Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene

Article abstract of DOI:10.1002/anie.201709712

The total synthesis of lycoricidine and narciclasine is enabled by an arenophile-mediated dearomative dihydroxylation of bromobenzene. Subsequent transpositive Suzuki coupling and cycloreversion deliver a key biaryl dihydrodiol intermediate, which is rapidly converted into lycoricidine through site-selective syn-1,4-hydroxyamination and deprotection. The total synthesis of narciclasine is accomplished by the late-stage, amide-directed C?H hydroxylation of a lycoricidine intermediate. Moreover, the general applicability of this strategy to access dihydroxylated biphenyls is demonstrated with several examples.

Full text of DOI:10.1002/anie.201709712

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Accepted Article
Title: Total Synthesis of Lycoricidine and Narciclasine via Chemical
Dearomatization of Bromobenzene
Authors: Emma Southgate, Daniel Holycross, and David Sarlah
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201709712
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10.1002/anie.201709712
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Total Synthesis of Lycoricidine and Narciclasine via Chemical
Dearomatization of Bromobenzene
Emma H. Southgate, Daniel R. Holycross, and David Sarlah*
Abstract: The total synthesis of lycoricidine and narciclasine is
enabled by the use of arenophile-mediated dearomative
dihydroxylation of bromobenzene. Subsequent transpositive Suzuki
We have recently reported an arenophile-mediated
dearomative dihydroxylation that provides access to dihydrodiol
derivatives that are complementary to those obtained through
coupling and cycloreversion deliver
a
key biaryl dihydrodiol
biotechnological processes (i.e. 6
vs. 7, Scheme 2a).[7]
intermediate, which is rapidly converted to lycoricidine through site-
selective syn-1,4-hydroxyamination and deprotection. The total
synthesis of narciclasine is accomplished via a late stage, amide-
directed C–H hydroxylation of a lycoricidine intermediate. Moreover,
the general applicability of this strategy to access dihydroxylated
biphenyls has been demonstrated with several examples.
Specifically, the chemical dihydroxylation of bromobenzene (5)
delivers bromo-3,4-dihydrodiol (6), a constitutional isomer that is
well-suited for the synthesis of lycoricidine (1) and narciclasine
(2), as the location of the vinyl bromide in 6 is properly situated
for appending on the aryl portion of these molecules. Therefore,
we envisioned that these natural products could be traced back
to bromobenzene (5) and aryl boronic acid 8 by using Suzuki
coupling and two olefin transformations to install the required
cis-1,2-diol and 1,4-syn-aminodiol, as shown retrosynthetically in
Scheme 2b. Additionally, we anticipated that the phenol moiety
that distinguishes 2 from 1 could be introduced at a late stage in
the synthesis, allowing for common intermediates to be used in
the construction of both molecules.
The isocarbostyril alkaloids from the Amaryllidaceae family
of plants are an important class of natural products with
impressive biological activities. Specifically, lycoricidine,
narciclasine, 7-deoxypancratistatin, and pancratistatin (1–4,
Scheme 1) are well-known anticancer agents,[1] exhibiting sub-
micromolar inhibitory activity against multiple cancer cell lines.[2]
Structurally, these alkaloids possess a highly functionalized
aminocyclitol core, with four contiguous stereocenters in the
case of lycoricidine (1) and narciclasine (2), and six in the case
of 7-deoxypancratistatin (3) and pancratistatin (4). Due to their
potential oncological relevance, as well as their low natural
abundance, these metabolites have attracted significant interest
in the synthetic community, resulting in numerous synthetic
studies and several dozen total syntheses reported to date.[3-5]
Nevertheless, the strategic applications of dearomative
processes[6] to access the polyfunctionalized cyclohexenyl or
cyclohexyl motifs of these natural products have been very
limited, with only microbial arene oxidation used successfully by
the Hudlickly[4g,5c] and Banwell groups.[4n,5f] Herein, we report the
total synthesis of lycoricidine (1) and narciclasine (2) using a
chemical-based dearomatization of bromobenzene, as well as a
general method for the preparation of 4-aryl substituted cis-
dihydrodiols.
Scheme 2. a) Chemical and biological dearomative dihydroxylation of
bromobenzene (5). b) Key retrosynthetic disconnections for lycoricidine (1)
and narciclasine (2). c) Preparation of 4-aryl substituted cis-dihydrodiols 11.
Scheme 1. Structures of lycoricidine (1), narciclasine (2), 7-
deoxypancratistatin (3), and pancratistatin (4).
Moreover, in order to increase the atom economy and
overall yield of this dearomative approach, we reasoned that
application of arenophile MTAD (9) with bromobenzene (5)
under Narasaka-Sharpless dihydroxylation conditions[8] would
permit expedited preparation of the required dihydroxylated
biphenyl intermediate 11 (Scheme 2c). Under this protocol, the
arylboronic acid serves as a turnover reagent for osmium and
becomes embedded within the dearomatized product as a cyclic
[*]
E. H. Southgate, D. R. Holycross, Prof. Dr. D. Sarlah
Roger Adams Laboratory, Department of Chemistry
University of Illinois
Illinois 61801 (USA)
E-mail: sarlah@illinois.edu
Homepage: http://www.sarlahgroup.com
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201709712
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Scheme 3. Total synthesis of (±)-lycoricidine (1) and (±)-narciclasine (2). Reagents and condition: a) PhBr (5), MTAD (9), white LEDs, CH2Cl2, −78 °C; then 8,
OsO4 (10 mol%), NMO, CH2Cl2, −78 to 0 °C, 63%. b) Pd(dppf)Cl2 (5 mol%), NEt3, THF:H2O = 9:1, 70 °C, 54%. c) PPTS (cat.), CH2Cl2:2,2-DMP = 1:1, 50 °C, 86%.
d) KOH, iPrOH, 100 °C; then CuCl2, pH = 7, RT, 93%. e) 14, THF, 0 °C to RT; then Zn, AcOH, RT, 60%. f) TBAF, THF, 0 °C, 98%. g) PIFA, MeCN: H2O = 9:1,
0 °C, then TFA, 0 °C, 95%. h) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C to RT, 77%. i) (TMP)2Cu(CN)Li2, THF, 0 °C; then tBuOOH, THF, −78 °C; then Ac2O, NEt3,
DMAP, 0 °C to RT, 50% + 10% of free phenol derivative. j) TBAF, THF, 0 °C, 82%. k) PIFA, MeCN: H2O = 9:1, 0 °C; then TFA, 0 °C, 92%. l) K2CO3, MeOH, 0 °C
to RT, 68%. NMO = N-methylmorpholine-N-oxide, THF = tetrahydrofuran, dppf = 1,1′-bis(diphenylphosphino)ferrocene, PPTS = pyridinium p-toluenesulfonate,
2,2-DMP
= 2,2-dimethoxypropane, TBAF = tetrabutylammonium fluoride, TIPSOTf = triisopropylsilyl trifluoromethanesulfonate, TMP = 2,2,6,6,-
tetramethylpiperidine, PIFA = bis(trifluoroacetoxy)iodobenzene, TFA = trifluoroacetic acid.
boronate ester (5→10). A subsequent transpositive Suzuki
coupling and cycloreversion of the arenophile moiety would
incorporate the aryl ring into the carbon framework of the
molecule and deliver 4-aryl substituted cis-dihydrodiol 11.
Importantly, the preparation of biaryl dihydrodiols of type 11 has
not been widely explored,[9] and the application of microbial
oxidation to biphenyl substrates generally gives alternative
constitutional isomers to the desired oxidation product 11.[10]
Only engineered enzymes can produce such compounds;
however, their synthetic application has not been explored.[11]
We commenced our studies by arenophile-assisted
dihydroxylation of bromobenzene (Scheme 3). Based on our
previous work, we chose to employ Narasaka-Sharpless
dihydroxylation, as this modification gave superior results with
halogenated aromatic substrates. Accordingly, visible-light
irradiation of bromobenzene (5) and arenophile MTAD (9) with
subsequent addition of osmium tetroxide, boronic acid 8, and
NMO, delivered bicycle 10a in 63% yield. Importantly, this
reaction was routinely run on a multigram scale and more than
100 g of 10a have been prepared to date in our laboratories.
With intermediate 10a in hand, which possesses both a vinyl
bromide and an arylboronic ester, we turned our attention to the
development of a transpositive Suzuki coupling to install the
benzodioxole ring into the carbon framework of these alkaloids.
Initial screening of reaction conditions using standard conditions
with Pd(PPh3)4 as catalyst gave sub-optimal results, with
protodeborylation as a major process. Extensive screening
identified Pd(dppf)Cl2 as an optimal catalyst in combination with
triethylamine as a base in THF and furnished coupling product
12 in 54% yield. Small amounts of water proved crucial for high
yields, likely for pre-hydrolysis of boronate ester to facilitate the
pre-transmetalation event.[12] Next, acid-catalyzed acetonide
protection of free diol with 2,2-dimethoxypropane and
subsequent cycloreversion (KOH, heat then CuCl2) cleanly
afforded intermediate dihydrodiol 11a'.
With the carbon skeleton completed and cis-1,2-diol
installed, we turned towards the introduction of the required 1,4-
syn-aminoalcohol moiety. To this end, we anticipated that
nitroso-Diels–Alder with subsequent reduction of the N–O bond
could deliver the desired motif, though we anticipated that
electronic tuning of the nitroso cycloaddend might be required to
obtain the desired constitutional isomer.[13] Indeed, we observed
that cycloaddition with electron-rich arylnitroso species 14
proceded exclusively with desired selectivity, while acyl- and
alkylnitroso species gave the opposite isomer. In order to
facilitate deprotection of the amide nitrogen, a TIPS protected
phenol nitroso was employed during the cycloaddition step; after
zinc-mediated N–O cleavage, lactam 15 was produced as a
single diastereo- and constitutional isomer. Deprotection of the
phenol with TBAF (15→16), followed by one-pot oxidative
cleavage and acetonide deprotection, afforded lycoricidine (1),
whose physical properties (1H and 13C NMR, MS data) matched
with those reported for the natural material.
Though more than
a dozen chemical syntheses of
lycoricidine (1) exist, its conversion to narciclasine (2) through
late-stage arene C–H hydroxylation has never been established.
We undertook this task and found that the amide 15 could serve
also as a viable intermediate to narciclasine (2). Inspired by the
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10.1002/anie.201709712
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recent work from Uchiyama group,[14] we reasoned that a
benzamide group could serve as a viable directing group for
deprotonative cupration and subsequent oxidation of the
resulting arylcuprate with tert-butyl hydroperoxide. Gratifyingly,
silylation of alcohol 15 and hydroxylation of 17 under
Uchiyama’s conditions, with in situ acetylation, afforded
intermediate 18. Protection of the phenol moiety after
hydroxylation stage proved crucial for subsequent oxidative
deprotection of the tertiary amide. Thus, global deprotection
(TBAF, PIFA then TFA, and K2CO3) afforded narciclasine (2).
Considering that dearomative dihydroxylation with
arenophiles provides a new entry into the synthesis of biaryl cis-
dihydrodiol derivatives from readily available bromobenzene and
arylboronic acids, we evaluated the generality of this synthetic
strategy (Table 1). Thus, a three step protocol involving: (1)
Narasaka–Sharpless
transpositive Suzuki coupling incorporated the aryl ring of a
boronic ester into the carbon skeleton, enabling rapid access to
dihydroxylation
and
subsequent
these molecules. Moreover,
a
unique deprotonative
cupration/oxidation hydroxylation sequence allowed for the
conversion of a late-stage lycoricidine intermediate into a
precursor for narciclasine. Finally, this approach provided a
concise entry into the synthesis of a variety of biaryl 3,4-
dihydrodiols, which could greatly advance the synthesis of
analogues of these important alkaloids.
Acknowledgements
Financial support for this work was provided by the University of
Illinois, the National Science Foundation (CAREER Award No.
CHE-1654110), and and the ACS Petroleum Research Fund
(57175-DNI1). D.S. is an Alfred P. Sloan Fellow. E.H.S.
acknowledges the National Institute of General Medical
Sciences (NIGMS)-NIH Chemistry-Biology Interface Training
Grant as well as Springborn Graduate Fellowship. We also
thank Dr. D. Olson and Dr. L. Zhu for NMR spectroscopic
assistance, Dr. D. L. Gray for X-ray crystallographic analysis
assistance, and F. Sun for mass spectrometric assistance.
dearomative
Narasaka-Sharpless
dihydroxylation
of
bromobenzene in the presence of a variety of aryl boronic acids,
(2) transpositive Suzuki coupling, and (3) cycloreversion,
furnished the desired biaryl dihydrodiol derivatives 11. Different
electronic and steric properties were tolerated during the course
of this reaction; electron-rich (e.g. 11c, 11d) and electron-
deficient (11h, 11i, and 11j) boronic acids could be employed,
as well as arenes with substituents in the ortho, meta, and para
positions relative to the boron atom. Finally, 2-naphthylboronic
acid was used to afford polynuclear dihydrodiol 11k.
Table 1. Synthesis of biaryl 3,4-dihydodiols derivatives.[a,b]
Keywords: lycoricidine • narciclasine • alkaloids • synthesis •
dearomatization
[1]
a) T. Okamoto, Y. Torii, Y. O. Isogai, Chem. Pharm. Bull. 1968, 16,
1860–1864; b) G. Ceriotti, Nature 1967, 213, 595; c) G. R. Pettit, V.
Gaddamidi, G. M. Cragg, J. Nat. Prod. 1984, 47, 1018; d) S. Ghosal, S.
K. Singh, Y. Kumar, R. S. Srivastava, Phytochem. 1989, 28, 611.
a) A. Kornienko, A. Evidente, Chem. Rev. 2008, 108, 1982–2014; b)
Ingrassia, F. Lefranc, V. Mathieu, F. Darro, R. Kiss, Transl. Oncol. 2008,
1, 1–13.
[2]
[3]
For reviews involving synthesis of isocarbostyril alkaloids, see: a) M.
Ghavre, J. Froese, M. Pour, T. Hudlicky, Angew. Chem. Int. Ed. 2016,
55, 5642; Angew. Chem. 2016, 128, 5732; b) Z. Jin, Nat. Prod. Rep.
2009, 26, 363; c) A. Kornienko, A. Evidente, Chem. Rev. 2008, 108,
1982; d) M. Manpadi, A. Kornienko, Org. Prep. Proced. Int. 2008, 40,
107; e) Y. Chapleur, F. ChrØtien, S. I. Ahmed, M. Khaldi, Curr. Org.
Synth. 2006, 3, 341; f) U. Rinner, T. Hudlicky, Synlett 2005, 365; g) O.
Hoshino, in The Alkaloids, Vol. 51 (Ed.: G. A. Cordell), Academic Press,
New York, 1998, p. 323; h) A. Bridges, Chemtracts: Org. Chem. 1996,
9, 101; i) S. F. Martin in The Alkaloids, Vol. 30 (Ed.: A. Brossi),
Academic Press, New York, 1987, p. 251; j) L. Yingjie, D. Zeyang, T.
Chong, Y. Hongliang, J. Yubin, Chin. J. Org. Chem. 2015, 35, 1009.
For previous syntheses of lycoricidine, see: a) S. Ohta, S. Kimoto,
Tetrahedron Lett. 1975, 16, 2279; b) H. Paulsen, M. Stubbe,
Tetrahedron Lett. 1982, 23, 3171; c) H. Paulsen, M. Stubbe, Liebigs
Ann. Chem. 1983, 535; d) B. G. Ugarkar, J. Dare, E.M. Schubert,
Synthesis 1987, 715; e) N. Chida, M. Ohtsuka, S. Ogawa, Tetrahedron
Lett. 1991, 32; f) N. Chida, M. Ohtsuka, S. Ogawa, J. Org. Chem. 1993,
58, 4441; g) T. Hudlicky, H. F. Olivo, J. Am. Chem. Soc. 1992, 114,
9694; h) T. Hudlicky, H. Olivo, B. McKibben, J. Am. Chem. Soc. 1994,
116, 5108; i) S. F. Martin, H.-H. Tso, Heterocycles 1993, 35, 85; j) G. E.
Keck, T. T. Wager, J. Org. Chem. 1996, 61, 8366; k) G. E. Keck, T. T.
Wagner, J. F. D. Rodriguez, J. Am. Chem. Soc., 1999, 121, 5176; l) S.
Elango, T.-H. Yan, Tetrahedron 2002, 58, 7335; m) A. Padwa, H.
Zhang, J. Org. Chem. 2007, 72, 2570; n) M. Matveenko, O. J. Kokas, M.
[4]
[a] Reaction conditions: Step 1: MTAD (9, 2.0 equiv), PhBr (5, 20 equiv),
visible light, CH2Cl2, –78 °C; then ArB(OH)2 (1.0 equiv), OsO4 (10 mol%), NMO
(2.4 equiv), -78 °C to r.t,. Step 2: Pd(dppf)Cl2 (5.0 mol%), Et3N (5.0 equiv.),
THF/H2O (9:1), 70 °C. Step 3: N2H4 (30 equiv) 100 °C, 12 h; then CuCl2 (1.0
equiv.) pH = 7, r.t., 5 min. [b] Yield of isolated product.
In conclusion, (±)-lycoricidine (1) and (±)-narciclasine (2)
have been synthesized using chemical dearomatization of
bromobenzene in 7 and 10 steps, respectively. Employment of
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G. Banwell, A. C. Willis, Org. Lett., 2007, 9, 3683; o) J. S. Yadav, G.
Satheesh, C. V. S. R. Murthy, Org. Lett. 2010, 12, 2544.
[9]
B. Maji, H. Yamamoto, J. Am. Chem. Soc. 2015, 137, 15957.
[10] a) R. A. Johnson, in Organic Reactions, Vol. 63, John Wiley & Sons,
Inc, New York, 2004, pp. 117; b) M. A. Endoma, V. P. Bui, J. Hansen, T.
Hudlicky, Org. Proc. Res. Dev. 2002, 6, 525.
[5]
For previous syntheses of narciclasine, see: a) J. H. Rigby, M. E. Mateo,
J. Am. Chem. Soc. 1997, 119, 12655; b) D. Gonzalez, T. Martinot, T.
Hudlicky, Tetrahedron Lett. 1999, 40, 3077; c) T. Hudlicky, U. Rinner, D.
Gonzalez, H. Akgun, S. Schilling, P. Siengalewicz, T. A. Martinot, G. R.
Petit, J. Org. Chem., 2002, 67, 8726; d) J. H. Rigby, U. S. M. Maharoof,
M. E. Mateo, J. Am. Chem. Soc. 2000, 122, 6624; e) S. Elango, T. Yan,
J. Org. Chem., 2002, 67, 6954; f) M. Matveenko, M. G. Banwell, A. C.
Willis, Tetrahedron 2008, 64, 4817.
[11] a) R. E. Parales, K. Lee, S. M. Resnick, H. Jiang, D. J. Lessner, D. T.
Gibson, J. Bacteriol. 2000, 182, 1641; b) J. D. Haddock, J. R. Horton, D.
T. Gibson, J. Bacteriol. 1995, 177, 20. c) D. R. Boyd, N. D. Sharma, G.
P. Coen, F. Hempenstall, V. Ljubez, J. F. Malone, C. C. R. Allen, J. T.
G. Hamilton, Org. Biomol. Chem. 2008, 6, 3957.
[12] A. A. Thomas, S. E. Denmark, Science, 2016, 352, 329.
[13] a) D. L. Boger, M. Patel, F. Takusagawa, J. Org. Chem. 1985, 50,
1911; b) A. G. Leach, K. N. Houk, J. Org. Chem. 2001, 66, 5192; c) G.
Galvani, R. Lett, C. Kouklovsky, Chem.-Eur. J. 2013, 19, 15604; d) For
[6]
[7]
S. P. Roche, J. A. Porco, Angew. Chem. 2011, 123, 4154; Angew.
Chem. Int. Ed. 2011, 50, 4068.
a) E. H. Southgate, J. Pospech, J. Fu, D. R. Holycross, D. Sarlah, Nat.
Chem. 2016, 8, 922. b) M. Okumura, S. M. Nakamata Huynh, J.
Pospech, D. Sarlah, Angew. Chem. Int. Ed. 2016, 55, 15910; Angew.
Chem. 2016, 128, 16142.
a recent review on this topic, see: Brulikova, A. Harrison, M. J. Miller, J.
́
́
Hlavac, Beilstein J. Org. Chem. 2016, 12, 1949.
̌
́
[14] N. Tezuka, K.Shimojo, K. Hirano, S. Komagawa, K. Yoshida, C. Wang,
K. Miyamoto, T. Saito, R. Takita, M. Uchiyama, J. Am. Chem.
Soc. 2016, 138, 9166.
[8]
a) N. Iwasawa, T. Kato, K. Narasaka, Chem. Lett. 1988, 17, 1721; b) A.
Gypser, D. Michel, D. S. Nirschl, K. B. Sharpless, J. Org. Chem. 1998,
63, 7322.
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Entry for the Table of Contents
COMMUNICATION
Emma H. Southgate, Daniel R.
Holycross, David Sarlah*
Page No. – Page No.
Total Synthesis of Narciclasine and
Lycoricidine via Chemical
Dearomatization of Bromobenzene
Dearomative dihydroxylation of bromobenzene enables rapid and controlled
access to the potent anticancer natural products narciclasine and lycoricidine. The
approach is based on arenophile- and aryl boronic acid-assisted dearomative
dihydroxylation and subsequent transpositive Suzuki coupling. The generality of this
sequence is demonstrated with preparation of several cis-dihydroxylated biphenyls.
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