Synthesis and reactivity of bicycles derived from tartaric acid and α- amino acids: A novel class of conformationally constrained dipeptide isosteres based upon enantiopure 3-aza-6,8-dioxabicyclo[3.2.1] octane-7- carboxylic acid

J . Org. Chem. 1999, 64, 7347-7364

7347

Syn th esis a n d Rea ctivity of Bicycles Der ived fr om Ta r ta r ic Acid

a n d r-Am in o Acid s: A Novel Cla ss of Con for m a tion a lly

Con str a in ed Dip ep tid e Isoster es Ba sed u p on En a n tiop u r e

3-Aza -6,8-d ioxa bicyclo[3.2.1]octa n e-7-ca r boxylic Acid

Antonio Guarna,*^,†Antonio Guidi,^‡Fabrizio Machetti,^†Gloria Menchi,^†Ernesto G. Occhiato,^†

Dina Scarpi,^†Sauro Sisi,^†and Andrea Trabocchi^†

Department of Organic Chemistry “U. Schiff”, and Center of Heterocyclic Compounds C.N.R.,

University of Florence, Via G. Capponi 9, I-50121 Florence, Italy, and Menarini Ricerche S.p.A.,

Chemistry Research Department, Via Sette Santi, 3, I-50131 Florence, Italy

Received March 22, 1999

3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acids (named BTAa) derived from (R,R)-, (S,S)-,

or meso-tartaric acid and natural (^L), unnatural (D), or unusual R-amino acids are described as

conformationally constrained dipeptide isosteres. The general strategy developed for their prepara-

tion has required the trasformation of the amino acids into the corresponding N-benzylamino

alcohols, followed by the PyBroP-promoted condensation with the monomethyl ester of the suitable

2,3-di-O-isopropylidenetartaric acid. Oxidation of the hydroxy group to aldheyde and subsequent

acid-catalyzed trans-acetalization with the two hydroxy groups of the tartaric acid moiety provided

3-aza-2-oxo-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid methyl esters [named BTAa(O)] in good

yield and, in most cases, as single enantiopure diastereoisomers. This strategy has been applied to

the preparation of BTAa(O) starting from (R,R)-, (S,S)-, or meso-tartaric acid and glycine, ^L- and

D-phenylalanine, L- and D-alanine, and (()-phenylglycine. In the cases of glycine, L- and D-phen-

ylalanine, and ^L- and D-alanine, the selective reduction by BH₃‚DMS of the amide group succeeding

to the cyclization step, or the reduction of both amide and ester functions followed by reoxidation

of the hydroxy to carboxylic group, provided in good yield the 3-aza-3-benzyl-6,8-dioxabicyclo[3.2.1]-

octane-7-carboxylic acids (or their methyl ester) BTAa, having the side chain of the amino acid

precursors at position 4. The stability and rigidity of the bicyclic skeleton, the complete control of

all the stereocenters, the possibility of introducing the side chains of ^L- or D-amino acids, and the

demonstrated compatibility with the conditions required for solid-phase peptide synthesis make

the BTAa compounds potential dipeptide isosteres useful for the synthesis of modified peptides.

In tr od u ction

(1) The synthesis should be easy and include only few

steps, starting from commercially available enantiopure

precursors, in both enantiomeric forms. Moreover, there

must be a stereochemistry control in each step of the

synthesis in order to have, starting from the appropriate

precursor, the desired configuration of the stereocenters

in the final compound.

Peptide isosteres are compounds that can replace one

or more amino acids in a bioactive peptide leading to

modified structures possibly displaying more favorable

pharmacological properties than the prototype. In several

cases, the modified peptide shows a higher metabolic

stability, better bioavailability, and higher receptor af-

finity or selectivity.¹

(2) A high number of positions should be functionalized

in order to increase the molecular diversity.

The isosteric substitution can occur at different levels,

from the simple modification of a single amino acid or

substitution of a single amide bond up to the complete

replacement of the amino acid backbone. The use of a

dipepetide isostere,^1-3replacing two neighboring amino

acids (Xaa-Yaa) at the same time, is a possible approach

to attaining modified peptides, whose flexibility, in

comparison with that of regular peptides, may be limited

by introducing conformational restrictions.¹

(3) The side chain of the ^L- or D-amino acids should be

introduced into at least one of the positions equivalent

to those of the Xaa-Yaa dipeptide prototype.

(4) The functionalities and protecting groups should

be compatible with the conditions required for solid-phase

peptide synthesis.

(5) The structure should have a limited number of

accessible conformations.

We have envisioned that some of the these features

could be found in the bicyclic structure based upon the

3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid skel-

eton shown in Figure 1. As shown in Scheme 1, these

novel amino acids can be prepared by reduction of the

corresponding 2-oxo derivatives, which, in turn, derive

from the condensation between R-amino aldehydes and

tartaric acid derivatives.^4,5Because R-amino aldehydes

are usually prepared from the corresponding R-amino

In designing a novel class of conformationally restricted

dipeptide isosteres, the following requirements should be

taken into account:

* To whom correspondence should be addressed. Tel.: 0039-055-

2757611. Fax: 0039-055-2476964. E-mail: guarna@chimorg.unifi.it

^†University of Florence.

^‡Menarini Ricerche S.p.A.

(1) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32,

1244-1267 and references therein.

(2) Chung, Y. J .; Ryu, E. J .; Keum, G.; Kim, B. H. Bioorg. Med.

Chem. 1996, 4, 209-225.

(3) Norman, B. H.; Kroin, J . S. J . Org. Chem. 1996, 61, 4990-4998.

Published on Web 09/14/1999

7348 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

F igu r e 1.

Sch em e 1

F igu r e 2.

The combination of all these elements determines

whether the polar and steric requirements of the native

peptide are maintained and, at the same time, can confer

modifications of the overall peptide structure. Moreover,

since the amide bond between the two amino acids is now

substituted by the acetal system, this can represent a

transition-state isostere of a scissile peptide bond in a

substrate-enzyme complex. A variety of transition-state

isosteres have been developed, including hydroxyethyl-

enes, reduced amides, hydroxyethylamines, and phos-

phinates, the high interest in these isosteres being also

related to their use in the synthesis of HIV protease

inhibitors, as recently reported.⁶

The most interesting feature of the new dipeptide

isostere BTAa is the possibility of setting the configura-

tion of the stereocenters by choosing the suitable starting

material. In Chart 1 the stereochemical relationships

between compounds BTAa and the amino acid precursors

and (R,R)-, (S,S)-, and meso-tartaric acids are illustrated.

The amino acid chosen as a starting material (^Lor D)

determines the nature and the configuration of the

substituent at C-4, whereas the stereochemistry of the

tartaric acid allows us to set the configuration of the other

two stereocenters of the skeleton. Thus, the combination

of ^L- and D-amino acids with (R,R)-, (S,S)-, and meso-

tartaric acid would produce eight possible stereoisomers.

Therefore, to simplify the nomenclature, we assign the

abbreviation BTX (with the capital X from the single

letter code of the amino acid used) to the stereoisomer

derived from natural (R,R)-tartaric acid and a natural

L-amino acid, whereas the lower case letters t and x are

used for compounds deriving from unnatural (S,S)-

tartaric acid and unnatural ^D-amino acids, respectively.

Thus, the combination of the two enantiomers of a chiral

amino acid with the two enantiomers of tartaric acid

produces the four different stereoisomers BTX, BTx, BtX,

and Btx. These stereoisomers have the carboxylic group

in the exo position, whereas the amino acid side chain

can be in the exo or endo position depending on the

absolute configuration of the tartaric acid and amino acid

precursors used.

acids, we named this novel class of dipeptide isosteres

BTAa, meaning bicyclic compounds derived from tartaric

acid and amino acids. By analogy, the corresponding

amide precursors were named BTAa(O).

Comparison of an extended structure of a peptide with

that of the modified one by introduction of dipeptide

isostere BTAa (Figure 2) allows the following comments

to be made:

The number of bonds between atoms 1 and 6 is the

same in both peptides, but in the modified peptide the

first amino acid contains a bisubstituted nitrogen with

two arms, one bearing the same side chain as the

unmodified peptide and the other one linked to the side

chain of the second amino acid making a seven-mem-

bered ring.

The position 3 (bearing the oxo group in the unmodified

peptide) in the first amino acid is now sp³-hybridized and

the oxygen lies out of plane, forming a second rigid ring.

The N-4 atom of the unmodified peptide is substituted

in the modified one by the O-4 atom.

The configuration of the two stereocenters at C-2 and

C-5 can either be identical to that of the original peptide

or inverted by choosing suitable amino acid and tartaric

acid precursors.

(4) Guidi, A.; Guarna, A.; Giolitti, A.; Macherelli, M.; Menchi, G.

Arch. Pharm. Med. Chem. 1997, 330, 201-202.

The introduction of the carboxylic group in the endo

position could be possible by starting from meso tartaric

acid. Also in this case, four different stereoisomers would

(5) This skeleton is not new in the literature. Indeed, it has been

already reported by Vogel et al., but only examples of glycine deriva-

tives as amido esters were described by the authors. (a) Dienes, Z.;

Vogel, P. J . Org. Chem. 1996, 61, 6958-6970. (b) Moismann, H.;

Dienes, Z.; Vogel, P. Tetrahedron 1995, 51, 6495-6510. (c) Dienes, Z.;

Antonsson, T.; Vogel, P. Tetrahedron Lett. 1993, 34, 1013-1016. (d)

Reymond, J .-L.; Vogel, P. J . Chem. Soc., Chem. Commun. 1990, 1070-

1072. (e) Reymond, J .-L.; Vogel, P. Tetrahedron: Asymmetry 1990, 1,

729-736.

(6) (a) Tucker, T. J .; Lumma, W. C., J r.; Payne, L. S.; Wai, J . M.; de

Solms, S. J .; Giuliani, E. A.; Darke, P. L.; Heimbach, J . C.; Zugay, J .

A.; Scleif, W. A.; Quintero, J . C.; Emini, E. A.; Huff, J . R.; Anderson,

P. S. J . Med. Chem. 1992, 35, 2525-2533 and references therein. (b)

Smallheer, J . M.; Seitz, S. S. Heterocycles 1996, 43, 2367-2376.

Synthesis and Reactivity of Bicycles Derived from BTAa

Ch a r t 1^a

J . Org. Chem., Vol. 64, No. 20, 1999 7349

a

Nomenclature for BTAa: relationship between absolute configuration of tartaric acid and amino acid derivative precursors with the

stereochemistry of BTAa.

Ta ble 1. P a n el of Com p ou n d s BTAa a n d BTAa (O) P r ep a r ed

BTAa(O)

R₁

BTAa

R₁

compd

R

R₂

compd

R

R₂

1

2

3

4

5

6

7

8

9

Bn

H

CO₂Me (exo)

CO₂Me (endo)

CO₂Me (exo)

CO₂H (exo)

16

17

18

19

20

Bn

H

Fmoc

H

CO₂Me (exo)

CO₂Me (endo)

CO₂Me (exo)

CO₂Me (endo)

CO₂Me (exo)

CO₂H (exo)

MPM

Bn

H

Bn (exo)

Bn (endo)

Me (exo)

Me (endo)

H

Bn (exo)

Bn (endo)

Me (exo)

Me (endo)

Ph (exo)

Ph (endo)

H

Bn (endo)

Me (endo)

H

Bn (exo)

H

(()-21

22

23

24

H

Bn (exo)

Bn (endo)

H

(()-10

(()-25

11

12

13

14

26

27

28

29

30

31

32

H

Bn (exo)

H

Bn

CO₂H (exo)

CO₂H (endo)

15

MPM

Fmoc

H

Bn (exo)

Me (endo)

be produced by combination with the enantiomers of a

chiral amino acid, all of them having the carboxylic group

in the endo position. Therefore, they are named endo-

BTX, endo-BTx, endo-BtX, and endo-Btx. If the synthesis

is extended to all 19 chiral natural ^L-amino acids and

the corresponding D-amino acids, 152 different com-

pounds could be synthesized besides the four steroiso-

mers derived from glycine (in total 156 different dipeptide

isosteres).

We report herein the preparation of several enan-

tiopure amido-esters BTAa(O), starting from (R,R)- or

meso-tartaric acid and glycine, ^L- and D-phenylalanine,

L- and D-alanine, and (()-phenylglycine. In the cases of

glycine, ^L- and D-phenylalanine, L- and D-alanine, the

corresponding 3-aza-3-benzyl-6,8-dioxabicyclo[3.2.1]octane-

7-carboxylic acids BTAa (orthogonally protected as N-

benzyl and methyl ester) have been synthesized, having

the 7-carboxylic group in either the exo or endo position.

All the corresponding compounds derived from (S,S)-

tartaric acid have been also prepared, but their synthesis

is not discussed in the text. A complete panel of the

BTAa(O) (1-15) and BTAa (16-32) prepared and char-

acterized is reported in Table 1 to which we refer in the

discussion throughout the text.

Finally, examples of selective protection/deprotection

reactions and the preparation of some N-Fmoc-protected

7350 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

Sch em e 2^a

a

Key: (a) CH₂Cl₂, 60 min, 25 °C; (b) SOCl₂, MeOH, 2 h, 50 °C; (c) H₂SO₄/SiO₂, toluene, reflux, 15 min, then distillation of one-third

of the solvent.

amino acids are reported. In the case of the glycine

33 (Scheme 2), prepared according to a reported method,⁷

was treated with commercially available (R,R)-2,3-di-O-

acetyltartaric anhydride 35 in CH₂Cl₂, affording the

corresponding amide 36. Crude 36 was dissolved in

MeOH and, when treated with thionyl chloride, afforded

cyclic acetal 38 as a mixture of epimers in 87% yield. The

final cyclization process to give Bn-BTG(O)-OMe 1 was

carried out by quickly adding a toluene solution of 38 to

a refluxing toluene suspension of H₂SO₄adsorbed on SiO₂

(H₂SO₄/SiO₂). After 15 min, one-third of the solvent was

distilled off, the hot reaction mixture was filtered through

a short pad of NaHCO₃, and the solvent was removed to

give Bn-BTG(O)-OMe 1 in 57% yield (after FCC). The

procedure was then extended to MPM-BTG-OMe 2

(which was obtained in 66% overall yield), to have a

N-protecting group removable by oxidation.

derivative BTG, the coupling with proline on the solid

phase has been realized to assess the compatibility of

these new dipeptide isosteres with the conditions re-

quired for solid-phase peptide synthesis.

Resu lts a n d Discu ssion

Syn th esis of BTAa (O). In the synthesis of the 3-aza-

2-oxo-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid skel-

eton of BTAa(O) (Scheme 1) from R-amino aldehydes and

tartaric acid derivatives two different processes are

involved:

Process 1: formation of an amide bond between the

amino group of the amino aldehyde and one of the two

carboxylic groups of the tartaric acid.

Process 2: formation of the acetal bridge between the

two hydroxy groups of the tartaric acid moiety and the

aldehyde function.

Therefore, the method to achieve these two distinct

processes would be strongly dependent on the nature of

the protecting groups of the amino aldehyde and tartaric

acid precursors. These groups would be very important

not only in the cyclization process but also in the further

transformations of BTAa(O) into BTAa.

The synthesis of (1R,5S,7R)- and (1S,5R,7S)-3-alkyl-

3-aza-2-oxo-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid

derivatives having R ) Me, Et, Pr; R₁) H; R₂) Et, H

and obtained from N-alkylglycine derivatives and 2,3-

di-O-acetyltartaric anhydride has been previously re-

ported by Vogel et al., who named these compounds

(alkyl)-RADO or -SADO, respectively.⁵The synthesis was

limited to a few examples of N-alkyl derivatives, and

while some transformations were carried out on the

carboxylic function, no attempts at converting the amide

moiety into other functionalities were made. We initially

extended this method to prepare Bn-BTG(O)-OMe 1,

MPM-BTG(O)-OMe 2 (MPM ) 4-methoxybenzyl), and

endo-Bn-BTG(O)-OMe (()-10 to introduce easily remov-

able N protecting groups and to modify the configuration

at C-7 of the carboxylic group (Scheme 2). Alternative

synthetic methods, more suitable for the use of chiral

amino acid derivatives as precursors, were then explored.

Thus, 2-(N-benzylamino)acetaldehyde dimethyl acetal

The cyclization procedure described above is the result

of the optimization of the method described by Vogel for

the synthesis of Me-BTG(O)-OMe. In particular, the

addition of compound 38 to the refluxing toluene and the

time of reflux were crucial points to obtaining good yields.

A slow heating of the reaction mixture containing 38 and

H₂SO₄/SiO₂up to reflux, or a prolonged refluxing time,

decreased the yield.

The same procedure (Scheme 2) was also applied to

the synthesis of racemic mixture of N-benzyl-7-endo-

carboxylic acid derivative (()-10 starting from meso-

tartaric acid and acetal 33. This required the synthesis

of meso-2,3-di-O-acetyltartaric anhydride 40, which, to

the best of our knowledge, has not been previously

described. Treatment of meso-tartaric acid under the

conditions used for the synthesis of (R,R)-2,3-di-O-acetyl-

tartaric anhydride⁸provided the desired product 40 in a

7:1 ratio with a racemic mixture of 2,3-di-O-acetyltartaric

anhydride 35. Owing to the instability of 40, no attempts

of purification were made. The succeding synthetic steps

were identical to those performed for the synthesis of Bn-

BtG(O)-OMe 1. The final product was a racemic mixture

(18% overall yield) of (()-10 containing, in a 7:1 ratio,

the racemic mixture of the 7-exo diastereoisomer 1

(7) Kermak, W. O.; Perkin, W. H.; Robinson, R. J . Chem. Soc., Trans.

1922, 121, 1872-1896.

(8) Lucas, H. J .; Baumgarten, W. J . Am. Chem. Soc. 1941, 63, 1653-

1657.

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7351

Sch em e 3^a

condensation between tartaric acid derivative 43 and the

amino acid derivatives was promoted by the activating

agent PyBroP (bromotripyrrolidinophosphonium hexa-

fluorophosphate)⁹in the presence of base. This reagent

has been reported to be a very useful coupling reagent

in peptide synthesis because it promotes amide bond

formation with relatively unreactive secondary amines

and, at the same time, avoids the racemization of the

amino acids.⁹

With regard to the synthesis of 1, intermediate 45,

obtained in 79% yield after the coupling of 43 with 33,

was treated in the usual way with H₂SO₄/SiO₂in reflux-

ing toluene. Monitoring of the reaction revealed that after

10 min 45 had already lost the protection on the tartaric

acid moiety, and as a consequence, cyclic acetal 38 shown

in Scheme 2 (as a 5:1 mixture of epimers at the acetalic

carbon) was formed as the major product, besides a

certain amount (20-30%) of final Bn-BTG(O)-OMe 1.

Prolonging the reflux time up to 40 min did not affect

the ratio of 38 to 1, whereas the reaction was completed

only by distillation of one-third of the toluene from the

reaction mixture. Presumably, this removes MeOH elimi-

nated during the trans-acetalization, shifting the reaction

equilibrium toward the final product. Thus, repeating the

reaction on 45 with a removal of toluene up to one-third

of the initial volume after 15 min of reflux afforded the

cyclization product in very high yield (91%) and in almost

pure form.¹⁰

Having in our hands a good procedure to perform the

two final steps, we applied the complete sequence to the

synthesis of compounds 3-7 and the two diastereoiso-

mers 8-9 derived from unnatural (()-R-phenylglycine

and (R,R)-tartaric acid (Scheme 3).

a

Key: (a) PyBrOP, DIPEA, CH₂Cl₂, 2-12 h, 25 °C; (b) Swern

oxidation; (c) H₂SO₄/SiO₂, toluene or benzene, reflux, 15 or 20 min,

then distillation of one-third of the solvent.

The synthesis of 3-7 required the preparation of amino

alcohols 48-52 obtained starting from the methyl ester

of the corresponding ^L- or D-amino acids. These were

treated with benzoyl chloride (or p-methoxybenzoyl chlo-

ride), then both the amide and ester groups were reduced

with LiAlH₄to give the corresponding â-amino alcohols

48-52 in very high yield. The condensation of amino

alcohols 48-52 with (R,R)-2,3-di-O-isopropylidenetar-

trate monomethyl ester (R,R)-43 was carried out by using

PyBroP and DIPEA (diisopropylethylamine) in CH₂Cl₂,

affording amides 53-57 in high yield (63-92%). The

condensation reaction was completely chemoselective

because the reaction of the OH group of 48-52 with the

carboxylic group of 43 to give an ester was never

observed. Compounds 53-57 were purified and charac-

terized and were found to be mixtures of rotamers in

solution (by ¹H NMR). Then, amido alcohols 53-57 were

transformed into the corresponding aldehydes 58-62 by

Swern oxidation in 65-95% yield in the presence of

DIPEA as a base. The use of Et₃N instead of DIPEA

caused in some cases a partial epimerization at the R

stereocenter of the aldehyde. Aldehydes 58-62 were,

with some exceptions, sufficiently stable to permit their

purification by flash column chromatography on silica gel

(FCC). More surprisingly, when some epimerization

occurred, the epimers were easily separatd by FCC. No

derived from the initial epimerization of the meso-tartaric

anhydride. The absence of changes in the diasteromeric

ratio indicated that no other racemization processes

occurred during the synthetic procedure.

Since the procedure described above is not suitable to

the synthesis of BTAa(O) derived from chiral amino acids,

we developed a different methodology that we employed

for the synthesis of different Bn-BTAa(O)-OMe: the

diastereoisomer 1 deriving from glycine and (R,R)-

tartaric acid; the two diastereoisomers 4-5 obtainable

from (R,R)-tartaric acid and ^L- and D-phenylalanine; the

two diastereoisomers 6-7 derived from ^L- and D-alanine

and (R,R)-tartaric acid; one of the two 7-endo diastereo-

isomers (11) derived from meso-tartaric acid and ^D-

phenylalanine; one of the two 7-endo diastereoisomers

derived from meso-tartaric acid and ^L-alanine (12), and

the two diastereoisomers 8-9 derived from R-phenyl-

glycine and (R,R)-tartaric acid.

In Scheme 3 the synthesis of 7-exo-BTAa(O) 1-9

derivatives is reported. It was based on the amide bond

formation between the monomethyl ester of (R,R)-2,3-

di-O-isopropylidentartaric acid 43 and the N-benzyl-R-

amino aldheyde derivatives 33 and 44 or N-benzyl-â-

amino alcohols 48-52, to give the condensation products

45-46 or 53-57, respectively. In the case of the dimethyl

acetal derivatives 45-46, the treatment with H₂SO₄/SiO₂

in refluxing solvent was sufficient to achieve the cycliza-

tion, whereas with alcohols 53-57 the cyclization was

realized after their transformation into aldehydes 58-

62 by Swern oxidation. In both the sequences, the

(9) Fre´rot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.; J ouin, P.

Tetrahedron 1991, 47, 259-270.

(10) Some attempts were made to find the conditions for direct

condensation of compound 33 with dimethyltartrate. The best yield of

1 (16%) was achieved by heating for 30 min a mixture of compound 33

and dimethyltartrate (previously activated by reaction with trimethyl-

ortoformate) in toluene in the presence of the H₂SO₄/SiO₂system.

7352 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

epimerization was instead observed at the stereocenters

of the tartaric acid moiety in aldehydes 58-62 during

the course of the oxidation reaction.

(Scheme 3). This compound was prepared according to a

reported procedure,¹¹starting from phenylacetaldehyde.

The condensation of 44 with tartaric acid derivative

(R,R)-43, performed by using PyBroP in the usual way,

afforded a 1:1 mixture of epimers 46 in 53% yield. These

epimers were not separable by FCC, and thus, the

mixture was subjected to different reaction conditions to

convert it into the final product. The usual method of

cyclization performed in boiling toluene with H₂SO₄/SiO₂

(1 equiv) for 20 min produced the desired product in very

low yield as a mixture of 4-exo/endo-phenyl diastero-

isomers 8 and 9, together with the partially cyclized

intermediate 47 and several decomposition products.

Intermediate 47 was isolated and submitted again to the

cyclization procedure for a further 10 min. In this way,

it was completely converted affording desired compounds

8 and 9 as a 4:1 exo/endo diastereoisomeric mixture (12%

yield). This result suggested that the large amount of

decomposition products could arise from the instability

of starting amides 46 more than that of 47 or the final

products. Thus, heating the mixture of amides 46 under

less drastic conditions [i.e., boiling benzene and in the

presence of the SiO₂/H₂SO₄(1 equiv) system for 20 min]

gave a mixture of the final compounds (as a 2:1 exo/endo

mixture in 75% yield), in a 6:1 ratio with 47. Finally,

using a 2-fold amount of SiO₂/H₂SO₄, the conversion of

46 to 8/9 was complete in boiling benzene after 20 min,

although affording the final product as a 1:1 exo/endo

mixture. In conclusion, from this set of experiments it

was clear that the kinetic enrichment into the 4-exo

compound 8 could be achieved only by decreasing the

conversion. Unfortunately, all attempts to separate the

epimeric mixture 46 or final products 8/9 by FCC failed.

Compound 8 was thus characterized as a 4:1 mixture

with its epimer 9.

The reaction sequence depicted in Scheme 3 was then

applied to the synthesis of two 7-endo compounds, i.e.,

7-endo-Bn-BTf(O)-OMe 11 and 7-endo-Bn-BtA(O)-OMe

12, derived from the initial condensation of racemic

(RS,SR) methyl hydrogen 2,3-di-O-isopropylidenetartrate

[(()-(R,S)-63] with (R)-N-benzyl-phenylalaninol 50 and

(S)-N-benzyl-alaninol 51, respectively (Scheme 4). The

partial hydrolysis of dimethyl meso-2,3-di-O-isopropy-

lidenetartrate was achieved by treatment with 1 equiv

of LiOH in MeOH/H₂O for 30 min at 0 °C. Under these

conditions, it was possible to limit significantly the extent

of epimerization to (R,R)- and (S,S)-43, although the

conversion was not complete. Pure (()-(R,S)-63 (48%

yield) was extracted with dichloromethane when the pH

of the reaction mixture was adjusted to 4. The use of

KOH as a base, under the conditions reported for the

monohydrolysis of dimethyl (R,R)-2,3-di-O-isopropylidene-

tartrate,¹²produced a complex reaction mixture contain-

ing to a large extent products of epimerization. The

condensation of (()-(R,S)-63 with amino alcohol 50

afforded a 1:1 mixture of diasteroisomers 64 (92%) having

the opposite configurations of the tartaric moiety stereo-

centers. This mixture was not separable, and thus, it was

transformed directly into the two corresponding dia-

steromeric aldehydes by Swern oxidation. One of the two

aldehydes in part decomposed during the chromato-

graphic separation, so that only epimer 66 (29%) was

At this point, the cyclization of the aldehydes to give

final compounds 3-7 was performed by using the H₂SO₄/

SiO₂system in refluxing toluene (or benzene in the case

of 61 and 62) and removing one-third of the solvent by

distillation. To obtain complete conversion, it was neces-

sary to reflux the reaction mixtures for at least 20 min

before distilling off the solvent, i.e., longer than in the

case of the synthesis of Bzl-BTG(O)-OMe 1. Interestingly,

when the side chain in the final product BTAa(O) was

in the 4-endo position, a longer reaction time was

necessary for a complete cyclization in comparison with

that required for the corresponding 4-exo-BTAa.

All the R-BTAa(O)-OMe, once formed, were stable

under the cyclization conditions because no epimerization

of the sterocenters at C-4 and/or C-7 was observed either

by prolonging the reaction time or by reheating the

compounds in refluxing toluene containing H₂SO₄/SiO₂.

A certain degree of epimerization was, however, observed

during the cyclization of aldehyde 61 (derived from

natural alanine), since compound 6 was obtained as a

3:1 mixture with its epimer 7 (separable by chromatog-

raphy). The cyclization of 61, however, took place without

epimerization when it was carried out in benzene.

Epimerization also occurred to a similar extent (20%)

when performing the reaction on 62, but once again it

was avoided by carrying out the reaction in benzene.

The observation that the formation of 4-endo com-

pounds was slower in comparison with that of the

corresponding 4-exo derivatives suggested the possibility

of realizing a kinetic enrichment of the 4-exo diastereo-

isomer Bn-BTF(O)-OMe 4 starting from a 1:1 epimeric

mixture of the two aldehydes 59 and 60 obtained from

racemic Phe as described above. In fact, while under the

usual cyclization conditions a 1:1 mixture of 4 and 5 was

obtained starting from a 1:1 mixture of 59 and 60,

reducing the reaction time (and so the conversion) or

increasing the amount of H₂SO₄/SiO₂provided an in-

crease of the 4/5 ratio up to 5:1 under the best conditions

found. However, owing to the difficulties in achieving a

complete separation of diasteroisomers 4 and 5 by

chromatography, this method does not appear to be of

synthetic utility. More convenient should be the separa-

tion by FCC of epimeric aldehydes prepared from racemic

amino acids, followed by the cyclization of the separated

aldehydes to obtain pure compounds BTAa(O). This goal

was achieved with the 1:1 mixture of the two epimeric

aldehydes 59 and 60 (from racemic Phe), which were

separated by chromatography in good yield (36 and 38%,

respectively) and cyclized to the corresponding BTF(O)

and BTf(O). In the condensation of the racemic N-

benzylphenylalaninol (49 + 50) with tartaric acid deriva-

tive (R,R)-43, no diastereoselectivity was observed in the

formation of 54 and 55.

The approach just described for the synthesis of BTAa-

(O) could be also very useful in the case of unnatural

amino acid precursors, which are usually prepared in

racemic form.

To test this hypothesis, we realized the synthesis of

enantiopure methyl (1R,4S,5S,7R)- and (1R,4R,5S,7R)-

3-aza-2-oxo-4-phenyl-6,8-dioxabicyclo[3.2.1]octane-7-car-

boxylates (8 and 9, respectively) through the use of the

dimethyl acetal of N-benzyl-R-phenylglycine aldehyde 44

(11) Boon, W. R. J . Chem. Soc. 1957, 2146-2158.

(12) Musich, J . A.; Rapoport, H. J . Am. Chem. Soc. 1978, 100, 4865-

4872.

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7353

Sch em e 4^a

Sch em e 5^a

a

Key: (a) PyBrOP, DIPEA, CH₂Cl₂, 12 h, 25 °C; (b) Swern

oxidation; (c) H₂SO₄/SiO₂, benzene, reflux, 20 min, then distillation

of one-third of the solvent.

recovered in pure form. This aldehyde was then treated

in the usual way with H₂SO₄/SiO₂in refluxing benzene,

affording pure 7-endo-Bn-BTf-OMe 11 in 23% overall

yield and without any epimerization. With the same

methodology we prepared 7-endo compound 12. After

oxidation of amido alcohol 65 (Scheme 4) to the 1:1

mixture of corresponding aldehydes, an attempt at

separating the two diastereoisomers by chromatography

afforded aldehyde 67 as a 3:1 mixture with its epimer

68. Also, in this case one of the two aldehydes decom-

posed to a certain extent. After cyclization in benzene of

the mixture and chromatography of the crude, 12 was

obtained in 70% yield as a 5:1 mixture in which the major

isomer had the 4-methyl in the endo position [7-endo-

Bn-BtA(O)-OMe]. The assignment of the endo position

for the 4-substituent in 11 and 12 will be discussed later.

Rea ctivity of BTAa (O) a n d Tr a n sfor m a tion in to

BTAa . Several reactions were carried out to test the

stability of R-BTAa(O)-OMe derivatives or transform

them into compounds suitable for peptide synthesis such

as N-Fmoc-protected amino acids or amino esters (Scheme

5). In particular, although the stability of the acetal

bridge has been already demonstrated by Vogel during

the transformations of the carbomethoxy into the corre-

sponding carboxylic or amide group,⁵the stability under

the conditions required for transformation into amino

acids or amino esters had yet to be assessed.

a

Key: (a) LiAlH₄, THF, reflux, 2 h; (b) H₂, Pd(OH)₂/C, MeOH,

12 h; (c) CAN, CH₃CN, H₂O, 5 h, 25 °C; (d) 1 M NaOH, 3 h, then

2 M HCl; (e) BH₃‚Me₂S, THF, reflux, 40 min, then TMEDA, Et₂O,

15 min; (f) 4 N HCl, 18 h; (g) KOH, MeOH, 3 h, then 5 N HCl; (h)

Fmoc-O-Su, CH₂Cl₂, 0 °C, 10 min, then 25 °C, 24 h; (i) 4 N HCl,

DMSO, 1-3 d, 25 °C; (j) Fmoc-O-Su, acetone, H₂O, Na₂CO₃, 0 °C,

then 25 °C, 12 h; (l) PDC, DMF, 24 h.

only by oxidation with CAN (cerium ammonium nitrate)¹³

when R was MPM (4-methoxybenzyl), i.e., on compounds

The conversion of R-BTAa(O)-OMe into H-BTAa(O)-

OMe by removal of the N-protecting group was feasible

(13) Yamamura, M.; Suzuky, T.; Hashimoto, H.; Yoshimura, J .;

Okamoto, T. Bull. Chem. Soc. J pn. 1985, 58, 1413-1420.

7354 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

2-3, affording amido esters 13-14 in 72-85% yield.

Instead, when the protecting group was the benzyl (in

1), the deprotection attempted by hydrogenation over

Pd(OH)₂/C failed to give the corresponding amido esters.

As already found by Vogel, the N-protected R-BTAa-

(O)-OMe derivatives were easily transformed into the

corresponding acids either under acid conditions with

aqueous 2 N HCl or basic conditions with KOH/MeOH.

However, N-deprotected amido esters 13-14 showed a

quite surprising reactivity: they were unstable both

under acid (1 N HCl) and basic conditions (aqueous

NaOH), undergoing a complete degradation of the bicyclic

skeleton. The same instability was observed when H-

BTAa(O)-OMe 13-14 were treated with strong bases

(such as NaH or n-BuLi) in attempting a possible

alkylation of the nitrogen or with LiAlH₄in order to

obtain the corresponding amino alcohols. This behavior

is clearly related to the presence of a secondary amide

because the corresponding N-protected amides R-BTAa-

(O)-OMe were stable under similar conditions. Indeed,

the reduction of R-BTAa(O)-OMe (R ) Bn, or MPM) with

LiAlH₄in THF at 0 °C afforded the corresponding amino

alcohols R-BTAa-CH₂OH 69-75 in fair to good yield

without decomposition or racemization. The N-deprotec-

tion of R-BTAa-CH₂OH was performed on N-benzyl

derivatives 69 and 75, affording amino alcohols 76 and

7-endo-77 quantitatively only by reduction with Pd-

(OH)₂/C in MeOH. On the contrary, the N-MPM pro-

tecting group in 70-71 was not removed by hydro-

genolysis, while CAN treatment decomposed the amino

alcohols.

Owing to the instability of the deprotected H-BTAa-

(O)-OMe, the selective reduction of the internal amide

bond was therefore carried out on Bn-BTAa(O)-OMe to

give the corresponding amino esters Bn-BTAa-OMe 16-

21, the two protections of BTAa being in this case

orthogonal. The reduction was carried with BH₃‚Me₂S

(BMS) in THF at reflux, followed by treatment with

TMEDA.¹⁴Bn-BTAa-OMe compounds were purified by

FCC, separating the amount of Bn-BTAa-CH₂OH often

present as byproduct. The precise control of the refluxing

time was a crucial point for limiting the formation of this

side product, albeit in all cases (with the reduction of 1

as an exception) it was impossible to avoid the formation

of ∼30% of the corresponding amino alcohol. The reduc-

tion of the amide function or the concomitant reduction

of the ester group did not lead to any epimerization of

the stereocenters.

group or by inverting this sequence. Thus, Bn-BTAa-OMe

16-18 and 21 (see Table 1) were quantitatively N-

deprotected with H₂and Pd(OH)₂/C in MeOH affording

the corresponding H-BTAa-OMe 22-25 (the same depro-

tection failed when the protecting group was MPM). Acid

or basic hydrolysis was then performed in particular on

amino ester 22 to give amino acid 28 in high yield as its

hydrochloride salt. The fully deprotected amino acid 28

was also prepared as its hydrochloride salt (96%) by acid

hydrolysis of the corresponding N-benzyl ester 16 to give

29 followed by debenzylation with H₂/Pd(OH)₂in MeOH

(100%). The N-Fmoc derivative 30 (84% yield) was finally

prepared by reaction of 28 with Fmoc-O-succinimide

(Fmoc-O-Su) and Na₂CO₃in acetone/water. Removal of

the solvent in vacuo allowed the recovery of Fmoc-BTG-

OH 30 sufficiently pure for the further coupling step.

As an alternative to the complete deprotection, the

amino esters H-BTAa-OMe can be protected as N-Fmoc

and then hydrolyzed by acidic treatment. Thus, Fmoc-

BTG-OMe 26, prepared by reaction of H-BTG-OMe 22

with Fmoc-O-Su in CH₂Cl₂, underwent hydrolysis of the

ester group by treatment with 4 N HCl in DMSO at room

temperature. However, the hydrolysis was slow (24 h)

and the yield (72%) lowered by the difficulty involved in

completely recovering the product from the solution, as

well as by the uncomplete conversion to Fmoc-BTG-OH.

With this strategy, Fmoc-BTF-OH 31 (66%) was prepared

as well. Also in this case, the hydrolysis of intermediate

27 was very slow (3 days) making this procedure not as

useful as the two previously described. Finally, as the

best methodology, we found that N-benzylamino alcohols

can be very productively employed for the conversion of

BTAa in N-Fmoc amino acids. This strategy also avoided

the use of BH₃‚DMS for the reduction of the amido esters

BTAa(O)-OMe to amino esters BTAa-OMe. Thus, protec-

tion of amino alcohols 76 and 77 (Scheme 5) as Fmoc

derivatives 78 (66%) and 79 (69%) was accomplished with

Fmoc-O-Su in CH₂Cl₂. Then, oxidation of alcohols 78 and

79 to carboxylic acids by PDC in DMF at room temper-

ature gave 30 and 32 in 89% and 91% yield, respectively.

P ep tid e Cou p lin g of BTAa . The compatibility of

these new dipeptide isosteres with the conditions re-

quired for peptide synthesis was not, in principle, obvi-

ous. Indeed, the peptide coupling reaction of a hindered

amino acid bearing a secondary amino group (as in

proline) is often difficult to realize, and the resistance of

BTAa’s to the acid (TFA) conditions required for the

cleavage of the peptide from the resin had to be ascer-

tained.

At this point we had in our hands six different

orthogonally protected BTAa amino acids (16-21). They

were stable under quite different conditions, either when

protected as N-benzyl and esters or when one or both the

functionalities were deprotected. To verify the possibility

of inserting these amino acids into peptides by using

solid-phase peptide synthesis, we evaluated four different

strategies (Scheme 5) to transform them in N-Fmoc-

protected amino acids (Fmoc-BTA-OH), usually employed

in peptide synthesis. In particular, we prepared three

different N-Fmoc amino acids, i.e., Fmoc-BTG-OH 30,

Fmoc-BTF-OH 31, and 7-endo-Fmoc-BtA-OH 32.

To verify the possible use of BTAa in peptide synthesis,

we synthesized the dipeptide BTG-ProOH 80 on a Wang-

type resin (Scheme 6).

H-Pro-{Wang resin} suspended in DMF was treated

during 4 days with a 2-fold excess of Fmoc-BTG-OH in

the presence of N,N′-diisopropylcarbodiimide (DIPCDI),

1-hydroxybenzotriazole (HOBt), and DIPEA. The dipep-

tide Fmoc-BTG-Pro-OH 80 (76%) was then cleaved from

the resin by treatment with TFA/H₂O (95:5) for 4 h. The

HPLC analysis showed a single peak, and FAB-MS was

in agreement with the molecular weight.

Str u ctu r e Assign m en t an d Con for m ation al An aly-

sis. The attribution of the correct stereochemistry to

R-BTAa(O)-OMe and R-BTAa-OMe (Figure 1) is possible

The first two methods included the complete depro-

tection of Bn-BTAa-OMe to free amino acids, either by

initial debenzylation followed by hydrolysis of the ester

1

by H NMR spectroscopy. Amides 1-9, having a 7-exo-

carbomethoxy group, are characterized by the presence

(14) Brown, H. C.; Choi, Y. M.; Narasimhan, S. J . Org. Chem. 1982,

47, 3153-3163.

in their ¹H NMR spectrum of three diagnostic signals,

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7355

Sch em e 6^a

constants between 1-H and the two protons on C-2 would

be very different from those found experimentally, since

at least one of them is about 9 Hz (and the other about

4 Hz). On the other hand, in the chairlike conformation,

the dihedral angles between protons on C-1 and C-2 (and

C-5 and C-4) are very close to 60°, thus accounting for

the very low coupling constants observed. The repulsion

between the N-3 and O-8 lone pairs in the boatlike

conformation should greatly contribute to the high strain

energy of this conformation for amines 16-21 which

should, therefore, be considered as conformationally

biased.

Both the introduction of an N-Fmoc protecting group

and the formation of an amide bond with the 7-carboxy

group cause an increase of the complexity of the ¹H NMR

spectra. This is due to the occurrence in solution of

isomers generated by hindered rotation about the Ns

a

Key: (a) DMF, diisopropylcarbodiimide, HOBt, DIPEA, 4 days,

then Ac₂O, DMF, DMAP, 3 h; (b) TFA, H₂O, 4 h.

1

CdO bonds. Thus, in the H NMR spectrum of 26, the

signals attributable to the protons on C-2 and C-4 are

split and it is possible to calculate a 1:1 ratio between

the two rotamers. Moreover, while in the ¹H NMR

spectrum of Fmoc-BTG-OMe 26 proton 5-H is a singlet,

in the spectrum of Fmoc-BTG-Pro 80 the signal of the

same proton is split in two singlets at 5.65 and 5.61 ppm

(the ratio between the areas is 2:1), apparently under-

going the field effects of two different conformations

assumed by the newly introduced proline residue. It is

known in fact that proline amides display an equal

tendency to assume both the cis- and trans-amide con-

formations.¹⁶

Since the aim of the present work is to prepare a novel

class of constrained dipeptide isosteres, it would also be

important to evaluate, once a BTAa isostere has been

introduced in a peptide, how the byciclic structure could

affect the orientation of the peptide chains at N-3 and

C-7. With this in mind, we performed a complete confor-

mational analysis on simple 7-exo and 7-endo model

compounds shown in Figure 3 in which an N-acetyl group

should mimic the first peptide bond and the C-7′-NHMe

bond the linkage of the acid moiety of the BTAa with a

second peptide. This analysis resulted in the observation

that, in both 7-endo and 7-exo models, only one orienta-

tion is favored (by ∼7 kcal/mol) for the amide group at

C-7, since an apparently strong H bond (d ≈ 2.1 Å)

formed between O-6 and N-H forces the CdO group to

assume an antiperiplanar orientation with respect to

the C-7-O-6 bond (dihedral angle Φ₁≈ (175°). Thus,

the presence of O-6 in BTAa is an important factor

that could govern the initial orientation of the peptide

chain at C-7. In the case of the 7-exo models, the

formation of an H bond with O-8 is also possible but the

corresponding conformation always collapsed to the

one showed in Figure 3 when minimized. Concerning

the substitution at N-3, the two conformations with the

CdO group eclipsed or antiperiplanar to the N-3-C-2

bond (Φ₂about 0 and -180°) were equally populated.

Only in the case of the 4-endo-substituted compounds

was the latter orientation favored (by 1.1 kcal/mol), due

to a greater steric hindrance between the methyl group

attributable to the bridgehead protons 1-H and 5-H

(equatorially orientated) and 7-H. 1-H and 7-H always

resonate as singlets in the 4.67 and 5.10 ppm range. In

1

the H NMR spectrum of compounds (()-10 and 11-12,

bearing a 7-endo-carbomethoxy group, the occurrence of

a coupling between 1-H and 7-H (J ≈ 5.1 Hz) is diagnostic

of the configurational change at the C-7. In all cases, the

more deshielded proton is 5-H, which resonates in the

5.17-5.87 ppm range and can be a singlet or doublet

depending on the stereochemistry at C-4. Thus, in the

4-exo-substituted amido esters 3, 4, 6, 8, and 14, 5-H

resonates always as a singlet, while in the 4-endo-

substituted amides 5, 7, 9, 11, and 12, it is a doublet,

having a small coupling constant (1.8-2.6 Hz) with the

exo proton on C-4. This coupling is diagnostic for 4-endo-

substituted compounds and is always visible for the exo-

4-H protons. The coupling between 5-H and exo-4-H is

also visible in the spectrum of Bn-BTG(O)-OMe 1 and

H-BTG(O)-OMe 13, wherein 5-H resonates as a doublet

at 5.85 (J ) 2.2 Hz) and 5.87 (J ) 1.8 Hz) ppm,

respectively.

N-Benzylamines 16-21 possess the same pattern of

¹H NMR signals as the corresponding amides, although

the 1-H proton undergoes an upfield shift and always

resonates as a broad singlet (or a doublet in the case of

(()-21 due to the endo stereochemistry of the COOMe

group) in the range 4.47-4.61 ppm. The coupling con-

stants of 1-H with the protons on C-2 and C-7 are in fact

very small (0-1.8 Hz) in compounds 16-20 and not

detectable at 200 MHz. Similarly, values of coupling

constants close to 0 Hz between 5-H and either endo- or

exo-4-H make the bridgehead 5-H proton appearing as a

singlet between 5.25 and 5.62 ppm. The only exception

is the 4-exo-methyl derivative 19, in which 5-H is a

doublet (J ) 1.8 Hz) at 5.37 ppm because of the coupling

with endo-4-H. In the case of amines 16-21, the occur-

1

rence of 5-H as a doublet in the H NMR spectrum is not

indicative of the presence a 4-endo substituent. The same

considerations apply in secondary amines 22-25 and 28.

In the amines, the six-membered ring should have a

chairlike conformation, as suggested by the very low

coupling constants of protons 1-H and 5-H with the

vicinal protons on C-2 and C-4, respectively. By molecular

modeling¹⁵of amine 16 it was found that the chairlike

conformation of the six-membered ring is thermodynami-

cally favored (by ∼6 kcal/mol) with respect to the boatlike

one. In the latter conformation, the calculated coupling

(15) MacroModel (v4.5) molecular modeling software was used for

the molecular mechanics calculations (Amber force field) and Monte

Carlo conformational search using the default values of this software.

Mohamadi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton,

M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput.

Chem. 1990, 11, 440-467.

(16) Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36,

191-194.

7356 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

domimetic synthesis. The synthesis of peptides contain-

ing them is now in progress and the results of the

conformational and biological proprieties of the modified

peptides will be reported in due course.

Exp er im en ta l Section

Melting points are uncorrected. Chromatographic separa-

tions were performed under pressure on silica gel using flash-

column techniques; R_fvalues refer to TLC carried out on 25-

mm silica gel plates (Merck F254), with the same eluant

indicated for column chromatography. ¹H and ¹³C NMR spectra

were recorded at 200 and 50.33 MHz, respectively, unless

otherwise stated. EI mass spectra were carried out at 70 eV

ionizing voltage. THF was distilled from Na/benzophenone.

CH₂Cl₂was distilled from CaH₂. All reactions requiring

anhydrous conditions were performed in flame-dried glass-

ware. Compounds 33-34, 44,^7,11(R,R)- and (S,S)-43,¹²and 48-

52^18-21were prepared as reported. Acid silica gel (H₂SO₄/SiO₂)

was prepared as reported.⁴Resin WANG-Pro-FMOC was

purchased from Advanced Chemtech. HPLC analysis of com-

pound 80 was performed with a RP18 5 µm column, using CH₃-

CN-H₂O as eluant.

F igu r e 3. Left: lowest energy conformer of 7-exo model

compound Ac-BTx-NHMe. Right: lowest energy conformer of

7-endo model compound Ac-Btx-NHMe. Dihedral angles Φ₁)

O-6-C-7-C-7′dO, Φ₂) C-2-N-3-C-3′dO.

(2R,6R/S)-(+)-(4-Ben zyl-6-m eth oxy-3-oxom or p h olin -2-

yl)-(R)-h yd r oxya cetic Acid Meth yl Ester (38). To a solu-

tion of anhydride 35 (8.4 g, 38.9 mmol) in dry CH₂Cl₂(100

mL) was added, under nitrogen atmosphere, 33 (8.0 g, 41.0

mmol) and the mixture stirred at room temperature for 60 min.

After evaporation of the solvent, the crude product was

dissolved in methanol (135 mL), thionyl chloride (2.7 mL, 37.0

mmol) was added dropwise, and the mixture was heated at

50 °C for 2 h. The solvent was then removed, and the crude

product was purified by chromatography (EtOAc-petroleum

ether, 1:2, R_f0.05) to give 38 (11.0 g, 87%) as a dark oil. The

same compound was obtained as a 1:1 mixture with 1 after

45 (200 mg, 0.52 mmol) was heated in a refluxing suspension

of H₂SO₄/SiO₂(105 mg) in toluene (32 mL) for 10 min. The

two products were separated by chromatography (EtOAc-

and the 4-endo substituent. These observations suggest

an important difference between 7-endo- and 7-exo-

BTA: the first class of compounds could be introduced

into a peptide to induce â-turnlike folding, since the

distance between atoms C-3′′ and C-7′′ is ∼3.9 Å, i.e.,

much lower than the maximum distance of 7 Å between

the corresponding atoms in a peptide required for the

formation of a â-turn.¹⁷7-exo-BTA, on the other hand,

should maintain a more planar and extended structure.

Experiments aimed at confirming these hypotheses are

now in progress.

petroleum ether, 1:2) obtaining pure 38 (80 mg) in 40% yield

Con clu sion s

1

as a 5:1 mixure of epimers: [R]²⁰+97.1 (c 0.38, CHCl₃); H

D

NMR (CDCl₃) δ 7.35-7.10 (m, 5 H), 4.92 (s, 1 H), 4.83 (s, 1

H), 4.79 (d, J ) 14.7 Hz, 1 H), 4.60 (s, 1 H), 4.47 (d, J ) 14.7

Hz, 1 H), 3.82 (s, 3 H), 3.50 (dd, J ) 12.4, 3.3 Hz, 1 H), 3.35 (s,

3 H), 3.08 (d, J ) 12.4 Hz, 1 H); ¹³C NMR (CDCl₃) δ 172.1 (s),

165.5 (s), 135.6 (s), 128.8 (d, 2 C), 127.9 (d, 2 C), 127.7 (d),

94.9 (d), 72.1 (d), 71.5 (d), 55.0 (q), 52.8 (q), 49.8 (t), 49.3 (t);

MS m/z 309 (M⁺, 6), 91 (100); IR (CDCl₃) 3547 (br), 1743, 1655

cm^-1. Anal. Calcd for C₁₅H₁₉NO₆: C, 58.25; H, 6.19; N, 4.53.

Found: C, 58.30; H, 6.00; N, 4.22.

Employing R-amino acid and tartaric acid derivatives,

we have developed a simple and straightforward method

for synthesizing novel potential dipeptide isosteres con-

taining the 3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxy-

lic acid structure. We found, as key features, that

complete control of all the stereocenters is possible by

appropriate choice of the starting precursors; the syn-

thesis can be applied to natural, unnatural, and unusual

amino acids, as well as to chiral or meso-tartaric acids,

also in racemic form, and allows the preparation of single

diastereoisomers either by separation of the intermedi-

ates or by kinetic enrichment during the cyclization

process. Despite the presence of the acetal moiety, the

skeleton of BTAa compounds is stable under different

reactions conditions, allowing a large number of synthetic

transformations, including oxidation, reduction, protec-

tion, and deprotection of the functionalities. The Fmoc-

protected amino acids (Fmoc-BTAa-OH) can be coupled

to other amino acids bound to a resin, and the resulting

peptide can be recovered without modifications of the

BTAa skeleton by the usual methods of solid-phase

peptide synthesis. Finally, the possibility of choosing the

orientation of the 7-carboxy group could allow the selec-

tion of a particular orientation of the peptide chains if

BTAa are introduced into peptides. All the features above

summarized indicate that BTAa could represent a novel

class of dipeptide isosteres potentially useful for pepti-

(2R,6R/S)-(+)-(6-Meth oxy-4-p-m eth oxyben zyl-3-oxom or -

p h olin -2-yl)-(R)-h yd r oxya cetic Acid Meth yl Ester (39).

Compound 39 was prepared according to the procedure for 38

from 35 (10 g, 47 mmol) and 34 (14 g, 55.3 mmol). The crude

product was purified by chromatography (EtOAc-petroleum

ether, 1:1, R_f0.1) to give 39 (13.0 g, 81%) as a red solid: mp

110 °C; [R]²⁰+124.5 (c 1.45, CHCl₃); ¹H NMR (CDCl₃) δ 7.20

D

(d, J ) 9.0 Hz, 2 H), 6.55 (d, J ) 9 Hz, 2 H), 4.83 (d, J ) 1.9

Hz, 1 H), 4.73 (d, J ) 2.5 Hz, 1 H), 4.60 (d, J ) 15 Hz, 1 H),

4.50 (d, J ) 1.9 Hz, 1 H), 4.30 (d, J ) 15 Hz, 1 H), 3.81 (s, 1

H), 3.68 (s, 3 H), 3.63 (s, 3 H), 3.38 (dd, J ) 12.5, 2.5 Hz, 1 H),

3.23 (s, 3 H), 2.96 (d, J ) 12.5 Hz, 1 H); ¹³C NMR (CDCl₃) δ

172.1 (s), 165.0 (s), 158.6 (s), 128.8 (d, 2 C), 127.2 (s), 113.6 (d,

2 C), 94.4 (d), 72.0 (d), 71.1 (d), 54.7 (q), 54.5 (q), 52.1 (q), 48.6

(t, 2 C); MS m/z 339 (M⁺, 2), 121 (100); IR (CDCl₃) 3450, 1752,

1673 cm^-1. Anal. Calcd for C₁₆H₂₁NO₇: C, 56.63; H, 6.24; N,

4.13. Found: C, 56.74; H, 6.25; N, 4.00.

m eso-2,3-Di-O-a cet ylt a r t a r ic An h yd r id e (40). Com-

pound 40 was prepared according to the procedure reported

(18) Hunt, J . H.; McHale, D. J . Chem. Soc. 1957, 2073-2077.

(19) Pfister, J . R. Synthesis 1984, 11, 969-970.

(20) Stoll, A.; Peyer, J .; Hofmann, A. Helv. Chim. Acta 1943, 26,

929-943.

(17) Ball, J . B.; Hughes, R. A.; Alewood, P. F.; Andrews, P. R.

Tetrahedron 1993, 49, 3467-3478.

(21) White, G. J .; Garst, M. E. J . Org. Chem. 1991, 56, 3177-3178.

Synthesis and Reactivity of Bicycles Derived from BTAa

for the preparation of 35, by adding, under nitrogen

atmosphere, meso-tartaric acid (5.0 g, 33.3 mmol) to a solution

of acetic anhydride (10.5 mL, 0.111 mol) and of 37% HCl (0.3

mL). Distillation of the formed acetic acid afforded 40 (3.70 g,

51%) as a dark oil that was immediately used in the next step

without further purification: ¹H NMR (CDCl₃) δ 5.50 (s, 2 H),

2.18 (s, 6 H); ¹³C NMR (CDCl₃) δ 169.4 (s, 2 C), 165.3 (s, 2 C),

65.9 (d, 2 C), 19.5 (q, 2 C).

(()-(R,S)-2,3-Di-O-isop r op ylid en eta r ta r ic Acid Mon o-

m eth yl Ester [(()-(R,S)-63]. LiOH‚H₂O (0.56 g, 13.3 mmol)

was slowly added to a stirring solution of meso-2,3-di-O-

isopropylidenetartaric acid dimethyl ester (2.65 g, 12.1 mmol)

in MeOH (80 mL) and water (27 mL) cooled at 0 °C. After 30

min at 0 °C, the MeOH was evaporated, and further water

(30 mL) was added to the residual suspension. After a first

extraction with Et₂O, the pH of the aqueous phase was

adjusted to 3.5 with 5% HCl and extracted with Et₂O and then

CH₂Cl₂. The combined organic phases were dried over Na₂-

SO₄and concentrated, affording (()-(R,S)-63 (1.18 g, 48%) as

a colorless oil: ¹H NMR (CDCl₃) δ 4.86 (AB system, J ) 7.3

Hz, 2 H), 3.76 (s, 3 H), 1.65 (s, 3 H), 1.42 (s, 3 H); ¹³C NMR

(CDCl₃) δ 172.3 (s), 168.5 (s), 113.3 (s), 76.3 (d), 75.8 (d), 52.6

(q), 26.5 (q), 25.6 (q).

J . Org. Chem., Vol. 64, No. 20, 1999 7357

a

(CDCl₃) (2:1 mixture of rotamers) major rotamer δ 7.35-7.00

(m, 8 H), 6.85 (m, 2 H), 5.29 (d, J ) 6.2 Hz, 1 H), 4.88 (d, J )

6.2 Hz, 1 H), 4.68 (d, J ) 16.5 Hz, 1 H), 3.99 (d, J ) 16.5 Hz,

1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.65 (m, 2 H), 3.50 (m, 1 H),

3.05 (m, 2 H), 1.54 (s, 3 H), 1.44 (s, 3 H); minor rotamer δ

7.35-7.20 (m, 8 H), 6.85 (m, 2 H), 5.43 (d, J ) 5.4 Hz, 1 H),

5.17 (d, J ) 5.4 Hz, 1 H), 4.82 (d, J ) 15.4 Hz, 1 H), 4.44 (d,

J ) 15.4 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 2.92 (dd, J )

14.0, 5.1 Hz, 1 H), 2.72 (dd, J ) 14.0, 9.2 Hz, 1 H), 1.54 (s, 3

H), 1.44 (s, 3 H); ¹³C NMR (CDCl₃) major rotamer δ 170.7 (s),

169.3 (s), 159.3 (s), 138.3 (s), 129.3 (d, 2 C), 129.0 (s), 128.6 (d,

2 C), 128.5 (d, 2 C), 126.5 (d), 114.3 (d, 2 C), 113.1 (s), 76.8 (d),

76.3 (d), 64.3 (d), 63.7 (t), 55.3 (q), 52.7 (q), 52.2 (t), 34.1 (t),

26.4 (s), 26.1 (s). Anal. Calcd for C₂₅H₃₁NO₇: C, 65.63; H, 6.83;

N, 3.06. Found: C, 65.48; H, 6.90; N, 2.98.

N-Ben zyl-N′-[(1S)-1-b en zyl-2-h yd r oxyet h yl]-(2R,3R)-

2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl Ester (54).

Prepared according to the procedure reported for 45, but the

reaction was left under stirring for 12 h. Starting from (R,R)-

43 (906 mg, 4.44 mmol) and 49 (1.07 g, 4.44 mmol), 54 was

obtained after chromatography (EtOAc-petroleum ether, 1:1,

R_f0.37) as a colorless oil (1.32 g, 69%): [R]²⁵-72.3 (c 0.6,

D

CHCl₃); ¹H NMR (CDCl₃) (2:1 mixture of rotamers) major

rotamer δ 7.40-7.05 (m, 10 H), 5.28 (d, J ) 6.0 Hz, 1 H), 4.81

(d, J ) 6.0 Hz, 1 H), 4.75 (d, J ) 16.4 Hz, 1 H), 4.00 (d, J )

16.4 Hz, 1 H), 3.79 (s, 3 H), 3.70 (m, 1 H), 3.60 (m, 1 H), 3.46

(m, 1 H), 3.04 (m, 2 H), 1.52 (s, 3 H), 1.49 (s, 3 H); minor

rotamer δ 7.40-7.05 (m, 10 H), 5.41 (d, J ) 5.5 Hz, 1 H), 5.13

(d, J ) 5.5 Hz, 1 H), 4.95 (d, J ) 15.2 Hz, 1 H), 4.42 (d, J )

15.2 Hz, 1 H), 3.79 (s, 3 H), 2.93 (dd, J ) 13.7, 5.0 Hz, 1 H),

(-)-N-Ben zyl-N′-(2,2-d im eth oxyeth yl)-(2R,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (45). To a

solution of 33 (669 mg, 3.43 mmol) in anhydrous CH₂Cl₂(3.5

mL) (CH₂Cl₂was filtered through a short pad of anhydrous

Na₂CO₃just before being used) were added, under a nitrogen

atmosphere, (R,R)-43 (700 mg, 3.43 mmol), PyBrOP (1.60 g,

3.43 mmol), and DIPEA (1.17 mL, 6.86 mmol). The mixture

was stirred at room temperature for 2 h, and then the solvent

was removed to give an oil that was dissolved in EtOAc. This

solution was washed with aqueous 5% KHSO₄, 5% NaHCO₃,

and brine and dried over Na₂SO₄. After evaporation of the

solvent, the crude product obtained was purified by chroma-

tography (EtOAc-petroleum ether, 1:3, R_f0.23), yielding 45

2.71 (dd, J ) 13.7, 8.9 Hz, 1 H), 1.52 (s, 3 H), 1.49 (s, 3 H); ¹³

C

NMR (CDCl₃) major rotamer δ 170.6 (s), 169.4 (s), 138.3 (s),

136.2 (s), 129.2 (d, 2 C), 129.0 (d, 2 C), 128.8 (d, 2 C), 127.9

(d), 127.3 (d, 2 C), 127.1 (d), 113.1 (s), 76.6 (d), 76.1 (d), 64.5

(d), 63.6 (t), 52.6 (t), 52.5 (q), 34.0 (t), 26.2 (q), 26.0 (q); MS

m/z 427 (M⁺, 1), 91 (100); IR (CDCl₃) 1730, 1642 cm^-1. Anal.

Calcd for C₂₄H₂₉NO₆: C, 67.43; H, 6.84; N, 3.28. Found: C

67.29; H 6.91; N, 3.12.

(1.038 g, 79%) as a colorless oil: [R]²⁵-30.9 (c 0.76, CHCl₃);

D

¹H NMR (CDCl₃) (1:1 mixture of rotamers) δ 7.40-7.10 (m, 5

H), 5.35 (d, J ) 5.5 Hz, 0.5 H), 5.33 (d, J ) 5.9 Hz, 0.5 H),

5.14 (d, J ) 5.9 Hz, 0.5 H), 4.94 (AB system, J ) 16.8 Hz, 0.5

H), 4.86 (d, J ) 5.5 Hz, 0.5 H), 4.84 (d, J ) 12.1 Hz, 0.5 H),

4.72 (AB system, J ) 16.8 Hz, 0.5 H), 4.58 (d, J ) 12.1 Hz, 0.5

H), 4.55 (m, 0.5 H), 4.35 (dd, J ) 6.9, 3.7 Hz, 0.5 H), 3.78 (s,

1.5 H), 3.75 (m, 0.5 H), 3.74 (s, 1.5 H), 3.59 (dd, J ) 13.6, 4.4

Hz, 0.5 H), 3.38 (s, 1.5 H), 3.36 (s, 1.5 H), 3.35 (m, 0.5 H), 3.34

(s, 1.5 H), 3.33 (s, 1.5 H), 3.21 (dd, J ) 13.6, 5.9 Hz, 0.5 H),

1.44 (m, 6 H); ¹³C NMR (CDCl₃) δ 170.9 (s), 170.8 (s), 168.9

(s), 168.5 (s), 137.0 (s), 136.4 (s), 128.7 (d, 2 C), 128.6 (d, 2 C),

128.0 (d, 2 C), 127.6 (d), 127.4 (d), 126.8 (d, 2 C), 113.0 (s),

112.9 (s), 103.0 (d), 102.9 (d), 76.1 (d, 2 C), 55.6 (q), 55.2 (q),

54.7 (q), 54.5 (q), 52.5 (q), 51.7 (q), 49.9 (t), 48.7 (t), 48.0 (t),

26.3 (q), 26.2 (q); MS m/z 381 (M⁺, 0.1), 75 (100); IR (CDCl₃)

1754, 1652. Anal. Calcd for C₁₉H₂₇NO₇: C, 59.83; H, 7.13; N,

3.67. Found: C, 59.82; H, 7.15; N, 3.83.

N-Ben zyl-N′-[(1R)-1-b en zyl-2-h yd r oxyet h yl]-(2R,3R)-

2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl Ester (55).

Prepared according to the procedure reported for 45, but the

reaction was left under stirring for 12 h. Starting from (R,R)-

43 (513 mg, 2.52 mmol) and 50 (608 mg, 2.52 mmol), 55 was

obtained after chromatography (EtOAc-petroleum ether, 1:1,

R_f0.38) as a colorless oil (675 mg, 63%): [R]²⁵+49.4 (c 0.5,

D

CHCl₃); ¹H NMR (CDCl₃) (2:1 mixture of rotamer) major

rotamer δ 7.40-7.05 (m, 10 H), 5.30 (d, J ) 5.8 Hz, 1 H), 4.80

(d, J ) 5.8 Hz, 1 H), 4.66 (d, J ) 16.1 Hz, 1 H), 3.93 (d, J )

16.1 Hz, 1 H), 3.80 (s, 3 H), 3.70-3.60 (m, 3 H), 3.05 (m, 2 H),

1.44 (s, 3 H), 1.41 (s, 3 H); ¹³C NMR (CDCl₃) major rotamer δ

170.6 (s), 169.5 (s), 138.5 (s), 136.2 (s), 129.2 (d, 2 C), 128.8 (d,

2 C), 128.6 (d, 2 C), 128.0 (d), 127.6 (d, 2 C), 127.4 (d), 113.2

(s), 76.7 (d), 76.2 (d), 63.1 (d), 61.3 (t), 52.6 (t), 52.5 (q), 33.9

(t), 26.3 (q), 26.1 (q); MS m/z 427 (M⁺, 4), 91 (100); IR (CDCl₃)

1730, 1642 cm^-1. Anal. Calcd for C₂₄H₂₉NO₆: C, 67.43; H, 6.84;

N, 3.28. Found: C, 67.11; H, 6.81; N, 3.02.

N-Ben zyl-N′-[(2,2-d im eth oxy)-1-p h en yleth yl]-(2R,3R)-

2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl Ester (46).

Prepared according to the procedure reported for 45. Starting

from 44 (0.865 g, 3.19 mmol) and (R,R)-43 (0.651 g, 3.19 mmol),

46 was obtained after chromatographic purification (EtOAc-

petroleum ether, 1:3, R_f0.20) as a 1:1 diastereomeric mixture

(0.774 g, 53%): ¹H NMR (CDCl₃) (each diastereoisomer as a

2:1 mixture of rotamers) δ 7.57-7.00 (m, 5 H), 5.62 (d, J )

8.8 Hz, 0.6 H), 5.45 (m, 1.2 H), 5.37 (d, J ) 5.9 Hz, 0.4 H),

5.29 (d, J ) 5.5 Hz, 0.4 H), 4.97 (d, J ) 7.3 Hz, 0.4 H), 4.84-

4.40 (m, 3 H), [3.82 (s), 3.74 (s), and 3.68 (s), 3 H], [3.40 (s),

3.30 (s), 3.23 (s), 3.17 (s), 3.14 (s), and 3.13 (s), 6 H], 1.60-

1.30 (m, 6 H); MS m/z 457 (M⁺, 0.2), 91 (100), 75 (100); IR

N-Ben zyl-N′-[(1S)-2-h yd r oxy-1-m et h ylet h yl]-(2R,3R)-

2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl Ester (56).

Prepared according to the procedure reported for 45, but the

reaction was left under stirring for 12 h. Starting from (R,R)-

43 (1.53 g, 7.5 mmol) and 51 (1.24 g, 7.5 mmol), 56 was

obtained after chromatography (Et₂O, R_f0.3) as a colorless oil

(2.025 g, 76%): [R]²⁰-21.9 (c 1, CHCl₃); ¹H NMR (CDCl₃)

D

(1:1 mixture of rotamers) δ 7.39-7.28 (m, 5 H), 5.43 (d, J )

5.4 Hz, 0.5 H), 5.33 (d, J ) 6.2 Hz, 0.5 H), 5.18 (d, J ) 5.4 Hz,

0.5 H), 4.90 (d, J ) 17.4 Hz, 1 H), 4.77 (d, J ) 14.6 Hz, 1 H),

4.75 (d, J ) 5.8 Hz, 0.5 H), 4.52 (d, J ) 17.4 Hz, 1 H), 4.39 (d,

J ) 14.6 Hz, 1 H), 4.00 (m, 0.5 H), 3.78 (s, 1.5 H), 3.74 (s, 1.5

H), 3.68 (m, 1 H), 3.47 (m, 1 H), 3.14 (m, 0.5 H), [1.49 (s) and

1.43 (s), 3 H], [1.45 (s) and 1.41 (s), 3 H], 1.17 (d, J ) 6.6 Hz,

1.5 H), 1.15 (d, 6.6 Hz, 1.5 H); ¹³C NMR (CDCl₃) δ 171.2 (s),

170.6 (s), 169.5 (s), 169.3 (s), 138.6 (s), 136.9 (s), 128.7 (d, 2

C), 128.5 (d, 2 C), 127.6 (d, 2 C), 126.9 (d, 2 C), 126.8 (d), 126.4

(d), 113.0 (s), 112.7 (s), 76.5 (d, 2 C), 76.1 (d), 76.0 (d), 64.9 (t),

63.8 (t), 55.8 (q, 2 C), 54.5 (d), 52.4 (d), 49.5 (t), 44.4 (t), 26.3

(CDCl₃) 1751, 1647 cm^-1

.

N-(p-Meth oxyben zyl)-N′-[(1S)-1-ben zyl-2-h ydr oxyeth yl]-

(2R,3R)-2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl

Ester (53). Prepared according to the procedure reported for

45, but the reaction was left under stirring for 12 h. Starting

from (R,R)-43 (268 mg, 1.32 mmol) and 48 (624 mg, 1.39

mmol), 53 was obtained after chromatography (EtOAc-

hexane,1:1, R_f0.41) as a colorless oil (565 mg, 87%): ¹H NMR

7358 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

(q), 26.2 (q), 26.1 (q), 26 (q), 15.4 (q), 13.5 (q); MS m/z 351 (M⁺,

(CDCl₃) 3631, 1745, 1642, cm^-1. Anal. Calcd for C₂₅H₂₉NO₇:

C, 65.92; H, 6.42; N, 3.07. Found: C, 66.0; H, 6.46; N, 2.98.

N-Ben zyl-N′-[(1S)-1-ben zyl-1-for m yl]-(2R,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (59). Pre-

pared as reported for 58. Starting from 54 (1.32 g, 3.09 mmol),

purification of the crude reaction mixture by chromatography

1), 91 (100); IR (CDCl₃) 1754, 1639 cm^-1. Anal. Calcd for C₁₈H₂₅

-

NO₆: C, 61.52; H, 7.17; N, 3.99. Found: C, 61.29; H, 7.05; N,

3.87.

N-Ben zyl-N′-[(1R)-2-h yd r oxy-1-m et h ylet h yl]-(2R,3R)-

2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl Ester (57).

Prepared according to the procedure reported for 45, but the

reaction was left under stirring for 12 h. Starting from (R,R)-

43 (682 mg, 3.34 mmol) and 52 (552 mg, 3.34 mmol), 57 was

obtained after chromatography (Et₂O, R_f0.3) as a colorless oil

(Et₂O-n-hexane, 1:1, R_f0.23) gave 59 (881 mg, 67%) as a

1

colorless oil: [R]²⁵-142.2 (c 0.26, CHCl₃); H NMR (CDCl₃)

D

δ 9.44 (s, 1 H), 7.40-7.00 (m, 10 H), 5.33 (d, J ) 6.2 Hz, 1 H),

4.92 (d, J ) 6.2 Hz, 1 H), 4.89 (d, J ) 18.7 Hz, 1 H), 3.79 (s,

3 H), 3.53 (dd, J ) 9.8, 4.3 Hz, 1 H), 3.44 (d, J ) 18.7 Hz, 1

H), 3.41 (dd, J ) 13.9, 4.3 Hz, 1 H), 3.12 (dd, J ) 13.9, 9.8 Hz,

1 H), 1.54 (s, 3 H), 1.45 (s, 3 H); ¹³C NMR (CDCl₃) δ 196.6 (d),

170.3 (s), 168.0 (s), 137.5 (s), 135.2 (s), 129.2 (d, 2 C), 128.8 (d,

2C), 128.6 (d, 2 C), 128.0 (d), 127.6 (d, 2C), 127.5 (d), 113.2 (s),

76.4 (d), 75.6 (d), 67.8 (d), 52.4 (t), 52.3 (q), 32.4 (t), 26.1 (q),

25.8 (q); MS m/z 425 (M⁺, 0.1), 91 (100); IR (CDCl₃) 3695, 1738,

1709, 1645 cm^-1. Anal. Calcd for C₂₄H₂₇NO₆: C, 67.75; H, 6.40;

N, 3.29. Found: C, 67.53; H, 6.31; N, 3.12.

(1.29 g, 92%): [R]²⁰-15.9 (c 1, CHCl₃); ¹H NMR (CDCl₃) (1:1

D

mixture of rotamers) δ 7.39-7.28 (m, 5 H), 5.38 (d, J ) 5.4

Hz, 0.5 H), 5.21 (d, J ) 6.2 Hz, 0.5 H), 5.00 (d, J ) 5.4 Hz, 0.5

H), 4.80-4.30 (m, 4.5 H), 4.05 (m, 0.5 H), 3.60-3.35 (m, 3 H),

[1.43 (s) and 1.37 (s), 3 H], [1.42 (s) and 1.41 (s), 3 H], 1.17 (d,

J ) 6.6 Hz, 1.5 H), 1.15 (d, 6.6 Hz, 1.5 H); ¹³C NMR (CDCl₃)

δ 170.6 (s, 2 C), 169.4 (s), 168.1 (s), 138.3 (s), 136.9 (s), 128.7

(d, 2 C), 128.4 (d, 2 C), 127.7 (d, 2 C), 126.9 (d, 2 C), 126.8 (d),

126.7 (d), 113.1 (s, 2 C), 76.3 (d, 2 C), 76.1 (d, 2 C), 64.8 (t),

64.1 (t), 56.0 (q, 2 C), 54.2 (d), 52.1 (d), 49.7 (t), 44.7 (t), 26.0

(q, 4 C), 15.9 (q), 13.8 (q); MS m/z 351 (M⁺, 1), 91 (100); IR

(CDCl₃) 1754, 1639 cm^-1. Anal. Calcd for C₁₈H₂₅NO₆: C, 61.52;

H, 7.17; N, 3.99. Found: C, 61.29; H, 7.05; N, 3.87.

N-Ben zyl-N′-[(1R)-1-ben zyl-1-for m yl]-(2R,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (60). Com-

pound 60 was prepared according to the procedure for 58.

Starting from 55 (677 mg, 1.58 mmol), the crude product was

purified by chromatography (Et₂O-n-hexane, 1:1, R_f0.32)

N-Ben zyl-N′-[(1R)-1-b en zyl-2-h yd r oxyet h yl]-(2R,3S)/

(2S,3R)-2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl

Ester (64). Prepared according to the procedure reported for

45, but the reaction was left under stirring for 12 h. Starting

from (()-(R,S)-63 (577 mg, 2.83 mmol) and 50 (682 mg, 2.83

mmol), 64 was obtained after chromatography (EtOAc-

petroleum ether, 1:1, R_f0.32) as a colorless oil (2.60 g, 92%).

¹H NMR (CDCl₃) (1:1 mixture of diastereoisomers) δ 7.47 (m,

10 H), 5.05 (d, J ) 6.6 Hz, 0.5 H), 5.03 (d, J ) 6.6 Hz, 0.5 H),

4.81 (d, J ) 6.6 Hz, 0.5 H), 4.78 (d, J ) 6.6 Hz, 0.5 H), 4.66 (d,

J ) 16.1 Hz, 0.5 H), 4.64 (d, J ) 16.7, 0.5 H), 4.25 (d, J ) 16.7

Hz, 0.5 H), 4.12 (d, J ) 16.1 Hz, 0.5 H), 3.85 (s, 3 H), 3.64 (m,

2 H), 3.46 (m, 2 H), 3.06-2.80 (m, 2 H), [1.59(s), 1.56 (s), 1.40

(s), and 1.36 (s), 6 H].

N-Ben zyl-N′-[(1S)-2-h yd r oxy-1-m et h ylet h yl]-(2R,3S)/

(2S,3R)-2,3-d i-O-isop r op ylid en eta r tr a m ic Acid Meth yl

Ester (65). Prepared according to the procedure reported for

45, but the reaction was left under stirring for 12 h. Starting

from (()-(R,S)-63 (2.26 g, 11.09 mmol) and 51 (1.83 g, 11.09

mmol), compound 65 (2.706 g, 69%) was obtained after

chromatography (EtOAc-petroleum ether, 2:1, R_f0.25) as a

yellow oil: ¹H NMR (CDCl₃) (1:1 mixture of diastereoisomer)

δ 7.40-7.15 (m, 5 H), 5.40 (d, J ) 6.6 Hz, 0.25 H), 5.23 (d, J

) 6.6 Hz, 0.25 H), 4.94 (d, J ) 7.0 Hz, 0.5 H), 4.82-4.40 (m,

3 H), 3.78 (s, 1.5 H), 3.76 (s, 1.5 H), 3.68-3.36 (m, 3 H), 1.57

(m, 6 H), 1.29 (d, J ) 7.0 Hz, 1.5 H), 1.11 (d, J ) 7.0 Hz, 1.5

H).

affording 60 (437 mg, 65%) as a yellow oil: [R]²⁵+125.9 (c

D

1

0.94, CHCl₃); H NMR (CDCl₃) δ 9.32 (s, 1 H), 7.40-7.00 (m,

10 H), 5.34 (dd, J ) 8.8, 4.4 Hz, 1 H), 4.90 (d, J ) 15.4 Hz, 1

H), 3.86 (s, 3 H), 3.36 (dd, J ) 13.9, 4.4 Hz, 1 H), 3.19 (d, J )

15.4 Hz, 1 H), 3.16 (dd, J ) 13.9, 8.8 Hz, 1 H), 1.49 (s, 3 H),

1.43 (s, 3 H); ¹³C NMR (CDCl₃) δ 196.9 (d), 170.6 (s), 168.2 (s),

137.7 (s), 135.5 (s), 129.5 (d, 2 C), 129.3 (d, 2 C), 128.8 (d, 2

C), 128.4 (d), 127.5 (d, 2 C), 127.0 (d), 113.5 (s), 76.1 (d), 75.8

(d), 67.0 (d), 53.4 (t), 52.3 (q), 32.7 (t), 26.3 (q), 26.1 (q); MS

m/z 425 (M⁺, 0.25), 91 (100); IR (CDCl₃) 3693, 1736, 1711, 1641

cm^-1. Anal. Calcd for C₂₄H₂₇NO₆: C, 67.75; H, 6.40; N, 3.29.

Found: C, 67.61; H, 6.74; N, 3.08.

N-Ben zyl-N′-[(1S)-1-for m yl-1-m eth yl]-(2R,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (61). Com-

pound 61 was prepared according to the procedure reported

for 58. Starting from 56 (936 mg, 2.67 mmol), after purification

of the crude reaction mixture by chromatography (Et₂O-

petroleum ether, 2:1, R_f0.39), 61 (839 mg, 90%) was obtained

as an oil: [R]²⁵-31.2 (c 1.0, CHCl₃); ¹H NMR (CDCl₃) δ 9.43

D

(s, 1 H), 7.36-7.31 (m, 5 H), 5.31 (d, J ) 6.0 Hz, 1 H), 5.04 (d,

J ) 16.4 Hz, 1 H), 4.93 (d, J ) 6.0 Hz, 1 H), 4.51 (d, J ) 16.4

Hz, 1 H), 3.76 (s, 3 H), 3.59 (q, J ) 7.0 Hz, 1 H), 1.43 (s, 3 H),

1.42 (s, 3 H), 1.30 (d, J ) 7.0 Hz, 3 H); ¹³C NMR (CDCl₃) δ

197.4 (d), 170.5 (s), 168.2 (s), 135.7 (s), 129.0 (d, 2 C), 128.3

(d), 127.2 (d, 2 C), 113.3 (s), 75.9 (d), 75.8 (d), 61.7 (q), 52.5

(d), 51.0 (t), 26.2 (q), 26.1 (q), 11.0 (q); MS m/z 349 (M⁺, 2), 91

N -(p -Me t h o x y b e n zy l)-N ′-[(1S )-1-b e n zy l-1-fo r m y l]-

(2R,3R)-2,3-d i-O-isop r op ylid en ta r tr a m ic Acid Meth yl Es-

ter (58). A solution of (COCl)₂(120 µL, 1.40 mmol) in 3 mL of

dry CH₂Cl₂was cooled to -60 °C under a nitrogen atmosphere,

and anhydrous DMSO (180 µL, 2.59 mmol) was added slowly

in order to keep the temperature constant. After 5 min, a

solution of 53 (565 mg, 1.23 mmol) in 4 mL of dry CH₂Cl₂was

added dropwise still mantaining the temperature at -60 °C.

The mixture was stirred for 15 min, DIPEA (1.07 mL, 6.27

mmol) was added and, after 10 min, the reaction mixture was

left to warm to room temperature, followed by addition of

water (10 mL). The organic phase was extracted with CH₂Cl₂

and dried over Na₂SO₄, and after evaporation of the solvent a

crude yellow oil was obtained. Purification by chromatography

(Et₂O-n-hexane, 1:1, R_f0.27) gave 58 (532 mg, 95%) as a

colorless oil: ¹H NMR (CDCl₃) δ 9.38 (s, 1 H), 7.27 (m, 2 H),

7.16 (m, 3 H), 6.99 (d, J ) 8.8 Hz, 2 H), 6.83 (d, J ) 8.8 Hz, 2

H), 5.33 (d, J ) 6.2 Hz, 1 H), 4.95 (d, J ) 6.2 Hz, 1 H), 4.81 (d,

J ) 16.1 Hz, 1 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 3.53 (dd, J ) 9.9,

4.3 Hz, 1 H), 3.39 (dd, J ) 12.8, 4.3 Hz, 1 H), 3.39 (d, J ) 16.1

Hz, 1 H), 3.08 (dd, J ) 12.8, 9.9 Hz, 1 H), 1.45 (s, 3 H), 1.39 (s,

3 H); ¹³C NMR (CDCl₃) δ 196.7 (d), 170.4 (s), 167.8 (s), 159.4

(s), 137.5 (s), 129.2 (d, 2 C), 129.0 (s), 128.7 (d, 2 C), 128.5 (d,

2 C), 127.0 (d), 114.3 (d, 2 C), 113.9 (s), 75.9 (d), 75.7 (d), 67.3

(d), 55.1 (q), 52.5 (t), 51.9 (q), 32.4 (t), 26.2 (q), 25.8 (q); IR

(100); IR (CDCl₃) 1739, 1644 cm^-1. Anal. Calcd for C₁₈H₂₃

-

NO₆: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.77; H, 6.29; N,

3.87.

N-Ben zyl-N′-[(1R)-1-for m yl-1-m eth yl]-(2R,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (62). Com-

pound 62 was prepared according to the procedure reported

for 58. Starting from 57 (1.175 g, 3.35 mmol), after purification

of the crude reaction mixture by chromatography (Et₂O-

petroleum ether, 2:1, R_f0.36), 62 (910 mg, 78%) was obtained

as an oil: [R]²⁵_D+22.0 (c 0.55, CHCl₃); ¹H NMR (CDCl₃) δ 9.38

(s, 1 H), 7.36-7.22 (m, 5 H), 5.28 (d, J ) 5.5 Hz, 1 H), 5.01 (d,

J ) 5.5 Hz, 1 H), 4.97 (d, J ) 15.8 Hz, 1 H), 4.56 (d, J ) 15.8

Hz, 1 H), 3.79 (s, 3 H), 3.53 (q, J ) 7.3 Hz, 1 H), 1.48 (s, 3 H),

1.44 (s, 3 H), 1.33 (d, J ) 7.3 Hz, 3 H); ¹³C NMR (CDCl₃) δ

197.2 (d), 170.6 (s), 168.2 (s), 135.7 (s), 128.9 (d, 2 C), 128.2

(d), 127.6 (d, 2 C), 113.3 (s), 76.0 (d), 75.8 (d), 61.5 (q), 52.6

(d), 51.3 (t), 26.2 (q), 26.0 (q), 11.1 (q); MS m/z 349 (M⁺, 2), 91

(100); IR (CDCl₃) 1739, 1647 cm^-1. Anal. Calcd for C₁₈H₂₃

-

NO₆: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.77; H, 6.29; N,

3.87.

N-Ben zyl-N′-[(1R)-1-ben zyl-1-for m yl]-(2S,3R)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (66). Starting

from the 1:1 diastereomeric mixture 64 (692 mg, 1.62 mmol),

the Swern oxidation was carried out as reported for 58. After

chromatography (Et₂O-petroleum ether, 2:1, R_f0.42), alde-

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7359

hyde 66 (200 mg, 29%) was obtained as a white solid. The other

mL of methanol, followed by the dropwise addition of thionyl

chloride (1.6 mL, 12.6 mmol). The reaction mixture was

allowed to react at 50 °C for 2 h, and after evaporation of the

solvent, the crude dark oil (42) was dissolved in toluene (30

mL) to give a solution that was quickly added to a refluxing

suspension of H₂SO₄/SiO₂(400 mg) in toluene (50 mL). After

15 min, one-third of the solvent was distilled off, the warm

solution was filtered through a short layer of NaHCO₃, and

the solvent evaporated to give a yellow oil. Purification by

chromatography (Et₂O, R_f0.46) gave (()-10 (870 mg, 18%) as

diastereoisomer in part decomposed during the purification

process obtaining only 66 in pure form. 66: mp 138.5 °C; [R]²⁵

D

1

+9.2 (c 0.22, CHCl₃); H NMR (CDCl₃) δ 9.28 (s, 1 H), 7.40-

7.00 (m, 10 H), 5.14 (d, J ) 6.3 Hz, 1 H), 4.91 (d, J ) 14.3 Hz,

1 H), 4.86 (d, J ) 6.3 Hz, 1 H), 3.83 (s, 3 H), 3.50-3.35 (m, 3

H), 3.30 (d, J ) 14.3 Hz, 1 H), 3.05 (dd, J ) 13.9, 9.9 Hz, 1 H),

1.59 (s, 3 H), 1.39 (s, 3 H); ¹³C NMR (CDCl₃) δ 196.9 (d), 169.4

(s), 168.3 (s), 138.2 (s), 135.5 (s), 129.3 (d, 2 C), 129.0 (d, 2 C),

128.9 (d, 2 C), 128.4 (d), 128.2 (d, 2 C), 126.9 (d), 113.2 (s),

76.2 (d), 75.4 (d), 67.0 (d), 52.6 (t), 52.5 (q), 32.6 (t), 27.0 (q),

25.8 (q); MS m/z 396 (M⁺-29, 10), 91 (100); IR (CDCl₃) 1731,

1649 cm^-1. Anal. Calcd for C₂₄H₂₇NO₆: C, 67.75; H, 6.40; N,

3.29. Found: C, 67.62; H, 6.24; N, 3.08.

1

a 7:1 mixture with (()-1: oil; H NMR (CDCl₃) δ 7.35-7.10

(m, 5 H), 5.70 (d, J ) 2.6 Hz, 1 H), 4.90 (d, J ) 5.2 Hz, 1 H),

4.60 (d, J ) 5.2 Hz, 1 H), 4.49 (AB system, J ) 15.1 Hz, 2 H),

3.73 (s, 3 H), 3.32 (dd, J ) 12.1, 2.6 Hz, 1 H), 3.20 (d, J ) 12.1

Hz, 1 H); ¹³C NMR (CDCl₃) δ 167.8 (s), 164.5 (s), 135.1 (s),

128.7 (d, 2 C), 128.3 (d, 2 C), 127.7 (d), 99.9 (d), 78.3 (d), 76.2

(d), 52.6 (t), 51.1 (q), 48.3 (t); MS m/z 277 (M⁺, 8), 91 (100); IR

N-Ben zyl-N′-[(1S)-1-m eth yl-1-for m yl]-(2R,3S)-2,3-d i-O-

isop r op ylid en eta r tr a m ic Acid Meth yl Ester (67). Starting

from the 1:1 diastereomeric mixture 65 (3.08 g, 8.76 mmol),

the Swern oxidation was carried out as reported for 58. After

chromatography (Et₂O-petroleum ether, 2:1, R_f0.23), alde-

hyde 67 (1.844 g, 60%) was obtained in a 3:1 mixture with its

diastereoisomer 68. The minor diastereoisomer partially de-

composed during the purification process: ¹H NMR (CDCl₃)

(major isomer 67) δ 9.38 (s, 1 H), 7.40-7.20 (m, 5 H), 5.12 (d,

J ) 6.6 Hz, 1 H), 4.90 (d, J ) 16.9 Hz, 1 H), 4.83 (d, J ) 6.6

Hz, 1 H), 4.49 (d, J ) 16.9 Hz, 1 H), 3.75 (s, 3 H), 3.50 (m, 1

H), 1.59 (s, 3 H), 1.37 (s, 3 H), 1.29 (d, J ) 6.6 Hz, 3 H).

Met h yl (1R,5S,7R)-3-Ben zyl-2-oxo-6,8-d ioxa -3-a za b i-

cyclo[3.2.1]octa n e-7-exo-ca r boxyla te (1). Meth od A. A

solution of 38 (11.0 g, 35.5 mmol) in toluene (60 mL) was

quickly added to a refluxing suspension of H₂SO₄/SiO₂(3.0 g)

in toluene (120 mL). The mixture was allowed to react for 15

min, and then one-third of the solvent was distilled off. The

hot reaction mixture was filtered through a short layer of

NaHCO₃, and after evaporation of the solvent, the crude

product was purified by chromatography (EtOAc-petroleum

ether, 1:2, R_f0.14), affording pure 1 as a white solid (5.6 g,

57%). Meth od B. A solution of 45 (1.038 g, 2.72 mmol) in

toluene (30 mL) was quickly added to a refluxing suspension

of H₂SO₄/SiO₂(500 mg) in toluene (60 mL). The mixture was

allowed to react for 15 min, and afterward, one-third of the

solvent was distilled off. The hot reaction mixture was filtered

through a short layer of NaHCO₃, and after evaporation of the

solvent, the crude product was purified by chromatography

(CDCl₃) 1760, 1672 cm^-1

.

Meth yl (1R,4S,5S,7R)-3-(p-Meth oxyben zyl)-2-oxo-4-exo-

ben zyl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e-7-exo-ca r box-

yla te (3). Prepared according to method B reported for the

synthesis of 1, but refluxed for 20 min before one-third of the

solvent was distilled off. Starting from 58 (532 mg, 1.17 mmol),

pure 3 (398 mg, 86%) was obtained after chromatography

(EtOAc-n-hexane, 1:3, R_f0.35) as a colorless oil: [R]²⁵_D-41.8

1

(c 2.16, CHCl₃); H NMR (CDCl₃) δ 7.40-7.00 (m, 7 H), 6.86

(d, J ) 8.8 Hz, 2 H), 5.49 (s, 1 H), 5.29 (d, J ) 15.1 Hz, 1 H),

4.94 (s, 1 H), 4.67 (s, 1 H), 3.95 (d, J ) 15.1 Hz, 1 H), 3.77 (s,

3 H), 3.72 (s, 3 H), 3.32 (dd, J ) 10.9, 4.0 Hz, 1 H), 3.17 (dd,

J ) 13.6, 4.0 Hz, 1 H), 2.75 (dd, J ) 13.6, 10.9 Hz, 1 H); ¹³C

NMR (CDCl₃) δ 169.0 (s), 165.5 (s), 159.2 (s), 135.8 (s), 129.1

(d, 2 C), 129.0 (d, 2 C), 128.9 (d, 2 C), 127.7 (s), 127.0 (d), 114.3

(d, 2 C), 101.1 (d), 77.9 (d), 77.5 (d), 60.3 (d), 55.2 (q), 52.6 (q),

45.2 (t), 36.1 (t); MS m/z 397 (M⁺, 9), 121 (100); IR (CDCl₃))

1754, 1664 cm^-1. Anal. Calcd for C₂₂H₂₃NO₆: C, 66.49; H, 5.83;

N, 3.52. Found: C, 66.58; H, 6.22; N, 3.23.

Meth yl (1R,4S,5S,7R)-3-Ben zyl-2-oxo-4-exo-ben zyl-6,8-

dioxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (4). Pre-

pared according to method B reported for the synthesis of 1,

but refluxed for 20 min before one-third of the solvent was

distilled off. Starting from 59 (881 mg, 2.07 mmol), pure 4 (631

mg, 83%) was obtained after chromatography (EtOAc-n-

hexane, 1:3, R_f0.31) as an oil: [R]²⁵-42.2 (c 1.0, CHCl₃); ¹H

D

as above affording pure 1 (686 mg, 91%): mp 82 °C; [R]²⁵

NMR (CDCl₃) δ 7.40-7.15 (m, 8 H), 7.03 (m, 2 H), 5.51 (s, 1

H), 5.33 (d, J ) 15.0 Hz, 1 H), 4.97 (s, 1 H), 4.71 (s, 1 H), 4.03

(d, J ) 15.0 Hz, 1 H), 3.75 (s, 3 H), 3.32 (dd, J ) 10.7, 3.7 Hz,

3 H), 3.15 (dd, J ) 13.5, 3.7 Hz, 1 H), 2.75 (dd, J ) 13.5, 10.7

Hz, 1 H); ¹³C NMR (CDCl₃) δ 169.1 (s), 165.8 (s), 137.9 (s),

135.9 (s), 129.3 (d, 2 C), 129.0 (d, 2C), 128.9 (d, 2 C), 128.8 (d,

2 C), 127.2 (d), 127.0 (d), 101.2 (d), 78.0 (d), 76.8 (d), 60.8 (d),

52.1 (q), 46.0 (t), 36.3 (t); MS m/z 367 (M⁺, 13), 91 (100); IR

(CDCl₃) 1758, 1666 cm^-1. Anal. Calcd for C₂₁H₂₁NO₅: C, 68.65;

H, 5.76; N, 3.81. Found: C, 69.02; H, 5.93; N, 3.67.

D

1

-48.6 (c 1.0, CHCl₃); H NMR (CDCl₃) δ 7.40-7.08 (m, 5 H),

5.85 (d, J ) 2.2 Hz, 1 H), 4.97 (s, 1 H), 4.75 (s, 1 H), 4.53 (s, 2

H), 3.79 (s, 3 H), 3.36 (dd, J ) 12.5, 2.2 Hz, 1 H), 3.10 (d, J )

12.5 Hz, 1 H); ¹³C NMR (CDCl₃) δ 169.1 (s), 165.5 (s), 135.2

(s), 129.0 (d, 2 C), 128.9 (d, 2 C), 127.9 (d), 100.0 (d), 77.7 (d),

77.5 (d), 52.8 (q), 51.0 (t), 48.3 (t); MS m/z 277 (M⁺, 20), 91

(100); IR (CDCl₃) 1750, 1668 cm^-1. Anal. Calcd for C₁₄H₁₅

-

NO₅: C, 60.64; H, 5.45; N, 5.05. Found: C, 60.27; H, 5.56; N,

4.74

Meth yl (1R,5S,7R)-3-(p-Meth oxyben zyl)-2-oxo-6,8-d i-

oxa -3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (2). Com-

pound 2 was prepared according to method A reported above

for the synthesis of 1. From 39 (13.0 g, 38.3 mmol), after

purification by chromatography (EtOAc-petroleum ether, 1:2,

R_f0.18), pure 2 (10.5 g, 82%) was obtained as a white solid:

Met h yl (1R,4R,5S,7R)-3-Ben zyl-2-oxo-4-en d o-b en zyl-

6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (5).

Prepared according to method B reported for the synthesis of

1, but refluxed for 30 min before one-third of the solvent was

distilled off. Starting from 60 (437 mg, 1.03 mmol), pure 5 (269

mg, 71%) was obtained after chromatography (EtOAc-n-

mp 139-140 °C; [R]²⁵-48.6 (c 1.0, CHCl₃); ¹H NMR (CDCl₃)

hexane, 1:3, R_f0.21) as a colorless oil: [R]²⁵-27.7 (c 0.24,

D

δ 7.09 (d, J ) 8.4 Hz, 2 H), 6.81 (d, J ) 8.4 Hz, 2 H), 5.81 (d,

J ) 2.2 Hz, 1 H), 4.91 (s, 1 H), 4.69 (s, 1 H), 4.57 (s, 2 H), 3.74

(s, 3 H), 3.30 (dd, J ) 12.3, 2.2 Hz, 1 H), 3.05 (d, J ) 12.3 Hz,

1 H); ¹³C NMR (CDCl₃) δ 169.3 (s), 165.4 (s), 159.2 (s), 129.5

(d, 2 C), 126.9 (s), 113.9 (d, 2 C), 99.9 (d), 77.6 (d), 77.4 (d),

55.4 (q), 52.8 (q), 50.9 (t), 47.6 (t); MS m/z 307 (M⁺, 20), 121

CHCl₃); ¹H NMR (CDCl₃) δ 7.40-7.15 (m, 8 H), 7.00 (m, 2 H),

5.38 (d, J ) 15.4 Hz, 1 H), 5.34 (s, 1 H), 4.97 (s, 1 H), 4.76 (s,

1 H), 4.14 (d, J ) 15.4 Hz, 1 H), 3.78 (s, 3 H), 3.50 (ddd, J )

12.8, 11.3, 2.6 Hz, 1 H), 3.09 (dd, J ) 12.8, 4.1 Hz, 1 H), 2.72

(dd, J ) 12.8, 11.3 Hz, 1 H); ¹³C NMR (CDCl₃) δ 169.1 (s),

166.7 (s), 135.8 (s), 135.4 (s), 129.3 (d, 2 C), 129.0 (d, 4 C),

128.0 (d, 2 C), 127.8 (d), 127.0 (d), 101.0 (d), 77.6 (d), 76.6 (d),

60.1 (d), 52.7 (q), 44.6 (t), 34.3 (t); MS m/z 367 (M⁺, 9), 91 (100);

IR (CDCl₃) 1756, 1667 cm^-1. Anal. Calcd for C₂₁H₂₁NO₅: C,

68.65; H, 5.76; N, 3.81. Found: C, 68.34; H, 5.82; N, 3.66.

Meth yl (1R,4S,5S,7R)-3-Ben zyl-2-oxo-4-exo-m eth yl-6,8-

dioxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (6). Pre-

pared according to method B reported for the synthesis of 1,

but benzene was used as a solvent and the mixture refluxed

for 20 min before one-third of the solvent was distilled off.

(100); IR (CDCl₃) 1756, 1670 cm^-1. Anal. Calcd for C₁₅H₁₇

-

NO₆: C, 58.63; H, 5.58; N, 4.56. Found: C, 58.67; H, 5.80; N,

4.20.

Met h yl 3-Ben zyl-2-oxo-6,8-d ioxa -3-a za b icyclo[3.2.1]-

octa n e-7-en d o-ca r boxyla te [(()-10]. To a solution of 40 (3.7

g, 17.12 mmol) in anhydrous CH₂Cl₂(50 mL) was added 33

(3.34 g, 17.11 mmol) dissolved in CH₂Cl₂(10 mL) and the

mixture stirred at room temperature for 30 min. The solvent

was then evaporated and the crude product dissolved in 60

7360 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

Starting from 61 (255 mg, 0.73 mmol), pure 6 (181 mg, 85%)

(12). Prepared according to method B reported for the syn-

thesis of 1 but benzene was used as a solvent and the mixture

was refluxed for 20 min before one-third of the solvent was

distilled off. Starting from 67 (1.824 g, 5.22 mmol), crude 12

(1.063 g, 70%) was obtained as a 5:1 diastereomeric mixture

used directly in the next reduction step: ¹H NMR (CDCl₃)

(major isomer) δ 7.40-7.15 (m, 5 H), 5.44 (d, J ) 2.6 Hz, 1 H),

5.24 (d, J ) 15.0 Hz, 1 H), 4.93 (d, J ) 5.2 Hz, 1 H), 4.61 (d,

J ) 5.2 Hz, 1 H), 3.91 (d, J ) 15.0 Hz, 1 H), 3.76 (s, 3 H), 3.43

(dq, J ) 6.9, 2.6 Hz, 1 H), 1.29 (d, J ) 6.9 Hz, 3 H); ¹³C NMR

(CDCl₃) δ 167.9 (s), 165.0 (s), 135.6 (s), 128.7 (d, 2 C), 127.9

(d, 2 C), 127.6 (d), 103.3 (d), 77.7 (d), 76.3 (d), 54.4 (d), 52.6

(q), 44.1 (t), 13.1 (q); MS m/z 291 (M⁺, 4), 91 (100).

was obtained after chromatography (EtOAc-petroleum ether,

1

1:2, R_f0.27) as an oil: [R]¹⁵-64.6 (c 0.79, CHCl₃); H NMR

D

(CDCl₃) δ 7.32-7.14 (m, 5 H), 5.54 (s, 1 H), 5.21 (d, J ) 15.4

Hz, 1 H), 4.94 (s, 1 H), 4.74 (s, 1 H), 3.93 (d, J ) 15.4 Hz, 1 H),

3.78 (s, 3 H), 3.26 (q, J ) 7.0 Hz, 1 H), 1.22 (d, J ) 7.0 Hz, 3

H); ¹³C NMR (CDCl₃) δ 169.1 (s), 165.6 (s), 135.9 (s), 128.8 (d,

2 C), 127.7 (d), 127.5 (d, 2 C), 103.9 (d), 77.8 (d), 77.4 (d), 55.4

(q), 52.7 (d), 45.6 (t), 15.8 (q); MS m/z 291 (M⁺, 28), 91 (100);

IR (CDCl₃) 1755, 1674 cm^-1. Anal. Calcd for C₁₅H₁₇NO₅: C,

61.85; H, 5.88; N, 4.81. Found: C, 61.80; H, 5.75; N, 4.49.

Meth yl (1R,4R,5S,7R)-3-Ben zyl-2-oxo-4-en d o-m eth yl-

6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (7).

Prepared according to method B reported for the synthesis of

1 but benzene was used as a solvent and the mixture was

refluxed for 20 min before one-third of the solvent was distilled

off. Starting from 62 (229 mg, 0.65 mmol), pure 7 (160 mg,

84%) was obtained after chromatography (EtOAc-petroleum

Meth yl (1R,5S,7R)-2-Oxo-6,8-d ioxa -3-a za bicyclo[3.2.1]-

octa n e-7-exo-ca r boxyla te (13). Compound 2 (500 mg, 1.6

mmol) was left to react for 5 h at room temperature with CAN

(2.5 g, 4.5 mmol) in CH₃CN (12 mL) and H₂O (4 mL). The

solution was then adjusted to pH 7 with Na₂CO₃and filtered

over a Celite layer washing with acetone. The organic phase

was extracted with Et₂O and CH₂Cl₂and dried over Na₂SO₄.

Evaporation of the solvent gave a crude product that was

purified by recrystallization from Et₂O-petroleum ether at 0

°C, yielding 13 (260 mg, 85%) as a white solid: mp 163-165

ether, 1:3, R_f0.24) as an oil: [R]¹⁵+12.6 (c 1.00, CHCl₃); H

1

D

NMR (CDCl₃) δ 7.34-7.03 (m, 5 H), 5.55 (d, J ) 2.6 Hz, 1 H),

5.21 (d, J ) 15.1 Hz, 1 H), 4.98 (s, 1 H), 4.69 (s, 1 H), 3.95 (d,

J ) 15.1 Hz, 1 H), 3.76 (s, 3 H), 3.41 (dq, J ) 6.6, 2.6 Hz, 1 H),

1.13 (d, J ) 6.6 Hz, 3 H); ¹³C NMR (CDCl₃) δ 169.1 (s), 166.0

(s), 135.4 (s), 129.7 (d, 2 C), 127.6 (d), 127.5 (d, 2 C), 102.9 (d),

77.7 (d, 2 C), 54.1 (q), 52.7 (d), 44.0 (t), 13.7 (q); MS m/z 291

(M⁺, 44), 91 (100); IR (CDCl₃) 1750, 1668 cm^-1. Anal. Calcd

for C₁₅H₁₇NO₅: C, 61.85; H, 5.88; N, 4.81. Found: C, 61.72;

H, 5.67; N, 4.71.

°C; [R]²⁵-6.9 (c 1.0, CHCl₃); ¹H NMR (CDCl₃) δ 5.88 (br s, 1

D

H), 5.87 (d, J ) 1.8 Hz, 1 H), 4.82 (s, 1 H), 4.73 (s, 1 H), 3.78

(s, 3 H), 3.49 (dd, J ) 12.1, 1.8 Hz, 1 H), 3.28 (d, J ) 12.1 Hz,

1 H); ¹³C NMR (CDCl₃) δ 169.1 (s), 167.6 (s), 99.4 (d), 77.8 (d),

77.4 (d), 52.9 (q), 47.0 (t); MS m/z 187 (M⁺, 2), 71 (100); IR

(CDCl₃) 1757, 1690 cm^-1. Anal. Calcd for C₇H₉NO₅: C, 44.92;

H, 4.84; N, 7.48. Found: C, 44.60; H, 4.91; N, 7.19.

Meth yl (1R,4S,5S,7R)-3-Ben zyl-2-oxo-4-exo-p h en yl-6,8-

dioxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (8) an d

Meth yl (1R,4R,5S,7R)-3-Ben zyl-2-oxo-4-en d o-p h en yl-6,8-

dioxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (9). Pre-

pared according to method B reported for the synthesis of 1

but benzene was used as a solvent, a double amount of H₂-

SO₄/SiO₂was used, and the mixture was refluxed for 20 min

before one-third of the solvent was distilled off. Starting from

the 1:1 diastereomeric mixture 46 (70 mg, 0.15 mmol), the 1:1

epimeric mixture of 8 and 9 (48 mg, 90%) was obtained as an

oil. When the reaction was carried out heating 46 (300 mg,

0.656 mmol) in toluene as described for 1 (method B) a 0.5:

0.5:1 mixture of 47 and 8 (this last in 3:1 mixture with 9) (42

mg) was obtained after chromatography (EtOAc-petroleum

ether, 1:1.5, R_f0.5), along with a larger amount of decomposi-

tion products. This mixture was dissolved again in toluene (10

mL) in the presence of H₂SO₄/SiO₂(19 mg), and two-thirds of

the solvent was distilled off, affording 8 (27 mg, 12%) as a 4:1

Meth yl (1R,4S,5S,7R)-2-Oxo-4-exo-ben zyl-6,8-d ioxa -3-

a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (14). Prepared

from 3 (80 mg, 0.20 mmol) as reported for 13. Pure 14 (30 mg,

72%) was obtained after recrystallization from Et₂O-petro-

leum ether at 0 °C: [R]²⁵-93.1 (c 1.0, CDCl₃); ¹H NMR

D

(CDCl₃) δ 7.35-7.13 (m, 5 H), 5.68 (s, 1 H), 4.86 (s, 1 H), 4.70

(s, 1 H), 3.77 (s, 3 H), 3.56 (ddd, J ) 9.2, 6.2, 2.2 Hz, 1 H),

2.90 (dd, J ) 13.5, 6.2 Hz, 1 H), 2.80 (dd, J ) 13.5, 9.2 Hz, 1

H); ¹³C NMR (CDCl₃) δ 169.0 (s), 166.5 (s), 135.4 (s), 129.1 (d,

4 C), 127.3 (d), 101.5 (d), 77.7 (d), 77.3 (d), 58.1 (d), 52.8 (q),

39.3 (t); MS m/z 277 (M⁺, 2), 91 (100); IR (CDCl₃) 1758, 1691

cm^-1. Anal. Calcd for C₁₄H₁₅NO₅: C, 60.64; H, 5.45; N, 5.05.

Found: C, 60.36; H, 5.73; N, 4.70.

Meth yl (1S,5S,7R)-3-Ben zyl-6,8-dioxa-3-azabicyclo[3.2.1]-

octa n e-7-exo-ca r boxyla te (16). To a refluxing solution of 1

(604 mg, 2.18 mmol) in anhydrous THF (12 mL) was added,

under a nitrogen atmosphere, a 1 M solution of BH₃‚Me₂S (0.4

mL) in 10 min and the mixture stirred for 30 min. After this

time, the mixture was immediately cooled with an ice bath.

The solvent was evaporated and the crude dissolved in 1,4-

dioxane (30 mL), followed by addition of TMEDA (0.4 mL, 2.65

mmol), and left to react at room temperature for 15 min. The

solvent was evaporated, and the residue was suspended in

diethyl ether and carefully filtrered through a short layer of

Celite. After evaporation of the solvent, the residue was

purified by chromatography (EtOAc-petroleum ether, 2:3, R_f

mixture with epimeric compound 9. Compound 8 (character-

1

ized as a 4:1 mixture with 9): [R]²⁰-17.0 (c 0.5, CHCl₃); H

D

NMR (CDCl₃) δ 7.40-7.00 (m, 10 H), 5.61 (s, 1 H), 5.41 (d, J

) 15.1 Hz, 1 H), 5.10 (s, 1 H), 4.81 (s, 1 H), 4.17 (s, 1 H), 3.78

(s, 3 H), 3.33 (d, J ) 15.1 Hz, 1 H); ¹³C NMR (CDCl₃) δ 168.8

(s), 165.7 (s), 135.7 (s), 134.7 (s), 129.2 (d, 2 C), 129.1 (d), 128.9

(d, 2 C), 128.5 (d), 128.1 (d, 2 C), 127.8 (d, 2 C), 104.2 (d), 77.9

(d), 77.5 (d), 63.9 (d), 52.8 (q), 45.7 (t); MS m/z 353 (M⁺, 1), 91

(100); IR (CDCl₃) 1761, 1667 cm^-1

.

Met h yl (1R,4R,5S,7S)-3-Ben zyl-2-oxo-4-en d o-b en zyl-

6,8-d ioxa -3-a za b icyclo[3.2.1]oct a n e-7-en d o-ca r b oxyla t e

(11). Prepared according to method B reported for the syn-

thesis of 1 but benzene was used as a solvent and the mixture

was refluxed for 20 min before one-third of the solvent was

distilled off. Starting from 66 (98 mg, 0.23 mmol), pure 11 (74

mg, 87%) was obtained after chromatography (EtOAc-petro-

0.5), affording pure 16 (512 mg, 89%) as a colorless oil: [R]²⁵

D

-61.8 (c 1.0, CHCl₃); ¹H NMR (CDCl₃) δ 7.30 (m, 5 H), 5.62 (s,

1 H), 4.78 (s, 1 H), 4.60 (s, 1 H), 3.74 (s, 3 H), 3.52 (AB system,

J ) 13.2 Hz, 2 H), 2.86 (d, J ) 11.6 Hz, 1 H), 2.77 (d, J ) 11.5

Hz, 1 H), 2.51 (dd, J ) 11.5, 1.5 Hz, 1 H), 2.30 (d, J ) 11.6 Hz,

1 H); ¹³C NMR (CDCl₃) δ 171.7 (s), 137.3 (s), 128.9 (d, 2 C),

128.4 (d, 2 C), 127.4 (d), 101.5 (d), 76.9 (d), 76.0 (d), 61.4 (t),

56.3 (t), 54.7 (t), 52.5 (q); MS m/z 263 (M⁺, 6), 91 (100); IR

(CDCl₃) 1755 cm^-1. Anal. Calcd for C₁₄H₁₇NO₄: C, 63.87; H,

6.51; N, 5.32. Found: C, 63.50; H, 6.59; N, 4.92.

leum ether, 1:3, R_f0.28) as an oil: [R]²⁵-2.4 (c 0.38, CHCl₃);

D

¹H NMR (CDCl₃) δ 7.40-7.00 (m, 10 H), 5.37 (d, J ) 15.4 Hz,

1 H), 5.17 (d, J ) 2.9 Hz, 1 H), 4.95 (d, J ) 5.1 Hz, 1 H), 4.62

(d, J ) 5.1 Hz, 1 H), 4.10 (d, J ) 15.4 Hz, 1 H), 3.80 (s, 3 H),

3.51 (ddd, J ) 8.0, 5.1, 2.9 Hz, 1 H), 3.17 (m, 2 H); ¹³C NMR

(CDCl₃) δ 168.2 (s), 165.6 (s), 136.1 (s), 135.4 (s), 129.5 (d, 2

C), 128.9 (d, 2 C), 128.7 (d, 2 C), 128.2 (d), 127.9 (d, 2 C), 126.9

(d), 101.4 (d), 77.6 (d), 76.7 (d), 60.3 (d), 52.7 (q), 44.7 (t), 33.7

Meth yl (1S,4S,5S,7R)-3-Ben zyl-4-exo-ben zyl-6,8-d ioxa -

3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (17). Com-

pound 17 was prepared according to the synthesis of 16,

starting from 4 (317 mg, 0.86 mmol). The crude was obtained

as a 2:1 mixture of 17 and amino alcohol 72. These were

separated by chromatography (EtOAc-petroleum ether, 1:4),

(t); MS m/z 367 (M⁺, 2), 91 (100); IR (CDCl₃) 1759, 1666 cm^-1

.

Anal. Calcd for C₂₁H₂₁NO₅: C, 68.65; H, 5.76; N, 3.81. Found:

C, 68.38; H, 5.44; N, 3.52.

Met h yl (1S,4S,5R,7R)-3-Ben zyl-2-oxo-4-en d o-m et h yl-

6,8-d ioxa -3-a za b icyclo[3.2.1]oct a n e-7-en d o-ca r b oxyla t e

obtaining pure 17 (170 mg, 56%, R_f0.40) and 72 (78 mg, 28%,

1

R_f0.12). 17: [R]²⁵-31.2 (c 0.12, CHCl₃); H NMR (CDCl₃) δ

D

7.40-7.00 (m, 10 H), 5.28 (s, 1 H), 4.73 (s, 1 H), 4.61 (s, 1 H),

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7361

3.81 (d, J ) 13.2 Hz, 1 H), 3.72 (s, 3 H), 3.64 (d, J ) 13.2 Hz,

1 H), 3.00 (ddd, J ) 11.0, 4.4, 1.8 Hz, 1 H), 2.98 (dd, J ) 11.7,

1.8 Hz, 1 H), 2.92 (dd, J ) 12.8, 4.4 Hz, 1 H), 2.77 (dd, J )

12.8, 11.0 Hz, 1 H), 2.56 (dd, J ) 11.7, 1.9 Hz, 1 H); ¹³C NMR

(CDCl₃) δ 171.9 (s), 138.2 (s), 129.1 (d, 2 C), 128.7 (d, 4 C),

128.5 (d, 2 C), 127.4 (d), 126.2 (d), 102.4 (d), 77.4 (d), 76.0 (d),

62.3 (d), 57.5 (t), 52.4 (q), 49.7 (t), 29.1 (t); MS m/z 353 (M⁺,

¹H NMR (CDCl₃) δ 7.25 (m, 5 H), 5.45 (s, 1 H), 4.31 (s, 1 H),

4.11 (d, J ) 10.8 Hz, 1 H), 4.10 (m, 1 H), 3.85 (d, J ) 10.8 Hz,

1 H), 3.65 (d, J ) 12.4 Hz, 1 H), 3.39 (d, J ) 12.4 Hz, 1 H),

3.02 (d, J ) 11.0 Hz, 1 H), 2.83 (d, J ) 11.4 Hz, 1H), 2.80 (dd,

J ) 11.4, 2.2 Hz, 1H), 2.29 (d, J ) 11.0 Hz, 1 H); ¹³C NMR

(CDCl₃) δ 137.8 (s), 129.5 (d, 2 C), 128.6 (d, 2 C), 127.9 (d),

99.1 (d), 78.4 (d), 74.5 (d), 61.9 (t), 59.3 (t), 55.7 (t), 53.4 (t);

0.3), 91 (100); IR (CDCl₃) 1731 cm^-1. Anal. Calcd for C₂₁H₂₃

-

MS m/z 235 (M⁺, 24), 91 (100); IR (CDCl₃) 3610, 3200 (br) cm^-1

.

NO₄: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.22; H, 6.48; N,

3.73.

Anal. Calcd for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95. Found:

C, 66.00; H, 7.32; N, 5.59.

Meth yl (1S,4R,5S,7R)-3-Ben zyl-4-en do-ben zyl-6,8-dioxa-

3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (18). Com-

pound 18 was prepared according to the synthesis of 16.

Starting from 5 (269 mg, 0.73 mmol), the crude was obtained

as a 2:1 mixture of 18 and amino alcohol 73. These were

separated by chromatography (EtOAc-petroleum ether, 1:3),

(1S,5S,7S)-3-Ben zyl-7-exo-h yd r oxym eth yl-6,8-d ioxa -3-

a za bicyclo[3.2.1]octa n e (69). To a suspension of LiAlH₄(85

mg, 2.2 mmol) in anhydrous THF (12 mL) was added dropwise

at 0 °C and under a nitrogen atmosphere a solution of 1 (270

mg, 0.97 mmol) in dry THF (12 mL). The mixture was refluxed

for 2 h, and then, after cooling to 0 °C, diethyl ether (3 mL)

and a saturated Na₂SO₄solution (3 mL) were added. The

mixture was filtered through a short layer of anhydrous Na₂-

SO₄, and the residue was suspended in 1 M KOH solution (50

mL), saturated with NaCl, and extracted with Et₂O and

EtOAc. The organic phases were combined, dried over anhy-

drous Na₂SO₄, concentrated, and purified by chromatography

(EtOAc-petroleum ether, 1:1, R_f0.28) to give pure 69 (163

mg, 64%) as a colorless oil: [R]²⁵_D-92.2 (c 1.0, CHCl₃); ¹H NMR

(CDCl₃) δ 7.29 (m, 5 H), 5.43 (s, 1 H), 4.41 (t, J ) 5.5 Hz, 1 H),

4.23 (s, 1 H), 3.62-3.40 (m, 4 H), 2.94 (br s, 1 H), 2.81 (d, J )

11.0 Hz, 1 H), 2.66 (d, J ) 11.4 Hz, 1 H), 2.45 (dd, J ) 11.4,

1.9 Hz, 1 H), 2.29 (d, J ) 11.0 Hz, 1 H); ¹³C NMR (CDCl₃) δ

137.5 (s), 128.9 (d, 2 C), 128.3 (d, 2 C), 127.2 (d), 100.2 (d),

78.4 (d), 74.5 (d), 64.1 (t), 61.7 (t), 56.8 (t), 54.9 (t); MS m/z

235 (M⁺, 2), 91 (100); IR (CDCl₃) 3438 (br) cm^-1. Anal. Calcd

for C₁₃H₁₇NO₃: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.70;

H, 7.52; N, 5.60.

yielding pure 18 (131 mg, 51%, R_f0.44) and 73 (60 mg, 25%,

1

R_f0.24). 18: mp 75-75 °C; [R]²⁵-120.0 (c 0.1, CHCl₃); H

D

NMR (CDCl₃) δ 7.35-7.08 (m, 10 H), 5.26 (s, 1 H), 4.67 (s, 1

H), 4.56 (br s, 1 H), 4.26 (d, J ) 14.0 Hz, 1 H), 3.73 (s, 3 H),

3.24 (d, J ) 14.0 Hz, 1 H), 3.17 (dd, J ) 12.1, 3.3 Hz, 1 H),

2.74 (m, 2 H), 2.67 (m, 1 H), 2.51 (dd, J ) 12.1, 1.7 Hz, 1 H);

¹³C NMR (CDCl₃) δ 171.6 (s), 138.3 (s), 137.9 (s), 129.5 (d, 2

C), 128.7 (d, 4 C), 128.5 (d, 2 C), 127.3 (d), 126.5 (d), 102.1 (d),

77.2 (d), 75.6 (d), 64.6 (d), 57.5 (t), 54.3 (t), 52.4 (q), 35.8 (t);

MS m/z 353 (M⁺, 1), 91 (100); IR (CDCl₃) 1747 cm^-1. Anal.

Calcd for C₂₁H₂₃NO₄: C, 71.37; H, 6.56; N, 3.96. Found: C,

71.57; H, 6.78; N, 3.74.

Meth yl (1S,4S,5S,7R)-3-Ben zyl-4-exo-m eth yl-6,8-d ioxa -

3-a za bicyclo[3.2.1]octa n e-7-exo-ca r boxyla te (19). Com-

pound 19 was prepared according to the synthesis of 16,

starting from 6 (150 mg, 0.51 mmol). The crude was obtained

as a 2:1 mixture of 19 with the corresponding amino alcohol.

Pure 19 (91 mg) was obtained by chromatography (EtOAc-

petroleum ether, 2:3, R_f0.50) in 65% yield as a colorless oil:

[R]²⁰_D-32.3 (c 0.70, CHCl₃); ¹H NMR (CDCl₃) δ 7.32-7.16 (m,

5 H), 5.37 (d, J ) 1.9 Hz, 1 H), 4.72 (s, 1 H), 4.54 (s, 1 H), 3.72

(s, 3 H), 3.53 (AB, J ) 13.4 Hz, 2 H), 2.93 (dq, J ) 6.6, 1.9 Hz,

1 H), 2.78 (dd, J ) 12.0, 1.9 Hz, 1 H), 2.44 (d, J ) 12.0 Hz, 1

H), 0.95 (d, J ) 6.6 Hz, 3 H); ¹³C NMR (CDCl₃) δ 171.7 (s),

138.2 (s), 128.5 (d, 2 C), 128.3 (d, 2 C), 127.1 (d), 105.0 (d),

77.1 (d), 75.4 (d), 57.1 (t), 56.0 (d), 52.3 (q), 43.1 (t), 7.5 (q);

MS m/z 277 (M⁺, 1), 91 (100). Anal. Calcd for C₁₅H₁₉NO₄: C,

64.97; H, 6.91; N, 5.05. Found: C, 64.61; H, 6.72; N, 4.77.

Met h yl (1S,4R,5S,7R)-3-Ben zyl-4-en d o-m et h yl-6,8-d i-

oxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (20). Com-

pound 20 was prepared according to the synthesis of 16,

starting from 7 (142 mg, 0.49 mmol). The crude was obtained

as a 2:1 mixture of 20 with the corresponding amino alcohol.

Pure 20 (85 mg) was obtained by chromatography (EtOAc-

(1S,5S,7S)-3-(p-Meth oxyben zyl)-7-exo-h yd r oxym eth yl-

6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (70). Prepared accord-

ing to the synthesis of 69. Starting from 2 (1.0 g, 3.3 mmol),

pure 70 (840 mg, 97%) was obtained after chromatography

(EtOAc-petroleum ether, 1:1, R_f0.30) as a colorless oil: [R]²⁵

D

1

-71.6 (c 1.0, CHCl₃); H NMR (CDCl₃) δ 7.19 (d, J ) 8.4 Hz,

2 H), 6.81 (d, J ) 8.4 Hz, 2 H), 5.42 (s, 1 H), 4.38 (t, J ) 5.5

Hz, 1 H), 4.21 (s, 1 H), 3.78 (s, 3 H), 3.56 (m, 2 H), 3.44 (AB

system, J ) 12.8 Hz, 2 H), 2.79 (d, J ) 10.6 Hz, 1 H), 2.65 (d,

J ) 11.3 Hz, 1 H), 2.41 (dd, J ) 11.3, 1.5 Hz, 1 H), 2.26 (d, J

) 10.6 Hz, 1 H); ¹³C NMR (CDCl₃) δ 158.8 (s), 130.0 (d, 2 C),

129.4 (s), 113.7 (d, 2 C), 100.2 (d), 78.4 (d), 74.4 (d), 64.2 (t),

61.0 (t), 56.7 (t), 55.2 (q), 54.7 (t); MS m/z 265 (M⁺, 1), 121

(100); IR (CDCl₃) 3591, 3482 (br) cm^-1. Anal. Calcd for C₁₄H₁₉

-

NO₄: C, 63.36; H, 7.22; N, 5.28. Found: C, 63.62; H, 7.42; N,

4.89.

(1S,4S,5S,7S)-3-(p-Meth oxyben zyl)-4-exo-ben zyl-7-exo-

h yd r oxym eth yl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (71).

Prepared from 3 (159 mg, 0.40 mmol) as reported for 69. After

purification by chromatography (EtOAc-petroleum ether, 1:4,

R_f0.16), pure 71 (124 mg, 87%) was obtained as a colorless

petroleum ether, 2:3, R_f0.50) in 63% yield as a colorless oil:

1

[R]²⁰-78.0 (c 1.0, CHCl₃); H NMR (CDCl₃) δ 7.27-7.13 (m,

D

5 H), 5.25 (s, 1 H), 4.55 (s, 1 H), 4.50 (s, 1 H), 3.97 (d, J ) 13.6

Hz, 1 H), 3.66 (s, 3 H), 3.05 (d, J ) 13.6 Hz, 1 H), 2.59 (dd, J

) 11.7, 1.4 Hz, 1 H), 2.46-2.33 (m, 2 H), 1.13 (d, J ) 6.6 Hz,

3 H); ¹³C NMR (CDCl₃) δ 171.5 (s), 138.1 (s), 128.6 (d, 2 C),

128.2 (d, 2 C), 127.0 (d), 104.8 (d), 77.0 (d), 75.5 (d), 58.2 (t),

56.8 (d), 53.6 (q), 49.0 (t), 15.3 (q); MS m/z 277 (M⁺, 1), 91

(100). Anal. Calcd for C₁₅H₁₉NO₄: C, 64.97; H, 6.91; N, 5.05.

Found: C, 65.12; H, 6.83; N, 5.01.

oil: [R]²⁵-33.8 (c 1.0, CHCl₃); ¹H NMR (CDCl₃) δ 7.40-7.05

D

(m, 8 H), 6.89 (d, J ) 8.8 Hz, 2 H), 5.12 (d, J ) 1.4 Hz, 1 H),

4.38 (t, J ) 5.5 Hz, 1 H), 4.26 (s, 1 H), 3.83 (s, 3 H), 3.78 (d, J

) 13.9 Hz, 1 H), 3.60 (d, J ) 13.9 Hz, 1 H), 3.56 (m, 2 H), 3.00

(m, 1 H), 2.95 (d, J ) 11.4 Hz, 1 H), 3.00-2.80 (m, 2 H), 2.47

(dd, J ) 11.4, 1.9 Hz, 1 H); ¹³C NMR (CDCl₃) δ 158.8 (s), 138.7

(s), 130.3 (s), 129.7 (d, 2 C), 129.4 (d, 2 C), 129.1 (d, 2 C), 128.5

(d), 126.0 (s), 113.7 (d, 2 C), 101.1 (d), 78.1 (d), 74.9 (d), 64.4

(t), 62.6 (d), 56.9 (t), 55.2 (q), 49.6 (t), 29.1 (t); MS m/z 355

(M⁺, 1), 121 (100). Anal. Calcd for C₂₁H₂₅NO₄: C, 70.96; H,

7.09; N, 3.94. Found: C, 70.68; H, 7.36; N, 3.74.

Met h yl 3-Ben zyl-6,8-d ioxa -3-a za b icyclo[3.2.1]oct a n e-

7-en d o-ca r boxyla te [(()-21]. Prepared according to the syn-

thesis of 16. Starting from (()-10 (870 mg, 3.14 mmol), the

crude product was obtained as a 2:1 mixture of 21 and amino

alcohol 74 and then separated by chromatography (EtOAc-

petroleum ether, 1:1.5), affording pure 21 (321 mg, 39%, R_f

0.48) and 74 (143 mg, 19%, R_f0.15). 21: ¹H NMR (CDCl₃) δ

7.22 (m, 5 H), 5.45 (s, 1 H), 4.62 (d, J ) 5.4 Hz, 1 H), 4.47 (d,

J ) 5.4 Hz, 1 H), 3.67 (s, 3 H), 3.41 (AB system, J ) 13.2 Hz,

2 H), 2.62 (m, 2 H), 2.43 (d, J ) 11.4 Hz, 1 H), 2.27 (d, J )

11.8 Hz, 1 H); ¹³C NMR (CDCl₃) δ 168.3 (s), 137.2 (s), 128.9

(d, 2 C), 128.3 (d, 2 C), 127.3 (d), 100.8 (d), 76.2 (d), 74.9 (d),

61.6 (t), 56.9 (t), 52.7 (t), 51.9 (q); MS m/z 263 (M⁺, 33), 91

(100); IR (CDCl₃) 1759 cm^-1. Anal. Calcd for C₁₄H₁₇NO₄: C,

63.87; H, 6.51; N, 5.32. Found: C, 63.51; H, 6.32; N, 5.28. 74:

(1S ,4S ,5S ,7S )-3-Be n zyl-4-exo-b e n zyl-7-exo-h yd r oxy-

m eth yl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (72). Prepared

from 4 (292 mg, 0.79 mmol) according to the synthesis of 69.

After purification by chromatography (EtOAc-petroleum ether,

1:4, R_f0.12) pure 72 (194 mg, 75%) was obtained as a colorless

oil: [R]²⁵-59.4 (c 0.17, CHCl₃); ¹H NMR (CDCl₃) δ 7.40-

D

7.00 (m, 10 H), 5.11 (s, 1 H), 4.39 (t, J ) 5.1 Hz, 1 H), 4.24 (s,

1 H), 3.81 (d, J ) 13.6 Hz, 1 H), 3.00-2.80 (m, 2 H), 3.63 (d,

J ) 13.6 Hz, 1 H), 3.52 (m, 2 H), 3.00 (m, 1 H), 2.94 (d, J )

11.6 Hz, 1 H), 2.45 (dd, J ) 11.6, 1.8 Hz, 1 H); ¹³C NMR

7362 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

(CDCl₃) δ 138.6 (s), 138.4 (s), 129.2 (d, 2 C), 128.7 (d, 2 C),

128.6 (d, 2 C), 128.4 (d, 2 C), 127.3 (d), 126.1 (d), 101.2 (d),

78.1 (d), 74.9 (d), 64.4 (t), 62.7 (t), 57.6 (d), 49.7 (t), 29.2 (t);

MS m/z 325 (M⁺, 0.1), 91 (100). Anal. Calcd for C₂₀H₂₃NO₃:

C, 73.82; H, 7.12; N, 4.30. Found: C, 73.49; H, 7.25; N, 4.19.

IR (CDCl₃) 1750 cm^-1. Anal. Calcd for C₁₄H₁₇NO₄: C, 63.87;

H, 6.51; N, 5.32. Found: C, 63.71.; H, 6.23.; N, 4.99.

Meth yl 6,8-Dioxa -3-a za bicyclo[3.2.1]octa n e-7-en d o-ca r -

boxyla te [(()-25]. Prepared from (()-21 (322 mg, 1.22 mmol)

as reported for 22. Pure (()-25 (196 mg, 93%) was obtained

as a colorless oil: ¹H NMR (CDCl₃) δ 5.34 (s, 1 H), 4.48 (d, J

) 4.6 Hz, 1 H), 4.37 (d, J ) 4.6 Hz, 1 H), 3.72 (s, 3 H), 3.35 (d,

J ) 14.2 Hz, 1 H), 2.94 (br s, 1 H), 2.88 (m, 2 H), 2.65 (d, J )

14.2 Hz, 1 H); ¹³C NMR (CDCl₃) δ 170.1 (s), 101.9 (d), 76.5 (d),

75.1 (d), 52.1 (q), 48.7 (t), 45.6 (t). Anal. Calcd for C₇H₁₁NO₄:

C, 48.55; H, 6.40; N, 8.09. Found: C, 48.18; H, 6.32; N, 7.91.

(1S,5S,7S)-7-exo-Hydr oxym eth yl-6,8-dioxa-3-azabicyclo-

[3.2.1]octa n e (76). Prepared from 69 (163 mg, 0.62 mmol) as

(1S,4R,5S,7S)-3-Ben zyl-4-en d o-b en zyl-7-exo-h yd r oxy-

m eth yl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (73). Prepared

from 5 (200 mg, 0.54 mmol) according to the procedure

reported for 69. After purification by chromatography (EtOAc-

petroleum ether, 1:1.5, R_f0.44), pure 73 (141 mg, 80%) was

obtained as a white solid: mp 104-105 °C; [R]²⁵_D-107 (c 0.04,

CHCl₃); ¹H NMR (CDCl₃) δ 7.40-7.05 (m, 10 H), 5.05 (s, 1 H),

4.31 (t, J ) 4.8 Hz, 1 H), 4.29 (s, 1 H), 4.27 (d, J ) 13.9 Hz, 1

H), 3.56 (m, 2 H), 3.23 (d, J ) 13.9 Hz, 1 H), 3.17 (dd, J )

11.3, 3.3 Hz, 1 H), 2.80-2.60 (m, 3 H), 2.47 (dd, J ) 11.3, 1.8

Hz, 1 H); ¹³C NMR (CDCl₃) δ 138.6 (s), 138.1 (s), 129.5 (d, 2

C), 128.7 (d, 2 C), 128.6 (d, 2 C), 128.4 (d, 2 C), 127.1 (d), 126.4

(d), 100.8 (d), 77.8 (d), 74.6 (d), 64.6 (d), 64.4 (t), 57.7 (t), 54.5

(t), 36.1 (t); MS m/z 325 (M⁺, 0.5), 234 (100), 91 (100). Anal.

Calcd for C₂₀H₂₃NO₃: C, 73.82; H, 7.12; N, 4.30. Found: C,

73.99; H, 7.49; N, 4.05.

reported for 22. Pure 76 (89 mg, 99%) was obtained as a white

1

solid: mp 116-117 °C; [R]²⁵-70.0 (c 1.0, CHCl₃); H NMR

D

(CDCl₃) δ 5.40 (s, 1 H), 4.38 (t, J ) 5.9 Hz, 1 H), 4.17 (s, 1 H),

3.60 (m, 2 H), 3.22 (dd, J ) 13.5, 1.8 Hz, 1 H), 2.92 (d, J )

13.5 Hz, 1 H), 2.77-2.65 (m, 2 H); ¹³C NMR (CDCl₃) δ 101.4

(d), 78.5 (d), 75.1 (d), 64.3 (t), 49.4 (t), 48.1 (t); MS m/z 145

(M⁺, 3), 100 (100). Anal. Calcd for C₆H₁₁NO₃: C, 49.65; H, 7.64;

N, 9.58. Found: C, 49.45; H, 7.32; N, 9.30.

(1R,4S,5R,7S)-4-en d o-Met h yl-7-en d o-h yd r oxym et h yl-

6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (77). Prepared from 75

(650 mg, 2.61 mmol) as described for 22. Crude 77 (380 mg,

91%) was obtained as a colorless oil and used directly in the

next step: ¹H NMR (CDCl₃) δ 5.15 (s, 1 H), 4.26 (m, 1 H), 4.15

(dd, J ) 11.4, 4.4 Hz, 1 H), 4.12 (s, 1 H), 3.82 (d, J ) 11.4 Hz,

1 H), 3.25 (dd, J ) 12.2, 2.2 Hz, 1 H), 3.05 (m, 2 H), 1.04 (d, J

) 6.6 Hz, 3 H); ¹³C NMR (CDCl₃) δ 102.3 (d), 78.0 (d), 73.8

(d), 58.9 (t), 52.5 (d), 45.1 (t), 16.6 (q).

(1R ,5S ,7R )-3-(p -Me t h oxyb e n zyl)-2-oxo-6,8-d ioxa -3-

a za bicyclo[3.2.1]octa n e-7-exo-ca r boxylic Acid (15). To a

suspension of 2 (50 mg, 0.163 mmol) in water (10 mL) was

added under stirring a 1 M aqueous solution of NaOH (10 mL).

After 3 h, the suspension was filtered over a Celite layer. To

the resulting solution was added 2 M HCl (5 mL) and then

NaCl up to saturation, and finally compound 15 was extracted

with Et₂O. The organic layer was dried over Na₂SO₄, concen-

trated, and evaporated, affording 15 (44 mg, 91%) as a white

solid: mp 170 °C; [R]²⁵_D-43.4 (c 1.0, DMSO); ¹H NMR (DMSO-

d₆) δ 7.16 (d, J ) 8.6 Hz, 2 H), 6.92 (d, J ) 8.6 Hz, 2 H), 5.94

(d, J ) 2.3 Hz, 1 H), 4.88 (s, 1 H), 4.77 (s, 1 H), 4.42 (AB

system, J ) 14.6 Hz. 2 H), 3.75 (s, 3 H), 3.33 (dd, J ) 12.5, 2.3

Hz, 1 H), 3.04 (d, J ) 12.5 Hz, 1 H); ¹³C NMR (DMSO-d₆) δ

170.6 (s), 165.5 (s), 158.9 (s), 129.5 (d, 2 C), 128.4 (s), 114.3

(d, 2 C), 99.6 (d), 77.3 (d), 77.2 (d), 55.3 (q), 50.9 (t), 46.7 (t);

MS m/z 293 (M⁺, 39), 121 (100). Anal. Calcd for C₁₄H₁₅NO₆‚

H₂O: C, 54.02; H, 5.50; N, 4.50. Found: C, 54.37; H, 5.66; N,

4.12.

(1S,5S,7R)-6,8-Dioxa -3-a za b icyclo[3.2.1]oct a n e-7-exo-

ca r boxylic Acid HCl Sa lt (28). Meth od A. To a stirred

solution of 16 (51.8 mg, 0.197 mmol) in MeOH (3 mL) cooled

at 0 °C was added dropwise a solution of KOH (11 mg, 0.197

mmol) in MeOH (3 mL). After 3 h, the solvent was evaporated,

water (3 mL) was added, and to the resulting solution a few

drops of 5 N HCl were added up to pH 1. The solution was

concentrated again, yielding a white solid containing salt 29

(71 mg): ¹H NMR (D₂O) δ 7.51 (m, 5 H), 5.91 (s, 1 H), 5.04 (s,

1 H), 4.92 (s, 1 H), 4.39 br s, 2 H), 3.70-3.30 (m, 4 H). Salt 29

was added to a suspension of 20% Pd(OH)₂/C (60 mg) in MeOH

(5 mL) and left under H₂atmosphere. After 16 h, the suspen-

sion was filtered through a Celite layer and concentrated,

obtaining 28 (38 mg, 100%) as HCl salt. Meth od B. Compound

28 was also obtained by dissolving 22 (60 mg, 0.35 mmol) in

4 N HCl (1.5 mL). After stirring 18 h at room temperature,

(1R,4S,5R,7S)-3-Ben zyl-4-exo-m eth yl-7-en d o-h yd r oxy-

m eth yl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e (75). Prepared

as described for compound 69. Starting from 12 (1.29 g, 4.43

mmol), pure 75 (680 mg, 62%) was obtained after chromatog-

raphy (CH₂Cl₂-MeOH, 40:1, R_f0.17) as a light yellow oil:

1

[R]²⁵-3.4 (c 1.28, CHCl₃); H NMR (CDCl₃) δ 7.40-7.15 (m,

D

5 H), 5.16 (s, 1 H), 4.25 (m, 1 H), 4.10-3.90 (m, 2 H), 4.00 (s,

1 H), 3.70 (dd, J ) 13.6, 2.9 Hz, 1 H), 3.24 (d, J ) 12.8 Hz, 1

H), 2.76 (d, J ) 12.1 Hz, 1 H), 2.57 (m, 2 H), 1.27 (d, J ) 6.2

Hz, 3 H); ¹³C NMR (CDCl₃) δ 135.2 (s), 129.9 (d, 2 C), 128.4

(d, 2 C), 127.8 (d), 102.4 (d), 77.8 (d), 74.5 (d), 59.2 (t), 58.6

(d), 57.7 (t), 51.3 (t), 15.1 (q); MS m/z 249 (M⁺, 2), 91 (100).

Anal. Calcd for C₁₄H₁₉NO₃: C, 67.45; H, 7.68; N, 5.62. Found:

C, 67.11; H, 7.91; N, 5.44.

Meth yl (1S,5S,7R)-6,8-Dioxa -3-a za bicyclo[3.2.1]octa n e-

7-exo-ca r boxyla te (22). Compound 16 (512 mg, 1.95 mmol)

was dissolved in MeOH (100 mL), and 20% Pd(OH)₂/C (140

mg) was added. The stirring suspension was left overnight at

room temperature under a H₂atmosphere, and then the

catalyst was removed by filtration over a Celite layer and

washed with MeOH. The solution was then filtered through a

column filled with Amberlyst A-21 beads giving, after evapora-

tion of the solvent, pure 22 (334 mg, 99%) as a colorless oil:

1

[R]²⁵-55.0 (c 0.64, CHCl₃); H NMR (CDCl₃) δ 5.53 (s, 1 H),

D

4.72 (s, 1 H), 4.49 (s, 1 H), 3.71 (s, 3 H), 3.17 (dd, J ) 13.6, 1.8

Hz, 1 H), 2.83 (m, 2 H), 2.68 (d, J ) 13.6 Hz, 1 H), 2.55 (br s,

1 H); ¹³C NMR (CDCl₃) δ 170.9 (s), 101.9 (d), 77.2 (d), 75.3 (d),

52.0 (q), 48.3 (t), 47.4 (t); MS m/z 173 (M⁺, 7), 57 (100); IR

(CDCl₃) 3345, 1755 cm^-1. Anal. Calcd for C₇H₁₁NO₄: C, 48.55;

H, 6.40; N, 8.09. Found: C, 48.19; H, 6.21; N, 8.00.

Met h yl (1S,4S,5S,7R)-4-exo-Ben zyl-6,8-d ioxa -3-a za b i-

cyclo[3.2.1]octa n e-7-exo-ca r boxyla te (23). Prepared from

17 (339 mg, 0.96 mmol) as reported for 22. Pure 23 (221 mg,

87%) was obtained as a colorless oil: [R]²⁵-75.8 (c 0.07,

D

1

CHCl₃); H NMR (CDCl₃) δ 7.32-7.10 (m, 5 H), 5.42 (s, 1 H),

4.73 (s, 1 H), 4.58 (br s, 1 H), 3.75 (s, 3 H), 3.43 (d, J ) 13.6

Hz, 1 H), 2.88 (m, 3 H), 2.69 (d, J ) 13.6 Hz, 1 H); ¹³C NMR

(CDCl₃) δ 171.6 (s), 138.5 (s), 129.1 (d, 2 C), 128.6 (d, 2 C),

126.5 (d), 104.1 (d), 78.3 (d), 75.3 (d), 57.2 (d), 52.5 (q), 44.1

(t), 35.3 (t); MS m/z 263 (M⁺, 2), 172 (100%); IR (CDCl₃) 1751

cm^-1. Anal. Calcd for C₁₄H₁₇NO₄: C, 63.87; H, 6.51; N, 5.32.

Found: C, 63.48; H, 6.34; N, 5.11.

Meth yl (1S,4R,5S,7R)-4-en d o-Ben zyl-6,8-d ioxa -3-a za bi-

cyclo[3.2.1]octa n e-7-exo-ca r boxyla te (24). Prepared from

18 (120 mg, 0.34 mmol) as reported for 22. Pure 24 (70 mg,

the solution was concentrated obtaining pure 28 (66 mg, 96%)

1

as the HCl salt: [R]²⁰-35.2 (c 0.5, H₂O); H NMR (D₂O) δ

D

78%) was obtained as a colorless oil: [R]²⁵-27.0 (c 0.38,

5.95 (s, 1 H), 5.03 (s, 1 H), 4.98 (s, 1 H), 3.57 (m, 2 H), 3.34 (m,

2 H). Anal. Calcd for C₆H₁₀NO₄Cl: C, 36.84; H, 5.15; N, 7.16.

Found: C, 36.64; H, 5.22; N, 6.98.

D

1

CHCl₃); H NMR (CDCl₃) δ 7.30-7.10 (m, 5 H), 5.36 (s, 1 H),

4.72 (s, 1 H), 4.56 (br s, 1 H), 3.76 (s, 3 H), 3.15 (dd, J ) 12.8,

1.8 Hz, 1 H), 3.02 (dd, J ) 8.1, 6.2 Hz, 1 H), 2.83 (d, J ) 12.8

Hz, 1 H), 2.63 (dd, J ) 13.6, 6.2 Hz, 1 H), 2.60 (dd, J ) 13.6,

6.2 Hz, 1 H); ¹³C NMR (CDCl₃) δ 171.6 (s), 137.5 (s), 129.2 (d,

2 C), 128.6 (d, 2 C), 126.6 (d), 103.9 (d), 77.3 (d), 75.8 (d), 58.5

(d), 52.5 (q), 48.1 (t), 38.3 (t); MS m/z 263 (M⁺, 1), 172 (100);

Met h yl (1S,5S,7R)-3-(9-F lu or en ylm et h oxyca r b on yl)-

6,8-dioxa-3-azabicyclo[3.2.1]octan e-7-exo-car boxylate (26).

To a stirred solution of 22 (250 mg, 1.44 mmol) in CH₂Cl₂(10

mL) cooled at 0 °C was added FMOC-O-Su (489 mg, 1.45

mmol). The solution was left under stirring for 10 min at 0 °C

Synthesis and Reactivity of Bicycles Derived from BTAa

J . Org. Chem., Vol. 64, No. 20, 1999 7363

and then 24 h at room temperature. The reaction mixture was

filtered through a Celite layer, washed with water, dried over

Na₂SO₄, and finally concentrated to give 26 (557 mg, 98%) as

a white foamy solid: mp 54-55 °C; ¹H NMR (CDCl₃) (1:1

mixture of rotamers) δ 7.75 (d, J ) 7.0 Hz, 2 H), 7.54 (d, J )

7.0 Hz, 2 H), 7.45-7.20 (m, 4 H), 5.66 (s, 1 H), 4.71-4.00 (m,

6 H), 3.78 (s, 3 H), 3.77-2.92 (m, 3 H); ¹³C NMR (CDCl₃) δ

170.5 (s, 1 C), 156.0 (s), 143.6 (s, 2 C), 141.3 (s, 2 C), 128.1 (d),

127.7 (d), 127.0 (d), 124.9 (d), 124.7 (d), 120.0 (d), 100.2 (d),

99.7 (d), 75.6 (d), 75.4 (d), 74.9 (d), 67.6 (t), 67.1 (t), 52.5 (q),

47.8 (t), 47.0 (d), 46.5 (t); MS m/z 178 [(C₁₄H₁₀)⁺, 100]. Anal.

Calcd for C₂₂H₂₁NO₆: C, 66.83; H, 5.35; N, 3.54. Found: C,

66.61; H, 5.52; N, 3.24.

by ¹H NMR analysis of the crude), and pure carboxylic acid

31 (223 mg, 66%) was obtained after chromatography through

a short layer of silica gel (CH₂Cl₂-MeOH, 30:1, R_f0.11) as a

white solid: mp 80-82 °C; [R]²⁰-17.4 (c 0.37, CHCl₃); ¹H

D

NMR (CDCl₃) (1.75:1 mixture of rotamers) δ 7.72 (m, 2 H),

7.53 (m, 2 H), 7.40-7.15 (m, 8 H), 6.83 (m, 1 H), [5.35 (d, J )

1.2 Hz) and 5.22 (d, J ) 1.2 Hz), 1 H], [4.70-4.40 (m) and

4.31 (s), 4 H], 4.20-3.90 (m, 2 H), 3.67-3.20 (m, 2 H), 2.80-

2.40 (m, 2 H); ¹³C NMR (CDCl₃) δ 173.1 and 172.8 (s), 155.8

and 155.2 (s), 143.8 (s), 143.4 (s), 141.4 (s), 136.4 (s), 129.3

(d), 128.8 (d), 128.7 (d), 128.1 (d), 127.9 (d), 127.8 (d), 127.2

(d), 126.9 (d), 126.8 (d), 124.7 (d), 124.6 (d), 120.2 (d), 120.1

(d), 101.4 and 100.9 (d), 76.1 and 75.6 (d), 74.8 (d), 66.9 and

66.7 (t), 57.2 and 56.8 (d), 47.5 and 47.4 (d), 44.4 and 43.9 (t),

34.7 and 34.5 (t); MS (electron-spray) m/z 472 (M⁺+ 1, 60),

413 (11), 250 (43), 264 (59), 179 (100); IR (CDCl₃) 1785, 1703

(1S,5S,7R)-3-(9-F lu or en ylm eth oxyca r bon yl)-6,8-d ioxa -

3-a za b icyclo[3.2.1]oct a n e-7-exo-ca r b oxylic a cid (30).

Meth od A. Salt 28 (28 mg, 0.1 mmol) was suspended in a

solution of Na₂CO₃(22 mg, 0.21 mmol) in water (0.5 mL) and,

after cooling to 0 °C, a solution of FMOC-O-Su (37 mg, 0.11

mmol) in acetone (250 µL) was slowly added under stirring.

Then an additional 250 µL of acetone was added and the

solution left under stirring at room temperature overnight.

Then water (2 mL), 1 M solution of NaHSO₄up to pH 3, and

NaCl up to saturation were added, and the resulting solution

was extracted with CH₂Cl₂. After evaporation of the solvent,

30 (32 mg, 84%) was obtained as a yellowish oil. Meth od B.

Compound 26 (395 mg, 1 mmol) was dissolved in DMSO (10

mL), and 4 N HCl in water (1 mL, 4 mmol) was added under

stirring at room temperature. After 24 h, water (40 mL) was

added and the pH of the solution adjusted to 9 with 3 M NaOH.

The solution was extracted with Et₂O and EtOAc, and the

aqueous layer was treated with 5% HCl to adjust the pH to

2-3 and finally extracted with Et₂O. The organic layer was

dried over Na₂SO₄and evaporated, affording 30 (275 mg, 72%)

as a yellowish oil. Meth od C. N-FMOC amino alcohol 78 (75

mg, 0.20 mmol) was dissolved in DMF (1.3 mL) and, after

cooling to 0 °C, treated with pyridinium dichromate (PDC) (376

mg, 1 mmol). After the mixture was stirred at room temper-

ature for 24 h, water (12 mL) was added, and the solution was

adjusted to pH 10 by 20% NaOH and extracted with Et₂O.

Then 5% HCl was added up to pH 2-3 and the solution

extracted again with Et₂O. The last organic layer was dried

over Na₂SO₄and evaporated affording pure 30 (68 mg, 89%):

¹H NMR (CDCl₃) (1:1 mixture of rotamers) δ 8.53 (br s, 1 H),

7.74 (d, J ) 7.7 Hz, 2 H), 7.53 (d, J ) 7.7 Hz, 2 H), 7.45-7.20

(m, 4 H), 5.67 (s, 1 H), 4.72-2.89 (m, 10 H); ¹³C NMR (CDCl₃)

δ 172.5 (s, 1 C), 155.9 (s), 143.5 (s, 2 C), 143.4 (s, 2 C), 127.8

(d), 127.6 (d), 126.9 (d), 125.0 (d), 124.8 (d), 124.6 (d), 119.9

(d), 100.0 (d), 99.4 (d), 75.4 (d), 75.3 (d), 74.9 (d), 67.5 (t), 67.1

cm^-1

.

(1S,5S,7S)-3-(9-F lu or en ylm eth oxyca r bon yl)-7-exo-h y-

dr oxym eth yl-6,8-dioxa-3-azabicyclo[3.2.1]octan e (78). Pre-

pared as described for compound 26. Starting from amino

alcohol 76 (190 mg, 1.32 mmol), pure 78 (332 mg, 66%) was

obtained after chromatography (CH₂Cl₂-MeOH, 40:1, R_f0.23)

as a colorless oil: [R]²⁰_D-27.3 (c 1.0, CHCl₃); ¹H NMR (CDCl₃)

(1.8:1 mixture of rotamers) δ 7.74 (d, J ) 7.0 Hz, 2 H), 7.54

(d, J ) 7.0 Hz, 2 H), 7.40-7.20 (m, 4 H), 5.49 (s, 1 H), 4.60-

4.15 (m, 5 H), 4.00-3.65 (m, 2 H), 3.54 (m, 2 H), 3.27 (m, 1

H), 3.02 (dd, J ) 25.0, 12.8 Hz, 1 H); ¹³C NMR (CDCl₃) δ 155.0

(s), 143.9 (s, 2 C), 141.4 (s, 2 C), 127.8 (d, 2 C), 127.1 (d, 2 C),

125.1 (d, 1 C), 124.9 (d, 1 C), 120.1 (d, 2 C), 99.2 and 98.7 (d),

78.2 and 78.1 (d), 73.2 and 72.8 (d), 67.7 and 67.1 (t), 64.0 (t),

48.2 (t), 47.0 (d), 46.9 (t); MS (electron-spray) m/z 368 (M⁺

1, 72), 179 (100); IR (CDCl₃) 1692 cm^-1. Anal. Calcd for C₂₁H₂₁

+

-

NO₅: C, 68.65; H, 5.76; N, 3.81. Found: C, 68.41; H, 5.94; N,

3.49.

(1R,4S,5R,7S)-3-(9-Flu or en ylm eth oxyca r bon yl)-4-en d o-

m et h yl-7-en d o-h yd r oxym et h yl-6,8-d ioxa -3-a za b icyclo-

[3.2.1]octa n e (79). Prepared as described for compound 26.

Starting from amino alcohol 77 (367 mg, 2.30 mmol), pure 79

(606 mg, 69%) was obtained after chromatography (CH₂Cl₂-

MeOH, 40:1, R_f0.10) as an oil: [R]²⁰-36.5 (c 0.17, CHCl₃);

D

¹H NMR (CDCl₃) δ 7.72 (d, J ) 6.9 Hz, 2 H), 7.53 (d, J ) 7.4

Hz, 2 H), 7.40-7.20 (m, 4 H), 5.12 (d, J ) 2.5 Hz, 1 H), 4.60-

4.40 (m, 3 H), 4.18 (t, J ) 5.8 Hz, 1 H), 4.03 (m, 1 H), 3.78 (m,

1 H), 3.60 (m, 1 H), 3.40-3.23 (m, 3 H), 1.13 (d, J ) 6.3 Hz, 3

H); ¹³C NMR (CDCl₃) δ 157.2 (s), 143.8 (s, 2 C), 141.3 (s, 2 C),

127.6 (d, 2 C), 127.0 (d, 2 C), 124.6 (d, 2 C), 119.9 (d, 2 C),

101.4 (d), 76.6 (d), 71.6 (d), 66.9 (t), 61.0 (t), 53.5 (d), 47.1 (d),

44.0 (t), 16.5 (q); MS (electron-spray) m/z 382 (M⁺+ 1, 100),

179 (55). Anal. Calcd for C₂₂H₂₃NO₅: C, 69.28; H, 6.08; N, 3.67.

Found: C, 69.01; H, 6.37; N, 3.42.

(t), 47.6 (t), 47.3 (d), 46.9 (t), 46.5 (t); FAB-MS m/z 382 (M⁺

+

1), 179 [(C₁₄H₁₁)⁺, 100].

Meth yl (1S,4S,5S,7R)-3-(9-Flu or en ylm eth oxycar bon yl)-

4-exo-b en zyl-6,8-d ioxa -3-a za b icyclo[3.2.1]oct a n e-7-exo-

ca r boxyla te (27). Prepared as described for compound 26.

Starting from 23 (200 mg, 0.76 mmol), pure 27 (359 mg, 97%)

was obtained after chromatography (CH₂Cl₂-MeOH, 30:1, R_f

(1R,4S,5R,7R)-3-(9-Flu or en ylm eth oxycar bon yl)-4-en do-

m et h yl-6,8-d ioxa -3-a za b icyclo[3.2.1]oct a n e-7-en d o-ca r -

boxylic Acid (32). Prepared by oxidation with PDC in DMF

of 79 (313 mg, 0.82 mmol) as reported for 30, Method C. Pure

acid 32 (295 mg, 91%) was obtained after chromatography

(CH₂Cl₂-MeOH, 40:1, 0.5% AcOH, R_f0.12) as a low-melting

0.82) as a white solid: mp 55-56 °C; [R]²⁰-20.7 (c 0.19,

D

CHCl₃); ¹H NMR (CDCl₃) (2.5:1 mixture of rotamers) δ 7.78-

7.65 (m, 2 H), 7.60-7.45 (m, 2 H), 7.40-7.00 (m, 8 H), 6.90

(m, 1 H), [5.34 (s) and 5.25 (d, J ) 1.5 Hz), 1 H], 4.70-3.88

(m, 6 H), [3.75 (s) and 3.73 (s), 3 H], 3.65-3.25 (m, 2 H), 2.76-

2.48 (m, 2 H); ¹³C NMR (CDCl₃) δ 170.6 and 168.5 (s), 155.8

(s), 143.8 (s), 143.5 (s), 141.4 (s), 136.6 (s), 129.3 (d), 129.2 (d),

128.7 (d), 128.6 (d), 127.8 (d), 127.7 (d), 127.2 (d), 126.7 (d),

124.7 (d), 120.2 (d), 120.1 (d), 101.1 and 100.8 (d), 75.9 (d),

75.3 (d), 66.8 (t), 57.4 (d), 52.6 (q), 47.4 (d), 44.0 (t), 34.8 (t);

MS (electron-spray) m/z 486 (M⁺+ 1, 45), 426 (10), 336 (16),

264 (59), 179 (100); IR (CDCl₃) 1745, 1699 cm^-1. Anal. Calcd

for C₂₉H₂₇NO₆: C, 71.74; H, 5.60; N, 2.89. Found: C, 71.62;

H, 5.84; N, 2.51.

solid: [R]²⁰-5.6 (c 0.5, CHCl₃); ¹H NMR (CDCl₃) δ 7.98 (s, 1

D

H), 7.73 (d, J ) 7.0 Hz, 2 H), 7.53 (d, J ) 7.0 Hz, 2 H), 7.40-

7.20 (m, 4 H), 5.28 (d, J ) 3.0 Hz, 1 H), 4.78 (t, J ) 5.0 Hz, 1

H), 4.58-4.14 (m, 5 H), 3.66 (d, J ) 13.4 Hz, 1 H), 3.48 (m, 2

H), 1.33 (d, J ) 6.6 Hz, 3 H); ¹³C NMR (CDCl₃) δ 170.0 (s),

156.5 (s), 143.5 (s, 2 C), 140.8 (s, 2 C), 127.3 (d, 2 C), 126.7 (d,

2 C), 124.6 (d, 2 C), 119.5 (d, 2 C), 102.3 (d), 75.8 (d), 71.6 (d),

66.9 (t), 61.0 (t), 53.4 (d), 46.7 (d), 44.1 (t), 15.4 (q); MS

(electron-spray) m/z 396 (M⁺+ 1, 100), 179 (58).

BTG-P r o-OH (80). Resin WANG-Pro-H (80 mg, 52 µmol,

loading capacity 0.65 mmol/g) was suspended in DMF (150

mL), and compound 30 (40 mg, 0.105 mmol) was added. To

this suspension was then added a solution (1.253 mL) prepared

dissolving diisopropylcarbodiimide (65 µL) and 1-hydroxyben-

zotriazole (57 mg) in 5 mL of DMF, followed by the addition

of N,N′-diisopropyl-N-ethylamine (27 µL). The resulting reac-

tion mixture was left under stirring 4 days. After filtration,

the resin was washed and then treated with Ac₂O (20 µL) in

DMF (1 mL), in the presence of a catalytic amount of

(1S,4S,5S,7R)-3-(9-F lu or en ylm eth oxyca r bon yl)-4-exo-

ben zyl-6,8-d ioxa -3-a za bicyclo[3.2.1]octa n e-7-exo-ca r box-

ylic Acid (31). The hydrolysis of 27 (350 mg, 0.72 mmol) was

carried out as reported for 26, but the resulting solution was

stirred at room temperature for 3 d after the addition of 4 N

HCl. Hydrolysis was not complete (30% of remaining ester 27

7364 J . Org. Chem., Vol. 64, No. 20, 1999

Guarna et al.

4-(dimethylamino)pyridine (40 µL, 0.1 M solution in DMF) for

3 h. The resin was then washed with DMF, MeOH, and CH₂-

Cl₂and dried. The resin was then suspended in a mixture of

CF₃COOH (0.95 mL) and water (50 µL) and left under stirring

for 4 h. After filtration, the suspension was concentrated and

lyophilized, obtaining 80 as a white solid (38 mg, 76%). HPLC

analysis of 80 showed the presence of only one a peak, having

the following FAB-MS spectrum: m/z 479 (M⁺+ 1, 60), 179

[(C₁₄H₁₁)⁺, 100].

for the solid-phase synthesis, TOCSY, and FAB-MS

analyses carried out in his laboratory and Dr. Thomas

Hack for suggesting the BTAa nomenclature. Prof. G.

Moneti (University of Florence) is acknowledged for

electron-spray MS spectra. The authors also thank Miss

N. Cini and Mr. M. Van Sterkenburg for carrying out

some experiments and Dr. C. Faggi, Mrs. B. Innocenti,

and Mr. S. Papaleo for technical assistance.

Ack n ow led gm en t. The authors thank Cofin 1998-

2000 and the University of Florence for financial sup-

port. E.G.O. thanks the University of Florence for a

cofinanced grant (Assegno di ricerca). A.T. thanks the

Socrates exchange program. Dr. R. J . Leatherbarrow

(Imperial College, London) is gratefully acknowledged

Su p p or tin g In for m a tion Ava ila ble: Tables 2 and 3

containing the most significant ¹H NMR resonance data of

compounds 1-14, 16-25, and 28-29. This material is avail-

able free of charge via the Internet at http://pubs.acs.org.

J O9904967

Article Doi

Synthesis and reactivity of bicycles derived from tartaric acid and α- amino acids: A novel class of conformationally constrained dipeptide isosteres based upon enantiopure 3-aza-6,8-dioxabicyclo[3.2.1] octane-7- carboxylic acid

DOI: 10.1021/jo9904967

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Full text of DOI:10.1021/jo9904967

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