Enantioselective synthesis of O-methoxycarbonyl cyanohydrins: Chiral building blocks generated by bifunctional catalysis with BINOLAM-AlCl

Article abstract of DOI:10.1002/ejoc.200500939

(R)- or (S)-BINOLAM-AlCl, generated in situ, work as bifunctional catalysts in promoting the enantioselective cyanoalkoxycarbonylation of aldehydes. The reaction is wide in scope and the mechanistic evidence gathered suggests the intervention of an indirect process involving enantioselective hydrocyanation by HCN, followed by O-alkoxycarbonylation. The resultant O-alkoxycarbonyl cyanohydrins are shown to be important chiral building blocks for synthesis. Chemoselective hydrolysis can thus be directed either to provide enantioenriched β-hydroxy esters, or acids, or instead to give O-methoxycarbonyl β-hydroxy acids, esters, or amides. In addition, the enantiopure cyanocarbonates can be converted into β-amino alcohols by reduction with lithiumaluminium hydride. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500939

FULL PAPER
DOI: 10.1002/ejoc.200500939
Enantioselective Synthesis of O-Methoxycarbonyl Cyanohydrins: Chiral
Building Blocks Generated by Bifunctional Catalysis with BINOLAM-AlCl
Alejandro Baeza,[a] Jesús Casas,[a] Carmen Nájera,*[a] José M. Sansano,[a] and
José M. Saá*[b]
Keywords: Cyanohydrin derivatives / Bifunctional catalysis / Asymmetric synthesis / BINOLAM / Aluminium
(R)- or (S)-BINOLAM-AlCl, generated in situ, work as bi-
functional catalysts in promoting the enantioselective cyano-
alkoxycarbonylation of aldehydes. The reaction is wide in
scope and the mechanistic evidence gathered suggests the
intervention of an indirect process involving enantioselective
hydrocyanation by HCN, followed by O-alkoxycarbonyl-
ation. The resultant O-alkoxycarbonyl cyanohydrins are
shown to be important chiral building blocks for synthesis.
Chemoselective hydrolysis can thus be directed either to pro-
vide enantioenriched β-hydroxy esters, or acids, or instead to
give O-methoxycarbonyl β-hydroxy acids, esters, or amides.
In addition, the enantiopure cyanocarbonates can be con-
verted into β-amino alcohols by reduction with lithiumalu-
minium hydride.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
asymmetric synthesis.[1] A successful one-step enantioselec-
tive cyanation (actually a cyanoalkoxycarbonylation) of
ketones (not aldehydes) promoted by cinchona alkaloid-de-
rived tertiary amines has been reported by Deng,[5] whilst
Shibasaki and co-workers have achieved the enantioselec-
tive cyanoalkoxycarbonylation of aldehydes in up to
98% ees by use of the heterobimetallic complex (S)-YLi3-
tris(binaphthoxide) (YLB) 1.[6] Belokon and North[7a] and
Moberg[7b] instead used the bimetallic titanium complex 2,
derived from a chiral salen ligand, as catalyst, thereby ob-
taining the desired O-alkoxycarbonyl cyanohydrins in up to
99% and 96% ees, respectively.
Introduction
The introduction of XCN across a double bond (generi-
cally defined as a cyanation reaction) is a useful C1 homolo-
gation methodology in organic synthesis. In particular, both
racemic and nonracemic cyanation[1] of carbon–oxygen or
carbon–nitrogen double bonds are of considerable impor-
tance because the introduced cyano group can easily be
transformed into numerous other functional groups. Un-
protected cyanohydrins resulting from hydrocyanations (X
= H) are unstable compounds, and O-protection is therefore
generally required for safe synthetic applications, as well as
for ensuring their configurational stability, if appropriate.
Some O-protected derivatives such as O-TMS cyanohydrins
are still too labile (partial desilylation is a common unde-
sired reaction taking place during manipulation). Easy ac-
cess to other enantiomerically pure O-protected cyanohyd-
rins is therefore a current goal of asymmetric catalysis, as
they should be valuable building blocks for organic synthe-
sis.
Racemic O-acyl,[2] O-bis-alkoxyphosphoryl,[3] and O-alk-
oxycarbonyl cyanohydrins[2b,2d,4] can be prepared in single
operations through a variety of procedures. However, the
catalytic, enantioselective cyanation of either C=O or C=N
double bonds is a topic of current interest in the field of
[a] Departamento de Química Orgánica, Facultad de Ciencias, and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
The power of bifunctional catalysis[8] has an especial rele-
vance for enantioselective cyanide addition onto C=X
bonds, and the pioneering dual-motif structures reported
by Shibasaki et al., based on a chiral BINOL skeleton 3
and a modified carbohydrate structure,[8e] were undoubt-
edly suitable ligands for the enantioselective cyanosilylation
Fax: +34-965903549
E-mail: cnajera@ua.es
[b] Departament de Química, Universitat de les Illes Balears,
07122 Palma de Mallorca, Spain
Fax: +34-971173426
E-mail: jmsaa@uib.es
Eur. J. Org. Chem. 2006, 1949–1958
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1949

A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. M. Saá
FULL PAPER
(S)-BINOLAM-AlCl 4, as well as some useful transforma-
tions of the resulting products into valuable enantiopure
building blocks for organic synthesis.
Results and Discussion
Enantioselective Cyano O-Alkoxycarbonylation
In our search for the ideal reaction conditions to achieve
this goal, we studied the reaction between benzaldehyde
and benzyl cyanoformate (1.5 equiv.), in dry toluene at
room temperature in the presence, or not, of some metal-
containing co-catalysts (10 mol-%, Scheme 1 and Table 1,
Entries 1–6) and enantiomerically pure (S)-BINOLAM
(10 mol-%). The reaction failed completely in the absence
of co-catalyst, as well as in the presence of Ti(OiPr)2Cl2
(Table 1, Entries 1 and 3), and gave a poor result when
Ti(OiPr)4 was added as co-catalyst (Table 1, Entry 2). When
working with aluminium-based catalysts we found that the
one made from Me3Al gave null results in terms of enantio-
selection (Table 1, Entry 4). Fortunately, we found that em-
ployment of catalyst 4, prepared in situ by mixing (R)-BI-
NOLAM 5 with commercial dimethylaluminium chloride
(Table 1, Entry 5), rather than diethylaluminium chloride
(Table 1, Entry 6), gave encouraging results. From previous
experiences it seems that diethylaluminium chloride does
not react as rapidly with ligand 5 as dimethylaluminium
chloride does, and can itself act as a Lewis acid, favoring
the racemic catalytic process. Methyl cyanoformate
(Table 1, Entry 7) was found to be the reagent of choice
(instead of benzyl cyanoformate), as in this way we were
able to avoid the presence of some benzyl alcohol in the
crude reaction mixtures after workup. Since the reaction
was quite slow even at room temperature, we then looked
for additives[14] and found that the reaction rate increased
significantly when 4 Å molecular sieves (50 mg/0.25 mmol
of aldehyde), previously dried at 120 °C for 4 h,[15] were
added to the reaction mixture (Table 1, Entry 8), albeit with
no change whatsoever in chemical yield and stereochemical
outcome. This behavior was suggestive of a slow turnover
reaction (probably that of O-alkoxycarbonylation, with the
concomitant freeing of HCN). Triphenylphosphane oxide
was also tested as additive, but no improvement was ob-
served (Table 1, Entry 9), in apparent contrast with obser-
vations for the enantioselective cyanosilylation of aldehydes,
also catalyzed by 4.[9] Working with toluene or dichloro-
methane (Table 1, Entries 8 and 10) gave similar values of
enantioselection (thoroughly expressed as er), the former
being selected as the optimal solvent due to some margin-
ally better chemical yields obtained. THF, however, was
found to be an inappropriate solvent for this reaction
(Table 1, Entry 11). The use of lower or higher temperatures
did not give rise to significant changes either in enantio-
selectivity or in chemical yield of the process. Finally, no
obvious improvement was observed by working with the
of aldehydes and ketones, respectively.[8e] Presumably the
scant enantioselection exhibited by these ligands in the
asymmetric cyanocarbonylation of aldehydes forced the de-
velopment of an alternative catalytic complex such as 1.
In contrast, we have recently found that the monometallic
bifunctional 4 is an excellent catalyst for the cyanosi-
lylation[9] or cyanophosphorylation[10] of aldehydes, whilst
the cyanobenzoylation of aldehydes was achieved with the
same catalytic complex but containing titanium() in-
stead.[11] For the current work,[12] we explored the enantio-
selective cyanoalkoxycarbonylation of aldehydes by use of
the monometallic bifunctional aluminium complexes (R)-
and (S)-BINOLAM-AlCl 4,[9–11] generated from the corre-
sponding chiral ligands (R)- and (S)-3,3Ј-bis(diethylamino-
methyl)-1,1Ј-bi(2-naphthol) (5).[13] These types of com-
plexes bear two non-canceling centers capable of acting a
priori either as an LALB (Lewis acid-Lewis base) or an
LABB (Lewis acid-Brönsted base) system capable of activa-
ting electrophilic and nucleophilic reagents simulta-
neously.[8] By using a combination of approaches, including
extensive DFT calculations, we have recently shown that
these reactions are in fact likely to be the result of a cata-
lytic cycle involving enantioselective hydrocyanation (an
LABB reaction) coupled to subsequent O-functionalization
in the turnover step.[10b]
We now report a detailed account of the enantioselective same reaction conditions tested for the asymmetric cyano-
cyanoalkoxycarbonylation of aldehydes catalyzed by the benzoylation of aldehydes, with Ti(OiPr)4/(S)-BINOLAM
monometallic, bifunctional aluminium complexes (R)- and catalyst (10 mol-%) in THF as solvent at room temperature
1950
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1949–1958

Enantioselective Synthesis of O-Methoxycarbonyl Cyanohydrins
FULL PAPER
(Table 1, Entry 12).[11] The enantiomeric ratios of products ated product (R)-7i is accordingly obtained in excellent
6a and 7a were determined by chiral HPLC analysis with a yield and with good enantioselectivity (86:14 er; see Table 2,
Daicel Chiralcel OD-H column (for more details, see Exp. Entry 11). This compound has been employed as a key in-
Sect.). Their absolute configurations were unambiguously termediate in the synthesis of epothilones A and B.[10,12,17]
assigned by comparison of their optical rotation values with Furfural reacted with a good chemical yield, but with only
those of pure samples obtained by treatment of enantiomer- modest enantioselectivity (Table 2, Entry 10). Both conju-
ically enriched cyanohydrins[9,12] with benzyl and/or methyl gated and aliphatic aldehydes also gave good enantiomeric
chloroformate in the presence of pyridine, in dichlorometh- ratios and almost quantitative chemical yields. Disappoint-
ane as solvent.
ingly, ketones did not undergo the reaction under the above
reaction conditions. As expected, enantiomerically enriched
carbonates (R)-7 were isolated in identical chemical yield
and enantiomeric purity when (S)-BINOLAM-AlCl (S)-4
was employed as catalyst (Scheme 2 and Table 2, Entries 1
and 2). This behavior is in full agreement with the SSR/
RRS mnemonic rule for the stereochemical outcome of cya-
nophosphorylations catalyzed by BINOLAM-AlCl,[10]
which states that the (S) catalyst promotes the attack at the
Si face, thereby giving rise to the (R)-cyanohydrin deriva-
tive, and the opposite: the (R) catalyst induces attack at the
Re face, thereby giving rise to the (S)-cyanohydrin deriva-
tive. The apparently anomalous case of furfural, which af-
fords (R)-7h with use of the complex (R)-4 (Table 2, En-
try 10) can be explained simply by the different priority of
substituents according to CIP rules. As described pre-
viously,[10–13] ligands (S)- or (R)-5 could be almost quanti-
tatively (95%) recovered by extractive workup and sub-
sequently reused without any loss of activity (Table 2, En-
try 3).
Scheme 1.
Overall, the results obtained for the above cyano O-alk-
oxycarbonylation were found to be similar, in terms of
chemical yield, to those found for the analogous cyano O-
alkoxyphosphorylation, though slightly poorer in terms of
enantioselectivity, a result a priori consistent with a slow
turnover step. The scope of cyano O-alkoxycarbonylation
also paralleled that of the cyano O-alkoxyphosphoryl-
ation,[10] as shown in Scheme 2 and Table 2. Aromatic alde-
hydes thus reacted almost quantitatively to give 7 in up to
78% ee (Table 2, Entries 1–8). As in the case of the cyano
O-alkoxyphosphorylation,[10] the reactions of heteroaro-
matic aldehydes such as pyridine-3-carboxaldehyde took
place with high chemical yields but with very low enantiose-
lection (2% ee; see Table 2, Entry 9), an indication that
both reactions probably proceed through a common mecha-
nism involving an LABB enantioselective hydrocyanation
followed by O-functionalization. In accordance with this
analysis, basic aldehydes such as pyridine-3-carboxaldehyde
showed strong competition by the racemic mechanism as
the pyridine nitrogen atom can act as a base in capturing
Scheme 2.
Several other pieces of indirect evidence suggest a com-
HCN, in competition with the amino arm. Apparently, the mon LABB dual mechanism involving enantioselective hy-
less basic thiazole nitrogen [pKa (thiazole) = 2.4][16] does not drocyanation followed by O-functionalization for both the
compete so efficiently, and so the cyano O-alkoxycarbonyl- cyano O-phosphorylation[10] and the cyano O-alkoxycarb-
Table 1. Optimization of the reaction conditions for the catalytic, enantioselective synthesis of O-alkoxycarbonylated cyanohydrins (S)-
6a and (S)-7a.
Entry
R
Co-catalyst[a] Additive
Solvent
Time [h][b] Product
Yield [%][c]
er[d]
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
–
–
–
–
–
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
96
24
48
3
72
5
72
28
60
6a
6a
6a
6a
6a
6a
7a
7a
7a
–
91
–
Ͼ95
53
Ͼ95
94
94
92
–
Ti(OiPr)4
Ti(OiPr)2Cl2
Me3Al
Me2AlCl
Et2AlCl
Me2AlCl
Me2AlCl
Me2AlCl
63:37
–
50:50
88:12
56:44
89:11
89:11
88:12
4-Å mol. sieves
4-Å, mol. sieves,
Ph3PO
10
11
12
Me
Me
Me
Me2AlCl
Me3Al
Ti(OiPr)4
4-Å mol. sieves
4-Å mol. sieves
–
CH2Cl2
THF
THF
28
44
8
7a
7a
7a
87
80
85
89:11
76:24
66:34
[a] Reactions were carried out in the presence of 10 mol-% of the BINOLAM-MX catalyst generated in situ from a 1:1 mixture of
1
enantiopure ligand and co-catalyst. [b] Reactions were monitored by GC. [c] Isolated yield of pure crude compounds determined by H
NMR spectroscopy. [d] Determined by chiral HPLC (Daicel Chiralcel OD-H).
Eur. J. Org. Chem. 2006, 1949–1958
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1951

A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. M. Saá
FULL PAPER
Table 2. Synthesis of cyanocarbonates 7.
[a] Isolated yield of pure crude compounds determined by 1H NMR spectroscopy and GC. [b] Determined by chiral HPLC (Daicel
Chiralcel OD-H). [c] Reaction carried out with a recovered chiral ligand (R)-3. [d] Determined by chiral HPLC (Daicel Chiralpak AD).
[e] 500 mg of 4 Å MS were used with 0.25 mmol of aldehyde. [f] Determined by chiral GC (γ-cyclodextrin).
onylation. Thus, as in the case of cyanophosphorylations, trated in Scheme 3. We suspect that the minor, though rel-
we found that the attempted cyanoalkoxycarbonylation of evant, differences between the two reactions occur at the
benzaldehyde carried out with (S)-BINOL-AlCl, which turnover step, which in the case of the cyano O-alkoxycar-
lacks the amino arm, was completely unsuccessful (0% bonylation of aldehydes is a slow step, thereby facilitating
yield after 48 h). Moreover, the addition of a competing the occurrence of racemic hydrocyanations. In an attempt
external base such as triethylamine (20 mol-%) to the other- to address this possibility we carried out the standard reac-
wise standard reactions conditions lowered the enantiose- tion with an excess of methyl cyanoformate (10 equiv. rela-
lection of the reaction (7a was obtained in 65:35 er), while tive to the aldehyde), the result being an acceleration of the
simultaneously increasing the reaction rate (3 h, 99% yield), overall process. In support of this proposal we found that
consistently with the proposed hydrocyanation plus O-al- (S)-mandelonitrile 8a was transformed in the corresponding
koxycarbonylation mechanism. In support of the involve- derivative 7a by treatment with methyl cyanoformate
ment of HCN in the hydrocyanation step we found that: (1.2 equiv.) and triethylamine (1.2 equiv.) in THF at room
a) commercial methyl cyanoformate contains trace amounts temperature, in excellent chemical yield and enantiomeric
of hydrogen cyanide observable by 13C NMR (δ excess (Scheme 4).[23]
=109.8 ppm), b) addition of D2O gives rise to a triplet cen-
We explored some basic chemistry and functional group
tered at δ = 111.0 ppm, and c) a suspension of 4-Å mol. transformations undergone by the obtained chiral cyano-
sieves and methyl chloroformate shows a small peak cen- carbonates 7. To the best of our knowledge, only Shibasaki
tered at δ = 109.8 ppm. In addition, a positive nonlinear et al. have demonstrated that chiral β,γ-unsaturated cy-
effect (NLE)[18] was also observed for the enantioselective anohydrin O-carbonates undergo thermal [3,3]-sigmatropic
cyano O-alkoxycarbonylation of aldehydes, though weaker rearrangements, to afford optically active γ-oxy-α,β-unsatu-
than that observed in the corresponding asymmetric cyano rated nitriles.[6b] In search of chemoselective hydrolysis of
O-alkoxyphosphorylations.[10] The existence of all these the functional group-containing cyanocarbonates, we there-
common features for both types of reactions suggest a com- fore first studied the transformation of cyanocarbonate (R)-
mon mechanism characterized by a catalytic cycle involving 7i into the corresponding α-hydroxy ester (R)-9i which we
a BINOLAM-AlCl species 4 with a highly coordinated[19,20] achieved in 82% yield simply by heating at reflux in aque-
central aluminium atom (supported by the wide band cen- ous, acidic ethanol by the procedure described in the litera-
tered at δ = 47.5 ppm detected by 27Al NMR spec- ture for the total syntheses of epothilones A and B[17]
troscopy[21]) capable of coordinating both HCN (through (Scheme 5). The observed operations, namely alcoholysis of
the amino arm) and an aldehyde through a strong Al–O the cyano group and transesterification at the carbonate
interaction and a weaker H–Cl one (complex B),[22] as illus- moiety, must take place at quite different rates, as shown by
1952
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1949–1958

Enantioselective Synthesis of O-Methoxycarbonyl Cyanohydrins
FULL PAPER
89:11 er, by GC with γ-cyclodextrin) by use of a 1:1 mixture
of hydrochloric acid (12 ) and methanol at room tempera-
ture (Scheme 5). Analogously, compound 7n could be con-
verted into the corresponding O-protected hydroxy ester
10n in quantitative yield and with no apparent racemization
(90:10 er). Accordingly, hydrolysis of (R)-7a with concen-
trated hydrochloric acid either at room temperature or at
100 °C furnished the (R)-O-methoxycarbonyl mandelic acid
(R)-11a and the (R)-mandelic acid (R)-12a, respectively, in
quantitative yields in both cases (Scheme 5). No noticeable
racemization was observed (Scheme 6), in spite of the high
temperature of operation applied. The enantiomeric puri-
ties of (R)-9i and (R)-12a were determined by comparison
of their optical rotations with those reported in the litera-
1
ture, whilst that of (R)-11a was determined by H NMR
experiments with use of (S)-1-phenylethylamine as chiral re-
solving agent. The direct transformation of the cyano com-
pound (R)-7a into the corresponding amide (R)-13a was
achieved quantitatively under milder reaction conditions,[24]
namely treatment with a mixture of TMSCl/H2O at room
temperature (Scheme 5). Under identical conditions, the cy-
anohydrin derivative 7n yielded the amide 13n quantita-
tively (see Experimental Section). Their enantiomeric puri-
ties (expressed as er) were determined by chiral HPLC
analysis (Daicel Chiralcel OD-H). α-Hydroxyamides of this
kind and their derivatives are frequently encountered as
parts of natural products such as, for example, the neuro-
peptide antho-RNamide.[25]
Scheme 3.
Reduction of cyanocarbonate (R)-7a with lithiumalumin-
ium hydride and subsequent standard N-Boc protection
gave rise to enantiopure, N-Boc-protected β-amino alcohol
(R)-14a in good yield (Scheme 6), with complete retention
of configuration. The optical purity of carbamate (R)-14a
was evaluated by comparison of its optical rotation with
that described in the literature.[26] In contrast, reduction of
Scheme 4.
the fact that working at room temperature results in
alcoholysis only of the cyano group: cyanocarbonate (R)-
7a can be cleanly converted into the methyl ester of the (R)-
O-methoxycarbonyl mandelic acid (R)-10a (95% yield,
Scheme 5.
Eur. J. Org. Chem. 2006, 1949–1958
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1953

A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. M. Saá
FULL PAPER
for each compound, the major enantiomer being marked in bold
format). For flash chromatography Merck silica gel 60 (0.040–
0.063 mm) was employed.
General Procedure for the Synthesis of Chiral Cyanocarbonates 6
and 7: Dimethylaluminium chloride (1  solution in hexanes,
0.025 mmol, 25 µL) was added under argon to a suspension of (R)-
or (S)-BINOLAM[13a,28] (11.4 mg, 0.025 mmol) and molecular
sieves (4 Å, 200 mg per mmol aldehyde, previously dried at 120 °C
for 4 h) in anhydrous toluene (1 mL), and the resulting mixture
was stirred at room temperature for 1 h. The corresponding freshly
distilled aldehyde (0.25 mmol) and the appropriate cyanoformate
(1.5–7 equiv., see Table 1 and Table 2) were then added in that or-
der. The reaction mixture was then stirred for the time given in
Table 1 or Table 2. When the reaction was judged complete (moni-
toring by 1H NMR spectroscopy), aqueous HCl (2 , 2 mL) and
ethyl acetate (2 mL) were added, and stirring was continued for
10 min. The biphasic mixture was filtered through a celite pad and
the organic phase was separated, dried (MgSO4), and concentrated
under vacuum. The residue was purified by percolation through a
silica gel column, thereby affording pure compounds 6 and 7. At
this point, the acidic aqueous phase was treated with a buffered
solution (1  NH3/1  NH4Cl) and extracted with ethyl acetate
(2×10 mL). The organic phases were combined, dried (MgSO4),
and evaporated, thereby yielding back (R)- or (S)-BINOLAM
(11 mg, 96%).
Scheme 6.
7a with nickel() chloride in the presence of di-tert-butyl
dicarbonate[27] gave the overreduced N-Boc-phenethylamine
in very high yield (82%).
Conclusion
In summary, we have developed a one-pot asymmetric
synthesis of chiral cyanocarbonates in good chemical yield
and with good enantioselection by means of a catalytic,
enantioselective cyano O-alkoxycarbonylation of aldehydes.
Methyl cyanoformate was used rather than benzyl cyano-
formate because higher yields were obtained and also be-
cause the reaction was cleaner, avoiding secondary reaction
products. Reaction conditions are very mild and allow one
to work at room temperature, and the chiral ligand (BINO-
LAM), recovered unaltered upon workup, can be reused.
All available evidence is consistent with a catalytic cycle in-
volving enantioselective hydrocyanation promoted by BI-
NOLAM-AlCl, followed by a turnover-limiting step involv-
ing O-alkoxycarbonylation. This dual mechanism (sup-
ported by the poor results obtained when optically active
BINOL was used) is analogous to that proposed for the
BINOLAM-AlCl cyanophosphorylation.[10b] Enantiopure
cyanocarbonates are configurationally very stable com-
pounds (much more so than the analogous cyanophos-
phates), useful for accessing a variety of α-hydroxyacid de-
rivatives, by means of simple transformations, which exhib-
ited very interesting chemoselectivity and very good chemi-
cal yields.
(S)-2-(Benzyloxycarbonyloxy)-2-phenylacetonitrile (6a):[29] Color-
less oil. [α]2D5 = –9.1 (c = 1.0, CHCl3) (78% ee by HPLC, Daicel
Chiralcel OD-H,
λ = 254 nm, n-hexane/propan-2-ol, 99:1,
0.7 mL min–1, tr = 17.7 and 20.1 min). TLC: Rf = 0.79 (n-hexane/
1
ethyl acetate, 3:2). H NMR: δH = 5.26 (s, 2 H, CH2), 6.29 (s, 1 H,
CNCH), 7.40 (s, 5 H, ArH), 7.42–7.56 (m, 5 H, ArH) ppm. 13C
NMR: δC = 66.5 (CH2), 70.9 (CHCN), 115.6 (CN), 127.8, 128.4,
128.5, 128.6, 128.8, 129.2, 131.0, 134.0 (ArC), 154.9 (OCOO) ppm.
IR (neat): ν = 2252, 1758 cm–1. MS (EI): m/z (%) = 151 [M – 116]+
˜
(1), 117 (79), 107 (34), 91 (100), 77 (28). HRMS calcd. for
C16H13NO3: 267.0895; found 267.0920.
(S)-2-(Methoxycarbonyloxy)-2-phenylacetonitrile (7a):[30] Colorless
oil. [α]2D5 = –10.1 (c = 1.8, CHCl3) (78% ee by HPLC, Daicel Chi-
ralcel OD-H,
λ
=
254 nm, n-hexane/propan-2-ol, 99:1,
1.0 mL min–1, tr = 11.0 and 14.0 min). TLC: Rf = 0.70 (n-hexane/
1
ethyl acetate, 3:2). H NMR: δH = 3.87 (s, 3 H, CH3O), 6.27 (s, 1
H, CHCN), 7.47 (m, 3 H, ArH), 7.54 (m, 2 H, ArH) ppm. 13C
NMR: δC = 55.8 (CH3O), 66.5 (CHCN), 115.6 (CN), 127.8, 129.2,
Experimental Section
130.6, 131.1 (ArC), 154.0 (OCOO) ppm. IR (neat): ν = 2250,
˜
1759 cm–1. MS (EI): m/z (%) = 191 [M]+ (30), 116 (100), 105 (49),
General Remarks: Melting points were determined with a Reichert
Thermovar hot plate apparatus, and are uncorrected. IR spectra
were recorded with a Nicolet 510 P-FT instrument, and only the
structurally most relevant bands are listed. NMR spectra were per-
formed with Bruker AC 300 and DRX 500 machines, with CDCl3
as solvent and TMS as internal standard, unless otherwise stated.
Low-resolution electron impact (EI) mass spectra were obtained at
70 eV with a Shimadzu QP-5000 instrument, and low-resolution
electrospray ionization (ESI) mass spectra were obtained with a
Finnigan VG Platform. HRMS (EI) were recorded with a Finnigan
MAT 95S. Microanalyses were carried out by the Microanalyses
Service of the University of Alicante. Optical rotations were mea-
sured with a Perkin–Elmer 341 polarimeter. Analytical TLC was
performed on Schleicher & Schuell F1400/LS silica gel plates, and
the spots were visualized under UV light at 254 nm. Chiral GC
analysis were performed in an HP-5890 apparatus with a WCOT
γ-cyclodextrin column (0.25 µm thick), and chiral HPLC analysis
were run with a Shimadzu LC-10AD detector SPD-10A and a Ja-
sco 2000 series (the chiral column and wavelength used are given
89 (25). HRMS calcd. for C11H21NO2: 191.0582; found 191.0559.
(S)-2-(Methoxycarbonyloxy)-2-(4-methoxyphenyl)acetonitrile (7b):
Pale yellow oil. [α]2D5 = +24.7 (c = 2.0, CHCl3) (78% ee by HPLC,
Daicel Chiralcel OD-H, λ = 254 nm, n-hexane/propan-2-ol, 99:1,
1.0 mL min–1, tr = 14.9 and 19.5 min). TLC: Rf = 0.65 (n-hexane/
1
ethyl acetate, 3:2). H NMR: δH = 3.86, 3.88 (2×s, 6 H, PhOCH3,
COOCH3), 6.23 (s, 1 H, CHCN), 6.98 (d, J = 8.8 Hz, 2 H, ArH),
7.50 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C NMR: δC = 55.3, 55.8
(COOCH3, PhOCH3), 66.3 (CHCN), 114.8 (ArC), 115.8 (CN),
123.1, 129.6 (ArC), 154.0 (OCOO), 161.3 (ArCOCH3) ppm. IR
(neat): ν = 2244, 1758 cm–1. MS (EI): m/z (%) = 221 [M]+ (15),
˜
146 (100), 145 (92), 135 (11), 116 (11), 103 (12). HRMS calcd. for
C11H11NO4: 221.0688; found 221.0684.
(S)-2-(Methoxycarbonyloxy)-2-(2-naphthyl)acetonitrile (7c):[29] Col-
orless oil. [α]2D5 = +9.3 (c = 2.0, CHCl3) (70% ee by HPLC, Daicel
Chiralcel OD-H,
λ = 254 nm, n-hexane/propan-2-ol, 99:1,
1.0 mL min–1, tr = 27.2 and 29.7 min). TLC: Rf = 0.62 (n-hexane/
1954
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1949–1958

Enantioselective Synthesis of O-Methoxycarbonyl Cyanohydrins
FULL PAPER
1
ethyl acetate, 3:2). H NMR: δH = 3.89 (s, 3 H, OCH3), 6.44 (s, 1 113.6 (CN), 143.4 (OCCH), 145.2 (OCHCH), 153.8 (OCOO) ppm.
H, CHCN), 7.57 (m, 3 H, ArH), 7.90 (m, 3 H, ArH), 8.04 (s, 1 H,
ArH) ppm. 13C NMR: δC = 55.8 (COOCH3), 66.7 (CHCN), 115.6
(CN), 124.0, 127.0, 127.6, 127.7, 128.0, 128.2, 128.3, 129.4, 132.7,
IR (neat): ν = 2254, 1763 cm–1. MS (EI): m/z (%) = 181 [M]+ (18),
106 (100), 95 (14), 77 (40). HRMS calcd. for C8H7NO4: 181.0375;
found 181.0376.
˜
133.9, (ArC), 154.0 (OCOO) ppm. IR (neat): ν = 2249, 1770 cm–1.
˜
(2R,3E)-2-(Methoxycarbonyloxy)-3-methyl-4-(2-methyl-1,3-thiazol-
4-yl)but-3-enenitrile (7i): Colorless oil. [α]2D5 = –20.2 (c = 1.1,
CHCl3) (72% ee by HPLC, Daicel Chiralpak AD, λ = 254 nm, n-
hexane/propan-2-ol, 80:20, 1.0 mL min–1, tr = 14.7 and 17.3 min).
MS (EI): m/z (%) = 241 [M]+ (20), 165 (100), 156 (23), 139 (21),
127 (22). HRMS calcd. for C14H11NO3: 241.0739; found 241.0732.
(R)-2-(Methoxycarbonyloxy)-2-(6-methoxy-2-naphthyl)acetonitrile
(7d): Pale yellow oil. [α]2D5 = –10.4 (c = 1.0, CHCl3) (70% ee by
1
TLC: Rf = 0.55 (n-hexane/ethyl acetate, 3:2). H NMR: δH = 2.23
HPLC, Daicel Chiralcel OD-H, λ = 254 nm, n-hexane/propan-2-ol, (s, 3 H, CH3CCH), 2.65 (s, 3 H, CH3CN), 3.80 (s, 3 H, COCH3),
99:1, 1.0 mL min–1, tr = 23.7 and 27.0 min). TLC: Rf = 0.64 (n- 5.70 (s, 1 H, CHO), 6.68 (s, 1 H, NCHC), 7.06 (s, 1 H, SCHC) ppm.
hexane/ethyl acetate, 3:2). 1H NMR: δH = 3.88, 3.94 (2×s, 6 H,
COOCH3 and ArOCH3), 6.45 (s, 1 H, CHCN), 7.21 (m, 2 H, ArH),
7.53 (m, 1 H, ArH), 7.80 (m, 2 H, ArH), 7.96 (s, 1 H, ArH) ppm.
13C NMR: δC = 55.2, 55.8 (COOCH3 and ArCOCH3), 66.8
(CHCN) 105.6 (ArC), 115.7 (CCN), 119.9, 124.7, 125.8, 127.9,
128.0, 129.8, 135.4 (ArC), 154.0 (OCOO), 158.9 (ArC) ppm. IR
13C NMR: δC = 14.7 (CH3CHCH), 19.2 (CH3CN), 55.5 (OCH3),
70.3 (CNCHO), 115.0 (CN), 119.5 (SCH), 125.7 (NCCH), 128.5
(SCHC), 150.8 (CH3CCH), 154.0 (OCOO), 165.5 (CH3CS) ppm.
IR (neat): ν = 2256, 1762 cm–1. MS (EI): m/z (%) = 252 [M]+ (18),
˜
220 (33), 193 (62), 177 (100), 166 (34), 151 (10), 135 (55), 109 (20),
97 (63). HRMS calcd. for C11H12SN2O3: 252.0568; found 252.0568.
(neat): ν = 2254, 1774 cm–1. MS (EI): m/z (%) = 271 [M]+ (25), 207
˜
(2R,3E)-2-(Methoxycarbonyloxy)pent-3-enenitrile (7j): Pale yellow
oil. [α]2D5 = –9.2 (c = 2.0, CHCl3) (74% ee by HPLC, Daicel Chi-
ralpak AD, λ = 210 nm, n-hexane/propan-2-ol, 99:1, 1.0 mL min–1,
tr = 7.6 and 9.2 min.). TLC: Rf = 0.83 (n-hexane/ethyl acetate, 3:2).
1H NMR: δH = 1.83 (d, J = 6.6 Hz, 3 H, CH3CH), 3.87 (s, 3 H,
COCH3), 5.58–5.68 (m, 2 H, CHCN and CNCHCH), 6.22 (m, 1
H, CHCH=CH) ppm. 13C NMR: δC = 17.6 (CH3CH), 55.6
(25), 196 (100), 185 (10), 167 (17), 153 (54), 127 (37), 114 (9).
HRMS calcd. for C15H13NO4: 271.0844; found 271.0839.
(S)-2-(2-Chlorophenyl)-2-(methoxycarbonyloxy)acetonitrile (7e):
Colorless oil. [α]2D5 = –10.3 (c = 2.0, CHCl3) (36% ee by HPLC,
Daicel Chiralcel OD-H, λ = 254 nm, n-hexane/propan-2-ol, 99:1,
1.0 mL min–1, tr = 10.0 and 11.8 min). TLC: Rf = 0.70 (n-hexane/
1
ethyl acetate, 3:2). H NMR: δH = 3.89 (s, 3 H, CH3O), 6.62 (s, 1 (COCH3), 65.0 (CHCN), 115.2 (CN), 120.8 (OCHCH), 136.4
H, CHCN), 7.39–7.45 (m, 3 H, ArH), 7.71–7.74 (m, 1 H, (CH CH), 153.9 (OCOO) ppm. IR (film): ν = 2254, 1759 cm–1. MS
˜
3
ArH) ppm. 13C NMR: δC = 55.9 (CH3O), 63.7 (CHCN), 114.8
(EI): m/z (%) = 155 [M]+ (7), 96 (19), 80 (95), 69 (40), 59 (45), 53
(CN), 127.6, 128.8, 129.3, 130.1, 131.9, 133.3 (ArC), 153.7
(100). HRMS calcd. for C7H9NO3: 155.0582; found 155.0582.
(OCOO) ppm. IR (neat): ν = 2247, 1765 cm–1. MS (EI): m/z (%) =
˜
(2R,3E)-2-(Methoxycarbonyloxy)-4-phenylbut-3-enenitrile (7k):
Colorless oil. [α]2D5 = –11.6 (c = 1.0, CHCl3) (68% ee by HPLC,
Daicel Chiralcel OD-H, λ = 254 nm, n-hexane/propan-2-ol, 99:1,
0.5 mL min–1, tr = 39.1 and 42.1 min). TLC: Rf = 0.71 (n-hexane/
ethyl acetate, 3:2). 1H NMR: δH = 3.89 (COCH3), 5.90 (d, J =
6.8 Hz, 1 H, CHCN), 6.22 (dd, J = 16.0, 6.8 Hz, 1 H, CHCHCN),
7.00 (d, J = 16.0 Hz, 1 H, CHAr), 7.35–7.42 (m, 5 H, ArH) ppm.
225 [M]+ (3), 224 (25), 150 (100), 149 (76), 139 (72), 114 (42), 75
(16). HRMS calcd. for C10H8NClO3: 225.0192; found 225.0193.
(R)-2-(4-Chlorophenyl)-2-(methoxycarbonyloxy)acetonitrile (7f):
Pale yellow oil. [α]2D5 = –3.4 (c = 1.1, CHCl3) (80% ee by HPLC,
Daicel Chiralpak AD, λ = 254 nm, n-hexane/propan-2-ol, 90:10,
1.0 mL min–1, tr = 12.4 and 13.6 min). TLC: Rf = 0.72 (n-hexane/
1
ethyl acetate, 3:2). H NMR: δH = 3.90 (s, 3 H, CH3O), 6.26 (s, 1 13C NMR: δC = 55.8 (COCH3), 65.2 (CHCN), 115.0 (CN), 117.7
H, CHCN), 7.44–7.53 (m, 4 H, ArH) ppm. 13C NMR: δC = 55.9
(CH3O), 65.7 (CHCN), 115.2 (CN), 128.1, 129.2, 129.5, 130.8 (OCOO) ppm. IR (neat): ν = 2255, 1769 cm–1. MS (EI): m/z (%) =
(OCHCH), 127.2, 128.8, 129.5, 134.2 (ArC), 138.4 (PhCH), 154.0
˜
(ArC), 153.8 (OCOO) ppm. IR (neat): ν = 2254, 1760 cm–1. MS
217 [M]+ (5), 185 (8), 158 (44), 141 (100), 131 (18), 115 (84), 103
˜
(EI): m/z (%) = 225 [M]+ (3), 224 (25), 149 (98), 148 (100), 139 (18), 89 (10). HRMS calcd. for C12H11NO3: 217.0738; found
(40), 123 (17), 114 (42). HRMS calcd. for C10H8NClO3: 225.0192;
found: 225.0188.
217.0718.
(S)-2-(Methoxycarbonyloxy)-4-methylpent-3-enenitrile (7l): Color-
less oil. [α]2D5 = +26.5 (c = 0.88, CHCl3) (82% ee by HPLC, Daicel
Chiralpak AD, λ = 210 nm, n-hexane/propan-2-ol, 99:1,
0.5 mL min–1, tr = 11.3 and 12.5 min). TLC: Rf = 0.87 (n-hexane/
ethyl acetate, 3:2). 1H NMR: δH = 1.81, 1.83 (2×s, 6 H, 2 ×CCH3),
2-(Methoxycarbonyloxy)-2-(3-pyridyl)acetonitrile (7g): Colorless
oil. HPLC: Daicel Chiralpak AD, λ = 254 nm, n-hexane/propan-2-
ol, 99:1, 1.0 mL min–1, tr = 19.2 and 20.4 min. TLC: Rf = 0.17 (n-
hexane/ethyl acetate, 3:2). 1H NMR: δH = 3.90 (s, 3 H, OCH3), 6.32
(s, 1 H, CHCN), 7.43 (dd, J = 7.9, 4.8 Hz, 1 H, NCHCH), 7.92 (d, 3.85 (s, 3 H, OCH3), 5.39 (d, J = 9.2 Hz, 1 H, CCH), 5.87 (d, J =
J = 7.9 Hz, 1 H, CCH), 8.74 (d, J = 4.8 Hz, 1 H, NCH), 8.79 (s, 1
H, NCHC) ppm. 13C NMR: δC = 55.9 (OCH3), 64.2 (CHCN),
114.8 (CN), 123.8, 127.2, 135.3, 148.8, 151.6 (ArC), 153.6
9.2 Hz, 1 H, CHCN) ppm. 13C NMR: δC = 18.6, 25.6 (2×CCH3),
55.6 (COCH3), 61.6 (CHCN), 115.1 (CHCHCN), 116.0 (CN),
145.0 [(CH ) C], 154.1 (OCOO) ppm. IR (neat): ν = 2243,
˜
3
2
(OCOO) ppm. IR (neat): ν = 2247, 1767 cm–1. MS (EI): m/z (%) =
1759 cm–1. MS (EI): m/z (%) = 169 [M]+ (11), 94 (81), 83 (12),
77 (22), 66 (100). HRMS calcd. for C8H10NO3: 168.0660; found
168.0682.
˜
192 [M]+ (42), 137 (13), 133 (17), 117 (100), 106 (81), 90 (27), 78
(22), 63 (34), 51 (22). HRMS calcd. for C9H8N2O3: 192.0535,
found: 192.0539.
(2R,3E)-2-(Methoxycarbonyloxy)hex-3-enenitrile (7m):[2b,4c] Color-
less oil. [α]2D5 = –14.7 (c = 1.0, CHCl3) (72% ee by HPLC, Daicel
Chiralcel OD-H, λ = 210 nm, n-hexane/propan-2-ol, 99:1,
0.5 mL min–1, tr = 12.0 and 12.8 min). TLC: Rf = 0.77 (n-hexane/
(R)-2-Furyl-2-(methoxycarbonyloxy)acetonitrile (7h): Pale yellow
oil. [α]2D5 = +6.4 (c = 1.0, CHCl3) (44% ee by HPLC, Daicel Chi-
ralpak AD, λ = 210 nm, n-hexane/propan-2-ol, 99:1, 1.0 mL min–1,
tr = 12.9 and 14.6 min). TLC: Rf = 0.78 (n-hexane/ethyl acetate, ethyl acetate, 3:2). 1H NMR: δH = 0.92 (t, J = 7.3 Hz, 3 H,
3:2). 1H NMR: δH = 3.89 (s, 3 H, OCH3), 6.36 (s, 1 H, CHCN), CH2CH3), 1.46 (qt, J = 22.0, 7.3 Hz, 2 H, CH2CH3), 2.12 (m, 2 H,
6.46 (dd, J = 3.3, 1.9 Hz, 1 H, OCHCH), 0.75 (d, J = 3.3 Hz, 1 H,
OCCH), 7.53 (d, J = 1.9 Hz, 1 H, OCHCH) ppm. 13C NMR: δC
55.9 (COOCH3), 59.3 (CHCN), 111.1 (OCHCH), 113.0 (OCCH),
CH2CH2CH3), 3.86 (s, 3 H, OCH3), 5.55–5.69 (m, 2 H, CHCN and
CNCHCH), 6.18 (m, 1 H, CH2CH) ppm. 13C NMR: δC = 13.4
(CH3CH2), 21.4 (CH3CH2), 33.9 (CH3CH2CH2), 55.6 (COCH3),
=
Eur. J. Org. Chem. 2006, 1949–1958
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1955

A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. M. Saá
FULL PAPER
65.1 (CHCN), 115.2 (CN), 119.6 (CHCHCN), 141.2 (CH2CH), Tdetector = 260 °C, Tcolumn = 90 °C, 3 min, final temperature 180 °C,
153.9 (OCOO) ppm. IR (neat): ν = 2254, 1759 cm–1. MS (EI): m/z
rate 10 °C min–1, P = 120 kPa, tr = 21.2 and 21.5 min). TLC: Rf =
0.66 (n-hexane/ethyl acetate, 3:2). H NMR: δH = 1.18–1.23 (m, 5
˜
1
(%) = 183 [M]+ (0.01), 154 (8), 142 (18), 106 (100), 92 (39), 80 (70),
66 (28), 59 (52), 52 (37). HRMS calcd. for C9H13NO3: 183.0895;
found 183.0896.
H, Cy), 1.80–1.94 (m, 6 H, Cy), 3.86 (s, 3 H, OCH3), 5.04 (d, J =
5.7 Hz, 1 H, CHCN) ppm. 13C NMR: δC = 25.1, 25.1, 25.5, 27.6,
27.8, 40.0 (Cy), 55.6 (COCH3), 69.0 (CHCN), 115.6 (CN), 154.3
(2R,3E)-2-(Methoxycarbonyloxy)oct-3-enenitrile (7n): Colorless oil.
[α]2D5 = –12.0 (c = 2.0, CHCl3) (80% ee by HPLC, Daicel Chiralcel
OD-H, λ = 210 nm, n-hexane/propan-2-ol, 95:5, 0.5 mL min–1, tr =
9.6 and 10.8 min). TLC: Rf = 0.72 (n-hexane/ethyl acetate, 3:2). 1H
NMR: δH = 0.89 (t, J = 6.7 Hz, 3 H, CH3CH2), 1.25–1.30 (m, 4 H,
(OCOO) ppm. IR (neat): ν = 2247, 1762 cm–1. MS (EI): m/z (%)
˜
= 197 [M]+ (0.03), 115 (83), 83 (100), 55 (83). HRMS calcd. for
C10H15NO3: 197.1052; found 197.1060.
Synthesis of 7a from Enantioenriched Cyanohydrin 8: A mixture of
2×CH2), 1.40–1.45 (m, 2 H, CH2), 2.13 (m, 2 H, CH2CH), 3.86 (s, commercially available mandelonitrile (Ͼ98 % ee, 0.5 mmol,
3 H, OCH3), 5.54–5.61 (m, 1 H, CNCHCH), 5.66–5.68 (m, 1 H,
CHCN), 6.20 (dt, J = 14.6, 7.2 Hz, 1 H, CH2CH) ppm. 13C NMR:
δC = 13.8 (CH3CH2), 22.3, (CH3CH2), 27.8 (CH3CH2CH2), 31.1
59 µL), methyl cyanoformate (41 µL, 0.51 mmol), and triethyl-
amine (71 µL, 0.51 mmol) in THF (2 mL) was stirred at room tem-
perature for 1 h. Water (10 mL) and ethyl acetate (5 mL) were
(CHCH2CH2), 31.9 (CHCH2), 55.6 (COCH3), 65.1 (CHCN), 115.2 added and the resulting biphasic mixture was separated. The aque-
(CN), 119.4 (CNCHCH), 141.5 (CH2CH), 154.0 (OCOO) ppm. IR ous phase was extracted with ethyl acetate (2×5 mL), the combined
(neat): ν = 2249, 1763 cm–1. MS (EI): m/z (%) = 211 [M]+ (2), 154 organic layers were dried (MgSO4) and concentrated under vac-
˜
(34), 136 (22), 120 (31), 106 (38), 93 (46), 80 (99), 69 (57), 55 (100). uum, and the residue was percolated through a silica gel column,
HRMS calcd. for C11H17NO3: 211.1208; found 211.1212.
thereby yielding enantiomerically enriched (Ͼ98% ee) compound
7a in quantitative yield.
(R)-2-(Methoxycarbonyloxy)-3-phenylpropanenitrile (7o):[2b,4d] Col-
orless oil. [α]2D5 = –2.3 (c = 1.0, CHCl3) (34% ee by HPLC, Daicel
Chiralpak AD, λ = 254 nm, n-hexane/propan-2-ol, 99:1,
1.0 mL min–1, tr = 20.5 and 21.5 min). TLC: Rf = 0.78 (n-hexane/
Hydrolysis of Cyanocarbonate (R)-7i. Synthesis of Ethyl (2R,3E)-2-
[17b]
Hydroxy-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenoate (9i):
Compound 7i (63 mg, 0.25 mmol) was dissolved in ethanol (3 mL)
ethyl acetate, 3:2). 1H NMR: δH = 3.25 (d, J = 7 Hz, 2 H, CH2CH), and concentrated HCl (3 mL) was added. The resulting mixture
3.86 (s, 3 H, OCH3), 5.37 (t, J = 7.0 Hz, 1 H, CHCN), 7.28–7.42 was stirred at 90 °C for 5 h. A saturated aqueous solution
(m, 5 H, ArH) ppm. 13C NMR: δC = 38.5 (CH2CH), 55.7 (OCH3), of NaHCO3 (70 mL) was added and the ethanol was evaporated
65.5 (CHCN), 115.9 (CN), 127.9, 128.8, 129.5, 132.8 (ArC), 154.0
under vacuum. The aqueous phase was then extracted with ethyl
acetate (3×50 mL), the organic phase was dried (MgSO4), and the
solvents were evaporated. The residue was purified by flash column
chromatography, thereby affording pure compound 9i as a colorless
oil. [α]2D5 = –83.6 (c = 1.0, CHCl3, 72% ee), {ref.[17b] [α]2D5 = –116 (c
= 0.72, CHCl3, 99% ee)}. 1H NMR: δH = 1.29 (t, J = 7.0 Hz, 3 H,
CH2CH3), 2.07 (s, 3 H, CH=CCH3), 2.71 (s, 3 H, N=CCH3), 4.26
(q, J = 7.0 Hz, 2 H, CH2CH3), 4.65 (s, 1 H, CHOH), 6.64 (s, 1 H,
CH=CCH3), 7.00 (s, 1 H, N=CCH3) ppm. 13C NMR: δC = 14.0,
14.1 (CH2CH3, CH=CCH3), 19.1 (N=CCH3), 62.2 (CH2CH3), 76.8
(CHOH), 116.7 (SCH=C), 122.6 (CH=CCH3), 135.8 (CH=CCH3),
(OCOO) ppm. IR (neat): ν = 2244, 1754 cm–1. MS (EI): m/z (%) =
˜
146 [M – 59]+, 0.1, 129 (100), 103 (9), 91 (86). HRMS calcd. for
C11H11NO3: 205.0739; found 205.0734.
(S)-2-(Methoxycarbonyloxy)-4-phenylbutanenitrile (7p):[4c,31] Color-
less oil. [α]2D5 = –14.9 (c = 4.1, CHCl3) (58% ee from GC, WCOT
γ-CD, FS-Lipodex-E stationary phase, Tinjector = 250 °C, Tdetector
= 260 °C, Tcolumn = 90 °C, 10 min and 180 °C final temperature,
rate 10 °C min–1, P = 100 kPa, tr = 44.7 and 45.2 min.), {ref.[30]
[α]2D5 = –7.0 (c = 1.465, CHCl3)}. TLC: Rf = 0.71 (n-hexane/ethyl
1
acetate, 3:2). H NMR: δH = 2.27 (m, 2 H, CH2CH), 2.85 (t, J =
152.3 (SCH=C), 164.7 (N=CCH ), 173.3 (C=O) ppm. IR (neat): ν
˜
3
7.7 Hz, 2 H, CH2Ph), 3.87 (s, 1 H, OCH3), 5.14 (t, J = 6.8 Hz, 1
= 3039, 1510 cm–1.
H, CHCN), 7.17–7.32 (m, 5 H, ArH) ppm. 13C NMR: δC = 30.5
(CH2CH), 33.8 (CH2Ph), 55.7 (OCH3), 64.1 (CHCN), 116.2 (CN), Synthesis of Compounds 10. General Procedure: Concentrated HCl
126.7, 128.3, 128.7, 138.7 (ArC), 154.1 (OCOO) ppm. IR (neat): ν (2 mL) was added at 0 °C to a methanol solution (2 mL) of a cya-
˜
= 2249, 1759 cm–1. MS (EI): m/z (%) = 219 [M]+ (0.02), 143 (100), nocarbonate 7 (0.25 mmol). The mixture was then stirred at room
116 (32), 91 (42), 65 (11). HRMS calcd. for C12H13NO3: 219.0973; temperature until the reaction was judged complete by GC. The
found 119.0980.
methanol was then evaporated under vacuum and water (10 mL)
was added. The aqueous phase was then extracted with ethyl ace-
tate (2×10 mL), the organic phase being dried (MgSO4) and con-
centrated under vacuum, thus affording the pure compounds 10.
(S)-2-(Methoxycarbonyloxy)octanenitrile (7q):[2b,4d] Colorless oil.
[α]D25 = –43.9 (c = 2.0, CHCl3) [68% ee from GC, WCOT γ-CD statio-
nary phase FS-Lipodex-E, Tinjector = 250 °C, Tdetector = 260 °C,-
Tcolumn = 90 °C (3 min), final temperature 180 °C, rate 3 °C min–1,
P = 70 kPa, tr = 42.9 and 43.3 min]. TLC: Rf = 0.89 (n-hexane/
Methyl (R)-2-(Methoxycarbonyloxy)-2-phenylacetate (10a): Color-
less oil. [α]2D5 = –85.1 (c = 1.0, CHCl3) (77% ee from GC, WCOT
ethyl acetate, 3:2). 1H NMR: δH = 0.87 (t, J = 6.7 Hz, 3 H, γ-CD, stationary phase FS-Lipodex-E, Tinjector = 250 °C, Tdetector
CH2CH3), 1.29–1.38 (m, 6 H, 3×CH2), 1.44–1.54 (m, 2 H, CH2),
1.92 (dd, J = 15.5, 6.8 Hz, CH2CH), 3.84 (s, 3 H, OCH3), 5.18 (t,
= 260 °C, Tcolumn = 90 °C, 5 min, final temperature 180 °C, rate
10 °C min–1, P = 100 kPa, tr = 24.9 and 25.3 min). TLC: Rf = 0.66
1
J = 6.8 Hz, 1 H, CHCN) ppm. 13C NMR: δC = 13.8 (CH3CH2), (n-hexane/ethyl acetate, 3:2). H NMR: δH = 3.73, 3.83 (2×s, 6 H,
22.3 (CH3CH2), 24.2 (CH3CH2CH2), 28.3 (CH3CH2CH2CH2), 2×OCH3), 5.95 (s, 1 H, CHCN), 7.37–7.39 (m, 3 H, ArH), 7.45–
31.3 (CNCHCH2CH2), 32.2 (CNCHCH2), 55.6 (COCH3), 64.8 7.47 (m, 2 H, ArH) ppm. 13C NMR: δC = 52.7 (CCOOCH3), 55.2
(CHCN), 116.4 (CN), 154.2 (OCOO) ppm. IR (neat): ν = 2235, (OCOOCH3), 77.0 (PhCH), 127.5, 128.7, 129.4, 133.1 (ArC), 154.9
˜
1763 cm–1. MS (EI): m/z (%) = 200 [M + 1]+, (0.04), 140 (5), 115 (OCOOCH ), 168.9 (CCOOCH ) ppm. IR (neat): ν = 1750 cm–1.
˜
3
3
(12), 108 (14), 95 (57), 81 (84), 55 (100). HRMS calcd. for MS (EI): m/z (%) = 224 [M]+ (2), 192 (37), 165 (31), 121 (100), 105
C10H17NO3: 199.1208; found 199.1203.
(33), 91 (38), 77 (62), 59 (53). HRMS calcd. for C11H12O5:
224.0689; found 224.0684.
(R)-2-Cyclohexyl-2-(methoxycarbonyloxy)acetonitrile (7r):[4d,2c,29]
Colorless oil. [α]2D5 = +32.1 (c = 1.0, CHCl3) (56% ee from GC,
WCOT γ-CD stationary phase FS-Lipodex-E, Tinjector = 250 °C,
Methyl (2R,3E)-2-(Methoxycarbonyloxy)non-3-enoate (10n): Color-
less oil. [α]2D5 = –16.9 (c = 1.0, CHCl3) (80% ee from GC, WCOT
1956
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1949–1958

Enantioselective Synthesis of O-Methoxycarbonyl Cyanohydrins
FULL PAPER
γ-CD, stationary phase FS-Lipodex-E, Tinjector = 250 °C, Tdetector
= 260 °C, Tcolumn = 90 °C, 5 min, final temperature 180 °C, rate
5 °C min–1, P = 75 kPa, tr = 52.4 and 52.8 min). TLC: Rf = 0.78
(n-hexane/ethyl acetate, 3:2). 1H NMR δH: 0.88 (t, J = 6.7 Hz, 3 H,
tate). 1H NMR: δH = 0.88 (t, J = 6.6 Hz, 3 H, CH2CH3), 1.26–
1.42 (m, 6 H, 3×CH2), 2.04–2.09 (m, 2 H, CHCH2), 3.82 (s, 3 H,
COCH3), 5.39 (d, J = 7.2 Hz, 1 H, CHCONH2), 5.54 (dd, J = 15.3
and 7.2 Hz, 1 H, CH=CH), 5.93–6.03 (m, 1 H, CH=CH), 6.27,
CH2CH3), 1.26–1.44 (m, 6 H, 3 × CH2), 2.02–2.11 (m, 2 H, 6.66 (2×br.s, 2 H, NH2) ppm. 13C NMR: δC = 13.9 (CH2CH3),
CHCH2), 3.76, 3.80 (2×s, 6 H, 2 ×OCH3), 5.32 (d, J = 12.5 Hz, 1
22.3, 28.0, 31.2, 32.1 (4×CH2), 55.2 (OCH3), 77.5 (CHCONH2),
H, CHCO2CH3), 5.53 (dd, J = 15.2 and 7.2, 1 H, CH=CH), 5.92– 122.2, 138.8 (2 × CH=CH), 154.2 (OCOOCH3), 171.3 (CO-
5.97 (m, 1 H, CH=CH) ppm. 13C NMR: δC = 13.9 (CH2CH3), 22.3, ONH ) ppm. IR (KBr): ν = 3388, 3203, 1745–1715, 1668 cm–1. MS
˜
2
28.0, 31.1, 32.1 (4 × CH2 ), 52.4, 55.0 (2 × OCH3 ), 75.9 (EI): m/z (%) = 229 [M]+ (0.7), 166 (43), 165 (31), 122(15), 121 (71),
(CHCO2CH3), 121.0, 138.6 (2× CH=CH), 154.8 (OCOOCH3), 107 (18), 105 (22), 91 (34), 77 (68), 59 (34), 44 (100). Microanalysis
169.1 (CCOOCH ) ppm. IR (neat): ν = 1752, 1669 cm–1. MS (EI): required for C10H11O4N: C 57.6, H 8.4, N 6.1; found C 57.7, H
˜
3
m/z (%) = 244 [M]+ (0.3), 111 (12), 81 (12), 71 (100), 67 (34), 59
(50), 41 (72). HRMS calcd. for C12H20O5: 244.1308; found
244.1299.
8.2, N 6.0.
Synthesis of (R)-2-(tert-Butoxycarbonylamino)-1-phenylethanol
(14a):[26] LiAlH4 (190 mg, 5 mmol) was added in small portions at
0 °C to a stirred solution of compound (R)-7a (191 mg, 1 mmol) in
anhydrous THF (6 mL). The reaction mixture was stirred at room
temperature for 4 h, the reaction was quenched with water (1 mL),
di-tert-butyl dicarbonate was added (262 mg, 1.2 mmol), and the
stirring was continued overnight at room temperature. The THF
was evaporated and the residue was extracted with ethyl acetate
(2×10 mL). The collected organic phase was dried (MgSO4) and
concentrated to give a residue that was purified by flash
chromatography, thereby affording pure 14a as a colorless oil.
[α]2D5 = –4.4 (c = 1.5, EtOH) (78% ee). {ref.[26] [α]2D5 = +3.5 (c = 1.0;
EtOH, 99% ee)}. 1H NMR: δH = 1.42 [s, 9 H, C(CH3)3], 3.14–3.26,
3.40–3.45 (2×m, 2 H, CH2), 4.75–4.79 (m, 1 H, CHOH), 7.24–7.33
(m, 5 H, Ar) ppm.
Synthesis of (R)-2-(Methoxycarbonyloxy)-2-phenylacetic Acid
(11a):[32] A suspension of compound (R)-7a (191 mg, 1 mmol) in
concentrated HCl (3 mL) was stirred at room temperature for 19 h.
The reaction was basified with sodium hydrogen carbonate and
ethyl acetate was added (10 mL). The aqueous phase was acidified
with hydrochloric acid (2 ) and extracted with ethyl acetate
(2×10 mL). The collected organic phase was dried (Mg2SO4) and
evaporated, thereby affording crude pure compound 11a (201 mg,
96%) as colorless prisms. M.p. 122–124 °C (n-hexane/ethyl acetate).
[α]2D5 = –135.6 (c = 1.0, CHCl3) (78% ee, see text). TLC: Rf 0.31
1
(ethyl acetate). H NMR: δH = 3.82 (s, 3 H, OCH3), 5.87 (s, 1 H,
CHPh), 7.38–7.39 (m, 3 H, ArH), 7.46–7.47 (m, 2 H, ArH), 10.78
(s, 1 H, COOH) ppm. 13C NMR: δC = 55.4 (COCH3), 76.6
(CHCOOH), 127.5, 128.8, 129.6, 132.4 (ArC), 154.9 (OCOO),
174.2 (COOH) ppm. IR (KBr): ν = 3064, 1751, 1717 cm–1. MS
˜
Acknowledgments
(EI): m/z (%) = 166 [M – 44]+ (2), 136 (27), 122 (14), 107 (100), 91
(80), 77 (93), 51 (29). Microanalysis required for C10H10O5: C 57.1,
H 4.8; found C 57.2, H 4.7.
This work was supported by the DGES of the Spanish Ministerio
de Educación y Cultura (MEC) (BQU2001-0724, CTQ2004-02375/
BQU and CTQ2004-00808/BQU), by the Generalitat Valenciana
(CTIOIB/2002/320, GRUPOS03/134, GRUPOS05/11 and GV05/
144), and by the University of Alicante. A. Baeza also thanks the
Generalitat Valenciana for a predoctoral fellowship (CTBPRB/
2002/107).
Synthesis of (R)-Mandelic Acid (12a):[33] A suspension of com-
pound (R)-7a (191 mg, 1 mmol) in concentrated hydrochloric acid
(12 , 3 mL) was heated at reflux for 19 h. The reaction was basi-
fied with sodium hydrogen carbonate and ethyl acetate was added
(10 mL). The aqueous phase was acidified with hydrochloric acid
(2 ) and then extracted with ethyl acetate (2×10 mL). The organic
phase was dried (Mg2SO4) and evaporated, affording crude pure
compound 12a (142 mg, 95%) as colorless needles. [α]2D5 = –122.6
(c = 1, CHCl3) (78% ee), {ref.[31] [α]2D5 = –157 (c = 1, CHCl3, 99%
ee)}. 1H NMR: δH = 5.26 (s, 1 H, CH), 7.37–7.44 (m, 5 H,
ArH) ppm.
[1] For recent reviews, see: a) M. North, Synlett 1993, 807–820; b)
F. Effenberger, Angew. Chem. Int. Ed. Engl. 1994, 33, 1555–
1563; c) R. J. H. Gregory, Chem. Rev. 1999, 99, 3649–3682; d)
M. North, Tetrahedron: Asymmetry 2003, 14, 147–176; e) Syn-
thesis and Applications of Non-Racemic Cyanohydrins and α-
Amino Acids. Tetrahedron Symposium in Print (Ed.: M. North),
2004, 60, 10371–10568; f) M. North, Science of Synthesis (Ed.:
S.-I. Murahashi), vol. 19, pp. 235–284, Thieme, Stuttgart, 2004;
g) J.-M. Brunel, I. P. Holmes, Angew. Chem. Int. Ed. 2004, 43,
2752–2778; h) P. Poechlauer, W. Skranc, M. Wubbolts, Asym-
metric Catalysis on Industrial Scale. (Eds.: H. U. Blaser, E.
Schmidt). Wiley-VCH, Weinheim, 2004, pp. 151–164.
[2] For the preparation of racemic O-acylcyanohydrins see: a)
H. M. R. Hoffmann, Z. M. Ismail, R. Hollweg, A. R. Zein,
Bull. Chem. Soc., Jpn. 1990, 63, 1807–1810; b) M. Scholl, C.-
K. Lim, G. C. Fu, J. Org. Chem. 1995, 60, 6229–6231; c) M.
Okimoto, T. Chiba, Synthesis 1996, 1188–1190; d) A. Baeza, C.
Nájera, M. G. Retamosa, J. M. Sansano, Synthesis 2005, 2787–
2797.
[3] For the preparation of racemic cyanohydrin-O-phosphates see:
a) I. Micó, C. Nájera, Tetrahedron 1993, 49, 4327–4332 and
references cited therein; b) A. Baeza, C. Nájera, J. M. Sansano,
Arkivoc 2005, ix, 353–363.
[4] a) A. T. Au, Synth. Commun. 1984, 14, 743–748; b) D.-S. Shin,
Y.-S. Jung, J.-J. Kim, C. Ahn, Bull. Korean Chem. Soc. 1998,
19, 119–120; c) D. Berthiaume, D. Poirier, Tetrahedron 2000,
56, 5995–6003; d) D. R. Deardorff, C. M. Taniguchi, S. A.
Synthesis of Amides 13: Amides 13 were prepared by the procedure
reported in the literature.[24]
(R)-2-(Methoxycarbonyloxy)-2-phenylacetamide (13a): Colorless
prisms. M.p. 148–149 °C (ethyl acetate). [α]2D5 = –104.0 (c = 1,
CHCl3) (78% ee by HPLC, Daicel Chiralcel OD-H, λ = 254 nm,
n-hexane/propan-2-ol, 90:10, 1.0 mL min–1, tr = 27.7 and 30.7 min).
1
TLC: Rf = 0.62 (ethyl acetate). H NMR ([D6]DMSO): δH = 2.48
(s, 2 H, NH2), 2.94 (s, 3 H, OCH3), 4.83 (s, 1 H, CHCN), 6.21–
7.13 (m, 5 H, ArH) ppm. 13C NMR ([D6]DMSO): δC = 54.9
(OCH3), 77.6 (CHO), 127.3, 128.4, 128.7, 135,3 (ArC), 154.3 (CO-
OCH ), 169.4 (CONH ) ppm. IR (KBr): ν = 3439, 3179, 1760–
˜
3
2
1710 cm–1. MS (EI): m/z (%) = 209 [M]+ (0.7), 166 (43), 165 (31),
122 (15), 121 (71), 107 (18), 105 (22), 91 (34), 77 (68), 59 (34), 44
(100). Microanalysis required for C10H11O4N: C 57.4, H 5.3, N 6.7;
found C 57.1, H 5.2, N 6.5.
(R)-2-(Methoxycarbonyloxy)non-3-enamide (13n): Colorless prisms.
M.p. 93–94 °C. [α]2D5 = –60.5 (c = 1, CHCl3) (81% ee, from HPLC,
Daicel Chiralcel OD-H, λ = 254 nm, n-hexane/propan-2-ol, 90:10,
1.0 mL min–1, tr = 15.8 and 19.0 min.). TLC: Rf = 0.7 (ethyl ace-
Eur. J. Org. Chem. 2006, 1949–1958
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1957

A. Baeza, J. Casas, C. Nájera, J. M. Sansano, J. M. Saá
FULL PAPER
Tafti, H. Y. Kim, S. Y. Choi, K. J. Downey, T. V. Nguyen, J.
Org. Chem. 2001, 66, 7191–7194; e) X. Linghu, D. A. Nicewicz,
J. S. Johnson, Org. Lett. 2002, 4, 2957–2960; f) N. Thanasa, V.
Prachywarakorn, S. Tontoolarug, S. Ruchirawat, Tetrahedron
Lett. 2003, 44, 1019–1021.
[16] J. A. Joule, K. Mills, G. F. Smith, Heterocyclic Chemistry, 3rd
ed., Chapman & Hall, London, 1995, p. 371.
[17] a) D. Sawada, M. Shibasaki, Angew. Chem. Int. Ed. 2000, 39,
209–213; b) D. Sawada, M. Kanai, M. Shibasaki, J. Am. Chem.
Soc. 2000, 122, 10521–10532; c) Y. Hamashima, D. Sawada, H.
Nogami, M. Kanai, M. Shibasaki, Tetrahedron 2001, 57, 805–
814.
[18] For some recent reviews of NLE see, for example: a) C. Girard,
H. B. Kagan, Angew. Chem. Int. Ed. 1998, 37, 2922–2959; b)
D. R. Fenwick, H. B. Kagan, in: Topics in Stereochemistry (Ed.:
S. E. Denmark), John Wiley & Sons, New York, 1999, vol. 22,
pp. 257–296; c) D. Heller, H.-J. Drexler, C. Fischer, H. Busch-
mann, W. Baumann, B. Heller, Angew. Chem. Int. Ed. 2000, 39,
495–499; d) K. Soai, T. Shibata, I. Sato, Acc. Chem. Res. 2000,
33, 382–390; e) H. B. Kagan, Synlett 2001, 888–899; f) H. B.
Kagan, Adv. Synth. Catal. 2001, 343, 227–233.
[19] T. Aoi, K. Kagoshima, K. Maruoka, J. Am. Chem. Soc. 1997,
119, 5754–5755.
[20] The X-ray structure of the pentacoordinate BINOL-AlMe-
(THF) dimer complex has been described: T. Arai, H. Sasai,
K. Yamaguchi, M. Shibasaki, J. Am. Chem. Soc. 1998, 120,
441–442.
[21] D. A. Atwood, M. J. Harvey, Chem. Rev. 2001, 101, 37–52.
[22] E. J. Corey, T. W. Lee, Chem. Commun. 2001, 1321–1329.
[23] C. Duplais, F. Bures, I. Sapountzis, T. J. Korn, G. Cahiez, P.
Knochel, Angew. Chem. Int. Ed. 2004, 43, 2968–2970.
[24] M. K. Basu, F.-T. Luo, Tetrahedron Lett. 1998, 39, 3005–3006.
[25] a) T. Nemoto, H. Kakei, V. Gnanadesikan, S. Tosaki, T. Ohsh-
ima, M. Shibasaki, J. Am. Chem. Soc. 2002, 124, 14544–14545;
b) J. M. Concellón, E. Bardales, Org. Lett. 2003, 5, 4783–4785.
[26] A. M. Kawamoto, M. Aparecida, M. Wills, J. Chem. Com.,
Perkin Trans. 1 2001, 1916–1928.
[5] S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195–6196.
[6] a) J. Tian, N. Yamagiwa, S. Matsunaga, M. Shibasaki, Angew.
Chem. Int. Ed. 2002, 41, 3636–3638; b) J. Tian, N. Yamagiwa,
S. Matsunaga, M. Shibasaki, Org. Lett. 2003, 5, 3021–3024.
[7] a) Y. N. Belokon’, A. J. Blacker, L. A. Clutterbuck, M. North,
Org. Lett. 2003, 5, 4505–4507; b) S. Lundgren, E. Wingstrand,
M. Penhoat, C. Moberg, J. Am. Chem. Soc. 2005, 127, 11592–
11593.
[8] For reviews about bifunctional catalysis see: a) H. Gröger,
Chem. Eur. J. 2001, 7, 5246–5251; b) G. J. Rowlands, Tetrahe-
dron 2001, 57, 1865–1882; c) M. Shibasaki, M. Kanai, K. Fun-
abashi, Chem. Commun. 2002, 1189–1199; d) S. Matsunaga, T.
Ohshima, M. Shibasaki, Adv. Synth. Catal. 2002, 344, 3–15; e)
M. Kanai, N. Kato, E. Ichikawa, M. Shibasaki, Synlett 2005,
1491–1508.
[9] a) J. Casas, C. Nájera, J. M. Saá, J. M. Sansano, Org. Lett.
2002, 4, 2589–2592; b) J. Casas, C. Nájera, J. M. Saá, J. M.
Sansano, Tetrahedron Symposium in Print 2004, 60, 10487–
10496.
[10] For the firstly reported preparation of enantiomerically en-
riched cyanohydrin O-phosphates, see: a) A. Baeza, J. Casas,
C. Nájera, J. M. Sansano, J. M. Saá, Angew. Chem. Int. Ed.
2003, 42, 3143–3146; b) A. Baeza, C. Nájera, J. M. Sansano,
J. M. Saá, Chem. Eur. J. 2005, 11, 3849–3862.
[11] A. Baeza, C. Nájera, J. M. Sansano, J. M. Saá, Tetrahedron:
Asymmetry 2005, 16, 2385–2389.
[12] For a preliminary communication see: J. Casas, A. Baeza, J. M.
Sansano, C. Nájera, J. M. Saá, Tetrahedron: Asymmetry 2003,
14, 197–200.
[27] S. Caddick, D. B. Judd, A. K. de K. Lewis, M. T. Reich, M. R.
Williams, Tetrahedron 2003, 59, 5417–5423.
[28] Commercially available from MEDALCHEMY S. L.
[13] For synthetic applications of (S)- and (R)-BINOLAM 5, see:
a) As suitable phase-transfer catalysts for the enantioselective [29] K. Iwakami, Y. Hinakubo, T. Oriyama, Tetrahedron Lett. 2005,
alkylation of the aldimine Schiff bases of alanine esters, see: J.
Casas, C. Nájera, J. M. Sansano, J. González, J. M. Saá, M.
Vega, Tetrahedron: Asymmetry 2001, 12, 699–702; b) In the ad-
dition of diethylzinc to aldehydes, see: H. Kitajima, K. Iti, T.
Katsuki, Chem. Lett. 1996, 343–344; c) In the enantioselective
Simmons–Smith cyclopropanation, see: H. Kitajima, K. Ito, T.
Katsuki, Chem. Lett. 1995, 1113–1114; d) In the enantioselec-
46, 5881–5883.
[30] P. G. M. Wuts, S. W. Ashford, A. M. Anderson, J. R. Atkins,
Org. Lett. 2003, 5, 1483–1485.
[31] D. R. Deardorff, C. M. Taniguchi, A. C. Nelson, A. P. Pace,
A. J. Kim, A. K. Pace, R. A. Jones, S. A. Tafti, C. Nguyen, C.
O’Connor, J. Tang, J. Chen, Tetrahedron: Asymmetry 2005, 16,
1655–1661.
tive Michael additions, see: H. Kitajima, K. Ito, T. Katsuki, [32] R. T. Buck, D. M. Coe, M. J. Drysdale, C. J. Moody, N. D. Pe-
Tetrahedron 1997, 53, 17015–17028.
[14] E. M. Vogl, H. Gröger, M. Shibasaki, Angew. Chem. Int. Ed.
1999, 38, 1570–1577.
[15] Thermogravimetric analysis revealed that 4-Å mol. sieves dried
at 120 °C for 4 h contained 7.5% of water.
arson, Tetrahedron Lett. 1998, 39, 7181–7184.
[33] Dictionary of Organic Compounds, Chapman and Hall, New
York, 1982, 5th ed., vol. 3, p. 3270.
Received: November 30, 2005
Published Online: February 16, 2006
1958
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1949–1958