SN2′ alkylation of chiral allylic cyanohydrin O-phosphates with organocuprates

Article abstract of DOI:10.1002/ejoc.200600822

Enantiomerically enriched cyanohydrin O-phosphates, prepared by enantioselective cyanophosphorylation of α,β-unsaturated aldehydes, react regioselectively at the γ-position with organocuprates derived from alkyl Grignard reagents and CuCN to afford chiral γ-alkyl-substituted α,β-unsaturated nitriles. The configuration of the new C-C double bond is mainly (E) when the reaction is performed at -78°C and (Z) when it is carried out at higher temperatures (0°C). A high level of transfer of the chirality in the new stereocentre, corresponding to a stereospecific anti attack onto the cyanophosphate, is observed. Enantiomerically enriched (E)-γ-alkylated α,β-unsaturated esters are prepared after subsequent methanolysis in a three-step sequence from the corresponding α,β-unsaturated aldehydes. In addition, the synthesis of (R)-4-methylnonan-1-ol, also known as the sex pheromone of the yellow mealworm Tenebrio molitor L, and its (S) enantiomer have been carried out in a four-step route from (E)-oct-2-enal. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200600822

FULL PAPER
DOI: 10.1002/ejoc.200600822
SN2Ј Alkylation of Chiral Allylic Cyanohydrin O-Phosphates with
Organocuprates
Alejandro Baeza,[a] Carmen Nájera,*[a] and José M. Sansano[a]
Dedicated to Prof. Henri B. Kagan for his pivotal contributions in asymmetric synthesis
Keywords: Copper / Allylic substitution / Asymmetric synthesis / Unsaturated nitriles / Cyanophosphates
Enantiomerically enriched cyanohydrin O-phosphates, pre-
pared by enantioselective cyanophosphorylation of α,β-un-
saturated aldehydes, react regioselectively at the γ-position
with organocuprates derived from alkyl Grignard reagents
and CuCN to afford chiral γ-alkyl-substituted α,β-unsatu-
rated nitriles. The configuration of the new C–C double bond
is mainly (E) when the reaction is performed at –78 °C and
(Z) when it is carried out at higher temperatures (0 °C). A
high level of transfer of the chirality in the new stereocentre,
corresponding to a stereospecific anti attack onto the cyano-
phosphate, is observed. Enantiomerically enriched (E)-γ-al-
kylated α,β-unsaturated esters are prepared after subsequent
methanolysis in a three-step sequence from the correspond-
ing α,β-unsaturated aldehydes. In addition, the synthesis of
(R)-4-methylnonan-1-ol, also known as the sex pheromone of
the yellow mealworm Tenebrio molitor L, and its (S) enanti-
omer have been carried out in a four-step route from (E)-oct-
2-enal.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
per(II) reagents,[5,7] and reactions performed with chiral
substrates and organocuprates,[5,8] with employment of al-
lylic acetates, carbonates and phosphates.
Introduction
The generation of a non-functionalised stereogenic cen-
tre is not a very easy task in modern organic chemistry.
Traditionally, the reaction between an organometallic rea-
gent and a chiral electrophilic substrate can be employed
for this purpose, but many side reactions – such as isomeris-
ations, eliminations and partial racemisations – are unfortu-
nately associated with these processes.[1] Nowadays, trans-
formations involving asymmetric Michael-type addition of
organometallics,[1,2] hydrogenations,[1–3] isomerisations,[1,2]
cyclopropanations,[1,2] some C–C or C–H insertions[1,2] and
allylic nucleophilic substitutions[1,2,4,5] are mainly employed
in order to achieve these fully alkylated/arylated stereo-
centers. In particular, in allylic nucleophilic substitution re-
actions, the palladium-catalysed process requires soft nu-
cleophiles, whilst copper catalysts allow the use of hard nu-
cleophiles including Grignard and organozinc reagents. Re-
cent advances in the asymmetric allylic substitutions pro-
moted by copper complexes make these transformations
much more interesting.[5a] Out of all the possible combina-
tions, the techniques most frequently used in organic syn-
thesis are the employment of chiral organocuprates in stoi-
chiometric amounts,[5,6] the use of chiral catalytic cop-
It has been demonstrated that simple allylic phosphates
are appropriate substrates with which to develop this pro-
cess efficiently through a γ-anti-SN2Ј stereocontrolled pro-
cess.[6] The enantiomerically enriched unsaturated cyano-
phosphates 1[9,10] (Scheme 1) would be promising candi-
dates to undergo these type of displacements. Previous
works have revealed their potential as chiral building blocks
in the synthesis of the optically active (E)- and (Z)-γ-substi-
tuted α,β-unsaturated nitriles 2 through palladium- or irid-
ium-catalysed allylic nucleophilic substitutions.[9] As part of
an ongoing survey of the synthetic applications of the cya-
nohydrin-O-phosphates 1 as chiral building blocks we fo-
cused our attention on their direct nucleophilic allylic sub-
stitution, mediated by organocuprates. Only the regioselec-
tive reactions between stoichiometric amounts of lithium
organocuprates and racemic cyanophosphates have been re-
ported, with different diastereoselectivities having been ob-
tained, depending on the reaction conditions applied, but
favouring the final (Z) configuration necessary for the syn-
thesis of racemic (Ϯ)-manicone, (Ϯ)-nuciferal and both iso-
mers of (Ϯ)-nuciferol.[11] In this article the results of SN2Ј
substitutions achieved through the addition of organocup-
rates onto enantiomerically enriched β,γ-unsaturated cya-
nophosphates 1 for the synthesis of the corresponding op-
tically active α,β-unsaturated nitriles 3 and their esters 4
are described (Scheme 1).[12] These chiral α,β-unsaturated
[a] Departamento de Química Orgánica, Facultad de Ciencias, and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: +34-965903549
E-mail: cnajera@ua.es
Eur. J. Org. Chem. 2007, 1101–1112
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Baeza, C. Nájera, J. M. Sansano
FULL PAPER
Scheme 1.
nitriles 3 can be regarded as direct precursors, through sim- Initially we searched for optimal reaction conditions for the
ple alcoholysis, of valuable chiral (E)-Michael acceptors, allylic substitution reaction, comparing the results with the
such as optically enriched α,β-unsaturated esters 4, mainly analogous findings published in the literature for racemic
with (E) configurations. These compounds 4 have recently cyanohydrin O-phosphates.[11] These tests were performed
been prepared by stereoselective methyl cuprate addition with the racemic cyanophosphate 1a as starting material,
onto allylic bromides followed by crossed metathesis with this being obtained in quantitative yield from crotonalde-
methyl acrylate.[7a] More highly functionalised chiral α,β- hyde and diethyl cyanophosphonate in the absence of sol-
unsaturated esters of type 4 have also been obtained vent and with the use of catalytic amounts of triethylamine
through a one-pot process involving a sequential organocat- (10 mol-%) over 5 min at room temperature.[14] When n-bu-
alytic asymmetric Mannich reaction and
a
Horner– tyllithium and stoichiometric amounts of CuCN were em-
ployed to form the corresponding organocopper reagent the
reaction was not reproducible, delivering the product de-
rived from the attack of the alkyl group onto the phospho-
rus atom, together with variable amounts of the γ-substitu-
Wadsworth–Emmons olefination.[13]
Results and Discussion
Reactions between organocopper reagents and allylic tion product (Z)-3ad and the α-substitution product 5ad
electrophiles are normally influenced by multiple param- (Scheme 2), as has been described previously.[11] However,
eters, many of them apparently negligible, but actually be- when an organocopper reagent, freshly generated by mixing
ing crucial at the end of the transformation for the regio- n-butylmagnesium bromide or chloride (instead of n-butyl-
selectivity, diastereoselectivity, reaction time, yields etc.[5] lithium) and a copper(I) source, was used under argon in
Scheme 2.
Table 1. Optimization of SN2Ј reactions between organocopper compounds and racemic cyanophosphate 1a.
Entry
nBuM[a]
CuY[b]
Additive
Solvent
T [°C]
t [h]
Conv. [%][c]
(E/Z)-3[d]
1
2
3
4
5
6
7
8
9
nBuMgCl
nBuMgBr
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuMgCl
nBuCu[f]
CuCN
CuCN
CuCN
CuCN
CuBr·SMe2
CuBr·SMe2
CuCN
CuCN
–
–
–
–
–
–
–
THF
THF
Et2O
THF
THF
THF
THF
THF
THF
–78
–78
–78
0
–78
0
–78
0
–78
1
1
1.5
1
2
1.5
1
1
100
100
20
100
35
70:30
55:45
40:60
40:60
12:88
–
44:56
38:62
37:63
–
TMSCl[e]
100
100
10
TMSCl[e]
[g]
BF3
1.5
[a] 3 Equiv. of Grignard reagent was added. [b] 1.5 Equiv. of copper(I) salt was added. [c] Determined on the crude reaction product by
1
1H NMR spectroscopy. [d] Determined on the crude reaction product by H NMR spectroscopy. [e] 1.5 Equiv. of TMSCl was added. [f]
Previously formed at –30 °C by mixing nBuLi (2.4 equiv.) and CuI (1.2 equiv.). [g] 1.2 Equiv. of BF3·Et2O was added.
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Alkylation of Chiral Allylic Cyanohydrin O-Phosphates
FULL PAPER
THF or diethyl ether as solvents, the reaction proceeded tives 1 being prepared in very high ers from aldehydes[9,10]
cleanly at low temperatures and with high conversions to in a one-step process with chiral bifunctional[16] (R)- or (S)-
give products 3ad regioselectively (Scheme 2 and Table 1). BINOLAM-AlCl complexes 6 as catalysts.[9] This method
The first parameter studied was the effect of the nature of required 10 mol-% of the catalyst (S)-6 and 3 equiv. of di-
the halide in the Grignard reagent, with use of CuCN as ethyl cyanophosphonate at room temperature under anhy-
copper salt in both reactions, at –78 °C and in THF as sol- drous conditions (Scheme 3).[9] The additional treatment of
vent (Table 1, Entries 1 and 2). The reaction took place with the reaction mixture in acidic media was made in order to
total conversion within 1 h, but the (E/Z) ratio of 3ad was recover the (S)-3,3Ј-bis(diethylaminomethyl)-1,1Ј-bi(2-
higher when nBuMgCl was employed than with nBuMgBr. naphthol) [(S)-BINOLAM] chiral ligand almost quantita-
The role of the solvent was impressive: the difference be- tively (up to 91%).[9] During the preparation of (R)-1a on
tween the use of anhydrous THF and diethyl ether at large scales (0.5 g) we noticed that its enantiomeric ratio
–78 °C is shown in Entries 1 and 3 in Table 1. The replace- (er) was very sensitive to the moisture present in the freshly
ment of THF with diethyl ether at this temperature re- distilled crotonaldehyde, the achieved enantiomeric excesses
sulted, after 15 h, in a very low degree of conversion (25%), being in the range of 88 to 92%.
approximately the same level of conversion that had origi-
nally been obtained after 1.5 h. When the reaction tempera-
ture was 0 °C the isomer (Z)-3ad was obtained as the major
product, but with low diastereoselectivity (Table 1; compare
Entries 1 and 4). When the CuI source was modified, with
use of CuBr·SMe2 in place of CuCN, the reaction at –78 °C
took place with a high level of diastereoselection for the
(Z)-3ad product, but unfortunately with a low conversion
(Table 1, Entry 5), whilst at 0 °C the reaction failed, a com-
plex mixture of undesired products being obtained in the
crude reaction mixture (Table 1, Entry 6).
Once we had found the optimal SN2Ј reaction conditions
for 1a [CuCN (1.5 equiv.) as CuI source, n-BuMgCl
(3 equiv.) in THF and at –78 °C], the influence of some ad-
ditives was evaluated. TMSCl (1.5 equiv.) was used as an
additive because it acts as a complexating agent with orga-
nocopper reagents, promoting the allylic substitution (SN2Ј)
process over the α-substitution (SN2) process.[15] When the
reaction was carried out at –78 °C it was complete after
1 hour, slightly favouring the formation of the (Z)-3 isomer
(Table 1, Entry 7), and this trend was slightly higher when
the reaction was carried out at 0 °C (Table 1, Entry 8). In
both cases the (E/Z) diastereoselectivity was similar to that
observed in the reactions run in the absence of additives
(Table 1, compare Entries 4 and 8). The employment of
[11]
nBuCu·BF3
at several temperatures resulted in very low
Scheme 3.
yields of compounds 3 (Table 1, Entry 9).
Reactions performed with substoichiometric amounts of
copper(I) salts and stoichiometric amounts of the organo-
The temperature range of the allylic nucleophilic substi-
magnesium reagent (at a range of temperatures of –78 to tution was adapted on the basis of the reactivity and steric
0 °C) did not give satisfactory results: complex mixtures of hindrance of the alkylmagnesium chlorides. In this way, the
decomposition products were obtained in the crude reac- reaction carried out with an excess of organocopper species
tion product due to the high reactivity of the cyanophos- (previously generated by mixing alkylmagnesium chlorides
phate 1a.[9] Identical behaviour was observed when or- with CuCN) in dry THF was carried out at –78 °C
ganozinc compounds were used instead of the Grignard (Method A), at 0 °C (Method B) or by addition of the orga-
reagents. Other Grignard reagents, such as arylmagnesium nocopper species at –78 °C and allowing the temperature to
halides, gave the γ-substitution products at very low levels reach 0 °C (Method C) (Scheme 4). The reactions between
of conversion, the major products being the biaryl com- the enantiomerically enriched allylic cyanophosphonate 1a,
pounds originating from homocoupling. In addition, reac- derived from crotonaldehyde, and the organocoppers
tions with cuprates also failed in the cases of other O-pro- formed with n-butyl- or benzylmagnesium chloride were
tected cyanohydrins, such as the methyl O-carbonate or the very fast at –78 °C, giving the (E) diastereoisomer 3a as
O-benzoyl cyanohydrin derived from crotonaldehyde.
the major product by Method A (Table 2, Entries 1 and 8),
The optimal reaction conditions were implemented with whereas Method B gave poorer diastereoselectivities. Un-
chiral cyanophosphates 1, these chiral cyanohydrin deriva- fortunately, a small reduction in er in the final products 3
Eur. J. Org. Chem. 2007, 1101–1112
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1103

A. Baeza, C. Nájera, J. M. Sansano
FULL PAPER
Scheme 4.
(in relation to the original enantiomeric ratio in cyanophos- (Table 2, Entries 5 and 7), whereas almost equimolecular
phate 1a) was observed. In addition, the reaction with the mixtures of both isomers (E/Z)-3 were obtained at –78 °C
n-butyl derivative in the presence of TMSCl also gave satis- (Method A) and in lower yields (Table 2, Entries 4 and 6).
factory results, although in this case the reduction in
Similar behaviour was observed when the chiral allylic
enantioselectivity was slightly larger (Table 2, Entry 3). In cyanophosphate 1b, derived from (E)-oct-2-enal, was em-
contrast, when isopropyl- or tert-butylmagnesium chloride ployed, with the use of methylmagnesium chloride as pre-
were used to form the organocopper reagent, better chiral- cursor for the organocopper reagent thus furnishing com-
ity transfer was achieved under Method B conditions, with pound (E)-3ba almost exclusively, in very high yield and
er values of 93.5:6.5 or 90:10, respectively, being obtained without any degree of racemisation by either Method A or
and the (Z) product being the major isomer in both cases B (Table 2, Entries 10 and 11). On the other hand, the use
Table 2. Allylic substitution onto enantioenriched cyanophosphates.
[a]
Entry
1 (er)
R2
Method
t [h]
3
(E)-3/(Z)-3
Yield [%][b]
er[c]
1
2
3
4
5
6
7
8
9
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
1a (94:6)
nBu
nBu
nBu
iPr
A
B
1
1
1
1
3ad
3ad
3ad
3ac
3ac
3ae
3ae
3af
3af
70:30[d]
40:60
38:62
48:52
35:65
58:42
37:63
92:8
87
88
83
67
89
72
85
92
43
86:14
86:14
82:18
93.5:6.5
93.5:6.5
90:10
90:10
88:12
88:12
B[e]
A
B
iPr
1
tBu
tBu
Bn
A
B
A
B
2.5
1.5
1.5
2
Bn
70:30
10
11
12
13
14
15
16
17
18
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
1b (97:3)
Me
Me
iPr
iPr
iPr
nBu
nBu
Bn
A
B
A
B
C
A
B
A
B
2
1
3
1.5
1.5
2
1
4
3ba
3ba
3bc
3bc
3bc
3bd
3bd
3bf
3bf
91:9
61:39
n.d.
27:73
51:49
54:46
32:68
85:15
61:39
82
89
Ͻ20
88
89
80
87
81
84
97:3
97:3
nd
97:3
97:3
97:3
97:3
93.5:6.5[f]
93.5:6.5[f]
Bn
2
19
20
21
22
23
24
25
27
28
29
30
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
1c (97.5:2.5)
Me
Me
Me
Et
A
B
C
A
B
A
B
B
C
B
C
2.5
1
3
1.5
1
1
1
1
3
2.5
3
3ca
3ca
3ca
3cb
3cb
3cd
3cd
3cc
3cc
3cf
3cf
n.d.
76:24
95:5
n.d.
89
88
86
88
86
Ͻ20
83
53
86
n.d.
92.5:7.5
92.5:7.5
90:10
69:31
52:48
87:13[g]
n.d.
39:61
60:40
70:30
68:32
Et
90:10
nBu
nBu
iPr
iPr
Bn
79:21[h]
nd
95:5
95:5
92.5:7.5
92.5:7.5
Bn
47
1
[a] Determined for the crude products by H NMR spectroscopy. [b] Isolated yield of pure compounds after flash chromatography. [c]
Determined by chiral HPLC analysis (CHIRALPAK AS), being the same for both pure isomers [(E) and (Z)]. [d] α-Substitution (7%)
was observed. [e] TMSCl (1.5 equiv.) was added. [f] Determined by chiral HPLC analysis (Chiralcel OJ), being the same for both isomers
[(E) and (Z)]. [g] α-Substitution (27%) was observed. [h] The er values in the γ- and α-substitution products were determined by chiral
HPLC analysis (Chiralcel OJ), being the same for all products; n.d. = not determined.
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Alkylation of Chiral Allylic Cyanohydrin O-Phosphates
FULL PAPER
of a bulkier group such as isopropyl in the organocopper Method B was essayed (Table 2, Entries 29 and 30). It can
reagent did not result in any reaction at all under the condi- be concluded that only slight reductions in the er were ob-
tions described for Method A (Table 2, Entry 12), but the served in the case of the cyanophosphate 1c.
(E/Z) isomers of 3bc were obtained in good yield and with
In summary, we note that (E) isomers 3 were mainly ob-
the same er as in the original cyanophosphate 1b in the tained at low temperatures, that (Z) isomers 3 were the
range of temperatures described for methods B and C major diastereoisomers isolated when the reactions were
(Table 2, Entries 13 and 14). At this point, in order to elim- performed at 0 °C, and that no carbon–carbon double bond
inate the carbon–carbon double bond isomerisation caused isomerisation was observed when the reactions were al-
by the cuprate residues in the initial addition, we ran two lowed to continue for 6 h. Cuprates containing iPr or tBu
experiments. In the first, a equimolar mixture of (E/Z)-3bc groups gave almost identical (E/Z) ratios in the products 3a
was added to a completed reaction with an excess of at the same temperature and, in particular, afforded equi-
iPrMgCl/CuCN to provide, after 1 h at 0 °C, just the sum molar diastereomeric mixtures at –78 °C. The highest pro-
of the known reaction (27:73, Table 2, Entry 13) and the portions of (E) isomers 3 were obtained when methyl- and
added 1:1 mixture. In a second test, the (E/Z) ratio in the benzylmagnesium chlorides were employed at very low tem-
resulting 3bc generated from the analogous reaction at 0 °C peratures, whereas the highest (Z) selectivities for molecules
(Table 2, Entry 13) was determined by 1H NMR spec- 3 were identified in the reactions run with cuprates derived
troscopy after 1.5, 3 and 6 h, with exactly the same dr from n-butyl- and isopropylmagnesium chlorides at 0 °C.
(27:73) always being measured.
The α-substitution product 5 was detected only when the
Surprisingly, the use of n-butylmagnesium chloride for cuprate generated with n-butylmagnesium chloride was al-
the generation of the organocopper reagent gave almost lowed to react with substrates 1a and 1c at –78 °C. Racemis-
equimolecular amounts of (E/Z)-3bd when the reaction was ation occurred to greater extents when n-butylmagnesium
carried out by Method A (Table 2, Entry 15). An increase chloride was allowed to react with phosphates 1a and 1c,
in temperature (Method B) resulted, predominantly, in the but isopropylmagnesium chloride hardly caused loses of en-
formation of the (Z) isomer of 3bd (Table 2, Entry 16), antiomeric purity. When benzyl-, methyl- and tert-butyl-
whilst in the case of benzylmagnesium chloride, (E)-3bf was magnesium chlorides were used, the final products 3 were
mainly obtained with a slight degree of racemisation obtained with low degrees of racemisation independently of
(Table 2, Entries 17 and 18). It is worth noting that com- the selected temperature of the reaction.
pounds 1b gave the corresponding SN2Ј products 3b with-
With the aims of determining the absolute configurations
out any loss of enantiomeric purity.
of compounds 3 and of confirming the predicted anti at-
The chiral allylic cyanohydrin-O-phosphate 1c, derived tack, the transformation of compounds 3 into the known
from cinnamaldehyde, has been characterised as a very re- aldehydes 7 was undertaken. Ozonolysis was carried out in
active and easily racemisable molecule in Pd-catalysed reac- dichloromethane at –78 °C and, after a reductive treatment
tions involving moderately to strongly basic reagents.[9] The with thiourea, the final aldehydes 7 were obtained in very
addition reaction with the cuprate generated from methyl- good yields (Scheme 5). In the reaction carried out with the
magnesium chloride was carried out by Methods A, B and pure (2E,4R)-3af, aldehyde (R)-7af was generated in high
C (Table 2, Entries 19–21), with a very high (E/Z) ratio in yield and without loss of enantiomeric purity, which was
3ca being obtained under the last set of reaction conditions confirmed by chiral HPLC analysis (CHIRACEL OJ). The
in very good yields and, surprisingly, with only a slight loss suggested the (R) absolute configuration (note the priority
of optical purity (Table 2, Entry 21). The reaction failed change around the new stereogenic centre from the original
with Method A, whilst in the case of Method B the (E/Z) allylic cyanophosphates), resulting from the expected anti
ratio in 3ca dropped to 76:24 (Table 2, Entries 19 and 20). attack of the copper species onto the allylic cyanophos-
With ethyl and n-butyl organocopper compounds (Table 2, phate, was confirmed by comparison of the specific rotation
Entries 22–25) Method A was better than Method B with the reported values.[17] When the ozonolysis was per-
(Table 2, Entries 23 and 25), because better yields and formed with the 70:30 (E/Z) mixture of compound 3ad, the
higher proportions of the (E)-3 compounds were obtained, aldehyde 7ad was obtained in high yield (83%). If we con-
whilst Method C gave the same result as Method A. Again, sider that (E) and (Z) isomers have opposite absolute con-
the more basic n-butyl group promoted the greatest racem- figuration, the expected enantiomeric ratio for this mixture
isation in this series, as had also been the case when 1a was should (according to the already mentioned anti addition
selected as starting material (Table 2, compare Entries 1 of the organocopper reagent) be around 70:30. Unfortu-
and 24). In this example, a considerable proportion of the nately, the separation of the two enantiomers either by chi-
α-substitution product 5cd was obtained (27%). When iso- ral HPLC or by GC was impossible, but the specific rota-
propyl- or benzylmagnesium chlorides were employed un- tion of the 7ad aldehyde mixture was compared with the
der the reaction conditions described by Method A the re- reported data[18] and confirmed the (R) absolute configura-
action failed. Nevertheless, Methods B and C were effective, tion of the more abundant enantiomer in the mixture.
product 3cc being obtained in both cases, with a reversal of
With regard to the mechanism of the alkylation process,
the diastereomeric ratio in the case of isopropylmagnesium when a substrate containing a good leaving group in an
chloride (Table 2, Entries 27 and 28). However, the benzylic allylic position is treated with a organocopper reagent, two
product (E)-3cf was isolated in a better yield when processes can occur: SN2 (attack at the α-position) and/or
Eur. J. Org. Chem. 2007, 1101–1112
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Baeza, C. Nájera, J. M. Sansano
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Scheme 5.
SN2Ј (attack at the γ-position). This regioselectivity is in conformations I and II (Scheme 6). Conformation II is
mainly determined by the natures of the starting material slightly more stable, due to the linear cyano group, which
(in terms of its steric and electronic properties), the leaving is not involved here in strong interactions with the rest of
group and the copper reagent used.[5a,5c] If we assume that the substituents. With this conformation anti substitution
the phosphate is a very good leaving group and is not coor- can take place if there is no coordination between leaving
dinated to the organocuprate, the more important effects to group and copper atom in the organocopper reagent attack-
explain the preference for the γ-position should involve the ing the allylic cyanophosphate, or syn substitution may
steric requirements of both the substrate and the reagent. occur if this coordination exists (Scheme 6).
It has been reported that the reaction takes place through
The anti attack at the less sterically hindered anti side
copper–double bond starting coordination, followed by oxi- in conformer II should result in the formation, with total
dative addition to the double bond to form the π-allyl cop- inversion of the configuration, of the diastereoisomer
per intermediate, which progresses through a reductive eli- (E,R)-3, whilst the same mode of attack on conformer I
mination to afford the SN2Ј product if this reductive elimi- should produce the diastereoisomer (Z,S)-3. It is necessary
nation is fast enough, or to afford the SN2 product if it is to note that, despite the mentioned configuration inversion,
not. This fast reductive elimination is favoured by the pres- the product 3 and the enantioenriched allylic cyanophos-
ence of electron-withdrawing groups in the organocopper phate have the same stereogenic descriptors, due to the
reagent, as in our case, which could explain the high re- change in priorities around the stereogenic centre
gioselectivity observed.[5a,5c] This stereospecific reaction (Scheme 6).
takes place with absolute configuration inversion, due to
the anti attack of the organocopper reagent with respect to
the leaving group.[5c] Corey et al. proposed an explanation
based on frontier orbital theory for this behaviour, in which
the organocopper reagents, unlike carbonucleophiles, have
d-filled orbitals which can interact with the double bond π*
orbital in the γ-position and more weakly with the σ* or-
bital of the carbon-leaving group bond (C–X)[19] (Figure 1).
Disregarding the coordination between phosphate group
and copper complexes, it was initially expected that the (E)
isomer should be the major product according to the pre-
cedent work, in which a isopropyl group was present in
compound 8 instead of the nitrile group.[6] However, the
amounts of the (Z) isomers obtained were unusually large.
We believe that the coordinative power between the nitrile
group and the copper species is responsible for this behav-
iour, so rotamers I and II have to be reconsidered, as well
as the nature of the Grignard reagent. The estimated values
of dissociation energies (D in kcalmol–1) for the C–Mg
Figure 1. Proposed interaction of the frontier orbitals previous to
the SN2Ј reaction.
As a consequence of such anti attacks onto optically bond in methyl-, ethyl-, n-butyl-, isopropyl- and tert-butyl-
active cyanophosphates, both the leaving group (phosphate) magnesium bromides are 60, 49, 51, 44 and 42, respec-
and the cuprate have to be essentially antiperiplanar (ap) in tively.[20] The higher dissociation energy of the methylmag-
the transition state. Of all of the possible conformations, nesium bromide would imply that magnesium cation should
the most effective overlapping between σ* orbital [C- remain closer to the coordination sphere of the copper
OPO(OEt)2] and d orbital of the copper atom takes place atom, so that the resulting metallic aggregate, coordinated
1106
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Eur. J. Org. Chem. 2007, 1101–1112

Alkylation of Chiral Allylic Cyanohydrin O-Phosphates
FULL PAPER
Scheme 6.
to the nitrile group, would be very bulky and would favour through the preparation of the α,β-unsaturated esters 4 by
the approach of the methyl group through the less sterically acidic hydrolysis of the nitrile group. The best reactions
hindered conformer II. In fact, the highest (E/Z) ratios of condition were found to involve the use of concentrated hy-
all the series of reactions were obtained with methylmagne- drochloric acid in methanol at reflux for 15 h, generating
sium bromide (Table 2, Entries 1, 10 and 21).
the products 4ba and 4ca in 80% and quantitative yields,
Obviously, the amount of the (Z) isomer increased when respectively (Scheme 7). This methodology represented a
the temperature of the reaction was higher (Methods B and simpler and more straightforward route than the already
C). At –78 °C (Method A), the highest percentage of the published one for the construction of the alkene 4ca.[7a] An-
(Z) isomer was achieved with use of the most dissociated other application of the α,β-unsaturated nitrile (E,S)-3ba,
isopropyl group, whilst ethyl-, n-butyl-, and tert-butylmag- prepared from the cyanohydrin O-phosphate (R)-1b, was
nesium bromides gave very similar (E/Z) ratios, demonstrat- the synthesis of the enantiomerically enriched (S)-4-meth-
ing that steric hindrance is not important in this mechanism ylnonan-1-ol (9), the enantiomer of the sex pheromone of
(Table 2, compare Entries 1, 2, 4, 5 6, 7 and 23). These data the yellow mealworm Tenebrio molitor L.[21] The enanti-
suggest that conformer I (or a rotamer very close in energy), omer (R)-4ba, obtained by the step described in Scheme 7,
in which the nitrile is coordinated to a more simple copper was reduced both at the carbon–carbon double bond and
complex (relatively free of magnesium), compete seriously at the ester group with lithium aluminium hydride to give
with the rotamer II.
the alcohol 9 in 48% yield. The low optical rotation value
The examples run with benzylmagnesium bromide de- {[α]D = –0.51 (c = 2, CHCl3); ref.[21] [α]D = +0.63 (CHCl3,
serve to be treated separately (Table 2, Entries 8, 9, 17 and unknown concentration)} was not a very reliable datum for
18) because the benzylic group is very large (compared with determining the er of the natural product (R)-9, but it was
Me, Et, iPr, nBu and tBu), but its dissociation energy is consistent with the expected 89:11 er from the precursor
47 kcalmol–1 (similar to EtMgBr, iPrMgBr, nBuMgBr and (E,R)- and (Z,S)-3ba mixtures obtained during the nucleo-
tBuMgBr), so that a higher (E/Z) ratio should be expected, philic allylic substitution reaction. Analogously, the natural
though not so elevated as that obtained when the MeMgBr product (R)-9 {[α]D = +0.48 (c = 2, CHCl3)} was also pre-
was used as reagent for the formation of cuprates.
pared (46% overall yield) by the same route, starting from
Finally, the racemisation observed in some cases can cyanohydrin O-phosphate (S)-1b, which was enantioselecti-
arise from the well known sensitivity of the cyanophos- vely generated by use of (R)-BINOLAM-AlCl
6
phates, especially compound 1c, in basic media.[9] Although (Scheme 7). This four-step access to enantiomerically en-
the alkyl cuprates are not so strong bases as Grignard rea- riched compounds 9 contrasts with the previously reported
gents, they can still promote this type of side processes.
syntheses, involving eight and seven steps starting from chi-
The potential of the enantiomerically enriched unsatu- ral (S)-(+)-dihydromyrcene[21a] and methyl (R)-3-methyl-
rated nitriles 3 as chiral building blocks was next examined glutarate,[21e] respectively.
Eur. J. Org. Chem. 2007, 1101–1112
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1107

A. Baeza, C. Nájera, J. M. Sansano
FULL PAPER
Scheme 7.
allowed the preparation of (E)-γ-alkylated α,β-unsaturated
esters in only three steps from the starting α,β-unsaturated
aldehydes. This strategy can be applied to the synthesis of
the sex pheromone (S)- and (R)-4-methylnonan-1-ol in a
straightforward manner in only four steps from the starting
aldehyde.
Conclusions
It can be concluded that enantiomerically enriched (E)-
α,β-unsaturated nitriles possessing alkyl groups at ste-
reogenic centres in their γ-positions can be prepared regio-
and diasteroselectively by alkylation of cyanohydrin O-
phosphates with organocuprates. These were the more ap-
propriate substrates for this transformation, because neither
enantiomerically enriched cyanoformates nor O-benzoyl cy-
anohydrins underwent this nucleophilic allylic substitution.
The reaction can be carried out in short times and with
low levels of racemisation and it could be regarded as a
complementary transformation to the palladium-catalysed
allylic substitution process, which allows the introduction of
heteronucleophiles and malonates. Although each substrate
required a different set of optimal reaction conditions, we
can state that: a) when substrates 1a and 1b (derived from
crotonaldehyde and oct-2-enal, respectively) were allowed
to react at lower temperatures (Method A) the (E) isomer
was the major isolated product and higher proportions of
the (Z) isomer were always achieved at 0 °C (Method B),
b) substrate 1c (derived from cinnamaldehyde) was more
sensitive to the reaction conditions and to the type of
cuprate, c) in most of cases the major (E) diastereoselectiv-
ity was obtained, especially with methyl and benzyl cup-
rates, whereas anomalously high proportions of the (Z) iso-
mers were observed when more dissociation-prone Grig-
nard reagents (n-butyl, isopropyl and tert-butyl) were em-
ployed, and d) in general, low degrees of racemisation were
observed, especially for the cyanohydrin O-phosphate 1b.
The reaction mechanism involved an anti attack of the or-
ganocopper species onto the allylic cyanophosphate, as can
deduced by the resulting configuration in the newly created
sterocentres in both (Z) and (E) diastereomers. The nitrile
group might possibly be able to assist the SN2Ј addition to
enantiomerically enriched cyanohydrin O-phosphates, fav-
ouring the formation of these isomers. Methanolysis of
Experimental Section
General Remarks: IR spectra were recorded on a Nicolet 510 P-FT
instrument, and only the structurally most relevant bands are
listed. NMR spectra were determined on a Bruker AC 300 ma-
chine, with CDCl3 as solvent and TMS as internal standard, unless
otherwise stated. Low-resolution electron impact (EI) mass spectra
were obtained at 70 eV on a Shimadzu QP-5000 instrument, and
low-resolution electrospray ionization (ESI) mass spectra were ob-
tained on a Finnigan VG Platform. HRMS (EI) were recorded on
a Finnigan MAT 95S machine. Microanalyses were carried out by
the Microanalyses Service of the University of Alicante. Optical
rotations were measured on a Perkin–Elmer 341 polarimeter. Ana-
lytical TLC was performed on Schleicher & Schuell F1400/LS silica
gel plates, and the spots were visualised under UV light at 254 nm.
GC analyses were carried out in a HP-5890SB instrument and chi-
ral HPLC analyses were run in a Jasco 2000 series (the chiral col-
umn and wavelength used is given for each compound, the major
enantiomer being denoted in bold format). The retention times for
each isomer are reported in cases in which it was possible to achieve
the perfect separation of the four isomers; otherwise only the reten-
tion times of the major isomers obtained are reported. Merck silica
gel 60 (0.040–0.063 mm) was employed for flash chromatography.
General Procedure for Allylic Substitution by Organocopper Ad-
dition
Method A: A solution of Grignard reagent (3 mmol, in THF) was
added under Ar at –78 °C to a cooled suspension of CuCN
(1.5 mmol, 134 mg) in dry THF (2 mL). The mixture was then
stirred for 30 min. and a solution of the corresponding allylic cya-
nophosphate 1 (1 mmol) in dry THF (1 mL) was added at the same
temperature. Stirring was continued at –78 °C until the reaction
these enantiomerically enriched α,β-unsaturated nitriles has was judged complete by GC. Ethyl acetate (10 mL) and aqueous
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Alkylation of Chiral Allylic Cyanohydrin O-Phosphates
FULL PAPER
saturated solution of NH4Cl (10 mL) were added at room tempera-
ture, the mixture was stirred for 30 min, and the organic layer was
separated, dried (MgSO4) and concentrated to provide the crude
compounds, which were purified by flash chromatography to afford
pure products 3.
(2Z,4S)-4,5,5-Trimethylhex-2-enenitrile (3ae): (Table 2, Entry 7,
116 mg, 85%). Colourless oil. [α]2D5 = –18.1 (c = 1.0, CHCl3 for the
(E)/(Z) mixture, 37:63) [80% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 215 nm, n-hexane, 0.8 mLmin–1,
tr = 12.9 and 13.4 min, (Z) isomer, and 17.3 and 18.6 min, (E) iso-
mer)]; TLC: Rf = 0.84 (n-hexane/ethyl acetate, 9:1).
Method B: Same as Method A but at 0 °C.
1
(E) Isomer: H NMR (300 MHz): δH = 0.87 [s, 9 H (CH3)3], 0.98
Method C: A solution of Grignard reagent (3 mmol, in THF) was
added under Ar at –78 °C to a cooled suspension of CuCN
(1.5 mmol, 134 mg) in dry THF (2 mL). The mixture was then
stirred for 30 min. and a solution of the corresponding allylic cya-
nophosphate 1 (1 mmol) in dry THF (1 mL) was added at the same
temperature. Stirring was continued whilst the temperature was al-
lowed to rise slowly to 0 °C (approx. 1.5 h). Ethyl acetate (10 mL)
and an aqueous saturated solution of NH4Cl (10 mL) were added
at room temperature. The mixture was stirred for 30 min and the
organic layer was separated, dried (MgSO4) and concentrated to
provide the crude compounds, which were purified by flash
chromatography to afford pure products 3.
(d, J = 6.9 Hz, 3 H, CH3CH), 2.08 (m, 1 H, CHCH3), 5.28 (d, J =
16.4 Hz,
1 H, CHCN), 6.70 (dd, J = 16.4, 9.0 Hz, 1 H,
CH=CHCN) ppm. 13C NMR (75 MHz): δC = 14.8 (CH3CH), 27.1
[(CH3)3], 46.7 [C(CH3)3], 48.3 (CHCH3), 98.6 (CHCN), 117.4
(CN), 158.6 (CH=CHCN) ppm.
1
(Z) Isomer: H NMR (300 MHz): δH = 0.90 [s, 9 H, (CH3)3], 0.99
(d, J = 6.9 Hz, 3 H, CH3CH), 2.58 (m, 1 H, CHCH3), 5.29 (d, J =
10.9 Hz,
1
H, CHCN), 6.39 (t,
J
=
10.9 Hz,
1
H,
CH=CHCN) ppm. 13C NMR (75 MHz): δC = 14.2 (CH3CH), 27.3
[(CH3)3], 46.7 [C(CH3)3], 48.3 (CHCH3), 99.3 (CHCN), 117.2
(CN), 159.4 (CH=CHCN) ppm. IR (neat): ν = 2222, 1631 cm–1.
˜
MS (EI): m/z (%) = 122 [M – Me]+ (27.5), 105 (11), 95 (13), 81
(59), 80 (21), 57 (100). HRMS: C8H12N [M – Me]+ calcd. 122.0969,
found 122.0970.
(2E,4R)-4-Methyloct-2-enenitrile (3ad): (Table 2, Entry 1, 119 mg,
87%). Pale yellow oil. [α]2D5 = –9.0 (c = 0.4, CHCl3 for the (E)/(Z)
mixture, 70:30) [72% ee for each isomer by HPLC; DAICEL
CHIRALPAK AS, λ = 206 nm, n-hexane, 1 mLmin–1, tr = 12.3 and
13.2 min, (E) isomer]. TLC: Rf = 0.82 (n-hexane/ethyl acetate, 4:1).
(2E,4R)-4-Methyl-5-phenylpent-2-enenitrile (3af): (Table 2, Entry 8,
158 mg, 92%). Colourless oil. [α]2D5 = –71.2 (c = 0.8, CHCl3)
(E) Isomer: 1H NMR (300 MHz): δH = 0.88 (t, J = 6.9 Hz, 3 H, [78% ee from HPLC; DAICEL CHIRALPAK AS, λ = 215 nm, n-
CH3), 1.07 (d, J = 6.6 Hz, 3 H, CH3), 1.24–1.40 (m, 6 H, 3ϫCH2),
2.29 (m, 1 H, CHCH3), 5.27 (d, J = 16.4 Hz, 1 H, CHCN), 6.60
hexane/propan-2-ol, 99:1, 1 mLmin–1, tr = 11.6 and 12.4 min, (E)
isomer, and tr = 10.9 and 13.6 min, (Z) isomer)]; TLC: Rf = 0.43
1
(dd, J = 16.4, 7.9 Hz, 1 H, CH=CHCN) ppm. 13C NMR (75 MHz): (n-hexane/ethyl acetate, 9:1). H NMR (300 MHz): δH = 1.07 (d, J
δC = 13.9 (CH3), 18.8 (CH3CH), 22.5 (CH2), 29.2 (CH2), 35.3
(CH2CH), 37.7 (CHCH3), 98.0 (CHCN), 117.7 (CN), 161.4
(CH=CHCN) ppm.
= 6.4 Hz, 3 H, CH3), 2.66 (m with s at 2.64, 3 H, CH2 and
CHCH3), 5.20 (d, J = 16.4 Hz, 1 H, CHCN), 6.67 (dd, J = 16.4,
6.7 Hz, 1 H, CH=CHCN), 7.11 (m, 2 H, ArH), 7.22–7.32 (m, 3 H,
ArH) ppm. 13C NMR (75 MHz): δC = 18.4 (CH3), 39.4 (CHCH3),
42.1 (CH2), 98.7 (CHCN), 117.5 (CN), 126.5, 128.5, 129.0 and
(Z) Isomer: 1H NMR (300 MHz): δH = 0.88 (t, J = 6.9 Hz, 3 H,
CH3), 1.07 (d, J = 6.4 Hz, 3 H, CH3), 1.24–1.40 (m, 6 H, 3ϫCH2),
2.74 (m, 1 H, CHCH3), 5.25 (d, J = 10.8 Hz, 1 H, CHCN), 6.25
(t, J = 10.8 Hz, 1 H, CH=CHCN) ppm. 13C NMR (75 MHz): δC
= 13.9 (CH3), 19.9 (CH3CH), 22.5 (CH2), 29.3 (CH2), 35.9
(CH2CH), 37.0 (CHCH3), 97.8 (CHCN), 116.1 (CN), 160.7
138.6 (ArC), 159.9 (CH=CHCN) ppm. IR (neat): ν = 2222,
˜
1632 cm–1. MS (EI): m/z (%) = 171 [M]+ (5.1), 91 (100), 65 (15),
106 (24), 92 (13), 91 (92). HRMS: C12H13N calcd. 171.1048, found
171.1052.
(CH=CHCN) ppm. IR (neat): ν = 2222, 1631 cm–1. MS (EI): m/z
˜
(2E,4S)-4-Methylnon-2-enenitrile (3ba): (Table 2, Entry 10, 124 mg,
82%). Pale yellow oil. [α]2D5 = +24.4 (c = 0.5, CHCl3 for the (E)/
(Z) mixture, 91:9) [94% ee from HPLC; DAICEL CHI-
RALPAK AS, λ = 215 nm, n-hexane, 1 mLmin–1, tr = 12.5 and
13.2 min, (E) isomer, and tr = 12.9 and 13.4 min, (Z) isomer)];
TLC: Rf 0.82 (n-hexane/ethyl acetate 9:1). 1H NMR (300 MHz): δH
= 0.88 (t, J = 6.6 Hz, 3 H, CH3CH2), 1.03 (d, J = 6.7 Hz, 3 H,
CH3CH), 1.21–1.35 (m, 8 H, 4ϫCH2), 2.29 (m, 1 H, CHCH3),
5.26 (d, J = 16.4 Hz, 1 H, CHCN), 6.60 (dd, J = 16.4, 7.9 Hz, 1
H, CH=CHCN) ppm. 13C NMR (75 MHz): δC = 13.8 (CH3CH2),
18.8 (CH2), 22.4 (CH3CH), 26.6, 31.1, 31.6 (3ϫCH2), 37.7
(CHCH3) 98.0 (CH.CN), 119.1 (CN), 161.3 (CH=CHCN) ppm. IR
(%) = 137 [M]+ (0.3), 94 (18), 84 (24), 83 (29), 82 (19), 81 (100), 80
(48). HRMS: C8H12N [M – Me]+ calcd. 122.0969, found 122.0968.
(2Z,4S)-4,5-Dimethylhex-2-enenitrile (3ac): (Table 2, Entry 5,
109 mg, 89%). Colourless oil. [α]2D5 = –19.3 (c = 1.0, CHCl3 for the
(E)/(Z) mixture, 35:65) [87% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 215 nm, n-hexane/propan-2-ol,
99:1, 1 mLmin–1, tr = 5.2 and 5.7 min, (Z) isomer, and 5.9 and
6.2 min, (E) isomer]. TLC: Rf = 0.87 (n-hexane/ethyl acetate, 9:1).
(E) Isomer: 1H NMR (300 MHz): δH = 0.86 and 0.88 [2ϫd, J =
6.7 Hz, 2ϫ3 H, CH(CH3)2], 1.01 (d, J = 6.9 Hz, 3 H, CH3CH),
1.64 [m, 1 H, CH(CH3)2], 2.15 (m, 1 H, CHCH=CH), 5.26 (dd, J
= 16.4, 1.1 Hz, 1 H, CHCN), 6.65 (dd, J = 16.4, 8.1 Hz, 1 H,
CH=CHCN) ppm. 13C NMR (75 MHz): δC = 17.3 (CH3), 19.6 and
19.9 [(CH3)2], 32.4 [CH(CH3)2], 43.2 (CHCH3), 98.8 (CHCN),
117.5 (CN), 159.5 (CH=CHCN) ppm.
(neat): ν = 2223, 1631 cm–1. MS (EI): m/z (%) = 151 [M]+ (1.0),
˜
136 (31), 122 (18), 109 (19), 108 (38), 98 (33), 97 (34), 94 (36), 83
(31), 82 (23), 81 (100), 80 (56). HRMS: C9H14N [M – Me]+ calcd.
136.1126, found 136.1124.
(2Z,4S)-4-Isopropylnon-2-enenitrile (3bc): (Table 2, Entry 13,
158 mg, 88%). Pale yellow oil. [α]2D5 = +25.1 (c = 0.5, CHCl3 for
the (E)/(Z) mixture, 27:73) [94% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 215 nm, n-hexane, 1 mLmin–1, tr
= 6.1 and 7.7 min, (Z) isomer, and 9.5 and 9.7 min, (E) isomer)];
TLC: Rf = 0.87 (n-hexane/ethyl acetate, 9:1).
1
(Z) Isomer: H NMR (300 MHz): δH = 0.88 and 0.93 [2ϫd, J =
6.8 Hz, 2ϫ3 H, CH(CH3)2], 1.04 (d, J = 6.7 Hz, 3 H, CH3CH),
1.60 [m, 1 H, CH(CH3)2], 2.56 (m, 1 H, CHCH=CH), 5.28 (d, J =
10.8 Hz,
1
H, CHCN), 6.32 (t,
J
=
10.8 Hz,
1
H,
CH=CHCN) ppm. 13C NMR (75 MHz): δC = 15.7 (CH3), 19.5,
19.6 [(CH3)2], 32.9 [CH(CH3)2], 44.0 (CHCH3), 98.4 (CHCN),
117.1 (CN), 160.2 (CH=CHCN) ppm. IR (neat): ν = 2221, (E) Isomer: 1H NMR (300 MHz): δH = 0.82–0.95 (m, 9 H, CH3CH2
˜
1626 cm–1. MS (EI): m/z (%) = 123 [M]+ (0.03), 81 (100), 80 (40), and 2ϫCH3CH), 1.25–1.34 (m, 8 H, 4ϫCH2), 1.56 (m, 1 H,
54 (19). HRMS: C8H13N calcd. 123.1048, found 123.1052.
CHCH3), 1.92 (m, 1 H, CHCH=CH), 5.25 (d, J = 16.4 Hz, 1 H,
Eur. J. Org. Chem. 2007, 1101–1112
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1109

A. Baeza, C. Nájera, J. M. Sansano
FULL PAPER
CHCN), 6.50 (dd, J = 16.4, 9.9 Hz, 1 H, CH=CHCN) ppm. 13C (2E,4R)-4-Phenylpent-2-enenitrile (3ca):[22] (Table 2, Entry 21,
NMR (75 MHz): δC = 14.2 (CH3CH2), 18.9 and 20.6 (2ϫCH3),
27.0, 31.2, 31.7 and 31.8 (4ϫCH2), 31.8 (CHCH2), 50.7 (CHCH2),
100.0 (CHCN), 117.2 (CN), 159.0 (CH=CHCN) ppm.
138 mg, 88%). Colourless oil. [α]2D5 = +58.7 (c = 1.0, CHCl3
for the mixture (E)/(Z) 95:5) (85% ee from HPLC; DAICEL
CHIRALPAK AS,
λ = 215 nm, n-hexane/propan-2-ol, 99:1,
1 mLmin–1, tr = 8.8 and 9.8 min); TLC: Rf = 0.52 (n-hexane/ethyl
(Z) Isomer: 1H NMR (300 MHz): δH = 0.82–0.95 (m, 9 H, CH3CH2
and 2ϫCH3CH), 1.25–1.34 (m, 8 H, 4ϫCH2), 1.68 (m, 1 H,
CHCH3), 2.45 (m, 1 H, CHCH=CH), 5.36 (d, J = 10.9 Hz, 1 H,
CHCN), 6.26 (t, J = 10.9 Hz, 1 H, CH=CHCN) ppm. 13C NMR
(75 MHz): δC = 14.0 (CH3CH2), 19.0, 20.6 (2ϫCH3), 22.5, 27.1,
31.4 and 31.8 (4ϫCH2), 31.8 (CHCH2), 48.9 (CHCH3), 99.9
1
acetate, 4:1). H NMR (300 MHz): δH = 1.42 (d, J = 7.1 Hz, 3 H,
CH3), 3.59–3.65 (m, 1 H, CHPh), 5.27 (dd, J = 16.4, 1.1 Hz, 1 H,
CHCN), 6.88 (dd, J = 16.4, 6.3 Hz, 1 H, CH=CHCN), 7.17–7.28
(m, 2 H, ArH), 7.33–7.36 (m, 3 H, ArH) ppm. 13C NMR
(75 MHz): δC = 19.7 (CH3), 43.0 (CHPh), 98.9 (CHCN), 117.2
(CN), 127.2, 127.3, 128.9 and 141.7 (ArC), 159.2
(CHCN), 117.1 (CN), 158.3 (CH=CHCN) ppm. IR (neat): ν =
˜
(CH=CHCN) ppm. IR (neat): ν = 2224, 1637 cm–1. MS (EI): m/z
˜
2224, 1625 cm–1. MS (EI): m/z (%) = 179 [M]+ (0.5), 137 (60), 108
(19), 95 (24), 94 (50), 81 (28), 80 (100). HRMS: C12H21N calcd.
179.1674, found 179.1677.
(%) = 157 [M]+ (67), 156 (71), 142 (100), 129 (25), 115 (81).
(2E,4R)-4-Phenylhex-2-enenitrile (3cb): (Table 2, Entry 22, 15 mg,
9%). Colourless oil. [α]2D5 = +8.3 (c = 0.7, CHCl3) (80% ee from
HPLC; DAICEL CHIRALPAK AD, λ = 215 nm, n-hexane/pro-
pan-2-ol, 99.5:0.5, 0.5 mLmin–1, tr = 17.6 and 20.2 min); Rf = 0.73
(2Z,4R)-4-Butylnon-2-enenitrile (3bd): (Table 2, Entry 16, 168 mg,
87%). Yellow oil. [α]2D5 = +2.1 (c = 1, CHCl3 for the (E)/(Z) mixture,
32:68) [94% ee from HPLC; DAICEL CHIRALPAK AS, λ =
215 nm, n-hexane, 0.8 mLmin–1, tr = 8.0 and 8.4 min, (Z) isomer];
TLC: Rf = 0.61 (n-hexane/ethyl acetate, 9:1).
1
(n-hexane/ethyl acetate, 4:1). H NMR (300 MHz): δH = 0.89 (m,
3 H, CH3), 1.82–1.93 (m, 2 H, CH2), 3.26–3.33 (m, 1 H, CHPh),
5.25 (d, J = 16.4 Hz, 1 H, CHCN), 6.84 (dd, J = 16.4, 7.3 Hz,
1 H, CH=CHCN), 7.12–7.27 (m, 2 H, ArH), 7.29–7.37 (m, 3 H,
ArH) ppm. 13C NMR (75 MHz): δC = 11.9 (CH3), 27.5 (CH2), 51.1
(CHPh), 99.4 (CHCN), 116.1 (CN), 127.2, 127.7, 128.9, 141.4
(E) Isomer: 1H NMR (300 MHz): δH = 0.88 (m, 6 H, 2ϫCH3CH2),
1.26–1.39 (m, 10 H, 5ϫCH2), 1.46 (m, 4 H, 2ϫCH2CH), 2.12 (m,
1 H, CHCH2), 5.26 (d, J = 16.4 Hz, 1 H, CHCN), 6.49 (dd, J =
(ArC), 158.4 (CH=CHCN) ppm. IR (neat): ν = 2221, 1613 cm–1.
16.4, 9.2 Hz, 1 H, CH=CHCN) ppm. 13C NMR (75 MHz): δC
=
˜
MS (EI): m/z (%) = 171 [M]+ (25.4), 143 (15), 142 (86), 116 (18),
13.9 (CH3), 16.1 (CH2), 22.5 (CH3), 22.7, 26.7, 29.3, 30.3, 31.7 and
33.9 (5ϫCH2), 44.1 (CHCH2), 99.1 (CHCN), 116.5 (CN), 160.0
(CH=CHCN) ppm.
115 (100). HRMS: C12H13N calcd. 171.1048, found 171.1049.
(2Z,4S)-4-Phenylhex-2-enenitrile (3cb): (Table 2, Entry 22, 148 mg,
86%). Colourless oil. [α]2D5 = +68.1 (c = 0.2, CHCl3) (80% ee from
HPLC; DAICEL CHIRALPAK AD, λ = 215 nm, n-hexane/pro-
pan-2-ol, 99.5:0.5, 0.5 mLmin–1, tr = 20.6 and 23.2 min); Rf = 0.73
(Z) Isomer: 1H NMR (300 MHz): δH = 0.88 (m, 6 H, 2ϫCH3CH2),
1.26–1.39 (m, 10 H, 5ϫCH2), 1.46 (m, 4 H, 2ϫCH2CH), 2.62 (m,
1 H, CHCH2), 5.31 (d, J = 10.9 Hz, 1 H, CHCN), 6.19 (t, J =
10.9 Hz, 1 H, CH=CHCN) ppm. 13C NMR (75 MHz): δC = 14.0
(CH3), 16.2 (CH2), 22.7 (CH3), 22.6, 26.8, 29.3, 30.9, 31.8 and 34.5
(5ϫCH2), 42.7 (CHCH2), 99.1 (CHCN), 117.6 (CN), 160.7
1
(n-hexane/ethyl acetate, 4:1). H NMR (300 MHz): δH = 0.93 (m,
3 H, CH3), 1.76–1.88 (m, 2 H, CH2), 3.75–3.82 (m, 1 H, CHPh),
5.33 (d, J = 10.8 Hz, 1 H, CHCN), 6.53 (t, J = 10.8 Hz, 1 H,
CH=CHCN), 7.12–7.27 (m, 2 H, ArH), 7.29–7.37 (m, 3 H,
ArH) ppm. 13C NMR (75 MHz): δC = 11.8 (CH3), 28.2 (CH2), 50.0
(CHPh), 98.6 (CHCN), 117.4 (CN), 127.1, 127.3, 128.9, 140.5
(CH=CHCN) ppm. IR (neat): ν = 2221, 1621 cm–1. MS (EI): m/z
˜
(%) = 193 [M]+ (0.5), 164 (27), 136 (31), 124 (50), 123 (27), 110
(35), 108 (31), 95 (29), 94 (39), 83 (29), 81 (36), 80 (100). HRMS:
C12H20N [M – Me]+ calcd. 178.1595, found 178.1600.
(ArC), 157.5 (CH=CHCN) ppm. IR (neat): ν = 2221, 1613 cm–1.
˜
MS (EI): m/z (%) = 171 [M]+ (25.4), 143 (15), 142 (86), 116 (18),
(2E,4R)-4-Benzylnon-2-enenitrile (3bf): (Table 2, Entry 17, 186 mg,
81%). Colourless, sticky oil. [α]2D5 = –22.1 (c = 1.4, CHCl3 for the
mixture (E)/(Z) 85:15) [87% ee from HPLC; DAICEL CHI-
115 (100). HRMS: C12H13N calcd. 171.1048, found 171.1049.
(2E,4R)-4-Phenyloct-2-enenitrile (3cd): (Table 2, Entry 24, 171 mg,
86%). Colourless oil [58% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 215 nm, n-hexane/propan-2-ol
99.5:0.5, 0.5 mLmin–1, tr = 21.0 and 22.4 min, (E) isomer) and
DAICEL CHIRACEL OJ, λ = 215 nm, n-hexane/propan-2-ol,
99:1, 0.5 mLmin–1, tr = 18.3 and 23.6 min, (Z) isomer), 32.5 and
35.0 min (α-substitution)]; TLC: Rf = 0.58 (n-hexane/ethyl acetate,
4:1)
RALCEL OJ,
λ
=
215 nm, n-hexane/propan-2-ol, 99.5:0.5,
0.8 mLmin–1, tr = 16.3 and 21.2 min, (E) isomer, and tr = 11.6 and
12.0, (Z) isomer]; TLC: Rf = 0.52 (n-hexane/ethyl acetate, 9:1).
1
(E) Isomer: H NMR (300 MHz): δH = 0.88 (m, 3 H, CH3), 1.25–
1.35 (m, 6 H, 3ϫCH2), 1.67 (m, 2 H, CH2CH), 2.44 (m, 1 H,
CHCH2), 2.58 and 2.78 (2ϫm, 2 H, CH2Ph), 5.11 (dd, J = 16.4,
0.6 Hz, 1 H, CHCN), 6.51 (dd, J = 16.4, 9.0 Hz, 1 H, CH=CHCN),
7.11–7.18 (m, 3 H, ArH), 7.21–7.31 (m, 2 H, ArH) ppm. 13C NMR
(75 MHz): δC = 13.9 (CH3), 22.5, 31.6, 33.5 and 37.9 (4ϫCH2),
40.7 (CHCH2), 45.8 (CH2Ph), 99.8 (CHCN), 117.4 (CN), 125.9,
128.3, 128.5 and 138.7 (ArC), 159.2 (CH=CHCN) ppm.
1
(E) Isomer: H NMR (300 MHz): δH = 0.84–0.96 (m, 3 H, CH3),
1.21–1.37 (m, 4 H, 2ϫCH2), 1.73–1.86 (m, 2 H, CH2), 3.39 (m, 1
H, CHPh), 5.25 (d, J = 16.4 Hz, 1 H, CHCN), 6.85 (dd, J = 16.4,
7.5 Hz, 1 H, CH=CHCN), 7.12–7.25 (m, 2 H, ArH), 7.29–7.40 (m,
3 H, ArH) ppm. 13C NMR (75 MHz): δC = 13.8 (CH3), 22.4, 29.4
and 34.2 (3ϫCH2), 49.4 (CHPh), 99.2 (CHCN), 117.1 (CN), 127.2,
127.7, 128.7 and 140.7 (ArC), 158.7 (CH=CHCN) ppm.
1
(Z) Isomer: H NMR (300 MHz): δH = 0.88 (m, 3 H, CH3), 1.25–
1.35 (m, 6 H, 3ϫCH2), 1.67 (m, 2 H, CH2CH), 2.58 and 2.78
(2ϫm, 3 H, CH2Ph and CHCH2), 5.24 (d, J = 10.8 Hz, 1 H,
CHCN), 6.19 (t, J = 10.8 Hz, 1 H, CH=CHCN), 7.11–7.18 (m, 3
H, ArH), 7.21–7.31 (m, 2 H, ArH) ppm. 13C NMR (75 MHz): δC
= 13.9 (CH3), 25.4, 31.7, 33.9 and 37.9 (4ϫCH2), 41.1 (CHCH2),
44.1 (CH2Ph), 99.7 (CHCN), 117.4 (CN), 126.3, 128.3, 129.0 and
1
(Z) Isomer: H NMR (300 MHz): δH = 0.84–0.96 (m, 3 H, CH3),
1.21–1.37 (m, 4 H, 2ϫCH2), 1.73–1.86 (m, 2 H, CH2), 3.90 (m, 1
H, CHPh), 5.72 (d, J = 10.8 Hz, 1 H, CHCN), 6.54 (t, J = 10.8 Hz,
1 H, CH=CHCN), 7.12–7.25 (m, 2 H, ArH), 7.29–7.40 (m, 3 H,
ArH) ppm. 13C NMR (75 MHz): δC = 13.9 (CH3), 22.5, 29.3 and
34.9 (CH2), 48.3 (CHPh), 98.4 (CHCN), 116.0 (CN), 127.1, 127.3,
140.8 (ArC), 158.5 (CH=CHCN) ppm. IR (neat): ν = 2221,
˜
1611 cm–1. MS (EI): m/z (%) = 227 [M]+ (12), 92 (9), 91 (100). 128.9 and 141.6 (ArC), 157.7 (CH=CHCN) ppm. IR (neat): ν =
˜
HRMS: C16H21N calcd. 227.1674, found 227.1669.
2221, 1617 cm–1. MS (EI): m/z (%) = 199 [M]+ (21.7), 143 (100), 142
1110
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1101–1112

Alkylation of Chiral Allylic Cyanohydrin O-Phosphates
FULL PAPER
(62), 116 (29), 115 (70). HRMS: C14H17N calcd. 199.1361, found
199.1358.
= –4.42 (c = 4, MeOH) 94% ee (S) enantiomer} (76% ee from
HPLC; DAICEL CHIRACEL OJ, λ = 254 nm, n-hexane/propan-
2-ol, 99:1, 0.7 mLmin–1, tr = 10.2 and 12.2 min). 1H NMR
(300 MHz): δH = 1.05 (d, J = 7.1 Hz, 3 H, CH3), 1.21 (m, 1 H,
CH), 3,35 (2ϫd, J = 12.5 Hz, 2 H, CH2), 7.14–7.35 (m, 5 H, ArH),
9.75 (d, 1 H, J = 1.7 Hz, CHO) ppm.
(2Z,4S)-5-Methyl-4-phenylhex-2-enenitrile (3cc): (Table 2, Entry 27,
154 mg, 83%). Colourless oil. [α]2D5 = +158.9 (c = 1.0, CHCl3 for
the (E)/(Z) mixture, 39:61) [90% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 215 nm, n-hexane, 1 mLmin–1, tr
= 16.5 and 19.9 min, (Z) isomer, and 27.0 and 30.0 min, (E) iso-
mer)]; TLC: Rf = 0.59 (n-hexane/ethyl acetate, 4:1).
(R)-2-Methylhexanal (7ad):[18] (24 mg, 83%). Colourless oil. [α]2D0
–10.2 (c = 1.0, CHCl3) (30% ee estimated), {ref.[18] [α]2D5 = –19.7 {c
= 5.8, CHCl3 99% ee (R) enantiomer}. 1H NMR (300 MHz): δH
=
=
1
(E) Isomer: H NMR (300 MHz): δH = 0.78 (d, J = 6.7 Hz, 3 H,
0.92 (m, 3 H, CH3), 1.10 (d, J = 7.1 Hz, 3 H, CH3CH), 1.22–1.74
(m, 6 H, 3ϫCH2), 2.42 (m, 1 H, CH), 9.62 (d, 1 H, J = 2.0 Hz,
CHO) ppm. MS (EI): m/z (%) = 114 [M]+ (1.3), 85 (6), 70 (6), 58
(100), 57 (26).
CH3), 0.98 (d, J = 6.7 Hz, 3 H, CH3), 2.04 (m, 1 H, CHCH3), 3.01
(t, J = 9.0 Hz, 1 H, CHCH=CH), 5.31 (dd, J = 16.2, 0.9 Hz, 1 H,
CHCN), 6.89 (dd, J = 16.2, 9.0 Hz, 1 H, CH=CHCN), 7.10–7.27
(m, 2 H, ArH), 7.31–7.38 (m, 3 H, ArH) ppm. 13C NMR
(75 MHz): δC = 20.7 and 20.8 (2ϫCH3), 32.6 (CHCH3), 57.9
(CHPh), 99.9 (CHCN), 116.1 (CN), 127.1, 128.0, 128.8 and 140.5
(ArC), 157.7 (CH=CHCN) ppm.
General Procedure for the Synthesis of the Enantioenriched Esters
4: A mixture of compound 3ba or 3ca (0.25 mmol), MeOH (2 mL)
and concentrated aqueous HCl (2 mL) was heated at 90 °C over-
night. An aqueous saturated solution of NaHCO3 (10 mL) was
then added to neutralise the acidic medium. MeOH was then re-
moved by evaporation, and ethyl acetate was added. The organic
layer was separated, dried (MgSO4) and concentrated to afford the
crude compounds, which were purified by flash chromatography to
provide the pure esters 4.
1
(Z) Isomer: H NMR (300 MHz): δH = 0.78 (d, J = 6.7 Hz, 3 H,
CH3), 1.01 (d, J = 6.7 Hz, 3 H, CH3), 2.04 (m, 1 H, CHCH3), 3.50
(t, J = 10.2 Hz, 1 H, CHCH=CH), 5.32 (d, J = 10.8 Hz, 1 H,
CHCN), 6.62 (t, J = 10.8, 9.0 Hz, 1 H, CH=CHCN), 7.10–7.27 (m,
2 H, ArH), 7.31–7.38 (m, 3 H, ArH) ppm. 13C NMR (75 MHz):
δC = 20.5 and 20.6 (2ϫCH3), 32.9 (CHCH3), 56.3 (CHPh), 98.9
(CHCN), 116.2 (CN), 127.0, 127.8, 128.9 and 141.1 (ArC), 157.0
Methyl (2E,4S)-4-Methylnon-2-enenoate [(S)-4ba]: (37 mg, 80%).
Pale yellow oil. [α]2D5 = +31.7 (c = 0.8, CHCl3 for the mixture (E)/
(Z) 91:9); TLC: Rf 0.39 (n-hexane/ethyl acetate, 4:1). 1H NMR
(300 MHz): δH = 0.88 (t, J = 6.6 Hz, 3 H, CH3CH2), 1.04 (d, J =
6.7 Hz, 3 H, CH3CH), 1.26–1.41 (m, 8 H, 4ϫCH2), 2.28 (m, 1 H,
CHCH3), 3.73 (s, 3 H, OCH3), 5.77 (d, J = 15.7 Hz, 1 H, CHCN),
6.86 (dd, J = 15.7, 7.9 Hz, 1 H, CH=CHCN) ppm. 13C NMR
(75 MHz): δC = 14.0 (CH3CH2), 18.8 (CH2), 22.4 (CH3CH), 26.6,
31.1, 31.6 (3ϫCH2), 37.7 (CHCH3), 51.4 (OCH3), 119.1 (CHCN),
(CH=CHCN) ppm. IR (neat): ν = 2222, 1619 cm–1. MS (EI): m/z
˜
(%) = 185 [M]+ (6.9), 143 (100), 115 (23). HRMS: C13H15N calcd.
185.1204, found 185.1206.
(2E,4R)-4,5-Diphenylpent-2-enenitrile (3cf): (Table 2, Entry 29,
200 mg, 86%). Colourless oil. [α]2D5 = +10.5 (c = 2.0, CHCl3 for the
(E)/(Z) mixture, 70:30) [85% ee for each isomer from HPLC;
DAICEL CHIRALPAK AS, λ = 209 nm, n-hexane/propan-2-ol,
99:1, 0.7 mLmin–1, tr = 16.5 and 17.2 min, (Z) isomer, and 25.1
and 26.7 min, (E) isomer)]; TLC: Rf = 0.45 for the (Z) isomer, 0.39
for the (E) isomer (n-hexane/ethyl acetate, 4:1).
155.1 (CH=CHCN), 161.4 (CO) ppm. IR (neat): ν = 2860, 1725,
˜
1655, 1265 cm–1. MS (EI): m/z (%) = 184 [M]+ (3.5), 153 (44), 128
(100), 127 (73), 114 (31), 110 (77), 109 (20), 97 (25), 96 (72), 95
(51). HRMS: C10H17O2 calcd. 169.1248, found 169.1244.
(E) Isomer: 1H NMR (300 MHz): δH = 3.07 (m, 2 H, CH2), 3.71
(m, 1 H, CHPh), 5.12 (dd, J = 16.4, 1.5 Hz, 1 H, CHCN), 6.87
(dd, J = 16.4, 7.2 Hz, 1 H, CH=CHCN), 7.12–7.25 (m, 4 H, ArH),
7.29–7.40 (m, 6 H, ArH) ppm. 13C NMR (75 MHz): δC = 29.7
(CH2), 51.2 (CHPh), 100.2 (CHCN), 117.2 (CN), 126.5, 126.6,
127.4, 127.7, 128.5, 128.9, 129.0 and 138.2 (ArC), 157.2
(CH=CHCN) ppm.
Methyl (2E,4R)-4-Methylnon-2-enenoate [(R)-4ba]: (36 mg, 78%).
Pale yellow oil. [α]2D5 = –31.8 (c = 0.8, CHCl3 for the (E)/(Z) mix-
1
ture, 91:9); TLC: Rf = 0.39 (n-hexane/ethyl acetate, 4:1). H NMR
(300 MHz): δH = 0.88 (t, J = 6.6 Hz, 3 H, CH3CH2), 1.04 (d, J =
6.7 Hz, 3 H, CH3CH), 1.26–1.41 (m, 8 H, 4ϫCH2), 2.28 (m, 1 H,
CHCH3), 3.73 (s, 3 H, OCH3), 5.77 (d, J = 15.7 Hz, 1 H, CHCN),
6.86 (dd, J = 15.7, 7.9 Hz, 1 H, CH=CHCN) ppm. 13C NMR
(75 MHz): δC = 14.0 (CH3CH2), 18.8 (CH2), 22.4 (CH3CH), 26.6,
31.1, 31.6 (3ϫCH2), 37.7 (CHCH3), 51.4 (OCH3), 119.1 (CHCN),
(Z) Isomer: 1H NMR (300 MHz): δH = 3.07–3.12 and 3.17–3.21
(2ϫm, 2 H, CH2), 4.18 (m, 1 H, CHPh), 5.24 (d, J = 10.8 Hz, 1
H, CHCN), 6.60 (t, J = 10.8 Hz, 1 H, CH=CHCN), 7.12–7.25 (m,
4 H, ArH), 7.29–7.40 (m, 6 H, ArH) ppm. 13C NMR (75 MHz):
δC = 29.3 (CH2), 49.9 (CHPh), 100.2 (CHCN), 115.1 (CN), 126.5,
127.2, 127.3, 127.4, 128.3, 128.4, 129.1 and 140.1 (ArC), 156.2
155.1 (CH=CHCN), 161.4 (CO) ppm. IR (neat): ν = 2860, 1725,
˜
1655, 1265 cm–1. MS (EI): m/z (%) = 184 [M]+ (3.5), 153 (44), 128
(100), 127 (73), 114 (31), 110 (77), 109 (20), 97 (25), 96 (72), 95
(51). HRMS: C10H17O2 calcd. 169.1248, found 169.1249.
(CH=CHCN) ppm. IR (neat): ν = 2221 (CN), 1629 (C=C) cm–1.
˜
Methyl (2E,4R)-4-Phenylpent-2-enenoate (4ca):[7a] (47 mg, 99%).
Colourless oil. [α]2D5 = +15.5 (c = 0.3, CHCl3 for the (E)/(Z) mix-
ture, 95:5). 1H NMR (300 MHz): δH = 1.43 (d, J = 7.0 Hz, 3 H,
CH3CH), 3.62 (m, 1 H, CHCH3), 3.72 (s, 3 H, CH3O), 5.80 (dd, J
= 15.7, 1.5 Hz, 1 H, CHCO2Me), 7.20 (dd, J = 15.7, 6.4 Hz, 1 H,
CH=CHCN), 7.25–7.39 (m, 3 H, ArH), 7.28–7.36 (m, 2 H,
ArH) ppm. MS (EI): m/z (%) = 190 [M]+ (20), 159 (21), 131 (100),
130 (59), 129 (40), 116 (20), 119 (58), 91 (28).
Synthesis of (S)- and (R)-4-Methylnonan-1-ol (9):[21] Crude com-
pound 4ba (0.5 mmol, 68 mg) was treated with LiAlH4 (1.5 mmol,
58 mg) in anhydrous THF (2 mL) at room temperature for 15 h.
The reaction mixture was quenched with H2SO4 (1 , 5 mL) and
MS (EI): m/z (%) = 233 [M]+ (6.2), 115 (7), 91 (100). HRMS:
C17H15N calcd. 233.1204, found 233.1199.
General Procedure for the Synthesis of the Enantioenriched Alde-
hydes 7 by Ozonolysis of Compounds 3a:[23] A stream of oxygen
and ozone was passed at –78 °C through a solution of product 3a
(0.25 mmol) in dichloromethane (3 mL) for 30 min. The blue solu-
tion was the purged with a stream of argon for 10 min, thiourea
(0.3 mmol, 34 mg) was added, and the resulting solution was al-
lowed to warm to room temperature overnight. The reaction mix-
ture was concentrated and the crude mixture was purified by flash
chromatography to yield pure aldehydes 7.
(R)-2-Methyldihydrocinnamaldehyde (7af):[17] (30 mg, 80%). ethyl acetate (10 mL) and the organic residue was purified by flash
Colourless oil. [α]2D0 = +7.0 (c = 0.7, MeOH, 76% ee) {ref.[17] [α]2D3
chromatography (36 mg, 48% overall yield from 3ba mixtures).
Eur. J. Org. Chem. 2007, 1101–1112
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1111

A. Baeza, C. Nájera, J. M. Sansano
FULL PAPER
Compound (S)-9: [α]2D5 = +0.51 (c = 2, CHCl3, 78% ee), ref.[21a]
[α]2D5 = +0.63 (CHCl3), ref.[21e] [α]2D5 = +1.97 (neat). 1H NMR
(300 MHz): δH = 0.92 (m, 6 H, 2ϫCH3), 0.99–1.77 (m, 13 H,
CHCH3 and 6ϫCH2), 2.8 (s, 1 H, OH), 3.61 ppm (t, J = 6.6 Hz,
2 H, CH2O). MS (EI): m/z (%) = 158 [M – 1]+ (2), 140 (3), 112
(16), 97 (24), 84 (36), 69 (100), 57 (93), 41 (100).
Compound (R)-9: [α]2D5 = +0.48 (c = 2, CHCl3, 78% ee), ref.[21a]
[α]2D5 = +0.63 (CHCl3), ref.[21e] [α]2D5 = +1.97 (neat). 1H NMR
(300 MHz): δH = 0.92 (m, 6 H, 2ϫCH3), 0.99–1.77 (m, 13 H,
CHCH3 and 6ϫCH2), 2.8 (s, 1 H, OH), 3.61 ppm (t, J = 6.6 Hz,
2 H, CH2O). MS (EI): m/z (%) = 158 [M – 1]+ (1), 140 (1), 112
(19), 97 (24), 84 (38), 69 (100), 57 (90), 41 (100).
A. J. Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 4493–4496;
g) U. Piarelli, C. Claverie, P. Danbos, M. Roux, C. Gennari,
Angew. Chem. Int. Ed. 2003, 42, 234–236.
[9] a) A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. Org. Chem.
2006, 71, 3837–3848; b) A. Baeza, C. Nájera, J. M. Sansano,
J. M. Saá, Chem. Eur. J. 2005, 11, 3849–3862; c) A. Baeza, J.
Casas, C. Nájera, J. M. Sansano, J. M. Saá, Angew. Chem. Int.
Ed. 2003, 42, 3143–3146.
[10] For other synthesis of chiral cyanophosphates, see: a) N. Yam-
agiwa, Y. Abiko, M. Sugita, J. Tian, S. Matsunaga, M. Shiba-
saki, Tetrahedron: Asymmetry 2006, 17, 566–573; b) Y. Abiko,
N. Yamagiwa, M. Sugita, J. Tian, S. Matsunaga, M. Shibasaki,
Synlett 2004, 2434–2436.
[11] R. Yoneda, S. Harusawa, T. Kurihara, J. Chem. Soc. Perkin
Trans. 1 1988, 3163–3168.
[12] Part of these results were presented at the 16th IUPAC Inter-
national Conference on Organic Synthesis, Mérida (Mexico),
June 2006.
Acknowledgments
This work has been supported by the DGES of the Spanish Minis-
terio de Educación y Ciencia (MEC) (CTQ2004-00808/BQU), the
Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134 and
GV05/144) and the University of Alicante. A. Baeza also thanks
the Generalitat Valenciana for a predoctoral fellowship (CTBPRB/
2002/107).
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Received: September 20, 2006
Published Online: January 8, 2007
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