A remarkable ring contraction en route to the chartelline alkaloids

Article abstract of DOI:10.1002/anie.200500522

Weinheim (Chemical Equation Presented) One-of-a-kind. A bromine-induced rearrangement has been designed for the formation of the spiro-β-lactam ring present in the structurally unique chartelline alkaloids (see picture of chartelline A). This method is used in combination with others to provide rapid access to the carbocyclic skeletons of the chartelline, securine, and securamine alkaloids.

Full text of DOI:10.1002/anie.200500522

Communications
Natural Product Synthesis
A Remarkable Ring Contraction En Route to the
Chartelline Alkaloids**
Scheme 1. Structures of the chartellines, chartellamides, securines,
and securamines, and the retrosynthetic analysis of the carbocyclic
skeleton.
Phil S. Baran,* Ryan A. Shenvi, and Christos A. Mitsos
Marine fauna continually produce molecules endowed with
potent bioactivities and extraordinary structures.[1] The secur-
ines (1, 2), securamines (3, 4), chartellines (5–7), and
chartellamides (8, 9; Scheme 1) are members of a structurally
unique class of natural products that were isolated by
Christophersen and co-workers from the bryozoa Chartella
papyracea and Securiflustra securifrons.[2] They contain an
interesting arrangement of various heterocyclic entities that
are wound around a prenyl unit and adorned with halogen
atoms. With such a dense array of sensitive and exotic
functionalities, such as spiro-b-lactam, indolenine, chloroena-
mide, and 2-bromoimidazole units, it is understandable why
no member of this family has yet succumbed to total synthesis
since their isolation over two decades ago.[3]
The belief that macrocyclic constructs such as 10 and 11
would behave differently than their individual heterocyclic
subunits was central to our synthetic plan. Specifically, late-
stage chemo- and regioselective halogenations and a bro-
mine-induced rearrangement of 11 to 10 were planned. The
presence of extensive halogen substitution in these natural
products perhaps suggests that many of the biotransforma-
tions that create such complex polycyclic structures are
indeed accomplished with electrophilic sources of bromine
and chlorine; it is this hypothesis that inspired the current
approach. However, there are no examples for such a ring
contraction of a pyrroloindoline unit and ample precedent
that suggests its failure (Scheme 2).[4] Pyrroloindoline inter-
mediates of type A have not been known to undergo ring
[*] Prof. Dr. P. S. Baran, R. A. Shenvi, Dr. C. A. Mitsos
Department of Chemistry
The Scripps Research Institute
10650 North Torrey Pines Road
La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] Steven Nguyen is gratefully acknowledged for his technical
contributions. We thank Dr. D. H. Huang and Dr. L. Pasternak for
assistance with the NMR spectroscopic analysis, and Dr. G. Suizdak
and Dr. R. Chadha for assistance with the mass-spectrometric and
X-ray crystallographic analysis, respectively. We are grateful to
Biotage for their generous donation of the microwave process vials
used extensively during these studies. Financial support for this
work was provided by The Scripps Research Institute, the Depart-
ment of Defense (predoctoral fellowship to R. A. S.), Eli Lilly & Co,
GlaxoSmithKline, and the Searle Scholarship Fund.
contraction to strained spiro systems of type
B (see
Scheme 2). Furthermore, an indolenine, such as C, can be
rapidly hydrated (D) and undergo a 1,2-shift to an oxindole
(E).[5] Notwithstanding this bleak outlook, we hypothesized
that p stacking and conformational effects in the macrocycle
11 would provide sufficient driving force for a bromine-
induced ring contraction to yield 10 (via an intermediate of
type A). Herein, we present the successful execution of this
approach, which resulted in a short and practical route to the
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500522
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Chemie
sponding primary alcohol of 14 has been previously synthe-
sized in nine steps[7] and was used in the total synthesis of the
anticancer agents phenylahistin and aurantiamine and libra-
ries that were based upon these compounds.[7,8] In preparation
for linking the imidazole and indole subunits, it was necessary
to convert the vinyl group of 14 into an alkynyl group. This
conversion was carried out by the Johnson–Lemieux oxida-
tion of 14 to the corresponding aldehyde followed by treat-
ment with reagent 15, developed by Ohira and Bestmann and
co-workers,[9] to furnish alkyne 16 in 63% yield. The coupling
of 16 and 2-bromoindole 17[10] was accomplished by employ-
ing the method of Sonogashira et al. for a copper-acceler-
ated[11] Heck alkyne synthesis[12] to afford 18 in 71% yield.
Subsequent hydrogenation to the cis olefin,[13] removal of the
TBS protecting group, and MnO2-mediated oxidation of the
resulting alcohol led to the crystalline aldehyde 19 (m.p. 50–
558C, CH2Cl2/hexanes), whose markedly folded structure was
discerned through X-ray crystallography (see Scheme 3 for
the ORTEP representation). After a number of abortive
attempts, the reliable Horner–Wadsworth–Emmons reaction
finally emerged as an effective means to mediate the macro-
Scheme 2. The known reactivity profile of oxidized indoles suggests
that the proposed rearrangement (11!10) is unlikely to occur.
carbocyclic skeleton of the chartelline, securine, and secur-
amine alkaloid families.
The synthetic pathway to 10 is outlined in Scheme 3. Thus,
treatment of the readily available serine-derivative 12 with
prenylmagnesium bromide furnished a-amino ketone 13
which could be easily transformed into imidazole 14 in 84%
yield via an imidazoline-2-thione intermediate.[6] The corre-
Scheme 3. Construction of the complete chartelline, securine, and securamine carbocyclic skeletons. Reagents and conditions: a) prenylmagne-
sium bromide, THF, ꢀ788C, 93%; b) 1. KNCS (20 equiv), NH4Cl (20 equiv), toluene 105–1108C, 4 h; 2. 6n HCl, 258C, 20 min; 3. i. H2O2
(11 equiv), THF, 258C, 6 h; ii. 2m NaOH/saturated aq NaHCO3 (4:1), 258C, 1 h; 4. TBSCl (1.0 equiv), Et3N (1.0 equiv), CH2Cl2, 258C, 84% from
13; c) NaIO4 (3.0 equiv), OsO4 (0.03 equiv), THF/H2O (2:1), 258C, 18 h; d) 15 (1 equiv), K2CO3 (1.5 equiv), MeOH, 258C, 6 h, 63% from 14;
e) [Pd(PPh3)4] (0.3 equiv), CuI (0.7 equiv), iPrNH2 (10 equiv), DME, 708C, 30 min, 71%; f) 1. H2, 10% Pd/C (0.1 equiv), MgSO4 (2 equiv), EtOH,
258C, 4 h; 2. TBAF (1.1 equiv), THF, 0!258C, 3 h; 3. MnO2 (20 equiv), CH2Cl2, 258C, 8 h, 98% from 18; g) 1. LiOH (3 equiv), THF/H2O (4:1),
258C, 5 h; 2. 20 (2.6 equiv), BOPCl (1.5 equiv), DIPEA (2.0 equiv), 08C, 2 h, 86% from 19; h) LiCl (9.0 equiv), DIPEA (20 equiv), CH3CN, 708C,
4 h, 75%; i) 1. 1808C, 8 min; 2. NBS (1.0 equiv), KHCO3 (20 equiv), THF/H2O, 35 min, 88% from 22. TBS=tert-butyldimethylsilyl , KNCS=potas-
sium thiocyanate, Boc=tert-butoxycarbonyl, DME=1,2-dimethoxyethane, TBAF=tetra butylammonium fluoride, BOPCl=bis(2-oxo-3-oxazolidi-
nyl)phosphinic chloride, DIPEA=diisopropylethylamine, NBS=N-bromosuccinimide.
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Communications
cyclization.[14] Aldehyde 19 was primed for this reaction
Completion of the total synthesis of the chartellines and
related alkaloids will be reported shortly.[19]
through saponification with LiOH and coupling with amine
20[15] in the presence of BOPCl to furnish phosphonate 21 in
86% yield. Macrocyclization under the conditions developed
by Masamune, Roush, and co-workers[16] produced macro-
cycle 22 in 75% yield and set the stage for the critical
rearrangement.
Macrocycle 22 was converted into the chartelline skeleton
10 in 88% yield and in a single operation by simple
thermolytic removal of the Boc protecting group in 22
(1808C, no solvent)[17] followed by treatment of the resulting
free indole (11, Scheme 1) with NBS and aqueous KHCO3.
The structure of this crystalline substance (m.p. 190–2208C
(decomp; CH3CN)) was verified by X-ray crystallographic
analysis (see Scheme 3 for the ORTEP representation).
Although we speculate that the reaction proceeds through
intermediate 23, several degenerate pathways to 10 could also
be envisaged.
As alluded to above, a number of unanticipated road-
blocks were encountered during our efforts to accomplish
macrocyclization. Some of these experiences are briefly
summarized in Scheme 4, with the resistance of 24 to undergo
ring-closing metathesis, the failure of a seemingly simple
macrolactamization (25), and the refusal of 26 to take part in a
Heck-type[18] ring closure.
Received: February 11, 2005
Published online: May 18, 2005
Keywords: cascade reactions · chartellines · natural products ·
.
securamines · total synthesis
[1] Marine natural products have
a proven track record for
improving human health; for a review of those that are in
current medical use, see: D. J. Newman, G. M. Cragg, Curr. Med.
Chem. 2004, 11, 1693 – 1713; for some early pioneering efforts in
this field, see: W. Fenical, Chem. Rev. 1993, 93, 1673 – 1683.
[2] a) L. Chevolot, A.-M. Chevolot, M. Gajhede, C. Larsen, U.
Anthoni, C. Christophersen, J. Am. Chem. Soc. 1985, 107, 4542 –
4543; b) U. Anthoni, L. Chevolot, C. Larsen, P. H. Nielsen, C.
Christophersen, J. Org. Chem. 1987, 52, 4709 – 4712; c) U.
Anthoni, K. Bock, L. Chevolot, C. Larsen, P. H. Nielsen, C.
Christophersen, J. Org. Chem. 1987, 52, 5638 – 5639; d) L.
Rahbaek, U. Anthoni, C. Christophersen, P. H. Nielsen, B. O.
Petersen, J. Org. Chem. 1996, 61, 887 – 889; e) L. Rahback, C.
Christophersen, J. Nat. Prod. 1997, 60, 175 – 177.
[3] a) X. Lin, S. M. Weinreb, Tetrahedron Lett. 2001, 42, 2631 – 2633;
b) S. C. Chaffee, PhD Thesis, Yale University, 2001; c) X. Lin,
PhD Thesis, Pennsylvania State University, 2002; d) J. L. Pinder,
S. M. Weinreb, Tetrahedron Lett. 2003, 44, 4141 – 4143; e) P.
Korakas, PhD Thesis, Yale University, 2003; f) T. Nishikawa, S.
Kajii, M. Isobe, Chem. Lett. 2004, 33, 440 – 441; g) P. Korakas, S.
Chaffee, J. B. Shotwell, P. Duque, J. L. Wood, Proc. Natl. Acad.
Sci. USA 2004, 101, 12054 – 12057; h) T. Nishikawa, S. Kajii, M.
Isobe, Synlett 2004, 2025 – 2027.
[4] See Ref. [3] and J. A. Joule, K. Mills, Heterocyclic Chemistry,
Blackwell, Oxford, 2000, p. 589; R. J. Sundberg, Indoles, Aca-
demic Press, San Diego, 1996, p. 175.
[5] For example, see: H. Wang, A. J. Ganesan, J. Org. Chem. 2000,
65, 4685 – 4693; ring contractions of six-membered rings to form
indolenines are also known, see: P. L. Feldman, H. Rapoport, J.
Am. Chem. Soc. 1987, 109, 1603 – 1604; M. Node, H. Nagasawa,
K. Fuji, J. Org. Chem. 1990, 55, 517 – 521.
[6] a) S. Grivas, E. Ronne, Acta Chem. Scand. 1995, 49, 225 – 229;
b) J. G. Schantl, I. M. Lagoja, Heterocycles 1998, 48, 929 – 938.
[7] Y. Hayashi, S. Orikasa, K. Tanaka, K. Kanoh, Y. Kiso, J. Org.
Chem. 2000, 65, 8402 – 8405.
[8] K. Kanoh, S. Kohno, J. Katada, J. Takahashi, I. Uno, Y. Hayashi,
Bioorg. Med. Chem. Lett. 1999, 7, 1451 – 1457; E. A. Coula-
douros, A. D. Magkos, personal communication.
[9] S. Mꢀller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett 1996,
521 – 522; S. Ohira, Synth. Commun. 1989, 19, 561 – 564.
[10] Prepared from methyl-3-indoleacetate by bromination with NBS
followed by protection with a Boc group using Boc2O and
catalytic dimethylaminopyridine.
[11] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
4467 – 4470.
[12] H. A. Dieck, R. F. Heck, J. Organomet. Chem. 1975, 93, 259 –
263.
[13] S. Shinjiro, K. Matsumoto, H. Tokuyama, T. Fukuyama, Org.
Lett. 2003, 5, 1891 – 1893.
[14] K. C. Nicolaou, M. W. Hꢁrter, J. L. Gunzner, A. Nadin, Liebigs
Ann. 1997, 1283 – 1301.
[15] U. Schmidt, A. Lieberknecht, J. Wild, Synthesis 1984, 53 – 60; see
also: B. M. Schiavi, D. J. Richard, M. M. Joulliꢂ, J. Org. Chem.
2002, 67, 620 – 624.
Scheme 4. Selected dead-end routes to the chartelline, securamine,
and securine carbocyclic skeletons.
Notable aspects of the approach described herein include
synthetic efficacy (approximately 19% overall yield and 10
steps); rapid access to the carbocyclic skeletons of the
chartelline, securine, and securamine alkaloids; and a remark-
able ring contraction (22!10) that proceeds in high yield,
despite the inherent ring strain of the b-lactam unit and an
abundance of discouraging literature precedent (Scheme 2).
The distinctive architecture of the chartelline alkaloids
inspired this approach, and it is possible that a similar
strategy is employed in nature to forge the intriguing spiro-b-
lactam ring in the chartellines from securine-like structures.
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[16] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. Roush, T. Sakai, Tetrahedron Lett. 1984, 25,
2183 – 2186.
[17] P. S. Baran, C. A. Guerrero, N. B. Ambhaikar, B. D. Hafen-
steiner, Angew. Chem. 2005, 117, 612 – 615; Angew. Chem. Int.
Ed. 2005, 44, 606 – 609; for the first report of this deprotection
method, see: V. H. Rawal, M. P. Cava, Tetrahedron Lett. 1985,
26, 6141 – 6142.
[18] P. S. Baran, E. J. Corey, J. Am. Chem. Soc. 2002, 124, 7904 – 7905.
[19] Detailed experimental procedures, copies of all spectral data,
and full characterization are contained in the Supporting
Information. CCDC-263124 (19) and -263125 (10) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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