Convenient formal synthesis of (+)-grandisol through Lewis acid promoted enantioselective pinacolic rearrangement

Article abstract of DOI:10.1055/s-0028-1083536

The titanium-mediated cyclopropanation of an easily prepared chiral a-siloxylactone leads efficiently to an enantiomerically pure cyclopropanol derivative. The trimethylsilyl trifluoromethane sulfonate induced pinacol rearrangement allows high level of chirality transfer into a cyclobutanone, which is a useful intermediate in the total synthesis of (+)-grandisol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083536

LETTER
2823
Convenient Formal Synthesis of (+)-Grandisol through Lewis Acid Promoted
Enantioselective Pinacolic Rearrangement
C
onvenient Forma
n
l
Synthesis
o
g
f
(+)-Grandi
e
sol lo Frongia,a Christian Girard,b Jean Ollivier,*b Pier Paolo Piras,*a Francesco Seccia,b
a
Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato,
S.S. 554, Bivio per Sestu, 09042 Monserrato, Cagliari, Italy
Fax +39(070)6754388; E-mail: pppiras@unica.it
Laboratoire de Synthèse Organique et Méthodologie, UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay,
Université de Paris-Sud XI, 91405 Orsay, France
b
Fax +33(1)69157252; E-mail: jollivie@icmo.u-psud.fr
Received 23 June 2008
H
Abstract: The titanium-mediated cyclopropanation of an easily
prepared chiral a-siloxylactone leads efficiently to an enantiomeri-
cally pure cyclopropanol derivative. The trimethylsilyl trifluoro-
methane sulfonate induced pinacol rearrangement allows high level
of chirality transfer into a cyclobutanone, which is a useful interme-
diate in the total synthesis of (+)-grandisol.
O
HO
HOOC
a
Br3C
COOH
COOH
O
O
3
4 87%
Scheme 2 Reagents and conditions: (a) bromal (1.2 equiv), H2SO4–
AcOH (1:1, 0.3 mL/mmol), 0 °C, 2 h.
Key words: antifugal agents, aldol reactions, rearrangements, ring
expansion, ketones
relative configuration was determined by NOESY two-di-
mensional NMR experiments.
Grandisol (1) is a natural monoterpenic pheromone isolat-
ed in 19671 presenting two chiral centers on a cyclobutane
ring. Used as the major component of grandlure to protect
cotton crops against various insects, grandisol is a sex at-
tractant of the cotton boll weevil (anthonomis grandis).
Over the years, various research groups2 have tried to pre-
pare grandisol (1; Scheme 1) in enantiomerically pure
form, but, for the most part, these syntheses require a large
number of steps, sometimes difficult, and the enantiomer-
ic excess can be disappointing.
Reduction of acid 4 using borane dimethylsulfide
complex6 directly afforded without basic treatment7 the
pure a-hydroxylactone 58 according to the mechanism de-
picted in the Scheme 3.
O
a
OH
4
O
5 83%
O
H
H
O
O
Br3C
Br3C
OBn
O–
O
OH
O
O
–O
1
2
O
Scheme 1 Retrosynthetic synthesis of (+)-(1R,2S)-grandisol
Scheme 3 Reagents and conditions: (a) 2 M BH3·SMe2 in THF (0.5
equiv), THF, –10 °C, 1 h, then MeOH, 20 °C, overnight.
Retrosynthetically, the chiral cyclobutanone 2 constitutes
an efficient precursor for the enantioselective synthesis of
(+)-grandisol (Scheme 1). Indeed, in our previous work,
we showed that the racemic cyclobutanone 2 can be trans-
formed into ( )-grandisol.3 Thus, access to enantiomeri-
cally pure cyclobutanone 2 would provide a formal
synthesis of (+)-grandisol (1). We decided to apply the
method described by Cha4 for the preparation of optically
enriched 2-substituted cyclobutanones. Thus acidic con-
densation of the commercially available (S)-citramalic
acid (3) with tribromoacetaldehyde5 afforded the corre-
sponding acid as a unique diastereomer 4 (Scheme 2). The
Attempts to perform the intermolecular cyclopropanation
reaction9 on the lactone 5 did not lead to the expected
cyclopropanol 6, but returned the lactone practically un-
changed, only the isopropyl ester 7 was isolated in very
low yield (10%) possibly resulting from the nucleophilic
attack of isopropyl anion on the lactone function. Such
titanium tetraisopropoxide promoted trans-esterification
has been previously reported in the Kulinkovich
reaction10 (Scheme 4).
To overcome this problem, the hydroxyl group of the lac-
tone 5 was protected as a silyl ether giving the a-(silyl-
oxy)lactone 88 which successfully underwent the
intermolecular cyclopropanation reaction using excess of
ethylmagnesium bromide in the presence of titanium
tetraisopropoxide. The cyclopropanol 9 was isolated as an
enantiomerically pure product in 88% yield (Scheme 5)
SYNLETT 2008, No. 18, pp 2823–2825
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083536; Art ID: D23608ST
© Georg Thieme Verlag Stuttgart · New York

2824
A. Frongia et al.
LETTER
the protected cyclopropanol 1213 which underwent pina-
col rearrangement to yield the desired chiral cyclo-
butanone 2.3 In order to examine the scope of this
transformation with a view to optimize enantioselectivity,
several attempts were effected in varying Lewis acids and
conditions were studied. Thus, a 95% ee was obtained by
performing the reaction with tert-butyldimethylsilyl tri-
fluoromethane sulfonate in dichloromethane at –78 °C
(Table 1).
OH
O
a
a
5
OH
OH
O
OH
OH
6
7 10%
Scheme 4 Reagents and conditions: (a) Ti(Oi-Pr)4 (0.5 equiv),
1.5 M EtMgBr (4 equiv), THF–Et2O (1:1), 0 °C, 4 h.
O
OH
a
b
OTBS
5
OH
O
Table 1 Transformation of Diol 9 into Cyclobutanone 2 via Pinacol
Rearrangement of Cyclopropanol 12a
OTBS
9 88%
8 96%
O
OH
Scheme 5 Reagents and conditions: (a) 2,6-lutidine (0.5 equiv),
tert-butyldimethylsilyl trifluoroacetate (1.5 equiv), 0–20 °C, 48 h;
(b) Ti(Oi-Pr)4 (0.5 equiv), 1.5 M EtMgBr (4 equiv), THF–Et2O (1:1),
0 °C, 4 h.
a
b
9
OBn
OTBS
OBn
12 88%
2
and the structure was confirmed by X-ray crystal-struc- Entry Lewis acid
ture analysis (Figure 1).11
Solvent
Temp
(°C)
Yield ee
(%)
97
95
91
92
89
–
(%)
Surprisingly, efforts to induce the pinacol-type rearrange-
ment using BF3 etherate as Lewis acid in dichloromethane
furnished not only the cyclobutanone 10 but additionally
the chiral dioxolane 11 through an internal cyclization
(Scheme 6). Unfortunately, the two products were found
to be inseparable by chromatography on silica gel.
1
2
3
4
5
6
SiO2
MeOH–CH2Cl2
CH2Cl2
20
–40
80
65
78
75
95
–
BF3·OEt2
BF3·OEt2
CH2Cl2
–78
BF3·OEt2–lutidine CH2Cl2
TBSOTf–lutidine CH2Cl2
TBSOTf–lutidine pentane
–78
To avoid hemiacetal formation, benzylation12 was carried
–78
out on the primary hydroxyl group of the diol 913 to give
–100
a Reaction conditions: (a) NaH (1 equiv), TBAI (3 equiv), BnBr (1 equiv),
0 °C, then 50 °C, 2 h; (b) Lewis acid.
In conclusion, we have developed a new and concise ac-
cess to useful chiral intermediate 213 for the efficient prep-
aration of (+)-grandisol. Two key steps allowed efficient
access to this compound: firstly, the reduction of a tribro-
modioxalane by borane dimethyl sulfide complex led to
an enantiomerically pure lactone and secondly the re-
markable transfer of chirality was induced by the tert-
butyldimethylsilyl trifluoromethane sulfonate–lutidine
couple at low temperature. Finally, starting from commer-
cially available (R)-citramalic acid, the same reaction
scheme should lead to the other antipode of grandisol.
Acknowledgement
Figure 1 ORTEP plot of X-ray crystal structure of cyclopropanol 9
We thank Mr Régis Guillot for running the X-ray analysis.
LA
+
O
References and Notes
(1) Tumlinson, J. H.; Hardee, D. D.; Gueldner, R. C.;
Thompson, A. C.; Hedin, P. A.; Minyard, J. P. Science 1969,
166, 1010.
OH
O
HO
(2) (a) Jones, J. B.; Finch, M. A. W.; Jakovac, I. J. Can. J. Chem.
1982, 60, 2007. (b) Meyers, A. I.; Fleming, S. A. J. Am.
Chem. Soc. 1986, 108, 306. (c) Demuth, M.; Palomer, A.;
Sluma, H.-D.; Dey, A. K.; Krüger, C.; Tsay, Y.-H. Angew.
Chem. 1986, 98, 128. (d) Rosini, G.; Marotta, E.; Raimondi,
A.; Righi, P. Tetrahedron: Asymmetry 1991, 2, 123.
(e) Hayashi, Y.; Narasaka, K. Bull. Chem. Soc. Jpn. 1991,
O
a
+
7
OH
11 41%
10 41%
Scheme 6 Reagents and conditions: (a) BF3·OEt2, –40 °C, CH2Cl2.
Synlett 2008, No. 18, 2823–2825 © Thieme Stuttgart · New York

LETTER
64, 1471. (f) Okano, K.; Ebata, T.; Koseki, K.; Kawakami,
Convenient Formal Synthesis of (+)-Grandisol
2825
(11) Crystallographic data for (–)-9: C13H28O3Si, M = 260.44,
monoclinic, space group C2, a = 12.359(5) Å, b = 7.468(5)
Å, c = 17.642(5) Å, b = 101.69°, Z = 2, V = 1594.54 Å3. Full
crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre CCDC as
supplementary publication number CCDC 697709. Copies
of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge, CB2 IEZ, UK, fax:
+44 (1223)336033, e-mail: deposit@ccdc.cam.ac.uk;
www.ccdc.cam.ac.uk/data_request/cif.
H.; Matsumoto, K.; Matsushita, H. Chem. Pharm. Bull.
1993, 41, 861. (g) Toya, T.; Nagase, H.; Honda, T.
Tetrahedron: Asymmetry 1993, 4, 1537. (h) Langer, K.;
Mattay, J. J. Org. Chem. 1995, 60, 7256. (i) de March, P.;
Figueredo, M.; Font, J.; Raya, J. Org. Lett. 2000, 2, 163.
(j) de March, P.; Figueredo, M.; Font, J.; Raya, J.; Alvarez-
Larena, A.; Piniella, J. F. J. Org. Chem. 2003, 68, 2437.
(k) Hamon, D. P. G.; Tuck, K. L. Tetrahedron Lett. 1999, 40,
7569. (l) Hamon, D. P. G.; Tuck, K. L. J. Org. Chem. 2000,
65, 7839. (m) Bernard, A. M.; Frongia, A.; Ollivier, J.; Piras,
P. P.; Secci, F.; Spiga, M. Tetrahedron 2007, 63, 4968.
(3) Bernard, A. M.; Frongia, A.; Secci, F.; Delogu, G.; Ollivier,
J.; Piras, P. P.; Salaün, J. Tetrahedron 2003, 59, 9433.
(4) Cho, S. Y.; Cha, J. K. Org. Lett. 2000, 2, 1337.
(5) James, K. D.; Ekwuribe, N. N. Tetrahedron 2002, 58, 5905.
(6) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40,
1313.
(7) Reduction Procedure: To a solution of [(4S)-4-methyl-5-
oxo-2-(tribromomethyl)-1,3-dioxolan-4-yl]acetic acid (4;
2.64 g, 6.45 mmol) in anhyd THF (15 mL) was added
dropwise at –10 °C under argon a solution of borane methyl
sulfide complex (1.75 mL, 3.48 mmol, 2 M in THF). After
stirring for an additional hour at –10 °C, the reaction mixture
was allowed to warm overnight to r.t. The mixture was
quenched with MeOH (1 mL) and concentrated under
reduced pressure and the resulting oil was diluted in Et2O
(50 mL). The ethereal phase was washed with brine (5 mL)
and then dried over Na2SO4. After evaporation of the
solvent, the residue was purified by flash chromatography to
afford pure (3S)-dihydro-3-hydroxy-3-methyl-2(3H)-
furanone (5; 0.65 g, 83%); [a]D20 –32.2 (c 0.1, CHCl3).
(8) Ohba, M.; Izuta, R.; Shimizu, E. Chem. Pharm. Bull. 2006,
54, 63.
(12) Yu, S.-H.; Park, J.-J.; Chung, S.-K. Tetrahedron: Asymmetry
2006, 17, 3030.
(13) Selected data:
1-[(1S)-1-(tert-Butyldimethylsilyloxy)-3-hydroxy-1-
methylpropyl]cyclopropanol (9): colorless needles; mp
65 °C; [a]D20 –12 (c 0.1, CHCl3). IR (KBr): 3289, 2957,
1464, 1254 cm–1. 1H NMR (300 MHz, CDCl3): d = 3.94–
4.03 (m, 1 H), 3.64–3.78 (m, 1 H), 2.02–2.07 (m, 1 H), 1.70–
1.87 (m, 1 H), 1.31 (s, 3 H), 0.82–0.97 (m, 2 H), 0.84 (s, 9
H), 0.59–0.64 (m, 2 H), 0.11 (s, 3 H), 0.07 (s, 3 H). 13C NMR
(62.9 MHz, CDCl3): d = 75.3, 60.1, 58.3, 43.0, 41.9, 25.2,
11.4, 8.2, 2.6, 2.3. HRMS (ES, +): m/z calcd for
C13H28O3SiNa: 283.17054; found: 283.17058.
1-[(1S)-3-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)-1-
methylpropyl]cyclopropanol (12): colorless oil; [a]D20 –34
(c 0.05, CHCl3). IR (neat): 3501, 2929, 1454, 1256 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.29–7.37 (m, 5 H), 4.54
(Abq, J = 3.3 Hz, 2 H), 3.96–4.03 (m, 1 H), 3.71–3.78 (m,
1 H), 3.69 (s, 1 H), 1.99–2.15 (m, 1 H), 1.89–1.97 (m, 1 H),
1.27 (s, 3 H), 0.76–0.93 (m, 2 H), 0.87 (s, 9 H), 0.59–0.63
(m, 2 H), 0.10 (s, 3 H), 0.06 (s, 3 H). 13C NMR (62.9 MHz,
CDCl3): d = 129.2, 128.4, 128.2, 126.9, 78.2, 58.6, 40.0,
37.3, 29.2, 26.2, 25.6, 9.4, 7.5, 2.8, 2.3. HRMS (ES, +): m/z
calcd for C19H34O3SiNa: 373.21749; found: 373.21712.
(2R)-2-(2-Benzyloxyethyl)-2-methylcyclobutanone (2):
colorless oil; [a]D24 +42 (c 0.1, CHCl3). IR (neat): 1765
cm–1. 1H NMR (300 MHz, CDCl3): d = 7.30 (m, 5 H), 4.43
(Abq, J = 11.7 Hz, 2 H), 3.56 (t, J = 6.3 Hz, 2 H), 2.98 (t,
J = 6.3 Hz, 2 H), 1.93–2.01 (m, 2 H), 1.86 (s, 3 H), 1.64–1.79
(m, 2 H). 13C NMR (62.9 MHz, CDCl3): d = 214.8, 138.1,
128.2, 127.4, 127.3, 72.8, 66.7, 62.2, 42.3, 35.3, 23.9, 21.3.
MS (EI): m/z (%) = 218 (1) [M+], 127 (12), 97 (11), 91 (100),
41 (38).
(9) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;
Savchenko, A. I.; Prityskaya, T. S. J. Org. Chem. USSR
(Engl. Transl.) 1989, 25, 2027. (b) Kulinkovich, O. G.;
Sviridov, S. V.; Vasilevski, D. A.; Savchenko, A. I.;
Prityskaya, T. S. J. Org. Chem. USSR (Engl. Transl.) 1991,
27, 250. (c) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski,
D. A. Synthesis 1991, 234.
(10) Garnier, J.-M.; Jida, M.; Ollivier, J. Synlett 2006, 2739.
Synlett 2008, No. 18, 2823–2825 © Thieme Stuttgart · New York

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