Total synthesis of platensimycin and related natural products

Article abstract of DOI:10.1021/ja9068003

Platensimycin is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B₁ and B₃, platensic acid, methyl platensinoate, platensimide A, homoplatensimide A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal enynes.

Full text of DOI:10.1021/ja9068003

Published on Web 10/29/2009
Total Synthesis of Platensimycin and Related Natural
Products
K. C. Nicolaou,* Ang Li, David J. Edmonds, G. Scott Tria, and Shelby P. Ellery
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research
Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, and Department of
Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, La Jolla, California 92093
Received August 11, 2009; E-mail: kcn@scripps.edu
Abstract: Platensimycin is the flagship member of a new and growing class of antibiotics with promising
antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its
congeners, platensimycins B1 and B3, platensic acid, methyl platensinoate, platensimide A, homoplatensimide
A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these
target molecules involved construction of their cage-like core followed by attachment of the various
side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to
the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and
another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate.
The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical
cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a
terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal
enynes.
Introduction
while ensuring the hits are active against a known cellular target,
has proven troublesome due to difficulties in realizing such
The discovery of new antibiotics is an urgent medical priority
due to the continuous emergence of drug-resistant strains of
pathogenic bacteria. As evolution drives the inevitable develop-
ment of bacterial resistance to existing drugs, so the search for
new treatments of bacteria-induced infections must continue.1,2
Natural antibiotics are produced by microorganisms as chemical
defenses in their fight for scarce resources. Such molecules have
been at the forefront of antibiotic research since the seminal
discovery of penicillin.3,4 The screening of compounds for
antibacterial activity is fraught with difficulty, however, due to
two conflicting sets of problematic circumstances.5 First, high-
throughput whole-cell assays of naturally occurring molecules
struggle to distinguish specific antibiotic action from nonspecific
toxicity and can lead to the re-isolation of known compounds.
Any hit must then be individually identified and its mechanism
of action determined, requiring a significant investment of effort
and resources. On the other hand, the use of target-based assays,
activity in whole-cell settings. A team led by Wang and Singh
at Merck recently addressed these problems by developing an
antisense RNA assay for antibiotic activity.5 Briefly, they
screened natural product isolates against a strain of Staphylo-
coccus aureus in which the expression of the FabH and FabF
condensing enzymes of the fatty acid biosynthesis pathway (FAS
II) was inhibited by the presence of antisense RNA correspond-
ing to the genes encoding both proteins. The strain is thus
sensitized to fatty acid biosynthesis inhibitors. By screening
samples against this strain and one expressing these enzymes
normally in parallel, samples containing compounds that act
through inhibition of FAS II could be identified by their
differential effects on the two strains.5
Using this technique, Wang, Soisson, Singh, and co-workers
identified several potent FAS II inhibitors, including platensi-
mycin (1, Figure 1), which was isolated from a strain of
Streptomyces platensis from a soil sample collected in South
Africa.6 They determined the complex polycyclic structure of
platensimycin and demonstrated that it acts through highly
potent and selective inhibition of the elongation condensing
enzyme FabF. As this mechanism of action is not shared by
any clinically used antibiotic, platensimycin showed no cross-
resistance and was found to be active against a broad range of
(1) (a) Pearson, H. Nature 2002, 418, 469. (b) Walsh, C. T. Nat. ReV.
Microbiol. 2003, 1, 65–70.
(2) For a series of reviews on antibiotic resistance, see: (a) Walsh, C. T.,
Wright, G., Eds. Chem. ReV. 2005, 105, 391-774. (b) Overbye, K. M.;
Barrett, J. F. Drug Disc. Today 2005, 10, 45–52.
(3) Sheehan, J. C. The Enchanted Ring: The Untold Story of Penicillin;
The MIT Press: Boston, 1984; p 248.
(4) (a) Singh, S. B.; Barrett, J. Biochem. Pharmacol. 2006, 71, 1006–
1015. (b) von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.;
Ha¨bich, D. Angew. Chem., Int. Ed. 2006, 45, 5072–5129. (c) Demain,
A. L.; Sanchez, S. J. Antibiot. 2009, 62, 5–16.
(6) (a) Wang, J.; et al. Nature 2006, 441, 358–361. (b) Singh, S. B.;
Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.; Zhang, C.; Zink, D. L.;
´
Tsou, N. N.; Ball, R. G.; Basilio, A.; Genilloud, O.; Diez, M. T.;
(5) (a) For an excellent overview of this program, see: Singh, S. B.;
Phillips, J. W.; Wang, J. Curr. Opin. Drug DiscoVery DeV. 2007, 10,
160–166. (b) Young, K.; et al. Antimicrob. Agents Chemother. 2006,
50, 519–526.
Vicente, F.; Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006,
128, 11916–11920. For an article on the significance of the discovery
of platensimycin, see: (c) Ha¨bich, D.; von Nussbaum, F. ChemMed-
Chem 2006, 1, 951–954.
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A R T I C L E S
Nicolaou et al.
platensimide A (4),10a which retains the right-hand structural
motif of platensimycin (1), was also found to be inactive, as
was homoplatensimide A (5).10b The relative stereochemistry
of the 2,4-diaminobutyrate unit of platensimide A (4) was
verified by the semisynthesis of 4 from 2.10a Homoplatensimide
A (5) and its methyl ester, homoplatensimide A methyl ester
(6), contain a carboxylate moiety with the complete C20 skeleton
of a diterpene, in keeping with the biosynthetic proposal for
these compounds, bound through an amide linkage to
glutamide.10b Platensimycins B1-B3 (7-9, Figure 1), three other
natural congeners of platensimycin (1) with modest changes in
the benzoic acid domain of the molecule, also show poor activity
due to the lack of a free carboxylic acid moiety.10c Platencin
(10, Figure 1) was also isolated from a strain of S. platensis.11
Although it shows an overall structural similarity with platen-
simycin (1), particularly in the common aromatic portion, the
latter compound has a less-oxygenated ketolide domain. Pla-
tencin (10) possesses a biological profile similar to that of
platensimycin (1) but, surprisingly, a slightly different mech-
anism of action.11
The novel and intricate chemical structure and vitally
important biological activity of platensimycin (1) made it an
attractive target for total synthesis, and a number of groups have
reported their synthetic studies toward this end. Following our
initial reports on the total synthesis of (()-platensimycin [(()-
1]12a and, later, of the natural (-)-enantiomer [(-)-1],12b several
groups reported alternative elegant approaches.12c-k Addition-
ally, our research group and others have prepared a number of
biologically active analogues of platensimycin.13 We present
here an improved synthesis of platensimycin (1) and a full
account of our studies on the total synthesis of this fascinating
target as well as the related compounds (2-7, 9) sharing its
Figure 1. Molecular structures of platensimycin (1) and related natural
products (2-10).
(11) (a) Wang, J.; et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 7612–
7616. (b) Jayasuriya, H.; Herath, K. B.; Zhang, C.; Zink, D. L.; Basilio,
´
A.; Genilloud, O.; Diez, M. T.; Vicente, F.; Gonzalez, I.; Salazar, O.;
Pelaez, F.; Cummings, R.; Ha, S.; Wang, J.; Singh, S. B. Angew.
Chem., Int. Ed. 2007, 46, 4684–4688.
pathogenic Gram-positive bacterial species. Platensimycin was
also shown to be effective in ViVo, clearing a model S. aureus
infection in mice, although only at relatively high, continuously
administered doses. Interestingly, the fatty acid inhibition
strategy to combat bacteria has recently been challenged on the
basis of experiments that showed their survival does not depend
crucially on their own production of fatty acids since they can
tap on the reserves of their hosts for such essential ingredients.7
Singh and co-workers also disclosed biosynthetic studies on
platensimycin (1), indicating the terpenoid nature of the tetra-
cyclic carboxylate “right-hand” portion,8 as well as preliminary
chemical studies9 and the structures of several related natural
products (Figure 1).10 Platensic acid (2) and its methyl ester
(3) were isolated as natural products in their own right,10a as
might be expected from the biosynthetic pathway, and were
found to have virtually none of the antibiotic activity of
platensimycin (1). The naturally occurring aliphatic amide
(12) (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed.
2006, 45, 7086–7090. (b) Nicolaou, K. C.; Edmonds, D. J.; Li, A.;
Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 3942–3945. (c) Zou, Y.;
Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett.
2007, 9, 1825–1828. (d) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem.
Commun. 2007, 1922–1923. (e) Li, P.; Payette, J. N.; Yamamoto, H.
J. Am. Chem. Soc. 2007, 129, 9534–9535. (f) Lalic, G.; Corey, E. J.
Org. Lett. 2007, 9, 4921–4923. (g) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed. 2007, 46, 8074–8075. (h) Nicolaou, K. C.; Pappo, D.;
Tsang, K. Y.; Gibe, R.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2008,
47, 944–946. (i) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.;
Lee, E. Angew. Chem., Int. Ed. 2008, 47, 4009–4011. (j) Matsuo, J.-
i.; Takeuchi, K.; Ishibashi, H. Org. Lett. 2008, 10, 4049–4052. (k)
Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163–1170. (l) Yun,
S. Y.; Zheng, J.-C.; Lee, D. J. Am. Chem. Soc. 2009, 131, 8413–
8415. For reviews on the synthesis of platensimycin and related
antibiotics, see: (m) Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.;
Estrada, A. A. Angew. Chem., Int. Ed. 2009, 48, 660–719. (n)
Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 2548–
2555.
(13) (a) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Montero, A.; Edmonds,
D. J. Angew. Chem., Int. Ed. 2007, 46, 4712–4714. (b) Nicolaou, K. C.;
Tang, Y.; Wang, J.; Stepan, A. F.; Li, A.; Montero, A. J. Am. Chem.
Soc. 2007, 129, 14850–14851. (c) Nicolaou, K. C.; Stepan, A. F.;
Lister, T.; Li, A.; Montero, A.; Tria, G. S.; Turner, C. I.; Tang, Y.;
Wang, J.; Denton, R. M.; Edmonds, D. J. J. Am. Chem. Soc. 2008,
130, 13110–13119. (d) Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2008,
10, 3877–3878. (e) Wang, J.; Lee, V.; Sintim, H. O. Chem.sEur. J.
2009, 15, 2747–2750. (f) Shen, H. C.; Ding, F.; Singh, S. B.;
Parthasarathy, G.; Soisson, S. M.; Ha, S. N.; Chen, X.; Kodali, S.;
Wang, J.; Dorso, K.; Tata, J. R.; Hammond, M. L.; MacCoss, M.;
Colletti, S. L. Bioorg. Med. Chem. Lett. 2009, 19, 1623–1627. (g)
Jang, K. P.; Kim, C. H.; Na, S. W.; Kim, H.; Kang, H.; Lee, E. Bioorg.
Med. Chem. Lett. 2009, 19, 4601–4602.
(7) Brinster, S.; Lamberet, G.; Staels, B.; Trieu-Cuot, P.; Gruss, A.; Poyart,
C. Nature 2009, 458, 83–86.
(8) Herath, K. B.; Attygalle, A. B.; Singh, S. B. J. Am. Chem. Soc. 2007,
129, 15422–15423.
(9) Singh, S. B.; Herath, K. B.; Wang, J.; Tsou, N.; Ball, R. G. Tetrahedron
Lett. 2007, 48, 5429–5433.
(10) (a) Herath, K. B.; Zhang, C.; Jayasuriya, H.; Ondeyka, J. G.; Zink,
D. L.; Burgess, B.; Wang, J.; Singh, S. B. Org. Lett. 2008, 10, 1699–
1702. (b) Jayasuriya, H.; Herath, K. B.; Ondeyka, J. G.; Zink, D. L.;
Burgess, B.; Wang, J.; Singh, S. B. Tetrahedron Lett. 2008, 49, 3648–
3651. (c) Zhang, C.; Ondeyka, J.; Zink, D. L.; Burgess, B.; Wang, J.;
Singh, S. B. Chem. Commun. 2008, 5034–5036.
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Total Synthesis of Platensimycin
A R T I C L E S
quaternary center. We considered a variety of disconnection
strategies at this stage. We hypothesized that disconnection of
the ether ring, as shown, was likely to be productive since it
not only simplified the target significantly but also offered the
chance to control the C15 stereocenter as a result of geometric
constraints and complete the cage-like structure by way of well-
understood chemistry. The most straightforward etherification
substrate, tricyclic enone 13, contains a 4-hydroxyketone
structural motif. Disconnection of the C9-C10 bond by way
of a retro 1,4-addition was an intriguing prospect. This discon-
nection resulted in a spirocyclic 4,5-cyclohexadienone bearing
a single stereogenic center (i.e., 14, Figure 2). Although the
success of the 1,4-addition reaction was by no means assured
and the preparation of a suitable substrate might prove chal-
lenging, we were attracted to this strategy by the possibility of
exploiting the local symmetry of the dienone unit to set the
all-carbon quaternary center at the heart of this subtarget.
Inspection of the three-dimensional structure of substrates such
as 14 indicated that, if a successful 1,4-addition reaction could
be achieved, the stereochemistry at C8 and C9 would follow as
a matter of course. Additionally, several reactions could be used
to effect the desired intramolecular 1,4-addition to the enone,
including radical and Stetter-type processes, giving the approach
some flexibility. Aldehyde 14 could act as a substrate (or suitable
precursor for such a substrate) for several of these reactions.
Setting the absolute stereochemistry of the single stereocenter
of 14 (C12) would be the key to realizing an asymmetric
synthesis of platensimycin, a challenge for which we envisioned
two separate possible solutions. The first (a, Figure 2) involved
forging the C12 stereocenter and the spirocyclic cyclopentyl
ring in a single cycloisomerization step from a symmetrical,
achiral 1,6-enyne precursor (15). This intermediate, in turn,
could be traced back, through Stork-Danheiser alkylation
chemistry, to enone 16. This route offered the advantages of a
direct and potentially catalytic asymmetric synthesis, but faced
the challenge of realizing an asymmetric cycloisomerization
reaction of terminal alkyne substrates, which at the time was
an unsolved problem. Our second strategy (b, Figure 2) involved
separating the tasks of forming the spirocyclic system and the
stereocenter. The former would result from a de-aromatizing
cyclization of a 4-substituted phenol such as 18. Our interest in
the chemistry of hypervalent iodine reagents led us to propose
an oxidative cyclization using an allyl silane as an internal
nucleophile. The substrate for this reaction (18) was easily
envisioned to derive from a ketone such as 19, which was
expected to be available in enantiopure form Via the alkylation
of pseudoephedrine amide 20. In this case, the advantages lay
in the likely ease of substrate preparation employing Myers’s
alkylation technology using readily available starting materials.
Within this route, a dearth of precedent for the de-aromatization
reaction gave us some concern. In the end, we would investigate
both asymmetric approaches; initially, however, we focused on
securing the relatively late key step, which was perceived to be
the most challenging aspect of the proposed synthesis: the
conversion of aldehyde 14 to cage structure 12 using racemic
material.
Figure 2. Retrosynthetic analysis of platensimycin (1).
tetracyclic enone structural motif. Our studies on the total
synthesis of platencin (10) are reported elsewhere.14
Results and Discussion
Retrosynthetic Analysis. We began our studies by pondering
a retrosynthetic analysis of the platensimycin molecule (1). The
final route developed is depicted in retrosynthetic format in
Figure 2. Our analysis began with the straightforward amide
disconnection to generate aromatic amine 11 and platensic acid
(2) as potential precursors. From here, a double disconnection
of the propionate and methyl R-substituents revealed the
tetracyclic ketolide 12 as the primary synthetic subtarget. The
inherent structural bias of cage-like intermediate 12 was
expected to impart stereocontrol in the construction of the C4
Construction of Racemic Aldehyde (()-14. Our urgent desire
to investigate reactions of aldehyde 14 led us to prepare this
compound in racemic form in the first instance. This endeavor
also served as a preliminary investigation for the first asymmetric
route to platensimycin [(-)-1]. Our optimized route to (()-14
is shown in Scheme 1. Starting from ketone 17, we carried out
sequential alkylation reactions using the established protocol
(14) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem., Int. Ed.
2008, 47, 1780–1783.
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A R T I C L E S
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Scheme 1. Optimized Synthesis of Aldehyde (()-14a
Scheme 2. Synthesis of Cycloisomerization Substrates 15, 31, and
32a
a Reagents and conditions: (a) LDA (1.2 equiv), 21 (1.5 equiv), THF,
-78 f 22 °C, 6 h, 92%; (b) LDA (1.4 equiv), propargyl bromide (3.0
equiv), THF, -78 f 22 °C, 13 h, 97%; (c) DIBAL-H (1.0 M in hexanes,
1.2 equiv), THF, -78 f -20 °C, 1 h; then 1 N aq HCl, 0 °C, 30 min,
88%; (d) [CpRu(MeCN)3]PF6 (0.02 equiv), acetone, 22 °C, 1.5 h, 92%, ca.
1:1 diastereomeric mixture; (e) TMSOTf (1.2 equiv), Et3N (1.5 equiv),
CH2Cl2, 0 °C, 30 min; (f) Pd2(dba)3 ·CHCl3 (0.05 equiv), diallyl carbonate
(2.0 equiv), MeCN, 22 °C, 12 h, 93% (two steps); (g) 1 N aq HCl/THF
(1:1), 22 °C, 2 h, 85%.
a Reagents and conditions: (a) TMSOTf (1.2 equiv), Et3N (1.5 equiv),
CH2Cl2, 0 °C, 30 min; (b) n-BuLi (1.2 equiv), TMSCl (1.5 equiv), THF,
-78 f -40 °C, 30 min; (c) n-BuLi (1.2 equiv), MeOC(O)CN (1.5 equiv),
THF, -78 f -40 °C, 30 min; (d) IBX (1.2 equiv), MPO (1.2 equiv),
DMSO, 22 °C, 3 h, 74% for 26 (two steps), 70% for 29 (three steps), 67%
for 30 (three steps); (e) LiHMDS (1.05 equiv), PhSeCl (1.05 equiv), THF,
-78 °C, 10 min; then m-CPBA (1.2 equiv), -78 f -40 °C, 30 min, 70%;
(f) 1 N aq HCl, THF, 0 °C, 1 h, 92% for 15, 95% for 31, 91% for 32.
of kinetic enolate generation with LDA. This allowed the
installation of what would eventually become the quaternary
center at C8 and all the carbon atoms needed for the lower
region of the platensimycin enone domain to afford intermediate
16 in excellent overall yield. Reduction of enone 16 with
DIBAL-H followed by treatment with aqueous HCl led to enone
22 in good yield.15 Keeping the reaction time short and
maintaining the mixture at 0 °C prevented significant loss of
the silyl ether. Treatment of enyne 22 with ruthenium catalyst
([CpRu(MeCN)3]PF6) in acetone resulted in a smooth and
efficient cycloisomerization reaction,16 furnishing spirocycle 23
as an inconsequential 1:1 mixture of diastereoisomers. Formation
of the TMS enol ether of enone 23 and oxidation gave dienone
24, which was converted into aldehyde (()-14 by acidic
hydrolysis of the TBS enol ether. The oxidation reaction could
be carried out using a stoichiometric amount of Pd(OAc)2, as
reported previously,17a but was accomplished most efficiently
using the mild catalytic system of Pd2(dba)3 ·CHCl3 in combina-
tion with diallyl carbonate.17b In either case, excellent selectivity
was observed for oxidizing the TMS enol ether to afford 24.
complexes.18 While, in general, excellent substrate scope and
enantiomeric excesses were noted in these reports, examples
incorporating terminal alkyne partners were conspicuously
absent. In order to investigate the possibility of an asymmetric
cycloisomerization, the synthesis had to be slightly modified to
incorporate the second olefin in the enone ring so as to produce
achiral substrate 15 (Scheme 2). We also prepared related
substrates with the alkyne moiety capped with various functional
groups, as shown in Scheme 2. Thus, activation of the ketone
group of 22 gave trimethylsilyl enol ether 25, which served as
a common intermediate for all required substrates (Scheme 2).
Oxidation of 25 with IBX·MPO19 led to dienone 26, with
deprotection of the TBS ether giving parent prochiral substrate
15. Alternatively, the oxidation of cyclohexenone 22 could be
achieved in a one-pot procedure through the introduction of a
phenylselenide group followed by selenoxide formation and syn
elimination, as summarized in Scheme 2. Two further substrate
analogues were prepared by taking advantage of the temporary
masking of the ketone group as enol ether 25. Lithiation of the
terminal alkyne followed by quenching with TMSCl or Mander’s
reagent gave enol ethers 27 and 28, respectively (Scheme 2).
In each case, oxidation with IBX ·MPO (to afford 29 and 30,
Catalytic Asymmetric Synthesis of Aldehyde (-)-14. We also
investigated an asymmetric version of the above route to
aldehyde 14. No asymmetric variant of the ruthenium-catalyzed
cycloisomerization reaction16 had been reported at the time;
however, Zhang and co-workers had described an equivalent
transformation catalyzed by chiral rhodium(I) diphosphine
(18) (a) Cao, P.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490–
6491. (b) Cao, P.; Zhang, X. Angew. Chem., Int. Ed. 2000, 39, 4104–
4106. (c) Lei, A.; He, M.; Wu, S.; Zhang, X. Angew. Chem., Int. Ed.
2002, 41, 3457–3460. (d) Lei, A.; Waldkirch, P.; He, M.; Zhang, X.
Angew. Chem., Int. Ed. 2002, 41, 4526–4529. (e) Lei, A.; He, M.;
Zhang, X. J. Am. Chem. Soc. 2002, 124, 8198–8199. (f) Lei, A.; He,
M.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 11472–11473. (g) Liu,
F.; Liu, Q.; He, M.; Zhang, X.; Lei, A. Org. Biomol. Chem. 2007, 5,
3531–3534.
(15) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775–1776.
(16) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 714–715.
(b) Trost, B. M.; Surivet, J.-P.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 15592–15602. For a review of Ru-catalyzed reactions, see: (c)
Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem., Int.
Ed. 2005, 44, 6630–6666.
(17) (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011–
1013. (b) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui,
R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028–16029.
(19) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.; Harrison, S. T. Angew.
Chem., Int. Ed. 2002, 41, 996–1000.
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A R T I C L E S
Scheme 3. Preliminary Asymmetric Cycloisomerization Reactions
with Enynes 15 and 31a
Scheme 4. Cycloisomerization of Ester Enyne 32 and Subsequent
Decarboxylation of the Producta
a Reagents and conditions: (a) [Rh(cod)Cl]2 (0.05 equiv), (S)-BINAP
(0.11 equiv), AgSbF6 (0.20 equiv), DCE, 22 °C, 8 h.
respectively) and acid-induced desilylation proceeded smoothly,
giving prochiral substrates 31 and 32, respectively, as shown
in Scheme 2.
As we expected from the lack of literature examples, our
initial investigations into the asymmetric cycloisomerization of
terminal enyne 15 proved disappointing. Exposure of this
terminal alkyne to a mixture of [Rh(cod)Cl]2, (S)-BINAP, and
AgSbF6, as reported by Zhang and co-workers,18c-g resulted
in sluggish conversion and significant decomposition of the
starting material upon prolonged reaction times and, thus, only
a very low yield of product aldehyde (-)-14 and poor recovery
of substrate alcohol 15 (Scheme 3). Increasing the catalyst
loading did not improve the yield of (-)-14 but accelerated the
decomposition of 15. However, we were encouraged by the
observation that aldehyde (-)-14, obtained in low yield (15%)
under these conditions, was formed with excellent enantiomeric
enrichment (95% ee). We made recourse to the “capped” alkynes
described above in an effort to improve the chemical yield of
the reaction and subjected alkynyl silane 31 to the same catalyst
system (Scheme 3). Unfortunately, the expected spirocyclic
aldehyde 33 was not detected in this case, presumably due to
the steric hindrance of the TMS group.20
a Reagents and conditions: (a) [Rh(cod)Cl]2 (0.05 equiv), (S)-BINAP
(0.11 equiv), AgSbF6 (0.20 equiv), DCE, 22 °C, 1 h, 91%; (b) (CH2OTMS)2
(2.0 equiv), TMSOTf (1.0 equiv), -78 °C, 1 h, 89%; (c) 0.6 N aq LiOH
(4.0 equiv), THF, 0 °C, 2 h, 86%; (d) EDC ·HCl (1.1 equiv), 37 (1.1 equiv),
CH2Cl2, 22 °C, 2 h; (e) visible light, 65 W lamp, t-BuSH (3.0 equiv), THF/
benzene, 22 °C, 54% (2 steps); (f) 1 N aq HCl/THF (1:1), 40 °C, 20 min,
90%.
Fortunately, the ester-bearing substrate 32 proved amenable
to cycloisomerization under asymmetric conditions, as shown
in Scheme 4. Exposure of 32 to the standard rhodium catalyst
system ([Rh(cod)Cl]2, (S)-BINAP, AgSbF6) rapidly gave spi-
rocyclic ester (-)-34 in excellent yield. HPLC analysis using a
chiral stationary phase indicated that (-)-34 was formed in
greater than 95% ee.21 The sense of asymmetric induction using
the rhodium(I)-BINAP system appeared to be uniformly con-
sistent throughout the published examples,18 which span a
variety of substrate types. We were, therefore, confident that
(S)-BINAP would provide the correct absolute configuration
required for our synthesis of (-)-platensimycin [(-)-1]. This
expectation was borne out by comparison of optical rotations
at a later stage (Vide infra). The use of 32 in the successful
asymmetric cycloisomerization reaction, however, came at the
cost of removing the superfluous carboxylate moiety from
product (-)-34. This was achieved by conversion of the
potentially sensitive aldehyde group to the corresponding
ethylene glycol acetal (-)-35, followed by saponification of the
methyl ester to give carboxylic acid (+)-36, during which the
exocyclic double bond had migrated to the endocyclic position,
presumably to release some strain. Formation of the Barton ester
(reaction with reagent 37 and EDC ·HCl, Scheme 4) followed
by photolysis in the presence of t-BuSH gave deacarboxylated
compound (+)-38.22 Finally, hydrolysis of the acetal group
within (+)-38 led to the corresponding aldehyde (+)-39, as
shown in Scheme 4.
The asymmetric synthesis of aldehyde (+)-39 allowed us to
demonstrate a formal asymmetric synthesis of (-)-platensimycin
(-)-1;12b however, the requirement for a multistep decarboxy-
lation sequence amounted to an unsatisfactory overall efficiency.
Obviously, the realization of an effective asymmetric cycloi-
somerization of enyne 15 would provide the most direct means
to access the key intermediate aldehyde (-)-14.
At this point, we decided to embark on the development of
an asymmetric enyne cycloisomerization reaction using terminal
alkynes as substrates.23 Employing 1,6-enyne 40 as a substrate,
we examined a number of Rh-based complexes in order to find
the optimum catalytic system; our results are summarized in
Table 1. Thus, while the performance of [Rh(cod)(MeCN)2]BF4
(22) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc.,
Chem. Commun. 1983, 939–941. For a recent review of the use of
Barton ester in organic synthesis, see: (b) Saraiva, M. F.; Couri,
M. R. C.; Le Hyaric, M.; de Almeida, M. V. Tetrahedron 2009, 65,
3563–3572.
(20) Trost’s ruthenium catalyst ([CpRu(MeCN)3]PF6) successfully cycloi-
somerized enynes 15 and 31, giving (()-14 and (()-33 in good yields,
respectively. See Supporting Information.
(21) HPLC conditions: Chiracel OD-H, hexane/i-PrOH 94:6, 0.1 mL
min-1, tR(major) ) 32.96 min, tR(minor) ) 39.63 min; (()-34 was prepared
by the cycloisomerization of 32 using [CpRu(MeCN)3]PF6.
(23) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J. Angew. Chem.,
Int. Ed. 2009, 48, 6293–6295.
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A R T I C L E S
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Table 1. Catalyst Screening for the Asymmetric
Cycloisomerization of Terminal Enyne 40a
Table 2. Asymmetric Cycloisomerization Reactions of Terminal
Enynesa
entry
catalyst
yield of 40a (%)
ee (%)b
1
2
3
4
[Rh(cod)(MeCN)2]BF4, (S)-BINAP
[Rh(cod)Cl]2, (S)-BINAP, AgOTf
[Rh(cod)Cl]2, (S)-BINAP, AgSbF6
[Rh((S)-BINAP)]SbF6
36
60
65
86
90
91
95
>99
a Reactions were run in DCE (0.4 M) in the presence of 5-10 mol %
catalyst at 23 °C for 12-16 h. b Measured by chiral HPLC (OD-H
column) after derivatization to the corresponding p-bromobenzoate ester.
Figure 3. X-ray-derived ORTEP of p-bromophenyl carbamate 40b. Non-
hydrogen atoms are shown as 30% ellipsoids.
Scheme 5. Preparation of Crystalline p-Bromophenyl Carbamate
40ba
a Reagents and conditions: (a) NaBH4 (1.5 equiv), EtOH, 0 °C, 15 min;
(b) p-bromophenyl isocyanate (1.05 equiv), Et3N (1.05 equiv), 0 °C, 1 h,
72% over two steps.
in the presence of (S)-BINAP was rather modest (36% yield of
product 40a after 12 h at 23 °C), the product was obtained with
significant enantiomeric enrichment (90% ee, Table 1, entry 1).
The complex generated in situ by mixing [Rh(cod)Cl]2 and
AgOTf in the presence of (S)-BINAP led to a 60% yield and a
comparable ee (91% ee, Table 1, entry 2), whereas the
combination of [Rh(cod)Cl]2, AgSbF6, and (S)-BINAP employed
by Zhang et al. with internal alkynes18c-g gave 40a in 65%
yield and 95% ee (Table 1, entry 3). Finally, it was found that
24
the preformed rhodium catalyst [Rh((S)-BINAP)]SbF6 gave
the best results, furnishing product 40a in 86% yield and >99%
ee (Table 1, entry 4). The absolute configuration of product 40a
was determined by X-ray crystallographic analysis (see ORTEP,
Figure 3) of its p-bromophenyl carbamate derivative25 (40b,
mp 99-101 °C, EtOAc/hexanes 1:1, prepared as shown in
Scheme 5).
The generality and scope of this new asymmetric reaction
was examined, and the results are summarized in Tables 2 and
3. As can be seen from entries 2-10 (Table 2), the process
tolerates well all cis allylic alcohols tested as substrates (42-50,
Table 2), leading to good to excellent yields and enantiomeric
excesses of the cycloisomerized products (42a-50a, Table 2).
a Reactions were run in DCE (0.4 M) in the presence of 10 mol %
[Rh((S)-BINAP)]SbF6 at 23 °C for 12-16 h. b Measured by 1H and 19F
NMR spectroscopic analysis of the corresponding Mosher ester.
c Reaction was run in acetone as solvent. d Measured by chiral HPLC
(OD-H column) after derivatization to the corresponding p-bromo-
benzoate ester or ethylene glycol acetal.
(24) Wender, P. A.; Haustedt, L. J.; Love, J. A.; Williams, T. J.; Yoon,
J. Y. J. Am. Chem. Soc. 2006, 128, 6302–6303.
The reaction, however, performed only modestly in the case of
trans allylic alcohol 41 (Table 2, entry 1), giving aldehyde 40a
(the same product obtained from the cis allylic alcohol 40, Table
(25) CCDC-723086 contains the supplementary crystallographic data for
40b and is available free of charge from The Cambridge Crystal-
lographic Data Centre Via www.ccdc.cam.ac.uk/data_request/cif.
9
16910 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Total Synthesis of Platensimycin
A R T I C L E S
Table 3. Further Examples of Asymmetric Cycloisomerization of
Scheme 6. Asymmetric Cycloisomerization of Enyne 15 to
Varying Enyne Substratesa
Aldehyde (-)-14a
a Reagents and conditions: (a) [Rh((S)-BINAP)]SbF6 (0.05 equiv), DCE,
23 °C, 12 h, 86% yield, > 99% ee.
substituents, respectively, on the ene side chain. Finally, it was
shown that a heteroatom is not necessary in the ene side chain
for the success of the reaction, as demonstrated with substrate
55 (Table 3, entry 5).
Much to our delight, substrate 15, the precursor to platensi-
mycin [(-)-1], entered the asymmetric cycloisomerization with
5 mol % catalyst ([Rh((S)-BINAP)]SbF6) to afford the desired
spiro dienone aldehyde (-)-14 in 86% yield and >99% ee, as
shown in Scheme 6. As mentioned above, application of Zhang’s
protocol18c-g to substrate 15 led to inferior yield (15%) and
lower ee (95%) (see Scheme 3). Although we cannot pinpoint
precisely the reasons for the observed difference between the
two catalyst systems at the present time, we can, however,
speculate that the observed results may have their origins in
the fact that our catalyst24 is more well-defined than the various
species that must be present in the previously employed catalyst
system.18c-g
Asymmetric Synthesis of Aldehyde (-)-14 through a De-
aromatizing Cyclization. Alongside our efforts to develop an
asymmetric cycloisomerization route to aldehyde (-)-14, we
also investigated the alternative approach outlined retrosyn-
thetically in Figure 2 (route b). In this approach, we planned to
forge the spirocyclic ring system through a de-aromatizing
cyclization. Such processes commonly employ the combination
of a phenol with a strong electrophile, such as a protonated
diazoketone or allyl halide.12f,g,26 The oxidation of phenols in
the presence of a suitable nucleophile has been used to achieve
a similar transformation, particularly using heteroatom or
aromatic nucleophiles,27 although examples with carbon-based
nucleophiles, aside from aromatic systems, are rare.28,29 We
favored the use of an allyl silane nucleophile under oxidative
conditions due to an interest in exploring the feasibility of such
a transformation and the potential ease with which a suitable
substrate might be prepared, although misgivings remained as
a Reactions were run in acetone (0.4 M) in the presence of 10 mol %
[Rh((S)-BINAP)]SbF6 at 23 °C for 12-16 h. b Measured by chiral
HPLC (OD-H column) after derivatization to the corresponding
c
p-bromobenzoate ester. [R]D20 ) -64.3 (c ) 0.79 in CHCl3); suitable
chiral HPLC conditions could not be found. d Measured by 1H NMR
spectroscopic analysis of the corresponding Mosher ester prepared
through
sequential
dihydroxylation-cleavage,
reduction,
and
esterification. e Measured by chiral HPLC (OD-H column) after
sequential acid hydrolysis, reduction, and derivatization to the
corresponding p-bromobenzoate ester.
1) in 45% yield and 29% ee. The reaction performed well with
substrates containing a wide range of structural motifs, linking
the two reactive ends of the molecule, namely sulfonamides
(Table 2, entry 2), amides (Table 2, entries 3 and 4), 1,1-diesters
(Table 2, entries 5 and 6), 1,1-sulfones (Table 2, entry 7), bis-
aromatic moieties (Table 2, entry 8), and ether linkages (Table
2, entry 9). It was also demonstrated that amide carbonyl groups
in conjugation with either the olefin or alkyne reactive moieties
are tolerated in this process (Table 2, entries 3 and 4,
respectively). Most notable is the success of this asymmetric
reaction with the bromoacetylenic substrate 50 (Table 2, entry
10), leading to vinyl bromide 50a, a product that could be
utilized in a variety of further transformations, thus expanding
considerably the scope of the method.
(26) For selected examples, see: (a) Winstein, S.; Baird, R. J. Am. Chem.
Soc. 1957, 79, 756–757. (b) Beames, D. J.; Mander, L. N. Aust.
J. Chem. 1974, 27, 1257–1268. (c) Johnson, D. W.; Mander, L. N.;
Masters, T. J. Aust. J. Chem. 1981, 34, 1243–1252.
(27) For a review of phenolic oxidation with hypervalent iodine reagents,
see: (a) Moriarty, R. M.; Prakash, O. Org. React. 2001, 57, 327–415.
For more general reviews of the use of hypervalent iodine reagents in
synthesis, see: (b) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656–
3665. (c) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523–
2584. (d) Moriarty, R. M.; Prakash, O. Org. React. 1999, 54, 273–
418. (e) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123–
1178.
(28) For selected examples of the use of carbon nucleophiles in the oxidative
de-aromatization of phenols, see: (a) Swenton, J. S.; Callinan, A.; Chen,
Y.; Rohde, J. J.; Kearns, M. L.; Morrow, G. W. J. Org. Chem. 1996,
61, 1267–1274. (b) Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney,
M. A. Tetrahedron 2001, 57, 319–329. (c) Lebrasseur, N.; Fan, G.-J.;
Oxoby, M.; Looney, M. A.; Quideau, S. Tetrahedron 2005, 61, 1551–
1562. (d) Honda, T.; Shigehisa, H. Org. Lett. 2006, 8, 657–659. (e)
Shigehisa, H.; Takayama, J.; Honda, T. Tetrahedron Lett. 2006, 47,
7301–7306.
Table 3 depicts a number of experiments undertaken in order
to explore further aspects of the asymmetric cycloisomerization.
Thus, TBS ether 51 and allylic acetate 52 (Table 3, entries 1
and 2, respectively) entered the reaction successfully to afford
enol ether 51a and vinyl acetate 52a, respectively, in high yield
and ee, whereas entries 3 (substrate 53) and 4 (substrate 54)
demonstrate that the reaction tolerates sulfur and nitrogen
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16911

A R T I C L E S
Nicolaou et al.
Thus, known carboxylic acid 5630 was coupled with (S,S)-
pseudoephedrine 57 to give amide (-)-20 in quantitive yield.
Alkylation according to Myers’s procedure31 with benzylic bromide
5832 gave amide (-)-59 in excellent yield, albeit with rather low
selectivity (crude de ∼85%) when compared with literature
examples. However, a single recrystallization of the crude product
provided (-)-59 as a single diastereoisomer in 75% yield. Cleavage
of the auxiliary group from (-)-59 with methyllithium then
provided methyl ketone (-)-19 in excellent yield with enantiomeric
excess of >98%.33 Treatment of ketone (-)-19 with KHMDS and
Comins reagent (60) gave enol triflate (-)-61 in excellent yield,
although the efficiency of this reaction was highly dependent on
the quality of the Comins reagent used. Kumada coupling of (-)-
61 with (trimethylsilyl)methyl Grignard reagent [2.5 mol %
Pd(PPh3)4, LiCl] and selective desilylation of the phenol under basic
conditions (NaOH) furnished de-aromatization substrate (-)-18 in
excellent overall yield.
Scheme 7. Synthesis of Aldehyde (-)-14 through Oxidative
De-aromatizationa
A wide range of conditions were screened for the proposed
oxidative cyclization reaction of (-)-18, some of which are
summarized in Table 4. Iodine(III) reagents were quickly deter-
mined to be the most effective promoters, with PhI(OAc)2,
PhI(O2CCF3)2, and PhIO all giving the desired spirocyclic product
(-)-62 in low to moderate yield under a variety of solvent and
temperature conditions. Non-nucleophilic polar solvents proved the
most effective media for this reaction, as might be expected for
this type of transformation.34 The combinations of the milder
reagent PhI(OAc)2 and either 2,2,2-trifluoroethanol (TFE) or
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) were equally effective,
with the former solvent favored on the basis of cost (entry 4, Table
4). Under the optimized conditions, phenolic allyl silane (-)-18
was converted to (-)-62 in 68% yield, as shown in Scheme 7.
Removal of the acetal protecting group from this intermediate
revealed aldehyde (-)-14 in high yield.
The de-aromatization reaction is presumed to proceed through
an initial interaction of the iodine reagent with the phenol, followed
by oxidation of the aromatic ring and either concomitant or stepwise
addition of the nucleophile. Such a mechanism is in accordance
with the accepted reactivity of phenols with iodine(III) reagents27
and with the results of Quideau mentioned above.28b,c Although
a Reagents and conditions: (a) 56 (1.3 equiv), PivCl (1.3 equiv), Et3N
(3.0 equiv), MeCN, 0 °C, 1 h; then 57 (1.0 equiv), Et3N (1.0 equiv), THF,
30 min, 100%; (b) LDA (2.1 equiv), LiCl (7.0 equiv), 58 (1.3 equiv), -78
f 0 °C, 1.5 h, 87%; (c) MeLi (1.36 M in Et2O, 4.0 equiv), THF, -78 f
-22 °C, 40 min, 91%; (d) KHMDS (0.5 M in toluene, 2.5 equiv), 60 (2.5
equiv), THF, -78 f 0 °C, 1 h, 92%; (e) TMSCH2MgCl (1.1 M in THF,
3.0 equiv), LiCl (3.0 equiv), Pd(PPh3)4 (2.5 mol %), THF, 22 °C, 30 min,
97%; (f) NaOH (2.5% w/v in MeOH), 0 f 22 °C, 2 h, 100%; (g) PhI(OAc)2
(1.2 equiv), TFE, -10 °C, 20 min, 68%; (h) 1 N aq HCl/THF (1:1), 40 °C,
3 h, 90%.
(29) The Kita group has employed aminoquinones in similar reactions;
however, these processes may operate by oxidation of the amino group
to provide an active electrophile, which reacts with a protected phenol
nucleophile; see, for example: (a) Kita, Y.; Yakura, T.; Tohma, H.;
Kikuchi, K.; Tamura, Y. Tetrahedron Lett. 1989, 30, 1119–1120. (b)
Kita, Y.; Tohma, H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am.
Chem. Soc. 1992, 114, 2175–2180. (c) Kita, Y.; Arisawa, M.; Gyoten,
M.; Nakajima, M.; Hamada, R.; Tohma, H.; Takada, T. J. Org. Chem.
1998, 63, 6625–6633. (d) Tohma, H.; Harayama, Y.; Hashizume, M.;
Iwata, M.; Kiyono, Y.; Egi, M.; Kita, Y. J. Am. Chem. Soc. 2003,
125, 11235–11240.
to the success of the key step. Allyl silane nucleophiles had
been employed only rarely in oxidative additions to phenols.
Quideau and co-workers have reported the intermolecular
addition of allyl trimethyl silane to naphthols mediated by
iodine(III) reagents; however, they observed that good yields
were obtained only when the phenolic partner was pretreated
with the oxidant followed by addition of the silane, suggesting
an incompatibility between allyl silanes and iodine(III)
oxidants.28b
As indicated in Figure 2, we adopted a plan which called for
the installation of the stereogenic center found within key aldehyde
14 prior to the de-aromatizing cyclization. As expected, the
substrate for the cyclization was prepared in a straightforward
manner using Myers’s asymmetric alkylation protocol (Scheme 7).
(30) Shea, K. J.; Wada, E. J. Am. Chem. Soc. 1982, 104, 5715–5719.
(31) (a) Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem.
Soc. 1997, 119, 656–673. (b) Myers, A. G.; Gleason, J. L.; Yoon, T.
J. Am. Chem. Soc. 1995, 117, 8488–8489. (c) Myers, A. G.; Yang,
B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L. J. Am.
Chem. Soc. 1997, 119, 6496–6511.
(32) Olszewski, J. D.; Marshalla, M.; Sabat, M.; Sundberg, R. J. J. Org.
Chem. 1994, 59, 4285–4296.
(33) HPLC conditions: Chiralpak AD, hexane/i-PrOH 98:2, 0.1 mL
min-1, tR(minor) ) 22.05 min, tR(major) ) 24.55 min; a pseudo-racemate
of 18 was obtained through the same sequence of reactions using a
1:1 mixture of (R,R)- and (S,S)-pseudoephedrine in the acylation step.
(34) For selected examples of the use of TFE as solvent in the oxidative
de-aromatization of phenols, particularly in natural product synthesis,
see: (a) Node, M.; Kodama, S.; Hamashima, Y.; Baba, T.; Hamamichi,
N.; Nishide, K. Angew. Chem., Int. Ed. 2001, 40, 3060–3062. (b)
Kodama, S.; Hamashima, Y.; Nishide, K.; Node, M. Angew. Chem.,
Int. Ed. 2004, 43, 2659–2661.
9
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Total Synthesis of Platensimycin
A R T I C L E S
Scheme 8. Further Oxidative Cyclizations of Phenolic Allyl Silanes
Scheme 9. Cyclization of Aldehyde (-)-14 via Cyanohydrin
to Spiro Systemsa
Formationa
a Reagents and conditions: (a) TMSCN (1.2 equiv), Et3N (0.2 equiv),
CH2Cl2, 22 °C, 1 h; 1 N aq HCl, 22 °C, 3 h; (b) ethyl vinyl ether/CH2Cl2
(1:3), PPTS (0.1 equiv), 0 °C, 5 h, 99% (two steps, mixture of four
diastereoisomers, ca. 1:1:1:1); (c) KHMDS (0.5 M in toluene, 1.5 equiv),
THF, 0 °C, 10 min, 86% (ca. 1:1 mixture of diastereoisomers); (d) 1 N aq
HCl/THF (1:1), 0 °C, 30 min; 2 N aq NaOH, 0 °C, 30 min, 89%; (e)
DIBAL-H (1.0 M in hexanes, 2.4 equiv, -78 °C, 1 h; (f) MnO2 (5.0 equiv),
EtOAc, 8 h, 82% (two steps, 13a:13b ca. 1:5).
a Reagents and conditions: (a) PhI(OAc)2 (1.2 equiv), TFE, -10 °C, 20
min.
Table 4. Optimization of the De-aromatization Reaction of Phenol
(-)-18 To Afford Spiro Hemiquinone (-)-62 (Scheme 7)a
(see Scheme 9). Our initial investigations focused on ionic
processes such as the nucleophilic carbene-catalyzed Stetter
reaction. However, treatment of (-)-14 with several hetereo-
cyclic carbene species reported to promote the Stetter reaction36
gave no tricyclic products. We attributed this failure to the strain
involved in forming the norbornane motif of the targeted
tricyclic structure. In an alternative approach from these
laboratories,12d it proved possible to forge the C9-C10 bond
using a Stetter reaction36 to form a decalin system lacking the
bridging ring, which was installed later. In an effort to increase
the reactivity of substrates along similar lines, we prepared the
TMS cyanohydrin of (-)-14 (structure not shown) and attempted
to induce cyclization through treatment with a strong base.
Again, the results were disappointing, and recourse was made
to the ethoxyethyl (EE)-protected cyanohydrin (-)-66, prepared
in excellent yield from (-)-14 through standard chemistry, as
shown in Scheme 9. In this case, treatment of (-)-66 with
KHMDS at 0 °C led to rapid cyclization to form tricyclic
product (-)-67 in high yield (86%). The stereocenters at C9
and C10 were both formed as shown with complete control,
although the product remained a mixture of two diastereoisomers
due to the stereocenter within the EE group. The cyanohydrin
moiety could be removed in one step by sequential treatment
with aqueous acid and base to give diketone (+)-68 in 89%
yield. The stereochemistry at C9, predicted on the basis of
geometric considerations in the 1,4-addition reaction, was
confirmed at this stage by NOE studies. Reduction of (+)-68
entry
oxidant
solvent
temp (°C)
yield of (-)-62 (%)b
1
2
3
4
5
PhI(OAc)2
PhI(O2CCF3)2
PhIO
PhI(OAc)2
PhI(OAc)2
MeCN
TFE
TFE
TFE
HFIP
0
0
-10
-10
-10
10
49
26
68
65
a Reactions were carried out at 0.030 M at the indicated temperature
under an argon atmosphere. b Yield of (-)-62 isolated by aqueous
workup, followed by flash column chromatography.
we have not identified and characterized any of the byproduct
formed from the reactions of (-)-18, we observed that when the
TBS ether of (-)-18 was treated with PhI(OAc)2 in TFE it
underwent rapid proto-desilylation. This result, while not involving
an oxidation reaction, indicates that the allyl silane group is indeed
reactive under the reaction conditions. On the basis of this
observation, we assume that at least some of the byproduct
generated under the de-aromatization conditions employed may
come through this parallel pathway.
The de-aromatization reaction of phenolic allyl silanes was
investigated further using several simpler substrates (Scheme
8). In each case, treatment of the phenol with the iodine(III)
reagent led to cyclization to give the products shown, suggesting
considerable generality of this process for the formation of
spirocyclic systems. As shown, both branched and linear allyl
silanes participated in this process satisfactorily. Canesi and co-
workers have recently reported similar reactivity involving both
allyl silane and enol ether nucleophiles in iodine(III)-mediated
reactions of phenols to generate a variety of products, including
(()-aspidospermidine.35
(35) (a) Be´rard, D.; Alexandre, J.; Canesi, S. Tetrahedron Lett. 2007, 48,
8238–8241. (b) Be´rard, D.; Racicot, L.; Sabot, C.; Canesi, S. Synlett
2008, 1076–1080. (c) Be´rard, D.; Giroux, M.-A.; Racicot, L.; Sabot,
C.; Canesi, S. Tetrahedron 2008, 64, 7537–7544. (d) Sabot, C.;
Commare, B.; Duceppe, M.-A.; Nahi, S.; Gue´rard, K. C.; Canesi, S.
Synlett 2008, 3226–3230. (e) Sabot, C.; Gue´rard, K. C.; Canesi, S.
Chem. Commun. 2009, 2941–2943.
Completion of the Synthesis of Platensimycin Core Struc-
ture (-)-12. Having secured access to aldehyde 14, in both its
racemic and enantioenriched forms, we began exploring the
possibility of converting it to the next intermediate, such as
tricyclic species 13, through formation of the C9-C10 bond
(36) For a selected review, see: Enders, D.; Niemeier, O.; Henseler, A.
Chem. ReV. 2007, 107, 5606–5655.
9
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A R T I C L E S
Nicolaou et al.
Table 5. Samarium Diiodide-Mediated Cyclization of Aldehyde
(()-14a
Scheme 10. Etherification Reactions of Hydroxy Olefin 13a/13ba
(()-13a/13b
(()-13a:13b
entry
conditions
yield (%)b
ratioc
a Reagents and conditions: (a) PhSeCl (1.5 equiv), K2CO3 (5.0 equiv),
CH2Cl2, -78 °C, 15 min, 98% [plus recovered (+)-13b]; (b) AIBN (0.2
equiv), n-Bu3SnH (5.0 equiv), toluene, 100 °C, 2 h, 85%; (c) TFA/CH2Cl2
(2:1), 0 °C, 1.5 h, 87% [plus recovered (+)-13b]; (d) TfOH (1.5 equiv),
CH2Cl2, -78 °C, 1 h, 90% [plus recovered (+)-13b and iso-13b with
endocyclic olefin bond]. Yields of steps a, c, and d are based on 13a
contained within the mixture of 13a:13b (ca. 2.2:1).
d
1
2
SmI2 (2.2 equiv), 0 °C, 15 min
-
-
0
d
SmI2 (2.2 equiv), HMPA
(10 equiv), 0 °C, 15 min
SmI2 (2.2 equiv), MeOH
(1.5 equiv), 0 °C, 15 min
SmI2 (2.2 equiv), HMPA
(10 equiv), MeOH (1.5 equiv),
-78 °C, 0.5 min
0
d
3
4
-
0
30
2:1
5
SmI2 (2.2 equiV), HMPA
(10 equiV), HFIP (1.5 equiV),
-78 °C, 0.5 min
51
2.2:1
isomer (()-13a. Notably, the best results were obtained when
the samarium reagent was added very rapidly, suggesting that
the mixing rate is important. The mixing rate was especially
crucial in preparative-scale experiments. This result, although
to some extent disappointing, allowed for the preparation of
sufficient quantities of 13a for further studies [the samarium
diiodide-induced ring closure (entry 5, Table 5) was also carried
out with (-)-14 to afford (-)-13a/(+)-13b38]. Other reagents
for the preparation of ketyl radical intermediates,39 for example,
titanium(III) species, AIBN/n-Bu3SnH, and Et3B/O2/n-Bu3SnH,
were investigated for this transformation (14 f 13a/13b)
without success.
The final bond construction required to complete the platen-
simycin cage-like structural motif was etherification between
the alcohol group at C10 (i.e., O16) and C15 (see Scheme 10).
Treatment of a mixture of (-)-13a and (+)-13b [obtained from
samarium diiodide-mediated cyclization with (-)-14] with
PhSeCl in the presence of K2CO340 at low temperature resulted
in the smooth and rapid etherification of the major component
(-)-13a, confirming its stereochemistry and providing C17-
selenated platensimycin cage structure (+)-69, which underwent
AIBN-induced radical reduction to give deselenated compound
(-)-12. We were encouraged by the ease with which the
proposed etherification reaction occurred, and we subsequently
discovered that exposure of the mixture of (-)-13a and (+)-
13b to either TFA (excess) at 0 °C or triflic acid (1.5 equiv) at
-78 °C was sufficient to induce cyclization, forming cage
structure (-)-12 in excellent yield (based on the proportion of
(-)-13a in the mixture of diastereomers, Scheme 10). This
finding made our two-step selenation-based route to (-)-12
unnecessary. Interestingly, alcohol (+)-13b was recovered
unchanged from the reactions with PhSeCl and TFA, while upon
the treatment with triflic acid its exocyclic double bond partially
migrated to the endocyclic position (structure not shown). A
sample of (-)-12 crystallized from CDCl3/CH2Cl2 to give
colorless needles (mp 65-67 °C) suitable for X-ray crystal-
a Reactions were carried out at 0.025 M in THF at the indicated
temperatures under an argon atmosphere, using thoroughly degassed
solvents and additives. b Yield of a pure mixture of (()-13a/13b isolated
by aqueous workup followed by flash silica column chromatography.
c Determined by 1H NMR spectroscopic analysis of the inseparable
mixture of (()-13a/13b after purification. d Complete consumption of
(()-14 with no identifiable products.
with DIBAL-H gave a diol, which could be oxidized selectively
with MnO2 to furnish alcohols 13a and 13b as a mixture of
inseparable diastereoisomers (13a:13b ca. 1:5). Unfortunately,
the major isomer (13b) was found to be the undesired
compound, as determined by the ability of only the minor isomer
(13a) to engage its exocyclic olefin in a ring-forming reaction
(Vide infra). Despite screening a range of reductants, we were
not able to improve the ratio of these products. Additionally,
alcohol 13b was found to be resistant to inversion, with
Mitsonobu conditions giving no reaction and displacement of
the corresponding mesylate or triflate proving fruitless.
In parallel with the studies outlined above, we also investi-
gated the potential of a samarium diiodide-mediated ketyl radical
cyclization as a means to convert (()-14 to (()-13a/13b. Such
a process has the advantage of giving (()-13a/13b directly in
a single step.37 Additionally, the inherent stereochemical bias
of these processes would be expected to favor the selective
formation of the desired stereoisomer (()-13a. Initial attempts
to cyclize (()-14 were uniformly unsuccessful, despite a range
of conditions being applied (Table 5). Optimization efforts were
hampered by a lack of identifiable byproduct. Small quantities
of (()-13a/13b (ca. 2:1 ratio) were isolated from a reaction
employing HMPA and MeOH at low temperature (entry 4). This
reaction was further optimized to provide a 2.2:1 mixture of
(()-13a and (()-13b in up to 51% yield (entry 5). In this case,
the major component in the reaction mixture was the desired
(37) For selected reviews of the use of SmI2 in organic synthesis, see: (a)
Molander, G. A. Chem. ReV. 1992, 92, 29–68. (b) Molander, G. A.
Org. React. 1994, 46, 211–367. (c) Molander, G. A.; Harris, C. R.
Chem. ReV. 1996, 96, 307–338. (d) Molander, G. A.; Harris, C. R.
Tetrahedron 1998, 54, 3321–3354. (e) Kagan, H. B.; Namy, J.-L.
Lanthanides: Chemistry and Use in Organic Synthesis: Kobayashi,
S., Ed.; Springer: Berlin, 1999; pp155-198. (f) Kagan, H. B.
Tetrahedron 2003, 59, 10351–10372. (g) Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. ReV. 2004, 104, 3372–3404. (h) Nicolaou,
K. C.; Ellery, S. P.; Chen, J. S. Angew. Chem., Int. Ed. 2009, 48,
7140–7165.
(38) Pure tricyclic hydroxy olefin (-)-13a was obtained through reaction
of the (-)-13a:(+)-13b mixture with TBSCl and imidazole in DMF,
which led to selective silylation of the undesired diastereomer [(+)-
13b] due to steric reasons. See Supporting Information for further
details.
(39) For a review of radical conjugate additions, see: Srikanth, G. S. C.;
Castle, S. L. Tetrahedron 2005, 61, 10377–10441.
(40) (a) Nicolaou, K. C.; Lysenko, Z. J. Am. Chem. Soc. 1977, 99, 3185–
3187. (b) Nicolaou, K. C.; Lysenko, Z. Tetrahedron Lett. 1977, 18,
1257–1260.
9
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Total Synthesis of Platensimycin
A R T I C L E S
Scheme 12. Attempted Formation of (-)-12 via Cyano Cage
Compound (+)-71a
Figure 4. X-ray-derived ORTEP of (-)-12. Non-hydrogen atoms are shown
a Reagents and conditions: (a) 1 N aq HCl/THF (1:1), 0 °C, 30 min; (b)
TFA, 0 f 22 °C, 2 h, 81% (two steps); (c) LiHMDS (1.0 M in THF, 1.1
equiv), -78 °C, 15 min; LDBB (1.0 M in THF, 5 equiv), -78 °C, 2 h.
as 30% ellipsoids.
Scheme 11. Conversion of Endocyclic Aldehyde (+)-39 to Cage
Compound (-)-12a
Scheme 13. Installation and Initial Manipulation of the Side Chaina
a Reagents and conditions: (a) SmI2 (0.1 M in THF, 2.2 equiv), HFIP
(1.5 equiv), THF/HMPA (10:1), -78 °C, 0.5 min; (b) TFA/CH2Cl2 (2:1),
0 °C, 1.5 h, 36% (two steps).
lographic analysis.41 The X-ray-derived ORTEP of (-)-12 is
shown in Figure 4.
Endocyclic aldehyde (+)-39 was also investigated as a
substrate for the samarium(II)-mediated cyclization/acid-induced
etherification sequence. The successful cyclization of this
substrate was essential to our early asymmetric synthesis efforts,
to ensure that the cycloisomerization of ester-capped alkyne 32
would lead to a total synthesis of platensimycin [(-)-1]. As
shown in Scheme 11, aldehyde (+)-39 proved to be a viable
substrate for the ketyl olefin cyclization reaction, leading to
alcohol 70 as a single diastereoisomer (1H NMR spectroscopic
analysis). Treatment of 70 with TFA resulted in clean conversion
(36% yield for two steps) to cage structure (-)-12, confirming
the stereochemistry of 70 and completing the formal asymmetric
total synthesis of platensimycin [(-)-1]. The dependency of the
stereochemical outcome of the samarium(II)-mediated cycliza-
tions on subtle differences in substrate structure is intriguing
and points to the sensitivity of the reaction to the precise
structure and conformation of the spirocyclic substrate.
The configuration at C10 of cyanohydrin cyclization product
(-)-67 is correct with respect to the orientation of the masked
hydroxyl group, and we sought to exploit this in an alternative
route to the platensimycin cage structure [(-)-12]. Thus,
hydrolysis of the ethoxyethyl ethyl (EE) group with aqueous
acid followed by etherification of the resulting product with TFA
(0 °C) gave C10-cyano cage compound (+)-71 in high yield
(81% for two steps), as shown in Scheme 12. Attempts to cleave
the undesired carbon-carbon bond by treatment of the lithium
anion of (+)-71 with LDBB42 failed to provide (-)-12 (Scheme
12). Although the cyanohydrin addition route did not provide
an efficient means to access the cage structure of platensimycin,
it did provide access to the bioactive analogue carbaplatensimy-
cin13b,c and may potentially lead to other analogues with
chemical modification on the cage, such as C10-cyano
platensimycin.
a Reagents and conditions: (a) KHMDS (0.5 M in toluene, 1.5 equiv),
MeI (4.0 equiv), THF/HMPA (5:1), -78 f -10 °C, 2 h, 95%; (b) KHMDS
(0.5 M in toluene, 2.0 equiv), allyl iodide (4.0 equiv), THF/HMPA (5:1),
-78 f -10 °C, 2 h, 83%; (c) BH3 ·THF (1.0 M in THF, 2.5 equiv), THF,
-78 °C, 20 min; (d) Dess-Martin periodinane (4.0 equiv), CH2Cl2, 22 °C,
1 h, 16% (two steps).
Completion of the Total Syntheses of Platensimycin and
Related Natural Products. With a viable route to the core
structure (12) of platensimycin in hand, we turned our attention
to the installation of the side chain and completion of the total
synthesis. Enone 12 could be methylated in excellent yield by
exposure to KHMDS followed by addition of MeI in a
THF-HMPA mixture (Scheme 13). The methyl group was
introduced with almost complete stereoselectivity, giving 72 as
1
essentially a single diastereoisomer, as judged by H NMR
spectroscopic analysis. A second alkylation was then investi-
gated using various electrophiles. As might be expected, the
enolate of 72 was found to be rather unreactive, and all attempts
to install a side chain using 3-oxygenated propyl iodides (e.g.,
73 or 74) failed. Treatment of the potassium enolate of 72 with
bromide 75 rapidly transferred the ester group to the enolate
oxygen of the substrate to form the corresponding enol
carbonate. However, this enolate did react with allyl bromide
to provide the desired allylated compound 76 along with
significant quantities of the O-allylated product. Recourse to
allyl iodide overcame this complication, giving 76 in good yield
(83%) and, again, essentially as a single diastereoisomer,
verifying our retrosynthetic hypothesis. The conversion of 76
into platensic acid (2) was also problematic at first. The allyl
side chain was not reactive toward bulky hydroboration reagents;
treatment with BH3 ·THF led to hydroboration of the allyl group
with concomitant reduction of the enone carbonyl moiety,
allowing isolation of diol 77 in low yield, along with several
byproducts. Oxidation of 77 with DMP then furnished aldehyde
78 in low overall yield from 76 (steps a and b were carried out
(41) CCDC-739776 contains the supplementary crystallographic data for
(-)-12 and is available free of charge from The Cambridge Crystal-
lographic Data Centre Via www.ccdc.cam.ac.uk/data_request/cif.
(42) (a) Rychnovsky, S. D.; Hoye, R. C. J. Am. Chem. Soc. 1994, 116,
1753–1765. (b) Sinz, C. J.; Rychnovsky, S. D. Angew. Chem., Int.
Ed. 2001, 40, 3224–3227.
9
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A R T I C L E S
Nicolaou et al.
Scheme 14. Synthesis of Platensic Acid [(()-2 and (-)-2] and
Methyl Platensinoate [(()-3 and (-)-3] via Cross-Metathesisa
Scheme 15. Synthesis of Platensic Acid [(-)-2] via Michael
Additiona
a Reagents and conditions: (a) tert-butyl acrylate (3.0 equiv), t-BuOK
(1.0 M in t-BuOH, 2.0 equiv), THF, -10 °C, 1 h, 84%; (b) TFA/CH2Cl2
(1:1), 0 °C, 12 h, 100%.
Scheme 16. Preparation of Aniline Derivatives 84, 86, and 89a
a Reagents and conditions: (a) 79 (6.0 equiv), 80 (25 mol %) or 81 (10
mol %), CH2Cl2, 40 °C, 6 h, 81%, ca. 6:1 E:Z; b) Me3NO (5.0 equiv),
THF, 70 °C, 2 h, 88%; c) NaClO2 (3.0 equiv), 2-methyl-2-butene (10 equiv),
NaH2PO4 (5.0 equiv), t-BuOH:H2O (1:1), 22 °C, 15 min, 95%; d)
TMSCHN2 (2.0 M in hexanes, 5.0 equiv), MeOH, 0 °C, 30 min, 100%.
a Reagents and conditions: (a) MOMCl (2.2 equiv), i-Pr2NEt (3.0 equiv),
DMF, 0 f 22 °C, 1.5 h, 98%; (b) H2 (balloon), 10% Pd/C (0.1 equiv),
EtOAc, 22 °C, 1 h, 99% for 86, 99% for 89; (c) Boc2O (3.0 equiv), 40 °C,
4 h, 100%; (d) n-BuLi (2.2 M in pentane, 1.0 equiv), TMSCl (1.0 equiv),
-78 °C, 15 min; then n-BuLi (2.2 M in pentane, 1.2 equiv), methyl
cyanoformate (1.2 equiv), THF, -78 °C, 30 min; then 1 N aq HCl, 22 °C,
30 min, 68%; (e) 1,2-dichlorobenzene, 205 °C, microwaves, 7 min, 83%;
(f) 28% aq NH4OH, 50 °C, 12 h, 42% (two steps).
with both racemic and enantiopure materials; steps c and d were
carried out only with racemic compounds).
Fortunately, the allyl side chain of 76 was amenable to
selective cross-metathesis, and this provided a mild method for
the required oxidation (Scheme 14). Thus, cross-metathesis of
76 with vinyl pinacol boronate (79)43 using Grubbs’s second-
generation initiator 8044 (25 mol %) gave olefinic boronate 82
in good yield (81%) as an inconsequential mixture of isomers
(E:Z ca. 6:1). The use of the Hoveyda-Grubbs second-
generation initiator 8145 gave similar results (81% yield) with
much lower catalyst loading (10 mol %). Oxidation of the
olefinic boronate 82 was accomplished by heating with trim-
ethylamine-N-oxide,46 to give aldehyde 78 in much higher
overall yield than the hydroboration route described above. This
two-step conversion of allyl groups to aldehydes was first
employed by Danishefsky et al. in connection with their work
on epothilone analogues47 and has subsequently proved ap-
plicable to a range of platensimycin analogues.13a-c Further
oxidation of 78 gave platensic acid [(()-2 and (-)-2] in high
yield,48 treatment of which with TMS-diazomethane gave
methyl platensinoate [(()-3 and (-)-3] in quantitative yield,
as shown in Scheme 14. The latter compound is also naturally
occurring.10a
Recently, Corey and Yeung reported the synthesis of a platen-
simycin analogue in which the propionate side chain was installed
using the more direct method of 1,4-addition to methyl acrylate.13d
Although we had investigated such a reaction initially with little
success, these recent results prompted us to re-investigate this
transformation. Under Corey’s conditions (methyl acrylate, t-
BuOK, THF/t-BuOH) we found that methylated cage intermediate
(-)-72 was transformed into methyl platensinoate (3) directly;
however, the yield of this transformation was modest, and the
desired compound was isolated along with several byproducts. This
situation was improved by switching to tert-butyl acrylate (Scheme
15), which allowed direct formation of tert-butyl platensinoate (-)-
83 in high yield (84%). tert-Butyl ester (-)-83 could be cleaved
quantitatively by treatment with TFA to give platensic acid [(-)-
2]. This is now the preferred method for the conversion of (-)-72
to (-)-2.
For the completion of platensimycin (1) from platensic acid (2),
we required a suitably substituted aniline coupling partner. We
chose to prepare aniline derivative 84 in the first instance, in which
the carboxylic acid is protected as the methyl ester and the phenols
are masked as MOM ethers. The choice of protecting groups was
influenced by their ease of removal and by synthetic considerations.
We prepared 84 from 2-nitroresorcinol (85, Scheme 16), a
convenient and inexpensive starting material that incorporates three
of the necessary substituents. MOM ether formation (MOMCl,
(43) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031–6034.
(44) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (b) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm,
T. E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 2546–2558.
(45) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791–799. (b) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179. (c) For a short review on these catalysts, see:
Hoveyda, A. H.; Gillingham, D. G.; Van Veldhuizen, J. J.; Kataoka,
O.; Garber, S. B.; Kingsbury, J. S.; Harrity, J. P. A. Org. Biomol.
Chem. 2004, 2, 1–16.
(46) Kabalka, G. W.; Hedgecock, H. C., Jr. J. Org. Chem. 1975, 40, 1776–
1779.
(47) Njardarson, J. T.; Biswas, K.; Danishefsky, S. J. Chem. Commun. 2002,
2759–2761.
(48) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
9
16916 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Total Synthesis of Platensimycin
A R T I C L E S
Scheme 17. Completion of the Asymmetric Total Synthesis of
Platensimycin [(-)-1]a
Scheme 18. Total Syntheses of Platensimycins B1 [(-)-7] and B3
[(-)-9]a
a Reagents and conditions: (a) (-)-2 (1.0 equiv), 89 (4.0 equiv), HATU
(2.0 equiv), Et3N (5.0 equiv), DMF, 22 °C, 12 h, 81%; (b) (-)-2 (1.0 equiv),
86 (3.0 equiv), HATU (2.0 equiv), Et3N (5.0 equiv), DMF, 22 °C, 12 h; (c)
1 N aq HCl/THF (1:1), 40 °C, 4 h, 85% (two steps).
Furthermore, platensimycins B1 [(-)-7] and B3 [(-)-9] were
efficiently synthesized in a similar manner from platensic acid [(-)-
2] and anilines 89 and 86, respectively, as shown in Scheme 18.
Notably, aniline 89, with two free hydroxyl groups, showed good
reactivity and stability under these amide-forming coupling condi-
tions, ensuring that platensimycin B1 [(-)-7] could be formed
directly in one step. However, the protecting-group-free version
of aniline 86 was not stable enough for handling, presumably due
to the lack of an electron-withdrawing functional group on the
aromatic ring. A two-step sequence was, therefore, necessary to
synthesize platensimycin B3 [(-)-9], as shown in Scheme 18. Thus,
coupling of bis-MOM-protected aniline 86 with platensic acid [(-)-
2] under the HATU-Et3N conditions, followed by removal of the
MOM groups from the resulting product under acidic conditions,
led to platensimycin B3 [(-)-9] in 85% overall yield. The physical
properties of both synthetic platensimycins B1 [(-)-7] and B3 [(-)-
9] matched those reported in the literature for the naturally derived
materials.10c
Naturally occurring platensimide A [(-)-4] consists of
platensic acid [(-)-2] coupled to (S)-N4-acetyl-2,4-diaminobu-
tyrate in place of the aniline component of platensimycin. Singh
et al. accomplished a semisynthesis of platensimide A [(-)-4]
from naturally occurring platensic acid [(-)-2] as part of their
isolation studies.10a They coupled platensic acid with mono-
Boc-protected methyl diaminobutyrate and subsequently in-
stalled the acetamide group. Within the context of a total
synthesis (i.e., using synthetic platensic acid), we hoped to
complete a more convergent route in which the acetamide was
already in place. To this end, we prepared amine (+)-91 from
Cbz-glutamine tert-butyl ester 92 (Scheme 19). Hoffmann
degradation of 92 was carried out according to the literature
procedure [PhI(O2CCF3)2];50 however, rather than isolating the
amine product, the latter was converted in situ to its acetamide
derivative (-)-93 with Ac2O (70% overall yield), which served
the dual role of saving one step and facilitating isolation.
Hydrogenolysis of the Cbz group from (-)-93 then gave amine
(+)-91 in 92% yield (Scheme 19). Coupling of (+)-91 with
the activated ester generated from platensic acid [(-)-2] and
a Reagents and conditions: (a) (-)-2 (1.0 equiv), 84 (4.0 equiv), HATU
(2.0 equiv), Et3N (4.0 equiv), DMF, 22 °C, 12 h, 86%; (b) 2.0 M aq LiOH/
THF(1:1), 45 °C, 2 h; then 2.0 M aq HCl, 45 °C, 10 h, 86%.
i-Pr2NEt) followed by hydrogenation of the nitro group (Pd/C, H2)
gave aniline derivative 86 in excellent yield, which later served as
a coupling partner for the synthesis of platensimycin B3 [(-)-9].
Boc protection of 86 (Boc2O, neat) gave the corresponding
carbamate in quantitative yield. Generation of the dilithio species
by treatment with 2.2 equiv of n-BuLi, followed by addition of
Mander’s reagent [MeOC(O)CN], did give the desired product (87);
however, yields were low due in part to incomplete ortho-lithiation
even at 5 °C, resulting in the generation of N-acylated byproduct.
This problem was overcome by in situ protection of the carbamate
anion with 1 equiv of TMSCl, followed by addition of a second
equivalent of n-BuLi to effect ortho-lithiation. Addition of Mander’s
reagent followed by mildly acidic workup then gave the desired
ester 87 in good yield. Removal of the Boc protecting group was
also problematic, with even 0.1% TFA in CH2Cl2 causing rapid
decomposition of 87. Fortunately, thermolysis of the Boc group
was clean; heating 87 in 1,2-dichlorobenzene at 205 °C for 7 min
gave aniline 84 in 83% yield. Shortly after us, Giannis et al.
reported another efficient synthesis of 84, employing ester 88 as a
key intermediate.49 Taking advantage of 88, we readily prepared
aniline 89, a coupling partner required for the platensimycin B1
synthesis, through ammonolysis with aqueous ammonium hydrox-
ide, followed by hydrogenation of the nitro group as described
above (see Scheme 16).
The coupling of platensic acid (2) with aniline derivative 84
was carried out by treatment with HATU and Et3N in DMF,
providing amide 90 in 86% yield (Scheme 17). Deprotection
of 90 was achieved through a one-pot procedure involving
methyl ester hydrolysis (aqueous LiOH in THF, 45 °C) followed
by MOM cleavage (addition of aqueous HCl and continued
heating at 45 °C), providing platensimycin (1) in high overall
yield. Both racemic and enantioenriched platensimycins were
prepared starting with (()-14 and enantioenriched (-)-14.
Enantioenriched platensimycin [(-)-1] was identical in every
respect to a reference sample of the natural material.6
(50) Hoffmann, M.; Burkhart, F.; Hessler, G.; Kessler, H. HelV. Chim. Acta
1996, 79, 1519–1532.
(49) Heretsch, P.; Giannis, A. Synthesis 2007, 2614–2616.
9
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A R T I C L E S
Nicolaou et al.
Scheme 19. Asymmetric Total Synthesis of Platensimide A [(-)-4]a
yield) and coupling of the crude product with glutamine tert-
butyl ester [(+)-98, obtained by hydrogenolysis of its Cbz
derivative 92] under the HOBt/EDC ·HCl conditions gave
homoplatensimide A tert-butyl ester [(-)-99] in 82% yield. Ester
hydrolysis of the latter compound with TFA was again suc-
cessful in revealing homoplatensimide A [(-)-5], which dis-
played physical properties in accord with those reported for the
natural material.10b Homoplatensimide A methyl ester [(-)-6]
was also prepared and fully characterized by treatment of (-)-5
with TMSCHN2 (98% yield) as shown in Scheme 20. Its
physical data matched those reported for the natural product.10b
Conclusion
a Reagents and conditions: (a) PhI(O2CCF3)2 (1.5 equiv), CH3CN, water,
22 °C, 2 h; then Et3N (10.0 equiv), Ac2O (8.0 equiv), 30 min, 70%; (b) H2
(balloon), 10% Pd/C (0.1 equiv), EtOAc, 22 °C, 1 h, 92%; (c) (-)-2 (1.0
equiv), HOBt (3.0 equiv), EDC ·HCl (3.0 equiv), CH2Cl2, 22 °C, 30 min;
then (+)-91 (3.0 equiv), 22 °C, 12 h, 94%; (e) TFA/CH2Cl2 (1:1), 0 °C,
12 h, 99%.
In conclusion, we developed several effective synthetic strategies
for the total synthesis of platensimycin (1), a newly discovered
antibiotic possessing a novel mechanism of action. In addition to a
racemic synthesis, two complementary asymmetric approaches to a
key synthetic intermediate [i.e., (-)-14] were devised. The first strategy
was based on well-known asymmetric alkylation technologies and a
novel de-aromatizing cyclization reaction of a phenolic allyl silane.
The reaction was developed as a viable and general method for the
oxidative cyclization of phenolic allyl silanes to spiro hemiquinones.
The second strategy featured a rhodium-catalyzed asymmetric cycloi-
somerization reaction especially developed for this total synthesis,
which, however, turned out to be of general applicability and scope,
accommodating a wide range of terminal enyne substrates. The
developed convergent total synthesis of platensimycin proceeded
through enone 9, representing the cage core of the molecule, and which
has been employed by all other syntheses reported to date12a-l of this
natural product. Efficient strategies to install the side chain were also
developed to ensure reliable syntheses of platensimycin and related
compounds. In addition to providing access to synthetic platensimycin,
this work has facilitated the total syntheses of a number of designed
platensimycin analogues13a-c and its naturally occurring congeners,
platensimide A [(-)-4], homoplatensimide A [(-)-5], homoplaten-
simide A methyl ester [(-)-6], and platensimycins B1 [(-)-7] and B3
[(-)-9]. The latter accomplishments represent the first total syntheses
of these natural products. The reported synthetic strategies and methods
are expected to facilitate the construction of further designed analogues
of platensimycin and to find further applications in chemical synthesis.
Scheme 20. Asymmetric Total Synthesis of Homoplatensimide A
[(-)-5] and Homoplatensimide A Methyl Ester [(-)-6]a
a Reagents and conditions: (a) 95 (2.0 equiv), CH2Cl2, 22 °C, 3 h; (b) 2
N aq LiOH/THF (1:1) 50 °C, 12 h, 94%; (c) H2 (balloon), 10% Pd/C (0.1
equiv), EtOAc, 22 °C, 1 h, 90%; (d) 97 (1.0 equiv), HOBt (3.0 equiv),
EDC·HCl (3.0 equiv), CH2Cl2, 22 °C, 30 min; then (+)-98 (3.0 equiv), 22
°C, 12 h, 82%; (e) TFA/CH2Cl2 (1:1), 0 °C, 12 h, 98%; (f) TMSCHN2 (2.0
M in hexanes, 5.0 equiv), MeOH, 0 °C, 30 min, 98%.
Acknowledgment. We thank Drs. D. H. Huang, R. Chadha, and
G. Siuzdak for NMR spectroscopic, X-ray crystallographic, and mass
spectrometric assistance, respectively. We also gratefully acknowledge
A. Nold and Dr. H. Zhang for assistance with chiral HPLC, and Profs.
X. Zhang, A. Lei, D. Crich, Drs. P. G. Bulger, L. A. McAllister, and
J. S. Chen for helpful discussions. We are especially grateful to Dr.
S. B. Singh for providing an authentic sample of natural platensimycin
and NMR spectra of homoplatensimide A, and verification of the
optical rotation of platensimide A. Financial support was provided by
grants from the National Institutes of Health (USA), National Science
Foundation (CHE-0603217), and Skaggs Institute for Research,
graduate fellowships from Bristol-Myers Squibb and Eli Lilly (both
to A.L.) and Novartis (to S.P.E.), and a postdoctoral fellowship from
Merck Sharp & Dohme (to D.J.E).
HOBt under the conditions of EDC ·HCl furnished platensimide
A tert-butyl ester (-)-94 in 94% yield. Hydrolysis of the latter
with TFA then yielded synthetic platensimide A [(-)-4] in high
yield (99%), whose physical properties were consistent with
those of the naturally occurring product.10a
A similar strategy was employed for the total synthesis of
the also naturally occurring homoplatensimide A [(-)-5, Scheme
20]. In this case, extension of the side chain of the platensimycin
core was required. This was achieved through the highly
selective Wittig reaction between stabilized ylide 95 and core
aldehyde (-)-78, which gave unsaturated ester (-)-96 in
excellent yield (88%) as a single geometrical isomer (Scheme
20). Hydrolysis to the corresponding carboxylic acid (97, 94%
Supporting Information Available: Complete refs 5b,6a, and
11a, experimental procedures, and compound characterization. This
material is available free of charge via the Internet at http://pubs.acs.org.
JA9068003
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16918 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009