Highly enantioselective intramolecular cyanoamidation: (+)-horsfiline, (-)-coerulescine, and (-)-esermethole

Article abstract of DOI:10.1021/ol902949d

(Figure Presented) The first asymmetric cyanoamidation with synthetically useful enantioselectivlty (ee up to 99%) to produce 3,3-disubstltuted oxindoles Is reported. Palladium catalysts with chi ral phosphoramldite ligands activate the cyanoformamide C-CN bond, which is subsequently functionalized with a tethered alkene to give all-carbon quaternary stereocenters. The use of the N,N-(i-Pr)₂ derivative of octahydro-MonoPhos allowed the production of oxindoles with high enantioselectivlties. Cyanoformamides bearing free N-H groups are now tolerated, potentially allowing protecting-group-free synthesis. Oxindole products of cyanoamidation are rapidly transformed into (+)-horsfiline, (-)-coerulescine, and (-)-esermethole.

Full text of DOI:10.1021/ol902949d

ORGANIC
LETTERS
2010
Vol. 12, No. 5
952-955
Highly Enantioselective Intramolecular
Cyanoamidation: (+)-Horsfiline,
(-)-Coerulescine, and (-)-Esermethole
Venkata Jaganmohan Reddy and Christopher J. Douglas*
Department of Chemistry, 207 Pleasant Street, SE, UniVersity of Minnesota,
Minneapolis, Minnesota 55455
cdouglas@umn.edu
Received December 23, 2009
This paper was withdrawn on May 19, 2011 (Org. Lett. 2010, 12, DOI: 10.1021/ol902949d).
ABSTRACT
The first asymmetric cyanoamidation with synthetically useful enantioselectivity (ee up to 99%) to produce 3,3-disubstituted oxindoles is
reported. Palladium catalysts with chiral phosphoramidite ligands activate the cyanoformamide C-CN bond, which is subsequently functionalized
with a tethered alkene to give all-carbon quaternary stereocenters. The use of the N,N-(i-Pr)2 derivative of octahydro-MonoPhos allowed the
production of oxindoles with high enantioselectivities. Cyanoformamides bearing free N-H groups are now tolerated, potentially allowing
protecting-group-free synthesis. Oxindole products of cyanoamidation are rapidly transformed into (+)-horsfiline, (-)-coerulescine, and
(-)-esermethole.
Carbon-carbon σ bond (C-C) activation and functional-
ization of unstrained bonds is a burgeoning strategy for
organic synthesis.1 Much of the recent work in this area has
focused on aryl nitriles, and independent reports of activation
of organonitriles (C-CN) and asymmetric alkene cyanoary-
lation highlights this new strategy’s potential in organic
synthesis.2 Less well developed is the catalytic activation
of cyanoformamide C-CN bonds. These easy-to-prepare
functional groups readily undergo C-C activation and allow
the addition of amide and nitrile functional groups across
alkenes or alkynes (cyanoamidation).3 While our study was
underway,4 Takemoto reported a similar asymmetric cy-
anoamidation obtaining a maximum ee of 86% for oxin-
doles.5
The synthetic potential of cyanoamidation for preparing
indole alkaloids bearing all-carbon quaternary stereocenters6
(Figure 1) led us to continue pursuing conditions with syntheti-
cally useful enantioselectivities. We now report that cyanoa-
midation reactions can achieve enantioselectivities in up to 99%
in the construction of all-carbon quaternary stereocenters, and
(1) Reviews: (a) Na´jara, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009,
48, 2452. (b) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008,
41, 222. (c) Nec¸as, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (d)
Murakami, M.; Eto, Y. In ActiVation of UnreactiVe Bonds and Organic
Synthesis; Murai, S., Ed.; Springer-Verlag: New York, 1999; p 97.
(2) Arylnitriles: (a) Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 12594. (b) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa,
M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874.
(4) Our work was initiated in the Fall of 2007 and a portion of this
study was previously disclosed: Reddy, V. J.; Douglas, C. J. Abstracts of
Papers, 238th National Meeting of the American Chemical Society, Aug
16-20, 2009; American Chemical Society: Washington, DC, 2009; ORGN
669.
(5) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303.
(6) Reviews: (a) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (b)
Christoffers, J.; Baro, A., Eds. Quaternary Stereocenters; Wiley-VCH Verlag
GmbH & Co. KGaA : Weinheim, Germany, 2005. (c) Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
(3) (a) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui, Y.; Yanada,
R.; Takemoto, Y. Tetrahedron 2007, 63, 2978. (b) Kobayashi, Y.; Kamisaki,
H.; Yanada, R.; Takemoto, Y. Org. Lett. 2006, 8, 2711.
10.1021/ol902949d  2010 American Chemical Society
Published on Web 01/27/2010

using the corresponding phosphorochloridite and amine.9 To
our delight, we were able to achieve enantiomeric excesses up
to 94% using L with DMPU as an additive (entry 2). There
was no longer a clear advantage in using decalin as solvent
with L,5 so we adopted THF as a more convenient solvent for
the remainder of our study. Reducing the amount of ligand L to
8 mol % decreased enantioinduction from 94% to 86% (entry 6).
Using our optimized conditions (Table 1, entry 2), we
explored the formation of other oxindoles (Table 2). Cy-
Table 2. Enantioselective Preparation of Oxindolesa
Figure 1. Quaternary carbon-bearing indole alkaloids.
we report demonstrative syntheses of (+)-horsfiline, (-)-
coerulescine, and (-)-esermethole with high enantioselectivity.
Our laboratory independently observed that catalytic Pd2dba3,
phosphoroamidite ligands, Lewis basic additives (HMPA, NMP,
DMPU),7 and solvents THF or decalin cyclized cyanoforma-
mide 1 to oxindole 2, presumably via intermediate 3 (Table 1).
Table 1. Optimization of Asymmetric Cyanoamidationa
entry
solvent
additive
yield
eeb
1
THF
THF
THF
decalin
decalin
THF
NMP
68%
72%
64%
66%
68%
70%
90%
94%
91%
89%
95%
86%
2c
3
DMPU
HMPA
NMP
DMPU
DMPU
4
5
6d
a Pd2dba3 (2 mol %), L (16 mol %), 100 °C. b Determined by HPLC
(Chiralcel OD-H, n-hexane:IPA (9:1), λ ) 220 nm) after column chroma-
tography on silica gel. c Conditions in entry 2 were used for the remainder
of the study. d L (8 mol %).
After examining the effects of the bidentate ligand BINAP and
several commercially available monodentate phosphoramidites,8
we concluded that commercially available ligands would only
give oxindole 2 with enantiomeric excesses in up to 86-91%,
only slightly better than the previous study.5 Postulating that
increasing ligand nitrogen substituent bulk and hydrogenating
the BINOL backbone would improve selectivity, we prepared
the N,N-(i-Pr)2 derivative of octahydro-MonoPhos L in one step
a Conditions: Pd2dba3 (2 mol %), L (16 mol %), DMPU (1 equiv), THF
(0.25 M in cyanoformamide), 100 °C. b Yields of product determined after
silica gel chromatography. c Determined by HPLC, absolute configuration
assigned in analogy to 25 (Scheme 1).
(7) We do not yet understand the role of these additives in asymmetric
cyanoamidation.
anoformamides were readily prepared from the corre-
sponding amines, using either tetracyanoethylene oxide
(8) Review on chiral monodentate phosphoramidites in asymmetric
catalysis: van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.;
Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars,
C. E. P.; Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Hubertus, H. J. W.;
de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308.
(9) Preparation of L: Zhang, F.-Y.; Chan, A. S. C. Tetrahedron:
Asymmetry 1998, 9, 1179.
Org. Lett., Vol. 12, No. 5, 2010
953

(TCEO) and dimethyl sulfide10 or carbonyl cyanide.11 Free
N-H containing compounds gave comparable enantiose-
lection to their protected congeners with only a moderate
decrease in yield (entries 1-4). Additional protection/
deprotection steps might offset decreases in yield associ-
ated with utilizing free N-H compounds in multistep
synthesis. Alkyl and silyloxymethyl ether substituents on
the alkene gave good yields and enantioselectivity (entries
3-9). Adding a methoxy group para to the cyanoforma-
mide (entries 7-9) increased yield and enantioselectivity
compared to their hydrogen counterparts (entries 2, 5, and
7). Notably, our use of chiral ligand L during the
cyanoamidation of 4 and 12 (entries 1 and 5) gave us much
higher enantiomeric excesses compared to previous work,
which used a commercially available ligand5 (88% vs
75%, and 97% vs 68%, respectively).
We highlighted the synthetic utility of cyanoamidation in
the total syntheses of (+)-horsfiline and (-)-coerulescine.13,14
A synthetic challenge of these alkaloids is the well-known,
acid-promoted, racemization of the quaternary stereocenter
via retro-Mannich/Mannich reactions (Scheme 2). Therefore,
Scheme 2
.
Acid-Promoted Retro-Mannich/Mannich
Racemization of Horsfiline
We assigned absolute stereochemistry of a cyanoamidation
product via chemical correlation with (-)-esermethole
(Scheme 1).2b Beginning with ester 22,12 two methyl groups
enantioselective routes require endgame strategies avoiding
the use of acid. In our approach, we envisioned that
mesylates, such as 37/38 (Scheme 3), could be converted to
the desired alkaloids in a one-pot chemoselective nitrile
reduction, which would cascade with cyclization and reduc-
tive amination via 39/40.
Scheme 1
.
Assignment of Absolute Configuration via Chemical
To realize the above approach, we began our syntheses
with the N-Boc-protected 2-bromoanilines 26/27. Boc-
protected bromoaniline 26 was produced in one step from
the commercially available 2-bromoaniline, while 27 was
available in two steps from commercially available 4-meth-
oxyaniline.15 Preparation of alkenes 31/32 proceeded with
use of a Pd-catalyzed Suzuki coupling16 of aryl boranes 28/
29 and iodoalkene 30.17 Boc-deprotection with TBSOTf in
2,6-lutidine generated the free anilines in 90% yield for both
substrates. We then prepared the corresponding cyanofor-
mamides using TCEO and dimethyl sulfide10 to give 33/34.
C-CN activation of cyanoformamides 35/36 provided the
corresponding oxindoles bearing a C3 silyloxymethyl group
with excellent enantioinduction. The silyl ethers (35/36) were
deprotected with TBAF, and the resulting alcohols were
converted to the corresponding mesylates (37/38). One-pot
reductive cyclization to form the spirocyclic skeleton was
readily accomplished by reaction of the nitriles with NaBH4/
CoCl2·6H2O,18,19 followed by reductive amination upon
addition of CH2O. We obtained (-)-coerulescine (ee 91%)
and (+)-horsfiline (ee 99%) in 54% and 49% yield from silyl
Correlation with (-)-Esermethole
were installed via alkylation with MeI. The resulting product
was subsequently converted to the alkene via attack with
excess MeMgBr followed by dehydration to form 23. After
installation of the cyanoformamide with carbonyl cyanide,11
cyanoamidation provided the corresponding oxindole 25
(82%, ee 99%). LiAlH4 reduction to the pyrrolidinylindoline
system and reductive amination installing the N-methyl group
(92%, 2 steps) completed the correlation with (-)-esermet-
hole. The stereochemistry of the remaining cyanoamidation
products was assigned in analogy to oxindole 25.
(14) Syntheses of (()-horsfiline or (()-coerulescine: (a) Murphy, J. A.;
Tripoli, R.; Khan, T. A.; Mali, U. W. Org. Lett. 2005, 7, 3287. (b) Chang,
M. Y.; Pai, C.-L.; Kung, Y.-H. Tetrahedron Lett. 2005, 46, 8463. (c) Lizos,
D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117. (d) Selvakumar,
N.; Azhagan, A. M.; Srinivas, D.; Krishna, G. G. Tetrahedron Lett. 2002,
43, 9175. (e) Kumar, U. K. S.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3,
4193. (f) Fischer, C.; Meyers, C.; Carreira, E. M. HelV. Chim. Acta 2000,
83, 1175. (g) Bascop, S.; Sapi, J. A.; Laroze, J.; Levy, J. Heterocycles 1994,
(10) Linn, W. J. Org. Synth. 1969, 49, 103.
(11) Martin, E. L. Org. Synth. 1971, 51, 268.
38, 725. (h) Jones, K.; Wilkinson, J. Chem. Commun. 1992, 1767.
(12) Prepared via Fischer esterification of the 5-hydroxyanthranillic acid
according to: Lippa, B.; Kauffman, G. S.; Arcari, J.; Kwan, T.; Chen, J.;
Hunderford, W.; Bhattacharya, S.; Zhao, X.; Williams, C.; Xiao, J.; Pustilnik,
L.; Su, C.; Moyer, J. D.; Ma, L.; Campbell, M.; Steyn, S. Bioorg. Med.
Chem. Lett. 2007, 17, 3081.
(15) Jensen, T.; Pedersen, H.; Bang-Anderson, B.; Madsen, R.; Jør-
gensen, M. Angew. Chem., Int. Ed. 2008, 47, 888–890.
(16) Conditions adapted from the following: Garg, N. K.; Sarpong, R.;
Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179.
(17) Preparation of 30: (a) Kamiya, N.; Chikami, Y.; Ishii, Y. Synlett
1990, 675. (b) Nicolaou, K. C.; Li, Y.; Uesaka, N.; Koftis, T. V.; Vyskocil,
S.; Ling, T.; Govindasamy, M.; Qian, W.; Bernal, F.; Chen, D. Y.-K. Angew.
Chem., Int. Ed. 2003, 42, 3643.
(13) Prior enantioselective syntheses: (a) Trost, B. M.; Brennan, M. K.
Org. Lett. 2006, 8, 2027. (b) Cravotto, G.; Giovenzana, C.; Pilati, T.; Sisti,
M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447. (c) Lakshmaiah, G.;
Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem. 1999, 64, 1699. (d)
Pellegrini, C.; Stra¨ssler, C.; Weber, M.; Borschberg, H. Tetrahedron:
Asymmetry 1994, 5, 1975.
(18) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron
Lett. 1969, 10, 4555
.
(19) Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1993, 58, 6451
.
954
Org. Lett., Vol. 12, No. 5, 2010

Scheme 3. Total Synthesis of (+)-Horsfiline and (-)-Coerulescine
ethers 35/36, respectively, with only one purification during
selectivity issues they encountered. Future work on additional
asymmetric cyanoamidation-based strategies for the synthesis
of alkaloids is ongoing.
the last three steps. The slight decrease in enantioselectivity
from oxindole 35 to (-)-coerulescine is attributed to slight
racemization, possibly during workup. Using our route, (-)-
coerulescine is available in eight steps from commercially
available materials, while (+)-horsfiline is available in nine.
We have reported a catalytic asymmetric cyanoamidation
of alkenes with excellent enantioselectivities. Free N-H
groups are tolerated, allowing for future protecting-group-
free synthesis of alkaloids. The utility of cyanoamidation is
exemplified by the syntheses of (-)-esermethole and spiro-
cyclic alkaloids (+)-horsfiline and (-)-coerulescine. Our
synthesis of (+)-horsfiline is similar in length to Trost’s13a
and Palmisano’s13b recent routes to (-)-horsfiline, while
circumventing some of the chemoselectivity and diastereo-
Acknowledgment. We thank the University of Minnesota
(UMN) for start-up funds, Prof. Andrew Harned (UMN) for
use of a shared HPLC, and Ms. Rosalind P. Douglas (UMN)
for assistance in manuscript preparation.
Supporting Information Available: Experimental pro-
cedures, 1H and 13C NMR spectra for new compounds, and
HPLC chromatograms for chiral compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL902949D
Org. Lett., Vol. 12, No. 5, 2010
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