Synthesis of γ-hydroxy-α,β-unsaturated esters and nitriles from chiral cyanohydrins

Article abstract of DOI:10.1016/S0040-4020(00)00085-5

The Horner-Wittig reaction of cyanomethyl- and carbethoxymethyl diphenylphosphine oxides with a range of O-protected chiral α-hydroxy aldehydes is described. The α-hydroxy aldehydes were prepared with high enantiomeric purity from chiral O-protected cyano

Full text of DOI:10.1016/S0040-4020(00)00085-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2491–2495
Synthesis of g-Hydroxy-a,b-unsaturated Esters and Nitriles from
Chiral Cyanohydrins
Jan Marcus, Pauline J. van Meurs, Adrianus M. C. H. van den Nieuwendijk, Mathieu Porchet,
*
Johannes Brussee and Arne van der Gen
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
Received 25 October 1999; revised 4 January 2000; accepted 20 January 2000
Abstract—The Horner–Wittig reaction of cyanomethyl- and carbethoxymethyl diphenylphosphine oxides with a range of O-protected
chiral a-hydroxy aldehydes is described. The a-hydroxy aldehydes were prepared with high enantiomeric purity from chiral O-protected
cyanohydrins. The g-hydroxy-a,b-unsaturated compounds formed were isolated in high enantiomeric purity and excellent yield. In all cases
complete E-selectivity was observed. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction1
To prevent decomposition and racemization in subsequent
transformations the hydroxyl group of the cyanohydrin has
to be protected. After protection, the nitrile moiety can be
reduced with diisobutylaluminum hydride (DIBAL-H). The
O-protected chiral a-hydroxy aldehydes formed can sub-
sequently be used in Wittig-type reactions, thus forming
chiral g-hydroxy-a,b-unsaturated compounds. The prepara-
tion and utilization of Horner–Wittig reagents (diphenyl-
phosphine oxides) is also part of the research in our
group.11
Over the past years chiral cyanohydrins (a-hydroxynitriles)
have become a versatile source for a variety of chiral
building blocks. Several classes of valuable intermediates
have already been synthesized, including b-hydroxy-a-
amino acids,2 a-hydroxy-b-amino acids,3 a-hydroxy
ketones4b and b-hydroxy nitrones.5 Although chiral
a-hydroxy aldehydes are compounds of considerable
interest, their synthesis from chiral cyanohydrins has
remained problematic. Some attempts towards the synthesis
of chiral a-hydroxy aldehydes have been published but the
results, both in yield and optical purity, seem to be contra-
dictory.4,6,7 It was our intention to synthesize O-protected
chiral a-hydroxy aldehydes of high enantiomeric purity
and subsequently employ these compounds in Wittig-type
reactions.
We hereby report the synthesis of O-protected chiral
a-hydroxy aldehydes starting from chiral cyanohydrins
and their application in the Horner–Wittig reaction.
Results and Discussion
The synthesis of chiral cyanohydrins is a well-studied
subject in our laboratories.8 Cyanohydrins can be prepared
in excellent enantiomeric purity by asymmetric addition of
hydrogen cyanide to aldehydes in a reaction catalyzed by
the enzyme R-hydroxynitrile lyase (E.C. 4.1.2.10), as
present in almond meal.9 A wide variety of substrates can
be employed in the R-hydroxynitrile lyase catalyzed
reaction, including aromatic, heterocyclic, and saturated as
well as v- and a,b-unsaturated aliphatic aldehydes.8b,9 The
cyanohydrins 1 thus obtained are known to possess the
(R)-configuration.10
Tetrahydropyranyl (THP) protected cyanohydrins 2 were
used as starting materials for the projected Horner–Wittig
reaction sequence. The motive for using this protecting
group was the resulting stability of the intermediate
aldehydes and the ease with which it can be removed. The
nitrile moiety was reduced with DIBAL-H at Ϫ78ЊC in a
nitrogen atmosphere whereupon an imine–aluminum
complex was formed. This complex was hydrolyzed to the
corresponding aldehyde by stirring the reaction mixture
for a brief period of time with 10% w/w sulfuric acid at
Ϫ15ЊC. Aldehydes 3a (RˆC6H5) and 3f (Rˆn-C3H7)
were sufficiently stable to be purified by column chromato-
graphy after which they were isolated in 57% and 60%
yield, respectively. The remaining aldehydes could not
be purified in this way because of their air- and
moisture sensitivity, and were used directly in the next
step (Scheme 1).
Keywords: asymmetric synthesis; cyanohydrins; Horner–Wittig reaction;
a-hydroxy aldehydes.
* Corresponding author. Fax: ϩ31-71-5274537;
e-mail: brussee@chem. leidenuniv.nl
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00085-5

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J. Marcus et al. / Tetrahedron 56 (2000) 2491–2495
Scheme 1. Synthesis of g-hydroxy-a,b-unsaturated esters and nitriles from chiral cyanohydrins; a RˆC6H5, R0ˆCOOEt; b RˆC6H5, R0ˆCN; c Rˆ4-Cl–
C6H4, R0ˆCOOEt; d Rˆ4-MeO–C6H4, R0ˆCOOEt; e Rˆ4-MeO–C6H4, R0ˆCN; f Rˆn-propyl, R0ˆCOOEt; g Rˆ3-butenyl, R0ˆCOOEt.
Table 1. Horner–Wittig products obtained from chiral cyanohydrins
Compound
Product
e.e. (%)a
Yield (%)
86
e.e. (%)b
E/Z
5a
Ͼ99
96
E
5b
5c
Ͼ99
Ͼ99
82
86
96
97
E
E
4d
4e
Ͼ99
Ͼ99
88
83
96c
E
E
96c
5f
89
97
82
79
86
96
E
E
5g
a e.e. of cyanohydrin.
b e.e. of product.
c Racemization occurred upon deprotection.

J. Marcus et al. / Tetrahedron 56 (2000) 2491–2495
2493
After addition of LDA at Ϫ78ЊC the appropriate diphenyl-
Experimental
phosphine oxide was added. The amounts of LDA and
diphenylphosphine oxide are specified in the Experimental
section. After work-up the crude product was subjected to a
deprotection step. The pure g-hydroxy-a,b-unsaturated
compounds were isolated upon column chromatography.
NMR spectroscopy showed that the Horner–Wittig
reaction had proceeded with complete E-selectivity.13
Compounds 4a–g were obtained in high yields and with
almost no loss of enantiomeric purity. The results are
shown in Table 1.
General methods and materials
1H and 13C NMR spectra were recorded on a Bruker DPX-
200 instrument. Samples were measured in CDCl3, with
Me4Si as an internal standard for H NMR, and CDCl3 as
1
an internal standard for 13C NMR; d in ppm, J in Hz. Infra-
red spectra (neat) were recorded on a Pye Unicam SP3-200
IR spectrometer. Enantiomeric purities were determined by
HPLC using a Chiralcel OD column (250×4.6 mm). As
eluents, mixtures of hexane (H) and isopropyl alcohol (I),
which are specified in each case, were applied. Flowˆ1 ml/
min, lˆ254 nm unless otherwise specified. All compounds
were also prepared in racemic form to optimize the condi-
tions for peak separation. Optical rotations were measured
using a Propol automatic polarimeter. HRMS spectra were
obtained with a Finnigan MAT ITD 700 electron impact
(70 eV). The cyanohydrins were prepared as described
earlier.9 The THP protection was performed according to
literature.12 THF was distilled from LiAlH4 prior to use.
Diethyl ether was dried over sodium wire. The phosphine
oxides were prepared via an Arbuzov reaction from ethyl
diphenylphosphinite [(C6H5)2P–OC2H5] and either ethyl
bromoacetate or chloroacetonitrile.
In a comparative study, the Horner–Wittig reagents
(diphenylphosphine oxides) were shown to be the most
successful. Application of other phosphorus compounds
like the Wittig reagent carbethoxymethyl–triphenylphos-
phonium bromide and the Horner–Wadsworth–Emmons
reagent triethylphosphono acetate resulted in lower yields
and often partial racemization.
Not all O-protected cyanohydrins studied could be reduced
to the corresponding aldehydes. The attempted synthesis of
aldehydes from the O-protected cyanohydrins of 5-methyl-
furfural and crotonaldehyde were unsuccessful. For the
former cyanohydrin this could be ascribed to the acid labile
furan ring, which decomposed upon addition of sulfuric
acid. For the latter cyanohydrin the reason for failure is
not obvious. Clearly the unsaturated character of the
compound is the causative factor, as compound 5f, contain-
ing the corresponding saturated side chain, was obtained
without difficulties. A similar observation has been reported
in the literature.7
Aldehyde synthesis
All reactions were carried out under a dry nitrogen
atmosphere. In a three-necked reaction flask 10 mmol of a
THP-protected cyanohydrin was dissolved in dry diethyl
ether. At Ϫ78ЊC, 14 ml (14 mmol) of 1 M DIBAL-H in
cyclohexane was added to the stirred solution. The cooling
bath was removed and the mixture was allowed to warm to
Ϫ15ЊC. Then 17 ml of a 10% w/w solution of H2SO4 in
water was added. After stirring the reaction mixture
vigorously for 10 min, 40 ml of an aqueous solution of satu-
rated NaHCO3 was added. The mixture was stirred for
5 min. The reaction mixture was poured into water and
extracted with diethyl ether (3×100 ml). The combined
organic layers were washed with brine and dried over
MgSO4. After evaporation of the solvent the crude aldehyde
was obtained as oil. The aldehyde was used immediately in
the next step.
During the deprotection of compounds 4d and 4e, both
containing a 4-methoxy substituted phenyl ring, with
para-toluenesulfonic acid in ethanol, the hydroxyl sub-
stituent turned out to have been replaced by an ethoxy
group. In addition, complete racemization had occurred.
This can be explained by assuming loss of water from
the initial product upon protonation of the deprotected
hydroxyl group. The resulting carbocation is stabilized by
the 4-methoxy phenyl substituent. Reaction with the
solvent, ethanol, then gives the corresponding ethoxy
compound with racemization of the chiral center. Other
deprotecting reagents like MgBr2 and a mixture of acetic
acid, THF and water (4:2:1) failed to give better results.
This impracticability to deprotect the O-THP group only
occurs with strongly electron-releasing aromatic ring sub-
stituents. Compounds with electron-withdrawing ring
substituents, like the unsaturated ester 4c, could be depro-
tected effectively by treatment with para-toluenesulfonic
acid in ethanol.
(2R) 2-(tetrahydropyran-2-yloxy)-phenylacetaldehyde
(3a). Prepared as described above. The crude product was
chromatographed (silica gel, petroleum ether 40–60/diethyl
ether 8/2) and 3a was obtained as a pale yellow oil (yield:
57%).
1
Diastereoisomer A H NMR: dˆ1.55–1.87 (m, 6H, THP),
3.48 (m, 2H, THP), 4.66 (t, 1H, Jˆ2.6 Hz, OCHO), 5.05
(d, 1H, Jˆ1.5 Hz, CH), 7.37–7.43 (m, 5H, H-arom), 9.62
(d, 1H, Jˆ1.5 Hz, CHO).
1
Conclusion
Diastereoisomer B H NMR: dˆ1.55–1.87 (m, 6H, THP),
3.48 (m, 2H, THP), 4.93 (t, 1H, Jˆ2.6 Hz, OCHO), 5.20
(d, 1H, Jˆ1.5 Hz, CH), 7.37–7.43 (m, 5H, H-arom), 9.65
(d, 1H, Jˆ1.5 Hz, CHO).
By performing a Horner–Wittig reaction on a series of
chiral hydroxy aldehydes a range of different chiral g-hy-
droxy-a,b-unsaturated compounds of high enantiomeric
purity could be prepared in excellent yield. In all cases
complete E-selectivity was found.
(2R) 2-(tetrahydropyran-2-yloxy)-pentanal (3f). Pre-
pared as described above. The crude product was

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J. Marcus et al. / Tetrahedron 56 (2000) 2491–2495
chromatographed (silica gel, petroleum ether 40–60/diethyl
ether 8/2) and 3f was obtained as a yellow oil (yield: 60%).
phosphine oxide and 1.45 equiv. DIPA. The crude product
was chromatographed (silica gel, petroleum ether 40–60/
ethyl acetateˆ7/3) and 5b was obtained as a colourless oil
(yield: 82%). [a]2D0ˆϪ87.0 (cˆ1, CHCl3); e.e. 96% (HPLC
eluent H:Iˆ95:5); IR: (liquid film) 3400 (br), 2220 cmϪ1; 1H
NMR: dˆ5.36 (m, 1H, CHO), 5.84 (dd, 1H, Jˆ16, 2.2 Hz),
6.82 (dd, 1H, Jˆ16, 3.7 Hz), 7.34 (m, 5H, H-arom). 13C
NMR: dˆ73.09 (CHO), 98.35 (CHvCH), 117.21 (CN),
126.52, 128.67, 128.92 (C-arom), 139.65 (Cipso), 155.15
(CHvCH); HRMS (EI): Mϩ, found 159.0681. C10H9NO
requires 159.0684.
1
Diastereoisomer A H NMR: dˆ0.88 (t, 3H, Jˆ7.2, CH3),
1.43–1.61 (m, 6H, THP), 1.63–1.84 (m, 4H, 2×CH2), 3.56
(m, 2H, THP), 4.18 (m, 1H, OCHO), 4.56 (m, 1H, CH), 9.63
(d, 1H, Jˆ1.5 Hz, CHO).
1
Diastereoisomer B H NMR: dˆ0.96 (t, 3H, Jˆ7.2 Hz,
CH3), 1.43–1.61 (m, 6H, THP), 1.63–1.84 (m, 4H,
2×CH2), 3.87 (m, 2H, THP), 4.18 (m, 1H, OCHO), 4.69
(m, 1H, CH), 9.65 (d, 1H, Jˆ1.5 Hz, CHO).
(4R) Ethyl 4-(4-chlorophenyl)-4-hydroxy-(E)-but-2-
enoate (5c). Prepared as described above starting from 2c.
Equivalents used: 1.2 equiv. BuLi, 1.2 equiv. (carbethoxy-
methyl)-diphenylphosphine oxide and 1.3 equiv. DIPA. The
crude product was chromatographed (silica gel, petroleum
ether 40–60/ethyl acetateˆ3/1) and 5c was obtained as
colourless oil (yield: 86%). [a]2D0ˆϪ52.3 (cˆ1, CHCl3);
e.e. 97% (HPLC eluent H:Iˆ95:5); IR: (liquid film) 3400
(br), 1700, 1100 cmϪ1; 1H NMR: dˆ1.29 (t, 3H, Jˆ7.2 Hz,
CH3), 4.20 (q, 2H, Jˆ7.2 Hz, CH2), 5.35 (dd, 1H, Jˆ4.6,
1.5 Hz, CH), 6.14 (dd, 1H, Jˆ15.4, 1.5 Hz, CHvCHC(O)),
6.99 (dd, 1H, Jˆ15.4, 4.6 Hz, CHvCHC(O)), 7.34 (m, 4H,
H-arom). 13C NMR: dˆ14.02 (CH3), 60.59 (CH2), 72.44
(CH), 120.25 (CHvCH), 127.78, 128.07, 128.71, 128.80
(C-arom), 133.77 (Cipso), 139.37 (Cl-Cipso), 148.31
(CHvCH), 166.47 (C(O)); HRMS (EI): Mϩ, found
240.0559. C12H13ClO3 requires 240.0553.
Horner–Wittig reaction
In a three-necked reaction flask 25 ml of dry THF was
cooled to Ϫ60ЊC. Then diisopropylamine (DIPA) and
n-butyllithium (BuLi) were added. The reaction mixture
was allowed to warm to Ϫ20ЊC and then cooled to
Ϫ78ЊC. At this temperature the diphenylphosphine oxide,
dissolved in a small amount of THF, was added. After stir-
ring the reaction mixture for 10 min, the aldehyde dissolved
in THF, was added. After reaching room temperature the
reaction mixture was poured into water and extracted with
dichloromethane. The organic layers were combined, dried
(MgSO4) and concentrated in vacuo. The amounts of DPA,
BuLi and diphenylphosphine oxide are case specific and are
given for each compound.
Deprotection
(4R) Ethyl 4-(4-methoxyphenyl)-4-(tetrahydropyran-2-
yloxy)-(E)-but-2-enoate (4d). Prepared as described
above starting from 2d. Equivalents used: 1.2 equiv. BuLi,
1.2 equiv. (carbethoxymethyl)-diphenylphosphine oxide
and 1.45 equiv. DIPA. The crude product was chromato-
graphed (silica gel, petroleum ether 40–60/ethyl acetateˆ
4/1 and 4d was obtained as a colourless oil (yield: 88%). IR:
(liquid film) 3400 (br), 1700 cmϪ1; HRMS (EI): Mϩ, found
320.1623. C18H24O5 requires 320.1624.
The resulting crude product was dissolved in ethanol and a
catalytic amount of p-toluenesulphonic acid was added.
After stirring overnight at room temperature, 10 ml of an
aqueous solution of saturated NaHCO3 was added. The
mixture was stirred vigorously for 5 min. The reaction
mixture was poured into water and extracted with dichloro-
methane. The organic layers were combined, dried (MgSO4)
and concentrated in vacuo. The products were purified by
column chromatography.
1
Diastereoisomer A H NMR: dˆ1.28 (t, 3H, Jˆ7.3 Hz,
CH3CH2O), 1.57–1.89 (m, 6H, OTHP), 3.74 (m, 2H,
OTHP), 3.75 (s, 3H, MeO), 4.18 (q, 2H, Jˆ7.3 Hz,
CH3CH2O), 4.53 (m, 1H, OCHO), 5.27 (m, 1H, CHO),
6.08 (dd, 1H, Jˆ1.5, 15.4 Hz, CHvCHC(O)), 6.97 (dd,
1H, Jˆ5.1, 15.4 Hz, CHvCHC(O)), 7.21–7.32 (m, 4H,
H-arom). 13C NMR: dˆ13.87 (OCH3CH2), 18.62 (THP),
25.11 (THP), 30.05 (THP), 54.80 (OCH3), 59.94
(OCH3CH2), 61.45 (THP), 74.41 (CH), 94.12 (THP),
113.57 (C-arom), 119.39 (CHvCH), 128.15 (C-arom),
130.19 (Cipso), 146.95 (CHvCH), 158.99 (Cipso), 165.79
(C(O)).
(4R) Ethyl 4-hydroxy-4-phenyl-(E)-but-2-enoate (5a).
Prepared as described above starting from 2a. Equivalents
used: 1.2 equiv. BuLi, 1.2 equiv. (carbethoxymethyl)-
diphenylphosphine oxide and 1.45 equiv. DIPA. The crude
product was chromatographed (silica gel, petroleum ether
40–60/ethyl acetate; first column 9/1; second column 3/1)
and 5a was obtained as a colourless oil (yield: 86%).
[a]2D0ˆϪ71.6 (cˆ1, CHCl3); e.e. 96% (HPLC eluent
H:Iˆ95:5); IR: (liquid film) 3400 (br), 1700 cmϪ1
;
1H
NMR: dˆ1.27 (t, 3H, Jˆ6.9 Hz, CH3), 2.41 (broad s, 1H,
OH), 4.18 (q, 2H, Jˆ7.0 Hz, CH2), 5.35 (dd, 1H, Jˆ4.6,
1.3 Hz, CH), 6.15 (dd, 1H, Jˆ15.4, 1.3 Hz, CHvCHC(O)),
7.04 (dd, 1H, Jˆ15.4, 4.6 Hz, CHvCHC(O)), 7.34 (m,
5H, H-arom). 13C NMR: dˆ14.02 (CH3), 60.44 (CH2),
73.15 (CH), 119.84 (CHvCH), 126.44, 128.01, 128.57
(C-arom), 140.86 (Cipso), 148.86 (CHvCH), 166.59
(C(O)); HRMS (EI): Mϩ, found 206.0954. C12H14O3
requires 206.0943.
1
Diastereoisomer B H NMR: dˆ1.29 (t, 3H, Jˆ7.3 Hz,
CH3CH2O), 1.57–1.89 (m, 6H, OTHP), 3.78 (m, 2H,
OTHP), 3.80 (s, 3H, MeO), 4.19 (q, 2H, Jˆ7.3 Hz,
CH3CH2O), 4.80 (m, 1H, OCHO), 5.30 (m, 1H, CHO),
6.13 (dd, 1H, Jˆ1.5, 15.4 Hz, CHvCHC(O)), 7.04 (dd,
1H, Jˆ5.1, 15.4 Hz, CHvCHC(O)), 7.21–7.32 (m, 4H,
H-arom). 13C NMR: dˆ13.87 (OCH3CH2), 18.71 (THP),
25.11 (THP), 30.05 (THP), 54.80 (OCH3), 60.07
(OCH3CH2), 61.45 (THP), 75.36 (CH), 95.99 (THP),
113.75 (C-arom), 121.06 (CHvCH), 128.60 (C-arom),
(4R) 4-Hydroxy-4-phenyl-(E)-but-2-enenitrile (5b).
Prepared as described above starting from 2a. Equivalents
used: 1.2 equiv. BuLi, 1.2 equiv. cyanomethyl diphenyl-

J. Marcus et al. / Tetrahedron 56 (2000) 2491–2495
2495
131.39 (Cipso), 147.80 (CHvCH), 159.32 (Cipso), 166.15
(C(O)).
3420 (br), 1700 cmϪ1; 1H NMR: dˆ1.30 (t, 3H, Jˆ7.3 Hz,
CH3), 1.72 (m, 2H, CH2), 2.20 (m, 2H, CH2), 4.21 (q, 2H,
Jˆ7.3 Hz, CH3CH2O), 4.32 (m, 1H, CH), 5.02 (m, 2H,
CH2vCH), 5.83 (m, 1H, CH2vCH), 6.05 (dd, 1H,
Jˆ15.4, 1.5 Hz, CHvCHC(O)), 6.95 (dd, 1H, Jˆ15.4,
5.1 Hz, CHvCHC(O)). 13C NMR: dˆ13.89 (CH3), 29.15,
35.21 (CH2), 60.26 (CH3CH2O), 69.90 (CH), 114.94
(CH2vCH), 119.76 (CHvCH(CO)), 137.50 (CH2ˆCH),
150.39 (CHvCH(CO)), 166.61 (C(O)); HRMS (EI): Mϩ,
found 184.1087. C10H16O3 requires 184.1099.
(4R) 4-(4-Methoxyphenyl)-4-(tetrahydropyran-2-yloxy)-
(E)-but-2-enenitrile (4e). Prepared as described above
starting from 2d. Equivalents used: 1.2 equiv. BuLi,
1.2 equiv. cyanomethyl diphenylphosphine oxide and
1.45 equiv. DIPA. The crude product was chromatographed
(silica gel, petroleum ether 40–60/ethyl acetate ˆ3/1 and 4e
was obtained as a colourless oil (yield: 83%). IR: (liquid
film) 3400 (br), 2215 cmϪ1; HRMS (EI): Mϩ, found
273.1356. C16H19NO3 requires 273.1365.
Diastereoisomer A 1H NMR: dˆ1.57–1.86 (m, 6H, OTHP),
3.40–3.70 (m, 2H, OTHP), 3.78 (s, 3H, MeO), 4.49 (m, 1H,
OCHO), 5.26 (m, 1H, CHO), 5.67 (dd, 1H, Jˆ1.5, 16 Hz,
CHvCHCN), 6.74 (dd, 1H, Jˆ5.1, 16 Hz, CHvCHCN),
6.88–7.26 (m, 4H, H-arom). 13C NMR: dˆ18.39 (THP),
24.91 (THP), 29.85 (THP), 54.77 (MeO), 61.38 (THP),
74.24 (CHO), 94.34 (THP), 97.92 (CHvCH), 113.69
(C-arom), 116.57 (CN), 127.91 (C-arom), 128.79 (Cipso),
153.56 (CHvCH), 159.20 (Cipso).
References
1. Marcus, J.; Brussee, J.; van der Gen, A. In Proceedings of
ECSOC-3, The Third International Electronic Conference on
Synthetic Organic Chemistry, http://www.mdpi.org/ecsoc-3.htm,
September 1–30, 1999; Pombo-Villar, E.; Neier, R.; Lin, S.-K.,
Eds.; CD-ROM ed.; ISBN 3-906980-04-9; 1999, MDPI, Basel.
2. Zandbergen, P.; Brussee, J.; van der Gen, A.; Kruse, C. G.
Tetrahedron: Asymmetry 1992, 3, 769–774.
3. Warmerdam, E. G. J. C.; van Rijn, R. D.; Brussee, J.; Kruse,
C. G.; van der Gen, A. Tetrahedron: Asymmetry 1996, 7, 1723.
4. (a) Matthews, B. R.; Gountzos, H.; Jackson, W. R.; Watson,
K. G. Tetrahedron Lett. 1989, 30, 5157–5158. (b) Jackson, W. R.,
Jacobs, H. A.; Jayatilake, G. S.; Matthews, B. R.; Watson, K. G.
Aust. J. Chem. 1990, 43, 2045–2062.
Diastereoisomer B 1H NMR: dˆ1.57–1.86 (m, 6H, OTHP),
3.40–3.70 (m, 2H, OTHP), 3.81 (s, 3H, MeO), 4.78 (m, 1H,
OCHO), 5.30 (m, 1H, CHO), 5.77 (dd, 1H, Jˆ1.5, 16 Hz,
CHvCHCN), 6.78 (dd, 1H, Jˆ5.1, 16 Hz, CHvCHCN),
6.88–7.26 (m, 4H, H-arom). 13C NMR: dˆ18.78 (THP),
24.91 (THP), 29.85 (THP), 54.77 (MeO), 61.72 (THP),
75.57 (CHO), 96.44 (THP), 99.13 (CHvCH), 113.90
(C-arom), 116.90 (CN), 128.55 (C-arom), 130.15 (Cipso),
153.96 (CHvCH), 159.57 (Cipso).
5. Hulsbos, E.; Marcus, J.; Brussee, J.; van der Gen, A. Tetrahedron:
Asymmetry 1997, 8, 1061–1067.
6. Effenberger, F.; Hopf, M.; Ziegler, T.; Hudelmayer J. Chem.
Ber. 1991, 124, 1651–1659.
7. Hayashi, M.; Yoshiga, T.; Nakatani, K.; Ono, K.; Oguni, N.
Tetrahedron 1994, 50, 2821–2830.
(4R) Ethyl 4-hydroxy-(E)-hept-2-enoate (5f). Prepared
as described above starting from 2f. Equivalents used:
1.02 equiv. BuLi, 1.02 equiv. (carbethoxymethyl)-di-
phenylphosphine oxide and 1.22 equiv. DIPA. The crude
product was chromatographed (silica gel, dichloro-
methane/diethyl ether ˆ8/2) and 5f was obtained as a
colourless oil (yield: 82%). [a]2D0ˆϪ16.7 (cˆ1, CHCl3);
e.e. 86% (HPLC eluent H:Iˆ 95:5); IR: (liquid film) 3410
(br), 1700 cmϪ1; 1H NMR: dˆ0.95 (t, 3H, Jˆ7.2 Hz, CH3),
1.30 (t, 3H, Jˆ 7.2 Hz, CH3CH2O), 1.39–1.66 (m, 4H,
CH2), 4.20 (q, 2H, Jˆ7.2 Hz, CH3CH2O), 4.34 (m, 1H,
CH), 6.03 (dd, 1H, Jˆ15.4, 1.5 Hz, CHvCHC(O)), 6.95
(dd, 1H, Jˆ15.4, 5.1 Hz, CHvCH(CO)). 13C NMR:
dˆ13.70 (CH3), 13.99 (CH3CH2O), 18.31, 38.49 (CH2),
60.30 (CH3CH2O), 70.49 (CH), 119.66 (CHvCH), 150.61
(CHvCH), 166.67 (C(O)); HRMS (EI): Mϩ, found 172.1091.
C9H16O3 requires 172.1099.
8. (a) Kruse, C. G. In Chirality in Industry; Collins, A. N.;
Sheldrake, G. N.; Crosby, J. Eds.; Wiley: New York; 1992;
p 279–299. (b) Brussee, J.; van der Gen, A. In Stereoselective
Biocatalysis; Patel, R., Ed., Marcel Dekker: New York; 1999, in press.
9. (a) Zandbergen, P.; van der Linden, J.; Brussee, J.; van der Gen,
A. Synth. Commun. 1991, 21, 1387–1391. (b) Marcus, J.; Brussee,
J.; van der Gen, A. Eur. J. Org. Chem. 1998, 2513–2517.
10. Provided that the cyano group has priority over substituent R.
11. (a) Otten, P. A.; Davies, H. M.; van der Gen, A. Tetrahedron
Lett. 1995, 36, 781. (b) Otten, P. A. Horner–Wittig Reagents in
Sulfur and Selenium Chemistry, Ph.D. Thesis, Leiden University,
1996.
12. van den Nieuwendijk, A. M. C. H.; Warmerdam, E. G. J. C.;
Brussee, J.; van der Gen, A. Tetrahedron: Asymmetry 1995, 6,
801–806.
13. Based on the coupling constant of the hydrogen atoms at the
double bond formed. The observed value of 15–16 Hz is typical of
an E double bond. No peaks belonging to the Z isomer could be
observed. E-selectivity was expected since the reagents used have
been shown to be E-selective. See: (a) Bottin-Strzalko, T. Tetrahedron
1973, 29, 4199. (b) Bottin-Strzalko, T.; Etemad-Moghadam, G.;
Seyden-Penne, J. Nouv. J. Chim. 1982, 7, 155. (c) Etemad-
Moghadam, G.; Seyden-Penne, J. Synth. Commun. 1984, 14, 565.
(d) Etemad-Moghadam, G.; Seyden-Penne, J. Tetrahedron 1984,
40, 5153.
(4R) Ethyl 4-hydroxy-(E)-octa-2,7-dienoate (5g).
Prepared as described above starting from 2g. Equivalents
used: 1.04 equiv. BuLi, 1.04 equiv. (carbethoxymethyl)-
diphenylphosphine oxide and 1.23 equiv. DIPA. The crude
product was chromatographed (silica gel, petroleum ether
40–60/ethyl acetateˆ8/2) and 5g was obtained as a colour-
less oil (yield: 79%). [a]2D0ˆϪ4.5 (cˆ1, CHCl3); e.e. 96%
(HPLC eluent H:Iˆ97:3 flow 0.7 ml/min); IR: (liquid film)