Total synthesis of (+)-bourgeanic acid utilizing o-DPPB-directed allylic substitution

Article abstract of DOI:10.1021/ol9011635

The lichen metabolite (+)-bourgeanic acid has been synthesized utilizing a new strategy for the construction of propionate motifs relying on the o-DPPB-directed copper-mediated allylic substitution. This synthesis features the o-DPPB-directed allylic substitution employing a chiral Grignard reagent, Sharpless asymmetric epoxidation, and reductive epoxide ring opening with a higher order dimethylcuprate to set the four stereogenic centers of the aliphatic depside.

Full text of DOI:10.1021/ol9011635

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3286-3289
Total Synthesis of (+)-Bourgeanic Acid
Utilizing o-DPPB-Directed Allylic
Substitution
Tomislav Reiss and Bernhard Breit*
Institut fu¨r Organische Chemie und Biochemie, Freiburg Institute for AdVanced Studies
(FRIAS), Albert-Ludwigs-UniVersita¨t Freiburg, Albertstrasse 21, 79115 Freiburg, Germany
bernhard.breit@chemie.uni-freiburg.de
Received May 25, 2009
ABSTRACT
The lichen metabolite (+)-bourgeanic acid has been synthesized utilizing a new strategy for the construction of propionate motifs relying on
the o-DPPB-directed copper-mediated allylic substitution. This synthesis features the o-DPPB-directed allylic substitution employing a chiral
Grignard reagent, Sharpless asymmetric epoxidation, and reductive epoxide ring opening with a higher order dimethylcuprate to set the four
stereogenic centers of the aliphatic depside.
Reactions which allow for stereospecific construction of a
carbon skeleton through carbon-carbon bond formation are
of particular value for organic synthesis. In this context, we
recently reported on the development of the o-diphenylphos-
phanylbenzoyl (o-DPPB)-directed allylic substitution with
Grignard-derived organocopper reagents which occurs with
complete control of chemo-, regio-, and stereochemistry
delivering the corresponding SN2′ substitution products with
either a tertiary or a quarternary stereogenic center with
Figure 1. o-DPPB-directed allylic substitution with Grignard-
perfect syn-1,3-chirality transfer (figure 1).1,2 Interestingly,
this reaction requires only a stoichiometric amount of the
Grignard reagent to achieve quantitative transformation. This
allows us to employ valuable functionalized Grignard
reagents and may be employed even in a fragment coupling
derived organocopper reagents.
step in the course of a total synthesis.3 Furthermore, based
on the directed allylic substitution, a new methodology for
the iterative construction of deoxypropionates has been
developed, and the strength and reliability of this methodol-
ogy has been proven.4,5
(1) Demel, P.; Keller, M.; Breit, B. Chem.sEur. J. 2006, 12, 6669. Breit,
B.; Demel, P.; Grauer, D.; Studte, C. Chem. Asian J. 2006, 1, 586. Breit,
B.; Demel, P.; Studte, C. Angew. Chem. 2004, 116, 3874; Angew. Chem.,
Int. Ed. 2004, 43, 3786. Breit, B.; Demel, P. AdV. Synth. Catal. 2001, 343,
We herein report on the total synthesis of the aliphatic depside
bourgeanic acid (1), which relies on our newly developed
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10.1021/ol9011635 CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

strategy for the stereospecific construction of propionate and
acetate-propionate motifs based on the o-DPPB-directed allylic
substitution with allylic o-DPPB ester 2.6,7
Both of them could originate from the same diol 4. As the
key step for the preparation of 4, we envisioned an o-DPPB-
directed allylic substitution of allylic o-DPPB ester 2 with
the chiral Grignard reagent, derived from bromide 5.
The synthesis of bromide 5 began with tosylation of the (R)-
3-(4-methoxybenzyloxy)-2-methylpropan-1-ol (6) (>99% ee)
(available in two steps from Roche ester)11 with tosyl chloride
in pyridine to provide 7 (Scheme 1).
(+)-Bourgeanic acid (1) was isolated as a metabolite from
several Ramalina species of lichen (Figure 2).8 The relative
Scheme 1
Figure 2. Structure of (+)-bourgeanic acid (1) and (-)-hemi-
bourgeanic acid (3).
configuration of 1 was established by degradation and
spectroscopic analysis; hence, Bodo concluded that 1 was
an esterification product of two molecules of 3-hydroxy-
2,4,6-trimethyloctanoic acid. The absolute configuration was
determined by X-ray crystallographic analysis of the deg-
radation product (-)-hemibourgeanic acid (3), as its p-
bromophenacyl ester.9 In 1990, White reported the first
enantioselective synthesis of 1.10
The missing methyl group was introduced utilizing a
copper-catalyzed sp3-sp3 cross-coupling reaction between
7 and methylmagnesium iodide to furnish 8 in a very good
yield.12 Subsequently, the PMB ether was cleaved by
catalytic hydrogenation with palladium on charcoal, and the
obtained alcohol was converted into the desired bromide 5
employing a Mukaiyama redox-condensation protocol.13
The bromide 5 was transformed with magnesium into the
corresponding Grignard reagent and subjected to the condi-
tions of the directed allylic substitution with allylic o-DPPB
ester 2 (99% ee, E/Z > 99:1), in the presence of 0.5 equiv of
copper bromide-dimethyl sulfide to give the protected allylic
alcohol 9 (dr syn/anti ) 99:1) with complete 1,3-chirality
transfer (Scheme 2). Liberation of the alcohol function
Figure 3 illustrates our synthesis plan for 1. Since 1 is a
self-esterification product of hemibourgeanic acid (3), dis-
Scheme 2
Figure 3. Synthesis plan.
connection of the ester linkage traces back to an appropriate
carboxylic acid and a complementary alcohol component.
(2) For other recent important contributions, see: Kioyotsuka, Y.;
Acharya, H. P.; Katayama, Y.; Hyodo, T.; Kobayashi, Y. Org. Lett. 2008,
10, 1719. Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F. Angew. Chem.
2005, 117, 4703; Angew. Chem., Int. Ed. 2005, 44, 4627. Harrington-Frost,
N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel, P. Org. Lett. 2003,
5, 2111. Spino, C.; Beaulieu, C. Angew. Chem. 2000, 112, 2006; Angew.
Chem., Int. Ed. 2000, 39, 1930. Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii,
S.; Yamamoto, Y. J. Org. Chem. 1989, 54, 4055.
occurred upon treatment with tetra-n-butylammonium fluo-
(3) Rein, C.; Demel, P.; Outten, R. A.; Netscher, T.; Breit, B. Angew.
Chem. 2007, 119, 8824; Angew. Chem., Int. Ed. 2007, 46, 8670.
ride. A subsequent Sharpless asymmetric epoxidation14 with
Org. Lett., Vol. 11, No. 15, 2009
3287

catalytic amounts of titanium(IV) isopropoxide and L-(+)-
diethyl tartrate as chiral ligand at -20 °C delivered the syn-
epoxide 11 in a diastereomer ratio of 93:7. Nucleophilic
epoxide ring-opening occurred upon reaction with the higher
order cuprate Me2CuCNLi215 introducing the missing methyl
substitutent to furnish the diol 4 with all four stereogenic
centers in place.16
of the corresponding alcohol 16 with PDC18 furnished the
desired carboxylic acid 13.
Completion of the synthesis began with a Yamaguchi-
Yonemitsu esterification of carboxylic acid 13 with alcohol
12.19 Subsequent cleavage of the silyl ether with TBAF
furnished the hydroxy ester 17 in 64% yield over two steps
(Scheme 4).20 It is worthy of note that applying the same
In order to avoid problems with potential epimerization
during the final esterification to form bourgeanic acid from
hemibourgeanic acid, we decided to couple a protected
hemibourgeanic acid with a complementary alcohol
component at the oxidation state of the diol 4. Thus, the
primary alcohol of the common diol intermediate 4 was
transformed to the TBS ether 12 upon reaction with TBSCl
and imidazole (Scheme 3). The synthesis of the acid 13
Scheme 4
Scheme 3
esterification conditions toward acid 13 and alcohol 14
did not give any esterification product at all, which is
presumably caused by steric reasons. Oxidation of the
primary alcohol function of 17 to the carboxylic acid
occurred smoothly applying PDC as the oxidant. Finally,
catalytic reductive cleavage of the benzyl ether liberated
(+)-bourgeanic acid (1) in a 94% yield. Spectroscopic and
analytical data of 1 were identical to those reported
previously.10
commenced with selective protection of the primary
alcohol function as a TBDPS ether to furnish 14.
Subsequently, the secondary alcohol was orthogonally
protected as the benzyl ether 15 upon reaction with benzyl
trichloroacetimidate in the presence of TfOH at 0 °C.17
Cleavage of the TBDPS ether with TBAF, and oxidation
The total synthesis of the aliphatic depside (+)-bourgeanic
acid (1) has been achieved in 12 steps with an overall yield of
10% starting from 5. The synthesis displays the efficiency of
methodology relying on the on the o-DPPB-directed allylic
substitution for stereoselective construction of propionate
structural motifs and thus complements more traditional strate-
gies relying on aldol and enolate alkylation chemistry.
(4) Herber, C.; Breit, B. Chem. Eur. J. 2006, 12, 6684. Herber, C.; Breit,
B. Angew. Chem. 2004, 116, 3878; Angew. Chem., Int. Ed. 2004, 43, 3790.
(5) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512. Herber, C.;
Breit, B. Angew. Chem. 2005, 117, 5401; Angew. Chem., Int. Ed. 2005,
44, 5267.
(13) Mukaiyama, T. Angew. Chem. 1976, 88, 111; Angew. Chem., Int.
Ed. Engl. 1976, 15, 94.
(6) Reiss, T.; Breit, B. Chem. Eur. J. 2009, 15, 6345.
(7) Bruch, A.; Gebert, A.; Breit, B. Synthesis 2008, 2169.
(8) Bodo, B.; Hebrord, P.; Molho, L.; Molho, D. Tetrahedron Lett. 1973,
14, 1631.
(14) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(15) Lipshutz, B. H.; Kozlowski, J.; Wilhelm, R. J. Am. Chem. Soc.
1982, 104, 2305.
(16) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(17) Iverson, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240.
(9) Bodo, B. Bull. Mus. Natl. Hist. Nat. (Paris) 1975, 349, 23. Bodo,
B.; Trowitzch-Kienast, W.; Schomberg, D. Tetrahedron Lett. 1986, 27, 847.
(10) White, J. D.; Johnson, A. T. J. Org. Chem. 1990, 55, 5938. White,
J. D.; Johnson, A. T. J. Org. Chem. 1994, 59, 3347.
(11) Walkup, R. D.; Boatman, P. D., Jr.; Kane, R. R.; Cunningham,
R. T. Tetrahedron Lett. 1991, 32, 3937.
(18) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(19) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989. (b) Hikotam, M.; Sakurai, Y.; Horita,
K.; Yonemitsu, O. Tetrahedron Lett. 1990, 31, 6367.
(20) Under the basic conditions, a slight epimerization at the R-position
of the carboxylic ester function was observed, and the diastereomeric ratio
could be determined as 92:8.
(12) (a) Tamura, M.; Kochi, J. Synthesis 1971, 303. (b) Fouquet, G.;
Schlosser, M. Angew. Chem. 1974, 86, 82; Angew. Chem., Int. Ed. Engl.
1974, 13, 701.
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Org. Lett., Vol. 11, No. 15, 2009

Acknowledgment. This work was supported by the DFG
including the International Research Training Group “Cata-
lysts and Catalytic Reactions for Organic Synthesis” (IRTG
1038) and the Krupp foundation (fellowship to T.R.). We
thank Novartis, BASF, and Wacker for generous gifts of
chemicals.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL9011635
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