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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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4,5-DISUBSTITUTEDD TRANS-FUSED BICYCLIC LACTAMS
3.11 Introduction
Fusedd bicyclic systems containing a pyrrolidine ring are important structural elementss of biologically active compounds. One structural feature, which frequently occurs inn biologically important alkaloids, is a nitrogen atom at a ring-fusion position, such as in indolizidines,, quinolizidines, pyrroloazocine and pyridoazocine ring systems. These elementss can be found in (-)-2-epilentiginosine (1), a metabolite of the fungus Rhizoctonia
leguminicolaleguminicola and (+)-lentiginosine (2), a strong inhibitor of the fungal a-glucosidase
amyloglucosidase,, both having cardiotonic activity.1 They also occur in croomine2 (3), an alkaloidd isolated from plant species of the Stemonaceae family, which has been used in traditionall Chinese folk medicine to prepare herbal teas for treating disorders such as pertussis,, pulmonary tuberculosis and bronchitis (Chart 1). Moreover, some of these alkaloidss exhibit insecticidal activity.
Chartt 1
11 (R)-OH: (-)-2-epilentiginosine 3 croomine 4 (-)-pumiliotoxin C 22 (S)-OH: (+)-lentiginosine
HH Me n
55 pretazettine 6 (+)-pancrastistatin 7
Anotherr structural feature is exemplified with (-)-pumiliotoxin C (4), which contains aa core skeleton having the nitrogen adjacent to a ring-fusion position.3 This compound is isolatedd from the skin of the Panamanian poisonous frog Dendrobates pumilio as the first memberr of a major class of dendrobatid alkaloids.4 It is one of the less toxic alkaloids from thiss family and acts as a reversible blocker of the nicotinic acetylcholine receptor channel. Manyy alkaloids of the Amaryllidaceae family also contain this structural feature. Examples of thesee alkaloids are pretazettine (5) and pancratistatin (6). The chemically labile compound pretazettinee 5 displays antiviral and anticancer activity particularly in Rauscher leukemia, 45 5
Lewiss lung carcinoma and spontaneous AKR lymphocytic leukemia. In addition, it has also beenn found to inhibit protein synthesis in eukaryotic cells by a mechanism which does not effectt DNA and RNA synthesis.5 Pancratistatin 6 was isolated from the roots of Pancratium
littoralelittorale and exhibits a range of antineoplastic properties, including activity against murine
P-50766 ovarian sarcoma and P-388 lymphocytic leukemia.6 Furthermore, many biologically relevantt alkaloids contain a nitrogen atom at the fi-position with respect to the ring-fusion. Thee synthetic 4oc-aryldecahydro-isoquinoline 7 is such an example and represents a structurall fragment of morphine with significant pharmacological activity.7 It exhibits potent affinityy for the u-opioid receptor and possesses antinociceptive properties.
3.22 Literature strategies
Thee combination of ring-closing metathesis and N-acyliminium ion chemistry has alreadyy been employed in the synthesis of fused bicyclic lactams with the nitrogen atom at thee ring-fusion position. These compounds are often used as intermediates in the synthesis of biologicallyy interesting azacyclic compounds,8 such as the indolizidines (16), quinolizidines (17),, pyrroloazocine (18) and pyridoazocine ring systems (19) mentioned previously. An expedientt way to synthesize these bicyclic lactams using ring-closing metathesis and N-acyliminiumm ion chemistry was described by Martin9 and Holmes10 (Scheme 3.1). Starting fromm either succinimide (8) or glutarimide (9), alkylation of the nitrogen with a series of unsaturatedd alcohols under Mitsunobu conditions afforded the alkylated imides. Subsequent reductionn with NaBH4 and acidic ethanolysis of the corresponding hydroxylactams yielded
ethoxylactamss 10 and 11. Introduction of the allyl substituent under N-acyliminium ion reactionn conditions using BF3-OEt2 as the Lewis acid and allyltrimethylsilane as the allylating agentt afforded dienes 12 and 13 in 60-90% yield.
1)) PPh3, DEAD R R 2)) NaBH4, HCl/EtOH H catalystt A DME,, rt 70-95% % BF3OEt2 2 allyll SiMe3 60-90% % 166 n = l , m = 0 177 n = 2, m = 0 188 n = 1, m = 2 199 n = 2, m = 2
Subsequentt ring-closing metathesis using molybdenum catalyst A in DME at room temperaturee led to bicyclic lactams 14 and 15 in 70-95% yield."-!2 These lactams could be convertedd in a few steps to the corresponding fused nitrogen heterocycles 16 - 19.
Barrettt et aXP reported the synthesis of bicyclic fi-lactam carboxylic esters via a similar strategy,, using N-acyliminium ion chemistry and subsequent alkene ring-closing metathesis (eqq 3.1). Starting from readily available lactams 20, reaction with ethyl glyoxylate, followed byy acetylation gave the corresponding acetates, which underwent N-acyliminium ion reactionn with allyltrimethylsilane and BF3OEt2 to arrive at dienes 21a-c as 1:1 mixtures of
diastereomers.. Attempted ring-closing metathesis of vinylazetidinone 21a with Ru-catalyst B too a 6-membered ring lactam failed, whereas dienes 21b and 21c underwent clean ring closuree to give 7-membered- and 8 membered-ring lactams 22b and 22c in 92% and 76% yield,, respectively. 20aa n = 0 20bb n = 1 20cc n = 2 1)) Et02CCHO 2)) Ac20, pyr. » » 3)) BF3OEt2
allyll SiMe3 Et0 2C C
21a-c c
(3.1) )
Thee combination of N-acyliminium ion chemistry and ring-closing metathesis, however,, has not yet been reported for the synthesis of bicyclic amides bearing the nitrogen adjacentt to the ring-fusion. In addition, the synthesis of fnms-fused heterocycles, which occur regularlyy in alkaloid structures (viz. 6), is not frequently encountered in literature syntheses. Thesee nitrogen heterocycles are usually prepared by catalytic hydrogenation of the correspondingg imines, which leads in most cases to cz's-products. The N-acyliminium ion-mediatedd ring closure of lactam 23, reported by Koot, also resulted selectively in ris-products 244 and 25 (eq 3.2)." CHOOH H HO O 23 3 nn H 244 63% O O 255 12% (3.2) )
Brownn et al.15 reported a stereoselective albeit laborious route to arrive at decahydroquinolinee systems with frans-selectivity (Scheme 3.2). Starting from bromocycloalkeness 26, hydroboration with dichloroborane in pentane at 0 °C gave the correspondingg bromocycloalkyldichloroboranes 27 in quantitative yields with complete
frans-selectivity.. H y d r o l y s i s t o t h e boronic a c i d s w i t h w a t e r , followed b y reaction w i t h N a N 3 i nn E t O H l e d t o t h e a z i d o c y c l o a l k y l b o r o n a t e s 28. T r e a t m e n t w i t h b o r o n t r i c h l o r i d e i n d i c h l o r o m e t h a n ee g e n e r a t e d t h e d i c h l o r o b o r a n e s , w h i c h g a v e i n t e r m e d i a t e s 29 b y a n i n t r a m o l e c u l a rr cyclization. T h e s e c o m p o u n d s w e r e h y d r o l y z e d t o t h e c o r r e s p o n d i n g free a m i n e ss (30) w i t h K O H in w a t e r . Schemee 3.2 BHCl2SMe2 2 . . BC13,, pentane quant. . Br r 1 ) H20 0 2)) N a N3 +~ +~ EtOH H 27 7 ^ B ( O E t )2 2 28 8 BC1, , CH2C12 2
CD D
29 9 BCI, , HzO O 40%% KOHCD D
30 0 76-82%% yield over 33 steps Recently,, a n e l e g a n t a p p r o a c h w a s p u b l i s h e d b y Pilli a n d c o w o r k e r s ,1 6 w h o u s e d t h e N - a c y l i m i n i u mm i o n / r i n g - c l o s i n g m e t a t h e s i s a p p r o a c h t o a r r i v e at frans-fused d e c a h y d r o q u i n o l i n ee s y s t e m s (Scheme 3.3). R e a d i l y available N - B o c - 6 - m e t h y l - 2 - p i p e r i d i n o n e 3 11 w a s a l l y l a t e d w i t h allyl b r o m i d e a n d L H M D S , y i e l d i n g 32 stereoselectively a s a trans-productproduct R e d u c t i o n w i t h LiEt3BH, followed by acidic e t h a n o l y s i s p r o v i d e d 2-e t h o x y p i p 2-e r i d i n 2-e2-e 3 3 i n 79% yi2-eld. S u b s 2-e q u 2-e n t N - a c y l i m i n i u m ion r2-eaction, u s i n g B F3O E t2 as t h ee L e w i s acid a n d a l l y l t r i b u t y l t i n as the n u c l e o p h i l e afforded t r i s u b s t i t u t e d p i p e r i d i n e 34 in 72%% y i e l d as a n 89:4:7 m i x t u r e of d i a s t e r e o i s o m e r s , of w h i c h t h e major p r o d u c t p r o v e d t o b e t h ee d e s i r e d frans-isomer 34.1 7 Schemee 3.3 LiHMDS,, ^ / / , allyll bromide *--44% % catalystt B CH2C12,, rt, l h h 97% % N N Boc c 32 2 1)) LiBEt3H 2)) H C l / E t O H fr fr 79% % HH N HH Boc 35 5 EtO O Boc c 33 3 1)) C F3C 02H 2)) H2, P d / C »--3)) HC1/ EtOH 60% % allyll SnBu3 64% % + + HH H2 cr
36 6Ring-closingg metathesis of this diolefin carried out with 4 mol% of catalyst B (see: Eq 3.1)) in CH2CI2 at room temperature yielded octahydroquinoline 35 in 97% yield with completee retention of the frans-configuration.18 Finally, nitrogen deprotection, double bond
hydrogenationn and salt formation led to the isolation of decahydroquinoline hydrochloride 366 in 60% yield.
Interestingly,, the group of Grubbs found that cyclic constrained dienes undergo ring-closingg metathesis to 8-membered rings much more facile when the two olefinic groups have thee frans-configuration on the cyclic precursor.19 This finding was supported by molecular mechanicss (MM3) calculations, indicating that there is a greater difference in free energy (AG)) between the diene and the cyclic olefin in the as-substituted substrate (AG2) than in the
frans-substitutedd one (AGi, Scheme 3.4). Schemee 3.4
cC==
* cO cO »
cO=
UU AG
X U ° AG2 °
AG22 - AG-, = 1.8 kj/mol
ReagentsReagents and conditions: (a) catalyst B (8 mol%), C6H6 (0.015 M), 2 h, 55 °C.
Thiss chapter describes our efforts to construct a series of fraws-fused bicyclic y-lactams withh the nitrogen adjacent to a ring-fusion position and with different ring sizes (eq 3.3). Thesee 4,5-disubstituted bicyclic lactams 37 were thought to arise from frans-diolefins 38 via ring-closingg metathesis. These diolefins were envisaged to be accessible from 39 by N-acyliminiumm ion chemistry of the dealkylated lactam, in which the substituents are trans with respectt to each other. The required olefins 39 were expected to be readily obtained from (enantiopure)) isopropoxylactam 40 via a 1,4-addition reaction.
Ac c 40 0
3.33 Preparation of starting isopropoxylactam
Enantiomericallyy pure 5-alkoxy-3-pyrrolin-2-ones are versatile building blocks for a widee range of stereoselective transformations, such as Diels-Alder cycloadditions, conjugate additionss and N-acyliminium ion reactions.14 They are also suitable intermediates for the synthesiss of natural products, such as gelsemine20 and roseophilin.21 Over the last decade,
ourr research group has obtained much experience in synthesizing these alkoxypyrrolinones, especiallyy lactam 4014. Starting from (S)-malic acid 41, imide 42 was obtained in a three-step reactionn sequence by successive treatment with acetyl chloride, ammonia and again acetyl chloridee (eq 3.4). This imide was reduced regioselectively with LiBH4 and the resulting
hydroxylactamm was treated with acidic isopropanol to arrive at a 20:80 cis/trans-ratio of isopropoxylactamm 43, the acetate being saponified under these reaction conditions. Subsequentt treatment of this mixture with trichloroacetic anhydride afforded selectively the
frans-lactam,, whereby the a's-lactam was epimerized to the frans-lactam. After elimination of thee trichloroacetate and acetylation at nitrogen, lactam (R)-40 was obtained enantiomerically puree in 30% overall yield over seven steps.
OHH l)AcCl -PAc 4)LiBH4 £>H 6) (Cl3CO)20
r~(r~(
2>
NH3. f~L
5)'
FrOH/H+. J~\
DMAP«HO Q4)
H02CC C02H 3 ) A c C 1 O ^ N - ^ 0 O^N-^O'PrTjA^Q W ^
HH H 411 42 43
Thiss reaction sequence is somewhat laborious and the frans-isomer is not always exclusivelyy formed in the trichloroacetylation step. Therefore, the enzymatic route, more recentlyy developed by Feringa, Kellogg and coworkers,22 was used to synthesize both enantiomerss of this 5-isopropoxylactam using lipase-catalyzed deacetylation and acetylation reactions.. Diacetate 47 was easily obtained in a three-step reaction procedure, starting from furfurall 44 (eq 3.5). Singlet oxygen photo-oxidation23 of freshly distilled furfural with O2 in MeOH,, irradiated with a 750 W immersion lamp and a catalytic amount of methylene blue as aa sensitizer, gave a Diels-Alder reaction to afford bicyclic ozonide 45, which after decarbonylationn and acetal formation yielded racemic methoxyfuranone 46 in almost quantitativee yield. Subsequent reaction with ammonia, followed by acetylation with acetic anhydride,, gave rac-47 in a satisfactory yield of 56%.
H-- / / W
OO MeOH O O MeO OH-Wo< <
.. HO O - O 1)NH3 3 2 )A c 2 Q Q O ^ Q ^ O M e -- — O ^ N ^ O A C ^ 98%% 56% A c 444 45 46 rac-47Withh a lipase from Candida antarctica at 20 °C in 3:1 w-hexane/n-butanol, (S)-47 was obtainedd as white crystals in 48% yield and >98% ee, together with hydroxylactam 48 in 49% yield,, which partially racemized during the transesterification (Scheme 3.5). These two productss could be easily separated using column chromatography. The hydroxy derivative wass then esterified with the same lipase from Candida antarctica in n-hexane/vinyl acetate (1:1)) at 70 °C to yield (R)-47 as white crystals in 98% yield and >98% ee. The higher temperaturee was needed to speed up the rate of racemization of the starting substrate.
Schemee 3.5 O ^ - M ^ O A C C Ac c rac-47 7 Cand.Cand. antarctica 1 \ — :: ; — * O ^ U ' N J H + rc-hexane/rc-hexane/ IN n-BuOHH A c 488 49% Cand.Cand. antarctica/ vinyll acetate O ^ NN O A c Ac c (R)-47 7 98%,, >98% ee 0
^
N> ' " O A c c
Ac c
(S)-47 7 48%,, >98% eeFinally,, palladium-catalyzed allylic substitution of the acetate by isopropanol yielded bothh (R)-40 as (S)-40 in 77% yield after recrystallization and >98% ee with complete retention off configuration (eq 3.6).72b In the same way, racemic 40 was synthesized, starting from racemicc 47, in 93% yield. It is noteworthy that racemic 40 turned out to be a colorless oil, whereass the enantiomerically pure (S)-40 and (R)-40 were colorless crystals (mp 49 °C). In thiss chapter, racemic 40 was used as starting material for further chemistry, except for the synthesiss of 73a and 73b (Table 3.6), which were prepared from (R)-40.
(3.6) ) PdCl2(MeCN)2 2 uu N isopropanol u N Acc Ac (R)-477 (R)-40 77% >98% ee m p 49 °C [a]D2 00 -149 (c = 1.04, CHC13)
rac-47rac-47 rac-40 93% oil (S)-477 (S)-40 77% >98% ee m p 49 °C
[a]D2 00 +149 (c = 1.04, CHCI3)
3.44 Synthesis of N-acyliminium ion precursors 3.4.11 Michael a d d i t i o n
Isopropoxylactamm 40 showed good reactivity in 1,4-additions, mainly due to the presencee of the N-acetyl function, which renders the double bond more electrophilic. Good stereoselectivityy was also obtained, as the isopropoxy group directs the incoming nucleophilee to react from the opposite side. For example, reaction of lactam 40 with dimethyl malonatee and Et3N as the base afforded after 48 h addition product 49 in almost quantitative
yieldd with complete frans-stereoselectivity (eq 3.7).14
O O N N Ac c (R)-40 0 O'Pr r OO O MeOO ^-^ OMe (2.22 equiv) Et3NN (1.0 equiv) DMF,, rt, 48 h Me02C C -C02Me e O'Pr r Ac c 499 95 % (3.7) )
Therefore,, Michael additions were thought to be a suitable way of introducing functionalityy in a stereoselective manner. It was envisaged that the malonate moiety with its activatedd methylene group could function as a 'scaffold' to introduce olefinic alkyl groups withh different lengths of the alkyl chain. Thus, in analogy with Koot, reaction of (R)-40 with alkylatedd dimethyl malonate 52a and DBU (0.5 equiv) in DMF at room temperature yielded 53aa in 90% isolated yield (Table 3.1, entry 7).24 As expected, only the fraws-isomer was found, whichh was easily deduced from the !H-NMR spectrum, in which H-5 of the pyrrolin-2-one
moietyy is a sharp singlet. In this manner, alkenyl chains with varying lengths (n = 1-6) were introducedd in good to excellent yields with complete frans-selectivity (entries 8-11). Reversal off the order of reaction -first Michael addition of 40 with dimethyl malonate and subsequent alkylation-- yielded 53a in good yield (85%), but introduction of longer olefinic chains was unsuccessful,, due to the lesser reactivity of alkenyl halides with n>l.
Tablee 3.1 O ^ N ^ °i p r r entry y 1 1 2 2 3 3 4 4 5 5 6 6 Ac c 40 0 substrate e 51aa (n = 1) 51bb (n = 2) 51b b 51cc (n = 3) 51dd (n = 4) 51ee (n = 6) + + Me02C C Me02C C NaH H (1.11 equiv) M e 02C . . Me02C C equiv v 1.05 5 1.06 6 0.20 0 1.05 5 1.06 6 1.06 6 50 0 product t 52a a 52b b 52b b 52c c 52d d 52e e
^ ^ r ^ ^
52a-e e B r ^ ^ ^ 51a-e e yieldd (%) 67 7 41 1 71 1 52 2 45 5 44 4 DBUU (0.5 equiv) DMF,, rt, 6 h dialkylatedd (%) entry 18 8 23 3 10 0 16 6 24 4 15 5 7 7 8 8 9 9 10 0 11 1 Me02CC C02Me 0 ^N/ " " OiP r r Ac c 53a-e e product t 53a a 53b b 53c c 53d d 53e e yieldd (%) 90 0 82 2 86 6 94 4 96 6T h ee a l k y l a t e d m a l o n a t e s 52 w e r e o b t a i n e d via a l k y l a t i o n of d i m e t h y l m a l o n a t e 50 w i t hh t h e c o r r e s p o n d i n g a l k e n y l b r o m i d e s 51 (1.05 e q u i v ) , u s i n g N a H (1.1 e q u i v ) a s t h e base (entriess 1, 2, 4-Ó).25 This r e a c t i o n n o t o n l y y i e l d e d t h e m o n o - a l k y l a t e d , b u t also t h e d i a l k y l a t e dd a d d u c t s . This p r o b l e m c o u l d n o t b e c o m p l e t e l y o v e r c o m e by u s i n g a l a r g e excess off t h e m a l o n a t e (5 e q u i v ) , b u t t h e a m o u n t of d i a l k y l a t e d p r o d u c t w a s s u b s t a n t i a l l y r e d u c e d (entryy 3).
I nn o r d e r t o p e r f o r m N - a c y l i m i n i u m i o n c h e m i s t r y for t h e i n t r o d u c t i o n of t h e s e c o n d olefinicc g r o u p , t h e n i t r o g e n a t o m n e e d s to b e d e a c e t y l a t e d , b e c a u s e N , N - d i a c y l i m i n i u m ion f o r m a t i o nn is n o t possible. Therefore, t h e acetyl g r o u p w a s first r e m o v e d u s i n g excess (>6 e q u i v )) d i m e t h y l a m i n e in CH2CI2 at 0 °C. Later, it w a s f o u n d that t h e s a m e t r a n s f o r m a t i o n c o u l dd b e c a r r i e d o u t m o r e c o n v e n i e n t l y u s i n g a n excess of p y r r o l i d i n e in t h e s a m e s o l v e n t at r o o mm t e m p e r a t u r e (eq 3.8) to give t h e p r o d u c t s 54a-e in excellent y i e l d s (86-98%). D e s p i t e t h e p o t e n t i a ll of intrinsic sensitivity t o h y d r o l y s i s at C-5, t h e p r o d u c t s c o u l d b e purified u s i n g c o l u m nn c h r o m a t o g r a p h y a n d s t o r e d for w e e k s at - 2 0 °C w i t h o u t d e c o m p o s i t i o n . MeQ2CC C02Me pyrrolidine e CH2C12,, rt, overnight t 86-98% % M e 02CC C 02M e " " O ' P r r (3.1 1 54a-e e
N o tt only olefins c o u l d b e i n t r o d u c e d in this m a n n e r , b u t t r i p l e b o n d s t o p e r f o r m e n y n ee m e t a t h e s i s i n a later s t a g e w e r e i n t r o d u c e d as well. E n y n e m e t a t h e s i s is a p o w e r f u l tooll to a d d m o r e functionality t h a n a single d o u b l e b o n d t o t h e n e w l y f o r m e d r i n g . T h e final r e s u l tt of this t r a n s f o r m a t i o n is a 1,3-diene (see: C h a p t e r 1), w h i c h c a n b e u s e d for further c o n v e r s i o n s . . Tablee 3.2 Ac c 40 0 M e 02C C M e 02C ' ' 55a-c c DBUU (0.5 equiv) 'O'Prr DMF, rt, 6 h MeQ2CC C02Me pyrrolidine e (>66 equiv) » » CH2C12,, rt, overnight t MeQ2CC C02Me 57a< < entry y 1 1 2 2 3 3 substrate e 55aa (n 55bb (n 55cc (n • == 1) == 2) == 4) product t 56a a 56b b 56c c yieldd (%) 96 6 98 8 86 6 entry y 4 4 5 5 6 6 product t 57a a 57b b 57c c yieldd (%) 91 1 96 6 93 3
Thee substrates for the eventual enyne metathesis reactions contain a triple bond attached to thee malonate (55a-c, Table 3.2) and were synthesized in the same manner as their olefinic counterparts. .
Thus,, reaction of lactam 40 with 55, obtained from dimethyl malonate and the correspondingg propargylic bromides (see also: Table 3.1),26 yielded lactams 56 in good to excellentt yields (entries 1-3). These products all possessed the frans-configuration, which couldd be clearly seen in the !H-NMR spectrum, in which H-5 is a singlet. Removal of the
acetyll group using excess pyrrolidine afforded deacylated lactams 57 in excellent yields with completee retention of the f raws-configuration (entries 4-6).
3.4.22 C u p r a t e a d d i t i o n
Inn Section 3.4.1, the introduction of the olefinic moiety was described by using the dimethyll malonate method. An alternative way could proceed via a cuprate addition. It is welll known that pyrrolin-2-one 40 is a good substrate to undergo cuprate additions, especiallyy when the nitrogen contains an electron-withdrawing group. Therefore, we set out too construct 4,5-disubstituted bicyclic lactams using this methodology.
Thee reaction conditions chosen were the optimized conditions found by Koot27 for the synthesiss of 58a (eq 3.9). Thus, the cuprate additions were carried out in THF, using cuprates preparedd from alkenyllithium species and CuCN as the copper source. The alkenyllithium speciess were synthesized by treating the corresponding alkenyl iodide with 2 equiv of 'BuLi inn THF at -78 °C. After preparing the cuprates, excess of chlorotrimethylsilane was added to preventt unwanted side reactions. Finally, a solution of 40 in THF was added to this mixture att -78 °C. The 1,4-addition of the cuprate of 4-iodo-l-butene (n = 1) yielded 58a in 80% yield andd the cuprate of 5-iodo-l-pentene (n = 2) yielded 58b in 83% yield. This addition reaction proceededd with high selectivity and only irar/s-products were obtained, which could be seen inn the 'H-NMR spectrum, in which H-5 is a sharp singlet. Removal of the acetyl group was achievedd with excess pyrrolidine in CH2CI2 to arrive at the deacylated lactams 59a and 59b in 78%% and 92% yield, respectively, with complete retention of the frans-configuration.
(4.55 equiv) 'BuLii (9.0 equiv)
CuCNN (3.5 equiv) / ^ f h T ^ - Pyrrolidine
J=\\ TMSC1 (10 equiv) /—f " (>6 equiv) CK^ivii ° 'P r THF, -78 °C to rt * O ^ N ""O'Pr CH 2Cl2,rt, " O Acc Ac overnight H 400 58a (n = l) 80% 59a 78% 58bb (n = 2) 83% 59b 92%
3.55 N - A c y l i m i n i u m i o n reaction 3.5.11 Ene-ene disubstituted lactams
Now,, the stage was set to introduce the second olefinic group via N-acyliminium ion chemistry.. Reaction of 54 with a Lewis acid afforded N-acyliminium ion 60, which reacted immediatelyy with a nucleophile to yield lactams 63 and 64 (Table 3.3). As an example, a mixturee of 54a and allyltrimethylsilane (61, 4 equiv) in CH2C12 at 0 °C was treated with
BF3-OEt22 (2 equiv) to afford 63a in 78% yield14 (entry 1). In this way, the five related diolefins
63a-ee were synthesized in reasonable to good yields (entries 1-5). These reactions also proceededd with complete trans-selectivity, according to !H-NMR spectroscopy. Because the H-55 signal was inconclusive, the assignment of the fraws-stereochemistry was based on the H-44 signal, which was a double triplet when the spectrum was measured in CDCI3. This patternn can be explained by the large coupling constant of 9.9 Hz between H-4 and H-3 cis, givingg a doublet, which is split up in a triplet by H-3 trans and H-5 with a coupling constant off 3.5 Hz. Consequently, H-4 and H-5 have a trans-relationship.
Tablee 3.3 Me02CC C02Me entry y O'Prr CH2C12,0°C 54a-e e substrate e Me02CC C02Me 60a-e e Me02CC C02Me RR = H2, CH2
nucleophile e product t yieldd (%)
54a a 54b b 54d d 54e e Me3Si' ' 1 1 2 2 3 3 4 4 5 5 54a a 54b b 54c c 54d d 54e e 61 1 61 1 61 1 61 1 61 1 62 2 62 2 62 2 62 2 -SiMe, , Me02CC C02Me 63aa (n = 1) 63bb (n = 2) 63cc (n = 3) 63dd (n = 4) 63ee (n = 6) Me02CC C02Me 64aa (n = 1) 64bb (n = 2) 64dd (n = 4) 64ee (n = 6) 78 8 84 4 87 7 74 4 74 4 19 9 24 4 40 0 45 5
Too introduce more functionality in the molecule, iminium ion 60 was also reacted withh allenylmethyltrimethylsilane (62). The use of allene 62 as a nucleophile for N-acyliminiumm ion intermediates was recently applied for the first time in our group by Mentink.288 Reaction of 54 under standard conditions with 62 afforded triolefin 64 in low to moderatee yields (entries 6-9). These trienes also had a fraws-configuration, according to a H-NMRR spectra, in which H-4 was a double triplet. Although the crude ^ - N M R spectrum indicatedd a fairly clean conversion, the final product could not be obtained in a yield higher thann 45% (entry 9). This is probably due to the instability of the compound during purificationn by column chromatography. Neither addition of Et3N to the eluent, nor column chromatographyy under nitrogen to avoid air oxidation, led to better yields. Besides, a so-calledd type 2 intramolecular Diels-Alder reaction could take place, although the resulting tricyclicc products were not found with unactivated dienophiles as present in the compounds 64a-d.. Usually high temperatures or Lewis acids are necessary to effect the reaction.29
Inn addition, lactams 59a and 59b were reacted with the two nucleophiles (Table 3.4). Reactionn of 59 with BF3OEt2 (2 equiv) and allyltrimethylsilane 61 (4 equiv) in CH2C12
affordedd diolefins 66a and 66b in excellent yields (92% and 93%, respectively). The use of allenee 62 as the nucleophile gave under the same reaction conditions the desired 1,3-dienes 67aa and 67b, albeit in lower yields. The reason for the lower yields is that the products were nott stable during purification by column chromatography, despite addition of Et3N to the
eluent,, similar to the results in the case of 64. Tablee 3.4 0 - ~ - N N ""O'Pr r H H 59a,b b CH2C12,, 0 °C 65a,b b
entryy substrate nucleophile product t yieldd (%)
59a a 59b b 59a a 59b b Me3Sr r 61 1 61 1 62 2 62 2 -SiMe3 3 66aa (n = 1) 66bb (n = 2) 67aa (n = 1) 67bb (n = 2) 92 2 93 3 24 4 32 2
3.5.22 E n y n e d i s u b s t i t u t e d l a c t a m s
L a c t a m ss 57 w e r e subjected to N - a c y l i m i n i u m ion r e a c t i o n c o n d i t i o n s (Lewis a c i d (2 e q u i v )) u s i n g a l l y l t r i m e t h y l s i l a n e 61 as a n u c l e o p h i l e (4 equiv)) to a r r i v e at e n y n e - s u b s t i t u t e d l a c t a m ss 69 (Table 3.5). T h u s , 57a w a s r e a c t e d w i t h B F3O E t2 a n d a l l y l t r i m e t h y l s i l a n e 6 1 in CH2CI22 a t 0 °C t o yield e n y n e 69a in 90% yield. T h e c o n f i g u r a t i o n w a s d e t e r m i n e d t o b e trans, ass d e d u c e d f r o m t h e d o u b l e triplet for H - 4 (see: Section 3.5.1). T h e s a m e p a t t e r n is s e e n i n t h e casess of 5 7 b (entry 2) a n d 57c (entry 3), w h i c h p r o v i d e d e n y n e p r e c u r s o r s 69b a n d 69c in m o d e r a t ee to g o o d y i e l d s w i t h c o m p l e t e trans-selectivity.
Y n e - d i e n e s ,, w h i c h c o n t a i n t w o r e a c t i v e sites for e n y n e m e t a t h e s i s , c o u l d a l s o b e m a d ee via this r o u t e . T h e y m a y b e accessible from 57 via N - a c y l i m i n i u m i o n r e a c t i o n w i t h allenee 62. T h u s , r e a c t i o n of 57a w i t h 2 e q u i v of BF3OEt2 a n d 4 e q u i v of allene 62 i n CH2C12 y i e l d e dd after 18 h y n e - d i e n e 70a in 4 5 % yield. A g a i n , o n l y t h e frans-isomer w a s f o r m e d , a c c o r d i n gg t o t h e ! H - N M R s p e c t r u m . In t h e s a m e w a y , 70b a n d 70c w e r e o b t a i n e d i n 25% a n d 37%% yield, respectively. Tablee 3.5 MeQ2CC C02Me CH2C12,00 °C entry y substrate e Me02CC C02Me 68a-c c Me02CC C02Me nucleophile e
nucleophile e product t yieldd (%)
57a a 57b b 57c c Me3Si' ' 1 1 2 2 3 3 57a a 57b b 57c c 61 1 61 1 61 1 -SiMe-, , 62 2 62 2 62 2 MeQ2CC C02Me 69aa (n = 1) 69bb (n = 2) 69cc (n = 4) MeQ2CC C02Me 70aa (n = 1) 70bb (n = 2) 70cc (n = 4) 90 0 H7 7 51 1 45 5 25 5 37 7
Itt was envisaged that differently substituted bicycles might be accessible by reversing thee position of the olefin and acetylene (e. g. 69) so that the vinyl substituent would end up at aa different position at the internal double bond after the metathesis reaction. Lactams 54 weree thought to be excellent precursors to arrive at these differently substituted lactams. Introductionn of the acetylenic group next to the nitrogen was achieved via an N-acyliminium ionn reaction with allenyltributyltin 71 as the nucleophile. All of these reactions proceeded smoothlyy under the same conditions as for allyltrimethylsilane 61 (BF3OEt2 (2 equiv) and 71
(44 equiv)) to arrive at enyne-substituted lactams 72 in reasonable yields (eq 3.10). Once again, onlyy frans-products were found, as was concluded from the ^ - N M R spectrum, in which H-4 iss a double triplet.
MeQ2CC C02Me 54aa (n = 1) 54bb (n = 2) 54dd (n = 4) 54ee (n = 6) 711 SnBu3 CH2C12,, 0 °C MeOzCC C02Me 72aa 59% 72bb 54% 72dd 58% 72ee 48% (3.10) ) 3.66 Ring-Closing Metathesis 3.6.11 Ene-ene m e t a t h e s i s
Withh all of these diolefins in hand, the stage was set for the ring-closing metathesis reactions.. Diolefins 63 were treated with a Ru-catalyst in the indicated solvent (0.05-0.1 M) to arrivee at 4,5-disubstiruted bicyclic lactams 73 (Table 3.6). Thus, diolefin 63a was treated with 5.77 mol% of catalyst C in dichloroethane at 70 °C for 6 h to afford bicyclic lactam 73a as colorlesss crystals (mp 168-170 °C) with a specific rotation [a]20D - 1 9 1 (c = 1.0, CHC13) in
almostt quantitative yield (entry 1). This reaction went smoothly and cleanly as a 7-memberedd ring is a favorable ring size. The formation of an 8-membered ring (73b) was moree difficult, as shown by a longer reaction time and lower yield (entry 2). Unfortunately, noo cyclization took place when 63c and 63d were subjected to the catalyst C in toluene at 70 °CC (entries 3 and 4). In these cases, no cyclization took place and only starting material was recovered. .
Tablee 3.6 entry y 1 1 2 2 3 3 4 4 5 5 Me02CC ,C02Me 0 ^ ^ substrate e 63a a 63b b 63c c 63d d 63e e
_ / ^ r ^ ^
>> / ^
V N N 63a-e e catalyst t CC (5.7 mol%) CC (5.6 mol%) B,, C, D C , D D DD (9.9 mol%) Ru-catalyst t solvent,, 70 °C solvent,, time DCE,, 6 h DCE,, 18 h DCE/toluene e DCE/toluene e toluene,, 18 h C 02M e e M e 02C - 4 - 4 1 " "// \ 1)
O ^ N N HH 73a-e product t 73aa (n = 1) 73bb (n = 2) 73cc (n = 3) 73dd (n = 4) 73ee (n = 6) yieldd ( 98 8 60 0 0 0 0 0 60 0%) )
[a]20D-191 1 (cl.0,CHCl3) ) [a]2 0 D-167 7 (cl.0,, CHCI3) H-l l Cl~ ~ C I ' ' PCy3 3 ; R U = \ \ PCy33 P h B B MesNN NMes C ll P C > h // \ MesNN NMesPC^Ph
D D Me02 C--H-88 H-9 H-5 5_AA A
>> .
H-7 7 H - 3aH 44 H-3P H-10aH-10fJULA A
5.55 5.0 4.5 4.0Figuree 3.1 ^H-NMR spectrum (7.0-1.5 ppm) of 73a.
Itt is known that 9- and 10-membered rings are the most difficult to form due to the inherentt ring strain of these medium-sized rings.30 However, they can be formed if the substratee adopts a favorable conformation for ring closure.31-32 Apparently, this is not the casee with these substrates. Changing the catalyst (catalyst B or D), the solvent (toluene) and thee temperature (room temperature) did not lead to cyclization either, while polymerization tookk place when the reaction was carried out at a higher concentration (0.5 M). Larger rings, however,, can be formed as is apparent from the reaction of 63e with catalyst C in toluene at 700 °C, yielding bicycle 73e in 60% yield (entry 5) as a single E-stereoisomer. All bicyclic lactamss formed were assumed to retain the frans-ring junction stereochemistry.
Next,, substrates 64 were subjected to the metathesis reaction conditions. The 1,3-dienee present in 64 is particularly interesting because there is a choice of two alkenes in the metathesiss reaction. The only difference between the double bonds is the degree of substitution,, which could influence their reactivity. The products that can be formed are eitherr lactams 74 which contain an exocyclic double bond (Table 3.4, pathway A) or lactams 755 which have a vinyl group attached to the newly formed ring (pathway B). In the event, reactionn of 64a with 5.3 mol% of catalyst D in toluene at 70 °C during 18 h yielded lactam 74a inn 86% yield. No trace of 75a was observed.33 The formation of 74a can be easily deduced fromm the ^ - N M R spectrum, in which the protons of the exocyclic double bond show two singletss at 4.99 and 5.03 ppm. In accordance with previous results, this formation of a 7-memberedd ring proceeded smoothly without any side reactions. However, the 8-membered ring,, formed from reaction of 64b with 4.3 mol% of catalyst D, yielded 74b in moderate yield (43%),, together with some unidentifiable products (entry 2). Also in this reaction, no trace of 75bb was formed, indicating that the disubstituted double bond is unreactive in these metathesiss reactions. Reaction of 64d with 5.4 mol% of catalyst D in toluene showed after 18 hh that some conversion had taken place, but after purification only starting material and unidentifiablee products (possibly Diels-Alder products) could be detected (entry 3). After reactionn of triene 64e with 8.9 mol% of catalyst D, only starting material could be isolated (entryy 4). Both results could not be improved by reaction with catalyst C a n d / o r using differentt reaction conditions. The obtained 1,3-dienes 74 may be useful for further transformations,, for example selective oxidation,34 cyclopropanation35 or epoxidation36 of the exocyclicc double bond.
Tablee 3.7 Me02CC C02Me MeOzC C02Me C02Me Me02C-- ' 75a,b,d,e e catalystt D i i toluene, , 700 °C Pathwayy B 64a,b,d,e e catalystt D »--toluene,, 70 °C Pathwayy A 74a,b,d,e e entry y substrate e product t yieldd (%)
64a a 64b b 64d d 64e e 74aa (n = 1) 74bb (n = 2) 74dd (n = 4) 74ee (n = 6) 43 3 0 0 0 0
Diolefinss 66 and 67 gave significantly lower yields in the metathesis than 63 and 64 (Tablee 3.8). These reactions were performed with catalyst D in toluene at 70 °C for 18 h. Subjectionn of 66a to these conditions, using 4.6 mol% of catalyst D, afforded the 7-membered ringg lactam 76a in 34% yield, together with some unidentifiable products (entry 1). This yield iss somewhat disappointing in comparison with the yield for 73a (Table 3.6). Probably, this
addition,, the 8-membered ring 76b was formed in 29% yield and some byproducts were obtainedd as well (entry 2). Obviously, these reactions did not proceed as cleanly as those to 73aa and 73b. From the NMR spectra, it was clear that only one isomer was formed. Its configurationn could not be determined by the NMR spectra, but in accordance with previous results,, it can be concluded that only the frans-isomer was formed.
Thee cyclizations of 67 also resulted in lower yields of the cyclized lactams compared too 64 after ring-closing metathesis. Reaction of 67a with 7.7 mol% of catalyst D gave after 18 hh diene 77a in 32% yield, together with some unidentifiable byproducts (entry 3). Triene 67b, however,, failed to cyclize and only starting material was recovered (entry 4). A reaction attemptedd with higher substrate concentration led only to polymeric material.
Tablee 3.8
catalystt D
>. >.
toluene,toluene, 70 °C 188 h
entry y substrate e product t yieldd (%)
' I ' ' ' ' 5 5
—[—[—I—p—i—T—r—r—j—1—7—f—r—i—I— —I—p—i—T—r—r—j—1—7—f—r—i—I—
44 3 II ' ' ' ' '
Figuree 3.2 !H-NMR spectrum (6.6-1.4 ppm) of 77a.
3.6.22 E n y n e m e t a t h e s i s
Too arrive at 4,5-disubstituted bicyclic lactams with an additional vinyl substituent at thee newly formed ring, precursors 69 and 70 were subjected to ring-closing metathesis conditions.. Reaction of 69a with 14 mol% of catalyst D in toluene at 70 °C gave a clean conversionn and 78a was isolated in 72% after 3 days (Table 3.9, entry 1). The catalyst had to bee added in portions to drive the reaction to completion. Unfortunately, formation of the 8-memberedd ring lactam 78b was not observed under these reaction conditions (entry 2). In thiss case, only starting material was recovered, even at higher concentration and by using catalystt C. Attempts to prepare the 10-membered ring lactam 78c also failed (entry 3). Again, onlyy starting material could be isolated.
Ass enynes afford dienes after ring-closing metathesis, yne-dienes seem to be good precursorss to arrive at trienes.37 However, subjection of yne-dienes 70 to ring-closing metathesiss conditions gave no conversion to the desired trienes 79 (entries 4-6). Catalysts C andd D were tried in several amounts (5 to 20 mol%) in toluene at different dilution conditions,, but in all cases only starting material was recovered or decomposition had taken place.. Apparently, the open yne-diene form is energetically more favorable than the ring-closedd triene, which contains three sp2-hybridized carbon atoms and ring-opening metathesiss takes place immediately after closure. Alternatively the lesser reactivity of the acetylenee might prevent ring closure.
Tablee 3.9 Me02CC C02Me catalystt D (144 mol%) toluene, , 700 °C, 3 d MeQ2C C C02Me e
entry y substrate e product t yieldd (%)
Me02CC C02Me Me02C C C02Me e 69aa (n = 1) 69bb (n = 2) 69cc (n = 4) Me02CC C02Me 70aa (n = 1) 70bb (n = 2) 72 2 0 0 0 0 Me02C C
C02Me e Me02C C H-ll l H-l l H-12"" H-1215
jtulJUU lILLAJk
Figuree 3.3 JH-NMR spectrum (7.0-2.1 ppm) of 78a.
Finally,, enyne metathesis precursors 72 were subjected to catalyst D in toluene at 70 °CC to arrive at 4,5-disubstituted bicyclic pyrrolin-2-ones 80 with the vinyl group at a different positionn compared to 78 (eq 3.11). Formation of a 7-membered ring was quite facile, yielding dienee 80a in 71% yield upon reaction with 5 mol% of D for 18 h. Surprisingly, this reaction proceededd much faster than that of 69a, in which the olefin and the acetylene are reversed, butt this does not influence the yield (71% vs. 72%). Moreover, formation of the 8-membered ringg lactam 80b was observed, although more catalyst (14.5 mol%) was necessary, providing thee product in 22% yield. The formation of a diene was concluded from the fl-NMR spectra becausee of the triplet at 5.80 ppm for the endocyclic double bond proton and the appearance off the vinylic protons at 6.28, 5.20 and 5.02 ppm. Despite several attempts, 72d and 72e could nott be cyclized to the 10-membered ring 80d and 12-membered ring 80e, as was experienced earlierr in the case of 78c. In these cases, only starting material was recovered or polymerizationn had taken place, depending on the concentration of the substrate. This remarkablee influence of the position of the substituents (69 vs. 72) on the reaction rate is not yett understood. M e 02CC C 02M e
]~\^^-]~\^^-33 N H H 72aa (n = 1) 72bb (n = 2) 72dd (n = 4) 72ee (n = 6) catalystt D toluene,, 70 °C, 188 h V V M e 02C - , , 0 * ^ N N H H 80a a 80b b 80d d 80e e i — H \n n
I] ]
'''// /
71% % 22% % 0% % 0% % (3.11) ) 63 33.77 D i s c u s s i o n , c o n c l u s i o n s and outlook
Thiss chapter presents a study towards the synthesis of 4,5-disubsritued frans-fused bicyclicc lactams with different ring sizes. Via a sequence of a 1,4-addition reaction, N-deacetylation,, N-acyliminium ion reaction with different olefin- and acetylene-containing groupss and ring-closing metathesis, several of these bicyclic structures were obtained. The mostt easily formed ring size is the 7-membered ring, followed by the 8- and the 12-memberedd ring. Unfortunately, no cyclization to 9- and 10-membered ring could be attained. Ring-closingg metathesis with dienes and acetylenes gave more highly substituted bicyclic amides,, but in lower yields, probably due to the lesser reactivity of the substrates and the lesserr stability of the products. The stereochemical outcome of all reactions proved to be exclusivelyy trans, without any exception.
Itt seems that the gem-dimethyl ester functionality has a positive effect on the formationn of the bicyclic lactam. This effect could be particularly seen in the ring-closing metathesiss reaction of 63 and 66. The reason for the higher yield could be that the dimethyl esterr forces the molecule in a conformation, which facilitates ring closure, thereby suppressingg possible dimerization and polymerization.
Possibly,, enynes 69, 70 and 72 could be used as precursors for the intramolecular Pauson-Khandd cyclization reaction, in which a formal [2+2+1] cycloaddition of an alkyne, an alkenee and CO takes place to produce a cyclopentenone (eq 3.12).38 In the case of enyne 72, interestingg tricyclic amides 81 could be obtained.
Me02Cxx /COzMe Me02C
QQQQ MeC^C
(3.12) )
Itt is clear that this N-acyliminium ion addition/ring-closing metathesis strategy is a rapidd approach to bicyclic lactams. These lactams can be seen as conformationally restricted peptidomimetics,, because the carbonyl function of the lactam moiety can be easily converted intoo a carboxylic acid. Because of the facile route to chiral alkoxypyrrolin-2-ones, this route offerss rapid access to derivatives of these peptidomimetics, which differ in stereochemistry andd functional groups.
3.88 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.. DSM is kindfully acknowledged for the generous gift of the enzyme Candida
antarctica.antarctica. Dr. A. J. Minnaard and E. Schudde of the University of Groningen are kindly
acknowledgedd for his help with the HPLC-measurements. G. Mentink is thanked for the generouss gift of allene 62.
3.99 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 53 and 73 has been used. Thee numbering is continued in the chain attached to the malonate functionality (in structure 533 for n = 1, the double bond carbons have number 8 and 9, for n = 2, they have number 9 andd 10 etc).
Me02CC C02Me C02Me
Me02C~ ~
5-Methoxy-5H-furan-2-onee (46)39: A solution of freshly distilled furfural 44 (200
iee g, 2.08 mol) in MeOH (560 mL) at 0 °C was irradiated using a 750 W immersion lamp,, equipped with a water cooled Jacket and a Kapton filter. A small stream off oxygen gas was passed through the solution. To this solution was added dropwise a solutionn of methyleneblue (25.0 mg) in MeOH (10 mL) overnight. After complete conversion too the hydroxyfuranone, the solution was heated at reflux for two days. The solvent was removedd in vacuo and the residue was purified by distillation to yield 46 (168 g, 1.18 mol, 71%)) as a colorless oil. iH-NMR: (CDC13, 300 MHz): 7.15 (d, ƒ = 5.5 Hz, 1H, COCH=CH), 6.17
(d,, ƒ = 5.5 Hz, 1H, COCH=CH), 5.80 (s, 1H, OCHO), 3.51 (s, 3H, OCH3).
___ 5-Acetoxy-N-acetyl-3-pyrrolin-2-one (4T)223: To a solution of NH3 in water
C XN> - O A CC (25%, 250 mL) at 0 °C was added methoxyfuranone 46 (25 mL, 0.26 mol). After
Acc stirring for 1.5 h at 0 °C, most of the NH3 was evaporated under vacuum, wherebyy the temperature did not exceed 30 °C. The residue was freeze dried in 48 h to yield aa orange-yellow solid (27.6 g, 0.28 mol). This was suspended in pyridine (250 mL) and at 0 °C weree added acetic anhydride (63 mL, 0.67 mol) and DMAP (3.04 g, 24.9 mmol). The resulting mixturee was allowed to warm to room temperature and stirred for 18 h. To this solution CH2CI22 was added and washed with aqueous saturated CuSG\4 (500 g) and NaHCÜ3 (90 g). Thee organic layer was dried over MgSO.} and concentrated in vacuo. Purification by column chromatographyy (EtOAcPE = 1:1) yielded 47 (27.5 g, 0.15 mmol, 56%) as a yellow oil, which crystallizedd under vacuum. Rf = 0.38. iH-NMR: (CDC13, 400 MHz): 7.17 (dd, J = 1.9; 6.0 Hz,
1H,, COCH=CH), 7.11 (d, ƒ = 1.9 Hz, 1H, COCH=CH), 6.25 (d, ƒ = 6.0 Hz, 1H, NCHO), 2.51 (s, 3H,, NAc), 2.11 (s, 3H, OAc).
/=\\ 5-Isopropoxy-iV-acetyl-3-pyrrolin-2-one (rac-40): To a suspension of rac-47 o^M^-o'Prr (13.0 g, 71.1 mmol) in isopropanol (350 mL) at room temperature was added
Acc
PdCl2(PPh3)2 (0.99 g, 3.79 mmol). After stirring overnight all solid particles were disappearedd and the solvent was removed in vacuo. Purification by column chromatography
( E t O A c P EE = 1:1) y i e l d e d rac-40 (12.1 g, 66.1 m m o l , 93%) a s a colorless oil. Rf = 0.61. ! H - N M R : (CDC13,, 400 M H z ) : 7.00 ( d d , ƒ = 2.0; 6.0 H z , 1H, C O C H = C H ) , 6.09 (d, ƒ = 6.0 H z , 1 H , C O C H = C H ) ,, 5.95 (d, ƒ = 1.8 H z , 1 H , N C H O ) , 4.27 (sept, ƒ = 6.0 H z , 1H, CH(CH3)2), 2.53 (s, 3 H , N A c ) ,, 1.23 (d, ƒ = 6.1 H z , 3H,CH(CH3)2), 1.18 (d, ƒ = 6.1 H z , 3 H ,CH(CH3)2). " C - N M R : (CDCI3, 1000 M H z ) : 8 = 169.8 (C-2), 168.5 (NCOCH3), 147.6 (C-3), 126.7 (C-4), 86.3 (C-5), 72.9 ( C H ( C H3)2) ,, 24.8 ( N C O C H3) , 23.0 (CH(CH3)2), 22.9 (CH(CH3)2).
G e n e r a ll procedure A for the a l k y l a t i o n of d i m e t h y l malonate: T o a s o l u t i o n of
s o d i u mm h y d r i d e (60 w t . % d i s p e r s i o n in m i n e r a l oil, 1.1 e q u i v ) in D M F (1 M) at 0 °C w a s a d d e dd a s o l u t i o n of d i m e t h y l m a l o n a t e i n D M F (1 M ) . T h e r e s u l t i n g m i x t u r e w a s stirred for 300 m i n u t e s a n d t h e c o r r e s p o n d i n g alkenyl- or a l k y n y l b r o m i d e (1.05 e q u i v ) w a s a d d e d . T h e s o l u t i o nn w a s s t i r r e d at 0 °C for 15 m i n u t e s a n d a l l o w e d to w a r m to r o o m t e m p e r a t u r e . T h e r e a c t i o nn w a s q u e n c h e d b y a d d i n g a q u e o u s s a t u r a t e d NH4CI. E t20 w a s a d d e d , t h e layers w e r ee s e p a r a t e d a n d t h e a q u e o u s phase w a s extracted w i t h E t20 (3x). T h e c o m b i n e d o r g a n i c l a y e r ss w e r e w a s h e d w i t h w a t e r (6x), dried over MgSCX a n d c o n c e n t r a t e d in vacuo.
Me02c.^^ 2 - A l l y l m a l o n i c acid dimethyl ester (52a)25: A c c o r d i n g to g e n e r a l p r o c e d u r e Me02cc ^ A / a l l y l b r o m i d e 51a (3.2 m L , 36.9 m m o l ) afforded m a l o n a t e 52a (4.04 g, 23.5 m m o l ,, 67%) a s a colorless oil after purification ( E t O A c P E = 1:9). Rf = 0.30. ^H-NMR: (CDC13, 4000 M H z ) : 8 = 5.68-5.79 (m, 1 H , C H = C H2) , 5.04 (dd, ƒ = 9.1; 15.4 H z , 2 H , C H = C H2) , 3.75 (s, 6 H ,, 2x C 02C H3) , 3.48 (t, ƒ = 7.4 H z , 1H, C H C O ) , 2.66 (t, ƒ = 6.8 H z , 2 H , C H2O C H ) .. " C - N M R : (CDC13,1000 M H z ) : 5 = 169.5 (2x C 02C H3) , 136.6 ( C H = C H2) , 115.7 ( C H = C H2) , 52.4 ( C H C O ) , 50.77 ( 2 x C 02C H 3 ) , 31.2.
Me02c.. 2-But-3-enylmalonic acid d i m e t h y l ester (52b)25: A c c o r d i n g to general M e 02c
>
^/^ ^^ p r o c e d u r e A, 4 - b r o m o - l - b u t e n e 51b (0.80 m L , 7.88 m m o l ) afforded 52b (611 m g ,, 3.28 m m o l , 41%) a s a colorless oil after purification ( E t O A c P E = 1:9). Rf = 0.30. ^H-NMR: (CDC13,, 400 M H z ) : 8 = 5.70-5.77 (m, 1H, C H = C H2) , 5.02 ( d d , ƒ = 9.1; 15.4 H z , 2 H , C H = C H2) , 3.711 (s, 6 H , 2x C 02C H3) , 3.38 (t, ƒ = 7.4 H z , 1H, C H C O ) , 2.04-2.10 (m, 2 H ) , 1.96-2.01 (m, 2H). " C - N M R :: (CDCI3,100 M H z ) : 8 = 169.6 (2x C 02C H3) , 136.6 ( C H = C H2) , 115.8 ( C H = C H2) , 52.3 ( C H C O ) ,, 50.7 (2x C 02C H 3 ) , 3 1 . 1 , 27.8.
M e
°2 C> \\ 2-Pent-4-enylmalonic acid d i m e t h y l ester (52c)40: A c c o r d i n g to g e n e r a l M e
°2 CC p r o c e d u r e A, 5 - b r o m o - l - p e n t e n e 51c (4.3 m L , 36.4 m m o l ) afforded 52c (3.644 g, 18.2 m m o l , 52%) a s a colorless oil after purification ( E t O A c P E = 1:5). Rf = 0.38. ' H -N M R :: (CDCI3, 400 M H z ) : 8 = 5.68-578 ( m , 1H, C H = C H2) , 4.95 (dd, ƒ = 10.2; 17.8 H z , 2 H , C H = C H2) ,, 3.70 (s, 6 H , 2x C 02C H3) , 3.33 (t, ƒ = 7.5 H z , 1 H , C H C O ) , 2.01-2.07 (m, 2 H ) , 1.84-1.900 (m, 2 H ) , 1.34-1.42 (m, 2 H ) . « C - N M R : (CDC13,100 M H z ) : 8 = 169.7 (2x C 02C H3) , 137.8 ( C H = C H2) ,, 114.9 ( C H = C H2) , 52.3 (CHCO), 51.5 (2x C 02C H3) , 33.1, 28.2, 26.4.
M eo2cc 2-Hex-5-enylmalonic acid d i m e t h y l ester (52d)40: A c c o r d i n g to g e n e r a l M e 02c ' ^ ^/~ ^ ^ ^ ~ ^^ p r o c e d u r e A, 6 - b r o m o - l - h e x e n e 51d (2.5 m L , 18.7 m m o l ) afforded 52d (1.955 g, 9.11 m m o l , 45%) a s a colorless oil after purification ( E t O A c P E = 1:9). Rf = 0.27. i H -N M R :: (CDCI3, 400 M H z ) : 8 = 5.68-5.79 ( m , 1H, C H = C H2) , 4.93 (dd, ƒ = 10.1; 17.3 H z , 2 H , C H = C H2) ,, 3.69 (s, 6 H , 2x C 02C H3) , 3.32 (t, ƒ = 7.6 H z , 1 H , C H C O ) , 1.98-2.10 (m, 2 H ) , 1.82-1.900 ( m , 2 H ) , 1.22-1.40 (m, 4 H ) . « C - N M R : (CDC13,100 M H z ) : 8 = 169.7 (2x C 02C H3) , 138.4 ( C H = C H2) ,, 114.5 ( C H = C H2) , 52.3 (CHCO), 51.5 (2x CQ2CH3), 33.2, 28.6,28.3, 26.6.
Me02c.. 2-Oct-7-enylmalonic acid dimethyl ester (52e): According to general Me
°2cc procedure A, 8-bromo-l-octene 51e (3.1 mL, 18.5 mmol) afforded 52e (1.888 g, 7.77 mmol, 44%) as a colorless oil after purification (EtOAcPE = 1:9). Rf = 0.27. « -NMR:: (CDCI3, 400 MHz): 5 = 5.70-5.81 (m, 1H, CH=CH2), 4.93 (dd, ƒ = 10.3; 17.6 Hz, 2H,
CH=CH2),, 3.70 (s, 6H, 2x CO2CH3), 3.32 (t, ƒ = 7.5 Hz, 1H, CHCO), 1.97-2.02 (m, 2H),
1.82-1.899 (m, 2H), 1.28-1.38 (m, 8H). "C-NMR: (CDCI3,100 MHz): 8 = 169.8 (2x CO2CH3), 138.8 (CH=CH2),, 114.1 (CH=CH2), 52.2 (CHCO), 51.6 (2x CO2CH3), 33.6,28.9,28.7,28,6 (2x), 27.1.
Generall procedure B for the Michael addition: To a solution of the alkylated malonatee 52 (1.05 equiv) in DMF (0.2 M) at room temperature was added DBU (0.5 equiv). Thee resulting mixture was stirred at room temperature for 5 minutes and a solution of lactam 400 in DMF (0.5 M) was added. The reaction is quenched by adding aqueous saturated NH4CI.. Et20 was added, the layers were separated and the aqueous phase was extracted withh Et20 (3x). The combined organic layers were washed with water (6x), dried over MgSÜ4 andd concentrated in vacuo.
Me02cvco2Mee 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-allylmalonic acid dimethyl
esterr (53a)14: According to general procedure B, lactam 40 (104.0 mg, 0.57 mmol)) was reacted with 52a (101.7 mg, 0.59 mmol) to give 53a (172.9 mg, 0.50 mmol,, 90%) as a colorless oil after purification (EtOAcPE = 1:5). R/= 0.32. iH-NMR:: (CiD6, 400 MHz): 8 = 6.15 (s, 1H, H-5), 5.38-5.49 (m, 1H, H-8), 4.84 (dd, ƒ = 9.5; 15.5 Hz,
2H,, H-9), 4.25 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.25 (s, 3H, OCH3) 3.18 (s, 3H, OCH3),
2.84-2.933 (m, 2H, H-3a, H-4), 2.60-2.75 (m, 2H, H-7), 2.53 (td, ƒ = 5.3; 17.2 Hz, 1H, H-3P), 2.39 (s, 3H,, COCH3), 1.25 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.18 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). 13C-NMR:
(C6D6,1000 MHz): 8 = 174.4 (C-2), 170.9 (2x CO2CH3), 170.5 (COCH3), 129.7 (C-8), 120.6 (C-9),
86.99 (C-5), 71.9 (CH(CH3)2), 59.4 (C-6), 52.7 (2x CO2CH3), 42.8 (C-4), 38.5, 34.6, 25.6 (COCH3),
23.77 (CH(CH3)2), 23.4 (CH(CH3)2). IR (film): v 2976, 1771, 1748, 1732. HRMS calculated for
C17H26O7NN 356.1709, found 356.1709.
MeOO c co Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-but-3-enylmalonic acid dimethyll ester (53b): According to general procedure B, lactam 40 (547 mg, 2.999 mmol) was reacted with 52b (597 mg, 3.21 mmol) to give 53b (905 mg, 2.455 mmol, 82%) as a colorless oil after purification (EtOAcPE = 1:5). Rf = 0.30.. iH-NMR: (C6D6,400 MHz): 5 = 6.10 (s, 1H, H-5), 5.48-5.58 (m, 1H, H-9), 4.899 (dd, ƒ = 9.5; 15.5 Hz, 2H, H-10), 4.24 (sept, ƒ = 6.1 Hz, 1H, CH(CHs)2) 3.25 (s, 3H, CO2CH3) 3.199 (s, 3H, CO2CH3), 2.83-2.90 (m, 2H, H-3a, H-4), 2.53 (td, ƒ = 5.2; 17.2 Hz, 1H, H-3P), 2.38 (s, 3H,, COCH3), 2.05-2.09 (m, 2H), 1.79-1.85 (m, 2H), 1.23 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.18 (d, ƒ == 6.1 Hz, 3H, CH(CH3)2). "C-NMR: (C6D6, 100 MHz): 8 = 174.7 (C-2), 171.2 (CO2CH3), 171.0 (CO2CH3),, 170.8 (COCH3), 137.5 (C-9), 116.3 (C-10), 87.0 (C-5), 72.0 (CH(CH3)2), 59.1 (C-6), 52.88 (2x CO2CH3), 42.8 (C-4), 34.7, 33.4, 29.3, 25.7 (COCH3), 23.8 (CH(CH3)2), 23.4 (CH(CH3)2).
IRR (film): v 2978,1773,1754,1731. HRMS calculated for C18H28O7N 370.1866, found 370.1871. 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-pent-4-enylmalonicc acid dimethyll ester (53c): According to general procedure B, lactam 40 (368 mg,, 2.01 mmol) was reacted with 52c (445 mg, 2.23 mmol) to give 53c (662 mg,, 1.73 mmol, 86%) as a colorless oil after purification (EtOAcPE = 1:3).
RRff = 0.30. iH-NMR: (C6D6, 400 MHz): 8 = 6.13 (s, 1H, H-5), 5.51-5.61 (m,
1H,, H-10), 4.90 (dd, ƒ = 11.1; 16.1 Hz, 2H, H - l l ) , 4.27 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2) 3.27 (s,
3H,, CO2CH3) 3.20 (s, 3H, CO2CH3), 2.85-2.93 (m, 2H, H-3a, H-4), 2.56 (td, ƒ = 4.6; 17.2 Hz, 1H, 67 7
H-3P),, 2.40 (s, 3H, COCH3), 1.91-1.99 (m, 2H), 1.77-1.82 (q, ƒ = 7.0 Hz, 2H), 1.26 (d, ƒ = 6.1 Hz, 3H,, CH(CH3)2), 1.19 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.11-1.21 (m, 2H). "C-NMR: (QDe, 100 MHz):: S = 174.8 (C-2), 171.4 (2x CO2CH3), 171.0 (COCH3), 138.3 10), 116.2 ll), 87.0 (C-5),, 72.0 (CH(CH3)2), 59.3 (C-6), 52.8 (2x C02CH3), 42.9 (C-4), 34.7, 34.4, 33.6, 25.7 (COCH3), 24.3,, 23.8 (CH(CH3)2), 23.4 (CH(CH3)2). IR (film): v 2975, 1772, 1753, 1730. HRMS calculated forr Ci9H30O7N 384.2022, found 384.2021.
Me02cc co2Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-hex-5-enylmalonic acid
dimethyll ester (53d): According to general procedure B, lactam 40 (247 mg,, 1.35 mmol) was reacted with 52d (298 mg, 1.39 mmol) to give 53d (5033 mg, 1.27 mmol, 94%) as a colorless oil after purification (EtOAcPE == 1:5). Rf = 0.35. iH-NMR: (CDC13, 400 MHz): 5 = 5.72-5.78 (m, 1H, H-ll), 5.75 (s, 1H, H-5), 4.933 (dd, ƒ = 10.1; 15.8 Hz, 2H, H-12), 4.02 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2) 3.68 (s, 3H, C02CH3)) 3.62 (s, 3H, C02CH3), 3.03 (dd, J = 9.1; 17.7 Hz, 1H, H-3a), 2.78 (d, ƒ = 9.1 Hz, 1H, H-4),, 2.53 (d, ƒ = 18.4 Hz, 1H, H-3P), 2.43 (s, 3H, COCH3), 1.88-2.00 (m, 4H), 1.27-1.36 (m, 4H), 1.211 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.11 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). «C-NMR: (CDC13,100 MHz):: 8 = 174.5 (C-2), 170.6 (2x CO2CH3), 170.4 (COCH3), 138.9 ll), 114.4 12), 86.0 (C-5),, 71.0 (CH(CH3)2), 58.5 (C-6), 52.5 (2x C02CH3), 41.7 (C-4), 33.7, 33.1, 29.5, 28.7, 26.1 (COCH3),, 24.0, 22.8 (CH(CH3)2), 22.5 (CH(CH3)2). IR (film): v 2929, 1758, 1730, 1710. HRMS
calculatedd for C20H32O7N 398.2128, found 398.2129.
Me02cc co2Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-oct-7-enylmalonic
acidd dimethyl ester (53e): According to general procedure B, lactam 400 (254 mg, 1.39 mmol) was reacted with 52e (339 mg, 1.40 mmol) to givee 53e (568 mg, 1.34 mmol, 96%) as a colorless oil after purification (EtOAcPEE = 1:8). R/= 0.32. ^H-NMR: (CDC13, 400 MHz): 5 = 5.71-5.80 (m, 1H, H-13), 5.75 (s, 1H,, H-5), 4.94 (dd, ] = 11.1; 16.1 Hz, 2H, H-14), 4.02 (sept, ƒ = 6.2 Hz, 1H, CH(CH3)2) 3.68 (s, 3H,, C02CH3) 3.62 (s, 3H, C02CH3), 3.04 (dd, ƒ = 9.2; 18.5 Hz, 1H, H-3a), 2.78 (d, ƒ = 9.4 Hz, 1H, H-4),, 2.53 (d, ƒ = 18.3 Hz, 1H, H-3P), 2.43 (s, 3H, COCH3), 1.92-2.06 (m, 4H), 1.36-1.43 (m, 2H), 1.08-1.344 (m, 6H), 1.21 (d, ƒ = 6.3 Hz, 3H, CH(CH3)2), 1.11 (d, ƒ = 6.3 Hz, 3H, CH(CH3)2). " C -NMR:: (CDC13, 100 MHz): 5 = 174.4 (C-2), 170.5 (COzCH3), 170.4 (C02CH3), 170.2 (COCH3), 138.11 (C-13), 114.8 (C-14), 85.9 (C-5), 71.0 ( C H ^ H s ) ^ , 58.4 (C-6), 52.5 (2x C02CH3), 41.4 (C-4), 33.4,, 32.8, 29.2, 28.4, 25.0 (COCH3), 23.3, 22.7 (CH(CH3)2), 22.5 (CH(CH3)2). IR (film): v 2975,
1758,1730,1709.. HRMS calculated for C ^ H M C W 426.2492, found 426.2497.
Generall procedure C for the deacetylation: To a solution of lactam 53 in CH2C12 (0.2
M)) at room temperature was added pyrrolidine (>6 equiv) and the resulting mixture was stirredd at room temperature overnight. The reaction is quenched by adding aqueous saturatedd NH4CL The layers were separated and the aqueous phase was extracted with CH2C12.. The combined organic layers were washed with water, dried over MgSOé and
concentratedd in vacuo.
Meoo c co Me 2-Allyl-2-(5-oxo-2-propoxypyrrolidin-3-yl)malonic acid dimethyl ester (54a)14:: According to general procedure C, lactam 53a (39.7 mg, 0.12 mmol) affordedd 54a (34.0 mg, 0.11 mmol, 98%) as a colorless oil after purification (EtOAc).. Rf = 0.40. !H-NMR: (CDCI3, 400 MHz): S = 7.45 (br s, 1H, NH),
4),, 2.71 (dd, ƒ = 9.7; 17.8 Hz, 1H, H-3a), 2.68 (d, ƒ = 7.4 Hz, 2H, H-7), 2.32 (dd, ƒ = 3.5; 17.8 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:
(CDC13,, 100 MHz): 6 = 177.6 (C-2), 170.2 (CO2CH3), 169.8 (CO2CH3), 131.7 (C-8), 119.9 (C-9),
85.22 (C-5), 69.8 (CH(CH3)2), 59.4 (C-6), 52.6 (CO2CH3), 52.5 (CO2CH3), 44.8 (C-4), 37.8, 31.9,
23.33 (CH(CH3)2), 21.9 (CH(CH3)2). IR (film): v 3264, 2970,1731,1706.
Meo2cc co2Me 2-But-3-enyI-2-(5-oxo-2-propoxypyrrolidin-3-yl)malonic acid dimethyl
/ \ z ^ ^^ ester (54b): According to general procedure C, lactam 53b (302 mg, 0.82
J^J^ >»0ipr mmol) afforded 54b (260 mg, 0.79 mmol, 97%) as a colorless oil after
HH purification (EtOAc). Rf = 0.40. iH-NMR: (C6D6, 400 MHz): 8 = 8.84 (br s, 1H,
NH),, 5.58-5.68 (m, 1H, H-9), 5.15 (s, 1H, H-5), 4.93 (ddd, ƒ = 1.5; 10.2; 17.1 Hz, 2H, H-10), 3.69 (sept,, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.37 (s, 3H, CO2CH3), 3.31 (s, 3H, CO2CH3), 3.00-3.04 (m, 1H,
H-4),, 2.78 (dd, ƒ = 9.5; 17.7 Hz, 1H, H-3a), 2.53 (dd, ƒ = 3.5; 17.8 Hz, 1H, H-3P), 2.08-2.17 (m, 3H),, 1.91-1.99 (m, 1H), 1.11 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.04 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2).
«C-NMR:: (GD6, 100 MHz): 8 = 178.9 (C-2), 171.5 (CO2CH3), 171.2 (CO2CH3), 138.1 (C-9),
116.00 (C-10), 86.3 (C-5), 70.4 (CH(CH3)2), 60.0 (C-6), 52.8 (CO2CH3), 52.7 (CO2CH3), 46.1 (C-4),
33.8,, 33.4, 29.6, 24.3 (CH(CH3)2), 22.5 (CH(CH3)2). IR (film): v 3226, 2972, 1729, 1713. HRMS
calculatedd for C16H2606N 328.1760, found 328.1761.
Me02cc co2Me 2-(5-Oxo-2-propoxypyrrolidin-3-yl)-2-pent-4-enylmalonic acid dimethyl
/ ^ ^ • ^ ^^ ester (54c): According to general procedure C, lactam 53c (354 mg, 0.92
^L^L y""o'Pr mmol) afforded 54c (309 mg, 0.90 mmol, 98%) as a colorless oil after
HH purification (EtOAc). Rf = 0.50. iH-NMR: (C6D6, 400 MHz): 8 = 8.67 (br s,
1H,, NH), 5.57-5.68 (m, 1H, H-10), 5.16 (s, 1H, H-5), 4.93 (dd, ƒ = 10.3; 17.4 Hz, 2H, H - l l ) , 3.69 (sept,, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.39 (s, 3H, CO2CH3), 3.33 (s, 3H, CO2CH3), 3.01-3.04 (m, 1H,
H-4),, 2.78 (dd, ƒ - 9.5; 17.7 Hz, 1H, H-3a), 2.55 (dd, ƒ = 3.3; 17.7 Hz, 1H, H-3P), 2.03 (t, ƒ = 8.5 Hz,, 2H, H-7), 1.87 (q, ƒ = 7.0 Hz, 2H), 1.22-1.45 (m, 2H), 1.12 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2),
1.066 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). 13C-NMR: (C6D6, 100 MHz): 8 = 178.9 (C-2), 171.7
(CO2CH3),, 171.4 (CO2CH3), 138.7 (C-10), 116.0 (C-ll), 86.3 (C-5), 70.2 (CH(CH3)2), 60.2 (C-6),
52.88 (CO2CH3), 52.7 (CO2CH3), 46.1 (C-4), 34.7, 34.0, 33.3, 24.6, 24.3 (CH(CH3)2), 22.5
(CH(CH3)2).. IR (film): v 3226, 2972, 1726, 1709. HRMS calculated for Ci7H2806N 342.1917,
foundd 342.1918.
Me02cc co2Me 2-Hex-5-enyl-2-(5-oxo-2-propoxypyrrolidin-3-yl)malonic acid dimethyl
j ^ ^ ~ ~ ^ ^ - ^^ ester (54d): According to general procedure C, lactam 53d (241 mg, 0.61
J^J^ 3""o'pr mmol) afforded 54d (186 mg, 0.52 mmol, 86%) as a colorless oil after
HH purification (EtOAcPE = 4:1). Rf = 0.36. iH-NMR: (CDCI3, 400 MHz): 8 =
6.899 (br s, 1H, NH), 5.70-5.81 (m, 1H, H-ll), 4.91-5.04 (m, 3H, H-5, H-12), 3.70 (s, 3H, CO2CH3),, 3.69 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.68 (s, 3H, CO2CH3), 2.87-2.91 (m, 1H, H-4),
2.744 (dd, ƒ = 9.6; 17.6 Hz, 1H, H-3a), 2.32 (dd, ƒ = 3.3; 17.6 Hz, 1H, H-3P), 2.01-2.08 (m, 2H),
1.88-1.966 (m, 2H), 1.35-1.44 (m, 2H), 1.28 (t, ƒ = 8.2 Hz, 2H, H-7), 1.18 (d, ƒ = 6.1 Hz, 6H, CH(CH3)2).. «C-NMR: (CDCI3, 100 MHz): 8 = 177.9 (C-2), 170.7 (CO2CH3), 170.5 (CO2CH3),
138.22 (C-ll), 114.6 (C-12), 85.2 (C-5), 69.7 (CH(CH3)2), 59.2 (C-6), 52.4 (2x CO2CH3), 44.7 (C-4),
33.11 (2x), 32.0, 28.8, 23.5, 23.3 (CH(CH3)2), 21.8 (CH(CH3)2). IR (film): v 3215, 2971,1730,1709.
HRMSS calculated for Ci8H30O6N 356.2073, found 356.2069.
Me02cc co2Me 2-Oct-7-enyl-2-(5-oxo-2-propoxypyrrolidin-3-yl)malonic acid
dimethyll ester (54e): According to general procedure C, lactam 53e (2511 mg, 0.59 mmol) afforded 54e (204 mg, 0.53 mmol, 90%) as a colorlesss oil after purification (EtOAc:PE = 4:1). Rf = 0.32. JH-NMR:
(CDC13,, 400 MHz): 5 = 6.93 (br s, 1H, NH), 5.67-5.78 (m, 1H, 13), 4.86-4.95 (m, 3H, 5,
H-14),, 3.67 (s, 3H, CO2CH3), 3.66 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.65 (s, 3H, C02CH3),
2.80-2.844 (m, 1H, H-4), 2.68 (dd, ƒ = 9.6; 17.8 Hz, 1H, H-3a), 2.27 (dd, ƒ = 3.4; 17.7 Hz, 1H, H-3"), 1.93-2.011 (m, 2H), 1.83-1.89 (m, 2H), 1.18-1.37 (m, 8H), 1.12 (d, / = 6.1 Hz, 6H, CH(CH3)2).
13C-NMR:: (CDCI3, 100 MHz): 5 = 177.5 (C-2), 170.8 (CO2CH3), 170.5 (CO2CH3), 138.8 (C-13), 114.33 (C-14), 85.2 (C-5), 69.8 (CH(CH3)2), 59.3 (C-6), 52.4 (2x C02CH3), 44.8 (C-4), 33.6, 33.4,
31.9,, 29.5, 28.6 (2x), 24.1, 23.2 (CH(CH3)2), 22.0 (CH(CH3)2). IR (film): v 3220, 2927,1729,1709.
HRMSS calculated for Q O H M C W 384.2386, found 384.2367.
Me02cc ^ 2-Prop-2-ynylmalonic acid dimethyl ester (55a)26: According to general
M e 02c ^ - ^^ procedure A, propargyl bromide (80 wt% in toluene, 5.9 mL, 54.7 mmol)
affordedd 55a (5.49 g, 32.3 mmol, 60%) as a colorless oil after purification (EtOAePE = 3:7). Rf
== 0.39. iH-NMR: (CDCI3, 400 MHz): 6 = 3.71 (s, 6H, 2x CO2CH3), 3.57 (t, ƒ = 7.4 Hz, 1H,
CHCO),, 2.72 (dd, ƒ = 2.8; 7.4 Hz, 2H, C H2O C H ) , 1.99 (t, ƒ = 2.8 Hz, 1H, O C H ) . «C-NMR:
(CDCI3,1000 MHz): S = 168.1 (2x C02CH3), 79.7 ( O C H ) , 70.3 ( O C H (reversed)), 52.6 (CHCO),
52.44 (2x C02CH3), 18.3 (CH2OCH).
Me02c^^ 2-But-3-ynylmalonic acid dimethyl ester (55b)41: According to general
Me02cc > ^ procedure A, 4-iodo-l-butyne (780 mg, 4.56 mmol) afforded 55b (306 mg,
1.666 mmol, 40%) as a colorless oil after purification (EtOAePE = 1:9). Rf = 0.29. !H-NMR:
(CDC13,, 400 MHz): 8 = 3.72 (s, 6H, 2x C02CH3), 3.59 (t, ƒ = 7.4 Hz, 1H, CHCO), 2.27 (dt, ƒ =
2.5;; 7.1 Hz, 2H, CH2OCH), 2.10 (td, ƒ = 7.1; 7.4 Hz, 2H, CHCH2), 1.98 (t, ƒ = 2.5 Hz, 1H,
O C H ) .. WC-NMR: (CDCI3, 100 MHz): 5 = 169.3 (2x C02CH3), 82.2 ( O C H ) , 69.7 ( O C H
(reversed)),, 52.5 (CHCO), 50.1 (2x C02CH3), 27.4,16.3.
2-Hex-5-ynylmalonicc acid dimethyl ester (55c)42: According to general proceduree A, 6-iodo-l-hexyne (239 mg, 1.15 mmol) afforded 55c (149 mg,, 0.70 mmol, 61%) as a colorless oil after purification (EtOAePE = 1:9). Rf= 0.29. JH-NMR:
(CDC13,, 400 MHz): 5 = 3.71 (s, 6H, 2x C02CH3), 3.58 (t, ƒ = 7.4 Hz, 1H, CHCO), 2.09-2.17 (m,
2H),, 1.98 (t, ƒ = 2.5 Hz, 1H, O C H ) , 1.86-1.95 (m, 2H), 1.45-1.56 (m, 2H), 1.19-1.28 (m, 2H). "C-NMR:: (CDCb, 100 MHz): 5 = 169.4 (2x CO2CH3), 82.3 ( O C H ) , 69.6 ( O C H (reversed)), 52.55 (CHCO), 50.4 (2x C02CH3), 27.4,26.3, 20.5,16.3.
Meoo c co Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-prop-2-ynylmalonic acid dimethyll ester (56a): According to general procedure B, lactam 40 (250 mg, 1.366 mmol) was reacted with 55a (241 mg, 1.42 mmol) to give 56a (462 mg, 1.311 mmol, 96%) as a colorless oil after purification (EtOAePE = 4:1). Rf = 0.46.. iH-NMR: (CDCI3, 400 MHz): 6 = 5.79 (s, 1H, H-5), 4.06 (sept, ƒ = 6.1 Hz, 1H,, CH(CH3)2), 3.71 (s, 3H, CO2CH3), 3.66 (s, 3H, C02CH3), 3.04-3.14 (m, 2H, H-4, H-3a), 2.88
(s,, 2H, H-7), 2.57 (d, ƒ = 10.4 Hz, 1H, H-315), 2.42 (s, 3H, COCH3), 2.07 (t, ƒ = 2.6 Hz, 1H, H-9), 1.222 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.13 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2). «C-NMR: (CDC13,100
MHz):: 6 = 174.1 (C-2), 170.3 (COCH3), 169.0 (CO2CH3), 168.9 (CO2CH3), 85.6 (C-5), 77.3 (C-8) 72.88 (C-9 (reversed)), 71.1 (CH(CH3)2), 57.5 (C-6), 53.0 (2x CO2CH3), 41.4 (C-4), 34.0 (C-3), 23.0
Me02cc co2Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-but-3-ynylmalonic acid
A ^ " N ^^ dimethyl ester (56b): According to general procedure B, lactam 40 (198 mg, , X >> "o'Pr 1 0 8 mmol) was reacted with 55b (200 mg, 1.09 mmol) to give 56b (387 mg,
Acc 105 mmol, 98%) as a colorless oil after purification (EtOAcPE = 4:1). Rf =
0.45.. iH-NMR: (CDC13, 400 MHz): 8 = 5.74 (s, 1H, H-5), 4.03 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.700 (s, 3H, CO2CH3), 3.64 (s, 3H, CO2CH3), 3.06 (dd, ƒ = 9.2; 18.4 Hz, 1H, H-3a), 2.80 (d, ƒ = 9.1 Hz,, 1H, H-4), 2.51 (d, ƒ = 18.4 Hz, 1H, H-3P), 2.44 (s, 3H, COCH3), 2.10-2.28 (m, 4H, H-7, H-8), 1.988 (t, ƒ = 2.6 Hz, 1H, H-10), 1.21 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 1.12 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2).. "C-NMR: (CDCI3, 100 MHz): 5 = 174.1 (C-2), 170.5 (COCH3), 169.8 (C02CH3), 169.66 (CO2CH3), 85.7 (C-5), 82.1 (C-9), 71.1 (CH(CH3)2), 69.4 (C-10 (reversed)), 57.8 (C-6), 52.6 (2xx CO2CH3), 42.1 (C-4), 34.1 (C-3), 32.0, 25.0 (COCH3), 22.6 (CH(CH3)2), 22.5 (CH(CH3)2), 14.0.
IRR (film): v 3285, 2975, 1750, 1732, 1703. HRMS calculated for C I S H K O N 368.1709, found 368.1709. .
Me02cc co2Me 2-(l-Acetyl-5-oxo-2-propoxypyrrolidin-3-yl)-2-hex-5-ynylmalonic acid
/ ^ ^ ^ ^ ^ ^ ^ .. dimethyl ester (56c): According to general procedure B, lactam 40 (124
00^L^L X'o'Pr mg, 0.68 mmol) was reacted with 55c (149 mg, 0.70 mmol) to give 56c
Acc (219 mg, 0.58 mmol, 86%) as a colorless oil after purification (EtOAcPE == 1:6). Rf = 0.22. ^H-NMR: (CDCI3, 400 MHz): 5 = 5.73 (s, 1H, H-5), 4.00 (sept, ƒ = 6.1 Hz, 1H,
CH(CH3)2),, 3.67 (s, 3H, CO2CH3), 3.60 (s, 3H, CO2CH3), 3.02 (dd, ƒ = 9.1; 18.4 Hz, 1H, H-3"),
2.777 (d, ƒ = 9.1 Hz, 1H, H-4), 2.51 (d, ƒ = 18.8 Hz, 1H, H-3P), 2.41 (s, 3H, COCH3), 2.16 (t, ƒ = 6.8 Hz,, 2H, H-7), 1.88-2.01 (m, 3H, H-12), 1,49 (hept, ƒ = 6.8 Hz, 2H), 1.19-1.30 (m, 2H), 1.19 (d, ƒ == 6.0 Hz, 3H, CH(CH3)2), 1.09 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2), 0.75-0.93 (m, 2H). «C-NMR:
(CDC13,500 MHz): 5 = 174.3 (C-2), 170.5 (COCH3), 170.3 (CO2CH3), 170.1 (CO2CH3), 85.8 (C-5),
83.55 (C-ll), 71.0 (CH(CH3)2), 68.7 (C-12 (reversed)), 58.3 (C-6), 52.4 (2x CO2CH3), 41.6 (C-4),
34.00 (C-3), 32.5, 28.1, 24.9 (COCH3), 22.9, 22.6 (CH(CH3)2), 22.5 (CH(CH3)2), 17.9. IR (film): v
3285,, 2954,1751,1730,1705. HRMS calculated for C20H30O7N 396.2022, found 396.2028.
Me02cc co2Me 2-(5-Oxo-2-propoxypyrrolidin-3-yl)-2-prop-2-ynylmalonic acid dimethyl
(^-"^(^-"^ ester (57a): According to general procedure C, lactam 56a (76.7 mg, 0.22
0AA ^"o'Pr mmol) afforded 57a (61.4 mg, 0.20 mmol, 91%) as a colorless oil after
HH purification (EtOAc). Rf = 0.45. iH-NMR: (CDCI3, 400 MHz): 5 = 7.60 (br s, 1H,
NH),, 5.02 (s, 1H, H-5), 3.73 (s, 3H, CO2CH3), 3,72 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.71 (s, 3H,
CO2CH3),, 3.05-3.09 (m, 1H, H-4), 2.85 (d, ƒ = 2.6 Hz, 2H, H-7), 2.76 (dd, ƒ = 9.5; 18.0 Hz, 1H, H-3a),, 2.38 (dd, ƒ = 3.7; 17.9 Hz, 1H, H-3P), 2.05 (t, ƒ ƒ = 2.6 Hz, 1H, H-9), 1.16 (d, ƒ = 6.1 Hz, 3H, CH(CH3)2),, 1.14 (d, / = 6.1 Hz, 3H, CH(CH3)2). 13C-NMR: (CDCI3,100 MHz): 8 = 177.5 (C-2),
169.44 (CO2CH3), 169.1 (CO2CH3), 85.1 (C-5), 77.9 (C-8), 72.3 (C-9 (reversed)), 69.8 (CH(CH3)2),
58.00 (C-6), 52.9 (2x CO2CH3), 44.9 (C-4), 31.8 (C-3), 23.5 (C-7), 23.1 (CH(CH3)2), 22.0
(CH(CH3)2).. IR (film): v 3277, 3200, 2972, 1733, 1704. HRMS calculated for C15H22O6N
312.1447,, found 312.1455.
Me02cc co2Me 2-But-3-ynyl-2-(5-oxo-2-propoxypyrrolidin-3-yl)malonic acid dimethyl
^ / ^ ^ ^ " ^^ ester (57b): According to general procedure C, lactam 56b (204 mg, 0.56
QQJ^J^ )""o'Pr mmol) afforded 57b (174 mg, 0.54 mmol, 96%) as a colorless oil after
HH purification (EtOAc). Rf = 0.45. iH-NMR: (CDC13, 400 MHz): 8 = 7.77 (br s,
1H,, NH), 4.96 (s, 1H, H-5), 3.72 (s, 3H, CO2CH3), 3,72 (sept, ƒ = 6.1 Hz, 1H, CH(CH3)2), 3.71 (s,
3H,, CO2CH3), 2.83 (br d, ƒ = 9.7 Hz, 1H, H-4), 2.73 (dd, / = 9.7; 17.6 Hz, 1H, H-3a), 2.33 (dd, ƒ = 4.1;; 17.6 Hz, 1H, H-3P), 2.14-2.32 (m, 4H, H-7, H-8), 1.96 (t, ƒ = 2.3 Hz, 1H, H-10), 1.16 (d, ƒ = 71 1
