γ-Amino alcohols via organocascade reactions involving dienamine catalysis

Article abstract of DOI:10.1021/jo3017007

Whereas cascade reactions catalyzed by secondary amines combine iminium- and/or enamine-catalyzed reactions, we introduce the feasibility of combining these modes of catalysis with dienamine-catalysis as a new general mechanism for cascade reactions. Enantioenriched β-functionalized-γ-amino alcohols were produced from simple achiral enals in one flask by combining dienamine- and iminium-catalyzed intermolecular reactions. Reaction products are precursors of γ-amino acids, γ-lactams, and pyrrolidines; one was employed in a synthesis of γ-amino acid (S)-vigabatrin, the bioactive enantiomer of Sabril.

Full text of DOI:10.1021/jo3017007

Note
pubs.acs.org/joc
γ‑Amino Alcohols via Organocascade Reactions Involving Dienamine
Catalysis
Chandrakumar Appayee, Americo J. Fraboni, and Stacey E. Brenner-Moyer*
Department of Chemistry, Brooklyn College and the City University of New York, 2900 Bedford Avenue, Brooklyn, New York
11210, United States
S
* Supporting Information
ABSTRACT: Whereas cascade reactions catalyzed by secon-
dary amines combine iminium- and/or enamine-catalyzed
reactions, we introduce the feasibility of combining these
modes of catalysis with dienamine-catalysis as a new general
mechanism for cascade reactions. Enantioenriched β-function-
alized-γ-amino alcohols were produced from simple achiral
enals in one flask by combining dienamine- and iminium-
catalyzed intermolecular reactions. Reaction products are
precursors of γ-amino acids, γ-lactams, and pyrrolidines; one was employed in a synthesis of γ-amino acid (S)-vigabatrin, the
bioactive enantiomer of Sabril.
n recent years, organocascade reactions have been
enamine-catalysis are well-established modes of catalysis for
chiral secondary amines, dienamine catalysis is a relatively
underexplored mode of catalysis for these catalysts. Perhaps this
is because dienamine intermediates of type 6 are prone to
multiple reaction motifs, rendering deliberate manipulation of
their reactivity challenging. For example, the olefin(s) in
dienamines can react to generate formal [2 + 2] and [4 + 2]
cycloaddition products.5−12 Alternatively, both the α- and γ-
carbons of dienamine 6 are nucleophilic, and either position
can react with discrete electrophiles.13−25 There are four
examples of dienamine catalyzed reactions producing γ-
functionalized-α,β-unsaturated carbonyl compounds (eq 2,
Scheme 1).20,23−25 We suspected that γ-functionalized-α,β-
unsaturated aldehydes of type 7 would be suitable substrates for
subsequent iminium-catalyzed intermolecular reactions (eq 3,
Scheme 1). This straightforward but heretofore unexplored
transformation is significant because, if successful, it would
introduce the feasibility of organocascade reactions entailing
some combination of iminium- and enamine-catalysis with
dienamine catalysis. Organocascade reactions proceeding by
these novel mechanisms would generate functionalized
aldehyde products that are not directly accessible via current
organocascade reactions. We report herein the first example of
a cascade reaction combining dienamine- and iminium-
catalyzed intermolecular reactions. This organocascade reaction
directly produces γ-amino alcohols, which are valuable synthetic
precursors of γ-amino acids and substituted γ-lactams and
pyrrolidines. In fact, one cascade product was employed in a
formal synthesis of non-natural γ-amino acid (S)-vigabatrin, the
biologically active enantiomer of the racemic anticonvulsant
drug marketed as Sabril.26
I
established as efficient green chemical methods for rapidly
building molecular complexity.1−4 Cascade reactions catalyzed
by chiral secondary amines (1, Scheme 1) entail some
combination of iminium- and/or enamine-catalysis. For
example, in a typical cascade reaction catalyzed by 1, an α,β-
unsaturated aldehyde is sequentially functionalized at the β- and
α-positions via iminium- and enamine-catalyzed reactions,
respectively (eq 1, Scheme 1).1,2 While iminium- and
Scheme 1. Reactions Catalyzed by Chiral Secondary
a
Amines
a
Eq 1: organocascade reactions via iminium- and enamine-catalysis; eq
2: γ-functionalization via dienamine catalysis; eq 3: proposed
organocascade reaction via dienamine- and iminium-catalysis.
Received: August 13, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3017007 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Cascade Reaction Development
step 1
step 2
yield 13a (%)
b
c
d
e
entry
solvent
toluene
conc. (M)
2
yield 11 (%)
ee 11 (%)
solvent
T (°C)
−20
ee 13a (%)
1
2
3
4
5
6
7
42
90
toluene
CHCl3
−
−
CHCl3
2
45
90
f
0
98
90
CHCl3
CHCl3
CHCl3
CHCl3
1
54
63
72
nd
nd
nd
0.5
0.25
0.25
g
8
0
63
92
a
Reaction conditions for step 1: 2a (1.5 equiv), 10a, 1a (0.1 equiv), PhCO2H (0.1 equiv), solvent, rt. Reaction conditions for step 2: (i) 11, 12 (1.1
b
equiv), 1a (0.1 equiv), PhCO2H (0.1 equiv), solvent (0.25 M), temp; (ii) NaBH4 (4.5 equiv), MeOH, 0 °C. 1H NMR yield using internal standard.
c
d
e
Determined by chiral phase HPLC of derivative of (corresponding) alcohol. Isolated yield. Determined by chiral phase HPLC of its
f
corresponding 4-chlorobenzoyl derivative, 22a. Reaction time was 5 h. Longer reaction times led to product decomposition at this temperature.
g
Reaction conditions: (i) 2a (1.5 equiv), 10a, 1a (0.1 equiv), PhCO2H (0.2 equiv), solvent, rt; (ii) 12 (1.5 equiv), 1a (0.1 equiv), 0 °C; (iii) NaBH4
(6 equiv), MeOH, 0 °C.
a
Both steps of the proposed cascade reaction were initially
optimized independently to identify a common set of reaction
conditions that would be suitable for a one-pot cascade reaction
(Table 1). Catalyst 1a was found to be effective for both steps.
Next, both steps were evaluated in the optimal solvents for the
γ-amination (toluene) and conjugate reduction (CHCl3)
reactions (entries 1−4).20,27 While the γ-amination proceeded
in either solvent, the conjugate reduction was ineffective in
toluene; the Hantzsch ester was insoluble in this solvent at low
temperature, and product decomposition was observed in this
solvent at rt. Thus, CHCl3 was identified as the optimal solvent
for the cascade reaction. While a number of variables were
examined in an effort to improve the yield of the first step,28 the
variable that was most impactful was reaction concentration
(entries 3, 5−7). In our hands, more dilute reaction conditions
led to higher yields in the γ-amination reaction. Interestingly,
this is opposite the trend observed by Jørgensen (in toluene
and CH2Cl2) for this reaction.20 Ultimately optimal reaction
conditions for the one-pot cascade reaction were identified,28
which provided γ-amino alcohol 13a in a single flask from 2a in
63% yield and 92% ee (entry 8).29
Table 2. Substrate Scope
b
c
entry
13
R
R1
yield 13 (%)
ee 13 (%)
1
2
3
4
5
6
13b
13c
13d
13e
13f
13g
13h
13i
Et
Et
Et
Et
Et
Et
Et
Bn
Bn
Bn
Et
72
70
72
57
49
45
44
37
35
44
92
93
93
92
94
93
87
72
73
93
nPr
C7H15
iBu
Bn
CH2SCH3
nPr
d
7
d
8
de
,
CH2OBn
CH2OBn
(CH2)4CN
9
13i
d
10
13j
a
With optimal reaction conditions for the one-pot cascade
reaction in hand, a variety of other α,β-unsaturated aldehydes
were examined in this transformation (Table 2). Enals with
unbranched aliphatic R groups provided γ-amino alcohols in
excellent yield (≥89% average yield per step) and ee (entries
1−3). Sterically demanding substituents at the δ-position of
enals were tolerated in this transformation (entries 4, 5), while
bulky substitution at the γ-position (R = iPr) was not (data not
shown). A heteroatom at the δ-position of enals was also
tolerated (entry 6). The use of dibenzyl azodicarboxylate
(DBAD; R1 = Bn) required that the second step of the cascade
reaction be run at lower temperatures to prevent product
decomposition and resulted in lower yields and slightly lower
ee’s (entry 7 vs entry 2). γ-Amino alcohol 13i was generated in
lower yield (72% average yield per step) and lower, but still
good, ee (entry 8). Use of enals with related δ-substituents (R =
Reaction conditions: (i) 2 (0.375 mmol), 10 (0.25 mmol), 1a (0.025
mmol), PhCO2H (0.050 mmol), CHCl3 (1 mL), rt, 16−48 h; (ii) 12
(0.375 mmol), 1a (0.025 mmol), 0 °C, 20−48 h; (iii) NaBH4 (1.5
b
c
mmol), MeOH, 0 °C. Isolated yield. Determined by chiral phase
HPLC of alcohol or of its corresponding 4-chlorobenzoyl derivative,
22. Step ii of cascade run at −20 °C. Reaction run on 2.5 mmol (of
10) scale.
d
e
CH2OTBS and CH2OMOM) gave similar results (data not
shown). This is possibly due to the combination of the use of
DBAD and the inductive effect of the electronegative oxygen at
the δ-position of the enal, which reduces the nucleophilicity of
the adjacent, γ-position of the dienamine in the first step of the
cascade reaction. Nonetheless, the reaction with this substrate
was readily scalable (entry 9). Finally, this transformation was
also compatible with remote reactive functionality (entry 10).
B
dx.doi.org/10.1021/jo3017007 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Cascade product 13i was elaborated to produce (S)-
vigabatrin, the biologically active enantiomer of the racemic
anticonvulsant drug Sabril (Scheme 2). It was found that
Scheme 3. Cascade Product with Vicinal, γ,β-Stereocenters
Scheme 2. Synthesis of (S)-Vigabatrin from Cascade Product
13i
a
Reaction conditions: (i) 2c (0.375 mmol), 10a (0.25 mmol), 1a
(0.025 mmol), PhCO2H (0.025 mmol), toluene (0.125 mL), rt, 21 h;
(ii) 20 (1.125 mmol), 1a (0.025 mmol), PhCO2H (0.025 mmol), 0
°C, 21 h; (iii) NaBH4 (0.565 mmol), MeOH, 0 °C.
reactions of this type furnish useful molecular scaffolds that
cannot be accessed directly by existing organocascade reactions.
EXPERIMENTAL SECTION
■
General Information. NMR data were acquired on a 400 MHz
NMR spectrometer and use the following abbreviations: s = singlet, d
= doublet, t = triplet, m = multiplet, dd = doublet of doublets, ddd =
doublet of doublets of doublets, brm = broad multiplet, brs = broad
singlet. Ee's were determined using chiral phase HPLC with Chiralpak
AD-H (0.46 × 25 cm) and Chiralpak AS-H (0.46 × 25 cm) columns.
HRMS spectra were acquired using an MS spectrometer with Q-TOF
mass analyzer. Flash chromatography was carried out with F60, 40−63
mm, 60 Å silica gel and EMD silica 60 F254 glass TLC plates. Solvents
were dried and kept air-free in a solvent purification unit, and were
evaporated using a standard rotovapor and high vacuum. All reactions
were carried out in oven-dried glassware, under an Ar atmosphere. All
enals were distilled freshly before use.
protection of the alcohol in 13i was necessary for the tandem
carbamate removal/N−N bond cleavage to proceed smoothly.
Alcohol 13i was therefore protected as a TBS ether (14).
Tandem carbamate removal/N−N bond cleavage, followed by
Boc protection of the resulting free amine produced 15.
Removal of the benzyl ether generated alcohol 16, which
underwent a two-step, oxidation/Wittig olefination protocol to
furnish 17. Deprotection of the TBS ether afforded alcohol 18.
Oxidation and in situ lactam formation produced 19, a known
penultimate intermediate in the total synthesis of (S)-
vigabatrin.30
Comparison of the optical rotation of γ-lactam 19 to the
literature value established the configuration of 19, and of the
corresponding stereocenter in cascade product 13i. The
configurations of all other cascade products were assigned by
analogy.
Thus, this formal synthesis of (S)-vigabatrin started from a
simple achiral α,β-unsaturated aldehyde, and utilized a cascade
reaction combining dienamine- and iminium-catalysis both to
install the γ-amino functionality and to establish the γ-
stereocenter. Presumably, this strategy could be employed in
the synthesis of other non-natural γ-amino acids (or substituted
γ-lactams or pyrrolidines). Inherent in this strategy is the ability
to access either enantiomer of a γ-amino acid from the same
starting material simply by using the appropriate enantiomer of
the catalyst in the cascade reaction.
Finally, this cascade reaction is amenable to the use of
nucleophiles other than 12, such as oxime 20 (Scheme 3).31
This result is illustrative of the capacity of cascade reactions
combining dienamine- and iminium catalysis to generate
enantiopure γ,β-difunctionalized alcohol products.
Preparation of Catalyst (1a), Enals (2e−g,i−j), and Oxime
(20). Catalyst 1a32 was prepared from the corresponding diary-
lprolinol33 using a known procedure. Enals 2e,34 2f,35 2g,35 2i,36 and
2j,37 and oxime 2038 were prepared using known procedures.
General Procedure for Dienamine−Iminium Cascade. To a
mixture of catalyst 1a (15 mg, 0.025 mmol) and benzoic acid (6 mg,
0.05 mmol) was added CHCl3 (1 mL), and the mixture was stirred at
rt. After 5 min enal 2 (0.375 mmol) was added. After 10 min 10 (0.25
mmol) was added, and the reaction was stirred in the dark until
1
complete consumption of 10 as observed by H NMR. The reaction
was cooled to 0 °C, catalyst 1a (15 mg, 0.025 mmol) was added
followed by 12 (95 mg, 0.375 mmol), and the reaction was stirred at 0
°C until complete consumption of enal as observed by 1H NMR. The
reaction was diluted with MeOH (2.5 mL), NaBH4 (57 mg, 1.5 mmol)
was added in portions, and the mixture was stirred at 0 °C for 30 min
and then quenched with saturated NH4Cl and extracted with CH2Cl2
(3 × 15 mL). The combined organic layers were dried over MgSO4
and filtered. After removal of solvent under reduced pressure, the
residue was purified by flash chromatography (EtOAc:petroleum
ether) to yield γ-amino alcohol 13.
(R)-Diethyl 1-(5-hydroxypentan-2-yl)hydrazine-1,2-dicar-
22
boxylate (13a). Colorless oil (41 mg, 63%): [α]D = −9.9 (c =
0.55 in CHCl3); IR (thin film, KBr) 3292, 2982, 2936, 1710, 1523,
1
1418, 1379, 1236, 1058, 761 cm−1; H NMR (400 MHz, CDCl3) δ
6.48 (brm, 1H), 4.21−4.09 (m, 5H), 3.67−3.60 (m, 2H), 1.88 (brs,
1H), 1.72−1.62 (m, 2H), 1.42−1.40 (m, 1H), 1.28−1.21 (m, 6H),
1.14 (d, J = 6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.4,
156.3, 62.6, 62.6, 62.2, 53.5, 30.3, 29.5, 18.4, 14.6, 14.5 ppm; HRMS
(ESI) [M + H]+ calcd. for [C11H23N2O5] 263.1607, found 263.1603.
(R)-Diethyl 1-(6-hydroxyhexan-3-yl)hydrazine-1,2-dicarbox-
In conclusion, we have developed the first cascade reaction
combining dienamine- and iminium-catalyzed intermolecular
reactions. This cascade reaction produces enantioenriched γ-
amino alcohols and was the key step in a formal synthesis of the
γ-amino acid (S)-vigabatrin, the bioactive enantiomer of the
anticonvulsant drug, Sabril. Additionally, this cascade reaction
was readily adapted to provide an enantiopure β-functionalized-
γ-amino alcohol, thereby demonstrating that the combination
of dienamine- and iminium-catalyzed reactions is a new, general
mechanism for organocascade reactions. Organocascade
23
ylate (13b). Colorless oil (50 mg, 72%): [α]D = 4.5 (c = 1.2 in
CHCl3); IR (thin film, KBr) 3284, 2979, 2935, 1693, 1525, 1416,1383,
1262, 1058, 937 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.14−6.67 (m,
1H), 4.15−3.87 (m, 5H), 3.61−3.53 (m, 2H), 2.53 (brs, 1H), 1.55−
1.39 (m, 6H), 1.24−1.20 (m, 6H), 0.87 (brs, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 157.6/157.4, 157.1/156.8, 62.6, 62.3, 62.0, 60.8/
C
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The Journal of Organic Chemistry
Note
59.6, 29.5, 28.5, 25.8/25.7, 14.5, 14.4, 11.1 ppm; HRMS (ESI) [M +
H]+ calcd. for [C12H25N2O5] 277.1763, found 277.1766.
(400 MHz, CDCl3) δ 7.31 (brs, 15H), 6.53−6.24 (brm, 1H), 5.20−
4.96 (m, 4H), 4.54−4.38 (m, 3H), 3.68−3.38 (m, 4H), 1.97−1.27 (m,
4H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.4, 156.9, 138.0, 136.1,
135.7, 128.7, 128.6, 128.5, 128.2, 127.9, 127.8, 72.8, 69.6, 68.4/68.1,
67.9, 62.2, 58.4/56.9, 29.4, 24.7 ppm; HPLC with an AS-H column (n-
hexane/i-PrOH = 95:5), 1.0 mL/min; major enantiomer tR = 83.5 min,
minor enantiomer tR = 74.3 min; HRMS (ESI) [M + H]+ calcd. for
[C28H33N2O6] 493.2339, found 493.2328.
(R)-Diethyl 1-(1-hydroxyheptan-4-yl)hydrazine-1,2-dicar-
23
boxylate (13c). Colorless oil (51 mg, 70%): [α]D = 3.6 (c = 1.0
in CHCl3); IR (thin film, KBr) 3466, 3283, 2960, 2933, 1711, 1417,
1
1257, 1060, 760 cm−1; H NMR (400 MHz, CDCl3) δ 6.35 (brm,
1H), 4.21−4.03 (m, 5H), 3.67−3.59 (m, 2H), 1.80−1.42 (m, 8H),
1.29−1.25 (m, 6H), 0.90 (t, J = 6.8 Hz, 3H) ppm; 13C NMR (100
MHz, CDCl3) δ 157.5/157.1, 156.5, 62.4, 62.4, 62.1, 58.4/57.5, 34.9,
29.5, 28.7, 19.7, 14.5, 14.4, 13.9 ppm; HRMS (ESI) [M + H]+ calcd.
for [C13H27N2O5] 291.1920, found 291.1920.
(R)-Diethyl 1-(8-cyano-1-hydroxyoctan-4-yl)hydrazine-1,2-
23
dicarboxylate (13j). Colorless oil (36 mg, 44%): [α]D = 8.9 (c =
1.62 in CHCl3); IR (thin film, KBr) 3473, 3285, 2934, 2869, 2246,
1
(R)-Diethyl 1-(1-hydroxyundecan-4-yl)hydrazine-1,2-dicar-
1752, 1708, 1417, 1260, 1233, 1058, 761 cm−1; H NMR (400 MHz,
23
boxylate (13d). Colorless oil (62 mg, 72%): [α]D = 3.8 (c = 1.58
CDCl3) δ 6.74 (brm, 1H), 4.19−4.00 (m, 5H), 3.65−3.58 (m, 2H),
2.33 (t, J = 6.6 Hz, 2H), 2.10 (brs, 1H), 1.91−1.24 (m, 10H), 1.26 (t, J
= 7.0 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 157.6, 157.1/
156.7, 119.9, 62.8, 62.6, 62.2, 58.6/57.4, 32.2/31.9, 29.3/28.8, 25.7,
25.3, 17.1, 14.6 ppm; HRMS (ESI) [M + H]+ calcd. for [C15H28N3O5]
330.2029, found 330.2030.
General Procedure for Preparation of Esters 22a−e, 22g,
22j. To alcohol 13 (1 equiv) in CH2Cl2 (0.1 M) was added Et3N (1.3
equiv) and 4-chlorobenzoyl chloride (1.3 equiv). After disappearance
of alcohol by TLC, the solvent was removed under reduced pressure,
and the product was purified by flash chromatography (EtOAc/
petroleum ether).
in CHCl3); IR (thin film, KBr) 3453, 3277, 2926, 2856, 1757, 1712,
1
1416, 1260, 1062, 760 cm−1; H NMR (400 MHz, CDCl3) δ 6.44
(brm, 1H), 4.18−3.99 (m, 5H), 3.66−3.57 (m, 2H), 1.99−1.24 (m,
16H), 1.28−1.24 (m, 6H), 0.86 (t, J = 6.6 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 157.6/157.2, 157.1/156.7, 62.5, 62.2, 62.1, 58.9/
57.9, 32.8, 31.9, 29.5, 29.4, 28.8, 26.6, 22.8, 14.6/14.5, 14.2 ppm;
HRMS (ESI) [M + H]+ calcd. for [C17H35N2O5] 347.2546, found
347.2555.
(S)-Diethyl 1-(1-hydroxy-6-methylheptan-4-yl)hydrazine-
23
1,2-dicarboxylate (13e). Colorless oil (43 mg, 57%): [α]D = 1.9
(c = 2.12 in CHCl3); IR (thin film, KBr) 3465, 3284, 2957, 2870,
1756, 1711, 1417, 1259, 1062, 760 cm−1; 1H NMR (400 MHz,
CDCl3) δ 6.39 (brm, 1H), 4.19−4.17 (m, 5H), 3.67−3.58 (m, 2H),
1.96−1.11 (m, 8H), 1.29−1.25 (m, 6H), 0.90−0.88 (m, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 157.8, 157.3/156.7, 62.8, 62.7, 62.5, 57.1/
56.0, 42.3/42.0, 29.8/29.3, 25.4/25.2, 23.6, 22.5/22.2, 14.8 ppm;
HRMS (ESI) [M + H]+ calcd. for [C14H29N2O5] 305.2076, found
305.2072.
(R)-Diethyl 1-(5-((4-chlorobenzoyl)oxy)pentan-2-yl)-
hydrazine-1,2-dicarboxylate (22a). Colorless oil (62 mg, 78%):
22
[α]D = −8.8 (c = 1.02 in CHCl3); IR (thin film, KBr) 3300, 2980,
1
2934, 1756, 1720, 1595, 1405, 1274, 1172, 760 cm−1; H NMR (400
MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H),
6.28 (brs, 1H), 4.31 (t, J = 6.4 Hz, 2H), 4.32−4.17 (m, 5H), 1.90−
1.67 (m, 3H), 1.48 (brs, 1H), 1.28−1.23 (m, 6H), 1.60 (d, J = 6.8 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.4, 156.1, 139.4,
131.1, 128.9, 128.8, 65.2, 62.5, 62.1, 53.4, 30.6, 25.8, 18.3, 14.6, 14.5
ppm; HPLC with an AS-H column (n-hexane/i-PrOH = 95:5), 1.0
mL/min; major enantiomer tR = 28.7 min, minor enantiomer tR = 38.9
min; HRMS (ESI) [M + H]+ calcd. for [C18H26ClN2O6] 401.1479,
found 401.1477.
(S)-Diethyl 1-(5-hydroxy-1-phenylpentan-2-yl)hydrazine-
23
1,2-dicarboxylate (13f). Colorless oil (41 mg, 49%): [α]D
=
14.4 (c = 0.94 in CHCl3); IR (thin film, KBr) 3285, 2981, 2929, 1712,
1414, 1291, 1233, 1063, 758, 702 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.31−7.19 (m, 5H), 6.31 (brm, 1H), 4.58−4.07 (m, 5H), 3.67−3.58
(m, 2H), 2.85−2.79 (m, 2H), 2.05−1.51 (m, 4H), 1.30−1.18 (m, 7H)
ppm; 13C NMR (100 MHz, CDCl3) δ 157.8/157.2, 156.7/156.4,
138.5, 128.9, 128.7, 126.7, 62.6, 62.4, 60.3, 39.6.1/39.3, 29.5, 28.3, 14.6
ppm; HPLC with an AS-H column (n-hexane/i-PrOH = 95:5), 1.0
mL/min; major enantiomer tR = 39.6 min, minor enantiomer tR = 33.5
min; HRMS (ESI) [M + H]+ calcd. for [C17H27N2O5] 339.1920,
found 339.1920.
(R)-Diethyl 1-(6-((4-chlorobenzoyl)oxy)hexan-3-yl)-
hydrazine-1,2-dicarboxylate (22b). Colorless oil (42 mg, 84%):
23
[α]D = −9.6 (c = 0.7 in CHCl3); IR (thin film, KBr) 3296, 2978,
1
2934, 1757, 1718, 1595, 1405, 1274, 1093, 1015, 928 cm−1; H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz,
2H), 6.13 (brs, 1H), 4.32 (t, J = 6.4 Hz, 2H), 4.19−3.97 (m, 5H), 1.99
(brs, 1H), 1.82 (brs, 1H), 1.53−1.41 (m, 4H), 1.29−1.21 (m, 6H),
0.90 (brs, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.5/
157.2, 156.8/156.7, 139.4, 131.1, 129.1, 128.8, 65.2, 62.5, 62.2, 60.3/
59.4, 29.0/28.9, 25.9, 25.7/25.6, 14.7, 14.6, 11.2 ppm; HPLC with an
AS-H column (n-hexane/i-PrOH = 95:5), 1.0 mL/min; major
enantiomer tR = 15.9 min, minor enantiomer tR = 25.2 min; HRMS
(ESI) [M + H]+ calcd. for [C19H28ClN2O6] 415.1636, found 415.1638.
(R)-Diethyl 1-(1-((4-chlorobenzoyl)oxy)heptan-4-yl)-
hydrazine-1,2-dicarboxylate (22c). Colorless oil (82 mg, 91%):
(S)-Diethyl 1-(5-hydroxy-1-(methylthio)pentan-2-yl)-
hydrazine-1,2-dicarboxylate (13g). Colorless oil (35 mg, 45%):
23
[α]D = 31.5 (c = 1.07 in CHCl3); IR (thin film, KBr) 3465, 3284,
1
2980, 2922, 2871, 1712, 1414, 1331, 1249, 1063, 760 cm−1; H NMR
(400 MHz, CDCl3) δ 6.47 (brm, 1H), 4.39−4.16 (m, 5H), 3.68−3.60
(m, 2H), 2.58 (brs, 2H), 2.08 (s, 3H), 2.02 (brs, 1H), 1.83−1.52 (m,
3H), 1.27 (t, J = 7.0 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ
157.8/157.3, 156.9/156.8, 62.9, 62.7, 62.3, 57.3/55.8, 37.3/36.7, 29.6,
28.3, 15.5/15.2, 14.6 ppm; HRMS (ESI) [M + H]+ calcd. for
[C12H25N2O5S] 309.1484, found 309.1492.
24
[α]D = −10.5 (c = 1.4 in CHCl3); IR (thin film, KBr) 3293, 2961,
1
2933, 1757, 1717, 1274, 1093, 1015, 851 cm−1; H NMR (400 MHz,
(R)-Dibenzyl 1-(1-hydroxyheptan-4-yl)hydrazine-1,2-dicar-
24
boxylate (13h). White solid (46 mg, 44%): mp 83−84 °C; [α]D
CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 6.25−6.18
(brm, 1H), 4.38−4.16 (m, 5H), 4.31 (t, J = 6.4 Hz, 2H), 1.99 (brs,
1H), 1.81−1.50 (m, 7H), 1.41−1.28 (m, 6H), 0.90 (t, J = 6.4 Hz, 3H)
ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.4/157.1, 156.8/
156.5, 139.4, 131.1, 129.0, 128.8, 65.2, 62.7/62.5, 62.2, 58.1/57.3, 34.9,
29.2, 25.9, 19.7, 14.6, 14.5, 14.0 ppm; HPLC with an AS-H column (n-
hexane/i-PrOH = 95:5), 1.0 mL/min; major enantiomer tR = 13.2 min,
minor enantiomer tR = 18.9 min; HRMS (ESI) [M + H]+ calcd. for
[C20H30ClN2O6] 429.1792, found 429.1788.
= 4.4 (c = 1.6 in CHCl3); IR (thin film, KBr) 3280, 3033, 2958, 2872,
1711, 1455, 1413, 1258, 1216, 1050, 740, 697 cm−1; H NMR (400
1
MHz, CDCl3) δ 7.31 (brs, 10H), 6.81 (brm, 1H), 5.68−4.65 (m, 4H),
4.23−4.05 (m, 1H), 3.57−3.34 (m, 2H), 2.10 (brs, 1H), 1.62−1.23
(m, 7H), 0.89−0.71 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
157.3/157.0, 156.9/156.4, 136.2/136.0, 135.7, 128.6, 128.7, 128.6,
128.5, 128.3, 128.2, 127.8, 68.4/68.1, 67.9, 62.5, 59.0/57.9, 34.9, 29.5,
28.7, 19.7, 14.0 ppm; HPLC with an AD-H column (n-hexane/i-PrOH
= 90:10), 1.0 mL/min; major enantiomer tR = 23.0 min, minor
enantiomer tR = 28.3 min; HRMS (ESI) [M + H]+ calcd. for
[C23H31N2O5] 415.2233, found 415.2228.
(R)-Diethyl 1-(1-((4-chlorobenzoyl)oxy)undecan-4-yl)-
hydrazine-1,2-dicarboxylate (22d). Colorless oil (33 mg, 49%):
23
[α]D = −8.8 (c = 1.0 in CHCl3); IR (thin film, KBr) 3299, 2957,
2928, 2856, 1759, 1721, 1405, 1274, 1228, 1118, 1104, 1093, 761
(S)-Dibenzyl 1-(1-(benzyloxy)-5-hydroxypentan-2-yl)-
hydrazine-1,2-dicarboxylate (13i). Colorless oil (46 mg, 37%):
[α]D26 = 7.2 (c = 1.7 in CHCl3); IR (thin film, KBr) 3279, 3032, 2942,
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.4 Hz, 2H), 6.13 (brm, 1H), 4.33−4.05 (m, 5H), 4.31 (t, J =
6.4 Hz, 2H), 2.00−1.25 (m, 16H), 1.29−1.25 (m, 6H), 0.87 (t, J = 6.8
1
2867, 1713, 1498, 1454, 1411, 1218, 1091, 739, 697 cm−1; H NMR
D
dx.doi.org/10.1021/jo3017007 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.4/157.1,
156.8/156.5, 139.4, 131.1, 129.0, 128.8, 65.2, 62.5, 62.2, 58.4/57.7,
32.7, 32.0, 29.5, 29.4, 26.6/25.9, 22.8, 14.7, 14.2 ppm; HPLC with an
AS-H column (n-hexane/i-PrOH = 95:5), 1.0 mL/min; major
enantiomer tR = 8.5 min, minor enantiomer tR = 11.0 min; HRMS
(ESI) [M + H]+ calcd. for [C24H38ClN2O6] 485.2418, found 485.2409.
(S)-Diethyl 1-(1-((4-chlorobenzoyl)oxy)-6-methylheptan-4-
yl)hydrazine-1,2-dicarboxylate (22e). Colorless oil (38 mg,
through a short pad of Celite, and the Celite was washed with CH2Cl2.
After solvents were removed, the crude product was diluted with
CH2Cl2 and refiltered through a short pad of Celite. After removal of
CH2Cl2 under vacuum, the crude product was subjected to Boc-
protection.
To a solution of the above crude product (0.31 mmol) in THF (2.1
mL) was added (Boc)2O (170 mL, 0.74 mmol) and Et3N (206 mL,
1.48 mmol). The reaction was stirred at rt for 16 h, then concentrated
under vacuum to give a residue, which was purified by flash
chromatography (25% Et2O/petroleum ether) to yield 15 (94 mg,
72% yield for two steps) as a colorless oil: [α]D26 = −10.3 (c = 0.55 in
CHCl3); IR (thin film, KBr) 3341, 2954, 2857, 1716, 1498, 1365,
23
77%): [α]D = −8.5 (c = 2.06 in CHCl3); IR (thin film, KBr)
3301, 2958, 2869, 1759, 1720, 1405, 1273, 1218, 1105, 1093, 761
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.4 Hz, 2H), 6.20−6.13 (brm, 1H), 4.33−4.17 (m, 5H), 4.31 (t,
J = 6.2 Hz, 2H), 1.99−0.74 (m, 7H), 1.28−1.27 (m, 6H), 0.90−0.88
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.4/156.9,
156.8/156.4, 139.4, 131.1, 129.0, 128.8, 65.4/65.2, 62.7/62.5, 62.2/
62.2, 56.4/55.6, 42.0/41.7, 29.5, 25.9, 25.2/25.0, 23.4, 22.3/22.0, 14.6
ppm; HPLC with an AS-H column (n-hexane/i-PrOH = 95:5), 0.5
mL/min; major enantiomer tR = 24.2 min, minor enantiomer tR = 30.0
min; HRMS (ESI) [M + H]+ calcd. for [C21H32ClN2O6] 443.1949,
found 443.1939.
1
1100, 836 cm−1; H NMR (400 MHz, CDCl3) δ 7.36−7.28 (m, 5H),
4.77 (brs, 1H), 4.54 (d, J = 12.0 Hz, 2H), 4.49 (d, J = 12.0 Hz, 2H),
3.74 (brs, 1H), 3.62 (t, J = 6.0 Hz, 2H), 3.48−3.47 (m, 2H), 1.67−
1.52 (m, 4H), 1.44 (s, 9H), 0.89 (s, 9H), 0.46 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 155.8, 138.4, 128.5, 127.7, 127.6, 79.2, 73.3,
72.3, 63.1, 50.3, 29.4, 28.6, 26.1, 18.5, −5.2 ppm; HRMS (ESI) [M +
H]+ calcd. for [C23H42NO4Si] 424.2883, found 424.2877.
Preparation of (S)-tert-Butyl (5-((tert-butyldimethylsilyl)-
oxy)-1-hydroxypentan-2-yl)carbamate (16). To a solution of 15
(17 mg, 0.040 mmol) in EtOAc (0.4 mL) was added NaHCO3 (4 mg,
0.048 mmol) and 10% Pd/C (3.1 mg), and the reaction was stirred
under a hydrogen atmosphere at rt for 16 h. The mixture was filtered
through a short pad of Celite, and the Celite was washed with EtOAc.
The solvent was removed under vacuum, and the residue was purified
by flash chromatography (50% EtOAc/petroleum ether) to give 16
(S)-Diethyl 1-(5-((4-chlorobenzoyl)oxy)-1-(methylthio)-
pentan-2-yl)hydrazine-1,2-dicarboxylate (22g). Colorless oil
23
(35 mg, 79%): [α]D = 7.9 (c = 0.71 in CHCl3); IR (thin film,
KBr) 3299, 2980, 2922, 1755, 1719, 1404, 1275, 1121, 1092, 760
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.40
(d, J = 8.4 Hz, 2H), 6.31 (brm, 1H), 4.35−4.18 (m, 5H), 4.33 (t, J =
6.0 Hz, 2H), 2.61 (brs, 2H), 2.09−1.60 (m, 7H), 1.29−1.25 (m, 6H)
ppm; 13C NMR (100 MHz, CDCl3) δ 165.9, 157.6, 156.8, 139.5,
131.1, 129.0, 128.8, 65.2/65.0, 63.0/62.7, 62.4, 56.8/55.5, 37.2/36.7,
28.7, 26.0, 15.5/15.2, 14.6 ppm; HPLC with an AS-H column (n-
hexane/i-PrOH = 95:5), 1.0 mL/min; major enantiomer tR = 26.6 min,
minor enantiomer tR = 41.5 min; HRMS (ESI) [M + H]+ calcd. for
[C19H28ClN2O6S] 447.1357, found 447.1347.
24
(13 mg, 97% yield) as a colorless oil: [α]D = −6.0 (c = 1.73 in
CHCl3); IR (thin film, KBr) 3349, 2954, 2885, 2858, 1690, 1516,
1
1391, 1366, 1254, 1174, 1100, 836, 776 cm−1; H NMR (400 MHz,
CDCl3) δ 4.92 (brs, 1H), 3.63−3.52 (m, 5H), 2.93 (brs, 1H), 1.58−
1.47 (m, 4H), 1.41 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 156.8, 79.6, 66.1, 62.9, 52.8, 29.1, 28.5, 27.8,
26.1, 18.4, −5.2 ppm; HRMS (ESI) [M + H]+ calcd. for
[C16H36NO4Si] 334.2414, found 334.2429.
Preparation of (S)-tert-Butyl (6-((tert-butyldimethylsilyl)-
oxy)hex-1-en-3-yl)carbamate (17). NaHCO3 (60 mg, 0.72
mmol) and Dess−Martin periodinane (152 mg, 0.36 mmol) were
added to a solution of 16 (80 mg, 0.24 mmol) in CH2Cl2 (1.2 mL) at
rt. After 30 min, the reaction was diluted with saturated aqueous
Na2S2O3 (0.5 mL), saturated aqueous NaHCO3 (0.2 mL), and H2O
(0.3 mL). The resulting solution was stirred vigorously until clear and
then was diluted further with saturated aqueous Na2S2O3 (2 mL),
saturated aqueous NaHCO3 (2 mL), and H2O (1 mL) and was
extracted with EtOAc. The organic layer was dried over MgSO4,
filtered, and the solvents were removed under vacuum. The crude
aldehyde was used directly in the Wittig reaction.
(R)-Diethyl 1-(1-((4-chlorobenzoyl)oxy)-8-cyanooctan-4-yl)-
hydrazine-1,2-dicarboxylate (22j). Purified by flash chromatog-
raphy (5% Et2O/CH2Cl2). Colorless oil (37 mg, 68%): [α]D23 = −1.9
(c = 1.42 in CHCl3); IR (thin film, KBr) 3298, 2934, 2869, 2246,
1
1755, 1717, 1405, 1274, 1232, 1093, 761 cm−1; H NMR (400 MHz,
CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.40−6.25
(brm, 1H), 4.32−4.07 (m, 5H), 4.31 (t, J = 6.2 Hz, 2H), 2.33 (t, J =
6.6 Hz, 2H), 1.90−1.20 (m, 10H), 1.28−1.24 (m, 6H) ppm; 13C NMR
(100 MHz, CDCl3) δ 165.9, 157.5, 156.9/156.5, 139.5, 131.5, 131.1,
128.8, 119.8, 65.1/64.9, 62.9/62.6, 62.3, 58.2/57.1, 32.1/31.8, 29.2,
25.9, 25.6, 25.3, 17.2, 14.6 ppm; HPLC with an AS-H column (n-
hexane/i-PrOH = 90:10), 1.0 mL/min; major enantiomer tR = 47.6
min, minor enantiomer tR = 36.2 min; HRMS (ESI) [M + H]+ calcd.
for [C22H31ClN3O6] 468.1901, found 468.1891.
To a slurry of Ph3PCH3Br (154 mg, 0.43 mmol) in THF (0.8 mL)
was added KHMDS (0.5 M in toluene, 0.8 mL, 0.41 mmol), and the
resulting yellow suspension was stirred at rt for 2 h and then cooled to
−78 °C. A solution of the above crude aldehyde (0.24 mmol) in THF
(0.2 mL) was slowly added. After the reaction was stirred at −78 °C
for 2 h, it was warmed to rt and stirred for another 14 h. Then the
reaction was cooled to 0 °C and quenched with H2O and extracted
with EtOAc. The organic layer was dried over MgSO4, filtered, and the
solvents were removed under vacuum. The residue was purified by
flash chromatography (5% EtOAc/petroleum ether) to give 17 (54
mg, 69% yield for two steps) as a colorless oil: [α]D25 = 5.6 (c = 1.0 in
CHCl3); IR (thin film, KBr) 3341, 2955, 2930, 2857, 1705, 1517,
Preparation of (S)-Dibenzyl 1-(1-(benzyloxy)-5-((tert-
butyldimethylsilyl)oxy)pentan-2-yl)hydrazine-1,2-dicarboxy-
late (14). To a solution of 13i (227 mg, 0.46 mmol) in CH2Cl2 (2.3
mL) was added 2,6-lutidine (110 mL, 0.92 mmol) and TBDMSOTf
(160 mL, 0.69 mmol) at −78 °C. After 2 h, MeOH (0.7 mL) was
added, and the reaction was warmed to rt. Solvents were removed
under vacuum and flash chromatography (25% Et2O/petroleum ether)
yielded 14 (270 mg, 97% yield) as a colorless oil: [α]D26 = 1.3 (c = 0.7
in CHCl3); IR (thin film, KBr) 3270, 2954, 2928, 2856, 1759, 1716,
1
1255, 1096 cm−1; H NMR (400 MHz, CDCl3) δ 7.31 (s, 15H),
6.71−6.43 (m, 1H), 5.20−5.11 (m, 4H), 4.54−4.34 (m, 3H), 3.67−
3.33 (m, 4H), 1.70−1.39 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H) ppm; 13C
NMR (100 MHz, CDCl3) δ 156.9, 156.4, 138.1, 136.2, 135.9, 128.6,
128.5, 128.4, 128.2, 128.1, 127.8, 127.7, 72.9, 69.9, 68.4/68.0, 67.8,
67.6, 62.7, 58.2/56.6, 29.3, 26.1, 25.1, 18.5, −5.2 ppm; HRMS (ESI)
[M + H]+ calcd. for [C34H47N2O6Si] 607.3203, found 607.3212.
Preparation of (S)-tert-Butyl (1-(benzyloxy)-5-((tert-
butyldimethylsilyl)oxy)pentan-2-yl)carbamate (15). To a slurry
of Raney−Nickel (∼210 mg, prewashed with MeOH) in MeOH (1
mL), was added AcOH (5 drops) and a solution of 14 (190 mg, 0.31
mmol) in MeOH (4 mL). The reaction was purged with a hydrogen
filled balloon for 15 min and stirred under a slightly positive pressure
of hydrogen (balloon) at rt for 16 h. The reaction was then filtered
1
1366, 1252, 1174, 1100, 1005, 835, 776 cm−1; H NMR (400 MHz,
CDCl3) δ 5.74 (ddd, J = 16.4, 10.4, 5.6 Hz, 1H), 5.37 (d, J = 17.2 Hz,
1H), 5.07 (d, J = 10.4 Hz, 1H), 4.62 (brs, 1H), 4.08 (brs, 1H), 3.61 (t,
J = 5.6 Hz, 2H), 1.60−1.47 (m, 4H), 1.43 (s, 9H), 0.88 (s, 9H), 0.03
(s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 155.5, 139.2, 114.4,
79.3, 62.8, 52.6, 31.5, 28.9, 28.5, 26.1, 18.4, −5.2 ppm; HRMS (ESI)
[M + H]+ calcd. for [C17H36NO3Si] 330.2464, found 330.2465.
Preparation of (S)-tert-Butyl (6-hydroxyhex-1-en-3-yl)-
carbamate (18). To a solution of 17 (50 mg, 0.15 mmol) in THF
(1 mL) was added TBAF (1 M in THF, 0.45 mL, 0.45 mmol) at rt.
After 3.5 h, the reaction was quenched with saturated aq NH4Cl (5
E
dx.doi.org/10.1021/jo3017007 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mL) and extracted with EtOAc (3 × 15 mL). The combined organic
layers were dried over MgSO4 and filtered. After removal of the
solvent under reduced pressure, the residue was passed through a short
pad of silica gel and washed with 7% EtOAc/petroleum ether (15 mL),
and the eluent was discarded. Then the silica gel pad was washed with
50% EtOAc/petroleum ether (10 mL), and the solvents were removed
under reduced pressure to yield 18 (32 mg, 98% yield) as a colorless
19, 21, 22a−e, 22g and 22j. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: SBrenner@brooklyn.cuny.edu.
25
oil: [α]D = 7.7 (c = 1.4 in CHCl3); IR (thin film, KBr) 3332, 2978,
1
2933, 2871, 1690, 1527, 1367, 1172, 1059, 993, 918 cm−1; H NMR
Notes
The authors declare no competing financial interest.
(400 MHz, CDCl3) δ 5.73 (ddd, J = 16.4, 10.4, 5.6 Hz, 1H), 5.13 (d, J
= 17.2 Hz, 1H), 5.07 (d, J = 10.4 Hz, 1H), 4.63 (brs, 1H), 4.08 (brs,
1H), 3.63 (t, J = 5.6 Hz, 2H), 2.40 (brs, 1H), 1.62−1.46 (m, 4H), 1.42
(s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 155.7, 138.9, 114.7,
79.5, 62.4, 52.6, 31.6, 28.8, 28.5 ppm; HRMS (ESI) [M + H]+ calcd.
for [C11H22NO3] 216.1600, found 216.1610.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1148295). The authors gratefully acknowledge Dr.
Furong Sun (University of Illinois) for his assistance with
mass spectrometry.
Preparation of (S)-tert-Butyl 2-oxo-5-vinylpyrrolidine-1-
carboxylate (19). To a solution of 18 (28 mg, 0.13 mmol) in
DMF (2.3 mL) was added PDC (294 mg, 0.8 mmol), and the reaction
was stirred at rt for 18 h. The reaction was diluted with H2O (5 mL),
extracted with EtOAc (3 × 15 mL), and the combined organic layers
were dried with MgSO4. The solution was filtered, and the solvents
were removed under reduced pressure. Crude product was purified by
flash chromatography (50% EtOAc/petroleum ether) to give 19 (26
mg, 95% yield) as a colorless oil: [α]D25 = −25.0 (c = 0.9 in CHCl3 for
72% ee); Lit.39 [α]D = −24.3 (c = 1.07 in CHCl3 for 72% ee); IR (thin
film, KBr) 2980, 2931, 1785, 1752, 1719, 1368, 1308, 1256, 1156, 922,
REFERENCES
■
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1
851, 784 cm−1; H NMR (400 MHz, CDCl3) δ 5.84 (ddd, J = 17.2,
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Angew. Chem., Int. Ed. 2011, 50, 8492−8509.
10.4, 6.0 Hz, 1H), 5.18 (dd, J = 16.0, 0.8 Hz, 1H), 5.17 (dd, J = 11.2,
1.2 Hz, 1H), 4.65−4.61 (m, 1H), 2.61−2.51 (m, 1H), 2.45−2.37 (m,
1H), 2.26−2.16 (m, 1H), 1.83−1.77 (m, 1H), 1.49 (s, 9H) ppm; 13C
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28.1, 24.4 ppm; HRMS (ESI) [M + Na]+ calcd. for [C11H17NO3Na]
234.1106, found 234.1113. This data matches that in the literature.39
Preparation of Diethyl 1-((3S,4R)-3-(((Z)-benzylideneamino)-
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To a mixture of catalyst 1a (15 mg, 0.025 mmol) and benzoic acid
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stirred at rt. After 5 min enal 2b (50 mL, 0.375 mmol) was added.
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was added, and the reaction was stirred in the dark. After 21 h
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Davis, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2012, 134, 2543−2546.
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Angew. Chem., Int. Ed. 2010, 49, 6418−6420.
1
(complete consumption of 10a observed by H NMR), the reaction
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was cooled to 0 °C and catalyst 1a (15 mg, 0.025 mmol) and benzoic
acid (3 mg, 0.025 mmol) were added, and the reaction was stirred for
5 min. Oxime 20 (122 mL, 1.125 mmol) was added, and the reaction
was stirred at 0 °C for 21 h (complete disappearance of enal peaks in
1H NMR). MeOH (0.75 mL) and NaBH4 (21 mg, 0.565 mmol) were
added simultaneously, and the reaction was stirred for 15 min and then
was quenched with saturated NH4Cl and extracted with CH2Cl2 (3 ×
15 mL). The combined organic layers were dried over MgSO4 and
filtered. After removal of solvent under reduced pressure, the residue
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20−25.
was purified by flash chromatography (cold column, 20% Et2O/
24
CH2Cl2) to yield 21 (58 mg, 57% yield) as a colorless oil: [α]D
=
(14) Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron Lett.
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−2.8 (c = 0.8 in CHCl3); IR (thin film, KBr) 3277, 2962, 2873, 1714,
1414, 1253, 1058, 947, 759, 695 cm−1; 1H NMR (400 MHz, CDCl3) δ
8.01 (s, 1H), 7.58−7.56 (m, 2H),7.38−7.36 (m, 3H), 6.46 (brs, 1H),
4.42−4.18 (m, 6H), 3.80−3.78 (m, 2H), 2.27−1.60 (m, 6H), 1.28−
1.25 (m, 6H), 0.91 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 157.5/157.0, 156.6/156.1, 149.0, 132.1, 130.1, 128.8, 127.2,
82.0/81.1, 62.9/62.7, 62.4, 60.9/60.0, 59.7, 34.6/34.5, 29.8/29.3, 19.6/
19.4, 14.5, 14.4, 14.0/13.9 ppm; HPLC with an AD-H column (n-
hexane/i-PrOH = 90:10), 1.0 mL/min; minor enantiomer tR = 12.1
min, major enantiomer tR = 14.4 min, minor diastereomer tR = 18.3
min; HRMS (ESI) [M + H]+ calcd. for [C20H32N3O6] 410.2291,
found 410.2289.
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ASSOCIATED CONTENT
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* Supporting Information
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