A bismuth(III)-catalyzed friedel-crafts cyclization and stereocontrolled organocatalytic approach to (-)-platensimycin

Article abstract of DOI:10.1021/ol102390t

A high yielding route to the (-)-platensimycin core is communicated. This entailed the discovery of Bi(OTf)₃ to catalyze a Friedel-Crafts cyclization of a free lactol, supplemented by LiClO₄ to suppress the Lewis basicity of the sulfonate group. After TBAF-promoted cyclodearomatization, a diastereoselective conjugate reduction of a dienone was achieved by adopting amine-based organocatalytic rationales to reverse the inherent steric control of the substrate.

Full text of DOI:10.1021/ol102390t

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5510-5513
A Bismuth(III)-Catalyzed Friedel-Crafts
Cyclization and Stereocontrolled
Organocatalytic Approach to
(-)-Platensimycin
Stanley T.-C. Eey and Martin J. Lear*
Department of Chemistry, Faculty of Science, and Medicinal Chemistry Program of the
Life Sciences Institute, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543, Singapore
Martin.Lear@nus.edu.sg
Received October 4, 2010
ABSTRACT
A high yielding route to the (-)-platensimycin core is communicated. This entailed the discovery of Bi(OTf)3 to catalyze a Friedel-Crafts
cyclization of a free lactol, supplemented by LiClO4 to suppress the Lewis basicity of the sulfonate group. After TBAF-promoted
cyclodearomatization, a diastereoselective conjugate reduction of a dienone was achieved by adopting amine-based organocatalytic rationales
to reverse the inherent steric control of the substrate.
Natural products continue to challenge even our most estab-
lished and advanced synthetic methods. They also inspire new
methods and new strategies. Platensimycin (-)-1 is a prime
example. Since its antisense/RNA-based identification from a
Streptomyces platensis strain, and structural disclosure by Merck
researchers in 2006,1 this potent broad-spectrum antibiotic has
succumbed to several total, formal, and analog syntheses.2-5
Amid a majority of chiral pool and racemic routes, the
catalytic Rh(I)/BINAP-based and Brønsted/Lewis acid
Diels-Alder methods stand out to be highly enantioselective
in forming intermediates to (-)-1.3 A common such inter-
mediate is Nicolaou’s tetracyclic enone 22,3a,c,d (Scheme 1).
Scheme 1. Retrosynthetic Analysis of (-)-Platensimycin (1)
(1) (a) Wang, J.; Soisson, S. M.; Young, K.; Shoop, W.; Kodali, S.;
Galgoci, A.; Painter, R.; Parthasarthy, G.; Tang, Y. S.; Cummings, R.; Ha,
S.; Dorso, K.; Motyl, M.; Jayasuriya, H.; Ondeyka, J.; Herath, K.; Zhang,
C.; Hernandez, L.; Allocco, J.; Basillo, A.; Tormo, J. R.; Genilloud, O.;
Vicente, F.; Pelaez, F.; Colwell, L.; Lee, S. H.; Michael, B.; Felcetto, T.;
Gill, C.; Silver, L. L.; Hermes, J. D.; Bartizal, K.; Barrett, J.; Schmatz, D.;
Becker, J. W.; Cully, D.; Singh, S. B. Nature 2006, 441, 358. (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.; Vicente,
F.; Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006, 128, 11916.
(c) Ha¨bich, D.; von Nussbaum, F. ChemMedChem 2006, 1, 951.
Installation of the required C8/C9 relative stereochemistry
has, however, been nontrivial under chiral reagent control,4
(2) First racemic total synthesis of (()-1: Nicolaou, K. C.; Li, A.;
Edmonds, D. J. Angew. Chem., Int. Ed. 2006, 45, 7086
.
10.1021/ol102390t  2010 American Chemical Society
Published on Web 10/29/2010

Scheme 2. Stereocontrolled Assembly of the Tetracyclic Enone Core 2 of (-)-Platensimycin
although high diastereoselectivity has been achieved under
in 98% yield and 91% ee.10 Regioselective epoxide opening
with allyl magnesium chloride11 established the desired
stereocenter at C12, after which Martinelli’s regioselective
catalytic monotosylation12 provided 7. Oxidative double-
bond cleavage with concomitant cyclization then furnished
the cis-tosyl lactol 4 in 85% yield.
high pressure hydrogenation conditions.3b,5g Herein, we
describe an enantioselective synthesis of (-)-23a,c,d through
the development of a direct Bi(III)-catalyzed Friedel-Crafts
cyclization of the free lactol 4 and a stereocontrolled
iminium-mediated conjugate reduction of a 6-methoxy-4,6-
dienone precursor of 3 from the sterically more congested
R-face.
(5) Other formal syntheses of 1 in racemic and enantioenriched forms:
(a) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B.
Org. Lett. 2007, 9, 1825. (b) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem.
Commun. 2007, 1922. (c) Matsuo, J.-i.; Takeuchi, K.; Ishibashi, H. Org.
Lett. 2008, 10, 4049. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D. J. Am. Chem.
Soc. 2009, 131, 8413. (e) McGrath, N. A.; Bartlett, E. S.; Sittihan, S.;
Njardarson, J. T. Angew. Chem., Int. Ed. 2009, 48, 8543. (f) Xing, S.; Pan,
W.; Liu, C.; Ren, J.; Wang, Z. Angew. Chem., Int. Ed. 2010, 49, 3215. (g)
Tiefenbacher, K.; Tro¨ndlin, L.; Mulzer, J.; Pfaltz, A. Tetrahedron 2010,
66, 6508. (h) Beaulieu, M.-A.; Sabot, C.; Achache, N.; Gue´rard, K. C.;
Canesi, S. Chem.sEur. J. 2010, 16, 11224. Reviews of synthetic routes to
1: (i) Nicolaou, K. C.; Chen, J. S.; Edmonds, D. J.; Estrada, A. A. Angew.
Chem., Int. Ed. 2009, 48, 660. (j) Tiefenbacher, K.; Mulzer, J. Angew.
Chem., Int. Ed. 2008, 47, 2548. (k) Palanichamy, K.; Kaliappan, K. P. Chem.
Asian. J. 2010, 5, 668.
Retrosynthetically, the 6-methoxy version of 23a,c,d (3) was
anticipated to impart greater electronic and steric control in
securing the cis-C8/C9-ring juncture (vide infra). This would
necessitate the realization of a diastereoselective Friedel-Crafts
(FC) cyclization6 of the lactol 4 to an oxabicyclo[3.2.1]octane
(8) via Marson-type oxocarbenium chemistry.7 A Masamune-
inspired intramolecular alkylative dearomatization strategy8
would then complete the cage-like core. A concise and
enantioselective assembly of the tetracyclic enone 2 is
outlined in Scheme 2.
(6) (a) Harmata, M.; Murray, T. J. Org. Chem. 1989, 54, 3761. (b) Fan,
J.-F.; Wu, Y.-K.; Wu, Y.-L. J. Chem. Soc., Perkin Trans. 1 1999, 1189. (c)
Wu, Y.; Li, Y.; Wu, Y.-L. HelV. Chim. Acta 2001, 84, 163. (d) Lo´pez, F.;
Castedo, L.; Mascaren˜as, J. L. Org. Lett. 2005, 7, 287.
Beginning with allyl alcohol 5,9 a catalytic Sharpless
epoxidation with L-(+)-DIPT afforded the epoxy alcohol 6
(7) Marson’s orginal migratory cyclization strategy: (a) Marson, C. M.;
Campbell, J.; Hursthouse, M. B.; Abdul Malik, K. M. Angew. Chem., Int.
Ed. 1998, 37, 1122. Related cyclizations: (b) Solorio, D. M.; Jennings, M. P.
J. Org. Chem. 2007, 72, 6621. (c) Solorio, D. M.; Jennings, M. P. Org.
Lett. 2009, 11, 189.
(3) Highly enantioselective methods to (-)-1: (a) Nicolaou, K. C.;
Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 3942.
(b) Lalic, G.; Corey, E. J. Org. Lett. 2007, 9, 4921. (c) Nicolaou, K. C.; Li,
A.; Ellery, S. P.; Edmonds, D. J. Angew. Chem., Int. Ed. 2009, 48, 6293.
(d) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.; Ellery, S. P. J. Am.
Chem. Soc. 2009, 131, 16905. (e) Li, P.; Payette, J. N.; Yamamoto, H.
J. Am. Chem. Soc. 2007, 129, 9534.
(8) (a) Masamune, S. J. Am. Chem. Soc. 1961, 83, 1009. (b) Boger,
D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.; Kitos, P. A.; Suntornwat,
O. J. Am. Chem. Soc. 1990, 112, 8961. (c) Boger, D. L.; McKie, J. A.;
Nishi, T.; Ogiku, T. J. Am. Chem. Soc. 1997, 119, 311. (d) Dai, M.;
Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6610.
(4) Stereoselective challenges in installing the C8/C9 cis-stereochemistry
in 2: (a) Tiefenbacher, K.; Mulzer, J. Angew. Chem., Int. Ed. 2007, 46,
8074. (b) Nicolaou, K. C.; Pappo, D.; Tsang, K. Y.; Gibe, R.; Chen, D. Y.-
K. Angew. Chem., Int. Ed. 2008, 47, 944. (c) Kim, C. H.; Jang, K. P.;
Choi, S. Y.; Chung, Y. K.; Lee, E. Angew. Chem., Int. Ed. 2008, 47, 4009.
(d) Ghosh, A. K.; Xi, K. J. Org. Chem. 2009, 74, 1163.
(9) Allyl alcohol 5 was readily prepared in 84% yield from eugenol,
see Supporting Information: Handa, M.; Scheidt, K. A.; Bossart, M.; Zheng,
N.; Roush, W. R. J. Org. Chem. 2008, 73, 1031.
(10) Meiries, S.; Marquez, R. J. Org. Chem. 2008, 73, 5015.
Org. Lett., Vol. 12, No. 23, 2010
5511

Under Marson-type FC conditions, initial efforts to cyclize
4 to the benzotetrahydrofuran 8 with BF3·Et2O were met with
limited success.7b,c,13 After screening, a large excess of SnCl4
was found to give optimal results at -78 °C.6a,d Notably,
this intramolecular arylation step proceeded with high stereo-
and regioselectivity at C9/C10. The alternative C7/C10-
regioisomer and C8/C10 ipso-isomer were not detected.
Quenching the reaction was, however, problematic. Typical
aqueous protocols led to significant decomposition of 8, with
significant reversion back to 4. After considerable experi-
mentation, quenching the remaining SnCl4 by pouring into
half-saturated Rochelle salt solution suppressed these side-
reactions and reliably provided 8 in good yields.14 As much
as 8 equivalents of SnCl4 were, however, required for the
conversion, suggesting a possible retardation of Lewis acid
reactivity by the sulfonate group.15
To further improve practical issues, we next decided to
develop a direct catalytic FC method to 8. Having screened
several oxophilic Lewis acids, a new catalytic combination of
5 mol % Bi(OTf)3 with 3 equiv of LiClO4 as a cocatalyst16
was eventually discovered to drive the FC cyclization to furnish
8 in 94% yield within 3.5 h.15 Interestingly, LiClO4 alone was
incapable of effecting the cyclization and one equivalent of
Bi(OTf)3 without LiClO4 gave inefficient conversions for
tosylates. In Mukaiyama’s SbCl5/LiClO4-catalyzed Friedel-
Crafts acylation,16a the formation of an active oxocarbenium
perchlorate species is suggested between SbCl5 and LiClO4 with
acid anhydrides.15 Likewise, the combination of Bi(OTf)3 and
LiClO4 could generate a more reactive cationic species with
the lactol 4 toward nucleophilic ring closure. From our findings,
we also reason that Li+ can compete for the Lewis basic
sulfonate group and release any trapped Bi(III), thereby allowing
a catalytic cycle to persist.
(at ambient pressures) or THF (in a sealed-tube) at 130 °C
efficiently afforded the dienone caged-core 10 in 86% yield
over two steps.
As introduced earlier, a chemo- and stereocontrolled
conjugate reduction at the electron-deficient C4-C9 olefin
of 10 to the enone 3a (versus its C9-epimer 3b) was
anticipated to be achievable by virtue of the C6-methoxy
group. A method to control the stereochemical outcome was,
however, difficult to achieve (Table 1, entries 1-3). Atmo-
Table 1. Conjugate Reduction Study of R-Methoxydienone 10
entry
1
conditions
yield (%) 3a:3ba
Pd-C cat., H2, EtOAc/ethanolic
KOH (2:1), 2 h
70
56
1:3b
2
(i) CuCl/NaOtBu/(R)-tol-BINAP (20 mol %),
PMHSc (2 equiv), toluene, 132 h; then
(ii) DMPd (3 equiv), CH2Cl2, 7 h
(S)-BINAP/Cu(OAc)2 (0.5 equiv),
1:4
3
4
5
6
17
30
10
61
0:1
PMHSc (6 equiv), BuOH/THF, 36 h
t
(-)-13 (1 equiv), 15 (2.4 equiv),
3.5:1
1.2:1
8:1e
dioxane, 60 °C, 48 h
20 mol % (S)-TRIP23/ D-Val-OtBu,
15 (5 equiv), nBu2O, 70 °C, 120 h
20 mol % (-)-14, 15 (3.2 equiv),
dioxane, 60 °C, 130 h
a Based on 1H NMR dr at C9. b 11a/11b isolated (1:3). c Polymethylhydro-
siloxane. d Dess-Martin periodinane. e 11a/11b also isolated in 17% yield
(∼1:1).
spheric hydrogenation of 10 over catalytic Pd/C afforded a
1:3 diastereomeric ratio (dr) in favor of undesired 11b over
11a (entry 1). Buchwald’s in situ prepared (R)-p-tol-BINAP-
stabilized Cu-H complex17 gave a 1:4 dr in favor of 3b
over 3a (entry 2) and alternative Cu-H conditions with (S)-
BINAP18 favored the undesired 3b exclusively (entry 3).
Having secured reliable FC cyclization conditions, the
benzyl deprotected tosyl-phenol 9 was freshly formed (see
Supporting Information for single-crystal X-ray data) and
directly subjected to intramolecular alkylative dearomatiza-
tion conditions. Boger’s methods were initially examined.8b,c
DBU in refluxing CH3CN or NaH in DMF/THF (and
Collectively, these results suggest an over-riding substrate-
controlled steric effect enforcing ꢀ-facial attack. They are
also consistent with Mulzer’s first investigation on using
Crabtree’s Ir-catalyst, which furnished a 1.3:1 C8/C9-cis/
trans decalin mixture at best from a C6-demethoxy analog
of 10 under 1 atm of H2.4a Nevertheless, exceptions to
substrate control have been achieved under high pressures
and with optimized chiral reagents. These include Corey’s
600-psi Rh(I)/DIOP-catalyzed hydrogenation3b and, recently,
Mulzer and Pfaltz optimized their Ir(I)/P,N-ligand-catalyzed
hydrogenation5g procedure at 50 bar of pressure. Neither
possessing the specialized apparatus nor reagents, we pursued
alternative methods to affect a stereocontrolled reduction
process (Table 1, entries 4-6).
Inspired by amine-based organocatalytic mechanistic
rationales, we explored the possibility of reversing the facial
preference of 10 toward hydride delivery by relaying steric
information via a C6-methoxy group-directed putative trans-
iminium species 16 (Figure 1). Although MacMillan-type
catalysts in the presence of Hantzsch hydride donors like
t
methods such as Na in BuOH or LDA in THF) gave poor
conversions with 9. Eventually, without the need to resort
to better leaving groups or phenyl silyl ether activation
methods,3b,5e,8b,d the treatment of 9 with TBAF in xylene
(11) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506
.
(12) Martinelli, M. J.; Nayyar, N. K.; Moher, E. D.; Dhokte, U. P.;
Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999, 1, 447
.
(13) (a) TfOH and TMSOTf were also unsuccessful. Other BF3·Et2O-
mediated electrophilic arylations: (b) Sugai, T.; Kakeya, H.; Ohta, H.
Tetrahedron 1990, 46, 3463. (c) Kim, H.; Wooten, C. M.; Park, Y.; Hong,
J. Org. Lett. 2007, 9, 3965
.
(14) Examples of using Rochelle salts in work-up procedures in titanium-
and aluminum-mediated reactions: Jung, M. E.; D’Amico, D. C. J. Am.
Chem. Soc. 1997, 119, 12150.
(15) A bromo-equivalent of the tosylate 4 could be cyclized with only
4 equivalents of SnCl4 or 5 mol % of Bi(OTf)3 in 1.5 h during FC screening
studies. This work will be described in full together with the conjugate
reduction study of 10 and a complete total synthesis of (-)-1.
(16) (a) Mukaiyama, T.; Suzuki, K.; Han, J. S.; Kobayashi, S. Chem.
Lett. 1992, 435. (b) Kawada, A.; Mitamura, S.; Kobayashi, S. Chem.
Commun. 1996, 183. (c) Chapman, C. J.; Frost, C. G.; Hartley, J. P.; Whittle,
A. J. Tetrahedron Lett. 2001, 42, 773. (d) Bartoli, G.; Locatelli, M.;
Melchiorre, P.; Sambri, L. Eur. J. Org. Chem. 2007, 2037.
(17) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 6797.
(18) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Nat. Acad. Sci.
2004, 101, 5821.
5512
Org. Lett., Vol. 12, No. 23, 2010

1H and 13C NMR spectra of (-)-2 were found identical to
those reported by Nicolaou.3d
The π-facial selectivity observed in the Hantzsch ester (15)
hydride delivery to the 6-methoxydienone 10 can be rational-
ized to occur via a phenylalanine-derived trans-iminium
intermediate (17), probably aided by an additional counter-
anion hydrogen bonding network20 (Figure 1). Conceivably,
the sterically more congested face of 10 would preferentially
relay the benzyl and tert-butyl ester groups to the opposite
face in 17, thereby making the bottom face more sterically
accessible. This steric reversal reasoning can account for the
low reactivity and diastereoselectivity of List’s TRIP23
catalyst, but also that the reduction of 10 gave similar yields
and selectivities irrespective of using (+)-, (-)- or (()-forms
of phenylalanine 14.
In summary, we achieved a new stereocontrolled route to
the tetracyclic enone (-)-2 of (-)-platensimycin (1) in 12
steps, 21% overall yield from the readily available allylic
alcohol 5.9 The tactic of employing a methoxy group to
impart needed electronic and steric control helped advance
three key transformations to 2: (1) a direct para-arylation
of an oxocarbenium species in a Bi(OTf)3-catalyzed Marson-
type FC cyclization of the free lactol 4; (2) a direct TBAF-
mediated alkylative dearomatization on the free phenol 9,
without silyl preactivation; and (3) a chemo- and diastereo-
selective conjugate reduction of the 6-methoxydienone 10
mediated by TFA salts of phenylalanine using readily
available laboratory resources and techniques. While total
synthesis efforts to (-)-1 are ongoing, nonchiral primary
amines are also being explored to further improve the π-facial
selectivity of this latter step.15
Figure 1. Proposed trans-iminium intermediate 16 and mechanistic
rationale20 for π-facial selectivity via 17.
15 were found unreactive,19 List’s D-valine TFA salt 1320,21
with 1522 gave a 3.5:1 dr in favor of desired 3a over 3b,
albeit in low yield (entry 4). List’s optimal antipodal catalyst
combination, the (S)-TRIP23 salt of D-valine tert-butyl ester,
gave poor conversions and 1.2:1 dr (3a/3b), suggesting
competing steric effects came into operation (entry 5).
Eventually,15 higher catalytic activity and selectivity were
achieved with the unreported tert-butyl ester21 of D-pheny-
lalanine 14, although further reduction of 3a/3b to 11a/11b
could not be avoided (entry 6).
To optimize the isolated yield of desired 11a, the
sequential Hantzsch-based and Pd/C-mediated reduction of
10 via 3a/3b to a separable mixture of C9-epimeric 6-meth-
oxyketones 11a/b was found favorable. This gave a 73%
yield over two steps and 4:1 dr at C9. The methoxyketones,
however, proved unstable on silica and 11a was best
separated from 11b with 90-95% purity under N2 through
Et3N-deactivated silica. Original dr ratios at C6 could not
be determined on crude mixtures of 11a/b. Although minor
amounts of 11a-(6S) could be isolated and characterized, the
newly formed C6 chiral center of 11a readily epimerized to
the major diastereomer 11a-(6R) during silica gel chromo-
tography. The C6 epimer of 11b-(6R) was never detected.
Finally, demethylation of 11a with AlCl3/TBAI,24 followed
by mesylation of 12 and heating with LiBr/Li2CO3 in
DMSO,25 furnished the targeted tetracyclic enone (-)-2. The
Acknowledgment. We thank the National University of
Singapore for a Graduate Scholarship (to S.T.-C.E.) and start-
up funding (to M.J.L). This work was latterly funded in part
by the National Research Foundation, Competitive Research
Program (NRF-G-CRP 2007-04). We are grateful to Ben-
jamin List and co-workers for the generous gift of (S)-TRIP
and advice in the preparation of the (S)-TRIP salt of D-valine
tert-butyl ester.
Supporting Information Available: Experimental pro-
cedures, compound characterization, NMR spectra, synthesis
of allyl alcohol 5, and X-ray characterization of tosyl-phenol
9. This material is available free of charge via the Internet
at http://pubs.acs.org.
(19) Tuttle, J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2006, 128, 12662.
(20) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368
.
(21) Preparation of tert-butyl esters of amino acids: Wright, S. W.;
Hageman, D. L.; Wright, A. S.; McClure, L. D. Tetrahedron Lett. 1997,
38, 7345.
(22) Wang, G.-W.; Xia, J.-J.; Miao, C.-B.; Wu, X.-L. Bull. Chem. Soc.
Jpn. 2006, 79, 454.
OL102390T
(23) TRIP ) 3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl
hydrogen phosphate.
(24) Akiyama, T.; Shima, H.; Ozaki, S. Tetrahedron Lett. 1991, 32,
5593.
(25) Moe¨ns, L.; Baizer, M. M.; Little, R. D. J. Org. Chem. 1986, 51,
4497.
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