Enantioselective synthesis of spirooxoindoles via chiral auxiliary (bicyclic lactam) controlled SNAr reactions

Article abstract of DOI:10.1039/c0ob00661k

A highly efficient enantioselective S_NAr reaction of chiral acyl bicyclic lactam with substituted-2,4-dinitrobenzenes was developed, affording products containing quarternary stereogenic centers. They are further utilized towards an enantiosele

Full text of DOI:10.1039/c0ob00661k

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 358
www.rsc.org/obc
COMMUNICATION
Enantioselective synthesis of spirooxoindoles via chiral auxiliary
(bicyclic lactam) controlled SNAr reactions†
Subhabrata Sen,*a Venkata R. Potti,a,b Ramu Surakanti,a,b Y. L. N. Murthyb and Raghavaiah Pallepoguc
Received 3rd September 2010, Accepted 13th October 2010
DOI: 10.1039/c0ob00661k
A highly efficient enantioselective SNAr reaction of chi-
ral acyl bicyclic lactam with substituted-2,4-dinitrobenzenes
was developed, affording products containing quarternary
stereogenic centers. They are further utilized towards an
enantioselective synthesis of spirooxoindoles.
Introduction
Fig. 1 Various bicyclic lactams.
The spiropyrrolidinyloxindole skeleton has garnered considerable
involving carbon nucleophiles, we employ these bicyclic lactams
interest in the area of natural product synthesis and pharmaceu-
as chiral auxiliaries.
tical research owing to their presence in the core of a number of
The nucleophilic aromatic substitution (SNAr) one of the most
alkaloids, which possess significant biological activity.1 They are
fundamental reactions in organic chemistry, mostly utilizes amines
interesting and challenging targets for chemical synthesis. Over
and phenols as nucleophiles.6,7 1,3-Dicarbonyl compounds are
the past years, various strategies have been developed for the con-
also sporadically utilized as carbon nucleophiles for arylation
struction of these interesting moieties.2 In this communication, we
under mild conditions.8 In spite of being known for more than
describe an efficient synthesis of spiro-pyrrolidone-3,3¢-oxoindole
structure in excellent enantioselectivity, in decent yields and with
high atom economy under mild reaction conditions via regio and
asymmetric C-selective SNAr reactions of a-acylated chiral bicyclic
lactams with o-nitro aryls, followed by a facile reduction of the
nitro group and in situ intramolecular amide formation.
a century, there are only few reports in SNAr of chiral induction
on quaternary or tertiary stereocenters formed when carbon
nucleophiles are involved, that too for intramolecular reactions
and with oxygen nucleophiles.9 To the best of our knowledge there
is only one report of organo catalytic chiral induction in SNAr
reactions involving carbon nucleophiles.10 Furthermore, there is
The utilitarian chiral bicyclic lactams have provided access
no report of chiral auxiliary controlled SNAr reactions have been
to a gamut of natural and unnatural products in high enan-
developed to our knowledge.
tiomeric purity.3 Their synthetic versatility generated a number
of enantiomerically pure compounds bearing quarternary carbon
centers.4 Chiral bicyclic lactams of type I–IV (Fig. 1) have been
extensively used as scaffolds in enantioselective synthesis primarily
Results and discussion
Our journey began with the synthesis of chiral bicyclic lactam
II, by condensation of succinic anhydride with (R)-(-)-phenyl
glycinol in the presence of triethyl amine with azeotropic removal
of water. The resulting crude was then reduced with NaBH4 in
presence of ethanolic HCl. Purification by column chromatogra-
phy generated a single diastereomer in 72% yield.11 Treatment of
lactam II with lithium bis(trimethylsilyl)amide at -78 ◦C followed
by reaction with chloromethylformate generated monoacylated
bicyclic lactam 2 as an inseparable 1 : 1 mixture of epimers at
the new chiral center at C7 in 72% yield. The SNAr reaction of
the lactam 2 commercially available 2,4-dinitro-fluorobenzene in
THF and with KOH as the base was completed in few hours and
in high yields. However, the diastereomeric excess of the product
10 was disappointing (entry 1, Table 1). An initial screening
at various temperatures indicated better diastereoselectivity at
lower temperature, but with poor conversion (entry 2–6). Finally
successful stereoselective SNAr reaction occurred at 0 ◦C with NaH
based on the initial alkylation of methylene group adjacent to the
amide carbonyl either by treatment of base followed by reaction
with an alkyl halide or by thio-Claisen rearrangement of the
corresponding thiolactams.5 To date synthetic methods for the
asymmetric arylation of a chiral bicyclic lactam have not been
reported. In a bid to develop an asymmetric SNAr reaction,
aMedicinal Chemistry Department, GVK Biosciences, Plot 28A, IDA
Nacharam, Hyderabad, India. E-mail: Subhabrata.sen@gvkbio.com;
Fax: +91 40 2715 2999; Tel: +91 40 6628 1426
bDepartment of Chemistry, Food, Drugs and Water, College of Sci-
ence and Technology, Andhra University, Vishakhapatnam, India. E-mail:
murthyyln@yahoo.co.in; Tel: +91 0891 2844 686
cSchool of Chemistry, University of Hyderabad, Hyderabad, India
† Electronic supplementary information (ESI) available: Supplemen-
tary information. CCDC reference number 796841. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00661k
358 | Org. Biomol. Chem., 2011, 9, 358–360
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 Acylation followed by asymmetric C selective arylation of II
Table 2 Asymmetric C-selective arylation of acylated bicyclic lactam 1–4
Entry Base
T/◦C Time/h Yielda (%) Diastereomeric ratio (dr)b
1
2
3
4
5
6
7
8
KOH
25
-40
-78
03
16
36
04
14
32
03
06
87
54
28
90
50
24
92
86
1 : 1
70 : 30
90 : 10
1 : 1
70 : 30
90 : 10
1 : 1
Cs2CO3 25
-40
-78
25
0
NaH
99 : 1
a Isolated yield. Entry 2, 3, 5 and 6 the reactions were quenched while the
starting material was not completely consumed. b dr by HPLC.
Acylated Fluoro
Entry lactam
Diastereomeric
aromatics Product Yielda (%) ratio (dr)b
as base (entry 8). We were pleased to observe that the extent of
diastereomeric excess under these conditions increased to 99 : 1.
In Table 2, the generic aspect of the regioselective and asym-
metric SNAr reaction is demonstrated for variety of aromatic
compounds 5–7 with several monoacyl lactams (1–4) in decent
yield and with up to 99% de. Substituted bicyclic lactam such as 1,
undergo SNAr reaction smoothly but with moderate diastereose-
lectivity of 70%. Since the final products are solid and crystalline,
the de was enhanced to 99% by recrystallization. The crystals
obtained were suitable to determine the absolute configuration by
X-ray analysis.12 The relative configuration is shown in Fig. 2.
1
2
3
4
5
6
7
8
1
2
5
6
6
7
5
5
6
7
8
72
75
58
75
65
80
69
59
70 : 30
70 : 30
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
9
11
12
13
14
15
16
3
4
a Isolated yield. b Diastereomeric ratio determined by HPLC.
toward this class of molecules (Scheme 1). Herein we present
relevant examples were 8, 10 and 14 are converted to protected
oxoindoles 17, 18 and 19 respectively via reduction of the ring
nitrogen followed by in situ amidation. Oxoindole 18 was further
treated with TFA to remove the chiral auxiliary and generate the
desired spirooxoindole 21. As for 17, it was treated with triethyl
silane and titanium(IV) chloride at 0 ◦C followed by an elimination
hydrolysis procedure where the alcohol was converted into the
corresponding chloride with carbon tetrachloride and triphenyl
Fig. 2 X-Ray crystal structure of 10 and 14.
These products are precursors of oxoindoles possessing a chiral
quarternary carbon center. This scaffold is present in a variety
of natural products. Hence this approach provides an easy route
Scheme 1 Conversion of arylated bicyclic lactams to spirooxoindoles.
Org. Biomol. Chem., 2011, 9, 358–360 | 359
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
phosphine, subsequent elimination with DBU and treatment of
the resulting styrene with HCl in methanol generated the desired
spirooxoindole 20.
Tamelin, J. P. Yardley, M. Miyano and W. B. Hinshaw Jr., J. Am. Chem.
Soc., 1969, 91, 7333–7338; (d) A. Pictet and T. Spenglar, Ber. Dtsch.
Chem. Ges., 1911, 44, 2030; (e) A. Bischler and B. Napiralski, Ber.
Dtsch. Chem. Ges., 1893, 26, 1903–1908; (f) N. Finch and W. I. Taylor,
J. Am. Chem. Soc., 1962, 84, 1318–1320; (g) K. Somei, K. Noguchi,
R. Yamagami, Y. Kawada, K. Yamada and F. Yamada, Heterocycles,
2000, 53, 7–10; (h) N. Finch, I. H. C. Hsu, C. W. Gemenden and W. I.
Taylor, J. Am. Chem. Soc., 1963, 85, 1520–1523; (i) H. Takayama, K.
Masubuchi, M. Kitajima, N. Aimi and S. Sakai, Tetrahedron, 1989, 45,
1327–1336.
3 (a) A. A. Meyers and B. A. Lefker, J. Org. Chem., 1986, 51, 1541–
1544; (b) A. I. Meyers and B. A. Lefker, Tetrahedron, 1987, 43, 5663–
5676; (c) A. I. Meyers, R. Hanreich and K. T. Wanner, J. Am. Chem.
Soc., 1985, 107, 7776–7778; (d) A. I. Meyers and D. J. Berney, J. Org.
Chem., 1989, 54, 4673–4676; (e) A. I. Meyers, J. L. Romine and
A. J. Robichaud, Heterocycles, 1990, 30, 339–340; (f) A. I. Meyers
and M. Sturgess, Tetlett., 1989, 30, 1741–1744; (g) D. Romo, J. L.
Romine, W. Midura and A. I. Meyers, Tetlett., 1989, 45, 4951–
4994.
Conclusion
In summary, we have developed an extremely novel regioselective
and asymmetric C-selective aromatic nucleophilic substitution
reaction in rigid systems like bicyclic lactams. A tremendous
improvement in enantioselectivity has been achieved by NaH
at 0 ◦C. This methodology has been further applied towards
an efficient diastereoselective synthesis of spiro[pyrrolidone-3,3¢-
oxoindole] bearing a quarternary carbon center in high enan-
tioselectivity, in excellent yields and with high atom economy.
Further investigations (theoretical and experimental studies) are
in progress to rationalize the mode of arylation and also utilize the
scaffold towards the synthesis of various spirooxoindole natural
products.
4 (a) D. Romo and A. I. Meyers, Tetrahedron, 1991, 47(46), 9503–9569;
(b) A. I. Meyers and G. P. Brengel, Chem. Commun., 1997, 1–8.
5 (a) A. I. Meyers, M. A. Seefeld, B. A. Lefker, J. F. Blake and P. G.
Willard, J. Am. Chem. Soc., 1998, 120, 7429–7438; (b) P. Devine and
A. I. Meyers, J. Am. Chem. Soc., 1994, 116, 2633–2634.
6 See e.g.: (a) M. B. Smith, J. March Advanced Organic Chemistry, 5 ed.
WILEY-INTERSCIENCE, New York, 2001, pp. 850; (b) E. Buncel,
J. M. Dust and F Terrier, Chem. Rev., 1995, 95, 2261–2280.
7 (a) R. J. Snow, T. Butz, A. Hammach, S. Kapadia, T. A. Morowick,
A. P. Propokowicz, H Takahashi, J. D. Tan, M. A. Tschantz and X. –J.
Wang, Tetrahedron Lett., 2002, 43, 7553–7560.
References
1 (a) A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet and B. Bodo,
J. Org. Chem., 1991, 56, 6527–6530; (b) C. B. Cui, H. Kakeya and
H. Osada, J. Antibiot, 1996, 49, 832–835; (c) C. Pelligrini, M. Weber
and H. J. Borschberg, Helv. Chim. Acta, 1996, 79, 151–168; (d) R. C.
Elderfield and R. E. Gilman, Phytochemistry, 1972, 11, 339–343; (e) K.
Ghedira, M. Z. Hanrot, B. Richard, G. Massiot, L. L. M. Oliver, T.
Sevener and S. H. Goh, Phytochemistry, 1988, 27, 3955–3962; (f) S.
Sakai, N. Aimi, K. Yamaguchi, H. Ohhira, K. Hori and J. Haginiwa,
Tetrahedron Lett., 1975, 16, 715–718; (g) N. Aimi, K. Yamaguchi,
S. Sakai, J. Haginiwa and A. Kubo, Chem. Pharm. Bull, 1978, 26,
3444–3449; (h) O. Diderberg, J. Lamotte-Brasseur, L. Dupont, H.
Campsteyn, M Vermeire and L. Angenot, Acta Crystallogr., Sect. B:
Struct. Crystallogr. Cryst. Chem., 1977, 33, 1796–1801.
8 (a) N. Selvakumar, B. Yadi Reddy, G. Sunil Kumar and J. Iqbal, Tetlett,
2001, 42, 8395–8398; (b) N. J. Lawrence, C. A. Davies and M. Gray,
Org. Lett., 2004, 6, 4957–4960.
9 (a) K. C Nicolau, H Li, C. N. C Boddy, J. M. Ramanjulu, T. Y Yue, S.
Natarajan, X. J Chu, S. Braise and F. Rubsam, Chem.–Eur. J., 1999, 5,
2584–2601; (b) T. Lais and J. Zhu, Tetlett., 1999, 40, 83–86.
10 (a) M. Bella, S. Kobbelgaard and K. A. Jørgensen, J. Am. Chem. Soc.,
2005, 127, 3670–3671; (b) S. Kobbelgaard, M Bella and K. A. Jørgensen,
J. Org. Chem., 2006, 71, 4980–4987.
¨
¨
11 (a) L. B. Burgess and A. I. Meyers, J. Am. Chem. Soc., 1991, 113, 9858–
2 (a) S. T. Hilton, T. C. T. Ho, G. Pjevaljcic and K. Jones, Org. Lett.,
2000, 2(17), 2639–2641; (b) X-H. Chen, Q. Wei, S-W. Luo, H Xiao and
L-Z. Gong, J. Am. Chem. Soc., 2009, 131, 13819–13825; (c) E. E. Van
¨
9859; (b) M. Penhoat, S. Leleu, G. Dupass, G. Papamicael, F. Marsais
and V. Levacher, Tetlett, 2005, 46, 8385–8389.
12 Please refer experimental section for X-ray analysis data.
360 | Org. Biomol. Chem., 2011, 9, 358–360
This journal is
The Royal Society of Chemistry 2011
©