Synthesis of E-vinylogous (R)-amino acid derivatives via metal-catalyzed allylic substitutions on enzyme-derived substrates

Article abstract of DOI:10.1016/j.tetasy.2005.03.018

Oxynitrilase-derived allylic (R)-cyanohydrin carbonates 3 and allylic (R)-α-hydroxy ester carbonates 6 were examined as substrates for a palladium(0)-catalyzed allylic azidation reaction. The enantioselectivities and cis/trans diastereoselectivities of the concomitant 1,3-chirality transposition step were studied. The cyano carbonates 3a-c were found to be unimpressive substrates producing γ-azido-α,β-unsaturated nitriles 4a-c with cis/trans ratios that approached unity and gave enantiomeric excesses that ranged from 57% to 85%. In contrast, ester carbonates 6a and b were excellent substrates for the reaction exclusively affording trans substitution products 7a and b in identical enantiomeric excesses of 95% ee.

Full text of DOI:10.1016/j.tetasy.2005.03.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1655–1661
Synthesis of E-vinylogous (R)-amino acid derivatives via
metal-catalyzed allylic substitutions on enzyme-derived substrates
*
Donald R. Deardorff, Cullen M. Taniguchi, Anna C. Nelson, Andrew P. Pace,
Alexander J. Kim, Aaron K. Pace, Regan A. Jones, SanazA. Tafti, Charles Nguyen,
Caitlin OÕConnor, Judy Tang and Judy Chen
Department of Chemistry, Occidental College, Los Angeles, CA 90041, USA
Received 31 January 2005; accepted 9 March 2005
Available online 14 April 2005
Abstract—Oxynitrilase-derived allylic (R)-cyanohydrin carbonates 3 and allylic (R)-a-hydroxy ester carbonates 6 were examined as
substrates for a palladium(0)-catalyzed allylic azidation reaction. The enantioselectivities and cis/trans diastereoselectivities of the
concomitant 1,3-chirality transposition step were studied. The cyano carbonates 3a–c were found to be unimpressive substrates pro-
ducing c-azido-a,b-unsaturated nitriles 4a–c with cis/trans ratios that approached unity and gave enantiomeric excesses that ranged
from 57% to 85%. In contrast, ester carbonates 6a and b were excellent substrates for the reaction exclusively affording trans sub-
stitution products 7a and b in identical enantiomeric excesses of 95% ee.
ꢀ
2005 Elsevier Ltd. All rights reserved.
1
.Introduction
OCO Et
2
NCCO2Et
DABCO
R
O
R
CN
The enantioselective preparation of natural and unnatu-
ral amino acids has been the subject of intense funda-
mental research. Our own interest in this area grew
from the notion that c-azido-a,b-unsaturated nitriles
ought to provide straightforward access to c-amino-
a,b-unsaturated carboxylic acids, an intriguing family
of conformationally restricted amino acids. The incor-
poration of vinylogous amino acids into peptides, with
special attention toward conformational analysis and
1
N3
NaN3
R
CN
Pd(PPh3)4
2
,3
Scheme 1. Racemic preparation of c-azido-a,b-unsaturated nitriles.
4
5
6
structure, has been described. Recently, we reported
an efficient, two-step route to a racemic series of
c-azido-a,b-unsaturated nitriles (Scheme 1). The
methodology involves the concomitant cyanation—
ethoxycarbonylation of an a,b-unsaturated aldehyde
followed by a regiospecific palladium(0)-catalyzed allylic
azidation of the intermediate cyanohydrin carbonate.
The resulting c-azido substitution products were iso-
lated as cis/trans mixtures with the E-isomer in predom-
inance. Overall yields for the sequence exceeded 80%.
Herein we report our findings on an asymmetric variant
of this reaction series.
2.Results and discussion
2.1. Synthesis of (E)(R)-c-azido-a,b-unsaturated nitriles
Our overarching strategy for the enantioselective prepa-
ration of (R)-c-azido-a,b-unsaturated nitriles 4 blends
the natural enantioselectivity of enzymes with the rich
7
chemistry of p-allylpalladium. The enantioselective
pathway is outlined in Scheme 2. Although chirality is
initially induced at the aldehydic carbon using the
8
almond enzyme (R)-oxynitrilase, a subsequent palla-
dium-catalyzed allylic substitution step with an azide
9
ion repositions the stereocenter to the c-carbon. Table
1
lists the chemical yields and enantiomeric excesses as
*
0
Corresponding author. Tel.: +1 323 259 2763; fax +1 323 341 4912;
e-mail: deardorff@oxy.edu
well as other pertinent data for the intermediates and
products associated with the three-step sequence.
957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.018

1656
D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
N3
OH
CN
OCO2Et
CN
HCN
ClCO2Et
pyridine
TMSN3
+
cis-4
R
O
R
R
R
CN
oxynitrilase
Pd(PPh3)4
1
2
3
trans-4
Scheme 2. Enantioselective preparation of (R)-c-azido-a,b-unsaturated nitriles 4.
Table 1. Two-step conversion of a,b-unsaturated (R)-cyanohydrins 2 and (R)-a-hydroxy ethyl esters 5 into (R)-c-azido-a,b-unsaturated nitriles 4 and
esters 7 via a palladium(0)-catalyzed azidation of intermediate allylic carbonates 3 and 6, respectively
a
b
% Ee (yield /%)
a
b
% Ee (yield /%)
a,c
c-Azide
d
% Ee (yield /%)
e
Cyanohydrin
Carbonate
OH
OCO2Et
CN
N3
CN
>95 (91)
>95 (95)
CN
81 (87)
2
a
3a
trans-4a
OH
OCO Et
N3
2
CN
>95 (77)
>95 (77)
CN
>95 (87)
>95 (89)
CN
CN
85 (85)
57 (86)
2
b
c
3b
3c
trans-4b
OH
CN
OCO2Et
CN
N3
2
trans, trans-4c
OH
OCO2Et
CO2Et
N3
CO2Et
OH
>95 (88)
>95 (85)
>95 (91)
>95 (91)
CO2Et
7a
95 (85)
5
a
6a
OCO2Et
CO Et
N3
CO2Et
CO Et
95 (84)
2
2
5
b
6b
7b
a
25
D
Compounds 2, 3, and 4 are known compounds. Experimentally determined optical rotations for the nitrile products are: 2a: ½aŠ ¼ À27:8 (c
2
D
5
25
D
25
D
25
D
1.345, CHCl
CHCl
3
); 2b: ½aŠ ¼ À22:05 (c 1.680, CHCl
3
); 2c: ½aŠ ¼ À29:2 (c 1.275, CHCl
3
); 3a: ½aŠ ¼ À7:0 (c 1.465, CHCl
3
); 3b: ½aŠ ¼ À12:8 (c 1.370,
2
D
5
25
D
25
22
3
); 3c: ½aŠ ¼ À46:0 (c 1.155, CHCl
3
); 4a: ½aŠ ¼ À38:7 (c 1.870, CHCl
3
); 4b: ½aŠD ¼ þ16:0 (c 1.735, CHCl
3
); 4c: ½aŠD ¼ À6:9 (c 0.57, CHCl
3
).
For the specific rotations of ester products 5, 6, and 7 see Experimental.
Isolated yields.
b
c
Nitrile products are a mixture of E–Z isomers. Only the major E-isomer displayed.
Enantiomeric excess data for E-isomer only.
Yield data for nitrile products based upon combined mass of E–Z isomers.
d
e
1
0
15
Oxynitrilase [EC 4.1.2.10] is well suited for our needs
since it is convenient, robust, and accepts a wide range
H O (1:1) under these catalytic conditions are com-
2
pletely regioselective as reorganized c-azido-a,b-unsatu-
rated nitriles 4 are the only substitution products
isolated. The thermodynamic forces that favor conjuga-
tive overlap are apparently responsible for the observed
regiochemistry. In the current study, however, the
aqueous azidation procedure has been abandoned in
favor of the operationally more practical anhydrous
1
1
of substrates in organic solvents. Although the purified
enzyme is an article of commerce, we found it more pru-
dent to prepare fresh, active oxynitrilase from defatted
almond meal. This in-house enzyme preparation effi-
ciently catalyzed the asymmetric hydrocyanation of
unsaturated aldehydes 1 with HCN and oxynitrilase in
diisopropyl ether. (R)-Cyanohydrins 2 were isolated in
chemical yields that range from 77% to 91% and enan-
tiomeric excesses that exceed 95% in all cases (vide
infra).
1
6
1
2
1
7
conditions of TMSN in CH Cl .
3
2
2
2.2. Stereochemical investigations
The metal-catalyzed allylic substitution with an azide ion
is the linchpin reaction for the three-step sequence. Due
to the success of this methodology depending heavily on
the enantiofidelity of the 1,3-transposition machinery, a
clear understanding of this mechanism was warranted.
We decided to first examine the relative configurations
of transposed cis- and trans-c-azido isomers 4a following
the synthetic strategy outlined in Scheme 3. The reaction
Conversion of 2 into the corresponding cyanohydrin
carbonate 3 was executed in high yield without notice-
able loss of enantiopurity using ethyl chloroformate in
pyridine at 0 ꢁC. This observation was confirmed by
4
00 MHzNMR experiments on 3 complexed with an
1
3
Eu-derived chiral shift reagent. Previously, we re-
ported that these unsaturated carbonates 3 are excellent
substrates for palladium(0)-catalyzed allylic substitu-
1
8
sequence of the Staudinger reduction, Boc protection,
19
and conjugated double-bond reduction yielded both
1
4
tions. Azidations performed with NaN3 in THF–

D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
1657
saturated nitriles uneventfully. With opposite but argu-
ably identical rotations within the margins of standard
deviation, we concluded that the Boc-protected 4-amin-
opentanenitrile products were enantiomeric. Although
no assumptions could be drawn regarding their absolute
configurations based upon these experiments, there is
evidence in the literature that palladium-catalyzed azida-
bute the slightly lower specific rotation for the (S)-enan-
tiomer in Scheme 4 to the known isomerization
mechanisms that can plague N-protected a-amino
2
1
aldehydes.
NHBoc
NHBoc
9
tions reactions occur with retention of configuration.
O
NaH, THF
+
cis
CN
NC CH2 PO(OEt)2
(
S)-alaninal
-28.2
1
. PPh3,
wet THF
NHBoc
*
NHBoc
*
CN
NaBH4
cis-4a
Scheme 4. Stereochemical correlation study.
CN
CN
2
. Boc2O
MeOH
+127.5±±.4
+1.8±±.2
2.3. Proposed palladium(0)-catalyzed 1,3-chirality trans-
fer mechanism
1
. PPh3,
NHBoc
*
NHBoc
The preponderance of experimental evidence supports a
2
2
NaBH4
MeOH
wet THF
mechanism of dynamic p–r–p-isomerization between
two competing p-allylpalladium complexes as repre-
sented in Scheme 5. The process begins with the stereo-
selective oxidative addition of a reactive palladium(0)
catalyst to the (R)-trans-3 carbonate, which necessarily
leads to the corresponding syn–syn metal p-allyl com-
plex. The syn–syn nomenclature refers to the relation-
ship between the p-allylÕs two terminal substituents
and its methinyl hydrogen (not shown) on the middle
carbon. With the ejection of the carbonate anion, a
separate sequence of cascading events is set into motion:
First, the carbonate moiety decomposes into CO and
2
ethoxide rendering the step irreversible; second, the
liberated ethoxide attacks TMSN on silicon displacing
the azide ion; and lastly, the nucleophilic azide is
trapped by the cationic syn–syn p-allylpalladium com-
plex affording the (R)-trans-4 product. Since nucleo-
philic attack selectively occurs at the distal end of the
p-allyl system on the face opposite the metal, only the
c-substituted product of the (R)-configuration is obtain-
able via this route.
trans-4a
CN
*
2
. Boc2O
+34.7±±.2
-1.5±±.1
Scheme 3. Determination of relative configurations for cis- and trans-
a.
4
The absolute configurations of cis-4a and trans-4a were
unequivocally established with the stereochemical corre-
lation study illustrated in Scheme 4. Commercially avail-
able Boc-protected (S)-alaninal was reacted with the
Wittig reagent derived from the cyanomethyl phospho-
nate to afford predominantly the E-isomer of (S)-4-
tert-butoxycarbonylamino)pent-2-enenitrile. Direct
comparison of this nitrile with the other bracketed
nitrile in Scheme 3 revealed that these two compounds
also had opposite rotations. This outcome denoted the
2
3
2
0
3
(
(
R)-configuration for trans-4a, the rearranged azido
product. Accordingly, the minor product, cis-4a, was as-
signed the (S)-configuration by inference. Therefore, the
substitutive 1,3-chirality transfer proceeds with reten-
tion of configuration for the trans product—relative to
the displaced carbonate moiety—and with inversion of
configuration for the cis product. Incidentally, we attri-
The (S)-cis-4 product is accessible via the opposing
pathway that involves a p–r–p-interconversion mecha-
nism of equilibrating p-allylpalladium complexes. The
(R)-trans-3
PdL2
OCO2Et
N
N3
N3
H
L
C
L
H
H
H
H
C
N
R
C
N
R
R
R
H
Pd
Pd
L
L
(
R)-trans-4
syn-syn π-bound
σ-bound
L
L
L
L
Pd
C
Pd
H
N
H
NC
H
R
H
R
C
H
N3
N3
N
(
S)-cis-4
syn-anti π-bound
σ-bound
Scheme 5. Proposed palladium(0)-catalyzed 1,3-chirality transfer mechanism.

1658
D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
p-bound syn–syn complex is also in dynamic equilibrium
with its r-bound counterpart. A subsequent 180ꢁ rota-
tion about the single bond followed by regeneration of
the planar p-allyl species leads to the syn–anti orienta-
tion for the metal complex. In general, syn–anti struc-
tures are considered higher in energy than the
corresponding syn–syn versions due to increased steric
congestion in the bay region of the p-allyl. As a result,
E-products tend to dominate over the thermodynami-
cally less-favorable Z-products in palladium-catalyzed
allylic substitutions. In this case, however, the anti-sub-
stituent is a sleek, sp-hybridized cyano group that points
away from the other anti group—hydrogen—minimiz-
ing the steric interaction between the atoms. Since
nucleophilic attack upon the syn–anti complex leads
inescapably to the (S)-cis-4 isomer, we believe this struc-
tural anomaly accounts for the unexpectedly high per-
centage of the cis-isomer isolated from the reaction
mixture. We have omitted from our analysis any discus-
sion of the anti–anti p allyl since it would seem highly
unlikely that an appreciable population of this complex
would ever form.
the cis pathway. A synthetic plan was devised and imple-
mented according to Scheme 7. The conversion of (R)-
trans-cyanohydrins 2a and b into a-hydroxy esters 5a
2
6
and b with ethanolic HCl was accomplished in >80%
yield without observable racemization. Subsequent
ethoxycarbonylation of the a-hydroxy functions on 5a
and b once more configured the alkenes for the allylic
substitution step. To our delight, the palladium-cata-
lyzed azidation of 6a and b afforded the unsaturated c-
azido esters 7a and b with exclusive trans-diastereoselec-
tivity. This exciting result suggested that the problematic
p–r–p-isomerization mechanism had been controlled,
which lent support to our hypothesis.
The enantiopurities of the azido esters 7 were quantified
with the same reductive-amidation procedure used for
the azido nitriles 4. Excellent levels of enantiomeric
enrichment were achieved for esters 7a and b as corrobo-
rated by the identical values of 95% ee (see Table 1).
We believe that these outcomes provide consummate
proof-of-concept for this novel methodology. Moreover,
the simple one-pot transformation of azido esters 7 into
Boc-protected amino esters 8 (Scheme 8) ultimately val-
idates our contention that E-vinylogous (R)-amino acids
are accessible from a,b-unsaturated (R)-cyanohydrins.
The enantiomeric compositions of (R)-trans-4a–c were
unequivocally determined by the GC analysis of the cor-
2
4
responding Mosher-derived amides on an HP-101 cap-
illary column. The diastereomers were obtained via a
one-pot reductive amination-derivation sequence using
N3
NHBoc
2
5
the protocol of Evans et al. as described in Scheme
1. SnCl2
MeOH
2
R
CO2Et
R
CO2Et
6. Table 1 lists the enantiomeric excesses for (R)-trans-
4a–c, which ranged from a low of 57 to a high of only
85%. Clearly, the combination of disappointing enantio-
2. Boc O
7
a R = Me
8a R = Me, 86%
b R = Pr, 8±%
7b R = Pr
8
meric excesses and poor control over double-bond
stereochemistry compromises the usefulness of this
methodology. This prompted us to retreat from our
original strategy and seek an alternative tactic.
Scheme 8. Preparation of Boc-protected (E)-vinylogous (R)-amino
acid ethyl esters 8.
O
Ph
3.Conclusions
CF3
N3
C
HN
C
1
. SnCl2, MeOH
. (S)-(-)-MTPA-Cl, Et3N
OMe
CN
We have investigated the enantiofidelity of palladium-
catalyzed allylic substitution/azidation reactions that in-
volve the transfer of chirality across the p-allyl systems
of conjugated nitriles and esters. Oxynitrilase-derived
allylic (R)-cyanohydrin carbonates 3 and allylic (R)-a-
hydroxy ester carbonates 6 were found to be efficient
progenitors of asymmetry to chiral p-allylpalladium
complexes. Although allylic carbonates 3 and 6 afforded
c-azido products 4 and 7 in high chemical yields,
the enantioselectivities and cis/trans diastereoselectivities
of these compounds varied greatly. The nitrile sub-
strates 3a–c accrued some disappointing results in both
categories. On the other hand, ester substrates 6a and b
gave superior results as underscored by the duplicate
values of 95% ee and exclusively trans double bond
R
CN
2
R
Scheme 6. One-pot reductive amidation of (R)-trans-4 with (À)-
MosherÕs acid chloride.
2
esters
.4. Synthesis of (E)(R)-c-azido-a,b-unsaturated ethyl
We were confident that the putative syn–anti p-complex
was at the root of our problems. We surmised that a
2
more bulky group, such as an sp -hybridized alkoxycar-
bonyl moiety, in place of the linear cyano function
would raise the energy of the p-allyl complex disfavoring
OH
CN
OCO Et
N3
OH
CO Et
2
TMSCl
EtOH
ClCO2Et
pyridine
TMSN3
R
R
R
CO Et
(dba) Pd
2
2
3
2
R
CO2Et
PPh3
2
5
6
7
Scheme 7. Enantioselective preparation of (E)(R)-c-azido-a,b-unsaturated ethyl esters 7.

D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
1659
geometries. Moreover, stereochemical correlation experi-
ments clearly showed that the (R)-configurational asym-
metry initially induced by oxynitrilase in the aldehydic
carbon was faithfully transmitted to the c-azido position
of trans products. Finally, through the judicious replace-
ment of a linear cyano function with a trigonal ester
moiety, we ostensibly shifted the equilibrium of the p–
r–p isomerization mechanism to a point where only
trans products were realized. The broader significance
of this new methodology and its application to natural
products synthesis are currently under investigation.
was wetted with 0.02 M pH 5.5 citrate buffer (6 mL).
The resulting thick paste was pressed against the side
of the flask and crotonaldehyde (1.5 mL, 1.25 g,
17.8 mmol) then added dropwise to the paste. The iso-
propyl ether/HCN solution was carefully poured into
the flask containing the almond mixture to initiate the
reaction. The flask was partially submerged in a 2 ꢁC
constant-temperature bath and monitored via TLC
(3:1 hexanes/EtOAc; Rf 0.33). After approximately
12 h, the reaction mixture was diluted by the addition
of ethyl ether (15 mL) and passed through a short plug
of SiO layered with MgSO (1:4 MgSO /SiO ). The fil-
2
4
4
2
trate was concentrated in vacuo via rotary evaporation
and the crude oil purified via radial chromatography
4.Experimental
(4 mm SiO plate; 4:1 hexanes/EtOAc) to afford 1.25 g
(72%) of colorless, clear oil.
2
4
.1. General methods
All reactions were carried out under nitrogen or argon
unless otherwise indicated. Aldehydes were purchased
from commercial sources, distilled, and stored under
nitrogen. Reagent grade solvents were further purified
by simple distillation under nitrogen as follows: MeOH
and EtOH were distilled from magnesium turnings and
iodine, pyridine and CH Cl were refluxed and distilled
Unsaturated cyanohydrins 2a, 2b, and 2c have been pre-
2
viously prepared with oxynitrilase.
7,28
4.3. Representative example for the preparation of
unsaturated ethyl carbonates 3 and 6 from cyanohydrins 2
and a-hydroxyesters 5, respectively
2
2
from CaH , and THF was distilled from a deep blue
2
4.3.1. Ethyl (E)(R)-2-hydroxypent-3-enoate ethyl carbon-
ate 6a. To an ice-cold, stirred solution (1 M) of a-
hydroxyester 5a (1.25 g, 8.66 mmol) in freshly distilled
pyridine was added dropwise (ꢀ4 drops/min) ethyl chlo-
roformate (0.50 mL, 1.89 g, 17.3 mmol). The tempera-
ture was maintained at 0 ꢁC and the reactionÕs
progress monitored via TLC (6:1 hexanes/EtOAc) until
judged complete after 45 min. The reaction mixture
was quenched by dilution with ether (50 mL). The or-
ganic layer was washed with saturated solutions of
solution of sodium benzophenone ketyl. TMSCl was
distilled as needed and ethyl chloroformate was used
as received. NMR spectra were acquired at 300 or
400 MHzon Bruker Avance spectrometers with CDCl 3
as the solvent. Optical rotations were measured in
CHCl on a JASCO 360-DIP polarimeter in water-jack-
3
eted microcells and FTIR spectra were collected on a
model 8300 Shimadzu spectrophotometer. Diastereo-
meric ratios of the Mosher-derived amides were deter-
mined on a Hewlett-Packard Series II 5890 gas
chromatograph equipped with a 25 m · 0.2 mm o.d.
HP-101 capillary column. TLC analyses were done on
glass-backed silica plates coated with a 0.25 mm
thickness of silica gel 60 F254 from J. T. Baker. Chro-
matographic separations were performed on silica
gel-coated glass rotors (1, 2, or 4 mm layers) via radial
chromatography on a Harrison Research Chromato-
tron. Elemental analyses were obtained at Desert Ana-
lytics and HRMS spectra were recorded at the
University of California, Riverside Mass Spectrometry
Facility.
NH Cl (3 · 15 mL), 0.1 M HCl (3 · 15 mL), and NaCl
4
(1 · 15 mL). The organic phase was dried over MgSO ,
4
concentrated in vacuo, and the crude oil purified via
radial chromatography (4 mm SiO plate, 7:1 hexanes/
2
EtOAc) to afford 1.7 g (91%) of colorless, clear oil. Rf
0.39 (SiO ; 6:1 hexanes/EtOAc); bp (bulb-to-bulb)
2
2
5:0
1
70 ꢁC at 0.50 Torr; ½aŠ ¼ À52:1 (c 1.428, CHCl ); H
D
3
NMR d 6.00 (ddq, J = 0.9, 6.6, 15.3 Hz, 1H), 5.57
(ddq, J = 1.5, 7.2, 15.3 Hz, 1H), 5.29 (ddq, J = 0.9, 0.9,
7.2, 1H), 4.29–4.19 (m, 4H), 1.76 (ddd, J = 0.9, 1.5,
6.6 Hz, 3H), 1.3133 (t, J = 7.2 Hz, 3H), 1.29 (t,
J = 7.2 Hz, 3H); C NMR d 168.7, 154.2, 133.4,
1
22.6, 75.9, 64.5, 61.6, 17.8, 14.1, 14.0; IR (film) 2985,
À1
CAUTION: Azido compounds may represent an explo-
sion hazard when concentrated under vacuum or stored
neat. A safety shield and appropriate handling proce-
dures are recommended.
1755, 1683, 1278, 1195 cm
C H O : C, 55.55; H, 7.46. Found: C, 55.27; H,
;
Anal. Calcd for
1
0
16
5
7.46.
4.3.2. Ethyl (E)(R)-2-hydroxyhept-3-enoate ethyl carbon-
ate 6b. R 0.35 (SiO ; 6:1 hexanes/EtOAc); bp (bulb-to-
4
.2. General procedure for the preparation of cyanohy-
f
2
25:0
drins 2 via asymmetric hydrocyanation of unsaturated
aldehydes 1 with HCN and oxynitrilase
bulb) 90 ꢁC at 0.65 Torr; ½aŠ ¼ À55:4 (c 1.705,
D
1
CHCl ); H NMR d 5.90 (dt, J = 7.2, 15.2 Hz, 1H),
3
5.48 (dd, J = 7.2, 15.2 Hz, 1H), 5.21 (d, J = 7.2 Hz,
4
.2.1. (E)(R)-Crotonaldehyde cyanohydrin 2a. An ice-
cold solution of KCN (6 g, 107.1 mmol) in water
45 mL) was acidified with HCl (6 M, 6 mL) to a pH
1H), 4.20–4.11 (m, 4H), 2.00 (dt, J = 7.2, 7.6 Hz, 2H),
1.4–1.3 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H) 1.20 (t,
1
3
(
J = 7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H); C NMR d
170.0, 155.3, 139.2, 122.4, 76.5, 65.0, 62.1, 34.6, 21.9,
of 1. The solution was extracted (3 · 15 mL) with iso-
propyl ether, and the organic layers collected. In a sep-
arate Erlenmeyer flask, almond meal (6 g, ground to a
fine powder and defatted with three washes with EtOAc)
À1
14.3, 14.2, 13.7; IR (film) 2941, 1751, 1373, 1028 cm
Anal. Calcd for C H O : C, 59.00; H, 8.25. Found:
;
1
2
20
5
C, 58.88; H, 8.25.

1660
D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
4
.4. General procedure for the preparation of c-azido
1H), 5.38 (ddq, J = 1.6, 6.0, 15.2 Hz, 1H), 4.59 (t,
J = 6.0 Hz, 1H), 4.3–4.22 (m, 2H), 2.88 (d, J = 6.0 Hz,
1H), 1.75 (dt, J = 1.6, 6.4 Hz, 3H), 1.36 (t, J = 7.2 Hz,
compounds 4 and 7 via a palladium(0)-catalyzed allylic
azidation of carbonates 3 and 6 with TMSN in CH Cl
2
3
2
1
3
3
1
H); C NMR d 175.1, 130.5, 128.3, 72.0, 62.5, 18.0,
4.4; IR (film) 3477, 2983, 1726, 1683, 1449, 1208,
À1
4
.4.1. Ethyl (E)(R)-4-azidopent-2-enoate 7a. To an ice-
cold, stirred 0.3 M solution of allylic carbonate 6a
107 mg, 0.535 mmol), TMSN3 (0.11 mL, 92.4 mg,
.80 mmol), and PPh (8.4 mg, 0.032 mmol) in freshly
1141 cm ; HRMS (DCI/NH ) calcd for C H NO
3
7
16
3
+
(MNH ) 162.1126, found 162.1130.
4
(
0
4.5.2. Ethyl (E)(R)-2-hydroxyhept-3-enoate 5b. R 0.20
f
3
distilled CH Cl was added catalytic DBA Pd
2
(SiO ; 6:1 hexanes/EtOAc); bp (bulb-to-bulb) 65 ꢁC at
2
3
2
2
25:4
1
(
7.4 mg, 0.008 mmol) in a single portion. The reaction
0.70 Torr; ½aŠ ¼ À60:75 (c 1.515, CHCl ); H NMR
D
3
was maintained at 0 ꢁC and monitored via TLC (SiO ,
d 5.89 (ddt, J = 1.2, 6.8, 15.2 Hz, 1H), 5.51 (ddt,
J = 1.2, 6.0, 15.2 Hz, 1H), 4.59 (d, J = 5.2 Hz, 1H),
4.23–4.29 (m, 2H), 2.91 (br s, 1H), 2.08–2.02 (m, 2H),
1.42 (tq, J = 7.2, 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H),
2
1
:1 CH Cl /hexanes). After 1.5 h, the reaction was di-
2 2
luted by the addition of ether and the resulting slurry
passed through a short plug of SiO layered with MgSO
2
4
1
3
(
MgSO /SiO , 1:4) with additional ether. The filtrate
4
0.91 (t, J = 7.2 Hz, 3H); C NMR d 175.0, 135.3,
127.2, 71.9, 62.3, 34.5, 22.2, 14.3, 13.7; IR (film) 3470,
2
was concentrated in vacuo via rotary evaporation, and
the crude oil was purified via radial chromatography
À1
2961, 2874, 1737, 1684, 1209, 1109 cm ; HRMS
(DCI/NH ) calcd for C H NO (MNH ) 190.1448,
found 190.1443.
+
(
2 mm SiO plate; 1:1 CH Cl /hexanes) to afford 70 mg
2
2
2
3
9
20
3
4
(
84%) of colorless clear oil. R 0.35 (SiO ; 1:1 hexanes/
f
2
CH Cl ); bp (bulb-to-bulb) 47 ꢁC at 0.50 Torr;
2
5:5
2
2
1
½
aŠ ¼ À13:0 (c 0.89, CHCl ); H NMR d 6.78 (dd,
4.6. General procedure for the preparation of Boc-carba-
mates 8a and 8b via a one-pot azido reduction-derivation
sequence on c-azido-a,b-unsaturated ethyl esters 7a and 7b
D
3
J = 6.0, 15.6 Hz, 1H), 5.98 (dd, J = 1.6, 15.6 Hz, 1H),
.18 (q, J = 7.2 Hz, 2H), 4.11–4.20 (m, 1H), 1.33 (d,
4
1
3
J = 6.8 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); C NMR d
1
2
65.8, 145.4, 122.2, 60.7, 57.4, 19.1, 14.2; IR (film)
.
4.6.1. Ethyl (E)(R)-4-(tert-butoxycarbonylamino)hept-2-
enoate 8b. To a stirred solution (0.1 M) of c-azido ester
À1
984, 2112, 1720, 1661, 1271 cm
7
b (200 mg, 1.02 mmol) in freshly distilled methanol was
4
.4.2. Ethyl (E)(R)-4-azidohept-2-enoate 7b. R 0.40
f
added SnCl2 (385 mg, 2.03 mmol). The reaction was
monitored via TLC (6:1 hexanes/EtOAc) for the disap-
pearance of the starting material. After 3 h, the reduction
was deemed complete and the slurry concentrated in
vacuo via rotary evaporation until a foamy oil appeared.
When this crude material had dissolved in freshly dis-
tilled 1,4-dioxane (9.2 mL, 0.11 M), an aqueous solution
(
SiO ; 1:1 hexanes/CH Cl ); bp (bulb-to-bulb) 50 ꢁC at
2
2
2
25:2
1
0
6
1
1
.50 Torr; ½aŠ ¼ 20:0 (c 1.56, CHCl ); H NMR d
D
3
.79 (dd, J = 6.8, 15.6 Hz, 1H), 6.02 (dd, J = 1.2,
5.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.05–3.98 (m,
H), 1.63–1.56 (m, 2H), 1.50–1.35 (m, 2H), 1.31 (t,
1
3
J = 6.8 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); C NMR d
1
IR (film) 2963, 2104, 1724, 1659, 1271, 1178, 1040 cm
66.9, 145.6, 123.8, 62.9, 61.2, 36.3, 19.1, 14.4, 13.8;
.
(1 mL, 1 M) of NaHCO (342 mg, 4.06 mmol, 4 equiv)
3
À1
was added in a single portion. After stirring for several
minutes, 1.5 equiv of di-tert-butyldicarbonate (332 mg,
1.52 mmol) were added and the reaction again moni-
tored via TLC (6:1 hexanes/EtOAc). The reaction was
judged complete after 22 h and quenched by dilution
with EtOAc and water. The stirred mixture was acidified
4
.5. Representative example for the preparation of b,c-
unsaturated a-hydroxy ethyl esters 5a and 5b from a,b-
unsaturated cyanohydrins 2
4
.5.1. Ethyl (E)(R)-2-hydroxypent-3-enoate 5a. To an
ice-cold, stirred 2 M solution of cyanohydrin 2a
255 mg, 2.62 mmol) in freshly distilled EtOH was added
to pH 1 with 2 M NaHSO , and the aqueous phase ex-
4
tracted with EtOAc (3 · 15 mL). The combined organic
extracts were washed with saturated solutions of NaH-
(
TMSCl (0.565 mL, 478 mg, 3.94 mmol) dropwise. The
reaction was maintained at 0 ꢁC and monitored via
TLC (6:1 hexanes/EtOAc) for the disappearance of
starting material. After the reaction was deemed com-
plete (ꢀ21 h), the mixture was diluted with the addition
of ether (15 mL) and the insoluble imine salt hydrolyzed
by the addition of water (0.25 mL). The aqueous phase
was extracted with ether (3 · 15 mL) and the combined
extracts washed with brine (1 · 10 mL) and then dried
CO (1 · 15 mL) and NaCl (1 · 15 mL). Concentration
3
under reduced pressure, followed by radial chromato-
graphy (2 mm SiO plate, 7:1 hexanes/EtOAc) afforded
2
216 mg (80%) of colorless oil that crystallized at 0 ꢁC.
R 0.30 (SiO ; 5:1 hexanes/EtOAc); bp (bulb-to-bulb)
f
2
2
5
1
90 ꢁC at 0.45 Torr; ½aŠ ¼ þ15:5 (c 1.36, CHCl ); H
D
3
NMR d 6.83 (dd, J = 5.2, 15.6 Hz, 1H), 5.89 (dd,
J = 1.6, 15.6 Hz, 1H), 4.57 (d, J = 8.0 Hz, 1H), 4.28 (s,
1H), 4.21–4.13 (m, 2H), 1.43 (s, 9H), 1.6–1.3 (m, 4H),
1
3
over MgSO . The organic phase was passed through a
1.27 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.2 Hz, 3H);
C
4
short plug of SiO layered with MgSO (MgSO /SiO ,
2
1:4) with additional ether, and the filtrate concentrated
in vacuo via rotary evaporation. The crude oil was puri-
NMR d 166.6, 155.3, 148.8, 120.7, 79.8, 60.6, 51.4,
36.9, 28.5, 19.1, 14.4, 13.9; IR (neat) 3350, 2978, 2875,
4
4
2
À1
1726, 1653, 1281, 1170 cm ; HRMS (DCI/NH ) calcd
3
+
for C H N O (MNH ) 289.2137, found 289.2127.
fied via radial chromatography (2 mm SiO plate; 4:1
2
14 29
2
4
4
hexanes/EtOAc) to afford 325 mg (88%) of colorless,
clear oil. R 0.19 (SiO ; 6:1 hexanes/EtOAc); bp (bulb-
4.6.2. Ethyl (E)(R)-4-(tert-butoxycarbonylamino)pent-2-
29
enoate 8a.
f
2
25:6
to-bulb) 47 ꢁC at 0.55 Torr; ½aŠ ¼ À70:4 (c 1.50,
Rf 0.30 (SiO ; 5:1 hexanes/EtOAc);
2
D
1
25
1
CHCl ); H NMR d 5.92 (ddq, J = 1.6, 6.4, 15.2 Hz,
½aŠD ¼ þ20:7 (c 1.78, CHCl ); H NMR d 6.85 (dd,
3
3

D. R. Deardorff et al. / Tetrahedron: Asymmetry 16 (2005) 1655–1661
1661
J = 4.8, 15.6 Hz, 1H), 5.87 (dd, J = 1.6, 15.6 Hz, 1H),
4
C.; Geneve, S.; Claudel, S.; Coutrot, P.; Marraud, M.
Tetrahedron Lett. 2003, 44, 2297–2300; (e) Chakraborty,
T. K.; Ghost, A.; Kumar, S. K.; Kunwar, A. C. J. Org.
Chem. 2003, 68, 6459–6462.
. Deardorff, D. R.; Taniguchi, C. M.; Tafti, S. A.; Kim, H.
Y.; Choi, S. Y.; Downey, K. J.; Nguyen, T. V. J. Org.
Chem. 2001, 66, 7191–7194.
.49 (br s, 1H), 4.38 (br s, 1H), 4.7 (q, J = 6.8 Hz,
H), 1.42 (s, 9H), 1.26 (t, J = 6.8 Hz, 3H), 1.24 (d,
2
1
3
J = 6.8 Hz, 3H); C NMR d 167.3, 155.8, 150.3,
6
7
8
1
2
20.7, 80.1, 60.7, 47.2, 28.4, 20.3, 14.2; IR (neat) 3353,
979, 2935, 1725, 1653, 1277, 1173, 1047 cm
À1
.
. (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley
& Sons: Chichester, 1995; pp 290–422; (b) Trost, B. M. J.
Org. Chem. 2004, 69, 5813–5837.
Acknowledgments
. For reviews see: (a) North, M. Synlett 1993, 807–820; (b)
Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33,
The authors would like to thank the donors of the Petro-
leum Research Fund, administered by the American
Chemical Society for support of this work. A.P.P. is the
grateful recipient of an award from the Arnold and Mabel
Beckman Scholars Program. A.C.N., A.P.P., C.M.T.,
R.A.J., and S.A.T. would like to acknowledge academic
year and summer research support from the Howard
Hughes Medical Institute. NSF AIRE summer research
stipends were kindly provided to A.C.N., A.K.P., and
C.N. Occidental College students C.O. and R.A.J., and
community college participants J.T. and J.C., received
summer support from the NSF REU Program. The
1
1
555–1564; (c) Johnson, D. V.; Griengl, H. Chim. Oggi
997, 15, 9–13; (d) Gregory, R. J. H. Chem. Rev. 1999, 99,
3649–3682; (e) Schmidt, M.; Griengl, H. Top. Curr. Chem.
1999, 200, 193–226; (f) Johnson, D. V.; Griengl, H. Adv.
Biochem. Eng. Biotechnol. 1999, 63, 32–55; (g) Johnson, D.
V.; Zabelinskaja-Mackova, A. A.; Griengl, H. Curr. Opin.
Chem. Biol. 2000, 4, 103–109; (h) North, M. Tetrahedron:
Asymmetry 2003, 14, 147–176.
9
. Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y.
J. Org. Chem. 1989, 54, 3292–3303.
1
1
0. Hickel, A.; Hasslacher, M.; Griengl, H. Physiol. Plant.
996, 98, 891–898.
1
3
00 MHzNMR spectrometer was purchased with a grant
1. Effenberger, F.; Ziegler, T.; Forster, S. Angew. Chem., Int.
Ed. Engl. 1987, 26, 458–460.
12. Zandbergen, P.; Van der Linden, J.; Brussee, J.; Van der
Gen, A. Synth. Commun. 1991, 21, 1387–1391.
3. Brussee, J.; Loos, W. T.; Kruse, C. G.; Van der Gen, A.
Tetrahedron 1990, 46, 979–986.
from the NSF MRI program. Finally, we wish to thank
Dr. Paul Shin of California State University, Northridge
for his assistance collecting polarimeter data.
1
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1