Gold-catalyzed highly enantioselective synthesis of axially chiral allenes

Article abstract of DOI:10.1021/ol702970r

Axially chiral allenes are synthesized from chiral propargylamines catalyzed by KAuCl₄ in high yields (up to 93% yield) and excellent enantioselectivities (up to 97% ee) in CH₃CN at 40 °C. The reaction has been applied to the synthes

Full text of DOI:10.1021/ol702970r

ORGANIC
LETTERS
2008
Vol. 10, No. 3
517-519
Gold-Catalyzed Highly Enantioselective
Synthesis of Axially Chiral Allenes
Vanessa Kar-Yan Lo, Man-Kin Wong,* and Chi-Ming Che*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of
Molecular Technology for Drug DiscoVery and Synthesis, The UniVersity of Hong
Kong, Pokfulam Road, Hong Kong, China
cmche@hku.hk; mkwong@hkusua.hku.hk
Received December 10, 2007
ABSTRACT
Axially chiral allenes are synthesized from chiral propargylamines catalyzed by KAuCl4 in high yields (up to 93% yield) and excellent
enantioselectivities (up to 97% ee) in CH3CN at 40 C. The reaction has been applied to the synthesis of novel allene-modified artemisinin
°
derivatives with the delicate endoperoxide moieties remaining intact. A tentative mechanism regarding gold(I)-catalyzed intramolecular hydride
transfer was proposed on the basis of deuterium-labeling experiments and ESI-MS analysis of the reaction mixture.
Allenes are important structural features of a variety of
biologically active natural products.1 The reactive orthogonal
π-bonds of chiral allenes render them versatile synthons in
synthetic organic chemistry.2 The synthesis of chiral allenes
mainly relies on SN2′ displacement reactions of chiral
propargyl alcohols by organometallic reagents, 3,3-sigmat-
ropic rearrangement of propargyl alcohol derivatives, and
asymmetric catalysis with chiral metal complexes.3 In view
of the importance of axially chiral allenes, there has been a
continuing interest in developing new methods for their
synthesis under mild reaction conditions.
Gold catalysis has emerged to be an active research area
in recent years.4,5 The success of propargyl alcohols in allene
synthesis prompts us to consider using chiral propargy-
lamines for the synthesis of axially chiral allenes.6 Our
previous study showed that chiral propargylamines could be
readily prepared by gold(III) salen complex-catalyzed syn-
thesis of chiral propargylamines via a three-component
coupling reaction of aldehydes, amines, and alkynes.5b Here,
we report the unprecedented synthesis of axially chiral allenes
from chiral propargylamines catalyzed by gold salts with
enantiomeric excess up to 97%.7,8
(4) (a) Dyker, G. Angew. Chem., Int. Ed. 2000, 39, 4237. (b) Hashmi,
A. S. K. Gold Bull. 2004, 37, 51. (c) Arcadi, A.; di Giuseppe, S. Curr.
Org. Chem. 2004, 8, 795. (d) Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol.
Chem. 2005, 3, 387. (e) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed.
2006, 45, 200. (f) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2005, 44, 6990.
(g) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896. (h) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (i) Marion, N.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (j) Hashmi, A. S. K.
Chem. ReV. 2007, 107, 3180.
(5) Recent work on gold catalysis developed by our group: (a) Zhou,
C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006, 8, 325. (b) Lo, V.
K.-Y.; Liu, Y.; Wong, M.-K.; Che, C.-M. Org. Lett. 2006, 8, 1529. (c)
Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (d) Liu, X.-Y.;
Ding, P.; Huang, J.-S.; Che, C.-M. Org. Lett. 2007, 9, 2645. (e) Zhou, C.-
Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129, 5828.
(6) For review, see: (a) ref 4i. Selected examples: (b) Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978. (c) Zhang, L.; Wang, S.
J. Am. Chem. Soc. 2006, 128, 1442. (d) Buzas, A.; Istrate, F.; Gagosz, F.
Org. Lett. 2006, 8, 1957. (e) Marion, N.; D´ıez-Gonza´lez, S.; de Fre´mont,
P.; Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (f)
Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027. (g) Wang, S.; Zhang,
L. Org. Lett. 2006, 8, 4585. (h) Zhao, J.; Hughes, C. O.; Toste, F. D. J.
Am. Chem. Soc. 2006, 128, 7436. (i) Sherry, B. D.; Maus, L.; Laforteza, B.
N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132. (j) Wang, S.; Zhang,
L. J. Am. Chem. Soc. 2006, 128, 8414. (k) Buzas, A.; Gagosz, F. J. Am.
Chem. Soc. 2006, 128, 12614. (l) Yu, M.; Zhang, G.; Zhang, L. Org. Lett.
2007, 9, 2147. (m) Lemie`re, G.; Gandon, V.; Cariou, K.; Fukuyama, T.;
Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207.
(1) Reviews: (a) Landor, S. R., Ed. The Chemistry of Allenes; Academic
Press: London. 1982. (b) Krause, N., Hashmi, A. S. K., Eds. Modern Allene
Chemistry; Wiley-VCH: Weinheim, 2004. (c) Hoffmann-Ro¨der, A.; Krause,
N. Angew. Chem., Int. Ed. 2004, 43, 1196.
(2) Reviews: (a) Rossi, R.; Diversi, P. Synthesis 1973, 25. (b) Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (c) Bates, R. W.;
Satcharoen, V. Chem. Soc. ReV. 2002, 31, 12. (d) Ma, S. Chem. ReV. 2005,
105, 2829.
(3) Reviews: (a) Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int.
Ed. 2002, 41, 2933. (b) Krause, N.; Hoffmann-Ro¨der, A. Tetrahedron 2004,
60, 11671. (c) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 795.
10.1021/ol702970r CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/09/2008

At the outset, we examined the catalytic activity of gold-
(III) salts toward the synthesis of chiral allene 2a from chiral
propargylamine 1a (99% ee) (Table 1, entry 1; see also Table
S1 in Supporting Information). The reaction was conducted
by heating KAuCl4 (0.01 mmol) and 1a (0.1 mmol) in CH3-
Table 1. KAuCl4-Catalyzed Synthesis of 2 from 1a
1
CN (2 mL) at 40 °C for 24 h. On the basis of H NMR
analysis of the crude reaction mixture, (R)-1,3-diphenylpropa-
1,2-diene (2a) was formed and subsequently isolated in 82%
yield based on 91% conversion. The ee value of 2a was 93%,
revealing an almost complete center-to-axis chirality transfer
from 1a to 2a. A slight increase in enantioselectivity (95%
ee) could be achieved when the reaction was conducted at
room temperature, or using water as the solvent. A combina-
tion of KAuCl4/AgOTf could also lead to 2a in 83% ee. [Au-
(Salen)Cl] (H2salen ) N,N-ethylenebis(salicylideneimine))
and [Au(TPP)Cl] (H2TPP ) meso-tetraphenylporphyrin)
were found to be inactive under similar conditions. Poor
substrate conversion was found for Pd(OAc)2 (8%), while
no conversion was observed for TfOH, ZnCl2, CuBr, CuCl2,
RuCl3, K2PtCl4, or Yb(OTf)3.
To examine the scope of this reaction, we extended our
study to chiral propargylamines bearing various functional-
ities (Table 1). Propargylamines 1a-g were converted into
(R)-allenes 2a-g in up to 93% yield and up to 93% ee
(entries 1-7). It is worth noting that the aldehyde group of
1g, which is sensitive toward Grignard or cuprate reagents
(a commonly used reagent in traditional allene synthesis from
propargyl alcohols) remained intact (entry 7). Interestingly,
2b containing the p-CF3 functionality could be obtained from
either propargylamine 1b or 1h in comparable ee values (93
vs 90%). Allenes 2i with a biphenyl group (83% ee), 2j with
a cyclohexyl group (94% ee), and 2k with a cyclohexenyl
group (50% ee) were generated from their corresponding
chiral propargylamines 1i-k (entries 9-11).
(R,R)-Bis-allene 2l could be synthesized from dipropar-
gylamine 1l in 97% ee (entry 12). (S)-2a in 88% ee was
obtained from 1m (the enantiomer of 1a) (entry 13). Apart
from prolinol-derived propargylamines, (methoxymethyl)-
pyrrolidine-derived 1n was converted into allene 2a with
86% ee (entry 14). Achiral pyrrolidine-derived 1o and 1p
were converted into racemic 2a (entries 15-16). These
results showed that the reaction is especially useful for the
synthesis of axially chiral 1,3-diarylallenes. The catalysis
could be scaled up to the gram scale. Thus, in a one-pot
reaction, 0.88 g of 1a gaVe 0.34 g of 2a in 90% ee for
a reaction time of 24 h (83% yield based on 70% conVer-
sion).
a Substrate/catalyst ) 1:0.1, ee of 1a-n ) 99%. b Determined by 1H
NMR analysis of the crude reaction mixture. c Isolated yield based on
conversion. d Determined by HPLC using Chiralcel-OD column.
(7) For palladium-catalyzed synthesis of achiral allenes from propargy-
lamines, see: (a) Nakamura, H.; Kamakura, T.; Ishikura, M.; Biellmann,
J.-F. J. Am. Chem. Soc. 2004, 126, 5958. (b) Nakamura, H.; Onagi, S.;
Kamakura, T. J. Org. Chem. 2005, 70, 2357. (c) Nakamura, H.; Tashiro,
S.; Kamakura, T. Tetrahedron Lett. 2005, 46, 8333. (d) Nakamura, H.;
Kamakura, T.; Onagi, S. Org. Lett. 2006, 8, 2095. (e) Nakamura, H.; Onagi,
S. Tetrahedron Lett. 2006, 47, 2539.
(8) During the preparation of this manuscript, Bertrand’s group reported
a cross-coupling of enamines and alkynes catalyzed by Au(I) to yield achiral
allenes, see: (a) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.;
Bertrand, G. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 13569. For previous
copper-catalyzed synthesis of achiral allenes via cross coupling of form-
aldehyde and alkynes in the presence of diisopropylamine, see: (b) Crabbe´,
P.; Andre´, D.; Fillion, H. Tetrahedron Lett. 1979, 20, 893.
The present protocol could be applied to the modification
of natural products having allene functionality. As depicted
in Scheme 1, allene-modified artemisinins 4a-d, which have
strong cytotoxicities (IC50 ) 0.64-4.62 µM) against a human
hepatocellular carcinoma cell line (HepG2), were synthesized
(9) For selected examples on the reduction of gold(III) by amines, see:
(a) Aslam, M.; Fu, L.; Su, M.; Vijayamohanan, K.; Dravid, V. P. J. Mater.
Chem. 2004, 14, 1795. (b) Newman, J. D. S.; Blanchard, G. J. Langmuir
2006, 22, 5882.
518
Org. Lett., Vol. 10, No. 3, 2008

Scheme 1. Synthesis of Allene-Modified Artemisinins 4a-d
Scheme 3. Deuterium-Labeling Experiments
as single diastereomers.5b The delicate endoperoxide moieties
remained intact during the course of reaction.
A tentative mechanism is depicted in Scheme 2. The Au-
-
(III) salt (AuCl4 ) is first reduced to Au(I), possibly by an
amine moiety of the substrate.9 Au(I) generated in situ
coordinates to the C-C triple bond to give intermediate I.
The reaction mixture of 1a and KAuCl4 (10 mol %) was
analyzed by ESI-MS, after stirring at rt for 1 h in CH3CN.
A peak at m/z 488.2 attributable to the adduct of 1a and
Au(I) was identified, supporting Au(I) possibly being a
reactive species. Moreover, the same ee value of (R)-allene
2a (93%) was obtained from the reaction of 1a individually
catalyzed by KAuCl4 or AuCl, in the latter case, albeit 30%
of AuCl was needed. The gold residue left after the reaction
was suggested to be Au(0) by XRD analysis.
reaction of 5b (eq 2). As no crossover of deuterium with
the allenes was observed by GC-MS analysis of the reaction
mixture using a 1:1 ratio of 5a and 1f (eq 3), the proposed
hydride transfer from I to II could occur intramolecularly,10
although we cannot exclude the possibility of transition from
intermediate I to II, involving the formation of alkylidene-
aziridine followed by a 1,4-hydrogen migration.11
To conclude, we have developed the first gold-catalyzed
synthesis of axially chiral allenes from chiral propargy-
lamines, with enantiomeric excess up to 97%.
Acknowledgment. We are thankful for the financial
support of The University of Hong Kong (University
Development Fund), Hong Kong Research Grant Council
(HKU 7052/07P), and the Areas of Excellence Scheme
established under the University Grants Committee of the
Hong Kong Special Administrative Region, China (AoE/P-
10/01). We thank the reviewers for their insightful comments
and suggestions on this work, particularly on the mechanistic
studies.
Scheme 2. Tentative Mechanism for Gold-Catalyzed
Synthesis of Axially Chiral Allenes
Supporting Information Available: Experimental pro-
cedures, compound characterization data, cytotoxicity studies
of artemisinin derivatives, and supports for mechanistic
studies. This material is available free of charge via the
Internet at http://pubs.acs.org.
To provide insight into the subsequent steps from I,
deuterium-labeling experiments were performed. The find-
ings are depicted in Scheme 3. Deuterium-labeled 5a (84%
D incorporation) was treated with KAuCl4 in CD3CN under
N2 at 40 °C for 24 h. By 1H NMR analysis, 82% D
incorporation in 6a was obtained with 58% isolated yield
(eq 1). Yet no deuterium incorporation was detected in the
OL702970R
(10) Attempts were not successful to detect the fate of the pyrrolidine
1
moiety after treatment of 1a with Au catalyst using GC-MS or H NMR
analysis.
(11) Inokuchi, T.; Matsumoto, S.; Tsuji, M.; Torii, S. J. Org. Chem.
1992, 57, 5023.
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