Enantioselective total synthesis of (-)-ericanone

Article abstract of DOI:10.1016/j.tetlet.2012.12.033

The first total synthesis of (-)-ericanone was achieved in 10 steps with a 16% overall yield from p-hydroxybenzaldehyde. Notable features of this stereocontrolled approach include a Keck allylation to install the stereocenter at C3 and a 1,5-anti aldol reaction to install the hydroxyl group at C7.

Full text of DOI:10.1016/j.tetlet.2012.12.033

Accepted Manuscript
Enantioselective total synthesis of (−)-ericanone
Luiz C. Dias, Paula K. Kuroishi, Ellen C. Polo, Emílio C. de Lucca Jr
PII:
S0040-4039(12)02163-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.12.033
TETL 42278
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 November 2012
7 December 2012
10 December 2012
Please cite this article as: Dias, L.C., Kuroishi, P.K., Polo, E.C., de Lucca Jr, E.C., Enantioselective total synthesis
of (−)-ericanone, Tetrahedron Letters (2012), doi: http://dx.doi.org/10.1016/j.tetlet.2012.12.033
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Enantioselective total synthesis of
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()-ericanone
Luiz C. Dias*, Paula K. Kuroishi, Ellen C. Polo, and Emílio C. de Lucca Jr.
OH
O
OH
OH
O
OH
3
7
3
7
HO
OH
HO
OH
1
1
(3S,7S)-
rel-(3R,7R)-
structure proposed
by Chulia's group
structure assigned
in this work

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Enantioselective total synthesis of ()-ericanone
Luiz C. Dias, Paula K. Kuroishi, Ellen C. Polo, and Emílio C. de Lucca Jr.
Instituto de Química, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13084-971, Campinas, SP, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first total synthesis of ()-ericanone was achieved in 10 steps with a 16% overall yield from
p-hydroxybenzaldehyde. Notable features of this stereocontrolled approach include a Keck
allylation to install the stereocenter at C3 and a 1,5-anti aldol reaction to install the hydroxyl
group at C7.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Total synthesis
Natural product
()-Ericanone
Aldol reaction
Boron enolate
In 2011, the Chulia group reported the structure of ()-
ericanone (1), a diarylnonanoid aglycone isolated in small
amounts from the aerial parts of Erica cinerea (48 mg from 4.5
kg of E. cinerea) (Figure 1).1 The structure of ()-ericanone was
determined to be rel-(3R,7R)-1,9-bis-(p-hydroxyphenyl)-3,7-
dihydroxynonan-5-one using NMR analyses. The 1,5-anti
relationship between C3 and C7 was determined on the basis of
its levorotatory nature ([α]D27 14 (c 0.042, MeOH)).1,2
Scheme 1: Preparation of aldehyde 5.
With aldehyde 5 in hand, we turned our attention to the
preparation of methylketone 9 (Scheme 2). First, asymmetric
Keck allylation of aldehyde 5 provided the homoallylic alcohol 7
in an 81% yield with an excellent enantiomeric excess (ee
96%).6,7 Then, the treatment of
7
with the 2,2,2-
trichloroacetimidate of p-methoxybenzyl (PMB-TCA) in the
presence of a catalytic amount of CSA gave olefin 8 in 60%
yield. Finally, Wacker oxidation of the terminal olefin of 8 led to
the formation of methylketone 9 in 87% yield.8
Figure 1: Proposed and assigned structures of ()-ericanone.
We describe herein our efforts toward the total synthesis of
ericanone (1) for the purposes of confirming Chulia’s structural
assignment, determining the absolute stereochemistry, obtaining
material for further biological evaluation and gaining access to
novel analogues.
Scheme 2: Preparation of methylketone 9.
Next, we performed the key aldol reaction between the boron
enolate generated from methylketone 9 with aldehyde 5 to
provide aldol adduct 10. This reaction favored the 1,5-anti
isomer (dr 94:06) (Scheme 3).9,10,11,12
The
synthesis
began
with
protection
of
p-
hydroxybenzaldehyde (2) using TBSCl and imidazole3 followed
by a Wittig reaction with known phosphorane 3 providing
unsaturated ester 4 in 83% yield for the two step sequence
(Scheme 1).4 Hydrogenation of 4 (94% yield) followed by
reduction of the ester functional group using DIBAL-H led to the
formation of aldehyde 5 (82% yield).5
Scheme 3: Completion of the synthesis of ()-ericanone (1).
———
 Corresponding author. E-mail address: ldias@iqm.unicamp.br (L.C. Dias).

2
Tetrahedron
Removal of the PMB ether using H2 and Pd(OH)2/C13 followed
by treatment with HF/MeCN14 gave ()-ericanone (1) in 60%
yield for the three step sequence. Spectral data (1H and 13C NMR,
IR, and HRMS) from the synthetic sample were in excellent
agreement with those reported in the literature for the natural
product.1 Furthermore, the specific rotation of the synthetic
material matched both the sign and magnitude reported for
27
natural ericanone (lit: [α]D 14 (c 0.042, MeOH)1, observed:
20
[α]D 17 (c 0.04, MeOH)). These results indicate that
compound 1 has been prepared as the naturally occurring
antipode. Based on the known absolute stereochemistry of
homoallylic alcohol 7,6 ultimately generated by Keck allylation,
the absolute stereochemistry of ()-ericanone (1) can now be
assigned as 3S,7S.
In conclusion, we have accomplished the first total
synthesis of ()-ericanone (1) in 10 steps with a 16% overall
yield starting from p-hydroxybenzaldehyde. The key step in this
approach is the 1,5-anti aldol coupling between the boron enolate
generated from methylketone 9 with aldehyde 5. Based on these
results we were able to determine the absolute stereochemistry of
()-ericanone (1) to be 3S,7S.
Acknowledgements
We are grateful to FAEP-UNICAMP, FAPESP, CAPES,
CNPq and INCT-INOFAR (Proc. CNPq 573.564/2008-6) for
financial support and Prof. Albert J. Chulia (France) for copies of
1H NMR and 13C NMR spectra.
Supplementary data
Experimental procedures and spectral data for the prepared
compounds associated with this article can be found, in the
online version, at

3
OH
O
OH
OH
O
OH
3
7
3
7
HO
OH
HO
OH
1
1
(3S,7S)-
rel-(3R,7R)-
structure proposed
by Chulia's group
structure assigned
in this work
Figure 1: Proposed and assigned structures of ()-ericanone.
1. TBSCl, imidazole
CHO
CO2Et
CH2Cl2, 0 ºC
2.
HO
TBSO
CO2Et
Ph3P
3
2
4, 83% (2 steps)
C6H6, reflux
1. H2 (balloon)
O
Pd(OH)2/C, EtOH (94%)
H
2. DIBAL-H
CH2Cl2, 78 ºC (82%)

TBSO
5
Scheme 1: Preparation of aldehyde 5.
Bu3Sn
6
(R)-BINOL, Ti(Oi-Pr)4
TFA, 4Å MS
O
OH


CH2Cl2, 78 to 20 ºC
H
81%, ee 96%
7
5
TBSO
TBSO
PMB-TCA, CSA
CH2Cl2
PMBO
PMBO
O
O2, PdCl2, CuCl
DMF:H2O (7:1)
Me
60%
87%
9
8
TBSO
TBSO
Scheme 2: Preparation of methylketone 9.

4
Tetrahedron
1. (c-Hex)2BCl, Et3N
PMBO
O

PMBO
O
OH
Et2O, 30 ºC
5 
2. , 78 ºC
Me
dr 94:06
9
10
TBSO
TBSO
OTBS
1. H2 (balloon),Pd(OH)2/C
MeOH (60%, 2 steps)
OH
O
OH
2. HF:py, MeCN (quantitative)

1
HO
( )-ericanone ( )
OH
Scheme 3: Completion of the synthesis of ()-ericanone (1).
12
For the preparation of (c-Hex)2BCl, see: Brown, H. C.; Dhar,
R. K.; Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 499.
Evans, D. A.; Côté, B.; Coleman, P. J.; Connell, B. T. J. Am.
1
Bennini, B.; Chulia, A. J.; Kaouadji, M.; Fondanèche, P.;
13
Allais, D. P. Tetrahedron Lett. 2011, 52, 1597.
Chem. Soc. 2003, 125, 10893.
2 The 1,5-syn isomer is a meso compound and optically inactive.
14 Rauniyar, V.; Hall, D. G. J. Org. Chem. 2009, 74, 4236.
3 Faler, C. A.; Joullié, M. M. Org. Lett. 2007, 9, 1987.
4
Vuppalapati, S. V. N.; Putapatri, S. R.; Kantevari, S. Arkivoc,
2009, (xiv), 217.
5
Schmidt, B.; Hölter, F.; Kelling, A.; Schilde, U. J. Org. Chem.
2011, 76, 3357.
6 Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883.
7
20
Alcohol 7 showed an specific rotation of [α]D 15 (c 1.7,
23
CHCl3); ref. 6: [α]D 11 (c 1.73, CHCl3). The enantiomeric
excess was determined on the basis of Mosher ester analysis:
Ph
OMe
F3C
Ph
F3C
OMe
O
Cl
OH
DMAP, Et3N
CH2Cl2
O
O
92%, dr 98:02
7
11
TBSO
TBSO
8
Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.;
Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem. Eur. J.
2006, 12, 1185.
9
For a seminal work in this area, see: a) Blanchette, M. A.;
Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T. J.
Org. Chem. 1989, 54, 2817. For fundamental contributions in this
area, see: b) Paterson, I.; Oballa, R. M.; Norcross, R. D.
Tetrahedron Lett. 1996, 37, 8581. c) Paterson, I.; Gibson, K. R.;
Oballa, R. M. Tetrahedron Lett. 1996, 37, 8585. d) Evans, D. A.;
Coleman, P. J.; Côté, B. J. Org. Chem. 1997, 62, 788.
10
For our recent work in this area, see: a) Dias, L. C.; de Lucca
Jr., E. C.; Ferreira, M. A. B.; Garcia, D. C.; Tormena, C. F. J.
Org. Chem. 2012, 77, 1765. b) Dias, L. C.; Polo, E. C.; Ferreira,
M. A. B.; Tormena, C. F. J. Org. Chem. 2012, 77, 3766.
11
For theoretical studies, see: a) Paton, R. S.; Goodman, J. M.
Org. Lett. 2006, 8, 4299. b) Goodman, J. M.; Paton, R. S. Chem.
Commun. 2007, 2124. c) Paton, R. S.; Goodman, J. M. J. Org.
Chem. 2008, 73, 1253.