Synthesis of the ABC- and D-ring systems of the indole alkaloid ambiguine G

Article abstract of DOI:10.1021/ol702247a

A glycine Schiff base Michael addition is used in sequence with free radical-mediated aryl amination to ultimately arrive at the ambiguine G ABC-tricycle convergently. Additionally, thermal Diels-Alder cycloaddition of β-chloromethacrolein with Cohen's di

Full text of DOI:10.1021/ol702247a

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5027-5029
Synthesis of the ABC- and D-Ring
Systems of the Indole Alkaloid
Ambiguine G
Aroop Chandra, Rajesh Viswanathan,† and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology,
Vanderbilt UniVersity, NashVille, Tennessee 37235-1822
jeffrey.n.johnston@Vanderbilt.edu
Received September 13, 2007
ABSTRACT
A glycine Schiff base Michael addition is used in sequence with free radical-mediated aryl amination to ultimately arrive at the ambiguine G
ABC-tricycle convergently. Additionally, thermal Diels Alder cycloaddition of -chloromethacrolein with Cohen’s diene is used to
diastereoselectively construct the -cyclohexane ring bearing a neopentyl chloride.
−
â
D
The blue-green algae Hapalosiphon delicatulus produces a
variety of indoloterpenes, including the hapalindole,1 fis-
cherindole,2 and welwitindolinone3 classes of natural products
(Figure 1). The ambiguines have been isolated from this
source as well, appearing formally as prenylated hapalindoles,
and often bearing an additional element of complexity in
the form of a fifth (fused) seven-membered ring (e.g.,
ambiguine G, 1).4 The entanglement between structural
diversity and apparent homology within these natural prod-
ucts has led to the proposal that the individual biosynthesis
pathways may overlap.
In contrast to total syntheses within the first three classes,5,6
the pentacyclic ambiguines and their highly ring-fused
skeletons remain without approach, much less a synthetic
† Current address: Department of Chemistry, University of Utah, Salt
Lake City, UT 84102.
(1) Moore, R. E.; Cheuk, C.; Yang, X. Q. G.; Patterson, G. M. L.;
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones, N.
D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52, 1036.
(2) Park, A.; Moore, R. E.; Patterson, G. M. L. Tetrahedron Lett. 1992,
33, 3257.
(3) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson,
G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994,
116, 9935.
Figure 1. Representative alkaloids from cyanobacteria.
(4) Smitka, T. A.; Bonjouklian, R.; Doolin, L.; Jones, N. D.; Deeter, J.
B.; Yoshida, W. Y.; Prinsep, M. R.; Moore, R. E.; Patterson, G. M. L. J.
Org. Chem. 1992, 57, 857. Huber, U.; Moore, R. E.; Patterson, G. M. L. J.
Nat. Prod. 1998, 61, 1304.
solution. Ambiguine G (1) further attracted our attention by
virtue of the challenge it poses on a strategic level to the
development of a convergent synthesis. Of the 19 atoms that
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comprise the structural core, eight (42%) are involved in ring
fusions. This uncharacteristically high level of ring interde-
pendence provides a unique challenge for traditional annu-
lation approaches whose implementation might result in a
rather linear approach. Figure 2 outlines the key elements
through the intermediate norcaradiene and regioselective cy-
clopropane ring-opening to deliver the â-tetralone.11 Regio-
selective dimethylation at the more acidic benzylic methylene
could be effected in 71% yield using potassium tert-butoxide
in tert-butanol and methyl iodide in slight excess.12 Treatment
of this intermediate with IBX in a DMSO-toluene binary
solvent mixture led in 65% yield to the key enone 4.13
Schiff base 5 (now available commercially, or prepared
in one step from benzophenone imine and R-chloro tert-butyl
acetate14) adds to enone 4 under conditions of standard phase
transfer catalysis to deliver the product of Michael addition
in 79% isolated yield, and as a single diastereomer as
observed by 1H NMR of the crude reaction mixture. We did
not determine the relative stereochemistry since the two chiral
centers would not be preserved in the targeted intermediate.
Conversion of the aryl bromide to the derived indoline
proceeded as anticipated after application of standard radical-
generating conditions (nBu3SnH, AIBN, 90 °C). The isolated
yield of the intermediate indoline was 66%, and notably, the
reduced aryl halide amounted to no more than 5% of the
crude reaction mixture when it could be detected. The
indoline was immediately oxidized to the desired intermedi-
ate 7 through the application of DDQ in benzene-ethyl
acetate at 60 °C. In this manner, indole 7 was retrieved in
60% yield in addition to 20% of unreacted indoline.
A solution to the construction of the stereochemically rich
D-ring of ambiguine G has also been developed. This region
of the indoloterpene natural products of interest here is a
substructure with functional and stereochemical diversity
(Figure 1). The Vicinal presentation of a chlorine atom and
gem-methyl/vinyl arrangement is identical between ambigu-
ines D and G, whereas hapalindole L and welwitindolinone
A present a diastereomeric relationship. In only the total
synthesis of hapalindole G has this substructure been
addressed. Specifically, the Fukuyama route began from (-)-
carvone and in nine steps converted the R-methyl enone to
a neopentyl chloride by way of a stereospecific cyclopropane
ring-opening by chloride.
Figure 2. Ambiguine G: key retrosynthetic disconnections.
of a global solution to this problem. Instead of reliance on
an indole template, we targeted the construction of the BC
rings by a Buchner reaction,7 followed by selective frag-
mentation of the norcaradiene intermediate. The Α-ring
would then be annulated using a sequence of carbon-carbon
and aryl-nitrogen bond formations. Separately, we sought
a means to validate the use of a Diels-Alder cycloaddition
to establish the chiral chlorocyclohexane.
We targeted intermediate 4 as a template for design of a
convergent indoline annulation. Our plan was to combine
the operationally mild nature of free radical-mediated aryl
amination8,9 with conjugate addition of a glycine Schiff base10
(5) to a suitably functionalized â-tetralone (4).
o-Bromobenzyl acetic acid (2) was homologated to
R-diazo ketone 3 in 88% overall yield by treatment of the
derived acid chloride with diazomethane. This intermediate
was then treated with rhodium(II) acetate at elevated tem-
perature to effect a formal aryl C-H insertion, proceeding
Our initial solution to the stereocontrolled construction of
this subunit utilizes the Diels-Alder cycloaddition shown
in Scheme 2. We first prepared the requisite â-chloro
methacrolein 8 using the Arnold synthesis.15 In practice
however, we were unable to obtain consistent outcomes
during our attempts to increase the scale of the preparation.
As an alternative, we modified the procedure developed by
Williard to convert methallyl chloride to E-enal 8 in four
steps.16 Following the final oxidation with manganese
dioxide, the olefin isomers were converged to desired E-8
by treatment with p-toluene sulfonic acid. This aldehyde is
(5) Hapalindoles J, M, O, H, U: Muratake, H.; Natsume, M. Tetrahedron
1990, 46, 6331. Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm.
Bull. 1994, 42, 1393. Muratake, H.; Kumagami, H.; Natsume, M.
Tetrahedron 1990, 46, 6351. Hapalindole Q: Vaillancourt, V.; Albizati,
K. F. J. Am. Chem. Soc. 1993, 115, 3499. Kinsman, A. C.; Kerr, M. A.
Org. Lett. 2001, 3, 3189. Hapalindole G: Fukuyama, T.; Chen, X. Q. J.
Am. Chem. Soc. 1994, 116, 3125. Welwitindolinone A, fischerindoles I, G:
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394.
Welwitindolinone A: Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith,
C. J.; Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448. (+)-Ambiguine H,
(-)-hapalindole U, (-)-fischerindole I, (+)-welwitindolinone A: Baran,
P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404.
(6) Selected reports toward these natural product classes: MacKay, J.
A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421.
(7) Buchner, E. Ber. 1896, 29, 106. Ye, T.; Mckervey, M. A. Chem.
ReV. 1994, 94, 1091. Maas, G. Top. Curr. Chem. 1987, 137, 75.
(8) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran, E.
N. Org. Lett. 2001, 3, 1009. Viswanathan, R.; Mutnick, D.; Johnston, J. N.
J. Am. Chem. Soc. 2003, 125, 7266. Viswanathan, R.; Prabhakaran, E. N.;
Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163. Srinivasan,
J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston, J. N. Synthesis-
Stuttgart 2005, 330.
(11) Cordi, A. A.; Lacoste, J. M.; Hennig, P. J. Chem. Soc., Perkin Trans.
1 1993, 3. Dias, H. V. R.; Browning, R. G.; Richey, S. A.; Lovely, C. J.
Organometallics 2005, 24, 5784. Lovely, C. J.; Browning, R. G.; Badari-
narayana, V.; Dias, H. V. R. Tetrahedron Lett. 2005, 46, 2453.
(12) Gorka, A.; Hazai, L.; Szantay, C.; Hada, V.; Szabo, L.; Szantay, C.
Heterocycles 2005, 65, 1359.
(9) Free radical-mediated vinyl amination: Nugent, B. M.; Williams,
A. L.; Prabhakaran, E. N.; Johnston, J. N. Tetrahedron 2003, 59, 8877.
Prabhakaran, E. N.; Nugent, B. M.; Williams, A. L.; Nailor, K. E.; Johnston,
J. N. Org. Lett. 2002, 4, 4197.
(10) (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis 2nd Ed.;
Ojima, I. Ed.; Wiley-VCH: New York, Chapter 10, 2000. (b) O’Donnell,
M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron Lett. 1978, 2641. (c)
O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, 4625.
(13) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T.
Angew. Chem. Int. Ed. 2002, 41, 996.
(14) Eils, S.; Rossen, K.; Jahn, W.; Klement, I. Eur. Patent 1207151,
2002. Siebum, A. H. G.; Woo, W. S.; Lugtenburg, J. Eur. J. Org. Chem.
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(15) Arnold, Z.; Zemlicka, J. Collect. Czech. Chem. Commun. 1959, 24,
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5028
Org. Lett., Vol. 9, No. 24, 2007

Scheme 1. Preparation of the ABC Tricycle Using a Free Radical-Mediated Amination-Based Indoline Annulation
best prepared just prior to the Diels-Alder cycloaddition,
were only able to detect the regioisomer as the minor product
in a 3:1 ratio. This ratio is similar to that observed when
using acrylonitrile (7:1).18 The cis relationship (endo) was
determined by NOE measurements, with the methyl and
allylic methine exhibiting 5% enhancement, and the aldehyde
and chloromethine exhibiting a nearly 10% enhancement.
The modest isolated yield is due to the known propensity
for the Z-vinyl ether to isomerize to the thermodynamically
favored, yet unreactive, E-olefin. This process, as well as
diene polymerization can be retarded by the addition of
Hu¨nig’s base and a radical inhibitor. Additional precautions
were found to improve reproducibility, and these included
deoxygenation of the reaction mixture and silylation of the
reaction glassware. There is clearly room for optimization;
however, the immediacy with which the desired relative
stereochemistry can be established is attractive. Further
conversion of the aldehyde to a terminal olefin (Scheme 2)
was accomplished in 51% yield by treatment with methyl
phosphonium ylide. Cleavage of the methyl enol ether using
sodium iodide/trimethyl silyl chloride19 furnished the R-phe-
nylthiocyclohexanone 11 in 58% yield.
In summary, the basis for a solution to a convergent total
synthesis of ambiguine G and its congeners has been de-
veloped. Key elements of this report include the use of
Cohen’s diene and a chlorinated methacrolein to establish
the chiral chlorocyclohexane. Additionally, free radical-medi-
ated aryl amination was employed as a key step in a three-
step sequence to generate the tricyclic indole required for
many of the natural products in this class (Figure 1). This
strategy may ultimately find broader application as an alterna-
tive to indole synthesis when mild conditions are required.
as some decomposition was noted during storage.
Scheme 2. Synthesis of the Neopentyl Cyclohexylchloride
Using a Stereocontrolled [4 + 2] Cycloaddition
Among the possible dienes that we considered to establish
the feasibility of this approach, Cohen’s diene17 (9) emerged
as one of the most promising candidates for two reasons:
(1) Cohen’s demonstration that a sulfur substituent can direct
regioselectivity in the cycloaddition was expected to facilitate
this rather demanding cycloaddition,18 and (2) its influence
would be opposite that of the 2-methoxy substituent, a group
that we anticipated would simulate the electronic effect of
the indole nitrogen in the diene derived from 7. The
thiophenyl substituent might be similarly incorporated when
transforming 7 to a derived diene, should enhancement of
regiocontrol be necessary, and its presence in the product
would be used to facilitate final functionalization.
Acknowledgment. We are grateful to the National
Institutes of Health for support of this work (GM-63557).
J.N.J. is a recipient of the Eli Lilly Grantee Award.
Note Added after ASAP Publication. The last citation
in ref 5 was not included in the version published ASAP
November 2, 2007; the revised version was published ASAP
November 5, 2007.
Supporting Information Available: Experimental pro-
cedures and complete analytical data for all new compounds
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
The Diels-Alder cycloaddition of Cohen’s diene to
â-chloromethacrolein proceeds thermally, delivering a 44%
isolated yield of the desired secondary chloride 10 after 40
h at 140 °C. The cycloaddition itself is very selective as we
(17) Cohen, T.; Ruffner, R. J.; Shull, D. W.; Fogel, E. R.; Falck, J. R.
Org. Synth. 1988, 59, 202. Cohen, T.; Mura, A. J.; Shull, D. W.; Fogel, E.
R.; Ruffner, R. J.; Falck, J. R. J. Org. Chem. 1976, 41, 3218.
(18) Cohen, T.; Ruffner, R. J.; Shull, D. W.; Daniewski, W. M.;
Ottenbrite, R. M.; Alston, P. V. J. Org. Chem. 1978, 43, 4052.
(19) Kosarych, Z.; Cohen, T. Tetrahedron Lett. 1980, 21, 3959. Jung,
M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761.
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