Enantioselective Synthesis of 2,2-Dialkyl-3-butenals by Alkylation of (4S,5S)-ADPD-imines

Article abstract of DOI:10.1021/jo970142k

(S)-2-Alkyl-2-methyl-3-butenals that have a quaternary stereogenic carbon atom at the α-position were obtained from 2-methyl-2-butenal (4S,5S)-ADPD-imine in good enantioselective excesses (up to 81% ee). Using this reaction, a novel sesquiterpene, (+)-(E)-2,5,9-trimethyl-2-vinyl-4,8-decadienal, was synthesized with moderate enantioselectivity (53% ee).

Full text of DOI:10.1021/jo970142k

J . Org. Chem. 1997, 62, 3981-3983
3981
En a n tioselective Syn th esis of 2,2-Dia lk yl-3-bu ten a ls by Alk yla tion
of (4S,5S)-ADP D-im in es
Takashi Mino, Munenobu Saitoh, and Masakazu Yamashita*
Department of Molecular Science and Technology, Faculty of Engineering, Doshisha University,
Kyotanabe, Kyoto 610-03, J apan
Received J anuary 27, 1997
(S)-2-Alkyl-2-methyl-3-butenals that have a quaternary stereogenic carbon atom at the R-position
were obtained from 2-methyl-2-butenal (4S,5S)-ADPD-imine in good enantioselective excesses (up
to 81% ee). Using this reaction, a novel sesquiterpene, (+)-(E)-2,5,9-trimethyl-2-vinyl-4,8-decadienal,
was synthesized with moderate enantioselectivity (53% ee).
Sch em e 1
The enantioselective synthesis of R-substituted carbo-
nyl compounds has been one of the most important goals
in organic synthesis. Especially R-substituted-â,γ-un-
saturated aldehyde or ketone subunits are found in a very
broad range of bioactive compounds and natural prod-
ucts, e.g., in vitamin E side chain,1 pseudomonic acid,2
stigmastatriene,3 and levuglandin.4 There are few meth-
ods for construction of an asymmetric quaternary carbon
atom such as R,R-disubstituted-â,γ-unsaturated alde-
hydes in organic synthesis. We have previously reported
the enantioselective synthesis of 2-alkyl-2-methyl-3-
butenenitriles which have a quaternary carbon at the
R-position by diastereoselective alkylation of 2-methyl-
2-butenal SAMP ((S)-1-amino-2-(methoxymethyl)pyrro-
lidinyl)-hydrazone.5 In the application of this method for
the synthesis of R,R-disubstituted-â,γ-unsaturated alde-
hyde, the cleavage of the SAMP-hydrazone unit was
difficult.6a On the other hand, in the synthesis of (()-
2,2-dialkylbutenals 4 by alkylation of 2-alkyl-2-butenal
cyclohexylimine or bisalkylation of 2-butenal cyclohexy-
limine, the cleavage of the imine unit was easy.6 Thus,
we speculated that the corresponding aldehydes could be
prepared from a chiral imine easier than SAMP-hydra-
zone. Thus we investigated the use of (4S,5S)-5-amino-
2,2-dimethyl-1,3-dioxane ((4S,5S)-ADPD, 2)7 as a chiral
alkylation of 2-alkyl-2-butenal (4S,5S)-ADPD-imines 3
(Scheme 1).
R-Alkyl-R,â-unsaturated aldehyde (4S,5S)-ADPD-imi-
nes 3 were conveniently prepared from R-alkyl-R,â-
unsaturated aldehydes such as 2-methyl-2-butenal (1a )
or 2-ethyl-2-butenal (1b ) and (4S,5S)-5-amino-2,2-di-
methyl-1,3-dioxane (2) using trifluoroacetic acid as a
catalyst in 85% (3a ) and 86% (3b) yields.
After deprotonation with lithium diisopropylamide
(LDA) at -5 °C and alkylation with a variety of alkyl
halides such as benzyl bromide, prenyl bromide, 1-iodo-
pentane, and 1-bromononane at -78 °C, R-alkylated
imines were hydrolyzed by 1 N hydrochloric acid. After
purification by flash column chromatography, the chiral
aldehydes 4 accompanied by double-bond migration were
obtained in acceptable to good yields and enantiomeric
excesses (Table 1).
The enantiomeric excesses of the aldehydes 4 are based
on the determination of the corresponding diastereomeric
excesses of SAMP-hydrazones 58 (Scheme 2). The SAMP-
hydrazones 5 were prepared from aldehydes 4 and 2
equiv of SAMP. This reaction was monitored by TLC.
Determination of the corresponding diastereomeric ex-
cesses of 5 by gas chromatography was accomplished by
employing cyclodextrin derivative phases9 or by 13C NMR
spectra after purification by TLC or column chromatog-
raphy.
auxiliary and herein describe the synthesis of chiral 2,2-
dialkyl-3-butenals 4 that have two different alkyl groups
and vinyl group at the R-position by diastereoselective
(1) Heathcock, C. H.; Finkelstein, B. L.; J arvi, E. T.; Radel, P. A.;
Hadley, C. R. J . Org. Chem. 1988, 53, 1922.
(2) O’Hanlan, P. J .; Rogers, N. H. Tetrahedron 1987, 43, 2165.
(3) Sucrow, W.; Polyzou, P.; Slopianka, M.; Snatzke, G. Tetrahedron
Lett. 1971, 3237.
(4) (a) Iyer, R. S.; Kobierski, M. E.; Salomon, R. G. J . Org. Chem.
1994, 59, 6038. (b) Kobierski, M. E.; Kim, S.; Murthi, K. K.; Iyer, R.
S.; Rajkimar, S.; Salomon, R. G. J . Org. Chem. 1994, 59, 6044. (c)
Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison, B.;
Salomon, R. G. J . Org. Chem. 1990, 55, 3164.
(5) Mino, T.; Takagi, K.; Yamashita, M. Synlett 1996, 645.
(6) (a) Mino, T.; Yamashita, M. Unpublished results. (b) Kiec-
zykowski, G. R.; Schlessinger, R. H.; Sulsky, R. B. Tetrahedron Lett.
1976, 597.
(7) (a) Weinges, K.; Brachmann, H.; Stahneker, P.; Rodewald, H.;
Nixdorf, M.; Irngartinger, H. Liebigs Ann. Chem. 1985, 566. (b)
Mitteilung, I.; Weinges, K.; Burne, G.; Droste, H. Liebigs Ann. Chem.
1980, 212. (c) Weinges, K.; Brachmann, H. Liebigs Ann. Chem. 1980,
207 and references cited therein. (d) Cheˆnevert, R.; Voyer, N. Synthesis
1985, 981. (e) Enders, D.; Kirchhoff, J .; Lausberg, V. Liebigs Ann.
Chem. 1996, 1361 and references cited therein.
(8) For comparsion, 1:1 mixture of diastereomer of SAMP-hydra-
zones 5 were prepared from SAMP and (()-2,2-dialkyl-3-butenals
which were obtained by alkylation of 2-alkyl-2-butenal dimethylhdra-
zones.9
(9) Mino, T.; Fukui, S.; Yamashita, M. J . Org. Chem. 1997, 62, 734.
S0022-3263(97)00142-4 CCC: $14.00 © 1997 American Chemical Society

3982 J . Org. Chem., Vol. 62, No. 12, 1997
Mino et al.
Ta ble 1. Dia ster eoselective Alk yla tion of
(4S,5S)-ADP D-im in e 3
Sch em e 3
corresponding alcohol 7 to AP-ester 813 by the reaction
with (S)-2-acetoxypropionyl chloride14 as shown in Scheme
3.
In conclusion, we found that (4S,5S)-ADPD-imine 3
which has no R-hydrogen to be alkylated at the R-position
by various alkyl halides accompanied by double bond
migration to give 2,2-dialkyl-3-butenals (S)-4 and 6 of
good enantiomeric purity.
Exp er im en ta l Section
a
Determined by GLC analysis with chiral column after the
Gen er a l P r oced u r es. 1H NMR spectra (400 MHz) and 13C
NMR spectra (100 MHz) were taken in the CDCl3 solvent and
recorded in parts per million (ppm, δ) downfield from internal
tetramethylsilane (Me4Si). Column chromatography was per-
formed on silica gel 60 (230-400 mesh), and thin-layer
chromatography (TLC) was performed on silica gel 60 plates
reaction of the corresponding aldehydes
4 with SAMP and
measured as de value except 4e. Isolated yields. c Determined
by 13C NMR analysis after the reaction of the corresponding
aldehydes 4e with SAMP and measured as de value.
b
Sch em e 2
F254
. THF was dried and deoxygenated by distillation from
potassium benzophenone under an argon atmosphere just
before use. Benzene was purified by distillation over CaCl2.
Diisopropylamine was dried by distillation from potassium
hydroxide. n-Butyllithium as a ca. 1.6 M hexane solution was
titrated with sec-butyl alcohol using o-phenanthroline as an
indicator just before use. The other organic compounds were
commercial products of the highest available purity.
Gen er a l P r oced u r e for th e P r ep a r a tion of (4S,5S)-
ADP D-im in es 3a a n d 3b. In a flask equipped with a trap
to remove water, a mixture of aldehyde (25 mmol), (4S,5S)-
ADPD (25 mmol, 4.8 mL), trifluoroacetic acid (0.05 mL), and
benzene (50 mL) was added under an argon atmosphere. The
mixture was heated under reflux for 5 h and then cooled to
room temperature. The reaction mixture was diluted with
ether and dried over MgSO4. The filtrate was concentrated
with a rotary evaporator.
The absolute configuration at a quaternary carbon was
assigned by the comparison with the retention time of
GLC of the SAMP-hydrazones 5 which were prepared
previously in our laboratory.10
Although (E)-2,5,9-trimethyl-2-vinyl-4,8-decadienal (6)
had been identified as a sesquiterpene of a beefsteak
plant 10 years ago,11 the absolute configuration of the
natural compound has not been determined. Thus using
this alkylation, the (+)-(E)-aldehyde 6 was enantioselec-
tively synthesized was conducted. After deprotonation
of 2-methyl-2-butenal (4S,5S)-ADPD-imine (3a ), alkyla-
tion with geranyl chloride and hydrolysis, the (+)-(E)-
aldehyde 612 was obtained in 73% yield and 53%ee. In
this case, the enantiomeric excess of the aldehyde 6 could
not be determined by the corresponding diastereomeric
excess of SAMP-hydrazone by gas chromatography em-
ploying cyclodextrin derivative phases or by 13C NMR
spectra. Thus the enantiomeric excess of 6 was deter-
mined by 1H and 13C NMR spectra after derivation of the
2-Meth yl-2-bu ten a l (4S,5S)-ADP D-im in e (3a ): [R]19
)
D
+161.3 (c 1.15, CHCl3); IR (Nujol) 1640 (CdN) cm-1; 1H NMR
δ 1.55-1.62 (m, 6H), 1.72-1.76 (m, 6H), 3.31-3.32 (m, 1H),
3.86-3.90 (m, 1H), 4.33-4.38 (m, 1H), 5.23 (d, J ) 2.9 Hz,
1H), 5.64-5.69 (m, 1H), 7.15-7.38 (m, 5H), 7.44 (s, 1H); MS
m/ z 274 (M+ + 1, 0.3). Anal. Calcd for C17H23NO2: C, 74.69;
H, 8.48; N, 5.12. Found: C, 74.60; H, 8.49; N, 5.05. mp 81-
83 °C.
2-Eth yl-2-bu ten a l (4S,5S)-ADP D-im in e (3b): [R]20
)
D
1
+134.8 (c 1.15, CHCl3); IR (neat) 1635 (CdN) cm-1; H NMR
δ 0.81 (t, 6.9 Hz, 3H), 1.54-1.60 (m, 6H), 1.71 (d, J ) 6.9 Hz,
3H), 2.16-2.21 (m, 1H), 2.35-2.40 (m, 1H), 3.32 (d, J ) 2.9
Hz, 1H), 3.82-3.89 (m, 1H), 4.28-4.33 (m, 1H), 5.22 (d, J )
2.9 Hz, 1H), 5.59 (q, J ) 6.9 Hz, 1H), 7.15-7.31 (m, 5H), 7.35
(10) Chrompack CP-cyclodextrin-â-236-M-19 column, 0.25 mm i.d.
× 50 m.
(11) Uji, Y.; Toyoda, T.; Muraki, S. 31st Symposium on the Chem-
istry of Terpenes, Essential Oils, and Aromatics, Kyoto, September
1987; Abstr. No. 1I02.
(13) For comparison, a 1:1 mixture of diastereomer of AP-ester 8
was prepared from APCl and (()-7 which was obtained by alkylation
of 2-methyl-2-butenal dimethylhdrazones and the subsequent reduc-
tion.
(12) The synthesis of (()-6 has been reported: Yamashita, M.;
Matsumiya, K.; Nakano, K. Bull. Chem. Soc. J pn. 1993, 66, 1759.
(14) Doolittle, R. E.; Heath, R. R. J . Org. Chem. 1984, 49, 5041.

Enantioselective Synthesis of 2,2-Dialkyl-3-butenals
J . Org. Chem., Vol. 62, No. 12, 1997 3983
(E)-2,5,9-Tr im eth yl-2-vin yl-4,8-d eca d ien a l (6): [R]24.5
(s, 1H); MS m/ z 288 (M+ + 1, 3). Anal. Calcd for C18H25NO2:
C, 75.23; H, 8.77; N, 4.87. Found: C, 75.37; H, 8.86; N, 4.77.
Gen er a l P r oced u r e for th e Syn th esis of Ald eh yd es 4
a n d 6. To a solution of diisopropylamine (3.1 mmol, 0.41 mL)
in THF (2 mL) in a dried reaction flask was added dropwise
with stirring n-butyllithium in hexane (3.2 mmol, 2.04 mL)
at -5 °C under an argon atmosphere. After 0.5 h, 2-alkyl-2-
butenal (4S,5S)-ADPD-imines 3 (3.0 mmol) was added at -78
°C. After the solution was stirred for 1 h at the same
temperature, alkyl halide (3.0 mmol) was added, and stirring
was continued for 20 h at room temperature. The reaction
mixture was quenched with water (25 mL), and THF (40 mL)
and aqueous 2 N HCl (25 mL) were added. After stirring for
5 h, the reaction mixture was diluted with water and ether,
washed with brine, and dried over MgSO4. Removal of the
solvents and column chromatography gave the pure aldehydes
4 and 6.
)
D
+11.4 (c 4.2, CHCl3) (53% ee); IR (neat) 1730 (CdO) cm-1; 1H
NMR δ 1.15 (s, 3H), 1.59 (s, 3H), 1.60 (s, 3H), 1.67 (s, 3H),
2.00-2.07 (m, 4H), 2.30 (dd, J ) 7.3 and 14.0 Hz, 1H), 2.32
(dd, J ) 7.3 and 14.0 Hz, 1H), 5.03-5.07 (m, 2H), 5.12 (d, J )
18.3 Hz, 1H), 5.26 (d, J ) 11.0 Hz, 1H), 5.82 (dd, J ) 11.0 and
18.3 Hz, 1H), 9.42 (s, 1H); 13C NMR δ 16.22, 17.69, 17.73,
25.72, 26.47, 33.99, 39.89, 53.28, 116.54, 118.34, 124.12,
131.46, 138.44, 138.72, 202.94; MS m/ z 220 (M+, 5).
Red u ction of Ald eh yd e 6. To a solution of aldehyde 6
(0.555 mmol, 0.122 g) in 5.0 mL of EtOH was added a solution
of sodium borohydride (1.0 mmol, 0.04 g) in 1.0 mL of EtOH
at room temperature. After 20 h, the reaction mixture was
quenched with aqueous 2 N HCl and diluted with ether. The
organic layer was washed with saturated aqueous NaHCO3
and brine and dried over MgSO4. After removal of the solvent,
the residue was purified by silica gel column chromatography
to give (-)-(E)-2,5,9-trimethyl-2-vinyl-4,8-decadienol (7) (0.546
2-Ben zyl-2-m eth yl-3-bu ten a l (4a ): [R]24 ) +22.6 (c 4.2,
D
1
ether) (40% ee); IR (neat) 1725 (CdO) cm-1; H NMR δ 1.13
mmol, 0.121 g, 99%): [R]23 ) -4.87 (c 0.62, ether); IR (neat)
(s, 3H), 2.88 (d, J ) 13.4 Hz, 1H), 2.97 (d, J ) 13.4 Hz, 1H),
5.09 (d, J ) 17.7 Hz, 1H), 5.28 (d, J ) 10.7 Hz, 1H), 5.86 (dd,
J ) 10.7 and 17.7 Hz, 1H), 7.09-7.28 (m, 5H), 9.51 (s, 1H);
13C NMR δ 17.80, 42.00, 53.75, 117.11, 126.58, 128.07, 130.37,
136.46, 138.45, 202.46; MS m/ z 174 (M+, 2).
D
1
3400 (OH) cm-1; H NMR δ 0.99 (s, 3H), 1.49 (s, 3H), 1.60 (s,
6H), 1.68 (d, J ) 1.2 Hz, 3H), 2.02-2.10 (m, 6H), 3.36 (d, J )
10.7 Hz, 1H), 3.41 (d, J ) 10.7 Hz, 1H), 5.04-5.17 (m, 4H),
5.77 (dd, J ) 10.7 and 17.4 Hz, 1H); 13C NMR δ 16.17, 17.69,
20.08, 25.73, 26.57, 35.33, 40.00, 42.93, 69.73, 114.28, 119.95,
124.31, 131.38, 137.23, 144.14; MS m/ z 222 (M+, 0.8).
2,5-Dim eth yl-2-vin yl-4-h exen a l (4b): [R]25.5 ) +25.7 (c
D
0.86, CHCl3) (61% ee); IR (neat) 1715 (CdO) cm-1; 1H NMR δ
1.15 (s, 3H), 1.61 (s, 3H), 1.70 (d, 1.2 Hz, 3H), 2.24-2.37 (m,
2H), 5.02-5.06 (m, 1H), 5.12 (dd, J ) 0.9 and 17.7 Hz, 1H),
5.26 (dd, J ) 0.9 and 11.0 Hz, 1H), 5.82 (dd, J ) 11.0 and 17.7
Hz, 1H), 9.42 (s, 1H); 13C NMR δ 17.84, 17.95, 25.93, 34.12,
53.26, 116.57, 118.28, 134.95, 138.75, 202.96; MS m/ z 152 (M+,
3).
P r ep a r a tion of Ester 8. To a solution of alcohol 7 (0.4
mmol, 0.089 g) in 2.0 mL of pyridine was added (S)-(-)-2-
acetoxypropionyl chloride (0.6 mmol, 0.09 g) at 0°C. The
reaction was monitored by TLC. After 3 h, the reaction
mixture was quenched with aqueous 2 N HCl and diluted with
ether. The organic layer was washed with saturated aqueous
NaHCO3 and brine and dried over MgSO4. After removal of
the solvent, the residue was purified by silica gel column
chromatography to give (-)-(E)-2,5,9-trimethyl-2-vinyl-4,8-
2-Meth yl-2-vin ylh ep ta n a l (4c): [R]24.5 ) +22.9 (c 1.15,
D
1
CHCl3) (81% ee); IR (neat) 1735 (CdO) cm-1; H NMR δ 0.88
(t, 7.0 Hz, 3H), 1.16 (s, 3H), 1.18-1.31 (m, 6H), 1.55-1.60 (m,
2H), 5.11 (d, 17.7 Hz, 1H), 5.22 (d, 10.7 Hz, 1H), 5.80 (dd, 10.7
and 17.7 Hz, 1H), 9.39 (s, 1H); 13C NMR δ 14.00, 17.67, 22.48,
23.56, 32.35, 35.50, 52.79, 116.43, 138.95, 203.05; MS m/ z 125
(M+ - CHO, 18); HRMS m/ z (M+ - CHO) calcd for C9H17
125.1326, Found 125.1319.
decadienyl AP-ester (8) (0.30 mmol, 0.10 g, 58%): [R]23
)
D
-26.1 (c 0.58, Ether); IR (neat) 1760 (CdO) cm-1; H NMR δ
1.00-1.02 (m, 3H), 1.47-1.50 (m, 3H), 1.59 (s, 3H), 1.60 (s,
3H), 1.67 (s, 3H), 1.95-2.13 (m, 6H), 2.12 (s, 3H), 3.83-3.94
(m, 1H), 3.99-4.07 (m, 1H), 4.97-5.14 (m, 5H), 5.75 (dd, J )
11.0 and 17.6 Hz, 1H); 13C NMR (major diastereomer) δ 16.16,
17.03, 17.70, 20.58, 20.67, 25.72, 26.54, 35.48, 39.99, 40.96,
68.57, 70.94, 113.49, 119.32, 124.26, 131.41, 137.79, 143.10,
170.28, 170.73; MS m/ z 336 (M+, 1.4).
1
2-Meth yl-2-vin ylu n d eca n a l (4d ): [R]26 ) +15.9 (c 1.0,
D
1
CHCl3) (76% ee); IR (neat) 1735 (CdO) cm-1; H NMR δ 0.88
(t, J ) 6.9 Hz, 3H), 1.16 (s, 3H), 1.26 (br, 14H), 1.55-1.59 (m,
2H), 5.11 (d, J ) 17.7 Hz, 1H), 5.26 (d, J ) 11.0 Hz, 1H), 5.79
(dd, J ) 11.0 and 17.7 Hz, 1H), 9.39 (s, 1H); 13C NMR δ 14.10,
17.67, 22.68, 23.90, 29.30, 29.54, 30.19, 31.88, 35.54, 52.78,
116.41, 138.96, 203.01; MS m/ z 210 (M+, 0.01); Anal. Calcd
for C14H26O: C, 79.94; H, 12.46. Found: C, 79.81; H, 12.40.
2-Eth yl-2-vin ylh ep ta n a l (4e): [R]24D ) -4.68 (c 1.28, ether)
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
4a -c, 4e, 6, 7, and 8 and 13C NMR spectra of 4e, 6, 7, and 8
(11 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
1
(63% ee); IR (neat) 1745 (CdO) cm-1; H NMR δ 0.82 (t, J )
7.5 Hz, 3H), 0.88 (t, J ) 6.9 Hz, 3H), 1.15-1.33 (m, 6H), 1.57-
1.72 (m, 4H), 5.11 (d, J ) 17.7 Hz, 1H), 5.32 (d, J ) 11.0 Hz,
1H), 5.72 (dd, J ) 11.0 and 17.7 Hz, 1H), 9.38 (s, 1H); 13C NMR
δ 8.13, 14.01, 22.49, 23.36, 25.20, 32.16, 32.45, 56.25, 117.29,
137.95, 203.67; MS m/ z 139 (M+ - CHO, 10).
J O970142K