Regio- and enantioselective alkylation of a N-protected pyrrolidin-3-one using Enders' chiral hydrazone method: A key step towards a new asymmetric total synthesis of (-)-quinocarcin and related analogues

Article abstract of DOI:10.1055/s-2002-34224

The synthesis of C-4-alkylated pyrrolidin-3-one 5 was achieved by regio- and diastereoselective alkylation of chiral hydrazone 8 with electrophile 7 followed by selective deprotection. Highly functionalised compound 5 is the first key intermediate in our approach towards a new asymmetric total synthesis of (-)-quinocarcin (1) and related structural analogues 2 and 3.

Full text of DOI:10.1055/s-2002-34224

LETTER
1669
Regio- and Enantioselective Alkylation of a N-Protected Pyrrolidin-3-one
Using Enders’ Chiral Hydrazone Method: A Key Step Towards a New
Asymmetric Total Synthesis of (–)-Quinocarcin and Related Analogues
R
egio- andEnantio
w
selective
A
lkylati
e
on of
a
N-Protect
S
edPyrrolidin-3
c
-
one hneider, Xavier Pannecoucke, Jean-Charles Quirion*
Laboratoire d’Hétérochimie Organique, Institut de Recherche en Chimie Organique Fine, Rue Lucien Tesnière, 76131 Mont-Saint-Aignan,
France
Fax +33(2)35522959; E-mail: quirion@ircof.insa-rouen.fr
Received 3 July 2002
Abstract: The synthesis of C-4-alkylated pyrrolidin-3-one 5 was
achieved by regio- and diastereoselective alkylation of chiral hydra-
zone 8 with electrophile 7 followed by selective deprotection. High-
ly functionalised compound 5 is the first key intermediate in our
approach towards a new asymmetric total synthesis of (–)-quinocar-
cin (1) and related structural analogues 2 and 3.
Key words: alkylation, hydrazones, heterocycles, regioselectivity,
stereoselectivity
(–)-Quinocarcin (1; Scheme 1), an isoquinoline alkaloid
isolated from Streptomyces melanovinaceus,1 is the sim-
plest member of a series of antitumor antibiotics, such as
tetrazomine,2 bioxalomycin3 and saframycin,4 and is
known for its wide spectrum of antitumor activity.5 The
aromatic methoxy group6 as well as a propensity to form
an iminium species on the C-ring of 17 are essential for
any biological activity.8 This was confirmed by the phar-
macological evaluation of different ABC-ring and ABCE-
ring substructures of 1, recently synthesised by Laschat6
and Williams.9 The complex ABCDE-ring system of
(–)-quinocarcin including six stereogenic centres is a par-
ticularly challenging target for total synthesis. In spite of
considerable synthetic efforts, there are currently only two
asymmetric total syntheses of 1,10,11 but the overall yields
are quite poor and the strategies are not very general.
Scheme 1 Retrosynthetic strategy for the asymmetric total synthe-
sis of (–)-quinocarcin (1) and related structural analogues 2 and 3.
The aim of our research was to develop a new and general
strategy for the total synthesis of 1 and analogues 2 and 3.
Our retrosynthetic strategy is based on a new approach via
chiral tricyclic lactam 4 by means of a diastereoselective
functionalisation sequence,12,13 already studied in our lab-
oratory.12 Tricyclic lactam 4 could be prepared via an in-
tramolecular Schmidt reaction14 as a key step, in several
steps starting from pyrrolidin-3-one 5, which is function-
alised enantioselectively at C-4 (Scheme 1).
the ring-nitrogen. In the case of pyrrolidin-3-ones,
methylation under modified reaction conditions occurred
preferentially at C-4. However, to the best of our knowl-
edge, nothing is known about the enantioselectivity of
alkylation of the pyrrolidin-3-one moiety.
Enders’ alkylation16 using chiral hydrazones is currently
the best method for the asymmetric functionalisation of
carbocyclic ketones such as cyclopentanone. Enders ob-
tained modest diastereoselectivities (up to 69% de) for the
methylation of cyclopentanone with the classic SAMP-
hydrazone and dimethylsulfate as electrophile.16 We
wished to extend this method to the regioselective and
asymmetric synthesis of key intermediate 5 of our total
synthesis approach using aryl bromide 7 and chiral hydra-
zones derived from ketone 6 (Scheme 1).
The influence of various parameters on the regioselectiv-
ity of enolisation and methylation of cyclic -aminoke-
tones such as pyrrolidin-3-one 6 was investigated by Garst
and co-workers.15 It was shown that the regioselectivity
could be strongly influenced by the protecting group on
Synlett 2002, No. 10, Print: 01 10 2002.
Art Id.1437-2096,E;2002,0,10,1669,1672,ftx,en;G18402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
N-protected pyrrolidin-3-ones 6 (PG = Boc, Bn) were ob-
tained from commercially available (2S,4R)-hydroxypro-

1670
U. Schneider et al.
LETTER
Table 1 Study of Regio- and Diastereoselective Alkylation of Chiral Hydrazones 8
Entry
R
PG
Base
E+
E
T
Regioselectivity De for 9 [%] Yield [%]
9:9
1
2
3
4
5
6
7
8
9
H
Boc
Boc
Boc
Boc
Boc
Bn
LDA
MeI
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
–78 °C
65:35
66:34
80:20
76:24
79:21
90:10
92:8
38
46
49
45
62
59
73
81
71
70
56
H
LDA
MeI
–100 °C
–78 °C
H
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
LHMDS
MeI
37
H
MeI
–100 °C
–100 °C
–100 °C
–100 °C
–78 °C
49
H
BnBr
BnBr
BnBr
BnBr
BnBr
41
H
45
Me
Me
Ph
Bn
>95
83
Bn
93:7
Bn
–100 °C
91:9
90
Experimental conditions: a: i) base (1.10 equiv), THF, –78 °C to 0 °C, 4–6 h at 0 °C; ii) E+ (1.00 equiv), 2 h at low temperature, low temperature
to r.t. within 12 h; iii) aq NH4Cl.
line via decarboxylation,17 followed by N-protection18 and Garst during the regioselective enolisation of different
Jones’ oxidation. Transformation to the corresponding pyrrolidin-3-ones.15
chiral hydrazones 8 was then achieved by reaction of
The observed diastereoselectivities for the alkylation of 8,
by the SAMP-hydrazone (R = H), were quite poor (de up
to 49%; entries 1–5). Increasing the steric hindrance of the
compounds 6 with various chiral hydrazines (R = H, Me,
Ph)19 under standard conditions (Na2SO4, CH2Cl2, r.t.).
First, we investigated the alkylation of chiral hydrazones chiral auxiliary (R = Me or Ph) combined with the modi-
8 in order to optimise the regio- and diastereoselectivity: fied N-protecting group (PG = Bn) at –100 °C gave
steric and electronic properties of the N-protecting group excellent diastereoselectivities (de up to >95% when
(PG = Boc, Bn) as well as the steric demand of the chiral R = Me; entries 7–9). These optimised alkylation condi-
auxiliary (R = H, Me) of substrates 8 were evaluated by tions were then extended to our total synthesis approach
using different bases (LDA, LHMDS) and electrophiles to 1.
(MeI, BnBr) at –78 °C or –100 °C (see Table 1).
The electrophile for this alkylation step, aryl bromide 7,
Table 1 shows a regioselectivity 9:9 of up to 80:20 for the was prepared in several steps starting from commercially
alkylation of 8, when the ring-nitrogen is protected as a available 2,3-dimethoxybenzoic acid (Scheme 2). Trans-
carbamate (PG = Boc) regardless of the reaction condi- formation of acid 10 to oxazoline, followed by regioselec-
tions (entries 1–5). The best results were obtained by us- tive substitution of the 2-methoxy group and oxazoline
ing LHMDS as base rather than LDA (entries 3–6). Only deprotection yielded the corresponding di-ortho-substi-
the use of N-benzylated hydrazone 8 (PG = Bn) led al- tuted styrene 11.20 After reduction of the acid function to
most exclusively to the desired regioisomer 9 (entries 6– alcohol 12 and bromination of the latter, compound 7 was
9). These results are consistent with those obtained by obtained in 41% overall yield.
Scheme 2 Synthesis of 2,6-disubstituted styrene 7. Experimental conditions: a: LiAlH4, Et2O, 0 °C to r.t., 3 h (yield: 95%); b: PBr3, pyridine,
CH2Cl2, 0 °C to r.t., 2 h (yield: 90%).
Synlett 2002, No. 10, 1669–1672 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Regio- and Enantioselective Alkylation of a N-Protected Pyrrolidin-3-one
1671
Scheme 3 Regio- and diastereoselective alkylation of chiral hydrazone 8 followed by smooth deprotection of C-4-alkylated hydrazone 10.
Experimental conditions: a: i) LHMDS (1.05 equiv), THF, –78 °C to 0 °C, 6 h at 0 °C; ii) compound 7 (1.20 equiv), –100 °C to r.t. within 12
h; iii) sat. aq NH4Cl (regioisomer 13: yield: 63%; de >95%); b: aq CuCl2, THF, r.t., 24 h (yield: 67%; ee >95%).
Tsuchiya, R.; Sasaki, Y.; Saijo, N. J. Pharmacobio.-Dyn.
1987, 10, 431. (e) Jett, J. R.; Saijo, N.; Hong, W.-S.; Sasaki,
The Enders’ alkylation sequence using electrophile 7 is
shown in Scheme 3: asymmetric transformation of chiral
Y.; Takahashi, H.; Nakano, H.; Nakagawa, K.; Sakurai, M.;
hydrazone 8 (R = Me, PG = Bn) into the alkylated com-
Suemasu, K.; Tesada, M. Invest. New Drugs 1987, 5, 155.
(6) (a) S. Laschat, lecture on the 37th IUPAC congress in Berlin,
- Germany, August 1999 (b) Monsees, A.; Laschat, S.;
Hotfilder, M.; Wolff, J.; Bergander, K.; Terfloth, L.;
Fröhlich, R. Bioorg. Med. Chem. Lett. 1997, 7, 2945.
(7) (–)-Quinocarcinol, the natural dihydro derivative of 1
lacking the oxazolidine moiety, is pharmacologically
inactive: Tomita, F.; Takahashi, K.; Tamaoki, T. J. Antibiot.
1984, 37, 1268.
pound 13 was performed in 60% yield and >95% diaste-
reoselectivity (regioselectivity 13:13 = 95:5).
After separation by flash chromatography on silica gel,
the desired regioisomer 13 had to be deprotected. Classi-
cal hydrazone deprotection (ozonolysis or acidic cleavage
of in situ generated methiodides) failed due to the pres-
ence of the terminal double bond and the tertiary amine
function in this highly functionalised compound. Only
aqueous copper(II)21 amongst the established methods22
proceeded smoothly and selectively to yield the desired
key intermediate 5.
(8) For mechanistic discussions concerning the biological
activity of (–)-quinocarcin: (a) Williams, R. M.; Glinka, T.;
Flanagan, M. E.; Gallegos, R.; Coffman, H.; Pei, D. J. Am.
Chem. Soc. 1992, 114, 733. (b) Hill, C. G.; Wunz, T. P.;
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(9) Herberich, B.; Scott, J. D.; Williams, R. M. Bioorg. Med.
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(10) (a) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993,
115, 10742. (b) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem.
Soc. 1992, 114, 2767.
(11) (a) Katoh, T.; Kirihara, M.; Nagata, Y.; Kobayashi, Y.; Arai,
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(b) Katoh, T.; Kirihara, M.; Nagata, Y.; Kobayashi, Y.; Arai,
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In summary, we have developed an efficient method for
the asymmetric synthesis of C-4 substituted pyrrolidin-3-
ones. These compounds are important intermediates. In
addition, the extension of the practical and selective
deprotection method to total synthesis is to our knowledge
without precedent.
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LETTER
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