Pd-catalyzed enantioselective aerobic oxidation of secondary alcohols: Applications to the total synthesis of alkaloids

Article abstract of DOI:10.1021/ja804738b

Enantioselective syntheses of the alkaloids (-)-aurantioclavine, (+)-amurensinine, (-)-lobeline, and (-)- and (+)-sedamine are described. The syntheses demonstrate the effectiveness of the Pd-catalyzed asymmetric oxidation of secondary alcohols in diverse contexts and the ability of this methodology to set the absolute configuration of multiple stereocenters in a single operation. The utility of an aryne C-C insertion reaction in accessing complex polycyclic frameworks is also described.

Full text of DOI:10.1021/ja804738b

Published on Web 09/18/2008
Pd-Catalyzed Enantioselective Aerobic Oxidation of
Secondary Alcohols: Applications to the Total Synthesis of
Alkaloids
Shyam Krishnan, Jeffrey T. Bagdanoff, David C. Ebner, Yeeman K. Ramtohul,
Uttam K. Tambar, and Brian M. Stoltz*
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis, DiVision of Chemistry and
Chemical Engineering, California Institute of Technology, 1200 East California BouleVard,
MC 164-30, Pasadena, California 91125
Received June 20, 2008; E-mail: stoltz@caltech.edu
Abstract: Enantioselective syntheses of the alkaloids (-)-aurantioclavine, (+)-amurensinine, (-)-lobeline,
and (-)- and (+)-sedamine are described. The syntheses demonstrate the effectiveness of the Pd-catalyzed
asymmetric oxidation of secondary alcohols in diverse contexts and the ability of this methodology to set
the absolute configuration of multiple stereocenters in a single operation. The utility of an aryne C-C insertion
reaction in accessing complex polycyclic frameworks is also described.
sponding enantioenriched product (Scheme 1a, path B).3 In
addition, kinetic resolution of a racemic, diastereomerically pure
Introduction
Chiral amines are a key functional group in numerous
biologically active natural products and synthetic drugs. The
enantioselective synthesis of amines has been extensively
investigated and continues to be a field of intense interest.1
Chiral amines can be accessed from the corresponding alcohols
using several possible approaches. This transformation could,
in principle, be achieved via functional group interconversion
of a hydroxyl to an amine functionality at a stereogenic carbon
(Scheme 1a, path A).2 Alternatively, desymmetrization of a
meso-substrate bearing multiple pro-stereogenic centers with
alcohol and amine functional groups could deliver the corre-
substrate with stereocenters bearing hydroxyl and amine func-
tionalities provides a route to chiral amino alcohols (Scheme
1a, path C). Finally, diastereoselective installation of a stereo-
center bearing an amine group can be accomplished from a
substrate that already features a hydroxyl-bearing stereocenter
(Scheme 1a, path D). In this article, we present syntheses of
natural products bearing chiral amines or chiral amino alcohols
employing each of the above strategies.
We sought to apply the Pd-catalyzed aerobic oxidative kinetic
resolution4 (Scheme 1b) developed in our laboratory toward the
synthesis of alkaloids. This transformation enables the catalytic
enantioselective synthesis of chiral alcohols, with benzylic
alcohols being particularly excellent substrates.5 We present here
syntheses of the natural products (-)-aurantioclavine ((-)-1),
(+)-amurensinine ((+)-2), (-)-lobeline ((-)-3), (-)-sedamine
((-)-4), and (+)-sedamine (Figure 1) by kinetic resolution or
desymmetrization of benzylic alcohols as the key steps.
(1) For recent reviews on the enantioselective synthesis of amines, see:
(a) Moody, C. J. Angew. Chem., Int. Ed. 2007, 46, 9148. (b) Ouellet,
S. G.; Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40,
1327. (c) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J.
Acc. Chem. Res. 2007, 40, 1394. (d) Masson, G.; Housseman, C.; Zhu,
J. Angew. Chem., Int. Ed. 2007, 46, 4614. (e) Li, G.; Saibau, K.;
Timmons, C. Eur. J. Org. Chem. 2007, 17, 2745. (f) Bra¨se, S.;
Baumann, T.; Dahmen, S.; Vogt, H. Chem. Commun. 2007, 1881. (g)
Maruoka, K.; Ooi, T.; Kano, T. Chem. Commun. 2007, 1487. (h)
Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (i) Roesky, P. W.;
Mueller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708. (j) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(-)-Aurantioclavine ((-)-1) is an ergot alkaloid that was first
isolated from Penicillium aurantioVirens.6 The alkaloid pos-
sesses a 3,4,5,6-tetrahydro-6-(2-methyl-1-propenyl)azepino[5,4,3-
(2) For selected examples of synthesis of amines directly from alcohols,
their corresponding esters, carbonates, sulfonate esters, or alkyl halides,
see: (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (b) Fujita,
K-i.; Fujii, T.; Yamaguchi, R Org. Lett. 2004, 6, 3525. (c) Evans,
P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121,
6761. (d) Scriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 297.
(e) Kolasa, T.; Miller, M. J. J. Org. Chem. 1987, 52, 4978. (f)
Bestmann, H. J.; Wo¨lfel, G. Chem. Ber. 1984, 117, 1250. (g) Trost,
B. M.; Keinan, E. J. Org. Chem. 1979, 44, 3451. (h) Nordlander, J. E.;
Catalane, D. B.; Eberlein, T. H.; Farkas, L. V.; Howe, R. S.; Stevens,
R. M.; Tripoulas, N. A.; Stansfield, R. E.; Cox, J. L. Tetrahedron
Lett. 1978, 50, 4987. (i) Jonczyk, A.; Ochal, Z.; Makosza, M. Synthesis
1978, 882. (j) Zwierzak, A.; Podstawczynska, I. Angew. Chem., Int.
Ed. Engl. 1977, 16, 702. (k) Hendrickson, J. B.; Joffee, I. J. Am. Chem.
Soc. 1973, 95, 4083. (l) Mitsunobu, O.; Wada, M.; Sano, T. J. Am.
Chem. Soc. 1972, 94, 679. (m) Gibson, M. S.; Bradshaw, R. W. Angew.
Chem., Int. Ed. Engl. 1968, 7, 919.
(3) For recent reviews of asymmetric desymmetrization, see: (a) Rendler,
S.; Ostreich, M. Angew. Chem., Int. Ed. 2008, 47, 248. (b) Rovis, T.
Recent Advances in Catalytic Asymmetric Desymmetrization Reac-
tions. In New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens,
M., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007; pp 275-
311. (c) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. ReV. 2007, 107,
5683. (d) Schneider, C. Synthesis 2006, 23, 3919. (e) Garcia-Urdiales,
E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005, 105, 313.
(4) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725.
(b) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc.
2001, 123, 7475.
(5) For an experimentally derived model for stereoselectivity in the
oxidative kinetic resolution of benzylic alcohols catalyzed by Pd-
(sparteine)Cl2, see: Trend, R. M.; Stoltz, B. M J. Am. Chem. Soc.
2004, 126, 4482.
(6) Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin, V. M.
Dokl. Akad. Nauk SSSR 1981, 260, 230.
9
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2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 13745–13754 13745

A R T I C L E S
Krishnan et al.
Scheme 1
Scheme 2
(-)-Amurensinine ((-)-2) belongs to a family of alkaloids,
the isopavines (Figure 2), originally isolated from Papaveraceae
plants.10 The isopavines display biological activity relevant to
neurological disorders such as Parkinson’s disease, Down’s
syndrome, Alzheimer’s disease, amyotropic lateral sclerosis, and
Huntington’s chorea. Despite the potential medicinal applica-
tions of the isopavines and their analogues,11 relatively few total
syntheses of these natural products have been reported.12 The
majority of these syntheses involve intramolecular acid-
promoted cyclization to form the azabicyclo[3.2.2]nonane core
cd]indole tricyclic ring system bearing a single stereocenter.
We were particularly interested in aurantioclavine as an
intermediate en route to the complex polycyclic alkaloids of
the communesin family7 (Scheme 2). While syntheses of
racemic aurantioclavine8 have been reported in the literature,
an asymmetric synthesis of aurantioclavine has not been
reported, to the best of our knowledge. Our objective was to
develop an enantioselective synthesis of (-)-1 as a means
toward an asymmetric synthesis of members of the communesin
family.9
Figure 1. Alkaloids with nitrogen-bearing stereocenters.
9
13746 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Pd-Catalyzed Oxidation of Secondary Alcohols
A R T I C L E S
the neurochemical and behavioral effects of methamphetamine
and is an inhibitor of dopamine and vesicular monoamine
transporter function. (-)-3 is thus a promising lead in the
development of treatments for methamphetamine abuse.17 While
it may be isolated from its natural source and crystallized as a
single isomer in salt form, in the solution state the free base of
(-)-3 is known to exist in equilibrium with its epimer at C(3).18
Due to this known equilibrium, early enantioselective synthe-
ses19 by Marazano and Lebreton report the synthesis of (-)-3
as a mixture with its C(3) epimer. Our goal was to access the
alkaloid 3 in diastereomerically pure form, and we believed that
the application of the Pd-catalyzed enantioselective oxidation
would allow efficient access to (-)-3 from a symmetric meso-
intermediate. We also believed that access to either enantiomer
of sedamine (4),20,21 a piperidine derivative found in various
Sedum species, would be possible through the application of a
Pd-catalyzed oxidative kinetic resolution.
Results and Discussion
Figure 2. Isopavine natural products.
Retrosynthesis of (-)-Aurantioclavine. Our retrosynthetic
analysis for (-)-aurantioclavine ((-)-1) is depicted in Scheme
of the isopavines. We envisioned a catalytic enantioselective
approach to rapidly access the isopavine core in a modular
fashion.13
(15) For syntheses of racemic (()-lobeline, see: (a) Wieland, H.; Drishaus,
I. Annalen 1929, 473, 102. (b) Wieland, H.; Koschara, W.; Dane, E.
Annalen 1929, 473, 118. (c) Scheuing, G.; Winterhalder, L. Justus
Liebigs Ann. Chem. 1929, 473, 126. (d) Wieland, H.; Koshara, W.;
Dane, E.; Renz, J.; Schwarze, W.; Linde, W. Justus Liebigs Ann. Chem.
1939, 540, 103. (e) Parker, W.; Raphael, R. A.; Wilkinson, D. I.
J. Chem. Soc. 1959, 2433. (f) For an X-ray crystallography study of
(-)-lobeline salts, see: Glaser, R.; Hug, P.; Drouin, M.; Michael, A.
J. Chem. Soc., Perkin Trans. 2 1992, 1071. (g) For a study of the
biosynthesis of (-)-lobeline, see: Keogh, M. F.; O’Donovan, D. G.
J. Chem. Soc. 1970, 2470.
(-)-Lobeline ((-)-3) is a primary alkaloid constituent of
Lobelia inflata, a plant commonly known as “Indian tobacco”
because it was previously used by native North Americans as
a tobacco substitute.14,15 A respiratory stimulant, the plant’s
crude extracts have been widely used for the treatment of
respiratory illnesses, including asthma, bronchitis, pneumonia,
and whooping cough. (-)-3 mildly mimics the effect of nicotine,
is an antagonist of nicotine acetylcholine receptors, and has thus
been applied as a smoking cessation agent.16 (-)-3 also inhibits
(16) (a) Millspaugh, C. F. Lobelia inflata. American medicinal plants: an
illustratiVe and descriptiVe guide to plants indigenous to and natural-
ized in the United States which are used in medicine; Dover: New
York, 1974; pp 385-388. (b) Dwoskin, L. A.; Crooks, P. A. Biochem.
Pharmacol. 2002, 63, 89. (c) Thayer, A. M. Chem. Eng. News 2006,
84 (39), 21.
(7) (a) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami,
Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron
Lett. 1993, 34, 2355. (b) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg,
A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod.
2004, 67, 78. (c) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci.
Biotechnol. Biochem. 2004, 68, 753. (d) Dalsgaard, P. W.; Blunt, J. W.;
Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod.
2005, 68, 258.
(17) Zheng, G.; Dwoskin, L. P.; Deacuic, A. G.; Norrholm, S. D.; Crooks,
P. A. J. Med. Chem. 2005, 48, 5551.
(18) The epimerization at C(3) is believed to be a base-catalyzed equilibra-
tion via transient retro-conjugate addition intermediate 19. See also
refs 19a, 19b, and 19d.
(8) For total syntheses of aurantioclavine, see: (a) Somei, M.; Yamada,
F. Heterocycles 2007, 74, 943. (b) Yamada, F.; Makita, Y.; Suzuki,
T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162. (c) Hegedus, L. S.;
Toro, J. L.; Miles, W. H.; Harrington, P. J. J. Org. Chem. 1987, 52,
3319.
(9) (a) May, J. A.; Stoltz, B. M. Tetrahedron 2006, 62, 5262. (b) May,
J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203.
(10) (a) Boit, H. G.; Flentje, H. Naturwissenschaften 1960, 47, 180. (b)
Go¨zler, B.; Lantz, M. S.; Shamma, M. J. Nat. Prod. 1983, 46, 293.
(11) For discussions of the biological activity of the isopavine alkaloids,
see: (a) Weber, E.; Keana, J.; Barmettler, P. PCT Int. Appl. 106019w,
1991; Chem. Abstr. 1991, 115, 106019w. (b) Childers, W. E.; Abou-
Gharbia, M. A. U.S. Patent 4,940,789, 1990; Chem. Abstr. 1990, 113,
191190w.
(19) For enantioselective syntheses of (-)-lobeline, see: (a) Compere, D.;
Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 4528. (b) Felpin,
F.-X.; Lebreton, J. J. Org. Chem. 2002, 67, 9192. (c) Klingler, F.-D.;
Sobotta, R. (Boehringer Ingelheim). U.S. Patent 2006014791, 2006.
(d) Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237.
(20) (a) Marion, L.; Lavigne, R.; Lemay, L Can. J. Chem. 1951, 29, 347.
(b) Franck, B. Chem. Ber. 1958, 91, 2803. (c) Logar, C.; Mesicek,
M.; Perpar, M.; Seles, E. Farm. Vestn. 1974, 21; Chem. Abstr. 1975,
82, 81926h. (d) Krasnov, E. A.; Petrova, L. V.; Bekker, E. F. Khim.
Prir. Soedin. 1977, 585; Chem. Abstr. 1977, 87, 164249k.
(21) For a review of syntheses of the Sedum alkaloids, see: (a) Bates, R. W.;
Sa-Ei, K. Tetrahedron 2002, 58, 5957. For recent syntheses of either
enantiomer of sedamine, see: (b) Bates, R. W.; Nemeth, J. A.; Snell,
R. H. Synthesis 2008, 1033. (c) Fustero, S.; Jime´nez, D.; Moscardo´,
J.; Catala´n, S.; del Pozo, C. Org. Lett. 2007, 9, 5283. (d) Yadav, J. S.;
Reddy, M. S.; Rao, P. P.; Prasad, A. R. Synthesis 2006, 4005. (e)
Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron
Lett. 2006, 47, 4397. (f) Bates, R. W.; Boonsoombat, J. Org. Biomol.
Chem. 2005, 3, 520. (g) Josephson, N. S.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2004, 126, 3734. (h) Zheng, G.; Dwoskin,
L. P.; Crooks, P. A. J. Org. Chem. 2004, 69, 8514. (i) Angoli, M.;
Barilli, A.; Lesma, G.; Passarella, D.; Riva, S.; Silvani, A.; Danieli,
B. J. Org. Chem. 2003, 68, 9525. (j) Cossy, J.; Willis, C.; Bellosta,
V.; BouzBouz, S. J. Org. Chem. 2002, 67, 1982.
(12) For selected syntheses of isopavine alkaloids, see: (a) Go¨zler, B. Pavine
and Isopavine Alkaloids. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1987; Vol. 31, pp 343-356. (b) Meyers, A. I.;
Dickman, D. A.; Boes, M. Tetrahedron 1987, 43, 5095. (c) Gottlieb,
L.; Meyers, A. I. J. Org. Chem. 1990, 55, 5659. (d) For a synthesis of
(-)-amurensinine, see: Carillo, L.; Bad´ıa, D.; Dom´ınguez, E.; Vicario,
J. L.; Tellitu, I. J. J. Org. Chem. 1997, 62, 6716. (e) Shinohara, T.;
Takeda, A.; Toda, J.; Sano, T. Heterocycles 1998, 48, 981. (f)
Hanessian, S.; Mauduit, M. Angew. Chem., Int. Ed. 2001, 40, 3810.
(g) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc.
2001, 123, 10127.
(13) For our preliminary communication of the enantioselective synthesis
of (+)-amurensinine, see: Tambar, U. K.; Ebner, D. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2006, 128, 11752.
(14) For a review of chemistry and biology of the Lobelia alkaloids, see:
Felpin, F.-X.; Lebreton, J. Tetrahedron 2004, 60, 10127.
9
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A R T I C L E S
Krishnan et al.
Scheme 3
Scheme 4
3. We believed that (-)-1 could be accessed from amino alcohol
derivative 9 via dehydration of the tertiary alcohol to form the
trisubstituted olefin and subsequent removal of the sulfonamide
protecting groups. Sulfonamide 9 could in turn be derived from
amino-diol derivative 10 via cyclization to form the 3,4,5,6-
tetrahydroazepino[5,4,3-cd]indole ring system of the natural
product. Diol 10 could then be derived from enantioenriched
diol 12 via amino alcohol derivative 11. Diol 12 could then be
accessed from the known aldehyde 13.
Retrosynthesis of (+)-Amurensinine. Our approach to the
isopavines, and specifically to amurensinine, is depicted in
Scheme 4. Disconnection of the bridging amine in the natural
product reveals azidoester 14, which can be derived from
hydroxyester (-)-15. We envisioned the enantioselective syn-
thesis of this benzylic alcohol by Pd-catalyzed oxidative kinetic
resolution. Hydroxyester (()-15 could then arise from ketoester
(()-16, which we believed could be derived from arylsilyl
triflate 17 and ꢀ-ketoester 18 via aryne C-C insertion22
methodology recently developed in our laboratory.
under equilibrating conditions via intermediate enone 19. Diol
20 could then be derived via disconnection of a C-C bond to
arrive at amino alcohol (()-21. Enantioselective oxidation of
amino alcohol derivative (()-21 in turn would allow us to access
either (-)-sedamine ((-)-4) or its enantiomer. We believed that
amino alcohol derivative (()-21 could be readily accessed from
aldehyde 22.
Synthesis of (-)-Aurantioclavine. Our synthesis of the ergot
alkaloid (-)-aurantioclavine commenced with aldehyde 13
(Scheme 6).23 Addition of the dianion derived from isobu-
tylene oxide24 to the aldehyde furnished racemic diol (()-
12. At this stage, application of a Pd-catalyzed oxidative
kinetic resolution delivered enantioenriched diol (-)-12 in
96% ee and 37% yield (91% of the theoretical maximum,
selectivity factor25 s ) 18.2). Product ketone 23 could be
readily recycled by reduction with lithium aluminum hydride,
affording diol (()-12 in 95% yield.
The enantioenriched diol (-)-12 was then transformed to
tricyclic alcohol 9 (Scheme 7). Diol (-)-12 was treated with
hydrazoic acid under Mitsunobu conditions26 to furnish azi-
doalcohol 24. This transformation was conducted at low
temperature to minimize racemization at the sensitive benzylic
stereocenter. Hydrogenation of the azide and protection of the
amine as a 2-nitrobenzenesulfonamide27 delivered sulfonamide
11. Bromination of the indole nucleus was followed by
Retrosynthesis of (-)-Lobeline. We believed that the late-
stage Pd-catalyzed oxidative desymmetrization of meso-diol 20,
a natural product known as lobelanidine, could deliver (-)-
lobeline ((-)-3, Scheme 5). We also envisioned that the
diastereoselective formation of the desired cis-2,6-disubstituted
piperidine moiety of amino alcohol (-)-3 could be achieved
(22) (a) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
Others have disclosed similar aryne insertions since our initial report,
see: (b) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3292. (c) Yoshida, H.; Watanabe, M.; Ohshita, J.;
Kunai, A. Tetrahedron Lett. 2005, 46, 6729.
(23) Kozikowski, A. P.; Ishida, H.; Chen, Y.-Y. J. Org. Chem. 1980, 45,
3350.
(24) Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1996, 7,
2997.
9
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Pd-Catalyzed Oxidation of Secondary Alcohols
A R T I C L E S
Scheme 5
Scheme 6
Scheme 7
vinylation of bromoindole 25 under Stille conditions28 to furnish
vinyl indole 26. Hydroboration-oxidation29 of the olefin of 26
to amino diol derivative 10 was followed by formation of the
azepine under Mitsunobu conditions to deliver tricyclic alcohol
9 in excellent yield. We then investigated the dehydration of
the tertiary alcohol 9 to (-)-aurantioclavine (Scheme 8).
Unfortunately, under various reaction conditions,30 dehydra-
tion of the tertiary alcohol delivered a mixture of inseparable
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13749

A R T I C L E S
Krishnan et al.
Scheme 8
Scheme 9
Scheme 10
olefin isomers, with the undesired isomer 28 predominating in
all cases. In an attempt to access the desired trisubstituted olefin
isomer, we then turned to dehydration of intermediate 26 prior
to formation of the azepine ring (Scheme 8).
We found that employing phosphorus oxychloride as the
dehydrating agent in pyridine as solvent delivered the desired
trisubstituted olefin isomer 29 as the major product. The olefin
isomers 29 and 30 were separable by employing silica gel
impregnated with silver nitrate.31
The completion of the synthesis of (-)-aurantioclavine is
depicted in Scheme 9. Selective hydroboration-oxidation of
the terminal olefin in vinyl indole 29 delivered the protected
amino alcohol 31, which was then transformed to the tricyclic
alcohol 27 under Mitsunobu conditions in excellent yield.
Removal of the o-nitrobenzenesulfonyl protecting group deliv-
ered amine 32. Subsequent removal of the tosyl group using
tetrabutylammonium fluoride (TBAF)32 then delivered (-)-
aurantioclavine ((-)-1).
Synthesis of (+)-Amurensinine. The synthesis of amurensinine
began from diazoketone 33, readily available in five steps and
95% overall yield from homoveratric acid (Scheme 10).
Selective intramolecular C-H insertion provided ꢀ-ketoester
18 in excellent yield.33 Treatment of ꢀ-ketoester 18 with arylsilyl
(25) The selectivity factor, s, for kinetic resolution is defined as the ratio
of the rate of reaction of the fast-reacting enantiomer of the racemic
substrate, kfast, to the rate of reaction of the slow-reacting enantiomer,
kslow, in the same transformation, i.e., s ) (kfast/kslow). The selectivity
factor can be expressed in terms of enantiomeric excess (ee) of the
remaining alcohol and the conversion (c) of the alcohol to the
corresponding ketone, i.e., s ) ln[(1- c)(1-ee)]/ln[(1- c)(1 +ee)].
For s > 10, synthetically useful quantities of enantioenriched alcohol
can be accessed. For example, an oxidative kinetic resolution with s
) 10 at 62% conversion would afford recovery of alcohol of 90% ee.
See also: Kagan, H. B., Fiaud, J. C. In Topics in Stereochemistry;
Eliel, E. L., Ed.; Wiley & Sons: New York, 1988; Vol. 18, pp 249-
330.
(26) Mitsunobu, O. Synthesis 1981, 1.
(27) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
(28) For reviews of the Stille cross-coupling reaction, see: (a) Stille, J. K.
Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina, V.; Krish-
namurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (c) Littke, A. F.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (d) Espinet, P.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
(29) (a) Knights, E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 5281.
(b) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am. Chem. Soc.
1974, 96, 7765.
(30) See Supporting Information for details.
(31) Morris, L. J. J. Lipid Res. 1966, 7, 717.
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Pd-Catalyzed Oxidation of Secondary Alcohols
A R T I C L E S
Scheme 11
Scheme 14
Scheme 12
Scheme 15
Scheme 13
triflate 17, available in five steps from sesamol, in the presence
of cesium fluoride22a,34 afforded ketoester (()-16, thereby
generating the polycyclic carbon framework of amurensinine
in rapid fashion.
Chemo- and diastereoselective reduction of the ketone of (()-
16 with L-Selectride generated hydroxyester (()-15 as a single
diastereomer, presumably resulting from equatorial delivery of
hydride to the ketone (Scheme 11).
We then examined the Pd-catalyzed oxidative kinetic resolu-
tion of hydroxyester (()-15. Under optimized reaction condi-
tions, the racemic alcohol could be resolved to highly enan-
tioenriched hydroxyester (-)-15 with good selectivity (Scheme
12). Though the overall mass recovery of (-)-15 and (+)-16
was not ideal, significant quantities of enantioenriched alcohol
(-)-15 could be accessed from this pathway.
We next investigated introduction of the amine required for
amurensinine from alcohol (-)-15. We found that alcohol (-)-
15 was unreactive to many common nitrogen-bearing nucleo-
philes under Mitsunobu conditions, or it reacted to form a
stilbene system by elimination. However, we were able to install
an azide by employing diphenylphosphoryl azide in a procedure
developed specifically for electron-rich benzylic alcohols by
Thompson and co-workers (Scheme 13).35 Reduction of the
resulting azide afforded bridged lactam (+)-34. Lactam reduc-
tion and reductive methylation afforded (+)-amurensinine ((+)-
2).
(32) Yasuhara, A.; Sakamoto, T. Tetrahedron Lett. 1998, 39, 595.
(33) (a) Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; Da Silva,
R. R.; Shulman, S.; Warnet, R. J.; Ceccherelli, D.; Curini, M.;
Pellicciari, R. J. J. Org. Chem. 1982, 47, 3242. (b) Taber, D. F.; Petty,
E. H. J. Org. Chem. 1982, 47, 4808.
(35) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.;
(34) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
Grabowski, E. J. J. J. Org. Chem. 1982, 47, 4808.
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A R T I C L E S
Krishnan et al.
Scheme 16
Scheme 18
a Isolated yield. b Measured by chiral HPLC after derivatization.
c Equivalents of phenoxide relative to Pd(sparteine)Cl2. The phenoxide was
stirred with Pd(sparteine)Cl2 for 1 h prior to introduction of substrate.
While (+)-amurensinine could be accessed by this route, the
sequence to (+)-2 from (()-15 was complicated by the
formation of several side products. Treatment of hydroxyester
(-)-15 with DBU in the absence of diphenylphosphoryl azide
produced lactone 35, demonstrating the sensitivity of the bis-
benzylic stereocenter to epimerization (Scheme 14). Of further
concern was the formation of lactam (+)-34 in only 57% ee.
This partial racemization required two stereocenters to be
inverted in the azide installation reaction, presumably via an
intermediate such as o-quinonedimethide 36.
Our difficulty in suppressing epimerization at the bis-benzylic
stereocenter bearing the ester in the azide displacement led us
to pursue an alternate route to amurensinine via intermediates
with attenuated acidity at the bis-benzylic carbon (Scheme 15).
Also, we hoped an alternate benzylic alcohol substrate would
lead to improved mass recovery in the oxidative kinetic
resolution. To this end, reduction of hydroxyester (()-15 was
followed by selective silylation of the primary alcohol to afford
alcohol (()-37. Oxidative kinetic resolution of this alcohol
proved highly selective (selectivity factor s > 47), providing
highly enantioenriched alcohol (-)-37. Interestingly, resolutions
that were allowed to proceed to high ee of (-)-37 did not afford
any of the expected ketone (+)-39. Instead, diketone (-)-38
was formed in good yield and high ee. Monitoring of the
reaction demonstrated that the ketone (+)-39 was being gener-
ated, but it slowly underwent further oxidation to the diketone
(-)-38. In fact, isolated samples of ketone 39 were slowly
oxidized to the diketone in C6D6. Handling of this ketone under
Scheme 19
argon delayed this oxidative decomposition. We hypothesized
that ketone (+)-39 was reacting with molecular oxygen via a
radical pathway to afford the diketone (-)-38. This hypothesis
is supported by our observations on non-enantioselective
oxidations performed on alcohol (()-37. Thus, oxidation of (()-
37 with Dess-Martin periodinane36 cleanly provided ketone
(()-39, while diketone (()-38 was obtained when either MnO2
37
or Pd(OAc)2/O2 was employed as the oxidant. We therefore
screened various radical inhibitors as additives in kinetic
resolutions of alcohol (()-37. Tetracyanoethylene led to little
alcohol oxidation. Neither BHT nor 2-methyl-2-butene sup-
pressed ketone overoxidation; however, incorporation of even
catalytic quantities of 2-methyl-2-butene enhanced mass recov-
ery and improved selectivity in the kinetic resolution. While
the role of 2-methyl-2-butene is not yet clear, it was included
in our preparative experiments because of its beneficial effect.
Thus, under our optimized conditions, (()-37 was resolved with
Pd(sparteine)Cl2 as a catalyst in the presence of O2 to 99% ee
and was isolated in 47% yield (94% of the theoretical
maximum).
Scheme 17
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Pd-Catalyzed Oxidation of Secondary Alcohols
A R T I C L E S
Scheme 20
Having accessed substantial quantities of highly enantioen-
riched alcohol (-)-37, we next proceeded with the installation
of the nitrogen required in the natural product. Azide displace-
ment under Thompson’s conditions was followed by desilylation
to afford azidoalcohol (-)-40 (Scheme 16). Gratifyingly, this
azide was obtained with clean inversion in 99% ee, indicating
that decreasing the acidity of the bis-benzylic center did indeed
minimize SN1 pathways. Oxidation of alcohol (-)-40 in two
steps to the corresponding carboxylic acid and subsequent azide
reduction delivered lactam (+)-34. Reduction and methylation
as before afforded (+)-amurensinine ((+)-2) in 99% ee.38
Synthesis of (-)-Lobeline and (-)- and (+)-Sedamine. Our
synthesis commenced from known aldehyde 22.39 Addition of
the anion derived from Horner-Emmons reagent 41 followed
by hydrolysis of the resulting methyl enol ether provided ketone
(()-42 in good overall yield (Scheme 17). DIBAL emerged as
the preferred reductant from a screen of conditions for the
subsequent reduction of aryl ketone (()-42, providing the amino
alcohol derivative (()-21 with 12:1 diastereoselectivity.40 The
diastereomers were separable by chromatography, and the
benzylic alcohol of the major diastereomer (()-21 was protected
as a TBS ether. Formylation with DMF under anionic conditions
furnished aldehyde 43 as a single diastereomer. Aldehyde 43
was then treated with the anion derived from Horner-Emmons
reagent 41. Hydrolysis of the intermediate enol ether afforded
ketone 44. As before, diastereoselective ketone reduction was
accomplished with DIBAL, providing a single alcohol diaste-
reomer. Subsequent desilylation with TBAF followed by
exhaustive reduction of the carbamate delivered the meso-diol
lobelanidine (20). The relative stereochemistry of lobelanidine
was confirmed by X-ray crystallography.
At this stage, we investigated the key desymmetrization of
20 to access (-)-lobeline ((-)-3). Our previously optimized
reaction conditions,41 involving catalytic Pd(sparteine)Cl2 in
chloroform under an oxygen atmosphere, furnished lobeline (3)
as a 1:1 mixture of diastereomers at C(3) in 70% yield and 95%
ee (Scheme 18).42 Synthetic alkaloid 3 was found to be
spectroscopically identical to the equilibrated natural isolate and
possessed identical optical rotation. Interestingly, a survey of
additives revealed that incubation of Pd(sparteine)Cl2 with the
sodium salt of 6-methoxy-2-naphthol (45) for 1 h prior to
exposure to meso-diol 20 had a dramatic impact on the reaction.
Inclusion of the phenoxide salt permitted smooth conversion
to amino alcohol (-)-3 with a lowered catalyst loading (10 mol
%) and reaction time (48 h) and furnished amino alcohol (-)-3
in enhanced isolated yield (87%) and ee (99%). Although the
role of the phenoxide is presently unclear, one possibility is
that the observed improvement in overall reaction profile may
result from the formation of a more reactive, catalytically
competent Pd(sparteine)phenoxide salt.
of equilibrating diastereomers, we began efforts to control the
epimerization at C(3) in order to access (-)-3 as a single
diastereomer. The rate of epimerization of natural (-)-3 was
found to increase with increasing basicity of the reaction medium
and by protic solvents.43 Furthermore, we found that the
hydrochloride salt 3·HCl (cis:trans ) 1:1) could be equilibrated
to a 3:1 mixture of the cis:trans isomers in i-PrOH. Prompted
by these observations, we developed a dynamic crystallization
method allowing for selective precipitation of the cis-isomer
of aminoketone 3 (Scheme 19). Heating a 1:1 mixture of cis:
trans isomers of the hydrochloride of aminoketone 3 in i-PrOH
followed by slow crystallization permitted a 69% recovery of
cis-(-)-3 after liberation of the free base.
Having demonstrated a concise total synthesis of isomerically
pure (-)-lobeline ((-)-3), we explored the utility of protected
amino alcohol (()-21 for the synthesis of related Sedum
alkaloids, namely, both enantiomers of sedamine (i.e., (-)- and
(+)-4, Scheme 20). Exposure of protected amino alcohol (()-
21 to our optimized Pd(II)-catalyzed aerobic oxidative kinetic
resolution conditions furnished protected amino alcohol (-)-
21 in 94% ee and the oxidation product, ketone (-)-42, in 81%
ee with excellent yield and selectivity.
Direct reduction of amino alcohol derivative (-)-21 with
lithium aluminum hydride provided natural (-)-sedamine ((-)-
4). Reiteration of the highly diastereoselective DIBAL reduction
of ketone (-)-42 generated enantiomeric alcohol (+)-21, and
further reduction of the carbamate delivered the non-natural (+)-
sedamine ((+)-4).
Conclusion
Herein, we have demonstrated the power of palladium-
catalyzed enantioselective aerobic oxidation toward the synthesis
of alkaloid natural products. We have developed an enantiose-
lective synthesis of the ergot alkaloid (-)-aurantioclavine, a
promising intermediate en route to the communesin family of
alkaloids. We have also demonstrated that the strategic com-
(36) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(37) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999,
64, 6750.
(38) We have recently accomplished a formal synthesis of the naturally
occurring enantiomer of amurensinine using a readily accessible
diamine ligand that serves as a mimic for (+)-sparteine in the oxidative
kinetic resolution. See: Ebner, D. C.; Trend, R. M.; Genet, C.;
McGrath, M. J.; O’Brien, P.; Stoltz, B. M Angew. Chem., Int. Ed.
2008, 47, 6367–6370.
(39) Molander, G. A.; Romero, J. A. C. Tetrahedron 2005, 61, 2631.
(40) A rationale for the observed selectivity follows from the calculated
conformational equilibria of cis,cis-1,4-cyclooctadiene. See: Anet,
F. A. L.; Yavari, I. J. Am. Chem. Soc. 1977, 99, 6986. Also see
Supporting Information for a stereochemical model.
(41) Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 353.
(42) The enantiomeric excess was determined after derivatization of lobeline
by the method described in ref 21h. See Supporting Information for
details.
After implementing a late-stage Pd-catalyzed oxidative de-
symmetrization to access (-)-lobeline ((-)-3) as a 1:1 mixture
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13753

A R T I C L E S
Krishnan et al.
Johnson & Johnson, Pfizer, Merck, Amgen, Abbott, Research
Corporation, Roche, and GlaxoSmithKline for generous funding.
bination of an aryne insertion followed by enantioselective
oxidation allows efficient access to the isopavine alkaloids,
exemplified by (+)-amurensinine. Finally, our concise enanti-
oselective synthesis of (-)-lobeline in diastereomerically pure
form, as well as the synthesis of either enantiomer of sedamine,
demonstrates the extraordinarily facile generation of multiple
stereogenic centers in a catalytic enantioselective manner in a
single operation.
Supporting Information Available: Full experimental details
and characterization data for all new compounds (PDF, CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA804738B
Acknowledgment. The authors thank the NIH-NIGMS (R01
GM65961-01), California TRDRP (postdoctoral fellowships to
Y.K.R. and S.K., and predoctoral fellowship to J.T.B.), NDSEG
(predoctoral fellowships to D.C.E. and U.K.T.), NSF (predoctoral
fellowship to D.C.E.), Caltech, AstraZeneca, Boehringer Ingelheim,
(43) Crooks and co-workers21h noted the rate of epimerization of diaste-
reomerically pure cis-lobeline to 46:54 cis:trans-lobeline in various
deuterated solvents by 1H NMR (CD3OD > CD3CN > CD3COCD3
> CDCl3). In our hands, the epimerization of diastereomerically pure
cis-lobeline to 1:1 cis:trans-lobeline was much slower in C6D6 (5 days)
as opposed to CDCl3 (2 days) and CD3OD (2 h).
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13754 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008