Total synthesis of phalarine

Article abstract of DOI:10.1002/anie.200604072

(Chemical Equation Presented) End of the expedition ... for now: Completion of the first total synthesis of phalarine from an advanced rearrangement product brought up interesting obstacles to overcome. Use of the Gassman oxindole synthesis and subsequent

Full text of DOI:10.1002/anie.200604072

Communications
DOI: 10.1002/anie.200604072
Natural Products
Total Synthesis of Phalarine**
Chaomin Li, Collin Chan, Annekatrin C. Heimann, and Samuel J. Danishefsky*
Our research group has been addressing the total synthesis of
an alkaloid, phalarine (1), with an unusual structure. Pursuant
to this goal, in the previous Communication we described a
novel rearrangement of an azaspiroindolenine 3 (derived
from 2) to a prototype precursor 4 to phalarine (Scheme 1).
Some interesting mechanistic issues associated with this
species versus access to the final target system from the
rearrangement step) became the hallmark of the expedition.
Under our first approach, we envisioned coupling the
[
2]
lithio species 9 (prepared from 8 ) with the oxindole 5
(Scheme 3). Unfortunately, yields from this coupling were
very low. Given these and the other failures encountered in
the coupling reactions of carbon-
[
1]
yl electrophiles with compli-
cated, hindered aryl lithium
reagents, we decided to attempt
the coupling of lithio derivative
1
2 (generated from bromo com-
pound 11) with oxindole 5.
Indeed, carbon–carbon coupling
was realized to afford ketone 13.
Scheme 1. Original strategy toward phalarine. Ts=toluene-4-sulfonyl.
Fortunately, the anticipated rear-
rearrangement were elucidated and we assumed that a total
synthesis of 1 would be a straightforward matter. As described
below, we were indeed able to accomplish the inaugural total
synthesis of phalarine using the rearrangement strategy,
although significant obstacles had to be overcome.
rangement of azaspiroindolenine
to the phalarine precursor took place under the conditions
shown in Scheme 3, to provide 14 in 72% yield.
For a total synthesis of phalarine, it would be best if the
rearrangement could be conducted on an advanced-stage
arylated ketone. This would reduce the complexity in going
from the rearrangement product to the desired phalarine.
However, as we were to learn, the key CꢀC bond-forming
step, which would join for example, an aryl species 6 to an
oxindole 5, became highly problematic if conducted with
complex C4 lithiated indoles (Scheme 2). As we conceded
ground in the complexity of the aryllithium species 6 in the
joining step, the pathway to phalarine from the post-
rearrangement product became increasingly challenging.
Harmonization of these competing vectors (the feasibility of
coupling the aryl nucleophile to the azaspiroindolenine
Scheme 2. Generalized strategy toward the rearrangement precursor.
PG=protecting group.
A two-step sequence accomplished the ortho amination of
14 (Scheme 4). Thus, reaction of 14 with azodicarboxylate
[
3]
derivative 15 provided adduct 16 which, under strongly
[
4]
reducing conditions, afforded amine derivative 17. Follow-
ing our plan, this compound was nitrosated. The resulting
diazonium chloride 18 was subjected to a Japp–Klingemann
[
*] Dr. A. C. Heimann, Prof. S. J. Danishefsky
The Laboratory for Bioorganic Chemistry
Sloan-Kettering Institute for Cancer Research
[
5]
condensation with the b-ketoester 19. The reaction worked
remarkably well and the elaborated phenylhydrazone 20 was
produced. Unfortunately, all attempts to accomplish Fischer
indolization to afford 21 were at best low yielding. While the
reaction pathways were not fully characterized, at least three
competitive lines could be discerned. One involved complete
loss of the carbazate side chain with apparent formation of 14.
Another involved the cleavage of the NꢀN bond with the
1275 York Avenue, New York, NY 10021 (USA)
Fax: (+1)212-772-8691
E-mail: s-danishefsky@ski.mskcc.org
Dr. C. Li, C. Chan, Prof. S. J. Danishefsky
The Department of Chemistry
Columbia University
Havemeyer Hall, New York, NY 10027 (USA)
[
**] This work was supported by the National Institutes of Health (Grant
HL25848) and by a postdoctoral fellowship from the German
Academic Exchange Service (DAAD) to A.C.H. We thank S. Zheng
for helpful discussions. We also thank Dr. G. Sucenik (NMR Core
Facility, Sloan-Kettering Institute) and Dr. Y. Itagaki (Columbia
University) for NMR and mass spectrometric analysis, respectively.
reappearance of the starting amine 17. Still another involved
ipso indolization at the methoxy-bearing carbon atom and
reductive demethoxylation to afford the undesired indole
[
6]
2
2. The failure to accomplish Fischer indolization of
substrate 20 is shown in Scheme 4.
Given the setbacks described above, we sought a method
from which we could construct a usable indole from 17,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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448
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Angewandte
Chemie
Scheme 3. Reagents and conditions: a) tBuLi or nBuLi; b) tBuLi, THF, ꢀ788C, 96%; c) TFA, CH Cl , 08C, 98%; d) CSA, toluene, 1308C, 72%.
2
2
CSA=camphorsulfonic acid, MOM=methoxymethyl, TFA=trifluoroacetic acid.
Scheme 4. Reagents and conditions: a) 15, TFA, 95%; b) Zn dust, AcOH, 88%; c) NaNO , aqueous HCl, ꢀ58C; d) 19, aq KOH, EtOH, ꢀ58C,
2
8
1%; e) TsOH, toluene, 808C, <5%. Troc=2,2,2-trichloroethoxycarbonyl.
[
9]
without interference from the adjacent ortho-methoxy group.
N,N-dimethylmethylene ammonium chloride (25) to pro-
Fortunately, the Gassman oxindole synthesis proved to be
duce a gramine intermediate, which upon cleavage of the
[
7]
1
very useful in this regard. Thus, treatment of compound 17
with the ethyl ester of thiomethylacetic acid followed by
reaction with sulfuryl chloride afforded oxindole 23
sulfonamide function, afforded (ꢁ )-phalarine (1). The H and
1
3
C NMR spectra of the racemic compound produced by the
total synthesis corresponded to those reported for natural
[
10]
(
Scheme 5). Following the mechanistic proposals of Gassman
phalarine.
et al., this cyclization is interpretable in terms of a [2,3] sig-
matropic rearrangement of the intermediate azasulfonium
In summary, the total synthesis of racemic phalarine has
been achieved, though not without the need to deal with
several serious, but manageable complications. Given what
we have learned about the fundamentals of the rearrange-
ment of azaspiroindolenine to the precursor to phalarine (3!
[
7]
ylide. Fortunately, this process, unlike the attempted Fischer
indolization, was not undermined by the presence of the
ortho-methoxy group. The oxindole 23 was converted into 24
[
8]
[1]
as shown. In another critical step, the indole reacted with
4), the application of this rearrangement (which provides
Angew. Chem. Int. Ed. 2007, 46, 1448 –1450
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
1449

Communications
Keywords: alkaloids · heterocycles · indoles · oxindoles ·
.
total synthesis
[
1] See the preceding Communication: C. Li, C. Chan, A. C.
Heimann, S. J. Danishefsky, Angew. Chem. 2006, DOI:
10.1002/ange.200604071; Angew. Chem. Int. Ed. 2006, DOI:
10.1002/anie.200604071.
[
2] A. K. Sinhababu, R. T. Borchardt, J. Am. Chem. Soc. 1985, 107,
622.
7
[
[
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[
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Yokoyama, Tetrahedron Lett. 1989, 30, 2099.
[
7] a) P. G. Gassman, T. J. Van Bergen, J. Am. Chem. Soc. 1974, 96,
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Am. Chem. Soc. 1974, 96, 5512; c) B. M. Savall, W. W.
McWhorter, J. Org. Chem. 1996, 61, 8696.
Scheme 5. Reagents and conditions: a) 1. MeSCH CO Et, SO Cl ,
2
2
2
2
CH Cl , ꢀ788C; 2. 17, proton sponge, CH Cl , ꢀ788C; 3. Et N, CH Cl ,
2
2
2
2
3
2
2
ꢀ
788C to RT; 4. AcOH, 2 h, 66% (78% based on recovered starting
material); b) BH , THF, 08C; c) Raney Ni, EtOH, 90% for 2 steps;
[8] a) W. Wierenga, J. Griffin, M. A. Warpehoski, Tetrahedron Lett.
1983, 24, 2437; b) M. A. Warpehoski, V. S. Bradford, Tetrahe-
dron Lett. 1986, 27, 2735.
3
d) 25, AcOH, 74%; e) Na(Hg), Na HPO , MeOH, 08C to RT, 90%.
2
4
[
9] G. Kinast, L. F. Tietze, Angew. Chem. 1976, 88, 261; Angew.
Chem. Int. Ed. Engl. 1976, 15, 239.
the racemate) to reach substantially enantiomerically pure
phalarine (without resolution) will require that one deals with
some additional challenging issues. Such research is under-
way.
[
10] N. Anderton, P. A. Cockrum, S. M. Colegate, J. A. Edgar, K.
Flower, D. Gardner, R. I. Willing, Phytochemistry 1999, 51, 153.
Received: October 3, 2006
Published online: January 19, 2007
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450
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 1448 –1450