Gold-Catalyzed Photoredox C(sp2) Cyclization: Formal Synthesis of (±)-Triptolide

Article abstract of DOI:10.1021/acs.orglett.6b00968

Photoexcitation of a dimeric gold complex showed the activation of a C(sp²)-Br bond to generate a vinyl radical in a mild photoredox catalysis process. Use of [Au₂(dppm)₂]Cl₂ with 365 nm LEDs in a photoredox catalysis process to produce polycyclic scaffolds using vinyl radicals is reported. This method achieved the synthesis of a small library of butenolide polycyclic compounds and naphthol polycyclic compounds. The efficacy of this photoredox process was further demonstrated by accomplishing the concise formal synthesis of (±)-triptolide.

Full text of DOI:10.1021/acs.orglett.6b00968

Letter
pubs.acs.org/OrgLett
2
Gold-Catalyzed Photoredox C(sp ) Cyclization: Formal Synthesis of
± )-Triptolide
(
́ ́
Alexandre Cannillo, Travis R. Schwantje, Maxime Begin, Francis Barabe, and Louis Barriault*
Centre for Catalysis, Research and Innovation, Department of Chemistry and Biomolecular Science, University of Ottawa, 10 Marie
Curie, Ottawa, Canada K1N 6N5
*
S Supporting Information
ABSTRACT: Photoexcitation of a dimeric gold complex
2
showed the activation of a C(sp )−Br bond to generate a vinyl
radical in a mild photoredox catalysis process. Use of
[
Au (dppm) ]Cl with 365 nm LEDs in a photoredox catalysis
2 2 2
process to produce polycyclic scaffolds using vinyl radicals is
reported. This method achieved the synthesis of a small library
of butenolide polycyclic compounds and naphthol polycyclic compounds. The efficacy of this photoredox process was further
demonstrated by accomplishing the concise formal synthesis of (±)-triptolide.
or over a century, radicals have been interesting to chemists,
process (Scheme 1, eq 2). Although these radical intermediates
can be more reactive than alkyl radicals, one can imagine that
their inherent reactivity could be harnessed for the formation of
1
F
becoming a powerful tool for building C−C bonds. Radical
C−C bond construction has been very useful for complex
2
2
2
molecule synthesis, such as for natural products. Recently,
new C(sp )−C(sp ) bonds. In particular, one can envisage
functionalization of γ-butenolides (Y = O, n = 1). These
structural motifs and their saturated derivatives are frequently
encountered in natural and synthetic product molecules, and
photoredox catalysis has emerged as an efficient method for the
generation of carbon-centered radicals through single-electron
transfer (SET) processes. These light-mediated methods have
shown high-yielding protocols for the generation of C−C, C−N,
and C−O bonds, offering an attractive alternative to the use of
potentially hazardous radical initiators (AIBN, Et B/O ,
8
these compounds are useful building blocks.
Despite the rich literature in radical chemistry, these types of
carbon-centered radicals have been occasionally used, and the
potential broad utility of such photoredox processes in organic
3
2
3
peroxides) and hydrogen atom donors such as organostannane.
4
5
9
In this context, we and others recently reported the use of the
synthesis warrants further investigation. Herein, we describe the
6
dimeric gold complex [Au (dppm) ]Cl 1 in combination with
2
2
2
development of a photoredox direct arylation of substituted
butenolides and cyclic enones using dimeric gold complexes and
its application to a short formal synthesis of (±)-triptolide.
Our investigation began with the irradiation of 3-bromobu-
tenolide 2a (UVA LED, 365 nm) in the presence of 1 (10 mol %)
and various bases in acetonitrile (Table 1). In the presence of
tertiary amine bases, the photoredox process proceeds through a
reductive quenching cycle in which the amine bases serve as a
sacrificial electron donor (Table 1, entries 1−4). Use of DIPEA
led to an inseparable mixture of the desired compound 4a and the
dehalogenated 9 in 50% yield as a 6:4 ratio (Table 1, entry 1).
Given that these radical intermediates are a more reactive species
than alkyl radicals, hindered or poor hydrogen donor alkyl amine
bases were tested to decrease the competitive reduction process.
No significant improvements were noticed when using
pempidine and DABCO (Table 1, entries 2 and 3). However,
a higher yield and ratio were observed with DBU (Table 1, entry
ultraviolet A (UVA, 365 nm) light irradiation to generate radical
intermediates from unactivated bromoalkanes/arenes in a mild
photoredox catalysis process (Scheme 1, eq 1). Further
mechanistic investigation showed that this photoredox process
proceeds through an inner-sphere mechanism via either an
oxidative or a reductive quenching cycle. Taking advantage of
this distinctive mechanism, we wondered if the generation of β-
enone radicals such as 3 could be achieved through a photoredox
7
Scheme 1. Photoredox Reaction Using a Dimeric Gold
Complex
4
). Switching to sodium carbonate, we obtained the exclusive
formation of 4a in 39% yield (Table 1, entry 5). Prolonged
irradiation substantially increased the reaction yield to 72%
(
Table 1, entry 6). Control experiments demonstrated the need
Received: April 4, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions and Control
Experiments
Table 2. Scope of the Reaction
a
a
Reaction conditions: vinyl bromide (0.1 M in MeCN), 1 (10 mol %),
b
Na CO (2 equiv), 365 nm LED, 12 h, rt. Yields of isolated products.
2
3
a
Unless otherwise noted, reactions were conducted with 2a (0.1 M in
b
MeCN), catalyst (10 mol %), base (2 equiv), and light at rt. 365 nm
LED or 410 nm LED or CFL bulb (14 W). Yields of isolated
products. Ratio determined by H NMR.
c
(Table 2, entry 6). Methyl and phenyl groups present on
substrates 2g and 2h gave the corresponding cyclized naphthols
d
1
4
g and 4h with 62 and 58% yields (Table 2, entries 7 and 8). 3-
of each reagent and light (Table 1, entries 7−9). In the absence of
catalyst, base, or light, only starting material was recovered.
Common photocatalysts such as Ru(bpy) (PF ) and Ir(ppy)
3
proved to be ineffective for this radical cyclization. Only starting
material was recovered after irradiation with a 14 W compact
fluorescent light (24 h) (Table 1, entries 10, 12, 14, and 16).
Irradiating the reaction mixture with a 410 nm LED in the
presence of DIPEA afforded a mixture of 4a and 5 in very low
yields (Table 1, entries 11 and 15). Combining sodium carbonate
Bromocyclohexenone with a gem-dimethyl group at position 5
(2i) was cyclized to obtain the corresponding product 4i with
67% yield (Table 2, entry 9). Presence of a chloride in the para
position of the aromatic ring and the gem-dimethyl group on the
cyclohexenone 2j gave cyclized product 4j with 69% yield (Table
2, entry 10).
Use of sodium carbonate to achieve this kind of photoredox
catalysis process is not frequently encountered. Indeed, most
reported studies use tertiary amine bases as sacrificial electron
donors and hydrogen sources. According to the value of the
redox potential of the CO3 /CO3 couple (1.5 V), the
carbonate species cannot turnover the catalyst in either reductive
or oxidative quench pathways. For this reason, we suggest the
mechanism shown in Figure 1.
Irradiation of [Au−Au] generates excited [Au−Au] *,
which could then reduce the C−Br bond through a SET to afford
the vinyl radical 3 (oxidative quenching cycle). This radical can
then cyclize to produce the tricyclic compound 5 bearing a
tertiary radical. Simultaneous oxidation of 5 and reduction of the
3
6 2
with Ir(ppy) produced 4a as the only product in 18% yield after
3
•
−
2−
10
2
4 h (Table 1, entry 17).
With optimized conditions in hand, the scope of the reaction
was explored using various substituents on the aromatic ring
Table 2). Methyl and phenyl groups afforded the corresponding
cyclized products 4b and 4c with 70 and 77% yields, respectively
Table 2, entries 2 and 3). The presence of an electron-
(
2+
2+
(
withdrawing group such as chloride 2d had no effect on the
cyclization, and product 4d was obtained in 79% yield (Table 2,
entry 4). However, a decrease in yield was observed when using
electron-rich arene 2e, and cyclic product 4e was isolated in 46%
yield (Table 2, entry 5). We then applied this photoredox process
to a range of 3-bromocyclohexenones. Cyclization of 2f and
subsequent tautomerization afforded naphthol 4f with 64% yield
3+
[Au−Au] complex should provide 4 and the dimeric gold
photocatalyst 1.
The utility of this photoredox process was demonstrated in a
concise synthesis of (±)-triptolide 6 (Scheme 2). Isolated from
B
DOI: 10.1021/acs.orglett.6b00968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
13
community and led to clever syntheses. We envisioned the
application of the gold-catalyzed photoredox reaction to
assemble 7, a known intermediate, via an intramolecular radical
cascade cyclization of the γ-butenolide derivative 8.
Allyl 10 was obtained in 79% yield by treatment of aldehyde 9
with allylmagnesium bromide followed by addition of dimethyl
sulfate (Scheme 3). Compound 10 was engaged in a cross-
metathesis reaction using methacrolein in the presence of
Grubbs second generation catalyst and a catalytic amount of
14
copper iodide to give the aldehyde 11 in 72% yield as a single E-
15
isomer. A carbon homologation using the Wittig reaction
transformed 11 into diene 12 in 89% yield. The latter was
quantitatively converted to the corresponding primary alcohol
1
6
1
3 through a hydroboration/oxidation sequence. Dess−
Martin oxidation of 13 led to aldehyde 14, which underwent a
Figure 1. Proposed mechanism.
one-pot proline-catalyzed coupling reaction with tetronic acid in
17
the presence of Hantzsch ester and triflation to afford triflate
5. The crude material was directly heated in THF with LiBr to
Scheme 2. Radical Cascade Cyclization as Key Step
1
furnish bromobutenolide 8 in 89% yield over three steps. All of
these steps were performed on a multigram scale.
Reaction of bromobutenolide 8 under our optimal conditions
was followed by treatment with H SO to provide tetracycle 17.
2
4
The relative stereochemistry of 17 was unequivocally established
18
by X-ray analysis. Radical cyclization provided 16 (1:1 dr) with
19
a cis ring junction rather than a trans junction. Epimerization at
C4 aimed at obtaining the trans ring junction under basic or
acidic conditions proved to be fruitless. Isomerization of 15 using
a catalytic amount of RuCl (PPh ) and DIPEA in toluene at 120
2
3 3
°
C provided 7 in 79% yield. Conversion of 7 into 6 was achieved
13d
in eight steps. Interception of this late-stage intermediate in
their synthesis thus completes the formal total synthesis of the
natural product.
In summary, a photoredox process using 1 (10 mol %) and a
65 nm LED to generate vinyl radicals from bromobutenolide
the chinese climbing vine Tripterygium wilfordii, 6 is a naturally
3
occurring diterpene containing three contiguous epoxides and a
1
1
and bromocyclohexenone was developed. This redox-neutral
method allows the formation of polycyclic compounds. This
effective reaction was demonstrated by a concise formal synthesis
of (±)-triptolide 6 in nine steps (17% overall yield) from readily
available 9. Further application of this gold-catalyzed photoredox
butenolide ring. This diterpene shows in vitro and in vivo
activity against polycystic kidney disease and pancreatic tumor
1
2a−c
12d
cells
ing therapeutic properties and challenging structure of triptolide
have resulted in considerable attention from the synthetic
and also has immunosuppressive activities. Promis-
6
Scheme 3. Formal Synthesis of (± )-Triptolide 6
C
DOI: 10.1021/acs.orglett.6b00968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
process, including the syntheses of other diterpenes, will be
reported in due course.
Rescifina, A.; Chiacchio, U. Mini-Rev. Org. Chem. 2005, 2, 59. (e) Langer,
P. Synlett 2006, 2006, 3369.
(
9) For an example of the formation and cyclization of β-enone and
unsaturated ester radical species using standard conditions, see:
a) Lathbury, D. C.; Parsons, P. J.; Pinto, I. J. Chem. Soc., Chem.
ASSOCIATED CONTENT
Supporting Information
■
(
*
S
Commun. 1988, 81. (b) Jasperse, C. P.; Curran, D. P. J. Am. Chem. Soc.
1990, 112, 5601. (c) Borthwick, A. D.; Caddick, S.; Parsons, P. J.
Tetrahedron Lett. 1990, 31, 6911. (d) Borthwick, A. D.; Caddick, S.;
Parsons, P. J. Tetrahedron 1992, 48, 10655. Brown, C. D. S.; Simpkins,
N. S.; Clinch, K. Tetrahedron Lett. 1993, 34, 131. (e) Sha, C.-K.; Hsu, C.-
W.; Chen, Y.-T.; Cheng, S.-Y. Tetrahedron Lett. 2000, 41, 9865. (f) Sha,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00968.
1
13
Experimental procedures and H and C NMR spectra for
all new compounds (PDF)
C.-K.; Lee, F.-C.; Lin, H.-H. Chem. Commun. 2001, 39. (g) Den
Beaufils, F.; Renaud, P. Synlett 2008, 2008, 2389.
10) Huie, R. E.; Clifton, C. L.; Neta, P. Radiat. Phys. Chem. 1991, 38,
́ ̀
es, F.;
AUTHOR INFORMATION
Corresponding Author
■
(
4
77.
*
E-mail: lbarriau@uottawa.ca.
(11) Kupchan, S. M.; Court, W. A.; Dailey, R. G.; Gilmore, C. J.; Bryan,
R. F. J. Am. Chem. Soc. 1972, 94, 7194.
12) (a) Yang, Y.; Liu, Z.; Tolosa, E.; Yang, J.; Li, L.
Notes
(
The authors declare no competing financial interest.
Immunopharmacology 1998, 40, 139. (b) Leuenroth, S. J.; Okuhara,
D.; Shotwell, J. D.; Markowitz, G. S.; Yu, Z.; Somlo, S.; Crews, C. M.
Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 4389. (c) Phillips, P. A.; Dudeja,
V.; McCarroll, J. A.; Borja-Cacho, D.; Dawra, R. K.; Grizzle, W. E.;
Vickers, S. M.; Saluja, A. K. Cancer Res. 2007, 67, 9407. (d) Chugh, R.;
Sangwan, V.; Patil, S. P.; Dudeja, V.; Dawra, R. K.; Banerjee, S.;
Schumacher, R. J.; Blazar, B. R.; Georg, G. I.; Vickers, S. M.; Saluja, A. K.
Sci. Transl. Med. 2012, 4, 156RA139.
ACKNOWLEDGMENTS
■
The authors thank the Natural Sciences and Engineering
Research Council (NSERC) (for Accelerator, Discovery, and
CREATE grants to L.B.) and the University of Ottawa for a
University Research Chair to L.B. F.B. and A.C. thank NSERC
and uOttawa for a CGS-D and Vision 2020 postdoctoral
scholarships, respectively. Acknowledgement is also made to the
donor of the American Chemical Society Petroleum Research
Fund for support of this research. We thank Dr. I. Korobkov
(13) (a) Buckanin, R. S.; Chen, S. J.; Frieze, D. M.; Sher, F. T.;
Berchtold, G. A. J. Am. Chem. Soc. 1980, 102, 1200. (b) Van Tamelen, E.
E.; Demers, J. P.; Taylor, E. G.; Koller, K. J. Am. Chem. Soc. 1980, 102,
5424. (c) Garver, L. C.; Van Tamelen, E. E. J. Am. Chem. Soc. 1982, 104,
867. (d) Lai, C. K.; Buckanin, R. S.; Chen, S. J.; Zimmerman, D. F.; Sher,
F. T.; Berchtold, G. A. J. Org. Chem. 1982, 47, 2364. (e) Van Tamelen, E.
E.; Leiden, T. M. J. Am. Chem. Soc. 1982, 104, 1785. (f) Yang, D.; Ye, X.-
Y.; Gu, S.; Xu, M. J. Am. Chem. Soc. 1999, 121, 5579. (g) Yang, D.; Ye, X.-
Y.; Xu, M. J. Org. Chem. 2000, 65, 2208. (h) Miller, N. A.; Willis, A. C.;
Sherburn, M. S. Chem. Commun. 2008, 1226. (i) Goncalves, S.; Hellier,
P.; Nicolas, M.; Wagner, A.; Baati, R. Chem. Commun. 2010, 46, 5778.
(University of Ottawa) for X-ray analysis.
REFERENCES
■
(
1) (a) Koert, U. Angew. Chem., Int. Ed. Engl. 1996, 35, 405. (b) Sibi, M.
P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263.
(
3
c) Edmonds, D. J.; Johnston, D.; Procter, D. J. Chem. Rev. 2004, 104,
371. (d) Wille, U. Chem. Rev. 2013, 113, 813.
2) (a) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis; Wiley-
(
j) Zhang, H.; Li, H.; Xue, J.; Chen, R.; Li, Y.; Tang, Y.; Li, C. Org.
Biomol. Chem. 2014, 12, 732. (k) Xu, H.; Tang, H.; Feng, H.; Li, Y. J. Org.
Chem. 2014, 79, 10110.
(
VCH: Weinheim, 2001. (b) Zard, S. Z. Radical Reactions in Organic
Synthesis; Oxford University Press: Oxford, 2003.
(
14) Voigtritter, K.; Ghorai, S.; Lipshutz, B. H. J. Org. Chem. 2011, 76,
697.
15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(
3) (a) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011,
0, 102. (b) Teply, F. Collect. Czech. Chem. Commun. 2011, 76, 859.
c) Reckenthaler, M.; Griesbeck, A. G. Adv. Synth. Catal. 2013, 355,
4
(
4
(
́
̈
2
2
727. (d) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
013, 113, 5322.
(
(
(
16) Cole, K. P.; Hsung, R. P. Org. Lett. 2003, 5, 4843.
17) Ramachary, D. B.; Kishor, M. Org. Biomol. Chem. 2010, 8, 2859.
18) CCDC 1471725 (16) contains the supplementary crystallo-
(
4) (a) Revol, G.; McCallum, T.; Morin, M.; Gagosz, F.; Barriault, L.
Angew. Chem., Int. Ed. 2013, 52, 13342. (b) McCallum, T.; Slavko, E.;
Morin, M.; Barriault, L. Eur. J. Org. Chem. 2015, 2015, 81. (c) Kaldas, S.;
Cannillo, A.; McCallum, T.; Barriault, L. Org. Lett. 2015, 17, 2864.
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(
5) (a) Xie, J.; Shi, S.; Zhang, T.; Mehrkens, N.; Rudolph, M.; Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2015, 54, 6046. (b) Nzulu, F.; Telitel, S.;
Stoffelbach, F.; Graff, B.; Morlet-Savary, F.; Lalevee, J.; Fensterbank, L.;
(
19) For selected examples of trans radical cyclization, see:
a) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J. Am. Chem. Soc.
990, 112, 2759. (b) Zoretic, P. A.; Weng, X.; Caspar, M. L.; Davis, D. G.
(
́
1
Goddard, J.-P.; Ollivier, C. Polym. Chem. 2015, 6, 4605. (c) Xie, J.;
Zhang, T.; Chen, F.; Mehrkens, N.; Rominger, F.; Rudolph, M.; Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2016, 55, 2934. (d) Huang, L.; Rominger,
F.; Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 4808.
Tetrahedron Lett. 1991, 32, 4819. (c) Chen, L.; Gill, G. B.; Pattenden, G.
Tetrahedron Lett. 1994, 35, 2593. (d) Heinemann, C.; Demuth, M. J. Am.
Chem. Soc. 1997, 119, 1129. (e) Zoretic, P. A.; Fang, H.; Ribeiro, A. A. J.
Org. Chem. 1998, 63, 7213. (f) Heinemann, C.; Demuth, M. J. Am.
Chem. Soc. 1999, 121, 4894. (g) Barrero, A. F.; Herrador, M. M.; Quílez
del Moral, J. F.; Arteaga, P.; Arteaga, J. F.; Piedra, M.; Sanchez, E. A. Org.
́
Lett. 2005, 7, 2301. (h) Rendler, S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2010, 132, 5027.
(
e) Huang, L.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. Chem.
Commun. 2016, 52, 6435.
6) (a) Che, C.-M.; Kwong, H.-L.; Yam, V. W.-W.; Cho, K.-C. J. Chem.
(
Soc., Chem. Commun. 1989, 885. (b) Li, D.; Che, C.-M.; Kwong, H.-L.;
Yam, V W.-W. J. Chem. Soc., Dalton Trans. 1992, 3325. (c) Ma, C.; Chan,
C. T.-L.; To, W.-P.; Kwok, W.-M.; Che, C.-M. Chem. - Eur. J. 2015, 21,
1
(
3888.
7) McTiernan, C. D.; Morin, M.; McCallum, T.; Scaiano, J. C.;
Barriault, L. Catal. Sci. Technol. 2016, 6, 201.
8) For selected reviews on the synthesis of γ-butenolides, see:
a) Bruckner, R. Curr. Org. Chem. 2001, 5, 679. (b) Ma, S. Acc. Chem.
Res. 2003, 36, 701. (c) Ma, S. Pure Appl. Chem. 2004, 76, 651.
d) Romeo, G.; Iannazzo, D.; Piperno, A.; Romeo, R.; Corsaro, A.;
(
(
(
D
DOI: 10.1021/acs.orglett.6b00968
Org. Lett. XXXX, XXX, XXX−XXX