A synthesis of a common intermediate to the lactone-pyrrolidinone ring systems in oxazolomycin A and neooxazolomycin

Tetrahedron 63 (2007) 6216–6231

A synthesis of a common intermediate to the lactone–

pyrrolidinone ring systems in oxazolomycin A and

neooxazolomycin

Nicholas J. Bennett,^aJeremy C. Prodger^band Gerald Pattenden^a,

*

^aSchool of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK

^bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK

Received 24 January 2007; revised 5 March 2007; accepted 6 March 2007

Available online 12 March 2007

Abstract—A 5-exo-dig radical cyclisation of the bromoamide 34 derived from the enantiopure a-ethynyl substituted amino alcohol 31 led to

a 2:1 mixture of b-C3 and a-C3 methyl epimers of the pyrrolidinone 35a–36a in a combined yield of 73%. Treatment of the homoallylic

alcohol 35b, derived from 35a, with OsO₄–TMEDA, gave a single diastereoisomer of the pyrrolidinone triol 37, resulting from selective di-

hydroxylation from the b-face, i.e. syn to the CH₂OH group of 35b. The pyrrolidinone triol 37 is a potential common precursor, cf. 9, to the

spiro b-lactone pyrrolidinone 8 and the g-lactone pyrrolidinone 10 ring systems in oxazolomycin A (1) and neooxazolomycin 2, respectively.

Sequential protection of the 1,2-diol functionality in 37 as the acetonide 39, and the primary alcohol group in 39 as the SEM ether 41a,

followed by methylation of the nitrogen centre in 41a, using NaH–MeI, then gave the selectively protected pyrrolidinone 42.

Ó 2007 Published by Elsevier Ltd.

N

1. Introduction

OH

O

OMe

OH

O

Oxazolomycin A (1) and neooxazolomycin 2 are the parent

compounds of a family of novel lactone/pyrrolidinone-based

metabolites, which were ﬁrst isolated in 1985 by Uemera

et al.,¹from the fermentation broth of Streptomyces sp.

Both compounds display potent antibiotic properties

and strong anticancer activity,²in addition to antiviral

activity against vaccinia, herpes simplex type I and

inﬂuenza.³Oxazolomycin A has also been found to inhibit

crown gall formation in plants caused by Agrobacterium

tumefacieus.^2,4

N

H

OH

O

N

Me

O

1

N

OH

O

N

H

OH

O

N

Me

O

2

Several Z/E geometrical isomers about the conjugated triene

unit in oxazolomycin A (1), designated oxazolomycins B, C

and D, were later isolated from S. albus.⁵In addition, the 16-

methyloxazolomycins 3a,⁶together with the ‘curromycins’

3b and 3c,⁷which contain an additional methyl group at

C-2 in their oxazole rings, have also been isolated from

Streptomyces sp. More recently, the unusual nitro-tetraene

antibiotic substance lajollamycin 4, which contains the

same spiro-b-lactone-g-lactam structural features common

to the oxazolomycins, has been isolated from the marine

actinomycete S. nodosus.^8,9

OH

N

R₁

OH

O

OMe

OH

O

N

H

R₂

O

OH

O

N

3

Me

O

a, R₁= H; R₂= Me (R and S)

b, R₁= Me; R₂= CH₃OCH₂

c, R₁= Me; R₂= Me

O₂N

OH

O

OMe

OH

N

H

OH

O

N

4

Me

O

* Corresponding author. E-mail: gp@nottingham.ac.uk

0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.

doi:10.1016/j.tet.2007.03.043

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6217

that the method of Schmidt and Hatakeyama,²³involving

the synthesis and ring opening of enantiopure 3,3-disubsti-

tuted 2-trichloromethyl oxazolines was particularly suitable

for the synthesis of the a-ethynyl serine derivative 13.^17a,c

Cl

O

HO

O

HO

S

O

HO

O

AcNH

HO₂C

HO

N

H

O

N

H

O

N

H

O

Thus, a Sharpless epoxidation of the known enynol 14,²⁴

under optimum conditions,²⁵using (ꢀ)-diisopropyl tartrate,

titanium tetraisopropoxide and cumene hydroperoxide at

ꢀ12 ^ꢁC for 15 h ﬁrst gave the (S)-(+)-epoxide 15a in 77%

yield, with an ee of 83%, as determined by a Mosher’s ester

analysis. When the same epoxidation was carried out at

lower temperatures, i.e. ꢀ20 ^ꢁC or ꢀ40 ^ꢁC, the yields and

the ee were considerably poorer. Treatment of the epoxide

15a with trichloroacetonitrile in the presence of DBU at

0 ^ꢁC next gave the corresponding acetimidate 15b, which

was then cyclised to the oxazoline 16a using AlEt₂Cl. In

our ﬁrst investigations, we next protected the alcohol group

in 16a as its acetate 16b. Treatment of the oxazoline 16b,

with dilute hydrochloric acid then gave the amino alcohol

17a, which was not isolated, but instead it was immediately

reacted with TBDPSCl leading to the crystalline silyl-ether

derivative 17b (Scheme 2).

6

5

7

The oxazolomycins 1–3, with their lactone ring-fused pyrro-

lidinone motifs, show an uncanny structural relationship to

the 20S proteasome inhibitors omuralide 5¹⁰(cf. lactacystin

6)¹¹and salinosporamide A 7,¹²which are showing potential

in therapy for the treatment of various cancers, also Alzeimer’s

disease and asthma.¹³Although there has been substantial

synthetic work directed towards lactacystin 6, omuralide 5

and salinsporamide 7,¹⁴a total synthesis of oxazolomycin

A (1) and its relatives 3 and 4 has yet to be achieved. How-

ever, several years ago Kende et al.¹⁵described a total syn-

thesis of neooxazolomycin 2, and a number of research

groups have developed and/or studied routes to the polyene

segments and to the b-lactone/pyrrolidinone ring system in

the oxazolomycins 1 and 3a.¹⁶In this paper we describe

our studies of the synthesis of the triol-substituted pyrrolidi-

none 9, which we plan to use as a common precursor to both

the b-lactone and g-lactone pyrrolidinone ring systems, 8

and 10, respectively, found in oxazolomycin A (1) and neo-

oxazolomycin 2.

i

iii

v

AcO

N

NH₂

HO

OR

OH

ii

O

CCl₃

OR

17

14

15

16

a, R = H

b, R = TBDPS

a, R = H

b, R = C(CCl₃)=NH

a, R = H

b, R = Ac

iv

vi

O

OH

R

OH

H

O

Br

HO

HO₂C

O

N

R

O

N

R

O

HO

O

N

R

vii

viii

AcO

O

N

O

AcO

N

H

O

N

H

8

9

OTBDPS

10

OTBDPS

18

19

20

Scheme 2. Reagents and conditions: (i) 20% Ti(OⁱPr)₄, 26% D-(ꢀ)-DIPT,

cumene hydroperoxide, CH₂Cl₂, ꢀ12 ^ꢁC, 15 h, 77%, 83% ee; (ii) CCl₃CN,

DBU, CH₂Cl₂, 0 ^ꢁC, 1 h, 81%; (iii) AlEt₂Cl, CH₂Cl₂, 0 ^ꢁC to rt, 15 h, 63%;

(iv) AcCl, DMAP, Et₃N, CH₂Cl₂, 0 ^ꢁC, 1.5 h, 94%; (v) 1 M HCl, THF, rt,

3 h; (vi) TBDPSCl, DMAP, Et₃N, CH₂Cl₂, rt, 5 h, 76% over two steps;

(vii) 2-bromopropionoyl chloride, Et₃N, CH₂Cl₂, rt, 15 h, 50%; (viii)

Bu₃SnH, AIBN, toluene, reﬂux, 2 h, 55%, 3:4 mixture of diastereoisomers.

2. Results and discussion

Our synthetic approach to the triol-substituted pyrrolidinone

9 was based on elaboration of the enantiopure 4-methylene-

pyrrolidinone 11, followed by diastereoselective dihydroxy-

lation. In turn, and in parallel with contemporaneous

synthetic work towards lactacystin 6,^17awe planned to syn-

thesise the 4-methylenepyrrolidinone 11, by way of a 5-exo-

dig radical cyclisation of the acetylenic bromoamide 12^17b

derived from the enantiopure amine 13 (Scheme 1).^18,19

Treatment of the a-ethynyl amine 17b with 2-bromopropio-

noyl chloride gave a 1:1 mixture of diastereoisomers of the

amide 18 in 50% yield.^17aWhen a solution of the acetylenic

bromoamide 18 in reﬂuxing toluene was treated dropwise,

via a syringe pump, with asolution of Bu₃SnH in toluene con-

taining catalytic AIBN, followed by heating under reﬂux for

2 h, work-up and chromatography gave the anticipated

4-methylenepyrrolidinone 19 but as a 4:3 mixture of C-3

methyl epimers, in 55% yield. The epimers 19 and 20 could

be separated by chromatography and NOE studies showed

that the major diastereoisomer, unfortunately, had the un-

wanted a-methyl stereochemistry at C-3, i.e. 20. The relevant

NOE data are collected on the structures in Figure 1. The poor

selectivity during the 5-exo-dig radical cyclisation of 18 was

disappointing but perhaps not too surprising. We had hoped

that the larger TBDPS protecting group on the hydroxy-

methyl group at the quaternary centre in 18 would favourcyc-

lisation to the diastereoisomer 19 where the C-3 methyl and

C-5 CH₂OTBDPS groups would have an anti-relationship.

Br

9

RO

RO₂C

RO

RO₂C

RO

RO₂C

O

N

R

N

R

O

NH₂

13

11

12

Scheme 1. Retrosynthesis of 9 from 13.

a,a-Disubstituted a-amino acid units are found in a number

of natural products and methods for their synthesis have

been the subject of a recent review.²⁰We evaluated a number

of these methods^17cen route to the a-ethynyl amino acid de-

rivative 13, including the ring opening of chiral aziridines,²¹

and the use of Seebach’s ‘self-regeneration of stereocentre’

protocol from chiral oxazolidines.²²Ultimately, we found

6218

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

3.5%

O

one diastereoisomer of the resulting triol 26 was produced.

The stereochemistry of 26 followed from studies, in associ-

ation with HMBC and ROESY experiments, of the H and

1.3%

1

13.8%

AcO

¹³C NMR spectra of the corresponding acetonide–pivalate

ester 27, which was produced from 26, in two straightfor-

ward steps. Furthermore, the relative stereochemistry of 27

was conﬁrmed by observing a number of key enhancements

in the ROESY experiments.

H

O

N

H

N

H

2.0%

OTBDPS

19

20

Figure 1. ¹H NOE enhancement data for the epimeric 4-methylenepyrroli-

dinones 19 and 20.

We were now in a position to convert the CH₂OTBDPS

group in 27 into the corresponding carboxylic acid ester,

and thereby complete a synthesis of a fully protected deriv-

ative, viz. 29b, of the target pyrrolidinone triol 9. It was to

our disappointment therefore that when the silyl ether 27

was treated with TBAF in THF at room temperature for

1.5 h, work-up gave a mixture of the isomeric alcohols

28a and 29a, resulting from deprotection and in situ partial

migration, i.e. transesteriﬁcation, of the adjacent pivalate

group (Scheme 3). Furthermore, the diastereoisomeric alco-

hol 28a with the ‘wrong’ stereochemistry for subsequent

elaboration to 9 was the major product resulting from the

deprotection, i.e. 3:1, 28a–29a. Nevertheless, this mixture

of alcohols was treated with RuO₂–NaIO₄, followed by

trimethylsilyldiazomethane, to give a mixture of the

Unperturbed, at this point the C-3 a- and b-methyl epimers,

20 and 19, were separately dihydroxylated using catalytic

OsO₄and NMO in acetone–water.²⁶Anticipating that the

C-3 methyl and C-5 CH₂OTBDPS groups in the epimer 20

would operate in concert to promote dihydroxylation from

the b-face of the 4-methylene group,²⁷we were not surprised

to observe the formation of a single diastereoisomeric

vicinal diol, i.e. 21, from dihydroxylation of 20. The stereo-

chemistry of 21 followed from NOE studies on the corre-

sponding acetonide derivative 22 produced by treatment of

21 with 2,2-dimethoxypropane in the presence of pTSA

(Scheme 3). It was all the more disappointing then to ﬁnd

that when we treated the corresponding C-3 b-methyl epimer

19 with OsO₄and NMO, under the same reaction conditions,

a 1:1 mixture of C-4 hydroxy epimers of the vicinal diol 23

was obtained. Clearly, in 19 the b-orientated C-3 methyl

group exercises a steric effect to render the b-face of the

C-4 methylene group equally unfavourable to vicinal di-

hydroxylation from this face of the molecule, and hence

no selectivity ensued.

OH

i

19

AcO

O

N

H

iii

OTBDPS

ii

23 1:1 mixture

HO

O

HO

OH

O

N

O

N

H

OH

O

OTBDPS

25

ii

i

OTBDPS

20

24

AcO

O

N

H

N

H

OTBDPS

iv

21

22

OH

O

Scheme 3. Reagents and conditions: (i) OsO₄, NMO, acetone/H₂O (1:1), rt,

4 days, 59%; (ii) 2,2-dimethoxypropane, pTSA, rt, 15 h, 88%.

O

v,vi

HO

O

PivO

O

N

H

N

In contemporaneous studies Donohoe et al.²⁸had extolled

the virtues of directed dihydroxylation of allylic and homo-

allylic alcohols using OsO₄in the presence of TMEDA at

ꢀ78 ^ꢁC. We were attracted to this procedure for the conver-

sion of the homoallylic alcohol 24, derived from the acetate

19, into the diastereoisomer 26 of the corresponding triol,

which had most of the functionality and, more importantly,

the stereochemical detail in our target pyrrolidinone triol

9. Thus, after optimisation of the reaction conditions, the

acetate 19 was hydrolysed to the corresponding alcohol 24

in 89% yield using 5 equiv of titanium isopropoxide in iso-

propanol at room temperature for 3 h.²⁹A signiﬁcant by-

product, using alternative methods, e.g., NaBH₄,³⁰LiBH₄,

NaBH₃CN, BF₃OEt₂,³¹(Bu₃Sn)₂O,³²was the positional iso-

mer 25 of the desired product 24; indeed when 19 was

treated with K₂CO₃in methanol at room temperature for

15 h, the isomer 25 of 24 was obtained in 80% yield (Scheme

4). Nevertheless, we were delighted to ﬁnd that when the

homoallylic alcohol 24 was treated with OsO₄–TMEDA only

H

OTBDPS

27

26

vii

O

R

O

PivO

O

N

H

R

H

OPiv

28

viii

29

a R = CH₂OH

b R = CO₂Me

Scheme 4. Reagents and conditions: (i) OsO₄, NMO, acetone/H₂O (1:1), rt,

4 days, 47%; (ii) Ti(OⁱPr)₄, IPA, rt, 3 h, 89%; (iii) K₂CO₃, MeOH, rt, 15 h,

80%; (iv) OsO₄, TMEDA, CH₂Cl₂, ꢀ78 ^ꢁC, 1 h, 35%; (v) 2,2-dimethoxy-

propane, pTSA, rt, 3 h, 48%; (vi) trimethylacetyl chloride, pyridine,

DMAP, 40 ^ꢁC, 24 h, 67%; (vii) TBAF, THF, rt, 1.5 h, 64%; (viii) NaIO₄,

RuO₂$H₂O, CH₃CN, CCl₄, rt, 5 h, then TMS–CHN₂, 1 h, 91%.

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6219

corresponding methyl esters 28b and 29b, respectively, from

which the major diastereoisomer 28b could be separated and

characterised.

the three contiguous asymmetric centres as those in the

pyrrolidinone core 9 of oxazolomycin A (1) and neooxazo-

lomycin 2.

We decided at this juncture to throw caution to the wind and

examine a more direct approach to the synthesis of the triol 9

using a radical cyclisation of the bromoamide 34, which

already had an ester function at the quaternary centre. The

hydroxyl group in the previously synthesised oxazoline

16a was therefore ﬁrst protected as its TBS ether 30. The

protected oxazoline 30 was next treated with dilute hydro-

chloric acid to reveal the a-ethynyl amine 31, which was

immediately converted into the corresponding amide 32 fol-

lowing treatment with 2-bromopropionoyl chloride (Scheme

5). The primary alcohol group in 32 was now oxidised, in se-

quence, to the aldehyde 33a and to the carboxylic acid 33b,

which was then esteriﬁed using trimethylsilyldiazomethane

leading to the corresponding methyl ester 34³³(Scheme 5).

i

+

34

RO

O

N

H

N

H

MeO₂C

35

36

a, R = TBS

b, R = H

ii

iii

OH

H

O

HO

O

N

HO

MeO₂C

O

H

N

H

O

37

38

Scheme 6. Reagents and conditions: (i) Bu₃SnH, AIBN, toluene, reﬂux, 2 h,

73%, 2:1 mixture of diastereoisomers; (ii) pTSA, THF/H₂O, rt, 15 h, 35b

39% and 36b 26%, 2:1 mixture of diastereoisomers; (iii) OsO₄, TMEDA,

CH₂Cl₂, ꢀ78 ^ꢁC to rt, 3 h, 99%.

i

ii

TBSO

16a

N

TBSO

NH₂

O

In anticipation of using the pyrrolidinone triol 37 as a com-

mon intermediate to both oxazolomycin A (1) and neo-

oxazolomycin 2, we prepared a number of its derivatives

including the acetonide 39, the SEM acetonide 41 and the

N-methyl derivatives 42 and 43. Thus, treatment of the triol

37 with 2,2-dimethoxypropane in CH₂Cl₂in the presence of

CCl₃

OH

30

31

Br

O

iii

Br

O

Br

iv

vi

TBSO

MeO₂C

TBSO

HO

TBSO

N

H

N

H

N

H

O

ROC

34

32

33

a R = H

b R = OH

v

O

OH

O

Scheme 5. Reagents and conditions: (i) TBSCl, imidazole, CH₂Cl₂, rt, 15 h,

83%; (ii) 1 M HCl, THF, rt, 3 h; (iii) 2-bromopropionoyl chloride, NaHCO₃,

CH₂Cl₂, rt, 2 h, 76% (for two steps); (iv) TPAP, NMO, CH₂Cl₂, rt, 2 h, 88%;

(v) NaClO₂, NaH₂PO₄, ^tBuOH, 2-methyl-2-butene, rt, 6 h, 83%; (vi) TMS–

CHN₂, MeOH/benzene (1:2.5), rt, 1 h, 75%.

i

37

O

HO

O

N

H

N

MeO₂C

H

39

40

ii or iii

Signiﬁcantly, when a solution of the bromoamide 34 in

reﬂuxing toluene was treated with Bu₃SnH–AIBN, under

the same conditions as those used with the substrate 18,

a much more stereoselective 5-exo-dig cyclisation ensued

leading to a 2:1 mixture of b- and a-C-3 epimers, i.e. 35a

and 36a, of the anticipated methylenepyrrolidinone, and in

a combined yield of 73%. The epimers 35a and 36a were

not separated at this stage but, instead, the mixture was

treated with pTSA in THF/H₂O, which gave a 2:1 mixture

of the corresponding homoallylic alcohols 35b and 36b in

a combined yield of 65%, which could be separated by chro-

matography (Scheme 6). The stereochemistries of the pyrro-

lidinones 35b and 36b were then conﬁrmed by selective

NOE enhancements in their ¹H NMR spectra, and compari-

son of these data with those of similar intermediates we had

synthesised in our contemporaneous studies towards lacta-

cystin 6.^17aTo our pleasure, when the 4-methylenepyrrolidi-

none 35b was treated with OsO₄–TMEDA in CH₂Cl₂at

ꢀ78 ^ꢁC for 1 h and then at room temperature for 2 h, a selec-

tive dihydroxylation occurred from the b-face, i.e. syn to the

CH₂OH group, leading to a single diastereoisomer of the

pyrrolidinone triol 37, which was obtained in an excellent

99% yield.³⁴The stereochemistry of the triol 37 followed

O

iv

R = SEM

SEMO

MeO₂C

O

RO

MeO₂C

N

Me

42

O

N

H

41

a, R = SEM

b, R = COCMe₃

v, R = COCMe₃

O

vii

vi

MeO₂C

39

RO

MeO₂C

O

N

Me

43

O

44

a, R = H

b, R = Me

Scheme 7. Reagents and conditions: (i) 2,2-dimethoxypropane, pTSA,

CH₂Cl₂, 15 h, rt, 39%; (ii) trimethylacetyl chloride, Et₃N, DMAP,

CH₂Cl₂, 40 ^ꢁC, 24 h, 67%; (iii) [2-(trimethylsilyl)ethoxy]methyl chloride,

TBAI, Et₃N, rt, 15 h, 23%; (iv) NaH, DMF, 0 ^ꢁC 10 min then MeI, 0 ^ꢁC,

1 h, 100%; (v) NaH, DMF, 0 ^ꢁC,10 min then MeI, 0 ^ꢁC, 1 h, 60% (43b);

(vi) (CHO)_n, MgSO₄, toluene, 110 ^ꢁC, 8 h, 57%; (vii) Et₃SiH, TFA,

CH₂Cl₂, 0 ^ꢁC to rt, 15 h, 23% (43a).

1

from NOE enhancements in the H NMR spectrum, and

the pertinent enhancements are collected on structure 38.

The pyrrolidinone triol 37 has the same stereochemistry at

6220

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

catalytic pTSA at room temperature for 15 h gave the

expected acetonide 39, albeit in a modest 39% yield

(Scheme 6). Interestingly, when the same reaction was ter-

minated after 3 h, the only product isolated was the isomeric

seven-membered ring ketal 40.³⁵We presume that 40 is the

kinetic product of the protection of the triol 37, which rear-

ranges to the thermodynamic product 39 with additional

time. The primary alcohol group in the acetonide 39 could

then be protected as the SEM ether 41a and as the pivalate

41b. However, although the SEM ether 41a could be meth-

ylated on nitrogen in quantitative yield using NaH–MeI,

leading to the N-methyl pyrrolidinone 42, similar treatment

of the pivalate ester 41b with NaH–MeI resulted in methyl

ether–pivalate exchange in addition to methylation on nitro-

gen leading to 43b in 60% yield. Finally, reaction of the

substituted pyrrolidinone 39 with paraformaldehyde in the

presence of MgSO₄and pTSA³⁶gave the corresponding

ring-fused oxazolidine 44 in 57% yield, which could be

cleaved with Et₃SiH–TFA to the N-methyl pyrrolidinone

43a (Scheme 7).

(400.13 MHz) and were used to conﬁrm ¹H and ¹³C assign-

ments, as appropriate.

IR spectra were recorded as dilute solutions in spectroscopic

grade chloroform on a Perkin Elmer FTIR 1600 instrument.

Optical rotations were recorded on a JASCO DIP 370 polar-

imeter.

Mass spectra were recorded on a VG Autospec MM-701CF

or Micromass LCT spectrometer using electro-ionisation

(EI), chemical ionisation (CI), fast atom bombardment

(FAB) or electrospray (ES) techniques. High-resolution

mass spectra were calculated from the molecular formula

corresponding to the observed signal, using the most abun-

dant isotopes of each element, to four decimal places.

Melting points (mps) were determined on a Bibby Stuart

Scientiﬁc SMP3 apparatus and are uncorrected.

Flash column chromatography was carried out on Merck sil-

ica gel 60 as the stationary phase, and the solvents used for

elution were of analytical grade. All reactions were moni-

tored by thin layer chromatography using silica gel 60 F₂₅₄

precoated aluminium backed plates, which were viewed

under UV light and then developed in basic potassium

permanganate or phosphomolybdic acid.

3. Summary and conclusion

In summary, we have developed a useful synthetic approach

to the pyrrolidinone triol 37 and its derivatives 39, 41a, 41b,

42, 43a, 43b and 44, which we plan to use as common precur-

sors to the lactone–pyrrolidinone ring systems, viz. 8 and 10,

in oxazolomycin A (1) and neooxazolomycin 2, and hence to

the natural products themselves. The syntheses of the pyrro-

lidinone triol derivatives are based on a diastereoselective 5-

exo-dig radical cyclisation of a bromoamide, i.e. 34, derived

from an enantiopure a-ethynyl substituted amino alcohol, i.e.

31, followed by a stereoselective vicinal dihydroxylation of

a 5-hydroxymethyl substituted 4-methylenepyrrolidinone

intermediate, viz. 35b, using OsO₄–TMEDA, as key steps.

Unless stated otherwise, reactions requiring anhydrous con-

ditions were conducted under an inert atmosphere of nitro-

gen or argon in ﬂame dried apparatus. Experiments were

generally performed using distilled organic solvents. Diethyl

ether and tetrahydrofuran were distilled from sodium metal

and benzophenone ketal under a nitrogen atmosphere. Tolu-

ene was distilled from sodium wire and dichloromethane

from calcium hydride. Anhydrous N,N-dimethylformamide

was purchased from Aldrich. Evaporations of organic solu-

tions were carried out using a Buchi rotary evaporator under

reduced pressure.

4. Experimental

4.1.1. (S)-2-Oxiranyl-but-3-yn-1-ol (15a). Titanium tetra-

isopropoxide (1.14 mL, 3.66 mmol) and diisopropyl-^D-

tartrate (1.00 mL, 4.76 mmol) were added in one portion

4.1. General details

˚

Proton NMR spectra were recorded on a Bruker DRX 360

(360.13 MHz), a Bruker AV 400 (400.13 MHz), or a Bruker

DRX 500 (500.12 MHz) spectrometer, at ambient tempera-

ture, as dilute solutions in deuterated chloroform. Data are

expressed as chemical shifts in parts per million (ppm) rela-

tive to the residual protonated solvent used as an internal

standard (d_H¼7.27 ppm for CDCl₃). The multiplicity of

a signal is designated by one of the following abbreviations:

s, singlet; d, doublet; t, triplet, q, quartet; br, broad and m,

multiplet. All coupling constants, J, are quoted in hertz

(Hz). ¹³C NMR spectra were recorded on a Bruker DRX

360 (90.03 MHz), a Bruker AV 400 (100.03 MHz), or

a Bruker DRX 500 (125 MHz) spectrometer, at ambient

temperature, as dilute solutions in deuterated chloroform.

Data are expressed as chemical shifts in parts per million

(ppm) relative to the residual solvent used as an internal stan-

dard (d_C¼77.0 ppm for the central peak of CDCl₃). Assign-

ments of ¹³C spectra were made on the basis of chemical

shift using a DEPT sequence with secondary pulses at 90^ꢁ

and 135^ꢁ, where appropriate. H–H COSY, HMQC, HMBC

and NOE experiments were recorded on a Bruker AM400

to a stirred suspension of powdered 3 A molecular sieves

(1.5 g) in dichloromethane (60 mL) at ꢀ12 ^ꢁC. The mixture

was stirred at ꢀ12 ^ꢁC for 30 min and then the enynol 14

(1.5 g, 18.3 mmol)²⁴was added in a single portion followed

by cumene hydroperoxide (10.1 mL, 54.9 mmol) in a single

portion. The mixture was stirred at ꢀ12 ^ꢁC for 15 h and then

diluted with a solution of citric acid (1.5 g) in diethyl ether/

acetone (9:1; 150 mL). The resulting suspension was ﬁltered

through a pad of Celite and the ﬁltrate was then concentrated

in vacuo. The residue was puriﬁed by ﬂash column chroma-

tography, on silica gel, eluting with pentane/diethyl ether

(1:1) to give the epoxide (1.40 g, 77%) as a colourless oil;

[a]²_D⁴48.4 (c 1.0, CHCl₃); n_max(CHCl₃) 3590, 3304, 2926,

2880 cm^ꢀ1; d_H(360 MHz, CDCl₃) 3.91 (1H, d, J¼12.7,

CH₂OH), 3.76 (1H, d, J¼12.7, CH₂OH), 3.07 (1H, d,

J¼5.5, CH₂OC), 3.03 (1H, d, J¼5.5, CH₂OC), 2.40 (1H, s,

C^CH); d_C(90 MHz, CDCl₃) 79.9 (C^CH), 73.3

(C^CH), 62.9 (CH₂OH), 51.2 (CH₂OC), 50.7 (quat. C).

4.1.2. (S),(S)-Mosher ester of the epoxide (15a). S-(ꢀ)-

Methoxytriﬂuoromethylphenylacetic

acid

(18 mL,

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6221

0.098 mmol) was added to a stirred solution of the epoxide

15 (8 mg, 0.082 mmol), triethylamine (23 mL, 0.16 mmol)

and N,N-dimethylaminopyridine (1 mg) in deuterated chlo-

roform (0.5 mL) at room temperature. The solution was

stirred at room temperature for 2 h and then diluted with

a saturated aqueous solution of sodium bicarbonate

(0.5 mL). The organic phase was separated and the aqueous

phase was extracted with dichloromethane (2ꢂ1 mL). The

organic extracts were combined, dried over MgSO₄and

evaporated in vacuo. The residue was puriﬁed by ﬂash col-

umn chromatography, on silica gel, eluting with pentane/

diethyl ether (1:1) to give the (S)-ester (5 mg, 32%) as a

colourless oil and as an 11:1 mixture of diastereoisomers

(corresponding to an enantiomeric excess of 83%) that

was not separated; Major diastereoisomer: [a]²_D⁴ꢀ12.5 (c

0.8, CHCl₃); n_max(CHCl₃) 3304, 2958, 1756 cm^ꢀ1; d_H

(360 MHz, CDCl₃) 7.59–7.57 (2H, m, Ar-H), 7.47–7.41

(3H, m, Ar-H), 4.66 (1H, d, J¼12.0, CH₂OCO), 4.41 (1H,

d, J¼12.0, CH₂OCO), 3.62 (3H, s, OCH₃), 3.08 (1H, d,

J¼5.4, CH₂OC), 2.90 (1H, d, J¼5.4, CH₂OC), 2.37 (1H, s,

C^CH); d_C(90 MHz, CDCl₃) 166.0 (C]O), 131.8 (Ar-

C), 129.7 (Ar-CH), 128.4 (Ar-CH), 127.7 (Ar-CH), 124.7

(CCF₃), 121.5 (CF₃), 78.7 (C^CH), 73.4 (C^CH), 66.1

(CH₂OCO), 55.6 (OCH₃), 52.1 (CH₂OC), 47.8 (quat. C);

d_F(282 MHz) ꢀ72.23; m/z found 315.0857, 337.0649,

378.0931 (M+H⁺, C₁₅H₁₄O₄F₃requires 315.0844; M+Na,

C₁₅H₁₃O₄F₃Na requires 337.0664; M+Na+CH₃CN,

C₁₇H₁₆O₄F₃NaN requires 378.0929).

pentane/diethyl ether (3:2) to give the trichloroacetimidate

(5.1 g, 81%) as a yellow oil; [a]²_D⁴19.6 (c 1.0, CHCl₃); n_max

(CHCl₃) 3305, 2958, 1669 cm^ꢀ1; d_H(360 MHz, CDCl₃)

8.46 (1H, br s, NH), 4.60 (1H, d, J¼12.0, CH₂O), 4.45 (1H,

d, J¼12.0, CH₂O), 3.13 (1H, d, J¼5.6, CH₂OC), 3.11 (1H,

d, J¼5.6, CH₂OC), 2.41 (1H, s, C^CH); d_C(90 MHz,

CDCl₃) 162.2 (C]NH), 79.1 (C^CH), 77.2 (CCl₃), 73.1

(C^CH), 68.8 (CH₂O), 52.1 (CH₂OC), 48.2 (quat. C); m/z

(CI, NH⁺₄) found 241.9544 (M+H⁺, C₇H₇O₂NCl₃requires

241.9542).

4.1.5. [(R)-2-Trichloromethyl-4-ethynyl-4,5-dihydro-ox-

azole]methanol (16a). A solution of diethylaluminium

chloride (1 M in hexanes; 10.3 mL, 10.3 mmol) was added

over 5 min to a stirred solution of the acetimidate 15b

(5.0 g, 20.7 mmol) in dichloromethane (100 mL) at 0 ^ꢁC.

The mixture was stirred at 0 ^ꢁC for 1 h and then allowed to

warm to room temperature over 15 h before being quenched

with a saturated aqueous solution of sodium bicarbonate

(50 mL). The organic phase was separated and the aqueous

phase was then extracted with dichloromethane (3ꢂ30 mL).

The combined organic extracts were dried over MgSO₄and

evaporated in vacuo. The residue was puriﬁed by ﬂash col-

umn chromatography, on silica gel, eluting with pentane/

ether (1:1) to give the oxazoline (3.14 g, 63%) as a colourless

oil; [a]²_D⁴ꢀ18.4 (c 1.0, CHCl₃); n_max(CHCl₃) 3595, 3305,

2937, 1655 cm^ꢀ1; d_H(360 MHz, CDCl₃) 4.82 (1H, d,

J¼8.4, CH₂O), 4.70 (1H, d, J¼8.4, CH₂O), 3.96 (1H, d,

J¼11.7, CH₂OH), 3.72 (1H, d, J¼11.7, CH₂OH), 2.62

(1H, s, C^CH), 2.25 (1H, br s, OH); d_C(90 MHz, CDCl₃)

165.2 (C]N), 80.9 (C^CH), 77.8 (CH₂O), 77.2 (CCl₃),

75.6 (C^CH), 69.9 (quat. C), 66.7 (CH₂OH); m/z (ES)

241.9553 (M+H⁺, C₇H₇O₂NCl₃requires 241.9542).

4.1.3. (R),(S)-Mosher ester of the epoxide (15a). The

Mosher ester was prepared from the epoxide 15 and R-(+)-

methoxytriﬂuoromethylphenylacetic acid using the same

procedure as that described for the diastereoisomer. Flash

column chromatography gave the (R)-ester (5 mg, 32%) as

a colourless oil and as an 11:1 mixture of diastereoisomers

(corresponding to an enantiomeric excess of 83%) that was

not separated; Major diastereoisomer: [a]²_D⁴+21.0 (c, 0.8,

CHCl₃); n_max(CHCl₃)/cm^ꢀ13304, 2953, 1756; d_H

(360 MHz, CDCl₃) 7.57–7.54 (2H, m, Ar-H), 7.45–7.38

(3H, m, Ar-H), 4.72 (1H, d, J¼12.1, CH₂OCO), 4.33 (1H,

d, J¼12.1, CH₂OCO), 3.60 (3H, s, OCH₃), 3.06 (1H, d,

J¼5.4, CH₂OC), 2.95 (1H, d, J¼5.4, CH₂OC), 2.41 (1H, s,

C^CH); d_C(90 MHz, CDCl₃) 166.0 (C]O), 131.8 (Ar-

C), 129.7 (Ar-CH), 128.4 (Ar-CH), 127.4 (Ar-CH), 124.7

(CCF₃), 121.5 (CF₃), 78.8 (C^CH), 73.4 (C^CH), 65.8

(CH₂OCO), 55.6 (OCH₃), 52.0 (CH₂OC), 48.4 (quat. C);

d_F(282 MHz) ꢀ72.15; m/z found 315.0825, 337.0639,

378.0917 (M+H⁺, C₁₅H₁₄O₄F₃requires 315.0844; M+Na,

C₁₅H₁₃O₄F₃Na requires 337.0664; M+Na+CH₃CN,

C₁₇H₁₆O₄F₃NaN requires 378.0929).

4.1.6. (S),(R)-Mosher ester of the alcohol (16a). S-(ꢀ)-Me-

thoxytriﬂuoromethylphenylacetic acid (9 mL, 0.045 mmol)

was added to a stirred solution of the oxazoline 16a

(10 mg, 0.041 mmol), triethylamine (9 mL, 0.06 mmol) and

N,N-dimethylaminopyridine (1 mg) in deuterated chloro-

form (0.5 mL) at room temperature. The solution was stirred

at room temperature for 2 h and then diluted with a saturated

aqueous solution of sodium bicarbonate (0.5 mL). The

organic phase was separated and the aqueous phase was

extracted with dichloromethane (2ꢂ1 mL). The combined

organic extracts were dried over MgSO₄and evaporated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy, on silica gel, eluting with pentane/diethyl ether (1:1)

to give the (S)-ester (11 mg, 64%) as a colourless oil and as

an 11:1 mixture of diastereoisomers (corresponding to an

enantiomeric excess of 83%) that was not separated; Major

diastereoisomer: [a]²_D⁴ꢀ12.8 (c 0.5, CHCl₃); n_max(CHCl₃)

3305, 2953, 1759, 1657 cm^ꢀ1; d_H(360 MHz, CDCl₃)

7.51–7.50 (2H, m, Ar-H), 7.43–7.41 (3H, m, Ar-H), 4.70

(1H, d, J¼8.8, CH₂O), 4.66 (1H, d, J¼8.8, CH₂O), 4.56

(1H, d, J¼11.3, CH₂O), 4.53 (1H, d, J¼11.3, CH₂O), 3.55

(3H, s, OCH₃), 2.66 (1H, s, C^CH); d_C(90 MHz, CDCl₃)

165.9 (C]O), 165.2 (C]N), 131.5 (Ar-C), 129.9 (2ꢂ

Ar-CH), 128.6 (Ar-CH), 128.5 (Ar-CH), 127.4 (Ar-CH),

124.7 (CCF₃), 121.5 (CF₃), 79.8 (C^CH), 77.9 (CH₂O),

77.2 (CCl₃), 76.2 (C^CH), 68.1 (CH₂O), 67.3 (quat. C),

55.5 (OCH₃); d_F(282 MHz) ꢀ72.12; m/z found 457.9937,

459.9955 (M+H⁺, C₁₇H₁₄O₄NF₃³⁵Cl₃requires 457.9941;

M+H⁺, C₁₇H₁₄O₄NF₃³⁵Cl₂³⁷Cl requires 459.9911).

4.1.4. 2,2,2-Trichloroacetimidic acid (S)-2-ethynyl-oxi-

ranylmethyl ester (15b). Trichloroacetonitrile (3.14 mL,

31.3 mmol)

and

1,8-diazabicyclo[5.4.0]undec-7-ene

(0.47 mL, 3.1 mmol) were added in a single portion to

a stirred solution of the epoxide 15a (2.56 g, 26.1 mmol) in

dichloromethane (100 mL) at 0 ^ꢁC. The mixture was stirred

at 0 ^ꢁC for 1 h and then diluted with water (50 mL). The

organic phase was separated and the aqueous phase was

extracted with dichloromethane (3ꢂ30 mL). The combined

organic extracts were dried over MgSO₄and evaporated in

vacuo. The residue was puriﬁed immediately by ﬂash column

chromatography through a short pad of silica gel, eluting with

6222

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

4.1.7. (R),(R)-Mosher ester of the alcohol (16a). The

Mosher ester was prepared from the alcohol 16a and R-

(+)-methoxytriﬂuoromethylphenylacetic acid using the

same procedure as that described for the diastereoisomer.

Flash column chromatography, on silica gel, eluting with

pentane/diethyl ether (1:1) gave the (S)-ester (10 mg, 53%)

as a colourless oil and as an 11:1 mixture of diastereoisomers

(corresponding to an enantiomeric excess of 83%) that was

not separated; Major diastereoisomer: [a]²_D⁴19.0 (c 0.2,

CHCl₃); n_max(CHCl₃) 3305, 1007 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 7.50–7.48 (2H, m, Ar-H), 7.43–7.41 (3H, m, Ar-

H), 4.68 (1H, d, J¼8.8, CH₂O), 4.61 (1H, d, J¼11.4,

CH₂O), 4.53 (1H, d, J¼8.8, CH₂O), 4.49 (1H, d, J¼11.4,

CH₂O), 3.54 (3H, s, OCH₃), 2.66 (1H, s, C^CH); d_C

(90 MHz, CDCl₃) 165.9 (C]O), 165.2 (C]N), 131.5 (Ar-

C), 129.9 (Ar-CH), 129.6 (Ar-CH), 128.6 (2ꢂAr-CH),

127.4 (Ar-CH), 124.7 (CCF₃), 121.5 (CF₃), 79.6 (C^CH),

77.8 (CH₂O), 77.2 (CCl₃), 76.4 (C^CH), 68.1 (CH₂O),

67.6 (quat. C), 55.5 (OCH₃); d_F(282 MHz) ꢀ71.99; m/z

found 457.9978 (M+H⁺, C₁₇H₁₄O₄NF₃³⁵Cl₃requires

457.9941).

(2ꢂ10 mL) and ethyl acetate (3ꢂ10 mL). The combined

organic extracts were dried over MgSO₄and evaporated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy, on silica gel, eluting with dichloromethane/metha-

nol (4:1) to give a yellow solid, which was recrystallised

from pentane/ethyl acetate (20:1) to give the amine (1.2 g,

76%) as a pale yellow solid; mp 67–68 ^ꢁC; [a]_D²⁴ꢀ3.2 (c

1.0, CHCl₃); n_max(CHCl₃) 3429, 3306, 2932, 2859 cm^ꢀ1

;

d_H(360 MHz, CDCl₃) 7.70–7.67 (4H, m, Ar-H), 7.47–7.38

(6H, m, Ar-H), 4.21 (1H, d, J¼10.7, CH₂O), 4.16 (1H, d,

J¼10.7, CH₂O), 3.72 (1H, d, J¼9.6, CH₂O), 3.68 (1H, d,

J¼9.6, CH₂O), 2.32 (1H, s, C^CH), 2.08 (3H, s, COCH₃),

1.73 (2H, br s, NH₂), 1.08 (9H, s, SiC(CH₃)₃); d_C(90 MHz,

CDCl₃) 170.4 (COCH₃), 135.6 (2ꢂAr-CH), 135.5 (2ꢂAr-

CH), 132.5 (Ar-C), 132.4 (Ar-C), 130.1 (4ꢂAr-CH), 127.9

(Ar-CH), 127.8 (Ar-CH), 81.2 (C^CH), 73.4 (C^CH),

66.6 (CH₂O), 66.3 (CH₂O), 57.6 (quat. C), 26.8 (SiCMe₃),

23.8 (COCH₃), 19.3 (SiCMe₃); m/z (ES+) found 418.1814

(M+Na, C₂₃H₂₉O₃NSiNa requires 418.1814).

4.1.10. (2R)-2-[(2-Bromopropanoyl)amino]-2-({[(1,1-

dimethylethyl)(diphenyl)silyl]oxy}methyl)-3-butyn-1-yl

acetate (18). 2-Bromopropionyl chloride (0.6 mL,

5.85 mmol) was added dropwise, over 5 min, to a stirred so-

lution of the amine 17b in dichloromethane (15 mL) and

triethylamine (0.5 mL) at room temperature. The mixture

was stirred at room temperature for 15 h and then diluted

with a saturated aqueous solution of potassium carbonate

(5 mL), water (5 mL) and dichloromethane (10 mL). The or-

ganic phase was separated and the aqueous phase was then

extracted with dichloromethane (3ꢂ10 mL). The combined

organic extracts were dried over MgSO₄and evaporated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy, on silica gel, eluting with pentane/ether (polarity

increasing from 7:3 to 1:1) to give a 1:1 mixture of diastereo-

isomers of the amide (1.01 g, 50% for three steps) as a pale

yellow oil; [a]_D²⁴ꢀ1.6 (c 3.0, CHCl₃); n_max(CHCl₃) 3397,

3306, 2932, 2860, 1746 cm^ꢀ1; d_H(360 MHz, CDCl₃)

7.74–7.67 (8H, m, Ar-Hꢂ2), 7.43–7.39 (12H, m, Ar-Hꢂ2),

7.05 (2H, s, NH), 4.60–4.57 (2H, m, CH₂O), 4.40–4.36 (4H,

m, CH₂O), 4.01–3.87 (4H, m, CH₂O and CHBr), 2.41 (2H, s,

CH^Cꢂ2), 2.02 (6H, s, CH₃CO), 1.90–1.87 (6H, m,

CH₃Cꢂ2), 1.11–1.06 (18H, s, SiC(CH₃)₃); d_C(90 MHz,

CDCl₃) 170.3 (COCH₃), 168.7 (CONH), 168.4 (CONH),

135.5 (8ꢂAr-CH), 132.2 (4ꢂAr-C), 130.0 (4ꢂAr-CH),

129.8 (4ꢂAr-CH), 127.8 (2ꢂAr-CH), 127.7 (2ꢂAr-CH),

79.6 (2ꢂC^CH), 73.5 (2ꢂC^CH), 64.9 (2ꢂCH₂O), 63.3

(CH₂O), 63.1 (CH₂O), 54.8 (quat. C), 54.5 (quat. C), 45.0

(CHBrCH₃), 44.7 (CHBrCH₃), 26.7 (2ꢂSiCMe₃), 22.8

(SiCMe₃), 22.4 (SiCMe₃), 20.6 (COCH₃), 19.2 (COCH₃);

m/z (ES) found 530.1347, 552.1217, 554.1197 (M+H⁺,

C₂₆H₃₃O₄NSi⁷⁹Br requires 530.1362; M+Na, C₂₆H₃₂O₄N-

Si⁷⁹BrNa requires 552.1182; M+Na, C₂₆H₃₂O₄NSi⁸¹BrNa

requires 554.1161).

4.1.8. [(R)-4-Ethynyl-2-(trichloromethyl)-4,5-dihydro-

1,3-oxazol-4-yl]methyl acetate (16b). Acetyl chloride

(0.88 mL, 12.4 mmol) was added over 5 min to a stirred so-

lution of the oxazoline 16a (2.0 g, 8.3 mmol), triethylamine

(2.3 mL, 16.6 mmol) and N,N-dimethylaminopyridine

(0.1 g, 0.83 mmol) in anhydrous dichloromethane (30 mL)

at 0 ^ꢁC. The solution was stirred at 0 ^ꢁC for 1.5 h and then

diluted with water (30 mL). The organic phase was sepa-

rated and the aqueous phase was then extracted with di-

chloromethane (3ꢂ30 mL). The combined organic extracts

were dried over MgSO₄and then evaporated in vacuo. The

residue was puriﬁed by ﬂash column chromatography, on sil-

ica gel, eluting with pentane/ether (1:1) to give the acetate

(2.2 g, 94%) as a yellow oil; [a]²_D⁴ꢀ6.0 (c 1.0, CHCl₃);

Found: C, 38.0; H, 3.1; N, 4.6; C₉H₈O₃NCl₃requires C,

38.2; H, 2.9; N, 5.0%; n_max(CHCl₃) 3305, 2959, 2130,

1731, 1651 cm^ꢀ1; d_H(360 MHz, CDCl₃) 4.73 (1H, d, J¼8.7,

CH₂O), 4.68 (1H, d, J¼8.7, CH₂O), 4.37 (1H, d, J¼11.4,

CH₂O), 4.31 (1H, d, J¼11.4, CH₂O), 2.65 (1H, s, C^CH),

2.09 (3H, s, COCH₃); d_C(90 MHz, CDCl₃) 170.1 (COCH₃),

164.7 (C]N), 85.9 (CCl₃), 79.9 (C^CH), 78.0 (CH₂O),

75.9 (C^CH), 67.9 (quat. C), 66.9 (CH₂OH), 20.6

(COCH₃); m/z (ES) found 283.9629 (M+H⁺C₉H₉O₃NCl₃

requires 283.9648).

4.1.9. Acetic acid (R)-2-amino-2-(tert-butyl-diphenyl-

silanyloxymethyl)-but-3-ynyl ester (17b). Aqueous hydro-

chloric acid (1 M, 3.9 mL, 3.9 mmol) was added in a single

portion to a stirred solution of the oxazoline 16b (1.1 g,

3.9 mmol) in tetrahydrofuran (22 mL) at room temperature.

The solution was stirred at room temperature for 3 h and then

the solvent was evaporated in vacuo to leave the amino

alcohol 17a. The alcohol was dissolved immediately in

dichloromethane (15 mL) and triethylamine (3 mL), and

then tert-butyldiphenylsilyl chloride (3.1 mL, 11.7 mmol)

and N,N-dimethylaminopyridine (50 mg, 0.39 mmol) were

added in one portion. The mixture was stirred at room tem-

perature for 5 h, and then diluted with a saturated aqueous

solution of sodium bicarbonate (10 mL) and dichlorome-

thane (10 mL). The organic phase was separated and the

aqueous phase was then extracted with dichloromethane

4.1.11. [(2R,4R)-2-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-4-methyl-3-methylidene-5-oxo-2-

pyrrolidinyl]methyl acetate (19) and [(2R,4S)-2-({[(1,1-

dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-methyl-3-

methylidene-5-oxo-2-pyrrolidinyl]methyl acetate (20). A

solution of tributyltin hydride (0.20 mL, 0.75 mmol) and

2,2⁰-azobisisobutyronitrile (20 mg, 0.12 mmol) in degassed

toluene (30 mL) was added dropwise over 0.5 h, via syringe

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6223

pump, to a reﬂuxing solution of the amide 18 (0.33 g,

0.62 mmol) in degassed toluene (125 mL) under an atmo-

sphere of argon. The solution was heated under reﬂux for

a further 2 h, then cooled to room temperature and evapo-

rated in vacuo. The residue was partitioned between acetoni-

trile (50 mL) and hexane (50 mL). The acetonitrile extract

was separated and the hexane phase extracted with acetoni-

trile (30 mL). The combined acetonitrile extracts were evap-

orated in vacuo and the residue was puriﬁed by ﬂash column

chromatography, on silica gel, eluting with pentane/diethyl

ether (7:3) then diethyl ether to give (i) the b-methyl pyrro-

lidinone 19 (eluted ﬁrst) (0.21 g, 27%) as a colourless oil;

[a]²_D⁴0.85 (c 0.7, CHCl₃); n_max(CHCl₃) 3427, 2932, 2859,

1708 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.68–7.60 (4H, m, Ar-

H), 7.48–7.37 (6H, m, Ar-H), 5.73 (1H, s, NH), 5.14 (1H,

s, C]CH₂), 5.13 (1H, s, C]CH₂), 4.45 (1H, d, J¼11.3,

CH₂O), 4.03 (1H, d, J¼11.3, CH₂O), 3.64 (1H, d, J¼10.2,

CH₂O), 3.62 (1H, d, J¼10.2, CH₂O), 3.07–3.03 (1H, m,

CHCH₃), 2.02 (3H, s, COCH₃), 1.33 (3H, d, J¼7.4,

CHCH₃), 1.06 (9H, s, SiC(CH₃)₃); d_C(90 MHz, CDCl₃)

177.3 (CONH), 170.5 (COCH₃), 148.4 (C]CH₂), 135.6

(2ꢂAr-CH), 135.5 (2ꢂAr-CH), 132.4 (2ꢂAr-C), 130.0

(4ꢂAr-CH), 127.9 (2ꢂAr-CH), 109.7 (C]CH₂), 67.0

(CH₂O), 66.3 (CH₂O), 64.8 (quat. C), 40.8 (CHCH₃), 26.8

(SiCMe₃), 20.7 (SiCMe₃), 19.2 (COCH₃), 16.0 (CHCH₃);

m/z (ES) found 452.2255, 515.2352 (M+H⁺, C₂₆H₃₄O₄NSi

requires 452.2257; M+Na⁺+CH₃CN C₂₈H₃₆O₄N₂SiNa

was added and the solution was stirred for a further 1 h.

The suspension was diluted with ethyl acetate (5 mL) and

the organic phase was then separated. The aqueous phase

was extracted with ethyl acetate (3ꢂ5 mL) and then with

isopropanol/chloroform (1:1; 10 mL). The combined or-

ganic extracts were evaporated in vacuo and the residue

was puriﬁed by ﬂash column chromatography, on silica

gel, eluting with ethyl acetate to give the vicinal diol

(0.23 g, 59%) as a colourless oil; [a]²_D⁴3.0 (c 0.1, CHCl₃);

n_max(CHCl₃) 3694, 2961, 1712, 1602, 1097 cm^ꢀ1; d_H

(360 MHz, CDCl₃) 7.65–7.62 (4H, m, Ar-H), 7.45–7.39

(6H, m, Ar-H), 5.85 (1H, s, NH), 4.43–4.35 (2H, m,

CH₂O), 3.95–3.60 (4H, m, CH₂Oꢂ2), 2.65 (1H, q, J¼7.7,

CH₃CH), 1.92 (3H, s, CH₃CO), 1.13–1.04 (12H, m,

SiC(CH₃)₃and CH₃CH); d_C(90 MHz, CDCl₃) 176.8

(COCH₃), 170.7 (CONH), 135.6 (2ꢂAr-CH), 135.2

(2ꢂAr-CH), 134.8 (2ꢂAr-C), 131.8 (Ar-CH), 131.6 (Ar-

CH), 130.3 (Ar-CH), 129.6 (Ar-CH), 128.0 (Ar-CH), 127.7

(Ar-CH), 79.8 (COH), 78.3 (quat. C), 65.6 (CH₂OH), 63.3

(CH₂O), 62.7 (CH₂O), 46.6 (CHCH₃), 26.8 (SiCMe₃),

20.8 (COCH₃), 19.1 (SiCMe₃), 10.7 (CHCH₃); m/z (EI)

found 486.2320, 549.2366 (M+H⁺, C₂₆H₃₆O₆NSi requires

486.2312, M+CH₃CN+Na⁺, C₂₈H₃₈O₆N₂SiNa requires

549.2397).

4.1.13. [(5S,6R,9S)-6-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-2,2,9-trimethyl-8-oxo-1,3-dioxa-7-

azaspiro[4.4]non-6-yl]methyl acetate (22). para-Toluene-

sulfonic acid (2 mg) was added to a stirred solution of the

diol 21 (0.23 g, 0.47 mmol) in 2,2-dimethoxypropane

(2 mL) and the mixture was stirred at room temperature

for 15 h. The mixture was diluted with a saturated aqueous

solution of sodium bicarbonate (2 mL) and ethyl acetate

(2 mL). The organic phase was separated and the aqueous

phase was then extracted with ethyl acetate (3ꢂ2 mL). The

combined organic extracts were dried over MgSO₄and

then evaporated in vacuo to leave the acetonide (0.22 g,

88%) as a colourless oil, which was used without further

puriﬁcation; [a]_D²⁴1.5 (c 0.2, CHCl₃); n_max(CHCl₃) 2929,

2857, 1708, 1114 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.65–7.60

(4H, m, Ar-H), 7.47–7.39 (6H, m, Ar-H), 5.71 (1H, s,

NH), 4.39 (1H, d, J¼11.4, CH₂O), 4.26 (1H, d, J¼11.4,

CH₂O), 4.11 (1H, d, J¼9.9, CH₂O), 3.96 (1H, d, J¼9.9,

CH₂O), 3.67 (2H, s, CH₂O), 2.81 (1H, q, J¼7.7, CHCH₃),

1.96 (3H, s, CH₃CO), 1.38 (3H, s, CH₃C), 1.30 (3H, s,

CH₃C), 1.17 (3H, d, J¼7.7, CHCH₃), 1.08 (9H, s,

SiC(CH₃)₃); d_C(90 MHz, CDCl₃) 176.1 (COCH₃), 170.2

(CONH), 135.6 (2ꢂAr-CH), 135.5 (2ꢂAr-CH), 132.0

(2ꢂAr-C), 130.2 (Ar-CH), 130.1 (Ar-CH), 129.5 (Ar-CH),

128.0 (Ar-CH), 127.9 (Ar-CH), 127.6 (Ar-CH), 109.3

(CMe₂), 87.2 (C(O)), 64.9 (CH₂O), 64.1 (quat. C), 63.6

(CH₂O), 63.2 (CH₂O), 45.5 (CHCH₃), 26.8 (SiCMe₃), 26.0

(CCH₃ꢂ2), 20.8 (COCH₃), 19.1 (SiCMe₃), 11.0 (CHCH₃);

m/z (ES) found 526.2646 (M+H⁺, C₂₉H₄₀O₆NSi requires

526.2625). In a ¹H NOE experiment (400 MHz, CDCl₃), ir-

radiation at d 4.11 gave enhancements at d 3.67 (12.7%) and

1.17 (0.7%); irradiation at d 3.96 gave enhancements at

d 3.67 (2.2%) and 1.17 (3.6%); irradiation at d 3.67 gave

enhancements at d 4.11 (11.5%), 3.96 (14.1%) and 1.17

(2.6%); irradiation at d 2.81 gave enhancements at d 4.26

(1.9%) and 1.38 (2.3%); irradiation at d 1.38 gave an en-

hancement at d 2.81 (2.5%) and irradiation at d 1.17 gave

an enhancement at d 3.96 (3.5%).

1

requires 515.2342); In a H NOE experiment (400 MHz,

CDCl₃), irradiation at d 4.45 gave an enhancement at

d 1.33 (1.3%); irradiation at d 4.03 gave an enhancement

at d 1.33 (1.3%); irradiation at d 3.05 gave an enhancement

at d 1.06 (2%); irradiation at d 2.02 gave an enhancement at

d 1.33 (3.5%) and irradiation at d 1.33 gave an enhancement

at d 2.02 (1.6%); and (ii) the a-methyl pyrrolidinone 20

(eluted second) (0.22 g, 28%); [a]²_D⁴ꢀ3.7 (c 0.6, CHCl₃);

n_max(CHCl₃) 3428, 2959, 2932, 2860, 1743, 1709, 1664,

1375, 1113 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.65–7.61 (4H,

m, Ar-H), 7.46–7.41 (6H, m, Ar-H), 5.92 (1H, s, NH),

5.09 (1H, s, C]CH₂), 5.08 (1H, s, C]CH₂), 4.43 (1H, d,

J¼11.0, CH₂O), 4.07 (1H, d, J¼11.0, CH₂O), 3.73 (1H, d,

J¼10.2, CH₂O), 3.57 (1H, d, J¼10.2, CH₂O), 3.12–3.08

(1H, m, CHCH₃), 2.02 (3H, s, CH₃CO), 1.27 (3H, d,

J¼7.4, CH₃CH), 1.09 (9H, s, SiC(CH₃)₃); d_C(90 MHz,

CDCl₃) 177.3 (CONH), 170.5 (COCH₃), 148.5 (C]CH₂),

135.6 (2ꢂAr-CH), 135.6 (2ꢂAr-CH), 132.4 (2ꢂAr-C),

130.1 (4ꢂAr-CH), 127.9 (Ar-CH), 127.9 (Ar-CH), 109.5

(C]CH₂), 66.3 (2ꢂCH₂O), 64.4 (quat. C), 41.0 (CHCH₃),

26.8 (SiCMe₃), 20.8 (COCH₃), 19.2 (SiCMe₃), 15.7

(CHCH₃); m/z found 474.2115 (M+Na, C₂₆H₃₃O₄NSiNa re-

quires 474.2077). In a ¹H NOE experiment (400 MHz,

CDCl₃), irradiation at d 3.73 gave an enhancement at

d 1.27 (13.8%) and irradiation at d 3.57 gave an enhance-

ment at d 1.27 (3.9%).

4.1.12. [(2R,3S,4S)-2-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-3-hydroxy-3-(hydroxymethyl)-4-methyl-

5-oxo-2-pyrrolidinyl]methyl acetate (21). A solution of

osmium tetroxide (4% in water; 0.26 mL) was added to

a stirred solution of the pyrrolidinone 20 (0.18 g, 0.4 mmol)

and N-methylmorpholine-N-oxide (61 mg, 0.6 mmol) in

acetone/water (1:1; 2.5 mL) at room temperature. The sus-

pension was stirred at room temperature for 4 days, and

then a saturated aqueous solution of sodium sulﬁte (5 mL)

6224

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

4.1.14. [(2R,4R)-2-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-3-hydroxy-3-(hydroxymethyl)-4-

4.1.16. (5R)-5-({[(1,1-Dimethylethyl)(diphenyl)silyl]-

oxy}methyl)-5-(hydroxymethyl)-3,4-dimethyl-1,5-dihy-

dro-2H-pyrrol-2-one (25). Potassium carbonate (15 mg,

0.11 mmol) was added to a stirred solution of the pyrrolidi-

none 19 (25 mg, 0.055 mmol) in methanol (0.2 mL) and the

suspension was stirred vigorously at room temperature for

15 h. The mixture was diluted with diethyl ether (5 mL),

then ﬁltered and the ﬁltrate was concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography,

on silica gel, eluting with diethyl ether to give the dihydro-

pyrrolone (16 mg, 80%) as a colourless oil; [a]²_D⁴ꢀ6.6

(c 2.0, CHCl₃); n_max(CHCl₃) 3442, 2931, 2859, 1692,

1113 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.72–7.68 (2H, m, Ar-H),

7.63–7.61 (3H, m, Ar-H), 7.44–7.40 (5H, m, Ar-H), 6.46

(1H, br s, NH), 3.93 (1H, dd, J¼11.4 and 5.3, CH₂OH),

3.80 (1H, d, J¼10.2, CH₂OSi), 3.65 (1H, d, J¼10.2,

CH₂OSi), 3.60 (1H, dd, J¼11.4 and 7.7, CH₂OH), 2.76 (1H,

dd, J¼7.7 and 5.3, OH), 1.81 (3H, s, C]CCH₃), 1.76 (3H, s,

C]CCH₃), 1.05 (9H, s, SiC(CH₃)₃); d_C(90 MHz, CDCl₃)

174.8 (CONH), 152.2 (H₃CC]CCH₃), 135.6 (2ꢂAr-CH),

135.5 (2ꢂAr-CH), 133.5 (H₃CC]CCH₃), 132.5 (Ar-C),

132.4 (Ar-C), 130.0 (2ꢂAr-CH), 129.6 (2ꢂAr-CH), 127.9

(Ar-CH), 127.7 (Ar-CH), 68.9 (CH₂O), 65.6 (CH₂O), 63.6

(quat. C), 26.7 (SiCMe₃), 19.1 (SiCMe₃), 11.7 (CH₃C]C),

8.3 (CH₃C]C); m/z found 410.2152, 432.1976 (M+H⁺,

C₂₄H₃₁O₃NSi requires 410.2151; M+Na, C₂₄H₃₀O₂NSiNa

requires 432.1971).

methyl-5-oxo-2-pyrrolidinyl]methyl acetate (23).

A

solution of osmium tetroxide (4% in water; 0.1 mL) was

added to a stirred solution of the pyrrolidinone 19 (70 mg,

0.16 mmol) and N-methylmorpholine-N-oxide (24 mg,

0.23 mmol) in acetone/water (1:1; 2.5 mL). The suspension

was stirred at room temperature for 6 days, and then diluted

with a saturated aqueous solution of sodium sulﬁte (2 mL).

The solution was stirred for a further 1 h and then diluted

with ethyl acetate (2 mL). The organic phase was separated

and the aqueous phase was extracted with ethyl acetate

(3ꢂ2 mL) and isopropanol/chloroform (1:1; 5 mL). The

combined organic extracts were evaporated in vacuo and

the residue was puriﬁed by ﬂash column chromatography,

on silica gel, eluting with ethyl acetate to give a 1:1 mixture

of diastereoisomers of the vicinal diol (37 mg, 47%) as a

colourless oil; [a]²_D⁴ꢀ3.0 (c 0.2, CHCl₃); n_max(CHCl₃)

2961, 1711, 1601, 1092 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.67–

7.61 (8H, m, Ar-H), 7.48–7.41 (12H, m, Ar-H), 5.96 (1H, s,

NH), 5.88 (1H, s, NH), 4.47–4.22 (4H, m, CH₂Oꢂ2), 3.94–

3.60 (8H, m, CH₂Oꢂ4), 2.81–2.67 (1H, m, CHCH₃), 2.53–

2.50 (1H, m, CHCH₃), 2.04 (3H, s, CH₃CO), 1.93 (3H, s,

CH₃CO), 1.29–1.05 (24H, m, SiC(CH₃)₃ꢂ2, CHCH₃ꢂ2);

d_C(90 MHz, CDCl₃) 177.0 (COCH₃), 176.9 (COCH₃),

170.8 (CONHꢂ2), 135.7 (Ar-CH), 135.6 (Ar-CH), 135.6

(4ꢂAr-CH), 135.5 (4ꢂAr-CH), 131.9 (2ꢂAr-C), 131.8 (2ꢂ

Ar-C), 130.3 (8ꢂAr-CH), 128.0 (4ꢂAr-CH), 80.3 (C(OH)),

75.1 (quat C), 66.8 (CH₂O), 66.1 (CH₂O), 65.0 (CH₂O), 64.9

(CH₂O), 63.9 (CH₂O), 63.6 (CH₂O), 44.2 (CHCH₃),

42.8 (CHCH₃), 26.8 (SiCMe₃ꢂ2), 20.7 (COCH₃ꢂ2), 19.1

(SiCMe₃ꢂ2), 10.6 (CHCH₃), 7.8 (CHCH₃); m/z found

486.2357, 508.2161 (M+H⁺, C₂₆H₃₆O₆NSi requires

486.2312; M+Na, C₂₆H₃₅O₆NSiNa requires 508.2131).

4.1.17. (3R,4S,5R)-5-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-4-hydroxy-4,5-bis(hydroxymethyl)-

3-methyl-2-pyrrolidinone (26). A solution of osmium

tetroxide (0.2 M in dichloromethane, 0.71 mL, 0.14 mmol)

was added to a stirred solution of the alcohol 24 (55 mg,

0.13 mmol) and N,N,N⁰,N⁰-tetramethylethylenediamine

(21 mL, 0.14 mmol) in dichloromethane (2.5 mL) at ꢀ78 ^ꢁC

under a nitrogen atmosphere. The resulting deep red solution

was stirred at ꢀ78 ^ꢁC for 1 h and then at room temperature

for 2 h. The solvent was removed in vacuo and the residue

was then diluted with acidic methanol (10 mL of methanol,

two drops of concentrated hydrochloric acid). The mixture

was stirred at room temperature for 4 h and then evaporated

under reduced pressure. The residue was puriﬁed by ﬂash

column chromatography, on silica gel, eluting with ethyl

acetate to give the pyrrolidinone (19 mg, 35%) as a pale

brown oil; [a]_D²⁴ꢀ36.5 (c 0.8, CHCl₃); n_max(CHCl₃) 3424,

2929, 2858, 1707 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.67–7.62

(4H, m, Ar-H), 7.49–7.40 (6H, m, Ar-H), 5.71 (1H, s,

NH), 3.88 (1H, d, J¼11.0, CH₂O), 3.83 (1H, d, J¼11.0,

CH₂O), 3.72 (1H, d, J¼10.7, CH₂O), 3.66 (1H, d, J¼

12.3, CH₂O), 3.64 (1H, d, J¼10.7, CH₂O), 3.55 (1H, d,

J¼12.3, CH₂O), 3.40 (1H, br s, OH), 2.40 (1H, q, J¼7.3,

CHCH₃), 1.14 (3H, d, J¼7.3, CHCH₃), 1.07 (9H, s,

SiC(CH₃)₃); d_C(125 MHz, CD₃OD) 180.0 (CONH), 138.3

(Ar-CH), 137.6 (Ar-CH), 134.8 (Ar-C), 134.7 (Ar-C),

131.9 (Ar-CH), 131.3 (Ar-CH), 129.8 (Ar-CH), 129.7

(Ar-CH), 82.7 (C(OH)), 70.2 (CH₂O), 67.5 (CH₂O), 65.6

(CH₂O), 64.4 (quat. C), 49.9 (CHCH₃), 28.1 (SiCMe₃),

21.1 (SiCMe₃), 9.1 (CHCH₃); m/z found 444.2245,

466.2067 (M+H⁺, C₂₄H₃₄O₅NSi requires 444.2206; M+Na,

C₂₄H₃₃O₅NSiNa requires 466.2026).

4.1.15. (3R,5R)-5-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-5-(hydroxymethyl)-3-methyl-4-

methylidene-2-pyrrolidinone (24). Titanium tetraisoprop-

oxide (33 mL, 0.11 mmol) was added to a stirred solution

of the acetoxypyrrolidinone 19 (10 mg, 0.022 mmol) in iso-

propanol (0.1 mL), and the mixture was stirred at room tem-

perature for 3 h. The mixture was then diluted with water

(2 mL) and ethyl acetate (2 mL) and the resulting colourless

precipitate was then removed by ﬁltration. The separated

aqueous phase was extracted with ethyl acetate (3ꢂ2 mL)

and the combined organic extracts were dried over MgSO₄

and evaporated in vacuo to leave the hydroxypyrrolidinone

(8 mg, 89%) as a colourless oil; [a]²_D⁴4.1 (c 1.6, CHCl₃);

n_max(CHCl₃) 3428, 2932, 2860, 1705 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 7.65–7.62 (4H, m, Ar-H), 7.44–7.40 (6H, m, Ar-

H), 6.13 (1H, s, NH), 5.10 (1H, d, J¼2.9, CH₂]C), 5.07

(1H, d, J¼2.9, CH₂]C), 3.89 (1H, d, J¼11.3, CH₂OH),

3.74 (1H, d, J¼10.2, CH₂O), 3.65 (1H, d, J¼10.2, CH₂O),

3.56 (1H, d, J¼11.3, CH₂OH), 3.06–3.03 (1H, m, CHCH₃),

1.32 (3H, d, J¼7.4, CHCH₃), 1.06 (9H, s, SiC(CH₃)₃); d_C

(90 MHz, CDCl₃) 177.8 (CONH), 149.0 (C]CH₂), 135.6

(4ꢂAr-CH), 132.3 (2ꢂAr-C), 130.0 (4ꢂAr-CH), 127.9 (2ꢂ

Ar-CH), 109.0 (C]CH₂), 77.0 (quat. C), 67.9 (CH₂O), 66.5

(CH₂O), 41.1 (CHCH₃), 26.8 (SiCMe₃), 19.2 (SiCMe₃),

15.8 (CHCH₃); m/z found 410.2138, 432.2014 (M+H⁺,

C₂₄H₃₂O₃NSi requires 410.2151; M+Na, C₂₄H₃₁O₂NSiNa

requires 432.1971), which was used without further

puriﬁcation.

4.1.18. [(5S,6R,9R)-6-({[(1,1-Dimethylethyl)(diphenyl)-

silyl]oxy}methyl)-2,2,9-trimethyl-8-oxo-1,3-dioxa-7-

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6225

azaspiro[4.4]non-6-yl]methyl 2,2-dimethylpropanoate

(27). 2,2-Dimethoxypropane (53 mL, 0.43 mmol) was added

to a stirred solution of the triol 26 (19 mg, 0.043 mmol) and

para-toluenesulfonic acid (1 mg) in dichloromethane

(0.25 mL) at room temperature. The mixture was stirred at

room temperature for 3 h and then diluted with a saturated

aqueous solution of sodium bicarbonate (0.5 mL). The or-

ganic phase was separated and the aqueous phase was then

extracted with ethyl acetate (3ꢂ2 mL). The combined or-

ganic extracts were dried over MgSO₄and evaporated in

vacuo. The residue was puriﬁed by ﬂash column chromato-

graphy, on silica gel, eluting with ethyl acetate to give the

corresponding acetonide (10 mg, 48%) as a colourless oil;

[a]²_D⁴4.5 (c 0.4, CHCl₃); n_max(CHCl₃) 3423, 2931,

1709 cm^ꢀ1; d_H(500 MHz, CDCl₃) 7.64–7.61 (4H, m, Ar-

H), 7.49–7.41 (6H, m, Ar-H), 5.77 (1H, br s, NH), 4.28 (1H,

d, J¼10.0, CH₂O), 3.93 (1H, d, J¼10.0, CH₂O), 3.82 (1H, d,

J¼11.6, CH₂OH), 3.66 (1H, dd, J¼11.6 and 4.0, CH₂OH),

3.64 (1H, d, J¼10.8, CH₂O), 3.57 (1H, d, J¼10.8, CH₂O),

2.68 (1H, q, J¼7.3, CHCH₃), 2.55 (1H, br s, OH), 1.48

(3H, s, CCH₃), 1.43 (3H, s, CCH₃), 1.20 (1H, d, J¼7.3,

CHCH₃), 1.06 (9H, s, SiC(CH₃)₃); d_C(125 MHz, CDCl₃)

176.3 (CONH), 135.6 (4ꢂAr-CH), 132.0 (Ar-C), 131.9

(Ar-C), 130.2 (4ꢂAr-CH), 128.0 (2ꢂAr-CH), 110.4

(CMe₂), 88.9 (C(O)), 67.8 (CH₂O), 66.3 (CH₂O), 65.2

(CH₂O), 62.3 (quat. C), 44.2 (CHCH₃), 29.7 (CCH₃), 26.8

(SiCMe₃), 25.6 (CCH₃), 19.1 (SiCMe₃), 9.0 (CHCH₃); m/z

found 484.2521, 506.2339 (M+H⁺, C₂₇H₃₈O₅NSi requires

484.2519; M+Na, C₂₇H₃₇O₅NSiNa requires 506.2339).

ﬂuoride (1 M in THF; 39 mL, 0.039 mmol) was added to

a stirred solution of the pivalate ester 27 (11 mg,

0.019 mmol) in THF (0.2 mL) at room temperature. The

mixture was stirred at room temperature for 1.5 h and then

diluted with water (1 mL) and ethyl acetate (1 mL). The

organic phase was separated and the aqueous phase was ex-

tracted with ethyl acetate (3ꢂ2 mL). The combined organic

extracts were dried over MgSO₄and evaporated in vacuo.

The residue was puriﬁed by ﬂash column chromatography,

on silica gel, eluting with ethyl acetate to give a 3:1 mixture

of diastereoisomers of the alcohols 28a and 29a (4 mg,

64%). A solution of sodium periodate (10 mg, 0.049 mmol)

in water (0.15 mL) was added to a stirred solution of the

alcohols (4 mg, 0.012 mmol) in acetonitrile (0.1 mL) and

carbon tetrachloride (0.1 mL). After 5 min, RuO₂$H₂O

(1 mg, 7 mmol) was added and the biphasic mixture was

then stirred vigorously for 5 h. A solution of trimethylsilyl-

diazomethane (2 M in hexanes; 30 mL, 0.17 mmol) was

added and the solution was stirred for a further 1 h. The mix-

ture was diluted with water (1 mL) and ethyl acetate (2 mL)

and the organic phase was then separated. The aqueous

phase was extracted with ethyl acetate (3ꢂ2 mL) and the

combined organic extracts were dried over MgSO₄and evap-

orated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, on silica gel, eluting with ethyl acetate to

give a 3:1 mixture of diastereoisomers of the esters 28b

and 29b (4 mg, 91%) as a colourless oil. Further puriﬁcation

by ﬂash column chromatography eluting with ethyl acetate

gave the major diastereoisomer 28b (1 mg, 23%) as an

oil; [a]²_D⁴1.5 (c 0.4, CHCl₃); n_max(CHCl₃) 3429, 2955,

1713 cm^ꢀ1; d_H(400 MHz, CDCl₃) 6.07 (1H, s, NH), 4.53

(1H, d, J¼11.2, CH₂O), 4.45 (1H, d, J¼9.7, CH₂O), 4.08

(1H, d, J¼11.2, CH₂O), 4.04 (1H, d, J¼9.7, CH₂O), 3.80

(3H, s, CO₂CH₃), 2.52 (1H, q, J¼7.3, CHCH₃), 1.45 (6H,

s, CCH₃), 1.31–1.20 (3H, m, CHCH₃), 1.15 (9H, s,

C(CH₃)₃); m/z (LCMS, EI) 371.23 (M+Na⁺, C₁₇H₂₈O₇NNa

requires 371.1866); ROESY experiment (700 MHz, CDCl₃)

d_H4.66 correlates to d_H4.08 and d_H4.04.

A solution of trimethylacetyl chloride (1 M in dichlorome-

thane; 110 mL, 0.11 mmol) was added to a stirred solution

of the acetonide (10 mg, 0.021 mmol) and N,N-dimethyl-

aminopyridine (1 mg, 7 mmol) in dichloromethane/pyridine

(1:1; 0.2 mL) at room temperature. The mixture was heated

at 40 ^ꢁC for 24 h and then diluted with water (1 mL) and

dichloromethane (1 mL). The organic phase was separated

and the aqueous phase was extracted with dichloromethane

(3ꢂ2 mL). The combined organic extracts were dried over

MgSO₄and then evaporated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography, on silica gel, eluting

with diethyl ether to give the pivalate ester (8 mg, 67%) as

a colourless oil; [a]²_D⁴20.0 (c 0.1, CHCl₃); n_max(CHCl₃)

2962, 1707, 1092 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.62–7.59

(4H, m, Ar-H), 7.44–7.40 (6H, m, Ar-H), 5.56 (1H, s,

NH), 4.42 (1H, d, J¼9.9, CH₂O), 4.22 (1H, d, J¼11.4, CH₂O),

4.15 (1H, d, J¼11.4, CH₂O), 4.04 (1H, d, J¼9.9,

CH₂O), 3.72 (1H, d, J¼11.3, CH₂O), 3.62 (1H, d, J¼11.3,

CH₂O), 2.85 (1H, q, J¼7.4, CHCH₃), 1.44 (6H, s,

C(CH₃)₂), 1.22 (3H, d, J¼7.4, CHCH₃), 1.03 (9H, s,

SiC(CH₃)₃), 1.00 (9H, s, C(CH₃)₃); d_C(125 MHz, CDCl₃)

176.6 (CONH), 176.6 (COOCH₂), 135.7 (2ꢂAr-CH),

135.5 (2ꢂAr-CH), 132.1 (2ꢂAr-C), 130.2 (Ar-CH), 130.1

(Ar-CH), 128.0 (4ꢂAr-CH), 110.5 (CMe₂), 87.7 (C(O)),

68.6 (quat. C), 65.3 (2ꢂCH₂O), 65.2 (CH₂O), 45.0

(CHCH₃), 26.9 (2ꢂCCH₃), 26.8 (SiCMe₃), 26.5 (CMe₃),

25.6 (C(CH₃)₃), 19.1 (SiCMe₃), 9.0 (CHCH₃); m/z found

568.3040, 590.2880 (M+H⁺, C₃₂H₄₆O₆NSi requires

568.3094; M+Na, C₃₂H₄₅O₆NSiNa requires 590.2914).

4.1.20. (R)-4-(tert-Butyl-dimethyl-silanyloxymethyl)-4-

ethynyl-2-trichloromethyl-4,5-dihydro-oxazole (30).

tert-Butyldimethylsilyl chloride (4.40 g, 29.1 mmol) was

added portionwise over 10 min to a stirred solution of the

oxazoline 16a (5.43 g, 22.4 mmol) and imidazole (2.30 g,

33.6 mmol) in dichloromethane (110 mL). The mixture

was stirred at room temperature for 15 h and then diluted

with water (50 mL). The organic phase was separated and

the aqueous phase was extracted with dichloromethane

(3ꢂ50 mL). The combined organic extracts were dried

over MgSO₄and evaporated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography, on silica gel, eluting

with pentane/ether (9:1) to give the TBS ether (6.62 g,

83%) as a colourless solid; mp 61–62 ^ꢁC; [a]_D²⁴ꢀ0.38

(c 1.05, CHCl₃); Found: C, 43.6; H, 5.6; N, 3.8; C₁₃H₂₀O₂N-

SiCl₃requires C, 43.9; H, 5.7; N, 3.9%; n_max(CHCl₃)

3306, 2955, 2930, 2859 cm^ꢀ1; d_H(360 MHz, CDCl₃)

4.85 (1H, d, J¼8.1, CH₂O), 4.61 (1H, d, J¼8.1, CH₂O),

3.94 (1H, d, J¼10.4, CH₂O), 3.74 (1H, d, J¼10.4, CH₂O),

2.56 (1H, s, C^CH), 0.90 (9H, s, SiC(CH₃)₃), 0.09 (6H, s,

2ꢂSiCH₃); d_C(90 MHz, CDCl₃) 164.1 (C]N), 81.5 (quat.

C), 77.4 (CH₂O), 76.6 (C^CH), 74.8 (C^CH), 70.0

(CCl₃), 67.0 (CH₂OH), 25.7 (SiCMe₃), 18.2 (SiCMe₃),

ꢀ5.3 (SiCH₃), ꢀ5.6 (SiCH₃); m/z (EI) found 356.0421,

4.1.19. Methyl (5S,6R,9R)-6-{[(2,2-dimethylpropanoyl)-

oxy]methyl}-2,2,9-trimethyl-8-oxo-1,3-dioxa-7-azaspiro-

[4.4]nonane-6-carboxylate (28b). Tetrabutylammonium

6226

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

358.0395 (M+H⁺, C₁₃H₂₁O₂NSiCl₃requires 356.0407;

C₁₃H₂₁O₂NSiCl₂³⁷Cl requires 358.0378).

CH₂O), 4.16 (1H, d, J¼8.7, CH₂O), 4.08 (1H, d, J¼10.3,

CH₂O), 4.07 (1H, d, J¼10.3, CH₂O), 2.61 (2H, s, 2ꢂC^

CH), 1.89 (3H, d, J¼7.1, CH₃BrCH), 1.88 (3H, d, J¼7.0,

CH₃BrCH), 0.87 (18H, s, 2ꢂSiC(CH₃)₃), 0.06 (12H, s,

4ꢂSiCH₃); d_C(90 MHz, CDCl₃) 191.5 (CHO), 191.4

(CHO), 168.8 (CONH), 168.7 (CONH), 76.5 (C^CH), 76.4

(C^CH), 76.0 (2ꢂC^CH), 64.1 (CH₂O), 64.0 (CH₂O),

62.0 (2ꢂquat. C), 44.0 (2ꢂCHBrCH₃), 25.7 (SiCMe₃), 25.6

(SiCMe₃), 22.8 (CH₃BrCH), 22.7 (CH₃BrCH), 18.0 (2ꢂ

SiCMe₃), ꢀ5.6 (4ꢂSiCH₃); m/z (CI, NH⁺₄) found 362.0784,

364.0772 (M⁺C₁₄H₂₅O₃N⁷⁹BrSi requires 362.0787;

C₁₄H₂₅O₃N⁸¹BrSi requires 364.0767).

4.1.21. 2-Bromo-N-[(S)-1-(tert-butyl-dimethyl-silanyloxy-

methyl)-1-hydroxymethyl-prop-2-ynyl]propionamide

(32). Aqueous hydrochloric acid (1 M, 16.0 mL, 16.0 mmol)

was added in a single portion to a stirred solution of the ox-

azoline 30 (5.7 g, 16.0 mmol) in THF (94 mL) at room tem-

perature. The mixture was stirred at room temperature for

3 h and then a saturated aqueous solution of sodium bicar-

bonate (w13 mL) was added until the mixture was pH 7.

The solvent was evaporated in vacuo to leave the amine

31, which was immediately suspended in dichloromethane

(9.4 mL), water (18.2 mL) and a saturated aqueous solution

of sodium bicarbonate (66.8 mL). 2-Bromopropionoyl chlo-

ride (1.60 mL, 16.0 mmol) was added dropwise over 5 min

to the biphasic mixture, which was then stirred vigorously

for 2 h. The mixture was diluted with dichloromethane

(10 mL), and the separated aqueous phase was then ex-

tracted with dichloromethane (2ꢂ20 mL) and ethyl acetate

(1ꢂ20 mL). The combined organic extracts were dried

over MgSO₄and evaporated in vacuo. The residue was puri-

ﬁed by ﬂash column chromatography, on silica gel, eluting

with pentane/ether (1:1) to give a 1:1 mixture of diastereo-

isomers of the amide (4.2 g, 72%) as a colourless oil; [a]_D²⁴

ꢀ5.8 (c 1.4, CHCl₃); Found: C, 46.4; H, 7.2; N, 4.0;

C₁₄H₂₆O₃NBrSi requires C, 46.3; H, 7.2; N, 3.9%; n_max

(CHCl₃) 3388, 3306, 2954, 2930, 2859, 1674 cm^ꢀ1; d_H

(360 MHz, CDCl₃) 7.20 (2H, br s, NH), 4.41 (2ꢂ1H, q,

J¼7.1, CHBrCH₃), 3.98 (1H, d, J¼9.9, CH₂O) 3.96 (1H,

d, J¼9.9, CH₂O), 3.92 (2ꢂ1H, dd, J¼11.4 and 4.1,

CH₂OH), 3.87 (1H, d, J¼9.9, CH₂O), 3.86 (1H, d, J¼9.9,

CH₂O), 3.83–3.79 (2H, m, CH₂OH), 3.49–3.45 (2H, m,

OH), 2.44 (2H, s, 2ꢂC^CH), 1.88 (2ꢂ3H, d, J¼7.1,

CH₃CHBr), 0.92 (18H, s, SiC(CH₃)₃), 0.12 (12H, s, 2ꢂ

SiCH₃); d_C(90 MHz, CDCl₃) 169.2 (CONH), 169.1

(CONH), 80.2 (C^CH), 77.2 (C^CH), 73.6 (C^CH), 73.6

(C^CH), 65.9 (2ꢂCH₂O), 65.7 (CH₂O), 65.5 (CH₂O),

56.5 (quat. C), 56.4 (quat. C), 44.8 (CHBrCH₃), 44.7

(CHBrCH₃), 25.6 (2ꢂSiCMe₃), 22.9 (CHBrCH₃), 22.7

(CHBrCH₃), 18.0 (2ꢂSiCMe₃), ꢀ5.6 (2ꢂSiCH₃), ꢀ5.7

(2ꢂSiCH₃); m/z (FAB) found 364.0945, 366.0932 (M+H⁺,

C₁₄H₂₇O₃N⁷⁹BrSi requires 364.0944; C₁₄H₂₇O₃N⁸¹BrSi

requires 366.0923).

4.1.23. (R)-2-(2-Bromo-propionylamino)-2-(tert-butyl-

dimethyl-silanyloxymethyl)-but-3-ynoic acid (33b). A so-

lution of sodium chlorite (3.36 g, 37.0 mmol) and sodium

hydrogen orthophosphate (4.39 g, 28.5 mmol) in water

(8 mL) was added in a single portion to a stirred solution

of a 1:1 mixture of diastereoisomers of the aldehyde 33a

(1.34 g, 3.70 mmol) in tert-butanol (20 mL) and 2-methyl-

2-butene (8 mL). The solution was stirred at room tempera-

ture for 6 h, and then diluted with ethyl acetate (20 mL). The

organic phase was separated, and then the aqueous phase ex-

tracted with ethyl acetate (5ꢂ20 mL). The combined organic

extracts were dried over MgSO₄and evaporated in vacuo to

leave a 1:1 mixture of diastereoisomers of the carboxylic

acid (1.16 g, 83%) as a colourless oil; [a]²_D⁴+1.5 (c 1.9,

CHCl₃); n_max(CHCl₃) 3383, 3306, 2930, 2858, 1731,

1680, 1104 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.52 (2H, br s,

2ꢂNH), 4.49–4.44 (2H, m, 2ꢂCHBrCH₃), 4.22–4.15 (4H,

m, 2ꢂCH₂O), 2.54 (2H, s, 2ꢂC^CH), 1.91 (3H, d, J¼

7.1, CH₃BrCH), 1.90 (3H, d, J¼7.1, CH₃BrCH), 0.90 (18H,

s, 2ꢂSiC(CH₃)₃), 0.10 (12H, s, 4ꢂSiCH₃); d_C(90 MHz,

CDCl₃) 170.3 (CO₂H), 170.2 (CO₂H), 169.4 (CONH),

169.4 (CONH), 77.2 (2ꢂC^CH), 74.1 (2ꢂC^CH), 66.1

(CH₂O), 65.9 (CH₂O), 58.4 (quat. C), 58.3 (quat. C), 44.4

(CHBrCH₃), 44.2 (CHBrCH₃), 25.6 (2ꢂSiCMe₃), 22.9

(CH₃BrCH), 22.7 (CH₃BrCH), 18.1 (2ꢂSiCMe₃), ꢀ5.5

(2ꢂSiCH₃), ꢀ5.6 (2ꢂSiCH₃); m/z (ES) found 378.0770,

380.0733 (M+H⁺, C₁₄H₂₅O₄N⁷⁹BrSi requires 3378.0736;

C₁₄H₂₅O₄N⁸¹BrSi requires 380.0716), which was used with-

out further puriﬁcation.

4.1.24. (R)-2-(2-Bromo-propionylamino)-2-(tert-butyl-

dimethyl-silanyloxymethyl)-but-3-ynoic acid methyl

ester (34). A solution of trimethylsilyldiazomethane (2 M

in diethyl ether; 5 mL, 10 mmol) was added dropwise over

10 min to a stirred solution of a 1:1 mixture of diastereoiso-

mers of the acid 33b (1.25 g, 3.31 mmol) in benzene/

methanol (5:2, 17 mL) at room temperature. The solution

was stirred at room temperature for 1 h, and then the solvent

was evaporated in vacuo. The residue was puriﬁed by ﬂash

column chromatography, on silica gel, eluting with pen-

tane/ether (1:1) to give a 1:1 mixture of diastereoisomers

of the methyl ester (0.96 g, 75%) as a yellow oil; [a]_D²⁴

ꢀ2.8 (c 1.0, CHCl₃); n_max(CHCl₃) 3390, 3306, 2955,

2930, 2858, 1749 cm^ꢀ1; d_H(360 MHz, CDCl₃) 7.46 (2H,

br s, 2ꢂNH), 4.47–4.43 (2H, m, 2ꢂCHBrCH₃), 4.29 (1H,

d, J¼9.7, CH₂O), 4.25 (1H, d, J¼9.7, CH₂O), 4.07 (1H,

J¼6.3, CH₂O), 4.05 (1H, d, J¼6.2, CH₂O), 3.87 (6H, s,

2ꢂCO₂CH₃), 2.52 (2H, s, 2ꢂC^CH), 1.92 (3H, d, J¼7.1,

CH₃BrCH), 1.91 (3H, d, J¼7.1, CH₃BrCH), 0.89 (18H, s,

2ꢂSiC(CH₃)₃), 0.08 (12H, s, 4ꢂSiCH₃); d_C(90 MHz,

4.1.22. 2-Bromo-N-[(S)-1-(tert-butyl-dimethyl-silanyloxy-

methyl)-1-formyl-prop-2-ynyl]propionamide (33a). Tet-

rapropylammonium perrutherate (0.20 g, 0.58 mmol) was

added to a stirred solution of the 1:1 mixture of diastereoiso-

mers of the amide 32 (4.20 g, 11.6 mmol), N-methylmor-

˚

pholine-N-oxide (2.30 g, 23.2 mmol) and powdered 3 A

molecular sieves (6.0 g) in dichloromethane (60 mL) at

room temperature. The suspension was stirred at room tem-

perature for 1 h, and then a second portion of tetrapropyl-

ammonium perrutherate (0.20 g, 0.58 mmol) was added. The

suspension was stirred for a further 1 h and then ﬁltered

through a pad of silica gel, eluting with diethyl ether. The

ﬁltrate was evaporated in vacuo to leave a 1:1 mixture of

diastereoisomers of the aldehyde (3.7 g, 88%) as a yellow

oil; [a]²_D⁴21.4 (c 1.6, CHCl₃); n_max(CHCl₃) 3390, 3304,

2955, 2930, 2859, 1746, 1678, 1116 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 9.36 (2H, s, 2ꢂCHO), 7.37 (2H, br s, 2ꢂNH),

4.47–4.42 (2H, m, 2ꢂCHBrCH₃), 4.19 (1H, d, J¼8.7,

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6227

CDCl₃) 168.4 (CONH), 168.3 (CONH), 168.1 (CO₂CH₃),

168.0 (CO₂CH₃), 77.4 (2ꢂC^CH), 73.6 (2ꢂC^CH),

66.2 (CH₂O), 66.0 (CH₂O), 58.7 (quat. C), 58.7 (quat. C),

53.7 (2ꢂCO₂CH₃), 44.5 (CHBrCH₃), 44.4 (CHBrCH₃),

25.5 (2ꢂSiCMe₃), 22.9 (CH₃BrCH), 22.8 (CH₃BrCH),

18.0 (2ꢂSiCMe₃), ꢀ5.5 (2ꢂSiCH₃), ꢀ5.7 (2ꢂSiCH₃); m/z

gel, eluting with diethyl ether to give: (i) the b-methyl epi-

mer 35b (eluted ﬁrst) (0.14 g, 39%) as a colourless oil;

[a]²_D⁴+2.7 (c 0.3, CHCl₃); n_max(CHCl₃) 2926, 1715,

1044 cm^ꢀ1; d_H(360 MHz, CDCl₃) 6.77 (1H, br s, NH),

5.41 (1H, d, J¼2.9, C]CH₂), 5.23 (1H, d, J¼2.5,

C]CH₂), 4.26 (1H, d, J¼11.2, CH₂OH), 3.80 (3H, s,

CO₂CH₃), 3.58 (1H, d, J¼11.2, CH₂OH), 3.15–3.07 (1H,

m, CHCH₃), 2.24 (1H, br s, OH), 1.31 (3H, d, J¼7.4,

CH₃CH); d_C(90 MHz, CDCl₃) 177.9 (CO₂CH₃), 171.4

(CONH), 145.5 (C]CH₂), 111.4 (C]CH₂), 69.8 (quat.

C), 68.3 (CH₂O), 53.3 (CO₂CH₃), 40.4 (CHCH₃), 15.6

(CHCH₃); m/z (CI, NH⁺₄) found 199.0828 (M⁺, C₉H₁₃O₄N

requires 199.0845) and (ii) the a-methyl epimer 36b (eluted

second) (94 mg, 26%) as a colourless oil; [a]²_D⁴ꢀ22.0 (c 1.6,

CHCl₃); n_max(CHCl₃) 3428, 2955, 2877, 1713 cm^ꢀ1; d_H

(360 MHz, CDCl₃) 7.46 (1H, br s, NH), 5.46 (1H, d,

J¼2.8, C]CH₂), 5.20 (1H, d, J¼2.3, C]CH₂), 4.16–4.11

(2H, m, CH₂OH and OH), 3.79 (3H, s, OCH₃), 3.68 (1H,

dd, J¼9.8 and 4.9, CH₂OH), 3.09–3.02 (1H, m, CHCH₃),

1.29 (3H, d, J 7.4, CH₃CH); d_C(90 MHz, CDCl₃) 178.7

(CO₂CH₃), 171.3 (CONH), 145.5 (C]CH₂), 111.4

(C]CH₂), 70.6 (quat. C), 68.3 (CH₂O), 53.2 (CO₂CH₃),

40.6 (CHCH₃), 16.3 (CHCH₃); m/z (CI, NH⁺₄) found

199.0843 (M⁺, C₉H₁₃O₄N requires 199.0845).

(CI, NH⁺₄) found 392.0889, 394.0876 (M+H⁺, C₁₅H₂₆O₄N⁷⁹

-

BrSi requires 392.0892; C₁₅H₂₆O₄N⁸¹BrSi requires

394.0872).

4.1.25. (R)-2-(tert-Butyl-dimethyl-silanyloxymethyl)-4-

methyl-3-methylene-5-oxo-pyrrolidine-2-carboxylic

acid methyl ester (35a). A solution of tributyltin hydride

(0.60 mL, 2.24 mmol) and AIBN (67 mg, 0.41 mmol) in de-

gassed toluene (60 mL) was added dropwise over 0.5 h, via

syringe pump, to a reﬂuxing solution of a 1:1 mixture of

diastereoisomers of the amide 34 (0.80 g, 2.04 mmol) in

degassed toluene (680 mL) under an atmosphere of argon.

The solution was heated under reﬂux for 2 h and then

allowed to cool to room temperature before the solvent

was evaporated in vacuo. The residue was partitioned be-

tween acetonitrile (50 mL) and hexane (50 mL). The aceto-

nitrile phase was separated and the hexane phase was

extracted with acetonitrile (50 mL). The combined acetoni-

trile extracts were evaporated in vacuo and the residue was

puriﬁed by ﬂash column chromatography, on silica gel, elut-

ing with pentane/diethyl ether (7:3) then diethyl ether to give

a 2:1 mixture of b- and a-methyl epimers of the pyrrolidi-

none (0.47 g, 73%) as a colourless oil; [a]²_D⁴+9.0 (c 0.8,

CHCl₃); Found: C, 57.8; H, 8.4; N, 4.2; C₁₅H₂₇O₄NSi re-

quires C, 57.5; H, 8.7; N, 4.5%; n_max(CHCl₃) 3435, 2954,

2930, 2858, 1745, 1712, 1662, 1097 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 6.24 (1H, br s, NH), 6.21 (1H, br s, NH), 5.51

(1H, d, J¼2.8, C]CH₂), 5.44 (1H, d, J¼2.9, C]CH₂),

5.20 (2H, m, 2ꢂC]CH₂), 4.23 (1H, d, J¼9.4, CH₂O),

4.15 (1H, d, J¼9.4, CH₂O), 3.77 (3H, s, CO₂CH₃), 3.76

(3H, s, CO₂CH₃), 3.55 (1H, d, J¼9.4, CH₂O), 3.47 (1H, d,

J¼9.4, CH₂O), 3.08–3.02 (2H, m, 2ꢂCHCH₃), 1.31 (6H,

d, J¼7.4, 2ꢂCH₃CH), 0.87 (18H, s, 2ꢂSiC(CH₃)₃), 0.07

(12H, s, 4ꢂSiCH₃); d_C(90 MHz, CDCl₃) 177.0 (CO₂CH₃),

176.9 (CO₂CH₃), 171.2 (CONH), 171.1 (CONH), 145.2

(C]CH₂), 145.1 (C]CH₂), 111.6 (C]CH₂), 111.4 (C]

CH₂), 70.0 (quat. C), 69.5 (2ꢂCH₂O), 52.9 (2ꢂCO₂CH₃),

40.4 (CHCH₃), 40.2 (CHCH₃), 25.6 (2ꢂSiCMe₃), 18.1

(2ꢂSiCMe₃), 16.4 (CHCH₃), 15.7 (CHCH₃), ꢀ5.5 (2ꢂ

SiCH₃), ꢀ5.7 (2ꢂSiCH₃); m/z (CI, NH⁺₄) 314.1771 (M+H⁺,

C₁₅H₂₈O₄NSi requires 314.1756).

4.1.27. (2S,3S,4R)-3-Hydroxy-2,3-bis-hydroxymethyl-

4-methyl-5-oxo-pyrrolidine-2-carboxylic acid methyl

ester (37). A solution of osmium tetroxide (0.2 M in

dichloromethane, 2.6 mL, 0.52 mmol) was added drop-

wise over 5 min to a stirred solution of the alcohol 35b

(98 mg, 0.49 mmol) and N,N,N⁰,N⁰-tetramethylethylenedi-

amine (81 mL, 0.54 mmol) in dichloromethane (8 mL) at

ꢀ78 ^ꢁC under a nitrogen atmosphere. The resulting deep

red solution was stirred at ꢀ78 ^ꢁC for 1 h and then at room

temperature for 2 h. The solvent was evaporated under re-

duced pressure and the residue was then diluted with acidic

methanol (10 mL of methanol, four drops of concentrated

hydrochloric acid). The mixture was stirred at room temper-

ature for 3 h and then evaporated in vacuo. The residue was

puriﬁed by ﬂash column chromatography, on silica gel,

eluting with ethyl acetate/methanol (4:1) to give the triol

(114 mg, 99%) as an oil; [a]²_D⁴+19.4 (c 1.3, MeOH); n_max

(CHCl₃) 3630, 2943, 2838, 1715, 1011 cm^ꢀ1; d_H(360 MHz,

CD₃OD) 4.04 (1H, d, J¼11.0, CH₂OH), 3.80 (1H, d,

J¼11.0, CH₂OH), 3.78 (1H, d, J¼11.4, CH₂OH), 3.78

(3H, s, CO₂CH₃), 3.71 (1H, d, J¼11.4, CH₂OH), 2.60 (1H,

q, J¼7.6, CHCH₃), 1.26 (3H, d, J¼7.6, CHCH₃); d_C

(90 MHz, CD₃OD) 180.9 (CONH), 172.4 (CO₂CH₃), 81.3

(C(OH)), 75.8 (quat. C), 63.9 (CH₂OH), 62.4 (CH₂OH),

52.7 (CO₂CH₃), 49.2 (CHCH₃), 11.3 (CHCH₃); m/z (ES)

found 297.1040 (M+Na+CH₃CN, C₉H₁₅O₆NCH₃CNNa re-

quires 297.1063); In a ¹H NOE experiment (400 MHz,

CD₃OD), irradiation at d 2.60 (CHCH₃) gave an enhance-

ment at d 3.78 (CO₂CH₃); irradiation at d 1.26 (CHCH₃)

gave enhancements at d 3.78 (CH₂OH) and 3.71 (CH₂OH).

4.1.26. (2R,4R)-2-Hydroxymethyl-4-methyl-3-methyl-

ene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester

(35b) and (2R,4S)-2-hydroxymethyl-4-methyl-3-methyl-

ene-5-oxo-pyrrolidine-2-carboxylic acid methyl ester

(36b). para-Toluenesulfonic acid (1.04 g, 5.44 mmol) was

added to a stirred solution of a 2:1 mixture of C3-methyl

epimers of the pyrrolidinone 36a (0.57 g, 1.82 mmol) in

THF/H₂O (20:1, 10 mL) at room temperature. The mixture

was stirred at room temperature for 15 h and then diluted

with a saturated aqueous solution of sodium bicarbonate

(10 mL) and ethyl acetate (10 mL). The organic phase was

separated, and then the aqueous phase was extracted with

ethyl acetate (3ꢂ20 mL). The combined organic extracts

were dried over MgSO₄and evaporated in vacuo. The resi-

due was puriﬁed by ﬂash column chromatography, on silica

4.1.28. (3R,3S,8S)-3a-Hydroxy-3,6,6-trimethyl-2-oxo-

tetrahydro-5,7-dioxa-1-aza-azulene-8a-carboxylic

acid methyl ester (40). 2,2-Dimethoxypropane (0.33 mL,

2.64 mmol) was added to a stirred solution of the diol 37

(77 mg, 0.33 mmol) and para-toluenesulfonic acid (1 mg)

in dichloromethane (3 mL) at room temperature. The mix-

ture was stirred at room temperature for 3 h and then diluted

6228

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

with a saturated aqueous solution of sodium bicarbonate

(5 mL) and ethyl acetate (5 mL). The organic phase was sep-

arated and the aqueous phase was then extracted with ethyl

acetate (3ꢂ5 mL). The combined organic extracts were

dried over MgSO₄and then evaporated in vacuo. The residue

was puriﬁed by ﬂash column chromatography, on silica gel,

eluting with ethyl acetate gave the acetonide (30 mg, 33%)

as a colourless oil; [a]²_D⁴7.7 (c 0.3, CHCl₃); n_max(CHCl₃)

3425, 2958, 1719 cm^ꢀ1; d_H(360 MHz, CDCl₃) 6.15 (1H,

br s, NH), 4.50 (1H, d, J¼14.3, CH₂O), 3.97 (1H, d,

J¼12.8, CH₂O), 3.78 (3H, s, CO₂CH₃), 3.62 (1H, d, J¼

14.3, CH₂O), 3.49 (1H, d, J¼12.8, CH₂O), 3.34 (1H, s,

OH), 2.95 (1H, q, J¼7.6, CHCH₃), 1.43 (3H, s, C(CH₃)₂),

1.35 (3H, s, C(CH₃)₂), 1.09 (3H, d, J¼7.6, CHCH₃); d_C

(90 MHz, CDCl₃) 176.7 (CONH), 171.0 (CO₂CH₃), 110.2

(CMe₂), 81.1 (C(O)), 70.4 (quat. C), 63.1 (CH₂O), 59.4

(CH₂O), 52.8 (CO₂CH₃), 42.8 (CHCH₃), 24.5 (CCH₃), 23.8

(CCH₃), 7.3 (CHCH₃); these assignments were conﬁrmed by

a HMQC experiment; in an HMBC experiment (400 MHz,

CDCl₃) d_H4.50 correlated to d_C110.2; d_H3.97 correlated

to d_C110.2; d_H3.62 correlated to d_C110.2, 81.1 and 70.4;

d_H3.49 correlates to d_C110.2, 81.1 and 70.4; m/z (CI,

NH⁺₄) found 274.1286 (M+H⁺, C₁₂H₂₀O₆N requires

274.1291).

at room temperature. The mixture was heated at 40 ^ꢁC

for 24 h, and then diluted with water (1 mL) and dichloro-

methane (1 mL). The organic phase was separated and the

aqueous phase was extracted with dichloromethane (3ꢂ2 mL).

The combined organic extracts were dried over MgSO₄

and then evaporated in vacuo. The residue was puriﬁed

by ﬂash column chromatography, on silica gel, eluting

with diethyl ether to give the pivalate ester (12 mg, 67%)

as a colourless oil; [a]²_D⁴ꢀ1.0 (c 0.2, CHCl₃); n_max

(CHCl₃) 2923, 1729, 1098 cm^ꢀ1; d_H(400 MHz, CDCl₃)

6.36 (1H, br s, NH), 4.77 (1H, d, J¼10.9, CH₂O), 4.15

(1H, d, J¼9.8, CH₂O), 4.07 (1H, d, J¼9.8, CH₂O), 4.02

(1H, d, J¼10.9, CH₂O), 3.79 (3H, s, CO₂CH₃), 2.87 (1H,

q, J¼7.8, CHCH₃), 1.40 (6H, s, 2ꢂC(CH₃)₂), 1.23 (3H,

d, J¼7.8, CHCH₃), 1.17 (9H, s, C(CH₃)₃); d_C(100 MHz,

CDCl₃) 177.5 (COC(CH₃)₃), 176.4 (CONH), 169.2

(CO₂CH₃), 110.4 (CMe₂), 87.5 (C(O)), 69.8 (quat. C), 65.4

(CH₂O), 64.6 (CH₂O), 52.8 (CO₂CH₃), 44.1 (CHCH₃),

38.8 (CMe₃), 27.1 (CMe₃), 27.0 (CCH₃), 25.6 (CCH₃),

11.0 (CHCH₃); these assignments were conﬁrmed by

a HMQC experiment; m/z (ES) found 358.1835 (M+H⁺,

C₁₇H₂₈O₇N requires 358.1866).

4.1.31. (5S,6S,9R)-2,2,9-Trimethyl-8-oxo-6-(2-trimethyl-

silanyl-ethoxymethoxymethyl)-1,3-dioxa-7-aza-spiro-

[4.4]nonane-6-carboxylic acid methyl ester (41a).

[2-(Trimethylsilyl)ethoxy]methyl chloride (19 mL, 0.11

mmol) was added to a stirred solution of the acetonide 39

(15 mg, 0.055 mmol), tetrabutylammonium iodide (45 mg,

0.12 mmol) and diisopropylethylamine (28 mL, 0.22 mmol)

in dichloromethane (0.3 mL) at room temperature. The

mixture was stirred at room temperature for 15 h and

then diluted with water (0.2 mL) and dichloromethane

(0.2 mL). The organic phase was separated and the aqueous

phase was extracted with dichloromethane (3ꢂ0.5 mL). The

combined organic extracts were dried over MgSO₄and evap-

orated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, on silica gel, eluting with diethyl ether

and then ethyl acetate to give the SEM ether (5 mg, 23%)

as a colourless oil; [a]²_D⁴2.0 (c 0.4, CHCl₃); n_max(CHCl₃)

2923, 1714, 1099, 1059 cm^ꢀ1; d_H(360 MHz, CDCl₃) 6.19

(1H, br s, NH), 4.64 (2H, s, OCH₂O), 4.16 (1H, d, J¼9.1,

CH₂O), 4.12 (1H, d, J¼9.6, CH₂O), 4.06 (1H, d, J¼9.6,

CH₂O), 3.80 (3H, s, CO₂CH₃), 3.57 (2H, t, J¼8.2,

OCH₂CH₂Si), 3.53 (1H, d, J¼9.1, CH₂O), 2.81 (1H, q, J¼

7.7, CHCH₃), 1.40 (3H, s, C(CH₃)₂), 1.38 (3H, s, C(CH₃)₂),

1.25 (3H, d, J¼7.7, CHCH₃), 0.94 (2H, t, J¼8.2,

OCH₂CH₂Si), 0.04 (9H, s, Si(CH₃)₃); d_C(90 MHz, CDCl₃)

176.4 (CONH), 169.7 (CO₂CH₃), 110.3 (CMe₂), 95.2

(OCH₂O), 87.4 (C(O)), 70.6 (quat. C), 69.6 (CH₂O), 65.7

(CH₂O), 64.6 (CH₂O), 52.7 (CO₂CH₃), 45.0 (CHCH₃), 27.1

(CCH₃), 25.6 (CCH₃), 18.0 (OCH₂CH₂Si), 11.3 (CHCH₃),

ꢀ1.4 (Si(CH₃)₃); m/z (EI) found 426.1935 (M+Na,

C₁₈H₃₂O₇NSi requires 426.1924).

4.1.29. (5S,6S,9R)-6-Hydroxymethyl-2,2,9-trimethyl-

8-oxo-1,3-dioxa-7-aza-spiro[4.4]nonane-6-carboxylic

acid methyl ester (39). 2,2-Dimethoxypropane (0.40 mL,

3.4 mmol) was added to a stirred solution of the diol 37

(80 mg, 0.34 mmol) and para-toluenesulfonic acid (13 mg,

0.07 mmol) in dichloromethane (2 mL) at room tempera-

ture. The mixture was stirred at room temperature for 15 h

and then diluted with a saturated aqueous solution of sodium

bicarbonate (5 mL) and ethyl acetate (5 mL). The organic

phase was separated and the aqueous phase was then ex-

tracted with ethyl acetate (3ꢂ5 mL). The combined organic

extracts were dried over MgSO₄and evaporated in vacuo.

The residue was puriﬁed by ﬂash column chromatography,

on silica gel, eluting with ethyl acetate to give the acetonide

(36 mg, 39%) as a colourless oil; [a]²_D⁴9.8 (c 1.0, CHCl₃);

n_max(CHCl₃) 3421, 2955, 1713, 1060 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 7.33 (1H, br s, NH), 4.13 (2H, s, CH₂O), 4.04

(1H, d, J¼11.7, CH₂O), 3.80 (3H, s, CO₂CH₃), 3.77 (1H,

app. d, J¼11.7, CH₂O), 2.95 (1H, q, J¼7.8, CHCH₃), 1.39

(3H, s, C(CH₃)₂), 1.34 (3H, s, C(CH₃)₂), 1.21 (3H, d,

J¼7.8, CHCH₃); d_C(100 MHz, CDCl₃) 178.0 (CONH),

170.1 (CO₂CH₃), 110.1 (CMe₂), 87.3 (C(O)), 72.5 (quat.

C), 64.8 (CH₂O), 64.0 (CH₂O), 52.8 (CO₂CH₃), 46.0

(CHCH₃), 27.0 (CCH₃), 25.6 (CCH₃), 11.1 (CHCH₃), these

assignments were conﬁrmed by a HMQC experiment; In

a HMBC experiment (400 MHz, CDCl₃) d_H4.13 correlated

to d_C110.1, 72.5 and 46.0; In a ¹H NOE experiment

(400 MHz, CDCl₃), irradiation at d 1.21 gave enhancements

at d 4.04 and 3.77; m/z (CI, NH⁺₄) found 274.1287 (M+H⁺,

C₁₂H₂₀O₆N requires 274.1291).

4.1.32. (5S,6S,9R)-2,2,7,9-Tetramethyl-8-oxo-6-(2-tri-

methylsilanyl-ethoxymethoxymethyl)-1,3-dioxa-7-aza-

spiro[4.4]nonane-6-carboxylic acid methyl ester (42). A

solution of the SEM ether 41a (5 mg, 0.011 mmol) in anhy-

drous DMF (50 mL) was added to a stirred dispersion of

sodium hydride (60% in mineral oil, 0.5 mg, 0.012 mmol)

in anhydrous DMF (50 mL) at 0 ^ꢁC. The suspension was

stirred at 0 ^ꢁC for 10 min and then iodomethane (30 mL,

4.1.30. (5S,6S,9R)-6-(2,2-Dimethyl-propionyloxymethyl)-

2,2,9-trimethyl-8-oxo-1,3-dioxa-7-aza-spiro[4.4]nonane-

6-carboxylic acid methyl ester (41b). A solution of trime-

thylacetyl chloride (1 M in dichloromethane; 0.2 mL,

0.2 mmol) was added to a stirred solution of the alcohol

39 (18 mg, 0.066 mmol) and N,N-dimethylaminopyridine

(1 mg, 7 mmol) in dichloromethane/pyridine (1:1; 0.2 mL)

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6229

0.22 mmol) was added in a single portion. The mixture was

stirred at 0 ^ꢁC for 15 min and then at room temperature for

1 h, before being diluted with ethyl acetate (0.5 mL) and

water (0.5 mL). The aqueous phase was separated and the

organic phase was extracted with water (3ꢂ0.5 mL). The or-

ganic extract was dried over MgSO₄and evaporated in vacuo

to leave the N-methylated pyrrolidinone (5 mg, 100%) as

a colourless oil; [a]²_D⁴ꢀ1.3 (c 0.6, CHCl₃); n_max(CHCl₃)

2929, 2356, 1738, 1689, 1058 cm^ꢀ1; d_H(360 MHz,

CDCl₃) 4.66 (1H, d, J¼6.8, OCH₂O), 4.60 (1H, d, J¼6.8,

OCH₂O), 4.19 (1H, d, J¼9.6, CH₂O), 4.13 (1H, d, J¼9.6,

CH₂O), 4.01 (1H, d, J¼11.3, CH₂O), 3.84 (1H, d, J¼9.1,

CH₂O), 3.78 (3H, s, CO₂CH₃), 3.58 (2H, t, J¼8.4,

OCH₂CH₂Si), 2.86 (3H, s, NCH₃), 2.76 (1H, q, J¼7.7,

CHCH₃), 1.40 (3H, s, C(CH₃)₂), 1.33 (3H, s, C(CH₃)₂),

1.24 (3H, d, J¼7.7, CHCH₃), 0.94 (2H, t, J¼8.4,

OCH₂CH₂Si), 0.04 (9H, s, Si(CH₃)₃); d_C(100 MHz,

CDCl₃) 175.9 (CONH), 168.7 (CO₂CH₃), 109.8 (CMe₂),

95.0 (OCH₂O), 86.0 (C(O)), 74.8 (quat. C), 65.9 (CH₂O),

65.6 (CH₂O), 64.8 (CH₂O), 52.4 (CO₂CH₃), 46.0

(CHCH₃), 27.3 (NCH₃), 27.2 (CCH₃), 25.6 (CCH₃), 18.1

(OCH₂CH₂Si), 11.3 (CHCH₃), ꢀ1.5 (Si(CH₃)₃; In a

HMBC experiment (400 MHz, CDCl₃) d_H4.66 correlated

to d_C65.9 and 65.6; d_H4.13 correlated to d_C109.8 and

46.0; d_H3.84 correlated to d_C86.0 and 74.8; d_H2.86 corre-

lated to d_C175.9 and 74.8; m/z (ES) found 418.2275,

440.2101 (M+H⁺, C₁₉H₃₆NO₇Si requires 418.2261; M+Na,

C₁₉H₃₅NO₇SiNa requires 440.2080).

ﬂash column chromatography, on silica gel, eluting with di-

ethyl ether and then ethyl acetate to give the oxazolidine

(6 mg, 57%) as a colourless oil; [a]²_D⁴16.5 (c 0.4, CHCl₃);

n_max(CHCl₃) 3425, 2955, 1704, 1383, 1059 cm^ꢀ1; d_H

(360 MHz, CDCl₃) 5.52 (1H, d, J¼11.6, OCH₂N), 4.44–4.42

(1H, br, OCH₂N), 4.24 (1H, d, J¼9.7, CH₂O), 4.19 (1H, d, J¼

9.7, CH₂O), 4.09–4.06 (2H, m, CH₂O), 3.80(3H, s, CO₂CH₃),

2.75 (1H, q, J¼7.8, CHCH₃), 1.40 (3H, s, C(CH₃)₂), 1.33(3H,

s, C(CH₃)₂), 1.25 (3H, d, J¼7.7, CHCH₃); d_C(100 MHz,

CDCl₃) 178.1 (CONH), 168.8 (CO₂CH₃), 109.9 (CMe₂),

85.8 (C(O)), 76.4 (quat. C), 65.8 (CH₂O), 65.2 (CH₂O),

61.8 (OCH₂N), 52.7 (CO₂CH₃), 46.6 (CHCH₃), 27.3

(CCH₃), 25.6 (CCH₃), 11.3 (CHCH₃); m/z (ES) found

286.1294 (M+H⁺, C₁₃H₂₀O₆N requires 286.1291).

4.1.35. (5S,6S,9R)-6-Hydroxymethyl-2,2,7,9-tetramethyl-

8-oxo-1,3-dioxa-7-aza-spiro[4.4]nonane-6-carboxylic

acid methyl ester (43a). Triethylsilane (4 mL, 0.033 mmol)

was added to a stirred solution of the oxazolidine 44 (6.0 mg,

0.021 mmol) in triﬂuoroacetic acid (15 mL) and dichlorome-

thane (0.15 mL). The solution was stirred at room tempera-

ture for 15 h before being diluted with a saturated aqueous

solution of sodium bicarbonate (0.5 mL) and dichloro-

methane (0.5 mL). The organic phase was separated and

the aqueous phase was extracted with dichloromethane

(2ꢂ0.5 mL) and ethyl acetate (0.5 mL). The combined or-

ganic extracts were dried over MgSO₄and the solvent evap-

orated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, on silica gel, eluting with ethyl acetate to

give the N-Me pyrrolidinone methanol (1.5 mg, 23%) as

a colourless oil; d_H(360 MHz, CDCl₃) 4.18–4.14 (3H, m,

CH₂O), 4.07–4.04 (1H, m, CH₂O), 3.78 (3H, s, CO₂CH₃),

2.90 (3H, s, NCH₃), 2.84 (1H, q, J¼7.1, CHCH₃), 1.38

(3H, s, C(CH₃)₂), 1.36 (3H, s, C(CH₃)₂), 1.23 (3H, d,

J¼7.1, CHCH₃); m/z (ES) found 288.1465 (M+H⁺,

C₁₃H₂₂NO₆requires 288.1447).

4.1.33. (5S,6S,9R)-6-Methoxymethyl-2,2,7,9-tetra-

methyl-8-oxo-1,3-dioxa-7-aza-spiro[4.4]nonane-6-carb-

oxylic acid methyl ester (43b). A solution of the pivalate

ester 41b (4 mg, 0.011 mmol) in anhydrous DMF (50 mL)

was added to a stirred dispersion of sodium hydride (60%

in mineral oil, 1 mg, 0.017 mmol) in anhydrous DMF

(50 mL) at 0 ^ꢁC. The solution was stirred at 0 ^ꢁC for

15 min before iodomethane (15 mL, 0.11 mmol) was added.

The solution was stirred at 0 ^ꢁC for 15 min and then at room

temperature for 3 h. The solution was diluted with ethyl ace-

tate (0.5 mL) and water (0.5 mL). The aqueous phase was

separated and the organic phase was extracted with water

(3ꢂ0.5 mL). The organic phase was dried over MgSO₄

and the solvent removed in vacuo. The residue was puriﬁed

by ﬂash column chromatography, on silica gel, eluting with

diethyl ether to give the methyl ether (2 mg, 60%) as a col-

ourless oil; d_H(360 MHz, CDCl₃) 4.18 (1H, d, J¼9.6,

CH₂O), 4.12 (1H, d, J¼9.6, CH₂O), 3.87 (1H, d, J¼10.9,

CH₂O), 3.78 (3H, s, CO₂CH₃), 3.66 (1H, d, J¼10.9, CH₂O),

3.34 (3H, s, OCH₃), 2.84 (3H, s, NCH₃), 2.75 (1H, q, J¼7.7,

CHCH₃), 1.40 (3H, s, C(CH₃)₂), 1.34 (3H, s, C(CH₃)₂), 1.23

(3H, d, J¼7.7, CHCH₃).

Acknowledgements

We thank GlaxoSmithKline (GSK) for a CASE-EPSRC stu-

dentship (to N.J.B.) and for ﬁnancial support. We also thank

C. J. Brennan for his useful contributions to the earlier part

of this synthetic work, and Dr. C. J. Hayes for his interest

in the development of this project.

References and notes

1. (a) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.

Tetrahedron Lett. 1985, 26, 1073; (b) Takahashi, K.;

Kawabata, M.; Uemura, D.; Iwadare, S.; Mitomo, R.;

Nakano, F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1077.

2. Kawai, S.; Kawabata, G.; Kobayashi, A.; Kawazu, K. Agric.

Biol. Chem. 1989, 53, 1127.

3. Tonew, E.; Tonew, M.; Grafe, U.; Zopel, P. Acta Virol. 1992,

36, 166.

4. Kawazu, K.; Kanzaki, H.; Kawabata, G.; Kawai, S.; Kobayashi,

A. Biosci. Biotechnol. Biochem. 1992, 56, 1382.

4.1.34. Oxazolidine (44). Paraformaldehyde (5 mg) was

added to a stirred solution of the acetonide 39 (10 mg,

0.037 mmol), magnesium sulfate (5 mg, 0.042 mmol) and

para-toluenesulfonic chloride (1 mg) in toluene (0.2 mL)

at room temperature. The suspension was heated under re-

ﬂux for 8 h and then allowed to cool before being diluted

with a saturated solution of sodium bicarbonate (0.5 mL)

and ethyl acetate (0.5 mL). The organic phase was separated

and then the aqueous phase was extracted with ethyl acetate

(3ꢂ0.5 mL). The combined organic extracts were dried over

MgSO₄and evaporated in vacuo. The residue was puriﬁed by

5. Kanzaki, H.; Wada, K.; Nitoda, T.; Kawazu, K. Biosci.

Biotechnol. Biochem. 1998, 62, 438.

6. (a) Ryu, G.; Hwang, S.; Kim, S.-K. J. Antibiot. 1997, 50, 1064;

(b) Ryu, G.; Kim, S.-K. J. Antibiot. 1999, 52, 193.

6230

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

7. (a) Ogura, M.; Nakayama, H.; Furihata, K.; Shimazu, A.; Seto,

H.; Otake, N. J. Antibiot. 1985, 38, 669; (b) Ogura, M.;

Nakayama, H.; Furihata, K.; Shimazu, A.; Seto, H.; Otake,

N. Agric. Biol. Chem. 1985, 49, 1909.

6031; (h) Donohoe, T. J.; Chiu, J. Y. K.; Thomas, R. E. Org.

Lett. 2007, 9, 421.

17. (a) Brennan, C. J.; Pattenden, G.; Rescourio, G. Tetrahedron

Lett. 2003, 44, 8757; (b) Clough, J. M.; Pattenden, G.;

Wight, P. Tetrahedron Lett. 1989, 30, 7469; (c) Brennan C. J.

Ph.D. Thesis, University of Nottingham, 2000.

8. Manam, R. R.; Teisen, T.; White, D. J.; Nicholson, B.;

Goodberg, J.; Neuteboom, S. T. C.; Lam, K. S.; Mosca,

D. A.; Lloyd, G. K.; Potts, B. C. M. J. Nat. Prod. 2005, 68, 240.

9. The oxazole triene units present in the oxazolomycins are also

found in the ‘phthoxazolin’ and ‘inthomycin’ families of natu-

ral products. See: (a) Omura, S.; Tanaka, Y.; Kanaya, I.;

Shinose, M.; Takahasi, Y. J. Antibiot. 1990, 43, 1034; (b)

Tanaka, Y.; Kanaya, I.; Takahashi, Y.; Shinose, M.; Tanaka,

H.; Omura, S. J. Antibiot. 1993, 46, 1208; (c) Tanaka, Y.;

Kanaya, I.; Shiomi, K.; Tanaka, H.; Omura, S. J. Antibiot.

1993, 46, 1214; (d) Shiomi, K.; Arai, N.; Shinose, M.;

Takahasi, Y.; Yoshida, H.; Iwabuchi, J.; Tanaka, Y.; Omura,

S. J. Antibiot. 1995, 48, 714; (e) Henkel, T.; Zeeck, A.

Liebigs Ann. Chem. 1991, 367.

10. (a) Corey, E. J.; Schreiber, S. L.; Choi, S.; Fenteany, G.;

Standeart, R. F.; Lane, W. S. Science 1995, 268, 726; (b)

Corey, E. J.; Li, W. D. Chem. Pharm. Bull. 1999, 47, 1.

11. Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.;

Moriguchi, R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991,

44, 113.

12. Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;

Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355.

13. See: Kisselev, A. F.; Goldberg, A. L. Chem. Biol. 2001, 8, 739.

14. For syntheses of lactacystin and omuralide, see: Panek, J. S.;

Masse, C. E.; Morgan, A. J.; Adams, J. Eur. J. Org. Chem.

2000, 2513 and references therein; see also: (a) Donohoe,

T. J.; Sintim, H. O.; Sisangia, L.; Ace, K. W.; Guyo, P. M.;

Cowley, A.; Harling, J. D. Chem.—Eur. J. 2005, 11, 4227;

(b) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.; Harling, J. D.

Angew. Chem., Int. Ed. 2004, 43, 2293; (c) Ooi, H.;

Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.; Hatekeyama, S.

J. Org. Chem. 2004, 69, 7765; (d) Wardrop, J. J.; Bowen,

E. G. Chem. Commun. 2005, 5106; (e) Hayes, C. J.;

Sherlock, A. E.; Selby, M. D. Org. Biomol. Chem. 2006, 4,

193; (f) Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai,

M.; Shibasaki, M. J. Org. Chem. 2006, 71, 1220; (g) Balskus,

E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 6810; (h)

Yoon, C. H.; Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J.

Org. Chem. 2007, 37; For syntheses of salinosporamide, see:

(a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem.

Soc. 2004, 126, 6230; (b) Reddy, L. R.; Fournier, J.-F.;

Reddy, B. V. S.; Corey, E. J. Org. Lett. 2005, 7, 2699; (c)

Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J.

J. Am. Chem. Soc. 2005, 127, 8974; (d) Endo, A.;

Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298; (e)

Mulholland, N.; Pattenden, G.; Walters, I. M. Org. Biomol.

18. For some other examples of 5-exo-dig radical cyclisations in

synthesis, see: (a) Curran, D. P.; Rakiewicz, D. M. J. Am.

Chem. Soc. 1985, 107, 1448; (b) Curran, D. P.; Rakiewicz,

D. M. Tetrahedron 1985, 41, 3943; (c) Bannai, K.; Tanaka,

T.; Okamura, N.; Hazato, A.; Suguira, S.; Manabe, K.;

Tomimori, K.; Kato, Y.; Kurozumi, S.; Noyori, R.

Tetrahedron 1990, 46, 6689; (d) Iqbal, J.; Sanghi, R.; Nandy,

J. P. Basic Principles; Renaud, P., Sibi, M. P., Eds.; Radicals

in Organic Synthesis; Wliey-VCH: Weinheim, 2001; Vol. 1,

p 137.

19. For some other radical cyclisation approaches to substituted

pyrrolidinones, see: (a) Stork, G.; Mah, R. Heterocycles

1989, 28, 723; (b) Baker, S. R.; Burton, K. I.; Parsons, A. F.;

Pons, J.-F.; Wilson, M. J. Chem. Soc., Perkin Trans. 1 1999,

427; (c) Boivin, J.; Yousﬁ, M.; Zard, S. Z. Tetrahedron Lett.

1994, 35, 5629; (d) Lizos, D.; Tripoli, R.; Murphy, J. A.

Chem. Commun. 2001, 2732; (e) Tamura, O.; Matsukida, H.;

Toyao, A.; Takeda, Y.; Ishibashi, H. J. Org. Chem. 2002, 67,

5537; (f) Sato, T.; Wada, Y.; Nishimoto, M.; Ishibashi, H.;

Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1989, 879.

20. Cativela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry

1998, 9, 3517.

21. (a) Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett.

1995, 36, 3639; (b) Wipf, P.; Venkatraman, S. Synlett 1997, 1.

22. Seebach, D.; Fadel, A. Helv. Chim. Acta 1985, 68, 1243.

23. (a) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J.;

Fischer, P. Synthesis 1989, 256; (b) Hatakeyama, S.;

Matsumoto, H.; Fukuyama, H.; Mukugi, Y.; Irie, H. J. Org.

Chem. 1997, 62, 2275.

24. (a) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett 1990, 675; (b)

Nicolaou, K. C.; Koide, K. Tetrahedron Lett. 1997, 38, 3667.

25. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,

H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.

26. VanRheenan, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.

1976, 17, 1973.

27. (a) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; La Greca, S.;

Tsuri, T.; Yue, E. W.; Yang, Z. Angew. Chem., Int. Ed. Engl.

1994, 33, 2187; (b) Sharpless, K. B.; Amberg, W.; Bennani,

Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong,

H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L.

J. Org. Chem. 1992, 57, 2768.

28. (a) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring, M. J.;

Winter, J. J. G.; Helliwell, M.; Newcombe, N. J.; Stemp, G.

J. Org. Chem. 2002, 67, 7946; (b) Donohoe, T. J.; Mitchell,

L.; Waring, M. J.; Helliwell, M.; Bell, A.; Newcombe, N. J.

Tetrahedron Lett. 2001, 42, 8951; (c) Donohoe, T. J.;

Mitchell, L.; Waring, M. J.; Helliwell, M.; Bell, A.;

Newcombe, N. J. Org. Biomol. Chem. 2003, 1, 2173; (d)

Donohoe, T. J. Synlett 2002, 1223.

29. Ranu, B. C.; Guchhait, S. K.; Saha, M. J. Indian Chem. Soc.

1999, 76, 547.

30. Vincze, I.; Somlai, C.; Schneider, G.; Dombi, G.; Mak, M,

Liebigs Ann. Chem. 1992, 187.

31. Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1987,

52, 622.

32. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. Tetrahedron Lett.

1991, 32, 4239.

ꢀ

Chem. 2006, 4, 2845; (f) Caubert, V.; Masse, J.; Retailleau,

P.; Langlois, N. Tetrahedron Lett. 2007, 48, 381.

15. Kende, A. S.; Kawamura, K.; DeVita, R. J. J. Am. Chem. Soc.

1990, 112, 4070.

16. (a) Henaff, N.; Whiting, A. Tetrahedron 2000, 56, 5193; (b)

Bulger, P. G.; Moloney, M. G.; Trippier, P. C. Synlett 2002,

1871; (c) Bulger, P. G.; Moloney, M. G.; Trippier, P. C. Org.

Biomol. Chem. 2003, 1, 3726; (d) Taylor, R. J. K.; Papillon,

J. Org. Lett. 2000, 2, 1987; (e) Taylor, R. J. K.; Papillon, J.

Abstr. Pap.—Am. Chem. Soc August 2001, 379, ORGN; (f)

Andrews, D.; Brewster, A. G.; Moloney, M. G. Synlett 1996,

612; (g) Mohapatra, D. K.; Mondal, D.; Gonnade, R. G.;

Chorghade, M. S.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,

N. J. Bennett et al. / Tetrahedron 63 (2007) 6216–6231

6231

33. The sequence 16a to 34 was earlier modelled with material

derived from racemic 15a.^17c

34. Interestingly, treatment of racemic 35a with OsO₄–NMO in 1:1

acetone/H₂O had earlier been shown to result in dihydroxylation

fromthea-face, i.e. antitotheCH₂OTBSgroup,in75%yield.^17c

35. A similar transformation on a related system has been reported

previously, see: Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am.

Chem. Soc. 1994, 116, 2139.

36. Kanemasa, S.; Nomura, M.; Yoshinaga, S.; Yamamoto, H.

Tetrahedron 1995, 51, 10463.

Article Doi

A synthesis of a common intermediate to the lactone-pyrrolidinone ring systems in oxazolomycin A and neooxazolomycin

DOI: 10.1016/j.tet.2007.03.043

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2007.03.043

Full text of DOI:10.1016/j.tet.2007.03.043

Products guided by the article

R&D Labs maybe for 944584-67-2

Relevant to this article

Hot Product