Halocarbocyclization entry into the oxabicyclo[4.3.1]decyl exomethylene-δ-lactone cores of linearifolin and zaluzanin A: Exploiting combinatorial catalysis

Article abstract of DOI:10.1021/ol203088g

A streamlined entry into the sesquiterpene lactone (SQL) cores of linearifolin and zaluzanin A is described. Stereochemistry is controlled through transformations uncovered by ISES (In Situ Enzymatic Screening). Absolute stereochemistry derives from kinet

Full text of DOI:10.1021/ol203088g

ORGANIC
LETTERS
2012
Vol. 14, No. 4
968–971
Halocarbocyclization Entry into the
Oxabicyclo[4.3.1]decyl Exomethylene-δ-
Lactone Cores of Linearifolin and
Zaluzanin A: Exploiting Combinatorial
Catalysis
Sandeep K. Ginotra, Jacob A. Friest, and David B. Berkowitz*
Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588-0304,
United States
dbb@unlserve.unl.edu
Received November 17, 2011
ABSTRACT
A streamlined entry into the sesquiterpene lactone (SQL) cores of linearifolin and zaluzanin A is described. Stereochemistry is controlled through
transformations uncovered by ISES (In Situ Enzymatic Screening). Absolute stereochemistry derives from kinetic resolution of 5-benzyloxypentene-1,2-
oxide, utilizing a β-pinene-derived-Co(III)-salen. Relative stereochemistry (1,3-cis-fusion) is set via formal halometalation/carbocyclization, mediated by
[Rh(O2CC3F7)2]2/LiBr. Subsequent ring-closing metathesis (RCM-Grubbs II) yields the title exomethylene-δ-lactone SQL cores. In complementary
fashion, RCM with Grubbs-I catalyst provides the oxabicyclo[3.3.1]nonyl core of xerophilusin R and zinagrandinolide.
ISES (In Situ Enzymatic Screening)-assisted catalyst
development has led to the (i) discovery of the first asym-
metric Ni(0)-mediated allylic amination chemistry,1 (ii)
new halometalation/carbocyclization transformations,2
and (iii) the identification of novel chiral salen ligands
for asymmetric catalysis.3 This Letter describes the deploy-
ment of the latter two methods for stereocontrolled entry
into bicyclic terpenoid natural product (NP) cores bearing
a reactive exomethylene δ-lactone functionality.
activity in such sesquiterpene lactones (SQLs).4 Against
this medicinal chemistry backdrop there has been vigorous
syntheticactivityinthe exomethylene SQLarea,5 including
approaches that permit core synthesis6 and chain exten-
sion.7 While a number of routes focus on end game
methylenation,8 we favored a convergent strategy in which
a formal halometalation/carbocyclization would at once
close the lactone, control ring fusion geometry, and set in
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This functional group has been linked to NFKB-inhibi-
tion via active site cysteine capture, leading Merfort to
propose a QSAR model for NFKB inhibition/anticancer
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Shen, W.; Berkowitz, D. B. J. Am. Chem. Soc. 2005, 127, 8610–8611.
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r
10.1021/ol203088g
Published on Web 02/08/2012
2012 American Chemical Society

Figure 3. ISES readout on salen-set/new reporting enzymes.
ISES screens for sense (þ S; ꢀ R) and magnitude of enantio-
preference for Co(III)-salen-mediated HKR with hexene oxide
(purple) and propylene oxide (green) and 1,2-Diamines:3a 4 (β-
pinene-derived); 5 (L-β-naphthyl-Ala-derived); 6 (L-Phe-derived);
7 (L-phenyl-Gly-derived). Hydroxybenzaldehydes: a (R-hydroxy-
β-naphthaldehyde); b (3,5-diiodosalicylaldehyde); c (3-t-Bu-
salicylaldehyde); d (3,5-di-t-Bu-salicylaldehyde). Note: For en-
tries 4c, 5b,c, 6aꢀd, and 7aꢀd new reporting enzymes (KRED
(Ketoreductase) 107 S-selective; KRED 119 R-selective) for the
HKR of hexene oxide were employed.
Figure 1. Targeted oxabicyclo[4.3.1]decyl SQL cores.
related to fastigilin A, a potent antineoplastic agent)11 and
zaluzanin A (muscle relaxant).12
Interestingly, these two terpenoid lactone cores have
opposite handedness; therefore efficient hydrolytic kinetic
resolution (HKR)3,13 should allow for assembly of both
cores from a common racemic epoxide building block
precursor (Figure 2), one from the diol product (as the
cyclic sulfate), the other from the remaining epoxide. Such
a convergent sequence would both allow for the effi-
cient assembly of the exomethylene δ-lactone and set the
cis-1,3-fusion stereochemistry in the key halometalationꢀ
carbocyclization step, a transformation for which both
Rh-perfluorocarboxylate and Pd(II) catalysts have been
uncovered recently in our lab.2,14
Toward this end, an improved ISES screen [Figure 3,
new KRED(ketoreductase) enzymes15] identifiedthe salen
4a catalyst, assembled from the β-pinene-derived diamine
and R-hydroxy-β-naphthaldehyde, in its Co(III)-OAc form
as a generally (S)-selective catalyst for terminal epoxides.
This KRED assay has advantages over the previously
reported hexene oxide screen,3a as the two reporting
enzymes show opposite enantioselectivities (see Support-
ing Information) and both are readily available. For the
synthesis at hand, efficient HKR of an O-protected
Figure 2. Retrosynthetic analysis.
place the reactive, conjugated exomethylene moiety.2 This
approach has an added benefit for chemical biology, as the
resultantβ-bromo-R, β-unsaturated carbonyl system should
be advantageous for library generation.9
Targeted herein are the cores of SQLs carrying this func-
tionality within a bridged oxabicyclo[4.3.1]decyl framework,
as in linearifolin angelate10 (Figure 1; from H. linearifolium,
(8) (a) Riofski, M. V.; John, J. P.; Zheng, M. M.; Kirshner, J.; Colby,
D. A. J. Org. Chem. 2011, 76, 3676–3683. (b) For an elegant Pausonꢀ
Khand entry into the related guaianolides, that introduces the R-methy-
lene lactone at an early stage, see: Grillet, F.; Huang, C.; Brummond,
K. M. Org. Lett. 2011, 13, 6304–6307.
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2011, 108, 6805–6810. (b) Dekker, F. J.; Koch, M. A.; Waldmann, H.
Curr. Opin. Chem. Biol. 2005, 9, 232–239.
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1585–1590.
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L. D. J. Org. Chem. 1978, 43, 1092–5.
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M.; Lesage, D. Can. J. Chem. 2008, 86, 1077–1084.
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5660–5661. (b) Nielsen, L. P. C; Stevenson, C. P.; Blackmond, D. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 1360–1362. (c) Schaus,
S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.;
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124, 1307–1315.
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11, 305–308.
Org. Lett., Vol. 14, No. 4, 2012
969

Table 1. HKR of AcO-Co(III)-4a across Potential Synthonsa
Scheme 2. Convergent Assembly of the Halometalation/
Carbocyclization Substrate
a Conditions: 1.3 mmol of epoxide; 0.67 mmol of H2O in 100 μL of
THF, with 2.5 mol % Co(III)-salen derived from 4a. Conversion
estimated by NMR and ee by HPLC-chiral stationery phase
(Supporting Information).
Scheme 1. HKR (Salen 4a) Provides Both SQL Building Blocks
Scheme 3. Halometalation/Carbocyclization-RCM Sequence
into the Linearifolin Core
5-hydroxy-1,2-pentene oxide was desired. Accordingly, a
series of such potential building blocks were screened for
HKR with Co(III)-4a-OAc. As can be seen (Table 1), this
catalyst is generally (S)-selective for substrates bearing
arylmethyl ether protecting groups.
In the event, when racemic 9 was treated with Co(III)-
4a-OAc, on a 13 g scale, both antipodal building blocks,
(R)-epoxide 9b and (S)-diol 12, were obtained in high ee
(Scheme 1) attesting to the potential3a of this new chiral
salen in asymmetriccatalysis. The diol waseasilyconverted
to the corresponding cyclic sulfate 13.
As is illustrated in Scheme 2, the requisite 3-carbon allylic
carbonate “acceptor” functionality for the carbocyclization
could be installed via cyclic sulfate opening with a lithiated
propargyl ether. Lindlar semihydrogenation and unveiling of
the masked terminal olefin were followed by selective carbony-
lation of the primary alcohol. The propiolate moiety then enters
with Mitsunobu inversion at the HKR-derived stereocenter.
The title bromorhodiation/carbocylization was car-
ried out on 18a,2 crafting both the Z-configured CꢀBr
bond and the ring-forming CꢀC bond, thereby setting
in place the requisite cis-1,3-ring fusion in 19a. More-
over, a detailed study (50 mg scale) showed that yields
could be increased to >90%, with 5 mol % catalyst,
by reducing the temperature and increasing the reac-
tion time (Supporting Information). Note that
this formal halometalation/carbocyclization bears
(16) (a) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645–
9660. (b) Lei, A.; Waldkirch, J. P.; He, M.; Zhang, X. Angew. Chem., Int.
Ed. 2002, 41, 4526–4529.
970
Org. Lett., Vol. 14, No. 4, 2012

Scheme 4. (R)-Epoxide Leads into the Zaluzanin A Core
Scheme 5. IsomerizationꢀRCM: Oxabicyclo[3.3.1]nonyl Cores
of Zinagrandinolide/Xerophilusin R
some resemblance, particularly in the product structure,
to Rh(I)-mediated carbocyclizations reported by
Zhang that involve formal Alder-ene alkyne/allyl
CꢀH cycloisomerization16 or alkyne/allylic CꢀCl con-
densation, with an accompanying halide shift.17 The
vinyl halide geometry obtained here is opposite
that found in the Zhang chemistry, and both the
Rh catalyst (Rh(II)-perfluorocarboxylate/LiBr) and
educts (allylic carbonates) employed here also differ.
Subsequent ring-closing metathesis (RCM, Grubbs II
catalyst)18 closes the bicyclo[4.3.1]decenyl linearifolin core.
The 3D-structure of the core was solved by X-ray crystal-
lography which also served to confirm absolute stereochem-
istry (Scheme 3). The antipodal series follows from the (R)-
epoxide obtained in the initial HKR of 5-benzyloxy-pentene
oxide mediated by Co(III)-4a-OAc (Scheme 1). The se-
quence mirrors that described for entry into the linearfolin
core with the exception that epoxide 9b, rather than a cyclic
sulfate, is opened by the lithiated propargyl ether, a reaction
found to proceed optimally in the presence of F3B-OEt2
(Scheme 4). Here too, X-ray crystallography established 3D
structure and absolute stereochemistry.
RuꢀH species, as studied by Schmidt,19 Grubbs,20 and
Snapper.21 This serves as an added benefit of this synthetic
route, with the Grubbs I catalyst22 giving ring contraction,
and thereby access, to the oxabicyclo[3.3.1]nonyl core in
zinagrandinolide23 and xerophilusin R24 (Scheme 5), both
antineoplastic natural products.23,24 Future studies will
be directed at the further exploration of this promising β-
pinene-based salen scaffold in asymmetric catalysis, and this
versatile halocarbocyclization transformation, and at the
deployment of these NP cores in chemical biology.
Acknowledgment. The NSF (CHE-0911732) is ac-
knowledged for support. Xiang Fei and Robert A. Swyka
are thanked for assistance. Douglas Powell (U. of Oklahoma)
is acknowledged for X-ray structures. D.B.B. currently serves
as a Program Director at the NSF. This research was
facilitated by the IR/D (Individual Research and Devel-
opment) program associated with that appointment.
The authors thank the NIH (SIG-1-510-RR-06307)/
NSF (CHE-0091975, MRI-0079750) (NMR) and NIH
(RR016544) (facilities).
In the course of this investigation, it was also discovered
that one could gain access to ring contracted cores by RCM
modification. Olefin isomerization is known to occasionally
accompany metathesis, presumably via the intermediacy of
Supporting Information Available. Experimental de-
tails, characterization, NMR spectra, and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Tong, X.; Li, D.; Zhang, Z.; Zhang, X. J. Am. Chem. Soc.
2004, 126, 7601–7607. (b) Tong, X.; Zhang, Z.; Zhang, X. J. Am. Chem.
Soc. 2003, 125, 6370–6371.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
(19) Schmidt, B. Eur. J. Org. Chem. 2004, 1865–1880.
(20) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160–17161.
(22) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100–110.
(23) Bashyal, B. P.; McLaughlin, S. P.; Gunatilaka, A. A. L. J. Nat.
Prod. 2006, 69, 1820–1822.
(24) Niu, X.-M.; Li, S.-H.; Na, Z.; Lin, Z.-W.; Sun, H.-D. Helv.
Chim. Acta 2004, 87, 1951–1957.
(21) (a) Finnegan, D.; Seigal, B. A.; Snapper, M. L. Org. Lett. 2006, 8,
2603–2606. (b) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper,
M. L. J. Am. Chem. Soc. 2002, 124, 13390–13391.
The authors declare no competing financial interest.
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