Synthesis of β- And γ-hydroxy α-amino acids via enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement

Article abstract of DOI:10.1021/jo502026a

A new strategy for stereoselective preparation of all four isomers of β- and γ-hydroxy α-amino acids is presented. The developed procedure is based on enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement as key steps. Stereocontrol is achieved by proper choice of the starting hydroxyacid, the course of kinetic resolution, and the stereospecific sigmatropic rearrangement step, which proceeds with full chirality transfer.

Full text of DOI:10.1021/jo502026a

Article
pubs.acs.org/joc
Synthesis of β- and γ‑Hydroxy α‑Amino Acids via Enzymatic Kinetic
Resolution and Cyanate-to-Isocyanate Rearrangement
Piotr Szczesniak,† Agnieszka Pazdzierniok-Holewa,‡ Urszula Klimczak,† and Sebastian Stecko*,†
́
́
†Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
‡Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4,
44-100 Gliwice, Poland
S
* Supporting Information
ABSTRACT: A new strategy for stereoselective preparation of all four isomers of β- and γ-hydroxy α-amino acids is presented.
The developed procedure is based on enzymatic kinetic resolution and cyanate-to-isocyanate rearrangement as key steps.
Stereocontrol is achieved by proper choice of the starting hydroxyacid, the course of kinetic resolution, and the stereospecific
sigmatropic rearrangement step, which proceeds with full chirality transfer.
molecules28 but also used as chiral catalysts and ligands29 for
INTRODUCTION
■
enantioselective transformations.30
β- and γ-hydroxy α-amino acids are important structural motifs
The importance of hydroxylated α-amino acids, either as a
of numerous naturally occurring molecules exhibiting interest-
structural element of bioactive peptides or as intermediates in
ing pharmacological properties.1−8 An excellent example of this
the synthesis of complex molecules and catalysts, resulted in the
class of compounds is threonine and its three isomers. L-
development of a multitude of methods for their asymmetric
Threonine can be found in several polypeptide drugs such as
synthesis. Typical approaches for the preparation of hydroxy-
sermoreline, used for the treatment of dwarfism,9 ceruletide, a
lated amino acids are based on Sharpless asymmetric
smooth muscle and digestive secretions stimulator,10 exenatide,
which is a GLP-1 antagonist for treatment of diabetes mellitus
type 2,11 or enfuvirtide, an HIV fusion inhibitor.12 D-Threonine
is also a structural motif in various natural products.4−6 The
diastereomers of threonines, allo-threonines, are also wide-
spread in nature, as representatives of nonproteinogenic amino
acids. L- and D-allo-threonine motifs were found in bioactive
peptides, for instance antiviral viscosin,13 antibiotic hormao-
mycin,14 antitumor astins15 and phytotoxic syringopeptins.16
Also other hydroxy amino acids, such as β-phenyl serines, β-
hydroxyleucines, or β-hydroxytyrosines, are found in the
structure of a number of cyclic polypeptides active against
HIV (e.g., callipeltines,17 neamphamide,18 papuamides,19
mirabamides,20 and celebesides21). Another non-natural
amino acid, (2R,3R)-β-cyclohexyl-serine, constitutes a part of
aplaviroc (GSK-873140), a CCR5 antagonist used in the
treatment of HIV infection.22 Finally, β-phenylserine and β-
hydroxytyrosine are present in antibiotics such as vancomy-
cin,23 bouvardin,24 chloramphenicol,25 hypeptin26 and katano-
sins.27
dihydroxylation or epoxidation of allyl alcohols,31 catalytic
hydrogenation of α-amino-β-keto esters,32 aldol reaction,33
biocatalyzed transformations,34 and others.35−37
Since all isomeric (enantiomeric and diasteromeric) forms of
hydroxy amino acids are interesting from a biological as well as
a synthetic point of view, synthetic protocols that enable the
preparation of all four isomers are desirable. Herein, we report
an efficient method for the selective preparation of diastereo-
meric hydroxy amino acids from simple precursors, hydroxy
carboxylic acids, via an enzymatic kinetic resolution and
enantiospecific cyanate-to-isocyanate sigmatropic rearrange-
ment reaction sequence.
RESULTS AND DISCUSSION
■
The key feature of our proposal is the stereoselective formation
of allyl alcohols 2a,b from the corresponding chiral hydroxyacid
with a general structure represented by 1 and the trans-
formation of 2a,b into allylamines 3a,b by a sigmatropic
rearrangement, as outlined in Scheme 1.
Functionalized β- and γ-hydroxy α-amino acids are not only
Received: October 19, 2014
attractive building blocks for the synthesis of complex organic
© XXXX American Chemical Society
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Scheme 1
The concerted nature of the rearrangement step should
transpose the stereogenic center with full chirality transfer to
provide the corresponding allylamine regardless of the
configuration of the other stereocenter, originating from the
starting hydroxyacid. Thus, varying the configuration of the
initial hydroxyacid and employing independent stereoselective
generation of a second allylic stereogenic center should enable
the furnishing of isomeric hydroxy allylamines after the
sigmatropic rearrangement. Simple transformations of the
double bond in hydroxy allylamines (3) will allow access to
the corresponding hydroxy amino acids and their derivatives.
Our first efforts were directed toward the synthesis of L-
threonine and its isomers starting from methyl L- and D-lactate.
Thus, methyl L-lactate was O-silylated with TBSCl to afford
ester 4a, which was converted into enone 5a via a one-pot
reduction and Horner−Wadsworth−Emmons olefination38
sequence in 80% after 2 steps (Scheme 2).
enone 5a was subjected to Luche reduction41 to afford a
mixture of alcohols 9a (Scheme 4). Enzymatic kinetic
resolution of 9a with vinyl acetate in the presence of lipase
Novozyme 435 provided alcohol 7a (dr > 95%, NMR) along
with acetate 10a (Scheme 4). Basic hydrolysis of the latter gave
alcohol 6a in 88% yield (dr > 95%, NMR, Scheme 4).
Subsequently, the transformation of allyl alcohol 6a and 7a
into the corresponding allylamines was carried out. In the
preliminary report,42 we demonstrated that such a trans-
formation can be efficiently performed through a cyanate-to-
isocyanate rearrangement reaction.43 We also demonstrated
that this procedure has several significant advantages over other
known processes, for example, Overman rearrangement (vide
infra).44
Thus, allylic alcohols 6a and 7a were transformed into
carbamates 11a and 12a by treatment with trichloroacetyl
isocyanate (TCA-NCO) (Scheme 5). The resulting carbamates
are stable and easier to handle than the corresponding
trichloroacetimidates used in the Overman reaction.
Scheme 2
Dehydration of 11a by treatment with trifluoroacetyl
anhydride (TFAA) in the presence of Et3N at 0 °C for 1 h
provided allyl cyanate 13, which spontaneously rearranged to
allyl isocyanate 14 (Scheme 6). This compound was not
isolated, but directly trapped with MeOLi to provide
stereospecifically carbamate 15 in 75% overall yield after 3
steps. Following the same one-pot, three-step protocol,
carbamate 12a was transformed into cyanate 16, which
rearranged to isocyanate 17. Direct treatment of 17 with
MeOLi gave carbamate 18 in 60% yield after 3 steps. Mild and
transition-metal-free reaction conditions, in contrast to Over-
man rearrangement, are additional advantages of the employed
process. Moreover, treatment of the resulting allyl isocyanate
(e.g., 14 or 17) with various nucleophiles opens a direct route
to variously N-functionalized allylamines and, in consequence,
differently protected amino acids (Table 1).
Next, we focused on the stereoselective transformation of
enone 5 into alcohols 6 and 7. Disappointingly, Corey−
Bakshi−Shibata reduction39 of enone 5a with BH3·Me2S in the
presence of chiral oxazaborolidine (S)-8 yielded a hardly
separable mixture of alcohols 6a and 7a in a 4:1 ratio (Scheme
3). Lowering the reaction temperature from −30 to −78 °C did
not increase the reaction selectivity. Therefore, due to lack of
synthetic attractiveness, this approach to the synthesis of
diastereomeric alcohols 6 and 7 was rejected.
Searching for an effective method of stereoselective synthesis
of alcohols of type 6 and 7, we turned to enzymatic kinetic
resolution40 of diastereomeric alcohols 9. For this purpose,
Finally, ozonolysis of 15 and 18 in the presence of 2.5 M
methanolic NaOH (Marshall’s procedure45) gave methyl L-allo-
threonate 29 and methyl D-threonate 30, respectively (Scheme
7). Similarly, allylamines 19−21 and 22−24 were converted
into the corresponding amino esters 31−33 and 34−36
(Scheme 7).
Scheme 3
Next, we prepared another two isomers of threonine, methyl
L-threonate ent-34 and methyl D-allo-threonate ent-31, starting
from methyl D-lactate and following the reaction sequence
presented in Scheme 8.
The same approach was used to prepare β-phenyl-serines 38,
40 and γ-phenyl-threonines 39 and 41, starting from methyl L-
mandelate and methyl L-phenyllactate, respectively (see
Schemes 4, 5, and 7).
The above strategy is also applicable to the preparation of γ-
hydroxy α-amino acids. This was exemplified by the synthesis
of the corresponding amino acids 43a/45a and 43b/45b
starting from commercially available methyl (S)-3-hydroxy-2-
B
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Scheme 4
Scheme 5
Table 1. Synthesis of N-Protected Allylamines via
Dehydration/Cyanate-to-Isocyanate Rearrangement
a
b
entry
carbamate
nucleophile
R2
yield [%]
1
2
11a
11a
11a
11a
12a
12a
12a
12a
11b
12b
11c
12c
MeOLi
BnOLi
Moc (15)
Cbz (19)
Boc (20)
Ac (21)
75
76
84
83
86
70
76
86
77
67
82
60
3
t-BuOLi
MeMgBr
MeOLi
BnOLi
4
5
Moc (18)
Cbz (22)
Boc (23)
Ac (24)
6
7
t-BuOLi
MeMgBr
BnOLi
8
9
Cbz (25)
Cbz (26)
Cbz (27)
Cbz (28)
10
11
12
BnOLi
BnOLi
methylpropanoate (Roche methyl ester) and methyl (R)-3-
BnOLi
hydroxybutanoate, as shown in Scheme 9.
a
Reaction conditions: A cooled solution of carbamate (1 equiv) and
Et3N (6 equiv) in dry THF was treated with TFAA (2 equiv). After 1
h, a solution of nucleophile (ROLi or RMgBr) was added; Isolated
yield after 3 steps. TFAA = trifluoroacetyl anhydride
CONCLUSIONS
b
■
In conclusion, we described a new strategy for stereoselective
preparation of all isomers of β-hydroxy α-amino acids. The
developed procedure is based on enzymatic kinetic resolution
and cyanate-to-isocyanate rearrangement as key steps. Proper
choice of the starting hydroxyacid and the course of kinetic
resolution enables the synthesis of all isomeric allyl diols.
These, in turn, allow the stereoselective synthesis of all isomeric
β-hydroxy α-amino acids, such as threonines, after rearrange-
ment and further oxidation of the double bond. We have also
presented an extension of this strategy that enables preparation
of γ-hydroxy α-amino acids. The incorporation of the amino
functionality in the cyanate-to-isocyanate rearrangement step
has several advantages. The reaction proceeds under mild
conditions and does not require any transition-metal catalyst.
The allyl carbamates, precursors of allyl isocyanates, are easily
prepared and handled. As shown, the stereochemical course of
sigmatropic rearrangement does not depend on the other
Scheme 6
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separated and dried over anhydr. Na2SO4. After removal of the solvent,
the residue was chromatographed on silica gel (5% AcOEt in
cyclohexane) to afford 31.3 g (80%) of product 4a as a colorless oil.
[α]2D2 −31.5 (c 1.4, CH2Cl2) [lit. −31.7 (c 0.66, CHCl3)46]; Spectral
data:47 1H NMR (400 MHz, CDCl3) δ: 4.33 (m, 3H, CH3O), 4.24−
4.10 (m, 1H, CH3CH), 1.39 (d, J 6.8 Hz, 3H, CH3CH), 0.90 (s, 9H, t-
BuSi), 0.10 (s, 3H, CH3Si), 0.07 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 174.6, 68.4, 51.8, 25.7, 21.4, 18.3, −5.1, −5.3; HRMS (ESI-
TOF) m/z calcd for C11H24O3SiNa [M + Na+] 255.1392. Found
255.1390.
Scheme 7
Ethyl (R)-O-(t-Butyldimethylsilyl)-lactate (ent-4a). Prepared in
the same manner as compound 4a. [α]2D2 +30.1 (c 1.0, CH2Cl2);
HRMS (ESI-TOF) m/z calcd for C11H24O3SiNa [M + Na+] 255.1392.
Found 255.1392.
Methyl (S)-2-(t-Butyldimethylsilyloxy)-2-phenylacetate (4b).
To a solution of methyl (S)-(+)-mandelate (5 g, 30 mmol) and
imidazole (4.1 g, 60 mmol) in dry CH2Cl2 (100 mL), a solution of
TBSCl (4.3 g, 28.5 mmol) in CH2Cl2 (20 mL) was added. The
reaction mixture was stirred overnight. Water (50 mL) was added, and
the resulting mixture was stirred for 15 min. The organic layer was
separated, and the aqueous layer was washed with CH2Cl2 (2 × 50
mL). The combined organic extracts were washed with brine (25 mL)
and dried over anhydr. MgSO4, and solvent was removed under
diminished pressure. The residue was chromatographed on silica gel
(5% AcOEt in hexanes) to afford 7.3 g of product 4b (87%) as a
colorless oil. [α]2D3 +52.8 (c 1.95, CH2Cl2) [lit.48 +51.3 (c 1.03,
CHCl3)]; Spectral data:48 1H NMR (500 MHz, CDCl3) δ: 7.51−7.27
(m, 5H, Ph), 5.25 (s, 1H, PhCH), 3.69 (s, 3H, CH3O), 0.92 (s, 9H, t-
BuSi), 0.12 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 172.7, 139.3, 128.5, 128.2, 126.5, 74.6, 52.3, 25.8, 18.5,
−4.9, −5.0; IR (ATR) v: 1761 cm−1; HRMS (ESI-TOF) m/z calcd for
C15H24O3SiNa [M + Na+] 303.1392. Found 303.1394.
stereogenic center present in the initial allyl carbamate. Thus,
the effective chirality transfer allows for stereospecific
preparation of either erythro or threo hydroxy allylamines. In
addition, the allyl isocyanates, formed during the sigmatropic
rearrangement, can be easily and directly functionalized by
treatment with a nucleophile, which enables the preparation of
differently protected allylamines.
Methyl (S)-2-((t-Butyldimethylsilyl)oxy)-3-phenyl-
propanoate (4c). Methyl L-phenyllactate (5.5 g, 30.5 mmol) and
imidazole (2.7 g, 40 mmol) were dissolved in dry CH2Cl2 (150 mL).
The solution was cooled to −15 °C, and a solution of TBSCl (4.5 g,
30 mmol) in dry CH2Cl2 (15 mL) was added. The reaction mixture
was stirred for 3 h at room temperature. After that time, water (10
mL) was added, and the organic phase was separated and dried over
anhydr. Na2SO4. After removal of solvent, the residue was chromato-
graphed on silica gel (5% AcOEt in cyclohexane) to afford 5.7 g (65%)
EXPERIMENTAL SECTION
■
Methyl (S)-O-(t-Butyldimethylsilyl)-lactate (4a). Methyl L-
lactate (20 g, 19.4 mL, 169 mmol) and imidazole (22 g, 320 mmol)
were dissolved in dry CH2Cl2 (350 mL). The solution was cooled to
−15 °C and a solution of TBSCl (23 g, 155 mmol) in dry CH2Cl2 was
added. The reaction mixture was stirred for 3 h at room temperature.
After that time, water (200 mL) was added and the organic phase was
of product 4c as a colorless oil. [α]2D4 −32.8 (c 2.05, CH2Cl2); H
1
a
Scheme 8
a
Reagents and conditions: (a) vinyl acetate, Novozyme 435, MS 4 Å, pentane, rt (92% of ent-6a and 94% of 37); (b) i. TCA-NCO, CH2Cl2, 0 °C; ii.
aq. K2CO3, MeOH, rt (91%); (c) i. TFAA, Et3N, THF, −10 °C; ii. BnOH, LiHMDS, THF (80%); (d) O3, NaOH, CH2Cl2/MeOH, −78 °C (73%);
(e) aq. K2CO3, MeOH, rt (84%); (f) i. TCA-NCO, CH2Cl2, 0 °C; ii. aq. K2CO3, MeOH, rt (90%); (g) i. TFAA, Et3N, THF, −10 °C; ii. BnOH,
LiHMDS, THF (75%); (h) O3, NaOH, CH2Cl2/MeOH, −78 °C (83%). TCA-NCO = trichloroacetyl isocyanate, TFAA = trifluoroacetyl anhydride.
D
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a
Scheme 9
a
Reagents and conditions: (a) i. DIBAL-H, CH2Cl2, −78 °C; ii. dimethyl(2-oxopropyl)phosphonate, NaH, THF, (77% for 4d, 75% for 4e); (b)
CeCl3·7H2O, NaBH4, CH2Cl2/MeOH, rt (90% for 9d, 86% for 9e); (c) vinyl acetate, Novozyme 435, MS 4 Å, pentane (94% for 10d, 94% for 7d,
92% for 10e, and 96% for 7e); (d) i. TCA-NCO, CH2Cl2, 0 °C; ii. aq. K2CO3, MeOH, rt (79% for 12d, 84% for 12e); (e) i. TFAA, Et3N, THF, −10
°C; ii. BnOH, LiHMDS, THF (87% for 42a, 78% for 42b); (f) O3, NaOH, CH2Cl2/MeOH, −78 °C (87% for 43a, 60% for 43b); (g) aq. K2CO3,
MeOH, rt (85% for 6d, 65% for 6e); (h) i. TCA-NCO, CH2Cl2, 0 °C; ii. aq. K2CO3, MeOH, rt (97% for 11d, 74% for 11e); (i) i. TFAA, Et3N,
THF, −10 °C; ii. BnOH, LiHMDS, THF (88% for 44a, 87% for 44b); (j) O3, NaOH, CH2Cl2/MeOH, −78 °C (87% for 45a, 93% for 45b); TCA-
NCO = trichloroacetyl isocyanate, TFAA = trifluoroacetyl anhydride.
NMR (500 MHz, CDCl3) δ: 7.35−7.12 (m, 5H, Ph), 4.34 (dd, J 9.0,
3.9 Hz, 1H, CHCOOMe), 3.72 (s, 3H, CH3O), 3.07 (dd, J 13.4, 3.9
Hz, 1H, PhCHH), 2.88 (dd, J 13.4, 9.0 Hz, 1H, PhCHH), 0.79 (s, 9H,
t-BuSi), −0.12 (s, 3H, CH3Si), −0.21 (s, 3H, CH3Si); 13C NMR (126
MHz, CDCl3) δ: 173.7, 137.6, 129.9, 128.3, 126.7, 74.0, 41.8, 27.1,
25.7, 18.4, −5.4, −5.5; IR (film) v: 1762 cm−1; HRMS (ESI-TOF) m/
z calcd for C16H26O3SiLi [M + Li+] 301.1811. Found 301.1804.
Methyl (S)-3-((t-Butyldimethylsilyl)oxy)-2-methyl-
propanoate (4d). Methyl (S)-(+)-3-hydroxy-2-methylpropionate
(5.0 g, 42.3 mmol) and imidazole (3.4 g, 50.0 mmol) were dissolved
in dry CH2Cl2 (150 mL). The solution was cooled to −15 °C, and a
solution of TBSCl (6.45 g, 43.0 mmol) in dry CH2Cl2 (20 mL) was
added. The reaction mixture was stirred for 3 h at room temperature.
After that time, water (100 mL) was added, and the organic phase was
separated and dried over anhydr. Na2SO4. After removal of solvent, the
residue was chromatographed on silica gel (10% AcOEt in
cyclohexane) to afford 8.6 g (88%) of product 4d as a colorless oil.
[α]D24 +20.3 (c 1.3 CH2Cl2) [lit.49 +18.8 (c 1, CHCl3)]; 1H NMR (500
MHz, CDCl3) δ: 3.77 (dd, J 9.7, 6.9 Hz, 1H, TBSOCHH), 3.67 (s,
3H, CH3O), 3.65 (dd, J 9.7, 6.1 Hz, 1H, TBSOCHH), 2.70−2.59 (m,
1H, CH3CH), 1.14 (d, J 7.0 Hz, 3H, CH3CH), 0.87 (s, 9H, t-BuSi),
0.07−0.01 (m, 6H, 2× CH3Si); 13C NMR (126 MHz, CDCl3) δ:
175.4, 65.2, 51.5, 42.5, 25.7, 18.2, 13.4, −5.5; IR (film) v: 1743, 1256,
1099, 838, 777 cm−1; HRMS (ESI-TOF) m/z calcd for C11H24O3SiNa
[M + Na+] 255.1392. Found 255.1388.
Methyl (R)-3-((t-Butyldimethylsilyl)oxy)butanoate (4e).
Methyl (R)-(−)-3-hydroxybutyrate (6.0 g, 50.79 mmol) and imidazole
(5.2 g, 76.38 mmol) were dissolved in dry CH2Cl2 (200 mL). The
solution was cooled to −15 °C, and a solution of TBSCl (7.6 g, 50.79
mmol) in dry CH2Cl2 (25 mL) was added. The reaction mixture was
stirred for 3 h at room temperature. After that time, water (100 mL)
was added, and the organic phase was separated and dried over anhydr.
Na2SO4. After removal of the solvent, the residue was chromato-
graphed on silica gel (10% AcOEt in cyclohexane) to afford 4.27 g
(63%) of product as a colorless oil. [α]2D4 −32.5 (c 1.34, CH2Cl2) [lit.50
−32 (c 1.3, CHCl3)]; Spectral data:47 1H NMR (500 MHz, CDCl3) δ:
4.37−4.19 (m, 1H, CH3CH), 3.66 (s, 3H, CH3O), 2.48 (dd, J 14.5, 7.7
Hz, 1H, CHHCOOMe), 2.37 (dd, J 14.5, 5.3 Hz, 1H, CHHCOOMe),
1.19 (d, J 6.1 Hz, 3H, CH3CH), 0.86 (s, 9H, t-BuSi), 0.06 (s, 3H,
CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ 172.2,
66.0, 51.5, 44.9, 25.8, 24.1, 18.1, −4.4, −4.9; IR (film) v: 2955, 2930,
1743, 1256, 1085, 837, 776 cm−1; HRMS (ESI-TOF) m/z calcd for
C11H24O3SiNa [M + Na+] 255.1392. Found 255.1392.
(S,E)-5-((t-Butyldimethylsilyl)oxy)hex-3-en-2-one (5a). To a
solution of ester 4a (10 g, 43 mmol) in dry CH2Cl2 (200 mL) at −78
°C, a 1 M solution of DIBAL-H in hexanes (43 mL, 43 mmol) was
added over 1 h (syringe pump). In a second flask, to a suspension of
NaH (2.24 g, 60% disp. in mineral oil, 56 mmol) in dry THF (200
mL), dimethyl (2-oxopropyl)phosphonate (9.3 g, 7.7 mL, 56 mmol)
was slowly added, and the mixture was stirred at room temperature for
1 h to produce the HWE reagent solution. When reduction was
completed (TLC control, 20% AcOEt in hexanes), a solution of HWE
reagent was cannulated into the aldehyde solution at −78 °C. The
resulting mixture was allowed to warm up slowly to room temperature
and was stirred for 3 h. Sat. aq. Rochelle salt (100 mL) was carefully
added to the mixture, and stirring was continued for 30 min. The
mixture was diluted with Et2O (300 mL). The organic layer was
separated, and the aqueous solution was extracted with Et2O (4 × 50
mL). The combined organic extracts were dried over Na2SO4, and
solvents were removed under reduced pressure. The residue was
purified by chromatography on silica gel (10% AcOEt/hexanes) to
give 7.95 g of 5a (80%) as a colorless oil. [α]2D2 +8.8 (c 2.0, CHCl3);
1H NMR (500 MHz, CDCl3) δ: 6.73 (dd, J 15.8, 3.9 Hz, 1H, CH
CHCOMe), 6.22 (d, J 15.8 Hz, 1H, CHCHCOMe), 4.52−4.41 (m,
1H, CHMe), 2.26 (m, 3H, CH3CO), 1.27 (d, J 6.4 Hz, 3H, CH3CH),
0.91 (s, 9H, t-BuSi), 0.07 (s, 3H, CH3Si), 0.06 (s, 3H, CH3Si); 13C
NMR (126 MHz, CDCl3) δ: 198.9, 150.8, 128.3, 67.9, 27.4, 25.9, 23.8,
18.4, −4.7; IR (film) v: 1681 cm−1; HRMS (ESI-TOF) m/z calcd for
C12H24O2SiNa [M + Na+] 251.1443. Found 251.1438.
(R,E)-5-((t-Butyldimethylsilyl)oxy)hex-3-en-2-one (ent-5a).
Prepared in the same manner as compound 5a. [α]2D2 −9.1 (c 1.5,
CHCl3); HRMS (ESI-TOF) m/z calcd for C12H24O2SiNa [M + Na+]
251.1443. Found 251.1441.
(R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-one
(5b). Compound 5b was prepared in the same manner as compound
5a. Yield 86%; colorless oil; [α]2D5 +46.2 (c 1, CHCl3); 1H NMR (500
MHz, CDCl3) δ: 7.40−7.23 (m, 5H, Ph), 6.77 (dd, J 15.8, 4.8 Hz, 1H,
CHCHCOMe), 6.34 (dd, J 15.8, 1.5 Hz, 1H, CHCHCOMe),
E
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5.39−5.29 (m, 1H, CHPh), 2.23 (s, 3H, CH3CO), 0.91 (s, 9H, t-BuSi),
0.07 (s, 3H, CH3Si), −0.04 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 198.9, 149.3, 141.8, 128.7, 128.2, 127.9, 126.3, 74.5, 27.2,
25.9, 18.4, −4.72, −4.74; IR (film) v: 1678, 1254, 838 cm−1; HRMS
(ESI-TOF) m/z calcd for C17H27O2Si [M + H+] 291.1780. Found
291.1777.
(S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-one
(5c). Compound 5c was prepared in the same manner as compound
5a. Purification by chromatography on silica gel (10% AcOEt/
hexanes). Yield 3.29 g (70%) starting from 4.53 g (15.38 mmol) of
ester 4c; colorless oil; [α]2D3 +4.2 (c 2.4, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.36−7.10 (m, 5H), 6.75 (dd, J 15.9, 4.9 Hz, 1H, CH
CH-COMe), 6.20 (dd, J 15.9, 1.5 Hz, 1H, CHCH−COMe), 4.55−
4.39 (m, 1H, CH3CO), 2.89−2.76 (m, 2H, PhCH2), 2.23 (s, 3H,
CH3CO), 0.86 (s, 9H, t-BuSi), −0.08 (s, 3H, CH3Si), −0.20 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 198.6, 149.2, 137.6, 129.9,
129.3, 128.4, 126.7, 73.4, 44.6, 27.4, 25.9, 18.3, −4.7, −5.2; IR (film) v:
1680, 1254, 1118 cm−1; HRMS (ESI-TOF) m/z calcd for C18H28-
O2SiNa [M + Na+] 327.1756. Found 327.1753.
(R,E)-6-(t-Butyldimethylsilyloxy)-5-methylhex-3-en-2-one
(5d). Compound 5d was prepared in the same manner as compound
5a. Purification by chromatography on silica gel (10% AcOEt/
hexanes). Yield 4.1 g (77%) starting from 5 g (21.6 mmol) of ester 4d;
colorless oil; [α]2D3 +25.3 (c 2.05, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 6.78 (dd, J 16.2, 7.1 Hz, 1H, CHCHCOMe), 6.08 (dd, J
16.2, 1.2 Hz, 1H, CHCHCOMe), 3.57−3.53 (m, 2H, CH2OTBS),
2.56−2.47 (m, 1H, −CHCH3), 2.24 (s, 3H, CH3CO), 1.06 (d, J 6.8
Hz, 3H, CH3CH), 0.89 (s, 9H, t-BuSi), 0.03 (s, 6H, 2 × CH3Si); 13C
NMR (125 MHz, CDCl3) δ: 198.7, 150.6, 130.7, 66.9, 39.3, 26.7, 25.8,
25.7, 15.5, −5.4; IR (film) v: 1679, 1254, 1098 cm−1; HRMS (ESI-
TOF): m/z calcd for C13H26O2SiNa [M + Na+] 265.1600. Found
265.1599.
(R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-one (5e). Com-
pound 5e was prepared in the same manner as compound 5a.
Purification by chromatography on silica gel (10% AcOEt/hexanes).
Yield 3.02 g (75%) starting from 3.8 g (16.35 mmol) of ester 4e;
colorless oil. [α]2D2 −14.9 (c 1.15, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 6.80 (dt, J 16.0, 7.4 Hz, 1H, CHCHCO), 6.07 (d, J 16.0
Hz, 1H, CHCHCO), 3.94 (hept, J 6.0 Hz, 1H, CH3CH), 2.38−2.28
(m, 2H, CH2CHCH), 2.23 (s, 3H, CH3CO), 1.16 (d, J 6.1 Hz, 3H,
CH3CH), 0.87 (s, 9H, t-BuSI), 0.05 (s, 3H, CH3Si), 0.03 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 198.4, 145.2, 133.2, 67.6,
42.6, 26.6, 25.7, 23.8, 18.0, −4.5, −4.8; IR (film) v: 1742, 1677, 1254,
836, 775 cm−1; HRMS (ESI-TOF) m/z calcd for C13H26O2SiNa [M +
Na+] 265.1600. Found 265.1591.
(5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (9a). To a
suspension of enone 5a (5 g, 21.9 mmol) and CeCl3·7H2O (9.86 g,
26 mmol) in CH2Cl2-MeOH (3:1 v/v, 100 mL), NaBH4 (910 mg,
24.1 mmol) was added portionwise. After stirring at ambient
temperature for 3 h, the reaction mixture was partitioned between
CH2Cl2 (120 mL) and sat. aq. sodium potassium tartrate (50 mL).
The organic layer was separated, and the aqueous layer was washed
with CH2Cl2 (4 × 50 mL). The combined organic solutions were dried
over anhydr. Na2SO4, and the solvent was removed under reduced
pressure. The residue was chromatographed on silica gel (20%
AcOEt/hexanes) to afford 4.59 g (91%) of a mixture of alcohols 9a.
HRMS (ESI-TOF) m/z calcd for C12H26O2SiNa [M + Na+] 253.1600.
Found 253.1596.
(5R,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (5-epi-9a).
Prepared in the same manner as compound 9a. Yield 89% (NMR);
HRMS (ESI-TOF) m/z calcd for C12H26O2SiNa [M + Na+] 253.1600.
Found 253.1598.
(5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-ol
(9b). Prepared in the same manner as compound 9a and was used
directly in the next step. Yield 91%; HPLC: Chiralpak IB, 5% i-PrOH/
hexanes, flow 1 mL/min, Rt 7.1 min (2R,5R) and 8.7 min (2S,5R).
(S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-ol (9c).
Prepared in the same manner as compound 9a. Purification by
chromatography on silica gel (10% AcOEt/hexanes). Yield 95%.
(5R,E)-6-(t-Butyldimethylsilyloxy)-5-methylhex-3-en-2-ol
(9d). Prepared in the same manner as compound 9a. Purification by
chromatography on silica gel (10% AcOEt/hexanes); Yield 90%.
(6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-ol (9e). Pre-
pared in the same manner as compound 9a and used without further
purification. Yield 86%.
Enzymatic Kinetic Resolution of Alcohols 9a. A suspension of
alcohols 9a (4.06 g, 17.2 mmol), Novozyme 435 (100 mg), 4 Å
molecular sieves (500 mg), and vinyl acetate (25 mL) in pentane (30
mL) was stirred overnight. The progress of the reaction was followed
by 1H NMR. The reaction mixture was filtered through Celite, and the
solvent was removed under diminished pressure. The residue was
chromatographed on silica gel (15% AcOEt/hexanes) to afford 2.28 g
of acetate 10a (96%) and 1.93 g of alcohol 7a (94%).
(2R,5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-yl Acetate
(10a). 1H NMR (500 MHz, CDCl3) δ: 5.69 (dd, J 15.5, 5.1 Hz,
1H, CHCH), 5.59 (ddd, J 15.5, 6.2, 1.1 Hz, 1H, CHCH), 5.38−
5.28 (m, 1H, CHOAc), 4.34−4.23 (m, 1H, CHOTBS), 2.02 (s, 3H,
CH3CO), 1.29 (d, J 6.5 Hz, 3H, CH3), 1.19 (d, J 6.4 Hz, 3H, CH3),
0.88 (s, 9H, t-BuSi), 0.04 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si); 13C
NMR (126 MHz, CDCl3) δ: 170.4, 136.7, 128.1, 70.6, 68.6, 26.0, 24.4,
21.5, 20.4, 18.4, −4.5, −4.6; IR (film) v: 1739, 1241, 1101, 836 cm−1;
HRMS (ESI-TOF) m/z calcd for C14H28O3SiNa [M + Na+] 295.1705.
Found 295.1703.
(2S,5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (7a). dr >
23
95:5 (NMR); [α]D −3.5 (c 1.0, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 5.70−5.60 (m, 2H, CHCH), 4.34−4.25 (m, 2H, 2 ×
CH), 1.25 (d, J 6.4 Hz, 3H, CH3), 1.20 (d, J 6.4 Hz, 3H, CH3), 0.89 (s,
9H, t-BuSi), 0.05 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (126
MHz, CDCl3) δ; 134.7, 132.6, 68.7, 68.4, 26.0, 24.5, 23.5, 18.4, −4.4,
−4.6; IR (film) v: 3348, 1254, 1084, 1058, 835 cm−1; HRMS (ESI-
TOF) m/z calcd for C12H26O2SiNa [M + Na+] 253.1600. Found
253.1593.
(2S,5R,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (ent-6a).
Yield 1.1 g (47%); [α]2D3 −31.6 (c 0.9, CH2Cl2); HRMS (ESI-TOF)
m/z calcd for C12H26O2SiNa [M + Na+]253.1600. Found 253.1597.
Enzymatic Kinetic Resolution of Alcohols 9b. A suspension of
alcohols 9b (1.96 g, 6.7 mmol), Novozyme 435 (100 mg), 4 Å
molecular sieves (500 mg), and vinyl acetate (25 mL) in pentane (30
mL) was stirred overnight. The progress of the reaction was followed
1
by H NMR. The reaction mixture was filtered through a Celite pad,
and solvents were removed under diminished pressure. The residue
was chromatographed on silica gel (10% AcOEt/hexanes) to afford
1.07 g of acetate 10b (96%) and 0.98 g of alcohol 7b (96%).
(2R,5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-
yl Acetate (10b). Colorless oil; [α]2D2 +64.9 (c 1.6, CHCl3); 1H NMR
(500 MHz, CDCl3) δ: 7.30−7.16 (m, 5H, Ph), 5.77−5.66 (m, 2H,
CHCH), 5.34−5.28 (m, 1H, CH3CH), 5.13 (d, J 4.5 Hz, 1H,
PhCH), 1.97 (s, 3H, CH3CO), 1.25 (d, J 6.5 Hz, 3H, CH3CH), 0.87
(s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), −0.05 (s, 3H, CH3Si); 13C NMR
(126 MHz, CDCl3) δ: 170.4, 143.6, 135.3, 128.9, 128.4, 127.3, 126.2,
74.9, 70.4, 26.0, 21.5, 20.3, 18.5, −4.4, −4.7; IR (film) v: 1740, 1241,
837 cm−1; HRMS (ESI-TOF) m/z calcd for C19H30O3SiNa [M + Na+]
357.1862. Found 357.1863.
(2S,5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-
ol (7b). Colorless oil; [α]2D2 +21.7 (c 1.49, CHCl3); H NMR (500
1
MHz, CDCl3) δ: 7.26−7.14 (m, 5H, Ph), 5.78−5.64 (m, 2H, CH
CH), 5.12 (d, J 4.8 Hz, 1H, PhCH), 4.31−4.20 (m, 1H, CH3CH), 1.20
(d, J 6.4 Hz, 3H, CH3CH), 0.86 (s, 9H, t-BuSi), 0.01 (s, 3H, CH3Si),
−0.06 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ: 143.9, 133.6,
133.5, 128.35, 127.2, 126.1, 75.0, 68.3, 26.0, 23.3, 18.5, −4.4, −4.6; IR
(film) v: 3348, 1255, 836 cm−1; HRMS (ESI-TOF) m/z calcd for
C17H28O2SiNa [M + Na+] 315.1756. Found 315.1760.
Enzymatic Kinetic Resolution of Alcohols 9c. A suspension of
alcohols 9c (2.8, 9.14 mmol), Novozyme 435 (135 mg), 4 Å molecular
sieves (680 mg), and vinyl acetate (14 mL) in pentane (40 mL) was
1
stirred overnight. The progress of the reaction was followed by H
NMR. The reaction mixture was filtered through a Celite pad, and
solvents were removed under diminished pressure. The residue was
F
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
chromatographed on silica gel (10% → 20% AcOEt/hexanes) to afford
1.33 g of acetate 10c (84%) and 1.28 g of alcohol 7c (92%).
(2R,5S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-yl
(2S,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-ol (7e).
Colorless oil; [α]2D2 −13.7 (c 2.5, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 5.68−5.59 (m, 1H, CHCH), 5.54 (dd, J 15.4, 6.4 Hz, 1H,
CHCH), 4.32−4.21 (m, 1H, CH), 3.86−3.77 (m, 1H, CH), 2.22−
2.07 (m, 2H, CH2), 1.25 (d, J 6.4 Hz, 3H, CH3), 1.12 (d, J 6.1 Hz,
3H), 0.88 (s, 9H, t-BuSi), 0.045 (s, 3H, CH3Si), 0.042 (s, 3H, CH3Si);
13C NMR (126 MHz, CDCl3) δ 136.3, 127.6, 68.9, 68.5, 42.4, 25.8,
23.5, 23.3, 18.1, −4.5, −4.7; IR (film) v: 3345, 1256, 1077, 1060, 833
cm−1; HRMS (ESI-TOF) m/z calcd for C13H28O2SiNa [M + Na+]
267.1756. Found 267.1754.
1
Acetate (10c). Colorless oil; H NMR (500 MHz, CDCl3) δ: 7.30−
7.09 (m, 5H, Ph), 5.71 (dd, J 15.4, 5.7 Hz, 1H, CHCH), 5.56 (ddd,
J 15.5, 6.3, 0.8 Hz, 1H, CHCH), 5.36−5.29 (m, 1H, CHO−), 4.26
(q, J 6.1 Hz, 1H, CHO−), 2.74 (d, J 6.5 Hz, 2H, CH2Ph), 2.02 (s, 3H,
CH3CO), 1.27 (d, J 6.5 Hz, 3H, CHCH3), 0.84 (d, J 9.4 Hz, 9H, t-
BuSi), −0.12 (s, 3H, CH3Si), −0.21 (s, 3H, CH3Si); 13C NMR (126
MHz, CDCl3) δ: 170.6, 138.6, 134.9, 130.1, 129.4, 128.2, 126.3, 74.2,
70.5, 45.2, 25.9, 21.5, 20.4, 18.34, −4.6, −5.1; HRMS (ESI-TOF) m/z
calcd for C20H32O3SiNa [M + Na+] 371.2018. Found 371.2012.
(2S,5S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-ol
(2R,5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (6a). To a
solution of acetate 10a (2.15 g, 7.89 mmol) in MeOH (12 mL), a
solution of K2CO3 (2.18 g, 15.77 mmol) in H2O (5 mL) was added,
and the resulting mixture was kept at ambient temperature. The
progress of hydrolysis was followed by TLC (20% AcOEt/hexanes).
After stirring overnight, MeOH was removed under diminished
pressure and the aqueous solution was extracted with CH2Cl2 (3 × 50
mL). The combined organic extracts were dried over anhydr. Na2SO4,
and the solvent was removed under diminished pressure. The residue
was chromatographed on silica gel (10% → 20% AcOEt/hexanes) to
afford 1.61 g of alcohol 6a (88%) as a colorless oil. [α]2D3 +32 (c 1.1,
(7c). Colorless oil; [α]D23 −9.7 (c 1, CHCl3); H NMR (500 MHz,
1
CDCl3) δ: 7.34−7.04 (m, 5H, Ph), 5.73−5.56 (m, 2H, CHCH),
4.34−4.20 (m, 2H, 2× CHO−), 2.76 (d, J 6.5 Hz, 2H, CH2Ph), 1.22
(d, J 6.4 Hz, 3H, CH3CH), 0.84 (s, 9H, t-BuSi), −0.09 (s, 3H, CH3Si),
−0.20 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ: 138.6, 133.8,
132.8, 129.9, 128.0, 126.1, 74.1, 68.3, 45.2, 25.8, 23.3, 18.2, −4.6, −5.2;
IR (film) v: 3353, 1254, 1078, 835 cm−1; HRMS (ESI-TOF) m/z calcd
for C18H30O2SiNa [M + Na+] 329.1913. Found 329.1908.
1
Enzymatic Kinetic Resolution of Alcohols 9d. A suspension of
alcohols 9d (2.45 g, 10 mmol), Novozyme 435 (150 mg), 4 Å
molecular sieves (750 mg), and vinyl acetate (11 mL) in pentane (50
mL) was stirred overnight. The progress of the reaction was followed
CH2Cl2); H NMR (500 MHz, CDCl3) δ: 5.74−5.57 (m, 2H, CH
CH), 4.40−4.22 (m, 2H, CH3CHOTBS, CH3CHOH), 1.27 (d, J 6.4
Hz, 3H, CH3CH), 1.21 (d, J 6.4 Hz, 3H, CH3CH), 0.90 (s, 9H, t-
BuSi), 0.06 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ 134.8, 132.6, 68.7, 68.6, 26.1, 24.5, 23.5, 18.4, −4.4, −4.6; IR
(film) v: 3342, 1255, 1080, 1062, 834 cm−1; HRMS (ESI-TOF) m/z
calcd for C12H26O2SiNa [M + Na+] 253.1600. Found 253.1591.
(2R,5R,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-ol (ent-7a).
1
by H NMR. The reaction mixture was filtered through a Celite pad,
and solvents were removed under diminished pressure. The residue
was chromatographed on silica gel (10% → 20% AcOEt/hexanes) to
afford 1.36 g of acetate 10d (94%) and 1.15 g of alcohol 7d (94%, dr
95:5, NMR).
23
Yield 752 mg (84%); colorless oil; [α]D +3.7 (c 1.2, CHCl3);
HRMS (ESI-TOF) m/z calcd for C12H26O2SiNa [M + Na+] 253.1600.
Found 253.1598.
(2R,5R,E)-6-(tert-Butyldimethylsilyloxy)-5-methylhex-3-en-2-
yl Acetate (10d). [α]2D3 +56.2 (c 1.9, CHCl3); H NMR (500 MHz,
1
CDCl3) δ: 5.64 (dd, J 15.6, 6.9 Hz, 1H, CHCH), 5.49 (dd, J 15.6,
6.5 Hz, 1H, CHCH), 5.32 (p, J 6.4 Hz, 1H, CHOAc), 3.47 (dd, J
9.7, 6.4 Hz, 1H, CHHOTBS), 3.41 (dd, J 9.7, 6.7 Hz, 1H,
CHHOTBS), 2.37−2.25 (m, 1H, CHCH3), 2.03 (s, 3H, CH3CO),
1.29 (d, J 6.4 Hz, 3H, CH3CHOAc), 0.98 (d, J 6.8 Hz, 3H, CH3CH),
0.89 (s, 9H, t-BuSi), 0.03 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz,
CDCl3) δ 170.5, 135.6, 129.3, 71.2, 67.9, 39.0, 26.1, 21.5, 20.5, 18.5,
16.3, −5.2, −5.2; HRMS (ESI-TOF) m/z calcd for C15H30O3SiNa [M
+ Na+] 309.1862. Found 309.1858.
(2R,5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-
ol (6b). Prepared in the same manner as compound 6a. Purification by
chromatography on silica gel (15% AcOEt/hexanes). Yield 0.76 g
(82%) starting from 1.07 g (3.21 mmol) of acetate 10b; colorless oil;
dr 95:5 (NMR); [α]2D3 +21.6 (c 1.1, CHCl3); H NMR (500 MHz,
1
CDCl3) δ: 7.27−7.14 (m, 5H, Ph), 5.75−5.62 (m, 2H, CHCH),
5.12 (d, J 5.0 Hz, 1H, PhCH), 4.28−4.20 (m, 1H, CH3CH), 1.21 (d, J
6.4 Hz, 3H, CH3CH), 0.85 (s, 9H, t-BuSi), 0.00 (s, 3H, CH3Si), −0.06
(s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ: 143.9, 133.7, 133.5,
128.4, 127.2, 126.1, 75.1, 68.4, 26.0, 23.3, 18.5, −4.4, −4.6; IR (film) v:
3348, 1255, 836 cm−1; HRMS (ESI-TOF) m/z calcd for C17H28-
O2SiNa [M + Na+] 315.1756. Found 315.1751.
(2S,5R,E)-6-(t-Butyldimethylsilyloxy)-5-methylhex-3-en-2-ol
(7d). Colorless oil; [α]D25 +4.5 (c 2.1, CHCl3); H NMR (500 MHz,
1
CDCl3) δ: 5.64−5.47 (m, 2H, CHCH), 4.32−4.22 (m, 1H,
CHOH), 3.48 (dd, J 9.7, 6.3 Hz, 1H, CHHOTBS), 3.40 (dd, J 9.7, 6.8
Hz, 1H, CHHOTBS), 2.37−2.21 (m, 1H, CHCH3), 1.26 (d, J 6.3 Hz,
3H, CH3CHOH), 0.99 (d, J 6.8 Hz, 3H, CH3CH), 0.89 (s, 9H, t-
BuSi), 0.04 (s, 6H, 2 × CH3Si); 13C NMR (125 MHz, CDCl3) δ:
134.1, 133.6, 69.2, 68.1, 39.0, 26.1, 23.6, 18.5, 16.6, −5.17, −5.19; IR
(film) v: 3350, 1255, 1120, 1091, 837 cm−1; HRMS (ESI-TOF) m/z
calcd for C13H28O2SiNa [M + Na+] 267.1756. Found 267.1756.
Enzymatic Kinetic Resolution of Alcohols 9e. A suspension of
alcohols 9e (2.4 g,), Novozyme 435 (146 mg), 4 Å molecular sieves
(730 mg), and vinyl acetate (23 mL) in pentane (45 mL) was stirred
overnight. The progress of the reaction was followed by 1H NMR. The
reaction mixture was filtered through a Celite pad, and solvents were
removed under diminished pressure. The residue was chromato-
graphed on silica gel (10% to 20% AcOEt/hexanes) to afford 1.28 g of
acetate 10e (92%) and 1.16 g of alcohol 7e (96%, dr 94:6, NMR).
(2R,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-yl Acetate
(10e). Colorless oil; [α]D22 +21.7 (c 2.2, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 5.74−5.62 (m, 1H, CHCH), 5.47 (ddt, J 15.4, 6.6, 1.2
Hz, 1H, CHCH), 5.35−5.26 (m, 1H, CH), 3.86−3.76 (m, 1H,
CH), 2.20−2.06 (m, 2H, CH2), 2.02 (s, 3H, CH3CO), 1.28 (d, J 6.5
Hz, 3H, CH3), 1.10 (d, J 6.1 Hz, 3H, CH3), 0.87 (s, 9H, t-BuSi), 0.03
(s, 3H, CH3Si), 0.03 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
170.3, 131.5, 129.9, 70.9, 68.3, 42.5, 25.8, 25.7, 23.6, 21.4, 20.2, 18.1,
−4.5, −4.8; HRMS (ESI-TOF) m/z calcd for C15H30O3SiNa [M +
Na+] 309.1862. Found 309.1862.
(2R,5S,E)-5-((t-Butyldimethylsilyl)oxy)-6-phenylhex-3-en-2-
ol (6c). Prepared in the same manner as compound 6a. Purification by
chromatography on silica gel (10% AcOEt/hexanes). Yield 0.98 g
(84%) starting from 1.33 g (3.82 mmol) of acetate 10c; as colorless
oil; [α]2D3 +0.6 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.29−
7.14 (m, 5H, Ph), 5.67 (dd, J 15.8, 5.4 Hz, 1H, CHCH), 5.61 (dd, J
15.8, 5.6 Hz, 1H, CHCH), 4.34−4.22 (m, 2H, CH3CH, BnCH),
2.76 (d, J 6.5 Hz, 2H, PhCH2CH), 1.23 (d, J 6.4 Hz, 3H, CH3CH),
0.83 (s, 9H, t-BuSi), −0.10 (s, 3H, CH3Si), −0.21 (s, 3H, CH3Si); 13
C
NMR (126 MHz, CDCl3) δ: 138.7, 134.0, 132.9, 130.1, 128.2, 126.3,
74.3, 68.5, 45.3, 26.0, 23.4, 18.3, −4.5, −5.1; IR (film) v: 3349, 1254,
1077, 855 cm−1; HRMS (ESI-TOF) m/z calcd for C18H30O2SiNa [M
+ Na+] 329.1913. Found 329.1910.
(2R,5R,E)-6-((t-Butyldimethylsilyl)oxy)-5-methylhex-3-en-2-
ol (6d). Prepared in the same manner as compound 6a. Purification by
chromatography on silica gel (10% AcOEt/hexanes). Yield 1.08 g
(85%) starting from 1.4 g (4.88 mmol) of acetate 10d; colorless oil; dr
94:6 (NMR); [α]2D3 +18 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 5.59 (dd, J 15.6, 6.0 Hz, 1H, CHCH), 5.54 (dd, J 15.6, 5.6 Hz,
1H, CHCH), 4.30−4.22 (m, 1H, CHCHCHOH), 3.49 (dd, J 9.7,
6.2 Hz, 1H, TBSOCHH), 3.40 (dd, J 9.7, 6.9 Hz, 1H, TBSOCHH),
2.36−2.27 (m, 1H, CHCH3), 1.26 (d, J 6.3 Hz, 3H, CH3), 0.99 (d, J
6.8 Hz, 3H, CH), 0.89 (s, 9H, t-Bu) 0.04 (s, 6H, 2 × CH3Si); 13C
NMR (126 MHz, CDCl3) δ 134.0, 133.5, 69.1, 68.1, 38.9, 26.1, 23.5,
18.5, 16.6, −5.2; IR (film) v: 3348, 1471, 1255, 1089, 838, 775 cm−1;
G
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (TOF-ESI) m/z calcd for C13H28O2SiNa [M + Na+] 267.1756.
Found 267.1748.
11a. Purification by chromatography on silica gel (15% AcOEt/
hexanes). Yield 1.16 g (97%) starting from 1 g (4.09 mmol) of alcohol
6d; yellowish oil; [α]2D1 +20.1 (c 1.09, CHCl3); H NMR (400 MHz,
1
(2R,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-ol (6e).
Prepared in the same manner as compound 6a. Purification by
chromatography on silica gel (10% AcOEt/hexanes). Yield 808 mg
(65%) starting from 1.45 g (5.1 mmol) of acetate 10e ; colorless oil; dr
95:5 (NMR); [α]2D2 +1.4 (c 0.7, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 5.67−5.58 (m, 1H, CHCH), 5.53 (dd, J 15.4, 6.4 Hz, 1H, CH
CH), 4.30−4.19 (m, 1H, CH), 3.81 (h, J 6.1 Hz, 1H, Ci), 2.20−2.06
(m, 2H, CH2), 1.24 (d, J 6.3 Hz, 3H, CH3), 1.10 (d, J 6.1 Hz, 3H,
CH3), 0.86 (s, 9H, t-BuSi), 0.03 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si);
13C NMR (126 MHz, CDCl3) δ: 136.3, 127.6, 68.9, 68.4, 42.5, 25.8,
CDCl3) δ: 5.65 (ddd, J 15.6, 6.8, 0.8 Hz, 1H, CHCH), 5.50 (ddd, J
15.6, 6.3, 1.1 Hz, 1H, CHCH), 5.26−5.18 (m, 1H, CH3CHO),
4.67−4.52 (br s, 2H, NH2), 3.48 (dd, J 9.7, 6.3 Hz, 1H, CHHOTBS),
3.40 (dd, J 9.7, 7.0 Hz, 1H, CHHOTBS), 2.37−2.27 (m, 1H,
CH3CHCH2OTBS), 1.62 (d, J 6.4 Hz, 3H, CH3CHCH2OTBS), 0.98
(d, J 6.8 Hz, 3H, CH3CHO), 0.88 (s, 9H, 3 × CH3C), 0.03 (s, 6H, 2 ×
CH3Si); 13C NMR (100 MHz, CDCl3) δ: 156.3, 135.1, 129.4, 71.8,
67.78, 38.8, 26.9, 25.9, 20.5, 18.3, 16.2, −5.36, −5.39; IR (film) v:
3501, 3442, 3341, 3205, 1717, 1379, 1050, 833 cm−1; HRMS (ESI-
TOF) m/z calcd for C14H29NO3SiNa [M + Na+] 310.1814. Found
310.1813.
23.5, 23.3, 18.1, −4.5, −4.7; IR (film) v: 3358, 1256, 836, 774 cm−1;
HRMS (ESI-TOF) m/z calcd for C13H28O2SiNa [M + Na+] 267.1756.
Found 267.1751.
(2R,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-yl Carba-
mate (11e). Prepared in the same manner as compound 11a.
Purification by chromatography on silica gel (10% AcOEt/hexanes).
Yield 870 mg (74%) starting from 770 mg (4.1 mmol) of alcohol 6e;
colorless oil; [α]2D2 +9.9 (c 2.0, CHCl3); 1H NMR (600 MHz, CDCl3)
δ: 5.73−5.65 (m, 1H, CHCH), 5.48 (ddt, J 15.5, 6.4, 1.2 Hz, 1H,
CHCH), 5.24−5.15 (m, 1H, CH), 4.55 (s, 2H, NH2), 3.86−3.71
(m, 1H, CH), 2.21−2.07 (m, 2H, CH2), 1.29 (d, J 6.5 Hz, 3H, CH3),
1.10 (d, J 6.1 Hz, 3H, CH3), 0.87 (s, 9H, t-BuSi), 0.03 (s, 3H, CH3Si),
0.03 (s, 3H, CH3Si); 13C NMR (151 MHz, CDCl3) δ: 156.2, 131.7,
129.7, 71.7, 68.3, 42.6, 25.8, 23.5, 20.4, 18.1, −4.5, −4.8; IR (film) v:
3509, 3447, 3347, 3203, 1714, 1377, 1049, 835 cm−1; HRMS (ESI-
TOF) m/z C14H29NO3SiNa [M + Na+] 310.1814. Found 310.1811.
(2S,5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-yl Carba-
mate (12a). Prepared in the same manner as compound 11a.
Purification by chromatography on silica gel (20% AcOEt/hexanes).
Yield 1.85 g (97%) starting from 1.61 g (7 mmol) of alcohol 7a;
(2R,5S,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-yl Carba-
mate (11a). To a solution of alcohol 6a (1.89 g, 8.2 mmol) in dry
CH2Cl2 (30 mL) cooled to −10 °C, neat TCA-NCO (1.88 g, 1.2 mL,
10.0 mmol) was added. The progress of the reaction was followed by
TLC (20% AcOEt/hexanes). After 1 h, the solvent was removed under
diminished pressure. The residue was dissolved in MeOH (40 mL)
and water (10 mL), and K2CO3 (4.2 g, 30.0 mmol) was added. The
progress of the reaction was followed by TLC (20% AcOEt/hexanes).
After 2 h, MeOH was removed under diminished pressure and the
aqueous solution was extracted with CH2Cl2. The combined organic
extracts were dried over Na2SO4, and the solvent was removed under
diminished pressure. The residue was chromatographed on silica gel
(20% AcOEt/hexanes) to afford 2.13 g of carbamate 11a (95%) as a
colorless oil. [α]2D4 +20.3 (c 1.5, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 5.70 (ddd, J 15.5, 5.0, 0.8 Hz, 1H, CHCH), 5.61 (ddd, J 15.5, 6.1,
1.1 Hz, 1H, CHCH), 5.24 (p, J 6.4 Hz, 1H, CH3CH), 4.60 (s, 2H,
NH2), 4.30 (p, J 6.0 Hz, 1H, CH3CH), 1.31 (d, J 6.5 Hz, 3H,
CH3CH), 1.20 (d, J 6.4 Hz, 3H, CH3CH), 0.89 (s, 9H, t-BuSi), 0.05
(s, 3H, CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
156.2, 136.4, 128.1, 71.2, 68.5, 25.8, 24.3, 20.4, 18.3, −4.6, −4.8; IR
(film) v: 3509, 3248, 3276, 1717 cm−1; HRMS (ESI-TOF) m/z calcd
for C13H27NO3SiNa [M + Na+] 296.1658. Found 296.1657.
colorless oil. [α]2D4.5 −23.5 (c 1.41, CHCl3); H NMR (500 MHz,
1
CDCl3) δ: 5.70 (dd, J 15.5, 5.0 Hz, 1H, CHCH), 5.61 (ddd, J 15.5,
5.9, 1.1 Hz, 1H, CHCH), 5.24 (m, 1H, CH), 4.72 (s, 2H, NH2),
4.28 (m, 1H, CH), 1.30 (d, J 6.5 Hz, 3H, CH3), 1.20 (d, J 6.4 Hz, 3H,
CH3), 0.89 (s, 9H, t-BuSi), 0.08−0.02 (m, 6H, 2 × CH3Si); 13C NMR
(126 MHz, CDCl3) δ: 156.4, 136.2, 128.1, 71.0, 68.5, 25.8, 24.2, 20.4,
18.2, −4.6, −4.8; IR (film) v: 3507, 3349, 1716 cm−1; HRMS (ESI-
TOF) m/z calcd for C13H27NO3SiNa [M + Na+] 296.1658; Found
296.1656.
(2S,5R,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-yl Carba-
mate (ent-11a). Prepared as compound 11a. Yield 872 mg (90%);
colorless oil; [α]2D1 −19.3 (c 2.0, CHCl3); HRMS (ESI-TOF) m/z
calcd for C13H27NO3SiNa [M + Na+] 296.1658; Found 296.1655.
(2R,5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-
yl Carbamate (11b). Prepared as compound 11a. Purification by
chromatography on silica gel (15% AcOEt/hexanes). Yield 724 mg
(90%) starting from 681 mg (2.33 mmol) of alcohol 6b; colorless oil;
(2R,5R,E)-5-(t-Butyldimethylsilyloxy)hex-3-en-2-yl Carba-
mate (ent-12a). Prepared as compound 11a. Yield 660 mg (91%);
colorless oil. [α]2D2 +23.0 (c 1.2 CHCl3); HRMS (ESI-TOF) m/z calcd
for C13H27NO3SiNa [M + Na+] 296.1658. Found 296.1656.
(2S,5R,E)-5-((t-Butyldimethylsilyl)oxy)-5-phenylpent-3-en-2-
yl Carbamate (12b). Prepared in the same manner as compound
11a. Purification by chromatography on silica gel (15% AcOEt/
hexanes). Yield 737 mg (92%) starting from 700 mg (2.4 mmol) of
[α]2D2 +40.5 (c 1.1, CHCl3); H NMR (600 MHz, CDCl3) δ: 7.29−
1
7.16 (m, 5H, Ph), 5.80−5.66 (m, 2H, CHCH), 5.25−5.17 (m, 1H,
CH3CH), 5.13 (d, J 4.7 Hz, 1H, PhCH), 4.64 (s, 2H, NH2), 1.26 (d, J
6.5 Hz, 3H, CH3CH), 0.86 (s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), −0.06
(s, 3H, CH3Si); 13C NMR (151 MHz, CDCl3) δ: 156.4, 143.6, 135.0,
129.1, 128.3, 127.2, 126.1, 74.8, 71.1, 26.0, 20.5, 18.5, −4.4, −4.7; IR
(film) v: 3503, 3352, 1718, 1047, 837 cm−1; HRMS (ESI-TOF) m/z
calcd for C18H29NO3SiNa [M + Na+] 358.1814. Found 358.1811.
(2R,5S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-yl
Carbamate (11c). Prepared in the same manner as compound 11a.
Purification by chromatography on silica gel (20% AcOEt/hexanes).
Yield 783 mg (77%) starting from 890 mg (2.9 mmol) of alcohol 6c;
colorless oil; [α]2D2 +30 (c 0.8, CHCl3); 1H NMR (500 MHz, CDCl3)
δ: 7.32−7.10 (m, 5H, Ph), 5.73 (ddd, J 15.5, 5.7, 1.0 Hz, 1H, CH
CH), 5.58 (ddd, J 15.5, 6.2, 1.2 Hz, 1H, CHCH), 5.23 (p, J 6.4 Hz,
1H, BnCHOTBS), 4.59 (s, 2H, NH2), 4.26 (q, J 6.0 Hz, 1H, CH3CH),
2.83−2.66 (m, 2H, PhCH2CH), 1.28 (d, J 6.5 Hz, 3H, CH3CH), 0.83
(s, 9H, t-BuSi), −0.11 (s, 3H, CH3Si), −0.21 (s, 3H, CH3Si); 13C
NMR (126 MHz, CDCl3) δ: 156.2, 138.5, 134.6, 129.9, 129.4, 127.9,
126.1, 74.0, 71.1, 45.1, 25.8, 20.4, 18.2, −4.7, −5.3; IR (film) v: 3499,
3345, 3273, 3204, 1717, 1388, 1255, 1051, 836, 777 cm−1; HRMS
(ESI-TOF) m/z calcd for C19H31NO3SiNa [M + Na+] 372.1971.
Found 372.1974.
alcohol 7b; colorless oil; [α]2D4 −2.8 (c 1.1, CHCl3); H NMR (600
1
MHz, CDCl3) δ: 7.27−7.16 (m, 5H, Ph), 5.78−5.65 (m, 2H, CH
CH), 5.25−5.18 (m, 1H, CH3CH), 5.12 (d, J 5.0 Hz, 1H, PhCH), 4.58
(br s, 2H, NH2), 1.26 (d, J 6.5 Hz, 3H, CH3CH), 0.86 (s, 9H, t-BuSi),
0.02 (s, 3H, CH3Si), −0.06 (s, 3H, CH3Si); 13C NMR (151 MHz,
CDCl3) δ: 156.4, 143.7, 134.8, 129.2, 128.3, 127.2, 126.2, 74.9, 70.9,
26.0, 20.5, 18.5, −4.4, −4.7; IR (film) v: 3492, 3347, 3273, 1717, 1052
cm−1; HRMS (ESI-TOF) m/z calcd for C18H29NO3SiNa [M + Na+]
358.1814. Found 358.1812.
(2S,5S,E)-5-(t-Butyldimethylsilyloxy)-6-phenylhex-3-en-2-yl
Carbamate (12c). Prepared in the same manner as compound 11a.
Purification by chromatography on silica gel (20% AcOEt/hexanes).
Yield 1.3 g (95%) starting from 1.2 g (3.92 mmol) of alcohol 7c; as
colorless oil; [α]2D5 −27.3 (c 3.1, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.31−7.12 (m, 5H, Ph), 5.73 (ddd, J 15.5, 5.8, 1.1 Hz, 1H,
CHCH), 5.59 (ddd, J 15.5, 6.2, 1.2 Hz, 1H, CHCH), 5.23 (p, J
6.2 Hz, 1H, CHOTBS), 4.61 (br s, 2H, NH2), 4.25 (q, J 6.0 Hz, 1H,
CHOCONH2), 2.81−2.68 (m, 2H, PhCH2CH), 1.27 (d, J 6.5 Hz, 3H,
CHCH3), 0.83 (s, 9H, t-BuSi), −0.11 (s, 3H, CH3Si), −0.22 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 156.4, 138.6, 134.7, 130.1,
129.6, 128.1, 126.3, 74.2, 71.2, 45.2, 25.9, 20.6, 18.3, −4.6, −5.1; IR
(film) v: 3504, 3342, 3273, 1718, 1387, 1053, 836, 778 cm−1; HRMS
(2R,5R,E)-6-((t-Butyldimethylsilyl)oxy)-5-methylhex-3-en-2-
yl Carbamate (11d). Prepared in the same manner as compound
H
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ESI-TOF) m/z calcd for C19H31NO3SiNa [M + Na+] 372.1971.
Found 372.1977.
(150 mg, 0.55 mmol) and Et3N (333 mg, 460 μL, 3.29 mmol) in dry
THF (10 mL), TFAA (230 mg, 150 μL, 1.1 mmol) was added, and the
resulting mixture was slowly warmed to room temperature. The
progress of the reaction was followed by TLC (20% AcOEt in
hexanes). In a separate flask, a 1 M soln. of LiHMDS in THF (3.3 mL,
3.29 mmol) was added to anhydr. BnOH (350 μL) in 10 mL of THF.
When rearrangement was completed (ca. 1 h), the solution of BnOLi
was cannulated, and the reaction mixture was stirred overnight at room
temperature. The progress of the reaction was followed by TLC (10%
AcOEt in hexanes). After removal of solvents, the crude product was
supported on silica gel and chromatographed (5% AcOEt in hexanes)
to give 138 mg of carbamate 19 (76%) as a colorless oil; [α]2D2 −3.3 (c
0.87, CHCl3); 1H NMR (500 MHz, DMSO-d6) δ: 7.34−7.23 (m, 5H,
Ph), 7.09 (d, J 8.1 Hz, 1H, NH), 5.47 (dd, J 16.0, 6.4 Hz, 1H, CH
CH), 5.36 (dd, J 16.0, 6.6 Hz, 1H, CHCH), 5.01−4.93 (m, 2H,
PhCH2O), 3.80−3.65 (m, 2H, CHOTBS, CHNHCbz), 1.59 (d, J 6.2
Hz, 3H, CH3), 0.98 (d, J 6.1 Hz, 3H, CH3), 0.80 (s, 9H, t-BuSi), −0.03
(s, 3H, CH3Si), −0.05 (s, 3H, CH3Si); 13C NMR (126 MHz, DMSO-
d6) δ: 155.5, 137.3, 129.2, 128.3, 127.7, 127.6, 126.43, 69.9, 65.1, 59.0,
25.7, 20.2, 17.7, 17.6, −4.6, −4.9; IR (film) v: 3450, 3334, 1723, 1255,
835, 776 cm−1; HRMS (ESI-TOF) m/z calcd for C20H33NO3SiNa [M
+ Na+] 386.2127. Found 386.2126.
(2R,5R,E)-6-((t-Butyldimethylsilyl)oxy)-5-methylhex-3-en-2-
yl Carbamate (12d). Prepared in the same manner as compound
11a. Purification by chromatography on silica gel (20% AcOEt/
hexanes). Yield 933 mg (79%) starting from 1 g (4.09 mmol) of
compound 7d; yellowish oil; [α]2D3 −11.3 (c 1.25, CHCl3); H NMR
1
(500 MHz, CDCl3) δ: 5.63 (dd, J 15.7, 7.1 Hz, 1H, CHCH), 5.49
(dd, J 15.7, 6.4 Hz, 1H, CHCH), 5.25−5.18 (m, 1H,
CH3CHOCONH2), 4.60 (s, 2H, NH2), 3.47 (dd, J 9.7, 6.3 Hz, 1H,
TBSOCHH), 3.40 (dd, J 9.7, 6.8 Hz, 1H, TBSOCHH), 2.36−2.26 (m,
1H, CHCH3), 1.30 (d, J 6.4 Hz, 3H, CH3CHOCONH2), 0.99 (d, J 6.8
Hz, 3H, CH3CH), 0.89 (s, 9H, t-BuSi), 0.03 (s, 6H, 2 × CH3Si); 13C
NMR (126 MHz, CDCl3) δ 156.5, 135.4, 129.6, 72.0, 67.9, 39.1, 26.1,
20.7, 18.5, 16.5, −5.19, −5.22; IR (film) v: 3344, 1715, 1372, 1040,
832, 777 cm−1; HRMS (ESI-TOF) m/z calcd for C14H29NO3SiNa [M
+ Na+] 310.1814. Found 310.1806.
(2S,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-3-en-2-yl Carba-
mate (12e). Prepared in the same manner as compound 11a.
Purification by chromatography on silica gel (15% AcOEt/hexanes).
Yield 1.09 g (84%) starting from 1.1 g (4.5 mmol) of alcohol 7e;
colorless oil; [α]2D3 −25.7 (c 0.64, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 5.68 (dtd, J 15.6, 7.3, 1.1 Hz, 1H, CHCH), 5.49 (dd, J
15.5, 6.4 Hz, 1H, CHCH), 5.20 (qt, J 6.7, 3.3 Hz, 1H, CH), 4.55 (s,
2H, NH2), 3.84−3.82 (m, 1H, CH), 2.22−2.14 (m, 1H, CHH), 2.14−
2.05 (m, 1H, CHH), 1.29 (d, J 6.5 Hz, 3H, CH3), 1.10 (d, J 6.1 Hz,
3H, CH3), 0.86 (s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), 0.02 (s, 3H,
CH3Si); 13C NMR (126 MHz, cdcl3) δ 156.3, 131.7, 129.5, 71.7, 68.4,
42.6, 25.8, 23.5, 20.4, 18.1, −4.5, −4.7; IR (film) v: 3349, 1717, 1377,
1049, 836, 775 cm−1; HRMS (ESI-TOF) m/z calcd for C14H29-
NO3SiNa [M + Na+] 310.1814. Found 310.1809.
Methyl ((2S,3R,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-
yl)carbamate (15). To a solution of carbamate 11a (100 mg, 0.366
mmol) and Et3N (222 mg, 305 μL, 2.196 mmol) in dry THF (5 mL)
cooled to −20 °C, TFAA (153 mg, 111 μL, 0.732 mmol) was added,
and the resulting mixture was slowly warmed to room temperature.
The progress of the reaction was followed by TLC (20% AcOEt in
hexanes). In a separate flask, a 1 M soln. of LiHMDS in THF (2.2 mL,
2.2 mmol) was added to anhydr. MeOH (2 mL) in dry THF (5 mL).
When the rearrangement reaction was completed (ca. 1 h), the
solution of MeOLi was cannulated, and reaction mixture was stirred
overnight at room temperature. The progress of the reaction was
followed by TLC (20% AcOEt in hexanes). After removal of solvents,
the crude product was absorbed on silica gel and chromatographed
(10% AcOEt in hexanes) to give 100 mg of carbamate 15 (95%) as a
colorless oil. [α]2D3 −7.6 (c 0.64, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 5.66 (dd, J 15.4, 6.4 Hz, 1H, CHCHCH3), 5.42 (ddd, J
15.4, 7.7, 1.4 Hz, 1H, CHCHCH3), 4.89 (s, 1H, NH), 4.04−3.82
(m, 2H, 2 × CH), 3.66 (s, 3H, CH3O), 1.70 (dd, J 6.4, 1.4 Hz, 3H,
CHCHCH3), 1.06 (d, J 6.2 Hz, 3H, CH3CH), 0.89 (s, 9H, t-BuSi),
0.05 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz, CDCl3) δ: 158.9,
131.8, 129.3, 72.9, 61.4, 54.6, 28.4, 23.0, 20.7, 20.5, −1.7, −2.3; IR
(film) v: 3334, 1714, 1254, 835 cm−1; HRMS (ESI-TOF) m/z calcd
for C14H29NO3SiNa [M + Na+] 310.1814. Found 310.1820.
Benzyl ((2R,3S,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (ent-19). Prepared in the same manner as compound 19.
Yield 163 mg (80%); colorless oil; [α]2D2 +3.5 (c 0.95, CHCl3); HRMS
(ESI-TOF) m/z calcd for C20H33NO3SiNa [M + Na+] 386.2127.
Found 386.2125.
Benzyl ((1S,2R,E)-1-((t-Butyldimethylsilyl)oxy)-1-phenyl-
pent-3-en-2-yl)carbamate (25). Prepared in the same manner as
compound 19; Purification by chromatography on silica gel (5%
AcOEt in hexanes); Yield 183 mg (77%) starting from 200 mg (0.56
mmol) of carbamate 11b; colorless oil; [α]2D2 +61.8 (c 1.3, CHCl3); 1H
NMR (500 MHz, C6D6) δ: 7.40−6.97 (m, 10H, 2 × Ph), 5.42 (dd, J
15.3, 6.8 Hz, 1H, CHCH), 5.33−5.22 (m, 1H, CHCH), 5.14 (d, J
12.3 Hz, 1H, OCHHPh), 5.09 (d, J 12.3 Hz, 1H, OCHHPh), 4.99 (br
s, 1H, NH), 4.84 (d, J 8.0 Hz, 1H, CH), 4.58−4.47 (m, 1H, CH), 1.38
(br d, J 6.3 Hz, 3H, CH3CHCH), 0.93 (s, 9H, t-BuSi), 0.03 (s, 3H,
CH3Si), −0.14 (s, 3H, CH3Si); 13C NMR (126 MHz, C6D6, signals at
range 129.5−127.7 ppm were omitted due to overlapping with solvent
residual peaks) δ: 155.6, 142.0, 137.5, 127.5, 126.8, 77.1, 66.7, 60.2,
26.0, 25.9, 18.4, 17.7, −4.6, −5.0; IR (film) v: 3451, 3332, 1724, 1495,
1255, 834, 697 cm−1; HRMS (ESI-TOF) m/z calcd for C25H35-
NO3SiNa [M + Na+] 448.2284. Found 448.2285.
Benzyl ((2S,3R,E)-2-((t-Butyldimethylsilyl)oxy)-1-phenylhex-
4-en-3-yl)carbamate (27). Prepared in the same manner as
compound 19. Purification by chromatography on silica gel (5%
AcOEt in hexanes). Yield 215 mg (82%) starting from 200 mg (0.572
mmol) of compound 11c; colorless oil; [α]2D3 −4.3 (c 1, CHCl3); H
1
NMR (500 MHz, CDCl3) δ: 7.53−6.97 (m, 10H, 2 × Ph), 5.75−5.61
(m, 1H, CHCH), 5.58−5.45 (m, 1H, CHCH), 5.14−5.02 (m,
2H, OCH2Ph), 4.94 (s, 1H, NH), 4.12−3.94 (m, 2H, 2 × CH), 2.82−
2.58 (m, 2H, CH2Ph), 1.75 (d, J 5.5 Hz, 3H, CH3CHCH), 0.86 (s,
9H, t-BuSi), 0.00 (s, 3H, CH3Si), −0.26 (s, 3H, CH3Si); 13C NMR
(126 MHz, CDCl3) δ 155.4, 138.0, 136.7, 130.0, 129.5, 128.4, 128.4,
128.3, 127.9, 126.4, 126.3, 75.5, 66.5, 57.0, 40.7, 25.9, 18.1, 18.0, −4.7,
−4.9; IR (film) v: 3453, 3335, 1720, 1497, 1254, 835, 698 cm−1;
HRMS (ESI-TOF) m/z calcd for C26H38NO3Si [M + H+] 440.2621.
Found 440.2618.
Methyl ((2S,3S,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (18). Prepared in the same manner as compound 15.
Purification by chromatography on silica gel (10% AcOEt in hexanes).
Yield 103 mg (86%) starting from 100 mg (0.366 mmol) of compound
12a; colorless oil; [α]D22 +0.5 (c 0.9, CHCl3); H NMR (500 MHz,
Benzyl ((2R,3R,E)-1-((t-Butyldimethylsilyl)oxy)-2-methylhex-
4-en-3-yl)carbamate (44a). Prepared in the same manner as
compound 19. Purification by chromatography (4% AcOEt in
hexanes). Yield 176 mg (88%) starting from 150 mg (0.522 mmol)
1
CDCl3) δ: 5.65−5.55 (m, 1H, CHCHCH3), 5.41 (ddd, J 15.3, 6.1,
1.6 Hz, 1H, CHCHCH3), 4.99 (s, 1H, NH), 4.03−3.91 (m, 1H,
CH), 3.89−3.81 (m, 1H, CH), 3.68 (s, 3H, CH3O), 1.70−1.67 (m,
3H, CHCHCH3), 1.14 (d, J 6.2 Hz, 3H, CH3CH), 0.88 (s, 9H, t-
BuSi), 0.04 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si); 13C NMR (151 MHz,
CDCl3) δ: 156.9, 130.6, 126.1, 70.5, 58.0, 52.0, 25.7, 20.9, 18.0, 17.6,
−4.5, −4.9; IR (film) v: 3449, 3341, 1733, 1718, 1504, 1254, 1070,
835, 776 cm−1; HRMS (ESI-TOF) m/z calcd for C14H29NO3SiNa [M
+ Na+] 310.1814; Found 310.1814.
1
of compound 11d; yellowish oil; [α]2D2 +7.2 (c 1, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.37−7.27 (m, 5H, Ph), 5.84 (s, 1H, NH),
5.66−5.56 (m, 1H, CH3CHCH), 5.39 (dd, J 15.0, 5.6 Hz, 1H,
CH3CHCH), 5.16−5.04 (m, 2H, CH2OPh), 4.17−4.09 (m, 1H,
CHNHCbz), 3.80−3.71 (m, 1H, TBSOCHHCH), 3.48 (dd, J 10.0,
4.3 Hz, 1H, TBSOCHHCH), 1.78−1.71 (m, 1H, CH3CH), 1.69 (d, J
6.4 Hz, 3H, CH3CHCH), 0.99 (d, J 6.9 Hz, 3H, CH3CH), 0.89 (s,
9H, (CH3)3CSi), 0.04 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz,
Benzyl ((2S,3R,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (19). To a cooled to −20 °C solution of carbamate 11a
I
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ: 156.1, 137.0, 130.5, 128.3, 127.75, 127.72, 126.1, 66.2, 65.1,
56.6, 38.4, 25.8, 18.1, 17.7, 14.4, −5.71, −5.73; IR (film) v: 3409, 3334,
1726, 1712, 1086 cm−1; HRMS (ESI-TOF) m/z calcd for C21H35-
NO3SiNa [M + Na+] 400.2284. Found 400.2288.
of compound 12d; colorless oil; [α]2D2 +4.3 (c 1.8, CHCl3)1H NMR
(500 MHz, CDCl3) δ: 7.38−7.26 (m, 5H, Ph), 5.97 (d, J 6.8 Hz, 1H,
NH), 5.63 (m, 1H, CH3CHCH), 5.38 (ddd, J 15.3, 6.6, 1.3 Hz, 1H,
CH3CHCH), 5.16−4.98 (m, 2H, OCH2Ph), 4.14 (m, 1H,
CHNHCbz), 3.53 (ps t, J 10.1, 9.1 Hz, 1H, CHHOTBS), 3.47 (dd,
J 10.1, 4.9 Hz, 1H, CHHOTBS), 2.04−1.91 (m, 1H, CH3CH), 1.71
(d, J 6.3 Hz, 3H, CH3CHCH), 0.90 (s, 9H, (CH3)3CSi), 0.81 (d, J
7.1 Hz, 3H, CH3CH), 0.05 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 155.6, 137.0, 128.3, 127.8, 127.7, 127.5, 66.2, 65.8, 56.4,
39.0, 25.8, 18.1, 17.8, 13.6, −5.7; IR (film) v: 3415, 3334, 1726, 1712,
1504, 1252, 1094, 837, 776 cm−1; HRMS (ESI-TOF) m/z calcd for
C21H35NO3SiNa [M + Na+] 400.2284. Found 400.2284.
Benzyl ((4S,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-2-en-4-
yl)carbamate (44b). Prepared in the same manner as compound
19. Purification by chromatography on silica gel (6% AcOEt in
hexanes). Yield 230 mg (87%) starting from 200 mg (0.697 mmol) of
compound 11e; colorless oil; [α]2D2 −16.5 (c 3.1, CHCl3); H NMR
1
(500 MHz, CDCl3) δ: 7.36−7.28 (m, 5H, Ph), 5.66−5.54 (m, 1H,
CHCH), 5.49−5.34 (m, 1H, CHCH), 5.16−5.02 (m, 2H, 2 ×
CH), 4.26−4.17 (m, 1H), 4.05−3.91 (m, 1H), 1.68 (d, J 6.3 Hz, 3H,
CH3), 1.15 (d, J 6.1 Hz, 3H, CH3), 0.89 (s, 9H, t-BuSi), 0.06 (s, 6H, 2
× CH3Si); 13C NMR (126 MHz, CDCl3) δ: 155.7, 136.9, 131.5, 128.3,
127.9, 127.8, 125.6, 66.3, 66.1, 50.7, 44.1, 25.9, 23.9, 17.9, 17.6, −4.1,
−4.8; IR (film) v: 3330, 1709, 1528, 1255, 836, 775 cm−1; HRMS
(ESI-TOF) m/z calcd for C21H35NO3SiNa [M + Na+] 400.2284.
Found 400.2282.
Benzyl ((4R,6R,E)-6-((t-Butyldimethylsilyl)oxy)hept-2-en-4-
yl)carbamate (42b). Prepared in the same manner as compound
19. Purification by chromatography on silica gel (10% AcOEt in
hexanes). Yield 206 mg (78%) starting from 200 mg (0.697 mmol) of
compound 12e; colorless oil; [α]2D1 −9.3 (c 0.81, CHCl3); H NMR
1
(600 MHz, CDCl3) δ: 7.35−7.27 (m, 5H, Ph), 5.70−5.52 (m, 1H,
CHCH), 5.44−5.29 (m, 1H, CHCH), 5.18−4.98 (m, 2H,
OCH2Ph), 4.80 (s, 1H, NH), 4.23−4.08 (m, 1H, CH), 3.92−3.76 (m,
1H, CH), 1.72−1.60 (m, 5H, CH2, CH3CHCH), 1.14 (d, J 5.6 Hz,
3H, CH3), 0.85 (s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), 0.00 (s, 3H,
CH3Si); 13C NMR (151 MHz, CDCl3) δ: 136.6, 131.7, 128.4, 128.0,
126.2, 126.0, 66.5, 58.1, 50.9, 45.4, 25.9, 24.1, 18.0, 17.7, −4.1, −4.7;
IR (film) v: 3330, 1708, 1530, 1254, 836, 774 cm−1; HRMS (ESI-
TOF) m/z calcd for C21H35NO3SiNa [M + Na+] 400.2284. Found
400.2285.
Benzyl ((2S,3S,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (22). Prepared in the same manner as compound 19.
Purification by chromatography on silica gel (10% AcOEt in hexanes);
Yield 140 mg (70%) starting from 150 mg (0.549 mmol) of compound
1
12a; colorless oil; [α]2D3 −12.1 (c 1.21, CHCl3); H NMR (500 MHz,
PhMe-d7, 70 °C) δ: 7.26−6.94 (m, 5H, Ph), 5.56−5.45 (m, 1H, CH
CH), 5.36 (dd, J 15.4, 4.6 Hz, 1H, CHCH), 5.12−4.99 (m, 2H,
PhCH2O), 4.86−4.75 (m, 1H, NH), 4.20−4.07 (m, 1H, CH), 3.79−
3.67 (m, 1H, CH), 1.53 (d, J 6.4 Hz, 3H, CH3CH), 1.03 (d, J 6.0 Hz,
3H, CH3CH), 0.86 (s, 9H, t-BuSi), −0.03 (s, 6H, 2 × CH3Si); 13C
NMR (126 MHz, CDCl3) δ: 156.3, 136.7, 130.5, 128.5, 128.4, 128.1,
128.0, 128.0, 126.3, 70.6, 66.7, 58.2, 25.8, 20.9, 18.0, 17.6, −4.5, −4.9;
IR (film) v: 3445, 3331, 1727, 1494, 1097 cm−1; HRMS (ESI-TOF)
m/z calcd for C20H33NO3SiNa [M + Na+] 386.2127. Found 386.2123.
Benzyl ((2R,3R,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (ent-22). Prepared in the same manner as compound 19.
Yield 155 mg (75%); colorless oil; [α]2D4 +11.8 (c 1.1, CHCl3); HRMS
(ESI-TOF) m/z calcd for C20H33NO3SiNa [M + Na+] 386.2127.
Found 386.2123.
t-Butyl ((2S,3R,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (20). To a cooled to −20 °C solution of carbamate 11a
(150 mg, 0.55 mmol) and Et3N (333 mg, 460 μL, 3.29 mmol) in dry
THF (10 mL), TFAA (230 mg, 150 μL, 1.1 mmol) was added, and the
resulting mixture was warmed to room temperature slowly. The
progress of the reaction was followed by TLC (20% AcOEt in
hexanes). In a separate flask, a 1 M soln. of LiHMDS in THF (3.3 mL,
3.29 mmol) was added to anhydr. t-BuOH (0.5 mL) in dry THF (10
mL). When rearrangement was completed (ca. 1 h), the solution of t-
BuOLi was cannulated, and the reaction mixture was stirred overnight
at room temperature. The progress of the reaction was followed by
TLC (20% AcOEt in hexanes). After removal of solvents, the crude
product was supported on silica gel and chromatographed (10%
AcOEt in hexanes) to give 151 mg of carbamate 20 (84%) as a
colorless oil. [α]2D2 +4.8 (c 1.4, CHCl3); 1H NMR (500 MHz, CDCl3)
δ 5.72−5.54 (m, 1H, CH3CHCH), 5.41 (ddd, J 15.3, 7.7, 1.3 Hz,
2H, CH3CHCH), 4.73 (s, 1H, NH), 4.03−3.73 (m, 2H, CHOTBS,
CHNHBoc), 1.70 (dd, J 6.5, 1.3 Hz, 3H, CH3CHCH), 1.43 (s, 9H,
(CH3)3CO), 1.05 (d, J 6.3 Hz, 3H, CH3CH), 0.90 (s, 9H, (CH3)3CSi),
0.06 (s, 3H, CH3Si), 0.05 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 158.1, 130.1, 126.7, 70.3, 28.4, 25.8, 20.4, 18.0, 17.9, −4.4,
−4.9; IR (film) v: 3458, 3349, 1716, 1494, 1175, 835, 776 cm−1;
HRMS (ESI-TOF) m/z calcd for C17H35NO3SiNa [M + Na+]
352.2284. Found 352.2275.
Benzyl ((1S,2S,E)-1-((t-Butyldimethylsilyl)oxy)-1-phenylpent-
3-en-2-yl)carbamate (26). Prepared in the same manner as
compound 19. Purification by chromatography on silica gel. Yield
127 mg (67%) starting from 150 mg (0.448 mmol) of compound 12b;
colorless oil; [α]2D1 +20.1 (c 1.09, CHCl3); 1H NMR (500 MHz,
CDCl3) δ: 7.39−7.24 (m, 10H, 2 × Ph), 5.67−5.55 (m, 1H, CH
CH), 5.49 (ddd, J 15.3, 5.9, 1.6 Hz, 1H, CHCH), 5.06−4.95 (m,
3H, CH, OCH2Ph), 4.75 (s, 1H, NH), 4.35−4.20 (m, 1H, CH), 1.69
(d, J 6.4 Hz, 3H, CH3CHCH), 0.89 (s, 9H, t-BuSi), 0.02 (s, 3H,
CH3Si), −0.13 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
155.8, 141.5, 136.6, 129.4, 128.4, 128.3, 128.0(x2), 127.9, 127.4, 126.9,
126.3(x2), 66.5, 59.1, 25.8, 18.2, 17.7, −4.7, −5.1; IR (film) v: 3447,
3336, 1724, 1499, 1096 cm−1; HRMS (ESI-TOF) m/z calcd for
C25H35NO3SiNa [M + Na+] 448.2284. Found 448.2284.
Benzyl ((2S,3S,E)-2-((t-Butyldimethylsilyl)oxy)-1-phenylhex-
4-en-3-yl)carbamate (28). Prepared in the same manner as
compound 19. Purification by chromatography (10% AcOEt in
hexanes). Yield 153 mg (60%) starting from 200 mg (0.573 mmol) of
t-Butyl ((2S,3S,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
carbamate (23). Prepared in the same manner as compound 20.
Purification by chromatography on a short pad of silica gel (20%
AcOEt in hexanes). Yield 138 mg (76%) starting from 150 mg (0.549
mmol) of compound 12a; yellowish oil; [α]2D2 −13.0 (c 0.48, CHCl3);
1H NMR (500 MHz, CDCl3) δ: 5.62−5.52 (m, 1H, CHCH), 5.40
1
compound 12c; colorless oil; [α]2D5 −6.3 (c 0.65, CHCl3); H NMR
(500 MHz, DMSO-d6/CD3OD 4:1) δ: 7.44−7.00 (m, 10H, 2 × Ph),
5.68−5.43 (m, 2H, CHCH), 5.11−5.02 (m, 2H, OCH2Ph), 4.14−
4.04 (m, 1H, CH), 3.82−3.71 (m, 3H), 2.83 (dd, J 13.4, 2.8 Hz, 1H,
CHHPh), 2.37 (dd, J 13.4, 9.0 Hz, 1H, CHHPh), 1.66 (d, J 5.7 Hz,
3H, CH3CHCH), 0.75 (s, 9H, t-BuSi), −0.11 (s, 3H, CH3Si), −0.50
(s, 3H, CH3Si); 13C NMR (126 MHz, DMSO-d6) δ: 155.6, 139.1,
137.1, 129.4, 128.3, 127.9, 127.8, 127.7, 127.7, 126.3, 125.9, 75.8, 65.3,
56.7, 38.7, 25.6, 17.7, 17.6, −5.0, −5.6; IR (film) v: 3444, 3340. 1724,
1497, 1086 cm-1; HRMS (TOF-ESI) m/z calcd for C26H37NO3SiNa
[M + Na+] 462.2440. Found 462.2434.
(ddd, J 15.4, 5.8, 1.3 Hz, 1H, CHCH), 4.89−4.71 (m, 1H, CH),
4.01−3.88 (m, 1H, NH), 3.89−3.79 (m, 1H, CH), 1.68 (d, J 6.4 Hz,
3H, CH3), 1.45 (s, 9H, t-BuO), 1.13 (d, J 6.2 Hz, 3H, CH3), 0.88 (s,
9H, t-BuSi), 0.04 (s, 3H, CH3Si), 0.02 (s, 3H, CH3Si); 13C NMR (126
MHz, CDCl3) δ: 155.9, 130.9, 125.7, 100.0, 70.7, 28.4, 25.8, 20.8, 18.0,
17.6, −4.4, −4.8; IR (film) v: 3453, 1721, 1494, 1173, 835, 776 cm−1;
HRMS (ESI-TOF) m/z calcd for C17H35NO3SiNa [M + Na+]
352.2284. Found 352.2283.
N-((2S,3R,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
acetamide (21). To a cooled to −20 °C solution of carbamate 11a
(300 mg, 1.1 mmol) and Et3N (668 mg, 920 μL, 6.6 mmol) in dry
THF (10 mL), TFAA (462 mg, 305 μL, 2.2 mmol) was added, and the
resulting mixture was warmed to room temperature slowly. The
Benzyl ((2R,3S,E)-1-((t-Butyldimethylsilyl)oxy)-2-methylhex-
4-en-3-yl)carbamate (42a). Prepared in the same manner as
compound 19. Purification by chromatography (4% AcOEt in
hexanes). Yield 173 mg (87%) starting from 150 mg (0.522 mmol)
J
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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progress of the reaction was followed by TLC (20% AcOEt in
hexanes). After 1 h, a solution was cooled to −10 °C and a 3 M soln.
of MeMgBr (6.6 mmol, 2.2 mL) was added. After 4 h, the reaction was
quenched by addition of sat. aq. NH4Cl. The organic layer was
separated, and the aqueous one was extracted with CH2Cl2. After
removal of solvents, the crude product was supported on silica gel and
chromatographed (25% AcOEt in hexanes) to give 250 mg of
carbamate 21 (83%) as a colorless oil. [α]2D3 −21.2 (c 0.86, CHCl3);
1H NMR (500 MHz, C6D6) δ: 5.59−5.49 (m, 1H, CHCH), 5.43
CHCl3); HRMS (ESI-TOF) m/z calcd for C19H31NO5SiNa [M +
Na+] 404.1869. Found 404.1861.
Methyl N-(tert-Butoxycarbonyl)-O-(t-butyldimethylsilyl)-L-
allo-threoninate (32). Prepared in the same manner as compound
25. Purification by chromatography on silica gel (20% AcOEt in
hexanes). Yield 58 mg (92%) starting from 60 mg (0.182 mmol) of
1
compound 20; colorless oil; [α]2D3 +33.8 (c 0.7, CHCl3); H NMR
(600 MHz, CDCl3) δ: 5.25 (d, J 7.5 Hz, 1H, NH), 4.26−4.17 (m, 1H,
CHNH), 4.10−4.01 (m, 1H, CHOTBS), 3.73 (s, 3H, CH3O), 1.43 (s,
9H, t-BuO), 1.22 (d, J 6.4 Hz, 3H, CH3CH), 0.85 (s, 9H, t-BuSi), 0.03
(s, 6H, 2 × CH3Si); 13C NMR (151 MHz, CDCl3) δ: 170.7, 155.1,
79.8, 69.9, 59.6, 52.0, 28.3, 25.6, 20.5, 17.9, −5.1; IR (film) v: 3447,
3365, 1747, 1719, 1499, 1167, 836, 777 cm−1; HRMS (ESI-TOF) m/z
calcd for C16H33NO5SiNa [M + Na+] 370.2026. Found 370.2018.
Methyl N-Acetyl-O-(t-butyldimethylsilyl)-L-allo-threonate
(33). Prepared in the same manner as compound 25. Purification by
chromatography on silica gel to (20% AcOEt in hexanes). Yield 130
mg (82%) starting from 150 mg (0.55 mmol) of compound 21;
colorless oil; [α]2D5 +52.8 (c 1.16, CHCl3) [lit.52 +47 (c 0.32, CHCl3)];
1H NMR (500 MHz, CDCl3) δ: 6.20 (d, J 8.0 Hz, 1H, NH), 4.53 (dd,
J 8.1, 3.4 Hz, 1H, CHNHCbz), 4.08 (qd, J 6.4, 3.4 Hz, 1H, CH3CH),
3.75 (s, 3H, CH3O), 2.02 (s, 3H, CH3CO), 1.26 (d, J 6.4 Hz, 3H,
CH3CH), 0.87 (s, 9H, t-BuSi), 0.04 (s, 3H, CH3Si), 0.04 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 170.6, 169.5, 70.1, 58.5,
52.2, 25.8, 23.4, 20.9, 18.0, −4.4, −4.9; IR (film) v: 3289, 1747, 1660,
1546, 1256, 835 cm−1; HRMS (ESI-TOF) m/z calcd for C13H27-
NO4SiNa [M + Na+] 312.1607. Found 312.1611.
Methyl (2S,3S)-2-(((Benzyloxy)carbonyl)amino)-3-((t-butyl-
dimethylsilyl)oxy)-3-phenylpropanoate (38). Prepared in the
same manner as compound 25. Purification by chromatography on
silica gel (20% AcOEt in hexanes); Yield 40 mg (86%) starting from
37 mg (0.106 mmol) of compound 25; colorless oil; [α]2D3 +75.9 (c
0.5, CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.36−7.27 (m, 10H, 2 ×
Ph), 5.30 (br d, J 7.6 Hz, 1H, NH), 5.06 (br d, J 4.2 Hz, 1H,
PhCHOTBS), 4.59 (br dd, J 8.5, 4.3 Hz, 1H, CHNH), 3.66 (s, 3H,
CH3O), 3.64−3.60 (m, 2H, OCH2Ph), 0.89 (s, 9H, t-BuSi), 0.06 (s,
3H, CH3Si), −0.14 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
170.2, 156.2, 140.1, 139.4, 128.1(x3), 127.9, 126.2(x2), 75.3, 61.1,
52.3, 51.9, 25.6, 18.1, −4.9, −5.4; IR (film) v: 3442, 3335, 1733, 1513,
1257, 838, 779 cm−1; HRMS (ESI-TOF) m/z calcd for C24H33-
NO5SiNa [M + Na+] 466.2026. Found 466.2029.
(ddd, J 15.4, 8.0, 1.5 Hz, 1H, CHCH), 5.21 (br d, J 7.0 Hz, 1H,
NH), 4.42 (td, J 8.3, 3.2 Hz, 1H, CHCHCH), 3.84 (qd, J 6.3, 3.4
Hz, 1H, CH3CH), 1.60 (s, 3H, CH3CO), 1.49 (dd, J 6.3, 1.1 Hz, 3H,
CH3CHCH), 0.93 (d, J 6.3 Hz, 3H, CH3), 0.89 (s, 9H, t-BuSi),
−0.05 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz, C6D6) δ: 167.2,
129.1, 126.8, 70.2, 56.9, 25.6, 22.8, 20.3, 17.8, 17.6, −4.7, −5.2; IR
(film) v: 3282, 1649, 1550, 835, 775 cm−1; HRMS (ESI-TOF) m/z
calcd for C14H29NO2SiNa [M + Na+] 294.1865. Found 294.1864.
N-((2S,3S,E)-2-((t-Butyldimethylsilyl)oxy)hex-4-en-3-yl)-
acetamide (24). Prepared in the same manner as compound 21.
Purification by chromatography on silica gel (25% AcOEt in hexanes).
Yield 184 mg (92%) starting from 200 mg (0.731 mmol) of compound
1
12a; colorless oil; [α]D22 −2.1 (c 2.0, CHCl3); H NMR (500 MHz,
CDCl3) δ: 5.76 (d, J 7.2 Hz, 1H, NH), 5.62−5.53 (m, 1H, CHCH),
5.43−5.35 (m, 1H, CHCH), 4.33−4.25 (m, 1H, CHCHCH),
3.92−3.82 (m, 1H, CHCH3), 2.03 (s, 3H, CH3CO), 1.67 (d, J 6.4 Hz,
3H, CH3CHCH), 1.11 (d, J 6.2 Hz, 3H, CH3CH), 0.88 (s, 9H, t-
BuSi), 0.05 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 169.6, 130.3, 126.2, 70.5, 56.0, 25.8, 23.5, 21.0, 18.0, 17.6,
−4.4, −4.9; IR (film) v: 3289, 1651, 1094, 835 cm−1; HRMS (ESI-
TOF) m/z calcd for C14H30NO2Si [M + H+] 272.2046. Found
272.2044.
Methyl O-(t-Butyldimethylsilyl)-N-(methoxycarbonyl)-L-allo-
threoninate (29). Ozone was passed through a stirred solution of
carbamate 15 (50 mg, 0.185 mmol) in 10 mL of CH2Cl2 and 0.64 mL
of 2.5 M methanolic NaOH at −70 °C. The progress of the reaction
was followed by TLC (AcOEt/hexane 1:4). After 1 h, yellow
precipitation occurred and reaction mixture became blue. At this point,
oxygen was bubbled through the reaction mixture for 20 min. It was
than diluted with water (15 mL) and CH2Cl2 (15 mL), and the
resulting mixture was warmed slowly to room temperature. The
organic layer was separated, and the aqueous one was extracted with
CH2Cl2 (3 × 15 mL). The combined organic layers were dried over
anhydrous Na2SO4, and the solvent was removed under diminished
pressure. The residue was chromatographed on silica gel to (20%
AcOEt in hexanes) to afford 47 mg of product 29 (85%) as a pale-
Methyl (2S,3S)-2-(((Benzyloxy)carbonyl)amino)-3-((t-butyl-
dimethylsilyl)oxy)-4-phenylbutanoate (39). Prepared in the
same manner as compound 25. Purification by chromatography on
silica gel (20% AcOEt in hexanes). Yield 74 mg (89%) starting from 80
mg (0.182 mmol) of compound 26; colorless oil; [α]2D3 +24.1 (c 0.7,
yellow oil. [α]2D2 +25.4 (c 1.3, CHCl3); H NMR (500 MHz, CDCl3)
1
1
CHCl3); H NMR (500 MHz, CDCl3) δ: 7.40−7.19 (m, 10H, 2 ×
δ: 5.41 (d, J 7.3 Hz, 1H, NH), 4.29−4.21 (m, 1H, CHNH), 4.10−4.00
(m, 1H, CHOTBS), 3.71 (s, 3H, CH3O), 3.65 (s, 3H, CH3O), 1.21 (d,
J 6.4 Hz, 3H, CH3CH), 0.83 (s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), 0.01
(s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ: 170.5, 156.3, 69.8,
60.0, 52.3, 52.0, 25.6, 20.4, 17.8, −4.6, −5.2; IR (film) v: 3443, 3345,
1732, 1512, 1254, 835, 777 cm−1; HRMS (ESI-TOF) m/z calcd for
C13H28NO5Si [M + H+] 306.1737. Found 306.1732.
Ph), 5.53 (d, J 6.9 Hz, 1H, NH), 5.09 (br s, 2H, OCH2Ph), 4.46−4.37
(m, 1H, CHNH), 4.30−4.18 (m, 1H, CHOTBS), 3.79 (s, 3H, CH3O),
2.93 (dd, J 13.6, 6.3 Hz, 1H, CHHPh), 2.82 (dd, J 13.6, 7.9 Hz, 1H,
CHHPh), 0.81 (s, 9H, t-BuSi), −0.02 (s, 3H, CH3Si), −0.33 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 169.4, 160.3, 137.7, 129.7,
128.5, 128.4, 128.1, 128.0, 126.6, 75.2, 66.9, 58.5, 52.2, 40.7, 25.7, 17.9,
−4.9, −5.2; IR (film) v: 3439, 3362, 1727, 1256, 1101, 837, 777, 699
cm−1; HRMS (ESI-TOF) m/z calcd for C25H36NO5Si [M + H+]
458.2363. Found 458.2363.
Methyl N-((Benzyloxy)carbonyl)-O-(t-butyldimethylsilyl)-L-
allo-threoninate (31). Prepared in the same manner as compound
25. Purification by chromatography on silica gel to (20% AcOEt in
hexanes). Yield 75 mg (71%) starting from 100 mg (0.275 mmol) of
compound 19; colorless oil; [α]2D5 +22 (c 3.65, CHCl3) [lit.51 +27.3 (c
Methyl (2S,3R)-2-(((Benzyloxy)carbonyl)amino)-4-((t-butyl-
dimethylsilyl)oxy)-3-methylbutanoate (45a). Prepared in the
same manner as compound 25. Purification by chromatography on
silica gel (10% AcOEt in hexanes). Yield 52 mg (87%) starting from 60
mg (0.159 mmol) of compound 44a; colorless oil; [α]2D2 −1.1 (c 0.8,
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.44−7.27 (m, 5H, Ph), 6.03
(d, J 8.3 Hz, 1H, NH), 5.21−4.97 (m, 2H, OCH2Ph), 4.35 (dd, J 8.6,
4.3 Hz, 1H, CHNH), 3.73 (s, 3H, CH3O), 3.63 (dd, J 10.4, 3.8 Hz,
1H, CHHOTBS), 3.50 (dd, J 10.4, 5.5 Hz, 1H, CHHOTBS), 2.24−
2.28 (m, 1H, CHCH3), 1.03 (d, J 7.1 Hz, 3H, CH3CH), 0.89 (s, 9H, t-
BuSi), 0.04 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (126 MHz,
CDCl3) δ: 172.5, 156.6, 136.5, 128.4, 127.9, 127.7, 66.7, 65.2, 57.8,
52.1, 36.6, 25.8, 18.1, 14.4, −5.7; IR (film) v: 3400, 1729, 838 cm−1;
1
0.55, CH2Cl2)]; H NMR (500 MHz, CDCl3) δ: 7.40−7.29 (m, 5H,
Ph), 5.50 (d, J 7.2 Hz, 1H, NH), 5.20−5.06 (m, 2H, OCH2Ph), 4.35−
4.26 (m, 1H, CH), 4.16−4.05 (m, 1H, CH), 3.74 (s, 3H, COOCH3),
1.24 (d, J 6.3 Hz, 3H, CH3CH), 0.86 (m, 9H, t-Bu), 0.04 (s, 3H, CH3),
0.03 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ: 170.5, 155.8,
136.5, 128.6, 128.3, 128.2, 70.01, 67.1, 60.2, 52.2 25.7, 20.6, 18.0, −4.4,
−5.0; IR (film) v: 3441, 3354, 1730, 1507 cm−1; HRMS (ESI-TOF)
m/z calcd for C19H31NO5SiNa [M + Na+] 404.1869. Found 404.1870.
Methyl N-((Benzyloxy)carbonyl)-O-(t-butyldimethylsilyl)-D-
allo-threoninate (ent-31). Prepared in the same manner as
compound 25. Yield 53 mg (73%); colorless oil; [α]2D2 −21 (c 1.5,
K
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI-TOF) m/z calcd for C20H34NO5Si [M + H+] 396.2206.
Found 396.2205.
6.3 Hz, 3H, CH3CH), 0.82 (s, 9H, t-BuSi), 0.02 (s, 3H, CH3Si), −0.03
(s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ: 171.1, 170.4, 68.8,
57.7, 52.2, 25.6, 23.2, 20.8, 17.8, −4.5, −5.4; IR (film) v: 3302, 1749,
1662, 1531, 1254, 1096, 838, 777 cm−1; HRMS (ESI-TOF) m/z calcd
for C13H28NO4Si [M + H+] 290.1788. Found 290.1787.
Methyl (2S,4R)-2-(((Benzyloxy)carbonyl)amino)-4-((t-butyl-
dimethylsilyl)oxy)pentanoate (45b). Prepared in the same manner
as compound 25. Purification by chromatography on silica gel (20%
AcOEt in hexanes). Yield 58 mg (93%) starting from 60 mg (0.159
mmol) of compound 44b; colorless oil; [α]2D2 −26.2 (c 0.5, CHCl3);
1H NMR (500 MHz, CDCl3) δ: 7.40−7.28 (m, 5H, Ph), 5.83 (d, J 6.7
Hz, 1H, NH), 5.14 (d, J 12.5 Hz, 1H, OCHHPh), 5.08 (d, J 12.5 Hz,
1H, OCHHPh), 4.46−4.39 (m, 1H, CHNH), 4.01−3.93 (m, 1H,
CHOTBS), 3.73 (s, 3H, CH3O), 1.96−1.86 (m, 1H, CHH), 1.85−
1.77 (m, 1H, CHH), 1.17 (d, J 6.1 Hz, 3H, CH3CH), 0.88 (s, 9H, t-
BuSi), 0.06 (s, 6H, 2 × CH3Si); 13C NMR (126 MHz, cdcl3) δ 173.0,
156.0, 136.5, 128.4, 127.9, 127.8, 66.7, 66.2, 52.2, 52.1, 40.3, 25.8, 23.8,
17.9, −4.2, −5.0; IR (film) v: 3343, 1725, 1255, 1217, 836, 776 cm−1;
HRMS (ESI-TOF) m/z calcd for C20H33NO5SiNa [M + Na+]
418.2026. Found 418.2026.
Methyl (2R,3S)-2-(((Benzyloxy)carbonyl)amino)-3-((t-butyl-
dimethylsilyl)oxy)-3-phenylpropanoate (40). Prepared in the
same manner as compound 25. Purification by chromatography on
silica gel (20% AcOEt in hexanes). Yield 48 mg (77%) starting from 60
mg (0.141 mmol) of compound 27; colorless oil; [α]2D2 +46.8 (c 1.1,
1
CHCl3); H NMR (500 MHz, CDCl3) δ: 7.41−7.22 (m, 10H, 2 ×
Ph), 5.51 (d, J 9.6 Hz, 1H, NH), 5.32 (s, 1H, PhCH), 5.02−4.91 (m,
2H, OCH2Ph), 4.49 (dd, J 9.8, 1.8 Hz, 1H, CHNH), 3.77 (s, 3H,
CH3O), 0.87 (s, 9H, t-BuSi), −0.02 (s, 3H, CH3Si), −0.15 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 170.8, 156.1, 140.4, 136.3,
128.5, 128.1, 128.1, 128.0, 127.8, 126.1, 74.6, 66.9, 61.1, 52.4, 29.7,
25.6, 18.1, −4.7, −5.6; IR (film) v: 3308, 1745, 1667, 1536, 1252,
1101, 836, 777 cm−1; HRMS (ESI-TOF) m/z calcd for C24H33-
NO5SiNa [M + Na+] 466.2026. Found 466.2029.
Methyl O-(t-Butyldimethylsilyl)-N-(methoxycarbonyl)-D-
threoninate (30). Prepared in the same manner as compound 25;
Purification by chromatography on silica gel (15% AcOEt in hexanes).
Yield 44 mg (88%) starting from 54 mg (0.164 mmol) of compound
Methyl (2R,3S)-2-(((Benzyloxy)carbonyl)amino)-3-((t-butyl-
dimethylsilyl)oxy)-4-phenylbutanoate (41). Prepared in the
same manner as compound 25a. Purification by chromatography on
silica gel (10% AcOEt in hexanes). Yield 76 mg (82%) starting from 90
mg (0.205 mmol) of compound 28; colorless oil; [α]2D3 +18.4 (c 1.5,
1
18; colorless oil; [α]2D3 +14.3 (c 1.1, CHCl3); H NMR (500 MHz,
CDCl3) δ: 5.35 (d, J 9.3 Hz, 1H, NH), 4.47−4.39 (m, 1H, CHOTBS),
4.24 (dd, J 9.3, 1.5 Hz, 1H, CHNH), 3.72 (s, 3H, CH3O), 3.71 (s, 3H,
CH3O), 1.20 (d, J 6.3 Hz, 3H, CH3CH), 0.84 (s, 9H, t-BuSi), 0.04 (s,
3H, CH3Si), −0.02 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
171.4, 157.3, 68.8, 59.9, 52.4, 52.2, 25.6, 20.8, 17.8, −4.4, −5.4; IR
(film) v: 3440, 3346, 1729, 1510, 1255, 836, 777 cm−1; HRMS (ESI-
TOF) m/z calcd for C13H27NO5SiNa [M + Na+] 328.1556. Found
328.1556.
Methyl N-((Benzyloxy)carbonyl)-O-(t-butyldimethylsilyl)-D-
threoninate (34). Prepared in the same manner as compound 25.
Purification by chromatography on silica gel (20% AcOEt in hexanes).
Yield 85 mg (82%) starting from 100 mg (0.275 mmol) of compound
22; a colorless oil; [α]D25 +8.6 (c 0.7, CHCl3) [lit.51 +9 (c 1, CHCl3)];
1H NMR (500 MHz, CDCl3) δ: 7.44−7.29 (m, 5H, Ph), 5.43 (d, J 9.5
Hz, 1H, NH), 5.14 (br s, 2H, OCH2Ph), 4.50−4.40 (m, 1H,
CH3CHOTBS), 4.28 (dd, J 9.6, 1.6 Hz, 1H, CHNHCbz), 3.73 (s, 3H,
OCH3), 1.21 (d, J 6.3 Hz, 3H, CH3CH), 0.84 (s, 9H, (CH3)3C), 0.04
(s, 3H, CH3), −0.01 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) δ:
171.3, 156.7, 136.3, 128.5, 128.1, 128.1, 68.8, 67.1, 59.9, 52.2, 25.6,
20.8, 17.8, −4.4, −5.4; IR (film) v: 3448, 3356, 1730, 1507 cm−1;
HRMS (ESI-TOF) m/z calcd for C19H31NO5SiNa [M + Na+]
404.1869. Found 404.1866.
Methyl N-((Benzyloxy)carbonyl)-O-(t-butyldimethylsilyl)-L-
threoninate (ent-34). Prepared in the same manner as compound
25. Yield 50 mg (83%); colorless oil; [α]2D2 −8.2 (c 1.1, CHCl3);
HRMS (ESI-TOF) m/z calcd for C19H31NO5SiNa [M + Na+]
404.1869. Found 404.1865.
1
CHCl3); H NMR (500 MHz, CDCl3) δ: 7.47−7.13 (m, 10H, 2 ×
Ph), 5.47 (d, J 9.8 Hz, 1H, NH), 5.22 (d, J 12.2 Hz, 1H, OCHHPh),
5.16 (d, J 12.2 Hz, 1H, OCHHPh), 4.48−4.36 (m, 1H, BnCHOSi),
4.27 (br d, J 9.8 Hz, 1H, CHNH), 3.68 (s, 3H, CH3O), 2.90−2.74 (m,
2H, CH2Ph), 0.86 (s, 9H, t-BuSi), −0.00 (s, 3H, CH3Si), −0.04 (s, 3H,
CH3Si); 13C NMR (126 MHz, CDCl3) δ: 171.6, 156.6, 136.8, 136.4,
129.5, 128.7, 128.5, 128.4, 128.2, 127.6, 126.9, 126.8, 74.3, 67.1, 56.7,
52.2, 41.2, 25.7, 17.9, −4.7, −5.2; IR (film) v: 3372, 1723, 834 cm−1;
HRMS (ESI-TOF) m/z calcd for C25H35NO5SiNa [M + Na+]
480.2182. Found 480.2180.
Methyl (2R,3R)-2-(((Benzyloxy)carbonyl)amino)-4-((t-butyl-
dimethylsilyl)oxy)-3-methylbutanoate (43a). Prepared in the
same manner as compound 25. Purification by chromatography on
silica gel (25% AcOEt in hexanes). Yield 64 mg (87%) starting from 60
mg (0.159 mmol) of compound 41a; colorless oil; [α]2D3 +9.8 (c 0.7,
CHCl3); 1H NMR (500 MHz, CDCl3) δ: 7.39−7.27 (m, 5H, Ph), 5.70
(d, J 8.5 Hz, 1H, NH), 5.16−5.03 (m, 2H, OCH2Ph), 4.50 (dd, J 8.8,
3.4 Hz, 1H, CHNH), 3.73 (s, 3H, CH3O), 3.57−3.45 (m, 2H,
CH2OTBS), 0.89 (s, 9H, t-BuSi), 0.03 (s, 6H, 2 × CH3Si); 13C NMR
(126 MHz, CDCl3) δ: 172.4, 156.1, 136.4, 128.4, 128.0, 127.9, 66.8,
65.2, 56.2, 52.1, 37.9, 25.8, 18.1, 12.3, −5.6; IR (film) v: 3375, 1725,
837 cm−1; HRMS (ESI-TOF) m/z calcd for C20H34NO5Si [M + H+]
396.2206. Found 396.2198.
Methyl (2R,4R)-2-(((Benzyloxy)carbonyl)amino)-4-((t-butyl-
dimethylsilyl)oxy)pentanoate (43b). Prepared in the same manner
as compound 25. Purification by chromatography on silica gel (10%
AcOEt in hexanes). Yield 62 mg (60%) starting from 100 mg (0.265
mmol) of compound 42b; colorless oil; [α]2D2 −4.8 (c 0.5, CHCl3); 1H
NMR (500 MHz, CDCl3) δ: 7.42−7.27 (m, 5H, Ph), 5.57 (d, J 5.8 Hz,
1H, NH), 5.15−5.10 (m, 2H, OCH2Ph), 4.43−4.26 (m, 1H, CHNH),
4.10−3.94 (m, 1H, CHOTBS), 3.73 (s, 3H, CH3O), 2.00−1.80 (m,
2H, CH2), 1.20−1.16 (m, 4H, CH3CH), 0.87 (s, 9H, t-BuSi), 0.05 (s,
3H, CH3Si), 0.04 (s, 3H, CH3Si); 13C NMR (126 MHz, CDCl3) δ:
173.0, 155.8, 136.3, 128.4, 128.0, 128.0, 66.9, 66.4, 52.2, 41.3, 29.7,
25.8, 23.6, 17.9, −4.4, −4.8; IR (film) v: 3370, 1721, 836 cm−1; HRMS
(ESI-TOF) m/z calcd for C20H33NO5SiNa [M + Na+] 418.2026.
Found 418.2019.
Methyl N-(t-Butoxycarbonyl)-O-(t-butyldimethylsilyl)-D-
threoninate (35). Prepared in the same manner as compound 25.
Purification by chromatography on silica gel (20% AcOEt in hexanes).
Yield 90 mg (80%) starting from 107 mg (0.325 mmol) of compound
23; colorless oil; [α]2D2 +3.3 (c 0.6, CHCl3) [lit.53 for ent-35: −1.1 (c
1
2.4, CHCl3)]; H NMR (600 MHz, C6D6) δ: 5.54 (d, J 9.7 Hz, 1H,
NH), 4.59 (dd, J 9.9, 1.9 Hz, 1H, CHNH), 4.37 (qd, J 6.2, 1.9 Hz, 1H,
CH3CHOTBS), 3.40 (s, 3H, CH3O), 1.52 (s, 9H, t-BuO), 1.17 (d, J
6.3 Hz, 3H, CH3CH), 0.92 (s, 9H, t-BuSi), 0.00 (s, 3H, CH3Si), −0.02
(s, 3H, CH3Si); 13C NMR (151 MHz, C6D6) δ: 171.1, 156.0, 79.1,
69.0, 59.5, 51.2, 28.0, 25.4, 20.4, 17.6, −4.8, −5.7; IR (film) v: 3457,
1755, 1721, 15000, 1168 cm−1; HRMS (ESI-TOF) m/z calcd for
C16H33NO5SiNa [M + Na+] 370.2026. Found 370.2020.
Methyl N-Acetyl-O-(t-butyldimethylsilyl)-D-threoninate (36).
Prepared in the same manner as compound 25. Purification by
chromatography on silica gel (25% AcOEt in hexanes). Yield 65 mg
(86%) starting from 70 mg (0.260 mmol) of compound 24; colorless
oil; [α]2D3 −5.3 (c 0.8, CHCl3) [lit.52 for ent-36: +6.5 (c 0.02,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for selected compounds.
1
CH2Cl2)]; H NMR (500 MHz, CDCl3) δ: 6.08 (d, J 9.0 Hz, 1H,
This material is available free of charge via the Internet at
http://pubs.acs.org.
NH), 4.54 (dd, J 9.4, 1.8 Hz, 1H, CHNH), 4.41 (qd, J 6.3, 1.8 Hz, 1H,
CH3CHOTBS), 3.69 (s, 3H, CH3O), 2.06 (s, 3H, CH3CO), 1.14 (d, J
L
dx.doi.org/10.1021/jo502026a | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sebastian.stecko@icho.edu.pl (S.S.).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Author is grateful to Polish Ministry of Science and Higher
Education for financial support of research (Iuventus Plus Grant
No. IP2011 051871 and IP2010 039070). The authors are
grateful to The Regional Council of Mazovia and European
Union within European Regional Development Fund for a
Ph.D. student scholarship (P.S.). The authors are also grateful
to The European Union within the Structural Funds No.
POKL.04.01.01-00-114/09-01 for a postdoctoral fellowship
(A.P.-H.)
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