Total synthesis of 7,11-cyclobotryococca-5,12,26-triene using an oxidative radical cyclization as a key step

Article abstract of DOI:10.1021/ol100794k

(Figure presented) An efficient total synthesis of the novel botryococcene-related hydrocarbon 7,11-cyclobotryococca-5,12,26-triene is reported that uses, as a key step, an oxidative radical cyclization of a 4-pentenyl malonate for the synthesis of a [3.3

Full text of DOI:10.1021/ol100794k

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2738-2741
Total Synthesis of
7,11-Cyclobotryococca-5,12,26-triene
Using an Oxidative Radical Cyclization
as a Key Step
Justin J. Davies,† Thomas M. Krulle,‡ and Jonathan W. Burton*,†
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford OX1 3TA, U.K., and Prosidion Limited, Windrush Court,
Watlington Road, Oxford OX4 6LT, U.K.
jonathan.burton@chem.ox.ac.uk
Received April 6, 2010
ABSTRACT
An efficient total synthesis of the novel botryococcene-related hydrocarbon 7,11-cyclobotryococca-5,12,26-triene is reported that uses, as a
key step, an oxidative radical cyclization of a 4-pentenyl malonate for the synthesis of a [3.3.0]-bicyclic γ-lactone.
In 2000, Albrecht and co-workers reported the isolation and
structure elucidation of a novel botryococcene-related hy-
drocarbon, 7,11-cyclobotryococca-5,12,26-triene 1 (Figure
1), from the sediments of Lake Cadagno, Switzerland.1 The
structure of 1 was assigned on the basis of NMR spectro-
scopic and mass spectrometric analysis as well as chemical
derivatization. On the basis of a slight splitting in the signal
of the C-29 methyl doublet in the 1H NMR spectrum, it was
suggested that the natural product was a 9:1 mixture of C-17
diastereomers.1 The triene 1 represents the first example of
a C30 botryoccene hydrocarbon with a midchain cyclopen-
tane.2,3 Synthetically, 1 contains a number of challenging
structural motifs including: adjacent tertiary, tertiary, and
quaternary stereocenters;4 two stereodefined trisubstituted
alkenes; and no heteroatom-based functionality. A racemic
total synthesis of the C-17 diastereomers of 1 would allow
confirmation that the natural product is a mixture of
diastereomers at this position as well as verify the overall
structure of the hydrocarbon. Furthermore, it would provide
a platform for the development of an enantioselective
(3) For discussions concerning the biosynthesis of 1 see ref 1 and Pan,
J.-J.; Bugni, T. S.; Poulter, C. D. J. Org. Chem. 2009, 74, 7562–7565
.
† University of Oxford.
(4) For reviews on the asymmetric synthesis of all carbon quaternary
stereocenters see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591–4597. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388–401. (c) Fuji, K. Chem. ReV. 1993, 93, 2037–2066.
(5) Kambara, H.; Yamada, T.; Tsujioka, M.; Matsunaga, S.; Tanaka,
R.; Ali, H. I.; Wiart, C.; Yusof, M.; Hassan, H.; Hanifah, A.; Fauzi, Z. M.;
Mazlan, N. H.; Jay, M.; Kunishima, M.; Akaho, E. Chem. BiodiVersity 2006,
3, 1301–1306.
‡ Prosidion Limited.
(1) Behrens, A.; Schaeffer, P.; Bernasconi, S.; Albrecht, P. Org. Lett.
2000, 2, 1271–1274.
(2) A C30 unsaturated hydrocarbon with the same carbon skeleton as
7,11-cyclobotryococca-5,12,26-triene may have previously been isolated.
See: ref 1 and Requejo, A. G.; Quinn, J. G. Geochim. Cosmochim. Acta
1983, 47, 1075–1090.
10.1021/ol100794k  2010 American Chemical Society
Published on Web 05/18/2010

Figure 1. Retrosynthetic analysis of 7,11-cyclobotryococca-5,12,26-triene 1.
synthesis of the natural product, and related compounds,5
which would ultimately allow the assignment of the C-17
stereocenter of each diastereomer of 1 relative to the ring
stereocenters.
We have recently reported an efficient methodology for
the synthesis of [3.3.0]-bicyclic γ-lactones based on the
oxidative radical cyclization of 4-pentenyl malonates medi-
ated by manganese(III) acetate.6,7 Herein we report the
application of this methodology to the total synthesis of racemic
7,11-cyclobotryococca-5,12,26-triene 1.
Retrosynthetic analysis of 1 is shown in Figure 1. The
two trisubstituted alkenes were to be installed from the
corresponding protected dihydroxymethyl-substituted cyclo-
pentane 3. The trisubstituted cyclopentane would be syn-
thesized by methylenation of the lactol 4 which would, in
turn, be made from the [3.3.0]-bicyclic γ-lactone 5. The
bicyclic γ-lactone 5 was to be prepared by an oxidative
radical cyclization of the 4-pentenyl malonate 6 according
to our recent report.6
the cyclization substrate 66 via the corresponding mesylate
9. Exposure of the 4-pentenyl malonate 6 to manganese(III)
acetate and copper(II) triflate9 in freeze-thaw degassed
acetonitrile at reflux delivered the [3.3.0]-bicyclic γ-lactone
5 in good yield.10 We have conducted this cyclization on
scales in excess of 15 g of substrate and always obtained
the [3.3.0]-bicyclic γ-lactone 5 in yields in excess of 75%
and with good diastereocontrol (>13:1 dr). The mechanism
for the formation of the bicyclic γ-lactone 5 most likely
involves formation of an electrophilic C-centered radical from
reaction of the malonate 6 with manganese(III) acetate. The
educt radical so formed undergoes 5-exo-trig cyclization via
the chairlike transition state 10 in accord with the
Beckwith-Houk11,12 model for 5-exo-trig radical cycliza-
tions, to deliver an adduct radical which is oxidized by
copper(II)7,13-15 to give the γ-lactone product.
The fused bicyclic γ-lactone 5 was readily decarboxylated
under Krapcho conditions to give the γ-lactone 11 as
previously demonstrated (Scheme 2).6,16 Exposure of the
γ-lactone 11 to LDA and methyl iodide introduced the
The known ester 7 was synthesized in two steps from cis-
2-butene-1,4-diol using a Johnson-Claisen rearrangement
as a key step (Scheme 1).8 The ester 7 was readily reduced
(6) Powell, L. H.; Docherty, P. H.; Hulcoop, D. G.; Kemmitt, P. D.;
Burton, J. W. Chem. Commun. 2008, 2559–2561
.
(7) For reviews of the use of manganese(III) acetate in organic synthesis
see: (a) Snider, B. B. Chem. ReV. 1996, 96, 339–363. (b) Melikyan, G. G.
Org. React. 1997, 49, 427–675. (c) Melikyan, G. G. Aldrichimica Acta 1998,
31, 50–64. (d) Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4,
Scheme 1. Synthesis of the [3.3.0]-Bicyclic γ-Lactone 5
323–351
(8) Gross, A.; Borcherding, D. R.; Friedrich, D.; Sabol, J. S. Tetrahedron
Lett. 2001, 42, 1631–1633
.
.
(9) For the use of copper(II) triflate in conjunction with manganese(III)
acetate, see: (a) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.; Muraoka,
O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42, 1729–1732. (b)
Hulcoop, D. G.; Burton, J. W. Chem. Commun. 2005, 4687–4689. (c)
Hulcoop, D. G.; Sheldrake, H. M.; Burton, J. W. Org. Biomol. Chem. 2004,
2, 965–967
.
(10) For the synthesis of γ-lactones using (a) manganese(III) acetate
and copper(II) acetate see: Snider, B. B.; McCarthy, B. A. J. Org. Chem.
1993, 58, 6217–6223. (b) Cerium(IV) ammonium nitrate see: Baciocchi,
E.; Paolobelli, A. B.; Ruzziconi, R. Tetrahedron 1992, 48, 4617–4622
.
(11) Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron Lett. 1985, 26,
373–376
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(12) Rudolf, K.; Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987,
52, 3708–3710
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(13) Freiberg, M.; Meyerstein, D. J. Chem. Soc., Faraday Trans. 1 1980,
76, 1825–1837
(14) Freiberg, M.; Mulac, W. A.; Schmidt, K. H.; Meyerstein, D.
J. Chem. Soc., Faraday Trans. 1 1980, 76, 1838–1848
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(15) Kochi, J. K. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York,
1973; Vol. 1, pp 594-623.
(16) This reaction was conducted on ca. 1 g scale. On a smaller scale
(ca. 300 mg), the yield can be as high as 90%.
with DIBAL-H to give the alcohol 8 (99%); LiAlH4 gave
nonreproducible results. The alcohol 8 was converted into
Org. Lett., Vol. 12, No. 12, 2010
2739

alcohol 14 which was readily transformed into the allylic
chloride 15 with good diastereocontrol (>8:1 C-12 E:Z) on
treatment with thionyl chloride (Scheme 3).27 After further
Scheme 2. Elaboration of the [3.3.0]-Bicyclic γ-Lactone 5
Scheme 3. Introduction of the C-11 Side Chain
bridgehead methyl group giving 12 with complete stereo-
control. The γ-lactone 12 was readily reduced to the
corresponding lactols 4, and methylenation of the lactols with
dimethyltitanocene17-19 gave the alcohol 3 with the C-10
quaternary stereocenter fully installed; the use of methylene
triphenylphosphorane or the Tebbe reagent20,21 was far less
efficient, resulting in protecting group loss or migration. The
primary alcohol in 3 was efficiently oxidized to the corre-
sponding aldehyde 13 with the Dess-Martin periodinane22,23
in readiness for introduction of the C-12 trisubstituted olefin.
The stereoselective formation of trisubstituted double
bonds is still a challenge in organic synthesis.24 We
investigated a large number of routes for the introduction of
the C-12 olefin including Wittig-type reactions on the
aldehyde 1325 and hydrometalation/cross-coupling reactions
on the methyl-substituted acetylene derived from the alde-
hyde 13; however, neither of these approaches proved
successful. The aldehyde 13 is sterically quite hindered, and
consequently, Wittig reactions were low yielding; addition-
ally, hydrometalation reactions of the acetylene derived from
the aldehyde 13 were complicated by the presence of the
C-26 terminal alkene.26 After considerable work, we found
that the use of a copper-catalyzed cross-coupling procedure
was effective. Thus, iso-propenylmagnesium bromide was
added to the aldehyde 13 in excellent yield to give the allylic
synthetic effort, we found that addition of a solution of the
allylic chloride and Kochi’s catalyst (Li2CuCl4)28,29 to a
solution of the commercially available racemic Grignard
reagent 16 in THF30 followed by treatment with TBAF
allowed isolation of the coupled product 17 as a single olefin
diastereomer in excellent yield.31
We were attracted to the use of organocopper methodology
for the synthesis of the trisubstituted C-5 olefin in the C-7
side chain (Scheme 4). Thus, the primary alcohol 17 was
readily oxidized to give the corresponsing aldehyde 1822,23
which was converted into the terminal acetylene 19 using
the Ohira-Bestmann reaction (89%).32,33 The terminal
acetylene 19 was converted into the corresponding substituted
methyl propiolate 20. Low temperature treatment of the
propiolate 20 with the Gilmann reagent, followed by a
methanol quench, gave the R,ꢀ-unsaturated ester 21 as a
single geometric isomer which was reduced to the allylic
alcohol 22 on exposure to DIBAL.34 The allylic alcohol 22
was converted into the natural product by initial chlorination
followed by treatment with iso-butylmagnesium chloride and
(17) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392–
(27) (a) Young, W. G.; Caserio, F.; Brandon, D. Science 1953, 117,
473. (b) Caserio, F. F.; Dennis, G. E.; Dewolfe, R. H.; Young, W. G. J. Am.
Chem. Soc. 1955, 77, 4182–4183. (c) Ireland, R. E.; Wrigley, T. I.; Young,
W. G. J. Am. Chem. Soc. 1958, 80, 4604–4606. (d) Young, W. G.; Caserio,
F. F.; Brandon, D. D. J. Am. Chem. Soc. 1960, 82, 6163–6168. (e) Pegolotti,
J.; Young, W. G. J. Am. Chem. Soc. 1961, 83, 3251–3258. For recent
examples in natural product synthesis see: (f) Wender, P. A.; Jesudason,
C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem.
Soc. 1997, 119, 12976–12977. (g) Smith, A. B.; Basu, K.; Bosanac, T. J. Am.
Chem. Soc. 2007, 129, 14872–14874. (h) Smith, A. B.; Bosanac, T.; Basu,
K. J. Am. Chem. Soc. 2009, 131, 2348–2358. (i) Paquette, W. D.; Taylor,
R. E. Org. Lett. 2004, 6, 103–106.
6394
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(18) Petasis, N. A.; Lu, S. P.; Bzowej, E. I.; Fu, D. K.; Staszewski,
J. P.; AkritopoulouZanze, I.; Patane, M. A.; Hu, Y. H. Pure Appl. Chem.
1996, 68, 667–670
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(19) Payack, J. F.; Huffman, M. A.; Cai, D. W.; Hughes, D. L.; Collins,
P. C.; Johnson, B. K.; Cottrell, I. F.; Tuma, L. D. Org. Process Res. DeV.
2004, 8, 256–259
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(20) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611–3613
(21) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am. Chem.
Soc. 1980, 102, 3270–3272
(22) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156
(23) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549–7552
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(28) Tamura, M.; Kochi, J. Synthesis 1971, 303–305
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(29) For a review on organocopper chemistry see: Lipshutz, B. H.;
(24) For a review on the Synthesis of highly substituted olefins see:
Flynn, A. B.; Ogilvie, W. W. Chem. ReV. 2007, 107, 4698–4745.
(25) For a recent example of difficulty encountered when using a Wittig
reaction to form a trisubstituted olefin see: Snyder, S. A.; Tang, Z.-Y.; Gupta,
R. J. Am. Chem. Soc. 2009, 131, 5744–5745.
Sengupta, S. Org. React. 1992, 41, 135–631.
(30) This is the procedure described by Monte and Lindbeck: Monte,
W. T.; Lindbeck, A. C. Org. Process Res. DeV. 2001, 5, 267–269.
1
(31) The crude H NMR of the coupled product 2 did not indicate the
presence of any other alkene diastereomers.
(26) For a recent example of competitive hydrometallation of a terminal
olefin in the presence of an internal acetylene see: Semmelhack, M. F.;
Hooley, R. J.; Kraml, C. M. Org. Lett. 2006, 8, 5203–5206.
(32) Ohira, S. Synth. Commun. 1989, 19, 561–564
(33) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521–522
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.
2740
Org. Lett., Vol. 12, No. 12, 2010

Scheme 4. Completion of the Synthesis of 1
Kochi’s catalyst.28,29 The crude 1H and 13C NMR indicated
the presence of approximately a 1:1 mixture of the natural
product 1 with other hydrocarbon byproducts; the structures
of the byproducts were tentatively assigned as the isomers
23 and 24.35 The natural product could be isolated as the
major constituent after argentation chromatography (53% 6:1
mixture with byproducts).36 The synthetic material is a 1:1
mixture of C-17 diastereomers and had spectroscopic data
entirely in accord with the natural material.37 Furthermore,
the synthetic material clearly showed two separate doublets
confirming that the natural material is indeed a 9:1 mixture
of C-17 diastereomers.
In conclusion, we have developed an efficient synthesis
of the hydrocarbon natural product, 7,11-cyclobotryococca-
5,12,26-triene 1, which features an oxidative radical cycliza-
tion for the diastereoselective synthesis of a [3.3.0]-bicyclic
γ-lactone as a key step, along with copper catalyzed coupling
reactions for the stereocontrolled synthesis of the two
trisubstituted olefins. Further reports on the use of oxidative
radical chemistry in the synthesis of natural products
containing all carbon quaternary stereocenters will be forth-
coming.
1
for the C-29 methyl group in the H NMR spectrum thus
(34) We followed the procedure of Uguen and co-worker for the
preparation of the allylic alcohol 22 from the acetylene 19: Zoller, T.; Uguen,
D.; DeCian, A.; Fischer, J.; Sable, S. Tetrahedron Lett. 1997, 38, 3409–
3412.
Acknowledgment. We thank Prosidion Limited and the
Royal Society (London) for funding this work; Prof. Albrecht
for providing copies of the NMR spectra of natural 1; and
Dr Sarah Aves for initial studies.
(35) The assignment of the structures 23 and 24 is only tentative as
isolation of pure compounds was not possible. The formation of 23 and 24
may be due to the formation of isomeric allylic chlorides in the previous
step.
(36) Further purification provided pure 1.
(37) The spectra of the synthetic material completely match the copies
of the original spectra kindly supplied by Prof. Albrecht (ref 1). There is a
typographical error in the reported 13C NMR data of the natural product
(ref 1). The C-15 13C NMR resonance is quoted at δ ) 25.79 ppm, whereas
in the original spectra, and the spectra of the synthetic material, C-15
resonates at δ ) 24.80 ppm.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100794K
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2741