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Total Synthesis of (–)-Xishacorene B from (R)Carvone using a C–C Activation Strategy Isabel Kerschgens, Alexander R Rovira, and Richmond Sarpong J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 23 Jul 2018 Downloaded from http://pubs.acs.org on July 23, 2018
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Journal of the American Chemical Society
Total Synthesis of (–)-Xishacorene B from (R)-Carvone using a C–C Activation Strategy Isabel Kerschgens, Alexander R. Rovira, and Richmond Sarpong* Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder ABSTRACT: The activation of C–C bonds that are traditionally viewed as unreactive, when coupled with other bond-forming processes, can offer new approaches to the synthesis of complex molecular scaffolds. In this manuscript, we demonstrate the conversion of carvone to unusual bicyclo[3.3.1] and [3.2.1] frameworks by exploiting a Pd(0)catalyzed C–C bond activation reaction and a radical cyclization process. This sequence is applied to a 10-step synthesis of the diterpene xishacorene B.
A. Concept: C–C Bond Activation/Coupling of Carvone O
Nu
Me
Me
O
Me Me
Nu
O Me
Nu
E Me
1
E
2
3
Me
B. Previous Work (Ref. 3a)
Me O Me
Cp2TiCl2 Zn
Me HO
O
Br
OH
Me
O
HO
Me
Pd(0)
Me
Me Me
The formation of carbon-carbon (C–C) bonds is paramount to the synthesis of complex organic molecules such as terpenoid natural products,1 which consist primarily of a carbon skeleton. Therefore, in developing strategies for the total synthesis of terpenoids, significant emphasis is often placed on methods that form new C–C bonds.2 As part of a program to exploit readily-available, ‘chiral pool’ reagents for terpene syntheses,3 we recognized that C–C activation of carvone, when coupled with new C–C bond forming processes, would yield novel structural frameworks that significantly expand the scope of complex molecules conventionally accessible from carvone (see 1®3, Figure 1A). We have shown previously that this type of transformation can be realized by converting epoxy carvone (4) to bis-hydroxylated pinene derivatives (see 5, Figure 1B) using a method by Bermejo,4 followed by Pd(0)-catalyzed cross coupling with vinyl or aryl halides to provide access to structures such as 6, which form the core of myriad natural products. In this communication, we demonstrate that vinylated adducts related to 6 are easily advanced to unusual bicyclo[3.3.1]nonane frameworks in one or two steps. We showcase the utility of this bicyclization sequence in a short synthesis of the natural product xishacorene B (7). Xishacorene B is a member of a new family of diterpenes recently isolated from the soft coral Sinularia polydactyla (0.0008% yield of dry coral material) off the coast of the Xisha Islands in China.5 Preliminary biological screening of these secondary metabolites revealed that they have activity as promoters of concanavalin A-induced T-lymphocyte proliferation. Thus, these molecules may prove useful as a starting point for the development of new small molecule immunopotentiators.
4
5
6
Me
C. This work: Application to [3.3.1] Bicycles and Xishacorene B Me Me
O Me
HO
Me
Me
Me
O Me
HO H R2
H
H
R1
Me
Me
OH
HO
Me
Me I
5
Me
Me Me xishacorene B (7)
Novel [3.3.1] bicycles
R2
Me
H
R1
OH Me
HO OH
9
Me
Me
Me
H
H
8
Me
OH
Figure 1. Use of C–C activation starting from carvone for natural product synthesis Retrosynthetically, we envisioned xishacorene B (7, Figure 1C) arising from bicyclo[3.3.1]nonane 8. In turn, 8 could be brought back to cyclobutanol 54 and vinyl iodide 9.6 We commenced our synthetic studies by optimizing the cross coupling of cyclobutanol 5 and vinyl iodide 9 (Table 1). On the basis of the precedent of Uemura,7 this coupling likely involves insertion of a Pd(0)-complex into 9 to provide a Pd(II)-species that undergoes ligand exchange to form alkenyl Pd-alkoxide 11. At this stage, β-carbon elimination/C–C bond activation would result in cleavage of the cyclobutanol to yield alkyl palladium intermediate 12. Reductive elimination to 13 would then complete the catalytic cycle. Key to the success of this coupling sequence would be to achieve reductive elimination from 12 over a competing b-hydride elimination.8 We hypothesized that this would be possible by the judicious
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Table 1. Optimization of the Pd-catalyzed C-C-activation/coupling sequence. Me
O Me
RO
R = H 13 R = Ac 14
H
Me
Me I
OH
9
reductive elimination
[Pd]0
OR
oxidative addition
Me
O Me
HO
Me PdII
I
H 12 PdII
OH
10 ligand exchange
Me
HO
Me Me
PdII
β-carbon elimination/
C-C activation
Me
O
5
11 Pd-complex
Me
Me
HO
entry
OH
OH HO
yield 13[a]
conversion[a]
solvent
yield 14[a]
1
Pd(PCy3)2
1,4-dioxane
> 98%
85%[b]
2
Pd(PCy3)2
1,4-dioxane
> 98%
74%[c]
-
3
Pd(PCy3)2
1,4-dioxane
67%
49%[d]
-
4
Pd(PPh3)4
1,4-dioxane
81%
63%
-
5
Pd[P(tBu)2Ph]2
1,4-dioxane
73%
56%
-
6
Pd(PCy3)2
benzene
92%
63%
-
7
Pd(PCy3)2
> 98%
EtOAc
-
free hydroxy groups, providing an opportunity for in-situ acyl-protection simply by choice of solvent (14, entry 7). As shown in Figure 2, the optimized conditions are readily extended to the coupling of 5 with a range of vinyl halides, providing the corresponding adducts in good to excellent yields. In general, vinyl iodides required lower reaction temperatures to proceed, whereas vinyl bromides required higher temperatures. In the coupling with 22, it is interesting to note that the product of the cross-coupling provides the skeleton of an isomer of the natural product cassiol.9 For the construction of bicyclic scaffolds including the [3.3.1]-framework of the xishacorene family, we sought to utilize the coupling products illustrated in Figure 2 in Mukaiyama-type hydrogen atom transfer (HAT) reactions. Inspired by the work of Baran,10 Shenvi11 and others,12 a variety of HAT conditions that would lead to cyclization were explored. The desired cyclization occurred with varying degrees of efficiency for several substrates (e.g., for 24 and 26, a 28% yield and 32% yield, respectively, of the [3.2.1] bicycles Table 2. Cyclization to bicyclo[3.3.1] and [3.2.1] bicycles. Method A: Fe(acac)3, Ph(i-PrO)SiH2, EtOH[a] enone
70%
17%
by 1H-NMR analysis using benzyl benzoate as an internal standard. [b] Reagents and conditions: 5 mol% of Pd-complex, 1.5 equiv of vinyl iodide, 2.0 equiv Cs2CO3, 30°C, 18 h. [c] 1.1 equiv vinyl iodide instead of 1.5 equiv [d] 18°C instead of 30°C.
entry
choice of ligands on the Pd complex. We identified Pd(PCy3)2 as the optimal palladium complex, and temperatures of 30–40 °C as well as the use of cyclobutanol 5 bearing free hydroxy groups to be ideal (Table 1, entry 1). The highest yields for the coupling were obtained using 1.5 equivalents of vinyl iodide 9. Lowering the amount of 9 to 1.1 equivalents and the reaction temperature to 18 °C resulted in lower yields (entries 2 and 3). Using benzene as a solvent (entry 6) gave the product in lower yield relative to 1,4-dioxane. Interestingly, with EtOAc as the solvent, the cross-coupling proceeded with attendant acylation of the
Me
Me
HO
Me
RX, Pd(PCy3)2, Cs2CO3, 1,4-dioxane, 40°C[a]
5 Ph
Me Br
Me 15 Me
53%[b] 16
I
Ph
Me 2
20
A H 26
O
32%
Me OH 27
Me Me
O
AcO
Me
3
H Me Me
B Br
H 28
Me
O
Me
Me
H
OAc
29
Me
H Me Me
B Br
75%
O
30
O
Br
69% 17
18
19
OH
Br
OTBS
89%
Me 31 OAc
53%[b] 21
Unsuccessful HAT-substrates: O Me Me HO
Me
O
HO
Me
Me
O
HO
Me
I H 32
OTBS
[a]
Me
H Me Me
Me
4
Me 68%
OTBS 77%
OH 25
O
HO
Me
Ph 78%[c]
Br
Me
O
28%[c]
Me
Me
I
Br
89%[b]
A H 24
H
Br
yield
Ph
H Me Me
Me
AcO
R
product
O
HO
O
HO
method
Ph
Figure 2. Scope of the Pd-catalyzed C–C-activation/coupling sequence OH
enone
1
bicycle
Method B: AIBN, HSnBu3, benzene, 80°C[b]
[a] Determined
Me
Page 2 of 5
50%[b]
38%[b][c]
22
23
Detailed conditions: 1.5 – 3 equiv vinyl halide, 0.5 – 0.1 equiv Pd(PCy3)2, 2 equiv Cs2CO3, 1,4-dioxane (0.2 M), 40°C, 18 h. [b] Elevated temperature required, see the SI for details. [c] Isolated as inseparable mixture of alkene isomers, see the SI for details.
HO
H 33
Me
H 13
HO [a]
Detailed conditions: 1 equiv Fe(acac)3, 2–2.5 equiv Ph(i-PrO)SiH2, EtOH (0.1 M – 0.2 M), 0°C – rt, 2 h. [b] Detailed conditions: 0.2 equiv AIBN, 4 equiv HSnBu3, benzene (0.1 M), 80°C, 50 min. [c] Isolated as an inseparable mixture containing minor side products.
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Journal of the American Chemical Society
Scheme 1. Synthesis of xishacorene B and 1-epi-xishacorene B (46). A. Me
Pd(PCy)2, 9, Cs2CO3
5
O Me
HO
1,4-dioxane, 30°C
Me HBr
H
Br Me
13
OH
O
Me
Me
42 KOt-Bu
Me
LiAlH4 THF, 0°C
35
H Me Me H HO OH 8
d.r.: 1.1:1 48% 92% total yield (major diastereomer drawn, no separation)
Me
THF, 0°C
Me
PCC, NaOAc
DCC⋅MeI THF, 55°C I
Me
Me
MS 3 Å, CH2Cl2, 0°C
Me
DMSO, 100°C
15
41 75%
O
KOt-Bu Me
HO
Me
98%
PO(OEt)2
7 88% xishacorene B
40 61%
H Me Me 12 15 H I OH 36
9
Me
55% (diastereomers separated)
I
Me H Me Me
[α]20D= – 19.5 (c = 0.58, MeOH) [α]20D= – 11.3 (c = 0.20, MeOH) [ref. 5]
H Me Me H O
Me
12
O I 37 (From DMP oxidation of 36) B. H Me Me H I OH 43
1
OAc
34
OAc
Me
H Me Me
H 1
d.r.: 1:1 73%
Me Me
AIBN, n-Bu3SnH benzene, 80°C
88%
Me
Me
AcO
AcOH, 0°C→RT Me
OH
OAc
O
Me
Me I
KOt-Bu
Me HO
Me
MS 3 Å, CH2Cl2, 0°C
DMSO, 100°C 44 58%
15
Me
Me 42, KOt-Bu
Me
Me
38
39
Me PCC, NaOAc
H Me Me 15 H I O
Me
Me
Me
THF, 0°C O
45 88%
46
Me
81% Me
were obtained, see entries 1 and 2 in Table 2). More challenging substrates such as 32 and 33 could not be cleanly transformed to the corresponding bicycles. In particular, enone 13, an intermediate in the xishacorene synthesis (Scheme 1), only gave small amounts of the Mukaiyamatype cyclization product along with numerous side products. Various HAT conditions using Fe, Co, or Mn-complexes,13 a range of silanes, and various solvents also resulted in competing side reactions including reduction of the enone double bond or both double bonds in the substrate to give inseparable mixtures of reduction products. Ultimately, a more effective two-step sequence was identified for bicyclization that began with installation of a tertiary bromide through hydrobromination of the more electron-rich double bond using HBr in AcOH.14 Cyclization to provide 29 or 31 proceeded smoothly under radical conditions (AIBN, n-Bu3SnH, 80 °C) in good yields (see Table 2, Method B). In the context of the synthesis of xishacorene B, bromination of 13 (Scheme 1, A) proceeded with concomitant acylation of both hydroxy groups to give 34 in 73% yield as a 1:1-diastereomeric ratio of epimers about the Br-bearing carbon. The radical cyclization proceeded smoothly in 92% yield to give 35 as a 1.1:1 diastereomeric mixture at C1 slightly favoring the desired diastereomer. Attempts to improve the diastereomeric ratio using other initiation conditions (e.g., lauroyl peroxide as an initiator) have not been successful, whereas some other methods including
photoredox conditions15 did not result in any conversion of starting material. With [3.3.1] bicycle 35 in hand, treatment with LiAlH4 effected global reduction of the two ester groups and the ketone carbonyl to give triol 8 in 98% yield.16 Subjecting triol 8 to 5 equivalents of DCC·MeI17 at 55 °C in THF selectively converted the two primary alcohols to the corresponding iodides in the presence of the secondary alcohol at C12.18 The secondary alcohol group was confirmed by DMP oxidation of the resulting diiodide (36) to afford ketone 37. At this stage, the two C1-epimers that had been carried along following the radical cyclization step (see 34®35) could be separated. Upon treatment of the desired isomer (36) with KOt-Bu at elevated temperature, elimination of the C9 primary iodide occurred to form a vinyl group. It is presumed that Williamson-etherification by displacement of the C15 iodide by the C12 hydroxyl yields oxetane intermediate 39,19,20 which gives alcohol 40 following elimination in an overall transposition of the C12 hydroxyl.21 Xishacorene B was accessed from 40 using a two-step sequence involving oxidation of the primary hydroxyl to aldehyde 41 (using pyridinium chlorochromate) followed by Horner-WadsworthEmmons olefination with phosphonate 42. The optical rotation of synthetic 7 was found to differ from the reported value of the isolated material (synthetic: –19.5; natural: – 11.3). We theorize this might arise from the poor solubility of the very lipophilic 7 in MeOH.
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Synthesis of the C1 epimer of xishacorene B (7) was also realized using the same sequence but starting with bicycle 43, the epimer of 36 (Scheme 1B). In conclusion, we have demonstrated the utility of a C–C activation/cross-coupling sequence for the construction of complex molecular frameworks. Specifically, carvone can be converted in two steps to a hydroxylated pinene derivative that sets the stage for a key cross-coupling. A Pd-catalyzed cyclobutanol C–C cleavage/coupling with vinyl halides followed by radical-mediated C–C bond construction provided rapid access to a variety of [3.3.1] bicycles. Using this approach, the first total synthesis of the marine diterpene xishacorene B has been achieved in 10 steps from carvone without using any protecting groups. Future studies will focus on applying this strategy to the synthesis of xishacorene congeners and their derivatives as well as the investigation of their bioactivity. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at http://pubs.acs.org.
Experimental detail and spectroscopic data. AUTHOR INFORMATION Corresponding Author *
[email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work was supported by the National Science Foundation (NSF, CHE-1566430 to R.S.). The Swiss National Science Foundation is kindly acknowledged for an Early Postdoc. Mobility Fellowship to support I. K. (P2BSP2_168732). Aduro Biotech is kindly acknowledged for a Postdoc Fellowship for A. R. R. Dr. Marcus Blümel is kindly acknowledged for generous donations of 5. REFERENCES 1
For a review on terpene synthesis see: Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396. 2 For a review see: Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Chem. Rev. 2017, 117, 11753. 3 a) Weber, M.; Owens, K.; Masarwa, A.; Sarpong, R. Org. Lett. 2015, 17, 5432. b) Masarwa, A.; Weber, M.; Sarpong, R. J. Am. Chem. Soc. 2015, 137, 6327. c) Finkbeiner, P.; Murai, K.; Röpke, M.; Sarpong, R. J. Am. Chem. Soc. 2017, 139, 11349. d) Kuroda, Y.; Nicacio, K. J.; da Silva, I. A.; Leger, P. R.; Chang, S.; Gubiani, J. R.; Deflon, V. M.; Nagashima, N.;Rode, A.; Blackford, K.; Ferreira, A. G.; Sette,
L. D.; Williams, D. E.; Andersen, R. J.; Jancar, S.; Berlinck, R. G. S.; Sarpong, R. Nat. Chem. 2018, NCHEM17102265B. 4 Bermejo, F. A.; Mateos, A. F.; Escribano, A. M.; Lago, R. M.; Burón, L. M.; López, M. R.; González, R. R. Tetrahedron 2006, 62, 8933. 5 Ye, F.; Zhu, Z.-D.; Chen, J.-S.; Li, J.; Gu, Y.-C.; Zhu, W.-L.; Li, X.-W.; Guo, Y.-W. Org. Lett. 2017, 19, 4183. 6 Original contribution: Wipf, P.; Lim, S. Angew. Chem. Int. Ed. 1993, 32, 1068. Procedure used from: Schaubach, S.; Gebauer, K.; Ungeheuer, F.; Hoffmeister, L.; Ilg, M. K.; Wirtz, C.; Fürstner, A. Chem. Eur. J. 2016, 22, 8494. 7 a) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862. b) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S. Tetrahedron Lett. 2002, 43, 3037. c) Nishimura, T.; Matsumura, S.; Maeda, Y.; Uemura, S. Chem. Commun. 2002, 50. 8 Competing b-hydride elimination has been observed to varying extent at elevated temperatures. 9 Shiraga, Y.; Okano, K.; Akira, T.; Fukaya, C.; Yokoyama, K.; Tanaka, S.; Fukui, H.; Tabata, M. Tetrahedron 1988, 44, 4703. 10 a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304. b) Lo, J. C.; Gui, J.; Yabe, Y.; Pan, C.-M.; Baran, P. S. Nature 2014, 516, 343. 11 Obradors, C.; Martinez, R. M.; Shenvi, R. A. J. Am. Chem. Soc. 2016, 138, 4962. 12 a) George, D. T.; Kuenstner, E. J.; Pronin, S. V. J. Am. Chem. Soc. 2015, 137, 15410. b) Xu, G.; Elkin, M.; Tantillo, D.; Newhouse, T.; Maimone, T. Angew. Chem. Int. Ed. 2017, 56, 12498. 13 Specifically, Fe(acac)3, Co(acac)3, Co(dmp)2, Mn(acac)3 and the Co-complex used in Ref. 12b were investigated as catalysts for this process. 14 a) Tabuchi, T.; Urabe, D.; Inoue, M. J. Org. Chem. 2016, 81, 10204. b) Hagiwara, K.; Tabuchi, T.; Urabe, D.; Inoue, M. Chem. Sci. 2016, 7, 4372. 15 a) Furst, L.; Narayanam, J. M. R.; Stephenson, C. R. J. Angew. Chem. Int. Ed. 2011, 50, 9655. b) Schnermann, M. J.; Overman, L. E. Angew. Chem. Int. Ed. 2012, 51, 9576. 16 The configuration of the secondary hydroxyl at C12 in 8 was determined by NOE-experiments. 17 Scheffold, R.; Saladin, E. Angew. Chem. Int. Ed. 1972, 11, 229. 18 Holtsclaw, J.; Koreeda, M. Org. Lett. 2004, 6, 3719. 19 For a review on oxetanes in synthesis see: a) Bull, J. A.; Croft, R. A.; Davis, O. A.; Doran, R.; Morgan, K. F. Chem. Rev. 2016, 116, 12150. b) Mahal, A. Eur. J. Chem. 2015, 6, 357. 20 For examples of oxetane formation from iodides see: a) Sevrin, M.; Krief, A. Tetrahedron Lett. 1980, 21, 585. b) Roy, B. G.; Roy, A.; Achari, B.; Mandal, S. B. Tetrahedron Lett. 2006, 47, 7783. 21 We are grateful to an insightful reviewer for suggesting this pathway for the formation of 40.
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radical cyclization Me
R1
Me R2
Me R1
O Me
Me
R2
Me
HO
RO
X
Me
Pd(0)coupling C–C activation
RO
Novel bridged bicycles
Me
New bonds
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xishacorene B Me 10-step synthesis enantiospecific protecting group free
5
