Asymmetric synthesis of monoprotected double allylic alcohols

Article abstract of DOI:10.1055/s-2002-33341

The enantioselective synthesis of mono-TBS protected, double allylic alcohols 5 (ee = 90-94%) employing the SAMP/RAMP-hydrazone methodology is reported. Acetonide protected, α-substituted ketodiols 2 were synthesized from SAMP-hydrazone 1 which were converted to exocyclic olefins 3 by a racemization-free Wittig reaction. Acidic acetal cleavage to 4 followed by selective TBS protection furnished title compounds 5 in very good overall yields and enantiomeric excesses.

Full text of DOI:10.1055/s-2002-33341

PAPER
1571
Asymmetric Synthesis of Monoprotected Double Allylic Alcohols
S
ynthesis of Mono
i
protect
e
e
d
D
ouble
t
Allylic
e
A
lcohols r Enders,* Matthias Voith
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 13 May 2002
alized alkyl substituents,17 as well as Michael18 and aldol
Abstract: The enantioselective synthesis of mono-TBS protected,
adducts.19 Differentiation between the primary and sec-
ondary hydroxy group can be achieved, which leads to the
synthesis of derivatives under preservation of the stereo-
double allylic alcohols 5 (ee = 90–94%) employing the SAMP/
RAMP-hydrazone methodology is reported. Acetonide protected,
-substituted ketodiols 2 were synthesized from SAMP-hydrazone
1 which were converted to exocyclic olefins 3 by a racemization- center. Finally, there is the feasibility to form a new ste-
free Wittig reaction. Acidic acetal cleavage to 4 followed by selec-
tive TBS protection furnished title compounds 5 in very good over-
all yields and enantiomeric excesses.
reogenic center at the prochiral olefinic position through
substrate-directed stereoselective reactions,20 such as, for
example, hydrogenation, epoxidation, cyclopropanation
or Diels–Alder reactions.
Key words: asymmetric synthesis, hydrazones, Wittig reaction, al-
lylic alcohols, protecting groups
In order to synthesize title double allylic alcohols of type
A, SAMP-hydrazone (S)-1, which was readily prepared
on a multigram scale by condensation of (S)-1-amino-2-
The double allylic alcohol moiety is a crucial structural
methoxymethylpyrrolidine (SAMP) and 2,2-dimethyl-
feature of many natural products found, for example, in
1,3-dioxan-5one,17 was converted into the acetal protected
metabolites of marine sponges and microorganisms with
ketodiols (S)-2 by stereoselective alkylation following
ionophoric activity.1,2 Moreover, due to their triple func-
the SAMP/RAMP-hydrazone protocol.21 Then, exometh-
tionality there is a great potential for derivatisation and
ylene derivatives (S)-3 were synthesized utilizing a race-
use as a versatile building block in asymmetric and natural
mizationfree Wittig reaction.22 Subsequent acidic acetal
product synthesis.3–13 However, to the best of our know-
cleavage to (S)-4 followed by tert-butyldimethylsilyl
ledge only two asymmetric approaches to this type of sub-
(TBS) protection of the primary hydroxy group afforded
strates with high enantiomeric excesses have been
the title compounds (S)-5 (Scheme).
reported. One is an olefination, epoxidation and rear-
rangement pathway.3,4,9 The other is the Baylis–Hillman14
reaction using either chiral auxiliaries15 or chiral cata-
OCH3
lysts.16 Both of them proceed with relatively low yields
and slow reaction rates or have restriction regarding the
choice of substrates.
N
N
CH2
R'O
R
O
O
OH
Herein, we present a straight forward five step synthesis
of monoprotected, double allylic alcohols A (Figure) with
very good enantiomeric excesses, which allow an enantio-
selective approach to these versatile building blocks for
asymmetric synthesis.
5 steps
20-77%
ee = 90-94%
H3C CH3
(S)-4 R' = H
(S)-5 R' = TBS
(S)-1
1. t-BuLi, THF,
−78 °C, RX,
−100 °C
1. TFA, THF/H2O, r.t.
61-87%
46-97%
Wittig
CH2
2. Imidazole, TBSCl,
to r.t.
THF, 0 °C to r.t.
2. O3, CH2Cl2,
−78 °C
PGO
R
SAMP-hydrazone
alkylation
OH
O
CH2
A
Ph3P=CH2, THF,
R
O
R
−78 °C to r.t.
Figure The general structure of the monoprotected double allylic
alcohols A.
O
O
O
71-99%
H3C CH3
H3C CH3
These highly flexible key intermediates should not only
be accessible in both enantiomeric forms and high
enantiomeric excesses, but also for a wide range of sub-
stituents R, for example nonfunctionalized and function-
(S)-2
(S)-3
Scheme
In this manner, a variety of -substituted ketones (S)-2
were prepared by a two step synthesis23 starting from
SAMP-hydrazone (S)-1 in good overall yields (61–87%)
and very good enantiomeric excesses (ee = 90–94%). Al-
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1571,1577,ftx,en;Z07302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1572
D. Enders, M. Voith
PAPER
Table 3 Asymmetric Synthesis of Double Allylic Alcohols
(S)-4a–e
iphatic and sterically hindered, as well as benzylic halides
were used as electrophiles for the stereoselective -alky-
lation. Oxidative auxiliary cleavage was accomplished
utilizing ozone at low temperature (Table 1).
a
(S)-4
R
Yield
(%)
Mp
(°C)
[ ]D
Table 1 Asymmetric Synthesis of 4-Subtituted 2,2-Dimethyl-1,3-
dioxan-5-ones (S)-2a–e
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(CH2)2Ph
99
98
97
86
85
-
–36.9
–28.2
–21.6
–17.0
–25.6
Bn
50
c
(S)-2
R
X
Yielda
(%)
eeb
(%)
[ ]D
4-t-BuC6H4CH2
62–63
49–50
-
i-Pr
(S)-2a (CH2)2Ph
(S)-2b Bn
I
87
84
67
68
94
90
92
92
–189.0
–231.9
–193.7
–284.4
–241.2
n-Bu
Br
Br
I
a All optical rotations were measured in Uvasol grade CHCl3 at
c = 1.00 0.07 and T = 25 2 °C.
(S)-2c 4-t-BuC6H4CH2
(S)-2d i-Pr
Finally, protection of the primary hydroxy group of (S)-4
with tert-butyldimethylsilyl chloride (TBSCl) in the pres-
ence of imidazole in THF at 0 °C gave the title com-
pounds (S)-5 in very good yields after purification by
column chromatography (54–99%)25 (Table 4). Monopro-
tected alcohols were observed exclusively.
(S)-2e n-Bu
I
74d; 82e 92
a Overall yield starting from (S)-1.
b Determined by GC on chiral stationary phase by comparison with
racemic samples.
c All optical rotations were measured in Uvasol grade CHCl3 at
c = 1.00 0.06 and T = 26 2 °C.
d Yield of -substituted SAMP-hydrazone.
e Yield of dioxanone (S)-2e after auxiliary cleavage.
Table 4 Asymmetric Synthesis of Mono-TBS-Protected, Double
Allylic Alcohols (S)-5a–e
b
The racemization-free Wittig olefination22 converted the
chiral key intermediates (S)-2 into exo-methylene deriva-
tives (S)-3 in very good yields (71–99%) (Table 2). Me-
thyltriphenylphosphonium bromide was deprotonated
using t-BuLi at –78 °C in anhydrous THF to furnish the
active Wittig species, which converted the ketones (S)-2
into the exocyclic olefins (S)-3.
(S)-5
R
Yielda
(%)
[ ]D
(S)-5a
(S)-5b
(S)-5c
(S)-5d
(S)-5e
(CH2)2Ph
90
99
99
98
54
–21.0
–12.4
–10.8
–1.0
Bn
4-t-BuC6H4CH2
i-Pr
Table 2 Asymmetric Synthesis of 5-exo-Methylene, 4-Substituted
2,2-Dimethyl-1,3-dioxan-5-ones (S)-3a–e
n-Bu
–10.5
a Based on isolated material after flash chromatography.
b All optical rotations were measured in Uvasol grade CHCl3 at
c = 1.00 0.06 and T = 26 3 °C.
Yielda
(%)
[ ]D
b
(S)-3
R
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(CH2)2Ph
93
94
99
73
71
–75.1
–91.7
–76.2
–132.5
–97.2
As a representative example, allylic alcohol (S)-5b was
converted into the respective Mosher ester, which indicat-
ed that no racemization has occurred during the last three
steps.
Bn
4-t-BuC6H4CH2
i-Pr
In summary, we have developed an efficient five step
asymmetric synthesis of monoprotected, double allylic al-
cohols in good overall yields and very good enantiomeric
excesses starting from commercially available 2,2-dime-
thyl-1,3-dioxan-5-one following the SAMP/RAMP-hy-
drazone protocol as stereoselective key step.
n-Bu
a Based on isolated material after flash chromatography.
b All optical rotations were measured in Uvasol grade CHCl3 at
c = 1.00 0.09 and T = 26 3 °C.
The acetal protecting group was removed by hydrolysis
with trifluoroacetic acid (TFA) in a mixture of THF and
water at room temperature to afford the double allylic al-
cohols (S)-4 in excellent yields after aqueous work up
(85–99%) (Table 3).24 No further purification was neces-
sary in order to obtain products in purities which show
suitable spectroscopic data and correct elemental analy-
ses.
All moisture sensitive reactions were carried out using standard
Schlenk techniques. Solvents were dried and purified by conven-
tional methods prior to use. THF was freshly distilled under argon
from Na/Pb alloy and benzophenone. Reagents of commercial qual-
ity were used from freshly opened containers. Analytical TLC: Sil-
ica gel 60 F254 plates, Merck, Darmstadt. Preparative column
chromatography: Silica gel 60, particle size 0.040–0.063 mm, Mer-
ck, Darmstadt. Optical rotation values were measured on a Perkin-
Elmer P 241 (589 nm), solvents used were Merck Uvasol quality.
Synthesis 2002, No. 11, 1571–1577 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of Monoprotected Double Allylic Alcohols
1573
Elemental analyses were obtained from a Heraeus CHNORapid El-
ementar Vario EL element analyzer. Melting points were measured
on a Büchi 510 apparatus and are uncorrected. Mass spectra: Finni-
gan SSQ7000 or Finnigan MAT 95 (CI 100 eV, EI 70 eV). IR spec-
tra: Perkin-Elmer FT/IR 1760 (measured in CHCl3; all solid
samples as KBr). 1H NMR spectra (300 MHz, 400 MHz), 13C NMR
(75 MHz, 100 MHz): Varian Gemini 300, Mercury 300, Inova 400
(solvent: CDCl3, TMS as internal standard). Enantiomeric excesses
were determined by gas chromatography on chiral stationary phase
(Siemens Sichromat; CP Chirasildex CB; 0.25 mm 25 m).
by syringe at –78 °C. After stirring for 2 h at this temperature, the
mixture was cooled to –100 °C and the electrophile (11 mmol), dis-
solved in anhyd THF (2 mL), was added slowly. After further stir-
ring for 2 h at –100 °C, the mixture was allowed to warm to r.t. over
15 h. The mixture was quenched with pH 7 buffer solution (2 mL)
and diluted with Et2O (80 mL). The organic layer was washed with
pH 7 buffer solution (10 mL) and brine (2 10 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo. The
obtained monoalkylated SAMP-hydrazone was dissolved in
CH2Cl2 (50 mL) and flushed with ozone (60 L h–1) at –78 °C for
15 min. The reaction mixture was allowed to warm to r.t. and
flushed with argon. After removal of the solvent under reduced
pressure, the crude product was purified by flash chromatography
(silica gel,; n-pentane–Et2O, 20:1 to 30:1) to afford the 4-substituted
dioxanones (S)-2 as colorless oils (Table 5).
SAMP hydrazone (S)-1 was prepared by modification26 of the meth-
od of Woodward and Vorbrüggen reported by Hoppe et al.27 on a
65 mmol scale.
4-Substituted Dioxanones (S)-2; General Procedure
SAMP-hydrazone (S)-1 (10 mmol) was dissolved in anhyd THF
(40 mL). t-BuLi (11 mmol, 15% in n-pentane) was added dropwise
Table
5
Spectroscopic Data of 4-Substituted Dioxanones (S)-2a–ea
(S)-2
IR (CHCl3)
(cm–1)
1H NMR (CDCl3, TMS)
, J (Hz)
13C NMR (CDCl3, TMS),
MS (70 eV)
m/z (%)
(S)-2a
(S)-2b
(S)-2c
3473, 3086, 3063, 3028, 2989, 2936, 1.42 (s, 3 H, CH3), 1.45 (s, 3 H, CH3), 24.1, 24.4 (2 C, CH3), 30.4, 236 (15), 235 (M+
2865, 2633, 2157, 1951, 1875, 1801, 1.86 (m, 1 H, CHCHH), 2.20 (m, 1 H, 31.2 (2 C, CH2), 66.7
+ 1, 100), 218 (7),
217 (64), 178 (11),
177 (93), 176 (14),
159 (36), 134 (11),
133 (11), 131 (5),
130 (6)b
1746, 1604, 1585, 1497, 1455, 1432, CHCHH), 2.68 (m, 1 H, PhCHH),
1379, 1323, 1250, 1225, 1173, 1105, 2.80 (m, 1 H, PhCHH), 3.95 (d,
1071, 1036, 991, 974, 918, 867, 853, J = 17.0, 1 H, OCHH), 4.15 (ddd,
(OCH2), 73.8 (CH), 101.1
(CCH3), 126.3 (pCH),
128.3, 128.6 (4 C, OCH,
774, 750, 701, 623, 605, 582, 538,
517, 490
J = 1.5, 3.6, 9.1, 1 H, CH), 4.24 (dd, mCH), 141.2 (CPh), 209.8
J = 1.5, 16.9, 1 H, OCHH), 7.16–7.29 (C=O)
(m, 5 H, PhH)
3841, 3752, 3676, 3454, 3090, 3061, 1.35 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 23.9, 24.3 (2 C, CH3), 34.8 220 (M+, 14), 162
3028, 2989, 2937, 2879, 2345, 2142, 2.79 (dd, J = 9.1, 14.8, 1 H, PhCHH), (PhCH2), 66.9 (OCH2), 75.9 (51), 131 (12), 129
1944, 1873, 1854, 1803, 1747, 1655, 3.24 (dd, J = 3.3, 14.8, 1 H, PhCHH), (CH), 101.2 (CCH3), 123.6 (35), 120 (38), 119
1605, 1582, 1562, 1499, 1454, 1423, 4.01 (d, J = 17.0, 1 H, OCHH), 4.26 (pCH), 128.4, 129.4
1383, 1332, 1254, 1223, 1173, 1151, (dd, J = 1.5, 17.2, 1 H, OCHH), 4.46 (4C, OCH, mCH), 137.9
(10), 104 (14), 103
(12), 92 (68), 91
(69), 72 (100), 65
(10), 59 (31)
1103, 1083, 1065, 1029, 991, 962,
911, 893, 841, 822, 786, 757, 721,
696, 614, 577, 537, 500, 475, 455
(ddd, J = 1.4, 3.3, 9.1, 1 H, CH),
7.20–7.31 (m, 5 H, PhH)
(CPh), 209.0 (C=O)
3477, 3093, 3056, 3027, 2963, 2905, 1.31 (s, 9 H, PhCCH3), 1.38 (s, 3 H, 24.0, 24.3 (2 C, OCCH3),
2870, 1906, 1749, 1608, 1573, 1516, OCCH3), 1.43 (s, 3 H, OCCH3), 2.77 31.8 (3 C, PhCCH3), 34.3
1463, 1425, 1375, 1325, 1269, 1252, (dd, J = 8.9, 15.0, 1 H, PhCHH), 3.22 (PhCH2), 34.8 (PhCCH3),
276 (M+, 31), 218
(12), 178 (20), 161
(31), 148 (12), 147
(100), 129 (20), 72
(19)
1222, 1174, 1099, 1068, 1021, 988,
962, 924, 901, 831, 817, 756, 707,
663, 601, 569, 543, 503, 473
(dd, J = 3.0, 15.1, 1 H, PhCHH), 4.00 66.9 (OCH2), 75.9 (CH),
(d, J = 17.0, 1 H, OCHH), 4.26 (dd, 101.2 (OCCH3), 125.4,
J = 1.5, 17.2, 1 H, OCHH), 4.47 (m, 129.0 (4 C, OCPh, mCPh),
1H, CH), 7.18–7.33 (m, 4 H, PhH)
134.8, 149.3 (2 C, pCPh,
CPh), 209.1 (C=O)
(S)-2d
(S)-2e
3472, 3387, 2970, 2939, 2878, 2638, 0.90 (d, J = 6.9, 3 H, CHCH3), 1.03
1804, 1749, 1464, 1427, 1375, 1326, (d, J = 6.9, 3 H, CHCH3), 1.44 (s, 6 H, 23.3, 24.1 (2 C, CCH3), 28.0 (14), 100 (16), 73
1286, 1251, 1226, 1165, 1132, 1103, CCH3), 2.24 (septd, J = 4.1, 6.9, 1 H, (CHCH3), 67.2 (OCH2),
1089, 1074, 1029, 975, 962, 925, 873, CHCH3), 3.95 (d, J = 16.8, 1 H,
16.5, 19.0 (2 C, CHCH3),
172 (M+, 3), 114
(10), 72 (100), 69
78.7 (OCH), 100.5 (CCH3), (11), 59 (42)
209.7 (C=O)
852, 769, 706, 663, 619, 555, 537,
510, 467
OCHH), 4.03 (dd, J = 1.4, 4.1, 1 H,
OCH), 4.19 (dd, J = 1.5, 16.9, 1 H,
OCHH)
3477, 2988, 2958, 2935, 2872, 2593, 0.91 (t, J = 7.1, 3 H, CH2CH3), 1.44
14.1 (CH2CH3), 22.7
186 (M+, 2), 128
2339, 1803, 1748, 1631, 1462, 1428, (s, 3 H, CCH3), 1.46 (s, 3 H, CCH3), (CH2CH3), 23.7, 24.2 (2 C, (11), 100 (20), 86
1380, 1326, 1272, 1224, 1180, 1164, 1.28–1.44 (m, 4 H, CH3CH2,
CCH3), 27.4, 28.3 (2 C,
CH3CH2CH2, CHCH2),
66.8 (OCH2), 76.9 (CH),
(10), 85 (11), 72
(100), 59 (32), 58
(12), 57 (11), 55
1121, 1095, 1067, 1019, 994, 975,
951, 916, 860, 788, 756, 728, 665,
605, 544, 518, 471
CH3CH2CH2), 1.48–1.59 (m, 1 H,
CHCHH), 1.83–1.92 (m, 1 H,
CHCHH), 3.98 (d, J = 17.0, OCHH), 100.9 (CCH3), 210.0 (C=O) (13)
4.21 (ddd, J = 1.5, 3.8, 8.4, 1 H, CH),
4.25 (dd, J = 1.5, 16.9, 1 H, OCHH)
a Satisfactory elemental analyses obtained: C, H 0.4.
b CI (isobutane).
Synthesis 2002, No. 11, 1571–1577 ISSN 0039-7881 © Thieme Stuttgart · New York

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D. Enders, M. Voith
PAPER
exo-Methylene Derivatives (S)-3; General Procedure
Diols (S)-4; General Procedure
t-BuLi (26.4 mmol, 15% in n-pentane) was added dropwise to a
stirred suspension of methyltriphenylphosphonium bromide
(26.4 mmol) in anhyd THF (125 mL) at –78 °C and the stirring was
continued for 15 min. The mixture was allowed to warm to r.t. over
30 min and cooled again to –78 °C. A solution of the ketone (S)-2
(4.4 mmol) in anhyd THF (8 mL) was added and the reaction mix-
ture was allowed to warm to r.t. over 15 h. The mixture was
quenched with H2O (10 mL) and the aqueous layer was extracted
with Et2O (3 20 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo. The crude products were puri-
fied by flash chromatography (silica gel, n-pentane–Et2O, 25:1 to
60:1) to afford the alkenes (S)-3 as colorless oils (Table 6).
exo-Methylene derivative (S)-3 (8.1 mmol) was dissolved in THF
(50 mL) and H2O (28 mL) at r.t. Trifluoroacetic acid (1.31 mL) was
added and the mixture was stirred at r.t. until the reaction was com-
plete (TLC control). The reaction was quenched with aq 25% NH3
(10 mL) and H2O (30 mL). The aqueous layer was extracted with
CH2Cl2 (3 20 mL), dried (MgSO4) and concentrated in vacuo. No
further purification was necessary as the crude diols (S)-4 already
showed suitable spectroscopic data and correct elemental analyses
(Table 7).
Monoprotected, Double Allylic Alcohols (S)-5; General Proce-
dure
Imidazole (1.3 mmol) and diol (S)-4 (0.54 mmol) were dissolved in
THF (5 mL) and cooled to 0 °C. tert-Butyldimethylsilyl chloride
(TBSCl, 0.62 mmol; 50% in toluene) was added slowly. The cool-
Table 6 Spectroscopic Data of exo-Methylene Derivatives (S)-3a–ea
(S)-3
IR (CHCl3)
(cm–1)
1H NMR (CDCl3, TMS)
, J (Hz)
13C NMR (CDCl3, TMS)
MS (70 eV)
m/z (%)
(S)-3a
3520, 3384, 3084, 3063, 3026, 2989, 1.42 (s, 3 H, CCH3), 1.44 (s, 3 H,
2938, 2854, 2587, 2310, 1946, 1874, CCH3), 1.87–1.98 (m, 1 H, OC-
1805, 1657, 1604, 1584, 1546, 1496, CHH), 2.00–2.10 (m, 1 H, OCCHH), PhCH2), 64.5
22.1 (CCH3), 27.6 (CCH3),
31.4, 34.2 (2 C, OCCH2,
233 (M+ + 1, 22),
175 (19), 158 (14),
157 (100)b
1454, 1414, 1379, 1348, 1261, 1224, 2.63–2.72 (m, 1 H, PhCHH), 2.86
(OCH2), 69.5 (CH), 99.9
1198, 1158, 1104, 1087, 1064, 1032, (m, 1 H, PhCHH), 4.24 (t, J = 1.1, 2 (CCH3), 106.6 (CCH2),
979, 958, 897, 854, 808, 778, 750,
700, 580, 517, 468
H, OCH2), 4.28 (d, J = 8.1, 1 H, CH), 126.1 (pCPh), 128.6, 128.9
4.82 (dt, J = 1.1, 5.2, 2 H, CCH2),
(4 C, OCPh, mCPh), 142.3
(CPh), 146.3 (CCH2)
7.15–7.31 (m, 5 H, PhH)
(S)-3b
(S)-3c
3377, 3085, 3064, 3028, 2989, 2938, 1.29 (s, 3 H, CCH3), 1.31 (s, 3 H,
22.4 (CCH3), 27.6 (CCH3),
220 (14), 219 (M+
2854, 2606, 1946, 1804, 1657, 1605, CCH3), 2.83 (dd, J = 8.5, 14.3, 1 H, 39.2 (PhCH2), 64.6 (OCH2), + 1, 100), 162
1497, 1454, 1416, 1378, 1349, 1253, PhCHH), 3.01 (dd, J = 4.3, 14.4, 1 H, 71.8 (CH), 100.0 (CCH3), (11), 161 (91), 143
1226, 1200, 1159, 1081, 1053, 1027, PhCHH), 4.19 (d, J = 0.8, 2 H,
107.3 (CCH2), 126.3 (pCPh), (64), 127 (14)b
OCH2), 4.54 (m, 1 H, CH), 4.82 (m, 128.3, 129.5 (4C, OCPh,
2 H, CCH2), 7.11–7.24 (m, 5 H, PhH) mCPh), 138.7 (CPh), 146.0
(CCH2)
965, 898, 825, 751, 699, 590, 564,
520, 502, 460
3887, 3521, 3371, 3083, 3056, 2962, 1.31 (s, 9 H, PhCCH3), 1.39 (s, 6 H, 22.3 (CCH3), 27.5 (CCH3),
2867, 2714, 2593, 2385, 1902, 1790, OCCH3), 2.88 (dd, J = 8.0, 14.6, 1 H, 31.7 (3 C, PhCCH3), 34.6
1658, 1610, 1515, 1462, 1413, 1377, PhCHH), 3.04 (dd, J = 4.4, 14.6, 1 H, (PhCCH3), 38.6 (OCCH2),
274 (M+, 3), 216
(15), 128 (10), 127
(100), 69 (23), 59
(15)
1268, 1253, 1226, 1200, 1158, 1096, PhCHH), 4.26 (d, J = 1.1, 2 H,
64.6 (OCH2), 71.7 (CH),
1061, 1028, 966, 899, 832, 750, 717, OCH2), 4.62 (m, 1 H, CH), 4.88 (m, 99.9 (CCH3), 107.4 (CCH2),
655, 569, 519, 479
2 H, CCH2), 7.19 (d, J = 8.2, 2 H,
PhH), 7.20 (d, J = 8.2, 2 H, PhH)
125.2, 129.1 (4 C, OCPh,
mCPh), 135.6 (CPh), 146.0
(CCH2), 149.1 (CPh)
(S)-3d
3356, 3079, 2988, 2967, 2937, 2902, 0.92 (d, J = 6.9, 3 H, CHCH3), 1.00
2874, 2855, 1785, 1656, 1459, 1414, (d, J = 6.9, 3 H, CHCH3), 1.37 (s, 3
16.1 (CHCH3), 19.8
(CHCH3), 23.3 (CCH3), 27.1 (100), 95 (27), 69
170 (M+, 0.2), 127
1379, 1371, 1340, 1259, 1223, 1201, H, CCH3), 1.40 (s, 3 H, CCH3), 2.03 (CCH3), 30.7 (CHCH3), 64.8 (39), 67 (18), 59
1183, 1167, 1130, 1107, 1065, 1014, (septd, J = 3.7, 6.8, 1 H, CHCH3),
(OCH2), 75.5 (OCH), 99.7
(33), 55 (12)
947, 930, 873, 831, 767, 718, 655,
608, 519
4.12 (dt, J = 1.1, 13.2, 1 H, OCHH), (CCH3), 106.8 (CCH2),
4.16 (m, 1 H, OCH), 4.26 (dq,
J = 1.6, 13.2, 1 H, OCHH), 4.79 (d,
J = 1.1, 1 H, CCHH), 4.89 (q,
J = 1.6, CCHH)
146.1 (CCH2)
(S)-3e
3556, 3082, 2989, 2958, 2859, 2728, 0.92 (t, J = 7.1, 3 H, CH2CH3), 1.29– 14.4 (CH2CH3), 22.3
1657, 1459, 1413, 1379, 1348, 1338, 1.40 (m, 3 H, CH2alkyl), 1.38 (d, (CCH3), 23.0 (CH2alkyl),
1262, 1227, 1198, 1165, 1119, 1090, J = 0.6, 3 H, CCH3), 1.45 (d, J = 0.6, 27.5 (CCH3), 27.7, 32.3 (2 C,
185 (M+, 74), 127
(100), 109 (10)
1064, 1050, 1023, 1005, 957, 904,
862, 792, 749, 715, 589, 519, 486,
467
3 H, CCH3), 1.47–1.63 (m, 2 H,
CH2alkyl, OCCHH), 1.70–1.81 (m, 1 70.7 (CH), 99.8 (CCH3),
H, OCCHH), 4.25 (q, J = 1.2, 2 H,
OCH2), 4.30 (m, 1 H, CH), 4.82 (qd,
J = 1.5, 4.6, 2 H, CCH2)
CH2alkyl), 64.5 (OCH2),
106.3 (CCH2), 146.6 (CCH2)
a Satisfactory elemental analyses obtained for: C, H 0.4.
b CI (isobutane).
Synthesis 2002, No. 11, 1571–1577 ISSN 0039-7881 © Thieme Stuttgart · New York

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Asymmetric Synthesis of Monoprotected Double Allylic Alcohols
1575
Table 7 Spectroscopic Data of Double Allylic Alcohols (S)-4a–ea
(S)-4
IR (CHCl3)
(cm–1)
1H NMR (CDCl3, TMS)
, J (Hz)
13C NMR (CDCl3, TMS),
MS (70 eV)
m/z (%)
(S)-4a
3941, 3782, 3352, 3085, 3062, 3026, 1.75–1.93 (m, 2 H, OCCH2), 2.55
2999, 2930, 2864, 1948, 1874, 1809, (ddd, J = 6.7, 9.3, 13.9, 1 H Ph-
1655, 1603, 1534, 1496, 1454, 1310, CHH), 2.66 (ddd, J = 6.1, 9.6, 13.9, 74.1 (CH), 113.1 (CCH2),
32.4, 37.5 (2 C, PhCH2,
HOCCH2), 64.1 (HOCH2),
193 (M+ + 1, 37),
175 (19), 158 (13),
157 (100)b
1205, 1145, 1112, 1032, 914, 845,
803, 749, 700, 620, 588, 532, 496
1 H, PhCHH), 3.01 (br s, 2 H, OH), 126.2 (pCPh), 128.7 (4
4.05 (d, J = 13.2, 1 H, HOCHH), C, OCPh, mCPh), 141.9
4.14 (dd, J = 5.9, 7.6, 1 H, CH), 4.19 (CPh), 149.6 (CCH2)
(d, J = 13.2, 1 H, HOCHH), 5.03 (d,
J = 13.4, 2 H, CCH2), 7.08–7.23 (m,
5 H, PhH)
(S)-4b
3934, 3815, 3719, 3359, 3086, 3062, 2.53 (br s, 2 H, OH), 2.79 (dd,
3028, 3000, 2921, 2871, 2632, 1950, J = 8.8, 13.7, 1 H, PhCHH), 2.87
1881, 1812, 1757, 1655, 1603, 1545, (dd, J = 4.9, 13.7, 1 H, PhCHH),
1496, 1454, 1309, 1238, 1181, 1154, 4.07 (d, J = 13.2, 1 H, HOCHH),
1111, 1030, 915, 852, 747, 701, 619, 4.20 (d, J = 13.2, 1 H, HOCHH),
43.2 (PhCH2), 64.4
(HOCH2), 75.2 (CH), 113.1 (100), 91 (59), 87
(CCH2), 126.9 (pCPh),
128.8, 129.6 (4 C, OCPh,
mCPh), 138.2 (CPh), 149.3
178 (M+, 1), 92
(47), 69 (23), 65
(10)
583, 542
4.37 (dd, J = 4.9, 8.8, 1 H, CH), 5.04 (CCH2)
(d, J = 12.4, 2 H, CCH2), 7.12–7.26
(m, 5 H, PhH)
(S)-4c
3904, 3856, 3840, 3822, 3803, 3752, 1.25 (s, 9 H, CCH3), 2.08 (br s, 2 H, 31.7 (3 C, CCH3), 34.8
234 (M+, 1), 148
3677, 3656, 3631, 3274, 3061, 3023, OH), 2.77 (dd, J = 9.1, 13.7, 1 H, Ph- (CCH3), 42.8 (PhCH2), 64.6 (57), 147 (64), 134
2998, 2960, 2931, 2860, 2739, 2678, CHH), 2.88 (dd, J = 4.3, 13.6, 1 H,
2588, 2453, 2372, 2345, 2312, 2050, PhCHH), 4.14 (d, J = 12.9, 1 H,
1904, 1846, 1793, 1656, 1561, 1513, HOCHH), 4.27 (d, J = 13.2, 1 H,
1460, 1411, 1361, 1330, 1270, 1228, HOCHH), 4.41 (dd, J = 4.3, 9.2, 1 H, (CPh), 149.4, 149.8 (2 C,
1203, 1158, 1117, 1067, 1046, 1023, CH), 5.09 (d, J = 4.4, 2 H, CCH2), CPh, CCH2)
(HOCH2), 75.3 (CH), 113.0 (10), 133 (100),
(CCH2), 125.8, 129.2 (4
C, OCPh, mCPh), 134.9
132 (21), 117 (22),
105 (13), 92 (11),
91 (12), 87 (28),
57 (12)
980, 920, 852, 838, 800, 751, 730,
687, 574, 529, 489, 457
7.11 (d, J = 8.5, 2 H, PhH), 7.28 (d,
J = 8.2, 2 H, PhH)
(S)-4d
3947, 3906, 3885, 3840, 3801,
3782,,3753, 3736, 3676, 3631, 3401, (d, J = 6.6, 3 H, CHCH3), 1.78 (oc- (CHCH3), 32.2 (CHCH3),
3089, 2959, 2925, 2897, 2870, 2676, tet, J = 6.7, 1 H, CHCH3), 2.33 (br s, 64.4 (HOCH2), 81.1
0.79 (d, J = 6.6, 3 H, CHCH3), 0.93 18.5 (CHCH3), 19.8
131 (M+ + 1, 13),
113 (100)b
2588, 2529, 2466, 2425, 2372, 2343, 2 H, OH), 3.80 (d, J = 7.7, 1 H,
2296, 2228, 2185, 2112, 2040, 1978, HOCH), 4.06 (d, J = 13.2, 1 H,
1812, 1658, 1562, 1545, 1498, 1467, HOCHH), 4.23 (d, J = 13.2, 1 H,
1384, 1344, 1319, 1297, 1249, 1167, HOCHH), 5.01 (d, J = 0.6, 1 H,
1114, 1059, 1028, 991, 957, 904, 868, CCHH), 5.11 (d, J = 1.4, 1 H,
(HOCH), 113.9 (CCH2),
148.9 (CCH2)
807, 742, 671, 633, 555, 503
CCHH)
(S)-4e
see Ref.28
0.84 (t, J = 7.0, 3 H, CH3), 1.13–1.34 14.3 (CH3), 22.8, 28.1, 35.4 145 (M+ + 1, 13),
(m, 4 H, CH2alkyl), 1.46–1.58 (m, 2 (3 C, CH2alkyl), 63.6 127 (100), 109
H, CH2alkyl), 3.47 (br s, 1 H, OH), (HOCH2), 64.6 (CH), 112.6 (15)b
3.62 (br s, 1 H, OH), 4.03 (d,
(CCH2), 149.9 (CCH2)
J = 13.5, 1 H, HOCHH), 4.11 (t,
J = 6.7, 1 H, CH), 4.18 (d, J = 13.5,
1 H, HOCHH), 5.00 (s, 1 H, CCHH),
5.04 (d, J = 0.6, 1 H, CCHH)
a Satisfactory elemental analyses obtained: C, H 0.4.
b CI (isobutane).
ing bath was removed and the reaction mixture was stirred at r.t. for
5 h. The suspension was filtered through silica gel and Celite,
washed with Et2O and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel; n-pentane–Et2O,
4:1 to 10:1) to yield the mono-TBS-protected, double allylic alco-
hols (S)-5 as colorless oils (Table 8).
BASF AG, Bayer AG and Wacker Chemie for the donation of che-
micals.
References
(1) König, W. A.; Drautz, H.; Zähner, H. Liebigs Ann. Chem.
1980, 1384.
(2) Faulkner, D. J.; Ravi, B. N. Tetrahedron Lett. 1980, 21, 23.
(3) Kang, S. H.; Jun, H. S.; Youn, J. H. Synlett 1998, 1045.
(4) Kang, S. H.; Jun, H. S. Chem. Commun. 1998, 1929.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank Degussa AG,
Synthesis 2002, No. 11, 1571–1577 ISSN 0039-7881 © Thieme Stuttgart · New York

1576
D. Enders, M. Voith
PAPER
Table 8 Spectroscopic Data of Mono-TBS-Protected, Double Allylic Alcohols (S)-5a–ea
(S)-5
IR (CHCl3)
(cm–1)
1H NMR (CDCl3, TMS)
, J (Hz)
13C NMR (CDCl3, TMS),
MS (70 eV)
m/z (%)
(S)-5a
3891, 3404, 3085, 3063, 3027, 2953,
2930, 2886, 2857, 2740, 2710, 1941,
1805, 1654, 1604, 1496, 1469, 1391,
1362, 1256, 1113, 1069, 1007, 969,
0.02 (s, 6 H, SiCH3), 0.84 (s, 9 H,
CCH3), 1.78–1.95 (m, 2 H,
–5.0 (2 C, SiCH3), 18.6
(CCH3), 26.2 (3C, CCH3),
308 (26), 307
(M+ + 1, 100),
290 (10), 289
HOCCH2), 2.53–2.63 (m, 2 H, Ph- 32.5, 37.8 (2 C, PhCH2,
CHH, OH), 2.67–2.76 (m, 1 H, Ph- HOCCH2), 65.0 (TBSOCH2), (38), 157 (41)b
912, 839, 778, 749, 699, 672, 620, 586, CHH), 4.09–4.15 (m, 1 H, CH),
73.8 (CH), 111.7 (CCH2),
494
4.14 (d, J = 13.2, 1 H, TBSOCHH), 126.0 (pCPh), 128.6, 128.7 (4
4.25 (d, J = 13.2, 1 H, TBSOCHH), C, OCPh, mCPh), 142.2
5.01 (s, 1H, CCHH), 5.04 (d,
J = 1.4 Hz, CCHH), 7.08–7.24 (m,
5 H, PhH)
(CPh), 149.5 (CCH2)
(S)-5b
(S)-5c
(S)-5d
(S)-5e
3417, 3086, 3063, 3029, 2954, 2930,
2887, 2854, 2739, 2710, 1943, 1809,
1655, 1603, 1496, 1469, 1391, 1362,
1256, 1181, 1111, 1078, 1007, 966,
911, 839, 778, 745, 700, 671, 619, 541, (dd, J = 4.9, 13.7, 1 H, PhCHH),
492
0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.86 (s, 9 H, CCH3), 2.37
(d, J = 4.4, 1 H, OH), 2.81 (dd,
J = 8.5, 13.7, 1 H, PhCHH), 2.90
–5.0 (2 C, SiCH3), 18.7
(CCH3), 26.3 (3C, CCH3),
43.2 (PhCH2), 65.0
(TBSOCH2), 75.0 (CH),
111.7 (CCH2), 126.6 (pCPh),
294 (21), 293
(M+ + 1, 100),
276 (18), 275
(82), 143 (19)b
4.18 (d, J = 13.2, 1 H, TBSOCHH), 128.6, 129.6 (4 C, OCPh,
4.25 (d, J = 13.2, 1 H, TBSOCHH), mCPh), 138.7 (CPh), 149.2
4.35 (m, 1 H, CH), 5.00 (s, 1 H,
CCHH), 5.04 (d, J = 1.4, 1 H,
CCHH), 7.13–7.26 (m, 5 H, PhH)
(CCH2)
3856, 3809, 3415, 3091, 3055, 3024,
2957, 2901, 2858, 2739, 2711, 1903,
1790, 1654, 1515, 1469, 1391, 1363,
1256, 1203, 1110, 1062, 1007, 967,
0.03 (s, 6 H, SiCH3), 0.86 (s, 9 H,
SiCCH3), 1.24 (s, 9 H, PhCCH3),
2.30 (d, J = 4.4, 1 H, OH), 2.76 (dd, SiCCH3), 31.8 (3C, PhCCH3), 143 (56), 133
J = 8.9, 13.7, 1 H, PhCHH), 2.87
–4.9 (2 C, SiCH3), 18.7
(SiCCH3), 26.3 (3C,
348 (M+, 1), 202
(13), 201 (90),
34.8 (PhCCH3), 42.8
(PhCH2), 65.0 (TBSOCH2),
(12), 129 (24),
105 (13), 75
(34), 73 (26), 71
(15), 57 (100)
938, 910, 839, 816, 778, 720, 669, 569 (dd, J = 4.8, 13.7, 1 H, PhCHH),
4.17 (d, J = 13.3, 1 H, TBSOCHH), 74.8 (CH), 111.5 (CCH2),
4.24 (d, J = 13.3, 1 H, TBSOCHH), 125.6, 129.2 (4 C, OCPh,
4.34 (m, 1 H, CH), 5.05 (dt, J = 1.3, mCPh), 135.5 (CPh), 149.4,
4.0, 2 H, CCH2), 7.10 (d, J = 8.1, 2 149.5 (2 C, CPh, CCH2)
H, PhH), 7.26 (d, J = 8.5, 2 H, PhH)
3438, 3091, 2957, 2931, 2894, 2858,
2740, 2711, 1822, 1654, 1481, 1388,
1363, 1256, 1171, 1093, 1023, 983,
956, 938, 909, 838, 778, 672, 610, 569, CHCH3), 1.74 (octet, J = 6.7, 1 H,
502
0.02 (s, 6 H, SiCH3), 0.79 (d,
–5.1 (2 C, SiCH3), 18.5
246 (19), 245
J = 6.6, 3 H, CHCH3), 0.85 (s, 9 H, (CHCH3), 18.6 (CCH3), 19.8 (M+ + 1, 100),
CCH3), 0.93 (d, J = 6.6, 3 H,
(CHCH3), 26.2 (3 C, CCH3), 228 (15), 227
32.3 (CHCH3), 64.8
(81), 187 (10),
CHCH3), 2.41 (d, J = 5.5, 1 H, OH), (TBSOCH2), 80.8 (HOCH),
3.71 (dd, J = 5.5, 7.4, 1 H, HOCH), 112.6 (CCH2), 148.7 (CCH2)
4.10 (d, J = 13.2, 1 H, TBSOCHH),
4.24 (d, J = 13.2, 1 H, TBSOCHH),
4.97 (s, 1H, CCHH), 5.06 (q,
95 (41)b
J = 1.6, 1 H, CCHH)
3857, 3395, 3092, 2957, 2931, 2859,
2739, 2710, 1823, 1654, 1464, 1390,
1362, 1259, 1094, 1006, 939, 909, 838, CH2CH3), 1.16–1.38 (m, 4 H,
0.03 (s, 6 H, SiCH3), 0.85 (s, 9 H,
CCH3), 0.85 (t, J = 3.3, 3 H,
–5.1 (2 C, SiCH3), 14.4
260 (17), 259
(CH2CH3), 18.6 (CCH3), 23.0 (M+ + 1, 89),
(CH2alkyl), 26.2 (3 C, CCH3), 242 (21), 241
777, 730, 670, 616, 546
CH2alkyl), 1.49–1.58 (m, 2 H,
CH2alkyl), 2.45 (d, J = 4.1, 1 H,
OH), 4.08 (m, 1 H, CH), 4.13 (d,
J = 13.2, 1 H, TBSOCHH), 4.24 (d,
J = 13.2, 1 H, TBSOCHH), 4.98 (s,
1 H, CCHH), 5.02 (d, J = 1.7, 1 H,
CCHH)
28.3, 35.8 (2 C, CH2alkyl),
(100), 201 (19),
64.8 (TBSOCH2), 74.6 (CH), 109 (12)b
111.4 (CCH2), 149.8 (CCH2)
a Satisfactory HRMS data or elemental analyses obtained: C, H 0.4.
b CI (isobutane).
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Synthesis 2002, No. 11, 1571–1577 ISSN 0039-7881 © Thieme Stuttgart · New York