Total synthesis of crisamicin A.
ABSTRACT Stereoselective total synthesis of natural product crisamicin A (1) was accomplished for the first time via the Pd/TMTU-catalyzed alkoxycarbonylative annulation to generate a unique cis-pyran-fused lactone, an intermolecular Diels-Alder reaction to construct the pyranonaphthoquinone unit, and a novel Pd-thiourea pincer complex-catalyzed homocoupling of functionalized naphthoquinones.
Total Synthesis of Crisamicin A
Zhengtao Li, Yingxiang Gao, Yefeng Tang, Mingji Dai, Guoxin Wang,
Zhigang Wang,* and Zhen Yang*
Laboratory of Chemical Genomics, Shenzhen Graduate School, Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing
National Laboratory for Molecular Science (BNLMS), College of Chemistry and the
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Science, Peking UniVersity, Beijing 100871
Received April 28, 2008
Stereoselective total synthesis of natural product crisamicin A (1) was accomplished for the first time via the Pd/TMTU-catalyzed
alkoxycarbonylative annulation to generate a unique cis-pyran-fused lactone, an intermolecular Diels-Alder reaction to construct the
pyranonaphthoquinone unit, and a novel Pd-thiourea pincer complex-catalyzed homocoupling of functionalized naphthoquinones.
Crisamicin A (1 in Figure 1), a natural product that contains
two pyran-fused lactones that are C2-symmetric to each other,
represents a prominent member of the dimeric pyranonaph-
thoquinone family of antibiotics (2-51in Figure 1) and was
first isolated in 1986 from the micro-organism Micromono-
spora purpureochromogenes that was obtained from a mud
sample in the Philippines.2Crisamicin A exhibited activity
against B16 murine melanoma cells, the herpes simplex, and
vesicular stomatitis viruses.3A more recent investigation also
uncovered important cytotoxic and antimicrobial activities
of its close structural analogues; for example, a new
pyranonaphthoquinone antibiotic termed GTRI-BB produced
by Micromonospora sp. SA-246, which is structurally
directly derived from crisamicin A through ring opening of
one of its two lactone rings, was found to be a stronger
inhibitor on the growth of tumor cell lines than the common
anticancer compound adriamycin.4
(1) (a) Fang, X.-P.; Anderson, J. E.; Chang, C.-J.; Fanwick, P. E.;
McLaughlin, J. L. J. Chem. Soc., Perkin Trans 1 1990, 1655. (b) Bergy,
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Figure 1. Biologically active pyranonaphthoquinones.
Vol. 10, No. 14
10.1021/ol800977n CCC: $40.75
Published on Web 06/14/2008
2008 American Chemical Society
While the syntheses of several monomeric antibiotics have
been reported, the total synthesis of such a dimeric pyra-
nonaphthoquinone as crisamicin A has yet to be achieved.5
Conceivably, these dimeric structures could be constructed
by homocoupling of their monomeric precursors, a particular
challenge that has defeated all the attempts so far6but, if
realized generally, should have greater implication in rapidly
assembling these structures. We report herein the identifica-
tion of a simple and versatile Pd-thiourea catalyst system
that improved the carbonylative annulation methodology
significantly thus providing an efficient way to construct the
pyran-fused lactone ring systems. The successful implemen-
tation of this strategy into the context of crisamicin A, in
conjunction with the discovery of a remarkably effective
Pd-thiourea pincer complex-catalyzed homocoupling pro-
tocol, accomplished its stereoselective total synthesis. The
work represents the first synthesis of a member of dimeric
pyranonaphthoquinone natural products.
As illustrated in Figure 2, a retrosynthetic disconnection
of the central aryl-aryl bond in crisamicin A (1) yielded a
monomeric triflate A which in turn could be accessed through
a Diels-Alder reaction between a functionalized quinine B
and an activated diene C. The pyran-fused lactone ring in B
could be constructed by the Pd-catalyzed alkoxycarbonylative
annulation of diol D that itself could be prepared by a
directed ortho-metalation-allylation sequence on amide E.
The synthesis of the key precursor 11 is outlined in
Scheme 1. The commercially available carboxylic acid 6 was
readily transformed into amide 7 in 93% yield. The amide-
directed ortho-metalation7on 7, followed by formylation with
DMF and MeMgCl addition to the resultant aldehyde,
delivered lactone 9 in 82% yield over four consecutive
manipulations. Reduction of 9 and subsequent diastereose-
lective ring opening of the hemiacetal by vinyl magnesium
chloride provided diol 11 in 59% yield.
With diol 11 in hand, we then set out to evaluate its Pd-
catalyzed alkoxycarbonylation-lactonization.8Initially, we
employed Kraus’ annulation conditions8jto construct lactone
12; however, we could not get the desired product according
to the published procedure (Scheme 2).
We reasoned that substrate 11 with a liable benzylic ether
moiety might undergo decomposition when exposed to Lewis
acid Pd(OAc)2.9Thus, electronic tuning of the Pd catalyst
through ligation with a certain type of ligand might poten-
tially afford a Pd complex with less Lewis acidity, which in
turn could be more compatible with substrates. We therefore
started to explore thioureas as ligands in this annulation in
consideration of their beneficial role in the metal-catalyzed
carbonylative reactions10and Au-catalyzed alkylation.11
To this end, we profiled the annulation in the presence of
various thioureas with 13 as the model substrate with regard
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Figure 2. Retrosyntehtic analysis of crisamicin A. Mechanistic
pathways involved in Pd-catalyzed alkoxycarbonylative annulation.
Scheme 1. Synthesis of Precursor 11
Scheme 2. Pd-Catalyzed Carbonylative Annulation: Total
Synthesis of Crisamicin A (1)
Org. Lett., Vol. 10, No. 14, 2008
to its easy synthetic accessibility and found that TMTU
(tetramethyl thiourea) could give the desired product 14 in
42% yield, together with three other side-products 15, 16,
and 17 (entry 2 in Table 1). It is worthwhile to mention that
the same reaction without the presence of TMTU yielded
no desired product (entry 1 in Table 1), indicating the unique
role of TMTU in the reaction.
To better understand the reaction and improve the yield
of the desired product, we proposed a catalytic cycle to
account for the formation of compounds 14-16.
We speculated that the overall process may first involve
attack of alcohol 13 on the PdIIX2Ln to generate complex
18, followed by an alkoxypalladation across the double bond
to yield the key pyran-fused metallocycle intermediate 20,
which might first undergo CO insertion to form the acyl
palladium intermediate 21, then reductive elimination to
produce the lactones 14 and 15.
We also envisioned that the complex 18 might undergo
an ionization to give the allyl-Pd species 19, followed by
nucleophilic attack of chloride on 19 that would release
allylic chloride 17. On the other hand, due to the existence
of an active ?-hydrogen, the intermediate 20 could undergo
consecutive reductive eliminations to afford alkyl-Pd species
22 and finally ketone 16 (Figure 3).
Since the formation of allylic chloride 17 could be
attributed to the existence of external chloride, we therefore
added propylene oxide (PO)12for removal of the Cl-in situ
generated from the oxidative turnover of Pd(0) f Pd(II)
assisted by CuCl2. Indeed, when we added 5 equiv of PO,
compound 17 was not observed (entry 7 in Table 1).
To eliminate the formation of compound 16 from the
annulation reaction, we suspected the base could play a
critical role in the formation of 22 (path B). Our earlier
work13suggested acetates to be a beneficial additive in the
Pd-catalyzed carbonylations, thus a few acetates including
NaOAc, CsOAc, and NH4OAc were employed in the
reaction. NaOAc and CsOAc, presumably due to their
stronger basicity, were found not to be compatible with the
substrate. Remarkably, the addition of NH4OAc (1.0 equiv)
to the reaction completely suppressed the formation of 16
(entries 5 and 6). Thus, an optimal catalytic system appeared
to consist of 10 mol % of Pd(OAc)2/TMTU, 2.5 equiv of
CuCl2, 5.0 equiv of PO, and 1.0 equiv of NH4OAc.
Thus, under the optimal conditions, substrate 11 was
annulated to give the key intermediate 12 in 88% yield
With compound 12 in hand, we began to synthesize
naphthoquinone 24. To this end, oxidation of 12 with cerium
ammonium nitrate (CAN) gave quinone 23, which subse-
quently underwent a Diels-Alder cyclization14with diene
H to furnish phenol 30 under Jones’ conditions in 85% yield.
It is worthwhile to mention that the regioselectivity in this
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Table 1. Pd/TMTU-Catalyzed Annulationa
aReaction conditions: substrate 13, Pd (OAc)2, TMTU, and CuCl2were
combined with or without other additives in THF, and the mixture was
allowed to react under a balloon pressure of CO at the indicated time.
Figure 3. Mechanistic pathways involved in Pd-catalyzed alkoxy-
Org. Lett., Vol. 10, No. 14, 20083019
step was remarkably high (>20:1), presumably due to the
stereoelectronic differentiation of the two quinone carbonyls
that was dictated by the pyran-fused lactone moieties.
To complete the total synthesis, a triflation-reductive
protection sequence efficiently transformed 24 into 26 which
was then employed in a Pd-catalyzed borylation to give
boronic ester 27. Without further purification, 27 was directly
treated with a catalytic amount (2% mol) of a newly
discovered Pd-thiourea pincer complex 2815to give the
homocoupling product 29, a full and functionalized crisami-
cin A skeleton, in 87% yield over two steps. It should be
noted that an extensive range of existing homocoupling
protocols reported in the literature,16including those employ-
ing various Pd, Ni, and Cu catalysts and aryl halides, triflates,
mesylates, and boronic esters as substrates, had been screened
in this transformation. Although several of them promoted
homocoupling on simpler naphthoquinone and naphthohy-
droquinone model compounds with various degrees of
success, none of them was found to be capable of effecting
such a reaction on more functionalized entities 24-27, a fact
that could be reflective of these dimeric pyranonaphtho-
quinones’ unique, highly oxygenated structural characteristic
and echoed with a previous finding by Brimble and co-
workers.6aIn sharp contrast, the catalyst 28 proved to be
generally successful with both simple and functionalized
substrates. Thus, the inherent robustness of 28 in overriding
a substrate’s individual reactivity profile promises further
applications in the context of natural product synthesis
involving homocoupling as a key strategy. Deprotection of
the hydroquinone moiety of 29 and its subsequent air
oxidation yielded bisquinone 30 in 93% yield. Finally,
demethylation of 30 by the action of BCl3gave crisamicin
A in 91% yield. Overall, the synthesis consisted of 19 steps
in its linear sequence, and the overall yield was 10%. The
synthetic material was fully characterized, and its1H and
13C NMR spectra were found to be identical to those of the
In summary, we have demonstrated Pd/TMTU to be an
efficient and general catalytic system in the Pd-catalyzed
alkoxycarbonylative annulation to generate pyran-fused lac-
tones in high yields. We also uncovered a robust Pd-thiourea
pincer complex that was capable of homocoupling function-
alized naphthoquinones and naphthahydroquinones. Imple-
mentation of these discoveries into the context of crisamicin
A has yielded its first stereoselective total synthesis success-
Acknowledgment. We thank Professor Ai-Wen Lei and
Ms. Jing Liu for ligand 28. Financial support from Peking
University Shenzhen Graduate School (grant to D.Z.W.) and
the National Science Foundation of China (grants 20325208
and 20272003 to Z.Y.) are gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedure and NMR and13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 3. Total Synthesis of Crisamicin A (1)
Org. Lett., Vol. 10, No. 14, 2008