Asymmetric synthesis of oxindoles containing a quaternary stereogenic centre by catalytic O/C-carboxyl rearrangement

Article abstract of DOI:10.1016/j.tetlet.2009.08.122

A catalysed O/C-carboxyl rearrangement generates the all-carbon stereogenic centre in phenyl 1,3-dimethyl-5-methoxy-2-oxoindoline-3-carboxylate (up to 57% ee). Crystallisation and removal of racemic crystals enhance the ee to 95%. The X-ray crystal struct

Full text of DOI:10.1016/j.tetlet.2009.08.122

Tetrahedron Letters 50 (2009) 6332–6334
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of oxindoles containing a quaternary stereogenic
centre by catalytic O/C-carboxyl rearrangement
Muhammad Ismail a, Huy V. Nguyen b, Gennadiy Ilyashenko a, Majid Motevalli b, Christopher J. Richards a,
*
a School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK
b School of Biological and Chemical Sciences, Queen Mary, University of London, E1 4NS, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2009
Revised 17 August 2009
Accepted 28 August 2009
Available online 2 September 2009
A catalysed O/C-carboxyl rearrangement generates the all-carbon stereogenic centre in phenyl 1,3-
dimethyl-5-methoxy-2-oxoindoline-3-carboxylate (up to 57% ee). Crystallisation and removal of racemic
crystals enhance the ee to 95%. The X-ray crystal structure of the cobalt metallocene–pyrrolidinopyridine
nucleophilic catalyst employed is reported.
Ó 2009 Elsevier Ltd. All rights reserved.
A number of oxindole-based naturally occurring alkaloids con-
tain an all-carbon quaternary stereogenic centre at C-3. Examples
include (ꢀ)-horsifiline 11a (Fig. 1) and more complex compounds
containing additional stereogenic centres such as gelsemine,1b
welwitindolinone A1c and spirotryprostatins A1d and B.1e Related
pyrroloindoline alkaloids containing a C-3 quaternary stereogenic
centre that also display biological activity have long attracted the
interest of synthetic chemists. In addition to (ꢀ)-physostigmine
2a2a and its congeners (ꢀ)-phenserine 1b2b and (ꢀ)-esermethole
1c,2a related examples include (ꢀ)-pseudophrynaminol2c and (ꢀ)-
flustramine B.2d
Me
N
Me
MeO
RO
NMe
O
H
N
H
N
Me
2a R = CONHMe (-)-physostigmine
2b R = CONHPh (-)-phenserine
2c R = Me (-)-esermethole
(-)-horsfiline
1
Figure 1. Representative oxindole and pyrroloindoline alkaloids containing an all-
carbon quaternary stereogenic centre.
Asymmetric catalysis may be used to control the absolute con-
figuration at C-3 during the synthesis of these natural products,
with methods employed ranging from palladium-catalysed Heck3a
and molybdenum-catalysed allylic alkylation reactions,3b to imini-
um ion catalysis.2d Chiral 4-aminopyridine-based nucleophilic cat-
alysts have been extensively developed in recent years for
enantioselective acyl and carboxyl transfer reactions.4 Although
the focus of this research has been largely on chiral secondary alco-
hol kinetic resolution, success has also been achieved with enan-
tioselective O/C-carboxyl transfer reactions for the synthesis of
quaternary stereogenic centres (Scheme 1).5,6
To this end we recently reported the synthesis of a cobalt metal-
locene–pyrrolidinopyridine nucleophilic catalyst 3, available in
three steps (22% unoptimised yield) from commercially available
(S,S)-hexane-2,5-diol (Scheme 2).7 Use of 1 mol % of this catalyst
resulted in the quantitative O/C-carboxyl rearrangement of azlac-
tone-derived enol carbonates in up to 76% ee. We now report on
the application of 3 to the generation of the C-3 stereogenic centre
of a 3-methyl-5-methoxyoxindole building block that has the po-
tential to be employed in the synthesis of natural products and re-
lated compounds.
R
X
Y
R
O
X
Y
nucleophilic
catalyst
O
*
CO2R1
R1
O
O
Scheme 1. O/C-Carboxyl rearrangement for the synthesis of quaternary stereogenic
centres.
Starting with commercially available N-methyl-4-methoxyani-
line 4, oxindole 5 was synthesised using a literature procedure
(Scheme 3).8 Subsequent deprotonation with potassium hexa-
methyldisilazide followed by chloroformate addition gave enol
carbonates 6a–d.9 The very low yield of 6c was mainly due to
the preferential formation of 3-benzyl-1,3-dimethyl-5-methoxy-
2-oxoindoline.2a This was also the major product when triethyl-
amine or sodium hydride was used with benzyl chloroformate,
these reactions also resulted in a very low yield (<2%) of 6c.
Addition of 5 mol % of catalyst 3 to 6a in toluene/dichlorometh-
ane (the latter solvent being required to completely solubilise the
substrate) resulted in clean rearrangement and isolation of 7a in
48% ee (Table 1, entry 1). Repetition of the reaction at 0 °C resulted
in no reaction (entry 2) and the use of dichloromethane alone also
* Corresponding author. Tel.: +44 0603 593890; fax: +44 0603 592003.
E-mail address: chris.richards@uea.ac.uk (C.J. Richards).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.122

M. Ismail et al. / Tetrahedron Letters 50 (2009) 6332–6334
6333
phenyl and benzyl congeners 6b and 6c resulted in essentially no
enantioselectivity (entries 5 and 6). In contrast the trichloro-tert-
butyl analogue 6d gave a 50% ee in toluene (with 10 mol % 3, entry
7), but much lower enantioselectivities in hexane/dichlorometh-
ane or THF (entries 8 and 9).11 Following lithium hydroxide-med-
iated hydrolysis of enantioenriched esters 7a and 7d, the resulting
acids were determined to contain the same major enantiomer by
chiral HPLC analysis. The absolute configuration of the major enan-
tiomer of 7a and 7d is tentatively assigned as S by comparison with
the major enantiomer resulting from the rearrangement of azlac-
tone-derived enol carbonates with catalyst 3.7 Other catalysts ap-
plied to the rearrangement of enol carbonates derived from both
azlactones and oxindoles have resulted in the same sense of
enantioselectivity.5a–d
Me
N
Me
N
OH
3 steps
ref. 7
Co
Ph
Ph
Ph
Ph
OH
3
small
N
up
C
N C
N
down
Recrystallisation of 7a (48% ee) from hexane/i-PrOH gave crys-
talline racemic 7a and a mother liquor consisting almost exclu-
sively of the major enantiomer (Scheme 4).12 The use of
preferential crystallisation to separate the enantiomers of a race-
mic compound (as opposed to a racemic mixture that forms a con-
glomerate) has recently been demonstrated, and requires the use
of an enantioenriched mixture of enantiomers.13 Thus, although
the enantioselectivity of the O/C-carboxyl rearrangement is rela-
tively modest, this crystallisation procedure provides a highly sca-
lemic intermediate for the synthesis of alkaloids of general
structure 2.
large
Scheme 2. Chiral nucleophilic catalyst 3 and the mechanism of chirality transfer to
the pyridine nitrogen environment of 3.
gave an ee of 48% (entry 3).10 This increased to 57% in THF, albeit
with a significantly longer reaction time and lower yield (entry
4). The replacement of the phenyl carbonate 6a with the p-nitro-
The X-ray crystal structure of 314 (Fig. 2) reveals the operation
of the chiral relay effect as represented in Scheme 2. That this con-
formation, with respect to rotation about the pyridine–cyclopenta-
dienyl bond, is maintained in solution has previously been
established by NMR (GOSEY) analysis.7 The deviation from co-pla-
narity of the pyridine and cyclopentadienyl rings is 38°, which is at
least in part due to the avoidance of interaction between the cyclo-
Me
i) ClCH2COCH3,
Et3N
MeO
MeO
O
ii) ZnCl2, EtOH
iii) HCl/DMSO
N
Me
NHMe
4
5
i) KHMDS,
THF
ii) RO2CCl
Crystals (48%)
Me
Me
CO2R
= rac
-7a
MeO
MeO
Recryst.
3
7a
O
OCO2R
hexane/
i-PrOH
Mother
48% ee
N
N
Me
liquor (48%)
Me
7a
=
95% ee
7a-d
6a R = Ph 63%, 6b R = p-NO2C6H4 55%,
6c 6d
R = Bn 3%,
R = C(CH3)2CCl3 36%
Scheme 4. Enantiomeric enrichment of 7a.
Scheme 3. Synthesis and rearrangement of oxindole-derived enol carbonates 6a–d.
Table 1
Rearrangement reactions of enol carbonates 6 with nucleophilic catalyst 3a
Entry Substrate/
product
Mol %
3
Solvent
Time
(h)
Yieldb
(%)
eec
(%)
1
6a/7a
6a/7a
5
5
PhMe/
CH2Cl2
PhMe/
CH2Cl2
24
36
83
0
48
—
e
2d
e
3
4
5
6a/7a
6a/7a
6b/7b
5
5
5
CH2Cl2
THF
18
72
48
50
43
70
48
57
5
PhMe/
f
CH2Cl2
6
6c/7c
5
PhMe/
CH2Cl2
36
78
5
f
7
8
6d/7d
6d/7d
10
10
PhMe
Hexane/
CH2Cl2
24
48
61
48
50
15
f
9
6d/7d
3
THF
24
43
7
a
b
c
d
e
f
All reactions at 25 °C unless otherwise stated.
After isolation by chromatography.
Determined by HPLC.
At 0 °C.
5:2 Ratio.
4:1 Ratio.
Figure 2. ORTEP representation of the X-ray crystal structure of 3. Key bond angles
and torsions: C(39)–N(2)–C(42) = 108.3(4)°, C(39)–N(2)–C(38) = 118.4(4)°, C(38)–
N(2)–C(42) = 117.7(4)°, C(30)–C(29)–C(34)–C(38) = ꢀ37.6(8)°, C(34)–C(38)–N(2)–
C(39) = 168.2(5)°, C(34)–C(38)–N(2)–C(42) = ꢀ58.3(7)°.

6334
M. Ismail et al. / Tetrahedron Letters 50 (2009) 6332–6334
J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925; (e) Busto, E.; Gotor-
Fernández, V.; Gotor, V. Adv. Synth. Catal. 2006, 348, 2626; (f) Duffey, T. A.;
Shaw, S. A.; Vedejs, E. J. Am. Chem. Soc. 2009, 131, 14.
pentadienyl and pyrrolidine moieties. The latter adopts an enve-
lope conformation with the out-of-plane carbon [C(42)] adjacent
to the cyclopentadienyl group, towards which is projected an
equatorial hydrogen. The pyridine carbon C(38) is bent 36° out of
the plane defined by C(42)–N(2)–C(39) which is indicative of some
sp3 character in the pyrrolidine nitrogen. This deviation from the
sp2 pyrrolidine nitrogen of 4-pyrrolidinopyridine (PPY), and the
resulting reduction in the magnitude of the nN?pꢁðC@ interaction,
6. N-Heterocyclic carbene and amidine catalysts have also been applied to the
rearrangement of oxindole derived enol carbonates: (a) Thomson, J. E.; Kyle, A.
F.; Gallagher, K. A.; Lenden, P.; Concellón, C.; Morrill, L. C.; Miller, A. J.;
Joannesse, C.; Slawin, A. M. Z.; Smith, A. D. Synthesis 2008, 2805; (b) Joannesse,
C.; Simal, C.; Concellón, C.; Thomson, J. E.; Campbell, C. D.; Slawin, A. M. Z.;
Smith, A. D. Org. Biomol. Chem. 2008, 6, 2900.
7. Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006, 8, 769.
8. Underwood, R.; Prasad, K.; Repic, O.; Hardtmann, G. E. Synth. Commun. 1992, 22,
343.
9. Synthesis of 6a: A solution of 1,3-dimethyl-5-methoxyindolin-2-one (0.592 g,
3.1 mmol) in THF (4 mL) was added slowly to a solution of KHMDS (0.743 g,
3.7 mmol) in THF (4 mL) at ꢀ78 °C. The solution was stirred at ꢀ78 °C for
30 min, then transferred via cannula to a solution of phenyl chloroformate
(0.47 mL, 3.7 mmol) in THF (5 mL) at ꢀ78 °C. The solution was allowed to
warm to rt, then poured into 0.1 M HCl, and extracted with Et2O. The combined
organic layers were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by flash chromatography
CÞ
accounts for the reduction in the activity of 3 compared to PPY and
4-dimethylaminopyridine (DMAP) as catalysts in alcohol acetyla-
tion reactions.7,15 The steric impediment of a cyclobutadiene-ap-
pended phenyl group may also be a factor. However, it must be
stressed that 3 is still a very active nucleophilic catalyst and the
relatively high catalyst loading of 5 mol % required for the rear-
rangement of oxindole-derived enol carbonates is a consequence
of the low activity and challenging nature of this class of substrate.
In summary, we have demonstrated that the synthetically
accessible chiral nucleophilic catalyst 3 is applicable to the asym-
metric rearrangement of an oxindole-derived enol carbonate, and
in particular to the generation of highly scalemic phenyl 1,3-di-
methyl-5-methoxy-2-oxoindoline-3-carboxlate following enant-
ioenrichment by recrystallisation. The utilisation of this building
block for the synthesis of indole alkaloids and related compounds
is currently in progress.
(silica gel, 20–60
colourless crystalline solid (0.61 g, 63%): Mp 59–61 °C; IR (Nujol) mmax 1781
(C@O) cmꢀ1 1H NMR (CDCl3, 400 MHz) d 7.44–7.39 (2H, m), 7.33–7.25 (3H, m),
lm) with EtOAc/hexane (5:95) as the eluent, yielding 6a as a
;
7.13 (1H, d, J = 7.1 Hz), 6.97 (1H, d, J = 1.5 Hz), 6.86 (1H, dd, J = 7.1, 1.5 Hz), 3.84
(3H, s), 3.60 (3H, s), 2.20 (3H, s); 13C NMR (CDCl3, 100 MHz) d 2 ꢂ 154.6, 151.3,
139.4, 2 ꢂ 130.0, 128.0, 126.8, 2 ꢂ 120.8, 111.8, 110.1, 101.5, 96.6, 56.3, 28.8,
7.7. HRMS (m/z, EI): found for MH+ 312.1234. C18H18NO4 requires 312.1230.
Analytical TLC, EtOAc/hexane (3:7), Rf = 0.65.
10. Synthesis of 7a:
A solution of catalyst 3 (5.1 mg, 0.008 mmol) in
dichloromethane (5.0 mL) was added to 6a (50 mg, 0.16 mmol). After 18 h,
the solution was concentrated in vacuo. The crude residue was dissolved in
dichloromethane and purified by flash column chromatography with CH2Cl2/
hexane (90:10) to yield 7a (50% yield, 48% ee): Mp 114–116 °C; IR (Nujol) mmax
1761 (C@O), 1717 (C@O) cmꢀ1 1H NMR (CDCl3, 400 MHz) d 7.27–7.23 (2H, m),
;
Acknowledgements
7.14–7.10 (1H, m), 6.91–6.86 (3H, m), 6.82 (1H, dd, J = 7.8, 1.5 Hz), 6.75 (1H, d,
J = 7.8 Hz), 3.75 (3H, s), 3.21 (3H, s), 1.69 (3H, s). 13C NMR (100 MHz) d 174.6,
168.6, 156.5, 150.6, 137.4, 131.3, 2 ꢂ 129.5, 126.3, 2 ꢂ 121.4, 113.7, 110.5,
109.3, 56.1, 26.9, 20.3. HRMS (m/z, EI): found for MH+ 312.1233. C18H18NO4
requires 312.1230. HPLC (Chiralcel OD, 0.46 cm ꢂ 25 cm, 95:05 hexane/i-
propanol, 1.0 mol/min) TR = 19.6 min (minor), TR = 23.5 min (major). Analytical
TLC, 35% EtOAc/hexane, Rf = 0.31.
We thank the EPSRC for a studentship (NVN) and the British
Council of Pakistan and Higher Education Commission of Pakistan
for financial support (MI). We also thank the EPSRC National Mass
Spectrometry Service Centre (Swansea University).
11. HPLC data for 7d (Chiralcel OD, 0.46 cm ꢂ 25 cm, 98:2 hexane/i-propanol,
1.0 mL/min). TR = 19.6 min (major), TR = 22.3 min (minor). Analytical TLC, 30%
EtOAc/hexane, Rf = 0.54.
References and notes
12. Recrystallisation of 7a: A solution of 7a (25 mg, 48% ee) in 4 mL of HPLC grade
hexane/i-propanol (6:1) was allowed to stand open to the atmosphere for one
week at room temperature. Pale yellow square shaped crystals surrounded by
a viscous liquid were obtained. The crystals were washed with a little amount
of hexane followed by a little amount of methanol. HPLC (Chiralcel OD)
revealed the crystals (12 mg, 48%) to be a perfect racemate of 7a, and the
evaporated mother liquor (12 mg, 48%) to be 7a with 95% ee.
13. (a) Lorenz, H.; Polenske, D.; Seidel-Morgenstern, A. Chirality 2006, 18, 828; (b)
Polenske, D.; Lorenz, H.; Seidel-Morgenstern, A. Cryst. Growth Des. 2007, 7,
1628.
1. (a) Pellegrini, C.; Strässler, C.; Weber, M.; Borschberg, H.-J. Tetrahedron:
Asymmetry 1994, 5, 1979; (b) Yokoshima, S.; Tokuyama, H.; Fukuyama, T.
Angew. Chem., Int. Ed. 2000, 39, 4073; (c) Baran, P. S.; Richter, J. M. J. Am. Chem.
Soc. 2005, 127, 15394; (d) Edmondson, S. D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 1138; (e) von Nussbaum, F.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2000, 39, 2175.
2. (a) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56, 872; (b) Huang, A.;
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T.; Ogawa, A.; Takashima, Y.; Sakamoto, M. Tetrahedron Lett. 2003, 44, 1591; (d)
Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C. Proc. Natl.
Acad. Sci. 2004, 101, 5482.
3. (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58,
6949; (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590.
4. Wurz, R. P. Chem. Rev. 2007, 107, 5570.
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Am. Chem. Soc. 2003, 125, 13368; (d) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf,
14. Crystal data 3: C44H39CoN2, M = 654.70, orthorhombic, a = 10.7478(13),
b = 11.808(2), c = 26.305(5) Å,
group P212121, Z = 4, Dc = 1.303 Mg/m3,
15287, reflections unique 6527 with R(int) = 0.0976, T = 120(2) K, final
indices [F2 > 2 (F2)] R1 = 0.0658, wR2 = 0.1059 and for all data R1 = 0.1683,
a
= 90°, b = 90°,
c
= 90°, V = 3338.4(9) Å3, space
l
= 0.549 mmꢀ1, reflections measured
R
r
wR2 = 0.1337. Absolute structure parameter = 0.02(2). CCDC No. = 720582.
15. Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436.