Oxazinanones as chiral auxiliaries: Synthesis and evaluation in enolate alkylations and aldol reactions

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Oxazinanones as chiral auxiliaries: synthesis and evaluation in enolate

alkylations and aldol reactions

Stephen G. Davies,* A. Christopher Garner, Paul M. Roberts, Andrew D. Smith, Miles J. Sweet and

James E. Thomson

Received 20th March 2006, Accepted 17th May 2006

First published as an Advance Article on the web 13th June 2006

DOI: 10.1039/b604073j

Homochiral b-amino esters (prepared on multigram scale by lithium amide conjugate addition) are

readily transformed into oxazinanones. N-Acyl derivatives of oxazinanones undergo stereoselective

enolate alkylation reactions, with higher stereoselectivities observed for the enolate alkylation of

(R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one than the corresponding Evans

oxazolidin-2-one. A C(4)-iso-propyl stereodirecting group within the oxazinanone conveys higher

stereoselectivity than the analogous C(4)-phenyl substituent. gem-Dimethyl substitution at C(6) within

the oxazinanone framework facilitates exclusive exocyclic cleavage upon hydrolysis to furnish

a-substituted carboxylic acid derivatives and the parent oxazinanone in good yield. Asymmetric aldol

reactions of a range of aromatic and aliphatic aldehydes with the chlorotitanium enolate of

(R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-2-one proceed with excellent diastereoselectivity.

Hydrolysis of the aldol products affords homochiral a-methyl-b-hydroxy-carboxylic acids.

As part of our ongoing programme of research concerned

with the development and synthetic applications of novel chiral

auxiliaries,^4,8an evaluation of the ability of oxazinanones 2

Introduction

The rapid development and widespread use of chiral auxiliaries in

to act as chiral auxiliaries was proposed.⁹The introduction

of an additional carbon within the backbone skeleton of an

oxazinanone, compared to a-amino acid-derived oxazolidinones,

suggested that these oxazinanones could be derived from the

corresponding b-amino acid derivatives 1. It was envisaged

that these starting materials could be readily prepared on a

multigram scale and in either enantiomeric form via the lithium

amide conjugate addition methodology that has been developed

within our laboratory and widely used.¹⁰Variation of the C(4)-

stereodirecting substituent in the oxazinanone would allow the

effect upon the diastereoselectivity of subsequent asymmetric

transformations of 3 to be evaluated. Furthermore, the ability

of a gem-dimethyl substituent at C(6) within the oxazinanone

structure to restrict the conformation of the C(4)-stereodirecting

group through minimisation of 1,3-interactions and to promote

exocyclic cleavage of the chiral fragment by suppression of any

endocyclic cleavage would also be appraised (Fig. 1).

synthetic applications has resulted in a profusion of asymmetric

templates for the preparation of enantiomerically enriched ma-

terials. The most commonly used chiral auxiliaries are derived

from a-amino acids, carbohydrates, or terpenes, as the commercial

availability of these naturally occurring compounds in both enan-

tiomeric forms makes them ideal starting materials. Oxazolidin-2-

ones, ﬁrst introduced by Evans and derived from a-amino acids,

are perhaps the most commonly used chiral auxiliaries in synthesis

and have been successfully applied for an enormous variety of

asymmetric transformations.¹While versatile, alkylations of the

enolates derived from N-acyl oxazolidinones often do not proceed

to completion and with incomplete stereocontrol.²Furthermore,

cleavage of the functionalised fragment from oxazolidinones may

be problematic, with the undesired endocyclic cleavage mode pre-

dominating with bulky a-substituted derivatives.³Within this area

we,⁴and then others,⁵have developed oxazolidinone analogues

with geminal substitution at C(5) that offer two-fold advantages

over traditional Evans oxazolidinones.⁶Primarily, this substi-

tution pattern suppresses the endocyclic cleavage pathway that

can compete upon cleavage of N-acyl oxazolidinones, facilitating

isolation of the enantiomerically enriched target and recycling

of the auxiliary. Furthermore, the C(5)-gem-dimethyl group also

biases the conformation of the adjacent C(4)-stereodirecting group

such that the combination of the gem-dimethyl- and 4-iso-propyl-

groups within an oxazolidinone framework mimics a C(4)-tert-

butyl group, showing enhanced stereoselectivity in a range of

reactions in comparison with the corresponding Evans analogue.⁷

Department of Organic Chemistry, University of Oxford, Chemistry Re-

search Laboratory, Mansﬁeld Road, Oxford, UK OX1 3TA. E-mail:

steve.davies@chem.ox.ac.uk

Fig. 1 b-Amino ester-derived oxazinanones as chiral auxiliaries.

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We detail herein preliminary investigations directed toward the

synthesis of a number of chiral oxazinanone auxiliaries and an

evaluation of their stereodirecting ability in enolate alkylation and

aldol reactions of their N-acyl derivatives.

Results and discussion

Synthesis of oxazinanones

Initial studies focused upon the development of a straightforward

route to the desired oxazinanones from the known b-amino esters

4 and 5, which were prepared following the literature protocol

on a multigram scale by the highly diastereoselective conjugate

addition of lithium (S)-N-benzyl-N-(a-methylbenzyl)amide to the

corresponding a,b-unsaturated esters.¹⁰Elaboration of 4 and 5 to

the corresponding oxazinanones was based around the established

route to the SuperQuat chiral auxiliaries utilising an N-Boc

protecting group as a sacriﬁcial carbonyl equivalent.¹¹b-Amino

esters 4 and 5 were converted to N-Boc protected b-amino esters

6 and 7 in excellent yield by hydrogenolysis and concomitant N-

Boc protection, and then reduced to the N-Boc amino alcohols 8

and 9. Base-promoted cyclisation of N-Boc amino alcohols 8 and

9 generated (R)-4-phenyl-(1,3)-oxazinan-2-one 10 and (R)-4-iso-

propyl-(1,3)-oxazinan-2-one 11 respectively (Scheme 1).

Scheme 2 Reagents and conditions: (i) HCl (g), MeOH, 2 h; (ii) H₂

(5 atm), Boc₂O, Pd(OH)₂/C, MeOH; (iii) MeMgBr, THF, −78 ^◦C to rt;

(iv) MeMgBr, CeCl₃, THF; (v) BuOK, THF, 0 ^◦C to rt. ‡ 20 was not

t

isolated from this reaction protocol.

An alternative strategy for the selective synthesis of N-Boc

alcohols 18 and 19 was also followed, with addition of MeMgBr

to methyl esters 12 and 13 giving the N-protected tertiary alcohols

22 and 23 in reasonable yields. Hydrogenolysis and concomitant

carbamate formation gave N-Boc alcohols 18 and 19 that, upon

treatment with ^tBuOK, gave oxazinanones 16 and 17 respectively

(Scheme 3).

Scheme 1 Reagents and conditions: (i) H₂(5 atm), Boc₂O, Pd(OH)₂/C,

MeOH; (ii) LiAlH₄, THF, 0 ^◦C to rt; (iii) ^tBuOK, THF, 0 ^◦C to rt.

A similar design strategy was applied toward the synthesis of

oxazinanone chiral auxiliaries with geminal dimethyl substitution

at C(6). Transesteriﬁcation of 4 and 5 to the corresponding

methyl esters 12 and 13 was followed by hydrogenolysis and

concomitant carbamate protection, giving 14 and 15 respectively.

Treatment of 14 and 15 with 4.0 equivalents of MeMgBr furnished

(R)-4-phenyl-6,6-dimethyl-(1,3)-oxazinan-2-one 16 and (R)-4-iso-

propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 17 directly, although in

low isolated yields (30 and 35%), along with alcohols 18 and 19

and the corresponding N-acetyl species 20 and 21 in the ratios

40 : 30 : 30 and 46 : 10 : 44 respectively. Reaction optimisation

showed that the addition of cerium chloride¹²to 15 before the

addition of the Grignard reaction suppressed N-acetyl formation,

giving a 50 : 50 mixture of oxazinanone 17 and alcohol 19, with

the resultant crude product mixture treated with ^tBuOK to yield

the oxazinanone 17 in a much improved 57% yield over two steps

from 15 (Scheme 2).

Scheme 3 Reagents and conditions: (i) MeMgBr, THF, −78 ^◦C to rt; (ii)

H₂(5 atm), Boc₂O, Pd(OH)₂/C, MeOH; (iii) ^tBuOK, THF, 0 ^◦C to rt.

X-Ray crystallographic analysis of the C(4)-phenyl oxazi-

nanones 10 and 16 allowed the solid state conformation of these

compounds to be probed. In the C(6)-unsubstituted heterocycle

10, the phenyl group at C(4) is situated in a pseudo-axial position,

whereas 1,3-interactions arising from the presence of geminal

methyl groups at C(6) in 16 may inﬂuence the pseudo-equatorial

orientation of the C(4)-phenyl group (Fig. 2).

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Scheme 4 Reagents and conditions: (i) LiH, CH₃CH₂COCl, THF, 0 ^◦C

to rt; (ii) LiHMDS, CH₃CH₂COCl, THF, −78 ^◦C to rt; (iii) LiHMDS,

PhCH₂COCl, THF, −78 ^◦C to rt.

transformation for the preparation of a-functionalised carboxylate

derivatives, with a number of experimental conditions having

been developed for this transformation. Within this laboratory,

optimised conditions for the alkylation of N-acyl SuperQuat

derivatives involves deprotonation with LiHMDS at −78 ^◦C,

followed by treatment with an electrophile and warming to

ambient temperature.⁶Initial studies applied these conditions to

the benzylation of N-propanoyl oxazinanone 24 giving, at 60%

conversion, a 67 : 33 ratio of the parent oxazinanone 10 and N-

benzyl oxazinanone 29, respectively. Such deacylation reactions

in attempted enolate alkylations are not uncommon^6a,16and this

product distribution presumably arises from decomposition of the

enolate to afford a ketene and the anion of the parent oxazinanone,

which is subsequently alkylated by benzyl bromide to afford N-

benzyl oxazinanone 29. To conﬁrm the nature of this product, an

authentic sample of 29 was prepared directly by deprotonation of

the oxazinanone 10 with LiHMDS, followed by the addition of

BnBr (Scheme 5).

Fig. 2 Chem3D representations of the X-ray crystal structures of

C(4)-phenyl oxazinanones 10 and 16 (some H atoms omitted for clarity).

N-Acylation of oxazinanone auxiliaries

Attention next turned toward the preparation of N-acyl derivatives

of oxazinanones 10, 11, 16 and 17, in order to assess their utility

in asymmetric transformations. A variety of methodologies are

available for N-acylation of a-amino acid-derived oxazolidinones,

and among the most popular is deprotonation with BuLi, followed

by the addition of an acid chloride,¹³although catalytic DMAP

and an organic base can be exploited for the N-acylation of

oxazolidinone auxiliaries, eliminating the need for strong base.¹⁴

Attempts to prepare N-propanoyl derivatives of oxazinanones 10,

11, 16 and 17 using either of these methodologies give disap-

pointing results. Treatment with BuLi and propanoyl chloride

resulted in a complex mixture of products whilst using DMAP

and either Et₃N or Hu¨nig’s base led to inconsistent and incomplete

(typically <50%) reaction conversion. Concurrent with this work,

Hitchcock and co-workers reported difﬁculty in the N-acylation

of their 1,3,4-oxadiazinan-2-one auxiliary,¹⁵with LiH as the base

of choice for this troublesome reaction. The efﬁcacy of LiH

to affect N-acylation of oxazinanone auxiliaries was therefore

investigated. N-Propanoyl oxazinanone 24 was readily prepared

in 83% isolated yield via acylation of oxazinanone 10 following

this procedure, although irreproducible reaction conversion was

noted for acylation of oxazinanones 11, 16 and 17. Treatment of

oxazinanones 11, 16 and 17 with LiHMDS and the requisite acid

chloride, however, proved the optimal synthetic strategy for the

preparation of N-acyl oxazinanone analogues, reliably proceeding

to afford N-acylated oxazinanones 25–28 in moderate to good

yield after puriﬁcation (Scheme 4).

Scheme 5 Reagents and conditions: (i) LiHMDS, THF, −78 ^◦C, then

BnBr to rt.

In order to circumvent this decomposition manifold, it was

proposed that alkylation with the more reactive tert-butyl bro-

moacetate would allow alkylation to occur at lower temperatures,

therefore prevailing over decomposition; a range of bases was

screened in order to determine the most effective reagent for this

protocol. Treatment of 25 with LDA or LiTMP at −78 ^◦C for

one hour, followed by addition of tert-butyl bromoacetate and

With a range of N-acyl derivatives of oxazinanones in hand,

their utility in asymmetric enolate alkylation and aldol reactions

was investigated.

◦

stirring at −78 C for a further hour prior to aqueous work-up,

returned only starting material, whilst LiHMDS and NaHMDS

gave complex product mixtures at poor conversion (<20%). The

more reactive potassium enolate, derived from deprotonation with

KHMDS under these reaction conditions, gave the alkylated

Evaluation of N-acyl oxazinanones in enolate alkylations

The asymmetric alkylation of lithium and sodium enolates of

oxazolidinone and camphor sultam auxiliaries is a common

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Scheme 6 Reagents and conditions: (i) KHMDS, THF, −78 ^◦C, 1 h; (ii) BrCH₂CO₂Bu, −78 ^◦C, 2 h; (iii) NH₄Cl (sat., aq), −78 ^◦C to rt.

t

product 31 in >98% de,¹⁷and in 96% yield and >98% de after

puriﬁcation by column chromatography (Scheme 6).

The effect of changing the C(4)-stereocontrolling group and

the incorporation of the C(6)-gem-dimethyl functionality upon

the stereoselectivity of the reaction was next evaluated, by

treatment of N-propanoyl oxazinanones 24, 26 and 27 under

Scheme 7 Reagents and conditions: LiOH, H₂O₂, THF–H₂O (3 : 1), 0 ^◦C

to rt.

the same conditions. Reaction of the C(4)-phenyl N-propanoyl

oxazinanones 24 and 26 both proceeded with poor conversion and

low stereoselectivity under these conditions. Thus, N-propanoyl

oxazinanone 24 gave, at 40% conversion, C(2^ꢀ)-alkylated product

30 in 39% de,¹⁷while N-propanoyl oxazinanone 26 gave, at 48%

conversion, a 12 : 63 : 25 mixture of oxazinanone 16, the C(2^ꢀ)-

alkylated product 32 (62% de)¹⁷and N-(2^ꢀ-tert-butoxy-2^ꢀ-oxo-

ethyl)oxazinanone 33,¹⁸respectively, indicating that partial enolate

decomposition is observed upon alkylation of 26. In contrast,

C(4)-iso-propyl N-propanoyl oxazinanone 27 proceeded to full

conversion, giving 34 with excellent diastereoselectivity (>98% de)

and in good isolated yield. These results indicate that a C(4)-

iso-propyl substituent conveys better stereofacial selectivity than

the analogous C(4)-phenyl substituent for asymmetric enolate

alkylations (Scheme 6).

To determine the absolute conﬁguration at C(2^ꢀ) within 31

and 34, cleavage of the functionalised fragment from the parent

oxazinanone was undertaken by treatment of 31 and 34 with

lithium hydroperoxide. While treatment of 31 gave a complex

mixture of indeterminable products, treatment of 34 afforded

the parent oxazinanone 17 and (R)-4-tert-butoxy-4-oxo-2-methyl-

butanoic acid 35 {[a]_D²⁵+3.9 (c 0.9 in DCM); lit.¹⁹[a]²_D⁵+3.9 (c 1.0 in

DCM)} in 73 and 68% yields, respectively, after puriﬁcation. These

data demonstrate that gem-dimethyl substitution at C(6) in the

oxazinanone template is necessary for effective exocyclic cleavage

to furnish the desired carboxylic acid derivatives (Scheme 7).

Having demonstrated that alkylation of N-acyl oxazinanone

27 occurs readily with a highly activated electrophile, attention

next turned to exploring the generality of this protocol. Noting

that these systems have a tendency to follow a decomposition

pathway upon warming, the effect of temperature on the sta-

bility of the potassium enolate of N-propanoyl oxazinanone

27 was investigated. Analysis of the product mixtures arising

from treatment of 27 with KHMDS at −78 ^◦C followed by

warming to various temperatures indicated that at −40 ^◦C, <20%

decomposition to the parent oxazinanone 17 occurred. Complete

deacylation was observed upon warming to room temperature.

It was therefore proposed that initial deprotonation at −78 ^◦C,

followed by addition of the electrophile and controlled warming

to −40 ^◦C would extend the range of electrophiles suitable for

alkylation. Using these improved reaction conditions, alkylation

of the potassium enolates of N-propanoyl oxazinanone 27 with

benzyl bromide and allyl bromide, and of N-hydrocinnamoyl

oxazinanone 28 with tert-butyl bromoacetate and methyl iodide

proceeded in moderate to complete conversion,¹⁷and in >98%

de in each case,¹⁷to afford a-substituted N-acyl oxazinanone

derivatives 36–39 which were isolated in moderate to good yields

after chromatography. The conﬁguration at C(2^ꢀ) within 36–39 was

assigned by analogy to that proven for 34 (Scheme 8).

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Scheme

8

Reagents and conditions: (i) KHMDS, THF, −78 ^◦C;

(ii) BrCH₂CO₂Bu, −78 ^◦C then NH₄Cl (sat., aq); (iii) BrCH₂Ph, −78

t

to −40 ^◦C, then NH₄Cl (sat., aq); (iv) BrCH₂CH CH₂, −78 to −40 ^◦C,

=

then NH₄Cl (sat., aq); (v) MeI, −78 to −40 ^◦C, then NH₄Cl (sat., aq).

Fig. 3 Proposed transition state 43 for enolate alkylations of N-acyl

oxazinanones 27 and 28.

The absolute conﬁgurations within 36, 38 and 39 were sub-

sequently determined by hydrolysis with lithium hydroperoxide,

affording both the parent oxazinanone 17 and the a-substituted

carboxylic acid derivatives 40–42 in quantitative yield in each case,

and with comparable spectroscopic properties to the literature in

each case {40 [a]_D²⁵−21.6 (c 0.8 in CHCl₃); lit.²⁰[a]²_D⁵−23.1 (c 1.0

in CHCl₃); 41 [a]²_D⁵+7.7 (c 1.0 in DCM); lit.¹⁹[a]²⁵+7.1 (c 1.0 in

DCM); 42 [a]²_D⁵+26.8 (c 0.6 in CHCl₃); lit.²¹[a]²_D⁵^D+25.5 (c 1.0 in

CHCl₃)} (Scheme 9).

mediated aldol reactions of N-acyl oxazolidinones, although these

reactions proceed with slightly lower selectivity (70–98% de) than

the corresponding dibutylboron enolates (>98% de).²³Similarly,

Hitchcock and co-workers have explored TiCl₄-mediated aldol

reactions of N-propanoyl oxadiazinones, although only moderate

levels of selectivity for a range of aldol products were observed

(50–92% de).¹⁵The titanium enolate of N-propanoyl oxazinanone

26 was generated by the addition of TiCl₄to a solution of

26 in DCM at 0 ^◦C and subsequent addition of Hu¨nig’s base.

The resultant enolate was cooled to −78 ^◦C and treated with

benzaldehyde, and the reaction mixtures were allowed to warm to

room temperature over four hours, giving (at 75% conversion) an

inseparable 76 : 24 mixture of diastereoisomeric aldol products 44

and 45 respectively, in 47% yield after puriﬁcation. Under identical

reaction conditions, the addition of benzaldehyde to C(4)-iso-

propyl N-propanoyl oxazinanone 27 proceeded to 73% conversion

to give (4R,2^ꢀR,3^ꢀR)-46 as a single diastereoisomer in 64% isolated

yield after puriﬁcation (Scheme 10). The relative conﬁguration

Scheme 9 Reagents and conditions: LiOH, H₂O₂, THF–H₂O (3 : 1), 0 ^◦C

to rt.

1

within 46 was initially assigned as syn using 400 MHz H NMR

ꢀ

spectroscopic analysis (J_{2 –3}2.9 Hz) on the assumption that the

hydroxycarbonyl aldol product 46 exists in an intramolecularly hy-

drogen bonded form in solution.²⁴X-Ray crystallographic analysis

of 46 unambiguously established the relative syn-conﬁguration,

with the absolute (4R,2^ꢀR,3^ꢀR)-conﬁguration assigned relative to

the known (R)-stereocentre at C(4). Crystallographic analysis also

showed that a hydrogen bond exists between the C(3^ꢀ) hydroxy

and the endocyclic carbonyl in the solid state, consistent with

The product conﬁguration for enolate alkylations of 27 and 28 is

consistent with preferential alkylation of an intermediate chelated

(Z)-enolate anti-to the C(4)-stereodirecting group, analogous to

that universally accepted for the diastereoselective alkylation of

N-acyl oxazolidinones (Fig. 3).

Having demonstrated the utility of N-acyl oxazolidinones for

the asymmetric synthesis of a-substituted carboxylic acids, their

ability to effect asymmetric aldol reactions was investigated.

1

the suppositions required for analysis of the H NMR coupling

constants to determine the syn-geometry (Fig. 4).

With a successful reaction protocol in hand, the generality of

aldol additions to titanium enolates of N-propanoyl oxazinanone

27 was examined. Although Hitchcock and co-workers have

reported that aldol reactions of N-propanoyl oxadiazinones and

aliphatic aldehydes are sluggish, with the dominant product being

the chiral auxiliary resulting from N-deacylation,^15bthe reactivity

of 27 withavarietyofsubstitutedbenzaldehydes andstraightchain

and a-branched aliphatic aldehydes was investigated for purposes

of comparison. In each case, the reaction proceeded in low to

moderate conversion, but gave each aldol product as essentially

a single diastereoisomer,¹⁷giving aldol products 47–51 in 12–58%

isolated yield and in >98% de after chromatographic puriﬁcation.

Evaluation of N-acyl oxazinanones in aldol reactions

Chiral auxiliary-mediated asymmetric aldol reactions are widely

applied for the synthesis of b-hydroxycarbonyls,²²with a number

of efﬁcient metal-mediated aldol reaction protocols having been

developed within this area. Initial investigations focused upon

boron-mediated aldol reactions of oxazinanone derivatives; how-

ever, both 9-BBN(OTf)- and Et₂BOTf-promoted reactions gave

mixtures of diastereoisomers, consistent with low stereocontrol in

this reaction manifold. As an alternative, the use of titanium(IV)

chloride and an amine base to promote the aldol reaction was

investigated. Within this area, Evans et al. have reported titanium-

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Scheme 10 Reagents and conditions: (i) TiCl₄, DIPEA, DCM, 0 ^◦C, 30 min then PhCHO, −78 ^◦C to rt, 4 h.

Fig. 4 Chem3D representation of the X-ray crystal structure of 46 (some

H atoms omitted for clarity).

Fig. 5 Chem3D representation of the X-ray crystal structure of 50 (some

H atoms omitted for clarity).

These results indicate that titanium enolates of N-propanoyl

oxazinanone 27 accommodate both electron-withdrawing and

electron-donating aromatic and both non-enolizable and eno-

lizable aldehydes in its reactions (Scheme 11).²⁵The relative

The observation of syn-aldol products suggests that the reac-

tions of the chlorotitanium enolate of 27 proceed via a chair-like

Zimmerman–Traxler transition state in which both the aldehyde

and the oxazinanone are co-ordinated to titanium (Fig. 6).²⁶

A

conﬁguration within each aldol product 47–51 was determined

1

similar transition state has been proposed for titanium enolates

ꢀ

to be syn from H NMR coupling constants (J_{2 ,3}2.2–3.3 Hz).

X-Ray crystallographic analysis of aldol product 50 unambigu-

ously conﬁrmed the relative syn-conﬁguration, with the absolute

(4R,2^ꢀR,3^ꢀS)-conﬁguration known relative to the known (R)-

stereocentre at C(4). An intramolecular hydrogen bond between

the C(3^ꢀ)-hydroxy and the endocyclic carbonyl was not present

in the solid state X-ray structure of 50; instead, intermolecular

hydrogen bonds were evident within the lattice (Fig. 5).

Scheme 11 Reagents and conditions: TiCl₄, DIPEA, DCM, 0 ^◦C, 30 min

then RCHO, −78 ^◦C to rt, 4 h.

Fig. 6 Proposed transition state 52 for titanium-mediated aldol reaction

of N-acyl oxazinanone 27.

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of N-acyl oxazolidinones, N-acyl oxazolidinethiones, and N-acyl

thiazolidinethiones to rationalise the observed non-Evans syn

aldol product.²⁷

Experimental

General experimental

Cleavage of the aldol products 46–50 to the corresponding a-

methyl-b-hydroxy-carboxylic acids was next investigated. Treat-

ment of aldol products 46–50 with lithium hydroperoxide afforded

the corresponding a-methyl-b-hydroxy-carboxylic acid derivatives

53–57 in high yield and as single diastereoisomers in each case,

consistent with no epimerisation in this cleavage step. The parent

oxazinanone 17 was also returned in quantitative yield in each case

(Scheme 12). Carboxylic acids 53, 56 and 57 showed comparable

spectroscopic properties to the reported literature values {53 [a]_D²²

+28.5 (c 1.0 in CHCl₃), lit.²⁸[a]_D²⁰+28.5 (c 1.2 in CHCl₃); 56

[a]²_D²−4.0 (c 0.8 in CHCl₃), lit.²⁹[a]_D²³−4.1 (c 0.7 in CHCl₃);

57 [a]_D²²+11.3 (c 0.7 in CHCl₃), lit.³⁰[a]²_D⁰+10.5 (c 0.1 in

CHCl₃)}. The conﬁgurations within 54 and 55 were assigned by

analogy.

All reactions involving organometallic or other moisture-sensitive

reagents were carried out under a nitrogen or argon atmosphere

using standard vacuum line techniques and glassware that was

ﬂame dried and cooled under nitrogen before use. Solvents were

dried by passing through a column of activated basic alumina

(Brockmann 1, standard grade, ca. 150 mesh) according to

the procedure outlined by Grubbs and co-workers.³¹Water was

R

puriﬁed by an Elix^ꢀUV-10 system. All other solvents were used

as supplied (analytical or HPLC grade) without prior puriﬁcation.

Organic layers were dried over MgSO₄. Thin layer chromatography

was performed on aluminium plates coated with 60 F₂₅₄silica.

Plates were visualised using UV light (254 nm), iodine, 1% aq

KMnO₄, or 10% ethanolic phosphomolybdic acid. Flash column

chromatography was performed on Kieselgel 60 silica.

Elemental analyses were recorded by the microanalysis service

of the Inorganic Chemistry Laboratory, University of Oxford,

UK. Melting points were recorded on a Gallenkamp Hot Stage

apparatus and are uncorrected. Optical rotations were recorded

on a Perkin-Elmer 241 polarimeter with a water-jacketed 10 cm

cell. Speciﬁc rotations are reported in 10⁻¹deg cm²g⁻¹and

concentrations in g/100 mL. IR spectra were recorded on Bruker

Tensor 27 FT-IR spectrometer as either a thin ﬁlm on NaCl

plates (ﬁlm) or a KBr disc (KBr), as stated. Selected characteristic

peaks are reported in cm⁻¹. NMR spectra were recorded on either

a Bruker Avance 500 or a Bruker Avance 400 spectrometer in

the deuterated solvent stated. The ﬁeld was locked by external

referencing to the relevant deuteron resonance. Low-resolution

mass spectra were recorded on either a VG MassLab 20-250 or a

Micromass Platform 1 spectrometer. Accurate mass measurements

were run on either a Bruker MicroTOF and were internally

calibrated with polyanaline in positive and negative modes, or

a Micromass GCT instrument ﬁtted with a Scientiﬁc Glass

Instruments BPX5 column (15 m × 0.25 mm) using amyl acetate

as a lock mass.

Scheme 12 Reagents and conditions: LiOH, H₂O₂, THF–H₂O (3 : 1), 0 ^◦C

to rt.

Conclusion

In conclusion, oxazinanones are readily prepared from b-amino

esters, and N-acylated by deprotonation with LiHMDS and addi-

tion of the desired acid chloride. Both counterion and temperature

play an important role in the stability of enolates generated

from N-acyl oxazinanones, with asymmetric alkylation readily

achieved by formation of the potassium enolate, addition of the

electrophile at −78 ^◦C and controlled warming to −40 ^◦C. A C(4)-

iso-propyl stereodirecting group conveys higher stereoselectivity

than the analogous C(4)-phenyl substituent in these alkylation

reactions, with gem-dimethyl substitution at C(6) facilitating

exclusive exocyclic cleavage upon hydrolysis to furnish the target

a-substituted carboxylic acids and the parent oxazinanone nearly

quantitatively. Furthermore, asymmetric aldol reactions of a range

of aromatic and aliphatic aldehydes with the chlorotitanium

enolate of (R)-N-propanoyl-4-iso-propyl-6,6-dimethyl-oxazinan-

2-one 27 proceed with excellent diastereoselectivity (>98% de)

for the non-Evans syn-conﬁguration. Treatment of the syn-aldol

products with lithium hydroperoxide affords homochirala-methyl-

b-hydroxy-carboxylic acids as single diastereoisomers in excellent

yield and returns the parent oxazinanone in quantitative yield.

Further applications of oxazinanones as chiral auxiliaries, and

the preparation and evaluation of alternative chiral auxiliaries

derived from b-amino acid derivatives, are currently underway in

this laboratory.

General procedure 1: tandem hydrogenolysis and N-carbamylation

Pd(OH₂)/C (catalytic) was added to a vigorously stirred solution

of the requisite amine (1.0 equiv.) and Boc₂O (1.1 equiv.) in

degassed MeOH at rt. The reaction vessel was ﬂushed with H₂

and the reaction mixture was left to stir under H₂(5 atm) for 24 h.

R

The reaction mixture was ﬁltered through Celite^ꢀ(eluent EtOAc)

and concentrated in vacuo.

General procedure 2: reduction of tert-butyl ester with LiAlH₄

A solution of substrate (1.0 equiv.) in THF at 0 ^◦C was treated with

LiAlH₄(5.0 equiv.). The reaction mixture was allowed to warm to

rt over 12 h, then cooled again to 0 ^◦C prior to the careful addition

of ice. The resulting mixture was diluted with EtOAc, stirred for

R

several hours, then ﬁltered through Celite^ꢀ(eluent EtOAc) and

concentrated in vacuo.

General procedure 3: cyclisation promoted by ^tBuOK

^tBuOK (1.5 equiv.) was added to a solution of N-Boc amino

alcohol (1.0 equiv.) in THF at 0 ^◦C. After being allowed to warm

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to rt over 12 h, NH₄Cl (sat., aq) was added. The resulting mixture

was extracted with EtOAc and the organic phase was washed with

brine, then dried and concentrated in vacuo.

(10 mL) under H₂(5 atm) at rt gave the crude reaction mixture.

Puriﬁcation via ﬂash column chromatography (eluent pentane–

◦

Et₂O 20 : 1) gave 6 as a white solid (1.50 g, 94%); mp 61–63 C

(Et₂O); [a]²_D⁵+21.0 (c 1.0 in CHCl₃); m_max(KBr) 3406 (N–H), 1731

General procedure 4: Grignard addition

=

(C O, ester), 1695 (C O, carbamate); d_H(400 MHz, CDCl₃) 1.34

(9H, s, CMe₃), 1.43 (9H, s, CMe₃), 2.62–2.80 [2H, m, C(2)H₂],

5.02–5.11 [1H, m, C(3)H], 5.49 (1H, br s, NH), 7.19–7.35 (5H,

m, Ph); d_C(100 MHz, CDCl₃) 27.9, 28.3, 42.2, 57.0, 81.1, 126.2,

127.3, 128.3, 128.4, 128.5, 155.0, 173.1; m/z (APCI⁺) 166 ([M −

MeMgBr (3.0 equiv.) was added to a solution of b-amino methyl

ester (1.0 equiv.) in THF at −78 ^◦C. After being allowed to warm

to rt over 12 h, the reaction mixture was cooled to 0 ^◦C and NH₄Cl

(sat., aq) was added. The resulting mixture was allowed to warm

to rt over 30 min, then extracted with DCM. The organic phase

was washed with brine, then dried and concentrated in vacuo.

C₉H₁₆O₂]⁺, 100%); HRMS (ESI⁺) C₁₈H₂₈NO₄(M + H⁺) requires

+

322.2018; found 322.2024.

tert-Butyl (R)-3-[N-(tert-butoxycarbonyl)amino]-4-

methylpentanoate 7

General procedure 5: N-acylation of oxazinanones

LiHMDS (1.2 equiv.) was added to a solution of oxazinanone

(1.0 equiv.) in THF at −78 ^◦C. After 30 min, the requisite acid

chloride (1.5 equiv.) was added. The reaction mixture was allowed

to warm to rt over 12 h, followed by addition of NH₄Cl (sat.,

aq). The resulting mixture was extracted with either EtOAc and

the organic phase was washed with NaHCO₃(sat., aq), dried, and

concentrated in vacuo.

Following General procedure 1, Pearlman’s catalyst (3.15 g), 5

(6.30 g, 16.0 mmol) and Boc₂O (3.90 g, 18.0 mmol) in MeOH

(10 mL) under H₂(5 atm) at rt gave the crude reaction mixture.

Puriﬁcation via ﬂash column chromatography (eluent pentan_◦e :

Et₂O 20 : 1) gave 7 as a white solid (4.20 g, 89%); mp 79–80 C

(Et₂O); [a]²_D³−24.7 (c 1.0 in CHCl₃); m_max(KBr) 3329 (N–H), 1728

=

(C O, ester), 1680 (C O, carbamate); d_H(400 MHz, CDCl₃)

0.91 [3H, d, J 6.8, C(5)H₃], 0.92 [3H, d, J 6.8, C(4)Me], 1.43

(9H, s, CMe₃), 1.45 (9H, s, CMe₃), 1.74–1.82 [1H, m, C(4)H],

2.33 [1H, dd, J 14.9, 7.6 Hz, C(2)H_A], 2.44 [1H, dd, J 14.9,

4.8 Hz, C(2)H_B], 3.72–3.79 [1H, m, C(3)H], 4.88 (1H, d, J 9.3 Hz,

NH); d_C(125 MHz, CDCl₃) 18.3, 19.1, 28.0, 28.3, 32.0, 38.5,

53.0, 78.8, 80.7, 155.4, 171.1; m/z (ESI⁺) 310 ([M + Na]⁺, 100%);

HRMS (ESI⁺) C₁₅H₂₉NO₄Na⁺([M + Na]⁺) requires 310.1994;

found 310.1990.

General procedure 6: carboximide hydrolysis with lithium

hydroperoxide

A solution of substrate (1.0 equiv.) in THF–H₂O (v : v, 3 : 1) at

0 ^◦C was treated with 35% aqueous H₂O₂(5.0 equiv.) and LiOH

(2.0 equiv.). After being allowed to warm to rt over 16 h, Na₂SO₄

(10%, aq) was added and the reaction mixture was stirred for a

further 30 min. The mixture was then buffered to pH 9–10 with

NaHCO₃(sat., aq) and extracted with DCM. The organic layer

was dried and concentrated in vacuo to afford the requisite oxazi-

nanone. The aqueous layer was acidiﬁed to pH 1–2 with HCl (2 M,

aq), extracted with EtOAc, and the organic extracts were dried and

concentrated in vacuo to afford the requisite carboxylic acid.

(R)-3-[N-(tert-Butoxycarbonyl)amino]-3-phenylpropan-1-ol 8

Following General procedure 2, LiAlH₄(1.0 M in THF, 4.0 mL,

◦

4.0 mmol) and 6 (254 mg, 0.79 mmol) in THF (20 mL) at 0 C

gave the crude reaction mixture. Puriﬁcation via ﬂash column

chromatography (eluent pentane : Et₂O 10 : 1, increased to MeOH)

gave 8 as a colourless oil (169 mg, 85%); [a]²_D⁵+55.4 (c 1.0 in

General procedure 7: alkylation of N-acyl oxazinanone

A solution of N-acyl oxazinanone (1.0 equiv.) in THF at −78 ^◦C

was treated with KHMDS (1.25 equiv.). After 1 h, the requisite

electrophile (1.5–3.0 equiv.) was added and the reaction mixture

=

CHCl₃); m_max(ﬁlm) 3350 (O–H, br), 1689 (C O); d_H(400 MHz,

CDCl₃) 1.42 (9H, s, CMe₃), 1.86–1.96 [2H, m, C(2)H₂], 3.49–

3.62 [2H, m, C(1)H₂], 4.68–4.72 [1H, m, C(3)H], 7.21–7.35 (5H,

m, Ph); d_C(100 MHz, CDCl₃) 27.8, 39.6, 52.1, 58.8, 79.1, 126.4,

126.5, 126.7, 127.0, 128.4, 128.5, 143.9, 156.9; m/z (APCI⁺) 152

([M − C₅H₈O₂]⁺, 100%); HRMS (ESI⁺) C₁₄H₂₂NO₃([M + H]⁺)

requires 252.1600; found 252.1600.

◦

was either: (Method A) stirred at −78 C for 3 h; or (Method B)

warmed to −40 ^◦C and stirred for 3–5 h. NH₄Cl (sat., aq) was

added and the reaction mixture was allowed to warm to rt, then

extracted with EtOAc. The organic phase was washed with brine,

then dried and concentrated in vacuo.

General procedure 8: aldol condensation with titanium(IV) chloride

(R)-3-[N-(tert-Butoxycarbonyl)amino]-4-methylpentan-1-ol 9

A solution of N-propanoyl oxazinanone (1.0 equiv.) in DCM at

0 ^◦C was treated with TiCl₄(1.05 equiv.) and DIPEA (1.1 equiv.).

The resultant dark red enolate was stirred for 30 min, then the

reaction mixture was cooled to −78 ^◦C. Freshly distilled aldehyde

was added, and the reaction mixture was allowed to warm to rt

over 4 h. NH₄Cl (sat., aq) was added and the organic phase was

washed with brine, then dried and concentrated in vacuo.

Following General procedure 2, LiAlH₄powder (2.80 g, 73.0 mmol)

and 7 (4.20 g, 14.6 mmol) in THF (200 mL) at 0 ^◦C gave the crude

reaction mixture. Puriﬁcation via ﬂash column chromatography

(eluent pentane : Et₂O 10 : 1, increased to MeOH) gave 9 as a

colourless oil (2.70 g, 84%); [a]²_D⁵−0.93 (c 1.2 in CHCl₃); m_max(ﬁlm)

=

3341 (O–H, br), 1688 (C O), 1530 (amide II); d_H(400 MHz,

CD₃OD) 0.92 [6H, app t, J 7.3 Hz, C(4)Me₂], 1.46 (9H, s,

CMe₃), 1.49–1.55 [1H, m, C(2)H_A], 1.67–1.79 [2H, m, C(2)H_Band

C(4)H], 3.42–3.46 [1H, m, C(3)H], 3.54–3.64 [2H, m, C(1)H₂];

d_C(100 MHz, CD₃OD) 18.9, 20.0, 29.2, 34.2, 36.4, 54.4, 60.8,

80.2, 159.2; m/z (ESI⁺) 240 ([M + Na]⁺, 100%); HRMS (ESI⁺)

tert-Butyl (R)-3-[N-(tert-butoxycarbonyl)amino]-3-

phenylpropanoate 6

Following General procedure 1, Pearlman’s catalyst (1.05 g), 4

(2.10 g, 5.10 mmol) and Boc₂O (1.20 g, 5.60 mmol) in MeOH

+

C₁₁H₂₄NO₃requires ([M + H]⁺) 218.1756; found 218.1753.

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=

(R)-4-Phenyl-(1,3)-oxazinan-2-one 10

1.0 in CHCl₃); m_max(KBr) 1698 (C O); d_H(400 MHz, CDCl₃)

1.44 [3H, s, C(6)Me_A], 1.52 [3H, s, C(6)Me_B], 1.83 [1H, dd, J 13.8,

11.8 Hz, C(5)H_A], 2.02 [1H, ddd, J 13.8, 4.7, 1.5 Hz, C(5)H_B], 4.62

[1H, dd, J 11.8, 4.7 Hz, C(4)H], 5.76 (1H, br s, NH), 7.31–7.47

(5H, m, Ph); d_C(100 MHz, CDCl₃) 25.6, 29.4, 42.0, 53.0, 78.5,

126.1, 128.5, 129.1, 140.9, 154.0; m/z (APCI⁺) 206 ([M + H]⁺,

t

Following General procedure 3, BuOK (60 mg, 0.54 mmol) and

8 (90 mg, 0.36 mmol) in THF at 0 ^◦C gave the crude reaction

mixture. Recrystallisation from EtOAc gave 10 as white crystals

(40 mg, 63%); C₁₀H₁₁NO₂requires C, 67.8; H, 6.3; N, 7.9%; found

◦

C, 67.6; H, 6.3; N, 7.8%; mp 148–154 C (EtOAc); [a]²_D⁵+58.5

100%); HRMS (ESI⁺) C₁₂H₁₆NO₂([M + H]⁺) requires 206.1181;

+

=

(c 1.0 in CHCl₃); m_max(KBr) 1674 (C O); d_H(400 MHz, CDCl₃)

found 206.1179.

1.97–2.03 [1H, m, C(5)H_A], 2.24–2.29 [1H, m, C(5)H_B], 4.29–4.32

[2H, m, C(6)H₂], 4.65–4.69 [1H, m, C(4)H], 5.76 (1H, br s, NH),

7.31–7.42 (5H, m, Ph); d_C(100 MHz, CDCl₃) 30.8, 54.9, 64.9,

126.0, 128.3, 129.0, 141.1, 154.0; m/z (APCI⁺) 178 ([M + H]⁺,

◦

Data for 18: mp 137–138 C (EtOAc); [a]²_D⁵+41.3 (c 1.1 in

=

CHCl₃); m_max(KBr) 3383 (O–H), 1682 (C O), 1528 (amide II);

d_H(400 MHz, CDCl₃) 1.26 [3H, s, C(CH₃)_A(CH₃)_B], 1.34 [3H, s,

C(CH₃)_A(CH₃)_B], 1.41 (9H, s, CMe₃), 1.84–1.98 [2H, m, C(3)H₂],

2.34 (1H, br s, OH), 4.84 [1H, app br s, C(4)H], 5.49 (1H, br s,

NH), 7.23–7.35 (5H, m, Ph); d_C(100 MHz, CDCl₃) 28.3, 31.1,

49.6, 52.5, 70.6, 79.7, 126.1, 127.1, 128.7, 144.0, 155.7; m/z (ESI⁺)

100%); HRMS (ESI⁺) C₁₀H₁₂NO₂([M + H]⁺) requires 178.0868;

+

found 178.0865.

X-Ray crystal structure determination for 10. Data were col-

lected using an Enraf-Nonius j-CCD diffractometer with graphite

monochromated Mo-Ka radiation using standard procedures at

190 K. The structure was solved by direct methods (SIR92),

all non-hydrogen atoms were reﬁned with anisotropic thermal

parameters. Hydrogen atoms were added at idealised positions.

The structure was reﬁned using CRYSTALS.³²

302 ([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₆H₂₆NO₃([M + H]⁺)

+

requires 280.1913; found 280.1912.

X-Ray crystal structure determination for 16. Data were col-

lected using an Enraf-Nonius j-CCD diffractometer with graphite

monochromated Mo-Ka radiation using standard procedures at

190 K. The structure was solved by direct methods (SIR92),

all non-hydrogen atoms were reﬁned with anisotropic thermal

parameters. Hydrogen atoms were added at idealised positions.

The structure was reﬁned using CRYSTALS.³²

X-Ray crystal structure data for 10 [C₁₀H₁₁NO₂]: M = 177.20,

orthorhombic, space group P2₁2₁2₁, a = 5.9454(2), b = 8.1078(3),

3

−1

˚

c = 18.0676(6) A, V = 870.93(5) A , Z = 4, l = 0.095 mm ,

colourless plate, crystal dimensions = 0.05 × 0.1 × 0.1 mm. A

total of 1167 unique reﬂections were measured for 5 < h < 27 and

1056 reﬂections were used in the reﬁnement. The ﬁnal parameters

were wR₂= 0.033 and R₁= 0.028 [I > 3r(I)].

X-Ray crystal structure data for 16 [C₁₂H₁₅NO₂]: M = 205.25,

orthorhombic, space group P2₁2₁2₁, a = 9.2401(1), b = 10.5810(1),

3

−1

˚

c = 46.9695(5) A, V = 4592.18(8) A , Z = 16, l = 0.081 mm ,

colourless block, crystal dimensions = 0.1 × 0.1 × 0.1 mm. A total

of 5748 unique reﬂections were measured for 5 < h < 27 and 4682

reﬂections were used in the reﬁnement. The ﬁnal parameters were

wR₂= 0.048 and R₁= 0.067 [I > 0.5r(I)].

CCDC reference number 280051. For crystallographic data in

CIF or other electronic format see DOI: 10.1039/b604073j.

CCDC reference number 280052. For crystallographic data in

CIF or other electronic format see DOI: 10.1039/b604073j.

(R)-4-iso-Propyl-(1,3)-oxazinan-2-one 11

Following General procedure 3, ^tBuOK (300 mg, 2.66 mmol) and

9 (385 mg, 1.77 mmol) in THF (20 mL) at 0 ^◦C gave the crude

reaction mixture. Puriﬁcation via ﬂash column chromatography

(eluent EtOAc) gave 11 as a white solid (80 mg, 32%); mp 62–64 ^◦C

Attempted preparation of (R)-4-iso-propyl-6,6-dimethyl-(1,3)-

oxazinan-2-one 17 by Grignard addition to 15, and concomitant

cyclisation

(EtOAc); [a]²_D⁵+23.8 (c 1.0 in CHCl₃); m_max(KBr) 1696 (C O); d_H

=

Following General procedure 4, MeMgBr (3.0 M in Et₂O, 1_◦.50 mL,

4.60 mmol) and 15 (285 mg, 1.2 mmol) in THF at −78 C gave

a 46 : 10 : 44 ratio of 17 : 19 : 21 respectively. Puriﬁcation via

ﬂash column chromatography (eluent pentane : EtOAc 1 :1, then

EtOAc, then MeOH) gave 17 as a colourless oil (ﬁrst to elute,

70 mg, 35%), 19 as a white solid (second to elute, 15 mg), and 21

as a colourless oil (third to elute, 66 mg).

(400 MHz, CDCl₃) 0.92 [3H, d, J 6.8 Hz, C(4)CMe_A], 0.96 [3H, d,

J 6.7 Hz, C(4)CMe_B], 1.67–1.79 [2H, m, C(5)H_Aand C(4)CHMe₂],

1.84–1.90 [1H, m, C(5)H_B], 3.22–3.27 [1H, m, C(4)H], 4.17 [1H,

app td, J 11.0, 2.7 Hz, C(6)H_A], 4.32 [1H, app dt, J 11.0, 3.9 Hz,

C(6)H_B], 6.29 (1H, br s, NH); d_C(100 MHz, CDCl₃) 17.5, 18.1,

23.9, 32.4, 56.5, 65.7, 154.9; m/z (APCI⁺) 144 ([M + H]⁺, 100%);

HRMS (ESI⁺) C₇H₁₄NO₂([M + H]⁺) requires 144.1025; found

+

Data for 17: [a]²_D⁵+3.3 (c 1.0 in CHCl₃): m_max(ﬁlm) 1703 (C O);

=

144.1020.

d_H(400 MHz, CDCl₃) 0.93 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B],

0.96 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 1.38 [3H, s, C(6)Me_A],

1.42 [3H, s, C(6)Me_B], 1.50–1.56 [1H, m, C(5)H_A], 1.67–1.75 [2H,

m, C(5)H_Band CHMe₂], 3.29 [1H, app dt, J 12.0, 5.3 Hz, C(4)H],

6.10 (1H, br s, NH); d_C(100 MHz, CDCl₃) 17.5, 18.0, 25.2, 29.7,

32.4, 35.0, 53.5, 78.0, 154.7; m/z (APCI⁺) 172 ([M + H]⁺, 100%);

Attempted preparation of (R)-4-phenyl-6,6-dimethyl-(1,3)-

oxazinan-2-one 16 by Grignard addition to 14, and concomitant

cyclisation

Following General procedure 4, MeMgBr (3.0 M in Et₂O, 0.97 mL,

2.90 mmol) and 14 (200 mg, 0.72 mmol) in THF at −78 ^◦C gave

a 40 : 30 : 30 ratio of 16 : 18 : 20 respectively. Puriﬁcation via

ﬂash column chromatography (eluent pentane : EtOAc 1 : 1, then

EtOAc) gave 16 as a white solid (ﬁrst to elute, 44 mg, 30%), and

18 as a colourless oil.

HRMS (ESI⁺) C₉H₁₈NO₂([M + H]⁺) requires 172.1338; found

+

172.1337.

Data for 19: mp 58–60 ^◦C (EtOAc); [a]_D²⁵−7.27 (c 1.1 in CHCl₃);

=

m_max(ﬁlm) 3384 (O–H), 1685 (C O), 1527 (amide II); d_H(500 MHz,

CDCl₃) 0.93 [3H, d, J 6.6 Hz, CH(CH₃)_A(CH₃)_B], 0.97 [3H,

d, J 7.1 Hz, CH(CH₃)_A(CH₃)_B], 1.30 [3H, s, C(CH₃)_A(CH₃)_B],

1.32 [3H, s, C(CH₃)_A(CH₃)_B], 1.49 [9H, s, OC(CH₃)₃], 1.51–1.56

Data for 16: C₁₂H₁₅NO₂requires C, 70.2; H, 7.4; N, 6.8%; found

◦

C, 70.2; H, 7.35; N, 6.8%; mp 82–84 C (EtOAc); [a]²_D⁵+31.8 (c

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[1H, m, C(3)H_A], 1.63–1.68 [1H, m, C(3)H_B], 1.78–1.82 [1H, m,

C(5)H], 3.73 [1H, app br s, C(4)H], 4.60 (1H, br s, NH); d_C

(100 MHz, CDCl₃) 17.4, 18.6, 28.3, 29.2, 30.3, 33.3, 45.4, 52.1,

69.9, 79.5, 157.0; m/z (ESI⁺) 268 ([M + Na]⁺, 100%); HRMS

1.12 [3H, s, C(CH₃)_A(CH₃)_B], 1.45 [3H, d, J 7.1 Hz, C(a)Me], 1.79

[1H, dd, J 14.5, 11.9 Hz, C(3)H_B], 2.24–2.31 [1H, m, CH(CH₃)₂],

3.10 [1H, dd, J 11.9, 2.0 Hz, C(4)H], 3.64 (1H, d, J 12.8 Hz,

NCH_AH_BPh), 4.00–4.04 [1H, m, C(a)H], 4.19 (1H, d, J 12.8 Hz,

NCH_AH_BPh), 6.32 (1H, br s, OH), 7.19–7.40 (10H, m, Ph); d_C

(100 MHz, CDCl₃) 14.1, 18.5, 22.7, 26.6, 32.4, 36.3, 50.4, 57.4,

69.9, 127.2, 128.2, 128.5, 128.9, 129.5, 139.2; m/z (APCI⁺) 340

([M + H]⁺, 100%); HRMS (ESI⁺) C₂₃H₃₃NO⁺([M + H]⁺) requires

340.2640; found 340.2642.

(ESI⁺) C₁₃H₂₇NNaO₃([M + Na]⁺) requires 268.1889; found

+

268.1878.

Data for 21: [a]²_D³−22.1 (c 2.4 in CHCl₃); m_max(ﬁlm) 3290 (O–H),

=

1652 (C O), 1557 (amide II); d_H(400 MHz, CD₃OD) 0.86–0.92

[6H, m, C(5)Me₂], 1.19 [6H, s, C(2)Me₂], 1.54 (1H, dd, J 14.4, 9.6

z, C(3)H_A], 1.65 [1H, dd, J 14.4, 1.9 Hz, C(3)H_B], 1.69–1.79 [1H,

m, C(5)H], 1.93 [1H, s, CH₃C(O)N], 3.88–3.92, [1H, m, C(4)H]; d_C

(100 MHz, CD₃OD) 17.1, 18.1, 21.8, 27.8, 29.1, 33.9, 44.8, 51.1,

70.1, 171.6; m/z (ESI⁺) 210 ([M + Na]⁺, 100%); HRMS (ESI⁺)

C₁₀H₂₁NO₂Na⁺([M + Na]⁺) requires 210.1470; found 210.1463.

(R)-2-Methyl-4-[N-(tert-butoxycarbonyl)amino]-4-phenylbutan-2-

ol 18

Following General procedure 1, Pearlman’s catalyst (185 mg), 22

(330 mg, 0.88 mmol) and Boc₂O (212 mg, 0.97 mmol) in MeOH

(5mL) under H₂(5 atm) at rt gave the crude reaction mixture.

Puriﬁcation via ﬂash column chromatography (eluent pentane :

EtOAc 5 : 1) gave 18 as a white solid (115 mg, 47%).

Alternative preparation of (R)-4-iso-propyl-6,6-dimethyl-(1,3)-

oxazinan-2-one 17 by modiﬁed Grignard addition to 15, and

cyclisation

Anhydrous cerium(III) chloride beads (442 mg, 1.80 mmol) were

added to a solution of 15 (100 mg, 0.41 mmol) in THF at room

temperature. After 4 h, MeMgBr (3.0 M in Et₂O, 0.90 mL,

2.70 mmol) was added dropwise. After 10 h, the reaction mixture

was treated with a 10% aqueous AcOH solution and stirred for a

further 3 h. The mixture was then diluted with Et₂O and washed

with NaHCO₃(sat., aq) and brine. The combined organic extracts

were dried and concentrated in vacuo to give a mixture of 17 and

19. This mixture was then treated with ^tBuOK (69 mg, 0.62 mmol)

in accordance with General procedure 3 to furnish 17 (40 mg, 57%

over two steps) as a colourless oil.

(R)-2,5-Dimethyl-4-[N-(tert-butoxycarbonyl)amino]hexan-2-ol 19

Following General procedure 1, Pearlman’s catalyst (140 mg), 23

(280 mg, 0.82 mmol) and Boc₂O (200 mg, 0.91 mmol) in MeOH

(5 mL) under H₂(5 atm) at rt gave the crude reaction mixture.

Puriﬁcation via ﬂash column chromatography (eluent pentane :

EtOAc 5 : 1) gave 19 as a white solid (160 mg, 79%).

(R)-4-Phenyl-6,6-dimethyl-(1,3)-oxazinan-2-one 16

Following General procedure 3, ^tBuOK (66 mg, 0.59 mmol) and 18

(110 mg, 0.39 mmol) in THF at 0 ^◦C gave the crude reaction

mixture. Puriﬁcation via ﬂash column chromatography (eluent

pentane : EtOAc 4 : 1, increased to EtOAc) gave 16 as a white

solid (72 mg, 90%).

(4R,aS)-2-Methyl-4-[N-benzyl-N-(a-methylbenzyl)amino]-4-

phenylbutan-2-ol 22

Following General procedure 4, MeMgBr (3.0 M in Et₂O, 1.33 mL,

4.00 mmol) and 12 (500 mg, 1.34 mmol) in THF (25 mL) at

−78 ^◦C gave the crude reaction mixture. Puriﬁcation via ﬂash

column chromatography gave 22 (330 mg, 66%) as a colourless

oil; [a]²_D⁵+54.9 (c 0.5 in CHCl₃); m_max(ﬁlm) 3400 (O–H, br); d_H

(400 MHz, CDCl₃) 0.63 [3H, s, C(CH₃)_A(CH₃)_B], 1.03 [3H, d, J

7.0 Hz, C(a)Me], 1.13 [3H, s, C(CH₃)_A(CH₃)_B], 1.41 [1H, dd, J

14.5, 3.1 Hz, C(3)H_A], 2.45 [1H, dd, J 14.5, 11.1 Hz, C(3)H_B], 3.60

[1H, d, J 13.2 Hz, NCH_AH_BPh], 4.12 [1H, q, J 7.0 Hz, C(a)H], 4.26

(1H, J 13.2 Hz, NCH_AH_BPh), 4.32 [1H, dd, J 11.1, 3.1 Hz, C(4)H],

5.83 (1H, s, OH), 7.23–7.42 (15H, m, Ph); d_C(100 MHz, CDCl₃)

13.6, 27.4, 31.9, 43.6, 50.4, 56.4, 57.6, 70.4, 127.2, 127.3, 128.3,

128.5, 128.7, 128.9, 129.5, 139.0, 141.3, 142.8; m/z (APCI⁺) 374

([M + H]⁺, 50%); HRMS (ESI⁺) C₂₆H₃₂NO⁺([M + H]⁺) requires

374.2484; found 374.2484.

(R)-4-iso-Propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 17

Following General procedure 3, ^tBuOK (69 mg, 0.61 mmol) and 19

(100 mg, 0.41 mmol) in THF at 0 ^◦C gave the crude reaction

mixture. Puriﬁcation via ﬂash column chromatography (eluent

pentane : EtOAc 1 : 1, increased to EtOAc) gave 17 as a colourless

oil (70 mg, quantitative).

(R)-3-Propanoyl-4-phenyl-(1,3)-oxazinan-2-one 24

LiH (9 mg, 1.12 mmol) was added to a solution of 10 (100 mg,

0.56 mmol) in THF (15.0 mL) at 0 ^◦C. After stirring for 30 min,

propanoyl chloride (58 mg, 0.63 mmol) was added dropwise. The

reaction mixture was allowed to warm to rt and stirred for 16 h.

H₂O was then added and the solvent was evaporated in vacuo. The

residue was partitioned between EtOAc and H₂O, and the organic

layer was dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent pentane : EtOAc 10 : 1) furnished

24 as a colourless oil (109 mg, 83%); [a]²_D⁵+36.9 (c 0.8 in CHCl₃);

(4R, aS)-2,5-Dimethyl-4-[N-benzyl-N-(a-

methylbenzyl)amino]hexan-2-ol 23

Following General procedure 4, MeMgBr (3.0 M, 1.18 mL,

3.54 mmol) and 13 (400 mg, 1.18 mmol) in THF (25 mL) at

−78 ^◦C gave the crude reaction mixture. Puriﬁcation via ﬂash

column chromatography gave 23 (215 mg, 54%) as a colourless

oil; [a]²_D¹+10.9 (c 0.6 in CHCl₃); m_max(ﬁlm) 3305 (O–H, br); d_H

(400 MHz, CDCl₃) 0.35 [3H, s, C(CH₃)_A(CH₃)_B], 0.97 [6H, app

t, J 5.6 Hz, CH(CH₃)₂) 1.05 [1H, dd, J 14.5, 2.0 Hz, C(3)H_A],

=

m_max(ﬁlm) 1732 (C O); d_H(400 MHz, CDCl₃) 1.12 (3H, t, J 7.3

z, CH₃CH₂CO), 2.13 [1H, app dq, J 14.1, 4.0 Hz, C(5)H_A], 2.42–

2.51 [1H, m, C(5)H_B], 2.98–3.13 (2H, m, CH₃CH₂CO], 4.17–4.30

[2H, m, C(6)H₂], 5.71 [1H, app t, J 5.1 Hz, C(4)H], 7.17–7.39 (5H,

m, Ph); d_C(125 MHz, CDCl₃) 9.0, 29.7, 32.2, 54.9, 64.3, 125.1,

127.6, 128.4, 128.8, 140.2, 151.6, 176.6; m/z (GCToF MS CI⁺)

2762 | Org. Biomol. Chem., 2006, 4, 2753–2768

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234 ([M + H]⁺, 100%); HRMS (GCToF MS CI⁺) C₁₃H₁₆NO₃

([M + H]⁺) requires 234.1130; found 234.1121.

(R)-3-(3^ꢀ-Phenylpropanoyl)-4-iso-propyl-6,6-dimethyl-(1,3)-

oxazinan-2-one 28

+

Following General procedure 5, LiHMDS (1.0 M in THF, 0.74 mL,

0.74 mmol), 17 (84 mg, 0.49 mmol) in THF at −78 ^◦C, and

hydrocinnamoyl chloride (166 mg, 0.98 mmol) gave the crude

reaction mixture. Puriﬁcation via ﬂash column chromatography

(eluent pentane : EtOAc 4 : 1) gave 28 as a colourless oil (54 mg,

(R)-3-Propanoyl-4-iso-propyl-(1,3)-oxazinan-2-one 25

Following General procedure 5, LiHMDS (1.0 M in THF, 2.35 mL,

2.35 mmol), 11 (280 mg, 1.96 mmol) in THF at −78 ^◦C, and

propanoyl chloride (271 mg, 2.93 mmol) gave the crude reaction

mixture. Puriﬁcation via ﬂash column chromatography (eluent

pentane : EtOAc 4 : 1) gave 25 as a colourless oil (250 mg, 65%);

36%); [a]²_D²+162.8 (c 0.5 in CHCl₃); m_max(ﬁlm) 1736 (C O_endo),

=

1693 (C O_exo); d_H(400 MHz, CDCl₃) 0.83 [3H, d, J 6.8 Hz,

CH(CH₃)_A(CH₃)_B], 0.88 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 1.23

[3H, s, C(6)(CH₃)_A], 1.45 [3H, s, C(6)(CH₃)_B], 1.91 [2H, app d, J

8.6 Hz, C(5)H₂], 2.27–2.36 [1H, m, CH(CH₃)₂], 2.92–3.10 [3H, m,

C(2^ꢀ)H_Aand C(3^ꢀ)H₂], 3.24–3.32 [2H, m, C(2^ꢀ)H_B], 4.40 [1H, app

td, J 8.6, 5.6 Hz, C(4)H], 7.16–7.30 (5H, m, Ph); d_C(100 MHz,

CDCl₃) 15.7, 18.7, 25.4, 29.8, 30.1, 31.1, 33.7, 38.7, 54.8, 79.7,

126.1, 128.2, 128.4, 128.5, 140.9, 153.3, 173.0; m/z (ESI⁺) 362

[a]²_D³+140.8 (c 1.0 in CHCl₃); m_max(ﬁlm) 1744 (C O_endo), 1701

=

(C O_exo); d_H(400 MHz, CDCl₃) 0.73–0.75 [6H, m, CH(CH₃)₂],

1.16 (3H, t, J 7.3 Hz, CH₃CH₂CO), 2.02–2.15 [3H, m, C(5)H₂and

CH(CH₃)₂], 2.75 (1H, dq, J 17.5, 7.3 Hz, CH₃CH_AH_BCO), 3.03

(1H, dq, J 17.5, 7.3 Hz, CH₃CH_AH_BCO), 4.18 [1H, ddd, J 11.3,

6.9, 5.8 Hz, C(6)H_A], 4.35 [1H, app dt, J 11.3, 5.8 Hz, C(6)H_B],

4.65 [1H, app q, J 7.1 Hz, C(4)H); d_C(100 MHz, CDCl₃) 9.3,

17.0, 19.0, 23.6, 30.5, 30.9, 55.2, 65.3, 153.3, 176.1; m/z (CI⁺) 200

([M + H]⁺, 100%); HRMS (CI⁺) C₁₀H₁₈NO₃⁺([M + H]⁺) requires

200.1287; found 200.1278.

([M + MeCN + NH₄]⁺, 50%); HRMS (ESI⁺) C₁₈H₂₆NO₃([M +

+

H]⁺) requires 304.1913; found 304.1908.

(R)-3-Benzyl-4-phenyl-(1,3)-oxazinan-2-one 29

LiHMDS (1.0 M in THF, 0.20 mL, 0.20 mmol) was added to a

solution of 10 (30 mg, 0.17 mmol) in THF at −78 ^◦C. After 30 min,

BnBr (43 mg, 0.25 mmol) was added. The reaction mixture was

allowed to warm to rt over 12 h, followed by addition of NH₄Cl

(sat., aq). The resulting mixture was extracted with EtOAc and the

organic phase was washed with brine, then dried and concentrated

in vacuo to give a 40 : 60 mixture of 10 : 29 respectively. Puriﬁcation

via ﬂash column chromatography (eluent pentane : EtOAc 5 : 1)

gave 29 as a colourless wax (24 mg, 53%); [a]²_D³+25.3 (c 1.6 in

(R)-3-Propanoyl-4-phenyl-6,6-dimethyl-(1,3)-oxazinan-2-one 26

Following General procedure 5, LiHMDS (1.0 M in THF, 1.40 mL,

1.40 mmol), 16 (240 mg, 1.17 mmol) in THF at −78 ^◦C, and

propanoyl chloride (162 mg, 1.75 mmol) gave the crude reaction

mixture. Puriﬁcation via ﬂash column chromatography (eluent

pentane : EtOAc 10 : 1) gave 26 as a colourless oil (268 mg,

88%); [a]²_D⁵+63.9 (c 0.9 in CHCl₃); m_max(ﬁlm) 1734 (C O_endo),

=

1701 (C O_exo); d_H(400 MHz, CDCl₃) 1.07 (3H, t, J 7.2 Hz,

CH₃CH₂CO), 1.40 [3H, s, C(6)(CH₃)_A], 1.48 [3H, s, C(6)(CH₃)_B],

2.07 [1H, dd, J 14.4, 10.8 Hz, C(5)H_A], 2.33 [1H, dd, J 14.4, 7.4 Hz,

C(5)H_B], 2.87 (1H, dq, J 18.4, 7.2 Hz, CH₃CH_AH_BCO), 3.02 (1H,

dq, J 18.4, 7.2 Hz, CH₃CH_AH_BCO), 5.31 [1H, dd, J 10.8, 7.4 Hz,

C(4)H], 7.19–7.35 (5H, m, Ph); d_C(100 MHz, CDCl₃) 9.0, 24.6,

29.0, 31.6, 43.1, 55.6, 79.5, 125.1, 127.4, 128.9, 142.3, 152.0, 176.0;

=

CHCl₃); m_max(ﬁlm) 1689 (C O); d_H(400 MHz, CDCl₃) 1.94 [1H,

app dq, J 14.0, 3.9 Hz, C(5)H_A], 2.31–2.40 [1H, m, C(5)H_B], 3.61

(1H, d, J 15.2 Hz, NCH_AH_BPh), 4.17–4.28 [2H, m, C(6)H₂], 4.47–

4.50 [1H, m, C(4)H], 5.37 (1H, d, J 15.2 Hz, NCH_AH_BPh), 7.21–

7.45 (10H, m, Ph); d_C(100 MHz, CDCl₃) 30.6, 50.2, 56.8, 62.9,

126.5, 127.7, 128.1, 128.2 128.7, 129.1, 136.7, 139.8, 154.5; m/z

m/z (ESI⁺) 284 ([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₀NO₃

+

(ESI⁺) 268 ([M + H]⁺, 100%); HRMS (ESI⁺) C₁₇H₁₈NO₂([M +

+

([M + H]⁺) requires 262.1443; found 262.1449.

H]⁺) requires 268.1338; found 268.1333.

(R)-3-Propanoyl-4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one

27

(4R,2^ꢀR)-3-(4^ꢀ-tert-Butoxy-4^ꢀ-oxo-2^ꢀ-methylbutanoyl)-

4-iso-propyl-(1,3)-oxazinan-2-one 31

Following General procedure 5, LiHMDS (1.0 M in THF, 0.35 mL,

0.35 mmol), 17 (50 mg, 0.29 mmol) in THF at −78 ^◦C, and

propanoyl chloride (41 mg, 0.44 mmol) gave the crude reaction

mixture. Puriﬁcation via ﬂash column chromatography (eluent

pentane : EtOAc 10 : 1) gave 27 as a colourless oil (52 mg,

Following General procedure 7, 25 (15 mg, 0.08 mmol) in

THF at −78 ^◦C was treated with KHMDS (0.5 M in PhMe,

0.20 mL, 0.09 mmol). After 1 h, tert-butyl bromoacetate (0.04 mL,

0.23 mmol) was added. Puriﬁcation via ﬂash column chromatog-

raphy (eluent pentane : Et₂O 10 : 1) gave 31 as a colourless oil

79%); [a]²_D⁴+182.5 (c 1.0 in CHCl₃); m_max(ﬁlm) 1737 (C O_endo),

(22 mg, 96%); [a]²_D⁵+163.7 (c 0.7 in CHCl₃); m_max(ﬁlm) 1731 (C O);

=

1696 (C O_exo); d_H(400 MHz, CDCl₃) 0.82 [3H, d, J 6.8 Hz,

d_H(400 MHz, CDCl₃) 0.89 [3H, d, J 2.4 Hz, CH(CH₃)_A(CH₃)_B],

0.91 [3H, d, J 2.3 Hz, CH(CH₃)_A(CH₃)_B], 1.13 [3H, d, J 7.0 Hz,

C(2^ꢀ)CH₃], 1.43 [9H, s, OC(CH₃)₃], 2.03–2.13 [3H, m, C(5)H₂and

CH(CH₃)₂], 2.28 [1H, dd, J 16.1, 6.3 Hz, C(3^ꢀ)H_A], 2.78 [1H, dd,

J 16.1, 8.1 Hz, C(3^ꢀ)H_B], 4.08–4.20 [2H, m, C(6)H_Aand C(2^ꢀ)H],

4.32–4.38 [1H, m, C(6)H_B], 4.51 [1H, app q, J 7.1 Hz, C(4)H];

d_C(100 MHz, CDCl₃) 17.0, 17.5, 19.0, 23.8, 28.0, 30.7, 36.0,

39.3, 55.6, 65.3, 80.4, 153.1, 171.0, 177.7; m/z (ESI⁺) 336 ([M +

Na]⁺, 100%), 314 (70); HRMS (ESI⁺) C₁₆H₂₇NNaO₅⁺([M + Na]⁺)

requires 336.1787; found 336.1784.

CH(CH₃)_A(CH₃)_B], 0.87 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B], 1.14

(3H, t, J 7.3 Hz, CH₃CH₂CO), 1.34 [3H, s, C(6)(CH₃)_A], 1.46

[3H, s, C(6)(CH₃)_B], 1.88–1.98 [2H, m, C(5)H₂], 2.25–2.37 [1H,

m, CH(CH₃)₂], 2.71 (1H, dq, J 17.4, 7.3 Hz, CH₃CH_AH_BCO),

3.01 (1H, dq, J 17.4, 7.3 Hz, CH₃CH_AH_BCO), 4.42 [1H, app

dt, J 8.7, 5.6 Hz, C(4)H); d_C(100 MHz, CDCl₃) 9.3, 15.7, 18.7,

25.5, 29.8, 30.1, 30.6, 33.7, 54.7, 79.5, 152.9, 175.6; m/z (ESI⁺)

250 ([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₂H₂₂NO₃([M + H]⁺)

+

requires 228.1600, found 228.1596.

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(4R,2^ꢀR)-3-(4^ꢀ-tert-Butoxy-4^ꢀ-oxo-2^ꢀ-methylbutanoyl)-

4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 34

work-up to afford a 50 : 50 mixture of 27 : 37. Puriﬁcation via ﬂash

column chromatography (eluent pentane : Et₂O 5 : 1) gave 37 as a

colourless oil (19 mg, 27%); [a]²_D¹+163.6 (c 1.0 in CHCl₃); mp 40–

Following General procedure 7, 27 (43 mg, 0.19 mmol) in

THF at −78 ^◦C was treated with KHMDS (0.5 M in PhMe,

0.50 mL, 0.24 mmol). After 1 h, tert-butyl bromoacetate (0.08 mL,

0.57 mmol) was added. Puriﬁcation via ﬂash column chromatog-

raphy (eluent pentane : Et₂O 10 : 1) gave 34 as a colourless oil

41 ^◦C (pentane–Et₂O); m_max(ﬁlm) 1736 (C O_endo), 1691 (C O_exo);

d_H(400 MHz, CDCl₃) 0.82 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B],

0.87 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 1.09 [3H, d, J 6.8 Hz,

C(2^ꢀ)CH₃], 1.35 [3H, s, C(6)(CH₃)_A], 1.47 [3H, s, C(6)(CH₃)_B],

1.88–1.98 [2H, m, C(5)H₂], 2.13–2.20 [1H, m, C(3^ꢀ)H_A], 2.23–2.31

[1H, m, CH(CH₃)₂], 2.56–2.63 [1H, m, C(3^ꢀ)H_B], 3.66–3.74 [1H, m,

C(2^ꢀ)H], 4.44 [1H, app td, J 8.7, 5.5 Hz, C(4)H], 5.01–5.10 [2H, m,

C(5^ꢀ)H₂], 5.77–5.88 [1H, m, C(4^ꢀ)H]; d_C(100 MHz, CDCl₃) 15.7,

17.0, 18.7, 25.4, 29.8, 30.2, 33.7, 38.1, 38.2, 54.8, 79.6, 116.7, 135.8,

152.7, 177.9; m/z (ESI⁺) 326 ([M + MeCN + NH₄]⁺, 100%), 290

=

(48 mg, 74%); [a]²_D⁵+120.1 (c 1.0 in CHCl₃); m_max(ﬁlm) 1733 (C O);

=

d_H(400 MHz, CDCl₃) 0.84 [3H, d, J 6.9 Hz, CH(CH₃)_A(CH₃)_B],

0.86 [3H, d, J 7.1 Hz, CH(CH₃)_A(CH₃)_B], 1.10 [3H, d, J 7.0 Hz,

C(2^ꢀ)CH₃], 1.34 [3H, s, C(6)(CH₃)_A], 1.42 [9H, s, OC(CH₃)₃], 1.45

[3H, s, C(6)(CH₃)_B], 1.93 [2H, app d, J 8.7 Hz, C(5)H₂], 2.24–2.33

[2H, m, C(3^ꢀ)H_Aand CH(CH₃)₂], 2.77 [1H, dd, J 16.1 Hz, 8.3,

C(3^ꢀ)H_B], 4.12–4.20 [1H, m, C(2^ꢀ)H], 4.37–4.43 [1H, m, C(4)H];

d_C(100 MHz, CDCl₃) 15.7, 17.3, 18.7, 25.5, 28.0, 29.8, 30.1, 33.7,

35.7, 39.3, 55.0, 79.6, 80.3, 152.6, 171.0, 177.2; m/z (ESI⁺) 364

(50); HRMS (ESI⁺) C₁₅H₂₆NO₃([M + H]⁺) requires 268.1913;

+

found 268.1904.

([M + Na]⁺, 100%); HRMS (ESI⁺) C₁₈H₃₁NNaO₅([M + Na]⁺)

+

(4R,2^ꢀR)-3-(4^ꢀ-tert-Butoxy-4^ꢀ-oxo-2^ꢀ-benzylbutanoyl)-

4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 38

requires 364.2100; found 364.2097.

Following General procedure 7, 28 (60 mg, 0.20 mmol) in

THF at −78 ^◦C was treated with KHMDS (0.5 M in PhMe,

0.50 mL, 0.25 mmol). After 1 h, tert-butyl bromoacetate (0.09 mL,

0.60 mmol) was added. Puriﬁcation via ﬂash column chromatogra-

phy (eluent pentane : Et₂O 10 : 1) gave 38 as a colourless oil (49 mg,

(R)-4-(tert-Butoxy)-4-oxo-2-methylbutanoic acid 35

Following General procedure 6, 34 (45 mg, 0.13 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.06 mL, 0.67 mmol), and

LiOH (6 mg, 0.26 mmol) gave 17 as a colourless oil (16 mg, 73%),

and 35 as a colourless oil (17 mg, 68%); [a]²_D⁵+3.9 (c 0.9 in DCM);

lit.¹⁹[a]_D²⁵+3.9 (c 1.0 in DCM); d_H(400 MHz, CDCl₃) 1.25 [1H, d,

J 7.2 Hz, C(2)CH₃], 1.45 [9H, s, OC(CH₃)₃], 2.37 [1H, dd, J 16.4,

5.9 Hz, C(3)H_A], 2.65 [1H, dd, J 16.4, 8.2 Hz, C(3)H_B], 2.86–2.95

[1H, m, C(2)H].

60%); [a]²_D⁰+108.1 (c 1.0 in CHCl₃); m_max(ﬁlm) 1733 (C O_endo), 1692

=

(C O_exo); d_H(400 MHz, CDCl₃) 0.82–0.86 [6H, m, CH(CH₃)₂],

1.36 [3H, s, C(6)(CH₃)_A], 1.45 [12H, s, C(6)(CH₃)_Band OC(CH₃)₃],

1.70–1.76 [1H, m, C(5)H_A], 1.81–1.91 [1H, m, C(5)H_B], 2.27–2.32

[1H, m, CH(CH₃)₂], 2.36 (1H, dd, J 15.9, 7.3 Hz, CH_AH_BCO₂),

2.70 (1H, dd, J 12.9, 6.3 Hz, CH_AH_BPh), 2.78 (1H, dd, J 15.9,

6.8 Hz, CH_AH_BCO₂), 2.97 (1H, dd, J 12.9, 8.6 Hz, CH_AH_BPh),

4.18–4.29 [2H, m, C(4)H and C(2^ꢀ)H], 7.12–7.29 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 15.8, 18.7, 28.1, 28.8, 30.0, 30.1, 33.7, 37.9,

38.0, 44.1, 54.9, 79.9, 80.6, 126.1, 128.4, 129.2, 139.2, 152.6, 170.7,

175.8; m/z (ESI⁺) 476 ([M + MeCN + NH₄]⁺, 100%), 418 (55);

(4R,2^ꢀR)-3-(2^ꢀ-Methyl-3^ꢀ-phenylpropanoyl)-4-iso-propyl-6,6-

dimethyl-(1,3)-oxazinan-2-one 36

Followi_◦ng General procedure 7, 27 (22 mg, 0.10 mmol) in THF

at −78 C was treated with KHMDS (0.5 M in PhMe, 0.24 mL,

0.12 mmol). After 1 h, BnBr (0.02 mL, 0.15 mmol) was added

and the reaction mixture was stirred at −40 ^◦C for 5 h before

work-up. Puriﬁcation via ﬂash column chromatography (eluent

pentane : Et₂O 5 : 1) gave 36 as a colourless oil (24 mg, 78%); [a]_D²¹

HRMS (ESI⁺) C₂₄H₃₆NO₅([M + H]⁺) requires 418.2593; found

+

418.2600.

(4R,2^ꢀS)-3-(2^ꢀ-Methyl-3^ꢀ-phenylpropanoyl)-4-iso-propyl-6,6-

dimethyl-(1,3)-oxazinan-2-one 39

=

+122.3 (c 1.2 in CHCl₃); m_max(ﬁlm) 1736 (C O_endo], 1692 (C O_exo);

d_H(400 MHz, CDCl₃) 0.77 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B],

0.84 [3H, d, J 6.9 Hz, CH(CH₃)_A(CH₃)_B], 1.05 [3H, d, J 6.7 Hz,

C(2^ꢀ)CH₃], 1.36 [3H, s, C(6)(CH₃)_A], 1.47 [3H, s, C(6)(CH₃)_B],

1.89–1.94 [2H, m, C(5)H₂], 2.18–2.25 [1H, m, CH(CH₃)₂], 2.56

[1H, dd, J 13.2, 9.0 Hz, C(3^ꢀ)H_A], 3.30 [1H, dd, J 13.2, 5.5 Hz,

C(3^ꢀ)H_B], 3.87–3.94 [1H, m, C(2^ꢀ)H], 4.45 [1H, app td, J 8.7,

5.6 Hz, C(4)H], 7.17–7.30 (5H, m, Ph); d_C(100 MHz, CDCl₃)

15.6, 16.6, 18.5, 25.4, 29.7, 30.1, 33.7, 39.8, 40.4, 54.7, 79.5, 126.0,

128.1, 129.2, 139.5, 152.6, 177.9; m/z (ESI⁺) 340 ([M + Na]⁺,

Following General procedure 7, 28 (50 mg, 0.16 mmol) in THF

at −78 ^◦C was treated with KHMDS (0.5 M in PhMe, 0.40 mL,

0.21 mmol). After 1 h, MeI (0.02 mL, 0.33 mmol) was added and

the reaction mixture was stirred at −40 ^◦C for 5 h before work-up

to give a 15 : 85 mixture of 28 : 39 respectively. Puriﬁcation via

ﬂash column chromatography (eluent pentane : Et₂O 10 : 1) gave

39 as a pale yellow oil (20 mg, 38%); [a]²_D⁰+207.0 (c 1.0 in CHCl₃);

100%); HRMS (ESI⁺) C₁₉H₂₈NO₃([M + H]⁺) requires 318.2069;

+

=

m_max(ﬁlm) 1736 (C O_endo), 1690 (C O_exo); d_H(400 MHz, CDCl₃)

0.80 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B], 0.85 [3H, d, J 6.9 Hz,

CH(CH₃)_A(CH₃)_B], 1.34 [3H, s, C(6)(CH₃)_A], 1.36 [3H, d, J 6.8 Hz,

C(2^ꢀ)CH₃], 1.57 [3H, s, C(6)(CH₃)_B], 1.67 [1H, dd, J 13.9, 8.8 Hz,

C(5)H_A], 1.79 [1H, dd, J 13.9, 8.3 Hz, C(5)H_B], 2.23–2.32 [1H, m,

CH(CH₃)₂], 2.65 [1H, dd, J 13.1, 4.8 Hz, C(3^ꢀ)H_A], 3.02 [1H, dd, J

13.1, 10.1 Hz, C(3^ꢀ)H_B], 3.66–3.74 [1H, m, C(2^ꢀ)H], 4.21 [1H, app

td, J 8.4, 6.1 Hz, C(4)H], 7.10–7.23 (5H, m, Ph); d_C(100 MHz,

CDCl₃) 14.0, 16.4, 19.0, 25.4, 29.8, 30.3, 33.8, 40.3, 42.6, 54.6, 79.8,

126.2, 128.3, 129.1, 139.6, 155.4, 175.3; m/z (ESI⁺) 376 ([M +

found 318.2070.

(4R,2^ꢀR)-3-(2^ꢀ-Methyl-4^ꢀ-pentenoyl)-4-iso-propyl-6,6-dimethyl-

(1,3)-oxazinan-2-one 37

Followi_◦ng General procedure 7, 27 (22 mg, 0.10 mmol) in THF

at −78 C was treated with KHMDS (0.5 M in PhMe, 0.24 mL,

0.12 mmol). After 1 h, allyl bromide (0.02 mL, 0.15 mmol) was

added and the reaction mixture was stirred at −40 ^◦C for 5 h before

2764 | Org. Biomol. Chem., 2006, 4, 2753–2768

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MeCN + NH₄]⁺, 100%), 340 (95); HRMS (ESI⁺) C₁₉H₂₈NO₃

([M + H]⁺) requires 318.2069; found 318.2063.

(4R,2^ꢀR,3^ꢀR)-3-(2^ꢀ-Methyl-3^ꢀ-hydroxy-3^ꢀ-phenylpropanoyl)-

4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 46

+

Following General procedure 8, 27 (72 mg, 0.32 mmol) in DCM

(0.3 M) at 0 C, TiCl₄(0.04 mL, 0.33 mmol), DIPEA (0.06 mL,

(R)-2-Methyl-3-phenylpropanoic acid 40

◦

0.35 mmol) and benzaldehyde (distilled from CaH₂, 0.04 mL,

0.35 mmol) at −78 ^◦C gave a 27 : 73 mixture of 27 : 46 respectively.

Puriﬁcation via ﬂash column chromatography (eluent pentane :

Et₂O 6 : 1) gave 46 as a white solid (67 mg, 64%); mp 93–

94 ^◦C; [a]²_D¹+148.3 (c 1.0 in CHCl₃); m_max(KBr) 3492 (O–H), 1735

Following General procedure 6, 36 (23 mg, 0.07 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.04 mL, 0.36 mmol),

and LiOH (4 mg, 0.15 mmol) gave 17 as a colourless oil (12 mg,

quantitative), and 40 as a colourless oil (12 mg, quantitative);

[a]²_D⁰−21.6 (c 0.8 in CHCl₃); lit.²⁰[a]_D²⁰−23.1 (c 1.0 in CHCl₃); d_H

(400 MHz, CDCl₃) 1.19 [3H, d, J 6.9 Hz, C(2)CH₃], 2.65–2.71

[1H, m, C(3)H_A], 2.73–2.82 [1H, m, C(2)H], 3.07–3.12 [1H, m,

C(3)H_B], 7.19–7.37 (5H, m, Ph).

=

(C O), 1693 (C O); d_H(400 MHz, CDCl₃) 0.83 [3H, d, J 6.8 Hz,

CH(CH₃)_A(CH₃)_B], 0.88 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B],

1.01 [3H, d, J 7.0 Hz, C(2^ꢀ)CH₃], 1.36 [3H, s, C(6)(CH₃)_A], 1.48

[3H, s, C(6)(CH₃)_B], 1.90–2.00 [2H, m, C(5)H₂], 2.26–2.34 [1H,

m, CH(CH₃)₂], 3.44 (1H, br s, OH), 4.04 [1H, qd, J 7.0 Hz, 2.9,

C(2^ꢀ)H], 4.43 [1H, app td, J 8.7, 5.5 Hz, C(4)H], 5.28 [1H, d, J

2.9 Hz, C(3^ꢀ)H], 7.22–7.45 (5H, m, Ph); d_C(100 MHz, CDCl₃)

10.7, 15.6, 18.6, 25.4, 29.8, 30.4, 33.6, 44.8, 55.1, 73.2, 80.1, 126.2,

127.2, 128.0, 141.3, 152.8, 178.3; m/z (ESI⁺) 356 ([M + Na]⁺,

(R)-4-(tert-Butoxy)-4-oxo-2-benzylbutanoic acid 41

Following General procedure 6, 38 (45 mg, 0.11 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.05 mL, 0.54 mmol),

and LiOH (5 mg, 0.22 mmol) gave 17 as a colourless oil (18 mg,

quantitative), and 41 as a colourless oil (28 mg, quantitative);

[a]_D²⁰+7.7 (c 1.0 in DCM); lit.¹⁹[a]_D²⁵+7.1 (c 1.0 in DCM); d_H

(400 MHz, CDCl₃) 1.42 [9H, s, OC(CH₃)₃], 2.35 [1H, dd, J 16.8,

4.2 Hz, C(3)H_A], 2.56 [1H, dd, J 16.8, 8.7 Hz, C(3)H_B], 2.77 (1H,

dd, J 15.4, 10.6 Hz, CH_AH_BPh), 3.09–3.14 [2H, m, C(2)H and

CH_AH_BPh], 7.18–7.33 (5H, m, Ph).

100%); HRMS (ESI⁺) C₁₉H₂₈NO₄([M + H]⁺) requires 334.2018;

+

found 334.2026.

X-Ray crystal structure determination for 46. Data were col-

lected using an Enraf-Nonius j-CCD diffractometer with graphite

monochromated Mo-Ka radiation using standard procedures at

190 K. The structure was solved by direct methods (SIR92),

all non-hydrogen atoms were reﬁned with anisotropic thermal

parameters. Hydrogen atoms were added at idealised positions.

The structure was reﬁned using CRYSTALS.³²

(S)-2-Methyl-3-phenylpropanoic acid 42

Following General procedure 6, 39 (20 mg, 0.06 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.03 mL, 0.32 mmol),

and LiOH (3 mg, 0.12 mmol) gave 17 as a colourless oil (11 mg,

quantitative), and 42 as a colourless oil (10 mg, quantitative);

[a]²_D⁵+26.8 (c 0.6 in CHCl₃); lit.²¹[a]_D²⁵+25.5 (c 1.0 in CHCl₃); d_H

(400 MHz, CDCl₃) 1.19 [3H, d, J 6.9 Hz, C(2)CH₃], 2.66–2.71

[1H, m, C(3)H_A], 2.74–2.83 [1H, m, C(2)H], 3.07–3.12 [1H, m,

C(3)H_B], 7.19–7.32 (5H, m, Ph).

X-Ray crystal structure data for 46 [C₁₉H₂₇NO₄]: M = 333.42,

monoclinic, space group C121, a = 17.9151(5), b = 9.5994(3), c =

◦

3

˚

12.1722(4) A, b = 119.6642(13) , V = 1819.0(1) A , Z = 4, l =

0.085 mm⁻¹, colourless block, crystal dimensions = 0.1 × 0.1 ×

0.1 mm. A total of 2192 unique reﬂections were measured for 5 <

h < 27 and 1765 reﬂections were used in the reﬁnement. The ﬁnal

parameters were wR₂= 0.037 and R₁= 0.032 [I > 2.0r(I)].

CCDC reference number 280053. For crystallographic data in

CIF or other electronic format see DOI: 10.1039/b604073j.

(4R,2^ꢀR,3^ꢀR)- and (4R,2^ꢀS,3^ꢀR)-3-(2^ꢀ-Methyl-3^ꢀ-hydroxy-3^ꢀ-

phenylpropanoyl)-4-phenyl-6,6-dimethyl-(1,3)-oxazinan-2-one 44

and 45

(4R,2^ꢀR,3^ꢀR)-3-[2^ꢀ-Methyl-3^ꢀ-hydroxy-3^ꢀ-(p-methoxyphenyl)-

propanoyl]-4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 47

Following General procedure 8, 26 (75 mg, 0.29 mmol) in DCM

◦

(0.2 M) at 0 C, TiCl₄(0.03 mL, 0.30 mmol), DIPEA (0.05 mL,

0.32 mmol) and benzaldehyde (distilled from CaH₂, 0.03 mL,

Following General procedure 8, 27 (75 mg, 0.33 mmol) in DCM

(0.3 M) at 0 C, TiCl₄(0.04 mL, 0.35 mmol), DIPEA (0.06 mL,

◦

0.32 mmol) at −78 C gave a 25 : 56 : 19 mixture of 26 : 44 : 45

respectively. Puriﬁcation via ﬂash column chromatography (eluent

pentane : Et₂O 6 : 1) gave a 76 : 24 mixture of 44 : 45 as a colourless

oil (ﬁrst to elute, 49 mg, 47%) and 44 as a colourless oil (second to

elute, 25 mg, 24%).

0.36 mmol) and p-methoxybenzaldehyde (distilled from CaH₂,

0.04 mL, 0.36 mmol) at −78 ^◦C gave a 41 : 59 mixture of 27 : 47

respectively. Puriﬁcation via ﬂash column chromatography (eluent

pentane : Et₂O 3 : 1) gave 47 as an orange oil (65 mg, 54%);

[a]²_D⁰+110.7 (c 1.0 in CHCl₃); m_max(ﬁlm) 3446 (O–H, br), 1733

Data for 44: [a]²_D¹+82.8 (c 1.0 in CHCl₃); m_max(ﬁlm) 3508 (O–

=

H, br), 1731 (C O); d_H(400 MHz, CDCl₃) 1.00 [3H, d, J 7.0,

(C O), 1694 (C O); d_H(400 MHz, CDCl₃) 0.83 [3H, d, J 6.8 Hz,

CH(CH₃)_A(CH₃)_B], 0.88 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 1.02

[3H, d, J 7.0 Hz, C(2^ꢀ)CH₃], 1.37 [3H, s, C(6)(CH₃)_A], 1.49 [3H, s,

C(6)(CH₃)_B], 1.96 [2H, app dd, J 8.8, 3.3 Hz, C(5)H₂], 2.26–2.34

[1H, m, CH(CH₃)₂], 3.36 (1H, br s, OH), 3.81 (3H, s, OCH₃), 4.01

[1H, qd, J 7.0, 3.1 Hz, C(2^ꢀ)H], 4.44 [1H, app td, J 8.8, 5.4 Hz,

C(4)H], 5.22 [1H, d, J 3.1 Hz, C(3^ꢀ)H], 6.88 (2H, app d, J 8.8 Hz,

Ar), 7.37 (2H, app d, J 8.4 Hz, Ar); d_C(100 MHz, CDCl₃) 10.8,

15.5, 18.5, 25.3, 29.7, 30.3, 33.6, 44.8, 54.9, 55.1, 72.9, 79.9, 113.3,

127.3, 133.4, 152.7, 158.7, 178.2; m/z (ESI⁺) 422 ([M + MeCN +

C(2^ꢀ)CH₃], 1.44 [3H, s, C(6)(CH₃)_A], 1.51 [3H, s, C(6)(CH₃)_B], 2.12

[1H, dd, J 14.5, 11.0 Hz, C(5)H_A], 2.39 [1H, dd, J 14.5, 7.5 Hz,

C(5)H_B], 2.98 (1H, br s, OH), 4.16 [1H, qd, J 7.0, 2.4 Hz, C(2^ꢀ)H],

5.19 [1H, d, J 2.4 Hz, C(3^ꢀ)H], 5.32 [1H, dd, J 11.0, 7.5 Hz,

C(4)H], 7.22–7.38 (10H, m, Ph); d_C(100 MHz, CDCl₃) 10.2, 24.3,

29.1, 43.1, 45.8, 56.0, 72.7, 80.0, 125.1, 126.1, 127.1, 127.6, 128.0,

129.0, 141.1, 142.0, 151.9, 178.7; m/z (ESI⁺) 426 ([M + MeCN +

NH₄]⁺, 100%), 390 (40); HRMS (ESI⁺) C₂₂H₂₆NO₄([M + H]⁺)

+

requires 368.1862; found 368.1875.

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NH₄]⁺, 100%), 386 (70); HRMS (ESI⁺) C₂₀H₂₉NNaO₅([M +

C(4^ꢀ)(CH₃)_A(CH₃)_B], 1.06 [3H, d, J 6.5 Hz, C(4^ꢀ)(CH₃)_A(CH₃)_B],

1.10 [3H, d, J 7.1 Hz, C(2^ꢀ)CH₃], 1.38 [3H, s, C(6)(CH₃)_A], 1.48

[3H, s, C(6)(CH₃)_B], 1.67–1.75 [1H, m, C(4^ꢀ)H], 1.91–2.01 [2H, m,

C(5)H₂], 2.27–2.36 [1H, m, C(4)CH(CH₃)₂], 3.65 [1H, dd, J 8.8,

2.2 Hz, C(3^ꢀ)H], 3.97 [1H, qd, J 7.1, 2.2 Hz, C(2^ꢀ)H], 4.42 [1H,

app td, J 8.7, 5.5 Hz, C(4)H); d_C(100 MHz, CDCl₃) 10.2, 15.6,

18.6, 18.7, 19.4, 25.4, 29.7, 30.3, 30.7, 33.6, 39.9, 55.0, 76.5, 79.9,

152.6, 179.4; m/z (ESI⁺) 322 ([M + Na]⁺, 100%); HRMS (ESI⁺)

+

Na]⁺) requires 386.1943; found 386.1946.

(4R,2^ꢀR,3^ꢀR)-3-(2^ꢀ-Methyl-3^ꢀ-hydroxy-3^ꢀ-(p-nitrophenyl)-

propanoyl)-4-iso-propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 48

Following General procedure 8, 27 (70 mg, 0.31 mmol) in DCM

(0.3 M) at 0 C, TiCl₄(0.04 mL, 0.32 mmol), DIPEA (0.06 mL,

0.34 mmol) and p-nitrobenzaldehyde (distilled from CaH₂, 51 mg,

0.34 mmol) at −78 ^◦C gave a 57 : 43 mixture of 27 : 48 respectively.

Puriﬁcation via ﬂash column chromatography (eluent pentane :

Et₂O 3 : 1) gave 48 as a yellow oil (23 mg, 20%); [a]²_D⁰+123.8 (c

◦

C₁₆H₃₀NO₄([M + H]⁺) requires 300.2175; found 300.2170.

+

X-Ray crystal structure determination for 50. Data were col-

lected using an Enraf-Nonius j-CCD diffractometer with graphite

monochromated Mo-Ka radiation using standard procedures at

190 K. The structure was solved by direct methods (SIR92),

all non-hydrogen atoms were reﬁned with anisotropic thermal

parameters. Hydrogen atoms were added at idealised positions.

The structure was reﬁned using CRYSTALS.³²

=

1.0 in CHCl₃); m_max(ﬁlm) 3453 (O–H), 1732 (C O), 1696 (C O);

d_H(400 MHz, CDCl₃) 0.87 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B],

0.92 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 0.96 [3H, d, J 7.1 Hz,

C(2^ꢀ)CH₃], 1.38 [3H, s, C(6)(CH₃)_A], 1.50 [3H, s, C(6)(CH₃)_B],

1.94–2.04 [2H, m, C(5)H₂], 2.32–2.39 [1H, m, CH(CH₃)₂], 3.73

(1H, br s, OH), 4.03 [1H, qd, J 7.0, 2.5 Hz, C(2^ꢀ)H], 4.43 [1H, app

td, J 8.7, 5.5 Hz, C(4)H], 5.38 [1H, d, J 2.5 Hz, C(3^ꢀ)H], 7.64 (2H,

d, J 8.8 Hz, Ar), 8.21 (2H, d, J 8.8 Hz, Ar); d_C(100 MHz, CDCl₃)

10.4, 15.6, 18.7, 25.4, 29.8, 30.4, 33.6, 44.4, 55.4, 72.5, 80.5, 123.3,

127.1, 147.2, 148.7, 153.0, 177.7; m/z (ESI⁺) 401 ([M + Na]⁺,

X-Ray crystal structure data for 50 [C₁₆H₂₉NO₄]: M = 299.41,

triclinic, space group P1, a = 8.8735(2), b = 9.7635(3), c =

◦

˚

11.2480(3) A, a = 89.749(2), b = 79.982(2), c = 64.9723(11) ,

3

−1

˚

V = 866.90(4) A , Z = 2, l = 0.081 mm , colourless plate, crystal

dimensions = 0.05 × 0.05 × 0.1 mm. A total of 3878 unique

reﬂections were measured for 5 < h < 27 and 3145 reﬂections were

used in the reﬁnement. The ﬁnal parameters were wR₂= 0.038

and R₁= 0.037 [I > 2.0r(I)].

60%); HRMS (ESI⁺) C₁₉H₂₇N₂O₆([M + H]⁺) requires 379.1869;

+

found 379.1873.

(4R,2^ꢀR,3^ꢀS)-3-(2^ꢀ-Methyl-3^ꢀ-hydroxypentanoyl)-4-iso-propyl-6,6-

CCDC reference number 280054. For crystallographic data in

CIF or other electronic format see DOI: 10.1039/b604073j.

dimethyl-(1,3)-oxazinan-2-one 49

Following General procedure 8, 27 (52 mg, 0.23 mmol) in

DCM (0.2 M) at 0 ^◦C, TiCl₄(0.03 mL, 0.24 mmol), DIPEA

(0.04 mL, 0.25 mmol) and propanal (distilled from CaH₂, 0.02 mL,

0.25 mmol) at −78 ^◦C gave a 37 : 63 mixture of 27 : 49 respectively.

Puriﬁcation via ﬂash column chromatography (eluent pentane :

Et₂O 3 : 1) gave 49 as a colourless solid (38 mg, 58%); mp 65–

67 ^◦C; [a]²_D⁴+156.5 (c 1.0 in CHCl₃); m_max(ﬁlm) 3467 (O–H), 1736

(4R,2^ꢀR,3^ꢀR)-3-(2^ꢀ,4^ꢀ,4^ꢀ-Trimethyl-3^ꢀ-hydroxypentanoyl)-4-iso-

propyl-6,6-dimethyl-(1,3)-oxazinan-2-one 51

Following General procedure 8, 27 (60 mg, 0.26 mmol) in DCM

◦

(0.3 M) at 0 C, TiCl₄(0.03 mL, 0.28 mmol), DIPEA (0.05 mL,

0.29 mmol), and pivalaldehyde (distilled from CaH₂, 0.03 mL,

0.29 mmol) at −78 ^◦C gave an 85 : 15 mixture of 27 : 51 respectively.

Puriﬁcation via ﬂash column chromatography (eluent pentane:

Et₂O 4:1) gave 51 as a colourless oil (10 mg, 12%); [a]¹_D⁸+131.6 (c

=

(C O), 1686 (C O); d_H(400 MHz, CDCl₃) 0.84 [3H, d, J 6.8 Hz,

CH(CH₃)_A(CH₃)_B], 0.89 [3H, d, J 7.0 Hz, CH(CH₃)_A(CH₃)_B], 0.99

[3H, t, J 7.4 Hz, C(5^ꢀ)H₃], 1.10 [3H, d, J 7.1 Hz, C(2^ꢀ)CH₃],

1.37 [3H, s, C(6)(CH₃)_A], 1.40–1.46 [1H, m, C(4^ꢀ)H_A], 1.48 [3H, s,

C(6)(CH₃)_B], 1.49–1.60 [1H, m, C(4^ꢀ)H_B], 1.90–2.00 [2H, m,

C(5)H₂], 2.26–2.37 [1H, m, CH(CH₃)₂], 3.78 [1H, qd, J 7.1, 2.6 Hz,

C(2^ꢀ)H], 3.91–3.95 [1H, m, C(3^ꢀ)H], 4.41 [1H, app td, J 8.7, 5.5 Hz,

C(4)H); d_C(100 MHz, CDCl₃) 10.5, 10.8, 15.7, 18.7, 25.4, 26.5,

29.8, 30.4, 33.7, 42.2, 55.0, 73.2, 80.1, 153.0, 178.8; m/z (ESI⁺) 344

([M + MeCN + NH₄]⁺, 100%); HRMS (ESI⁺) C₁₅H₂₈NO₄⁺([M +

H]⁺) requires 286.2018; found 286.2013.

=

0.5 in CHCl₃); m_max(ﬁlm) 3521 (O–H), 1735 (C O), 1689 (C O);

d_H(400 MHz, CDCl₃) 0.84 [3H, d, J 6.8 Hz, CH(CH₃)_A(CH₃)_B],

0.88 [3H, d, J 7.1 Hz, CH(CH₃)_A(CH₃)_B], 0.99 [9H, s, C(CH₃)₃],

1.15 [3H, d, J 7.1 Hz, C(2^ꢀ)CH₃], 1.38 [3H, s, C(6)(CH₃)_A], 1.48

[3H, s, C(6)(CH₃)_B], 1.93–1.96 [2H, m, C(5)H₂], 2.28–2.36 [1H,

m, CH(CH₃)₂], 3.75 [1H, d, J 3.3 Hz, C(3^ꢀ)H], 4.11 [1H, qd, J

7.1, 3.3 Hz, C(2^ꢀ)H], 4.39 [1H, app td, J 8.8, 5.4 Hz, C(4)H); d_C

(100 MHz, CDCl₃) 13.3, 15.6, 18.7, 25.4, 26.8, 29.8, 30.2, 33.6,

39.1, 55.1, 77.9, 79.9, 80.0, 153.1, 173.5; m/z (ESI⁺) 372 ([M +

+

MeCN + NH₄]⁺, 100%), 336 (60); HRMS (ESI⁺) C₁₇H₃₂NO₄

(4R,2^ꢀR,3^ꢀS)-3-(2^ꢀ,4^ꢀ-Dimethyl-3^ꢀ-hydroxypentanoyl)-4-iso-propyl-

6,6-dimethyl-(1,3)-oxazinan-2-one 50

([M + H]⁺) requires 314.2331; found 314.2331.

Following General procedure 8, 27 (50 mg, 0.22 mmol) in

DCM (0.2 M) at 0 ^◦C, TiCl₄(0.03 mL, 0.23 mmol), DIPEA

(0.04 mL, 0.24 mmol) and iso-butyraldehyde (distilled from CaH₂,

0.02 mL, 0.24 mmol) at −78 ^◦C gave a 41 : 59 mixture of 27 :

50 respectively. Puriﬁcation via ﬂash column chromatography

(eluent pentane : Et₂O 3 : 1) gave 50 as a colourless solid

(2R,3R)-2-Methyl-3-hydroxy-3-phenylpropanoic acid 53

Following General procedure 6, 46 (60 mg, 0.18 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.09 mL, 0.90 mmol),

and LiOH (9 mg, 0.36 mmol) gave 17 as a colourless oil (31 mg,

quantitative), and 53 as a colourless oil (32 mg, quantitative);

[a]²_D²+28.5 (c 1.0 in CHCl₃); lit.²⁸[a]_D²⁰+28.5 (c 1.2 in CHCl₃);

d_H(400 MHz, CDCl₃) 1.16 [3H, d, J 7.2 Hz, C(2)CH₃], 2.84–

2.90 [1H, m, C(2)H], 5.19 [1H, d, J 3.9 Hz, C(3)H], 7.29–7.38

(5H, m, Ph).

◦

(30 mg, 45%); mp 85–86 C; [a]²_D⁴+136.4 (c 1.0 in CHCl₃); m_max

=

(KBr) 3458 (O–H), 1738 (C O), 1681 (C O); d_H(400 MHz,

CDCl₃) 0.85 [3H, d, J 6.8 Hz, C(4)CH(CH₃)_A(CH₃)_B], 0.89 [3H,

d, J 7.0 Hz, C(4)CH(CH₃)_A(CH₃)_B], 0.91 [3H, d, J 6.8 Hz,

2766 | Org. Biomol. Chem., 2006, 4, 2753–2768

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(2R,3R)-2-Methyl-3-hydroxy-3-(p-methoxyphenyl)propanoic acid

54

5 K. Alexander, S. Cook, C. L. Gibson and A. R. Kennedy, J. Chem.

Soc., Perkin Trans. 1, 2001, 1538; C. L. Gibson, K. Gillon and S. Cook,

Tetrahedron Lett., 1998, 39, 6733.

6 (a) S. D. Bull, S. G. Davies, S. Jones and H. J. Sanganee, J. Chem. Soc.,

Perkin Trans. 1, 1999, 387; (b) S. D. Bull, S. G. Davies, R. L. Nicholson,

H. J. Sanganee and A. D. Smith, Org. Biomol. Chem., 2003, 1, 2886 and

refs. cited therein.

7 S. D. Bull, S. G. Davies, M.-S. Key, R. L. Nicholson and E. D. Savory,

Chem. Commun., 2000, 1721.

8 G. J. Baird and S. G. Davies, J. Organomet. Chem., 1983, 248, Cl–C3;

S. G. Davies, Aldrichimica Acta, 1990, 23, 31; S. G. Davies and A. A.

Mortlock, Tetrahedron Lett., 1991, 32, 4787; S. G. Davies, G. J.-M.

Doisneau, J. C. Prodger and H. J. Sanganee, Tetrahedron Lett., 1994,

35, 2369.

Following General procedure 6, 47 (60 mg, 0.17 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.08 mL, 0.83 mmol),

and LiOH (8 mg, 0.33 mmol) gave 17 as a colourless oil (28 mg,

quantitative), and 54 as a colourless oil (35 mg, quantitative);³³

[a]²_D²+19.2 (c 1.0 in CHCl₃); d_H(400 MHz, CDCl₃) 1.16 [3H, d, J

7.2 Hz, C(2)CH₃], 2.78–2.84 [1H, m, C(2)H], 3.81 (3H, s, OCH₃),

5.10 [1H, d, J 4.2 Hz, C(3)H], 6.89 (2H, d, J 8.6 Hz, Ar), 7.28 (2H,

d, J 8.5 Hz, Ar).

9 For another oxazinanone chiral auxiliary, see: K. H. Ahn, S. Lee and

A. Lim, J. Org. Chem., 1992, 57, 5065.

(2R,3R)-2-Methyl-3-hydroxy-3-(p-nitrophenyl)propanoic acid 55

10 For a review, see: S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:

Asymmetry, 2005, 16, 2833. For selected representative examples, see:

S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183;

S. G. Davies, O. Ichihara and I. A. S. Walters, Synlett, 1993, 461; S. G.

Davies and D. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 2629; S. D.

Bull, S. G. Davies and A. D. Smith, J. Chem. Soc., Perkin Trans. 1, 2001,

2931; S. D. Bull, S. G. Davies and A. D. Smith, Tetrahedron: Asymmetry,

2001, 12, 2191; S. D. Bull, S. G. Davies, P. M. Roberts, E. D. Savory

and A. D. Smith, Tetrahedron, 2002, 58, 4629; A. Chippindale, S. G.

Davies, K. Iwamoto, R. M. Parkin, C. A. P. Smethurst, A. D. Smith and

H. Rodriguez-Solla, Tetrahedron, 2003, 59, 3253; M. E. Bunnage, A. J.

Burke, S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts

and A. D. Smith, Org. Biomol. Chem., 2003, 1, 3708; S. G. Davies,

R. L. Nicholson, P. D. Price, P. M. Roberts and A. D. Smith, Synlett,

2004, 901; A. J. Burke, S. G. Davies, A. C. Garner, T. D. McCarthy,

P. M. Roberts, A. D. Smith, H. Rodriguez-Solla and R. J. Vickers, Org.

Biomol. Chem., 2004, 2, 1387; S. G. Davies, G. Hermann, A. D. Smith

and M. J. Sweet, Chem. Commun., 2004, 1128; S. G. Davies, A. C.

Garner, M. J. C. Long, A. D. Smith, M. J. Sweet and J. M. Withey,

Org. Biomol. Chem., 2004, 2, 3355; S. G. Davies, A. C. Garner, M. J. C.

Long, R. M. Morrison, P. M. Roberts, E. D. Savory, A. D. Smith, M. J.

Sweet and J. M. Withey, Org. Biomol. Chem., 2005, 3, 2762.

11 S. D. Bull, S. G. Davies, S. Jones, M. E. C. Polywka, R. S. Prasad and

H. J. Sanganee, Synlett, 1998, 519.

Following General procedure 6, 48 (20 mg, 0.05 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.03 mL, 0.26 mmol),

and LiOH (3 mg, 0.10 mmol) gave 17 as a colourless oil (9 mg,

quantitative), and 55 as a colourless oil (12 mg, quantitative);³⁴

[a]²_D²+18.3 (c 0.6 in CHCl₃); d_H(400 MHz, CDCl₃) 1.13 [3H, d, J

7.2 Hz, C(2)CH₃], 2.84–2.90 [1H, m, C(2)H], 5.33 [1H, d, J 2.9 Hz,

C(3)H], 7.56 (2H, d, J 8.6 Hz, Ar), 8.24 (2H, d, J 8.5 Hz, Ar).

(2R,3S)-2-Methyl-3-hydroxypentanoic acid 56

Following General procedure 6, 49 (35 mg, 0.11 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.06 mL, 0.61 mmol),

and LiOH (6 mg, 0.25 mmol) gave 17 as a colourless oil (21 mg,

quantitative), and 56 as a colourless oil (15 mg, 94%); [a]²_D²−4.0

(c 0.8 in CHCl₃); lit.²⁹[a]_D²³−4.1 (c 1.7 in CHCl₃); d_H(400 MHz,

CDCl₃) 0.99 [3H, t, J 7.4 Hz, C(5)H₃], 1.21 [3H, d, J 7.2 Hz,

C(2)CH₃], 1.44–1.60 [2H, m, C(4)H₂], 2.61–2.65 [1H, m, C(2)H],

3.87–3.91 [1H, m, C(3)H].

12 T. Imamoto, T. Kusumoto, Y. Tawarayama, T. Mita, Y. Hatanaka and

M. Yokoyama, J. Org. Chem., 1984, 49, 3904; T. Imamoto, N. Takiyama

and K. Nakamura, Tetrahedron Lett., 1985, 26, 4763; T. Imamoto, N.

Takiyama, K. Nakamura, T. Hatajima and Y. Kamiya, J. Am. Chem.

Soc., 1989, 111, 4392; T. Imamoto, Pure Appl. Chem., 1990, 62, 747.

13 J. R. Gage and D. A. Evans, Org. Synth., 1990, 68, 83; S. S. Canan

Koch and A. R. Chamberlin, J. Org. Chem., 1993, 58, 2725.

14 D. A. Evans and J. R. Gage, J. Org. Chem., 1992, 57, 1958; D. A. Evans,

J. R. Gage and J. L. Leighton, J. Am. Chem. Soc., 1992, 114, 9434; G.-J.

Ho and D. J. Mathre, J. Org. Chem., 1995, 60, 2271; D. J. Ager, D. R.

Allen, D. E. Froen and D. R. Schaad, Synthesis, 1996, 1283.

15 (a) D. M. Casper, D. Kieser, J. R. Blackburn and S. R. Hitchcock,

Synth. Commun., 2004, 34, 835; (b) D. M. Casper, J. R. Burgeson, J. M.

Esken, G. M. Ferrence and S. R. Hitchcock, Org. Lett., 2002, 4, 3739;

(c) D. M. Casper and S. R. Hitchcock, Tetrahedron: Asymmetry, 2003,

14, 517.

(2R,3S)-2,4-Dimethyl-3-hydroxypentanoic acid 57

Following General procedure 6, 50 (30 mg, 0.10 mmol) in THF–

H₂O (v : v, 3 : 1, 4 mL) at 0 ^◦C, H₂O₂(0.05 mL, 0.50 mmol),

and LiOH (5 mg, 0.20 mmol) gave 17 as a colourless oil (17 mg,

quantitative), and 57 as a colourless oil (14 mg, quantitative);

[a]²_D²+11.3 (c 0.7 in CHCl₃); lit.³⁰[a]_D²⁰+10.5 (c 0.1 in CHCl₃);

d_H(400 MHz, CDCl₃) 0.90 [3H, d, J 6.7 Hz, C(4)(CH₃)_A], 1.03

[3H, d, J 6.5 Hz, C(4)(CH₃)_B], 1.22 [3H, d, J 7.1 Hz, C(2)CH₃],

1.69–1.77 [1H, m, C(4)H], 2.70–2.76 [1H, m, C(2)H], 3.64 [1H,

dd, J 8.3, 3.3, C(3)H].

16 For initial observations of the ketene decomposition pathway in

oxazolidinone systems, see: (a) D. A. Evans, M. C. Ennis and D. J.

Mathre, J. Am. Chem. Soc., 1982, 104, 1737 and refs. cited therein.

For other selected examples, see: (b) A. Struder, T. Hintermann and

D. Seebach, Helv. Chim. Acta, 1995, 78, 1185; (c) D. M. Casper, J. R.

Blackburn, C. D. Maroules, T. Brady, J. M. Esken, G. M. Ferrence,

J. M. Standard and S. M. Hitchcock, J. Org. Chem., 2002, 67, 8871.

17 As indicated by peak integration of the 400 MHz ¹H NMR spectrum

of the crude reaction product.

18 To determine unambiguously the identity of 33, an authentic sample

was prepared by lithiation of the parent auxiliary 16 by treatment with

LiHMDS and alkylation with tert-butyl bromoacetate, giving 33 in

quantitative yield.

19 D. A. Evans, L. D. Wu, J. J. M. Wiener, J. S. Johnson, D. H. B. Ripin

and J. S. Tedrow, J. Org. Chem., 1999, 64, 6411.

20 E. Tyrell, M. W. H. Tsang, G. A. Skinner and J. Fawcett, Tetrahedron,

1996, 52, 9841.

21 W. Oppolzer, R. Moretti and S. Thomi, Tetrahedron Lett., 1989, 30,

5603.

Acknowledgements

The authors wish to thank Barbara Odell for the acquisition of

NMR spectra, and Robin Procter and Joanna Kirkpatrick for the

acquisition of mass spectra.

References and notes

1 For reviews, see: D. A. Evans, Aldrichimica Acta, 1982, 15, 2; D. J. Ager,

I. Prakash and D. R. Schaad, Aldrichimica Acta, 1997, 30, 3; D. J. Ager,

I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835; M. P. Sibi,

Aldrichimica Acta, 1999, 32, 93.

2 D. A. Evans and J. Bartroli, Tetrahedron Lett., 1982, 23, 807.

3 D. A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett., 1987,

28, 6141; S. G. Davies, D. J. Dixon, G. J.-M. Doisneau, J. C. Prodger

and H. J. Sanganee, Tetrahedron: Asymmetry, 2002, 13, 647.

4 S. G. Davies and H. J. Sanganee, Tetrahedron: Asymmetry, 1995, 6, 671.

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22 E. Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay,

M. Simson and D. Seebach, Synthesis, 1993, 1271 and refs. cited

therein.

23 D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and G. S.

Sheppard, J. Am. Chem. Soc., 1990, 112, 866; D. A. Evans, F. Urpi, T. C.

Somers, J. S. Clark and M. T. Bilodeau, J. Am. Chem. Soc., 1990, 112,

8215.

24 Using this assumption, J_a,bis usually in the range of 2–6 Hz for syn-aldol

products, and 7–10 Hz for anti-aldol products. For leading references,

see: M. Stiles, R. W. Winkler, Y.-L. Chang and L. Traynor, J. Am. Chem.

Soc., 1964, 86, 3337; H. O. House, D. S. Crumrine, A. Y. Teranishi and

H. D. Olmstead, J. Am. Chem. Soc., 1973, 95, 3310; C. H. Heathcock,

M. C. Pirrung and J. E. Sohn, J. Org. Chem., 1980, 45, 1066; C. H.

Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung, J. E. Sohn and

J. Lampe, J. Org. Chem., 1979, 44, 4294.

27 B. M. Kim, S. F. Williams and S. Masamune, in Comprehensive Organic

Synthesis, ed. B. M. Trost, Pergamon Press, Oxford, 1991, vol. 2,

pp. 239–275.

28 N. A. Van Draanen, S. Arseniyadis, M. T. Crimmins and C. H.

Heathcock, J. Org. Chem., 1991, 56, 2506.

29 T. Katsuki and M. Yamaguchi, Tetrahedron Lett., 1985, 26, 5807.

30 D. A. Evans and T. R. Taber, Tetrahedron Lett., 1980, 21, 4675.

31 A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen and F. J.

Timmers, Organometallics, 1996, 15, 1518.

32 D. J. Watkin, C. K. Prout, J. R. Carruthers, P. W. Betteridge and R. I.

Cooper, CRYSTALS, Chemical Crystallography Laboratory, Oxford,

UK, 2003, Issue 12.

33 Compound 54 has been reported previously by P. Galatsis, J. J. Manwell

and J. M. Blackwell, Can. J. Chem., 1994, 72, 1656, although no optical

rotation data are available for comparison.

34 Compound 55 has been reported previously by M. Tanaka, O. Oota,

H. Hiramatsu and K. Fujiwara, Bull. Chem. Soc. Jpn., 1988, 61, 2473,

although no optical rotation data are available for comparison.

25 C. R. Harrison, Tetrahedron Lett., 1987, 28, 4135.

26 M. T. Crimmins, B. W. King, E. A. Tabet and K. Chaundhary, J. Org.

Chem., 2001, 66, 894.

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Article Doi

Oxazinanones as chiral auxiliaries: Synthesis and evaluation in enolate alkylations and aldol reactions

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