Total synthesis of (+)-bourgeanic acid utilizing desymmetrization strategy

Article abstract of DOI:10.1002/ejoc.201001199

A highly stereoselective total synthesis of an aliphatic depside (+)-bourgeanic acid via (-)-hemibourgeanic acid and bourgeanic lactone is described. The key steps involved in this synthesis are desymmetrization of bicyclic olefin with Brown's asymmetric

Full text of DOI:10.1002/ejoc.201001199

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001199
Total Synthesis of (+)-Bourgeanic Acid Utilizing Desymmetrization Strategy
Jhillu S. Yadav,*[a] K. V. Raghavendra Rao,[a] K. Ravindar,[a] and B. V. Subba Reddy[a]
Keywords: Total synthesis / Asymmetric synthesis / Natural products / Bourgeanic acid
A highly stereoselective total synthesis of an aliphatic de-
pside (+)-bourgeanic acid via (–)-hemibourgeanic acid and
bourgeanic lactone is described. The key steps involved in
this synthesis are desymmetrization of bicyclic olefin with
Brown’s asymmetric hydroboration, Gillman’s reaction,
TEMPO-BAIB mediated selective oxidation of 1,3-diol, Yam-
aguchi macro-lactonization and LiOH-mediated partial hy-
drolysis of unusually stable eight-membered cyclic dilactone.
Introduction
The first member of the lichen metabolites of a new class
of naturally occurring aliphatic depsides, (+)-bourgeanic
acid (1) was isolated by Bodo group in 1973 from the spe-
cies of lichen Ramalina.[1] The structure of 1 was deduced
by the same group as an esterification product of two mole-
cules of (–)-hemibourgeanic acid 3 [(2S,3S,4R,6R)-3-hy-
droxy-2,4,6-trimethyloctanoic acid], which was further con-
firmed by the saponification of 1. The absolute configura-
tion of (–)-hemibourgeanic acid 3 was proposed by the X-
ray crystallographic analysis of its p-bromophenacyl es-
ter.[2,3] An interesting property of the (+)-bourgeanic acid
Figure 1. Chemical structures of (+)-bourgeanic acid (1), bourge-
anic lactone (2) and (–)-hemibourgeanic acid (3).
(1), discovered by Bodo et al. During the degradative stud- metrization of bicyclic olefin and substrate-controlled ster-
ies was the formation of an eight-membered dilactone eoselective transformations to create contiguous stereocen-
(bourgeanic lactone) 2 under mild dehydrating conditions.[2] ters. This strategy was successfully employed in our labora-
The conformational analysis of this dilactone showed that, tory for the total synthesis of several biologically potent
it contains an eight-membered ring, which adopts a crown- and structurally novel natural products.[6] Herein we report
shaped conformation with C2-axis of symmetry with all the a highly stereoselective total synthesis of an aliphatic de-
substituent’s in equatorial orientation. This special feature pside, (+)-bourgeanic acid (1) via the unusual and remarka-
undoubtedly contributes to the ready formation of the bly stable bourgeanic lactone (2) and (–)-hemibourgeanic
eight-membered structure (Figure 1).[3]
acid (3), radically different from the procedures reported so
The first total synthesis of (+)-bourgeanic acid (1) was far.
reported by White et al. using (S)-N-propionylprolinol-
mediated asymmetric alkylation followed by condensation
with (E)-crotylboronate (Roush’s modified procedure).[4]
Recently, Breit et al. reported the second total synthesis
using the o-DPPB-directed [o-DPPB = o-(diphenylphos-
phanyl)benzoyl] organocopper-mediated allylic substitution
and the Sharpless asymmetric epoxidation as the key
steps.[5] For the last few years, our laboratory has explored
the potentials of desymmetrization strategy in natural prod-
uct synthesis. Our approach typically involves in the desym-
Results and Discussion
Retrosynthetic analysis of (+)-bourgeanic acid (1) via the
formation of bourgeanic lactone (2) and (–)-hemibourge-
anic acid (3) is depicted in Scheme 1, which illustrates that
(+)-bourgeanic acid could be achieved by the partial hydrol-
ysis of bourgeanic lactone (2), which in turn could easily be
obtained from (–)-hemibourgeanic acid using Yamaguchi
macrolactonization. Compound 3 could be prepared from
triol 4, which would be easily achieved by the LiAlH4 medi-
ated reductive opening of exo-alkylated bicyclic lactone 5.
Lactone 5 can be easily prepared from bicyclic olefin 6
through desymmetrization using Brown’s asymmetric hy-
droboration and subsequent substrate-controlled transfor-
mations.
[a] Organic Chemistry Division I, Indian Institute of Chemical,
Technology (CSIR),
Hyderabad 500007, India
Fax: +91-40-27160512
E-mail: yadavpub@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001199.
58
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 58–61

Total Synthesis of (+)-Bourgeanic Acid
δ = 1.13 (J = 6.7 Hz) ppm, respectively and the two benzylic
proton signals appeared as ABq at δ = 4.67 ppm, and the
IR spectrum revealed the hydroxy absorption at 3430 cm–1.
Thus, the prepared triol 4 was extensively utilized by our
group as a key building block in the synthesis of various
natural products.[6] The chemoselective protection of 1,3-
diol 4 using 2,2-DMP, pTsA (catalytic) in acetone:ether
(9:1) afforded the corresponding acetonide 8 in 83% yield,[8]
which was confirmed by the 13C NMR spectrum analysis (δ
= 98.0 ppm for the acetonide carbon flanked by two oxygen
atoms). Tosylation of primary alcohol 8 using TsCl, Et3N,
DMAP in CH2Cl2 afforded the tosylate 9 in 86% yield,[9]
1H NMR spectrum of the compound 9 revealed the pres-
Scheme 1. Retrosynthetic analysis of (+)-bourgeanic acid (1).
As outlined in Scheme 2, the key fragment 14, which ence of two ortho aromatic protons resonating as doublet
contains all the required stereocenters of target molecule 1 at δ = 7.76 ppm, and the methyl protons of the tosyl group
was prepared mainly on the basis of desymmetrization of at δ = 2.45 ppm as a singlet. Then compound 9 was sub-
bicyclic olefin 6 using Brown’s chiral hydroboration with jected to Gillman’s reaction with 6.0 equiv. of dimethyllith-
diisopinocamphenylborane [(–)-Ipc2BH]. High enantio- ium cuprate (Me2CuLi) (prepared from 6 equiv. of CuI and
meric purity (97% ee) was achieved in hydroboration using 12 equiv. of MeLi, 1 m solution in Et2O) in Et2O at –30 °C
1
(–)-Ipc2BH prepared from borane–dimethyl sulfide complex to afford methylated product 10 in 91% yield.[10] The H
and excess of (+)-α-pinene. The chiral bicyclic alcohol 7 was NMR spectrum of the compound 10 revealed the disap-
converted into the exo-alkylated bicyclic lactone 5 by fol- pearance of tosyl signals at their positions. Debenzylation
lowing standard procedures.[7a] LiAlH4 mediated reductive of compound 10 under radical conditions using Li-naph-
opening of exo-alkylated bicyclic lactone 5 gave the triol 4 thalenide in anhydrous THF at 30 °C gave the alcohol 11
in 83% yield,[7] the structure of which was confirmed by the in 89% yield.[11] The C-5 oxygen of the compound 11 needs
1H NMR spectrum in which three methyl doublets ap- to be deoxygenated to get the complete stereochemistry of
peared at δ = 0.73 (J = 6.7 Hz), 0.96 (J = 6.7 Hz) ppm and the target molecule. Accordingly, compound 11 was con-
Scheme 2. Synthesis of diol 14.
Eur. J. Org. Chem. 2011, 58–61
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
59

J. S. Yadav, K. V. R. Rao, K. Ravindar, B. V. S. Reddy
SHORT COMMUNICATION
Scheme 3. Synthesis of (+)-bourgeanic acid (1).
verted into xanthate ester 12 using NaH, carbon disulfide
and methyl iodide. The H NMR spectrum of xanthate es-
Conclusions
1
In conclusion, an efficient and highly stereoselective total
synthesis of (+)-bourgeanic acid 1 via bourgeanic lactone
(2) and (–)-hemibourgeanic acid (3) has been achieved. The
salient features of this strategy are the utilization of our
desymmetrization strategy to construct all the asymmetric
centers of the natural product 1. Thus an efficient synthetic
route was developed for the remarkably stable lactone 2
using Yamaguchi’s macrolactonization of sterically more
hindered acid 3 and lithium hydroxide-mediated partial hy-
drolysis of the eight-membered cyclic dilactone 2. The syn-
thesis follows 11-step linear synthetic sequence proceeding
from the readily available triol 4, which gave an overall yield
of 11%.
ter 12 showed a characteristic signal as dd (doublet of
doublet) at δ = 5.81 ppm for methine proton attached to
xanthate group, a singlet at δ = 2.47 ppm for methyl protons
attached to sulfur in the xanthate group. Then it was deoxy-
genated by tri-n-butyltin hydride in the presence of a cata-
lytic amount of AIBN as radical initiator (Barton–McCom-
bie deoxygenation) to afford compound 13 in 92% yield,[12]
which was confirmed by H NMR analysis. H NMR of
the compound 13 showed the absence of proton resonance
at δ = 5.81 ppm corresponds to methine attached to the
xanthate group. Treatment of acetonide 13 with 2 n HCl in
THF/H2O (1:1) afforded the desired 1,3-diol 14 in 80%
yield, which was confirmed by the absence of proton reso-
nance at δ = 1.33 ppm corresponds to gem-dimethyl group
and IR spectrum showed absorption band at 3372 cm–1 for
O–H stretching frequency (Scheme 2).[13]
1
1
Experimental Section
General: All reactions were carried out under an inert atmosphere
of argon or nitrogen by applying standard syringe, septa, and can-
nula techniques unless otherwise mentioned. Commercial reagents
were used without further purification. All solvents were purified
by standard techniques. Infrared (IR) spectra were recorded with
a Perkin–Elmer 683 spectrometer with NaCl optics. Spectra were
calibrated against the polystyrene absorption at 1610 cm–1. Sam-
ples were either scanned neat, in KBr wafers, or in chloroform as
a thin film. 1H NMR spectra were recorded in CDCl3 with a
Bruker 300, Varian Unit 500 MHz NMR spectrometer. 13C NMR
spectra were recorded at 75 MHz in CDCl3 using tetramethylsilane
(TMS) as the reference standard. Column chromatography was
performed using silica gel (60–120 mesh) and the column was usu-
ally eluted with ethyl acetate/petroleum ether. Visualization of the
spots on TLC plates was achieved either by exposure to iodine
vapor or UV light or by dipping the plates to sulfuric acid/β-naph-
thol or to ethanolic anisaldehyde/sulfuric acid/acetic acid or to
phosphomolybdic acid-sulfuric acid solution and heating the plates
at 120 °C. Mass spectra were obtained on a Finnigan MAT1020B
or micromass VG 70-70H spectrometer operating at 70 eV using a
direct inlet system. Optical rotations were recorded with a Perkin–
Elmer 241 polarimeter in 1.0 dm, 1.0 mL cells.
Selective oxidation of 1,3-diol 14 using TEMPO-BAIB
afforded the β-hydroxy aldehyde, which was used as such in
the next step without further purification. Oxidation of β-
hydroxy aldehyde under Pinnick’s conditions (NaClO2,
NaH2PO4·2H2O)[14] cleanly furnished the acid 3 in 74%
yield.[15] 1H and 13C NMR analysis and optical rotation
[α]D = –3.5 were in good agreement with literature.[4b] Yam-
aguchi macrolactonization (2,4,6-trichlorobenzoyl chloride,
Et3N, DMAP) of hemibourgeanic acid under dilute condi-
tions afforded the bourgeanic lactone 2 in 87% yield.[16]
This was confirmed by the 13C NMR analysis, which clearly
showed only 11 signals (including cyclic ester C=O at δ =
176.4 ppm), indicating that the dilactone possesses C2 sym-
metry (Scheme 3).[4]
Notably, the partial hydrolysis of dilactone 2 was ob-
served within 30 min using 1.0 equiv. of LiOH in THF/H2O
(1:1) to afford the target natural product, (+)-bourgeanic
acid (1) ([α]D = +7.0) in 54% yield. The complete hydrolysis
of dilactone 2 was achieved with extra time and reagent
(1.5 h, 2.5 equiv. of LiOH) to furnish (–)-hemibourgeanic
acid 3 quantitatively. The spectral and physical data of (+)-
bourgeanic acid, bourgeanic lactone and (–)-hemibourge-
anic acid were in good agreement with the literature
(Scheme 3).
(1S,2R,4R)-1-[(S)-1-Carboxyethyl]-2,4-dimethylhexyl (2S,3S,4R,6R)-
3-Hydroxy-2,4,6-trimethyloctanoate (1): To the eight-membered
bourgeanic lactone 2 (16 mg, 43 μmol) in THF/H2O (1:1) (4 mL)
was added LiOH (1.3 mg, 54 μmol) and stirred at room tempera-
60
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 58–61

Total Synthesis of (+)-Bourgeanic Acid
[2] B. Bodo, Bull. Mus. Natn. Hist. Natn. Paris 1975, 349, 23–97.
[3] B. Bodo, W. Trowitzsch-Kienast, D. Schomburg, Tetrahedron
Lett. 1986, 27, 847–848.
[4] a) J. D. White, A. T. Johnson, J. Org. Chem. 1990, 55, 5938–
5940; b) J. D. White, A. T. Johnson, J. Org. Chem. 1994, 59,
3347–3358.
[5] T. Reiss, B. Breit, Org. Lett. 2009, 11, 3286–3289.
[6] a) J. S. Yadav, C. S. Rao, S. Chandrasekhar, A. V. Rama Rao,
Tetrahedron Lett. 1995, 36, 7717–7720; b) J. S. Yadav, S. Abra-
ham, M. M. Reddy, G. Sabitha, A. R. Sanker, A. C. Kunwar,
Tetrahedron Lett. 2001, 42, 4713–4716; c) J. S. Yadav, M. M.
Ahmed, Tetrahedron Lett. 2002, 43, 7147–7150; d) J. S. Yadav,
R. Srinivas, K. Sathaiah, Tetrahedron Lett. 2006, 47, 1603–
1606; e) J. S. Yadav, T. V. Pratap, V. Rajender, J. Org. Chem.
2007, 72, 5882–5885; f) J. S. Yadav, K. Ravindar, B. V. S. Reddy,
Synlett 2007, 1957–1959.
ture for 30 min. After the formation of required product (moni-
tored by TLC), the reaction mixture was acidified with 2 n HCl to
pH 2 and then tetrahydrofuran was removed under reduced pres-
sure. The combined organic phases were dried with Na2SO4, and
the solvent was removed under vacuo and the resulting aqueous
layer was extracted with ethyl acetate (3ϫ10 mL) concentrated un-
der vacuum, and the residue was purified by silica gel chromatog-
raphy (1:1, ethyl acetate/hexane) to afford 1 (9 mg, 54%) as a white
solid. [α]D = +7.0 (c = 1.0, CHCl ). IR (KBr): ν = 3446, 2923,
˜
3
2854, 1728, 1639, 1460 cm–1. 1H NMR (300 MHz, CDCl3): δ =
5.16 (dd, J = 9.0, 3.0 Hz, 1 H, 3-H), 3.70 (dd, J = 9.8, 2.2 Hz, 1
H, 3-HЈ), 2.86–2.74 (m, 1 H, 2-H), 2.67–2.54 (m, 1 H, 2-HЈ), 1.96–
1.85 (m, 1 H, 4-H), 1.79–1.59 (m, 2 H, 4-HЈ, 6-HЈ), 1.54–1.38 (m,
2 H, 5-HЈ), 1.34–1.23 (m, 3 H, 5-H, 6-H), 1.18 (d, J = 6.7 Hz, 3
H, 9-H), 1.10 (d, J = 7.5 Hz, 3 H, 9-HЈ), 1.14–1.01 (m, 3 H, 7-H,
7-HЈ), 0.94 (d, J = 7.5 Hz, 3 H, 10-H), 0.96–0.90 (m, 1 H, 7-HЈ),
0.89 (t, J = 6.7 Hz, 3 H, 8-HЈ), 0.87 (d, J = 6.0 Hz, 3 H, 10-HЈ),
[7] a) J. S. Yadav, Sk. S. Hossain, M. Madhu, D. K. Mohapatra, J.
Org. Chem. 2009, 74, 8822–8825; b) J. S. Yadav, V. Rajender,
Y. G. Ra o, Org. Lett. 2010, 12, 348–350.
0.85 (d, J = 6.0 Hz, 3 H, 11-H), 0.84 (t, J = 7.5 Hz, 3 H, 8-H), 0.82 [8] B. H. Lipshutz, J. C. Barton, J. Org. Chem. 1988, 53, 4495–
(d, J = 6.7 Hz, 3 H, 11-HЈ) ppm. 13C NMR (CDCl3, 75 MHz): δ
= 177.1, 175.7, 76.5, 74.8, 44.0, 41.9, 41.0, 40.6, 31.2, 30.9, 30.9,
29.4, 29.2, 19.4, 19.3, 14.4, 13.8, 12.7, 11.2, 11.1 ppm. MS (ESI):
m/z = 385 [M – H]–. HRMS: calcd. for C22H42O5 [M – H]–
385.2953; found 385.2966.
4499.
[9] X. Kong, T. B. Grindley, Can. J. Chem. 1994, 72, 2396–2404.
[10] H. Kotsuki, I. Kadota, M. Ochi, J. Org. Chem. 1990, 55, 4417–
4422.
[11] H.-J. Liu, J. Yip, K.-S. Shia, Tetrahedron Lett. 1997, 38, 2253–
2256.
[12] D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans.
1 1975, 1574–1585.
[13] T. Ohgi, T. Kondo, T. Goto, Tetrahedron Lett. 1977, 18, 4051–
4054.
Supporting Information (see also the footnote on the first page of
this article): Synthesis and characterization for compounds 2–4 and
8–14.
[14] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancat-
elli, J. Org. Chem. 1997, 62, 6974–6977.
[15] B. S. Bal, W. E. Childers Jr., H. W. Pinnick, Tetrahedron 1981,
37, 2091–2096.
[16] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi,
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993; b) M. Hikota, Y.
Sakurai, K. Horita, O. Yonemitsu, Tetrahedron Lett. 1990, 31,
6367–6370.
Acknowledgments
K. V. R. R. thanks the Council of Scientific & Industrial Research
(CSIR), New Delhi, India for the award of a fellowship.
[1] B. Bodo, B. Hebrard, L. Molho, D. Molho, Tetrahedron Lett.
1973, 14, 1631–1634.
Received: August 25, 2010
Published Online: November 12, 2010
Eur. J. Org. Chem. 2011, 58–61
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
61