Novel approach to the (-)-sparteine-mediated synthesis of kainoids: Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated deprotonation

FULL PAPER

Novel Approach to the (–)-Sparteine-Mediated Synthesis of Kainoids:

Total Synthesis of (–)-α-Kainic Acid by (–)-Sparteine-Mediated Deprotonation

M. Montserrat Martínez^[a]and Dieter Hoppe*^[a]

Keywords: Natural products / Asymmetric synthesis / Pyrrolidines / (–)-Sparteine / Allyl carbamates

We report a new synthesis of kainoids via allyllithium com-

pounds using an intramolecular cycloalkylation as the key

step. Preparation of different substituted pyrrolidines was

carried out by using carbamates, that react with the chiral

base n-BuLi/(–)-sparteine with strong selection between the

diastereotopic protons adjacent to the carbamate group in

favour for the pro-S proton. (–)-α-Kainic acid was synthetized

diate carbamate that, by stereospecific anti-S_NЈS_EЈ intramol-

ecular cycloalkylation, leads to the pyrrolidine ring precursor

of (–)-α-kainic acid, in high yield and diastereoselectivity. Re-

lated approaches, starting from L-glutamic acid failed. The

intermediate pyrrolidine was further transformed to (–)-α-

kainic in three steps.

from

D

-serine methyl ester hydrochloride, based on a (–)-

Germany, 2005)

sparteine-mediated asymmetric deprotonation of an interme-

Introduction

Kainoids are an important class of natural non-pro-

teinogenic amino acids which have a common characteristic

structure consisting in a pyrrolidine nucleus with two car-

boxylic groups. Some of the members of this family like α-

kainic acid,^[1]domoic acid or acromelic acids A and B show

interesting biological properties (Figure 1). The natural pro-

duct (–)-α-kainic acid (1), which is the parent member of

kainoids, shows a potent inhibitor neurotransmitting ac-

tivity of the central nervous system.^[2]In recent years, elec-

trophysiologic studies about the mammalian CNS, show

that the specific activity of these receptors is principally due

to an unsaturated isopropylidene chain on C–4 of the pyr-

rolidine system.^[3]Analogues with an unsaturated chain in

this position with inverted configuration in C–4 or without

substituent in C–4 have very low agonist activity.^[4]

The importance of these natural products in pharmaco-

logical investigations has attracted the attention of number

of synthetic groups. Synthesis of kainoids needs to address

the formation of a pyrrolidine-2-carboxylic acid with de-

fined stereochemistry at the three continuous chiral centers

of the ring, where is essential to achieve a cis stereochemis-

try for the 3 and 4 positions. Since the first synthesis of

(–)-α-kainic acid was carried out by Oppolzer,^[5]several to-

tal syntheses of this compound have been published,^[6]al-

though only a few lead to the enantiopure product. Our

diastereoselective approach to the pyrrolidine ring compris-

ing the (–)-α-kainic acid relies on the (–)-sparteine-mediated

Figure 1. Structure of kainoids.

asymmetric cycloalkylation. Past experience in our group

has shown that (–)-sparteine-mediated carbocyclizations of

allyllithium compounds lead to cyclopentanes with favored

cis-stereochemistry.^[7]This method was extended to the syn-

thesis of a cis-3,4-divinylpyrrolidine with high enantio- and

diastereoselectivity.^[8]We suggested that this methodology

could be well suitable for the synthesis of (–)-α-kainic acid

and its analogues. Herein we report an alternative route for

the synthesis of kainoids based on the (–)-sparteine-medi-

ated carbocyclization of an allyllithium compound (C), fol-

lowing the strategy described in Scheme 1.

Results and Discussion

[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-

versität Münster,

Synthetic Plan A by Cycloalkylation of Carbamate C

Corrensstrasse 40, 48149, Germany

Fax: +49-251-833-9772

E-mail: dhoppe@uni-muenster.de

Our initial strategy was focused on the preparation of

carbamate C (Scheme 1, R = Cb or Cby) as a late-stage

Eur. J. Org. Chem. 2005, 1427–1443

DOI: 10.1002/ejoc.200400824

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M. Montserrat Martínez, D. Hoppe

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to the (–)-α-kainic acid synthesis. Asymmetric (–)-sparteine- lylation of oxazolidinone 3 with (E)-4-bromo-1-(tert-butyl-

mediated deprotonation, followed by an anti-S_NЈS_EЈ cyclo- silyloxy)-2-methyl-2-butene (4d, Scheme 5).^[10]The use of

alkylation of carbamate C (prepared starting from oxazoli- potassium tert-butoxide/18-crown-6 turned out to be the

dinone A and isoprenoid B), would lead to bicycle D with best method for deprotonation, compound 5 was obtained

the desired stereochemistry of (–)-α-kainic acid. After cleav- in 92% yield ([α]²_D⁰= –34, c = 1.0, CHCl₃). α,β-Unsaturated

age of carbamate moiety, followed by hydrolysis of the ox- ester 6 ([α]²_D⁰= +19.9, c = 1.0, CHCl₃) was synthesized via

azolidinone ring and subsequent oxidation, intermediate D silyl enol ether formation followed by oxidation with

would be converted into (–)-α-kainic acid. The oxazolidi- Pd(OAc)₂in acetonitrile in 83%.^[11]Both stereogenic

none ring was chosen because of promising C–2 stereo- double bonds in structure 6 were found in an E/Z ratio of

chemical control during the synthesis of key intermediate C Ͼ 99% as determined by NOE experiments. 1,2-Reduction

(Scheme 1).

of the ester moiety in compound 6 by treatment with DI-

BAL-H (for optimal result, Lewis acid must be added be-

fore introduction the metal hydride reagent) followed by

carbamoylation with the oxazolidinecarbonyl chloride

(CbyCl, Scheme 1) by the sodium hydride method^[12]fur-

nished carbamate 8 ([α]²_D⁰= –6.9, c = 0.41, CHCl₃) in 76%

overall yield. Therefore the reaction sequence was com-

pleted by deprotection with TBAF^[13]providing the allylic

alcohol 9 (98% yield, ([α]²_D⁰= +15.0, c = 0.80, CHCl₃) fol-

lowed by dehydroxychlorination to the key precursor 10

([α]²_D⁰= +9.2, c = 1.2, CHCl₃) in 47% yield (the low yield

is presumably caused by the instability of the product).

Synthesis of Intermediate Carbamate C

The synthesis of key precursor C (Scheme 2, compound

10) commenced with l-glutamic acid 5-methyl ester, which

was transformed into the known alcohol 2 in good yield

([α]²_D⁰= –12.4, c = 1.20, CHCl₃) vs. ([α]²_D⁰= –13.2, c = 1.0,

CHCl₃).^[9]Formation of the oxazolidinone 3 ([α]²_D⁰= –29.3,

c = 1.1, CHCl₃) was carried out without any racemization

(as determined by ¹H NMR shift experiment) using thionyl

chloride in 77% yield. Further synthesis required N-al-

Scheme 1. Retrosynthetic analysis of (–)-α-kainic acid.

Scheme 2. Reagents and conditions: (a) Cl₂SO, THF, room temp., 3 h, 77%; (b) KOtBu, THF, 18-crown-6, 0 °C to room temp., 30 min,

then 4d (Scheme 5), 3 h, room temp., 92%; (c) TMSCl, THF, –78 °C, KHMDS, THF, 30 min, then Pd(OAc)₂, room temp., CH₃CN, 6 h,

83%; (d) BF₃·OEt₂, –78 °C, CH₂Cl₂, 1 h, then DIBAL-H, 2 h, –78 °C, quant.; (e) NaH, THF, room temp., 30 min, then CbyCl (Scheme 1),

70 °C, 12 h, 76% over two steps; (f) TBAF, Et₂O, room temp., 2 h, 98%; (g) NEt₃, CH₂Cl₂, –40 °C, CH₂Cl₂, MsCl, 1 h, then LiCl, THF,

room temp., 12 h, 47%; (h) nBuLi, (–)-sparteine, toluene, 5 h, –90 °C, no products isolated.

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(–)-Sparteine-Mediated Synthesis of Kainoids

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Studies of Cyclization with the Carbamate 10

Subsequent formation of the pyrrolidine ring was investi-

gated, but the resulting carbamate 10 failed to undergo the

(–)-sparteine-mediated asymmetric cycloalkylation. When

carbamate 10 was treated with the chiral base nBuLi/(–)-

sparteine in toluene at –78 °C for 5 h, only a mixture of

unidentified compounds was found. Different attempts by

changing the solvent (e.g., Et₂O, pentane), temperature

(–90 °C, –78 °C), pre-complexation of nBuLi and even high

dilution conditions, were unsuccessful. The same negative

result was obtained when sBuLi/(–)-sparteine was used, and

even when TMEDA was used as a diamine no cycloalky-

lation products could be detected.

Although several side reactions are conceivable, these un-

successful experiments can be understand as a consequence

of the presence of oxazolidinone moiety: the α-protons clos-

est to the carbonyl group of the oxazolidinone group have a

similar kinetic acidity as the α-protons of the OCby moiety

Scheme 3. Alternative retrosynthetic analysis of (–)-α-kainic acid

by (–)-sparteine-mediated deprotonation.

(Scheme 1). This assumption is supported by Bertini–Gross unsaturated ester 15 ([α]²_D⁰= +9.7, c = 0.37, CHCl₃) as a

and Beak^[14]who demonstrated that conformationally re- single (E,E) stereoisomer (determined by ¹H NMR) in 70%

stricted bicyclic carbamates undergo rapid diastereoselec- overall yield. In the next step, selective removal of the TBS

tive deprotonation with sBuLi/TMEDA, where one of the group in compound 15 could be only achieved by treatment

methylene protons closest to the carbonyl group is preferen- of the bis-silyl ether 15 with pyridinium p-toluenesulfonate

tially removed. The installation of sterically bulky groups (PPTS)^[17]in ethanol at 58 °C for several hours, furnishing

in the oxazolidinone ring was necessary, according to these allylic alcohol 16 ([α]²_D⁰= +6.8, c = 0.74, CHCl₃) in 100%

authors to prevent addition of the nBuLi onto the carba- yield. The conversion of the hydroxyl group into chloro 17

mate carbonyl group.^[14]

([α]²_D⁰= +5.2, c = 0.64, CHCl₃) was carried out via the mes-

ylate with LiCl in 83% yield.

Subsequent chemoselective reduction of α,β-unsaturated

ester 17 with diisobutylaluminium hydride (DIBAL-H) af-

forded the corresponding allylic alcohol, which was sub-

jected without further purification to standard carbamo-

ylation conditions^[12]using N,N-diisopropylcarbamoyl chlo-

Synthetic Plan B by Cyclization of Carbamate F

Failing to provide a suitable substrate to synthesize (–)-

α-kainic acid starting from oxazolidinone C, a different ac-

cess was needed. In this new approach an N-benzyl group

and a O-silyl group were selected as protecting group in-

stead of an oxazolidinone moiety leading to key intermedi-

ate F (Scheme 3). We kept the same key step based on an

asymmetric anti-S_NЈS_EЈ cycloalkylation reaction, to achieve

the desired configuration of (–)-α-kainic acid in pyrrolidine

G, but using key precursor F, synthesized from building

blocks A and E as depicted in Scheme 3.

ride (CbCl, Scheme 1). The required carbamate 19 ([α]_D²⁰

=

+4.2, c = 0.45, CHCl₃) was obtained in 60% yield (over

two steps). Carbamate 20 ([α]²_D⁰= +2.3, c = 1.9, CHCl₃)

was also prepared in similar way in 68% yield (over two

steps), but using CbyCl instead of CbCl.

Synthesis of Trisubstituted Pyrrolidines

The crucial cyclization of carbamate (E,E)-19 (Scheme 6)

was carried out in toluene at –87 °Cby slow addition of 2.2

equivalents of nBuLi/(–)-sparteine, to furnish the expected

Synthesis of Intermediate Carbamates 19 and 20

The synthesis of the precursor F (Scheme 4, compound cyclized product 21a ([α]²_D⁰= –7.1, c = 0.52, CHCl₃) in 16%

19) arising from d-serine methyl ester hydrochloride began yield (entry 1, Table 1), with cis stereochemistry at positions

with the O-silylation of N-benzyl-d-serine methyl ester 11^[15]3 and 4 in a diastereomeric ratio of 21a:21b nearly to 95:5.

using tert-butyldiphenylsilyl chloride (TBDPSCl) in 88% No trans products in respect to the C3–C4 bond were de-

1

yield, followed by reduction of the ester moiety with LiBH₄tected, as evidenced by H NMR spectroscopy. A similar

to afford alcohol 13 ([α]²_D⁰= –1.6, c = 1.90, CHCl₃) in 56% result was obtained by employing sBuLi/(–)-sparteine in

yield.^[16]Best conditions for N-allylation of alcohol 13 with toluene at –78 °C (entry 2, Table 1). The preference for the

isoprenoid 4d (Scheme 5) were heating at reflux in acetoni- formation of one diastereoisomer (21a), demonstrates the

trile in the presence of NaHCO₃. Compound 14 was ob- effect of the kinetic control in the deprotonation step,^[7,8]

tained in 81% yield ([α]²_D⁰= –11.8, c = 0.52, CHCl₃). although yields of 16% to 27% were unsatisfying even if

Alcohol 14 was then subjected to Swern oxidation followed the starting material was recovered in high yield. These

in situ by olefination employing (ethoxycarbonylmethylene) moderate yields prompted us to investigate the cyclization

triphenylphosphorane in a single operation to afford α,β- reaction of carbamate 19, employing TMEDA as a ligand

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M. Montserrat Martínez, D. Hoppe

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Scheme 4. Reagents and conditions: (a)TBDPSCl, NEt₃, DMAP, CH₂Cl₂, room temp., 12 h, 88% of 12; (b) NEt₃, TBSCl, DMAP,

CH₂Cl₂, room temp., 12 h, 89% of 26; (c) LiBH₄, THF/toluene (4:1), reflux, 20 min, 56% of 13 and 47% of 27; (d) NaHCO₃, CH₃CN,

room temp., 30 min, then 4d (Scheme 5), reflux, 3 h, 81% of 14; (e) NaHCO₃, CH₃CN, room temp., 30 min, then 28d (Scheme 5),

reflux, 3 h, 82% of 29; (f) (COCl)₂, DMSO, CH₂Cl₂, –78 °C, 20 min, then NEt₃, –78 to –15 °C, 1 h, then (ethoxycarbonylmethylene)

triphenylphosphorane, –15 °C to room temp., 3 h, 70% overall yield of 15 and 75% overall yield of 30; (g) PPTS, EtOH, 55 °C, 48 h,

100% of 16; (h) TBAF, THF, 0 °C, 5 min, 81% of 31; (i) NEt₃, CH₂Cl₂, –40 °C, MsCl, 1 h, then LiCl, THF, room temp., 3 h, 83% of

17 and 71% of 32; (j) DIBAL-H, CH₂Cl₂, –78 °C, 2 h, quant. of 18 and 70% of 33; (k) NaH, CbCl (Scheme 1), THF, reflux, 12 h, 60%

(over two steps) of 19 and 53% of 34; (l) NaH, THF, reflux, CbyCl (Scheme 1), 12 h, 68% (over two steps) of 20.

rolidines 21a and 21b (separated by flash chromatography)

could not be determined by NOE studies, the stereochemi-

cal assignment of structures to 21a and 21b is based on the

fact that the two olefinic protons of the isopropenyl chain

1

appear as two singlets in the H NMR spectra, as is typical

for similar kainoids^[18](see later for further discussion). The

(Z)-geometry of the enol carbamate moiety is based on the

small olefinic coupling constant (6.4 Hz) observed, in agree-

ment with previous studies in our group.^[7,8]A possible

reason for why the cyclization is slower when using (–)-spar-

teine as diamine, might be either electrophile’s reactivity de-

pendence on the temperature or the fact the C–2 substituent

influence the efficiency of the cyclization to produce the

required 2,3-trans arrangement. To prove the first assump-

tion, carbamate 19 was treated with nBuLi/(–)-sparteine in

Scheme 5. Reagents and conditions: (a) NEt₃, DMAP, TBSCl,

CH₂Cl₂, room temp., 12 h, then KOtBu, triethyl phosphonoacetate,

toluene at –78 °C, and through raising the temperature

from –78 °C to –45 °C for 4 h,^[19]an enhancement from

16% up to 45% yield was possible (entry 5, Table 1, dr =

95:5, by ¹H NMR). When Et₂O was used as solvent (entries

3 and 6, Table 1), at –78 °C or lower temperatures, the cycli-

zation did not take place. The addition of 10% of THF to

the solvent toluene led to higher yield (77%, entry 8,

18-crown-6, CH₂Cl₂, 0 °C to room temp., 12 h, 76% over two steps

of 4b, (b) NEt₃, 0 °C, DMAP, TESCl, CH₂Cl₂, room temp., 12 h,

then KOtBu, triethyl phosphonoacetate, 18-crown-6, CH₂Cl₂, 0 °C

to room temp., 12 h, 85% over two steps of 28b, (c) DIBAL-H,

–78 °C, CH₂Cl₂, 2 h, 96% of 4c and 91% of 28c, (d) NEt₃, MsCl,

CH₂Cl₂, –40 °C, 1 h, then LiCl, THF, room temp., 12 h, quant.

for the nBuLi instead of the chiral diamine (–)-sparteine. Table 1), but the diastereoselectivity decreased to 65:35. Fi-

The best conditions were the use of 2.2 equivalents of nally, when carbamate 20 (Cby instead of Cb) was subjected

nBuLi/TMEDA in THF at –45 °C for 3 h, affording 21a under standard conditions (nBuLi/(–)-sparteine in toluene

and 21b in 88% yield with a diastereomeric ratio of 60:40 at –78–45 °C for 4 h), cyclized pyrrolidines 22a and 22b

(entry 4, Table 1). Since the relative configuration of pyr- (Scheme 6) were furnished under these conditions in similar

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(–)-Sparteine-Mediated Synthesis of Kainoids

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Scheme 6. Asymmetric cycloalkylation of 19 by S_NЈS_EЈ substitution.

Table 1. Conditions employed in the cycloalkylation reaction on carbamate 19.

Entry

Base

Solvent

T (°C)

Time (h)

21 (%)

dr (21a:21b)

1

2

3

4

5

6

7

8

nBuLi/(–)-sp

sBuLi/(–)-sp

nBuLi/(–)-sp

nBuLi/TMEDA

nBuLi/(–)-sp

toluene

Et₂O

THF

toluene

Et₂O

–87

–78

–90

–45

–78–45

–45

–78–40

3

6

24

3

4

2

16

1

16

27

–

88

95:5

–

60:40

95:5

65:35

48

30

toluene

toluene/10%THF –78–45

32^[a,b]

77

[a] Fritsch–Buttenberg–Wiechell rearrangement^[19]to form alkyne 23 (Scheme 6) takes place in 25%. [b] 1 equiv. of LiCl was added.

yield (54%) and diastereoselectivity (dr = 95:5, by ¹H

It was surprising that the problem of racemization

NMR).

emerged during the preparation of α,β-unsaturated ester 17

The result of these experiments, together led to the fol- when TBDPS was used as a protecting group. However, this

lowing considerations: a) there is a risk of partial racemiza- unsatisfactory result is supported by Hanessian et al.^[20]

tion on the stage of the α,β-unsaturated ester 17 (Scheme 4) who observed racemization as well during the formation

which, in principle, would lead to ent-21a and ent-21b in of an oxazolidinone ring from d-serine alcohol derivative

the (–)-sparteine-mediated cyclization. Epimerization on bearing a TBDPS group, most probably due to a 1,3-silyl

the stage of the corresponding lithium compound of type shift.

H·sp (Scheme 8) most probably is the origin for the forma-

We conclude that: a) in the cyclization reaction of the

tion of 21b, b) the ring closure of this functionalized cycli- carbamates 19 and 20, the major diastereomer was obtained

zation precursors 19 and 20 provided preferentially one dia- from pro-S-proton abstraction in the presence of (–)-sparte-

stereomer although in lower to moderate yields, made us to ine, but in lower yield as compared with TMEDA, b) a

prove the ee before the cycloalkylation reaction. Thus, the second diastereomer all-cis-substituted pyrrolidine 21b was

optical purity of ester 17 was determined to be 26% ee (by achieved when TMEDA was used instead of (–)-sparteine

¹H NMR), which was carried through the synthesis. and when employing higher temperatures. Obviously, the

Mosher ester 25 was derived from enantiomerically en- enantiomeric carbamate ent-19 has quite lower reactivity

riched and, as well, from racemic alcohol 24 by esterifica- under the reaction conditions. If this is true, rac-19 might

tion using (–)-MPTA chloride in 65% overall yield be employed in a kinetic resolution.

(Scheme 7).

Total Synthesis of (–)-α-Kainic Acid

In the light of these results, an alternative plan was de-

vised following the retrosynthetic analysis described in

Scheme 3, in which TBS was chosen instead of TBDPS

group. In the event precursor 34 was prepared using the

established work on precursor 19 (Scheme 4). Thus, alcohol

11 was subjected to a) O-silylation (TBSCl, 89% yield,

[α]²_D⁰= +3.9, c = 0.94, CHCl₃), b) reduction of ester moiety

on 26 with LiBH₄led to alcohol 27 in 47% (84% based on

26, ([α]²_D⁰= –8.2, c = 1.10, CHCl₃), c) N-allylation of

alcohol 27 was carried out by refluxing (E)-configured

isoprenoid 28d (prepared in a similar fashion of 4d,

Scheme 7. Reagents and conditions: (a) TBAF, THF, 3 h, room

temp., quant.; (b) Py, CCl₄, (–)-R-MPTACl, room temp., 4 h, 65%

overall yield.

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1

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Scheme 5)^[21]using NaHCO₃in acetonitrile, yielding yield (83%, 37a:37b, dr 80:20, as determined by H NMR).

alcohol 29 ([α]²_D⁰= –3.6, c = 0.91, CHCl₃) in 82% yield, d) The stereochemical assignment of structures to 37a and 37b

Swern oxidation followed by in situ olefination using is based on the H NMR spectra as was described before

1

(ethoxycarbonylmethylene)triphenylphosphorane, in a sin- for pyrrolidines 21 and 22 (TBDPS instead of TBS

gle operation to provide 30 ([α]²_D⁰= +8.2, c = 1.59, CHCl₃) group).^[18]Further, experimental vicinal coupling constants

3

in 75% overall yield with an E/Z ratio Ͼ 99% (determined (³J_2,3and J_3,4) observed for 37a and 37b were within the

1

by H NMR). Then next step of the synthesis required se- range of calculated ones by computational studies based on

lective removal of TES group in compound 30, which was the Karplus–Conroy equation.^[23]Further support to this

achieved with TBAF at low temperature in 81% yield. Al- assignment is provided by the conversion of 37a to (–)-α-

lylic alcohol 31 ([α]_D²⁰= +14.7, c 0.61, CHCl₃) was then kainic acid (1). The stereochemical outcome of the asym-

subjected to chlorine-substitution giving (E,E)-allylic chlo- metric cycloalkylation reaction is supported by the follow-

ride 32 ([α]_D= +22.0, c 0.78, CHCl₃) in 71% yield. An ing mechanistic considerations: 1) The chiral base nBuLi/

optical purity of Ͼ 95% enantiomeric excess was deter- (–)-sparteine stereoselectively removes the α-pro-S-pro-

1

mined for 32 by H NMR analysis of the corresponding ton^[24]of carbamate 34, generating the configurationally la-

(–)-MPTA ester 37 (Scheme 7). 1,2-Reduction of the ester bile intermediate H·sp. Intramolecular cycloalkylation of

moiety in compound 32 with DIBAL-H led to the allylic H·sp occurs under regioselective C–C bond formation be-

alcohol 33 in 70% yield ([α]²_D⁰= +7.2, c 0.76 CHCl₃). Car- tween both γ,γЈ positions, and simultaneous elimination of

bamate 34 ([α]_D²⁰= +9.7, c 0.71, CHCl₃) was prepared from lithium chloride.^[8]Although these (–)-sparteine-lithium ion

allylic alcohol 33 by using standard conditions^[12]with CbCl pairs of primary allyl carbamates have been recognized to

(Scheme 1) in 53% yield.

have limited configurational stability, the cycloalkylation is

slightly more rapid than epimerization to form I·sp. 2) An

endo conformation of the allylic moieties in an anti-mode

is required for the S_NЈS_EЈ cycloalkylation.^[25]The chair-like

transition state H·sp allows the π–π* overlap of the elec-

tron-rich and electron-deficient allyl moieties, presumably

being the origin of the high cis-diasteroselectivity. Com-

pound 37b is most probably formed by intramolecular cy-

cloalkylation of the (R)-configured lithium derivative I·sp,

formed by incomplete stereoselectivity of the deprotonation

step and, as well, by competing epimerization. To confirm

the proposed mechanism, knowledge of the configurations

of pyrrolidines 37a and 37b is required. The configuration

Cyclization Mechanism of Carbamate 34 and Structure

Determination

Intramolecular anti-S_NЈS_EЈ cycloalkylation of (E,E)-car-

bamate 34 (Scheme 8), the key step for the synthesis of (–)-

α-kainic acid, commenced with α-deprotonation by means

of nBuLi/(–)-sparteine at –78 °C in toluene.^[22]After 1 h, a

high C3–C4 cis-selectivity was achieved without formation

of trans products in respect to the C3–C4 bond, giving the

two separable diastereomers 37a ([α]²_D⁰= –22.6, c = 0.57,

CHCl₃) and 37b ([α]_D²⁰= –6.4, c = 0.75, CHCl₃) in high

Scheme 8. Mechanism of cycloalkylation. Reagents and conditions: (a) nBuLi/(–)-sparteine (sp) (2.2 equiv.), toluene, –78 °C, 1 h, then

MeOH, 83%, dr = 80:20 (37a:37b).

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Scheme 9. Reagents and conditions: (a) MeLi or TMSOTf; (b) tBuLi, THF, –78 °C, TMEDA, 1 h, MeSSMe,1 h, room temp., quant.; (c)

MeOC(=O)Cl, ClCH₂CH₂Cl, reflux, 3 h, 84% overall yield of 40a and 82% overall yield of 40b; (d) MeSO₃H, MeOH, H₂O, reflux, 16

h, 55% overall yield of 41a and 48% overall yield of 42b; (e) Jones reagent; (f) 40% NaOH aq., reflux, 18 h; (g) Dowex 50WX-200

(elution with 1 n NH₄OH), Amberlite CG-50 (elution with H₂O); (h) recryst. EtOH aq., 38% overall yield.

of the latter has been determined by transformation of 37a tical rotation with the protected enantiomeric derivative of

into the alcohol 41a and subsequent conversion into (–)-α- the so-called β-kainic acid 42b, recently described by

kainic acid (Scheme 9), whereas 37b was converted into the Campbell: 42b ([α]²_D⁰= –28.1, c = 0.30, CHCl₃) vs. ent-42b

enantiomer of so-called β-kainic acid 42b (see Scheme 9). ([α]²_D⁰= +32.1, c = 1.20, CHCl₃).^[6j]

By comparison of the sense of the optical rotations, 37a

and 37b could be assigned the 2S,3R,4S-configuration and following literature precedents:^[6i]Jones oxidation of the

2S,3S,4R-configuration, respectively. primary alcohol 41a, followed by hydrolysis with 40% aque-

The final steps to the natural product were carried out

To complete the synthesis of (–)-α-kainic acid, oxidative ous sodium hydroxide, and purification by using ion-ex-

removal of the carbamate group in 37a is necessary change chromatography afforded enantiopure (–)-α-kainic

(Scheme 9). The usual oxidative methods^[26]are not appli- acid as colourless needles after recrystallization from aque-

cable to vinyl carbamates 37a and 37b due to the reactive ous ethanol (38% overall yield). Our final product possesses

additional trisubstituted double bond. Moreover, attempts the same physical properties reported for (–)-α-kainic acid:

to convert the vinyl carbamate 37a into aldehyde 38a by m.p. 243–245 °C (dec.) vs. m.p.^[6i]241–244 °C (dec.); ([α]²_D⁰

using methyllithium^[27]or TMSOTf^[28]failed. In light of = –14.3, c = 0.40, H₂O) vs. ([α]_D²⁰= –14.6, c = 0.25, H₂O).^[6i]

these results, we used an indirect oxidation method con-

sisting in a vinylic deprotonation by applying tert-BuLi fol-

lowed by quench with MeSSMe.^[29]The obtained ketene

monothioacetal 39a was submitted without further purifi-

Conclusions

cation to N-debenzylation by treatment with methyl chloro-

We provide a 7-step synthesis of the oxazolidinone 10 in

formate,^[30]providing 40a ([α]_D²⁰= –19.0, c = 0.5, CHCl₃) in 20.6% overall yield from l-glutamic acid methyl ester. An

84% overall yield. Treatment of monothioketene acetal 40a asymmetric deprotonation and cycloalkylation was planned

with excess of methanesulfonic acid, resulted in the depro- as the key reaction, however it did not take place, presum-

tection of the hydroxyl group and simultaneous hydrolysis ably because of two functional groups (OCby and oxazolidi-

of the ketene monothioacetal moiety giving alcohol 41a in none) are competing for the nBuLi.

55% overall yield. Eludicidation of the structure of 41a was

The high diastereoselectivity obtained in the asymmetric

carried out by H NMR spectra and NOE studies.^[31]The cycloalkylation with carbamates 19 and 20, supported the

absolute configuration was confirmed by comparing its re- validity of the synthesis of stereochemically defined trisub-

spective [α]_Dvalue with published one: 41a ([α]²_D⁰= –41.2, stituted pyrrolidine systems and for the creation of two ste-

c = 0.52, CH₂Cl₂) vs. ([α]²_D⁰= –43.0, c = 1.25, CH₂Cl₂).^[6i]reogenic centers in a single stage. This route proved to be

In a similar fashion, lactone 42b ([α]²_D⁰= –28.1, c = 0.30, inefficient as well, due to racemization before the key step.

1

CHCl₃) in turn derived from 37b, resulted by deprotection

A new and efficient asymmetric total synthesis of (–)-α-

of silyl ether in 40b followed by cyclization of both, C–2 kainic acid, was accomplished in 12 steps (longest linear

and C–3 chains, in 48% yield (Scheme 9). The all-cis-rela- sequence) in 1.4% overall yield from alcohol 11. Similar

tioship of the C–2, C–3, and C–4 protons was unequivo- synthetic strategies might be useful for the preparation of

cally demonstrated by comparison of the ¹H NMR and op- other members of the kainic natural product family.

Eur. J. Org. Chem. 2005, 1427–1443

www.eurjoc.org

1433

M. Montserrat Martínez, D. Hoppe

FULL PAPER

10% aqueous solution of tartaric acid in CH₂Cl₂(250 mL) and

stirred at room temperature for 1 h. The aqueous phase was ex-

tracted with CH₂Cl₂(3×250 mL), the organic phase dried

(MgSO₄), and the solvents were evaporated. The crude product was

purified by flash chromatography, R_f= 0.5 (SiO₂, Et₂O/petroleum

ether, 90:10) affording 4c (6.02 g, 96%, E/Z 100:0) as a colorless

Experimental Section

General: All moisture-sensitive reactions were carried out under an

atmosphere of argon in flame-dried glassware with dried solvents.

The solvents (THF, toluene, CH₂Cl₂, CH₃CN, dimethyl sulfoxide,

acetone, Et₂O, etc.) were dried according to standard procedures

and distilled prior to use. Flash chromatography was performed

using Merck silica gel 60 (particle size 0.040–0.055 mm, 230–400

mesh) at a pressure of about 1.5 bar. Solvents for chromatography,

diethyl ether (Et₂O), petroleum ether (PE) and ethyl acetate

(EtOAc), were distilled prior to use. For analytic thin-layer

chromatography (TLC), Merck plastic sheets (60F₂₅₄silica gel)

were used. Visualization was accomplished with UV light or by

staining with a basic I₂, permanganate, vanillin or cerium molydate

solutions. NMR spectra were recorded on a Bruker ARX 300 and

AMX 400 and on a Varian Unity plus (Varian Inc., Palo Alto, CA,

USA) 600 spectrometer. Chemical shifts are given in ppm (δ) and

J values are in Hz, with TMS (¹H) and CDCl₃(¹³C) as internal

standards. Infrared (IR) spectra were recorded on a Nicolet FT-IR

5DXC spectrometer. Optical rotations were measured at 20 °C with

a Perkin–Elmer 341 at the sodium D line. Mass spectra and elemen-

tal analyses were performed at the Department of the Organic

Chemistry of the University of Münster. Exact mass determination

(MS-ESI) was carried out with a Quattro LCZ (Waters-Micromass,

Manchester, UK) with manospray inlet.

oil. IR (film): ν (cm^–1) = 3420–3300 (OH), 2959–2858, 1478, 1397,

˜

1364. ¹H NMR (400 MHz, CDCl₃): δ = 0.00 (s, 6 H, Si(CH₃)₂),

0.84 (s, 9 H, SiC(CH₃)₃), 1.58 (s, 3 H, C(CH₃)=CH), 3.96 (s, 2 H,

CH₂OSi), 4.13 (d, 2 H, ³J = 7.2 Hz, CH₂OH), 5.60 (t, 1 H, ³J

= 6.9 Hz, C(CH₃)=CH). ¹³C NMR (100 MHz, CDCl₃): δ = –5.1

(Si(CH₃)₂), 13.3 (C(CH₃)=CH), 18.3 (SiC(CH₃)₃), 25.8 (SiC-

(CH₃)₃), 58.9 (CH₂OH), 67.6 (CH₂OSi), 122.6 (C(CH₃)=CH),

138.0 (C(CH₃)=CH). EI-MS, m/z (%) = 185 (2) [M⁺– CH₂OH],

159 (27) [M⁺– C(CH₃)₃], 75 (100). C₁₁H₂₄O₂Si (216.39): calcd. (%)

C 61.05, H 11.18; found: C 60.65, H 10.95.

{[(2E)-4-Bromo-2-methyl-2-butenyl]oxy}(tert-butyl)dimethylsilane

(4d): To a solution of (E)-4c (6.80 g, 31.5 mmol) in 75 mL of

CH₂Cl₂at –40 °C NEt₃(7.06 mL, 50.2 mmol) and methanesulfonyl

chloride (3.17 mL, 40.9 mmol) were added. The reaction mixture

was stirred at –40 °C for 1 h and then was added via cannula to a

solution of dry LiBr (10.9 g, 126 mmol) in 50 mL of THF. The

reaction mixture was allowed to warm to room temperature over-

night and quenched by addition of H₂O (50 mL). The solution was

poured into petroleum ether (100 mL) and washed several times

with H₂O (5×70 mL). The organic phase was dried (MgSO₄) and

the solvents were evaporated. Crude 4d (8.65 g) was used freshly

without further purification in N-allylation reaction of 3. IR (film):

Ethyl (2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methyl-2-butenoate

(4b): NEt₃(11.5 mL, 81.8 mmol) was added to a stirred solution of

α-hydroxyacetone (5.05 g, 68.2 mmol) in dry CH₂Cl₂(75 ml).

TBSCl (12.3 g, 81.8 mmol) and DMAP (0.42 g, 3.4 mmol) were

then added. After 12 h at room temperature, the reaction mixture

was diluted with H₂O (30 mL), the organic phase was separated,

and the aqueous phase was extracted with CH₂Cl₂(3×50 mL). The

combined organic phases were dried (MgSO₄) and the solvents

evaporated in vacuo; no further purification of the crude product.

To a suspension ofKOtBu (7.51 g, 66.9 mmol) in CH₂Cl₂(90 mL)

was added at 0 °C, a solution of triethyl phosphonoacetate (13.8 g,

61.4 mmol) and 18-crown-6 (0.89 g, 3.4 mmol) in CH₂Cl₂(70 mL).

The reaction mixture was stirred at room temperature for 1 h. A

solution of crude product O-TBS-α-hydroxyacetone (10.5 g,

55.8 mmol) in CH₂Cl₂(100 mL) was added at 0 °C. After stirring

at room temperature for 12 h, sat. aqueous NH₄Cl (200 mL) was

added and the aqueous phase was extracted with CH₂Cl₂

(3×200 mL), the combined organic phases were dried (MgSO₄),

and the solvents evaporated in vacuo. The crude product was puri-

fied by flash chromatography, R_f= 0.61 (SiO₂, Et₂O/petroleum

ether, 1:10) affording 4b (13.4 g, 76% over two steps, E/Z 85:15) as

ν (cm^–1) = 2963–2864, 1472, 1465, 1401. ¹H NMR (300 MHz,

˜

CDCl₃): δ = 0.00 (s, 6 H, Si(CH₃)₂), 0.84 (s, 9 H, SiC(CH₃)₃), 1.61

(s, 3 H, C(CH₃)=CH), 3.97 (m, 4 H, CH₂Br and CH₂OSi), 5.74 (t,

1 H, ³J = 8.8 Hz, C(CH₃)=CH). ¹³C NMR (100 MHz, CDCl₃):

δ = –5.2 (Si(CH₃)₂), 12.9 (C(CH₃)=CH), 18.2 (SiC(CH₃)₃), 25.8

(SiC(CH₃)₃), 28.4 (CH₂Br), 67.2 (CH₂OSi), 119.3 (C(CH₃)=CH),

141.7 (C(CH₃)=CH). EI-MS, m/z (%) = 220 (68) [M⁺– C(CH₃)₃],

199 (46) [M⁺– HBr], 137 (76), 73 (100). C₁₁H₂₃BrOSi (279.29).

Methyl (S)-3-(2-Oxo-1,3-oxazolidin-4-yl)propanoate (3): Thionyl

chloride (5.49 mL, 75.7 mmol) was added at room temperature to

a solution of alcohol 2^[9](6.24 g, 25.2 mmol) in THF (80 mL). The

reaction mixture was stirred for 3 h and the excess of SOCl₂re-

moved in vacuo. The crude product was purified by flash

chromatography, R_f= 0.34 (SiO₂, AcOEt), affording 3 (3.36 g,

77%) as a pale yellow solid which was crystallized from Et₂O: m.p.

63.8–63.5 °C. [α]²_D⁰= –29.3 (c = 1.1, CHCl ). IR (KBr): ν (cm^–1) =

˜

3

3375 (NH), 2990–2934, 1752 (CO), 1710 (NCO), 1539, 1487, 1446.

¹H NMR (300 MHz, CDCl₃): δ = 1.92 (m, 2 H, CH₂), 2.41 (t, 2

H, ³J = 7.8 Hz, CH₂CO₂Me), 3.69 (s, 3 H, OMe), 3.96 (m, 1 H,

CHCH₂O), 4.02 (t, 1 H, ³J = 8.2 Hz, CH₂O), 4.51 (t, 1 H, ³J =

7.8 Hz, CH₂O), 6.68 (br. s, NH). ¹³C NMR (75 MHz, CDCl₃): δ =

29.8, 30.3 (CH₂), 49.3 (CHCH₂O), 51.9 (OMe), 70.3 (CH₂O), 159.9

(NCO), 173.0 (CO). ESI-MS, m/z (%) = 196 (65) [M⁺+ Na], 174

(100) [M⁺+ H]. C₇H₁₁NO₄(173.17): calcd. (%) C 48.55, H 6.40,

N 8.09; found: C 48.51, H 6.23, N 8.08.

a colorless oil. IR (film): ν (cm^–1) = 2967–2868, 1729 (CO), 1670,

˜

1479. ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 6 H, Si(CH₃)₂),

3

0.85 (s, 9 H, SiC(CH₃)₃), 1.20 (t, 3 H, J = 7.2 Hz, CO₂CH₂CH₃),

1.98 (s, 3 H, C(CH₃)=CH), 4.09 (m, 4 H, CO₂CH₂CH₃and

CH₂OSi), 5.88 (s, 1 H, C(CH₃)=CH). ¹³C NMR (75 MHz, CDCl₃):

δ = –5.1 (Si(CH₃)₂), 14.7, 15.8 (C(CH₃)=CH and CO₂CH₂CH₃),

18.7 (SiC(CH₃)₃), 26.2 (SiC(CH₃)₃), 59.9 (CO₂CH₂CH₃), 67.5

(CH₂OSi), 113.9 (CH=C(CH₃)), 157.4 (CH=C(CH₃)), 167.4 (CO).

EI-MS, m/z (%) = 258 (8) [M⁺], 243 (4) [M⁺– CH₃], 201 (100)

[M⁺– C(CH₃)₃], 173 (36), 75 (73). C₁₃H₂₆O₃Si (258.43): calcd. (%)

C, 60.42, H 10.14; found: C 60.31, H 10.17.

Methyl 3-[(4S)-3-((2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methyl-

2-butenyl)-2-oxo-1,3-oxazolidin-4-yl]propanoate (5): To a solution

of 3 (3.37 g, 19.5 mmol) in THF (50 mL) was added at 0 °C a solu-

(2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methyl-2-buten-1-ol (4c): tion of KOtBu (2.62 g, 23.4 mmol) and 18-crown-6 (0.52 g,

To a 1 m solution of diisobutylaluminium hydride in heptane 1.9 mmol) in THF (20 mL). After stirring for 30 min at room tem-

(87.1 mL, 87.1 mmol) at –78 °C was added a solution of (E)-4b perature, a solution of freshly prepared crude isoprenoid 4d (8.65 g,

(7.50 g, 29.0 mmol) in 50 mL of CH₂Cl₂. The reaction mixture was

stirred at –78 °C for 2 h and then quenched with a 5 m solution of

acetic acid in CH₂Cl₂(50 mL). The solution was poured into a

31.0 mmol) in THF (30 mL) was added and the mixture was stirred

for a further 3 h. The reaction was quenched with sat. aqueous

NH₄Cl (80 mL) and the mixture extracted with AcOEt (3×80 mL).

1434

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1427–1443

(–)-Sparteine-Mediated Synthesis of Kainoids

FULL PAPER

The combined organic phases were dried (MgSO₄) and concen-

trated in vacuo to dryness. The crude product was purified by flash

chromatography, R_f= 0.57 (SiO₂, AcOEt/petroleum ether, 70:30)

affording 5 (6.67 g, 92%) as a colorless oil. [α]²_D⁰= –34.4 (c = 1.0,

(3×50 mL) and the combined organic phases were washed with

NaHCO₃(3×25 mL), brine (3×25 mL), dried (MgSO₄), and the

solvents evaporated in vacuo. The crude 7 was used without further

purification. To a suspension of NaH (60% suspension mineral oil,

CHCl ). IR (film): ν (cm^–1) = 2958–2864, 1764, 1731 (NCO and 0.14 g, 3.6 mmol) in THF (10 mL), a solution of crude 7 (0.76 g,

˜

3

1

CO), 1444, 1419, 1370. H NMR (600 MHz, CDCl₃): δ = 0.04 (s, 2.2 mmol) in THF (10 mL) was added dropwise at room tempera-

6 H, Si(CH₃)₂), 0.89 (s, 9 H, SiC(CH₃)₃), 1.67 (s, 3 H, ture. The mixture was stirred for 1 h and treated dropwise with a

CH=C(CH₃)), 1.82 (m, 1 H, CH₂CO₂Me), 2.02 (m, 1 H, solution of CbyCl (0.85 g, 4.5 mmol) in THF (5 mL). After being

CH₂CO₂Me), 2.29 (m, 2 H, CH₂CH₂CO₂Me), 3.67 (s, 3 H, OMe),

refluxed for 12 h, the reaction mixture was worked up by addition

of sat. aqueous NH₄Cl (15 mL) and water (15 mL). The aqueous

3.71 (dd, 1 H, ³J = 7.9, 15.0 Hz, CH₂N), 3.80 (m, 1 H, CHCH₂O),

3

3.93 (t, 1 H, J = 8.7 Hz, CH₂O), 4.0 (s, 2 H, CH₂OSi), 4.11 (dd, phase was extracted with AcOEt (3×30 mL). The combined or-

3

1 H, J = 6.7, 15.1 Hz, CH₂N), 4.33 (t, 1 H, J = 8.5 Hz, CH₂O),

ganic phases were dried (MgSO₄) and concentrated in vacuo. The

5.42 (t, 1 H, ³J = 6.7 Hz, CH=C(CH₃)). ¹³C NMR (150 MHz, crude product was purified by flash chromatography, R_f= 0.46

CDCl₃): δ = –5.3 (Si(CH₃)₂), 13.4 (CH=C(CH₃)), 18.2 (SiC(CH₃)₃), (SiO₂, AcOEt/petroleum ether, 70:30) affording 8 (1.20 g, 76% over

25.8 (SiC(CH₃)₃), 26.7 (CH₂CH₂CO₂Me), 28.4 (CH₂CH₂CO₂Me), two steps) as a colorless oil. [α]²_D⁰= –6.9 (c = 0.41, CHCl₃). IR

39.3 (CH₂N), 51.8 (OMe), 53.6 (CHCH₂O), 66.5 (CH₂O), 67.4 (film): ν (cm^–1) = 2963–2864, 1742 (NCO), 1680, 1436. H NMR

1

˜

(CH₂OSi), 116.9 (C(CH₃)=CH), 139.9 (C(CH₃)=CH), 157.8 (600 MHz, CDCl₃): δ = 0.04 (s, 6 H, Si(CH₃)₂), 0.88 (s, 9 H,

(NCO), 172.5 (CO). EI-MS, m/z (%) = 356 (36) [M⁺– CH₃], 314

(100) [M⁺– C(CH₃)₃], 230 (25), 141 (69), 89 (44), 73 (56).

C₁₈H₃₃NO₅Si (371.54): calcd. (%) C 58.19, H 8.95, N 3.77; found:

C 58.32, H 8.68, N 3.51.

SiC(CH₃)₃), 1.35, 1.40, 1.50 and 1.54 (4×s, 12 H, CH_3Cby), 1.60 (s,

3

3 H, CH=C(CH₃)), 3.56 (dd, 1 H, J = 8.6, 16.9 Hz, CH₂N), 3.72

3

(s, 2 H, CH_2Cby), 3.91 (t, 1 H, J = 9.3 Hz, CHCH₂O), 3.99 (s, 2

3

H, CH₂OSi), 4.08 (dd, 1 H, J = 8.4, 16.5 Hz, CH₂N), 4.21 (m, 1

3

H, CHCH₂O), 4.39 (t, 1 H, J = 9.4 Hz, CHCH₂O), 4.61 (m, 2 H,

Methyl (2E)-3-[(4S)-3-((2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3-

methyl-2-butenyl)-2-oxo-1,3-oxazolidin-4-yl]-2-propenoate (6): To a

solution of oxazolidinone 5 (3.45 g, 9.28 mmol) in THF (40 mL)

freshly distilled TMSCl (2.37 mL, 18.6 mmol), followed by

KHMDS (0.5 min toluene) (37.2 mL, 18.6 mmol), were added at –

78 °C and the mixture was stirred for further 30 min. To a stirred

solution of Pd(OAc)₂(2.29 g, 10.2 mmol) in CH₃CN (30 mL) at

room temperature under argon was added via cannula the forego-

ing solution of 5. After 6 h at room temperature the reaction was

quenched by addition of sat. aqueous NH₄Cl (60 mL), and the salts

were removed by filtration through Celite. The filtrate was washed

with brine (3×50 mL), dried (MgSO₄), and concentrated in vacuo.

The crude product was purified by flash chromatography, R_f= 0.47

(SiO₂, AcOEt/petroleum ether, 1:1), affording 6 (2.85 g, 83%) as a

3

CH₂OCby), 5.39 (t, 1 H, J = 6.4 Hz, C(CH₃)=CH), 5.58–5.63 (m,

3

1 H, CHCH=CH), 5.83–5.88 (m, 1 H, J_(CH=CH)= 15.6 Hz,

CHCH=CH). ¹³C NMR (150 MHz, CDCl₃): δ = –5.3 (Si(CH₃)₂),

13.6 (CH=C(CH₃)), 18.4 (SiC(CH₃)₃), 24.1, 25.2, 25.3 (CH_3Cby),

25.9 (SiC(CH₃)₃), 26.5 (CH_3Cby), 39.2 (CH₂N), 57.2 (CHCH₂O),

63.5 (CH₂OCby), 67.0, 67.5 (CHCH₂O), 76.0, 76.3 (CH_2Cby), 116.8

(C(CH₃)=CH), 129.9 (CHCH=CH), 139.7 (CHCH=CH), 139.9

(C(CH₃)=CH), 157.7 (NCO). ESI-MS, m/z (%): 519 (100) [M⁺

+

Na], 497 (30) [M⁺+ H]. Daughter peaks resulting from m/z 497:

365 (100) [M⁺– OTBS]; 324 (12); 230 (10). C₂₅H₄₄N₂O₆Si (496.71):

calcd. (%) C 60.45, H 8.93, N 5.64; found: C 60.11, H 9.03, N 5.97.

(2E)-3-{(4S)-3-[(2E)-4-Hydroxy-3-methyl-2-butenyl]-2-oxo-1,3-ox-

azolidin-4-yl}-2-propenyl 2,2,4,4-Tetramethyl-1,3-oxazolidine-3-car-

boxylate (9): To a solution of 8 (1.32 g, 2.66 mmol) in Et₂O (20 mL)

was added dropwise a 1 m solution of tetrabutylammonium fluo-

colorless oil. [α]²_D⁰= +19.9 (c = 1.0, CHCl ). IR (film): ν (cm^–1) =

˜

3

2956–2856, 1760, 1735 (CO and CON), 1478, 1441, 1403, 1360. ¹H

NMR (600 MHz, CDCl₃): δ = 0.05 (s, 6 H, Si(CH₃)₂), 0.89 (s, 9 H, ride in THF (5.32 mL, 5.32 mmol). The reaction mixture was

SiC(CH₃)₃), 1.57 (s, 3 H, CH=C(CH₃)), 3.61 (dd, 1 H, ³J = 8.0, stirred at room temperature for 2 h, and quenched with H₂O

16.0 Hz, CH₂N) 3.76 (s, 3 H, OMe), 3.95–3.99 (m, 3 H, CHCH₂O

(10 mL). The aqueous phase was extracted with EtO₂(3×20 mL)

and the combined organic phases were washed with brine

3

and CH₂OSi), 4.10 (dd, 1 H, J = 5.8, 15.4 Hz, CH₂N), 4.32 (m, 1

3

H, CHCH₂O), 4.41 (t, 1 H, J = 11.5 Hz, CHCH₂O), 5.39 (t, 1 H, (3×15 mL) and dried (MgSO₄). The solvent was removed by evap-

³J = 6.9 Hz, C(CH₃)=CH), 5.99 (d, 1 H, ³J = 15.8 Hz, oration (bath temperature Ͻ 30 °C) affording 9 (1.00 g, 98%) as an

3

CHCH=CH), 6.75 (dd, 1 H, J = 7.5, 15.3 Hz, CHCH=CH). ¹³C oil. [α]²_D⁰= +15.0 (c = 0.80, CHCl ). IR (film): ν (cm^–1) = 3560–

˜

3

NMR (150 MHz, CDCl₃): δ = –5.3 (Si(CH₃)₂), 13.7 (CH=C(CH₃)),

18.2 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 39.6 (CH₂N), 52.0 (OMe), 56.4

(CHCH₂O), 66.1 (CH₂O), 67.2 (CH₂OSi), 116.3 (C(CH₃)=CH),

3225 (OH), 2988–2871, 1756 and 1694 (NCO), 1412. ¹H NMR

(300 MHz, CDCl₃): δ = 1.35, 1.40, 1.51 and 1.54 (4 × s, 12 H,

CH_3Cby), 1.58 (s, 3 H, CH=C(CH₃)), 3.71–3.79 (m, 3 H, CH₂N and

3

125 (CHCH=CH), 140.6 (C(CH₃)=CH), 143.0 (CHCH=CH), CH_2Cby), 3.91 (t, 1 H, J = 9.1 Hz, CHCH₂O), 4.02–4.08 (m, 3 H,

165.4 (NCO), 174.8 (CO). EI-MS, m/z (%) = 312 (100) [M⁺

–

CH₂N and CH₂OH), 4.25 (m, 1 H, CHCH₂O), 4.42 (t, 1 H, J =

3

C(CH₃)₃], 228 (15), 141 (56), 89 (29), 73 (56). C₁₈H₃₁NO₅Si 9.3 Hz, CHCH₂O), 4.63 (br. m, 2 H, CH₂OCby), 5.41 (t, 1 H, J =

(369.53): calcd. (%) C 58.51, H 8.46, N 3.79; found: C 58.30, H

8.80, N 3.65.

6.5 Hz, C(CH₃)=CH), 5.55–5.62 (m, 1 H, CHCH=CH), 5.83–5.90

(m, 1 H, CHCH=CH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.2

(CH=C(CH₃)), 23.9, 24.5, 25.6 and 26.0 (CH_3Cby), 26.9 (C-

(CH₃)_2Cby), 39.9 (CH₂N), 60.2 (CHCH₂O), 63.8 (CH₂OCby), 67.3,

67.5 (CH₂O), 67.9 (CH₂OH), 76.5, 76.7 (CH_2Cby), 118.4

(C(CH₃)=CH), 130.1 (CHCH=CH), 132.1 (CHCH=CH), 140.4

(C(CH₃)=CH), 158.2 (NCO). EI-MS, m/z (%): 382 (2) [M⁺], 367

(52) [M⁺– CH₃], 156 (32) [Cby⁺], 126 (99). C₁₉H₃₀N₂O₆(382.45):

calcd. (%) C 59.67, H 7.91, N 7.32; found: C 59.27, H 7.75, N 7.06.

(2E)-3-[(4S)-3-((2E)-4-{[tert-Butyl(dimethyl)silyl]oxy}-3-methyl-2-

butenyl)-2-oxo-1,3-oxazolidin-4-yl]-2-propenyl 2,2,4,4-Tetramethyl-

1,3-oxazolidine-3-carboxylate (8): To a solution of 6 (1.18 g,

3.19 mmol) in CH₂Cl₂(20 mL) at –78 °C, BF₃·OEt₂(0.44 mL,

3.51 mmol) was added and stirred for 1 h. A 1 m solution of DI-

BAL-H in hexane (9.57 mL, 9.57 mmol) was added dropwise. The

mixture was stirred at –78 °C for 2 h before carefully quenching

the reaction with 5 m acetic acid in CH₂Cl₂(10 mL). The reaction

was allowed to warm up to room temperature and poured into a

10% aqueous solution of tartaric acid (30 mL) and stirred at room

temperature for 1 h. The aqueous phase was extracted with CH₂Cl₂

(2E)-3-{(4S)-3-[(2E)-4-Chloro-3-methyl-2-butenyl]-2-oxo-1,3-oxaz-

olidin-4-yl}-2-propenyl 2,2,4,4-Tetramethyl-1,3-oxazolidine-3-carbox-

ylate (10): To a solution of 9 (0.86 g, 2.2 mmol) in CH₂Cl₂(20 mL),

NEt₃(0.49 mL, 3.52 mmol), followed by methanesulfonyl chloride

Eur. J. Org. Chem. 2005, 1427–1443

www.eurjoc.org

1435

M. Montserrat Martínez, D. Hoppe

FULL PAPER

(0.22 mL, 2.9 mmol), were added at –40 °C. After being stirred for

1 h at –40 °C, the reaction mixture was transferred via cannula to

a suspension of anhydrous LiCl (0.37 g, 8.8 mmol) in THF (10 mL)

at room temperature. The reaction mixture was stirred for 12 h.

The resulting slurry was poured into pentane (20 mL) and washed

several times with H₂O (5×15 mL). The organic layer was dried

(MgSO₄) and concentrated in vacuo. The crude product was puri-

fied by flash chromatography, R_f= 0.43 (SiO₂, AcOEt/petroleum

ether, 1:1) affording 10 (0.41 g, 47%) as a yellow oil. [α]²_D⁰= +9.2

from rac-12 (2.50 g, 5.60 mmol). IR (film): ν (cm^–1) = 3518–3263

˜

(OH + NH), 2933–2864, 1475, 1410. ¹H NMR (300 MHz, CDCl₃):

δ = 1.33 (s, 9 H, SiC(CH₃)₃), 2.62 (br. s, 2 H, NH + OH), 3.10 (m,

3

1 H, CHCH₂OH), 3.75 (dd, 1 H, J = 3.7, 10.4 Hz, CH₂OSi), 3.92

3

(dd, 1 H, J = 3.8, 11.0 Hz, CH₂OSi), 4.01–4.07 (m, 4 H, CH₂OH

and NCH₂Ar), 7.52–7.70 (m, 11 H, ArH), 7.91 (d, 4 H, ³J = 8.1 Hz,

ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 19.7 (SiC(CH₃)₃), 27.4

(SiC(CH₃)₃), 51.6 (NCH₂), 60.4 (CHCH₂O), 61.9 and 64.1

(CH₂OH, CH₂OSi), 127.5, 128.1, 128.2, 128.5, 128.6, 128.9, 129.4,

(c = 1.2, CHCl ). IR (film): ν (cm^–1) = 2988–2871, 1763 and 1701

130.3, 133.6, 136.0 and 140.7 (Ar). EI-MS, m/z (%) = 418 (2) [M⁺

–

˜

3

1

(NCO), 1446, 1412, 1371. H NMR (600 MHz, CDCl₃): δ = 1.34, H], 404 (56) [M⁺– Me], 388 (46), 91 (100) [PhCH₂⁺]. C₂₆H₃₃NO₂Si

1.39, 1.49, and 1.52 (4 × s, 12 H, CH_{3 C by}), 1.75 (s, 3 H,

(419.63): calcd. (%) C, 74.42, H 7.93, N 3.34; found: C 74.10, H

CH=C(CH₃)), 3.58–3.64 (m, 1 H, CH₂N), 3.71 (s, 2 H, CH_2Cby), 7.72, N 3.21.

3.87–3.90 (m, 1 H, CHCH₂O), 3.95–4.01 (m, 3 H, CH₂N and

(2S)-2-[Benzyl-((2E)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-2-

3

CH₂Cl), 4.18–4.21 (m, 1 H, CHCH₂O), 4.39 (t, 1 H, J = 7.2 Hz,

butenyl)amino]-3-{[tert-butyl(diphenyl)silyl]oxy}-1-propanol (14): To

a suspension of NaHCO₃(2.14 g, 25.4 mmol) in CH₃CN (30 mL)

at room temperature was added over 5 min a solution of 13 (4.27 g,

10.2 mmol) in CH₃CN (30 mL). The reaction mixture was stirred

for additional 30 min at room temperature. Freshly prepared iso-

prenoid 4d (8.49 g, 30.4 mmol) in CH₃CN (50 mL) was added and

the mixture was refluxed for 5 h. The reaction mixture was

quenched with sat. aqueous NH₄Cl (50 mL) and the aqueous phase

extracted with AcOEt (3×100 mL). The combined organic phases

were washed with brine, dried (MgSO₄), and concentrated in vacuo.

The crude product was purified by flash chromatography, R_f= 0.48

(SiO₂, AcOEt/petroleum ether, 5:95) affording 14 (5.10 g, 81%) as

a colourless oil. [α]²_D⁰= –11.8 (c = 0.52, CHCl₃). rac-14 (1.11 g,

84%) was obtained by the same procedure from rac-13 (900 mg,

CHCH₂O), 4.60 (m, 2 H, CH₂OCby), 5.47–5.60 (m, 2 H,

C(CH₃)=CH and CHCH=CH), 5.84–5.91 (m, 1 H, CHCH=CH).

¹³C NMR (150 MHz, CDCl₃): δ = 14.5 (CH=C(CH₃)), 24.0, 25.2,

25.3 and 26.5 (4×CH_3Cby), 30.9 (C(CH₃)_2Cby), 39.6, 39.8 (CH₂N),

50.9 (CH₂Cl), 57.6 (CHCH₂O), 63.4 (CH₂OCby), 67.1 (CH₂O),

75.9, 76.2 (CH_{2 C by}), 123.5, 123.9 (C(CH₃)=CH), 129.3

(CHCH=CH), 132.2 (CHCH=CH), 136.7 (C(CH₃)=CH), 157.6

(NCO). EI-MS, m/z (%) = 385 (69) [M⁺– H – CH₃], 365 (100)

[M⁺– HCl], 228 (15), 191 (16), 67 (81). C₁₉H₂₉ClN₂O₅(400.90).

Methyl (2R)-2-(Benzylamino)-3-{[tert-butyl(diphenyl)silyl]oxy}pro-

panoate (12): To a solution of N-benzoyl-d-serine methyl ester

(11)^[15](8.47 g, 40.5 mmol) in CH₂Cl₂(100 mL) at room tempera-

ture was added NEt₃(6.83 mL, 48.6 mmol), followed by tert-butyl-

diphenylsilyl chloride (13.4 g, 48.6 mmol) and DMAP (0.25 g,

2.0 mmol). The reaction mixture was stirred at room temperature

for 12 hours and then diluted with H₂O (50 mL). The mixture was

then poured into a separating funnel containing CH₂Cl₂(100 mL).

The separated organic phase was washed with brine (3×75 mL),

dried (MgSO₄) and concentrated in vacuo. The crude product was

purified by flash chromatography, R_f= 0.55 (SiO₂, AcOEt/petro-

leum ether, 90:10) affording 12 (15.9 g, 88%) as a white solid: m.p.

(recrystallized from CH₂Cl₂): 61.6–62.3 °C. [α]²_D⁰= +4.2 (c = 0.84,

CHCl₃). rac-12 (2.85 g, 95%) was obtained by the same procedure

2.15 mmol). IR (film): ν (cm^–1) = 3538–3339 (OH), 2960–2857,

˜

1

1481, 1432, 1310. H NMR (600 MHz, CDCl₃): δ = 0.04 (s, 6 H,

Si(CH₃)₂), 0.90 (s, 9 H, SiC(CH₃)₃), 1.06 (s, 9 H, SiC(CH₃)₃), 1.53

(s, 3 H, CH=C(CH₃)), 3.09 (m, 1 H, CHCH₂OH), 3.19–3.28 (m, 2

H, NCH₂), 3.45 (t, 1 H, ³J = 10.1 Hz, CH₂OH), 3.53–3.57 (m, 3

H, NCH₂Ar and CH₂OSiPh₂), 3.67 (dd, 1 H, ³J = 11.5 Hz,

3

CH₂OH), 3.83 (dd, 1 H, J = 10.1 Hz, CH₂OSiPh₂), 3.98 (s, 2 H,

CH₂OSi(CH₃)₂), 5.44 (t, 1 H, ³J = 6.2 Hz, C(CH₃)=CH), 7.22–7.30

(m, 5 H, ArH), 7.39–7.46 (m, 6 H, ArH), 7.66 (d, 4 H, ³J = 5.6 Hz,

ArH). ¹³C NMR (150 MHz, CDCl₃): δ = –5.3 (Si(CH₃)₂), 13.6

(CH=C(CH₃)), 19.1, 19.5 (SiC(CH₃)₃), 25.9, 26.8 (SiC(CH₃)₃), 46.8

(NCH₂), 54.2 (CH₂OSiPh₂), 59.3 (NCH₂Ar), 60.9 (CHCH₂OH),

61.3 (CH₂OH), 68.2 (CH₂OSi(CH₃)₂), 122.3 (C(CH₃)=CH), 127.0,

127.8, 128.3, 128.8, 129.8, 129.9, 133.0, 133.1, 135.5, 135.6 and

from rac-11 (1.30 g, 6.70 mmol). IR (KBr): ν (cm^–1) = 3346 (NH),

˜

1

2961–2864, 1742 (CO), 1474, 1426. H NMR (300 MHz, CDCl₃):

δ = 1.05 (s, 9 H, SiC(CH₃)₃), 3.41 (t, 1 H, ³J = 3.7 Hz, CHCO₂Me),

3.71 (s, 3 H, OMe), 3.87–3.95 (m, 4 H, CH₂N and CH₂OSi), 7.29–

7.43 (m, 11 H, ArH), 7.65–7.68 (m, 3 H, ArH), 7.71 (d, 1 H, J = 137.6, 139.7 (C(CH₃)=CH). EI-MS, m/z (%) = 617 (1) [M⁺– H],

3

8.1 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 19.7 (SiC(CH₃)₃),

27.1 (SiC(CH₃)₃), 52.1 (OMe), 52.3 (NCH₂Ar), 62.6 (CHCO₂Me),

65.7 (CH₂OSi), 127.4, 128.1, 128.6, 128.8, 130.2, 130.1, 133.6,

135.2, 135.7, 136.0 and 140.3 (Ar), 174.2 (CO). EI-MS, m/z (%) =

447 (2) [M⁺], 390 (60) [M⁺– C(CH₃)₃], 310 (13), 178 (22), 91 (100).

C₂₇H₃₃NO₃Si (447.64): calcd. (%) C 72.44, H 7.43, N 3.13; found:

C 72.72, H 7.49, N 3.13.

586 (89), 560 (5) [M⁺– C(CH₃)₃], 348 (100). ESI-HRMS

₃₇H₅₅NO₃Si₂(618.01): [M⁺+ H] calcd. 618.3799; found:

C

618.3817.

Ethyl (2E,4S)-4-[Benzyl-((2E)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-

methyl-2-butenyl)amino]-5-{[tert-butyl(diphenyl)silyl]oxy}-2-

pentenoate (15): A solution of dimethyl sulfoxide (0.54 mL,

7.6 mmol) in dichloromethane (6 mL) was added to a solution of

oxalyl chloride (0.30 mL, 3.5 mmol) in dichloromethane (15 mL)

(2S)-2-(Benzylamino)-3-{[tert-butyl(diphenyl)silyl}oxy}-1-propanol

(13): To a 2 m solution of LiBH₄(4.17 mL, 8.34 mmol) in THF at –78 °C, and the reaction mixture was stirred for 5 more min at

(15 mL), a solution of N-benzyl-O-TBS-d-serine methyl ester (12) the same temperature. A solution of the alcohol 14 (1.80 g,

(6.72 g, 15.0 mmol) in THF/toluene (4:1) (50 mL) was slowly 2.91 mmol) in dichloromethane (3 mL) was added over 5 min and

added. Toluene (12.5 mL) was added to avoid caking of the residue

and to serve as a heat-transfer medium. The reaction mixture was

heated at 100 °C for 20 min and then treated with sat. aqueous

NH₄Cl (30 mL). The aqueous phase was extracted with AcOEt

(3×50 mL), the combined organic phases were dried (MgSO₄), and

concentrated in vacuo. The crude product was purified by flash

chromatography, R_f= 0.36 (SiO₂, AcOEt/petroleum ether, 80:20)

affording 13 (3.52 g, 56%) as a colourless oil. [α]²_D⁰= –1.6 (c = 1.9,

CHCl₃). rac-13 (970 mg, 42%) was obtained by the same procedure

stirring was continued for another 20 min after which NEt₃

(2.05 mL, 14.6 mmol) was added and the solution brought to

–15 °C over 2 h. A solution of (ethoxycarbonylmethylene)triphenyl-

phosphorane (2.95 g, 8.47 mmol) in dichloromethane (16 mL) was

added to the reaction mixture and the temperature was allowed to

reach at 25 °C over 3 h. The reaction mixture was poured into

brine (25 mL) and the solution was extracted with dichloromethane

(3×30 mL). The combined organic phases were dried (MgSO₄) and

concentrated in vacuo. The crude product was purified by flash

1436

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1427–1443

(–)-Sparteine-Mediated Synthesis of Kainoids

FULL PAPER

IR (film): ν (cm^–1) = 2910–2833, 1707 (CO), 1442, 1407, 1368. H

NMR (300 MHz, CDCl₃): δ = 1.09 (s, 9 H, SiC(CH₃)₃), 1.30 (t, 3

H, ³J = 7.1 Hz, CO₂CH₂CH₃), 1.67 (s, 3 H, CH=C(CH₃)), 3.15–

3.21 (m, 2 H, NCH₂), 3.48 (m, 1 H, CHCH=CH), 3. 61 (d, 1 H,

³J = 10.1 Hz, CH₂Ar), 3.75–3.82 (m, 3 H, CH₂OSiPh₂and CH₂Ar),

1

chromatography, R_f= 0.45 (SiO₂, AcOEt/petroleum ether, 10:90)

affording 15 (1.40 g, 70%) as a pale yellow oil. [α]²_D⁰= +9.7 (c =

0.37, CHCl₃). rac-15 (865 mg, 78%) was obtained by the same pro-

˜

cedure from rac-14 (1.00 g, 1.62 mmol). IR (film): ν (cm^–1) = 2976–

˜

1

2856, 1728 (CO), 1474, 1447, 1370. H NMR (600 MHz, CDCl₃):

δ = 0.04 (s, 6 H, Si(CH₃)₂), 0.89 (s, 9 H, SiC(CH₃)₃), 1.03 (s, 9 H, 3.97 (s, 2 H, CH₂Cl), 4.21 (q, ³J = 7.2 Hz, 2 H, 14.0 Hz,

3

SiC(CH₃)₃), 1.30 (t, 3 H, J = 7.2 Hz, CO₂CH₂CH₃), 1.53 (s, 3 H, CO₂CH₂CH₃), 5.56 (t, 1 H, J = 7.3 Hz, C(CH₃)=CH), 6.01 (d, 1

CH=C(CH₃)), 3.12 (m, 1 H, NCH₂), 3.22 (m, 1 H, NCH₂), 3.50

H, ³J = 15.0 Hz, CHCH=CH), 7.00 (dd, 1 H, ³J = 7.4, 15.1 Hz,

3

(m, 1 H, CHCH=CH), 3.59 (d, 1 H, J = 10.1 Hz, NCH₂Ar) 3.76 CHCH=CH), 7.28–7.46 (m, 11 H, ArH), 7.61 (d, 4 H, ³J = 6.1 Hz,

(m, 2 H, CH₂NAr and CH₂OSiPh₂), 3.88 (m, 1 H, CH₂OSiPh₂),

ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.3 (CH=C(CH₃)), 19.2

(CH₂CH₃), 22.4 (SiC(CH₃)₃), 26.9 (SiC(CH₃)₃), 44.6 (NCH₂), 51.8

3

3.98 (s, 2 H, CH₂OSi(CH₃)₂), 4.22 (q, 2 H, J = 7.1 Hz, 14.1 Hz,

3

CO₂CH₂CH₃) 5.47 (t, 1 H, J = 7.5 Hz, C(CH₃)=CH), 6.01 (d, 1 (CH₂Cl), 60.4 (CH₂CH₃), 61.7 (CHCH=CH), 64.0 (CH₂OSiPh₂),

H, ³J = 15.1 Hz, CHCH=CH), 7.01 (dd, 1 H, ³J = 15.2, 7.5 Hz,

CHCH=CH), 7.21 (t, 1 H, ³J = 7.1 Hz, ArH), 7.22–7.42 (m, 10 H, 127.8, 128.2, 128.3, 128.4, 128.9, 129.8, 133.2, 133.6, 135.6, 136.3

ArH), 7.63 (d, 4 H, ³J = 6.4 Hz, ArH). ¹³C NMR (150 MHz,

and 138.5 (Ar), 139.7 (C(CH₃)=CH), 145.8 (CHCH=CH), 179.6

CDCl₃): δ = –5.3 (Si(CH₃)₂), 13.7 (CH=C(CH₃)), 14.3 (CH₂CH₃), (CO). ESI-MS, m/z (%) = 612 (50) [M⁺+ Na], 590 (38) [M⁺

69.9 (NCH₂Ar), 116.2 (C(CH₃)=CH), 123.9 (CHCH=CH), 127.0,

+

19.1, 19.5 (SiC(CH₃)₃), 25.9, 26.8 (SiC(CH₃)₃), 47.6 (NCH₂), 54.8

(NCH₂Ar), 60.3 (CH₂CH₃), 61.5 (CHCH=CH), 63.9 (CH₂OS-

H]. HRMS (TOF-CI) C₃₅H₄₄ClNO₃Si (589.28): [M⁺+ H] calcd.

590.2852; found: 590.2844, [M⁺+ Na] calcd. 612.2671; found

iPh₂), 68.3 (CH₂OSi(CH₃)₂), 122.6 (C(CH₃)=CH), 123.7 612.2659.

(CHCH=CH), 126.7, 127.7, 128.2, 128.4, 129.7, 133.3, 135.6 and

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-

137.2 (Ar), 140.1 (C(CH₃)=CH), 146.5 (CHCH=CH), 166.4 (CO).

EI-MS, m/z (%) = 685 (8) [M⁺– H], 628 (3) [M⁺– H – C(CH₃)₃],

hydroxy-2-pentenoate (24): To a solution of 17 (50 mg, 0.08 mmol)

in THF (10 mL) was added TBAF (0.17 mL, 0.17 mmol) at room

temperature. After being stirred at the same temperature for 3 h,

the reaction mixture was poured into ether (10 mL) and washed

with H₂O several times (5×6 mL). The organic phase was dried

416 (100), 199 (26), 73 (35). ESI-MS, m/z (%) = 709 (10) [M⁺

+

Na], 686 (100) [M⁺+ H]. C₄₁H₅₉NO₄Si₂(686.08): calcd. (%) C,

71.78, H 8.67, N 2.04; found: C 71.39, H 8.61, N 1.93.

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-hydroxy-3-methyl-2-butenyl]amino}- (MgSO₄) and concentrated in vacuo. The crude product 24 was

5-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenoate (16): Pyridinium p-

toluenesulfonate (PPTS) (0.79 g, 3.0 mmol) was added with stirring

at room temperature to a solution of 15 (1.30 g, 1.90 mmol) in ab-

solute ethanol (20 mL). The reaction mixture was stirred for 48 h

at 55 °C and the solvent was evaporated to dryness. The residue

was purified by a short flash chromatography, R_f= 0.37 (SiO₂,

AcOEt/petroleum ether, 20:80) affording 16 (1.08 g, 100%) as a col-

orless oil. [α]²_D⁰= +6.8 (c = 0.74, CHCl₃). rac-16 (645 mg, 97%)

was obtained by the same procedure from rac-15 (800 mg,

used in next step without further purification. Crude product rac-

24 was obtained by the same procedure from rac-17 (60 mg,

0.51 mmol). IR (film): ν (cm^–1) = 3526–3313 (OH), 2926–2852,

˜

1717 (CO), 1647, 1447, 1365. ¹H NMR (400 MHz, CDCl₃): δ =

1.27 (t, 3 H, ³J = 7.2 Hz, CO₂CH₂CH₃), 1.68 (s, 3 H, CH=C(CH₃)),

2.9 (br. s, 1 H, OH), 3.12–3.22 (m, 2 H, NCH₂), 3.35 (m, 1 H,

CHCH=CH), 3.42–3.55 (m, 2 H, CH₂OH and NCH₂Ar), 3.58 (m,

3

1 H, CH₂OH), 3.82 (d, 1 H, J = 10.6 Hz, NCH₂Ar), 3.90 (s, 2 H,

CH₂Cl), 4.20 (q, 2 H, ³J = 7.2 Hz, 14.0 Hz, CO₂CH₂CH₃), 5.60

1.16 mmol). IR (film): ν (cm^–1) = 3553–3298 (OH), 2961–2864, (t, 1 H, ³J = 7.3 Hz, C(CH₃)=CH), 5.98 (d, 1 H, ³J = 15.0 Hz,

˜

1

1729 (CO), 1639, 1445, 1410, 1350. H NMR (300 MHz, CDCl₃):

CHCH=CH), 7.40 (dd, 1 H, ³J = 6.8, 15.7 Hz, CHCH=CH), 7.48–

δ = 0.98 (s, 9 H, SiC(CH₃)₃), 1.21 (t, 3 H, ³J = 7.0 Hz, 7.67 (m, 5 H, ArH). HRMS (TOF-CI) C₁₉H₂₆ClNO₃(351.87): [M⁺

CO₂CH₂CH₃), 1.48 (s, 3 H, CH=C(CH₃)), 3.11 (m, 2 H, NCH₂),

3.42 (m, 1 H, CHCH=CH), 3. 55 (d, 1 H, ³J = 10.2 Hz, NCH₂Ar),

3.70–3.79 (m, 3 H, NCH₂Ar and CH₂OSiPh₂), 3.88 (m, 2 H,

CH₂OH), 4.12 (q, 2 H, ³J = 7.2 Hz, 14.0 Hz, CO₂CH₂CH₃) 5.38

(t, 1 H, ³J = 7.3 Hz, C(CH₃)=CH), 5.91 (d, 1 H, ³J = 15.0 Hz,

CHCH=CH), 6.92 (dd, 1 H, ³J = 15.0, 7.5 Hz, CHCH=CH), 7.19–

+ H] calcd. 352.1674; found: 352.1667.

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-

5-[(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)oxy]-2-pentenoate

(25): To a solution of 24 (21 mg, 0.06 mmol) in CCl₄(1 mL) were

added three drops of pyridine followed by (R)-(–)-α-methoxy-α-(tri-

fluoromethyl)phenylacetyl chloride (14 μL, 0.07 mmol) at 0 °C. Af-

ter being stirred at room temperature for 4 h, the reaction mixture

was dried (MgSO₄) and concentrated in vacuo. The crude product

was purified by flash chromatography, R_f= 0.51 (1:1 Et₂O/petro-

leum ether) affording 25 and its epimer as a diastereomeric mixture,

which could not be separated by flash chromatography (29 mg,

65% overall yield) as a pale colorless oil. rac-25 (41 mg, 71%) was

obtained by the same procedure from rac-24 (33 mg, 0.94 mmol).

3

7.40 (m, 11 H, ArH), 7.55 (d, 4 H, J = 6.1 Hz, ArH). ¹³C NMR

(75 MHz, CDCl₃): δ = –5.3 (Si(CH₃)₂), 13.5 (CH=C(CH₃)), 14.3

(CH₂CH₃), 19.6 (SiC(CH₃)₃), 27.2 (SiC(CH₃)₃), 48.4 (NCH₂), 55.8

(CH₂OH), 60.7 (CH₂CH₃), 62.7 (CHCH=CH), 64.5 (CH₂OSiPh₂),

68.9 (NCH₂Ar), 123.9 (C(CH₃)=CH), 124.6 (CHCH=CH), 127.2,

128.1, 128.6, 128.8, 129.2, 130.1, 133.7, 135.2, 136.0 and 137.5 (Ar),

140.6 (C(CH₃)=CH), 146.9 (CHCH=CH), 179.9 (CO). ESI-MS,

m/z (%) = 572 (94) [M + H]. Daughter peaks resulting from m/z

572: 488 (10); 410 (30), 231 (42); 120 (40), 91 (100) [PhCH₂⁺].

HRMS (TOF-CI) C₃₅H₄₅NO₄Si (571.82): [M⁺+ H] calcd.

572.3191; found: 572.3184.

IR (film): ν (cm^–1) = 2917–2848, 1752 and 1721 (CO), 1656, 1456,

˜

1

3

1374. H NMR (600 MHz, CDCl₃): δ = 1.23 (t, 3 H, J = 7.2 Hz,

CO₂CH₂CH₃), 1.62 (s, 3 H, CH=C(CH₃)), 3.11–3.16 (m, 2 H,

3

NCH₂), 3.42 (s, 3 H, OMe), 3.50 (d, 1 H, J = 10.2 Hz, NCH₂Ar),

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5- 3.60–3.65 (m, 1 H, CHCH=CH), 3.70 (d, 1 H, ³J = 10.2 Hz,

{[tert-butyl(diphenyl)silyl]oxy}-2-pentenoate (17): Compound 16

(1.59 g, 2.78 mmol) was treated under the conditions described for

10 to produce 17 (1.36 g, 83 %) as a colourless oil after flash

chromatography, R_f= 0.47 (SiO₂, AcOEt/petroleum ether, 5:95).

[α]_D²⁰= +5.2 (c = 0.64, CHCl₃, Ϸ26% ee). rac-17 (365 mg, 71%) was

obtained by the same procedure from rac-16 (500 mg, 0.88 mmol).

NCH₂Ar), 3.96 (s, 2 H, CH₂Cl), 4.20 (q, 2 H, ³J = 7.2 Hz, 14.0 Hz,

CO₂CH₂CH₃), 4.30–4.37 (m, 1 H, CHCH₂O), 4.51–4.58 (m, 1 H,

CHCH₂O), 5.48–5.55 (m, 1 H, C(CH₃)=CH), 5.86–5.91 (m, 1 H,

CHCH=CH), 6.80–6.85 (m, 1 H, CHCH=CH), 7.20–7.50 (m, 10

H, ArH). HRMS C₂₉H₃₃ClF₃NO₅(568.02): calcd. 568.2078; found:

568.2049.

Eur. J. Org. Chem. 2005, 1427–1443

www.eurjoc.org

1437

M. Montserrat Martínez, D. Hoppe

FULL PAPER

In the ¹H NMR spectrum (600 MHz, CDCl₃) one of the CH₂O

protons of 25 and its epimer could be detected separately at δ =

4.32 and 4.35 ppm (dr = 63:37 or 26% ee).

127.5, 128.1 (C(CH₃)=CH), 128.6 and 129.2 (CHCH=CH), 129.2,

129.6, 132.4, 132.6 and 134.6 (Ar), 139.3 (C(CH₃)=CH), 154.4

(NCO). EI-MS, m/z (%) = 674 (0.2) [M⁺– H], 639 (5) [M⁺– HCl],

405 (100), 320 (33), 91 (67). HRMS C₄₀H₅₅ClN₂O₃Si (675.41):

calcd. 675.374324; found: 675.373151.

(2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-

5-{[tert-butyl(diphenyl)silyl]oxy}-2-penten-1-ol (18): To a solution of

DIBAL-H (1 min hexane) (8.29 mL, 8.29 mmol) in dichlorometh-

ane (40 mL) at –78 °C was added dropwise a solution of ester 17

(1.57 g, 2.76 mmol) in dichloromethane (25 mL) under an argon

atmosphere. After being stirred at the same temperature for 3 h, a

solution of AcOH (1 min dichloromethane) (15 mL) was added and

the reaction mixture was poured into a funnel containing a 10%

solution of tartaric acid (30 mL), extracted with dichloromethane

(3×50 mL), dried (MgSO₄), and concentrated under reduced pres-

sure. The crude product 18 as a colourless oil was used in next step

without further purification. [α]²_D⁰= +12.0 (c = 0.32, CHCl₃, Ϸ26%

(2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-

5-{[tert-butyl(diphenyl)silyl]oxy}-2-pentenyl 2,2,4,4-Tetramethyl-1,3-

oxazolidine-3-carboxylate (20): The crude product obtained by

using Method B was purified by flash chromatography, R_f= 0.46

(SiO₂, Et₂O/petroleum ether, 5:95) affording 20 (1.32 g, 68% overall

yield) as a colorless oil. [α]²_D⁰= +2.3 (c = 1.9, CHCl₃, Յ 26% ee).

IR (film): ν (cm^–1) = 2922–2852, 1700 (NCO), 1456, 1404, 1343.

˜

¹H NMR (400 MHz, CDCl₃): δ = 1.12 (s, 9 H, SiC(CH₃)₃), 1.37,

1.57, 1.63 and 1.65 (4 × s, 12 H, CH_{3 C by}), 1.68 (s, 3 H,

CH=C(CH₃)), 3.15 (m, 2 H, CH₂N), 3.34 (m, 1 H, CHCH=CH),

3.45–3.51 (m, 3 H, NCH₂Ar and CH₂OSi), 3.71–3.80 (m, 3 H,

NCH₂Ar and CH₂OCby), 3.97 (s, 2 H, CH₂Cl), 4.60 (s, 2 H,

ee). IR (film): ν (cm^–1) = 3574–3254 (OH), 2963–2864, 1592, 1470,

˜

1

1408. H NMR (300 MHz, CDCl₃): δ = 0.98 (s, 9 H, SiC(CH₃)₃),

3

1.59 (s, 3 H, CH=C(CH₃)), 3.05–3.11 (m, 2 H, NCH₂), 3.29 (m, 1

CH_2Cby), 5.58 (t, 1 H, J = 6.4 Hz, C(CH₃)=CH), 5.71 (br. m, 2 H,

3

H, CHCH=CH), 3.47 (d, 1 H, J = 10.1 Hz, CH₂NAr), 3.65–3.82

CHCH=CH), 7.10–7.23 (m, 11 H, ArH), 7.55 (m, 4 H, ArH).

HRMS C₄₁H₅₅ClN₂O₄Si (703.42): calcd. 703.3698; found:

703.3678.

(m, 3 H, CH₂OSiPh₂and NCH₂Ar), 3.89 (s, 2 H, CH₂Cl), 4.08 (d,

2 H, ³J = 4.9 Hz, CH₂OH), 5.48 (t, 1 H, ³J = 7.3 Hz, C(CH₃)=CH),

5.61–5.69 (m, 2 H, CHCH=CH), 7.11–7.38 (m, 11 H, ArH), 7.55

Cyclization of Carbamates 19 and 20 with nBuLi/Diamine. General

Procedures. Method A: The carbamate 19 or 20 (0.20 mmol) and

(–)-sparteine (103 mg, 0.44 mmol) were dissolved in toluene (5 mL),

cooled to –78 °C, and a 1.6 m solution of nBuLi in hexane

(0.27 mL, 0.44 mmol) was added to the solution dropwise. The re-

action mixture was stirred for 4 h at –45 °C. MeOH (1 mL) and

sat. aqueous NH₄Cl (0.5 mL) were added, and the reaction mixture

was allowed to warm to room temperature. The organic layer was

separated and the aqueous phase was extracted with Et₂O

(3×15 mL). The combined organic phases were dried (MgSO₄),

and concentrated in vacuo.

3

(d, 4 H, J = 6.2 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 13.5

(CH=C(CH₃)), 18.2 (SiC(CH₃)₃), 25.9 (SiC(CH₃)₃), 47.1 (CH₂N),

51.0 (CH₂Cl), 54.0 (NCH₂Ar) 61.7 (CHCH=CH), 62.4 (CH₂OH),

64.1 (CH₂OSi), 125.7 (C(CH₃)=CH), 126.6 (CHCH=CH), 127.1,

127.5, 127.6, 128.7, 132.0, 132.3 and 132.6 (Ar), 132.7

(CHCH=CH), 134.6 (Ar), 139.4 (C(CH₃)=CH). EI-MS, m/z (%) =

529 (4) [M⁺– H₂O], 512 (7) [M⁺– HCl], 278 (100), 199 (15), 91

(100) [PhCH₂⁺]. HRMS C₃₃H₄₂ClNO₂Si (548.23): calcd.

548.274610; found: 548.272864.

Carbamoylation of Allylic Alcohol 18. General Procedures. Method

A: To a suspension of sodium hydride (60% suspension in mineral

oil) (0.13 g, 3.3 mmol) in THF (15 mL) was added over 10 min a

solution of 18 (1.20 g, 2.19 mmol) in THF (25 mL). The reaction

mixture was stirred at room temperature for 1 h, after which time

a solution of CbCl (1.07 g, 6.57 mmol) in THF (15 mL) was added

and the reaction mixture was heated to 70 °C for 12 h. The reaction

mixture was allowed to chill to room temperature and treated with

sat. aqueous NH₄Cl (30 mL) and H₂O (30 mL). The phases were

separated and the aqueous phase was extracted with diethyl ether

(3×50 mL). The combined organic phases were dried (MgSO₄) and

concentrated in vacuo.

Method B: In Method B, THF was used instead of toluene. (–)-

Sparteine was replaced by TMEDA (51 mg, 0.44 mmol) and the

reaction mixture was stirred for 3 h.

(Z)-2-[(2S,3R,4S)- and (2S,3S,4R)-1-Benzyl-2-({[tert-butyl(diphenyl)-

silyl]oxy}methyl)-4-isopropenylpyrrolidinyl]ethenyl Diisopropylcar-

bamate (21a and 21b): The crude product 21, obtained from carba-

mate 19 (135 mg, 0.20 mmol) by Method A, was purified by flash

chromatography, R_f= 0.33 (SiO₂, Et₂O/petroleum ether, 5:95) af-

1

fording 21 (61 mg, 48%, dr = 95:5 by H NMR) as a colorless oil.

21a: [α]²_D⁰= –7.1 (c = 0.52, CHCl , ee unknown). IR (film): ν (cm^–1)

˜

3

Method B: In Method B, CbyCl (1.26 g, 6.57 mmol) was used in-

stead of CbCl.

= 2916–2850, 1686 (NCO), 1420, 1365. ¹H NMR (600 MHz,

CDCl₃): δ = 1.03 (s, 9 H, SiC(CH₃)₃), 1.12 (s, 6 H, 2×CH_3Cb), 1.13

3

(2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-{[tert-

butyl(diphenyl)silyl]oxy}-2-pentenyl Diisopropylcarbamate (19): The

crude product obtained by Method A was purified by flash

chromatography, R_f= 0.36 (SiO₂, Et₂O/petroleum ether, 5:95) af-

(s, 6 H, 2×CH_3Cb), 1.64 (s, 3 H, CH=C(CH₃)), 2.49 (dd, 1 H, J

= 6.0, 10.8 Hz, CH₂N), 2.65 (m, 1 H, CHCH₂OSi), 2.89 (m, 1 H,

3

CHC(CH₃)=CH₂), 2.97 (dd, 1 H, J = 10.8, 6.0 Hz, CH₂N), 3.26

3

(m, 1 H, CHCH=CH), 3.41 (d, 1 H, J = 11.3 Hz, NCH₂Ar), 3.76

fording 19 (1.12 g, 60% overall yield) as a colourless oil. [α]²_D⁰

=

(br. s, 2 H, CH₂OSi), 3.98–4.11 (br. m, 2 H, CH_Cb), 4.21 (d, 1 H,

+4.2 (c = 0.45, CHCl , Յ 26% ee). IR (film): ν (cm^–1) = 2956–

³J = 11.3 Hz, NCH₂Ar), 4.54 (s, 1 H, C(CH₃)=CH₂), 4.58 (dd, 1

˜

3

1

3

2865, 1658 (NCO), 1413, 1345. H NMR (400 MHz, CDCl₃): δ = H, J = 11.6, 8.2 Hz, CH=CHOCb), 4.73 (s, 1 H, C(CH₃)=CH₂),

0.99 (s, 9 H, SiC(CH₃)₃), 1.12 (s, 6 H, 2×CH_3Cb), 1.13 (s, 6 H,

7.00 (d, 1 H, ³J = 6.4 Hz, CH=CHOCb), 7.23–7.40 (m, 11 H, ArH),

2×CH_3Cb), 1.60 (s, 3 H, CH=C(CH₃)), 3.08 (m, 2 H, CH₂N), 3.29 7.70 (m, 4 H, ArH). ¹³C NMR (150 MHz, CDCl₃): δ = 19.4

(m, 1 H, CHCH=CH), 3.41 (d, 1 H, ³J = 10.4 Hz, NCH₂Ar), 3.63– (SiC(CH₃)₃), 20.6, 23.2 (CH_3Cb), 23.2 (CH=C(CH₃)), 26.8

3.79 (m, 4 H, CH₂NAr, CH₂OSi and CH_Cb), 3.88 (m, 3 H, CH₂Cl

(SiC(CH₃)₃), 27.1 (CH_{C b}), 39.8 (CHCH=CHOCb), 47.6

3

and CH_Cb), 4.45 (br. s, 2 H, CH₂OCb), 5.49 (t, 1 H, J = 6.4 Hz, (CHC(CH₃)=CH₂), 56.1 (CH₂N), 60.6 (NCH₂Ar), 67.6 (CH₂OSi),

C(CH₃)=CH), 5.71 (br. s, 2 H, CHCH=CH), 7.10–7.23 (m, 11 H, 72.8 (CHCH₂OSi), 110.4 (C(CH₃)=CH₂), 111.0 (CH=CHOCb),

ArH), 7.55 (m, 4 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 13.4

(CH=C(CH₃)), 18.2 (SiC(CH₃)₃), 19.9 (CH_3Cb), 25.8 (SiC(CH₃)₃),

126.9, 127.8, 127.9, 128.0, 128.4, 128.9, 129.0, 129.8, 129.9, 133.8,

134.0, 134.6 and 135.0 (Ar), 135.9 (CH=CHOCb), 140. 0 (Ar),

28.7 (CH_Cb), 47.1 (CH₂N), 51.0 (CH₂Cl), 53.9 (NCH₂Ar), 61.5 144.1 (C(CH₃)=CH₂), 153.8 (NCO). EI-MS, m/z (%) = 638 (0.6)

(CHCH=CH), 63.9 (CH₂OSi), 64.1 (CH₂OCb), 125.7, 126.3, 127.1,

[M⁺], 581 (2) [M⁺– C(CH₃)₃], 369 (100) [M⁺– OTPS], 128 (12),

1438

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1427–1443

(–)-Sparteine-Mediated Synthesis of Kainoids

FULL PAPER

86 (43). ESI-HRMS C₄₀H₅₄N₂O₃Si (638.95): [M⁺+ H] calcd.

639.3982; found: 639.3972.

(m, 4 H, NCH₂Ar and CH₂OSi), 7.21–7.32 (m, 5 H, ArH). ¹³C

NMR (75 MHz, CDCl₃): δ = –5.1 (Si(CH₃)₂), 18.6 (SiC(CH₃)₃),

26.1 (SiC(CH₃)₃), 52.0 (OMe), 52.3 (NCH₂Ar), 62.7 (CHCO₂Me),

65.0 (CH₂OSi), 127.4, 128.6, 128.7 and 140.3 (Ar), 174.2 (CO). EI-

MS, m/z (%) = 308 (2) [M⁺– CH₃], 264 (36) [M⁺– CO₂CH₃], 234

(12), 178 (36), 106 (34), 91 (100) [PhCH₂⁺]. C₁₇H₂₉NO₃Si (323.50):

calcd. (%) C, 63.12, H 9.04, N 4.33; found: C 62.90, H 9.26, N

4.20.

The crude 21 obtained from carbamate 19 (140 mg, 0.21 mmol)

by Method B was purified by flash chromatography, affording a

separable mixture of diastereomers 21a and 21b (118 mg, 88%, dr

= 60:40) as a colourless oil. R_f= 0.33 and 0.18 (SiO₂, Et₂O/petro-

leum ether, 5:95).

21b: [α]²_D⁰= –3.2 (c = 0.91, CHCl₃, ee unknown), 21a: [α]²_D⁰= –4.8

1

(2S)-2-Benzylamino-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propanol

(27): Compound 26 (10.6 g, 32.8 mmol) was treated under the con-

ditions described for 13 to produce 27 (4.55 g, 47%) as an oil after

flash chromatography, R_f= 0.23 (SiO₂, AcOEt). [α]²_D⁰= –8.2 (c =

1.1, CHCl₃). rac-27 (346 mg, 48%) was obtained by the same pro-

(c = 0.42, CHCl₃, ee unknown). H NMR (600 MHz, CDCl₃): δ =

1.03 (s, 9 H, SiC(CH₃)₃), 1.12 (s, 6 H, 2×CH_3Cb), 1.13 (s, 6 H,

2×CH_3Cb), 1.63 (s, 3 H, CH=C(CH₃)), 2.56 (m, 1 H, CH₂N), 2.82

(m, 1 H, CHC(CH₃)=CH₂), 3.18–3.23 (m, 2 H, CHCH₂OSi and

CH₂N), 3.45–3.52 (m, 2 H, NCH₂Ar and CHCH=CH), 3.71–3.79

cedure from rac-26 (790 mg, 2.44 mmol). IR (film): ν (cm^–1) =

3

˜

(m, 2 H, CH₂OSi), 3.9–3.97 (br. m, 2 H, CH_Cb), 4.21 (d, 1 H, J =

3245–3503 (OH), 2790–2986, 1448, 1231. ¹H NMR (CDCl₃,

300 MHz): δ = 0.02 (s, 6 H, Si(CH₃)₂), 0.89 (s, 9 H, SiC(CH₃)₃),

2.20 (br. s, 1 H, NH), 3.75 (m, 1 H, CHCH₂OH), 3.41 (dd, 1 H, ³J

= 4.7, 10.8 Hz, CH₂OSi), 3.55 (m, 3 H, CH₂OH and CH₂OSi), 3.69

(s, 2 H, NCH₂Ar), 7.20–7.30 (m, 5 H, ArH). ¹³C NMR (CDCl₃):

δ = –5.2 (Si(CH₃)₂), 18.1 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 51.1

(NCH₂), 59.1 (CHCH₂O), 61.4, 63.0 (CH₂OH and CH₂OSi), 126.9,

3

11.1 Hz, NCH₂Ar), 4.54 (s, 1 H, C(CH₃)=CH₂), 4.65 (dd, 1 H, J

= 6.8, 11.6 Hz, CH=CHOCb), 4.73 (s, 1 H, C(CH₃)=CH₂), 7.05 (d,

3

1 H, J = 6.3 Hz, CH=CHOCb), 7.23–7.40 (m, 11 H, ArH), 7.68

(m, 4 H, ArH). ¹³C NMR (150 MHz, CDCl₃): δ = 19.1 (SiC(CH₃)₃),

20.4, 21.8 (CH_3Cb), 22.8 (CH=C(CH₃)), 26.5 (CH_Cb), 26.8

(SiC(CH₃)₃), 41.0 (CHCH=CH), 47.2 (CHC(CH₃)=CH₂), 54.5

(CH₂N), 60.1 (NCH₂Ar), 65.9 (CH₂OSi), 69.7 (CHCH₂OSi), 106.7

(CH=CHOCb), 110.4 (C(CH₃)=CH₂), 126.5, 127.5, 127.6, 127.7,

128.1, 128.3, 129.4, 129.5, 129.6, 133.6, 135.6, 135.7 and 135.8 (Ar),

136.3 (CH=CHOCb), 140.6 (Ar), 143.7 (C(CH₃)=CH₂), 157.0

(NCO).

127.9, 128.4 and 140.2 (Ar). ESI-MS, m/z (%) = 318 (10) [M⁺

+

Na], 296 (100) [M⁺+ H]. C₁₆H₂₉NO₂Si (295.49): calcd. (%) C,

65.03, H 9.89, N 4.74; found: C 64.75, H 9.85, N 4.55.

Ethyl (2E)-3-Methyl-4-[(triethylsilyl)oxy]-2-butenoate(28b): α-Hy-

droxyacetone (2.95 g, 39.8 mmol) was treated under the conditions

described for 4b to produce 28b (8.74 g, 85% over two steps, E/Z

85:15) as a colorless oil after flash chromatography, R_f= 0.53

(Z)-2-[(2S,3R,4S)- and (2S,3S,4R)-1-Benzyl-2-({[tert-butyl(diphen-

yl)silyl]oxy}methyl)-4-isopropenylpyrrolidinyl]ethenyl 2,2,4,4-Tet-

ramethyl-1,3-oxazolidine-3-carboxylate (22a and 22b): The crude

product 22 obtained from carbamate 20 (141 mg, 0.20 mmol) by

Method A was purified by flash chromatography, affording 22a

(72 mg, 54%, dr = 95:5) as a colorless oil. R_f= 0.43 (SiO₂, AcOEt/

petroleum ether, 5:95). [α]²_D⁰= –5.4 (c = 0.73, CHCl₃, ee unknown).

(SiO , Et O/petroleum ether, 2:8). IR (film): ν (cm^–1) = 2910–2861,

˜

2

2343, 1693 (CO), 1630, 1309. ¹H NMR (300 MHz, CDCl₃): δ =

3

0.61 (q, 6 H, J = 7.4 Hz, 13.8 Hz, Si(CH₂CH₃)₃), 0.98 (t, 9 H, J

= 7.6 Hz, Si(CH₂CH₃)₃), 1.30 (t, 3 H, J = 7.2 Hz, CO₂CH₂CH₃),

3

IR (film): ν (cm^–1) = 2965–2856, 1695 (NCO), 1457, 1400, 1387.

˜

2.19 (s, 3 H, C(CH₃)=CH), 4.11–4.20 (m, 4 H, CO₂CH₂CH₃and

CH₂OSi), 6.08 (s, 1 H, C(CH₃)=CH). ¹³C NMR (75 MHz, CDCl₃):

δ = 5.1 (Si(CH₂CH₃)₃), 7.0 (Si(CH₂CH₃)₃), 14.6 (C(CH₃)=CH),

15.7 (CO₂CH₂CH₃), 59.9 (CO₂CH₂CH₃), 67.1 (CH₂OSi), 113.8

(CH=C(CH₃)), 157.3 (CH=C(CH₃)), 167.4 (CO). EI-MS, m/z (%)

= 258 (14) [M⁺], 229 (100) [M⁺– CH₂CH₃], 201 (32), 131 (81), 103

(71), 75 (42). C₁₃H₂₆O₃Si (258.43): calcd. (%) C, 60.42, H 10.14;

found: C 60.08, H 10.37.

¹H NMR (600 MHz, CDCl₃): δ = 1.12 (s, 9 H, SiC(CH₃)₃), 1.40,

1,43, 1.55 and 1.58 (4 × s, 12 H, CH_{3 C by}), 1.62 (s, 3 H,

CH=C(CH₃)), 2.44 (m, 1 H, CH₂N), 2.65 (m, 1 H, CHCH₂OSi),

2.78 (m, 2 H, CHC(CH₃)=CH₂and CH₂N), 2.96 (m, 1 H,

3

CHCH=CH), 3.42 (d, 1 H, J = 11.0 Hz, NCH₂Ar), 3.63 (m, 2 H,

CH₂OSi), 3.77 (s, 2 H, CH_2Cby), 4.03 (d, 1 H, ³J = 11.1 Hz,

NCH₂Ar), 4.52 (s, 1 H, C(CH₃)=CH₂), 4.71 (s, 1 H, C(CH₃)=CH₂),

5.18 (m, 1 H, CH=CHOCby), 7.00 (d, 1 H, ³J = 6.2 Hz,

CH=CHOCby), 7.21–7.40 (m, 11 H, ArH), 7.70 (m, 4 H, ArH).

¹³C NMR (150 MHz, CDCl₃): δ = 19.2 (CH=C(CH₃)), 23.1

(SiC(CH₃)₃), 23.9, 25.1, 25.2 and 25.5 (CH_3Cby), 26.9 (SiC(CH₃)₃),

42.1 (CH₂N), 47.1 (CHC(CH₃)=CH₂), 55.4 (CHCH=CH), 60.1

(NCH₂Ar), 66.3 (CH₂OSi), 72.1 (CHCH₂OSi), 73.3 (CH_2OCby),

110.3 (C(CH₃)=CH₂), 111.9 (CH=CHOCby), 126.7, 127.7, 127.7,

128.1, 128.4, 128.5, 128.7, 129.5, 129.6, 133.7, 134.8 and 135.6 (Ar),

1 3 5 . 7 ( C H = C H O C by ) , 1 3 5 . 7 , a n d 1 3 9 . 7 ( A r ) , 1 4 3 . 5

(C(CH₃)=CH₂), 152.8 (NCO). ESI-HRMS C₄₁H₅₄N₂O₄Si (666.96):

[M⁺+ H] calcd. 667.3931; found: 667.3954.

(2E)-3-Methyl-4-[(triethylsilyl)oxy]-2-buten-1-ol (28c): Compound

(E)-28b (6.07 g, 23.5 mmol) was treated under the conditions de-

scribed for 4c to produce 28c (4.62 g, 91%, E/Z 100:0) as a colorless

oil after flash chromatography, R_f= 0.48 (SiO₂, Et₂O/petroleum

ether, 2:8). IR (film): ν (cm^–1) = 3434–3161 (OH), 2890–2855, 1428.

˜

3

¹H NMR (300 MHz, CDCl₃): δ = 0.49–0.68 (q, 6 H, J = 6.9 Hz,

13.4 Hz, Si(CH₂CH₃)₃), 0.91–1.00 (t, 9 H, ³J = 7.4 Hz, Si(CH₂-

CH₃)₃), 2.67 (s, 3 H, C(CH₃)=CH), 3.38 (s, 2 H, CH₂OSi), 4.10 (d,

1 H, J = 8.7 Hz, CH₂OH), 4.19 (d, 1 H, CH₂OH), 5.63 (m, 1 H,

3

C(CH₃)=CH). ¹³C NMR (75 MHz, CDCl₃): δ = 4.8 (Si(CH₂CH₃)

₃), 6.2 (Si(CH₂CH₃)₃), 14.0 (C(CH₃)=CH), 59.9 (CH₂OH), 67.8

(CH₂OSi), 124.4 (CH=C(CH₃)), 138.2 (CH=C(CH₃)). EI-MS,

m/z (%) = 217 (100) [M⁺], 189 (49), 161 (27), 105 (13). ESI-HRMS

C₁₁H₂₄O₂Si (216.39): [M⁺+ Na] calcd. 239.143778; found:

239.142952.

Methyl (2R)-2-(Benzylamino)-3-{[tert-butyl(dimethyl)silyl]-oxy}-

propanoate (26):N-Benzyl-d-serine methyl ester (11) (6.00 g,

28.7 mmol) was treated under the same conditions as described for

12, but using TBSCl (5.18 g, 34.4 mmol) instead of TPSCl, to pro-

duce 26 (8.36 g, 90%) as a colourless oil after flash chromatog-

raphy, R_f= 0.42 (SiO₂, AcOEt/petroleum ether, 1:1). [α]²_D⁰= +3.9

(c = 0.94, CHCl₃). rac-26 (848 mg, 91%) was obtained by the same

{[(2E)-4-Bromo-2-methyl-2-butenyl]oxy}(triethyl)silane (28d): Com-

pound (E)-28c (5.89 g, 27.2 mmol) was treated under the conditions

described for 4d to produce 28d (6.81 g). The freshly prepared

procedure from rac-11 (602 mg, 2.88 mmol). IR (film): ν (cm^–1) =

˜

1

2910–2840, 1721 (CO), 1442, 1231. H NMR (300 MHz, CDCl₃):

crude product 28d was used in the N-allylation of 27 without fur-

1

δ = 0.00 (s, 6 H, Si(CH₃)₂), 0.81 (s, 9 H, Si(CH₃)₃), 2.10 (br. s, 1

H, NH) 3.38 (m, 1 H, CHCO₂Me), 3.69 (s, 3 H, OMe), 4.78–4.90

ther purification. IR (film): ν (cm^–1) = 2928–2865, 1675, 1339. H

˜

NMR (300 MHz, CDCl₃): δ = 0.61 (q, 6 H, Si(CH₂CH₃)₃), 0.98 (t,

Eur. J. Org. Chem. 2005, 1427–1443

www.eurjoc.org

1439

M. Montserrat Martínez, D. Hoppe

FULL PAPER

9 H, J = 7.3 Hz, Si(CH₂CH₃)₃), 1.70 (s, 3 H, C(CH₃)=CH), 4.13–

4.29 (m, 4 H, CH₂OSi and CH₂OH), 5.63 (m, 1 H, C(CH₃)=CH).

¹³C NMR (75 MHz, CDCl₃): δ = 6.1 (Si(CH₂CH₃)₃), 8.2

(Si(CH₂CH₃)₃), 14.8 (C(CH₃)=CH), 30.1 (CH₂Br), 68.7 (CH₂OSi),

3

of tetrabutylammonium fluoride (3.01 mL, 3.01 mmol) in THF

(10 mL) was added with stirring at 0 °C to a solution of 30 (1.54 g,

2.74 mmol) in THF (10 mL). The reaction mixture was stirred an

additional 5 min, diluted with H₂O (10 mL) and extracted with

121.2 (CH=C(CH₃)), 143.4 (CH=C(CH₃)). EI-MS, m/z (%) = 249 Et₂O (3 × 20 mL). The combined organic phases were dried

(25) [M⁺– CH₂CH₃]; 199 (55) [M⁺– Br], 165 (100), 115 (46). (MgSO₄) and the solvents evaporated to dryness. The residue was

C₁₁H₂₃BrOSi (279.29).

purified by a flash chromatography, R_f= 0.35 (SiO₂, AcOEt/petro-

leum ether, 1:1) on a short column affording 31 (1.00 g, 81%) as a

pale yellow oil oil. [α]²_D⁰= +14.7 (c = 0.61, CHCl₃). rac-31 (182 mg,

85%) was obtained by the same procedure from rac-30 (270 mg,

(2S)-2-(Benzyl{(2E)-3-methyl-4-[(triethylsilyl)oxy]-2-

butenyl}amino]-3-{[tert-butyl(dimethyl)silyl]oxy}-1-propanol (29):

Compound 28 (6.02 g, 20.4 mmol) was treated under the same con-

ditions described for 13, but refluxing with freshly prepared isop-

renoid 28d instead of 4d (6.81 g, 24.5 mmol) for 3 h, to produce 29

(8.25 g, 82%) as a colourless oil after flash chromatography, R_f=

0.42 (SiO₂, Et₂O/petroleum ether, 1:1). [α]²_D⁰= –3.6 (c = 0.91,

CHCl₃). rac-29 (431 mg, 86%) was obtained by the same procedure

0.48 mmol). IR (film): ν (cm^–1) = 3526–3318 (OH), 2952–2851,

˜

1721 (CO), 1650, 1470, 1369. ¹H NMR (400 MHz, CDCl₃): δ =

3

0.04 (s, 6 H, Si(CH₃)₂), 0.86 (s, 9 H, SiC(CH₃)₃), 1.29 (t, 3 H, J =

7.4 Hz, CO₂CH₂CH₃), 1.59 (s, 3 H, CH=C(CH₃)), 3.19 (m, 2 H,

NCH₂), 3.40 (m, 1 H, CHCH=CH), 3.60 (d, 1 H, ³J = 7.1 Hz,

NCH₂Ar), 3.70–3.82 (m, 3 H, CH₂OSi and NCH₂Ar), 3.91 (s, 2 H,

from rac-28 (300 mg, 1.02 mmol). IR (film): ν (cm^–1) = 3553–3343

˜

3

(OH), 2916–2890, 1441, 1238. ¹H NMR (300 MHz, CDCl₃): δ =

0.03 (s, 6 H, Si(CH₃)₂), 0.55 (q, 6 H, ³J = 7.1 Hz, 14.2 Hz,

CH₂OH), 4.19 (q, 2 H, J = 7.5 Hz, 14.8 Hz, CO₂CH₂CH₃), 5.45

(t, 1 H, ³J = 7.3 Hz, C(CH₃)=CH), 5.98 (d, 1 H, ³J = 14.9 Hz,

CHCH=CH), 6.98 (dd, 1 H, ³J = 6.2, 15.7 Hz, CHCH=CH), 7.19–

7.31 (m, 5 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = –3.7

(Si(CH₃)₂), 13.8 (CH=C(CH₃)), 14.2 (CO₂CH₂CH₃), 18.1

(SiC(CH₃)₃), 25.7 (SiC(CH₃)₃), 48.0 (NCH₂), 55.3 (NCH₂Ar), 60.2

(CO₂CH₂CH₃), 61.9 (CHCH=CH), 63.4 and 68.4 (CH₂OSi and

CH₂O), 123.3 (CH=C(CH₃)), 124.2 (CHCH=CH), 126.7, 128.1,

128.3, 137.0 and 140.2 (CH=C(CH₃) and Ar), 146.6 (CHCH=CH),

166.4 (CO). ESI-MS, m/z (%) = 917 (10) [2 M⁺+ Na], 448 (100)

[M⁺+ H]. ESI-HRMS C₂₅H₄₁NO₄Si (447.68): [M⁺+ H] calcd.

448.2883; found: 448.2913.

3

Si(CH₂CH₃)₃), 0.81 (s, 9 H, SiC(CH₃)₃), 0.90 (t, 9 H, J = 7.3 Hz,

Si(CH₂CH₃)₃), 1.49 (s, 3 H, CH=C(CH₃)), 2.92 (m, 1 H,

CHCH₂OH), 3.18 (m, 2 H, NCH₂), 3.37 (dd, 1 H, ³J = 3.7,

10.1 Hz, CH₂OH), 3.51 (m, 3 H, CH₂OSi and CH₂OH), 3.60 (d, 1

H, ³J = 7.2 Hz, NCH₂Ar), 3.81 (d, 1 H, ³J = 7.2 Hz, NCH₂Ar),

3.91 (s, 2 H, CH₂OSi(Et)₃), 5.41 (t, 1 H, ³J = 6.1 Hz, CH=C(CH₃)),

7.11–7.20 (m, 5 H, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = –5.2

(Si(CH₃)₂), 4.9 (Si(CH₂CH₃)₃), 7.15 (Si(CH₂CH₃)₃), 14.1

(CH=C(CH₃)), 18.5 (SiC(CH₃)₃), 26.4 (SiC(CH₃)₃), 47.4 (NCH₂),

54.6 (CH₂OSi), 59.8 (NCH₂Ar), 60.0 (CHCH₂OH), 61.2 (CH₂OH),

68.4 (CH₂OSi), 122.9 (C(CH₃)=CH), 127.3, 128.7, 129.2, 137.9 and

140.3 (CH=C(CH₃) and Ar). EI-MS, m/z (%) = 493 (0.5) [M⁺]; 478

(2) [M⁺– CH₃]; 462 (66); 348 (100) [M⁺– OTES], 199 (47), 91

(70). HRMS (TOF-CI) C₂₇H₅₁NO₃Si₂(493.87): [M⁺+ H] calcd.

494.348024; found 494.346344. C₂₇H₅₁NO₃Si₂(493.87): calcd. (%)

C, 65.66, H 10.41, N 2.84; found: C 65.63, H 10.52, N 2.72.

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-

{[tert-butyl(dimethyl)silyl]oxy}-2-pentenoate (32): Compound 31

(3.77 g, 8.42 mmol) was treated under the conditions described for

17 to produce 32 (2.68 g, 71 %) as a colourless oil after flash

chromatography, R_f= 0.48 (SiO₂, Et₂O/petroleum ether, 5:95).

[α]_D²⁰= +22.0 (c = 0.78, CHCl₃). rac-32 (103 mg, 80%) was obtained

Ethyl (2E,4S)-4-(Benzyl{(2E)-3-methyl-4-[(triethylsilyl)oxy]-2-

butenyl}amino)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-pentenoate (30):

Compound 29 (3.18 g, 6.44 mmol) was treated under the conditions

described for 15 to produce 30 (2.71 g, 75%) as a pale yellow oil

after flash chromatography, R_f= 0.58 (SiO₂, Et₂O/petroleum ether,

5:95). [α]²_D⁰= +8.2 (c = 1.6, CHCl₃). rac-30 (295 mg, 68%) was

by the same procedure from rac-31 (130 mg, 0.29 mmol). IR (film):

˜

1

ν (cm^–1) = 2956–2857, 1687 (CO), 1426, 1385. H NMR (300 Mz,

CDCl₃): δ = 0.03 (s, 6 H, Si(CH₃)₂), 0.84 (s, 9 H, SiC(CH₃)₃), 1.26

(t, 3 H, ³J = 8.5 Hz, CO₂CH₂CH₃), 1.67 (s, 3 H, CH=C(CH₃)),

3

3.12 (dd, 1 H, J = 6.8, 14.7 Hz, NCH₂), 3.24 (dd, 1 H, J = 6.8,

14.4 Hz, NCH₂), 3.37 (m, 1 H, CHCH=CH), 3.59 (d, 1 H, ³J =

14.0 Hz, NCH₂Ar), 3.69–3.83 (m, 3 H, CH₂OSi and NCH₂Ar),

3.94 (s, 2 H, CH₂Cl), 4.18 (q, 2 H, ³J = 7.0 Hz, 15.0 Hz,

obtained by the same procedure from rac-29 (380 mg, 0.77 mmol).

1

IR (film): ν (cm^–1) = 2930–2833, 1693 (CO), 1441, 1246. H NMR

˜

(300 MHz, CDCl₃): δ = 0.04 (s, 6 H, Si(CH₃)₂), 0.55 (q, ³J = 7.0 Hz,

6 H, 13.6 Hz, Si(CH₂CH₃)₃), 0.86 (s, 9 H, SiC(CH₃)₃), 0.92 (t, 9 H,

³J = 7. 1 Hz, Si(CH₂CH₃)₃), 1.26 (t, 3 H, ³J = 7.2 Hz,

CO₂CH₂CH₃), 1.52 (s, 3 H, CH=C(CH₃)), 3.11 (m, 1 H, NCH₂),

3

CO₂CH₂CH₃), 5.61 (t, 1 H, J = 6.0 Hz, CH=C(CH₃)), 5.97 (d, 1

H, ³J = 16.3 Hz, CHCH=CH), 6.92 (dd, 1 H, ³J = 16.7 Hz, 6.9 Hz,

CHCH=CH), 7.18–7.32 (m, 5 H, ArH). ¹³C NMR (75 Mz, CDCl₃):

δ = –3.0 (Si(CH₃)₂), 16.7 (CH=C(CH₃)), 16.9 (CH₂CH₃), 20.6

(SiC(CH₃)₃), 28.2 (SiC(CH₃)₃), 50.6 (NCH₂), 54.2 (NCH₂Ar), 57.6

(CO₂CH₂CH₃), 62.7 (CH₂Cl), 64.2 (CHCH=CH), 65.9 (CH₂OSi),

126.1 (CH=C(CH₃)), 129.3 (CHCH=CH), 130.6, 130.8, 131.6 and

136.4 (Ar), 142.3 (CH=C(CH₃)), 148.7 (CHCH=CH), 168.7 (CO).

HRMS C₂₅H₄₀ClNO₃Si (446.13): calcd. 466.2544; found: 466.2551.

3

3.21 (m, 1 H, NCH₂), 3.40 (m, 1 H, CHCH=CH), 3.62 (d, 1 H, J

= 7.2 Hz, NCH₂Ar), 3.79–3.88 (m, 3 H, CH₂OSi(CH₃)₂and

3

NCH₂Ar), 4.11 (s, 2 H, CH₂OSi(Et)₃), 4.21 (q, 2 H, J = 7.1 Hz,

14.1 Hz, CO₂CH₂CH₃) 5.55 (t, 1 H, ³J = 7.5 Hz, CH=C(CH₃)),

3

6.05 (d, 1 H, J = 15.1 Hz, CHCH=CH), 7.03 (dd, 1 H, J = 6.0,

15.6 Hz, CHCH=CH), 7.21–7.35 (m, 5 H, ArH). ¹³C NMR

(75 MHz, CDCl₃): δ = –5.1 (Si(CH₃)₂), 4.9 (Si(CH₂CH₃)₃, 7.2

(Si(CH₂CH₃)₃, 14.1 (CH=C(CH₃)), 14.6 (CO₂CH₂CH₃), 18.6

(SiC(CH₃)₃), 26.2 (SiC(CH₃)₃), 48.2 (NCH₂), 55.3 (NCH₂Ar), 60.6

(CO₂CH₂CH₃), 61.9 (CHCH=CH), 63.9 and 68.4 (CH₂OSi), 123.2

(CH=C(CH₃)), 123.9 (CHCH=CH), 127.1, 128.5, 128.8, 137.6 and

140.6 (Ar and CH=C(CH₃), 147.1 (CHCH=CH), 166.8 (CO). EI-

MS, m/z (%) = 561 (3) [M⁺]; 532 (4) [M⁺– CH₂CH₃]; 416 (100),

199 (27), 115 (40), 91 (35). C₃₁H₅₅NO₄Si₂(561.94): calcd. (%) C,

66.26, H 9.87, N 2.49; found: C 65.90, H 10.04, N 2.35.

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-

[(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl)oxy]-2-pentenoate

(36): Compound 32 (40 mg, 0.09 mmol) was treated under the con-

ditions described for 25 to produce 36 (36 mg, 70%, dr = 100:0) as

a pale colorless oil.

(2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-

{[tert-butyl(dimethyl)silyl]oxy}-2-penten-1-ol (33): Compound 32

(2.30 g, 5.16 mmol) was treated under the conditions described for

18 to produce 33 (1.53 g, 70 %) as a colourless oil after flash

Ethyl (2E,4S)-4-{Benzyl[(2E)-4-hydroxy-3-methyl-2-butenyl]amino}- chromatography, R_f= 0.27 (SiO₂, Et₂O/petroleum ether, 4:6).

5-{[tert-butyl(dimethyl)silyl]oxy}-2-pentenoate (31): A 1 m solution

[α]²_D⁰= +7.2 (c = 0.76, CHCl ). IR (film): ν (cm^–1) = 3491–3226

˜

3

1440

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1427–1443

(–)-Sparteine-Mediated Synthesis of Kainoids

FULL PAPER

(br. s, 1 H, C(CH₃)=CH₂), 6.97 (d, 1 H,³J = 5.6 Hz, CH=CHOCb),

1

(OH), 2956–2856, 1461, 1426, 1365. H NMR (400 MHz, CDCl₃):

δ = 0.00 (s, 6 H, Si(CH₃)₂), 0.85 (s, 9 H, SiC(CH₃)₃), 1.66 (s, 3 H, 7.22–7.35 (m, 5 H, ArH). ¹³C NMR (150 MHz, CDCl₃): δ = –5.4

CH=C(CH₃)), 3.05–3.26 (m, 3 H, NCH₂and CHCH=CH), 3.53

(d, 1 H, J = 13.4 Hz, NCH₂Ar), 3.64–3.78 (m, 3 H, CH₂OSi and (CH=C(CH₃)), 25.9 (SiC(CH₃)₃), 27.9 (CH_Cb), 39.4 (CHCH=CH),

(Si(CH₃)₂), 19.1 (SiC(CH₃)₃), 20.6, 21.3 (CH_{3 C b}), 22.9

3

NCH₂Ar), 3.94 (s, 2 H, CH₂Cl), 4.14 (m, 2 H, CH₂OH), 5.57 (t, 1

H, ³J = 6.8 Hz, CH=C(CH₃)), 5.64–5.81 (m, 2 H, CHCH=CH),

7.15–7.33 (m, 5 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = –4.6

47.0 (CHC(CH₃)=CH₂), 56.1 (NCH₂), 60.4 (NCH₂Ar), 66.6

(CH₂OSi), 72.4 (CHCH₂OSi), 110.1 (C(CH₃)=CH₂), 111.0

(CH=CHOCb), 126.7, 128.1 and 128.8 (Ar), 134.4 (CH=CHOCb),

(Si(CH₃)₂), 14.4 (CH=C(CH₃)), 18.1 (SiC(CH₃)₃), 25.8 (SiC- 139.8 (Ar), 143.9 (C(CH₃)=CH₂), 153.6 (NCO). ESI-MS, m/z (%)

(CH₃)₃), 48.1 (NCH₂), 51.4 (CH₂Cl), 54.9 (CH₂NAr), 62.3 = 515 (100)[M⁺+ H]. ESI-HRMS C₃₀H₅₀N₂O₃Si (514.82): [M⁺

+

( CHCH=CH), 63. 4 (CH ₂OH), 64 . 1 (C H ₂O S i ) , 1 2 6 . 6

(CH=C(CH₃)), 126.9 (CHCH=CH), 128.0, 128.4, 128.7, 129.6 and

132.7 (Ar and CH=C(CH₃)), 133.3 (CHCH=CH). ESI-MS, m/z

(%) = 446 (5) [M⁺+ Na], 424 (100) [M⁺+ H]. C₂₃H₃₈ClNO₂Si

(424.09): calcd. (%) C. 65.14, H. 9.03, N. 3.30; found C. 64.85, H.

9.34, N. 2.99.

H] calcd. 515.3669 found: 515.3658.

37b: [α]²_D⁰= –6.4 (c = 0.75, CHCl₃). H NMR (600 MHz, CDCl₃):

1

δ = 0.00 (s, 6 H, Si(CH₃)₂), 0.83 (s, 9 H, SiC(CH₃)₃), 1.18–1.24 (m,

3

12 H, CH_3Cb), 1.632 (s, 3 H, CH=C(CH₃)), 2.52–2.56 (d, 1 H, J

= 1 1 . 0 H z , C H ₂N ) , 2 . 7 7 ( dd , 1 H , ³J = 8 . 7 , 1 4 . 9 H z ,

3

CHC(CH₃)=CH₂), 3.07 (m, 1 H, CHCH₂OSi), 3.18 (d, 1 H, J =

11.0 Hz, CH₂N), 342–3.47 (m, 2 H, CHCH=CH and NCH₂Ar),

3.61–3.68 (m, 2 H, CH₂OSi), 3.89–4.07 (br. s, 2 H, CH_Cb), 4.22 (d,

1 H, ³J = 14.2 Hz, NCH₂Ar), 4.52 (br. s, 1 H, C(CH₃)=CH₂), 4.66

(dd, 1 H, ³J = 11.3 Hz, CH=CHOCb), 4.72 (br. s, 1 H,

C(CH₃)=CH₂), 7.09 (d, 1 H,³J = 5.6 Hz, CH=CHOCb), 7.20–7.36

(m, 5 H, ArH). ¹³C NMR (150 MHz, CDCl₃): δ = –5.3 (Si(CH₃)₂),

16.1 (SiC(CH₃)₃), 17.4, 19.5 (CH_3Cb), 23.1 (CH=C(CH₃)), 26.3

( S i C ( C H ₃) ₃) , 3 2 . 1 ( C H _{C b}) , 4 1 . 1 ( C H C H = C H ) , 4 7 . 2

(CHC(CH₃)=CH₂), 54.8 (NCH₂), 60.3 (NCH₂Ar), 65.7 (CH₂OSi),

69.6 (CHCH₂OSi), 107.2 (C(CH₃)=CH₂), 110.6 (CH=CHOCb),

126.7, 128.1 and 128.8 (Ar), 136.5 (CH=CHOCb), 139.8 (Ar), 140.9

(C(CH₃)=CH₂), 153.6 (NCO).

(2E,4S)-4-{Benzyl[(2E)-4-chloro-3-methyl-2-butenyl]amino}-5-

{[tert-butyl(dimethyl)silyl]oxy}-2-pentenyl Diisopropylcarbamate

(34): Compound 33 (1.30 g, 3.07 mmol) was treated under the con-

ditions described for 19 to produce 34 (0.89 g, 53%) as a colourless

oil after flash chromatography, R_f= 0.44 (SiO₂, Et₂O/petroleum

ether, 2:8). [α]²_D⁰= +9.7 (c = 0.71, CHCl ). IR (film): ν (cm^–1) =

˜

3

2952–2852, 1721 (NCO), 1469, 1430, 1365. ¹H NMR (400 MHz,

CDCl₃): δ = 0.03 (s, 6 H, Si(CH₃)₂), 0.90 (s, 9 H, SiC(CH₃)₃), 1.19

(s, 6 H, 2 × CH_3Cb), 1.21 (s, 6 H, 2 × CH_3Cb), 1.70 (s, 3 H,

CH=C(CH₃)), 3.09–3.28 (m, 2 H, NCH₂), 3.29 (m, 1 H,

3

CHCH=CH), 3.50 (d, 1 H, J = 13.0 Hz, NCH₂Ar), 3.68–3.80 (m,

4 H, NCH₂Ar, CH₂OSi and CH_Cb), 3.97 (br. s, 3 H, CH₂Cl and

CH_Cb), 4.60 (s, 2 H, CH₂OCb), 5.68 (t, 1 H, ³J = 6.1 Hz,

CH=C(CH₃)), 5.69–5.80 (m, 2 H, CHCH=CH), 7.26–7.48 (m, 5

H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = –5.2 (Si(CH₃)₂), 14.3

(CH=C(CH₃)), 18.1 (SiC(CH₃)₃), 21.0 (CH_3Cb), 25.8 (SiC(CH₃)₃),

28.7 (CH_Cb), 48.1 (NCH₂), 51.9 (CH₂Cl), 54.9 (NCH₂Ar), 62.3

(CHCH=CH), 64.6 (CH₂OSi), 64.8 (CH₂OCb), 126.6, 128.0, and

128.4 (Ar), and 128.9 (CHCH=CH), 129.6 (CH=C(CH₃)), 130.8

(CHCH=CH), 133.3 and 140.3 (CH=C(CH₃) and Ar), 155.3

(NCO). ESI-MS, m/z (%) = 551 (100) [M⁺]. C₃₀H₅₁ClN₂O₃Si

(551.28): calcd. (%) C, 65.36, H 9.32, N 5.08; found: C 65.38, H

9.35, N 4.89.

Methyl (2S,3R,4S)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[(E)-

2-{[(diisopropylamino)carbonyl]oxy}-2-(methylsulfanyl)ethenyl]-4-iso-

propenyl-1-pyrrolidinecarboxylate (40a): To a solution (pre-cooled

to –78 °C) of 37a (110 mg, 0.21 mmol) and TMEDA (55 mg,

0.47 mmol) in THF (10 mL), a solution of tBuLi (1.7 min pentane)

(0.28 mL, 0.47 mmol) was added dropwise. The reaction mixture

was then quenched with MeSSMe (75 μL, 0.86 mmol) at –78 °C.

Aqueous workup was performed of the resulted solution after stir-

ring for 1 h at –78 °C and 30 min at room temperature. The aque-

ous phase was extracted with Et₂O (3×10 mL). The combined or-

ganic phases were washed with brine, dried (MgSO₄), and concen-

trated in vacuo affording the crude product 39a as a yellow oil

which was used in the next step without further purification. To a

solution of crude product 39a in dry 1,2-dichloroethane (10 mL),

methyl chloroformate (81 μL, 1.1 mmol) was added dropwise at

room temperature. The resulted solution was refluxed for 3 h, after

that, the solvent was evaporated in vacuo. The crude product was

purified by flash chromatography, R_f= 0.48 (SiO₂, Et₂O/petroleum

ether, 1:1) affording 40a (93 mg, 84%). [α]²_D⁰= –19.0 (c = 0.57,

(1Z)-2-[(2S,3R,4S)- and (2S,3S,4R)-1-Benzyl-2-({[tert-butyl(dimeth-

yl)silyl]oxy}methyl)-4-isopropenylpyrrolidinyl]ethenyl Diisopro-

pylcarbamate (37a and 37b): The chloride 34 (116 mg, 0.21 mmol)

and (–)-sparteine (114 mg, 0.46 mmol) were dissolved in toluene

(10 mL) and cooled to –78 °C. After slow addition of nBuLi

(1.6 min hexane) (0.30 mL, 0.46 mmol), the solution was stirred for

90 min at –78 °C. MeOH (1 mL) and NH₄Cl (0.5 mL) were added,

and the reaction mixture was allowed to warm to room tempera-

ture. The organic layer was separated and the aqueous phase was

extracted with Et₂O (3 ×10 mL). The combined organic phases

were dried (MgSO₄), and concentrated in vacuo. The crude product

was separated by flash chromatography, R_f= 0.48 and 0.33 (SiO₂,

Et₂O/petroleum ether, 20:80) affording 37a and 37b, respectively

(90 mg, 83%, dr 80:20) as a colourless oil.

CHCl ). IR (film): ν (cm^–1) = 2952–2856, 1708 (NCO), 1447, 1382.

˜

3

¹H NMR (400 MHz, CDCl₃): δ = 0.00 (s, 6 H, Si(CH₃)₂), 0.89

(s, 9 H, SiC(CH₃)₃), 1.20–1.23 (m, 12 H, CH_3Cb), 1.50 (s, 3 H,

CH=C(CH₃)), 2.20 (s, 3 H, SMe), 2.40–2.45 (m, 1 H, CHCH₂OSi),

3.32–3.40 (m, 2 H, CHCH=C(SMe) and NCH₂), 3.61 (s, 3 H,

NCO₂Me), 3.65 (m, 2 H, NCH₂, CHC(CH₃)=CH₂), 3.85 (m, 2 H,

CH₂OSi), 3.88–3.99 (br. s, 2 H, CH_{C b}), 4.60 (br. s, 1 H,

3

37a: [α]²_D⁰= –22.6 (c = 0.57, CHCl ). IR (film): ν (cm^–1) = 2960–

C(CH₃)=CH₂)), 4.80 (br. s, 1 H, C(CH₃)=CH₂), 5.55 (d, 1 H, J =

˜

3

2852, 1713 (NCO), 1465, 1430, 1365. ¹H NMR (600 MHz, CDCl₃): 10.3 Hz, CH=C(SMe)). ¹³C NMR (100 MHz, CDCl₃): δ = –5.6

δ = 0.01 (s, 6 H, Si(CH₃)₂), 0.86 (s, 9 H, SiC(CH₃)₃), 1.23–1.25 (m,

(Si(CH₃)₂), 17.1 (SMe), 18.0 (SiC(CH₃)₃), 20.3, 21.5 (CH_3Cb), 22.8

12 H, CH_3Cb), 1.62 (s, 3 H, CH=C(CH₃)), 2.46–2.50 (m, 1 H, (CH=C(CH₃)), 25.8 (SiC(CH₃)₃), 45.9 (CH_Cb), 46.7 (NCH₂), 47.6

CH₂N), 2.57 (m, 1 H, CHCH₂OSi), 2.81–2.85 (m, 1 H, (CH₂OSi), 48.5 (CHCH=C(SMe)), 52.0 (OMe), 61.7 (CHCH₂OSi),

CHC(CH₃)=CH₂), 2.95 (d, 1 H, ³J = 8.7 Hz, CH₂N), 3.17–3.21 (m,

110 (C(CH₃)=CH₂), 120.4 (CH=C(SMe)), 142.2 (C(CH₃)=CH₂),

1 H, CHCH=CH), 3.46 (d, 1 H, ³J = 13.2 Hz, NCH₂Ar), 3.61– 144.4 (CH=C(SMe)), 152.3 (NCO). ESI-MS, m/z (%) = 1080 (80)

3.63 (m, 2 H, CH₂OSi), 3.89 (br. s, 1 H, CH_Cb), 3.98 (br. s, 1 H,

[2 M⁺+ Na], 551 (68) [M⁺+ Na], 529 (75) [M⁺+ H]. ESI-HRMS

C₂₆H₄₈N₂O₅SSi (528.82): [M⁺+ H] calcd. 529.312596; found:

529.310321; [M⁺+ Na] calcd. 551.294541; found: 551.292223.

CH_Cb), 4.19 (d, 1 H, ³J = 13.4 Hz, NCH₂Ar), 4.53 (br. s, 1 H,

3

C(CH₃)=CH₂)), 4.60 (dd, 1 H, J = 11.9 Hz, CH=CHOCb), 4.71

Eur. J. Org. Chem. 2005, 1427–1443

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1441

M. Montserrat Martínez, D. Hoppe

FULL PAPER

Methyl (2S,3S,4S)-2-(Hydroxymethyl)-4-isopropenyl-3-(2-methoxy-

2-oxoethyl)-1-pyrrolidinecarboxylate (41a): To a solution of 40a

(109 mg, 0.21 mmol) in MeOH (10 mL), methanesulfonic acid

(54 μL, 0.82 mmol) and 3 drops of water were added. The reaction

mixture was refluxed for 16 h. The mixture was diluted with H₂O

(5 mL) and the aqueous phase was extracted with diethyl ether

(3 × 10 mL). The organic phase was washed with saturated

NaHCO₃(3×5 mL), dried (MgSO₄), and concentrated in vacuo.

The crude product was purified by flash chromatography, R_f= 0.39

crude acid which was used without purification. The crude acid

was dissolved in MeOH (1 mL) and was refluxed with 1 mL of a

40% aqueous NaOH solution for 18 h. The reaction mixture was

diluted with water (1 mL) and was extracted with CH₂Cl₂

(3×5 mL). Water was removed under reduced pressure, and the

residue was first passed through an ion-exchange DOWEX

50WX8-200 column, eluting with 1 n NH₄OH. Water was removed

under reduced pressure, and the residue was then passed through

a short Amberlite CG-50 ion-exchange column, eluting with water.

(SiO₂, AcOEt/Et₂O, 70:30) affording 41a (31 mg, 55%) as a colour- Water evaporation and recrystalization from aqueous EtOH af-

less oil which was identical spectroscopically (NMR) with the pro-

forded 8.0 mg (38% overall yield) of a (–)-α-kainic acid (1). m.p.

243–245 °C (dec.); [ref.^[6i]241–244 °C (dec.)]. [α]²_D⁰= –14.3 (c =

0.40, H₂O); {ref.^[6i][α]²_D⁰= –14.6 (c = 0.25, H₂O)}. ¹H NMR (D₂O,

duct obtained by Chevliakov et al.^[6i][α]²_D⁰= –41.2 (c = 0.52,

CH₂Cl₂); {ref.^[6i][α]²_D⁰= –43.0 (c = 1.25, CH Cl )}. IR (film): ν

˜

2

(cm^–1) = 3578–3283 (OH), 2952–2883, 1739 and 1686 (NCO, CO),

1452, 1346, 1330. ¹H NMR (600 Mz, CDCl₃): δ = 1.67 (s, 3 H,

CH=C(CH₃)), 2.13–2.27 (m, 2 H, CH₂CO₂Me), 2.50–2.54 (m, 1 H,

500 Mz): δ = 1.65 (s, 3 H, CH=C(CH₃)), 2.25 (dd, 1 H, J = 7.6,

3

15.0 Hz, CH₂CO₂H), 2.30 (dd, 1 H, J = 15.3, 8 Hz, CH₂CO₂H),

2.88–2.94 (m, 2 H, CHC(CH₃)=CH₂and CHCH₂CO₂H), 3.33 (dd,

3

CHCH₂CO₂Me), 2.90–2.94 (m, 1 H, CHC(CH₃)=CH₂), 3.41–3.49 1 H, J = 13.2, 8.0 Hz, CH₂N), 3.52 (dd, 1 H, J = 12.6, 8.0 Hz,

(m, 2 H, CH₂N), 3.52–3.64 (m, 5 H, CO₂Me and CH₂OH), 3.67 CH₂N), 3.94 (d, 1 H, ³J = 2.5 Hz, CHCO₂H), 4.66 (br. s, 1 H,

(s, 3 H, NCO₂Me), 3.81 (m, 1 H, CHCH₂OH), 4.62 (br. s, 1 H,

C(CH₃)=CH₂), 4.87 (br. s, 1 H, C(CH₃)=CH₂). ¹³C NMR (150 Mz,

CDCl₃): δ = 22.8 (CH=C(CH₃)), 32.9 (CH₂CO₂Me), 38.8

(CHCH₂CO₂Me), 45.5 (CHC(CH₃)=CH₂), 48.3 (CH₂N), 52.4

(CO₂Me), 53.4 (NCO₂Me), 65.5 (CHCH₂OH), 66.5 (CH₂OH),

113.3 (C(CH₃)=CH₂), 141.6 (C(CH₃)=CH₂), 158.0 (NCO), 173.3

(CO). ESI-MS, m/z (%) = 294 (100) [M⁺+ Na], 272 (5) [M⁺+ H].

HRMS (TOF-CI) C₁₃H₂₁NO₅(271.31): [M⁺+ Na] calcd.

294.130890; found: 294.131194.

C(CH₃)=CH₂), 4.94 (br. s, 1 H, C(CH₃)=CH₂). ESI-MS, m/z (%)

= 427 (90) [2 M⁺+ H], 214 (45) [M⁺+ H]. HRMS (TOF-CI)

C₁₀H₁₅NO₄(213.23): [M⁺– H] calcd. 212.0928; found: 212.0920.

Acknowledgments

This work was supported by the Deutsche Forschunsgemeinschaft

(Sonderforschungsbereich 424), the Fonds der Chemischen In-

dustrie and the Alexander von Humboldt Foundation. M. M. M.

thanks the Spanish “Ministerio de Educación Cultura y Deporte”

for a grant. We thank Mrs. E. Izgorodina for theoretical calcula-

tions of NMR coupling constants.

Methyl (3R,3aR,7aS)-3-Isopropenyl-5-oxohexahydropyrano[3,4-

b]pyrrole-1(2H)-carboxylate (42b): To a solution of 40b (80 mg,

0.68 mmol, obtained from 37b using the same procedure described

for 40a) in MeOH (8 mL), methanesulfonic acid (18 μL, 2.7 mmol)

and 2 drops of water were added. The reaction mixture was re-

fluxed for 15 h. The mixture was diluted with H₂O (4 mL) and the

aqueous phase was extracted with diethyl ether (3×10 mL). The

organic phase was washed with saturated NaHCO₃(3 ×5 mL),

dried (MgSO₄), and concentrated in vacuo. The crude product was

purified by flash chromatography, R_f= 0.20 (SiO₂, AcOEt/petro-

leum ether, 1:2) affording 42b (17 mg, 48 %) as a colourless oil

which was identical NMR spectroscopically with the product ob-

tained by Campbell et al.^[6j][α]²_D⁰= –28.1 (c = 0.30, CHCl₃); {ref.^[6j]

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ent-42b [α]²_D⁰= +32.1 (c = 1.20, CH Cl )}. IR (film): ν (cm^–1) =

˜

2

2952–2926, 1748 and 1704 (NCO, CO), 1456, 1383. ¹H NMR (400

Mz, CDCl₃): δ = 1.70 (s, 3 H, CH=C(CH₃)), 2.34 (d, 2 H, ³J =

7.0 Hz, CHCH₂CO), 2.79–2.83 (m, 1 H, CHC(CH₃)=CH₂), 2.92–

2.98 (m, 1 H, CHCH₂CO), 3.25–3.30 (m, 1 H, CH₂N), 3.70–3.76

(m, 4 H, NCO₂Me and CH₂N), 4.33–4.36 (m, 1 H, NCHCH₂O),

4.39–4.53 (m, 2 H, NCHCH₂O), 4.71 (br. s, 1 H, C(CH₃)=CH₂),

5.02 (br. s, 1 H, C(CH₃)=CH₂). ¹³C NMR (100 Mz, CDCl₃): δ

= 23.1 (CH=C(CH₃), 28.4 (CHCH₂CO), 36.5 (CHCH₂CO), 47.2

(CH₂N), 52.8 (NCO₂Me), 55.2 (NCHCH₂O), 67.9 (NCHCH₂O),

113.6 (C(CH₃)=CH₂), 139.7 (C(CH₃)=CH₂), 172.7 (CO). ESI-MS,

m/z (%) = 501 (10) [2 M⁺+ Na], 262 (100) [M⁺+ Na], 240 (40) [M⁺

+ H]. HRMS (TOF-CI) C₁₂H₁₇NO₄(239.27): [M⁺+ Na] calcd.

262.1050; found: 262.1039; [M⁺+ H] calcd. 240.1230; found:

240.1221.

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(–)-α-Kainic Acid(1): A 8 n solution of Jones reagent (141 μL,

1.1 mmol) was added to solution of 41a (27 mg, 0.11 mmol) in ace-

tone (2 mL) at 0 °C. After stirring for 5 min at 0 °C the reaction

mixture was allowed to warm to room temperature, and 0.1 mL of

water was added. The resulted mixture was stirring at room tem-

perature for 2 h, diluted with water (2 mL) and extracted with di-

ethyl ether (3×5 mL). The organic phase was washed with brine,

dried (MgSO₄) and the solvents evaporated in vacuo to afford the

[7] A. Deiters, D. Hoppe, J. Org. Chem. 2001, 66, 2842–2849.

1442

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Eur. J. Org. Chem. 2005, 1427–1443

(–)-Sparteine-Mediated Synthesis of Kainoids

FULL PAPER

[8] A. Deiters, B. Wibbeling, D. Hoppe, Adv. Synth. Catal. 2001,

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1

[31] The H NMR exhibits two broad singlets at δ = 4.62 and 4.91

ppm for the alkene protons, indicating the C3–C4 cis-relation-

ship (see refs.^[6i,6j]). The NOE studies were carried out at low

temperature because of the broad signals.

Received: November 19, 2004

Eur. J. Org. Chem. 2005, 1427–1443

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1443

Article Doi

Novel approach to the (-)-sparteine-mediated synthesis of kainoids: Total synthesis of (-)-α-kainic acid by (-)-sparteine-mediated deprotonation

DOI: 10.1002/ejoc.200400824

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Full text of DOI:10.1002/ejoc.200400824

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