Total Synthesis of Avrainvilleol

Article abstract of DOI:10.1021/acs.joc.7b02028

The first total synthesis of the marine natural product avrainvilleol is reported. The total synthesis features the first application of the transition-metal-free coupling of a tosyl hydrazone and a boronic acid to the preparation of a complex natural product, and the first example of this coupling with a hindered diortho substituted hydrazone substrate.

Full text of DOI:10.1021/acs.joc.7b02028

Subscriber access provided by LAURENTIAN UNIV
Note
Total Synthesis of Avrainvilleol
Aaron Wegener, and Kenneth A. Miller
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02028 • Publication Date (Web): 05 Oct 2017
Downloaded from http://pubs.acs.org on October 5, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
The Journal of Organic Chemistry
1
2
3
4
5
Total Synthesis of Avrainvilleol
6
7
Aaron Wegener and Kenneth A. Miller*
8
9
Department of Chemistry, Fort Lewis College
1000 Rim Drive, Durango, CO 81301
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
miller_k@fortlewis.edu
Abstract. The first total synthesis of the marine natural product avrainvilleol is reported.
The total synthesis features the first application of the transition metal-free coupling of a
tosyl hydrazone and a boronic acid to the preparation of a complex natural product, and
the first example of this coupling with a hindered di-ortho substituted hydrazone
substrate.
The diarylmethane motif is commonly encountered in a wide array of biologically
active molecules.1 Diarylmethanes have been reported to exhibit HIV reverse
transcriptase inhibition,2 antibacterial activity,3 HMG-CoA reductase inhibition,4
antioxidant activity,5 and cytotoxicity to human cancer cell lines.6 While there are a
myriad of reports on methods to prepare simple diarylmethanes,1 few of these methods
have been utilized in the synthesis of more complex naturally occurring diarylmethanes.
One report of the synthesis of several biologically active diarylmethanes includes a
Friedel-Crafts alkylation as the key step and a low yielding, late-stage benzylic
bromination.7 Other reports focus on the addition of a benzyllithium nucleophile to a
benzaldehyde.8 However, selective deoxygenation of a secondary benzylic alcohol in the
presence of a primary alcohol proved problematic. The condensation of phenols with
formaldehyde has been reported, but this approach is limited to coupling electron rich
aromatic moieties and is often low yielding.9
Avrainvilleol (1) is an example of a brominated diarylmethane natural product
isolated from red algae in 1983.10 At that time, biological activities for 1 including
antibacterial activity and feeding deterrence were reported. Since then, potent
antioxidant activity has also been measured.11 In addition to avrainvilleol, numerous
brominated phenol-containing diarylmethanes with varying substitution patterns have
been isolated.12 Despite the structural diversity of these compounds and the variety of
biological activities observed, no unified approach to the synthesis of these halogenated
diarylmethanes has been disclosed. This is likely because obvious transition metal
catalyzed cross-coupling approaches13 would require discrimination of a single halogen
in one coupling partner in the presence of multiple other halogens present in the reagents.
The presence of these halogens would also thwart an approach that relied on lithiation
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 8
1
2
3
4
5
6
7
8
9
and addition to a suitable electrophile. A search for a high-yielding, scalable, and
convergent approach to avrainvilleol that would also be amenable to other brominated
phenol-containing diarylmethanes revealed the recent report of a transition metal-free
coupling of a tosyl hydrazone with a boronic acid (Scheme 1).14 This approach would
have several advantages. Functional groups like free phenols, methyl ethers, and
halogens are well tolerated. If such a key step proved successful, adaptation of the route
and altering the substitution pattern of the hydrazone and/or the boronic acid would allow
the rapid preparation of other brominated phenol-containing diarylmethanes and libraries
of analogues for structure-activity studies. In theory, 1 could arise from two possible
unions of a functionalized tosylhydrazone and boronic acid. Reaction of the hydrazone 3
with the diortho-substituted boronic acid 2 could lead to avrainvilleol after removal of the
methyl ethers. Alternatively, hydrazone 4 and known boronic acid 515 could be merged
to give rise to 1. Preliminary14 and subsequent16 reports of these hydrazone/boronic acid
couplings revealed that a single ortho-, meta-, or para-substituent was well tolerated in
either the hydrazone or boronic acid coupling partner. However to our knowledge, no
one has reported such a coupling with the more sterically demanding diortho-substitution
in either substrate.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Retrosynthetic analysis
Before embarking on the synthesis of avarinvilleol, the susceptibility of di-ortho
substituted substrates, either hydrazones and/or boronic acids, in the coupling reaction
would need to be assessed. Initial feasibility studies (Scheme 2) revealed that steric
hindrance in the boronic acid coupling partner is deleterious to the efficacy of this
coupling reaction. For example, all attempts to couple hydrazone 10 with di-ortho
substituted boronic acids such as commercially available 9 returned starting material or
products of hydrazone dimerization. In contrast, the 2,6-dimethoxy substituted
hydrazone 6 cleanly coupled with phenylboronic acid (7) to give the corresponding
diarylmethane 8. Clearly, only the retrosynthesis combining diortho-substituted
hydrazone 4 and boronic acid 5 would enable the completion of avrainvilleol.
ACS Paragon Plus Environment

Page 3 of 8
The Journal of Organic Chemistry
1
2
3
4
Scheme 2. Di-ortho substitution in the coupling of tosylhydrazones and boronic acids
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following a known procedure (Scheme 3),15 the desired boronic acid 5 could be
synthesized in three steps from commercially available 4-methoxyphenyl boronic acid.
Protection of the boronic acid moiety as the corresponding pinacol ester 14 proceeded
uneventfully. Monobromination ortho to the methoxy group followed by deprotection
with two equivalents of BCl3 gave the necessary 3-bromo-4-methoxyphenyl boronic acid
(5) in high yield.
Scheme 3. Synthesis of the boronic acid 5
Preparation of the hydrazone coupling partner commenced with treatment of
vanillyl alcohol (16) with acidic methanol to deliver the methoxy ether 17 (Scheme 4).
Previous studies indicated that 17 is regioselectively deprotonated with excess of nBuLi
at the most sterically hindered position, presumably due to chelation from the two
adjacent methyl ethers. Quenching with DMF delivered the known aldehyde 18 as a
single regioisomer.17 While treatment of 18 with Br2 in various solvents (MeOH,
CH2Cl2) led to indiscriminate bromination, regioselective monobromination was
achieved by the addition of Br2 to a buffered solution of 18 in acetic acid.18 It should be
noted here that 19 could easily and quantitatively be transformed to the corresponding
tosyl hydrazone. But all attempts to couple this hydrazone with boronic acid 5 led to
rapid decomposition under the basic conditions, presumably through the intermediacy of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 8
1
2
3
4
5
a para quinone methide. Fortunately, straightforward methylation under standard
conditions gave 20 in excellent yield.
6
7
8
Scheme 4. Synthesis of the aldehyde 20
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Refluxing aldehyde 20 in the presence of tosylhydrazine, a slight excess of the
boronic acid 5, potassium carbonate led to the tetramethyl avrainvilleol 21, presumably
through the intermediate hydrazone 4 (Scheme 5). However, the deprotection and
purification of avrainvilleol proved challenging. Treatment of tetramethyl avrainvilleol
with excess BBr3 led to a single product devoid of methyl ether peaks in the NMR
spectrum. But the chemical shift of the two methylenes did not match those reported for
avrainvilleol. Based on the upfield shift (4.3 ppm in 22 and 4.5 ppm in 1) of the singly
benzylic methylene, we reasoned that bromination of the highly reactive benzylic alcohol
occurred delivering bromo avrainvilleol 22. Gratifyingly, simply stirring this crude
bromide in a THF/H2O mixture rapidly delivered avrainvilleol. In our hands, synthetic 1
rapidly decomposed in CDCl3 perhaps due to trace amounts of HCl or DCl. One can
imagine that 1 might form a highly reactive para-quinone methide under acidic conditions
leading to decomposition. Luckily, spectroscopic data of naturally occurring 1 in d6-
acetone has also been reported,19 and the spectral data for synthetic 1 (1H and 13C NMR)
were identical with those previously reported.10,19
Scheme 5. Coupling and deprotection to complete the synthesis of avrainvilleol (1)
This work shows the promise of the transition-metal free coupling of readily
available boronic acids and tosylhydrazones to prepare complex, biologically active
ACS Paragon Plus Environment

Page 5 of 8
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
diarylmethanes. Specifically, the synthesis of avrainvilleol was completed in six steps
(longest linear sequence) starting with commercially available vanillyl alcohol. Efforts
are currently underway to apply this method to other challenging diarylmethane
containing natural products. In addition, the convergent nature of this approach lends
itself well to the rapid preparation of a library of synthetic analogues. Collaborative
efforts to probe the relationship between diarylmethane substitution pattern and
biological activity are also underway and will be reported in due course.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
All solvents were degassed with nitrogen and passed through activated molecular
sieves prior to use. Reactions involving air or moisture sensitive reagents or
intermediates were performed under an inert atmosphere of nitrogen in glassware that had
been oven or flame dried. Reagents were used without further purification unless
indicated otherwise. The H and C NMR spectra were obtained on a JEOL ECX-400
spectrometer, operating at 400 and 100 MHz respectively. Unless indicated otherwise, all
spectra were run as solutions in CDCl3. The 1H NMR chemical shifts are reported in parts
per million (ppm) downfield from tetramethylsilane (TMS) and are, in all cases,
referenced to the residual protio-solvent present (δ 7.24 for CHCl3). The 13C NMR
chemical shifts are reported in ppm relative to the center line of the multiplet for
deuterium solvent peaks (δ 77.0 (t) for CDCl3).
1
13
2-benzyl-1,3-dimethoxybenzene (8). A mixture of 620 (167 mg, 0.5 mmol),
phenylboronic acid (92 mg, 0.75 mmol), and K2CO3 (104 mg, 0.75 mmol) in dioxane (2
mL) was refluxed for 5 h. The mixture was concentrated to remove dioxane and sat.
NaHCO3 (5 mL) was added. The mixture was extracted with CH2Cl2 (3 x 15 mL) and the
organic layers were washed with sat. NaHCO3 (10 mL), brine (10 mL), dried (Na2SO4),
and concentrated under reduced pressure.
chromatography eluting with EtOAc/hexane (1:19) to give 66 mg (58%) of 8 as a
The residue was purified by flash
1
colorless oil that solidified upon standing; H NMR (400 MHz) δ 7.32-7.16 (m, 6 H),
6.59 (d, J = 8.2 Hz, 2H), 4.07 (s, 2H), 3.83 (s, 6 H); 13C NMR (100 MHz) δ 158.4, 142.0,
128.7, 128.1, 127.4, 125.5, 117.8, 103.9, 55.8, 28.8; IR (neat) 3028, 2835. 1593, 1493,
1473, 1453, 1280, 1153, 1105, 767, 725; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C15H17O2 229.1223; Found 229.1234.
4-bromo-3-hydroxy-2-methoxy-6-(methoxymethyl)benzaldehyde (19). A solution of
bromine in AcOH (5.1 mL, 1 M, 5.1 mmol) was added dropwise to a solution of 3-
hydroxy-2-methoxy-6-(methoxymethyl)benzaldehyde (18)17 (1.00 g, 5.1 mmol) and
NaOAc (450 mg, 5.5 mmol) in AcOH (10 mL). The mixture was stirred 12 h at rt and
then poured into H2O (100 mL). Solid NaHCO3 was added until bubbling ceased. The
slurry was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed
with sat. NaHCO3 (50 mL), brine (50 mL), dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by flash chromatography eluting with
1
EtOAc/hexane (1:3) to give 1.28 g (91%) of 19 as a pale yellow solid; H NMR (400
MHz) δ 10.43 (s, 1H), 7.59 (s, 1H), 5.78 (s, 1H), 4.70 (s, 2H), 3.98 (s, 3H), 3.47 (s, 3H);
13C NMR (100 MHz) δ 191.0, 151.4, 145.8, 133.9, 126.5, 125.8, 116.9, 71.4, 63.4, 58.8;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 8
1
2
3
4
5
IR (neat) 3317, 2939, 1682, 1573, 1479, 1389, 1279, 994, 907, 735; HRMS (ESI-TOF)
m/z: [M+Na]+ Calcd for C10H11BrNaO4 296.9733; Found 296.9737.
6
7
8
9
4-bromo-2,3-dimethoxy-6-(methoxymethyl)benzaldehyde (20). MeI (2.1 g, 0.918 mL,
14.8 mmol) was added to a mixture of 19 (926 mg, 3.4 mmol) and K2CO3 (1.4 g, 10.1
mmol) in DMF (15 mL) and the reaction was stirred for 4 h. H2O (20 mL) was added
and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with
brine (25 mL), dried (MgSO4), and concentrated under reduced pressure. The residue
was purified by flash chromatography eluting with EtOAc/hexane (1:9) to give 0.968 g
(99%) of 20 as a white solid; 1H NMR (400 MHz) δ 10.43 (s, 1H), 7.66 (s, 1H), 4.73 (s,
2H), 4.00 (s, 3H), 3.89, (s, 3H), 3.47 (s, 3H); 13C NMR (100 MHz) δ 191.4, 157.8, 149.5,
138.3, 126.5, 126.4, 125.3, 71.5, 62.5, 60.9, 59.0; IR (neat) 2988, 1688, 1553, 1381,
1264, 1121, 1027, 981, 809; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C11H13BrNaO4
310.9889; Found 310.9863.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-bromo-4-(3-bromo-4-methoxybenzyl)-2,3-dimethoxy-5-(methoxymethyl)benzene
(21). A mixture of aldehyde 20 (106 mg, 0.37 mmol), tosyl hydrazine (69 mg, 0.37
boronic acid 515 (132 mg, 0.571 mmol), and K2CO3 (79 mg, 0.571 mmol) in dioxane (1
mL) was refluxed for 4 h. The mixture was cooled to rt and concentrated under reduced
pressure. Sat. NaHCO3 (5 mL) was added and extracted with CH2Cl2 (3 x 15 mL). The
combined organic extracts were washed with brine (10 mL), dried (MgSO4), and
concentrated under reduced pressure. The residue was purified by flash chromatography
eluting with EtOAc/hexane (1:9) to give 102 mg (58%) of 21 as a colorless oil; 1H NMR
(400 MHz) δ 7.34 (s, 1H), 7.29 (s, 1 H), 6.95 (d, J = 6.3 Hz, 1H), 6.76 (d, J = 6.3 Hz),
13
4.27 (s, 2 H), 3.95 (s, 2 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.69 (s, 3 H), 3.34 (s, 3 H); C
NMR (100 MHz) δ 154.2, 152.7, 150.2, 134.2, 133.9, 133.0, 132.7, 128.4, 128.0, 115.8,
111.9, 111.6, 72.1, 60.9, 60.6, 58.5, 56.3, 30.5; IR (neat) 2930, 1494, 1397, 1281, 1254,
1183, 1150, 1036, 815; HRMS (ESI-TOF) m/z: [M+NH4]+ Calcd for C18H24Br2NO4
476.0067; Found 476.0066.
Avrainvilleol (1): A solution of BBr3 (2 mL, 1 M in CH2Cl2, 2 mmol) was added
dropwise to a solution of 21 (92 mg, 0.20 mmol) in CH2Cl2 (4 mL) at 0 °C. The reaction
was allowed to slowly warm to rt and stirred overnight. The mixture was poured into ice
water (20 mL) and concentrated to remove CH2Cl2. THF (10 mL) and H2o (2 mL) was
added and the mixture was stirred for 1 h. The mixture was extracted with Et2O (20 mL)
and the organic layer was washed with sat. NaHCO3 (2 x 10 mL), brine (10 mL), dried
(MgSO4), and concentrated under reduced pressure. The residue was purified by flash
chromatography eluting with Et2O/hexane (7:3) to give 66 mg (82%) of 1 as a pale
1
yellow oil; H NMR (400 MHz, Me2CO-d6) δ 7.30 (d, J = 1.8 Hz, 1 H), 7.13 (s, 1 H),
13
7.02 (dd, J = 8.2, 1.8 Hz, 1 H), 6.85 (d, J = 8.2 Hz, 1 H), 4.50 (s, 2 H), 3.99 (s, 2H); C
NMR (100 MHz, Me2CO-d6) δ 153.1, 145.8, 142.3, 135.1, 134.1, 133.4, 129.6, 125.9,
122.9, 117.1, 110.3, 108.8, 62.0, 30.4; IR (neat) 3412, 1595, 1573, 1494, 1257, 1094;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C14H12Br2NaO4 424.9000; Found 424.8955.
Acknowledgements
ACS Paragon Plus Environment

Page 7 of 8
The Journal of Organic Chemistry
1
2
3
4
The authors would like to thank Fort Lewis College for financial support.
5
6
Supplementary Data
7
8
9
Comparison of isolated and synthetic avrainvilleol and copies of NMR spectra of
all new compounds associated with this article can be found in the online version at:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
References and Notes
1. Mondal, S.; Panda, G. RSC Adv. 2014, 4, 28517-28358.
2. Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.;
Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. J. Med. Chem. 2015, 58, 651-
664.
3. Oh, K. B.; Lee, J. H.; Lee, J. W.; Yoon, K. M.; Chung, S. C.; Jeon, H. B.; Shin, J.; Lee,
H. S. Bioorg. Med. Chem. Lett. 2009, 19, 945-948
4. Carte, B. K.; Troupe, N.; Chan, J. A.; Westley, J. W.; Faulkner, D. J. Phytochem. 1989,
28(11), 2917-2919.
5. Chen, L.; Fang, Y.; Zhu, T.; Gu, Q.; Zhu, W. J. Nat. Prod. 2008, 71, 66-70.
6. Sharma, V. J. Plant Biochem. Biotechnol. 2011, 20, 190–195.
7. Guo, S.; Li, J.; Li, T.; Shi, D.; Han, L. Chinese J. Oceanol. Limnol. 2011, 29(1), 69-74.
8. Wright, N. E.; ElSohly, A. M.; Snyder, S. A. Org. Lett. 2014, 16, 3644-3647.
9. Li, Y.; Yu, B.; Wang, R. Tetrahedron Lett. 2016, 57, 1856-1859.
10. Sun, H. H.; Paul, V. J.; Fenical, W. Phytochem. 1983, 22(3), 743-745.
11. Takamatsu, S.; Hodges, T. W.; Rajbhandari, I.; Gerwick, W. H.; Hamann, M. T.;
Nagle, D. G. J. Nat. Prod. 2003, 66, 605-608.
12. a) Fan, X.; Xu, N.-J.; Shi, J. –G. J. Nat. Prod. 2003, 66, 455-458. b) Zhao, J.; Ma. M.;
Wang, S.; Li, S.; Cao, P.; Yang, Y.; Lü, Y.; Shi, J.; Xu, N.; Fan, Z.; He, L. J. Nat. Prod.
2005, 68, 691-694.
13. Langle, S.; Abarbri, M.; Duchêne, A. Tetrahedron Lett., 2003, 44, 9255.
14. Barluenga, J.; Tomás,-Gamasa, M.; Aznar, F.; Valdés, C. Nat. Chem. 2009, 1, 494-
499.
15. Ahn, S. –J.; Lee, C. –Y.; Kim, N. –K.; Cheon, C. –H. J. Org. Chem. 2014, 79, 7277-
7285.
16. (a) Li, X.; Feng, Y.; Lin, L.; Zou, G. J. Org. Chem. 2012, 77, 10991-10995. (b)
Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala,
J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. J. Med. Chem. 2015, 58, 651-664. (c)
Plaza, M.; Valdés, C. J. Am. Chem. Soc. 2016, 138, 12061-12064. (d) Allwood, D. M.;
Blakemore, D. C.; Brown, A. D.; Ley, S. V. J. Org. Chem. 2014, 79, 328-338. (e) Wu,
G.; Deng, Y.; Luo, H.; Zhou, J.; Li, T.; Zhang, Y.; Wang, J. Chem. Commun. 2016, 52,
5266-5268. (f) Plaza, M.; Pérez-Aguilar, M. C.; Valdés, C. Chem. Eur. J. 2016, 22, 6253-
6257. (g) Yang, Y.; Liu, Z.; Porta, A.; Zanoni, G.; Bi, X. Chem. Eur. J. 2017, 23, 9009-
9013. (h) Shen, X.; Gu, N.; Liu, P.; Ma, X.; Xie, J.; Liu, Y.; He, L.; Dai, B. RSC Adv.
2015, 5, 63726-63731.
17. Saá, J. M.; Llobera, A.; Garciá-Raso, A.; Costa, A.; Deyá, P. M. J. Org. Chem. 1988,
53, 4263-4273.
18. Fishlock, D.; Williams, R. M. J. Org. Chem. 2008, 73(24), 9594-9600.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 8
1
2
3
4
5
6
19. Chen, J. L.; Gerwick, W. H.; Schatzman, R.; Laney, M. J. Nat. Prod. 1994, 57(7),
947-952.
7
8
20. Huang, Z.; Wang, C.; Dong, G. Angew. Chem Int. Ed. 2016, 55(17), 5299-5303.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment