Biomimetic total syntheses of spirobacillenes A and B

Article abstract of DOI:10.1039/c3cc42686f

The first total syntheses of spirobacillenes A and B were achieved concisely. The key transformation leading to spirobacillene A features a biomimetic intramolecular phenol-enol oxidative coupling reaction, and that leading to spirobacillene B highlights a bio-inspired intramolecular indole-ketone enolate oxidative coupling reaction.

Full text of DOI:10.1039/c3cc42686f

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Biomimetic total syntheses of spirobacillenes A and B†
Hongzhi Yang,z Juan Fengz and Yefeng Tang*
Cite this: Chem. Commun., 2013,
49, 6442
Received 12th April 2013,
Accepted 29th May 2013
DOI: 10.1039/c3cc42686f
www.rsc.org/chemcomm
The first total syntheses of spirobacillenes A and B were achieved
concisely. The key transformation leading to spirobacillene A features
a biomimetic intramolecular phenol–enol oxidative coupling reaction,
and that leading to spirobacillene B highlights a bio-inspired intra-
molecular indole–ketone enolate oxidative coupling reaction.
Microorganisms derived from extreme environments have been
recognized as one of the rich resources for the discovery of
bioactive secondary metabolites.1 Recently, a pair of indole
alkaloids, named spirobacillenes A (1) and B (2) (Scheme 1),
were isolated by Kwon and co-workers from the broth culture of
L. fusiformis KMC003, a bacterial strain collected from an acidic
coal mine drainage that was highly contaminated with iron-rich
heavy-metal ions and sulfuric acid.2 Structurally, the cores of 1
and 2 feature two highly functionalized spiro-cyclopentenone
motifs that are respectively incorporated into a cyclohexadienone
and indolenine scaffold, both of which are rarely found in the realm
of natural products. Moreover, preliminary biological evaluation
showed that 1 exhibited an inhibitory effect against the production
of NO and ROS in LPS-induced RAW264.7 macrophages,2 rendering
it an attractive target for further biomedical studies.
Scheme 1 Structures and proposed biosynthetic pathways of spirobacillenes A
(1) and B (2).
In addition to their unusual molecular architectures and
potentially important biological profiles, the intriguing bio- This assumption, to some extent, is substantiated by the
synthetic pathways of 1 and 2 also attracted our attention. The following facts: (1) 3 was isolated as a coexisting substance with
isolation team2 suggested that 1 and 2 could be biogenetically 1 and 2 from the same natural source; (2) L. fusiformis KMC003,
derived from pre-spirobacillene A (3) and pre-spirobacillene B (4), the bacterial strain that produced 1 and 2, survived in an iron-
respectively.3 As further rationalization of this hypothesis, we rich environment,2 which might provide the requisite oxidative
proposed that 1 could be generated from 3 via an intramolecular conditions for the aforementioned transformations to occur.
phenol–enol oxidative coupling reaction (path a, Scheme 1),
Keeping the hypothesis in mind, we set out to synthesize the
while 2 might be derived from 4 via an intramolecular precursors 3 and 4. As depicted in Scheme 2, protection of 54
indole–enol oxidative coupling reaction (path b, Scheme 1). with the TES group under the standard conditions5 followed by
treatment with Grignard reagent 66 afforded 7 in 76% yield in
two steps. Selective removal of the TES group of 7 with PPTS in
MeOH–THF7 followed by oxidation of the resulting alcohol with
DMP afforded the diketone 8 as a major product, which was
found to gradually tautomerize into the enol–ketone 9. Without
isolation, a mixture of 8 and 9 was treated with TBAF–AcOH to
yield pre-spirobacillene A (3) as the dominant product. Careful
analysis of the 1H NMR of 3 indicated that it was contaminated
The Comprehensive AIDS Research Center, Department of Pharmacology &
Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084,
China. E-mail: yefengtang@tsinghua.edu.cn; Fax: +86 10 62797732;
Tel: +86 10 62798236
† Electronic supplementary information (ESI) available: Experimental details and
spectroscopic data. CCDC 933153. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc42686f
‡ These authors contributed equally to this work.
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Table 1 Conditional screening of phenol–enol oxidative coupling reaction
leading to spirobacillene A (1)
Entry Conditions
Yield of 1 a (%)
1
2
3
4
5
6
7
8
9
10
PIDA (1.2 equiv.), CF3CH2OH, RT, 0.5 h
None
None
None
None
PIFA (1.2 equiv.), CF3CH2OH, RT, 0.5 h
PIDA (1.2 equiv.), (CF3)2CHOH, RT, 0.5 h
PIDA (1.2 equiv.), CH3CN, RT, 0.5 h
PIDA (1.2 equiv.), K2CO3, CH3CN, 0 1C, 0.5 h None
FeCl3 (excess), DCM, 0 1C, 0.5 h
K3Fe(CN)6 (excess), H2O–Et2O, RT, 0.5 h
[Fe(DMF)3C12][FeC14] (excess), Et2O, RT, 1 h None
DDQ (2.0 equiv.), dioxane, RT, 15 min
Ag2O (excess), DCM, RT, 24 h
Scheme 2 Synthesis of pre-spirobacillene A. (a) TESCl, imid., CH2Cl2, RT, 0.5 h,
80%; (b) 6, THF, 0 1C to RT, 5 h, 95%; (c) PPTS, MeOH–THF, (3 : 1), 0 1C to RT, 2 h,
82%; (d) DMP, CH2Cl2, RT, 0.5 h, 60%; (e) TBAF–AcOH, THF, RT, 2 h, 65%.
None
None
25
42b
The results of entries 1–8 were judged by crude 1H NMR, while those
a
with a minor product, whose structure was assigned to be
pre-spirobacillene B (4) based on the characteristic signals
(for details, see ESI†).8
With pre-spirobacillene A in hand, the stage was set to
explore the bio-inspired intramolecular phenol–enol oxidative
b
of entries 9 and 10 refer to isolated yields. The combined yield for
two runs of reaction (see the text). PIDA = phenyliodonium diacetate.
PIFA = phenyliodonium bis(trifluoroacetate). DDQ = 2,3-dichloro-5,6-
dicyanobenzoquinone.
coupling reaction. At the outset, the hypervalent iodine(III) well-known single-electron transfer reagents. However, the
reagents,9 such as PhI(OAc)2 (PIDA) and PhI(CF3CO2)2 (PIFA), possibility of generation of a p-quinone methide intermediate
were attempted, since we assumed that dearomatization of the C cannot be ruled out,14 since it can also account for the
phenol 3 would generate a carbocation intermediate A which formation of 1 from 3 via a Nazarov reaction (Table 1).
could be trapped by the internal enolic carbon (C-10) to furnish
Having achieved the target 1, we then moved towards the
the target 1.10 To validate this assumption, we performed a synthesis of 2. Since the equilibrium between 3 and 4 favoured
systematic screening of the choice of hypervalent iodine(III) 3 as the dominant isomer, we were precluded from exploring
reagents, solvents and bases (entries 1–5, Table 1). To our the originally proposed indole–enol oxidative coupling reaction
disappointment, all of the reactions failed to afford satisfactory (path b, Scheme 1). Alternatively, a bio-inspired strategy featured
results. In most of the cases, indole-3-carbaldehyde was gener- by an intramolecular indole–ketone enolate oxidative coupling
ated as a major by-product, presumably through a competitive reaction was adopted. Indeed, both inter- and intramolecular
oxidative cleavage of the enolic double bond of 3.11 We then indole–ketone enolate oxidative coupling reactions have been well
turned to evaluate Fe(III)-derived oxidants (e.g. FeCl3, K3Fe(CN)6 established recently, mainly attributed to the seminal contribu-
and [Fe(DMF)3C12][FeC14]), given that they have been success- tions from Baran’s group15 and Ma’s group.16 Thus, following the
fully applied to various oxidative coupling reactions with the protocol developed by Ma and co-workers, 7 was first treated with
phenol type of substrates.12 However, none of them gave LiHMDS at ꢀ40 1C, and then with I2 at ꢀ78 1C, leading to the
promising outcomes, only leading to decomposition of the formation of a major product. However, the product appeared to
starting material (entries 6–8). Encouragingly, after extensive be unstable and quickly transferred into another compound
trials we found that DDQ13 displayed unique reactivity to during the routine work-up process, whose structure was
promote the desired transformation by affording 1 in 25% determined to be 11 on the basis of extensive spectroscopic
yield (entry 9). More pleasingly, when Ag2O was employed, 1 studies (for details, see ESI†). Mechanistically, 11 might be
was obtained in 30% yield together with the recovery of sub- generated from 7 through a tandem indole–ketone enolate
stantial amounts of 3 (40%). The recovered material could be oxidative coupling, cyclic peroxide formation17 and Kornblum–
further converted into 1 with comparable efficiency, thus DeLaMare rearrangement18 (Scheme 3).
increasing the overall yield to 42% (entry 10). To the best of
Albeit the desired product was not obtained, the above
our knowledge, this work represents the first example of results suggested that the indole–ketone enolate oxidative
phenol–enol oxidative coupling reaction. Mechanistically, a coupling reaction did work. Encouraged by this clue, we sought
cation-radical intermediate B was most likely involved in the to explore the effective work-up procedures that could allow for
transformation from 3 to 1, given that both DDQ and Ag2O are obtaining the oxidative coupling product 10. After several trials
c
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Notes and references
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3 In the isolation paper, 3 was named as (Z)-3-hydroxy-4-(3-indolyl)-1-
hydroxyphenyl-2-butenone. Herein, we name 3 and 4 as pre-
spirobacillenes A and B respectively, based on their biogenetic
relationships with 1 and 2.
4 (a) S. T. Nguyen, M. M. Butler, L. Varady, N. P. Peet and T. L. Bowlin,
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8 Efforts to obtain the pure samples of 3 and 4 for fully structural
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Zhdankin and P. J. Stang, Chem. Rev., 2008, 108, 5299; (b) V. V.
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Scheme 3 Total synthesis of spirobacillene B. (a) LiHMDS, ꢀ40 1C, THF, 0.5 h; then
I2, ꢀ78 1C, 0.5 h; (b) quenched with sat. Na2S2O3 sol., 58% from 7; (c) PPTS–MeOH,
RT, 12 h, 27% of 14 and 10% of 2 from 7; (d) TBAF–AcOH, THF, RT, 2 h, 65%.
we were delighted to find that direct treatment of the reaction
mixture with PPTS–MeOH, followed by stirring at room tem- 11 (a) K. Miyamoto, N. Tada and M. Ochiai, J. Am. Chem. Soc., 2007,
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12 For selected example, see: (a) B. Franck and H. J. Lubs, Angew. Chem.,
perature for 12 h, led to the formation of two products. One of
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14 by the X-ray crystallographic study.19 The other, isolated in
10% yield, turned out to be spirobacillene B (2). Thus, an
unexpected one-pot reaction involving sequential indole–
Int. Ed. Engl., 1968, 7, 223; (b) A. S. Kende, F. H. Ebetino and T. Ohta,
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O. Ohmori, K. Iwasaki and M. Inoue, Tetrahedron, 2000, 58, 1289.
14 For a relevant case that inspired our studies, see: S. R. Angle and
group, autoxidation of the resulting alcohol and deprotection
of the TBS group was serendipitously achieved. Moreover,
K. D. Turnbull, J. Am. Chem. Soc., 1989, 111, 1136.
removal of the TBS group of 14 could be effected with TBAF– 15 For a review, see: (a) P. S. Baran, N. B. Ambhaikar, C. A. Guerrero,
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AcOH to afford 2 in 65% yield, thus increasing the overall yield
of 2 to 28% in four steps.
In summary, the total syntheses of spirobacillenes A (1) and
B (2),20 two newly isolated indole alkaloids, were achieved in a
biomimetic manner. The key transformation leading to 1
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phenol–enol oxidative coupling reaction and that leading to 2
highlighted an I2-promoted intramolecular indole–ketone
enolate oxidative coupling reaction. Our work provides decisive 17 The cyclic peroxide 12 might be generated from 10 through an
autoxidation of C-13 to form the corresponding hydroperoxide
which was then trapped by the internal imine.
18 For selected examples of Kornblum–DeLaMare rearrangements, see:
evidence for the proposed biogenetic pathways toward 1 and 2.
Meanwhile, it affords rapid access to the titled natural products
as well as their analogs for further biomedical studies.
We gratefully acknowledge the financial support from the
NSFC (21102081, 21272133), New Teachers’ Fund for Doctor
(a) N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,
73, 880; (b) D. R. Kelly, H. Bansalb and J. J. G. Morgan, Tetrahedron
Lett., 2002, 43, 9331; (c) B. W. Greatrex, N. F. Jenkins, D. K. Taylor
and E. R. T. Tiekink, J. Org. Chem., 2003, 68, 5205.
Stations Ministry of Education (20110002120011), Scientific 19 CCDC 933153 (14)†.
20 Notably, both 1 and 2 were reported as optically active substances in
Research Foundation for the Returned Overseas Chinese Scholars,
Ministry of Education (20121027968) and Beijing Natural Science
Foundation (2132037).
ref. 2, however, we think it is questionable. Actually, 1 is obviously
an achiral compound, and the naturally occurring 2 maybe a
racemic substance. For detailed analysis, see ESI†.
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6444 Chem. Commun., 2013, 49, 6442--6444
This journal is The Royal Society of Chemistry 2013