AcOLeDMAP and BnOLeDMAP: Conformationally restricted nucleophilic catalysts for enantioselective rearrangement of indolyl acetates and carbonates

Full text of DOI:10.1021/ja805541u

Published on Web 12/18/2008
AcOLeDMAP and BnOLeDMAP: Conformationally Restricted Nucleophilic Catalysts
for Enantioselective Rearrangement of Indolyl Acetates and Carbonates
Trisha A. Duffey, Scott A. Shaw, and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received July 16, 2008; E-mail: edved@umich.edu
The catalytic asymmetric synthesis of all-carbon oxindole quaternary
centers has been a difficult challenge. Significant advances have been
described using phase-transfer,1 transition metal,2-5 and chiral nucleophilic
catalysts.6-9 Examples of the latter process include the highly enantiose-
lective rearrangement of indolyl carbonates 1 to the oxindoles 2 catalyzed
by planar-chiral pyridines (2 days, 35 °C, 10 mol% catalyst).6 Catalyst 3
(TADMAP) also promoted the rearrangement, but a marginal enantiose-
lectivity/reactivity profile at 10% catalyst loading discouraged detailed
optimization.7 Herein, we report a dramatic substitution effect that solves
the reactivity problem. We also describe the development of practical new
catalysts featuring a chiral side chain that prefers a uniquely advantageous
conformation. These advances enable enantioselective acyl and carboxyl
migration in the oxindole series.
Preparation of versatile substrates related to 1 from N-protected
oxindoles was challenging due to competing reaction at O and C, but
kinetic O-acetylation of oxindole 4 with acetyl chloride/2,6-lutidine
afforded enol acetate 5 in acceptable 81% yield.10 Deprotonation of 5
followed by trapping with reactive electrophiles then gave differentially
protected indolyl acetates 6 for initial evaluation. Upon catalysis with
DMAP (3%), the N-benzyl (6a) or N-alkoxcarbonyl (6b) derivatives
rearranged slowly to the oxindoles rac-7 (89% and 78% conversion,
5 h, rt) (Scheme 1). On the other hand, the N-nosyl (6c) or N-acyl
(6d-f; 8) analogues rearranged completely within 20 min (>95%)
while 6g rearranged to the extent of 84%. Therefore, reactivity increases
when more electron-withdrawing substituents are placed at indole N.
When 3 was used to catalyze the rearrangement of indolyl acetate 6d
to 7d, much improved reactivity was observed (98% isolated after 3 h, rt;
10% catalyst), but the 20% ee prompted a re-evaluation of the catalyst.
One concern was that synthesis of enantiopure 3 requires classical
resolution. Also the trityl group offers few options for catalyst modification
short of repeating the entire five-step synthesis/resolution sequence.
Accordingly, a new family of catalysts was designed that incorporates
both electronic and steric factors expected to favor a specific side chain
conformer. Thus, (S)-N-benzoylvalinol11 was oxidized to aldehyde 10a
and 3-Li-DMAP (from the bromide)7 was added to afford the alcohol
11a. Subsequent acylation yielded 12a (AcOVaDMAP, 6:1 dr, 72% from
10a, Scheme 2). A similar route from (S)-tert-leucinol afforded 12b
(AcOLeDMAP, >98:2 dr; 60% from 10b). Because diastereomer separa-
tion was not necessary with 12b, this catalyst was used for most of the
optimization studies. A third catalyst 13b (BnOLeDMAP) was prepared
by O-benzylation of isolated 11. The stereochemistry and the expected
geometry of 12 and 13 (anti DMAP and tBu groups; gauche OAc and
NHBz substituents) were confirmed by X-ray crystallography as shown
in 12b* and by J1,2 < 1 Hz for the OCHCHNBz protons of 12b and 13b.
This points to a strong preference for a well-defined catalyst geometry
having the benzamido substituent near the catalytic site at the nucleophilic
pyridine nitrogen.
Catalyst 12b effected rearrangement of the N-acetyl substrate 6d
to 7d with 61% ee (THF, rt). N-nosyl indole 6c gave similar results
(58% ee), while the N-isobutyryl indole 6e rearranged with increased
selectivity (77% ee). Reactivity dropped significantly with the N-pivalyl
analogue 6g, but the N-diphenylacetyl (N-DPA) indole 6f gave good
enantioselectivity in THF (89% ee) without impeding the reaction.
Optimal 92% ee was obtained in ethyl acetate at 0 °C, although other
common solvents also gave good results.
Preparation of 6f according to Scheme 1 afforded modest yields,
so a new route to N-DPA indolyl esters was developed. Heating 4 in
neat Ph2CHCOCl (1.5 equiv) yielded 14 (85%), and reaction with
AcCl/Et3N afforded the easily purified, crystalline indolyl acetate 15a
as well as ca. 5% of the C-acetylated isomer (Scheme 3). Various
indolyl acetates prepared in this way were then subjected to catalysis
by 12b (Table 1). Unbranched alkyl groups at the 3-position promoted
rearrangement to 16 with good selectivity and reactivity (entries 1-6).
A branched alkyl group (i-Pr) decreased the rate but gave oxindole
16f with 94% ee, while the more reactive 3-phenyl derivative 15g
rearranged with lower selectivity (entry 8).12 The 5-bromoindolyl
acetate 17 reacted completely within 20 min, and the purified major
Scheme 1
Scheme 2
9
14 J. AM. CHEM. SOC. 2009, 131, 14–15
10.1021/ja805541u CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
oxindole 18 was found to have the (S) configuration by X-ray
crystallography (anomalous dispersion). Since the oxindoles 16 and
18 have the same sign of optical rotation and similar chromophores,
and also have similar relative mobility for major vs minor enantiomers
on chiral hplc supports, 16a-g and 18 were assigned the same
configuration by analogy.
Using 1 mol% of 12b, 15a rearranged on gram scale within 24 h
(entry 2), and recrystallization upgraded the resulting 16a to 99% ee.
The valine derived catalyst 12a (AcOVaDMAP) was also effective
(16a: 88% yield, 90% ee). If desired, the N-DPA products 16 can be
deprotected to the N-H oxindoles 19. Strong base13 or primary amines
removed DPA as well as acetyl groups in 16, but diethyl amine
selectively cleaved DPA to give the parent oxindole (19a, 75%; 19c
65%). Retention of configuration was confirmed in the latter case (94%
ee). To further illustrate synthetic potential, 16a (88% ee) was converted
into 20a (73% yield; 87% ee) under Baeyer-Villiger conditions
(MCPBA/NaHCO3, CH2Cl2/reflux).
(12b) and BnOLeDMAP (13b) are the most practical and versatile
nucleophilic catalysts reported to date for enantioselective rearrange-
ment of indolyl acetates and carbonates to oxindoles containing chiral
quaternary carbon. The interplay between migrating group substituents
and catalyst modifications at the benzylic oxygen has striking
consequences, as illustrated by the complementary enantiofacial
selectivity for 13b with 21/23 vs 12b with 15/17.16 Furthermore, the
catalyst design highlights a conformationally restricted side chain that
may have other uses in situations where convergent functionality in a
chirotopic environment is required.
Acknowledgment. This work was supported by the National
Institutes of Health (CA17918). The authors thank Jeff W. Kampf
for X-ray crystallographic analysis and E. McGreevy for correlation
of 24a with 22a.
Supporting Information Available: Experimental procedures and
characterization (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Catalyst 12b was also evaluated with the indolyl carbonate substrates.
Rearrangement from 8 to 9 occurred readily (5 h, rt), but enantioselectivity
was low (4% ee). The reason became clear when NMR/MS assay of
recovered catalyst revealed clean conversion of 12b to an oxazoline
resulting from loss of the O-acetyl group.14 Stable 13b catalyzed the
conversion from 8 to 9 with modest 33% ee, but good enantioselectivity
was achieved by optimizing substituents. Thus, the N-DPA indolyl
carbonates 21 or 23 (available from 1-naphthylmethyl chloroformate) were
converted into oxindoles 22 or 24 with 90-94% ee using 13b in several
representative examples (entries 10-14; CHCl3, -20 °C). Remarkably,
these reactions afforded oxindoles having the opposite configuration
compared to 16 or 18 obtained using catalyst 12b according to X-ray
crystallography data for 25, obtained in 94% yield by treatment of 24a
with diethyl amine (Scheme 4).15
References
(1) Poulsen, T. B.; Bernardi, L.; Alema´n, J.; Overgaard, J.; Jørgensen, K. A.
J. Am. Chem. Soc. 2007, 129, 441.
(2) (a) Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem.
Soc. 1998, 120, 6477. (b) Dounay, A. B.; Hatanaka, K.; Kodanko, J. J.;
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(3) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
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E. P.; Seidel, T. M.; Jia, Y.-X.; Bernardinelli, G. Angew. Chem., Int. Ed.
2007, 46, 8484.
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(7) (a) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,
13368. (b) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.;
Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925.
In summary, carboxyl and acetyl migration of indolyl esters is
strongly accelerated by N-acyl groups. Easily accessible AcOLeDMAP
(8) For reviews of chiral nucleophilic amines see: (a) Spivey, A. C.; Maddaford,
A.; Redgrave, A. J. Org. Prep. Proced. Int. 2000, 32, 331. (b) France, S.;
Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103, 2985. (c)
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Table 1
(9) For other examples of chiral nucleophile catalyzed carboxyl rearrangements,
see: (a) Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006,
8, 769. (b) Busto, E.; Gotor-Ferna´ndez, V.; Gotor, V. AdV. Synth. Catal.
2006, 348, 2626.
entry
indole
R4
time
product
ee
1
2
3
4
5
6
7
8
15a
15a
15b
15c
15d
15e
15f
15g
17
21a
21b
21c
21d
23a
Me
”
Et
Bn
2 ha
16a 94%
16a 99%
16b 98%
16c 96%
16d 94%
16e 98%
16f 82%
16g 98%
18 95%
22a 91%
22b 98%
22c 99%
22d 98%
24a 90%
92%
92%
91%
94%c
91%
86%
94%
66%
85%
90%
92%
94%
91%
90%
(10) The use of less hindered or more basic amines led to nonselective oxindole
acetylation as did less reactive acetyl donors.
24 hb
2.5 ha
3 ha
(11) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713.
(12) Enantiopurity remained the same upon resubjecting oxindole 15b to the
reaction conditions, ruling out a reversible reaction.
(CH2)2OTBDPS
3 ha
2.5 ha
42 ha
2 ha
(13) Kawasaki, T.; Takamiya, W.; Okamoto, N.; Nagaoka, M.; Hirayama, T.
Tetrahedron Lett. 2006, 47, 5379.
Allyl
i-Pr
Ph
Me
Me
Bn
(14) The oxazoline is formed with retention, suggesting that ester cleavage to
the alcohol may be the initiating event. Decomposition of catalyst 12b was
not detected in any of the analogous indolyl actetate rearrangements.
(15) Oxindole 22a has the same configuration as 24a according to correlation
by debromination of 24a with Bu3SnH. Oxindoles 22 and 24a have the
opposite sense of optical rotation compared to 16 and 18. The chemical
correlation of 22a with 24a also supports the analogies used to assign the
absolute configurations of 16.
9
0.33 ha
23 hd
23 hd
23 hd
2 hd,e
5 hd,e
10
11
12
13
14
(CH2)2OTBDPS
Ph
Me
(16) Using 13b in place of 12b for Table 2, entry 1, affords the same major
enantiomer of 16a (77% ee; E. McGreevy, unpublished results).
a 10 mol % 12b, 0.2 M, EtOAc, 0 °C. b 1 mol % 12b. c Ee of
deprotected NH oxindole. d 10 mol% 13b, 0.8M, CHCl3, -20 °C. e 0.2 M.
JA805541U
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