W N Speckamp

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New applications of chiral N-acyliminium precursors
Speckamp, W.N.
Published in:
Pure and  Applied Chemistry
DOI:
10.1351/pac199668030695
Link to publication
Citation for published version (APA):
Speckamp, W. N. (1996). New applications of chiral N-acyliminium precursors. Pure and  Applied Chemistry, 68,
695-698. https://doi.org/10.1351/pac199668030695
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Download date: 01 Jul 2019
Pure & Appl. Chem., Vol. 68, No. 3, pp. 695-698, 1996. 
Printed in Great Britain. 
Q 1996 IUPAC 
New applications of chiral N-acyliminium 
precursors 
W.N. Speckamp 
Laboratory for Organic Chemistry, University of Amsterdam, 
Nieuwe Achtergracht 129,1018 WS Amsterdam, The Netherlands. 
Abstract - The optically pure cis and trans iron-carbonyl complexes of the chiral 
C-5 isopropoxy enelactam 6 react with allyltrimethylsilane under influence of 
BF3.0Et2 through a N-acyliminium intermediate to yield enantiocontrolled 
substitution products. 
Enantioselective introduction of substituents at C-2 of pyrrolidine 1 (fig. 1) is nowadays 
possible by making use of asymmetric deprotonation.1 The electrophilic counterpart, i.e. the 
direct substitution at C-5 of a chiral alkoxylactam 2 sofar has never indicated the formation of 
optically active lactams.2 Only in case of the nitrogen carrying chiral substituents asymmetric 
induction was e~tablished.~ 
ioc 1 
Acid F-[ xo R $.I Nu N 9  0 
2 eow 
Fig. 1 
Numerous studies have been connected with the use of appropriate N-acyliminium intermediates 
derived from chiral pool materials, such as tartaric acid4 threonine5 and malic acid.6 In the latter 
cases it is to be noted that diastereoselective reactions are occurring, the results depending on the 
degree of control exerted by the ring substituent. Thus in case of malic acid the outcome will be 
determined by the type of OX present in 3 (fig. 2), while also the structure and nucleophilic 
character of the incoming substituent have a distinct influence. Conversely if the precursor 4 
could be synthesized in a chiral manner from 3, the type of stereocontrol then would originate 
from the C-5 oxysubstituent in nucleophilic additions to the enelactam resulting in different 
types of N-acyliminium precursors. Finally the direct treatment of 4 under acid conditions 
would result in a structure which due to its pancake format would not be expected to lead to 
xb 0 RO xb- 0 9 0 - N I xo * Acid Nu 1.’ 
D O  RO OQo - Qo - N Acid Nu 
I I @  I 
Racemate J- 4 
CHIRAL COMPLEX 7 d E N A N T I M E R  EXCESS 7 
Fig. 2 
695 
696 W. N. SPECKAMP 
optically pure enantiomers.The effect of the size of the nucleophile is convincingly demonstrated 
in fig. 3. Upon reaction of the PMB substituted diacetate 5 with a series of closely related silyl 
enol ethers the results show a complete addition with the hisubstituted derivatives while the 
less hindered mmethylsilyloxystyrene affords a 12538 cis/trans mixture.7 
AcO cbo I 
PMB 
5 
+ d' 
+ K 
M e O  
TMSOTf 
CHzC12 
-780C-lti 
71 % 
 
____t 
95% 
Fig. 3 
As a chiral precursor for direct introduction of the nucleophile we have selected the enelactam 6, 
the synthesis of which is outlined in fig. 4. Of high value herein is the synthesis of the 
enantiopure trichloroacetate which can be used as the starting material for a number of 
differently N-substituted enelactam derivatives.8 
1) UBH4, THF. -20 OC 
0 2) H 6 0 4  In I-PrOH 
OQC -+ reflux 'Pro i 
1) AcCI, reflux. 1.5 h 
3) AcCI, rellux, 2 h 
m ?  2)NHhTHF 
wooc 
I 
50% H 55% k 
transleis I 4:l 
AczO, pyridine lp#@p; 
______.). 
(CIJCCO)~. DMAP 
ether, - 60 'C + ti O D M A P ( ~ ~ ~ )  0 
6 85% 
bClJCC 'Pro) 
CI 86% 
pure stereoisomer, mp 100-102 OC 
[aID = 16 (c = 0.60, CHCls) 
mp 4849.5 OC 
[ a ] ~  = -149 (c = 0.50, CHCId 
Fig. 4 
The enelactam 6 has been applied in 2 4  cycloadditions9 while also the conjugate addition of 
amines and thiols has been studied.10 Of particular interest is the application as a chiral 
dienophile in the construction of a precursor for the total synthesis of the alkaloid gelsemine.11 
While the approaches outlined do give rise to novel applications of chiral N-acyliminium ions in 
practice one problem still exists. 
How to keep stereocontrol In a plane 
Intermmilacy Q 
0 R N / ~ O  R of achlral I 
Nu 
Lewis Acid xo" 
R I 
(or inversion) B 
Fig. 5 
Direct substitution (fig. 5) of the chiral enelactam 7 has to proceed through the intermediacy of 
achiral 8 and it would be therefore expected that a net control of retenrion or inversion at C-5 
will be impossible. A second obstacle is inherent to the structure of 7 which formally can be 
considered as a N, N diacylamine. Since generation of the cationic intermediate requires the 
participation of the nitrogen lone pair, one of the acyl substituents has to be removed. Although 
chemically this can be done by treatment with an amine the resulting N-H enelactam is not 
suitable to study the desired transformation. Due to instability of the corresponding cation only 
0 1996 IUPAC, Pure and Applied Chemistry 68,695-698 
Applications of chiral N-acyliminium precursors 697 
polymer formation is observed upon treatment with acid. In search for other possibilities to 
eliminate the electronic influence of the second carbonyl substituent we considered the possible 
complex formation with an appropriate metal. (Fig. 6) 
MIA 
chiral complex diastereofacial metal controlled substitution 3 
Fig. 6 
Such a process would obviate the negative influence of a second carbonyl without making the 
system inherently unstable. Although a metal atom would be expected to draw electron density 
out of the ring the overall process could still be beneficial in terms of backdonation. This type of 
metal complex has been studied before12 and it has been established that iron-carbonyl 
complexes show photoelectron spectral3 which clearly indicate a net charge flow into the ring 
through metal-to-ligand backdonation. Upon acid treatment the system then might form a chiral 
complex which after reaction with an appropriate nucleophile and removal of the metal would 
lead to the desired substitution. Of added interest is the fact that the introduction of the 
nucleophile would take place under stereocontrol of the metal ligand moiety, MLn, thus 
effectively promoting the approach from the least hindered side. Formation of the Fe(CO)4 
complex of 6 by treatment with Fe2(CO)9 in ether proceeded smoothly and afforded a mixture 
of cis and trans complexes in the ratio indicated (fig. 7). 
“ . 7 H 0  N-Ac + - 
dPr ( W 4 k  d p r  
cis 
afler 3 h c 5  : > 95 kinetic rat10 
after 18h 33 : 67 thermodynamicratio 
(separable by flash chromatography) 
Fig. 7 
Interestingly, while the cis isomer appeared to be the kinetically preferred product a slow 
isomerization to a 67:33 cishrans mixture was observed upon standing.14 Both isomers were 
readily separated by flash chromatography thus allowing each isomer to be investigated. 
Although we have no definite proof on the mechanism of the Fe2(CO)9 addition it seems likely 
that the preferred cis addition is the result of a weak coordinative influence of the isopropoxy 
function. Having available both Fe(CO)4 complexes separate nucleophilic substitutions could be 
studied. For the cis-isomer inversion at C-5 would be expected since the approach from the least 
hindered side of the intermediate will be determined by the position of the Fe(CO)4 group. By 
the same reasoning the trans-isomer is expected to show retenrim at C-5. 
+ ,pmHJ&o FeACOh(1.0 0qW benzene or ether 
M~ 354OoC,18h 
73% trans 
20 [u15,,,= +368 (c = 0.10, pentane) [a]&= 328 (c = 0.52, penlane) 
Ac 
t a n s  
(Fig. 8) In practice the latter phenomenon was indeed observed upon reaction with 
allyluimethylsilane in presence of BF3.0Et2. In a rather fast reaction a 51% yield of the 
substitution product 9 was obtained after oxidative removal of the iron substituent. According to 
‘H-NMR chiral shift measurements the ee was determined as >95%. On the contrary the cis 
isomer reacted much slower to produce 10 with an ee of 55%. Since we were not able to 
0 1996 IUPAC, Pure and Applied Chemistry 08.695698 
698 W. N. SPECKAMP 
improve on these results by variation of the reaction parameters other N-substituents were 
examined. Therefore the N-tosyl derivative 11 was prepared (fig. 9) in a manner already 
described. 
0 0 
TS Ts TS yellow crystals 
510% trans air stable 
(nd isdatod) u. 70% 
Values in boxes are chemical shifts in ppm, multipllcity in parentheses (250 MHz, CDCIJ). 
Fig. 9 
Quite unexpectedly almost all of the material obtained proved to possess the cis-structure of the 
complex and could be easily purified by crystallization. Most remarkably, however, the cis-N- 
tosyl complex 11 reacted rapidly with allylmmethylsilane to produce a quantitative yield of the 
inverted (fig. 10) substitution product which after work-up and purification afforded the 
enantiopure enelactam 12 in 72% yield. Investigations on the precise role of the N-substituent 
as well as the influence of different types of metal complexes are currently being carried out. 
MeJNO 
BF+OEI (10oqUiV) * *O  
CH&lr. tt, 1 h 
quantitathro 7 s  
Fig. 10 
TS 
-12 
[a10 = 227 
mp 1 47-1 40 OC 
(C = 0.225, CHCIJ) 
crude ~ 9 5 %  ma 
Also the nature of the nucleophile is varied to gain a better insight in this transformation. Results 
on these experiments will be reported elsewhere. 
Acknowledgement: 
The work presented here has been performed by a number of excellent and devoted co-workers 
to whom I wish to express my warmest thanks. Their names are listed in the appropriate 
references. This investigation was supported by the Netherlands Foundation for Chemical 
Research (SON) with financial aid from the Netherlands Organization for the Advancement of 
Pure Research (NWO). 
REFERENCES 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 
10. W.J. Koot, H. Hiemstra, W.N. Speckamp, Tetrahedron Letters 33,7969 (1992). 
11. N.J. Newcombe, Fang Ya, R.J. Vijn, H. Hiemstra, W.N. Speckamp, J.Chem.Soc., 
Chem.Commun., 767 (1994). 
12. D. Enders, B. Jandeleit, G. Ranke, Angew.Chem. 33, 1949 (1994). 
13. H. van Dam, A. Oskam, J.Elecrron Spectros. Relat.Phenom. 16,307 (1979). 
14. W.J. Koot, H. Hiemstra, W.N. Speckamp, J.Chem.Soc., Chem.Comm. 156 (1993). 
15. J.C.P. Hopman, forthcoming Ph.D. Thesis. University of Amsterdam. 
P. Beak, S.T. Kerrick, S. Wu, J. Chu, JAmChemSoc.,  116, 3231 (1994). 
Unreported observations from this laboratory. 
L.E. Burgess, A.I. Meyers, J.Am.Chem.Soc., 113, 9858 (1991) and references cited 
therein. 
B.P. Wijnberg, W.N. Speckamp, Tetrahedron Leners, 1987 (1980). 
A. Zietlow, E. Steckhan, J.Org.Chem., 59,5658 (1994). 
W.J. Koot, R. van Ginkel, M. Kranenburg, H. Hiemstra, S. Louwrier, M.J. Moolenaar, 
W.N. Speckamp, Tetrahedron Letters, 32, 1491 (1991). 
S .  Louwrier, part of the forthcoming Ph.D. Thesis, University of Amsterdam. 
W.J. Koot, Ph.D. Thesis (1993), University of Amsterdam. 
W.J. Koot, H. Hiemstra, W.N. Speckamp, J.Org.Chem. 48, 3445 (1992). 
0 1996 IUPAC, Pure and Applied Chemistry 68,695-698 


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