Catalytic diastereo- and enantioselective annulations between transient nitrosoalkenes and indoles

Article abstract of DOI:10.1002/chem.201203435

Caught in transition: An efficient catalytic system is the key to the successful development of the first highly diastereo- and enantioselective annulation reaction between indoles and transient nitrosoalkenes. This robust reaction affords structurally unique architectures with up to three new chiral centers. The products can be readily elaborated into other indoline-based chiral heterocyclic motifs, including those of pyrrolidinoindoline alkaloids. Copyright

Full text of DOI:10.1002/chem.201203435

DOI: 10.1002/chem.201203435
Catalytic Diastereo- and Enantioselective Annulations between Transient
Nitrosoalkenes and Indoles
Yu Zhang, David Stephens, Graciela Hernandez, Rosalinda Mendoza, and
Oleg V. Larionov*[a]
Asymmetric reactions of nitroso compounds offer unique
À
À
advantages for the formation of C O and C N bonds espe-
cially in the area of biomedically relevant heterocycles.[1]
Heretofore, however, diastereo- and enantioselective trans-
formations of nitroso compounds have been limited to stoi-
chiometric chiral auxiliary-controlled processes.[2] Several
recent examples of catalytic enantioselective transforma-
tions of nitrosoarenes have demonstrated the potential of
this class of nitroso compounds in the context of asymmetric
catalysis.[3] On the other hand, highly enantioselective cata-
lytic reactions of related nitrosoalkenes, in particular annu-
lations have largely remained elusive.[4]
In part, this disparity is due to the differences in physical
properties of the nitroso compounds. Whereas nitrosoal-
kanes and nitrosoarenes display adequate ambient stability,
nitrosoalkenes are both more reactive and, with the excep-
tion of several sterically hindered examples, highly unstable,
with half-lives measured in minutes even at low tempera-
tures.[5] The fleeting character of these species renders devel-
opment of the catalytic asymmetric reactions of nitrosoal-
kenes a challenging task. We now report the first example
of a copper-catalyzed, asymmetric interceptive [4+2] annu-
lation of nitrosoalkenes generated in situ from 2-chloroox-
imes with substituted indoles (Scheme 1).
These catalytic reactions furnish heterocycles that have so
far been unavailable as single enantiomers, and produce up
to three new chiral centers in the 1,2-oxazine ring in one
step. 1,2-Oxazines are broadly represented among molecules
of biomedical interest such as highly potent antibiotic natu-
ral products FR66979 and FR900482[6] and cytotoxic tricho-
dermamides[7] (Scheme 1).
Scheme 1. Annulation reaction of indoles with transient nitrosoalkenes
and select natural products containing pyrrolidinoindoline and 1,2-oxa-
zine frameworks.
annulation reaction of nitrosoalkenes with electron-rich al-
kenes[9] (furans, enol ethers, indoles, and 1,3-dienes) by Gil-
christ et al., the mechanistic and synthetic aspects of the re-
action have been revealed in a series of elegant studies by
the groups of Reissig, Houk, Denmark and others.[2,10] Evi-
dence suggests that, at least in the case of sterically unhin-
dered dienophiles, the reaction proceeds through an endo
transition state by an asynchronous concerted mechanism.
Indoles are especially interesting substrates for this reac-
tion. Tricyclic 1,2-oxazines 3 possess structurally unique and
hitherto unexplored architectures. In addition, they can be
envisaged as precursors to a number of natural products and
their derivatives, such as pyrrolidinoindoline alkaloids (e.g.
acetylcholinesterase inhibitor physostigmine, Scheme 1)[11]
and as unconventional and new scaffolds[12] for drug discov-
ery applications.
An initial screen of Lewis acids revealed that copper(I)
triflate was singularly competent in promoting the reaction
between indole 1a and chlorooxime 2a at 238C. Lowering
the temperature to À158C effectively precluded the forma-
tion of the product (Table 1, entries 1 and 2). Phosphines
were then identified as promising chiral ligands that were
also capable of restoring some of the catalytic activity of
copper. Bisphosphines with axially chiral binaphthyl back-
bone proved superior to other ligands of the class.
The intermediacy of nitrosoalkenes in the reactions of 2-
halooximes with nucleophiles[8] has been confirmed by spec-
troscopic and kinetic measurements and, in few cases by
direct isolation of less reactive nitrosoalkenes.[5] Following
the initial discovery of the inverse electron demand [4+2]
[a] Dr. Y. Zhang, D. Stephens, G. Hernandez, R. Mendoza,
Prof. Dr. O. V. Larionov
Department of Chemistry
The University of Texas at San Antonio
San Antonio, TX 78249 (USA)
Fax : (+1)210-458-7428
When Cu[(S)-Binap]OTf was used as a catalyst in the
presence of NaHCO3 the 1,2-oxazine 3aa was formed in
12% yield and in 70% ee. The counterion had a notable
E-mail: oleg.larionov@utsa.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203435.
16612
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16612 – 16615

COMMUNICATION
Table 1. Select experiments in the optimization study of the asymmetric
Interestingly, the presence of coordinating ligands such as
acetonitrile in [CuACTHNUTRGNEUNG(MeCN)4]BF4 had a detrimental effect on
reaction of indoles 1 with 2-chlorooximes 2a.[a]
the enantioselectivity. Copper(II) triflate was also catalyti-
cally competent, although somewhat lower enantioselectivi-
ty was observed. The influence of the architecture of the
chiral ligand on the enantioselectivity was evidenced in the
decreased enantioselectivity with H8-Binap (wider dihedral
angle) and Segphos (narrower dihedral angle). Notably,
highly sterically encumbered DTBM-Segphos proved far in-
ferior to Binap. On the other hand, structurally close DM-
Binap provided the product in 86% ee. Further improve-
ment of the enantioselectivity was achieved by replacing the
allyl substituent on the nitrogen atom of the indole (Table 1,
entry 15) with the N-benzyl group culminating in the 91%
ee for 1,2-oxazine 3ba. Subsequent inquiry has established
that a benzyl group is advantageous but not essential for
achieving high enantioselectivity with other 2-chlorooximes
(Scheme 2).[13] In addition, a variety of substituents in the ar-
omatic ring of the N-benzyl group are also well-tolerated.
Under the optimized conditions, very good yields and
high enantioselectivities were achieved in the reactions of
variously decorated indoles with 2-chlorooxime precursors
of nitrosoalkenes (Scheme 2). Primary and secondary alkyl
substituents as well as an acetoxy group in the C3-position
of the indoles are well tolerated as are substituents in the 4-,
5-, and 6-positions. The 1’-naphthyl 1,2-oxazine is produced
with high enantioselectivity albeit in a somewhat lower yield
reflecting the increased steric bulk of the 1-naphthyl moiety.
Ester and heterocyclic (2-thiophyl) groups in the oximes
are equally permissible. Interestingly, 2,2-dichloroximes are
also viable nitrosoalkene precursors and furnish single dia-
stereomers of the corresponding products. This remarkable
result is consistent with the previously reported observation
of the endo-preference in the formation of sterically unhin-
dered 4-halo-substituted 1,2-oxazines.[14] It is noteworthy
that, while DM-Binap was generally the ligand of choice
DTBM-Segphos and Binap afforded higher enantioselectivi-
ty with 2,2-dichlorooximes and 1’-naphthyl oxime 2e pre-
sumably due to varied steric requirements of these sub-
strates.
Entry[a] CuX
Ligand Base
Yield[b] [%] ee[c] [%]
1
2
3
–
–
–
NaHCO3 <2
NaHCO3
NaHCO3
–
CuOTf·1= PhMe
6
12
–
70
–
2
CuOTf·1= PhMe L1
2
4
5
6
7
CuCl
L1
NaHCO3 <2
CuOTf·1= PhMe L1
Ag2CO3
Ag3PO4
Ag2O
80
16
67
81
77
82
68
82
61
53
76
71
41
44
68
65
64
63
86
59
51
91
2
CuOTf·1= PhMe L1
2
CuOTf·1= PhMe L1
2
8
9
Cu
Cu
G
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
L1
10[d]
11
12
13
14
15[e]
2
CuOTf·1= PhMe L2
2
CuOTf·1= PhMe L3
2
CuOTf·1= PhMe L4
2
CuOTf·1= PhMe L5
2
CuOTf·1= PhMe L3
2
[a] Reaction conditions: CuX (10 mol%), Ligand (10 mol%), 3 ꢁ MS,
CH2Cl2, À158C. [b] Determined by HPLC using 4-chlorofluorobenzene
as an internal standard. [c] Determined by chiral HPLC. [d] 2-Bromoace-
tophenone oxime was used instead of 2a. [e] N-Benzyl-3-allylindole (1b)
(R1 =CH2Ph) was used instead of 1a.
effect on the overall efficiency of the reaction. Strongly co-
ordinating halide anions interfered with the catalytic activity
(Table 1, entry 4). Weakly coordinating anions were optimal
with triflate being the counterion of choice due to the ease
of handling and ready availability of the corresponding cop-
per(I) triflate–toluene complex. At this point the low yield
of 3aa was deemed a major obstacle to the development of
an efficient catalytic system. A comprehensive screen of in-
organic and organic bases was performed, however, none of
the bases was able to surpass the initial result obtained with
NaHCO3.
Hypothesizing that the low yield was due to the inactiva-
tion of the cationic copper(I) catalyst by the chloride anion
ejected from the chlorooxime en route to nitrosoakene, we
tested silver carbonate as a base that can efficiently seques-
ter the chloride. We were delighted to observe a remarkable
surge in the catalytic activity evidenced by the 80% yield of
the 1,2-oxazine without erosion of the enantioselectivity.
Further study of the silver counterion effect (Table 1, en-
tries 8–10) demonstrated that the carbonate furnished 3aa
in distinctively higher enantioselectivity and yield than other
silver salts (Ag3PO4, Ag2O, AgF, AgCN, Ag2B4O7).
The 1,2-oxazine framework 3 serves as an excellent pre-
cursor to a number of other chiral heterocyclic scaffolds
(Scheme 3). The hexahydropyrroloACTHNUGTRNEUNG[2,3-b]indole architecture
that is vastly abundant among indole alkaloids[11] is accessed
by a PBr3-catalyzed Beckmann rearrangement. Subsequent
reduction reveals the frameworks of pyrrolidinoindoline al-
kaloids. Alternatively, reduction of the 1,2-oxazine to oxime
and the rearrangement afford pyrrolidine 5 featuring a C3-
all-carbon quaternary stereocenter.
Before this work, no examples of highly enantioselective
catalytic [4+2] annulations of unstable and extremely reac-
tive nitrosoalkenes were known. Our investigations have es-
tablished an approach to solving this problem through dis-
covery of the synergistic combination a copper catalyst and
a silver base. The catalytic reaction affords highly enantio-
merically enriched and structurally unique heterocyclic
Chem. Eur. J. 2012, 18, 16612 – 16615
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16613

O. V. Larionov et al.
motifs that, in addition, can serve as an entry to other chiral
heterocycles.
Experimental Section
1
General procedure: A solution of CuOTf · = PhMe (3.7 mg, 14.2 mmol,
2
10 mol%) and (S)-DM-BINAP (11.5 mg, 14.2 mmol, 10 mol%) in dry di-
chloromethane (0.5 mL) was stirred at 238C for 30 min. Oven-dried 3 ꢁ
molecular sieves (50 mg), indole (0.142 mmol), and oxime (0.142 mmol)
were added at 238C. The solution was cooled to À788C and silver carbo-
nate (117 mg, 0.426 mmol) was introduced in one portion. The reaction
mixture was stirred at À158C for 36–64 h. For workup, the mixture was
diluted with water (2 mL) and chloroform (5 mL), then filtered through a
plug of Celite. The organic layer was separated, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The crude
product was purified by column chromatography [hexanes/ethyl acetate]
to yield the corresponding 1,2-oxazine.
Acknowledgements
Financial support was provided by the Max and Minnie Tomerlin Voelck-
er Fund, the San Antonio Life Sciences Institute (SALSI), the University
of Texas at San Antonio, and the Welch Foundation (Grant No.: AX-
1788).
Keywords: asymmetric
catalysis
·
copper
·
enantioselectivity · indoles · nitroso compounds
[1] a) B. S. Bodnar, M. J. Miller, Angew. Chem. 2011, 123, 5746–5764;
Angew. Chem. Int. Ed. 2011, 50, 5630–5647; b) H. Yamamoto, M.
Kawasaki, Bull. Soc. Chem. Jpn. 2007, 80, 595–607; c) Y. Yamamo-
to, H. Yamamoto, Eur. J. Org. Chem. 2006, 2031–2043; d) J. Streith,
A. Defoin, Synthesis 1994, 1107–1117.
[2] a) T. Arnold, B. Orschel, H.-U. Reissig, Angew. Chem. 1992, 104,
1084–1086; Angew. Chem. Int. Ed. Engl. 1992, 31, 1033–1035; b) T.
Arnold, H.-U. Reissig, Synlett 1990, 514–516.
[3] a) Y. Yamamoto, N. Moniyama, H. Yamamoto, J. Am. Chem. Soc.
2004, 126, 5962–5963; b) Y. Yamamoto, H. Yamamoto, J. Am.
Chem. Soc. 2004, 126, 4128–4129; c) M. Kawasaki, P. Li, H. Yama-
moto, Angew. Chem. 2008, 120, 3855–3857; Angew. Chem. Int. Ed.
2008, 47, 3795–3797; d) A. Yanagisawa, S. Takeshita, Y. Izumi, K.
Yoshida, J. Am. Chem. Soc. 2010, 132, 5328–5329; e) M. Dochnahl,
G. Fu, Angew. Chem. 2009, 121, 2427–2429; Angew. Chem. Int. Ed.
2009, 48, 2391–2393.
Scheme 2. Substrate scope of the 1,2-oxazine formation. [a] Reaction
conditions: CuOTf·1= PhMe (10 mol%), (S)-DM-Binap (10 mol%),
2
Ag2CO3, 3 ꢁ MS, CH2Cl2, À158C. [b] (S)-DTBM-Segphos was used as a
ligand. [c] (S)-Binap was used as a ligand.
[4] A chiral amine-mediated reaction of 2-halooxime with an aldehyde
has been reported to produce a formal annulation product in 42%
ee: T. C. Wabnitz, S. Saaby, K. A. Jørgensen, Org. Biomol. Chem.
2004, 2, 828–834. An enantioselective organocatalytic addition of
thiols to 1-nitrosocyclohexene generated in situ form 2-chlorocyclo-
hexenone oxime: J. M. Hatcher, M. C. Kohler, D. M. Coltart, Org.
Lett. 2011, 13, 3810–3813.
[5] T. L. Gilchrist, Chem. Soc. Rev. 1983, 12, 53–73.
[6] a) H. Terano, S. Takase, J. Hosoda, M. Kohsaka, J. Antibiot. 1989,
42, 145–148; b) I. Uchida, S. Takase, H. Kayakiri, S. Kiyoto, M. Ha-
shimoto, T. Tada, S. Koda, Y. Morimoto, J. Am. Chem. Soc. 1987,
109, 4108–4109.
[7] E. Garo, C. M. Starks, P. R. Jensen, W. Fenical, E. Lobkovsky, J.
Clardy, J. Nat. Prod. 2003, 66, 423–426.
[8] a) R. Sengupta, J. A. Witek, S. M. Weinreb, Tetrahedron 2011, 67,
8229–8234; b) I. Korboukh, P. Kumar, S. M. Weinreb, J. Am. Chem.
Soc. 2007, 129, 10342–10343; c) E. J. Corey, L. S. Melvin, M. F. Has-
langer, Tetrahedron Lett. 1975, 16, 3117–3120.
Scheme 3. Elaboration of pyrrolidinoindoline and indoline frameworks
from 1,2-oxazines 3ba and 3la.
16614
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16612 – 16615

Catalytic Diastereo- and Enantioselective Annulations
COMMUNICATION
[9] a) T. L. Gilchrist, R. Faragher, J. Chem. Soc. Chem. Commun. 1976,
581; b) T. L. Gilchrist, T. G. Roberts, J. Chem. Soc. Chem. Commun.
1978, 847b; c) T. L. Gilchrist, D. A. Lingham, T. G. Roberts, J.
Chem. Soc. Chem. Commun. 1979, 1089; d) R. Faragher, T. L. Gil-
christ, J. Chem. Soc. Perkin Trans. 1 1979, 249–257; e) D. E. Davies,
T. L. Gilchrist, T. G. Roberts, J. Chem. Soc. Perkin Trans. 1 1983,
1275–1281; f) T. L. Gilchrist, T. G. Roberts, J. Chem. Soc. Perkin
Trans. 1 1983, 1283.
[10] a) S. E. Denmark, M. S. Dappen, J. Org. Chem. 1984, 49, 798–806;
b) S. E. Denmark, M. S. Dappen, J. A. Sternberg, J. Org. Chem.
1984, 49, 4741–4743; c) J. Liu, S. Niwayama, Y. You, K. N. Houk, J.
Org. Chem. 1998, 63, 1064–1073; d) L. R. Domingo, M. T. Picher, P.
Arroyo, Eur. J. Org. Chem. 2006, 2570–2580; e) J. C. Monbaliu, G.
Dive, J. Marchand-Brynaert, D. Peeters, J. Mol. Struct. 2010, 959,
49–54.
[11] P. Ruiz-Sanchis, S. A. Savina, F. Albericio, M. Alvarez, Chem. Eur.
J. 2011, 17, 1388–1408.
[12] C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514–5533.
[13] The absolute configuration of 1,2-oxazines 3 was determined by
preparation of the known (R)-2-(1-benzyl-3-methylindolin-3-yl)ace-
tonitrile from 1,2-oxazine 3la. The relative configuration of the C4-
stereocenter (C-Cl) was determined by NOE difference spectroscop-
ic analysis of 3eb and 3kd. See Supporting Information for further
details.
[14] S. C. Yoon, K. Kim, Y. J. Park, J. Org. Chem. 2001, 66, 7334–7341.
Received: September 26, 2012
Published online: November 30, 2012
Chem. Eur. J. 2012, 18, 16612 – 16615
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16615