Total synthesis of (±)-chartelline C

Article abstract of DOI:10.1021/ja0659673

The first total synthesis of (±)-chartelline C in a concise 10-step sequence is reported. Highlights of the completion of this decades-old puzzle include (1) chemo- and position-selective installation of the heteroaromatic halogens, (2) halogen-sparing mo

Full text of DOI:10.1021/ja0659673

Published on Web 10/06/2006
Total Synthesis of (()-Chartelline C
Phil S. Baran* and Ryan A. Shenvi
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
Received August 17, 2006; E-mail: pbaran@scripps.edu
Scheme 1. Postuated Biosynthetic Origins of the Chartelline
Alkaloids [Chartelline C (1): R1 ) H, R2 ) H; Chartelline A (2): R1
) Br, R2 ) Br; Chartelline B (3): R1 ) H, R2 ) Br] and Some
Informative Dead-Ends
The chartellines are a small family of marine-derived, architec-
turally unique alkaloids that have remained unsolved synthetic puz-
zles since their isolation by Christophersen and co-workers over
two decades ago.1,2 Chartelline C (1, Scheme 1), the family’s scar-
cest member (∼4:6:90 1/3/2 mass isolated), is composed of indol-
enine, imidazole, and â-lactam heterocycles arrayed in a dense, π-
stacking framework that poses numerous challenges for its synthesis.
In 2005, we put forth a hypothesis, supported by the empirical find-
ings of a model study, for the origin of the chartellines in nature.3
In this Communication, a biosynthetically inspired and strategically
designed synthesis of 1 is reported, which addresses the remaining
challenges of chemoselectivity and connectivity in a concise way.
Since our initial report,3 several unanticipated events conspired
to delay the total synthesis of 1; the most informative of these
impasses are briefly summarized in Scheme 1. For instance, indole
4 favors bromination of C17 (4 f 5) over both C16 and C6, where
bromine atoms are conserved throughout the chartellines. Further-
more, despite the ease with which model compound 6 undergoes
ring contraction (6 f 4), the seemingly minor changes introduced
into intermediates 7 and 8 prevent a similar rearrangement from
taking place. Instead, facile elimination leads to acrylamides 9 and
10, presumably because of an increase in the pKa of N-bound proton
H1 relative to the similarly acidic R-proton H2 (vide infra for
mechanistic details). Consequently, a very specific sequence of
events was choreographed to alter or install the requisite functional-
ity of the chartellines: the successfully revised route to chartelline
C is illustrated in Scheme 2.
The synthesis commences with a site-selective Heck-Sonogash-
ira4 coupling between the doubly halogenated indole 116 (see
Supporting Information) and the previously reported alkyne 123,5
to yield 85% of indole-imidazole 13. After extensive screening,
the alkyne could be chemoselectively reduced in 80% yield using
Raney nickel and then converted into the key macrocycle 17 by
the following sequence:3 (a) TBAF-mediated deprotection, (b)
MnO2 benzylic oxidation to aldehyde 14 (60% over two steps), (c)
saponification, (d) BOPCl coupling with amine 15 (89% over two
steps), and (e) intramolecular Horner-Wadsworth-Emmons reac-
tion (56%) to furnish macrocycle 17 in 24% overall yield from 13.
At this point, macrocycle 17 could be chemoselectively halo-
genated with bromine (in the presence of CaCO3) at the â-position
of the carboxyenamide. After filtration of CaCO3, the action of N-
bromoacetamide delivered the corresponding bromoenamide-bro-
moimidazole 18 (albeit in low conversion), along with recovered
dibrominated material. With 18 in hand, the tasks of Boc-depro-
tection, â-lactam formation, and bromine-chlorine exchange could
be accomplished in a single flask. Thus, thermolysis of 18 at 185
°C delivered in nearly quantitative yield the corresponding free
indole, which was cooled to ambient temperature and treated with
NBS in the presence of molecular sieves to give an unstable
intermediate, tentatively assigned as tetrabromide 19. Addition of
18-crown-6 and K2CO3 to the reaction mixture provided the
tribromo-â-lactam 21, which upon aqueous workup with brine
underwent efficient halogen exchange at the vinylogous bromo-
formate to afford the desired â-chloro-carboxyenamide 22.
Deprotection of the TMSE ester with TFA7 smoothly delivered
carboxylic acid 23. Unfortunately, all attempts to remove this vinyl
carboxylate using standard CuI/II catalysis failed to deliver the na-
tural product, owing mainly to the propensity of chloroenamide 23
(or 11b) to undergo rapid nucleophilic substitution at C3 with either
solvent or Cu-ligands. However, mass spectrometric analysis of
23 hinted at the possible thermal lability of the pendant carboxylic
acid: a strong fragment peak indicated its departure. Indeed, simple
thermolysis of 23 in inert reaction solvent delivered (in 64% isolated
yield) 1, whose spectroscopic values were identical to those reported
in the literature for natural chartelline C.8 Subtle electronic features
are suspected to be responsible for these surprisingly mild decar-
boxylation conditions, namely, stabilization by chlorine lone pairs
of the developing positive charge at C3 of 24.9 Indeed, thermal
decarboxylation was not possible with substrates lacking the vinyl
chloride.
The crucial transformation (18 f 22) warrants some added com-
mentary. During our model study, hydroxy-pyrroloindoline 26
(Scheme 3) was consistently isolated in minor amounts (5-10%),
suggesting that a complex mechanism is operative. The interme-
diacy of dearomatized 2H-indoles10 25 and 20 explains the C20-
OH byproduct 26 and the driving-force required to form the strained
â-lactam rings 21 and 4.10,11 On the basis of these findings, the de-
aromatization of a 3-halo-indolenine to a 2H-indole is also believed
to be operative in the proposed biosynthesis of welwitindolinone
A from fischerindole I.12
9
14028
J. AM. CHEM. SOC. 2006, 128, 14028-14029
10.1021/ja0659673 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Total Synthesis of (()-Chartelline Ca
a Reagents and conditions: (a) 12 (0.9 equiv), CuI (0.2 equiv), Pd(PPh3)4 (0.1 equiv), DME/Et3N (1:1), 50 °C, 7 h, 85%; (b) Raney Ni, MeOH, 20 °C,
5 h, 80%; (c) TBAF (1.1 equiv), THF, 20 °C, 4 h; (d) MnO2 (20 equiv), CH2Cl2, 20 °C, 8 h, 60% overall; (e) LiOH‚H2O (3 equiv), THF/H2O 4:1, 20 °C,
3.5 h; (f) 15 (2.6 equiv), BOPCl (1.5 equiv), DIPEA (2 equiv), CH2Cl2, 0 °C, 9 h, 89% overall; (g) LiCl (10 equiv), DIPEA (20 equiv), MeCN, 70 °C, 6
h, 56%; (h) Br2, (1.0 equiv), CaCO3 (20 equiv), PhH, 20 °C, 6 h; then NBA (1 equiv), PhH, 20 °C, 12 h, 36%, 60% (see above); (i) 185 °C, 1.5 min (×
4); MeCN, 3 Å m.s., NBS (1 equiv), 20 °C; then 18-C-6, K2CO3, 20 °C, 1 h; then NaHCO3 (sat. aq), then brine, 15 min, 93% (j) TFA/DCE 1:1, 20 °C, 4
h; o-DCB, 200 °C, 5 min, 64%.
Scheme 3. C-20 Hydroxy-Pyrroloindoline Formed During the
Rearrangement of 6 f 4
References
(1) For the debut of a chartelline alkaloid, see (a) Chevolot, L.; Chevolot,
A.-M.; Gajhede, M.; Larsen, C.; Anthoni, U.; Christophersen, C. J. Am.
Chem. Soc. 1985, 107, 4542-4543. For the isolation of chartelline C,
see (b) Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christo-
phersen, C. J. Org. Chem. 1987, 52, 4709-4712.
(2) For studies towards the chartellines and related alkaloids, see: (a) Lin,
X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42, 2631-2633. (b) Chaffee,
S. C. PhD Thesis, Yale University, 2001. (c) Lin, X. Ph.D. Thesis,
Pennsylvania State University, 2002. (d) Pinder, J. L.; Weinreb, S. M.
Tetrahedron Lett. 2003, 44, 4141-4143. (e) Korakas, P. Ph.D. Thesis,
Yale University, 2003. (f) Nishikawa, T.; Kajii, S.; Isobe, M. Chem. Lett.
2004, 33, 440-441. (g) Korakas, P.; Chaffee, S.; Shotwell, J. B.; Duque,
P.; Wood, J. L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12054-12057.
(h) Nishikawa, T.; Kajii, S.; Isobe, M. Synlett 2004, 2025-2027. (i) Rohde,
J. Ph.D. Thesis, The Scripps Research Institute, 2005. (j) Sun, C.; Lin,
X.; Weinreb, S. M. J. Org. Chem. 2006, 71, 3159-3166. (k) Sun, C.;
Camp, J. E.; Weinreb, S. M. Org. Lett. 2006, 8, 1779-1781.
(3) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed. 2005,
44, 3714-3717.
The longstanding synthetic challenge posed by the chartelline
alkaloids has been answered for the first time by a short route
influenced by a logical biosynthetic rationale. The idiosyncratic
facility with which certain steps proceed (e.g. 18 f 22, 23 f 1)
points to possible intermediates in a chartelline biosynthesis.
Highlights of this 10 step (from 11) synthesis include (1) chemo-
and position-selective installation of the heteroaromatic halogens,
(2) halogen-sparing monoreduction of alkyne 13, (3) a simple
strategy for placement of the sensitive â-chloroenamide, (4)
unusually facile thermolysis of a vinyl carboxylic acid, and (5) a
powerful ring contraction (18 f 22) whose potential utility in
heterocyclic chemistry merits further investigation.
(4) (a) Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259-263.
(b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(5) Prepared in four steps (50% yield) from O-TBS D,L-serine methyl ester,
see ref 3.
(6) Prepared in six steps (44% yield) from 6-bromoindole.
(7) Wood, J. L.; Thompson, B. D.; Yusuff, N.; Pflum, D. A.; Mattha¨us, M.
S. P. J. Am. Chem. Soc. 2001, 123, 2097-2098.
(8) Confirmed unequivocally by X-ray diffraction spectroscopy. 1H NMR,
13C NMR, HMQC, HMBC, HPLC, HRMS, IR, and TLC are included in
Supporting Information.
Acknowledgment. Mr. Steven Nguyen and Dr. Christos Mitsos
are gratefully acknowledged for their technical contributions. We
thank Dr. D.-H. Huang and Dr. L. Pasternack for NMR spectro-
scopic assistance and Dr. G. Siuzdak and Dr. R. Chadha for mass
spectrometric and X-ray crystallographic assistance, respectively.
Financial support for this work was provided by The Scripps
Research Institute, Amgen, AstraZeneca, Bristol-Myers Squibb,
DuPont, Eli Lilly, GlaxoSmithKline, Roche, the Searle Scholarship
Fund, the Sloan Foundation, the NSF (Career), and the Department
of Defense (predoctoral fellowship to R.A.S.).
(9) Li, J.; Brill, T. B. J. Phys. Chem. A 2003, 107, 2667-2673.
(10) For early implications of 1,5 sigmatropy via 2H-indoles, see (a) Hugel,
G.; Royer, D.; Sigaut, F.; Le´vy, J. J. Org. Chem. 1991, 56, 4631-4636.
(b) Gu¨ller, R.; Borschberg, H.-J. Tetrahedron Lett. 1994, 35, 865-868.
For elegant work on related indole-2-ones, see (c) Funk, R. L.; Fuchs, J.
R. Org. Lett. 2005, 7, 677-680.
(11) Conformational effects and π-stacking interactions are also believed to
contribute significantly to the energetic landscape, as well as to determine
the regiochemical outcome of the reaction, that is, which C-2 substituent
shifts.
(12) For the execution of this rearrangement, see Baran, P. S.; Richter, J. M.
Supporting Information Available: Detailed experimental pro-
cedures, copies of all spectral data, and full characterization. This
material is available free of charge via the Internet at http://pubs.acs.org.
J. Am. Chem. Soc. 2005, 127, 15394-15396.
JA0659673
9
J. AM. CHEM. SOC. VOL. 128, NO. 43, 2006 14029