Asymmetric synthesis of functionalized bicyclic β-amino alcohols by cascade hydrometallation-cyclization-reduction of glycinyl-substituted alkenylsulfoximines - Application to the synthesis of an aggrecanase inhibitor mimic

FULL PAPER

DOI: 10.1002/ejoc.201100868

Asymmetric Synthesis of Functionalized Bicyclic β-Amino Alcohols by Cascade

Hydrometallation–Cyclization–Reduction of Glycinyl-Substituted

Alkenylsulfoximines – Application to the Synthesis of an Aggrecanase Inhibitor

Mimic

Serdar Acikalin,^[a][‡]Gerhard Raabe,^[a]Jan Runsink,^[a]and Hans-Joachim Gais*^[a]

Keywords: Asymmetric synthesis / Cascade reactions / Cyclization / Hydrometallation / Enzyme inhibitors / β-Amino

alcohols / Sulfoximines / Aggrecanase inhibitor mimic

The treatment of exocyclic alkenylsulfoximines, which carry

an α-glycinyl group at the allylic position, with HAliBu₂

caused cascade hydroalumination–cyclization–reduction and

delivered the corresponding enantio- and diastereopure sulf-

oximine-substituted bicyclic β-amino alcohols with a bicy-

clo[3.3.0]octane and bicyclo[4.3.0]nonane skeleton in high

yields. Three consecutive stereogenic C atoms of the bicyclic

β-amino alcohols were generated in the cascade reactions

with high diastereoselectivities. Application of the hydro-

alumination–cyclization–reduction to a ketal-substituted six-

membered exocyclic alkenylsulfoximine afforded the corre-

sponding sulfoximine-substituted β-amino alcohol with a

treatment of a sulfoximine-substituted β-amino alcohol with

chloro- and iodoformates stereoselectively furnished the cor-

responding chloro- and iodo-substituted β-amino alcohols.

Finally, the feasibility of a dehydration and elimination of

sulfoximine-substituted β-amino alcohols with formation of

the corresponding amino-substituted alkenylsulfoximine and

allylic amine was demonstrated. An enantio- and dia-

stereopure protected aggrecanase inhibitor mimic was syn-

thesized in high yield starting from the sulfoximine-substi-

tuted bicyclic β-amino alcohol with a bicyclo[4.3.0]nonane

skeleton and (R)-2-(3-benzyloxy)benzyl-4-tert-butoxy-4-

oxobutanoic acid. Coupling of both building blocks gave the

ketal-functionalized bicyclo[4.3.0]nonane skeleton. Reduction corresponding succinamide, the tert-butoxycarbonyl group

of a sulfoximine-substituted β-amino alcohol gave the parent

β-amino alcohol, whereas its oxidative deamination afforded

the corresponding sulfonyl-substituted β-amino alcohol. The

of which was converted into the corresponding O-benzyl-hy-

droxycarbamoyl group.

oped for the asymmetric synthesis of carbocyclic β-amino

alcohols including the ring opening of bicyclic epoxides,^[7]

reductive cyclization of C=O and C=N group-containing

Introduction

Carbocyclic β-amino alcohols are of considerable impor-

tance as chiral auxiliaries and catalysts^[1]and building

blocks of enzyme inhibitors.^[2]For example, bicyclic β-

amino alcohols serve as key components of potent aggre-

canase^[3]and HIV-1 protease^[4]inhibitors. We envisioned a

stereoselective synthesis of the sulfoximine-substituted bicy-

clic β-amino alcohols I through metal hydride mediated cas-

cade hydrometallation–cyclization–reduction of the glycin-

yl-substituted alkenylsulfoximines II through the metallated

sulfoximines III and keto sulfoximines IV with the genera-

tion of three stereogenic centres (C*, Scheme 1). We have

previously described an asymmetric synthesis of glycinyl-

substituted alkenylsulfoximines II through γ-aminoalk-

ylation of the allylic sulfoximines V with the imino ester VI

(Scheme 2).^[5,6]Although several methods have been devel-

[a] Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

Fax: +49-241-8092665

Scheme 1. Bicyclic β-amino alcohols from cascade hydrometalla-

tion–cyclization–reduction of glycinyl-substituted alkenylsulf-

oximines.

E-mail: gais@rwth-aachen.de

[‡] Present address: De Villegas De Clercamp 182/4,

1853 Strombeek-Bever, Belgium

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precursors^[8,9]and hydrogenation of amino cycloalk- interest are the sulfoximine-substituted derivatives X [R =

anones,^[10]

a

cascade hydrometallation–cyclization–re- S(O)(NMe)Ph] because of the possibility of a specific in-

duction has rarely been applied.^[11,12]

hibitory coordination of the Lewis basic sulfoximine

group^[13]to the Zn atom in the active site of aggrecanase.^[3]

Scheme 2. Asymmetric synthesis of glycinyl-substituted alkenyl-

sulfoximines.

Because of the particular reactivity of the sulfoximine

group,^[13,14]the β-amino alcohols I should also allow the

synthesis of substituted bicyclic β-amino alcohols of type

VII and VIII carrying a sulfonyl group, H, Cl and I atom

instead of the sulfoximine group (Scheme 3).

Scheme 4. Aggrecanase inhibitor IX and aggrecanase inhibitor

mimics X and XI.

Results and Discussion

Hydroalumination–Cyclization–Reduction

According to Scheme 1 the synthesis of the bicyclic

amino alcohols I from the alkenylsulfoximines II require

chemo- and stereoselective hydrometallations in the first

and third steps. Diisobutylaluminumhydride was selected as

the reagent because of its ability to perform hydroalumi-

nations of both C=C and C=O double bonds.^[16]Model

experiments with alkenylsulfoximines 1^[17]and 3^[5]

(Scheme 5) were performed in order to seek answers to the

following questions: 1) do the double bonds of alkenyl-

sulfoximines react with HAliBu₂? 2) is hydroalumination of

the C=C double bond with HAliBu₂faster than that of the

C=O double bond? and 3) is the hydroalumination stereo-

selective?

Scheme 3. Substituted bicyclic β-amino alcohols.

Here we report on the asymmetric synthesis of sulfox-

imine-substituted bicyclic β-amino alcohols of type I featur-

ing stereoselective cascade hydroalumination–cyclization–

reduction of II using diisobutylaluminumhydride as the

metal hydride. Also reported are the syntheses of β-amino

alcohols of type VII and VIII through chemo- and stereose-

lective transformations of the sulfoximine group of I. Fi-

nally, we describe the asymmetric synthesis of a protected

aggrecanase inhibitor mimic of type X [R = S(O)(NMe)Ph]

using the corresponding sulfoximine-substituted β-amino

alcohol I as the starting material (Scheme 4). The metallo-

protease aggrecanase (ADAMTS5)^{[15a,15b,15d]}plays an im-

portant role in cartilage aggrecan degradation, a process

believed to be a leading cause of osteoarthritis and rheuma-

toid arthritis.^[15]The quest for better arthritis therapy led

to an intensive study of aggrecanase inhibitors.^[3,15c,15e]It

was recently found that the hydroxamic acid derivative IX

containing a bicyclic β-amino alcohol moiety is an efficient

but unspecific aggrecanase inhibitor.^[3]Crucial to the ac-

tivity of IX is the structure of the β-amino alcohol. There-

fore, we became interested in the synthesis of hydroxamic

acid derivatives X and XI, which carry a bicyclic β-amino

alcohol component of type I, VII and VIII, as potential

aggrecanase inhibitors. The structural variation provided by

the β-amino alcohols I, VII and VIII could perhaps serve

Scheme 5. Hydroalumination of exocyclic alkenylsulfoximines 1

to find new potent inhibitors of aggrecanase. Of particular and 3.

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Asymmetric Synthesis of Bicyclic β-Amino Alcohols

The treatment of alkenylsulfoximine 1 with 1.2 equiv. of mine 3 with 5.0 equiv. of HAliBu₂resulted in the envisioned

HAliBu₂gave alkylsulfoximine 2 in 81% yield. A similar cascade hydroalumination–cyclization–reduction to give β-

treatment of glycinyl-substituted alkenylsulfoximine 3 with amino alcohol 5 with Ն 98% de (NMR) in 86% yield and

2.0 equiv. of HAliBu₂afforded glycinyl-substituted alkyl- the diastereomeric β-amino alcohol 6 with Ն 98% de

sulfoximine 4 with Ն 98% de in 35% yield. The low yield (NMR) in 7% yield (Scheme 6). The application of

of 4 was in part due to isolation problems. The cis configu- 3.0 equiv. of HAliBu₂afforded 5 in only 50% yield. The

ration of 4 was determined by NOE experiments, which re- configuration of β-amino alcohol 5 was determined by X-

vealed a strong correlation between the H atoms at the ray crystal structure analysis (Figure 1)^[18]and that of dia-

stereogenic C atoms of the cyclohexane ring. Although the stereomeric alcohol 6 was secured by NOE experiments.

diastereoselectivity of the hydroalumination of 3 was high, Strong NOEs were recorded not only between H-3a and H-

not much can be said about the competition between the 7a but also between H-1 and H-2, H-1 and H-3, and H-2

hydroalumination of the C=C and C=O double bonds be- and H-3. No NOEs were observed between H-2 and H-3a

cause of the low yield of 4.

or H-2 and H-7a.

Having obtained favourable results concerning the dia-

The three new stereogenic centres of 5 were formed in

stereoselectivity of the hydroalumination of II, the next the cascade reactions of 3 with high diastereoselectivities.

steps following the hydroalumination, the cyclization of the This is rationalized as follows: according to X-ray crystal

putative α-diisobutylaluminosulfoximine III and the re- structure analysis and NMR spectroscopy the cyclohexane

duction of ketone IV were studied. After some experimen- ring of 3^[5]preferentially adopts a chair-like conformation

tation it was found that the treatment of the alkenylsulfoxi- in which the glycinyl group occupies a pseudoaxial position

(Scheme 7). Because of the Lewis basicity of N-methylsulf-

oximines,^[13]sulfoximine 3 and HAliBu₂perhaps engaged in

the formation of complex 7, which underwent a HAliBu₂

addition^[16]by the four-membered cyclic transition state 7A

to the C=C double bond from the Si–Re side and stereose-

lectively gave R-configured C_α-metallated sulfoximine 8.

Sulfoximine 8 is perhaps configurationally unstable and suf-

fers a migration of the diisobutylaluminum group to the N

atom (or O atom) with formation of aminosulfoxonium

ylide 9. Both the ylide and organoaluminum species are per-

haps in equilibrium. C_α-Titanated sulfoximines show a dy-

namic C,N-migratory behaviour of this type.^[19]Alterna-

tively, 7 may have undergone a HAliBu₂addition to the C

and N atoms through the six-membered cyclic transition

state 7B and directly delivered ylide 9. The stereoselective

cyclization of 9 by transition state 9A involving an attack

of the carbonyl group at the Si side of the C_αatom afforded

ketone 10. The attack of the carbonyl group at the Re side

of the C_αatom, as depicted in transition state 9B, seems to

be unfavoured because of steric reasons. Subsequently,

ketone 10 perhaps reacted with a second equivalent of HAl-

iBu₂with coordination to the sulfoximine group and

formed 11, which underwent an intramolecular H–Al bond

addition to the carbonyl group at the Si side and stereose-

lectively afforded alcoholate 12.

Scheme 6. Hydroalumination–cyclization–reduction of the cyclo-

hexanoid alkenylsulfoximine 3.

The highly selective cascade reactions of alkenylsulfox-

imine 3 prompted a study of the analogous ketal-substi-

tuted alkenylsulfoximine 13 (Scheme 8), which was obtained

from the corresponding cyclic allylic sulfoximine and N-

tert-butylsulfonyl imino ester in 75% yield with Ն 98%

de.^[20]Gratifyingly, treatment of 13 with 5.0 equiv. of HAl-

iBu₂afforded β-amino alcohol 14 with Ն 98% de (NMR)

in 72% yield and the diastereomeric alcohol 15 with Ն 98%

de (NMR) in 15% yield. The configurations of 14 and 15

were determined by NOE experiments. In the case of 14 a

medium NOE was observed between H-7a and H-2, and

strong NOEs were recorded between H-3a and H-7a, and

H-2 and H-3a. In addition, a strong NOE was observed

between H-1 and H-3 and a NOE between H-3 and H-3a

Figure 1. Crystal structure of β-amino alcohol 5. Color code: C

black, S yellow, O red, N green.

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Scheme 8. Hydroalumination–cyclization–reduction of the cyclo-

hexanoid alkenylsulfoximine 13.

Because of the ready formation of β-amino alcohols 5,

6, 14 and 15, which have a bicyclo[4.3.0]nonane skeleton, it

was of interest to see whether β-amino alcohols of this type

with a bicyclo[3.3.0]octane skeleton were also accessible by

this route. The similar treatment of cyclopentanoid alkenyl-

sulfoximine 16^[5]with 5.0 equiv. of HAliBu₂afforded β-

amino alcohol 17 with Ն 98% de (NMR) in 50% yield and

the diastereomeric alcohol 18 with Ն 98% de (NMR) in

21% yield (Scheme 9). The configuration of β-amino

alcohol 17 was determined by X-ray crystal structure analy-

sis (Figure 2),^[18]and that of diastereomeric alcohol 18 was

secured by NOE experiments. Strong NOEs were observed

not only between H-3a and H-6a but also between H-1 and

H-2, H-1 and H-3, and H-2 and H-3. No NOEs were re-

corded between H-3 and H-3a or H-1 and H-6a.

Scheme 7. Rationalization of the stereochemical course of cascade

hydroalumination–cyclization–reduction.

was not observed. For 15 strong NOEs were observed be-

tween H-1 and H-2, H-2 and H-3, and H-3a and H-7a. No

NOEs were recorded between H-2 and H-3a or H-2 and

H-7a.

Scheme 9. Hydroalumination–cyclization–reduction of the cyclo-

pentanoid alkenylsulfoximine 16.

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Asymmetric Synthesis of Bicyclic β-Amino Alcohols

and H-3a and H-8a. No NOEs were observed between H-

1 and H-8a or H-3 and H-3a. In the case of diastereomer

21 strong NOEs were not only recorded between H-3a and

H-8a but also between H-1 and H-2, H-2 and H-3, and H-

1 and H-3. In the case of 22 strong NOEs between the H-

atoms at the stereogenic ring C atoms gave proof of cis con-

figuration. Although the hydroalumination and cyclization

occurred in the case of 19 with high diastereoselectivities,

the low yields of 20 and 21 show that the attainment of

bicyclic amino alcohols of type I with a bicyclo[5.3.0]decane

skeleton by the cascade reactions is less feasible.

So far only the hydroalumination–cyclization–reduction

of cyclic alkenylsulfoximines has been studied. This led to

the question of whether the cascade reactions are also appli-

cable to acyclic alkenylsulfoximines. The treatment of the

alkenylsulfoximine 23^[5]with 5.0 equiv. of HAliBu₂afforded

cyclopentanoid β-amino alcohol 24 with Ն 98% de (NMR)

in 19% yield and diastereomeric alcohol 25 with Ն 98% de

(NMR) in 6% yield (Scheme 11). In addition, alkylsulfox-

imine 26 was obtained in 13% yield. The configurations of

diastereomeric alcohols 24 and 25 were determined by NOE

experiments. For 24 strong NOEs were recorded between

H-1 and H-3, and H-2 and H-5, and weak NOEs between

H-1 and H-2, H-2 and H-3, and H-1 and H-5. In the case

of 25 strong NOEs were observed between H-1 and H-2,

H-1 and H-3, and H-2 and H-3. The low yields of 24, 25

and 26 were in part due to isolation problems. Optimization

experiments were, however, not carried out. An indication

that the hydroalumination of 23 might have occurred with

Figure 2. Crystal structure of β-amino alcohol 17. Color code: C

black, S yellow, O red, N green.

Finally, the feasibility of the hydroalumination–cycliza-

tion–reduction of cycloheptanoid alkenylsulfoximine 19 was

probed. The similar treatment of alkenylsulfoximine 19^[5]

with 5.0 equiv. of HAliBu₂afforded β-amino alcohol 20

with Ն 98% de (NMR) in 17% yield and the diastereomeric

alcohol 21 with Ն 98% de (NMR) in 16% yield

(Scheme 10). However, the major product was hy-

droxymethyl-substituted alkylsulfoximine 22, which was

isolated with Ն 98% de (NMR) in 50% yield. The configu-

rations of the diastereomeric alcohols 20 and 21 and of the

primary alcohol 22 were determined by NOE experiments.

For 20 strong NOEs were observed between H-1 and H-3,

Scheme 10. Hydroalumination–cyclization–reduction of cyclohept-

anoid alkenylsulfoximine 19.

Scheme 11. Hydroalumination–cyclization–reduction of the acyclic

alkenylsulfoximine 23.

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high chemoselectivity at the C=C double bond was pro- haps unfavoured because of a steric interaction between the

vided by the reaction of the N-allyl derivative of 23 with phenyl group and the glycinyl group at the allylic position.

2 equiv. of HAliBu₂, which gave the corresponding alkyl- Finally, alcohols 32 and 33 experienced a diastereoselective

sulfoximine ester in 91% yield.^[21]Interestingly, the cycliza- cyclization^[22,23e]as such or at the stage of the correspond-

tions of the intermediate acyclic aminosulfoxonium ylides ing aluminum alcoholates with formation of the furan de-

(not shown) leading to 24 and 25 occurred with similarly rivatives 28 and 30, respectively.

high diastereoselectivities as those of the ylides derived

from the exocyclic alkenylsulfoximines (cf. Scheme 7).

The synthesis of the E-configured alkenylsulfoximines 3

and 19 from the corresponding sulfoximine-substituted al-

lyltitanium complexes and N-tert-butylsulfonyl imino ester

was accompanied by the formation of the corresponding

diastereomeric Z-configured alkenylsulfoximines 27 and 29

(Scheme 12).^[5]Having the isomers 27 and 29 in hand, it

was of interest to study their reactivity towards HAliBu₂.

Surprisingly, the treatment of 27 with 5.0 equiv. of HAliBu₂

did not give 5 or a diastereomer thereof but the aminofuran

derivative 28 with Ն 98% de (NMR) in 48% yield. The

relatively low yield was in part due to isolation problems.

Similarly, cycloheptanoid alkenylsulfoximine 29 afforded af-

ter treatment with 5.0 equiv. of HAliBu₂the amino furan

derivative 30 with Ն 98% de (NMR) in 77% yield. The

configurations of 28 and 30 were assigned based on NOE

experiments, which revealed strong NOEs between the H

atom at the bridgehead positions and the H atoms at the α-

position to the sulfoximine group.

Scheme 13. Rationalization of the formation of furans 28 and 30.

Selective Transformations of Sulfoximine-Substituted β-

Amino Alcohols

The transformation of the sulfoximine group of the bicy-

clic β-amino alcohols to other functional groups would sig-

nificantly enhance their versatility as building blocks for the

synthesis of drug candidates and as chiral auxiliaries and

catalysts. Thus, sulfoximine-substituted β-amino alcohol 5

was subjected to a number of transformations, which we

and others have developed for sulfoximines. The treatment

Scheme 12. Reduction–cyclization of the Z-configured cyclic alken-

ylsulfoximines 27 and 29.

In order to rationalize the diastereoselective hydroalumi- of sulfoximine 5 with iodophenylformate led to the forma-

nation of alkenylsulfoximine 3, the prior formation of com- tion of iodo-substituted β-amino alcohol 35, which was iso-

plex 7 was proposed, which underwent an intramolecular lated with Ն 98% de (NMR) in 77% yield (Scheme 14).

C,C/C,N addition of the hydride through transition states

We have previously shown that this type of substitution

7A and 7B, respectively (cf. Scheme 7). The Z-configured of the sulfoximine group commences with an acylation at

alkenylsulfoximines 27 and 29 are also expected to form the N atom of the sulfoximine group,^[23]which should have

complexes of type 31 with HAliBu₂(Scheme 13). Because afforded in the present case the aminosulfoxonium salt 34.

of the Z-configuration of complexes 31, they can, unlike Salt 34 then underwent a S_N2 reaction and delivered under

the E-configured 7, undergo both an intramolecular C,C/ inversion of configuration the iodide 35. It is noteworthy

C,N hydroalumination through transition states 31A and a that the substitution of the aminosulfoxonium group of 34

C,O hydroalumination by transition state 31B leading to a by iodide was not accompanied by an intramolecular sub-

reduction of the ester group with formation of the corre- stitution by the hydroxyl group under epoxide formation.

sponding alcohols 32 and 33. Transition state 31A is per- The sulfinamide 36^[23e,23f]was isolated in 75% yield. We

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Asymmetric Synthesis of Bicyclic β-Amino Alcohols

Scheme 14. Substitution of the sulfoximine group of 5 by an I

atom.

Scheme 15. Substitution of the sulfoximine group of 5 by a Cl

atom.

have previously shown that the substitution of the N-meth-

ylsulfoximine group with iodoformate proceeds with com-

plete retention of the configuration at the S atom.^[23e,23f]

The configuration of iodide 35 was determined by NOE

experiments, which showed strong correlations between H-

2 and H-3, H-3 and H-3a, and H-3a and H-7a.

Generally, the reaction of an alkylsulfoximine with a

chloroformate gives the corresponding chloride.^[23]There-

fore, sulfoximine 5 was treated with 1-chloroethyl chloro-

formate, which afforded chloride 40 with Ն 98% de (NMR)

in 41% yield (Scheme 15). Sulfoximine 5 was most likely

converted by the formate to the N-(acylamino)sulfoxonium

chloride 37, which underwent a S_N2 reaction with the chlo-

ride ion and gave 40. The configuration of chloride 40 was

determined by NOE experiments, which revealed strong

correlations between H-2 and H-3, H-3 and H-3a, and H-

3a and H-7a. Surprisingly, ketone 41 was also isolated in

27% yield. Because of the lower nucleopilicity of the chlo-

ride compared to the iodide ion, salt 37 presumably lost in

a competing reaction sulfinamide 38 with formation of the

carbenium ion 39, which underwent a 1,2-H shift^[24]and,

after deprotonation, gave ketone 41. The sulfinamide 38,

whose formation has been demonstrated in similar cases,^[23]

was not isolated.

Scheme 16. Oxidative deamination of sulfoximine 5.

Alkenylsulfoximines offer a considerable synthetic poten-

tial through the application of, for example, Michael^[5]and

cross-coupling reactions.^[27]Therefore, the dehydration of

the alcohol 5 was studied. The treatment of 5 with ethyl

azodicarboxylate and triphenylphosphane^[28]gave alkenyl-

sulfoximine 43 in 90% yield (Scheme 17).

The sulfoximine group conveys additional basicity to the

cyclic β-amino alcohols, which can perhaps be detrimental

in some synthetic application of the β-amino alcohols.

Therefore, sulfoximine 5 was submitted to an oxidative de-

Scheme 17. Dehydration of the hydroxy sulfoximine 5.

Finally, the reduction of the sulfoximine group^[29,30]of 5

amination with m-chloroperbenzoic acid,^[25]which afforded was probed. The treatment of sulfoximine 5 with aluminum

sulfone 42 in 83% yield (Scheme 16). The sulfonyl group amalgam caused, however, a reductive elimination^[31]and

is considerably less basic than the sulfoximine group and gave alkene 44 in 80% yield (Scheme 18). The alkene can

provides further possibilities for the synthetic application of perhaps serve as a versatile starting material for the synthe-

the β-amino alcohols.^[26]

sis of the corresponding dihydroxy- and hydroxyamino-sub-

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stituted bicyclic β-amino alcohols. A clean reduction of

sulfoximine 5 was achieved upon treatment with Raney

nickel, which furnished β-amino alcohol 45 in 92% yield.

Scheme 20. Deprotection of sulfonamide 5.

The acid 51, which was required as the starting material

for the synthesis of succinic acid 48, was obtained in 72%

overall yield through alkylation of the lithium enolate of

tert-butylacetate with bromide 49^[33]and hydrolysis of the

thus formed ester 50 (Scheme 21). The asymmetric synthe-

sis of succinic acid 48 was carried out by the oxazolidinone

method,^[34]which has already been successfully applied to

the synthesis of structurally related acids.^[35,36]Coupling of

acid 51 with chiral auxiliary 52 gave oxazolidinone 53 in

82% yield. The successive treatment of 53 with sodium

hexamethyldisilazide and tert-butylbromoacetate afforded

substituted amide 54 with Ն 98% de (NMR) in 71% yield.

Amide 54 was assigned as the R-configuration on the basis

of literature precedent.^[34–36]Hydrolysis of amide 54 with

LiOH/H₂O₂furnished the R-configured succinic acid 48 in

97% yield.

Scheme 18. Elimination and reduction of the hydroxy sulfoximine

5.

Synthesis of a Protected Aggrecanase Inhibitor Mimic

The hydroxamic acid derivative IX (cf. Scheme 4) is a po-

tent aggrecanase inhibitor,^[3]the activity of which crucially

depends on the β-amino alcohol moiety. The cyclic β-amino

alcohols 5, 6, 14, 15, 17, 18, 20, 21, 24, 25, 35, 40, 42 and

45 should serve to further probe the relevance of this struc-

tural unit for the activity of aggrecanase inhibitors of type

IX. In the first step, we envisioned the synthesis of the pro-

tected aggrecanase inhibitor mimic 46 with a sulfoximine

group through coupling of β-amino alcohol 47 with suc-

cinic acid derivative 48 (Scheme 19). The amide coupling

would ensure a high degree of structural flexibility in regard

to both key components of X and XI, the amine and acid.

In the case of IX an elegant and efficient, but less flexible,

synthetic strategy in regard to the two components was fol-

lowed featuring the establishment of the stereogenic centre

in α-position to the carbonyl group as the last step.^[13]

Scheme 21. Asymmetric synthesis of the succinic acid 48.

The crucial coupling of the two building blocks, the en-

antio- and diastereopure amine 47 containing 0.5 equiv. of

CF₃SO₃H and acid 48, proceeded readily using the phos-

phonium salt 55^[37]and gave the amide 56 in 95% yield

(Scheme 22). According to NMR spectroscopy, amide 56

Scheme 19. Retrosynthesis of the aggrecanase inhibitor mimic 46.

Cleavage of sulfonamide 5 with CF₃SO₃H in the presence was diasteromerically pure (Ն 98% de). Thus, the hydrolysis

[32]

of anisol in dry CH₂Cl₂

gave amine 47 containing of amide 54 occurred without racemization. It has been

shown previously that the cleavage of amides of type 54

0.5 equiv. of CF₃SO₃H in 94% yield (Scheme 20).

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Asymmetric Synthesis of Bicyclic β-Amino Alcohols

with LiOH/H₂O₂is free of racemization.^[34]Hydrolysis of formations of the sulfoximine group of the β-amino

ester group of 56 furnished the corresponding acid, which alcohols including substitution, oxidative deamination, and

was coupled without isolation with O-benzylhydroxyamine reduction gave access to synthetically interesting enantio-

by applying uronium salt 57.^[38]This afforded the O,O-di- and diastereopure substituted β-amino alcohols. Elimi-

1

benzylhydroxamic acid derivative 46 in 85% yield. The H nation of either both the sulfoximine and hydroxy groups

and ¹³C NMR spectra of 46 at room temperature in CDCl₃or only the hydroxy group afforded the allylic amine and

showed the presence of two species in a ratio of approxi- amino-substituted alkenylsulfoximine, respectively. Because

mately 4:1. At 55 °C reversible coalescence phenomena of of the ready coupling of the bicyclic β-amino alcohol with

the signals of the two species were observed. On the basis the chiral succinic acid derivative, a large number of en-

of these observations we ascribe the two species of 46 to antio- and diastereopure aggrecanase inhibitor mimics with

conformersinrespecttotheC,NbondoftheO-benzyl-hydroxy- different bicyclic β-amino alcohol moieties should be ac-

carbamoyl group.^[39]

cessible.

Experimental Section

General Methods: All reactions involving oxygen- and water-sensi-

tive compounds were carried out under argon using standard

Schlenk and syringe techniques in oven-dried glassware. THF and

toluene were distilled with sodium benzophenone ketyl. CH₂Cl₂,

HNiPr₂, NEt₃, EtNiPr₂, DMF and MeCN were distilled from

CaH₂. Unless otherwise specified, all reagents were purchased from

commercial suppliers and used without further purification. The

enantiopure alkenylsulfoximine 1^[16]was prepared from enantio-

pure (S)-N,S-dimethylphenylsulfoximine^[40,41]and cyclohexanone

according to the literature. The enantio- and diastereopure glycinyl-

substituted alkenylsulfoximines 3,^[5]13,^[21]16,^[5]19,^[5]23,^[5]27^[5]and

29^[5]were synthesized starting from the corresponding enantiopure

allylic sulfoximines and ethyl 2-(tert-butylsulfonylimino)acetate^[6]

according to the literature. The benzylic bromide 49 was prepared

from the corresponding benzylic alcohol according to literature.^[33]

Solutions of HAliBu₂in THF were prepared from neat HAliBu₂

and absolute THF. The concentration of nBuLi in THF was deter-

mined by titration with diphenylacetic acid.^{[42] 1}H NMR spectra

were recorded with Varian VXR 300 (300 MHz), Varian Gemini

300 (300 MHz), Inova 400 (400 MHz) and Unity 500 (500 MHz)

spectrometers. Chemical shifts are given in ppm using Me₃Si (δ =

0.00 ppm) as internal standard. The following abbreviations are

used in order to describe the signals observed in the ¹H NMR

spectra: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet;

m, multiplet; br, broad signal and combinations thereof. Assign-

ments in ¹H NMR spectra were made by GMQCOSY, GNOE and

GTOCSY experiments. ¹³C NMR spectra were ¹H broad band-

decoupled and measured with Varian VXR 300 (75 MHz), Varian

Gemini 300 (75 MHz), Inova 400 (100 MHz) and Unity 500

(125 MHz) spectrometers. The chemical shifts are given in ppm

using Me₃Si (δ = 0.00 ppm) as internal standard. Peaks in the ¹³C

NMR spectra are assigned as u for carbons with zero or two at-

tached protons and d for carbons with one or three attached pro-

tons, as determined from APT experiment. Assignments in ¹³C

NMR spectra were made by DEPT, HETCOR or GHMQC experi-

ments. Mass spectra were recorded with a Finnigan MAT 95 spec-

trometer using either electron ionization (EI, 70 eV) or chemical

ionization (CI, CH₄and isobutane). HRMS were recorded with a

Varian MAT 95 using electron ionization (EI, 70 eV). FTMS analy-

sis was performed with a LTQ Orbitrap XL™ instrument (Thermo

Scientific, Bremen, Germany). Infrared spectra were recorded with

a Perkin–Elmer FTIR 1760 S instrument. Only bands with inten-

sities Ն 10% were listed and the following abbreviations were used:

w = weak, m = middle, s = strong and vs. = very strong. Optical

rotations were measured with a Perkin–Elmer Polarimeter PE 241

and given in gradϫmL/dmϫg, and the concentration c in g/

Scheme 22. Synthesis of the protected aggrecanase inhibitor mimic

46.

Conclusions

Cascade hydroalumination–cyclization–reduction of the

glycinyl-substituted E-configured exocyclic alkenylsulfox-

imines provided an efficient access to enantio- and dia-

stereopure sulfoximine-substituted bicyclic β-amino

alcohols. Although the hydroalumination and cyclization

proceeded with high diastereoselectivities, the selectivities

of the reduction were lower depending on the structure of

the bicyclic ring system. Chemo- and stereoselective trans- 100 mL. The measurements were run at approximately 22 °C. TLC

Eur. J. Org. Chem. 2011, 5991–6008

www.eurjoc.org

5999

S. Acikalin, G. Raabe, J. Runsink, H.-J. Gais

FULL PAPER

was performed using precoated aluminum sheets (Merck silica gel

60 F₂₅₄). Column and flash chromatography were conducted using

silica gel 60 (Merck, 40–63 μm). HPLC separations were performed

with a Varian SD-1 Pump with built-in UV detector (Prostar 320)

and RI detector (Knauer) using a Kromasil Si 100 (100 mmϫ

30 mm) column.

(w), 3113 (w), 3070 (w), 2928 (vs), 2865 (s), 2769 (w), 2694 (w),

2639 (w), 2588 (w), 2508 (w), 2238 (w), 1735 (m), 1580 (w), 1445

(vs), 1314 (m), 1245 (w), 1120 (s), 1025 (m), 912 (w), 874 (w), 750

(w) cm^–1. HRMS: calcd. for C₁₉H₃₁N₂O₃S₂[M – C₃H₅O₂]⁺

399.177613; found 399.177727.

N-[(1S,2R,3R,3aS,7aR)-2-Hydroxy-3-{(S)-N-methylphenylsulfon-

imidoyl}octa-hydro-1H-inden-1-yl]-2-methylpropane-2-sulfonamide

(5) and N-[(1S,2S,3R,3aS,7aR)-2-Hydroxy-3-{(S)-N-methylphenyl-

sulfonimidoyl}octahydro-1H-inden-1-yl]-2-methylpropane-2-sulfon-

amide (6): To a solution of 3 (400 mg, 0.85 mmol) in THF (40 mL)

was added HAliBu₂(3.79 mL of 1.12 m in THF, 4.25 mmol) drop-

wise whilst stirring at 0 °C. After the reaction mixture was warmed

to room temperature over 3 h, pieces of ice were added until hydro-

gen gas evolution ceased. The mixture was stirred for a further

30 min. The gel-like mixture was suction filtered through filter pa-

per, the residue was washed with hot EtOAc (ca. 50 °C, 300 mL)

and the filtrate was concentrated in vacuo. Purification and separa-

[{(S)-N-Methylphenylsulfonimidoyl}methyl]cyclohexane (2): To

a

solution of 1 (487 mg, 1.95 mmol) in THF (20 mL) was added HAl-

iBu₂(2.01 mL of 1.12 m in THF, 2.25 mmol) dropwise whilst stir-

ring at 0 °C. After the mixture was warmed to room temperature

over 4 h, pieces of ice were added until hydrogen gas evolution ce-

ased. Then the mixture was further stirred for 30 min. The gel-like

mixture was suction filtered through filter paper, the residue was

washed with hot EtOAc (ca. 50 °C, 300 mL) and the filtrate was

concentrated in vacuo. Purification by column chromatography

(pentane/Et₂O, 1:4) furnished 2 (395 mg, 81%) as pale yellow oil.

R_f= 0.27 (pentane/Et₂O, 1:4). [α]_D= +86.7 (c = 1.02, in CH₂Cl₂).

¹H NMR (300 MHz, CDCl₃): δ = 0.85–1.37 (m, 5 H), 1.56–1.78 tion by flash chromatography (EtOAc/cyclohexane, increasing po-

(m, 4 H), 1.87–1.92 (m, 1 H), 2.01–2.06 (m, 1 H, SCH₂CH), 2.64 larity from 1:9 to 1:1) furnished 5 (313 mg, 86%) and 6 (26 mg,

(s, 3 H, NCH₃), 2.96 (dd, J = 6.5, J = 14.3 Hz, 1 H, SCHH), 3.12 7%) as white solids. For 5: M.p. 213 °C. [α]_D= +32.2 (c = 1.0, in

(dd, J = 5.7, J = 14.3 Hz, 1 H, SCHH), 7.53–7.64 (m, 3 H, Ph),

7.84–7.88 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 25.7

(u), 25.76 (u), 25.82 (u), 29.5 (d), 32.8 (d), 33.1 (u), 33.3 (u), 63.2

CH₂Cl₂). R_f= 0.35 (EtOAc/cyclohexane, 1:1). ¹H NMR (500 MHz,

CDCl₃): δ = 1.01–1.11 (m, 3 H), 1.34–1.60 (m, 4 H), 1.87–1.90 (m,

1 H), 1.47 [s, 9 H, C(CH₃)₃], 1.96–1.99 (m, 1 H, NCHCHCH₂),

(u), 129.1 (d), 129.4 (d), 132.6 (d), 138.8 (u) ppm. MS (EI, 70 eV): 2.16–2.21 (m, 1 H, SCHCHCH₂), 2.62 (s, 3 H, NCH₃), 3.08 (dd, J

m/z (%) = 251 (4) [M]⁺, 173 (11), 172 (20), 171 (8), 156 (27), 155 = 3.8, J = 6.6 Hz, 1 H, SCH), 3.74 (ddd, J = 7.7, J = 10.1, J =

(15), 154 (5), 140 (28), 127 (5), 126 (20), 125 (77), 109 (5), 108 (9), 11.5 Hz, 1 H, NCH), 4.35 (d, J = 10.1 Hz, 1 H, NH), 4.59 (dd, J

107 (100), 106 (14), 105 (14), 97 (15), 95 (8), 94 (7), 91 (20), 81 (9), = 6.6, J = 7.7 Hz, 1 H, O-CH), 7.57–7.66 (m, 3 H, Ph), 7.85–7.87

79 (5), 78 (22), 77 (18), 67 (6), 55 (49), 54 (6), 53 (7). IR (capillary):

ν = 3061 (w), 2924 (vs), 2855 (s), 2801 (m), 2362 (w), 1448 (m),

(m, 2 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.9 (u), 23.5

(u), 24.3 (d), 24.4 (u), 29.2 (d), 30.1 (u), 35.2 (d), 41.7 (d), 60.2 (u),

˜

1401 (w), 1242 (vs), 1147 (s), 1105 (m), 1080 (m), 915 (w), 863 (w), 61.7 (d), 73.2 (d), 76.8 (d), 129.6 (d), 129.6 (d), 133.2 (d), 136.5 (u)

779 (m), 740 (s) (m) cm^–1. HRMS: calcd. for C₁₄H₂₁NOS [M]⁺ppm. MS (EI, 70 eV): m/z (%) = 429 (1) [M + 1]⁺, 355 (1), 292 (8),

251.134387; found 251.134370.

260 (2), 198 (4), 156 (100), 152 (24), 136 (55), 125 (48), 77 (4), 57

(24). IR (KBr): ν = 3984 (w), 3911 (w), 3856 (w), 3450 (w), 3271

˜

(S)-Ethyl 2-(1,1-Dimethylethylsulfonamido)-2-[(1R,2S)-2-({(S)-N-

(vs), 3065 (w), 2971 (m), 2930 (s), 2864 (m), 2803 (w), 1453 (s),

1398 (w), 1305 (vs), 1235 (vs), 1178 (w), 1125 (vs), 1082 (s), 1013

(m), 962 (w), 916 (m), 870 (m), 828 (m), 804 (m), 760 (m) cm^–1.

C₂₀H₃₂N₂O₄S₂(428.61): calcd. C 56.05, H 7.53, N 6.54; found C

56.28, H 7.62, N 6.56. For 6: M.p. 148 °C. [α]_D= +12.3 (c = 1.0, in

CH₂Cl₂). R_f= 0.19 (EtOAc/cyclohexane, 1:1). ¹H NMR (300 MHz,

CDCl₃): δ = 1.28–1.92 (m, 7 H), 1.85–1.92 (m, 1 H), 1.43 [s, 9 H,

C(CH₃)₃], 2.23–2.33 (m, 1 H, NCHCHCH₂), 2.66 (s, 3 H, NCH₃),

2.78–2.89 (m, 1 H, SCHCHCH₂), 2.95 (dd, J = 5.0, J = 5.3 Hz, 1

H, SCH), 3.50 (ddd, J = 4.0, J = 10.1, J = 11.1 Hz, 1 H, NCH),

4.15 (dd, J = 4.0, J = 5.0 Hz, 1 H, OCH), 4.64 (d, J = 10.1 Hz, 1

H, NH), 7.57–7.66 (m, 3 H, Ph), 7.91–7.94 (m, 2 H, Ph) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 20.7 (u), 23.6 (u), 23.7 (u), 24.3 (d),

28.7 (d), 31.2 (u), 35.0 (d), 40.4 (d), 59.7 (u), 60.4 (d), 69.2 (d), 69.9

(d), 129.3 (d), 129.8 (d), 133.5 (d), 137.7 (u) ppm. MS (EI, 70 eV):

m/z (%) = 429 (1) [M + 1]⁺, 307 (8), 292 (17), 198 (9), 156 (36),

methylphenyl-sulfonimidoyl}methyl)cyclohexyl]acetate (4): To

a

solution of 3 (468 mg, 0.99 mmol) in THF (40 mL) was added HAl-

iBu₂(1.78 mL of 1.12 m in THF, 1.99 mmol) dropwise whilst stir-

ring at 0 °C. After the mixture was warmed to room temperature

over 4 h, pieces of ice were added until hydrogen gas evolution ce-

ased. Then the mixture was further stirred for 30 min. The gel-like

mixture was suction filtered through filter paper, the residue was

washed with hot EtOAc (ca. 50 °C, 300 mL) and the filtrate was

concentrated in vacuo. Purification by flash chromatography

(EtOAc/cyclohexane, increasing polarity from 1:9 to 4:1) furnished

4 (165 mg, 35%) as white solid; m.p. 55–57 °C. [α]_D= +65.4 (c

1

= 1.0, in CH₂Cl₂). R_f= 0.48 (EtOAc/cyclohexane, 4:1). H NMR

(300 MHz, CDCl₃): δ = 0.88–0.94 (m, 1 H), 1.26–1.60 (m, 4 H),

1.71–1.92 (m, 3 H), 1.31 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 1.40 [s, 9

H, C(CH₃)₃], 1.98–2.08 (m, 1 H, NCHCH), 2.63 (s, 3 H, NCH₃),

2.93 (dd, J = 8.4, J = 14.1 Hz, 1 H, SCHH), 3.04–3.11 (m, 1 H,

SCH₂CH), 3.75–3.80 (m, 1 H, SCHH), 4.12 (dd, J = 9.1, J =

10.4 Hz, 1 H, NCH), 4.21 (dt, J = 7.1, J = 12.6 Hz, 2 H, OCH₂),

7.38 (d, J = 10.4 Hz, 1 H, NH), 7.55–7.63 (m, 3 H, Ph), 7.94–7.98

(m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.3 (d), 20.4

(u), 24.3 (d), 25.3 (u), 25.9 (u), 29.0 (d), 29.2 (d), 31.4 (u), 44.4 (d),

53.9 (u), 59.7 (u), 59.8 (d), 61.6 (u), 129.3 (d), 129.4 (d), 132.8 (d),

138.6 (u), 173.0 (u) ppm. MS (EI, 70 eV): m/z (%) = 473 (3) [M +

152 (100), 136 (20), 125 (25), 107 (13), 78 (4), 57 (23). IR (KBr): ν

˜

= 3602 (w), 3281 (s), 3056 (w), 2932 (s), 2808 (m), 1735 (w), 1446

(s), 1366 (w), 1315 (s), 1246 (s), 1125 (vs), 1082 (m), 1025 (w), 986

(m), 927 (m), 900 (m), 850 (m), 805 (m), 754 (m) cm^{– 1}

.

C₂₀H₃₂N₂O₄S₂(428.61): calcd. C 56.05, H 7.53, N 6.54; found C

56.14, H 7.64, N 6.45.

N-[(1ЈR,2ЈR,3ЈS,3aЈR,7aЈS)-2Ј-Hydroxy-5,5-dimethyl-1Ј-{(S)-N-

1]⁺, 399 (18), 352 (7), 351 (34), 275 (7), 274 (40), 250 (5), 202 (9), methylphenyl-sulfonimidoyl}octahydrospiro[1,3-dioxane-2,5Ј-indene]-

198 (19), 197 (18), 196 (100), 173 (6), 172 (9), 170 (13), 169 (5), 168

3Ј-yl]-2-methylpropane-2-sulfonamide (14) and N-[(1ЈR,2ЈS,3ЈS,

(6), 157 (6), 156 (60), 155 (7), 140 (33), 126 (6), 125 (47), 124 (72), 3aЈR,7aЈS)-2Ј-Hydroxy-5,5-dimethyl-1Ј-{(S)-N-methylphenylsulfon-

108 (6), 107 (57), 106 (5), 105 (7), 102 (28), 95 (19), 91 (11), 81 (7), imidoyl}octahydrospiro[1,3-dioxane-2,5Ј-indene]-3Ј-yl]-2-methyl-

79 (5), 77 (7), 67 (6), 57 (46). IR (capillary): ν = 3986 (w), 3957

propane-2-sulfonamide (15): To a solution of 13 (260 mg,

˜

(w), 3876 (m), 3841 (w), 3768 (w), 3722 (w), 3697 (w), 3604 (w), 0.46 mmol) in THF (20 mL) was added HAliBu₂(2.03 mL of

3571 (m), 3520 (m), 3413 (m), 3375 (m), 3331 (w), 3279 (m), 3204 1.12 m in THF, 2.28 mmol) dropwise whilst stirring at 0 °C. After

6000

www.eurjoc.org

Eur. J. Org. Chem. 2011, 5991–6008

Asymmetric Synthesis of Bicyclic β-Amino Alcohols

the mixture was warmed to room temperature over 3 h, pieces of

ice were added until hydrogen gas evolution ceased. Then the mix-

ture was further stirred for 30 min. The gel-like mixture was suction

filtered through filter paper, the residue was washed with hot

EtOAc (ca. 50 °C, 300 mL), and the filtrate was concentrated in

vacuo. Purification and separation by flash chromatography

(EtOAc/cyclohexane, increasing polarity from 1:9 to 1:1) furnished

14 (174 mg, 72%) and 15 (36 mg, 15%) as white solids. For 14:

M.p. 121 °C. [α]_D= –12.8 (c = 1.0, in CH₂Cl₂). R_f= 0.21 (EtOAc/

and the filtrate was concentrated in vacuo. Purification and separa-

tion by HPLC (Kromasil Si 100, 30 mm, EtOAc/cyclohexane, 3:7,

254 nm + RI, 20 mL/min) furnished 17 (120 mg, 51 %) and 18

(52 mg, 20 %) as white solids [R_f(18) Ͼ R_f(17)]. For 17: M.p.

1

221 °C. [α]_D= +101.7 (c = 1.0, in CH₂Cl₂). H NMR (300 MHz,

CDCl₃): δ = 0.42–0.46 (m, 1 H), 1.05–1.15 (m, 1 H), 1.25–1.35 (m,

1 H), 1.40–1.53 (m, 2 H), 1.94–1.99 (m, 1 H), 1.47 [s, 9 H, C(CH₃)

₃], 2.24–2.32 (m, 1 H, NCHCH), 2.63 (s, 3 H, NCH₃), 2.65–2.73

(m, 1 H, SCHCH), 2.93 (t, J = 9.4 Hz, 1 H, SCH), 3.28–3.38 (m,

1 H, NCH), 4.16 (d, J = 9.7 Hz, 1 H, NH), 4.30 (t, J = 9.4 Hz, 1

1

cyclohexane, 1:1). H NMR (400 MHz, CDCl₃): δ = 0.82 (s, 3 H,

CH₂CCH₃), 0.99 (s, 3 H, CH₂CCH₃), 1.21–1.33 (m, 3 H), 1.95–2.08 H, OCH), 7.57–7.68 (m, 3 H, Ph), 7.82–7.85 (m, 2 H, Ph) ppm.

(m, 2 H, NCHCHCHH, SCHCHCH₂, SCHCHCH₂CH₂), 1.47 [s, ¹³C NMR (75 MHz, CDCl₃): δ = 24.3 (d), 25.1 (u), 28.9 (d), 29.9

9 H, C(CH₃)₃], 1.80 (dd, J = 5.0, J = 14.3 Hz, 1 H, NCHCHCHH), (u), 32.4 (u), 37.6 (d), 47.6 (d), 60.3 (u), 65.0 (d), 71.3 (d), 74.8 (d),

2.18–2. 27 (m, 1 H, NCHCHCH₂), 2. 40–2. 48 (m, 1 H,

SCHCHCH₂), 2.63 (s, 3 H, NCH₃), 3.16 (t, J = 5.8 Hz, 1 H, SCH),

3.36–3.41 (m, 3 H, OCH₂, OCHH), 3.50 (d, J = 11.5 Hz, 1 H,

129.6 (d), 129.8 (d), 133.6 (d), 136.5 (u) ppm. MS (EI, 70 eV): m/z

(%) = 414 (1) [M]⁺, 293 (21), 198 (6), 156 (53), 140 (15), 139 (17),

138 (100), 125 (34), 122 (19), 110 (15), 107 (14), 106 (5), 96 (10),

OCHH), 3.79–3.86 (m, 1 H, NCH), 4.48 (s, 1 H, OH), 4.55–4.58 78 (7), 77 (8), 69 (8), 57 (58), 56 (17). IR (KBr): ν = 3282 (vs), 3066

˜

(m, 1 H, OCH), 4.63 (d, J = 9.6 Hz, 1 H, NH), 7.55–7.65 (m, 3 H, (w), 2939 (m), 2871 (m), 2803 (w), 2370 (w), 2344 (w), 1627 (w),

Ph), 7.85–7.89 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 22.4 (d), 22.7 (d₃), 24.3 (d), 25.2 (u), 28.2 (u), 29.2 (d), 29.9 (u),

1455 (m), 1384 (w), 1359 (w), 1305 (s), 1229 (s), 1122 (vs), 1026 (w),

1001 (w), 917 (m), 878 (m), 830 (m), 765 (m) cm^–1. C₁₉H₃₀N₂O₄S₂

32.5 (u), 35.4 (d), 41.4 (d), 60.2 (u), 65.0 (d), 69.7 (u), 69.9 (u), 72.1 (414.58): calcd. C 55.04, H 7.29, N 6.76; found C 55.14, H 7.04, N

1

(d), 78.6 (d), 97.0 (u), 129.4 (d), 129.5 (d), 133.0 (d), 136.7 (u) ppm.

MS (EI, 70 eV): m/z (%) = 529 (1) [M + 1]⁺, 392 (8), 373 (7), 253

(18), 252 (100), 237 (6), 236 (32), 197 (8), 167 (19), 166 (29), 156

6.62. For 18: M.p. 169 °C. [α]_D= +14.3 (c = 1.0, in CH₂Cl₂). H

NMR (300 MHz, CDCl₃): δ = 1.38 [s, 9 H, C(CH₃)₃], 1.42–1.49

(m, 1 H), 1.59–1.82 (m, 5 H), 2.63–2.70 (m, 1 H, NCHCH), 2.69

(27), 150 (12), 141 (7), 125 (19), 107 (6), 69 (11). IR (KBr): ν = (s, 3 H, NCH₃), 2.71–2.74 (m, 1 H, SCH), 3.17 (dt, J = 2.9, J =

˜

3248 (m), 3062 (w), 2952 (s), 2871 (m), 2810 (w), 1738 (w), 1638

9.9 Hz, 1 H, NCH), 3.36–3.44 (m, 1 H, SCHCH), 4.03 (t, J =

(w), 1450 (m), 1396 (w), 1364 (m), 1309 (s), 1241 (s), 1189 (w), 1125 2.9 Hz, 1 H, OCH), 4.63 (d, J = 9.9 Hz, 1 H, NH), 7.58–7.68 (m,

(vs), 1015 (w), 972 (w), 901 (m), 834 (w), 794 (m), 753 (m) cm^–1. 3 H, Ph), 7.85–7.88 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz,

HRMS: calcd. for C₂₅H₄₀N₂O₆S₂[M]⁺528.232782; found

528.232902. For 15: M.p. 104 °C. [α]_D= +20.7 (c = 1.0, in CH₂Cl₂).

R_f= 0.37 (EtOAc/cyclohexane, 1:1). ¹H NMR (300 MHz,

CD₃OD): δ = 0.86 (s, 3 H, CH₂CCH₃), 0.98 (s, 3 H, CH₂CCH₃),

CDCl₃): δ = 24.3 (d), 25.2 (u), 28.5 (d), 30.4 (u), 33.1 (u), 40.5 (d),

49.1 (d), 59.6 (u), 64.4 (d), 69.0 (d), 73.1 (d), 129.3 (d), 129.9 (d),

133.6 (d), 137.8 (u) ppm. IR (KBr): ν = 3056 (w), 2960 (m), 2872

˜

(m), 2810 (w), 1446 (s), 1310 (s), 1247 (s), 1129 (vs), 1018 (w), 984

1.36–1.47 (m, 2 H, SCHCHCHH, SCHCHCH₂CHH), 1.39 [s, 9 H, (w), 915 (m), 850 (m), 819 (w), 788 (w), 760 (w) cm^–1. MS (EI,

C(CH₃)₃], 1.55–1.59 (m, 1 H, SCHCHCHH), 1.81 (dd, J = 6.6, J

= 14.0 Hz, 1 H, NCHCHCHH), 2.05 (dd, J = 6.6, J = 14.0 Hz, 1

70 eV): m/z (%) = 415 (1) [M + 1]⁺, 293 (7), 157 (9), 156 (100), 140

(16), 139 (26), 138 (42), 126 (6), 125 (55), 122 (28), 110 (7), 107

H, NCHCHCHH), 2.11–2.15 (m, 1 H, SCHCHCH₂CHH), 2.40– (11), 96 (8), 81 (5), 78 (6), 77 (7), 58 (48), 57 (11). HRMS: calcd.

2.46 (m, 1 H, NCHCHCH₂), 2.64 (s, 3 H, NCH₃), 2.67–2.71 (m, 1

H, SCHCHCH₂), 3.36 (dd, J = 4.0, J = 6.3 Hz, 1 H, SCH), 3.40–

3.47 (m, 3 H), 3.55–3.58 (m, 1 H, OCH₂, OCH₂), 3.54–3.57 (m, 1

H, NCH), 4.22 (t, J = 4.0 Hz, 1 H, OCH), 7.64–7.74 (m, 3 H, Ph),

7.88–7.92 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CD₃OD): δ =

21.2 (d), 21.7 (d), 23.3 (d), 26.3 (u), 27.6 (u), 29.44 (d), 29.44 (u),

31.6 (u), 34.1 (d), 38.7 (d), 59.3 (u), 61.8 (d), 69.1 (d), 69.60 (u),

69.60 (u), 71.3 (d), 98.0 (u), 129.2 (d), 129.5 (d), 133.4 (d), 137.3

(u) ppm. MS (EI, 70 eV): m/z (%) = 529 (2) [M + 1]⁺, 392 (20),

373 (7), 254 (5), 253 (18), 252 (100), 237 (6), 236 (14), 235 (6), 234

(22), 198 (10), 196 (28), 168 (8), 166 (29), 156 (18), 148 (6), 141 (6),

for C₁₉H₃₀N₂O₄S₂[M]⁺414.164703; found 414.164641.

N-[(1S,2R,3R,3aS,8aR)-2-Hydroxy-3-{(S)-N-methylphenylsulfon-

imidoyl}decahydroazulen-1-yl]-2-methylpropane-2-sulfonamide (20),

N-[(1S,2S,3R,3aS,8aR)-2-Hydroxy-3-{(S)-N-methylphenylsulfon-

imidoyl}decahydroazulen-1-yl]-2-methylpropane-2-sulfonamide (21)

and N-[(1S)-2-Hydroxy-1-{(1R,2S)-2-({(S)-N-methylphenylsulfon-

imidoyl}methyl)cycloheptyl}ethyl]-2-methylpropane-2-sulfonamide

(22): To a solution of 19 (320 mg, 0.66 mmol) in THF (10 mL) was

added HAliBu₂(2.95 mL of 1.12 m in THF, 3.30 mmol) dropwise

whilst stirring at 0 °C. After the mixture was warmed to room tem-

perature over 4 h, pieces of ice were added until hydrogen gas evol-

ution ceased. Then the mixture was stirred for a further 30 min.

The gel-like mixture was suction filtered through filter paper and

the residue was washed with hot EtOAc (ca. 50 °C, 400 mL). The

filtrate was concentrated in vacuo. Purification by column

chromatography (EtOAc/cyclohexane, 1:1) afforded 22 (144 mg,

50%) as white solid and a mixture of the alcohols 20 and 21 (R_f=

125 (12), 57 (15). IR (CH Cl ): ν = 3482 (w), 3364 (w), 3272 (w),

˜

2

3061 (m), 2956 (s), 2871 (m), 2806 (w), 1472 (m), 1449 (m), 1397

(w), 1366 (w), 1308 (s), 1278 (m), 1242 (s), 1126 (vs), 1015 (w), 968

(w), 900 (w), 811 (w), 778 (w), 707 (m) cm^–1. HRMS: calcd. for

C₂₁H₃₀NO₄S [M – C₄H₁₀NO₂S]⁺392.189556; found 392.189601.

N-[(1S,2R,3R,3aS,6aR)-2-Hydroxy-3-{(S)-N-methylphenylsulfon-

imidoyl}octahydropentalen-1-yl]-2-methylpropane-2-sulfonamide 0.54, EtOAc/cyclohexane, 1:1). Separation by HPLC (Kromasil Si

(17) and N-[(1S,2S,3R,3aS,6aR)-2-Hydroxy-3-{(S)-N-methyl- 100, 30 mm, Et₂O/cyclohexane, 1:2, 254 nm + RI, 30 mL/min) gave

phenylsulfonimidoyl}octahydropentalen-1-yl]-2-methylpropane-2-sul-

fonamide (18): To a solution of 16 (260 mg, 0.57 mmol) in THF

(20 mL) was added HAliBu₂(2.85 mL of 1.0 m in THF, 2.85 mmol)

dropwise whilst stirring at 0 °C. After the mixture was warmed to

room temperature over 3 h, pieces of ice were added until hydrogen

gas evolution ceased. Then the mixture was stirred for a further

30 min. The gel-like mixture was suction filtered through filter pa-

per, the residue was washed with hot EtOAc (ca. 50 °C, 300 mL)

20 (49 mg, 17%) and 21 (46 mg, 16%) as white solids [R_f(20) ϾR_f

(21)]. For 20: M.p. 228 °C. [α]_D= +51.4 (c = 1.0, in CH₂Cl₂). H

1

NMR (400 MHz, CDCl₃): δ = 0.39–0.44 (m, 1 H), 0.83–0.89 (m, 1

H), 1.01–1.43 (m, 4 H), 1.61–1.67 (m, 2 H), 1.81–1.87 (m, 1 H),

2.11–2.19 (m, 1 H), 1.47 [s, 9 H, C(CH₃)₃], 1.88–1.97 (m, 1 H,

NCHCHCH₂), 2.35–2.43 (m, 1 H, SCHCHCH₂), 2.61 (s, 3 H,

NCH₃), 3.00 (dd, J = 8.0, J = 9.1 Hz, 1 H, SCH), 3.37–3.45 (m, 1

H, NCH), 4.04 (d, J = 9.9 Hz, 1 H, NH), 4.32–4.36 (m, 1 H, OCH),

Eur. J. Org. Chem. 2011, 5991–6008

www.eurjoc.org

6001

S. Acikalin, G. Raabe, J. Runsink, H.-J. Gais

FULL PAPER

5.20 (s, 1 H, OH), 7.56–7.66 (m, 3 H, Ph), 7.82–7.85 (m, 2 H, Ph)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 24.3 (d), 27.1 (u), 28.7 (u),

28.9 (d), 29.8 (u), 30.8 (u), 31.8 (u), 38.6 (d), 46.4 (d), 60.2 (u), 64.3

(d), 72.1 (d), 74.1 (d), 129.4 (d), 129.5 (d), 133.3 (d), 136.4 (u) ppm.

MS (EI, 70 eV): m/z (%) = 443 (2) [M + 1]⁺, 306 (10), 168 (12),

167 (25), 166 (65), 157 (9), 156 (100), 150 (59), 149 (16), 148 (10),

126 (5), 125 (53), 124 (6), 107 (16), 106 (7), 81 (5), 78 (7), 77 (8),

67 (6), 58 (57), 57 (24), 56 (10). MS (CI, CH₄): m/z (%) = 471 (6)

[M + C₂H₅]⁺, 445 (11), 444 (25), 443 (100), 441 (13), 168 (5), 166

Ethyl (2S,3S)-2-(1,1-Dimethylethylsulfonamido)-3-isopropyl-5-[(S)-

N-methylphenylsulfonimidoyl]pentanoate (26): To a solution of 23

(300 mg, 0.65 mmol) in THF (20 mL) was added HAliBu₂

(3.27 mL of 1.0 m in THF, 3.27 mmol) dropwise whilst stirring at

0 °C. After the mixture was warmed to room temperature over 4 h,

pieces of ice were added until hydrogen gas evolution ceased. Then

the mixture was stirred for a further 30 min. The gel-like mixture

was suction filtered through filter paper and the residue was

washed with hot EtOAc (ca. 50 °C, 300 mL). The filtrate was con-

centrated in vacuo. Purification by column chromatography

(EtOAc/cyclohexane, 1:1) afforded 26 (39 mg, 13%) as a white solid

and a mixture of 24 and 25 (R_f: 0.43, EtOAc/cyclohexane, 1:1).

Separation of the mixture by HPLC (Kromasil Si 100, 30 mm,

EtOAc/cyclohexane, 35:65, 254 nm + RI, 25 mL/min) gave 24

(51 mg, 19%) and 25 (16 mg, 6%) as white solids [R_f(14) ϾR_f(15)].

(9), 156 (19), 150 (8), 125 (10). IR (CHCl ): ν = 3957 (w), 3872 (w),

˜

3

3831 (w), 3789 (w), 3727 (w), 3698 (w), 3578 (w), 3512 (w), 3458

(w), 3283 (s), 3063 (w), 3017 (m), 2925 (s), 2857 (m), 2809 (w), 1452

(s), 1365 (m), 1308 (s), 1234 (s), 1124 (vs), 1081 (s), 1026 (m), 918

(m), 865 (m), 812 (w), 757 (vs) cm^{– 1}. HRMS: calcd. for

C₂₁H₃₅N₂O₄S₂[M + H]⁺443.203828; found 443.204662. For 21:

M.p. 119 °C. [α]_D= –7.8 (c = 1.0, in CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ = 0.84–0.90 (m, 1 H), 1.19–1.49 (m, 4 H), 1.81–1.92 (m,

3 H), 2.02–2.08 (m, 1 H), 2.15–2.20 (m, 1 H), 1.37 [s, 9 H, C(CH₃)

₃], 2.39–2.48 (m, 1 H, NCHCHCH₂), 2.70 (s, 3 H, NCH₃), 2.80

(dd, J = 3.3, J = 9.3 Hz, 1 H, SCH), 3.03–3.12 (m, 1 H,

SCHCHCH₂), 3.16 (dt, J = 3.3, J = 10.2 Hz, 1 H, NCH), 3.94 (t,

J = 3.3 Hz, 1 H, OCH), 4.45 (d, J = 10.2 Hz, 1 H, NH), 7.42 (s, 1

H, OH), 7.57–7.65 (m, 3 H, Ph), 7.86–7.89 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 24.3 (d), 28.0 (u), 28.5 (d), 29.5

(uH₂), 29.7 (u), 31.2 (u), 32.4 (u), 40.3 (d), 47.1 (d), 59.6 (u), 64.1

(d), 68.5 (d), 70.8 (d), 129.0 (d), 129.6 (d), 133.3 (d), 137.7 (u) ppm.

MS (EI, 70 eV): m/z (%) = 443 (11) [M + 1]⁺, 321 (8), 306 (18),

303 (6), 198 (13), 168 (17), 167 (32), 166 (100), 157 (8), 156 (73),

151 (7), 150 (32), 149 (19), 148 (31), 138 (14), 137 (8), 136 (8), 132

(5), 126 (6), 125 (54), 124 (11), 123 (6), 109 (7), 108 (5), 107 (28),

106 (13), 105 (7), 97 (8), 96 (5), 95 (6), 94 (5), 91 (6), 82 (5), 81 (9),

80 (5), 79 (5), 78 (10), 77 (11), 72 (6), 71 (5), 69 (5), 67 (9), 58 (64),

57 (53), 56 (16). MS (CI, CH₄): m/z (%) = 471 (1) [M + C₂H₅]⁺,

1

For 24: M.p. 76 °C. [α]_D= +15.7 (c = 1.0, in CH₂Cl₂). H NMR

(400 MHz, CDCl₃): δ = 0.80 (d, J = 7.1 Hz, 3 H, CHCH₃), 0.86

(d, J = 7.1 Hz, 3 H, CHCH₃), 1.39–1.44 (m, 1 H, CHCHH), 1.47

[s, 9 H, C(CH₃)₃], 1.79–1.87 (m, 1 H, CH₃CHCH), 1.95 (ddd, J =

7.4, J = 10.4, J = 14.0 Hz, 1 H, CHCHH), 2.08–2.15 (m, 1 H,

CH₃CH), 2.62 (s, 3 H, NCH₃), 3.30 (dt, J = 8.6, J = 10.4 Hz, 1 H,

SCH), 3.52–3.57 (m, 1 H, NCH), 4.20 (d, J = 9.9 Hz, 1 H, NH),

4.40–4.44 (t, J = 8.6 Hz, 1 H, OCH), 7.57–7.68 (m, 3 H, Ph), 7.81–

7.85 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.8

(d), 20.1 (u), 21.7 (d), 24.4 (d), 26.3 (d), 29.2 (d), 47.9 (d), 60.3 (u),

62.8 (d), 65.6 (d), 75.8 (d), 129.5 (d), 129.7 (d), 133.4 (d), 136.4 (u)

ppm. MS (CI, CH₄): m/z (%) = 445 (6) [M + C₂H₅]⁺, 419 (11), 418

(22), 417 (100), 415 (7), 206 (6), 156 (21), 125 (10). IR (capillary):

ν = 3062 (w), 3028 (w), 2955 (vs), 2802 (m), 1463 (s), 1370 (m),

˜

1250 (vs), 1198 (w), 1145 (s), 1090 (s), 979 (m), 922 (w), 864 (s), 838

(s), 777 (m) cm^–1. HRMS: calcd. for C₁₅H₂₃N₂O₃S₂[M – C₄H₉O]⁺

343.115013; found 343.114980. For 25: M.p. 89–90 °C. [α]_D= –12.8

1

(c = 1.0, in CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.83 (d, J

443 (12), 125 (5), 101 (7), 87 (12), 85 (65), 83 (100). IR (CHCl ): ν

˜

3

= 6.6 Hz, 3 H, CHCH₃), 0.97 (d, J = 6.6 Hz, 3 H, CHCH₃) 1.38

[s, 9 H, C(CH₃)₃], 1.85–2.01 (m, 2 H, CH₃CH, CHCHH), 2.17–2.25

(m, 1 H, CH₃CHCH), 2.53 (ddd, J = 9.9, J = 11.3, J = 13.7 Hz, 1

H, CHCHH), 2.68 (s, 3 H, NCH₃), 3.08 (dt, J = 3.3, J = 9.9 Hz, 1

H, SCH), 3.37 (dt, J = 3.3, J = 10.2 Hz, 1 H, NCH), 4.04 (t, J =

3.3 Hz, 1 H, OCH), 4.54 (d, J = 10.2 Hz, 1 H, NH), 7.21 (s, 1 H,

OH) 7.57–7.65 (m, 3 H, Ph), 7.85–7.88 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 16.2 (d), 21.2 (u), 22.0 (d), 24.2 (d),

27.1 (d), 28.5 (d), 47.6 (d), 59.5 (u), 61.2 (d), 62.5 (d), 71.1 (d),

129.1 (d), 129.7 (d), 133.5 (d), 137.2 (u) ppm. MS (EI, 70 eV): m/z

(%) = 416 (1) [M]⁺, 295 (14), 280 (13), 210 (33), 156 (50), 154 (5),

142 (12), 141 (14), 140 (100), 126 (8), 125 (39), 124 (7), 123 (7), 122

(35), 107 (14), 98 (10), 86 (11), 85 (17), 77 (8), 70 (17), 69 (8), 57

= 3521 (w), 3271 (m), 3020 (m), 2924 (s), 2855 (m), 1448 (m), 1311

(m), 1237 (m), 1128 (s), 1082 (m), 1023 (w), 921 (w), 864 (w), 820

(w), 756 (vs) cm^–1. HRMS: calcd. for C₂₁H₃₅N₂O₄S₂[M + 1]⁺

443.203828; found 443.204473. For 22: M.p. 109 °C. [α]_D= +48.5

(c = 1.0, in CH₂Cl₂). R_f= 0.20 (EtOAc/cyclohexane, 1:1). ¹H NMR

(400 MHz, CDCl₃): δ = 1.42–1.61 (m, 9 H), 1.86–1.94 (m, 1 H),

1.45 [s, 9 H, C(CH₃)₃], 2.15–2.22 (m, 1 H, NCHCH), 2.61 (s, 3 H,

NCH₃), 2.96 (dd, J = 7.7, J = 14.0 Hz, 1 H, SCHH), 3.05–3.09 (m,

1 H, SCH₂CH), 3.51–3.55 (m, 2 H, SCHH, NCH), 3.85 (dd, J =

3.0, J = 11.8 Hz, 1 H, OCHH), 3.93 (dd, J = 3.0, J = 11.8 Hz, 1

H, OCHH), 5.74 (d, J = 9.6 Hz, 1 H, NH), 7.57–7.67 (m, 3 H, Ph),

7.84–7.89 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

24.5 (d), 24.7 (u), 26.4 (u), 26.6 (u₂), 28.5 (u), 29.1 (d), 31.3 (d),

34.0 (u), 46.3 (d), 56.2 (u), 59.6 (d), 59.8 (u), 63.3 (u), 129.0 (d),

129.6 (d), 133.2 (d), 138.1 (u) ppm. MS (EI, 70 eV): m/z (%) = 445

(7) [M + 1]⁺, 413 (19), 323 (6), 308 (6), 293 (10), 258 (10), 246 (12),

216 (7), 180 (7), 170 (12), 169 (11), 168 (56), 157 (5), 156 (49), 152

(8), 140 (13), 139 (12), 138 (100), 126 (6), 125 (41), 124 (10), 108

(6), 107 (42), 105 (9), 97 (5), 95 (6), 81 (6), 78 (10), 77 (8), 69 (5),

(69), 55 (12). IR (KBr): ν = 3238 (m), 3058 (w), 2955 (m), 2875

˜

(m), 2810 (w), 1451 (s), 1385 (m), 1308 (s), 1239 (s), 1126 (vs), 1081

(s), 1014 (m), 997 (w), 905 (s), 847 (m), 789 (w) cm^–1. HRMS: calcd.

for C₁₅H₂₃N₂O₂S [M – C₄H₉SO₂]⁺295.148026; found 295.147926.

For 26: M.p. 137 °C. [α]_D= +23.8 (c = 1.0, in CH₂Cl₂). R_f= 0.15

1

(EtOAc/cyclohexane, 1:1). H NMR (400 MHz, CDCl₃): δ = 0.84

(d, J = 6.9 Hz, 3 H, CHCH₃), 0.91 (d, J = 6.9 Hz, 3 H, CHCH₃),

1.20 (t, J = 7.1 Hz, 3 H, CH₂CH₃), 1.30 [s, 9 H, C(CH₃)₃], 1.56–

1.68 (m, 2 H, CHCH₂), 1.86–1.96 (m, 2 H, CH₃CH, CH₂CH), 2.58

(s, 3 H, NCH₃), 3.13–3.19 (m, 1 H, SCHH), 3.34–3.41 (m, 1 H,

SCHH), 4.09–4.15 (m, 3 H, NCH, CH₃CH₂), 5.91 (d, J = 8.2 Hz,

1 H, NH), 7.48–7.57 (m, 3 H, Ph), 7.78–7.81 (m, 2 H, Ph) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 14.3 (d), 19.7 (d), 21.0 (u), 21.9

(d), 24.4 (d), 29.5 (d), 29.7 (d), 47.4 (d), 54.9 (u), 58.6 (d), 60.2 (u),

61.8 (u), 129.3 (dH), 129.5 (d), 132.9 (dH), 137.5 (u), 172.2 (u)

ppm. MS (EI, 70 eV): m/z (%) = 460 (5) [M]⁺, 387 (12), 339 (7),

325 (8), 324 (44), 238 (14), 232 (5), 186 (28), 185 (5), 184 (35), 182

67 (11), 60 (30), 59 (15), 57 (52), 56 (8), 55 (8). IR (KBr): ν = 3965

˜

(w), 3896 (w), 38.42 (w), 3749 (w), 3469 (s), 2928 (vs), 2807 (m),

2370 (w), 2344 (w), 2323 (w), 2250 (w), 1629 (m), 1520 (m), 1455

(s), 1303 (s), 1235 (s), 1123 (vs), 912 (m), 865 (m), 737 (s) cm^–1.

HRMS: calcd. for C₂₀H₃₃N₂O₃S₂[M – CH₃O]⁺413.193263; found

413.193663.

N-(1S,2R,3R,5S)-2-Hydroxy-5-isopropyl-3-[(S)-N-methylphenyl-

sulfonimidoyl]cyclopentyl-2-methylpropane-2-sulfonamide (24), N-

(1S,2S,3R,5S)-2-Hydroxy-5-isopropyl-3-[(S)-N-methylphenyl-

sulfonimidoyl]cyclopentyl-2-methylpropane-2-sulfonamide (25) and

6002

www.eurjoc.org

Eur. J. Org. Chem. 2011, 5991–6008

Asymmetric Synthesis of Bicyclic β-Amino Alcohols

(6), 170 (6), 169 (27), 157 (6), 156 (38), 155 (18), 141 (6), 140 (21), 23.2 (u), 24.5 (d), 27.0 (u), 29.6 (d), 30.4 (u), 30.6 (u), 38.1 (u), 53.1

126 (7), 125 (43), 113 (8), 112 (76), 111 (8), 110 (6), 108 (8), 107

(d), 59.6 (u), 62.9 (d), 66.0 (u), 72.5 (u), 86.3 (u), 129.1 (d), 129.3

(93), 106 (8), 105 (8), 102 (15), 97 (7), 96 (9), 95 (9), 91 (6), 83 (18), (d), 133.0 (d), 139.3 (u) ppm. MS (EI, 70 eV): m/z (%) = 443 (1)

78 (13), 77 (12), 70 (11), 69 (8), 68 (6), 57 (100), 57 (12), 56 (23), [M + 1]⁺, 385 (7), 321 (9), 307 (8), 306 (32), 287 (5), 227 (7), 180

46 (7). IR (CHCl ): ν = 3685 (w), 3622 (w), 3021 (vs), 2976 (m), (10), 171 (15), 170 (100), 169 (10), 166 (25), 165 (13), 156 (59), 152

˜

3

2934 (w), 2900 (w), 2736 (w), 2582 (w), 2402 (m), 2268 (w), 2115 (47), 151 (24), 150 (62), 141 (12), 140 (84), 138 (23), 137 (30), 136

(w), 1733 (m), 1524 (w), 1477 (w), 1426 (w), 1322 (w), 1230 (s),

(18), 135 (6), 125 (57), 109 (13), 108 (10), 107 (33), 106 (18), 105

1203 (m), 1131 (w), 1041 (m), 929 (w), 793 (vs) cm^–1. HRMS: calcd. (8), 97 (6), 96 (7), 95 (9), 94 (11), 93 (8), 91 (21), 82 (6), 85 (11), 80

for C₂₁H₃₆N₂O₅S₂[M]⁺460.206567; found 460.206441.

(8), 79 (9), 78 (11), 77 (17), 67 (19), 60 (14), 59 (7), 57.4 (99), 56.6

(11), 56 (22), 55 (6). IR (CHCl ): ν = 3281 (w), 3057 (w), 2927 (s),

˜

3

2-Methyl-N-[(3S,3aS,7aS)-7a-({(S)-N-methylphenylsulfon-

imidoyl}methyl)octa-hydrobenzofuran-3-yl]propane-2-sulfonamide

(28): To a solution of 27 (497 mg, 1.06 mmol) in THF (35 mL)

was added HAliBu₂(5.5 mL of 1.0 m in THF, 5.49 mmol) dropwise

whilst stirring at 0 °C. After the mixture was stirred at 0 °C for 2 h,

it was warmed to room temperature over 3 h. Pieces of ice were

added until hydrogen gas evolution ceased. Then the mixture was

stirred for a further 30 min. The gel-like mixture was suction fil-

tered through filter paper, the residue was washed with hot EtOAc

(ca. 50 °C, 400 mL) and the filtrate was concentrated in vacuo. Pu-

rification by flash chromatography (EtOAc/cyclohexane, increasing

polarity from 1:9 to 1:1) furnished 28 (215 mg, 48%) as white solid;

m.p. 117 °C. [α]_D= +168.7 (c = 1.0, in CH₂Cl₂). R_f= 0.35 (cyclo-

hexane/EtOAc, 1:1). ¹H NMR (500 MHz, CD₃OD, H₂O): δ = 1.26

2685 (m), 2806 (w), 1398 (w), 1367 (w), 1306 (s), 1127 (vs), 1086

(s), 1052 (s), 996 (w), 962 (w), 921 (w), 862 (w), 803 (w) cm^–1.

C₂₁H₃₄N₂O₄S₂·1/2H₂O (442.64 + 1/2H₂O): calcd. C 55.85, H 7.81,

N 6.20; found C 55.90, H 7.54, N, 6.25.

N-[(1S,2R,3S,3aS,7aR)-2-Hydroxy-3-iodooctahydro-1H-inden-1-yl]-

2-methylpropane-2-sulfonamide (35) and (S)-Phenylmethyl(phenyl-

sulfinyl)carbamate (36): To a solution of NaI (669 mg, 4.5 mmol)

in CH₃CN (7 mL) was added ClCO₂Ph (0.25 mL, 1.9 mmol) and

the resulting mixture was stirred at 70 °C for 1.5 h. Formation of

a colourless precipitate was observed. After the mixture was cooled

to room temperature, 5 (200 mg, 0.47 mmol) was added. After the

mixture was stirred for 2 h, the volatiles were removed in vacuo.

Purification by column chromatography (pentane/Et₂O, 9:1) gave

[s, 9 H, C(CH₃)₃], 1.30–1.57 (m, 7 H), 2.05–2.11 (m, 1 H), 2.34– 36 (95 mg, 75%) as a viscous oil and 35 (145 mg, 77%) of Ն 98%

2.38 (m, 1 H, NCHCH), 2.47 (s, 3 H, NCH₃), 3.34 (d, J = 15.3 Hz, de as a white solid. For 35: M.p. 163 °C. [α]_D= –20.8 (c = 1.0, in

1 H, SCHH), 3.37 (dd, J = 6.7, J = 9.0 Hz, 1 H, OCHH), 3.64 (d,

J = 15.3 Hz, 1 H, SCHH), 3.83–3.87 (m, 1 H, NCH), 3.96 (dd, J

CH₂Cl₂). R_f= 0.32 (pentane/Et₂O, 9:1). ¹H NMR (400 MHz,

CDCl₃): δ = 1.11–1.36 (m, 3 H), 1.50–1.60 (m, 2 H), 1.69–1.85 (m,

= 6.7, J = 8.0 Hz, 1 H, OCHH), 4.87 (br. s, H₂O), 7.51–7.60 (m, 3 3 H), 1.43 [s, 9 H, C(CH₃)₃], 1.90–1.94 (m, 1 H, NCHCH), 2.01–

H, Ph), 7.77–7.80 (m, 2 H, Ph) ppm. ¹³C NMR (125 MHz,

CD₃OD): δ = 20.6 (u), 21.7 (u), 23.3 (d), 23.7 (u), 28.1 (d), 32.7

(u), 46.9 (d), 57.1 (d), 59.1 (u), 60.7 (u), 71.5 (u), 81.4 (u), 128.8

(d), 129.2 (d), 132.9 (d), 138.7 (u) ppm. MS (EI, 70 eV): m/z (%) =

2.08 (m, 1 H, ICHCH), 2.91 (d, J = 2.2 Hz, 1 H, OH), 3.78 (dt, J

= 3.3, J = 9.6 Hz, 1 H, NCH), 3.92–3.96 (m, 1 H, OCH), 4.26 (d,

J = 9.6 Hz, 1 H, NH), 4.53 (t, J = 7.1 Hz, 1 H, ICH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 21.0 (u), 24.1 (u), 24.3 (d), 25.3 (u),

428 (5) [M]⁺, 371 (11), 293 (8), 292 (47), 277 (15), 213 (6), 171 (10), 28.9 (u₂), 38.7 (d), 43.4 (d), 44.9 (d), 60.1 (u), 62.8 (d), 78.7 (d)

170 (100), 169 (11), 156 (55), 154 (10), 152 (13), 151 (8), 140 (52),

138 (15), 137 (14), 136 (37), 125 (42), 124 (31), 123 (25), 122 (19),

ppm. MS (CI, CH₄): m/z (%) = 402 (10) [M + 1]⁺, 328 (81), 282

(60), 264 (45), 247 (27), 202 (16), 154 (100). IR (KBr): ν = 3731

˜

107 (34), 95 (13), 91 (12), 77 (12), 57 (58), 55 (14). IR (KBr): ν = (w), 3676 (w), 3505 (s), 3285 (s), 3070 (w), 2936 (s), 2861 (s), 2373

˜

3447 (w), 3076 (m), 2932 (s), 2864 (m), 1636 (w), 1477 (m), 1446

(w), 2345 (w), 1606 (m), 1448 (m), 1372 (m), 1311 (s), 1266 (s),

(m), 1404 (w), 1366 (w), 1312 (vs), 1232 (s), 1189 (w), 1155 (s), 1181 (m), 1120 (s), 1052 (w), 981 (m), 917 (m), 728 (m) cm^–1

.

1129 (vs), 1104 (s), 1077 (m), 1048 (m), 1020 (w), 991 (m), 947 C₁₃H₂₄INO₃S (401.30): calcd. C 38.91, H 6.03, N 3.49; found C

(w), 909 (w), 888 (w), 856 (w), 835 (w), 802 (w), 784 (w) cm^–1. 39.21, H 6.24, N 3.45.

C₂₀H₃₂N₂O₄S₂·1/2H₂O (428.61+1/2H₂O): calcd. C 55.31, H 7.81,

N-[(1S,2R,3S,3aS,7aR)-3-Chloro-2-hydroxyoctahydro-1H-inden-1-

N 6.29; found C 55.42, H 7.41, N 6.39.

yl]-2-methylpropane-2-sulfonamide (40) and 2-Methyl-N-[(1S,3a-

2-Methyl-N-[(3S,3aS,8aS)-8a-({(S)-N-methylphenylsulfonimid-

R,7aR)-2-oxooctahydro-1H-inden-1-yl]propane-2-sulfonamide (41):

oyl}methyl)octahydro-2H-cyclohepta[b]furan-3-yl]propane-2-sulfon- To a solution of 5 (300 mg, 0.70 mmol) in CH₂Cl₂(10 mL) was

amide (30): To a solution of 29 (200 mg, 0.41 mmol) in THF

(20 mL) was added HAliBu₂(1.8 mL of 1.12 m in THF, 2.05 mmol)

dropwise whilst stirring at 0 °C. The reaction mixture was allowed

to stir at 0 °C for 1 h and warmed to room temperature over 6 h.

Afterwards pieces of ice were added until hydrogen gas evolution

ceased. The mixture was stirred for a further 30 min. The gel-like

mixture was suction filtered through filter paper and the residue

was washed with hot EtOAc (ca. 50 °C, 300 mL). The filtrate was

concentrated in vacuo. Purification by flash chromatography

added ClCO₂CH(Cl)Me (97 μL, 0.91 mmol) and the mixture was

stirred at room temperature for 3 h. Concentration in vacuo and

purification by column chromatography (pentane/Et₂O, 2:3) gave

40 (90 mg, 41%) of Ն 98% de and 41 (51 mg, 27%) as white solids.

For 40: M.p. 144 °C. [α]_D= –12.9 (c = 1.0, in CH₂Cl₂). R_f= 0.51

(pentane/Et₂O, 2:3). ¹H NMR (400 MHz, CDCl₃): δ = 1.12–1.23

(m, 1 H), 1.33–1.48 (m, 2 H), 1.55–1.64 (m, 2 H), 1.73–1.83 (m, 3

H), 1.85–1.90 (m, 1 H), 1.44 [s, 9 H, C(CH₃)₃], 2.17–2.25 (m, 1 H,

ClCHCH), 2.81 (d, J = 2.5 Hz, 1 H, OH), 3.76 (dt, J = 4.1, J =

(EtOAc/Et₂O, 6:4) furnished 30 (140 mg, 77%) as a white solid; 9.6 Hz, 1 H, NCH), 4.07–4.10 (m, 1 H, OCH), 4.19 (d, J = 9.6 Hz,

m.p. 51 °C. [α]_D= +63.6 (c = 1.0, in CH₂Cl₂). R_f= 0.53 (EtOAc/

Et₂O, 6:4). H NMR (400 MHz, CDCl₃): δ = 1.43 [s, 9 H, C(CH₃)

1 H, NH), 4.35 (t, J = 6.5 Hz, 1 H, ClCH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 20.7 (u), 23.8 (u), 24.0 (u), 24.2 (u), 24.3

(d) 42.3 (d), 42.7 (d) 60.0 (u), 63.9 (d), 64.1 (d), 78.2 (d) ppm. MS

1

₃], 1.36–1.47 (m, 2 H), 1.56 (br. s, H₂O), 1.57–1.70 (m, 3 H), 1.76–

1.86 (m, 4 H), 1.96–2.03 (m, 1 H), 2.67 (s, 3 H, NCH₃), 2.98–3.03 (CI, CH₄): m/z (%) = 310 (15) [M + 1]⁺, 238 (36), 236 (100), 190

(m, 1 H, NCHCH), 3.48 (d, J = 14.6 Hz, 1 H, SCHH), 3.64 (d, J (31), 154 (47), 136 (12), 119 (15), 82 (10). IR (KBr): ν = 3504 (s),

˜

= 14.6 Hz, 1 H, SCHH), 3.66–3.71 (m, 1 H, NCH), 3.72 (dd, J =

3.9, J = 9.1 Hz, 1 H, OCHH), 3.97 (dd, J = 5.0, J = 9.1 Hz, 1 H,

3293 (s), 2930 (s), 2863 (m), 1453 (m), 1371 (w), 1295 (s), 1241 (m),

1212 (w), 1120 (s), 1063 (m), 989 (m), 923 (m), 886 (m), 758 (m)

OCHH), 7.01 (d, J = 8.5 Hz, 1 H, NH), 7.56–7.61 (m, 3 H, Ph), cm^–1. C₁₃H₂₄ClNO₃S (309.85): calcd. C 50.39, H 7.81, N 4.52;

7.88–7.91 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = found C 50.48, H 7.88, N 4.40. For 41; m.p. 142 °C. [α]_D= +40.5

Eur. J. Org. Chem. 2011, 5991–6008

www.eurjoc.org

6003

S. Acikalin, G. Raabe, J. Runsink, H.-J. Gais

FULL PAPER

(c = 1.0, in CH₂Cl₂). R_f= 0.35 (pentane/Et₂O, 2:3). ¹H NMR

(w), 1309 (vs), 1236 (s), 1123 (vs), 1022 (m), 999 (m), 893 (s), 756

(400 MHz, CDCl₃): δ = 1.11–1.21 (m, 2 H), 1.24–1.32 (m, 1 H), (w) cm^–1. MS (CI, CH₄): m/z (%) = 439 (13) [M + C₂H₅]⁺, 429 (8),

1.48–1.67 (m, 3 H), 1.73–1.77 (m, 2 H), 1.47 [s, 9 H, C(CH₃)₃], 413 (11), 412 (23), 411 (100), 410 (6), 409 (12), 289 (7), 274 (5).

1.96–2.00 (m, 1 H, NCHCH), 2.08–2.15 (m, 1 H, COCHH), 2.19– HRMS: cacld. for C₁₆H₂₁N₂OS [M – C₄H₉SO₂]⁺289.137461;

2.25 (m, 1 H, CH₂CHCH₂), 2.39 (dd, J = 8.4, J = 19.3 Hz, 1 H,

COCHH), 3.99 (d, J = 8.8 Hz, 1 H, NH), 4.13 (dd, J = 8.8, J =

12.9 Hz, 1 H, NCH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.6

(u), 24.1 (u), 24.2 (d), 25.0 (u), 29.5 (u), 31.2 (d), 42.7 (d), 43.1 (u),

60.57 (u), 60.63 (d), 215.3 (u) ppm. MS (EI, 70 eV): m/z (%) =

273.1 (5) [M]⁺, 189 (4), 164 (14), 163 (33), 153 (15), 152 (38), 125

found 289.137707.

N-[(1R,3aR,7aR)-3a,4,5,6,7,7a-Hexahydro-1H-inden-1-yl]-2-meth-

ylpropane-2-sulfonamide (44): HgCl₂(1.0 g) was dissolved in H₂O

(50 mL) and small pieces of aluminum (1.5 g) were added. After

the mixture was stirred for 2 min, it was filtered and the residue

suspended in THF/H₂O/AcOH (2:1:1, 40 mL). Then the slurry was

added to a solution of 5 (200 mg, 0.47 mmol) in THF (10 mL).

After the mixture was stirred for 3 h at room temperature, it was

filtered and the filtrate was concentrated in vacuo. Purification by

column chromatography (pentane/Et₂O, 4:1) gave 44 (97 mg, 80%)

as a viscous colourless oil. [α]_D= –90.9 (c = 1.0, in CH₂Cl₂). R_f=

(21), 124 (18), 82 (17), 57 (100), 56 (41). IR (KBr): ν = 3889 (w),

˜

3314 (s), 2925 (vs), 1752 (s), 1450 (m), 1304 (vs), 1234 (w), 1126

(vs), 1071 (m), 983 (w), 899 (m), 870 (m) cm^–1. HRMS: cacld. for

C₁₃H₂₃NO₃S [M]⁺273.139866; found 273.139783.

N-[(1S,2R,3R,3aS,7aR)-2-Hydroxy-3-(phenylsulfonyl)octahydro-

1H-inden-1-yl]-2-methylpropane-2-sulfonamide (42): Sulfoximine 5

(107 mg, 0.25 mmol), m-ClC₆H₄CO₃H (60 mg, 0.35 mmol) and

HCl (0.1 m, 18 μL) were dissolved in THF (2 mL) and the mixture

was heated to reflux for 7 h. After the mixture was cooled to room

temperature, it was treated with NaOH (1 m, 1.2 mL), and the mix-

ture was extracted into Et₂O (3ϫ 15 mL). The combined organic

phases were dried (MgSO₄) and concentrated in vacuo. Purification

by column chromatography (Et₂O) afforded 42 (86 mg, 83%) as a

white solid; m.p. 87 °C. [α]_D= –54.5 (c = 1.0, in CH₂Cl₂). R_f= 0.59

(Et₂O). ¹H NMR (300 MHz, CDCl₃): δ = 1.21–1.68 (m, 7 H), 1.83–

1.87 (m, 1 H), 1.43 [s, 9 H, C(CH₃)₃], 2.19–2.27 (m, 1 H,

NCHCHCH₂), 2.45–2.52 (m, 1 H, SCHCHCH₂), 3.08 (dd, J = 1.7,

J = 4.7 Hz, 1 H, SCH), 3.61 (d, J = 2.2 Hz, 1 H, OH), 3.67–3.76

(m, 1 H, NCH), 4.38–4.44 (m, 1 H, OCH), 4.47 (d, J = 9.4 Hz, 1

H, NH), 7.56–7.71 (m, 3 H, Ph), 7.92–7.95 (m, 2 H, Ph) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 20.5 (u), 23.5 (u), 24.3 (d), 25.1 (u),

30.0 (u), 36.8 (d), 41.5 (d), 60.3 (u), 64.0 (d), 74.3 (d), 78.7 (d),

128.5 (d), 129.4 (d), 134.0 (d), 137.8 (u) ppm. MS (CI, CH₄): m/z

(%) = 444 (4) [M + C₂H₅]⁺, 416 (11), 342 (6), 298 (6), 297 (15), 296

1

0.26 (pentane/Et₂O, 4:1). H NMR (400 MHz, CDCl₃): δ = 1.03–

1.12 (m, 1 H), 1.16–1.45 (m, 2 H), 1.47–1.63 (m, 3 H), 1.67–1.85

(m, 2 H), 1.41 [s, 9 H, C(CH₃)₃], 1.93–1.99 (m, 1 H, NCHCHCH₂),

2.58–2.65 (m, 1 H, CH=CHCHCH₂), 4.06 (d, J = 9.9 Hz, 1 H,

NH), 4.17–4.23 (m, 1 H, NCH), 5.75 (dt, J = 1.6, J = 5.8 Hz, 1 H,

NCHCH=CH), 5.94 (dt, J = 2.2, J = 5.8 Hz, 1 H, NCHCH=CH)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.5 (u), 23.7 (u), 24.5 (d),

24.9 (u), 29.5 (u), 42.2 (d), 46.6 (d), 59.7 (u), 63.4 (d), 131.7 (d),

139.9 (d) ppm. MS (EI, 70 eV): m/z (%) = 257 (3) [M]⁺, 200 (7),

137 (93), 136 (100), 120 (44), 108 (16), 94 (19), 82 (15), 57 (92). IR

(KBr): ν = 3273 (s), 3052 (w), 2926 (s), 2857 (s), 2256 (w), 1447

˜

(m), 1212 (w), 1126 (s), 1076 (m), 1018 (w), 977 (w), 914 (s), 732

(s) cm^–1. HMRS: calcd. for C₁₃H₂₃NO₂S [M]⁺257.144952; found

257.144917.

N-[(1S,2S,3aR,7aR)-2-Hydroxyoctahydro-1H-inden-1-yl]-2-meth-

ylpropane-2-sulfonamide (45): To a solution of 5 (80 mg, 0.19 mmol)

in THF (5 mL) was added Raney nickel (50 %-slurry in H₂O,

880 mg, 7.47 mmol) and the mixture was stirred at room tempera-

ture for 10 h. Then mixture was filtered through celite and the fil-

trate was concentrated in vacuo. Purification by column

chromatography (pentane/Et₂O, 1:2) yielded 45 (47 mg, 92%) as a

white solid; m.p. 121 °C. [α]_D= –82.4 (c = 1.0, in CH₂Cl₂). R_f=

(100), 274 (70), 154 (16), 74 (7). IR (KBr): ν = 3955 (w), 3482 (s),

˜

3284 (s), 2930 (s), 2863 (m), 1627 (w), 1454 (s), 1298 (vs), 1130 (vs)

1005 (m), 911 (m), 826 (w) cm^–1. C₁₉H₂₉NO₅S₂(415.57): calcd. C

54.91, H 7.03, N 3.37; found C 54.73, H 7.32, N 3.17.

1

0.48 (pentane/Et₂O, 1:4). H NMR (400 MHz, CDCl₃): δ = 1.17–

2-Methyl-N-[(1S,3aS,7aR)-3-(N-methylphenylsulfonimidoyl)-

3a,4,5,6,7,7a-hexahydro-1H-inden-1-yl]propane-2-sulfonamide (43):

To a solution of 5 (203 mg, 0.47 mmol) and PPh₃(128 mg,

0.49 mmol) in THF (10 mL) was added diethyl azodicarboxylate

(85 μL, 0.54 mmol) at room temperature. After the mixture was

stirred for 16 h at room temperature, the volatiles were removed in

vacuo. Purification by chromatography (EtOAc/cyclohexane, 4:1)

gave 43 (172 mg, 90%) as a white solid; m.p. 109 °C. [α]_D= –62.2

(c = 1.0, in CH₂Cl₂). R_f= 0.39 (EtOAc/cyclohexane, 4:1). ¹H NMR

(400 MHz, CDCl₃): δ = 0.78–0.89 (m, 1 H), 1.02–1.12 (m, 1 H),

1.17–1.28 (m, 1 H), 1.37–1.49 (m, 1 H), 1.53–1.62 (m, 2 H), 1.77–

1.84 (m, 1 H), 1.93–2.00 (m, 1 H), 1.42 [s, 9 H, C(CH₃)₃], 2.11–

2.17 (m, 1 H, NCHCH), 2.68–2.72 (m, 1 H, SCHCH), 2.70 (s, 3

H, NCH₃), 4.48 (t, J = 10.2 Hz, 1 H, NCH), 4.83 (d, J = 10.2 Hz,

1 H, NH), 6.69 (d, J = 1.1 Hz, 1 H, NCHCHC), 7.52–7.67 (m, 3

H, Ph), 7.88–7.92 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 21.5 (u), 24.0 (u), 24.0 (u), 24.4 (d), 29.5 (d), 29.6 (u), 42.3 (d),

48.7 (d), 60.0 (u), 60.8 (d), 129.0 (d), 129.3 (d), 132.9 (d), 138.0 (u),

142.1 (d), 151.0 (u) ppm. MS (EI, 70 eV): m/z (%) = 410 (3) [M]⁺,

291 (8), 290 (32), 289 (74), 276 (6), 275 (13), 274 (72), 260 (6), 244

1.39 (m, 2 H), 1.48–1.73 (m, 6 H), 1.44 [s, 9 H, C(CH₃)₃], 1.79–

1.85 (m, 1 H, NCHCHCH₂), 1.89–1.97 (m, 1 H, CH₂CHCH₂),

2.15–2.23 (m, 2 H, OCHCH₂), 3.40 (d, J = 1.9 Hz, 1 H, OH), 3.55

(dt, J = 5.0, J = 9.9 Hz, 1 H, NCH), 4.10 (ddd, J = 1.7, J = 5.0, J

= 9.2 Hz, 1 H, OCH), 4.28 (d, J = 9.9 Hz, 1 H, NH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 21.3 (u), 24.3 (d), 24.7 (u), 24.9 (u),

29.6 (u), 36.3 (d), 37.9 (u), 44.3 (d), 60.1 (u), 66.3 (d), 80.4 (d) ppm.

MS (EI, 70 eV): m/z (%) = 276 (2) [M + 1]⁺, 155 (27), 154 (100),

138 (9), 137 (8), 136 (17), 111 (12), 110 (89), 109 (20), 95 (15), 94

(6), 93 (11), 82 (8), 81 (7), 79 (6), 72 (18), 69 (6), 67 (13), 59 (6), 58

(10), 57 (98), 56 (31), 55 (18), 54 (6), 53 (5). IR (CHCl ): ν = 3501

˜

3

(s), 3272 (s), 2926 (vs), 28.59 (vs), 2663 (w), 1728 (w), 1586 (w),

1453 (s), 1396 (w), 1366 (w), 1297 (s), 1216 (m), 1121 (s), 1000 (m),

917 (m), 892 (m), 833 (w), 757 (vs) cm^–1. HRMS: calcd. for

C₉H₁₆NO [M – C₄H₉SO₂]⁺154.123189; found 154.123076.

(1S,2R,3R,3aS,7aR)-1-Amino-3-[(S)-N-methylphenylsulfonimid-

oyl]octahydro-1H-inden-2-ol (47): To a solution of 5 (300 mg,

0.70 mmol) and anisole (0.1 mL, 0.70 mmol) in CH₂Cl₂(30 mL)

was added CF₃SO₃H (60 mL, 0.12 m solution in CH₂Cl₂) at 0 °C.

(6), 226 (17), 165 (13), 156 (21), 152 (5), 148 (6), 139 (5), 136 (19), The mixture was warmed to room temperature over 2 h and its

135 (37), 134 (100), 125 (39), 119 (7), 117 (11), 110 (7), 109 (10), pH value was adjusted to 8 by the addition of saturated aqueous

107 (15), 106 (19), 97 (7), 94 (6), 91 (15), 83 (10), 79 (11), 77 (12), NaHCO₃. The aqueous phase was extracted into CH₂Cl₂(3 ϫ

57.4 (82), 56.6 (14), 56 (11). IR (KBr): ν = 3458 (w), 3263 (w), 3076 100 mL) and the combined organic phases were dried (MgSO₄) and

(m), 2927 (s), 2807 (m), 2745 (w), 2253 (w), 1611 (w), 1454 (s), 1384 concentrated in vacuo. Purification by flash chromatography

˜

6004

www.eurjoc.org

Eur. J. Org. Chem. 2011, 5991–6008

Asymmetric Synthesis of Bicyclic β-Amino Alcohols

(Et₂O/MeOH, 9:1) gave 47·1/2CF₃SO₃H (202 mg, 94%) as a white (w), 2936 (w), 1703 (vs), 1594 (m), 1493 (w), 1444 (m), 1381 (w),

solid; m.p. 51 °C. [α]_D= +48.9 (c = 1.0, in CH₂Cl₂). R_f= 0.33

1315 (m), 1256 (s), 1165 (m), 1082 (w), 1017 (m), 915 (w), 853 (w),

(Et₂O/MeOH, 1:4). ¹H NMR (300 MHz, CDCl₃): δ = 0.93–1.08 793 (m) cm^–1. C₁₆H₁₆O₃(256.30): calcd. C 74.98, H 6.29; found C

(m, 3 H), 1.16–1.30 (m, 1 H), 1.35–1.54 (m, 3 H), 1.71–1.80 (m, 2

H), 2.11–2.18 (m, 1 H, SCHCHCH₂), 2.63 (s, 3 H, NCH₃), 2.86

(br. s, 2 H, NH₂), 3.04–3.08 (m, 1 H, SCH), 3.11–3.15 (m, 1 H,

NCH), 4.31 (t, J = 7.7 Hz, 1 H, OCH), 7.55–7.65 (m, 3 H, Ph),

7.85–7.89 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 21.0

(u), 23.6 (u), 24.6 (u), 29.2 (d), 30.6 (u), 35.6 (d), 41.3 (d), 57.9 (d),

75.24, H 5.99.

(4S)-4-Benzyl-3-[3-{3-(benzyloxy)phenyl}propanoyl]oxazolidin-2-one

(53): Carboxylic acid 51 (1.56 g, 6.09 mmol) was dissolved in THF

(30 mL) and the solution was cooled to –30 °C. NEt₃(2.1 mL,

15.2 mmol) and tBuC(O)Cl (0.75 mL, 6.09 mmol) were added and

the mixture was stirred at –30 °C for 2 h. Then LiCl (284 mg,

6.7 mmol) and 52 (1.03 g, 5.79 mmol) were added at once and the

mixture was allowed to stir for 1 d whereby the temperature of the

mixture slowly rose to room temperature. The mixture was diluted

with Et₂O (200 mL) and washed successively with saturated aque-

ous NH₄Cl, NaOH (1.0 m) and brine. The organic phase was dried

(MgSO₄) and concentrated in vacuo. Purification by column

chromatography (EtOAc/cyclohexane, 2:3) afforded 53 (1.97 g,

82%) as a colourless oil. [α]_D= +53.6 (c = 1.0, in CH₂Cl₂). R_f=

73.7 (d), 78.8 (d), 129.5 (d), 129.6 (d), 133.0 (d), 136.8 (u) ppm. ¹⁹

F

NMR (376 MHz, CDCl₃): δ = –78.3 (s) ppm. MS (EI, 70 eV): m/z

(%) = 309 (17) [M + 1]⁺, 156 (12), 155 (11), 154 (83), 153 (55), 137

(16), 13 (80), 125 (89), 110 (39), 110 (17), 109 (18), 108 (15), 107

(25), 106 (22), 97 (40), 95 (14), 94 (13), 93 (16), 91 (17), 82 (13), 81

(15), 80 (11), 79 (15), 78 (18), 77 (55), 67 (24), 56 (100), 55 (13), 53

(15), 51 (18), 51 (14). IR (CHCl ): ν = 3062 (w), 3011 (w), 2928

˜

3

(s), 28.58 (m), 2804 (w), 1589 (w), 1448 (m), 1348 (w), 1236 (s),

1145 (m), 1107 (m), 1079 (m), 993 (w), 869 (w), 827 (w), 795 (w),

754 (vs) cm^–1. C₁₆H₂₄N₂O₂S·1/2 (CF₃SO₃H) (383.48): calcd. C

51.68, H 6.44, N 7.31; found C 51.88, H 6.40, N 7.24. HRMS:

calcd. for C₁₆H₂₅N₂O₂S [M + H]⁺309.163676; found 309.163596.

1

0.51 (EtOAc/cyclohexane, 2:3). H NMR (400 MHz, CDCl₃): δ =

2.73 (dd, J = 9.4, J = 13.5 Hz, 1 H, OCHHCH), 2.93–3.04 (m, 2

H, COCH₂CH₂), 3.17–3.34 (m, 3 H, OCHHCH, COCH₂), 4.10 (d,

J = 5.2 Hz, 2 H, PhCH₂CH), 4.60 (m, 1 H, NCH), 5.00 (s, 2 H,

PhCH₂O), 6.79–6.92 (m, 3 H, Ph), 7.12–7.43 (m, 11 H, Ph) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 30.2 (u), 36.9 (u), 37.7 (u), 54.9

(d), 66.0 (u), 69.7 (u), 112.3 (d), 115.0 (d), 120.9 (d), 127.0 (d),

127.3 (d), 127.7 (d), 128.3 (d), 128.7 (d), 129.2 (d), 129.3 (d), 135.0

(u), 136.8 (u), 141.9 (u), 153.1 (u), 158.7 (u), 172.0 (u) ppm. MS

(EI, 70 eV): m/z (%) = 416 (15) [M + 1]⁺, 415 (56), 324 (11), 239

tert-Butyl 3-[3-(Benzyloxy)phenyl]propanoate (50): To a solution of

HNiPr₂(2.0 mL, 14.3 mmol) in THF (15 mL) at 0 °C was added

nBuLi (6.86 mL, 1.6 m in THF, 10.98 mmol) and the mixture was

stirred for 15 min. After the mixture was cooled to –78 °C, tert-

butyl acetate (1.48 mL, 10.98 mmol) was added dropwise and the

mixture was warmed to –30 °C over 1 h and then cooled to –78 °C.

Then a solution of 49 (2.49 g, 9.0 mmol) in THF (8 mL) was added.

After the mixture was stirred for 1 h, saturated aqueous NH₄Cl

was added and the mixture was extracted into Et₂O (4ϫ 100 mL).

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

trated in vacuo. Purification by flash column chromatography

(pentane/Et₂O, increasing polarity from 19:1 to 1:1) furnished 50

(2.46 g, 88%) as a white solid; m.p. 47 °C. R_f= 0.53 (pentane/Et₂O,

9:1). ¹H NMR (400 MHz, CDCl₃): δ = 1.42 [s, 9 H, C(CH₃)₃], 2.53

(t, J = 7.9 Hz, 2 H, COCH₂), 2.88 (t, J = 7.9 Hz, 2 H,

COCH₂CH₂), 5.04 (s, 2 H, PhCH₂O), 7.17–7.21 (m, 3 H, Ph), 7.30–

7.34 (m, 1 H, Ph), 7.36–7.44 (m, 5 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 28.1 (d), 31.1 (u), 36.9 (u), 69.8 (u), 80.2

(u), 112.2 (d), 114.8 (d), 120.8 (d), 127.3 (d), 127.7 (d), 128.4 (d),

129.2 (d), 136.9 (u), 142.3 (u), 158.7 (u), 172.0 (u) ppm. MS (EI,

70 eV): m/z (%) = 312 (15) [M]⁺, 256 (19), 239 (8), 196 (7), 165 (7),

(7), 238 (23), 147 (7), 92 (11), 90 (100), 65 (6). IR (CHCl ): ν =

˜

3

3062 (w), 3028 (w), 2920 (w), 2868 (w), 1781 (vs), 1700 (s), 1586

(m), 1490 (m), 1450 (m), 1385 (s), 1353 (m), 1256 (s), 1214 (s), 1159

(m), 1109 (m), 1077 (w), 1046 (m), 920 (w), 875 (w), 847 (w), 755

(vs) cm^–1. HRMS: calcd. for C₂₆H₂₅NO₄[M]⁺415.178358; found

415.178285.

tert-Butyl (3R)-4-[(S)-4-Benzyl-2-oxooxazolidin-3-yl]-3-[3-(benz-

yloxy)benzyl]-4-oxobutanoate (54): To a solution of 53 (1.38 g,

3.33 mmol) in THF (40 mL) at –65 °C was added NaN(SiMe₃)₂

(3.66 mL of 1.0 m in THF, 3.66 mmol) dropwise over 10 min. After

the mixture was stirred for 45 min at –65 °C, tert-butyl-2-bromo-

acetate (0.63 mL, 4.33 mmol) was added dropwise over 12 min. Af-

ter the mixture was stirred for 3 h at –70 °C, saturated aqueous

NH₄Cl was added and the mixture was stirred for 12 h. The vola-

tiles were removed in vacuo and the remaining aqueous phase was

extracted into EtOAc (3ϫ 250 mL). The combined organic phases

were successively washed with HCl (1.0 m), saturated aqueous

NaHCO₃and brine. The organic phase was dried (MgSO₄) and

concentrated in vacuo. Purification by flash column chromatog-

raphy (EtOAc/cyclohexane, increasing polarity from 1:9 to 2:3) fur-

123 (7), 92 (9), 91 (100), 57 (8). IR (KBr): ν = 2969 (m), 2934 (m),

˜

2881 (m), 1724 (vs), 1608 (s), 1580 (s), 1486 (s), 1452 (s), 1371 (s),

1305 (s), 1281 (s), 1228 (m), 1149 (vs), 1026 (s), 933 (w), 905 (m),

850 (m), 786 (m), 752 (s) cm^–1. C₂₀H₂₄O₃(312.40): calcd. C 76.89,

H 7.74; found C 76.99, H 7.48.

3-[3-(Benzyloxy)phenyl]propanoic Acid (51): To a solution of 50

(4.37 g, 14 mmol) in CH₂Cl₂(90 mL) was added CF₃CO₂H

(10.8 mL, 140 mmol) at 0 °C. The mixture was warmed to room

temperature and stirred for 10 h. The volatiles were removed in

vacuo and the residue dissolved in EtOAc (100 mL). The mixture

was washed with saturated aqueous NaHCO₃and brine, dried

(MgSO₄) and concentrated in vacuo. Purification by column

chromatography (EtOAc/cyclohexane, 3:2) furnished 51 (2.98 g,

nished 54 (1.26 g, 71%) of Ն 98% de as a colourless oil. [α]_D=

+94.9 (c = 1.0, in CH₂Cl₂). R_f= 0.59 (EtOAc/cyclohexane, 2:3). ¹H

NMR (300 MHz, CDCl₃): δ = 1.40 [s, 9 H, C(CH₃)₃], 2.36 (dd, J

= 4.2, J = 17.0 Hz, 1 H, COCHH), 2.60 (dd, J = 9.2, J = 13.1 Hz,

1 H, CCHHCHCO), 2.73 (dd, J = 9.9, J = 13.4 Hz, 1 H,

OCHHCH), 2.82 (dd, J = 10.9, J = 17.0 Hz, 1 H, COCHH), 2.99

(dd, J = 6.2, J = 13.1 Hz, 1 H, CCHHCHCO), 3.30 (dd, J = 3.2,

J = 13.4 Hz, 1 H, OCHHCH), 3.91 (m, 1 H, PhCHHCHN), 4.06

(dd, J = 2.5, J = 8.9 Hz, 1 H, PhCHHCHN), 4.42–4.56 (m, 2 H,

83%) as a white solid; m.p. 74–76 °C. R_f= 0.35 (EtOAc/cyclohex-

1

ane, 2:3). H NMR (400 MHz, CDCl₃): δ = 2.61 (t, J = 8.0 Hz, 2 NCH, NCOCH), 5.05 (s, 2 H, PhCH₂O), 6.80–6.93 (m, 3 H, Ph),

H, COCH₂), 2.89 (t, J = 8.0 Hz, 2 H, COCH₂CH₂), 4.98 (s, 2 H,

7.16–7.44 (m, 11 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ =

PhCH₂O), 6.76–6.81 (m, 3 H, Ph), 7.29–7.40 (m, 6 H, Ph) ppm.

28.1 (d), 36.7 (u), 37.6 (u), 38.3 (u), 41.2 (d), 55.6 (d), 65.9 (u), 69.9

¹³C NMR (100 MHz, CDCl₃): δ = 30.9 (u), 36.1 (u), 69.8 (u), 112.3 (u), 80.8 (u), 113.3 (d), 115.6 (d), 121.9 (d), 127.2 (d), 127.6 (dH),

(d), 114.8 (d), 120.7 (d), 127.3 (d), 127.7 (d), 128.3 (d), 129.3 (d),

127.9 (d), 128.5 (d), 128.9 (d), 129.45 (d), 129.53 (d), 135.7 (u),

136.8 (u), 141.9 (u), 158.7 (u), 178.6 (u) ppm. MS (EI, 70 eV): m/z 137.0 (u), 139.6 (u), 153.0 (u), 158.8 (u), 171.2 (u), 175.3 (u) ppm.

(%) = 256 (25) [M]⁺, 91 (100), 65 (7). IR (KBr): ν = 3032 (w), 2973 MS (EI, 70 eV): m/z (%) = 529 (3) [M]⁺, 474 (10), 473 (31), 456 (8),

˜

Eur. J. Org. Chem. 2011, 5991–6008

www.eurjoc.org

6005

S. Acikalin, G. Raabe, J. Runsink, H.-J. Gais

FULL PAPER

382 (7), 187 (6), 178 (32), 117 (9), 92 (9), 91 (100), 57 (13). IR (d), 129.7 (d), 132.9 (d), 137.1 (u), 140.5 (u), 159.0 (u), 171.7 (u),

(CHCl ): ν = 2928 (w), 1780 (vs), 1723 (s), 1700 (s), 1597 (m), 1488

175.9 (u) ppm. MS (EI, 70 eV): m/z (%) = 660 (4) [M]⁺, 449 (14),

315 (15), 314 (85), 279 (10), 154 (26), 152 (18), 137 (19), 136 (98),

135 (16), 125 (38), 107 (45), 97 (10), 91 (100), 79 (16), 78 (15), 58

˜

3

(w), 1451 (m), 1389 (m), 1356 (m), 1289 (w), 1255 (m), 1217 (m),

1154 (s), 1110 (w), 1022 (m), 955 (w), 843 (w), 757 (vs) cm^–1

.

C

₃₂H₃₅NO₆(529.62): calcd. C 72.57, H 6.66, N 2.64; found C

(24), 57 (29), 55 (18), 52 (12). IR (KBr): ν = 3331 (m), 3249 (w),

˜

72.80, H 6.63, N 2.57.

3061 (m), 2932 (vs), 2863 (m), 2343 (w), 2330 (w), 2249 (w), 1727

(vs), 1643 (m), 1588 (w), 1544 (m), 1491 (w), 1450 (m), 1369 (m),

1316 (w), 1254 (s), 1151 (s), 1083 (w), 1028 (m), 953 (w), 911 (w),

846 (w), 795 (w), 735 (s) cm^–1. C₃₈H₄₈N₂O₆S (570.74): calcd. C

69.06, H 7.32, N 4.24; found C 68.96, H 7.05, N 4.15.

(3R)-2-[3-(Benzyloxy)benzyl]-4-tert-butoxy-4-oxobutanoic Acid (48):

To a solution of 54 (2.83 g, 5.34 mmol) in THF/H₂O (4:1, 12.5 mL)

at 0 °C were added H₂O₂(1.84 mL, 35 % solution in H₂O,

21.4 mmol) and LiOH (205 mg, 8.55 mmol) and the resulting mix-

ture was stirred for 3 h. The mixture was diluted with H₂O and the

volatiles were removed in vacuo. The mixture was cooled to 0 °C

and EtOAc (50 mL) was added. The pH of the mixture was ad-

justed to 4–5 upon addition of 10% aqueous citric acid under in-

tensive stirring. The organic phase was separated and the aqueous

phase was extracted into EtOAc (3ϫ 150 mL). The combined or-

ganic phases were washed with brine, dried (MgSO₄) and concen-

trated in vacuo. Purification by column chromatography (pentane/

Et₂O/AcOH, 1:4:0.1) gave 48 (1.92 g, 97%) as a colourless oil and

52 (843 mg, 89%) (R_f= 0.15, pentane/Et₂O/AcOH, 1:4:0.1) as a

white solid. For 48: [α]_D= +7.9 (c = 1.0, in CH₂Cl₂). R_f= 0.76

(2R)-N⁴-Benzyloxy-2-[3-(benzyloxy)benzyl]-N¹-[(1S,2R,3R,3aS,

7aR)-2-hydroxy-3-{(S)-N-methylphenylsulfonimidoyl}octahydro-1H-

inden-1-yl]succinamide (46): To

a solution of 56 (208 mg,

0.31 mmol) in CH₂Cl₂(6 mL) and H₂O (0.55 mL) was added

CF₃CO₂H (5.5 mL, 71 mmol) dropwise and the resulting mixture

was stirred at room temperature for 3 h. The mixture was concen-

trated to half of its original volume in vacuo. Then the residue was

dried by coevaporation with toluene (3ϫ 15 mL). The resulting

crude acid, PhCH₂ONH₃Cl (99 mg, 0.62 mmol) and 57 (100 mg,

0.31 mmol) were dissolved in DMF (10 mL) and the solution was

cooled to 0 °C followed by the addition of EtNiPr₂(0.26 mL,

1.55 mmol). The mixture was stirred at 0 °C for 15 min and then

warmed to room temperature. After the mixture was stirred for 2 h,

it was poured into a mixture of EtOAc (20 mL) and 5% aqueous

citric acid (20 mL). The mixture was extracted into EtOAc (3ϫ

25 mL). The combined organic phases were successively washed

with 5% aqueous citric acid, H₂O, saturated aqueous NaHCO₃and

brine, dried (MgSO₄) and concentrated in vacuo. Purification by

HPLC (Kromasil Si 100, 30 mm, EtOAc, 254 nm + RI, 25 mL/min)

1

(pentane/Et₂O/AcOH, 1:4:0.1). H NMR (300 MHz, CDCl₃): δ =

1.41 [s, 9 H, C(CH₃)₃], 2.33 (dd, J = 4.5, J = 16.8 Hz, 1 H,

HOOCCHC HH), 2. 54 (dd, J = 8. 7, J = 16 . 8 Hz , 1 H,

HOOCCHCHH), 2.71 (dd, J = 10.5, J = 15.2 Hz, 1 H,

CCHHCHCO), 3.03–3.13 (m, 2 H, CCHHCHCO, HOOCCH),

5.03 (s, 2 H, PhCH₂O), 6.75–6.86 (m, 3 H, Ph), 7.17–7.22 (m, 1 H,

Ph), 7.30–7.44 (m, 5 H, Ph), 11.35 (br. s, 1 H, COOH) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 28.1 (d), 36.1 (u), 37.5 (u), 43.2 (d),

70.0 (u), 81.2 (u), 113.1 (d), 115.7 (d), 121.7 (d), 127.5 (d), 128.0

(d), 128.6 (d), 129.6 (d), 136.9 (u), 139.7 (u), 158.9 (u), 170.9 (u),

180.6 (u) ppm. MS (EI, 70 eV): m/z (%) = 370 (8) [M]⁺, 314 (29),

afforded 46 (188 mg, 85%) as a white solid; m.p. 84 °C. [α]_D

=

+16.4 (c = 1.0, in CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃, room

temperature): δ = 0.85–1.46 (m, 8 H), 1.81–1.84 (m, 1 H,

NCHCHCH₂), 2.07–2.15 (m, 2 H, NCOCH₂) 2.26–2.32 (m, 1 H,

SCHCHCH₂), 2.50 (s, 3 H, NCH₃), 2.63 (dd, J = 6.9, J = 13.5 Hz,

1 H, NCOCH₂CHCHH), 2.81–2.86 (m, 1 H, NCOCH₂CHCHH),

2.93–2.98 (m, 1 H, NCOCH), 3.01 (dd, J = 6.0, J = 9.3 Hz, 1 H,

205.0 (11), 91 (100), 57 (11). IR (capillary): ν = 2976 (s), 2931 (m),

˜

2874 (m), 1725 (vs), 1593 (m), 1489 (m), 1450 (m), 1371 (m), 1259

(s), 1155 (vs), 1030 (m), 951 (w), 847 (w), 781 (w), 740 (m) cm^–1.

C₂₂H₂₆O₅(370.44): calcd. C 71.33, H 7.07; found C 71.38, H 7.08.

tert-Butyl (3R)-3-[3-(Benzyloxy)benzyl]-4-[(1S,2R,3R,3aS,7aR)-2- SCH), 4.12 (dt, J = 6.0, J = 11.0 Hz, 1 H, NCH), 4.33 (t, J =

hydroxy-3-{(S)-N-methylphenylsulfonimidoyl}octahydro-1H-inden-

1-ylamino]-4-oxobutanoate (56): To a mixture of 47 (591 mg,

1.92 mmol) and 48 (591 mg, 1.60 mmol) in DMF (20 mL) at 0 °C

6.0 Hz, 1 H, OCH), 4.72 (s), 4.75 (s, 2 H, NOCH₂Ph), 4.95 (s, 2

H, COCH₂Ph), 6.51 (br. s, 1 H, CHNH), 6.70–6.77 (m, 3 H, Ph),

7.10–7.51 (m, 14 H, Ph), 7.72–7.77 (m, 2 H, Ph), 9.01 (br. s), 9.20

was added 55 (708 mg, 1.60 mmol) followed by EtNiPr₂(0.74 mL, (br. s), (1 H, ONH) ppm. ¹³C NMR (100 MHz, CDCl₃, room tem-

4.48 mmol). The mixture was warmed to room temperature and perature): δ = 21.1 (u, CH₂), 23.8 (u, CH₂), 24.7 (u, CH₂), 29.5 (d,

stirred for 5 h. The mixture was quenched with 10% aqueous citric

acid and extracted into EtOAc (3ϫ 100 mL). The combined or-

ganic phases were successively washed with H₂O, aqueous

NaHCO₃and brine, dried (MgSO₄) and concentrated in vacuo.

Purification by column chromatography (CHCl₃/Et₂O, 1:1) fur-

nished 56 (1.0 g, 95%) as a white solid; m.p. 71 °C. [α]_D= +13.8 (c

= 1.0, in MeOH). R_f= 0.51 (CHCl₃/Et₂O, 1:1). ¹H NMR

(300 MHz, CDCl₃): δ = 0.98–1.52 (m, 8 H), 1.40 [s, 9 H, C(CH₃)

CH₃), 29.9 (u, CH₂), 33.6 (u, CH₂), 35.2 (u, CH₂), 36.6 (d, CH),

38.7 (u, CH₂), 40.1 (d, CH), 43.5 (d, CH), 45.0 (d, CH), 57.6 (d,

CH), 69.9 (u, CH₂), 74.0 (d, CH), 76.8 (d, CH), 78.2, 79.3 (u, CH₂),

113.1 (d, CH), 115.7 (d, CH), 121.8 (d, CH), 127.6 (d, CH), 127.8

(d, CH), 128.5 (d, CH), 129.0 (d, CH), 129.4 (d, CH), 129.6 (d,

CH), 132.9 (d, CH), 135.4 (u, C), 136.7 (u, C), 137.0 (u, C), 140.1

(u, C), 140.7 (u, C), 158.8 (u, C), 169.1 (u, C), 175.2, 175.9 (u, C)

ppm. ¹H NMR (400 MHz, CDCl₃, 55 °C): δ = 0.89–1.45 (m, 8 H),

₃], 1.92–2.00 (m, 1 H, NCHCHCH₂), 2.17–2.27 (m, 1 H, 1.91–1.87 (m, 1 H, NCHCHCH₂), 2.12–2.41 (m, 3 H, SCHCHCH₂,

S C H C H C H ₂) , 2 . 3 6 ( d d , J = 4 . 0 , J = 1 7 . 1 H z , 1 H , NCOCH₂), 2.51 (s, 3 H, NCH₃), 2.65 (dd, J = 6.9, J = 13.5 Hz, 1

COCHCHHC O ), 2 . 6 1 ( dd, J = 9. 9, J = 17 . 1 Hz , 1 H, H, NCOCH₂CHCHH), 2.83–2.88 (m, 1 H, NCOCH₂CHCHH),

COCHCHHCO), 2.63 (s, 3 H, NCH₃), 2.69 (dd, J = 7.2, J =

13.0 Hz, 1 H, COCH₂CHCHH), 2.77–2.87 (m, 1 H, NCOCH), 2.97

(dd, J = 7.4, J = 13.0 Hz, 1 H, COCH₂CHCHH), 3.05–3.08 (m, 1

2.93–2.95 (m, 1 H, NCOCH), 3.01 (dd, J = 5.8, J = 9.3 Hz, 1 H,

SCH), 4.09 (dt, J = 5.8, J = 11.0 Hz, 1 H, NCH), 4.30 (t, J =

5.8 Hz, 1 H, OCH), 4.74 (s, 2 H, NOCH₂Ph), 4.96 (s, 2 H,

H, SCH), 4.11–4.19 (m, 1 H, NCH), 4.30 (s, 1 H, OH), 4.35–4.40 COCH₂Ph), 6.23 (br. s, 1 H, CHNH), 6.71–6.77 (m, 3 H, Ph), 7.10–

(m, 1 H, OCH), 5.08 (s, 2 H, PhCH₂O), 5.79 (d, J = 6.4 Hz, 1 H,

7.49 (m, 14 H, Ph), 7.71–7.74 (m, 2 H, Ph), 8.84 (br. s, 1 H, ONH)

NH), 6.81–6.89 (m, 3 H, Ph), 7.22–7.59 (m, 9 H, Ph), 7.81–7.85

ppm. ¹³C NMR (100 MHz, CDCl₃, 55 °C): δ = 21.1 (u, CH₂), 23.9

(m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 20.7 (u), 23.6 (u, CH₂), 24.6 (u, CH₂), 29.3 (d, CH₃), 29.8 (u, CH₂), 35.0 (u,

(u), 24.8 (u), 28.0 (d), 29.4 (d), 30.1 (u), 36.7 (d), 37.3 (u), 38.1 (u),

40.1 (d), 44.5 (d), 57.9 (d), 70.0 (u), 74.3 (d), 77.9 (d), 81.0 (u),

113.1 (d), 115.7 (d), 121.8 (d), 127.6 (d), 127.9 (d), 128.6 (d), 129.4

CH₂), 36.6 (d, CH), 38.7 (u, CH₂), 40.2 (d, CH), 44.9 (d, CH), 57.9

(d, CH), 70.1 (u, CH₂), 74.2 (d, CH), 76.8 (d, CH), 78.4 (u, CH₂),

113.2 (d, CH), 115.9 (d, CH), 121.8 (d, CH), 127.4 (d, CH), 127.7

6006

www.eurjoc.org

Eur. J. Org. Chem. 2011, 5991–6008

Asymmetric Synthesis of Bicyclic β-Amino Alcohols

[12]

[13]

For the synthesis of α-sulfonyl cycloalkanones through hydroa-

lumination–cyclization of ethoxycarbonyl-substituted alkenyl-

sulfones, see: a) D. N. Jones, M. W. J. Maybury, S. Swallow,

N. C. O. Tomkinson, Tetrahedron Lett. 1993, 34, 8553–8556; b)

D. N. Jones, M. W. J. Maybury, S. Swallow, N. C. O. Tomkin-

son, W. W. Wood, Tetrahedron Lett. 2001, 42, 2193–2195.

a) C. R. Johnson, Aldrichimica Acta 1985, 18, 3–10; b) S. G.

Pyne, Sulfur Rep. 1992, 12, 57–89; b) M. Mikołajczk, J. Dra-

bowicz, P. Kiełbasin´ski, Chiral Sulfur Reagents, CRC Press,

Boca Raton, 1997, pp. 195–240; c) S. G. Pyne, Sulfur Rep. 1999,

21, 281–334; d) M. Reggelin, C. Zur, Synthesis 2000, 1–64; e)

H.-J. Gais, in: Asymmetric Synthesis with Chemical and Bio-

logical Methods (Eds.: D. Enders, K.-E. Jaeger), Wiley-VCH,

Weinheim, Germany, 2007, pp. 75–115; f) H.-J. Gais, Heteroat.

Chem. 2007, 18, 472–481; g) C. Worch, A. C. Mayer, C. Bolm,

in: Organosulfur Chemistry in Asymmetric Synthesis (Eds.: T.

Toru, C. Bolm), Wiley-VCH, Weinheim, Germany, 2008, pp.

209–232.

(d, CH), 128.4 (d, CH), 129.0 (d, CH), 129.3 (d, CH), 129.6 (d,

CH), 132.7 (d, CH), 137.2 (u, C), 137.3 (u, C), 140.3 (u, C), 159.0

(u, C), 175.2 (u, C) ppm. MS (EI, 70 eV): m/z (%) = 709 (1) [M]⁺,

156 (6), 136 (13), 125 (14), 108 (11), 107 (20), 106 (13), 105 (10),

97 (5), 91 (100), 79 (10), 78 (10), 77 (22), 65 (10), 52 (13). MS (CI,

isobutane): m/z (%) = 710 (1) [M + 1]⁺, 309 (10), 181 (5), 156 (24),

136 (5), 125 (41), 108 (10), 107 (68), 105 (7), 93 (10), 92 (8), 91

(100), 79 (39), 77 (6). IR (CHCl ): ν = 3552 (w), 3276 (m), 3068

˜

3

(w), 3012 (w), 2927 (s), 2860 (m), 2805 (w), 1652 (s), 1588 (w), 1548

(w), 1492 (w), 1448 (m), 1384 (w), 1240 (s), 1153 (m), 1108 (w),

1080 (w), 1030 (w), 908 (m), 877 (m), 755 (vs) cm^–1. HRMS

(FTMS-ESI): calcd. for C₄₁H₄₇N₃O₆S [M + H]⁺710.32583; found

710.32585.

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Received: June 14, 2011

Published Online: August 24, 2011

6008

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Asymmetric synthesis of functionalized bicyclic β-amino alcohols by cascade hydrometallation-cyclization-reduction of glycinyl-substituted alkenylsulfoximines - Application to the synthesis of an aggrecanase inhibitor mimic

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