First asymmetric synthesis of the cyclohexanone subunit of baconipyrones A and B. Revision of its structure

Article abstract of DOI:10.1021/ol048988f

(Chemical Equation Presented) An asymmetric synthesis of the 3,5-dihydroxycyclohexanone subunit of baconipyrones A and B, as well as that of the hydroxydiketone subunit of baconipyrones C and D ((-)-(4S,6S)-4,6-dimethyl- 5-hydroxynonan-3,7-dione), is desc

Full text of DOI:10.1021/ol048988f

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3031-3034
First Asymmetric Synthesis of the
Cyclohexanone Subunit of
Baconipyrones A and B. Revision of Its
Structure
Ma¯ris Turks, M. Carmen Murcia, Rosario Scopelliti, and Pierre Vogel*
Laboratory of Glycochemistry and Asymmetric Synthesis, BCH,
Swiss Federal Institute of Technology (EPFL), CH-1015 Lausanne, Switzerland
pierre.Vogel@epfl.ch
Received June 1, 2004
ABSTRACT
An asymmetric synthesis of the 3,5-dihydroxycyclohexanone subunit of baconipyrones A and B, as well as that of the hydroxydiketone
subunit of baconipyrones C and D ((−)-(4S,6S)-4,6-dimethyl-5-hydroxynonan-3,7-dione), is described. Key steps include sulfur dioxide-induced
additions of enoxysilanes to 1,3-dioxy-1,3-dienes, followed by retro-ene desulfitations (retro-ene elimination of SO ).
2
Baconipyrones A-D (Figure 1) were isolated in 1989 by
Faulkner and co-workers from Siphonaria baconi.1 They
constitute an exception to the normal polypropionic skeleton
with their noncontiguous, ester-type backbone.2 The first total
synthesis of (-)-baconipyrone C was presented by Paterson
and co-workers3 in 2000. This work established the absolute
configuration of this natural product. In 2001, Plumet and
co-workers4 reported a total synthesis of the 3,5-dihydroxy-
cyclohexanone unit of baconipyrone A and B starting from
furan via the “naked sugar”methodology.5 Applying our new
C-C bond-forming reaction6 based on the sulfur dioxide-
induced condensation of 1,3-dioxy-1,3-dienes to enoxysi-
lanes, very short and stereoselective synthesis of nonracemic
(+)-(2S,3S,4S,5S,6S)-3-ethyl-3,5-dihydroxy-2,4,6-trimethyl-
cyclohexanone (1), the cyclohexane unit of baconipyrones
A and B, stereomeric derivatives 2-5, and (-)-(4S,6S)-4,6-
dimethyl-5-hydroxynonan-3,7-dione (6), the subunit of ba-
conipyrones C and D, have been realized (Figure 2). As the
(1) Manker, C. D.; Faulkner, D, J.; Stout, J. T.; Clardy, J. J. Org. Chem.
1989, 54, 5371.
(2) Brecknell, D. J.; Collett, L. A.; Davies-Coleman, M. T.; Garson, M.
J.; Jones, D. D. Tetrahedron 2000, 56, 2497.
(3) Paterson, I.; Chen, D. Y.-K.; Acen˜a, J. L.; Franklin, A. S. Org. Lett.
2000, 2, 1513.
(4) Arjona, O.; Menchaca, R.; Plumet, J. Org. Lett. 2001, 3, 107.
(5) (a) Black, K. A.; Vogel, P. J. Org. Chem. 1986, 51, 5341. (b) Warm,
A.; Vogel, P. J. Org. Chem. 1986, 51, 5348. (c) Vogel, P.; Fattori, D.;
Gasparini, F.; Le Drian, C. Synlett 1990, 173. (d) Arjona, O.; Cossy, J.;
Plumet, J.; Vogel, P. Tetrahedron 1999, 55, 13521.
(6) (a) Narkevitch, V.; Schenk, K.; Vogel P. Angew. Chem., Int. Ed.
2000, 39, 1806. (b) Narkevitch, V.; Megevand, S.; Schenk, K.; Vogel P. J.
Org. Chem. 2001, 66, 5080. (c) Narkevitch, V.; Vogel, P.; Schenk, K. HelV.
Chim. Acta 2002, 85, 1674.
Figure 1.
10.1021/ol048988f CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/06/2004

Scheme 2a
a (i) TiCl4, -78 °C, 82%.
appeared immediately (formation of diene‚SO2 complexes)
that started to vanish after 24 h of stirring at -78 °C. After
evaporation of SO2 at -78 °C and solvent at 20 °C (vac.
line), the crude reaction mixture was transferred to a flask
containing Pd(OAc2), Ph3P, and K2CO3 in i-PrOH/MeCN
and heated to 80 °C. After aqueous workup and purification
by flash chromatography on silica gel, two diastereomeric
products 11 and 12 were isolated in 67 and 13% yields,
respectively (Scheme 1).
Our first attempt to promote an intramolecular aldol
reaction of enol isobutyrate moiety with the ethyl ketone
group of 11 used TiCl4 in CH2Cl2 at -78 °C. This led to a
clean deprotection of phenylethyl auxiliary in 82% yield;
no cyclic product was observed (Scheme 2). In a second
attempt, 11 was dissolved in a 8:1 mixture of TFA/anisole
at 0 °C. After 1 h a mixture of at least five products (both,
cyclic and acyclic) was formed.
Figure 2.
spectral data we obtained for 1 were quite different than those
reported by Plumet and co-workers for this compound, we
established its structure by X-ray crystallography. It allows
us to claim that this report represents the first total asym-
metric synthesis of the cyclohexanone subunit of baconipy-
rones A and B.
In an earlier report,7 we demonstrated that enantiomerically
enriched dienes 7a and 7b derived from the inexpensive (S)-
1-phenylethanol (chiral auxiliary) can be condensed with
allylsilanes in the presence of an excess of SO2 and a catalytic
amount of an acid promoter. This generates â,γ-unsaturated
silyl sulfinates 8 that, after workup with Et3NH+TfO- in
MeOH, undergo quick methanolysis, giving products 10 in
good yield and high diastereoselectivity (Scheme 1).
With these unsatisfactory results, we turned to conditions
that could maintain the phenylethyl ether moiety intact. We
found that the treatment of enol butyrate 11 with tributyltin
methoxide8 (neat, 70 °C) led to the formation of a single
product 16 that was isolated pure in 86% yield (Scheme 3).
Scheme 1
Scheme 3a
a (i) Bu3SnOMe, 70 °C, 86%. (ii) H2, Pd/C, quant. (iii) (1S,4R)-
camphanyl chloride, pyridine, quant.
We have now found that enoxysilanes can also be reacted
with 1-alkoxy-3-acyloxy-1,3-dienes in a similar way as with
1-alkoxy-1,3-dienes.6 For instance, when a 1:2 mixture of
diene 7a and (Z)-trimethylsilyl enol ether derived from
pentan-3-one was added to a 1:1 mixture of SO2/toluene
containing 0.25 equiv of Tf2NH, a very intense yellow color
Debenzylation of 16 (H2/Pd-C) was quantitative, furnishing
the dihydroxy cyclohexanone 1, the relative configuration
of which was established by X-ray single-crystal crystal-
(8) (a) Pereyre, M.; Bellegarde, B.; Mendelsohn, J, Valade, J. J.
Organomet. Chem. 1968, 11, 97. (b) Labadie, S. S.; Stille, J. K. Tetrahedron
1984, 40, 2329.
(7) Turks, M.; Fonquerne, F.; Vogel, P. Org. Lett. 2004, 6, 1053.
3032
Org. Lett., Vol. 6, No. 18, 2004

Scheme 4a
Scheme 5
a (i) Bu3SnOMe, 70 °C, 84%. (ii) L-Selectride, -78 °C, 80%.
lography.9 The absolute configuration of 1 was confirmed
by X-ray analysis of the 1-(1S,4R)-camphanyl derivative 17.
Mosher’s esters10 showed a 97% ee for 1. As (S)-1-
phenylethanol with 97% ee was used to prepare diene 7a,
this work demonstrates that the chirality transfer from the
chiral auxilialry to the final product 16 is complete (no
epimerization of the benzyl ethers during the SO2 induced
oxyallylation/retro-ene elimination of SO2 cascade). The
structure of 17 proves that of 11.
The good diastereoselectivity observed for the conversion
of 11 to 16 induced by tributyltin methoxide can be ascribed
to the formation of the tin enolate 14, which equilibrates
with a quasicyclic conformer 15 because of the Lewis acidity
of the tin enolate that allows interaction with the carbonyl
group of the ethyl ketone. A transition state that minimizes
steric repulsions (as shown with 15) favors the formation of
16 (Scheme 3). Similarly, 16 was obtained as a single product
in 83% yield on treating 11 with Sc(OTf)3 at 20 °C.
Previous synthesis of racemic isomer of 1 required 15 steps
from furan and gave a 4% overall yield.4,11 Our approach
converts the readily available diene 7a into 1 in three steps
and with 58% overall yield. Diene 7a is generated from
2-methyl-3-oxopentanal following Danishefsky’s method12
in four steps with 61% yield. On the basis of 2-methyl-3-
oxopentanal, our asymmetric synthesis of 1 requires only
seven steps for an overall yield of 30%.
The absolute configuration of diastereomer 12 was estab-
lished in a similar way by X-ray crystallography of diol 19,
which was obtained by cyclization of 12 followed by
diastereoselective reduction of carbonyl group in intermediate
18 (Scheme 4). Mosher’s esters showed also a 97% ee for
19.
The high diastereoselectivity observed in the reaction of
7a f 11 + 12 (Scheme 2) is better than that observed for
the reactions of related 1-alkoxy-1,3-dienes with enoxysilanes.6b
It can be interpreted in terms of a highly diastereoselective
hetero-Diels-Alder addition of SO2 to diene 7a in which
the C-H bond of the phenylethyl ether resides in the π-plane
of the cis-butadiene moiety (Scheme 5). Thus, the SO2
coordinated to the Lewis acid promoter attacks the face of
the diene syn with respect to the methyl group of the
phenylethyl ether group, giving a sultine 20 that is ionized
irreversibly into zwitterion 21. There are two possible
orientations, 22a and 22b, for the enoxysilane that command
the R,â-relative configuration in 23.13 As 11 is the major
product, orientation 22a must be favored.
When 1-alkoxy-1,3-dienes are used instead of 1,3-dioxy-
dienes,7 the formation of the sulfinic acid intermediate 24
and its desulfitation (retro-ene elimination of SO2) is usually
low-yielding, unless Pd(OAc)2/Ph3P is used as a catalyst in
the presence of K2CO3/i-PrOH/CH3CN and heating to 90
°C.14 The high degree of chirality transfer from the ꢀ-center
of 24 to the γ-center of 11 can be explained by invoking
chairlike transitions states 25a and 25b. For steric reasons
(allylic strain), 25a is more stable than 25b, and the former
controls the stereoselectivity of the reaction.15
As our synthesis of 1 is very short, we explored the
possibility of using it to generate stereoisomers of 1. The
(9) Crystallographic data for 1, 17, 19, and 3a have been deposited with
the Cambridge Crystallographic Data Center as supplementary publication
nos. CCDC-245521, 245648, 245522, and 245520, respectively.
(10) Dale, J. A.; Mosher, H, S. J. Am. Chem. Soc. 1973, 95, 512.
(11) For further comments on the structure reported in ref 4, see
Supporting Information.
(12) (a) Danishefsky, S.; Kitahara, J. J. Am. Chem. Soc. 1974, 96, 7807.
(b) Danishefsky, S.; Bednarsky, M.; Izawa, J.; Maring, C. J. Org. Chem.
1984, 49, 2290. For silyl-acyl exchange, see: Limat, D.; Schlosser, M.
Tetrahedron 1995, 51, 5799.
(13) Electrostatic interaction between the cationic and anionic part of
zwitterion 21 prohibits rotation about C-C bonds in these species, thus
forcing the enoxysilane to attack 21 onto the face anti with respect to the
sulfinate moiety.
(14) Huang, X.; Craita, C.; Vogel, P. J. Org. Chem. 2004, 69, 4272.
(15) (a) Mock, W. L.; Nogent, R. M. J. Org. Chem. 1978, 43, 3483. (b)
Roulet, J. M.; Puhr, G.; Vogel, P. Tetrahedron Lett. 1997, 38, 6201.
Org. Lett., Vol. 6, No. 18, 2004
3033

mixture of 3 and 4 (72%), whereas in CH2Cl2 at -50 °C, a
3.5:1 mixture of 4 and 5 was formed in 76% yield.
Compounds 3, 4, and 5 could be obtained pure by flash
chromatography. Compounds 3 and 4 result from the
transition states 28 (major) and 29 (minor) that should give
2,6-trans-dimethylcyclohexanones. Obviously, enolization
isomerizes them into 2,6-cis-dimethylderivatives (both 2,6-
methyl groups occupy equatorial positions in 3 and 4). In
nonpolar medium (CH2Cl2) and at lower temperature (-50
°C), 27 reacts with TBAF giving 5 as major product
(transition state 29). The latter is then isomerized into 4 above
-50 °C, which is the major isolated product. Heating
enantiomerically enriched 27 derived from 11 (ee 97%) with
MeOH and NH4Cl to 130 °C led to the formation of a
mixture from which diketone 31 was isolated in 41% yield.
Catalytic hydrogenolysis of 31 provided the dihydroxyketone
moiety of baconipyrones C and D (6).17
Scheme 6a
Our SO2-induced oxyallylation of (Z)-3-(trimethylsilyl-
oxy)pent-2-ene followed by retro-ene elimination of SO2 has
a higher yield and is more stereoselective with (E,Z)-2-
methyl-1-(1-phenylethoxy)-penta-1,3-dien-3-yl isobutyrate
than with (E,E)-1-alkoxy-2-methylpenta-1,3-dienes. Com-
plete chirality transfer occurs between the phenylethyl moiety
and final products. This has allowed a very efficient, total
synthesis of the 3,5-dihydroxycyclohexanone subunit of
baconipyrones A and B, as well as that of the dihydroxyke-
tone moiety of baconipyrones C and D. The same approach
also allows one to obtain stereoisomers of 1.
a (i) TESOTf, NEt3, quant. (ii) MeLi, 90%. (iii) (a) BF3‚OEt2/
CH2Cl2/-78 °C, 3:4 ) 9:1, 75%; (b) TBAF/THF/-15 °C, 3:4 )
5:1, 72%. (c) TBAF/CH2Cl2/-50 °C, 4:5 ) 3.5:1, 76%. (iv) MeOH,
NH4Cl, 130 °C. (v) H2, Pd/C, quant.
Acknowledgment. This work was supported by the Swiss
National Science Foundation (Grant 200020-100002) and the
Office Fe´deral de l’Enseignement et de la Recherche (CODT
D13/010/01). M.C.M thanks MECD (Spain) for a postdoc-
toral grant. We thank Mr. S. Reddy Dubbaka for HRMS.
3-epimer of 16, the phenylethyl ether 2, was formed as a
minor compound next to 16 when 11 was treated with
TMSOTf or TMSI in dichloromethane at -78 °C. Compound
2 could be isolated by chromatography from 3:1 mixtures
obtained in 52 and 71% yields, respectively. Treatment of
11 with TESOTf and Et3N provided enoxysilane 26 in
quantitative yield. Reaction of 26 with MeLi gave ethyl
ketone 27 in 90% yield. Intramolecular Mukaiyama aldol
reaction of 27 (Scheme 6) promoted by BF3‚Et2O in CH2-
Cl2 at -78 °C provided a 9:1 mixture of 3 and 4 in 75%
yield.16 With Bu4NF in THF at -15 °C, 28 gave a 5:1
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL048988F
(16) These and following cyclization studies were done in racemic series.
(17) This compound showed spectral data identical to those reported3
([R]D25 ) -15.8 (c ) 0.9 CHCl3); lit.3 [R]D25 ) -16.4 (c ) 1.1 CHCl3)).
3034
Org. Lett., Vol. 6, No. 18, 2004