Sulfoximine-based modular enantioselective synthesis of azaspirocycles featuring sulfoximine displacement, dianion cycloalkylation, RCM and N-acyliminium ion formation

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DOI: 10.1002/ejoc.201400068

Sulfoximine-Based Modular Enantioselective Synthesis of Azaspirocycles

Featuring Sulfoximine Displacement, Dianion Cycloalkylation, RCM and

N-Acyliminium Ion Formation

Adeline Köhler (née Adrien),^[a][‡]Gerhard Raabe,^[a]Jan Runsink,^[a][†]Franz Köhler,^[a][‡]and

and Hans-Joachim Gais*^[a]

Keywords: Ring-closing metathesis / Nucleophilic substitution / Carbanions / Spiro compounds / Enantioselectivity /

Sulfoximine

We describe a modular, enantioselective synthesis of func-

tionalised azaspirocycles with a range of ring sizes. The syn-

thesis exploits the special features of sulfoximines, including

chirality, carbanion-stabilisation, nucleophilicity, and nucleo-

fugacity. Diastereoselective intramolecular amination of hy-

droxyalkyl-substituted cycloalkenylsulfoximines by the carb-

amate method gave bicyclic oxazinanones containing an

amino-substituted tertiary C atom. Cycloalkylation of the

corresponding C,N-dianions with biselectrophiles afforded

sulfoximine-substituted spirocycles. Monoalkylation of the

C,N-dianions with functionalised electrophiles, having a

double bond and acetal group, furnished the corresponding

C-alkylated bicyclic sulfoximines. Displacement of the sulf-

oximine group of bicyclic and spirocyclic sulfoximines by

haloformate reactions gave the corresponding halides (Cl, I).

Alkylation of the bicyclic halides with functionalised cup-

rates and reduction of the sulfoximine-substituted bicycles,

carrying an alkyl group at the Cα atom, gave starting materi-

als for a step-wise construction of the heterocyclic ring. Ring-

closing metathesis of a bicyclic C,N-dienyl derivative fur-

nished the corresponding spirocycle with an unsaturated pi-

peridine ring. Cyclisation of an acetal group containing bicy-

clic oxazinanone gave spirocycles containing O,N-acetal and

enamide groups. The diastereoselective reaction of a spirocy-

clic O,N-acetal with an allylsilane furnished the correspond-

ing spirocycle, carrying an allyl group at the C atom adjacent

to the N atom. Attempts to lithiate a bicyclic carbamate at

the CH₂group adjacent to the N atom were not successful.

anium complexes IV, which will serve as the starting mate-

rial for the synthesis of Ia–c, have previously been used in

a modular enantioselective synthesis of oxaspirocycles.^[5]

Complexes IV of different ring sizes are readily available

from the corresponding allylic sulfoximines through lithi-

ation and Li–Ti exchange (see below).^[6]Because of the

availability of both enantiomers of the allylic sulfox-

imines,^[6,7]access to both enantiomers of the azaspirocycles

Ia–c will be assured.

Titanium complexes IV serve as ring A+C*_Bbuilding

blocks. In the first step, the hydroxyalkyl group and two

stereogenic C atoms of Ia–c are established through regio-

and stereoselective reaction of IV with aldehydes, furnishing

cycloalkenylsulfoximines III.^[6,8]In the second step, the

amino-substituted stereogenic tertiary carbon centre of Ia–

c is set up through an intramolecular amination of the sulf-

oximine-activated double bond of III by the carbamate

method, leading to oxazinanone IIa.^[6c,9,10]Oxazinanone

IIb, which is synthetically complementary to IIa, will be

generated through sulfoximine displacement by halide. In

the finals steps, functionalised rings B of Ia–c are con-

structed by the following four different routes: (1) C,N-di-

anion cycloalkylation of IIa followed by sulfoximine dis-

placement by halide, (2) alkylation of IIb with organometal-

lics followed by cyclisation through N-acyliminium ion for-

Introduction

The 1-azaspirocycle structural motif is found in a

number of alkaloids and other compounds with interesting

biological activities and intricate molecular architectures.^[1]

This has led to the development of notable total syntheses

and imaginative methods for the construction of 1-azaspiro-

cyclic skeletons.^[1–4]Most of these methods were, however,

developed for specific targets and are less suited to gain

access to a broader range of 1-azaspirocycles. We became

interested in a modular enantioselective synthesis of azaspi-

rocycles Ia–c, which could serve as building blocks for the

synthesis of a number of naturally occurring and non-natu-

ral 1-azaspirocycles (Scheme 1). The fused rings of Ia–c

have different sizes and carry functional groups X¹–X³.

This should allow the annulations of rings, including either

the N atom and the adjacent C atom, or the N atom and

the hydroxyalkyl group. Sulfoximine-substituted bisallyltit-

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

Landoltweg 1, 52074 Aachen, Germany

E-mail: gais@rwth-aachen.de

http://ww w .oc.rwth-aachen.de/akgais/akgais_d.html

[‡] Present address: Heimchenweg 9, 40764 Langenfeld, Germany

[†] Deceased, 2012.

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201400068.

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corresponding homoallylic alcohols 3 and 4 with 84 and

74%de, respectively (Scheme 2).

Scheme 2. Synthesis of hydroxyalkyl-substituted cycloalkenyl-

sulfoximines.

Generally, titanium complexes derived from 1 and 2 react

with aldehydes with diastereoselectivities of 98%de or

higher.^[6]The apparently lower diastereoselectivities of the

reactions of the bisallyltitanium complexes with acetalde-

hyde were most likely due to incomplete Li–Ti exchange of

the corresponding lithioallylsulfoximines, the reactions of

which with aldehydes have low diastereoselectivities.^[6a]Dia-

stereomerically pure alcohols 3 and 4 were obtained in

yields of 78 and 75%, respectively, through chromatography

and extraction, respectively.

We have previously described the diastereoselective syn-

thesis of further hydroxyalkyl-substituted cycloalkenyl-

sulfoximines of type III, which carry functional groups X¹

and X²and have five-, six- and seven-membered rings, from

IV and aldehydes (see Figure S1 in the Supporting Infor-

mation).^[6,13]Therefore, various ring A+C*_Bbuilding blocks

of type III are available for the synthesis of Ia–c.

Scheme 1. Sulfoximine-based route to azaspirocycles.

Amination

Stereoselective generation of the C–N bond of Ia–c was

accomplished by the carbamate method,^[9]which we have

successfully used for the stereoselective amination of mainly

acyclic δ-hydroxy alkenylsulfoximines (see below).^[6c,10]

Thus, treatment of alcohols 3 and 4 with trichloroacetyl

isocyanate and subsequent hydrolysis of the corresponding

N-trichloroacetyl carbamates with ammonium carbonate in

methanol furnished the corresponding crude carbamates 5

and 6, respectively. The carbamates were not purified but

subjected to treatment with 1.3 equiv. nBuLi in THF

(Scheme 3). This procedure gave oxazinanones 7 and 8 in

79 and 77% overall yields, respectively, based on the corre-

sponding starting alcohols 3 and 4. The synthesis of 6 was

accompanied by the formation in 9% of the corresponding

E-configured diastereomer, which, however, also gave oxaz-

inanone 8. The amino-substituted stereogenic tertiary car-

mation, (3) alkylation of IIb with organometallics followed

by N-alkylation and ring-closing metathesis (RCM), and

(4) C-alkylation of IIa followed by sulfoximine reduction

and cyclisation.

Herein, we report a sulfoximine-based modular, enantio-

selective synthesis of substituted azaspirocycles of type Ia–

c, with fused rings of different sizes endowed with a range

of functional groups. The synthesis takes advantage of the

special features of the sulfoximine group, including chiral-

ity, carbanion stabilisation, nucleofugacity, and nucleophi-

licity.^[11,12]

Results and Discussion

Functionalised Cycloalkenylsulfoximines

bon centres of 7 and 8 were generated with diastereoselec-

1

Successive treatment of allylic sulfoximines 1 and 2 tivities of 98%de or higher, as revealed by H NMR spec-

(Scheme 2) on a 20 mmol scale with 1 equiv. n-butyllithium troscopic analysis.

(nBuLi) and 2.1 equiv. ClTi(OiPr)₃in tetrahydrofuran

The configuration of oxazinanone 7 was determined by

(THF) gave the corresponding bisallyltitanium complexes, X-ray crystal structure analysis (Figure 1).^[14]The heterocy-

which were admixed with ClTi(OiPr)₃and Ti(OiPr)₄.^[6a]clic ring of 7 adopts a boat-like conformation in which the

The reactions of the bisallyltitanium complexes with acet- methyl group is in pseudoequatorial position, as indicated

aldehyde in the presence of titanium isopropoxides gave the by the dihedral angles C2–O2–C1–N1 (–13.9°), C7–N1–

2

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Enantioselective Synthesis of Azaspirocycles

anone 16 could be particularly useful as a starting material

en route to Ia–c, X²= CO₂H, because of the furan ring,

which can be converted into the carboxy group.^[10]

Figure 2. Sulfoximine-substituted oxazinanones with intramolecu-

lar H-bonds in the crystal.

C,N-Dianion Cycloalkylation

Cycloalkylation of C,N-dianions of sulfoximines IIa

should give functionalised 1-azaspirocycles Ia [X³

=

Scheme 3. Intramolecular amination of hydroxyalkyl-substituted

cycloalkenylsulfoximines.

S(O)(NMe)Ph] (cf. Scheme 1). We had previously studied

the lithiation of sulfoximine-substituted oxazinanones of

type 13 (Figure 3).^[6c,10]Double deprotonation of 13 at the

NH and CH groups gave C,N-dianions 14, which were

stable at ambient temperatures in solution and diastereo-

selectively reacted with electrophiles at the anionic C atom

(50–80%de) to give the substituted sulfoximines 15. Pre-

sumably, because of the azaenolate group of 14, elimination

under cleavage of the C–N bond is suppressed. Elimination

would lead to the corresponding alkenylsulfoximine con-

taining a dilithiated carbamate group. These findings led us

to probe the construction of ring B of Ia through the syn-

thesis and cycloalkylation of the C,N-dianions 16 and 19

(Scheme 4). Cycloalkylations of the C,N-dianion of a β-(N-

Boc-amino)propylsulfone with biselectrophiles have been

reported previously.^[15]

C1–O2 (–23.6°), and C7–N1–C1–O1 (156.6). The H atoms

at C2 and C3 are arranged anti to each other. According

1

to H NMR spectroscopic analysis of oxazinanones 7 and

8, the heterocyclic rings in solution also preferentially adopt

a conformation with the methyl groups arranged in pseudo-

equatorial positions (³J_2-H,3-H= 10.2 Hz). An intramolecu-

lar H bond between the oxazinanone N1 atom and the O3

atom of the sulfoximine group further characterises the

structure of 7 in the crystal. The structurally related oxazin-

anone 11 also exhibits an intramolecular N1–H··O bond in

the crystal, whereas oxazinanone 12, the N atom of which

bears a secondary C atom, has an intramolecular N–H··N

bond in the crystal (Figure 2).^[6c]Presumably, formation of

N–H··N bonds in 7 and 11 is unfavourable because of de-

stabilising steric interactions between the phenyl group and

either the carbocycle or the methyl group. We had already

prepared, in the context of the synthesis of γ-hydroxy β-

amino acids, bicyclic oxazinanones 9 and 10, each with

98%de or higher, by the carbamate method.^[10]Oxazin-

Figure 3. C,N-Dianions of sulfoximine-substituted oxazinanones.

Whereas C,N-dianions of type 14 contain a secondary C

atom adjacent to the N atom, C,N-dianions 16 and 19 have

tertiary C atoms. This could result in a higher propensity

for elimination as compared to 14 and lead to the ultimate

formation of alkenylsulfoximines 3 and 4, respectively.

Double lithiation of sulfoximine-substituted oxazinanone

7, containing a five-membered carbocycle, with 2.2 equiv.

nBuLi in THF at low temperatures generated the N,C-di-

anion 16. Gratifyingly, the dianion proved to be stable in

solution at room temperature and gave, upon cycloalkyl-

ation with the C₃bistosylate 17, spirocycle 18 with Ն98%de

Figure 1. X-ray crystal structure of bicyclic oxazinanone 7 (the

numbering scheme differs from that used in the experimental part). in 75% yield. Similar double lithiation of the sulfoximine-

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Scheme 4. Syntheses of spirocycles through cycloalkylations of C,N-dianions of 7 and 8.

substituted oxazinanone 8, having a six-membered carbocy- revealed by the deuteration experiments, further deproton-

cle, with nBuLi in THF afforded the stable C,N-dianion ation of the N-anion of 7 gave only the C,N-dianion 16,

19, the cycloalkylation of which with the C₂bistosylate 20, whereas deprotonation of the N-anion of 8 furnished a mix-

furnished spirocycle 21 with Ն98%de in 57% yield (73% ture of the C,N-dianion 19 and the corresponding C_ortho,N-

based on conversion). Finally, reaction of N,C-dianion 19 dianion. We had previously shown that ortho-lithiation of

with the C₃bistosylate 17 gave spirocycle 22 with Ն98%de S-alkyl-S-phenylsulfoximines with nBuLi can, at low tem-

in 59% yield (72% based on conversion).

peratures, efficiently compete with α-lithiation, depending

Although the yields of spirocycles 18, 21 and 22 based on the structure of the sulfoximine.^[18]

on conversion of the starting sulfoximines were in the same

Support for the assignment of the configurations of tricy-

range, the yields of the isolated spirocycles 21 and 22, which clic sulfoximines 18, 21 and 22 at the C atoms bearing the

are derived from 8, were significantly lower. To find an ex- sulfoximine group came from the magnitudes of the vicinal

planation for this divergence, deprotonation–deuteration coupling constant for H_ain the ¹H NMR spectra and from

experiments with sulfoximines 7 and 8 were performed. The NOE experiments. Strong NOEs were recorded between H_a

successive treatment of sulfoximine 7 with 2.2 equiv. nBuLi and H_bof 18, 21 and 22. In addition, strong effects were

in THF and CD₃CO₂D, under the same conditions used found between H_aand the Me group of 18 and 22 (Table 1).

for the cycloalkylations, afforded the starting sulfoximine

containing one D atom at the C_αatom.^[16]When sulfox-

imine 8 was submitted to a similar deprotonation–deutera-

tion sequence, the recovered starting sulfoximine had D

atoms incorporation at both the C_αatom and the C_ortho

atom of the phenyl ring. The deprotonation of sulfoximines

7 and 8 with nBuLi most likely commenced with formation

of the corresponding N-anions, because of the higher acid-

ity of carbamates as compared to alkylsulfoximines.^[17]As

Table 1. Selected ¹H NMR spectroscopic data and decisive NOE

effects for tricyclic sulfoximines 24, 27 and 28.

Tricycle

³J(H_a,H_d)/³J(H_a,H_c) [Hz]

NOE

18

21

22

13.2/3.3

11.6/8.4

12.9/4.1

H_a↔ H_b, H_a↔ Me

H_a↔ H_b

H_a↔ H_b, H_a↔ Me

4

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Enantioselective Synthesis of Azaspirocycles

The configuration of sulfoximine-substituted spirocycle C-alkylated sulfoximine 26 with Ն98%de in 68% yield. The

18 was finally secured by X-ray crystal structure analysis S configuration was assigned to 24 and 26 by analogy to

(Figure 4).^[14]The oxazinanone ring of 18 adopts a boat- that of the spirocyclic sulfoximine 18.

like conformation, in which the methyl group is in the

Alkylations of the C,N-dianions 16 and 19 at the C

pseudoequatorial position. The N atom of 18 is slightly py- atoms occurred with high diastereoselectivities. The C,N-

ramidalised (ΣЄN 352°) and the carbamate group is non- dianion salts contain the structural elements of lithium α-

planar, as shown by the dihedral angles C12–N1–C8–C3 sulfoximine carbanions^[19]and lithium azaenolates,^[20]the

(–177.0°), C1–N1–C8–C3 (35.8°) and C2–O2–C1–N1 structures of which have been determined by crystal struc-

(–19.3°). The piperidine ring adopts a chair-like conforma- ture analyses and calculations. Based on these structural in-

tion, containing the sulfoximine group in the pseudoequa- vestigations, the chelate complexes Va/b–VIIIa/b are pro-

torial position and the carbonyl group in the pseudoaxial- posed for salts 16 and 19, which differ in respect to the

like position. According to ¹H NMR spectroscopic analysis, coordination of the Li atoms, the presence or absence of a

the oxazinanone ring of spirocycle 18 in solution also pref- C_α–Li bond, the C_α–S conformation, and the configuration

erentially adopts a conformation in which the methyl group of the C_αatom (Scheme 6). The complexes should be in

is in the pseudoequatorial position (³J_2-H,3-H= 10.2 Hz). fast equilibrium in THF, because of expected low barriers

The piperidine ring of 18 adopts a similar conformation in towards C_α–S bond rotation and C_αinversion,^[19]and be-

solution and in the crystal.

cause of the presence of THF molecules, which can occupy

vacant coordination sites at the Li atoms generated during

equilibration. Complexes Va/b are presumably the most re-

active towards electrophiles, because of the lack of C_α–Li

bonds and the lesser shielding of the anionic C atoms (see

below). The Li atom of the azaenolate moiety of Va/b is

coordinated by the N atom of the sulfoximine group and,

perhaps, also by the carbonyl O atom. The second Li atom

of Va/b is coordinated to the O atom of the sulfoximine

group. Electrophiles preferentially attack complexes Va/b

from the top face to give the substituted N-anions IXa/b.

Attack from the bottom face of Va/b, furnishing the epi-

meric N-anions, is sterically hindered by the phenyl group

and the carbocyclic rings. The structurally related com-

plexes VIa/b should be less reactive than Va/b because of

shielding of the top and bottom faces of the anionic C atom

by the phenyl group and carbocyclic ring, respectively.

Figure 4. X-ray crystal structure of spirocyclic sulfoximine 18 (the

numbering scheme differs from that used in the experimental part).

C,N-Dianion Monoalkylation

Because of the successful cycloalkylations of the C,N-

dianions 16 and 19, monoalkylation was also studied. Selec-

tive alkylations of the C,N-dianions at the C_αatom could

set the stage for a stepwise construction of ring B of azaspi-

rocycles Ib (cf. Scheme 1). Reaction of C,N-dianion 16 with

the acetal-substituted bromide 23 gave the C-alkylated sulf-

oximine 24 with Ն98%de in 62% yield (Scheme 5). A sim-

ilar reaction of 16 with unsaturated tosylate 25 afforded the

Scheme 6. Rationalisation of the stereoselectivity of the reactions

of C,N-dianion dilithium salts (coordination of the Li atoms by

THF molecules has been omitted).

Because of the selective monoalkylation of 16 at the C

atom, the cycloalkylations of the C,N-dianions 16 and 19

Scheme 5. C-Alkylations of C,N-dianion 16.

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with the bistosylates presumably commenced with similar was of interest to obtain further synthetically useful build-

stereoselective C-alkylations. The N-anions of type IXa/b ing blocks. In addition, a halide displacement of the sulfox-

thereby formed, subsequently experienced intramolecular imine group of IIa could yield IIb, which would provide a

N-alkylations to give the spirocycles. The selective C-alkyl- means for the synthesis of Ib and Ic starting by alkylation

ation of the C,N-dianions is in line with the higher nucleo- with organometallics (cf. Scheme 1). We had previously

philic reactivity of carbanions as compared to carbamate found that S-alkylsulfoximines can be converted into the

anions with similar pK_bvalues.^[15,21]

corresponding alkyl halides upon reaction with haloforma-

Having obtained the spirocyclic sulfoximines 18, 21 and tes.^{[6c,6d,10,13,22]}Treatment of sulfoximine 7 with chloro-

22, we were interested to see whether the corresponding α- formate in dichloromethane at room temperature thus gave

sulfoximine carbanions would be stable or would suffer chloride 31 in 81% yield in addition to the R-configured

cleavage of the C–N bond and thus ring opening. In con- sulfinamide 30 (Scheme 8). We had already described,

trast to the lithium azaenolate group of C,N-dianions 16 within our γ-hydroxy β-amino acid synthesis,^[10]the synthe-

and 19, the carbamate group of the spirocyclic sulfoximines sis of the analogous chloride, containing a six-membered

ought to be a better nucleofuge in β-elimination. The syn- carbocycle and an isopropyl group. The reaction of sulfox-

thesis of derivatives of sulfoximines 18, 21 and 22 through imine 7 with iodoformate in acetonitrile, which was pre-

reactions of the carbanions with electrophiles could allow pared in situ from chloroformate and sodium iodide,^[23]fur-

the attainment of azaspirocycles Ia and Ib, the rings B of nished iodide 32 in 76% yield.

which contain further substituents. Sulfoximine 21 was

treated with nBuLi in THF, and the obtained carbanion 28

was kept for 12 h at room temperature and then protonated

with aqueous ammonium chloride (Scheme 7). This pro-

cedure gave sulfoximine 27, having opposite configuration

at the C_αatom, with Ն98%de in 85% yield.

Scheme 7. Epimerisation of the sulfoximine-substituted spirocycle

21 through carbanion formation (coordination of the Li atoms by

THF molecules has been omitted).

The lithioalkylsulfoximine 28 presumably has a pyrami-

dalised anionic C atom and a Li atom that is coordinated

to the O and N atoms of the sulfoximine group.^[19]Carban-

ion salt 28 should have a low configurational stability be-

cause of expected low barriers towards C_αinversion and

C_α–S bond rotation.^[19]Fast equilibration of 28 thus gave

the diastereomeric carbanion salt 29. Carbanion 28 should

be less stable than 29 because of destabilising steric interac-

Scheme 8. Displacement of the sulfoximine group by halides.

tions between the sulfoximine group and the cyclohexane

ring. Protonation of carbanion 29 from the direction of py-

It was of particular interest to see whether sulfoximines

ramidalisation of the C_αatom gave epimeric sulfoximine 27.

18 and 26, the C_αatoms of which carry two substituents,

Carbanions 28 and 29 were surprisingly stable towards

would also undergo displacement by halides. Previous

cleavage of the C–N bond at room temperature.

attempts to achieve a conversion of the structurally related

sulfoximine 35 into the corresponding chloride had failed;

Sulfoximine Displacement

instead, alkene 36 was isolated in high yield (Scheme 9).^[22a]

Having synthesised 1-azaspirocycles Ia [X³= S(O)- Gratifyingly, treatment of sulfoximine 26 with iodoformate

(NMe)Ph], displacement of the sulfoximine group by halide in acetonitrile at room temperature gave iodide 33 with

6

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Enantioselective Synthesis of Azaspirocycles

Ն98%de in 76% yield. Similar reaction of the spirocyclic configuration (18), others had proceeded under inversion of

sulfoximine 18 with chloroformate afforded chloride 34 configuration (see Figure S2 in the Supporting Infor-

with Ն98%de in 74% yield. The configuration of 34 at the mation).

C atom bearing the Cl atom was determined by NOE ex-

1

periments based on an assignment of the signals in the H

NMR spectrum by TOCSY experiments. Strong NOE ef-

fects were observed between H_aand H_b, and between H_a

Alkylation of β-Aminoalkyl Halides

and the Me group (Table 2). Chloride 34, like 18, is another

Iodide 32 was used as starting material for the synthesis

of derivatives required for the construction of Ib and Ic

example of a 1-azaspirocycle of type 1a (X³= Cl).

through RCM and N-acyliminium ion formation, respec-

tively. Alkene (Z/E)-41 was thus obtained in 82% yield in

an Z/E ratio of 2:1 through reaction of iodide 32 with cupr-

ate 40 in THF (Scheme 11). Similarly, acetal 43 was synthe-

sised in 72% yield upon treatment of iodide 32 with cuprate

42 in THF.^[24]Alkylation of iodide 32 with unsaturated cup-

rates 44a and 44b^[25]in THF could not be achieved. Instead,

Scheme 9. Elimination of sulfoximine 35 with chloroformate.

the impure methyl-substituted bicycle 45 was isolated in ap-

proximately 55% yield together with a mixture of several

Table 2. Selected ¹H NMR spectroscopic data and decisive NOE

effects of the tricyclic chloride 34.

unidentified compounds. The corresponding alkene (see be-

1

low) was produced only in small amounts according to H

³J(H_a,H_d) [Hz]

³J(H_a,H_c) [Hz]

NOE

NMR spectroscopic analysis of the crude reaction mixture.

For an unequivocal structure conformation of 45, the bicy-

cle was synthesised in 74% yield through reduction of sulf-

oximine 7 with Raney nickel^[26]in water/THF. The failure

to achieve an alkylation of 32 with cuprates 44a and 44b

was surprising. For example, the primary iodide, derived

from Cbz-protected norvaline, had been alkylated with

cuprate 44b in high yield.^[27]

11.9

4.0

H_a↔ H_b,H_a↔ Me

The configuration of iodide 33 at the C atom bearing the

I atom was assigned by analogy to that of 34.

The isolation of sulfinamide 30, which was obtained as

a byproduct in the haloformate reaction, was also signifi-

cant. We had already shown that this compound can be

converted via (R)-methylphenylsulfoxide into (R)-N,S-di-

methyl-S-phenylsulfoximine with Ն98%ee, which is the chi-

ral starting material for the synthesis of IV.^[6c,22b]

N-Methylsulfoximines, containing a methyl group, a pri-

mary or secondary alkyl group, or an allyl group at the S

atom, readily undergo dealkylation under cleavage of the

S–C bond upon treatment with haloformates.^[6d,13,22]Al-

though most of the sulfoximines studied contained func-

tional groups that were capable of exerting a neighbouring

group effect in the displacement, some were devoid of such

a group or contain one in a sterically disabling position (see

Figure S2 in the Supporting Information). The isolation of

sulfinamide 30 points to the formation of S-alkyl-N-acyl

aminosulfoxonium salts 38 in the first step of the halo-

formate reaction of sulfoximines 37 (Scheme 10). The

mechanisms of the reaction of the aminosulfoxonium ion

of 38 with halide ions to give alkylhalide 39 are unknown.

In all the cases studied, the displacements proceeded under

retention of configuration at the S atom. So far, no clear

picture has emerged as to the factors determining the ste-

reochemical course of the substitution at the C atom.

Whereas some reactions had occurred under retention of

Scheme 10. Haloformate reaction of N-methylsulfoximines.

Scheme 11. Syntheses of functionalised carbocycles from halides.

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Chloride 31 was converted into nitrile 46 in 94% yield

upon treatment with potassium cyanide in N,N-dimethyl-

formamide (DMF) at 100 °C. We had already described the

synthesis of the analogous nitrile, containing a six-mem-

bered carbocycle and an isopropyl group.^[10]Previous stud-

ies of the reaction of the iodide derived from sulfoximine

13 (R¹= isopropyl, R²= furanyl) with potassium cyanide in

DMF had shown that the synthesis of the nitrile proceeded

through intermediate formation of the corresponding bicy-

clic N-acylaziridine.^[28]Whether the reaction of chloride 31,

which carries a tertiary C atom at the N atom, with potas-

sium cyanide takes a similar course is not known. Nitrile

46 and its analogue, containing a six-membered carbocycle,

can eventually serve as starting materials for a complemen-

tary synthesis of bicycles of type 18, 21 and 22, carrying a

nitrile instead of a sulfoximine group, through cycloalkyl-

ation of the corresponding C,N-dianion (cf. Scheme 4).

Sulfoximines 24, 26 and 33 were synthesised as potential

intermediates in stepwise routes to azaspirocycles Ib and Ic

starting from IIa (cf. Scheme 1). The failure to synthesise

alkene 47, which could also be used for the stepwise route,

through reaction of iodide 32 with cuprates 44a and 44b

prompted an alternative synthesis of the alkene through re-

duction of iodide 33 (Scheme 12). Thus, iodide 33 was

treated with tributyltinhydride in benzene in the presence

of azobis(isobutyrylnitrile) (AIBN) at elevated tempera-

tures, which gave alkene 47 in 85% yield. Because of the

facile reduction of sulfoximine 7, reductions of sulfoximines

18 and 24 were also investigated to obtain a sulfoximine-

free spirocyclic carbamate for deprotonation studies (see be-

low), and to probe an alternative route to acetal 43. The

reduction of sulfoximine 24 with Raney nickel in THF/

water gave acetal 43 in 90% yield, and a similar reduction

of spirocyclic sulfoximine 18 with Raney nickel furnished

spirocycle 48 in 96% yield. The route to acetal 43 from

sulfoximine 7 via sulfoximine 24 is somewhat less efficient

than that from 7 via iodide 32, because of the reductive

degradation of the sulfoximine group.

Ring-Closing Metathesis

We envisioned a synthesis of unsaturated azaspirocycles

Ic through RCM of the corresponding dienes, derived from

halide IIb (cf. Scheme 1). RCM has infrequently been used

in the synthesis of the heterocyclic ring of azaspirocy-

cles.^[2b,29]Its application in the synthesis of azaspirocycles

Ic required derivatives of alkenes 26, 33, (Z/E)-41 or 47,

containing an alkenyl group at the N atom. Treatment of

the sodium salts of carbamates (Z/E)-41 with allyl bromide

in DMF thus afforded dienes (Z/E)-49 in a ratio of 1:1 in

85% yield (Scheme 13). The reaction of dienes (Z/E)-49

with 5 mol-% of the ruthenium catalyst 50^[30]in dichloro-

methane at room temperature gave spirocyclic alkene 51 in

95% yield.

Scheme 13. Spirocycle synthesis through RCM.

Functionalisation of 51 at the N atom requires cleavage

of the oxazinanone ring, which turned out to be rather

stable towards hydrolysis. The exceptional stability of oxaz-

inanones of this type towards bases had previously been

noted.^[10,31]Cleavage was finally achieved upon treatment

of 51 with aqueous caesium hydroxide in methanol at reflux

for 3 d, which gave spirocyclic 1,3-amino alcohol 52 in 72%

yield.

Attempted Carbamate Lithiation

The carbamate groups of 48 and 51 allow the possibility

of functionalisation of the piperidine rings at the C atom

adjacent to the N atom through lithiation and electrophilic

incorporation, thereby providing an alternative route to

azaspirocycles Ib with various substituents X³(cf.

Scheme 1). Precedent for the lithiation of bicyclic oxazin-

anones of this type was, however, scarce.^[32,33]The success-

ive treatment of oxazinanone 48 with N,N,N,N-tetramethyl-

ethylenediamine (TMEDA), sec-butyllithium (sBuLi) and

allyl bromide in THF at –40 °C did not result in an allyl-

ation of the piperidine ring. Instead, the oxazinanone was

recovered almost quantitatively (Scheme 14). When the

same procedure was applied to oxazinanone 48 at 0 °C, the

starting material was recovered in only 62% yield. In ad-

Scheme 12. Reductions of halogen- and sulfoximine-substituted bi-

and tricyles.

8

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Enantioselective Synthesis of Azaspirocycles

Scheme 14. Attempted functionalisation of carbamate 48 through

lithiation at the C atom adjacent to the N atom.

dition amides 53 and epi-53 were isolated as a 1:1 mixture

in 24% yield. Chromatography gave the pure amides, the

configurations of which were not assigned.

The reason for the failure of a lithiation of carbamate

48 is not clear. It is generally assumed that lithiation of

carbamates commences with complexation of RLi by the O

atom of the carbamate carbonyl group.^[34]Crucial factors

for the subsequent removal of the H atom are the distance

between the H atom removed and the carbonyl O atom and

the dihedral angle between the H–C–N and N–C–O pla-

nes.^[33]The pertinent distances and dihedral angles of 48,

the sulfoximine-substituted analogue of 18, in the crystal

are O1··H12a, 2.495 Å; O1··H12b, 3.527 Å; H12a–C12–N1/

N1–C1–O1, 40.4°, and H12b–C12–N1/–N1–C1–O1, 33.2°.

If one assumes that the hexahydropyrido-oxazinanone units

of 18 and 48 have similar structures, then 48 would fulfil

the structural requirements for a lithiation.^[33]Whether ox-

azinanone 51 is a better candidate for α-lithiation, because

of the allylic double bond, remains to be seen.

Scheme 15. Syntheses of spirocycles through N-acyliminium ion

formation.

Table 3. ¹H NMR spectroscopic data and decisive NOE signals for

tricycle sulfoximines 55 and 56.

N-Acyliminium Ion Formation

The bicyclic derivatives 26, 33, 43 and 47 are potential

starting materials for the synthesis of azaspirocycles Ib (cf.

Scheme 1), the most appealing of which seemed to be acetal

43. Therefore, acetal 43 was treated with para-toluenesulf-

onic acid in toluene at reflux.^[35,36]This afforded the spi-

rocyclic enamide 54 in 74% yield (Scheme 15). The comple-

mentary reaction of acetal 43 with sulfuric acid in methanol

Tricycle

³J(H_a,H_b)/³J(H_a,H_c) [Hz]

NOE

55

56

4.0/1.8

OMe ↔ H_d

H_e↔ H_d

Spirocycles 54–56 are potential starting materials, for ex-

gave the spirocyclic N,O-acetal 55 with Ն98%de in 69% ample, for the annulation of further rings to Ib, including

yield. C–C bond formation at the C atom adjacent to the the N atom and the adjacent C atom. In addition, enamide

N atom of acetal 55 was probed through reaction with allyl- 54 should provide possibilities for the introduction of sub-

trimethylsilane in the presence of boron trifluoride in stituents at the α- and β-positions.^[36]

dichloromethane.^[37]Gratifyingly, substituted spirocycle 56

The stereochemical course of the reactions leading to

was obtained with Ն98%de in 74% yield. As a side prod- acetal 55 and alkene 56 is noteworthy. Presumably, the spi-

uct, enamide 54 was isolated in 20% yield.

rocyclic N-acyliminium ion 57 (Figure 5) is the key interme-

The configurations of spirocycles 55 and 56 at the C diate in the formation of both derivatives.^[38]Whereas the

atoms bearing the methoxy group and allyl group, respec- formation of acetal 55 could be thermodynamically di-

tively, were determined by NOE experiments on the basis rected, that of alkene 56 is expected to be kinetically di-

1

of an assignment of the signals in the H NMR spectra by rected. Formation of alkene 56, having the S configuration

TOCSY experiments. According to the magnitudes of the at the C atom adjacent to the N atom, requires addition of

vicinal coupling constants, the piperidine ring of 55 adopts the allylsilane from the bottom face of 57. The spirocyclic

a chair-like conformation, in which the methoxy group is in iminium ion perhaps adopts structure 57ax, the tetra-

the pseudo-axial position (Table 3). It seems reasonable to hydropyridinium ring of which has a half-chair-like confor-

assume that the piperidine ring of 56 adopts a similar con- mation and the oxazinium ring has a boat-like conforma-

formation, with the allyl group in the pseudoaxial position. tion. Attack of the allylsilane at 57ax from the bottom face

Decisive NOE effects were observed between H_aand the should be preferred because the pseudo-axial methyl group

methoxy group of 55 and between H_eand H_dof 56.

will hinder attack from the top face.

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FULL PAPER

[M⁺], 262 (20), 235 (18), 189 (25), 187 (15), 157 (13), 156 (59), 155

(46), 154 (10), 129 (22), 126 (10), 125 (100), 124 (11), 123 (14), 110

(12), 109 (25), 108 (14), 107 (88), 97 (10), 91 (12), 81 (15).

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

64.29, H 7.40, N 4.92.

Isomer (S,1R)-3: ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (d, J =

6.0 Hz, 3 H, Me), 1.58–1.85 (m, 4 H, CH₂), 2.33–2.44 (m, 1 H,

CH₂), 2.62–2.73 (m, 4 H, Me, CH₂), 3.50 (dq, J = 9.6, 6.0 Hz, 1 H,

CHO), 3.66 (br. t, J = 9.0 Hz, 1 H, CHCHO), 6.14 (br. d, J =

1.1 Hz, 1 H, C=CH), 7.52–7.63 (m, 3 H, Ph), 7.79–7.85 (m, 2 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.4 (u, CH₂), 23.6

(d, Me), 29.2 (d, Me), 30.1 (u, CH₂), 34.4 (u, CH₂), 50.3 (d,

CHCHO), 68.4 (d, CHO), 122.7 (d, C=CH), 128.4 (d, Ph), 129.4

(d, Ph), 132.7 (d, Ph), 139.4 (u, Ph), 164.0 (u, C=CH) ppm. IR

Figure 5. Possible conformation of the bicyclic N-acyliminium ion

57.

Conclusions

The developed sulfoximine route allows a modular, enan-

tioselective synthesis of azaspirocycles, the heterocyclic and

carbocyclic rings of which have different sizes and contain

functional groups. The syntheses take advantage of the spe-

cial features of the sulfoximine group including chirality,

carbanion stabilisation, nucleofugacity, and nucleophilicity.

The characteristics of the sulfoximine route are: (1) the in-

clusion of the carbocyclic ring in the starting allylic sulfox-

imines, (2) the establishment of the spirocyclic C atom

through intramolecular amination, (3) the construction of

the heterocyclic ring through C,N dianion cycloalkylation,

ring-closing metathesis, and N-acyliminium ion formation,

and (4) high diastereoselectivities of the various steps. The

application of allylic sulfoximines containing a substituted

ring as starting materials should also permit access to aza-

spirocycles functionalised on the carbocyclic rings.

(CHCl ): ν = 3971 (w), 3455 (m), 3184 (w), 3061 (w), 2967 (s), 2875

˜

3

(s), 2803 (m), 1629 (s), 1447 (s), 1372 (m), 1302 (w), 1237 (s), 1150

(s), 1109 (s), 1081 (s), 1011 (m), 964 (m), 933 (w), 878 (s), 854 (s),

817 (m) cm^–1. MS (EI): m/z (%) = 279 (19) [M⁺], 262 (33), 249 (12),

235 (12), 189 (13), 187 (10), 157 (11), 156 (53), 155 (27), 154 (10),

129 (12), 126 (11), 125 (100), 123 (15), 110 (12), 109 (24), 108 (11),

107 (54), 91 (11), 81 (18).

(R)-1-((1S,Z)-2-{[(R)-N-Methylphenylsulfonimidoyl]methylene}-

cyclohexyl)ethanol (4): To a solution of allylic sulfoximine 2 (4.99 g,

20.0 mmol) in THF (200 mL) at –78 °C was added nBuLi (1.60 m

in n-hexane, 13.2 mL, 21.0 mmol). After stirring the mixture at

–78 °C for 10 min, neat ClTi(OiPr)₃(10.1 mL, 42.0 mmol) was

added, then the mixture was stirred at –78 °C for 10 min, warmed

to 0 °C, stirred at this temperature for 45 min, and cooled to

–78 °C. Acetaldehyde (5.60 mL, 100 mmol) was added and the mix-

ture was warmed to room temperature within 12 h. The mixture

was added to saturated aqueous (NH₄)₂CO₃(50 mL) and water

(50 mL) and extracted with EtOAc (3ϫ 200 mL). The combined

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

Washing with Et₂O (3ϫ 40 mL) gave alcohol 4 (4.40 g, 75%) as a

Experimental Section

1

colourless solid; m.p. 111 °C; [α]_D= +11.2 (c = 1.00, CH₂Cl₂). H

(R)-1-((1S,Z)-2-{[(R)-N-Methylphenylsulfonimidoyl]methylene}-

cyclopentyl)ethanol (3): To a solution of allylic sulfoximine 1

(4.71 g, 20.0 mmol) in THF (200 mL) at –78 °C was added nBuLi

(1.60 m in n-hexane, 13.2 mL, 21.0 mmol). After stirring the mix-

ture at –78 °C for 10 min, neat ClTi(OiPr)₃(10.1 mL, 42.0 mmol)

was added. Subsequently, the mixture was stirred at –78 °C for

10 min, warmed to 0 °C, stirred at this temperature for 45 min and

then cooled to –78 °C. Acetaldehyde (5.6 mL, 100 mmol) was

added and the mixture was warmed to room temperature within

12 h. The mixture was added to saturated aqueous (NH₄)₂CO₃

(50 mL) and H₂O (50 mL) and extracted with EtOAc (3ϫ 200 mL).

The combined organic phases were dried (MgSO₄) and concen-

trated in vacuo. Purification by HPLC (Et₂O/iPrOH, 95:5) gave

alcohol 3 (4.36 g, 78%) as a colourless solid and its (S,1R)-config-

ured diastereomer (384 mg, 7%) as a colourless oil.

NMR (300 MHz, CDCl₃): δ = 1.35 (d, J = 5.9 Hz, 3 H, Me), 1.27–

1.60 (m, 4 H, CH₂), 1.68–1.81 (m, 1 H, CH₂), 1.82–1.95 (m, 1 H,

CH₂), 2.05–2.13 (m, 1 H, CH₂), 2.35–2.55 (m, 1 H, CH₂), 2.60 (s,

3 H, Me), 3.60–3.70 (m, 1 H, CHCHO), 3.95 (dq, J = 11.9, 5.9 Hz,

1 H, CHO), 5.27 (br. s, 1 H, OH), 6.30 (br. d, J = 2.0 Hz, 1 H,

C=CH), 7.52–7.64 (m, 3 H, Ph), 7.86–7.93 (m, 2 H, Ph) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 20.3 (u, CH₂), 23.2 (d, Me), 27.4 (u,

CH₂), 28.3 (u, CH₂), 29.2 (d, Me), 33.0 (u, CH₂), 45.8 (d,

CHCHO), 67.1 (d, CHO), 126.7 (d, C=CH), 128.9 (d, Ph), 129.3

(d, Ph), 132.7 (d, Ph), 139.7 (u, Ph), 160.7 (u, C=CH) ppm. IR

(KBr): ν = 3467 (s), 3059 (m), 2934 (s), 1863 (s), 2796 (m), 1611

˜

(s), 1447 (s), 1376 (m), 1229 (s), 1130 (s), 1070 (s), 928 (m), 853 (s),

820 (s) cm^–1. MS (EI): m/z (%) = 293 (3) [M⁺], 201 (12), 171 (11),

169 (16), 156 (78), 138 (11), 125 (100), 123 (28), 107 (25), 95 (24).

C₁₆H₂₃NO₂S (293.4): calcd. C 65.49, H 7.90, N 4.77; found C

65.31, H 8.15, N 4.80.

1

Isomer (R,1S)-3: M.p. 65 °C; [α]_D= +96.3 (c = 1.16, CH₂Cl₂). H

NMR (400 MHz, CDCl₃): δ = 1.34 (d, J = 6.1 Hz, 3 H, Me), 1.60–

1.72 (m, 3 H, CH₂, OH), 1.72–1.95 (m, 2 H, CH₂), 2.30–2.42 (m, (R)-1-((1S,Z)-2-{[(R)-N-Methylphenylsulfonimidoyl]methylene}-

1 H, CH₂), 2.62–2.73 (m, 4 H, Me, CH₂), 3.54 (dq, J = 9.9, 6.0 Hz, cyclopentyl)ethyl Carbamate (5): To a solution of alcohol 3 (1.26 g,

1 H, CHO), 3.61–3.69 (m, 1 H, CHCHO), 6.25 (m, 1 H, C=CH), 3.90 mmol) in CH₂Cl₂(50 mL) was added at room temperature tri-

7.52–7.63 (m, 3 H, Ph), 7.87–7.92 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 21.4 (u, CH₂), 23.8 (d, Me), 29.1 (d, Me),

30.2 (u, CH₂), 34.1 (u, CH₂), 50.6 (d, CHCHO), 69.4 (d, CO), 123.7

(d, C=CH), 128.7 (d, Ph), 129.3 (d, Ph), 132.7 (d, Ph), 139.6 (u,

chloroacetyl isocyanate (0.60 mL, 5.07 mmol). The mixture was

stirred until TLC showed complete conversion (5 h) of the alcohol,

then MeOH (25 mL) and (NH₄)₂CO₃(1.87 g, 19.5 mmol) were

added and the mixture was stirred at room temperature for 12 h.

Ph), 163.7 (u, C=CH) ppm. IR (capillary): ν = 3345 (w), 3203 (w), Saturated aqueous NH₄Cl (30 mL) was added and the mixture was

˜

3060 (w), 2965 (s), 2875 (m), 2800 (w), 2236 (w), 1628 (m), 1448

(m), 1371 (w), 1234 (s), 1146 (s), 1110 (s), 1081 (s), 1012 (m), 963 were dried (MgSO₄) and concentrated in vacuo. Purification by

(w), 925 (m), 858 (m), 801 (m) cm^–1. MS (EI): m/z (%) = 279 (3)

chromatography (EtOAc) gave carbamate 5 (1.06 g, 84%) as a

extracted with CH₂Cl₂(3ϫ 60 mL). The combined organic phases

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Enantioselective Synthesis of Azaspirocycles

colourless solid; m.p. 45 °C; [α]_D= +17.7 (c = 1.02, CH₂Cl₂). ¹H

123 (13), 121 (14), 119 (10), 109 (12), 107 (11), 105 (12), 95 (29),

NMR (400 MHz, CDCl₃): δ = 0.98–1.17 (m, 1 H, CH₂), 1.23–1.40 93 (26), 91 (30).

(m, 5 H, Me, CH₂), 1.42–1.58 (m, 1 H, CH₂), 1.70–1.85 (m, 1 H,

(4R,4aS,8aR)-4-Methyl-8a-{[(R)-N-methylphenylsulfonimidoyl]-

CH₂), 2.32–2.47 (m, 1 H, CH₂), 2.68 (s, 3 H, Me), 4.00–4.09 (m,

1 H, CHCHO), 4.90 (dq, J = 9.4, 6.2 Hz, 1 H, CHO), 6.05 (br. s,

2 H, NH₂), 6.56 (br. d, J = 1.7 Hz, 1 H, C=CH), 6.95–7.12 (m, 3 H,

Ph), 8.00–8.07 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 19.0 (d, Me), 21.1 (u, CH₂), 28.9 (u, CH₂), 29.1 (d, Me), 34.4 (u,

CH₂), 45.8 (d, CHCHO), 69.8 (d, CHO), 123.8 (d, C=CH), 129.0

(d, Ph), 129.1 (d, Ph), 131.7 (d, Ph), 140.4 (u, Ph), 158.0 (u), 160.6

methyl}hexahydro-1H-benzo[d][1,3]oxazin-2(4H)-one (8): To a solu-

tion of alcohol 4 (1.94 g, 6.62 mmol) in CH₂Cl₂(60 mL) at room

temperature was added trichloroacetyl isocyanate (1.18 mL,

8.61 mmol). The solution was stirred until TLC showed complete

conversion (5 h) of the alcohol. MeOH (30 mL) and (NH₄)₂CO₃

(3.18 g, 33.0 mmol) were added and the mixture was stirred at room

temperature for 12 h, then H₂O (30 mL) was added and the mixture

was extracted with CH₂Cl₂(3ϫ 100 mL). The combined organic

phases were dried (MgSO₄) and concentrated in vacuo. Crude carb-

amate 6 was dissolved in THF (50 mL) and the mixture was cooled

to –78 °C, then nBuLi (1.60 m in n-hexane, 5.4 mL, 8.60 mmol) was

added. The mixture was warmed to room temperature within 12 h,

then saturated aqueous NH₄Cl (50 mL) was added and the mixture

was extracted with CH₂Cl₂(3ϫ 60 mL). The combined organic

phases were dried (MgSO₄) and concentrated in vacuo. Washing of

the solid residue with Et₂O (3ϫ 20 mL) gave oxazinone 8 as a

colourless solid. Concentration of the mother liquor in vacuo and

purification by chromatography (EtOAc/iPrOH, 95:5) afforded an

additional crop of 8 as a colourless solid. Combined yield: 1.72 g

(77%), m.p. 152 °C (decomp.); [α]_D= –77.1 (c = 1.08, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 1.04–1.21 (m, 2 H, CH₂), 1.32 (d, J

= 6.3 Hz, 3 H, Me), 1.43–1.59 (m, 4 H, CH₂), 1.65–1.81 (m, 2 H,

CH₂), 2.54–2.62 (m, 1 H, CH₂), 2.71 (s, 3 H, Me), 3.06 (dd, J =

14.3, 1.4 Hz, 1 H, CH₂S), 3.93 (d, J = 14.6 Hz, 1 H, CH₂S), 4.58

(dq, J = 10.4, 6.3 Hz, 1 H, CHO), 7.56–7.68 (m, 4 H, Ph), 7.85–

7.90 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.9 (d,

Me), 19.7 (u, CH₂), 22.2 (u, CH₂), 22.8 (u, CH₂), 29.6 (d, Me), 33.5

(u, CH₂), 43.2 (d, CHCHO), 55.8 (u, CN), 62.4 (u, CH₂), 71.7 (d,

CHO), 128.6 (d, Ph), 129.5 (d, Ph), 133.1 (d, Ph), 139.7 (u, Ph),

(u) ppm. IR (KBr): ν = 3424 (s), 3176 (m), 3061 (w), 2965 (s), 2874

˜

(m), 2801 (m), 1722 (s), 1608 (m), 1450 (m), 1381 (s), 1325 (s), 1236

(s), 1149 (s), 1076 (s), 852 (s) cm^–1. MS (EI): m/z (%) = 322 (3)

[M⁺], 278 (31), 263 (17), 262 (100), 125 (30), 107 (11). HRMS: m/z

calcd. for C₁₆H₂₂N₂O₃S [M⁺] 322.13512; found 322.13518.

(R)-1-((1S,Z)-2-{[(R)-N-Methylphenylsulfonimidoyl]methylene}-

cyclohexyl)ethyl Carbamate (6): To a solution of alcohol 4 (700 mg,

2.39 mmol) in CH₂Cl₂(20 mL) was added at room temperature,

trichloroacetyl isocyanate (0.37 mL, 3.11 mmol). The mixture was

stirred until TLC showed complete conversion (5 h) of the alcohol,

then MeOH (10 mL) and (NH₄)₂CO₃(1.15 g, 12.0 mmol) were

added and the mixture was stirred at room temperature for 12 h.

Saturated aqueous NH₄Cl (20 mL) was added and the mixture was

extracted with CH₂Cl₂(3ϫ 50 mL). The combined organic phases

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

chromatography (EtOAc) gave carbamate 6 (587 mg, 73%) (R_f=

0.20; EtOAc) as a colourless solid and its E-configured dia-

stereomer (72 mg, 9%) (R_f= 0.35; EtOAc) as a colourless oil.

1

Isomer (Z)-6: M.p. 52–54 °C; [α]_D= +182.1 (c = 1.06, EtOAc). H

NMR (400 MHz, CDCl₃): δ = 1.06–1.20 (m, 1 H, CH₂), 1.21–1.39

(m, 4 H, Me, CH₂), 1.40–1.52 (m, 2 H, CH₂), 1.61–1.70 (m, 1 H,

CH₂), 1.84–1.94 (m, 1 H, CH₂), 2.01–2.11 (m, 1 H, CH₂), 2.48 (ddt,

J = 13.5, 5.0, 1.9 Hz, 1 H, CH₂), 2.68 (s, 3 H, Me), 3.67 (m, 1 H,

CHCHO), 4.90 (br. s, 2 H, NH₂), 5.08 (dq, J = 10.4, 6.0 Hz, 1 H,

CHO), 6.29 (d, J = 1.6 Hz, 1 H, C=CH), 7.53–7.63 (m, 3 H, Ph),

7.91–7.97 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

18.9 (d, Me), 20.4 (u, CH₂), 28.2 (u, CH₂), 28.4 (u, CH₂), 29.4 (d,

Me), 33.7 (u, CH₂), 41.6 (d, CHCHO), 69.7 (d, CHO), 125.6 (d,

C=CH), 128.8 (d, Ph), 129.1 (d, Ph), 132.3 (d, Ph), 140.6 (u, Ph),

152.2 (u, CO) ppm. IR (KBr): ν = 3356 (s), 3256 (m), 3059 (w),

˜

2934 (m), 2876 (m), 2795 (w), 1707 (s), 1618 (m), 1449 (m), 1390

(m), 1324 (m), 1237 (s), 1178 (w), 1141 (m), 1102 (m), 1075 (m),

1046 (w), 1010 (m), 929 (w), 904 (w), 875 (w), 832 (m) cm^–1. MS

(CI, CH₄): m/z (%) = 337 (100) [M⁺+ 1], 210 (14), 182 (12), 170

(27), 156 (10). C₁₇H₂₄N₂O₃S (336.5): calcd. C 60.69, H 7.19, N

8.33; found C 61.00, H 7.13, N 8.41.

(1S,7R,7aS,11aR)-7-Methyl-1-[(R)-N-methylphenylsulfonimidoyl]-

octahydrobenzo[d]pyrrolo[1,2-c][1,3]oxazin-5(1H)-one (21): Treat-

ment of sulfoximine 8 (100 mg, 0.30 mmol) with nBuLi (1.60 m in

n-hexane, 0.41 mL, 0.66 mmol) and ditosylate 20 (122 mg,

0.33 mmol) as described in GP1 and purification by chromatog-

raphy (EtOAc/cyclohexane, 2:1) gave spirocycle 21 (64 mg, 57%)

as a colourless solid and sulfoximine 8 (22 mg, 22%); m.p. 193 °C

157.0 (u), 159.7 (u) ppm. IR (KBr): ν = 3480 (s), 3172 (w), 3059

˜

(w), 2935 (s), 2865 (s), 2801 (m), 1720 (s), 1612 (s), 1451 (s), 1381

(s), 1326 (s), 1238 (s), 1144 (s), 1111 (s), 1072 (s), 1010 (s), 921 (w),

854 (s), 816 (m) cm^–1. MS (EI): m/z (%) = 336 (6) [M⁺], 292 (12),

276 (25), 156 (100), 138 (16), 137 (11), 125 (50), 123 (15), 121 (13),

93 (20), 91 (14). HRMS: m/z calcd. for C₁₇H₂₄N₂O₃S [M⁺]

336.15077; found 336.15075.

1

(decomp.); [α]_D= +11.2 (c = 1.00, CH₂Cl₂). H NMR (400 MHz,

CDCl₃): δ = 1.20–1.36 (m, 1 H, CH₂), 1.40 (d, J = 6.3 Hz, 3 H,

Isomer (E)-6: ¹H NMR (400 MHz, CDCl₃): δ = 1.25 (d, J = 6.3 Hz,

3 H, Me), 1.32–1.56 (m, 3 H, CH₂), 1.59–1.80 (m, 3 H, CH₂), 1.97– Me), 1.51–1.78 (m, 5 H, CH₂), 1.80–1.95 (m, 1 H, CHCHO), 2.23–

2.09 (m, 1 H, CH₂), 2.26–2.35 (m, 1 H, CHCHO), 2.64 (s, 3 H, 2.47 (m, 3 H, CH₂), 2.64 (s, 3 H, Me), 3.24–3.52 (m, 3 H, CHS,

Me), 2.96–3.06 (m, 1 H, CH₂), 4.80 (br. s, 2 H, NH₂), 4.98 (dq, J CH₂), 3.82–3.92 (m, 1 H, NCH₂), 4.63 (dq, J = 10.4, 6.3 Hz, 1 H,

= 9.6, 6.0 Hz, 1 H, CHO), 6.44 (br. s, 1 H, C=CH), 7.50–7.59 (m,

CHO), 7.53–7.66 (m, 3 H, Ph), 7.76–7.81 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 18.9 (d, Me), 19.3 (u, CH₂), 21.6 (u,

3 H, Ph), 7.90–7.96 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 18.7 (d, Me), 21.3 (u, CH₂), 26.3 (u, CH₂), 27.0 (u, CH₂), 22.5 (u, CH₂), 25.2 (u, CH₂), 29.3 (d, Me), 29.8 (u, CH₂),

CH₂), 28.8 (d, Me), 29.6 (u, CH₂), 50.8 (d, CHCHO), 70.0 (d, 40.8 (u, NCH₂), 44.0 (d, CHCHO), 67.5 (u, NC), 71.8 (d, CHS),

CHO), 125.3 (d, C=CH), 128.4 (d, Ph), 129.1 (d, Ph), 132.5 (d,

73.0 (d, CHO), 128.9 (d, Ph), 129.4 (d, Ph), 132.8 (d, Ph), 139.0 (u,

Ph), 140.2 (u, Ph), 156.0 (u), 160.5 (u) ppm. IR (KBr): ν = 3906 Ph), 152.5 (u, CO) ppm. IR (KBr): ν = 3055 (w), 2933 (s), 2864

˜

(w), 3747 (w), 3675 (w), 3418 (s), 3194 (m), 3056 (w), 2936 (s), 2866

(m), 2801 (w), 2344 (w), 1798 (m), 1723 (s), 1621 (m), 1449 (m),

1384 (s), 1322 (m), 1237 (s), 1144 (s), 1108 (s), 1070 (s), 1004 (m),

923 (w), 855 (s), 819 (w) cm^–1. MS (EI): m/z (%) = 336 (11) [M⁺],

276 (22), 244 (21), 227 (37), 200 (15), 197 (14), 196 (46), 195 (24),

181 (10), 167 (15), 156 (100), 141 (12), 138 (14), 137 (14), 125 (94),

(m), 2800 (w), 1688 (s), 1422 (s), 1378 (w), 1332 (m), 1267 (w), 1217

(m), 1143 (m), 1105 (m), 1075 (m), 994 (w), 957 (w), 881 (w), 855

(m) cm^–1. MS (EI): m/z (%) = 362 [M⁺], 285 (24), 284 (41), 241

(18), 240 (60), 208 (17), 207 (97), 206 (10), 183 (13), 182 (100), 164

(34), 163 (28), 162 (24), 153 (11), 148 (22), 138 (25), 136 (11), 135

(28), 134 (22), 125 (26), 122 (15), 120 (15), 109 (11), 108 (12), 107

Eur. J. Org. Chem. 0000, 0–0

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11

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H.-J. Gais et al.

FULL PAPER

(18), 106 (12), 95 (15), 91 (11), 81 (11), 80 (12). C₁₉H₂₆N₂O₃S

(362.5): calcd. C 62.96, H 7.23, N 7.73; found C 62.80, H 7.37, N

7.70.

0.68 mmol). The mixture was warmed to –10 °C within 1 h, cooled

to –50 °C, and then treated with tosylate 25 (77 mg, 0.34 mmol).

Subsequently, the mixture was warmed to room temperature within

12 h, then saturated aqueous NaHCO₃(10 mL) was added and the

mixture was extracted with CH₂Cl₂(3ϫ 30 mL) and the combined

organic phases were dried (MgSO₄). Removal of the solvents in

vacuo and purification by chromatography (EtOAc) gave sulfox-

imine 26 (80 mg, 68%) as a colourless oil; [α]_D= –113.7 (c = 1.00,

CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.30–2.20 (m, 10 H,

CH, CH₂), 1.30 (d, J = 6.2 Hz, 3 H, Me), 2.76 (s, 3 H, Me), 2.86

(m, 1 H, CH₂), 3.07 (dd, J = 7.2, 1.2 Hz, 1 H, CHS), 3.96 (dq, J

= 10.3, 6.2 Hz, 1 H, CHO), 4.92 (m, 2 H, CH=CH₂), 5.54 (m, 1

H, CH=CH₂), 7.22 (br. s, 1 H, NH), 7.54–7.66 (m, 3 H, Ph), 7.82–

7.88 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.0 (d,

Me), 22.0 (u, CH₂), 25.32 (u, CH₂), 26.3 (u, CH₂), 29.6 (d, Me),

33.6 (u, CH₂), 38.8 (u, CH₂), 46.8 (d, CH), 68.0 (u, CH₂), 68.2 (u,

CN), 69.3 (d, Me), 74.6 (d, CHS), 74.8 (d, CHO), 117.0 (u,

CH=CH₂), 129.4 (d, CH), 129.6 (d, CH), 133.1 (d, CH), 136.2 (d,

(1S,8R,8aS,12aR)-8-Methyl-1-[(R)-N-methylphenylsulfonimidoyl]-

octahydro-1H-benzo[d]pyrido[1,2-c][1,3]oxazin-6(2H)-one (22):

Treatment of oxazinone 8 (100 mg, 0.30 mmol) with nBuLi (1.60 m

in n-hexane, 0.41 mL, 0.66 mmol) and ditosylate 23 (127 mg,

0.33 mmol) as described in GP1 and purification by chromatog-

raphy (EtOAc/cyclohexane, 2:1) gave spirocycle 22 (66 mg, 59%) as

a colourless solid and sulfoximine 8 (18 mg, 18%); m.p. 157–158 °C

1

(decomp.); [α]_D= –48.1 (c = 0.90, CH₂Cl₂). H NMR (400 MHz,

CDCl₃): δ = 1.24–1.42 (m, 1 H, CH₂), 1.47–1.72 (m, 7 H, CH₂),

1.69 (d, J = 6.8 Hz, 3 H, Me), 1.88–1.98 (m, 1 H, CH₂), 2.09–2.22

(m, 2 H, CH₂), 2.37–2.46 (m, 1 H, CH₂), 2.57 (s, 3 H, Me), 2.91–

3

3.01 (m, 1 H, NCH₂), 3.55 (dd, J = 12.9, J = 4.1 Hz, 1 H, CHS),

3.70–3.78 (m, 1 H, CH), 4.11–4.19 (m, 1 H, NCH₂), 4.26 (dq, J =

6.8, 4.4 Hz, 1 H, CHO), 7.53–7.64 (m, 3 H, Ph), 7.72–7.77 (m, 2 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.0 (u, CH₂), 21.8

(u, CH₂), 22.0 (u, CH₂), 22.1 (d, Me), 23.6 (u, CH₂), 27.1 (u, CH₂),

27.2 (u, CH₂), 29.8 (d, Me), 39.06 (u, NCH₂), 39.12 (u, CH), 61.9

(u, CN), 66.8 (d, CHS), 77.5 (d, CHO), 129.3 (d, Ph), 129.5 (d,

CH), 139.8 (u, Ph), 155.1 (u, CO) ppm. IR (CHCl ): ν = 3376 (w),

˜

3

3233 (w), 2956 (m), 2880 (m), 1703 (s), 1444 (m), 1387 (m), 1323

(m), 1230 (s), 1138 (s), 1075 (m), 1025 (m), 913 (m), 860 (m) cm^–1.

MS (EI): m/z (%) = 377 (3) [M⁺+ 1], 251 (5), 223 (11), 222 (16),

183 (16), 182 (100), 180 (14), 178 (29), 167 (19), 156 (21), 145 (21),

136 (23), 125 (23). HRMS: m/z calcd. for C₂₀H₂₈N₂O₃S [M⁺]

376.18151; found 376.18200.

Ph), 132.6 (d, Ph), 137.3 (u, Ph), 154.5 (u, CO) ppm. IR (KBr): ν

˜

= 3422 (m), 2932 (m), 2960 (m), 2792 (w), 1673 (s), 1444 (m), 1400

(s), 1261 (m), 1228 (m), 1141 (s), 1100 (m), 1074 (m), 1051 (m), 937

(w), 861 (m) cm^–1. MS (EI): m/z (%) = 376 (23) [M⁺], 221 (12), 209

(20), 182 (16), 179 (15), 178 (100), 177 (43), 176 (13), 162 (23), 150

(16), 149 (29), 148 (21), 139 (31), 136 (10), 134 (13), 125 (20), 124

(11), 122 (11), 109 (19), 108 (13), 107 (28), 106 (13), 97 (14).

HRMS: m/z calcd. for C₂₀H₂₈N₂O₃S [M⁺] 373.18207; found

376.18208.

(1R,7R,7aS,11aR)-7-Methyl-1-[(R)-N-methylphenylsulfonimidoyl]-

octahydrobenzo[d]pyrrolo[1,2-c][1,3]oxazin-5(1H)-one (27)

Synthesis through Cycloalkylation of C,N-Dianion 21 in the Presence

of Excess nBuLi: To a solution of oxazinone 14 (100 mg,

0.30 mmol) in THF (5 mL) at –78 °C was added nBuLi (1.60 m in

n-hexane, 0.56 mL, 0.90 mmol). The mixture was warmed to –10 °C

within 1 h, then cooled to –50 °C and treated with ditosylate 22

(244 mg, 0.67 mmol). The mixture was warmed to room tempera-

ture within 12 h, then saturated aqueous NH₄Cl (5 mL) was added

and the mixture was extracted with CH₂Cl₂(3ϫ 10 mL). The com-

bined organic phases were dried (MgSO₄) and concentrated in

vacuo. Purification by chromatography (EtOAc) gave spirocycle 27

(73 mg, 67%) as a colourless solid.

(4R,4aS,7aR)-7a-{(1S)-3-(1,3-Dioxolan-2-yl)-1-[(R)-N-methyl-

phenylsulfonimidoyl]propyl}-4-methylhexahydrocyclopenta[d][1,3]-

oxazin-2(1H)-one (24): To a solution of sulfoximine 7 (1.50 g,

4.64 mmol) in THF (150 mL) was added at –50 °C, nBuLi (1.60 m

in n-hexane, 6.4 mL, 10.2 mmol). The mixture was warmed to

–10 °C within 1 h, cooled to –50 °C, and then treated with bromide

23 (0.60 mL, 5.12 mmol). The mixture was warmed to room tem-

perature within 12 h, then saturated aqueous NH₄Cl (150 mL) was

added and the mixture was extracted with CH₂Cl₂(3ϫ 100 mL)

and the combined organic phases were dried (MgSO₄). Removal of

the solvents in vacuo and purification by chromatography (EtOAc

then EtOAc/iPrOH, 9:1) gave sulfoximine 24 (1.28 g, 65%) as a

colourless oil and sulfoximine 7 (152 mg, 10%); [α]_D= –80.6 (c =

1.16, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.30–1.45 (m,

1 H, CH₂), 1.32 (d, J = 6.0 Hz, 3 H, Me), 1.53–1.67 (m, 3 H, CH₂),

1.75–1.90 (m, 3 H, CH₂), 1.97–2.12 (m, 3 H, CH, CH₂), 2.72–2.87

(m, 1 H, CH₂), 2.76 (s, 3 H, Me), 3.34 (br. d, J = 7.7 Hz, 1 H,

CHS), 3.74–3.99 (m, 5 H, CHO, CH₂O), 4.66 (t, J = 4.1 Hz, 1 H,

CHO₂), 7.24 (br. s, 1 H, NH), 7.54–7.66 (m, 3 H, Ph), 7.82–7.88

(m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.2 (d, Me),

20.5 (u, CH₂), 22.2 (u, CH₂), 26.7 (u, CH₂), 29.7 (d, Me), 32.8 (u,

CH₂), 39.1 (u, CH₂), 46.6 (d, CH), 64.7 (u, CH₂), 65.0 (u, CH₂),

68.2 (u, CN), 70.4 (d, CHS), 74.8 (d, CHO), 103.5 (d, CHO₂), 129.4

(d, CH), 129.6 (d, CH), 133.1 (d, Ph), 139.7 (u, Ph), 155.2 (u,

Synthesis through Isomerisation of Sulfoximine 21: To a solution of

sulfoximine 21 (68 mg, 0.19 mmol) in THF (4 mL) at –50 °C was

added nBuLi (1.60 m in n-hexane, 0.14 mL, 0.23 mmol). The mix-

ture was warmed to room temperature within 12 h, then saturated

aqueous NH₄Cl (5 mL) was added and the mixture was extracted

with CH₂Cl₂(3ϫ 10 mL). The combined organic phases were dried

(MgSO₄) and concentrated in vacuo. Purification by chromatog-

raphy (EtOAc) gave spirocycle 27 (58 mg, 85%) as a colourless so-

lid; m.p. 184–186 °C; [α]_D= –88.4 (c = 0.92, CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ = 1.16–1.40 (m, 3 H, CH₂), 1.45 (s, 3 H, Me),

1.48–1.62 (m, 1 H, CH₂), 1.63–1.81 (m, 2 H, CH₂), 1.82–1.93 (m,

1 H, CH₂), 2.05–2.32 (m, 3 H, CH₂), 2.70 (s, 3 H, Me), 2.99–3.09

(br. d, J = 10.6 Hz, 1 H, CHCHO), 3.36 (dt, J = 9.7, J = 2.2 Hz,

1 H, NCH₂), 3.50 (d, J = 7.2 Hz, 1 H, CHS), 4.04 (q, J = 9.4 Hz,

1 H, NCH₂), 4.68 (dq, J = 10.6, J = 6.2 Hz, 1 H, CHO), 7.55–7.66

(m, 3 H, Ph), 7.79–7.87 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 18.7 (d, Me), 19.9 (u, CH₂), 23.8 (u, CH₂), 24.4 (u,

CH₂), 25.5 (u, CH₂), 29.2 (d, Me), 35.9 (u, CH₂), 28.2 (d,

CHCHO), 44.0 (u, NCH₂), 66.7 (u, CN), 68.1 (d, CHS), 73.1 (d,

CHO), 129.5 (d, Ph), 129.7 (d, Ph), 133.0 (d, Ph), 138.3 (u, Ph),

CO) ppm. IR (CHCl ): ν = 3377 (w), 3275 (w), 2957 (m), 2883 (m),

˜

3

1710 (s), 1446 (m), 1392 (m), 1322 (m), 1235 (s), 1138 (s), 1078 (m),

861 (w) cm^–1. MS (CI, isobutane): m/z (%) = 423 (3) [M⁺+ 1], 269

(14), 268 (84), 224 (15), 206 (24), 181 (10), 156 (100).

152.9 (u, CO) ppm. IR (KBr): ν = 3371 (w), 2943 (m), 2807 (w),

˜

(4R,4aS,7aR)-4-Methyl-7a-{(1S)-1-[(R)-N-methylphenylsulfon- 2243 (w), 1688 (s), 1419 (s), 1330 (w), 1250 (m), 1197 (w), 1140

imidoyl]pent-4-en-1-yl}hexahydrocyclopenta[d][1,3]oxazin-2(1H)-one (m), 1074 (m), 914 (m), 867 (w) cm^–1. MS (EI): m/z (%) = 362 (9)

(26): To a solution of sulfoximine 7 (100 mg, 0.31 mmol) in THF

(10 mL) at –50 °C, was added nBuLi (1.60 m in n-hexane, 0.43 mL, calcd. C 62.96, H 7.23, N 7.73; found C 62.90, H 7.11, N 7.62.

[M⁺], 183 (11), 182 (100), 164 (14), 163 (11). C₁₉H₂₆N₂O₃S (362.5):

12

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Enantioselective Synthesis of Azaspirocycles

(4R,4aS,7aR)-7a-(Chloromethyl)-4-methylhexahydrocyclopenta-

[d][1,3]oxazin-2(1H)-one (31): 1-Chloroethyl chloroformate

(304 μL, 2.82 mmol) was added at room temperature to a solution

of sulfoximine 7 (700 mg, 2.17 mmol) in CH₂Cl₂(10 mL). The mix-

ture was stirred at room temperature until TLC indicated almost

complete conversion of the sulfoximine (4 h). Concentration in

vacuo and purification by chromatography (EtOAc/cyclohexane,

2:1) afforded chloride 31 (356 mg, 81%) as a colourless solid. R_f=

0.55 (33), 0.90 (30) (EtOAc), m.p. 118–120 °C; [α]_D= +1.1 (c =

1.02, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 1.39 (d, J =

6.2 Hz, 3 H, Me), 1.48–2.12 (m, 7 H, CH, CH₂), 3.49 (d, J =

11.4 Hz, 1 H, CH₂Cl), 3.56 (d, J = 11.1 Hz, 1 H, CH₂Cl), 4.02 (dq,

J = 9.6, 6.2 Hz, 1 H, CHO), 6.19 (br. s, 1 H, NH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 19.1 (d, Me), 23.0 (u, CH₂), 28.3 (u, CH₂),

37.9 (u, CH₂), 46.2 (d, CH), 52.7 (u, CH₂Cl), 65.0 (u, NC), 75.9

MS (EI, 70 eV): m/z (%) = 350 (3) [M⁺+ 1], 264 (3), 222 (36),

178 (18), 154 (100), 135 (26), 110 (100). HRMS: m/z calcd. for

C₁₃H₂₀INO₂S [M⁺] 349.05332; found 349.05390.

(4R,4aS,7aS)-7a-(But-2-enyl)-4-methylhexahydrocyclopenta-

[d][1,3]oxazin-2(1H)-one (41): To a suspension of CuI (1.16 g,

6.07 mmol) in THF (3 mL at –30 °C) was added 1-propenylmagne-

sium bromide (0.50 m in THF, 24.3 mL, 12.1 mmol). The turbid

mixture was stirred for 30 min at this temperature whereby it be-

came yellow-brown. Subsequently, the mixture containing cuprate

40 was added to a solution of iodide 32 in THF (3 mL) at –30 °C.

The mixture, which successively became red, orange and finally yel-

low-brown, was stirred for 2 h at –30 °C. It was then warmed to

room temperature within 12 h, whereby it became black. Saturated

aqueous (NH₄)₂CO₃(30 mL) and concentrated aqueous NH₃

(10 mL) were added and the aqueous phase was extracted with

CH₂Cl₂(3 ϫ 15 mL). The combined organic phases were dried

(MgSO₄) and concentrated in vacuo. Purification by chromatog-

raphy (EtOAc/cyclohexane, 1:1) gave alkene 41 as an Z/E mixture

in a ratio of 2:1 (208 mg, 82%) as a colourless oil.

(d, CHO), 156.2 (u, CO) ppm. IR (KBr): ν = 3337 (m), 3248 (m),

˜

3132 (m), 2976 (s), 2940 (m), 2889 (m), 1704 (s), 1457 (m), 1431

(m), 1391 (s), 1321 (s), 1281 (m), 1213 (w), 1162 (w), 1119 (w), 1086

(m), 1054 (m), 1014 (m), 975 (w), 938 (w), 865 (w) cm^–1. MS (CI,

CH₄): m/z (%) = 204 (100) [M⁺+ 1]. C₉H₁₄ClNO₂(203.1): calcd.

C 53.08, H 6.93, N 6.88; found C 53.16, H 6.95, N 6.75.

Isomer (Z)-41: ¹H NMR (300 MHz, CDCl₃): δ = 1.33 (d, J =

6.2 Hz, 3 H, Me), 1.41–1.52 (m, Ͼ1 H, CH₂), 1.60–2.00 (m, Ͼ9 H,

CH₂, CH, Me), 2.05–2.38 (m, 2 H, CH₂CH=CH), 3.97 (dq, J =

10.1, 6.0 Hz, Ͼ1 H, CHO), 5.35–5.50 (m, Ͼ1 H, CH=CH), 5.72

(tdq, J = 10.9, 6.7, 1.2 Hz, 1 H, CH=CHMe), 6.10 (br. s, 1 H,

NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 13.1 (d, Me), 19.2 (d,

Me), 22.6 (u, CH₂), 27.7 (u, CH₂), 38.5 (u, CH₂), 39.3 (u,

CH₂CH=CHMe), 47.0 (d, CHCHO), 64.2 (u, CN), 76.0 (d, CHO),

123.7 (d, CH=CHMe), 129.0 (d, CH=CHMe), 156.3 (u, CO) ppm.

(4R,4aS,7aR)-7a-(Iodomethyl)-4-methylhexahydrocyclopenta-

[d][1,3]oxazin-2(1H)-one (32): To a mixture of sulfoximine 7

(500 mg, 1.55 mmol) and NaI (1.16 g, 7.75 mmol) in CH₃CN

(7 mL) at room temperature was added 1-chloroethyl chloro-

formate (338 μL, 3.10 mmol). The mixture was stirred at room tem-

perature until TLC indicated almost complete conversion of the

sulfoximine (3 h). Concentration in vacuo and purification by

chromatography (EtOAc/cyclohexane, 4:1) afforded iodide 32

(348 mg, 76%) as a brown solid. R_f= 0.45 (32), 0.90 (30) (EtOAc);

1

Isomer (E)-41: H NMR (300 MHz, CDCl₃): δ (in part) = 1.32 (d,

1

M.p. 85 °C; [α]_D= +2.0 (c = 0.93, CH₂Cl₂). H NMR (400 MHz,

J = 6.2 Hz, 3 H, Me), 5.51–5.66 (m, 1 H, CH=CHMe), 6.04 (br. s,

1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 18.1 (d, Me),

19.2 (d, Me), 22.5 (u, CH₂), 27.5 (u, CH₂), 39.0 (u, CH₂), 44.5 (u,

CH₂CH=CHMe), 46.7 (d, CHCHO), 63.8 (u, CN), 75.9 (d, CHO),

124.4 (d, CH=CHMe), 131.3 (d, CH=CHMe), 156.3 (u, CO) ppm.

CDCl₃): δ = 1.39 (d, J = 6.3 Hz, 3 H, Me), 1.49–1.58 (m, 1 H,

CH₂), 1.59–1.70 (m, 1 H, CH₂), 1.75–1.87 (m, 2 H, CH₂), 1.94–2.08

(m, 3 H, CHCHO, CH₂), 3.35 (d, J = 10.4 Hz, 1 H, CH₂I), 3.41

(d, J = 10.4 Hz, 1 H, CH₂I), 4.02 (dq, J = 10.2, 6.3 Hz, 1 H, CHO),

5.92 (br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.1 IR (capillary; Z/E-mixture): ν = 3851 (m), 3743 (m), 3251 (m), 3121

˜

(u, Me), 20.7 (u, CH₂I), 23.0 (u, CH₂), 28.1 (u, CH₂), 40.1 (u,

(w), 2949 (m), 2353 (s), 1710 (s), 1549 (m), 1461 (w), 1394 (m),

CH₂), 47.4 (d, CHCHO), 63.5 (u, CN), 76.2 (d, CHO), 155.3 (u, 1318 (m), 1083 (m) cm^–1. MS (EI; Z/E-mixture): m/z (%) = 210 (19)

CO) ppm. IR (CHCl ): ν = 3250 (m), 3123 (m), 2956 (s), 2879 (m), [M⁺+ 1], 209 (0.3) [M⁺], 154 (63), 110 (100), 93 (13). C₁₂H₁₉NO₂

˜

3

1712 (s), 1455 (m), 1393 (s), 1323 (s), 1205 (m), 1092 (m), 1059 (m), (209.1) (Z/E-mixture): calcd. C 68.87, H 9.15, N 4.75; found C

1007 (m), 968 (w), 918 (w), 873 (w) cm^–1. MS (EI): m/z (%) = 295 69.25, H 9.08, N 7.05.

(1) [M⁺], 154 (100), 110 (45), 81 (11). C₉H₁₄INO₂(295.1): calcd. C

(4R,4aS,7aS)-7a-[3-(1,3-Dioxolan-2-yl)propyl]-4-methylhexahydro-

36.63, H 4.78, N 4.75; found C 36.53, H 4.85, N 4.61.

cyclopenta[d][1,3]oxazin-2(1H)-one (43)

(4R,4aS,7aR)-7a-[(S)-1-Iodopent-4-en-1-yl]-4-methylhexahydro-

Synthesis through Cuprate Reaction of Iodide 32: To a solution of

cyclopenta[d][1,3]oxazin-2(1H)-one (33): To a solution of sulfox-

2-(2-bromoethyl)-1,3-dioxolane (0.32 mL, 2.72 mmol) in THF

imine 26 (600 mg, 1.59 mmol) in MeCN (10 mL) at room tempera-

(20 mL) at –78 °C, was added tBuLi (1.60 m in n-pentane, 3.63 mL,

ture were added NaI (715 mg, 4.77 mmol) and 1-chloroethyl

5.44 mmol). The mixture was stirred at this temperature for 2 h,

chloroformate (455 mg, 3.18 mmol) and the mixture was stirred for

then it was added to a solution of CuI (259 mg, 1.36 mmol) in THF

3 h at room temperature. Concentration in vacuo and purification

(5 mL) and Me₂S (1 mL) at –30 °C. The mixture was stirred at this

by chromatography (EtOAc) gave a mixture of iodide 33 and

temperature for 30 min, whereby it became black. The mixture con-

EtOAc in a ratio of 76:24 containing 403 mg (76%) of the iodide;

taining cuprate 42 was then added to a solution of iodide 32

[α]_D= –24.9 (c = 1.00, CHCl₃/EtOAc). ¹H NMR (300 MHz,

(100 mg, 0.34 mmol) in THF (2 mL) at –30 °C. The mixture was

CDCl₃): δ = 1.26 (EtOAc), 1.39 (d, J = 6.2 Hz, 3 H, Me), 1.50–

warmed to room temperature within 2 h. TLC showed a complete

2.20 (m, 10 H, CH, CH₂), 2.05 (EtOAc), 2.43 (m, 1 H, CH₂), 3.98

conversion of the iodide. Saturated aqueous (NH₄)₂CO₃(10 mL)

(dq, J = 10.7, 6.1 Hz, 1 H, CHO), 4.04 (dd, J = 9.1, 2.2 Hz, 1 H,

and concentrated NH₃(10 mL) were added, the mixture was ex-

CHI), 4.12 (EtOAc), 5.04 (m, 1 H, CH=CH₂), 5.11 (m, 1 H,

tracted with EtOAc (3ϫ 20 mL), and the combined organic phases

CH=CH₂), 5.65 (br. s, 1 H, NH), 5.71 (m, 1 H, CH=CH₂) ppm.

were dried (MgSO₄). Removal of the solvents in vacuo and purifi-

¹³C NMR (100 MHz, CDCl₃): δ = 19.4 (d, Me), 21.0 (EtOAc), 22.8

cation by chromatography (EtOAc) gave acetal 43 (66 mg, 72%) as

(u, CH₂), 29.4 (u, CH₂), 33.6 (u, CH₂), 34.2 (u, CH₂), 45.2 (u,

a colourless oil.

CH₂), 46.4 (d, CH), 52.3 (d, CH), 60.5 (EtOAc), 68.2 (u, CN),

76.4 (d, CHO), 116.6 (u, CH=CH₂), 136.3 (d, CH=CH₂), 156.4 (u,

Synthesis through Reduction of Sulfoximine 24: Sulfoximine 24

CO) ppm. IR (CHCl ): ν = 3245 (m), 3121 (w), 2944 (m), 1713 (s), (1.21 g, 2.86 mmol) was added to a suspension of Raney nickel

˜

3

1447 (m), 1388 (m), 1324 (m), 1220 (w), 1089 (m), 1041 (w) cm^–1.

(prepared from 10.0 g Ni/Al alloy) in THF and water and the mix-

13

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H.-J. Gais et al.

FULL PAPER

ture was stirred for 24 h at room temperature. The suspension was

filtered through Celite and NaCl was added to the filtrate. The

aqueous layer was extracted with EtOAc (2ϫ 50 mL) and the com-

bined organic phases were dried (MgSO₄). Removal of the solvents

in vacuo and purification by chromatography (EtOAc) gave acetal

43 (692 mg, 90 %) as a colourless oil; [α]_D= +11.8 (c = 1.80,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.35 (d, J = 6.0 Hz,

100 °C for 2 h. Removal of the solvent in vacuo and purification

by chromatography (EtOAc) gave nitrile 46 (329 mg, 94%) as a

1

colourless solid; m.p. 120 °C; [α]_D= +27.6 (c = 1.03, CH₂Cl₂). H

NMR (300 MHz, CDCl₃): δ = 1.43 (d, J = 6.4 Hz, 3 H, Me), 1.52–

2.15 (m, 7 H, CH, CH₂), 2.63 (d, J = 16.8 Hz, 1 H, CH₂CN), 2.71

(d, J = 16.6 Hz, 1 H, CH₂CN), 3.97–4.09 (m, 1 H, CHO), 7.12

(br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.2 (d,

3 H, Me), 1.40–1.97 (m, 13 H, CH₂), 3.82–3.87 (m, 2 H, CH₂O), Me), 23.0 (u, CH₂), 28.3 (u, CH₂), 31.1 (u, CH₂CN), 40.0 (u, CH₂),

3.93–4.01 (m, 3 H, CHO, CH₂O), 4.84 (t, J = 4.7 Hz, 1 H, CHO₂), 47.4 (d, CH), 62.2 (u, CN), 76.2 (d, CHO), 116.8 (u, CH₂CN),

5.83 (br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.1 156.2 (u, CO) ppm. IR (KBr): ν = 3294 (s), 3116 (w), 2961 (m),

˜

(u, CH₂), 19.2 (d, Me), 22.6 (u, CH₂), 27.7 (u, CH₂), 33.7 (u, CH₂), 2934 (m), 2254 (w), 1671 (s), 1471 (m), 1416 (s), 1317 (s), 1215 (w),

39.9 (u, CH₂), 41.6 (u, CH₂), 46.7 (d, CH), 64.1 (u, CN), 64.8 (u, 1168 (m), 1126 (w), 1081 (m), 1052 (m), 1026 (m), 943 (w), 865

CH₂O), 75.9 (d, CHO), 104.0 (d, CHO₂), 156.1 (u, CO) ppm. IR

(CHCl ): ν = 3247 (m), 3115 (w), 2954 (s), 2882 (m), 1706 (s), 1458

(w) cm^–1. MS (EI): m/z (%) = 194 (0.5) [M⁺], 154 (72), 121 (14),

110 (100), 107 (11), 93 (11), 82 (15). C₁₀H₁₄N₂O₂(194.2): calcd. C

˜

3

(m), 1404 (m), 1317 (m), 1220 (m), 1137 (m), 1048 (m), 941 61.84, H 7.27, N 14.42; found C 61.69, H 7.22, N 14.33.

(w) cm^–1. MS (EI): m/z (%) = 269 (5) [M⁺], 226 (17), 154 (82), 153

(4R,4aS,7aR)-7a-(Pent-4-en-1-yl)-4-methylhexahydrocyclopenta-

(20), 136 (20), 127 (10), 110 (100), 99 (12), 93 (11). HRMS: m/z

[d][1,3]oxazin-2(1H)-one (47): To a solution of iodide 33 (200 mg,

calcd. for C₁₄H₂₃NO₃[M⁺] 269.16271; found 269.16283.

0.57 mmol) containing a small amount of EtOAc and AIBN (2 mg)

in benzene (20 mL) at room temperature was added HSnBu₃

(498 mg, 1.71 mmol). After the mixture was kept at 60 °C for 4 h,

it was concentrated in vacuo. The residue was dissolved in a mix-

ture of MeCN (30 mL) and n-hexane (20 mL). The n-hexane phase

was washed with MeCN (40 mL) and the combined MeCN phases

were concentrated in vacuo. Purification by chromatography

(EtOAc/cyclohexane, 1:1) gave oxazinone 47 (109 mg, 85%) as a

colourless oil; [α]_D= +26.5 (c = 1.00, CHCl₃). ¹H NMR (300 MHz,

CDCl₃): δ = 1.36 (d, J = 6.0 Hz, 3 H, Me), 1.40–2.00 (m, 11 H,

CH, CH₂), 2.04 (m, 1 H, CH₂), 3.96 (dq, J = 9.9, 6.2 Hz, 1 H,

CHO), 5.09 (m, 2 H, CH=CH₂), 5.75 (m, 1 H, CH=CH₂), 6.00

(br. s, 1 H, NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 19.3 (d,

Me), 22.6 (u, CH₂), 22.8 (u, CH₂), 27.8 (u, CH₂), 33.7 (u, CH₂),

40.0 (u, CH₂), 41.3 (u, CH₂), 46.9 (d, CH), 64.7 (u, CN), 76.0 (d,

CHO), 115.1 (u, CH=CH₂), 138.1 (d, CH=CH₂), 156.6 (u,

(4R,4aS,7aR)-4,7a-Dimethylhexahydrocyclopenta[d][1,3]oxazin-

2(1H)-one (55)

Isolation in an Attempted Synthesis of Alkene 47: To a solution of

4-bromobut-1-ene (0.42 mL, 4.07 mmol) in THF (5 mL) at –78 °C

was added tBuLi (1.60 m in n-pentane, 5.40 mL, 8.16 mmol). The

mixture was stirred at this temperature for 2 h, then it was added

to a solution of CuI (388 mg, 2.04 mmol) in THF (5 mL) and Me₂S

(1 mL) at –30 °C. The mixture was stirred at this temperature for

30 min, whereby it became black. Then the mixture containing

cuprate 44a was added to a solution of iodide 32 (150 mg,

0.51 mmol) in THF (2 mL) at –30 °C. The mixture was warmed to

room temperature within 2 h. TLC showed complete conversion of

32. Saturated aqueous (NH₄)₂CO₃(10 mL) and conc. NH₃(10 mL)

were added, the mixture was extracted with EtOAc, and the com-

bined organic layers were dried (MgSO₄). Concentration in vacuo

and chromatography (EtOAc) gave a colourless oil (54 mg), which

contained oxazinone 55 in approximately 55% yield according to

¹H NMR spectroscopy. Similar results were obtained when iodide

32 was treated with cuprate 44b^[28]under these conditions.

CO) ppm. IR (CHCl ): ν = 3237 (w), 3119 (w), 2937 (m), 2883 (m),

˜

3

1703 (s), 1454 (m), 1397 (s), 1312 (m), 1224 (w), 1089 (m), 1057

(m), 991 (w), 909 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 224 (28)

[M⁺+ 1], 182 (36), 162 (16), 154 (95), 138 (28), 110 (100). HRMS:

m/z calcd. for C₁₃H₂₁NO₂[M⁺] 223.15668; found 223.15673.

Synthesis through Reduction of Sulfoximine 7: Sulfoximine 7

(310 mg, 0.961 mmol) was added to a suspension of Raney nickel

(prepared from 3.30 g Ni/Al alloy) in THF and water and the mix-

ture was stirred for 24 h at room temperature. The suspension was

filtered through Celite and brine was added to the filtrate. The

aqueous layer was extracted with EtOAc (2ϫ 50 mL) and the com-

bined organic phases were dried (MgSO₄). Removal of the solvent

in vacuo and purification by chromatography (EtOAc) gave oxazin-

(3aS,4R,11aS)-4-Methyloctahydrocyclopenta[d]pyrido[1,2-c][1,3]-

oxazin-6(1H)-one (48): Sulfoximine 18 (162 mg, 0.447 mmol) was

added to a suspension of Raney nickel (prepared from 1.54 g Ni/

Al alloy) in THF and water and the mixture was stirred for 24 h

at room temperature. The suspension was filtered through Celite

and brine (15 mL) was added to the filtrate. The aqueous phase

was extracted with EtOAc (2ϫ 20 mL) and the combined organic

phases were dried (MgSO₄). Removal of the solvents in vacuo and

purification by chromatography (EtOAc) gave spirocycle 48 (90 mg,

96%) as a colourless oil; [α]_D= +18.5 (c = 1.04, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 1.27–1.38 (m, 4 H, Me, CH₂), 1.39–1.84

(m, 10 H, CH, CH₂), 1.91–2.03 (m, 1 H, CH₂), 2.24–2.36 (m, 1 H,

CH₂), 2.75–2.85 (m, 1 H, NCH₂), 3.91 (dq, J = 10.7, 6.3 Hz, 1 H,

CHO), 4.21–4.30 (m, 1 H, NCH₂) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 18.7 (d, Me), 20.8 (u, CH₂), 22.3 (u, CH₂), 24.4 (u,

CH₂), 26.9 (u, CH₂), 34.2 (u, CH₂), 36.8 (u, CH₂), 42.8 (u, NCH₂),

51.4 (d, CH), 65.4 (u, CN), 74.0 (d, CHO), 154.9 (u, CO) ppm. IR

one 45 (120 mg, 74%) as a colourless oil; m.p. 76–78 °C; [α]_D

=

1

+31.2 (c = 1.20, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 1.22

(s, 3 H, Me), 1.27 (d, J = 6.3 Hz, 3 H, Me), 1.34–1.44 (m, 1 H,

CH₂), 1.50–1.73 (m, 5 H, CH, CH₂), 1.85–1.96 (m, 1 H, CH₂), 3.93

(dq, J = 10.2, 6.3 Hz, 1 H, CHO), 6.76 (br. s, 1 H, NH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 19.2 (d, Me), 22.5 (u, CH₂), 27.3 (u,

CH₂), 29.5 (d, Me), 41.0 (u, CH₂), 48.5 (d, CH), 61.1 (u, CN), 76.0

(d, CHO), 156.1 (u, CO) ppm. IR (KBr): ν = 3247 (m), 3112 (m),

˜

2963 (m), 2878 (m), 1705 (s), 1412 (m), 1324 (m), 1223 (w), 1174

(w), 1084 (m), 1058 (m), 979 (w) cm^–1. MS (EI): m/z (%) = 169 (22)

[M⁺], 154 (33), 127 (100), 126 (19), 112 (45), 110 (56), 97 (11), 96

(63), 83 (16), 82 (30), 81 (13). HRMS: m/z calcd. for C₉H₁₅NO₂

[M⁺] 169.11028; found 169.11033.

(KBr): ν = 2929 (s), 2877 (m), 1679 (s), 1517 (w), 1449 (m), 1415

˜

(s), 1374 (w), 1332 (m), 1266 (s), 1178 (m), 1147 (w), 119 (m), 1071

(m), 1042 (m), 977 (m), 893 (w) cm^–1. MS (EI): m/z (%) = 209 (41)

[M⁺], 168 (10), 167 (100), 166 (17), 152 (74), 150 (17), 136 (31), 122

(19), 108 (15), 97 (19). HRMS: m/z calcd. for C₁₂H₁₉NO₂[M⁺]

209.14158; found 209.14167.

2-[(4R,4aS,7aS)-4-Methyl-2-oxooctahydrocyclopenta[d][1,3]oxazin-

7a-yl]acetonitrile (46): KCN (234 mg, 3.56 mmol) was added at

room temperature to a solution of chloride 31 (365 mg, 1.80 mmol)

in DMF (9 mL). The resulting mixture was heated with stirring at

(4R,4aS,7aS)-1-Allyl-7a-(but-2-enyl)-4-methylhexahydrocyclo-

penta[d][1,3]oxazin-2(1H)-one (49): To a solution of alkene (Z/E)-

14

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Enantioselective Synthesis of Azaspirocycles

41 (208 mg, 0.99 mmol) in DMF (5 mL) at room temperature was

added NaH (50% in mineral oil, 63 mg, 1.31 mmol). The mixture

was stirred for 30 min and allyl bromide (113 μL, 1.31 mmol) was

added. After the mixture was stirred for 12 h at room temperature,

it was concentrated in vacuo. Purification by chromatography

(EtOAc/cyclohexane, 1:2) gave diene 49 as an Z/E mixture in a

ratio of 2:1 (211 mg, 85%) as a colourless oil.

(CHCl₃/MeOH/NEt₃, 90:10:1) gave amino alcohol 52 (71 mg, 72%)

as a colourless oil; [α]_D= –33.0 (c = 1.62, CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ = 1.23 (d, J = 8.9 Hz, 3 H, Me), 1.27–1.60

(m, 2 H, CH₂), 1.64–1.85 (m, 5 H, CH, CH₂), 1.86–1.98 (m, 1 H,

NCH₂), 2.61 (br. d, J = 17.8 Hz, 1 H, NCH₂), 3.52 (br. s, 2 H,

CCH₂CH=CH), 3.90 (dq, J = 9.9, 6.2 Hz, 1 H, CHO), 5.30 (br. s,

2 H, OH, NH), 5.64–5.80 (m, 2 H, CH=CH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 23.0 (d, Me), 23.5 (u, CH₂), 29.5 (u, CH₂),

36.1 (u, CH₂), 37.9 (u, NCH₂), 40.6 (u, NCCH₂CH=CH), 56.7 (d,

CHCHO), 62.3 (u, CN), 68.7 (d, CHO), 122.9 (d, CH), 125.4 (d,

1

Isomer (Z)-49: H NMR (300 MHz, CDCl₃): δ (in part) = 1.30 (d,

J = 6.2 Hz, Ͼ3 H, Me), 1.38–1.51 (m, Ͼ1 H, CH₂), 1.61 (br. d, J

= 6.9 Hz, 3 H, Me), 1.70–2.13 (m, Ͼ6 H, CH, CH₂), 2.21–2.44 (m,

Ͼ2 H, CH₂CH=CHMe), 3.50–3.64 (m, Ͼ1 H, NCH₂), 3.82–3.93

(m, Ͼ1 H, CHO), 4.15–4.27 (m, Ͼ1 H, NCH₂), 5.07–5.22 (m,

Ͼ2 H, CH=CH₂), 5.23–5.36 (m, Ͼ1 H, CH=CHMe), 5.60–5.73 (m,

1 H, CH=CHMe), 5.86–6.01 (m, Ͼ1 H, CH=CH₂) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ (in part) = 13.3 (d, Me), 18.8 (d, Me), 23.1 (u,

CH₂), 28.2 (u, CH₂), 35.6 (u, CH₂CH=CHMe), 39.5 (u, CH₂), 47.2

(u, NCH₂), 47.9 (d, CHCHO), 69.4 (u, CN), 74.6 (d, CHO), 115.9

(u, CH=CH₂), 123.6 (d, CH=CHMe), 128.2 (d, CH=CHMe), 134.8

(d, CH=CH₂), 156.5 (u, CO) ppm.

CH) ppm. IR (capillary): ν = 3950 (w), 3902 (w), 3813 (w), 3729

˜

(w), 3664 (w), 3369 (s), 3024 (m), 2958 (s), 2801 (m), 2726 (w), 2676

(w), 2560 (w), 2470 (w), 2401 (w), 1629 (s), 1569 (s), 1452 (s), 1330

(m), 1260 (w), 1219 (m), 1175 (w), 1137 (s), 1109 (m), 1062 (s),

1010 (m), 958 (m), 931 (m), 881 (m), 812 (m) cm^–1. MS (EI): m/z

(%) = 181 (40) [M⁺], 180 (100), 162 (61), 120 (13), 108 (37), 106

(11), 95 (11), 94 (10). HRMS: m/z calcd. for C₁₁H₁₉NO [M⁺]

181.14666; found 181.14664.

1-{(1S,5S)-1-[(R)-1-Hydroxyethyl]-6-azaspiro[4.5]decan-6-yl}-2-

methylbutan-1-one (53): To a solution of oxazinone 48 (100 mg,

0.48 mmol) and TMEDA (72 μL, 0.48 mmol) in THF (7 mL) at

0 °C, was added secBuLi (1.40 m in cyclohexane, 0.51 mL,

0.72 mmol). The mixture was stirred at this temperature for 40 min,

then allyl bromide (62 μL, 0.717 mmol) was added and the mixture

was stirred at 0 °C for 2 h. Saturated aqueous NH₄Cl (10 mL) was

added, the mixture was extracted with EtOAc (3ϫ 10 mL), and

the combined organic phases were dried (MgSO₄). Removal of the

solvents in vacuo and chromatography (EtOAc/cyclohexane, 1:2,

then EtOAc) gave a mixture of amides 53 and epi-53 in a ratio of

1:1 (31 mg, 24%) and 42 (62 mg, 62%). Small amounts of the pure

amides 53 and epi-53 were obtained by chromatography (EtOAc/

cyclohexane, 1:2). R_f= 0.75 (53), 0.63 (epi-53), 0.33 (48) (Et₂O).

Isomer (E)-49: ¹H NMR (300 MHz, CDCl₃): δ (in part) = 1.63

(br. d, J = 5.2 Hz, 3 H, Me), 5.46–5.58 (m, 1 H, CH=CHMe) ppm.

¹³C NMR (75 MHz, CDCl₃): δ (in part) = 18.1 (d, Me), 28.3 (u,

CH₂), 39.4 (u, CH₂), 41.8 (u, CH₂CH=CHMe), 47.1 (u, NCH₂),

47.6 (d, CH), 74.7 (d, CHO), 124.4 (d, CH=CHMe), 130.7 (d,

CH CH=CH ) ppm. IR (capillary; Z/E-mixture): ν = 3080 (w),

˜

2

3018 (w), 2956 (m), 2880 (m), 1701 (s), 1538 (w), 1438 (m). 1397

(m), 1309 (m), 1237 (m), 1106 (m), 1067 (m), 970 (m), 920 (m) cm^–1.

MS (EI; Z/E-mixture): m/z (%) = 250 (4) [M⁺+ 1], 195 (13), 194

(100), 150 (67). HRMS: m/z calcd. for C₁₅H₂₃NO₂[M⁺] (Z/E-mix-

ture) 250.18053; found 250.18070.

(3aS,4R,11aS)-4-Methyl-2,3,3a,4,8,11-hexahydrocyclopenta[d]-

pyrido[1,2-c]-[1,3]oxazin-6(1H)-one (51): To a solution of diene

(Z/E)-42 (211 mg, 0.85 mmol) in CH₂Cl₂(85 mL, 0.01 m) at room

temperature, was added catalyst 50 (37 mg, 0.042 mmol). After the

mixture was stirred at room temperature for 1 h, TLC showed com-

plete conversion of the diene. DMSO (0.2 mL) was added and the

mixture was stirred at room temperature for 1 h. Concentration in

vacuo and purification by chromatography (Et₂O) gave spirocycle

51 (166 mg, 95 %) as a colourless oil; [α]_D= –72.2 (c = 1.58,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.35 (d, J = 6.3 Hz,

3 H, Me), 1.43–1.92 (m, 5 H, CH, CH₂), 1.95–2.19 (m, 4 H, CH₂),

3.51–3.60 (m, 1 H, NCH₂), 3.99 (dq, J = 9.9, 6.3 Hz, 1 H, CHO),

4.65–4.75 (m, 1 H, NCH₂), 6.65–6.79 (m, 2 H, CH=CH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 18.9 (d, Me), 22.4 (u, CH₂), 27.8 (u,

CH₂), 36.3 (u, CH₂), 37.3 (u, CNCH₂CH=CH), 41.9 (u, NCH₂),

50.3 (d, CHCHO), 63.1 (u, CN), 74.3 (d, CHO), 122.9 (d, CH),

1

Isomer 59: H NMR (300 MHz, CDCl₃): δ = 0.92 (t, J = 7.4 Hz,

3 H, CH₂CH₃), 1.07 (d, J = 6.7 Hz, 3 H, CHCH₃), 1.14 (d, J =

6.2 Hz, 3 H, Me), 1.26–1.48 (m, 3 H, CH₂), 1.50–1.76 (m, 9 H, CH,

CH₂), 1.78–1.90 (m, 1 H, CH₂), 1.97–2.16 (m, 2 H, CH₂), 2.39–

2.53 (m, 1 H, CH₂), 2.50–2.63 (m, 1 H, CHMe), 3.54–3.70 (m, 2 H,

NCH₂), 3.72–3.85 (m, 1 H, CHO) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 12.1 (d, CH₂CH₃), 17.1 (u, CH₂), 17.2 (d, CHCH₃),

22.8 (u, CH₂), 23.9 (d, Me), 24.3 (u, CH₂), 27.1 (u, CH₂), 30.4 (u,

CH₂), 34.2 (u, CH₂), 37.4 (u, CH₂), 39.3 (d, CHMe), 41.9 (u,

NCH₂), 60.4 (d, CH), 68.6 (u, NC), 69.6 (d, CHO), 176.7 (u,

CO) ppm. IR (CHCl ): ν = 3423 (m), 2943 (s), 2869 (s), 1723 (w),

˜

3

1618 (s), 1463 (s), 1427 (s), 1371 (w), 1321 (w), 1228 (m), 1148 (m),

1116 (m), 1062 (m), 971 (w), 924 (w), 869 (w) cm^–1. MS (EI): m/z

(%) = 267 (15) [M⁺], 249 (31), 210 (30), 184 (14), 182 (34), 181 (33),

180 (44), 169 (10), 168 (62), 166 (45), 138 (24), 110 (60), 98 (42),

97 (100), 84 (31).

124.2 (d, CH), 154.6 (u, CO) ppm. IR (capillary): ν = 3859 (w),

˜

3364 (m), 2964 (s), 1693 (s), 1609 (m), 1413 (s), 1308 (m), 1265 (m),

1198 (w), 1128 (m), 1067 (m) cm^–1. MS (EI): m/z (%) = 207 (100)

[M⁺], 192 (18), 164 (11), 163 (12), 162 (62), 150 (17), 148 (17), 146

(13), 134 (23), 124 (12), 120 (37), 107 (13), 106 (21), 95 (11), 94

(13), 93 (11), 81 (12), 80 (17). HRMS: m/z calcd. for C₁₅H₂₇NO₂

[M⁺] 207.12593; found 207.12606.

Isomer epi-53: ¹H NMR (300 MHz, CDCl₃): δ = 0.86 (t, J = 7.7 Hz,

3 H, CH₂CH₃), 1.09 (d, J = 6.9 Hz, 3 H, CHCH₃), 1.15 (d, J =

6.2 Hz, 3 H, Me), 1.28–1.46 (m, 4 H, CH₂), 1.48–1.74 (m, 8 H, CH,

CH₂), 1.77–1.90 (m, 1 H, CH₂), 1.99–2.17 (m, 2 H, CH₂), 2.46–2.63

(m, 2 H, CHMe, CH₂), 3.50–3.82 (m, 3 H, CHO, NCH₂) ppm. ¹³

C

NMR (75 MHz, CDCl₃): δ = 12.1 (d, CH₂CH₃), 17.0 (u, CH₂),

17.7 (d, CHCH₃), 22.6 (u, CH₂), 24.1 (d, Me), 24.4 (u, CH₂), 27.3

(R)-1-[(1S,5S)-6-Azaspiro[4.5]dec-8-en-1-yl]ethanol (52): A mixture

of oxazinone 51 (113 mg, 0.546 mmol), CsOH·H₂O (1.373 g, (u, CH₂), 30.7 (u, CH₂), 34.2 (u, CH₂), 37.6 (u, CH₂), 39.4 (d,

8.18 mmol), MeOH (3 mL) and H₂O (3 mL) was heated at reflux

for 3 d. The mixture was cooled to room temperature and adjusted

to pH 7.0 by the careful addition of concentrated aqueous HCl.

MeOH was removed in vacuo and the residue was lyophilised. The

remaining colourless solid was triturated with CHCl₃/MeOH (1:1)

(3ϫ 10 mL) and the combined organic phases were dried (MgSO₄)

and concentrated in vacuo. Purification by chromatography

CHMe), 41.5 (u, NCH₂), 60.6 (d, CH), 68.6 (u, NC), 69.5 (d,

CHO), 176.5 (u, CO) ppm. IR (CHCl ): ν = 3409 (m), 2943 (s),

˜

3

2869 (s), 1618 (s), 1463 (s), 1430 (s), 1372 (m), 1320 (m), 1147 (m),

1117 (m), 1059 (m), 974 (w), 924 (w), 868 (w) cm^–1. MS (EI): m/z

(%) = 267 (18) [M⁺], 249 (28), 210 (34), 184 (14), 182 (34), 181 (34),

180 (44), 169 (10), 168 (67), 166 (45), 138 (22), 110 (60), 98 (41),

97 (100), 84 (31).

Eur. J. Org. Chem. 0000, 0–0

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15

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Pages: 18

H.-J. Gais et al.

FULL PAPER

(3aS,4R,11aS)-4-Methyl-2,3,3a,4,10,11-hexahydrocyclopenta[d]-

pyrido[1,2-c][1,3]oxazin-6(1H)-one (54): To a solution of acetal 43

(105 mg, 0.390 mmol) in toluene (2 mL) was added p-toluenesulf-

onic acid (7 mg, 0.04 mmol) and the mixture was stirred and heated

at reflux for 1 h. Saturated aqueous NaHCO₃(5 mL) was added,

the aqueous layer was extracted with EtOAc (3ϫ 10 mL), and the

combined organic layers were dried (MgSO₄). Removal of the sol-

vents in vacuo and purification by chromatography (EtOAc/cyclo-

hexane, 1:1) gave enamide 54 (60 mg, 74%) as a colourless solid;

m.p. 99–102 °C; [α]_D= +67.3 (c = 1.15, CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ = 1.38 (d, J = 6.2 Hz, 3 H, Me), 1.48–1.90

(m, 7 H, CH, CH₂), 1.93–2.09 (m, 2 H, CH₂), 2.09–2.14 (m, 2 H,

CH₂), 4.18 (dq, J = 9.6, 6.2 Hz, 1 H, CHO), 5.04–5.13 (m, 1 H,

NCH=CH), 6.86–6.93 (dt, J = 8.4, 2.0 Hz, 1 H, NCH=CH) ppm.

¹³C NMR (75 MHz, CDCl₃): δ = 19.1 (d, Me), 19.3 (u, CH₂), 20.5

(u, CH₂), 25.7 (u, CH₂), 30.9 (u, CH₂), 33.7 (u, CH₂), 48.0 (d,

CH), 63.5 (u, CN), 74.1 (d, CHO), 108.8 (d, NCH=CH), 125.7 (d,

Acknowledgments

Financial support of this work by the Deutsche Forschungsgemein-

schaft (DFG) (SFB 380 and GK 440) is gratefully acknowledged.

The authors thank Björn Sommer for technical assistance.

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NCH=CH) ppm. IR (KBr): ν = 3061 (w), 2965 (m), 2903 (m), 1673

˜

(s), 1516 (w), 1459 (w), 1406 (s), 1373 (m), 1315 (s), 1205 (w), 1168

(w), 1124 (m), 1054 (m), 977 (w), 945 (w), 912 (w), 809 (w) cm^–1.

MS (EI): m/z (%) = 207 (100) [M⁺], 163 (12), 162 (47), 148 (85),

135 (20), 134 (98), 120 (26), 108 (21), 95 (43), 94 (28), 91 (12), 82

(16), 80 (15). C₁₂H₁₇NO₂(207.1): calcd. C 69.54, H 8.27, N 6.76;

found C 69.63, H 7.88, N 6.61.

(3aS,4R,8S,11aS)-8-Allyl-4-methyloctahydrocyclopenta[d]pyrido-

[1,2-c][1,3]oxazin-6(1H)-one (56): To a solution of acetal 55 (31 mg,

0.129 mmol) in CH₂Cl₂(4 mL) at –78 °C was added BF₃·OEt₂

(98 μL, 0.774 mmol) and allyltrimethylsilane (123 μL, 0.774 mmol).

The mixture was warmed to room temperature within 5 h, then

saturated aqueous NaHCO₃(10 mL) was added and the aqueous

layer was extracted with CH₂Cl₂(3ϫ 10 mL). The combined or-

ganic layers were dried (MgSO₄) and the solvents were removed

1

in vacuo. H NMR spectroscopy of the crude product showed the

presence of a mixture of alkene 56 (Ն98%de) and enamide 54 in a

ratio of 3:1. Separation by chromatography (n-pentane/iPrOH,

16:1) gave 56 (23 mg, 71%) as a colourless oil and 54 (6 mg, 22%)

as a colourless solid. R_f= 0.50 (56), 0.40 (54) (n-pentane/iPrOH,

[4]

1

16:1); [α]_D= –7.1 (c = 0.56, CH₂Cl₂). H NMR (500 MHz, C₆D₆):

δ = 0.72 (ddt, J = 13.1, 4.0, 1.5 Hz, 1 H, CH₂), 0.84–0.94 (m, 1 H,

CH₂), 0.99 (d, J = 6.1 Hz, 3 H, Me), 1.00–1.14 (m, 3 H, CH₂),

1.15–1.48 (m, 7 H, CH₂, CH), 1.67–1.75 (m, 1 H, CH₂), 2.04–2.13

(m, 1 H, CH₂CH=CH₂), 2.28–2.36 (m, 1 H, CH₂CH=CH₂), 3.51

(dq, J = 9.8, 6.4 Hz, 1 H, CHO), 5.00–5.07 (m, 2 H, CH=CH₂),

5.07–5.12 (m, 1 H, CHN), 5.80–5.90 (m, 1 H, CH=CH₂) ppm. ¹³C

NMR (125 MHz, C₆D₆): δ = 15.5 (u, CH₂), 18.6 (d, Me), 20.7 (u,

CH₂), 23.9 (u, CH₂), 26.7 (u, CH₂), 35.3 (u, CH₂), 35.6 (u, CH₂),

38.3 (u, CH₂CH=CH₂), 50.1 (d, CH), 51.4 (d, NCH), 63.4 (u, NC),

71.5 (d, CHO), 116.3 (u, CH=CH₂), 136.7 (d, CH=CH₂), 153.1 (u,

CO) ppm. IR (KBr): ν = 3074 (w), 2938 (s), 1680 (s), 1452 (w),

˜

1405 (s), 1369 (m), 1308 (m), 1276 (m), 1128 (m), 1089 (m), 997

(w), 916 (m) cm^–1. MS (EI): m/z (%) = 250 (37) [M⁺+ 1], 249 (1)

[M⁺], 209 (13), 208 (100), 165 (12), 164 (93), 147 (23), 121 (37), 108

(11), 105 (14), 93 (19), 82 (10). HRMS: m/z calcd. for C₁₅H₂₃NO₂

[M⁺] 249.17288; found 249.17276.

[5]

[6]

Supporting Information (see footnote on the first page of this arti-

cle): General information and general experimental procedures. Ex-

perimental procedures, analytical data and spectroscopic data for

compounds 7, 18, 34 and 55. Figure S1 showing previously synthe-

sised cycloalkenylsulfoximines of type III together with references.

Figure S2 showing sulfoximines, which had undergone haloformate

reactions. Copies of the ¹H and ¹³C NMR spectra of all com-

pounds.

[7]

J. Brandt, H.-J. Gais, Tetrahedron: Asymmetry 1997, 8, 909–

912.

16

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Enantioselective Synthesis of Azaspirocycles

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Published Online: ᭿

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17

Job/Unit: O40068

/KAP1

Date: 14-04-14 10:47:28

Pages: 18

H.-J. Gais et al.

FULL PAPER

Spiro Compounds

A modular, enantioselective synthesis of

azaspirocycles was devised based on the

special features of sulfoximines, including

chirality, carbanion stabilization, nucleofu-

gacity, and nucleophilicity. Key steps are

intramolecular amination, C,N-dianion

cycloalkylation, sulfoximine displacement,

N-acyliminium ion formation, and ring-

closing metathesis.

A. Köhler (née Adrien), G. Raabe,

J. Runsink, F. Köhler,

H.-J. Gais* ..................................... 1–18

Sulfoximine-Based Modular Enantioselec-

tive Synthesis of Azaspirocycles Featuring

Sulfoximine Displacement, Dianion Cyclo-

alkylation, RCM and N-Acyliminium Ion

Formation

Keywords: Ring-closing metathesis

/

Nucleophilic substitution / Carbanions /

Spiro compounds / Enantioselectivity

Sulfoximine

/

18

www.eurjoc.org

Eur. J. Org. Chem. 0000, 0–0

Article Doi

Sulfoximine-based modular enantioselective synthesis of azaspirocycles featuring sulfoximine displacement, dianion cycloalkylation, RCM and N-acyliminium ion formation

DOI: 10.1002/ejoc.201400068

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Authors:

Article abstract of DOI:10.1002/ejoc.201400068

Full text of DOI:10.1002/ejoc.201400068

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