Efficient asymmetric synthesis of Reissert compounds

Article abstract of DOI:10.1055/s-2003-37118

Asymmetric synthesis of Reissert compounds 5, 12 was achieved using chiral acyl halides such as amino acid fluorides or (-)-(R)-menthylchloroformate and TMSCN. These are the first cases of asymmetric synthesis of unsubstituted isoquinoline-derived Reisser

Full text of DOI:10.1055/s-2003-37118

LETTER
337
Efficient Asymmetric Synthesis of Reissert Compounds
Efficient
Asymme
x
tric Synthesis
a
of Reisser
n
t
Compound
a
s
Sieck,a Steffen Schaller,a Stefan Grimme,b Jürgen Liebscher*a
a
Institut für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
b
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstraße 40, 48149 Münster, Germany
Received 25 November 2002
Dedicated to Erhard Matthes on the occasion of his 80th birthday.
tosylamino group at position 1 of the isoquinoline ring. In-
terestingly, N-arylsulfonylamino acid chlorides could be
used by Ohsawa et al. for asymmetric 1,2-addition of
silylenol ethers or allylstannane to isoquinolines.5 We sur-
Abstract: Asymmetric synthesis of Reissert compounds 5, 12 was
achieved using chiral acyl halides such as amino acid fluorides or
(–)-(R)-menthylchloroformate and TMSCN. These are the first
cases of asymmetric synthesis of unsubstituted isoquinoline-de-
rived Reissert compounds with high stereoselectivities. The chiral mised that less acidifying protective groups at the amino
Reissert compound 12 could be alkylated in position 1 affording
acid fluoride 2 would prevent the intramolecular attack af-
1-substituted Reissert compound 13 highly stereoselectively. The
fording 4 and thus could open the way to the addition of
products are potential starting materials for unnatural amino acids
cyanide to obtain the anticipated Reissert compounds
and alkaloid analogues.
such as 5.
Key words: Reissert compounds, asymmetric synthesis, isoquinol-
Indeed, treatment of Z- or FMOC-protected amino acid
fluorides 2 (PG = Z or FMOC) with isoquinoline, AlCl3
and TMSCN according to the procedure previously ap-
plied for the synthesis of 4 afforded Reissert compounds
5 in a stereoselective manner (Scheme 1, Table 1).6,7
Proof for the configuration of these products could be pro-
vided by stepwise transformation of 5a into the FMOC-
protected tetrahydroisoquinoline-1-carboxylic acid 8,
which is commercially available and has been obtained by
separation of the racemate so far.8 The transformation of
5a into 8 (Scheme 1) includes basic hydrolysis to the
amide 6, catalytic hydrogenation of the enamine moiety to
7, acid hydrolysis of both, the peptide and the amide
group, and introduction of the FMOC protective group.
From the configuration of products 5 it can be deduced
that the attack of the cyanide is likely to occur via the con-
formation of N-acyliminium salt 3 shown in Figure 1.
ines, amino acid fluorides, menthylchloroformate
Reissert compounds formed by addition of cyanide in the
presence of acyl chlorides to the C-N double bond of iso-
quinolines, quinolines or pyridines via intermediate N-
acyliminium salts have found wide synthetic application.1
Their α-acylamino nitrile moiety can be hydrolysed to
cyclic amino acids, they can be alkylated in position 1 and
were used in ring annelations affording alkaloid related
structures. It was just recently that asymmetric synthesis
of Reissert compounds was developed. Thus Shibasaki et
al. reported a catalytic version using achiral acyl chlorides
and chiral Lewis acids derived from BINOL.2 Although
high asymmetric induction could be achieved with quino-
lines and with 1-substituted isoquinolines the method
revealed drawbacks with respect to isoquinolines.
3-Methyl-isoquinoline gave just an ee of 71% and even
less satisfactory results were obtained with isoquinoline
itself.3 Further 1-alkylation of such Reissert compounds
obtained by asymmetric catalysis would undoubtly result
in racemisation because the deprotonated intermediates
are not chiral. Thus, the problem of satisfactory asymmet-
ric synthesis of Reissert compounds of isoquinolines has
not yet been solved.
We further applied commercially available (–)-(R)-meth-
ylchloroformate 10 and its enantiomer in the asymmetric
Table 1 Reissert Compounds 5, 12 and Methylation Product 13
Product
5a
R or R1
Me
PG
Yielda (%) drb
Z
89c
44
47
51
98
96
87
>95:5
Our prior attempts to the asymmetric synthesis of Reissert
compounds using a-tosylaminoacyl fluorides 2 (PG = Ts)
of natural a-amino acids as chiral inducer in the presence
of anhydrous AlCl3 and TMSCN provided dihydroimid-
azoisoquinolones 4 rather than the anticipated cyano com-
pounds 5.4 Obviously, the N-acylisoquinolinium salts 3
primarily formed did not add cyanide but cyclised by in-
tramolecular nucleophilic attack of the deprotonated
5b
Me
FMOC
FMOC
Z
71:29
70:30
82:18
>95:5
>95:5
<95:5
5c
i-Pr
CH2Ph
H
5d
12a
12b
13
Br
H
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2003,0,02,0337,0340,ftx,en;G32302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
a Isolated yields after chromatography, crude yields >90%.
b Stereoisomers separable by column chromatography.
c Crude yield.

338
O. Sieck et al.
LETTER
R1
N
NHPG
R
NHPG
R
AlCl3
TMSCN
1
N
+
N+
(R1 = H)
(PG = Z or
3
NHPG
CN
O
FMOC)
O
5a-d
F
R
(PG = Ts)
O
2
H2O2/NH4OHcat
(PG = Z)
NHZ
R
N
O
N
H
N
O
NH2
Ts
R
O
6
4
Pd/H2/AcOH/MeOH
1. aq.HCl,refl
2. FMOC-Cl
NHZ
R
N
N
FMOC
O
NH2
CO2H
O
8
7
Scheme 1
TMSCN at –78 °C. The desired Reissert compounds 12
were obtained in excellent yields and stereoselectivities
(dr >95%, Table 1).6,10
The configuration of 12 was deduced by comparison of
experimental and theoretical optical rotation (OR). Re-
cently, it has been shown11 that reliable theoretical predic-
tions for the OR of large chiral molecules can be obtained
by time-dependent density functional response theory
(TDDFT). According to our computations,12 5a has an
[a]D of –158 which is in good agreement with the experi-
mental value of –118.7 demonstrating the reliability of
our theoretical approach. Applying the same treatment to
12a gives a [a]D of –392 and –437 for two different con-
formers (rotation around C-N-bond). The measured value
of 12a has the same sign (–59.6). On the other hand, the
1-(R) epimer of 12a gives a calculated α-value of +503.
These results show that the sign of the OR is mainly deter-
mined by the configuration at position 1 of the dihydroiso-
quinoline ring and give evidence for the configuration of
12a.
Figure 1 MM2-Optimized structure of N-acylisoquinolinium salt 3
(R = Me, PG = Z) attacked by TMSCN
synthesis of Reissert compounds (Scheme 2). (8-Phenyl-
menthyl)-chloroformate was successfully used in asym-
metric 1,2-addition of Grignard reagents to isoquinoline
via intermediate N-acyliminium salts by Comins et al.9
This chloroformate as well as 10 were also useful in anal-
ogous Grignard reactions in the pyridine series.9
The chiral menthylcarbonyl substituent in the Reissert
compounds 12 should further allow diastereoselective in-
troduction of alkyl substituents in position 1 by deproto-
nation followed by alkylation with alkyl halides. Indeed,
treatment of 12a with LDA and methyl iodide gave the
anticipated alkylation product 13 in excellent yield and
stereoselectivity (Scheme 2). It has to be mentioned that
the reaction of 1-methylisoquinoline with amino acyl
Our investigations revealed that reaction of isoquinolines
9 with 10 and AlCl3 in dichloromethane or THF at –40 °C
gave the corresponding iminium salts 11, which could be
isolated, or, more conveniently, were directly treated with
Synlett 2003, No. 3, 337–340 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Asymmetric Synthesis of Reissert Compounds
339
R1
R1
AlCl3
+
i-Pr
i-Pr
N
–40 °C
N+
O
Cl
O
9
10
O
O
11
TMSCN
–78 °C
R1
R1
1. LDA
2. MeI
i-Pr
i-Pr
N
O
N
O
CN
O
CN
13
O
12a,b
Scheme 2
fluorides and TMSCN as an alternative way to Reissert
compounds with alkyl substituents in position 1 failed.
This fact underlines the importance of the alkylation
method resulting in 13. In addition, such 1-substitued iso-
quinoline starting materials are not readily available. Thus
it is very convenient to start with the unsubstituted iso-
quinoline and to introduce both, the cyano group and the
alkyl rest in stereoselective fashion.
References
(1) (a) Sriven, E. F. V. In Comprehensive Heterocyclic
Chemistry, Vol. 2; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 165. (b) Popp, F. D. In
Advances in Heterocyclic Chemistry, Vol. 9; Katritzky, A.
R., Ed.; Academic Press: London, 1968, 1.
(2) (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2000, 122, 6327. (b) Funabashi, K.;
Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001,
123, 10784.
(3) Funabashi, K.; Takamura, M.; Kanai, M.; Shibasaki, M.
Abstract of Papers, 18th International Congress of
Heterocyclic Chemistry; ICHC: Yokohama, 2001, ; Abstract
number 30-PO-56: 203.
(4) Surygina, O.; Ehwald, M.; Liebscher, J. Tetrahedron Lett.
2000, 41, 5479.
(5) Itoh, T.; Nagata, K.; Miyazaki, M.; Kameoka, K.; Ohsawa,
A. Tetrahedron 2001, 57, 8827.
(6) Liebscher, J.; Surygina, O. presented at ICOS, Christchurch,
New-Zealand, 2002.
Ongoing investigations of the synthetic utility of menthyl-
chloroformate 10 in other asymmetric 1,2-additions to
isoquinolines have given first promising results with
Grignard reactions and organostannanes as well as with
aldehydes.
In summary, we have developed a straightforward asym-
metric route to Reissert compounds using chiral acyl ha-
lides. The achieved stereoselectivities are high and 1-
unsubstituted isoquinoline gives excellent results. Prod-
ucts similar to 8, 12, 13 but with opposite configuration at
position 1 of the isoquinoline ring should also be accessi-
ble by our method using the other enantiomer of chiral
acyl halides 2 and 10. The latter is commercially available
too.
(7) Reissert Compound 5a: Anhyd AlCl3 (30 mg, 0.2 mmol)
was added to a solution of (S)-N-cbz-alanoyl fluoride (500
mg, 2.22 mmol) in anhyd CH2Cl2 (50 mL) at –40 °C. A
solution of isoquinoline (300 mg, 2.32 mmol) in anhyd
CH2Cl2 (10 mL) was added at –40 °C over a period of 30
min. After stirring at this temperature for 2 h, the
temperature was lowered to –78 °C and a solution of
TMSCN (230 mg, 2.32 mmol) in anhyd CH2Cl2 (10 mL) was
added at this temperature over a period of 1 h. After 4 h
stirring at –78 °C and combining with ice water (100 mL) the
mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with sat. aq NH4Cl
and 5% aq NaHCO3, dried (MgSO4) and concentrated under
vacuum. Yield 830 mg (93%). Further purification by flash
chromatography (CH2Cl2–MeOH) is possible but causes
decomposition of a part of the product. [α] D20 –118.7 (c 1,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.40 (d, J = 7.16
Hz, 3 H, CH3), 4.72 (q, J = 7.16 Hz, 1 H, CH3CH), 5.00 (s, 2
H, CH2), 6.06 (d, J = 7.54 Hz, 1 H, CHCH-N), 6.57 (s, 1 H,
CH-CN), 7.11 (d, J = 7.54 Hz, 1 H, CHCH-N), 7.20 (m, 1 H,
Since most of the optically active products 5, 8, 12, 13 ei-
ther represent precursors for bridged chiral a-amino acids,
which are interesting building blocks for peptidomimetics
or are promising starting materials for new alkaloid ana-
logues we presently investigate the scope of the 1,2-addi-
tion to other isoquinolines and other heterocycles at one
side and synthetic transformations of the products on the
other side.
Acknowledgement
We gratefully acknowledge financial support by the Fonds der
Chemischen Industrie.
NH), 7.25 (m, 5 H, CHar), 7.32–7.27 (m, 4 H, CHar). 13
C
Synlett 2003, No. 3, 337–340 ISSN 0936-5214 © Thieme Stuttgart · New York

340
O. Sieck et al.
LETTER
(12) All quantum chemical calculations have been performed
NMR (75 MHz, CDCl3): δ = 18.3 (CH3), 43.7 (CH), 46.9
(CH), 67.1 (CH2), 112.2 (CH), 116.1 (CN), 124.3 (Cq), 126.1
(CH), 126.7 (CH), 128.0 (CH), 128.2 (CH), 128.2 (CH),
128.4 (CH), 128.5 (CH), 128.8 (CH), 129.4 (Cq), 130.2
(CH), 151.8 (CO), 170.7 (CO). HRMS calcd for
with the TURBOMOLE suite of programs:
(a) TURBOMOLE (Vers. 5.5): Ahlrichs, R.; Bär, M.; Baron,
H.-P.; Bauernschmitt, R.; Böcker, S.; Ehrig, M.; Eichkorn,
K.; Elliott, S.; Furche, F.; Hase, F.; Häser, M.; Horn, H.;
Huber, C.; Huniar, U.; Kattannek, M.; Kölmel, C.; Kollwitz,
M.; May, K.; Ochsenfeld, C.; Öhm, H.; Schäfer, A.;
Schneider, U. Treutler, O.; von Arnim, M.; Weigend, F.;
Weis, P.; Weiss, H. Universität Karlsruhe 2002. The
structures of 5 (Ph substituent replaced by a methyl group)
and 12 have been fully optimised at the density functional
(DFT) level employing the BP86 functional (b), a Gaussian
AO basis of valence-double-zeta quality including
polarisation functions (SVP) (c)and the RI-approximation
for the two-electron integrals (d). The structures have been
used in subsequent calculations of the frequency-dependent
optical rotatory dispersion ([α]) at the sodium-D-line
wavelength. These calculations have been performed in the
framework of time-dependent DFT (e)as described in detail
in (f). In the TDDFT approach the SVP basis sets augmented
with diffuse basis functions (C, O: [1s1p1d], H: [1s1p]) have
been used. (b) Becke, A. D. Phys. Rev. A. 1988, 38, 3098.
(c) Perdew, J. P. Phys. Rev. B 1986, 33, 8822. (d) Schäfer,
A.; Horn, H.; Ahlrichs, R. J. Chem. Phys. 1992, 97, 2571.
(e) Eichkorn, K.; Treutler, O.; Öhm, H.; Häser, M.; Ahlrichs,
R. Chem. Phys. Lett. 1995, 240, 283. (f) Bauernschmitt, R.;
Ahlrichs, R. Chem. Phys. Lett. 1996, 256, 454. (g)Grimme,
S.; Furche, F.; Ahlrichs, R. Chem. Phys. Lett. 2002, 361,
321.
C21H19N3O3: 361.1426. Found: 361.1420.
(8) Observed [α]D20 +27.4 (c 1.05, Et2O), reference sample
provided from Catalogue Special amino acids, building
blocks of Neosystem groupe SNPE, Strasbourg, France:
[α]D20 25.8 (c 1, DMF)
(9) (a) Comins, D. L.; Badawi, M. M. Heterocycles 1991, 32,
1869. (b) Comins, D. L.; Joseph, S. P.; Goehring, R. R. J.
Am. Chem. Soc. 1994, 116, 4719. (c) Comins, D. L.;
Goehring, R. R.; Foseph, S. P.; O’Connor, S. J. Org. Chem.
1990, 55, 2574.
(10) Preparation of Reissert Compounds 12: The isoquinoline
9 (2.0 mmol) dissolved in CH2Cl2 (50 mL) was slowly added
to a solution of (–)-(R)-menthylchloroformate (2.2 mmol)
and AlCl3 (20 mol%) in CH2Cl2 (20 mL) under argon at
–40 °C. After 30 min the yellow solution was cooled to
–78 °C and a solution of TMSCN (2.0 mmol) in CH2Cl2
(1 mL) was slowly added. After stirring for 3 h, the
colourless solution was brought to r.t. and poured onto ice/
water. The organic phases were separated, dried over
MgSO4 and concentrated. Crude products could be purified
by column chromatography (silica, dichloromethane). 12a:
[α]D20 –59.6 (c 1, CH2Cl2).
(11) (a) Grimme, S. Chem. Phys. Lett. 2001, 339, 380.
(b) Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch,
M. J. J. Phys. Chem. A 2001, 105, 5356.
Synlett 2003, No. 3, 337–340 ISSN 0936-5214 © Thieme Stuttgart · New York