, 1114 cm^{–1 1}H NMR bined organic extracts were washed with saturated aqueous NH₄Cl

.

(400 MHz, CDCl₃, 60 °C): δ = 7.36–7.24 (m, 5 H), 5.78 (ddd, J =

17.0, 10.3, 5.1 Hz, 1 H), 5.10 (m, 2 H), 4.89 (m, 1 H), 4.66 (s, 1 H),

4.50 (d, J = 12.4 Hz, 1 H), 4.46 (d, J = 12.4 Hz, 1 H), 4.28–4.18

and brine. The resulting organic phase was dried with anhydrous

sodium sulfate, filtered, and evaporated under reduced pressure.

The crude product was purified by silica gel column chromatog-

(m, 1 H), 3.68 (s, 3 H), 3.56–3.41 (m, 4 H), 2.92–2.82 (m, 1 H), raphy (ethyl acetate/hexane, 3:1) to give 34 (120 mg, 100%) as a

2.20–2.13 (m, 1 H), 1.70 (s, 3 H), 1.65–1.53 (m, 1 H), 1.40–1.28 (m,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C; this material was

observed as a mixture of two rotamers): δ = 156.0 (C), 155.6 (C),

142.3 (C), 142.1 (C), 138.4 (2 C), 138.2 (CH), 137.7 (CH), 128.3 (2

white foam. This material was obtained as a mixture of two dia-

stereomers. [α]²_D⁶= 25.9 (c = 0.68, CHCl ). IR (film): ν = 3437,

˜

3

2951, 2876, 1686, 1455, 1389, 1081 cm^–1

.

¹H NMR (400 MHz,

CDCl₃, 25 °C; this material was observed as a mixture of two rota-

CH), 127.5 (2 CH), 127.5 (2 CH), 114.7 (CH₂), 114.3 (CH₂), 112.1 mers for each diastereomer): δ = 3.82–3.40 [m, 4 H + (1/2)1 H],

(CH₂), 112.0 (CH₂), 73.0 (CH₂), 72.9 (CH₂), 68.5 (CH₂), 68.3 3.74 (s, 3 H), 3.30 [d, J = 11.0 Hz, (1/2)1 H], 3.25–3.00 (m, 2 H),

(CH₂), 64.3 (CH), 63.9 (CH), 52.3 (2 CH₃), 47.5 (CH₂), 47.3 (CH₂), 2.53–2.15 (m, 2 H), 1.67–1.43 (m, 4 H), 1.44 [s, (1/2)3 H], 1.20 [s,

45.4 (CH), 44.5 (CH), 43.1 (CH), 42.0 (CH), 27.2 (2 CH₂), 22.6 (2 (1/2)3 H] ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C; this material

CH₃) ppm. HRMS (ESI⁺): calcd. for C₂₀H₂₇NaNO₃[M + Na]⁺was observed as a mixture of two rotamers for each diastereomer):

352.1889; found 352.1881.

δ = 157.6 (C), 157.4 (C), 156.0 (2 C), 71.6 (2 C), 70.4 (2 C), 66.9

(CH), 66.7 (CH), 65.9 (CH), 65.7 (CH), 64.5 (CH₂), 64.4 (CH₂),

62.9 (2 CH₂), 61.3 (2 CH₂), 60.0 (2 CH₂), 52.9 (2 CH₃), 52.6 (2

CH₃), 46.9 (CH₂), 46.5 (CH₂), 45.0 (CH₂), 44.7 (CH₂), 41.3 (CH),

40.2 (CH), 39.7 (CH), 38.6 (CH), 36.3 (CH), 35.8 (CH), 35.5 (CH),

35.0 (CH), 26.5 (CH₂), 26.3 (CH₂), 26.2 (2 CH₃), 25.7 (CH₂), 25.6

(CH₂), 23.3 (CH₃), 23.1 (CH₃), 15.8 (CH₂), 15.5 (CH₂), 15.3 (CH₂),

15.0 (CH₂) ppm. HRMS (ESI⁺): calcd. for C₁₂H₂₀INaNO₄[M +

Na]⁺392.0335; found 392.0332.

Methyl (1R,3aR,7aS)-4-(Iodomethyl)-4-methyl-1-vinylhexahydro-

pyrano[3,4-c]pyrrole-2(3H)-carboxylate (33): Iodine (200 mg,

0.789 mmol) was added to a solution of methyl (2R,3S,4S)-3-[2-

(benzyloxy)ethyl]-4-(prop-1-en-2-yl)-2-vinylpyrrolidine-1-carboxyl-

ate (29; 173 mg, 0.526 mmol) in dichloromethane (5 mL) at 0 °C.

The solution was gradually warmed to room temperature over 4 h,

and then the reaction mixture was quenched with saturated aque-

ous Na₂S₂O₃. The mixture was extracted with ethyl acetate (3ϫ),

and the combined organic extracts were washed with water and

brine. The resulting organic phase was dried with anhydrous so-

dium sulfate, filtered, and evaporated under reduced pressure. The

crude product was purified by silica gel column chromatography

Methyl (2S,3S,4S)-3-(2-Hydroxyethyl)-2-(hydroxymethyl)-4-(prop-

1-en-2-yl)pyrrolidine-1-carboxylate (35): Methyl (1S,3aR,7aS)-1-

(hydroxymethyl)-4-(iodomethyl)-4-methylhexahydropyrano[3,4-c]-

pyrrole-2(3H)-carboxylate (34; 91.0 mg, 0.246 mmol, a mixture of

Eur. J. Org. Chem. 0000, 0–0

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M. Fujii, S. Yokoshima, T. Fukuyama

FULL PAPER

two diasteromers) was dissolved in ethanol (0.8 mL), and a suspen-

sion of zinc in ethanol (3 mL) was added at 75 °C [the zinc was

preliminarily activated with dibromoethane (6 μL) and chlorotri-

methylsilane (9 μL) in ethanol suspension at 75 °C]. The mixture

was stirred for 5 min, and then acetic acid (300 μL, 5.24 mmol) was

added. The mixture was stirred for an additional 2 h at 75 °C, then

it was filtered through a Celite pad, and the filter cake was rinsed

with methanol. The filtrate was evaporated under reduced pressure

to give the crude diol. The crude product was purified by silica gel

column chromatography (methanol/dichloromethane, 1:25) to give

35 (56.0 mg, 93.4%) as a pale yellow oil. [α]²_D⁶= –31.6 (c = 0.30,

combined organic extracts were washed with saturated aqueous

NaHCO₃and brine. The resulting organic phase was dried with

anhydrous sodium sulfate, filtered, and evaporated under reduced

pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 1/4) to give 38a (2.44 g,

95.1%) as a pale red oil. [α]²_D⁶= –19.4 (c = 0.50, CHCl₃). IR (film):

ν = 2936, 1738, 1603, 1496, 1464, 1249, 1153, 1113, 1030, 969 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.36–7.21 (m, 6 H), 7.17

(dd, J = 7.5, 1.6 Hz, 1 H), 6.89 (ddd, J = 7.5, 7.2, 0.9 Hz, 1 H),

6.84 (dd, J = 8.2, 0.9 Hz, 1 H), 5.78 (dt, J = 15.3, 7.2 Hz, 1 H),

5.53 (dd, J = 15.3, 6.9 Hz, 1 H), 5.45 (dt, J = 6.9, 5.5 Hz, 1 H),

4.59 (d, J = 6.6 Hz, 1 H), 4.57 (d, J = 6.6 Hz, 1 H), 4.50 (s, 2 H),

CHCl ). IR (film): ν = 3382, 2950, 2888, 1677, 1460, 1394 cm^–1.

˜

3

¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 4.95 (br. s, 1 H), 4.91 (s, 3.77 (s, 3 H), 3.65 (s, 2 H), 3.60 (d, J = 5.5 Hz, 2 H), 3.49 (t, J =

1 H), 4.66 (s, 1 H), 4.05–3.97 (m, 1 H), 3.85–3.68 (m, 4 H), 3.76 (s, 6.9 Hz, 2 H), 3.31 (s, 3 H), 2.36 (dt, J = 7.0, 5.3 Hz, 2 H) ppm. ¹³

C

3 H), 3.55–3.42 (m, 2 H), 2.95–2.85 (m, 1 H), 2.70 (br. s, 1 H),

2.35–2.25 (m, 1 H), 1.74 (s, 3 H), 1.60–1.50 (m, 1 H), 1.44–1.32 (m,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 157.6 (C),

NMR (100 MHz, CDCl₃, 25 °C): δ = 171.1 (C), 157.6 (C), 138.5

(C), 131.6 (CH), 130.9 (CH), 128.6 (CH), 128.5 (CH), 127.7 (CH),

127.7 (CH), 127.0 (CH), 123.2 (C), 120.5 (CH), 110.4 (CH), 96.5

142.1 (C), 112.6 (CH₂), 64.8 (CH₂), 64.4 (CH), 61.0 (CH₂), 53.3 (CH₂), 73.3 (CH), 73.0 (CH₂), 69.5 (CH₂), 69.0 (CH₂), 55.4 (CH₃),

(CH₃), 48.2 (CH₂), 46.0 (CH), 38.8 (CH), 30.0 (CH₂), 22.6 (CH₃) 55.3 (CH₃), 36.2 (CH₂), 32.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for

ppm. HRMS (ESI⁺): calcd. for C₁₂H₂₁NaNO₄[M + Na]⁺

266.1368; found 266.1374.

Kainic Acid (2): Jones reagent^[29](8 n; 84 μL, 0.670 mmol) was oxyphenyl)hex-4-enoic Acid (39a): (R,E)-6-(Benzyloxy)-1-(meth-

added to a solution of methyl (2S,3S,4S)-3-(2-hydroxyethyl)-2- oxymethoxy)hex-3-en-2-yl 2-(2-methoxyphenyl)acetate (38a;

C₂₄H₃₀NaO₆[M + Na]⁺437.1940; found 437.1956.

(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-(2-meth-

(hydroxymethyl)-4-(prop-1-en-2-yl)pyrrolidine-1-carboxylate (35;

16.3 mg, 0.0670 mmol) in acetone at 0 °C. The mixture was stirred

for 10 min, then water (160 μL) was added. The mixture was stirred

for an additional 20 min, then it was warmed to room temperature.

After 90 min, additional Jones reagent (8 n; 42 μL, 0.335 mmol)

was added. The mixture was stirred for another 50 min, then water

(500 μL) was added, and it was stirred for an additional 40 min.

The reaction mixture was quenched with isopropyl alcohol

(300 μL), and then it was saturated with NaCl (ca. 230 mg). The

aqueous layer was extracted with ethyl acetate (5ϫ). The combined

organic extracts were evaporated under reduced pressure. The resi-

due was dissolved in NaOH solution (8% aq.; 2 mL), and this solu-

tion was washed with diethyl ether (2ϫ). The aqueous phase was

stirred at 100 °C for 17.5 h, and then cooled to room temperature.

The crude suspension was then filtered through two separate col-

umns of ion-exchange resin^[30][Amberlyst A-26 (OH^–form; water,

2.43 g, 5.86 mmol) was dissolved in diethyl ether (75 mL), and the

solution was cooled to –78 °C. Lithium bis(trimethylsilyl)amide

(1.17 m in tetrahydrofuran; 10.0 mL, 11.7 mmol) was added over

15 min, and then chlorotrimethylsilane (1.48 mL, 11.7 mmol) was

added dropwise. The mixture was stirred for 15 min, then it was

warmed to –20 °C. The mixture was stirred for another 2.5 h, then

it was quenched with saturated aqueous NH₄Cl. The mixture was

extracted with ethyl acetate (4ϫ), and the combined organic ex-

tracts were washed with brine. The resulting organic phase was

dried with anhydrous sodium sulfate, filtered, and evaporated un-

der reduced pressure. The crude product was purified by silica gel

column chromatography (ethyl acetate/hexane, 2:1) to give 39a

(2.10 g, 86.3%) as a pale yellow oil. This material was obtained as

a 33:1 mixture of diastereomers. [α]²_D⁶= +19.2 (c = 0.50, CHCl₃).

IR (film): ν = 2940, 1731, 1705, 1599, 1494, 1464, 1246, 1149, 1103,

˜

1

1029 cm^–1. H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.16 (m,

then 5% aqueous HCO₂H) and DOWEX 50WX8 (H⁺form, 200– 6 H), 7.19 (dd, J = 8.2, 7.4 Hz, 1 H), 6.89 (dd, J = 7.4, 7.3 Hz, 1

400 mesh; water, then 3% aqueous NH₃)] to give a pale yellow so-

lid. This material was purified by reverse-phase preparative TLC

(methanol/water, 3:97) to give 2 (7.2 mg, 50.4%) as a white solid.

H), 6.82 (d, J = 8.2 Hz, 1 H), 5.30 (d, J = 15.6 Hz, 1 H), 5.25 (d,

J = 15.6 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.43 (d, J = 11.9 Hz,

1 H), 4.30 (d, J = 6.2 Hz, 1 H), 4.23 (d, J = 6.2 Hz, 1 H), 4.17 (d,

J = 9.6 Hz, 1 H), 3.83–3.74 (m, 2 H), 3.79 (s, 3 H), 3.54–3.43 (m,

2 H), 3.23 (s, 3 H), 3.01–2.89 (m, 1 H), 2.07–1.97 (m, 1 H), 1.67–

m.p. 241–245 °C (decomp.). [α]²_D⁴= –14.4 (c = 0.36, H₂O). IR (film):

1

ν = 3411, 2971, 1624, 1588, 1399, 886 cm^–1. H NMR (400 MHz,

˜

D₂O, 25 °C): δ = 5.04 (s, 1 H), 4.76 (s, 1 H), 4.10 (d, J = 3.2 Hz, 1 1.56 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 178.2

H), 3.64 (dd, J = 11.9, 7.3 Hz, 1 H), 3.44 (dd, J = 11.9, 11.0 Hz, 1

H) 3.12–2.96 (m, 2 H), 2.45 (dd, J = 16.5, 6.4 Hz, 1 H), 2.35 (dd,

J = 16.5, 8.3 Hz, 1 H), 1.77 (s, 3 H) ppm. ¹³C NMR (100 MHz,

(C), 157.1 (C), 138.6 (C), 134.1 (CH), 129.3 (CH), 128.6 (CH),

128.5 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH), 125.7 (C), 120.8

(CH), 110.9 (CH), 94.5 (CH₂), 72.9 (CH₂), 68.3 (CH₂), 67.0 (CH₂),

D₂O, 25 °C): δ = 180.5 (C), 174.3 (C), 140.9 (C), 113.6 (CH₂), 66.6 55.7 (CH₃), 55.2 (CH₃), 47.8 (CH), 42.4 (CH), 33.1 (CH₂) ppm.

(CH), 47.0 (CH₂), 46.5 (CH), 42.6 (CH), 36.8 (CH₂), 22.8 (CH₃)

ppm. HRMS (ESI⁺): calcd. for C₁₀H₁₅NaNO₄[M + Na]⁺

236.0899; found 236.0898.

HRMS (ESI⁺): calcd. for C₂₄H₃₀NaO₆[M + Na]⁺437.1940; found

437.1935.

(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-(2-meth-

(R,E)-6-(Benzyloxy)-1-(methoxymethoxy)hex-3-en-2-yl 2-(2-Meth- oxyphenyl)hex-4-enamide (40a): Di-tert-butyl dicarbonate (1.52 g,

oxyphenyl)acetate (38a): 2-Methoxyphenylacetic acid (37a; 1.54 g,

9.28 mmol), N,NЈ-dicyclohexylcarbodiimide (2.17 g, 10.5 mmol),

and 4-(dimethylamino)pyridine (227 mg, 1.86 mmol) were added to

6.96 mmol) and pyridine (483 μL, 6.01 mmol) were added to a solu-

tion of (2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-(2-

methoxyphenyl)hex-4-enoic acid (39a; 1.92 g, 4.63 mmol) in ethyl

a solution of (R,E)-6-(benzyloxy)-1-(methoxymethoxy)hex-3-en-2- acetate (20 mL) at room temperature. The mixture was stirred for

ol (20; 1.65 g, 6.19 mmol) in dichloromethane (80 mL) at 0 °C. The

mixture was stirred for 3 h, then it was quenched with saturated

aqueous NH₄Cl. The resulting suspension was filtered through a

Celite pad, and the filter cake was rinsed with dichloromethane.

The filtrate was extracted with dichloromethane (3 ϫ), and the

3.5 h, then aqueous ammonia (14 m solution; 728 μL, 10.2 mmol)

was added. The mixture was stirred for an additional 1 h, then it

was quenched with HCl (1 m aqueous), and then neutralized with

saturated aqueous NaHCO₃. The mixture was extracted with ethyl

acetate (5ϫ), and the combined organic extracts were washed with

8

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Pages: 15

A Unified Strategy for Kainoid Synthesis

saturated aqueous NH₄Cl and brine. The resulting organic phase

was dried with anhydrous sodium sulfate, filtered, and evaporated

under reduced pressure. The crude product was purified by silica

gel column chromatography (ethyl acetate/hexane, 1:1 to 2:1) to

give 40a (1.79 g, 93.4%) as a pale yellow oil. [α]²_D⁶= +41.8 (c =

(CH), 41.9 (CH), 32.2 (CH₂) ppm. HRMS (ESI⁺): calcd. for

C₂₆H₃₅NaNO₆[M + Na]⁺480.2362; found 480. 2384.

Methyl {(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-hydroxy-2-(2-meth-

oxyphenyl)hex-4-en-1-yl}carbamate (43a): A solution of hydrogen

chloride in methanol [prepared from acetyl chloride (4 mL) and

methanol (25 mL)] was added to a flask containing methyl

{(2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-(2-

methoxyphenyl)hex-4-en-1-yl}carbamate (42a; 1.32 g, 2.88 mmol)

at 0 °C. The mixture was gradually warmed to room temperature

over 1.5 h. The mixture was stirred for an additional 6.5 h, then it

was cooled to 0 °C, and quenched with saturated aqueous

NaHCO₃. The mixture was extracted with ethyl acetate (4ϫ), and

the combined organic extracts were washed with saturated aqueous

NaHCO₃and brine. The resulting organic phase was dried with

anhydrous sodium sulfate, filtered, and evaporated under reduced

pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 1:2 to 4:1) to give 43a

(1.06 g, 88.9%) as a colorless oil. [α]²_D⁶= –61.7 (c = 0.50, CHCl₃).

0.50, CHCl ). IR (film): ν = 2939, 2868, 1680, 1491, 1244,

˜

3

1102 cm^–1. H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.38–7.21 (m,

1

6 H), 7.17 (ddd, J = 8.2, 7.4, 1.8 Hz, 1 H), 6.91 (ddd, J = 7.7, 7.4,

0.9 Hz, 1 H), 6.84 (dd, J = 8.2, 0.9 Hz, 1 H), 5.76 (br. s, 1 H), 5.33

(dt, J = 15.1, 6.0 Hz, 1 H), 5.25 (dd, J = 15.1, 9.2 Hz, 1 H), 5.19

(br. s, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 4.46 (d, J = 11.9 Hz, 1 H),

4.28 (d, J = 6.4 Hz, 1 H), 4.20 (d, J = 6.4 Hz, 1 H), 3.95 (d, J =

10.5 Hz, 1 H), 3.83 (s, 3 H), 3.78 (m, 2 H), 3.57–3.49 (m, 2 H), 3.22

(s, 3 H), 3.16–3.06 (m, 1 H), 2.12–2.03 (m, 1 H), 1.67–1.55 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 175.2 (C), 156.7

(C), 138.7 (C), 134.8 (CH), 129.5 (CH), 128.4 (CH), 128.2 (CH),

127.9 (CH), 127.7 (CH), 127.6 (CH), 126.6 (C), 121.1 (CH), 110.6

(CH), 94.4 (CH₂), 72.9 (CH₂), 68.4 (CH₂), 67.1 (CH₂), 55.6 (CH₃),

55.2 (CH₃), 48.9 (CH), 41.1 (CH), 33.2 (CH₂) ppm. HRMS (ESI⁺):

calcd. for C₂₄H₃₁NaNO₅[M + Na]⁺436.2100; found 436. 2082.

IR (film): ν = 3414, 2941, 2863, 1703, 1526, 1493, 1456, 1244 cm^–1.

˜

¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.25 (m, 5 H), 7.19

(dd, J = 8.2, 7.4 Hz, 1 H), 7.05 (d, J = 7.2 Hz, 1 H), 6.90 (dd, J =

7.4, 7.2 Hz, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 5.48 (dt, J = 15.2,

6.0 Hz, 1 H), 5.31 (dd, J = 15.2, 9.4 Hz, 1 H), 4.52 (m, 1 H), 4.47

(d, J = 12.1 Hz, 1 H), 4.40 (d, J = 12.1 Hz, 1 H), 3.96–3.89 (m, 2

H), 3.78 (s, 3 H), 3.76–3.63 (m, 1 H), 3.60 (s, 3 H), 3.47–3.40 (m,

1 H), 3.40–3.30 (m, 3 H), 2.61–2.53 (m, 1 H), 2.00–1.89 (m, 1 H),

1.43–1.32 (m, 1 H), 1.05 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 158.0 (C), 157.1 (C), 138.6 (C), 133.4 (CH),

131.3 (CH), 129.1 (CH), 128.4 (CH), 128.3 (C), 127.8 (CH), 127.8

(CH), 127.6 (CH), 120.5 (CH), 110.7 (CH), 72.9 (CH₂), 68.3 (CH₂),

63.4 (CH₂), 55.3 (CH₃), 52.0 (CH₃), 42.9 (CH₂), 42.1 (CH), 41.7

(CH), 32.0 (CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₄H₃₁NaNO₅

[M + Na]⁺436.2100; found 436.2108.

Methyl {(2S,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-

(2-methoxyphenyl)hex-4-en-1-yl}carbamate (42a): Aluminium

chloride (5.74 g, 43.1 mmol) was added to a stirred suspension of

lithium aluminium hydride (4.98 g, 131 mmol) in diethyl ether

(450 mL) at 0 °C, and the resulting suspension was stirred for

30 min. The supernatant solution was added to a stirred solution

of (2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-(methoxymethoxy)-2-(2-

methoxyphenyl)hex-4-enamide (40a; 1.78 g, 4.31 mmol) in tetra-

hydrofuran (70 mL) at 0 °C. The solution was stirred for 21 h, then

the reaction was quenched with Rochelle salt (30% aqueous solu-

tion), and the mixture was stirred for 8 h. The mixture was ex-

tracted with ethyl acetate (5ϫ), then with the mixed solvent (meth-

anol/dichloromethane, 1:9; 3ϫ), and the combined organic extracts

were washed with Rochelle salt (30% aqueous solution) and brine.

The resulting organic phase was dried with anhydrous sodium sulf-

ate, filtered, and evaporated under reduced pressure to give a crude

primary amine.

Methyl (2R,3S,4S)-3-[2-(Benzyloxy)ethyl]-4-(2-methoxyphenyl)-2-

vinylpyrrolidine-1-carboxylate (44a): Bis(acetonitrile)dichloropalla-

dium(II) (3.11 mg, 0.0120 mmol) was added to a solution of methyl

{(2S,3R,E)-3-[2-(benzyloxy)ethyl]-6-hydroxy-2-(2-methoxyphen-

yl)hex-4-en-1-yl}carbamate (43a; 990 mg, 2.39 mmol) in tetra-

The crude amine was dissolved in dichloromethane (50 mL) and

triethylamine (1.20 mL, 8.61 mmol) and methyl chloroformate hydrofuran (20 mL) at 0 °C. The mixture was stirred for 1.5 h, then

(562 μL, 7.32 mmol) were added at 0 °C. The mixture was stirred it was quenched with saturated aqueous NaHCO₃. The mixture

for 1 h, then it was quenched with saturated aqueous NH₄Cl. The

was extracted with ethyl acetate (3ϫ), and the combined organic

mixture was extracted with ethyl acetate (3ϫ), and the combined

extracts were washed with saturated aqueous NaHCO₃and brine.

organic extracts were washed with Rochelle salt (30 % aqueous The resulting organic phase was dried with anhydrous sodium sulf-

solution) and brine. The resulting organic phase was dried with

anhydrous sodium sulfate, filtered, and evaporated under reduced

pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 1:4 to 1:2) to give 42a

(1.37 g, 69.5%) as a colorless oil. [α]²_D⁶= –61.2 (c = 0.50, CHCl₃).

ate, filtered, and evaporated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 1:9 to 1:4) to give 44a (870 mg, 91.9%) as a color-

less oil. [α]²_D⁶= –53.1 (c = 0.50, CHCl ). IR (film): ν = 2951, 2862,

˜

3

1699, 1601, 1585, 1495, 1449, 1385, 1245, 1120, 1029, 919 cm^–1. ¹H

IR (film): ν = 3341, 2942, 2882, 1725, 1523, 1494, 1456, 1244, 1102,

NMR (400 MHz, CDCl₃, 60 °C): δ = 7.33–7.23 (m, 5 H), 7.20 (dd,

˜

1

1030 cm^–1. H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.26 (m, J = 7.7, 7.4 Hz, 1 H), 7.05 (d, J = 7.4 Hz, 1 H), 6.89 (dd, J = 7.8,

5 H), 7.18 (ddd, J = 8.3, 7.3, 1.4 Hz, 1 H), 7.04 (dd, J = 7.3, 1.4 Hz,

1 H), 6.89 (dd, J = 7.3, 7.3 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H),

7.7 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 5.88 (ddd, J = 16.8, 10.6,

6.1 Hz, 1 H), 5.16 (d, J = 16.8 Hz, 1 H), 5.14 (d, J = 10.6 Hz, 1

5.42 (dt, J = 15.2, 5.7 Hz, 1 H), 5.31 (dd, J = 15.2, 9.4 Hz, 1 H), H), 4.36 (s, 2 H), 4.27–4.21 (m, 1 H), 3.90 (m, 1 H), 3.85–3.66 (m,

4.49 (m, 1 H), 4.47 (d, J = 11.9 Hz, 1 H), 4.45 (d, J = 6.9 Hz, 1

H), 4.41 (d, J = 11.9 Hz, 1 H), 4.40 (d, J = 6.9 Hz, 1 H), 3.90 (d,

2 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 3.36 (t, J = 6.6 Hz, 2 H), 2.54–

2.46 (m, 1 H), 1.45–1.24 (m, 2 H) ppm. ¹³C NMR (100 MHz,

J = 5.7 Hz, 2 H), 3.77 (s, 3 H), 3.70–3.55 (m, 1 H), 3.59 (s, 3 H), CDCl₃, 25 °C; this material was observed as a mixture of two rota-

3.49–3.32 (m, 4 H), 3.30 (s, 3 H), 2.64–2.55 (m, 1 H), 1.99–1.89 (m, mers): δ = 157.4 (2 C), 156.2 (C), 155.7 (C), 138.6 (CH), 138.5 (2

1 H), 1.44–1.32 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, C), 138.1 (CH), 128.4 (2 CH), 127.8 (2 CH), 127.7 (2 CH), 127.7

25 °C): δ = 158.1 (C), 157.0 (C), 138.7 (C), 135.0 (CH), 129.1 (CH),

128.4 (CH), 128.3 (C), 128.0 (CH), 127.8 (CH), 127.8 (CH), 127.6

(2 CH), 127.6 (2 CH), 127.3 (C), 127.0 (C), 120.1 (2 CH), 115.2

(CH₂), 114.5 (CH₂), 110.3 (2 CH), 72.8 (2 CH₂), 68.9 (CH₂), 68.6

(CH), 120.5 (CH), 110.8 (CH), 94.9 (CH₂), 73.0 (CH₂), 68.4 (CH₂), (CH₂), 64.7 (CH), 64.3 (CH₂), 55.3 (2 CH₃), 52.4 (2 CH₃), 49.0

67.4 (CH₂), 55.3 (CH₃), 55.2 (CH₃), 52.0 (CH₃), 43.2 (CH₂), 42.1 (CH₂), 48.8 (CH₂), 44.1 (CH), 43.3 (CH), 38.1 (CH), 37.5 (CH),

Eur. J. Org. Chem. 0000, 0–0

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M. Fujii, S. Yokoshima, T. Fukuyama

FULL PAPER

27.9 (2 CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₄H₂₉NaNO₄[M +

alcohol (300 μL). The mixture was extracted with diethyl ether

(5ϫ), and the combined organic extracts were evaporated under

reduced pressure. The residue was dissolved in NaOH solution (8%

aq.; 5 mL), and this solution was washed with diethyl ether (2ϫ).

The aqueous phase was stirred at 100 °C for 5 h, and then cooled

to room temperature. The crude suspension was then filtered

through two separate columns of ion-exchange resin [Amberlyst A-

26 (OH^–form; water, then 5% aqueous HCO₂H) and DOWEX

50WX8 (H⁺form, 200–400 mesh; water, then 3% aqueous NH₃)]

to give a pale yellow solid. This material was purified by reverse-

phase silica gel column chromatography (only water to methanol/

water, 1:4) to give 6 (24.5 mg, 47.6%) as a white solid. m.p. 230–

Na]⁺418.1994; found 418.1988.

Methyl (2S,3S,4S)-3-[2-(Benzyloxy)ethyl]-2-(hydroxymethyl)-4-(2-

methoxyphenyl)pyrrolidine-1-carboxylate (45a): Dichloromethane

saturated with ozone was added to a solution of methyl (2R,3S,4S)-3-

[2-(benzyloxy)ethyl]-4-(2-methoxyphenyl)-2-vinylpyrrolidine-1-carb-

oxylate (44a; 143 mg, 0.362 mmol) in methanol (1 mL) at –78 °C.

After TLC indicated the complete consumption of the starting ma-

terial, argon was passed through the reaction mixture, and then

sodium borohydride (137 mg, 3.62 mmol) was added. The resulting

suspension was warmed to 0 °C, and then stirred for an additional

1 h. The reaction mixture was quenched with saturated aqueous

NH₄Cl. The mixture was extracted with dichloromethane (3ϫ),

and the combined organic extracts were washed with saturated

aqueous NH₄Cl and brine. The resulting organic phase was dried

with anhydrous sodium sulfate, filtered, and evaporated under re-

duced pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 1:1) to give 45a (131 mg,

232 °C (decomp.). [α]²_D³= +5.94 (c = 1.05, H O). IR (film): ν =

˜

2

3415, 3066, 1623, 1584, 1396, 1248 cm^{–1 1}H NMR (400 MHz,

.

D₂O, 25 °C): δ = 7.38 (dd, J = 7.8, 7.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz,

1 H), 7.08 (d, J = 8.2 Hz, 1 H), 7.00 (dd, J = 7.3, 7.3 Hz, 1 H),

4.08 (d, J = 7.4 Hz, 1 H), 3.96 (ddd, J = 8.3, 8.0, 8.0 Hz, 1 H), 3.87

(s, 3 H), 3.83 (dd, J = 12.2, 8.0 Hz, 1 H), 3.74 (dd, J = 12.2, 8.0 Hz,

1 H), 3.19–3.11 (m, 1 H), 2.36 (dd, J = 16.0, 5.5 Hz, 1 H), 1.90

(dd, J = 16.0, 9.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, D₂O, 25 °C):

δ = 179.4 (C), 174.5 (C), 157.9 (C), 130.5 (CH), 129.9 (CH), 125.1

(C), 121.4 (CH), 111.9 (CH), 66.3 (CH), 55.9 (CH₃), 48.5 (CH₂),

43.7 (CH), 42.2 (CH), 36.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for

C₁₄H₁₇NaNO₅[M + Na]⁺302.1004; found 302.1014.

90.3%) as a colorless oil. [α]²_D⁶= –47.8 (c = 1.39, CHCl₃). IR (film):

1

ν = 3446, 2951, 2873, 1683, 1495, 1456, 1389, 1241, 1122 cm^–1. H

˜

NMR (400 MHz, CDCl₃, 25 °C): δ = 7.35–7.25 (m, 5 H), 7.22 (dd,

J = 7.3, 7.3 Hz, 1 H), 6.98 (d, J = 7.3 Hz, 1 H), 6.90 (dd, J = 7.8,

7.3 Hz, 1 H), 6.84 (d, J = 7.8 Hz, 1 H), 4.40 (s, 2 H), 4.33 (m, 1

H), 3.96–3.70 (m, 5 H), 3.76 (s, 3 H), 3.76 (s, 3 H), 3.67 (dd, J =

10.6, 7.4 Hz, 1 H), 3.43–3.33 (m, 2 H), 2.48–2.37 (m, 1 H), 1.46–

1.22 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 158.1

(C), 157.3 (C), 138.4 (C), 128.5 (CH), 128.0 (CH), 127.8 (CH),

127.8 (CH), 127.7 (C), 127.7 (CH), 120.8 (CH), 110.4 (CH), 73.0

(CH₂), 68.5 (CH₂), 67.3 (CH₂), 65.6 (CH), 55.3 (CH₃), 53.1 (CH₃),

50.7 (CH₂), 40.9 (CH), 38.3 (CH), 28.6 (CH₂) ppm. HRMS (ESI⁺):

calcd. for C₂₃H₂₉NaNO₅[M + Na]⁺422.1943; found 422.1932.

(R,E)-6-(Benzyloxy)-1-(methoxymethoxy)hex-3-en-2-yl 2-Cyclo-

propylacetate (38b): Cyclopropylacetic acid (37b; 439 mg,

4.39 mmol), N,NЈ-dicyclohexylcarbodiimide (969 mg, 4.698 mmol),

and 4-(dimethylamino)pyridine (115 mg, 0.940 mmol) were added

to a solution of (R,E)-6-(benzyloxy)-1-(methoxymethoxy)hex-3-en-

2-ol (20; 834 mg, 3.13 mmol) in dichloromethane (40 mL) at 0 °C.

The mixture was stirred for 7.5 h, then it was quenched with satu-

rated aqueous NH₄Cl. The resulting suspension was filtered

through a Celite pad, and the filter cake was rinsed with dichloro-

methane. The filtrate was extracted with dichloromethane (3ϫ),

and the combined organic extracts were washed with saturated

aqueous NaHCO₃and brine. The resulting organic phase was dried

with anhydrous sodium sulfate, filtered, and evaporated under re-

duced pressure. The crude product was purified by silica gel column

chromatography (ethyl acetate/hexane, 1:9 to 1:4) to give 38b

Methyl (2S,3S,4S)-3-(2-Hydroxyethyl)-2-(hydroxymethyl)-4-(2-

methoxyphenyl)pyrrolidine-1-carboxylate (46a): Palladium hydrox-

ide (20 % on carbon; wetted with ca. 50 % water; 12.6 mg,

9.03 μmol) was added to a solution of methyl (2S,3S,4S)-3-[2-

(benzyloxy)ethyl]-2-(hydroxymethyl)-4-(2-methoxyphenyl) pyrrol-

idine-1-carboxylate (45a; 120 mg, 0.301 mmol) in methanol

(10 mL). The flask was charged with hydrogen gas (1 atm) at room

temperature. The mixture was stirred for 1.5 h at room temperature,

then it was filtered through a Celite pad, and concentrated under

reduced pressure. The crude product was purified by silica gel col-

umn chromatography (ethyl acetate/hexane, 7:3, then methanol/

dichloromethane, 1:9) to give 46a (85.9 mg, 92.2%) as a pale yellow

(1.04 g, 95.4%) as a colorless oil. [α]²_D⁴= –20.9 (c = 0.50, CHCl₃).

1

IR (film): ν = 2934, 2881, 2855, 1953, 1112, 1038 cm^–1. H NMR

˜

(400 MHz, CDCl₃, 25 °C): δ = 7.38–7.24 (m, 5 H), 5.84 (dt, J =

15.6, 6.6 Hz, 1 H), 5.55 (dd, J = 15.6, 6.8 Hz, 1 H), 5.46 (dt, J =

6.8, 5.3 Hz, 1 H), 4.64 (d, J = 6.4 Hz, 1 H), 4.62 (d, J = 6.4 Hz, 1

H), 4.50 (s, 2 H), 3.62 (m, 2 H), 3.51 (t, J = 6.6 Hz, 2 H), 3.35 (s,

3 H), 2.38 (dt, J = 6.6, 6.6 Hz, 2 H), 2.24 (d, J = 7.3 Hz, 2 H),

1.10–1.00 (m, 1 H), 0.56–0.50 (m, 2 H), 0.18–0.12 (m, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 172.5 (C), 138.4 (C),

131.8 (CH), 128.5 (CH), 127.7 (CH), 127.7 (CH), 127.0 (CH), 96.5

(CH₂), 73.0 (CH), 73.0 (CH₂), 69.5 (CH₂), 69.1 (CH₂), 55.4 (CH₃),

39.6 (CH₂), 32.9 (CH₂), 7.0 (CH), 4.5 (CH₂), 4.4 (CH₂) ppm.

HRMS (ESI⁺): calcd. for C₂₀H₂₈NaO₅[M + Na]⁺371.1834; found

371.1827.

oil. [α]²_D⁶= –79.1 (c = 0.63, CHCl ). IR (film): ν = 3402, 2952, 1679,

˜

3

1494, 1461, 1391, 1244, 1123, 1051 cm^–1

.

¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 7.24 (dd, J = 7.6, 7.6 Hz, 1 H), 7.00 (d, J =

7.6 Hz, 1 H), 6.92 (dd, J = 7.6, 7.6 Hz, 1 H), 6.88 (d, J = 7.6 Hz,

1 H), 4.30 (m, 1 H), 3.96–3.73 (m, 5 H), 3.83 (s, 3 H), 3.77 (s, 3

H), 3.69 (dd, J = 10.6, 6.9 Hz, 1 H), 3.64–3.52 (m, 2 H), 2.48–2.38

(m, 1 H), 1.55 (br. s, 1 H), 1.40–1.17 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, 25 °C): δ = 157.7 (C), 157.2 (C), 128.1 (CH),

127.6 (CH), 127.6 (C), 120.8 (CH), 110.5 (CH), 66.2 (CH₂), 65.2

(CH), 61.0 (CH₂), 55.5 (CH₃), 53.0 (CH₃), 50.5 (CH₂), 40.7 (CH),

38.3 (CH), 31.3 (CH₂) ppm. HRMS (ESI⁺): calcd. for

C₁₆H₂₃NaNO₅[M + Na]⁺332.1474; found 332.1466.

(2R,3R,E)-3-[2-(Benzyloxy)ethyl]-2-cyclopropyl-6-(methoxymeth-

oxy)hex-4-enoic Acid (39b): (R,E)-6-(Benzyloxy)-1-(methoxymeth-

oxy)hex-3-en-2-yl 2-cyclopropylacetate (38b; 1.02 g, 2.91 mmol)

was dissolved in diethyl ether (35 mL), and the solution was cooled

to –78 °C. Lithium bis(trimethylsilyl)amide (1.17 m in tetra-

hydrofuran; 5.28 mL, 6.17 mmol) was added over 10 min, and then

chlorotrimethylsilane (780 μL, 6.17 mmol) was added dropwise.

MFPA (6): A solution of methyl (2S,3S,4S)-3-(2-hydroxyethyl)-2-

(hydroxymethyl)-4-(2-methoxyphenyl) pyrrolidine-1-carboxylate

(46a; 57.0 mg, 0.184 mmol) in acetone (2 mL) was added dropwise

to a solution of Jones reagent (8 n; 230 μL, 1.84 mmol) in acetone

(0.5 mL) at 0 °C. The mixture was stirred for 10 min, then it was The mixture was stirred for 10 min, then it was warmed to 0 °C.

warmed to room temperature, and water (30 μL) was added. The

mixture was stirred for 1.5 h, then it was quenched with isopropyl

The mixture was stirred for another 4.5 h, and then it was

quenched with saturated aqueous NH₄Cl. The mixture was ex-

10

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A Unified Strategy for Kainoid Synthesis

tracted with ethyl acetate (4ϫ), and the combined organic extracts

were washed with brine. The resulting organic phase was dried with

anhydrous sodium sulfate, filtered, and evaporated under reduced

pressure. The crude product was purified by silica gel column

chromatography (two separate columns: methanol/dichlorometh-

ane, 1:99 to 1:9, then ethyl acetate/hexane, 1:2 to 1:0) to give 39b

ammonia (7 n aqueous), and the mixture was stirred for 6 h. The

mixture was extracted with the mixed solvent (methanol/dichloro-

methane, 1:9; 5ϫ), and the combined organic extracts were washed

with Rochelle salt (30% aqueous solution) and brine. The resulting

organic phase was dried with anhydrous sodium sulfate, filtered,

and evaporated under reduced pressure to give a crude primary

(949 mg, 93.4%) as a pale yellow oil. This material was obtained amine.

as a 17:1 mixture of diastereomers. [α]²_D⁴= –1.39 (c = 0.50, CHCl₃).

The crude amine was dissolved in dichloromethane (20 mL), and

IR (film): ν = 3070, 2936, 1731, 1704, 1454, 1366, 1104 cm^–1. ¹H

˜

triethylamine (600 μL, 4.31 mmol) and methyl chloroformate

(281 μL, 3.66 mmol) were added at 0 °C. The mixture was stirred

for 100 min, then the mixture was quenched with saturated aque-

ous NH₄Cl. The mixture was extracted with dichloromethane

(4ϫ), and the combined organic extracts were washed with brine.

The resulting organic phase was dried with anhydrous sodium sulf-

ate, filtered, and evaporated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 1:4 to 1:2) to give 42b (635 mg, 75.3%) as a color-

NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.26 (m, 5 H), 5.61 (dt,

J = 15.6, 5.5 Hz, 1 H), 5.53 (dd, J = 15.6, 9.2 Hz, 1 H), 4.62 (d, J

= 6.4 Hz, 1 H), 4.60 (d, J = 6.4 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1

H), 4.44 (d, J = 11.9 Hz, 1 H), 4.02 (d, J = 5.5 Hz, 2 H), 3.54–3.40

(m, 2 H), 3.36 (s, 3 H), 2.78–2.67 (m, 1 H), 1.95–1.85 (m, 1 H),

1.70–1.58 (m, 1 H), 1.62 (dd, J = 10.1, 7.8 Hz, 1 H), 0.96–0.86 (m,

1 H), 0.65–0.55 (m, 1 H), 0.55–0.45 (m, 1 H), 0.27–0.20 (m, 1 H),

0.20–0.13 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ =

180.4 (C), 138.4 (C), 134.2 (CH), 128.6 (CH), 128.4 (CH), 127.9

(CH), 127.7 (CH), 95.3 (CH₂), 73.0 (CH₂), 68.2 (CH₂), 67.5 (CH₂),

55.5 (CH), 55.3 (CH₃), 42.7 (CH), 32.6 (CH₂), 11.7 (CH), 6.5

(CH₂), 2.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₀H₂₈NaO₅[M

+ Na]⁺371.1834; found 371.1852.

less oil. [α]²_D⁵= –10.6 (c = 0.53, CHCl ). IR (film): ν = 3347, 2940,

˜

3

2879, 1726, 1531, 1258, 1103, 1030 cm^–1

.

¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 7.37–7.25 (m, 5 H), 5.63, (dd, J = 15.6, 9.2 Hz,

1 H), 5.54 (dt, J = 15.6, 5.5 Hz, 1 H), 4.84 (m, 1 H), 4.62 (s, 2 H),

4.50 (d, J = 11.9 Hz, 1 H), 4.44 (d, J = 11.9 Hz, 1 H), 4.02 (d, J =

5.5 Hz, 2 H), 3.65 (s, 3 H), 3.50–3.35 (m, 2 H), 3.36 (s, 3 H), 3.28–

3.13 (m, 2 H), 2.44–2.36 (m, 1 H), 1.84–1.76 (m, 2 H), 0.87–0.77

(m, 1 H), 0.58–0.40 (m, 3 H), 0.23–0.15 (m, 1 H), 0.15–0.05 (m, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 157.1 (C), 138.6

(C), 134.5 (CH), 128.6 (CH), 128.4 (CH), 127.8 (CH), 127.6 (CH),

95.5 (CH₂), 73.1 (CH₂), 68.7 (CH₂), 67.8 (CH₂), 55.3 (CH₃), 52.1

(CH₃), 48.1 (CH), 44.5 (CH₂), 41.8 (CH), 32.8 (CH₂), 10.6 (CH),

4.8 (CH₂), 2.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₂H₃₃NaNO₅

[M + Na]⁺414.2256; found 414.2243.

(2R,3R,E)-3-[2-(Benzyloxy)ethyl]-2-cyclopropyl-6-(methoxymeth-

oxy)hex-4-enamide (40b): Di-tert-butyl dicarbonate (1.10 g,

5.03 mmol) and pyridine (242 μL, 3.02 mmol) were added to a solu-

tion of (2R,3R,E)-3-[2-(benzyloxy)ethyl]-2-cyclopropyl-6-(meth-

oxymethoxy)hex-4-enoic acid (39b; 876 mg, 2.51 mmol) in ethyl

acetate (10 mL) at room temperature. The mixture was stirred for

3.5 h, then aqueous ammonia (14 m solution; 359 μL, 5.03 mmol)

was added. The mixture was stirred for another 1.5 h, then ad-

ditional aqueous ammonia (14 m solution; 180 μL, 2.52 mmol) was

added. The mixture was stirred for 2.5 h, thn the reaction mixture

was quenched with saturated aqueous NH₄Cl, and then neutralized

with saturated aqueous NaHCO₃. The mixture was extracted with

ethyl acetate (4ϫ), and the combined organic extracts were washed

with brine. The resulting organic phase was dried with anhydrous

sodium sulfate, filtered, and evaporated under reduced pressure.

The crude product was purified by silica gel column chromatog-

raphy (ethyl acetate/hexane, 1:2 to 1:0) to give 40b (778 mg, 89.1%)

as a white solid. m.p. 80.5–82.3 °C. [α]²_D⁵= +6.84 (c = 0.50, CHCl₃).

Methyl {(2R,3R,E)-3-[2-(Benzyloxy)ethyl]-2-cyclopropyl-6-hydroxy-

hex-4-en-1-yl}carbamate (43b): A solution of hydrogen chloride in

methanol [prepared from acetyl chloride (3 mL) and methanol

(15 mL)] was added to a flask containing methyl {(2R,3R,E)-3-[2-

(benzyloxy)ethyl]-2-cyclopropyl-6-(methoxymethoxy)hex-4-en-1-

yl}carbamate (42b; 604 mg, 1.54 mmol) at 0 °C. The mixture was

gradually warmed to room temperature over 2 h. The mixture was

stirred for an additional 5 h, then it was cooled to 0 °C and

quenched with saturated aqueous NaHCO₃. The mixture was ex-

tracted with ethyl acetate (3ϫ), then the aqueous layer was satu-

rated with NaCl, and then extracted again with ethyl acetate (2ϫ).

The resulting organic phase was dried with anhydrous sodium sulf-

ate, filtered, and evaporated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 1:2 to 4:1) to give 43b (477 mg, 88.9%) as a color-

IR (film): ν = 3378, 3187, 2930, 2895, 2865, 1652, 1118 cm^–1. ¹H

˜

NMR (400 MHz, CDCl₃, 25 °C): δ = 7.37–7.25 (m, 5 H), 5.74 (br.

s, 1 H), 5.68–5.56 (m, 2 H), 5.41 (br. s, 1 H), 4.62 (d, J = 6.2 Hz,

1 H), 4.60 (d, J = 6.2 Hz, 1 H), 4.49 (d, J = 11.9 Hz, 1 H), 4.44 (d,

J = 11.9 Hz,1 H), 4.02 (d, J = 4.2 Hz, 2 H), 3.55–3.39 (m, 2 H),

3.35 (s, 3 H), 2.80–2.73 (m, 1 H), 1.94–1.85 (m, 1 H), 1.78–1.67 (m,

1 H), 1.49 (dd, J = 10.1, 6.4 Hz, 1 H), 0.92–0.82 (m, 1 H), 0.68–

0.60 (m, 1 H), 0.57–0.47 (m, 1 H), 0.27–0.13 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃, 25 °C): δ = 176.9 (C), 138.5 (C), 134.4

(CH), 128.4 (CH), 127.8 (CH), 127.8 (CH), 127.6 (CH), 95.4 (CH₂),

73.0 (CH₂), 68.4 (CH₂), 67.7 (CH₂), 56.4 (CH), 55.3 (CH₃), 42.6

(CH), 32.6 (CH₂), 11.2 (CH), 6.6 (CH₂), 3.1 (CH₂) ppm. HRMS

(ESI⁺): calcd. for C₂₀H₂₉NaNO₄[M + Na]⁺370.1994; found

370.1991.

less oil. [α]²_D⁵= –13.4 (c = 0.54, CHCl ). IR (film): ν = 3339, 3000,

˜

3

2937, 2866, 1703, 1535, 1264, 1099 cm^–1

.

¹H NMR (400 MHz,

CDCl₃, 25 °C): δ = 7.36–7.24 (m, 5 H), 5.66–5.54 (m, 2 H), 4.76

(m, 1 H), 4.50 (d, J = 12.2 Hz, 1 H), 4.44 (d, J = 12.2 Hz, 1 H),

4.10–4.04 (m, 2 H), 3.65 (s, 3 H), 3.50–3.35 (m, 2 H), 3.30–3.15 (m,

2 H), 2.46–2.36 (m, 1 H), 1.83–1.73 (m, 2 H), 1.60–1.50 (m, 1 H),

0.85–0.77 (m, 1 H), 0.55–0.42 (m, 3 H), 0.22–0.14 (m, 1 H), 0.12–

0.06 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 157.2

(C), 138.5 (C), 132.5 (CH), 131.8 (CH), 128.4 (CH), 127.8 (CH),

127.6 (CH), 73.0 (CH₂), 68.6 (CH₂), 63.4 (CH₂), 52.1 (CH₃), 48.1

(CH), 44.2 (CH₂), 41.5 (CH), 32.6 (CH₂), 10.4 (CH), 4.8 (CH₂),

2.9 (CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₀H₂₉NaNO₄[M + Na]

Methyl {(2R,3R,E)-3-[2-(Benzyloxy)ethyl]-2-cyclopropyl-6-(meth-

oxymethoxy)hex-4-en-1-yl}carbamate (42b): Aluminium chloride

(2.00 g, 15.0 mmol) was added to a stirred suspension of lithium

aluminium hydride (1.74 g, 45.8 mmol) in diethyl ether (250 mL) at

0 °C, and the suspension was stirred for 70 min. The supernatant

solution was added to a stirred solution of (2R,3R,E)-3-[2-(benz-

yloxy)ethyl]-2-cyclopropyl-6-(methoxymethoxy)hex-4-enamide

+

370.1994; found 370.1988.

Methyl (2R,3S,4R)-3-[2-(Benzyloxy)ethyl]-4-cyclopropyl-2-vinylpyr-

(40b; 748 mg, 2.15 mmol) in tetrahydrofuran (30 mL) at 0 °C. The rolidine-1-carboxylate (44b): Bis(acetonitrile)dichloropalladium(II)

solution was stirred for 16.5 h, then the reaction was quenched with (1.50 mg, 5.79 μmol) was added to a solution of methyl

Eur. J. Org. Chem. 0000, 0–0

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M. Fujii, S. Yokoshima, T. Fukuyama

FULL PAPER

{(2R,3R,E)-3-[2-(benzyloxy)ethyl]-2-cyclopropyl-6-hydroxyhex-4-

en-1-yl}carbamate (43b; 453 mg, 1.16 mmol) in tetrahydrofuran

(8 mL) at 0 °C. The mixture was stirred for 1.5 h, then it was

quenched with H₂O. The mixture was extracted with ethyl acetate

(3ϫ), and the combined organic extracts were washed with brine

(2ϫ). The resulting organic phase was dried with anhydrous so-

dium sulfate, filtered, and evaporated under reduced pressure. The

crude product was purified by silica gel column chromatography

acetate/hexane, 2:1, then methanol/dichloromethane, 3:37) to give

46b (77.9 mg, 90.8%) as a colorless oil. [α]²_D⁶= –8.08 (c = 0.54,

CHCl ). IR (film): ν = 3403, 2945, 2878, 1681, 1457, 1390 cm^–1.

˜

3

¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 4.29 (br. s, 1 H), 3.84–

3.60 (m, 5 H), 3.73 (s, 3 H), 3.48–3.38 (m, 2 H), 2.10–2.00 (m, 2

H), 1.70–1.53 (m, 2 H), 1.52–1.40 (m, 1 H), 0.67–0.53 (m, 2 H),

0.53–0.43 (m, 1 H), 0.24–0.12 (m, 1 H), 0.12–0.03 (m, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 157.6 (C), 65.5 (CH₂),

(ethyl acetate/hexane, 1:4) to give 44b (363 mg, 84.5%) as a color- 64.4 (CH), 60.9 (CH₂), 52.8 (CH₃), 51.8 (CH₂), 45.2 (CH), 40.4

less oil. [α]²_D⁵= –2.90 (c = 0.49, CHCl ). IR (film): ν = 3079, 2949,

(CH), 30.9 (CH₂), 10.0 (CH), 4.8 (CH₂), 3.6 (CH₂) ppm. HRMS

˜

3

2868, 1704, 1449, 1384, 1105 cm^–1. ¹H NMR (400 MHz, CDCl₃, (ESI⁺): calcd. for C₁₂H₂₁NaNO₄[M + Na]⁺266.1368; found

60 °C): δ = 7.37–7.24 (m, 5 H), 5.69 (ddd, J = 17.4, 10.1, 6.0 Hz, 266.1377.

1 H), 5.14–5.00 (m, 2 H), 4.50 (s, 2 H), 4.16–4.06 (m, 1 H), 3.66 (s,

3 H), 3.58–3.52 (m, 2 H), 3.50–3.42 (m, 1 H), 3.42–3.30 (m, 1 H),

CPKA (7): Jones reagent (8 n; 114 μL, 0.913 mmol) was added to

a solution of methyl (2S,3S,4R)-4-cyclopropyl-3-(2-hydroxyethyl)-

2-(hydroxymethyl)pyrrolidine-1-carboxylate (46b; 22.2 mg,

0.0912 mmol) in acetone (2 mL) at 0 °C. The mixture was stirred

for 5 min, then water (240 μL) was added, and the mixture was

warmed to room temperature. After 2.3 h, additional Jones reagent

(8 n; 57.0 μL, 0.456 mmol) and water (800 μL) were added. The

mixture was stirred for 1 h, then it was quenched with isopropyl

alcohol (500 μL). The aqueous mixture was saturated with NaCl

(ca. 450 mg), then extracted with ethyl acetate (5ϫ), and the com-

bined organic extracts were evaporated under reduced pressure.

The residue was dissolved in NaOH solution (12% aq.; 2 mL), and

2.05–1.95 (m, 2 H), 1.68–1.56 (m, 1 H), 1.52–1.42 (m, 1 H), 0.65–

0.55 (m, 1 H), 0.55–0.42 (m, 2 H), 0.12–0.03 (m, 2 H) ppm. ¹³C

NMR (100 MHz, CDCl₃, 25 °C; this material was observed as a

mixture of two rotamers): δ = 155.8 (C), 155.4 (C), 138.4 (CH),

138.2 (2 C), 137.9 (CH), 128.2 (2 CH), 127.5 (2 CH), 127.4 (2 CH),

114.8 (CH₂), 114.2 (CH₂), 72.8 (2 CH₂), 68.6 (CH₂), 68.5 (CH₂),

64.0 (CH), 63.7 (CH), 52.0 (2 CH₃), 50.8 (CH₂), 50.6 (CH₂), 44.8

(2 CH), 43.9 (CH), 43.8 (CH), 27.5 (2 CH₂), 9.4 (2 CH), 4.0 (2

CH₂), 3.6 (2 CH₂) ppm. HRMS (ESI⁺): calcd. for C₂₀H₂₇NaNO₃

[M + Na]⁺352.1889; found 352.1880.

Methyl (2S,3S,4R)-3-[2-(Benzyloxy)ethyl]-4-cyclopropyl-2-(hydroxy-

methyl)pyrrolidine-1-carboxylate (45b): Dichloromethane saturated

with ozone was added to a solution of methyl (2R,3S,4R)-3-[2-

(benzyloxy)ethyl]-4-cyclopropyl-2-vinylpyrrolidine-1-carboxylate

(44b; 152 mg, 0.460 mmol) in methanol (1 mL) at –78 °C. After

TLC indicated complete consumption of the starting material, ar-

gon was passed through the reaction mixture, and then sodium

borohydride (87.0 mg, 2.30 mmol) was added. Then, the resulting

suspension was warmed to 0 °C, and stirred for an additional 1.5 h.

The reaction mixture was quenched with saturated aqueous NH₄Cl

and brine. The mixture was extracted with dichloromethane (3ϫ),

and the combined organic extracts were washed with brine (2ϫ).

The resulting organic phase was dried with anhydrous sodium sulf-

ate, filtered, and evaporated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

acetate/hexane, 1:2 to 2:1) to give 45b (133 mg, 86.8%) as a color-

the resulting solution was washed with diethyl ether (2 ϫ). The

aqueous phase was stirred at 100 °C for 21.5 h, and then cooled to

room temperature. The crude suspension was then filtered through

two separate columns of ion-exchange resin [Amberlyst A-26 (OH^–

form; water, then 5% aqueous HCO₂H) and DOWEX 50WX8 (H⁺

form, 200–400 mesh; water, then 3% aqueous NH₃)] to give a pale

yellow solid. This material was purified by reverse-phase prepara-

tive TLC (methanol/water, 3:97) to give 7 (10.4 mg, 53.3%) as a

white solid. m.p. 252–254 °C (decomp.). [α]²_D⁴= 23.1 (c = 0.46,

1

H O). IR (film): ν = 3402, 3003, 1714, 1623, 1400 cm^–1. H NMR

˜

2

(400 MHz, D₂O, 25 °C): δ = 3.95 (d, J = 8.3 Hz, 1 H), 3.58 (dd, J

= 11.8, 6.9 Hz, 1 H), 3.38 (dd, J = 11.8, 4.3 Hz, 1 H), 2.97–2.77

(m, 3 H), 1.88–1.75 (m, 1 H), 0.73–0.60 (m, 2 H), 0.60–0.50 (m, 1

H), 0.24–0.10 (m, 2 H) ppm. ¹³C NMR (100 MHz, D₂O, 25 °C): δ

= 177.3 (C), 174.1 (C), 64.5 (CH), 50.9 (CH₂), 46.3 (CH), 43.2

(CH), 34.4 (CH₂), 9.7 (CH), 5.5 (CH₂), 2.9 (CH₂) ppm. HRMS

(ESI⁺): calcd. for C₁₀H₁₅NaNO₄[M + Na]⁺236.0899; found

less oil. [α]²_D¹= –7.04 (c = 0.50, CHCl ). IR (film): ν = 3437, 2947,

˜

3

2871, 1699, 1680, 1454, 1389, 1110 cm^–1

.

¹H NMR (400 MHz, 236.0897.

CDCl₃, 25 °C): δ = 7.37–7.25 (m, 5 H), 4.51 (s, 2 H), 4.37 (dd, J =

8.2, 2.3 Hz, 1 H), 3.82–3.75 (m, 1 H), 3.75–3.67 (m, 1 H), 3.73 (s,

3 H), 3.63–3.52 (m, 3 H), 3.44 (dd, J = 10.5, 5.0 Hz, 1 H), 3.38

(dd, J = 10.5, 6.1 Hz, 1 H), 2.12–2.02 (m, 1 H), 2.04–1.94 (m, 1

H), 1.76–1.66 (m, 1 H), 1.42–1.34 (m, 1 H), 0.64–0.51 (m, 2 H),

0.51–0.42 (m, 1 H), 0.17–0.10 (m, 1 H), 0.08–0.01 (m, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 158.0 (C), 138.3 (C),

128.5 (CH), 127.8 (CH), 127.8 (CH), 73.1 (CH₂), 68.7 (CH₂), 66.9

(CH₂), 64.9 (CH), 52.9 (CH₃), 52.1 (CH₂), 45.2 (CH), 41.2 (CH),

28.3 (CH₂), 10.1 (CH), 5.1 (CH₂), 3.4 (CH₂) ppm. HRMS (ESI⁺):

calcd. for C₁₉H₂₇NaNO₄[M + Na]⁺356.1838; found 356.1825.

(R,E)-6-(Benzyloxy)-1-(methoxymethoxy)hex-3-en-2-yl 3-Meth-

ylbut-2-enoate (30): Sodium hydride (60% in mineral oil; 6.4 mg,

0.160 mmol) was added to a solution of (R,E)-6-(benzyloxy)-1-

(methoxymethoxy)hex-3-en-2-ol (20; 32.8 mg, 0.123 mmol) in

tetrahydrofuran (1.0 mL) at 0 °C. The mixture was stirred for

30 min, then pentafluorophenyl 3-methylcrotonate^[31](98.4 mg,

0.370 mmol) was added. The mixture was stirred for an additional

45 min at 0 °C, then it was quenched with saturated aqueous

NaHCO₃. The mixture was extracted with ethyl acetate (3ϫ), and

the combined organic extracts were dried with anhydrous sodium

sulfate, filtered, and evaporated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

Methyl (2S,3S,4R)-4-Cyclopropyl-3-(2-hydroxyethyl)-2-(hydroxy-

methyl)pyrrolidine-1-carboxylate (46b): Palladium hydroxide (20% acetate/hexane, 1:9 to 1:4) to give 30 (containing 22 as a 6.6:1 mix-

on carbon; wetted with ca. 50% water; 14.8 mg, 10.6 μmol) was

added to a solution of methyl (2S,3S,4R)-3-[2-(benzyloxy)ethyl]-4-

cyclopropyl-2-(hydroxymethyl)pyrrolidine-1-carboxylate (45b;

118 mg, 0.353 mmol) in methanol (10 mL). The flask was put un-

der hydrogen gas (1 atm) at room temperature. The mixture was

stirred for 2 h at room temperature, then it was filtered through a

Celite pad, and concentrated under reduced pressure. The crude

product was purified by silica gel column chromatography (ethyl

ture; 32.5 mg, 75.6%) as a colorless oil. [α]²_D³= –20.3 (c = 0.31,

CHCl ). IR (film): ν = 2935, 1718, 1562, 1517, 1454, 1277,

˜

3

1147 cm^–1. H NMR (400 MHz, CDCl₃, 25 °C): δ = 7.36–7.26 (m,

1

5 H), 5.83 (dt, J = 15.3, 7.3 Hz, 1 H), 5.72 (s, 1 H), 5.56 (dd, J =

15.3, 6.9 Hz, 1 H), 5.46 (dt, J = 6.5, 5.5 Hz, 1 H), 4.64 (d, J =

6.8 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 1 H), 4.50 (s, 2 H), 3.64 (d, J =

5.5 Hz, 2 H), 3.51 (t, J = 6.6 Hz, 2 H), 3.34 (s, 3 H), 3.05 (s, 2 H),

2.37 (dt, J = 7.3, 6.6 Hz, 2 H), 2.16 (s, 3 H), 1.89 (s, 3 H) ppm. ¹³

C

12

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A Unified Strategy for Kainoid Synthesis

Gayte-Sorbier, C. Cavalli, Ann. Pharm. Fr. 1982, 40, 527–534;

NMR (100 MHz, CDCl₃, 25 °C): δ = 165.9 (C), 157.4 (C), 138.5

(C), 131.5 (CH), 128.5 (CH), 127.8 (CH), 127.7 (CH), 127.4 (CH),

116.2 (CH), 96.5 (CH₂), 73.0 (CH₂), 72.2 (CH), 69.5 (CH₂), 69.2

(CH₂), 55.4 (CH₃), 32.9 (CH₂), 27.6 (CH₃), 20.4 (CH₃) ppm.

HRMS (ESI⁺): calcd. for C₂₀H₂₈NaO₅[M + Na]⁺371.1834; found

371.1819.

c) G. Impellizzeri, S. Mangiafico, G. Oriente, M. Piattelli, S.

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(2R,3R,E)-3-[2-(Benzyloxy)ethyl]-6-(methoxymethoxy)-2-(prop-1-

en-2-yl)hex-4-enoic Acid (32): (R,E)-6-(Benzyloxy)-1-(meth-

oxymethoxy)hex-3-en-2-yl 3-methylbut-2-enoate [30; 12.3 mg,

0.0353 mmol; prepared as a 6.6:1 mixture with (R,E)-6-(benz-

yloxy)-1-(methoxymethoxy)hex-3-en-2-yl 3-methylbut-3-enoate

(22)] was dissolved in tetrahydrofuran (0.5 mL), and the solution

was cooled to –78 °C. Lithium bis(trimethylsilyl)amide (1.17 m in

tetrahydrofuran; 60.3 μL, 0.0706 mmol) was added over 10 min,

and then chlorotrimethylsilane (8.91 μL, 0.0706 mmol) was added.

The mixture was stirred for 10 min, then it was warmed to room

temperature. The mixture was stirred for an additional 4.5 h, then

it was quenched with saturated aqueous NH₄Cl. The mixture was

extracted with ethyl acetate (4ϫ), and the combined organic ex-

tracts were dried with anhydrous sodium sulfate, filtered, and evap-

orated under reduced pressure. The crude product was purified by

preparative thin-layer chromatography (methanol/dichlorometh-

ane, 1:19) to give 32 (containing 24 as a 6.6:1 mixture; 6.9 mg,

56%) as a colorless oil. [α]²_D⁵= –60.3 (c = 0.35, CHCl₃). IR (film):

[8]

[9]

[10]

[11]

ν = 2944, 2864, 1732, 1708, 1454, 1151, 1102, 1030 cm^–1. ¹H NMR

˜

(400 MHz, CDCl₃, 25 °C): δ = 7.36–7.26 (m, 5 H), 5.60 (dt, J =

15.6, 6.9 Hz, 1 H), 5.46 (dd, J = 15.6, 9.2 Hz, 1 H), 4.99 (s, 2 H),

4.58 (d, J = 6.7 Hz, 1 H), 4.56 (d, J = 6.7 Hz, 1 H), 4.50 (d, J =

11.9 Hz, 1 H), 4.43 (d, J = 11.9 Hz, 1 H), 3.98 (d, J = 6.0 Hz, 2

H), 3.51–3.36 (m, 2 H), 3.33 (s, 3 H), 2.98 (d, J = 10.5 Hz, 1 H),

2.71 (dddd, J = 10.5, 9.2, 9.0, 2.8 Hz, 1 H), 1.90–1.82 (m, 1 H),

1.81 (s, 3 H), 1.38–1.24 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃, 25 °C): δ = 176.7 (C), 140.5 (C), 138.6 (C), 134.1 (CH),

129.3 (CH), 128.5 (CH), 127.8 (CH), 127.7 (CH), 116.7 (CH₂), 95.2

(CH₂), 73.1 (CH₂), 68.0 (CH₂), 67.5 (CH₂), 58.7 (CH), 55.3 (CH₃),

39.5 (CH), 31.7 (CH₂), 20.0 (CH₃) ppm. HRMS (ESI⁺): calcd. for

C₂₀H₂₈NaO₅[M + Na]⁺371.1834; found 371.1839.

[12]

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Supporting Information (see footnote on the first page of this arti-

cle): Copies of the ¹H and ¹³C NMR spectra for all key intermedi-

ates and final products.

Acknowledgments

This work was financially supported by Grants-in-Aid for Scientific

Research from Japan Society for the Promotion of Science

(KAKENHI grant numbers 20002004, 25221301, and 26713001),

the Platform for Drug Discovery, Informatics, and Structural Life

Science from the Ministry of Education, Culture, Sports, Science

and Technology, Japan, the Sumitomo Foundation, and the Tokyo

Biochemical Research Foundation. M. F. is grateful to the Gradu-

ate Program for Leaders in Life Innovation (GPLLI) and JSPS

Research Fellowships for Young Scientists.

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M. Fujii, S. Yokoshima, T. Fukuyama

FULL PAPER

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[27] To facilitate the Claisen–Ireland rearrangement (38bǞ39b),

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Received: April 19, 2014

Published Online: ᭿

14

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Date: 18-06-14 18:24:55

Pages: 15

A Unified Strategy for Kainoid Synthesis

Natural Product Synthesis

M. Fujii, S. Yokoshima,

T. Fukuyama* ................................. 1–15

A Unified Strategy for Kainoid Synthesis

Keywords: Synthesis design / Total syn-

thesis / Natural products / Alkaloids /

Cyclization / Rearrangement

The syntheses of kainic acid, MFPA, and a

cyclopropyl analog of kainic acid (CPKA)

have been accomplished from a common

intermediate. A unified strategy was used,

featuring a Claisen–Ireland rearrangement

to construct the contiguous stereogenic

centers, and a palladium-catalyzed forma-

tion of the pyrrolidine ring with complete

stereoselectivity.

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

15

Article Doi

A unified strategy for kainoid synthesis

DOI: 10.1002/ejoc.201402452

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Article abstract of DOI:10.1002/ejoc.201402452

Full text of DOI:10.1002/ejoc.201402452

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