The stereoselective synthesis of 2-substituted 3- azabicyclo[3.2.0]heptanes by intramolecular [2+2]-photocycloaddition reactions

FEATURE ARTICLE

305

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes by

Intramolecular [2+2]-Photocycloaddition Reactions

Thorsten Bach,* Christa Krüger, Klaus Harms^#

Philipps-Universität Marburg, Fachbereich Chemie, D-35032 Marburg, Germany

Fax +49(6421)2828917; E-mail: bach@chemie.uni-marburg.de

Received 31 August 1999; revised 23 October 1999

cleavage of bond b is expected to yield 3,4-cis-substituted

Abstract: The stereoselective synthesis of the 3-azabicyc-

pyrrolidines C.

lo[3.2.0]heptanes 6, 12, 13, 17, 22, 23 and 24 by an intramolecular

[2+2]-photocycloaddition is described. The product yield was good

to excellent in almost all cases studied (65-87%) except for a single

example (21 → 24) in which a low yield was recorded (22%). The

facial diastereoselectivity of the reaction is high if a-branched N,N-

diallylamines are employed as starting materials which either bear

a comparably bulky a-substituent (25) or the a-substituent of which

is connected to the nitrogen atom via an oxazolidinone ring (16, 19,

20, 21). These diallylamines were readily prepared from methionine

and it was shown that their preparation proceeded free of racemiza-

tion. The photocycloaddition could be conducted in two ways. The

more general method is based on the Cu-catalyzed reaction which

was carried out with Cu(OTf)₂in diethyl ether and is applicable to

essentially all substrates under scrutiny. The N-cinnamyl substitut-

ed substrates 5, 11, 16 and 25 which possess a comparably low lying

T₁state reacted well in a triplet-sensitized process employing ace-

tophenone as the sensitizer and acetone as the solvent.

An additional feature which was recently disclosed makes

azabicyclo[3.2.0]heptanes interesting target molecules in

their own right. It was found that they are promising phar-

macophores for the treatment of schizophrenia and related

psychotic diseases.⁴In in vivo assays, 6-aryl-3-azabicyc-

lo[3.2.0]heptanes linked to a quinazoline-2,4-dione via an

ethylene chain emerged as potent D₄/5-HT_2Areceptor an-

tagonists which are effective in nanomolecular concentra-

tions.⁵The most active compound named LU-111995 (1)

was successfully tested in clinical trials and it is consid-

ered a promising candidate for the treatment of schizo-

phrenia. The depicted absolute configuration of the

azabicyclo[3.2.0]heptane is required for optimum activity

and, indeed, the drug is currently applied in enantiomeri-

cally pure form. The desired antipode is obtained from

the racemic material by conventional fractional crystalli-

zation of diastereoisomeric tartrates.⁶

Key words: photochemistry, cycloadditions, stereoselective syn-

thesis, bicyclic compounds, heterocycles

F

Introduction

H

O

Strained molecules have been recognized for a long time

as interesting intermediates in organic synthesis. Their

ring opening can lead to acyclic or cyclic structures of

synthetic relevance.¹In this respect the cyclobutane ring

is a prototypical example and it has been frequently ex-

ploited due to the fact that it is readily formed by cycload-

dition reactions²and that a variety of ring opening

reactions are available for its further transformations.³We

have recently become interested in the stereoselective

synthesis of 3-azabicyclo[3.2.0]heptanes A as these com-

pounds appear to offer access to other monocyclic hetero-

cycles upon cyclobutane ring fission (Scheme 1,

PG = protective group). The cleavage of the central en-

docyclic bond a should lead to azepanes B whereas the

N

H

N

O

H

1

In the study which is described in the following account

we attempted to prepare azabicyclo[3.2.0]heptanes in a

diastereoselective fashion starting from chiral N,N-dial-

lylamines by [2+2]-photocycloaddition.⁷By this means

enantiomerically pure products should be directly avail-

able from enantiomerically pure starting materials. We

were particularly interested in vinylglycine-derived sub-

strates D as depicted in Scheme 2. Along the lines previ-

azepanes

a

b

PG

N

(B)

H

b

a

N

PG

substituted

pyrrolidines

R

PG

N

(C)

R¹

A

Scheme 1

Scheme 2

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

306

T. Bach et al.

FEATURE ARTICLE

ously discussed they contain a versatile functional group employing acetophenone or benzophenone as the sensitiz-

(e.g. CO₂H, CR₂OH) at the stereogenic center which can er.⁶The Cu(I)-catalyzed process on the other hand is not

be used for possible ring opening reactions succeeding the limited to specific alkene substrates. It was reported by

[2+2]-photocycloaddition. Radical type cleavage reac- Salomon et al. that it can be applied to simple N,N-diallyl-

tions of carboxylic acid derivatives,⁸for example, gener- amines provided that the nitrogen atom is N-substituted by

ate a radical center after decarboxylation which in the case an alkoxycarbonyl group.⁹In addition, it was shown in the

of the azabicyclo[3.2.0]heptane skeleton may lead to a same study that a chiral a-methyl substituted N,N-diallyl-

ring fission according to path a (Scheme 1). It was pro- carbamate reacts stereoselectively yielding the corre-

jected that compounds of type D can be readily synthe- sponding 2-substituted azabicyclo[3.2.0]heptane as a

sized from amino acids as precursors. Possible starting single diastereoisomer (60% yield).⁹

materials we had in mind were vinylglycine methyl ester

hydrochloride (2) or methionine (3).

Preliminary Experiments

The planned key photocycloaddition can be conducted in

two ways, either catalyzed by Cu(I)-salts or sensitized by

We planned to carry out the [2+2]-photocycloaddition re-

a suitable triplet sensitizer. Both reaction types have been

actions with N-protected substrates although it has been

successfully applied to N,N-diallylamines.^6,9In the latter

known that unprotected N-allyl-N-cinnamylamines can be

successfully converted to azabicyclo[3.2.0]heptanes by

sensitized excitation in acidic media (vide supra). In the

variant one of the alkenes must possess a low lying triplet

pp*-state in order to allow for a sensitation by carbonyl

compounds. This is the case for aryl-substituted alkenes

Cu-catalyzed reaction N-protection is mandatory. We in-

and the photocycloaddition of N-allyl-N-cinnamylamines

vestigated the properties of three different protective

has previously been performed in acetone as the solvent

groups with regard to the facility of protection and depro-

Biographical Sketches

Thorsten Bach was born in joined the group of Prof. M. 1997 he moved to his cur-

Ludwigshafen/Rhein

in T. Reetz as a Kekulé fellow rent position as professor of

April 1965. He studied and received his Ph.D. in organic chemistry at the

chemistry at the University 1991 from the University of University of Marburg. His

of Heidelberg and at the Marburg. After a postdoc- prime research interests are

University of Southern Cal- toral stay at Harvard with preparative organic photo-

ifornia where he carried out Prof. D. A. Evans he started chemistry, organometallic

his Diploma thesis under the his independent research at chemistry and stereoselec-

guidance of Prof. G. A. the University of Münster in tive synthesis.

Olah. Subsequently, he 1992. In the beginning of

Christa Krüger, née Pelk- of Prof. T. Bach was con- the intramolecular photocy-

mann, was born in Ibben- cerned with the develop- cloaddition of amino acid

büren

(Westphalia)

in ment of new UV-A- derivatives and its applica-

December 1971. She started absorbers for cosmetic sun- tion in stereoselective or-

studying chemistry at the screens. In 1997, she moved ganic synthesis.

University of Münster in to the University of Mar-

1991 where she received her burg where she conducted

Diploma in 1996. Her Di- her Ph.D. work in the group

ploma work which she car- of Prof. T. Bach. Her current

ried out under the guidance research interests focus on

Klaus Harms was born in Prof. L. F. Tietze. After a are methods of crystal struc-

Iheringsfehn (Germany) in postdoctoral stay with Prof. ture determination, crystal-

1953. He studied chemistry G. M. Sheldrick he became lographic computing, and

at the University of Göttin- a member of the X-ray service crystallography.

gen where he received his structure division of the De-

Diploma in 1980 with Prof. partment of Chemistry at the

G. M. Sheldrick and his University of Marburg in

Ph.D. degree in 1984 with 1986. His research interests

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

307

tection and with regard to the stability of the protective ter allylation. This plan could be realized by N-allylation

group in the photochemical reaction. As the test system of racemic methionine methyl ester¹²with cinnamyl bro-

we selected N-allyl-N-cinnamylamine¹⁰(4) which was mide (Scheme 4). The protection of amine 8 with the Z

converted to the N-protected derivatives 5a-c (Scheme group proceeded quantitatively and yielded sulfide 9. Its

3). Preliminary photocycloaddition experiments were oxidation was conducted according to the procedure by

conducted in acetone with acetophenone as the sensitizer. Rapoport et al.¹³and the intermediate sulfoxide 10 was di-

They yielded the azabicyclo[3.2.0]heptanes 6a-c which rectly taken into the thermolytic elimination step without

were subsequently deprotected to the free amine 7. The further purification. Despite several attempts to increase

benzyloxycarbonyl group Z emerged as the protective the yield of vinylglycine derivative 11 by variation of the

group of choice as it showed good performance in all three elimination conditions there was no tremendous improve-

steps.

ment. The desired b,g-unsaturated ester was always con-

taminated with the corresponding conjugated ester and the

separation of these compounds was difficult. Still, we

could prepare a sufficient amount of material to study the

intramolecular [2+2]-photocycloaddition.

Reagents and conditions: (a) ZCl/KHCO₃/H₂O-EtOAc(1:1);

(b) Boc₂O/Et₃N/CH₂Cl₂; (c) Ac₂O/Et₃N; (d) Pd(OH)₂-C/MeOH;

(e) TFA/CH₂Cl₂; (f) 2 N HCl/H₂O

Scheme 3

A slight drawback of both the Z and the tert-butyloxycar-

bonyl (Boc) group in comparison with the acetyl (Ac)

group was the somewhat lower exo-selectivity observed

in the photocycloaddition. Whereas compound 6c was

formed as a single diastereoisomer, the exo-6-phenyl-3-

azabicyclo[3.2.0]heptanes 6a and 6b were contaminated

with the endo-isomer. The exo/endo-selectivity was deter-

mined to be 10:1 in the case of the Z-derivative and 6:1 in

the case of the Boc-derivative. Still, in further experi-

ments the Z-protective group was exclusively used, in

particular as it also showed perfect stability in the Cu-cat-

alyzed reaction (vide infra).

Scheme 4

The photocycloaddition reaction was performed in ace-

tone employing acetophenone as the triplet sensitizer. We

obtained two products in a ratio of 2:1 which could be sep-

arated by chromatography (12a: 53%; 12b: 27%). By ¹H

and ¹³C NMR studies it was established that the relative

configuration within the cyclobutane ring is 6-exo and

1,5-cis in both products and that the two products are con-

sequently the result of a diastereoface differentiating reac-

tion step. Although the facial diastereoselectivity was low

it was of interest to us to elucidate the relative configura-

tion. This was successfully done by Grignard addition to

ester 12a (Scheme 5) and comparison of the product 13

obtained with the material, the relative configuration of

which was known (vide infra). Additional proof for the

structural assignment came from the ¹H NMR spectra re-

corded for compounds 12a and 12b. Whereas the cou-

pling of H-1 and H-2 in 12b (dihedral angle 0°) is

comparably large (³J = 9.7 Hz), the corresponding ³J cou-

pling constant is below the resolution limit in 12a due to

the 90° dihedral angle between the protons under scrutiny.

Low Facial Diastereoselectivity in the [2+2]-Photocy-

cloaddition of Compound 11

Initial attempts to synthesize a suitable vinylglycine-de-

rived N,N-diallylamine of type D centered on the allyla-

tion of vinylglycine. However, neither the N-Z-protected

vinylglycine methyl ester which was readily available in

racemic form by a known procedure¹¹nor the correspond-

ing amine hydrochloride 2 could be successfully alkylated

by cinnamyl halides under a variety of conditions. Migra-

tion of the double bond was a frequently encountered

problem which precluded the isolation of pure material.

Consequently, we decided to establish the double bond af-

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308

T. Bach et al.

FEATURE ARTICLE

Intramolecular Sensitized [2+2]-Photocycloaddition

of N-Cinnamyl-4-vinyloxazolidinones 16

H

Ph

5

MeMgI

(Et₂O)

ZN

1

12a

The first idea we pursued was to construct the N-cin-

namyl-4-vinyloxazolidinones 16 (Scheme 7) which

would provide the neccessary bias for a conformational

restriction in the photocycloaddition step. The ideal start-

ing material for their synthesis was the vinylglycine ester

14 which could be obtained from methionine (3) in four

steps. The elimination of the sulfoxide to the olefin in this

sequence¹³was carried out according to the procedure by

Suzuki et al.¹⁵and we showed in later examples that this

transformation and the consecutive steps proceed racem-

ization-free. For the conversion of ester 14 to the vinyl-

glycinol 15a a known reduction protocol (LiBH₄in Et₂O/

MeOH)¹⁶was employed. The tertiary alcohol 15b was

prepared by Grignard addition to the ester 14. The cycliza-

tion to the oxazolidinone and the N-allylation could be

carried out in a single operation as it was previously

shown for related systems by Blechert and Huwe.¹⁶The

desired starting materials 16a and 16b were thus obtained

in total yields of 40 and 47% starting from methionine (3).

44%

13

OH

Scheme 5

The relative configuration of the major diastereoisomer

12a can be explained based on a preferred conformation

11’ of compound 11 as shown in Scheme 6. The 1,3-allyl-

ic strain is minimized and the methoxycarbonyl group

adopts a pseudoequatorial position. Upon sensitized pp*-

triplet excitation the pyrrolidine ring is formed and the rel-

ative configuration at C-1 and C-5 of the products is estab-

lished. The resulting triplet 1,4-biradical intermediate

collapses to the product 12a the 6-exo-configuration of

which can be explained based on the free rotation in the

biradical intermediate in which the phenyl group can

adopt the less hindered position. Similar arguments are

valid for the formation of the minor exo-diastereoisomer

12b via conformation 11’’ in which the methoxycarbonyl

group resides in the pseudoaxial position. Apparently, the

bulk of the relatively small methoxycarbonyl (A = 1.3

kcal mol^-1)¹⁴substituent was not sufficient to favor a pre-

dominant conformation 11’ which was hoped to be re-

sponsible for the selection.

Scheme 6

Scheme 7

In search for a remedy to improve the low facial diastere-

oselectivity in the [2+2]-photocycloaddition we speculat-

ed that a conformation related to 11’ had to be more

strongly fixed in order to guarantee sufficient face differ-

entiation and that this could be done by connecting the

substituent at the stereogenic center directly with the ni-

trogen atom in a suitable heterocycle. The most obvious

choice was to use an oxazolidinone derived from vinyl-

glycinol for this purpose. Alternatively, a larger substi-

tutent at the stereogenic center should disfavor a confor-

mation such as 11’’ and lead to the prevalent formation of

compounds related to 12a.

The [2+2]-photocycloaddition reactions carried out with

compounds 16 proceeded smoothly under standard condi-

tions employing acetophenone as the sensitizer in acetone

as the solvent. We were pleased to note that the yield of

the desired tricyclic products 17 was high and that a single

diastereoisomer was formed. The structure elucidation of

both compounds 17a and 17b was performed by single

crystal X-ray crystallography. The structure of compound

17a is depicted in Figure 1.¹⁷The structure of compound

17b has already been disclosed in our preliminary com-

munication.⁷Since the cyclobutane ring of 17 closely re-

sembles its diolefinic predecessor it is fairly easy to get an

impression on the steric situation in the N-cinnamyl-4-vi-

nyloxazolidinones 16. The preferred conformation in the

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The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

309

diastereoface differentiating step which can be deduced

from the product configuration is similar to the conforma-

tion 11’depicted in Scheme 6 for the open chain case. Ob-

viously, the attack of the pp*-triplet excited styrene which

is attached via the methylene group to the nitrogen atom

of the oxazolidinone is forced to occur at the a-carbon

atom of the vinyl group from its re-face forming the cen-

tral C-C bond in a diastereoselective fashion.

H

Ph

KOH

ZCl, KHCO₃

(H₂O, EtOH)

(EtOAc, H₂O)

HN

17b

13

98%

94%

H

18

OH

Scheme 8

Compound (+)-17a was prepared in enantiomerically

pure form starting from L-methionine [(+)-3] by the same

route which was described earlier for the racemic material

(Scheme 7). The enantiomeric purity (> 95% ee) was con-

firmed by chiral HPLC (column: Daicel Chiracel OD, elu-

ent:hexane/propan-2-ol = 80:20).

Intramolecular Cu-Catalyzed [2+2]-Photocycloaddi-

tion of N-Allyl-4-vinyloxazolidinones

As it was already implied in the introduction, the intramo-

lecular [2+2]-photocycloaddition can also be achieved by

a CuOTf-catalyzed process.¹⁹The advantage of this meth-

od is the fact that its application is not restricted to sub-

strates with low lying T₁-states. We consequently hoped

that the diastereoselective [2+2]-photocycloaddition reac-

tion would equally well proceed with simple N-allyl-4-vi-

nyloxazolidinones in the presence of a Cu catalyst. The

starting materials for this study were available from the N-

Z-protected amino alcohols 15 (15a: R = H; 15b:

R = CH₃) by the previously discussed one-pot cyclization/

allylation²⁰reaction depicted in Scheme 9. Table 1 shows

that the yields for this transformation were moderate to

good. Compounds 20 were obtained as E/Z-mixtures

(70:30) because the allylation reagent was used as a mix-

ture of diastereoisomers.

Figure 1 A molecule of compound 17a in the crystal.¹⁷

A beneficial side effect of the oxazolidinone moiety we

used to induce the facial diastereoselection was the clearer

and more readily accessible NMR assignments in both

1

starting materials and products. The H and ¹³C NMR

spectra of the azabicyclo[3.2.0]heptanes 12a and 12b had

to be obtained at 100 °C in DMSO-d₆as the solvent which

inevitably precluded a simple reisolation of the products.

On the contrary, the NMR data of compounds 16 and re-

lated products were obtained at room temperature as the

carbamate N-C bond is embedded in the heterocyle and

cannot rotate. NOESY studies could be readily carried out

with 17a and 17b which supported the crystallographic

data and which were useful for further assignments of re-

lated compounds (vide infra).

R¹

NaH

BrCH₂CHCHR¹

O

N

ZHN

(DME)

O

R

HO

see table 1

R

19, R¹= H; 20, R¹= CH₃; 21, R¹= t Bu

From the crystal structures obtained from compounds 17a

and 17b it became also quite clear that the tricyclic prod-

ucts are fairly strained. The strain is not only reflected by

the expected Baeyer strain within the cyclobutane ring but

also by the fact that the torsional angle of the amide bond

in the oxazolidinones, i.e. C(5)-N-C=O, was determined

to be 164.5° in 16b and 167.5° in 16a and it is significant-

ly different from the value (180°) expected for a conjugat-

ed system. As a consequence the oxazolidinone 17b was

readily saponified upon treatment with base.¹⁸The other-

wise much more tedious ring opening (vide infra) pro-

ceeded smoothly within one hour and generated the amino

alcohol 18 which was subsequently N-Z-protected to the

azabicyclo[3.2.0]heptane 13 (Scheme 8). The compound

so obtained proved to be identical in all respects with the

one previously prepared from ester 12a by Grignard addi-

tion (cf. Scheme 5).

15

Scheme 9

Table 1 Substitution Pattern and Yield of the N-Allyl-4-vinylox-

azolidinones 19-21 Obtained by Cyclization/N-Allylation from the

N-Z-Protected Amino Alcohols 15

R

Substrate

R¹

Product

Yield^a

(%)

H

Me

15a

15b

H

19a

20a^b

21^c

76

80

79

63

84

Me

t-Bu

H

19b

Me

20b^b

^aYield of isolated product after chromatographic purification.

^bObtained as a mixture of diastereoisomers (E/Z = 70:30).

^cObtained as pure E-diastereoisomer (E/Z = >95:5).

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T. Bach et al.

FEATURE ARTICLE

CuOTf was used as the catalyst in the initial irradiation hydrogen atoms H-5 and H-7 and no interactions between

experiments carried out with the dienes 19-21. It turned H-5 and H-6. This result is in full accord with the assumed

out, however, that the handling of CuOTf is somewhat trans-orientation of cyclobutane and oxazolidinone ring

awkward and that the yields suffered dramatically unless (relative configuration between C-5 and C-6) which are

the reaction was conducted under the strict exclusion of both annulated to the central pyrrolidine ring. The relative

air and moisture. Based on precedence described earlier configuration between C-6 and C-9 is cis as expected for

by Mattay et al.²¹we attempted the very same reaction a fused azabicyclo[3.2.0]heptane. With regard to the rela-

with the air-stable Cu(OTf)₂as the catalyst employing di- tive configuration at C-5, C-6 and C-9, compounds 23 be-

ethyl ether as the solvent. These conditions proved ex- haved similar to compound 22. In this case, however, the

tremely well-suited to achieve the desired reaction and the additional stereogenic center at C-8 led to exo- and endo-

azabicycloheptanes 17, 22 and 23 were obtained in good isomers the relative configuration of which could be as-

yields (63-87%) according to Scheme 10 (Table 2). It is signed based on their ¹³C NMR and on their NOESY spec-

assumed²¹that an in situ reduction of Cu(II) to Cu(I) takes tra. Significant NOESY signals for exo-23a are depicted

place in this reaction which generates the active catalyst.

in Figure 2. The exo-isomer showed a contact of the CH₃-

protons and the hydrogen atom H-9, a contact which was

absent in the endo-isomer. In addition, the ¹³C NMR sig-

nals for C-9 and C-10 are shifted upfield (Dd -5 ppm)

in the endo-isomer endo-23a as compared to the exo-iso-

mer exo-23a. This phenomenon appears to be common to

all azabicyclo[3.2.0]heptanes and it has been previously

observed in related cases.⁶

H

R¹

hν

R¹

Cu(OTf)₂

(Et₂O)

1

N

O

N

O

7

5

O

4

O

see table 2

R

16

R¹= Ph

R

¹= H

R¹= CH₃

R¹= t Bu

17

22

23

24

19

20

21

Scheme 10

Only the sterically congested alkene 21 reacted sluggishly

and the yield of cyclobutane 24 remained low even after

prolonged irradiation (156 h). In the case of the N-cin-

namyl derivatives 16, the Cu(OTf)₂-catalyzed process

was even superior to the sensitized reaction. Single dias-

tereoisomers were obtained which proved to be the exo-

products 17 based on comparison with the products ob-

tained earlier. The enantiomerically pure (+)-17a was pre-

pared starting from the previously used starting material

(-)-16a. Apparently, the Cu(OTf)₂-catalyzed photocy-

cloaddition also proceeded without racemization.

Figure 2 Significant NOESY contacts in the tricyclic irradiation

products 22 and exo-23a

We have currently no conclusive explanation why the exo/

endo-ratio for the phenyl substituted products 17 is signif-

icantly better than for the tert-butyl substituted product 24

although the starting materials 16 and 23 were used in di-

astereomerically pure form. It is known, however, that

Cu(I) catalyzes the E/Z-isomerization of olefins²²and it is

therefore easy to understand that the reaction is not fully

stereospecific in particular if the photocycloaddition pro-

ceeds slowly. Indeed, the ¹H NMR spectrum and GC anal-

ysis of the crude reaction product 21 → 24 revealed that

the non-converted starting material 21 was no longer dias-

tereomerically pure and contained detectable amounts of

another isomer, which was presumed to be the Z-isomer

according to MS (ratio: 83:17).

Further assignments for 22 and 23 were based on NOESY

experiments carried out with the major diastereoisomers.

Compound 22a which does not carry a substituent in 8-

position showed a strong NOESY contact (Figure 2) of

Table 2 Cu(OTf)₂-Catalyzed Photocycloaddition of N-Allyl-4-vi-

nyloxazolidinones 16 and 19-21

R

R¹

Substrate

Product

Yield^a

(%)

Exo/endo

Ratio

H

Me

Ph

H

Me

t-Bu

Ph

H

16a^b

19a

17a

22a

23a

24

17b

22b

23b

87

65

75

22

82

72

63

>95/5

–

69/31

85/15

>95/5

–

20a^c

21^b

Acyclic Stereocontrol in the Intramolecular [2+2]-

Photocycloaddition of Compound 25

16b^b

19b

20b^c

Me

68/32

In final experiments, we returned to the question of acy-

clic stereocontrol in vinylglycine-derived substrates.

Compound 11 had led to unsatisfactory results in its pho-

^aYield of isolated product after chromatographic purification.

^bUsed as pure E-diastereoisomer (E/Z = 95:5).

^cUsed as a mixture of diastereoisomers (E/Z = 70:30).

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The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

311

distilled prior to use. Anhyd CH₂Cl₂was distilled from CaH₂, anhyd

Et₂O and THF from K/Na immediately prior to use. Dimethoxy-

ethane and Et₃N were distilled from CaH₂. All other reagents and

solvents were used as received. Melting points (uncorrected):

Reichert hot bench. IR: Bruker IFS 88 FT-IR or Nicolet 510M FT-

tocycloaddition (Scheme 4) and it was speculated that a

larger substituent in the 2-position might cause an im-

proved selectivity. Starting from the readily available ox-

azolidinone 16b we had easy access to a system with

which we could check this hypothesis. To this end, the ox-

azolidinone 16b was converted to the N-cinnamyl vinyl-

glycinol 25 (Scheme 11). In the first step compound 16b

was saponified. In contrast to the facile saponification of

the strained compound 17b which was complete after 1

hour this transformation took 24 hours. In the second step

the resulting amino alcohol was N-Z-protected. Irradia-

tion of the compound 25 so obtained in the presence of ac-

etophenone as the sensitizer yielded a major product

1

IR. MS: Varian CH7 (EI). H and ¹³C NMR: Bruker ARX-200,

1

Bruker AC-300, Bruker AM-400, Bruker AMX-500. H and ¹³C

NMR spectra were recorded in CDCl₃as solvent at ambient temper-

ature unless stated otherwise. Chemical shifts are reported relative

to TMS as an internal reference. Interchangeable assignments are

marked with an asterisk (*). NOESY contacts are reported as weak

(‘), medium (‘‘) or strong (‘‘‘). Elemental analyses: Elementar vario

EL. Optical rotations: Perkin-Elmer 241, determined at r.t. HPLC:

Merck-Hitachi L6200A equipped with an UV spectrometer detector

(254 nm). TLC: Merck aluminum sheets (0.2 mm silica gel 60 F₂₅₄

.

which proved identical to the previously prepared azabi- Detection by UV or by coloration with ceric ammonium molybdate

(CAM), potassium permanganate (PM), iodoplatinate (IP) or ninhy-

cycloheptane 13 (cf Schemes 5 and 7). Its selective forma-

tion can be readily explained by a transition state similar

to the one depicted in Scheme 6 with the HOMe₂C-group

drine (NH). - Flash chromatography:²³Merck silica gel 60 (230-

400 mesh ASTM) (ca. 50 g for 1 g of material to be separated).

residing in the pseudoequatorial position.

N-Allyl-N-benzyloxycarbonyl-N-cinnamylamine (5a)

Benzyl chloroformate (0.78 mL, 940 mg, 5.5 mmol) was added

dropwise over a period of 30 min to an ice-cold solution of N-allyl-

1. KOH (H₂O, EtOH)

N-cinnamylamine¹⁰(4; 870 mg, 5 mmol) and KHCO₃(2.50 g) in a

2. ZCl, KHCO₃

(EtOAc, H₂O)

hν, PhCOMe

mixture of H₂O and EtOAc (50 mL, 1:1, v/v). After the mixture was

stirred for 4 h the organic layer was separated, washed with dil HCl

(20 mL), H₂O (20 mL) and brine (20 mL), and subsequently dried

(MgSO₄). After filtration, the solvent was evaporated in vacuo. A

colorless oily residue remained (1.54 g, quant) which was used

without further purification; R_f0.49 (pentane/t-BuOMe, 75:25).

Ph

(acetone)

ZN

13

16b

77%

71%

HO

25

Scheme 11

IR (film): n = 3083 (w, C_arH), 3062 (w, C_arH), 3030 (w, C_arH), 2983

(w, C_alH), 2944 (w, C_alH), 1700 (vs, CO), 1460 (m), 1413 (m), 1237

(s), 746 (m, Ph), 695 cm^-1(m, Ph).

Interestingly, a second diastereoisomer was isolated from

the product mixture in 9% yield which proved to be the

endo-isomer of 13 (endo-13).

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 3.92 (d, 2 H, J = 5.6

Hz, CH₂CHCH₂N), 4.03 (d, 2 H, J = 6.1 Hz, CHCHCH₂N), 5.14 (s,

2 H, CH₂Ph), 5.12-5.19 (m, 2 H, CH₂CHCH₂N), 5.83 (ddt, 1 H,

J = 5.6, 10.3, 17.1 Hz, CH₂CHCH₂N), 6.20 (dt, 1 H, J = 6.1, 15.9

Hz, CHCHPh), 6.50 (d, 1 H, J = 15.9 Hz, CHPh), 7.21-7.39 (m, 10

H_arom).

Conclusion and Outlook

¹³C NMR (50.3 MHz): δ = 48.5 (CH₂N), 49.2 (CH₂N), 67.1

(CH₂Ph), 116.9 (CH₂CHCH₂N), 124.8 (CHCHPh), 126.3 (C_arH),

127.6 (C_arH), 127.7 (C_arH), 127.8 (C_arH), 128.4 (C_arH), 128.5

(C_arH), 132.4 (CH₂CHCH₂N), 133.4 (CHPh), 136.5 (C_ar), 136.7

(C_ar), 155.9 (CO).

In the study presented above we have shown that a stereo-

selective access to various 3-azabicyclo[3.2.0]heptanes is

possible by the intramolecular [2+2]-photocycloaddition

of vinylglycine derivatives. Both the sensitized and the

Cu(I)-catalyzed variant of this cycloaddition were suc-

cessfully applied to various N,N-diallyl amines and yield-

ed the desired products in good to excellent yields. In a

single step two carbon-carbon bonds and up to three ste-

reogenic centers were formed with good diastereofacial

control. The reaction is a viable alternative to other ring

closure reactions, in particular to the recently much ap-

plied metathesis. This will hold more true if the cyclobu-

tane ring can be regioselectively cleaved in successive

reactions. A straightforward and stereoselective synthesis

of pyrrolidines and azepines for example should be possi-

ble by this means. Studies along these lines are currently

underway in our laboratories and will be reported in due

course.

MS (EI, 70 eV): m/z (%) = 216 (18) [M⁺- C₇H₇], 133 (10), 117 (16)

+

[C₉H₉], 115 (22), 91 (100) [C₇H₇], 41 (15) [C₃H₅].

Anal. C₂₀H₂₁NO₂(307.4): calcd C, 78.15; H, 6.89; N, 4.56; found

C, 77.98; H, 6.91; N, 4.69.

N-Allyl-N-tert-butyloxycarbonyl-N-cinnamylamine (5b)

A solution of di-tert-butyl dicarbonate (1.20 g, 5.5 mmol) in anhyd

CH₂Cl₂(10 mL) was slowly added to a cooled solution of N-allyl-

N-cinnamylamine¹⁰(940 mg, 5.4 mmol) and Et₃N (0.77 mL, 560

mg, 5.5 mmol) in anhyd CH₂Cl₂(20 mL). The mixture was stirred

at r.t. overnight and the solvent was evaporated in vacuo. H₂O (20

mL) was added to the residue, and the mixture was extracted with

EtOAc (3 î 30 mL). The combined organic layers were washed

with brine (30 mL) and dried (MgSO₄). After filtration, the solvent

was evaporated in vacuo. Flash chromatography (pentane/t-

BuOMe, 95:5) yielded compound 5b (1.41 g, 96%) as a colorless

oil; R_f0.60 (pentane/t-BuOMe, 75:25).

IR (film): n = 3027 (w, C_arH), 3005 (w, C_arH), 2977 (m, C_alH), 2929

(w, C_alH), 1694 (vs, CO), 1454 (s), 1407 (s), 1365 (s), 1170 (s), 744

(m, Ph), 693 cm^-1(m, Ph).

All reactions involving water-sensitive compounds were carried out

in flame-dried glassware with magnetic stirring under Ar. Common

solvents (t-BuOMe, Et₂O, EtOAc, pentane, CH₂Cl₂, CHCl₃, ace-

tone, MeOH and EtOH), acetic anhydride and acetophenone were

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

312

T. Bach et al.

FEATURE ARTICLE

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 1.43 [s, 9 H, C(CH₃)₃],

3.82 (dt, 2 H, J = 1.4, 5.8 Hz, CH₂CHCH₂N), 3.94 (dd, 2 H, J = 1.4,

6.2 Hz, CHCHCH₂N), 5.12 (pseudo dq, 1 H, J = 1.4, 10.3 Hz,

IR (film): n = 3061 (w, C_arH), 3028 (w, C_arH), 2962 (m, C_alH), 2933

(m, C_alH), 2867 (m, C_alH), 1703 (vs, CO), 1415 (s), 1357 (m), 1228

(m), 1098 (m), 748 (m, Ph), 698 cm^-1(m, Ph).

CHHCHCH₂N), 5.15 (pseudo dq,

1 H, J = 1.4, 17.1 Hz,

¹H NMR (400 MHz, 373 K, C₆D₅NO₂): δ = 2.13 (ddd, 1 H, J = 2.8,

9.5, 12.1 Hz, CHHCHCH₂N), 2.30 (pseudo. dt, 1 H, J = 8.3, 12.1

Hz, CHHCHCH₂N), 2.86-2.98 (m, 2 H, CHCH₂N, CHCH₂N), 3.24

(pseudo. q, 1 H, J = 7.2 Hz, CHPh), 3.39 (dd, 1 H, J = 6.0, 11.5 Hz,

CHCHCHHN), 3.54 (dd, 1 H, J = 7.5, 11.5 Hz, CH₂CHCHHN),

3.77 (dd, 1 H, J = 2.3, 11.5 Hz, CH₂CHCHHN), 3.85 (d, 1 H,

J = 11.5 Hz, CHCHCHHN), 5.31 (s, 2 H, CH₂Ph), 7.25-7.50 (m, 10

CHHCHCH₂N), 5.82 (ddt, H, J = 5.8, 10.3, 17.1 Hz,

1

CH₂CHCH₂N), 6.18 (dt, 1 H, J = 6.2, 15.8 Hz, CHCHPh), 6.49 (br

d, 1 H, J = 15.8 Hz, CHPh), 7.20-7.41 (m, 5 H_arom).

¹³C NMR (100 MHz, 373 K, DMSO-d₆): δ = 27.8 [C(CH₃)₃], 47.9

(CH₂N), 48.4 (CH₂N), 78.5 [C(CH₃)₃], 115.8 (CH₂CHCH₂N), 125.7

(CHCHPh), 125.8 (C_arH), 127.0 (C_arH), 128.1 (C_arH), 131.1

(CH₂CHCH₂N), 134.1 (CHPh), 136.4 (C_ar), 154.3 (CO).

H_arom).

MS (EI, 70 eV): m/z (%) = 217 (38) [M + H⁺- t-Bu], 176 (13), 172

¹³C NMR (100 MHz, 373 K, C₆D₅NO₂): δ = 31.5 (CH₂CHCH₂N),

34.0 (CH₂CHCH₂N), 42.6 (CHCHCH₂N), 45.9 (CHPh), 52.3

(CH₂N), 52.5 (CH₂N), 66.1 (CH₂Ph), 125.6 (C_arH), 125.7 (C_arH),

127.2 (C_arH), 127.3 (C_arH), 128.0 (C_arH), 128.1 (C_arH), 137.5 (C_ar),

144.8 (C_ar), 154.8 (CO).

(15) [M⁺- Boc], 156 (10) [M⁺- C₉H₉], 130 (22), 126 (20), 117 (82)

[C₉H₉], 115 (75), 91 (27) [C₇H₇], 82 (19), 57 (76) [t-Bu⁺], 41 (100)

+

[C₃H₅].

Anal. C₁₇H₂₃NO₂(273.4): calcd C, 74.69; H, 8.48; N, 5.12; found

C, 74.47; H, 8.32; N, 5.36.

MS (EI, 70 eV): m/z (%) = 307 (<1) [M⁺], 216 (11) [M⁺- C₇H₇],

172 (8) [M⁺- Z], 104 (22) [C₈H₈], 91 (100) [C₇H₇].

+

N-Allyl-N-cinnamylacetamide (5c)

Anal. C₂₀H₂₁NO₂(307.4): calcd C,78.15; H, 6.89; N, 4.56; found C,

77.91; H, 7.19; N, 4.66.

Et₃N (4.2 mL, 3.05 g, 30.1 mmol) was added dropwise to a solution

of N-allyl-N-cinnamylamine¹⁰(3.48 g, 20.1 mmol) in Ac₂O (6.6

mL, 7.10 g, 70 mmol) at r.t. The reaction was complete after 15 min

as monitored by TLC. The solvent was evaporated in vacuo and the

residue purified by flash chromatography (pentane/t-

BuOMe, 60:40) to yield 5c as a colorless syrup (4.28 g, 99%);

R_f0.30 (pentane/t-BuOMe, 25:75).

exo-(1SR,5RS,6SR)-N-tert-Butyloxycarbonyl-6-phenyl-3-azabi-

cyclo[3.2.0]heptane (6b)

According to the General Procedure A, 5b (833 mg, 3.05 mmol) and

acetophenone (0.53 mL, 530 mg, 4.9 mmol) were irradiated in ace-

tone (30 mL) for 6.5 h. The exo-diastereoisomer prevailed (exo/

endo, 6:1) and could be separated from the endo-product by flash

chromatography (pentane/t-BuOMe, 95:5). The combined yields of

exo-6b (414 mg, 50%) and endo-6b (75 mg, 9%) which were both

obtained as a colorless syrup amounted to a total of 59%. Analytical

data are provided for the major exo-isomer; R_f0.44 (pentane/t-

BuOMe, 75:25).

IR (film): n = 3082 (w, C_arH), 3059 (w, C_arH), 3026 (w, C_arH), 2982

(w, C_alH), 2928 (w, C_alH), 1651 (vs, CO), 1469 (s), 1415 (s), 1244

(m), 981 (m), 970 (m), 742 (m, Ph), 694 cm^-1(m, Ph).

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 2.05 (s, 3 H, CH₃), 3.96

(d, 2 H, J = 5.3 Hz, CH₂N), 4.06 (d, 2 H, J = 6.0 Hz, CH₂N), 5.15

(br d, 1 H, J = 10.4 Hz, CHHCHCH₂N), 5.16 (br d, 1 H, J = 16.9

Hz, CHHCHCH₂N), 5.77-5.90 (m, 1 H, CH₂CHCH₂N), 6.15-6.26

(m, 1 H, CHCHPh), 6.52 (br d, 1 H, J = 15.9 Hz, CHPh), 7.20-7.43

(m, 5 H_arom).

¹³C NMR (100 MHz, 373 K, DMSO-d₆): δ = 20.7 (CH₃), 46.9 (br,

CH₂N), 49.2 (br, CH₂N), 116.0 (CH₂CHCH₂N), 125.3 (CHCHPh),

125.9 (C_arH), 127.1 (C_arH), 128.1(C_arH), 131.3 (CH₂CHCH₂N),

133.8 (CHPh), 136.4 (C_ar), 169.1 (CO).

IR (film): n = 3084 (w, C_arH), 3061 (w, C_arH), 3026 (w, C_arH), 2972

(s, C_alH), 2931 (m, C_alH), 2865 (m, C_alH), 1695 (vs, CO), 1395 (s),

1157 (m), 749 (m, Ph), 699 cm^-1(m, Ph).

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 1.46 [s, 9 H, C(CH₃)₃],

2.12 (ddd, 1 H, J = 2.7, 9.3, 11.8 Hz, CHHCHCH₂N), 2.24-2.31

(m, 1 H, CHHCHCH₂N), 2.87-2.97 (m, 2 H, CHCH₂N, CHCH₂N),

3.17-3.24 (m, 1 H, CHPh), 3.24 (dd, 1 H, J = 6.1, 11.6 Hz, CHCH-

CHHN), 3.38 (dd, 1 H, J = 7.4, 11.6 Hz, CH₂CHCHHN), 3.55 (dd,

1 H, J = 2.2, 11.6 Hz, CH₂CHCHHN), 3.59 (d, 1 H, J = 11.6 Hz,

CHCHCHHN), 7.15-7.33 (m, 5 H_arom).

¹³C NMR (100 MHz, 373 K, DMSO-d₆): δ = 28.0 [C(CH₃)₃], 31.3

(CH₂CHCH₂N), 33.3 (CH₂CHCH₂N), 42.0 (CHCHCH₂N), 45.3

(CHPh), 51.9 (CH₂N), 52.0 (CH₂N), 78.0 [C(CH₃)₃], 125.5 (C_arH),

125.8 (C_arH), 127.9 (C_arH), 144.7 (C_ar), 154.0 (CO).

MS (EI, 70 eV): m/z (%) = 215 (30) [M⁺], 174 (49) [M⁺- C₃H₅],

132 (100), 124 (48) [M⁺- C₇H₇], 117 (48) [C₉H₉], 115 (69), 91

+

(35) [C₇H₇], 56 (27), 43 (67) [Ac⁺].

HRMS: m/z calcd for C₁₄H₁₇NO: 215.1310; found 215.1304.

Triplet-Sensitized [2+2]-Photocycloadditions;General Proce-

dure A

MS (EI, 70 eV): m/z (%) = 273 (3) [M⁺], 217 (40) [M + H⁺- t-Bu],

173 (22), 172 (16) [M⁺- Boc], 112 (53) [M⁺- C₈H₈- Boc], 104

In a quartz tube, the N-protected N,N-diallylamine (1.0 mmol) and

acetophenone (1.6 mmol) were dissolved in acetone (10 mL). The

solution was irradiated at λ = 300 nm (light source: Rayonet RPR

3000) and the course of the reaction was monitored by TLC. Upon

complete conversion of the amine, the solvent was evaporated in

vacuo and the residue was purified by flash chromatography em-

ploying the eluent indicated below.

+

(78) [C₈H₈], 91 (35) [C₇H₇], 68 (69), 57 (100) [C₄H₉], 41 (69)

[C₃H₅].

+

HRMS: m/z calcd for C₁₇H₂₃NO₂: 273.1729; found 273.1724.

exo-(1SR,5RS,6SR)-N-Acetyl-6-phenyl-3-azabicyclo[3.2.0]hep-

tane (6c)

According to the General Procedure A, 5c (2.81 g, 13.1 mmol) and

acetophenone (2.28 mL, 2.26 g, 20.9 mmol) were irradiated in ace-

tone (60 mL) for 10.5 h. After purification by flash chromatography

(t-BuOMe/MeOH, 95:5), azabicycloheptane 6c was obtained as a

colorless syrup (2.02 g, 72%); R_f0.22 (t-BuOMe/MeOH, 95:5).

exo-(1SR,5RS,6SR)-N-Benzyloxycarbonyl-6-phenyl-3-azabicy-

clo[3.2.0]heptane (6a)

According to the General Procedure A, 5a (2.17 g, 7.1 mmol) and

acetophenone (1.23 mL, 1.22 g, 11.3 mmol) were irradiated in ace-

tone (70 mL) for 8.5 h. The exo-diastereoisomer prevailed (exo/en-

do, 10:1) and could be separated from the endo-product by flash

chromatography (pentane/t-BuOMe, 90:10). The combined yields

of exo-6a (1.46 g, 67%) and endo-6a (155 mg, 7%) which were both

obtained as a colorless syrup amounted to a total of 74%. Analytical

data are provided for the major exo-isomer; R_f0.30 (pentane/t-

BuOMe, 75:25).

IR (film): n = 3059 (w, C_arH), 3027 (w, C_arH), 2965 (s, C_alH), 2934

(m, C_alH), 2866 (m, C_alH), 1645 (vs, CO), 1446 (m), 1423 (m), 750

(m, Ph), 700 cm^-1(m, Ph).

¹H NMR (200 MHz): Two rotamers (ratio: 50:50), all signals ap-

peared twice: δ = 2.10-2.25 (m, 1 H), 2.14 (s, 3 H, CH₃), 2.15 (s, 3

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

313

H, CH₃), 2.29-2.45 (m, 3 H), 2.87-3.15 (m, 4 H), 3.20-3.36 (m, 3

H), 3.40-3.58 (m, 3 H), 3.59-3.67 (m, 2 H), 3.90 (dd, 1 H, J = 2.9,

12.9 Hz, CH₂CHCHHN), 4.02 (d, 1 H, J = 12.5 Hz, CHCHCHHN),

7.00-7.38 (m, 10 H_arom).

¹³C NMR (50.3 MHz): Two rotamers (ratio: 50:50), most of the sig-

nals appeared twice: δ = 22.8 (CH₃), 22.9 (CH₃), 32.0

(CH₂CHCH₂N), 32.3 (CH₂CHCH₂N), 33.0 (CH₂CHCH₂N), 34.7

(CH₂CHCH₂N), 42.6 (CHCHCH₂N), 45.3 (CHPh), 46.5 (CHPh),

51.6 (CH₂N), 52.0 (CH₂N), 53.8 (CH₂N), 54.2 (CH₂N), 126.1

(C_arH), 126.2 (C_arH), 128.3 (C_arH), 128.4 (C_arH), 144.4 (C_ar), 144.6

(C_ar), 169.7 (CO).

(SR)-N-Cinnamylmethionine Methyl Ester (8)

Methionine methyl ester¹²(5.27 g, 32.3 mmol) was dissolved in an-

hyd THF (120 mL). After addition of cinnamyl bromide (6.67 g,

32.6 mmol) and NaI (1.59 g, 10 mmol), the mixture was kept at re-

flux for 3 h. Et₃N (9.0 mL, 6.53 g, 64.5 mmol) was added and heat-

ing was continued for 1 h. The mixture was evaporated in vacuo and

the residue was partitioned between ice-water (100 mL) and t-

BuOMe (170 mL). The aqueous phase was separated and extracted

with t-BuOMe (3 î 50 mL). The combined organic layers were

washed with brine (50 mL) and dried (MgSO₄). After filtration, the

solvent was removed and the crude product purified by flash chro-

matography (pentane/t-BuOMe, 75:25), yielding 3.86 g (13.8

mmol, 43%) of a colorless oil; R_f0.29 (pentane/t-BuOMe, 75:25).

MS (EI, 70 eV): m/z (%) = 215 (56) [M⁺], 132 (29), 111 (27), 110

+

(28), 104 (100) [C₈H₈], 69 (78), 68 (79), 43 (64) [C₃H₅].

IR (film): n = 3327 (m, NH), 3025 (m, C_arH), 2998 (s, C_alH), 2949

(s, C_alH), 2916 (s, C_alH), 1733 (vs, CO), 1443 (m), 1198 (s), 1167

(s), 969 (m), 744 (m, Ph), 693 cm^-1(m, Ph).

HRMS: m/z calcd for C₁₄H₁₇NO: 215.1310; found 215.1304.

exo-(1SR,5RS,6SR)-6-Phenyl-3-azabicyclo[3.2.0]heptane (7)

Compound 6a (316 mg, 1.03 mmol) was dissolved in MeOH (25

mL) and Pd(OH)₂/C (20% w/w) (71 mg, 0.1 mmol) was added. The

mixture was stirred under an atmosphere of H₂at r.t. for 5 h. After

filtration, the solvent was evaporated in vacuo to yield the unpro-

tected azabicycloheptane 7 (155 mg, 87%) as a colorless oil; R_f0.20

(CH₂Cl₂/MeOH, 50:50, TLC plate pretreated with Et₃N).

¹H NMR (300 MHz): δ = 1.76 (br s, 1 H, NH), 1.80-2.20 (m, 2 H,

CH₂), 2.08 (s, 3 H, CH₃S), 2.60 (t, 2 H, J = 7.8 Hz, CH₂S), 3.28

(ddd, 1 H, J = 1.4, 6.3, 13.8 Hz, CHHN), 3.41 (ddd, 1 H, J = 1.4,

6.3, 13.8 Hz, CHHN), 3.44 (dd, 1 H, J = 5.6, 7.7 Hz, CHN), 3.70 (s,

3 H, OCH₃), 6.21 (dt, 1 H, J = 6.3, 15.9 Hz, CHCHPh), 6.45 (br d,

1 H, J = 15.9 Hz, CHPh), 7.19-7.39 (m, 5 H_arom).

¹³C NMR (75.5 MHz): δ = 15.3 (CH₃S), 30.4 (CH₂S), 32.8 (CH₂),

50.1 (OCH₃), 51.7 (CH₂N), 59.3 (CHN), 126.2 (C_arH), 127.3 (C_arH),

127.8 (CHCHPh), 128.4 (C_arH), 131.5 (CHPh), 136.9 (C_ar), 175.5

(CO).

IR (film): n = 3270 (m, br, NH), 3058 (m, C_arH), 3025 (m, C_arH),

2945 (s, C_alH), 2856 (m, C_alH), 1668 (m, C=C), 1601 (m, C=C),

1492 (m), 1453 (m), 747 (m, Ph), 699 cm^-1(m, Ph).

¹H NMR (300 MHz): δ = 2.03 (ddd, 1 H, J = 3.7, 9.8, 12.4 Hz,

CHHCHCH₂N), 2.24-2.34 (m, 1 H, CHHCHCH₂N), 2.71-2.91

(m, 4 H, CH₂CHCHHN, CHCHCHHN), 2.98-3.06 (m, 3 H,

CH₂CHCHHN, CHCHCHHN), 3.23 (br s, 1 H, NH), 7.15-7.36 (m,

5 H_arom).

MS (EI, 70 eV): m/z (%) = 279 (<1) [M⁺], 220 (8) [M⁺- COOCH₃],

+

162 (5), 132 (45), 117 (100) [C₉H₉], 115 (18), 91 (9) [C₇H₇], 61

(8).

Anal. C₁₅H₂₁NO₂S (279.4): calcd C, 64.48; H, 7.58; N, 5.01; found

C, 64.44; H, 7.60; N, 5.11.

¹³C NMR (75.5 MHz): δ = 31.5 (CH₂CHCH₂N), 34.8

(CH₂CHCH₂N), 41.8 (CHCHCH₂N), 46.8 (CHPh), 53.6 (2 î

CH₂N), 125.7 (C_arH), 126.3 (C_arH), 128.2 (C_arH), 146.4 (C_ar).

(SR)-N-Benzyloxycarbonyl-N-cinnamylmethionine Methyl Es-

ter (9)

MS (EI, 70 eV): m/z (%) = 173 (42) [M⁺], 129 (18), 104 (34)

Benzyl chloroformate (1.6 mL, 1.88 g, 11 mmol) was added drop-

wise over a period of 30 min to an ice-cold solution of 8 (2.80 g, 10

mmol) and KHCO₃(5.0 g) in a mixture of H₂O and EtOAc (100 mL,

1:1, v/v). After the mixture was stirred for 4 h, the organic layer was

separated, washed with dil HCl (40 mL), H₂O (40 mL) and brine (40

mL), and subsequently dried (MgSO₄). After filtration, the solvent

was evaporated in vacuo and the residue purified by flash chroma-

tography (pentane/t-BuOMe, 90:10 → 75:25). The protected amine

9 was obtained as a colorless syrup (4.14 g, quant); R_f0.34 (pentane/

t-BuOMe, 60:40).

+

[C₈H₈], 91 (21) [C₇H₇], 82 (22), 69 (68), 68 (100) [C₄H₆N⁺], 43

+

(49), 41 (42) [C₃H₅].

HRMS: m/z calcd for C₁₂H₁₅N 173.1204; found 173.1208.

Deprotection of exo-N-tert-Butyloxycarbonyl-6-phenyl-3-azabi-

cyclo[3.2.0]heptane (6b)

Compound 6b (280 mg, 1.03 mmol) was dissolved in CH₂Cl₂(10

mL) and CF₃CO₂H (0.31 mL, 470 mg, 4.1 mmol) was added drop-

wise at r.t. After stirring for 4 h, the solution was concentrated in

vacuo. The excess of CF₃CO₂H was removed by azeotropic distilla-

tion with toluene (2 î 1 mL). The residue was dissolved in aq sat.

NaHCO₃(10 mL) and the aqueous layer was extracted with CH₂Cl₂

(4 î 5 mL). The combined organic layers were washed with brine

(5 mL) and dried (MgSO₄). After filtration, the solvent was evapo-

rated in vacuo to afford 7 as a light yellow oil (166 mg, 93%). The

spectroscopic data were in full agreement with the data given above.

IR (film): n = 3060 (w, C_arH), 3029 (w, C_arH), 2950 (m, C_alH), 2917

(m, C_alH), 1742 (vs, CO), 1702 (vs, CO), 1452 (s), 1224 (s), 969

(m), 745 (m, Ph), 696 cm^-1(m, Ph).

¹H NMR (300 MHz): Two rotamers (ratio: 55:45); major rotamer:

δ = 2.04 (s, 3 H, CH₃S), 2.06-2.26 (m, 2 H, CH₂), 2.45-2.61 (m, 2

H, CH₂S), 3.63 (s, 3 H, OCH₃), 4.18 (dd, 1 H, J = 6.2, 15.6 Hz,

CHHN), 4.47 (dd, 1 H, J = 6.2, 15.6 Hz, CHHN), 4.62 (dd, 1 H,

J = 5.3, 9.1 Hz, CHN), 5.08-5.25 (m, 2 H, CH₂Ph), 6.34-6.12 (m,

1 H, CHCHPh), 6.46 (d, 1 H, J = 16.0 Hz, CHPh), 7.20-7.40 (m, 10

H_arom); minor rotamer: δ = 1.99 (s, 3 H, CH₃S), 2.26-2.41 (m, 2 H,

CH₂), 2.45-2.61 (m, 2 H, CH₂S), 3.52 (s, 3 H, OCH₃), 3.96 (dd, 1

H, J = 6.2, 15.6 Hz, CHHN), 4.02 (dd, 1 H, J = 6.2, 15.6 Hz,

CHHN), 4.41 (dd, 1 H, J = 5.3, 8.5 Hz, CHN), 5.08-5.25 (m, 2 H,

CH₂Ph), 6.34-6.12 (m, 1 H, CHCHPh), 6.54 (d, 1 H, J = 16.0 Hz,

CHPh), 7.20-7.40 (m, 10 H_arom).

¹³C NMR (75.5 MHz): Two rotamers (ratio: 55:45); major rotamer:

δ = 15.2 (CH₃S), 28.8 (CH₂), 30.8 (CH₂S), 49.1 (OCH₃), 52.2

(CH₂N), 58.3 (CHN), 67.5 (CH₂Ph), 125.3 (CHCHPh), 126.4

(C_arH), 127.7 (C_arH), 128.0 (C_arH), 128.4 (C_arH), 128.5 (C_arH),

132.7 (CHPh), 136.5 (C_ar), 156.0 (CO), 171.6 (CO); minor rotamer:

Deprotection of exo-N-Acetyl-6-phenyl-3-azabicyclo[3.2.0]hep-

tane (6c)

Compound 6c (224 mg, 1.04 mmol) was dissolved in dil HCl (5 mL)

and kept under reflux for 9.5 h. Upon cooling, the mixture was made

alkaline with aq 50% NaOH and subsequently extracted with

CH₂Cl₂(4 î 10 mL). The combined organic layers were washed

with brine (10 mL) and dried (MgSO₄). After filtration the solvent

was evaporated in vacuo to give 7 as a yellowish oil (155 mg, 86%).

The spectroscopic data were in full agreement with the data given

above.

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

314

T. Bach et al.

FEATURE ARTICLE

δ = 15.2 (CH₃S), 29.3 (CH₂), 30.8 (CH₂S), 50.2 (OCH₃), 52.2

(CH₂N), 57.6 (CHN), 67.5 (CH₂Ph), 125.0 (CHCHPh), 126.4

(C_arH), 127.7 (C_arH), 128.0 (C_arH), 128.4 (C_arH), 128.5 (C_arH),

133.2 (CHPh), 136.5 (C_ar), 156.0 (CO), 171.6 (CO).

129.1 (C_arH), 129.4 (C_arH), 132.7 (CHCHN), 133.0 (CHPh), 137.5

(C_ar), 137.6 (C_ar), 156.0 (CO), 170.8 (CO).

MS (EI, 70 eV): m/z (%) = 266 (1.5) [M⁺- C₅H₇O₂], 230 (42) [M⁺

+

- Z], 117 (60) [C₉H₉], 115 (16), 91 (100) [C₇H₇].

+

MS (EI, 70 eV): m/z (%) = 278 (23) [M⁺- Z], 117 (54) [C₉H₉], 115

Anal. C₂₂H₂₃NO₄(365.4): calcd C, 72.31; H, 6.34; N, 3.83; found

C, 72.02; H, 6.62; N, 4.02.

(13), 91 (100) [C₇H₇], 61 (20) [C₂H₅S⁺].

+

Anal. C₂₃H₂₇NO₄S (413.5): calcd C, 66.80; H, 6.58; N, 3.39; found

C, 66.54; H, 6.61; N, 3.68.

N-Benzyloxycarbonyl-2-methoxycarbonyl-6-phenyl-3-azabicy-

clo[3.2.0]heptane (12)

According to the General Procedure A, compound 11 (227 mg, 0.62

mmol) and acetophenone (120 mL, 120 mg, 1.0 mmol) were irradi-

ated in acetone (10 mL) for 2.5 h. Flash chromatography (pentane/

t-BuOMe, 90:10) yielded azabicycloheptane 12a (121 mg, 53%)

and its diastereoisomer 12b (61 mg, 27%) as colorless oils.

Methyl 2-(N-Benzyloxycarbonyl-N-cinnamylamino)-4-

(methyloxosulfanyl)butanoate (10)

A solution of NaIO₄(1.69 g, 7.9 mmol) in H₂O (9 mL) was added

dropwise to a vigorously stirred ice-cold solution of sulfide 9 (3.15

g, 7.6 mmol) in MeOH (23 mL). The mixture was stirred for 3 h un-

der cooling with ice, then the precipitated iodate was filtered off and

washed with MeOH (10 mL). The filtrate was concentrated to 8 mL

and extracted with CHCl₃(5 î 10 mL). The combined organic lay-

ers were washed with brine (15 mL), dried (MgSO₄), and after fil-

tration the solvent was removed in vacuo. The sulfoxide 10 was

obtained as a yellow syrup (3.30 g, quant.) and used in the next step

without further purification.

(1SR,2SR,5RS,6SR)-Diastereoisomer 12a

R_f0.48 (pentane/t-BuOMe, 40:60)

IR (film): n = 3061 (w, C_arH), 3029 (w, C_arH), 2953 (m, C_alH), 1745

(vs, CO), 1706 (vs, CO), 1349 (s), 1261 (s), 1203 (s), 750 (m, Ph),

699 cm^-1(m, Ph).

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 2.27-2.44 (m, 2 H,

CH₂CHCHN), 2.98-3.06 (m, 1 H, CHCHN), 3.24-3.32 (m, 1 H,

CHCH₂N), 3.47-3.57 (m, 2 H, CHCHCHHN), 3.62 (s, 3 H, OCH₃),

3.79 (d, 1 H, J = 11.2 Hz, CHHN), 4.51 (s, 1 H, CHN), 5.12-5.20

(m, 2 H, CH₂Ph), 7.15-7.42 (m, 10 H_arom).

IR (film): n = 3060 (w, C_arH), 3029 (w, C_arH), 3001 (w, C_arH), 2951

(m, C_alH), 1741 (vs, CO), 1700 (vs, CO), 1450 (s), 1416 (s), 1230

(s), 1028 (m, SO), 748 (m, Ph), 697 cm^-1(m, Ph).

¹H NMR (400 MHz, 373 K, DMSO-d₆): Two diastereoisomers (ra-

tio: 50:50), some signals appeared twice: δ = 2.18-2.30 (m, 1 H,

CHH), 2.33-2.43 (m, 1 H, CHH), 2.46 (2.47) (s, 3 H, CH₃S), 2.62-

2.75 (m, 1 H, CHHS), 2.75-2.88 (m, 1 H, CHHS), 3.60 (3.61) (s, 3

H, OCH₃), 4.03-4.19 (m, 2 H, CH₂N), 4.52 (dd, 1 H, J = 5.7, 8.8

Hz, CHN), 5.15 (s, 2 H, CH₂Ph), 6.25 (dt, 1 H, J = 6.4, 15.9 Hz,

CHCHPh), 6.49 (d, 1 H, J = 15.9 Hz, CHPh), 7.21-7.40 (m, 10

¹³C NMR (50.3 MHz): Two rotamers (ratio: 52:48); major rotamer:

δ = 32.1 (CH₂CHCH₂N), 40.2 (CHCHN), 42.5 (CHPh), 45.2

(CHCH₂N), 52.1 (OCH₃), 53.4 (CH₂N), 65.7 (CHN), 67.0 (CH₂Ph),

126.2 (C_arH),126.3 (C_arH), 127.7 (C_arH), 127.9 (C_arH), 128.4 (C_arH),

136.4 (C_ar), 144.4 (C_ar), 155.1 (CO), 172.4 (CO); minor rotamer:

δ = 32.0 (CH₂CHCH₂N), 39.2 (CHCHN), 42.5 (CHPh), 46.0

(CHCH₂N), 52.0 (OCH₃), 53.0 (CH₂N), 65.9 (CHN), 67.1 (CH₂Ph),

126.2 (C_arH), 126.3 (C_arH), 127.7 (C_arH), 127.9 (C_arH), 128.4

(C_arH), 136.4 (C_ar), 144.4 (C_ar), 155.7 (CO), 172.3 (CO).

H_arom).

¹³C NMR (75.5 MHz): Two diastereoisomers (ratio: 50:50), some

signals appeared twice: δ = 22.3 (22.6) (CH₃S), 37.9 (38.1) (CH₂),

48.7 (48.8) (CH₂S), 49.9 (50.2) (OCH₃), 51.5 (CH₂N), 58.4 (58.6)

(CHN), 66.5 (CH₂Ph), 125.4 (CHCHPh), 125.9 (C_arH), 127.1

(C_arH), 127.2 (C_arH), 127.4 (C_arH), 127.9 (C_arH), 128.1 (C_arH),

132.0 (CHPh), 136.3 (C_ar), 155.0 (CO), 170.3 (CO).

MS (EI, 70 eV): m/z (%) = 365 (<1) [M⁺], 306 (10) [M⁺- CO₂CH₃],

+

230 (11) [M⁺- Z], 91 (100) [C₇H₇], 117 (7), 104 (8).

HRMS: m/z calcd for C₂₂H₂₃NO₄: 365.1627; found 365.1629.

(1SR,2RS,5RS,6SR)-Diastereoisomer 12b

R_f0.42 (pentane/t-BuOMe, 40:60).

MS (EI, 70 eV): m/z (%) = 429 (<1) [M⁺], 412 (6), 294 (25) [M⁺-

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 2.03 (dddd, J = 0.9,

2.4, 8.8, 12.4 Hz, 1 H, CHHCHCHN), 2.22 (pseudo ddt, J = 0.7,

8.7, 12.4 Hz, 1 H, CHHCHCHN), 3.06-3.12 (m, 1 H, CHCHN),

3.27-3.39 (m, 2 H, CHCHCH₂N), 3.61-3.68 (m, 2 H, CH₂N), 3.68

(s, 3 H, OCH₃), 4.54 (d, 1 H, J = 9.7 Hz, CHN), 5.01-5.15 (m, 2 H,

CH₂Ph), 7.16-7.39 (m, 10 H_arom).

+

Z], 117 (44) [C₉H₉], 115 (17), 91 (100) [C₇H₇].

(SR)-N-Benzyloxycarbonyl-N-cinnamylvinylglycine Methyl Es-

ter (11)

The sulfoxide 10 (975 mg, 2.27 mmol) was distilled in a Kugelrohr

apparatus at 145 °C/0.006 mbar for 6 h. The yellow distillation

product was purified by flash chromatography (pentane/t-

BuOMe, 90:10) to afford 11 as a light yellow oil (429 mg, 52%)

which was contaminated with 15% of its a,b-unsaturated isomer;

R_f0.57 (pentane/t-BuOMe, 60:40).

(1SR,2SR,5RS,6SR)-N-Benzyloxycarbonyl-2-(1-hydroxy-1-me-

thylethyl)-6-phenyl-3-azabicyclo[3.2.0]heptane (13)

A solution of 12a (183 mg, 0.5 mmol) in anhyd Et₂O (2 mL) was

added dropwise to an ethereal solution of MeMgI (0.95 mL, 2.6 M

in Et₂O, 2.5 mmol). After complete addition, the mixture was kept

at reflux for 45 min. The cooled mixture was hydrolyzed carefully

with ice (5 g) and aq NH₄Cl (5 mL). The aqueous layer was extract-

ed with Et₂O (3 î 10 mL). The combined organic layers were

washed with brine (5 mL) and dried (MgSO₄). After filtration the

solvent was evaporated in vacuo and the crude product was purified

by flash chromatography (pentane/t-BuOMe, 75:25). The tertiary

alcohol 13 was obtained as a colorless oil (81 mg, 44%). Its spectro-

scopic data were in full agreement with the data given below.

IR (film): n = 3061 (w, C_arH), 3030 (w, C_arH), 2849 (w, C_alH), 1745

(sh, CO), 1709 (vs, CO), 1450 (m), 1408 (m), 1269 (s), 746 (m, Ph),

669 cm^-1(m, Ph).

¹H NMR (400 MHz, 373 K, DMSO-d₆): δ = 3.60 (s, 3 H, OCH₃),

4.06 (ddd, 1 H, J = 1.4, 6.1, 16.1 Hz, CHHN), 4.14 (ddd, 1 H,

J = 1.4, 6.1, 16.1 Hz, CHHN), 4.90 (br d, 1 H, J = 6.7 Hz, CHN),

5.12 (s, 2 H, CH₂Ph), 5.27 (pseudo dt, 1 H, J = 1.3, 17.2 Hz, CHH-

CHCHN), 5.29 (pseudo dt, 1 H, J = 1.3, 10.5 Hz, CHHCHCHN),

6.10 (ddd, 1 H, J = 6.7, 10.5, 17.2 Hz, CHCHN), 6.20 (dt, 1 H,

J = 6.1, 16.0 Hz, CHCHPh), 6.54 (br d, 1 H, J = 16.0 Hz, CHPh),

7.27-7.38 (m, 10 H_arom).

(SR)-3-N-Benzyloxycarbonylamino-2-methylpent-4-en-2-ol

(15b)

¹³C NMR (100 MHz, 373 K, DMSO-d₆): δ = 49.7 (OCH₃), 52.7

(CH₂N), 62.8 (CHN), 67.7 (CH₂Ph), 119.9 (CH₂CHCHN), 126.9

(CHCHPh), 127.0 (C_arH), 128.3 (C_arH), 128.4 (C_arH), 128.6 (C_arH),

A solution of the N-Z-protected vinylglycine methyl ester^13,1514

(1.90 g, 7.5 mmol) in anhyd Et₂O (7 mL) was added dropwise to an

ethereal solution of MeMgI (12.5 mL, 3.0 M in Et₂O, 37.5 mmol).

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

(S)-(-)-N-Cinnamyl-4-vinyloxazolidin-2-one [(-)-16a]

315

After complete addition, the mixture was kept at reflux for 1.5 h.

The cooled mixture was hydrolyzed carefully with ice (50 g) and aq

NH₄Cl (50 mL). The aqueous layer was extracted with Et₂O (3 î

100 mL). The combined organic layers were washed with brine (50

mL) and dried (MgSO₄). After filtration, the solvent was evaporated

in vacuo and the crude product was purified by flash chromatogra-

phy (pentane/t-BuOMe, 60:40). The tertiary alcohol 15b was ob-

tained as a colorless oil (1.48 g, 79%); R_f0.33 (pentane/t-

BuOMe, 40:60).

Synthesized as described for (±)-16a starting from (S)-N-benzylox-

ycarbonylvinylglycinol; [α]_D-30.2 (c = 3.12, CHCl₃) {Lit.²⁴

[α]_D-32.1 (c = 3.1, CHCl₃)}. The specific optical rotation of the

product (-)-16a was [α]_D-59.6 (c = 1.05, CHCl₃).

(SR)-N-Cinnamyl-5,5-dimethyl-4-vinyloxazolidin-2-one (16b)

The reaction was carried out as described in the General Procedure

B starting from the tertiary alcohol 15b (1.35 g, 5.4 mmol) and cin-

namyl bromide (5.33 g, 27.0 mmol). The oxazolidinone 16b was

obtained after flash chromatography (pentane/t-BuOMe, 75:25) as

a light yellow oil (1.33 g, 96%); R_f0.48 (pentane/t-BuOMe, 40:60).

IR (film): n = 3429 (m, br, NH), 3338 (m, br, NH), 3067 (w, C_arH),

3034 (w, C_arH), 2978 (s, C_alH), 2935 (m, C_alH), 1701 (vs, CO), 1529

(s), 1319 (m), 1240 (s), 1039 (m), 738 (m, Ph), 698 cm^-1(m, Ph).

¹H NMR (200 MHz): δ = 1.18 (s, 3 H, CH₃), 1.23 (s, 3 H, CH₃), 2.43

(br s, 1 H, OH), 4.05 (br pseudo t, 1 H, J = 8.1 Hz, CHN), 5.01 (s, 2

H, CH₂Ph), 5.21 (d, 1 H, J = 10.3 Hz, CHHCH), 5.24 (d, 1 H,

J = 17.3 Hz, CHHCH), 5.47 (br d, 1 H, J = 8.5 Hz, NH), 5.87 (ddd,

1 H, J = 6.8, 10.3, 17.3 Hz, CH₂CH), 7.33 (s, 5 H_arom).

IR (film): n = 3059 (w, C_arH), 3026 (w, C_arH), 2980 (m, C_alH), 2931

(m, C_alH), 1751 (vs, CO), 1429 (m), 1404 (m), 1290 (m, C-O), 1085

(m, C-O), 968 (m), 950 (m), 750 (m, Ph), 690 cm^-1(m, Ph).

¹H NMR (300 MHz): δ = 1.28 (s, 3 H, CH₃), 1.42 (s, 3 H, CH₃), 3.62

(ddd, 1 H, J = 0.7, 8.1, 15.3 Hz, CHHN), 3.83 (d, 1 H, J = 9.0 Hz,

CHN), 4.26 (ddd, 1 H, J = 1.5, 5.1, 15.3 Hz, CHHN), 5.34 (dd, 1 H,

J = 1.0, 16.9 Hz, CHHCHCHN), 5.40 (dd, 1 H, J = 1.0, 10.1 Hz,

CHHCHCHN), 5.70 (ddd, 1 H, J = 9.0, 10.1, 16.9 Hz, CHCHN),

6.11 (ddd, 1 H, J = 5.1, 8.1, 15.8 Hz, CHCHPh), 6.49 (br d, 1 H,

J = 15.8 Hz, CHPh), 7.21-7.38 (m, 5 H_arom).

¹³C NMR (50.3 MHz): δ = 22.7 (CH₃), 27.1 (CH₃), 44.1 (CH₂N),

67.8 (CHN), 80.4 [C(CH₃)₂], 121.6 (CH₂CH), 122.9 (CHCHPh),

126.2 (C_arH), 127.8 (C_arH), 128.4 (C_arH), 132.4 (CH₂CH), 133.7

(CHPh), 136.0 (C_ar), 156.8 (CO).

¹³C NMR (50.3 MHz): δ = 26.6 (CH₃), 26.9 (CH₃), 61.9 (CHN),

66.8 (CH₂Ph), 72.1 (COH), 117.5 (CH₂CH), 127.9 (C_arH), 128.0

(C_arH), 128.4 (C_arH), 134.6 (C_ar), 136.2 (CH₂CH), 156.3 (CO).

MS (EI, 70 eV): m/z (%) = 191 (3) [M⁺-C₃H₆O], 100 (98), 95 (20),

91 (100) [C₇H₇], 59 (38) [C₃H₇O⁺], 56 (34).

+

Anal. C₁₄H₁₉NO₃(249.3): calcd C, 67.45; H, 7.62; N, 5.62; found

C, 67.23; H, 7.73; N, 5.68.

MS (EI, 70 eV): m/z (%) = 257 (10) [M⁺], 176 (37), 134 (15), 117

(52) [C₉H₉], 115 (48), 91 (30) [C₇H₇], 82 (100), 67 (43).

Preparation of N-Substituted 4-Vinyloxazolidin-2-ones; Gener-

al Procedure B

+

NaH (180 mg, 6 mmol, 80% suspension in paraffin) was washed

with pentane (3 î 5 mL) and suspended in anhyd dimethoxyethane

(30 mL). A solution of 15 (3 mmol) in anhyd DME (9 mL) was add-

ed to this suspension. After stirring for 24 h at r.t., the substituted

allyl bromide was added and stirring was continued for 24 h. The

solvent was removed in vacuo, the residue dissolved in H₂O (10

mL) and extracted with t-BuOMe (3 î 10 mL). The combined or-

ganic layers were washed with brine (15 mL) and subsequently

dried (MgSO₄). After filtration, the solvent was evaporated in vacuo

and the residue purified by flash chromatography.

Anal. C₁₆H₁₉NO₂(257.3): calcd C, 74.68; H, 7.44; N, 5.44; found

C, 74.42; H, 7.47; N, 5.57.

(5SR,6SR,8SR,9RS)-1-Aza-3-oxa-8-phenyltricyclo[5.3.0.0^6,9]de-

can-2-one (17a)

According to the General Procedure A, compound 16a (230 mg, 1

mmol) and acetophenone (190 mL, 192 mg, 1.6 mmol) were irradi-

ated in acetone (10 mL) for 20 h. Flash chromatography (pentane/t-

BuOMe, 75:25) yielded the azabicycloheptane 17a as a colorless

solid (173 mg, 0.75 mmol, 75%); mp 124°C; R_f0.19 (pentane/t-

BuOMe, 40:60).

(SR)-N-Cinnamyl-4-vinyloxazolidin-2-one (16a)

IR (KBr): n = 3081 (w, C_arH), 3024 (w, C_arH), 2968 (m, C_alH), 2938

(m, C_alH), 1745 (vs, CO), 1405 (s, CH₂), 1246 (m), 1224 (m), 1070

(m, C-O), 754 (m, Ph), 698 cm^-1(m, Ph).

¹H NMR (200 MHz): δ = 2.25 (ddd, 1 H, J = 2.4, 8.4, 12.0 Hz,

CHHCHPh), 2.38 (ddd, 1 H, J = 7.4, 8.8, 12.0 Hz, CHHCHPh),

2.59 (pseudo qd, 1 H, J = 2.0, 8.0 Hz, CHCHN), 3.14-3.30 (m, 2 H,

CHCHHN), 3.41 (pseudo q, 1 H, J = 8.2 Hz, CHPh), 4.00 (dd, 1 H,

J = 8.8, 12.8 Hz, CHHN), 4.15-4.27 (m, 2 H, CHHO, CHN), 4.63

(dd, 1 H, J = 8.7, 9.7 Hz, CHHO), 7.14-7.40 (m, 5 H_arom).

The reaction was carried out as described in the General Procedure

B starting from 15a¹⁶(1.11 g, 5.0 mmol) and cinnamyl bromide

(4.93 g, 25.0 mmol). The oxazolidinone 16a was obtained after

flash chromatography (pentane/t-BuOMe, 75:25 → 60:40) as a yel-

low oil (1.05 g, 92%); R_f0.34 (pentane/t-BuOMe, 40:60).

IR (film): n = 3084 (w, C_arH), 3059 (w, C_arH), 3024 (w, C_arH), 2986

(w, C_alH), 2910 (w, C_alH), 1755 (vs, CO), 1433 (m), 1410 (m), 1244

(m, C-O), 1224 (m, C-O), 1060 (m), 968 (m), 750 (m, Ph), 736 (m,

Ph), 694 cm^-1(m, Ph).

NOESY experiment (500 MHz): H (2.59)-H (3.14-3.30)’; H

(4.15-4.27)-H (2.25)’’; H (2.25)-H (3.41)’; H (3.41)-H (4.15-

4.27)’’.

¹³C NMR (50.3 MHz): δ = 29.5 (CH₂CHPh), 41.3 (CHCHN), 44.6

(CHPh), 48.8 (CHCH₂N), 53.0 (CH₂N), 66.0 (CHN), 68.1 (CH₂O),

126.1 (C_arH), 126.4 (C_arH), 128.4 (C_arH), 143.4 (C_ar), 160.8 (CO).

¹H NMR (300 MHz): δ = 3.68 (ddd, 1 H, J = 0.9, 8.1, 15.3 Hz,

CHHN), 3.97 (dd, 1 H, J = 7.0, 8.5 Hz, CHHO), 4.23-4.31 (m, 2 H,

CHHN, CHN), 4.44 (pseudo t, 1 H, J = 8.6 Hz, CHHO), 5.34 (dd, 1

H, J = 0.9, 16.9 Hz, CHHCHCHN), 5.38 (dd, 1 H, J = 0.9, 10.3 Hz,

CHHCHCHN), 5.72 (ddd, 1 H, J = 8.8, 10.3, 16.9 Hz, CHCHN),

6.11 (ddd, 1 H, J = 5.2, 8.1, 15.8 Hz, CHCHPh), 6.50 (d, 1 H,

J = 15.8 Hz, CHPh), 7.22-7.39 (m, 5 H_arom).

¹³C NMR (50.3 MHz): δ = 43.8 (CH₂N), 58.3 (CHN), 66.9 (CH₂O),

121.1 (CH₂CH), 122.7 (CHCHPh), 126.2 (C_arH), 127.7 (C_arH),

128.4 (C_arH), 133.8 (CH₂CH), 134.4 (CHPh), 135.9 (C_ar), 157.5

(CO).

MS (EI, 70 eV): m/z (%) = 229 (9) [M⁺], 184 (1), 174 (6), 130 (32),

+

115 (6), 104 (100) [C₈H₈], 91 (8) [C₇H₇], 55 (6) [C₄H₇].

Anal. C₁₄H₁₅NO₂(229.3): calcd C, 73.34; H, 6.59; N, 6.11; found

C, 73.05; H, 6.54; N, 6.01.

(5S,6S,8S,9R)-(+)-1-Aza-3-oxa-8-phenyltricyclo[5.3.0.0^6,9]de-

can-2-one [(+)-17a]

Synthesized as described for (±)-17a starting from (-)-16a;

[α]_D+44.6 (c = 1.03, CHCl₃). Enantiomeric excess: >95% ee. (The

enantiomeric excess was determined by chiral HPLC employing a

MS (EI, 70 eV): m/z (%) = 229 (52) [M⁺], 184 (55), 174 (100), 156

+

(48), 138 (65), 131 (96), 117 (52) [C₉H₉], 103 (84) [C₇H₇], 91

(93), 77 (70), 65 (36), 54 (94), 39 (43).

Anal. C₁₄H₁₅NO₂(229.3): calcd C, 73.34; H, 6.59; N, 6.11; found

C, 72.99; H, 6.54; N, 5.86.

Synthesis 2000, No. 2, 305–320 ISSN 0039-7881 © Thieme Stuttgart · New York

316

T. Bach et al.

FEATURE ARTICLE

Daicel Chiracel OD column. Eluent: hexane/i-PrOH (80:20); flow

rate: 0.5 mL/min).

(10 mL), H₂O (10 mL) and brine (10 mL), and subsequently dried

(MgSO₄). After filtration, the solvent was evaporated in vacuo and

the residue purified by flash chromatography (pentane/t-

BuOMe, 75:25) to give 825 mg (94%) of 13 as a colorless oil. The

spectroscopic data are in full agreement with the data given below

for 13.

(5SR,6SR,8SR,9RS)-1-Aza-4,4-dimethyl-3-oxa-8-phenyltricyc-

lo[5.3.0.0^6,9]decan-2-one (17b)

According to the General Procedure A, 16b (269 mg, 1.05 mmol)

and acetophenone (190 mL, 192 mg, 1.6 mmol) were irradiated in

acetone (10 mL) for 24 h. Flash chromatography (pentane/t-

BuOMe, 80:20) yielded the azabicycloheptane 17b as a colorless

solid (191 mg, 74%); mp 110 °C; R_f0.40 (pentane/t-

BuOMe, 40:60).

(SR)-N-Allyl-5,5-dimethyl-4-vinyloxazolidin-2-one (19b)

The reaction was carried out as described in General Procedure B

starting from tertiary alcohol 15b (2.49 g, 10 mmol) and allyl bro-

mide (4.3 mL, 6.05 g, 50 mmol). The oxazolidinone 19b was ob-

tained after flash chromatography (pentane/t-BuOMe, 75:25) as a

colorless liquid (1.19 g, 65%); R_f0.47 (pentane/t-BuOMe, 40:60).

IR (KBr): n = 3056 (w, C_arH), 3024 (w, C_arH), 2980 (w, C_alH), 2934

(w, C_alH), 1737 (vs, CO), 1399 (m, CH₃), 1363 (m, CH₃), 1283 (m,

C-O), 1060 (m, C-O), 747 (m, Ph), 706 cm^-1(m, Ph).

¹H NMR (200 MHz): δ = 1.39 (s, 3 H, CH₃), 1.60 (s, 3 H, CH₃), 2.16

(ddd, 1 H, J = 1.8, 8.7, 11.5 Hz, CHHCHPh), 2.36 (ddd, 1 H,

J = 7.6, 8.9, 11.5 Hz, CHHCHPh), 2.59 (pseudo qd, 1 H, J = 1.8, 7.7

Hz, CHCHN), 3.10-3.28 (m, 2 H, CHCHHN), 3.43 (pseudo q, 1 H,

J = 8.3 Hz, CHPh), 3.85 (d, 1 H, J = 7.1 Hz, CHN), 3.98 (dd, 1 H,

J = 8.8, 12.8 Hz, CHHN), 7.15-7.39 (m, 5 H_arom).

¹³C NMR (50.3 MHz): δ = 23.2 (CH₃), 29.3 (CH₃), 29.5

(CH₂CHPh), 35.5 (CHCHN), 44.8 (CHPh), 48.6 (CHCH₂N), 52.4

(CH₂N), 75.5 (CHN), 79.8 [C(CH₃)₂], 126.1 (C_arH), 126.3 (C_arH),

128.4 (C_arH), 143.4 (C_ar), 159.8 (CO).

IR (film): n = 3084 (m, C_arH), 2982 (s, C_alH), 2933 (s, C_alH), 1751

(vs, CO), 1402 (s, CH₃), 1074 (s, C-O), 945 (s), 765 (m), 727 cm^-1

(m).

¹H NMR (300 MHz): δ = 1.29 (s, 3 H, CH₃), 1.44 (s, 3 H, CH₃), 3.45

(dd, 1 H, J = 7.6, 15.4 Hz, CHHN), 3.80 (d, 1 H, J = 8.9 Hz, CHN),

4.11 (ddt, 1 H, J = 1.1, 4.7, 15.4 Hz, CHHN), 5.17 (dd, 1 H, J = 1.1,

16.8 Hz, CHHCHCH₂N), 5.20 (dd, 1 H, J = 1.1, 10.2 Hz,

CHHCHCH₂N), 5.32 (d, 1 H, J = 17.2 Hz, CHHCHCHN), 5.38 (dd,

1 H, J = 1.1, 10.0 Hz, CHHCHCHN), 5.68 (ddd, 1 H, J = 8.9, 10.0,

17.2 Hz, CHCHN), 5.74 (dddd, 1 H, J = 4.7, 7.6, 10.2, 16.8 Hz,

CHCH₂N).

¹³C NMR (75.5 MHz): δ = 22.8 (CH₃), 27.3 (CH₃), 44.6 (CH₂N),

68.0 (CHN), 80.4 [C(CH₃)₂], 118.4 (CH₂CHCH₂N), 121.7

(CH₂CHCHN), 131.5 (CHCHN), 132.4 (CHCH₂N), 156.9 (CO).

MS (EI, 70 eV): m/z (%) = 181 (26) [M⁺], 123 (68), 95 (80), 94 (85),

82 (100), 67 (43), 54 (53), 41 (85).

+

MS (EI, 70 eV): m/z (%) = 257 (7) [M⁺], 176 (20), 117 (16) [C₉H₉],

+

115 (48), 104 (100) [C₈H₈], 91 (14) [C₇H₇], 82 (61), 67 (39), 43

(13), 41 (14).

Anal. C₁₆H₁₉NO₂(257.3): calcd C, 74.68; H, 7.44; N, 5.44; found

C, 74.42; H, 7.38; N, 5.40.

Anal. C₁₀H₁₅NO₂(181.2): calcd C, 66.27; H, 8.34; N, 7.73; found

C, 66.38; H, 8.22; N, 7.40.

(1SR,2SR,5RS,6SR)-2-(1-Hydroxy-1-methylethyl)-6-phenyl-3-

azabicyclo[3.2.0]heptane (18)

(SR)-N-Crotyl-4-vinyloxazolidin-2-one (20a)

A solution of 17b (257 mg, 1 mmol) and KOH (1.12 g, 20 mmol) in

a mixture of EtOH and H₂O (10 mL, 7:3, v/v) was kept at reflux. Af-

ter 1.5 h, TLC control showed complete conversion of the starting

material. EtOH was evaporated in vacuo and the aqueous residue

was acidified with dil HCl. After washing with Et₂O (5 mL) the

aqueous layer was made alkaline with aq 50% NaOH solution and

then extracted with CH₂Cl₂(5 î 10 mL). The combined CH₂Cl₂lay-

ers were washed with brine (10 mL) and dried (MgSO₄). After fil-

tration, the solvent was removed in vacuo yielding the crude amino

alcohol 18 as a colorless solid (227 mg, 98%); mp 68 °C.

The reaction was carried out as described in the General Procedure

B starting from vinylglycinol 15a¹⁶(663 mg, 3 mmol) and (E)/(Z)-

crotyl bromide (2.03 g, 15 mmol). The oxazolidinone 20a was ob-

tained after flash chromatography (pentane/t-BuOMe, 75:25) as a

colorless oil (400 mg, 80%); R_f0.41 (pentane/t-BuOMe, 40:60).

IR (film): n = 3086 (m), 3009 (m), 2968 (m, C_alH), 2918 (m, C_alH),

1751 (vs, CO), 1410 (s, CH₃), 1224 (s, C-O), 1058 (s, C-O), 968 (s),

763 cm^-1(s).

¹H NMR (300 MHz): Two isomers (ratio: 70:30); (E)-isomer:

δ = 1.69 (d, 3 H, J = 6.3 Hz, CH₃), 3.45 (dd, 1 H, J = 8.1, 15.1 Hz,

CHHN), 3.95 (dd, 1 H, J = 7.0, 8.5 Hz, CHHO), 4.04 (ddd, 1 H,

J = 1.5, 5.1, 15.1 Hz, CHHN), 4.24 (pseudo br q, 1 H, J = 8.2 Hz,

CHN), 4.42 (pseudo t, 1 H, J = 8.5 Hz, CHHO), 5.33 (d, 1 H,

J = 16.8 Hz, CHHCHCHN), 5.35 (d, 1 H, J = 10.2 Hz, CHH-

CHCHN), 5.36-5.44 (m, 1 H, CHCH₃), 5.56-5.70 (m, 1 H,

CHCHCH₃), 5.67 (ddd, 1 H, J = 8.5, 10.2, 16.8 Hz, CHCHN); (Z)-

isomer: δ = 1.65 (d, 3 H, J = 7.0 Hz, CH₃), 3.68 (dd, 1 H, J = 8.8,

15.1 Hz, CHHN), 3.95 (dd, 1 H, J = 7.0, 8.5 Hz, CHHO), 4.05 (dd,

1 H, J = 5.1, 15.1 Hz, CHHN), 4.24 (pseudo br q,1 H, J = 8.2 Hz,

CHN), 4.42 (pseudo t, 1 H, J = 8.5 Hz, CHHO), 5.33 (d, 1 H,

J = 16.8 Hz, CHHCHCHN), 5.35 (d, 1 H, J = 10.2 Hz, CHH-

CHCHN), 5.36-5.44 (m, 1 H, CHCH₃), 5.56-5.70 (m, 1 H,

CHCHCH₃), 5.73 (ddd, 1 H, J = 8.5, 10.2, 16.8 Hz, CHCHN).

¹³C NMR (75.5 MHz): Two isomers (ratio: 70:30); (E)-isomer:

δ = 17.4 (CH₃), 43.6 (CH₂N), 58.1 (CHN), 68.8 (CH₂O), 120.8

(CH₂CHCHN), 124.2* (CHCHCH₃), 130.2* (CHCH₃), 134.6

(CHCHN), 157.6 (CO); (Z)-isomer: δ = 12.8 (CH₃), 38.3 (CH₂N),

58.4 (CHN), 68.8 (CH₂O), 120.8 (CH₂CHCHN), 123.6*

(CHCHCH₃), 128.7* (CHCH₃), 134.7 (CHCHN), 157.7 (CO).

IR (film): n = 3327 (br s, NH, OH), 3059 (w, C_arH), 3026 (w, C_arH),

2969 (s, C_alH), 2932 (s, C_alH), 1602 (w, C=C), 1581 (w, C=C), 1381

(m), 1165 (m), 747 (m, Ph), 699 cm^-1(m, Ph).

¹H NMR (200 MHz): δ = 0.97 (s, 3 H, CH₃), 1.12 (s, 3 H, CH₃), 2.03

(ddd, 1 H, J = 3.4, 9.1, 12.3 Hz, CHHCHCHN), 2.20-2.35 (m, 1 H,

CHHCHCHN), 2.50-2.70 (m, 1 H, CHCHN), 2.80-3.20 (m, 5 H,

CHN, CHCHCH₂N), 3.15 (br s, 1 H, NH), 7.10-7.30 (m, 5 H_arom).

¹³C NMR (50.3 MHz): δ = 25.1 (CH₃), 27.1 (CH₃), 31.8

(CH₂CHCHN), 35.1 (CHCHN), 42.8 (CHPh), 49.0 (CHCH₂N),

53.9 (CH₂N), 71.2 (COH), 75.9 (CHN), 125.8 (C_arH), 126.2 (C_arH),

128.2 (C_arH), 145.5 (C_ar).

MS (EI, 70 eV): m/z (%) = 216 (4) [M⁺- CH₃], 172 (100)

+

[C₁₂H₁₄N⁺], 129 (8), 117 (24) [C₉H₉], 68 (60), 41 (20).

HRMS: m/z calcd for C₁₅H₂₁NO: 231.1623; found 231.1622.

(1SR,2SR,5RS,6SR)-N-Benzyloxycarbonyl-2-(1-hydroxy-1-me-

thylethyl)-6-phenyl-3-azabicyclo[3.2.0]heptane (13)

Benzyl chloroformate (370 mL, 450 mg, 2.6 mmol) was added drop-

wise over a period of 30 min to an ice-cold solution of the crude

azabicycloheptane 18 (553 mg, 2.4 mmol) and KHCO₃(1.2 g) in a

mixture of H₂O and EtOAc (24 mL, 1:1, v/v). After the mixture was

stirred for 4 h, the organic layer was separated, washed with dil HCl

MS (EI, 70 eV): m/z (%) = 167 (7) [M⁺], 152 (11) [M⁺- CH₃], 126

(8), 112 (13), 94 (17), 86 (12), 68 (16), 55 (78), 54 (100), 41 (16).

FEATURE ARTICLE

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

317

Anal. C₁₀H₁₅NO₂(167.2): calcd C, 64.65; H, 7.84; N, 8.38; found

C, 64.44; H, 8.06; N, 8.63.

Cu(OTf)₂-Catalyzed [2+2]-Photocycloadditon; General Proce-

dure C

In a quartz tube the N-protected N,N-diallylamine (1.0 mmol) was

dissolved in anhyd Et₂O (10 mL). After addition of Cu(OTf)₂(30

mg, 0.083 mmol, 8.3 mol%) the tube was sealed with a septum cap

and the mixture was shaken until the Cu(OTf)₂had completely dis-

solved. The solution was irradiated at λ = 254 nm (light source:

Rayonet RPR 2540) and the course of the reaction was monitored

by TLC. Upon complete conversion of the substrate, the resulting

solution was diluted with Et₂O (20 mL) and washed with a mixture

of ice (10 g) and concd NH₃(10 mL) and subsequently with brine

(10 mL). The organic layer was dried (MgSO₄), filtered, the solvent

was evaporated in vacuo and the residue purified by flash chroma-

tography.

(5S,6S,8S,9R)-1-Aza-3-oxa-8-phenyltricyclo[5.3.0.0^6,9]decan-2-

one [(+)-17a]

According to the General Procedure C, the oxazolidinone (-)-16a

(229 mg, 1 mmol) was irradiated for 17.5 h. Flash chromatography

(pentane/t-BuOMe, 60:40) yielded the tricyclic compound (+)-17a

as a colorless solid (200 mg, 87%). The spectroscopic data are in

full agreement with the data given above; >95% ee.

(SR)-N-Crotyl-5,5-dimethyl-4-vinyloxazolidin-2-one (20b)

The reaction was carried out as described in the General Procedure

B starting from tertiary alcohol 15b (748 mg, 3 mmol) and (E)/(Z)-

crotyl bromide (2.03 g, 15 mmol). The oxazolidinone 20b was ob-

tained after flash chromatography (pentane/t-BuOMe, 75:25) as a

colorless oil (423 mg, 84%); R_f0.56 (pentane/t-BuOMe, 40:60).

IR (film): n = 3016 (sh), 2980 (s, C_alH), 2935 (s, C_alH), 1751 (vs,

CO), 1404 (s, CH₃), 1294 (s), 1080 (s, C-O), 958 (s), 765 (m), 738

cm^-1(m).

¹H NMR (300 MHz): Two isomers (ratio: 67:33); (E)-isomer:

δ = 1.28 (s, 3 H, CH₃), 1.43 (s, 3 H, CH₃), 1.69 (d, 3 H, J = 6.3 Hz,

CHCH₃), 3.38 (dd, 1 H, J = 8.1, 15.1 Hz, CHHN), 3.80 (d, 1 H,

J = 9.0 Hz, CHN), 4.04 (ddd, 1 H, J = 1.5, 5.1, 15.1 Hz, CHHN),

5.32 (dd, 1 H, J = 1.0, 16.9 Hz, CHHCHCHN), 5.38 (dd, 1 H,

J = 1.0, 10.3 Hz, CHHCHCHN), 5.32-5.43 (m, 1 H, CHCH₃),

5.55-5.69 (m, 1 H, CHCHCH₃), 5.68 (ddd, 1 H, J = 9.0, 10.3, 16.9

Hz, CHCHN); (Z)-isomer: δ = 1.28 (s, 3 H, CH₃), 1.42 (s, 3 H,

CH₃), 1.63 (d, 3 H, J = 7.0 Hz, CHCH₃), 3.62 (dd, 1 H, J = 8.6, 15.1

Hz, CHHN), 3.77 (d, 1 H, J = 9.0 Hz, CHN), 4.05 (ddd, 1 H, J = 1.5,

5.1, 15.1 Hz, CHHN), 5.32 (dd, 1 H, J = 1.0, 16.9 Hz, CHH-

CHCHN), 5.38 (dd, 1 H, J = 1.0, 10.3 Hz, CHHCHCHN), 5.32-

5.43 (m, 1 H, CHCH₃), 5.55-5.69 (m, 1 H, CHCHCH₃), 5.73 (ddd,

1 H, J = 9.0, 10.3, 16.9 Hz, CHCHN).

¹³C NMR (75.5 MHz): Two isomers (ratio: 67:33); (E)-isomer:

δ = 17.4 (CHCH₃), 22.7 (CH₃), 27.2 (CH₃), 43.8 (CH₂N), 67.8

(CHN), 80.2 [C(CH₃)₂], 121.3 (CH₂CHCHN), 124.3* (CHCHCH₃),

130.0* (CHCH₃), 132.7 (CHCHN), 156.8 (CO); (Z)-isomer:

δ = 12.8 (CHCH₃), 22.7 (CH₃), 27.2 (CH₃), 38.5 (CH₂N), 67.8

(CHN), 80.2 [C(CH₃)₂], 121.3 (CH₂CHCHN), 123.8* (CHCHCH₃),

128.5* (CHCH₃), 132.7 (CHCHN), 156.8 (CO).

(5SR,6SR,8SR,9RS)-1-Aza-4,4-dimethyl-3-oxa-8-phenyltricyc-

lo[5.3.0.0^6,9]decan-2-one (17b)

According to the General Procedure C, oxazolidinone 16b (265 mg,

1 mmol) was irradiated for 21 h. Flash chromatography (pentane/t-

BuOMe, 75:25) yielded the tricyclodecanone 17b as a colorless sol-

id (165 mg, 63%). The spectroscopic data are in full agreement with

the data given above.

(5SR,6SR,9RS)-1-Aza-3-oxatricyclo[5.3.0.0^6,9]decan-2-one (22a)

According to the General Procedure C, oxazolidinone 19a¹⁶(153

mg, 1 mmol) was irradiated for 6 h. Flash chromatography (pen-

tane/t-BuOMe, 75:25) yielded the tricyclodecanone 22a as a color-

less syrup (100 mg, 65%); R_f0.21 (pentane/t-BuOMe, 40:60).

MS (EI, 70 eV): m/z (%) = 195 (6) [M⁺], 180 (3) [M⁺- CH₃], 137

(3), 114 (8), 94 (4), 82 (100), 55 (88), 41 (12).

IR (film): n = 2976 (s, C_alH), 2940 (s, C_alH), 1748 (vs, CO), 1395

(s), 1209 (s), 1053 (m, C-O), 1003 (m), 776 cm^-1(m).

Anal. C₁₁H₁₇NO₂(195.2): calcd C, 67.66; H, 8.78; N, 7.17; found

C, 67.41; H, 9.00; N, 7.56.

¹H NMR (500 MHz): δ = 1.70-1.77 (m, 2 H, CH₂CHCHN), 2.18-

2.29 (m, 2 H, CH₂CHCH₂N), 2.49-2.55 (m, 1 H, CHCHN), 2.95

(dd, 1 H, J = 4.5, 11.4 Hz, CHHN), 2.95-3.02 (m, 1 H, CHCH₂N),

3.94 (dd, 1 H, J = 7.9, 11.4 Hz, CHHN), 3.98 (ddd, 1 H, J = 3.8, 5.2,

8.1 Hz, CHN), 4.05 (dd, 1 H, J = 3.8, 8.8 Hz, CHHO), 4.49 (dd, 1

H, J = 8.1, 8.8 Hz, CHHO).

(SR)-N-(4,4-Dimethyl-2-pentenyl)-4-vinyloxazolidin-2-one (21)

The reaction was carried out as described in the General Procedure

B starting from vinylglycinol 15a¹⁶(663 mg, 3 mmol) and (E)-1-

bromo-4,4-dimethylpent-2-ene²⁰(2.66 g, 15 mmol). The oxazolidi-

none 21 was obtained after flash chromatography (pentane/t-

BuOMe, 75:25) as a colorless oil (498 mg, 79%); R_f0.57 (pentane/

t-BuOMe, 40:60).

NOESY experiment (500 MHz): H (2.18-2.29)-H (2.95-3.02)’’,

H (2.49-2.55)-H (4.05)’, H (2.95)-H (1.70-1.77)’’, H (3.98)-H

(1.70-1.77)’’, H (3.98)-H (4.49)’’.

¹³C NMR (75.5 MHz): δ = 23.8 (CH₂CHCHN), 25.8

(CH₂CHCH₂N), 40.8 (CHCHN), 45.8 (CHCH₂N), 54.5 (CH₂N),

67.1 (CHN), 69.2 (CH₂O), 161.0 (CO).

IR (film): n = 3068 (w), 3009 (m), 2958 (s, C_alH), 2904 (m, C_alH),

2866 (m, C_alH), 1759 (vs, CO), 1408 (s, CH₃), 1224 (m), 1172 (m),

1060 (s, C-O), 976 cm^-1(m).

¹H NMR (300 MHz): δ = 1.01 [s, 9 H, C(CH₃)₃], 3.46 (ddd, 1 H,

J = 0.8, 8.4, 14.9 Hz, CHHN), 3.94 (dd, 1 H, J = 7.2, 8.6 Hz,

CHHO), 4.09 (ddd, 1 H, J = 1.5, 5.0, 14.9 Hz, CHHN), 4.21 (pseudo

br q, 1 H, J = 7.9 Hz, CHN), 4.43 (pseudo t, 1 H, J = 8.6 Hz,

CHHO), 5.25 [ddd, 1 H, J = 5.0, 8.4, 15.6 Hz, CHCHC(CH₃)₃], 5.30

(d, 1 H, J = 16.4 Hz, CHHCHCHN), 5.34 (d, 1 H, J = 9.8 Hz, CHH-

CHCHN), 5.62 [pseudo dt, 1 H, J = 1.1, 15.6 Hz, CHC(CH₃)₃], 5.68

(ddd, 1 H, J = 8.6, 9.8, 16.4 Hz, CHCHN).

¹³C NMR (75.5 MHz): δ = 29.2 [C(CH₃)₃], 32.9 [C(CH₃)₃], 44.1

(CH₂N), 58.2 (CHN), 66.8 (CH₂O), 117.6 (CH₂CHCHN), 120.9

[CHCHC(CH₃)₃], 134.6 (CHCHN), 146.9 [CHC(CH₃)₃], 157.6

(CO).

MS (EI, 70 eV): m/z (%) = 153 (27) [M⁺], 126 (17), 108 (37), 95

(66), 80 (19), 67 (79), 55 (100), 41 (57).

HRMS: m/z calcd for C₈H₁₁NO₂: 153.0790; found 153.0791.

(5SR,6SR,9RS)-1-Aza-4,4-dimethyl-3-oxatricyclo[5.3.0.0^6,9]de-

can-2-one (22b)

According to the General Procedure C, oxazolidinone 19b (181 mg,

1 mmol) was irradiated for 19 h. Flash chromatography (pentane/t-

BuOMe, 75:25) yielded the tricyclodecanone 22b as a colorless sol-

id (130 mg, 72%); mp 64°C; R_f0.35 (pentane/t-BuOMe, 40:60).

IR (KBr): n = 2971 (s, C_alH), 2892 (m, C_alH), 1727 (vs, CO), 1395

(s), 1281 (s), 1016 (s), 1002 (s), 774 cm^-1(m).

MS (EI, 70 eV): m/z (%) = 209 (6) [M⁺], 194 (9) [M⁺- CH₃], 152

¹H NMR (200 MHz): δ = 1.25 (s, 3 H, CH₃), 1.48 (s, 3 H, CH₃),

+

(55) [M⁺- t-Bu], 126 (36), 96 (27), 81 (44), 67 (21), 57 (7) [C₃H₉],

1.63-1.93 (m,

2 H, CH₂CHCHN), 2.18-2.39 (m, 2 H,

55 (100), 35 (32).

CH₂CHCH₂N), 2.66-2.83 (m, 1 H, CHCHN), 3.02 (ddd, 1 H,

J = 1.9, 4.5, 13.2 Hz, CHHN), 3.01-3.13 (m, 1 H, CHCH₂N), 3.73

Anal. C₁₂H₁₉NO₂(209.3): calcd C, 68.87; H, 9.15; N, 6.69; found

C, 68.57; H, 9.11; N, 6.99.

318

T. Bach et al.

FEATURE ARTICLE

(d, 1 H, J = 5.8 Hz, CHN), 3.98 (ddd, 1 H, J = 0.8, 9.4, 13.2 Hz,

CHHN).

H, CHCH₂N), 3.28 (dd, 1 H, J = 6.8, 12.3 Hz, CHHN), 3.84 (dd, 1

H, J = 9.0, 12.3 Hz, CHHN).

¹³C NMR (50.3 MHz): δ = 23.2 (CH₃), 25.6 (CH₂CHCHN,

CH₂CHCH₂N), 29.2 (CH₃), 39.1 (CHCHN), 40.1 (CHCH₂N), 53.0

(CH₂N), 75.9 (CHN), 80.2 [C(CH₃)₂], 159.8 (CO).

MS (EI, 70 eV): m/z (%) = 181 (26) [M⁺], 143 (9), 123 (19), 95 (83),

82 (15), 67 (100), 54 (11), 41 (20).

¹³C NMR (75.5 MHz): Two diastereoisomers (ratio: 68:32). exo-

23b: δ = 21.0 (CHCH₃), 23.3 (CH₃), 29.3 (CH₃), 30.1

(CH₂CHCHN), 34.9 (CHCH₃), 35.5 (CHCHN), 48.3 (CHCH₂N),

52.2 (CH₂N), 76.0 (CHN), 79.9 [C(CH₃)₂], 159.8 (CO); endo-23b:

δ = 16.7 (CHCH₃), 23.2 (CH₃), 27.3 (CHCH₃), 28.9 (CH₃), 33.4

(CH₂CHCHN), 33.4 (CHCHN), 43.2 (CHCH₂N), 46.1 (CH₂N),

75.8 (CHN), 80.9 [C(CH₃)₂], 159.8 (CO).

Anal. C₁₀H₁₅NO₂(181.2): calcd C, 66.27; H, 8.34; N, 7.73; found

C, 65.88; H, 8.12; N, 7.68.

MS (EI, 70 eV): m/z (%) = 195 (7) [M⁺], 180 (<1) [M⁺- CH₃], 137

(9), 109 (61), 94 (34), 81 (59), 67 (100), 55 (17), 41 (27).

1-Aza-8-methyl-3-oxatricyclo[5.3.0.0^6,9]decan-2-one (23a)

According to the General Procedure C, oxazolidinone 20a (153 mg,

1 mmol) was irradiated for 16.5 h. Flash chromatography (pentane/

t-BuOMe, 50:50) afforded the tricyclodecanone 23a as a colorless

syrup (126 mg, 75%); R_f0.31 (pentane/t-BuOMe, 40:60).

HRMS: m/z calcd for C₁₁H₁₇NO₂: 195.1259; found 195.1261.

1-Aza-8-(tert-butyl)-3-oxatricyclo[5.3.0.0^6,9]decan-2-one (24)

According to the General Procedure C, oxazolidinone 21 (209 mg,

1 mmol) was irradiated for 156 h. The photocycloaddition of the ox-

azolidinone 21 was incomplete but no attempt was made to recover

the starting material. Flash chromatography (pentane/t-

BuOMe, 80:20) yielded the tricyclodecanone 24 as a colorless syr-

up that became waxy upon standing (47 mg, 22%); R_f0.40 (pentane/

t-BuOMe, 40:60).

IR (film): n = 2952 (s, C_alH), 2929 (s, C_alH), 1749 (vs, CO), 1395

(s), 1207 (s), 1065 (m), 1010 (m), 774 cm^-1(m).

¹H NMR (300 MHz): Two diastereoisomers (ratio: 69:31);

(5SR,6SR,8SR,9RS)-isomer (exo-23a): δ = 1.13 (d, 3 H, J = 6.8 Hz,

CH₃), 1.80 (dt, 1 H, J = 7.7, 12.0 Hz, CHHCHCHN), 1.95 (ddd, 1

H, J = 2.6, 8.1, 12.0 Hz, CHHCHCHN), 2.23 (pseudo sept, br, 1 H,

J = 7.2 Hz, CHCH₃), 2.43-2.57 (m, 1 H, CHCHN), 2.57-2.69 (m,

1 H, CHCH₂N), 3.03 (dd, 1 H, J = 3.7, 12.1 Hz, CHHN), 3.90 (dd,

1 H, J = 8.1, 12.1 Hz, CHHN), 4.00-4.07 (m, 1 H, CHN), 4.13 (dd,

1 H, J = 3.7, 8.8 Hz, CHHO), 4.56 (dd, 1 H, J = 8.1, 8.8 Hz,

CHHO); (5SR,6SR,8RS,9RS)-isomer (endo-23a): δ = 1.02 (d, 3 H,

J = 6.8 Hz, CH₃), 1.42-1.51 (m, 1 H, CHHCHCHN), 2.42-2.69

(m, 3 H, CHHCHCHN, CHCH₃), 3.02-3.07 (m, 1 H, CHCH₂N),

3.27 (dd, 1 H, J = 6.6, 12.1 Hz, CHHN), 3.83 (dd, 1 H, J = 7.5, 12.1

Hz, CHHN), 3.88-3.95 (m, 1 H, CHHO), 4.00-4.07 (m, 1 H,

CHN), 4.52 (pseudo t, 1 H, J = 8.6 Hz, CHHO).

IR (nujol): n = 2948 (m, C_alH), 2862 (m, C_alH), 1737 (vs, CO), 1461

(s), 1397 (s), 1214 (m), 1075 (m), 1005 (m), 773 cm^-1(m).

¹H NMR (300 MHz): Two diastereoisomers (ratio: 85:15);

(5SR,6SR,8SR,9RS)-isomer (exo-24): δ = 0.82 [s, 9 H, C(CH₃)₃],

1.62-1.72 (m, 1 H, CHHCHCHN), 1.91-2.06 [m, 2 H, CHH-

CHCHN, CHC(CH₃)₃], 2.36 (pseudo q, 1 H, J = 6.7 Hz, CHCHN),

2.84 (pseudo dq, 1 H, J = 3.3, 8.5 Hz, CHCH₂N), 2.97 (dd, 1 H,

J = 3.3, 11.8 Hz, CHHN), 3.91 (dd, 1 H, J = 8.2, 11.8 Hz, CHHN),

4.04 (ddd, 1 H, J = 3.4, 8.0, 10.8 Hz, CHN), 4.16 (dd, 1 H, J = 3.4,

8.8 Hz, CHHO), 4.57 (pseudo t, 1 H, J = 8.5 Hz, CHHO);

(5SR,6SR,8RS,9RS)-isomer (endo-24): δ = 0.87 [s, 9 H, C(CH₃)₃],

1.17 (ddd, 1 H, J = 2.2, 7.0, 12.2 Hz, CHHCHCHN), 2.21-2.30 [m,

2 H, CHHCHCHN, CHC(CH₃)₃], 2.49 (pseudo dq, 1 H, J = 2.2, 7.7

Hz, CHCHN), 2.81-2.90 (m, 1 H, CHCH₂N), 3.47 (dd, 1 H, J = 9.2,

12.1 Hz, CHHN), 3.78-3.84 (m, 1 H, CHHO), 3.91 (dd, 1 H,

J = 8.2, 12.1 Hz, CHHN), 3.99-4.07 (m, 1 H, CHN), 4.52 (pseudo

t, 1 H, J = 8.6 Hz, CHHO).

¹³C NMR (75.5 MHz): Two diastereoisomers (ratio: 85:15); exo-24:

δ = 23.2 (CH₂CHCHN), 26.1 [C(CH₃)₃], 28.6 [C(CH₃)₃], 40.5

[CHC(CH₃)₃], 42.3 (CHCHN), 51.5 (CHCH₂N), 53.6 (CH₂N), 68.2

(CHN), 68.3 (CH₂O), 160.9 (CO); endo-24: δ = 28.2 [C(CH₃)₃],

29.8 [CHC(CH₃)₃], 31.3 (CH₂CHCHN), 31.4 [C(CH₃)₃], 43.3

(CHCHN), 44.7 (CHCH₂N), 46.9 (CH₂N), 64.1 (CHN), 69.1

(CH₂O), 160.9 (CO).

NOESY experiment (500 MHz): exo-23a: H (1.80)-H (1.13)’’, H

(1.95)-H (2.23)’, H (2.23)-H (3.03)’’’, H (2.49-2.57)-H (2.57-

2.69)’’, H (2.57-2.69)-H (1.13)’’’, H (4.00-4.07)-H (1.95)’’’.

endo-23a: H (3.27)-H (1.02)’’, H (4.46)-H (4.00-4.07)’’’.

¹³C NMR (75.5 MHz): Two diastereoisomers (ratio: 69:31); exo-

23a: δ = 20.9 (CH₃), 30.1 (CH₂CHCHN), 34.7 (CHCH₃), 41.2

(CHCHN), 48.2 (CHCH₂N), 52.6 (CH₂N), 66.0 (CHN), 68.2

(CH₂O), 160.7 (CO); endo-23a: δ = 16.6 (CH₃), 26.8 (CHCH₃),

32.5 (CH₂CHCHN), 42.1 (CHCHN), 42.5 (CHCH₂N), 46.5

(CH₂N), 66.3 (CHN), 68.3 (CH₂O), 161.2 (CO).

MS (EI, 70 eV): m/z (%) = 167 (56) [M⁺], 152 (7) [M⁺- CH₃], 126

(17), 108 (39), 95 (32), 81 (39), 67 (100), 55 (89), 41 (37).

HRMS: m/z calcd for C₉H₁₃NO₂: 167.0946; found 167.0943.

MS (EI, 70 eV): m/z (%) = 209 (1.5) [M⁺], 194 (1.4) [M⁺- CH₃],

1-Aza-3-oxa-4,4,8-trimethyltricyclo[5.3.0.0^6,9]decan-2-one

(23b)

According to the General Procedure C, oxazolidinone 20b (98 mg,

0.5 mmol) was irradiated for 21.5 h. Flash chromatography (pen-

tane/t-BuOMe, 80:20) yielded the tricyclodecanone 23b as a color-

less oil (80 mg, 82%); R_f0.45 (pentane/t-BuOMe, 40:60).

136 (4), 122 (12) 109 (15), 99 (81), 95 (27), 81 (20), 69 (16), 57 (58)

+

[C₄H₉], 55 (100).

HRMS: m/z calcd for C₁₂H₁₉NO₂: 209.1416; found 209.1410.

(SR)-3-(N-Cinnamylamino)-2-methylpent-4-en-2-ol

A solution of oxazolidinone 16b (760 mg, 3 mmol) and KOH (3.36

g, 60 mmol) in a mixture of EtOH and H₂O (30 mL, 7:3, v/v) was

heated under reflux. After 12 h, TLC control showed complete con-

version of the starting material. EtOH was evaporated in vacuo and

the aqueous residue was acidified with dil HCl. After washing with

Et₂O (10 mL), the aqueous layer was made alkaline with aq 50%

NaOH solution and then extracted with CH₂Cl₂(5 î 20 mL). The

combined CH₂Cl₂layers were washed with brine (20 mL) and dried

(MgSO₄). After filtration, the solvent was removed in vacuo and the

residue purified by flash chromatography (pentane/t-

BuOMe, 40:60 with 0.1% Et₃N) to give 3-(N-cinnamylamino)-2-

methylpent-4-en-2-ol (530 mg, 78%); R_f0.34 (t-BuOMe, TLC plate

pretreated with Et₃N).

IR (film): n = 2952 (s, C_alH), 2933 (s, C_alH), 1748 (vs, CO), 1395

(m), 1375 (m), 1285 (m), 1056 (m), 966 (m), 771 cm^-1(m).

¹H NMR (300 MHz): Two diastereoisomers (ratio: 68:32);

(5SR,6SR,8SR,9RS)-isomer (exo-23b): δ = 1.12 (d, 3 H, J = 6.6 Hz,

CHCH₃), 1.34 (s, 3 H, CH₃), 1.55 (s, 3 H, CH₃), 1.78-1.92 (m, 2 H,

CH₂CHCHN), 2.25 (pseudo sept, br, 1 H, J = 7.2 Hz, CHCH₃),

2.59-2.78 (m, 2 H, CHCHN, CHCH₂N), 3.05 (dd, 1 H, J = 3.0, 12.1

Hz, CHHN), 3.68 (d, J = 5.8 Hz, CHN), 3.91 (dd, 1 H, J = 7.9, 12.1

Hz, CHHN); (5SR,6SR,8RS,9RS)-isomer (endo-23b): δ = 1.01 (d, 3

H, J = 7.4 Hz, CHCH₃), 1.30 (s, 3 H, CH₃), 1.51 (s, 3 H, CH₃),

1.74-1.82 (m, 1 H, CHHCHCH₃), 2.40-2.52 (m, 1 H, CHH-

CHCHN), 2.52-2.66 (m, 2 H, CHCHN, CHCH₃), 2.91-3.06 (m, 1

FEATURE ARTICLE

The Stereoselective Synthesis of 2-Substituted 3-Azabicyclo[3.2.0]heptanes

319

IR (film): n = 3420 (m, br, OH), 3327 (sh, NH), 3061 (w, C_arH),

3026 (w, C_arH), 2974 (s, C_alH), 2931 (w, C_alH), 1639 (w, C=C),

1599 (w, C=C), 1375 (m), 966 (m), 923 (m), 744 (m, Ph), 692 cm^-

¹(m, Ph).

¹H NMR (200 MHz): δ = 1.08 (s, 3 H, CH₃), 1.19 (s, 3 H, CH₃), 2.86

(d, 1 H, J = 8.5 Hz, CHN), 3.24 (ddd, 1 H, J = 1.3, 6.3, 13.8 Hz,

CHHN), 3.51 (ddd, 1 H, J = 1.3, 6.3, 13.8 Hz, CHHN), 5.17 (ddd, 1

H, J = 0.8, 2.0, 17.0 Hz, CHHCHCHN), 5.27 (dd, 1 H, J = 2.0, 10.3

Hz, CHHCHCHN), 5.61 (ddd, 1 H, J = 8.5, 10.3, 17.0 Hz,

CHCHN), 6.26 (dt, 1 H, J = 6.3, 16.0 Hz, CHCHPh), 6.52 (br d, 1

H, J = 16.0 Hz, CHPh), 7.17-7.42 (m, 5 H_arom).

CHCHCH₂N), 3.51 (dd, 1 H, J = 6.3, 12.0 Hz, CHHN), 3.99 (d, 1

H, J = 12.0 Hz, CHHN), 4.07 (4.14) (s, 1 H, CHN), 5.23 (s, 2 H,

CH₂Ph), 7.14-7.44 (m, 10 H_arom).

¹³C NMR (50.3 MHz): Two rotamers (ratio: 82:12); major rotamer:

δ = 24.7 (CH₃), 27.6 (CH₃), 31.8 (CH₂CHCHN), 36.6 (CHCHN),

42.5 (CHPh), 45.5 (CHCH₂N), 54.2 (CH₂N), 67.4 (CH₂Ph), 72.9

(CHN), 73.7 (COH), 126.1 (C_arH), 126.2 (C_arH), 127.6 (C_arH),

127.9 (C_arH), 128.3 (C_arH), 128.4 (C_arH), 136.4 (C_ar), 144.6 (C_ar),

157.6 (CO); minor rotamer: δ = 24.7 (CH₃), 27.6 (CH₃), 32.1

(CH₂CHCHN), 36.8 (CHCHN), 42.5 (CHPh), 45.8 (CHCH₂N),

53.8 (CH₂N), 67.4 (CH₂Ph), 74.2 (CHN), 74.7 (COH), 126.1

(C_arH), 126.2 (C_arH), 127.6 (C_arH), 127.9 (C_arH), 128.3 (C_arH),

128.4 (C_arH), 136.4 (C_ar), 144.3 (C_ar), 156.1 (CO).

¹³C NMR (50.3 MHz): δ = 24.1 (CH₃), 27.0 (CH₃), 49.7 (CH₂N),

70.4 (CHN), 70.8 (COH), 118.4 (CH₂CHCHN), 126.3 (CHCHPh),

127.4 (C_arH), 128.2 (C_arH), 128.5 (C_arH), 136.6 (CHPh), 137.0

(C_ar).

MS (EI, 70 eV): m/z (%) = 307 (8) [M⁺- C₃H₆O], 306 (41), 262

(60) [M⁺- C₈H₈], 216 (94), 112 (26), 104 (71) [C₈H₈], 91 (100)

+

[C₇H₇], 82 (27), 59 (25), 41 (21).

MS (EI, 70 eV): m/z (%) = 231 (1) [M⁺], 172 (37), 117 (100)

+

[C₉H₉], 91 (11) [C₇H₇], 56 (9), 43 (3).

Anal. C₂₃H₂₇NO₃(365.48): calcd C, 75.59; H, 7.62; N, 3.83; found

C, 75.46; H, 7.47; N, 3.99.

Anal. C₁₅H₂₁NO (231.3): calcd C, 77.88; H, 9.15; N, 6.05; found C,

77.60; H, 9.43; N, 6.37.

(1SR,2SR,5RS,6RS)-Diastereoisomer

R_f0.28 (pentane/t-BuOMe, 40:60).

¹H NMR (200 MHz): δ = 1.09 (s, 3 H, CH₃), 1.24 (s, 3 H, CH₃),

1.99-2.12 (m, 1 H, CHHCHCHN), 2.43-3.63 (m, 1 H, CHH-

CHCHN), 2.90 (pseudo q, 1 H, J = 7.5 Hz, CHCH₂N), 3.15-3.37

(m, 2 H, CHHN, CHCHN), 3.50-3.82 (m, 2 H, CHCHCHHN), 3.93

(s, 1 H, CHN), 6.94-7.44 (m, 10 H_arom).

¹³C NMR (50.3 MHz): δ = 24.8 (CH₃), 27.9 (CH₃), 29.7

(CH₂CHCHN), 36.3 (CHCH₂N), 37.8 (CHCHN), 43.8 (CHPh),

47.4 (CH₂N), 67.1 (CH₂Ph), 73.4 (CHN), 74.5 (COH), 126.1

(C_arH), 127.2 (C_arH), 127.5 (C_arH), 127.8 (C_arH), 128.3 (C_arH),

136.5 (C_ar), 140.8 (C_ar), 157.3 (CO).

(SR)-3-(N-Benzyloxycarbonyl-N-cinnamylamino)-2-methyl-

pent-4-en-2-ol (25)

Benzyl chloroformate (400 mL, 470 mg, 2.78 mmol) was added

dropwise over a period of 30 min to an ice-cold solution of 3-(N-cin-

namylamino)-2-methylpent-4-en-2-ol (586 mg, 2.53 mmol) and

KHCO₃(1.2 g) in a mixture of H₂O and EtOAc (25 mL, 1:1, v/v).

The mixture was stirred for 4 h, the organic layer separated and

washed with dil HCl (10 mL), H₂O (10 mL) and brine (10 mL), and

dried (MgSO₄). After filtration, the solvent was evaporated in vacuo

and the residue purified by flash chromatography (pentane/t-

BuOMe, 80:20). Compound 25 was obtained as a colorless oil (892

mg, 96%); R_f0.54 (pentane/t-BuOMe, 40:60).

IR (film): n = 3425 (m, br, OH), 3063 (w, C_arH), 3030 (w, C_arH),

2978 (m, C_alH), 2937 (m, C_alH), 1678 (vs, CO), 1468 (m), 1415 (s),

1235 (m), 962 (s), 746 (m, Ph), 694 cm^-1(m, Ph).

¹H NMR (200 MHz): δ = 1.20 (s, 3 H, CH₃), 1.24 (s, 3 H, CH₃), 3.67

(br d, 1 H, J = 8.3 Hz, CHN), 4.10 (d, 2 H, J = 6.3 Hz, CH₂N), 4.79

(br s, 1 H, OH), 5.10-5.32 (m, 4 H, CH₂Ph, CH₂CHCHN), 6.02-

6.40 (m, 2 H, CHCHPh, CHCHN), 6.45 (d, 1 H, J = 16.0 Hz,

CHPh), 7.16-7.49 (m, 10 H_arom).

Acknowledgement

This research was generously supported by the Fonds der Chemi-

schen Industrie. We thank Lin Müller (undergraduate research par-

ticipant, spring 1999), Felix Westkämper (undergraduate research

participant, fall 1998), and Gregor Willanzheimer for skillful tech-

nical assistance. In addition, we would like to thank Prof. J. Mattay

(University Bielefeld) and Dr. G. Steiner (BASF AG, Ludwigsha-

fen) for fruitful discussions.

¹³C NMR (50.3 MHz): δ = 26.9 (CH₃), 28.2 (CH₃), 51.4 (CH₂N),

67.5 (CH₂Ph), 71.1 (COH), 72.2 (CHN), 119.1 (CH₂CHCHN),

125.4 (CHCHPh), 126.2 (C_arH), 127.6 (CHCHN), 127.8 (C_arH),

128.0 (C_arH), 128.2 (C_arH), 128.4 (C_arH), 128.5 (C_arH), 131.7

(CHPh), 136.2 (C_ar), 136.4 (C_ar), 157.1 (CO).

References

#

To whom inquiries about the X-ray analysis should be

addressed.

MS (EI, 70 eV): m/z (%) = 307 (2) [M⁺- C₃H₆O], 216 (18), 176

(1) Winterfeldt, E. Prinzipien und Methode der Stereoselektiven

Synthese, Vieweg: Braunschweig, 1988; pp 31-47.

(2) Margaretha, P. In Methoden der Organischen Chemie

(Houben-Weyl), 4^thed., Vol. E 17e; de Mejiere, A., Ed..;

Thieme: Stuttgart, 1997; pp 149-162.

+

(29), 117 (100) [C₉H₉], 91 (83), 82 (71), 67 (38), 41 (13).

N-Benzyloxycarbonyl-2-(1-hydroxy-1-methylethyl)-6-phenyl-

3-azabicyclo[3.2.0]heptane

According to the General Procedure A, 25 (470 mg, 1.3 mmol) and

acetophenone (250 mL, 248 mg, 2.1 mmol) were irradiated in ace-

tone (10 mL) for 2.5 h. After purification by flash chromatography

(pentane/t-BuOMe, 75:25), azabicycloheptane 13 (363 mg, 0.99

mmol, 77%) and its diastereoisomer (45 mg, 10%) were obtained as

colorless oils.

Pete, J.-P. Adv. Photochem. 1996, 21, 135.

Mattay, J.; Conrads, R.; Hoffmann, R. In Methoden der

Organischen Chemie (Houben-Weyl), 4^thed., Vol. E 21c;

Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,

Eds; Thieme: Stuttgart, 1995; pp 3085-3178.

Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297.

Schuster, D. I. In The Chemistry of Enones; Patai, S.;

Rappoport, Z., Eds; Wiley-Interscience: New York, 1989; pp

623-756.

Crimmins, M. T. Chem. Rev. 1988, 88, 1453.

Weedon, A. C. In Synthetic Organic

Photochemistry;Horspool, W. M., Ed.; Plenum: New York,

1984; pp 61-144.

(1SR,2SR,5RS,6SR)-Diastereoisomer (13)

R_f0.36 (pentane/t-BuOMe, 40:60).

IR (film): n = 3448 (br, OH), 3061 (w, C_arH), 3029 (w, C_arH), 2943

(w, C_alH), 2932 (w, C_alH), 1693 (vs, CO), 1678 (vs, CO), 1417 (m),

1361 (m), 1160 (m), 1094 (m), 749 (m, Ph), 698 cm^-1(m, Ph).

¹H NMR (200 MHz): Two rotamers (ratio: 82:12), some signals ap-

peared twice: δ = 1.11 (1.15) (s, 3 H, CH₃), 1.23 (s, 3 H, CH₃),

2.05-2.50 (m, 2 H, CH₂CHCHN), 2.79-3.24 (m, 3 H, CHCHN,

320

T. Bach et al.

FEATURE ARTICLE

Baldwin, S. W. Org. Photochem. 1981, 5, 123.

Bauslaugh, P. G. Synthesis 1970, 287.

(3) Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. Top. Curr. Chem.

1986, 133, 85.

R = 4.5%; GOF = 0.793. Data collection: Data were collected

on as Stoe IPDS instrument at 193 K employing Mo Ka

irradiation (71.073 pm). The two orientiation matrices of the

twin species could be determined using the program RECIPE

(Stoe IPDS Program System, Vers. 2.03, 1997). The

integration of the intensities was performed using the matrix

of the main species. The resulting data set was treated with the

program TWINXL (Hahn, F.; Massa, W. TWINXL, Program

for Handling Diffraction Data of Twinned Crystals, Marburg,

1997) so that a twin refinement with SHELXL-97 (Sheldrick,

G. M. SHELXL-97, Program for the Refinement of Crystal

Structures, Göttingen, 1997) could be carried out. 8201 non

merged reflections, 3846 reflections with I > 2s(I); θ

range:2.55-25.89°. One of the two independent moelecules

happened to be disordered. Selected bond lengths [Å]: N(1)-

C(10) 1.480(2); C(6)-C(7) 1.545(2); C(9)-C(8) 1.559(2);

C(6)-C(9) 1.551(3); C(9)-C(10) 1.538(3). Selected bond

angles [°]: C(2)-N(1)-C(5) 110.62(16); C(5)-C(6)-C(9)

102.90(16); N(1)-C(5)-C(4) 101.00(15); C(7)-C(6)-C(9)

89.28(13); C(10)-C(9)-C(6) 108.04; C(6)-C(9)-C(8)

88.18(15). Further details of the crystal structure

Wong, H. N. C., Fitjer, L.; Heuschmann, M. In Methoden der

Organischen Chemie (Houben-Weyl), 4^thed.,Vol. E 17e, de

Mejiere, A., Ed.; Thieme: Stuttgart, 1997; pp 435-610.

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Höger, T.; Jochims, K.; Munschauer, R.; Neumann, B.;

Teschendorf, H.-J.; Traut, M.; Unger, L.; Gross, G. Drugs Fut.

1998, 23, 191.

(5) Steiner, G.; Unger, L.; Behl, B.; Teschendorf, H. J.;

Munschauer, R. DE 92-4243287, WO 94/00458, Chem. Abstr.

1994, 121, 205375.

(6) Steiner, G.; Munschauer, R.; Klebe, G.; Siggel, L.

Heterocycles 1995, 40, 319.

(7) Preliminary communication: Bach, T.; Pelkmann, C.; Harms,

K. Tetrahedron Lett. 1999, 40, 2103.

(8) Barton, D. H. R.; Dowlatshahi, H. A.; Motherwell, W. B.;

Villemin, D. J. Chem. Soc., Chem. Commun. 1980, 732.

Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron

1985, 41, 3901.

(9) Salomon, R. G.; Ghosh, S.; Raychaudhuri, S. R.; Miranti, T.

S. Tetrahedron Lett. 1984, 25, 3167.

(10) Crozet, M. P.; Kaafarani, M.; Surzur, J.-M. Bull. Chim. Soc.

Fr. 1984, 390.

(11) Castelhano, A. L.; Horne S.; Billedeau, R.; Krantz, A.

Tetrahedron Lett. 1986, 27, 2435.

(12) Dehmer, K. H. In Methoden der Organischen Chemie

(Houben-Weyl), 4^thed., Band 15, Teil 1; Wünsch, E., Ed.;

Thieme: Stuttgart, 1974; pp 315-327.

(13) Afzali-Ardakani, A.; Rapoport, H. J. Org. Chem. 1980, 45,

4817.

(14) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic

Compounds, Wiley: New York, 1994; pp 695-697.

(15) Fukuchi, N.; Isogai, A.; Nakayama, J.; Takayama, S.;

Yamashita, S.; Suyama, K.; Takemoto, J. Y.; Suzuki, A. J.

Chem. Soc. Perkin Trans. 1 1992, 1149.

investigations related to this compound may be obtained from

the Director of the Cambridge Crystallographic Data Centre,

12 Union Road, GB-Cambridge CB2 1EZ, on quoting the full

literature citation.

(18) Delgado, A.; Hospital, S.; Mauleón, D.; Pérez, F. Synth.

Commun. 1988, 18, 2017.

(19) Review: Salomon, R. G. Tetrahedron 1983, 39, 485.

(20) (E)-1-Bromo-4,4-dimethyl-2-pentene was prepared according

to: Lion, C.; Dubois, J.-E. Bull. Soc. Chim. Fr. 1976, 1875.

(21) Langer, K.; Mattay, J.; Heidbreder, A.; Möller, M. Liebigs

Ann. Chem. 1992, 257.

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J. Am. Chem. Soc. 1982, 104, 998, and references cited

therein.

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29235.

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(16) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621.

Huwe, C. M.; Blechert, S. Synthesis 1997, 61.

(17) 17a: C₁₄H₁₅NO₂; Crystal Data: colorless needles; twinned

triclinic, P^¯1, a = 643.4(1) pm, b = 749.3(1) pm, c = 2410.8(4)

pm; a = 96.28(2)°, b = 90.192(19)°, g = 98.240(19)°; Z = 2;

Article Identifier:

1437-210X,E;2000,0,02,0305,0320,ftx,en;Z06299SS.pdf

Article Doi

The stereoselective synthesis of 2-substituted 3- azabicyclo[3.2.0]heptanes by intramolecular [2+2]-photocycloaddition reactions

DOI: 10.1055/s-2000-6261

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Article abstract of DOI:10.1055/s-2000-6261

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