Asymmetric α-alkylation of α,β-unsaturated esters. Application to the synthesis of (R)-lavandulol, (R)-sesquilavandulol and related trifluoromethyl compounds

Article abstract of DOI:10.1055/s-1998-1960

Diastereoselective α-alkylation/deconjugation of esters of diacetone D-glucose has been performed and applied to the syntheses of (R)-lavandulol, (R)-sesquilavandulol with de up to 74%. The same reaction performed with trifluoromethyl derivatives was also

Full text of DOI:10.1055/s-1998-1960

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Asymmetric α-Alkylation of α,β-Unsaturated Esters. Application to the Synthesis of
R)-Lavandulol, (R)-Sesquilavandulol and Related Trifluoromethyl Compounds
(
S. Faure, O. Piva*
UMR 6519 C.N.R.S. "Réactions sélectives et applications", UFR Sciences - Université de Reims - Champagne - Ardenne
B.P. 1039 - 51687 Reims cedex - France
Fax 00 33 (0)3 26 05 31 66 ; e-mail olivier.piva@univ-reims.fr.
Received 5 August 1998
Abstract: Diastereoselective α-alkylation/deconjugation of esters of
diacetone D-glucose has been performed and applied to the syntheses of
The diastereoselective alkylations were performed under different
experimental conditions changing the nature of the base and solvents.
Results are summarized in table 1.
(
R)-lavandulol, (R)-sesquilavandulol with de up to 74%. The same
reaction performed with trifluoromethyl derivatives was also achieved
but without significant diastereoselectivity.
Some years ago, we reported the synthesis of (R)-Lavandulol 1 using a
highly diastereoselective photoisomerization of a α,β-unsatured ester1
using as chiral moiety the cheap and commercially available diacetone
2
D-glucose (DAG-OH) (Scheme 1).
Scheme 1
While this powerful method appeared difficult to scale up, we decided
recently to carry out an alternative approach to lavandulol and
other terpene alcohols based on the diastereoselective alkylation of
α-unsubstituted-α,β-unsaturated esters bearing the same chiral alkoxy
group (Scheme 2).
According to table 1, NaHMDS seems the more suitable base to obtain
the monoalkylated compound in convenient yields and acceptable de
(up to 74%). When LDA was used, diastereoselectivity was
significantly lower as well as the efficiency of the process. The low
yield measured could result from the formation of a vinylketene and
DAG-OH as it has been already pointed out for similar alkylations of
Scheme 2
4,5
sugar esters . Finally, the β,γ-unsaturated esters 3 and 4 were
respectively reduced by LiAlH4 into (R)-sesquilavandulol 5 and (R)-
1
lavandulol 1 according a previous procedure . In order to develop an
3
,3-Dimethyl acrylic acid was easily transformed into the diacetone
3
access to trifluoromethyl analogues of 1 on 5 which could exhibit new
D-glucose ester 2 in 91 % using DCC activation (Scheme 3).
6
fragrance properties or biological activities, we have submitted to the
same alkylation conditions ester 6 obtained in high yield from 3,3,3-
7
trifluoroacetone by a Wittig-Horner reaction (Scheme 4).
The alkylation occurred in good yields but without diastereoselectivity
(Scheme 5).
By comparison with the non fluorinated compounds, the lack of
selectivity observed for 6 could be due to an increase of the acidity of
the proton in α-position of the carboxylic group in 7 and 9. Such an
Scheme 3

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1415
Scheme 4
Scheme 7
The reaction delivered 12 in moderate yield but with a very similar level
of diastereoselectivity observed with ester 2. It is noteworthy that such a
process allows the preparation of compounds with a quaternary chiral
9
center .
In conclusion, we have developed an alternative and efficient reaction to
prepare by diastereoselective alkylation (R)-lavandulol and (R)-ses-
quilavandulol with de up to 74%. We have also been able to prepare for
the first time trifluoroanalogues of these two terpenes but without
significant enantioselectivities due to an easy racemization of the new
chiral center. However, the isomerisation procedure described therein
allows the preparation of terminal alkenes bearing one trifluoromethyl
group at an internal position. In the non fluorinated serie, work is now
underway to increase the diastereoselectivity by changing the nature of
the sugar moiety and also to generalize this reaction to the synthesis of
chiral compounds especially those bearing quaternary centers.
Acknowledgments : S.F. warmly thanks M.E.N.R.T for a grant.
References and notes
(1) Piva, O. J. Org. Chem. 1995, 60, 7879 and references therein.
(2) For a recent review on chiral induction by carbohydrates : Hultin,
P.G. ; Earle, M.A. ; Sudharshan, M. Tetrahedron 1997, 53, 14823.
(3) Neises, B. ; Steglich, W. Angew. Chem. Int. Ed. Engl. 1978, 17,
5
22.
(4) Kunz, H.; Mohr, J. J. Chem. Soc., Chem. Commun. 1988, 1315.
(5) Mulzer, J.; Hiersemann, M.; Buschmann, J.; Luger, P. Liebigs
Ann. 1996, 649.
(
6) a) Nagai, T.; Ohtsuka, H.; Koyama, M.; Ando, A.; Miki, T.
Kumadaki, I. Heterocycles 1992, 33, 51. b) Patani, G.A.; La Voie,
E.J. Chem. Rev. 1996, 3147. c) Prié, G.; Thibonnet, J.; Abarbri,
M.; Duchêne, A.; Parrain, J.L. Synlett 1998, 839. d) Peng, S.;
Qing, F-L.; Guo, Y. Synlett 1998, 859.
Scheme 5
(7) a) Zhu, C.D. ; Van Lancker, B ; Van Haver, D. ; De Clercq, P.J.
Bull. Soc. Chim. Belg. 1994, 103, 263. b) Nemoto, H. ; Satoh, A. ;
Fukumoto, K. ; Kabuto, C. J. Org. Chem. 1995, 60, 594.
increase of acidity by the withdrawing electron group CF3 has been
already observed for related esters . In the case of 7 and 9, an
epimerization could occur rapidly leading to the formation of a 1:1
mixture of diastereoisomers (Scheme 6).
(8) Schlosser, M. Angew. Chem. Int. Ed. Engl. 1998, 37, 1496.
8
(
9) a) Fuji, K. Chem. Rev. 1993, 93, 2037. b) Jung, M.E.; D'Amico,
D.C. J. Am. Chem. Soc. 1995, 117, 7379. c) Mino, T.; Takagi, K.;
Yamashita, M. Synlett 1996, 645. d) Yamamoto, Y.; Hara, S.;
Suzuki, A. Synlett 1996, 883. e) Enders, D.; Backhaus, D.;
Runsink, J. Tetrahedron 1996, 52, 1503. f) Yang, X.; Wang, R.
Tetrahedron: Asymmetry 1997, 8, 3275. g) Alves, J.C.F.; Simas,
A.B.C.; Costa, P.R.R.; d'Angelo, J. Tetrahedron: Asymmetry 1997,
8
, 1963. h) Belokon', Y.N.; Kotchetkov, K.A.; Churkina, T.D.;
Scheme 6
Ikonnikov, N.S.; Chesnokov, A.A.; Larionov, O.V.; Parmar, V.S.;
Kumar, R.; Kagan, H.B. Tetrahedron: Asymmetry 1998, 9, 851.
(
10) Typical experimental procedure for the alkylation step:
This hypothesis has been confirmed by examining the α-alkylation of
ester 11 which is already substituted by one alkyl group on carbon 2
To a solution of ester (2.5 mmol) in THF (25 ml) under argon was
added at -78°C
a
1.0M THF solution of sodium
(
Scheme 7).
bis(trimethylsilyl)amide (2.75 ml). The resulting mixture was

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+
.
-1
21
stirred at this temperature for 2 hours. The bromide (2.75 mmol)
previously dissolved in THF (2 ml) was dropwise added via
syringe. The solution was stirred for an additional time of 3 hours
at -78°C and subsequently quenched with brine (10 ml). After
extraction with ether (3 x 20 ml), the organic layers were dried
(M ). IR (CHCl ): 1745, 1455 and 1150 cm . [α]
= -44.4
D
3
(0.9, CHCl3).
1
6: White solid, mp= 80°C. H-NMR (250 MHz, CDCl ) δ 1.32
3
(6H, s); 1.42 (3H, s); 1.54 (3H, s); 2.28 (3H, d, J = 1.1 Hz); 3.95-
4.30 (4H, m); 4.54 (1H, d, J = 3.4 Hz); 5.35 ( 1H, s); 5.89 (1H, d, J
= 3.8 Hz); 6.33(1H, sl). 19F-NMR (235 MHz, CDCl ) δ -71.8.
over MgSO , concentrated under vacuum and the alkylated
4
3
product was purified by flash-chromatography (hexane : ethyl of
acetate / 93:7).
Analysis calcd for C17
H
O F : C 51.51%, H 5.85%. Found: C
23 7 3
= -45.0 (1.0, CHCl3).
2
1
51.60%, H 5.79%. [α]
D
1
All new compounds gave satisfactory spectroscopic and analytical
8: oil. H-NMR (250 MHz, CDCl ): δ 1.57 (OH, bs); 1.63 (3H, s);
3
1
9
data. F NMR spectra were measured relative to CFCl . Selected
1.70 (3H, s); 2.15-2.40 (2H, m); 2.51 (1H, ddt, J = 5.7 Hz, J = 5.3
Hz, J = 7.2 Hz); 3.64 ( 1H, dd, J = 5.3 Hz, JAB = 11.0 Hz); 3.72 (
1H, dd, J = 5.7 Hz, JAB = 11.0 Hz); 5.09 ( 1H, tq, J = 7.2 Hz, J < 1
Hz); 5.45 ( 1H, m); 5.87 (1H, q, J = 1.5 Hz). 13C-NMR (62.5
3
1
data of 2: Colorless oil H-NMR (250 MHz, CDCl ): δ 1.30
3
(
(
3H,s); 1.31 (3H, s); 1.41 (3H, s); 1.52 (3H, s); 1.91 (3H, s); 2.18
3H, s); 4.01-4.09 (2H, m); 4.15-4.35 (2H, m); 4.50 (1H, d, J = 3.7
Hz); 5.26 (1H, d, J = 2.4 Hz); 5.67 (1H, t, 1.1 Hz); 5.86 (1H, d, 3.7
MHz, CDCl ) δ 17.6 (CH ); 25.6 (CH ); 29.5 (CH ); 41.9 (CH);
3 3 3 2
1
3
1
Hz). C-NMR (62.5 MHz, CDCl ): 20.3; 25.3; 26.2; 26.7; 27.4;
64.2 (CH ); 119.3 (C=CH ); 120.9 (C=CH); 123.7 (q, JC-F =
2 2
3
2
6
1
6.9; 72.6; 75.3; 79.7; 83.5; 105.0; 109.1; 112.1; 115.1; 158.8;
273.6 Hz, CF ); 131.9 (C(CH ) ); 139.1 (q, JC-F = 28 Hz,
3 3 2
-
1
21
19
64.9. IR (CHCl ): 1730 and 1655 cm . [α]
= -46 (1.0,
((CF )C=CH ).
F-NMR (235 MHz, CDCl ) δ -68.3. IR
3
3
D
3
2
-
1
CHCl ). Analysis calcd for C17H26O : C 59.63%, H 7.65%.
(CHCl ): 3600-3100, 1165 and 1120 cm .
10: oil. H-NMR (250 MHz, CDCl ): δ 1.53 (OH, bs); 1.61 (3H,
3
7
3
1
Found: C 60.02%, H 7.85%.
3
1
3
: H-NMR (250 MHz, CDCl ): δ 1.28 (3H, s); 1.29 (3H, s); 1.39
s); 1.62 (3H, s); 1.68 (3H, s); 2.03 (4H, m); 2.29 (2H, m); 2.53
(1H, ddt, J = 5.3 Hz, J = 5.7 Hz, J = 6.9 Hz); 3.64 ( 1H, dd, J = 5.3
Hz, JAB = 9.1 Hz); 3.72 (1H, dd, J = 5.7 Hz, JAB = 9.1 Hz); 5.08
(1H, tq, J = 6.9 Hz, J = 1.5 Hz); 5.11 (1H, tq, J = 6.9Hz, J < 1 Hz);
5.46 (1H, s); 5.87 (1H, d, J = 1.5 Hz). 13C-NMR (62.5 MHz,
3
(
(
3H, s); 1.54 (3H, s); 1.58 (3H, s); 1.62 (3H, s); 1.67 (3H, s); 1.74
3H, s); 1.92-2.10 (4H, m); 2.30 (1H, ddd, J = 7.7 Hz, J = 7.5 Hz, J
=
14.9 Hz); 2.52 (1H, ddd, J = 7.7 Hz, J = 7.5 Hz, J = 14.9 Hz);
3
4
.05 (1H, t, 7.7 Hz); 3.92-4.20 (4H, m); 4.41 (1H, d, J = 3.7 Hz);
.90 (2H, sb); 5.01-5.10 (2H, m); 5.28 (1H, d, J = 1.7 Hz); 5.82
CDCl ) δ 16.0 (CH ); 17.6 (CH ); 25.6 (CH ); 26.5 (CH ); 29.4
3
3
3
3
2
(
3
1H, d, J = 3.5 Hz, minor diastereoisomer) and 5.86 ( 1H, d, J =
.7 Hz, major diastereoisomer). C-NMR (62.5 MHz, CDCl3)
(CH ); 39.7 (CH ); 42.0 (CH); 64.3 (CH ); 119.3 (C=CH ); 120.9
2 2 2 2
1
3
1
(C=CH); 123.8 (q, J
= 270 Hz, CF ); 124.1 (C=CH); 131.5
C-F
3
2
Major diastereoisomer: δ 14.0; 16.0; 17.5; 20.0; 25.0; 25.6; 26.1;
2
1
(=C(CH ) ); 137.5 (=C(CH ));139.1 (q, JC-F
=
28 Hz,
3
2
3
19
6.5; 26.6; 28.5; 39.6; 53.2; 67.4; 70.6; 75.8; 80.2; 83.3; 105.0;
09.1; 112.2; 114.1; 120.6; 123.9; 137.3; 141.7; 171.9. MS: 478
(CF )C=CH ). F-NMR (235 MHz, CDCl ) δ -68.5. IR (CHCl ):
3 2 3 3
-
1
3360, 1454 and 1315 cm .