Asymmetric synthesis of protected β-substituted and β,β-disubstituted β-amino acids bearing branched hydroxyalkyl side chains and of protected 1,3-amino alcohols with three contiguous stereogenic centers from allylic sulfoximines and aldehydes

FULL PAPER

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-

Amino Acids Bearing Branched Hydroxyalkyl Side Chains and of Protected

1,3-Amino Alcohols with Three Contiguous Stereogenic Centers from Allylic

Sulfoximines and Aldehydes

Hans-Joachim Gais,*^[a]Ralf Loo,^[a]Daniel Roder,^[a]Parthasarathi Das,^[a]and

Gerhard Raabe^[a]

Keywords: Amino alcohols / Amino acids / Asymmetric synthesis

We describe a new method for the asymmetric synthesis,

from allylic sulfoximines and aldehydes, of N,O-protected,

cyclic and acyclic, β-substituted and β,β-disubstituted δ-hy-

acted readily with a number of electrophiles to give the cor-

responding α-substituted sulfoximines in good yields. Reduc-

tion of the sulfoximines with Raney nickel afforded the cor-

droxy-β-amino acids and of N,O-protected 1,3-amino alco- responding protected monocyclic and bicyclic 1,3-amino al-

hols, both possessing three contiguous stereogenic centers.

Treatment of enantiomerically pure, acyclic allylic sulfoxim-

ines with aldehydes after successive lithiation and titanation

afforded sulfonimidoyl-substituted homoallylic alcohols with

high regio- and diastereoselectivities. Diastereomerically

pure, cyclic, sulfonimidoyl-substituted homoallylic alcohols

were synthesized in a similar manner from the corresponding

enantiomerically pure, cyclic allylic sulfoximines and isobu-

tyraldehyde. A highly diastereoselective amination of the

cohols and the protected acyclic and cyclic β-amino acids in

good yields. The substitution route involves: (1) a facile sub-

stitution of the sulfonimidoyl group by a Cl atom, and (2) a

substitution of the Cl atom of the protected β-amino chlorides

by a cyano group. Treatment of the sulfoximines with

ClCO₂Me readily afforded the corresponding β-amino chlor-

ides in good yields, and so treatment of alkyl sulfoximines

with chloroformates seems to be a general method for the

replacement of an N-methylsulfonimidoyl group by a Cl

sulfonimidoyl-substituted homoallylic alcohols with the gen- atom. Introduction of a cyano group was achieved through

eration of secondary and tertiary C atoms and formation of

the sulfonimidoyl-substituted, protected 1,3-amino alcohols

(oxazinones) was achieved by the carbamate method,

through cyclization of the corresponding carbamates after

their lithiation with nBuLi. The sulfonimidoyl-substituted,

treatment of chlorides with NaCN, which gave the corres-

ponding β-amino nitriles in good yields. Finally, hydrolysis

of the nitriles afforded the protected acyclic and cyclic, β-

substituted and β,β-disubstituted β-amino acids. Treatment

of the protected β-amino sulfoximines with ClCO₂Me gave −

monocyclic and bicyclic oxazinones were converted into pro- besides the corresponding chlorides − methyl (S)-N-phenyl-

tected, acyclic and cyclic, β-substituted and β,β-disubstituted

β-amino acids and protected 1,3-amino alcohols by two dif-

ferent routes: the carbanion route and the substitution route.

The carbanion route involves: (1) a double lithiation of the

protected β-amino sulfoximines, (2) treatment of the di-

lithiated sulfoximines with electrophiles, and (3) reductive

removal of the sulfonimidoyl group. By the carbanion route,

double lithiation of the sulfonimidoyl-substituted oxazinones

with nBuLi gave the corresponding dilithium salts, which re-

sulfinylcarbamate with Ն 99% ee in good yield. Treatment

of the sulfinamide with MeMgCl afforded (S)-methyl phenyl

sulfoxide with 97% ee, and this could be converted with com-

plete retention of configuration into (S)-N,S-dimethyl-S-

phenylsulfoximine, the starting material for the synthesis of

the allylic sulfoximines used in this work.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2003)

Background and Synthetic Concept

ever-growing interest in the asymmetric synthesis of β-am-

ino acids.^[4]Cyclic and acyclic β,β-disubstituted β-amino

acids are currently of much interest because of anticipated

unusual structural and pharmacological properties of their

derived β-peptides.^{[1i,3b,3c,3e]}While numerous imaginative

and efficient asymmetric syntheses of β-substituted β-amino

acids have been described,^[1,4]methods for the asymmetric

synthesis of β,β-disubstituted β-amino acids are scarce.^[5]

The well established ArndtϪEistert homologation of α-

amino acids, for example, fails in the case of α,α-disubsti-

tuted α-amino acids.^[1i]Methods described for the asymmet-

ric synthesis of β,β-disubstituted β-amino acids include the

β-Amino acids have attracted much attention^[1]because

of their incorporation in naturally occurring peptides and

other biologically active compounds and their utilization as

starting materials for the synthesis of β-lactams^[2]and β-

peptides,^[3]oligomers of β-amino acids. This has resulted in

[a]

Institut für Organische Chemie der Rheinisch-Westfälischen

Technischen Hochschule-(RWTH) Aachen,

Prof.-Pirlet-Str. 1, 52056 Aachen, Germany

Fax (internat.) ϩ49-(0)241/8092665

E-mail: Gais@RWTH-Aachen.de

1500

 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1500 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

addition of nucleophiles to N-sulfinylimines,^[5aϪ5c]the

hydrogenation of N-sulfinylimine-derived aziridines,^[5d]and

the functionalization of aspartic acid derivatives.^[5e]While

the sulfinylimine method has been restricted to the syn-

thesis of β-methyl-substituted derivatives and seems to be

limited by syn and anti isomerization of ketosulfinimines,

the selectivities of the aziridine method tend to be variable,

while the aspartic acid method is confined to particular ex-

amples. As well as β,β-disubstituted derivatives, β-amino

acids bearing hydroxy groups in their side chains are of par-

ticular interest. Hydroxy-β-amino acids occur as structural

motifs in natural products and have been used as starting

materials for the synthesis of biologically active

compounds.^[6aϪ6i,6k]The most interesting application of

these functionalized β-amino acids, however, should be in

the field of β-peptides,^[6j]in particular in the synthesis of

glycosylated β-peptides.^[6l,6m]Glycosylated α-peptides,^[7]oli-

gomers of α-amino acids, are of high biological relevance,

and so their glyco-β-peptide analogues may also exhibit

interesting biological activities and structures.

We felt that β-substituted and β,β-disubstituted δ-

hydroxy-β-amino acids of type I, with three contiguous

stereogenic centers (Figure 1), ought to be particularly at-

tractive as starting materials for the synthesis of glyco-β-

peptides and peptide mimetics. Variation of R¹to R³and

the incorporation of R¹and R²of I into a cyclic skeleton

should provide a high degree of synthetic and structural

flexibility. Asymmetric syntheses of acyclic derivatives of I

bearing hydroxy groups at their γ-positions (R¹

ϭ

OH)^[6aϪ6c]had been accomplished previously by use of the

corresponding δ-hydroxy-α,β-unsaturated esters as starting

materials and application of a stereoselective amination by

ˆ

the HirmaϪIto carbamate method. The asymmetric syn-

thesis of β-amino acids of type I bearing functions other

than a hydroxy group at the γ-position by this route, how-

ever, has with a few exemptions not been achieved.^[6c,6i]

This is perhaps due to the lack of direct methods for the

asymmetric synthesis of the required γ-substituted δ-

hydroxy-α,β-unsaturated esters from aldehydes,^[8,9]which

necessitates the use of indirect, albeit efficient, methods

such as aldol or allylation reactions and Wittig homol-

ogation.^[10]

Structurally closely related to I are the 1,3-amino al-

cohols IV, which have also aroused much attention because

of their occurrence as structural motifs in natural prod-

ucts,^[11]their use as starting materials for the synthesis of,

for example, analgesics,^[12]and their demonstrated or po-

tential application as chiral auxiliaries and ligands in asym-

metric synthesis.^[13]As a consequence, much activity has

Figure 1. The carbanion and the substitution routes from δ-

hydroxy-α,β-unsaturated sulfoximines to β-amino acids and 1,3-

amino alcohols

been directed towards the asymmetric synthesis of 1,3-am- duction of β-amino ketones,^{[16a,16b,16e]}prepared through re-

ino alcohols. While a number of methods have been devel- duction of chiral dihydropyrimidines^[16a,16b]or by asymmet-

oped,^[14,15]those suitable for the asymmetric synthesis of ric Mannich-type reactions,^[17]and (3) asymmetric 1,3-di-

type IV compounds with three contiguous stereogenic cen- polar cycloadditions with alkenes.^{[14b,14f,16d]}While the selec-

ters, situated either in a cyclic or in an acyclic carbon skel- tivities of the allenylmetal and allylmetal routes tend to be

eton, are much less abundant.^[16]Known methods include: variable, access to β-amino ketones with two stereogenic C

(1) the addition of amino-substituted allenylindium,^[16f]al- atoms and a broad range of substituents is limited at pre-

lylindium,^[16g]and allyltitanium^[16c]compounds (derived sent, and the 1,3-dipolar cycloaddition gives access only to

from α-amino acids, for example) to aldehydes, (2) the re- 1,3-amino alcohols with particular substituents. Thus, in

Eur. J. Org. Chem. 2003, 1500Ϫ1526

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H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

view of the current strong interest both in β-amino acids sulfonimidoyl group by a Cl atom by treatment with

and in 1,3-amino alcohols, we considered it desirable to ClCO₂R works well for simple alkyl and allyl sulfoximines,

have a method for the asymmetric synthesis of the β-amino nothing is known about the feasibility of the substitution

acids I and the 1,3-amino alcohols IV, both with three con- of sulfoximines of type VII with secondary or tertiary car-

tiguous stereogenic centers. In our view, sulfonimidoyl-sub- bon atoms at their β-positions. The nucleophilic substi-

stituted homoallylic alcohols of type VIII should be par- tution of chlorides VI by cyanide, for example, should pose

ticularly attractive as starting materials for the asymmetric no problem in the case of R²ϭ H,^[4a]but might face one

synthesis of I and IV.^[18,19]Firstly, cyclic and acyclic deriva- in the case of R²϶ H and the cyclic derivatives of VI.

tives of VIII with various substituents, including sterically

In this paper we describe a new method for the asymmet-

demanding ones, are readily available enantiomerically and ric synthesis of N,O-protected, cyclic and acyclic δ-hydroxy

diastereomerically pure through treatment of the corre- β-amino acids of type I and of N,O-protected, cyclic and

sponding chiral, sulfonimidoyl-substituted bis(allyl)titan- acyclic 1,3-amino alcohols of type IV from the bis(allyl)tit-

ium complexes IX with aldehydes.^[18]Secondly, the sulfoni- anium complexes IX and aldehydes.^[25]This adds consider-

midoyl group, because of its almost unique array of features ably to the synthetic usefulness of complexes IX, which have

Ϫ including nucleofugacity, basicity, nucleophilicity, car- previously been shown to be excellent reagents not only for

banion-stabilizing and electron-withdrawing character, and the asymmetric synthesis of branched homopropargylic al-

favorable redox potential Ϫ offers a number of synthetic cohols from aldehydes,^[21]but also for that of branched γ,δ-

possibilities for the introduction of substituents and also for unsaturated α-amino acids from N-sulfonyl α-imino es-

its replacement.^[20]Some of these properties of the sulfoni- ters.^[26]

midoyl group have already been advantageously exploited

in the conversion of VIII (R²ϭ H) into the corresponding

Results and Discussion

enantiomerically and diastereomerically pure branched

homopropargylic alcohols.^[21]Synthesis of both the β-am-

ino acids I and the 1,3-amino alcohols IV from VIII would

require in a first step the installation of the amino group of

the target molecules with the stereoselective generation of a

I. Stereoselective Synthesis and Amination of δ-Hydroxy-

α,β-Unsaturated Sulfoximines

Treatment of the enantiomerically and diastereomerically

secondary or tertiary C atom. This transformation could pure homoallylic alcohols 2aϪc, synthesized in good yields

perhaps be accomplished through cyclization of the carba- from the allylic sulfoximines 1aϪc^[18c,27Ϫ29]and the corre-

mates^[6b]derived from the hydroxyalkenyl sulfoximines VIII sponding aldehydes as described previously, with trichlo-

with formation of N,O-protected δ-hydroxy-β-amino sulfox- roacetyl isocyanate and subsequent cleavage of the N-tri-

imines VII, since alkenyl sulfoximines are known to be good chloroacetyl carbamates 3aϪc with aqueous ammonia gave

Michael acceptors for N-nucleophiles.^[22]In a second step, a mixture of the (Z)-configured carbamate (Z)-4a and the

the sulfonimidoyl group of VII would have to be replaceable (E)-configured carbamate (E)-4a in a ratio of 3:1, the pure

by various groups, including a carboxy group. Because of (Z)-configured carbamate (Z)-4b, and a mixture of the (Z)-

the ability of the sulfonimidoyl group to act not only to configured carbamate (Z)-4c and the (E)-configured carba-

stabilize a carbanion but also as a nucleofuge,^[20]two differ- mate (E)-4c in a ratio of 4.7:1, in 85%, 90% and 92% yields,

ent but complementary routes, the carbanion route and the respectively (Scheme 1). Carbamates 4aϪc were purified by

substitution route, for the achievement of this goal could be chromatography, which also allowed separation of carbam-

envisaged. The carbanion route would include: (1) double ates (Z)-4c and (E)-4c. The N-trichloroacetyl carbamates

deprotonation of the protected β-amino sulfoximines VII at 3aϪc were not generally isolated, but ¹H NMR spec-

the N atom and at the Cα atom with formation of the dili- troscopy of the reaction product derived from alcohol 2b

thiated sulfoximines III, (2) treatment of III with electro- and the isocyanate showed the formation of a mixture of

philes including ClCO₂R with formation of the substituted (Z)-3b and (E)-3b in a ratio of approximately 11:1. This

sulfoximines II, and (3) reduction of II with formation of I indicates that the isomerization of the CϭC double bond

or IV after deprotection. While the feasibility of (1) lithi- has already taken place at the stage of the N-trichloroacetyl

ation of alkyl sulfoximines, (2) the facile reaction of lithi- carbamates. Isomerization of the (Z) isomer to the more

ated alkyl sulfoximines with electrophiles, and (3) the re- stable (E) isomer perhaps occurs through a reversible ad-

duction of alkyl sulfoximines have been amply demon- dition of the N atom of the fairly acidic trichloroacetyl car-

strated,^[20]nothing is known, however, about the stability of bamate group to the activated double bond after proton

the lithioalkyl sulfoximines III with potential nucleofuges transfer to the basic sulfonimidoyl group. Treatment of the

at their β-positions. The substitution route would en- mixture of carbamates (Z)-4a and (E)-4a, and also of the

compass: (1) substitution of the sulfonimidoyl group of VII, pure carbamates (Z)-4b and (Z)-4c, each with 2Ϫ3 equiv.

with formation of the protected β-amino chlorides VI by of nBuLi at Ϫ78 °C and warming of the reaction mixtures

the chloroformate method developed recently in our labora- to room temperature resulted in highly diastereoselective

tories,^[23,24]and (2) the replacement of the Cl atom of VI, cyclization reactions (Ն 95% de) and afforded the oxazi-

with the formation of derivatives V, upon treatment with nones 5aϪc after aqueous workup, each as a single dia-

various nucleophiles, including cyanide, to afford either I stereomer, in 93%, 94%, and 83% yields, respectively.^[30]The

or IV after deprotection. Although the substitution of a configuration of the newly generated stereogenic center of

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Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

oxazinone 5b was determined indirectly by X-ray crystal also studied. Treatment of (E)-4c with nBuLi under the

structure analysis of a derivative (vide infra). ¹H NMR same conditions as used in the case of (Z)-4c resulted in a

spectroscopy of oxazinones 5aϪc showed that oxazinones highly stereoselective cyclization reaction (Ն 95% de) to

5a and 5c also have the same configuration as 5b. Ox- give oxazinone 5c as a single diastereomer in 82% yield.

azinones 5aϪc are characterized by high magnitudes of the These results indicate that the formation of (E/Z) mixtures

vicinal coupling constants for all protons in their oxazinone in the case of 4a and 4c is not detrimental to the success of

rings, which clearly demonstrates their trans-trans relation- the highly stereoselective amination of 2a and 2c.

ships. In solution, according to the NMR and IR data, ox-

Sulfoximines 5aϪc can serve as starting materials only

azinones 5aϪc preferentially if not exclusively adopt a for the synthesis of acyclic β-amino acids of type I (R²ϭ

structure of type 5-A, characterized by an intramolecular H) and of acyclic 1,3-amino alcohols of type IV (R²ϭ H)

hydrogen bond between the N atoms of the oxazinone ring (cf. Figure 1). Synthesis of acyclic β,β-disubstituted β-am-

and the sulfonimidoyl group and a conformation of the ox- ino acids of type I (R²϶ H) and of acyclic 1,3-amino al-

azinone ring in which all substituents are in pseudoequa- cohols of type IV (R²϶ H) requires the successful exten-

torial positions. A structure of this type was also found in sion of the highly selective hydroxyalkylation of the mono-

the crystal in the case of the derivative of 5b (vide infra).

substituted bis(allyl)titanium complexes IX (R²ϭ H) with

aldehydes to that of the disubstituted titanium complexes

IX (R²϶ H). The hydroxyalkylation of the allylic sulfoxim-

ine (E)-6^[27]was therefore studied (Scheme 2). Titanation of

the allylic sulfoximine (E)-6 with ClTi(OiPr)₃after depro-

tonation with nBuLi furnished the corresponding bis(allyl)-

titanium complex, which upon treatment with isobutyral-

dehyde gave the anti-configured homoallylic alcohol (Z)-7

with high regioselectivity (Ն 95%) and diastereoselectivity

(Ն 95% de), isolated as a single diastereomer in 59% yield.

The allylic sulfoximine (E)-6 was recovered in 25% yield.

The depicted configuration of (Z)-7 was determined by X-

ray crystal structure analysis (Figure 2).

Scheme 2. Amination of acyclic (E)-configured δ-hydroxy-α,β-un-

saturated sulfoximines with formation of a tertiary C atom

Successive treatment of alcohol (Z)-7 with trichloroacetyl

isocyanate and aqueous ammonia afforded carbamate (Z)-

8 in 89% yield. Besides (Z)-8, a small amount of the corre-

sponding N-trichloroacetyl carbamate was also isolated. To

our delight, cyclization of carbamate (Z)-8 upon treatment

with nBuLi also proceeded with high diastereoselectivity (Ն

95% de) to give the oxazinone 9 as a single diastereomer in

Scheme 1. Amination of acyclic δ-hydroxy-α,β-unsaturated sulfox-

imines with formation of a secondary C atom

Formation of the diastereomerically pure oxazinone 5a 84% yield after aqueous workup. The configuration of 9

from the mixture of carbamates (Z)-4a and (E)-4a points was verified by X-ray crystal structure analysis (Figure 3).

to a stereoselective cyclization of both carbamates with the Interestingly, sulfoximine 9 features an intramolecular hy-

same sense and with similar degrees of asymmetric induc- drogen bond in the crystal, between the N atom of the oxaz-

tion (stereoconvergence). In order to test this hypothesis, inone ring and the O atom of the sulfoximine group incor-

the cyclization of the (E)-configured carbamate (E)-4c was porated in a six-membered ring. In the absence of a steri-

Eur. J. Org. Chem. 2003, 1500Ϫ1526

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H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

silyl ether (Z)-10, derived from alcohol (Z)-7, with MeLi in

Et₂O at Ϫ35 °C initially afforded the alkenyllithium deriva-

tive (Z)-11, which rapidly isomerized to (E)-11. Protonation

of (E)-11 with water yielded the (E)-configured alkenyl sul-

foximine (E)-10 in 93% yield based on (Z)-10. Deprotection

of the silyl ether (E)-10 gave alcohol (E)-7, which was con-

verted in two steps into carbamate (E)-8 (78% yield based

on (E)-10). Cyclization of carbamate (E)-8 under the same

conditions as employed for that of (Z)-8 delivered a mixture

of the oxazinones 9 and epi-9 in a ratio of 4.4:1 in 76%

yield. Thus, cyclization of (E)-8 occurred with a lower dia-

stereoselectivity than that of the isomer (Z)-8.

Figure 2. Structure of the δ-hydroxy-α,β-unsaturated sulfoximine

(Z)-7 in the crystal

cally demanding substituent at the N atom of the sulfonimi-

doyl group^[19a]it is normally the N atom and not the O

atom that engages in hydrogen bonding with hydroxy

groups, as demonstrated by 2aϪc, 5aϪc, a derivative of 5b

(vide infra), and other sulfoximines.^[18c]Formation of a hy-

drogen bond to the N atom of 9 is perhaps less favorable

than to the O atom because of an otherwise resulting steric

1,3-interaction between the methyl group at the C atom and

the S-phenyl group.

Scheme 3. Amination of acyclic (Z)-configured δ-hydroxy-α,β-un-

saturated sulfoximines with formation of a tertiary C atom

Having been shown that a stereoselective amination of

acyclic homoallylic alcohols of type VIII with generation of

secondary and tertiary carbon atoms can be accomplished

efficiently by the carbamate method, its extension to cyclic

homoallylic alcohols of type VIII was studied. Firstly, the

feasibility of a regio- and stereoselective synthesis of the

cyclic five-membered homoallylic alcohol 13a was exam-

ined (Scheme 4). Treatment of a mixture of Ti(OiPr)₄and

the corresponding bis(allyl)titanium complex, prepared

from the cyclopentenyl sulfoximine 12a^[29]by lithiation and

Figure 3. Structure of sulfonimidoyl-substituted 1,3-amino alcohol

derivative 9 in the crystal; H···O1 223.3, N2···O1 297.9(3), N2ϪH

97.1 pm, N2ϪH···O1 132.7°

The cyclization of both carbamates (Z)-4c and (E)-4c, subsequent titanation with one equivalent of ClTi(OiPr)₃,

each possessing a disubstituted double bond, occurred with with isobutyraldehyde proceeded with high regioselectivity

the same sense and with the same high degree of asymmet- (Ն 95%) and diastereoselectivity (Ն 95% de) to give the

ric induction. Although the synthesis of carbamate (Z)-8, homoallylic alcohol 13a, which was purified through con-

with a trisubstituted double bond, was not accompanied by version into the corresponding triethylsilyl ether, as a single

formation of the isomeric carbamate (E)-8, we were inter- diastereomer in 68% yield. The diastereomerically pure cyc-

ested in whether (E)-8 would also selectively give oxazinone lic six-membered homoallylic alcohol 13b was obtained

9 upon treatment with nBuLi. The synthesis of (E)-8 was from the allylic sulfoximine 12b^[31]as described pre-

accomplished as shown in Scheme 3. Thus, treatment of the viously.^[18c]Successive treatment of alcohols 13a and 13b

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Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

Figure 4. Cyclization of sulfonimidoyl-substituted lithiated homo-

allylic carbamates

Scheme 4. Amination of cyclic sulfonimidoyl-substituted homo-

allylic alcohols with formation of a tertiary C atom

with trichloroacetyl isocyanate and aqueous ammonia gave

carbamates 14a and 14b, respectively, both in 90% yield;

small amounts of the corresponding N-trichloroacetyl car-

bamates were also isolated. The cyclizations of carbamates

14a and 14b also occurred with high diastereoselectivities

(Ն 95% de) upon treatment with 2 equiv. of nBuLi and gave

the bicyclic oxazinones 15a and 15b, respectively, each as a

single diastereomer, in 80% and 84% yields. The configura-

tion of 15b was determined indirectly by X-ray crystal

structure analysis of derivatives (vide infra).

Stereochemical Consideration of the Intramolecular

Amination

The formation of the oxazinones from the corresponding

carbamates (cf. Schemes 1Ϫ4) most probably starts with de-

protonation of the amino groups, with formation of the

lithium salts 4-Li, 8-Li, and 14-Li, respectively (Fig-

ure 4).^[32]These lithium salts then undergo cyclization to

give the C-lithiated sulfoximines 5-Li_C, 9-Li_C, and 15-Li_C,

respectively.^[33,34]Since the acidity of the carbamates is

much higher than that of alkyl sulfoximines,^[35]the lithiated

sulfoximines 5-Li_C, 9-Li_C, and 15-Li_Cwould be expected to

undergo transmetalation, with formation of the O-lithiated

oxazinones 5-Li_O, 9-Li_O, and 15-Li_O, respectively. This

transmetalation may be crucial to the success of the intra-

molecular amination, since the lithiated oxazinones should

be much less prone to retro-Michael reaction than the lithi-

ated sulfoximines because of the poorer leaving groups in

their β-positions.

The generation of the new stereogenic centers in the mon-

ocyclic oxazinones and the bicyclic oxazinones occurs with

the same sense and with the same high degree of asymmet-

ric induction. The highly selective formation of the oxazi-

nones 5aϪc from (Z)-4a-Li, (E)-4a-Li, (Z)-4b-Li, (Z)-4c-Li,

and (E)-4c-Li, of oxazinone 9 from (Z)-8-Li, and of oxazi-

nones 15a and 15b from 14a-Li and 14b-Li, respectively,

implies that the CϭC double bond of the lithiated carbam- Figure 5. Transition state models for the intramolecular amination

Eur. J. Org. Chem. 2003, 1500Ϫ1526 1505

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

ates is attacked by the N atom from the Si face. This can

be explained by invoking transition state models of type

TS-1 for the acyclic (Z) isomers and TS-3 for the acyclic

(E) isomers, in which the substituents R¹and R²and the

CϭC double bond adopt pseudoequatorial positions (Fig-

ure 5). The alternative transition states TS-2 and TS-4,

which would feature attack of the N atom at the double

bond from the Re face and afford the epimeric oxazinones,

seem to be less favorable because of severe steric 1,3-interac-

tions involving the sulfonimidoyl group and the double

bond. Similar arguments can be applied to the transition

states TS-5 and TS-6 for the cyclization of the (Z)-config-

ured methyl-substituted lithiated carbamate and to TS-7

and TS-8 for the cyclization of the (E)-configured isomer.

Why the selectivity is lower in the case of the cyclization of

the latter salt is difficult to ascertain by these models. For

the cyclization of the cyclic lithiated carbamates, transition

state model TS-9 has to be invoked, resulting in the bicyclic

oxazinones with the cis ring fusion. The alternative tran-

sition state model TS-10, which would give isomeric bicyclic

oxazinones with a trans ring fusion, is highly strained and

destabilized by an unfavorable interaction between the sul-

fonimidoyl group and the lithiated carbamoyl group.

II. The Carbanion Route

Synthesis of Protected Dilithiated β-Amino Sulfoximines

and Treatment with Electrophiles

We were delighted to see that the protected β-amino sul-

foximines 5a and 5b readily afforded the dilithiated sulfoxi-

mines 5a-Li₂and 5b-Li₂, respectively, upon treatment with

2.1 equiv. of nBuLi in THF at Ϫ10 °C (Scheme 5). The

dilithiated sulfoximines 5a-Li₂and 5b-Li₂were stable in

THF solution at Ϫ78 °C for at least 2 h. Treatment of 5a-

Li₂with MeI gave a mixture of 16a and epi-16a in a ratio of

9:1, chromatography delivering the diastereomerically pure

derivative 16a in 68% yield. No C,N-dimethylation of 5a-

Li₂was observed under these conditions, within the limits

1

of detection by H NMR spectroscopy. Deuteration of 5b-

Scheme 5. Synthesis and reactivity of dilithium salts of protected

β-amino sulfoximines having a secondary C atom

Li₂with CD₃OD afforded a mixture of sulfoximines 16b

and epi-16b in a ratio of 3:1, with a D-content of Ն 98%,

in 99% yield. Methylation of 5b-Li₂yielded a mixture of 16c

and epi-16c in a ratio of 5:1 in 82% yield, chromatography

furnishing diastereomerically pure 16c in 75% yield. Simi- fonimidoyl group incorporated in a six-membered ring. The

larly, treatment of 5b-Li₂with PhCH₂OCH₂Cl proceeded methyl group and the phenyl group adopt pseudoaxial posi-

readily and diastereoselectively to give the diastereomer- tions. From the magnitudes of the vicinal coupling con-

ically pure sulfoximine 16d in 70% yield after chromatogra- stants of the protons of the oxazinone ring and the proton

phy of the crude reaction mixture. As a final example, treat- in the α-position in the ¹H NMR spectrum and NOE

ment of 5b-Li₂with acetaldehyde was carried out, yielding experiments, 16c in solution preferentially adopts a struc-

a mixture consisting of alcohols 16e and epi-16e in a ratio ture similar to that in the crystal. On the basis of the unam-

of 1.7:1 (67% yield) and of starting material 5b (27% yield). biguous assignment of the configuration of 16c, we tenta-

The configurations both of the newly generated stereog- tively assign the configurations depicted in Scheme 5 to the

enic C atom of 16c, at the position α to the sulfonimidoyl major diastereomers of sulfoximines 16aϪd. Treatment of

group, and, of no less importance, of the stereogenic C 5b-Li₂with MeCHO gave a mixture of two diastereomers in

atom bearing the N atom were determined by X-ray crystal a ratio of 1.7:1. Because of the almost unselective reaction

structure analysis (Figure 6). The structure of 16c in the between lithiated alkyl sulfoximines and aldehydes in gen-

crystal is characterized by an intramolecular hydrogen bond eral^[20]and the observation of a 5:1 selectivity in the meth-

between the N atoms of the oxazinone ring and of the sul- ylation of this dilithium salt with MeI, we tentatively assign

1506

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

the structures 16e and epi-16e, which differ in the configura-

tion of the C atom bearing the hydroxy group.

Scheme 6. Synthesis and reactivity of dilithium salts of protected

β-amino sulfoximines having a tertiary C atom

dilithiated sulfoximines and their treatment with electro-

philes. Completion of the asymmetric synthesis of 1,3-am-

ino alcohols by this route requires replacement of the sul-

fonimidoyl group, which should be possible either by re-

duction or by Cl-substitution (cf. Figure 1). Thus, treatment

of the monocyclic sulfoximines 5b and 16c with Raney

nickel^[37]readily afforded the 1,3-amino alcohol derivatives

17a and 17b, respectively, each in 88% yield (Scheme 7).

Similarly, reduction of the bicyclic sulfoximine 15b fur-

nished the cyclic 1,3-amino alcohol derivative 18 in 86%

yield. The configuration of 18 and hence that of the oxazi-

none 15b was determined by X-ray crystal structure analy-

sis (Figure 7). The reductive substitution of the sulfonimi-

doyl groups of the β-hydroxy sulfoximines 16e and epi-16e

Figure 6. Structure of the sulfonimidoyl-substituted 1,3-amino al-

cohol derivative 16c in the crystal; H···N2 198.8, N2···N1 280.5(5),

N1ϪH 100.5 pm, N1ϪH···N2 136.7°

From previous structural investigations of lithiated alkyl

and allyl sulfoximines,^[33,34]a transition state model of type

TS-11 is proposed for the reaction of the dilithiated sulfoxi-

mines 5a-Li₂and 5b-Li₂giving rise to the major dia-

stereomer. This transition state model is characterized by

the lack of a CϪLi bond and by the coordination of one

of the two Li atoms by the two N atoms of the oxazinone

ring and of the sulfonimidoyl group. Coordination of the N

atom of the sulfonimidoyl group to the Li atom results in a

C_αϪS conformation of the carbanion, in which the lone

pair orbital at the C_αatom and the SϪPh bond are approxi-

mately in one plane.^[36]Theoretical calculations on α-sul-

fonimidoyl carbanions predict that this conformation

should be energetically preferred because of a stabilizing

n_CϪσ_SPh* interaction.^[33c]The preferential formation of the

(R)-configured methyl derivative 16c in the reaction be-

tween 5b-Li₂and MeI may be interpreted by assuming a

preferential attack of MeI from the Re face of the car-

banionic centers as depicted in TS-11 because of steric

shielding of the Si face by R¹and the phenyl group. It is

proposed that the reactions between 5a-Li₂and 5b-Li₂and

the other electrophiles take a similar stereochemical course.

It is not only sulfoximines 5a and 5b, each with a second-

ary C atom in the β-position, that can be deprotonated

twice; the procedure is also successful with sulfoximines in-

corporating tertiary C atoms. Treatment of sulfoximine 9

with 2 equiv. of nBuLi and trapping of the dilithium salts 9-

Li₂with CD₃OD thus afforded a mixture of the deuterated

sulfoximine 9-D and epi-9-D in a ratio of approximately

1.1:1 in 99% yield (Scheme 6).

Synthesis of Protected 1,3-Amino Alcohols

The above results show that substituents at the α-posi-

tions of protected β-amino sulfoximines 5a and 5b can read-

ily be introduced through formation of the corresponding cohols by reduction

Scheme 7. Synthesis of protected acyclic and cyclic 1,3-amino al-

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1507

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

was accomplished with the generation of a double bond.

Thus, treatment of 16e and epi-16e (admixed with 15b) with

Al/Hg^[38]afforded a mixture of the unsaturated protected

1,3-amino alcohols (E)-19 and (Z)-19 in a ratio of 1:1 in

85% yield, together with 17a in 46% yield.

Figure 7. Structure of the protected 1,3-amino alcohol 18 in the

crystal

Scheme 8. Synthesis of protected acyclic β-substituted β-amino

acids and protected 1,3-amino alcohols by the carbanion route

Synthesis of Protected β-Amino Acids

Conversion of the sulfonimidoyl-substituted monocyclic

and bicyclic oxazinones to β-amino acid derivatives by the

carbanion route first requires the introduction of a carboxy

group into the molecules. Thus, treatment of the dilithiated

sulfoximine 5b-Li₂, derived from 5b, with ClCO₂Me fur-

nished a mixture of the esters 20 and epi-20 in a ratio of

5.2:1 in 64% yield (Scheme 8). The configurations of the

esters 20 and epi-20 were tentatively assigned as depicted.

Finally, reduction of the sulfoximines 20 and epi-20 with

Raney nickel gave the protected β-amino acid 21 in 87%

yield.

It was now of particular interest to see whether the car-

banion route could also be successfully implemented for the

synthesis of protected cyclic and acyclic β-amino acids with

tertiary C_βatoms. Deprotonation of sulfoximine 9 with

nBuLi in THF at Ϫ78 °C gave the dilithiated sulfoximine

9-Li₂, which upon treatment with ClCO₂R (R ϭ Me, iPr,

iBu, and CH₂tBu) furnished mixtures of esters 22aϪd and

epi-22a؊d and the starting sulfoximine 9, the last of which

was separated by chromatography (Scheme 9). Because of

partial transmetalation between 9-Li₂and the esters

formed, conversion of sulfoximine 9 was incomplete and

7Ϫ18% of the sulfoximine was recovered. Reduction of sul-

foximines 22aϪd and epi-22aϪd with Raney nickel afforded

the protected β,β-disubstituted β-amino acids 23aϪd in

48% to 74% yields, based on 9. The highest overall yield in

the conversion of sulfoximine 9 into one of the β-amino

ester derivatives was achieved in the case of ester 23c (74%),

for which isobutyl chloroformate was used for the introduc-

tion of the ester group into 9-Li₂.

Scheme 9. Synthesis of protected acyclic β,β-disubstituted β-amino

acids and protected 1,3-amino alcohols by the carbanion route

in THF at Ϫ78 °C cleanly gave the dilithiated sulfoximine

15b-Li₂(Scheme 10), which upon treatment with ClCO₂Me

Finally, the conversion of the bicyclic sulfoximine 15b delivered ester 24 as a single diastereomer in 70% yield.

into the amino acid derivative 25 by this route was investi- Reduction of sulfoximine 24 with Raney nickel furnished

gated. Double deprotonation of sulfoximine 15b with nBuLi the protected cyclic β-amino acid 25 in 86% yield. The

1508

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

structure of 25 was verified by X-ray crystal structure analy- carbanion route and at the same time open new synthetic

sis (Figure 8).

possibilities, in particular for the synthesis of functionalized

1,3-amino alcohols. We were delighted to see that treatment

of sulfoximines 5aϪc with ClCO₂Me at room temperature

in CH₂Cl₂for 3 days gave clean substitution of the sulfoni-

midoyl group and afforded the β-chloroamines 27aϪc in

84%, 85% and 81% yields, respectively (Scheme 11). In ad-

dition, the sulfinamide 26 was isolated (vide infra). Treat-

ment of chloride 27c with NaCN in DMF readily gave the

β-amino nitrile 28 in 87% yield.

Scheme 10. Synthesis of protected cyclic β,β-disubstituted β-amino

acids and protected 1,3-amino alcohols by the carbanion route

Scheme 11. Synthesis of protected acyclic β-amino chlorides and

nitriles by the substitution route

The sulfoximine 5c having successfully been converted

into the nitrile 28 by double substitution, it was of particu-

lar interest to see whether such transformations would also

be feasible in the cases of sulfoximines 9, 15a, and 15b and

the corresponding chlorides with tertiary C atoms at their

β-positions. To our delight, treatment of sulfoximine 9 with

ClCO₂Me in CH₂Cl₂at room temperature for 2.5 days gave

(besides sulfinamide 26) the protected β-amino chloride 29

in 81% yield (Scheme 12). Treatment of chloride 29 with

NaCN in DMF for 2 h furnished nitrile 30 in 87% yield,

hydrolysis of nitrile 30 delivering the protected acyclic β-

amino acid 31 in 72% yield. Interestingly, the oxazinone

ring of 31 was not cleaved under these conditions. The

structure of acid 31 was confirmed by X-ray crystal struc-

ture analysis (Figure 9).

Figure 8. Structure of the protected cyclic β-amino ester 25 in the

crystal; O3···H 214.9, N1···O3 285.5(8), N1ϪH 101.9 pm,

N1ϪH···O3 124.7°

III. The Substitution Route

Synthesis of Protected β-Amino Chlorides and Protected β-

Amino Acids

The carbanion route allows access to protected cyclic and

acyclic β-amino acids of type I and to protected cyclic and

acyclic 1,3-amino alcohols of type IV. This route ought to

be particularly well suited for the synthesis of 1,3-amino

alcohols IV with various substitution patterns, because of

the potential for the introduction of a wide range of sub-

stituents R⁴through the reaction between the dilithiated

sulfonimidoyl-substituted oxazinones and electrophiles. A

principle shortcoming of the carbanion route may be seen,

however, in the fact that the chirality of the sulfonimidoyl

group is lost in the reduction step. The envisaged substi-

tution route from sulfoximines VII to amino acids I and

1,3-amino alcohols IV via protected β-amino chlorides VI

would not have this shortcoming, since we had found pre-

viously that the sulfonimidoyl groups of alkyl and allyl sul-

foximines can readily be replaced by chlorine, proceeding

with complete retention of configuration at the S atom, by

Finally, the extension of the substitution route to the con-

version of sulfoximines 15a and 15b into amino acid deriva-

tives 34a and 34b, respectively, was attempted in order to

study the scope and limitation of the substitution route.

Substitution of the cyclic sulfoximines 15a and 15b pro-

ceeded uneventfully on treatment with ClCO₂Me and gave,

besides 26, the protected β-amino chlorides 32a in 83%

yield and 32b in 86% yield, respectively (Scheme 13). The

structure of chloride 32b was confirmed by X-ray crystal

structure analysis (Figure 10). Treatment of chlorides 32a

and 32b with NaCN in DMF readily furnished the nitrile

treatment with ClCO₂Me.^[23,24]The substitution route 33a in 92% yield and the nitrile 33b in 95% yield, respec-

could perhaps therefore provide a valuable alternative to the tively. Finally, hydrolysis of nitriles 33a and 33b with aque-

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1509

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

Figure 10. Structure of the chlorine-substituted cyclic 1,3-amino

alcohol derivative 32b in the crystal

ous NaOH at reflux afforded the protected cyclic β-amino

acids 34a in 70% yield and 34b in 69% yield, respectively.

Recycling of the Chiral Auxiliary

Scheme 12. Synthesis of protected acyclic β,β-disubstituted β-am-

ino acids by the substitution route

Treatment of sulfoximines 5aϪc, 9, 15a, and 15b with

ClCO₂Me in all cases delivered Ϫ in addition to the chlo-

rides 27aϪc, 29, 32a, and 32b, respectively Ϫ the sulfin-

amide 26 as a second reaction product, isolated in the case

of Ϫ for example Ϫthe synthesis of 29 with Ն 99% ee in

73% yield (Scheme 14). These results, together with those

obtained previously,^[23,24]indicate that treatment of S-alkyl-

N-methyl-S-phenylsulfoximines with a chloroformate seems

to be a general method for the replacement of the sulfon-

imidoyl group by a Cl atom. We assume that the substi-

tution proceeds through the intermediate formation of the

aminooxosulfonium chlorides 35. It was now of interest to

see whether the sulfoxide 36^[39]could be prepared from the

sulfinamide 26 with complete inversion of configuration,

Figure 9. Structure of the protected acyclic β-amino acid 31 in

the crystal

Scheme 13. Synthesis of protected cyclic β,β-disubstituted β-amino

acids by the substitution route

Scheme 14. Substitution of the sulfonimidoyl group and recycling

of the chiral auxiliary

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Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

since a two-step conversion of 36 to sulfoximine 37 with regio- and stereoselective addition of the cyclic and acyclic

complete retention of configuration had already been sulfonimidoyl-substituted bis(allyl)titanium complexes to

described.^[40,41]Sulfoximine 37, which is normally prepared aldehydes, (2) the stereoselective intramolecular amination

through an efficient resolution,^[29,42,43]can readily be meth- of sulfonimidoyl-substituted homoallylic alcohols by the

ylated to give sulfoximine 38,^[44]the starting material for carbamate method, (3) the substitution of protected β-am-

the synthesis of the allylic sulfoximines used in this work. ino sulfoximines with formation of protected β-amino chlo-

Treatment of sulfinamide 26 with methylmagnesium chlo- rides, (4) the generation of lithiated alkyl sulfoximines with

ride in THF at Ϫ78 °C resulted in the isolation of the protected lithiated β-amino groups, (5) their treatment with

sulfoxide 36 with 97% ee in 70% yield, so the synthesis of electrophiles, and (6) the reduction of the substituted sul-

36 from 26 represents a recycling of the chiral auxiliary.

foximines. The δ-hydroxy-β-amino acids and 1,3-amino al-

cohols described in this paper have protecting groups at the

O and the N atom. We are currently studying the conver-

sion of the β-amino nitriles into differently protected δ-

hydroxy-β-amino acids.

Substitution of an α-Methylated Sulfoximine

Substitution of the sulfonimidoyl groups of 5aϪc, 9, 15a,

and 15b, without further substituents at their α-positions,

by a Cl atom having been achieved, it was now of interest

to study the reactivity of the α-methylated sulfoximine 16a

towards chloroformates (Scheme 15). Interestingly, treat-

ment of sulfoximine 16a with ClCO₂CH(Cl)Me in the pres-

ence of pyridine in CH₂Cl₂at room temperature for 1 h

afforded a mixture of the unsaturated 1,3-amino alcohol

derivative 39 and the chloride 40 in a ratio of 8:1 in 91%

yield. This transformation could perhaps open a further

Experimental Section

General: The enantiomerically and diastereomerically pure homo-

allylic alcohols 2aϪc and 13b were synthesized from the allylic sul-

foximines 1aϪc and 12b, respectively, by literature procedures.^[18c]

The enantiomerically pure allylic sulfoximines 1aϪc,^[27](E)-6,^[27]

12a,^[31]and 12b^[31]were prepared from sulfoximine 38 by the one-

route to synthetically highly valuable unsaturated 1,3-amino pot procedure described previously.^[18c]All reactions were carried

out in absolute solvents under an argon atmosphere by use of syr-

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

Et₂O were distilled under argon from lead/sodium/benzophenone.

CH₂Cl₂and DMF were distilled from CaH₂. TLC: Merck silica

gel 60 F₂₅₄plates. Column chromatography: Merck silica gel 60

(0.063Ϫ0.200 mm. Melting points: Büchi, melting points are un-

corrected. Optical rotations: PerkinϪElmer Model 241, measure-

ments were made at approximately 22 °C, specific rotations are in

grad·mL/dm·g, and c is in g/100 mL. ¹H and ¹³C NMR: Varian

VXR 300, Varian Gemini 300, Varian Inova 400, and Varian Unity

500. Peaks in the ¹³C NMR spectra are denoted as ’’u’’ for carbons

with zero or two attached protons or ’’d’’ for carbons with one or

three attached protons, as determined from APT pulse sequences.

The following abbreviations are used to designate the multiplicity

of the peaks in ¹H NMR spectra: s ϭ singlet, d ϭ doublet, t ϭ

triplet, q ϭ quadruplet, quin ϭ quintet, sept ϭ septet, m ϭ mul-

tiplet, br. ϭ broad, symm. ϭ symmetrical and combinations

thereof. IR spectra: PerkinϪElmer PE 1759 FT, only peaks of ν˜ Ͼ

1000 cm^Ϫ1are listed, vs ϭ very strong, s ϭ strong, m ϭ medium,

and w ϭ weak. GC-MS (CI): Magnum Finnigan (HT-5: 25 m,

0.25 mm; 50 kPa He, 40 eV, MeOH). MS (EI): Varian MAT 212S,

70 eV. MS (CI): Finnigan SSQ 7000, 100 eV; only peaks of m/z Ͼ

80 and intensity Ͼ 10%, except for decisive ones, are listed.

alcohols (cf. Scheme 7).

Scheme 15. Substitution of an α-methylated sulfoximine

Conclusion

X-ray Analyses: The crystal data and the most salient experimental

parameters used in the X-ray measurements and in the crystal

structure analyses are reported in Table 1. The crystal structures

were solved by direct methods as implemented in the XTAL3.7

package of crystallographic routines.^[45]The molecular structures

were illustrated by use of the SCHAKAL 92 program.^[46,47]

We have presented a new method for the asymmetric syn-

thesis of protected cyclic and acyclic β-substituted and β,β-

disubstituted δ-hydroxy β-amino acids from aldehydes

through the use of sulfonimidoyl-substituted bis(allyl)titan-

ium complexes. The δ-hydroxy-β-amino acids are poten-

tially useful not only for the synthesis of glycosylated β-

peptides, but also for further derivatization of the amino

acids. The method described also permits the asymmetric

synthesis of protected cyclic and acyclic, unfunctionalized

and sulfonimidoyl-, chlorine-, and cyano-functionalized

1,3-amino alcohols with three contiguous stereogenic C

atoms and a secondary or tertiary C atom bearing the am-

General Procedure for the Conversion of Alcohols into Carbamates

(GP1): Trichloroacetyl isocyanate (1.05 mmol) was added at room

temperature to a solution of the alcohol (1.00 mmol) in THF

(20 mL). After the mixture had been stirred at room temperature

for 2 h, concentrated aqueous ammonia (3 mL) was added. Stirring

of the mixture was continued at room temperature for 1 h. Satu-

rated aqueous NH₄Cl (20 mL) was then added, and the mixture

ino group. The key steps of this method are: (1) the highly was extracted with CH₂Cl₂. The combined organic phases were

Eur. J. Org. Chem. 2003, 1500Ϫ1526 1511

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

Table 1. Crystal data and parameters of data collection for (Z)-7, 9, 16c, 18, 25, 31, and 32b

[a]

(Z)-7

9

16c

18

25

31

32b

Empirical formula

M_r

Color and habit

C₂₁H₂₇NO₂S

357.52

colorless,

irregular

C₂₂H₂₈N₂O₃S

400.54

colorless,

irregular

C₁₇H₂₆N₂O₃S 2 ϫ (C₁₂H₂₁NO₂)^[a]C₁₄H₂₃NO₄

C₁₆H₂₁NO₄

291.35

Colorless,

block

C₁₂H₂₀ClNO₂

245.75

Colorless,

irregular

338.47

2 ϫ 211.31

Colorless,

irregular

269.34

colorless,

irregular

colorless,

irregular

Crystal size, ca. mm

Crystal system

space group

0.6 ϫ 0.5 ϫ 0.2 0.13 ϫ 0.24 ϫ 0.56 0.3 ϫ 0.3 ϫ 0.3 0.3 ϫ 0.3 ϫ 0.3

orthorhombic monoclinic orthorhombic monoclinic

0.3 ϫ 0.3 ϫ 0.3 0.18 ϫ 0.28 ϫ 0.44 0.3 ϫ 0.3 ϫ 0.3

monoclinic

P2₁

5.8447(7)

12.713(2)

9.6417(9)

90.0

trigonal

P3₁21

9.9834(7)

27.063(3)

90.0

orthorhombic

P 2₁2₁2₁

9.138(4)

11.581(4)

12.053(5)

90.0

P2₁2₁2₁

7.394(2)

10.175(3)

26.481(5)

90.0

P2₁

P2₁2₁2₁

8.338(1)

9.397(1)

23.093(4)

90.0

P2₁

˚

a, A

11.625(1)

8.230(1)

12.144(2)

90.0

11.494(2)

9.266(1)

11.685(3)

90.0

˚

b, A

˚

c, A

α, °

β, °

γ, °

90.0

114.952(2)

90.0

101.69(2)

90.0

103.696(1)

90.0

120.0

90.0

3

˚

V, A

1992.3(9)

4

1053.4(2)

2

1809.4(4)

4

1218.7(4)

2 ϫ 2

696.9(2)

2

2336.0(4)

6

1275.5(9)

4

Z

D_calcd., g cm^Ϫ3

µ, mm^Ϫ1

1.192

1.263

1.242

1.152

1.283

1.243

1.280

1.537

0.178

1.677

0.615

0.764

0.089

2.544

Data collection

Diffractometer

CDA4

Bruker

CDA4

Bruker

CDA4

EnrafϪNonius SMART APEX

EnrafϪNonius EnrafϪNonius

EnrafϪNonius SMART

EnrafϪNonius

APEX

T, K

150

298

200

150

293

150

Radiation

λ, A

Scan method

Cu-K_α

1.54179

ω/2θ

Mo-K_α

0.71073

ω

Cu-K_α

1.54179

ω/2θ

Cu-K_α

1.54179

ω/2θ

Cu-K_α

1.54179

ω/2θ

Mo-K_α

0.71073

ω

Cu-K_α

1.54179

ω/2θ

˚

Θ_max., °

74.8

4612

3967

I Ͼ 2σ(I)

28.3

14686

5232

74.8

4148

3591

I Ͼ 2σ(I)

74.9

5373

4848

I Ͼ 2σ(I)

75.0

3000

2678

I Ͼ 2σ(I)

26.1

34565

3100

74.9

3038

2599

I Ͼ 2σ(I)

No. of data colld

No. of unique data

Obsevation criterion

Refinement

F Ͼ 4σ(F)

No. of parameters refined 226

No. of data observed in 3548

253

3668

209

2149

270

4478

172

2662

190

1886

145

2239

refinement

[b]

R, R_w

∆(ρ), e·A

0.059, 0.069

Ϫ0.90/ϩ0.70

1.969

0.042/0.042^[c]

Ϫ0.24/ϩ0.32

0.944

0.057, 0.061^[c]0.056/0.070

0.073/0.088

Ϫ0.53/ϩ0.52

4.675^[e]

0.090/0.101^[d]

Ϫ0.58/ϩ0.74

1.031

0.056/0.076

Ϫ0.63/ϩ0.65

2.908

Ϫ3

˚

Ϫ1.73/ϩ0.88

Ϫ0.33/ϩ0.37

GOF

1.351

2.700

[a]

[b]

Two symmetrically independent molecules. R ϭ Σ| |F_o| Ϫ |F_c| |/Σ|F_o|; Rw ϭ [Σw(|F_o| Ϫ |F_c|)²/Σw |F_o|²]⁰·⁵; w ϭ 1/σ²(F_o) where F_oand

[c]

2

[d]

[e]

F_care observed and calculated structure factors. w ϭ 1/[σ²(F_o) ϩ 0.0004·F_o]. w ϭ 1/[11·σ²(F_o)]. Poor crystal quality.

dried (MgSO₄) and concentrated in vacuo. Purification of the resi-

due by chromatography or crystallization afforded the carbamate.

General Procedure for the Reduction of Sulfoximines with Raney

Nickel (GP4): Raney nickel was prepared as follows: nickel alu-

minium alloy powder (50:50, 2.5 g) was suspended in desalted H₂O

(100 mL) and treated with KOH until the evolution of hydrogen

ceased. Subsequently, the suspension was heated at 80 °C for 30 min.

After the mixture had cooled to room temperature, the aqueous layer

was decanted, and the Raney nickel was washed with desalted H₂O

(10 ϫ 50 mL) and suspended in THF/H₂O (4:1, 50 mL).

General Procedure for the Conversion of Carbamates into Oxa-

zinones (GP2): nBuLi in hexane (1.05Ϫ1.30 mmol) was added at

Ϫ78 °C to a solution of the carbamate (1.0 mmol) in THF (40 mL).

The reaction mixture was then allowed to warm to room tempera-

ture over 18 h. Saturated aqueous NH₄Cl (40 mL) was added, and

the aqueous phase was extracted with CH₂Cl₂. The combined

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

Purification of the residue by chromatography or crystallization af-

forded the oxazinone.

The suspension was then added at room temperature to a solution

of the sulfoximine (0.71 mmol) in THF/H₂O (4:1, 5 mL). Sub-

sequently, the reaction mixture was stirred at room temperature

until TLC or GC indicated complete conversion of the sulfoximine.

The solution was then filtered, and the Raney nickel was washed

with THF (5 ϫ 25 mL). The combined organic phases were concen-

trated in vacuo, and the residue was dissolved in CH₂Cl₂. The aque-

ous phase was extracted with CH₂Cl₂and the combined organic

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

of the residue by chromatography or crystallization afforded the

reduction product.

General Procedure for the Introduction of Substituents at the α-Posi-

tions of Sulfoximines (GP3): nBuLi in hexane (3.00 mmol) was ad-

ded at Ϫ50 °C to a solution of the sulfoximine (1.00 mmol) in THF

(40 mL). The mixture was allowed to warm to Ϫ10 °C over 1 h,

cooled to Ϫ50 °C, and then treated with the electrophile. The mix-

ture was then allowed to warm to room temperature over 6 h, and

saturated aqueous NH₄Cl (50 mL) was added. The aqueous phase

was extracted with CH₂Cl₂, and the combined organic phases were

dried (MgSO₄). Concentration in vacuo gave the sulfoximine, which

was purified by chromatography or crystallization.

General Procedure for the Conversion of Sulfoximines into Esters by

the Carbanion Route (GP5): nBuLi in hexane (2.1 mmol) was added

1512

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

at Ϫ78 °C to a solution of the sulfoximine (1.0 mmol) in THF (2.02 g, 7.18 mmol) with trichloroacetyl isocyanate (0.89 mL,

FULL PAPER

(35 mL). After the mixture had been stirred at this temperature

for 2 h, the chloroformate (2.1 mmol) was added and stirring was

continued for 90 min. Subsequently, saturated aqueous NH₄Cl was orless solid: M.p. 209 °C. H NMR (300 MHz, CDCl₃): δ ϭ 0.47

7.54 mmol) according to GP1 and purification by crystallization

(Et₂O/CH₂Cl₂, 25:1) gave carbamate (Z)-4b (2.09 g, 90%) as a col-

1

added, and the aqueous phase was extracted with CH₂Cl₂. The

combined organic phases were concentrated in vacuo, and the ester

and the remaining starting sulfoximine were separated by chroma-

tography (EtOAc). The obtained functionalized sulfoximine was re-

duced with Raney nickel as in GP4, and the ester was purified by

chromatography (EtOAc/cyclohexane, 4:1).

(d, J ϭ 6.9 Hz, 3 H, iPr), 0.80 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.33 (d,

J ϭ 6.4 Hz, 3 H, Me), 1.60 (m, 1 H, iPr), 2.68 (s, 3 H, NMe), 3.31

(ddd, J ϭ 11.5, J ϭ 6.7, J ϭ 4.4 Hz, 1 H, CHiPr), 4.78 (br. s, 2 H,

NH₂), 5.04 (qd, J ϭ 6.4, J ϭ 4.4 Hz, 1 H, CHO) 6.13 (t, J ϭ

11.5 Hz, 1 H, SCHϭCH), 6.52 (d, J ϭ 11.5 Hz, 1 H, SCHϭCH),

7.50Ϫ7.60 (m, 3 H, Ph), 7.90 (m, 2 H, Ph) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 19.10 (d), 19.47 (d), 20.63 (d), 28.61 (d),

29.24 (d), 47.41 (d), 70.90 (d), 129.13 (d), 129.31 (d), 132.71 (d),

133.38 (d), 145.03 (d), 140.12 (u), 156.55 (u) ppm. IR (KBr): ν˜ ϭ

3856 (w), 3437 (s), 3328 (s), 3290 (s), 3201 (m), 3052 (m), 2999 (m),

2966 (s), 2926 (m), 2903 (m), 2862 (s), 2792 (m), 1735 (vs), 1701

(vs), 1627 (m), 1611 (m), 1582 (w), 1474 (m), 1446 (s), 1391 (s),

1360 (s), 1333 (s), 1317 (s), 1253 (vs), 1214 (s), 1144 (vs), 1103 (s),

1081 (s), 1070 (s), 1048 (vs), 1010 (m) cm^Ϫ1. MS (EI): m/z (relative

intensity, %) ϭ 325 [M^ϩϩ 1] (2), 324 [M^ϩ] (8), 265 (10), 264 (54),

236 (17), 156 (58), 126 (16), 125 (100), 111 (14), 109 (28), 108 (23),

107 (25), 97 (22), 96 (14), 93 (35), 91 (41), 83 (19), 81 (38).

C₁₆H₂₄N₂O₃S (324.44): calcd. C 59.23, H 7.46, N 8.63; found C

58.77, H 7.22, N 8.75.

General Procedure for the Conversion of Sulfoximines into Chlorides

(GP6): ClCO₂Me (15.0 mmol) was added at room temperature to

a solution of the sulfoximine (1.00 mmol) in CH₂Cl₂(12 mL). The

mixture was stirred at room temperature until TLC or GC indi-

cated almost complete conversion of the sulfoximine. Concen-

tration in vacuo and purification of the residue by chromatography

afforded the chloride.

General Procedure for the Conversion of Chlorides into Nitriles

(GP7): NaCN (2.00 mmol) was added at room temperature to a

solution of the chloride (1.00 mmol) in DMF (15 mL), and the re-

sulting mixture was heated with stirring at 105 °C for 2 h. After

the mixture had cooled to room temperature, the solvent was re-

moved in vacuo. The remaining solid was purified by chromatogra-

phy or recrystallization.

(2S,3R,4Z)- and (2S,3R,4E)-3-(1-Methylethyl)-5-[(S)-N-

methyl-S-phenylsulfonimidoyl]-5-penten-2-yl N-Trichloroacetyl-

carbamate [(Z)-3b and (E)-3b]: Trichloroacetyl isocyanate (49 µL,

0.41 mmol) was added at 0 °C to a solution of alcohol (Z)-2b

(78 mg, 0.28 mmol) in CH₂Cl₂(8 mL). After the mixture had been

stirred at 0 °C for 3.5 h, it was concentrated in vacuo to give a

mixture of (Z)-3b and (E)-3b in a ratio of 11:1, together with trich-

loroacetyl isocyanate (¹H NMR). Purification by chromatography

(EtOAc/hexane, 4:1) afforded a mixture of carbamates (Z)-3b and

(E)-3b (75 mg, 58%) in a ratio of 6:1 as a colorless solid.

General Procedure for the Conversion of Nitriles into Acids (GP8):

Aqueous NaOH (2 , 2 mL) was added to a solution of the nitrile

(0.32 mmol) in EtOH (8 mL), and the mixture was heated at reflux

for 3 h. After the mixture had cooled to room temperature, EtOH

was removed in vacuo and the solution was acidified with aqueous

3  HCl until a colorless solid precipitated. The mixture was then

extracted with CHCl₃, whereupon the solid dissolved, and the com-

bined organic phases were concentrated in vacuo. Purification by

chromatography or crystallization afforded the amino acid.

1

Compound (Z)-3b: H NMR (300 MHz, CDCl₃): δ ϭ 0.63 (d, J ϭ

6.7 Hz, 3 H, iPr), 0.78 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.45 (d, J ϭ

6.3 Hz, 3 H, Me), 1.74 (m, 1 H, iPr), 2.67 (s, 3 H, NMe), 3.52 (dt,

J ϭ 11.1, J ϭ 6.3 Hz, 1 H, CHiPr), 5.08 (quin, J ϭ 6.3 Hz, 1 H,

CHO), 6.17 (t, J ϭ 11.1 Hz, 1 H, SCHϭCH), 6.50 (d, J ϭ 11.1 Hz,

1 H, SCHϭCH), 7.54Ϫ7.66 (m, 3 H, Ph), 7.86 (m, 2 H, Ph), 9.65

(br. s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 17.71 (d),

18.90 (d), 21.01 (d), 28.01 (d), 29.46 (d), 47.50 (d), 73.92 (d), 77.38

(u), 129.27 (d), 129.70 (d), 133.24 (d), 133.97 (d), 143.56 (d), 139.07

(u), 150.30 (u), 158.56 (u) ppm, signal of CCl₃was not observed.

(3S,4R,5Z)- and (3S,4R,5E)-4-Methyl-6-[(S)-N-methyl-S-phenylsul-

fonimidoyl]-5-hexen-3-yl Carbamate [(Z)-4a and (E)-4a]: Treatment

of alcohol 2a (560 mg, 2.09 mmol) with trichloroacetyl isocyanate

(0.26 mL, 2.19 mmol) according to GP1 and purification by chro-

matography (EtOAc) gave a mixture of carbamates (Z)-4a and (E)-

4a (550 mg, 85%) in a ratio of 3:1 as a colorless solid:

1

Compound (Z)-4a: H NMR (300 MHz, CDCl₃): δ ϭ 0.68 (d, J ϭ

6.7 Hz, 3 H, CHMe), 0.93 (t, J ϭ 7.4 Hz, 3 H, Et), 1.42Ϫ1.70 (m,

2 H, Et), 2.69 (s, 3 H, NMe), 3.67 (m, 1 H, CHMe), 4.63 (m, 1 H,

CHO), 4.95 (br. s, 2 H, NH₂), 6.14 (t, J ϭ 11.1 Hz, 1 H, SCHϭ

CH), 6.39 (d, J ϭ 11.1 Hz, 1 H, SCHϭCH), 7.56 (m, 3 H, Ph),

7.91 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 9.62 (d),

15.96 (d), 26.12 (u), 29.27 (d), 35.27 (d), 78.37 (d), 128.88 (d),

129.34 (d), 131.71 (d), 132.69 (d), 146.82 (d), 140.50 (u), 157.23

(u) ppm.

1

Compound (E)-3b: H NMR (300 MHz, CDCl₃): δ ϭ 0.88 (d, J ϭ

6.7 Hz, 3 H, iPr), 0.98 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.19 (d, J ϭ

6.3 Hz, 3 H, Me), 1.85 (m, 1 H, iPr), 2.06 (m, 1 H, CHiPr), 2.77

(s, 3 H, NMe), 5.22 (quin, J ϭ 6.3, J ϭ 4.4 Hz, 1 H, CHO), 6.42

(d, J ϭ 15.0 Hz, 1 H, SCHϭCH), 6.78 (dd, J ϭ 15.0, J ϭ 10.4 Hz,

1 H, SCHϭCH), 7.50Ϫ7.64 (m, 3 H, Ph), 7.88 (m, 2 H, Ph), 8.50

(br. s, 1 H, NH) ppm.

(ϩ)-(3S,4R,5Z)-2-Methyl-6-[(S)-N-methyl-S-phenylsulfonimid-

1

Compound (E)-4a: H NMR (300 MHz, CDCl₃): δ ϭ 0.84 (t, J ϭ

oyl]-4-phenyl-5-hexen-3-yl

Carbamate

[(Z)-4c)]

and

(ϩ)-

7.4 Hz, 3 H, Et), 1.09 (d, J ϭ 6.9 Hz, 3 H, CHMe), 1.42Ϫ1.70 (m,

2 H, Et), 2.74 (s, 3 H, NMe), 2.60 (m, 1 H, CHMe), 4.63 (m, 1 H,

CHO), 4.82 (br. s, 2 H, NH₂), 6.39 (d, J ϭ 15.0 Hz, 1 H, SCHϭ

CH), 6.81 (dd, J ϭ 15.0, J ϭ 8.2 Hz, 1 H, SCHϭCH), 7.56 (m, 3

H, Ph), 7.91 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ

9.68 (d), 15.66 (d), 25.05 (u), 29.47 (d), 39.79 (d), 77.74 (d), 128.76

(d), 129.38 (d), 131.23 (d), 132.63 (d), 147.16 (d), 139.44 (u), 156.80

(u) ppm.

(3S,4R,5E)-2-Methyl-6-[(S)-N-methyl-S-phenylsulfonimidoyl]-4-

phenyl-5-hexen-3-yl Carbamate [(E)-4c]: Treatment of alcohol 2c

(1.47 g, 4.28 mmol) with trichloroacetyl isocyanate (0.53 mL,

4.49 mmol) according to GP1 and purification by chromatography

(EtOAc/iPrOH, 4:1) gave carbamates (Z)-4c (1.26 g, 76%) and (E)-

4c (270 mg, 16%) as colorless solids.

Compound (Z)-4c: M.p. 46Ϫ49 °C. [α]_Dϭ ϩ68.6 (c ϭ 0.60,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.89 (d, J ϭ 6.9 Hz, 3

H, iPr), 0.91 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.57 (septd, 1 H, J ϭ 6.9,

J ϭ 3.5 Hz, iPr), 2.68 (s, 3 H, NMe), 4.86 (m, 1 H, CHPh), 4.97

(2S,3R,4Z)-3-(1-Methylethyl)-5-[(S)-N-methyl-S-phenylsulfonimid-

oyl]-4-penten-2-yl Carbamate [(Z)-4b]: Treatment of alcohol 2b

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1513

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

(br. s, 2 H, NH₂), 4.98 (dd, J ϭ 9.4, J ϭ 3.5 Hz, 1 H, CHO), 6.39

82 (18), 81 (10). C₁₅H₂₂N₂O₃S (310.41): calcd. C 58.04, H 7.14, N

(d, J ϭ 11.0 Hz, 1 H, SCHϭCH), 6.47 (dd, J ϭ 11.0, J ϭ 11 Hz,1 9.02; found C 57.86, H 7.05, N 8.97.

H, SCHϭCH), 6.93Ϫ6.96 (m, 2 H, Ph), 7.15Ϫ7.21 (m, 3 H, Ph),

(؉)-(4S,5R,6S)-Tetrahydro-6-methyl-5-(1-methylethyl)-4-

7.43Ϫ7.57 (m, 3 H, Ph), 7.82Ϫ7.86 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 15.52 (d), 19.75 (d), 28.90 (d), 29.18 (d),

45.03 (d), 79.82 (d), 126.96 (d), 127.66 (d), 128.58 (d), 128.60 (d),

128.97 (d), 131.17 (d), 132.32 (d), 138.16 (u), 139.90 (u), 144.98 (d),

157.16 (u) ppm. IR (KBr): ν˜ ϭ 3428 (m), 3356 (m), 3171 (w), 3061

(w), 3030 (w), 2965 (m), 2935 (m), 2875 (m), 2803 (w), 1724 (s),

1600 (m), 1495 (m), 1448 (m), 1390 (s), 1331 (m), 1305 (m), 1246

{[(S)-N-methyl-S-phenylsulfonimidoyl]methyl}-2H-1,3-ox-

azin-2-one (5b): Treatment of carbamate 4b (1.63 g, 5.02 mmol)

with nBuLi (4.10 mL of 1.60  in hexane, 6.56 mmol) according to

GP2 and purification by crystallization (Et₂O) gave oxazinone 5b

(1.54 g, 94%) as a colorless solid. M.p. 113 °C, [α]_Dϭ ϩ130.5 (c ϭ

0.55, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.66 (d, J ϭ

7.1 Hz, 3 H, iPr), 0.79 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.32 (m, 1 H,

CHiPr), 1.35 (d, J ϭ 6.2 Hz, 3 H, Me), 1.63 (m, 1 H, iPr), 2.73 (s,

3 H, NMe), 3.14Ϫ3.26 (m, 2 H, CH₂S), (td, J ϭ 8.5, J ϭ 2.7 Hz,

1 H, CHNH), 4.15 (dq, J ϭ 9.4, J ϭ 6.2 Hz, 1 H, CHO), 7.22 (s,

1 H, NH), 7.60Ϫ7.73 (m, 3 H, Ph), 7.87 (m, 2 H, Ph) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ ϭ 18.80 (d), 18.98 (d), 20.02 (d), 27.29

(d), 29.20 (d), 47.42 (d), 48.16 (d), 62.21 (u), 74.30 (d), 129.35 (d),

129.90 (d), 133.69 (d), 137.13 (u), 154.03 (u) ppm. IR (KBr): ν˜ ϭ

3451 (m), 3241 (s), 3156 (s), 3046 (m), 3007 (m), 2971 (vs), 2930

(s), 1214 (m), 1184 (w), 1147 (s), 1110 (m), 1080 (m), 1041 (s) cm^Ϫ1

.

MS (EI): m/z (relative intensity, %) ϭ 387 [M^ϩϩ 1] (4), 386 (16),

343 (35), 326 (32), 300 (10), 271 (18), 171 (42), 170 (97), 156 (43),

155 (60), 146 (11), 145 (21), 144 (21), 143 (17), 129 (15), 128 (11),

127 (13), 125 (68), 118 (12), 117 (77), 116 (28), 115 (100), 109 (19),

97 (13), 91 (32). C₂₁H₂₆N₂O₃S (386.51): calcd.C 65.26, H 6.78, N

7.25; found C 64.97, H 6.79, N 7.24.

Compound (E)-4c: M.p. 56Ϫ58 °C. [α]_Dϩ62.1 (c ϭ 0.38, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ ϭ 0.81 (d, J ϭ 6.7 Hz, 3 H, iPr), (s), 2899 (s), 2874 (s), 2809 (m), 1733 (vs), 1579 (m), 1551 (w), 1465

0.82 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.57 (septd, 1 H, J ϭ 6.7, J ϭ 3.7 Hz,

(m), 1445 (s), 1425 (m), 1414 (m), 1394 (s), 1385 (s), 1369 (m), 1354

iPr), 2.70 (s, 3 H, NMe), 3.65 (7, J ϭ 9.1, 1 H, CHPh), 4.64 (s, 2 (m), 1345 (m), 1321 (m), 1294 (s), 1232 (s), 1187 (m), 1173 (m),

H, NH₂), 5.00 (dd, J ϭ 9.1, J ϭ 3.7 Hz, 1 H, CHO), 6.35 (dd, J ϭ

15.1, J ϭ 0.8 Hz, 1 H, SCHϭCH), 7.04 (dd, J ϭ 15.1, J ϭ 9.1 Hz,

1157 (s), 1147 (s), 1127 (m), 1110 (s), 1079 (s), 1066 (s), 1045 (m),

1007 (m) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ 325 [M^ϩ

ϩ

1 H, SCHϭCH), 7.19Ϫ7.34 (m, 5 H, Ph), 7.48Ϫ7.56 (m, 3 H, Ph), 1] (3), 296 (10), 295 (15), 171 (10), 170 (62), 156 (20), 154 (12), 140

7.85Ϫ7.89 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ (48), 128 (16), 127 (27), 126 (39), 125 (100), 112 (29), 110 (20), 109

15.39 (d), 19.62 (d), 28.99 (d), 29.30 (d), 50.88 (d), 78.97 (d), 127.36

(37), 107 (41), 106 (30), 105 (14), 97 (27), 94 (16), 91 (34), 88 (25),

(d), 127.93 (d), 128.64 (d), 128.91 (d), 129.04 (d), 131.39 (d), 132.33 84 (23), 83 (50), 82 (22), 81 (10). C₁₆H₂₄N₂O₃S (324.44): calcd. C

(d), 137.94 (u), 138.97 (u), 145.75 (d), 156.34 (u) ppm. IR (KBr):

ν˜ ϭ 3840 (m), 3426 (s), 3060 (w), 3030 (w), 2965 (m), 2935 (m),

2875 (m), 2804 (w), 2373 (w), 1725 (s), 1602 (m), 1563 (w), 1545

(w), 1496 (w), 1448 (m), 1385 (s), 1331 (m), 1243 (s), 1184 (w),

1150 (m), 1109 (w), 1081 (w), 1040 (s) cm^Ϫ1. MS (EI): m/z (relative

intensity, %) ϭ 387 [M^ϩϩ 1] (3), 386 (17), 271 (18), 270 (33), 261

(10), 248 (14), 225 (24), 200 (42), 193 (12), 191 (10), 171 (24), 170

(32), 158 (24), 156 (23), 146 (14), 145 (44), 144 (60), 125 (62), 117

(28), 116 (39), 115 (100), 107 (19), 106 (10), 91 (38). C₂₁H₂₆N₂O₃S

(386.51): calcd. C 65.26, H 6.78, N 7.25; found C 65.00, H 6.87,

N 7.02.

59.23, H 7.46, N 8.63; found C 58.89, H 7.46, N 8.63.

(؉)-(4S,5R,6S)-Tetrahydro-6-(1-methylethyl)-4-{[(S)-N-

methyl-S-phenylsulfonimidoyl]methyl}-5-phenyl-2H-1,3-ox-

azin-2-one (5c). From Carbamate (Z)-4c: Treatment of carbamate

(Z)-4c (1.63 g, 4.21 mmol) with nBuLi (2.76 mL of 1.60  in hex-

ane, 4.42 mmol) according to GP2 and purification by crystalliza-

tion (EtOAc/iPrOH, 1:1) and chromatography (EtOAc) of the re-

maining mother liquor gave oxazinone 5c (1.34 g, 83%) as a color-

less solid, together with sulfoximine 1c (20 mg, 2%).

From Carbamate (E)-4c: Treatment of carbamate (E)-4c (221 mg,

0.57 mmol) with nBuLi (0.37 mL of 1.60  in hexane, 0.60 mmol)

according to GP2 and purification by crystallization (EtOAc/iP-

rOH, 1:1) and chromatography (EtOAc) of the mother liquor gave

oxazinone 5c (183 mg, 82%) as a colorless solid, together with sul-

foximine 1c (5 mg, 3%).

(؉)-(4S,5R,6S)-Tetrahydro-6-ethyl-5-methyl-4-{[(S)-N-

methyl-S-phenylsulfonimidoyl]methyl}-2H-1,3-oxazin-2-one

(5a): Treatment of a mixture of carbamates (Z)-4a and (E)-4a

(928 mg, 2.99 mmol, in a ratio of 3:1) with nBuLi (2.43 mL of 1.60

 in hexane, 3.89 mmol) according to GP2 and purification by crys-

tallization (Et₂O) gave oxazinone 5a (863 mg, 93%) as a colorless 5c: M.p. 180 °C (dec.). [α]_Dϭ ϩ98.6 (c ϭ 0.70, CH₂Cl₂). ¹H NMR

1

solid. M.p. 240 °C, [α]_Dϭ ϩ179.1 (c ϭ 0.45, CH₂Cl₂). H NMR

(300 MHz, CDCl₃): δ ϭ 0.83 (d, J ϭ 6.9 Hz, 3 H, iPr), 0.96 (d,

(300 MHz, CDCl₃): δ ϭ 0.75 (d, J ϭ 6.7 Hz, 3 H, CHMe), 0.99 (t, J ϭ 6.9 Hz, 3 H, iPr), 1.40 (septd, J ϭ 6.9, J ϭ 1.7 Hz, 1 H, iPr),

J ϭ 7.4 Hz, 3 H, Et), 1.53 (m, 2 H, CHMe, Et), 1.80 (dqd, J ϭ 2.62 (t, J ϭ 10.6 Hz, 1 H, CHPh), 2.71 (s, 3 H, NMe), 2.76 (dd,

14.4, J ϭ 7.4, J ϭ 3.0 Hz, 1 H, Et), 2.71 (s, 3 H, NMe), 3.09 (dd, J ϭ 14.1, J ϭ 1.2 Hz, 1 H, CH₂S), 3.06 (dd, J ϭ 14.1, J ϭ 10.7 Hz,

J ϭ 14.0, J ϭ 10.3 Hz, 1 H, CH₂S), 3.26 (dd, J ϭ 14.0, J ϭ 1.0 Hz,

1 H, CH₂S), 3.31 (td, J ϭ 10.3, J ϭ 1.0 Hz, 1 H, CHNH), 3.85

1 H, CH₂S), 3.65 (ddd, J ϭ 10.7, J ϭ 10.6, J ϭ 1.2 Hz, 1 H,

CHNH), 4.20 (dd, J ϭ 10.6, J ϭ 1.7 Hz, 1 H, CHO), 6.75Ϫ6.78

(ddd, J ϭ 10.0, J ϭ 7.4, J ϭ 3.0 Hz, 1 H, CHO), 7.48 (s, 1 H, NH), (m, 2 H, Ph), 7.12Ϫ7.24 (m, 3 H, Ph), 7.49Ϫ7.56, 7.60Ϫ7.67 (m, 6

7.60Ϫ7.72 (m, 3 H, Ph), 7.86 (m, 2 H, Ph) ppm. ¹³C NMR H, Ph, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.12 (d),

(75 MHz, CDCl₃): δ ϭ 8.24 (d), 12.61 (d), 24.93 (u), 29.32 (d), 20.01 (d), 29.04 (d), 29.58 (d), 46.43 (d), 52.93 (d), 58.83 (u), 84.01

34.63 (d), 52.74 (d), 59.66 (u), 81.11 (d), 129.44 (d), 129.98 (d), (d), 127.97 (d), 128.49 (d), 129.41 (d), 129.60 (d), 129.85 (d), 133.65

133.80 (d), 136.89 (u), 153.20 (u) ppm. IR (KBr): ν˜ ϭ 3271 (s), (d), 134.97 (u), 136.51 (u), 153.12 (u) ppm. IR (KBr): ν˜ ϭ 3822 (s),

3061 (w), 2973 (m), 2929 (m), 2877 (m), 2802 (w), 1710 (vs), 1581 3278 (m), 3089 (w), 3066 (w), 3028 (w), 3003 (w), 2969 (m), 2916

(w), 1529 (w), 1469 (s), 1445 (s), 1418 (m), 1403 (m), 1386 (m), (m), 2880 (m), 2809 (w), 2734 (w), 2659 (w), 2579 (w), 2373 (w),

1362 (m), 1341 (m), 1310 (m), 1271 (m), 1242 (vs), 1143 (vs), 1106

2343 (w), 2183 (w), 2106 (w), 2001 (w), 1956 (w), 1931 (w), 1906

(s), 1078 (s), 1018 (s) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ (w), 1708 (s), 1604 (m), 1583 (m), 1525 (w), 1497 (w), 1449 (s), 1420

311 [M^ϩϩ 1] (2), 282 (12), 281 (21), 157 (13), 156 (75), 154 (14), (w), 1373 (m), 1326 (m), 1298 (w), 1246 (s), 1143 (s), 1105 (m),

140 (42), 126 (18), 125 (100), 112 (26), 107 (39), 106 (27), 105 (38),

98 (10), 97 (24), 96 (32), 95 (24), 94 (15), 91 (31), 88 (40), 83 (11), %) ϭ 387 [M^ϩϩ 1] (29), 235 (13), 234 (69), 233 (15), 132 (74), 156

1080 (m), 1037 (m), 1001 (w) cm^Ϫ1. MS (CI): m/z (relative intensity,

1514

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

(100). C₂₁H₂₆N₂O₃S (386.51): calcd. C 65.26, H 6.78, N 7.25; found

C 65.09, H 6.84, N 7.17.

N-Trichloroacetyl Carbamate: ¹H NMR (400 MHz, CDCl₃): δ ϭ

0.94 (d, J ϭ 6.9 Hz, 3 H, iPr), 0.99 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.72

(d, J ϭ 1.4 Hz, 3 H, Me), 1.87 (septd, J ϭ 6.9, J ϭ 1.9 Hz, 1 H,

iPr), 2.73 (s, 3 H, NMe), 5.39 (dd, J ϭ 11.0, J ϭ 1.9 Hz, 1 H,

CHO), 5.62 (d, J ϭ 11.0 Hz, 1 H, CHPh), 6.19 (d, J ϭ 1.4 Hz, 1

H, CϭCH), 7.05Ϫ7.09 (m, 2 H, Ph), 7.20Ϫ7.29 (m, 3 H, Ph),

7.56Ϫ7.66 (m, 3 H, Ph), 7.94Ϫ7.98 (m, 2 H, Ph), 9.24 (br. s, 1 H,

NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 14.71 (d), 20.20 (d),

20.65 (d), 29.01 (d), 29.22 (d), 46.23 (d), 77.78 (d), 127.22 (d),

128.50 (d), 128.55 (d), 128.87 (d), 128.92, (d), 129.35 (d), 132.51

(d), 136.90 (u), 139.69 (u), 152.57 (u), 154.17 (u), 154.62 (u) ppm,

signal of CCl₃was not observed.

(ϩ)-(3S,4R,5Z)-2,5-Dimethyl-6-[(S)-N-methyl-S-phenylsulfonimid-

oyl]-4-phenyl-5-hexen-3-ol [(Z)-7]: nBuLi (10.7 mL of 1.60  in hex-

ane, 17.0 mmol) was added at Ϫ78 °C to a solution of the allylic

sulfoximine (E)-6 (4.42 g, 15.5 mmol) in THF (85 mL). After the

mixture had been stirred at this temperature for 10 min,

ClTi(OiPr)₃(4.44 mL, 18.6 mmol) was added. The mixture was

then stirred at Ϫ78 °C for 10 min, allowed to warm to 0 °C, and

stirred at this temperature for 45 min. Subsequently, the mixture

was cooled to Ϫ78 °C and isobutyraldehyde (2.8 mL, 31.0 mmol)

was added dropwise. After the mixture had been stirred at Ϫ78 °C

for 80 min, it was poured into saturated aqueous (NH₄)₂CO₃and

extracted with EtOAc. The combined organic phases were dried

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

phy (EtOAc/cyclohexane, 4:1) gave alcohol (Z)-7 (3.27 g, 59%) as

a colorless solid, together with sulfoximine (E)-6 (1.01 g, 25%).

M.p. 105 °C. [α]_Dϭ ϩ194.7 (c ϭ 1.02, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 0.90 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.05 (d,

J ϭ 6.9 Hz, 3 H, iPr), 1.68 (septd, J ϭ 7.3, J ϭ 1.1 Hz, 1 H, iPr),

1.74 (d, J ϭ 1.4 Hz, 3 H, Me), 2.64 (s, 3 H, NMe), 4.10 (dd, J ϭ

11.1, J ϭ 1.3 Hz, 1 H, CHO), 5.04 (br. s, 1 H, OH), 5.21 (d, J ϭ

11.1 Hz, 1 H, CHPh), 6.32 (p, J ϭ 1.1 Hz, 1 H, CϭCH), 7.00Ϫ7.03

(m, 2 H, Ph), 7.17Ϫ7.28 (m, 3 H, Ph), 7.57Ϫ7.68 (m, 3 H, Ph),

7.94Ϫ7.98 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

13.80 (d), 19.64 (d), 20.94 (d), 29.36 (d), 29.74 (d), 50.68 (d), 74.74

(d), 126.87 (d), 128.34 (d), 128.82 (d), 128.90 (d), 128.94 (d), 129.29

(d), 132.66 (d), 138.00 (u), 139.59 (u), 156.94 (u) ppm. IR (KBr):

ν˜ ϭ 3222 (m), 3067 (m), 3032 (w), 2960 (s), 2935 (m), 2903 (s),

2869 (s), 2769 (m), 2319 (w), 1619 (m), 1601 (m), 1582 (w), 1494

(m), 1467 (m), 1444 (s), 1385 (m), 1298 (w), 1217 (s), 1159 (m),

1139 (s), 1100 (s), 1079 (s), 1034 (m), 1009 (m) cm^Ϫ1. MS (EI): m/

z (relative intensity, %) ϭ 358 [M^ϩϩ 1] (5), 314 (42), 206 (14), 205

(18), 202 (12), 185 (12), 184 (54), 160 (15), 159 (65), 158 (13), 156

(73), 132 (12), 131 (100), 130 (30), 129 (57), 128 (23), 127 (11), 125

(79), 116 (12), 115 (33), 91 (40). C₂₁H₂₇NO₂S (357.51): calcd. C

70.55, H 7.61, N 3.92; found C 70.88, H 7.63, N 3.89.

(؉)-(4S,5R,6S)-Tetrahydro-4-methyl-6-(1-methylethyl)-4-

{[(S)-N-methyl-S-phenylsulfonimidoyl]methyl}-5-phenyl-2H-

1,3-oxazin-2-one (9): Treatment of carbamate (Z)-8 (2.19 g,

5.47 mmol) with nBuLi (3.76 mL of 1.60  in hexane, 6.02 mmol)

according to GP2 and purification by crystallization (Et₂O) and

chromatography (EtOAc/iPrOH, 8:1) of the mother liquor gave ox-

azinone 9 as a colorless solid (1.83 g, 84%), together with the allylic

sulfoximine (E)-6 (160 mg, 10%). M.p. 178 °C. [α]_Dϭ ϩ59.8 (c ϭ

1.01, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.75 (d, J ϭ

7.0 Hz, 3 H, iPr), 1.05 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.52Ϫ1.59 (m, 1

H, iPr), 1.53 (s, 3 H, Me), 2.64 (s, 3 H, NMe), 3.03 (d, J ϭ 11.4 Hz,

1 H, CHPh), 3.19 (d, J ϭ 14.3 Hz, 1 H, CH₂S), 3.25 (d, J ϭ

14.3 Hz, 1 H, CH₂S), 4.66 (dd, J ϭ 11.4, J ϭ 1.8 Hz, 1 H, CHO),

7.10Ϫ7.12 (m, 2 H, Ph), 7.30Ϫ7.36 (m, 3 H, Ph), 7.71 (br. s, 1 H,

NH), 7.54Ϫ7.65 (m, 3 H, Ph), 7.78Ϫ7.82 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 14.43 (d), 19.78 (d), 23.90 (d), 28.79

(d), 28.59 (d), 50.85 (d), 56.53 (u), 64.83 (u), 79.42 (d), 128.15 (d),

128.54 (d), 128.77 (d), 129.54 (d), 133.12 (d), 133.76 (u), 139.45 (u),

154.59 (u) ppm. IR (KBr): ν˜ ϭ 3676 (m), 3653 (w), 3404 (s), 3067

(w), 3027 (w), 2971 (s), 2930 (m), 2878 (m), 2806 (m), 2285 (w),

1978 (w), 1706 (s), 1607 (m), 1583 (m), 1498 (m), 1459 (s), 1426 (s),

1390 (s), 1361 (m), 1333 (s), 1304 (m), 1240 (s), 1226 (s), 1184 (s),

1136 (s), 1097 (s), 1046 (s) cm^Ϫ1. MS (CI): m/z (relative intensity,

%) ϭ 401 [M^ϩϩ 1] (13), 249 (18), 248 (85), 246 (30), 156 (100).

C₂₂H₂₈N₂O₃S (400.54): calcd. C 65.97, H 7.05, N 6.99; found C

65.90, H 6.72, N 6.92.

(ϩ)-(3S,4R,5Z)-2,5-Dimethyl-6-[(S)-N-methyl-S-phenylsulfonimid-

oyl]-4-phenyl-5-hexen-3-yl Carbamate [(Z)-8]: Treatment of alcohol

(Z)-7 (4.21 g, 11.78 mmol) with trichloroacetyl isocyanate

(1.47 mL, 12.37 mmol) according to GP1 and purification by chro-

matography (EtOAc/iPrOH, 8:1) gave carbamate (Z)-8 (4.31 g,

89%) as a colorless solid, together with the corresponding N-trich-

loroacetyl carbamate (450 mg, 7%). M.p. 62Ϫ64 °C. [α]_Dϭ ϩ169.1

(c ϭ 0.72, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.90 (d, J ϭ

6.9 Hz, 3 H, iPr), 0.96 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.75 (septd, J ϭ

6.9, J ϭ 1.8 Hz, 1 H, iPr), 1.81 (d, J ϭ 1.1 Hz, 3 H, Me), 2.68 (s,

3 H, NMe), 5.15 (br. s, 2 H, NH₂), 5.31 (d, J ϭ 11.1 Hz, 1 H,

CHPh), 5.38 (dd, J ϭ 11.1, J ϭ 1.8 Hz, 1 H, CHO), 6.25 (d, J ϭ

1.4 Hz, 1 H, CϭCH), 6.84Ϫ6.87 (m, 2 H, Ph), 7.16Ϫ7.18 (m, 3 H,

Ph), 7.57Ϫ7.66 (m, 3 H, Ph), 7.97Ϫ7.99 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 14.76 (d), 20.01 (d), 20.88 (d), 29.07

(d), 29.18 (d), 46.66 (d), 75.86 (d), 126.99 (d), 128.17 (d), 128.34

(d), 128.83 (d), 128.91 (d), 129.27 (d), 132.36 (d), 137.36 (u), 140.42

(u), 154.59 (u), 157.32 (u) ppm. IR (KBr): ν˜ ϭ 3421 (s), 3357 (s),

3179 (m), 3061 (m), 3030 (m), 2965 (s), 2932 (m), 2875 (m), 2803

(w), 1724 (s), 1615 (s), 1601 (s), 1496 (m), 1467 (m), 1446 (s), 1393

(s), 1383 (s), 1334 (m), 1308 (m), 1236 (s), 1147 (s), 1105 (s), 1081

(s), 1047 (s), 1001 (w) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ

401 [M^ϩϩ 1] (3), 185 (24), 184 (100), 169 (30), 159 (17), 156 (25),

141 (11), 131 (12), 129 (25), 128 (16), 125 (23), 115 (11), 191 (14).

C₂₂H₂₈N₂O₃S (400.54): calcd. C 65.67, H 7.05, N 6.99; found C

65.63, H 7.12, N 6.91.

(؉)-(S)-S-[(1Z,3R,4S)-2,5-dimethyl-3-phenyl-4-(triethylsilyl-

oxy)hex-1-enyl]-N-methyl-S-phenylsulfoximine [(Z)-10]: Imidazole

(1.34 g, 19.65 mmol) and ClSiEt₃(1.0 mL, 5.9 mmol) were success-

ively added at room temperature to a solution of alcohol (Z)-7

(1.76 g, 4.92 mmol) in DMF (35 mL). After the mixture had been

stirred at room temperature for 12 h, half-saturated aqueous

NaHCO₃was added and the resulting mixture was extracted with

diethyl ether. The combined organic layers were dried (MgSO₄) and

concentrated in vacuo. Chromatography (EtOAc/cyclohexane, 1:1)

gave silyl ether (Z)-10 (2.30 g, 99%) as a colorless oil. [α]_D

ϭ

ϩ123.6 (c ϭ 2.04, EtOAc). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.55

(q, J ϭ 8.0 Hz, 6 H, Et), 0.80 (d, J ϭ 6.9 Hz, 3 H, iPr), 0.93 (t,

J ϭ 8.0 Hz, 9 H, Et), 1.02 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.66 (septd,

J ϭ 6.9, J ϭ 3.1 Hz, 1 H, iPr), 1.96 (d, J ϭ 1.4 Hz, 3 H, Me), 2.74

(s, 3 H, NMe), 4.21 (dd, J ϭ 8.7, J ϭ 3.2 Hz, 1 H, CHO), 5.33

(qd, J ϭ 8.7 Hz, 1 H, CHPh), 6.11 (q, J ϭ 1.1 Hz, 1 H, CϭCH),

6.98Ϫ7.02 (m, 2 H, Ph), 7.10Ϫ7.16 (m, 3 H, Ph), 7.35Ϫ7.44 (m, 3

H, Ph), 7.46Ϫ7.51 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 5.93 (u), 7.59 (d), 17.15 (d), 20.46 (d), 22.41 (d), 29.72

(d), 32.47 (d), 47.63 (d), 78.78 (d), 126.67 (d), 128.48 (d), 128.60

(d), 128.81 (d), 128.98 (d), 129.10 (d), 132.22 (d), 139.81 (u), 141.13

(u), 156.26 (u) ppm. IR (KBr): ν˜ ϭ 3060 (m), 3027 (w), 2958 (s),

2912 (s), 2876 (s), 2802 (m), 1614 (m), 1600 (m), 1583 (w), 1582

(w), 1494 (w), 1446 (m), 1415 (w), 1385 (w), 1373 (w), 1243 (s),

1182 (w), 1147 (s), 1107 (s), 1079 (s), 1010 (s) cm^Ϫ1. MS (EI): m/z

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1515

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

(relative intensity, %) ϭ 471 [M^ϩ] (1), 442 (24), 429 (17), 428 (56), (11), 160 (18), 156 (100), 140 (12), 133 (29), 132 (38), 131 (50), 129

316 (17), 301 (14), 287 (21), 274 (10), 273 (43), 206 (11), 205 (14), (13). C₂₁H₂₇NO₂S (357.51): calcd. C 70.55, H 7.61, N 3.92; found

187 (16), 185 (22), 184 (55), 159 (17), 156 (27), 129 (19), 125 (11), C 70.55, H 7.75, N 3.78.

116 (12), 115 (100), 103 (19). CI 472 [M^ϩ

1] (100).

ϩ

(؉)-(3S,4R,5E)-2,5-Dimethyl-6-[(S)-N-methyl-S-phenylsulfonimid-

oyl]-4-phenyl-5-hexen-3-yl Carbamate [(E)-8): Treatment of alcohol

(E)-7 (418 mg, 1.17 mmol) in THF (15 mL) with trichloroacetyl

isocyanate (0.15 mL, 1.23 mmol) according to GP1 and purifi-

cation by chromatography (EtOAc/iPrOH, 8:1) gave carbamate (E)-

8 (443 mg, 95%) as a colorless solid. M.p. 64Ϫ70 °C. [α]_Dϭ ϩ23.6

C₂₇H₄₁NO₂SSi (471.77): calcd. C 68.74. H 8.76, N 2.97; found C

68.36, H 8.93, N 3.15.

(؉)-(S)-S-[(1E,3R,4S)-2,5-Dimethyl-3-phenyl-4-(triethylsilyl-

oxy)-1-hexenyl]-N-methyl-S-phenylsulfoximine

[(E)-10]:

MeLi

(0.40 mL of 1.60  in Et₂O, 0.64 mmol) was added at Ϫ78 °C to a

solution of silyl ether (Z)-10 (200 mg, 0.42 mmol) in Et₂O (20 mL).

The mixture was warmed to Ϫ35 °C and stirred at this temperature

for 2 h. It was then cooled to Ϫ78 °C, and saturated aqueous

NH₄Cl was added. The aqueous phase was extracted with diethyl

ether and the combined organic layers were dried (MgSO₄) and

concentrated in vacuo. Chromatography (EtOAc/cyclohexane, 1:1)

1

(c ϭ 0.95, Et₂O). H NMR (400 MHz, CDCl₃): δ ϭ 0.77 (d, J ϭ

6.9 Hz, 3 H, iPr), 0.87 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.70 (septd, J ϭ

6.9, J ϭ 2.7 Hz, 1 H, iPr), 1.88 (d, J ϭ 0.8 Hz, 3 H, Me), 2.67 (s,

3 H, NMe), 3.59 (d, J ϭ 10.5 Hz, 1 H, CHPh), 4.69 (s, 2 H, NH₂),

5.28 (dd, J ϭ 10.5, J ϭ 2.7 Hz 1 H, CHO), 6.61 (br. d, J ϭ 0.8 Hz,

1 H, CϭCH), 7.16Ϫ7.19 (m, 2 H, Ph), 7.21Ϫ7.31 (m, 3 H, Ph),

7.47Ϫ7.56 (m, 3 H, Ph), 7.89Ϫ7.92 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 14.88 (d), 14.98 (d), 19.94 (d), 29.14 (d),

29.18 (d), 57.86 (d), 76.14 (d), 127.43 (d), 127.92 (d), 128.40 (d),

128.43 (d), 128.61 (d), 128.81 (d), 132.05 (d), 137.05 (u), 140.34 (u),

154.73 (u), 156.31 (u) ppm. IR (KBr): ν˜ ϭ 3428 (m), 3175 (w), 3061

(w), 3029 (w), 2965 (m), 2934 (m), 2874 (m), 2802 (w), 1724 (s),

1620 (m), 1496 (m), 1448 (m), 1389 (s), 1333 (s), 1236 (s), 1144 (s),

1107 (s), 1081 (m), 1043 (s) cm^Ϫ1. MS (EI): m/z (relative intensity,

%) ϭ 401 [M^ϩϩ 1] (3), 400 (30), 340 (40), 298 (14), 285 (12), 265

(32), 260 (19), 259 (14), 237 (18), 236 (14), 217 (11), 214 (17), 206

(40), 205 (52), 204 (11), 194 (11), 185 (11), 184 (23), 183 (10), 172

(12), 169 (28), 159 (11), 158 (30), 157 (11), 156 (33), 145 (31), 143

(18), 142 (100), 141 (21), 131 (24), 130 (47), 129 (100), 128 (64),

127 (18), 126 (11), 125 (64), 117 (16), 116 (11), 115 (43), 109 (12),

107 (10), 105 (25), 103 (10), 97 (10), 91 (72). C₂₂H₂₈N₂O₃S (400.54):

calcd. C 65.97, H 7.05, N 6.99; found C 65.82, H 7.21, N 6.94.

afforded silyl ether (E)-10 (186 mg, 93%) as a colorless oil. [α]_D

ϭ

ϩ27.4 (c ϭ 0.90, Et₂O). ¹H NMR (400 MHz, CDCl₃): δ ϭ

0.30Ϫ0.46 (m, 6 H, Et), 0.73 (d, J ϭ 6.7 Hz, 3 H, iPr), 0.82 (t, J ϭ

8.0 Hz, 9 H, Et), 0.89 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.68Ϫ1.73 (m, 1

H, iPr), 1.99 (d, J ϭ 1.1 Hz, 3 H, Me), 2.64 (s, 3 H, NMe), 3.42

(d, J ϭ 7.4 Hz, 1 H, CHPh), 4.02 (dd, J ϭ 7.4, J ϭ 4.0 Hz, 1 H,

CHO), 6.70 (br. s, 1 H, CϭCH), 7.07Ϫ7.11 (m, 2 H, Ph), 7.16Ϫ7.26

(m, 3 H, Ph), 7.46Ϫ7.56 (m, 3 H, Ph), 7.86Ϫ7.89 (m, 2 H, Ph)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 5.55 (u), 7.35 (d), 17.03

(d), 17.74 (d), 20.48 (d), 29.54 (d), 31.92 (d), 59.70 (d), 79.47 (d),

127.251 (d), 128.343 (d), 128.75 (d), 128.84 (d), 128.94 (d), 129.16

(d), 132.35 (d), 139.94 (u), 140.90 (u), 156.19 (u) ppm. IR (CHCl₃):

ν˜ ϭ 3061 (m), 3026 (m), 2957 (s), 2912 (s), 2876 (s), 2801 (m), 2732

(w), 1626 (m), 1600 (w), 1584 (w), 1494 (w), 1448 (m), 1416 (m),

1382 (m), 1243 (s), 1145 (s), 1106 (s), 1080 (s), 1009 (s) cm^Ϫ1. MS

(EI): m/z (relative intensity, %) ϭ 272 [M^ϩϩ 1] (3), 442 (21), 428

(10), 287 (12), 286 (11), 285 (50), 273 (24), 270 (10), 245 (11), 244

(26), 237 (17), 214 (17), 206 (38), 205 (43), 187 (55), 185 (14), 184

(15), 160 (17), 159 (56), 158 (14), 157 (11), 156 (24), 143 (10), 131

(17), 130 (29), 129 (40), 128 (15), 125 (19), 116 (15), 115 (100), 103

(23), 91 (16), 87 (69). C₂₇H₄₁NO₂SSi (471.77): calcd. C 68.74, H

8.76, N 2.97; found C 68.40, H 8.71, N 3.19.

(؉)-(4S,5R,6S)- and (؊)-(4R,5R,6S)-Tetrahydro-4-methyl-6-(1-

methylethyl)-4-{[(S)-N-methyl-S-phenylsulfonimidoyl]-

methyl}-5-phenyl-2H-1,3-oxazin-2-one (9 and epi-9): Treatment of

carbamate (E)-8 (453 mg, 1.13 mmol) with nBuLi (0.78 mL of 1.60

 in hexane, 1.24 mmol) according to GP2 and purification by

chromatography (EtOAc/iPrOH, 8:1) gave oxazinones 9 (279 mg,

62%) and epi-9 (65 mg, 14%) as colorless solids, together with (E)-

6 (32 mg, 10%) and (Z)-6 (26 mg, 8%).

(؉)-(3S,4R,5E)-2,5-Dimethyl-6-[(S)-N-methyl-S-phenyl-

sulfonimidoyl]-4-phenyl-5-hexen-3-ol [(E)-7]: Aqueous HCl (0.15 ,

13 mL) was added at room temperature to a vigorously stirred solu-

tion of the silyl ether (E)-10 (1.06 g, 2.25 mmol) in THF (15 mL)

and acetic acid (3 mL). Stirring of the mixture was continued at

this temperature for 2 h. The mixture was then neutralized by the

addition of saturated aqueous NaHCO₃and extracted with EtOAc.

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

trated in vacuo. Chromatography (EtOAc/cyclohexane, 4:1) af-

forded alcohol (E)-7 (660 mg, 82%) as a colorless solid. M.p. 135

°C. [α]_Dϭ ϩ4.0 (c ϭ 0.60, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃):

δ ϭ 0.81 (d, J ϭ 7.0 Hz, 3 H, iPr), 0.92 (d, J ϭ 7.0 Hz, 3 H, iPr),

1.51 (septd, J ϭ 7.0, J ϭ 2.8 Hz, 1 H, iPr), 1.89 (d, J ϭ 1.1 Hz, 3

H, Me), 2.60 (br. s, 1 H, OH), 2.65 (s, 3 H, NMe), 3.41 (d, J ϭ

9.9 Hz, 1 H, CHPh), 3.96 (dd, J ϭ 9.9, J ϭ 2.8 Hz, 1 H, CHO),

6.74 (br. s, 1 H, CϭCH), 7.09Ϫ7.13 (m, 2 H, Ph), 7.18Ϫ7.28 (m,

3 H, Ph), 7.46Ϫ7.55 (m, 3 H, Ph), 7.89Ϫ7.92 (m, 2 H, Ph) ppm.

¹³C NMR (100 MHz, CDCl₃): δ ϭ 14.16 (d), 16.78 (d), 20.52 (d),

29.22 (d), 29.27 (d), 59.42 (d), 75.16 (d), 127.12 (d), 127.40 (d),

128.18 (d), 128.37 (d), 128.54 (d), 128.83 (d), 132.00 (d), 138.21 (u),

140.26 (u), 156.17 (u) ppm. IR (KBr): ν˜ ϭ 3676 (w), 3652 (w), 3400

epi-9: M.p. 183Ϫ187 °C. [α]_Dϭ Ϫ63.4 (c ϭ 0.55, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ ϭ 0.75 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.03

(d, J ϭ 7.0 Hz, 3 H, iPr), 1.62 (septd, J ϭ 7.0, J ϭ 1.8 Hz, 1 H,

iPr), 1.67 (s, 3 H, Me), 2.59 (s, 3 H, NMe), 2.97 (m, 2 H, CH₂S),

3.56 (d, J ϭ 13.7 Hz, 1 H, CHPh), 4.46 (dd, J ϭ 11.4, J ϭ 1.9 Hz,

1 H, CHO), 7.02Ϫ7.03 (m, 2 H, Ph), 7.30Ϫ7.34 (m, 3 H, Ph),

7.54Ϫ7.65 (m, 4 H, Ph, NH), 7.78Ϫ7.81 (m, 2 H, Ph) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ ϭ 13.24 (d), 19.74 (d), 27.04 (d), 28.59

(d), 29.39 (d), 53.72 (d), 56.01 (u), 63.31 (u), 79.34 (d), 128.14 (d),

128.69 (d), 128.74 (d), 129.54 (d), 132.99 (d), 133.44 (u), 138.97 (u),

152.85 (u) ppm. IR (KBr): ν˜ ϭ 3676 (w), 3405 (m), 3060 (m), 3030

(w), 2967 (m), 2931 (m), 2875 (m), 2803 (w), 1710 (s), 1583 (w),

1498 (w), 1445 (m), 1384 (m), 1335 (w), 1302 (w), 1235 (s), 1182

(w), 1148 (m), 1105 (w), 1075 (m), 1044 (w) cm^Ϫ1. MS (CI): m/z

(relative intensity, %) ϭ 401 [M^ϩϩ 1] (34), 248 (21), 247 (18), 246

(100), 156 (73). C₂₂H₂₈N₂O₃S (400.54): calcd. C 65.97, H 7.05, N

6.99; found C 65.57, H 6.28, N 6.77.

(؊)-(αS,1R,2Z)-α-(1-Methylethyl)-2-{[(S)-N-methyl-S-phenyl-

(m), 3256 (m), 3062 (w), 3039 (w), 2967 (s), 2930 (m), 2905 (m), sulfonimidoyl]methylene}cyclopentylmethanol (13a): nBuLi (16.1 mL

2873 (m), 2802 (m), 2370 (w), 2343 (w), 1736 (w), 1703 (w), 1617 of 1.6  in hexane, 25.7 mmol) was added at Ϫ78 °C to a solution

(m), 1493 (m), 1465 (m), 1446 (s), 1381 (m), 1335 (w), 1302 (m), of the allylic sulfoximine 12a (5.77 g, 24.5 mmol) in THF (130 mL).

1229 (s), 1135 (s), 1108 (s), 1083 (s), 1004 (s) cm^Ϫ1. MS (CI): m/z After the mixture had been stirred at this temperature for 1 h,

(relative intensity, %) ϭ 358 [M^ϩϩ 1] (41), 287 (14), 286 (69), 187 ClTi(OiPr)₃(12.3 mL, 51.5 mmol) was added. The mixture was

1516

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

then stirred at Ϫ78 °C for 1 h, allowed to warm to 0 °C, and stirred

at this temperature for 2 h. Subsequently the mixture was cooled

to Ϫ78 °C, and isobutyraldehyde (4.7 mL, 51.5 mmol) was added

dropwise. The mixture was then allowed to warm to room tempera-

ture over a period of 5 h and was then poured into saturated aque-

ous (NH₄)₂CO₃and extracted with EtOAc. The combined organic

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

by chromatography (cyclohexane/EtOAc, 4:1) gave a mixture of al-

cohol 13a, sulfoximine 12a, and N-methyl-S-phenylsulfinamide in

a ratio of 45:12:1. This mixture was dissolved in DMF (200 mL),

and imidazole (7.06 g, 103.7 mmol) and ClSiEt₃(6.4 mL,

38.4 mmol) were added successively. After the mixture had been

stirred at room temperature for 12 h, half-saturated aqueous

NaHCO₃was added and the mixture was extracted with diethyl

ether. The combined organic layers were dried (MgSO₄) and con-

centrated in vacuo. Chromatography (EtOAc/hexane, 3:1) gave silyl

ether 13a-SiEt₃(7.34 g, 71%) as a colorless oil, together with sulfox-

imine 12a (750 mg, 13%). The silyl ether 13a-SiEt₃(7.34 g,

17.45 mmol) was dissolved in THF (200 mL), and acetic acid

(40 mL) and aqueous HCl (0.15 , 210 mL) were added to the vig-

orously stirred solution at room temperature. Stirring of the mix-

ture was continued at this temperature for 2 h. The mixture was

then neutralized by the addition of saturated aqueous NaHCO₃

solution and extracted with EtOAc. The combined organic phases

were dried (MgSO₄) and concentrated in vacuo. Chromatography

(EtOAc) afforded alcohol 13a (5.11 g, 68%, based on 12a) as a

colorless solid.

(307.44): calcd. C 66.41, H 8.20, N 4.55; found C 66.51, H 8.36,

N 4.55.

(Ϫ)-(αS,1R,2Z)-α-(1-Methylethyl)-2-{[(S)-N-methyl-S-phenyl-

sulfonimidoyl]-methylene]cyclopentylmethyl Carbamate (14a): Treat-

ment of alcohol 13a (2.38 g, 7.44 mmol) with trichloroacetyl isocy-

anate (0.96 mL, 8.13 mmol) according to GP1 and purification by

chromatography (EtOAc/iPrOH, 8:1) gave carbamate 14a (2.44 g,

90%) as a colorless solid, together with the corresponding N-tri-

chloroacetyl carbamate (370 mg, 10%). M.p. 45Ϫ47 °C. [α]_D

ϭ

Ϫ237.7 (c ϭ 1.85, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 1.03

(d, J ϭ 6.9 Hz, 3 H, iPr), 1.05 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.50Ϫ1.61

(m, 1 H, CH₂), 1.63Ϫ1.70 (m, 2 H, CH₂), 1.78Ϫ1.90 (m, 1 H, CH₂),

2.00 (septd, J ϭ 6.9, J ϭ 3.6 Hz, 1 H, iPr), 2.21Ϫ2.31 (m, 1 H,

CH₂), 2.61 (s, 3 H, NMe), 2.60Ϫ2.70 (m, 1 H, CH₂), 3.90Ϫ3.97

(m, 1 H, CHCϭC), 4.42 (dd, J ϭ 10.0, J ϭ 3.6 Hz, 1 H, CHO),

5.85 (br. s, 2 H, NH₂), 6.35 (m, 1 H, CϭCH), 7.52Ϫ7.58 (m, 3 H,

Ph), 7.86Ϫ7.89 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ ϭ 16.38 (d), 20.37 (d), 20.98 (u), 29.28 (d), 29.66 (u), 30.46 (d),

34.51 (u), 42.28 (d), 76.80 (d), 122.80 (d), 128.76 (d), 128.17 (d),

132.10 (d), 139.56 (u), 158.38 (u), 161.59 (u) ppm. IR (KBr): ν˜ ϭ

3410 (m), 3159 (m), 3062 (m), 2964 (s), 2875 (m), 2803 (m), 1723

(s), 1609 (m), 1467 (w), 1446 (m), 1380 (s), 1333 (s), 1306 (m), 1235

(s), 1152 (s), 1104 (m), 1079 (s), 1047 (s) cm^Ϫ1. MS (EI): m/z (rela-

tive intensity, %) ϭ 351 [M^ϩϩ 1] (2), 307 (29), 306 (81), 291 (20),

290 (100), 264 (14), 236 (13), 235 (87), 189 (12), 187 (15), 157 (12),

156 (39), 155 (37), 135 (25), 134 (26), 129 (12), 125 (60), 110 (10),

109 (26), 107 (17), 105 (11), 97 (12), 93 (11), 91 (17), 81 (16).

C₁₈H₂₆N₂O₃S (350.48): calcd. C 61.69, H 7.48, N 7.99; found C

61.56, H 7.48, N 7.91.

Compound 13a؊SiEt₃: [α]_Dϭ Ϫ249.5 (c ϭ 0.20, EtOAc). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 0.65Ϫ0.73 (m, 6 H, Et), 0.92 (d, J ϭ

6.9 Hz, 3 H, iPr), 0.96Ϫ1.02 (m, 12 H, Et, iPr), 1.41Ϫ1.53 (m, 1

H, CH₂), 1.63Ϫ1.81 (m, 3 H, iPr, CH₂), 2.06Ϫ2.16 (m, 1 H, CH₂),

2.30Ϫ2.38 (m, 1 H, CH₂), 2.51Ϫ2.63 (m, 1 H, CH₂), 2.71 (s, 3 H,

NMe), 3.54Ϫ3.62 (m, 1 H, CHCϭC), 4.33Ϫ4.37 (m, 1 H, CHO),

6.17Ϫ6.19 (m, 1 H), 7.49Ϫ7.58 (m, 3 H, Ph), 7.88Ϫ7.92 (m, 2 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 5.51 (u), 7.48 (d),

18.61 (d), 22.71 (d), 23.03 (u), 27.74 (u), 29.78 (d), 31.36 (d), 38.07

(u), 47.50 (d), 77.56 (d), 122.35 (d), 128.74 (d), 129.29 (d), 132.37

(d), 140.77 (u), 164.04 (u) ppm. IR (KBr): ν˜ ϭ 3062 (m), 2957 (s),

2876 (s), 2801 (m), 1624 (m), 1461 (s), 1447 (s), 1416 (m), 1389 (w),

1374 (w), 1241 (s), 1152 (s), 1118 (s), 1080 (s), 1008 (s) cm^Ϫ1. MS

(EI): m/z (relative intensity, %) ϭ 422 [M^ϩϩ 1] (2), 394 (10), 393

(31), 392 (95), 391 (93), 379 (14), 378 (56), 345 (11), 344 (47), 270

(32), 266 (13), 251 (24), 238 (16), 237 (15), 235 (74), 235 (11), 223

(19), 191 (14), 189 (14), 188 (11), 187 (67), 159 (48), 157 (15), 156

(28), 155 (27), 149 (12.84), 135 (13), 125 (15), 125 (14), 116 (14),

115 (100), 110 (11), 109 (19), 107 (17), 105 (11), 103 (33), 97 (13),

93 (10), 91 (13), 87 (86), 85 (10), 81 (14). C₂₃H₃₉NO₂SSi (421.72):

calcd. C 65.51, H 9.32, N 3.32; found C 65.38, H 9.23, N 3.65.

N-Trichloroacetyl Carbamate: ¹H NMR (400 MHz, CDCl₃): δ ϭ

1.07 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.09 (d, J ϭ 6.9 Hz, 3 H, iPr),

1.55Ϫ1.88 (m, 4 H, CH₂), 2.08 (septd, 1 H, J ϭ 6.9, J ϭ 3.4 Hz,

iPr), 2.22Ϫ2.34 (m, 1 H, CH₂), 2.48Ϫ2.58 (m, 1 H, CH₂), 2.69 (s,

3 H, NMe), 4.38Ϫ4.42 (m, 1 H, CHCϭC), 4.39 (dd, J ϭ 10.0, J ϭ

3.4 Hz, 1 H, CHO), 6.26 (br. d, J ϭ 1.4 Hz, 1 H, CϭCH),

7.49Ϫ7.62 (m, 3 H, Ph), 7.86Ϫ7.90 (m, 2 H, Ph), 10.43 (br. s, 1 H,

NH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 16.49 (d), 20.41 (d),

21.39 (u), 29.10 (d), 29.93 (u), 30.82 (d), 34.53 (u), 42.03 (d), 75.86

(d), 123.29 (d), 128.89 (d), 129.27 (d), 132.33 (u), 138.71 (u), 154.66

(u), 155.18 (u), 159.78 (u) ppm, signal of CCl₃was not observed.

(؊)-(αS,1R,2Z)-α-(1-Methylethyl)-2-{[(S)-N-methyl-S-phenyl-

sulfonimidoyl]methylene}cyclohexylmethyl Carbamate (14b): Treat-

ment of alcohol 13b (1.26 g, 3.92 mmol) with trichloroacetyl isocy-

anate (0.49 mL, 4.12 mmol) according to GP1 and purification by

chromatography (EtOAc/iPrOH, 4:1) gave carbamate 14b (1.29 g,

90%) as a colorless solid, together with the corresponding N-tri-

chloroacetyl carbamate (190 mg, 10%). M.p. 53Ϫ55 °C, [α]_D

ϭ

Ϫ210.0 (c ϭ 0.20, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.85

(d, J ϭ 6.8 Hz, 3 H, iPr), 0.91 (d, J ϭ 6.8 Hz, 3 H, iPr), 0.90Ϫ0.95

(m, 1 H), 1.10Ϫ1.40 (m, 3 H), 1.80Ϫ2.00 (m, 4 H), 2.50Ϫ2.60 (m,

4 H), 3.60 (dd, J ϭ 10.5, J ϭ 2.4 Hz, 1 H, CHCϭC), 4.95 (dd, J ϭ

10.5, J ϭ 2.2 Hz, 1 H, CHO), 5.00 (br. s, 2 H, NH₂), 6.30 (d, J ϭ

1.4 Hz, 1 H, CϭCH), 7.45Ϫ7.55 (m, 3 H, Ph), 7.80Ϫ7.85 (m, 2 H,

Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 14.70 (d), 20.15 (d),

20.33 (d), 20.46 (u), 27.76 (u), 28.60 (d), 29.33 (d), 33.61 (u), 38.35

(d), 75.47 (d), 126.73 (d), 129.10 (d), 129.26 (d) 132.37 (d), 141.32

1

Compound 13a: M.p. 53 °C. [α]_Dϭ Ϫ94.1 (c ϭ 1.70, CH₂Cl₂). H

NMR (400 MHz, CDCl₃): δ ϭ 0.99 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.07

(d, J ϭ 6.9 Hz, 3 H, iPr), 1.61Ϫ1.89 (m, 5 H, iPr, CH₂), 2.30Ϫ2.40

(m, 1 H, CH₂), 2.63 (s, 3 H, NMe), 2.64Ϫ2.74 (m, 1 H, CH₂), 3.22

(dd, J ϭ 10.6, J ϭ 2.0 Hz, 1 H, CHCϭC), 3.87Ϫ3.93 (m, 1 H,

CHO), 6.00 (br. s, 1 H, OH), 6.20Ϫ6.22 (m, 1 H, CϭCH),

7.52Ϫ7.62 (m, 3 H, Ph), 7.88Ϫ7.92 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 14.67 (d), 21.54 (d), 21.65 (u), 29.31 (d),

30.16 (u), 31.30 (d), 34.52 (u), 46.38 (d), 77.26 (d), 123.52 (d), (u), 157.83 (u), 159.84 (u) ppm. IR (KBr): ν˜ ϭ 3431 (s), 3356 (s),

128.89 (d), 129.48 (d), 132.89 (d), 139.97 (u), 164.21 (u) ppm. IR 3177 (m), 1723 (vs), 1654 (s), 1446 (s), 1240 (vs), 1148 (s) 1070 (s)

(KBr): ν˜ ϭ 3144 (s), 3024 (w), 2957 (s), 2870 (m), 2800 (w), 1627 cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ 365 [M^ϩϩ 1] (3), 364

[M^ϩ] (3), 304 (10), 116 (16), 156 (100), 149 (55), 148 (28), 133 (40),

125 (63), 123 (59), 105 (27), 91 (18). C₁₉H₂₈N₂O₃S (364.50): calcd.

C 62.61, H 7.69, N 7.69; found C 62.27, H 7.88, N 7.52.

(s), 1582 (w), 1447 (s), 1383 (w), 1365 (w), 1289 (w), 1218 (s), 1142

(s), 1101 (s), 1077 (s), 1020 (s) cm^Ϫ1. MS (CI): m/z (relative inten-

sity, %) ϭ 308 [M^ϩϩ 1] (100), 236 (43), 156 (48). C₁₇H₂₅NO₂S

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1517

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

N-Trichloroacetyl Carbamate: ¹H NMR (300 MHz, CDCl₃): δ ϭ

with nBuLi (1.09 mL of 1.60  in hexane, 1.74 mmol) and MeI

0.97 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.01 (d, J ϭ 6.7 Hz, 3 H, iPr), (0.50 mL, 8.03 mmol) according to GP3 gave a mixture of sulfoxi-

1.21Ϫ1.54 (m, 4 H, CH₂), 1.60Ϫ1.71 (m, 2 H, CH₂), 2.02Ϫ2.07 mines 16a, epi-16a, and 5a in a ratio of 18:2:1. Purification by chro-

(m, 4 H, iPr, CH₂), 2.41Ϫ2.47 (m, 1 H, CH₂), 2.67 (s, 3 H, NMe), matography (EtOAc/cyclohexane, 4:1) and crystallization (Et₂O)

3.95Ϫ4.05 (m, 1 H, CHCϭCH), 5.10 (dd, J ϭ 11.0, J ϭ 2.1 Hz, 1 afforded sulfoximine 16a (154 mg, 68%) as a colorless solid. M.p.

1

H, CHO), 6.26 (d, J ϭ 1.7 Hz, 1 H, CϭCH), 7.52Ϫ7.62 (m, 3 H,

147 °C. [α]_Dϭ ϩ134.0 (c ϭ 0.70, CH₂Cl₂). H NMR (500 MHz,

Ph), 7.88Ϫ7.94 (m, 2 H, Ph), 8.70 (br. s, 1 H, NH) ppm. ¹³C NMR CDCl₃): δ ϭ 0.68 (d, J ϭ 6.5 Hz, 3 H, CHMe), 1.00 (t, J ϭ 7.3 Hz,

(75 MHz, CDCl₃): δ ϭ 14.51 (d), 20.11 (d), 20.30 (u), 27.33 (u), 3 H, Et), 1.38 (d, J ϭ 7.0 Hz, 3 H, CH(Me)S], 1.51 (dquin, J ϭ

27.89 (u), 28.49 (d), 29.05 (d), 33.20 (u), 37.38 (d), 77.47 (d), 126.23 14.8, J ϭ 7.3 Hz, 1 H, Et), 1.57 (tq, J ϭ 10.0, J ϭ 6.5 Hz, 1 H,

(d), 128.70 (d), 129.10 (d), 132.35 (d), 139.83 (u), 153.74 (u), 154.42 CHMe), 1.78 (dqd, J ϭ 14.8, J ϭ 7.3, J ϭ 3.0 Hz, 1 H, Et), 2.71

(u), 157.65 (u) ppm, signal of CCl₃was not observed.

(s, 3 H, NMe), 3.07 (brq, J ϭ 7.0 Hz, 1 H, CHS), 3.50 (dd, J ϭ

10.0, J ϭ 1.0 Hz, 1 H, CHNH), 3.81 (ddd, J ϭ 10.0, J ϭ 7.3, J ϭ

3.0 Hz, 1 H, CHO), 7.12 (s, 1 H, NH), 7.62 (m, 2 H, Ph), 7.68 (m,

1 H, Ph), 7.82 (m, 2 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ ϭ 5.82 (d), 8.32 (d), 12.44 (d), 24.89 (u), 29.06 (d), 32.58 (d),

55.09 (d), 59.94 (d), 80.91 (d), 129.71 (d), 133.52 (d), 136.07 (u),

154.17 (u) ppm. IR (KBr): ν˜ ϭ 3397 (m), 3226 (vs), 3089 (m), 3066

(m), 2974 (vs), 2944 (s), 2921 (s), 2880 (s), 2805 (m), 1708 (vs), 1582

(w), 1529 (w), 1463 (s), 1448 (s), 1417 (s), 1405 (s), 1387 (m), 1377

(m), 1358 (s), 1332 (m), 1304 (s), 1268 (s), 1237 (vs), 1227 (vs), 1174

(؉)-(4S,4aR,7aS)-Hexahydro-4-(1-methylethyl)-7a-{[(S)-N-methyl-

S-phenylsulfonimidoyl]methyl}cyclopenta[d][1,3]oxazin-2(1H)-one

(15a): Treatment of carbamate 14a (2.35 g, 6.71 mmol) with nBuLi

(4.39 mL of 1.6  in hexane, 7.02 mmol) according to GP2 and

purification by crystallization (Et₂O) and chromatography (EtOAc/

iPrOH, 8:1) of the mother liquor gave oxazinone 15a as a light

yellow solid (1.88 g, 80%), together with sulfoximine 12a (93 mg,

6%). M.p. 147 °C. [α]_Dϭ ϩ84.5 (c ϭ 0.40, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 0.89 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.05 (d,

J ϭ 7.0 Hz, 3 H, iPr), 1.46Ϫ1.54 (m, 1 H, CH₂), 1.61Ϫ1.71 (m, 1

H, CH₂), 1.76Ϫ2.00 (m, 5 H, CH₂, iPr), 2.62Ϫ2.69 (m, 1 H,

CHCNH), 2.67 (s, 3 H, NMe), 3.26 (dd, J ϭ 14.3, J ϭ 0.8 Hz, 1

H, CH₂S), 3.55 (d, J ϭ 14.3 Hz, 1 H, CH₂S), 3.72 (dd, J ϭ 9.9,

J ϭ 3.0 Hz, 1 H, CHO), 6.82 (s, 1 H, NH), 7.56Ϫ7.66 (m, 3 H,

(m), 1148 (s), 1133 (vs), 1107 (s), 1078 (s), 1060 (m), 1028 (s) cm^Ϫ1

.

MS (EI): m/z (relative intensity, %) ϭ 325 [M^ϩϩ 1] (5), 183 (20),

170 (22), 169 (76), 156 (39), 154 (20), 126 (44), 125 (100), 110 (90),

107 (17), 106 (18), 105 (31), 97 (18), 96 (44). C₁₆H₂₄N₂O₃S (324.44):

calcd. C 59.23, H 7.46, N 8.63; found C 58.99, H 7.40, N 8.59.

Ph), 7.84Ϫ7.88 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): (4S,5R,6S)-Tetrahydro-6-methyl-5-(1-methylethyl)-4-{[(S)-

δ ϭ 15.10 (d), 19.82 (d), 22.93 (u), 27.16 (u), 28.90 (d), 29.67 (d), N-methyl-S-phenylsulfonimidoyl)deuteriomethyl}-2H-1,3-ox-

38.52 (u), 44.78 (d), 63.28 (u), 65.64 (u), 82.80 (d), 128.47 (d), azin-2-one (16b and epi-16b): Successive treatment of sulfoximine

129.57 (d), 133.00 (d), 139.59 (u), 154.83 (u) ppm. IR (KBr): ν˜ ϭ 5b (46 mg, 0.14 mmol) with nBuLi (0.27 mL of 1.60  in hexane,

3404 (w), 3309 (m), 2968 (s), 2918 (m), 2888 (m), 2805 (m), 1707 0.43 mmol) and CD₃OD (0.5 mL) according to GP3 gave a mixture

(s), 1579 (w), 1447 (m), 1432 (m), 1415 (m), 1396 (m), 1372 (m),

1330 (m), 1295 (m), 1237 (s), 1196 (w), 1141 (s), 1103 (m), 1074

(m), 1015 (s) cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ 351 [M^ϩ

ϩ 1] (16), 199 (17), 198 (100), 196 (26), 156 (67). C₁₈H₂₆N₂O₃S

(350.48): calcd. C 61.69, H 7.48, N 7.99; found C 61.64, H 7.45,

N 7.75.

of sulfoximines 16b and epi-16b in a ratio of 3:1 (46 mg, 99%) as a

yellow oil. H NMR (300 MHz, CDCl₃): δ ϭ 0.66 (d, J ϭ 7.1 Hz,

1

3 H, iPr), 0.79 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.32 (td, J ϭ 9.2, J ϭ

2.5 Hz, 1 H, CHiPr), 1.35 (d, J ϭ 6.2 Hz, 3 H, Me), 1.63 (septd,

J ϭ 7.1, J ϭ 2.5 Hz, 1 H, iPr), 2.73 (s, 3 H, NMe), 3.18 (br. d, J ϭ

10.2 Hz, 0.25 H, CH₂S), 3.24 (br. s, 0.75 H, CH₂S), 3.58 (br. d, J ϭ

9.0 Hz, 1 H, CHNH), 4.15 (dq, J ϭ 9.2, J ϭ 6.2 Hz, 1 H, CHO),

7.22 (s, 1 H, NH), 7.60Ϫ7.73 (m, 3 H, Ph), 7.87 (m, 2 H, Ph) ppm.

¹³C NMR (75 MHz, CDCl₃): δ ϭ 18.80 (d), 18.98 (d), 20.02 (d),

27.29 (d), 29.20 (d), 47.42 (d), 48.16 (d), 62.21 (u), 74.30 (d), 129.35

(d), 129.90 (d), 133.69 (d), 137.13 (u), 154.03 (u) ppm.

(؉)-(4S,4aR,8aS)-Octahydro-4-(1-methylethyl)-8a-{[(S)-

N-methyl-S-phenylsulfonimidoyl]methyl}-2H-3,1-benzox-

azin-2-one (15b): Treatment of carbamate 14b (1.15 g, 3.15 mmol)

with nBuLi (2.1 mL of 1.60  in hexane, 3.32 mmol) according to

GP2 and purification by crystallization (EtOAc) gave oxazinone

15b (965 mg, 84%) as a light yellow solid. M.p. 206Ϫ207 °C, [α]_Dϭ

ϩ89.3 (c ϭ 0.70, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.80

(؉)-(4S,5R,6S)-Tetrahydro-6-methyl-5-(1-methylethyl)-4-{(1R)-

1-[(S)-N-methyl-S-phenylsulfonimidoyl]ethyl}-2H-1,3-oxazin-

(d, J ϭ 6.7 Hz, 3 H, iPr), 1.10 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.15Ϫ1.80 2-one (16c): Successive treatment of sulfoximine 5b (162 mg,

(m, 8 H, CH₂), 1.95 (septd, J ϭ 7.0, J ϭ 2.0 Hz, 1 H, iPr), 0.50 mmol) with nBuLi (0.80 mL of 1.60  in hexane, 1.28 mmol)

2.55Ϫ2.60 (m, 1 H, CHCNH), 2.70 (s, 3 H, NMe), 3.10 (dd, J ϭ and MeI (0.40 mL, 6.43 mmol) according to GP3 gave a mixture

14.4, J ϭ 1.6 Hz, 1 H, CH₂S), 3.90 (dd, J ϭ 14.4, J ϭ 2.2 Hz, 1 of sulfoximines 16c, epi-16c, and 5b in a ratio of 10:2:1. Purification

H, CH₂S), 4.30 (dd, J ϭ 10.4, J ϭ 2.0 Hz, 1 H, CHO), 7.50 (s, 1

by chromatography (EtOAc/cyclohexane, 4:1) afforded sulfoximine

H, NH), 7.55Ϫ7.65 (m, 3 H, Ph), 7.80Ϫ7.85 (m, 2 H, Ph) ppm. 16c (127 mg, 75%) and a mixture of epi-16c and 5b (16 mg) in a

¹³C NMR (75 MHz, CDCl₃): δ ϭ 13.44 (d), 19.84 (d), 20.05 (u),

22.31 (u), 28.01 (d), 29.67 (d), 33.55 (u), 39.00 (d), 55.88 (u), 62.66

(u), 78.39 (d) 128.81 (d), 128.95 (d), 129.76 (d), 133.31 (d), 140.06

(u), 153.18 (u) ppm. IR (KBr): ν˜ ϭ 3390(s), 2967 (s), 2934 (s), 2884

ratio of 5:1 as colorless solids.

Compound 16c: M.p. 134 °C, [α]_Dϭ ϩ140.4 (c ϭ 0.29, CH₂Cl₂).

¹H NMR (500 MHz, CDCl₃): δ ϭ 0.55 (d, J ϭ 7.1 Hz, 3 H, iPr),

0.73 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.34 (d, J ϭ 6.4 Hz, 3 H, CHMe),

1.33Ϫ1.58 (m, CHiPr), 1.40 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.40 [d, J ϭ

7.0 Hz, 3 H, CH(Me)S], 1.58 (m, 1 H, iPr), 2.73 (s, 3 H, NMe),

3.03 (m, 1 H, CHS), 3.76 (br. d, J ϭ 9.0 Hz, 1 H, CHNH), 4.08

(dq, J ϭ 10.4, J ϭ 6.1 Hz, 1 H, CHO), 6.98 (s, 1 H, NH), 7.62 (m,

2 H, Ph), 7.68 (m, 1 H, Ph), 7.84 (m, 2 H, Ph) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ ϭ 5.82 (d), 18.46 (d), 18.66 (d), 19.76 (d),

(m), 1699 (vs), 1580 (w), 1441 (s), 1373 (m), 1277 (s), 1169 (s) cm^Ϫ1

.

MS (EI): m/z (relative intensity, %) ϭ 365 [M^ϩϩ 1] (1), 364 [M^ϩ]

(1), 336 (28), 321 (14), 210 (45), 170 (34), 167 (16), 166 (37), 156

(17), 150 (57), 140 (100), 138 (28), 125 (50), 95 (39). C₁₉H₂₈N₂O₃S

(364.50): calcd. C 62.61, H 7.69, N 7.69; found C 62.30, H 7.91,

N 7.55.

(؉)-(4S,5R,6S)-Tetrahydro-6-ethyl-5-methyl-4-{(1R)-1-[(S)- 27.03 (d), 28.95 (d), 45.84 (d), 50.34 (d), 62.76 (d), 74.19 (d), 129.74

N-methyl-S-phenylsulfonimidoyl]ethyl}-2H-1,3-oxazin-2-one (d), 129.84 (d), 133.52 (d), 136.52 (u), 155.65 (u) ppm. IR (KBr):

(16a): Successive treatment of sulfoximine 5a (216 mg, 0.70 mmol) ν˜ ϭ 3854 (m), 3399 (w), 3231 (s), 3089 (m), 3061 (m), 2995 (s),

1518

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

2975 (vs), 2938 (s), 2901 (s), 2878 (s), 2813 (m), 1718 (vs), 1713 2.79 (s, 3 H, NMe), 3.04 (br. d, J ϭ 5.6 Hz, 1 H, CHS), 3.69 (br.

(vs), 1581 (w), 1531 (w), 1466 (s), 1445 (s), 1423 (m), 1403 (m), d, J ϭ 10.1 Hz, 1 H, CHNH), 4.04 (m, 1 H, CHO), 4.64 (quin,

1392 (s), 1375 (s), 1364 (m), 1350 (m), 1330 (w), 1307 (s), 1284 (m), J ϭ 6.3 Hz, 1 H, CHOH), 6.55 (s, 1 H, NH), 7.60Ϫ7.76 (m, 3 H,

1268 (m), 1244 (vs), 1233 (vs), 1188 (m), 1150 (s), 1129 (s), 1112

Ph), 7.85Ϫ7.92 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃):

(s), 1078 (s), 1051 (s), 1018 (s) cm^Ϫ1. MS (EI): m/z (relative inten- δ ϭ 17.03 (d), 19.92 (d), 20.22 (d), 23.14 (d), 26.68 (d), 29.06 (d),

sity, %) ϭ 339 [M^ϩϩ 1] (1), 184 (18), 183 (70), 156 (34), 154 (24), 45.47 (d), 51.33 (d), 65.84 (d), 70.50 (d), 74.58 (d), 129.92 (d),

141 (100), 138 (11), 126 (66), 125 (65), 124 (30), 112 (11), 110 (17),

109 (10), 107 (23), 106 (18), 105 (30), 98 (10), 97 (23), 96 (22), 83

(13), 82 (17), 81 (15). C₁₇H₂₆N₂O₃S (338.5): calcd. C 60.33, H 7.74,

N 8.28; found C 60.08, H 7.71, N 8.18.

130.10 (d), 134.15 (d), 137.12 (u), 154.53 (u).

1

Compound epi-16e: H NMR (300 MHz, CDCl₃) signals for epi-16

are partially superposed by those for 16; only those signals that

could be unequivocally assigned are listed: δ ϭ 0.37 (d, J ϭ 7.1 Hz,

3 H, iPr), 0.67 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.33 (d, J ϭ 6.0 Hz, 3 H,

CHMe), 1.76 [d, J ϭ 6.5 Hz, 3 H, CH(OH)Me], 1.83 (td, J ϭ 9.5,

J ϭ 2.0 Hz, 1 H, CHiPr), 2.77 (s, 3 H, NMe), 3.14 (bdd, J ϭ 3.7,

J ϭ 1.0 Hz, 1 H, CHS), 3.62 (br. d, J ϭ 9.5 Hz, 1 H, CHNH), 4.04

(m, 1 H, CHO), 4.53 (m, 1 H, CHOH), 7.17 (s, 1 H, NH),

7.60Ϫ7.76 (m, 3 H, Ph), 7.85Ϫ7.92 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃) only those signals are listed, which could be

unequivocally assigned: δ ϭ 17.85 (d), 23.20 (d), 27.00 (d), 45.38

(d), 50.75 (d), 65.29 (d), 71.07 (d), 74.42 (d), 136.19 (u), 155.33

(u) ppm.

Compound epi-16c: ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.84 (d, J ϭ

6.7 Hz, 3 H, iPr), 0.88 (d, J ϭ 6.5 Hz, 3 H, iPr), 1.21 [d, J ϭ 7.2 Hz,

3 H, CH(Me)S], 1.41 (d, J ϭ 6.7 Hz, 3 H, CHMe), 1.52 (m, 1 H,

CHiPr), 1.68 (m, 1 H, iPr), 2.73 (s, 3 H, NMe), 3.33 (dq, J ϭ 8.7,

J ϭ 7.2 Hz, 1 H, CHS), 3.63 (m, 1 H, CHNH), 4.40 (qd, J ϭ 6.7,

J ϭ 3.7 Hz, 1 H, CHO), 7.45 (s, 1 H, NH), 7.58Ϫ7.72 (m, 3 H,

Ph), 7.81 (m, 2 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ ϭ

12.85 (d), 19.40 (d), 20.44 (d), 20.69 (d), 29.45 (d), 30.86 (d), 43.48

(d), 52.49 (d), 66.02 (d), 73.58 (d), 129.60 (d), 130.66 (d), 133.59

(d), 137.36 (u), 153.27 (u) ppm.

(؉)-(4S,5R,6S)-Tetrahydro-6-methyl-5-(1-methylethyl)-4-[(1S)-

1-[(S)-N-methyl-S-phenylsulfonimidoyl)-2-(phenylmethoxy)-

ethyl]-2H-1,3-oxazin-2-one (16d): Successive treatment of sulfox-

imine 5b (207 mg, 0.64 mmol) with nBuLi (1.21 mL of 1.60  in

hexane, 1.93 mmol) and PhCH₂OCH₂Cl (0.67 mL, 4.79 mmol) ac-

cording to GP3 and purification by chromatography (EtOAc/cyclo-

hexane, 4:1) afforded sulfoximine 16d (198 mg, 70%) as a slightly

(؉)-(4S,5R,6S)-Tetrahydro-4-methyl-6-(1-methylethyl)-4-{[(S)-

N-methyl-S-phenylsulfonimidoyl]deuteriomethyl}-5-phenyl-2H-

1,3-oxazin-2-one (9-D and epi-9-D): Successive treatment of sulfox-

imine 9 (85 mg, 0.21 mmol) with nBuLi (0.29 mL of 1.60  in hex-

ane, 0.46 mmol) and CD₃OD (0.75 mL) according to GP3 gave a

mixture of sulfoximines 9-D and epi-9-D in a ratio of 1.1:1 (84 mg,

1

99%) as a light yellow oil. H NMR (400 MHz, CDCl₃): δ ϭ 0.75

1

yellow oil. [α]_Dϭ ϩ81.2 (c ϭ 1.05, CH₂Cl₂). H NMR (300 MHz,

(d, J ϭ 6.9 Hz, 3 H, iPr), 1.05 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.52Ϫ1.59

(m, 1 H, iPr), 1.53 (s, 3 H, Me), 2.64 (s, 3 H, NMe), 3.03 (d, J ϭ

11.3 Hz, 1 H, CHPh), 3.18 (s, 0.5 H, CHD), 3.23 (s, 0.5 H, CHD),

4.65 (dd, J ϭ 11.3, J ϭ 1.9 Hz, 1 H, CHO), 7.10Ϫ7.13 (m, 2 H,

Ph), 7.30Ϫ7.37 (m, 3 H, Ph), 7.54Ϫ7.65 (m, 3 H, Ph), 7.70 (br. s,

1 H, NH), 7.78Ϫ7.82 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 14.44 (d), 19.79 (d), 23.90 (d), 28.81 (d), 28.58 (d),

50.87 (d), 56.47 (u), 64.50 (d), 79.44 (d), 128.15 (d), 128.56 (d),

128.78 (d), 129.54 (d), 133.12 (d), 133.79 (u), 139.46 (u), 152.54

(u) ppm.

(؊)-(4R,5R,6S)-Tetrahydro-4,6-dimethyl-5-(1-methyl-

ethyl)-2H-1,3-oxazin-2-one (17a): Treatment of sulfoximine 5b

(230 mg, 0.71 mmol) with Raney nickel, prepared from 2.5 g Ni/

Al, for 5.5 h according to GP4 and purification by chromatography

(EtOAc/cyclohexane, 4:1) afforded oxazinone 17a (107 mg, 88%) as

a colorless solid. M.p. 54 °C. [α]_Dϭ Ϫ44.7 (c ϭ 0.55, CH₂Cl₂). ¹H

NMR (300 MHz, CDCl₃): δ ϭ 0.97 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.01

(d, J ϭ 7.1 Hz, 3 H, iPr), 1.26 [d, J ϭ 6.1 Hz, 3 H, CH(N)Me],

1.31 (td, J ϭ 9.3, J ϭ 2.2 Hz, 1 H, CHiPr), 1.40 [d, J ϭ 6.1 Hz, 3

H, CH(O)Me], 1.92 (septd, J ϭ 7.1, J ϭ 2.2 Hz, 1 H, iPr), 3.37

(dq, J ϭ 8.8, J ϭ 6.1 Hz, 1 H, CHN), 4.23 (dq, J ϭ 9.5, J ϭ

6.1 Hz, 1 H, CHO), 6.48 (br. s, 1 H, NH) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ ϭ 19.11 (d), 19.78 (d), 20.46 (d), 23.18 (d), 27.13 (d),

48.43 (d), 49.96 (d), 75.76 (d), 155.68 (u) ppm. IR (KBr): ν˜ ϭ 3383

(m), 3245 (m), 3136 (m), 2963 (s), 2904 (m), 1708 (vs), 1489 (m),

1458 (s), 1416 (s), 1390 (s), 1372 (s), 1343 (m), 1305 (s), 1245 (m),

1197 (s), 1151 (m), 1110 (m), 1054 (s) cm^Ϫ1. MS (EI): m/z (relative

intensity, %) ϭ 172 [M^ϩϩ 1] (1), 171 [M^ϩ] (2), 112 (13), 84 (51).

C₉H₁₇NO₂(171.24): calcd. C 63.13. H 10.01. N 8.18; found C

62.87, H 10.09, N 8.10.

CDCl₃): δ ϭ 0.50 (d, J ϭ 7.1 Hz, 3 H, iPr), 0.70 (d, J ϭ 7.1 Hz, 3

H, iPr), 1.27 (d, J ϭ 6.1 Hz, 3 H, Me), 1.50 (septd, J ϭ 7.1, J ϭ

2.0 Hz, 1 H, iPr), 1.83 (td, J ϭ 9.9, J ϭ 2.0 Hz, 1 H, CHiPr), 2.70

(s, 3 H, NMe), 3.29 (dd, J ϭ 6.4, J ϭ 3.7 Hz, 1 H, CHS), 3.73 (d,

J ϭ 9.5 Hz, 1 H, CHNH), 3.96 (dd, J ϭ 10.4, J ϭ 6.4 Hz, 1 H,

CH₂O), 4.03 (dq, J ϭ 10.2, J ϭ 6.1 Hz, 1 H, CHO), 4.23 (dd, J ϭ

10.4, J ϭ 3.7 Hz, 1 H, CH₂O), 4.40 (symm m, 2 H, PhCH₂O), 7.00

(s, 1 H, NH), 7.23Ϫ7.36 (m, 5 H, Ph), 7.57Ϫ7.70 (m, 3 H, Ph),

7.84 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 18.03

(d), 18.99 (d), 19.93 (d), 26.81 (d), 29.14 (d), 44.73 (d), 50.61 (d),

63.10 (u), 73.71 (u), 66.65 (d), 74.52 (d), 127.94 (d), 128.05 (d),

128.44 (d), 129.83 (d), 130.00 (d), 133.73 (d), 136.42 (u), 137.27 (u),

155.41 (u) ppm. IR (neat): ν˜ ϭ 3381 (w), 3290 (m), 3062 (m), 3031

(w), 2964 (s), 2937 (s), 2878 (s), 2809 (w), 2337 (w), 1724 (vs), 1582

(w), 1496 (w), 1447 (s), 1422 (s), 1373 (s), 1303 (s), 1246 (s), 1146

(s), 1109 (s), 1077 (s), 1047 (s), 1025 (m) cm^Ϫ1. MS (EI): m/z (rela-

tive intensity, %) ϭ 445 [M^ϩ] (1), 290 (4), 289 (4), 288 (4), 198 (16),

183 (10), 182 (11), 156 (13), 155 (14), 141 (14), 125 (21), 124 (22),

107 (27), 91 (100). C₂₄H₃₂N₂O₄S (444.59): calcd. C 64.84, H 7.25,

N 6.30; found C 64.95, H 7.34, N 6.54.

(4S,5R,6S)-Tetrahydro-4-{(1S,2S)-2-hydroxy-1-[(S)-N-methyl-

S-phenylsulfonimidoyl]propyl}-6-methyl-5-(1-methylethyl)-

2H-1,3-oxazin-2-one (16e) and (4S,5R,6S)-Tetrahydro-4-{(1S,2R)-2-

hydroxy-1-[(S)-N-methyl-S-phenylsulfonimidoyl]propyl}-6-methyl-5-

(1-methylethyl)-2H-1,3-oxazin-2-one (epi-16e): Successive treatment

of sulfoximine 5b (78 mg, 0.24 mmol) with nBuLi (0.45 mL of 1.60

 in hexane, 0.72 mmol) and ethanal (0.3 mL, 5.3 mmol) according

to GP3 and purification by chromatography (EtOAc/cyclohex-

ane, 4:1) gave a mixture of sulfoximines 16e, epi-16e, and 5b (78 mg)

in a ratio of 1.7:1:1 as a colorless solid.

(؊)-(4R,5R,6S)-Tetrahydro-4-ethyl-6-methyl-5-(1-methyl-

ethyl)-2H-1,3-oxazin-2-one (17b): Treatment of sulfoximine 16c

(94 mg, 0.28 mmol) with Raney nickel, prepared from 1.6 g Ni/Al,

for 18 h according to GP4 and purification by chromatography

Compound 16e: ¹H NMR (300 MHz, CDCl₃): δ ϭ 0.47 (d, J ϭ

7.1 Hz, 3 H, iPr), 0.78 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.35 (d, J ϭ

6.0 Hz, 3 H, CHMe), 1.30Ϫ1.38 (m, 1 H, iPr), 1.48 [d, J ϭ 6.5 Hz,

3 H, CH(OH)Me], 1.71 (td, J ϭ 10.1, J ϭ 1.7 Hz, 1 H, CHiPr), (EtOAc/cyclohexane, 4:1) afforded oxazinone 17b (45 mg, 88%) as

Eur. J. Org. Chem. 2003, 1500Ϫ1526 1519

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

a colorless oil. [α]_Dϭ Ϫ28.0 (c ϭ 0.69, CH₂Cl₂). ¹H NMR

26.66 (d), 47.88 (d), 48.03 (d), 49.57 (d), 56.03 (d), 75.63 (d), 75.75

(300 MHz, CDCl₃): δ ϭ 0.97 (d, J ϭ 7.0 Hz, 3 H, iPr), 0.97 (t, J ϭ (d), 128.73 (d), 130.17 (d), 131.08 (d), 131.98 (d), 154.58 (u) ppm.

7.4 Hz, 3 H, Et), 1.00 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.41 (d, J ϭ 6.3 Hz, IR (neat): ν˜ ϭ 3251 (m), 3127 (m), 2962 (s), 2937 (s), 2878 (m),

3 H, Me), 1.44 (ddd, J ϭ 8.8, J ϭ 7.7, J ϭ 2.7 Hz, 1 H, CHiPr), 1713 (vs), 1456 (m), 1407 (s), 1378 (s), 1351 (m), 1330 (m), 1307

1.53 (sept, J ϭ 7.2 Hz, 1 H, Et), 1.68 (dqd, J ϭ 14.4, J ϭ 7.4, J ϭ (m), 1294 (m), 1264 (m), 1223 (w), 1187 (w), 1165 (m), 1135 (m),

3.9 Hz, 1 H, Et), 1.87 (septd, J ϭ 7.0, J ϭ 2.7 Hz, 1 H, iPr), 3.19 1048 (m), 1019 (w) cm^Ϫ1. GC-MS: m/z (relative intensity, %) ϭ 199

(ddd, J ϭ 7.7, J ϭ 7.2, J ϭ 3.9 Hz, 1 H, CHNH), 4.23 (dq, J ϭ

[M^ϩϩ 2] (10), 198 [M^ϩϩ 1] (100), 114 (24), 110 (13). C₁₁H₁₉NO₂

8.8, J ϭ 6.3 Hz 1 H, CHO), 5.76 (br. s, 1 H, NH) ppm. ¹³C NMR (197.27): calcd. C 66.97, H 9.71, N 7.10; found C 66.41, H 9.22, N

(75 MHz, CDCl₃): δ ϭ 9.05 (d), 18.92 (d), 19.82 (d), 20.57 (d), 6.98. C₁₁H₁₉NO₂: calcd. 197.14158; found (HRMS, EI) 197.14154.

27.84 (d), 29.31 (u), 46.84 (d), 53.48 (d), 75.35 (d), 156.42 (u) ppm.

Methyl (αS,4S,5R,6S)- and (αR,4S,5R,6S)-[Tetrahydro-6-methyl-5-

IR (neat): ν˜ ϭ 3256 (m), 3136 (w), 2965 (s), 2938 (m), 2879 (m),

(1-methylethyl)-2-oxo-2H-1,3-oxazin-4-yl][(S)-N-methyl-S-phenyl

2240 (w), 1713 (s), 1462 (m), 1417 (m), 1392 (m), 1381 (m), 1353

sulfonimidoyl]acetate (20 and epi-20): Successive treatment of sul-

(w), 1301 (m), 1268 (w), 1185 (w), 1143 (w), 1098 (w), 1068 (m),

foximine 5b (220 mg, 0.68 mmol) with nBuLi (1.06 mL of 1.60  in

1031 (w), 1010 (w) cm^Ϫ1. GC-MS: m/z (relative intensity, %) ϭ 187

hexane, 1.70 mmol) and ClCO₂Me (0.13 mL, 1.69 mmol) according

[M^ϩϩ 2] (4), 186 [M^ϩϩ 1] (26), 156 (10), 112 (40), 102 (9), 89

to GP3 and purification by chromatography (EtOAc/cyclohex-

(12). C₁₀H₁₉NO₂(185.26): calcd. C 64.83, H 10.34, N 7.56; found

ane, 1:1) gave a mixture of esters 20 and epi-20 (165 mg, 64%) in a

C 64.74, H 10.47, N 7.85.

ratio of 5.2:1 as a colorless solid.

(؊)-(4S,4aR,8aS)-Octahydro-4-(1-methylethyl)-8a-methyl-

Compound 20: ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.91 (d, J ϭ

2H-3,1-benzoxazin-2-one (18): Treatment of 15b (320 mg,

7.1 Hz, 3 H, iPr), 0.96 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.45 (d, J ϭ

0.88 mmol) with Raney nickel, prepared from 2.6 g Ni/Al, for 6 h

6.3 Hz, 3 H, Me), 1.64Ϫ1.78 (m, 2 H, CHiPr, iPr), 2.61 (s, 3 H,

according to GP4 and purification by chromatography (EtOAc/

NMe), 3.78 (s, 3 H, CO₂Me), 4.04Ϫ4.16 (m, 3 H, CHN, CHS,

cyclohexane, 1:1) afforded 18 (160 mg, 86%) as a colorless solid.

CHO), 6.60 (br. s, 1 H, NH), 7.60Ϫ7.70 (m, 3 H, Ph), 7.85Ϫ7.90

M.p. 190 °C, [α]_Dϭ Ϫ37.3 (c ϭ 0.23, CH₂Cl₂). ¹H NMR

(m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 18.71 (d),

(300 MHz, CDCl₃): δ ϭ 0.80 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.10 (d,

19.29 (d), 20.12 (d), 27.89 (d), 29.86 (d), 46.25 (d), 50.82 (d), 53.64

J ϭ 6.7 Hz, 3 H, iPr), 1.07Ϫ1.80 (m, 12 H, CH₂), 1.95 (septd, J ϭ

(d), 73.02 (d), 74.02 (d), 129.86 (d), 130.05 (d), 134.10 (d), 137.23

6.8, J ϭ 2.3 Hz, 1 H, iPr), 4.30 (dd, J ϭ 10.08, J ϭ 2.02 Hz, 1 H,

(u), 155.25 (u), 163.89 (u) ppm.

CHNH), 6.30 (br. s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃):

δ ϭ 13.68 (d), 20.02 (d), 20.55 (u), 22.75 (u), 22.92 (u), 26.85 (d),

1

Compound epi-20: H NMR (400 MHz, CDCl₃): δ ϭ 0.78 (d, J ϭ

28.14 (d), 36.92 (u), 39.02 (d), 52.83 (u), 79.99 (d), 155.02 (u) ppm. 7.1 Hz, 3 H, iPr), 0.90 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.38 (d, J ϭ

IR (KBr): ν˜ ϭ 3242 (w), 2945 (s), 2870 (m), 1700 (s), 1446 (s), 1371 6.4 Hz, 3 H, Me), 2.75 (s, 3 H, NMe), 3.65 (s, 3 H, CO₂Me), 4.38

(m) 1141 (m), 1070 (m) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ (m, 1 H), 4.42 (d, J ϭ 10.0 Hz, 1 H), 6.25 (br. s, 1 H, NH) ppm.

211 [M^ϩ] (12), 169 (10), 168 (100). C₁₂H₂₁NO₂(211.30): calcd. C

68.21, H 10.02, N 6.63; found C 68.08, H 10.14, N 6.59.

¹³C NMR (75 MHz, CDCl₃): δ ϭ 20.00 (d), 20.43 (d), 21.99 (d),

31.09 (d), 51.64 (d), 53.33 (d), 75.61 (d) ppm. IR (KBr): ν˜ ϭ 3303

(s), 2960 (m), 1754 (vs), 1725 (s), 1447 (m), 1338 (w), 1260 (s), 1163

(m), 1018 (m) cm^Ϫ1. MS (EI): m/z, relative intensity, %) ϭ 354 (2),

228 (89), 227 (40), 198 (27), 196 (38), 185 (21), 170 (18), 154 (59),

146 (21), 125 (100), 107 (57). C₁₈H₂₆N₂O₅S (382.48): calcd. C

56.52, H 6.85, N 7.32; found C 56.35, H 7.01, N 7.24.

(4R,5R,6S)-Tetrahydro-6-methyl-5-(1-methylethyl)-4-

[(1E)-propenyl]-2H-1,3-oxazin-2-one [(E)-19] and (4R,5R,6S)-Tetra-

hydro-6-methyl-5-(1-methylethyl)-4-[(1Z)-propenyl]-2H-1,3-oxazin-

2-one [(Z)-19]: Amalgamated aluminium was prepared as follows:

aluminium powder (1.5 g) was treated with a solution of HgCl₂in

water (2%, 50 mL) for 2 min. The aqueous phase was decanted and

Methyl (؉)-(4R,5R,6S)-[Tetrahydro-6-methyl-5-(1-methylethyl)-2-

the residue was washed with water (2 ϫ 25 mL). A suspension of oxo-2H-1,3-oxazin-4-yl]acetate (21): Treatment of sulfoximines 20

the obtained amalgamated aluminium in THF/H₂O/HOAc (2:1:1, and epi-20 (230 mg, 0.60 mmol) with Raney nickel, prepared from

40 mL) was added at room temperature to a rapidly stirred solution 1.8 g Ni/Al, for 8 h according to GP4 and purification by chroma-

of a mixture of 16e, epi-16e, and 5b (190 mg, in a ratio of 1.8:1:1)

in THF (20 mL). After the mixture had been stirred for 2 h, it was

filtered through a pad of Celite. The residue was washed with

CH₂Cl₂(4 ϫ 25 mL). The combined organic phases were washed

with water (2 ϫ 25 mL) and aqueous NaOH (10%, 2 ϫ 25 mL),

dried (MgSO₄), and concentrated in vacuo. Purification by chroma-

tography (EtOAc/cyclohexane, 4:1) gave a mixture of alkenes (E)-

19 and (Z)-19 (66 mg, 85%) in a ratio of 1:1, together with oxazi-

none 17a (11 mg, 46%) as colorless solids.

tography (EtOAc/cyclohexane, 1:1) afforded 21 (120 mg, 87%) as a

viscous liquid. [α]_Dϭ ϩ51.42 (c ϭ 0.70, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 0.85 (d, J ϭ 7.1 Hz, 3 H, iPr), 0.95 (d,

J ϭ 7.1 Hz, 3 H, iPr), 1.40 (d, J ϭ 6.5 Hz, 3 H, Me), 1.40 (symm.

m, 1 H, CHiPr), 1.80Ϫ1.85 (m, 1 H, iPr), 2.50 (dd, J ϭ 17.1, J ϭ

10.1 Hz, 1 H, CH₂), 2.65 (dd, J ϭ 17.1, J ϭ 2.7 Hz, 1 H, CH₂),

3.60 (m, 1 H, CHNH), 3.70 (s, 3 H, CO₂Me), 4.20 (dq, J ϭ 9.3,

J ϭ 6.5 Hz, 1 H, CHO), 5.80 (br. s, 1 H, NH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 19.53 (d), 19.61 (d), 20.55 (d), 28.34 (d),

42.12 (u), 48.36 (d), 49.12 (d), 52.42 (d), 75.17 (d), 155.17 (u),

171.94 (u) ppm. IR (CHCl₃): ν˜ ϭ 3261 (m), 3141 (w), 2961(s), 1714

(vs), 1439 (s), 1373 (m), 1047 (m) cm^Ϫ1. MS (EI): m/z (relative

intensity, %) ϭ 229 [M^ϩ] (8), 198 (8), 186 (18), 170 (11), 156 (28),

142 (100), 112 (32), 84 (17). C₁₁H₁₉NO₄(229.27): calcd. C 57.62,

H 8.35, N 6.11; found C 57.08, H 8.30, N 6.34.

1

Compounds (E)-19/(Z)-19: H NMR (300 MHz, CDCl₃): δ ϭ 0.94

(d, J ϭ 7.1 Hz, 3 H, Me), 0.95 (d, J ϭ 7.1 Hz, 3 H, Me), 0.99 (br.

d, J ϭ 7.1 Hz, 6 H, 2 ϫ Me), 1.40 [d, J ϭ 6.1 Hz, 3 H, CH(O)Me],

1.41 [d, J ϭ 6.2 Hz, 3 H, CH(O)Me], 1.44 (m, 2 H, 2 ϫ CHiPr),

1.71 (m, 6 H, 2 ϫ CHϭCHMe), 1.93 (m, 2 H, 2 ϫ iPr), 3.71 (t,

J ϭ 9.1 Hz, 1 H, CHNH), 4.14 (t, J ϭ 9.6 Hz, 1 H, CHNH), 4.23

(dq, J ϭ 9.7, J ϭ 6.2 Hz, 1 H, CHO), 4.27 (dq, J ϭ 9.9, J ϭ 6.1 Hz

1 H, CHO), 5.27 (m, 1 H, CHϭCHMe), 5.33 (dq, J ϭ 8.6, J ϭ

Methyl (Ϫ)-(4R,5R,6S)-[Tetrahydro-4-methyl-6-[(1-methylethyl)-2-

oxo-5-phenyl-2H-1,3-oxazin-4-yl]acetate (23a): Successive treatment

1.7 Hz, 1 H, CHϭCHMe), 5.62Ϫ5.76 (m, 4 H, 2 ϫ CHϭCHMe, of sulfoximine 9 (223 mg, 0.56 mmol) with nBuLi (0.77 mL of 1.60

2 ϫ NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 13.16 (d), 17.63  in hexane, 1.23 mmol) and ClCO₂Me (0.09 mL, 1.23 mmol) and

(d), 18.72 (d), 18.84 (d), 19.95 (d), 20.09 (d), 20.24 (d), 26.53 (d),

1520

reduction of the functionalized sulfoximine 22a with Raney nickel,

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

prepared from 3.5 g Ni/Al, according to GP5 and purification by (d), 127.90 (d), 128.57 (d), 134.43 (u), 153.06 (u), 170.52 (u) ppm.

chromatography afforded ester 23a (82 mg, 48%) as a colorless IR (KBr): ν˜ ϭ 3413 (s), 3085 (w), 3063 (w), 3030 (w), 2968 (s),

solid, together with sulfoximine 9 (16 mg, 7%). M.p. 104 °C. [α]_Dϭ 2896 (m), 1712 (s), 1604 (w), 1497 (w), 1471 (m), 1438 (s), 1394

Ϫ53.0 (c ϭ 0.77, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.78

(m), 1372 (m), 1346 (m), 1222 (s), 1179 (m), 1146 (s), 1120 (m),

(d, J ϭ 7.0 Hz, 3 H, iPr), 1.06 (d, J ϭ 7.0 Hz, 3 H, iPr), 1.29 (s, 3 1103 (m), 1056 (m) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ

H, Me), 1.62 (septd, J ϭ 6.9, J ϭ 1.9 Hz, 1 H, iPr), 2.37 (d, J ϭ 348 [M^ϩϩ 1] (100). C₂₀H₂₉NO₄(347.45): calcd. C 69.14, H 8.41,

15.7 Hz, 1 H, CH₂), 2.48 (d, J ϭ 15.7 Hz, 1 H, CH₂), 2.98 (d, J ϭ N 4.03; found C 68.96, H 8.21, N 4.00.

11.4 Hz, 1 H, CHPh), 3.67 (s, 1 H, OMe), 4.66 (dd, J ϭ 11.4, J ϭ

Neopentyl (Ϫ)-(4R,5R,6S)-[Tetrahydro-4-methyl-6-(1-methylethyl)-

1.9 Hz, 1 H, CHO), 6.48 (br. s, 1 H, NH), 7.06Ϫ7.12 (m, 2 H, Ph),

2-oxo-5-phenyl-1,3-oxazine-4-yl]acetate (23d): Successive treatment

7.23Ϫ7.33 (m, 3 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ

of sulfoximine 9 (226 mg, 0.56 mmol) with nBuLi (0.77 mL of 1.60

13.79 (d), 20.23 (d), 23.56 (d), 29.08 (d), 44.87 (u), 51.04 (d), 52.32

 in hexane, 1.23 mmol) and ClCO₂CH₂tBu (0.18 mL, 1.23 mmol),

(d), 55.05 (u), 80.17 (d), 128.32 (d), 128.96 (d), 134.70 (u), 153.48

reduction of the functionalized sulfoximine 22d with Raney nickel,

(u), 171.22 (u) ppm. IR (KBr): ν˜ ϭ 3375 (m), 3253 (w), 3088 (w),

prepared from 3.3 g of Ni/Al, according to GP5, and purification

3033 (w), 2966 (m), 2920 (m), 2877 (w), 1715 (s), 1499 (w), 1439

by chromatography afforded ester 23d (104 mg, 51%) as a colorless

(s), 1422 (m), 1389 (m), 1370 (m), 1355 (m), 1332 (w), 1300 (m),

solid, together with sulfoximine 9 (38 mg, 17%). M.p. 133 °C.

1266 (w), 1243 (m), 1227 (m), 1204 (w), 1178 (m), 1159 (w), 1114

[α]_Dϭ Ϫ3.7 (c ϭ 0.83, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ

(m), 1096 (m), 1055 (s), 1004 (w) cm^Ϫ1. MS (CI): m/z (relative

0.79 (d, J ϭ 6.9 Hz, 3 H, iPr), 0.91 (s, 9 H, tBu), 1.07 (d, J ϭ

intensity, %) ϭ 306 [M^ϩϩ 1] (100), 248 (14). C₁₇H₂₃NO₄(305.37):

7.1 Hz, 3 H, iPr), 1.33 (s, 3 H, Me), 1.63 (septd, J ϭ 6.9, J ϭ

calcd. C 66.86, H 7.59, N 4.59; found C 66.88, H 7.48, N 4.59.

1.8 Hz, 1 H, iPr), 2.37 (d, J ϭ 15.7 Hz, 1 H, CH₂), 2.52 (d, J ϭ

Isopropyl (Ϫ)-(4R,5R,6S)-[Tetrahydro-4-methyl-6-(1-methylethyl)-2-

oxo-5-phenyl-2H-1,3-oxazin-4-yl]acetate (23b): Successive treatment

of sulfoximine 9 (114 mg, 0.28 mmol) with nBuLi (0.39 mL of 1.60

 in hexane, 0.63 mmol) and ClCO₂iPr (0.63 mL of 1.0  in tolu-

ene, 0.63 mmol), reduction of the functionalized sulfoximine 22b

with Raney nickel, prepared from 1.7 g Al-Ni, according to GP5,

and purification by chromatography afforded ester 23b (56 mg,

59%) as a colorless solid, together with sulfoximine 9 (21 mg, 18%).

M.p. 151 °C. [α]_Dϭ Ϫ42.7 (c ϭ 0.95, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 0.73 (d, J ϭ 6.6 Hz, 3 H, iPr), 1.01 (d,

J ϭ 6.9 Hz, 3 H, iPr), 1.15 (d, J ϭ 6.0 Hz, 3 H, iPr), 1.17 (d, J ϭ

5.8 Hz, 3 H, iPr), 1.31 (s, 3 H, Me), 1.56 (septd, J ϭ 7.0, J ϭ

1.8 Hz, 1 H, iPr), 2.28 (d, J ϭ 15.4 Hz, 1 H, CH₂), 2.40 (d, J ϭ

15.4 Hz, 1 H, CH₂), 2.96 (d, J ϭ 11.5 Hz, 1 H, CHPh), 4.61 (dd,

J ϭ 11.4, J ϭ 1.8 Hz, 1 H, CHO), 4.98 (sept, J ϭ 6.3 Hz, 1 H,

OiPr), 6.58 (s, 1 H, NH), 7.10Ϫ7.16 (m, 2 H, Ph), 7.26Ϫ7.34 (m,

3 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 13.41 (d), 19.88

(d), 21.70 (d), 21.78 (d), 23.34 (d), 28.71 (d), 44.90 (u), 50.54 (d),

54.85 (u), 68.78 (d), 79.88 (d), 128.05 (d), 128.74 (d), 134.66 (u),

153.36 (u), 170.21 (u) ppm. IR (KBr): ν˜ ϭ 3415 (s), 3029 (m), 2975

(m), 2934 (m), 2879 (m), 1721 (s), 1497 (m), 1442 (m), 1388 (m),

1369 (m), 1334 (m), 1226 (m), 1179 (m), 1149 (m), 1105 (m), 1059

(m) cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ 334 [M^ϩϩ 1]

(100). C₁₉H₂₇NO₄(333.42): calcd. C 68.44. H 8.16. N 4.20; found

C 68.35, H 8.04, N 4.04.

15.7 Hz, 1 H, CH₂), 3.03 (d, J ϭ 11.5 Hz, 1 H, CHPh), 3.79 (symm

m, 2 H, OCH₂), 4.68 (dd, J ϭ 11.4, J ϭ 1.8 Hz, 1 H, CHO), 6.60

(br. s, 1 H, NH), 7.16Ϫ7.21 (m, 2 H, Ph), 7.32Ϫ7.41 (m, 3 H, Ph)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 13.40 (d), 19.85 (d), 23.28

(d), 26.37 (d), 28.66 (d), 31.16 (u), 44.51 (u), 50.62 (d), 54.65 (u),

74.25 (u), 79.75 (d), 127.88 (d), 128.56 (d), 134.41 (u), 153.07 (u),

170.59 (u) ppm. IR (KBr): ν˜ ϭ 3368 (m), 3035 (w), 2959 (m), 2920

(m), 2876 (m), 1711 (s), 1499 (m), 1467 (m), 1439 (m), 1411 (m),

1383 (m), 1368 (m), 1352 (m), 1339 (w), 1299 (w), 1268 (w), 1241

(m), 1228 (m), 1178 (m), 1110 (m), 1095 (m), 1057 (m) cm^Ϫ1. MS

(CI): m/z (relative intensity, %) ϭ 362 [M^ϩϩ 1] (100). C₂₁H₃₁NO₄

(361.48): calcd. C 69.78, H 8.64, N 3.87; found C 69.26, H 8.71,

N 3.74.

Methyl (؉)-(αR,4S,4aR,8aS)-{Octahydro-4-(1-methylethyl)-2-oxo-

8aH-3,1-benzoxazin-8a-yl}-α-[(S)-N-methyl-S-phenylsulfonimidoyl]-

acetate (24): Successive treatment of sulfoximine 15b (538 mg,

1.48 mmol) with nBuLi (2.31 mL of 1.60  in hexane, 3.70 mmol)

and ClCO₂Me (0.28 mL, 3.70 mmol) according to GP3 and purifi-

cation by chromatography (EtOAc/cyclohexane, 2:1) gave ester 24

(437 mg, 70%) as a colorless solid. M.p. 64Ϫ65 °C, [α]_Dϭ ϩ49.3

(c ϭ 0.15, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.90 (d, J ϭ

6.8 Hz, 3 H, iPr), 1.05 (d, J ϭ 6.8 Hz, 3 H, iPr), 1.10Ϫ1.80 (m, 8

H, CH₂), 1.90 (septd, J ϭ 6.8, J ϭ 2.2 Hz, 1 H, iPr), 2.75 (s, 3 H,

NMe), 2.95 (m, 1 H), 3.70 (s, 3 H, CO₂Me), 4.20 (dd, J ϭ 10.9,

J ϭ 2.2 Hz, 1 H, CHO), 4.70 (s, 1 H, CHS), 6.09 (s, 1 H, NH),

7.50Ϫ7.70 (m, 3 H, Ph), 7.75Ϫ7.80 (m, 2 H, Ph) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 13.62 (d), 19.84 (u), 20.08 (u), 22.47 (u),

28.20 (d), 29.86 (d), 32.60 (d), 37.31 (u), 53.36 (d), 56.98 (u), 70.28

(d), 70.66 (d), 129.57 (d), 129.76 (d), 133.72 (d), 138.04 (u), 152.94

(u), 166.96 (u) ppm. IR (KBr): ν˜ ϭ 3394 (s), 2943 (s), 2876 (m),

1711 (s), 1446 (s), 1379 (m), 1263 (s), 1073 (m) cm^Ϫ1. MS (EI):

m/z (relative intensity, %) ϭ 394 (1), 278 (3), 228 (6), 227 (8), 198

(9), 195 (21), 156 (10), 154 (100), 150 (11), 136 (21), 125 (46), 108

(32). C₂₁H₃₀N₂O₅S (422.54): calcd. C 59.69, H 7.16, N 6.63; found

C 59.18, H 7.09, N 6.33.

Isobutyl (Ϫ)-(4R,5R,6S)-[Tetrahydro-4-methyl-6-(1-methylethyl)-2-

oxo-5-phenyl-2H-1,3-oxazin-4-yl]acetate (23c): Successive treatment

of sulfoximine 9 (1.18 g, 2.94 mmol) with nBuLi (3.86 mL of 1.60

 in hexane, 6.18 mmol) and ClCO₂iBu (0.81 mL, 2.95 mmol), re-

duction of the functionalized sulfoximine 22c with Raney nickel,

prepared from 1.8 g Ni/Al, according to GP5, and purification by

chromatography furnished ester 23c (754 mg, 74%) as a colorless

solid, together with sulfoximine 9 (141 mg, 12%). M.p. 119 °C.

[α]_Dϭ ϩ34.0 (c ϭ 1.21, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃):

δ ϭ 0.79 (d, J ϭ 6.9 Hz, 3 H, iPr), 0.91 (dd, J ϭ 6.6, J ϭ 3.1 Hz,

6 H, iPr), 1.07 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.32 (s, 3 H, Me), 1.63

(septd, J ϭ 6.9, J ϭ 1.9 Hz, 1 H, iPr), 1.83Ϫ1.96 (m, 1 H, iPr),

2.36 (d, J ϭ 15.7 Hz, 1 H, CH₂), 2.50 (d, J ϭ 15.7 Hz, 1 H, CH₂),

3.01 (d, J ϭ 11.4 Hz, 1 H, CHPh), 3.86 (dd, J ϭ 12.2, J ϭ 6.7 Hz,

1 H, OCH₂), 3.88 (dd, J ϭ 12.2, J ϭ 6.7 Hz, 1 H, OCH₂), 4.67

(dd, J ϭ 11.4, J ϭ 1.7 Hz, 1 H, CHO), 6.60 (br. s, 1 H, NH),

7.16Ϫ7.18 (m, 2 H, Ph), 7.32Ϫ7.40 (m, 3 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 13.42 (d), 19.04 (d), 19.85 (d), 23.23 (d),

Methyl

(؉)-(4S,4aR,8aR)-{Octahydro-4-(1-methylethyl)-2-oxo-

8aH-[3,1]benzoxazin-8a-yl}acetate (25): Treatment of sulfoximine

24 (160 mg, 0.38 mmol) with Raney nickel, prepared from 1.6 g Ni/

Al, according to GP4 and purification by chromatography (EtOAc/

cyclohexane, 1:1) afforded 20 (80 mg, 78%) as a colorless solid.

M.p. 132 °C, [α]_Dϭ ϩ23.33 (c ϭ 0.24, CH₂Cl₂). ¹H NMR

(300 MHz, CDCl₃): δ ϭ 0.90 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.05 (d,

27.55 (d), 28.70 (d), 44.59 (u), 50.70 (d), 54.68 (u), 71.09 (u), 79.80 J ϭ 6.7 Hz, 3 H, iPr), 1.10Ϫ1.30 (m, 4 H), 1.50Ϫ1.85 (m, 9 H),

Eur. J. Org. Chem. 2003, 1500Ϫ1526 1521

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

1.95 (septd, J ϭ 7.0, J ϭ 2.1 Hz, 1 H, iPr), 2.40 (dd, J ϭ 15.5, J ϭ CHPh), 3.28 (dd, J ϭ 11.6, J ϭ 6.0 Hz, 1 H, CH₂), 3.52 (dd, J ϭ

FULL PAPER

1.5 Hz, 1 H, CH₂CO), 3.02 (d, J ϭ 15.5 Hz, 1 H, CH₂CO), 3.70

(s, 3 H, CO₂Me), 4.30 (dd, J ϭ 10.6, J ϭ 2.1 Hz, 1 H, CHO), 6.35

(br. s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 13.54 (d),

19.93 (d), 20.43 (u), 22.43 (u), 22.66 (u), 28.12 (d), 33.98 (u), 38.55

(d), 41.66 (u), 52.12 (d), 53.90 (u), 79.06 (d), 153.76 (u), 171.28 (u)

ppm. IR (KBr): ν˜ ϭ 3372 (s), 3000 (w), 2961 (s), 2930 (s), 1697

(vs), 1525 (w), 1464 (s), 1379 (m), 1207 (s) cm^Ϫ1. MS (EI): m/z

(relative intensity, %) ϭ 269 [M^ϩ] (2), 238 (2), 227 (13), 226 (100),

213 (35), 196 (25), 194 (19), 170 (63), 152 (15). C₁₄H₂₃NO₄(269.34):

calcd. C 62.43, H 8.61, N 5.20; found C 62.25, H 8.56, N 4.90.

11.6, J ϭ 2.7 Hz, 1 H, CH₂), 3.86 (ddd, J ϭ 10.6, J ϭ 6.0, J ϭ

2.7 Hz, 1 H, CHN), 4.67 (dd, J ϭ 10.7, J ϭ 1.9 Hz, 1 H, CHO),

6.75 (br. s, 1 H, NH), 7.17Ϫ7.21 (m, 2 H, Ph), 7.31Ϫ7.42 (m, 3 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 13.66 (d), 19.66 (d),

28.43 (d), 44.05 (d), 46.04 (u), 57.60 (d), 83.50 (d), 127.98 (d),

128.07 (d), 129.23 (d), 135.46 (u), 154.62 (u) ppm. IR (KBr): ν˜ ϭ

3362 (w), 3231 (s), 3138 (m), 3029 (m), 2972 (s), 2935 (m), 2877

(m), 1697 (s), 1605 (m), 1496 (m), 1473 (s), 1435 (s), 1387 (m), 1369

(m), 1338 (m), 1313 (m), 1289 (s), 1251 (w), 1210 (m), 1130 (s),

1087 (w), 1062 (m), 1036 (s) cm^Ϫ1. MS (CI): m/z (relative intensity,

%) ϭ 268 [M^ϩϩ 1] (100), 234 (16), 232 (12). C₁₄H₁₈ClNO₂

(267.75): calcd. C 62.80, H 6.78, N 5.23; found C 62.73, H 6.85,

N 5.13.

(؊)-(4S,5R,6S)-4-(Chloromethyl)-tertahydro-6-ethyl-5-

methyl-2H-1,3-oxazin-2-one (27a): Treatment of sulfoximine 5a

(77 mg, 0.25 mmol) with ClCO₂Me (0.28 mL, 3.7 mmol) at room

temperature for 3 days (95% conversion) according to GP6 and

purification by chromatography (EtOAc) afforded chloride 27a

(40 mg, 84%) as a colorless solid. M.p. 138 °C. [α]_Dϭ Ϫ1.0 (c ϭ

0.67, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ ϭ 1.01 (d, J ϭ

6.7 Hz, 3 H, CHMe), 1.04 (t, J ϭ 7.4 Hz, 3 H, Et), 1.59 (dquin,

J ϭ 14.4, J ϭ 7.4 Hz, 1 H, Et), 1.75 (tq, J ϭ 10.0, J ϭ 6.7 Hz, 1

H, CHMe), 1.86 (dqd, J ϭ 14.4, J ϭ 7.4, J ϭ 3.0 Hz, 1 H, Et),

3.33 (ddd, J ϭ 9.7, J ϭ 7.1, J ϭ 2.7 Hz, 1 H, CHNH), 3.48 (dd,

J ϭ 11.4, J ϭ 7.1 Hz, 1 H, CH₂Cl), 3.78 (dd, J ϭ 11.4, J ϭ 2.7 Hz,

1 H, CH₂Cl), 3.93 (ddd, J ϭ 10.1, J ϭ 7.4, J ϭ 3.0 Hz, 1 H, CHO),

6.29 (s, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 8.27 (d),

13.02 (d), 24.74 (u), 33.16 (d), 46.76 (u), 57.58 (d), 81.51 (d), 154.59

(u) ppm. IR (KBr): ν˜ ϭ 3310 (s), 3172 (m), 2980 (s), 2930 (s), 2883

(s), 1712 (vs, br), 1664 (s), 1531 (m), 1478 (s), 1435 (s), 1411 (s),

1386 (s), 1358 (s), 1327 (s), 1304 (s), 1269 (s), 1244 (s), 1216 (s),

1140 (s), 1117 (s), 1075 (s), 1045 (m), 1023 (s) cm^Ϫ1. MS (EI): m/z

(relative intensity, %) ϭ 192 [M^ϩϩ 1] (3), 162 (2), 143 (5), 142

(61), 117 (3), 99 (7), 98 (100), 81 (36). C₈H₁₄ClNO₂(191.66): calcd.

C 50.13, H 7.36, N 7.31; found C 50.15, H 7.28, N 7.06.

(ϩ)-(4R,5R,6S)-4-(Cyanomethyl)-tertahydro-6-(1-methyl-

ethyl)-5-phenyl-2H-1,3-oxazin-2-one (28): Treatment of chloride 27c

(440 mg, 1.64 mmol) with NaCN (160 mg, 3.27 mmol) according

to GP7 gave nitrile 28 (370 mg, 87%) as a colorless solid. Nitrile

28 was isolated by filtration of the reaction mixture after addition

of water. M.p. 244Ϫ246 °C (decomposition). [α]_Dϭ ϩ30.6 (c ϭ

0.31, DMSO). ¹H NMR (400 MHz, [D₆]DMSO): δ ϭ 0.74 (d, J ϭ

6.9 Hz, 3 H, iPr), 0.86 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.30 (septd, J ϭ

6.9, J ϭ 1.8 Hz, 1 H, iPr), 2.11 (dd, J ϭ 17.2, J ϭ 3.1 Hz, 1 H,

CH₂), 2.65 (dd, J ϭ 17.2, J ϭ 4.3 Hz, 1 H, CH₂), 2.70 (t, J ϭ

10.4 Hz, 1 H, CHPh), 3.86 (ddd, J ϭ 10.6, J ϭ 4.3, J ϭ 3.1 Hz, 1

H, CHN), 4.52 (dd, J ϭ 10.5, J ϭ 1.8 Hz, 1 H, CHO), 7.27Ϫ7.39

(m, 5 H, Ph), 7.71 (s, 1 H, NH) ppm. ¹³C NMR (100 MHz,

[D₆]DMSO): δ ϭ 14.38 (d), 20.29 (d), 22.41 (u), 28.85 (d), 46.18

(d), 52.54 (d), 80.60 (d), 117.72 (u), 128.64 (d), 129.03 (d), 129.85

(d), 136.49 (u), 153.48 (u) ppm. IR (KBr): ν˜ ϭ 3220 (m), 3123 (m),

2969 (m), 2929 (m), 2879 (m), 2245 (w), 1693 (s), 1500 (w), 1473

(w), 1428 (m), 1386 (w), 1369 (w), 1351 (w), 1327 (w), 1290 (m),

1260 (w), 1220 (m), 1187 (w), 1151 (m), 1132 (w), 1107 (w), 1089

(w), 1065 (w), 1034 (s) cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ

259 [M^ϩϩ 1] (100). C₁₅H₁₈N₂O₂(258.32): calcd. C 69.74, H 7.02,

N 10.84; found C 69.53, H 7.02, N 10.83.

(؉)-(4S,5R,6S)-4-(Chloromethyl)-tertahydro-6-methyl-5-

(1-methylethyl)-2H-1,3-oxazin-2-one (27b): Treatment of sulfoxim-

ine 5b (280 mg, 0.86 mmol) with ClCO₂Me (0.33 mL, 4.32 mmol)

for 3 days (95% conversion) according to GP6 and purification by

chromatography (EtOAc/pentane, 1:1) afforded chloride 27b

(151 mg, 85%) as a low-melting, colorless solid. [α₎ ϭ ϩ4.0 (c ϭ

0.30, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.90 (d, J ϭ

1.4 Hz, 3 H, iPr), 0.95 (d, J ϭ 1.6 Hz, 3 H, iPr), 1.35 (d, J ϭ 6.3 Hz,

3 H, CHMe), 1.55 (ddd, J ϭ 9.0, J ϭ 6.7, J ϭ 3.0 Hz, 1 H, CHMe),

1.85 (septd, J ϭ 7.1, J ϭ 3.0 Hz, 1 H, iPr), 3.45 (dd, J ϭ 14.1, J ϭ

7.6 Hz, 1 H, CH₂Cl), 3.60 (dd, J ϭ 14.8, J ϭ 7.1 Hz, 1 H, CH₂Cl),

4.15 (dq, J ϭ 9.0, J ϭ 2.7 Hz, 1 H, CHO), 6.30 (br. s, 1 H, NH)

ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 19.15 (d), 19.89 (d), 20.46

(d), 28.23 (d), 46.13 (d), 49.39 (u), 53.55 (d), 75.20 (d), 155.94 (u)

ppm. IR (KBr): ν˜ ϭ 3253 (m), 2879 (s), 1709 (vs), 1412 (s), 1301

(s), 1116 (m), 1039 (m) cm^Ϫ1. MS (EI): m/z (relative intensity, %) ϭ

205 [M^ϩ] (1), 157 (6), 155 (90), 112 (100), 95 (10). C₉H₁₆ClNO₂

(205.68): calcd. C 52.56, H 7.84, N 6.81; found C 52.56, H 7.86,

N 6.85.

(؊)-(4S,5R,6S)-4-(Chloromethyl)-tertahydro-4-methyl-6-

(1-methylethyl)-5-phenyl-2H-1,3-oxazin-2-one (29) and Methyl (S)-

N-Phenylsulfinylcarbamate (26): Treatment of sulfoximine

9

(204 mg, 0.51 mmol) with ClCO₂Me (0.39 mL, 5.10 mmol) accord-

ing to GP5 and purification by chromatography (EtOAc) gave chlo-

ride 29 (116 mg, 81%) as a colorless solid, carbamic acid ester 26

(79 mg, 73%) of Ն99% ee (GC, permethyl-β-cyclodextrin, chemi-

cally bound, t_R(R) ϭ 24.61 min, t_R(S) ϭ 24.71 min) as a colorless

oil, and oxazinone 9 (28 mg, 14%).

1

Compound 29: M.p. 161 °C. [α]_Dϭ Ϫ57.2 (c ϭ 1.25, CH₂Cl₂). H

NMR (400 MHz, CDCl₃): δ ϭ 0.81 (d, J ϭ 6.6 Hz, 3 H, iPr), 1.09

(d, J ϭ 6.9 Hz, 3 H, iPr), 1.26 (s, 3 H, Me), 1.72 (septd, J ϭ 6.9,

J ϭ 1.8 Hz, 1 H, iPr), 3.33 (d, J ϭ 11.4 Hz, 1 H, CHPh), 3.41

(symm. m, 2 H, CH₂), 4.67 (dd, J ϭ 11.4, J ϭ 1.8 Hz, 1 H, CHO),

6.95 (br. s, 1 H, NH), 7.17Ϫ7.22 (m, 2 H, Ph), 7.30Ϫ7.39 (m, 3 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 13.44 (d), 19.88 (d),

23.18 (d), 28.60 (d), 46.05 (d), 51.79 (u), 56.73 (u), 79.96 (d), 127.90

(d), 128.59 (d), 134.14 (u), 154.73 (u) ppm. IR (KBr): ν˜ ϭ 3239

(m), 3111 (w), 2971 (m), 2932 (m), 2876 (w), 1702 (s), 1604 (w),

1583 (w), 1497 (w), 1469 (m), 1456 (m), 1430 (s), 1413 (s), 1386

(m), 1368 (m), 1352 (m), 1335 (m), 1312 (m), 1300 (s), 1267 (w),

1251 (m), 1193 (m), 1146 (m), 1115 (m), 1092 (m), 1071 (w), 1048

(s) cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ 282 [M^ϩϩ 1] (100).

C₁₅H₂₀ClNO₂(281.78): calcd. C 63.94, H 7.15, N 4.97; found C

63.68, H 7.00, N 4.82.

(؉)-(4S,5R,6S)-4-(Chloromethyl)tetrahydro-6-(1-methyl-

ethyl)-5-phenyl-2H-1,3-oxazin-2-one (27c) and Methyl (S)-N-Phe-

nylsulfinylcarbamate (26): Treatment of sulfoximine 5c (1.30 g,

3.36 mmol) with ClCO₂Me (2.60 mL, 33.50 mmol) according to

GP6 and purification by HPLC (EtOAc) gave chloride 27c (730 mg,

81%) as a colorless solid, carbamic acid ester 26 (540 mg, 75%) as

a colorless oil, and oxazinone 5c (190 mg, 15%). 27c: M.p. 154 °C.

[α]_Dϭ ϩ1.4 (c ϭ 1.05, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ

0.87 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.02 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.53

(septd, J ϭ 7.1, J ϭ 1.9 Hz, 1 H, iPr), 2.95 (t, J ϭ 10.7 Hz, 1 H,

1522

Eur. J. Org. Chem. 2003, 1500Ϫ1526

Asymmetric Synthesis of Protected β-Substituted and β,β-Disubstituted β-Amino Acids

FULL PAPER

Compound 26: [α]_Dϭ Ϫ78.1 (c ϭ 0.78, Et₂O). ¹H NMR (400 MHz,

CDCl₃): δ ϭ 2.69 (s, 3 H, Me), 3.30 (s, 3 H, OMe), 7.52Ϫ7.57 (m,

3 H, Ph), 7.61Ϫ7.67 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ ϭ 25.67 (d), 54.01 (d), 125.15 (d), 129.33 (d), 131.85 (d),

142.31 (u), 155.55 (u) ppm. IR (neat): ν˜ ϭ 3058 (w), 3001 (w), 2955

(m), 2844 (w), 1725 (s), 1582 (w), 1444 (s), 1414 (m), 1313 (s), 1201

(m), 1145 (s), 1108 (s), 1078 (m), 1066 (m), 1023 (w) cm^Ϫ1. MS

(CI): m/z (relative intensity, %) ϭ 214 [M^ϩϩ 1] (7), 125 (100), 97

(24). C₉H₁₁NOS (213.25): calcd. C 50.69, H 5.20, N 6.57; found C

50.69, H 5.41, N 6.89.

(؊)-(4S,4aR,7aS)-7a-(Chloromethyl)-hexahydro-4-(1-methyl-

ethyl)-cyclopenta[d][1,3]oxazin-2(1H)-one (32a) and Methyl (S)-N-

Phenylsulfinylcarbamate (26): Treatment of sulfoximine 15a (1.02 g,

2.91 mmol) with ClCO₂Me (3.5 mL, 45.45 mmol) according to

GP5 and purification by double chromatography (EtOAc/cyclohex-

ane, 4:1; aluminium oxide, EtOAc/MeOH, 10:1) gave chloride 32a

(560 mg, 83%) as a white solid and carbamic acid ester 26 (420 mg,

68%) as a colorless oil. 32a: M.p. 96 °C. [α]_Dϭ Ϫ9.8 (c ϭ 1.20,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ ϭ 1.01 (d, J ϭ 6.9 Hz, 3

H, iPr), 1.10 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.49Ϫ1.68 (m, 2 H, CH₂),

1.74Ϫ2.06 (m, 5 H, CH₂, iPr), 2.28 (ddd, J ϭ 10.2, J ϭ 8.5, J ϭ

4.1 Hz, 1 H, CHCN), 3.54 (symm. m, 2 H, CH₂Cl), 3.74 (dd, J ϭ

10.2, J ϭ 3.0 Hz, 1 H, CHO), 6.84 (s, 1 H, NH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 15.16 (d), 19.91 (d), 23.29 (u), 28.77 (u),

29.31 (d), 38.11 (u), 41.28 (d), 52.72 (u), 64.79 (u), 83.77 (d), 157.25

(u) ppm. IR (KBr): ν˜ ϭ 3249 (w), 3128 (w), 2964 (s), 2878 (m),

1713 (s), 1469 (w), 1407 (m), 1371 (w), 1333 (m), 1303 (w), 1144

(w), 1085 (w), 1038 (w), 1021 (w) cm^Ϫ1. MS (CI): m/z (relative

intensity, %) ϭ 332 [M^ϩϩ 1] (100). C₁₁H₁₈ClNO₂(231.72): calcd.

C 57.02, H 7.83, N 6.04; found C 57.08, H 7.48, N 5.83.

(Ϫ)-(4R,5R,6S)-4-(Cyanomethyl)-tertahydro-4-methyl-6-

(1-methylethyl)-5-phenyl-2H-1,3-oxazin-2-one (30): Treatment of

chloride 29 (1.14 g, 4.05 mmol) with NaCN (40 mg, 0.82 mmol) ac-

cording to GP6 and purification by chromatography (EtOAc) gave

nitrile 30 (960 mg, 87%) as a colorless solid. M.p. 164 °C. [α]_D

ϭ

1

Ϫ28.7 (c ϭ 0.55, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ ϭ 0.84

(d, J ϭ 6.9 Hz, 3 H, iPr), 1.09 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.34 (s, 3

H, Me), 1.70 (septd, J ϭ 6.9, J ϭ 1.7 Hz, 1 H, iPr), 2.38 (d, J ϭ

17.0 Hz, 1 H, CH₂), 2.61 (d, J ϭ 17.0 Hz, 1 H, CH₂), 3.30 (d, J ϭ

11.4 Hz, 1 H, CHPh), 4.69 (dd, J ϭ 11.4, J ϭ 1.9 Hz, 1 H, CHO),

7.24Ϫ7.27 (m, 2 H, Ph), 7.34Ϫ7.42 (m, 3 H, Ph), 7.73 (s, 1 H, NH)

ppm. ¹³C NMR (100 MHz, CDCl₃): δ ϭ 13.51 (d), 19.88 (d), 24.81

(d), 28.77 (d), 30.30 (u), 48.40 (d), 55.08 (u), 80.52 (d), 116.08 (u),

128.51 (d), 129.07 (d), 133.73 (u), 154.92 (u) ppm. IR (KBr): ν˜ ϭ

3455 (w), 3219 (w), 3108 (w), 2961 (m), 2931 (w), 2876 (w), 2257

(w), 1700 (s), 1451 (w), 1418 (s), 1389 (w), 1371 (m), 1350 (m), 1338

(m), 1315 (m), 1268 (w), 1189 (w), 1167 (w), 1101 (w), 1056 (m)

cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ 273 [M^ϩϩ 1] (100).

C₁₆H₂₀N₂O₂(272.34): calcd. C 70.56, H 7.40, N 10.29; found C

70.30, H 7.49, N 10.04.

(؉)-(4S,4aR,8aS)-8a-(Chloromethyl)-octahydro-4-(1-methyl-

ethyl)-2H-3,1-benzoxazin-2-one (32b): Treatment of sulfoximine 15b

(392 mg, 1.08 mmol) with ClCO₂Me (1.25 mL, 16.2 mmol) for 3

days according to GP5 and purification by chromatography

(EtOAc/pentane, 1:1) afforded chloride 32b (227 mg, 86%) as a col-

orless solid and carbamic acid ester 26 (152 mg, 66%). M.p.

145Ϫ146 °C, [α]_D

؍

ϩ4.8 (c ϭ 0.25, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ ϭ 0.85 (d, J ϭ 6.8 Hz, 3 H, iPr), 1.00 (d, J ϭ 6.8 Hz, 3

H, iPr), 1.10Ϫ1.80 (m, 8 H), 1.92 (septd, J ϭ 6.8, J ϭ 2.2 Hz, 1

H, iPr), 2.00Ϫ2.05 (m, 1 H), 3.45 (dd, J ϭ 11.3, J ϭ 1 Hz, 1 H,

CH₂Cl), 3.85 (d, J ϭ 11.3 Hz, 1 H, CH₂Cl), 4.25 (dd, J ϭ 10.4,

J ϭ 2.2 Hz, 1 H, CHO), 5.65 (br. s, 1 H, NH) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ ϭ 14.05 (d), 20.21 (d), 20.76 (u), 22.57 (u),

22.99 (u), 28.44 (d), 33.10 (u), 36.20 (d), 51.05 (u), 55.59 (u), 80.01

(d), 154.59 (u) ppm. IR (KBr): ν˜

؍

3351 (m), 2935 (s), 1725 (s),

1678 (s), 1433 (m), 1332 (m), 1031 (s) cm^؊1. MS (EI): m/z (relative

intensity, %) ϭ 205 (1), 204 (9), 202 (33), 196 (100), 152 (88), 145

(14), 95 (25), 80 (14). C₁₂H₂₀ClNO₂(245.75): calcd. C 58.65, H

8.20, N 5.70; found C 58.46, H 8.00, N 5.67.

(؊)-(4R,5R,6S)-{Tetrahydro-4-methyl-6-(1-methylethyl)-

2-oxo-5-phenyl-2H-[1,3]-oxazin-4-yl}acetic Acid (31). From Nitrile

30: Treatment of 30 (170 mg, 0.62 mmol) with NaOH (2 , 5 mL)

according to GP8 and purification by recrystallization (CHCl₃/hex-

ane, 5:1) afforded amino acid 31 (130 mg, 72%) as fine, colorless

needles.

From Ester 23b: Aqueous NaOH (2 , 2 mL) was added to a solu-

tion of the amino ester 23b (101 mg, 0.29 mmol) in EtOH (6 mL)

and the mixture was heated at 55 °C for 3 h. After the mixture had

cooled to room temperature, EtOH was removed in vacuo and the

solution was acidified with aqueous 3  HCl until a colorless solid

precipitated. The mixture was then extracted with CHCl₃, where-

upon the solid dissolved, and the combined organic phases were

concentrated in vacuo. Purification by recrystallization (CHCl₃/

hexane, 5:1) afforded the amino acid 31 (70 mg, 82%) as fine, color-

less needles.

(؊)-(4R,4aR,7aS)-7a-(Cyanomethyl)-hexahydro-4-(1-methyl-

ethyl)-2H-3,1-cyclopenta[d][1,3]oxazin-2(1H)-one (33a): Treatment

of chloride 32a (348 mg, 1.50 mmol) with NaCN (147 mg,

3.00 mmol) according to GP6 and purification by chromatography

(EtOAc) gave nitrile 33a (308 mg, 92%) as a colorless solid. M.p.

132 °C. [α]_Dϭ Ϫ34.8 (c ϭ 1.63, CH₂Cl₂). ¹H NMR (400 MHz,

CDCl₃): δ ϭ 0.96 (d, J ϭ 6.9 Hz, 3 H, iPr), 1.05 (d, J ϭ 6.9 Hz, 3

H, iPr), 1.47Ϫ1.69 (m, 2 H), 1.73Ϫ2.03 (m, 5 H), 2.28 (td, J ϭ 0.9,

J ϭ 9.8, J ϭ 4.1 Hz, 1 H, CHCN), 2.59 (d, J ϭ 16.7 Hz, 1 H,

CH₂CN), 2.66 (d, J ϭ 16.8 Hz, 1 H, CH₂CN), 3.69 (dd, J ϭ 10.0,

J ϭ 3.4 Hz, 1 H, CHO), 7.53 (s, 1 H, NH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 15.76 (d), 20.15 (d), 23.60 (u), 29.12 (u),

29.79 (d), 31.27 (u), 40.43 (u), 43.04 (d), 62.41 (u), 84.51 (d), 117.12

(u), 157.48 (u) ppm. IR (KBr): ν˜ ϭ 3326 (s), 2971 (m), 2937 (m),

2880 (m), 2256 (m), 1716 (s), 1456 (w), 1412 (m), 1386 (m), 1334

(m), 1301 (m), 1272 (w), 1254 (w), 1192 (w), 1158 (w), 1126 (w),

1055 (w), 1036 (m), 1018 (m) cm^Ϫ1. MS (EI): m/z (relative intensity,

%) ϭ 223 [M^ϩϩ 1] (1), 182 (84), 180 (12), 179 (21), 139 (10), 138

(100), 137 (23), 136 (51), 135 (12), 122 (12), 121 (69), 110 (21), 109

(10), 108 (60), 107 (21), 96 (16), 95 (22), 94 (13), 93 (54), 82 (54),

81 (50), 80 (19). C₁₂H₁₈N₂O₂(222.28): calcd. C 64.84, H 8.16, N

12.60; found C 64.83, H 8.33, N 12.64.

Compound 31: M.p. 185 °C (dec.). [α]_Dϭ Ϫ26.7 (c ϭ 0.45, MeOH).

¹H NMR (400 MHz, CD₃OD): δ ϭ 0.82 (d, J ϭ 6.9 Hz, 3 H, iPr),

1.10 (d, J ϭ 7.1 Hz, 3 H, iPr), 1.30 (s, 3 H, Me), 1.70 (septd, J ϭ

6.9, J ϭ 1.7 Hz, 1 H, iPr), 2.37 (d, J ϭ 15.7 Hz, 1 H, CH₂), 2.53

(d, J ϭ 15.7 Hz, 1 H, CH₂), 3.44 (d, J ϭ 11.5 Hz, 1 H, CHPh),

4.88 (dd, J ϭ 11.5, J ϭ 1.9 Hz, 1 H, HCO), 7.33Ϫ7.45 (m, 5 H,

Ph) ppm. ¹³C NMR (100 MHz, CD₃OD): δ ϭ 12.76 (d), 19.04 (d),

23.46 (d), 28.79 (d), 43.21 (u), 48.52 (d), 54.89 (u), 80.35 (d), 127.82

(d), 128.43 (d), 135.01 (u), 155.38 (u), 172.75 (u) ppm. IR (KBr):

ν˜ ϭ 3372 (m), 3266 (m), 3068 (m), 2974 (m), 2935 (m), 2881 (m),

2734 (w), 2557 (w), 1730 (s), 1717 (s), 1667 (s), 1500 (w), 1469 (m),

1432 (s), 1389 (m), 1377 (m), 1346 (m), 1317 (m), 1288 (w), 1237

(m), 1206 (m), 1192 (m), 1154 (w), 1113 (w), 1101 (w), 1062 (m)

cm^Ϫ1. MS (CI): m/z (relative intensity, %) ϭ 292 [M^ϩϩ 1] (100),

267 (34), 248 (18), 183 (16), 165 (33), 141 (31), 123 (10), 99 (11).

Eur. J. Org. Chem. 2003, 1500Ϫ1526

1523

H.-J. Gais, R. Loo, D. Roder, P. Das, G. Raabe

FULL PAPER

was added and the aqueous phase was extracted with EtOAc. The

combined organic phases were dried (MgSO₄) and concentrated in

vacuo. Chromatography (EtOAc/iPrOH, 8:1) afforded sulfoxide 36

(131 mg, 70%) of 97% ee [GC, octakis(2,6-di-O-pentyl-3-O-bu-

tyryl)-γ-cyclodextrin, t_R(36) ϭ 25.10, t_R(ent-36) ϭ 21.40 min] as

a colorless oil. [α]_Dϭ Ϫ140.2 (c ϭ 2.05, acetone). ¹H NMR

(400 MHz, CDCl₃): δ ϭ 2.73 (s, 3 H, CH₃), 7.47Ϫ7.56 (m, 3 H,

Ph), 7.63Ϫ7.67 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ ϭ 43.89 (d), 123.28 (d), 129.15 (d), 130.82 (d), 145.47 (u) ppm.

(؉)-(4R,4aR,8aS)-8a-(Cyanomethyl)-octahydro-4-(1-methyl-

ethyl)-2H-3,1-benzoxazin-2-one (33b): Treatment of chloride 32b

(186 mg, 0.76 mmol) with NaCN (74 mg, 1.51 mmol) according to

GP6 and purification by chromatography (EtOAc) afforded nitrile

33b (170 mg, 95%) as a colorless solid. M.p. 48Ϫ50 °C. [α]_D

ϭ

ϩ2.86 (c ϭ 0.21, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ ϭ 0.97

(d, J ϭ 6.7 Hz, 3 H, iPr), 1.13 (d, J ϭ 6.7 Hz, 3 H, iPr), 1.19Ϫ1.35

(m, 2 H), 1.51Ϫ1.61 (m, 2 H), 1.69Ϫ1.76 (m, 1 H), 1.80Ϫ1.90 (m,

3 H), 2.00 (septd, J ϭ 6.9, J ϭ 3.0 Hz, 1 H, iPr), 2.08 (dt, J ϭ 9.8,

J ϭ 2.2, J ϭ 2.2 Hz, 1 H, CHCN), 2.74 (d, J ϭ 17.1 Hz, 1 H,

CH₂CN), 2.86 (d, J ϭ 17.1 Hz, 1 H, CH₂CN), 4.28 (dd, J ϭ 9.8,

J ϭ 3.0 Hz, 1 H, CHO), 7.42 (s, 1 H, NH) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ ϭ 14.13 (d), 19.76 (d), 20.40 (u), 22.29 (u),

22.98 (u), 28.10 (u), 28.52 (d), 35.54 (u), 36.23 (d), 53.83 (u), 80.59

(d), 116.26 (u), 155.42 (u) ppm. IR (KBr): ν˜ ϭ 3677 (w), 3652 (w),

3340 (m), 3123 (w), 2939 (s), 2875 (m), 2247 (w), 1707 (s), 1468

(m), 1421 (m), 1383 (m), 1334 (m), 1276 (w), 1244 (w), 1192 (w),

1166 (w), 1142 (w), 1102 (w), 1077 (w), 1034 (m) cm^Ϫ1. MS (CI):

(4R,5R,6S)-Tetrahydro-4-ethenyl-6-ethyl-5-methyl-2H-

1,3-oxazin-2-one (39): ClCO₂CH(Cl)Me (0.13 mL, 1.20 mmol) and

four drops of pyridine were added at room temperature to a solu-

tion of 16a (40 mg, 0.12 mmol) in CH₂Cl₂(2 mL). The yellow mix-

ture was stirred at room temperature for 1 h and then concentrated

in vacuo. Purification by chromatography (EtOAc) gave a mixture

of 39 and 40 in a ratio of 8:1 (119 mg) as a colorless solid.

Compound 39: ¹H NMR (400 MHz, CDCl₃): δ ϭ 0.92 (d, J ϭ

6.7 Hz, 3 H, CHMe), 1.03 (t, J ϭ 7.4 Hz, 3 H, Et), 1.61 (tq, J ϭ

10.0, J ϭ 6.7 Hz, 1 H, CHMe), 1.58 (dquin, J ϭ 14.8, J ϭ 7.4 Hz,

1 H, Et), 1.85 (dqd, J ϭ 14.8, J ϭ 7.4, J ϭ 3.0 Hz, 1 H, Et), 3.46

(dd, J ϭ 10.0, J ϭ 8.3 Hz, 1 H, CHN), 3.93 (ddd, J ϭ 10.0, J ϭ

7.4, J ϭ 3.0 Hz, 1 H, CHO), 5.28 (br. d, J ϭ 9.9 Hz, 1 H, CHϭ

CH₂), 5.29 (br. d, J ϭ 17.1 Hz, 1 H, CHϭCH₂), 5.38 (s, 1 H, NH),

5.65 (ddd, J ϭ 17.1, J ϭ 9.9, J ϭ 8.3 Hz, 1 H, CHϭCH₂) ppm.

¹³C NMR (100 MHz, CDCl₃): δ ϭ 8.25 (d), 12.54 (d), 24.94 (u),

35.16 (d), 61.02 (d), 82.19 (d), 119.75 (u), 136.84 (d), 154.18 (u)

ppm. GC-MS: m/z (relative intensity, %) ϭ 170 [M^ϩϩ 1] (99), 109

(13), 100 (21), 96 (22), 86 (10), 84 (18), 82 (14).

Compound 40: ¹H NMR (400 MHz, CDCl₃) (signals for 40 are par-

tially superposed by those for 39, so only those signals that could

be unequivocally assigned are listed): δ ϭ 1.00 (d, J ϭ 6.7 Hz, 3

H, Me), 1.04 (t, J ϭ 7.4 Hz, 3 H, Et), 3.13 (dd, J ϭ 9.3, J ϭ 1.7 Hz,

1 H, CHNH), 3.90 (m, 1 H, CHO), 4.20 (qd, J ϭ 7.0, J ϭ 1.7 Hz,

1 H, CHCl) ppm. ¹³C NMR (100 MHz, CDCl₃) (only those signals

are listed, which could be unequivocally assigned): δ ϭ 8.37, 13.40,

21.89, 24.88, 33.09, 56.85, 61.99, 81.42 ppm.

m/z (relative intensity, %) ϭ 237 [M^ϩϩ 1] (100). C₁₃H₂₀N₂O₂

Ϫ

CH₂CN: calcd. 196.1338; found (HRMS, EI) 196.1337.

(؊)-(4R,4aR,7aS)-[Hexahydro-4-(1-methylethyl)-2-oxocyclo-

penta[d][1,3]oxazin-7a(4H)-yl]acetic Acid (34a): Treatment of nitrile

33a (107 mg, 0.48 mmol) with aqueous NaOH (2 , 1 mL) accord-

ing to GP8 and purification by chromatography (EtOAc/AcOH,

95:5) afforded amino acid 33a (81 mg, 70%) as a colorless oil.

[α]_Dϭ Ϫ4.4 (c ϭ 1.45, MeOH). ¹H NMR (400 MHz, CDCl₃): δ ϭ

0.95 (d, J ϭ 6.6 Hz, 3 H, iPr), 1.09 (d, J ϭ 6.9 Hz, 3 H, iPr),

1.45Ϫ1.69 (m, 2 H, CH₂), 1.73Ϫ2.02 (m, 5 H, CH₂, iPr, CHCN),

2.25Ϫ2.35 (m, 1 H, CH₂), 2.59 (d, J ϭ 17 Hz, 1 H, CH₂CO), 2.65

(d, J ϭ 17 Hz, 1 H, CH₂CO), 3.69 (dd, J ϭ 10.2, J ϭ 2.8 Hz, 1 H,

CHO), 7.72 (s, 1 H, NH), 10.6 (br. s, 1 H, CO₂H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ ϭ 14.91 (d), 19.90 (d), 22.58 (u), 26.95 (u),

28.71 (d), 38.55 (u), 43.95 (d), 44.94 (u), 61.83 (u), 83.39 (d), 157.97

(u), 173.85 (u) ppm. IR (KBr): ν˜ ϭ 3376 (m), 2970 (s), 2879 (m),

2727 (w), 2627 (w), 1718 (s), 1640 (s), 1545 (w), 1440 (s), 1417 (m),

1394 (w), 1372 (w), 1333 (w), 1287 (w), 1239 (m), 1217 (s), 1182

(m), 1138 (w), 1106 (w), 1070 (m), 1050 (w) cm^Ϫ1. MS (EI): m/z

(relative intensity, %) ϭ 242 [M^ϩϩ 1] (1), 199 (28), 198 (13), 182

(11), 156 (100), 155 (11), 138 (22), 137 (22), 101 (23), 93 (10), 82

(10), 81 (17).

Acknowledgments

Financial support of this work by the Deutsche Forschungsgemein-

schaft (SFB, 380, ‘‘Asymmetric Synthesis with Chemical and Bio-

logical Methods’’ and GKR 440 ‘‘Methods in Asymmetric Syn-

thesis’’) and Grünenthal GmbH, Aachen, is gratefully acknowl-

edged. We thank Dr. J. Runsink for NOE experiments and a re-

viewer for helpful suggestions.

(؊)-(4R,4aR,8aS)-Octahydro-4-(1-methylethyl)-2-oxo-

8aH-3,1-benzoxazin-8a-yl)acetic Acid (34b): Treatment of nitrile

33b (78 mg, 0.33 mmol) with aqueous NaOH (2 , 2 mL) according

to GP8 and purification by chromatography (EtOAc/AcOH, 95:5)

afforded the amino acid 34b (58 mg, 69%) as a colorless solid. M.p.

215 °C (dec.). [α]_Dϭ Ϫ2.6 (c ϭ 1.25, MeOH). ¹H NMR (300 MHz,

CDCl₃): δ ϭ 0.90 (d, J ϭ 6.6 Hz, 3 H, iPr), 1.13 (d, J ϭ 6.9 Hz, 3

H, iPr), 1.18Ϫ1.42 (m, 2 H, CH₂, CHCN), 1.49Ϫ1.84 (m, 6 H,

CH₂), 1.98 (septd, J ϭ 6.9, J ϭ 1.9 Hz, 1 H, iPr), 2.30Ϫ2.43 (m, 2

H, CH₂CO, CHCNH), 3.10 (d, J ϭ 16.8 Hz, 1 H, CH₂CO), 4.39

(dd, J ϭ 10.5, J ϭ 1.9 Hz, 1 H, CHO), 7.67 (s, 1 H, NH), 8.3 (br.

s, 1 H, CO₂H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ ϭ 13.41 (d),

19.79 (d), 20.39 (u), 22.20 (u), 22.50 (u), 27.64 (d), 33.03 (u), 39.17

(d), 40.86 (u), 53.77 (u), 79.27 (d), 156.07 (u), 173.93 (u) ppm. IR

(KBr): ν˜ ϭ 3360 (m), 2985 (m), 2944 (m), 2882 (w), 2515 (w), 1716

(s), 1646 (s), 1442 (s), 1386 (w), 1340 (w), 1307 (w), 1263 (m), 1209

(m), 1169 (w), 1140 (w), 1123 (w), 1101 (w), 1044 (m) cm^Ϫ1. MS

(CI): m/z (relative intensity, %) ϭ 256 [M^ϩϩ 1] (100).

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Article Doi

Asymmetric synthesis of protected β-substituted and β,β-disubstituted β-amino acids bearing branched hydroxyalkyl side chains and of protected 1,3-amino alcohols with three contiguous stereogenic centers from allylic sulfoximines and aldehydes

DOI: 10.1002/ejoc.200390210

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Full text of DOI:10.1002/ejoc.200390210

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