Asymmetric synthesis of (+)-loline

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Asymmetric synthesis of (؉)-loline, a pyrrolizidine alkaloid from

rye grass and tall fescue

Paul R. Blakemore, Sung-Kee Kim, Volker K. Schulze, James D. White* and

Alexandre F. T. Yokochi

1

Department of Chemistry, Oregon State University, Corvallis, Oregon, 97331-4003, USA.

E-mail: james.white@orst.edu

Received (in Cambridge, UK) 2nd May 2001, Accepted 13th June 2001

First published as an Advance Article on the web 18th July 2001

(ϩ)-Loline (1) was synthesized via a pathway that employed intramolecular [4 ϩ 2] cycloaddition of an

acylnitrosodiene, 25 or 26, as a key step. The acylnitrosodienes, which were used in situ, were obtained

by oxidation of the corresponding hydroxamic acids, 17 and 24, and these were prepared from either

glucose via aldehyde 9 or more directly from (S)-malic acid (18). The endo dihydrooxazines 27 and 29,

obtained in a mixture with their exo stereoisomer, were transformed by reductive N–O bond cleavage

and reannulation into pyrrolizines 34 and 35. The latter was subjected to Sharpless aminohydroxylation

in the presence of (DHQD)₂PHAL to give 50 along with its regioisomer 51. N-Methylation of tosyl

amide 50, followed by mesylation of alcohol 52 and reduction of the γ-lactam 53 with borane, aﬀorded

pyrrolizidine 54. Cleavage of the p-methoxybenzyl ether and subsequent thermal treatment of 55 resulted

in intramolecular etheriﬁcation to yield N-tosylloline (57). Final reductive cleavage of the N-tosyl residue

produced (ϩ)-loline, characterized as its dihydrochloride.

to be toxic to larvae of the horn ﬂy Haematobia irritans, an

important ectoparasite of cattle.¹³The convergence of chemical

and biological incentives, particularly the absence of an

asymmetric synthesis of 1, led us to devise a route to (ϩ)-loline

which could be generalized in principle to all members of that

alkaloid family.¹⁴

Introduction

The rye grass Lolium cuneatum and the tall fescue Festuca

arundinacea are important pasture grasses in the United States

that provide feedstock for grazing cattle in regions where

drought or poor drainage is commonplace.¹The alkaloidal

content of these grasses was ﬁrst investigated after cattle

grazing on F. arundinacea were found to develop a lameness

known as “fescue foot”.²Subsequent reports of abdominal fat

necrosis³and increased respiration⁴in cattle feeding on this

grass added impetus to investigations directed towards identi-

ﬁcation of the causative agent(s) of these symptoms.⁵This led

to the isolation of seven closely related alkaloids, of which (ϩ)-

loline (1) is the principal member and all of which have been

chemically interrelated.⁶Other members of the Lolium family

include norloline (2) and the N-acyl derivatives 3 and 4. Most

recently, 1 was discovered in the roots of the tropical liana

Argyreia mollis.⁷

The strategy envisioned for assembling the 2-oxa-6-azatri-

cyclo[4.2.1.0^3,7]nonane core of 1 is outlined in Scheme 1 and

Scheme 1

postulates formation of the internal ether linkage at a late stage

from a hydroxylated pyrrolizidine 5. A critical feature of this

plan is the placement of appropriate substituents, denoted as

X and Y, on the exo face of the pyrrolizidine nucleus at C1

and C2. The dehydropyrrolizidine 6 therefore became a focal

intermediate in our plan, and a route to this substance was

projected employing chemistry along lines developed by Keck

and Kibayashi in their studies of the synthesis of indolizidine,¹⁵

and pyrrolizidine¹⁶alkaloids. The key step in this sequence

is an intramolecular hetero-Diels–Alder cycloaddition of an

acylnitrosodiene 8, in which the center bearing the oxygen

substituent controls the stereochemical outcome of the reaction

that leads to dihydrooxazine 7. The latter can be converted to

a pyrrolizidine through a reannulation sequence involving

reductive scission of the N–O bond.

The isolation of 1 from L. cuneatum was complicated initially

by misassignment of its structure.^6a,bThis was later corrected by

X-ray crystallographic analysis of loline dihydrochloride,⁸

which proved that the parent alkaloid contains a pyrrolizidine

nucleus possessing a unique ether linkage bridging C2 and C7.

Numerous synthetic approaches to loline failed to reach the

target^8c,d,9until a successful route to ( )-1 was reported in 1986

by Tufariello et al.¹⁰

Although fescue toxicity in cattle does not appear to be

directly associated with the alkaloidal content of F. arundin-

acea,¹¹sustained interest in the pharmacology of loline and

its congeners¹²has revealed new biological properties of this

family. For example, acylated derivatives of 1 are now known

DOI: 10.1039/b103936a

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

This journal is © The Royal Society of Chemistry 2001

1831

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Results and discussion

Our initial approach to the acylnitrosodiene 8 commenced from

the known aldehyde 9,¹⁷available in three steps from glucose

bisacetonide (Scheme 2). Addition of allylmagnesium chloride

Scheme 3 Reagents and conditions: (i), BH₃ؒSMe₂, B(OMe)₃, THF,

0 ЊC to rt; (ii), PMPCH(OMe)₂, PPTS, CH₂Cl₂, reﬂux, 64% (2 steps);

(iii), (COCl)₂, DMSO, CH₂Cl₂, Ϫ60 ЊC, then Et₃N, Ϫ60 ЊC to rt; (iv),

allyltriphenylphosphonium bromide, BuLi, THF, Ϫ30 ЊC to rt, 40%

(2 steps); (v), DIBAL-H, CH₂Cl₂, 0 ЊC to rt; (vi), I₂, hν, C₆H₆, rt, 63%

(2 steps); (vii), NaClO₂, NaH₂PO₄ؒH₂O, 2-methylbut-2-ene, t-BuOH-

H₂O, 0 ЊC to rt; (viii), CF₃CO₂SUC, Py, THF, rt; (ix), HONH₂ؒHCl,

Et₃N, CH₂Cl₂, 0 ЊC, 75% (4 steps).

gave the protected hydroxamic acid 24. The overall yield for the

ten steps from 18 to 24 was only 19%, but this route was more

amenable to the preparation of 24 on multi-gram scale than

that shown in Scheme 2.

Oxidation of hydroxamic acids 17 and 24 was carried out

with tetra-n-butylammonium periodate under a variety of con-

ditions (Scheme 4 and Table 1). The resultant acylnitrosodienes

Scheme 2 Reagents and conditions: (i), allylmagnesium chloride, THF,

0 ЊC, 80%; (ii), MsCl, Et₃N, CH₂Cl₂, 0 ЊC; (iii), DBU, toluene, 90 ЊC,

64% (2 steps); (iv), TFA–H₂O–THF (1 : 1 : 5), reﬂux, 89%; (v), NaIO₄,

Et₂O, pH 7 buﬀer; (vi), NaClO₂, NaH₂PO₄ؒH₂O, 2-methylbut-2-ene,

t-BuOH–H₂O; (vii), CH₂N₂, Et₂O; (viii), K₂CO₃, MeOH, 87% (4 steps);

(ix), TBDMSCl, imidazole, DMF, 97%; (x), HONH₂ؒHCl, KOH,

MeOH, 91%.

to 9 gave alcohol 10 as a mixture of stereoisomers, which, after

mesylation and treatment with 1,8-diazabicyclo[5.4.0]undec-7-

ene (DBU), aﬀorded conjugated diene 11. Hydrolysis of 11

under acid catalysis yielded diol 12, and subsequent oxidative

cleavage with sodium periodate gave the formate aldehyde 13.

Oxidation of this aldehyde to a carboxylic acid,¹⁸followed by

treatment with diazomethane, produced the methyl ester 14.

The formate of ester 14 was cleaved selectively employing basic

methanolysis to furnish hydroxy ester 15, which was protected

as its tert-butyldimethylsilyl ether 16 before exposure to

hydroxylamine hydrochloride in basic methanol. The resultant

hydroxamic acid 17 was obtained in 35% overall yield for the

ten steps from 9.

Although the synthesis of 17 from glucose bisacetonide was

relatively eﬃcient, a more direct route to this hydroxamic acid

which incorporated the single stereogenic center without eras-

ing three additional conﬁgurations would obviously possess

greater economy. It was also felt that a protecting group

diﬀerent from the tert-butyldimethylsilyl ether of 17 should be

examined as a controlling element in the intramolecular

cycloaddition of 8. To this end, a modiﬁed version of a route

developed by Kibayashi¹⁹was employed in which (S)-(Ϫ)-

malic acid (18) was reduced with borane,²⁰and the resultant

triol was converted to its p-methoxyphenyl acetal 19 as a single

diastereomer (Scheme 3). The unstable aldehyde obtained by

Swern oxidation of 19 was subjected to a Wittig reaction

with allylidenetriphenylphosphorane to yield diene 20 as a 3 : 7

mixture of E and Z isomers, respectively. The diene mixture

was reduced with excess diisobutylaluminium hydride, after

which isomerization of the mixture with catalytic iodine under

irradiation with a medium pressure mercury lamp produced

the diene 21 with an E : Z ratio that was now ≥95 : 5. Oxidation

of this primary alcohol, ﬁrst to an aldehyde and then to carb-

oxylic acid 22 using buﬀered sodium chlorite,¹⁸was followed

by treatment with N-triﬂuoroacetoxysuccinimide²¹to give O-

succinimidyl ester 23. Displacement with hydroxylamine then

Scheme 4 Reagents and conditions: (i), DDQ, CH₂Cl₂–H₂O (20 : 1), rt,

100%; (ii), TBSOTf, collidine, CH₂Cl₂, 0 ЊC, 70%.

25 and 26 in each case underwent spontaneous intramolecular

cycloaddition to give stereoisomeric bicyclic dihydrooxazines

27–30, accompanied by variable quantities of carboxylic acids

22 and 31. It was found that in benzene or toluene as the

solvent, 17 gave predominantly the endo isomer 27, with the

yield increasing but selectivity decreasing as the temperature of

the reaction was raised from Ϫ20 to 80 ЊC (entries 1–4). In

chlorocarbon solvents (dichloromethane and chloroform), the

yield of dihydrooxazines improved but the selectivity for 27

diminished to near zero (entries 5–7). Although the pairs of

stereoisomeric dihydrooxazines were readily separable by

chromatography, structural assignment to endo (27 and 29) and

exo (28 and 30) isomers was diﬃcult to make on the basis

of NMR experiments alone. Fortunately, 28 proved to be

crystalline and its structure was conclusively established by an

X-ray crystallographic analysis (Fig. 1). A simple two step

sequence converted 30 into 28 and thus provided indirect con-

ﬁrmation of structure for dihydrooxazines 29 and 30. Oxidation

of hydroxamic acid 24 with tetra-n-butylammonium periodate

in chloroform (entry 8) gave a result very similar to that noted

1832

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

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Table 1 Oxidation of hydroxamic acids to acylnitrosodienes and in situ [4 ϩ 2] cycloaddition

Entry

Hydroxamic acid

Oxidant

Solvent

Temp./ЊC)

Yield^a(%)

Product (ratio)^b

1

2

3

4

5

6

7

8

9

17

24

17

Bu₄NIO₄

NaIO₄

PhMe

C₆H₆

CH₂Cl₂

CHCl₃

THF–H₂O (1 : 1)

Ϫ20

0

22

80

Ϫ78

0

22

0

49

60

64

80

86

73

91

87

97

27 : 28 (70 : 30)

27 : 28 (71 : 29)

27 : 28 (70 : 30)

27 : 28 (60 : 40)

27 : 28 (50 : 50)

27 : 28 (45 : 55)

27 : 28 (55 : 45)

29 : 30 (57 : 44)

27 : 28 (27 : 73)

^aIsolated yield. ^bDetermined by ¹H NMR spectroscopy.

Fig. 1 ORTEP representation of one of the two chemically identical

molecules in the asymmetric unit of 28.

Scheme 6 Reagents and conditions: (i), dimethyldioxirane, acetone,

0 ЊC, pH 11 work-up, 92%; (ii), AcOH, CH₂Cl₂, 100%; (iii), MCPBA,

2,6-di-tert-butyl-4-methylphenol (BHT), Na₂CO₃, (CH₂Cl)₂, reﬂux,

50%; (iv), TBAF, THF, 97%; (v), EtO₂CNHONs (39; Ns = p-nitro-

benzenesulfonyl), CaO, CH₂Cl₂, rt; (vi), TBAF, THF, 22% (2 steps);

(vii), LAH, THF, rt, 34%; (viii), OsO₄, NMO, acetone–H₂O (5 : 1),

89%.

for 17 under the same conditions (entry 7). However, when

17 was oxidized with sodium periodate in an aqueous

THF medium, selectivity was reversed in favor of the exo cyclo-

adduct 28 (entry 9). The eﬀect of water on the stereoselectivity

of a closely related cycloaddition has also been noted by

Kibayashi and co-workers¹⁹but is without a satisfactory

explanation at this time.

The endo dihydrooxazines 27 and 29 were each reduced with

6% sodium amalgam to give the lactam alcohols 32 and 33,

respectively, resulting from N–O bond cleavage (Scheme 5).

preference to epoxidation, although unusual, is precedented.²²

Exposure of 36 to acetic acid led in quantitative yield to pyrrole

37. In contrast to its reaction with dimethyldioxirane, 34 gave

exclusively the desired epoxide when treated with buﬀered

m-chloroperbenzoic acid, although in only modest yield.

Subsequent cleavage of the silyl ether of this oxirane aﬀorded

alcohol 38, but all attempts to eﬀect opening of the epoxide by

intramolecular attack across the endo face of the pyrrolizidine

with the hydroxy function at C7 were unsuccessful.

An alternative and more direct entry to the loline skeleton

from 34 would be via aziridination of the double bond, and

to this end 34 was reacted with an excess of the p-nitro-

benzenesulfonate of N-hydroxyurethane (39) in the presence of

calcium oxide.²³The nitrene generated by this means underwent

in situ addition to 34 and yielded an aziridine in which

the alcohol was immediately deprotected to give 40. Again, the

endo alcohol 40 failed to participate in intramolecular opening

of the aziridine. The negative outcome with both 38 and 40

led to speculation that the lactam carbonyl was inhibiting

transannular attack by the C7 hydroxy function at the three-

membered ring, and a conformational analysis of these struc-

tures clearly showed that the ﬂattened γ-lactam ring prevented

close approach of the two reacting sites. Conversely, removal of

the lactam carbonyl would permit the pyrrolizidine to adopt a

“puckered” conformation²⁴which should bring the hydroxy

group and three-membered ring into suﬃcient proximity for

transannular displacement to occur. With the intent of testing

this hypothesis, 34 was reduced with lithium aluminium hydride

Scheme 5 Reagents and conditions: (i), 6% Na(Hg), Na₂HPO₄, EtOH,

0 ЊC; (ii), MsCl, Et₃N, CH₂Cl₂, 0 ЊC; (iii), LDA, THF, Ϫ78 to 0 ЊC.

Each of these allylic alcohols was converted to the correspond-

ing mesylate and then treated with lithium diisopropylamide.

The intermediate metallated lactams immediately cyclized to

the corresponding dehydropyrrolizidinones 34 and 35, in which

a double bond is conveniently placed for the further elaboration

needed to transform this template into the tricyclic nucleus of

loline. Exploratory experiments along these lines were carried

out with 34, which was oxidized with dimethyldioxirane in the

expectation that an epoxide of exo conﬁguration would be

formed (Scheme 6). Surprisingly, the sole product was alcohol

36, the result of angular hydroxylation rather than epoxidation.

Abstraction of an allylic hydrogen by dimethyldioxirane in

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

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Fig. 2 ORTEP representation of one of the two chemically identical

molecules in the asymmetric unit of 42.

to 41. Unfortunately, this pyrrolizidine was now more suscep-

tible to oxidation at the basic nitrogen atom and, not surpris-

ingly, eﬀorts to secure a derivative of 41 in which the double

bond was functionalized by oxidative means were completely

unsuccessful. This result indicated that the pyrrolizidinone

double bond must be modiﬁed prior to reduction of the lactam

carbonyl, and a promising development in this direction was

realized with osmylation of 34. The crystalline exo diol 42 was

obtained in high yield, and its conﬁguration was conﬁrmed by

X-ray crystallographic analysis (Fig. 2).

For a variety of reasons, including the greater ease of scale-

up, it proved to be more practical to move forward from the

p-methoxybenzyl ether 35 than the corresponding silyl ether 34.

The osmylation of 35 aﬀorded diol 43 which underwent quanti-

tative reduction of the lactam carbonyl with excess borane

(Scheme 7). The product isolated from this reduction was the

Fig. 3 ORTEP representation of 44.

atography. Cleavage of the p-methoxybenzyl ether from 46

occurred cleanly with 2,3-dichloro-5,6-dicyano-1,4-benzo-

quinone (DDQ), but when the resulting alcohol was exposed to

potassium carbonate in reﬂuxing aqueous methanol, we were

surprised to ﬁnd that the sole product was the oxetane 47,

resulting from displacement of the proximal tosylate rather

than the expected tricyclic skeleton characteristic of 1. The

structure of 47 was evident from the unusually high chemical

shift of H7 (5.05 pm) and the absence of coupling between

H1 and H2 (J_1,2= 0 Hz). In contrast to 46, debenzylation of 45

was more problematic, DDQ being ineﬀective while ceric

ammonium nitrate (CAN) gave a mixture of diol 48 and the

p-methoxybenzoate 49. Neither of these substances was useful

as platforms from which to launch the ﬁnal moves towards

loline.

It was recognized at this point that the diﬃculties attending

cyclization of tosylate 46 could probably be circumvented if

aminohydroxylation rather than dihydroxylation of 35 was

used to functionalize the double bond (see Scheme 8 and Table

Scheme 8

2). Osmylation of 35 in the presence of excess chloramine-T

under the original catalytic conditions reported by Sharpless²⁵

yielded principally the diol 43 together with small amounts of

the masked amino alcohols 50 and 51 (entry 1). More recent

results from Sharpless,²⁶and others,²⁷have demonstrated the

profound inﬂuence of added biscinchona alkaloid ligands on

the facial selectivity and regioselectivity of osmium catalyzed

oleﬁn aminohydroxylation. Furthermore, solvent systems

incorporating water, which encourage high catalyst turn-over

rates, can be utilized in the presence of these ligands without

their usual promotion of an intrusive dihydroxylation path-

way.²⁶Cognizant of these results, aminohydroxylation of 35

was attempted in the presence of hydroquinidine phthalazine-

1,4-diyl diether [(DHQD)₂PHAL] in an acetonitrile–water mix-

ture (entry 2). To our surprise, an even greater proportion of

diol 43 was produced and only traces of the desired hydroxy-

sulfonamides could be found. Fortunately, the yield of amino-

hydroxylation products 50 and 51 was considerably improved

Scheme 7 Reagents and conditions: (i), OsO₄, NMO, acetone–H₂O

(5 : 1), 65%; (ii), BH₃ؒSMe₂, THF, rt, 100%; (iii), TsCl, Et₃N, CH₂Cl₂, rt;

(iv), Pd(OH)₂/C, MeOH, rt; (v), DDQ, CH₂Cl₂–H₂O (20 : 1), rt, 80%;

(vi), K₂CO₃, MeOH–H₂O (5 : 1), reﬂux, 76%; (vii), CAN, MeCN–H₂O

(5 : 1), rt.

stable, crystalline pyrrolizidine–borane 44 whose crystal struc-

ture is shown in Fig. 3. Protection of the basic pyrrolizidine

nitrogen in this way permitted tosylation of the diol without

complication, but a mixture of mono- and bis-tosylates 45 and

46 resulted from this reaction. After removal of the borane

by methanolysis in the presence of Pearlman’s catalyst, the

mono- and bis-tosylates were readily separated by chrom-

1834

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

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Table 2 Aminohydroxylation of dehydropyrrolizidinone 35^a

Yield^b(%)

Entry

Os cat. (mol %)

Additive (mol%)

Solvent

Temp./ЊC

Time/h

50 ϩ 51

43

Ratio^c50 : 51

1

2

3

4

5

OsO₄(5)

None

t-BuOH

60

22

43

3

24

72

24

18

<5

47

52

38

29

73

48

21

39

85 : 15

—

80 : 20

75 : 25

65 : 35

K₂OsO₂(OH)₄(8)

K₂OsO₂(OH)₄(4)

K₂OsO₂(OH)₄(1 × 3)

K₂OsO₂(OH)₄(4)

(DHQD)₂PHAL^d(8)

(DHQD)₂PHAL^d(25)

(DHQ)₂PHAL^e(8)

MeCN–H₂O (1 : 1)

t-BuOH–H₂O (1 : 1)

^aChloramine-T dihydrate (2–3 equiv.) added to each reaction. ^bIsolated yield. ^cDetermined by ¹H NMR spectroscopy. ^d(DHQD)₂PHAL =

hydroquinidine phthalazine-1,4-diyl diether. ^e(DHQ)₂PHAL = hydroquinine phthalazine-1,4-diyl diether.

if the reaction was run in a tert-butyl alcohol–water mixture

(entry 3), and optimization studies revealed that maintaining a

high ligand to Os() ratio further suppressed diol formation.

Slow addition of the potassium osmate pre-catalyst gave an

acceptable yield of 50 and 51 with a 3 : 1 regioselectivity

in favor of 50 (entry 4). The use of hydroquinine phthalazine-

1,4-diyl diether [(DHQ)₂PHAL] as additive resulted in a lower

proportion of aminohydroxylation products, although the

predominant regioisomer was again 50 (entry 5).

Incorporation of the secondary amino function of 50 as

its sulfonamide during the aminohydroxylation of 35 provided

a convenient opportunity to introduce the N-methyl substituent

characteristic of loline. This was accomplished by treatment

of the potassium salt of the tosyl amide 50 with methyl iodide,²⁸

after which the hydroxy group of 52 was converted to its

mesylate in quantitative yield (Scheme 9). Reduction of

Fig. 4 ORTEP representation of 55.

eﬀect this ﬁnal ring closure were unpromising, however. Bases

such as potassium hexamethyldisilazane, which presumably

generate an alkoxide from 55, gave exclusively the product

56 from 1,2-elimination. Evidently, the hydrogen at C1 is

abstracted in preference to displacement at C2 under these

conditions. The problem was conveniently circumvented by

subjecting 55 to a purely thermal cyclization, and in o-dichloro-

benzene at 180 ЊC. Compound 55 underwent clean cyclization

to N-tosylloline (57). Removal of the tosyl group by reductive

cleavage with sodium naphthalenide aﬀorded (ϩ)-loline (1),

isolated as its dihydrochloride salt. The ¹H and ¹³C NMR spec-

tra of synthetic material were in good agreement with those

reported for natural loline (Tables 3 and 4).²⁹Additional con-

ﬁrmation of the identity of our synthesized material was made

by converting a sample of the natural alkaloid to its N-tosyl

derivative 57, at which point the complete identity of the

synthetic and naturally prepared materials was unambiguous.

N-Tosylloline (57), derived in 21 steps from (Ϫ)-malic acid (18),

exhibited [α]²_D²ϩ40.9 (c 0.11, CHCl₃) while that obtained from

natural (ϩ)-loline had [α]²_D²ϩ38.0 (c 0.10, CHCl₃).

Experimental

All reactions requiring anhydrous conditions were conducted

in ﬂame-dried glass apparatus under an atmosphere of Ar.

DME, THF and Et₂O were freshly distilled from sodium–

benzophenone ketyl prior to use. DMSO was distilled from

CaH₂at 15 mmHg. CH₂Cl₂was freshly distilled from CaH₂.

Anhydrous ethanol was obtained by distillation from its

magnesium alkoxide and stored under Ar over activated 4 Å

molecular sieves. Preparative chromatographic separations

were performed on EM Science silica gel 60 (35–75 µm), and

reactions were followed by TLC analysis using EM Science

silica plates with ﬂuorescent indicator (254 nm) and were

visualized with UV, phosphomolybdic acid or potassium per-

manganate. All commercially available reagents were purchased

from Aldrich and were typically used as supplied.

Scheme 9 Reagents and conditions: (i), MeI, t-BuOK, t-BuOH, 50 ЊC,

76%; (ii), MsCl, Et₃N, CH₂Cl₂, 0 ЊC, 99%; (iii), BH₃ؒSMe₂, THF, rt; (iv),

Pd(OH)₂/C, MeOH, rt, 73% (2 steps); (v), DDQ, CH₂Cl₂–H₂O (20 : 1),

rt, 70%; (vi), KHMDS, THF, 0 ЊC, 70%; (vii), o-Cl₂C₆H₄, 180 ЊC, 75%;

(viii), sodium naphthalenide, DME, Ϫ60 ЊC, 48%; (ix), TsCl, DMAP,

Et₃N, CHCl₃, rt, 77%.

γ-lactam 53 again proceeded smoothly with borane–dimethyl

sulﬁde to give the pyrrolizidine–borane complex, from which

54 was liberated with methanol in the presence of Pearlman’s

catalyst. Removal of the p-methoxybenzyl ether from 54 with

DDQ furnished the crystalline alcohol 55, our intended

substrate for the intramolecular etheriﬁcation that would yield

the loline framework. An X-ray crystallographic structure

determination of 55 (Fig. 4) conﬁrmed that the C7 hydroxy

group of 55 is indeed in suﬃcient proximity to C2 to eﬀect

displacement and consequent cyclization. Initial attempts to

Melting points were recorded using open capillary tubes on a

Büchi melting point apparatus and are uncorrected. Speciﬁc

optical rotations were measured at ambient temperature (23 ЊC)

from CHCl₃solutions on a Perkin-Elmer 243 polarimeter using

a 1 mL cell with 1 dm path length. Infra-red spectra were

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

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Table 3 ¹H NMR data for natural and synthetic loline dihydrochloride

Natural (ϩ)-loline dihydrochloride^ab

Synthetic (ϩ)-loline dihydrochloride^a

Position

δ (ppm)

Multiplicity

J/Hz

δ (ppm)

Multiplicity

J/Hz

H1

H2

4.23

4.79

4.15

3.55

3.73

2.28

2.37

4.72

4.79

4.76

2.79

dd

d

ddd

dddd

ddd

dd

br m

s

<2, 1.9

<2, 1.0

4.23

4.77–4.80

4.12

3.57

3.70

br d

m

dd

2.3

—

H3_A

H3_B

H5_A

H5_B

H6_A

H6_B

H7

H8

NH

NMe

13.9, 1.0

13.9

12.8, 8.2, 7.7

12.8, 9.6, 5.0

14.6, 8.2, 5.0, 4.8

14.6, 9.6, 7.7

4.8, 2.2

2.2, 1.9

—

13.9, 1.3

12.8, 9.5, 7.8

12.8, 8.8, 5.5

15.4, 9.5, 5.5, 4.6

d

ddd

dddd

ddd

—

m

—

3.75

2.38

2.27

15.4, 8.8, 7.8

Not observed^c

4.77–4.80

Obscured^c

2.79

—

s

^aRecorded in D₂O at 300 MHz. ^bData taken from ref. 29. ^cObscured by HOD.

Table 4 Comparison of ¹³C NMR data for natural and synthetic

The structures were solved using direct methods as

programmed in SHELXS-97,³³and any remaining atoms were

subsequently found by diﬀerence Fourier map techniques using

the program SHELXL-97.³³Unless otherwise stated, hydrogen

atoms were included in geometrically idealized positions, and

reﬁned as riding groups with an isotropic displacement par-

ameter equal to 1.5 (methyl group) or 1.2 (all other types) times

the U_eqof the atom to which it is attached. Where appropriate,

an absolute structure parameter (Flack X parameter)³⁴was

reﬁned in order to conﬁrm or determine the absolute conﬁg-

uration of the structure under study.

loline dihydrochloride

δ (ppm)

Position

Natural^ab

Synthetic^a

∆δ

C1

C2

C3

C5

C6

C7

C8

NMe

65.9

73.9

64.2

58.1

31.6

83.2

72.2

36.5

66.0

74.0

64.2

58.2

31.6

83.4

72.2

36.4

Ϫ0.1

0.0

Ϫ0.1

0.0

Ϫ0.2

0.0

ϩ0.1

1-[(3aR,6aR)-2,2-Dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-

yl]but-3-en-1-ol (10)

^aRecorded in D₂O at 75 MHz. ^bData taken from ref. 29.

A solution of 9¹⁷(37 mg, 0.21 mmol) in THF (10 mL) was

stirred over 4 Å molecular sieves for 30 min and then added

dropwise to allylmagnesium chloride (0.16 mL, 2.0 M in THF,

0.32 mmol) in THF (10 mL) at 0 ЊC. The resulting mixture was

stirred at 0 ЊC for 2 h and sat. aq. NH₄Cl (15 mL) and Et₂O (15

mL) were added. The phases were separated and the aqueous

phase extracted with Et₂O (3 × 15 mL). The combined organic

extracts were washed with brine (5 mL), dried (Na₂SO₄) and

concentrated in vacuo. The residue was further puriﬁed by col-

umn chromatography (eluting with 33–50% EtOAc in hexanes)

to yield 10 (36 mg, 0.17 mmol, 80%) as a 1 : 1 mixture of dias-

tereoisomers: IR (neat) 3478, 2984, 2936, 1374, 1216, 1163,

1054, 1020, 918, 850 cm^Ϫ1; ¹H NMR (400 MHz, CDCl₃) δ 1.32

(s, 6H), 1.51 (s, 6H), 1.74–2.01 (m, 4H), 2.20 (t, J = 7 Hz, 2H),

2.31 (t, J = 7 Hz, 2H), 2.47 (br s, 2H), 3.53–3.60 (m, 1H), 3.95

(br s, 1H), 4.15–4.22 (m, 2H), 4.75 (br s, 2H), 5.10–5.16 (m,

4H), 5.79–5.91 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 26.1,

26.2, 26.7, 26.8, 31.7, 34.8, 37.4, 38.6, 69.8, 72.0, 80.4, 80.5,

80.6, 80.7, 105.2, 105.4, 111.2, 111.4, 117.7, 117.8, 134.1, 134.3;

MS (EI) m/z 215 (M ϩ H)^ϩ, 199, 173, 157, 143, 139, 115;

HRMS (EI) m/z 199.0969 (M Ϫ CH₃)^ϩ(calcd for C₁₀H₁₅O₄:

199.1029).

recorded on a Nicolet 5DXB spectrometer using a thin ﬁlm

supported between NaCl plates or KBr discs. ¹H and ¹³C NMR

spectra were recorded in Fourier transform mode at the ﬁeld

strength speciﬁed either on a Bruker AC300 or AM400

spectrometer. Spectra were obtained from CDCl₃solutions in

5 mm diameter tubes, and the chemical shift in ppm is quoted

relative to the residual signals of chloroform (δ_H= 7.25 ppm, or

δ_C= 77.0 ppm). Multiplicities in the ¹H NMR spectra are

described as: s = singlet, d = doublet, t = triplet, q = quartet,

m = multiplet, br = broad; coupling constants are reported in

Hz. Low (MS) and high (HRMS) resolution mass spectra were

determined using a Kratos MS50 spectrometer. Ion mass/

charge (m/z) ratios are reported as values in atomic mass units.

X-Ray crystallographic structure determinations† were con-

ducted on a Siemens P4 instrument controlled by the program

XSCANS V2.20,³⁰and equipped with a sealed tube Cu anode, a

graphite monochromator, and a modiﬁed Siemens LT2 low

temperature device. After verifying the quality of the crystal by

means of a rotational photograph, the crystal was oriented

using a set of reﬂections found by an automated search routine.

This cell was then transformed to its highest symmetry setting,

reﬁned using high-angle reﬂections, and ambiguous symmetry

elements checked by means of axial photographs and/or auto-

mated methods. Data were collected based on the assumed

crystal system, including at least all the unique data for the

particular Laue class, and their Bijvoet pairs. Data were auto-

matically corrected for Lorentz and polarization eﬀects by the

diﬀractometer control program. Unless otherwise indicated,

correction for eﬀects of absorption anisotropy was carried out

based on semi-empirical methods (psi-scans)³¹as programmed

in XEMP V4.3.³²

(3aR,6aR)-5-(Buta-1,3-dienyl)-2,2-dimethyltetrahydrofuro-

[2,3-d][1,3]dioxolane (11)

To a solution of 10 (867 mg, 4.05 mmol) and triethylamine (819

mg, 8.10 mmol) in CH₂Cl₂(50 mL) at 0 ЊC was added dropwise

methanesulfonyl chloride (557 mg, 4.86 mmol). The solution

was allowed to warm to rt and stirred for 2 h. Sat. aq. NH₄Cl

(15 mL) was added and the phases separated. The aqueous

phase was extracted with CH₂Cl₂(3 × 15 mL), and the com-

bined organic extracts were washed with brine (10 mL), dried

(Na₂SO₄) and concentrated in vacuo. The resulting crude

mesylate was dissolved in toluene (50 mL) and treated with 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU, 3.08 g, 20.3 mmol) at

100 ЊC for 9 h. The mixture was allowed to cool to rt, and sat.

† CCDC reference numbers 163574–163577. See http://ww w .rsc.org/

suppdata/p1/b1/b103936a/ for crystallographic ﬁles in .cif or other elec-

tronic format.

1836

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

View Article Online

1

aq. NH₄Cl (25 mL), H₂O (5 mL) and Et₂O (25 mL) were added.

The layers were separated and the aqueous phase extracted with

Et₂O (3 × 20 mL). The combined organic extracts were washed

with brine (10 mL), dried (Na₂SO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (eluting

with 10–15% EtOAc in hexane) to yield crude 11 (∼1 g) as a

15 : 1 mixture of E and Z isomers, respectively. The mixture was

dissolved in MeOH (6 mL), H₂O (30 mL) was added slowly, and

the product was allowed to crystallize at 5 ЊC. The resulting ﬁne

yellow plates were collected by ﬁltration and dried to aﬀord 11

(508 mg, 2.59 mmol, 64% for two steps) with E : Z = 40 : 1

(determined by ¹H NMR analysis): [α]_D²³Ϫ34.3 (c 1.23, CH₂Cl₂);

IR (neat) 2987, 2976, 2961, 2931, 2882, 1371, 1256, 1157, 1081,

1048, 1013, 966, 928, 912, 858, 845 cm^Ϫ1; ¹H NMR (300 MHz,

CDCl₃) δ 1.30 (s, 3H), 1.51 (s, 3H), 1.60 (ddd, J = 13, 11, 5 Hz,

1H), 2.15 (dd, J = 13, 4 Hz, 1H), 4.66 (ddd, J = 11, 7, 4 Hz, 1H),

4.72 (t, J = 4 Hz, 1H), 5.09 (dm, J = 10 Hz, 1H), 5.21 (dm,

J = 15 Hz, 1H), 5.65 (ddm, J = 15, 7 Hz, 1H), 5.82 (d, J = 4 Hz,

1H), 6.24–6.38 (2H, m); ¹³C NMR (75 MHz, CDCl₃) δ 26.1,

26.6, 39.6, 77.9, 80.5, 105.3, 111.0, 118.3, 131.3, 133.2, 136.1;

MS (EI) m/z 196 M^ϩ, 181, 138, 121; HRMS (EI) m/z 196.1099

(calcd for C₁₁H₁₆O₃: 196.1099).

1438, 1276, 1176, 1100, 1006, 907 cm^Ϫ1; H NMR (300 MHz,

CDCl₃) δ 2.50–2.64 (m, 2H), 3.00 (br s, OH), 3.70 (s, 3H), 4.58

(q, J = 6 Hz, 1H), 5.11 (dm, J = 10 Hz, 1H), 5.22 (dm, J = 16

Hz, 1H), 5.70 (ddm, J = 15, 6 Hz, 1H), 6.25–6.39 (m, 2H); ¹³C

NMR (75 MHz, CDCl₃) δ 41.1, 51.8, 68.3, 118.2, 131.5, 133.8,

136.0, 172.5; MS (CI) m/z 156 M^ϩ, 139, 124; HRMS (CI) m/z

156.0786 (calcd for C₈H₁₂O₃: 156.0786).

Methyl (E,3S)-3-[(tert-butyldimethylsilyl)oxy]hepta-4,6-

dienoate (16)

To a stirred solution of 15 (561 mg, 3.59 mmol) and imidazole

(416 mg, 6.1 mmol) in DMF (20 mL) at rt was added tert-

butyldimethylsilyl chloride (676 mg, 4.49 mmol). After stirring

of the solution for 24 h, H₂O (50 mL) and Et₂O (150 mL) were

added and the phases separated. The organic phase was washed

with H₂O (20 mL) and brine (20 mL), dried (Na₂SO₄), and

concentrated in vacuo. The slightly volatile residue was puriﬁed

by column chromatography (eluting with 25% Et₂O in pentane)

to yield 16 (942 mg, 3.48 mmol, 97%) as a colourless oil: [α]_D²³

Ϫ2.2 (c 2.77, CH₂Cl₂); IR (neat) 2954, 2857, 1742, 1437, 1361,

1256, 1107, 1004, 836, 778 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃)

δ 0.02 (s, 3H), 0.03 (s, 3H), 0.85 (s, 9H), 2.43 (dd, J = 15, 5 Hz,

1H), 2.54 (dd, J = 15, 8 Hz, 1H), 3.65 (s, 3H), 4.62 (q, J = 6 Hz,

1H), 5.08 (dm, J = 10 Hz, 1H), 5.19 (dm, J = 15 Hz, 1H), 5.67

(dd, J = 15, 7 Hz, 1H), 6.18 (dd, J = 15, 10 Hz, 1H), 6.29 (dt,

J = 16, 10 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.2, Ϫ4.4,

18.0, 25.7 (3C), 43.6, 51.5, 70.1, 117.6, 130.7, 135.5, 136.2,

171.4; MS (CI) m/z 271 (M ϩ H)^ϩ, 255, 213, 197, 139; HRMS

(CI) m/z 271.1730 (calcd for C₁₄H₂₇SiO₃: 271.1729).

(E,3R,5S)-5-(Buta-1,3-dien-1-yl)-2,3-dihydroxyoxolane (12)

A solution of 11 (1.15 g, 5.88 mmol) in TFA–THF–H₂O

(5 : 1 : 1, 40 mL) was stirred at 60 ЊC for 5 h. The mixture was

allowed to cool and sat. aq. NaHCO₃added until pH 7 was

reached (ca. 40 mL). EtOAc (30 mL) was added and the phases

separated. The aqueous phase was extracted with EtOAc

(5 × 40 mL), and the combined organic phases were washed

with brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (eluting

with 50–66% EtOAc in hexanes) to yield 12 (820 mg, 5.25

mmol, 89%) as a variable mixture of anomers: IR (neat) 3348,

(E,3S)-N-Hydroxy-3-[(tert-butyldimethylsilyl)oxy]hepta-4,6-

dienamide (17)

To a solution of hydroxylamine hydrochloride (1.21 g, 17.4

mmol) in MeOH (10 mL) at rt was added a solution of potas-

sium hydroxide in MeOH (16 mL, 1.8 M, 29 mmol). After stir-

ring the mixture for 30 min, the precipitated potassium chloride

was allowed to settle and the supernatant liquor added to the

neat ester 16 (942 mg, 3.48 mmol) during 3 h (10 mL was added

during the ﬁrst 10 min). The solution was stirred at 35 ЊC for

a further 5 h, H₂O (60 mL) was added, and the mixture was

acidiﬁed to pH 3 with 10% aq. HCl. The solution was extracted

with Et₂O (6 × 90 mL), and the combined organic extracts were

dried (Na₂SO₄) and concentrated in vacuo. The residue was

puriﬁed by column chromatography (eluting with 50% EtOAc

in hexanes) to give 17 (860 mg, 3.17 mmol, 91%) as a colourless

oil: [α]²_D³Ϫ2.3 (c 0.87, CH₂Cl₂); IR (neat) 3211, 3086, 3040,

3002, 2955, 2928, 2885, 2856, 1650, 1606, 1471, 1463, 1389,

1361, 1255, 1109, 1074, 1004, 950, 904, 837, 778; ¹H NMR (300

MHz, CDCl₃) δ 0.05 (s, 3H), 0.07 (s, 3H), 0.89 (s, 9H), 2.34 (dd,

J = 15, 7 Hz, 1H), 2.45 (dd, J = 14, 4 Hz, 1H), 4.55 (q, J = 6 Hz,

1H), 5.10 (dm, J = 10 Hz, 1H), 5.20 (dm, J = 16 Hz, 1H), 5.64

(dd, J = 15, 7 Hz, 1H), 6.18 (dd, J = 15, 10 Hz, 1H), 6.28 (dt,

J = 16, 10 Hz, 1H), 8.0–9.5 (br s, NHOH); ¹³C NMR (75 MHz,

CDCl₃) δ Ϫ5.1, Ϫ4.5, 18.1, 25.8 (3C), 42.2, 69.8, 118.2, 131.4,

134.2, 135.9, 168.7; MS (CI) m/z 272 (M ϩ H)^ϩ, 271 M^ϩ, 270,

256, 245, 214, 199, 140; HRMS (CI) m/z 272.1681 (calcd for

C₁₃H₂₆NO₃Si: 272.1682).

1

2940, 1610, 1417, 1358, 1009, 961, 970 cm^Ϫ1; H NMR (300

MHz, CDCl₃) δ 1.8–2.2 (m, 4H), 3.0–3.6 (m, 4H), 4.2–4.35 (m,

2H), 4.7–4.85 (m, 2H), 5.05–5.45 (m, 6H), 5.55–5.8 (m, 2H),

6.15–6.4 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 38.1, 39.0,

71.5, 76.9, 80.0, 96.9, 102.6, 118.2, 132.2, 132.6, 133.1, 134.7,

135.9; MS (CI) m/z 156 M^ϩ, 139, 138, 110; HRMS (CI) m/z

156.0786 (calcd for C₈H₁₂O₃: 156.0786).

Methyl (E,3S)-3-hydroxyhepta-4,6-dienoate (15)

To a stirred suspension of 12 (820 mg, 5.25 mmol) and sodium

periodate (1.46 g, 6.83 mmol) in ether (80 mL) at rt was added

dropwise a pH 7 aqueous phosphate buﬀer solution (1.5 mL).

After stirring for 3 h, Et₂O (100 mL) was added and the mixture

was dried (Na₂SO₄), ﬁltered, and concentrated in vacuo. The

resulting crude aldehyde 13 was dissolved in t-BuOH (100 mL)

and 2-methylbutene (25 mL), and the solution was cooled to

0 ЊC and treated with a solution of NaClO₂(4.37 g, 48.3 mmol)

and NaH₂PO₄ؒH₂O (5.07 g, 36.8 mmol) in H₂O (50 mL). The

resulting mixture was stirred for 1 h while warming to ambient

temperature and H₂O (150 mL) was added. The aqueous phase

was separated, acidiﬁed to pH 3 with 10% aq. HCl, and

extracted with CH₂Cl₂(5 × 100 mL). The combined organic

extracts were dried (MgSO₄) and concentrated in vacuo to yield

crude carboxylic acid 31. The acid was immediately dissolved in

Et₂O (40 mL) and diazomethane (ca. 22 mL, 0.25 M in Et₂O,

5.5 mmol) was added until a light yellow colour persisted. The

solution was stirred at rt overnight and concentrated in vacuo to

give 950 mg of crude methyl ester 14. The ester was dissolved in

MeOH (50 mL), K₂CO₃(100 mg, 0.72 mmol) and H₂O (10

drops) were added, and the resulting mixture was stirred at rt

for 1 h. Solid NH₄Cl was added (100 mg) and the mixture was

concentrated in vacuo. The residue was puriﬁed by column

chromatography (eluting with 15–25% EtOAc in hexanes) to

give 15 (717 mg, 4.59 mmol, 87% for four steps) as a colourless

oil: [α]²_D³ϩ5.7 (c 2.11, CH₂Cl₂); IR (neat) 3448, 2953, 1732,

[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]methanol (19)

A stirred biphasic mixture of (S)-butane-1,2,4-triol²⁰(2.80 g,

26.4 mmol) and anhydrous CH₂Cl₂(80 mL) at rt under Ar, was

treated with 4-methoxybenzaldehyde dimethyl acetal (4.70 mL,

ρ = 1.07, 5.03 g, 27.6 mmol). After addition of PPTS (330 mg,

1.31 mmol), the mixture was heated at reﬂux for 20 h. The

resulting homogeneous solution was allowed to cool and was

concentrated in vacuo, and the crude residue was puriﬁed by

column chromatography (eluting with 50% EtOAc in hexanes)

to aﬀord 19 (3.81 g, 17.0 mmol, 64%) as a colourless oil: [α]_D²³

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

1837

View Article Online

ϩ9.9 (c 0.96, CHCl₃); IR (neat) 3500, 2835, 1613, 1587, 1514,

(E,S)-3-(4-Methoxybenzyloxy)hepta-4,6-dien-1-ol (21)

1

1507, 1392, 1302, 1242, 1171, 1028, 827, 778 cm^Ϫ1; H NMR

To a stirred solution of 20 (319 mg, 1.30 mmol) in anhydrous

CH₂Cl₂(10 mL) at 0 ЊC under Ar was added dropwise a solu-

tion of diisobutylaluminium hydride (12.7 mL, 0.51 M in

CH₂Cl₂, 6.5 mmol). The cooling bath was removed and the

clear mixture allowed to stir at rt for 1.5 h. The reaction was

quenched with H₂O (1 mL, CARE!) and stirred vigorously for

10 min. After dilution of the mixture with CH₂Cl₂(50 mL),

solid Na₂SO₄(20 g) was added and the resulting suspension

stirred vigorously for 10 min. Solids were removed by ﬁltration

through a Celite pad and the residue was washed thoroughly

with CH₂Cl₂(4 × 50 mL). The combined ﬁltrate and washings

were concentrated in vacuo to yield 319 mg of crude dienol

isomers. The mixture of isomers (E : Z = 3 : 7) was dissolved in

PhH (30 mL) and the solution was treated with iodine (4 mg, 16

µmol, ca. 1 mmol%). After transfer to a photolysis apparatus

(quartz window) and a 10 min sparge with Ar, the solution was

irradiated with a medium-pressure Hanovia Hg discharge lamp

(120 V, 450 W) for 1 h. The solution was diluted with EtOAc

(20 mL), and the combined organic solutions were washed suc-

cessively with 10% w/v aq. Na₂S₂O₃(20 mL) and brine (10 mL),

and dried (Na₂SO₄). The organic solution was concentrated in

vacuo, and the residue was puriﬁed by column chromatography

(eluting with 40% EtOAc in hexanes) to yield 21 (204 mg, 0.82

mmol, 63%) as a clear oil (E : Z > 95 : 5 by ¹H NMR analysis):

[α]²_D³Ϫ60.3 (c 1.10, CHCl₃); IR (neat) 2829, 1609, 1584, 1507,

1462, 1300, 1240, 1171, 1030, 954, 906, 821 cm^Ϫ1; ¹H NMR (300

MHz, CDCl₃) δ 1.70–1.94 (m, 2H), 2.49 (br s, 1H), 3.65–3.80

(m, 2H), 3.80 (s, 3H), 4.05 (td, J = 8, 5 Hz, 1H), 4.28 (d, J = 11

Hz, 1H), 4.55 (d, J = 11 Hz, 1H), 5.15 (dd, J = 10, 1 Hz, 1H),

5.25 (dd, J = 16, 1 Hz, 1H), 5.65 (dd, J = 15, 8 Hz, 1H), 6.23

(dd, J = 15, 11 Hz, 1H), 6.38 (dt, J = 17, 10 Hz, 1H), 6.88 (d,

J = 9 Hz, 2H), 7.24 (d, J = 9 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 37.9, 55.2, 60.6, 69.9, 78.6, 113.8 (2C), 118.0, 129.4

(2C), 130.2, 133.3, 133.6, 136.1, 159.2; MS (CI) m/z 248 (M^ϩ),

137, 121, 109; HRMS (CI) m/z 248.1409 (calcd for C₁₅H₂₀O₃:

248.1412).

(300 MHz, CDCl₃) δ 1.39 (dm, J = 13 Hz, 1H), 1.85 (qd, J = 13,

5 Hz, 1H), 2.51 (t, J = 6 Hz, 1H), 3.60 (t, J = 5 Hz, 2H), 3.78 (s,

3H), 3.86–3.97 (m, 2H), 4.25 (dd, J = 12, 5 Hz, 1H), 5.46 (s,

1H), 6.88 (d, J = 9 Hz, 2H), 7.41 (d, J = 9 Hz, 2H); ¹³C NMR

(75 MHz, CDCl₃) δ 26.7, 55.2, 65.5, 66.4, 77.4, 101.0, 113.5

(2C), 127.3 (2C), 130.8, 159.9; MS (FAB) m/z 225 (M ϩ H)^ϩ,

223, 193, 137; HRMS (FAB) m/z 225.1128 (calcd for C₁₂H₁₇O₄:

225.1127).

(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxane-4-carbaldehyde

To a stirred solution of oxalyl chloride (3.84 mL, 5.61 g, 44.1

mmol) in anhydrous CH₂Cl₂(60 mL) at Ϫ60 ЊC under Ar was

added dropwise a solution of dimethyl sulfoxide (5.46 mL, 6.01

g, 77.0 mmol) in anhydrous CH₂Cl₂(50 mL) during 20 min.

After stirring the mixture for an additional 25 min a solution of

19 (6.15 g, 27.4 mmol) in anhydrous CH₂Cl₂(40 mL) was added

during 20 min. The resulting cloudy mixture was stirred for a

further 20 min, treated with triethylamine (26.8 mL, ρ = 0.726,

19.5 g, 193 mmol), and was allowed to warm to rt during 1 h.

The reaction mixture was quenched with H₂O (100 mL), and

the layers were vigorously shaken and then separated. The

aqueous phase was extracted with CH₂Cl₂(3 × 50 mL), and the

combined organic extracts were washed successively with H₂O

(50 mL) and brine (20 mL), and dried (Na₂SO₄). The extract

was concentrated in vacuo (CARE! stench), and the crude

residue was puriﬁed by column chromatography (eluting with

50–80% EtOAc in hexanes) to yield a mixture of the aldehyde

and inseparable oligomers (5.42 g) as a clear oil: ¹H NMR (300

MHz, CDCl₃, selected for free aldehyde) δ 1.79 (dm, J = 13 Hz,

1H), 1.97 (qd, J = 13, 5 Hz, 1H), 3.82 (s, 3H), 4.01 (td, J = 12, 3

Hz, 1H), 4.30–4.40 (m, 2H), 5.57 (s, 1H), 6.92 (d, J = 9 Hz, 2H),

7.46 (d, J = 9 Hz, 2H), 9.73 (s, 1H).

(2S,4S)-4-(Buta-1,3-dienyl)-2-(4-methoxyphenyl)-1,3-dioxane

(20)

A stirred suspension of allyltriphenylphosphonium bromide

(14.0 g, 36.6 mmol) in anhydrous THF (250 mL) at Ϫ30 ЊC

under Ar was treated dropwise with n-butyllithium (21.6 mL,

1.47 M in hexanes, 31.8 mmol) and the resulting orange solu-

tion was stirred for 40 min. A solution of the aldehyde and its

oligomers obtained (5.42 g) in anhydrous THF (20 mL) was

added dropwise, causing a lightening in colour to yellow and

the formation of a precipitate. The mixture was allowed to

warm to rt over 2 h and quenched by the addition of H₂O (50

mL). After dilution with Et₂O (200 mL), the layers were shaken

vigorously and separated. The aqueous phase was extracted

with Et₂O (2 × 50 mL) and the combined organic extracts were

washed with brine (50 mL), dried (Na₂SO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 20% Et₂O in hexanes) to yield 20 (2.68 g, 10.9

mmol, 40% from 19, colourless oil) as an inseparable mixture of

isomers (E : Z = 3 : 7 by ¹H NMR): IR (neat) 2955, 2834, 1724,

1613, 1588, 1515, 1462, 1392, 1370, 1301, 1241, 1212, 1170,

(E,3S)-N-Hydroxy-3-(4-methoxybenzyloxy)hepta-4,6-dienamide

(24)

A stirred solution of oxalyl chloride (1.0 mL, 1.46 g, 11.5

mmol) in anhydrous CH₂Cl₂(20 mL) at Ϫ60 ЊC under Ar was

treated dropwise by cannula with a cold solution of anhydrous

dimethyl sulfoxide (1.45 mL, 1.60 g, 20.5 mmol) in anhydrous

CH₂Cl₂(20 mL) over 10 min. After an additional 20 min, a

solution of 21 (1.82 g, 7.33 mmol) in anhydrous CH₂Cl₂(10

mL) was added dropwise during 5 min. The resulting cloudy

mixture was stirred for 25 min and treated with triethylamine

(7.1 mL, 5.15 g, 51.0 mmol). The mixture was allowed to warm

to rt during 1.5 h, H₂O (30 mL) was added, and the layers were

separated. The aqueous phase was extracted with CH₂Cl₂

(3 × 20 mL), and the combined organic extracts were washed

successively with H₂O (20 mL) and brine (20 mL), and dried

(Na₂SO₄). The extract was oncentrated in vacuo to yield 2.44 g

of crude (E,S)-3-(4-methoxybenzyloxy)hepta-4,6-dienal. This

material was immediately dissolved in a mixture of t-BuOH

(150 mL) and 2-methylbut-2-ene (36 mL), and the resulting

solution was cooled to 0 ЊC with stirring. A solution of NaClO₂

(3.30 g, 36.7 mmol) and NaH₂PO₄ؒH₂O (5.0 g, 36.2 mmol) in

H₂O (75 mL) was added, the cooling bath was removed, and the

biphasic mixture was stirred vigorously for 40 min. H₂O (100

mL) and CH₂Cl₂(100 mL) were added and the pH of the

aqueous layer was adjusted to 3 by careful addition of 1 M

HCl. The layers were separated and the aqueous phase was

extracted with CH₂Cl₂(3 × 30 mL). The combined organic

extracts were washed with H₂O (50 mL) and brine (50 mL),

dried (Na₂SO₄), and concentrated in vacuo to aﬀord 2.67 g of

crude 22. Without further puriﬁcation, 22 was dissolved in

anhydrous THF (50 mL), the solution was placed under an

1116, 1066, 911, 880, 828, 779 cm^Ϫ1¹H NMR (300 MHz,

;

CDCl₃, E–Z mixture) δ 1.47–1.61 (m, 1H_{E ϩ Z}), 1.85–2.04 (m,

1H_{E ϩ Z}), 3.78 (s, 3H_Z), 3.79 (s, 3H_E), 3.92–4.10 (m, 1H_{E ϩ Z}),

4.26 (dd, J = 12, 5 Hz, 1H_{E ϩ Z}), 4.40 (ddd, J = 11, 5, 2 Hz, 1H_E),

4.81 (ddd, J = 11, 9, 2 Hz, 1H_Z), 5.07–5.32 (m, 2H_{E ϩ Z}), 5.49–

5.57 (m, 2H_Zϩ 1H_E), 5.78 (dd, J = 15, 6 Hz, 1H_E), 6.09 (t,

J = 11 Hz, 1H_Z), 6.22–6.40 (m, 2H_E), 6.68 (dt, J = 17, 11 Hz,

1H_Z), 6.88 (d, J = 7 Hz, 2H_{E ϩ Z}), 7.42 (d, J = 7 Hz, 2H_Z), 7.43

(d, J = 5 Hz, 2H_E); ¹³C NMR (75 MHz, CDCl₃, E–Z mixture)

δ 31.1_E, 31.2_Z, 55.0_{E ϩ Z}, 66.5_{E ϩ Z}, 73.6_Z, 76.7_E, 100.8_{E ϩ Z}

,

113.3_{E ϩ Z}(2C), 117.7_E, 119.3_Z, 127.2_{E ϩ Z}(2C), 130.5_Z, 130.8_Z,

131.0_E, 131.0_E, 131.1_Z, 131.6_Z, 132.9_E, 136.2_E, 159.7_{E ϩ Z}; MS

(CI) m/z 246 M^ϩ, 221, 200, 173, 137, 121, 109, 93; HRMS (CI)

m/z 246.1256 (calcd for C₁₅H₁₈O₃: 246.1256).

1838

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

View Article Online

atmosphere of Ar, and pyridine (1.20 mL, 1.17 g, 14.9 mmol)

was added. The resulting solution was treated with N-(triﬂuoro-

acetyloxy)succinimide (2.32 g, 11.0 mmol), and the mixture was

stirred for 20 h at rt The mixture was diluted with EtOAc (100

mL) and washed successively with 0.2 M HCl (50 mL), sat. aq.

NaHCO₃(50 mL) and brine (20 mL), and dried (Na₂SO₄). The

solution was concentrated in vacuo to yield 3.13 g of 23. In a

separate ﬂask, a stirred suspension of HONH₂ؒHCl (2.54 g,

36.5 mmol) in anhydrous CH₂Cl₂(20 mL) at 0 ЊC under Ar, was

treated dropwise with a solution of Et₃N (10.2 mL, 7.41 g,

73.3 mmol) in anhydrous CH₂Cl₂(20 mL) during 15 min. The

resulting suspension was stirred for 20 min and treated drop-

wise with a solution of the previously prepared succinimidyl

ester 23 (3.13 g) in anhydrous CH₂Cl₂(20 mL) during 10 min.

The mixture was allowed to warm to rt and stirred for a further

3 h, after which EtOAc (100 mL) was added and the solution

shaken with sat. aq. NH₄Cl (75 mL). The layers were separated

and the aqueous phase extracted EtOAc (3 × 20 mL). The

combined organic extracts were washed with brine (20 mL),

dried (Na₂SO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (eluting with 5% MeOH in

CH₂Cl₂) to yield pure 24 (1.51 g, 5.44 mmol, 75%) as a pale

golden oil: [α]²_D³Ϫ30.2 (c 0.97, CHCl₃); IR (neat) 3200, 2900,

1H), 2.64 (dd, J = 17, 8 Hz, 1H), 4.04–4.14 (m, 2H), 4.29 (td,

J = 16, 3 Hz, 1H), 4.66 (dd, J = 16, 2 Hz, 1H), 5.88–5.99 (m,

2H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ4.9, Ϫ4.7, 17.9, 25.6, 39.1,

61.4, 69.0, 124.1, 125.3, 166.5; MS (CI) m/z 270 (M ϩ H)^ϩ, 254,

212, 170, 123, 109, 101, 97, 71, 69; HRMS (CI) m/z 270.1522

(calcd for C₁₃H₂₄NO₃Si: 270.1526).

C₁₃H₂₃NO₃Si, M = 269.41, monoclinic, space group P2₁,

a = 13.645(2), b = 6.180(1) c = 18.791(3) Å, β = 94.73(1)Њ,

V = 1579.2(4) Å³, T = 290 K, Z = 4, µ(Cu-Kα) = 1.327 mm^Ϫ1

,

colorless block, crystal dimensions 0.20 × 0.20 × 0.20 mm.

The crystal was oriented from a total of 63 reﬂections with

5.23 < θ < 23.34Њ. A total of 3443 data were measured (2.4

< θ < 57.1Њ), with 2862 independent reﬂections (merging

R_int= 0.039). Full matrix least squares based on F²yielded

the residuals of R1 = 0.068, wR2 = 0.188, for 328 reﬁned

parameters and 7 restraints (ﬂoating origin restraint, and

distance restraints to aid in the modeling of the disordered

TBDMS groups).

The TBDMS groups of both independent molecules found

in the asymmetric unit were found to be disordered over two

positions, and careful examination of the diﬀerence Fourier

maps revealed the positions of all the atoms. Two models were

considered in the ﬁnal reﬁnement of the structure: one where

the TBDMS group atoms were kept with isotropic displace-

ment parameters (a), and one with fully anisotropic ones (b).

Though model (b) yielded slightly lower residuals than (a),

it also added several new reﬁned variables. Thus, in order to

maintain a favorable data-to-parameter ratio, model (a) was

selected as the end point in this reﬁnement. For this reﬁne-

ment, the ﬁnal value of the absolute structure parameter was

Ϫ0.01(10) conﬁrming the fact that the depicted model accur-

ately represents the enantiomer of the molecule under study.

1651, 1614, 1514, 1463, 1302, 1249, 1175, 1071, 1034, 823 cm^Ϫ1

;

¹H NMR (300 MHz, CDCl₃) δ 2.28–2.43 (m, 2H), 3.78 (s, 3H),

4.19 (q, J = 7 Hz, 1H), 4.27 (d, J = 11 Hz, 1H), 4.48 (d, J = 11

Hz, 1H), 5.16 (d, J = 10 Hz, 1H), 5.26 (d, J = 16 Hz, 1H), 5.56

(dd, J = 14, 7 Hz, 1H), 6.23 (dd, J = 14, 10 Hz, 1H), 6.33 (dt,

J = 16, 10 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz,

2H); ¹³C NMR (75 MHz, CDCl₃) δ 38.8, 55.2, 70.4, 75.6, 113.9

(2C), 118.8, 129.5, 129.5 (2C), 131.6, 134.2, 135.7, 159.3, 168.7;

MS (FAB) m/z 278 (M ϩ H)^ϩ, 121; HRMS (FAB) m/z 278.1391

(calcd for C₁₅H₂₀O₄N: 278.1392).

(4aS,5S)-5-(4-Methoxybenzyloxy)-2,4a,5,6-tetrahydro-7H-

pyrrolo[1,2-b]oxazin-7-one (29). Mp 80–90 ЊC (Et₂O); [α]_D²³

ϩ86.0 (c 0.71, CHCl₃); IR (neat) 2898, 2834, 1721, 1610, 1513,

Oxidation of hydroxamic acids 17 and 24 to acylnitrosodienes 25

and 26 and their in situ cycloaddition (Table 1)

1

1462, 1354, 1247, 1173, 1090, 1031, 983, 823, 669 cm^Ϫ1; H

A solution of the hydroxamic acid (17 or 24, 5 mmol) in the

speciﬁed solvent (40 mL) was added dropwise during 30 min

to a stirred solution of the periodate oxidant (10 mmol) in

the same solvent (60 mL) at the indicated temperature. After

stirring for an additional 2 h, the reaction was quenched with

sat. aq. Na₂S₂O₃(40 mL). The biphasic mixture was stirred

vigorously for 45 min at rt and the layers were separated. The

aqueous phase was extracted with CH₂Cl₂(3 × 20 mL) and

the combined organic extracts were washed successively with

H₂O (2 × 10 mL) and brine (10 mL), dried (Na₂SO₄), and

concentrated in vacuo. The residue was puriﬁed by column

chromatography (eluting with 60–75% EtOAc). In each case

the less polar endo isomer (27 or 29) was eluted before the

corresponding exo isomer (28 or 30).

NMR (300 MHz, CDCl₃) δ 2.40 (dd, J = 17, 5 Hz, 1H), 2.63

(dd, J = 17, 7 Hz, 1H), 3.81 (s, 3H), 4.20–4.30 (m, 2H), 4.45 (d,

J = 12 Hz, 1H), 4.46–4.55 (m, 1H), 4.54 (d, J = 12 Hz, 1H), 4.80

(dm, J = 17 Hz, 1H), 5.95–6.05 (m, 2H), 6.89 (d, J = 9 Hz, 2H),

7.25 (d, J = 9 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 35.1, 55.2,

56.8, 68.3, 69.8, 71.3, 113.9 (2C), 122.4, 125.7, 129.0, 129.3

(2C), 159.4, 168.4; MS (CI) m/z 276 (M ϩ H)^ϩ, 121; HRMS

(CI) m/z 276.1239 (calcd for C₁₅H₁₈NO₄: 276.1236).

(4aR,5S)-5-(4-Methoxybenzyloxy)-2,4a,5,6-tetrahydro-7H-

pyrrolo[1,2-b]oxazin-7-one (30). Oil; [α]²_D³Ϫ75.5 (c 2.45, CHCl₃);

IR (neat) 2905, 1731, 1614, 1514, 1455, 1359, 1247, 1174, 1030,

821 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 2.52 (dd, J = 17, 5 Hz,

1H), 2.66 (dd, J = 17, 8 Hz, 1H), 3.81 (s, 3H), 3.90 (ddd, J = 8, 6,

4 Hz, 1H), 4.21–4.35 (m, 2H), 4.48 (d, J = 11 Hz, 1H), 4.53 (d,

J = 11 Hz, 1H), 4.68 (dd, J = 15, 3 Hz, 1H), 5.87–5.93 (m, 2H),

6.90 (d, J = 8 Hz, 2H), 7.26 (d, J = 8 Hz, 2H); ¹³C NMR (75

MHz, CDCl₃) δ 35.7, 55.2, 59.0, 68.6, 71.2, 73.9, 113.9 (2C),

124.4, 125.3, 128.9, 129.3 (2C), 159.5, 167.0; MS (CI) m/z

276 (M ϩ H)^ϩ, 121; HRMS (CI) m/z 276.1238 (calcd for

C₁₅H₁₈NO₄: 276.1236).

(4aS,5S)-5-[(tert-Butyldimethylsilyl)oxy]-2,4a,5,6-tetrahydro-

7H-pyrrolo[1,2-b]oxazin-7-one (27). Mp 69–71 ЊC; [α]²_D³ϩ93.9

(c 1.99, Et₂O); IR (CDCl₃) 2955, 2929, 2899, 2858, 1712, 1471,

1

1463, 1387, 1258, 1129, 1101, 1062, 839; H NMR (300 MHz,

CDCl₃) δ 0.71 (s, 3H), 0.79 (s, 3H), 0.87 (s, 9H), 2.26 (dd, J = 17,

4 Hz, 1H), 2.65 (dd, J = 17, 7 Hz, 1H), 4.23–4.30 (m, 1H), 4.37–

4.40 (m, 1H), 4.47–4.53 (m, 1H), 4.72–4.79 (m, 1H), 5.88–5.99

(m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.0, Ϫ4.8, 18.0, 25.6,

38.6, 58.2, 64.8, 68.6, 122.7, 125.6, 168.2; MS (CI) m/z 270

(M ϩ H)^ϩ, 254, 212, 170, 101, 75; HRMS (CI) m/z 270.1523

(calcd for C₁₃H₂₄NO₃Si: 270.1526).

(Z,4S,5S)-4-[(tert-Butyldimethylsilyl)oxy]-5-(3-hydroxyprop-

enyl)pyrrolidin-2-one (32)

The oxazine 27 (195 mg, 0.72 mmol) was reduced to 32 (185 mg,

0.68 mmol, 94%) by the protocol below for the conversion of 29

to 33. Compound 32: colourless solid; mp 97–98 ЊC; [α]²_D³ϩ18.8

(c 0.66, CH₂Cl₂); IR (neat) 3417, 3221, 2926, 1650, 1362, 1256,

(4aR,5S)-5-[(tert-Butyldimethylsilyl)oxy]-2,4a,5,6-tetra-

hydro-7H-pyrrolo[1,2-b]oxazin-7-one (28). Mp 110–111 ЊC; [α]_D²³

Ϫ91.0 (c 2.90, CHCl₃); IR (neat) 2950, 2927, 2856, 1719, 1470,

1462, 1445, 1371, 1359, 1350, 1283, 1259, 1214, 1090, 1049,

1

1098, 1038, 949, 840, 775 cm^Ϫ1; H NMR (300 MHz, CDCl₃)

δ 0.03 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H), 2.29 (dd, J = 17, 4 Hz,

1H), 2.56 (dd, J = 17, 6 Hz, 1H), 4.14 (dd, J = 13, 5 Hz, 1H),

4.29 (dd, J = 13, 7 Hz, 1H), 4.46 (td, J = 6, 3 Hz, 1H), 4.53 (dd,

1

1004, 977, 922, 899, 837, 780; H NMR (300 MHz, CDCl₃)

δ 0.78 (s, 3H), 0.90 (s, 3H), 0.89 (s, 9H), 2.43 (dd, J = 17, 6 Hz,

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

1839

View Article Online

J = 9, 5 Hz), 5.67 (ddt, J = 11, 9, 1 Hz, 1H), 5.87 (ddd, J = 11, 7,

5 Hz, 1H), 6.49 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.0,

Ϫ4.9, 18.0, 25.6 (3C), 41.0, 56.1, 58.0, 70.1, 127.2, 133.1, 176.5;

MS (CI) m/z 272 (M ϩ H)^ϩ, 254, 214, 198, 122; HRMS (CI) m/z

272.1679 (calcd for C₁₃H₂₆NO₃Si: 272.1682).

amide (2.0 mmol) in anhydrous THF (30 mL) at Ϫ78 ЊC under

Ar. After stirring at Ϫ78 ЊC for 1.5 h, the mixture was allowed

to warm to rt, stirred for a further 30 min, and quenched with

aq. NH₄Cl (20 mL). The mixture was diluted with H₂O (10 mL)

and EtOAc (15 mL), the layers were shaken, and the phases

were separated. The aqueous phase was extracted with EtOAc

(3 × 10 mL) and the combined organic extracts were washed

with brine (15 mL), dried (Na₂SO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (eluting

with 5% MeOH in CH₂Cl₂) to yield 35 (326 mg, 1.26 mmol,

88%) as a colourless oil which slowly crystallised upon stand-

ing: mp 55–56 ЊC; [α]²_D³Ϫ72.0 (c 0.50, CHCl₃); IR (neat) 2920,

1693, 1612, 1513, 1463, 1392, 1352, 1301, 1246, 1172, 1076,

(Z,4S,5S)-5-(3-Hydroxypropenyl)-4-(4-methoxybenzyloxy)-

pyrrolidin-2-one (33)

A stirred suspension of 29 (548 mg, 1.99 mmol) and Na₂HPO₄

(3.40 g, 23.9 mmol) in anhydrous EtOH (40 mL) at 0 ЊC under

Ar was treated with 3 equal portions of 6 wt% Na(Hg) (total of

7.60 g, 19.8 mmol e^Ϫ) at 2 hourly intervals. After an additional

14 h at 0 ЊC, the reaction was quenched with sat. aq. NH₄Cl (20

mL) and the mixture was stirred vigorously for 20 min. The

mixture was diluted with H₂O (20 mL) and EtOAc (20 mL) and

ﬁltered to remove residual Hg. The collected solids were washed

successively with H₂O (10 mL) and EtOAc (3 × 10 mL), and

the two layers of the ﬁltrate and combined washings were sep-

arated. The aqueous phase was extracted with EtOAc (3 × 20

mL), and the combined organic extracts were washed with

brine (20 mL), dried (Na₂SO₄), and concentrated in vacuo to

yield pure 33 (504 mg, 1.82 mmol, 91%) as a colorless solid: mp

112–114 ЊC (EtOAc); [α]_D²³ϩ26.8 (c 0.91, CHCl₃); IR (KBr)

3253, 1676, 1611, 1510, 1443, 1351, 1304, 1244, 1063, 1033,

1002, 816 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 2.45 (dd, J = 17,

5 Hz, 1H), 2.53 (dd, J = 17, 7 Hz, 1H), 3.10 (br s, 1H), 3.79 (s,

3H), 4.08 (dd, J = 13, 5 Hz, 1H), 4.19–4.30 (m, 2H), 4.39 (d,

J = 11 Hz, 1H), 4.44 (d, J = 11 Hz, 1H), 4.66 (dd, J = 9, 6 Hz,

1H), 5.77 (t, J = 10 Hz, 1H), 5.91 (dt, J = 10, 7 Hz, 1H), 6.87 (d,

J = 8 Hz, 2H), 7.09 (br s, 1H), 7.22 (d, J = 8 Hz, 2H); ¹³C NMR

(75 MHz, CDCl₃) δ 37.1, 54.6, 55.2, 58.1, 71.3, 75.1, 113.9 (2C),

127.2, 129.3 (2C), 129.3, 133.2, 159.4, 175.8; MS (FAB) m/z

278 (M ϩ H)^ϩ, 121; HRMS (FAB) m/z 278.1397 (calcd for

C₁₅H₂₀NO₄: 278.1392).

1

1031, 939, 820 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 2.48 (d,

J = 17 Hz, 1H), 2.79 (dd, J = 17, 5 Hz, 1H), 3.70 (dm, J = 15 Hz,

1H), 3.79 (s, 3H), 4.29 (t, J = 4 Hz, 1H), 4.37 (d, J = 12 Hz, 1H),

4.43 (ddd, J = 14, 4, 2 Hz, 1H), 4.50 (d, J = 12 Hz, 1H),

4.73–4.80 (m, 1H), 5.86–5.91 (m, 1H), 5.92–5.98 (m, 1H), 6.87

(d, J = 9 Hz, 2H), 7.20 (d, J = 9 Hz, 2H); ¹³C NMR (75 MHz,

CDCl₃) δ 40.8, 49.6, 55.2, 70.3, 72.8, 76.4, 113.7 (2C), 126.0,

129.0 (2C), 129.2, 129.6, 159.2, 175.9; MS (CI) m/z 260

(M ϩ H)^ϩ, 138, 121; HRMS (CI) m/z 260.1283 (calcd for

C₁₅H₁₈NO₃: 260.1287).

(1S,7aR)-1-[(tert-Butyldimethylsilyl)oxy]-7a-hydroxy-1,2,5,7a-

tetrahydro-3H-pyrrolizin-3-one (36)

A solution of dimethyldioxirane in acetone (1.8 mL, ca. 45

µmol) was added to 34 (7.6 mg, 30 µmol) at 0 ЊC. After stirring

of the solution for 2 h, a solution of KOH (1.0 mL, 0.05 M in

EtOH) was added, the mixture was ﬁltered through silica gel,

and the collected solids were washed with EtOAc–Et₃N (10 : 1).

The ﬁltrate and combined washings were concentrated in vacuo

and the residue was puriﬁed by column chromatography [elut-

ing with hexanes–EtOAc–Et₃N (10 : 20 : 1)] to yield 36 (7.4 mg,

28 µmol, 92%) as a colourless oil: ¹H NMR (300 MHz, CDCl₃)

δ 0.06 (s, 6H), 0.83 (s, 9H), 2.18 (d, J = 16 Hz, 1H), 3.19 (dd,

J = 16, 4 Hz, 1H), 3.83 (br d, J = 16 Hz, 1H), 4.24 (dt, J = 16, 1

Hz, 1H), 4.41 (d, J = 4 Hz, 1H), 5.40 (br OH), 5.86 (dt, J = 6, 2

Hz, 1H), 6.06 (br d, J = 6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)

δ Ϫ4.9, Ϫ4.7, 18.0, 25.6 (3C), 43.2, 48.5, 75.2, 105.2, 129.3,

130.6, 177.3; MS (CI) m/z 270 (M ϩ H)^ϩ, 252 (M Ϫ OH)^ϩ, 194,

152; HRMS (CI) m/z 270.1527 (calcd for C₁₃H₂₄NO₃Si:

270.1526).

(1S,7aS)-1-[(tert-Butyldimethylsilyl)oxy]-1,2,5,7a-tetrahydro-

3H-pyrrolizin-3-one (34)

The hydroxylactam 32 (104 mg, 0.39 mmol) was transformed to

34 (57.4 mg, 0.23 mmol, 58%) by the protocol below for the

conversion of 33 to 35. The product was puriﬁed by column

chromatography (eluting with 35% EtOAc in hexanes) to give

34 as a colourless oil: [α]²_D³Ϫ71.3 (c 1.37, CH₂Cl₂); IR (neat)

2926, 2854, 1704, 1471, 1378, 1254, 1085, 942, 837, 778 cm^Ϫ1

;

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 3H), 0.01 (s, 3H), 0.79 (s,

9H), 2.17 (d, J = 16 Hz, 1H), 2.81 (dd, J = 16, 4 Hz, 1H), 3.64

(dm, J = 15 Hz, 1H), 4.33 (ddt, J = 15, 4, 2 Hz, 1H), 4.52 (t,

J = 4 Hz, 1H), 4.62–4.65 (m, 1H), 5.67 (dq, J = 6, 2 Hz, 1H),

5.85 (dd, J = 6, 2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.1,

Ϫ4.7, 18.0, 25.5 (3C), 44.8, 50.0, 71.2, 74.1, 126.2, 128.6, 176.5;

MS (CI) m/z 254 (M ϩ H)^ϩ, 238, 196; HRMS (CI) m/z

254.1577 (calcd for C₁₃H₂₄NO₂Si: 254.1576).

(1S)-1-[(tert-Butyldimethylsilyl)oxy]-1,2-dihydro-3H-pyrrolizin-

3-one (37)

A solution of acetic acid (2 mL, 50% v/v in CH₂Cl₂) was added

to 36 (1.0 mg, 3.7 µmol). After stirring at rt for 10 min, the

solution was concentrated in vacuo to yield pure 37 (0.9 mg, 3.7

µmol, 100%) as a colourless oil: [α]²_D³Ϫ24.7 (c 1.79, CH₂Cl₂); IR

(neat) 2953, 2927, 2856, 1763, 1463, 1393, 1294, 1274, 1086,

936, 837, 779 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 0.13 (s, 3H),

0.15 (s, 3H), 0.91 (s, 9H), 2.88 (dd, J = 18, 3 Hz, 1H), 3.34 (dd,

J = 18, 7 Hz, 1H), 5.28 (ddd, J = 7, 3, 1 Hz, 1H), 6.13 (dd, J = 2,

(1S,7aS)-1-(4-Methoxybenzyloxy)-1,2,5,7a-tetrahydro-3H-

pyrrolizin-3-one (35)

1 Hz, 1H), 6.46 (t, J = 3 Hz, 1H), 7.02 (dd, J = 3, 1 Hz, 1H); ¹³

C

A stirred solution of 33 (400 mg, 1.44 mmol) in anhydrous

CH₂Cl₂(60 mL) at 0 ЊC under Ar was treated with Et₃N (0.40

mL, 290 mg, 2.87 mmol) followed by methanesulfonyl chloride

(0.17 mL, 252 mg, 2.20 mmol). After stirring for 30 min, the

mixture was allowed to warm to rt and stirred for a further 20

min. Sat. aq. NH₄Cl (20 mL) was added and the mixture was

stirred vigorously for 5 min. H₂O (10 mL) was added, and the

layers were shaken and the phases were separated. The aqueous

phase was extracted with CH₂Cl₂(3 × 10 mL), and the com-

bined organic extracts were washed with brine (10 mL), dried

(Na₂SO₄), and concentrated in vacuo to yield 553 mg of the

crude mesylate. This material was immediately dissolved in

anhydrous THF (10 mL) and the solution was added dropwise

to a stirred solution of freshly prepared lithium diisopropyl-

NMR (75 MHz, CDCl₃) δ Ϫ4.7, Ϫ4.6, 18.1, 25.7 (3C), 46.2,

62.9, 106.2, 111.5, 119.1, 142.0, 169.5; MS (CI) m/z 252

(M ϩ H)^ϩ, 194, 152, 120; HRMS (CI) m/z 252.1420 (calcd for

C₁₃H₂₂NO₂Si: 252.1420).

(1R,2R,4S,9S)-9-[(tert-Butyldimethylsilyl)oxy]-3-oxa-6-azatri-

cyclo[4.3.0.0^2,4]nonan-7-one

A stirred suspension of 34 (14.0 mg, 55 µmol) and sodium

carbonate (11.7 mg, 0.11 mmol) in 1,2-dichloroethane (3 mL)

was treated with 2,6-di-tert-butyl-4-methylphenol (BHT, 0.6

mg) followed by anhydrous 3-chloroperbenzoic acid (43 mg,

0.25 mmol). The stirred mixture was heated at reﬂux for 3 h,

additional portions of sodium carbonate and 3-chloroperoxy-

1840

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

View Article Online

benzoic acid (as before) were added, and heating was continued

for a further 2 h. The mixture was allowed to cool, diluted with

CH₂Cl₂(10 mL), and shaken with 5% w/v aq. NaOH (5 mL).

The layers were separated and the aqueous phase extracted with

CH₂Cl₂(3 × 10 mL). The combined organic extracts were

washed successively with 5% w/v aq. NaOH (5 mL) and brine

(5 mL), dried (Na₂SO₄), and concentrated in vacuo. The residue

was puriﬁed by column chromatography (eluting with 50–60%

EtOAc in hexanes) to yield the title compound (7.5 mg, 28

µmol, 50%) as a colourless oil: [α]²_D³Ϫ2.1 (c 1.67, CH₂Cl₂); IR

(neat) 2926, 2854, 1705, 1357, 1255, 1169, 1081, 944, 836, 778

cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 0.09 (s, 3H), 0.11 (s, 3H),

0.87 (s, 9H), 2.18 (d, J = 16 Hz, 1H), 2.77 (dd, J = 16, 4 Hz, 1H),

3.28 (d, J = 13 Hz, 1H), 3.78 (d, J = 3 Hz, 1H), 3.83 (dd, J = 13,

2 Hz, 1H), 3.89 (t, J = 3 Hz, 1H), 4.05 (d, J = 4 Hz, 1H), 4.58 (t,

J = 4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.1, Ϫ4.5, 17.9,

25.6 (3C), 44.3, 46.5, 58.2, 59.6, 68.6, 70.0, 176.5; MS (CI) m/z

270 (M ϩ H)^ϩ, 254, 212, 196; HRMS (CI) m/z 270.1523 (calcd

for C₁₃H₂₄NO₃Si: 270.1526).

(1S,7aS)-1-[(tert-Butyldimethylsilyl)oxy]-2,3,5,7a-tetrahydro-

1H-pyrrolizine (41)

A solution of 34 (5.6 mg, 22 µmol) in THF (2 mL) at rt was

treated with lithium aluminium hydride (7 mg, 0.18 mmol) and

stirred for 4 h, after which Na₂SO₄ؒ10H₂O (250 mg) was added

and the mixture was stirred for a further 15 min. The resulting

suspension was ﬁltered through a Celite pad and the collected

solids were washed with MeOH–CHCl₃(1 : 9, 20 mL). The

ﬁltrate and combined washings were concentrated in vacuo and

the residue was puriﬁed by column chromatography (eluting

with 10% MeOH in CHCl₃) to yield 41 (1.8 mg, 7.5 µmol, 34%)

as a colourless oil: IR (neat) 2950, 2925, 2852, 1461, 1256, 1176,

1

1125, 1062, 931, 840, 783; H NMR (300 MHz, CDCl₃) δ 0.09

(s, 3H), 0.10 (s, 3H), 0.87 (s, 9H), 1.95–2.09 (m, 1H), 2.27 (tdd,

J = 12, 7, 3 Hz, 1H), 3.06 (td, J = 11, 6 Hz, 1H), 3.55–3.69 (m,

1H), 3.95–4.03 (m, 1H), 4.45–4.55 (m, 2H), 4.95–5.02 (m, 1H),

5.65–5.85 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.1, Ϫ4.8,

17.9, 25.6 (3C), 29.8, 36.1, 60.5, 62.8, 70.7, 124.7, 125.0; MS

(CI) m/z 240 (M ϩ H)^ϩ, 238, 224, 182; HRMS (CI) m/z

240.1777 (calcd for C₁₃H₂₆NOSi: 240.1784).

(1R,2R,4S,9S)-9-Hydroxy-3-oxa-6-azatricyclo[4.3.0.0^2,4]nonan-

7-one (38)

(1R,2S,7S,7aS)-7-[(tert-Butyldimethylsilyl)oxy]-1,2-dihydroxy-

hexahydro-1H-pyrrolizin-5-one (42)

To a stirred solution of (1R,2R,4S,9S)-9-[(tert-butyldimethyl-

silyl)oxy]-3-oxa-6-azatricyclo[4.3.0.0^2,4]nonan-7-one prepared

above (2.5 mg, 9.3 µmol) in THF (1 mL) at 0 ЊC was added

a solution of tetra-n-butylammonium ﬂuoride (TBAF, 10 µL,

10 µmol, 1.0M in THF). After stirring at 0 ЊC for 1 h, the

mixture was ﬁltered through a pad of silica gel and the collected

solids were washed with MeOH–CHCl₃(1 : 9, 30 mL). The

ﬁltrate and combined washings were concentrated in vacuo to

give pure 38 (1.4 mg, 9.0 µmol, 97%) as a colourless oil which

crystallized upon standing: ¹H NMR (300 MHz, CDCl₃) δ 2.26

(d, J = 17 Hz, 1H), 2.89 (dd, J = 17, 4 Hz, 1H), 3.28 (d, J = 13

Hz, 1H), 3.87 (dd, J = 13, 2 Hz, 1H), 3.92–3.96 (m, 2H), 4.07 (d,

J = 4 Hz, 1H), 4.66 (t, J = 4 Hz, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 29.7, 44.6, 46.3, 57.7, 59.9, 68.1, 69.3, 176; MS (CI)

m/z 156 (M ϩ H)^ϩ, 155, 154, 140, 138, 126; HRMS (CI) m/z

156.0659 (calcd for C₇H₁₀NO₃: 156.0661).

The oleﬁn 34 (6.5 mg, 26 µmol) was oxidized to 42 (6.6 mg, 23

µmol, 89%) by the same protocol used below for the conversion

of 35 to 43. The crystalline diol 42 exhibited the following

spectral characteristics: ¹H NMR (300 MHz, CDCl₃) δ 0.10 (s,

3H), 0.11 (s, 3H), 0.89 (s, 9H), 2.25 (d, J = 17 Hz, 1H), 2.83 (dd,

J = 17, 5 Hz, 1H), 3.11 (dd, J = 13, 6 Hz, 1H), 3.88 (dd, J = 13, 5

Hz, 1H), 3.98 (t, J = 6 Hz, 1H), 4.27–4.35 (m, 2H), 4.57 (t, J = 5

Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ Ϫ5.0, Ϫ4.7, 18.1, 25.7

(3C), 44.6, 48.0, 68.0, 69.7, 70.1, 73.0, 174.0.

C₁₃H₂₅NO₄Si, M = 287.43, monoclinic, space group C2,

a = 14.546(1), b = 6.262(1), c = 35.155(3) Å, β = 98.72(1)Њ, V =

3165.2(6) Å³, T = 290 K, Z = 8, µ(Cu-Kα) = 1.401 mm^Ϫ1

,

colorless block, crystal dimensions 0.20 × 0.20 × 0.20 mm.

The crystal was oriented from a total of 92 reﬂections with

5.09 < θ < 24.73Њ. A total of 3443 data were measured (5.1

< θ < 67.6Њ), with 3006 independent reﬂections (merging

R_int= 0.046). Full matrix least squares based on F²yielded

the residuals of R1 = 0.0510, wR2 = 0.1329, for 346 reﬁned

parameters and one restraint (ﬂoating origin restraint). The

absolute structure coeﬃcient reﬁned to a value of 0.00(4)

indicating the model presented corresponds to the correct enan-

tiomer of the compound examined.

Ethyl [(1R,2R,4S,9S)-9-hydroxy-7-oxo-3,6-diazatricyclo-

[4.3.0.0^2,4]nonan-3-yl]formate (40)

To a solution of 34 (27.6 mg, 0.11 mmol) in CH₂Cl₂(1 mL) was

added O-ethyl N-(4-nitrophenyl)sulfonyloxycarbamate^23a(39,

95 mg, 0.33 mmol) followed by calcium oxide (18 mg, 0.33

mmol). The mixture was stirred for 8 h at rt and then a further

quantity of 39 (95 mg, 0.33 mmol) and calcium oxide (18 mg,

0.33 mmol) were added. After stirring for an additional 20 h,

the mixture was ﬁltered through a Celite pad and the collected

solids were washed with CH₂Cl₂. The ﬁltrate and combined

washings were concentrated in vacuo and the residue was

puriﬁed by column chromatography (eluting with 66% EtOAc

in hexanes) to yield 12.7 mg of the desired aziridine contam-

inated by some diethyl azodicarboxylate. The crude aziridine

was immediately dissolved in THF (1 mL), and the solution

was cooled to 0 ЊC and treated with tetra-n-butylammonium

ﬂuoride (36 µL, 1.0 M in THF, 36 µmol). After stirring for 2 h,

silica gel was added to the mixture which was concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 10% MeOH in CHCl₃) to give 40 (5.5 mg, 25

µmol, 22% for two steps) as a colourless oil: [α]²_D³ϩ31.5 (c 0.27,

CH₂Cl₂); IR (neat) 3329, 2982, 1694, 1462, 1373, 1252, 1182,

(1R,2S,7S,7aS)-1,2-Dihydroxy-7-(4-methoxybenzyloxy)hexa-

hydro-1H-pyrrolizin-5-one (43)

A stirred solution of 35 (100 mg, 386 µmol) in acetone (5 mL) at

rt was treated with a solution of N-methylmorpholine N-oxide

(137 mg, 1.17 mmol) in H₂O (1 mL) followed by 4 wt% aq.

osmium tetraoxide (0.24 mL, 250 mg, 39 µmol). After stirring

for 30 h, sat. aq. Na₂S₂O₃(5 mL) was added to the mixture

which was vigorously stirred for a further 10 min. The mixture

was diluted with H₂O (10 mL) and CH₂Cl₂(15 mL), and the

layers were shaken and separated. The aqueous phase was

extracted with CH₂Cl₂(3 × 5 mL), and the combined organic

extracts were washed with brine (5 mL), dried (Na₂SO₄), and

concentrated in vacuo. The residue was puriﬁed by column

chromatography (eluting with 7% MeOH in CH₂Cl₂) to give 43

(74 mg, 252 µmol, 65%) as a colourless oil: [α]²_D³ϩ15.4 (c 2.35,

CHCl₃); IR (neat) 1653, 1512, 1440, 1301, 1246, 1173, 1073,

1065 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 1.30 (t, J = 7 Hz,

1

3H), 2.28 (d, J = 17 Hz, 1H), 2.88 (dd, J = 17, 4 Hz), 3.26 (d,

J = 13 Hz, 1H), 3.52 (t, J = 5 Hz, 1H), 3.59 (d, J = 5 Hz, 1H),

3.90 (dd, J = 13, 4 Hz, 1H), 4.08 (d, J = 4 Hz, 1H), 4.19 (q, J = 7

Hz, 2H), 4.64 (t, J = 4 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)

δ 14.3, 42.9, 44.5, 45.7, 45.8, 63.0, 68.2, 69.1, 161.5, 175.5; MS

(CI) m/z 227 (M ϩ H)^ϩ, 197, 154, 138; HRMS (CI) m/z

227.1028 (calcd for C₁₀H₁₅N₂O₄: 227.1032).

1

1030, 823 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 2.48 (d, J = 17

Hz, 1H), 2.76 (dd, J = 17, 5 Hz, 1H), 3.12 (d, J = 13 Hz, 1H),

3.22 (br s, 1H), 3.42 (br s, 1H), 3.77 (d, J = 5 Hz, 1H), 3.80 (s,

3H), 4.04 (dd, J = 6, 6 Hz, 1H), 4.25–4.36 (m, 3H), 4.43 (d,

J = 11 Hz, 1H), 4.52 (d, J = 11 Hz, 1H), 6.87 (d, J = 9 Hz, 2H),

7.23 (d, J = 9 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 41.3, 48.2,

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

1841

View Article Online

55.2, 68.9, 69.2, 71.0, 72.8, 73.1, 113.8 (2C), 129.2 (2C), 129.4,

159.3, 173.8; MS (FAB) m/z 294 (M ϩ H)^ϩ, 148, 121; HRMS

(FAB) m/z 294.1346 (calcd for C₁₅H₂₀NO₅: 294.1342).

CDCl₃) δ 21.7, 32.3, 53.0, 55.3, 55.9, 70.2, 70.7, 73.1, 77.0, 82.1,

113.9 (2C), 127.9 (2C), 129.0 (2C), 129.9 (2C), 130.2, 133.3,

145.0, 159.2; MS (FAB) m/z 434 (M ϩ H)^ϩ, 280, 149, 121;

HRMS (FAB) m/z 434.1634 (calcd for C₂₂H₂₈NO₆S: 434.1637).

(1R,2S,7S,7aS)-1,2-Dihydroxy-7-(4-methoxybenzyloxy)hexa-

hydro-1H-pyrrolizine–borane (44)

(1R,2S,7S,7aR)-1,2-Bis{[(4-methylphenyl)sulfonyl]oxy}-7-

[(4-methoxybenzyl)oxy]hexahydro-1H-pyrrolizine (46). [α]_D²³

ϩ13.2 (c 0.37, CHCl₃); IR (neat) 2919, 1513, 1365, 1176, 1033,

A stirred solution of 43 (74 mg, 252 µmol) in anhydrous THF

(25 mL) at rt under Ar was treated dropwise with borane–

dimethyl sulﬁde complex (0.75 mL, 600 mg, 7.89 mmol). The

resulting mixture was stirred for 4 h and MeOH (10 mL) was

added. After a further 30 min the solvent was removed in vacuo,

and the residue was re-dissolved in MeOH (5 mL). The solution

was again concentrated in vacuo to yield pure 44 (74 mg, 252

µmol, 100%) as a colourless crystalline solid: mp 117–119 ЊC

(CHCl₃); [α]²_D³ϩ35.8 (c 1.20, CHCl₃); IR (KBr) 3460, 2928,

1611, 1513, 1459, 1343, 1303, 1252, 1220, 1158, 1104, 1081,

1034, 955, 825 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 2.02 (ddt,

J = 13, 6, 3 Hz, 1H), 2.20 (dddd, J = 13, 11, 7, 4 Hz, 1H), 2.87

(br s, 1H), 2.98 (td, J = 11, 6 Hz, 1H), 3.08 (br s, 1H), 3.20 (dd,

J = 12, 6 Hz, 1H), 3.31 (ddd, J = 10, 7, 3 Hz, 1H), 3.39 (dd,

J = 12, 7 Hz, 1H), 3.75 (dd, J = 6, 2 Hz, 1H), 3.81 (s, 3H), 4.20–

4.25 (m, 1H), 4.32–4.40 (m, 2H), 4.40 (d, J = 11 Hz, 1H), 4.51

(d, J = 11 Hz, 1H), 6.89 (d, J = 8 Hz, 2H), 7.22 (d, J = 8 Hz,

2H); ¹³C NMR (75 MHz, CDCl₃) δ 30.8, 55.3, 62.7, 66.6, 71.3,

71.7, 72.2, 77.6, 82.0, 113.9 (2C), 129.3 (2C), 129.3, 159.4; MS

(FAB) m/z 292 (M Ϫ H)^ϩ, 280, 162, 148, 121; HRMS (FAB)

m/z 280.1552 (calcd for C₁₅H₂₂NO₄: 280.1549).

1

813, 670, 554 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 1.70 (tdd,

J = 13, 7, 3 Hz, 1H), 2.06 (dd, J = 13, 5 Hz, 1H), 2.42 (s, 6H),

2.42–2.50 (m, 1H), 2.71 (dd, J = 12, 5 Hz, 1H), 3.09 (t, J = 8 Hz,

1H), 3.17 (dd, J = 12, 6 Hz, 1H), 3.66 (t, J = 4 Hz, 1H), 3.84 (s,

3H), 3.89 (t, J = 4 Hz, 1H), 4.26 (d, J = 11 Hz, 1H), 4.45 (d,

J = 11 Hz, 1H), 4.89 (q, J = 5 Hz, 1H), 5.04 (dd, J = 5, 4 Hz,

1H), 6.90 (d, J = 9 Hz, 2H), 7.17 (d, J = 9 Hz, 2H), 7.24 (d,

J = 8 Hz, 2H), 7.25 (d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 4H); ¹³

C

NMR (75 MHz, CDCl₃) δ 21.7 (2C), 32.2, 52.9, 55.3, 55.9, 70.5,

71.3, 76.8, 77.2, 78.4, 113.9 (2C), 128.0 (4C), 129.0 (2C), 129.7

(4C), 130.1, 133.3, 144.8, 159.3; MS (FAB) m/z 588 (M ϩ H)^ϩ,

434, 121; HRMS (FAB) m/z 588.1715 (calcd for C₂₉H₃₄NO₈S₂:

588.1726).

(1R,2S,7S,7aR)-1,2-Bis{[(4-methylphenyl)sulfonyl]oxy}-7-

hydroxyhexahydro-1H-pyrrolizine

A

solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DDQ, 2.3 mg, 10.1 µmol) in CH₂Cl₂(0.5 mL) was added to 46

(3.0 mg, 5.1 µmol) and the mixture was stirred for 3.5 h at rt. At

this time, H₂O (25 µL) was added and stirring was continued for

1.5 h. Solid Na₂SO₄(1 g) was added, and the mixture was

ﬁltered and concentrated in vacuo. The residue was puriﬁed by

column chromatography (eluting with 5% MeOH in CH₂Cl₂) to

yield the title compound (1.9 mg, 4.1 µmol, 80%) as a colourless

oil: [α]²_D³ϩ7.1 (c 0.09, CHCl₃); IR (neat) 2921, 1364, 1190, 1175,

C₁₅H₂₄NO₄B, M = 293.16, orthorhombic, space group

P2₁2₁2₁, a = 8.480(1), b = 9.322(2), c = 20.143(3) Å, V =

1592.3(5) Å³, T = 290 K, Z = 4, µ(Cu-Kα) = 0.702 mm^Ϫ1

,

colorless block, crystal dimensions 0.40 × 0.40 × 0.10 mm. The

crystal was oriented from a total of 65 reﬂections with

7.25 < θ < 26.48Њ.

A total of 3209 data were measured

1

(4.4 < θ < 67.8Њ), with 2654 independent reﬂections (merging

R_int= 0.069). Full matrix least squares based on F²yielded

the residuals of R1 = 0.0447, wR2 = 0.0955, for 214 reﬁned

parameters. The absolute structure coeﬃcient reﬁned to a value

of 0.1(3) indicating the model presented corresponds to the

correct enantiomer of the compound examined.

1031, 813, 554 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 1.91–2.10

(m, 2H), 2.45 (s, 3H), 2.47 (s, 3H), 2.58 (ddd, J = 11, 9, 7 Hz,

1H), 2.73 (dd, J = 12, 4 Hz, 1H), 3.11 (t, J = 8 Hz, 1H), 3.25 (dd,

J = 12, 3 Hz, 1H), 3.73 (dd, J = 5, 5 Hz, 1H), 4.27 (t, J = 4 Hz,

1H), 4.97–5.05 (m, 2H), 7.31 (d, J = 9 Hz, 2H), 7.34 (d, J = 9

Hz, 2H), 7.74 (d, J = 8 Hz, 2H), 7.77 (d, J = 8 Hz, 2H); ¹³C

NMR (75 MHz, CDCl₃) δ 21.7 (2C), 37.2, 52.6, 56.6, 69.3, 70.9,

75.6, 81.0, 128.0 (2C), 129.8, 129.9, 132.9, 133.5, 144.9, 145.3;

MS (FAB) m/z 468 (M ϩ H)^ϩ, 314; HRMS (FAB) m/z 468.1156

(calcd for C₂₁H₂₆NO₇S₂: 468.1151).

Tosylation of 44

A solution of 44 (18 mg, 61.4 µmol) and Et₃N (43 µL, 31 mg,

0.31 mmol) in anhydrous CH₂Cl₂(2.5 mL) at rt under Ar was

treated with toluene-4-sulfonyl chloride (23 mg, 0.12 mmol)

and stirred for 44 h. The mixture was diluted with additional

CH₂Cl₂(5 mL) and shaken with sat. aq. NaHCO₃(10 mL). The

layers were separated and the aqueous phase was extracted

with CH₂Cl₂(3 × 5 mL). The combined organic extracts

were washed with sat. aq. NaHCO₃–H₂O (1 : 1, 5 mL), dried

(Na₂SO₄), and concentrated in vacuo. The residue (31 mg) was

dissolved in MeOH (5 mL), treated with Pearlman’s catalyst (40

mg, 20 wt% Pd, 50% wetted), and stirred for 30 h. After ﬁltra-

tion through a Celite pad, the ﬁltrate was concentrated in vacuo

and the residue puriﬁed by column chromatography (eluting

with 3–10% MeOH in CH₂Cl₂) to yield, in order of elution, the

ditosylate 46 (7.5 mg, 12.8 µmol, 21%) and monotosylate 45

(15.3 mg, 35.3 µmol, 57%), both as colourless oils.

[(3S,4S,6S,9R)-5-Oxa-1-azatricyclo[4.2.1.0^4,9]nonan-3-yl]

4-methylbenzenesulfonate (47)

A solution of the alcohol prepared above (2.3 mg, 4.9 µmol) in

MeOH–H₂O (5 : 1, 1.2 mL) was treated with K₂CO₃(2.7 mg, 20

µmol) and the mixture was stirred at a gentle reﬂux for 5 h. The

mixture was allowed to cool and was concentrated in vacuo. The

residue was taken up into CH₂Cl₂(5 mL) and H₂O (5 mL), and

the layers were shaken and separated. The aqueous phase was

extracted with CH₂Cl₂(3 × 3 mL), and the combined organic

extracts were washed with brine (5 mL), dried (Na₂SO₄), and

concentrated in vacuo. The crude oil was puriﬁed by column

chromatography (eluting with 5% MeOH in CH₂Cl₂) to furnish

47 (1.1 mg, 3.7 µmol, 76%) as a colourless oil: IR (neat) 2915,

1

1366, 1176, 973, 834, 554 cm^Ϫ1; H NMR (300 MHz, CDCl₃,

(1R,2S,7S,7aS)-1-Hydroxy-7-[(4-methoxybenzyl)oxy]-2-{[(4-

methylphenyl)sulfonyl]oxy}hexahydro-1H-pyrrolizine (45). [α]_D²³

ϩ6.2 (c 0.33, CHCl₃); IR (neat) 2931, 1513, 1359, 1247, 1175,

loline numbering is used for assignment) δ 1.84 (dtd, J = 15, 8, 4

Hz, 1H, H6_A), 2.00 (ddd, J = 15, 7, 5 Hz, 1H, H6_B), 2.46 (s, 3H,

Ts), 2.95 (dt, J = 11, 7 Hz, 1H, H5_A), 3.10 (dd, J = 13, 5 Hz, 1H,

H3_A), 3.24 (ddd, J = 11, 8, 4 Hz, 1H, H5_B), 3.45 (dd, J = 13, 6

Hz, 1H, H3_B), 4.18 (t, J = 3 Hz, 1H, H8), 4.84 (d, J = 3 Hz, 1H,

H1), 4.92 (t, J = 5 Hz, 1H, H2), 5.05 (t, J = 4 Hz, 1H, H7), 7.36

(d, J = 8 Hz, 2H, Ts), 7.79 (d, J = 8 Hz, 2H, Ts); ¹³C NMR (75

MHz, CDCl₃) δ 21.7, 33.8, 55.1, 60.7, 68.6, 83.5, 83.9,

84.4, 127.9 (2C), 130.0 (2C), 133.2, 145.1; MS (FAB) m/z 296

(M ϩ H)^ϩ, 142; HRMS (FAB) m/z 296.0961 (calcd for

C₁₄H₁₈NO₄S: 296.0957).

1

1034, 815, 667 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 1.72–1.85

(m, 1H), 2.05 (dd, J = 13, 6 Hz, 1H), 2.10–2.25 (m, OH), 2.43 (s,

3H), 2.50 (ddd, J = 12, 9, 6 Hz, 1H), 2.73 (dd, J = 12, 5 Hz), 3.09

(t, J = 8 Hz, 1H), 3.17 (dd, J = 12, 6 Hz, 1H), 3.50 (t, J = 4 Hz,

1H), 3.82 (s, 3H), 4.00 (t, J = 4 Hz, 1H), 4.37 (d, J = 11 Hz, 1H),

4.43 (t, J = 4 Hz, 1H), 4.50 (d, J = 11 Hz, 1H), 4.95 (q, J = 5 Hz,

1H), 6.90 (d, J = 9 Hz, 2H), 7.22 (d, J = 9 Hz, 2H), 7.28 (d,

J = 10 Hz, 2H), 7.76 (d, J = 10 Hz, 2H); ¹³C NMR (75 MHz,

1842

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

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1

Deprotection of 45

1328, 1246, 1157, 1091, 815, 678, 565 cm^Ϫ1; H NMR (300

MHz, CDCl₃) δ 2.41 (s, 3H), 2.46 (d, J = 17 Hz, 1H), 2.72 (dd,

J = 17, 5 Hz, 1H), 3.10 (d, J = 13 Hz, 1H), 3.75 (dd, J = 13,

6 Hz, 1H), 3.80–3.84 (m, 1H), 3.83 (s, 3H), 4.07 (dd, J = 8, 5 Hz,

1H), 2.10 (t, J = 5 Hz, 1H), 4.22–4.27 (m, 1H), 4.31 (d, J = 11

Hz, 1H), 4.39 (d, J = 11 Hz, 1H), 5.23 (br d, J = 7 Hz, NH), 6.89

(d, J = 9 Hz, 2H), 7.20 (d, J = 9 Hz, 2H), 7.22 (d, J = 8 Hz, 2H),

7.69 (d, J = 8 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 21.6, 40.6,

49.3, 53.3, 55.3, 67.7, 70.9, 72.0, 72.8, 113.9 (2C), 127.2 (2C),

129.3, 129.5 (2C), 129.9 (2C), 136.4, 144.0, 159.4, 173.4; MS

(FAB) m/z 469 (M ϩ Na)^ϩ, 447 (M ϩ H)^ϩ, 121; HRMS (FAB)

m/z 447.1591 (calcd for C₂₂H₂₇N₂O₆S: 447.1590).

A solution of 45 (4.0 mg, 9.2 µmol) in MeCN–H₂O (5 : 1, 1.2

mL) at rt was treated with ceric ammonium nitrate (CAN, 30

mg, 55 µmol) and the mixture was stirred for 21 h. A further

quantity of CAN (10 mg, 18 µmol) was added and stirring was

continued for 2 h. The mixture was diluted with CH₂Cl₂

(10 mL) and shaken with sat. aq. NaHCO₃(5 mL). The layers

were separated and the aqueous phase was extracted with

CH₂Cl₂(3 × 5 mL). The combined organic extracts were

washed with brine (5 mL), dried (Na₂SO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 5–15% MeOH in CH₂Cl₂) to aﬀord, in order of

elution, 49 (1.0 mg, 2.2 µmol, 24%) followed by 48 (1.0 mg, 3.2

µmol, 35%), both as colourless oils.

N-[(1R,2S,7S,7aS)-1-Hydroxy-7-(4-methoxybenzyloxy)-5-

oxohexahydro-1H-pyrrolizin-2-yl]-4-methylbenzenesulfonamide

(51). [α]²_D³Ϫ16.6 (c 1.16, CHCl₃); IR (neat) 2917, 1670, 1336,

(1R,2S,7S,7aR)-1,7-Dihydroxy-2-{[(4-methylphenyl)sulfonyl]-

oxy}hexahydro-1H-pyrrolizine (48). [α]²_D³ϩ5.9 (c 0.09, CHCl₃);

1246, 1160, 1091, 1031, 815, 680 cm ^Ϫ1; H NMR (300 MHz,

1

CDCl₃) δ 2.42 (s, 3H), 2.45 (d, J = 17 Hz, 1H), 2.63 (dd, J = 17,

5 Hz, 1H), 2.80 (dd, J = 12, 9 Hz, 1H), 3.52–3.58 (m, 1H), 3.82–

3.86 (m, 1H), 3.83 (s, 3H), 3.94 (dd, J = 5, 3 Hz, 1H), 4.26 (t,

J = 5 Hz, 1H), 4.27 (d, J = 11 Hz, 1H), 4.40 (dd, J = 6, 3 Hz,

1H), 4.49 (d, J = 11 Hz, 1H), 4.98–5.03 (m, NH), 6.91 (d, J = 7

Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 7.21 (d, J = 8 Hz, 2H), 7.66 (d,

J = 8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.5, 39.4, 45.4,

55.3, 56.0, 69.1, 70.4, 71.4, 74.3, 113.9 (2C), 127.1 (2C), 129.2

(2C), 129.3, 129.9 (2C), 136.5, 143.9, 159.4, 175.0; MS (FAB)

m/z 447 (M ϩ H)^ϩ, 121; HRMS (FAB) m/z 447.1593 (calcd for

C₂₂H₂₇N₂O₆S: 447.1590).

IR (neat) 2914, 1352, 1174, 1018, 910, 814, 670, 554 cm^Ϫ1; H

1

NMR (300 MHz, CDCl₃) δ 1.85–1.92 (m, 1H), 1.98 (ddd,

J = 12, 8, 4 Hz, 1H), 2.46 (s, 3H), 2.60 (ddd, J = 11, 9, 6 Hz,

1H), 2.78 (dd, J = 12, 5 Hz, 1H), 3.13 (tm, J = 7 Hz, 1H), 3.21

(dd, J = 12, 5 Hz, 1H), 3.47 (t, J = 5 Hz, 1H), 4.37 (td, J = 4, 1

Hz, 1H), 4.44 (t, J = 6 Hz, 1H), 5.05 (q, J = 5 Hz, 1H), 7.36 (d,

J = 8 Hz, 2H), 7.84 (d, J = 8 Hz, 1H); ¹³C NMR (75 MHz,

CDCl₃) δ 21.7, 36.9, 52.8, 56.2, 70.0, 73.6, 82.7, 128.0 (2C),

130.0 (2C), 133.3, 145.2; MS (FAB) m/z 314 (M ϩ H)^ϩ, 154,

136; HRMS (FAB) m/z 314.1058 (calcd for C₁₄H₂₀NO₅S:

314.1062).

N-[(1R,2S,7S,7aS)-2-Hydroxy-7-(4-methoxybenzyloxy)-5-oxo-

hexahydro-1H-pyrrolizin-1-yl]-4,N-dimethylbenzenesulfonamide

(52)

(1R,2S,7S,7aS)-1-Hydroxy-7-[(4-methoxybenzoyl)oxy]-2-

{[(4-methylphenyl)sulfonyl]oxy}hexahydro-1H-pyrrolizine (49).

IR (neat) 2911, 2845, 1714, 1604, 1360, 1256, 1174, 1097, 1022,

1

769 cm^Ϫ1; H NMR (300 MHz, CDCl₃) δ 2.12–2.18 (m, 2H),

A solution of 50 (62 mg, 139 µmol) in t-BuOH (4 mL) at rt was

treated with potassium tert-butoxide (20 mg, 180 µmol), and the

mixture was stirred for 15 min. Methyl iodide (0.17 mL, 388

mg, 2.73 mmol) was added and the solution was heated at

50 ЊC. After 16 h the solution was allowed to cool, and H₂O (10

mL) and CH₂Cl₂(15 mL) were added. The layers were shaken

and separated, and the aqueous phase was extracted with

CH₂Cl₂(3 × 5 mL). The combined organic extracts were

washed with brine (5 mL), dried (Na₂SO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 5% MeOH in CH₂Cl₂) to yield 52 (48.5 mg, 105

µmol, 76%) as a clear oil: [α]²_D³ϩ49.0 (c 0.55, CHCl₃); IR (neat)

2.44 (s, 3H), 2.63 (q, J = 9 Hz, 1H), 2.87 (dd, J = 12, 5 Hz, 1H),

3.20–3.27 (m, 1H), 3.30 (dd, J = 12, 5 Hz, 1H), 3.73 (t, J = 5 Hz,

1H), 3.89 (s, 3H), 4.24 (t, J = 4 Hz, 1H), 5.12 (q, J = 5 Hz, 1H),

5.48 (dt, J = 5, 3 Hz, 1H), 6.96 (d, J = 7 Hz, 2H), 7.30 (d, J = 8

Hz, 2H), 7.79 (d, J = 8 Hz, 2H), 7.97 (d, J = 8 Hz, 2H); ¹³C

NMR (75 MHz, CDCl₃, quaternary carbons not observed)

δ 21.7, 34.3, 53.1, 55.5, 55.7, 70.5, 72.2, 73.7, 81.8, 113.9 (2C),

127.9 (2C), 129.9 (2C), 131.7 (2C); MS (FAB) m/z 448

(M ϩ H)^ϩ, 294, 135; HRMS (FAB) m/z 448.1489 (calcd for

C₂₂H₂₆NO₇S: 448.1430).

Aminohydroxylation of 35 (Table 2, entry 4)

3373, 2929, 1687, 1514, 1335, 1249, 1155, 1088, 1032, 817 cm^Ϫ1

;

¹H NMR (300 MHz, CDCl₃) δ 2.40 (s, 3H), 2.48 (d, J = 17 Hz,

1H), 2.64 (dd, J = 17, 5 Hz, 1H), 2.76–2.79 (m, 1H), 2.89 (s,

3H), 3.12 (dd, J = 13, 3 Hz, 1H), 3.82 (s, 3H), 3.85 (dd, J = 13, 6

Hz, 1H), 3.94 (t, J = 5 Hz, 1H), 4.09 (dd, J = 8, 5 Hz, 1H), 4.10

(d, J = 11 Hz, 1H), 4.21 (dd, J = 8, 5 Hz, 1H), 4.30 (d, J = 12 Hz,

1H), 4.60–4.66 (m, 1H), 6.84 (d, J = 9 Hz, 2H), 6.99 (d, J = 9

Hz, 2H), 7.25 (d, J = 8 Hz, 2H), 7.65 (d, J = 8 Hz, 2H); ¹³C

NMR (75 MHz, CDCl₃) δ 21.6, 34.2, 39.8, 48.2, 55.3, 58.2,

65.0, 69.9, 72.8, 73.7, 113.9 (2C), 127.6 (2C), 128.7, 129.5 (2C),

129.8 (2C), 134.4, 144.0, 159.5, 172.7; MS (FAB) m/z 461

(M ϩ H)^ϩ, 121; HRMS (FAB) 461.1740 (calcd for C₂₃H₂₉-

N₂O₆S: 461.1746).

A stirred solution of 35 (39.1 mg, 151 µmol) and (DHQD)₂-

PHAL (29 mg, 38 µmol, 25 mol%) in t-BuOH–H₂O (1 : 1, 3.5

mL) at rt was treated with chloramine-T dihydrate (99 mg, 376

µmol, 2.5 eq.). Potassium osmate was added in three equal

portions of 0.6 mg (1.6 µmol, 1 mol%) at 24 h intervals and

after addition of the ﬁnal portion, the mixture was stirred for a

further 24 h. Sat. aq. NaHSO₃(5 mL) was added and the

mixture was stirred vigorously for 15 min. The mixture was

diluted with H₂O (5 mL) and CH₂Cl₂(10 mL), and the resultant

layers were shaken and separated. The aqueous phase was

extracted with CH₂Cl₂(3 × 5 mL), and the extract was washed

with brine (5 mL), dried (Na₂SO₄), and concentrated in vacuo.

The residue was puriﬁed by column chromatography (eluting

with 5–10% MeOH in CH₂Cl₂) to aﬀord, in order of elution,

a mixture of sulfonamides 50 and 51 (35.2 mg, 79 µmol, 52%,

colourless oil) followed by 43 (9.5 mg, 32 µmol, 21%, colourless

oil). ¹H NMR analysis of the mixture of sulfonamides indicated

a ratio 50 : 51 = 75 : 25. The isomers could be separated by

careful column chromatography (eluting with 5% MeOH in

CH₂Cl₂) with 51 eluting ﬁrst.

{(1R,2S,7S,7aS)-7-(4-Methoxybenzyloxy)-1-[methyl(4-tolyl-

sulfonyl)amino]-5-oxohexahydro-1H-pyrrolizin-2-yl} methane-

sulfonate (53)

To a stirred solution of 52 (48.5 mg, 105 µmol) in anhydrous

CH₂Cl₂(5 mL) at 0 ЊC under Ar, was added Et₃N (50 µL, 36 mg,

359 µmol) followed by methanesulfonyl chloride (16 µL, 24 mg,

207 µmol) using dropwise addition. After stirring for 15 min,

the mixture was shaken with sat. aq. NaHCO₃(5 mL), and the

layers were separated. The aqueous phase was extracted with

CH₂Cl₂(3 × 5 mL), and the combined organic extracts were

washed with brine (5 mL), dried (Na₂SO₄), and concentrated

N-[(1R,2S,7S,7aS)-2-Hydroxy-7-(4-methoxybenzyloxy)-5-

oxohexahydro-1H-pyrrolizin-1-yl]-4-methylbenzenesulfonamide

(50). [α]²_D³Ϫ15.4 (c 0.07, CHCl₃); IR (neat) 1667, 1513, 1435,

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

1843

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in vacuo to yield pure 53 (56 mg, 104 µmol, 99%) as a colourless

solid: mp 187–190 ЊC (decomp.); [α]²_D³ϩ66.1 (c 0.70, CHCl₃); IR

(KBr) 2928, 1696, 1517, 1350, 1247, 1166, 1071, 981, 907, 679,

548 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H), 2.46 (d,

J = 17 Hz, 1H), 2.61 (dd, J = 17, 5 Hz, 1H), 2.88 (s, 3H), 3.14 (s,

3H), 3.44 (dd, J = 14, 2 Hz, 1H), 3.81 (s, 3H), 3.94 (t, J = 5 Hz,

1H), 4.04 (dd, J = 14, 6 Hz, 1H), 4.09 (d, J = 12 Hz, 1H), 4.22

(dd, J = 9, 5 Hz, 1H), 4.24 (d, J = 12 Hz, 1H), 4.56 (dd, J = 9, 6

Hz, 1H), 5.35 (td, J = 5, 3 Hz, 1H), 6.83 (d, J = 9 Hz, 2H), 6.93

(d, J = 9 Hz, 2H), 7.26 (d, J = 8 Hz, 2H), 7.68 (d, J = 8 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃) δ 21.5, 33.0, 38.4, 39.4, 47.9, 55.3,

56.2, 64.1, 69.7, 71.3, 83.0, 114.0 (2C), 127.5 (2C), 128.3, 129.5

(2C), 129.8 (2C), 135.5, 144.0, 159.6, 172.7; MS (FAB) m/z 534

(M ϩ H)^ϩ, 185, 121; HRMS (FAB) m/z 539.1517 (calcd for

C₂₄H₃₁N₂O₈S₂: 539.1522).

Hz, 1H), 3.03 (s, 3H), 3.05 (s, 3H), 3.14 (tm, J = 9 Hz, 1H), 3.34

(dd, J = 12, 2 Hz, 1H), 3.60 (dd, J = 8, 4 Hz, 1H), 3.99–4.03 (m,

1H), 4.64 (dd, J = 8, 5 Hz, 1H), 5.15 (dd, J = 5, 2 Hz, 1H), 7.33

(d, J = 8 Hz, 2H), 7.76 (d, J = 8Hz, 2H); ¹³C NMR (100 MHz,

CDCl₃) δ 21.5, 32.1, 37.3, 38.6, 52.5, 55.4, 59.6, 67.7, 69.7, 85.3,

127.3 (2C), 129.8 (2C), 136.0, 143.9; MS (FAB) m/z 405

(M ϩ H)^ϩ; HRMS (FAB) m/z 405.1158 (calcd for C₁₆H₂₅-

N₂O₆S₂: 405.1154).

C₁₆H₂₄N₂O₆S₂, M = 404.49, tetragonal, space group P4₁,

a = 9.649(1), c = 20.808(3) Å, V = 1937.3(3) Å³, T = 290 K,

Z = 4, µ(Cu-Kα) = 2.801 mm^Ϫ1, colorless block, crystal dimen-

sions 0.40 × 0.10 × 0.10 mm. The crystal was oriented from a

total of 40 reﬂections with 12.12 < θ < 36.35Њ. A total of 4372

data were measured (5.6 < θ < 67.6Њ), with 1912 independent

reﬂections (merging R_int= 0.108). Full matrix least squares

based on F²yielded the residuals of R1 = 0.0665, wR2 = 0.180,

for 236 reﬁned parameters and one restraint (ﬂoating origin).

The absolute structure coeﬃcient reﬁned to a value of Ϫ0.04(3)

indicating the model presented corresponds to the correct enan-

tiomer of the compound examined.

{(1R,2S,7S,7aS)-7-(4-Methoxybenzyloxy)-1-[methyl(4-tolylsulf-

onyl)amino]hexahydro-1H-pyrrolizin-2-yl} methanesulfonate

(54)

A stirred solution of 53 (21.2 mg, 39.4 µmol) in anhydrous THF

(10 mL) at rt under Ar, was treated with a large excess of

borane–dimethyl sulﬁde complex (0.12 mL, 10 M neat, 1.2

mmol, 30 eq.). The solution was stirred for 5 h, MeOH (5 mL)

was added, and the solution was concentrated in vacuo. The

residual oil was redissolved in MeOH (5 mL), and palladium

hydroxide on carbon (25 mg, 20 wt% Pd content) was added.

After stirring at rt for 14 h, the suspension was ﬁltered through

a Celite pad and the ﬁltrate was concentrated in vacuo. The

residual oil was puriﬁed by column chromatography (eluting

with 2.5 to 5% MeOH in CH₂Cl₂) to give 54 (15.0 mg, 28.6

µmol, 73%) as a clear oil: [α]²_D³ϩ73.3 (c 0.51, CHCl₃); IR (neat)

2933, 1705, 1610, 1519, 1334, 1248, 1177, 1029, 920, 810, 663,

549 cm^Ϫ1; ¹H NMR (300 MHz, CDCl₃) δ 1.70 (dddd, J = 14, 11,

8, 4 Hz, 1H), 2.10 (ddm, J = 14, 6 Hz, 1H), 2.39 (s, 3H), 2.57

(ddd, J = 11, 10, 6 Hz, 1H), 2.91 (dd, J = 12, 5 Hz, 1H), 2.92 (s,

3H), 3.08 (s, 3H), 3.09–3.15 (m, 1H), 3.31 (dd, J = 12, 4 Hz,

1H), 3.32 (t, J = 5 Hz, 1H), 3.55 (t, J = 4 Hz, 1H), 3.82 (s, 3H),

4.22 (d, J = 12 Hz, 1H), 4.49 (d, J = 12 Hz, 1H), 4.90 (t, J = 6

Hz, 1H), 5.23 (td, J = 6, 4 Hz, 1H), 6.93 (d, J = 9 Hz, 2H), 7.18

(d, J = 8 Hz, 2H), 7.23 (d, J = 9 Hz, 2H), 7.57 (d, J = 8 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃) δ 21.5, 31.9, 32.2, 38.4, 52.7, 55.3,

55.8, 59.7, 68.2, 70.1, 83.4, 114.0 (2C), 127.2 (2C), 129.0 (2C),

129.6 (2C), 129.9, 136.1, 143.4, 159.3; MS (FAB) m/z 525

(M ϩ H)^ϩ, 121; HRMS (FAB) m/z 525.1722 (calcd for

C₂₄H₃₃N₂O₇S₂: 525.1729).

(7S)-7-Hydroxy-1-{methyl[(4-methylphenyl)sulfonyl]amino}-

5,6,7,7a-tetrahydro-3H-pyrrolizine (56)

A stirred solution of 55 (1.6 mg, 4.0 µmol) in anhydrous THF

(0.5 mL) at 0 ЊC under Ar, was treated with potassium hexa-

methyldisilazane (0.14 mL, 0.056 M in THF–toluene, 8 µmol).

After 20 min, the reaction was quenched by the addition of

H₂O (5 mL) and the mixture was diluted with CH₂Cl₂(5 mL).

The layers were shaken and separated, and the aqueous phase

was extracted with CH₂Cl₂(3 × 2 mL). The combined organic

extracts were washed with brine (5 mL), dried (Na₂SO₄), and

concentrated in vacuo to yield 56 (∼0.9 mg, 2.8 µmol, 70%) as a

colourless oil: IR (neat) 2917, 1345, 1159, 1095, 809, 687, 547

cm^Ϫ1; ¹H NMR (400 MHz, CDCl₃) δ 1.95–2.02 (m, 2H), 2.43 (s,

3H), 2.76 (ddd, J = 11, 9, 7 Hz, 1H), 3.02 (s, 3H), 3.24 (ddd,

J = 9, 6, 3 Hz, 1H), 3.35 (ddd, J = 15, 5, 2 Hz, 1H), 3.83 (dt,

J = 15, 2 Hz, 1H), 4.55–4.61 (m, 2H), 5.08 (q, J = 2 Hz, 1H),

7.32 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H); ¹³C NMR (100

MHz, CDCl₃) δ 21.6, 35.2, 37.6, 54.7, 60.9, 71.8, 116.4, 127.2,

127.6 (2C), 129.8 (2C), 137.7, 144.2; MS (FAB) m/z 309

(M ϩ H)^ϩ, 185, 93; HRMS (FAB) m/z 309.1276 (calcd for

C₁₅H₂₁N₂O₃S: 309.1273).

N-Tosylloline (57)

A. From 55. A stirred solution of 55 (4.1 mg, 10.1 µmol) in

1,2-dichlorobenzene (1 mL) under Ar was heated at a gentle

reﬂux for 22 h. The resulting black mixture was allowed to cool

to rt and partitioned between CH₂Cl₂(5 mL) and 10% w/v aq.

NaOH (5 mL). The layers were shaken and separated, and the

aqueous phase was extracted with CH₂Cl₂(2 × 5 mL). The

combined organic extracts were washed with brine (5 mL),

dried (Na₂SO₄), and concentrated in vacuo. The residue was

puriﬁed by column chromatography (eluting with 10% MeOH

in CH₂Cl₂) to yield 57 (2.3 mg, 7.5 µmol, 74%) as a clear oil: [α]_D²³

ϩ40.9 (c 0.11, CHCl₃); IR (neat) 2921, 1458, 1368, 1168, 1096,

{(1R,2S,7S,7aS)-7-Hydroxy-1-[methyl(4-tolylsulfonyl)amino]-

hexahydro-1H-pyrrolizin-2-yl} methanesulfonate (55)

A stirred biphasic solution of 54 (10.2 mg, 19.4 µmol) in

CH₂Cl₂–H₂O (20 : 1, 2.1 mL) at rt was treated with 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 9 mg, 40 µmol).

After stirring of the mixture for 22 h, TLC analysis indicated

that the reaction was only ca. 40% complete. Additional

quantities of DDQ (9 mg) and H₂O (0.1 mL) were added at this

time, and a further quantity of DDQ (5 mg) was added after a

further 26 h. After an additional 16 h, TLC analysis indicated

complete consumption of 54. The mixture was partitioned

between sat. aq. NaHCO₃(10 mL) and CH₂Cl₂(5 mL), and the

layers shaken and separated. The aqueous phase was extracted

with CH₂Cl₂(3 × 5 mL), and the combined organic extracts

were washed successively with half-saturated aq. NaHCO₃

(10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated

in vacuo. The crude residue was puriﬁed by column chrom-

atography (eluting with 10% MeOH in CH₂Cl₂) to aﬀord 55

(5.5 mg, 13.6 µmol, 70%) as a colourless crystalline solid: mp

175 ЊC (decomp.) (CH₂Cl₂); [α]²_D³ϩ45.8 (c 0.28, CHCl₃); IR

(neat) 3415, 2956, 1333, 1254, 1170, 1092, 1041, 948, 823, 790,

1

1023, 957, 812, 661, 546 cm^Ϫ1; H NMR (300 MHz, CDCl₃)

δ 1.92 (dddd, J = 14, 9, 4, 4 Hz, 1H), 2.06 (ddd, J = 14, 9, 7 Hz),

2.44 (s, 3H), 2.46 (dm, J ≈ 10 Hz, 1H), 2.90 (s, 3H), 2.94 (ddd,

J = 13, 9, 7 Hz, 1H), 3.10 (ddd, J = 12, 8, 3 Hz, 1H), 3.12 (t,

J = 2 Hz, 1H), 3.29–3.31 (m, 1H), 3.71 (dd, J = 11, 1 Hz, 1H),

4.32 (dd, J = 5, 2 Hz, 1H), 4.59 (dm, J = 2 Hz, 1H), 7.36 (d,

J = 8Hz, 2H), 7.71 (d, J = 8 Hz, 2H); ¹³C NMR (100 MHz,

CDCl₃) δ 21.6, 33.5, 35.6, 54.9, 61.5, 65.6, 69.9, 76.4, 81.0, 128.0

(2C), 129.8 (2C), 132.4, 143.9; MS (FAB) m/z 309 (M ϩ H)^ϩ;

HRMS (FAB) m/z 309.1267 (calcd for C₁₅H₂₁N₂O₃S: 309.1273).

B. From loline (1). A stirred solution of loline dihydro-

chloride (1.9 mg, 8.4 µmol) in CHCl₃(1 mL) was treated with

Et₃N (6 µL, 4.4 mg, 44 µmol) followed by toluene-4-sulfonyl

1

656 cm^Ϫ1; H NMR (400 MHz, CDCl₃) δ 1.98–2.10 (m, 2H),

2.44 (s, 3H), 2.65 (ddd, J = 12, 9, 6 Hz, 1H), 2.84 (dd, J = 12, 4

1844

J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

View Article Online

20, 1040; (e) E. K. Batirov, S. A. Khanidkhodzhaev, V. M. Malikov

chloride (3.2 mg, 17 µmol). After stirring of the solution for 1 d,

additional quantities of Et₃N (10 µL, 73 µmol) and toluene-

4-sulfonyl chloride (6 mg, 31 µmol) were added together with

4-(dimethylamino)pyridine (DMAP, 1 mg, 8 µmol). After

stirring for a further 1 d, the mixture was diluted with CH₂Cl₂

(5 mL) and shaken with 10% w/v aq. NaOH (5 mL). The layers

were separated and the aqueous phase was extracted with

CH₂Cl₂(3 × 2 mL). The combined organic extracts were

washed with brine (5 mL), dried (Na₂SO₄), and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(eluting with 10% MeOH in CH₂Cl₂) to yield N-tosylloline (57,

2.0 mg, 6.5 µmol, 77%) as a colourless oil: [α]²_D³ϩ38.0 (c 0.10,

CHCl₃). Spectral properties (¹H NMR, ¹³C NMR and IR) were

identical to those obtained for 57 prepared from 55.

and Y. S. Yunusov, Chem. Nat. Compd. (Engl. Transl.), 1976, 12, 50.

7 B. Tofern, M. Kaloga, L. Witte, T. Hartmann and E. Eich,

Phytochemistry, 1999, 51, 1177.

8 (a) A. J. Aasen and C. C. Culvenor, Aust. J. Chem., 1969, 22, 2021;

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12 For a recent review of the pharmacology and chemistry of loline

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13 C. T. Dougherty, F. W. Knapp, L. P. Bush, J. E. Mail and

J. Van Willigen, J. Med. Entomol., 1998, 35, 798.

Loline dihydrochloride

A solution of 57 (4.5 mg, 15 µmol) in anhydrous DME (1 mL)

at Ϫ60 ЊC under Ar was treated dropwise with a freshly

prepared solution of sodium naphthalenide (0.7 mL, ca. 0.25 M

in DME) until a green colour persisted. After 20 min, the reac-

tion was quenched with 1.5 M aq. HCl (2 mL) and was allowed

to warm to rt. The mixture was diluted with H₂O (3 mL) and

washed with Et₂O (4 × 3 mL). The aqueous phase was made

basic (pH 12) with 10% w/v aq. NaOH and extracted with

CHCl₃(6 × 4 mL). The resulting solution of 1 in CHCl₃

was dried (Na₂SO₄), treated with methanolic HCl (3 mL,

half-saturated), and concentrated in vacuo to yield loline di-

hydrochloride (1.6 mg, 48%) as a colourless oil. Spectral data

are given in Tables 3 and 4.

14 For a preliminary account of this work see P. R. Blakemore, V. K.

Schulze and J. D. White, Chem. Commun., 2000, 1263.

15 (a) G. E. Keck and D. R. Romer, J. Org. Chem., 1993, 58, 6083; (b) C.

Kibayashi and S. Aoyagi, Synlett, 1995, 873; (c) H. Abe, S. Aoyagi

and C. Kibayashi, Tetrahedron Lett., 2000, 41, 1205; (d ) T. Ozawa,

S. Aoyagi and C. Kibayashi, J. Org. Chem., 2001, 66, 3338.

16 (a) G. E. Keck, Tetrahedron Lett., 1978, 4767; (b) G. E. Keck and

D. G. Nickell, J. Am. Chem. Soc., 1980, 102, 3632.

17 M. E. Maier, B.-V. Haller, R. Stumpf and H. Fisher, Synlett, 1993,

863.

18 S. B. Balkrishna, W. E. Childers and H. W. Pinnick, Tetrahedron,

1981, 37, 2091.

19 M. Naruse, S. Aoyagi and C. Kibayashi, J. Org. Chem., 1994, 59,

1358.

20 S. Hanessian, A. Ugolini, D. Dubé and A. Glamyan, Can. J. Chem.,

1984, 62, 2146.

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Lett., 1991, 32, 533.

23 (a) W. Lwowski and J. Maricich, J. Am. Chem. Soc., 1965, 87, 3630;

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24 B. A. Hanson and J. D. White, J. Am. Chem. Soc., 1988, 110, 6314.

25 K. B. Sharpless, A. O. Chong and K. Oshima, J. Org. Chem., 1976,

41, 177; E. Herranz and K. B. Sharpless, J. Org. Chem., 1978, 43,

2544.

26 G. Li, H.-T. Chang and K. B. Sharpless, Angew. Chem., Int. Ed.

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Chem., Int. Ed. Engl., 1997, 36, 2637.

27 For a recent review of the asymmetric aminohydroxylation and its

use in synthesis, see P. O’Brien, Angew. Chem., Int. Ed., 1999, 38,

326.

28 J.-E. Bäckvall, K. Oshima, R. E. Palermo and K. B. Sharpless,

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29 R. J. Petroski, S. G. Yates, D. Weisleder and R. G. Powell, J. Nat.

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30 XSCANS version 2.2. Serial Diﬀractometer Control and Data

Collection Program, Siemens Analytical X-ray Instruments Inc.,

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Acknowledgements

We are grateful to Professor Lowell P. Bush, University of

Kentucky, for a sample of loline dihydrochloride, and to

Professor Joseph J. Tufariello, State University of New York

at Buﬀalo, for the NMR spectra of ( )-loline and its dihydro-

chloride. V.K.S. thanks the Deutsche Forschungsgemeinschaft

for a Fellowship. Financial support was provided by the US

National Institutes of Health through grant GM58889.

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J. Chem. Soc., Perkin Trans. 1, 2001, 1831–1845

1845

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Asymmetric synthesis of (+)-loline

DOI: 10.1039/b103936a

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