Asymmetric synthesis of ageliferin

Article abstract of DOI:10.1021/ja207386q

We describe herein an asymmetric synthesis of ageliferin. A Mn(III)-mediated oxidative radical cyclization reaction was used as the key step to construct the core skeleton of this pyrrole-imidazole dimer. This approach resembles the biogenic [4 + 2] dimerization in an intramolecular fashion.

Full text of DOI:10.1021/ja207386q

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pubs.acs.org/JACS
Asymmetric Synthesis of Ageliferin
Xiao Wang, Zhiqiang Ma, Jianming Lu,† Xianghui Tan,‡ and Chuo Chen*
Division of Chemistry, Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States
S Supporting Information
b
ABSTRACT: We describe herein an asymmetric synthesis
of ageliferin. A Mn(III)-mediated oxidative radical cycliza-
tion reaction was used as the key step to construct the core
skeleton of this pyrroleꢀimidazole dimer. This approach
resembles the biogenic [4 + 2] dimerization in an intramo-
lecular fashion.
yrroleꢀimidazole alkaloids are a family of highly nitroge-
P
nated and halogenated natural products that possess unique
molecular skeletons and significant biological activities.1 Ageli-
ferin (1) is a dimeric member found in many Agelas and Stylissa
sponges.2 Conceptually, it is a [4 + 2] dimer of two molecules of
hymenidin (2) (Figure 1). Together with the [2 + 2] and [3 + 2]
congeners, these alkaloids provide valuable opportunities for
studying chemistry. Over the past decades, chemists have devel-
oped various strategies to address the issues associated with their
laboratory synthesis.3 Notably, the synthesis of the [2 + 2] dimer
sceptrin has been achieved by Baran4 and Birman,5 and the [4 + 2]
and [3 + 2] dimers ageliferin (1),6 axinellamine,7 massadine,8 and
palau0amine9 by Baran. Ohta has also reported a synthesis of
12,120-dimethylageliferin.10 Complementary to these elegant
approaches, we seek to examine the potential of radical addition
reactions in mimicking the putative [4 + 2] biosynthesis pathway.
We further wish to use laboratory synthesis to support the viability
of the biosynthetic hypotheses. We report herein the successful
implementation of such an approach in the synthesis of 1.
Figure 1. Ageliferin and its hypothetical biosynthetic pathway.
Scheme 1. Preparation of 7 and 9a
One prevailing biosynthesis proposal for these alkaloids is that
the [2 + 2] and [4 + 2] dimers are generated by direct dimeri-
zation11 while the [3 + 2] dimers are derived from the [4 + 2]
dimers through an oxidative ring-contraction reaction.12 We
therefore sought to explore the hypothetical central role of 1 in
the biosynthesis of this family of natural products. This direction
of research has also been pursued by Romo, Lovely, and Baran.13
Regarding the [4 + 2] dimerization, a DielsꢀAlder reaction has
been used by Romo, Lovely, and Ohta in their biomimetic
synthesis.14 We envisioned that oxidation of β-ketoester 3 would
initiate a radical tandem cyclization reaction affording 4 after
removing the tether (Figure 1). We anticipated that mimicking
this dimerization in an intramolecular way would allow for better
efficiency and stereochemical controls. In addition, an asym-
metric synthesis can be achieved with a chiral R* group. This
transformation resembles the biogenic formation of the C9ꢀC90
and C10ꢀC150 bonds in producing 1.
a Conditions: (a) n-BuLi, NCS, THF, ꢀ78 °C; then n-BuLi, DMF, THF,
ꢀ78 °C, 56% yield after recrystallization. (b) NaN3, DMF, 50 °C, 92%
crude yield. (c) Boc-β-Ala-OH, DCC, DMAP, CH2Cl2, 23 °C.
convert the imidazolinone groups to aminoimidazole groups
failed. We therefore redesigned our route and introduced the
13- and 130-amino groups at an early stage. An allylic γ-imidazolyl-
β-ketoester (3, X = N) was employed despite the difficulty of
radical addition to imidazole.17
Starting from BOM-protected imidazole 5,18 chlorination at
the 2-position and formylation at the 4-position can be carried
out in one-pot to give 6 (Scheme 1). The BOM group serves as a
good directing group for the second lithiation reaction providing
good regioselectivity. The azido group can then be introduced easily
by aromatic substitution to give 7. Separately, allylic alcohol 8,
We have recently demonstrated that oxidation of an allylic
γ-imidazolinoyl-β-ketoester (3, X = O) with Mn(OAc)3 readily
provides the core skeleton of 1,15,16 which can further be
transformed to 13,130-dioxoageliferin. However, all attempts to
Received: August 5, 2011
Published: September 04, 2011
r
2011 American Chemical Society
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Scheme 2. Completion of the Synthesis of Ageliferina
a Conditions: (a) LiHMDS, THF, ꢀ78 °C. (b) Dess-Martin periodinane, H2O, CH2Cl2, 23 °C. (c) Mn(OAc)3 2H2O, HOAc, 50ꢀ60 °C, 11: 18ꢀ25%,
3
12: ca. 9% yield for four steps. (d) LiOH, THF, H2O, 23 °C. (e) MsCl, NEt3, CH2Cl2, 23 °C. (f) NaI, acetone, 70 °C. (g) NaN3, DMSO, 60 °C, 36% yield
for four steps. (h) PPh3, H2O, THF, 70 °C. (i) TFA, CH2Cl2, 23 °C. (j) 4-Bromo-2-(trichloroacetyl)pyrrole, NEt3, DMF, 0 °C, 66% yield for three steps.
(k) 1-[N,N'-(di-Boc)amidino]pyrazole, NEt3, DMAP, CH3CN, 40 °C, 60% yield. (l) IBX, DMSO, 40 °C; then TFA 40 °C, 54% yield. (m) TFA,
CH2Cl2, 23 °C. (n) Ca(BH4)2 2THF, THF, 23 °C. (o) NaBH3CN, HOAc, 50 °C, 38% yield for three steps. (p) BCl3, CH2Cl2, ꢀ10 °C. (q) NH4OH,
3
H2O, CH3CN, 23 °C, 77% yield for two steps. (r) HCl, EtOH, H2O, 60 °C, 88% yield.
obtained from Garner’s aldehyde according to known proce-
dures,19 was coupled to Boc-β-Ala-OH to afford 9. Both crude 7
and 9 were used directly in the subsequent reaction.
ring.23 Considering the propensity of this C90 epimerization, we
decided to correct this stereochemical issue at a late stage and
focus on the installation of the remaining functional groups.
Converting the hydroxyl group of 13 to an amino group was
surprisingly difficult, due presumably to the congested steric
environment. After extensive studies, we found that 13 can first
be mesylated and then converted to an iodide. Reaction of this
iodide with NaN3 in warm DMSO gave 14 in moderate yields.
To install the pyrrole side chains, the azido groups were first
reduced by a Staudinger reaction. Interestingly, we found the
triphenylphosphine imide of aminoimidazole to be quite stable
toward hydrolysis, rendering it a good protecting group for our
synthesis. The acetonide and Boc groups can be removed
selectively to yield triamine 15, which was crashed out from
the ether solution to remove the excess reagents and triphenyl-
phosphine oxide. Installation of the pyrrole groups was done with
good regioselectivity, giving a 3:1 ratio of 16 and the mono-
pyrrole product, which can be resubjected to the reaction to
improve the overall efficiency.
β-Ketoester 10 for the critical Mn-oxidation reaction was
synthesized from 7 and 9 through an aldol reaction and Dess-
Martin oxidation (Scheme 2). Treating 10 with Mn(OAc)3 in
acetic acid at 50ꢀ60 °C or Mn(picolinate)3 in methanol at 90 °C
gave 11 and 12 in a 2.5ꢀ3:1 ratio. The major product 11 was
isolated in 18ꢀ25% yield and the minor product 12 in ca. 9%
yield over four steps based on 8.20 Lactones 11 and 12 differ only
in their C90 stereochemistry as the two compounds gave rise to
the same product 13 after decarboxylation. These results suggest
that only one face of the olefin was accessible for the radical
addition. However, the facial selectivity is opposite to that
predicted based on the A1,3 strain model,21 giving ent-1 at the
end of the synthesis. The stereoselectivity for reactions of homo-
logated Garner’s aldehyde derivatives has been shown to be less
predictable.22
Removal of the tether for the manganese oxidation reaction
can be done under mild conditions. As previously described,
decarboxylation of both 11 and 12 gave 13. The initial trans
decarboxylation product epimerized rapidly at the C90 position
to give cis-13. This rather unexpected stereochemical preference
presumably helps release the unfavorable steric interactions
among the three side chains while maintaining the carbonylꢀ
imidazole conjugation on a flattened half-chair cyclohexenone
With the pyrrole side chains in place, our next task was to
introduce the second aminoimidazole group. After evaluating
several routes, we found the following one most efficient and
reliable. A guanidine group was first introduced selectively to 16.
Oxidation of the hydroxyl group then gave an aldehyde that slowly
cyclized with the guanidine to give aminoimidazole 17. Addition of
0.5 equiv of TFA after oxidation facilitated this cyclization.
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COMMUNICATION
At this stage, we found that the C90 epimerization can be easily
done to provide the correct C90 configuration under acidic
conditions. The C100 carbonyl group was then removed with
sequential reductions to afford 18. The BOM protecting group
was subsequently removed by a two-step process. The benzyl group
was first cleaved by BCl3. The resulting hydroxymethyl group was
then removed by basic hydrolysis. Finally, the triphenylphosphine
imide group was hydrolyzed by HCl at 60 °C to afford ageliferin,
whose CD spectrum indicated that ent-1 was obtained. The absolute
configuration of 1 has been assigned by Baran.6b
In summary, utilizing an oxidative radical tandem cyclization
reaction as the key step, we successfully synthesized ent-ageliferin
(ent-1) in a biomimetic fashion. Our synthesis supports the
possibility that a single-electron transfer (SET) reaction is used
in nature to dimerize 2 to form 1.24 We are currently applying this
strategy to the biomimetic synthesis of the [3 + 2] pyrroleꢀ
imidazole dimers.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, and
b
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(8) Su, S.; Seiple, I. B.; Young, I. S.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 16490–16491.
Corresponding Author
Chuo.Chen@UTSouthwestern.edu
(9) (a) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.;
Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095–1098.(b) Seiple, I. B.;
Su, S.; Young, I. S.; Nakamura, A.; Yamaguchi, J.; Jørgensen, L.;
Rodriguez, R. A.; O’Malley, D. P.; Gaich, T.; K€ock, M.; Baran, P. S.
J. Am. Chem. Soc. [Online early access]. DOI: 10.1021/ja2047232.
Published online: Aug 23, 2011.
Present Addresses
†PerkinElmer, Boston, Massachusetts.
‡ChemPacific Corporation, Baltimore, Maryland.
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’ ACKNOWLEDGMENT
We dedicate this communication to Prof. David A. Evans on
the occasion of his 70th birthday. Financial Support was provided
by NIH (NIGMS R01-GM079554, 4R01-GM079554-S1), the
Welch Foundation (I-1596), and UT Southwestern. C.C. is a
Southwestern Medical Foundation Scholar in Biomedical Research.
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therefore isolated as TFA salts. The byproduct produced from IBX
oxidation decomposed 17 upon concentration. While ageliferin (1) is
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