Synthesis of the tetracyclic core of tetrapetalone a enabled by a pyrrole reductive alkyation

Article abstract of DOI:10.1021/ol1018536

The tetracyclic framework of the tetrapetalone A aglycon has been secured through synthesis. A reductive pyrrole alkylation enables the formation of a key tetrasubstituted carbon stereocenter, and the tetramic acid portion of the molecule can be accessed through silicon or boronic ester conjugate addition to an ene-lactam.

Full text of DOI:10.1021/ol1018536

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4560-4563
Synthesis of the Tetracyclic Core of
Tetrapetalone A Enabled by a Pyrrole
Reductive Alkyation
Andrew P. Marcus and Richmond Sarpong*
Department of Chemistry, UniVersity of California, Berkeley,
California 94720, United States
rsarpong@berkeley.edu
Received August 7, 2010
ABSTRACT
The tetracyclic framework of the tetrapetalone A aglycon has been secured through synthesis. A reductive pyrrole alkylation enables the
formation of a key tetrasubstituted carbon stereocenter, and the tetramic acid portion of the molecule can be accessed through silicon or
boronic ester conjugate addition to an ene-lactam.
The tetrapetalones (1-4, Figure 1) are a unique class of
alkaloids first isolated by Komoda and co-workers in 2003
from a soil sample of Streptomyces sp. USF-4727 strain.1,2
Following an initial structural misassignment, the molecular
framework of these compounds was finally secured by
comprehensive two-dimensional NMR and derivatization
studies.3 The tetrapetalones display significant soybean
lipoxygenase (SBL) inhibitory activity. For example, 1
inhibits SBL with an IC50 ) 190 µM, which is comparable
to the activity of the known SBL inhibitors nordihydrogua-
iareic acid (NDGA, IC50 ) 290 µM) and kojic acid (IC50
)
110 µM). Komoda et al. have also recently reported the
isolation of ansaetherone (5), a modest radical scavenger,
Figure 1. Tetrapetalone natural products.
(1) (a) Komoda, T.; Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.;
Hirota, A. Tetrahedron Lett. 2003, 44, 1659–1661. (b) Komoda, T.;
Sugiyama, Y.; Abe, N.; Imachi, M.; Hirota, H.; Koshino, H.; Hirota, A.
Tetrahedron Lett. 2003, 44, 7417–7419. (c) Komoda, T.; Yoshida, K.; Abe,
N.; Sugiyama, Y.; Imachi, M.; Hirota, H.; Koshino, H.; Hirota, A. Biosci.,
which they suggest as a biogenetic precursor of the tetra-
petalones.4
The biological relevance of ansa-bridged compounds such
as 5 to the genesis of the tetrapetalones was first proposed
Biotechnol., Biochem. 2004, 68, 104–111
.
(2) Komoda, T.; Kishi, M.; Abe, N.; Sugiyama, Y.; Hirota, A. Biosci.,
Biotechnol., Biochem. 2004, 68, 903–908
(3) For a discussion, see ref 1b.
.
(4) Komoda, T.; Akasaka, K.; Hirota, A. Biosci., Biotechnol., Biochem.
2008, 72, 2392–2397.
10.1021/ol1018536  2010 American Chemical Society
Published on Web 09/15/2010

by Porco and Wang in their attempted synthesis of the
tetrapetalone tetracyclic core from the ansamycins.5
To date, there has been no report of a total synthesis of
any member of the tetrapetalone family. Recently, Hong et
al. reported the use of a Speckamp cyclization to build an
early stage tetracyclic core structure.6
Our synthetic analysis of the tetrapetalones was guided
by the desire to effect sequential late-stage oxygenation
chemistry, which would unveil the tetramic acid and para-
quinol moieties from a surrogate pyrrole and phenol,
respectively. In this communication, we report a partial
realization of this synthetic approach, which has led to the
racemic synthesis of an advanced tetracycle en route to the
tetrapetalone A aglycon.
the pyrrole or arene and, as such, presented an untested
extension of the Donohoe dissolving metal reduction chem-
istry. Tetracycle 7 could arise from aryl dienone 8, building
on pentannulation chemistry using the Nazarov cyclization,
which we have previously described.8 The advantage of using
8 as a substrate resided in the chemo-differentiation of the
substituents on the benzene ring, which would positively
impact subsequent functionalization chemistry.
The synthesis commenced with the preparation of aryl
dienone 8 (Scheme 2), which was readily obtained in 88%
Scheme 2. Synthesis of Pyrrole 13
Scheme 1. Retrosynthetic Analysis of the Tetrapetalone Core
a Reagents and conditions: (a) 9 (1.05 equiv), n-butyllithium (1.08 equiv,
2.5 M in hexanes), ether, -78 °C, 5 min, then 10 (1.0 equiv) in THF, -78
°C, 45 min. (b) AlCl3 (1.0 equiv), toluene, rt, 2 h, 9:1 dr. (c) K2CO3 (0.2
equiv), dioxane, 80 °C, 10 h, 4:1 dr. (d) NaBH4 (1.0 equiv), MeOH, 0 °C,
30 min. (e) TBSCl (1.1 equiv), imidazole (1.5 equiv), DMF, 80 °C, 10 h.
(f) t-Buytllithium (2.05 equiv), THF, -78 °C, 5 min, then Ts-N3 (1.2 equiv),
-78 °C to rt, 2 h. (g) LiAlH4 (0.67 equiv), THF, 0 °C, 1 h. (h)
2,5-Dimethoxytetrahydrofuran (1.2 equiv), acetic acid (0.1 equiv), 1,2-
dichloroethane/H2O (4:1), 80 °C, 4 h.
yield from the coupling of the known dibromide 9 and
Weinreb amide 10.9 It was discovered that 8 undergoes
Nazarov cyclization with good regiocontrol (13:1) using
stoichiometric AlCl3 in toluene at room temperature. Pre-
sumably, the major regioisomer is favored because of the
more significant para directing influence of the methoxy
substituent.10 It was necessary to effect epimerization of the
methyl-bearing stereocenter to achieve the trans relationship
of the Me and isopropenyl groups as shown in 11. This was
readily accomplished by heating with K2CO3 in dioxane,
which produced a mixture of diastereomers (4:1 dr) with 11
as the major compound. Reduction of the carbonyl group of
11 and protection of the resulting hydroxyl group with TBSCl
installed a TBS ether. At this stage, a bromide for azide
exchange was accomplished via halogen-metal exchange
followed by addition of tosyl azide to provide 12.11 Of note,
a variety of palladium and copper-mediated C-N bond-
forming reactions failed to accomplish the desired C-N bond
Our retrosynthetic analysis of 1 (Scheme 1) returns the
natural product to tetracycle 6, with the intention of a
concluding stage introduction of the ꢀ-rhodinose fragment
and an oxidative dearomatization of the A ring to install the
para-quinol moiety. We envisioned 6 arising from acylated
pyrrole 7 using a reductive alkylation of the relatively
electron-deficient pyrrole to install the angular ethyl group
at C4. This ambitious alkylation builds on precedent from
Donohoe, who has previously demonstrated the reductive
alkylation of pyrroles bearing carbamate, ester, or amide
groups.7 Although we hoped to accomplish an analogous
transformation in the conversion of 7 to 6, we recognized
that Birch-type reduction of 7 could conceivably reduce either
(5) Porco’s earlier report of an advanced tetracyclic intermediate has
been retracted, see: (a) Wang, X.; Porco, J. A. Angew. Chem., Int. Ed. 2006,
45, 6607. (b) Wang, X.; Porco, J. A. Angew. Chem., Int. Ed. 2005, 44,
3067–3071.
(6) Li, C.; Li, X.; Hong, R. Org. Lett. 2009, 11, 4036–4039.
(7) For selected examples, see: (a) Donohoe, T. J.; Guyo, P. M.; Beddoes,
R. L.; Helliwell, M. J. Chem. Soc., Perkin Trans. 1 1998, 667–676. (b)
Donohoe, T. J.; Ace, K. W.; Guyo, P. M.; Helliwell, M.; McKenna, J.
Tetrahedron Lett. 2000, 41, 989–993. (c) Donohoe, T. J.; Harji, R. R.;
Cousins, R. P. C. Tetrahedron Lett. 2000, 41, 1331–1334. (d) Turner, P. G.;
Donohoe, T. J.; Cousins, R. P. C. Chem. Commun. 2004, 1422–1423. (e)
Donohoe, T. J.; Thomas, R. E. Nat. Protoc. 2007, 2, 1888–1895.
(8) Marcus, A. P.; Lee, A. S.; Davis, R. L.; Tantillo, D. J.; Sarpong, R.
Angew. Chem., Int. Ed. 2008, 47, 6379–6383.
(9) Tisserand, S.; Baati, R.; Nicolas, M.; Mioskowski, C. J. Org. Chem.
2004, 69, 8982–8983, For details see, Supporting Information.
(10) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165–195.
(11) Matsumoto, T.; Ishida, T.; Koga, N.; Iwamura, H. J. Am. Chem.
Soc. 1992, 114, 9952–9959.
Org. Lett., Vol. 12, No. 20, 2010
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formation.12 The azide 12 was cleanly reduced with LAH
to afford an aniline, which upon exposure to modified Paal-
Knorr conditions13,14 yielded the pyrrole 13 in 97% yield.
The synthetic sequence up to this point is easily amenable
to scale-up, which has provided 13 on a multigram scale.
The next major challenge of the synthesis became the
installation of the functionalized azepine ring. To set the stage
for this task, hydroboration of 13 (Scheme 3) provided
undergo further oxidation to produce tetracyclic ketone 7.
This mechanistic scenario is corroborated by the observation
of mixtures of 15, 16, and 7 when less than 2 equiv of
Dess-Martin reagent was used for this transformation.
With a route to the tetracyclic core of the tetrapetalones
secured, we next turned our attention to the installation of
the angular ethyl group at C4. Donohoe and co-workers have
shown previously that pyrroles bearing amide or ester groups
at the 2-position can be reduced under dissolving metal
conditions and quenched with a variety of alkylating and
acylating reagents.7 In the context of the existing precedent,
pyrrole tetracycle 7 represents an ambitious extension from
several vantage points: (1) the participation of pyrroles
bearing ketone groups is not known (only esters and amides
were used previously) and (2) substrates bearing an aryl
group on the pyrrole nitrogen have not been demonstrated
as viable reaction partners; generally, the pyrrole nitrogen
bears a highly electron-withdrawing group such as a BOC
group. Importantly, an arene moiety is also susceptible to
single-electron reduction, which inherently introduces a
kinetic competition.
Scheme 3. Oxidative C-C Bond-Forming Construction of 7
In the event, exposure of 7 to sodium in ammonia/THF
in the presence of bis(methoxyethyl)amine7c for 45 min
followed by quenching with ethyl iodide resulted in the
formation of pyrrolidine 17 (Scheme 4). Notably, the arene
a Reagents and conditions: (a) borane-THF complex (10 equiv), rt, 12 h,
then EtOH, 30% aq H2O2, 10% aq NaOH, 0 °C to rt, 24 h. (b) Dess-Martin
periodinane (2.5 equiv), H2O (2.5 equiv), CH2Cl2, 50 °C, 16 h.
Scheme 4. Elaboration of Tetracycle 7
primary alcohol 14 following oxidative workup in 87% yield.
We had anticipated that oxidation of 14 to the corresponding
carboxylic acid (via an aldehyde intermediate using the
Pinnick conditions) would be necessary. At that juncture,
we expected that subjection of the acid to intramolecular
Friedel-Crafts acylation conditions would effect closure to
the seven-membered ring. Although an initial survey of
oxidation conditions (e.g., Swern, Parikh-Doering, PCC, or
PDC) failed to produce an intermediate aldehyde (see 15)
from 14, we were gratified to find that treatment of 14 with
2.5 equiv of Dess-Martin periodinane15 resulted in the
formation of tetracycle 7 in excellent yield. Presumably, this
transformation proceeds via the intermediate aldehyde (15)
followed by activation of the carbonyl group (by the
hypervalent iodine species or residual acetic acid),16 which
leads to attack by the proximal pyrrole. The resulting
pseudobenzylic secondary hydroxyl group (see 16) can then
a Reagents and conditions: (a) sodium (5 equiv), bis(methoxyethyl)amine
(20 equiv), NH3/THF (3:1), -78 °C, 45 min, then EtI (5 equiv), -78 °C,
1 h. (b) Mn(OAc)3·2H2O (0.1 equiv), TBHP (5.0 equiv), EtOAc, rt, 48 h.
(c) Ph2(Et2N)SiLi (6.0 equiv), CuCN (2.5 equiv), THF, -78 °C, 30 min,
then MeI (10.0 equiv), -78 °C, 1 h, then sat. NH4Cl in EtOH, rt, 16 h. (d)
30% aq H2O2 (3.0 equiv), KHF2 (3.0 equiv), DMF, rt, 12 h.
moiety remained intact, and the ethyl group was introduced
on the R-face of the tetracycle with excellent diastereocontrol.
We next focused on the construction of the tetramic acid,
which began with oxidation of the pyrrolidine moiety (see
17) to R,ꢀ-unsaturated lactam 18. Our initial attempts at this
oxygenation sequence employed chromium trioxide and 3,5-
dimethylpyrazole, following the precedent of Donohoe.7a
However, this led to variable yields of the desired product.
Additionally, this reaction was not easily amenable to scale
up. We found that the desired transformation could be
accomplished in improved yield using catalytic manga-
(12) Several conditions including those popularized by Buchwald and
Hartwig were attempted, see: (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000,
2, 1101–1104. (b) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem.
Soc. 1998, 120, 12459–12467. (c) Taillefer, M.; Xia, N.; Ouali, A. Angew.
Chem., Int. Ed. 2007, 46, 934–936. (d) Andersen, J.; Madsen, U.; Bjo¨rkling,
F.; Liang, X. Synlett 2005, 14, 2209–2213. (e) Zhu, W.; Ma, D. Chem.
Commun. 2004, 888–889.
(13) Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095–3110.
(14) For details, see the Supporting Information.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549–7552.
(16) The addition of NaHCO3 inhibits this oxidation reaction, suggesting
the importance of acid for the transformation.
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Org. Lett., Vol. 12, No. 20, 2010

nese(III) acetate along with TBHP as a stoichiometric oxidant
to afford 18.17 Silyl conjugate addition (see 18 to 19) was
effected with diethylaminodiphenylsilyllithium18 in the pres-
ence of CuCN, which afforded 19 following quenching with
MeI. To complete the tetramic acid fragment, a modified
Tamao-Fleming oxidation was planned.19 Treatment of 19
with either m-CPBA or H2O2 and potassium hydrogenfluoride
produced alcohol 20.
accomplished in 52% yield (along with 47% recovered
starting material) using a modification of a procedure recently
reported by Hoveyda.21,22 Immediate oxidation of the boronic
ester adduct yielded 20 in quantitative yield. Swern oxida-
tion23 at this stage completed the installation of the tetramic
acid moiety to give 22 in 65% yield.24
In summary, we report the synthesis of a tetracycle bearing
a tetramic acid en route to tetrapetalone A. This late-stage
intermediate contains all the carbons of the aglycon of the
natural product. Our synthetic sequence proceeds in 15 steps
from dibromide 9 and provides tetracycle 7 on a multigram
scale. Key developments include the use of oxidative
conditions for the construction of the tetracyclic core of
tetrapetalone A and a reductive alkylation reaction for the
installation of the angular ethyl group.
Given the modest yield for the oxidation of the dihydro-
pyrrolidone (see 18f20), we have developed an alternative
approach to the tetramic acid as outlined in Scheme 5.
Scheme 5. Alternative Installation of the Tetramic Acid
Acknowledgment. A.P.M. and R.S. are grateful to UC
Berkeley, the NSF (CAREER 0643264), EliLilly, Glaxo-
SmithKline, Johnson and Johnson, Amgen. and AstraZeneca
for generous financial support and the Ellman group (UC
Berkeley) for the use of their glovebox and a gift of catalyst
23.
Supporting Information Available: Experimental details
and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Reagents and conditions: (a) LDA (5 equiv), then MeI. (b) B2(pin)2
(1.1 equiv), CuCl (0.08 equiv), NaOtBu (0.16 equiv), 23 (0.08 equiv), THF,
rt, 18 h. (c) NaBO3 (5.0 equiv), 1:1 THF/H2O, rt, 2 h. (d) (COCl)2, DMSO,
Et3N, DCM, -78 °C.
OL1018536
(20) Deprotonation alpha to the ketone group is presumably not favorable
because of poor orbital overlap of the C-H bond and the π* of the CdO
bond.
(21) Lee, K.-s.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2009, 131, 7253–7255
(22) Modification of the original conditions included addition of a
CuCl.
(23) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(24) Prolonged exposure of 20 to Dess-Martin periodinane resulted in
the formation of 24, which is closely related to the tetracyclic core of
tetrapetalones C and D.
.
Sequential treatment of tetracycle 18 with LDA and MeI
resulted in methylation of the ene-lactam moiety to provide
21 without competing methylation alpha to the ketone
functional group in the seven-membered ring.20 Conjugate
addition of boron pinacolato ester to ene-lactam 21 was
(17) Shing, T. K. M.; Yeung, Y.-Y.; Su, P. L. Org. Lett. 2006, 8, 3149–
3151.
(18) Kawachi, A.; Tamao, K. Bull. Chem. Soc. Jpn. 1997, 70, 945–955.
(19) (a) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694–1696. (b) Tamao, K.; Ishida, N.; Kumada, M. J. Org. Chem.
1983, 48, 2120–2122. (c) Tamao, K.; Ishida, N. J. Organomet. Chem. 1984,
269, C37–C39.
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