Spirocyclic systems derived from pyroglutamic acid

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Spirocyclic systems derived from pyroglutamic acid†

Andrew R. Cowley,^aThomas J. Hill,^aPetr Kocis,^bMark G. Moloney,*^aRobert D. Stevenson^aand

Amber L. Thompson^a

Received 4th May 2011, Accepted 8th July 2011

DOI: 10.1039/c1ob05708a

The synthesis and likely conformational structure of rigid spirocyclic bislactams and lactam-lactones

derived from pyroglutamic acid, and their suitability as lead structures for applications in drug

development programmes using cheminformatic analysis, has been investgated.

The re-examination of the function and availability of natural

products, and natural product inspired synthesis,^1–3has proved

to be a key impetus in recent drug development.^4,5Spiro-

cyclic lactams have become of considerable interest, as a result

of their occurrence in structurally complex (e.g. the spiropy-

rrolidinyloxindole alkaloids^6,7) or bioactive natural products⁸

(e.g. alstonisine,⁹amathaspiramide,¹⁰azaspirene,¹¹elacomine,¹²

horsﬁline,¹³pseurotin,¹⁴and spiroptryprostatin¹⁵(Fig. 1)). They

are also of note due to their resemblance to natural products,¹⁶

and novel spiropyrrolizidines as potent antimicrobial agents for

human and plant pathogens,¹⁷spiroindolones as antimalarials¹⁸

and spirocyclic lactams as inhibitors of p53:MDM2 have all been

reported.¹⁹These systems have also come to prevalence for their

Fig. 1 Some Spirocyclic Natural Products.

use in templates, scaffolds and bioisosteres due to the orthogonal

relationship between the two key planes of the intersecting

heterocyclic rings²⁰which offers interesting opportunities for

conformational control and the design of well-deﬁned molecular

architecture, and spiro-bis-d-lactams based on pyroglutamate²¹

and proline²²templates have been prepared for their potential

as b-turn mimetics. However, the core spirocyclic system is of

further interest since it obeys the ‘Rule of Three’ (M <300;

Number of Hydrogen bond donors £3 and acceptors £3; cLogP =

concept, suitable for access to enantiopure spirocyclic lactam-

lactam and lactam-lactone systems; some of this work has

been reported in preliminary form³¹and very similar synthetic

work has recently been published.³²Various approaches for

the rapid asymmetric synthesis of spiro-2-pyrrolidin-5-ones have

recently been reported,^33–35including by a-diazocarbonyl insertion

chemistry,³⁶Pd-catalyzed intramolecular amidations³⁷and iodo-

carbocyclisations,³⁸and lactone-lactam spirocyclic systems as

mimics of lycoperdic acid have recently been reported.³⁹

We used as our starting point the bicyclic lactam system 2b,

readily prepared from ethyl pyroglutamate 1a in three steps using

literature methodology;⁴⁰for the acylation of lactam 2a to ethoxy-

carbonyl derivative 2b, it was found that ethyl chloroformate gave

a substantially better yield (90%) than the literature approach

using diethyl carbonate.⁴⁰Alkylation of ester 2b with several

bromonitriles/NaH in THF gave products 3a and 4a,b in good

yields of 65, 68, and 42%, respectively (Scheme 1). Lactam 3a was

obtained as a 2:1 diastereomeric but inseparable mixture, for which

the stereochemistry of the major isomer was assigned as 7R, arising

by exo- attack of the electrophile; this assignment was made by

comparison of the chemical shift difference of the C(6)H protons

(Dd 0.1) (bicyclic lactams formed via exo-alkylation reliably have

a small chemical shift difference for the C(6)H protons of Dd

0.2, but those from endo-alkylation show a larger difference of

Dd 0.8).^40,41This structural assignment was conﬁrmed by selective

crystallisation and single crystal X-ray analysis for one of the

diastereomers (Fig. 2).†⁴²Lactam 4a was similarly assigned the 7R

2

˚

3; Number of rotatable bonds £3; Polar Surface Area = 60 A )

which has been suggested to be optimal for the construction

of fragment libraries,^23,24and ring modiﬁcation giving natural

product analogues might easily be envisaged. Since the neglect

of chiral centres has been recognized as a key deﬁciency of

drug discovery methodology,²⁵we have been interested in the

development of novel chiral template systems suitable for library

synthesis against diverse disease states^26,27and have shown that

conformationally controlled amino acid analogues may be readily

accessed^28,29by, for example, cycloadditions³⁰and by electrophile-

mediated ring closure.²⁶We report here an extension of this

^aDepartment of Chemistry, Chemistry Research Laboratory, The University

of Oxford, Mansﬁeld Road, Oxford, UK, OX1 3TA

^bAstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA, 02451,

USA

† Electronic supplementary information (ESI) available. CCDC reference

numbers 814550 and 814551. For ESI and crystallographic data in CIF or

other electronic format see DOI: 10.1039/c1ob05708a

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Scheme 1

stereochemistry (Dd 0.35), but was epimeric at C-1¢ as shown by

the doubling of the signals of C(1¢)Me in the ¹³C NMR spectrum;

this analysis was conﬁrmed by NOE results (Fig. 3). Lactam 4b

was obtained as a single crystalline diastereomer, assigned as the

exo- stereochemistry from the chemical shift difference of the

C(6)H protons (Dd 0.17), and this was conﬁrmed by X-ray analysis

allowing unequivocal assignment as (7R,1¢S) (Fig. 2).†⁴²The C(7)-

alkylation reactions of the enolate derived from 2b with substituted

halonitriles therefore give high levels of exo- diastereoselectivity,

and in the case of the phenyl substituted product 4b, also excellent

C(1¢) diastereoselectivity.

Reduction of nitriles 3a, 4a and 4b (NaBH₄, CoCl₂·H₂O

or NaBH₄, NiCl₂·H₂O)²⁹followed by in situ cyclisation of the

Fig. 2 X-ray structures for 3a and 4b (ellipsoids at 50% probability level).

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Fig. 3 NOE Data for Selected Compounds.

resulting amine gave the desired spirolactam systems 6a,b (25%

combined yield) and 7a–c (10, 10 and 21%, respectively). The

low yields are likely to be due to the formation of the strained

spirobislactam system, and their very high polarity and water sol-

ubility (typically, a MeOH/EtOAc mixture is required for efﬁcient

elution in column chromatography) further complicated isolation;

their polar nature was conﬁrmed by estimation of their cLogP and

PSA values using Marvin (Table 1).⁴³Interestingly, despite their

expected well-deﬁned conformation, stereochemical assignment

was unexpectedly difﬁcult. Spirocyclisation was accompanied by

large changes in the chemical shifts of the C(6)H protons relative

to the starting lactams; for example, for 6a, whose stereochemistry

was established by NOE (Fig. 3), the C(6)H protons exhibited Dd

0.9, but for 6b, the value was Dd 0.5. For lactams 7a,b, the isomers

were also obtained as a diastereomeric mixture (ratio 7a : 7b =

1 : 1) with C(6)H proton chemical shift difference values of Dd

0.1 and Dd 0.6, respectively; 2D-NOESY analysis convincingly

indicated the proximal relationship of C(1¢)Me, C(6)H_exoand

C(5)H of lactam 7b, with the C(1)Me substituent located under the

pyroglutaminyl ring. The stereochemistry of 7c follows from the

unequivocal assignment of precursor 4b; the C(1¢)S conﬁguration

in which the phenyl substituent is located under the pyroglutaminyl

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Table 1 Cheminformatic data for selected compounds

spirolactone-lactam system, might also be feasible. Alkylation of

lactam 2b gave lactams 12a,b (59 and 72% respectively), each as

inseparable mixtures of diastereomers (Scheme 2). Reduction of

lactam 12a (NaBH₄) was followed by spontaneous cyclisation to

give the lactone-lactam system 13a, conﬁrmed by the presence

of carbonyl absorptions at 1752 and 1708 cm^-1, but in low yield

(25%) and as a mixture of three stereoisomers. The major one

was obtained in pure form without difﬁculty, but the two minor

ones were more difﬁcult to isolate; the stereochemistry of two of

them was easily established by NOE analysis (Fig. 3) as being

C(7)R, C(5¢)R and C(7)S, C(5¢)S and the third was assigned as

possessing the C(7)R, C(5¢)S stereochemistry, on the basis that

Compound

cLogP^a

PSA^a

MSA^a

%PSA^a

2b

1.77

0.77

1.13

2.27

-0.01

1.59

-1.15

2.87

3.28

0.87

2.68

0.51

55.8

58.6

84.5

84.7

104.5

58.6

55.8

76.1

55.8

102.1

402.3

381.0

409.9

484.1

399.9

442.0

325.5

455.1

480.8

415.9

430.0

501.1

13.9

15.4

14.3

12.1

21.1

19.2

32.1

12.9

11.6

18.3

13.0

20.4

6a

6b

7a

7b

7c

8c

9

10

11a

11b

15a

15b

16a

16b

19

1

it had a very similar H NMR spectrum to the C(7)R, C(5¢)R

isomer but a large difference in the chemical shift value for the

C(5¢)H. Dihydroxylation of allyl derivative 12b using potassium

osmate/N-methylmorpholine oxide was also followed by spon-

taneous cyclisation, giving the lactone-lactam system 13b in low

yield (15%), for which careful chromatography allowed partial

separation (Scheme 2); NOE analysis on these puriﬁed materials

indicated the C(7)R, C(5¢)R and C(7)S, C(5¢)S stereochemistry

(Fig. 3). Alternatively, ester hydrolysis (KOH, MeOH, H₂O) of

lactam 12b followed by immediate iodolactonisation (I₂, KI) gave

the tricycles 14a and 14b in 20% yield, again as a partially separable

mixture. Assignment of stereochemistry was achieved by NOE

analysis (Fig. 3), and found to be C(7)R, C(5¢)R and C(7)S, C(5¢)S;

it would appear therefore that the C(7) stereochemistry dictates

the cyclisation outcome at the C(5¢) centre. In all of this work,

it was again observed that differences of the ¹H chemical shift of

the H(6) proton allow assignment of the stereochemistry at C(7);

thus, a small difference in the dH(6) proton (typically 0.1–0.4 ppm)

occurs for C(7)R, thereby placing the lactone carbonyl on the endo

face, and a large difference (typically 0.9 ppm) indicates the C(7)S

stereochemistry.

^aPartition coefﬁcient (LogP), polar surface area (PSA), molecular surface

area (Van der Waals MSA), %polar surface area (PSA/MSA ¥ 100%) were

all calculated using Marvin (www.chemaxon.org)⁴³

ring was further conﬁrmed by NOE analysis (Fig. 3) and by

an anisotropic shielding effect from the nearby aromatic ring on

C(6)H_exo(d 1.9 as opposed to d 2.8 in the unsubstituted lactam

6a,b). Deprotection of 7c efﬁciently yielded the pyroglutaminyl

system 8a; this compound is very polar (DMSO soluble only) and

was not puriﬁed, but was readily converted to the corresponding

ester 8c in a two-step oxidation–esteriﬁcation process in 15%

overall yield.

Examination of a C(7) aminoaryl substituted system was also

of interest; although we have previously reported that related

systems are readily available by an unusual ligand coupling

using organolead triacetates.^41,44–49In this case the required

aminoaryl system 5a was most readily accessible by nucleophilic

aromatic substitution; similar arylation in related systems has

been reported.^32,50,51Thus, reaction of lactam 2b with sodium

hydride followed by 2,4-dinitro-1-ﬂuorobenzene gave the exo-

arylated product 5a in 74% yield, whose stereochemistry was

readily established by NOE analysis (Fig. 3); in this case, an

observed DdH(6) difference of 0.9 ppm was in contravention of

the general trend described above, and we attribute this to an

anisotropic effect from the adjacent aromatic ring. An attempted

reduction of lactam 5a using 10% Pd/C and ammonium formate

gave only the partially reduced product 5b in poor yield (23%),

and longer reaction times or additional equivalents of ammonium

formate gave complex reaction mixtures.⁵²Application however

of iron powder/ammonium chloride⁵³reliably gave the required

reduction, and this was followed by spontaneous lactamisation to

give the desired product in 15% yield; the stereochemical outcome

was again demonstrated by NOE analysis (Fig. 3), and in this

case a small DdH(6) difference of 0.17 ppm was also observed.

Deprotection (TFA) gave alcohol 10 in 60% yield. A similar

process has been recently reported by Sen, who developed this

sequence for several bicyclic lactam series, and who identiﬁed

better conditions for the reduction and achieved better overall

yields by using the less bulky methyl ester system.³²

Scheme 2

An attempt to develop this concept with appropriately func-

tionalised benzyl systems met with varied success (Scheme 1);

alkylation of lactam 2b with NaH/2-nitrobenzyl bromide or 2-

(O-TBDMS)benzyl bromide⁵⁴gave the corresponding products

3b,c in good yield (36 and 47% respectively). Exo-alkylation in

both cases was conﬁrmed by NOE analysis (Fig. 3), and by

the fact that the chemical shift difference was small (0.2 ppm).

Deprotection (TBAF) gave the expected alcohol 3d, but without

Given the facility of the ring closures with appropriately

positioned amine groups, it was of interest to examine whether

hydroxyl-mediated ring closure, to give the corresponding

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Scheme 3

Fig. 4 Formation of Spirolactone-lactam systems.

any lactonisation being observed; conditions to promote this

cyclisation could not be identiﬁed. On the other hand, reduction of

3b (Fe, NH₄Cl, MeOH, H₂O, reﬂux) gave the expected spirocyclic

bislactam product, but as a mixture of two diastereomers 11a,b in

36% yield. The stereochemistry of each isomer was established by

NOE analysis, and conﬁrmed by the existence of a small difference

of the ¹H chemical shift of the H(6) proton of the C(7)R isomer 11b

(0.44 ppm) but a larger difference in C(7)S isomer 11a (0.94 ppm).

We further examined the application of this process to simple

pyroglutamates; spontaneous lactamisation leading to spirocyclic

products has been observed previously in simple lactam systems.⁵¹

Ethyl pyroglutamate 1a (Scheme 3) was BOC-protected to give

lactam 15a according to the literature precedent^55,56and the

C-4 ethoxycarbonyl residue introduced by treatment ﬁrst with

LiHMDS followed by ethyl chloroformate, giving the product

15b in good yield (65%) as a mixture of two diastereomers.

Arylation using a mixture of triethylamine/DMF with 2,4-dinitro-

1-ﬂuorobenzene gave the desired C-4 aryl product 16a in excellent

yield (79%) as a single diastereomer, whose stereochemistry was

again established by NOE analysis (Fig. 3), arising by attack of

the electrophile from the least hindered face.^57–61Application of

the iron–ammonium chloride conditions gave product 16b in 31%

yield, arising by reduction of both nitro groups, but cyclisation to

give lactam 17 was neither spontaneous nor could be induced. An

attempt to emulate the approach of Bella^50,51by removal of the

nitrogen protecting group prior to reduction and ring closure like-

wise did not lead to product formation; we assume that the slightly

greater degree of freedom accessible in this system, compared

to the bicyclic lactam series, renders ring closure reaction more

difﬁcult. In order to investigate this system further, we examined

the reaction of the enolate of 15b with bromoacetonitrile; this

reaction gave two separable diastereomeric products 18a,b as a 2 : 3

mixture in 92% yield, whose stereochemistry was again established

by NOE analysis (Fig. 3). Treatment of the diastereomeric mixture

of 18a,b with NaBH₄/CoCl₂gave the desired lactam 19, but in very

poor yield (5%), along with some uncyclised amine 20. The C(4)

stereochemistry of these compounds was not determined due to

the low yield.

Modelling of representative structures was instructive using

Marvin;⁴³the near orthogonal relationship of the spirosystem

carbonyl groups is illustrated for the energy minimised structures

of 7c, 8c and 9 (Fig. 4) and also noteworthy is the parallel rela-

tionship of the aromatic rings in 7c compared to their orthogonal

relationship in 9. More detailed molecular modelling of the elabo-

rated forms of both the bicyclic and pyroglutaminyl templates was

conducted in an effort to analyse their different conformational

constraints. The preferred (lowest energy) conformations of these

structures were calculated using the Hartree–Fock method (3-21G

basis set)⁶²after the initial starting conformation was obtained

from a sequential conformational search using the GAMESS

interface of the Chem3D Ultra v.10 software. After obtaining the

lowest energy conformations of the compounds, the magnitude of

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the dihedral angle between the nitrogen substituent and the C2

(or C5) hydrogen was determined; the bicyclic template exhibits

dihedral angles of 93.0^◦and 92.4^◦for 5c and 9, respectively, whilst

the BOC pyroglutamate template gives 45.7^◦, 65.1^◦, 46.4^◦, and

47.6^◦dihedral angles for 16b, 17, 18b and 19 respectively. This

implies that systems derived from the bicyclic template 2a exhibit

axial hydrogen and equatorial alkyl at its C-5 position whilst

those from the BOC template 15b exhibit equatorial hydrogen

and axial ester at the equivalent C-2 position (Fig. 5), consistent

with minimisation of A_1,3strain⁶³in the conformationally more

mobile pyroglutaminyl structure. The alternative conformer of

the pyroglutamate system appears to suffer from destabilising 1,3-

diaxial and/or dipole–dipole interactions between the C-2/C-4

substituents, and is therefore not preferred.

Conclusion

We have demonstrated that spirocyclic lactams are readily avail-

able from pyroglutamate templates, and their cheminformatic

parameters are within desired norms for lead-like structures. Their

combination of chemical functionality, stereochemical conforma-

tion and cheminformatic parameters offers a unique system of

potential value for the design of novel architectures suitable for

application in the drug discovery process.

Experimental

(2S)-2-Ethoxycarbonyl-5-oxo-pyrrolidine 1a was prepared from

pyroglutamic acid, (2S)-2-hydroxymethyl-5-oxo-pyrrolidine 1b,

(2R,5S)-8-oxo-2-phenyl-1-aza-3-oxa-bicyclo[3.3.0] octane 2a

and

(2R,5S,7R,S)-1-aza-7-allyl-7-(ethoxycarbonyl)-3-oxo-8-

oxa-2-phenylbicyclo[3.3.0]-octane 12b were all prepared using

literature methodology.^30,40,41Bromophenylacetonitrile was

prepared according to Molina.⁶⁸(2-(Bromomethyl)phenoxy)(tert-

butyl)dimethylsilane was prepared from tert-butyldimethyl(o-

tolyloxy)silane⁶⁹using the method of Stern and Swenton.⁷⁰

(2R,5R)-1-Aza-7-ethyloxycarbonyl-3-oxa-8-oxo-2-

phenylbicyclo[3.3.0]octane 2b

Fig. 5 Minimised Conformations for Selected Compounds.

To a stirred solution of lactam 2a (4.00 g, 19.7 mmol) in THF

(75 ml) was added sodium hydride ((oil dispersion 60%) 0.55 g,

13.7 mmol) at RT and the mixture was left to stir for 1 h. Ethyl

chloroformate (2.7 ml, 27.9 mmol) was added and the mixture was

reﬂuxed for 16 h. The reaction was quenched with glacial acetic

acid (6 ml), water (30 ml) was added to dissolve the gelatinous

precipitate formed and the mixture was extracted with EtOAc (4

¥ 20 ml). The organics were shaken with brine, dried over MgSO₄

and concentrated under vacuum and the residue puriﬁed by ﬂash

column chromatography to give 2b as a yellow oil, which slowly

crystallised to give a yellow solid consisting of a 1 : 1 mixture of

7S and 7R diastereoisomers (4.86 g, 90%), with data as previously

reported.^30,40

Cheminformatic analysis of these compounds was of interest,

and cLogP, PSA, and MSA values were calculated using Marvin

(Table 1).⁴³The polar surface area parameter (PSA), which corre-

lates the presence of polar atoms with membrane permeability and

therefore gives an indication of drug transport properties,⁶⁴has

2

˚

been reported to have an optimal value of 70 < PSA < 120 A for

a non-CNS orally absorbable drug.⁶⁵Moreover, recently reported

ADMET rules of thumb⁶⁶indicate that neutral molecules with

MW <400 and clogP <4 are likely to exhibit average values

for a variety of indicators (including solubility, bioavailability,

plasma protein binding, P-gp efﬂux and in vivo clearance), and

therefore provide good library start points. It has also recently

been established using a Random Forest statistical analysis that

lipophilicity strongly correlates with adverse toxicity in vivo, with

(2R,5S,7R) and (2R,5S,7S)-1-Aza-7-(cyanomethyl)-7-(ethoxy-

carbonyl)-3-oxo-8-oxa-2-phenylbicyclo-[3.3.0]octane 3a

a signiﬁcantly higher probability of an adverse indication if cLogP

2

˚

and PAS are less than 3 and 70 A respectively, than if they are

To a stirred suspension of pre-washed NaH (0.046 g, 1.9 mmol)

in dry THF (5 ml) at 0 ^◦C under nitrogen atmosphere was added

a solution of lactam 2b (0.315 g, 1.1 mmol) in THF (10 ml),

and the mixture was stirred at RT for 20 min. A solution of

bromoacetonitrile (0.19 g, 1.6 mmol) in THF (5 ml) was added

and the mixture stirred at RT 16 h. The reaction was quenched by

pouring the mixture into NH₄Cl (aq.)/EtOAc (25 ml, 1 : 1) and

the aqueous portion was extracted with EtOAc (2 ¥ 10 ml). The

organic extracts were combined, washed with water (20 ml) and

sat. brine (20 ml), dried over MgSO₄and the solvent removed

in vacuo to give an oil, which was puriﬁed by ﬂash column

chromatography [(40–60) Petrol/EtOAc, 7 : 3] to give the product

3a (0.33 g, 65%) as a solid consisting of an inseparable 2 : 1

mixture of diastereomers. R_f= 0.16 [(40–60) Petrol/EtOAc, 7 : 3];

m_max/cm^-1(thin ﬁlm) 3089 (m), 3064 (m), 3027 (m), 2958 (s), 2940

(s), 2901 (s), 2249 (m), 1745 (s), 1704 (s), 1586 (m), 1546 (m);

d_H(CDCl₃, 200 MHz) 1.15–1.40 (6H, m, CH₃CH₂O, (A+B)),

2.05 (1H, dd, J 13.5 and 7.2, H(6)(B)), 2.45 (1H, dd, J 20.8 and

greater than 3 and in the range 100–130 respectively.⁶⁷For the

spirocyclic systems reported here, it was found that cLogP values

were typically in the range 0.7–2.9, but deprotection signiﬁcantly

reduced these values (compounds 8c and 10); this is to be expected

after the removal of hydrophobic protecting group residues and is

consistent with their observed low solubility in organic solvents.

Polar Surface Area (PSA), with some exceptions, is generally

˚

less than 60 A, and expressed as a percentage of the Molecular

Surface Area (MSA), is typically in the range 12–18%. However,

some compounds, notably the deprotected 8c, 9, 10 and Spiro-

19, are noticeably higher both in PSA and %PSA, again as

might be expected by the absence of hydrophobic residues. The

spirocyclic compounds reported herein therefore generally fall

within the rule-of-thumb criteria outlined above, and moreover

their chemical functionality and well-deﬁned three-dimensional

conformation places them in unusual chemical space ideally suited

for optimisation of drug-like properties.

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14.5, H(6)(A)), 2.55 (1H, dd, J 14.3 and 4.3, H(6)(A)), 2.80–3.15

(5H, m, H(6)(B)+CH₂CN(A+B)), 3.55–3.75 (2H, m, H(4)(A+B)),

4.1–4.4 (8H, m, CH₃CH₂O(A+B)+H(5)(A+B)+H(4)(A+B)) 6.25

(2H, s, H(2)(A+B)), 7.20–7.50 (10H, m, ArH(A+B)); d_C(CDCl₃,

100.6 MHz) 13.9 (CH₃CH₂O(A+B)), 22.8, 23.5 (CH₂CN(A+B)),

31.7 (C(6)(A)), 35.2 (C(6)(B)), 56.4, 56.6 (C(5)(A+B)), 63.0,

63.0 (CH₃CH₂O(A+B)), 71.4 (C(4)(A)), 71.9 (C(4)(B)), 87.0,

87.3 (C(2)(A+B)), 116.5, 116.7 (CN(A+B)), 125.9, 126.0, 128.3,

128.4, 128.5, 128.6, 128.8, 128.9 (ArCH(A+B)), 137.4, 137.7

(ArC(A+B)), 168.3, 168.8, 169.8, 172.4 (C O(A+B)); m/z (ESI⁺)

337 (M+Na⁺,100%), 315 (M+H⁺, 62%); HRMS: [M+H⁺] Calcu-

lated for C₁₇H₁₉O₄N₂315.1346, Found: 315.1345.

(m), 3034 (m), 2956 (m), 2932 (m), 2886 (m), 2859 (m), 1743

(s), 1709 (m), 1600 (w), 1581 (w), 1492 (s), 1256 (s); d_H(400

MHz, CDCl₃) 0.20 (3H, s, MeSi), 0.25 (3H, s, MeSi), 1.00 (9H, s,

^tBuSi), 1.33 (3H, t, J 7.1, CH₃CH₂O), 2.37 (1H, dd, J 13.7 and

5.2, H(6)endo), 2.57 (1H, dd, J 13.7 and 8.0, H(6)exo), 3.20 (1H,

d, J 13.8, CHHPh), 3.27–3.35 (1H, m, H(5)), 3.50–3.60 (2H, m,

H(4)endo+CHHPh), 4.05 (1H, t, J 7.0, H(4)exo), 4.30 (2H, q, J

7.1, CH₃CH₂O), 6.27 (1H, s, H(2)), 6.73 (1H, t, J 7.5, ArH), 6.80

(1H, d, J 8.1, ArH), 7.05–7.13 (2H, m, ArH), 7.23–7.30 (2H, m,

ArH), 7.30–7.35 (3H, m, ArH); d_C(100.6 MHz, CDCl₃) -4.4,

-3.9 (Me₂Si), 18.2 (SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 30.8 (C(6)),

32.8 (CH₂Ph), 56.4 (C(5)), 61.9 (CH₃CH₂O), 71.9 (C(4)), 87.0

(C(2)), 118.8, 121.4, 128.1, 128.5, 132.1 (ArCH), 126.1, 128.2

(ArCH), 126.7, 132.1, 154.1 (ArC), 171.5, 174.6 (C O); m/z

(ESI⁺) 554 (M+NH₄+MeCN⁺, 100%); HRMS [M+H⁺] Calculated

for C₂₈H₃₈NO₅Si 496.2519, Found: 496.2520.

(2R,5S,7S)-1-Aza-7-(2-nitrobenzyl)-7-(ethoxycarbonyl)-3-oxo-8-

oxa-2-phenylbicyclo[3.3.0] octane 3b

To a stirred suspension of pre-washed NaH (0.12 g, 5.0 mmol)

in dry THF (15 ml) at 0 ^◦C under a nitrogen atmosphere was

added a solution of lactam 2b (0.43 g, 1.6 mmol) in THF (15 ml),

and the mixture was stirred at RT for 20 min. A solution of 1-

(bromomethyl)-2-nitrobenzene (0.50 g, 2.3 mmol) in THF (15 ml)

was added and the mixture stirred at RT for 16 h. The reaction was

quenched by pouring the mixture into NH₄Cl (aq.)/EtOAc (1 : 1)

(100 ml) and the aqueous portion was extracted with EtOAc (2 ¥

50 ml). The organic extracts were combined, washed with water

(50 ml) and sat. brine (50 ml), dried over MgSO₄and the solvent

removed in vacuo to give the product 3b as a yellow solid (0.23 g,

36%). R_f= 0.17 [EtOAc/(40–60) Petrol, 1 : 4], [a]²_D⁶+46 (c = 3.9 in

MeOH); m.p. 79–80 ^◦C; m_max/cm^-1(thin ﬁlm) 3066 (m), 2983 (m),

2874 (m), 1743 (s), 1707 (bs), 1609 (m), 1577 (m), 1527 (s), 1353

(s); d_H(CDCl₃, 200 MHz) 1.33 (3H, t, CH₃CH₂O), 2.35 (1H, dd,

J 14.3 and 7.6, H(6)), 2.55 (1H, dd, J 14.3 and 5.0, H(6)), 3.43–

3.63 (3H, m, H(4)+H(5)+CHHPh), 3.85 (1H, d, J 14.3, CHHPh),

4.10–4.40 (3H, m, H(4)+CH₃CH₂O), 6.27 (1H, s, H(2)), 7.20–

7.45 (8H, m, ArH), 7.80–7.90 (1H, m, ArH); d_C(CDCl₃, 100.6

MHz), 14.0 (CH₃CH₂O), 31.3 (C(6)), 34.5 (CH₂Ph), 56.2 (C(5)),

61.5 (C(7)), 62.4 (CH₃CH₂O), 71.8 (C(4)), 87.1 (C(2)), 124.6, 125.9,

126.0, 128.2, 128.4, 128.7, 132.6 (ArCH),133.1, 138.1 (ArC), 170.7,

(2R,5S,7S)-1-Aza-7-(2-hydroxybenzyl)-7-(ethoxycarbonyl)-3-oxo-

8-oxa-2-phenylbicyclo[3.3.0] octane 3d

The substrate 3c (0.099 g, 0.20 mmol) was dissolved in THF (6 ml)

and TBAF (0.6 ml of a 1 M solution in THF) was added and the

solution was allowed to stir for 24 h under nitrogen. The reaction

mixture was washed with sat. NH₄Cl (aq.) (3 ml), the organic

layer separated extracted with ether (3 ml), the organic extracts

combined and dried over MgSO₄and the solvent removed in vacuo.

Puriﬁcation was by ﬂash column chromatography with an eluent

of [EtOAc/(40–60) Petrol, 1 : 3] to furnish the product 3d as a white

solid (8 mg, 11%). R_f= 0.16 [EtOAc/(40–60) Petrol, 1 : 3]; [a]²_D³+2.4

◦

(c = 0.13 in DCM); m.p. 165–167 C; m_max/cm^-1(thin ﬁlm) 3328

(bm), 2982 (w), 1739 (s), 1681 (s), 1595 (m), 1507 (w), 1456 (m),

1367 (m), 1261 (s), 1222 (s); d_H(CDCl₃, 200 MHz) 1.33 (3H, t, J

7.1, CH₃CH₂O), 2.47 (1H, dd, J 13.7 and 5.7, H(6)endo), 2.55 (1H,

dd, J 13.7 and 7.3, H(6)exo), 3.35 (2H, dd, J 21.9 and 4.3, CH₂Ph),

3.63 (1H, t, J 8.0, H(4)endo), 3.67–3.85 (1H, m, H(5)), 4.20 (1H, dd,

J 7.5 and 5.9, H(4)exo), 4.27 (2H, q, CH₃CH₂O, J 7.1), 6.30 (1H, s,

H(2)), 6.60 (1H, bs, OH), 6.73–6.85 (2H, m, ArH), 7.05–7.20 (2H,

m, ArH), 7.23–7.43 (3H, m, ArH); d_C(CDCl₃, 100.6 MHz) 14.0

(CH₃CH₂O), 32.0 (C(6)), 33.7 (CH₂Ph), 56.4 (C(5)), 61.9 (C(7)),

62.6 (CH₃CH₂O), 71.8 (C(4)), 87.0 (C(2)), 117.2, 120.6, 125.9,

128.4, 128.7, 128.8, 132.4 (ArCH), 122.3, 138.0, 154.8 (ArC),

172.2, 175.0 (C O); m/z (ESI⁺) 440 (M+NH₄+MeCN⁺, 100%);

HRMS [M+Na⁺] Calculated for C₂₂H₂₃NO₅Na 404.1475, Found:

404.1468.

174.0 (C O); m/z (ESI⁺) 469 (M+MeCN+NH₄, 100%); HRMS

+

[M+H⁺] Calculated for C₂₂H₂₃N₂O₆411.1556, Found: 411.1566.

(2R,5S,7S)-1-Aza-7-((2-t-butyldimethylsilyloxy)benzyl)-7-

(ethoxycarbonyl)-3-oxo-8-oxa-2-phenylbicyclo[3.3.0] octane 3c

To a stirred suspension of pre-washed NaH (0.038 g, 1.6 mmol)

in dry THF (5 ml) at 0 ^◦C under a nitrogen atmosphere was

added a solution of lactam 2b (0.36 g, 1.3 mmol) in THF

(10 ml), and the mixture was stirred at RT for 20 min. A solution

of 2-(bromomethyl)phenoxy)(tert-butyl)dimethylsilane (0.70 g,

2.3 mmol) in THF (5 ml) was added and the mixture reﬂuxed

for 2 h and then stirred at RT for 16 h. The reaction was quenched

by pouring into NH₄Cl (aq.)/EtOAc (60 ml, 1 : 1) and the aqueous

portion extracted with EtOAc (2 ¥ 60 ml). The organic extracts

were combined, washed with water (60 ml) and sat. brine (60 ml),

dried over MgSO₄and the solvent removed in vacuo, and the

resulting oil was puriﬁed by ﬂash column chromatography [(40–

60) Petrol/EtOAc, 85 : 15] to give the product 3c as a single

diastereomer (309 mg, 47%). R_f= 0.19 [EtOAc/(40–60) Petrol,

15 : 85]; [a]²_D³-38 (c = 3.6 in MeOH); m_max/cm^-1(thin ﬁlm) 3064

Alkylations—general method

To a stirred suspension of pre-washed NaH (0.30 g, 1.7 equiv) in

dry THF (10 ml) at 0 ^◦C under a nitrogen atmosphere was added a

solution of lactam 2b (2.01 g, 7.30 mmol) in THF (15 ml), and the

mixture was stirred at RT for 20 min. A solution of the electrophile

(1.6equiv.) inTHF (10ml)was added andthe mixture stirredeither

at RT or reﬂux for 16 h. The reaction was quenched by pouring the

mixture into NH₄Cl (aq.)/EtOAc (175 ml, 1 : 1) and the aqueous

portion was extracted with EtOAc (2 ¥ 70 ml). The organic extracts

were combined, washed with water (50 ml) and sat. brine (50 ml),

dried over MgSO₄and the solvent removed in vacuo to give an oil,

which was puriﬁed by ﬂash column chromatography.

7048 | Org. Biomol. Chem., 2011, 9, 7042–7056

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(2R,5S,7R,1¢R) and (2R,5S,7R,1¢S)-1-Aza-7-(1¢-cyano-1¢-ethyl)-

7-(ethoxycarbonyl)-3-oxo-8-oxa-2-phenyl-bicyclo[3.3.0]octane 4a

(1H, s, H(2)), 7.37–7.60 (5H, m, ArH), 7.73 (1H, d, J 8.7, ArH),

8.45 (1H, dd, J 8.6 and 2.4, ArH), 8.97 (1H, d, J 2.4, ArH); d_C

(CDCl₃, 100.6 MHz) 13.8 (CH₃CH₂O), 36.3 (C(6)), 56.1 (C(5)),

63.4 (CH₃CH₂O), 66.6 (C(7)), 71.7 (C(4)), 87.9 (C(2)), 121.5, 125.9,

128.7 (ArCH), 128.1 (ArC), 129.2 (ArC), 131.4 (ArC), 137.9,

140.9, 147.3, 148.1 (ArC), 167.8, 172.1 ((C O); HRMS [M+H⁺]

Calculated for C₂₁H₂₀N₃O₈Found 442.1251, Calculated: 442.1250.

Solid; (1.63 g, 68% as inseparable diastereomers); R_f= 0.3

[(40–60) Petrol/EtOAc, 7 : 3]; m_max/cm^-1(Nujol) 2921 (s), 2842

(s), 2237 (w), 1724 (m), 1697 (m), 1500 (w), 1454 (m), 1329

(m), 1296 (m); d_H(CDCl₃, 200 MHz) 1.30 (3H, t, J 7.1,

CH₃CH₂O), 1.40 (3H, d, J 7.1, MeCHCN), 2.45 (1H, dd, J

14.5 and 8.0, H(6)exo), 2.7 (1H, dd, J 14.4 and 3.5, H(6)endo),

3.50–3.80 (2H, m, H(4)endo+MeCHCN), 4.10–4.40 (4H, m,

CH₃CH₂O+H(4)exo+H(5)), 6.3 (1H, s, H(2)), 7.20–7.50 (5H, m,

ArH); d_C(CDCl₃, 50.3 MHz) 14.4, 14.8 (MeCHCN+CH₃CH₂O),

28.8 (C(6)), 31.1 (CHCN), 56.8 (C(5)), 62.6 (C(7)) 63.4

(CH₃CH₂O), 71.6 (C(4)), 88.2 (C(2)), 120.9 (CN), 126.2, 129.0,

129.3 (ArCH), 138.1 (ArC), 168.4, 172.6 (C O); m/z (ESI⁺)

351 (M+Na⁺, 100%); HRMS [M+H⁺] Calculated for C₁₈H₂₁O₄N₂

329.1501, Found 329.1491.

(2R,5S,7R)-1-Aza-7-(4-amino-2-nitrophenyl)-7-(ethoxycarbonyl)-

3-oxo-8-oxa-2-phenylbicyclo[3.3.0]octane 5b

To a stirred suspension of 5a (0.30 g, 0.68 mmol) and 10%

Pd/C (0.03 g) in methanol (2 ml) was added ammonium formate

(0.21 g, 3.4 mmol) in a single portion and the mixture was reﬂuxed

under nitrogen for 72 h. The mixture was ﬁltered and the solvent

removed in vacuo. The resulting oil was dissolved in DCM (10 ml)

and washed with water (2 ¥ 5 ml). The organics were washed

with brine (2 ¥ 5 ml), dried over MgSO₄and concentrated in

vacuo. The crude product was puriﬁed by ﬂash chromatography

[Petrol/EtOAc (2 : 1)] yielding compound 5b (0.065 g, 23%). R_f

0.25 [EtOAc/(40/60) Petrol, 1 : 2]; [a]²_D²+134 (c = 0.25 in CHCl₃);

m_max/cm^-1(thin ﬁlm) 3363 (bm), 1726 (m), 1635 (s), 1511 (s), 1339

(s), 1167 (s); d_H(400 MHz, CDCl₃) 1.22 (3H, t, J 7.1, CH₃CH₂O),

2.53 (1H, dd, J 14.3 and 7.7, H(6)exo), 3.38 (1H, dd, J 14.3 and

5.6, H(6)endo), 3.86 (1H, t, J 8.3, H(4)endo), 4.02–4.09 (1H, m,

H(5)), 4.11 (2H, NH₂), 4.18–4.23 (2H, m, CH₃CH₂O), 4.33 (1H,

dd, J 8.0 and 6.1, H(4)exo), 6.40 (1H, s, H(2)), 6.71 (1H, dd,

J 8.5 and 2.7, ArH), 7.11 (1H, d, J 8.5, ArH), 7.36 (1H, d, J

2.7, ArH), 7.37–7.44 (3H, m, PhH), 7.49–7.53 (2H, m, PhH);

d_C(100 MHz, CDCl₃) 13.8 (CH₃CH₂O), 37.3 (C6), 56.3 (C5),

62.6 (CH₃CH₂O), 66.43 (C7), 71.7 (C4), 87.6 (C2), 111.7 (ArC),

119.4 (ArC), 123, 138.2, 147.3, 148.0 (ArC), 126.0, 128.6, 128.9

(ArC), 169.4, 173.6 (C O); HRMS: [M+Na⁺.] Calculated for

C₂₁H₂₁NNaO₆, 434.1323, Found: 434.1313.

(2R,5S,7R,1¢S)-1-Aza-7-(1¢-cyano-1¢-phenylmethyl)-7-

(ethoxycarbonyl)-3-oxo-8-oxa-2-phenylbicyclo[3.3.0]octane 4b

Solid; (1.19 g, 42%); R_f= 0.2 [(40–60) Petrol/EtOAc, 3 : 1]; [a]_D²³

-11.4 (c = 0.18 in CHCl₃); m.p. 125–126 ^◦C; m_max/cm^-1(thin ﬁlm)

3064–2874 (bs), 2245 (m), 1959 (m), 1891 (m), 1811 (m), 1760 (s),

1708 (s), 1602 (m), 1586 (m), 1586 (m); d_H(CDCl₃, 200 MHz) 1.37

(3H, t, J 7.2, CH₃CH₂O), 2.63 (1H, dd, J 14.5 and 8.0, H(6)exo),

2.8 (1H,dd, J 14.6 and 5.3, H(6)endo), 3.1–3.3 (1H, m, H(5)), 3.53

(1H, t, J 8.4, H(4)exo), 4.17 (1H, t, J 7.8, H(4)endo), 4.37 (2H, q, J

7.2, CH₃CH₂O), 4.85 (1H, s, PhCHCN), 6.1 (1H, s, H(2)), 6.8–7.7

(10H, m, ArH); d_C(CDCl₃, 100.6 MHz) 14.0 (CH₃CH₂O), 28.8

(C(6)), 40.9 (CHCN), 56.2 (C(5)), 63.4 (CH₃CH₂O), 65.4 (C(7)),

71.7 (C(4)), 86.8 (C(2)), 118.7 (CN), 125.7, 126.0, 126.1, 128.2,

128.5, 128.6, 128.7, 128.9, 129.1, 130.0 (ArCH) 137.2 (ArC), 168.6,

169.7 (C O); m/z (ESI⁺) 412 (M+Na⁺,100%), 391 (M+H⁺, 18%);

HRMS [M+H⁺] Calculated for C₂₃H₂₃O₄N₂391.1658, Found:

391.1650.

(2R,5S,7R) and (2R,5S,7S)-Spiro[1-aza-8-oxo-2-phenyl-3-oxa-

bicyclo[3.3.0]octane]-7,3¢-[pyrrolidin-2¢-one] 6a and 6b

(2R,5S,7R)-1-Aza-7-(2,4-dinitrophenyl)-7-(ethoxycarbonyl)-3-

oxo-8-oxa-2-phenylbicyclo-[3.3.0] octane 5a

To a solution of the nitrile 3a (1.21 g, 3.80 mmol) in ethanol

(150 ml) was added CoCl₂·6H₂O (1.77 g, 7.40 mmol) and the

mixture was stirred for 5 min. NaBH₄(1.19 g, 31.5 mmol) was then

added portion-wise to the purple solution which was accompanied

by effervescence. After stirring for 16 h at RT, the ethanol was

removed in vacuo and NH₄OH (aq.) (45 ml, 0.1 M) and EtOAc

(150 ml) were added to the black residue with stirring. After

30 min, the black residue was removed by ﬁltration through

To a stirred suspension of pre-washed NaH (0.032 g, 0.22 mmol)

in dry THF (5 ml) at 0 ^◦C under a nitrogen atmosphere was added

a solution of lactam 2b (0.18 g, 0.60 mmol) in THF (5 ml), and the

mixture was stirred at RT for 20 min. A solution of 2,4-dinitro-1-

ﬂuorobenzene (0.1 ml, 0.8 mmol) in THF (5 ml) was added and the

mixture stirred initially at RT for 1 h followed by gentle reﬂux for 24

h. The reaction was quenched by pouring the mixture into NH₄Cl

(aq.)/EtOAc (1 : 1) (10 ml) and the aqueous portion extracted

with EtOAc (3 ¥ 10 ml). The organic extracts were combined,

washed with water (10 ml) and brine (10 ml), dried over MgSO₄

and the solvent removed in vacuo to give an oil, which was puriﬁed

by ﬂash column chromatography [(40/60) Petrol/EtOAc, 17 : 1]

to give the product 5a as a yellow solid as a single diastereomer

(1.0 g, 74%). R_f= 0.14 [EtOAc/(40–60) Petrol, 15 : 85]; [a]²_D²+7

R

Celite^ꢀ. The organic phase was washed with water (50 ml),

and the aqueous phase was extracted with EtOAc (50 ml). The

combined organic phase was dried over MgSO₄and concentrated

in vacuo to give the product as a dark oil. Puriﬁcation by ﬂash

column chromatography [MeOH/EtOAc, 1 : 19] gave 6a and 6b

(0.26 g, 25%) as a white solid as a mixture of partially separable

diastereomers.

◦

(c = 0.13 in DCM); m.p. 208–210 C; m_max/cm^-1(thin ﬁlm) 2945

Data for 6a. R_f= 0.24 [MeOH/EtOAc (1 : 19)]; m_max/cm^-1(thin

ﬁlm) 3300 (bm), 2944 (m), 2885 (m), 2247 (m), 1702 (s), 1694

(m), 1377 (m), 1355 (m); d_H(CDCl₃, 200 MHz) 2.0–2.3 (2H,

m, H(6)+H(4¢)), 2.5–2.8 (2H, m, H(6)+H(4¢)), 3.2–3.4 (1H, m,

H(5¢)), 3.5–3.65 (1H, m, H(5¢)), 3.7–3.85 (1H, m, H(4)), 4.0–

4.2 (1H, m, H(5)), 4.2–4.35 (1H, m, H(4)), 6.25 (1H, m, H(2)),

(m), 2254 (w), 1740 (s), 1704 (s), 1609 (m), 1542 (m), 1350 (m); d_H

(CDCl₃, 200 MHz) 1.23 (3H, t, J 7.1, CH₃CH₂O), 2.57 (1H, dd,

J 14.7 and 7.9, H(6)exo), 3.47 (1H, dd, J 14.7 and 7.8, H(6)endo),

3.90 (1H, t, J 8.3, H(4)endo), 4.03–4.15 (1H, m, H(5)), 4.23 (2H,

q, J 7.1, CH₃CH₂O), 4.43 (1H, dd, J 7.7 and 5.8, H(4)exo), 6.43

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6.9 (1H, bs, NH), 7.2–7.6 (5H, m, ArH); d_C(CDCl₃, 100.6

MHz) 31.8 (C(4¢)), 33.9 (C(6)), 39.9 (C(5¢)), 56.4 (C(5)), 56.5

(C(7)) 71.6 (C(4)), 87.2 (C(2)), 125.9, 128.5, 128.6 (ArCH), 138.8

1690 (m), 1496 (m); d_H(CDCl₃, 400 MHz) 1.15 (3H, d, J 7.0,

CHMe), 2.37 (2H, dd, J 7.7 and 4.9, 2xH(6)), 2.87 (1H, m, H(4¢)),

2.97 (1H, m, H(5a¢)), 3.83 (2H, m, H(5b¢)+H(4endo)), 4.1 (1H,

m, H(5)), 4.3 (1H, m, H(4exo)), 5.85 (1H, bs, NH), 6.3 (1H, s,

H(2)), 7.25–7.5 (5H, m, ArH); d_C(CDCl₃, 100.6 MHz) 15.3 (Me),

26.0 (C(6)), 37.2 (C(4¢)), 47.5 (C(5¢)), 56.5 (C(5)), 61.4 (C(7)), 71.8

(C(4)), 87.2 (C(2)), 128.6, 128.4, 125.9 (ArCH), 138.8 (ArC), 176.7,

(ArC), 176.2, 177.0 (C O); m/z (ESI⁺) 331 (M+MeCN+NH₄,

+

100%); HRMS [M+MeCN+Na⁺]: Calculated for C₁₇H₁₉O₃N₃Na

336.1324, Found: 336.1332.

Data for 6b. R_f= 0.36 [MeOH/EtOAc, 1 : 19]; m_max/cm^-1(thin

ﬁlm) 3279 (bm), 2895 (m), 1706 (s), 1493 (m), 1452 (m), 1356

(m), 1274 (m), 1222 (m); d_H(CDCl₃, 200 MHz) 1.75–1.9 (1H, m,

H(6)endo), 1.95–2.15 (1H, m, H(4¢)), 2.6–2.9 (2H, m, H(6)exo

+H(4¢)), 3.2–3.4 (1H, m, H(5¢)), 3.5 (1H, t, J 7.9, H(4)endo),

3.55–3.7 (1H, m, H(5¢)), 4.15–4.25 (1H, m, H(4)exo), 4.3–4.55

(1H, m, H(5)), 6.3 (1H, s, H(2)), 6.5–6.9 (1H, bs, NH), 7.2–7.6

(5H, m, ArH); d_C(CDCl₃, 100.6 MHz) 21.1 (C(4¢)), 35.8 (C(6)),

40.0 (C(5¢)), 56.4 (C(5)), 57.5 (C(7)), 72.0 (C(4)), 87.0 (C(2)),

126.0, 126.1, 128.5, 128.7, 129.1 (ArCH), 137.8 (ArC) 174.9,

176.1 (C O); m/z (ESI⁺) 297 (M+Na⁺, 100%); HRMS [M+H⁺]:

Calculated for C₁₅H₁₇O₃N₂274.1317, Found: 274.1304.

176.2 (C O); m/z (ESI⁺) 345 (M+MeCN+NH₄, 100%); HRMS:

+

[M+H⁺] Calculated for C₁₆H₁₉O₃N₂287.1396, Found 287.1392.

(2R,5S,7S,4¢S)-(4¢-Phenyl)-spiro[1-aza-8-oxo-2-phenyl-3-oxa-

bicyclo[3.3.0]octane]-7,3¢-[pyrrolidin-2¢-one] 7c

(37 mg, 21%); R_f= 0.25 [EtOAc]; [a]²_D⁵-63 (c = 0.24 in CHCl₃); m.p.

189–191 ^◦C; m_max/cm^-1(thin ﬁlm) 3278 (bm), 3063 (m), 3032 (m),

2884 (m), 2248 (m), 1702 (bs), 1603 (m); d_H(CDCl₃, 200 MHz)

1.9 (1H, dd, J 14 and 7.2, H(6)exo), 2.2 (1H, dd, J 13.9 and 4.5,

H(6)endo), 3.50–3.80 (3H, m, H(4)endo+H(5)+H(5¢)), 3.85–4.25

(3H, m, H(4)exo+H(5¢)+H(4¢)), 6.37 (1H, s, H(2)), 6.8 (1H, bs,

NH), 7.1–7.5 (10H, m, ArH); d_C(CDCl₃, 100.6 MHz) 27.6 (C(6)),

46.2 (C(5¢)), 48.4 (C(4¢)), 56.3 (C(5)), 62.5 (C(7)), 71.7 (C(4)), 87.3

(C(2)), 126.0, 127.7, 127.9, 128.4, 128.6, 129.1 (ArCH), 138.6,

139.1 (ArC) 175.4, 176.1 (C O); m/z (ESI+) 371 (M+Na⁺, 90%),

349 (M+H⁺, 79%), 542 (100%); HRMS: [M+H⁺]: Calculated for

C₂₁H₂₁O₃N₂349.1552, Found 349.1559.

Spirocyclisations: general method

To a solution of the nitriles 4a,b (0.5 mmol, 1 equiv.) in ethanol

(30 ml) was added CoCl₂·6H₂O or NiCl₂·6H₂O (1 mmol, 2.0 equiv.)

and the mixture was stirred for was stirred for 5 min. NaBH₄

(4.8 mmol, 9.7 equiv.) was then added portion-wise to the purple

solution which was accompanied by effervescence. After stirring

for 16 h at RT, the ethanol was removed in vacuo and NH₄OH

(aq.) (0.1 M, 10 ml) and EtOAc (20 ml) were added to the black

residue with stirring. After 30 min of stirring, the black residue

(3R,5S,9S)-3-Hydroxymethyl-9-phenyl-2,7-diaza-

spiro[4.4]nonane-1,6-dione 8a

To a solution of the spirolactam 7c (0.12 g, 0.34 mmol) in DCM

(10 ml) at RT was added TFA (0.30 ml, 3.89 mmol) drop-wise

with stirring. After 1 h of stirring at RT, the solvent was removed

in vacuo to yield a white solid 8a on puriﬁcation by ﬂash column

chromatography on alumina [MeOH] (0.074 g, 83%). R_f= 0.44

[MeOH] (on silica); m.p. 132–134 ^◦C; [a]_D²²-16 (c = 1.3 in MeOH);

m_max/cm^-1(thin ﬁlm) 3425 (bs), 2095 (w), 1676 (bs), 1434 (m),

1266 (m), 1205 (m), 1139 (m); d_H(DMSO, 200 MHz) 1.50–

2.00 (2H, m, 2xH(4)), 2.95–3.15 (1H, m, H(3)), 3.25–4.10 (5H,

m, 2xH(8)+H(9)+CH₂OH), 7.1–7.5 (5H m, ArH); d_C(DMSO,

100.6 MHz) 29.3 (C(4)), 45.5 (C(9)), 47.8 (C(8)), 53.6 (C(3)), 58.3

(C(5)), 65.8 (CH₂OH), 128.0, 128.6, 129.2, 129.5 (ArCH), 140.4

(ArC), 175.9, 176.5 (C O); m/z (ESI⁺) 283 (M+Na⁺, 100%),

261 (M+H⁺, 48%); HRMS [M+H⁺]: Calculated for C₁₄H₁₇O₃N₂

261.1239, Found: 261.1243.

R

was removed by ﬁltration through Celite^ꢀ. The organic phase

was washed with water (20 ml), and the aqueous phase extracted

with EtOAc (3 ¥ 10 ml). The combined organic phase was dried

over MgSO₄and concentrated in vacuo to give dark oil. After

puriﬁcation by ﬂash column chromatography, all products were

obtained as white solids.

(2R,5S,7S,4¢S)-(4¢-Methyl)-spiro[1-aza-8-oxo-2-phenyl-3-oxa-

bicyclo[3.3.0]octane]-7,3¢-[pyrrolidin-2¢-one] 7a

A mixture of partially separable diastereomers was formed (ratio

1:1) (14.5 mg, 10%); R_f= 0.41 [EtOAc/MeOH, 19 : 1]; m_max/cm^-1

(thin ﬁlm) 3283 (bm), 2926 (m), 1693 (s), 1452 (m), 1381 (m), 1355

(m), 1266 (m), 1156 (m); d_H(CDCl₃, 200 MHz) 1.2 (3H, d, J 7.9,

CHMe), 2.05 (1H, dd, J 7.9 and 4.4, H(6)exo), 2.30–2.60 (1H, m,

H(4¢)), 2.67 (1H, dd, J 13.8 and 4.4, H(6)endo) 3.35 (2H, d, J 9.1,

2xH(5¢)), 3.55–3.75 (1H, m, H(4)endo), 4.00–4.15 (1H, m, H(5)),

4.20–4.35 (1H, m, H(4)exo), 5.85 (1H, bs, NH), 6.25 (1H, s, H(2)),

7.2–7.5 (5H, m, ArH); d_C(CDCl₃, 100.6 MHz) 13.0 (MeCH),

30.6 (C(6)), 41.2 (C(4¢)), 46.6 (C(5¢)), 56.7 (C(5)), 61.8 (C(7)), 72.0

(C(4)), 87.1 (C(2)), 125.9, 128.4, 128.5 (ArCH), 138.8 (ArC), 174.7,

175.9 (C O); m/z (ESI+) 287 (M+H⁺, 100%), 304 (M+Na⁺,

65%); HRMS: [M+MeCN+Na⁺] Calculated for C₁₈H₂₁O₃N₃Na

350.1481, Found: 350.1488.

(3R,5S,9S)-3-Methyloxycarbonyl-9-phenyl-2,7-diaza-

spiro[4.4]nonane-1,6-dione 8c

To a stirred solution of lactam 8a (0.76 g, 2.9 mmol) in acetonitrile

(35 ml) was added a solution of NaIO₄(4.78 g, 22.0 mmol) in

water (50 ml) and the reaction mixture was stirred at RT for 10

min. RuCl₃.H₂O (0.09 g, 0.4 mmol) was added and the reaction

mixture was allowed to stir for 16 h. The solvents were removed

in vacuo and the residue was dissolved in THF (50 ml). A solution

of diazomethane in ether was then added until in excess, and

stirring continued for 1 h. Water (70 ml) was added to the mixture,

the layers separated and the product extracted with EtOAc (3

¥ 70 ml). The organic phases were combined, dried over MgSO₄

and the solvent was removed in vacuo. Puriﬁcation by ﬂash column

chromatography with EtOAc and then MeOH gave the product

(2R,5S,7S,4¢R)-(4¢-Methyl)-spiro[1-aza-8-oxo-2-phenyl-3-oxa-

bicyclo[3.3.0]octane]-7,3¢-[pyrrolidin-2¢-one] 7b

(14.5 mg, 10%); R_f= 0.29 [EtOAc/MeOH, 19 : 1]; m_max/cm^-1(thin

ﬁlm) 3380 (bw), 3035 (m), 2968 (s), 2249 (w), 1747 (m), 1716 (m),

7050 | Org. Biomol. Chem., 2011, 9, 7042–7056

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as a single diastereomer 8c (0.126 g, 15%) as a pale oil. R_f= 0.03

[EtOAc]; m_max/cm^-1(thin ﬁlm) 3233 (s), 3011 (s), 1720 (bs), 1438

(s); d_H(CDCl₃, 400 MHz) 1.97–2.10 (1H, m, H(4)exo), 2.43 (1H,

dd, J13.7 and 4.1, H(4)endo), 3.53–3.60 (1H, m, H(9)), 3.73 (3H,

s, OMe), 3.83–3.90 (1H, m, H(3)), 3.93–4.03 (2H, m, 2xH(8)),

7.15–7.40 (5H, m, ArH), 6.9–7.1 (2H, bs, NH); d_C(CDCl₃, 100.6

MHz) 30.1 (C(4)), 46.4, 46.5 (C(8)+C(9)), 52.6 (MeO), 53.1 (C(3)),

127.8, 127.8, 129.1 (ArCH), 140.0 (ArC), 171.2, 171.5, 175.6, 175.7

(C O); m/z (ESI+) 311 (M+Na⁺, 72%), 289 (M+H⁺, 29%), 599

(100%); HRMS [M+H⁺]: Calculated for C₁₅H₁₇N₂O₄289.1188,

Found 289.1187.

The resultant mixture was heated at a gentle reﬂux for 2.5 h.

Subsequent workup involved hot ﬁltration and a hot methanol

wash (2 ¥ 2 ml), and the solvent was removed from the combined

washings in vacuo. Puriﬁcation by ﬂash column chromatography

with an eluent of [EtOAc/(40–60) Petrol, 3 : 7] gave white solids

(20 mg, 32%) in a ratio of 1 : 1.

Data for 11a. R_f= 0.05 [EtOAc/Petrol (40–60), 3 : 7]; [a]²_D³+10

◦

(c = 0.12 in DCM); m.p. 246–248 C; m_max/cm^-1(thin ﬁlm) 3265

(m), 2917 (m), 1700 (m), 1672 (m), 1595 (m), 1497 (m), 1374 (m);

d_H(CDCl₃, 200 MHz) 2.23 (1H, dd, J 13.8 and 7.6, H(6)exo), 2.67

(1H, dd, J 13.8 and 4.5, H(6)endo), 3.13 (1H, d, J 16.0, CHHPh),

3.47 (1H, d, J 16.0, CHHPh), 3.75 (1H, t, J 8.1, H(4)exo), 4.10–

4.25 (1H, m, H(5)), 4.30 (1H, dd, J 7.45 and 6.05, H(4)endo), 6.30

(1H, s, H(2)), 6.8 (1H, d, J 7.2, ArH), 6.95–7.57 (6H, m, ArH), 8.1

(1H, bs, NH); d_c(125.75 MHz, CDCl₃) 32.3 (C(6)), 36.7 (CH₂Ph),

54.8 (C(7)), 55.8(C(5)), 71.5 (C(4)), 87.5(C(2)), 115.0, 123.5, 126.0,

128.1, 128.3, 128.4, 128.7 (ArCH), 120.8, 136.5, 138.7 (ArC),

169.4, 175.3 (C O); m/z (ESI⁺) 393 (M+NH₄+MeCN⁺,100%);

HRMS [M+Na⁺] Calculated for C₂₀H₁₈N₂O₃Na 357.1215, Found

357.1221.

(2R,5S,7S)-Spiro[1-aza-8-oxo-2-phenyl-3-oxa-bicyclo[3.3.0]-

octane-7,3¢-[1¢,3¢-dihydro-2¢-oxo-7¢-aminoindolinone] 9

To a mixture of iron powder (340 mg, 0.0061 M) and ammonium

chloride solution (aq.) (0.60 g, 0.012 M) in distilled water (10 ml)

was added a methanolic solution of the substrate 5a (0.45 g,

0.0011 M in 50 ml) over 10 min at RT. The resultant mixture

was heated at gentle reﬂux for 2.5 h. Subsequent work up involved

R

suction ﬁltration through Celite^ꢀ, washing with methanol (50 ml)

and evaporation of the combined washings to dryness in vacuo.

Puriﬁcation by ﬂash column chromatography with an eluent of

[EtOAc/(40–60) Petrol, 3 : 7] gave the product 9 as a white solid

(42 mg, 15%) as a single isomer. R_f= 0.36 [EtOAc]; [a]²_D³+ 190 (c

= 0.3 in DCM); m.p. 152–155 ^◦C; m_max/cm^-1(thin ﬁlm) 3369 (bs),

1724 (s), 1692 (s), 1636 (s), 1512 (m), 1471 (m), 1340 (m), 1264 (m);

d_H(400 MHz, CDCl₃) 1.69 (2H, bs, NH₂), 2.53 (1H, dd, J 13.6 and

7.2, H(6)), 2.69 (1H, dd, J 13.7 and 5.1, H(6)) 3.85–3.95 (1H, m,

H(4)), 4.33–4.45 (2H, m, H(4)+H(5)), 6.15–6.20 (1H, m, H(8¢)),

6.28 (1H, dd, J 8.0 and 1.5 H(6¢)), 6.37 (1H, s, H(2)), 6.99 (1H, d, J

8.1, H(5¢)), 7.35–7.52 (5H, m, ArH), 8.27 (1H, bs, NH); d_C(CDCl₃,

100.6 MHz) 33.6 (C(6)), 56.9 (C(5)), 71.9 (C(4)), 87.3 (C(2)), 97.9

(C8¢), 109.0 (C(6)_¢), 123.5 (C(5¢)), 126.0, 128.5 (ArCH), 128.7

138.4, 142.2, 147.9 (ArC), 174.2, 176.70 (C O); m/z (ESI+) 358

(100%, M+Na⁺), 336 (57%, M+H⁺); HRMS [M+Na⁺] Calculated

for C₁₉H₁₇N₃O₄Na 358.1168, Found: 358.1162.

Data for 11b. R_f= 0.13 [EtOAc/(40–60) Petrol, 3 : 7]; [a]²_D³+250

◦

(c = 0.35 in DCM); m.p. 101–103 C; m_max/cm^-1(thin ﬁlm) 2922

(s), 2851 (m), 1709 (s), 1675 (s), 1597 (m), 1461 (m), 1374 (m),

1322 (m), 1249 (m); d_H(CDCl₃, 200 MHz) 1.83 (1H, dd, J 13.1

and 7.1, H(6)), 2.77 (1H, dd, J 13.1 and 6.7, H(6)), 2.95 (1H,

d, J 16.2, CHHPh), 3.50–3.63 (2H, m, H(4)+CHHPh), 4.20–4.30

(1H, m, H(5)), 4.37 (1H, t, J 6.9, H(4)), 6.37 (1H, s, H(2)), 6.70–

6.78 (1H, m, ArH), 7.0–7.57 (7H, m, ArH), 8.60 (1H, bs, NH);

d_C(CDCl₃, 100.6 MHz) 35.2 (C(6)), 37.4 (CH₂Ph), 56.0 (C(7)),

56.4 (C(5)), 72.0 (C(4)), 87.0 (C(2)), 115.0, 123.7, 126.2, 127.8,

128.4, 128.5, 128.7 (ArCH), 121.6, 135.8, 137.6 (ArC), 169.3,

172.9 (C O); m/z (ESI⁺) 393 (M+NH₄+MeCN⁺, 100%); HRMS:

[M+H⁺] Calculated for C₂₀H₁₉N₂O₃335.1396, Found: 335.1389.

(2R,5S,7R) and (2R,5S,7S)-1-Aza-7-(2-oxo-2-phenylethyl)-7-

(ethoxycarbonyl)-3-oxo-8-oxa-2-phenyl-bicyclo[3.3.0] octane 12a

7¢-Amino-3¢-hydroxymethyl-1H-spiro[indole-3,3¢-pyrrolidine]-1,2¢-

dione 10

To a stirred suspension of pre-washed NaH (0.15 g, 6.0 mmol) in

dry THF (40 ml) at 0 C under nitrogen atmosphere was added

◦

a solution of lactam 2b (0.88 g, 3.2 mmol) in THF (20 ml),

and the mixture was stirred at RT for 20 min. A solution of a-

bromoacetophenone (1.05 g, 2.70 mmol) in THF (20 ml) was

added and the mixture was stirred at RT for 16 h. The reaction

was quenched by pouring the mixture into NH₄Cl (aq.)/EtOAc

(1 : 1) (100 ml) and the aqueous portion was extracted with EtOAc

(2 ¥ 50 ml). The organic extracts were combined, washed with

water (50 ml) and sat. brine (50 ml), dried over MgSO₄and the

solvent removed in vacuo, which was puriﬁed by ﬂash column

chromatography [(40/60) Petrol/EtOAc, 40 : 1] to give 12a (0.74 g,

59%) as a pale yellow oil and as an inseparable mixture of

diastereomers A and B (ratio B : A 1 : 2). R_f= 0.20 [EtOAc/(40–60)

Petrol, 1 : 4]; m_max/cm^-1(thin ﬁlm) 3064 (m), 2983 (m), 2253 (m),

1721 (s), 1707 (s), 1699 (s); d_H(CDCl₃, 200 MHz) 1.23–1.37 (6H,

m, CH₃CH₂O(A+B)) 1.93 (1H, dd, J 13.3 and 7.0, H(6)(B)), 2.40

(1H, dd, J 14.5 and 8.2, H(6)(A)), 3.03 (1H, dd, J 14.5 and 3.9,

H(6)(A)), 3.25 (1H, dd, J13.3 and 7.3, H(6)(B)), 3.27–3.5 (2H, d, J

18.7, CHHCOPh(A+B)), 3.70 (1H, t, J 7.9, H(4)(B)), 3.80 (1H, t,

J 8.3, H(4)(A)), 4.03–4.57 (10H, m, H(5) (A+B)+H(4)(A+B)+

To a stirred solution of spirolactam 9 (0.075 g, 0.20 mmol) in

DCM (8 ml) at RT was added TFA (0.3 ml, 6.5 mmol). After 2

h at RT, the solvent was removed in vacuo to yield the product

10 as a viscous oil (33 mg, 60%) as a single isomer. d_H(D₂O, 200

MHz) 2.37 (1H, dd, J 14.0 and 6.7, H(4)), 2.53 (1H, dd, J 13.9

and 7.7, H(4)), 3.60 (1H, dd, J 11.6 and 6.4, CHHOH), 3.73 (1H,

dd, J 11.6 and 4.5, CHHOH), 4.07–4.20 (1H, m, H(3)), 6.95 (1H,

d, J 1.8, ArH), 7.0 (1H, d, J 2.0, ArH), 7.05 (1H, d, J 2.1, ArH),

7.37 (1H, d, J 8.0, ArH); d_C(D₂O, 125.75 MHz) 32.6 (C(4)), 54.2

(C₃), 64.0 (CH₂OH), 105.8, 124.3 (ArCH); HRMS (Probe EI/FI):

Calculated for C₁₂H₁₃N₃O₃247.0957, Found: 247.1657.

(2R,5S,7S/R)-Spiro-[1-aza-8-oxo-2-phenyl-3-oxa-bicyclo-

[3.3.0]octane]-7,3¢-[3¢,4¢-dihydro-2¢-oxo-3¢-quinoline] 11a,b

A methanolic solution of the substrate 3b (0.18 g, 0.43 mmol)

in water (2.3 ml) was added to a stirred slurry of iron powder

(77.5 mg, 1.4 mmol) and ammonium chloride (0.12 g, 2.3 mmol)

in distilled water (2.2 ml) over a duration of 10 min at RT.

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CHHCOPh (A+B)+CH₃CH₂O(A+B)), 6.27 + 6.35 (2H, s,

H(2)(A+B)), 7.05–7.67+ 7.67–8.10 (20H, m, ArH (A+B)); d_C

(CDCl₃, 100.6 MHz) 13.9 (CH₃CH₂O(A+B)), 31.6 (C(6)(A)),

36.2 (C(6)(B)), 43.4 (CH₂COPh(B)), 44.0 (CH₂COPh(A)), 56.6

(C(5)(A)), 57.2 (C(5)(B)), 57.6 (C(7)(A)), 58.6 (C(7)(B)), 62.0, 62.1

(CH₃CH₂O(A+B)), 71.4 (C(4)(A)), 72.3 (C(4)(B)) 87.2 (C(2)(B)),

87.6 (C(2)(A)), 126.0, 126.1, 128.0, 128.1, 128.3, 128.5, 128.70,

129.7, 133.6, 133.6 (ArCH(A+B)), 136.1, 136.2, 138.1, 138.6

(ArC(A+B)), 170.1, 172.7, 196.5, 196.8(C O(A+B)); m/z (ESI⁺)

(2R,5S,7R,5¢R) and (2R,5S,7S,5¢S)-Spiro[1-oxa-8-oxo-2-phenyl-

3-oxa-bicyclo[3.3.0]octane]-7,3¢-[5¢-hydroxymethyldihydrofuran-

2¢-one] 13b and 13b¢

The lactam 12b (0.25 g, 0.80 mmol) was dissolved in acetone

(60 ml) and distilled water (7 ml). At -10 ^◦C with stirring,

K₂OsO₄·2H₂O (0.03 g, 0.08 mmol) was added and the reaction

mixture was allowed to stir at RT for 2 days, after which the

reaction had produced a black precipitate which was ﬁltered

under suction. The ﬁltrate was diluted with Na₂SO₃(aq.) (20 ml)

and extracted with EtOAc (2 ¥ 40 ml). The organic layers were

combined, dried over Na₂SO₄and the solvent removed in vacuo.

Puriﬁcation was by ﬂash column chromatography with an eluent

of [EtOAc/(40–60) Petrol, 3 : 1] to give a white solid as a partially

separated mixture of diastereomers 13b and 13b¢ (35 mg, 15%).

452 (M+MeCN+NH₄,100%); HRMS [M+H⁺] Calculated for

+

C₂₃H₂₄NO₅394.1654, Found: 394.1646.

(2R,5S,7R,5¢R), (2R,5S,7S,5¢S) and (2R,5S,7R,5¢S)-Spiro[1-

oxa-8-oxo-2-phenyl-3-oxa-bicyclo[3.3.0]octane]-7,3¢-[5¢-

phenyldihydrofuran-2¢-one] 13a

Data for 13b. R_f= 0.31 [EtOAc/(40–60) Petrol, 3 : 1]; [a]_D²³

◦

+89 (c = 0.04 in CHCl₃); m.p. 156–158 C; m_max/cm^-1(thin ﬁlm)

The lactam 12a (0.83 g, 2.1 mmol) were dissolved in EtOH (55 ml).

At 0 ^◦C, NaBH₄(0.094 g, 2.5 mmol) was added portion-wise

and the mixture was stirred for 2 h. The reaction mixture was

acidiﬁed with glacial acetic acid until the solution was neutral in

3490 (bm), 3030 (s), 1748 (s), 1691 (s), 1349 (m), 1158 (m), 1048

(m); d_H(CDCl₃, 400 MHz) 2.27–2.47 (2H, m, H(6)+H(4¢)), 2.60–

2.80 (2H, m, H(4¢)+H(6)), 3.60 (1H, bd, J 11.2, CHHOH), 3.75

(1H, t, J 8.3, H(4)), 4.03 (1H, bd, J 12.3, CHHOH), 4.15 (1H,

bs, H(5)), 4.3 (1H, t, J 6.6, H(4)), 4.93 (1H, bs, H(5¢)), 6.25

(1H, s, H(2)), 7.30–7.55 (5H, m, ArH); d_C(CDCl₃, 100.6 MHz)

32.3, 35.4 (C(6)+C(4¢)), 56.6 (C(5)), 57.7 (C(7)), 62.3 (CH₂OH),

71.6 (C(4)), 78.6 (C(5¢)), 87.4 (C(2)), 125.9, 128.5, 128.9 (ArCH),

138.2 (ArC), 174.8, 175.5 (C O); m/z (ESI-) 302 (M–H^-, 48%),

362 (100%); HRMS [M+H⁺] Calculated for C₁₆H₁₈NO₅304.1185,

Found: 304.1184.

R

pH, ﬁltered through a bed of Celite^ꢀand the solvent removed in

vacuo. Puriﬁcation by ﬂash column chromatography [EtOAc/(40–

60) Petrol, 1 : 5] gave the product isomers as white solids (0.18 g,

25%).

Data for 13a. R_f= 0.17 [EtOAc/(40–60) Petrol, 3.5 : 6.5]; [a]_D²¹

◦

+155 (c = 0.2 in CHCl₃); m.p. 197–200 C; m_max/cm^-1(thin ﬁlm)

1752 (m), 1708 (m), 1458 (m), 1387 (w), 1332 (w); d_H(CDCl₃,

200 MHz) 2.45–2.95 (4H, m, 2xH(6)+2xH(4¢)), 3.85 (1H, dd, J

8.6 and 7.8, H(4) endo), 4.10–4.25 (1H, m, H(5)), 4.35 (1H, dd,

J 7.5 and 6.1, H(4)exo), 5.5 (1H, dd, J 9.6 and 6.8, H(5¢)), 6.4

(1H, s, H(2)), 7.30–7.55 (10H, m, ArH); d_C(CDCl₃, 100.6 MHz),

33.2 (C(6)), 42.7 (C(4¢)), 56.5 (C(5)), 57.0 (C(7)), 71.1 (C(4)),

79.7 (C(5¢)), 87.7 (C(2)), 125.9, 126.0, 128.5, 128.8, 128.9, 129.0

(ArCH), 137.9, 138.3 (ArC), 174.8 + 175.6 (C O); m/z (ESI⁺)

Data for 13b¢. R_f= 0.19 [EtOAc/(40–60) Petrol, 3 : 1],

m_max/cm^-1(thin ﬁlm) 3427 (bs), 2931 (w), 1773 (m), 1697 (m), 1448

(m); d_H(CDCl₃, 200 MHz) 1.97 (1H, dd, J 13.1 and 7.3, H(6)), 2.2

(1H, dd, J 12.9 and 8.7, H(4¢)), 2.83 (1H, dd, J 12.9 and 6.9, H(4¢)),

2.87 (1H, dd, J 13.1 and 6.9, H(6)) 3.57 (1H, t, J 7.9, H(4)), 3.63

(1H, d, J 12.5, CHHOH), 4.03 (1H, d, J 12.6, CHHOH) 4.23 (1H,

dd, J 8.3 and 6.5, H(4)), 4.45–4.55 (1H, m, H(5)), 4.9–4.97 (1H,

m, H(5¢)), 6.3 (1H, s, H(2)), 7.3–7.5 (5H, m, ArH); d_C(CDCl₃,

100.6 MHz) 32.6 (C(4¢)), 36.4 (C(6)), 56.3 (C(5)), 58.2 (C(7)),

62.8 (CH₂OH), 71.7 (C(4)), 79.1 (C(5¢)), 87.0 (C(2)), 126.0, 128.6,

128.9 (ArCH), 137.2 (ArC), 172.2, 175.2 (C O); m/z (ESI⁺) 362

(M+NH₄+MeCN⁺, 100%); HRMS [M+MeCN+Na⁺] Calculated

for C₁₈H₂₀N₂O₅Na 367.1270, Found: 367.1270.

408 (M+MeCN+NH₄, 100%); HRMS: [M+H⁺] Calculated for

+

C₂₁H₂₀NO₄350.1392, Found: 350.1405.

Data for 13a¢. R_f= 0.07 [EtOAc/(40–60) Petrol, 1 : 5], d_H

(CDCl₃, 200 MHz) 1.95 (1H, dd, J 13 and 7.3, H(6) endo), 2.15

(1H, dd, J 12.9 and 9.7, H(4b¢)), 2.87 (1H, dd, J 12.9 and 6.8,

H(6)exo), 3.20 (1H, dd, J 13, 6.3, H(4a¢)), 3.60 (1H, dd, J 8.35 and

7.2, H(4)endo), 4.25 (1H, dd, J 8.3 and 6.5, H(4)exo), 4.50–4.67

(1H, m, H(5)), 5.90(1H, dd, J 9.7and6.2, H(5¢)), 6.37(1H, s, H(2)),

7.30–7.63 (10H, m, ArH); d_C(CDCl₃, 100.6 MHz), 36.0 (C(6)),

40.8 (C(4¢)), 56.4 (C(5)), 58.4 (C(7)), 71.7 (C(4)), 79.9 (C(5¢)), 87.1

(C(2)), 125.5, 126.0, 128.6, 128.7, 128.8, 129.0 (ArCH), 137.1,

138.6 (ArC), 172.2, 174.9 (C O).

(2R,5S,7R,5¢R)- and (2R,5S,7S,5¢R)-Spiro[1-oxa-8-oxo-2-phenyl-

3-oxa-bicyclo[3.3.0]-octane]-7,3¢-[5¢-iodomethyldihydrofuran-2¢-

one] 14a,b

The lactam 12b (0.17 g, 0.50 mmol) was dissolved in a mixture

of MeOH/water (3 : 1) (11 ml) containing LiOH·H₂O (0.090 g,

2.1 mmol) and stirred at RT for 16 h. The resulting reaction mixture

was then diluted with EtOAc (25 ml), washed with 1% HCl (aq.)

(25 ml) and then extracted with EtOAc (2 ¥ 25 ml). The organic

layers were combined and washed with water (10 ml). The solvent

was removed in vacuo to yield the acid (0.15 g, 100%) as a mixture

diastereomers A and B (2 : 1 A : B). m_max/cm^-1(thin ﬁlm) 2982

(bs), 1708 (bs), 1378 (s), 1026 (s); d_H(CDCl₃, 200 MHz) 1.93

(1H, dd, J 13.5 and 6.4, H(6)(B)), 2.47–2.95 (7H, m, 2xH(6)(A)+

H(6) (B)+ 2xH(8)(A+B))), 3.47–3.70 (2H, m, H(4)(A+B)), 4.03–

4.20 (1H, m, H(5)(A)), 4.20–4.40 (3H, m, H(5)(B)+H(4)(A+B)),

Data for 13a¢¢. R_f= 0.04 [EtOAc/(40–60) Petrol, 1 : 5]; d_H(200

MHz, CDCl₃) 2.20–2.40 (2H, m, H(6) exo+H(4a¢)), 2.75 (1H, dd,

J 14.0 and 4.4, H(6)endo), 3.13 (1H, dd, J 13.0 and 3.0, H(4b¢)),

3.80 (1H, m, H(4)exo), 4.07–4.25 (1H, m, H(5)), 4.30–4.43 (1H,

m, H(4)endo), 5.83–5.97 (1H, m, H(5¢)), 6.30 (1H, s, H(2)), 7.20–

7.60 (10H, m, ArH); d_C(CDCl₃, 100.6 MHz), 31.9 (C(6)), 43.5

(C(4¢)), 56.6 (C(5)), 58.1 (C(7)), 71.7 (C(4)), 79.2 (C(5¢)), 87.5

(C(2)), 125.5, 126.0, 128.6, 128.8, 128.9, 128.9 (ArCH), 138.1,

138.2 (ArC), 174.6, 175.0 (C O).

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5.03–5.33 (4H, m, 2xH(10)(A+B)), 5.60–5.90 (2H, m, H(9)(A+B)),

6.33 (2H, s, H(2)(A+B)) 7.30–7.55 (10H, m, ArH(A+B)), 8.63

(2H, bs, CO₂H(A+B)); d_C(CDCl₃, 100.6 MHz) 31.7 (C(6)(A)),

33.8 (C(6)(B)), 38.6 (C(8) (B)), 40.3 (C(8) (A)), 56.1 (C(5) (A)),

56.3 (C(5)(B)), 71.9 (C(4)(A)), 72.0 ((C(4)(B)), 87.0 (C(2)(B)), 87.1

(C(2)(A)) 120.0 (C(10) (B)), 120.7 (C(10)(A)), 125.9, 126.1, 128.5,

128.6, 128.8, 129.0(ArCH (A+B)), 137.6, 137.7 (ArC), 131.3, 132.4

(C(9)(A+B)), 172.8, 176.0 (C O(A)), 173.4, 174.2 (C O(B));

m/z (ESI^-) 242 (M–CO₂–H^-, 100%) 286 (M–H^-, 80%); HRMS

[M+H⁺]: Calculated for C₁₆H₁₈NO₄288.1236 Found: 288.1234.

The above acid (0.21 g, 0.70 mmol) was dissolved in NaHCO₃

(4 ml, 1 M) and a solution of I₂(0.18 g, 0.70 mmol) and KI (0.36 g,

2.0 mmol) in water (13 ml) added drop-wise. The mixture was left

to stir for 1 h at RT. The product was then extracted into ether

(20 ml) and then washed with 5% Na₂SO₃·5H₂O (aq.) (20 ml), sat.

brine (20 ml) and then dried over MgSO₄. The organic layer was

then ﬁltered and concentrated in vacuo which was puriﬁed by ﬂash

column chromatography [(40–60) Petrol/EtOAc, 7 : 3] to give a

mixture of 14a and 14b diastereomers as partially separable white

solids (60 mg, 20%).

(2.12 g, 65%). R_f0.54 [EtOAc]; d_H(400 MHz, CDCl₃) 1.24 (3H, t,

J 7.1, CH₃CH₂O), 1.43 (9H, s, (CH₃)₃O), 1.92–2.06 (1H, m, H(3)),

2.22–2.36 (1H, m, H(3)), 2.38–2.51 (1H, m, H(4)), 2.52–2.66 (1H,

m, H(4)), 4.18 (2H, q, J 7.1, CH₃CH₂O), 4.55 (1H, dd, J 9.2,

3.0, H(4)); d_C(100 MHz, CDCl₃) 14.0 (CH₃CH₂O), 21.4 (C(3)),

27.7 ((CH₃)₃CO), 31.0 (C(4)), 58.8 (C(2)), 61.5 (CH₃CH₂O), 83.4

((CH₃)₃CO), 149.1, 171.2, 173.3 (C O); m/z (ESI⁺) 280 (100%,

M+Na⁺.).

(S)-1-(tert-Butoxycarbonyl)-4-(ethoxycarbonyl)pyroglutamate

15b⁷¹

To a stirred solution of 15a (0.37 g, 1.44 mmol) in dry THF (5 ml) at

-78 ^◦C was added a 1 M solution of lithium hexamethyldisilazide

(2.93 ml, 2.88 mmol) in THF (5 ml). After stirring for 1 h,

ethyl chloroformate (0.16 ml, 1.73 mmol) was added and stirring

continued for 16 h, allowing the reaction to warm to RT.

The reaction mixture was quenched with saturated ammonium

chloride solution (10 ml) and extracted with EtOAc (3 ¥ 5 ml).

The combined organics were dried over MgSO₄and concentrated

in vacuo. The resulting oil was puriﬁed by ﬂash chromatography

[40/60 Petrol : EtOAc (4 : 1)] yielding 15b as an inseparable mixture

of two diastereoisomers in the ratio of 2 : 1 (0.31 g, 65%). R_f

0.21 [EtOAc/(40/60) Petrol, 1 : 2]; [a]²_D²-10.6 (c = 2.6 in CHCl₃);

m_max/cm^-1(thin ﬁlm) 2983 (bm), 1797 (s), 1736 (s), 1459 (s), 1371

(m), 1153 (m), 1028 (m); d_H(500 MHz, C₆D₆) 0.86–0.94 (6H,

t, J 7.1, CH₃CH₂O), 1.35 (9H, s, (CH₃)₃CO(A)), 1.39 (4.5H, s,

(CH₃)₃CO(B)), 1.62–1.72 (1.5H, m, H(3)(A+B)), 2.29–2.41 (1.5H,

m, H(3)(A+B)), 3.00 (0.5H, dd, J 9.8 and 4.9, H(4)(B)), 3.47 (1H,

dd, J 10.7 and 9.0, H(4)(A)), 3.81–4.07 (8H, m, CH₃CH₂O(A+B)),

4.33 (0.5H, dd, J 9.5 and 4.1, H(2)(B)), 4.43 (1H, dd, J 9.6 and

2.1, H(2)(A)); d_C(100 MHz, C₆D₆) 14.4 (CH₃CH₂O(A+B)), 24.9

(C(3)(A)), 25.7 (C(3)(B)), 28.2 ((CH₃)₃CO(A+B)), 49.3 (C(4)(A)),

49.5 (C(4)(B)), 57.6 (C(2)(A)), 58.0 (C(2)(B)), 61.8 (CH₃CH₂O(B)),

61.9 (CH₃CH₂O(A)), 62.1 (CH₃CH₂O(B)), 62.2 (CH₃CH₂O(A)),

83.6 ((CH₃)₃CO(B)), 83.8 ((CH₃)₃CO(A)), 150.6, 150.7, 166.8,

167.6, 168.1, 168.6, 170.9, 171.4 (C O); HRMS: [M+Na⁺.]

Calculated for C₁₅H₂₃NNaO₇352.1367, Found: 352.1358.

Data for 14a. R_f= 0.20 [EtOAc/(40–60) Petrol, 3 : 7]; [a]²_D³+150

◦

(c = 0.69 in DCM), m.p. 179–180 C; m_max/cm^-1(thin ﬁlm) 2916

(w), 1772 (s), 1699 (s), 1495 (m), 1453 (m), 1352 (m); d_H(CDCl₃,

200 MHz) 2.05 (1H, dd, J 13.1 and 9.5, H(4b¢)) 2.30 (1H, dd, J

14.1 and 7.8, H(6)exo), 2.73 (1H, dd, J 14.1 and 4.4, H(6)endo),

2.95 (1H, dd, J 13.1 and 6, H(4a¢)), 3.35 (1H, dd, J 10.6 and 4.2,

CHHI), 3.45 (1H, dd, J 10.5 and 7.3, CHHI), 3.75 (1H, t, J 8.1,

H(4)endo), 4.07–4.27 (1H, m, H(5)), 4.83 (1H, dd, J 7.8 and 6.0,

H(4)exo), 4.75–4.95 (1H, m, H(5¢)), 6.33 (1H, s, H(2)), 7.27–7.60

(5H, m, ArH); d_C(CDCl₃, 100.6 MHz) 6.5 (CH₂I), 31.8 (C(6)),

41.4 (C(4¢)), 56.6 (C(5)), 58.1 (C(7)), 71.8 (C(4)), 76.1 (C(5¢)),

87.5 (C(2)), 125.9, 128.6, 128.9 (ArCH), 138.1 (ArC), 174.4, 174.5

(C O); m/z APCI (NH₃) 414 (M+H⁺, 100%); HRMS [M+H⁺]

Calculated for C₁₆H₁₇O₄IN 414.0202, Found: 414.0198.

Data for 14b. R_f= 0.11 [EtOAc/(40–60) Petrol, 3 : 7]; [a]²_D¹+1.4

◦

(c = 0.03 in DCM); m.p. 136–138 C; d_H(CDCl₃, 200 MHz) 2.0

(1H, dd, J 13.1 and 7.8, H(6)endo), 2.37 (1H, dd, J 13.9 and 8.1,

H(4b¢)), 2.75–2.95 (2H, m, H(6)exo+H(4a¢)), 3.43–3.70 (3H, m,

H(4)endo+CH₂I), 4.25 (1H, dd, J 8.45 and 6.4, H(4)exo), 4.45–4.55

(1H, m, H(5)), 4.55–4.85 (1H, m, H(5¢)), 6.33 (1H, s, H(2)), 7.30–

7.57 (5H, m, ArH); d_C(CDCl₃, 100.6 MHz) 6.0 (CH₂I) 36.2 (C(6)),

37.7 (C(4¢)), 56.3 (C(5)), 58.0 (C(7)), 71.7 (C(4)), 77.9 (C(5¢)),

87.2 (C(2)), 125.9, 128.7, 129.0 (ArCH), 137.0 (ArC), 174.7, 175.6

(C O).

(2S)-1-(tert-Butoxycarbonyl)-2,4-diethyl-4-(2,4-dinitrophenyl)-5-

oxopyrrolidine-2,4-dicarboxylate 16a

To a stirred suspension of 15b (1.58 g, 4.8 mmol) in dry DMF

(35 ml) was added Et₃N (0.53 g, 5.3 mmol). The mixture was left

stirring for 20 min and then 2,4-dinitro-1-ﬂuorobenzene (1.07 g,

5.7 mmol) was added. The reaction was left to stir for 72 h. The

reaction was worked up by the addition of saturated ammonium

chloride (30 ml). The aqueous layer was separated and extracted

with EtOAc (3 ¥ 10 ml). The combined organics were then

concentrated in vacuo. The crude oil was dissolved in EtOAc

(10 ml) and washed with distilled water (2 ¥ 5 ml), brine (5 ml)

and dried over MgSO₄and concentrated in vacuo. The solid was

puriﬁed by ﬂash chromatography [40/60 Petrol : EtOAc (3 : 1)]

yielding 16a (2.1 g, 79%). R_f0.46 [EtOAc/(40/60) Petrol, 1 : 2];

[a]_D²²-38.4 (c = 1 in CH₂Cl₂); m_max/cm^-1(thin ﬁlm) 3734 (m), 2984,

(s), 2361 (s), 2341 (s), 1735 (m), 1607 (s), 1540 (s), 1457 (m), 1353

(bm); d_H(400 MHz, CDCl₃) 1.19 (3H, t, J 7.14, CH₃CH₂O), 1.35

(3H, t, J 7.14, CH₃CH₂O), 1.55 (9H, s, (CH₃)₃CO), 2.63 (1H,

dd, J 14.3 and 10.2, H(3)), 3.53 (1H, dd, J 14.3 and 3.7, H(3)),

(S)-1-tert-Butyl-2-ethyl-5-oxopyrrolidine-1,2-dicarboxylate 15a⁵⁵

To a stirred mixture of 1a (2.0 g, 12.7 mmol) in DCM (5 ml)

was added triethylamine (2.7 ml 19 mmol) and DMAP (0.16 g,

1.2 mmol) and a further 15 ml of DCM added. Boc₂O (3.10 g,

13.7 mmol) dissolved in DCM (5 ml) was then added slowly. The

reaction was left for 24 h at RT under a nitrogen atmosphere.

The mixture was worked up by adding 30 ml of 0.1 M HCl and

separating the aqueous and organic layers. The aqueous layer

was washed with DCM (3 ¥ 30 ml) and the combined organics

were dried and concentrated in vacuo. The crude product was

passed through a silica plug (20 ml) and eluted with EtOAc (3 ¥

40 ml). On solvent removal, a pale orange oil 15a was obtained

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Data for 18b. R_f0.19 [EtOAc/(40/60) Petrol, 1 : 2]; [a]²_D²-12.7

(c = 1 in CH₂Cl₂); m_max/cm^-1(thin ﬁlm) 2982 (s), 2240 (m), 1775 (s),

1753 (s), 1753 (s), 1372 (s) 1342 (s), 1310 (s); d_H(400 MHz, CDCl₃)

1.23–1.30 (6H, m, CH₃CH₂O), 1.51 (9H, s, (CH₃)₃CO), 2.52 (1H,

dd, J 14.1 and 10.4, H(3)), 2.87 (1H, d, J 17.0, CH₂CN), 2.93

(1H, dd, J 14.2 and 2.2, H(3)), 3.09 (1H, d, J 17.0, CH₂CN), 4.15–

4.35 (4H, m, CH₃CH₂O), 4.73 (1H, dd, J 10.4 and 2.2, H(2));

d_C(100 MHz, CDCl₃) 13.8, 14.1 (CH₃CH₂O), 23.7 (CH₂CN),

27.7 ((CH₃)₃CO), 30.4 (C(3)), 54.0 (C(4)), 56.2 (C(2)), 62.0, 63.4

(CH₃CH₂O), 84.6 ((CH₃)₃CO), 115.8 (CN), 148.5, 166.9, 167.4,

169.4 (C O); HRMS: [M+Na⁺.] Calculated for C₁₇H₂₄N₂NaO₇

391.1476, Found: 391.1476.

4.09–4.24 (2H, m, CH₃CH₂O), 4.32 (2H, q, J 7.0, CH₃CH₂O),

4.69 (1H, dd, J 10.2 and 3.7, H(2)), 7.68 (1H, d, J 8.8, H(2)¢), 8.46

(1H, dd, J 8.8 and 2.5, H(3)¢), 8.88 (1H, d, J 2.5, H(5)¢); d_C(100

MHz, CDCl₃) 13.64, 14.13 (CH₃CH₂O), 27.8 ((CH₃)₃CO), 34.5

(C3), 56.4 (C2), 62.1 (CH₃CH₂O), 62.6 (C4), 63.6 (CH₃CH₂O),

85.0 ((CH₃)₃CO), 121.2 (C5¢), 127.7 (C(3)¢), 131.7 (C(2)¢), 139.8

(ArC), 147.2, 148.6, 148.8 (CNO₂+Boc C O), 166.1, 167.8,

169.4 (C O); HRMS: [M+Na⁺.] Calculated for C₂₁H₂₅N₃NaO₁₁

518.1381, Found: 518.1379.

(2S)-1-(tert-Butoxycarbonyl)-2,4-diethyl-4-(2,4-diaminophenyl)-5-

oxopyrrolidine-2,4-dicarboxylate 16b

To a stirred mixture of iron powder (0.182 g, 3.25 mmol) and

aqueous ammonium chloride (0.316 g, 5.96 mmol in 7 ml H₂O)

was added 16a (0.30 g, 0.54 mmol) in 35 ml of MeOH over

the course of 10 minutes, and then reﬂuxed for 2.5 h. The

(3S)-2-tert-Butyl-3-ethyl-1,6-dioxo-2,7-diazaspiro[4.4]nonane-2,3-

dicarboxylate 19 and (2S)-1-(tert-butoxycarbonyl)-2,3-diethyl-

4-(2-aminoethyl)-5-oxopyrolidine-2,4-dicarboxylate 20

R

mixture was ﬁltered through Celiteꢀ with MeOH (3 ¥ 10 ml).

To a solution of 17a,b (0.62 g, 1.69 mmol) in EtOH (75 ml) was

added CoCl₂·6H₂O (0.80 g, 3.4 mmol) and the mixture was stirred

for 5 min. NaBH₄(0.51 g, 13.5 mmol) was then added portion-

wise to the blue solution which was accompanied by effervescence

and a colour change through green to black. After stirring for 16

h at RT, the ethanol was removed in vacuo and NH₄OH (24 ml,

0.1 M) and EtOAc (75 ml) were added with stirring. After 30

An excess of EtOAc was then added and the organics were washed

both with water (10 ml) and brine (10 ml), dried over MgSO₄

and concentrated in vacuo. Puriﬁcation by ﬂash chromatography

[(40/60)Petrol : EtOAc, 1 : 2] yielded 16b (0.08 g, 31%). R_f0.41

[EtOAc]; d_H(400 MHz, CDCl₃) 1.08–1.31 (6H, m, CH₃CH₂O),

1.37 (9H, s, (CH₃)₃CO), 2.5–3.0 (2H, m, H(3)), 4.03–4.19 (5H,

m, H(2)+CH₃CH₂O), 6.24 (1H, s, ArH), 6.32 (1H, d, J 7.5,

ArH), 6.99 (1H, d, J 7.7, ArH); d_C(100 MHz, CDCl₃) 13.9,

14.1 (CH₃CH₂O), 28.3 ((CH₃)₃CO), 34.8 (C(3)), 50.4 (C(2)),

57.5 (C(2)), 61.5, 62.1 (CH₃CH₂O), 79.7 ((CH₃)₃CO), 97.9, 109.1

(ArC), 116.0 (ArC), 124.6 (ArC), 142.7 (CNH₂), 148.2, 154.9,

169.5, 172.3, 175.3 (C O); HRMS: [M+Na⁺.] Calculated for

C₂₁H₂₉N₃NaO₇458.1903, Found: 458.1899.

R

min, the green solution was ﬁltered through Celiteꢀ and washed

with EtOAc (40 ml). The organic phase was separated and washed

with water (15 ml), brine (15 ml), dried over MgSO₄and then

concentrated in vacuo to give a pale yellow oil which was puriﬁed

by ﬂash chromatography [EtOAc] to yield 19 (0.025 g, 5%) and 20

(0.025 g, 4%).

Data for 19. R_f0.40 [EtOAc]; [a]²_D²+8.0 (c = 0.5 in CH₂Cl₂);

m_max/cm^-1(thin ﬁlm) 2981 (m), 1789 (s), 1705 (m), 1369 (s), 1309 9

(m); d_H(400 MHz, CDCl₃) 1.3 (3H, t, J 7.1, CH₃CH₂O), 1.5 (9H,

s, (CH₃)₃CO), 1.85 (1H, dd, J 13.5 and 4.4, H(3)), 2.02–2.16 (1H,

m, H(1¢)), 2.68–2.75 (1H, m, H(1¢)), 2.94 (1H, dd, J 13.5 and 9.4,

H(3)), 3.30–3.37 (1H, m, H(2¢)), 3.62–3.70 (1H, m, H(2¢)), 4.24

(2H, q, J 7.07, CH₃CH₂O), 4.74 (1H, dd, J 9.4 and 4.4, H(2)),

6.48 (1H, bs, NH); d_C(100 MHz, CDCl₃) 14.1 (CH₃CH₂O), 27.8

((CH₃)₃CO), 31.4 (C(3)), 32.8 (C(1¢)), 39.6 (C(2¢)), 53.8 (C(4)), 56.9

(C(2)), 61.8 (CH₃CH₂O), 84.1 ((CH₃)₃CO), 149.0, 171.5, 172.1,

174.9 (C O); HRMS: [M+Na⁺.] Calculated for C₁₅H₂₂N₂NaO₆:

349.1370, Found: 349.1370.

(2S,4R) and (2S,4S))-1-tert-Butyl-2,4-diethyl-4-(cyanomethyl)-5-

oxopyrrolidine-1,2,4-tricarboxylate 18a,b

To a stirred suspension of 15b (0.50 g, 1.5 mmol) in dry THF

(15 ml) was added NaH (0.044 g, 1.82 mmol) and the mixture

stirred at RT for 30 min. A solution of bromoacetonitrile

(0.274 g, 2.3 mmol) in THF (5 ml) was added and the mix-

ture stirred at RT for 16 h. The reaction was quenched with

ammonium chloride (10 ml) and the organic layer separated

and the aqueous layer extracted with EtOAc (3 ¥ 5 ml). The

combined organics were washed with brine (10 ml), dried over

MgSO₄and concentrated in vacuo. Puriﬁcation by ﬂash chro-

matography [(40/60)petrol : EtOAc (3 : 1)] yielded a waxy white

solid 18a,b (0.52 g, 92%) as a mixture of two diastereoisomers

(1 : 1.5), which were separated by further ﬂash chromatography

[(40/60)petrol : EtOAc (5 : 1)].

Data for 20. R_f0.53 [EtOAc]; [a]²_D²+5.6 (c = 0.5 in CH₂Cl₂);

m_max/cm^-1(thin ﬁlm) 3355 (bm), 2980 (bm), 1710 (bm), 1513 (bm),

1368 (s); d_H(400 MHz, CDCl₃) 1.19–1.33 (6H, m, CH₃CH₂O),

1.41 (9H, s, (CH₃)₃CO), 2.04–2.18, 2.52–2.68 (4H, m, H H(3)

and CH₂CH₂NH₂), 3.28–3.40, 3.44–3.58 (2H, m, CH₂NH₂), 4.04–

4.27 (4H, m, CH₃CH₂O), 6.71, 6.59 (2H, bs, NH₂); d_C(100

MHz, CDCl₃) 14.0 (CH₃CH₂O), 28.2 ((CH₃)₃CO), 34.9 (C(3)),

36.0 (CH₂CH₂NH₂), 40.0 (CH₂NH₂), 50.7 (C(2)), 53.2 (C(4)),

61.5 (CH₃CH₂O), 61.9 (CH₃CH₂O), 80.0 ((CH₃)₃CO), 155.21,

160.0, 160.7, 172.1 (C O); HRMS: [M+Na⁺.] Calculated for

C₁₇H₂₈N₂NaO₇395.1789, Found: 395.1785.

Single crystal X-ray diffraction data were collected at low

temperature⁷²for 3a and 4b on a Nonius Kappa CCD

diffractometer.⁷³Both structures were solved using SIR92⁷⁴and

reﬁned using the CRYSTALS software suite⁷⁵as per the ESI†

(CIF ﬁle). The Flack x parameter⁷⁶for 3a reﬁned to -0.6(16),

Data for 18a. R_f0.26 [EtOAc/(40/60) Petrol, 1 : 2]; [a]²_D²-19.5

(c = 1 in CH₂Cl₂); m_max/cm^-1(thin ﬁlm) 2983 (bs), 2250 (m), 1796 (s),

1743 (s), 1371 (s) 1313 (s); d_H(400 MHz, CDCl₃) 1.32 (6H, t, J 7.0,

CH₃CH₂O), 1.50 (9H, s, (CH₃)₃CO), 2.12 (1H, dd, J 14.1 and 6.3,

H(3)), 2.8 (1H, d, J 17.0, CH₂CN), 3.03 (1H, dd, J 13.9 and 9.0,

H(3)), 3.23 (1H, d, J 17.0, CH₂CN), 4.22–4.34 (4H, m, CH₃CH₂O),

4.73 (1H, dd, J 9.0 and 6.3, H(2)); d_C(100 MHz, CDCl₃) 13.9,

14.0 (CH₃CH₂O), 22.8 (CH₂CN), 27.7 ((CH₃)₃CO), 30.5 (C3), 54.4

(C(4)), 56.8 (C(2)), 62.2, 63.5 (CH₃CH₂O), 85.0 ((CH₃)₃CO), 116.1

(CH₂CN), 148.5, 167.5, 167.7, 170.7 (C O); HRMS: [M+Na⁺.]

Calculated for C₁₇H₂₄N₂NaO₇391.1476, Found: 391.1476.

7054 | Org. Biomol. Chem., 2011, 9, 7042–7056

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however analysis of the Bijvoet pairs to gave a Hooft y parameter⁷⁷

of -0.4(5) giving a 97.6% probability that the structure is the

correct hand (assuming enantiopurity).⁷⁸Similarly, the Flack x

parameter⁷⁶for 4b reﬁned to 0.7(11), however analysis of the

Bijvoet pairs to gave a Hooft y parameter of 0.0(5) giving a

91.3% probability that the structure is the correct hand (given

enantiopurity).⁷⁷In the absence of a strong anomalous signal,

the Friedel pairs were merged for the ﬁnal reﬁnement for both

structures. Crystallographic data (excluding structure factors)

have been deposited with the Cambridge Crystallographic Data

Centre (CCDC 814550 & 814551†) and copies of these data

can be obtained free of charge via www.ccdc.cam.ac.uk/data_

request/cif.

28 E. L. Bentz, R. Goswami, M. G. Moloney and S. M. Westaway, Org.

Biomol. Chem., 2005, 3, 2872.

29 R. Goswami and M. G. Moloney, Chem. Commun., 1999, 2333.

30 J. H. Bailey, D. T. Cherry, K. M. Crapnell, M. G. Moloney, S. B. Shim,

M. Bamford and R. B. Lamont, Tetrahedron, 1997, 53, 11731.

31 T. Hill, P. Kocis and M. G. Moloney, Tetrahedron Lett., 2006, 47, 1461.

32 S. Sen, V. R. Potti, R. Surakanti, Y. L. N. Murthy and R. Pallepogu,

Org. Biomol. Chem., 2011, 9, 358.

33 A. A. Bahajaj, M. H. Moore and J. M. Vernon, Tetrahedron, 2004, 60,

1235.

34 A. A. Bahajaj, J. M. Vernon and G. D. Wilson, Tetrahedron, 2004, 60,

1247.

35 C. Marti and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209.

36 S. Muthusamy, D. Azhagan, B. Gnanaprakasam and E. Suresh,

Tetrahedron Lett., 2010, 51, 5662.

37 H. Kamisaki, Y. Yasui and Y. Takemoto, Tetrahedron Lett., 2009, 50,

2589.

38 H.-L. Wei, T. Piou, J. Dufour, L. Neuville and J. Zhu, Org. Lett., 2011,

13, 2244.

Acknowledgements

39 J. L. Cohen and A. R. Chamberlin, J. Org. Chem., 2007, 72, 9240.

40 M. J. Beard, J. H. Bailey, D. T. Cherry, M. G. Moloney, S. B. Shim, K.

Statham, M. Bamford and R. B. Lamont, Tetrahedron, 1996, 52, 3719.

41 J. H. Bailey, D. Cherry, J. Dyer, M. G. Moloney, M. J. Bamford, S.

Keeling and R. B. Lamont, J. Chem. Soc., Perkin Trans. 1, 2000, 2783.

42 Crystallographic data (excluding structure factors) have been deposited

with the Cambridge Crystallographic Data Centre (CCDC 814550 &

814551) and copies of these data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif.

43 Marvin was used for drawing, displaying and characterizing chem-

ical structures, substructures and reactions, Marvin 5.2.1, 2009,

ChemAxon (http://ww w .chemaxon.com). Calculator Plugins were

used for structure property prediction and calculation, Marvin 5.2.5.1,

2009, ChemAxon (http://ww w .chemaxon.com).

44 A. G. Brewster, S. Broady, C. E. M. n. Davis, T. D. Heightman, S. A.

Hermitage, M. Hughes, M. G. Moloney and G. A. Woods, Org. Biomol.

Chem., 2004, 2, 1031.

45 A. G. Brewster, S. Broady, M. Hughes, M. G. Moloney and G. A.

Woods, Org. Biomol. Chem., 2004, 2, 1800.

46 J. Dyer, S. Keeling, A. King and M. G. Moloney, J. Chem. Soc., Perkin

Trans. 1, 2000, 2793.

We gratefully acknowledge AstraZeneca for support of this

work, the EPSRC Chemical Database Service at Daresbury⁷⁹

and the EPSRC National Mass Spectrometry Service Centre at

Swansea.

References

1 A. M. Rouhi, Chem. Eng. News, 2003, 81, 77.

2 R. B. Breinbauer, I. R. Vetter and H. Waldmann, Angew. Chem., Int.

Ed., 2002, 41, 2878.

3 A. Ganesan, Curr. Opin. Biotechnol., 2004, 15, 584.

4 J. T. Njardarson, C. Gaul, D. Shan, X.-Y. Huang and S. J. Danishefsky,

J. Am. Chem. Soc., 2004, 126, 1038.

5 F. vonNussbaum, M. Brands, B. Hinzen, S. Weigand and D. Habich,

Angew. Chem., Int. Ed., 2006, 45, 5072.

6 D. E. Lizos and J. A. Murphy, Org. Biomol. Chem., 2003, 1, 117.

7 N. Selvakumar, A. M. Azhagan, D. Srinivas and G. G. Krishna,

Tetrahedron Lett., 2002, 43, 9175.

47 J. Dyer, S. Keeling and M. G. Moloney, Chem. Commun., 1998, 461.

48 J. Morgan and J. T. Pinhey, J. Chem. Soc., Perkin Trans. 1, 1990, 715.

49 M. G. Moloney and J. T. Pinhey, Chem. Commun., 1984, 965.

50 S. Kobbelgaard, M. Bella and K. A. Jorgensen, J. Org. Chem., 2006,

71, 4980.

8 S. A. A. E. Bialy, H. Braun and L. F. Tietze, Synthesis, 2004, 2249.

9 R. C. Elderﬁeld and R. E. Gilman, Phytochemistry, 1972, 11, 339.

10 B. D. Morris and M. R. Princep, J. Nat. Prod., 1999, 62, 688.

11 Y. Asami, H. Kakeya, R. Onose, A. Yoshida, H. Matsuzaki and H.

Osada, Org. Lett., 2002, 4, 2845.

51 M. Bella and K. A. Jorgenson, J. Am. Chem. Soc., 2005, 127, 3670.

52 S. Ram and R. E. Ehrenkaufer, Tetrahedron Lett., 1984, 25, 3415.

53 K. Ramadas and N. Srinivasan, Synth. Commun., 1992, 22, 3189.

54 S. Takano, N. Sato, M. Akigama and K. Ogasawara, Heterocycles,

1985, 23, 2859.

55 Z. Q. Gu and M. Li, Tetrahedron Lett., 2003, 44, 3203.

56 D. L. Flynn, R. E. Zelle and P. A. Grieco, J. Org. Chem., 1983, 48, 2424.

57 J. E. Baldwin, T. Miranda, M. Moloney and T. Hokelek, Tetrahedron,

1989, 45, 7459.

58 D. K. Dikshit and S. K. Panday, J. Org. Chem., 1992, 57, 1920.

59 D. K. Dikshit, A. Maheshwari and S. K. Panday, Tetrahedron Lett.,

1995, 36, 6131.

60 S. K. Panday, J. Prasad and D. K. Dikshit, Tetrahedron: Asymmetry,

2009, 20, 1581.

12 C. Pellegrini, M. Weber and H. J. Borschberg, Helv. Chim. Acta, 1996,

79, 151.

13 A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet and B. Bodo, J. Org.

Chem., 1991, 56, 6527.

14 P. Bloch and C. Tamm, Helv. Chim. Acta, 1981, 64, 304.

15 C. B. Cui, H. Kakeya and H. Osada, J. Antibiot., 1996, 49, 832.

16 J. C. Hodges, W. Wang and F. Riley, J. Org. Chem., 2004, 69, 2504.

17 G. Periyasami, R. Raghunathan, G. Surendiranb and N. Mathivananb,

Bioorg. Med. Chem. Lett., 2008, 18, 2342.

18 B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana, S. H.

Ang, S. Y. Leong, J. Tan, J. Wong, S. Keller-Maerki, C. Fischli, A.

Goh, E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen, D. Plouffe, K.

Henson, T. Wagner, E. A. Winzeler, F. Petersen, R. Brun, V. Dartois,

T. T. Diagana and T. H. Keller, J. Med. Chem., 2010, 53, 5155.

19 G. Zinzalla and D. E. Thurston, Future Med. Chem., 2009, 1, 65.

20 L. Planas, J. Perard-Viret and J. Royer, Tetrahedron: Asymmetry, 2004,

2399.

21 M. F. Brana, M. Garranzo, B. de Pascual-Teresa, J. Perez-Castells and

M. R. Torres, Tetrahedron, 2002, 58, 4825.

22 M. M. Fernandez, A. Diez, M. Rubiralta, E. Montenegro, N. Casamit-

jana, M. J. Kogan and E. Giralt, J. Org. Chem., 2002, 67, 7587.

23 D. C. Rees, M. Congreve, C. W. Murray and R. Carr, Nat. Rev. Drug

Discovery, 2004, 3, 660.

61 C. Najera and M. Yus, Tetrahedron: Asymmetry, 1999, 10, 2245.

62 A. J. Lucke, J. D. A. Tyndall, Y. Singh and D. P. Fairlie, J. Mol. Graphics

Modell., 2003, 21, 341.

63 R. W. Hoffmann, Chem. Rev., 1989, 1841.

64 P. Ertl, B. Rohde and P. Selzer, J. Med. Chem., 2000, 43, 3714.

65 P. Ertl, in ‘Polar Surface Area’, ed. R. Mannhold, Weinheim, 2007.

66 M. P. Gleeson, J. Med. Chem., 2008, 51, 817.

67 D. A. Price, J. Blagg, L. Jones, N. Greene and T. Wager, Expert Opin.

Drug Metab. Toxicol., 2009, 5, 921.

68 P. Molina, C. L. Leonardo, J. L. Botia, C. Foces-Foces and C. F.

Castano, Tetrahedron, 1996, 52, 9629.

69 E. J. Corey and A. Venkateswarlen, J. Am. Chem. Soc., 1972, 94,

6190.

70 A. J. Stern and J. S. Swenton, J. Org. Chem., 1989, 54, 2953.

71 J. Ezquerra, C. Pedregal, A. Rubio, B. Yruretagoyena, A. Escribano

and F. Sanchez-Ferrando, Tetrahedron, 1993, 49, 8665.

24 M. Congreve, R. Carr, C. Murray and H. Jhoti, Drug Discovery Today,

2003, 8, 876.

25 M. Feher and J. M. Schmidt, J. Chem. Inf. Comput. Sci., 2003, 43, 218.

26 C. J. Matthews, M. G. Moloney, A. L. Thompson, H. Winiarska and

H. T. Winney, Synlett, 2011, 378–382.

27 M. Anwar, A. R. Cowley and M. G. Moloney, Tetrahedron: Asymmetry,

2010, 21, 1758.

This journal is

The Royal Society of Chemistry 2011

Org. Biomol. Chem., 2011, 9, 7042–7056 | 7055

©

View Article Online

72 J. Cosier and A. M. Glazer, J. Appl. Crystallogr., 1986, 19, 105.

73 Z. Otwinowski and W. Minor, Methods Enzymol., 1997, 276,

307.

74 A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M. C.

Burla, G. Polidori and M. Camalli, J. Appl. Cryst., 1994, 27, 435.

75 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout and D. J.

Watkin, J. Appl. Crystallogr., 2003, 36, 1487.

76 H. D. Flack and G. Bernardinelli, J. Appl. Crystallogr., 2000, 33, 1143.

77 R. W. W. Hooft, L. H. Straver and A. L. Spek, J. Appl. Crystallogr.,

2008, 41, 96.

78 A. L. Thompson and D. J. Watkin, Tetrahedron: Asymmetry, 2009, 20,

712.

79 D. A. Fletcher, R. F. McMeeking and D. Parkin, J. Chem. Inf. Comput.

Sci., 1996, 36, 746.

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Spirocyclic systems derived from pyroglutamic acid

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