Zirconium mediated total synthesis of crinitol, 9-hydroxyfarnesoic acid, 9-hydroxyfarnesol, 9-hydroxysargaquinone and the selectively-protected aglycone of moritoside and euplexide A

Article abstract of DOI:10.1039/b508524a

Tandem formation of an unsaturated zirconacycle, insertion of methallyl carbenoid, and addition of an aldehyde provides a rapid synthetic route to several linear terpenoid and terpene-polyketide natural products. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b508524a

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Zirconium mediated total synthesis of crinitol, 9-hydroxyfarnesoic
acid, 9-hydroxyfarnesol, 9-hydroxysargaquinone and the
selectively-protected aglycone of moritoside and euplexide A{
Sally Dixon, George J. Gordon and Richard J. Whitby*
Received (in Cambridge, UK) 16th June 2005, Accepted 14th July 2005
First published as an Advance Article on the web 5th August 2005
DOI: 10.1039/b508524a
substituted zirconacyclopentene 7 (Scheme 1). The regiochemistry
is consistent with that reported for the addition to trimethylsilyl-
propyne.11 The carbenoid 1-lithio-1-chloro-2-methylpropene, gene-
rated in situ by deprotonation of methallyl chloride with lithium
tetramethylpiperidide (LiTMP), selectively inserted into the alkyl–
zirconium bond2 of 7 to afford allylzirconocene 8. Subsequent
addition of 3-methyl-2-butenal or geranial gave the alcohols 9a
and 9b respectively in modest isolated yield, based on 1-tributyl-
stannylpropyne. In previous work, similar aldehyde additions
occurred in excellent yield in the presence of boron trifluoride
etherate.2 Unfortunately the alkenyl tin moiety in 8 was not stable
to BF3?Et2O or a range of other strong Lewis acids we tried.
Relying on the MgCl2 present in the reaction flask to activate the
Tandem formation of an unsaturated zirconacycle, insertion of
methallyl carbenoid, and addition of an aldehyde provides a
rapid synthetic route to several linear terpenoid and terpene–
polyketide natural products.
Organotransition metal chemistry provides many novel ways to
rapidly assemble organic molecules. The zirconium mediated
intramolecular co-cyclisation of a,v-dienes or -enynes to form
zirconacycles has already found several applications in total
synthesis.1 To make efficient use of the metal, we have developed
the insertion of carbenoids (R1R2CLiX) into intermediate
zirconacycles to afford new organozirconium species, which may
then be further elaborated.2 Particularly successful has been the
insertion of allyl carbenoids, since the so-formed intermediates add
well to carbonyl compounds, as used in our recent total synthesis
of the bicyclo[9.3.0]tetradecane (dolabellane) diterpene, acetoxyo-
dontoschismenol.3 Herein, we present a short synthesis of
naturally-occurring linear terpenoids and terpene–polyketides
using the tandem formation of a monocyclic zirconacyclopentene,
allyl carbenoid insertion, and aldehyde addition.
Our targets (Fig. 1) included the sesquiterpene stress
metabolites from the sweet potato, 9-hydroxyfarnesoic acid4 (1)
and 9-hydroxyfarnesol4,5 (2a) and the diterpene crinitol (2b).
Crinitol, isolated from marine brown algae, has insect growth
inhibition and antimicrobial activity.6 We also report the
synthesis of the mixed biogenetic terpene–polyketide compounds
9-hydroxysargaquinone (3) and the selectively-protected aglycone
of moritoside 48 and euplexide A 5.9 9-Hydroxysargaquinone was
isolated from marine brown algae and shows significant
cytotoxicity against cultured P-388 lymphocytic leukaemia cells
(ED50 5 0.7 mg ml21).7 Moritoside 48 and euplexide A 59 were
isolated from the gorgonian Euplexaura sp. Moritoside inhibits cell
division in the fertilized starfish embryo assay at 1mg ml21 8
,
and euplexide A is cytotoxic against human leukaemia cells
(IC50 5 2.6 mg ml21), inhibits PLA2 and has significant antioxidant
properties.9
Reaction of zirconocene(ethylene) (6) generated in situ from
zirconocene dichloride and 2 equivalents of ethylmagnesium
chloride,10 with tributylstannylpropyne gave the a-tributylstannyl
School of Chemistry, University of Southampton, Highfield,
Southampton, Hampshire, UK SO17 1BJ. E-mail: rjw1@soton.ac.uk;
Fax: +44 (0) 2380593781; Tel: +44 (0)23 80592777
{ Electronic Supplementary Information (ESI) available: Tabulation of
13C NMR data for compounds 2a, 2b, 3 and 14 against that reported for
the natural products. Full data for the synthesis of 1 and its methyl ester.
See http://dx.doi.org/10.1039/b508524a
Fig. 1 Natural product targets.
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Scheme 2 Reagents and conditions: (i) Pd2(dba)3?CHCl3 (0.4 mol%),
AsPh3 (3.2 mol%), THF, 15 min, rt, then 9 (1.0 equiv.), 11 or 12
(1.0 equiv.), 65 uC, 1.5 h. (ii) 10%, aq. KF, rt, 4 d. (iii) Bu4NF–THF, rt,
12 h.
Scheme 1 Reagents and conditions: (i) EtMgCl (2.0 equiv.), 278 uC,
20 min. (ii) 1-tributylstannylpropyne, 278 uC to 0 uC, 1 h, then 0 uC to rt,
2 h. (iii) 3-chloro-2-methylpropene, LiTMP, 278 uC to 270 uC, 40 min.
(iv) R1CHO (2.0 equiv.), 270 uC to rt, 3 h. (v) MeOH, aq. NaHCO3, rt,
12 h. (vi) tBuMe2SiOTf, DMAP, imidazole, THF, rt, 24 h. (vii) a: Add to
Pd2(dba)3?CHCl3 (0.4 mol%) AsPh3 (3.2 mol%) and HMPA (10 mol%)
pre-mixed in THF for 15 min at rt, then heat to 65 uC. b: Methyl
chloroformate (1.5 equiv.) added over 1 h at 65 uC, then rt, 12 h. c:
We then targeted the mixed terpenoid–polyketide compounds
3–5. We were delighted to find that Stille coupling of 9b with
quinone 11 gave directly and in excellent yield 9-hydroxysarga-
quinone (3) which has not previously been synthesised (Scheme 2).
Compound 11 was made by the oxidation of 1-(bromomethyl)-2,5-
dimethoxy-3-methylbenzene16 with ceric ammonium nitrate
(65% yield). To access the desired selectively-protected aglycone
14 of moritoside (4) and euplexide A (5) the differentially-protected
bis-phenol derivative 12 was prepared from 3-methyl-4-methoxy-
phenol17 by ortho-selective monohydroxymethylation,18 exhaustive
tert-butyldimethylsilyl ether formation followed by selective
deprotection of the primary alcohol (pyridinium tosylate), and
bromination (CBr4, PPh3). Palladium catalysed coupling of 12
with the alkenyltin 9a gave 13 in good yield; removal of the silyl
protecting group affording the desired selectively-protected
aglycone 14. The NMR properties of 14{ were consistent with
those reported for the aglycone portions of 4 and 5.8,9
t
10% aq. KF, 2 d. (viii) BuOH/H2O (1 : 1), 1M NaOH, 48 h, rt. (ix)
Bu4NF–THF, rt, 24 h. (x) DIBAL-H, CH2Cl2, 278 uC, 2 h.
aldehydes gave the best result. Nevertheless, our key intermediates
9a and 9b had been assembled from four components in one
reaction sequence with complete control over both double bond
geometries.
Alkoxycarbonylation of the alkenylstannanes 9a and 9b was
accomplished, after tert-butyldimethylsilyl protection of the free
hydroxyl group, by palladium-catalysed reaction with methyl
chloroformate.12 The use of triphenylarsane as a ligand on
palladium to accelerate the rate of transmetallation,13 and slow
addition of the chloroformate to minimise its decomposition, gave
good yields of 10a and 10b. Cleavage of the silyl ether in 10a with
Bu4NF gave a product having spectroscopic data consistent with
the methyl ester of 9-hydroxyfarnesoic acid, the form in which
the natural product was isolated and characterised.4
9-Hydroxyfarnesoic acid 1 was obtained via saponification of
10a followed by silyl ether cleavage.
Overall, we used tandem reactions on a zirconium template to
provide very short synthetic routes to a variety of natural products,
several with interesting biological properties.
Notes and references
1 P. Wipf and P. D. G. Coish, Tetrahedron Lett., 1997, 38, 5073;
D. F. Taber and Y. Wang, J. Am. Chem. Soc., 1997, 119, 22; E. Negishi,
S. M. Ma, T. Sugihara and Y. Noda, J. Org. Chem., 1997, 62, 1922;
A. N. Kasatkin, G. Checksfield and R. J. Whitby, J. Org. Chem., 2000,
65, 3236; M. Mori, S. Kuroda, C. S. Zhang and Y. Sato, J. Org. Chem.,
1997, 62, 3263.
2 G. J. Gordon, T. J. Luker, M. W. Tuckett and R. J. Whitby,
Tetrahedron, 2000, 56, 2113; S. Dixon, S. M. Fillery, A. Kasatkin,
D. Norton, E. Thomas and R. J. Whitby, Tetrahedron, 2004, 60,
1401.
Diisobutylaluminium hydride reduction of the methyl ester 10a
followed by cleavage of the silyl ether gave 9-hydroxyfarnesol 2a,
previously synthesised in 6 steps from geraniol.5 In the same way,
10b was converted to the diterpene crinitol 2b. The only
previous synthesis of crinitol took 10 steps from geranyl acetate.14
Corey synthesised 1-tert-butyldimethylsilyl-protected crinitol in 6
steps from geraniol as an intermediate in the synthesis of
geranylgeraniol.15
3 I. R. Baldwin and R. J. Whitby, Chem. Commun., 2003, 2786.
4 J. A. Schneider, J. Lee, Y. Naya, K. Nakanishi, K. Oba and I. Uritani,
Phytochemistry, 1984, 23, 759.
4304 | Chem. Commun., 2005, 4303–4305
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5 L. T. Burka, L. J. Felice and S. W. Jackson, Phytochemistry, 1981, 20,
647.
11 T. Xi, R. Hara and T. Takahashi, J. Org. Chem., 1995, 60,
4444.
6 I. Kubo, T. Matsumoto and N. Ichikawa, Chem. Lett., 1985, 249;
I. Kubo and L. R. Smith, J. Nat. Prod., 1995, 58, 1608.
7 P. Rivera, F. Podesta, M. Norte, F. Cataldo and A. G. Gonzalez, Can.
J. Chem., 1990, 68, 1399; A. Numata, S. Kanbara, C. Takahashi,
R. Rujiki, M. Yoneda, Y. Usami and E. Fujita, Phytochemistry, 1992,
31, 1209.
12 L. Balas, B. Jousseaume, H. Shin, J. P. Verlhac and F. Wallian,
Organometallics, 1991, 10, 366.
13 V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113,
9585.
14 T. Kato, H. Takayanagi, T. Uyehara and Y. Kitahara, Chem. Lett.,
1977, 1009.
8 N. Fusetani, K. Yasukawa, S. Matsunaga and K. Hashimoto,
Tetrahedron Lett., 1985, 26, 6449.
9 J. Shin, Y. Seo, K. W. Cho, S. S. Moon and Y. J. Cho, J. Org. Chem.,
1999, 64, 1853.
10 T. Takahashi, M. Kageyama, V. Denisov, R. Hara and E. Negishi,
Tetrahedron Lett., 1993, 34, 687.
15 B. Radeetich and E. J. Corey, Org. Lett., 2002, 4, 3463.
16 R. G. F Giles, P. R. K. Mitchell and M. V. Sargent, J. Chem. Soc.,
Perkin Trans. 1, 1983, 2147.
17 E. C. Jorgensen and W. J. Murray, J. Med. Chem., 1974, 17, 434.
18 G. Casiraghi, G. Casnati, G. Puglia and G. Sartori, Synthesis, 1980,
124.
This journal is ß The Royal Society of Chemistry 2005
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