Combined metalation-cross coupling strategies: A synthesis of schumanniophytine by a key biaryl O-carbamate remote anionic fries rearrangement

Article abstract of DOI:10.1002/ejoc.200701116

A short synthesis of the alkaloid schumanniophytine (1) starting from simple building blocks and involving directed ortho metalation (DoM), Suzuki-Miyaura cross coupling, and a key ortho-silicon-induced O-carbamate remote anionic Fries rearrangement (3) is described. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701116

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200701116
Combined Metalation–Cross Coupling Strategies: A Synthesis of
Schumanniophytine by a Key Biaryl O-Carbamate Remote Anionic Fries
Rearrangement
Todd K. Macklin,[a] Mark A. Reed,[b] and Victor Snieckus*[a]
Dedicated to the memory of Makoto Kumada[‡]
Keywords: Total synthesis / Metalation / Directed remote metalation / C–C coupling
A short synthesis of the alkaloid schumanniophytine (1) start-
ing from simple building blocks and involving directed ortho
metalation (DoM), Suzuki–Miyaura cross coupling, and a key
ortho-silicon-induced O-carbamate remote anionic Fries re-
arrangement (3) is described.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
We disclose a synthesis of schumanniophytine (1), a rep-
resentative of a minor class of alkaloids isolated[1] from the
root bark of Schumanniophyton problematicum, which
shows central and autonomic system depressant properties
and may have potential antiviral activity.[2] Schumannio-
phytine co-occurs with isoschumanniophytine (2), into
which it may be converted by base-catalyzed scission and
reassembly of the pyrone ring.[3] In spite of the rare tetra-
cyclic pyranobenzopyranopyridine framework,[4] schuman-
niophytine has elicited only a single total synthesis, reported
by Kelly, which features a Stille cross-coupling reaction of
a 4-stannylated nicotinate ester with an easily procurable 8-
bromochromone.[5]
Herein we describe a route that takes advantage of the
directed ortho metalation (DoM)–Suzuki–Miyaura cross-
coupling strategy[6] and incorporates a key ortho-silicon-di-
rected O-carbamate remote anionic Fries rearrangement (3)
for construction of the lactone ring. Whereas a route
towards schumanniophytine through an anionic remote
Fries–Michael addition sequence (4) Ϫ a rational extension
of concept 3[7] Ϫ proved unapproachable,[8] initial model
studies[9] confirmed correctness of concept and resulted in
the development of new general and regioselective synthetic
methodologies for 4H-1-benzopyran-4-ones (chromones),
which is the subject of a separate communication.[10]
Results and Discussion
The synthesis of schumanniophytine was initiated
(Scheme 1) by metalation of symmetrical O-carbamate 8,
whose regioselectivity takes advantage of the powerful car-
bamate-directed metalation group (DMG)[11] to give, after
iodination and boronation, intermediates 9a and 9b, respec-
tively, in excellent yields. Stille cross coupling of 9a with 4-
tributylstannylpyridine[12] or, more efficiently, Suzuki–Mi-
yaura coupling of 9b with commercial 4-bromopyridine hy-
drochloride led to azabiaryl 10. The expected, regioselective
second DoM reaction was followed by silylation with
TMSCl and TESCl to afford highly hindered derivatives
11a and 11b, respectively.[13] With silicon protection in
[a] Department of Chemistry, Queen’s University
Kingston, Ontario K7L 3N6, Canada
Fax: +1-613-533-6089
E-mail: snieckus@chem.queensu.ca
[b] Schering-Plough Research Institute
320 Bent Street, Cambridge, MA 02141, USA
[‡] Deceased: June 28, 2007. Like the sunrise, his work awakened
the important theme of transition-metal-catalyzed cross coup-
ling, which has momentously enriched synthetic organic chem-
istry.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 1507–1509
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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T. K. Macklin, M. A. Reed, V. Snieckus
SHORT COMMUNICATION
Scheme 1. Synthesis of schumanniophytine 1. Reagents and conditions: (a) sBuLi (1.3 equiv.), TMEDA (1.3 equiv.), THF, –78 °C, 10 min,
then I2 (1.5 equiv.), 86%; (b) LDA (1.2 equiv.), B(OiPr)3 (2.5 equiv.), THF, –78 °C, 1 h, Ǟ 0 °C, then 1  HCl, pinacol (1.1 equiv.), 97%;
(c) 9a, [PdCl2(PPh3)2] (0.1 equiv.), 4-tributylstannylpyridine (1.5 equiv.), DMF, 160 °C, 1 h, 73%; (d) 9b, [Pd(PPh3)4] (0.04 equiv.), 4-
bromopyridine·HCl (1 equiv.), Na2CO3 (4 equiv.), DME/H2O (2:1), 20 h, 99%; (e) LDA (3.5 equiv.), Me3SiCl (4.5 equiv.), THF, –78 °C
Ǟ room temp., 10 h, 94%; (f) nBuLi (1.2 equiv.), THF, –100 °C, 5 min, then Et3SiCl (2.5 equiv.), –100 °C, 1.5 h, 91%; (g) LDA (4 equiv.),
THF, 0 °C Ǟ room temp., 1 h, then Ac2O or BzCl (5 equiv.), 0 °C Ǟ room temp., 12a 75%, 12b 65%; (h) BCl3 (5 equiv.), CH2Cl2, 0 °C,
30 min; (i) HCl (80 equiv.), EtOH/H2O (1:1), 90 °C, 12 h; (j) Ac2O (5 equiv.), NEt3 (5 equiv.), CH2Cl2, 0 °C Ǟ room temp., 1 h, 84% for
the three steps; (k) NaHCO3 (10 equiv.), MeOH/H2O (1:1), room temp., 4 h; (l) 2-butynoic acid (2 equiv.), P2O5/MsOH (1:10, 5 mL per
mmol), 80 °C, 12 h, 52% for the two steps; (m) BCl3 (4 equiv.), CH2Cl2, 0 °C, 30 min, 96%. Ac = acetyl, Bn = benzyl, DME = 1,2-
dimethoxyethane, DMF = N,N-dimethylformamide, TMEDA = N,N,NЈ,NЈ-tetramethylethylenediamine.
place, remote anionic Fries rearrangement of TES deriva- completed in 10 steps and 24% overall yield (optimum se-
tive 11b resulted in smooth pyridine-ring carbamoyl trans- quence, Scheme 1). The synthesis compares favorably with
location, to furnish, after direct acetylation and benzo- that described by Kelly[5] (six steps and 5% overall yield).
ylation, aryl nicotinamides 12a and 12b, respectively.[14] Al- In view of the connections to DoM[11] and cross-coupling
though TMS derivative 11a also underwent clean re- strategies,[6] the route provides opportunity for incorpora-
arrangement to give the corresponding phenol in 80–90% tion of functionality in the aromatic, pyridyl, and pyranyl
yield, this product underwent rapid decomposition, which moieties for potential SAR profiling studies. This and re-
thus precluded its further synthetic use.[15] In order to avoid lated contributions from our[20] and other laboratories[21]
alternative regiochemical lactonization of 12a under acidic further demonstrate the increasing value of carbanionic
conditions,[16] 12b was subjected to treatment with BCl3, chemistry for the regioselective construction of aromatics
which resulted in regioselective demethylation,[17] to give, and heteroaromatics.
after acidic protodesilylation, debenzylation, and reacyl-
ation (for convenient isolation), lactone 13 in high overall
yield.
Supporting Information (see footnote on the first page of this arti-
cle): Full procedures and spectroscopic data for all compounds,
React-IR diagram of DreM for 11b.
After numerous unsuccessful attempts to effect pyrone
ring annulation,[18] liberation of the free phenol from 13 by
using sodium hydrogen carbonate followed by adaptation
of the versatile Eaton’s reagent (P2O5/MsOH, 1:10)[19] gave
the desired tetracycle 14. To conclude, demethylation
proceeded efficiently under BCl3 conditions[17] to furnish
schumanniophytine (1), whose physical and spectroscopic
properties were found to be in full accord with those of the
natural product[1,2a,3,5] (see Supporting Information).
Acknowledgments
We thank NSERC Canada for support through the Discovery
Grants program and Merck Frosst Canada for unrestricted grant
support. We are grateful to the Canadian Foundation for Innova-
tion (CFI) for infrastructure support to establish our high-field
NMR and HRMS facilities.
[1] E. Schlittler, U. Spitaler, Tetrahedron Lett. 1978, 19, 2911–2914.
[2] a) P. J. Houghton in The Alkaloids (Ed.: A. Brossi), Academic
Press, London, 1987, vol. 31, pp. 67–100; b) P. J. Houghton,
T. Z. Woldemariam, A. I. Khan, A. Burke, N. Mahmood, Anti-
vir. Res. 1994, 25, 235–244.
Conclusions
A synthesis of schumanniophytine (1) involving a key or-
tho-silicon-induced remote anionic Fries rearrangement was [3] P. J. Houghton, H. Yang, Planta Med. 1985, 23–27.
1508 Eur. J. Org. Chem. 2008, 1507–1509
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Biaryl O-Carbamate Remote Anionic Fries Rearrangement
[4] The isolation, structural elucidation, and bioassays of schum-
anniophytine stimulated the synthesis of heterocycles contain-
ing combined chromone–pyridine systems, but studies of their
bioactivities were apparently not pursued, see: O. H. Hishmat,
N. M. A. El-Ebrashi, Sh. E. El-Naem, Synthesis 1982, 1075–
1077.
[5] T. R. Kelly, M. H. Kim, J. Org. Chem. 1992, 57, 1593–1597.
Prepared from phloroacetophenone in four steps and 21%
overall yield.
[6] a) E. J.-G. Anctil, V. Snieckus, J. Organomet. Chem. 2002, 653,
150–160; b) E. J.-G. Anctil, V. Snieckus in Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed. (Eds.: F. Diederich, A.
de Meijere), Wiley-VCH, Weinheim, 2004, pp. 761–819.
[7] For a successful model reaction, see: W. Wang, V. Snieckus, J.
Org. Chem. 1992, 57, 424–426. For the scope of such directed
remote metalation (DreM) reactions in context of the syntheti-
cally useful and mechanistically interesting complex induced
proximity effect (CIPE) concept, see: M. C. Whisler, S. Mac-
Neil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed. 2004, 43,
2206–2225.
[8] T. K. Macklin, PhD Thesis, Queen’s University, Canada, 2007.
[9] For an instructive discussion of the delicate pro/con intricacies
of model studies, see: C. J. Suckling, K. E. Suckling, C. W.
Suckling, Chemistry Through Models, Cambridge University
Press, UK, 1978, p. 149ff. For recent case studies, see M. A.
Sierra, M. C. de la Torre, Dead Ends and Detours, Wiley-VCH,
Weinheim, 2004, pp. 41, 59, 61, 108. For a precise statement
(“A theory has only the alternative of being right or wrong. A
model has a third possibility: it may be right, but irrelevant”),
see: M. Eigen in The Physicist’s Conception of Nature (Ed.: J.
Mehra), Dordrecht, Reidel, 1973.
Zhao, V. Snieckus, Org. Lett. 2005, 7, 2523–2526), attempts to
effect ipso-ortho-Fries and ipso-Friedel–Crafts acylation on
both 12a and 12b, respectively, as a prelude for chromone ring
annulation, resulted only in desilylation and other undesired
products, see ref.[8]
For similar amide coordinative-assisted demethylation, see: a)
M. J. Sharp, V. Snieckus, Tetrahedron Lett. 1985, 26, 5997–
6000; b) B. I. Alo, A. Kandil, P. A. Patil, M. J. Sharp, V.
Snieckus, P. D. Joseph, J. Org. Chem. 1991, 56, 3763–3768; c)
A. V. Kalinin, M. A. Reed, B. H. Norman, V. Snieckus, J. Org.
Chem. 2003, 68, 5992–5999.
Subjection of compound 13 to classical Lewis acid Fries re-
arrangement [H. Heaney, Comprehensive Organic Synthesis
(Ed.: B. M. Trost), Pergamon, Oxford, 1991, vol. 2, pp. 733–
752] followed by reacylation afforded a 1:1 mixture of the cor-
responding 9- and 7-acetyl derivatives. Attempts to effect a
Baker–Venkataraman chromone ring syntheses (I. Hirao, M.
Yamaguchi, M. Hamada, Synthesis 1984, 1076–1078. For use
in natural product synthesis, see S. Gattinoni, L. Merlini, S.
Dallavalle, Tetrahedron Lett. 2007, 48, 1049–1051) on the 9-
acetyl derivative as well as on the corresponding C-10 phenol
afforded 14 albeit in low and poorly reproducible yields, see
ref.[8] Attempts to adapt recent electrophilic Meldrum’s acid
chemistry were also unsuccessful, see: E. Fillion, A. M. Dumas,
B. A. Kuropatwa, N. R. Malhotra, T. C. Sitler, J. Org. Chem.
2006, 71, 409–412.
[17]
[18]
[19]
[20]
P. E. Eaton, G. R. Carlson, J. T. Lee, J. Org. Chem. 1973, 38,
4071–4073. For application to chromone ring construction, see:
L. W. McGarry, M. R. Detty, J. Org. Chem. 1990, 55, 4349–
4356.
See, inter alia: N-anionic Fries rearrangement: S. L. MacNeil,
B. J. Wilson, V. Snieckus, Org. Lett. 2006, 8, 1133–1136; remote
metalation route to fluorenones: J. A. McCubbin, X. Tong, R.
Wang, Y. Zhao, V. Snieckus, R. P. Lemieux, J. Am. Chem. Soc.
2004, 126, 1161–1167; vinylogous Fries rearrangement: M. A.
Reed, M. T. Chang, V. Snieckus, Org. Lett. 2004, 6, 2297–2300;
remote metalation to indolocarbazoles: X. Cai, V. Snieckus,
Org. Lett. 2004, 6, 2293–2295; carbamoyl Baker–Venkatara-
man reaction: A. V. Kalinin, A. J. M. da Silva, C. C. Lopes,
R. S. C. Lopes, V. Snieckus, Tetrahedron Lett. 1998, 39, 4995–
4998.
See, inter alia: regiospecific arene metalation: T.-H. Nguyen,
N. T. T. Chau, A.-S. Castanet, K. P. P. Nguyen, J. Mortier, J.
Org. Chem. 2007, 72, 3419–3429; regiocontrolled ferrocene
metalation: D. Herault, K. Aelvoet, A. J. Blatch, A. Al-Majid,
C. A. Smethurst, A. Whiting, J. Org. Chem. 2007, 72, 71–75;
regioselective heteroarene metalation: C. Berghian, E. Conda-
mine, N. Ple, A. Turck, I. Silaghi-Dumitrescu, C. Maiereanu,
M. Darabantu, Tetrahedron 2006, 62, 7339–7354; anionic or-
tho-quinone methide generation: R. M. Jones, R. W.
Van De Water, C. C. Lindsey, C. Hoarau, T. Ung, T. R. R.
Pettus, J. Org. Chem. 2001, 66, 3435–3441.
[10] T. K. Macklin, J. Panteleev, V. Snieckus, Angew. Chem. Int. Ed.,
DOI: 10.1002/anie.200704360.
[11] For recent reviews on the DoM reaction and its connection
to cross-coupling chemistry, see: a) T. Macklin, V. Snieckus in
Handbook of C–H Transformations (Ed.: G. Dyker), Wiley-
VCH, Weinheim, 2005, vol. 1, pp. 106–118; b) C. G. Hartung,
V. Snieckus in Modern Arene Chemistry (Ed.: D. Astruc),
Wiley-VCH, Weinheim, 2002, pp. 330–367.
[12] Handling and purification of this material proved difficult and
was an unpleasant odiferous experience.
[13] The hindrance is corroborated by the need to use –100 °C tem-
peratures for the TESCl reaction owing to its slower reactivity
over TMSCl, which thus allowed the faster (intramolecular)
anionic ortho-Fries rearrangement to occur, see ref.[8]
[14] The migration was conveniently followed by React IR by ob-
serving the disappearance of the carbamoyl group
[21]
(ν=1725 cm–1) and the appearance of the amide carbonyl group
˜
stretching frequencies (ν=1635 cm–1); the latter was only ob-
˜
served upon aqueous quench, which suggests the potential for
trapping of the tetrahedral intermediate (see Supporting Infor-
mation).
[15] M. A. Reed, V. Snieckus, unpublished results.
[16] Although compound 12a, upon treatment with ICl, gave the
corresponding ipso-Friedel–Crafts product in 89% yield (Z.
Received: November 27, 2007
Published Online: February 11, 2008
Eur. J. Org. Chem. 2008, 1507–1509
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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