Total synthesis of (±)-trichodermamide B and of a putative biosynthetic precursor to aspergillazine A using an oxaza-cope rearrangement

Article abstract of DOI:10.1002/anie.200801652

(Chemical Equation Presented) Coping with tandem reactions: The total synthesis of marine fungal metabolite, trichodermamide B, is accomplished using a tandem nitrosation/oxaza-Cope rearrangement as the key step to establish the characteristic heterocyclic ring system of the natural product. Preparation of the putative biosynthetic precursor of aspergillazine A provides further insight into the possible biosynthetic pathway to aspergillazines.

Full text of DOI:10.1002/anie.200801652

Angewandte
Chemie
DOI: 10.1002/anie.200801652
Natural Product Synthesis
Total Synthesis of (Æ )-Trichodermamide B and of a Putative Biosyn-
thetic Precursor to Aspergillazine A Using an Oxaza-Cope
Rearrangement**
Chong-Dao Lu and Armen Zakarian*
Dedicated to Professor Larry E. Overman on the occasion of his 65th birthday
Trichodermamides A and B are modified dipeptides recently
isolated from a marine-derived fungus Trichoderma virens.[1]
Trichodermamide A has been demonstrated to be identical to
penicillazine,[2] obtained from a culture of another marine
fungus, Penicillium sp. (strain #386) in 2000.[3] In contrast to
trichodermamide A, which displayed no activity in bioassays,
trichodermamide B (1) was found to have significant in vitro
activity against HCT-116 human colon carcinoma (IC50
0.32 mgmLÀ1) and moderate antimicrobial activity against
certain drug-resistant bacterial strains, indicating that the
chlorine atom in 1 is essential for bioactivity. In 2005, a group
of related metabolites, aspergillazines A–E, was characterized
by Capon and co-workers.[2] Their biological evaluation was
prevented by the lack of material available from biological
sources.
The presence of a 4H-5,6-dihydro-1,2-oxazine fragment
fused with a highly functionalized cyclohexene ring is a
distinguishing structural attribute of these natural products,
making them compelling targets for chemical synthesis.[4,5]
Owing to the lack of mild methods for the direct assembly of
the oxazine rings,[6,7] we recently developed a tandem reaction
sequence that integrates nitrosation of ester enolates and a
novel Lewis acid mediated hetero-Cope rearrangement, the
oxaza-Cope rearrangement (Equation (1) in Scheme 1),
which directly provides bicyclic oxazines from esters.[8,9]
Herein, we report an application of this method to the first
total syntheses of (Æ )-trichodermamide B and the putative
biosynthetic precursor of aspergillazine A (2) from a common
intermediate.
Scheme 1. Overall synthetic strategy. LDA=Lithium diisopropylamide.
Our strategy required a late-stage amide formation from
functionalized carboxylic acid 3 and aminocoumarin 4[5]
(Scheme 1). Thus, acid 3 became our key sub-target. SN2-
type substitution at C5 served as the strategic basis for the
divergent introduction of the appropriate functionality found
in trichodermamide B and in aspergillazine A.
[*] Prof. Dr. A. Zakarian
Department of Chemistry and Biochemistry, University of California
at Santa Barbara
Santa Barbara, CA 93106-9510 (USA)
Fax: (+1)850-644-8281
E-mail: zakarian@chem.ucsb.edu
The preparation of the substrate for the key oxaza-Cope
rearrangement began with the Diels–Alder reaction between
3-benzyloxy-2,2-dimethoxy-3,5-cyclohexadienone (5) and
vinylene carbonate according to the method described by
Liao and co-workers (Scheme 2).[10] Remarkably, hydrolysis
of the carbonate with lithium hydroxide in aqueous THF
resulted in a rapid, virtually complete inversion of stereo-
chemistry at C7. Presumably, a retroaldol-aldol pathway is
operative in this process, favoring the thermodynamically
more stable trans-diol 9.[11] Methyl ester 11 was obtained from
9 in seven straightforward steps in 78% overall yield.[12]
Dr. C.-D. Lu
Department of Chemistry and Biochemistry, Florida State University
Tallahassee, FL 32306-4390 (USA)
[**] This work was supported by the Department of Chemistry and
Biochemistry, Florida State University, the ACS Petroleum Research
Fund (43838-G1), and NSF (CAREER CHE-0746881). C.-D.L. thanks
the MDS Research Foundation for a postdoctoral fellowship. We
thank Dr. U. Goli (FSU) for assistance with HRMS experiments. We
thank Dr. Capon for a copy of the 1H NMR spectrum of aspergilla-
zine A.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801652.
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Communications
Scheme 2. Synthesis of the key substrate. 9-BBN=9-Borabicyclo-
[3.3.1]nonane, TBS=tributylsilyl, TMS=trimethylsilyl.
The crucial nitrosation/oxaza-Cope rearrangement
employing 11 was studied next (Scheme 3). A mixture of
isoamyl nitrite and silyl ketene acetal 12 derived from 11 was
Scheme 4. Completion of the synthesis of trichodermamide B.
DDQ=2,3-Dicyano-5,6-dichloro-parabenzoquinone, sm=starting
material, EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-
chloride, DMAP=4-dimethylaminopyridine, Py=pyridine,
brsm=based on recovered starting material, TBSDPOTf=tert-butyldi-
phenylsilyl trifluoromethanesulfonate.
Scheme 3. The key oxaza-Cope rearrangement.
by Taylor and co-workers,[5] we have found that amide 18
could be formed directly on treatment of the carboxylic acid
and aminocoumarin 4 with 1-ethyl-3-(3-dimethylaminopro-
pyl)carbodiimide hydrochloride (EDC) and 4-dimethylami-
nopyridine (DMAP) in dichloromethane in 79% yield.
Removal of the benzylidene protecting group was
effected with zinc triflate in the presence of ethanethiol in
88% yield. Mesylation of the diol regioselectively afforded 19
in 90% yield. The total synthesis of trichodermamide B was
accomplished upon treatment of the mesylate with LiCl in
DMF and subsequent desilylation, which provided the
racemic natural product displaying identical physical data
(UV, 1H, 13C NMR spectroscopy, HRMS-ESI) to those
reported by Clardy, Fenical and co-workers.[1a]
Recently, Capon and co-workers proposed that aspergil-
lazine A and trichodermamides could arise through a similar
biosynthetic pathway, where a C5 thiol analog of trichoderm-
amides functions as a putative biosynthetic precursor to 2
(Figure 1).[2] This hypothesis also stipulates that the proximity
of the oximino and thiol groups predisposes the substrate for
facile thiolane formation.
treated with titanium tetrachloride in dichloromethane at
À788C, according to the standard reaction conditions.[8] The
resultant blue solution of the intermediate nitrosoester was
warmed to 08C, which effected the oxaza-Cope rearrange-
ment to the desired oxazine 13. We have found that the
conversion was substantially higher when excess of the Lewis
acid was used, however, partial debenzylation was also
detected. The optimal stoichiometry for titanium tetrachlor-
ide was found to be 2.1 equivalents, giving an overall 82%
yield of the desired product.
Subsequent transformations were aimed at allylic trans-
position of the hydroxy group at C6 with inversion of
configuration (Scheme 4). Complete desilylation followed
by oxidative formation of the benzylidene acetal afforded a
approximately 1.7:1 mixture of diastereomers (14). The allylic
alcohol was converted to the corresponding allylic selenide
with inversion of configuration using the Grieco protocol.[13]
The formation of about 10% of the allylic regioisomer was
detected. With other protecting groups at C4 and C5
(triethylsilyl (TES), tert-butyldimethylsilyl (TBS)), the regio-
selectivity was substantially lower. Oxidation of the selenide
followed by the in situ [2,3]-sigmatropic rearrangement of the
intermediate selenoxide furnished 15.[14]
To gain further insight into the chemistry of aspergilla-
zines, we used our synthetic strategy for the synthesis of the
C5 thiol analogue of trichodermamides (21, Scheme 5).
Displacement of the methanesulfonyl group in 19 with
potassium thioacetate followed by desilylation smoothly
provided 20 in 70% overall yield. The thioacetate was
cleaved by treatment with hydrazine under mild conditions
(08C, 15 min), cleanly delivering 21. Thiol 21 did not undergo
After silylation of the allylic alcohol, the methyl ester was
hydrolyzed with lithium hydroxide in advance of the amide
formation (77%, 87% yields based on recovered starting
material). In contrast to the model studies described recently
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involved in the biosynthesis of aspergillazine A, its cyclization
to 2 is not spontaneous.
Received: April 8, 2008
Published online: July 24, 2008
Keywords: heterocycles · natural products · peptides ·
sigmatropic rearrangement · total synthesis
.
Figure 1. Proposed biosynthesis of aspergillazine A.
[1] a) E. Garo, C. M. Starks, P. R. Jensen, W. Fenical, E. Lobkovsky,
J. Clardy, J. Nat. Prod. 2003, 66, 423 – 426; b) P. Seephonkai, P.
Kongsaeree, S. Prabpai, M. Isaka, Y. Thebtaranonth, Org. Lett.
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[2] R. J. Capon, R. Ratnayake, M. Stewart, E. Lacey, S. Tennant, H.
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[3] Y. Lin, Z. Shao, G. Jiang, S. Zhou, J. Cai, L. L. P. Vrijmoed,
E. B. G. Jones, Tetrahedron 2000, 56, 9607 – 9609.
[4] X. Wan, G. Doridot, M. Joullie, Org. Lett. 2007, 9, 977 – 980.
[5] J. R. Donald, M. G. Edwards, R. J. K. Taylor, Tetrahedron Lett.
2007, 48, 5201 – 5204.
[6] The hetero-Diels–Alder reaction with nitrosoalkenes is an
alternative method for the direct synthesis of 4H-5,6-dihydro-
1,2-oxazines: a) T. L. Gilchrist, D. A. Lingham, T. G. Roberts, J.
Chem. Soc. Chem. Commun. 1979, 1089 – 1090; b) T. L. Gil-
christ, T. G. Roberts, J. Chem. Soc. Chem. Commun. 1978, 847 –
849; c) D. E. Davies, T. L. Gilchrist, T. G. Roberts, J. Chem. Soc.
Perkin Trans. 1 1983, 1275 – 1281; d) S. C. Yoon, K. Kim, Y. J.
Park, J. Org. Chem. 2001, 66, 7334 – 7341. Reviews: e) T. L.
Gilchrist, Chem. Soc. Rev. 1983, 12, 53 – 73; f) C. Hippeli, H.-U.
Reissig, Liebigs Ann. Chem. 1990, 217 – 226.
Scheme 5. Synthesis of putative biosynthetic precursor of asper-
gillazine A (top) and products of attempted final cyclization step
(bottom)
[7] For examples of stepwise methods via oximes, see: R. A. Al-
Quawasmeh, T. H. Al-Tel, R. J. Abdel-Jalil, W. Voelter, Chem.
Lett. 1999, 541 – 542; and refs. [3] and [4].
[8] A. Zakarian, C.-D. Lu, J. Am. Chem. Soc. 2006, 128, 5356 – 5357.
[9] A. Jabbari, K. N. Houk, Org. Lett. 2006, 8, 5975 – 5977.
[10] a) H.-F. Hou, R. K. Peddinti, C.-C. Liao, Org. Lett. 2002, 4,
2477 – 2480; b) C.-C. Liao, R. K. Peddinti, Acc. Chem. Res. 2002,
35, 856 – 866.
[11] For related studies, see: a) V. Thornqvist, S. Manner, O. F.
Wendt, T. Freid, Tetrahedron 2006, 62, 11793 – 11800; b) V.
Thornqvist, S. Manner, M. Wingstrand, T. Freid, J. Org. Chem.
2005, 70, 8609 – 8612; c) L. A. Paquette, H.-C. Tsui, J. Org.
Chem. 1996, 61, 142 – 145.
a spontaneous cyclization to 2 and, under a variety of reaction
conditions (DMSO or PhMe, > 1308C, CF3CO2H/DMSO
708C, CH3CO2H/H2O 708C, Me3Al, THF[15]) no ring closure
was detected. The major products formed in these reactions
were diastereomeric racemic disulfides 22 and 23. These
experimental results suggest that conversion of the putative
biosynthetic precursor 21 into 2 is not spontaneous or even
facile, as no ring closure is detected under rather harsh
reaction conditions.
[12] See Supporting Information for details.
[13] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41,
1485 – 1486.
[14] a) K. B. Sharpless, R. F. Lauer, J. Am. Chem. Soc. 1972, 94,
7154 – 7155; b) D. L. J. Clive, G. Chittattu, N. J. Curtias, S. M.
Menchen, J. Chem. Soc. Chem. Commun. 1978, 770 – 771; c) H. J.
Reich, J. Org. Chem. 1975, 40, 2570 – 2572.
In conclusion, we reported a successful completion of the
first total synthesis of trichodermamide B. An application of
an efficient tandem nitrosation/oxaza-Cope rearrangement
for the assembly of the characteristic bicyclic oxazine of
trichodermamide B is one of the key transformations in the
synthesis. Using a similar approach, we have also prepared
thiol 21, the proposed biosynthetic precursor of aspergillazi-
ne A. Based on our results, it appears that, if 21 is indeed
[15] D. J. Hart, N. A. Magomedov, J. Am. Chem. Soc. 2001, 123,
5892 – 5899.
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