Nucleophilic addition of organometallic reagents to cinchona alkaloids: Simple access to diverse architectures

Article abstract of DOI:10.1002/anie.200701341

(Chemical Equation Presented) Aminal pharm: Grignard reagents undergo a surprising nucleophilic aromatic addition reaction to cinchona alkaloids to stereoselectively produce cyclic aminals. Structurally diverse alkaloid derivatives with rigid cores that b

Full text of DOI:10.1002/anie.200701341

Communications
DOI: 10.1002/anie.200701341
Synthetic Methods
Nucleophilic Addition of Organometallic Reagents to Cinchona
Alkaloids: Simple Access to Diverse Architectures**
Lukas Hintermann,* Marco Schmitz, and Ulli Englert
Cinchona alkaloids, with their fascinating structures and long-
standing medicinal tradition, continue to attract the attention
of organic chemists.[1] These compounds have played a
prominent role in the study of stereochemistry[2] and the
development of asymmetric catalysis.[3,4] Modification of the
structure of the catalyst is a key factor when optimizing and
fine-tuning the performance of a catalytic reaction. Modifi-
cations of cinchona alkaloids are mostly confined to a few
reactive positions (Scheme 1),[3a] but changes to the carbon
reveal is the formal addition product of C6H6 to the alkaloid.
The structure 4’-Ph-QNA (Scheme 2)[8] is in line with these
observations, and was further confirmed by X-ray crystallo-
graphic analysis (Figure 1). This structure shows that a
conjugate addition of the organometallic reagent to the
heteroaromatic core and ring closure to an aminal had taken
place.
Scheme 2. The reaction of quinine with a Grignard reagent.
Scheme 1. Cinchona alkaloids and typical sites of modification.
skeleton tend to be laborious.[1c,5,6] We now describe a simple
and surprising derivatization of the core of cinchona alkaloids
by the stereoselective 1’,4’-nucleophilic aromatic addition of
Grignard reagents. Taken together with the complementary
1’,2’-addition of organolithium reagents,[7] core-modified
cinchona alkaloid derivatives with rigid and tunable struc-
tures are readily available; such compounds are of interest as
potential catalysts and supramolecular building blocks.
The reaction of quinine with an excess of phenylmagne-
sium chloride in toluene results what spectroscopic data
Figure 1. X-ray crystallographic structure determination of two
aminals: a) 4’-Ph-QNA and b) 4’-iPr-CDA.[8,10]
Cinchona alkaloid derivatives with extended rigid carbon
frameworks incorporating reactive amine functional groups
should be interesting candidates for applications as structur-
ally tunable chiral catalysts, provided their synthesis is
sufficiently general; which is indeed the case here: All four
major cinchona alkaloids and a dihydro derivative react with
Grignard reagents to give aminals as single diastereoisomers
in satisfactory yields (Table 1).[9] Aryl Grignard reagents with
either electron-donating or -accepting groups were readily
transferred (Table 1, entries 3–5), including the bulky 1-
naphthyl group (Table 1, entry 7). Primary and secondary
alkyl groups were also added to the quinoline nucleus to give
aminals (Table 2, entries 1–6), as was an alkenyl group
(Table 1, entry 17). Very bulky nucleophiles (entry 15)
afforded the 2’-alkylated alkaloid as the major product
instead (Table 2, entry 1). The structure of the aminal 4’-iPr-
CDA was also determined by X-ray crystallography
(Figure 1).[10] Surprisingly, the substituent at the 4’-carbon
[*] Dr. L. Hintermann, Dipl.-Chem. M. Schmitz
Institut für Organische Chemie
RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
Fax: (+49)241-80-92391
E-mail: lukas.hintermann@oc.rwth-aachen.de
Prof. Dr. U. Englert
Institut für Anorganische Chemie
RWTH Aachen
Landoltweg 1, 52074 Aachen (Germany)
[**] This work was supported by the DFG (Emmy Noether Programm,
SPP 1179 Organokatalyse). We thank Prof. Carsten Bolm for
continued support and Chininfabrik Buchler GmbH, Braunschweig,
for alkaloid samples.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Table 1: Conjugate arylation of cinchona alkaloids with Grignard reagents.
Entry SM[a]
Reagent[b] (equiv)
Product
Yield [%] Entry SM[a] Reagent[b] (equiv)
Product
Yield [%]
1
2
3
4
5
QN
QN
QN
QN
QN
PhMgBr (3)
PhMgCl (4)
X=OMe, R=H
X=OMe, R=H
X=OMe, R=Me
X=OMe; R=Cl
35
59
59
51
9
10
11
QD
CN
QN
PhMgBr (5)
PhMgBr (5)
MeMgCl (8)
X=OMe; R=H
X=H; R=H
53
65
62
p-MeC6H4MgBr (5)
p-ClC6H4MgBr (5)
p-MeOC6H4MgBr (5) X=OMe; R=OMe 55
6
7
CD
QN
PhMgBr (3)
X=H; R=H
80
32
12
13
14
QN
CD
CD
EtMgBr (6)
X=OMe; R=Et
51
1-NapMgBr (5)[d]
n-C10H21MgCl (3.5) X=H; R=n-C10H21 35
iPrMgCl (4)
X=H; R=iPr
35
8
DHQN[c] PhMgBr (5)
63
15
16
CD
CN
CyMgCl (6)
X=H; R=Cy
5[e]
53
iPrMgCl (8)
17
CD
42[f]
[a] Starting material. [b] Reactions were performed in toluene at 50–708C for 1 h to 1 day.[9] Cy =cyclohexyl. [c] DHQN=dihydroquinine. [d] 1-Nap=1-
naphthyl. [e] 2’-Cy-CD is the main reaction product (43%), see Table 2. [f] E/Z=70:30.
Table 2: Alkylation of cinchona alkaloids at the 2’-position.
ments) amounts to 968 in 4’-Ph-
QNA, but to 1798 (or 1758) in 4’-iPr-
CDA,[11] which implies that the
conformation of the cinchona ami-
nals can be adjusted by choice of the
group that is introduced at the C-4’-
position.
Entry
SM[a]
Reagent[b] (equiv)
Product
Yield [%]
Notably, the organometallic
reagent adds to the sterically less
available 4’-position of the quino-
line moiety rather than at the C-2’-
position, and single diastereoiso-
mers were isolated from all reac-
tions. Both observations are
explained by assuming a group
1
CD
CyMgCl (6)
X=H, R=Cy
+ 4’-Cy-CDA
43
5
2
3
4
5
6
7
8
CD
CD
CD
CD
CD
QN
QN
iPr2Mg (1.9)
BnMgBr (6)
NapMgBr (3.6)
nBuLi (3)
PhLi (3)
nBuLi (3)
X=H, R=iPr
X=H, R=Bn
X=H, R=1-Nap
X=H, R=nBu
X=H, R=Ph
X=OMe, R=nBu
X=OMe, R=Ph
29
35
17
66
27
37
32
PhLi (3)
transfer
within
a
chelate
(Scheme 3a)[12] having the same
quinoline conformation as observed
earlier in a metal complex of qui-
nine (Scheme 3b).[13] The choice of
toluene as a solvent that will not
break up aggregates is a key factor
for obtaining good results in the
conjugate addition.
9
10
11
CN
CN
CN
nBuLi (2.1)
UdcLi (2.5)[c]
PhLi (2.2)
X=H, R=Bu
X=H, R=Udc
X=H, R=Ph
55
48
7[d]
[a] Starting material. [b] Conditions with RLi: tBuOMe, À208C–RT, 3 h; workup with H2O, HOAc, and I2
or MnO2. Conditions with RMgX: PhMe/ethereal solvent, 65–908C, 5–20 h.[9] [c] Udc=n-undec-10-en-1-
yl. [d] Without oxidative workup.
The 4’-addition was accompa-
nied or overturned by 2’-substitu-
tion with bulky Grignard reagents
atom of the alkaloid decisively influences the conformation of
the resulting aminals: The dihedral angle O-C-C-N (around
the bond joining the quinuclidine and bicyclic aminal frag-
(Table 2, entries 1–4). 1-Naphthylmagnesium bromide
afforded either 4’- (Table 1, entry 7) or 2’-alkylation products
(Table 2, entry 4), depending on the reaction conditions. If 2’-
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Scheme 3. a) Mechanistic description of a chelate-directed transfer of
an R group from RMgX to the quinoline unit. b) Structure of a metal–
chelate complex of quinine.[13]
alkylation is desired, organolithium nucleophiles are advanta-
geous:[7] After an oxidative workup, C-2’-substituted alkaloids
were obtained in fair yields (Table 2, entries 5–11).
Direct alkylation of the core of cinchona alkaloids with
organometallic reagents opens the way to assemble complex
molecular architectures in a predictable manner: for example,
the fascinating dinuclear derivatives 1 and 2 (Scheme 4) were
obtained from divalent Grignard reagents.[14]
Scheme 5. Structural diversity from cinchona alkaloids by alkylative
reaction sequences. RCM=ring-closing metathesis.
Keywords: cinchona alkaloids · Grignard reaction · heterocycles ·
.
neighboring-group effects · nucleophilic addition
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À
[5] Alkaloid functionalization by C C bond formation at the vinyl
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tolyl.
Structural diversity is further enhanced by performing
serial 2’- and 4’-alkylations, as in the synthesis of
(Scheme 5a). Another notable reaction sequence has intro-
duced the unsaturated 10-undecenyl chain by 1’,2’-addition,
followed by ring-closing metathesis to give cycloalkaloid 4
(Scheme 5b).[15]
In conclusion, simple modifications of the basic carbon
skeleton of cinchona alkaloids are rare, but we have now
found that the direct nucleophilic alkylation of organometal-
lic reagents provides a powerful tool to access structurally
diverse derivatives with rigid cores that bear reactive func-
tional groups. Such derivatives are of interest for applications
in organo or metal catalysis; last but not least, the surprising
course of the reaction of Grignard reagents with cinchona
alkaloids has been elucidated, and has yielded an unexpected
result.[9]
3
À
[6] Alkaloid derivatization by C C bond formation at the C-2’-
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Daines, WO 9709046, 1997.
[7] Direct 1’,2’-addition of PhLi to quinine: a) Ref. [6a]; b) addition
of RLi to O-alkylated alkaloids: C. C. C. Johansson, N. Bre-
meyer, S. V. Ley, D. R. Owen, S. C. Smith, M. J. Gaunt, Angew.
Received: March 27, 2007
Published online: May 30, 2007
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Chemie
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angles correspond to independent molecular units within the
asymmetric cell.
[8] 4’-Ph-QNA corresponds to the aminal product of addition of
PhMgX to the C-4’-position of the alkaloid (QN).
[9] See the Supporting Information for experimental details and
characterization of the reaction products.
[10] CCDC-639151 (4’-iPr-CDA) and -639152 (4’-Ph-QNA) contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[12] Metal-directed transfer of hydride to C-4’ of cinchona alkaloids:
H. M. R. Hoffmann, T. Plessner, C. von Riesen, Synlett 1996,
690 – 692.
[13] R. Hubel, K. Polborn, W. Beck, Eur. J. Inorg. Chem. 1999, 471 –
482.
[14] Since an excess of divalent Grignard reagent favors mononu-
clear reaction products, the yields are low, even though the
reactions were performed in the presence of excess “dummy”
Grignard reagent (iPrMgCl or oTolMgBr).
[11] The conformational difference is retained in CDCl3 solution, as
evident from a shielded H NMR signal for H-14in the spectrum
of 4’-Ph-QNA, which is absent for 4’-iPr-CDA. The two torsion
[15] Only the E isomer was isolated; for the cyclization protocol, see:
A. Fꢀrstner, K. Langemann, Synthesis 1997, 792 – 803.
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