Deslongchamps annulations with benzoquinone monoketals

Article abstract of DOI:10.1021/ol202809y

The so-called Deslongchamps annulation of deprotonated γ, δ-unsaturated β-ketoesters 15 to 2-(alkoxycarbonyl)cyclohex-2-en-1- ones or similarly activated cyclohex-2-en-1-ones offers a versatile access to various kinds of decalindiones. The scope of Deslon

Full text of DOI:10.1021/ol202809y

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6524–6527
Deslongchamps Annulations with
Benzoquinone Monoketals
ꢀ
Denis Petrovic and Reinhard Bruckner*
€
€
Institut fu€r Organische Chemie und Biochemie, Albert-Ludwigs-Universitat,
Albertstr. 21, 79104 Freiburg im Breisgau, Germany
reinhard.brueckner@organik.chemie.uni-freiburg.de
Received October 19, 2011
ABSTRACT
The so-called Deslongchamps annulation of deprotonated γ,δ-unsaturated β-ketoesters 15 to 2-(alkoxycarbonyl)cyclohex-2-en-1-ones or
similarly activated cyclohex-2-en-1-ones offers a versatile access to various kinds of decalindiones. The scope of Deslongchamps
annulations was extended by establishing acceptor-substituted benzoquinone monoketals such as 13 as viable substrates. They gave
octalindiones such as 35 with diastereoselectivities g 95:5.
Decalins are a structural motif from a large number of
natural products.1 The most famous decalins are the
steroid hormones.2 Tetracycline antibiotics3 are cis-octa-
lins, and there is a strong demand for new variants.4
Mevastatin, or compactin, is a hexalin, which lowered
cholesterol production in man in an unprecedented way.5
Its pharmacophore initiated the development of the statin
family6 of blockbuster drugs in the pharmaceutical indus-
try. Azadirachtin is a crop-protecting cis-decalin with a
THF bridge; it was an exceptionally tough synthetic
target.7
Reflecting this significance, decalin syntheses abound.8,9
Preferred approaches are by DielsÀAlder reactions10 or
Robinson annulations.11 The HajosÀParrishÀWiechertÀ
EderÀSauer variant12 provides enantiomerically pure oc-
talindiones that include the WielandÀMiescher ketone,13
a
key intermediate en route to synthetic steroids. Tandem
cyclizations are particularly suited for making decalins and
cyclohex-annulated or(oligocyclohex)-annulateddecalins.
(1) E. g.: (a) Breitmaier, E. Terpenes; Wiley-VCH: Weinheim, 2006. (b)
Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 2004, 21, 449–477. (c) Wu,
Q.-X.; Shi, Y.-P.; Jia, Z.-J. Nat. Prod. Rep. 2006, 23, 699–734. (d) Fraga,
B. M. Nat. Prod. Rep. 2010, 27, 1681–1708. (e) Hill, R. A.; Connolly,
J. D. Nat. Prod. Rep. 2011, 28, 1087–1117. (f) Fraga, B. M. Nat. Prod.
Rep. 2011, 28, 1580–1610. (g) Frija, L. M. T.; Frade, R. F. M.; Afonso,
C. A. M. Chem. Rev. 2011, 111, 4418–4452. (h) Hanson, J. R. Nat. Prod.
Rep. 2011, 28, 1755–1772.
(8) Reviews: (a) Varner, M. A.; Grossman, R. B. Tetrahedron 1999,
55, 13867–13886. (b) Tokoroyama, T. Synthesis 2000, 611–633. (c)
Singh, V.; Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197–9231.
(9) Recent syntheses of decalin natural products include: (a) Hsu, D.-S.
Hsu, P.-Y.; Lee, Y.-C.; Liao, C.-C. J. Org. Chem. 2008, 73, 2554–2563.
(b) Fleming, F. F.; Gudipati, S. Eur. J. Org. Chem.2008, 5365–5374.
(c) Enev, V. S.; Drescher, M.; Mulzer, J. Org. Lett. 2008, 10, 413–416. (d)
(2) (a) Lednicer, L. Steroid Chemistry at a Glance; Wiley: New York,
2011. (b) Fraser, I. S. Med. J. Aust. 2000, 173, 541–544. (c) Djerassi, C.
This Man’s Pill. Reflections on the 50th Birthday of the Pill; Oxford
University Press: 2004. (d) Loose, D. S.; Stancel, G. M. Estrogens and
Progestins. In Goodman & Gilman’s The Pharmacological Basis of Ther-
apeutics, 11th ed.; Brunton, L. L., Lazo, J. S., Parker, K. L., Eds.; McGraw-
Hill: New York, 2006; pp 1541À1571.
€
Hampel, T.; Bruckner, R. Org. Lett. 2009, 11, 4842–4845. (g) Chen, K.;
Baran, P. S. Nature 2009, 459, 824–828. (e) Chen, K.; Ishihara, Y.;
ꢀ
Galan, M. M.; Baran, P. S. Tetrahedron 2010, 66, 4738–4744. (f)
References 4 and 7.
(10) Reviews: (a) Marsault, E.; Toro, A.; Nowak, P.; Deslong-
champs, P. Tetrahedron 2001, 57, 4243–4260. (b) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. E. Angew. Chem.,
Int. Ed. 2002, 41, 1668–1698. (c) Takao, K.; Munakata, R.; Tadano, K.
Chem. Rev. 2005, 105, 4779–4807.
(3) Nelson, M., Hillen, W., Greenwald, R. A., Eds. Tetracyclines in
€
Biology, Chemistry and Medicine; Birkhauser: Basel, 2001.
(4) Kummer, D. A.; Li, D.; Dion, A.; Myers, A. G. Chem. Sci. 2011,
2, 1710–1718.
(11) Reviews: Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.;
McLoughlin, J. I. Org. React. 1995, 47, 315–552.
(5) (a) Chakravarti, R.; Sahai, V. Appl. Microbiol. Biotechnol. 2004,
64, 618–624. (b) Hudlicky, T.; Reed, J. W. The Way of Synthesis; Wiley-
(12) Hajos, Z. G.; Parrish, D. R. Ger. Pat. DE 2102623, July 29, 1971.
Eder, U.; Sauer, G.; Wiechert, R. Ger. Pat. DE 2014757, October 7, 1971.
ꢀ
VCH: Weinheim, 2007; pp 431À448.
€
(13) (a) Buchschacher, P.; Furst, A.; Gutzwiller, J. Org. Synth. Coll.
€
(6) Schafer, B. Chem. Unserer Zeit 2010, 44, 344–364.
1990, Vol. 7, 368–372. (b) Bradshaw, B.; Etxebarria-Jardı, G.; Bonjoch,
´
ꢀ
ꢀ
(7) Veitch, G. E.; Boyer, A.; Ley, S. V. Angew. Chem., Int. Ed. 2008,
47, 9402–9429.
J.; Viozquez, S. F.; Guillena, G.; Najera, C. Org. Synth. 2011, 88, 330–
341.
r
10.1021/ol202809y
Published on Web 11/15/2011
2011 American Chemical Society

Originally cationic approaches predominated,14 but now
radical-induced15 or radical-cation-induced16 (poly)cyc-
lizations exist as well.
β-ketosulfoxides 1932,34 and of the analogous β-ketosul-
fone 2032 react like Nazarov reagents (Scheme 3).
Scheme 2. Scope of Deslongchamps Annulations with Respect
to Cyclohexenones or Cyclohexadienones
Scheme 1. Deslongchamps Annulation of Nazarov Reagents 2
to Electron-Deficient Cyclohexenones 1a
a Usually a defunctionalization of 3f4 follows.
ꢀ
Deslongchamps and Lavallee contributed a decalin
synthesis,17 referred to as the “Deslongchamps annula-
tion”. It fuses the cesium enolate of a “Nazarov reagent” 2
(i.e., a γ,δ-unsaturated β-ketoester18) to an ester- or a
similarly substituted cyclohexenone 1(Scheme1).19À34 Such
annulations35 give decalindiones with cis-fused rings at
both the initial (3) and the de(alkoxycarbonylated) stage
(4). A variety of structural changes in the cyclohexenone
(Scheme 2) and in the Nazarov reagent are tolerated
(Scheme 3); cesium enolates of the γ,δ-unsaturated
Deslongchamps products 3 and 4 contain four and three
functional groups, respectively. These functional groups
increase in number when cyclohexa-2,5-dien-1-ones 1020,32
or 1120,33 rather than cyclohex-2-en-1-ones (5-9) are in-
corporated. We describe the first Deslongchamps annula-
tions of benzoquinone monoketals, namely compounds
12À14. They deliver the most densely functionalized Des-
longchamps products to date.
(14) Yoder, R. A.; Johnston, J. N. Chem. Rev. 2005, 105, 4730–4756.
(15) (a) Boehm, H. M.; Handa, S.; Pattenden, G.; Roberts, L.; Blake,
A. J.; Li, W.-S. J. Chem. Soc., Perkin Trans. 1 2000, 3522–3538. (b)
~
Justicia, J.; de Cienfuegos, L. A.; Campana, A. G.; Miguel, D.; Jakoby,
Scheme 3. Scope of Deslongchamps Annulations with Respect
to the Nazarov or Related Reagent (18b: This Work)
€
V.; Gansauer, A.; Cuerva, J. M. Chem. Soc. Rev. 2011, 40, 3525–3537.
(16) Rendler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027–5029.
ꢀ
(17) Lavallee, J. F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29,
5117–5118.
(18) Nazarov, I. N.; Zauyalou, S. I. Zh. Obshch. Khim. 1953, 23,
1703–1706. (Chem. Abs. 1954, 48, 77597).
ꢀ
(19) Lavallee, J. F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29,
6033–6036.
(20) Ruel, R.; Hogan, K. T.; Deslongchamps, P. Synlett 1990, 516–
518.
(21) Chapdelaine, D.; Bezile, J.; Deslongchamps, P. J. Org. Chem.
2002, 67, 5669–5672.
(22) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett. 2002, 4,
1091–1094.
(23) Yang, Z.; Shannon, D.; Truong, V. L.; Deslongchamps, P. Org.
Lett. 2002, 4, 4693–4696.
Benzoquinone monoketal 12 was obtained like its ana-
logue containing C(OEt)236 instead of C(OMe)2, by oxidiz-
38
ing a solution of ester 2137 in methanol with PhI(OAc)2
(24) Lepage, O.; Deslongchamps, P. J. Org. Chem. 2003, 68, 2183–
2186.
(25) Chen, L.; Deslongchamps, P. Can. J. Chem. 2005, 83, 728–740.
(26) Ruel, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 28, 3961–
3964.
(Scheme 4). Quinone spiroketal 13 resulted from the
commercially available acid 22 after a regioselective ether-
ification with chloroethanol and esterification with H2SO4
and methanol. The resulting ester 2439 decomposed when
exposedtoPhI(OAc)2 but gave93% 13whenoxidized with
PhI(O2CCF3)2.40 While ester-substituted benzoquinone
(27) Ruel, R.; Deslongchamps, P. Can. J. Chem. 1992, 70, 1939–1949.
€
(28) Tricotet, T.; Bruckner, R. Eur. J. Org. Chem. 2007, 1069–1074.
(29) Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832–
836.
(30) Caron, P.-Y.; Deslongchamps, P. Org. Lett. 2010, 12, 508–511.
(31) Hzang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P.
Angew. Chem., Int. Ed. 2008, 47, 1272–1275.
ꢀ
(36) Grecian, S.; Wrobleski, D. A.; Aube, J. Org. Lett. 2005, 7, 3167–
3170.
ꢀ
(32) Lavallee, J. F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslong-
(37) Compound 21 was prepared from 5-methoxysalicylic acid:
Chaudhury, D. N.; King, H. I.; Robertson, A. J. Chem. Soc. 1948,
2220–2222.
(38) First respective application of this reagent: Pelter, A.; Elgendy,
S. M. A. J. Chem. Soc., Perkin Trans. I 1993, 1891–1896.
(39) Compound 24 was synthesized differently by Corey, E. J.;
Hideo, K. Tetrahedron Lett. 1991, 32, 5025–5028.
champs, P. Can. J. Chem. 1992, 70, 1406–1426.
(33) Rouillard, A.; Bonin, M. A.; Deslongchamps, P. Helv. Chim.
Acta 2003, 86, 3730–3739.
(34) Guay, B.; Deslongchamps, P. J. Org. Chem. 2003, 68, 6140–
6148.
(35) Whether Deslongchamps annulations are DielsÀAlder reac-
tions or proceed by an inter- plus an intramolecular Michael addition
has not been clarified.
(40) First respective application of this reagentTamura, Y.; Yakura,
T.; Haruta, J.; Kita, Y. J. Org. Chem. 1987, 52, 3927–3930.
Org. Lett., Vol. 13, No. 24, 2011
6525

monoketals were described earlier,36,41 the ketone-substi-
tuted monoketal 14 is the first of its kind. It was prepared
from phenol 2542 via isobutyrate 26. A photo-Fries rear-
rangement (λ = 254 nm) provided ketone 27, which was
oxidized with PhI(O2CF3)2.40
A suspension of benzoquinone monoketal 12, Nazarov
reagent 15a, and Cs2CO3 in CH2Cl2 underwent a Deslong-
champs annulation at room temp within 21 h (Scheme 6).
It afforded 68% of the octalindione 32 as a single
stereoisomer.48 Benzoquinone monoketal 13 and the same
Nazarov reagent required 3 h to form 89% of the octal-
indione 34a with the same amount of diastereocon-
trol.48,49 The increases in reactivity and yield suggest that
Scheme 4. Synthesis of Benzoquinone Monoketals 12À14
Scheme 6. Deslongchamps Annulations I to Benzoquinone
Monoketals Plus Subsequent De(tert-butoxy)carbonylations
Nazarov reagents 15a17,20,32 and 15d43 and analogs 15b
and 15c were synthesized trans-selectively by HornerÀ
WadsworthÀEmmons reactions of an appropriate aldehyde
with the dianion of phosphonoketoester 2932 (Scheme 5). We
found it advantageous to access 29 by fragmenting the
phosphonodioxinone 2844 in tert-butanol/toluene at
reflux (i.e., differently than described27).45 Nazarov reagents
18a46 and 18b emerged from aldol addition/oxidation47
sequences engaging γ-butyrolactone (30a) and δ-valero-
lactone (30b), respectively, with crotonaldehyde.
the dioxolane ring exerts less steric hindrance in 13than the
C(OMe)2 moiety in 12. Another beneficial dioxolane effect
was that octalindione 34a, in contrast to 32, was cleanly de-
tert-butylated at 0 °C by CF3CO2H (25% solution in
CH2Cl2). Decarboxylation of the resulting β-ketoacid in
refluxing toluene provided octalindione 35a in 64% yield.
Scheme 5. Synthesis of Nazarov Reagents 15aÀ15d and
18aÀ18ba
(43) Compound 15d was obtained differently by Hartzell, S. L.;
Rathke, M. W. Tetrahedron Lett. 1976, 2757–2760.
(44) Boeckman, R. K.; Thomas, A. J., Jr. J. Org. Chem. 1982, 47,
2823–2824.
(45) We developed this access because the condensation between the
bis(enolate) of tert-butyl acetoacetate and diethyl chlorophosphonate32
provided 29 in unsatisfactory yields and with inseparable contaminants.
(46) Hiroshi, S.; Tsuyoshi, O.; Hiroshi, O. Tetrahedron 2007, 63,
10345–10353.
(47) Dess, A. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
(48) This was concluded from the virtual absence of extraresonances
in the respective 1H (400 MHz, CDCl3) and 13C NMR spectra (100 MHz,
CDCl3). We assume that such spectra should have revealed the presence
of another diastereomer if the latter represented more than 5% of the
material.
(49) When the Nazarov reagent 15a was deprotonated by K2CO3 or
n-BuLi in the presence of the benzoquinone monoketal 13 or before the
latter was added, respectively, the Deslongchamps adduct 34a did not
form at all.
a Keto/enol ratios in CDCl3 solution (400 MHz, 1H NMR spectra):
for 15a, 60:40; for 15b, 73:27; for 15c, 69:31; for 15d, 57:43; for, 18a
17:83; for 18b, 6:94.
(41) Tsai, Y.-F.; Peddinti, R. K.; Liao, C.-C. Chem. Commun. 2000,
475–476.
(42) Crombie, L.; Ryan, A. P.; Whiting, D. A.; Yeboah, S. O.
J. Chem. Soc., Perkin Trans. 1 1987, 2783–2786.
(50) CCDC 849007 (35a), 849008 (38a), and 849006 (38b) contain the
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via the link
www.ccdc.cam.ac.uk/data_request/cif.
6526
Org. Lett., Vol. 13, No. 24, 2011

Its X-ray analysis50 proved the cis-fusion of the rings and the
cis-orientation of the substituents at C-4a and C-5. Both
features are typical for Deslongchamps annulations.19À34
The ester-substituted benzoquinone monoketal 13 ac-
cepted the somewhat bulkier Nazarov reagents 15bÀd
almost as readily as 15a and again with excellent diastereo-
selectivities (ds g 95:5;48 Scheme 7). Subsequent defunc-
tionalizations by trifluoroacetolysis/thermolysis were fea-
sible, too. They delivered the octalindiones 35bÀd as single
diastereomers. The relative configuration of the stereocen-
ters of 35bÀd should be the same as that in the parent
compound 35a.51 The ketone-substituted benzoquinone
monoketal 14 and the Nazarov reagent 15a were processed
similarly. This led to the ketone-substituted octalindione
37 selectively.48 It, too, should be configured like analogue
35a.51
Scheme 8. Deslongchamps Annulations III to Benzoquinone
Monoketals
Scheme 7. Deslongchamps Annulations II to Benzoquinone
Monoketals Plus Subsequent De(tert-butoxy)carbonylations
enolate, which would be (Z)-configured, if these annula-
tions were 1-step reactions.35
In summary we synthesized a number of acceptor-sub-
stituted benzoquinone monoketals (12À14). We found
that they undergo Deslongchamps annulations with stan-
dard Nazarov reagents (15aÀd) or their lactone-contain-
ing variants (18a,b). These annulations proceeded with a
high degree of both simple and induced diasteroselectivity.
The initially obtained octalindiones (32, 34aÀd, 36) or
their readily prepared de(tert-butoxy)carbonylation pro-
ducts (35aÀd, 37) exhibit five to six functional groups. The
lactone-based Nazarov reagents 18a,b furnished the tri-
cyclic annulation products 38a,b, respectively. They
feature six functional groups and a spirolactone moi-
ety. Since diterpenoids with a spirolactone-substituted
decalin scaffold are widespread52 and their syntheses
are an area of current activity,53 accessing such com-
pounds by the strategy shown in Scheme 8 is an inter-
esting perspective.
A while ago we established that lactone-containing
Nazarov reagents undergo Deslongchamps annulations
with type-5 cyclohexenones.28,46 We have found since that
they also annulate to the benzoquinone monoketal 13
(Scheme 8). Nazarov reagent 18a delivered 90% diaster-
eomerically purespiro-γ-lactone 38a, and Nazarovreagent
18b, 74% diastereomerically pure spiro-δ-lactone 38b.48
Both products were elucidated configurationally by X-ray
crystallography.50 It is noteworthy that the cis-orientation
of their C-5;Me and C-8;CdO bonds would follow with
necessity from the intermediacy of a cesium-chelating
Acknowledgment. The authors thank Dr. Jens Geier
€
and Dr. Manfred Keller (Institut fur Organische Chemie
und Biochemie, Albert-Ludwigs-Universitat Freiburg) for
€
the X-ray analyses.
Supporting Information Available. Experimental pro-
cedures, characterization data, copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(51) This conclusion is not only based on a plausible analogy but also
on circumstantial 1H NMR evidence. In CDCl3 solutions 8a-H is
significantly deshielded (35a: δ = 3.40 ppm; 35b: δ = 3.43 ppm; 35c:
δ = 3.39 ppm; 35d: δ = 4.05À4.10 ppm (includes deshielding effect of R-
phenyl group); 37: δ = 3.22 ppm) compared to 5-H (35a: δ = 2.79 ppm;
35b: δ = 2.68 ppm; 35c: δ = 2.58 ppm; 35d: δ = 3.48 ppm (includes
deshielding effect of R-phenyl group); 37: δ = 2.56À2.68 ppm). This
indicates that 8a-H is cis-oriented and 4-H trans-oriented relative to the
ester substituent at C-4a.
(52) Review: Bruno, M.; Piozzi, F.; Rosselli, S. Nat. Prod. Rep. 2002,
19, 357–378.
(53) Review: Bartoli, A.; Rodier, F.; Commeiras, L.; Parrain, J.-L.;
Chouraqui, G. Nat. Prod. Rep. 2011, 28, 763–782.
Org. Lett., Vol. 13, No. 24, 2011
6527