Studies on enol carbonate chemistry: Stereoselective construction of vicinal quaternary benzylic centers in the bis-oxindole series

Article abstract of DOI:10.3987/com-07-s(k)59

The Steglich-type intramolecular acyl transfer of bis-oxindole enol carbonate derivatives 9a-c affords selectively the monorearranged products 11a-c. In turn, Pd(0)-mediated allyl transfer of the bis-Alloc derivative 9c allows an efficient double C-allyla

Full text of DOI:10.3987/com-07-s(k)59

HETEROCYCLES, Vol. 72, 2007
199
HETEROCYCLES, Vol. 72, 2007, pp. 199 - 205. © The Japan Institute of Heterocyclic Chemistry
Received, 11th January, 2007, Accepted, 5th March, 2007, Published online, 6th March, 2007. COM-07-S(K)59
STUDIES ON ENOL CARBONATE CHEMISTRY: STEREOSELECTIVE
CONSTRUCTION OF VICINAL QUATERNARY BENZYLIC CENTERS
IN THE BIS-OXINDOLE SERIES‡
Candice Menozzi, Peter I. Dalko*§ andJanine Cossy
Laboratoire de Chimie Organique associé au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05 - France;
Fax: +33 (0)140794660; e-mail: peter.dalko@univ-paris5.fr
Abstract - The Steglich-type intramolecular acyl transfer of bis-oxindole enol
carbonate derivatives 9a-c affords selectively the monorearranged products 11a-c.
In turn, Pd(0)-mediated allyl transfer of the bis-Alloc derivative 9c allows an
efficient double C-allylation leading preferentially to the d/l isomer.
INTRODUCTION
The synthesis of natural products having contiguous quaternary benzylic centers remains one of the most
challenging problems in organic chemistry.1,2 Recently, we described a short synthesis of
Nb-desmethyl-meso-chimonanthine2 possessing desymmetrized hexacyclic 3a,3a’-bis-pyrrolidinoindoline
skeleton.3 Members of the Calycanthaceous alkaloid family,4 such as chimonanthines5,6 1 and 3 or the
more complex leptosins7 4, and verticillins8 5 exhibit promising biological activity (Figure 1). Indeed,
(d)-chimonanthine 3 shows analgesic activity9 whereas antimicrobial,8a antinemodal activity8c against
Caenorhabditis elegans and Panagrellus redivivus as well as cytotoxic activity are observed for
verticillins.10 Leptosins possess significant antitumour activity against the murine P388 cell line7 and in
addition, leptosin M shows cytotoxic activities against 39 human cancer cell lines.7a
‡
This article is dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday.
Current address: Laboratoire de Chimie et de Biochimie Pharmacologique et Toxicologique, Université
René Descartes, 75270 Paris Cedex 06, France.
§

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HETEROCYCLES, Vol. 72, 2007
Me
N
H
N
H
N
Me
N
H
H
N
N
R
N
H
N
R
H
H
Me
3 (d)-chimonanthine
1 R = Me meso-chimonanthine
2 R = H N -desmethyl-meso-chimonanthine
b
R1
R
O
H
Me
O
Me
O
O
N
N
H
N
Sy
H
N
Sy
H
N
N
OH
OH
HO
OH
N
O
O
N
H
N
N
H
N
H
O
Sx
H
O
Sx
R2
N
Me
Me
Me
Me
1
2
5a verticillin A x = y = 2, R = R = CH
4a leptosin G x = 3, y = 4, R = CH OH
4b leptosin K x = 2, y = 2, R = i-Pr
3
2
1
2
5b verticillin D x = y = 2, R = R = CH (OH)CH
2
3
Figure 1. Naturally occuring bis-pyrrolidinoindoline alkaloids.
The synthetic access to bis-pyrrolidinoindoline alkaloids requires a flexible strategy allowing the
preparation of both the meso and the optically active (d/l) skeleton. Considering the inherent symmetry
propriety of the molecules, a bidirectionnal synthesis allowing the simultaneous control of the C-3a and
C-3a’ stereogenic centers in 3a,3a’-bispyrrolodino[2,3-b]indoline unit seemed to be the most appealing.
P
Bn
O
O
N
O
N
P
N
Steglich
rearrangement
allyl-transfer
reaction
RO
RO
O
O
O
O
OR
R = allyl
N
O
OR
N
P
O
N
O
P
Bn
P = protecting group
Figure 2. Bidirectional strategy in preparing functionalized bis-oxindole skeleton having vicinal
quaternary benzylic centers.

HETEROCYCLES, Vol. 72, 2007
201
We speculated, that an intramolecular acyl transfer, or allyl transfer may overcome the inherent low
reactivity of the benzylic/neopentylic centers, and may also be amenable for sequential transformations.
Here, we wish to report our results concerning the Steglich acyl rearrangement of bis-enol carbonates
derived from bis-oxindoles, and also the Pd(0)-catalyzed allyl transfer in Alloc derivatives (Figure 2).
RESULTS AND DISCUSSION
Electron rich O-acylated oxazolinones can be transformed to the corresponding C-acylated products in the
presence of acyl transfer catalysts, such as DMAP.11 One advantage of this methodology appeared to be
that the reaction is amenable under asymmetric conditions as enantioselective versions of this reaction
were developed using chiral DMAP derivatives,12 N-heterocyclic carbene13 metallocene-
pyrrolidinopyridine14 as catalysts. By using a double Steglich rearrangement, the two quaternary centers
of the axially symmetric d/l-chimonanthine core would be controlled from intermediate 9 (Scheme 1). A
close analogy, reported recently in the 3-methyl oxindole series12 encouraged us to consider the feasibility
of such a double rearrangement.
O
1) NaH ,BnBr,
DMF, rt, 12 h
H
N
N
H
O
O
O
2) PtO2, H2 (1 atm.)
AcOEt, rt, 12 h
AcOH, HCl
reflux, 12 h
O
87%
N
H
87% (2 steps)
N
H
6
7
O
Bn
N
Bn
N
1) KHMDS,
OR
OR
THF, - 78 °C, 30 min
2) ClCO2R,
THF, rt, 1 h
O
O
H
H
O
O
O
N
Bn
N
Bn
8
9a R = C(Me)2CCl3
9b R = Me
79%
56%
9c R = CH2CH=CH2 60%
Scheme 1. Synthetic sequence for the preparation of bis-enol carbonates 9a-c.

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HETEROCYCLES, Vol. 72, 2007
For this study the protected bis-oxindole 8, was prepared in 3 steps (Scheme 1). At first, isatin 6 and
oxindole were condensed under acidic conditions (AcOH, HCl, reflux)15 to produce isoindigo 7 in 87%
yield. After bis N-benzylation (NaH, BnBr, DMF)4a followed by hydrogenation of the olefin on platinum
oxide,16 bis-oxindole 8 was isolated in 87% yield. The required bis-enol esters were prepared by treatment
of 8 with KHMDS at –78 °C and the bis-enolates were quenched with chlorocarbonates such as
ꢀ,ꢀ,ꢀ-trichloro-tert-butyl chloroformate (TcBoc-Cl), methyl chloroformate (ClCO2Me) and
allyloxycarbonyl chloride (Alloc-Cl), leading to 9a (79%), 9b (56%) and 9c (60%), respectively. The
obtained compounds were stable and were purified by chromatography on silica gel. This short and
efficient sequence allowed the isolation of the enol carbonates required for the Steglich rearrangement.
Different conditions for the Steglich rearrangement were applied to compounds 9a-c. The best results
were obtained in the presence of DMAP (10 mol%) in tert-amyl alcohol at 80 °C (Scheme 2). Under
these conditions, a rapid mono-rearrangement took place and compounds 11a-c were isolated in 83%,
85% and 43% yields, respectively (Scheme 2). Unfortunately, no conditions, allowing the double
rearrangement were found.
Bn
N
Bn
N
O
O
Bn
N
O
O
O
RO
DMAP (10 mol%)
tert-amyl alcohol,
80 °C
RO
O
O
+
OR
OR
O
O
OR
N
N
O
N
O
Bn
Bn
Bn
9
10
Reaction Time
11
a R = C(Me)2CCl3
b R = Me
30 min
1 h
0%
0%
0%
83%
85%
43%
c R = CH2CH=CH2
1 h
Scheme 2. Steglich rearrangement applied to compounds 9a-c.
Moreover, when the Steglich conditions (DMAP, tert-amyl alcohol) were applied to enol carbonate 12
(Scheme 3), prepared from the mono-rearranged oxindole 11a (KHMDS, ClCO2C(Me)2CCl3 at –78 °C),
no acyl transfer was observed and the only isolated product was compound 11a, formed by the loss of the
enol carbonate appendage. This result indicated, that the combination of steric and electronic factors may
compromise the formation of the second quaternary center.

HETEROCYCLES, Vol. 72, 2007
203
Bn
N
Me
Bn
N
Me
Cl3C
O
1) KHMDS, THF,
-78 °C, 1 h
O
O
2) ClCO2C(Me)2CCl3,
THF, -78 °C to rt, 30 min
O
O
Me
Me
O
Me
O
Me
51%
CCl3
CCl3
N
O
N
O
Bn
Bn
11a
12
Bn
O
O
N
DMAP
tert-amyl
alcohol, 80 °C
Cl3C
O
O
Me
O
Me
CCl3
Me Me
X
N
O
Bn
10a
Scheme 3. Reiteration of the Steglich rearrangement of enol carbonate 12.
Bn
Bn
N
Bn
N
O
N
O
O
O
Pd(PPh ) (6 mol%)
3 4
CH Cl rt, 30 min
O
2
2,
O
+
N
O
O
Bn
N
O
N
O
Bn
Bn
46 %
13
19%
14
9c
Scheme 4. Allyl transfer reaction of the bis-Alloc derivative 9c.

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HETEROCYCLES, Vol. 72, 2007
As alternative strategy, allyl transfer of the bis-Alloc enolate 9c was examined under Stoltz’s conditions.17
Under these conditions a fast O- to C-allyl transfer was observed, in CH2Cl2 at room temperature in the
presence of a catalytic amount of Pd(PPh3)4 (6 mol%) and the reaction provided the two diastereoisomers
13 and 14 in 46% and 19% yields, respectively (Scheme 4). Products were separated by chromatography
on silica gel, and the structure of the major isomer was established by X-ray analysis, and revealed to be
the d/l isomer 13.
In summary, the DMAP-mediated intramolecular acyl transfer of bis-oxindole enol carbonates 9a-c under
Steglich’s conditions afforded selectively esters 11a-c which correspond to the mono-rearranged products.
The Pd(0)-mediated allyl transfer of the bis-Alloc derivative 9c created simultaneously two adjacent
quaternary benzylic stereogenic centers, leading preferentially to the d/l isomer. Further studies of this
transformation allowing the selective preparation of the optically active isomers are currently underway
and will be reported in due course.
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