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Asymmetric PictetЦSpengler Reactions Employing N N-Phthaloyl Amino Acids as Chiral Auxiliary Groups.

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Asymmetric Pictet -Spengler Reactions
Employing N,N-Phthaloyl Amino Acids
as Chiral Auxiliary Groups**
H e r b e r t Waldmann," G u n t h e r Schmidt,
H e n n i n g H e n k e , and Michael B u r k a r d
1
Ti(OnPr),
The Pictet-Spengler reaction is one of the most important
methods in heterocyclic and natural product chemistry.*'] In
particular, it has proven to be a very powerful tool for the
construction of complex alkaloids, for example those belonging
to the tetrahydroisoquinoline and P-carboline classes. Therefore, the development of methods that allow this transformation
to be performed asymmetrically by employing a removable chiral auxiliary group is of great importance to organic synthesis.
However, in only a few cases has this problem been addressed,
and the techniques developed so far either remained restricted to
a special application in a particular total synthesis, or they suffer
from being not generally applicable.[" "I The purpose of
this paper is to report that high levels of stereoselectivity
(diastereomeric ratio can be greater than 99: 1 ) are reached in
Pictet -Spengler reactions employing both aliphatic and aromatic Schiff bases by using N,N-phthaloyl amino acids (Pht
amino acids) as chiral auxiliary groups.
During a research program directed at the use of the readily
available amino acid esters as chiral auxiliary groups,'31 we recently showed that asymmetric steering of the Pictet -Spengler
reaction can be achieved by generating intermediate N-alkyliminium salts derived from amino acid esters.'"] But, because of
the low reactivity of these Schiff base derivatives, only aromatic
aldehydes could be converted into the desired products with
preparatively useful yields. However, chiral nitrogen heterocycles derived from aliphatic aldehydes, which are much more
relevant to the synthesis of alkaloids and their analogs, cannot
be obtained by this method. In addition, the chiral auxiliaries
can only be removed from the resulting N-alkylated Pictet
Spengler adducts by a laborious multistep procedure. We reasoned that these serious limitations might be overcome by the
intermediacy of N-ricjdiminium salts like 3 rather than N-cilkyliminium salts. Because of the electron-withdrawing influence of
the N-acyl group, these electrophiles should be more susceptible
to a nucleophilic attack ofaromatic residues on the C = N bond,
and the resulting Pictet -Spengler adducts would be linked to
the chiral auxiliary by an amide rather than an N-alkyl bond,
thereby allowing for a straightforward removal of the mediator
of chirality.
If the Schiff bases 1, which are derived from tryptamine, are
treated with the N,N-phthaloyl-protected amino acid chlorides
2Is1i n the presence of titanium alkoxides like Ti(OnPr), and
Ti(OiPr), in CH,CI, at room temperature. the desired tetrahydro-/karbolines 4 and 5 are formed i n a smooth reaction
in satishctory yields and with excellent diastereoselectivity
(Fable 1 ) . If imines of aliphatic aldehydes are employed the
~
Prof. Dr. H. Waldinann, Dipl.-Chem. G. Schmidt
lnstitut fur Organische Chemie der Universitit
Richard-Willstdtter-Allee 2. D-7612 Karlvuhe (Germany)
Telefax. Int. code f(721) 6OX-4825
Dr H. Henke, M Burkard
liistitut fur Anorganische Chemie der Univeraitit Karlsruhc
[**I This work
I
Ti(O/Pr), or CH2C12,
RT. 30 min-8 d
Drdicrilrd to Puq&sor Ivnu Ugi
on [lie occasion i$iiis 65th birtiiduy
['I
2
was supported by the Deutsche Forachungsgcnieinrchiift and thc
Fonds der Cheinischen Industrie. We thank Degussa AG for thc donatmn of
inninc acids.
L
J
3
4
5
Table 1. Reaults of the Pictet Spsiigler reactions of I employing N,N-phthaloyl
amino ;icids as chiral auxiliary groups yielding 4 and 5 .
No. 4 R '
R'
Lewis
acid
[r];' [ ]
M.p.
Yield
((.=1,
[C]
[%][a]
247-250
265
30
52
4:5 [b]
CHCI,)
1
2
3
4
5
6
7
X
0
10
11
12
13
Ph
b Ph
b Ph
c Ph
d 4-N02C,H,
e 4-N0,C,H4
f 4-CIC,,H4
f 4-CIC,H,
g Me
h Me
i Et
k Et
1 tPr
a
Me
iPr
rPr
tBu
iPr
rBu
tBU
IBU
tPr
tBU
iPr
rBu
rPr
Ti(OnPr),
Ti(OnPr),
Ti(OiPr),
Ti(OnPr),
Ti(017Pr)~
Ti(OnPr)+
Ti(OirPr),
Ti( OiPr),
Ti(OnPr),
Ti(OtiPr),
Ti(OnPr),
Ti(OiiPr),
Ti(OuPr),
-102[c]
-150
58
60
284
56
2x3
54
250 ~ 2 5 2 44
-209
- 1x5 [d]
-232
-205
29X
-154
-267
300
214
228
60
-131
-194
-111
262
254
84:16
9O:lO
96:4
>Y9:1
%:I4
93:7
89:ll
96:4
31
83:17
66
57
5Y
99
96:4
97:3
95:5
>99:1
[a] Thc yields are based on pure diastereomer 4.All tetrahydro-/i-carbolines 4 were
identified from 250- or 400-MHz ' H N M R spectra (CDCI,) and gave correct ele-
inental nnalyses. [h] Determined from the crude reaction mixture by HPLC.
[c] c = 0.5. [d] c = 0.27.
cyclization is complete within 5 min to 1 h; in the case of aromatic Schiff bases, however, several days are required. Presumably the reaction proceeds by attack of the acid chlorides on
the nitrogen of the C - N double bond to give rise to the N-acyliminium intermediates 3, which then are subject to a cyclization
by attack of the electron-rich nucleophilic indole on the electrophilic carbon of the C = N bond. With aromatic Schiff bases,
the diastereomer ratio increases with increasing steric demand
of the amino acid side chain R 2 (Pht-alanine and Pht-valine are
clearly less favorable auxiliaries than Pht-teut-leucine; Table 1,
compare nos. 1.2, and 4 as well as 5 and 6). The same observation is made for aliphatic Schiff bases if the aliphatic group R 1
is small (for example methyl: Table 1, nos. 9 and 10). However,
with increasing steric demand of R ' this trend may be reversed
(Table 1. nos. 11 and 12) and for R ' = iPr, N,N-Pht-valine is
an excellent auxiliary group, which makes the desired PictetSpengler adduct available in 99 YOyield in diastereomerically
form (Tiible 1. no. 13; the second diastereomer could not be
detected by 400 MHz N M R spectroscopy or by HPLC). The
steric demand of the alkyl groups of the titanium Lewis acids
employed may have ;i marked influence on the diastereoselectivity. Thuh. although high diastereomer ratios can. in general, be
induced with titanium tetra-n-propylate (see, for instance,
Table 1. nos. 4. 6, 10-13). the stereoselectivity in some cases is
more efficient in the presence of titanium tetra-iso-propylate
(Tablc 1 . compare no. 2 with 3 and 7 with 8).
The best results are obtained if the amino acid chlorides 2, the
titanium alkoxide. and the imines I . Lowering the temperature
to -40 C reduces the rate of reaction. but does not improve the
diastereoselectivity. The presence of the phthaloyl protecting
group is important. If 94uorenylmethoxycarbonyl- (Fmoc) or
benqloxycarbonyl (Z)-protected Pht amino acid chlorides are
used. the levels of stereoselectivity are consistently lower. In
addition. V.:Y-phthaloyl amino acid chlorides are not prone to
racemization15' and. in contrast to the Fmoc- or Z analogs, the
Pht-protected Pictet-Spengler adducts 4 and 5 are highly crystalline compounds from which the major isomers 4 are obtained
in analytically and enantiomerically pure form by a single recrystallization (in general from a mixture of ethyl acetate and
hexane o r diethyl ether and hexane). These advantageous physical properties also enabled a rigorous determination of the
absolute configuration of the major diastereomers by crystal
structure analysis of the tetrahydro-/karboline (4d) .Ihi
To explain the high stereoselectivity attained through the
Piclet -Spengler reactions detailed above. we assume that the
reaction proceeds preferentially via transition states A . In A the
titanium atom coordinates to
OR
thecarbonyl oxygen atoms of
the amino acid and the
dral
phthaloyl group. isAn thereby
octahe-
Q'\i:&
'
formed in which the top-side
of the C = N bond is shielded
by a substituent of the activating Lewis acid. This is in accord with a related finding
for TiCI, mediated DielsAlder reactions of r,/&unsaturated proline ester amide~."~
In this arrangement the bulky
A
M
amino acid side chain points
away from the ethylene
bridge between the indole nucleus and the iminium nitrogen;
consequently. unfavorable steric interactions are avoided. Furthermore, by analogy with the configuration of %$-unsaturated
amides.1'1 substituent R' of the C-N double bond and the
amino acid carbonyl function are in an .r-cIs orientation. If these
two groups were in an s - m n s orientation, R 1 would come close
to the %-carbonof the amino acid a situation which for steric
reasons would also be unfavorable. In the 3-indolylethyl-substituted iminium intermediate A. the imine substituent R' is tram
to the ethylene bridge. This is the favored configuration because
a 1.3-interaction between R' and the protons of a CH, group
would develop upon ring closure if R' was cis to the ethylene
Potential involvement of the transition states A also
explains wli) stereoselectivity in the Pictet -Spengler cyclizations is more efficient if a bulkier alkyl residue is present in the
titanium I.ewis acid (for example, i-Pr vs. n-Pr): one of the
diastereotopic faces of the C = N bond is more efficiently
shielded.
From thc Pictet -Spengler adducts 4 the chiral auxiliary can
readily be removed by cleavage of the amide bond with reducing
.
reagents like LiAIH,. The enantiomerically pure tetrahydro-/]carboline 6, for instance, is readily obtained I'rom 4 c by this
straight forward procedure."
In conclusion, N,N-phthaloyl amino acids are the first generally applicable chiral auxiliary groups for the Pictet -Spengler
reaction that efficiently control the stereochemical course of this
important transformation of alkaloid chemistry.
Received: J u n e 311. 1995 [Z 8153 IE]
German version: A I I ~ I ' I IC%mii.
.
1995. 107. 2608 2610
Keywords: amino acids . asymmetric syntheses . chiral
auxiliaries . Pictet -Spengler reactions tetrahydrocarbolines
W. M. Whale?. T. R. Govindachari. U,xmii< RM(~IOI~\.Vol. 6. Wile).. New
York. 19Sl. pp. 151 -206.
a ) C.Bolilmann. R Bohlmann. E G. Rivera. c' Vopcl, M . D. M:iii;indhar. E
Winterfddt. Lich;g.s A i i i i . C'hcm. 1985, 1752 -1763: b) I). I- Comins. M.M.
Badawi. Erru/icdio/i Lprr. 1991, 31. 2995 -2996; c ) R. Aiiianri. D Spitmer.
,411,ycii.. ( ' / w i n 1991, 103. 1373 1374; .AIi,yrll.. Chwl. //ii Ed D i ~ l 1991.
.
1/13.
1320 1321: d) T. Soe. T. Kawate. N Fuhui. M. P.;akag,ii\a. 7i,rw/rc,i/voii Lprr.
1995. 36. 1857 1860.
RCWW: H . Waldmann. . S v i k r r 1995. 133 141
H. Waldmaiin. G . Schmidt. hl Jaiircn. J . Ceh. E w d i d r m i 1994. .W. 11x65
11xx4.
n) J. Sheehan. D. U: Chapman. R . W. Roth. .I Am. </iwii .So( 1952. 74, 3 8 2 2 ~
3x25: b) C. R. McArthur. P. M . Worater. A . U . Okoii. .SWI/I C o i m i . 1983. 13.
311 318.
Ci-ystal structure detrrinination of 4d ( C , o H 2 < , N 4 0 , iii~iicentros)'iniiietric.
~
monoclinic, P 2 , (no.4). LI =1201.3(1). A = 987.4(1). = 1 2 3 8 . l ( l ) p m . / I =
114.48(2). Z = 3. pLrlid=1.298(I)gcm-'. T = - 85 ( . 32% unique reflcctions, [,):/I scan, (Stoe four-circle diffractoineter. :~rapliitrmonochromator.
Mo,, radiation. 20,,,,= 55 ). lcarnt profiles lit The \tructure \+';is d \ e d by
dircct methods (SHELXS-X6), and refined o n t;:data ISHELXL-03) with ;LIP
isotropic temperature factors for C . N and 0 . All H a t o i n s werc 1oc;rlized by a
difrerence Fourier \ynthesis. R , = 0.030 for 17131.;,> 4a/:,t and II /<, = 0.0741.
431 structure parameters. T h e absolute coiiligui-atioii 01' 4 d wiis
sible on the basis t h a t the chirality of thcvaline dcriwd c l i i r a l auxi
k n w c n . Further details of !lie crystal structure dcteriniii.i~iinim a y be obtaincd
1i.oni the Fnchinforma~ionsrentruinKarlsruhc. D-76344 EgFenstrln-l,s[,poldshafen (Germany). o n quoting thc deposirory numbci- C'SD-59OXI
H. Waldmann. LII,/J@A i l t i . C h c n i . 1990. 671 680. and I6 . [?];' = - 4.3 (<,=1.0. CHCI,): m p . 186 C : publi+
-4.4 ( < = I 0. CHCIi): in.['. 167 C 141. b) ( R ) - 6 . [ 7 J i 5 = t4.37 ( L =l.lY.
EtOH). 27% W ; ( S ) - 6 : [?If'= -16.4 ( c = 0.38. E t O H ) (M.Nnkagdua. 7.
Knwate. T. Kakikaua. H. Yhiada. T. M;itsui. T. Hinv. / i w d i d i m 1993. 49.
1739 1748)
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