Synthesis and derivatization of substituted (R)- and (S)-C-allylglycines

FULL PAPERS

Synthesis and Derivatization of Substituted (R)- and (S)-

C-Allylglycines

Nong Zhang,^aWinfried Münch,^aUdo Nubbemeyer^b,*

a

Institut für Chemie – Organische Chemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany

Institut für Organische Chemie, Johannes Gutenberg Universität Mainz, Duesbergweg 10-14, 55128 Mainz, Germany

b

Fax: (þ49)-6131-392-4533, e-mail: nubbemey@uni-mainz.de

Received: April 4, 2004; Accepted: July 30, 2004

Dedicated to Prof. Dr. J. Mulzer on the occasion of his 60^thbirthday.

Abstract: Various (R)- and (S)-C-allylglycine deriva- High diastereoselectivities were obtained (>15:1).

tives were synthesized by means of an auxiliary con- The auxiliary could be efficiently removed by organo-

trolled diastereoselective aza-Claisen rearrangement. lithium reactions of the amides furnishing a-amino

Starting from (S)-configured auxiliaries derived ketones. Another allyllithium addition allowed us to

from optically active proline, an aza-Claisen rear- introduce a second allyl chain with high diastereose-

rangement enabled us to synthesize a(R)-configured lectivity. Final ring closures by means of metatheses

g,d-unsaturated amides. Since (R)-allylglycine deriva- using Grubbsꢀ (I) catalyst gave raise to the formation

tives could be directly generated by reacting N-allyl- of enantiopure phenanthridines and cyclohexenes dis-

proline derivatives and various protected glycine flu- playing defined substitution patterns ready for alka-

orides, the corresponding (S)-enantiomers were loid total syntheses.

built-up via an initial a-chloroacetyl chloride rear-

rangement and a subsequent chloride azide substitu- Keywords: allylation; C-allylglycine; aza-Claisen rear-

tion with complete inversion of the configuration. rangement; chiral auxiliary; ring closing metathesis

Introduction

desired amides 4 with>15:1 diastereoselectivity in fa-

vour of the (R)-configured product. However, the rear-

(R)- and (S)-C-allylglycine derivatives are widely used rangements employing the (S)-prolinol derivatives 2 ex-

in organic synthesis.^[1]Because of the high price of the clusively produced the (R)-C-allylglycines 5 independ-

commercially available compound, a set of syntheses ently of the nitrogen substituent. Finally, the removal

had been developed to allow the generation of suitably of the chiral auxiliary amide succeeded by means of

substituted material for extensive preparative investiga- acid-mediated cleavage, iodolactonization and an aryl-

tions. Generally, the chiral information had been intro- lithium addition to generate aryl ketones, i.e., isoquino-

duced by means of an auxiliary directed strategy.^[2]

lone 6, respectively. It should be pointed out that no loss

The ketene aza-Claisen rearrangement (zwitterionic of chiral information had been detected with the remov-

aza-Claisen rearrangement) could be developed as a re- al of the auxiliary (Scheme 1).

liable and flexible reaction to generate various function-

In continuation of our program, we report here on the

alized (R)-C-allylglycine derivatives with high diaster- synthesis of further new (R)- and (S)-C-allylglycine de-

eoselectivity and high yield.^[3]Starting from (S)-N-allyl- rivatives via the auxiliary directed strategy. Focussing on

proline methyl ester 1 and N-allylprolinol ethers 2 the use of the so obtained defined configured amino acid

(PG¼Bn, TBS), the treatment with diverse protected building blocks for heterocycle and carbocycle synthe-

glycyl fluorides 3 furnished C-allylglycine amides 4 ses, the auxiliary amide moiety of suitably substituted

and 5. In all cases, the new stereogenic centre of the ma- compounds was replaced by means of an organolithium

jor diastereomer 4/5 displayed the (R)-configuration. reagent affording optically active g,d-unsaturated-a-

The (S)-proline methyl ester reactant 1 and acid fluo- amino ketones. Then, a stereoselective Grignard addi-

rides 3 bearing small nitrogen substituents (R/R’¼N₃, tion to the ketone function enabled us to introduce a sec-

NPht) resulted in mixtures of diastereomers 4 (predom- ond unsaturated side chain. Finally, ring closing meta-

inantly R) indicating a non-complete auxiliary directed theses allowed us to generate cyclohexenes and phenan-

chiral induction. In contrast, acid fluorides carrying bul- thridines displaying a defined substitution pattern.

ky N substituents (R¼BOC, CBZ, R’¼Alkyl) gave the These optically active target compounds should serve

Adv. Synth. Catal. 2004, 346, 1335–1354

DOI: 10.1002/adsc.200404102

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Nong Zhang et al.

FULL PAPERS

as versatile building blocks in Amaryllidaceae alkaloid tection of the newly formed OH group under standard

total syntheses.

conditions (98–99% yield). The substitution pattern is

detailed in Table 1 (Scheme 2).

The glycine fluorides 13a and 13b had been synthe-

sized via four steps starting from 2-aminoacetaldehyde

dimethyl acetal 11a and bromopiperonylamine 11b.^[12]

The amines 11 were alkylated with ethyl bromoacetate

to give the intermediate glycine esters. Then, the nitro-

gen was protected as a t-butyl carbamate. After basic

Results and Discussion

Auxiliary Controlled Aza-Claisen Rearrangements

Planning the synthesis of (S)-C-allylglycine derivatives aqueous cleavage of the ester function, the correspond-

via the auxiliary directed zwitterionic aza-Claisen rear- ing carboxylic acids 12a and 12b could be isolated with

rangement strategy as depicted in Scheme 1, the altered high yield (66–93% over three steps). Finally, the reac-

the absolute configuration of the new stereogenic centre tion with cyanuric fluoride under standard conditions af-

had to be taken in account. On one hand, it suggested it- forded the acid fluorides 13a and 13b (94.5–99.5%).^[13]

self that the change of the auxiliary configuration must The so activated acid derivatives were used as crude

enforce the generation of the enantiomeric C-allylgly- compounds. No extensive purification was necessary

cine. The crucial point of such an aim is the significantly to obtain satisfactory reactive material. Additionally,

higher price of the (R)-proline derivatives, preventing chloroacetyl chloride 13c and azidoacetyl fluoride 13d

the use of the material in bulk quantities. On the other were used as reactants in diverse ketene aza-Claisen re-

hand, a suitable alternative turned out to be the (S)-pro- arrangements^[13](Scheme 3).

line directed introduction of an (R)-a-halogen amide

First zwitterionic aza-Claisen rearrangements were

and the subsequent substitution of the leaving group conducted with the N-allylproline methyl esters 1a – d

by means of nitrogen nucleophile (S_N2).^[4]Hence, (S)- and acid halides 13c and 13d. Focussing on the synthesis

N-allylproline methyl ester and (S)-N-allylprolinol de- of (S)-C-allylglycine, the N-allylamino ester 1a was

rivatives and a-chloroacetyl halides were recommended treated with chloroacetyl chloride 13c to give the a-

to serve as starting materials. Furthermore, additional chloroamide 14a in 70% yield as a single diastereomer.

allyl systems should be tested to enhance the scope As expected, the formation of the desired amide 14a

and limitations of the ketene aza-Claisen rearrange- was accompanied by the generation of some von Braun

ment.

degradation products (allyl chloride and N-chloroace-

Starting from (S)-proline methyl ester 7^[5]and (2S)- tylpyrrolidide of 7),^[14]pointing out the efficiency of

trans-4-hydroxyproline methyl ester 8 hydrochloride,^[6]

respectively, the treatment with allyl bromide 9 and allyl

mesylate 10^[7]in the presence of potassium carbonate

gave raise to the formation of the N-allyl esters 1a – c

in 77 to 89% yield.^[8]Then, the hydroxy group of ester

1c was protected as the TBS ether 1d (98%).^[9]The pro-

linol derivatives 2a^[10]and 2b were obtained from ester

1a after DIBALH reduction^[11]and the consecutive pro-

Scheme 2. Syntheses of optically active N allylpyrrolidines.

Table 1. Substitution patterns of the allylamines

No.

R¹

R²

R³

X

1a

1b

1c

1d

2a

2b

7

8

9

10

H

OH

OTBS

H

OH

–

H

–

TBS

TPS

–

CH₂OTBS

H

–

H

Br

OMes

Scheme 1. Overview: diastereoselective aza-Claisen rear-

rangements of N-allylamines 1 and 2.

CH₂OTBS

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Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

Figure 1. NOESY analyses of piperazinediones 15 and 17.

Significant correlations are marked with arrows, pivotal ef-

fects are marked with“!”.

Scheme 3. Syntheses of glycyl fluorides.

this competing reaction even in the presence of the high-

ly rearrangement-active starting material. However, the

decrease of the yield was acceptable (<10%). A further

optimization would have been achieved using chloro-

acetyl fluoride. The (2R)-chloroamide 14a was then sub-

jected to a nucleophilic substitution (S_N2). The reaction

with sodium azide in DMF afforded the (2S)-azido-

amide 16 in nearly quantitative yield.^[4]The spectral

data of the (S)-C-allylglycine derivative displayed sig-

nificant differences to that obtained for the correspond-

ing (R)-material. Finally, the Staudinger reaction^[12c]and

the aqueous work-up of the phosphine imine induced

the immediate cyclization of the new amino group and

Scheme 4. Methyl ester auxiliary-directed aza-Claisen rear-

rangements.

the auxiliary ester function. The piperazinedione 17 Consequentially, the (S)-prolinol derivatives 2a/b were

was isolated in 91% yield. The relative configuration used as chiral allylation compounds. The treatment of

of the stereogenic centres could be unequivocally TPS-prolinol 2b with azidoacetyl fluoride 13d (X¼F)

proven by means of NOESY analysis, the new centre under standard conditions afforded the amide 18d

of the C-allylglycine moiety selectively exhibited the (R³¼TPS, R⁴¼N₃) in 76% yield as a single diastereom-

(S)-configuration (Figure 1; Scheme 4).

er.^[15]The intermolecular rearrangement involving

The reactions of the allylamino esters 1b and 1d with chloroacetyl chloride 13c (X¼Cl) and allylamine 2a

azidoacetyl fluoride produced the (2R)-azidoamides (R³¼TBS) selectively gave the corresponding (aR)-

14b and 14c with 75 and 79% yield, respectively. Accord- chloroamide 18c in 69% yield (d.r.>20:1). Again,

ing to extensive spectroscopic and HPLC analyses, both some degradation products (allyl chloride, chloroacetyl-

rearrangements were found to be diastereoselective, prolinol amide) were formed during the course of the

pointing out the highly simple and highly auxiliary di- process pointing out the superiority of the acyl fluo-

rected asymmetric induction. In analogy to the (2S)-ex- ride-mediated rearrangements. The substitution of the

periment mentioned above, the amide 14c was subjected chloride in 18c by means of sodium azide in DMF gave

to the Staudinger reaction and aqueous work-up of the the (2S)-configured a-azidoamide 19 in 99% yield. In

phosphine imine. The immediate cyclization of the analogy to previous experiments, the reaction of allyla-

new amino group and the auxiliary ester function fur- mine 2a (R³¼TBS) and the fluorides 13a and 13b

nished the piperazinedione 15 in 85% yield. The relative smoothly gave the C-allylglycine derivatives 18a (72%)

configuration of the stereogenic centres could be un- and 18b (82%). As expected, a single diastereomer had

equivocally proven by means of NOESY analysis, the been formed, respectively, according extensive spectral

new centre of the C-allylglycine moiety selectively dis- and HPLC analyses. The generation of a mixture of dia-

played the (R)-configuration (d.r.>20:1, Figure 1; stereomers could be enforced uponrefluxing the pure C-

Scheme 4).

allylglycine derivative 18b in DMFin the presence of po-

Although the ester auxiliary directed rearrangements tassium carbonate. After about 20 h a second compound

described above were characterized by high yields and 18b-epi occurred, which could be separated by means of

high asymmetric induction, the methyl ester function HPLC (56% of 18b, 36% of 18b-epi). All spectral and

of the proline moiety prevented any Grignard type re- analytical data supported the formation ofa diastereom-

moval of the amide. The envisaged organolithium reac- er of 18b.^[16]Consequentially; the rearrangement build-

tions (like 5 ! 6, Scheme 1) required the absence of any ing-up the amides 18a–d must have been diastereose-

additional reactive carbonyl and carboxyl functions. lective. The removal of the chiral auxiliary of amide

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18b proceeded with moderate 41.5% yield resulting iso- tion) to the allylamines 1 and 2, respectively. Presuming

quinolizidinone 20.^[17]Obviously, the treatment of 18b a favored amine conformation with minimized repulsive

with n-BuLi induced the bromine-lithium exchange. interactions, especially bulky ketene equivalents 13*

The so formed aryllithium moiety suffered from two should attack the lone pair in the favored arrangement

competing reactions: the first part delivered the desired 2* to generate diastereoselectively the syn-allylammo-

ketone20 attacking the amide function. A second part of nium enolate. The so formed zwitterion was character-

the lithium reagent might have attacked the BOC car- ized by a (Z)-enolate geometry as known for related sys-

bonyl function in terms of a 5-exo-trig process removing tems.^[19]Finally, the allylammonium enolate underwent

the protecting group. Consecutive processes destroyed the 3,3 sigmatropic conversion, the charge neutraliza-

this part of the material resulting in the relatively low tion should serve as a highly efficient driving force. In ac-

yield of the conversion. The substitution pattern of the cordance to well known Claisen rearrangements, a

amides is detailed in Table 2 (Scheme 5).

chair-like transition state should be involved minimizing

The analysis of the stereochemical outcome of all ke- 1,3 repulsive interactions.^[20]Consequentially, the small

tene aza-Claisen rearrangements was found to be in CH₂part of the auxiliary must have been placed quasi-

strong accordance with that published earlier support- axial, the bulky chain branched centre must have been

ing the given working hypothesis.^[3]Thus, only a brief arranged in the quasi-equatorial position. Overall, the

summary of the mechanistic discussion will be outlined (S)-configuration of the auxiliary centre caused the dia-

here.^[18]

stereoselective formation of the (aR)-configuration in

The reaction path of the auxiliary controlled intermo- the newly formed amide (Figure 2, for allyl ester 1a – d

lecular rearrangement was thought to start with the ad- replace CH₂OR³of 2a/b by CO₂Me).

dition of the Lewis acid activated ketene moiety 13* (de-

rived from acid halide 13 and Me₃Al, methane evolu-

Synthesis of Phenanthridines and Cyclohexenes

The amides 5, 14, 16, 18 and 19 represent useful starting

materials for further synthetic investigations. The gener-

Scheme 5. Prolinol auxiliary directed aza-Claisen rearrange-

ments.

Figure 2. Stereochemical rationalization of the auxiliary con-

trolled aza-Claisen rearrangement: working hypothesis.

Table 2. Substitution patterns of the acid halides 13 and the g,d unsaturated amides 14 – 19.

No.

R¹

R²

R³

R⁴

13a

13b

13c*

13d

14a

14b

14c

16

18a

18b

18c*

18d

19

–

(MeO)₂CHCH₂-N-BOC

3,4-methylenedioxy-6-bromobenzyl-N-BOC

Cl

N₃

Cl

N₃

(MeO)₂CHCH₂-N-BOC

3,4-methylenedioxy-6-bromobenzyl-N-BOC

Cl

N₃

H

OTBS

H

Ester

TBS

TPS

TBS

CH₂OTBS

H

13: X¼F except *: X¼Cl.

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Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

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ation of optically active isoquinolones 6 and 20 via intra- chromatography and upon storing even at ꢀ208C

molecular Grignard-type cyclization enabled us to re- (Scheme 6).^[29]

move the chiral auxiliary in a highly efficient man-

Upon treating the diallylquinoline 23 with aqueous

ner.^[3,17]Starting from isoquinolone 6, the keto function HCl^[30]and CeCl₃/AcCl^[31]in CHCl₃, no b-elimination

should be converted into an exocyclic olefin intending of H₂O had been observed. In contrast, a transacetaliza-

to prepare the material for another ring annulation. Sev- tion gave raise to the formation of isoquinoline 27 in

eral attempts using Wittig- and Horner-type olefinations 62% (HCl) and 85% (CeCl₃) yields. Prolonged reaction

failed in spite of abroad variation ofthe reagents and the times and increased acid concentrations did not cause

reaction conditions. Finally, the introduction of an exo- the complete cleavage of the remaining ethoxy function.

methylene group succeeded using a Peterson proto- Obviously, the basic isoquinoline nitrogen prevented an

col.^[21]Initially, trimethylsilylmethyllithium^[22]was add- efficient acetal cleavage by an effective trapping of pro-

ed to isoquinolone 6 to give carbinol 21 in 76.6% yield ton and Lewis acid, respectively. However, isoquinoline

as a single diastereomer.^[23]A NOESY analysis proved 27 had been subjected to the RCM conditions as out-

the syn-configuration of the hydroxy group and the allyl lined for the phenanthridine 25 synthesis. Analogously,

side chain (Figure 3). Then, b-elimination of OH and the corresponding ring closure afforded the phenanthri-

TMS functions could be achieved under basic (NaH, dine 28 in 68% yield. Again, the RCM was very slow and

THF, 81.5%)^[24]and acidic conditions (AcOH, CHCl₃, 20 mol % ruthenium reagent were necessary to obtain a

85%),^[25]respectively, generating the isoquinoline 22. It complete consumption of the reactant 27 (complexation

was noteworthy that no cleavage of the diethyl acetal ability of the electron-rich nitrogen centre) (Scheme 6).

was observed. Obviously, the basic isoquinoline nitro-

gen trapped all protons before affecting the acetal moi- pyrrolidine by means of an intermolecular lithium or-

ety (Scheme 6). ganyl addition had been investigated. The reaction of

Starting from amide 18a, the removal of the auxiliary

The success of the diastereoselective lithium organyl amide 18a and piperonyllithium under standard condi-

addition to isoquinolone 6 mentioned above motivated tions resulted ketone 29 in 67.5% yield. The absence

us to investigate a further reagent. Allyllithium had of racemization has been demonstrated satisfactorily

been generated by a transmetallation of allyltributyltin (chiral HPLC, NMR). The a-aminoketone 29 was then

and butyllithium.^[26]The reaction with ketone 6 deliv- treated with allyllithium to give the diallylamino alcohol

ered the vicinal diallylquinoline 23 in 88% yield as a sin- 30 in almost quantitative yield as a single diastereomer.

gle diastereomer. Again, the syn-arrangement of the

OH group and the adjacent allyl side chain could be pro-

ven by means of a NOESY analysis.^[27]First attempts to

enforce the b-elimination of H₂O had been conducted

under basic conditions. Treatment of carbinol 23 with

MsCl in the presence of t-BuOK gave the butadiene 24

in 38% yield. The newly formed double bond selectively

displayed the (Z) geometry. Unfortunately the diene

tended to decompose easily preventing extensive subse-

quent experiments (Scheme 6).

Olefin metathesis is known as a powerful reaction to

close 6-membered rings.^[28]Planning to involve such a

process to generate phenanthridine 25 from the vicinal

diallyl quinoline 23, an electron-rich nitrogen centre

(as present in 23) was known to interfere with a smooth

metathesis because of the effective complexation of the

catalyst metal centre. As expected, the RCM of diallyl-

quinoline 23 was found to be very slow but the ring clo-

sure could be enforced by refluxing in CHCl₃for 4 days

in the presence of Grubbs (I) catalyst (benzylidenebis-

[dicyclohexylphosphine] ruthenium dichloride). Com-

plete conversion of the starting material could be ach-

ieved by adding 5 mol % portions of the catalyst every

24 h, overall 20 mol % of the ruthenium complex were

needed. Finally, the phenanthridine 25 could be isolated

in 66% yield. Again, the b-elimination of H₂O was found

to be difficult. Treatment of carbinol 25 with MsCl in the

presence of t-BuOK gave the cyclohexadiene 26 in 21%

yield. The phenanthridine 26 was unstable upon column phenanthridines.

Scheme 6. Syntheses of optically active isoquinolines and

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Figure 3. NOESY Analyses of allyl adducts 21 and 31. Signif-

icant correlations are marked with arrows, pivotal effects are

marked with“!”.

The so obtained crude material was used without further

purification. Surprisingly, treatment of carbinol 30 with

KHMDS in THF at 08C led to a smooth cyclization to

give carbamate 31 in 86% yield. Obviously, the 5-exo-

trig situation of the intermediate alcoholate and the

BOC carbonyl function enabled us to remove the tert-

butyl alcohol under basic conditions (transesterifica-

tion). An NOESYanalysis proved the cis-configuration

of the allyl side chains in 31 (Figure 3, vide supra) point-

ing out the diastereoselective allylation of the ketone 29.

A final RCM process afforded the cyclohexene 32 in

86% yield. The less electron-rich nitrogen centre al-

Scheme 7. Syntheses of optically active cyclohexenes.

lowed us to conduct the metathesis under well known give the (aR)-chloroamide, which underwent a smooth

conditions: only 5 mol % Grubbs (I) catalyst were nec- substitution with azide to give the (aS)-azidoamides

essary to achieve complete consumption of the reactant with complete inversion of the configuration. As expect-

31 within 3 h at 608C (Scheme 7).

ed, the employment of carboxylic acid chlorides caused

Treatment of carbinol 30 with CeCl₃/AcCl in CHCl₃some von Braun degradation within the reaction, point-

and with wet DMSO at 80–908C^[32]induced a transace- ing out the superiority of the acyl fluorides as key com-

talization to give the carbamate 33 as a mixture of two pounds in ketene aza Claisen rearrangements. The aux-

diastereomers (not separated). The final RCM afforded iliary moiety of the g,d-unsaturated amides could be re-

ꢀ

the cyclohexenes 34 in 88% yield. Again, the less elec- moved by conducting a C C bond forming step. Treat-

tron-rich nitrogen centre allowed us to conduct the ment with organolithium compounds gave raise to the

metathesis under well known conditions: only 5 mol % formation of (aR)-amino ketones.

Grubbs (I) catalyst were necessary to achieve complete

Since direct olefinations of the aryl ketones gave no

consumption of the reactant 31 within 3 h at 608C. Over- satisfactory results, another organolithium addition to

all, the RCM strategy enabled us to synthesize optically the ketone function enabled us to introduce a new side

active phenanthridines and cyclohexenes , respectively, chain with high 1,2 asymmetric induction. Subsequent

displaying suitable substitution patterns for further in- elimination allowed us to generate defined olefins. Fo-

vestigations (Scheme 7).

cussing on the formation of new ring systems, 1,2-diallyl

compounds were subjected to RCM conditions. The iso-

quinoline derivatives bearing an electron-rich (basic) ni-

trogen required long reaction times and high catalyst

concentrations to achieve the formation of phenanthri-

Conclusion

(R)- and (S)-C-allylglycine derivatives have been syn- dines in>65% yield. In contrast, the carbamate-pro-

thesized using an auxiliary directed a-C-allylation of tected open chain amino alcohols furnished cyclohex-

glycine and chloroacetyl halides. Always the (S)-config- enes with 5% catalyst in short times with>80% yield.

ured auxiliary pyrrolidine substituent derived from l- The so formed compounds represent suitable precursors

proline caused the formation of (aR)-g,d-unsaturated for Amaryllidaceae alkaloid total syntheses.

amides with high diastereoselectivity using a zwitterion-

ic aza-Claisen rearrangement as the key step. Various

(R)-C-allylglycines have been obtained directly via the

reaction of N-protected glycyl fluorides and N-allylpyr-

rolidines. In contrast, the (S)-C-allylglycine synthesis re-

quired one intermediate step when intending to use the

same (S)-configured auxiliary series. Initially, chloro-

acetyl chloride and the allylamine were combined to corded on Bruker AC 250 or on a Bruker AC 550 spectrometer

Experimental Section

General Remarks

¹H NMR, ¹³C NMR spectra and NOESYexperiments were re-

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at room temperature unless specified otherwise. Tetramethyl-

silane was used as internal standard. IR spectra were obtained

from a Perkin Elmer 257 or 580B spectrophotometer. Optical

rotations were measured with a Perkin Elmer P 241 polarime-

ter in a 1 dm cell. Mass spectra were recorded on a Varian MAT

711 or 112S, The high resolution mass spectra (HRMS) were

obtained with a Varian MAT 711 spectrometer. PFK was

used as reference, the results were determined via a peak

matching method, resolution:>10000. Ion source temperature

was 2508C, electron energy was 0.8 mA. The melting points

(not corrected) were measured with a Büchi SMP 20. For

HPLC, Knaur pumps, UV-and RI detectors, and Rheodyne in-

jection systems were used. Preparative amounts of several

compounds were separated with a 32 mmꢁ250 mm column

and 5 mm Nucleosil 50–5 obtained from Macherey & Nagel,

with a flow of about 80 mL/min. Chiral HPLC analyses were

run using Chirobiotic-V and Chirobiotic-T columns (Baker).

Column chromatography was carried out with Merck silica

gel 0.063–0.2 mm, 70–230 mesh A. The progress of the reac-

tions was monitored by thin layer chromatography (TLC) per-

formed on aluminium sheets pre-coated with silica gel 60

(thickness 0.25 mm). All solvents were dried before use follow-

ing standard procedures.

(2S,4R)-N-Allyl-4-hydroxyproline Methyl Ester (1c)

To a suspension of hydroxyproline methyl ester 8 (2 g,

11 mmol) in dry CH₂Cl₂(50 mL) was added Et₃N (1.56 mL)

and freshly distilled allyl bromide 9 (1.12 mL, 13.2 mmol, d¼

1.43). The mixture was stirred overnight at 208C. Then H₂O

(30 mL) was added. The aqueous layer was extracted with

CH₂Cl₂(3ꢁ15 mL), the combined organic layers were dried

over MgSO₄, and the solvent was removed under vacuum.

The crude material was purified by column chromatography

(ethyl acetate) to give allylhydroxyproline methyl ester 1c as

pale yellow oil; yield: 1.66 g (81.5%); [a]²_D⁰: ꢀ87.38 (c 1.8,

1

CHCl₃); H NMR (500 MHz, CDCl₃): d¼1.90–1.98 (m, 1H,

HOCHCH₂), 2.01–2.09 (m, 1H, HOCHCH₂), 2.29–2.35

(ddd, 1H, J¼9.90 Hz, 5.45 Hz, 4.45 Hz, NCHH), 3.01–3.07

¼

(m, 1H, CHHCH CH₂), 3.17–3.23 (m, 1H, CHHCH CH₂),

3.23–3.29 (ddd, 1H, J¼10.40 Hz, 5.45 Hz, 4.95 Hz, NCHH),

3.34–3.40 (m, 1H, NCH), 3.43–3.55 (br, s, OH), 3.55 (s,

¼

OCH₃), 4.96–5.01 (dd, 1H, J¼10.03 Hz, 0.98 Hz, CH CHH),

¼

), 5.03–5.09 (dd, 1H, J¼17.05 Hz, 1.24 Hz, CH CHH), 5.70–

5.80 (m, 1H, CH CH₂) ppm; ¹³C NMR (125 MHz, CDCl₃):

¼

d¼39.3 (HOCHCH₂), 51.6 (OCH₃), 57.1 (CH₂CH CH₂),

61.0 (NCH₂), 63.4 (NCHCOOCH₃), 69.3 (CHOH), 117.6

¼

(CH CH₂), 134.4 (CH CH₂), 173.9 (COO); IR (KBr, film):

1/l¼3173 (br, m, OH), 3072 (m), 3024 (m), 3007 (m), 2985

(m), 2975 (m), 2953 (m), 2945 (m), 2866 (m), 2823 (m), 1878

(w), 1747 (s, COO), 1706 (w), 1644 (w), 1462 (m), 1453 (m),

1432 (m), 1377 (m), 1364 (w), 1340 (m), 1320 (m), 1287 (w),

1266 (w), 1235 (m), 1218 (m), 1196 (s), 1174 (s), 1142 (m),

1127 (m), 1091 (s), 1061 (w), 1019 (m) cm^ꢀ1; MS (EI, 80 eV,

308C): m/z (%)¼185 (7.4, [M]^þ), 126 (100, [M – C₂H₃O₂]^þ),

108 (7, [M – C₂H₅O₃]^þ), 41 (19, [C₃H₅]^þ); HRMS (80 eV,

308C): calcd. for C₉H₁₅NO₃: 185.10519; found: 185.10733.

(S)-N-(2-tert-Butyldimethylsilyloxymethyl) 2-

propenylproline Methyl Ester (1b)

Proline methyl ester hydrochloride (7; 1.14 g, 6.90 mmol) in

DMF (100 mL) was treated with Et₃N (1.3 g, 6.90 mmol) and

mesylate 10 (1.61 g, 5.75 mmol) at 08C. The mixture was stirred

overnight at 208C, then H₂O (50 mL) was added. The aqueous

layer was extracted with Et₂O (4ꢁ20 mL), the combined or-

ganic layers were dried over MgSO₄. After removal of the sol-

vent, the crude material was purified by column chromatogra-

phy (n-hexane/ethyl acetate¼5:1) to give N-allylproline

methyl ester 1b as pale yellow oil; yield: 1.4 g (77%); [a]²_D⁰:

(2S,4R)-N-Allyl-4-tert-butyldimethylsilyloxyproline

Methyl Ester (1d)

1

ꢀ51.78 (c 1.7, CHCl₃); H NMR (270 MHz, CDCl₃): d¼0.05

N-Allylhydroxyproline methyl ester (1c; 1.4 g, 7.57 mmol),

imidazole (1.13 g, 16.6 mmol) and DMAP (10 mg) in anhy-

drous THF (20 mL) were treated with TBSCl (2.28 g,

15.14 mmol) at 08C. After 3hours of stirring at 208C (TLC con-

trol), the mixture was quenched with MeOH (20 mL) and H₂O

(20 mL). The aqueous layer was extracted with Et₂O (4ꢁ

10 mL) and the combined organic layers were dried over

MgSO₄. After removal of the solvent, the crude material was

purified by column chromatography (hexane-EtOAc, 5:1) to

give silyl ether 1d as pale yellow oil; yield: 2.2 g (98%); [a]²_D⁰:

[s, 6H, Si(CH₃)₂], 0.90 [s, 9H, SiC(CH₃)₃], 1.65–1.97 (m, 3H,

CH₂CHH), 1.99–2.15 (m, 1H, CH₂CHH), 2.26–2.38 (dd, 1H,

J¼16.60 Hz, 8.30 Hz, NCHHCH₂), 2.96–3.07 (m, 2H,

¼

NCHHCH₂, NCHHCH CH₂), 3.11–3.18 (dd, 1H, J¼

8.79 Hz, 5.37 Hz, NCHCO₂), 3.20–3.28 (d, 1H, J¼12.70 Hz,

¼

NCHHCH CH₂), 3.65 (s, 3H, CO₂CH₃), 4.07–4.25 (dd, 2H,

¼

J¼21.49 Hz, 14.65 Hz, TBSOCH₂), 4.95 (s, 1H, CHH C),

5.05 (s, 1H, CHH C) ppm; ¹³C NMR (68 MHz, CDCl₃): d¼

¼

ꢀ5.4 [Si(CH₃)₂], 18.3 [SiC(CH₃)₃], 23.0 (CH₂CH₂), 25.8

[SiC(CH₃)₃], 29.3 (CH₂CH₂), 51.5 (OCH₃), 53.3 (NCHCO₂),

1

ꢀ47.88 (c 1.5, CHCl₃); H NMR (270 MHz, CDCl₃): d¼0.00

¼

57.5 (NCH₂CH₂), 64.4 (NCH₂C CH₂), 65.4 (TBSOCH₂),

[s, 6H, Si(CH₃)₂], 1.35 [s, 9H, SiC(CH₃)₃], 1.87–1.99 (ddd, 1H,

J¼12.69 Hz, 8.30 Hz, 3.91 Hz, NCHCHH), 1.99 (ddd, 1H,

J¼12.70 Hz, 7.81 Hz, 7.25 Hz, NCHCHH), 2.24–2.32 (dd,

1H, J¼9.76 Hz, 6.88 Hz, NCHHCHO), 3.00–3.11 (dd, 1H,

¼

111.3 (CH₂C), 146.2 (CH₂C), 174.6 (CO₂CH₃); IR (KBr,

film): 1/l¼3092 (w), 2954 (s), 2929 (s), 2884 (m), 2856 (s),

1752 (s, COO), 1737 (s, COO), 1658 (w), 1472 (m), 1462 (m),

1435 (m), 1406 (w), 1388 (w), 1361 (m), 1251 (s), 1196 (s),

¼

1171 (s), 1108 (s), 1040 (w), 1006 (m), 938 (w), 906 (m) cm^ꢀ1

;

J¼13.19 Hz, 7.33 Hz, CHHCH CH₂), 3.19–3.30 (m, 2H,

¼

MS (EI, 80 eV, 408C): m/z (%)¼313 (3, [M]^þ), 298 (3, [M –

NCHHCHO, CHHCH CH₂), 3.31–3.39 (dd, 1H, J¼

CH₃]^þ), 254 (100, [M

– –

CO₂CH₃]^þ), 185 (19, [M

8.30 Hz, 7.81 Hz, NCH), 3.65 (s, 3H, OCH₃), 4.27–4.37 (m,

1H, TBSOCH), 4.97–5.09 (dd, 1H, J¼9.76 Hz, 0.98 Hz,

C₆H₁₀NO₂]^þ), 128 (33, [M – C₆H₁₁NO₂– C₄H₉]^þ); HRMS

(80 eV, 408C): calcd. for C₁₆H₃₁NO₃Si: 313.20732; found:

313.20722.

¼

CH CHH), 5.09–5.15 (dd, J¼17.09 Hz, 1.47 Hz, CH CHH),

H), 5.71–5.88 (dddd, 1H, J¼17.09 Hz, 10.25 Hz, 9.76 Hz,

6.83 Hz, CH CH₂); ¹³C NMR (68 MHz, CDCl₃): d¼ ꢀ5.0

¼

[Si(CH₃)₂], 17.8 [SiC(CH₃)₃], 25.6 [SiC(CH₃)₃], 39.6

¼

(OCHCH₂), 51.7 (OCH₃), 58.1 (NCH₂CH CH₂), 61.6

(NCH₂), 64.0 (NCHCOOCH₃), 70.3 (OCHCH₂), 117.6

Adv. Synth. Catal. 2004, 346, 1335–1354

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ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

1341

Nong Zhang et al.

FULL PAPERS

¼

(CH CH₂), 134.8 (CH CH₂), 174.2 (CO); IR (KBr, film): 1/

a-amino ester was treated with 1 M NaOH (438 mL) and

LiCl (1.86 g, 43.8 mmol). After stirring at 808C for 3 hours

and at 208C for 1 hour, the solution was extracted with Et₂O

(3ꢁ50 mL). The aqueous layer was acidified with aqueous sa-

turated KHSO₄until the solution reached a pH of 4–5. The

aqueous solution was extracted with Et₂O (4ꢁ100 mL) and

the organic layers were dried over MgSO₄. After removal of

the solvent, the carboxylic acid 12a was isolated sufficiently

pure for further transformations; yield: 7.60 g (66%);

¹H NMR (270 MHz, CDCl₃): d¼1.25 [2ꢁs, 9H, C(CH₃)₃],

3.2 (s, 6H, OCH₃), 3.08–3.23 [m, 2H, NCH₂CH(OCH₃)₂],

3.81 (2ꢁs, 2H, NCH₂COOH), 4.15–4.50 [2ꢁdd, 1H, J¼

5.37 Hz, 4.88 Hz, CH(OCH₃)₂], 8.80 (br, s, 1H, COOH);

¹³C NMR (68 MHz, CDCl₃): d¼27.7, 27.9 [C(CH₃)₃], 49.1,

49.6 [CH₂CH(OCH₃)₂], 49.9, 50.0 (CH₂COOH), 80.5, 80.6

[C(CH₃)₃], 103.7, 103.9 [CH(OCH₃)₂], 155.2, 155.3 (NCO),

173.4, 173.6 (COO); IR (film): 1/l¼3443 (br, m, OH), 3200

(br, m, OH), 2977 (s), 2939 (s), 2836 (m), 1745 (s, COO),

1702 (s, CON), 1478 (s), 1458 (s), 1395 (s), 1368 (s), 1307

(m), 1252 (m), 1166 (s), 1125 (s), 1077 (s), 1024 (m), 968

(m) cm^ꢀ1; MS (EI, 80 eV, 808C): m/z (%)¼263 (2.33, [M]^þ),

190 (6, [M – C₄H₉O]^þ), 176 (13, [M – C₅H₁₁O]^þ), 132 (11, [M

– C₆H₁₁O₃]^þ, 75 (100, [C₃H₇O₂]^þ); HRMS (80 eV, 408C): calcd.

for C₁₁H₂₁NO₆: 263.13688; found: 263.13885.

l¼3079 (w), 2954 (s), 2929 (s), 2896 (m), 2857 (s), 2803 (m),

2710 (w), 1751 (s, CO), 1659 (w), 1643 (w), 1472 (m), 1463

(m), 1436 (m), 1420 (w), 1361 (m), 1312 (w), 1257 (s), 1198

(s), 1173 (s), 1131 (m), 1099 (s), 1033 (m), 1006 (m), 995 (m)

cm^ꢀ1; MS (EI, 80 eV, 408C): m/z (%)¼299 (3, [M]^þ), 284 (2,

[M – CH₃]^þ), 240 (100, [M – C₂H₃O₂]^þ); HRMS (80 eV,

408C): calcd. for C₁₅H₂₉NO₃Si: 299.19167; found: 299.19192.

(S)-N-Allyl-2-tert-

butyldiphenylsilyloxymethylpyrrolidine (2b)

(S)-N-Allylprolinol (1 g, 7.08 mmol; prepared and character-

ized as reported^[10]), imidazole (1 g, 14.7 mmol) and DMAP

(10 mg) in anhydrous THF (50 mL) were treated with TPSCl

(2.9 g, 10.5 mmol) at 08C. After 3 hours of stirring at 208C

(TLC control), the mixture was quenched with H₂O (20 mL).

The aqueous layer was extracted with Et₂O (4ꢁ10 mL) and

the combined organic layers were dried over MgSO₄. After re-

moval of the solvent, the crude material was purified by column

chromatography (n-hexane/ethyl acetate, 4:1) to give TPS-

prolinol 2b as a colourless oil; yield: 2.68 g (99%); [a]²_D⁰:

1

ꢀ46.28 (c 1.9, CHCl₃); H NMR (270 MHz, CDCl₃): d¼1.10

[s, 9H, SiC(CH₃)₃], 1.60–1.85 (m, 3H, CH₂CHH), 1.85–2.01

(m, 1H, CH₂CHH), 2.20–2.31 (m, 1H, NCHHCH₂), 2.62–

2.74 (m, 1H, NCHCH₂O), 2.89–2.99 (dd, 1H, J¼13.18 Hz,

N-tert-Butyloxycarbonyl-N-(2-bromopiperonyl)

aminoacetic Acid (12b)

¼

7.32 Hz, NCHHCH CH₂), 3.03–3.11 (m, 1H, NCHHCH₂),

3.47–3.56 (m, 1H, NCHHCH₂), 3.49–3.58 (dd, 1H, J¼

10.25 Hz, 6.84 Hz, CHHOTPS), 3.73–3.81 (dd, 1H, J¼

10.26 Hz, 6.36 Hz, CHHOTPS), 5.01–5.08 (dd, 1H, J¼

Piperonylamine 11b (300 mg, 1.31 mmol) and Et₃N (132 mg,

184 mL, 1.31 mmol) in anhydrous THF (20 mL) were cooled

to 08C. Ethyl bromoacetate (219 mg, 146 mL, 1.31 mmol) in an-

hydrous THF (5 mL) was added slowly and the mixture was

stirred overnight at 08C. Di-tert-butyl dicarbonate

(1.31 mmol) in anhydrous THF (5 mL) was added and the mix-

ture was stirred at room temperature for 5 hours. 1 N HCl

(10 mL) was added to the mixture and the aqueous layer was

extracted with Et₂O (4ꢁ20 mL). The combined organic layers

were dried over MgSO₄and the solvent was removed under

vacuum. The crude material was purified by column chroma-

tography (n-hexane/ethyl acetate, 6:1) to give N-tert-butylox-

ycarbonyl-N-(2-bromopiperonyl) aminoacetic acid ethyl ester

¼

10.26 Hz, 0.98 Hz, CH CHH), 5.09–5.19 (dd, 1H, J¼

¼

17.09 Hz, 1.46 Hz, CH CHH), 5.79–5.96 (dddd, 1H, J¼

¼

17.09 Hz, 10.25 Hz, 7.32 Hz, 5.86 Hz, CH CH₂), 7.30–7.55

(m, 5H, Ph), 7.65–7.82 (m, 3H, Ph). ¹³C NMR (68 MHz,

CDCl₃): d¼19.1 [SiC(CH₃)₃], 22.8 (CH₂CH₂), 26.8

¼

[SiC(CH₃)₃], 28.4 (CH₂CH₂), 54.4 (NCH₂CH CH₂), 58.5

(NCH₂CH₂), 64.6 (NCHCH₂O), 67.5 (NCHCH₂O), 116.4

¼

(CH CH₂), 127.5, 129.4, 133.7, 136.2 (Ph), 135.5 (CH CH₂);

IR (CHCl₃): 1/l¼3072 (m), 3045 (m), 2807 (m), 3017 (s),

2964 (s), 2931 (s), 2859 (s), 2807 (m), 1472 (m), 1463 (w),

1428 (m), 1391 (w), 1215 (s), 1112 (s), 1050 (m) cm^ꢀ1; MS

(EI, 80 eV, 408C): m/z (%)¼379 (5, [M]^þ), 322 (6, [M –

C₄H₉]^þ), 280 (4, [M – C₄H₉– C₃H₆]^þ), 199 (43, [HOSiPh₂]^þ),

110 (100, [C₇H₁₂N]^þ); HRMS (80 eV, 30–408C): calcd. for

C₂₄H₃₃NOSi: 379.23314; found: 379.23454.

1

as colourless oil; yield: 540 mg (99%); H NMR (270 MHz,

CDCl₃): d¼1.20 (2ꢁt, 3H, J¼7.36 Hz, CH₂CH₃), 1.42 [2ꢁs,

9H, C(CH₃)₃], 3.83 (2ꢁs, 2H, NCH₂Ar), 4.14 (q, 2H, J¼

7.36 Hz, CH₂CH₃), 4.48 (2ꢁs, 2H, NCH₂COO), 5.92 (2ꢁs,

2H, OCH₂O), 6.80 (2ꢁs, 2H, NCH₂CCH), 6.92 (2ꢁs, 2H,

BrCCH); ¹³C NMR (68 MHz, CDCl₃): d¼14.1, 14.2

(CH₂CH₃), 28.1, 28.2 [C(CH₃)₃], 47.8, 48.5 (NCH₂Ar), 50.8,

51.3 (NCH₂COO), 60.9 (CH₂CH₃), 80.6, 80.7 [C(CH₃)₃],

101.7 (OCH₂O), 108.7, 109.5, 112.4, 112.6, 113.5, 129.7, 147.6

(Ph), 155.5 (NCO), 169.6, 169.7 (COOEt); IR (CHCl₃): 1/l¼

3019 (s), 2981 (s), 2935 (m), 2901 (m), 1747 (s, COO), 1697 (s,

CON), 1504 (s), 1479 (s), 1410 (s), 1455 (s), 1406 (s), 1368 (s),

1216 (s), 1122 (s), 1108 (s), 1040 (s), 956 (m), 935 (s), 896 (m),

862 (m) cm^ꢀ1; MS (EI, 80 eV, 908C): m/z (%)¼415 (1.6,

[M]^þ), 336 (4.3, [M – Br]^þ), 314 (11, [M – C₅H₉O₂]^þ), 280

(100, [M – C₄H₈Br]^þ), 234 (14, [M – C₆H₁₄BrO]^þ), 213

(37, [C₈H₆BrO₂]^þ); HRMS (80 eV, 308C): calcd. for

C₁₇H₂₂NO₆⁷⁹Br: 415.06304; found: 415.06622.

N-tert-Butyloxycarbonyl-N-(2,2-

dimethoxyethyl)aminoacetic Acid (12a)

Aminoacetaldehyde dimethyl acetal (11a; 4.60 g, 43.8 mmol)

and Et₃N (44.2 g, 61.3 mL, 43.8 mmol) in anhydrous Et₂O

(250 mL) were cooled to 08C. Ethyl bromoacetate (73.1 g,

48.6 mL, 43.8 mmol) in anhydrous Et₂O (100 mL) was added

slowly and the mixture was stirred overnight at 08C. Di-tert-bu-

tyl dicarbonate (43.8 mmol) in anhydrous Et₂O (50 mL) was

added and the mixture was stirred at room temperature for 5

hours. 1 M HCl (150 mL) was added to the mixture and the

aqueous layer was extracted with Et₂O (4ꢁ80 mL). The com-

bined organic layers were dried over MgSO₄and the solvent

was removed to give the crude protected a-amino esters. The

The ethyl ester (500 mg, 1.20 mmol) was treated with NaOH

(0.1 M, 12 mL) and LiCl (63 mg, 1.48 mmol). After stirring at

1342

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

asc.wiley-vch.de

Adv. Synth. Catal. 2004, 346, 1335–1354

Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

808C for 3 hours and at 208C for 1 hour, aqueous saturated

KHSO₄was added until the solution displayed a pH of 4–5.

The aqueous solution was extracted with Et₂O (4ꢁ20 mL)

and the organic layers were dried over MgSO₄. The solvent

was evaporated to give protected aminoacetic acid 12b as col-

ourless crystals; yield: 433 mg (93%); mp 122–1238C; ¹H NMR

(270 MHz, CDCl₃): d¼1.40 [2ꢁs, 9H, C(CH₃)₃], 3.80 (2ꢁs,

2H, NCH₂COOH), 4.40 (2ꢁs, 2H, NCH₂Ar), 5.85 (2ꢁs, 2H,

OCH₂O), 6.70 (2ꢁs, 1H, NCH₂CCH), 6.85 (2ꢁs, 1H,

BrCCH), 10.3 (s, 1H, COOH); ¹³C NMR (68 MHz, CDCl₃):

d¼28.0, 28.1 [C(CH₃)₃], 47.5, 48.0 (NCH₂COOH), 50.7, 51.3

(NCH₂Ar), 81.0, 81.2 [C(CH₃)₃], 101.7 (OCH₂O), 108.7,

109.4, 112.4, 112.6, 113.4, 113.8, 129.3, 147.6, 17.7 (Ph), 15.5,

155.8 (CON), 174.2, 174.3 (COOH); IR (CHCl₃): 1/l¼3100

(s, br, COOH), 3018 (s), 2980 (s), 2928 (s), 2896 (s), 2703 (m),

2644 (m), 2567 (m), 1725 (s, COO), 1701 (s, CON), 1504 (s),

1476 (s), 1423 (s), 1398 (s), 1369 (s), 1265 (s), 1216 (s), 1158

(s), 1108 (s), 1040 (s), 959 (m), 934 (s) cm^ꢀ1; MS (EI, 80 eV,

1408C): m/z (%)¼387 (1.95, [M]^þ), 331 (1.86, [M – C₄H₈]^þ),

314 (2, [M – C₄H₉O]^þ), 308 (3.8, [M – Br]^þ), 286 (9, [M –

C₅H₉O₂]^þ), 252 (100, [M – C₄H₈Br]^þ), 213 (40, [C₈H₆BrO₂]^þ),

57 (90, [C₄H₉]^þ); HRMS (80 eV, 1208C): calcd. for C₁₅H₁₈

NO₆⁷⁹Br: 387.03174; found: 387.03421.

N-tert-Butyloxycarbonyl-N-(2-

bromopiperonyl)aminoacetyl Fluoride (13b)

Reaction with acid 12b (1.80 g, 4.65 mmol) following the stand-

ard procedure, work-up method B to afford 13b as a pale yel-

1

low oil; yield: 1.80 g (99.5%); H NMR (270 MHz, CDCl₃):

d¼1.40 [2ꢁs, 9H, C(CH₃)₃], 3.95–4.12 (2ꢁd, 2H,

³J[¹H,¹⁹F]¼2.94 Hz, CH₂COF), 4.50 (2ꢁs, 2H, NCH₂Ar),

5.92 (s, 2H, OCH₂O), 6.70–6.85 (2ꢁs, 1H, NCH₂CCH), 6.95

(2ꢁs, 1H, BrCCH); ¹³C NMR (68 MHz, CDCl₃): d¼28.0,

28.1 [C(CH₃)₃], 45.4 (2ꢁd, ²J[¹³C,¹⁹F]¼68 Hz, CH₂COF),

50.3, 50.9 (NCH₂Ar), 81.7 [C(CH₃)₃], 101.8 (OCH₂O), 109.0,

109,7, 112.5, 112.7, 114.1, 128.8, 147.8, 148.0 (Ph), 154.5

(CON), 157.4 (d, ¹J[¹³C,¹⁹F]¼367 Hz, COF).

Zwitterionic Aza-Claisen Rearrangement (Standard

Procedure)

Under argon N-allylpyrrolidine and Na₂CO₃(3 equivs.) in an-

hydrous CH₂Cl₂were treated with freshly prepared acid fluo-

ride in anhydrous CH₂Cl₂. Then AlMe₃(2 M in heptane) was

injected slowly. A gas was evolved and the mixture darkened

to light brown. The mixture was stirred until no reactant re-

mained according TLC control. Then, MeOH was added drop-

wise and stirring was continued for a further 30 min at 208C.

The polar side products and salts were filtered off by passing

the mixture through a short silica gel column. The filtrate

was concentrated and crude material was purified by column

chromatography and HPLC (if necessary).

Standard Procedure to Generate Carboxylic Acid

Fluorides (for details see Refs.^[3,13]

)

The amino acid (500 mg) in anhydrous CH₂Cl₂(70 mL) at 08C

was treated with pyridine (0.6 equivs.) and cyanuric fluoride

(0.6 equivs.) with stirring. The mixture was stirred at 08C for

about 1.5 h (TLC monitoring: 0.5 mL sample of the reaction

mixture was quenched with MeOH and detected on a TLC

plate with n-hexane/ethyl acetate¼1:1).

(R)-2-Chloropent-4-enoic acid [(2S)-

methoxycarbonylpyrrolidinyl]amide (14a)

Work-up method A: Dry pentane (17 mL) was added to

complete the precipitation of polar compounds. The solids

were filtered off to leave a clear solution. The solvents were

carefully removed to give the carboxylic acid fluoride, which

was found to be pure enough for further transformations.

Work-up method B: The mixture was quenched with ice/wa-

ter (50 mL), the aqueous layer was extracted with CH₂Cl₂(3ꢁ

20 mL), the combined organic layers were dried over MgSO₄,

and concentrated to give the amino acid fluoride, which was

immediately used without any further purification.

Reaction of allylamine 1a (500 mg, 2.95 mmol), chloroacetyl

chloride 13c (470 mL, 5.91 mmol, d¼1.418, M_R¼113) and

AlMe₃(3 mL) following the standard procedure. Reaction

temperature ꢀ208C, reaction time 1 hour. Purification via col-

umn chromatography (n-hexane/ethyl acetate¼3:1) to afford

14a as a brown oil; yield: 510 mg (70%); [a]²_D⁰: ꢀ93.78 (c 1.3,

1

CHCl₃); H NMR (500 MHz, CDCl₃): d¼1.78–2.25 (m, 4H,

¼

NCH₂CH₂CH₂), 2.51–2.62 (m, 1H, CHHCH CH₂), 2.72–

¼

2.81 (m, 1H, CHHCH CH₂), 3.46–3.60 (m, 1H, NCHH),

3.65 (2ꢁs, 3H, OCH₃), 3.78–3.85 (m, 1H, NCHH), 4.01, 4.24

(2ꢁd, 1H, J¼7.28 Hz, 5.91 Hz, ClCH), 4.45, 4.62 (2ꢁd, 1H,

J¼9.94 Hz, 3.99 Hz, NCHCO₂CH₃), 5.02–5.14 (m, 2H,

¼

CH CH₂), 5.66–5.79 (2ꢁdddd, 1H, J¼17.18 Hz, 10.17 Hz,

7.14 Hz, 6.88 Hz, CH CH₂); ¹³C NMR (125 MHz, CDCl₃):

¼

N-tert-Butyloxycarbonyl-N-(2,2-

dimethoxyethyl)aminoacetyl Fluoride (13a)

d¼22.2, 24.5 (NCH₂CH₂), 28.8, 30.8 (NCH₂CH₂CH₂), 38.0

¼

(CH₂CH CH₂), 40.7, 54.2 (ClCH), 46.7, 46.8 (NCH₂), 52.1,

¼

Reaction with acid 12a (500 mg, 1.9 mmol) following the stand-

ard procedure, work-up method B to afford 13a as a pale yellow

52.7 (CO₂CH₃), 58.9, 59.0 (NCHCO₂), 118.4, 118.7 (CH CH₂),

), 132.8, 132.9 (CH CH₂), 166.7, 167.1 (CON), 171.8, 172.0

¼

1

oil; yield: 480 mg (94.5%); H NMR (270 MHz, CDCl₃): d¼

(CO₂CH₃); IR (film): 1/l¼3079 (w), 2980 (m), 2954 (m),

2883 (w),1746 (s, COO), 1660 (s, CON), 1436 (s), 1364 (m),

1337 (m), 1282 (m), 1197 (s), 1175 (s), 1118 (w), 1095 (w),

1044 (w), 998 (m), 924 (m) cm^ꢀ1; MS (EI, 80 eV, 408C): m/z

(%)¼245 (10, [M]^þ), 210 (11, [M – Cl]^þ), 186 (75, [M –

C₂H₃O₂]^þ), 150 (6, [M – C₂H₄O₂Cl]^þ), 128 (16, [C₆H₁₀NO₂]^þ),

89 (12, [C₄H₆Cl]^þ), 70 (100, [C₄H₈N]^þ), 41 (12, [C₃H₅]^þ).

HRMS: (80 eV, 408C): calcd. for C₁₁H₁₆O₃N³⁵Cl: 245.08188;

found: 245.08255.

1.35 [2ꢁs, 9H, C(CH₃)₃], 3.25 (2ꢁs, 6H, OCH₃), 3.22–3.30

[m, 2H, NCH₂CH(OCH₃)₂], 4.03 (2ꢁd, 2H, ³J[¹H,¹⁹F]¼

3.42 Hz, CH₂COF), 4.20–4.28 [2ꢁdd, 1H, J¼5.37 Hz,

4.88 Hz, CH(OCH₃)₂]; ¹³C NMR (68 MHz, CDCl₃): d¼27.7,

27.9 [C(CH₃)₃], 47.7 (2ꢁd, ²J[¹³C,¹⁹F]¼68 Hz, CH₂COF),

50.0, 50.3 [CH₂CH(OCH₃)₂], 54.5, 54.6 (OCH₃), 80.8, 81.1

[C(CH₃)₃], 103.9, 104.0 [CH(OCH₃)₂], 154.3, 154.7 (CON),

157.4 (2ꢁd, ¹J[¹³C,¹⁹F]¼374 Hz, COF).

Adv. Synth. Catal. 2004, 346, 1335–1354

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1343

Nong Zhang et al.

FULL PAPERS

1470 (m), 1462 (m), 1434 (s), 1367 (m), 1324 (w), 1258 (m),

1240 (m), 1202 (m), 1192 (m), 1169 (s), 1150 (m), 1085 (s),

1023 (s), 1004 (m), 974 (m), 924 (m), 915 (m) cm^ꢀ1; MS (EI,

80 eV, 908C): m/z (%)¼382 (0.55, [M]^þ), 367 (1.63, [M –

CH₃]^þ), 325 (100, [M – C₄H₉]^þ), 258 (12, [C₁₂H₂₄NO₃Si]^þ);

HRMS (80 eV, 908C): calcd. for C₁₇H₃₀N₄O₄Si: 382.203634;

found: 382.20578; calcd. for C₁₆H₂₇N₄O₄Si ([M – CH₃]^þ):

367.180159; found: 367.18466; calcd. for C₁₃H₂₁N₄O₄Si ([M –

C₄H₉]^þ): 325.133209; found: 325.13534.

(R)-2-Azido-4-(tert-

butyldimethylsilyloxymethyl)pent-4-enoic Acid [(2S)-

Methoxycarbonylpyrrolidinyl]amide (14b)

Reaction of N-allylproline methyl ester 1b (1 g, 3.19 mmol)

and azidoacetyl fluoride 13d (1 g, 9.9 mmol, prepared from azi-

doacetic acid following the standard fluorination procedure,

work-up method A)^[3]following the standard procedure. Reac-

tion temperature 08C, reaction time 3 h. Purification via col-

umn chromatography (n-hexane/ethyl acetate, 3:1) to afford

14b as a yellow oil; yield: 1.0 g (79%); [a]²_D⁰: ꢀ75.58 (c 2.1,

CHCl₃); ¹H NMR (270 MHz, CDCl₃): d¼0.01 [s, 6H,

Si(CH₃)₂], 0.85 [s, 9H, C(CH₃)₃], 1.65–2.24 (m, 4H, CH₂CH₂),

2.46–2.68 (m, 2H, N₃CHCH₂), 3.45–3.78 (m, 5H, OCH₃,

NCH₂CH₂), 3.85–3.94 (m, 1H, NCHCOO), 4.03–4.22 (m,

2H, TBSOCH₂), 4.40–4.57 (m, 1H, N₃CH), 4.99 (2ꢁs, 1H,

(3S,6R)-6-Allyl-3,4-(2-tert-

butyldimethylsilyloxyl)propylidene-1,4-piperazine-2,5-

dione (15)

Azidopentenoic acid amide 14c (110 mg, 0.28 mmol) in THF

(20 mL) was treated with PPh₃(91 mg, 0.34 mmol) and H₂O

(1 mL). The mixture was stirred at 208C for 16 hours. H₂O

(10 mL) was added and the aqueous layer was extracted with

Et₂O (4ꢁ15 mL). The combined organic layers were dried

over MgSO₄. After removal of the solvent, the crude material

was purified by column chromatography (ethyl acetate) to give

piperazine 15 as colourless crystals; yield: 80 mg (85%); mp

139–1408C; [a]_D²⁰: ꢀ48.18 (c 0.6, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): d¼0.00 [s, 6H, Si(CH₃)₂], 0.80 [s, 9H,

SiC(CH₃)₃], 1.87–1.95 (ddd, 1H, J¼12.51 Hz, 12.09 Hz,

4.12 Hz, CHHCHOTBS), 2.23–2.30 (dd, 1H, J¼12.93 Hz,

C CHH), 5.15 (2ꢁs, 1H, C CHH); ¹³C NMR (68 MHz,

CDCl₃): d¼ ꢀ5.4 [Si(CH₃)₂], 18.2 [SiC(CH₃)₃], 23.1, 24.6

(CH₂CH₂), 25.8 [SiC(CH₃)₃], 28.9, 29.3 (CH₂CH₂), 33.7

(N₃CHCH₂), 46.8 (NCH₂CH₂), 52.1, 51.2 (OCH₃), 57.9, 58.3

(NCHCOO), 58.7, 58.9 (N₃CH), 65.3, 66.0 (TBSOCH₂),

¼

112.2, 113.2 (C CH₂), 143.2 (C CH₂), 168.7, 172.0 (COOCH₃);

IR (CHCl₃): 1/l¼3079 (w), 2955 (s), 2930 (s), 2885 (m), 2857

(s), 2106 (s, N₃), 1747 (s, COO), 1658 (s, CON), 1472 (m),

1435 (s), 1389 (m), 1362 (m), 1343 (m), 1252 (s), 1197 (s),

1176 (s), 1112 (m), 1006 (m), 939 (w), 908 (m) cm^ꢀ1; MS (EI,

80 eV, 808C): m/z (%)¼396 (0.67, [M]^þ), 381 (0.91, [M –

CH₃]^þ), 354 (5.9, [M – N₃]^þ), 339 (44, [M – CH₃N₃]^þ), 223

(100, [M – C₆H₁₅N₃OSi]^þ), 128 (58, [C₆H₁₀NO₂]^þ); HRMS

(80 eV, 808C): calcd. for C₁₈H₃₂N₄O₄Si: 396.21928; found:

396.21969.

¼

5.91 Hz, CHHCHOTBS), 2.47–2.61 (m, 2H, CH₂CH CH₂),

3.37 (d, 1H, J¼12.92 Hz, NCHHCHOTBS), 3.73–3.75 (dd,

1H, J¼12.93 Hz, 4.54 Hz, NCHHCHOTBS), 3.93–3.99 (m,

1H, NHCH), 4.36–4.45 (m, 2H, NHCOCH, CHOTBS),

¼

5.14–5.23 (m, 2H, CH CH₂), 5.72–5.83 (dddd, 1H, J¼

¼

17.32 Hz, 10.17 Hz, 7.44 Hz, 7.15 Hz, CH CH₂), 7.30 (br, s,

1H, NH); ¹³C NMR (125 MHz, CDCl₃): d¼ ꢀ5.0, ꢀ4.8

(R)-2-Azidopent-4-enoic Acid [(2S)-

Methoxycarbonyl-(4R)-tert-

butyldimethylsilyloxypyrrolidinyl]amide (14c)

[Si(CH₃)₂], 17.8 [SiC(CH₃)₃], 25.6 [SiC(CH₃)₃], 38.7

¼

(CH₂CHOTBS), 38.9 (CH₂CH CH₂), 55.2 (NCH₂), 56.5

(CHOTBS), 57.4 (NHCH), 68.2 (NHCOCH), 120.2

¼

(CH CH₂), 131.7 (CH CH₂), 165.2 (NCO), 169.8 (NHCO);

IR (film): 1/l¼3213 (m), 3165 (w), 3122 (w, NH), 2956 (m),

2928 (m), 2889 (w), 2856 (m), 1680 (s, CONH), 1646 (s,

CON), 1498 (w), 1471 (m), 1461 (m), 1439 (m), 1419 (m),

1376 (m), 1361 (w), 1328 (w), 1308 (m), 1285 (w), 1256 (m),

1210 (w), 1161 (w), 1142 (w), 1109 (m), 1086 (m), 1026 (m),

1006 (m), 940 (w), 917 (m) cm^ꢀ1; MS (EI, 80 eV, 1608C): m/z

(%)¼324 (0.17, [M]^þ), 309 (5, [M – CH₃]^þ), 267 (100, [M –

C₄H₉]^þ), 239 (67, [M – C₆H₁₃]^þ); HRMS (80 eV, 1608C): calcd.

for C₁₂H₁₉N₂O₃Si ([M – C₄H₉]^þ): 267.11649; found: 267.11733.

Reactionof allylamine 1d(500 mg, 1.67 mmol) and azidoacetyl

fluoride 13d (506 mg, 5.01 mmol, prepared from azidoacetic

acid following the standard fluorination procedure, work-up

method A)^[3]following the general procedure. Reaction tem-

perature 08C, reaction time 3 hours. Purification via column

chromatography (n-hexane/ethyl acetate, 3:1) to afford 14c

as colourless crystals; yield: 480 mg (75%); mp 678C; [a]²_D⁰:

1

ꢀ115.48 (c 0.5, CHCl₃); H NMR (270 MHz, CDCl₃): d¼0.00

[s, 6H, Si(CH₃)₂], 0.85 [s, 9H, SiC(CH₃)₃], 1.95–2.06 (ddd, 1H,

J¼13.19 Hz, 12.69 Hz, 2.99 Hz, CHHCHCO₂CH₃), 2.12–

2.21 (m, 1H, CHHCH-CO₂CH₃), 2.47–2.67 (ddd, 2H, J¼

¼

14.65 Hz, 14.16 Hz, 3.17 Hz, CH₂CH CH₂), 3.32–3.42 8 (dd,

1H, J¼10.25 Hz, 1.46 Hz, NCHH), 3.60–3.80 (m, 5H, OCH₃,

NCHH, N₃CH), 4.45–4.55 (m, 1H, TBSOCH), 4.50–4.57

(dd, 1H, J¼11.72 Hz, 7.82 Hz, NCHCO₂CH₃), 5.07–5.17 (dd,

(S)-2-Azidopent-4-enoic Acid [(2S)-

methoxycarbonylpyrrolidinyl]amide (16)

¼

1H, J¼10.25 Hz, 1.47 Hz, CH CHH), 5.17–5.22 (dd, 1H,

The chloroamide 14a (500 mg, 2.04 mmol) in DMF (50 mL)

was treated with NaN₃(600 mg, 9.23 mmol). The mixture was

stirred at room temperature for 16 hours. H₂O (20 mL) was

added and the aqueous layer was extracted with Et₂O (4ꢁ

10 mL), and the combined organic layers were dried over

MgSO₄. After removal of the solvent, the crude product was

purified by column chromatography (n-hexane / ethyl acetate,

1:1) to give 16 as a yellow oil; yield: 500 mg (97%); [a]²_D⁰:

ꢀ26.88 (c 1.4, CHCl₃); ¹H NMR (270 MHz, CDCl₃): d¼1.78–

2.01 (m, 3H, NCH₂CHHCH₂), 2.01–2.20 (m, 1H, NCH₂

¼

J¼17.09 Hz, 1.47 Hz, CH CHH), 5.70–5.87 (dddd, 1H, J¼

17.09 Hz, 10.25 Hz, 7.32 Hz, 6.84 Hz, CH CH₂); ¹³C NMR

¼

(68 MHz, CDCl₃): d¼ ꢀ5.0, ꢀ4.8 [Si(CH₃)₂], 18.2

¼

[SiC(CH₃)₃], 25.5 [SiC(CH₃)₃], 34.8 (CH₂CH CH₂), 37.8, 40.0

(CH₂CHCO₂CH₃), 52.3 (OCH₃), 55.2 (NCH₂), 58.8 (N₃CH),

59.6 (NCHCO₂CH₃), 70.5 (TBSOCH), 118.9 (CH CH₂),

¼

132.3, 132.4 (CH CH₂), 168.1 (CON), 172.1 (COOCH₃); IR

(CHCl₃): 1/l¼3087 (w), 2992 (w), 2953 (m), 2928 (m), 2893

(w), 2856 (m), 2122 (s, N₃), 1765 (s, COO), 1647 (s, CON),

1344

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

¼

CHH), 2.45–2.66 (m, 2H, CH₂CH CH₂), 3.31–3.55 (m, 2H, N₃

CH, NCHH), 3.60 (s, 3H, CO₂CH₃), 3.60–3.69 (m, 1H,

NCHH), 4.41–4.48 (m, 1H, NCHCO₂CH₃), 5.02–5.11 (d,

(2R)-2-[(N-tert-Butyloxycarbonyl)-N-(2,2-

dimethoxyethyl)]aminopent-4-enoic Acid [(2S)-tert-

Butyldimethylsilyloxymethylpyrrolidinyl]amide (18a)

¼

1H, J¼10.74 Hz, CH CHH), 5.10–5.21 (d, 1H, J¼17.09 Hz,

Reaction of N-allylamine 1a (500 mg, 1.96 mmol) and acid flu-

oride 13a (1.0 g, 3.77 mmol) following the standard procedure.

Reaction temperature 08C, reaction time 16 hours. After

quenchingwith methanol, the mixture was filtered. The solvent

was removed under vacuum. If necessary, reintroduction of the

BOC protecting group as follows. The residue was dissolved in

THF (30 mL). Di-tert-butyl dicarbonate (2 mmol) was added

and the mixture was stirred at room temperature for 16 hours.

H₂O (20 mL) was added and the aqueous layer was extracted

with Et₂O (4ꢁ20 mL). The combined organic layers were

dried over MgSO₄. After removal of the solvent, the crude ma-

terial was purified by column chromatography (n-hexane/ethyl

acetate, 1:1) to give 18a as a yellow oil; yield: 710 mg (72%);

¼

CH CHH), 5.58–5.86 (2ꢁdddd, 1H, J¼17.09 Hz, 10.25 Hz,

7.32 Hz, 6.84 Hz, CH CH₂); ¹³C NMR (68 MHz, CDCl₃): d¼

¼

21.9, 24.6 (NCH₂CH₂), 28.7, 31.0 (NCH₂CH₂CH₂), 34.9, 35.5

¼

(CH₂CH CH₂), 46.6, 46.7 (NCH₂), 52.0, 52.7 (CO₂CH₃), 58.7,

58.8 (NCHCO₂CH₃), 59.1, 59.3 (N₃CH), 118.8, 118.9

¼

(CH CH₂), 132.2 (CH CH₂), 168.3 (CON), 171.9 (CO₂CH₃);

IR (film): 1/l¼3078 (w), 2979 (m), 2881 (m), 2841 (w), 2101

(s, N₃), 1746 (s, COO), 1657 (s, CON), 1435 (s), 1363 (m),

1340 (m), 1324 (m), 1280 (m), 1197 (s), 1175 (s), 1119 (w),

1095 (m), 1044 (w), 999 (m) cm^ꢀ1; MS (EI, 80 eV, 608C): m/z

(%)¼252 (1, [M]^þ), 224 (1, [M – N₂]^þ), 221 (1, [M – CH₃O]^þ),

210 (3, [M – N₃]^þ), 193 (6, [M – C₂H₃O₂]^þ), 165 (8, [M –

C₂H₃O₂N₂]^þ), 137 (20, [M

–

C₃H₅O₂N₃]^þ),128 (100,

1

[a]²_D⁰: þ14.98 (c 1.4, CHCl₃); H NMR (500 MHz, CDCl₃):

[C₆H₁₀NO₂]^þ), 68 (37, [C₄H₆N]^þ), 41 (36, [C₃H₅]^þ); HRMS:

(80 eV, 608C): calcd. for C₁₁H₁₆N₄O₃: 252.12224; found:

252.12422.

d¼0.00 [s, 6H, Si(CH₃)₂], 0.80 [s, 9H, SiC(CH₃)₃], 1.40 [s, 9H,

NCOOC(CH₃)₃], 1.71–2.05 (m, 4H, NCH₂CH₂CH₂), 2.36–

¼

2.49 (m, 1H, CHHCH CH₂), 2.49–2.57 (m, 1H,

¼

CHHCH CH₂), 3.08–3.81 [m, 12H, CH₂OSi, CH(OCH₃)₂,

NCH₂CH₂, NCH₂CH(OCH₃)₂], 4.02–4.18 (m, 1H,

NCHCH₂OSi), 4.38–4.58 [m, 1H, CH(OCH₃)₂], 4.60–4.67

(3S,6S)-6-Allyl-3,4-propylidene-1,4-piperazine-2,5-

dione (17)

¼

and 4.83–4.91 (2ꢁm, 1H, CHCH₂CH CH₂), 4.94–5.02 (d,

¼

1H, J¼10.04 Hz, CH CHH), 5.03–5.10 (d, 1H, J¼17.18 Hz,

Azidopentenoic acid amide 16 (200 mg, 0.79 mmol) in THF

(20 mL) was treated with PPh₃(230 mg, 0.87 mmol) and H₂O

(1 mL). The mixture was stirred at 208C for 16 hours. H₂O

(20 mL) was added and the aqueous layer was extracted with

CH₂Cl₂(4ꢁ15 mL). The combined organic layers were dried

over MgSO₄. After removal of the solvent, the crude material

was purified by column chromatography (n-hexane/ethyl ace-

tate,1:2) to give piperazinedione 17 as a pale yellow oil; yield.

140 mg (91%); [a]_D²⁰: ꢀ108.88 (c 1.5, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): d¼1.77–1.90 (m, 1H, NCH₂CHH),

1.90–2.07 (m, 2H, NCH₂CHH, NCH₂CH₂CHH), 2.22–2.32

CH CHH), 5.62–5.77 (m, 1H, CH CH₂); ¹³C NMR

(125 MHz, CDCl₃): d¼ ꢀ5.5 [Si(CH₃)₂], 18.0 [SiC(CH₃)₃],

24.1 (NCHCH₂CH₂), 25.8 [SiC(CH₃)₃], 26.5 (NCHCH₂CH₂),

¼

28.2 [NCOOC(CH₃)₃), 34.4 (CH₂CH CH₂), 44.6, 45.6

[NCH₂CH(OCH₃)₂], 46.8 (CH₂OSi), 53.3, 53.7 [CH(OCH₃)₂],

¼

53.9 (CHCH₂CH CH₂), 58.7 (NCHCH₂OSi), 62.3, 65.0

(CH₂OSi), 80.2 [NCOOC(CH₃)₃], 103.1 [CH(OCH₃)₂], 117.0

¼

(CH CH₂), 134.4, 134.7 (CH CH₂), 154.9, 155.7

[NCOOC(CH₃)₃], 176.5 (CON); IR (film): 1/l¼3076 (w),

2954 (s), 2930 (s), 2884 (m), 2758 (m), 1695 (s, OCON), 1648

(s, CON), 1471 (m), 1438 (m), 1402 (m), 1390 (m), 1366 (m),

1348 (w), 1308 (w), 1253 (m), 1168 (m), 1125 (s), 1079 (m),

1025 (w), 996 (w), 977 (w) cm^ꢀ1; MS (EI, 80 eV, 908C): m/z

(%)¼500 (3, [M]^þ), 485 (10, [M – CH₃]^þ), 468 (5, [M –

CH₄O]^þ), 443 (16, [M – C₄H₉]^þ), 429 (8, [M – C₅H₁₁]^þ), 413

(13, [M – C₅H₁₁O]^þ), 369 (23, [M – C₆H₁₁O₃]^þ), 355 (78, [M –

C₇H₁₇OSi]^þ), 299 (17, [M – C₁₁H₂₅OSi]^þ); HRMS: (80 eV,

908C): calcd. for C₂₅H₄₈N₂O₆Si: 500.32816; found: 500.32655.

¼

(m, 1H, NCH₂CH₂CHH), 2.35–2.44 (m, 1H, CHHCH CH₂),

¼

2.77–2.85 (m, 1H, CHHCH CH₂), 3.43–3.58 (m, 2H,

NCH₂), 3.97–4.02 (dd, 1H, J¼8.39 Hz, 3.30 Hz,

¼

CHCH₂CH CH₂), 4.02–4.09 (dd, 1H, J¼8.94 Hz, 7.56 Hz,

¼

NCHCO), 5.08–5.17 (m, 2H, CH CH₂), 5.66–5.76

(m, 1H, CH CH₂); ¹³C NMR (125 MHz, CDCl₃): d¼22.3,

¼

(NCH₂CH₂), 27.9 (NCH₂CH₂CH₂), 34.4 (CH₂CH CH₂), 45.1

¼

(NCH₂), 53.9 (CHCH₂CH CH₂), 58.8 (NCHCO), 119.5

¼

(CH CH₂), 132.8 (CH CH₂), 164.9 (NCO), 169.7 (NHCO);

IR (film): 1/l¼3480 (br, m, NH), 3234 (br, m, NH), 3079

(m), 2982 (m), 2954 (m), 2882 (m), 1668 (s, CONH, CON),

1558 (w), 1540 (w), 1429 (s), 1339 (m), 1305 (m), 1276 (m),

1212 (w), 1231 (w), 1212 (w), 1162 (w), 1146 (w), 1119 (w),

1002 (m), 922 (m) cm^ꢀ1; MS (pos. FAB): m/z (%)¼195 (100,

[MþH]^þ), 194 (18, [M]^þ), 193 (22, [M – H]^þ), 153 (13,

[M – C₃H₅]^þ), 125 (25, [M – C₄H₇N]^þ), 69 (96, [C₄H₇N]^þ), 42

(29, [C₃H₆]^þ); MS (EI, 80 eV, 408C): m/z (%)¼194 (56, [M]^þ

), 153 (18, [M –C₃H₅]^þ), 125 (50, [C₆H₇NO₂]^þ), 70(100,

[C₄H₈N]^þ), 41 (38, [C₃H₅]^þ); HRMS (80 eV, 408C): calcd. for

C₁₀H₁₄N₂O₂: 194.10553; found: 194.10633.

(2R)-2-[N-(2-Bromo-4,5-

methylenedioxyphenyl)methyl]-N-(tert-

butyloxycarbonyl)-aminopent-4-enoic Acid [(2S)-tert-

butyldimethylsilyloxymethyl-pyrrolidinyl]amide (18b)

Reaction of N-allylamine 2b (1.0 g, 4.33 mmol) and acid fluo-

ride 13b (2.5 g, 8.66 mmol) following the standard procedure.

Reaction temperature 08C, reaction time 20 hours. If necessary

reintroduction of the BOC protecting group. The crude mate-

rial was dissolved in CH₂Cl₂(30 mL). Et₃N (1.2 mL) and di-

tert-butyl dicarbonate (4.5 mmol) were added. The mixture

was stirred for 3 hours. H₂O (20 mL) was added and the aque-

ous layer was extracted with CH₂Cl₂(3ꢁ20 mL), and the com-

bined organic layers were dried over MgSO₄. After removal of

the solvent, the crude material was purified by column chroma-

tography (n-hexane/ethyl acetate, 6:1) to give 18b as a pale yel-

Adv. Synth. Catal. 2004, 346, 1335–1354

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Nong Zhang et al.

FULL PAPERS

low oil; yield: 1.79 g (82%); [a]²_D⁰: þ12.58 (c 1.6, CHCl₃);

¹H NMR (270 MHz, CDCl₃): d¼0.00 [s, 6H, Si(CH₃)₂], 0.85

[s, 9H, SiC(CH₃)₃], 1.40, 1.50 [2ꢁs, 9H, OC(CH₃)₃], 1.55–

2.02 (m, 4H, CH₂CH₂), 2.30–2.45 (ddd, 1H, J¼14.71 Hz,

2858 (s), 1812 (w), 1682 (s, OCON), 1642 (s, CON), 1504 (s),

1480 (s), 1452 (s), 1412 (s), 1368 (s), 1340 (m), 1313 (m), 1216

(s), 1161 (s), 1105 (s), 1041 (s), 999 (m) cm^ꢀ1; MS (EI, 80 eV,

1408C): m/z (%)¼624 (16, [M]^þ), 567 (11, [M – C₄H₉]^þ), 523

(13, [M – C₅H₉O₂]^þ), 511 (30, [M – C₆H₁₅Si]^þ), 297 (100, [M

– C₁₄H₂₀O₂BrSi]^þ), 213 (97, [C₈H₆O₂Br]^þ), 70 (25, [C₄H₈N]^þ),

57 (15, [C₄H₉]^þ). HRMS (80 eV, 1408C): calcd. for

C₂₉H₄₅N₂O₆Si⁷⁹Br: 624.22302; found: 624.22564.

¼

7.36 Hz, 7.35 Hz, CHHCH CH₂), 2.46–2.66 (dd, 1H, J¼

¼

13.97 Hz, 7.35 Hz, CHHCH CH₂), 2.88, 3.13 (2ꢁm, 1H,

NCHHCH₂), 3.40–3.69 (m, 3H, NCHHCH₂, OCH₂), 4.05 (m,

1H, NCHCH₂), 4.20–4.56 (m, 2H, ArCH₂), 4.97–5.25 (m,

¼

3H, BOCNCH, CH CH₂), 5.61–5.81 (m, 1H, CH CH₂), 5.90

(2ꢁs, 2H, OCH₂O), 6.35, 6.55 (2ꢁs, 1H, NCH₂CCH), 6.90

(2ꢁs, 1H, BrCCH); ¹³C NMR (68 MHz, CDCl₃): d¼ ꢀ5.5

[Si(CH₃)₂], 18.0, 18.2 [SiC(CH₃)₃], 23.8 (CH₂CH₂), 25.8, 25.9

[SiC(CH₃)₃], 26.5, 27.3 (CH₂CH₂), 28.0, 28.2 [OC(CH₃)₃], 34.2

(R)-2-Chloropent-4-enoic Acid [(2S)-tert-

Butyldimethylsilyloxymethylpyrrolidinyl]amide (18c)

¼

(CH₂CH CH₂), 46.8, 47.1 (NCH₂CH₂), 55.6 (NCH), 58.1

(NCHCH₂OTBS), 58.6 (TBSOCH₂), 61.6 (NCH₂Ar), 80.5

(OC(CH₃)₃), 101.4 (OCH₂O), 107.0, 118.0, 133.8, 146.6 (Ar),

Reaction of allylamine 2a (500 mg, 1.96 mmol), chloroacetyl

chloride 13c (310 mL, 3.89 mmol, d¼1.418, M_R¼113) and

AlMe₃(2 mL) following the standard procedure. Reaction

temperature ꢀ208C, reaction time 1 hour. Purification via col-

umn chromatography (n-hexane/ethyl acetate, 7:1) to afford

18c as a pale yellow oil; yield: 450 mg (69%); [a]²_D⁰: ꢀ72.58 (c

3.0, CHCl₃); ¹H-NMR (270 MHz, CDCl₃): d¼0.00 [s, 6H,

Si(CH₃)₂], 0.70 [s, 9H, SiC(CH₃)₃], 1.68–2.10 (m, 4H,

¼

112.4 (CH CH₂), 133.9 (CH CH₂), 155.6 (OCON), 168.6

(CON); IR (film): 1/l¼3077 (w), 2954 (s), 2929 (s), 2883 (s),

2857 (s), 1694 (s, OCON), 1649 (s, CON), 1503 (s), 1480 (s),

1449 (s), 1412 (s), 1400 (s), 1391 (s), 1367 (s), 1342 (m), 1310

(s), 1252 (s), 1163 (s), 1102 (s), 1038 (s), 996 (m), 963 (m)

cm^ꢀ1; MS (EI, 80 eV, 1608C): m/z (%)¼624 (8.8, [M]^þ), 568

(8.2, [M – C₄H₈]^þ), 523 (7.4, [M – C₅H₉O₂]^þ), 511 (17,

[M – C₆H₁₅Si]^þ), 489 (6.4, [M – C₄H₈Br]^þ), 445 (8.6,

[M – C₅H₈O₂Br]^þ), 297 (93, [M – C₁₄H₂₀O₂BrSi]^þ), 213 (90,

[C₈H₆O₂Br]^þ), 70 (100, [C₄H₈N]^þ), 57 (85, [C₄H₉]^þ); HRMS:

(80 eV, 1608C): calcd. for C₂₉H₄₅N₂O₆Si⁷⁹Br: 624.22302; found:

624.22631.

¼

NCH₂CH₂CH₂), 2.49–2.71 (m, 2H, CH₂CH CH₂), 3.29–3.50

(m, 2H, NCH₂), 3.50–3.71 (m, 2H, OCH₂), 4.01–4.18 (m, 1H,

NCH), 4.18–4.23, 4.50–4.62 (2ꢁm, 1H, ClCH), 5.01–5.15

(m, 2H, CH CH₂), 5.64–5.81 (m, 1H, CH CH₂); ¹³C NMR

(68 MHz, CDCl₃): d¼ ꢀ5.5, ꢀ5.6 [Si(CH₃)₂], 17.9, 18.2

[SiC(CH₃)₃], 21.7, 24.0 (NCH₂CH₂CH₂), 25.6, 25.7

[SiC(CH₃)₃], 26.7, 27.8 (NCH₂CH₂CH₂), 38.0, 38.1

¼

(CH₂CH CH₂), 45.7, 47.1 (NCH₂), 54.5, 54.6 (NCH), 58.5,

58.7 (NCHCH₂OTBS), 61.8, 65.2 (ClCH), 118.4 (CH CH₂),

¼

133.2 (CH CH₂), 166.6, 167.3 (CON); IR (film): 1/l¼3080

(2S)-2-[N-(2-Bromo-4,5-

(w), 2954 (s), 2929 (s), 2883 (m), 2856 (m), 1652 (s, CON),

1576 (w), 1558 (w), 1539 (w), 1521 (w), 1471 (m), 1436 (s),

1386 (w), 1360 (w), 1340 (w), 1254 (m), 1189 (w), 1165 (w),

1102 (m), 1054 (m), 997 (m), 920 (m), 836 (s, CCl) cm^ꢀ1; MS

(EI, 80 eV, 708C): m/z (%)¼331 (0.62, [M]^þ), 316 (3, [M –

CH₃]^þ), 296 (1, [M – Cl]^þ), 274 (100, [M – C₄H₉]^þ), 186 (19,

[M – C₇H₁₇OSi]^þ), 70 (53, [C₄H₈N]^þ); HRMS: (80 eV, 708C):

calcd. for C₁₆H₃₀NO₂Si³⁵Cl: 331.17343; found: 331.17466; calcd.

methylenedioxyphenyl)methyl]-N-(tert-

butyloxycarbonyl)-aminopent-4-enoic Acid [(2S)-tert-

Butyldimethylsilyloxymethyl-pyrrolidinyl]amide (epi-

18b)

Amide 18b (250 mg) was dissolved in DMF (10 mL) and treat-

ed with Na₂CO₃(5 equivs.). The reaction mixture was refluxed

for 20 h. After cooling to room temperature, H₂O was added

and the aqueous layer was extracted with Et₂O. The combined

organic layers were dried over MgSO₄. After removal of the

solvent, the diastereomers were separated by means of

HPLC: (20% ethyl acetate/n-hexane, Nucleosil 50–5, 32ꢁ

110 mm, flow 64 mL/min, retention time: t_epi-18b¼6.86 min,

t_18b¼8.09 min ); yield: 90 mg 18b (36%) and 140 mg epi-18b

(56%). Data of amide epi-18b: [a]²_D⁰: ꢀ52.88 (c 1.6, CHCl₃);

¹H NMR (500 MHz, CDCl₃): d¼0.00 [s, 6H, Si(CH₃)₂], 0.80

[s, 9H, SiC(CH₃)₃], 1.30 [s, 9H, OC(CH₃)₃], 1.70–2.15 (m, 4H,

for C₁₅H₂₇NO₂Si³⁵Cl ([M

–

CH₃]^þ): 316.14996; found:

316.14866; calcd. for C₁₂H₂₁NO₂Si³⁵Cl ([M

274.10300; found: 274.10288.

–

C₄H₉]^þ):

(R)-2-Azidopent-4-enoic Acid [(2S)-tert-

Butyldiphenylsilyloxymethylpyrrolidinyl]amide (18d)

Reactionof allylamine 2b(540 mg, 1.42 mmol) and azidoacetyl

fluoride 13d (510 mg, 4.95 mmol, prepared from azidoacetic

acid following the standard fluorination procedure, work-up

method A)^[3]following the standard procedure. Reaction tem-

perature 08C, reaction time 3 hours. Purification via column

chromatography (n-hexane/ethyl acetate, 5:1) to afford 18d

as a yellow oil; yield: 500 mg (76%); [a]²_D⁰: ꢀ49.18 (c 1.9,

CHCl₃); ¹H NMR (270 MHz, CDCl₃): d¼1.05 [s, 9H,

SiC(CH₃)₃], 1.80–2.20 (m, 4H, CH₂CH₂), 2.4–2.7 (2ꢁm, 1H,

¼

CH₂CH₂), 2.35–2.58 (m, 2H, CH₂CH CH₂), 3.36–3.62 (m,

2H, NCHHCH₂, OCHH), 3.62–3.81 (m, 2H, NCHHCH₂,

OCHH), 3.90 (m, 1H, BOCNCH), 4.35 (d, 1H, J¼16.92 Hz,

NCHHAr), 4.51 (d, 1H, J¼16.92 Hz, NCHHAr), 4.96–5.15

¼

(m, 3H, NCH, CH CH₂), 5.60–5.77 (m, 1H, CH CH₂), 5.90

(s, 2H, OCH₂O), 6.50 (s, 1H, Ar-H), 6.90 (s, 1H, Ar-H);

¹³C NMR (125 MHz, CDCl₃): d¼ ꢀ5.5 [Si(CH₃)₂], 18.0

[SiC(CH₃)₃], 22.1, 24.5 (CH₂CH₂), 25.7 [SiC(CH₃)₃], 26.8, 27.3

(CH₂CH₂), 28.0 [OC(CH₃)₃], 31.5 (NCHCH₂OTBS), 34.3

¼

NCHHCH₂), 3.35–3.50 (m, 2H, CH₂CH CH₂), 3.50–3.60

¼

(CH₂CH CH₂), 46.9, 47.4 (NCH₂CH₂), 55.2 (NCH), 58.6

(m, 1H, NCHHCH₂), 3.70–3.82 (m, 2H, NCH, OCHH),

3.83–3.95 (m, 1H, OCHH), 4.20–4.36 (m, 1H, N₃CH), 5.12–

(TBSOCH₂), 62.4 (NCH₂Ar), 80.5 [OC(CH₃)₃], 101.4

¼

5.19 (2ꢁd, 1H, J¼11.23 Hz, CH CHH), 5.20–5.29 (2ꢁd,

(OCH₂O), 106.7, 118.1, 132.1, 147.1 (Ar), 112.3 (CH CH₂),

¼

133.5 (CH CH₂), 155.6 (OCON), 168.6 (CON); IR (CHCl₃):

1H, J¼17.09 Hz, CH CHH), 5.73–5.90 (2ꢁdddd, 1H, J¼

17.09 Hz, 11.23 Hz, 7.32 Hz, 6.84 Hz, CH CH₂); ¹³C NMR

¼

1/l¼3070 (w), 3017 (s), 2976 (s), 2956 (s), 2930 (s), 2885 (s),

1346

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

asc.wiley-vch.de

Adv. Synth. Catal. 2004, 346, 1335–1354

Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

(68 MHz, CDCl₃): d¼19.0, 19.1 [SiC(CH₃)₃], 21.4, 24.1

(CH₂CH₂), 26.7, 26.9 [SiC(CH₃)₃], 27.9 (CH₂CH₂), 34.6, 34.8

(CH₂CH CH₂), 45.8, 47.2 (NCH₂CH₂), 58.3, 58.5 (NCH),

added to the mixture, the aqueous layer was extracted with

Et₂O (4ꢁ10 mL), and the combined organic layers were dried

over MgSO₄. After removal of the solvent, the crude material

was purified by column chromatography (n-hexane/ethyl ace-

tate, 5:1) to give 20 as a yellow oil; yield: 110 mg (41.5%); [a]²_D⁰:

ꢀ4.78 (c 1.3, CHCl₃); ¹H NMR (270 MHz, CDCl₃): d¼1.40 [s,

¼

58.6, 59.4 (N₃CH), 63.2, 64.8 (CH₂O), 118.7 (CH CH₂),

127.5, 129.5, 129.9, 132.0, 132.6, 134.9, 135.4 (Ph), 132.7, 133.3

¼

(CH CH₂), 167.4, 167.7 (CON); IR (film): 1/l¼3070 (m),

¼

3048 (m), 2958 (s), 2930 (s), 2857 (s), 2245 (w), 2100 (N₃),

1827 (w), 1749 (w), 1651 (CON), 1588 (w), 1567 (w), 1471

(m), 1428 (s), 1390 (m), 1360 (m), 1341 (m), 1260 (m), 1235

9H, C(CH₃)₃], 2.30–2.55 (m, 2H, CH₂CHCH₂), 4.12–4.35 (m,

¼

1H, NCHCO), 4.65–5.25 (m, 4H, NCH₂Ar, CH CH₂), 5.62–

¼

5.87 (m, 1H, CH CH₂), 5.98 (s, 2H, OCH₂O), 6.60 (s, 1H, Ar-

(m), 1192 (m), 1164 (w), 1113 (s), 1054 (m), 997 (m) cm^ꢀ1

;

H), 7.35 (s, 1H, Ar-H); ¹³C NMR (68 MHz, CDCl₃): d¼28.2

MS (EI, 80 eV, 1308C): m/z (%)¼462 (0.58, [M]^þ), 447 (0.32,

[M – CH₃]^þ), 434 (0.77, [M – N₂]^þ), 405 (100, [M – C₄H₉]^þ),

377 (8, [M – C₄H₉N₂]^þ), 310 (14, [M – C₁₂H₈]^þ), 280 (11, [M –

C₁₄H₁₄]^þ); HRMS (80 eV, 1308C): calcd. for C₂₆H₃₄N₄O₂Si:

462.24510; found: 462.24298.

[C(CH₃)₃], 34.4 (CH₂CHCH₂), 40.8 (NCHCO), 60.1

¼

(NCH₂Ar), 80.7 [C(CH₃)₃], 101.9 (OCH₂O), 105.3, 106.1, 147.6,

¼

152.7, 154.2 (Ar), 118.3 (CH CH₂), 133.5 (CH CH₂), 192.8

(CO); IR (CHCl₃): 1/l¼3019 (s), 2978 (m), 2900 (w), 1681 (s,

CO), 1619 (m), 1505 (m), 1482 (s), 1412 (s), 1369 (m), 1350

(w), 1316 (m), 1282 (m), 1245 (s), 1215 (s), 1162 (s), 1122 (w),

1041 (m) cm^ꢀ1; MS (EI, 80 eV, 1108C): m/z (%)¼331 (1.26,

[M]^þ), 290 (17, [M – C₃H₅]^þ), 274 (1.59, [M – C₄H₉]^þ), 258

(3, [M – C₄H₉O]^þ), 234 (12, [M – C₇H₁₃]^þ), 190 (62, [M –

C₈H₁₃O]^þ), 57 (100, [C₄H₉]^þ); HRMS (80 eV, 1008C): calcd.

for C₁₈H₂₁NO₅: 331.14197; found: 331.14422.

(S)-2-Azidopent-4-enoic Acid [(2S)-tert-

Butyldimethylsilyloxymethylpyrrolidinyl]amide (19)

Chloroamide 18c (200 mg, 0.60 mmol) in DMF (20 mL) was

treated with NaN₃(200 mg, 3.07 mmol). The mixture was stir-

red at room temperature for 16 hours. H₂O (20 mL) was added

and the aqueous layer was extracted with Et₂O (4ꢁ10 mL),

and the combined organic layers were dried over MgSO₄. After

removal of the solvent, the crude product was purified by col-

umn chromatography (n-hexane/ethyl acetate, 5:1) to give 19

as a yellow oil; yield: 200 mg (99%); [a]²_D⁰: ꢀ4.28 (c 2.1,

CHCl₃); ¹H NMR (270 MHz, CDCl₃): d¼0.00 [s, 6H,

Si(CH₃)₂], 0.85 [s, 9H, SiC(CH₃)₃], 1.72–2.11 (m, 4H, CH₂

(3R,4R)-3-Allyl-N-(2,2-diethoxyethyl)-4-hydroxy-4-

trimethylsilylmethyl-6,7-methylenedioxy-1,2,3,4-

tetrahydroisoquinoline (21) and (3R)-3-Allyl-N-(2,2-

diethoxyethyl)-4-methylene-6,7-methylenedioxy-

1,2,3,4-tetrahydroisoquinoline (22)

Under argon, isoquinolone 6 (250 mg, 0.72 mmol)^[3a]in anhy-

drous THF (10 mL) was cooled to ꢀ788C. Trimethylsilylme-

thyllithium (870 mL, 0.87 mmol, 1 M in heptane) was injected

dropwise. The mixture was stirred at ꢀ788C for 3 hours

(TLC monitoring). Saturated aqueous NH₄Cl (10 mL) was

added to the mixture, the aqueous layer was extracted with

Et₂O (4ꢁ10 mL), and the combined organic layers were dried

over MgSO₄. After removal of the solvent, the crude material

was purified by column chromatography (n-hexane/ethyl ace-

tate, 7:1) to afford carbinol 21 as a yellow oil; yield: 240 mg

¼

CH₂), 2.05 (m, 2H, CH₂CHCH₂), 3.31–3.52 (m, 3H, NCHH,

CHHO, NCHCH₂O), 3.52–3.78 (m, 2H, NCHH, CHHO),

3.78–3.85, 4.08–4.10 (2ꢁm, 1H, N₃CH), 5.11 (d, 1H, J¼

¼

10.26 Hz, CH CHH), 5.18 (dt, 1H, J¼17.08 Hz, 1.47 Hz

¼

CH CHH), 5.75 (dddd, 1H, J¼17.08 Hz, 10.26 Hz, 7.33 Hz,

6.84 Hz, CH CH₂); ¹³C NMR (68 MHz, CDCl₃): d¼ ꢀ5.6

¼

(SiCH₃), 17.9 [SiC(CH₃)₃], 21.5, 24.3 (NCH₂CH₂CH₂), 25.6,

25.7 [SiC(CH₃)₃], 26.7, 28.1 (NCH₂CH₂CH₂), 35.2, 35.6 (CH₂

¼

CH CH₂), 45.7, 47.4 (NCH₂CH₂), 58.6, 58.8 (NCHCH₂O),

¼

1

59.1 (CH₂OTBS), 62.3, 64.5 (N₃CH), 118.7, 118.8 (CH CH₂),

(76.6%). Data of carbinol 21: H NMR (500 MHz, CDCl₃):

¼

132.5 (CH CH₂), 168.9 (NCO); IR (film): 1/l¼3080 (w),

d¼0.00 [s, 9H, Si(CH₃)₃], 1.12 [2ꢁt, 6H, J¼7.35 Hz,

(CH₃CH₂O)₂], 1.35 (d, 1H, J¼4.71 Hz, SiCHH), 1.63 (d, 1H,

J¼5.44 Hz, SiCHH), 1.84 (s, 1H, OH), 2.10–2.19 (m, 1H,

2954 (s), 2929 (s), 2883 (m), 2857 (s), 2099 (s, N₃), 1652 (s,

CON), 1471 (m), 1462 (m), 1429 (s), 1381 (w), 1360 (w), 1319

(w), 1257 (s), 1193 (w), 1165 (w), 1103 (s), 1055 (m), 1004

(m), 956 (w), 919 (m) cm^ꢀ1; MS (EI, 80 eV, 708C): m/z (%)¼

338 (0.36, [M]^þ), 323 (1, [M – CH₃]^þ), 310 (2, [M – N₂]^þ), 281

(100, [M – C₄H₉]^þ), 253 (32, [M – C₄H₆N₃]^þ), 242 (21,

[C₁₂H₂₄NO₂]^þ); HRMS: (80 eV, 708C): calcd. for C₁₅H₂₇N₄O₂Si

([M – CH₃]^þ): 323.19034; found: 323.19111; calcd. for

C₁₆H₃₀N₂O₂Si ([M – N₂]^þ): 310.20764; found: 310.20833; calcd.

for C₁₂H₂₁N₄O₂Si ([M – C₄H₉]^þ): 281.14337; found: 281.14533.

¼

CHHCH CH₂), 2.28–2.36 (m, 1H, CHHCH CH₂), 2.68–

2.75 (dd, 1H, J¼13.24 Hz, 5.15 Hz, NCHHCH), 2.78–2.85

(dd, 1H, J¼13.24 Hz, 5.15 Hz, NCHHCH), 2.99–3.03 (dd,

1H, J¼6.61 Hz, 5.89 Hz, NCH), 3.46–3.57 (m, 2H, CH₃CH₂O),

3.60–3.70 (m, 3H, CH₃CH₂O, NCHHAr), 3.82 (d, 1H,

J¼5.44 Hz, NCHHAr), 4.57 (t, 1H, J¼5.15 Hz, CH(OEt)₂),

¼

4.93–5.05 (m, 2H, CH CH₂), 5.85 (2ꢁs, 2H, OCH₂O), 5.90–

¼

6.00 (m, 1H, CH CH₂), 6.40 (s, 1H, Ar-H), 7.04 (s, 1H, Ar-

H);¹³C NMR (125 MHz, CDCl₃): d¼0.4, 0.6 [Si(CH₃)₃], 15.3

¼

(CH₃CH₂O), 28.8 (CH₂CH CH₂), 34.0 (SiCH₂), 51.2

(NCH₂Ar), 57.7 (NCH₂CH), 61.6, 62.1 (CH₃CH₂O), 67.6

(NCH), 76.7 (HOC), 100.6 (OCH₂O), 100.9 (CH(OEt)₂),

(3R)-3-Allyl-(N-tert-butyloxycarbonyl)-6,7-

methylenedioxy-1,2,3,4-tetrahydro-4-isoquinolone (20)

¼

105.1, 106.8, 126.0, 136.5, 146.1, 146.4 (Ar), 115.7 (CH CH₂),

¼

Under argon, N-piperonylprolinol silyl ether amide 18b

(500 mg, 0.80 mmol) in anhydrous THF (20 mL) was cooled

to ꢀ788C. BuLi (575 mL, 0.92 mmol, 1.6 M in hexane) was in-

jected dropwise. The temperature was raised to ꢀ408C and the

mixture was stirred under these conditions for a further 3 hours

(TLC monitoring). Saturated aqueous NH₄Cl (10 mL) was

138.7 (CH CH₂).

Elimination Method A: Under argon, NaH (14 mg,

0.47 mmol, 80% in mineral oil) in anhydrous THF (10 mL)

was cooled to 08C. Isoquinoline 21 (170 mg, 0.39 mmol) in an-

hydrous THF (10 mL) was added. The mixture was stirred at

08C for 1 hour and then refluxed for a further 3 hours. The mix-

Adv. Synth. Catal. 2004, 346, 1335–1354

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ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

1347

Nong Zhang et al.

FULL PAPERS

¼

ture was cooled to 08C again, saturated aqueous NH₄Cl

(10 mL) was added dropwise. The aqueous layer was extracted

with Et₂O (4ꢁ10 mL), and the combined organic layers were

dried over MgSO₄. After removal of the solvent, the crude ma-

terial was purified by column chromatography (n-hexane/ethyl

acetate, 6:1) to give 22 as a yellow oil; yield: 110 mg (81.5%).

Elimination Method B: Isoquinoline 21 (150 mg, 0.34 mmol)

in dry CHCl₃(10 mL) was treated with acetic acid (5 mL). The

mixture was stirred at 208C for 3 hours (TLC monitoring). Sa-

turated aqueous K₂CO₃was added until the solution reached a

pH of 10. The aqueous layer was extracted with CHCl₃(4ꢁ

10 mL), the combined organic layers were dried over

Na₂SO₄. The solvent was evaporated, and the crude material

was purified by column chromatography (n-hexane/ethyl ace-

tate, 6:1) to give 22 as yellow oil; yield: 100 mg (85%); [a]²_D⁰:

þ31.08 (c 1.7, CHCl₃). Data of olefin 22: ¹H NMR (270 MHz,

CDCl₃): d¼1.20 [2ꢁt, 6H, J¼7.35 Hz, (CH₃CH₂O)₂], 2.06–

12.93 Hz, 6.98 Hz, CHHCH CH₂), 2.98–3.02 (dd, 1H, J¼

6.09 Hz, 5.43 Hz, NCH), 3.40–3.50 (m, 2H, [CH₃CH₂O)₂],

3.56–3.65 [m, 3H, (CH₃CH₂O)₂, NCHHAr], 3.78 (d, 1H, J¼

¼

14.74 Hz, NCHHAr), 4.50 [t, 1H, J 5.04 Hz, CH(OEt)₂],

4.87–4.96 (m, 2H, NCHCH₂CH CH₂), 5.05–5.12 (m, 2H,

HOCCH₂CH CH₂), 5.80 (s, 2H, OCH₂O), 5.80–5.91 (m, 2H,

¼

2ꢁCH CH₂), 6.38 (s, 1H, Ar-H), 6.92 (s, 1H, Ar-H);

¹³C NMR (125 MHz, CDCl₃): d¼15.1, 15.2 [(CH₃CH₂O)₂],

¼

28.3 (NCHCH₂CH CH₂), 47.4 (HOCCH₂CH CH₂), 50.7

(NCH₂Ar), 58.4 [NCH₂CH(OEt)₂], 61.8, 61.9 [(CH₃CH₂O)₂],

64.6 (NCH), 75.3 (HOCAr), 100.6 (OCH₂O), 102.0

[CH(OEt)₂], 105.0, 106.1, 126.9, 133.5, 146.2, 146.3 (Ar),

¼

115.7 (NCHCH₂CH CH₂), 119.0 (HOCCH₂CH CH₂), 134.2

¼

(HOCCH₂CH CH₂), 138.7 (NCHCH₂CH CH₂); IR

(CHCl₃): 1/l¼3019 (s), 2977 (m), 2896 (w), 1637 (w), 1503

(w), 1483 (m), 1433 (w), 1390 (w), 1216 (s), 1127 (w), 1042

(m), 929 (w) cm^ꢀ1; MS (EI, 80 eV, 80–1008C): m/z (%)¼389

(0.4, [M]^þ), 348 (100, [M – C₃H₅]^þ), 307 (53, [M – C₆H₁₀]^þ),

245 (23, [M – C₈H₁₆O₂]^þ), 204 (25, [M – C₁₁H₂₁O₂]^þ), 103

(20, [C₅H₁₁O₂]^þ); HRMS (80 eV, 1008C): calcd. for

C₁₉H₂₆NO₅([M-C₃H₅]^þ): 348.18110; found: 348.18123.

¼

2.20 (m, 1H, CHHCH CH₂), 2.30–2.42 (m, 1H,

¼

CHHCH CH₂), 2.60–2.66 (dd, 2H, J¼5.15 Hz, 4.68 Hz,

NCH₂CH), 3.36–3.44 (dd, 1H, J¼8.09 Hz, 6.62 Hz, NCH),

3.44–3.68 (m, 4H, (CH₃CH₂O)₂), 3.68–3.78 (d, 1H, J¼

6.91 Hz, NCHHAr), 3.96–4.07 (d, 1H, J¼7.65 Hz, NCHHAr),

¼

4.59 (t, 1H, J¼5.15 Hz, CH(OEt)₂), 4.79 (s, 1H, CHH C),

¼

4.91–5.03 (m, 2H, CH CH₂), 5.35 (s, 1H, CHH C), 5.70–

¼

5.90 (m, 1H, CH CH₂), 5.85 (s, 2H, OCH₂O), 6.43 (s, 1H, Ar- Z-(3R)-3-Allyl-4-allylidene-N-(2,2-diethoxyethyl)-6,7-

H), 7.04 (s, 1H, Ar-H); ¹³C NMR (68 MHz, CDCl₃): d¼15.3

methylenedioxy-1,2,3,4-tetrahydroisoquinoline (24)

¼

[(CH₃CH₂O)₂], 35.0 (CH₂CH CH₂), 50.6 (NCH₂CH), 56.7

Under argon, allylisoquinoline 23 (100 mg, 0.25 mmol) in an-

hydrous DMSO (10 mL) was treated with MsCl (35 mg,

0.30 mmol) and t-BuOK (34 mg, 0.30 mmol). The mixture

(NCH₂Ar), 61.9, 62.0 [(CH₃CH₂O)₂], 65.1 (NCH), 100.7

(OCH₂O), 102.6 [CH(OEt)₂], 103.8, 106.0, 125.6, 127.2, 146.6,

¼

147.6 (Ar), 107.8 (CH₂C), 115.8 (CH CH₂), 136.1

was stirred at 208C for 2 days. H₂O (10 mL) and Et₂O

(10 mL) were added. The aqueous layer was extracted with

Et₂O (4ꢁ10 mL), and the combined organic layers were dried

over MgSO₄. After removal of the solvent under vacuum, the

crude material was purified by column chromatography (n-

hexane/ethyl acetate, 5:1) to give butadiene 24 as a brown oil

which easily tended to decompose; yield: 37 mg (38%);

¹H NMR (500 MHz, CDCl₃): d¼1.13 [2ꢁt, 6H, J¼6.83 Hz,

¼

(CH CH₂), 140.1 (CH₂C); IR (CHCl₃): 1/l¼3019 (s), 2977

(m), 2896 (m), 1504 (m), 1482 (s), 1421 (w), 1389 (w) cm^ꢀ1

;

MS (EI, 80 eV, 80–1008C): m/z (%)¼344 (0.1, [M – H]^þ),

304 (100, [M – C₃H₅]^þ), 300 (15, [M – OC₂H₅]^þ), 242 (32, [M

– C₅H₁₁O₂]^þ), 103 (24, [C₅H₁₁O₂]^þ), 75 (25, [C₃H₇O₂]^þ);

HRMS (80 eV, 1008C): calcd. for C₁₇H₂₂NO₄([M – C₃H₅]^þ):

304.15488; found: 304.15643.

¼

(CH₃CH₂O)₂], 2.01–2.15 (m, 1H, CHHCH CH₂), 2.29–2.42

¼

(m, 1H, CHHCH CH₂), 2.51–2.57 (dd, 1H, J¼13.67 Hz,

4.88 Hz, NCHHCH), 2.58–2.65 (dd, 1H, J¼13.67 Hz,

5.38 Hz, NCHHCH), 3.38–3.50 (m, 2H, CH₃CH₂O), 3.53–

3.65 (m, 3H, CH₃CH₂O, NCHHAr), 3.93–3.98 (dd, 1H, J¼

(3R,4R)-3,4-Diallyl-N-(2,2-diethoxyethyl)-4-hydroxy-

6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline

(23)

¼

7.81 Hz, 7.32 Hz, NCH), 4.01 (d, 1H, J 17.09 Hz, NCHHAr),

Under argon, allyltriphenyltin (576 mg, 1.47 mmol) was dis-

solved in anhydrous THF (3 mL). Phenyllithium (816 mL,

1.47 mmol, 1.8 M in cyclohexane/ether) was added. The mix-

ture was stirred at 208C for 30 minutes, during this time a white

precipitate occurred and the mixture changed from colourless

to green. The so formed allyllithium was then cooled to ꢀ788C

and isoquinolone 6 (390 mg, 1.27 mmol) was injecteddropwise.

The mixture was stirred at ꢀ608C for a further 1 hour (TLC

monitoring). Methanol (10 mL) was added and the solid was

filtered off. The solvent was evaporated, and the crudematerial

was purified by column chromatography (n-hexane/ethyl ace-

tate, 6:1) to give diallylisoquinoline 23 as a yellow oil; yield:

390 mg (88%); [a]_D²⁰: þ87.28 (c 0.4, CHCl₃); ¹H NMR

(500 MHz, CDCl₃): d¼1.12 [2ꢁt, 6H, J¼6.59 Hz,

(CH₃CH₂O)₂], 2.05 (s, 1H, OH), 2.09–2.16 (m, 1H,

NCHCHH), 2.16–2.25 (m, 1H, NCHCHH), 2.40–2.46 (dd,

4.51–4.59 [dd, 1H, J¼5.37 Hz, 4.88 Hz, CH(OEt)₂], 4.88–4.98

¼

(m, 2H, CH₂CH CH₂), 5.06–5.10 (dd, 1H, J¼9.77 Hz,

¼

1.95 Hz, C CHCH CHH), 5.21–5.26 (dd, 1H, J¼16.11 Hz,

¼

1.95 Hz, C CHCH CHH), 5.70–5.80 (dddd, 1H, J¼

¼

17.09 Hz, 9.77 Hz, 7.32 Hz, 6.84 Hz, CH₂CH CH₂), 5.81 (s,

2H, OCH₂O), 6.38 (s, 1H, Ar-H), 6.45 (d, 1H, J¼11.23 Hz,

¼

C CHCH CH₂), 6.54–6.63 (ddd, 1H, J¼16.11 Hz, 11.23 Hz,

9.77 Hz, C CHCH CH₂), 6.99 (s, 1H, Ar-H); ¹³C NMR

¼

(125 MHz,

CDCl₃):

d¼15.2

[(CH₃CH₂O)₂],

34.7

¼

(CH₂CH CH₂), 49.9 (NCH₂Ar), 57.3 (NCH₂CH), 58.4 (NCH),

61.8, 62.0 [(CH₃CH₂O)₂], 100.7 (OCH₂O), 102.5 [CH(OEt)₂],

103.4, 106.0, 127.3, 133.9, 135.7, 146.7, 147.3 (Ar), 116.0

¼

(CH₂CH CH₂),

117.7

126.0

(C CHCH CH₂),

123.2

132.5

¼

(C CHCH CH₂),

¼

(C CHCH CH₂), 135.7 (CH₂CH CH₂); IR (CHCl₃): 1/l¼

3076 (m), 3018 (s), 2978 (s), 2933 (s), 2897 (s), 2775 (w) 1639

(m), 1616 (m), 1504 (s), 1481 (s), 1444 (m), 1375 (m), 1332

(m), 1231 (s), 1217 (s), 1175 (m), 1126 (m), 1042 (s), 987 (m)

cm^ꢀ1; MS (EI, 80 eV, 1008C): m/z (%)¼330 (100, [M –

¼

1H, J¼12.93 Hz, 6.98 Hz, CHHCH CH₂), 2.64–2.70 (dd,

1H, J¼12.80 Hz, 4.78 Hz, NCHHCH), 2.77–2.82 (dd, 1H,

J¼12.93 Hz, 5.17 Hz, NCHHCH), 2.77–2.82 (dd, 1H, J¼

1348

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

asc.wiley-vch.de

Adv. Synth. Catal. 2004, 346, 1335–1354

Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

C₃H₅]^þ), 284 (15, [M – C₄H₇O₂]^þ), 268 (16, [M – C₅H₁₁O₂]^þ),

212 (41, [M – C₉H₁₉O₂]^þ), 103 (13, [C₅H₁₁O₂]^þ), 75 (14, [C₃H₇

O₂]^þ), 41 (12, [C₃H₅]^þ).

oil, which easily tended to decompose; yield: 20 mg (21%);

1

[a]²_D⁰: þ162.98 (c 0.47, CHCl₃); H NMR (500 MHz, CDCl₃):

d¼1.15 (2ꢁt, 6H, J¼7.33 Hz, CH₃CH₂), 2.11–2.28 (m, 1H,

CHHCHN), 2.44–2.57 (m,1H, CHHCHN), 2.61–2.69 [dd,

1H, J¼14.16 Hz, 5.37 Hz, NCHH CH(OEt)₂], 2.69–2.77 [dd,

1H, J¼14.16 Hz, 4.88 Hz, NCHHCH(OEt)₂], 3.40–3.50 (m,

2H, CH₃CH₂), 3.53–3.65 (m, 2H, CH₃CH₂), 3.65–3.78 (d,

1H, J¼15.63 Hz, NCHHAr), 3.83–3.92 (d, 1H, J¼15.13 Hz,

NCHHAr), 4.52–4.59 [dd, 1H, J¼5.37 Hz, 4.88 Hz,

CH(OEt)₂], 5.82 (2ꢁs, 2H, OCH₂O), 5.80–5.88 (m, 1H,

(4aR,10bR)-N-(2,2-Diethoxyethyl)-8,9-

methylenedioxy-1,4,4a,5,6,10b–

hexahydrophenanthridine (25)

Diallylisoquinoline 23 (100 mg, 0.25 mmol) in CH₂Cl₂(50 mL)

was treated with benzylidenebis(tricyclohexylphosphine)di-

chlororuthenium (Grubbsꢀ catalyst, 10 mg, 0.012 mmol). The

mixture was refluxed at 608C. Another portion of Grubbsꢀ cat-

alyst (10 mg, 0.012 mmol) was added every 24 hours. After 96

hours, the reaction mixture was stirred at room temperature

for 2 hours. The mixture was filtered over silica gel and the sol-

vent was evaporated. The residue was purified by HPLC (ethyl

acetate/n-hexane, 1:1, Nucleosil 50–5, 32ꢁ110 mm, flow

64 mL/min, retention time: 5.0 min) to give phenanthridine

25 as a brownish oil; yield: 60 mg (66%); [a]²_D⁰: ꢀ144.58 (c 1.6,

¼

CH₂CH CH), 5.95–6.02 (m, 1H, CH CHCH C), 6.02–6.24

¼

(m, 1H, CH CHCH C), 6,43 (s, 1H, CHCCH₂N), 6.97 (s,

1H, CHCC CH); ¹³C NMR (125 MHz, CDCl₃): d¼15.2

¼

(CH₃CH₂), 28.2 (CH₂CHN), 53.6 [NCH₂CH(OEt)₂], 56.2

(NCH₂Ar), 59.9 (NCH), 61.8, 62.0 (CH₃CH₂), 100.6 (OCH₂O),

102.0 [CH(OEt)₂], 102.4, 106.7, 128.9, 132.9, 146.8, 146.9

¼

(Ar), 115.7 (CH₂CH CH), 124.7 (CH CHCH C), 125.7

(CH CHCH C), 126.3 (CH C); IR (CHCl₃): 1/l¼3019 (s),

¼

2977 (m), 2928 (m), 2897 (m), 2413 (w), 1602 (w), 1503 (m),

1481 (s), 1377 (w), 1215 (s), 1122 (m), 1043 (m), 939 (m) cm^ꢀ1

;

MS (EI, 80 eV, 1008C): m/z (%)¼343 (100, [M]^þ), 298 (8, [M

– C₂H₅O]^þ), 240 (25, [M – C₅H₁₁O₂]^þ), 211 (30, [M –

C₆H₁₄NO₂]^þ), 181 (60, [M – C₇H₁₄O₄]^þ), 103 (35, [C₅H₁₁O₂]^þ),

75 (25, [C₃H₇O₂]^þ); HRMS (80 eV, 1008C): calcd. for

C₂₀H₂₅NO₄: 343.17835; found: 343.17654.

1

CHCl₃); H NMR (500 MHz, CDCl₃): d¼1.15 (2ꢁt, 6H, J¼

7.01 Hz, CH₃CH₂), 2.10–2.20 (m, 2H, CHHCHN, CHHCOH),

2.34–2.42 (m, 1H, CHHCHN), 2.51–2.57 [dd, 1H, J¼

13.88 Hz, 4.81 Hz, NCHHCH(OEt)₂], 2.67–2.73 (dd, 1H, J¼

10.76 Hz, 5.50 Hz, NCH), 2.78–2.85 (m, 1H, CHHCOH),

2.86 (s, br, 1H, OH), 3.02–3.08 [dd, 1H, J¼13.88 Hz,

5.67 Hz, NCHHCH-(OEt)₂], 3.48–3.56 (m, 2H, CH₃CH₂),

3.56–3.61 (d, 1H, J¼14.85 Hz, NCHHAr), 3.62–3.74 (m,

2H, CH₃CH₂), 3.91–3.97 (d, 1H, J¼14.99 Hz, NCHHAr),

4.62–4.66 [dd, 1H, J¼5.49 Hz, 5.09 Hz, CH(OEt)₂], 5.63–

(5R,9R)-3,4-Diallyl-2,4-(2-ethoxy-3-oxapropylidine)-

6,7-methylenedioxyisoquinoline (27)

¼

5.68 (m, 1H, CH CHCH₂COH), 5.69–5.75 (m, 1H, CH CH-

CHN), 5.88 (d, 2H, J¼1.37 Hz, OCH₂O), 6.39 (s, 1H, Ar-H),

6.89 (s, 1H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): d¼15.31,

15.32 (CH₃CH₂), 26.4 (CH₂CHN), 35.8 (CH₂COH), 53.5

[NCH₂CH(OEt)₂], 56.3 (NCH₂Ar), 61.4 (CH₃CH₂), 61.6

(CH₂CHN), 62.4 (CH₃CH₂), 68.1 (COH), 100.7 (OCH₂O),

101.4 [CH(OEt)₂], 105.3, 105.5, 127.4, 133.7, 146.5, 146.6

Method A: Under argon, diallylisoquinoline 23 (200 mg,

0.51 mmol) was dissolved in anhydrous CHCl₃(30 mL) and

SmCl₃(5 mg) and acetyl chloride (140 mL) were added at

room temperature. The reaction mixture was stirred for

30 min. (TLC monitoring) at room temperature. NaOH

(1 M) was added until the pH reached 9–10 and the aqueous

layer was extracted with CHCl₃(4ꢁ10 mL). The combined or-

ganic layers were dried over MgSO₄and the solvent was re-

moved. The residue was purified by column chromatography

(n-hexane/ethyl acetate, 3:1) to give acetal 27 as a yellow oil;

yield: 150 mg (85%).

Method B: Diallylisoquinoline 23 (200 mg, 0.51 mmol) was

treated with aqueous HCl (1 M, 20 mL). The reaction mixture

was heated to 508C for 20 hours. NaOH (1 M) was added until

the pH reached 9–10 and the aqueous layer was extracted with

CHCl₃(4ꢁ10 mL). The combined organic layers were dried

over MgSO₄and the solvent was removed. The residue was pu-

rified by column chromatography (n-hexane/ethyl acetate,

3:1) to give acetal 27 as a yellow oil; yield: 110 mg (62%);

¹H NMR (500 MHz, CDCl₃): d¼1.05 (t, 3H, J¼7.33 Hz,

CH₃CH₂), 2.40–2.60 (m, 3H, CHHCAr, CHHCHN,

NCHHCH), 2.70–2.92 (m, 4H, CH₂CHN, CHHCAr,

CHHCHN, NCHHCH), 3.12–3.26 (m, 1H, CH₃CHH),

3.64–3.76 (m, 1H, CH₃CHH), 3.77–3.85 (d, 1H, J¼17.58 Hz,

NCHHAr), 4.23–4.30 (m, 2H, NCH₂CH(OEt), NCHHAr),

¼

(Ar), 123.5 (CH CHCH₂COH), 124.2 (CH CHCH₂CHN);

IR (CHCl₃): 1/l¼3320 (w, OH), 3019 (s), 2978 (m), 2897 (m),

1605 (w), 1504 (m), 1486 (m), 1389 (w), 1294 (w), 1215 (s),

1126 (m), 1043 (m), 909 (s) cm^ꢀ1; MS (EI, 80 eV, 1208C): m/z

(%)¼361 (1.37, [M]^þ), 343 (9, [M – H₂O]^þ), 316 (6, [M –

C₂H₅O]^þ), 258 (100, [M – C₅H₁₁O₂]^þ), 103 (7, [C₅H₁₁O₂]^þ);

HRMS (80 eV, 1008C): calcd. for C₂₀H₂₇NO₅: 361.18892;

found: 361.18744; calcd. for C₂₀H₂₅NO₄([M – H₂O]^þ):

343.17835; found: 343.17654; calcd. for C₁₈H₂₂NO₄([M –

C₂H₅O]^þ): 316.15488; found: 316.15622; calcd. for C₁₅H₁₆NO₃

([M – C₅H₁₁O₂]^þ): 258.11301; found: 258.11633.

(3R)-N-(2,2-Diethoxyethyl)-8,9-methylenedioxy-

4,4a,5,6-tetrahydrophenanthridine (26)

Under argon, phenanthridine 25 (100 mg, 0.27 mmol) in anhy-

drous DMSO (10 mL) was treated with MsCl (35 mg,

0.30 mmol) and t-BuOK (34 mg, 0.30 mmol). The mixture

was stirred at 208C for 2 days. H₂O (10 mL) and Et₂O

(10 mL) were added, the aqueous layer was extracted with

Et₂O (4ꢁ10 mL), and the combined organic layers were dried

over MgSO₄. After removal of the solvent in vacuum, the crude

material was purified by column chromatography (n-hexane/

ethyl acetate, 1:1) to afford cyclohexadiene 26 as a brown

¼

4.91–5.15 (m, 4H, CH₂CHCH₂CHN, CH₂CHCH₂CAr),

¼

5.31–5.47 (m, 1H, CH₂CHCH₂CAr), 5.72–5.88 (m, 1H,

¼

CH₂CHCH₂N), 5.91 (s, 2H, OCH₂O), 6.42 (s, 1H,

Ar-H), 6.92 (s, 1H, Ar-H); ¹³C NMR (125 MHz, CDCl₃):

¼

d¼15.0 (CH₃CH₂O), 29.8 (NCHCH₂CH CH₂), 38.3

¼

(ArCCH₂CH CH₂), 50.5 (NCH₂Ar), 57.4 (NCH₂CH),

57.8 (CH₃CH₂), 64.3 (NCH), 71.9 (CH₂CAr), 94.3

Adv. Synth. Catal. 2004, 346, 1335–1354

asc.wiley-vch.de

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

1349

Nong Zhang et al.

FULL PAPERS

[NCH₂CH(OEt)₂], 100.8 (OCH₂O), 104.6, 105.9, 131.6, 131.7,

146.8, 147.0 (Ar), 115.9 (NCHCH₂CH CH₂), 118.5

was cooled to ꢀ788C. Butyllithium (360 mL, 0.90 mmol, 2.5

M in hexane) was injected dropwise. The mixture was stirred

at ꢀ788C for 15 min. A solution of amide 18a (400 mg,

0.80 mmol) in 5 mL anhydrous THF was added slowly. The

mixture was stirred at ꢀ788C for a further 30 min (TLC mon-

itoring). Saturated aqueous NH₄Cl (10 mL) was added to the

mixture, the aqueous layer was extracted with Et₂O (4ꢁ

10 mL), and the combined organic layers were dried over

MgSO₄. After removal of the solvent, the crude material was

purified by column chromatography (n-hexane/ethyl acetate,

5:1) to give ketone 29 as a yellow oil; yield: 220 mg (67.5%);

¼

(ArCCH₂CH CH₂), 128.3 (ArCHCH₂CH CH₂), 138.7

¼

(NCHCH₂CH CH₂); IR (CHCl₃): 1/l¼3079 (m), 3017 (s),

2979 (s), 2932 (m), 2896 (m), 1713 (w), 1641 (m), 1504 (s),

1486 (s), 1454 (m), 1440 (m), 1380 (m), 1332 (m), 1310 (m),

1266 (m), 1243 (s), 1215 (s), 1163 (m), 1129 (m), 1105 (m),

1041 (s), 939 (m) cm^ꢀ1; MS (EI, 80 eV, 808C): m/z (%)¼343

(50, [M]^þ), 284 (27, [M – C₃H₇O]^þ), 269 (44, [M – C₃H₆O₂]^þ

), 228 (77, [M – C₆H₁₁O₂]^þ), 202 (100, [M – C₉H₁₇O]^þ).

1

[a]²_D⁰: þ110.78 (c 1.2, CHCl₃); H NMR (270 MHz, CDCl₃):

¼

d¼1.40 [s, 9H, OC(CH₃)₃], 2.44–2.59 (m, 2H, CH₂CH CH₂),

(4aR,10bR)-4,10b-(2-Ethoxy-3-oxapropylidine)-8,9-

methylenedioxy-1,4,4a,5,6,10b–

hexahydrophenanthridine (28)

2.95, 3.06 (2ꢁs, 3H, OCH₃), 2.98–3.17 [m, 2H,

CH₂CH(OCH₃)₂], 3.19, 3.27 (2ꢁs, 3H, OCH₃), 4.20–4.27,

4.37–4.45 [2ꢁdd, 1H, J¼4.88 Hz, 4.39 Hz, CH(OCH₃)₂],

¼

4.92–4.98 (d, 1H, J¼11.23 Hz, CH CHH), 5.01–5.09 (d, 1H,

Acetal 27 (120 mg, 0.35 mmol) in CH₂Cl₂(80 mL) was treated

with benzylidenebis(tricyclohexylphosphine)dichlororutheni-

um (Grubbsꢀ catalyst, 14 mg, 0.017 mmol), the mixture was re-

fluxed at 608C. Another portion of Grubbsꢀ carbene (14 mg,

0.017 mmol) was added every 24 hours. After 96 hours, the re-

action mixture was stirred at room temperature for 2 hours.

The mixture was filtered over silica gel and the solvent was

evaporated. The residue was purified by HPLC (ethyl ace-

tate/n-hexane, 3:1, Nucleosil 50–5, 32ꢁ110 mm, flow

64 mL/min, retention time: 5.0 min) to give phenanthridine

28 as brown crystals; yield: 75 mg (68%); mp 138–1398C;

¼

J¼17.09 Hz, CH CHH), 5.43–5.52 (dd, 1H, J¼7.82 Hz,

¼

6.83 Hz, CHCON), 5.61–5.84 (m, 1H, CH CH₂), 5.94 (2ꢁs,

2H, OCH₂O), 6.71–6.79 (d, 1H, J¼8.30, Ar-H), 7.39–7.45

(d, 1H, J¼5.86 Hz, Ar-H), 7.50–7.67 (dd, 1H, J¼24.90 Hz,

8.30 Hz, Ar-H); ¹³C NMR (68 MHz, CDCl₃): d¼28.1

¼

[OC(CH₃)₃], 32.8, 33.4 (CH₂CH CH₂), 46.2, 48.0

[CH₂CH(OCH₃)₂], 54.3, 54.5, 54.6 (OCH₃), 58.2, 61.1

(CHCON), 80.6, 81.0 [OC(CH₃)₃], 101.5 (OCH₂O), 103.1,

103.5 [CH(OCH₃)₂], 107.6, 108.1, 124.1, 124.6, 130.7, 147.8,

¼

151.4 (Ar), 117.3 (CH CH₂), 134.2, 134.5 (CH CH₂), 154.8,

155.4 (NCOO), 194.6, 195.3 (ArCO); IR (CHCl₃): 1/l¼3076

(w), 2977 (m), 2932 (m), 1685 (s, CO, NCO), 1642 (w), 1605

(w), 1505 (m), 1489 (m), 1447 (s), 1402 (m), 1367 (m), 1305

1

[a]²_D⁰: ꢀ49.18 (c 1.3, CHCl₃); H NMR (500 MHz, CDCl₃):

d¼1.02 (t, 3H, J¼7.15 Hz, CH₃CH₂), 2.11–2.19 (m, 1H,

¼

CH CHCHHCHN), 2.36–2.44 (m, 1H, CH CHCHHCAr),

2.59–2.65 (dd, 1H, J¼14.57 Hz , 3.57 Hz, NCHHCHOEt),

(w), 1252 (s), 1166 (m), 1123 (m), 1075 (m), 1039 (m) cm^ꢀ1

;

MS (EI, 80 eV, 1108C): m/z (%)¼407 (2, [M]^þ), 334 (4, [M –

C₄H₉O]^þ), 276 (9, [M – C₆H₁₁O₃]^þ), 258 (78, [M – C₈H₅O₃]^þ),

202 (28, [M – C₁₂H₁₃O₃]^þ), 158 (100, [M – C₁₃H₁₃O₅]^þ);

HRMS (80 eV, 1108C): calcd. for C₂₁H₂₉NO₇: 407.19440;

found: 407.19533.

¼

2.75–2.84 (m, 2H, CH CHCHHCHN, CH CHCHHCAr),

2.94–2.99 (dd, 1H, J¼10.86 Hz, 6.19 Hz, NCHCH₂), 3.09–

3.15 (dd, 1H, J¼14.57 Hz, 10.03 Hz, NCHHCHOEt), 3.18–

3.25 (m, 1H, CH₃CHH), 3.71–3.77 (m, 1H, CH₃CHH), 3.81–

3.87 (d, 1H, J¼17.05 Hz, NCHHAr), 4.24–4.35 (d, 1H, J¼

17.05 Hz, NCHHAr), 4.33–4.37 (dd, 1H, J¼10.05 Hz,

¼

3.71 Hz, EtOCHO), 5.50–5.60 (m, 1H, CH CHCH₂CAr),

¼

5.65–5.75 (m, 1H, CH CHCH₂CHN), 5.90 (s, 2H, OCH₂O),

(4R,5R)-4-(3,4-Methylenedioxyphenyl)-5-N-(tert-

butyloxycarbonyl)-N-(2,2-dimethoxyethyl)amino-1,7-

octadien-4-ol (30; crude material)

6.42 (s, 1H, Ar), 6.85 (s, 1H, Ar); ¹³C NMR (125 MHz,

CDCl₃): d¼15.0 (CH₃CH₂), 24.7 (NCHCH₂), 36.3

¼

(CH CHCH₂CAr), 51.1 (NCH₂CH), 54.6 (NCHCH₂), 57.7

(NCH₂Ar),

64.3

(CH₃CH₂),

67.4

(OCAr),

95.2

Under argon, allyltriphenyltin (210 mg, 0.53 mmol) was dis-

solved in anhydrous THF (10 mL). Phenyllithium (298 mL,

0.53 mmol, 1.8 M in cyclohexane/ether) was added. The mix-

ture was stirred at 208C for 30 minutes, during this time a white

precipitate occurred and the mixture changed from colourless

to green. The so formed allyllithium was then cooled to ꢀ788C

and ketone 29 (200 mg, 0.49 mmol) was injected dropwise. The

mixture was stirred at ꢀ608C for a further 1 hour (TLC mon-

itoring). Methanol (10 mL) was added and the solid was fil-

tered off. The solvent was evaporated to give diallyl carbinol

30 as a yellow oil, which was used without further purification.

¹H NMR (270 MHz, CDCl₃): d¼1.40 [2ꢁs, 9H, OC(CH₃)₃],

(NCH₂CHOEt), 100.8 (OCH₂O), 104.4, 105.4, 130.3, 131.0,

¼

146.9, 147.0 (Ar), 122.9 (CH CHCH₂CAr), 124.7

(CH CHCH₂CHN); IR (CHCl₃): 1/l¼3016 (s), 2978 (s),

¼

2928 (s), 2896 (s), 2775 (w), 2654 (w), 1665 (w), 1622 (w),

1504 (s), 1483 (s), 1450 (m), 1424 (m), 1380 (m), 1349 (m),

1333 (m), 1307 (m), 1260 (m), 1237 (s), 1214 (s), 1185 (m),

1161 (m), 1141 (m), 1111 (s), 1040 (s), 991 (w), 970 (w) cm^ꢀ1

;

MS (EI, 80 eV, 1108C): m/z (%)¼315 (7, [M]^þ), 270 (1, [M –

C₂H₅O]^þ), 241 (51, [M – C₃H₆O₂]^þ), 226 (21, [M – C₄H₉O₂]^þ),

212 (100, [M – C₄H₉NO₂]^þ); HRMS (80 eV, 1008C): calcd.

for C₁₈H₂₁NO₄: 315.14705; found: 315.14932.

¼

2.09 (m, 1H, OH), 2.25–2.90 (m, 4H, CHCH₂CH CH₂,

¼

CCH₂CH CH₂), 2.90–3.37 [m, 8H, NCH₂, CH(OCH₃)₂],

3.95–4.12 [2ꢁm, 1H, CH(OCH₃)₃], 4.21–4.35, 4.50–4.61

(2R)-2-[(N-tert-Butyloxycarbonyl)-N-(2,2-

dimethoxyethyl)]amino-3,4-methylenedioxyphenyl-4-

penten-1-one (29)

¼

(2ꢁm, 1H, NCH), 4.76–5.11 (m, 4H, CHCH₂CH CH₂,

¼

CCH₂CH CH₂), 5.73–5.98 (m, 2H, CHCH₂CH CH₂,

¼

CCH₂CH CH₂), 6.81 (s, 2H, OCH₂O), 6.60–7.01 (m, 3H,

Under argon, 1-bromo-3,4-methylenedioxybenzene (110 mL,

0.91 mmol, d¼1.678, M_R¼201) in anhydrous THF (20 mL)

Ar-H); ¹³C NMR (68 MHz, CDCl₃): d¼28.0 [OC(CH₃)₃],

¼

30.9, 32.0 (CHCH₂CH CH₂), 44.0, 45.7 (CCH₂CH CH₂),

1350

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

asc.wiley-vch.de

Adv. Synth. Catal. 2004, 346, 1335–1354

Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

FULL PAPERS

46.7, 46.9 [CH₂CH(OCH₃)₂], 53.8, 54.5 (OCH₃), 58.5, 60.4

(NCH), 78.8, 79.0 [OC(CH₃)₃], 79.7 (ArC), 100.6 (OCH₂O),

104.0, 104.2 [CH(OCH₃)₂], 106.7, 106.9, 115.9, 116.9, 128.4,

128.9, 136.6, 137.0, 138.8, 139.1, 146.8, 147.3 (Ar), 117.2, 117.8

umn chromatograph (n-hexane/ethyl acetate, 3:1) to give cy-

clohexene 32 as a pale yellow oil; yield: 80 mg (86%); [a]²_D⁰:

ꢀ37.38 (c 1.7, CHCl₃); ¹H NMR (500 MHz, CDCl₃): d¼

2.17–2.25 (m, 1H, NCHCHH), 2.36–2.43 (m, 1H, ArCCHH),

2.48–2.53 (ddd, 1H, J¼15.63 Hz, 5.37 Hz, 2.93 Hz,

NCHCHH), 2.58–2.65 (dd, 1H, J¼16.60 Hz, 5.86 Hz,

ArCCHH), 2.91–2.96 (dd, 1H, J¼14.65 Hz, 6.35 Hz,

NCHH), 3.21 (s, 3H, OCH₃), 3.32 (s, 3H, OCH₃), 3.51–3.56

(dd, 1H, J¼14.65 Hz, 4.39 Hz, NCHH), 4.07–4.12 (dd, 1H,

J¼4.89 Hz, 2.93 Hz, NCH), 4.33–4.38 [dd, 1H, J¼5.86 Hz,

¼

(CHCH₂CH CH₂), 118.9, 119.1 (CCH₂CH CH₂), 133.8,

¼

134.9 (CHCH₂CH CH₂), 136.6, 137.0 (CCH₂CH CH₂),

156.3, 157.4 (NCO).

(4R,5R)-3-(2,2-Dimethoxyethyl)-4,5-diallyl-5-(3,4-

methylenedioxyphenyl)-2-oxazolidinone (31)

¼

4.40 Hz, CH(OCH₃)₂], 5.89–5.93 (m, 1H, CH CH), 5.92 (s,

¼

2H, OCH₂O), 5.93–6.01 (m, 1H, CH CH), 6.67–6.71 (d, 1H,

J¼8.30 Hz, Ar-H), 6.78–6.83 (dd, 1H, J¼8.30 Hz, 1.96 Hz,

Ar-H), 6.83–6.85 (d, 1H, J¼1.46 Hz, Ar-H); ¹³C NMR

(125 MHz, CDCl₃): d¼25.6 (NCHCH₂), 36.0 (ArCCH₂), 43.5

(NCH₂), 54.4, 55.1 (OCH₃), 63.0 (NCHCH₂), 82.9 (NCOOC),

101.1 (OCH₂O), 102.9 [CH(OCH₃)₂], 105.0, 107.9, 117.2,

Under argon, the crude carbinol 30 in anhydrous THF (20 mL)

was treated with KHMDS (1.0 mL, 0.5 M in toluene) at 08C.

The reaction mixture was stirred at 08C for 30 min (TLC con-

trol). Saturated aqueous NH₄Cl (20 mL) was added to the mix-

ture. The aqueous layer was extracted with Et₂O (4ꢁ10 mL).

The combined organic layers were dried over MgSO₄. After re-

moval of the solvent, the crude material was purified by column

chromatography (n-hexane/ethyl acetate, 5:1) to give oxazoli-

dinone 31 as a pale yellow oil; yield: 150 mg (81.4% from ke-

¼

138.6, 147.0, 147.8 (Ar), 125.8 (CH CH), 127.4 (CH CH),

157.3 (NCO); IR (film): 1/l¼3086 (w), 3052 (w), 2992 (w),

2948 (m), 2898 (m), 2835 (m), 1847 (w), 1732 (s, CON), 1635

(w), 1612 (w), 1507 (s), 1490 (s), 1438 (s), 1420 (s), 1392 (m),

1383 (m), 1357 (m), 1347 (m), 1326 (m), 1316 (m), 1296 (s),

1283 (m), 1251 (s), 1210 (m), 1192 (m), 1178 (m), 1145 (m),

1121 (m), 1071 (s), 1035 (s), 1020 (s), 999 (m), 972 (m), 964

(m), 928 (s) cm^ꢀ1; MS (EI, 80 eV, 1208C): m/z (%)¼347 (8,

[M]^þ), 200 (8, [C₁₃H₁₂O₂]^þ), 75 (100, [C₃H₇O₂]^þ); HRMS

(80 eV, 1208C): calcd. for C₁₈H₂₁NO₆: 347.13690; found:

347.13588.

1

tone 29); [a]²_D⁰: þ10.08 (c2.4, CHCl₃); H NMR (500 MHz,

¼

CDCl₃): d¼2.46–2.57 (m, 2H, CHCH₂CH CH₂), 2.57–2.62

(dd, 1H, J¼14.43 Hz, 7.42 Hz, ArCCHH), 2.75–2.81 (dd,

1H, J¼14.44 Hz, 6.32 Hz, ArCCHH), 2.92–2.98 [dd, 1H, J¼

14.71 Hz, 7.01 Hz, NCHHCH(OCH₃)₂], 3.01 (s, 3H, OCH₃),

3.21 (s, 3H, OCH₃), 3.54–3.59 [dd, 1H, J¼14.71 Hz, 3.99 Hz,

NCHHCH(OCH₃)₂], 3.91–3.96 (dd, 1H, J¼6.46 Hz, 5.50 Hz,

NCH), 4.10–4.14 [dd, 1H, J¼7.01 Hz, 3.99 Hz, CH(OCH₃)₂],

5.43–5.53 (dddd, 1H, J¼17.58 Hz, 10.26 Hz, 7.32 Hz,

¼

6.35 Hz, ArCCH₂CH CH₂), 5.73–5.82 (dddd, 1H, J¼

(4R,5R)-4-(3,4-Methylenedioxyphenyl)-5-(4-methoxy-

2-oxazolidinonyl)-1,7-octadien-4-ol (33)

¼

17.09 Hz,10.17 Hz, 7.02 Hz, 6.88 Hz, NCHCH₂CH CH₂),

5.90 (s, 2H, OCH₂O), 6.71–6.74 (d, 1H, J¼6.11 Hz, Ar-H),

6.75–6.80 (m, 2H, Ar-H); ¹³C NMR (125 MHz, CDCl₃): d¼

Method A: Crude diallyl carbinol 30 (150 mg, 0.33 mmol) in

DMSO (30 mL) and H₂O (1 mL) was heated to 80–908C for

20 hours. The mixture was then cooled to room temperature

and H₂O (10 mL) was added. The aqueous layer was extracted

with Et₂O (4ꢁ10 mL), and the combined organic layers were

dried over MgSO₄. After removal of the solvent, the crude ma-

terial was purified by column chromatography (n-hexane/ethyl

acetate, 2:1) to give methoxyoxazolidinone 33 as a yellow oil;

yield: 90 mg (74% from ketone 29).

Method B: Under argon, the crude diallyl carbinol 30

(150 mg, 0.33 mmol) in anhydrous CHCl₃(20 mL) was treated

with cat. SmCl₃and acetyl chloride (90 mL) at room tempera-

ture. The reaction mixture was stirred for 30 min (TLC moni-

toring). Saturated aqueous NaHCO₃(20 mL) was added until

the pH reached 9–10 and the aqueous layer was extracted

with CHCl₃(4ꢁ10 mL). The combined organic layers were

dried over MgSO₄and the solvent was removed. The residue

was purified by column chromatography (n-hexane/ethyl ace-

tate, 2:1) to give methoxyoxazolidinone 33 as a yellow oil;

yield: 80 mg (66% from ketone 29).

¼

33.0 (CHCH₂CH CH₂), 39.6 (ArCCH₂CH CH₂), 44.0

(CH₂CH(OCH₃)₂), 54.3, 55.1 (CH(OCH₃)₂), 65.9 (NCH),

84.9 (NCOOC), 101.0 (OCH₂O), 103.1 [CH(OCH₃)₂], 105.6,

¼

107.9, 118.1, 136.9, 146.7, 147.7 (Ar), 118.8, 118.9 (CH CH₂),

¼

131.3 (ArCCH₂CH CH₂), 133.2 (CHCH₂CH CH₂), 156.7

(NCO); IR (film): 1/l¼3086 (w), 3052 (w), 2992 (m), 2948

(s), 2898 (s), 2835 (m), 1732 (br, s, NCOO), 1635 (w), 1612

(m), 1507 (s), 1490 (s), 1438 (s), 1420 (s), 1392 (m), 1383 (m),

1357 (m), 1347 (m), 1316 (m), 1296 (m), 1283 (m), 1251 (s),

1210 (m), 1192 (m), 1178 (m), 1145 (m), 1121 (s), 1071 (s),

1035 (s), 1020 (s), 999 (m), 972 (m), 964 (m), 928 (m) cm^ꢀ1

;

MS (EI, 80 eV, 1108C): m/z (%)¼375 (13.9, [M]^þ), 344

(4, [M – CH₃O]^þ), 334 (14, [M – C₃H₅]^þ), 315 (10, [M –

C₂H₄O₂]^þ), 293 (3, [M – C₆H₁₀]^þ), 274 (4, [M – C₅H₉O₂]^þ),

258 (23, [M – C₅H₉O₃]^þ), 228 (7, [M – C₆H₁₁O₄]^þ), 75 (100,

C₃H₇O₂); HRMS (80 eV, 1108C): calcd. for C₂₀H₂₅O₆N:

375.16818; found: 375.16911.

Method C: Crude diallyl carbinol 30 (150 mg, 0.33 mmol) in

anhydrous CH₃OH (30 mL) at 08C was treated with SOCl₂

(1 mL). The mixture was stirred at 08C for 3 hours. After re-

moval of the solvent, Na₂CO₃(10 mL) was added. The aqueous

layer was extracted with Et₂O (4ꢁ10 mL), and the combined

organic layers were dried over MgSO₄. After removal of the

solvent, the crude material was purified by column chromato-

graphy (n-hexane/ethyl acetate, 2:1) to give methoxyoxazoli-

dinone 33 as a yellow oil; 70 mg (58% from ketone 29). The me-

(3aR,7aR)-3-(2,2-Dimethoxyethyl)-7a-(3,4-

methylenedioxyphenyl)-3a,4,7,7a–

tetrahydrobenzooxazol-2-one (32)

Oxazolidinone 31 (100 mg, 0.27 mmol) in CH₂Cl₂(80 mL) was

treated with benzylidenebis(tricyclohexylphosphine)dichlor-

oruthenium (Grubbsꢀ catalyst, 11 mg, 0.013 mmol). The reac-

tion mixture was refluxed at 608C for 3 hours (TLC control).

After removal of the solvent, the residue was purified by col-

Adv. Synth. Catal. 2004, 346, 1335–1354

asc.wiley-vch.de

ꢁ 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

1351

Nong Zhang et al.

FULL PAPERS

¼

thoxyoxazolidinone 33 was obtained as an inseparable mixture

of diastereomers.

5.54–5.64 (m, 1H, ArCCH₂CH CH), 5.72–5.82 (m, 1H,

ArCCH₂CH CH), 5.90 (s, 2H, OCH₂O), 6.75 (d, 1H, J¼

¼

Data obtained from the mixture, separated peaks of diaster-

7.81 Hz, Ar-H), 6.88–6.93 (dd, 1H, J¼8.31 Hz, 1.96 Hz,

Ar-H), 7.01 (d, 1H, J¼1.46 Hz, Ar-H); ¹³C NMR (125 MHz,

CDCl₃): d¼25.9 (NCHCH₂), 43.9 (ArCCH₂), 50.8 (NCH₂),

55.2 (NCH), 55.3 (OCH₃), 74.8 (ArCCH₂), 98.4

(CH₃OCHO), 100.9 (OCH₂O), 105.9, 107.9, 118.0, 138.8,

1

eomer 1: H NMR (500 MHz, CDCl₃): d¼2.39–2.70 (m, 4H,

¼

2ꢁCH₂CH CH₂), 3.02–3.08 (dd, 1H, J¼10.59 Hz, 3.02 Hz,

NCHH), 3.29 (s, 3H, OCH₃), 3.49–3.54 (dd, 1H, J¼10.59 Hz,

6.60 Hz, NCHH), 3.80–3.90 (m, 1H, NCH), 4.93–5.09

¼

(m, 5H, 2ꢁCH CH₂, CHOCH₃), 5.22–5.30 (m, 1H,

146.5, 147.6 (Ar), 124.2 (ArCCH₂CH CH), 125.7

¼

ArCCH₂CH CH₂), 5.60–5.71 (m, 1H, NCHCH₂CH CH₂),

5.82 (2ꢁs, 2H, OCH₂O), 6.62–6.67 (d, 1H, J¼1.46 Hz, Ar-

H), 6.73–6.78 (dd, 1H, J¼8.31 Hz, 1.96 Hz, Ar-H), 6.80–6.84

(d, 1H, J¼7.81 Hz, Ar-H); ¹³C NMR (125 MHz, CDCl₃): d¼

(ArCCH₂CH CH).

Data obtained from the mixture, separated peaks of diaster-

1

eomer 2: H NMR (500 MHz, CDCl₃): d¼2.13–2.36 (m, 2H,

NCHCHH, ArCCHH), 2.48–2.60 (m, 1H, ArCCHH), 2.62–

2.73 (m, 1H, NCHCHH), 3.32–3.36 (dd, 1H, J¼10.45 Hz,

2.61 Hz, NCHH), 3.29 (s, 3H, OCH₃), 3.41–3.49 (dd, 1H, J¼

10.45 Hz, 6.35 Hz, NCHH), 4.01–4.07 (dd, 1H, J¼10.45 Hz,

5.37 Hz, NCH), 5.14–5.17 (dd, 1H, J¼6.32 Hz, 2.61 Hz, CH₃

¼

30.4 (NCHCH₂), 44.4 (ArCCH₂CH CH₂), 55.4 (OCH₃), 61.0

(NCH), 78.4 (ArC), 98.4 (OCHOCH₃), 100.8 (OCH₂O),

106.8, 107.7, 120.1, 137.6, 146.4, 147.7 (Ar), 118.2 (CH CH₂),

118.9 (CH CH₂), 132.6 (CH CH₂), 134.5 (CH CH₂), 157.5

(CON).

¼

OCHO), 5.54–5.64 (m, 1H, ArCCH₂CH CH), 5.72–5.82 (m,

¼

Data obtained from the mixture, separated peaks of diaster-

1H, ArCCH₂CH CH), 5.90 (s, 2H, OCH₂O), 6.77 (d, 1H, J¼

1

eomer 2: H NMR (500 MHz, CDCl₃): d¼2.39–2.70 (m, 4H,

8.31 Hz, Ar-H), 6.88–6.93 (dd, 1H, J¼8.31 Hz, 1.96 Hz, Ar-

H), 7.01 (d, 1H, J¼1.96 Hz, Ar-H); ¹³C NMR (125 MHz,

CDCl₃): d¼25.7 (NCHCH₂), 43.2 (ArCCH₂), 49.0 (NCH₂),

55.7 (OCH₃), 57.2 (NCH), 75.0 (ArCCH₂), 98.4

(CH₃OCHO), 100.9 (OCH₂O), 106.3, 107.8, 118.2,

¼

2ꢁCH₂CH CH₂), 3.22–3.28 (dd, 1H, J¼10.17 Hz, 2.20 Hz,

NCHH), 3.22–3.28 (m, 4H, OCH₃, NCHH), 3.90–4.00 (m,

¼

1H, NCH), 4.93–5.09 (m, 5H, 2ꢁCH CH₂, CHOCH₃),

¼

5.30–5.39 (m, 1H, ArCCH₂CH CH₂), 5.60–5.71 (m, 1H,

¼

NCHCH₂CH CH₂), 5.82 (2ꢁs, 2H, OCH₂O), 6.62–6.67 (d,

138.2, 146.5, 147.7 (Ar), 124.5 (ArCCH₂CH CH), 125.1

¼

1H, J¼1.46 Hz, Ar-H), 6.73–6.78 (dd, 1H, J¼8.31 Hz,

1.96 Hz, Ar-H), 6.80–6.84 (d, 1H, J¼7.81 Hz, Ar-H);

¹³C NMR (125 MHz, CDCl₃): d¼30.4 (NCHCH₂), 45.0

(ArCCH₂CH CH) ppm.

Data of diasteoromers 1 and 2: IR (film): 1/l¼3375 (br, m,

OH), 3073 (w), 3063 (w), 3031 (w), 3000 (w), 2962 (w), 2925

(w), 2904 m), 2836 (w), 1733 (s, CON), 1654 (w), 1612 (w),

1505 (s), 1483 (s), 1447 (s), 1424 (s), 1389 (s), 1364 (s9, 1347

(w), 1338 (w), 1329 (w), 1315 (w), 1271 (s), 1247 (s), 1236 (s),

1216 (s), 1192 (m), 1151 (w), 1133 (w), 1125 (w), 1112 (m),

1100 (w), 1091 (w), 1068 (w), 1047 (s), 1040 (s), 1020 (s), 977

(s) cm^ꢀ1; MS (EI, 80 eV, 1508C): m/z (%)¼333 (37, [M]^þ),

216 (26, [M – C₄H₇NO₃]^þ), 149 (100, [C₈H₅O₃]^þ), 121 (8,

[C₇H₅O₂]^þ). HRMS (80 eV, 1508C): calcd. for C₁₇H₁₉NO₆:

333.12125; found: 333.12322.

¼

(ArCCH₂CH CH₂), 55.7 (OCH₃), 61.5 (NCH), 78.3 (ArC),

98.6 (OCHOCH₃), 100.8 (OCH₂O), 106.1, 107.8, 120.3, 137.3,

146.5, 147.6 (Ar), 117.6 (CH CH₂), 118.3 (CH CH₂), 132.3

(CH CH₂), 134.0 (CH CH₂), 156.8 (CON).

¼

Data of diastereomers 1 and 2: IR (film): 1/l 3423 (br, m,

OH), 3077 (m), 3005 (m), 2977 (m), 2957 (m), 2938 (m), 2843

(w), 2777 (w), 2249 (w), 1734 (s, CON), 1640 (m), 1610 (w),

1504 (s), 1488 (s), 1433 (s), 1377 (s), 1335 (m), 1238 (s), 1183

(m), 1125 (m), 1074 (m), 1040 (s), 1017 (m), 971 (m), 915 (m)

cm^ꢀ1; MS (EI, 80 eV, 1508C): m/z (%)¼361 (8, [M]^þ), 343

(1, [M – H₂O]^þ), 330 (2, [M – CH₃O]^þ), 288 (2, [M –

C₃H₅O₂]^þ), 191 (47, [M – C₈H₁₀O₄]^þ), 149 (100, [C₈H₅O₃]^þ),

121 (6, [C₇H₅O₂]^þ); HRMS (80 eV, 1508C): calcd. for C₁₉H₂₃

NO₆: 361.15253; found: 361.15366.

Acknowledgements

We thank the DFG the FCI and the Schering AG for support of

this research. We are grateful to Dr. Harald Waldeck, Solvay

AG, for the donation of trans-4-hydroxy-l-proline.

(1R,6R)-1-(3,4-Methylenedioxyphenyl)-6-N-(4-

methoxy-2-oxazolidinonyl)-3-cyclohexen-1-ol (34)

References and Notes

Methoxyoxazolidinone 33 (160 mg, 0.44 mmol) in CH₂Cl₂

(100 mL) was treated with benzylidenebis(tricyclohexylphos-

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phine)dichlororuthenium

(Grubbsꢀ

catalyst,

16 mg,

0.022 mmol). The reaction mixture was refluxed at 608C for 3

hours (TLC control). After removal of the solvent, the residue

was purified by column chromatography (ethyl acetate) to give

cyclohexene 34 as colourless crystals; yield: 130 mg (88%); mp

188–1898C. Cyclohexene 34 was obtained as an inseparable

mixture of diastereomers.

Data obtained from the mixture, separated peaks of diaster-

1

eomer 1: H NMR (500 MHz, CDCl₃): d¼2.13–2.36 (m, 2H,

NCHCHH, ArCCHH), 2.48–2.63 (m, 2H, NCHCHH,

ArCCHH), 3.18–3.25 (dd, 1H, J¼10.74 Hz, 2.44 Hz,

NCHH), 3.37 (s, 3H, OCH₃), 3.50–3.56 (dd, 1H, J¼10.74 Hz,

6.34 Hz, NCHH), 4.29–4.37 (dd, 1H, J¼10.72 Hz, 5.91 Hz,

NCH), 5.07–5.10 (dd, 1H, J¼6.46 Hz, 2.47 Hz, CH₃OCHO),

1352

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Article Doi

Synthesis and derivatization of substituted (R)- and (S)-C-allylglycines

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