Total synthesis of (±)-communesin F via a cycloaddition with indol-2-one

Article abstract of DOI:10.1021/ja307277w

A concise total synthesis of (±)-communesin F has been completed in 15 linear steps from 4-bromotryptophol in an overall yield of 6.7%. A key step features the cycloaddition of indol-2-one with 3-(2-azidoethyl)-4-bromoindole and facilitates the rapid construction of the lower aminal-containing tetracyclic core of the natural product.

Full text of DOI:10.1021/ja307277w

Communication
pubs.acs.org/JACS
Total Synthesis of ( )-Communesin F via a Cycloaddition with Indol-
2-one
Johannes Belmar and Raymond L. Funk*
Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
antiaromatic compounds function as reactive dienes in Diels−
ABSTRACT: A concise total synthesis of ( )-commune-
sin F has been completed in 15 linear steps from 4-
bromotryptophol in an overall yield of 6.7%. A key step
features the cycloaddition of indol-2-one with 3-(2-
azidoethyl)-4-bromoindole and facilitates the rapid con-
struction of the lower aminal-containing tetracyclic core of
the natural product.
Alder cycloadditions, in this case to provide the strained
bridged bicyclic lactam 3 which undergoes a retrocheletropic
reaction to furnish the quinoline 4. A related intermolecular
indol-2-one cycloaddition was employed to quickly and
stereoselectively introduce the vicinal quaternary centers of
perophoramidine (Scheme 2). Thus, the endo-cycloadduct 7
Scheme 2
he communesins1 are a group of eight architecturally
intriguing natural products and are also biosynthetically
and, as a consequence, structurally related to the natural
product perophoramidine2 (Figure 1). In addition, commune-
T
was presumably generated from bromooxindole 5 and
protected tryptophol 6 which underwent concomitant ring-
opening to the indolenine/lactam 8 as a single stereoisomer.
One could conceivably exploit this methodology in a
communesin total synthesis if an analogous indol-2-one
cycloaddition could be channeled through an exo-transition
state. This is mandated since the presumed tryptamine derived
2-aminoethyl substituents at C(7) and C(8) bear a cis
relationship as opposed to the trans orientation found in
perophoramidine. We hoped that a C(4) substituent on the
indole reactant, necessary for eventual construction of the
benzazepine substructure, might alter the stereochemical
preference. Unfortunately, an initial scouting experiment
using the 4-vinyl derivative of indole 6 also proceeded
exclusively through the endo cycloaddition pathway.
Figure 1. Communesins B, F, and perophoramidine.
sin B is uniformly the most active of these natural products in a
variety of biological assays and is moderately cytotoxic against
P-388 (ED50 = 0.88 mM), LoVo (MIC = 3.9 mM) and KB
(MIC = 8.8 mM) cells whose mechanism of action may involve
the disruption of microfilaments.1a Accordingly, the commu-
nesins3 as well as perophoramidine4 have been the subject of
numerous synthetic investigations and total syntheses of
communesin A,5 B,5 F6 and perophoramidine7 have been
recorded.
Nonetheless, it was still considered desirable to utilize this
methodology for the rapid construction of the lower aminal-
containing tetracyclic core of the communesins and then
introduce the vicinal quaternary centers at a stage late in the
synthesis. Our retrosynthetic plan is outlined in Scheme 3.
Thus, it was envisaged that stereoselective alkylation of the
enolate of twisted, bridged lactam 9 with 2-iodoethylazide,
reduction of the azide to an amino group, reductive amination
with the reactive bridged lactam carbonyl10 and acetylation
would afford communesin F. The benzazepine ring of lactam 9
could be constructed by allylic substitution of the carbamate
Our own perophoramidine total synthesis took advantage of
an indol-2-one cycloaddition.7a Thus, in our methodological
studies,8 we gathered firm evidence that indol-2-ones such as 2
(Scheme 1) are indeed generated via dehydrohalogenations of
3-alkyl-3-bromooxindoles,9 for example, 1, and that these quasi-
Scheme 1
Received: July 24, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja307277w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3
Scheme 4
functionality as precedented in the Qin pioneering synthesis6a
followed by deprotection and lactamization to afford twisted
lactam 9. N-Methylation, transformation of the azide
functionality of 11 to the Boc-protected amine, and
deprotection of the tosyl amine were expected to be
straightforward. Moreover, Heck reactions analogous to the
one that would afford the allylic alcohol 10 had been
documented in the Qin6a and Ma6c studies. The construction
of the lower aminal functionality of 11 would draw upon a
strategy similar to that employed in our perophoramidine total
synthesis. Thus, it seemed likely that the tosyl imide derivative
of lactam 12 would undergo methanolysis and concomitant
closure of a tosyl amide intermediate upon the indolenine
functionality. Finally, cycloaddition of indol-2-one, in turn
generated by dehydrohalogenation of 3-bromooxindole (14),
with indole 15 would afford indolenine 12 by way of endo
adduct 13.
A caveat of this overall plan was the identification of
conditions that would allow cycloaddition/conjugate addition
with the parent indol-2-one, a limitation in our initial
methodological study.8 Indeed, subjection of indole 15 and
bromooxindole 14 (Scheme 4) to our standard conditions (2.2
equiv Cs2CO3, CH2Cl2, rt) gave none of the desired product,
indolenine 12. However, after screening several bases and
solvents, it was found that treatment of indole 15 (1 equiv) and
freshly recrystallized 3-bromoindol-2-one (14, 1.6 equiv) with
silver carbonate (0.8 equiv) in acetonitrile did deliver
indolenine 12 in good yield as a single diastereomer. Our
tentative stereochemical assignment for indolenine 12 was
quickly confirmed by tosylation and in situ methanolysis to
afford the tetracyclic tosylamide 11 whose structure was
confirmed by X-ray crystallographic analysis. Methylation of
the nitrogen atom of indoline 11 proved to be problematic.
After an exhaustive screening of traditional methylating
reagents and protocols (NaH, MeI; KOtBu, MeI; Cs2CO3,
MeI; HCHO, NaBH3CN; HCHO, Ti(OiPr)4, NaBH3CN;
MeOTf), we discovered that we could effect the desired
transformation with Meerwein’s reagent and cesium carbonate.
Subsequent reduction of the azide functionality with in situ
protection of the resulting amine as a Boc-carbamate and
detosylation provided aminal 16. It was found that the Heck
reaction of bromide 16 with 2-methyl-3-buten-2-ol could be
best accomplished by employing the conditions reported by
Jew and Park in their clavicipitic acid total synthesis11 to
produce the allylic alcohol 10 (Scheme 3) in excellent yield.
Attempted cyclization of alcohol 10 under conditions (H+;
MsCl, NEt3) utilized in the previous syntheses of communesin
F by Qin, Weinreb and Ma afforded none of the desired
benzazepine 17 and instead led exclusively to a diene product
resulting from dehydration. Analogous dienes were also
obtained as substantial byproducts (24−26%) in the Qin and
Weinreb syntheses. Fortunately, the mild protocol recently
reported by the Nishizawa group12 for the mercuric triflate-
catalyzed five-membered cyclizations of sulfonylated anilines
bearing 2-(2-butene-4-ol) substituents was applicable to our
problem. In the case at hand, a smooth seven-membered
cyclization of carbamate 10 took place in excellent yield to
furnish only the desired benzazepine 17, whose structure was
secured by X-ray crystallographic analysis. Finally, removal of
the carbamate functionality of 17 could be accomplished using
the Ohfune procedure13 to provide an amino ester that resisted
cyclization upon thermolysis (140 °C, DMSO, 16 h), but did
provide the twisted, bridged lactam 9 upon treatment with
trimethylaluminum. To the best of our knowledge, this
represents the first example of the construction of a twisted,
B
dx.doi.org/10.1021/ja307277w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
bridged lactam14 using this valuable protocol for the
preparation of amides.15
REFERENCES
■
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The stage was now set for the introduction of the remaining
quaternary carbon, aminal moiety and completion of the total
synthesis. Attempts to alkylate the bridged lactam 9 with 2-
iodoethylazide using conditions we had previously employed
using structurally related fused lactams that lacked the N(10),
C(11) bond proved unsuccessful. Fortuitously, while this
investigation was underway, Ma reported the total syntheses of
communesins A and B from a bridged lactam very similar to
lactam 9 that has a protected vicinal diol in place of the
carbon−carbon double bond. Thus, we elected to adopt their
endgame and the first two steps were uneventful, namely,
stereoselective alkylation of the enolate derivative of lactam 9
from the convex face to afford nitrile 18 which was then
reduced with lithium aluminum hydride to afford lactol 19.
However, we were quite surprised to discover that reductive
amination of lactol 19 with sodium triacetoxyborohydride
(MeOH, NH4OAc, rt, 48 h) gave none of the desired aminal
21, but instead the N-ethylaminal 20 (1″-deoxocommunesin F)
in good yield (70% from nitrile 18). Indeed, it has been
previously observed that slow reductive aminations (>24 h)
employing sodium triacetoxyborohydride produce up to 5% N-
ethyl derivatives from acetaldehyde generated by self-reduction
of the reagent.16 In this case, the initial reductive amination of
the lactol is sufficiently suppressed to allow competitive
reductive amination of the resulting primary amine. Fortu-
nately, we eventually were able to discover conditions that
avoided the use of sodium triacetoxyborohydride to provide the
crude aminal 21 which was directly acetylated to give
( )-communesin F whose spectroscopic properties were
identical to those previously reported.
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In summary, we have completed a concise total synthesis of
( )-communesin F in 15 linear steps from 4-bromotryptophol
in an overall yield of 6.7%. Highlights of this synthesis include:
(1) a stereoselective cycloaddition with the parent indol-2-one;
(2) an underutilized intramolecular mercuric triflate catalyzed
cyclization of a carbamate with an allylic alcohol; and (3) the
preparation of a twisted, bridged lactam from an amino ester
using trimethylaluminum. This total synthesis further docu-
ments the value of indol-2-one cycloadditions for the rapid
construction of complex natural products that embody
indolines bearing C(3) quaternary carbons. Additional
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, product characterization and crys-
tallographic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
rlf@chem.psu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate the financial support provided by the National
Institutes of Health (GM28663).
C
dx.doi.org/10.1021/ja307277w | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX