Total synthesis of schilancitrilactones B and C

Article abstract of DOI:10.1002/anie.201501169

The first total syntheses of schilancitrilactones B and C have been accomplished in 17 steps (longest linear sequence) from commercially available materials. Key steps include an intramolecular radical cyclization to provide the seven-membered ring, late-stage iodination, and an intermolecular radical addition reaction to complete the total synthesis. In step: The first total syntheses of schilancitrilactones B and C have been accomplished by using an intramolecular radical cyclization to provide the seven-membered ring, late-stage iodination, and an intermolecular radical addition reaction as key steps. The approach provides a sequence for the syntheses of compounds related to the schilancitrilactones, as well as their derivatives and analogues.

Full text of DOI:10.1002/anie.201501169

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501169
German Edition: DOI: 10.1002/ange.201501169
Natural Products
Total Synthesis of Schilancitrilactones B and C**
Liang Wang, Hengtao Wang, Yihang Li, and Pingping Tang*
Abstract: The first total syntheses of schilancitrilactones B and
C have been accomplished in 17 steps (longest linear sequence)
from commercially available materials. Key steps include an
intramolecular radical cyclization to provide the seven-mem-
bered ring, late-stage iodination, and an intermolecular radical
addition reaction to complete the total synthesis.
Recently, the total synthesis of Schisandraceae triterpe-
noids has been of great interest to synthetic organic chemists
because of the intriguing structures and diverse biological
activities.[3] In 2011, Yang and co-workers reported the first
total synthesis of schindilactone A.[4] Recently, the group of Li
disclosed the first asymmetric total synthesis of rubriflordi-
lactone A.[5] Herein we report our efforts on developing a new
strategy to solve the chemical synthesis of 1 and 2, and
a pathway for the synthesis of their analogues and derivatives
for medicinal studies. Our retrosynthetic analysis is shown in
Scheme 1. It was hypothesized that 1 and 2 might be
S
chilancitrilactones B and C (1 and 2; Figure 1)[1] were
isolated in 2012 by Sun and co-workers from the stems of
Schisandra Lancifolia, which have been used in traditional
Chinese medicine for the treatment of neurasthenia and
related diseases.[2] Preliminary biological assays indicated that
Figure 1. Schilancitrilactones B and C.
schilancitrilactone C showed biological activities for inhibit-
ing HIV-1 while schilancitrilactone B was not bioactive. The
structures of these compounds were striking in that they
contain a 5/7/5/5/5-fused pentacyclic ring system bearing nine
stereogenic centers. In addition, the three cis-fused five-
membered rings (rings C–E), all with the envelope confor-
mations, and seven contiguous chiral centers (including two
quaternary centers) form a structurally rigid tricyclic ring
system. Construction of these highly oxygenated unique
motifs remains challenging. Herein, we present the first
total synthesis of schilancitrilactones B and C. The key steps
include the successful implementation of an intramolecular
radical cyclization to prepare a seven-member ring, late-stage
Scheme 1. Retrosynthetic analysis of schilancitrilactones B and C.
À
iodination, and an intermolecular radical C C bond forma-
tion.
accessible by an intermolecular radical addition reaction
between the alkyl iodide 3 and vinyl stannane 4. The alkyl
iodide 3 was expected to arise by late-stage iodination at C20
from the compound 5, which in turn could be prepared from
the compound 6 by a series of steps including an intra-
[*] L. Wang, H. Wang, Y. Li, Prof. Dr. P. Tang
State Key Laboratory and Institute of Elemento-Organic Chemistry
Collaborative Innovation Center of Chemical Science and Engi-
neering (Tianjin), Nankai University
À
molecular radical cyclization at the C7 C8 bond to prepare
the seven-membered ring.[6] The compound 6 was further
Tianjin 300071 (China)
E-mail: ptang@nankai.edu.cn
À
deconstructed at the C10 C19 bond into the two simple
building blocks 7 and 8, which could be put together by an
aldol reaction. The building blocks 4, 7, and 8 could be
prepared from the commercially available compounds citra-
conic anhydride (16), l-carvone (9), and 1,3-cyclohexadiene
(19), respectively.
[**] We gratefully acknowledge the State Key Laboratory of Elemento-
Organic Chemistry for generous start-up financial support. This
work was supported by the “1000 Youth Talents Plan”, NSFC
(21402098, 21421062), and the Natural Science Foundation of
Tianjin (13JCYBJC36500). Prof. Biao Yu and Prof. Guangxin Liang
are greatly acknowledged for helpful comments.
Our work began with the synthesis of the alkyl iodide 7
(Scheme 2). Following the procedure by Fukuyama and co-
workers,[7] l-carvone (9) was converted into the correspond-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501169.
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Scheme 2. Reagents and conditions: a) 30% H2O2, NaOH (aq),
MeOH, 08C; b) H2SO4, THF/H2O (5:1), reflux; c) NaIO4, iPrOH/H2O
(1:1), 08C to RT; d) I2, KI, NaHCO3, CH2Cl2/H2O (1:3), 08C, 51% for 4
steps; e) NaBH4, MeOH, 08C, 85%; f) AIBN, Bu3SnH, toluene, 1008C,
90%; g) PPh3, I2, imidazole, 08C to RT, THF, 84%. AIBN=
2,2’-azobis(2-methylpropionitrile), THF=tetrahydrofuran.
ing aldehyde 13 in a four-step sequence involving epoxidation,
epoxide hydrolysis, oxidative cleavage of diols, and iodolac-
tonization in 51% overall yield (4 steps). The aldehyde 13 was
selectively reduced with NaBH4 to provide the alcohol 14 in
85% yield. The deiodination of 14 with AIBN and Bu3SnH
afforded the compound 15, which was converted into the
corresponding 7 with I2 in the presence of Ph3P and imidazole
in 84% yield.[8]
Scheme 4. Reagents and conditions: a) TPP, O2, hu, CCl4, À108C then
thiourea, MeOH; b) BzCl, Et3N, DMAP, CH2Cl2, RT, 73% for 2 steps;
c) [{Pd(allyl)Cl}2] (3 mol%), ligand A, 22, K2CO3, MeOH, THF, 08C;
then DIPEA, 558C; 70%; d) NaH, CH3I, DMF, 08C, 90%, d.r. (at
C13)=4:1; e) NaBr, DMF, 1808C, 88%, d.r. (at C13)=1:1; f) LDA,
BrCH2CO2tBu, THF, À788C; g) TFA, CH2Cl2, 08C to RT, 93% for 2
steps; h) EtMgBr, THF/Et2O (1:1), À788C to RT, 80%; i) O3, CH2Cl2/
MeOH (1:1), À788C, then Me2S, À788C to RT; j) (Bn2NH2)(OCOCF3),
toluene, 638C, 80% for 2 steps. Bz=benzoyl, DIPEA=diisopropyl-
ethylamine, DMAP=4-(N,N-dimethylamino)pyridine, LDA=lithium-
diisopropyl amide, TPP=5,10,15,20-tetraphenyl-21H,23H-porphine.
Thermal ellipsoids are shown at 50% probability.[21]
Depicted in Scheme 3 is the construction of the vinyl
stannane compound 4. The vinyl bromide 18 was prepared
Trost and co-workers,[11] the lactone 23 was obtained in
a reported three-step process from the commercially available
1,3-cyclohexadiene (19). The steps included asymmetric
palladium-catalyzed allylic alkylation. Methylation of 23
with NaH and CH3I provided the compound 24 in 90%
yield with 4:1 diastereoselectivity at C13, and was then
subjected to decarboxylation mediated by NaBr to produce
a 1:1 mixture of the lactone 25 in 88% yield. Alkylation of 25
with tert-butyl bromoacetate gave the single diastereomer 26.
Deprotection of 26 was achieved using trifluoroacetic acid
and gave the acid 27 in 93% yield (two steps). Addition of
ethyl magnesium bromide followed by acidic workup gave
rise to the tricycle 28, having an ethyl group installed
stereoselectively onto the tricyclic framework.[12] The abso-
lute configuration of 28 was determined by X-ray crystallo-
graphic analysis. The cyclohexene ring in 28 was oxidatively
cleaved by ozonolysis and the resulting dialdehyde 29 was
directly subjected to intramolecular aldol condensation, thus
yielding the ring-closed unsaturated aldehyde 8 (80% yield
for two steps).[13]
Scheme 3. Reagents and conditions: a) PPh3CHCO2tBu, toluene, RT,
54%; b) TFA, CH2Cl2, 08C; c) Br2, TFA, CDCl3/CCl4 (1:1), RT; (d) Et3N,
DMF, 08C to RT, 76% for 3 steps; (e) [{Pd(allyl)Cl}2] (5 mol%),
(Bu3Sn)2, LiCl, 1,4-dioxane, RT, 49%. DMF=N,N-dimethylformamide,
TFA=trifluoromethanesulfonyl.
from the commercially available compound citraconic anhy-
dride (16) in a reported four-step process in a 41% overall
yield.[9] Stannylation of 18 was achieved and afforded 4 with
[{Pd(allyl)Cl}2] and (Bu3Sn)2 in 49% yield.[10] It is noteworthy
that 4 is not stable during purification, thus resulting in a low
yield.
We then moved on to construct the aldehyde compound 8
(Scheme 4). By using the reaction conditions developed by
2
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Scheme 5. Reagents and conditions: a) LDA, THF, À788C, then 8, 86%, d.r. (at C19)=17:1; b) CuCl2, EDC, toluene, 808C, 83%; c) CuI, Zn, Pyr/
H2O (1:4), ultrasound, RT, 55% for 31, 4% for 31’; d) mCPBA, NaHCO3, CH2Cl2, À158C, 51%; e) NaOMe, MeOH, RT; then NiCl2·6H2O, NaBH4,
MeOH/THF (1:5), À158C, 73%; (f) ICl, THF, RT, 63%, d.r. (at C20)=1.5:1; (g) 4, AIBN, Bu3SnH, toluene, 4 ꢀ M.S., 1008C, 9% for 1, 36% for 2.
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimidem mCPBA=m-chloroperbenzoic acid. Thermal ellipsoids are shown at 50% probability.[21]
With the key intermediates 4, 7, and 8 in hand, we finished
the total synthesis of schilancitrilactones B and C as shown in
Scheme 5. The iodo compound 7 was converted into the
lithium enolate with LDA at À788C and then reacted with 8
to give the aldol adduct 30 in 86% yield (d.r. = 17:1 at C19).
Dehydration of 30 with 2 equivalents of EDC and a catalytic
amount of CuCl2 provided a 2:1 mixture of the inseparable
diene lactone 6 in 83% yield.[14] The structure of the E isomer
was confirmed by X-ray crystallographic analysis. Then we
investigated the intramolecular radical cyclization to form the
seven-membered ring. Initially, the conventional radical
conditions (AIBN, Bu3SnH) led to rapid decomposition of 6
and trace amounts of cyclization product was observed.
Photoredox catalysis[15] was also evaluated and no desired
product was found. By using the method (CuI, Zn under
ultrasound) for conjugate additions in aqueous media dis-
covered by Luche et al.,[16] we were pleased to observe the
cyclization product 31 in 55% yield, together with the isomer
31’ in 4% yield. The structure of 31’ was confirmed by X-ray
crystallographic analysis. We reasoned that the conformation
of 6 was suited for cyclization to give the seven-membered
ring over the five-membered ring.[17] Epoxidation of 31 with
mCPBA provided the epoxide 32 in 51% yield, and under-
went ring opening with NaOMe/NiCl2·6H2O/NaBH4 to give
the alcohol 5 in 73%.[18] During this transformation, the
epoxide 32 was converted into the intermediate 33 with
NaOMe and then further reduced to give the desired product
5 with NiCl2·6H2O and NaBH4. Finally, we investigated the
late-stage iodination and intermolecular radical addition
reaction. It was found that treatment of 5 with ICl delivered
the iodo compound 3 as a mixture of diastereomers (d.r. =
1.5:1 at C20) in 63% yield,[18] and when 3 was heated with the
vinyl stannane 4, AIBN, and Bu3SnH provided the schilanci-
trilactones B (1, 9%) and C (2, 36%) in 45% total yield.
Around 25% yield of other isomers were observed based on
the1H NMR analysis of the crude reaction mixture.[20] The
characterization data obtained for synthetic 1 and 2 were in
accord with the reported data for the natural products.
In summary, the first total synthesis of schilancitrilacto-
nes B and C has been accomplished by employing an intra-
molecular radical cyclization, late-stage iodination, and
intermolecular radical addition as key steps in the 17 step
synthesis (longest linear sequence) from commercially avail-
able materials. This strategy opens a pathway for the
syntheses of other compounds related to schilancitrilacto-
nes B and C, as well as their derivatives and analogues.
Keywords: cyclizations · natural products · radical chemistry ·
total synthesis · terpenoids
How to cite: &&
[1] X. Luo, Y.-M. Shi, R.-H. Luo, S.-H. Luo, X.-N. Li, R.-R. Wang,
S.-H. Li, Y.-T. Zheng, X. Du, W.-L. Xiao, J.-X. Pu, H.-D. Sun,
Org. Lett. 2012, 14, 1286.
[2] a) W.-L. Xiao, R.-T. Li, S.-X. Huang, J.-X. Pu, H.-D. Sun, Nat.
Prod. Rep. 2008, 25, 871; b) Y.-M. Shi, W.-L. Xiao, J.-X. Pu, H.-D.
Sun, Nat. Prod. Rep. 2015, 32, 367.
[3] Selected examples of synthetic efforts on Schisandraceae
triterpenoids: a) Y. Tang, L. Deng, Y. Zhang, G. Dong, J.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Chen, Z. Yang, Org. Lett. 2005, 7, 593; b) Y. Tang, Y. Zhang, M.
Dai, T. Luo, L. Deng, J. Chen, Z. Yang, Org. Lett. 2005, 7, 885;
c) Y. Zhang, Y. Tang, T. Luo, J. Shen, J. Chen, Z. Yang, Org. Lett.
2006, 8, 107; d) D. Fischer, E. A. Theodorakis, Eur. J. Org. Chem.
2007, 4193; e) Y. Zhang, W. Ren, Y. Lan, Q. Xiao, K. Wang, J.
Xu, J. Chen, Z. Yang, Org. Lett. 2008, 10, 665; f) Q. Wang, C.
Chen, Org. Lett. 2008, 10, 1223; g) L. A. Paquette, K. W. Lai,
Org. Lett. 2008, 10, 2111; h) K. W. Lai, L. A. Paquette, Org. Lett.
2008, 10, 2115; i) L. A. Paquette, K. W. Lai, Org. Lett. 2008, 10,
3781; j) M. F. Hossain, K. Matcha, S. Ghosh, Tetrahedron Lett.
2011, 52, 6473; k) A. Bartoli, G. Chouraqui, J.-L. Parrain, Org.
Lett. 2012, 14, 122; l) V. A. Ignatenko, Y. Han, G. P. Tochtrop, J.
Org. Chem. 2013, 78, 12229; m) B. Gockel, S. S. Goh, E. J.
Puttock, H. Baars, G. Chaubet, E. A. Anderson, Org. Lett. 2014,
16, 4480.
[9] T. Benneche, Z. Hussain, A. A. Scheie, J. Lçnn-Stensrud, New J.
Chem. 2008, 32, 1567.
[10] W. D. Wulff, G. A. Peterson, W. E. Bauta, K.-S. Chan, K.-L.
Faron, S. R. Gilbertson, R. W. Kaesler, D. C. Yang, C. K.
Murray, J. Org. Chem. 1986, 51, 277.
[11] a) B. M. Trost, S. Tanimori, P. T. Dunn, J. Am. Chem. Soc. 1997,
119, 2735; b) Y.-H. Wang, L.-L. Zhu, Y.-X. Zhang, Z. Chen,
Chem. Commun. 2010, 46, 577.
[12] K. Harrar, O. Reiser, Chem. Commun. 2012, 48, 3457.
[13] a) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret,
G. E. Keck, J.-L. Gras, J. Am. Chem. Soc. 1978, 100, 8031; b) G.
Coulthard, W. Erb, V. K. Aggarwal, Nature 2012, 489, 278.
[14] a) H. Sai, H. Ohmizu, Tetrahedron Lett. 1999, 40, 5019; b) H. Sai,
T. Ogiku, H. Ohmizu, Tetrahedron 2007, 63, 10345.
[15] For selected reviews, see: a) K. Zeitler, Angew. Chem. Int. Ed.
2009, 48, 9785; Angew. Chem. 2009, 121, 9969; b) T. P. Yoon,
M. A. Ischay, J. Du, Nat. Chem. 2010, 2, 527; c) J. M. R.
Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40,
102; d) J. Xuan, W. Xiao, Angew. Chem. Int. Ed. 2012, 51, 6828;
Angew. Chem. 2012, 124, 6934; e) C. K. Prier, D. A. Rankic,
D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322.
[16] J. L. Luche, C. Allavena, Tetrahedron Lett. 1988, 29, 5369.
[17] a) E. Lee, C. H. Yoon, T. H. Lee, J. Am. Chem. Soc. 1992, 114,
10981; b) E. Lee, C. H. Yoon, Tetrahedron Lett. 1996, 37, 5929;
c) C. S. Swindell, M. C. Chander, J. M. Heerding, P. G. Klimko,
L. T. Rahman, J. V. Raman, H. Venkataraman, J. Org. Chem.
1996, 61, 1101.
[18] T. Satoh, K. Nanba, S. Suzuki, Chem. Pharm. Bull. 1971, 19, 817.
[19] a) G. Giordano, L. Coppi, A. Restelli, J. Org. Chem. 1990, 55,
5400; b) P. S. Baran, A. L. Zografos, D. P. OꢃMalley, J. Am.
Chem. Soc. 2004, 126, 3726.
[20] J. E. Baldwin, D. R. Kelly, J. Chem. Soc. Chem. Commun. 1985,
682.
[4] a) Q. Xiao, W.-W. Ren, Z.-X. Chen, T.-W. Sun, Y. Li, Q.-D. Ye, J.-
X. Gong, F.-K. Meng, L. You, Y.-F. Liu, M.-Z. Zhao, L.-M. Xu,
Z.-H. Shan, Y. Shi, Y.-F. Tang, J.-H. Chen, Z. Yang, Angew.
Chem. Int. Ed. 2011, 50, 7373; Angew. Chem. 2011, 123, 7511;
b) T.-W. Sun, W.-W. Ren, Q. Xiao, Y.-F. Tang, Y.-D. Zhang, Y. Li,
F.-K. Meng, Y.-F. Liu, M.-Z. Zhao, L.-M. Xu, J.-H. Chen, Z.
Yang, Chem. Asian J. 2012, 7, 2321; c) Y. Li, Z.-X. Chen, Q. Xiao,
Q.-D. Ye, T.-W. Sun, F.-K. Meng, W.-W. Ren, L. You, L.-M. Xu,
Y.-F. Wang, J.-H. Chen, Z. Yang, Chem. Asian J. 2012, 7, 2334;
d) W.-W. Ren, Z.-X. Chen, D. Xiao, Y. Li, T.-W. Sun, Z.-Y.
Zhang, Q.-D. Ye, F.-K. Meng, L. You, M.-Z. Zhao, L.-M. Xu, Y.-
F. Tang, J.-H. Chen, Z. Yang, Chem. Asian J. 2012, 7, 2341.
[5] J. Li, P. Yang, M. Yao, J. Deng, A. Li, J. Am. Chem. Soc. 2014,
136, 16477.
[6] Selected reviews for radical cyclization: a) J. M. Cuerva, J.
Justicia, J. L. Oller-Lꢀpez, J. E. Oltra, Top. Curr. Chem. 2006,
264, 63; b) J. Justicia, L. Cienfuegos, A. G. CampaÇa, D. Miguel,
V. Jakoby, A. Gansꢁuer, J. M. Cuerva, Chem. Soc. Rev. 2011, 40,
3525; c) T. Taniguchi, H. Ishibashi, Heterocycles 2013, 87, 527.
For selected example, see: J. Justicia, J. L. Oller-Lꢀpez, A. G.
CampaÇa, J. E. Oltra, J. M. Cuerva, E. BuÇuel, D. J. Cꢂrdenas, J.
Am. Chem. Soc. 2005, 127, 14911.
[21] CCDC 1034710 (28), 1046754 (6), and 1034713 (31’) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[7] a) S. Takita, S. Yokoshima, T. Fukuyama, Org. Lett. 2011, 13,
2068; b) S. Takita, S. Yokoshima, T. Fukuyama, Synthesis 2011,
23, 3848.
[8] E. J. Corey, S. G. Pyne, W.-G. Su, Tetrahedron Lett. 1983, 24,
4881.
Received: February 6, 2015
Published online: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Natural Products
In step: The first total syntheses of
schilancitrilactones B and C have been
accomplished by using an intramolecular
radical cyclization to provide the seven-
membered ring, late-stage iodination,
and an intermolecular radical addition
reaction as key steps. The approach
provides a sequence for the syntheses of
compounds related to the schilancitrilac-
tones, as well as their derivatives and
analogues.
L. Wang, H. Wang, Y. Li,
P. Tang*
&&&& — &&&&
Total Synthesis of Schilancitrilactones B
and C
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!