Synthesis of oxygen and nitrogen heterocycles via stabilized carbocations and ring closing metathesis. - CHAPTER 4 BRIDGED AZABICYCLIC SYSTEMS

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Synthesis of oxygen and nitrogen heterocycles via stabilized carbocations and

ring closing metathesis.

Doodeman, R.

Publication date

2002

Link to publication

Citation for published version (APA):

Doodeman, R. (2002). Synthesis of oxygen and nitrogen heterocycles via stabilized

carbocations and ring closing metathesis.

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BRIDGEDD AZABICYCLIC SYSTEMS

4.11 Introduction

Everr since their discovery/ there has been considerable chemical and pharmaceutical interestt in the synthesis of tropane alkaloids. These alkaloids, isolated from plants, usually containn the 8-azabicyclo[3.2.1]octane skeleton. One of the most striking examples is {-)-cocaine11 (1, chart 1), which is isolated from the leaves of Erythroxylon coca and has many physiologicall effects. It is a local anesthetic and it is a powerful vasoconstrictant, which explainss its use in medicine. Besides, it has very potent effects on the sympathetic nervous systemm and is responsible for the increase in heart rate and blood pressure. It acts by blockingg a neurotransmitter reuptake transporter that normally removes dopamine from a synapsee in the reward pathway of the central nervous system. It amplifies neurotransmission inn this pathway resulting in reinforcement of antecedent behavior.2

(-)-Epibatidine33 _{(2) is the first natural product which represents a new class of} alkaloidss containing a 7-azabicyclo[2.2.1]heptane (7-azanorbornane) skeleton. It is a unique alkaloid,, isolated in trace amounts from the skin of the Ecuadorian poison frog Epipedobates

tricolor.tricolor.44 It has very high analgesic activity (the compound is 200-500 times more potent than morphinee in mice) resulting from its high potency as an agonist at nicotinic acetylcholine receptorss (nAChRs) in the central and autonomic nervous system.5 However, the potential benefitt of this high activity is compensated by its toxicity. Therefore numerous analogs (e.g. homoepibatidine)) have been synthesized and screened for their potential activity.6

Anatoxine-aa (3) belongs to yet another class of alkaloids of which the core skeleton consistss of an unusual 9-azabicyclo[4.2.1]nonane (homotropane) structure.7 _{It is a low} molecularr weight neurotoxin, which is often referred to as "very fast death factor", because off its potency to induce respiratory paralysis. Because of its presence in the freshwater blue-greenn algae Anabaena flos-aquae, this alkaloid has been responsible for fatal poisoning of wildlifee in Europe and North America.8

Completelyy different classes of natural products are those containing a polycyclic coree skeleton in which the nitrogen is at a bridgehead position. A representative example is stemofolinee (4), isolated from stems and leaves of the Asian tree Stemona japonica. This structurallyy intricate alkaloid has a rigid pentacyclic core with a pendent conjugated butenolidee and exhibits insecticidal activity.9 Another example is maritinamine (5), a crinine alkaloid,, isolated from Sternbergia lutea. These crinine alkaloids represent an important sub-classs within the family of Amaryllidaceae alkaloids, which display interesting biological properties,, such as immuno-stimulatory, cytotoxic and anti-malarial activities.10

Chartt 1

/"-OCOPh h H H

11 (-)-cocaine 22 (-)-epibatidine _{33 anatoxine-a}

MeO O HO O

55 maritinamine

4.22 Literature strategies

Becausee of the very interesting properties of these alkaloids, substantial effort has beenn put in the synthesis of both the natural products as well as unnatural analogues. The mostt common synthesis of the tropane skeleton is the venerable Mannich condensation of a primaryy amine with succinaldehyde and acetone (derivatives) to arrive at tropinone (6, eq 4.1),, which can be further elaborated to several biologically active tropanes.11

CHO O CHO O ++ H2NR + RR = Me, Ph, Bn,, C H2C 02E t 0 0 R11 _{= H, C 0} 2H , C02alkyl l (4.1) )

Rapoportt and coworkers12 described the use of more sophisticated iminium ion cyclizationss to arrive at functionalized tropanes. Starting from keto acid 7, decarbonylation withh (COCl)2, followed by iminium ion cyclization by heating in 1,2-DCE/ toluene gave the desiredd 2,4 disubstituted tropanes 8 and 9 in 62 and 27% yield, respectively (eq 4.2).

Ho

2

crr ^

Nx Bnn C02Me 1)) (COCl)2 2)) A, 1,2-DCE/ toluene e 88 62% C02Mee (4 2) 88 8

Anotherr elegant approach towards this type of bicyclic system is the IV-acyliminium ionn cyclization reaction, as has been investigated in our group by Esch.13 This cyclization was carriedd out by stirring the hemi-aminal 10 in neat formic acid at room temperature for 15 minutess to arrive at 8-azabicyclo[3.2.1]octane 11 in 75% as a single ewio-isomer (eq 4.3). This highh endo-selectivity can be explained by assuming a chair-like transition state A.

Me02C. . OH H

M M

SiMe33 HCOOH rt,, 15 min 10 0 Me02C^^ + N N SiMe-- Me02C, , (4.3) ) 11 1

AA route, which has been extensively used to synthesize homotropanes is described by Malpasss and Smith (eq 4.4).14 The core skeleton is constructed starting from cycloocta-1,3-dienee 12. A Diels-Alder reaction with nitrosocarbonylbenzene (13), generated in situ from benzohydroxamicc acid and tetramethylammonium periodate, gave cycloadduct 14 in reasonablee yield. Transformation into the cis-amino-alcohol 15 was accomplished using standardd reduction methods. Conversion into the frans-bromoamine was achieved using thionyll bromide and subsequent cyclization occurred by basification with 2,2',6,6'-tetramethylpiperidinee (TMP), giving N-benzylnorhomotropane 16 in 54% overall yield. In a similarr way homotropenes could be synthesized when the hydrogenation step was omitted. Additionally,, starting from a different conjugated cyclodiene, several tropanes, tropenes, norbornaness and norbornenes have been obtained.15

^, ,

12 2 13 3 P h C O N = 0 0 COPh h N N

?1 1

^

> >

144 46% 1)) A l / H g 2 ) H2, P d / C C 3)LAH H NHBn n

ff 1

HO O 155 97% 1)) SOBr2 2)) TMP Bn n N N (4.4) ) 166 54%

Thee use of ring-closing metathesis as a tool to construct medium-sized bridged compoundss is still scarce.16 The synthesis of medium-sized azabicyclic[n.m.l]alkenes using thiss tool was reported by our group for the construction of 9- to 12-membered ring systems (see:: Eq 4.9; n = 6-10, m = 2).17 Very recently, after we had completed our experiments, the groupp of Martin used this methodology to synthesize several smaller azabicyclo[n.3.1]alkeness of type 20 (eq 4.5, n = 3-5).18 Starting from glutarimide 17, reduction withh NaBH4, transformation into the sulfone and reaction with an alkenylmagnesium halide yieldedd lactams 18. Protection of the nitrogen with a Cbz-group, reduction with DIBALH to thee N,0-acetal followed by reaction with allyltrimethylsilane in the presence of BF3-OEt2 affordedd an inseparable mixture of ris/trans-2,6-dialkenylpiperidines 19 in a ratio of ca. 20:1 inn favor of the ris-isomer. Ring-closing metathesis with Grubbs' catalyst A (see Scheme 4.3) gavee the bicyclic nitrogen heterocycles 20 in good yields.

HH 1) NaBH4 0 Y -N ^ °° 2)PhS02Na °

V JJ 3) RMgX

17 7 188 48-51% nn = 0,1,2 6)) BF3OEt2 allyll SiMe3 NCbz z (4.5) ) 199 48-65% 200 83-91%

Ann elegant route to arrive at the core skeleton of the crinine alkaloids was described byy Pearson et al.19 (Scheme 4.1). Cyclization precursor (2-azaallyl) stannane 21 was synthesizedd in several steps starting from 4-butenol. Generation of the anion with n-BuLi gavee 22, which was cyclized in an intramolecular [JT4S + jr2s]-cycloaddition reaction with the electron-richh exocyclic double bond to arrive at cycloadduct 23 as a single diastereomer in 80%% yield. Completion of the synthesis of the core skeleton was achieved by performing a Pictet-Spenglerr reaction with aqueous formaldehyde, in which an aminomethylation of the arenee and deprotection of the MOM protective group occurred in one step. This yielded 6-epi-crininee 21 in 75% yield as a single diastereomer.

Schemee 4.1

XT T

MOMO'' - M ' Ar r

21 1

-SnBu3 3 n-BuLi i _{MOMO"" " " ^ N "}

. 0 0

Ar r H H 22 2 MOMO" " 233 80% 1)) aq. CHzO 2)) 6M HC1

S A A

ff V

HO"" ^ N 244 75% e e

Theree is little literature precedent to construct polycyclic bridged amides with the nitrogenn at the bridgehead position and a bridging carbonyl functionality. Toshimitsu et al.20 reportedd an organoselenium-induced cyclization of olefinic lactam 25 with benzeneselenyl chloridee leading to bicyclic bridged amides 26 and 27 in 91% yield as a 3:1 mixture of diastereomerss (eq 4.6).

H H 25 5 O O PhSeCl l MeCN, , rt,, 10 h PhSe e PhSe e (4.6) ) 91%% (75:25)

Anotherr example was described by Schill et «/., in which the bicyclic bridged amide 322 was an intermediate in the synthesis of vinblastin derivatives21 (Scheme 4.2). Tryptamine 288 was reacted in a Pictet-Spengler reaction with acetal 29 to afford lactam ester 30 in 94% yield.. After some functional group transformations, C / D ring cleavage with benzyl chloroformatee and aqueous sodium cyanide in acetone and again several functional group transformationss gave cyclization precursor 31 in <10% yield. Hydrogenolysis of the Cbz-groupp afforded the free amino ester, which cyclized upon heating to afford bridged tetracyclicc lactam 32 in 73% yield. This cyclization is not generally applicable and in order for cyclizationn to occur some spatial and electronical requirements have to be met.

Schemee 4.2 EtOzCC C02Et ++ ( E t O )2H C ^ C ^ ^ O B z aceticc acid, reflux,, 2.5 h 29 9 OBz z Et02C C 300 94% OBz z l_ll C02C6F5 311 <10% H2,, Pd/C EtOAc c 455 °C, 24 h 322 73%

Becausee of these limitations, we set out to develop a generally applicable method to constructt bridged bicyclic amides 34, containing the nitrogen at a bridgehead position and a bridgingg carbonyl functionality. These bicyclic amides might undergo an intramolecular N-acyliminiumm ion reaction to arrive at the tricyclic amides 33. Amides 34 were envisaged to arisee from ring-closing metathesis of diolefins 35. The latter should be accessible in a few stepss from imides 36 (eq 4.7).

Ox Ox

:: = = >

o ^

N

^ o

(47)

35 5

H H

4.33 Imides as substrates

Thee synthesis of the cyclization precursors 35 was started with succinimide 36a (n = 1)) and glutarimide 36b (n = 2). For the introduction of the first olefinic moiety and the reductionn of the imide, literature procedures were followed.22 Thus, deprotonation of the nitrogenn with NaH (1.1 equiv), followed by alkylation with several alkenyl bromides (m = 1-3,, 1.1 equiv) afforded the alkylated imides (Table 4.1). Partial reduction to the hydroxylactamss was achieved using NaBHi (6.5 equiv) in EtOH and subsequent ethanolysis withh 2 M H2SO4 in EtOH afforded ethoxylactams 3T23 in reasonable yields (entries 1-5). These lactamss were alkylated with allyl bromide (p = 1, entries 6, 8, 10,11 and 13) and 5-bromo-l-pentenee (p = 3, entries 7, 9, 12 and 14), using LHMDS (1.1 equiv) as the base to arrive at diolefinss 35. In general, allyl bromide is a better alkylating agent than 5-bromo-l-pentene, resultingg in higher yields, cleaner reactions and shorter reaction times. As an example, deprotonationn of lactam 37d with LHMDS (1.06 equiv) in THF at -78 °C, followed by alkylationn with allyl bromide (1.06 equiv) at -78 °C for 3 h and at room temperature for anotherr 3 h yielded diolefin 35f in 52% isolated yield (entry 11). When this reaction was performedd with 5-bromo-l-pentene as the alkylating agent under identical reaction conditions,, the reaction mixture had to be stirred overnight at room temperature to obtain diolefinn 35g in only 40% yield, together with unreacted starting material (entry 12).

Alll alkylation products proved to be inseparable mixtures of diastereomers. The ratioss varied between 20:80 (entry 7) and 50:50 (entries 12 and 14), which were determined byy comparison of the integrals of the peaks in the !H-NMR spectra. As can be seen in Table 4.1,, the 5-membered ring lactams 35a-d (entries 6-9) have a slightly higher ratio than the correspondingg 6-membered ring lactams 35e-i (entries 10-14).

Tablee 4.1 H H 36aa (n = 1) 36bb (n = 2) l)NaH H 2)) NaBH4, HCl/EtOH H OEt t 37a-e e LHMDS S

^ x

B rr t THF,, -78 °C O O _{N N} 'In, , 35a-i i OEt t

entry y mm product yield (%) entry productt yield (%) ratio

37a a 37b b 37c c 37d d 37e e 47 7 46 6 45 5 33 3 40 0 6 6 7 7 8 8 9 9 10 0 11 1 12 2 13 3 14 4 1 1 3 3 1 1 3 3 1 1 1 1 3 3 1 1 3 3 35a a 35b b 35c c 35d d 35e e 35f f 35g g 35h h 35i i 72 2 31 1 61 1 7 7 63 3 52 2 40 0 66 6 45 5 24:76 6 20:80 0 33:66 6 24:76 6 38:62 2 43:57 7 50:50 0 40:60 0 50:50 0 92 2

Thesee diolefins were subjected to ring-closing metathesis catalysts in order to prepare bicyclicc bridged amides. Treatment of lactam 35a with catalyst A (5 mol%) in dichloromethanee at room temperature for 18 h gave no conversion (Scheme 4.3). Repeating thiss reaction with more catalyst and at a higher temperature did not lead to cyclization either,, again only starting material being recovered. This was partially due to rapid decompositionn of the catalyst at this temperature. This trend was observed with all metathesiss precursors; when subjected to catalyst A, only starting material was recovered.

Becausee of its higher reactivity, it was decided to try catalyst B for the ring-closing metathesiss reactions. Thus, reaction of diolefin 35a with 5 mol% of catalyst B inn toluene (0.02 M)) at 80 °C for 18 h gave only starting material in low yield, together with unidentifiable products,, probably polymeric structures. Longer reaction times gave smaller amounts of recoveredd starting material and more polymeric structures. Performing the reaction at a higherr concentration (50 mM) only afforded polymeric structures, even after short reaction timess (2 h). These reactions were repeated for all other diolefins and the same results as for

35aa were obtained. No cyclization products could be isolated.

Schemee 4.3 0 ^ -N^ O E t t 35a-i i catalystt A CH2C12,, rt catalystt B toluenee (2 mM), 60-800 °C catalystt B toluenee (50 mM), 60-800 °C startingg material CI I CI I startingg material or polymerization n polymerization n PCy3 3 ; RU = X X PCy33 Ph MesN N CU U NMes s C '' PCy3 Ph B B

r~\ r~\

MesNff ^NMes CI I : R U = \ \ PCy33 Ph C C

Onlyy once, a small amount of a bridged bicyclic amide could be purified. When lactamm 35c was reacted with catalyst B (16 mol%) in toluene at 80 °C for 18 h, the 9-memberedd ring bicyclic amide 34c was obtained in 7% isolated yield (eq 4.8). Unfortunately, thiss result was not reproducible.

OEt t 35c c catalystt B (166 mol%)

». .

toluene,, 80 °C 188 h OEt t EtO O (4.8) ) 34cc 7%

4.44 Isopropoxylactams as substrates

Becausee all RCM-cyclization reactions described in Section 4.2 failed to work and gavee either starting material or polymerization products, it was anticipated that the spatial positioningg of the terminal alkenyl moieties with respect to one another is unfavorable, so thatt polymerization takes place rather than ring closure. Therefore, a different precursor was soughtt in which the pre-organization of the molecule would allow the olefinic groups to be inn close proximity, so that cyclization will be favored compared to polymerization. This pre-organizationn already proved to be of crucial importance in the macrocyclic ring-closing metathesiss reaction of sulfone 39 in the construction of the bridged tricyclic structure of roseophilin244 (eq 4.9). A 'chiral relay effect' was mentioned as an explanation of the diastereoselectivityy of the alkylation reaction, in which the tosyl group plays an important rolee in the stereochemical outcome of this reaction. Because of the same effect, the olefinic partss are brought in close proximity, thereby facilitating the metathesis reaction.

S02Ph h N N Ts s alkylation n 65-99% % 38 8 Tss S02Ph 399 n = l-4 diastereomeric c ratioo > 5:1 catalystt A (200 mol%) 48-84% % N N Ts s 40 0 'SO,Ph h (4.9) )

Additionally,, the precursor should contain a functional group, which could act as a relayy for the evolving carbene species that assembles the reacting sites within the coordinationn sphere of the metal (viz. D and E, Fig. 4.1).25 _{In this way, it was hoped that this} ligationn would bring the two olefins closer together and would facilitate the ring closure. However,, if this ligation is too strong, as might be the case in 5- or 6-membered ring chelate structures,, the catalyst can become unreactive and cyclization will not occur (viz. F, Fig. 4.1). Figuree 4.1

j.prOO i-Pr<X Me02C C02Me

^ - ^^ Ru

Me0

2

CC [Wo'Jf> Me0

2

C^\^iG

; K U Q

'

J£f*J£f* OEt RÜ,

D D

Isopropoxylactamss 41-44 (eq 4.10) and 50 (eq 4.12) were envisaged to be good candidatess that might meet the criteria stated above. Because of the frans-relationship betweenn the isopropoxy group and the olefinic moiety (see: Chapter 3), it was expected that thee olefinic group on the nitrogen would also have a pseudo frans-relationship with the isopropoxyy group, which could lead to a preferred conformation with the two olefinic 94 4

moietiess on the same side of the molecule. Besides, these lactams contain a dimethyl ester functionality,, which could act as the complexing group.

Thus,, alkylation of lactam 41 with allyl bromide (5 equiv) and NaH (1.3 equiv) in DMFF at 0 °C gave the corresponding diolefin 45 in 58% yield with complete retention of the frans-stereochemistryy (eq 4.10). This trans-relationship could be clearly seen in the !H-NMR spectrum,, in which H-5 appeared as a singlet. In the same manner, diolefins 46, 47 and 48 weree obtained in 56-60% yield, all of them possessing a frans-configuration. Unfortunately, subjectionn of these diolefins to ring-closing metathesis conditions did not give any cyclized product.. After stirring overnight in toluene at 60 °C with either catalyst B or C only starting materiall was recovered or polymerization products were obtained, depending on the concentrationn of the substrate, just as in the case of lactams 35 in Scheme 4.3. Obviously, via thiss route, no 8-, 9-, 10- and 11-membered bridged bicyclic lactams could be formed.

M e 02C C H H 4 1 nn = l 4 2 nn = 2 4 3 nn = 3 4 4 nn = 4 C 02M e e '"O'Pr r N a H H allyll bromide DMF,, 0 °C, 188 h Me02CC C 02M e

O^V""O

l

Pr r

455 58% 466 56% 477 60% 488 60% catalystt B, C toluene,, 60 °C, 188 h (4.10) )

Introductionn of olefinic alkyl groups at nitrogen with longer alkyl chains in order to preparee larger rings after cyclization (12-membered ring) met with difficulties. After extensivee investigation, varying the base, the solvent and the temperature, reaction of 43 withh 5-bromo-l-pentene (5 equiv) in THF at 70 °C, using KOBu as the base, gave diolefin 49 inn a low yield of 28% (eq 4.11). Unfortunately, no cyclized product could be isolated after reactionn with either catalyst B or catalyst C in toluene at 60 °C, only polymeric structures beingg formed. Me02CC C02Me 43 3 THF,, 70 °C, 1 h Me02CC C02Me O ^ N N 499 28% catalystt B, C toluene,, 60 °C, 188 h XX (4.11)

Thee last attempt to form a bridged bicyclic lactam via this route aimed at the constructionn of a 13-membered ring. Starting with lactam 50, alkylation with allyl bromide (R == H, 5.0 equiv) and NaH (1.5 equiv) in THF at 0 °C gave in good yield diolefin 51 with retentionn of the frans-configuration (eq 4.12). We were very pleased to see that subjection of thiss diolefin to 4 mol% of catalyst C in toluene at 70 °C for 18 h gave bicyclic lactam 53 in 23%

yieldd as a mixture of (E)/(Z)-isomers. Although the yield was disappointing, this was the firstt time that such a bicyclic amide was obtained via a reproducible ring-closing metathesis reaction.. To avoid potential stable chelate formation of the Ru-alkylidene intermediate, formedd after reaction of the Ru-catalyst with the olefin at nitrogen, with the carbonyl oxygen off the lactam, thereby forming a stable, unreactive 6-membered ring Ru-complex (viz. F, Fig. 4.1),, the initial metathesis reaction was forced to start at the long chain olefin by adding a methyll substituent at the terminal carbon atom of the olefin at nitrogen. Thus, reaction of lactamm 50 with l-bromo-2-butene (R = Me) in DMF at 0 °C for 18 h yielded in 71% yield diolefinn 52. Ring-closing metathesis with catalyst C (4 mol%) in toluene at 70 °C for 18 h gave lactamm 53 in the same yield as for 51, indicating that it was not the formation of a stable chelatee that caused the low yield.

Me02CC CQ2Me Me02CC C02Me catalystt C (44 mol%) »--toluene,, O 700 °C, 18 h MeO,aa /C M e (4.12) ) 50 0 51RR = H 75% % 533 23% 52RR = Me 71%

4.55 Nitrogen adjacent to a bridgehead position

Becausee the metathesis reactions towards bicyclic amides with an amide nitrogen atomm at a bridgehead position remained without success, it was assumed that the planarity off the lactam moiety was the reason that the majority of the reactions did not afford any cyclizedd product. Probably, due to the planarity of the system, the allyl group remains too far awayy from the other alkene, so that no metathesis reaction can occur. In addition, introductionn of a longer chain at nitrogen met with difficulties and low yields (see eq 4.11). Forr these reasons it was decided to change the strategy and to synthesize bridged lactams in whichh the nitrogen is adjacent to a bridgehead position. Ethoxylactam 56 was envisaged to bee a good precursor to arrive at these bicyclic lactams, because it contains the two sites where olefinicc chains can be introduced and it has a stereocenter, which can influence the stereochemicall relationship between the two alkenes.

Lactamm 56 was synthesized following a literature procedure26 (eq 4.13). The synthesis commencedd with (S)-malic acid 54, which was treated with acetyl chloride, benzylamine and acetyll chloride to obtain enantiopure imide 55. Regioselective reduction with NaBÜ4, followedd by acidic ethanolysis with 2 M H2SO4 in EtOH gave a mixture of acylated and deacylatedd products. Complete deacylation was achieved by treatment with K2CO3 in MeOH too afford ethoxylactam 56 as a 1:5 mixture of cis/ frans-diastereomers at C-5.

4DHH 1) AcCl / — \\ 2) BnNH, H 02CC C02H 3 ) A c C 1 544 (S)-malic acid NOAc c 555 78% 4)) NaBH^ then 22 M H2S04, EtOH 5)) K2C03 / MeOH 566 89% a s :: trans = 1:5 (4.13) )

Doublee deprotonation of 56 using 2.2 equiv of LDA in THF at -78 °C, followed by alkylationn with allyl bromide afforded alkene 57 in 60% yield (eq 4.14). This alkylation proceededd with complete trans-selectivity with respect to the stereocenter at C-4, as expected fromm the work of Klaver.27 _{Subjection of this ethoxylactam to BF3-OEt2 and} allyltrimethylsilanee (5.0 equiv) in CH2CI2 at roomm temperature gave after 18 h dimer 58 as the solee product in 89% yield. This result is surprising, because it was reported that this type of dimerss was only found as a minor byproduct.28

-OH H OEt t Ph.' ' 56 6 LDAA (2.2 equiv) allyll bromide »--THF,-78°C, , 188 h .OH H (( -OH

J3~ J3~

OEt t P h ' ' 577 60% BF3OEt2 2 allyll SiMe3 »--CH2C12// rt, 188 h 588 89%

Hence,, before introduction of the second alkene, the hydroxy group had to be protected.. This was achieved by reacting alcohol 57 with acetic anhydride, Et3N and catalytic DMAPP to afford acetate 59 in almost quantitative yield (Scheme 4.4). Subsequent reaction withh BF3-OEt2 and allyltrimethylsilane in MeCN for 18 h yielded diolefin 60 in 70% with a trans-relationshipp with respect to C-4, together with 18% of the 4,5-ris-product. The formationn of the trans-isomer as the major product could be explained by the possible anchimericc stabilization of the cation by the acetoxy function, thus favoring trans-addition of thee nucleophile.29 Gratifyingly, subjection of this mixture to catalyst C (5.0 mol%) in toluene att 60 °C for 18 h afforded the 7-membered ring bicyclic lactam 61 in 33% yield as a single diastereomerr (41% yield based upon the trans-isomer). Logically, the ris-isomer was unreactivee in this metathesis reaction.

Thiss is the first example of constructing this type of ring system via ring-closing metathesis.. The only method reported so far to arrive at this skeleton is the intramolecular N-acyliminiumm ion-allene cyclization, reported by our group.30 The formation of this bicyclic lactamm can clearly be seen in the ^ - N M R spectrum, which showed signals of the olefinic protonss at 5.52 and 5.31 ppm. In addition, H-4 is a singlet, which proved the trans-relationshipp with both bridgehead protons.

Schemee 4.4 Et3N,, Ac20 DMAP P THF,, rt, 2 h BF3OEt2 2 allyll SiMe3 MeCN,, rt, 188 h 599 97% AcO O 600 70% +18%% 4,5-ris catalystt C toluene, , ,, 60 °C, 18 h OAc c 611 33% [a]DD -83.4 (c = 1.0)

i i

AcO O Ph h H-10" " H-8 8 H-7 7 r\_A_ _

i i

H-4 4 H-10 pp H-5

II L

H-3 3 H-99 H.6

A A

M^Afw^,J M^Afw^,J

_{L L}

!! i ] 2 2

Figuree 4.2. iH-NMR spectrum (7.5-1.8 ppm) of 61.

Althoughh the yield was a somewhat disappointing, it showed that the new strategy workedd and that bridged bicyclic amides can be formed under mild conditions using ring-closingg metathesis. To determine the scope of this strategy, it was tried to make larger rings byy introduction of longer olefinic chains. Thus, reaction of ethoxylactam 56 with LDA (2.2 equiv)) and 5-bromo-l-pentene gave the alkylated lactam 62 in 30% yield with complete fraws-selectivityy (eq 4.15). Performing this reaction with 6-bromo-l-hexene and 8-bromo-l-octenee gave no alkylation, even when the corresponding more reactive iodides were used. Acylationn of the hydroxy group with acetic anhydride (quantitative yield), followed by an N-98 8

acyliminiumm ion reaction with allyltrimethylsilane and BF3OEt2 afforded the metathesis precursorr 63 in 40% yield as a 1:3 mixture of cis/1nws-diastereomers. Unfortunately, this diolefinn did not cyclize to the desired 9-membered ring bicyclic lactam when subjected to catalystt C in toluene at 60 °C for 18 h.

PH H 1 ) A C 2 °° , T \ ) catalyst C „ ^ O BB 2)BF3.OEt2 0 ^N - ^ - / toluene, * ( ' allyll SiMe, I 60 °C, 18 h 33 3 Ph 633 40% asas Itrans 1:3 4.66 Azabicyclo[4.x.l]alkenes 4.6.11 Precursor synthesis

Next,, we turned our attention to the synthesis of 9-azabicyclo[4.2.1]non-3-enes and 10-azabicyclo[4.3.1]dec-3-eness (Chart 2). Despite their interesting biological properties, no reportss of constructing these molecules via ring-closing metathesis had appeared in literature att the time we started this investigation. The idea was to start with an imide, to functionalize bothh a-positions next to the nitrogen with olefinic groups (these groups have to be in a cis-configurationn to be able to cyclize) and then ring close them to the desired azabicyclic compounds.. In order to explore the scope of the metathesis reaction for these compounds, wee required an expedient route towards the metathesis precursors.

Chartt 2

RR R NN N

9-azabicyclo[4.2.1]non-3-enee 10-azabicyclo[4.3.1]dec-3-ene

Thee first target molecules were the 9-azabicyclo[4.2.1]non-3-enes, which should be accessiblee from succinimide 36a. A one-pot procedure was used for the introduction of the allyll group and reduction of the intermediate N-acyliminium ion to form the allylated lactam

644 in 84% yield (eq 4.16).31 It was thought that the substituent on nitrogen could influence the

cis/trans-Tatiocis/trans-Tatio of the olefins in the metathesis precursor. Thus, lactam 64 was equipped with

aa tosyl, a ferf-butoxycarbonyl and a methoxycarbonyl group using standard conditions to arrivee at substituted lactams 65, 66 and 67 in 80%, 88% and 92%, respectively. Partial reductionn of the lactam carbonyl with DIBALH provided the N,0-acetals, which were

convertedd into the corresponding methyl aminals 68, 69 and 70 in moderate to reasonable yieldss by stirring with PPTS in methanol (eq 4.16). Now the stage was set to introduce the secondd olefinic group via an N-acyl- or N-tosyliminium ion reaction.

OMee (4_-16_> 36a a 644 84% 655 R=Ts 666 R = Boc 677 R = COzMe 80% % 88% % 92% % 688 73% 699 60% 700 48%

ReagentsReagents and conditions: (a) allylmagnesium bromide (3.0 equiv), Et20, 0 °C, 3 h; NaCNBH3, 6 M HC1, rt,, 18 h; (b) 65:1. n-BuLi (1.1 equiv), THF, -78 °C, 2 h; 2. TsCl (1.3 equiv), -78 °C -4 rt; 66: Boc20 (2.0

equiv),, DMAP (0.1 equiv), Et3N/THF, 30 min; 67: ClC02Me (2.0 equiv), DMAP (0.1 equiv), Et3N/THF, 11 h; (c) DIBALH (1.5 equiv), THF, -78 °C, 1 h; PPTS (0.1 equiv), MeOH, rt, 3 h.

Thee second target molecules were the 10-azabicyclo[4.3.1]dec-3-enes, which contain onee more carbon in the bicyclic framework. This synthesis was started from glutarimide 36b, followingg the same sequence of reactions as described above. Thus, the allyl group was introducedd in a one-pot reaction to yield allyllactam 71 in 87% yield (eq 4.17). Subsequent substitutionn at nitrogen with a tosyl group using standard conditions afforded lactam 72 in 17%% yield, together with 72% starting material. This result could not be improved using excesss tosyl chloride (5.0 equiv) or by reaction in a biphasic system with TsCl, NaOH and Bu4NHS044 as the phase-transfer catalyst. Substitution with a methoxycarbonyl group using M-BuLii (1.2 equiv) and methyl cyanoformate32 (1.5 equiv) not only gave N-alkylation, but also C-alkylationn next to the carbonyl. This dialkylation could be overcome by using LHMDS (2 equiv)) as the base, yielding lactam 73 in 73%. Partial reduction with DIBALH in THF at -78 °C,, followed by stirring with PPTS in MeOH afforded the corresponding aminals 74 and 75 inn 17% and 42% yield, respectively.

O O N N H H 36b b OMe e (4.17) ) 711 87% 722 R = Ts 733 R = C02Me 13% % 73% % 744 17% 755 42%

ReagentsReagents and conditions: (a) allylmagnesium bromide (3.0 equiv), Et20, 0 °C, 3 h; NaCNBH3, 6 M HC1, rt,, 18 h; (b) 72:1. n-BuLi (1.1 equiv), THF, -78 °C, 2 h; 2. TsCl (1.3 equiv), -78 °C -> rt; 73: CNC02Me (5.0

equiv),, LHMDS (2.0 equiv), THF, -78 °C -> rt; (c) DIBALH (1.5 equiv), THF, -78 °C, 1 h; PPTS (0.1 equiv),, MeOH, rt, 3 h.

4.6.22 N - A c y l i m i n i u m ion chemistry

Thee iminium ion precursors 68-70 all gave cis/ trans-mixtures of diolefinic products 80,, 81 and 82 after the BF3OEt2-mediated reaction with allyltrimethylsilane 77. When tosyl-substitutedd N,0-acetal 68 was subjected to these reaction conditions, diolefin 80 was 100 0

o b t a i n e dd in a n excellent 9 1 % y i e l d as a n i n s e p a r a b l e 1.6:1 m i x t u r e of d i a s t e r e o m e r s (Table 4.2,, e n t r y 1), i n w h i c h t h e d e s i r e d ris-isomer p r o v e d to b e t h e major p r o d u c t . T h e Boc-s u b Boc-s t i t u t e dd N , 0 - a c e t a l 69 g a v e i n m o d e r a t e y i e l d diolefin 81 aBoc-s a 2:1 m i x t u r e of d i a s t e r e o i s o m e r ss (entry 2), w h e r e a s t h e C 02M e - s u b s t i t u t e d N , 0 - a c e t a l 70 a f f o r d e d in g o o d y i e l dd diolefin 82 as a 3:1 m i x t u r e (entry 3). T h e m o d e r a t e yield of 81 c a n b e e x p l a i n e d b y t h e i n c o m p a t i b i l i t yy of t h e B o c - g r o u p w i t h B F3O E t2, l e a d i n g t o several b y p r o d u c t s . T h e u s e of differentt L e w i s acids (Sc(OTf)3 or Sn(OTf)2) or s o l v e n t ( M e C N ) d i d n o t i m p r o v e t h e

cis/trans-ratio. cis/trans-ratio.

Tablee 4.2

BF3-OEt22 (2 equiv) -QMee Nucleophile (4 equiv)

CH2C12 /0°C C

76 6

entry y precursor r nn nucleophile product t yieldd (%) cis/'trans

688 (R = Ts) /TMS S 77 7 80 0 911 1.6:1 699 (R = Boc) 77 7 N N Boc c 81 1 54 4 2:1 1 700 (R = COzMe) 77 7 N N C02Me e 82 2 89 9 3:1 1 44 68 (R = Ts) 55 70 (R = C02Me) 1 66 68 (R = Ts) 77 75 (R = C02Me) 2 788 ^ - T M S 78 8 799 SnBu, 77 7 70 0 58 8 1.5:1 1 4:1 1 599 1.3:1 577 8:1 a

Reactionn mixture was stirred for 30 min.

Too introduce additional functionality in the molecule and to broaden the scope of thesee cyclizations, N,0-acetals 68 and 70 were reacted with allenylmethyltrimethylsilane 78 underr Lewis acid-catalyzed conditions to afford triolefins 83 and 84 in 70% and 58% yield, respectively.. Again, the N-substituent had a substantial influence on the cis/1raws-ratio of the olefins.. A tosyl group gave a 1.5:1 ratio of isomers (entry 4), while a methoxycarbonyl yieldedd an improved 4:1 ratio (entry 5), both in favor of the ris-isomer. N,0-Acetal 68 was alsoo reacted with allenyltributyltin (79) to yield enyne 85 in 59% yield as an inseparable 1.3:1 mixturee of diastereomers (entry 6).

Thee introduction of the second allyl group via N-tosyliminium ion chemistry of piperidinee derivative 74 with allyltrimethylsilane as the nucleophile met with difficulties. Dependingg on the Lewis acid, different products were obtained, but in neither case were the objectedd diallylated products found. When BF3-OEt2 was used as the Lewis acid, the only productt that could be isolated was azabicyclo[3.3.1]non-2-ene 87 in 17% yield (eq 4.18), while alll starting material was consumed after 2 h. The formation of this product can be explained byy intramolecular attack of the olefin on the formed iminium ion, followed by elimination of aa proton to form the double bond. It is known that these cyclizations can be performed in the presencee of an electrophile or strong Lewis acids (TiCL),33 so that the electrophile captures thee formed cation after cyclization, but double bond formation only takes place as a minor sidee reaction. The use of catalytic amounts of Sc(OTf)3 gave enamide 88 in 52% yield as a resultt of elimination of MeOH.34

Tss BF3-OEt2 Sc(OTf)3

allyll SiMe3 f ^ ^ l allyl SiMe3 MeCN,, 0 °C ^ ^ " " " ^ OMe C H2C 1> ~78 °c 22 h Ts 18 h

877 17% 74 88 52% (4.18) )

Next,, we turned our attention to the methoxycarbonyl-substituted piperidine 75. This time,, the N-acyliminium ion reaction with BF3OEt2 and allyltrimethylsilane afforded 2,6-diallylatedd piperidine 86 in 57% yield as a 8:1 mixture of cis/ frans-diastereomers (Table 4.2, entryy 7). The selectivity of this reaction is much better than that of the corresponding 2,5-disubstitutedd pyrrolidines because of the well known preference of N-acyl-2,6-disubstituted piperidiness to exist in the chair conformation, in which the substituents at the 2- and 6-positionn are in an axial position in order to avoid A1-3-strain.35

4.6.33 RCM to 9-azabicyclo[4.2.1]non-3-enes

Thee ris/frans-mixtures of dienes 80-86 were then subjected to ring-closing metathesis conditionss in order to arrive at the desired azabicyclic compounds. Reaction of 80 with catalystt C (5 mol%) in toluene at 60 °C gave a smooth conversion of the ris-isomer to the 9-azabicyclo[4.2.1]non-3-enee 89 in 44% yield (72% based upon the ris-isomer), whereas the 102 2

trans-isomeitrans-isomei remained unaffected (Table 4.3, entry 1). This is the first example of the

formationn of an 9-azabicyclo[4.2.1]alkene via ring-closing metathesis. Similarly, dienes 81 and 822 were reacted to afford bicycles 90 and 91 in 32% and 55% yield, respectively, (48% and 73%% yield, based upon pure ris-81 and cis-82), together with the unreacted rrans-dienes (entriess 2 and 3). From these series, it can be concluded that, apart from the Boc-substituted bicyclee 90, the substituent at nitrogen does not have a significant influence on the outcome of thee RCM reaction. The tosyl and the methoxycarbonyl group gave approximately the same yieldd of the desired bicycle, whereas the yield with the Boc group was significantly lower.

Thee trienes 83 and 84 could react in two different ways in the metathesis reaction, leadingg to azabicycles with difference in ring size and substitution pattern. However, reactionn of 83 with 5 mol% of catalyst C in toluene at 60 °C for 18 h only gave metathesis reactionn with the least substituted double bond (see Chapter 3), leading to tosyl-substituted 9-azabicyclo[4.2.1]nonenee 92 in 19% yield (32% based upon pure ris-83), together with the unreactedd rrans-triene (entry 4).

Tablee 4.3. entry y substrate e Ts s 80 0 Boc c 81 1 C02Me e 82 2 catalystt C (55 mol%) ^ toluene, , 600 °C, 18 h R R N N R' ' product t Ts s N N 89 9 Boc c N N 90 0 C02Me e N N 91 1 Ts s N N 92 2 C02Me e N N yieldd (%)a 444 (72) 32(48) ) 555 (73) 199 (32) 566 (70) 93 3 a

Yieldd in brackets is based upon the cis-isomer.

Ts s

L./1 1

H-10" " H-1015 5 H-5 5 H-88 H-7 H-2 2

~_AAA_JL L

- T - r - r - i - r - 7 - T --7 --7 Ts s H-6" " H-6P P

iJlL L

Figuree 4.3. iH-NMR spectrum (7.9-1.5 ppm) of 92.

Thee exclusive formation of 92 could be concluded from the ^ - N M R spectrum, which showedd two singlets at 5.03 en 4.89 ppm for the exocyclic double bond protons and a doublet forr H-8 (Figure 4.3). Triene 84 reacted in the same fashion, yielding 9-azabicyclo[4.2.1]nonene 933 in 56% yield (70% based upon pure ris-84, entry 5). In this set of cyclizations, there is a significantt influence of the N-substituent on the yield of the cyclization; the methoxycarbonyl groupp gave better results than the tosyl group.

Unfortunately,, no enyne-metathesis reaction to bicyclic carbamate 94 occurred when 855 was reacted with catalyst C (5 mol%) in toluene at 60 °C (eq 4.19). Only starting material wass recovered. Ts s 85 5 catalystt C (55 mol%) toluene, , 600 °C, 18 h

-X X

R R N N (4.19) ) 94 4 4.6.44 RCM to azabicyclo[4.3.1]dec-3-enes

Thee last step in the synthesis of azabicyclo[4.3.1]decene 95 was the ring-closing metathesiss reaction of piperidine 86 (eq 4.20). Subjection of 86 to catalyst C (5 mol%) in toluenee at 60 °C for 18 h smoothly afforded the desired bicyclic compound 95 in a good yield off 85% (96% based upon ris-86).

catalystt C (55 mol%) t toluene, , 600 °C, 18 h C02Me e N N (4.20) ) 955 85 % (96%) 104 4

Comparedd to the synthesis of these azabicyclo[4.3.1]decenes published by Neipp and Martin188 after we completed our work (see: Section 4.2), our approach has the advantage that itt is shorter (5 vs. 7 steps). On the other hand, their strategy allows the introduction of alkenyll chains of various lengths and the cis/trans-ratio of the 2,6-disubstituted piperidines iss better (8:1 vs. 17:1). The difference in selectivity can probably be explained by the different naturee of the N-substituent.

4.77 Conclusions

Inn this chapter the efforts to synthesize bicyclic amides with a bridgehead nitrogen via ring-closingg metathesis are described. Unfortunately, no products could be obtained in a reproduciblee manner starting from dienes 35, which were obtained from an imide via N-alkylation,, partial reduction of the imide and C-alkylation adjacent to the carbonyl. In the casee of isopropoxylactams 45-49, 51 and 52, only the 13-membered ring bicyclic lactam 53 wass isolated, though in low yield. All other dienes gave either starting material or polymeric substances,, depending on the concentration of the substrate.

Ring-closingg metathesis towards azabicyclic heterocycles was successful where the nitrogenn was adjacent to a bridgehead position. Starting from ethoxylactam 56, easy functionalizationn to diene 60 and cyclization of the ris-isomer afforded the 7-membered ring bicyclicc amide 61 in low, but reproducible yield.

Thee most successful cyclizations, however, took place in the synthesis of 9-azabicyclo[4.2.1]non-3-eness 89-93 and 10-azabicycIo[4.3.1]dec-3-ene 95. Starting from either succinimidee or glutarimide, a convenient route was developed in which introduction of the firstt alkene in a one-pot procedure, substitution at nitrogen, partial reduction with DIBALH andd iminium ion reaction with Jt-nucleophiles led to cis/trans-mixtures of RCM-precursors

80-86.. The ratio of these mixtures strongly depended on the substituent at nitrogen and the

ringg size. Smooth cyclization of the ds-diastereomers led to the corresponding bridged heterocycless in moderate to good yields. The double bond(s) in the bicyclic skeleton make furtherr functionalization possible.36

4.88 A c k n o w l e d g e m e n t s

B.. W. Truijens and J. Helder are gratefully acknowledged for their contribution to this chapter.. G. Mentink is thanked for a generous gift of allene 78.

4.99 Experimental section

Generall information. For experimental details, see: Section 2.8. For the NMR assignments of

thee products in this chapter the numbering as shown for structures 35a, 35e, 45-48,57, 64 and

722 has been used. The numbering is continued in the chain which carbon atom is already

numberedd (in structure 35a for n = 1, the double bond carbons have number 8 and 9, for n = 2,, they have number 9 and 10 etc). The nuclear magnetic resonance spectra of a number of

compoundss described in this chapter show line broadening or double lines due to the relativee slow rotation around the OC-N bond. This phenomenon is indicated with the term 'rotamers'' in the data lists. When interpretation of spectra at room temperature was cumbersome,, the spectra were recorded in deuterated DMSO at elevated temperatures (120 °C) )

Me02CC C02Me

OEt t

35e e 45-48 8

3-Allyl-l-but-3-enyl-5-ethoxypyrrolidin-2-onee (35a): To a solution of 37a (196 mg,, 1.07 mmol) in THF (5 mL) at -78 °C was added LHMDS (1 M solution in N'' 0 E t THF, 1.20 mL, 1.20 mmol).The reaction mixture was stirred at -78 °C for 45 \ ^ XX minutes and allyl bromide (100 p.L, 1.15 mmol) was added. After stirring at -78 °CC for 3 h, the mixture was allowed to warm to room temperature and stirred for another 3 h. Thee reaction was quenched by adding aqueous saturated NH4C1. The aqueous phase was extractedd with Et20, the combined organic layers were dried over MgS04 and concentrated

inin vacuo. Purification by column chromatography (EtOAciPE = 1:4) afforded diolefin 35a (171

mg,, 0.77 mmol, 72%) as an inseparable mixture of diastereomers (24:76). Rf = 0.33. Major

isomer:: ^H-NMR: (C6D6,100 MHz): Ö = 5.58-5.83 (m, 2H, H-8, CH=CH2), 4.92-5.13 (m, 4H, H-9,, CH=CH2), 4.43-4.52 (m, 1H, H-5), 3.58-3.73 (m, 1H, H-6a), 2.94-3.24 (m, 3H, H-6P, OCH2CH3),, 2.40-2.65 (m, 4H), 2.05-2.34 (m, 2H), 1.65-1.90 (m, 1H), 1.03 (t, ƒ = 7.0 Hz, 3H, OCH2CH3).. "C-NMR: (C6D6, 50 MHz): 8 = 177.0 (C-2), 136.0 (C-8), 134.2 (CH=CH2), 118.5 (CH=CH2),, 115.9 (C-9), 87.5 (C-5), 62.2 (OCHzCHs), 42.1 (C-6), 41.4 (C-3), 33.8, 32.2, 31.7,15.4 (OCH2CH3).. IR (film): v 2978,1770,1241.

l-But-3-enyl-5-ethoxy-3-pent-4-enylpyrrolidin-2-onee (35b): Following the

samee procedure as outlined for the preparation of 35a, ethoxylactam 37a (1199 mg, 0.66 mmol) was reacted overnight with 5-bromo-l-pentene (84 uL, 0.711 mmol) to give diolefin 35b (50.5 mg, 0.20 mmol, 31%) as a colorless oil afterr purification (EtOAcPE = 1:4) as an inseparable mixture of diastereomers (20:80). Rf = 0.32.. Major isomer: iH-NMR: (QDe, 400 MHz): 8 = 5.66-5.79 (m, 2H, H-8, CH=CH2), 4.92-5.077 (m, 4H, H-9, CH=CH2), 4.38 (dd, ƒ = 4.5; 6.2 Hz, 1H, H-5), 3.55-3.64 (m, 1H, H-6a), 3.13-3.222 (m, 1H, H-6p), 3.00-3.09 (m, 2H, OCH2CH3), 2.18-2.33 (m, 2H), 1.88-2.00 (m, 3H), 1.74-1.822 (m, 1H), 1.24-1.50 (m, 5H), 1.01 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). "C-NMR: (CeDs, 50 MHz): 88 = 177.0 (C-2), 138.6 (C-8), 135.9 (CH=CH2), 116.2 (CH=CH2), 114.4 (C-9), 87.1 (C-5), 62.2 (OCH2CH3),, 42.7 (C-6), 39.8 (C-3), 37.6, 35.9, 34.1, 32.3,23.9 15.3 (OCH2CH3). IR (film): v 2977, 1769,1242. .

—vv 3-Allyl-5-ethoxy-l-pent-4-enylpyrrolidin-2-one (35c): Following the same proceduree as outlined for the preparation of 35a, ethoxylactam 37b (114 mg, ° ^ NN 0 E t _{0.59 mmol) afforded diolefin 35c (84 mg, 0.36 mmol, 61 %) as a brown oil after} \ / ^ ^^ purification (EtOAc:PE = 1:4) as an inseparable mixture of diastereomers (33:66).. Rf = 0.32. Major isomer: ^H-NMR: (C6D6, 400 MHz): 8 = 5.58-5.80 (m, 2H, H-9, CH=CH2),, 4.86-5.06 (m, 4H, H-10, CH=CH2), 4.43 (dd, ƒ = 1.1; 6.3 Hz, 1H, H-5), 3.42-3.56 (m, 1H,, H-6°), 2.96-3.20 (m, 3H, H-6P, OCH2CH3), 2.42-2.66 (m, 1H, H-3), 1.65-2.24 (m, 4H), 1.28-1.600 (m, 4H), 0.98 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). "C-NMR: (CéD6, 50 MHz): 8 = 176.3 (C-2), 139.00 (C-9), 136.8 (CH=CH2), 117.6 (CH=CH2), 115.9 (C-10), 88.4 (C-5), 62.0 (OOHbOt), 41.4 (C-6),, 40.1 (C-3), 36.5, 32.4, 32.2, 28.3, 16.2 (OCH2CH3). Minor isomer: ^H-NMR: (CéD6, 400 MHz):: 8 = 5.58-5.80 (m, 2H, H-9, CH=CH2), 4.86-5.06 (m, 4H, H-10, CH=CH2), 4.33 (dd, ƒ = 3.8;; 6.3 Hz, 1H, H-5), 3.42-3.56 (m, 1H, H-6a), 2.96, 3.20 (m, 3H, H-6P, OCH2CH3), 2.42-2.66 (m,, 1H, H-3), 1.65-2.24 (m, 4H), 1.28-1.60 (m, 4H), 0.96 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). 13 C-NMR:: (G,D6, 50 MHz): 8 = 176.3 (C-2), 137.4 (C-9), 136.8 (CH=CH2), 117.6 (CH=CH2), 117.3 (C-10),, 89.2 (C-5), 62.9 (OCH2CH3), 41.2 (C-6), 41.1 (C-3), 37.6, 32.4, 31.6, 28.2, 16.3 (OCH2CH3).. IR (film): v 2977,1769,1242.

5-Ethoxy-l,3-dipent-4-enylpyrrolidin-2-onee (35d): Following the same

proceduree as outlined for the preparation of 35b, ethoxylactam 37b (113 mg,, 0.58 mmol) afforded diolefin 35d (10.5 mg, 0.042 mmol, 7%) as a brownn oil after purification (EtOAcPE = 1:4) as an inseparable mixture of diastereomerss (24:76). Rf = 0.30. Major isomer: iH-NMR: (C6D6, 400 MHz): 8 = 5.65-5.85 (m, 2H,, H-9, CH=CH2), 4.92-5.11 (m, 4H, H-10, CH=CH2), 4.52 (dd, ƒ = 1.2; 6.2 Hz, 1H, H-5), 3.48-3.633 (m, 1H, H-6a), 3.03-3.25 (m, 3H, H-6P, OCH2CH3), 2.41-2.53 (m, 1H, H-3), 1.60-2.11 (m, 6H),, 1.18-1.43 (m, 6H), 1.04 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). «C-NMR: (C6D6, 50 MHz): 8 = 176.1 (C-2),, 137.6 (C-9), 136.9 (CH=CH2), 117.6 (CH=CH2), 117.1 (C-10), 88.8 (C-5), 62.6 (OCH2CH3), 41.22 (C-6), 41.0 (C-3), 37.3, 35.4, 31.5, 28.8, 28.1, 22.6, 16.3 (OCH2CH3). Minor isomer: J H-NMR:: (C6D6, 400 MHz): 8 = 5.65-5.85 (m, 2H, H-9, CH=CH2), 4.92-5.11 (m, 4H, H-10, CH=CH2),, 4.41 (dd, ƒ = 3.6; 6.2 Hz, 1H, H-5), 3.48-3.63 (m, 1H, H-6a), 3.03-3.25 (m, 3H, H-6P, OCH2CH3),, 2.41-2.53 (m, 1H, H-3), 1.60-2.11 (m, 6H), 1.18-1.43 (m, 6H), 1.02 (t, ƒ = 7.0 Hz, 3H,, OCH2CH3). "C-NMR: (C6D6,50 MHz): 8 = 176.1 (C-2), 137.3 (C-9), 136.4 (CH=CH2), 117.6 (CH=CH2),, 116.5 (C-10), 88.5 (C-5), 62.6 (OCH2CH3), 42.0 (C-6), 41.3 (C-3), 37.4, 35.4, 31.6, 28.8,28.4,22.4,16.33 (OCH2CH3). IR (film): v 2978,1768,1241.

l,3-Diallyl-6-ethoxypiperidin-2-onee (35e): Following the same procedure as

I j T j LL outlined for the preparation of 35a, ethoxylactam 37c (193 mg, 1.06 mmol) oo N OEI afforded diolefin 35e (149 mg, 0.67 mmol, 63%) as a colorless oil after

^ * ** purification (EtOAcPE = 1:4) as an inseparable mixture of diastereomers (38:62).. Rf = 0.35. Major isomer: iH-NMR: (C6D6, 400 MHz): 8 = 5.70-5.85 (m, 2H, H-8, CH=CH2),, 4.94-5.05 (m, 4H, H-9, CH=CH2), 4.62-1.66 (m, 1H, H-7"), 4.15 (br s, 1H, H-6), 3.55 (dd,, ƒ = 7.3; 15.3 Hz, 1H, H-713), 3.00-3.10 (m, 2H, OCHzCHs), 2.82-2.89 (m, 1H), 2.32-2.40 (m, 1H),, 2.05-2.13 (m, 1H), 1.72-1.85 (m, 1H), 1.35-1.69 (m, 2H), 1.14-1.25 (m, 1H), 0.98 (t, ƒ = 7.0 Hz,, 3H, OCH2CH3). «C-NMR: (ODe, 50 MHz): 8 = 171.6 (C-2), 137.9 (C-8), 137.7 (CH=CH2), 117.22 (C-9), 117.1 (CH=CH2), 86.4 (C-6), 63.9 (OCH2CH3), 48.4 (C-7), 42.8 (C-3), 37.0, 27.5, 22.2, 16.11 (OCH2CH3). Minor isomer: iH-NMR: (QDe, 400 MHz): 8 = 5.70-5.85 (m, 2H, H-8, CH=CH2),, 4.94-5.05 (m, 4H, H-9, CH=CH2), 4.62-4.66 (m, 1H, H-70), 4.22 (t, ƒ = 4.1 Hz, 1H, H-6),, 3.55 (dd, ƒ = 7.3; 15.3 Hz, 1H, H-713), 2.95-3.06 (m, 2H, OCH2CH3), 2.68-2.76 (m, 1H), 2.32-2.400 (m, 1H), 2.20-2.28 (m, 1H), 1.72-1.85 (m, 1H), 1.35-1.69 (m, 2H), 1.14-1.25 (m, 1H), 0.97

(t,, ƒ = 7.0 Hz, 3H, OCH2CH3). «C-NMR: (C6D6, 50 MHz): 8 = 172.8 (C-2), 135.5 (C-8), 135.4 (CH=CH2),, 117.0 (C-9), 116.9 (CH=CH2), 86.6 (C-6), 63.3 (OCH2CH3), 47.8 (C-7), 41.3 (C-3), 37.0,, 26.2, 21.6,16.1 (OCH2CH3). IR (film): v 2977,1770,1244. HRMS calculated for Q3H22O2N 224.1651,, found 224.1651.

3-Allyl-l-but-3-enyl-6-ethoxypiperidin-2-onee (35f): Following the same

proceduree as outlined for the preparation of 35a, ethoxylactam 37d (55.6 mg, 0.288 mmol) afforded diolefin 35£ (34.8 mg, 0.15 mmol, 52%) as a colorless oil afterr purification (EtOAcPE = 1:8) as an inseparable mixture of diastereomers (43:57).. Rf = 0.25. Major isomer: iH-NMR: (C6D6, 400 MHz): 5 = 5.68-5.84 (m, 2H, H-9, CH=CH2),, 4.96-5.06 (m, 4H, H-10, CH=CH2), 4.09 (br s, 1H, H-6), 3.71-3.82 (m, 1H, H-7a), 3.11-3.200 (m, 1H, H-/*), 3.00-3.09 (m, 2H, OCH2CH3), 2.82-2.91 (m, 1H), 2.21-2.49 (m, 4H), 1.13-1.844 (m, 4H), 0.98 (t, ƒ = 6.8 Hz, 3H, OCH2CH3). "C-NMR: (C6D6,50 MHz): 8 = 172.8 (C-2),, 138.0 (C-9), 137.2 (CH=CH2), 117.1 (CH=CH2), 117.0 (C-10), 88.1 (C-6), 63.8 (OCH2CH3), 47.11 (C-7), 42.7 (C-3), 37.4, 33.9, 27.5, 22.1, 16.2 (OCH2CH3). Minor isomer: iH-NMR: (C6D6, 4000 MHz): 8 = 5.68-5.84 (m, 2H, H-9, CH=CH2), 4.96-5.06 (m, 4H, H-10, CH=CH2), 4.17 (t, ƒ = 4.11 Hz, 1H, H-6), 3.84-3.94 (m, 1H, H-T01), 2.93-3.09 (m, 3H, H-7^, OCH2CH3) 2.71-2.79 (m, 1H),, 2.05-2.49 (m, 4H), 1.13-1.84 (m, 4H), 0.97 (t, ƒ = 6.8 Hz, 3H, OCH2CH3). "C-NMR: (C6D6, 500 MHz): 8 = 171.8 (C-2), 137.7 (C-9), 137.1 (CH=CH2), 117.1 (CH=CH2), 116.9 10), 88.1 (C-6),, 63.2 (OCH2CH3), 46.2 (C-7), 41.2 (C-3), 37.3, 33.9, 26,3, 21.8, 16.2 (OCH2CH3). IR (film): v 2940,1769,1250.. HRMS calculated for Ci4H2402N 238.1807, found 238.1788.

l-But-3-enyl-6-ethoxy-3-pent-4-enylpiperidin-2-onee (35g): Following the

samee procedure as outlined for the preparation of 35b, ethoxylactam 37d (51.99 mg, 0.26 mmol) afforded diolefin 35g (28.1 mg, 0.11 mmol, 40%) as a colorlesss oil after purification (EtOAcPE = 1:1) as an inseparable mixture of diastereomerss (50:50). Rf = 0.36. Isomer A: iH-NMR: (C6D6, 400 MHz): 8 = 5.71-5.84 (m, 2H, H-9,, CH=CH2), 4.95-5.07 (m, 4H, H-10, CH=CH2), 4.10 (br s, 1H, 6), 3.64-3.71 (m, 1H, H-7°),, 3.00-3.20 (m, 3H, H-T", OCH2CH3), 1.14-2.10 (m, 13H), 1.00 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). "C-NMR:: (C6D6, 50 MHz): 8 = 173.2 (C-2), 139.8 (C-9), 139.5 (CH=CH2), 115.7 (CH=CH2), 115.55 (C-10), 87.8 (C-6), 64.0 (OCH2CH3), 47.3 (C-7), 42.8 (C-3), 34.9, 32.6, 32.3, 27.9, 27.5, 22.4, 16.33 (OCH2CH3). Isomer B: ^H-NMR: (C6D6, 400 MHz): 8 = 5.71-5.84 (m, 2H, H-9, CH=CH2), 4.95-5.077 (m, 4H, H-10, CH=CH2), 4.18 (t, ƒ = 4.0 Hz, 1H, H-6), 3.73-3.81 (m, 1H, H-711), 3.00-3.200 (m, 3H, H-713, OCH2CH3), 1.14-2.10 (m, 13H), 1.02 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). «C-NMR:: (C6D6, 50 MHz): 8 = 172.5 (C-2), 139.6 (C-9), 139.2 (CH=CH2), 115.5 (CH=CH2), 115.2 (C-10),, 87.7 (C-6), 63.7 (OCH2CH3), 46.9 (C-7), 41.8 (C-3), 34.8, 32.4, 32.1, 27.7, 27.3, 22.3,16.2 (OCH2CH3).. IR (film): v 2972, 1770, 1244. HRMS calculated for Ci6H2802N 266.2045, found 266.2032. .

3-Alryl-6-ethoxy-l-pent-4-enylpiperidin-2-onee (35h): Following the same

proceduree as outlined for the preparation of 35a, ethoxylactam 37e (107 mg, 0.511 mmol) afforded diolefin 35h (83.3 mg, 0.33 mmol, 66%) as a colorless oil afterr purification (EtOAcPE = 1:5) as an inseparable mixture of diastereomerss (40:60). Rf = 0.20. Major isomer: « - N M R : (C6D6, 400 MHz): 8 = 5.73-5.84 (m, 2H,, H-10, CH=CH2), 4.95-5.05 (m, 4H, H-ll, CH=CH2), 4.09 (br s, 1H, H-6), 3.61-3.72 (m, 1H, H-70),, 3.04-3.20 (m, 3H, H-7*, OCH2CH3), 2.84-2.92 (m, 1H), 2.34-2.43 (m, 1H), 2.04-2.13 (m, 1H),, 1.96-2.00 (m, 2H), 1.58-1.88 (m, 3H), 1.14-1.54 (m, 3H), 0.99 (t, ƒ = 7.0 Hz, 3H, OCH2CH3).. "C-NMR: (C6D6, 50 MHz): 8 = 172.7 (C-2), 139.3 (C-10), 137.9 (CH=CH2), 117.2 (CH=CH2),, 115.6 (C-ll), 87.8 (C-6), 63.8 (OCH2CH3), 47.0 (C-7), 42.7 (C-3), 37.4, 32.3, 28.4, 108 8

2727 A, 12.1, 16.2 (OCH2CH3). Minor isomer: ^H-NMR: (G,D6, 400 MHz): 5 = 5.73-5.84 (m, 2H, H-10,, CH=CH2), 4.95-5.05 (m, 4H, H - l l , CH=CH2), 4.16 (t, ƒ = 4.0 Hz, 1H, H-6), 3.72-3.79 (m, 1H,, H-701_{), 2.94-3.11 (m, 3H, H-7}9_{, OCH2CH3), 2.68-2.78 (m, 1H), 2.34-2.43 (m, 1H), 2.22-2.30} (m,, 1H), 1.96-2.00 (m, 2H), 1.58-1.88 (m, 3H), 1.14-1.54 (m, 3H), 1.00 (t, ƒ = 7.0 Hz, 3H, OCH2CH3).. «C-NMR: (C6D6, 50 MHz): S = 171.8 (C-2), 139.2 (C-10), 137.7 (CH=CH2), 117.2 (CH=CH2),, 115.5 (C-ll), 87.8 (C-6), 63.3 (OCHzCHs), 46.4 (C-7), 41.8 (C-3), 37.3, 32.3, 28.4, 26,4,, 21.7, 16.2 (OCH2CH3). IR (film): v 2976, 1770, 1243. HRMS calculated for CisH2602N 252.1964,, found 252.1956.

l,3-Dipent-4-enyl-6-ethoxypiperidin-2-onee (35i): Following the same

proceduree as outlined for the preparation of 35b, ethoxylactam 37e (109 mg,, 0.52 mmol) afforded diolefin 35i (65.0 mg, 0.23 mmol, 45%) as a colorlesss oil after purification (EtOAcPE = 1:4) as an inseparable mixture off diastereomers (50:50). Rf = 0.24. Isomer A: !H-NMR: (C6D6, 400 MHz): 8 = 5.72-5.82 (m, 2H,, H-10, CH=CH2), 4.93-5.05 (m, 4H, H - l l , CH=CH2), 4.10 (br s, 1H, H-6), 3.73-3.81 (m, 1H, H-7"),, 3.03-3.19 (m, 3H, H-T3, OCH2CH3), 1.11-2.08 (m, 15H), 1.00 (t, ƒ = 6.9 Hz, 3H, OCH2CH3).. «C-NMR: (C6D6, 50 MHz): 8 = 173.3 (C-2), 139.8 (C-10), 139.3 (CH=CH2), 115.6 (CH=CH2),, H5.5 (C-ll), 87.9 (C-6), 63.8 (OCH2CH3), 47.1 (C-7), 42.9 (C-3), 34.9, 32.5, 32.3, 28.4,, 27.9, 27.4, 22.4,16.2 (OCH2CH3). Isomer B: « - N M R : (C6D6, 400 MHz): 8 = 5.72-5.82 (m, 2H,, H-10, CH=CH2), 4.93-5.05 (m, 4H, H - l l , CH=CH2), 4.18 (t, J = 3.9 Hz, 1H, H-6), 3.64-3.71 (m,, 1H, H-7"), 2.98-3.11 (m, 3H, H-7*1, OCH2CH3), 1.11-2.08 (m, 15H), 1.02 (t, ƒ = 6.9 Hz, 3H, OCH2CH3).. wC-NMR: (C6D6, 50 MHz): 8 = 172.4 (C-2), 139.7 (C-10), 139.2 (CH=CH2), 115.5 (CH=CH2),, 115.3 (C-ll), 87.8 (C-6), 63.3 ( O C H J C H B ) , 46.4 (C-7), 41.6 (C-3), 34.9, 32.4, 32.1, 27,9,, 27.5, 27.2, 22.4, 16.1 (OCH2CH3). IR (film): v 2975, 1770, 1245. HRMS calculated for C16H28O2NN 266.2045, found 266.2032.

5-Ethoxy-l-azabicyclo[6.2.1]undec-9-en-2-onee (34c): A solution of diolefin

35cc (25.0 mg, 0.11 mmol) in toluene (2 mL) was degassed thoroughly with

\\ argon. To this solution was added catalyst B (1.5 mg, 1.77 omol). The reaction E t 0_{'' ^ y mixture was heated to 80 °C and stirred overnight. After cooling to room} temperature,, the solvent was evaporated in vacuo. Purification by column chromatography (EtOAc:PEE = 1:5) afforded bicycle 34c (1.5 mg, 7.17 [imol, 7%) as a white solid. M.p. 78-80 °C.

RRff = 0.28. iH-NMR: (C6D6, 400 MHz): 8 = 5.37-5.53 (m, 1H, CH=CH), 5.14-5.31 (m, 1H, CH=CH),CH=CH), 4.51 (dd, ƒ = 4.5; 6.3 Hz, 1H, H-5), 3.82-3.97 (m, 1H, H-6°), 2.99-3.14 (m, 2H, OCH2CH3),, 2.70-2.83 (m, 1H, H-6P), 2.50-2.58 (m, 1H, H-3), 1.72-1.97 (m, 3H), 1.55-1.70 (m, 2H),, 1.18-1.46 (m, 3H), 1.04 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). "C-NMR: (G,D6,50 MHz): 8 = 174.8 (C-2),, 133.8 (CH=CH), 124.8 (CH=CH), 86.1 (C-5), 60.5 (OCH2CH3), 39.1 (C-6), 38.8 (C-3), 31.8, 30.4,28.1,27.3,15.00 (OCH2CH3).

co2Mee 2-Allyl-2-(l-allyl-5-oxo-2-propoxypyrrolidin-3-yl)malonic acid dimethyl

esterr (45): To a dispersion of sodium hydride (60 wt. % dispersion in mineral

oil,, 8.2 mg, 0.19 mmol) in DMF (2 mL) at 0 °C was added dropwise a solution off isopropoxylactam 41 (50.4 mg, 0.16 mmol) in DMF (1 mL). The resulting mixturee was stirred for 30 minutes at 0 °C and allyl bromide (43 (iL, 0.50 mmol)) was added dropwise. The solution was stirred for 30 minutes at 0 °C and subsequentlyy at room temperature. After stirring overnight, aqueous saturated NH4CI was addedd and the resulting mixture was stirred for 15 minutes. Et20 was added, the layers were separatedd and the aqueous phase was extracted with Et20 (3x). The combined organic layers weree washed with water, dried over MgSC>4 and concentrated in vacuo. Purification by

columnn chromatography (EtOAcPE = 2:1) afforded diolefin 45 (33.0 mg, 0.093 mmol, 58%) as aa colorless oil. Rf = 0.40. iH-NMR: (C6D6, 400 MHz): S = 5.78-5.88 (m, 1H, H-8), 5.52-5.61 (m, 1H,, CH=CH2), 5.09 (s, 1H, H-5), 5.04 (ddd, ƒ = 1.3; 10.1; 17.1 Hz, 2H, H-9), 4.90 (ddd, / = 1.5; 10.9;; 17.6 Hz, 2H, CH=CH2), 4.35-4.40 (m, 1H, NCH2a), 3.92 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.644 (dd, ƒ = 7.7; 15.1 Hz, 1H, NCH2% 3.31 (s, 3H, C02CH3), 3.27 (s, 3H, C02CH3), 2.84 (dd, / = 9.3;; 17.0 Hz, 1H, H-3a), 2.74-2.82 (m, 1H, H-4), 2.70 (d, ƒ = 7.3 Hz, 2H, H-7), 2.54 (d, ƒ = 16.9 Hz,, 1H, H-3P), 1.16 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.15 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). " C -NMR:: (C6D6, 50 MHz): 5 = 173.8 (C-2), 171.3 (C02CH3), 170.8 (C02CH3), 134.7 (C-8), 132.8 (CH=CH2),, 120.2 (CH=CH2), 118.6 (C-9), 89.3 (C-5), 69.7 (CH(CH3)2), 60.2 (C-6), 52.7 (2x C02CH3),, 44.3 (NCH2), 43.4 (C-4), 38.9, 32.8, 24.2 (CH(CH3)2), 23.0 (CH(CH3)2). IR (film): v 2972,1740,1701.. HRMS calculated for Ci8H2806N 354.1917, found 354.1896.

MeO,CC C02Me 2-(l-Allyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-but-3-enylmalonicc acid

dimethyll ester (46): Following the same procedure as outlined for the

preparationn of 45, isopropoxylactam 42 (33.0 mg, 0.10 mmol) afforded diolefinn 46 (20.9 mg, 0.057 mmol, 56%) as a colorless oil after purification (EtOAcPEE = 2:1). R/= 0.40. « - N M R : (C6D6, 400 MHz): 5 = 5.77-5.87 (m, 1H, H-9),, 5.54-5.64 (m, 1H, CH=CH2), 5.02 (ddd, ƒ = 1.2; 10.2; 17.2 Hz, 2H, H-10), 4.92 (ddd, ƒ = 1.4;; 10.2; 17.2 Hz, 2H, CH=CH2), 5.05 (s, 1H, H-5), 4.36 (dd, ƒ = 5.2; 15.2 Hz, 1H, NCH2a), 3.88 (sept,, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.62 (dd, ƒ = 7.9; 15.2 Hz, 1H, NCH2P), 3.32 (s, 3H, C02CH3), 3.266 (s, 3H, C02CH3), 2.73-2.86 (m, 2H, H-3°, H-4), 2.53 (d, ƒ = 17.1 Hz, 1H, H-3"), 1.87-2.18 (m,, 4H), 1.12 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.05 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). 13C-NMR: (C6D6,, 100 MHz): 8 = 173.8 (C-2), 171.7 (2x C02CH3), 137.8 (C-9), 134.7 (CH=CH2), 118.7 (CH=CH2),, 116.2 (C-10), 89.3 (C-5), 69.9 (CH(CH3)2), 59.8 (C-6), 52.8 (2x C02CH3), 44.3 (NCH2),, 43.4 (C-4), 33.7, 33.0, 29.7, 24.2 (CH(CH3)2), 23.1 (CH(CH3)2). IR (film): v 2972, 1730, 1709.. HRMS calculated for GOHJOOÖN 368.2073, found 368.2085.

Me02C.. C02Me 2-(l-Allyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-pent-4-enylmalonicc acid

dimethyll ester (47): Following the same procedure as outlined for the

preparationn of 45, isopropoxylactam 43 (44.8 mg, 0.13 mmol) afforded diolefinn 47 (30.3 mg, 0.080 mmol, 60%) as a colorless oil after purification (EtOAcPEE = 2:1). Rf= 0.40. iH-NMR: (C6D6, 400 MHz): 5 = 5.79-5.88 (m, 1H,, H-10), 5.55-5.63 (m, 1H, CH=CH2), 5.07 (s, 1H, H-5), 5.04 (ddd, ƒ = 1.3; 10.1; 16.5 Hz, 2H, H - l l ) ,, 4.94 (ddd, ƒ = 2.0; 9.9; 17.1 Hz, 2H, CH=CH2), 4.38 (dd, ƒ = 5.2; 15.2 Hz, 1H, NCH2a), 3.933 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.64 (dd, ƒ = 7.9; 15.2 Hz, 1H, NCH2P), 3.33 (s, 3H, C02CH3),, 3.28 (s, 3H, C02CH3), 2.74-2.87 (m, 2H, H-3a, H-4), 2.54 (d, ƒ = 17.0 Hz, 1H, H-3P), 1.91-2.088 (m, 2H), 1.80-1.88 (m, 2H), 1.18-1.33 (m, 2H), 1.13 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.077 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). "C-NMR: (C6D6, 100 MHz): 8 = 173.9 (C-2), 171.9 (C02CH3),, 171.3 (C02CH3), 138.5 (C-10), 134.8 (CH=CH2), 118.7 (CH=CH2), 116.2 (C-ll), 89.4 (C-5),, 69.9 (CH(CH3)2), 60.0 (C-6), 52.8 (2x C02CH3), 44.3 (NCH2), 43.5 (C-4), 34.6, 33.8, 33.0, 24.6,, 24.2 (CH(CH3)2), 23.1 (CH(CH3)2). IR (film): v 2973, 1731, 1710. HRMS calculated for C20H32O6NN 382.2230, found 382.2257.

MeOjCC C 02M e 2-(l-Allyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-hex-5-enylmalonicc acid

dimethyll ester (48): Following the same procedure as outlined for the

preparationn of 45, isopropoxylactam 44 (286 mg, 0.81 mmol) afforded diolefinn 48 (192 mg, 0.49 mmol, 60%) as a light yellow oil after purificationn (EtOAcPE = 2:1). R/= 0.40. ^H-NMR: (CDC13, 400 MHz): 5 = 5.60-5.766 (m, 2H, H - l l , CH=CH2), 5.16 (dd, ƒ = 9.7; 15.8 Hz, 2H, H-12), 4.92 (ddd, ƒ = 1.5; 10.9; 110 0

17.33 Hz, 2H, CH=CH2), 4.83 (s, 1H, H-5), 4.13 (dd, ƒ = 5.2; 15.2 Hz, 1H, NCH2a), 3.82 (sept, ƒ = 6.11 Hz, 1H, CH(CH3)2), 3.66 (s, 3H, C02CH3), 3.64 (s, 3H, C02CH3), 3.50 (dd, ƒ = 8.0; 15.0 Hz, 1H,, N C H / ) , 2.68-2.76 (m, 2H, H-3a, H-4), 2.35 (d, ƒ = 15.7 Hz, 1H, H-3P), 1.84-2.03 (m, 5H), 1.31-1.388 (m, 3H), 1.14 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.12 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). 13 C-NMR:: (CDCk, 50 MHz): 5 = 173.8 (C-2), 170.7 (COzCHs), 170.4 (C02CHi), 138.1 (C-ll), 132.7 (CH=CH2),, 118.4 (CH=CH2), 114.7 (C-12), 88.3 (C-5), 69.2 (CH(CH3)2), 59.0 (C-6), 52.4 (2x CO2CH3),CO2CH3), 43.2 (NCH2), 42.2 (C-4), 33.2 (2x), 32.2, 28.8, 23.5, 23.2 (CH(CH3)2), 22.2 (CH(CH3)2). IRR (fUm): v 2971,1731,1711. HRMS calculated for CnHwOéN 396.2386, found 396.2590.

Meoo c co2Me 2-(5-Oxo-l-pent-4-enyl-2-propoxypyrrolidin-3-yl)-2-pent-4-enylmalonic

acidd dimethyl ester (49): To a solution of isopropoxylactam 43 (28.0 mg,

0.0822 mmol) in THF (2 mL) at room temperature was added KO'Bu (1 M solutionn in THF, 128 (iL, 0.13 mmol). The resulting mixture was stirred for 55 minutes and 5-bromo-l-pentene (50 \xL, 0.42 mmol) was added. The solutionn was allowed to warm to 70 °C and stirred for 1 h. After the mixture was cooled to roomm temperature, aqueous saturated NH4CI was added, the layers were separated and the aqueouss layer was extracted with EtOAc. The combined organic layers were dried over MgSOéé and concentrated in vacuo. Purification by column chromatography (EtOAcPE = 1:5) affordedd diolefin 49 (9.5 mg, 0.023 mmol, 28%) as a colorless oil. Rf = 0.33. ^H-NMR: (C6D6, 4000 MHz): 5 = 5.71-5.80 (m, 1H, H-10), 5.56-5.70 (m, 1H, CH=CH2), 5.09 (s, 1H, H-5), 4.92-5.066 (m, 4H, H - l l , CH=CH2), 3.95 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.50 (ddd, ƒ = 5.8; 9.9; 15.6 Hz,, 1H, NCH2"), 3.35 (s, 3H, C02CH3), 3.29 (s, 3H, C02CH3), 3.18-2.25 (m, 1H, N C H / ) , 2.74-2.877 (m, 2H, H-3°, H-4), 2.52 (d, ƒ = 17.1 Hz, 1H, H-3P), 1.91-2.07 (m, 4H), 1.61-1.80 (m, 4H), 1.22-1.366 (m, 2H), 1.14 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.08 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). «C-NMR:: (C6D6, 100 MHz): 5 = 174.1 (C-2), 171.3 (2x COzCH3), 138.8 (C-10), 138.5 (CH=CH2), 116.22 (CH=CH2), 115.8 (C-ll), 90.4 (C-5), 69.5 (CH(CH3)2), 60.1 (C-6), 52.7 (2x C02CH3), 43.5 (C-4),, 41.6 (NCH2), 34.6,33.8, 33.0, 32.3, 28.2, 24.7,24.3 (CH(CH3)2), 23.0 (CH(CH3)2). IR (film): vv 2972,1730,1705. HRMS calculated for CaH^C^N 410.2543, found 410.2545.

Meo2cc co2Me 2-(l-Allyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-oct-7-enylmalonic

acidd dimethyl ester (51): Following the same procedure as outlined

forr the preparation of 45, isopropoxylactam 50 (35.2 mg, 0.092 mmol) affordedd diolefin 51 (29.0 mg, 0.69 mmol, 75%) as a light yellow oil afterr purification (EtOAcPE = 2:1). Rf = 0.40. !H-NMR: (CDC13, 400 MHz):: 5 = 5.63-5.82 (m, 2H, H-13, CH=CH2), 5.19 (ddd, ƒ = 1.2; 9.8; 17.0 Hz, 2H, H-14), 4.95 (ddd,, ƒ = 1.5; 10.2; 17.1 Hz, 2H, CH=CH2), 4.85 (s, 1H, H-5), 4.15 (dd, ƒ = 5.2; 15.2 Hz, 1H, NCH2a),, 3.85 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.69 (s, 3H, COzCH3), 3.67 (s, 3H, C02CH3), 3.53 (dd,, ƒ = 7.9; 15.2 Hz, 1H, N C H / ) , 2.73-2.81 (m, 2H, H-3a, H-4), 2.38 (d, ƒ = 15.6 Hz, 1H, H ^ ) , 1.82-2.044 (m, 5H), 1.23-1.39 (m, 7H), 1.17 (d, ƒ = 5.8 Hz, 3H, CH(CH3)2), 1.15 (d, ƒ = 5.7 Hz, 3H,, CH(CH3)2). «C-NMR: (CDCh, 50 MHz): 8 = 173.8 (C-2), 170.8 (C02CH3), 170.5 (C02CH3), 138.88 (C-13), 132.8 (CH=CH2), 118.4 (CH=CH2), 114.3 (C-14), 88.4 (C-5), 69.2 (CH(CH3)2), 59.0 (C-6),, 52.4 (2x C02CH3), 43.2 (NCH2), 42.2 (C-4), 33.6, 33.3, 32.3, 29.5, 28.6 (2x), 24.2, 23.3 (CH(CH3)2),, 22.3 (CH(CH3)2). IR (film): v 2972, 1730, 1711. HRMS calculated for CaHwOeN 424.2699,, found 424.2702.

Me02cc co2Me

2-(l-But-2-enyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-oct-7-enylmalonicc acid dimethyl ester (52): Following the same

proceduree as outlined for the preparation of 45, isopropoxylactam 50 (35.22 mg, 0.092 mmol) was reacted with l-bromo-but-2-ene (50 (xL,

0.499 mmol) to give 52 (28.4 mg, 0.065 mmol, 71%) as a light yellow oil after purification (EtOAc:PEE = 2:1). Rf = 0.40. ^H-NMR: (CDOb, 400 MHz): 8 = 5.75-5.81 (m, 1H, H-13), 5.61-5.655 (m, 1H, CH=CH), 5.30-5.34 (m, 1H, CH=CH), 4.96 (ddd, ƒ = 1.5; 10.2; 16.9 Hz, 2H, H-14), 4.844 (s, 1H, H-5), 4.04 (m, 1H, NCH2a), 3.84 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.69 (s, 3H, CO2CH3),, 3.67 (s, 3H, CO2CH3), 3.49 (dd, ƒ = 7.7; 16.0 Hz, 1H, N C H / ) , 2.72-2.81 (m, 2H, H-3a, H-4),, 2.36 (d, ƒ = 16.0 Hz, 1H, H-3P), 1.99-2.04 (m, 2H), 1.85-1.96 (m, 2H), 1.69 (d, ƒ = 6.5 Hz, 3H,, CH=CHCH3), 1.25-1.37 (m, 8H), 1.17 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.15 (d, ƒ = 6.1 Hz, 3H,, CH(CH3)2). "C-NMR: (CDC13/ 50 MHz): 5 = 173.7 (C-2), 170.8 (C02CH3), 170.6 (C02CH3), 138.88 (C-13), 129.5 (CH=CH), 125.5 (CH=CH), 114.3 (C-14), 88.4 (C-5), 69.0 (CH(CH3)2), 59.1 (C-6),, 52.4 (2x C02CH3), 42.5 (NCH2), 42.2 (C-4), 33.6, 33.3, 32.5, 29.5, 28.7 (2x), 24.2, 23.3 (CH(CH3)2),, 22.3 (CH(CH3)2), 17.6 (CH=CHCH3). IR (film): v 2928, 1731, 1710. HRMS calculatedd for C24H4o06N 438.2856, found 438.2838.

14-Oxo-15-propoxy-l-aza-bicyclo[10.2.1]pentadec-3-ene-ll,ll-dicarboxylic c

Me0Me022c.F°^c.F°^ee a ci d dimethyl ester (53): A solution of diolefin 51 (29.0 mg, 0.069 mmol) in

11——(( \ toluene (7 mL) was degassed thoroughly with argon. To this solution was

O ^ NN "0 P r <\ added catalyst C (2.3 mg, 2.71 umol). The reaction mixture was heated to 70 \ # ^^ °C and stirred overnight. After cooling to room temperature, the solvent was evaporatedd in vacuo. Purification by column chromatography (EtOAcPE = 3:1) afforded bicyclee 53 (6.7 mg, 0.017 mmol, 23%) as a lightbrown oil. Rf = 0.30. iH-NMR: (CDC13, 400 MHz):: 8 = 5.61-5.71 (m, 1H, CH=CH), 5.21-5.31 (m, 1H, CH=CH), 4.88 (s, 1H, H-5), 4.31-4.38 (m,, 1H, NCH2a), 3.71 (s, 3H, C02CH3), 3.69 (sept, / = 6.1 Hz, 1H, CH(CH3)2), 3.67 (s, 3H, C02CH3),, 3.45 (dd, ƒ = 7.7; 15.9 Hz, 1H, NCH2P), 3.18-3.27 (m, 1H), 2.70-2.86 (m, 2H, H-3a, H-4),, 2.25-2.34 (m, 1H, H-3"), 1.88-2.03 (m, 3H), 1.15-1.43 (m, 8H), 1.13 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2),, 1.12 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). «C-NMR: (CDCb, 100 MHz): 5 = 173.7 (C-2), 171.33 (C02CH3), 170.1 (COzCH3), 136.0 (CH=CH), 124.0 (CH=CH), 86.5 (C-5), 68.9 (CH(CH3)2), 59.33 (C-6), 53.8 (2x C02CH3), 43.3 (NCH2), 41.6 (C-4), 33.5, 32.2, 30.0, 29.2, 28.9, 28.7, 25.0, 23.4 (CH(CH3)2),, 22.2 (CH(CH3)2). IR (film): v 2928, 1730, 1709. HRMS calculated for C2iH3406N 396.2386,, found 396.2378.

3-Allyl-l-benzyl-5-ethoxy-4-hydroxypyrrolidin-2-onee (57): To a solution of

diisopropylaminee (1.3 mL, 6.31 mmol) in THF (10 mL) was added dropwise at -788 °C, n-butyllithium (1.6 M solution in hexanes, 4.0 mL, 6.30 mmol). The resultingg mixture was stirred at -78 °C for 1 h. Then a solution of ethoxylactam 566 (668 mg, 2.84 mmol) in THF (2 mL) was added dropwise at -78 °C. The resultingg mixture was stirred for 30 minutes at -78 °C, then warmed to -20 °C andd stirred for an additional 30 minutes at -20 °C. The solution was cooled to -78 °C and thenn allyl bromide (260 uL, 3.00 mmol) was added. The reaction mixture was allowed to w a r mm to room temperature and stirred overnight. Then, aqueous saturated NH4CI was addedd and the aqueous phase was extracted with CH2C12. The combined organic layers were driedd over MgS04 and concentrated in vacuo. Purification by column chromatography (CH2Cl2:acetonee = 5:1) afforded 57 (469 mg, 1.70 mmol, 60%) as a colorless oil. Rf = 0.32. J H-NMR:: (CDCI3, 400 MHz): 5 = 7.20-7.30 (m, 5H), 5.77-5.87 (m, 1H, H-7), 5.08 (ddd, ƒ = 1.5; 10.2;; 17.1 Hz, 2H, H-8), 4.88 (d, ] = 14.9 Hz, 1H, N C H / ) , 4.44 (d, ƒ = 1.8 Hz, 1H, H-5), 4.01 (d, ƒ == 14.9 Hz, 1H, NCH2P), 3.94 (br s, 1H, H-4), 3.51-3.58 (m, 1H, OCH2a), 3.46 (d, ƒ = 4.3 Hz, 1H, OH),, 3.39-3.47 (m, 1H, O C H / ) , 2.53-2.60 (m, 1H, H-6a), 2.40-2.44 (m, 1H, H-3), 2.20-2.26 (m, 1H,, H-6P), 1.14 (t, ƒ = 7.0 Hz, 3H, OCH2CH3). "C-NMR: (CDC13, 100 MHz): 6 = 174.2 (C-2), 135.99 (C, ar), 135.2 7), 128.5 (2x ar), 128.0 (2x ar), 127.4 (ar), 117.2 8), 93.8 5), 74.2

(C-0H H