Four-component benzyne coupling reactions: A concise total synthesis of dehydroaltenuene B

Article abstract of DOI:10.1021/ol8015435

(Chemical Equation Presented) A four-component coupling reaction of 3,5-dimethoxybenzyne with 2-methyl-2-cyclohexenylmagnesium chloride, carbon dioxide, and iodine was utilized as a key step in the first total synthesis of dehydroaltenuene B.

Full text of DOI:10.1021/ol8015435

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3833-3835
Four-Component Benzyne Coupling
Reactions: A Concise Total Synthesis of
Dehydroaltenuene B
Darunee Soorukram, Tao Qu, and Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, London SW7 2AZ, England
agm.barrett@imperial.ac.uk
Received July 8, 2008
ABSTRACT
A four-component coupling reaction of 3,5-dimethoxybenzyne with 2-methyl-2-cyclohexenylmagnesium chloride, carbon dioxide, and iodine
was utilized as a key step in the first total synthesis of dehydroaltenuene B.
One-pot multicomponent reactions have emerged as powerful
methods in synthetic organic chemistry.1 They have proven
to provide elegant and rapid entry to access complex
structures from simple building blocks. Among various
multicomponent reactions, which have been developed,
considerable recent attention has been focused on the
reactions with arynes.2 Arynes react with diverse myriad
nucleophiles. The sequential three-component reaction of an
aryne with a nucleophile and an electrophile provides an
attractive synthetic method, especially with the nitrogen-
centered nucleophiles and carbanions,3 for introducing
multiple functional groups on aromatic rings. Recently, our
group reported the total synthesis of the antifungal (ent)-
clavilactone, which employed a three-component benzyne
coupling strategy as the key step.4 In an extension of this
strategy to elaborate diverse aromatic structures, we now
report a four-component reaction of a benzyne intermediate
and demonstrate here its utility in the first total synthesis of
the antibacterial marine natural product dehydroaltenuene B.
Dehydroaltenuenes A and B (1 and 2), along with dihy-
droaltenuenes A and B (3 and 4) (Figure 1), were isolated
(1) (a) Zhu, J.; Bienayme, H., Eds. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005. (b) Tietze, L. F.; Brasche, G.; Gericke, K., Eds.
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes; Academic
Press: New York, 1967. For reviews on the use of arynes in organic
synthesis, see: (b) Kessar, S. V. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 4, pp
483-515. (c) Biehl, E. R.; Khanapure, S. P. Acc. Chem. Res. 1989, 22,
275. (d) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701. (e) Wenk,
H. H.; Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502.
(3) For recent examples, see: (a) Gilmore, C. D.; Allan, K. M.; Stoltz,
B. M. J. Am. Chem. Soc. 2008, 130, 1558. (b) Yoshida, H.; Fukushima,
H.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43, 3935. (c)
Uchiyama, M.; Kobayashi, Y.; Furuyama, T.; Nakamura, S.; Kajihara, Y.;
Miyoshi, T.; Sakamoto, T.; Kondo, Y.; Morokuma, K. J. Am. Chem. Soc.
2008, 130, 472. (d) Jayanth, T. T.; Jeganmohan, M.; Cheng, M. J.; Chu,
S. Y.; Cheng, C. H. J. Am. Chem. Soc. 2006, 128, 2232. (e) Liu, Z.; Larock,
R. C. J. Am. Chem. Soc. 2005, 127, 13112.
Figure 1. Structures of the altenuenes.
in 2006 by Gloer from cultures of an unidentified freshwater
aquatic fungal species from the Tubeufiaceae family.5 The
absolute configuration of these new compounds has not been
10.1021/ol8015435 CCC: $40.75
Published on Web 08/02/2008
2008 American Chemical Society

assigned. Interestingly, the difference in the relative stere-
ochemistry of these compounds led to the significant varia-
tion in their biological activities. Therefore, a concise total
synthesis of this class of natural products would be of
considerable interest to assign the absolute configuration and
to further define structure-activity relationships. Our ret-
rosynthetic analysis, based on benzyne coupling, is outlined
in Scheme 1.
regioselectively afford the arylmagnesium chloride 12.11 This
was trapped with carbon dioxide12 to give the resulting
arylcarboxylate 13, which, on iodolactonization, provided
iodide 7 in 56% yield (Scheme 2). Interestingly, substrate-
Scheme 2. Four-Component Benzyne Coupling Reaction
Scheme 1. Retrosynthetic Analysis of Dehydroaltenuene B
Dehydroaltenuene B (2) should be obtained from tricyclic
lactone 5 using an R-hydroxylation and selective de-O-
methylation. Lactone 5 should be derived from alkene 6
which should be available from the dehydroiodination of
iodide 7. In turn, we planned to construct iodide 7 in a one-
pot operation using a four-component benzyne coupling
reaction. Thus, regioselective nucleophilic addition of the
unsymmetrical benzyne 8 with the Grignard reagent 9
followed by carboxylation and iodolactonization should
provide iodide 7. The lithiation and elimination of com-
mercially available fluorobenzenes have been successfully
used to generate benzynes.4,6,7 In this work, we have
extended the scope of this transformation to 1-fluoro-3,5-
dimethoxybenzene (10). Reaction of fluoride 10 with n-
BuLi (1 equiv) gave the ortho-fluorolithium 11,8 which was
allowed to fragment to the benzyne 89 upon warming to room
temperature in the presence of the Grignard reagent 910 to
controlled diastereoselective cyclization13 was observed, and
iodide 7 was obtained as a single diastereoisomer. The
relative stereochemistry of the tricyclic product 7 was
established by H NMR NOESY experiment as shown in
Figure 2.
1
Figure 2. NOESY correlation of lactone 7.
The observed regioselectivity in the reaction of the
unsymmetrical aryne 8 with the Grignard reagent 9 can be
explained by the electron-withdrawing inductive effect
together with a steric effect,14 which directs the nucleophilic
attack toward the meta position of the two methoxy moieties.
Having the key iodide 7 containing the complete carbon
skeleton of the target natural product in hand, we focused
our attention on oxidation to complete the synthesis of
dehydroaltenuene B (Scheme 3).
(4) Larrosa, I.; Da Silva, M. I.; Gomez, P. M.; Hannen, P.; Ko, E.;
Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M.
J. Am. Chem. Soc. 2006, 128, 14042.
(5) Jiao, P.; Gloer, J. B.; Campbell, J.; Shearer, C. A. J. Nat. Prod.
2006, 69, 612.
(6) (a) Riggs, J. C.; Ramirez, A.; Cremeens, M. E.; Bashore, C. G.;
Candler, J.; Wirtz, M. C.; Coe, J. W.; Collum, D. B. J. Am. Chem. Soc.
2008, 130, 3406. (b) Ramirez, A.; Candler, J.; Bashore, C. G.; Wirtz, M. C.;
Coe, J. W.; Collum, D. B. J. Am. Chem. Soc. 2004, 126, 14700
(7) (a) Morton, G. E.; Barrett, A. G. M. J. Org. Chem. 2005, 70, 3525.
(b) Morton, G. E.; Barrett, A. G. M. Org. Lett. 2006, 8, 2859
.
(11) In preliminary model studies, reaction of 2-cyclohexenylmagnesium
chloride with benzyne 8 and quenching with water gave 1-(2-cyclohexenyl)-
3,5-dimethoxybenzene in 55% yield.
.
(8) Reaction of the ortho-fluorolithium 11 with iodine at -78 °C gave
the corresponding iodoarene in 83% yield.
(12) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem.
Soc. 2006, 128, 11040.
(9) For related generation of benzyne from ortho-fluorolithium, sodium,
and magnesium species, see: (a) Caster, K. C.; Keck, C. G.; Walls, R. D.
J. Org. Chem. 2001, 66, 2932. (b) Fossatelli, M.; Brandsma, L. Synthesis
1992, 756. (c) Gingrich, H. L.; Huang, Q.; Morales, A. L.; Jones, M. J.
Org. Chem. 1992, 57, 3803.
(13) See, for examples: (a) Garnier, J. M.; Robin, S.; Rousseau, G. Eur.
J. Org. Chem. 2007, 3281. (b) Ranganathan, S.; Muraleedharan, K. M.;
Vaish, N. K.; Jayaraman, N. Tetrahedron 2004, 60, 5273.
(14) Xin, H. Y.; Biehl, E. R. J. Org. Chem. 1983, 48, 4397. See also
ref 12.
(10) The Grignard reagent 9 was prepared using Rieke-magnesium from
the corresponding 2-methyl-2-cyclohexenyl chloride. See also: (a) Yanag-
isawa, A.; Habaue, S.; Yasue, K.; Yamamoto, H. J. Am. Chem. Soc. 1994,
116, 6130. (b) Burns, T. P.; Rieke, R. D. J. Org. Chem. 1987, 52, 3674.
(15) (a) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc.
2004, 126, 13622. (b) Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula,
S.; Doyle, M. P. Org. Lett. 2005, 7, 5167.
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Org. Lett., Vol. 10, No. 17, 2008

oxidation of lithium enolate derived from 5 can be explained
by the stereoelectronic effect as depicted in Figure 3. Attack
Scheme 3. Total Synthesis of Dehydroaltenuene B (2)
Figure 3. Stereoelectronic control leading to the syn-product 16.
of the lithium enolate derived from 5, represented as A, with
an electrophile from the same face as the methyl group (Path
a) led to the more favored chair conformation B having both
methyl and hydroxyl groups axial. In contrast, attack from
the opposite face (Path b) led to the twist boat conformation
C, which is apparently less favored. Finally, the syn-R-
hydroxy ketone 16 was subjected to selective de-O-methy-
lation using boron trichloride in dichloromethane20 to give
dehydroaltenuene B (2) in 81% yield starting from 5.
Comparison of the spectral data of the synthetic racemic
compound 2 with spectral data reported for the natural
product confirmed the identity of the synthetic material.
In conclusion, we have developed a concise and convenient
four-component benzyne coupling reaction for the conversion
of a simple arene into a tricyclic compound 7 in a one-pot
operation. We have successfully applied this method to the
first total synthesis of antibacterial dehydroaltenuene B (2).
On the basis of this approach, enantioselective reactions of
benzynes with allylmetallic species are currently under
investigation including second generation routes to the
altenuenes and other target systems.
Dehydroiodination of iodide 7 using DBU as base in THF
gave the corresponding alkene 6 (95%). Rhodium(II) capro-
lactam catalyzed allylic oxidation15,16 of alkene 6 in the
t
presence of BuOOH and K2CO3 in CH2Cl2 afforded R,ꢀ-
unsaturated ketone 14 (77%). Transformation of the R,ꢀ-
unsaturated ketone 14 to the corresponding isomer 5 was
performed in two steps, via the dienone 15. Thus, oxidation
of enone 14 using benzeneseleninic anhydride and camphor-
sulfonic acid in THF17 gave the dienone 15 (71%). This
procedure was superior to enolate phenylselenylation and
selenoxide elimination. Reaction of the delicate dienone 15
with Stryker’s reagent18 resulted in the selective conjugate
reduction at the less-substituted R,ꢀ-unsaturated double bond
to afford the desired enone 5 in 82% yield. Deprotonation
of ketone 5 using LiHMDS followed by the oxidation with
Davis’ oxaziridine reagent19 gave the corresponding R-hy-
droxy-ketone 16. The syn-product 16, of which the relative
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B.), the Royal Society and
the Wolfson Foundation for a Royal Society Wolfson
Research Merit Award (to A.G.M.B.), the Engineering and
Physical Sciences Research Council (UK) and the Com-
monwealth Scientific and Industrial Research Organization
(Melbourne, Australia) for generous support, and Professor
1
stereochemistry was confirmed by the H NMR NOESY
spectrum of 2, was obtained as a major product. The anti-
isomer was also obtained, but only in less than 5%, as
observed by 1H NMR. Fortunately, both could be separated
by chromatography. The stereochemical outcome for the
1
James B. Gloer, University of Iowa, for comparing the H
and 13C NMR spectral data of our synthetic dehydroaltenuene
B with the spectral data of the natural product.
(16) For the preparation of Rh2(cap)4, see: Doyle, M. P.; Westrum, L. J.;
Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M.
J. Am. Chem. Soc. 1993, 115, 958
.
(17) (a) Ninomiya, I.; Hashimoto, C.; Kiguchi, T.; Naito, T.; Barton,
D. H. R.; Lusinchi, X.; Milliet, P. J. Chem. Soc., Perkin Trans. 1 1990,
707. (b) Barton, D. H. R.; Lester, D. J.; Ley, S. V. J. Chem. Soc., Perkin
Trans. 1 1980, 1212. (c) Barton, D. H. R.; Boivin, J.; Lelandais, P. J. Chem.
Soc., Perkin Trans. 1 1989, 463.
Supporting Information Available: Experimental pro-
1
cedure, spectroscopic data, and copies of H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc.
1989, 111, 8818.
OL8015435
(19) (()-trans-2-(Phenylsulfonyl)-3-phenyloxaziridine was readily syn-
thesized according to the reported procedure. See: Vishwakarma, L. C.;
Stringer, O. D.; Davis, F. A. Org. Synth., Coll. 1993, 8, 546.
(20) Mazza, S. M.; Lal, K.; Salomon, R. G. J. Org. Chem. 1988, 53,
3681.
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