Radical cyclization in heterocycle synthesis. Part 13: Sulfanyl radical addition-cyclization of oxime ethers and hydrazones connected with alkenes for synthesis of cyclic β-amino acids

TETRAHEDRON

Pergamon

Tetrahedron 58 22002) 4459±4479

Radical cyclization in heterocycle synthesis. Part 13: Sulfanyl

radical addition±cyclization of oxime ethers and hydrazones

connected with alkenes for synthesis of cyclic b-amino acids^q

Okiko Miyata, Kanami Muroya, Tomoko Kobayashi, Rina Yamanaka, Seiko Kajisa, Junko Koide

and Takeaki Naito^p

Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan

Received 8 March 2002;accepted 10 April 2002

AbstractÐA combination of sulfanyl radical addition±cyclization of the oxime ethers and hydrazones connected with alkenes and

subsequent conversion of a phenylsulfanylmethyl group to a carboxyl group provides a novel method for the construction of the cyclic

b-amino acids. Upon treatment with thiophenol in the presence of AIBN, the oxime ethers and hydrazones smoothly underwent sulfanyl

radical addition-cyclization to give the 2-2phenylsulfanylmethyl)cycloalkylamine. This method was successfully applied to the practical

synthesis of 2-aminocyclopentanecarboxylic acid and 4-amino-3-pyrrolidinecarboxylic acid. q 2002 Elsevier Science Ltd. All rights

reserved.

1. Introduction

We have recently explored a new ef®cient carbon±carbon

bond-forming reaction based on sulfanyl radical addition±

cyclization,^6,7which proceeds via the formation of a carbon

centered radical species generated by the addition of a

sulfanyl radical to a multiple bond and the following intra-

molecular addition of the resulting carbon-centered radical

to a multiple bond. The synthetic potential has been demon-

strated by the syntheses of anantine,^7b,hoxo-parabenzl-

actone,^7e,ka-kainic acid,^7f,g,jcispentacin,⁷ⁱand A-ring

fragment of 1a,25-dihydroxyvitamin D₃.^7lWe have also

found a new ef®cient carbon±carbon bond-forming reaction

based on the radical addition±cyclization⁸of oxime ethers

tethered to the carbonyl group. We disclose herein the full

details of the sulfanyl radical addition±cyclization⁷ⁱof

oxime ethers and hydrazones connected with alkenes and

the successful application of the reaction to synthesis of

cyclic b-amino acids such as 2-aminocyclopentane-

carboxylic acid 1 and 4-amino-3-pyrrolidinecarboxylic

acid 2 both of which are crucial components of b-17.

The b-amino acids²have aroused considerable attention due

to their important biological properties in the ®elds of drugs

and natural products. Furthermore, they have been known as

useful tools in the synthesis of modi®ed peptides with

increased activity and stability in vivo. Although much

less abundant than their a-analogs, b-amino acids are also

present in nature. b-Amino acid structures are found, for

instance, in the anticancer agent taxol, macrocyclic

peptides, and antibiotics 2b-lactam, cispentacin, etc.).

Recently, Seebach's^3,4and Gellman's^3,5groups found that

peptide analogs 2b-peptides) formed from b-amino acids

fold into de®ned three-dimensional structures 2helical struc-

tures) similar to those of natural peptides and they are much

more resistant than the corresponding a-peptide to be

cleavaged by pepsin and peptidase enzymes. b-Peptide 3

called as b-17⁵which was developed by Gellman's

group,^3,5is active against four species of bacteria, including

vancomycin-resistant Enterococcus faecium and methi-

cillin-resistant Staphylococcus aureus. b-17 is composed

of the b-amino acids, trans-2-aminocyclopentanecarboxylic

acid 1 and trans-4-amino-3-pyrrolidinecarboxylic acid 2

2Fig. 1).

The radical addition±cyclization using carbon±nitrogen

multiple bonds as radical acceptor has been extensively

studied for the preparation of cyclic amine derivatives by

several organic chemists including our group.^6,8

Our approach is shown in Scheme 1. Sulfanyl radical would

attack the terminal alkenyl group in the substrates 4 to

provide the alkyl radical species A which is expected to

form the substituted cyclic amines 5 via the aminyl radical

B as a result of 5-exo-trig cyclization of A. Subsequent

conversion of the phenylsulfanylmethyl group into the car-

boxyl group would furnish the desired b-amino acids 6. The

^qFor part 12 see Ref. 1.

Keywords: b-amino acid;thiophenol;radical cyclization;oxime ether;

hydrazone.

p

Corresponding author. Tel.: 181-78-441-7554;fax: 181-78-441-7556;

e-mail: taknaito@kobepharma-u.ac.jp

PII: S0040-4020202)00412-X

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O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

Figure 1. Cyclic b-amino acids and b-peptides.

Scheme 1.

nitrogen radical stability is dependent upon the attached

groups. The developing radical B would form a two-center,

three-electron bond⁸with the lone pair of either second

nitrogen present in the hydrazones or oxygen present in

oxime ethers. This three-electron bond will be responsible

for the stabilization of the developing nitrogen radical

during the course of cyclization. Consequently, the cycliza-

tion of radical A proceeds smoothly to form the stable

radical B.

malonate 11 by alkylation with an appropriate alkyl chloride

12. The alkylation of allylamine followed by either tosyla-

tion or t-butoxycarbonylation gave 7c and 7d in 38 and 36%

yields, respectively. The alkylation of allyl alcohol 15 with

16 followed by hydrolysis of the resulting acetal 17 and

subsequent treatment with methoxyamine gave the oxime

ether 7e. The amino acetals 18f, g were, respectively,

converted into 7f, g via tosylation, alkylation, deacetaliza-

tion, and ®nally condensation with methoxyamine. The

oxime ethers 7h and 7i having a chiral center were prepared

from the corresponding 2^)-amino esters 20h and 20i via

alkylation, t-butoxycarbonylation, reduction of the ester to

aldehyde, and ®nally, treatment with methoxyamine hydro-

chloride. The E/Z geometrical ratios of the aldoxime ether

2. Results and discussion

2.1. Preparation and radical addition±cyclization of the

alkenyl-tethered-oxime ethers

1

group in 7a±i thus prepared were deduced by H NMR

spectroscopy. In general, the signal due to the imino hydro-

gen of the E-aldoxime ether is shifted down®eld by the

in¯uence of the alkoxy group of the aldoxime ether

moiety.^8i,jIn the case of 7a, a signal due to the imino hydro-

gen of the E-isomer 2d 7.37) was shifted down ®eld with

respect to that of Z-isomer 2d 6.63).

The requisite substrates 7a±i for the radical reaction were

prepared as follows 2Scheme 2). The aldehyde 10, prepared

either by reduction of the ester 8 with diisobutylaluminum

hydride 2DIBAH) or by Swern or Dess±Martin oxidation of

the alcohol 9, was treated with methoxyamine hydro-

chloride in the presence of sodium acetate to give the

oxime ether 7a in 42±78% yield. The oxime ether 7b having

a quaternary carbon was prepared from diethyl allyl-

We then investigated the radical cyclization of oxime ethers

7a±g 2Table 1). As a typical example, a solution containing

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4461

Scheme 2.

thiophenol 21 equiv.) and AIBN 20.5 equiv.) in benzene was

added dropwise by a syringe pump over 2 h to a solution of

the oxime ether 7b in boiling benzene with stirring under

nitrogen. The solution was then re¯uxed for further 2 h and

concentrated to give a 4.0:1 mixture of the cis- and trans-

cyclopentylamines 22b and 23b in good yield 2entry 1).

Under the same reaction conditions, sulfanyl radical addi-

tion±cyclization of the simple substrate 7a gave a mixture

of cis-22a and trans-23a in 49% combined yield 2entry 2).

Sulfanyl radical addition±cyclization of the oxime ethers 7c

and 7d having the nitrogen atoms 2XNTs, NBoc) as a X

group, proceeded smoothly to give the cyclized products

22c and 23c, and 22d and 23d in 88 and 62% yields, respec-

tively 2entries 3 and 4). Similarly, 7e having oxygen atom as

a X group gave almost the same result leading to the forma-

tion of a 3.0:1 mixture of cis-22e and trans-23e in good

yield 2entry 5). The newly found radical addition±cycliza-

tion was successfully extended to the formation of

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O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

Table 1. Sulfanyl radical addition±cyclization of oxime ethers

Entry

Substrate

X

R

m

n

PhSH 2equiv.)

AIBN 2equiv.)

Yield 2%)

cis-22/trans-23 ratio

1

2

3

4

5

6

7

8

9

7b

7a

7c

7d

7e

7f

7g

C2COOEt)₂

CH₂

NTs

NBoc

O

NTs

Me

Bn

Me

1

2

1

2

1

3

1

3

0.5

1.5

0.5

1.5

76

49

88

62

72

14

41

34

47

4.0:1

3.3:1

2.0:1

3.0:1

1.2:1

1.6:1

1:2.0

Table 2. Sulfanyl radical addition±cyclization of oxime ethers

Entry

Substrate

R

PhSH 2equiv.)

AIBN 2equiv.)

Yield 2%)

Ratio of 24/25/26/27

1

2

7h

7i

Me

Ph

1

0.5

75

3:1:1:1

4:1 2an isomer)

6-membered ring product. Employment of PhSH 21 equiv.)

and AIBN 20.5 equiv.) gave the products 22f and 23f in only

14% yield 2entry 6) while an increased amount of PhSH

23 equiv.) and AIBN 21.5 equiv.) improved the yield to

41% 2entry 7). Under the same conditions, radical addi-

tion±cyclization of 7g gave 6-membered ring products

22g and 23g of which trans-isomer 23g was the major

product 2entry 9).

We next examined the radical addition±cyclization of

a-substituted oxime ethers 7h and 7i 2Table 2).

The radical addition±cyclization of oxime ether having the

methyl group at a-position of the oxime ether group

proceeded smoothly to give four cyclized products 24h,

25h, 26h, and 27h in 75% combined yield, of which 2,3-

trans-3,4-cis-24h was the major product. Similarly, the

substrate 7i having the phenyl group gave 2,3-trans-3,4-

cis-24i as the major product with better stereoselectivity

than that of 7h, in addition to one minor stereoisomer

which could not be isolated.

Figure 2. NOE correlations of compounds cis-31 and trans-32.

hand, the NOE in trans-32 was observed between PhSCH₂

and 1-H, and 2-H and NHBoc. The stereostructures of cis-

and trans-piperidines 22f, g and 23f, g were established by

coupling constants between 2-H and 3-H, and 3-H and 4-H

1

in the H NMR spectra.

The stereostructures of the cyclized products 22a-e, 23a-e,

24h, i, 25h, 26h, and 27h were ®rmly established by

NOESY of the H NMR spectra of either alkoxyamines

2.2. Preparation and radical addition±cyclization of the

alkenyl-tethered-hydrazones

1

22b-e, 23 b, d, e, 24h, i, 25h, 26h, and 27h, or the corre-

sponding carbamates 31, 32, and 45c 2see Fig. 2, Scheme 3,

and Table 5). Taking cis-31 and trans-32, prepared from 22a

and 23a, as a typical example, the assignment of those

con®gurations is based on the observed NOE correlations

as shown in Fig. 2. In the case of cis-31, the NOE was

observed between NHBoc and PhSCH₂. On the other

After successful cyclization of the oxime ethers 7a±i, we

then investigated the sulfanyl radical addition±cyclization

of the hydrazones 28a±d 2Table 3). According to the proc-

edure of the corresponding oxime ethers, the 2E)-hydra-

zones 28a±d were exclusively prepared. It is known^8fthat

the condensation of carbonyl compounds with N,N-

diphenylhydrazine provides only 2E)-hydrazone as a sole

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4463

Scheme 3.

Table 3. Sulfanyl radical addition±cyclization of hydrazones

Entry

Substrate

X

m

n

PhSH 2equiv.)

AIBN 2equiv.)

Yield 2%)

cis-29/trans-30 ratio

1

2

3

4

28a

28b

28c

28d

CH₂

NTs

O

1

2

1

3

0.5

1.5

73

75

84

30

2.0:1

1.5:1

1.3:1

1:1.6

NTs

product. Radical addition±cyclization of the hydrazone 28a

proceeded smoothly to give a 2.0:1 mixture of cis-29a and

trans-30a in 73% combined yield 2entry 1). This result

represents a much more ef®cient cyclization of the hydra-

zones than that of the oxime ether 7a. Similar tendencies

were observed for heterocycle synthesis, although stereo-

selectivities in the radical cyclization were lower 2entries

2 and 3). In the case of the hydrazone 28d, the 6-membered

ring products cis-29d and trans-30d were obtained in lower

yield and with reversed cis/trans ratio 2entry 4). The stereo-

structures of the cyclized products 29a±d and 30a±d were

®rmly established by coupling constants and NOESY of the

¹H NMR spectra.

in exo±trig manner, and no endo±trig products were

formed. 2b) In the case of the 5-membered ring products,

the cis-isomers were preferentially formed. Beckwith⁹has

explained that the preferential formation of the cis-product

from the 1-substituted hexenyl radical is ascribed to the

effects of orbital symmetry. In the case of 6-membered

products, the stable trans-isomers were formed except for

radical cyclization of 7f. 2c) In spite of existence in a stable

zig-zag conformer which is unfavorable to intramolecular

cyclization, the radical cyclization of 7a and 28a proceeded

smoothly to give the desired products. 2d) The cyclization

yield of 5-membered product was higher than that of

6-membered product. In general, it is known^6fthat cycliza-

tion of 6-heptenyl radical proceeds about 40 times slower

than that of the corresponding hexenyl radical.

The sulfanyl radical addition±cyclization of the alkenyl-

tethered-oxime ethers and hydrazones can be summarized

as follows 2Scheme 1). 2a) Addition of sulfanyl radical to the

terminal alkene and subsequent cyclization to the imine

moieties proceeded regioselectively to give the desired

products. Therefore, the reaction takes place exclusively

Thus, we have now succeeded in sulfanyl radical addition±

cyclization of the alkenyl-tethered-oxime ethers and

hydrazones for preparation of the multi-substituted cyclic

amines.

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Table 4. Sulfanyl radical addition±cyclization of oxime ethers in aqueous media

Entry

Substrate

m

PhSH 2equiv.)

VA-044 2equiv.)^a

Solvent

Yield 2%)

Ratio of 22/23

1

2

3

4

7g

7c

2

1

3

0.5

1.5

H₂O

20 245)^b

39 263)^b

65 283)^b

76 289)^b

1:1.5

1:1.8

2.0:1

MeOH±H₂O 23:2)

a

b

Yield taking recovered starting material into account.

2.3. Radical addition±cyclization of the alkenyl-

tethered-oxime ethers 7g and 7c in aqueous media

addition±cyclization in methanolic water to give a 2.0:1

mixture of 5-membered cis-22c and trans-23c 2entry 4).

Thus, we have established that radical cyclization in metha-

nolic water is an effective method for the formation of 5-

and 6-membered products and also amount of organic

solvents might be decreased as small as possible.

Due to the natural abundance of water as well as the inherent

advantages of using water as a solvent, much interest has

been recently growing in developing organic synthetic

reaction in water.^10,11We next investigated radical

addition±cyclization of oxime ethers 7g and 7c in water

using 2,2⁰-azobis[2-22-imidazolin-2-yl)propane] dihydro-

chloride 2VA-044) as water-soluble radical initiator 2Table

4). Radical cyclization of 7g in water 2without methanol)

using thiophenol 21 equiv.) and VA-044 20.5 equiv.) gave

the cyclized products 22g and 23g in only 20% yield

because of a low water-solubility of the substrate 2entry

1). Radical cyclization of the oxime ether 7g in MeOH±

H₂O 23:2) improved the cyclization yield 2entry 2). The

yield of 6-membered products 22g and 23g improved

from 39 to 65% yield when an increased equivalent of thio-

phenol 23 equiv.) and VA-044 21.5 equiv.) were used 2entry

3). Under the same conditions, 7c underwent smooth radical

2.4. Synthesis of 2-aminocyclopentanecarboxylic acids

Conversion of the radically cyclized cyclopentylamines

22a, 23a, 29a, and 30a to the cis-2-aminocyclopentane-

carboxylic acids 2cispentacin) and its trans-isomer was

readily achieved via the conventional reaction sequence as

shown in Schemes 3 and 4. Cispentacin¹²is an antifungal

antibiotic isolated from the culture broth of a Bacillus

cereus strain. At ®rst, the cis-methoxyamine 22a and cis-

hydrazine 29a were converted step by step into the exo-

methylene 35 as follows. Reductive cleavage of the N-meth-

oxy group in cis-22a followed by t-butoxycarbonylation of

Scheme 4.

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4465

Scheme 5.

the resulting cis-amine gave cis-31 in 75% yield, which was

also obtained from cis-hydrazine 29a via hydrogenolysis^8f

of the N±N bond and subsequent t-butoxycarbonylation.

Oxidation of cis-31 with mCPBA gave the cis-sulfoxide

33 as a 1:1 diastereomeric mixture, which was then

subjected to pyrolysis to afford the exo-methylene 35.

Similarly, trans-23a and 30a were converted into 35.

Hydroboration±oxidation of 35 with 9-BBN-H₂O₂gave

the desired cis-alcohol 36 with high regio- and diastereo-

selectivities as a result of attack of 9-BBN from the opposite

face of the substituent. Finally, the oxidation of 36 with

RuO₄afforded the desired cis-N-Boc-amino acid 37. The

spectral data of 37 were identical with those reported in

the literature.^12cSince 2^)-37 had previously been trans-

formed into 22)-cispentacin 29b) via the optical resolution

and removal of t-butoxycarbonyl group, the present method

provides a new synthesis of 22)-cispentacin.¹²ⁱ

coupling of the sulfurane D¹³or the attack of tri¯uoroacetate

anion on C-6 position of the isothiazolidinium salt E leading

to the CH₂±S bond cleavage followed by hydrolysis of the

resulting tri¯uoroacetate F 2Scheme 5). The alcohol 39 was

converted into trans-2-aminocyclopentanecarboxylic acid

44 via reductive cleavage of N±S bond, oxidation of the

alcohol, and hydrolysis. The spectral data of the correspond-

ing methyl ester 43 of the acid 42 were identical with those

reported in the literature.¹⁴Furthermore, the melting point

of 2^)-trans-amino acid 44 2mp 236±2388C 2dec.)) was

identical with that 2lit.¹⁵mp 2408C 2dec.)) reported in the

literature.

2.5. Synthesis of 4-amino-3-pyrrolidinecarboxylic acids

We next investigated synthesis of trans-4-amino-3-pyr-

rolidinecarboxylic acid 54 and the related compound 60

2Schemes 6 and 7). According to the procedure established

in the reaction of the cyclopentanes 22a and 23a, we ®rst

attempted reductive cleavage of N±O bond 2Table 5).

Treatment of N-tosyl-trans-pyrrolidine 23c with LiAlH₄

followed by t-butoxycarbonylation of the resulting amine

We next investigated conversion of trans-sulfoxide 34 into

trans-2-aminocyclocpentanecarboxylic acid 44, a compo-

nent amino acid of b-peptide, b-17. The trans-sulfoxide

34 was subjected to the Pummerer rearrangement and subse-

quent hydrolysis to give unexpectedly the alcohol 39 in 76%

yield with no isolation of the corresponding aldehyde 40.

The alcohol 39 would be formed via either the ligand

16

gave N-Boc-45c in low yield 2entry 1). When Mo2CO)₆

was used as reagent for N±O bond ®ssion, the desired

45c was obtained in good yield 2entry 2). However, the

Scheme 6.

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O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

Scheme 7.

Table 5. Conversion of N-methoxyamine 23 into N-Boc-45

hydrolysis of ester 53 with LiOH gave the carboxylic acid

which was ®nally deprotected by treatment with 4 M-HCl to

give the amino acid 54.^5c,17

In order to prepare the related cyclic b-amino acids, we

®nally investigated conversion of cyclized product 24i

into amino acid 60 by the similar sequence 2Scheme 7).

The t-butoxycarbonylation of 24i followed by oxidation of

the sul®des with mCPBA gave the sulfoxide as a mixture of

the diastereomers which was subjected to Pummerer

reaction to provide a 1:2 mixture of 2,3-trans-3,4-cis- and

2,3-trans-3,4-trans-aldehydes 55 and 56 as a result of

plausible isomerization of the unstable 3,4-cis-aldehyde

55. Actually, the fact that the aldehyde 55 was readily

isomerized into the isomeric aldehyde 56 just by treatment

with silica gel at room temperature clearly established that

the aldehyde 55 is 3,4-cis-isomer while the aldehyde 56 is

3,4-trans-isomer. The oxidation of trans-aldehyde 56 with

NaClO₂followed by the methylation of the resulting

carboxylic acid with diazomethane afforded the ester 58.

According to the procedure in the synthesis of 54 from 52,

58 was treated with Mo2CO)₆in re¯uxing MeCN. However,

58 was completely recovered with no formation of 59.

When the higher reaction temperature 2re¯uxing in EtCN

2978C)) was used, the desired dicarbamate 59 was obtained

in 50% yield. Finally, 59 was converted into the amino acid

60 via the hydrolysis by treatment with LiOH and deprotec-

tion with 4 M-HCl.

Entry

Substrate

Reagent

Yield 45 2%)

1

2

3

23c

22d

LiAlH₄

Mo2CO)₆

18

74

38

conversion of N-Boc-cis-methoxyamine 22d into N-Boc-

amine 45d via removal of the methoxy group with

Mo2CO)₆was not effective as shown in low yield of 45d

2entry 3). Consequently, we next examined the alternative

conversion of cyclized products 23d and 22d into the amino

acids by the sequence shown in Scheme 6. The t-butoxy-

carbonylation of 23d in the presence of Et₃N and DMAP

gave the dicarbamate 46. The oxidation of the trans-sul®de

46 with mCPBA followed by Pummerer rearrangement of

the resulting sulfoxide 47 in the presence of TFAA and

subsequent hydrolysis gave the trans-aldehyde 48.

Similarly, the cis-sul®de 22d was converted into the cis-

sulfoxide 50 via t-butoxycarbonylation and oxidation.

Pummerer rearrangement of cis-50 followed by hydrolysis

gave trans-aldehyde 48 in place of cis-aldehyde. This result

suggests that transiently formed cis-aldehyde isomerizes to

stable trans-isomer 48 under the hydrolytic basic condi-

tions. The oxidation of aldehyde 48 with NaClO₂in the

presence of 2-methyl-2-butene gave the carboxylic acid

51, which was treated with TMSCHN₂to give the ester

52. The cleavage of N±O bond in 52 with Mo2CO)₆

proceeded smoothly under re¯uxing MeCN 2818C) to give

the ester 53 in good yield while attempted N±O bond ®ssion

of 52 by treatment with Na±Hg was unsuccessful. The

3. Conclusion

We have succeeded in the synthesis of cyclic b-amino acids

based on the phenylsulfanyl radical addition±cyclization of

oxime ethers and hydrazones connected with alkenes.

The new methodology provides a synthetic approach to a

wide range of both natural and unnatural cyclic b-amino

acids.

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4467

4. Experimental

water. The organic phase was dried over Na₂SO₄and

concentrated under reduced pressure to give the crude alde-

hyde 10 as a pale yellow oil which was converted into the

identical oxime ether 7a 24.4 g, 42% from 9) as a colorless

oil by condensation with MeONH₂. This compound was

identical with 7a prepared from methyl 5-hexenoate 28).

4.1. General

1

Melting points are uncorrected. H and ¹³C NMR spectra

were recorded at 200, 300, or 500 MHz and at 75 or

125 MHz, respectively. IR spectra were recorded using

FTIR apparatus. Mass spectra were obtained by EI method.

Flash column chromatography 2FCC) was performed using

E. Merck Kieselgel 60 2230±400 mesh). Medium-pressure

column chromatography 2MPCC) was performed using

22)-2 Dess±Martin oxidation: to a stirred solution of 5-

hexene-1-ol 29) 22.9 mL, 24 mmol) in CH₂Cl₂2294 mL)

was added Dess±Martin periodinane¹⁸220 g, 48 mmol) at

room temperature under a nitrogen atmosphere. After the

solution was stirred at the same temperature for 4 h,

saturated aqueous NaHCO₃2208 mL) and Na₂S₂O₃252 g,

329 mmol) were added to the reaction mixture. The reaction

mixture was extracted with Et₂O and the organic phase was

washed with saturated aqueous NaCl, dried over Na₂SO₄,

and concentrated under reduced pressure to give the crude

aldehyde 10 as a pale yellow oil which was converted into

the identical oxime ether 7a 21.9 g, 63% from 9) as a color-

less oil by condensation with MeONH₂. This compound was

identical with 7a prepared from methyl 5-hexenoate 28).

È

Lobar groûe B 2E. Merck 310-25, Lichroprep Si60). Short

column chromatography 2SCC) was performed on a short

glass ®lter using Silica gel 60F-254 2Merck) under reduced

pressure. Preparative TLC 2PTLC) was performed on pre-

coated Silica gel 60F-254 plates 20.5 mm thick, Merck).

4.1.1. 3E/Z)-5-Hexenal O-methyloxime 37a). 21) Prepara-

tion from methyl 5-hexenoate )8). To a stirred solution of

methyl 5-hexenoate 28) 20.42 mL, 3 mmol) in Et₂O

26.2 mL) was added dropwise DIBAH 20.95 M in hexane)

25.05 mL, 4.8 mmol) at 2788C under

a

nitrogen

4.1.2. Diethyl 3E/Z)-[2-3methoxyimino)ethyl-2-pro-

penyl]propanedioate 37b). To a stirred solution of NaOEt

in EtOH prepared from Na 20.7 g, 30 mmol) and EtOH

25 mL) was added dropwise diethyl allylmalonate 211)

26 g, 30 mmol) at room temperature under a nitrogen

atmosphere. After being stirred at the same temperature

for 0.5 h, 2-chloroacetaldehyde O-methyloxime 212)

23.2 g, 30 mmol) was added dropwise at room temperature.

After being re¯uxed for 2 h, the reaction mixture was

diluted with water and extracted with CHCl₃. The organic

phase was washed with water, dried over Na₂SO₄, and

concentrated under reduced pressure. The residue was puri-

®ed by MPCC 2hexane/AcOEt 9:1) to afford 7b 25.7 g, 71%)

as a pale yellow oil and a 3:1 mixture of E- and Z-isomers;

atmosphere. After the solution was stirred at the same

temperature for 4 h, MeOH 21.2 mL) was added to the reac-

tion mixture. After being stirred at 08C for 10 min, 36%

aqueous potassium sodium tartrate 222 mL) was added and

then the reaction mixture was stirred at room temperature

for 1.5 h. The reaction mixture was diluted with CH₂Cl₂and

washed with water. The organic phase was dried over

Na₂SO₄and concentrated under reduced pressure to give

the crude aldehyde 10 as a pale yellow oil. After being

1

characterized by H NMR spectrum, 10 was immediately

subjected to the following reaction. To a stirred solution of

the crude aldehyde 10 in CH₂Cl₂250 mL) was added

AcONa 2492 mg, 6 mmol) and MeONH₂´HCl 2251 mg,

3 mmol) at room temperature under a nitrogen atmosphere.

After being stirred at room temperature for 2.5 h, the reac-

tion mixture was diluted with water and extracted with

CH₂Cl₂. The organic phase was washed with water and

dried over Na₂SO₄and concentrated under reduced

pressure. The residue was distilled to afford the oxime

ether 7a 2297 mg, 78%) as a colorless oil and a 4:3 mixture

of E- and Z-isomers;bp 140 8C;IR 2CHCl ₃) 1640

1

IR 2CHCl₃) 1729 2COO), 1653 2CvN) cm²¹; H NMR

2200 MHz, CDCl₃) d 1.26 26H, t, J7 Hz), 2.62±2.70

22H, m), 2.73 26/4H, d, J7 Hz), 2.83 22/4H, d, J5 Hz),

3.80 29/4H, s), 3.86 23/4H, s), 4.23 22/4H, q, J7 Hz), 5.18±

5.08 22H, m), 5.67 21H, m), 6.89 21/4H, t, J5 Hz), 7.33

23/4H, t, J7 Hz);HRMS 2EI, m/z) calcd for C₁₃H₂₁NO₅

2M¹) 271.1419, found 271.1417.

1

2CvN) cm²¹; H NMR 2200 MHz, CDCl₃) d 1.52±1.65

4.1.3. 3E/Z)-N-[2-3Methoxyimino)ethyl]-4-methyl-N-32-

propenyl)benzenesulfonamide 37c). To a stirred solution

of allylamine 213) 23.99 g, 70 mmol) in benzene 246.8 mL)

was added a solution of chloroacetaldehyde O-methyloxime

212) 22.5 g, 23 mmol) in benzene 211.7 mL) at room

temperature under a nitrogen atmosphere. After being stir-

red at 808C for 5 h, the reaction mixture was concentrated

under reduced pressure. The residue was puri®ed by SCC

2AcOEt) to afford 2E/Z)-22-propenylamino)acetaldehyde

O-methyloxime 214) 21.2 g, 41%) as a pale yellow oil. To

a solution of 14 21.28 g, 10 mmol) in CH₂Cl₂211.4 mL)

were added Et₃N 21.89 mL, 13.6 mmol) and TsCl 22.29 g,

12 mmol) at 08C under a nitrogen atmosphere. After being

stirred at room temperature for 3 h, Et₃N 20.95 mL,

6.8 mmol) and TsCl 21.15 g, 6 mmol) at 08C were added

monitoring the reaction by TLC. After being stirred at

room temperature for 1 h, the reaction mixture was diluted

with water and extracted with CH₂Cl₂. The organic phase

was washed with water, dried with Na₂SO₄, and

22H, m), 2.05±2.15 22H, m), 2.20 28/7H, br td, J7,

6 Hz), 2.33 26/7H, td, J7.5, 5 Hz), 3.81 212/7H, s), 3.86

29/7H, s), 5.07±4.95 22H, m), 5.80 21H, m), 6.63 23/7H, t,

J5 Hz), 7.37 24/7H, t, J6 Hz).;HRMS 2EI, m/z) calcd for

C₇H₁₃NO 2M¹) 127.1003, found 127.0997.

22) Preparation from 5-hexen-1-ol )9)

22)-1 Swern oxidation: to a stirred solution of oxalyl

chloride 28 mL, 92 mmol) in CH₂Cl₂260 mL) was added

dropwise a solution of DMSO 213 mL, 183 mmol) in

CH₂Cl₂220 mL) at 2788C under a nitrogen atmosphere.

After the solution was stirred at the same temperature for

0.5 h, a solution of 5-hexen-1-ol 29) 210 mL, 83.2 mmol) in

CH₂Cl₂283 mL) was added to the reaction mixture. After

being stirred at the same temperature for 20 min, Et₃N

258 mL, 416 mmol) was added and then the reaction

mixture was stirred at room temperature for 0.5 h. The reac-

tion mixture was diluted with CH₂Cl₂and washed with

4468

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

concentrated under reduced pressure. The residue was puri-

®ed by FCC 2hexane/AcOEt 1:1) to afford 7c 22.6 g, 92%) as

a pale yellow oil and a 3:2 mixture of E- and Z-isomers;IR

stirred for 2 h at room temperature, the reaction mixture was

diluted with water and extracted with CHCl₃. The organic

phase was dried over MgSO₄and concentrated under

reduced pressure to give the crude tosylate. To a solution

of the crude tosylate and K₂CO₃25.6 g, 0.04 mol) in acetone

255 mL) was added allyl bromide 23.63 g, 0.03 mol) under a

nitrogen atmosphere. After being re¯uxed for 5 h, the

reaction mixture was diluted with water and extracted

with CHCl₃. The organic phase was dried over MgSO₄

and concentrated under reduced pressure. Puri®cation of

the residue by MPCC 2hexane/AcOEt 5:1) affored N-22-pro-

penyl)-N-[2-21,3-dioxolan-2-yl)ethyl]-4-methylbenzenesul-

fonamide 219f) 21.69 g, 63%) as yellow oil. To a solution of

the acetal 19f 25.12 g, 4.2 mmol) in acetone 236 mL) was

added 2 M-HCl 225 mL) under a nitrogen atmosphere at

room temperature. After being stirred for a further 3 h, the

reaction mixture was extracted with CHCl₃. The organic

phase was dried over MgSO₄and concentrated under

reduced pressure to give the crude aldehyde as a yellow

oil. According to the procedure given for the conversion

of 10 into 7a, the crude aldehyde was treated with AcONa

2673 mg, 8.2 mmol) and MeONH₂´HCl 2342 mg, 4.1 mmol)

to afford the oxime ether 7f 2939 mg, 77%) as a pale yellow

oil and a mixture 1:1 of E- and Z-isomers;IR 2CHCl ₃) 1599

1

2CHCl₃) 1645 2CvN), 1344, 1159 2NSO₂) cm²¹; H NMR

2300 MHz, CDCl₃) d 2.43 23H, s), 3.76±3.82 22H, m), 3.79

29/5H, s), 3.84 26/5H, s), 3.88 26/5H, d, J6 Hz), 3.99

24/5H, d, J4 Hz), 5.13±5.22 22H, m), 5.66 21H, m), 6.62

22/5H, t, J4 Hz), 7.18 23/5H, t, J6 Hz), 7.31 22H, br dd,

J8, 2 Hz), 7.70 22H, br dd, J8, 2 Hz);HRMS 2EI, m/z)

calcd for C₁₃H₁₈N₂O₃S 2M¹) 282.1038, found 282.1008.

4.1.4. 1,1-Dimethylethyl 3E/Z)-N-[2-3methoxyimino)-

ethyl]-N-32-propenyl)carbamate 37d). To a solution of

14 21.43 g, 11 mmol) in CH₂Cl₂211.4 mL) were added

Et₃N 21.89 mL, 13.6 mmol) and 2Boc)₂O 22.43 g,

11.2 mmol) at room temperature under

a nitrogen

atmosphere. After being stirred at room temperature for

7 h, the reaction mixture was diluted with water and

extracted with CH₂Cl₂. The organic phase was washed

with water, dried with MgSO₄, and concentrated under

reduced pressure. The residue was puri®ed by FCC 2hexane/

AcOEt 5:1) to afford 7d 22.24 g, 88%) as a pale yellow oil

and a 1:1 mixture of E- and Z-isomers;IR 2CHCl ) 1690

3

2NCOO) cm²¹; ¹H NMR 2200 MHz, CDCl₃) d 1.46 29H, s),

3.85 22H, d, J6 Hz), 3.87 23H, s), 4.05 22H, m), 5.11 22H,

m), 5. 76 21H, m), 6.62 21/2H, br t, J5 Hz), 7.30 21/2H, t,

J6 Hz);HRMS 2EI, m/z) calcd for C₁₁H₂₀N₂O₃2M¹)

228.1473, found 228.1466.

1

2CvN, CvC) cm²¹; H NMR 2300 MHz, CDCl₃) d 2.43

23H, s), 2.41±2.55 22H, m), 3.30 22H, m), 3.80 23/2H, s),

3.82 22H, m), 3.85 23/2H, s), 5.13±5.24 22H, m), 5.65 21H,

m), 7.26 21/2H, t, J5 Hz), 7.31 21/2H, t, J6 Hz), 7.32

22H, br d, J8 Hz), 7.70 22H, br d, J8 Hz);HRMS 2EI,

m/z) calcd for C₁₄H₂₀N₂O₃S 2M¹) 296.1194, found

296.1190.

4.1.5. 3E/Z)-32-Propenyloxy)acetaldehyde O-3phenyl-

methyl)oxime 37e). To a stirred solution of the acetal 17¹⁹

23.18 g, 21.8 mmol), prepared from allyl alcohol 215) and

the acetal 16, in acetone 2137 mL) was added 2 M-HCl

212.7 mL) at 108C under a nitrogen atmosphere. After the

solution was stirred at room temperature for 3.5 h, the reac-

tion mixture was diluted with water, extracted with CH₂Cl₂.

The organic phase was dried over Na₂SO₄and concentrated

under reduce pressure to give the crude aldehyde as yellow

oil. After being characterized by NMR spectrum, the crude

aldehyde was immediately subjected to the following reac-

tion. To a stirred solution of the crude aldehyde in MeOH

2102 mL) was added AcONa 23.57 g, 43.6 mmol) and

BnONH₂´HCl 25.23 g, 32.7 mmol) at room temperature

under a nitrogen atmosphere. After being stirred at room

temperature for 19 h, the reaction mixture was diluted

with water and extracted with CH₂Cl₂. The organic phase

was washed with water and dried over Na₂SO₄and concen-

trated under reduced pressure. The residue was puri®ed by

FCC 2hexane/AcOEt 5:1) to afford 7e 22.8 g, 64%) as a pale

yellow oil and a 3:2 mixture of E- and Z-isomers;IR

4.1.7. 3E/Z)-N-33-Butenyl)-N-[2-3methoxyimino)ethyl]-4-

methylbenzenesulfonamide 37g). To a solution of 2-

aminoacetoaldehyde

dimethylacetal

218g)

23.15 g,

0.03 mol) in CH₂Cl₂250 mL) were added Et₃N 24.05 g,

0.04 mol) and then TsCl 27.63 g, 0.04 mol) in CH₂Cl₂

under a nitrogen atmosphere at 08C. After being stirred for

2 h at room temperature, the reaction mixture was diluted

with water and extracted with CHCl₃. The organic phase

was dried over MgSO₄and concentrated under reduced

pressure to give the crude tosylate. To a solution of the

crude tosylate and K₂CO₃25.6 g, 0.04 mol) in acetone

255 mL) was added 4-bromo-1-butene 24.05 g, 0.03 mol)

under a nitrogen atmosphere. After being re¯uxed for 5 h,

the reaction mixture was diluted with water and extracted

with CHCl₃. The organic phase was dried over Mg₂SO₄and

concentrate under reduced pressure. Puri®cation of the resi-

due by MPCC 2hexane/AcOEt 5:1) afforded N-23-butenyl)-

N-22,2-dimethoxyethyl)-4-methylbenzenesulfonamide 219g)

24.32 g, 46%) as a pale yellow oil. To a solution of the acetal

19g 21.61 g, 5.14 mmol) in acetone 250 mL) was added 2 M-

HCl 231 mL) under a nitrogen atmosphere at room tempera-

ture. After being stirred for 1 h, 2 M-HCl 231 mL) was again

added to the reaction mixture. After being stirred a further

1 h, the reaction mixture was extracted with CHCl₃. The

organic phase was dried over MgSO₄and concentrated

under reduced pressure to give the crude aldehyde as a

yellow oil. According to the procedure given for the conver-

sion of 10 into 7a, the crude aldehyde was treated with

AcONa 2845 mg, 10.3 mmol) and MeONH₂´HCl 2429 mg,

5.14 mmol) to afford the oxime ether 7g 2718 mg, 47%) as a

pale yellow oil and a mixture 1:1 of E- and Z-isomers;IR

1

2CHCl₃) 1644 2CvN) cm²¹; H NMR 2300 MHz, CDCl₃)

d 3.95±4.01 22H, m), 4.08 26/5H, d, J6 Hz), 4.32 24/5H, d,

J3.5 Hz), 5.10 22H, s), 5.30±5.68 22H, m), 5.89 21H, m),

6.89 22/5H, t, J3.5 Hz)), 7.26±7.40 210H, m), 7.52 23/5H,

t, J6 Hz);HRMS 2EI, m/z) calcd for C₁₂H₁₅NO₂2M¹)

205.1103, found 205.1098.

4.1.6. 3E/Z)-N-[3-3Methoxyimino)propyl]-4-methyl-N-

32-propenyl)benzenesulfonamide 37f). To a solution of

1,3-dioxolane-2-ethanamine 218f) 23.48 g, 0.03 mol) in

CH₂Cl₂250 mL) were added Et₃N 24.05 g, 0.04 mol) and

then a solution of TsCl 27.63 g, 0.04 mol) in CH₂Cl₂

250 mL) under a nitrogen atmosphere at 08C. After being

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4469

1

2CHCl₃) 1599 2CvN, CvC) cm²¹; H NMR 2300 MHz,

CH₂Cl₂2300 mL) were added Et₃N 24.2 mL, 30 mmol)

and 2Boc)₂O 26.6 g, 30 mmol) at room temperature under

a nitrogen atmosphere. After being stirred at room tempera-

ture for 48 h, the reaction mixture was diluted with water

and extracted with CHCl₃. The organic phase was washed

with water, dried with Na₂SO₄, and concentrated under

reduced pressure. The residue was puri®ed by FCC 2hexane/

AcOEt 10:1) to afford 21i 21.2 g, 26%) as a pale yellow oil;

IR 2CHCl₃) 1686 2NCOO), 1746 2COOMe) cm²¹; ¹H NMR

2200 MHz, CDCl₃) d 1.48 29H, s), 3.60 21H, br dd, J16,

6 Hz), 3.76 23H, s), 3.87 21H, dm, J16 Hz), 4.88 22H, m),

5.40±5.90 22H, m), 7.26±7.34 25H, m);HRMS 2EI, m/z)

calcd for C₁₇H₂₃NO₄2M¹) 305.1625, found 305.1634.

CDCl₃) d 2.30 22H, q, J7 Hz), 2.43 23H, s), 3.21 22H, t,

J7 Hz), 3.80 23/2H, s), 3.86 23/2H, s), 3.89 21H, d,

J6 Hz), 4.02 21H, d, J6 Hz), 5.01±5.12 22H, m), 5.71

21H, m), 6.62 21/2H, t, J5 Hz), 7.18 21/2H, t, J6 Hz),

7.31 22H, br d, J8 Hz), 7.69 22H, br d, J8 Hz);HRMS

2EI, m/z) calcd for C₁₄H₂₀N₂O₃S 2M¹) 296.1194, found

296.1168.

4.1.8. Methyl N-[31,1-dimethylethoxy)carbonyl]-N-32-

propenyl)alaninate 321h). To a stirred solution of 2^)-

alanine methyl ester hydrochloride 220 h) 25.6 g,

40 mmol) in CH₂Cl₂220 mL) were added Et₃N 25.6 mL,

40 mmol) and allyl bromide 23.5 mL, 40 mmol) at 08C

under a nitrogen atmosphere. After being stirred at room

temperature for 24 h, the reaction mixture was diluted

with water and extracted with CHCl₃. The organic phase

was washed with water, dried with Na₂SO₄, and concen-

trated under reduced pressure to give the crude allylamine.

4.1.11. 1,1-Dimethylethyl 3E/Z)-N-[2-3methoxyimino)-1-

phenylethyl]-N-32-propenyl)carbamate 37i). According

to the procedure given for the conversion of 8 into 7a, the

reduction of the ester 21i 2300 mg, 1 mmol) with DIBAH

20.95 M in hexane) 21.37 mL, 1.3 mmol) followed by the

treatment of the resulting aldehyde with AcONa 2328 mg,

4 mmol) and MeONH₂´HCl 2166 mg, 2 mmol) to afford the

oxime ether 7i 2139 mg, 46%) as pale yellow oil and a

mixture 1:2 of E- and Z-isomers;IR 2CHCl ₃) 1687

To a solution of the crude allylamine 2215 mg, 1.5 mmol) in

CH₂Cl₂230 mL) were added Et₃N 20.2 mL, 1.5 mmol) and

2Boc)₂O 2327 mg, 1.5 mmol) at room temperature under a

nitrogen atmosphere. After being stirred at room tempera-

ture for 24 h, the reaction mixture was diluted with water

and extracted with CHCl₃. The organic phase was washed

with water, dried over Na₂SO₄, and concentrated under

reduced pressure. The residue was puri®ed by MPCC

2hexane/AcOEt 1:1) to afford 21h 2309 mg, 85%) as a

1

2NCOO) cm²¹; H NMR 2300 MHz, CDCl₃) d 1.36 29H,

s), 3.75 21H, m), 3.88 22H, s), 3.86 21H, s), 3.98 21H, m),

5.09±5.15 22H, m), 5.51±5.85 22H, m), 6.81 22/3H, d,

J6 Hz), 7.22±7.35 25H, m), 7.39 21/3H, dm, J5 Hz);

HRMS 2EI, m/z) calcd for C₁₇H₂₄N₂O₃2M¹) 304.1786,

found 304.1792.

pale yellow oil;IR 2CHCl

) 1687 2NCOO), 1742

3

2COOMe) cm²¹; H NMR 2200 MHz, CDCl₃) d 1.41 23H,

d, J7 Hz), 1.44 29H, s), 3.70 23H, s), 3.63±4.60 23H, m),

5.12±5.23 22H, m), 5.78±5.90 21H, m);HRMS 2EI, m/z)

calcd for C₁₂H₂₁NO₄2M¹) 243.1469, found 243.1482.

1

4.2. General procedure for radical cyclization of oxime

ethers

To a boiling solution of the oxime ether 7a±i 21 mmol) in

benzene 210 mL) under a nitrogen atmosphere was added a

solution of thiophenol 21 or 3 mmol) and AIBN 20.5 or

1.5 mmol) in benzene 220 mL) by a syringe pump 25 mL/

h) over 2 h. After the reaction mixture was heated at re¯ux

for a further 2 h, the solvent was evaporated under reduced

pressure. Puri®cation of the residue by MPCC afforded the

cyclized products 22a±g, 23a±g, and 24±27h, i as shown in

Tables 1 and 2. In the case of 22d, 23d, 24h, i, 25h, 26h, and

27h, the presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.1.9. 1,1-Dimethylethyl 3E/Z)-N-[2-3methoxyimino)-1-

methylethyl]-N-32-propenyl)carbamate 37h). According

to the procedure given for the conversion of 8 into 7a, the

reduction of the ester 21h 2140 mg, 0.58 mmol) with

DIBAL 20.95 M in hexane) 21.53 mL, 1.45 mmol) followed

by the treatment of the resulting aldehyde with AcONa

295 mg, 1.16 mmol) and MeONH₂´HCl 248 mg,

0.58 mmol) to afford the oxime ether 7h 294 mg, 68%) as

a pale yellow oil and a mixture 2:3 of E- and Z-isomers;IR

2CHCl₃) 1684 2NCOO) cm²¹; ¹H NMR 2300 MHz, CDCl₃)

d 1.31 26/5H, d, J7 Hz) 1.34 29/5H, d, J7 Hz), 1.46 29H,

s), 3.74±3.94 23H, m), 3.83 23H, s), 3.86 29/5H, s), 5.09±

5.15 22H, m), 5.72±5.85 21H, m), 6.81 23/5H, d, J6 Hz),

7.39 22/5H, dm, J5 Hz);HRMS 2EI, m/z) calcd for

C₁₂H₂₂N₂O₃2M¹) 242.1629, found 242.1631.

4.2.1. cis-N-Methoxy-2-[3phenylsulfanyl)methyl]cyclo-

pentanamine 322a). Pale yellow oil;IR 2CHCl ₃) 3450

2NH) cm²^{1 1}H NMR 2200 MHz, CDCl₃) d 1.64±2.16

;

26H, m), 2.38 21H, m), 3.11 21H, dd, J12.5, 8.5 Hz),

3.41 21H, dd, J12.5, 7 Hz), 3.73 21H, m), 3.74 23H, s),

5.75 21H, br s), 7.30±7.60 25H, m);HRMS 2EI, m/z) calcd

for C₁₃H₁₉NOS 2M¹) 237.1187, found 237.1180.

4.1.10. Methyl N-[31,1-dimethylethoxy)carbonyl]-2-

phenyl-N-32-propenyl)glycininate 321i). To a stirred solu-

tion of 2^)-phenylglycine methyl ester hydrochloride 220i)

210 g, 50 mmol) in CH₂Cl₂2100 mL) were added Et₃N

26.8 mL, 50 mmol) and allyl bromide 24 mL, 50 mmol) at

08C under a nitrogen atmosphere. After being stirred at

room temperature for 24 h, the reaction mixture was diluted

with water and extracted with CHCl₃. The organic phase

was washed with water, dried over Na₂SO₄, and concen-

trated under reduced pressure to give the crude allylamine.

4.2.2. trans-N-Methoxy-2-[3phenylsulfanyl)methyl]cyclo-

pentanamine 323a). Pale yellow oil;IR 2CHCl ₃) 3455

2NH) cm²^{1 1}H NMR 2300 MHz, CDCl₃) d 1.21±2.00

;

27H, m), 2.81 21H, dd, J12.5, 7.5 Hz), 3.01 21H, dd,

J12.5, 6.5 Hz), 3.19 21H, m), 3.43 23H, s), 5.45 21H, br

s), 7.05±7.30 25H, m);HRMS 2EI,

m/z) calcd for

C₁₃H₁₉NOS 2M¹) 237.1187, found 237.1196.

4.2.3. Diethyl cis-3-3methoxyamino)-4-3phenylsulfanyl)-

methyl-1,1-cyclopentanedicarboxylate 322b). Pale yellow

To a solution of the crude allylamine 23 g, 15 mmol) in

4470

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

1

oil;IR 2CHCl ) 3566 2NH), 1725 2COO) cm²¹; H NMR

4.2.8.

[3phenylsulfanyl)methyl]pyrrolidine-1-carboxylate 323d).

Pale yellow oil;IR 2CHCl 3550 2NH), 1687

1,1-Dimethylethyl

trans-3-methoxyamino-4-

3

2500 MHz, CDCl₃) d 1.22 23H, t, J7 Hz), 1.25 23H, t,

J7 Hz), 2.26 21H, dd, J12.5, 11 Hz), 2.32 21H, m),

2.41±2.49 23H, m), 2.95 21H, dd, J13, 8 Hz), 3.11 21H,

dd, J13, 7.5 Hz), 3.48 23H, s), 3.58 21H, br td, J6, 4 Hz),

4.18 22H, q, J7 Hz), 4.55 22H, q, J7 Hz), 5.63 21H, br s),

7.16±7.36 25H, m). NOE was observed between NH 2d

5.63) and CH₂SPh 2d 3.11) in NOESY spectroscopy.

HRMS 2EI, m/z) calcd for C₁₉H₂₇NO₅S 2M¹) 381.1610,

found 381.1600.

)

3

2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.45 29H,

s), 2.33 21H, m), 2.88 21H, m), 3.06 21H, m), 3.22 21H,

m), 3.27 21H, m), 3.48±3.70 23H, m), 3.49 23H, s), 5.58

21H, br s), 7.18±7.8 25H, m); ¹³C NMR 275 MHz, CDCl₃)

d 28.09, 28.34, 35.67, 38.95, 39.77, 45.84, 49.21, 49.69,

61.67, 62.19, 34.16, 79.41, 82.13, 126.47, 128.90, 129.84,

130.13, 135.56, 154.18, 156.52;HRMS 2EI, m/z) calcd for

C₁₇H₂₆N₂O₃S 2M¹) 338.1663, found 338.1664. The

presence of rotamers precluded a comprehensive assign-

ment of all proton and carbon resonances.

1

4.2.4. Diethyl trans-3-3methoxyamino)-4-3phenylsulfanyl)-

methyl-1,1-cyclopentanedicarboxylate 323b). Pale yellow

1

oil;IR 2CHCl ) 3525 2NH), 1726 2COO) cm²¹; H NMR

3

2500 MHz, CDCl₃) d 1.23 23H, t, J7 Hz), 1.24 23H, t,

J7 Hz), 1.97 21H, dd, J13, 9 Hz), 2.17 21H, br sext,

J7 Hz), 2.28 21H, dd, J14, 6 Hz), 2.51, 21H, dd, J14,

8 Hz), 2.67, 21H, dd, J13, 8 Hz), 2.92 21H, dd, J13,

8 Hz), 3.16 21H, dd, J13, 6.5 Hz), 3.37 21H, br q,

J7 Hz), 3.47 23H, s), 4.17 22H, q, J7 Hz), 4.18 22H, q,

J7 Hz), 5.63 21H, br s), 7.16±7.36 25H, m). NOE was

observed between NH 2d 5.63) and 4-H 2d 2.17), and

CH₂SPh 2d 2.92, 3.16) and 3-H 2d 3.36) in NOESY spectro-

scopy. HRMS 2EI, m/z) calcd for C₁₉H₂₇NO₅S 2M¹)

381.1610, found 381.1603.

4.2.9. cis-Tetrahydro-N-phenylmethoxy-4-3phenylsul-

fanyl)methyl-3-furanamine 322e). Pale yellow oil;IR

1

2CHCl₃) 3452 2NH) cm²¹; H NMR 2500 MHz, CDCl₃) d

2.51, 21H, m), 2.92 21H, dd, J13, 9 Hz), 3.19 21H, dd,

J13, 7.5 Hz), 3.65 21H, t, J8.5 Hz), 3.73 21H, m), 3.87

21H, dd, J9.5, 3.5 Hz), 3.90 21H, dd, J9.5, 5 Hz), 3.96

21H, t, J8.5 Hz), 4.72 and 4.70 22H, ABq, J11 Hz), 5.69

21H, br s), 7.18±7.36 210H, m). NOE was observed between

NH 2d 5.69) and CH₂SPh 2d 2.92, 3.19) in NOESY spectro-

scopy. HRMS 2EI, m/z) calcd for C₁₈H₂₁NO₂S 2M¹)

315.1293, found 392.1315.

4.2.5. cis-N-Methoxy-1-34-methylphenyl)sulfonyl-4-3phenyl-

sulfanyl)methyl-3-pyrrolidinamine 322c). Pale yellow oil;

IR 2CHCl₃) 3540 2NH), 1345, 1161 2NSO₂) cm²¹; ¹H NMR

2500 MHz, CDCl₃) d 2.33 21H, br sext, J7 Hz), 2.42 23H,

s), 2.75 21H, dd, J13, 8.5 Hz), 3.00 21H, dd, J13, 7 Hz),

3.11 21H, br t, J9 Hz), 3.27 23H, s), 3.37 21H, dd, J11.5,

3.5 Hz), 3.40 21H, dd, J11.5, 6.5 Hz), 3.53 21H, dd, J10,

7.5 Hz), 3.57 21H, m), 5.41 21H, br s), 7.19±7.32 27H, m),

7.71 22H, br d, J8 Hz). NOE was observed between NH 2d

5.41) and CH₂SPh 2d 3.00) in NOESY spectroscopy. HRMS

2EI, m/z) calcd for C₁₉H₂₄N₂O₃S₂2M¹) 392.1228, found

392.1242.

4.2.10. trans-Tetrahydro-N-phenylmethoxy-4-3phenyl-

sulfanyl)methyl-3-furanamine 323e). Pale yellow oil;IR

1

2CHCl₃) 3484 2NH) cm²¹; H NMR 2500 MHz, CDCl₃) d

2.29, 21H, m), 2.91 21H, dd, J13, 8 Hz), 3.05 21H, dd,

J13, 7 Hz), 3.56 21H, dd, J9, 5.5 Hz), 3.58 21H, m),

3.71 21H, dd, J10, 3.5 Hz), 3.87 21H, dd, J10, 6 Hz),

4.00 21H, dd, J9, 7 Hz), 4.67 and 4.69 22H, ABq,

J11.5 Hz), 5.50 21H, br s), 7.18±7.35 210H, m). NOE

was observed between NH 2d 5.50) and 4-H 2d 2.29), and

3-H 2d 3.58) and CH₂SPh 2d 3.05) in NOESY spectroscopy.

HRMS 2EI, m/z) calcd for C₁₈H₂₁NO₂S 2M¹) 315.1293,

found 315.1300.

4.2.6. trans-N-Methoxy-1-34-methylphenyl)sulfonyl-4-

3phenylsulfanyl)methyl-3-pyrrolidinamine 323c). Pale

4.2.11. cis-N-Methoxy-1-[34-methylphenyl)sulfonyl]-3-

[3phenylsulfanyl)methyl]-4-piperidinamine 322f). Pale

yellow oil;IR 2CHCl

)

3556 2NH), 1346, 1162

yellow oil;IR 2CHCl ₃) 3485 2NH) cm^{21 1}H NMR

;

3

2NSO₂) cm²¹; H NMR 2500 MHz, CDCl₃) d 2.17, 21H,

m), 2.43, 23H, s), 2.70 21H, dd, J13.5, 8.5 Hz), 2.94

21H, dd, J13.5, 6.5 Hz), 3.08 21H, dd, J10, 5.5 Hz),

3.17 21H, dd, J10, 4 Hz), 3.37 23H, s), 3.38 21H, dd,

J10, 6 Hz), 3.41 21H, m), 3.46 21H, dd, J10, 7 Hz),

5.37 21H, br s), 7.19±7.32 27H, m), 7.70 22H, br d,

J8 Hz);HRMS 2EI, m/z) calcd for C₁₉H₂₄N₂O₃S₂2M¹)

392.1228, found 392.1227.

2500 MHz, CDCl₃) d 1.63 21H, m) 1.71 21H, dtd, J14,

9, 4 Hz), 2.12 21H, m), 2.43 23H, s), 2.71 21H, m), 2.68±

2.75 22H, m), 2.91 21H, dd, J13, 10 Hz), 3.08 21H, dt,

J9, 4 Hz), 3.16 21H, dd, J13, 4.5 Hz), 3.42 23H, s),

3.47 21H, br dt, J10, 5 Hz), 3.57 21H, br dd, J11,

5 Hz), 5.33 21H, br s), 7.17±7.40 27H, m), 7.64 22H, br d,

J8 Hz). NOE was observed between NH 2d 5.33) and

CH₂SPh 2d 3.16), CH₂SPh 2d 2.91) and 5-Hax 2d 1.71),

and 4-H 2d 3.08) and 6 and 2-H 2d 2.68±2.75) in NOESY

spectroscopy. HRMS 2EI, m/z) calcd for C₂₀H₂₆N₂O₃S₂

2M¹) 406.1383, found 406.1367.

1

4.2.7. 1,1-Dimethylethyl cis-3-methoxyamino-4-[3phenyl-

sulfanyl)methyl]pyrrolidine-1-carboxylate 322d). Pale

yellow oil;IR 2CHCl ) 3556 2NH), 1686 2NCOO) cm²¹

;

3

¹H NMR 2500 MHz, CDCl₃) d 1.45 29H, s), 2.46 21H, m),

2.94 21H, m), 3.12 21H, m), 3.20 21H, m), 3.40 21H, m),

3.48±3.66 24H, m), 3.52 23H, s), 5.59 21H, br s), 7.18±7.8

25H, m); ¹³C NMR 275 MHz, CDCl₃) d 28.38, 31.68, 31.80,

40.36, 41.21, 49.16, 49.35, 49.57, 49.85, 59.91, 60.43, 62.03,

79.23, 126.32, 128.94, 129.52, 135.57, 154.41;HRMS 2EI,

m/z) calcd for C₁₇H₂₆N₂O₃S 2M¹) 338.1663, found

338.1676. The presence of rotamers precluded a comprehen-

sive assignment of all proton and carbon resonances.

4.2.12. trans-N-Methoxy-1-[34-methylphenyl)sulfonyl]-3-

[3phenylsulfanyl)methyl]-4-piperidinamine 323f). Pale

yellow oil. IR 2CHCl₃) 3485 2NH) cm²¹

;

¹H NMR

2500 MHz, CDCl₃) d 1.63 21H, dtd, J14, 10, 5 Hz 1.93

21H, m), 2.00 21H, m), 2.42 21H, dd, J12, 9 Hz), 2.43 23H,

s), 2.55 21H, ddd, J12, 10, 3 Hz), 2.75 21H, td, J9, 4 Hz),

2.85 21H, dd, J14, 8.5 Hz), 3.31 21H, dd, J14, 4 Hz),

3.42 23H, s), 3.52 21H, br dt, J12, 5 Hz), 3.72 21H, ddd,

J12, 4, 2 Hz), 5.33 21H, br s), 7.20±7.38 27H, m), 7.58

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4471

22H, br d, J8 Hz). NOE was observed between NH 2d

5.33) and CH₂SPh 2d 2.85), and 4-H 2d 2.75) and 6-Hax

2d 2.85) in NOESY spectroscopy. HRMS 2EI, m/z) calcd for

C₂₀H₂₆N₂O₃S₂2M¹) 406.1383, found 406.1362.

comprehensive assignment of all proton and carbon

resonances.

4.2.17. 1,1-Dimethylethyl 32a,3a,4b)-3-3methoxyamino)-

2-methyl-4-[3phenylsulfanyl)methyl]pyrrolidine-1-car-

boxylate 326h). Pale yellow oil;IR 2CHCl ) 3556 2NH),

4.2.13. cis-N-Methoxy-1-[34-methylphenyl)sulfonyl]-4-

[3phenylsulfanyl)methyl]-3-piperidinamine 322g). Pale

3

1

1685 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.07

yellow oil;IR 2CHCl ₃) 3490 2NH) cm²¹

;

¹H NMR

23H, br dm, J6 Hz), 1.45 29H, s), 2.17 21H, m), 2.88 21H,

m), 3.15 21H, m), 3.29 21H, s), 3.46 21H, m), 3.50 23H, s),

3.62 21H, m), 5.67 21H, br s), 7.19±7.37 25H, m). NOE was

observed between 4-H 2d 2.17) and NH 2d 5.67) in NOESY

spectroscopy. ¹³C NMR 2125 MHz, CDCl₃) d 14.12, 28.51,

36.44, 37.66, 38.83, 49.11, 49.57, 54.40, 54.80, 61.63,

65.23, 65.87, 79.36, 126.41, 129.03, 129.66, 135.87,

154.23;HRMS 2EI, m/z) calcd for C₁₈H₂₈N₂O₃S 2M¹)

352.1819, found 352.1801. The presence of rotamers

precluded a comprehensive assignment of all proton and

carbon resonances.

2500 MHz, CDCl₃) d 1.42 21H, qd, J12, 5 Hz), 1.56

21H, m), 1.72 21H, qd, J12, 3 Hz), 2.12 21H, dd, J12,

2 Hz), 2.19 21H, td, J12, 3 Hz), 2.42 23H, s), 2.86 21H, dd,

J13.5, 8 Hz), 3.13 21H, dd, J13.5, 8 Hz), 3.34 21H, br s),

3.76 21H, dquint. J12, 2 Hz), 4.06 21H, br dt, J12, 3 Hz),

5.85 21H, br s), 7.13±7.32 27H, m), 7.63 21H, br d, J8 Hz).

NOE was observed between 4-H 2d 1.56) and 2-Hax 2d

2.12), and 4-H 2d 1.56) and 6-Hax 2d 2.19) in NOESY

spectroscopy. HRMS 2EI, m/z) calcd for C₂₀H₂₆N₂O₃S₂

2M¹) 406.1383, found 406.1376.

4.2.14. trans-N-Methoxy-1-[34-methylphenyl)sulfonyl]-4-

[3phenylsulfanyl)methyl]-3-piperidinamine 323g). Pale

4.2.18. 1,1-Dimethylethyl 32a,3a,4a)-3-3methoxyamino)-

2-methyl-4-[3phenylsulfanyl)methyl]pyrrolidine-1-car-

boxylate 327h). Pale yellow oil;IR 2CHCl ) 3556 2NH),

yellow oil. IR 2CHCl₃) 3490 2NH) cm²¹

;

¹H NMR

3

1

2500 MHz, CDCl₃) d 1.44±1.54 22H, m), 2.09 21H, m),

2.18 21H, dd, J11, 9.5 Hz), 2.24 21H, br td, J11, 3 Hz),

2.43 23H, s), 2.69 21H, dd, J13, 8 Hz), 2.94 21H, br td,

J9.5, 4 Hz), 3.41 21H, dd, J13, 3 Hz), 3.44 23H, s), 3.68

21H, dtd, J12, 4, 2 Hz), 3.95 21H, ddd, J11, 4, 2 Hz),

5.43 21H, br s), 7.14±7.33 27H, m), 7.63 22H, br d, J8 Hz);

HRMS 2EI, m/z) calcd for C₂₀H₂₆N₂O₃S₂2M¹) 406.1383,

found 406.1380.

1684 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.29

23H, br dm, J6 Hz), 1.45 29H, s), 2.42 21H, m), 2.87 21H,

dd, J13, 9.5 Hz), 3.30 22H, m), 3.52 23H, s), 3.59 22H, m),

3.93 21H, m), 5.66 21H, br s), 7.18±7.37 25H, m). NOE was

observed between 4-H 2d 2.42) and 2-H 2d 3.93), and NH 2d

5.66) and CH₂SPh 2d 2.87) in NOESY spectroscopy. ¹³C

NMR 2125 MHz, CDCl₃) d 14.11, 15.75, 28.52, 28.67,

32.82, 39.89, 40.65, 50.38, 55.35, 61.36, 61.68, 63.22,

63.61, 79.72, 126.19, 128.99, 129.36, 136.00, 154.82;

HRMS 2EI, m/z) calcd for C₁₈H₂₈N₂O₃S 2M¹) 352.1819,

found 352.1833. The presence of rotamers precluded a

comprehensive assignment of all proton and carbon

resonances.

4.2.15. 1,1-Dimethylethyl 32a,3b,4b)-3-3methoxyamino)-

2-methyl-4-[3phenylsulfanyl)methyl]pyrrolidine-1-car-

boxylate 324h). Pale yellow oil;IR 2CHCl ) 3556 2NH),

3

1

1684 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.15

23H, br dm, J6 Hz), 1.45 29H, s), 2.59 21H, m), 2.94 21H,

m), 3.07 21H, m), 3.21 21H, m), 3.27 21H, m), 3.49 23H, s),

3.51 23H, s), 3.58 21H, m), 3.96 21H, m), 5.58 21H, br s),

7.20±7.38 25H, m). NOE was observed between 4-H 2d

2.59) and 2-Me 2d 1.15), 3-H 2d 2.27) and 2-Me 2d 1.15),

and NH 2d 5.58) and CH₂SPh 2d 3.07) in NOESY spectro-

scopy. ¹³C NMR 2125 MHz, CDCl₃) d 19.11, 19.48, 28.52,

32.12, 32.82, 38.10, 39.07, 49.61, 50.06, 55.35, 57.12,

61.35, 62.15, 66.73, 66.96, 79.27, 126.19, 126.48, 128.99,

129.05, 129.35, 129.73, 129.76, 135.78, 154.50;HRMS 2EI,

m/z) calcd for C₁₈H₂₈N₂O₃S 2M¹) 352.1819, found

352.1837. The presence of rotamers precluded a compre-

hensive assignment of all proton and carbon resonances.

4.2.19. 1,1-Dimethylethyl 32a,3b,4b)-3-3methoxyamino)-

2-phenyl-4-[3phenylsulfanyl)methyl]pyrrolidine-1-car-

boxylate 324i). Pale yellow oil;IR 2CHCl ) 3556 2NH),

3

1

1686 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.56

29H, s), 2.58 21H, m), 2.95 21H, dd, J12.5, 8 Hz), 3.09

21H, m), 3.39±3.51 22H, m), 3.58 23H, s), 3.86 21H, br t,

J10 Hz), 3.89 21H, m), 4.94 21H, br s), 5.64 21H, d,

J5 Hz), 7.13±7.32 210H, m). NOE was observed between

2-H 2d 5.64) and NH 2d 4.94), and 2-H 2d 5.64) and CH₂SPh

2d 3.09) in NOESY spectroscopy. ¹³C NMR 2125 MHz,

CDCl₃) d 28.13, 28.47, 32.21, 37.60, 38.38, 50.27, 50.90,

62.07, 65.05, 68.82, 69.28, 79.60, 125.48, 126.47, 126.88,

128.29, 128.49, 128.98, 129.82, 135.77, 154.62;HRMS 2EI,

m/z) calcd for C₂₃H₃₀N₂O₃S 2M¹) 414.1975, found

414.1975. The presence of rotamers precluded a compre-

hensive assignment of all proton and carbon resonances.

4.2.16. 1,1-Dimethylethyl 32a,3b,4b)-3-3methoxyamino)-

2-methyl-4-[3phenylsulfanyl)methyl]pyrrolidine-1-car-

boxylate 325h). Pale yellow oil;IR 2CHCl ) 3556 2NH),

3

1

1684 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.30

23H, br d, J6 Hz), 1.45 29H, s), 2.27 21H, m), 2.92 21H, dd,

J13.5, 8.5 Hz), 3.05 21H, m), 3.07 21H, br dd, J13.5,

9 Hz), 3.21 21H, dd, J13.5, 5.5 Hz), 3.49 23H, s), 3.71

21H, m), 3.89 21H, m), 5.64 21H, br s), 7.19±7.38 25H,

m). NOE was observed between 4-H 2d 2.27) and 2-H 2d

3.71) in NOESY spectroscopy. ¹³C NMR 2125 MHz,

CDCl₃) d 19.99, 28.50, 29.70, 36.46, 40.01, 49.51, 56.65,

62.42, 72.87, 79.40, 126.43, 129.03, 129.70, 135.76, 154.29;

HRMS 2EI, m/z) calcd for C₁₈H₂₈N₂O₃S 2M¹) 352.1819,

found 352.1835. The presence of rotamers precluded a

4.2.20. 3E)-5-Hexenal diphenylhydrazone 328a). To a stir-

red solution of the aldehyde 10 2735 mg, 7.5 mmol) in

CH₂Cl₂2125 mL) was added Ph₂NNH₂´HCl 21.66 g,

7.5 mmol) at room temperature under

a

nitrogen

atmosphere. After being stirred at room temperature for

2.5 h, the reaction mixture was diluted with water and

extracted with CH₂Cl₂. The organic phase was washed

with water, dried over Na₂SO₄, and concentrated under

reduced pressure. The residue was puri®ed by FCC 2hexane/

AcOEt 20:1) to afford the hydrazone 28a 21.51 g, 76%) as a

4472

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

yellow oil;IR 2CHCl ₃) 1639 2CvN) cm²¹

;

¹H NMR

4 mmol), prepared by hydrolysis of dimethyl acetal 17, in

MeOH 29.6 mL) was added Ph₂NNH₂´HCl 2136 mg,

0.62 mmol) at 108C under a nitrogen atmosphere. After

being stirred at room temperature for 10 min, the reaction

mixture was diluted with water and extracted with CH₂Cl₂.

The organic phase was washed with water, dried over

Na₂SO₄, and concentrated under reduced pressure. The resi-

due was puri®ed by MPCC 2hexane/AcOEt 9:1) to afford

2200 MHz, CDCl₃) d 1.59 22H, quint., J7.5 Hz), 2.08

22H, br q, J7 Hz), 2.29 22H, td, J7.5, 5.5 Hz), 4.91±

5.06 22H, m), 5.80 21H, ddt, J17, 10, 6.5 Hz), 6.53 21H,

t, J5.5 Hz), 7.03±7.18 26H, m), 7.28±7.44 24H, m);

HRMS 2EI, m/z) calcd for C₁₈H₂₀N₂2M¹) 264.1626,

found 264.1631.

4.2.21. 4-Methyl-N-[3diphenylhydrazono)ethyl]-N-32-pro-

penyl)benzenesulfonamide 328b). To a stirred solution of

allylamine 213) 21.56 mL, 21 mmol) in benzene 212.6 mL)

was added a solution of 1-bromo-2,2-dimethoxyethane 216)

20.83 mL, 7 mmol) in benzene 23.5 mL) at room tempera-

ture under a nitrogen atmosphere. After being stirred at 808C

for 4.5 h, the reaction mixture was washed with water and

the organic phase was dried over Na₂SO₄and concentrated

under reduced pressure. The residue was puri®ed by FCC

2AcOEt) to afford 2E)-22-propenylamino)acetaldehyde

dimethylacetal 2437 mg, 43%) as a yellow oil. To a solution

of the acetal 2437 mg, 3.01 mmol) in CH₂Cl₂29.0 mL) were

added Et₃N 20.5 mL, 3.61 mmol) and TsCl 2746 mg,

3.91 mmol) at 08C under a nitrogen atmosphere. After

being stirred at room temperature for 3 h, Et₃N 20.25 mL,

1.81 mmol) and TsCl 2373 mg, 1.96 mmol) at 08C were

again added monitoring the reaction by TLC. After being

stirred at room temperature for 1 h, the reaction mixture was

diluted with water and extracted with CH₂Cl₂. The organic

phase was washed with water, dried over Na₂SO₄, and

concentrated under reduced pressure. The residue was

puri®ed by MPCC 2hexane/AcOEt 3:1) to afford N-22,2-

dimethoxyethyl)-4-methyl-N-22-propenyl)benzenesulfona-

28c 2132 mg, 24%) as a pale yellow oil;IR 2CHCl ) 1646

3

2CvN) cm²¹; ¹H NMR 2200 MHz, CDCl₃) d 4.00 22H, br d,

J6 Hz), 4.18 22H, d, J5.5 Hz), 5.14±5.34 22H, m), 5.91

21H, m), 6.54 21H, t, J5.5 Hz), 7.06±7.44 210H, m);

HRMS 2EI, m/z) calcd for C₁₇H₁₈N₂O 2M¹) 266.1419,

found 266.1431.

4.2.23. 4-Methyl-N-[3diphenylhydrazono)propyl]-N-32-

propenyl)benzenesulfonamide 328d). To a solution of

acetal 19f 2207 mg, 0.664 mmol) in acetone 210 mL) was

added 2 M-HCl 25 mL) under a nitrogen atmosphere at

room temperature. After being stirred for 2 h, the reaction

mixture was extracted with CHCl₃. The organic phase was

dried over MgSO₄and concentrated under reduced pressure

to give the crude aldehyde as a yellow oil. To a solution of

the crude aldehyde in CH₂Cl₂was added Ph₂NNH₂´HCl

2122.3 mg, 0.664 mmol) under a nitrogen atmosphere at

room temperature. After being stirred for 1.5 h, the reaction

mixture was extracted with CHCl₃. The organic phase was

dried over MgSO₄and concentrated under reduced pressure.

Puri®cation of the residue by MPCC 2hexane/AcOEt 5:1)

affored 28d 2101 mg, 35%) as a pale yellow oil;IR 2CHCl ₃)

1

1594 2CvC, CvN) cm²¹; H NMR 2500 MHz, CDCl₃) d

1

2.41 23H, s), 2.52 22H, br dt, J7, 5 Hz), 3.36 22H, t,

J7 Hz), 3.81 22H, d, J7 Hz), 5.10±5.22 22H, m), 5.63

21H, m), 6.45 21H, t, J5 Hz), 7.02±7.40 212H, m), 7.70

mide 2814 mg, 92%) as a yellow oil; H NMR 2200 MHz,

CDCl₃) d 2.43 23H, s), 3.22 22H, d, J6 Hz), 3.38 26H, s),

3.95 22H, br d, J6 Hz), 4.52 21H, t, J6 Hz), 5.05±5.20

22H, m), 5.56 21H, m), 7.30 22H, br d, J8 Hz), 7.70 22H, br

d, J8 Hz).

22H, br d, J8 Hz);HRMS 2EI,

m/z) calcd for

C₂₄H₂₇N₃O₂S₂2M¹) 433.1823, found 433.1832.

To a stirred solution of the sulfonamide 2300 mg,

1.02 mmol) in acetone 26.38 mL) was added 2 M-HCl

21.5 mL) at 108C under a nitrogen atmosphere. After the

solution was stirred at room temperature for 24 h, the reac-

tion mixture was diluted with water and extracted with

CH₂Cl₂. The organic phase was washed with water, dried

over Na₂SO₄, and concentrated under reduce pressure to

give the crude aldehyde as a yellow oil. To a stirred solution

of the crude aldehyde in MeOH 24.76 mL) was added

Ph₂NNH₂´HCl 2150 mg, 0.61 mmol) at room temperature

under a nitrogen atmosphere. After being stirred at room

temperature for 1 h, the reaction mixture was diluted with

water and extracted with CH₂Cl₂. The organic phase was

washed with water, dried over Na₂SO₄, and concentrated

under reduced pressure. The residue was puri®ed by

MPCC 2hexane/Et₂O 5:1) to afford 28b 2183 mg, 43%) as

colorless amorphous;IR 2CHCl ₃) 1643 2CvN), 1345, 1160

4.3. General procedure for radical cyclization of

hydrazones

According to the procedure given for radical cyclization of

oxime ethers, to a boiling solution of the hydrazone 28a±d

21 mmol) in benzene 210 mL) under a nitrogen atmosphere

was added a solution of thiophenol 21 or 3 mmol) and AIBN

20.5 or 1.5 mmol) in benzene 220 mL) by a syringe pump

25 mL/h) over 2 h. After the reaction mixture was heated at

re¯ux for a further 2 h, the solvent was evaporated under

reduced pressure. Puri®cation of the residue by MPCC

afforded the cyclized products 29a±d and 30a±d as

shown in Table 3.

4.3.1.

cyclopentyl]hydrazine 329a). Colorless crystals;mp 85±

868C 2MeOH);IR 2CHCl ₃) 3378 2NH) cm^{21 1}H NMR

cis-1,1-Diphenyl-2-[2-[3phenylsulfanyl)methyl]-

;

1

2NSO₂) cm²¹; H NMR 2300 MHz, CDCl₃) d 2.40 23H, s),

2500 MHz, CDCl₃) d 1.51±1.95 26H, m), 2.13 21H, m),

3.04 21H, dd, J12.5, 7.5 Hz), 3.14 21H, dd, J12.5,

8.5 Hz), 3.43 21H, br td, J5, 4 Hz), 4.14 21H, br s), 6.99

22H, br tt, J8, 2 Hz), 7.17±7.30 213H, m). NOE was

observed between NH 2d 4.14) and CH₂SPh 2d 3.14) in

NOESY spectroscopy. HRMS 2EI, m/z) calcd for

C₂₄H₂₆N₂S 2M¹) 374.1817, found 374.1832. Anal. calcd

for C₂₄H₂₆N₂S:C, 76.96;H, 7.00;N, 7.48;S, 8.56. Found:

C, 76.84;H, 6.99;N, 7.51;S, 8.48.

3.79 22H, d, J6 Hz), 4.00 22H, d, J6.5 Hz), 5.13±5.22

22H, m), 5.65 21H, ddt, J16.5, 10, 6.5 Hz), 6.22 21H, t,

J6 Hz), 6.95±7.02 24H, m), 7.11±7.28 28H, m), 7.64 22H,

br d, J8 Hz);HRMS 2EI, m/z) calcd for C₂₄H₂₅N₃O₂S

2M¹) 419.1667, found 419.1683.

4.2.22. 32-Propenyloxy)acetaldehyde diphenylhydrazone

328c). To a stirred solution of the crude aldehyde 2400 mg,

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4473

4.3.2. trans-1,1-Diphenyl-2-[2-3phenylsulfanyl)methyl-

4.3.7. cis-1-[34-Methylphenyl)sulfonyl]-4-32,2-diphenyl-

hydrazino)-3-[3phenylsulfanyl)methyl]piperidine 329d).

cyclopentyl]hydrazine 330a). Pale yellow oil;IR 2CHCl )

3

3378 2NH) cm²¹; ¹H NMR 2500 MHz, CDCl₃) d 1.39 21H,

m), 1.61±1.70 23H, m), 1.80 21H, m), 2.04±2.14 22H, m),

2.84 21H, dd, J13, 7 Hz), 2.88 21H, dd, J13, 7.5 Hz),

3.27 21H, m), 4.13 21H, br s), 6.96±7.30 215H, m). NOE

was observed between NH 2d 4.13) and 2-H 2d 2.01±2.14),

1-H 2d 3.27) and CH₂SPh 2d 2.84, 2.88) in NOESY spectro-

scopy. HRMS 2EI, m/z) calcd for C₂₄H₂₆N₂S 2M¹)

374.1817, found 374.1831.

Pale yellow oil;IR 2CHCl

)

3490 2NH), 1589

3

2CvC) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.59 21H,

m), 1.88 21H, dtd, J13, 9, 4 Hz), 2.05±2.12 21H, m),

2.45 23H, s), 2.64 22H, m), 2.95 21H, m), 3.00 21H, dd,

J13.5, 10.5 Hz), 3.26 21H, br dd, J13, 4.5 Hz), 3.42

21H, m), 3.64 21H, m), 3.71 21H, br s), 6.97±7.28 215H,

m), 7.31 22H, br d, J8 Hz), 7.63 22H, br d, J8 Hz);

HRMS 2EI, m/z) calcd for C₃₁H₃₃N₃O₂S₂2M¹) 543.2012,

found 543.2000.

1

4.3.3. cis-1-[34-Methylphenyl)sulfonyl]-3-32,2-diphenyl-

hydrazino)-4-[3phenylsulfanyl)methyl]pyrrolidine 329b).

Colorless crystals;mp 157±160 8C 2Et₂O);IR 2CHCl ₃) 3500

4.3.8.

trans-1-[34-Methylphenyl)sulfonyl]-4-32,2-di-

phenylhydrazino)-3-[3phenylsulfanyl)methyl]piperidine

330d). Pale yellow oil;IR 2CHCl ₃) 3490 2NH), 1589

2NH), 1350, 1150 2NSO₂) cm²^{1 1}H NMR 2500 MHz,

;

2CvC) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.61 21H,

1

CDCl₃) d 2.29 21H, m), 2.42 23H, s), 2.82 21H, dd, J13,

7.5 Hz), 3.01 21H, dd, J13, 8 Hz), 3.32 21H, dd, J11,

5.5 Hz), 3.34 21H, t, J9.5 Hz), 3.42 21H, dd, J11,

3 Hz), 3.55 21H, m), 3.60 21H, dd, J9.5, 7.5 Hz), 3.99

21H, br d, J2 Hz), 6.98±7.04 26H, m), 7.18±7.28 211H,

m), 7.69 22H, br dd, J8 Hz). NOE was observed between

NH 2d 3.99) and CH₂SPh 2d 3.01) in NOESY spectroscopy.

HRMS 2EI, m/z) calcd for C₃₀H₃₁N₃O₂S₂2M¹) 529.1857,

found 529.1866. Anal. calcd for C₃₀H₃₁N₃O₂S₂: C, 68.02;H,

5.90;N, 7.93;S, 12.10. Found: C, 67.93;H, 5.90;N, 7.88;S,

12.20.

m), 1.92 21H, m), 2.03 21H, m), 3.04 21H, dd, J11,

7 Hz), 2.48 23H, s), 2.94±3.14 25H, m), 3.27 21H, br dd,

J11, 4 Hz), 3.76 21H, br s), 6.92±7.28 215H, m), 7.33

22H, br d, J8 Hz), 7.61 22H, br d, J8 Hz);HRMS 2EI,

m/z) calcd for C₃₁H₃₃N₃O₂S₂2M¹) 543.2012, found

543.2007.

4.4. General procedure for radical cyclization of oxime

ethers 7g and 7c in aqueous media

To a boiling solution of oxime ether 20.34 mmol) in

MeOH±H₂O 23:2) 25.2 mL) was added a solution of thio-

phenol 21.02 mmol) and VA-044 20.51 mmol) in MeOH±

H₂O 23:2) 29.2 mL) under nitrogen atmosphere by a syringe

pump 24 mL/h) over 2.5 h. After being heated at re¯ux for a

further 2.5 h, the reaction mixture was neutralized with 5%

KOH and extracted with CHCl₃. The organic phase was

dried over MgSO₄and concentrated under reduced pressure.

Puri®cation of the residue by MPCC 2hexane/AcOEt 5:1)

afforded the cyclized compounds as shown in Table 4.

4.3.4. trans-1-[34-Methylphenyl)sulfonyl]-3-32,2-diphenyl-

hydrazino)-4-[3phenylsulfanyl)methyl]pyrrolidine 330b).

White amorphous;IR 2CHCl ₃) 3524 2NH), 1346, 1136

1

2NSO₂) cm²¹; H NMR 2500 MHz, CDCl₃) d 2.30 21H,

m), 2.43 23H, s), 2.66 21H, dd, J13, 7.5 Hz), 2.69 21H,

dd, J13, 8 Hz), 3.17 21H, dd, J11, 3 Hz,), 3.29 21H, dd,

J10, 3.5 Hz), 3.39 21H, dd, J11, 6 Hz), 3.46 21H, m),

3.53 21H, dd, J10, 7 Hz), 3.74 21H, br d, J2 Hz), 6.90±

6.93 24H, m), 6.99±7.25 22H, m), 7.16±7.32 211H, m), 7.71

22H, br d, J8 Hz). NOE was observed between NH 2d

3.74) and 4-H 2d 2.30), 3-H 2d 3.46) and CH₂SPh 2d 2.66,

2.69) in NOESY spectroscopy. HRMS 2EI, m/z) calcd for

C₃₀H₃₁N₃O₂S₂2M¹) 529.1857, found 529.1868.

The products were identical with pyrrolidines 22g, c and

23g, c prepared by the radical reaction in benzene 2Table 1).

4.4.1. 1,1-Dimethylethyl cis-[2-[3phenylsulfanyl)methyl]-

cyclopentyl]carbamate 331). 21) Preparation from cis-

methoxyamine 22a. To a stirred solution of cis-methoxy-

amine 22a 2237 mg, 1 mmol) in THF 248.5 mL) was

added LiAlH₄2380 mg, 10 mmol) at room temperature

under a nitrogen atmosphere. After the solution was re¯uxed

for 8 h, usual work-up gave the crude amine as a yellow oil.

After being characterized by NMR spectrum, the crude

amine was subjected to the following reaction. To a stirred

solution of the crude amine in CH₂Cl₂256 mL) were added

Et₃N 20.21 mL, 1.5 mmol) and a solution of 2Boc)₂O

20.34 mL, 1.5 mmol) in CH₂Cl₂221 mL) at room tempera-

ture under a nitrogen atmosphere. After being stirred at

room temperature for 5 h, the reaction mixture was diluted

with water and extracted with CH₂Cl₂. The organic phase

was washed with water, dried over Na₂SO₄, and concen-

trated under reduced pressure. The residue was puri®ed by

MPCC 2hexane/AcOEt 5:1) to afford 31 2239 mg, 75%) as

colorless crystals 2mp 89±908C 2hexane));IR 2CHCl ₃) 3444

4.3.5. cis-2-[Tetrahydro-4-3phenylsulfanyl)methyl-3-fur-

anyl]-1,1-diphenylhydrazine 329c). Pale yellow oil;IR

1

2CHCl₃) 3446 2NH) cm²¹; H NMR 2500 MHz, CDCl₃) d

2.53 21H, m), 3.09 21H, dd, J13, 7.5 Hz), 3.13 21H, dd,

J13, 9 Hz), 3.65 21H, m), 3.74 21H, dd, J9.5, 5 Hz), 3.88

21H, dd, J9, 8 Hz), 3.98 21H, dd, J9.5, 2 Hz), 4.04 21H, t,

J8 Hz), 4.38 21H, br s), 7.00±7.32 215H, m). NOE was

observed between NH 2d 4.38) and CH₂SPh 2d 3.09, 3.13)

in NOESY spectroscopy. HRMS 2EI, m/z) calcd for

C₂₃H₂₄N₂OS 2M¹) 376.1609, found 376.1635.

4.3.6. trans-2-[Tetrahydro-4-3phenylsulfanyl)methyl-3-

furanyl]-1,1-diphenylhydrazine 330c). Pale yellow oil;

1

IR 2CHCl₃) 3448 2NH) cm²¹; H NMR 2500 MHz, CDCl₃)

d 2.37 21H, m), 2.85 21H, dd, J13, 8 Hz), 2.91 21H, dd,

J13, 7.5 Hz), 3.57 21H, m), 3.66 21H, dd, J9, 4.5 Hz),

3.77 21H, dd, J9.5, 3 Hz), 3.83 21H, dd, J9.5, 6 Hz), 4.02

21H, br s), 4.18 21H, dd, J9, 7 Hz), 7.00±7.30 215H, m).

NOE was observed between NH 2d 4.02) and 4-H 2d 2.37),

3-H 2d 3.57) and CH₂SPh 2d 2.85, 2.91) in NOESY spectro-

scopy. HRMS 2EI, m/z) calcd for C₂₃H₂₄N₂OS 2M¹)

376.1609, found 376.1615.

1

2NH), 1705 2NCOO) cm²¹; H NMR 2500 MHz, CDCl₃) d

1.40±1.65 23H, m), 1.45 29H, s), 1.69 21H, m), 1.90±2.00

22H, m), 2.22 21H, m), 2.69 21H, br dd, J12, 10 Hz), 3.18

21H, br dd, J12, 5 Hz), 4.10 21H, m), 4.48 21H, br s),

4474

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

7.34±7.12 25H, m). NOE was observed between NH 2d

4.48) and CH₂SPh 2d 2.69) in NOESY spectroscopy.

HRMS 2EI, m/z) calcd for C₁₇H₂₅NO₂S 2M¹) 307.1606,

found 307.1597;Anal. calcd for C ₁₇H₂₅NO₂S:C, 66.41;H,

8.20;N, 4.56;S, 10.43. Found: C, 66.37;H, 8.39;N, 4.31;S,

10.62.

2M¹) 307.1606, found 307.1619;Anal. calcd for

C₁₇H₂₅NO₂S:C, 66.41;H, 8.20;N, 4.56;S, 10.43. Found:

C, 66.38;H, 8.40;N, 4.53;S, 10.68.

22) Preparation from trans-hydrazine 30a. According to the

procedure described in the preparation of cis-N-Boc 31 from

29a, the demethoxylation and t-butoxycarbonylation of the

trans-hydrazine 30a 268 mg, 0.18 mmol) afforded trans-N-

Boc 32 218 mg, 33%) as colorless crystals.

22) Preparation from cis-hydrazine 29a. To a stirred solu-

tion of cis-hydrazine 29a 279 mg, 0.21 mmol) in MeOH

216.5 mL) was hydrogenated in the presence of 20%

Pd2OH)₂±C 2165 mg) and 2^)-10-camphorsulfonic acid^8f

2106 mg, 0.42 mmol) at room temperature under a hydrogen

atmosphere for 19.5 h. Usual work-up gave the crude amine

as a yellow oil. To a stirred solution of the crude amine in

CH₂Cl₂212 mL) were added Et₃N 20.06 mL, 0.43 mmol)

and a solution of 2Boc)₂O 20.1 mL, 0.42 mmol) in CH₂Cl₂

26 mL) at room temperature under a nitrogen atmosphere.

After being stirred at room temperature for 4 h, the reaction

mixture was diluted with water and extracted with CH₂Cl₂.

The organic phase was washed with water, dried over

Na₂SO₄, and concentrated under reduced pressure. The

residue was puri®ed by MPCC 2hexane/AcOEt 5:1) to

afford 31 265 mg, 84%) as colorless crystals which was

identical with 31 prepared from 22a.

This compound was identical with 32 prepared from 23a.

4.4.4.

1,1-Dimethylethyl

trans-[2-[3phenylsul®nyl)-

methyl]cyclopentyl]carbamate 334). According to the

procedure described in the preparation of cis-sulfoxide 33,

the oxidation of trans-32 2137 mg, 0.45 mmol) with

mCPBA gave 34 2127 mg, 99%) as colorless powders and

as a 1:1 diastereomeric mixture based on the sul®nyl group;

IR 2CHCl₃) 3440 2NH), 1703 2NCOO) cm²^{1 1}H NMR

;

2500 MHz, CDCl₃) d 1.35±2.30 27H, m), 1.40 29/2H, s),

1.44 29/2H, s), 2.62 21/2H, br t, J12 Hz), 2.84 21/2H, dd,

J13.5, 7 Hz), 3.01 21/2H, dd, J13.5, 7.5 Hz), 3.11 21/2H,

dd, J13, 3.5 Hz), 3.69 21/2H, m), 3.75 21/2H, m), 4.54

21/2H, br s), 4.79 21/2H, br s), 7.46±7.52 23H, m), 7.61±

7.67 22H, m);HRMS 2CI, isobutane, m/z) calcd for

C₁₇H₂₅NO₃S1H 2QM¹) 323.1555, found 323.1577.

4.4.2. 1,1-Dimethylethyl cis-[2-[3phenylsul®nyl)methyl]-

cyclopentyl]carbamate 333). To a stirred solution of cis-

N-Boc 31 2316 mg, 1.03 mmol) in CH₂Cl₂226 mL) was

added dropwise mCPBA 2assay 70%) 2177 mg,

1.03 mmol) in CH₂Cl₂237.5 mL) over 4 h under nitrogen

atmosphere at 08C. After being stirred at the same tempera-

ture for 30 min, the reaction mixture was neutralized with

saturated aqueous NaHCO₃and extracted with CH₂Cl₂. The

organic phase was washed with water, dried over MgSO₄,

and concentrated under reduced pressure. The residue was

puri®ed by MPCC 2hexane/AcOEt 5:1!AcOEt) to afford

33 2332 mg, 99%) as colorless powders and as a 1:1 dia-

stereomeric mixture based on the sul®nyl group;IR 2CHCl ₃)

4.4.5. 1,1-Dimethylethyl [2-3methylene)cyclopentyl]car-

bamate 335). 21) Preparation from cis-sulfoxide 33. A

stirred solution of cis-sulfoxide 33 2182 mg, 0.56 mmol)

and NaOAc 2300 mg, 3.66 mmol) in o-dichlorobenzene

22.7 mL) was re¯uxed under nitrogen atmosphere for 3 h.

The reaction mixture was ®ltered to remove NaOAc and the

®ltrate was concentrated under reduced pressure. The

residue was puri®ed by MPCC 2hexane/AcOEt 9:1) to

afford 35 285 mg, 76%) as a pale yellow oil;IR 2CHCl )

3

1

3444 2NH), 1707 2NCOO), 1656 2CvC) cm²¹; H NMR

2500 MHz, CDCl₃) d 1.38±2.14 24H, m), 1.46 29H, s),

2.29±2.42 22H, m), 4.34 21H, m), 4.51 21H, br s), 4.96

21H, q-like, J2 Hz), 4.99 21H, br s);HRMS 2EI, m/z)

calcd for C₁₁H₁₉NO₂2M¹) 197.1416, found 197.1422.

3444 2NH), 1705 2NCOO) cm²^{1 1}H NMR 2500 MHz,

;

CDCl₃) d 1.35±2.20 26H, m), 1.38 29/2H, s), 1.43 29/2H,

s), 2.36 21/2H, m), 2.42 21/2H, m), 2.54 21/2H, br t,

J12 Hz), 2.77 21/2H, dd, J13, 7 Hz), 2.90 21/2H, dd,

J13, 7.5 Hz), 3.11 21/2H, br dd, J12, 3 Hz), 4.05

21/2H, m), 4.20 21/2H, m), 4.51 21/2H, br s), 4.62 21/2H,

br s), 7.47±7.54 23H, m), 7.62±7.70 22H, m);HRMS 2CI,

isobutane, m/z) calcd for C₁₇H₂₅NO₃S1H 2QM¹) 323.1555,

found 323.1537.

22) Preparation from trans-sulfoxide 34. According to the

procedure described for pyrolysis of cis-sulfoxide 33,

pyrolysis of trans-sulfoxide 34 2183 mg, 0.57 mmol) gave

35 282 mg, 75%). This compound was identical with 35

prepared from cis-sulfoxide 33.

4.4.3. 1,1-Dimethylethyl trans-[2-[3phenylsulfanyl)-

methyl]cyclopentyl]carbamate 332). 21) Preparation

from trans-methoxyamine 23a. According to the procedure

described in the preparation of cis-N-Boc 31 from 22a, the

demethoxylation and t-butoxycarbonylation of the trans-

methoxyamine 2355 mg, 1.5 mmol) afforded trans-N-Boc

32 2345 mg, 75%) as colorless crystals 2mp 84±868C

4.4.6. 1,1-Dimethylethyl cis-[2-3hydroxymethyl)cyclo-

pentyl]carbamate 336). To a stirred solution of the exo-

ole®n 35 2110 mg, 0.51 mmol) in THF 20.71 mL) was

added 9-BBN 20.5 M in hexane) 23.05 mL, 1.52 mmol) at

08C under a nitrogen atmosphere. After the solution was

stirred at room temperature for 1 h, 9-BBN 20.5 M in

hexane) 23.05 mL, 1.52 mmol) was again added at 08C.

After being stirred at room temperature for 7 h, 6 M-

NaOH 21.38 mL) and 30% H₂O₂21.38 mL) were added at

08C. After being stirred at room temperature for 16 h, the

reaction mixture was diluted with water and extracted with

Et₂O. The organic phase was washed with water, dried over

Na₂SO₄, and concentrated under reduce pressure. The

residue was puri®ed by FCC 2hexane/AcOEt 3:1) to

afford the alcohol 36 266 mg, 55%) as colorless crystals

2hexane));IR 2CHCl ) 3442 2NH), 1705 2NCOO) cm²¹

;

3

¹H NMR 2500 MHz, CDCl₃) d 1.36±1.48 22H, m), 1.45

29H, s), 1.58±1.67 22H, m), 1.85 21H, m), 1.98 21H, m),

2.07 21H, m), 2.78 21H, dd, J12, 10 Hz), 3.28 21H, br

dd, J12, 4 Hz), 3.70 21H, m), 4.45 21H, br s), 7.14±7.34

25H, m). NOE was observed between NH 2d 4.45) and 2-H

2d 1.85), 1-H 2d 3.70) and CH₂SPh 2d 2.78) in NOESY

spectroscopy. HRMS 2EI, m/z) calcd for C₁₇H₂₅NO₂S

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4475

2mp 113±1148C 2hexane)) [lit.^12cmp 111±1128C];IR

4.4.9. 1,1-Dimethylethyl trans-[2-3hydroxymethyl)cyclo-

pentyl]carbamate 341). To a solution of the alcohol 39

251 mg, 0.16 mmol) in MeOH 24.7 mL) was added NaBH₄

259 mg, 1.56 mmol) at room temperature under a nitrogen

atmosphere. After being stirred at the same temperature for

1.5 h, usual work-up gave the crude product, which was

puri®ed by SCC 2hexane!AcOEt) to afford the alcohol

1

2CHCl₃) 3445 2OH, NH), 1685 2NCOO) cm²¹; H NMR

2300 MHz, CDCl₃) d 1.13 21H, m), 1.45 29H, s), 1.75±

1.40 24H, m), 2.00 21H, m), 2.14 21H, m), 3.38 21H, br t,

J10 Hz), 3.57 21H, td, J10, 4 Hz), 3.89 21H, br dd, J10,

3 Hz), 4.10 21H, m), 4.49 21H, br d, J5 Hz);HRMS

2EI, m/z) calcd for C₁₁H₂₁NO₃2M¹) 215.1521, found

215.1519.

41 234 mg, 99%) 2mp 74±768C 2hexane)) as colorless crys-

tals;IR 2CHCl ) 3440 2OH, NH), 1686 2NCOO) cm²¹; H

1

3

4.4.7. Methyl cis-2-[[31,1-dimethylethoxy)carbonyl]ami-

no]cyclopentanecarboxylate 337). To a stirred solution of

the cis-alcohol 36 257 mg, 0.26 mmol) in water±acetone

23:2) 21.3 mL) were added NaIO₄2180 mg, 0.84 mmol)

and RuO₂´H₂O 215 mg, 0.12 mmol) at room temperature

under a nitrogen atmosphere. After being stirred at room

temperature for 7 h, i-PrOH 21.3 mL) was added and the

reaction mixture was acidi®ed with 1 M-HCl and extracted

with AcOEt. The organic phase was washed with water,

dried over Na₂SO₄, and concentrated under reduced pres-

sure to afford the crude N-Boc-carboxylic acid 37 as color-

less oil; ¹H NMR 2200 MHz, CDCl₃) d 1.20±2.25 26H, m),

1.45 29H, s), 3.06 21H, br q, J7 Hz), 4.30 21H, m), 5.10

21H, br s). The spectral data of 37 were identical with those

reported in the literature.^12c

NMR 2500 MHz, CDCl₃) d 1.36 21H, m), 1.39 21H, m), 1.44

29H, s), 1.56±1.70 22H, m), 1.87±1.78 22H, m), 2.04 21H,

dtd, J13, 8, 6 Hz), 3.50 21H, m), 3.63 21H, m), 3.68 21H,

m), 3.74 21H, m), 4.64 21H, br s);HRMS 2EI, m/z) calcd for

C₁₁H₂₁NO₃2M¹) 215.1521, found 215.1532;Anal. calcd for

C₁₁H₂₁NO₃: C, 61.37;H, 9.83;N, 6.51. Found: C, 61.20;H,

10.11;N, 6.63.

4.4.10. trans-2-[31,1-Dimethylethoxy)carbonyl]amino]-

cyclopentanecarboxylic acid 342). To a stirred solution

of the trans-alcohol 41 225 mg, 0.12 mmol) in water±

acetone 23:2) 20.6 mL) were added NaIO₄281 mg,

0.38 mmol) and RuO₂´H₂O 27 mg, 0.05 mmol) at room

temperature under a nitrogen atmosphere. After being

stirred at room temperature for 14 h, i-PrOH 20.6 mL) was

added and the reaction mixture was acidi®ed with 1 M-HCl

and extracted with AcOEt. The organic phase was washed

with water, dried over Na₂SO₄, and concentrated under

reduced pressure to afford the N-Boc-carboxylic acid 42

226 mg, 92%) 2mp 142±1458C 2hexane±Et₂O)) as colorless

crystals;IR 2CHCl ₃) 3444 2NH), 3440±2500, 1742

To a stirred solution of the crude N-Boc-carboxylic acid in

MeOH 210 mL) was added a solution of CH₂N₂20.52 mmol)

in Et₂O at 08C under a nitrogen atmosphere. After being

stirred at room temperature for 1 h, the reaction mixture

was concentrated under reduced pressure. The residue was

puri®ed by PTLC 2hexane/AcOEt 3:1) to afford the ester 38

2COOH), 1709 2NCOO) cm²¹

;

¹H NMR 2500 MHz,

237 mg, 57%) as a pale yellow oil;IR 2CHCl ) 3440 2NH),

3

CDCl₃) d 1.45 29H, s), 1.46 21H, m), 1.71 22H, br quint.,

J7 Hz), 1.89 21H, m, 5-H), 2.10 21H, m), 2.13 21H, m),

2.75 21H, m), 4.03 21H, m), 4.92 21H, br s);HRMS 2EI, m/z)

calcd for C₁₁H₁₉NO₄2M¹) 229.1314, found 229.1285;Anal.

calcd for C₁₁H₁₉NO₄: C, 57.63;H, 8.35;N, 6.11. Found: C,

57.35;H, 8.22;N, 6.10.

1

1725 2COO), 1710 2NCOO) cm²¹; H NMR 2500 MHz,

CDCl₃) d 1.43 29H, s), 1.52±2.01 26H, m), 3.00 21H, br q,

J8 Hz), 3.69 23H, s), 4.22 21H, br quint., J8 Hz), 4.92

21H, br d, J7 Hz);HRMS 2CI, isobutene, m/z) calcd for

C₁₂H₂₁NO₄1H 2QM¹) 243.1470, found 243.1456. The

spectral data of 38 were identical with those reported in

the literature.^12c

4.4.11. Methyl trans-2-[[31,1-dimethylethoxy)carbonyl]-

amino]cyclopentanecarboxylate 343). To a stirred solution

of the trans-N-Boc-carboxylic acid 42 210 mg, 0.04 mmol)

in MeOH 210 mL) was added a solution of CH₂N₂

20.1 mmol) in Et₂O at 08C under a nitrogen atmosphere.

After being stirred at room temperature for 1 h, the reaction

mixture was concentrated under reduced pressure. The

residue was puri®ed by PTLC 2hexane/AcOEt 3:1) to afford

the ester 43 28 mg, 77%) 2mp 62±638C 2hexane)) [lit.¹⁴22)-

43 mp 73±748C, 21)-43 mp 66±678C] as colorless crystals;

4.4.8. 1,1-Dimethylethyl trans-N-[2-3hydroxymethyl)-

cyclopentyl]-N-3phenylsulfanyl)carbamate 339). To a

solution of the sulfoxide 34 266 mg, 0.21 mmol) and g-colli-

dine 20.08 mL, 0.61 mmol) in dry MeCN 23.3 mL) was

added a solution of TFAA 20.06 mL, 0.41 mmol) in dry

MeCN 21.5 mL) under a nitrogen atmosphere at 08C.

After being stirred at same temperature for 1 h, a solution

of NaHCO₃2310 mg, 3.69 mmol) in H₂O 25.2 mL) was

added to the reaction mixture. The resulting solution was

stirred at same temperature for 2 h. The reaction mixture

was diluted with water and extracted with CH₂Cl₂. The

organic phase was washed with 5% HCl, saturated

aqueous NaHCO₃, and water, and then dried over Na₂SO₄,

and concentrated at reduce pressure. Puri®cation of the

residue by MPCC 2hexane/AcOEt 3:1) afforded the

IR 2CHCl₃) 3448 2NH), 1720 2COO), 1710 2NCOO) cm²¹

;

¹H NMR 2500 MHz, CDCl₃) d 1.44 29H, s), 1.40±2.02 26H,

m), 2.59 21H, br q, J8 Hz), 3.69 23H, s), 4.11 21H, br

quint., J8 Hz), 4.58 21H, br s);HRMS 2CI, isobutene,

m/z) calcd for C₁₂H₂₁NO₄1H 2QM¹) 243.1470, found

243.1492.

alcohol 39 250 mg, 76%) as colorless oil;IR 2CHCl

;

)

The spectral data of 43 were identical with those reported in

3

3463 2OH), 1676 2NCOO) cm²¹

¹H NMR 2500 MHz,

the literature.¹⁴

CDCl₃) d 1.44 29H, s), 1.45 21H, m), 1.55 21H, m), 1.69

21H, m), 1.73±1.80 22H, m), 1.86 21H, m), 2.00 21H, m),

3.52 21H, dd, J11.5, 5.5 Hz), 3.56 21H, dd, J11.5,

4.5 Hz), 4.52 21H, br q, J8 Hz), 7.12±7.31 25H, m);

HRMS 2EI, m/z) calcd for C₁₇H₂₅NO₃S 2M¹) 323.1555,

found 323.1537.

4.4.12. trans-2-Aminocyclopentanecarboxylic acid 344).

A solution of the N-Boc-carboxylic acid 43 234 mg,

0.15 mmol) in 4 M-HCl-dioxane 20.32 mL, 1.19 mmol)

was stirred at room temperature under a nitrogen

atmosphere for 2 h and then concentrated under reduced

4476

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

pressure. The residue was dissolved in H₂O and loaded on

resin 2Amberlite IR-120B) in a column and washed with

water, and then 0.5 M-NH₄OH. After concentration of the

eluate under reduced pressure, the residue was recrystallized

from EtOH to give the amino acid 44 214 mg, 72%) as

colorless crystals: mp 236±2388C 2dec.) [lit.²⁰mp 2408C

2dec.)];IR 2nujol) 3320, 3138±2363, 1627, 1568 2N ¹H₃,

4.4.15. 1,1-Dimethylethyl trans-3-[3methoxy)31,1-di-

methylethoxycarbonyl)amino]-4-[3phenylsulfanyl)methyl]-

1-pyrrolidinecarboxylate 346). To a solution of trans-

methoxyamine 23d 2324 mg, 0.96 mmol) in CH₂Cl₂

214 mL) were added Et₃N 20.13 mL, 0.96 mmol), DMAP

250 mg, 0.41 mmol), and 2Boc)₂O 21.0 g, 4.8 mmol) at

room temperature under a nitrogen atmosphere. After

being stirred at room temperature for 48 h, the reaction

mixture was concentrated under reduced pressure. The

residue was puri®ed by MCC 2hexane/AcOEt 3:1) to afford

46 2199 mg, 49%) 2mp 72±738C 2hexane)) as colorless

1

COO²) cm²¹; H NMR 2200 MHz, CDCl₃) d 1.55±2.25

26H, m), 2.69 21H, br q, J8 Hz), 3.76 21H, br q,

J8 Hz);HRMS 2EI, m/z) calcd for C₁₀H₁₁NO₂2M¹)

129.0790, found 129.0817.

;

crystals;IR 2CHCl ₃) 1688 2NCOO) cm^{21 1}H NMR

4.4.13. 1,1-Dimethylethyl trans-[1-34-methylphenyl)-

sulfonyl-4-3phenylsulfanyl)methyl-3-pyrrolidinyl]carba-

mate 345c). To a stirred solution of trans-23c 2500 mg,

1.28 mmol) in H₂O±MeCN 21:15) 225 mL) was added

Mo2CO)₆2236 mg, 0.89 mmol) at room temperature under

a nitrogen atmosphere. After the solution was re¯uxed for

2 h, the reaction mixture was diluted with saturated aqueous

NaHCO₃and extracted with CH₂Cl₂. The organic phase was

washed with water, dried over Na₂SO₄and concentrated

under reduced pressure to give the crude amine as a yellow

oil. To a stirred solution of the crude amine in CH₂Cl₂

2109 mL) were added Et₃N 20.27 mL, 1.91 mmol) and a

solution of 2Boc)₂O 20.44 mL, 1.91 mmol) in CH₂Cl₂

241 mL) at room temperature under a nitrogen atmosphere.

After being stirred at room temperature for 3 h, the reaction

mixture was diluted with water and extracted with CH₂Cl₂.

The organic phase was washed with water, dried over

Na₂SO₄, and concentrated under reduced pressure. The

residue was puri®ed by MPCC 2hexane/AcOEt 5:1) to

afford 45c 2438 mg, 74%) as colorless crystals 2mp 181±

2300 MHz, CDCl₃) d 1.46 29H, s), 1.52 29H, s), 2.50±2.88

22H, m), 3.02±3.16 21H, m), 3.19 21H, dd, J12, 3.5 Hz),

3.28±3.48 21H, m), 3.50±3.87 22H, m), 3.62 23H, s), 4.39

21H, br q, J8.5 Hz), 7.15±7.40 25H, m);HRMS 2EI, m/z)

calcd for C₂₂H₃₄N₂O₅S 2M¹) 438.2186, found 438.2173.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.4.16. 1,1-Dimethylethyl cis-3-[3methoxy)31,1-dimethyl-

ethoxycarbonyl)amino]-4-[3phenylsulfanyl)methyl]-1-

pyrrolidinecarboxylate 349). According to the procedure

given for the conversion of 23d into 46, t-butoxycarbonyl-

ation of cis-methoxyamine 22d 2324 mg, 0.96 mmol) with

2Boc)₂O 21.0 mg, 4.8 mmol) afford N-Boc-49 2248 mg,

61%) as pale yellow oil;IR 2CHCl ) 1687 2NCOO) cm²¹

;

3

¹H NMR 2300 MHz, CDCl₃) d 1.46 29H, s), 1.52 29H, s),

2.46 21H, m), 2.80±2.92 21H, m), 3.15 21H, dd, J13,

5 Hz), 3.33 21H, br q, J10 Hz), 3.52±3.78 23H, m), 3.70

23H, s), 4.63 21H, m), 7.16±7.36 25H, m);HRMS 2EI, m/z)

calcd for C₂₂H₃₄N₂O₅S 2M¹) 438.2187, found 438.2175.

1848C 2hexane));IR 2CHCl ) 3437 2NH), 1710 2NCOO),

3

1

1161 2NSO₂) cm²¹; H NMR 2500 MHz, CDCl₃) d 1.41

29H, s), 2.14 21H, m), 2.43 23H, s), 2.52 21H, br dd, J13,

10 Hz), 2.96 21H, br t, J8 Hz), 3.04 21H, br dd, J13,

5 Hz), 3.09 21H, m), 3.46 21H, br t, J8 Hz), 3.59 21H, br

t, J8 Hz), 3.87 21H, m), 4.54 21H, br d, J7 Hz), 7.18±

7.34 27H, m), 7.68 22H, br d, J8 Hz);NOE was observed

between NH 2d 4.54) and 4-H 2d 2.14), and CH₂SPh 2d

3.04) and 3-H 2d 3.87) in NOESY spectroscopy. HRMS

2EI, m/z) calcd for C₂₃H₃₀N₂O₄S₂2M¹) 462.1647, found

462.1661;Anal. calcd for C ₂₃H₃₀N₂O₄S₂: C, 59.71;H,

6.54;N, 6.06;S, 13.86. Found: C, 59.46;H, 6.52;N, 6.04;

S, 13.82.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.4.17. 1,1-Dimethylethyl trans-3-formyl-4-[3methoxy)-

31,1-dimethylethoxycarbonyl)amino]-1-pyrrolidinecar-

boxylate 348). 21) Preparation from trans-46. To a solution

of 46 2172 mg, 0.39 mmol) in CH₂Cl₂214 mL) was added

dropwise

a solution mCPBA 270% assay) 267 mg,

0.39 mmol) in CH₂Cl₂221 mL) under a nitrogen atmosphere

at 08C. The reaction mixture was made alkaline with satu-

rated aqueous NaHCO₃and then extracted with CH₂Cl₂.

The organic phase was washed with water, dried over

Na₂SO₄, and concentrated under reduced pressure. Puri®ca-

tion of the residue by MPCC 2hexane/AcOEt 1:5) afforded

the sulfoxide 47 2147 mg, 83%) as a pale yellow oil and as a

1:1 diastereomeric mixture based on a sul®nyl group;

HRMS 2CI, isobutene, m/z) calcd for C₂₂H₃₄N₂O₆S1H

2QM¹) 455.2214, found 455.2218. To a solution of the sulf-

oxide 47 262 mg, 0.14 mmol) and 2,6-lutidine 20.06 mL,

0.55 mmol) in dry MeCN 21.5 mL) was added a solution

of TFAA 20.08 mL, 0.55 mmol) in dry MeCN 20.4 mL)

under a nitrogen atmosphere at 08C. After being stirred at

same temperature for 2 h, a solution of NaHCO₃2140 mg,

1.66 mmol) in H₂O 23 mL) was added to the reaction

mixture. The resulting solution was stirred at same tempera-

ture for 2 h. The reaction mixture was diluted with water

and extracted with CH₂Cl₂. The organic phase washed with

5% HCl, saturated aqueous NaHCO₃, and water, and then

dried over Na₂SO₄and concentrated under reduced

4.4.14. 1,1-Dimethylethyl cis-3-[31,1-dimethylethoxycar-

bonyl)amino]-4-[3phenylsulfanyl)methyl]-1-pyrrolidine-

carboxylate 345d). According to the procedure given for the

conversion of 23c into 45c, demethoxylation of the cis-

methoxyamine 22d 239 mg, 0.12 mmol) with Mo2CO)₆

242 mg, 0.12 mmol) followed by t-butoxycarbonylation of

the resulting amine with 2Boc)₂O 225 mg, 0.12 mmol) afford

N-Boc-45d 218 mg, 38%) as a pale yellow oil;IR 2CHCl )

3

1

1689 2NCOO) cm²¹; H NMR 2300 MHz, CDCl₃) d 1.46

218H, s) 2.38±2.60 21H, br s), 2.66±2.84 21H, m), 3.10 21H,

dd, J11, 9 Hz), 3.05±3.40 22H, m), 3.51 21H, m), 3.42±

3.76 21H, m), 4.28 21H, br s), 4.65 21H, br s), 7.20±7.40 25H,

m);HRMS 2EI, m/z) calcd for C₂₁H₃₂N₂O₄S 2M¹) 408.2081,

found 408.2089.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

4477

pressure. Puri®cation of the residue by MPCC 2hexane/

AcOEt 2:1) afforded the aldehyde 48 243 mg, 91%) as a

pale yellow oil; H NMR 2300 MHz, CDCl₃) d 1.47 29H,

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

1

4.4.20. trans-4-Amino-3-pyrrolidinecarboxylic acid 354).

To a solution of 53 217 mg, 0.05 mmol) in MeOH/H₂O 23:1)

21.5 mL) was added a solution of LiOH 224 mg, 0.57 mmol)

at 08C under nitrogen atmosphere. After being stirred at the

same temperature for 1 h, the reaction mixture was acidi®ed

to pH 3 and extracted with CHCl₃. The organic phase was

washed with water, dried over Na₂SO₄, and concentrated

under reduced pressure to give the crude N-Boc-carboxylic

acid. A solution of the carboxylic acid 217 mg, 0.05 mmol)

in 4 M-HCl-dioxane 20.1 mL, 0.4 mmol) was stirred at room

temperature under a nitrogen atmosphere for 1 h and

concentrated under reduced pressure. The residue was

dissolved in H₂O and loaded on resin 2Amberlite IR-

120B) in a column and washed with water and then

0.5 M-NH₄OH. After concentration of the eluate under

reduced pressure, b-amino acid 54 26 mg, 94%) was

obtained as yellow amorphous;IR 2nujol) 3390, 3165±

s), 1.51 29H, s), 3.20±3.36 21H, m), 3.46±3.52 21H, m),

3.60±3.74 23H, s), 4.85 21H, br s), 9.67 21H, d, J3 Hz).

After being characterized by NMR spectrum, the

aldehyde 48 was immediately subjected to the following

reaction.

22) Preparation from cis-49. According to the procedure

given for the conversion of 46 into 48, the oxidation of

cis-methoxyamine 49 2324 mg, 0.96 mmol) with mCPBA

21.0 mg, 4.8 mmol) followed by Pummerer rearrangement

afford aldehyde 48 2102 mg, 44% from 49) as pale yellow

oil. This compound was identical with 48 prepared from

trans-46.

4.4.18. 1-31,1-Dimethylethyl) 3-methyl trans-4-[3meth-

oxy)31,1-dimethylethoxycarbonyl)amino]-1,3-pyrroli-

dinedicarboxylate 352). To a solution of the aldehyde 48

243 mg, 0.125 mmol) in a mixture of THF 20.53 mL),

t-BuOH 20.53 mL), and H₂O 20.19 mL) were added

2-methyl-2-butene 22.0 M in THF, 0.51 mL), NaH₂PO₄

21.0 M in H₂O, 0.38 mL), and then 80% NaClO₂243 mg,

0.38 mmol) under nitrogen atmosphere at room tempera-

ture. The reaction mixture was stirred at the same tempera-

ture for 24 h and then concentrated under reduced pressure.

After dilution with aqueous KHSO₄20.5 M), the aqueous

phase was extracted with AcOEt. The organic phase was

washed with water, saturated aqueous Na₂SO₃, and brine,

and then dried over MgSO₄and concentrated under reduced

pressure to give the crude carboxylic acid 51 as pale yellow

amorphous. To a stirred solution of the carboxylic acid 51

236 mg, 0.1 mmol) in MeOH/benzene 22:7) 20.86 mL) was

added a solution of TMSCHN₂22 M in hexane, 0.07 mL,

2373, 1585, 1561 2N¹H₃, COO²) cm²¹

;

¹H NMR

2300 MHz, CD₃OD) d 2.59 21H, ddd, J7.5, 6, 5 Hz),

2.79 21H, dd, J12, 5 Hz), 3.16 21H, m), 3.26 21H, dd,

J12, 6 Hz), 3.28±3.32 22H, m), 3.67 21H, dt, J6,

5 Hz);HRMS 2CI, isobutene, m/z) calcd for C₅H₁₁N₂O₂

2QM¹) 131.0820, found 131.0835.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.5. Conversion of sul®de 24i into aldehydes 55 and 56

According to the procedure given for the conversion of 23d

into 48, t-butoxycarbonylation of 24i with 2Boc)₂O, oxida-

tion with mCPBA, and then Pummerer rearrangement gave

the cis-55 223%) and trans-56 246%).

0.14 mmol) at room temperature under

a nitrogen

atmosphere. After being stirred at the same temperature

for 1 h, the reaction mixture was concentrated under

reduced pressure. The residue was puri®ed by MPCC

2hexane/AcOEt 2:1) to afford the ester 52 219 mg, 42%)

2mp 63±648C 2Et₂O/hexane)) as colorless crystals;IR

4.5.1. 1,1-Dimethylethyl 32a,3b,4b)-4-formyl-3-[3meth-

oxy)31,1-dimethylethoxycarbonyl)amino]-2-phenyl-1-

pyrrolidinecarboxylate 355). Pale yellow oil; H NMR

2300 MHz, CDCl₃) d 1.27 29H, br s), 1.47 29H, br s), 1.51

29H, s), 3.22 21H, br q, J7 Hz), 3.72 23H, s), 3.83 21H, m),

4.10 21H, br dd, J10, 7 Hz), 5.16 21H, m), 7.17±7.40 25H,

m), 9.71 21H, br s). The presence of rotamers precluded a

comprehensive assignment of all proton resonances. After

being characterized by NMR spectrum, the aldehyde 55 was

immediately subjected to the following reaction.

1

2CHCl₃) 3448 2NH), 1720 2COO), 1710 2NCOO) cm²¹

;

¹H NMR 2300 MHz, CDCl₃) d 1.46 29H, s), 1.51 29H, s),

3.26±3.47 22H, m), 3.55 21H, dd, J11, 9 Hz), 3.72 23H, s),

3.76 23H, s), 4.82 21H, m);HRMS 2EI, m/z) calcd for

C₁₇H₃₀N₂O₇2M¹) 374.2051, found 374.1058.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.5.2. 1,1-Dimethylethyl 32a,3b,4a)-4-formyl-3-[3meth-

oxy)31,1-dimethylethoxycarbonyl)amino]-2-phenylpyr-

rolidine-1-carboxylate 356). Pale yellow oil; ¹H NMR

2300 MHz, CDCl₃) d 1.18 29H, br s), 1.27 29H, br s), 3.33

21H, br qd, J8, 3 Hz), 3.84 23H, s), 3.81±4.08 22H, m),

4.72±4.93 22H, m), 7.18±7.38 25H, m), 9.66 21H, br d,

J3 Hz). The presence of rotamers precluded a comprehen-

sive assignment of all proton resonances. After being

characterized by NMR spectrum, the aldehyde 56 was

immediately subjected to the following reaction.

4.4.19. 1-31,1-Dimethylethyl) 3-methyl trans-4-[1,1-

dimethylethoxycarbonyl)amino]-3-pyrrolidinecarboxyl-

ate 353). According to the procedure given for the

demethoxylation of 23c, 52 219 mg, 0.05 mmol) was

treated with Mo2CO)₆218 mg, 0.07 mmol) to afford

N-Boc-53 215 mg, 87%) as pale yellow oil;IR 2CHCl )

3

1

3441 2NH), 1736 2COO), 1692 2NCOO) cm²¹; H NMR

2300 MHz, CDCl₃) d 1.45 29H, s), 1.46 29H, s), 2.97

21H, br q, J7 Hz), 3.18 21H, br dd, J11, 6 Hz), 3.64

22H, br d, J8 Hz), 3.76 21H, dd, J11, 6 Hz), 3.73 23H,

s), 4.36 21H, br quint. J6.5 Hz), 4.71 21H, br s);HRMS

2EI, m/z) calcd for C₁₆H₂₈N₂O₆2M¹) 344.1945, found

344.1958.

4.6. Isomerization of the cis-aldehyde 55 to the trans-

aldehyde 56

A suspension of the cis-aldehyde 55 29 mg, 0.02 mmol) and

4478

O. Miyata et al. / Tetrahedron 58 )2002) 4459±4479

SiO₂239 g) in CH₂Cl₂21 mL) was stirred at room

temperature for 2 h. SiO₂was ®ltered off and the ®ltrate

was concentrated to give the trans-aldehyde 56 26 mg,

67%) whose spectral data were identical with those of an

authentic sample obtained from the sul®de 24i.

References

1. Part 12: Miyata, O.;Nakajima, E.;Naito, T. Chem. Pharm.

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4.6.1. 1-31,1-Dimethylethyl) 3-methyl 33a,4b,5a)-4-

[3methoxy)31,1-dimethylethoxycarbonyl)amino]-5-phen-

yl-1,3-pyrrolidinedicarboxylate 358). According to the

procedure given for the conversion of 48 into 52, oxidation

of 56 with NaClO₂followed by methylation of the resulting

carboxylic acid 57 with TMSCHN₂afforded the ester 58

280%) as a pale yellow oil;IR 2CHCl ) 3441 2NH), 1731

3

2COO), 1690 2NCOO) cm²¹; ¹H NMR 2300 MHz, CDCl₃) d

1.12 29H, s), 1.21 29H, s), 3.39 21H, td, J10, 8 Hz), 3.72

and 3.84 2each 3H, s), 3.77 21H, t, J10 Hz), 4.11 21H, dd,

J10, 8 Hz), 4.68±4.84 22H, m), 7.18±7.36 25H, m);

HRMS 2EI, m/z) calcd for C₂₃H₃₄N₂O₇2M¹) 450.2363,

found 450.2365.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

3. 2a) Borman, S. Chem. Engng News 1997, 75, 32±35. 2b) Koert,

U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836±1837.

4. 2a) Seebach, D.;Ciceri, P. E.;Overhand, M.;Jaun, B.;Rigo,

4.6.2. 1-31,1-Dimethylethyl) 3-methyl 33a,4b,5a)-4-[1,1-

dimethylethoxycarbonyl)amino]-5-phenyl-1,3-pyrroli-

dinedicarboxylate 359). According to the procedure

given for the demethoxylation of 23c, a solution of 58

D.;Oberer, L.;Hommel, U.;Amstutz, R.;Widmer, H.

Helv.

Chim. Acta 1996, 79, 2043±2066. 2b) Hintermann, T.;

Seebach, D. Synlett 1997, 437±438. 2c) Seebach, D.;Abele,

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Matthews, J. L.;Schreiber, J. V. Helv. Chim. Acta 1998, 81,

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84, 2924±2937.

228 mg,

0.062 mmol)

and

Mo2CO)₆

246 mg,

0.174 mmol) in EtCN/H₂O 215:1) 21 mL) was re¯uxed

for 4 h to give N-Boc-59 213 mg, 50%) 2mp 172±1748C

2Et₂O)) as colorless crystals;IR 2CHCl

2NH), 1731 2COO), 1690 2NCOO) cm²¹

)

3440

3

;

¹H NMR

2300 MHz, CDCl₃) d 1.15 29H, s), 1.42 29H, s), 3.16

21H, m), 3.56 23H, br s), 3.96 22H, m), 4.28 21H, m),

4.67 21H, m), 4.79 21H, m), 7.18±7.36 25H, m);HRMS

2EI, m/z) calcd for C₂₂H₃₂N₂O₆2M¹) 420.2259, found

420.2254.

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Jonathan, R.;LePlae, P. R.;Gellman, S. H. Org. Lett. 2001,

3, 3963±3966.

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

4.6.3.

33a,4b,45a)-4-Amino-5-phenyl-3-pyrrolidine-

carboxylic acid 360). According to the procedure

given for the conversion of 53 into 54, the deprotection

of 59 afforded b-amino acid 60 292%) 2mp 234±2368C

2EtOH));IR 2nujol) 3445, 3269±2357, 1627, 1545

6. For reviews: 2a) Giese, B. In Radicals in Organic Synthesis:

Formation of Carbon±Carbon Bonds;Baldwin, J. E., Ed.;

Pergamon: Oxford, 1996. 2b) Ramaiah, M. Tetrahedron

1987, 43, 3541±3676. 2c) Curran, D. P. Synthesis 1988,

417±439, see also pp 489±513. 2d) Jasperse, C. P.;Curran,

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Organosulfur Chemistry: Synthetic Aspects;Page, P., Ed.;

Academic: London, 1995;Vol. 1, pp 49±88. 2f) Giese, B.;

2N¹H₃, COO²) cm²^{1 1}H NMR 2300 MHz, CD₃OD) d

;

2.80±4.20 26H, m), 7.38 25H, m);HRMS 2CI, iso-

butene, m/z) calcd for C₁₁H₁₅N₂O₂1H 2QM¹)

207.1133, found 207.1124.

È

Kopping, B.;Go bel, T.;Dickhaut, J.;Thoma, G.;Kulicke,

The presence of rotamers precluded a comprehensive

assignment of all proton resonances.

K. J.;Trach, F. In Organic Reactions;Paquette, L. A., Ed.;

Wiley: New York, 1996;Vol. 48, pp 301±856. 2g) Ryu, I.;

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Acknowledgements

This work was supported in part by Grant-in-Aid for

Scienti®c Research from the Ministry of Education,

Science, Sports and Culture, Japan and a research grant

from the Science Research Promotion Fund of the Japan

Private School Promotion Foundation.

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Article Doi

Radical cyclization in heterocycle synthesis. Part 13: Sulfanyl radical addition-cyclization of oxime ethers and hydrazones connected with alkenes for synthesis of cyclic β-amino acids

DOI: 10.1016/S0040-4020(02)00412-X

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Full text of DOI:10.1016/S0040-4020(02)00412-X

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