Synthesis of the tetracyclic core of Illicium sesquiterpenes using an organocatalyzed asymmetric Robinson annulation

Article abstract of DOI:10.3762/bjoc.9.126

An enantioselective synthesis of the core framework of neurotrophic Illicium majucin-type sesquiterpenes is described here. This strategy is based on an organocatalyzed asymmetric Robinson annulation and provides an efficient approach for a diversity-oriented synthesis of Illicium natural products that holds remarkable therapeutic potential for neurodegenerative diseases.

Full text of DOI:10.3762/bjoc.9.126

Synthesis of the tetracyclic core of Illicium sesqui-
terpenes using an organocatalyzed asymmetric
Robinson annulation
Lynnie Trzoss, Jing Xu, Michelle H. Lacoske and Emmanuel A. Theodorakis*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1135–1140.
Department of Chemistry and Biochemistry, University of California,
San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA
doi:10.3762/bjoc.9.126
Received: 03 April 2013
Accepted: 24 May 2013
Published: 12 June 2013
Email:
Emmanuel A. Theodorakis* - etheodor@ucsd.edu
* Corresponding author
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
Keywords:
natural products; neurodegenerative diseases; neurotrophic small
molecule; organocatalysis; total synthesis
Guest Editors: D. Y.-K. Chen and D. Ma
© 2013 Trzoss et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An enantioselective synthesis of the core framework of neurotrophic Illicium majucin-type sesquiterpenes is described here. This
strategy is based on an organocatalyzed asymmetric Robinson annulation and provides an efficient approach for a diversity-oriented
synthesis of Illicium natural products that holds remarkable therapeutic potential for neurodegenerative diseases.
Introduction
Neurotrophins are a family of endogenous proteins that are vital Majucin-type Illicium sesquiterpenes (Figure 1) [13], such as
for neuron function, survival, and regeneration [1-3]. As such, majucin (1) [14,15], jiadifenolide (2) [16], jiadifenin (3) [17],
they have prompted intense studies toward the treatment of jiadifenoxolane A (4) [16] and (2R)-hydroxynorneomajucin (5)
various neurodegenerative diseases including Alzheimer’s [18], share a caged tetracyclic scaffold (6). These compounds
disease [4] and Parkinson’s disease [5]. Despite their unam- (2–5) have shown a great potential in enhancing
biguous importance, approaches to neurotrophin-based drug neurite outgrowth in primary cultured rat cortical neurons
development have encountered problems associated with their at low nanomolar to low micromolar concentrations.
limited oral availability, insufficient delivery to the central Thus, to develop an efficient synthetic approach toward
neural system and considerable manufacturing cost [6,7]. These the complex core skeleton of these natural products is
limitations have stimulated the search for small molecules that of paramount importance. Consequently, this family of
can enhance or mimic neurotrophin activity as potential drug neurotrophic sesquiterpenes has been the focus of extensive
leads [8-12].
synthetic studies in which asymmetric and efficient
1135

Beilstein J. Org. Chem. 2013, 9, 1135–1140.
annulation that allows access to the enantiomerically enriched
bicyclic motif 8 from achiral diketone 11 (Figure 2).
Results and Discussion
During the past 20 years, organocatalysis has emerged as an
important field in asymmetric stereoselective synthesis due to
its advantages, which include high enantioselectivity, environ-
mental friendliness and ease of handling [27-50]. Organocat-
alyzed asymmetric Robinson annulation has long been proven
to be one of the most powerful strategies to construct bicyclic
systems with a chiral quaternary center [51-58]. Among them,
the Hajos–Wiechert and Wieland–Miescher ketones represent
two of the most famous examples [59-65]. With this back-
ground information in mind, we devised an enantioselective
synthesis of 8 starting from commercially available dione 12,
and the synthesis of 8 was previously published [25,26].
Tsuji–Trost allylation [66-68] of 12 produced compound 11,
which was readily converted to 13 by an acid-catalyzed Michael
Figure 1: Representative majucin-type Illicium sesquiterpenes.
construction of the tetracyclic core presents the principal chal- addition with methyl vinyl ketone (MVK) (two steps, 63%
lenge [19-23].
overall yield) [69-71]. The organocatalyzed cyclization of 13
was achieved by optimizing the previously reported Tu/Zhang
We have recently reported a unified synthetic strategy of 2, 3 conditions [71] using D-prolinamide as the organocatalyst
and designed analogues using scaffold 7 as the key intermedi- (Scheme 1). Performing this reaction at 80 °C gave rise to
ate (Figure 2) [24-26]. A potential drawback of this strategy is bicyclic motif 8 in about 70% ee (70 % yield after 12 h), while
the late-stage modification of the A ring motif of 7 that requires decreasing the temperature to 25 °C increased the enantio-
additional steps for the synthesis of the target molecules. In an selectivity to over 99% (70% yield after 60 days). To compro-
effort to overcome this issue, we describe here a second-genera- mise between high enantioselectivity and short reaction time,
tion strategy of framework 9 in which the C-1 center has been we decided to pursue this conversion at 40 °C where we
methylated early in the synthesis. As such, it represents an effi- obtained an enantiomeric excess of 90% (70% yield after 14
cient route toward a diversity-oriented synthesis of several Illi- days).
cium sesquiterpenes. The enantioselective entry to these mole-
cules is based on an organocatalyzed asymmetric Robinson The enantiomerically enriched Hajos–Wiechert-like diketone 8
(ee > 90%) was then subjected to a selective protection of the
C-6 enone motif to yield dithioketal 14 (86% yield) [72-74].
Figure 2: Comparison of core skeleton synthetic strategies.
Scheme 1: Organocatalyzed asymmetric Robinson annulation.
1136

Beilstein J. Org. Chem. 2013, 9, 1135–1140.
Wittig olefination of the C-1 ketone with methoxymethylenet- produced the corresponding C-6/C-14 diol motif. Selective TBS
riphenylphosphine [75] yielded the corresponding enol methyl protection of the C-14 primary alcohol followed by an IBX oxi-
ether, which was hydrolyzed to the aldehyde under acidic dation of the C-6 secondary alcohol yielded ketone 19 in 80%
conditions and reduced with NaBH4 to form alcohol 15 with combined yield over three steps. Triflation of the C-6 ketone
desired diastereoselectivity at the C-1 center (dr = 9:1) in 81% with McMurry’s reagent (PhNTf2) [83-86] followed by a Pd(0)-
yield (over three steps) [76]. The stereochemistry of 15 was catalyzed carbomethoxylation [87-90] produced the desired
unambiguously confirmed by single-crystal X-ray analysis of C-ring lactone 20 in 61% yield. Epoxidation of the C-6/C-7
the related tosylate derivative 16 [77]. Deoxygenation of the enone with NaOH/H2O2 followed by oxidative cleavage of the
C-15 primary alcohol was performed by: (a) mesylation of the C-11 terminal alkene under OsO4/NaIO4 conditions [91,92]
alcohol with MsCl; and (b) reductive deoxygenation with afforded the corresponding C-11 aldehyde. Exposure of this
LiEt3BH (super hydride). The thioketal protecting group was intermediate to Jones oxidation triggered a highly efficient oxi-
then removed under oxidative conditions with [bis(trifluoroace- dation–epoxide opening [93-98] reaction cascade [99,100] to
toxy)iodo]benzene (PIFA) to yield ketone 10 in good yield construct the critical D-ring of 9 (46% yield, over 3 steps).
(66% over three steps, Scheme 2) [78]. This approach allowed Notably, this scalable approach rendered us several hundred
us to produce a sufficient amount of enone 10 (>10 grams) for milligrams of compound 9, paving the way for a diversity-
further functionalization.
oriented synthesis. For example, a Mn(III) promoted C-2 allylic
oxidation [24,101,102] would provide a C-2 oxygenated func-
tionality. Similarly, C-10 α-substitution would provide a large
diversity of neurotrophic analogues based on our recent find-
ings [26].
Scheme 2: Early stage A-ring functionalization.
Conversion of 10 to 9 was accomplished based on our previ-
ously reported strategy (Scheme 3) [25]. Treatment of 10 with
magnesium methyl carbonate (MMC) [79-81] yielded the C-5
carboxylic acid that, without further purification, was esterified
under Meerwein’s conditions to afford β-ketoester 17. Treat-
ment of 17 with TMSOTf/Et3N followed by enolate alkylation
[82] under TBAF/MeI conditions afforded the desired C-5
quaternary center of 18 as a single isomer (35% over four
steps). Global reduction of 18 with lithium aluminium hydride
Scheme 3: Synthesis of core scaffold 9.
1137

Beilstein J. Org. Chem. 2013, 9, 1135–1140.
12. Williams, P.; Sorribas, A.; Howes, M.-J. R. Nat. Prod. Rep. 2011, 28,
48–77. doi:10.1039/c0np00027b
Conclusion
We describe here an efficient and enantioselective approach to
tetracyclic lactone 9 representing a key motif toward the syn-
thesis of various neurotrophic [103-110] Illicium sesquiter-
penes. Key to the strategy was a highly enantioselective
Robinson annulation reaction that proceeded under organocat-
alytic conditions to form the Hajos–Wiechert-like enone 8. The
overall strategy highlights the importance of organocatalytic
approaches in the modern synthesis of bioactive natural prod-
ucts [111-116].
13. Urabe, D.; Inoue, M. Tetrahedron 2009, 65, 6271–6289.
doi:10.1016/j.tet.2009.06.010
14. Yang, C.-S.; Kouno, I.; Kawano, N.; Sato, S. Tetrahedron Lett. 1988,
29, 1165–1168. doi:10.1016/S0040-4039(00)86678-2
15. Kouno, I.; Baba, N.; Hashimoto, M.; Kawano, N.; Takahashi, M.;
Kaneto, H.; Yang, C.-S.; Sato, S. Chem. Pharm. Bull. 1989, 37,
2448–2451. doi:10.1248/cpb.37.2448
16. Kubo, M.; Okada, C.; Huang, J.-M.; Harada, K.; Hioki, H.;
Fukuyama, Y. Org. Lett. 2009, 11, 5190–5193. doi:10.1021/ol9021029
17. Yokoyama, R.; Huang, J. M.; Yang, C. S.; Fukuyama, Y. J. Nat. Prod.
2002, 65, 527–531. doi:10.1021/np010571k
18. Kubo, M.; Kobayashi, K.; Huang, J.-M.; Harada, K.; Fukuyama, Y.
Tetrahedron Lett. 2012, 53, 1231–1235.
Supporting Information
doi:10.1016/j.tetlet.2011.12.107
Supporting Information File 1
Experimental procedures for the syntheses of all new
compounds.
19. Cho, Y. S.; Carcache, D. A.; Tian, Y.; Li, Y. M.; Danishefsky, S. J.
J. Am. Chem. Soc. 2004, 126, 14358–14359. doi:10.1021/ja045939p
20. Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y.-M.;
Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1016–1022.
doi:10.1021/ja056980a
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-126-S1.pdf]
21. Harada, K.; Imai, A.; Uto, K.; Carter, R. G.; Kubo, M.; Hioki, H.;
Fukuyama, Y. Org. Lett. 2011, 13, 988–991. doi:10.1021/ol103024z
22. Mehta, G.; Shinde, H. M.; Kumaran, R. S. Tetrahedron Lett. 2012, 53,
4320–4323. doi:10.1016/j.tetlet.2012.06.001
Acknowledgements
23. Yang, Y.; Fu, X.; Chen, J.; Zhai, H. Angew. Chem., Int. Ed. 2012, 51,
9825–9828. doi:10.1002/anie.201203176
We gratefully acknowledge the National Institutes of Health
(NIH) for financial support of this work through Grant Number
CA 133002. We thank the National Science Foundation for
instrumentation grants CHE9709183 and CHE0741968. We
also thank Dr. Anthony Mrse (UCSD NMR Facility), Dr.
Yongxuan Su (UCSD MS Facility) and Dr. Arnold L. Rhein-
gold and Dr. Curtis E. Moore (UCSD X-Ray Facility).
24. Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A.
Org. Lett. 2011, 13, 4554–4557. doi:10.1021/ol201742j
25. Xu, J.; Trzoss, L.; Chang, W. K.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2011, 50, 3672–3676.
doi:10.1002/anie.201100313
26. Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A.
Chem.–Eur. J. 2013, 20, 6398–6408. doi:10.1002/chem.201300198
27. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175.
doi:10.1002/anie.200400650
References
1. Sofroniew, M. V.; Howe, C. L.; Mobley, W. C. Annu. Rev. Neurosci.
2001, 24, 1217–1281. doi:10.1146/annurev.neuro.24.1.1217
2. Chao, M. V. Nat. Rev. Neurosci. 2003, 4, 299–309.
doi:10.1038/nrn1078
28. List, B. Acc. Chem. Res. 2004, 37, 548–557. doi:10.1021/ar0300571
29. Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79–87.
30. Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543. doi:10.1002/anie.200503132
3. Huang, E. J.; Reichardt, L. F. Annu. Rev. Neurosci. 2001, 24,
677–736. doi:10.1146/annurev.neuro.24.1.677
4. Querfurth, H. W.; LaFerla, F. M. N. Engl. J. Med. 2010, 362, 329–344.
doi:10.1056/NEJMra0909142
31. Marion, N.; Díez-González, S.; Nolan, I. P. Angew. Chem., Int. Ed.
2007, 46, 2988–3000. doi:10.1002/anie.200603380
32. Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T.
Drug Discovery Today 2007, 12, 8–27.
5. Shulman, J. M.; De Jager, P. L.; Feany, M. B.
Annu. Rev. Pathol.: Mech. Dis. 2011, 6, 193–222.
doi:10.1146/annurev-pathol-011110-130242
doi:10.1016/j.drudis.2006.11.004
33. Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178–2189. doi:10.1039/b903816g
6. Skaper, S. D. CNS Neurol. Disord.: Drug Targets 2008, 7, 46–62.
doi:10.2174/187152708783885174
34. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395–2396. doi:10.1021/ja994280y
7. Skaper, S. D. Curr. Pharm. Des. 2011, 17, 2704–2718.
doi:10.2174/138161211797415995
35. Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 9874–9875. doi:10.1021/ja005517p
8. Me, Y.; Longo, F. M. Prog. Brain Res. 2000, 128, 333–347.
doi:10.1016/S0079-6123(00)28030-8
36. Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243–4244. doi:10.1021/ja000092s
9. Massa, S. M.; Xie, Y. M.; Longo, F. M. J. Mol. Neurosci. 2003, 20,
323–326. doi:10.1385/JMN:20:3:323
37. Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.;
MacMillan, D. W. C. Science 2007, 316, 582–585.
10. Longo, F. M.; Yang, T.; Knowles, J. K.; Xie, Y. M.; Moore, L. A.;
Massa, S. M. Curr. Alzheimer Res. 2007, 4, 503–506.
doi:10.2174/156720507783018316
38. Zhu, S. L.; Wang, Y.; Ma, D. W. Adv. Synth. Catal. 2009, 351,
2563–2566. doi:10.1002/adsc.200900449
39. Marques-Lopez, E.; Herrera, R. P.; Christmann, M. Nat. Prod. Rep.
2010, 27, 1138–1167. doi:10.1039/b924964h
11. Joyner, P. M.; Cichewicz, R. H. Nat. Prod. Rep. 2011, 28, 26–47.
doi:10.1039/c0np00017e
1138

Beilstein J. Org. Chem. 2013, 9, 1135–1140.
40. Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178.
doi:10.1038/nchem.539
67. Trost, B. M.; Fullerto, T. J. Am. Chem. Soc. 1973, 95, 292–294.
doi:10.1021/ja00782a080
41. Zhu, S. L.; Yu, S. Y.; Wang, Y.; Ma, D. W. Angew. Chem., Int. Ed.
2010, 49, 4656–4660. doi:10.1002/anie.201001644
42. Knowles, R. R.; Carpenter, J.; Blakey, S. B.; Kayano, A.;
Mangion, I. K.; Sinz, C. J.; MacMillan, D. W. C. Chem. Sci. 2011, 2,
308–311. doi:10.1039/c0sc00577k
68. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422.
doi:10.1021/cr9409804
69. Ruprah, P. K.; Cros, J.-P.; Pease, J. E.; Whittingham, W. G.;
Williams, J. M. J. Eur. J. Org. Chem. 2002, 3145–3152.
doi:10.1002/1099-0690(200209)2002:18<3145::AID-EJOC3145>3.0.C
O;2-3
43. Sun, X.; Ma, D. Chem.–Asian J. 2011, 6, 2157–2164.
doi:10.1002/asia.201100219
70. Lacoste, E.; Vaique, E.; Berlande, M.; Pianet, I.; Vincent, J.-M.;
Landais, Y. Eur. J. Org. Chem. 2007, 167–177.
doi:10.1002/ejoc.200600664
44. Pham, P. V.; Ashton, K.; MacMillan, D. W. C. Chem. Sci. 2011, 2,
1470–1473. doi:10.1039/c1sc00176k
45. Wang, Y.; Zhu, S.; Ma, D. Org. Lett. 2011, 13, 1602–1605.
doi:10.1021/ol200004s
71. Zhang, X.-M.; Wang, M.; Tu, Y.-Q.; Fan, C.-A.; Jiang, Y.-J.;
Zhang, S.-Y.; Zhang, F.-M. Synlett 2008, 2831–2835.
doi:10.1055/s-0028-1083542
46. Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C.
Nature 2011, 475, 183–188. doi:10.1038/nature10232
47. Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 9126–9129.
doi:10.1021/ja303602f
72. Coates, R. M.; Shaw, J. E. Chem. Commun. 1968, 515–516.
doi:10.1039/c19680000515
73. Williams, J. R.; Sarkisia, G. M. Synthesis 1974, 32–33.
doi:10.1055/s-1974-23227
48. Huo, L.; Ma, A.; Zhang, Y.; Ma, D. Adv. Synth. Catal. 2012, 354,
991–994. doi:10.1002/adsc.201100903
74. Bosch, M. P.; Camps, F.; Coll, J.; Guerrero, A.; Tatsuoka, T.;
Meinwald, J. J. Org. Chem. 1986, 51, 773–784.
doi:10.1021/jo00356a002
49. Simonovich, S. P.; Van Humbeck, J. F.; MacMillan, D. W. C.
Chem. Sci. 2012, 3, 58–61. doi:10.1039/c1sc00556a
50. Zhang, Y.; Xing, H.; Xie, W.; Wan, X.; Lai, Y.; Ma, D.
Adv. Synth. Catal. 2013, 355, 68–72. doi:10.1002/adsc.201200782
51. Ling, T.; Xiang, A. X.; Theodorakis, E. A. Angew. Chem., Int. Ed.
1999, 38, 3089–3091.
75. Pu, X.; Ma, D. Angew. Chem., Int. Ed. 2004, 43, 4222–4225.
doi:10.1002/anie.200460128
76. Paquette, L. A.; Wang, T.-Z.; Philippo, C. M. G.; Wang, S.
J. Am. Chem. Soc. 1994, 116, 3367–3374. doi:10.1021/ja00087a023
77. CCDC 931875 contains the supplementary crystallographic data for
compound 16. This data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via
doi:10.1002/(SICI)1521-3773(19991018)38:20<3089::AID-ANIE3089>
3.0.CO;2-W
52. Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.; Theodorakis, E. A.
J. Am. Chem. Soc. 2002, 124, 12261–12267. doi:10.1021/ja027517q
53. Brady, T. P.; Kim, S. H.; Wen, K.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 739–742.
http://www.ccdc.cam.ac.uk/products/csd/request/.
78. Angeles, A. R.; Dorn, D. C.; Kou, C. A.; Moore, M. A. S.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 1451–1454.
doi:10.1002/anie.200604308
doi:10.1002/anie.200352868
54. Ling, T.; Poupon, E.; Rueden, E. J.; Theodorakis, E. A. Org. Lett.
2002, 4, 819–822. doi:10.1021/ol025501z
79. Finkbeiner, H. L.; Stiles, M. J. Am. Chem. Soc. 1963, 85, 616–622.
doi:10.1021/ja00888a031
55. Ghosh, S.; Rivas, F.; Fischer, D.; González, M. A.; Theodorakis, E. A.
Org. Lett. 2004, 6, 941–944. doi:10.1021/ol036492c
56. Brady, T. P.; Kim, S. H.; Wen, K.; Kim, C.; Theodorakis, E. A.
Chem.–Eur. J. 2005, 11, 7175–7190. doi:10.1002/chem.200500513
57. Nguyen, T. X.; Dakanali, M.; Trzoss, L.; Theodorakis, E. A. Org. Lett.
2011, 13, 3308–3311. doi:10.1021/ol200966z
80. Micheli, R. A.; Hajos, Z. G.; Cohen, N.; Parrish, D. R.; Portland, L. A.;
Sciamanna, W.; Scott, M. A.; Wehrli, P. A. J. Org. Chem. 1975, 40,
675–681. doi:10.1021/jo00894a003
81. Frie, J. L.; Jeffrey, C. S.; Sorensen, E. J. Org. Lett. 2009, 11,
5394–5397. doi:10.1021/ol902168g
82. Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D. J. Am. Chem. Soc.
2008, 130, 16864–16865. doi:10.1021/ja8071918
83. Mcmurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979–982.
doi:10.1016/S0040-4039(00)81581-6
58. Peng, F.; Dai, M.-J.; Angeles, A. R.; Danishefsky, S. J. Chem. Sci.
2012, 3, 3076–3080. doi:10.1039/c2sc20868g
See for a recent update of Robinson annulation.
59. Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215–2228.
doi:10.1002/hlca.19500330730
84. Scott, W. J.; Mcmurry, J. E. Acc. Chem. Res. 1988, 21, 47–54.
doi:10.1021/ar00146a001
60. Eder, U.; Sauer, G.; Weichert, R. Angew. Chem., Int. Ed. Engl. 1971,
10, 496–497. doi:10.1002/anie.197104961
85. Nicolaou, K. C.; Peng, X.-S.; Sun, Y.-P.; Polet, D.; Zou, B.; Lim, C. S.;
Chen, D. Y.-K. J. Am. Chem. Soc. 2009, 131, 10587–10597.
doi:10.1021/ja902939t
61. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1973, 38, 3239–3243.
doi:10.1021/jo00959a002
86. Ding, H.; Chen, D. Y. K. Angew. Chem., Int. Ed. 2011, 50, 676–679.
doi:10.1002/anie.201006367
62. Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.
doi:10.1021/jo00925a003
87. Cowell, A.; Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193–4198.
doi:10.1021/ja00532a034
63. Bradshaw, B.; Bonjoch, J. Synlett 2012, 337–356.
doi:10.1055/s-0031-1290107
88. Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109–1112. doi:10.1016/S0040-4039(00)98525-3
89. Magro, A. A. N.; Robb, L. M.; Pogorzelec, P. J.; Slawin, A. M. Z.;
Eastham, G. R.; Cole-Hamilton, D. J. Chem. Sci. 2010, 1, 723–730.
doi:10.1039/c0sc00276c
64. Zhou, P.; Zhang, L.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2012, 77,
2526–2530. doi:10.1021/jo202433v
65. Winterfeldt, E. Angew. Chem., Int. Ed. 2013, 52, 4723.
doi:10.1002/anie.201301415
66. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6,
4387–4388. doi:10.1016/S0040-4039(00)71674-1
90. Nicolaou, K. C.; Ding, H.; Richard, J.-A.; Chen, D. Y.-K.
J. Am. Chem. Soc. 2010, 132, 3815–3818. doi:10.1021/ja9093988
1139

Beilstein J. Org. Chem. 2013, 9, 1135–1140.
91. Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226–13228.
doi:10.1021/ja106739g
115.Xu, J.; Caro-Diaz, E. J. E.; Trzoss, L.; Theodorakis, E. A.
J. Am. Chem. Soc. 2012, 134, 5072–5075. doi:10.1021/ja300807e
116.Xu, J.; Caro-Diaz, E. J. E.; Lacoske, M. H.; Hung, C.-I.; Jamora, C.;
Theodorakis, E. A. Chem. Sci. 2012, 3, 3378–3386.
doi:10.1039/c2sc21308g
92. Richard, J.-A.; Chen, D. Y.-K. Eur. J. Org. Chem. 2012, 484–487.
doi:10.1002/ejoc.201101629
93. Nicolaou, K. C.; Majumder, U.; Roche, S. P.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2007, 46, 4715–4718.
doi:10.1002/anie.200701947
94. Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2009, 48, 7616–7620.
License and Terms
doi:10.1002/anie.200904588
95. Nicolaou, K. C.; Wu, T. R.; Kang, Q.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2009, 48, 3440–3443.
This is an Open Access article under the terms of the
Creative Commons Attribution License
doi:10.1002/anie.200900438
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
96. Nicolaou, K. C.; Kang, Q.; Wu, T. R.; Lim, C. S.; Chen, D. Y.-K.
J. Am. Chem. Soc. 2010, 132, 7540–7548. doi:10.1021/ja102623j
97. Peixoto, P. A.; Richard, J.-A.; Severin, R.; Chen, D. Y.-K. Org. Lett.
2011, 13, 5724–5727. doi:10.1021/ol202053m
98. Peixoto, P. A.; Severin, R.; Tseng, C.-C.; Chen, D. Y.-K.
Angew. Chem., Int. Ed. 2011, 50, 3013–3016.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
doi:10.1002/anie.201008000
(http://www.beilstein-journals.org/bjoc)
99. Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134–7186. doi:10.1002/anie.200601872
100.Wasilke, J.-C.; Obrey, S. J.; Baker, R.-T.; Bazan, G. C. Chem. Rev.
2005, 105, 1001–1020. doi:10.1021/cr020018n
The definitive version of this article is the electronic one
which can be found at:
101.Nicolaou, K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem. Soc. 2008,
130, 11292–11293. doi:10.1021/ja804588r
doi:10.3762/bjoc.9.126
102.Leung, G. Y. C.; Li, H.; Toh, Q.-Y.; Ng, A. M.-Y.; Sum, R. J.;
Bandow, J. E.; Chen, D. Y.-K. Eur. J. Org. Chem. 2011, 183–196.
doi:10.1002/ejoc.201001281
103.Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Am. Chem. Soc.
2010, 132, 5924–5925. doi:10.1021/ja101956x
104.Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010, 132, 5926–5927.
doi:10.1021/ja101893b
105.Jana, C. K.; Hoecker, J.; Woods, T. M.; Jessen, H. J.; Neuburger, M.;
Gademann, K. Angew. Chem., Int. Ed. 2011, 50, 8407–8411.
doi:10.1002/anie.201101869
106.Scott, L. E.; Telpoukhovskaia, M.; Rodriguez-Rodriguez, C.;
Merkel, M.; Bowen, M. L.; Page, B. D. G.; Green, D. E.; Storr, T.;
Thomas, F.; Allen, D. D.; Lockman, P. R.; Patrick, B. O.; Adam, M. J.;
Orvig, C. Chem. Sci. 2011, 2, 642–648. doi:10.1039/c0sc00544d
107.Tun, M. K. M.; Wüstmann, D.-J.; Herzon, S. B. Chem. Sci. 2011, 2,
2251–2253. doi:10.1039/c1sc00455g
108.Cheng, X.; Harzdorf, N.; Khaing, Z.; Kang, D.; Camelio, A. M.;
Shaw, T.; Schmidt, C. E.; Siegel, D. Org. Biomol. Chem. 2012, 10,
383–393. doi:10.1039/c1ob06363d
109.Elamparuthi, E.; Fellay, C.; Neuburger, M.; Gademann, K.
Angew. Chem., Int. Ed. 2012, 51, 4071–4073.
doi:10.1002/anie.201200515
110.Newton, J. N.; Fischer, D. F.; Sarpong, R. Angew. Chem., Int. Ed.
2013, 52, 1726–1730. doi:10.1002/anie.201208571
111.Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121,
456–457. doi:10.1021/ja983429n
112.Tisdale, E. J.; Slobodov, I.; Theodorakis, E. A.
Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 12030–12035.
doi:10.1073/pnas.0401932101
113.Vong, B. G.; Kim, S. H.; Abraham, S.; Theodorakis, E. A.
Angew. Chem., Int. Ed. 2004, 43, 3947–3951.
doi:10.1002/anie.200460203
114.Guizzunti, G.; Brady, T. P.; Malhotra, V.; Theodorakis, E. A.
J. Am. Chem. Soc. 2006, 128, 4190–4191. doi:10.1021/ja058259a
1140