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Highly Enantioselective Alkylation of Tetrahydroisoquinolines via a Valine Chiral Auxiliary; Asymmetric Synthesis of (S)-Isoquinoline Alkaloids.

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Highly Enantioselective Alkylation of
Tetrahydroisoquinolines via a Valine Chiral
Auxiliary; Asymmetric Synthesis of (9-Isoquinoline
Alkaloids
By A . I . Meyers*, Michael Boes, and Daniel A . Dickman
The utilization of natural amino acids as a source of chirality for the preparation of various enantiomerically enriched compounds has been reviewed recently"]. We have
reported that tetrahydroisoquinolines, via their N-iminomethyl derivatives (i.e. as formamidine derivatives), are
metalated and alkylated to give l-alkyltetrahydroisoquinolines in good
while enantioselective alkylations via chiral formamidines provide these products in
high enantiomeric excessE4].These enantioselective alkylations were performed using the disilyl ethers of (1S,2S)(+)-2-amino-l-phenyl-1,3-propanediol,whose availability
and stability posed some technical problems. We now report that the tert-butyl ether 8d of valinol 8a can not only
be conveniently prepared, but also leads to higher enantioselectivity than the propanediol derivative when transformed into the formamidine 9. By simple exchange between the isoquinolines 1 or 2 and 9, the chiral formamidines 3a or 3b are obtained in 70-90% yield'']. Metalation
with lithium diisopropylamide (for 3a) and tert-butyllithium (for 3b) gave the lithiated formamidines, which
were alkylated with alkyl halides and then hydrazinolyzed
to remove the iminomethyl group@'.The high efficiency of
this process is outlined in Table 1. The enantiomeric excesses of 4 were determined by chiral-column HPLC analysis, as developed by Pirkle, and applied to chiral N-heterocycles and other amine~[~.*I.
The optical rotations in Table
1 were obtained on purified 4. The amines were released
from the recrystallized hydrochlorides 4 .HCl, converted
into N-(a-naphthoyl)amides, and resubjected to HPLC
analysis. These derivatives showed > 99% enantiomeric
2, R = M e 0
purity, and thus the rotations are for pure materials. Clearly, recrystallization of the hydrochlorides increased the optical purity of 4.
Several naturally occurring isoquinoline alkaloids were
prepared using this method. Thus -)-salsolidine 4ff9]was
formed from 3b and Me1 (Table 1), whereas (-))-norcoralydine 6 ([aID-273, c = 1.17, CHCl,) was obtained in
98.5% ee by cyclizing 4g (from 3b and dimethoxybenzyl
bromide) with formaldehyde and 2~ HCl (reflux, 30
min)"''. The alkaloid (S)-( )-homolaudanosine 7 , recently
isolated["], was readily prepared from 3b and dimethoxyphenethyl iodide to give the corresponding l-substituted isoquinoline, which was N-methylated (46Y0, ethyl
formate, LiAlH,) to the natural material [(aID10.4", c=0.2,
+
Table 1. Synthesis of (S)-l-alkyl-I.2,3,4-tetrahydroisoquinolines4 [6].
Educt
[a1
R'X
3a
3a
3a
3a
3a
3b
3b
3b
Me1
4a
nBuI
4b
4c
AllylBr
PhCH2CI
4d
4e
PhCH2CH2Br
4f
Me1
4g
3,4-(Me0)2PhCHZBr
3,4-(Me0)2PhCH2CH21 4h
Prod- Yield
uct
[Yo][b]
50
56
63
66
67
61
75
75
[all,
[c]
-71.3"
-78.4"
-83.1"
-62.2'
-23.5"
-56.5'
[fI
[fI
ee
[W[dl
(0.64)
(0.96)
(0.61)
(1.24)
(5.71)
(4.15) [el
99
96
96
98
93
95
99
95
[a] 3a was metalated with 1.05 equiv. LiN(iPr)2 in THF at -78°C; 3b was
metalated with 1.1 equiv. tBuLi (2.3M in THF). [b] Based on overall yield for
3 - 4 . [c] Based on amine released from hydrochloride salts after recrystallization. The values reflect optical purities >99%, as determined by chiral
HPLC analyses of the N-(a-naphthoy1)amides. [d] Determined by chiral
HPLC analyses of the N-(a-naphthoy1)amides from products obtained by
metalation-alkylation before purification of hydrochloride salts. [fI In EtOH;
cf. [9]. [fl Not determined since 4g and 4b were carried forward to 6 and 7 ,
respectively. Enantiomeric excess was determined through the N-(a-naphthoy1)amides and comparison with the rotation values of the natural products [lo, 111.
4
3a, R-H
3b, R=MeO
@OMe
[*] Prof. Dr. A. 1. Meyers, Dr. M. Boes, D. A. Dickman
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
458
0 Verlag Chemie GmbH, 0.6940 Weinheim, 1984
CHCl,). Finally, the benzoquinolizidine 5 , a degradation
product of securine, was prepared by treatment of 3a with
l-bromo-4-chlorobutane, which cyclized to 5 concurrently
0570-0833/84/0606-0458 $02.50/0
Airgew. Chem Int. Ed. Engl. 23 (1984) No. 6
with hydrazinolysis (50-60%, [a], -206", c=O.O17, pyridine, 93-95% ee)"'].
The asymmetric synthesis described here provides the
(S)-enantiomer of all the products obtained, as indicated
by comparison of the absolute configuration of the natural
isoquinolines, and should provide ready access to a wide
variety of enantiomerically pure isoquinoline alkaloids.
Received: March 6, 1984 [Z 745 IE]
German version: Angew. Chem. 96 (1984) 448
[I] Review: K. Drauz, A. Kleeman, J. Martens, Angew. Chem. 94 (1982)
590; Angew. Chem. Int. Ed. Engl. 21 (1982) 584.
[2] A. I. Meyers, S . Hellring, W. ten Hoeve, Tetrahedron Lett. 22 (1981)
5115.
see D.
131 For other useful approaches to I-alkyltetrahydroisoquinolines,
Seebach, J.-J. Lohman, M. A. Syfrig, M. Yoshifuji, Tetrahedron 39
(1983) 1963, and references cited therein.
[4] A. 1. Meyers, L. M. Fuentes, J . Am. Chem. SOC.105 (1983) 117.
[5] Procedure for 9 and 3: Valinol 8a was treated with excess ethyl formate
(reflux, 3 h) and concentrated to afford crude 8b, which was stirred with
excess isobutene ( O T, dioxane, trace of HiSO4, 3 equiv. BF,. OEtz) for
3 h and gave, after kugelrohr distillation, the ether 8c (92%, [a]:: - 55.7,
c = 1.08, tetrahydrofuran (THF)). Hydrolysis of 8c with 1 : 1 of 50%
KOH ethanol (reflux, 4 h) gave the crude amine 8d, which was dried
prior to addition of 1.1 equiv. Me,NCH(OMe),, and heated at 50" for
12 h. Concentration and kugelrohr distillation (7O0C/O.03 torr) gave 9
(80% [a]:: - 15.9", c=0.98, THF). 3a and 3b were formed by heating 1
or 2 with 10-50% excess 9 in toluene for 48 h and concentrating the
solution. The residue was first chromatographed (silica gel, 5% Et,Nhexane) and then distilled (kugelrohr) to give 3a and 3b as oils. Correct
elemental and spectral analyses were obtained; [alD -3.96, c= 1.06,
THF, and -30.3, c=2.7, CHCI,, respectively.
[6] Procedure for 4 : A 0.03 M solution of 3 in THF was lithiated at -78°C.
The deep red solution was cooled to - 100°C and the alkyl halide added. After 30 min the reaction was quenched in CHiC12-H20, and the
organic layer dried (K2C03) and concentrated. The residue was dissolved in 60% aqueous ethanol (3 mL/mmol) and 3-5 equiv. hydrazine
and 3-5 equiv. acetic acid added. After being stirred at 25°C or refluxed overnight, the mixture was quenched in CH2Clz-H20. The organic layer was dried (K2C03), concentrated, and distilled (kugelrohr).
For ee-determinations, the N-(a-naphthoy1)amides of 4 were prepared
and analyzed by HPLC 171.
[7] A. 1. Meyers, L. M. Fuentes, Y. Kubota, Tetrahedron 40 (1984) 1361.
[8] W. H. Pirkle, C. J. Welsh, J . Org. Chem. 49 (1984) 138; W. H. Pirkle, C.
J. Welsh, G. S. Mohler. A . 0. Meyers, L. M . Fuentes, J . Org. Chem., in
press.
-59.5
[9] A. R. Battersby, T. P. Edwards, J. Chem. Soc. 1960, 1214; [a]:
(c=4.39, EtOH).
[lo] H. Carrodi, E. Hardegger, Helu. Chem. Acra 39 (1956) 127, reports [alD
-277 (c= 1.0, CHCI,).
[Ill A. J. Aladesamm, C. J. Kelley, J. D. Leary, J. Nor. Prod. 46 (1983) 127;
[a10 11.0 (c=0.21, CHCII).
[I21 Z . Horii, M. Ikeda, Y. Yamawaki, Y. Tamura, S. Saito, K. Kodera, Tetrahedron 19 (1963) 210; [a12 -222 (c=0.022, pyridine).
First Evidence for an
Intermediate Nitri1o-k5-phosphane >PEN**
By Ghislaine Sicard, Antoine Baceiredo, Guy Bertrand*,
and Jean-Pierre Majoral*
During the last twenty years, one of the most fascinating
areas in the chemistry of the heavier main group elements
has been the synthesis and reactivity of pn-pn multiply
bonded compounds"'. Whereas a number of investigations
have been devoted to double bonded derivatives, in con-
trast, only a few reports have appeared on compounds
possessing a triple bond between elements of the first and
the second rows of the periodic table: some phosphaalkynes A["], the trifluoroethylidynesulfur trifluoride BLIq,
and only one transient h5-phosphaacetylene C['].
R-C=P
A
Ph2P=C-SiMes
C
F~C-CESF~
B
Recently, ab initio effective potential calculations indicated that the structure of singlet h3-phosphinonitrene
H'P-N is better formulated as a nitrilo-h5-phosphane
HZPGN due to delocalization of the lone pairs
n,(P)+p,(N)
and n,(N)-+d,(P)[31. These findings
prompted us to investigate the possibility of generating a
"h3-phosphinonitrene-nitrilo-h5-phosphane"
by photolysis of an azidophosphane.
We chose to study the photochemical behavior of azidobis(diisopropy1amino)phosphane lL4]
in order 1) to prevent
Staudinger reactions by steric effectsL5],and 2) to avoid formation of a tricoordinated h5-phosphane R2N-P(=NR),'"]
by using poor migrating groups.
McOH
-
_ j
2
( 1 <2 N ) 2 P- N I I
I
OMe
MciNIl
-
-+
(KAN)~P-NH
3
I
NIMez
-MclSiCI
(R2N)p-N-SiMe3
I
4
(N2N)ZP-0
5
c1
1
1I2O
-
I
NHz
I'hN=C=O
~
R
-+
(RZN)zP-~N-Ph
I
6
N-C-O
= iPr
1 was photolyzed at room temperature in benzene at
A= 300 nm"] in the presence of a stoichiometric amount of
trapping agent AX. Products 2 to 6 were obtained in near
quantitative yield[*].
It seems reasonable to postulate that compounds 2 to 5
result from 1,2-addition of the trapping agent AX to the
phosphorus-nitrogen triple bond of an intermediate
bis(diisopropylamino)nitrilo-h5-phosphane 7. The diamino(imino)isocyanato-h5-phosphane 6 probably arises from
[2 + 21-cycloaddition of phenyl isocyanate to 7 followed by
ring opening of the resulting strained cyclic adduct 8 .
[*] Dr. G. Bertrand, G. Sicard, A. Baceiredo
Laboratoire des Organomktalliques, ERA 829
Universite Paul Sabatier
118, route de Narbonne, F-31062 Toulouse ckdex (France)
Dr. J. P. Majoral
Laboratoire des HCtCrocycles du Phosphore et de I'Azote, ERA 926
Universite Paul Sabatier
118, route de Narbonne, F-31062 Toulouse cCdex (France)
[**I This work was supported by CNRS. Dr. G. Trinquier is thanked for
helpful discussions.
Angew. Chem. Int. Ed. Engl. 23 (1984) No. 6
2 - 5
+ 6
L
H
= iPr
J
8
1,l-Adducts of type 9 were not observed, and we therefore note that they cannot be the precursors of products 2
0 Verlag Chemie GmbH. 0-6940 Weinheim, 1984
0570-0833/84/0606-0459 $02.50/0
459
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chiral, asymmetric, synthesis, isoquinolines, tetrahydroisoquinoline, alkaloid, alkylation, enantioselectivity, auxiliaren, via, highly, valine
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