Kärtner, Annerose

Wanner, Klaus Th.

English

Universität München: Elektronischen Publikationen

lnterna9iO|ial 
~ and + ©mmumcalons 
HgterocKib 
lemistry 
Volume 26 
Number 4 
ISSN 0 3 8 5 - 5 4 1 4 
HETEROCYCLES 
An Internat ional Journa l fo r Reviews and Communica t ions 
in Heterocycl ic Chemis t ry 
C O N T E N T S 
C O M M U N I C A T I O N S 
GHEORGHE SURPATEANU, A L A I N LABLACHE-COMBIER, PIERRE 
G R A N D C L A U D O N , and BERNARD M O U C H E L . Cyc loaddi t ion 
Reaction of 1,2,4-Triazol ium Phenacyl ides w i t h Cinnamic Esters 8 6 3 
ISTVÄN BITTER, GABOR T Ö T H , ISTVÄN HERMECZ, and ZOLTÄN 
MESZÄROS. Nitrogen Bridgehead Compounds Part 59 . Nucleophilic 
Subst i tut ion Reactions of 9 - B r o m o - 6 , 7 , 8 , 9 - t e t r a h y d r o - 4 # - p y r i d o -
[1 ,2 -a ]py r im id in -4 -ones 8 6 9 
YASUOKI M U R A K A M I , Y U U S A K U Y O K O Y A M A , CHIYOKO A O K I , 
CHIEMI MIYAGI , T O S H I K O W A T A N A B E , and TAICHI O H M O T O . 
A N e w Route to 4 - 0 x y g e n a t e d /?-Carbolines: The Tota l Synthesis 
of Crenat ine 8 7 5 
HANH DUFAT-TRINH VAN, ELISABETH SEGUIN, FRANQOIS TILLEQUIN, 
and MICHEL K O C H . Tota l Synthesis of 7 - H y d r o x y - " 9 - o x a " - a n t h r a -
cycl inone and Glycoside Derivat ives 8 7 9 
SHIZUAKI MURATA, T A K A S H I S U G I M O T O , and S A D A O M A T S U U R A . 
A Novel Ring Format ion of 1 ,2-Dihydroquinoxal ines 8 8 3 
HANS LUDESCHER, CHING-PONG M A K , GERHARD SCHULZ, and 
H A N S FLIRI. Chemis t ry of Penicill in Diazoketones. Part I I : From 
Beta-Iactam to Beta-Iactone 8 8 5 
M A S A N O R I SOMEI , F U M I O Y A M A D A , and YOSHIH IKO M A K I T A . 
Total Syntheses of (± ) -Agroc lav ine - l , (± ) -6 -Nor -chanoc lav ine- l l , 
and (±) -Chanoc lav ine- l l 8 9 5 
MONA HASSAN M O H A M E D , NADIA SOBHY IBRAHIM, and M O H A M E D 
HILMY ELNAGDI . Nitr i les in Heterocycl ic Synthesis : Synthesis of 
Some N e w Pyridine, Pyridazine and Pyr imidine Derivat ives — 8 9 9 
EBTISAM ABDEL AZIZ HAFEZ, M O H A M E D H I L M Y ELNAGDI , ABDEL 
G H A N I ALI ELAGAMEY, and FATHY M O H A M E D ABDEL AZIZ 
EL-TAWEEL. Nitr i les in Heterocycl ic Synthes is : Nove! Synthesis of 
Benzo[c]coumarin and of Benzo[c]pyrano[3,2-c]quinoline Derivatives 9 0 3 
JUZO NAKAYAMA, MASAHIRO SHIBUYA, and M A S A M A T S U HOSHINO. 
Preparat ion of 2 ,5-Diacy lse lenophenes by Condensat ion of a , a -
Diketo Selenides w i t h Glyoxal 9 0 9 
M A S A K A T S U M A T S U M O T O and N O B U K O W A T A N A B E . A Facile 
Synthesis of 4 -Mercap to indo les 9 1 3 
K L A U S T H . W A N N E R and ANNEROSE KÄRTNER. Isomerizat ion of 
A/-Acyl-1,2,5,6-tetrahydropyridines to /V-Acyl-enamines by Palladium 
on Carbon 9 1 7 
K L A U S T H . W A N N E R and ANNEROSE KÄRTNER. Asymmet r ie a-
Amidoa lky la t ion . Synthesis of a -Subst i tuted Piperidines of High 
Enant iomer ic Purity 9 2 1 
J U N K O K O Y A M A , TERUYO O K A T A N I , KIYOSHI T A G A H A R A , YUKIO 
SUZUTA, and HIROSHI IRIE. Synthesis of Guaipyr id ine, Epiguai-
pyr id ine, and Related Compounds 9 2 5 
M A K O T O W A D A , HIDEKI A IURA, and KIN-YA AKIBA. Synthesis of 
Pyrrol id ine Derivat ives by Improved Aminose lenat ion via Add i t ion 
of Boron Tr i f luor ide Complex of D ihomoal ly lcuprate to Ald imines 
Conta in ing a -Hydrogen 9 2 9 
YOSHITERU O S H I M A , M A K I O K A M O T O , and HIROSHI HIK INO. 
Epimedins A, B and C, Flavonoid Glycosides of Epimedium koreanum 
Herbs 9 3 5 
J U Z O N A K A Y A M A , YOICHI N A K A M U R A , SHIGERU M U R A B A Y A S H I , 
and M A S A M A T S U H O S H I N O . Preparat ion of ^-Quinque- and a-
Sept i th iophenes and Their Posit ional Isomers 9 3 9 
YANG-CHANG W U , T IAN-SHUNG W U , MASATAKE NIWA, SHENG-TEH 
LU, and YOSHIMASA HIRATA. Thalicsessine, a New C 2 o-Diterpenoid 
Alkaloid f r o m Thalictrum sessile Hayata 9 4 3 
HETEROCYCLIC PAPERS 
L A J O S KOVÄCS, PAL HERCZEGH, GYULA BATTA, and ISTVÄN 
FARKAS. T w o Acyc l ic Analogues of 2-/?-D-Ribofuranosylthiazole-4-
carboxamide (Tiazofurin) 9 4 7 
GURY Z V I L I C H O V S K Y and M O R D E C H A I DAVID. Molecular St ructure 
and Stabi l i ty of Isoxazolium Enolates 9 6 1 
SHARON MARINUZZI-BROSEMER, BHALCHANDRA H. PATWARDHAN, 
KENNETH A. GREENBERG, and D O N A L D C. DITTMER. In teract ion 
of Thietes w i t h Electron-def ic ient Molecules 9 6 9 
JOSE M. A L O N S O , M. ROSARIO M A R T I N , JAVIER DE M E N D O Z A , 
T O M A S TORRES, and JOSfE ELGUERO. Proton-ionizable Macrocycles 
Conta in ing 1,2,4-Triazole and 4 -Amino-1 ,2 ,4 - t r iazo le Subunits 9 8 9 
C H I N G - P O N G M A K , GERHARD SCHULZ, and H A N S FLIRI. Chemis t ry 
of Penicil l in Diazoketones. Part I I I : T rans fo rma t ion of Tr icyc l ic 
Beta-Iactams 1 0 0 1 
ETSUKO K A W A S H I M A , Y U K O A N D O , K A T S U M I TABEI, and HIROSHI 
M I Y A M A E . Cyclization of C- and O-Acyl Derivat ives of p-Toluamide 
O-Acetoacety lox ime 1 0 1 5 
PAUL D. W O O D G A T E , J O H N M. HERBERT, and W I L L I A M A. DENNY. 
The Preparation of Pyrido[4,3,2-Gfe]quinazoline and Pyrido[3,4,5-ofe]-
quinazoline 1 0 2 9 
J O H N M. HERBERT, PAUL D. W O O D G A T E , and W I L L I A M A. DENNY. 
Format ion of pe/v-Fused Heterocyc les by Int ramolecular Displace-
men t of Halide 1 0 3 7 
J O H N M. HERBERT, PAUL D. W O O D G A T E , and W I L L I A M A. DENNY. 
Behaviour of Some Perimidines t o w a r d s Oxidants 1 0 4 3 
REVIEWS 
A H M E D K A M A L and PRALHAD B. SATTUR. Chlorosulfonyl Isocyanate:. 
A Novel Reagent fo r the Synthesis of Heterocycles 1 0 5 1 
ARYA K. MUKERJEE. Azlactones: Retrospect and Prospect 1 0 7 7 
N E W HETEROCYCLIC NATURAL PRODUCTS 
Polyacetates 1 0 9 9 
Aromat ics 1 1 0 2 
Terpenes 1 1 1 1 
Steroids 1 1 2 9 
Alkaloids 1 1 3 0 
Ant ib io t ics 1 1 3 9 
Miscel laneous 1 1 4 4 
TOTAL SYNTHESIS OF HETEROCYCLIC NATURAL PRODUCTS 
Polyacetates 1 1 4 5 
Aromat ics 1 1 4 8 
Terpenes 1 1 5 0 
Alkaloids 1 1 5 1 
Ant ib iot ics 1 1 5 8 
Miscellaneous 11 5 9 
HETEROCYCLES, Vol. 26, N o . 4, 1987 
ASYMMETRIC Cfc-AMI DOALKY LATION. 
SYNTHESIS OF a-SUBSTITUTED PIPERIDINES OF HIGH ENANTIOMERIC PURITY 
Klaus Th. Wanner* and Annerose Kärtner 
I n s t i t u t für Pharmazie und Lebensmittelchemie der Universität München, 
Sophienstr. 10, 8000 München 2, FRG 
Abstract - A s t e r e o s e l e c t i v e a-amidoalkylation was performed employing the 
c h i r a l and c y c l i c enamide The r e s u l t i n g amides 6 v i e r e employed i n the 
synthesis of the t i t l e products. 
Designing highly e f f i c i e n t methods for asymmetric synthesis c o n s t i t u t e s one of the most challenging 
and e x c i t i n g problems i n synthetic organic chemistry and there i s an unabating search for new 
enantio- and d i a s t e r e o s e l e c t i v e bond forming r e a c t i o n s 1 . Most of the w e l l established methods 
comprise the reaction of c h i r a l nucleophiles such as enolates, 
wherein the c h i r a l i t y stems from a c h i r a l a u x i l i a r y , with a c h i r a l 
2 
e l e c t r o p h i l e s . In contrast thereto reactions of e l e c t r o p h i l i c 
equivalents provided with a c h i r a l a u x i l i a r y are few and have 
appeared i n the l i t e r a t u r e only recently 3.We have designed a 
novel asymmetric synthesis based on the concept of a-amidoalky-
l a t i o n which i n general i s accomplished by trapping an e l e c t r o -
p h i l i c N-acyliminium ion (e.g.I_) with a nucleophile. I t occurred 
to us that a c h i r a l appendix adjacent to the iminium subunit i n I could favour the approach of 
a nucleophile along one path ( e i t h e r A or B) r e s u l t i n g i n a s t e r e o s e l e c t i v e bond formation. Sub-
sequent removal of the c h i r a l a u x i l i a r y would then a f f o r d substituted p i p e r i d i n e s i n o p t i c a l l y 
a c t i v e form. 
In t h i s l e t t e r we wish to report the successful implementation of t h i s plan. Enamides can act 
as a-amidoalkylation agents and therefore 2JL which i s r e a d i l y a v a i l a b l e even i n 20 g q u a n t i t i e s 
by c a t a l y t i c isomerization seemed best s u i t e d f o r our purposes. Indeed 2 could be coupled with 
various s i l y l enolethers (4) to give a mixture of the diastereomeric a-substituted amides 5̂  and 
6. 
— 9 2 1 -
The transformation was effected by adding 2 i n C H 2 C 1 2 t o a s o l u t i o n o f H C 1 i n C H 2 C 1 ^ a t _ 7 8 ° c ' 
S t r i p p i n g o f f excess HCl, t r e a t i n g the remaining Solution with T i C l ^ or S n C l 4 (1.05 eq, 0.5 h) 
and subsequent addition of the respective enol ether 4 (1.25-2.0 eq, 0.5-1.O h, -78°C). Aqueous 
workup then yielded a residue containing almost e x c l u s i v e l y the desired amidoalkylation products 
5 6 and 6 6 (as established by TLC) beside some ketone r e s u l t i n g from s i l y l enol ether h y d r o l y s i s . 
We assume that the r e a c t i o n proceeds v i a the orchloroamide 2 and the iminium ion 3 having the 
indicated s t r u c t u r e s . The s t e r e o s e l e c t i v i t y of the bond forming reaction was determined by HPLC 
and ranged from a modest 35.3:64.7 r a t i o (entry 1) to a q u i t e reasonable 6.2:93.8 r a t i o when the 
s t e r i c a l l y demanding enolether 4c was applied (entry 4). 
Table Enol ether Ratio a-Subst. Amide 6 
entry Lewis-Acid 4 R 1 R 2 5/6 3 b % y i e l d [a 578° conf. 
1 T i C l 4 a H 35 .3/64. 7 47.0 + 2 03° R 
2 SnCl . 4 a H C<?5 30 7/69. 3 d -
3 T i C l M 4 b H 21 8/78. 2 57.9 + 0 99° R 
4 T i C l 4 c C H 3 C f ? 5 6 2/93. 8 30.4 76. 60° e 
a) Determined by HPLC on a LiChrosorb S i 60 column eluted with 10-20% EtOAc i n hexane. b) Y i e l d 
of pure diastereomer 6, from f l a s h or r a d i a l chromatography c) S p e c i f i c r o t a t i o n (c=1.0 i n CH3OH). 
d) Not determined. e) The absolute c o n f i g u r a t i o n of the newly produced asymmetric center i s pre-
s e n t l y unknown. However, i t i s reasonably expected that the major product belongs to (R)-series 
(6c), by taking i n t o account the r e s u l t s obtained with 4a,b. 
- 922 — 
HETEROCYCLES, Vol. 26, No. 4, 1987 
In each case the major diastereomer could be separated from i t s epimer by chromatography and subse-
quent c r y s t a l l i s a t i o n . The Compounds 6a-c are valuable intermediates i n the synthesis of enantiome-
r i c a l l y pure p i p e r i d i n e d e r i v a t i v e s . This i s best demonstrated by t h e i r transformation to sedamine 
10 , a p i p e r i d i n e a l k a l o i d of the sedamine family, homopipecolic acid Y2 and the phenacylpiperidine 
13 as o u t l i n e d below. Said reactions a l s o enabled us to assign the conf i g u r a t i o n f o r the newly 
created Stereocenter at C-2 i n some cases. 
Scheme 2 
Reduction of the amide 6a with L i A l H ^ (0.5 eq., Et^O: THF= 80:1,1.5 h, -78°C) occurred i n a notably 
s t e r e o s e l e c t i v e manner, y i e l d i n g the alcohol 1^ as the major product along with the minor isomer !B_6 
i n a 91.5: 8.5 r a t i o . The epimer 7 was r e a d i l y separated from 8 by chromatography (83.7% y i e l d ) and 
cleaved to the aminoalcohol 9 6(90.1% y i e l d ; [a] 5 7 8= + 32.0°, c=2.03, CH3OH) using 0.5 M KOH i n 
CĤ OH and heating t o r e f l u x for 18 h. Methylation of 9 (CH20,2.5 eq. NaCNBH^) followed by chromato-
graphy afforded o p t i c a l l y pure (+)-sedamine (j_0) i n 9 3.0 % y i e l d . The ph y s i c a l data of the p i p e r i -
dine a l k a l o i d _1_0 were i n good accord with those of the natural 2S, 8S-(-) -sedamine, except f o r the 
7 8 sign of s p e c i f i c r o t a t i o n [2S, 8S-(-)-sedamine : [aJD= -82.4°, c=5.0, CH3OH); j _ 0 : [ c J D = + 9 2 - 9 ° » 
c=1.0,CH3OH] i n d i c a t i n g that the major product (6a) from the amidoalkylation has 2R-configuration. 
In order t o synthesize homopipecolic acid ( V 2 ) , 7a was subjected to a Baeyer V i l l i g e r o x i d a t i o n 
(3 eq.CF 3C0 3H, 0-20°C, 1h) which afforded the N-protected amino acid _n6(87.6% y i e l d ) . Treatment 
of the amide JM with 1.5 M H^SO^ (4h, 95°C) furnished a f t e r chromatography pure R-(-)-homopipecolic 
a c i d (j_2)in 90.6% y i e l d . The R stereochemistry has been established by a comparison of the s p e c i f i c 
8 9 r o t a t i o n of Y2 ([a] D = -36.9° , c=0.37, H 20) with reported l i t e r a t u r e values (R:[al D = "24°, 
c=0.4, H 20; S:fat] D= +29°, c=1.0, H 20). F i n a l l y 6c was converted to the aminoketone VS6 i n 61.6% 
i s o l a t e d y i e l d by the action of HC1/CH OH (25°C, 72h; [a] = + 9.9°8, c=1.8, CH 0H). 
- 923 -
In order to unequivocally v e r i f y that no racemization had occured during h y d r o l y s i s (6c- J_3 and 
1 1-12) a sample of each J 3 and V2 was treated with (-) -camphanic acid C h l o r i d e . 6c and JH were 
formed each as a Single d i a s t e r e o m e r 1 ^ i n d i c a t i n g that the p i p e r i d i n e d e r i v a t i v e s (J_2 and J_3) were 
v i r t u a l l y enantiomerically pure. 
In summary we have developed a method for the asymmetric amidoalkylation mediated by a c h i r a l 
enamide M) and demonstrated i t s U t i l i t y i n the synthesis of a - s u b s t i t u t e d p i p e r i d i n e s of high 
enantiomeric p u r i t y . Currently we are engaged in further expand the scope of the r e a c t i o n . 
ACKNOWLEDG EMENT 
We are greatly indebted to Prof. F. Eiden f o r generous support. We a l s o thank Dr. S. Jendrzejewski 
for NMR measurements. 
REFERENCES AND FOOTNOTES 
(1) J.D. Morrison, Ed.; "Asymmetric Synthesis"; Academic Press, New York 1984, V o l . 1-5. 
(2) See r e f . 1, Vol. 2 p 243 and V o l . 3 pp 1-341. 
(3) For asymmetric synthesis using c h i r a l acetals, see: J.M. McNamara and Y. K i s h i , J . Am. Chem. 
Soc.,104, 7371(1982); W.S. Johnson, C. Edington, J . D . E l l i o t t , and R. Silvermann, ibid.,106, 7588 
(1984) and references t h e r e i n . See al s o : A. Mori, K. Ishikara, and H. Yamamoto, Tetrahedron L e t t . , 
27, 987 (1986); A. Alexakis, P. Mangeney, and J . F. Normant, ib i d . , 2 6 , 4197 (1985) and references 
t h e r e i n . C h i r a l 1,3-dioxolan-4-ones: S.H. Mashraqui and R. M. Kellogg, J.Org. Chem.,49, 251 3 ( 1984). 
C h i r a l cyanooxazolopiperidine: M. Bonin, J . Royer, D.S. Grierson, and H.P. Husson, Tetrahedron 
Lett.,27, 1569 (1986) and references t h e r e i n . C h i r a l g l y c i n a t e s : P.J. S i n c l a i r , D. Zhai, J . Reiben-
spies, and R.M. Williams, J.Am.Chem. Soc.,108, 1103 (1986). 
(4) For Reviews, see: H.E. Zaugg, Synthesis, 1 984, 85; H.E. Zaugg, i b i d . , 1984, 181 . For a review 
on intramolecular amidoalkylations, see: W. N. Speckamp and H. Hiemstra, Tetrahedron, 41, 4367(1985). 
(5) See the preceding l e t t e r . 
(6) S a t i s f a c t o r y spectroscopic data (1H-NMR, JR, MS) and elemental analyses were obtained f o r the 
Compounds reported i n t h i s paper. 
(7) C. Schöpf, G. Dummer, and W. Wüst, L i e b i g s Ann. Chem., 626,134 (1959). 
(8) Calculated from [od 5 4 6 and [ a ] 5 7 Q . 
(9) T. Wakabayashi and K. Watanabe ( T e i j i n L t d . ) , Jpn Kokai Tokkyo Koho 78103490(1978); Chem. 
Abstr.,90, 87280 w (1979). See a l s o : T. Wakabayashi, K. Watanabe, and Y. Kato, Synthet. Commun., 
7, 239 (1977). 
(10) Determined by HPLC (5c/6c) and 360 MHz 1H-NMR( JM) . A c o n t r o l experiment had revealed that 
the 1H-NMR Signals of V\_ and i t s epimer derived from 5b can c l e a r l y be resolved. 
Received, 22nd December, 1986 


Asymmetric α-amidoalkylation. Synthesis of α-substituted piperidines of high enantiomeric purity

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Asymmetric α-amidoalkylation. Synthesis of α-substituted piperidines of high enantiomeric purity

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