Modular Construction of Protected 1,2/1,3-Diols, -Amino Alcohols, and -Diamines via Catalytic Asymmetric Dehydrative Allylation: An Application to Synthesis of Sphingosine

Article abstract of DOI:10.1021/acs.joc.7b01181

A new enantioselective catalysis has been developed for the one-step construction of methylene-bridged chiral modules of 1,2- and 1,3-OH and/or NH function(s) from δ- or λ-OH/NHBoc-substituted allylic alcohols and H₂C=O / H₂C=NBoc . A protonic nucleophile, either in situ-generated CH₂OH or CH₂NHBoc, is intramolecularly allylated to furnish eight possible 1,2- or 1,3-O,O, -O,N, -N,O, and -N,N chiral modules equipped with an ethenyl group in high yields and enantioselectivities. The utility of this method has been demonstrated in the five-step synthesis of sphingosine.

Full text of DOI:10.1021/acs.joc.7b01181

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Note
Modular Construction of Protected 1,2/1,3-Diols, -Amino
Alcohols, and -Diamines via Catalytic Asymmetric Dehydrative
Allylation: An Application to Synthesis of Sphingosine
Shinji Tanaka, Ramachandran Gunasekar, Tatsuya
Tanaka, Yoko Iyoda, Yusuke Suzuki, and Masato Kitamura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01181 • Publication Date (Web): 25 Jul 2017
Downloaded from http://pubs.acs.org on July 25, 2017
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Page 1 of 13
The Journal of Organic Chemistry
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Modular Construction of Protected 1,2/1,3-Diols, -Amino Alcohols,
and -Diamines via Catalytic Asymmetric Dehydrative Allylation: An
Application to Synthesis of Sphingosine
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Shinji Tanaka, Ramachandran Gunasekar, Tatsuya Tanaka, Yoko Iyoda, Yusuke Suzuki, and Masato
Kitamura*
Graduate School of Pharmaceutical Sciences, Research Center for Materials Science, and Graduate School of Science, Na-
goya University
Chikusa, Nagoya, 464-8601 (Japan)
Supporting Information Placeholder
O
PF6
– H+
ABSTRACT: A new enantioselective catalysis has been
developed for the one-step construction of methylene-
bridged chiral modules of 1,2- and 1,3-OH and/or NH
function(s) from δ- or λ-OH/NHBoc-substituted allylic
O
N
OH
N
O
R
R
Ru
Cl
Cl
(
R)-Cl-Naph-PyCOOH
(R)-1
alcohols and “H
cleophile, either in situ generated CH
CH NHBoc, is intramolecularly allylated to furnish
2
C=O”/”H
2
C=NBoc.” A protonic nu-
a Previous work
2
OH or
2
OH
n
n
(
R)- or (S)-1
n
eight possible 1,2- or 1,3-O,O, -O,N, -N,O, and -N,N
chiral modules equipped with an ethenyl group in high
yields and enantioselectivities. The utility of this meth-
od has been demonstrated in the five-step synthesis of
sphingosine.
+
+
H O
2
A
A
O
AH
O
O
A = O, NCOR, etc.
quant, up to >99:1 er
n = 1–3
b This work
OH
A
n
Z
H+
AH
Z=A
cat 1
H+
Z=A
chiral modules
Chiral 1,2- and 1,3-oxygen- and/or nitrogen-
units are ubiquitous in natural products ranging from
small molecules, such as sugars, amino acids, and lipids,
1
2
HA
A
*
Z
A
Z
O
1
A
n
1,2-A,A
β
to huge molecules. Efficient construction of these chi-
A
n
OH
Z
HA
n
AH
γ
α
Z
Ru
ral modules with an appropriate functionality for the
continuing reaction is needed toward a target molecule,
and many excellent methods have been developed on the
1
3
AH
n = 1 or 2
*
A
A
H+
Z=A
Z
1,3-A,A
2
3
cat 1
HA
n
basis of asymmetric oxydation, reduction, aldol reac-
A = O or NR
4
5
Ru
tion, and allylation. However, these methods lack
generality; therefore, we have aimed to develop a meth-
od that can furnish all eight possible 1,2- and 1,3-O,O, -
O,N, -N,O, and -N,N modules with a single chiral cata-
lyst. Figure 1 illustrates our basic concept. The mono-
cationic CpRu(II) complex 1 of chiral picolinic acid, Cl-
undesired
pathways
by-products
Figure 1. Dehydrative asymmetric allylation approach for
construction of chiral 1,2- and 1,3-bifunctional modules.
Naph-PyCOOH
(6-(2-chloronaphthalen-1-yl)-5-
methylpyridine-2-carboxylic acid), catalyzes an intramo-
lecular asymmetric dehydrative Tsuji-Trost type allyla-
tion of protonic nucleophiles, e.g., OH, NHCOR, and
COOH, to furnish 5- and 6-membered cyclic ethers, am-
ides, and esters with high enantiomeric ratios (er) (Figu
+
which the CpRu/H operates. Addition of the protonic
nucleophile AH (A = O or NCOR) in a δ- or λ-AH-
substituted allylic alcohol to an electron-deficient un-
saturated “Z=A” bridging unit should be accelerated by
H to generate the two-atom inserted A–Z–AH species;
this species would undergo a smooth cyclization to the
+
6
re 1a). Figure 1b illustrates our envisioned strategy
that catalyzes upon the slightly acidic conditions under
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 13
corresponding 5- and 6-membered 1,2- and 1,3-A,A mo-
tifs bridged by “Z.” Although many possible species
exist in equilibria, catalyst 1 will only furnish the prod-
uct-forming species. However, if a π-allyl intermediate
is generated more quickly than A–Z–AH formation, the
undesired pathways would become predominant. The
appropriate selection of “Z=A” is the key in the complex
network system.
Table 1
of (E)-But-2-ene-1,4-diol (2).
:
Screening of ‘‘Z=A’’ in the O and N Allylation
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
mol% (R)-1
’
’Z=A’’
O
*
OH
O
O
C
A
*
*
HO
1
00 °C
R
O
3
NBoc
2
R
5
1
00 mM
1,2-O,A module
b
e
c
d
entry
‘‘Z=A’’
solvent
DMA
DMA
DMA
DMA
DMA
DMA
t-BuOH
THF
% yield
R:S
f
1
O=C=O
—
—
The bridging unit “Z=A” was screened in the
reaction of (E)-but-2-ene-1,4-diol (2) under the standard
conditions of “[2] = 100 mM; [(R)-1] = 1 mM; 10 mol
amount of “Z=A”; DMA; 100 °C.” Among many poten-
f
2
CH
CCl
(CH
(CF
3
CH=O
CH=O
C=O
C=O·nH
—
—
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
3
3
—
—
f
4
3
)
2
—
—
g
g
tially usable “Z=A,” “Z” was fixed to a C1 unit, R
2
C,
5
3
)
2
2
O
(52)
(77:23)
98:2
76:24
90:10
87:13
88:12
96:4
96:4
and “A” was selected as “O.” Table 1 summarizes the
representative results. With the generally utilized bridg-
6
HCH=O (37% formalin)
HCH=O (37% formalin)
HCH=O (37% formalin)
HCH=O (37% formalin)
HCH=O (37% formalin)
96
94
94
40
45
66
7
ing units, O=C=O, CH
3 3
CH=O, CCl CH=O, and
8
(
CH C=O, substrate 2 was completely consumed, but
3 2
)
9
2 2
CH Cl
none of the desired 1,2-O,O module, 4-ethenyl-1,3-
dioxorane, was obtained (entries 1–4). Most likely, the
intermediary π-allyl complex underwent β-elimination
to form a dienal and/or self-condensation with 2 to form
10
toluene
DMA
DMA
h
11
HCH=O (praformaldehyde)
g
i
j
1
2
HO-CH
2
-NHBoc(4)
92
allyl ethers.
Use of highly electrophilic
a
Conditions: [2] = 100 mM; [(R)-1] = 1 mM; 100 °C;
(
CF
3
)
2
C=O·nH
2
O furnished the unprotected but-3-ene-
0.5 mmol scale. Allyl ester of Cl-Naph-PyCOOH was
used for easier manipulation. The (R)-1 catalyst is gen-
erated in situ. 10 mol amount of Z=A was used other-
wize specified. Determined by H-NMR analysis oth-
1
,2-diol in a 77:23 er and 52% yield (entry 5), qualita-
+
tively confirming the validity of H -catalyzed A–Z–AH
generation, as illustrated in Figure 1b. Finally, use of a
b
c
1
3
7% aqueous solution of formaldehyde, HCH=O + H
2
O
d
e
erwise specified. Determined by HPLC analysis.
8
7
⇆
HOCH
2
OH, furnished the desired methylene-
f
atm. The substrate 2 was completely consumed, but no
g
bridged 1,2-O,O module (3) with a 98:2 R/S er in 96%
NMR yield (entry 6). Enantioselectivity decreased in t-
desired module was obtained. The values in parentheses
are the data of but-3-ene-1,2-diol obtained under the re-
h
2 2
BuOH, THF, CH Cl , and toluene. Yields tended to be
action conditions. 100 mol amount of H
2
O was added.
i
j
lower in hydrophobic solvents (entries 7–10). Anhy-
2 mol amount of 4. Isolated yield.
8
drous paraformaldehyde lowered the yield, and the ad-
dition of H
2
O increased the yield and er (entry 11). Tri-
The generality of the present method was inves-
oxane showed low reactivity no matter of whether the
8
H
2
O exist or not. Furthermore, HOCH
2
NHBoc (4) was
tigated with the use of 2, λ-OH-substituted allylic alco-
hol 6, δ-BocNH-substituted allylic alcohol 7, and λ-
BocNH-substituted allylic alcohol 8. The results are
shown in Figure 2. All of the eight possible chiral
modules, 1,2-O,O (3), 1,2-O,N (5), 1,3-O,O, 1,3-O,N,
1,2-N,O, 1,2-N,N, 1,3-N,O, and 1,3-N,N were obtained
with >94:6 ers in >86% yields. Under the standard con-
ditions, the yields of 1,3-O,N and 1,3-N,N were halved
and the enantioselectivity of 1,3-O,N was low (R/S =
25:75). However, increasing the catalyst loading from 1
mol% to 10 mol% improved the yields and ers to 86%
with 98:2 er and 88% with 99:1 er for 1,3-O,N and 1,3-
N,N, respectively. The reliability of the present method
was confirmed by the synthesis of 1,2-O,O, 1,2-O,N,
and 1,3-O,O on a 1–5 g scale of 2 and 6. The present
method could not be applied to the synthesis of 1,4-type
modules, because intramolecular cyclization of
found to be an excellent bridging unit that facilitated the
efficient construction of methylene-bridged 1,2-O,N
module (5) with a 96:4 R/S er in 92% isolated yield (en-
try 12). Use of 2 mol amount of 4 was sufficient. In
both cases, the absolute configurations matched the en-
antioselectivity observed in the (R)-1-catalyzed intramo-
6
lecular OH and NHBoc allylation. Replacement of Boc
with Cbz, Bz, Piv, TFA, and Ts dramatically decreased
8
the reactivity. A complicated equilibria exists between
various chemical species that are generated from 2, the
π-allyl intermediate and “HCH=A” (A = O or NCOR)
(
Figure 1b). The equilibrium concentration of the de-
sired product-forming species should be strongly affect-
ed by the acidity, polarity, and the H O content of the
reaction media. A subtle change in the bridging unit
significantly affects reactivity. The C=O
andH C=NBoc bridging units satisfy the requirements
for the desired reaction pathway, as shown in Figure 1b.
2
H
2
6
a
2 3 2
HO(CH ) CH=CHCH OH more quickly occurres.
2
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Page 3 of 13
The Journal of Organic Chemistry
OH
HO
OH
10 mol amt
Z)-but-2-ene-1,4-diol
3 mol% HG-II
HO
60 mol amt H O
3 mol% cat 1
(
γ
α
2
1
2
3
4
5
6
7
8
9
2
6
R
R
O
O
δ
β
OH
I
II
I
II
NBoc
5
6:4 er
NBoc
10
65% yield
acetone, rt, 4 h
DMA, 100 °C, 15 h
9
O
O
9
6:4 er
O
NBoc
O
O
O
NBoc
a
1,2-O,O (3)
1,2-O,N (5)
6% NMR yield 92% yield
1,3-O,O
92% yield
96:4 er
1,3-O,N
86% yield
98:2 er
Ru
9
k5
S
+
S
HO
R O
HO
S
O
9
8:2 er
-g scaleb
96:4 er
5-g scaleb
HO
BocN
BocN
1-g scaleb
BocN
OH
5
1
1
epi-11
IntNCH2OH
2
(
R)-1:
74% yield, 80:20 dr
BocN
BocN
11: 98:2 er
epi-11: 98:2 er
O
NBoc
BocN
O
BocN
NBoc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
9
9
,2-N,O
1% yield
6:4 er
1,2-N,N
92% yield
99:1 er
1,3-N,O
90% yield
94:6 er
1,3-N,Na
88% yield
99:1 er
(S)-1:
29% yield, 78:22 dr
OH
Ru
O
O
O
O
I
II
I
II
+
O
k6
OH
BocHN
OH
NHBoc
NHBoc
NHBoc
BocHN
IntOCH 22 OH
12
epi-12
7
8
not obtained
1
0 mol amt
1-pentadecene
mol% HG-II
11
Figure 2. Synthesis of eight possible chiral modules. All
of yields except for that of 3 are isolated ones. Conditions
I: [allylic alcohol] = 100 mM, [HCHO aq] = 1 M, [(R)-1] =
mM, DMA, 100 °C, 3 h. Conditions II: [allylic alcohol]
100 mM, [4] = 200 mM, [(R)-1] = 1 mM, DMA, 100 °C,
h. Results obtained by use of 10 mM (R)-1. [2] or [6] =
00 mM, [HCHO aq] = 5 M or [4] = 1 M, [(R)-1] = 5 mM,
DMA, 100 °C, 12 h. A longer time was required for com-
pletion probably due to less efficient phase separation of
a)10 mol amt
HONH2·HCl
3
1
1 + epi-11
HO
O
CH2Cl2, rt, 4 h
74:1 CH OH–H O
reflux, 19 h
quantitative yield
3
2
BocN
1
=
3
13
8% yield
7
b) separation by
silica-gel column
chromatography
a
b
OH
3
1
S
HO
R
2
5
NH2
D-erythro-sphingosine (9)
H
2
O. Isolation of 3 was problematic.
Figure 3. Synthesis of sphingosine (9) from 1,2-O,N mod-
ule (5) via methylene-relayed dehydrative allylation com-
bined with olefin metathesis. All of yields are isolated
ones. amt: amount.
An ethenyl group that was simultaneously in-
stalled into the chiral modules during the course of the
asymmetric cyclization process is advantageous for the
9
subsequent reaction toward a target molecule. For ex-
(
E)-10 with a 93:7 er. The reactivity of the enantio-
ample, metathesis with an allylic alcohol can furnish the
δ-O/N substituted allylic alcohol moiety, which could be
used for the next O/N introduction with our strategy.
meric catalyst (S)-1 was significantly lowered (29%
yield), and the dr hardly changed. Thus, the slight en-
hancement of the product er from 96:4 to 98:2 can be
ascribed to the kinetic resolution of the 96:4 R/S mixture
of (E)-10 by (R)-1. Inthis specific case, the substrate
control is predominant over the catalyst control.
this second diastereoselective allylation, the OCH
type product 12 was not generated at all, indicating that
Among many potentially applicable target molecules, -
D
erythro-sphingosine (9), which is representative of
sphingolipids, was selected for demonstration of our
strategy because of its structural expediency and signifi-
1
2,13
In
O-
2
1
0
cant biological characteristics.
Figure 3 shows the
synthetic pathways. The 1,2-O,N module ((R)-5) ob-
tained above as a 96:4 R/S mixture was subjected to ole-
fin metathesis using 3 mol% of 2nd-generation Hov-
eyda-Grubbs catalyst (HG-II) in acetone containing 10
mol amount of (Z)-but-2-ene-1,4-diol gave 10 as a
95:5 E/Z mixture, the E product of which was isolated
in 65% yield. (E)-10 was converted to 11 in a 80:20
diastereomeric ratio (dr) in the presence of (R)-1 in
DMA containing 60 mol amount of H
of H C=O. The “NCH OH” unit was in situ generated
from the methylene-bridged and δ-NBoc-substituted
allylic alcohol (E)-10, realizing an atom economical
methylene relay process. The second allylation was
roughly one order slower than the first one (100 °C, 3 h:
the reactivity of the 5-membered ring formation (k ) of
the NCH OH-type intermediate Int
5
2
NCH OH
is much high-
2
er than that of the 6-membered ring formation (k
OCH OH-type intermediate IntOCH OH (k >> k
6
) of the
). The
2
5
6
1
1
2
oxazolidine product 11 and 1-pentadecene (10 mol
amount) were coupled in CH Cl in the presence of HG-
II (3 mol%) to give 13 as a sole product in 78% isolated
yield. The methylene bridge and Boc protecting group
were quantitatively removed using Harding’s conditions
2
2
2
O without the use
14
2
2
(
2 3 2
HONH ·HCl, 74:1 CH OH–H O, reflux, 19 h) to fur-
nish a 80:20 mixture of D-erythro-sphingosine (9) and
epi-9. The mixture was purified to give the target mole-
1
13
cule. The H- and C-NMR spectra, as well as the opti-
22
cal rotation ([α]
D
=–3.99 (c=0.465 in CHCl
3
)), were all
1
8
00% conversion vs 100 °C, 15 h: 78% conversion). An
0:20 mixture of 11 (98:2 er) and epi-11 (98:2 er) was
isolated in 74% yield together with ca 15% recoverty of
21
consistent with authentic 9 ([α]
D
=–3.29 (c=0.460 in
15
3
CHCl )).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 13
In summary, we have successfully developed
a general method for the construction of chiral 1,2-
and 1,3-O,O, -O,N, -N,O, and -N,N eight modules
equipped with a terminal ethenyl group; the reaction
proceeds in the presence of our CpRu complex of chiral
picolinic acid, Cl-Naph-PyCOOH, in combination with
2
dimethylacetamide (DMA) from CaH ; tetrahydrofuran (THF)
and toluene from Na/benzophenone; acetone from MS 4A. These
were degassed by three freeze–thaw cycles before use. First grade
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
solvents including chloroform (CHCl
,4-dioxane (dioxane), ethyl acetate (EtOAc), diethyl ether
Et O), hexane, THF, methanol (CH OH), pentane, and 2-
3 2 2
), CH Cl , ethanol (EtOH),
1
(
2
3
propanol (iPrOH) were used without purification for extraction,
partition, silica-gel column chromatography, measurement of
optical rotations, and usual organic synthesis. Solvents for HPLC
were used after filtration (0.5 µM pored PTFE filter).
Reagents and chemicals. All of reagents, which were pur-
chased from companies, were used without further purification
unless otherwise specified. These are listed below in the alpha-
betical order neglecting the number suffix.
2 2
“H C=O” or “HOCH NHBoc” with δ- or λ-OH/NHBoc-
substituted allylic alcohol substrates. The success of this
+
method can be ascribed to two factors: i) the Ru/H -
catalyzed allylation functioning under slightly acidic
conditions; and ii) the use of a methylene bridging unit,
H C=A (A = O or NBoc). The slightly acidic conditions
2
facilitate the formation an acetal, aminal, and a Ru-π-
allyl species directly from the allylic alcohol. The
methylene bridging unit enables the facile generation of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Aldrich: acetaldehyde, Hoveyda-Grubbs catalyst 2nd genera-
tion
((1,3-bis-(2,4,6-trimethylphenyl)-2-
imidazolidinylidene)dichloro(o-
isopropoxyphenylmethylene)ruthenium, HG II), hydroxylamine
hydrochloride (HONH ·HCl), triphenylphosphine (PPh ), Quad-
AP, and D-erythro-sphingosine. Ark Pharm: (1,3-
dioxolan-4-yl)methanol. Kishida: pyridine. Nacalai: aqueous
NH , distilled water (H O), triethylamine (N(C ), formalin
36–38%) aqueous solution of fromaldehyde (CH O) (stabilized
with 5–10% CH OH; amount of CH O was calculated as 37.0
the sterically less-demanding ACH
2
OH acetal and
2
3
TM
ACH NHBoc aminal (A = O or NBoc). Removal of the
2
rasil
methylene group is straightforward, and the ethenyl
group can function as the basis for the generation of the
next allylic alcohol motif via HG-II-catalyzed metathe-
sis. By using these advantages, we have realized a
unique and short-step asymmetric synthesis of sphingo-
sine from commercially available (E)-but-2-ene-1,4-diol.
On-going projects in our group include the application
of this strategy to other O/N-multi-functionalized natural
products.
3
2
2 5 3
H )
(
2
3
2
wt%), and 12 M aqueous hydrogen chloride (HCl). Organo:
+
Amberlite IR120B (H form). Strem: trisacetonitrilecyclopenta-
dienylruthenium hexafluorophosphate ([CpRu(CH CN) ]PF ).
3
3
6
TCI: (Z)-but-2-ene-1,4-diol, di-tert-butyl dicarbonate (Boc
2
O),
tert-butyl methyl iminodicarbonate, trichloroacetaldehyde, tri-
fluoroacetic acid, hexafluoroacetone hydrate, diisopropyl azodi-
carboxylate (DAID), 1-pentadecene, 1,1'-thiocarbonyldiimidazole
(
TCDI), and p-toluenesulfonyl chloride (TsCl).
E)-But-2-ene-1,4-diol (2) was purchased from TCI and puri-
fied by silica-gel column chromatography before use, or synthe-
(
EXPERIMENTAL SECTION
16
sized from but-2-yne-1,4-diol according to the reference.
Boc-aminomethanol (4),
aminomethanol,
trifluoroacetylaminomethanol, N,N'-bistosylaminal, (E)-pent-
2-ene-1,5-diol (6), (E)-N-Boc-4-aminobut-2-en-1-ol (7), and
(E)-N-Boc-5-aminopent-2-en-1-ol (8) were synthesized accord-
N-
N-Bz-
N-
17
18
All of Figure S1–S35 and Table S1 were attached in the sup-
N-Cbz-aminomethanol,
8
19
20
porting information.
N-pivaloylaminomethanol,
2
1
22
(1) Instruments. Nuclear magnetic resonance (NMR) spectra
1
23
24
were recorded on JEOL JNM-ECA-600 (600 MHz for H, 152
1
3
25
MHz for C), and the chemical shifts are expressed in parts per
million (ppm) downfield from Si(CH or in ppm relative to the
solvent peaks (δ 7.26 (CHCl ), 2.49 (CD SOCHD ), and 3.31
OD) in H NMR; δ 77.0 (CDCl ) and 49.0 (CD
3
)
4
ing to the reported methods.
Silica gels. Analytical thin-layer chromatography (TLC) and
preparative TLC (PTLC) were performed using Merck Glass TLC
plates, silica gel 60 coated with F254 (layer thickness, 0.25 mm
(TLC) and 1 mm (PTLC)). The product spots were visualized by
3
3
2
1
13
(
CHD
2
3
3
OD) in C
1
NMR, respectively). The signal patterns of H NMR are indicated
as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
1
13
and br, broad signal. The resolutions of H- and C-NMR spectra
are 0.69 Hz and 1.44 Hz, respectively. NMR spectra were meas-
ured with samples of 5–15 mM at 25 °C unless otherwise speci-
fied. High-resolution mass spectra (HRMS) were measured by
ESI ionization method on a Bruker Daltonics microTOF-QII sys-
tem. High performance liquid chromatography (HPLC) analyses
were performed on Shimadzu LC-10AD, LC-20AD, and LC-
use of
anisaldehyde, iodine (I
potassium permanganate, or UV irradiation. Silica-gel column
a
solution of phosphomolybdic acid (PMA), o-
2
), cerium ammonium molybdate (CAM),
2
chromatography, which is abbreviated as SiO -chromatography
afterward, was performed using AP 300.
+
Catalyst. CpRu(II)/H catalyst (R)-1 or (S)-1, which can be
3 3 6
prepared by mixing [CpRu(CH CN) ]PF with (R)- or (S)-Cl-
2
0TA systems. Gas chromatography (GC) analyses were per-
Naph-PyCOOH in a 1:1 ratio, is air sensitive. For the operational
3
formed on a Shimazu GC-2014 system. Optical rotations were
measured on a JASCO P-1010-GT system.
simplicity, the corresponding Ru(IV) π-allyl complex, [CpRu(η -
C
3
H
5
)((R)-Cl-Naph-PyCOO)]PF
the present asymmetric allylation. The Ru(IV) complex was pre-
pared by mixing [CpRu(CH CN) ]PF with one mol amount of
(R)- or (S)-Cl-Naph-PyCOOAll (All: CH CH=CH ). In the reac-
tion system, (R)-1 or (S)-1 is generated. The procedure for prepa-
6
or its S enantiomer, was used in
(2) Materials.
Gases. Argon (Ar) gas was purified by being passed through
a column of BASF R3-11 catalyst at 80 °C and then through a
3
3
6
2
2
column of granular CaSO
O <0.005%) and O were purchased from AIR WATER INC.
Ozone (O ) gas was generated by NIPPON OZONE O generator
100 V, 5 A, 25 mL/min O ).
Solvents. Solvents for the present catalytic allylation and
4 2
. Carbon dioxide (CO , >99.9% purity,
3
H
2
2
2 2 3 5
ration of a 10-mM CH Cl solution of [CpRu(η -C H )(Cl-Naph-
3
3
PyCOO)]PF has been described in the supporting information of
6
6a
(
2
the previously reported paper.
Synthesis of authentic racemic modules. Authentic race-
mic samples were prepared by use of (±)-Cl-Naph-PyCOOAll
instead of optically pure ligand under the same conditions as those
described in sections (4), (5), and (6).
Grubbs olefin metathesis were dried and degassed at the reflux
temperature in the presence of appropriate drying agents (2.5 g/L)
under Ar stream for 6 h and distilled into Schlenk flasks: di-
2 2
chloromethane (CH Cl ), tert-butyl alcohol (tBuOH), and N,N-
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(
3) General manipulation for allylation and synthesis
layer was extracted with pentane (5 mL x 3). The combined or-
ganic layers were washed with H O (5 mL x 2), dried over
Na SO (ca. 2 g), and filtrated. The filtrate was concentrated at
600 hPa by use of a rotary evaporator to ca. 1 mL, which contains
ca. 10 mg of 3. During the concentration process, a large part of 3
was evaporated. The enantiomeric ratio (er) was determined by
HPLC analysis of the residue to be 98:2 (R:S) (conditions:
CHIRALCEL OD-H column (0.46 cm φ x 250 mm); hexane–
iPrOH 99.9:0.1 eluent; 1.0 mL/min flow rate; 254-nm light detec-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
of sphingosine. A Teflon-coated magnetic bar was used for
2
stirring of a reaction mixture. Room temperature (rt) was in the
range of 25 °C to 28 °C. Cold bath at –78 °C was prepared by use
of dry-ice methanol bath or EYELA PSL-2500 equipment. Sol-
vents after general workup process were removed by means of a
rotary evaporator. Concentration of a reaction mixture in a
Schlenk tube was performed by connecting to a vacuum-Ar line
2
4
via a cold trap cooled by liquid N
general partition-based workup was dried over anhydrous Na
2
. Organic extract obtained by a
SO
2
4
tion; t = 9.8 min (S) and 10.9 min (R)) (Figure S2).
R
for ca. 30 min. “Aqueous” and “saturated” were abbreviated as
“aq” and “sat,” respectively. All of metal-catalyzed reactions
were carried out under Ar atmosphere by use of a general Schlenk
technique unless otherwise specified. A Schlenk tube with Teflon
J. Young valve was specified by “Young-type Schlenk tube.”
Liquid reagents were introduced by use of a syringe via a septum
rubber. After introduction, the septum was replaced with a glass
stopper or with a Young valve. Heating in a closed system was
carried out after reducing the pressure of the whole system or after
raising the temperature followed by closing the system. Degassed
solvents and degassed solutions of reagents, catalysts, and sub-
strates were transferred to another Schlenk tube by use of a gas-
tight syringe or cannulation method. Cannulation was performed
by use of a Teflon or stainless tube through a septum rubber under
a slightly positive pressure of Ar. One freeze-thaw cycle consists
of i) freezing a liquid mixture, ii) evacuation of the system at the
freezing stage, iii) closing the system, iv) thawing the frozen liq-
uid, and v) releasing the negative pressure to atmospheric pressure
by filling Ar gas.
Reaction with 500-mM 2. The reaction mixture obtained
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
under the above conditions except for the concentration of 2 (1.14
mL (500-mM DMA solution of 2), 0.570 mmol (50.2 mg)) was
used for preparation of a 100–300 mM solution of 3. The reaction
mixture was partitioned between pentane (3 mL) and H O (5 mL).
2
The aq layer was further extracted with pentane (3 mL x 4). The
combined organic layers were washed with H O (5 mL), and dried
2
over Na SO (ca. 2 g). Filtration gave a ca. 15 mL pentane solu-
2
4
tion of 3 containing 30% of DMA. The amount of 3 in the solu-
tion was determined to be ca. 40 mg/15 mL (ca. 25 mM) by the
mesitylene method (0.100 mL; 0.500 mL (100-mM CDCl mesit-
3
ylene solution, 0.0500 mmol (6.00 mg)); 0.50 mL CDCl3;
3.00:1.60 signal ratio at δ 4.04 and δ 6.78), indicating that the
extraction efficiency was 80%. A 20-mL Young-type Schlenk
tube was charged with the above solution (5 mL), closed, and
connected to a vacuum line via a trap. The Young-type Schlenk
tube was cooled to –78 °C and the trap was inserted into a liquid
N bath. After the inner pressure of the vacuum line reached to
2
<0.02 mmHg, the Young’s valve was carefully opened. Pentane
(4) Synthesis of 1,2-O,O module (3). All of screening
data for the reaction conditions were listed in Table S1.
in the Young Schlenk tube was distilled into the trap to concen-
trate the pentane solution to <0.5 mL (5 h). The Young’s valve
was closed, and the tube was warmed to rt. Another 5 mL of the
25-mM pentane solution of 3 was added to the Young-type
Schlenk tube, and concentrated in the same way as described
above. This concentration process was repeated 5 times. The
2
6
The boiling point of compound 3 is 110 °C, therefore
1
isolation is very difficult. The yield was determined by H-NMR
analysis using mesitylene as an internal standard, and the pure
sample for measurement of the physical property was obtained in
very low yield on a 5-g scale reaction. Compound 3 was isolated
as a 100–300 mM pentane solution in ca. 60% yield from a 500-
mM reaction mixture, and the solution was directly used for con-
version to but-3-ene-1,2-diol (14) by hydrolysis and to (1,3-
1
H-NMR analysis using mesitylene determined the amounts of 3
in the Young-type Schlenk tube and the trap to be 30 mg/mL (300
mM containing 10% DMA) and 5 mg/15 mL, respectively. Iso-
lated yield of 3 as the pentane solution was calculated to be 60%
yield. Er of 98:2 was confirmed by the HPLC analysis of the 300-
mM solution of 3 under the same conditions as those described
above. The 100–300 mM solution of 3 prepared in a different
batch was used for conversion of 3 to other compounds.
Direct conversion of 3 in the extracted pentane solu-
tion and determination of absolute configuration (abs
confign).
4
dioxolan-4-yl)methanol (15) by ozonolysis/NaBH process. The
details were described below.
Procedure for 0.5-mmol scale reaction and determina-
1
tion of H-NMR yield and conversion.
Reactioin with 100 mM 2. A 10-mM CH
CpRu(CH CN) ]PF (0.570 mL, 5.70 µmol (2.475 mg)) and a
0-mM CH Cl solution of (R)-Cl-Naph-PyCOOAll (0.570 mL,
2 2
Cl solution of
[
1
3
3
6
2
2
5.70 µmol (1.925 mg)) were charged in a 100-mL Young-type
Schlenk tube, and concentrated. To this was added a 100-mM
DMA solution of (E)-but-2-ene-1,4-diol (2) (5.70 mL, 0.570
Acid hydrolysis to but-3-ene-1,2-diol (14). To the 117-mM
pentane solution (1.9 mL; 3 (22.3 mg, 0.222 mmol)) derived from
the reaction using (R)-Cl-Naph-PyCOOAll was added CH
3
OH (2
+
mmol (50.2 mg)) and 37% formalin (424 µL, 5.70 mmol as CH
2
O
mL), CH Cl (2 mL) and Amberlite IR120B (H form) (100 mg).
2 2
(
171 mg)). The mixture was heated to 100 °C under Ar, and then
The mixture was heated at 60 °C (oil bath temperature) for 48 h.
After being cooled to rt, the whole mixture was filtered through
membrane filter (1 µm pore size), and the filtrate was concentrat-
the tube was sealed. After being stirred at 100 °C for 3 h, the
resulting yellow-colored solution was cooled to rt. To this was
added mesitylene (100-mM CDCl
mmol (22.8 mg)). A portion of the mixture (ca. 0.2 mL) was
transferred to an NMR tube and diluted with CDCl (0.5 mL).
3
solution; 1.90 mL, 0.190
ed to give a yellow oil (ca. 120 mg). This was purified by SiO
2
-
chromatography (SiO , 5 g; CHCl –CH OH 50:1 eluent) to give
2
3
3
(R)-but-3-ene-1,2-diol (14) (17.5 mg, 89% yield) as a colorless
3
1
1
The solution was subjected to the H-NMR analysis with 10-sec
repetition time so that the signal intensities become accurate as
much as possible. The 0.960:1.00 ratio of the signal intensities of
the 1,2-O,O module product 3 (δ 4.04 (dd, J = 7.92, 6.89 Hz, 1H;
CHCHHO)) and mesitylene (3H at δ 6.78 (s; 3 x ArH)) deter-
mined the yield to be 96% (Figure S1). No signal of the substrate
oil: H NMR (CDCl ) δ 2.33 (br, 2H; OH), 3.51 (t, J = 11.02 Hz,
3
1H; CHHOH), 3.68 (d, J = 11.02 Hz, 1H; CHHOH), 4.26 (br, 1H;
CH CHCH), 5.23 (d, J = 10.33 Hz; 1H, CH=CHH), 5.37 (d, J =
2
17.21 Hz; 1H, CH=CHH), 5.85 (ddd, J = 17.04, 10.33, 6.89 Hz,
1
1H; CH=CH
2
). Figure S3 shows the H-NMR spectrum. The
2
7
spectrum was consistent with the reported one. Comparison of
21
2
(
was observed within the error range of signal/noise (S/N) ratio
200), determining the conversion to be >99%. The reaction mix-
ture obtained under the above conditions in a different batch was
partitioned between pentane (5 mL) and H O (10 mL). The aq
the [α]
(c=0.82 in iPrOH); [α]
D D
value determined the abs confign to be R ([α] =+36.1
20
27
D
=–44.4 (c=3.02 in iPrOH) for S ).
2
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R
tra. The concentration of 3 in CDCl
was determined by use of
solution; 0.1 mL (100-mM
3
HO
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the mesitylene method (0.1 mL CDCl
3
HO
CDCl
CDCl
3
mesitylene solution, 0.0100 mmol (1.20 mg)); 0.5 mL
; 0.15:3 signal ratio at δ 4.04 and d 6.78) to be c=0.15.
1
4
3
(
5) Synthesis of 1,2-O,N module (5). To a 300-mL
Ozonolysis/NaBH
yl)methanol (15). To the 130-mM pentane solution (1.9 mL; 3
(24.7 mg, 0.247 mmol)) derived from the reaction using (R)-Cl-
4
reduction
to
(1,3-dioxolan-4-
Young-type Schlenk tube was added a 10.0-mM solution of
CpRu(CH
56.8 mL, 5.68 mmol); the solution was concentrated under vacu-
[
(
3 3 6 2 2
CN) ]PF and (R)-Cl-Naph-PyCOOAll in CH Cl
Naph-PyCOOAll was added CH
The mixture was cooled to –78 °C, and then O
until the color of solution became a pale blue (10 min). NaBH
56.1 mg, 1.48 mmol) was added at –78 °C, and the temperature
was raised to rt. After being stirred for 12 h, the whole mixture
was concentrated, and the residue was subjected to SiO
chromatography (SiO , 5 g; hexane–EtOAc 2:1 eluent) to give
1,3-dioxolan-4-yl)methanol (15) (21.7 mg, 84% yield) as color-
3
OH (2 mL) and CH
2 2
Cl (2 mL).
um to furnish an orange residue. To this was added N-Boc-
aminomethanol (4) (16.7 g, 114 mmol) and 500-mM solution of
(E)-but-2-ene-1,4-diol (2) in DMA (113 mL, 56.8 mmol) under an
Ar atmosphere. After 12-h stirring at 100 °C, the yellow solution
was diluted with H
mL x 4). The combined organic layers were washed with H
100 mL x 2), dried over Na SO (15 g), filtered, and evaporated
under 600 hPa. The resulting crude oil (ca. 10 g) was purified by
SiO -chromatography (SiO 100 g, pentane:Et O = 9:1) to give N-
Boc-4-ethenyl-1,3-oxazolidine (5) (10.4 g, 92%) as a colorless oil:
H NMR (CDCl
.61, 4.82 Hz, 1H; OCHHCH), 4.09 (dd, J = 8.61, 6.89 Hz, 1H;
OCHHCH), 4.31 (br, 1H; CHCH=CH ), 4.76 (d, J = 4.13 Hz, 1H;
OCHHN), 4.97 (d, J = 2.75 Hz, 1H; OCHHN), 5.16 (d, J = 10.3
Hz, 1H; CH=CHH), 5.22 (d, J = 17.2 Hz, 1H; CH=CHH), 5.77
ddd, J = 16.9, 10.3, 6.89 Hz, 1H; CH=CH ); C NMR (CDCl ,
2 3
ca. 100 mM, 60 °C) δ 28.3, 57.8, 72.4, 79.1, 80.2, 116.3, 136.1
52.9; HRMS (ESI) calcd for C10
found 222.1115; [α]
(HPLC conditions: CHIRALPAK IA-3 column (0.46 cm φ x 250
mm); hexane–iPrOH 99.7:0.3 eluent; 1.0 mL/min flow rate; 254-
nm light detection; t = 11.5 min (S) and 14.6 min (R)). Figure
R
S6 and S7 showed the H- and C-NMR spectra and HPLC
charts, respectively.
Abs confign was determined by comparison of the optical rota-
tion of N-Boc-2-aminobut-3-en-1-ol (16), which was obtained by
deprotection of 5 followed by N-Boc protection.
3
was introduced
4
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
O (120 mL) and extracted with pentane (250
2
-
2
O
2
(
2
4
(
1
less oil: H NMR (CDCl
Hz, 1H; CHHOH), 3.68 (d, J = 11.02 Hz, 1H; CHHOH), 4.26 (br,
1H; CH CHCH), 5.23 (d, J = 10.33 Hz, 1H; CH=CHH), 5.37 (d, J
17.21 Hz, 1H; CH=CHH), 5.85 (ddd, J = 17.04, 10.33, 6.89 Hz,
3
) δ 2.33 (br, 2H; OH), 3.51 (t, J = 11.02
2
2
2
2
1
3 3 3
, 60 °C) δ 1.45 (s, 9H; C(CH ) ), 3.73 (dd, J =
=
1
8
2
0
2 D 3
H; CH=CH ); [α] =+3.62 (c=1.09 in CHCl ). Figure S4
1
2
shows the H-NMR spectrum of the synthetic product together
with that of the commercially available sample, which is the mix-
28
ture with 5-hydroxy-1,3-dioxane. The spectrum was consistent
with that of commercially available sample.
13
(
+
1
H
17NNaO
3
[M+Na] 222.1106,
); R:S = 96.5:3.5
19
D
=–12.4 (c=1.06 in CHCl
3
R
OH
O
O
15
1
13
Five-g scale reaction for obtaining pure sample of 3 in
CDCl
CpRu(CH
µmol (26.3 mg)) and (R)-Cl-Naph-PyCOOAll (10.0-mM CH
3
.
To a 200-mL Young-type Schlenk tube was added
CN) ]PF (10.0-mM CH Cl solution; 60.7 mL, 607
Cl
[
3
3
6
2
2
2
2
solution; 60.7 mL, 607 µmol (20.5 mg)), the solution was concen-
trated under vacuum. To the orange residue was added 37% for-
R
malin (45.6 mL, 607 mmol of CH
DMA solution of (E)-but-2-ene-1,4-diol (2) (121 mL, 60.7 mmol
5.35 g)) under Ar. The solution was stirred at 100 °C for 12 h,
and then cooled to rt. The yield was determined to be 96% in the
same way as that described above (0.100 mL; 0.500 mL (100-mM
2
O (18.2 g)) and a 500-mM
HO
NHBoc
(
1
6
The compound 5 (500 mg, 2.18 mmol) dissolved in CH
8.60 mL) was charged into a 30-mL round-bottom flask. To this
was added TFA (1.70 mL, 22.2 mmol). After 1-h stirring at rt,
CH OH (9.00 mL) was added, and the mixture was heated at 65
°C for 2 h. Concentration gave crude 2-ammoniobut-3-en-1-ol
trifluoroacetate (ca. 500 mg) as an oil, which was used for the
next reaction without further purification. The ammonium salt
104 mg, 0.483 mmol) was dissolved in a 4:1 dioxoane–H
ture, and the solution was transferred to a 5-mL Young-type
Schlenk tube. To this was added N(C (195 µL, 1.40 mmol)
and Boc O (161 µL, 0.701 mmol). The mixture was stirred at rt
for 2 h, and then concentrated to give a crude N-Boc protected
compound (ca. 100 mg). This was purified by SiO
chromatography (SiO , 10 g; CHCl –CH OH 9:1 eluent) to afford
N-Boc-2-aminobut-3-en-1-ol (16) (74.3 mg, 74%): H NMR
2 2
Cl
CDCl
signal ratio at δ 4.04 and δ 6.78). The reaction mixture was parti-
tioned between pentane (200 mL) and H O (300 mL). The aq
layer was further extracted with pentane (200 mL x 4). The com-
bined organic layers (ca. 1000 mL) were washed with H O (200
mL x 2), dried over Na SO (ca. 20 g), and filtered. The filtrate
ca. 1000 mL) was concentrated at 40 °C to ca. 100 mL by use of
3
mesitylene solution, 0.0500 mmol (6.00 mg)); 3.00:1.60
(
2
3
2
2
4
(
(
2
O mix-
a general distillation apparatus. The distillate (ca. 900 mL) and
the residue (ca. 100 mL) contained 2.4 g and 2.0 g of 3, respec-
5 3
H )
1
2
tively ( H-NMR analysis using mesitylene). The residue was
2
further concentrated to give a yellow oil (320 mg), which con-
tained a small amount of DMA and no pentane. A small portion
2
-
of the yellow oil (ca. 10 mg) was dissolved in CDCl
passed through a pad of SiO (7 mm φ x 7 mm). The CDCl
trate was subjected to the NMR measurement: H NMR (CDCl
δ 3.54 (dd, J = 7.23, 6.89 Hz, 1H; OCHHCH), 4.05 (dd, J = 7.92,
.89 Hz, 1H; OCHHCH), 4.44 (ddd, J = 6.89, 6.89, 6.89 Hz, 1H;
CHCH=CH ), 4.95 (s, 1H; OCHHO), 5.06 (s, 1H; OCHHO), 5.25
(d, J = 10.3 Hz, 1H; CH=CHH), 5.37 (d, J = 17.2 Hz, 1H;
3
(1 mL), and
2
3
3
2
3
fil-
1
1
3
)
(
(
CDCl
br, 1H; OCHHCH), 3.69 (br, 1H; OCHHCH), 4.23 (br, 1H;
CH), 4.79 (br, 1H; NH), 5.22 (d, J = 11.0 Hz, 1H; CH=CHH),
.26 (d, J = 17.2 Hz, 1H; CH=CHH), 5.77 (ddd, J = 17.4, 10.7,
3 3 3
, 60 °C) δ 1.45 (s, 9H; C(CH ) ), 2.04 (s, 1H; OH), 3.64
6
CH
2
2
5
5
1
2
.51 Hz, 1H; CH=CH ). Figure S8 showed the H-NMR spec-
trum. The spectrum was consistent with the reported one.
Comparison of the [α] value determined the abs confign to be R
[α] =+22.4 (c=0.825 in CHCl ); [α] =+31 (c=1.03 in CHCl )
D 3 D 3
for R ).
1
3
CH=CHH), 5.84 (ddd, J = 17.2, 10.3, 6.89 Hz, 1H; CH=CH
NMR (CDCl ) δ 69.5, 77, 95.4, 118.2, 135.2, the signal resonated
at 77 ppm is overlapped with the signal of CDCl , and identified
by HMQC analysis; HRMS, no peak observed; [α]
2
);
C
29
3
D
3
20
20
(
1
D
9
=–57.4
3
c=0.15 in CDCl ). Figure S5 showed H- and C-NMR spec-
29
1
13
(
ACS Paragon Plus Environment

Page 7 of 13
The Journal of Organic Chemistry
(
6) Synthesis of other modules.
The synthetic proce-
extraction of aq layer with pentane (20 mL x 3); washing of the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
dures using formalin and N-Boc-aminomethanol (4) followed
those described in section (4) and section (5), respectively. The
product isolation process is essentially the same as that for 1,2-
O,N module (5) in all cases. Listed below are the detailed data for
the reaction conditions, isolation (work up and purification),
product (weight, isolated yield), and physical property. The reten-
tion times of the synthetic products with high ers were sometimes
slightly different from those of the racemic samples. In these
cases, the data of racemic ones were reported.
combined organic layers with H
(ca. g); filtration/evaporation.
chromatography (SiO , 5 g; pentane–Et
O (30 mL); dryness over Na
2
SO
2
4
3
Purification: SiO
2
-
2
2
O 8:2 eluent). Product:
N-Boc-4-ethenyl-1,3-oxazinane (1,3-O,N module) (368 mg,
1
86%). Physical property: H NMR (CDCl , 60 °C) δ 1.47 (s, 9H;
3
C(CH ) ), 1.61 (d, J = 13.1 Hz, 1H; CH CHHCH), 2.18 (ddd, J =
3
3
2
19.1, 13.1, 6.20 Hz, 1H; CH CHHCH), 3.71 (dd, J = 11.7, 11.4
2
Hz, 1H; OCHHCH ), 3.88 (dd, J = 11.4, 4.82 Hz, 1H;
2
OCHHCH ), 4.43 (d, J = 10.3 Hz, 1H; OCHHN), 4.90 (br, 1H;
2
1,3-O,O module. (E)-Pent-2-ene-1,5-diol (6) (1.03 g, 12.5
mmol), 37% formalin (9.38 mL, 125 mmol), DMA (25.1 mL),
CH CHCH=CH ), 5.14 (dd, J = 16.9, 1.38 Hz, 1H; CH=CHH),
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5.29 (dd, J = 11.7, 1.38 Hz, 1H; CH=CHH ), 5.39 (d, J = 7.57 Hz,
[
CpRu(CH
µmol), (R)-Cl-Naph-PyCOOAll (12.5 mL of 10.0 mM CH
solution, 125 µmol), 100 °C, 12 h. Isolation: partition between
O (50 mL) and pentane (50 mL); extraction of aq layer with
pentane (25 mL x 5); washing of the combined organic layers
with H O (50 mL); dryness over Na SO (ca. 25 g); filtra-
tion/evaporation. Purification: SiO -chromatography (SiO , 50 g;
pentane–Et O 9:1 eluent). Product: 4-ethenyl-1,3-dioxane (1,3-
O,O module) (1.31 g, 92%). Physical property:
(CDCl ) δ 1.61 (d, J = 13.1 Hz, 1H; CH CHHCH), 2.18 (ddd, J =
9.1, 13.1, 6.20 Hz, 1H; CH CHHCH), 3.71 (dd, J = 11.7, 11.4
Hz, 1H; OCHHCH ), 3.88 (dd, J = 11.4, 4.82 Hz, 1H;
OCHHCH ), 4.43 (d, J = 10.3 Hz, 1H; OCHHO), 4.90 (br, 1H;
CH CHCH=CH ), 5.14 (dd, J = 16.9, 1.38 Hz, 1H; CH=CHH),
.29 (dd, J = 11.7, 1.38 Hz, 1H; CH=CHH), 5.39 (d, J = 7.57 Hz,
H; OCHHO), 5.82 (ddd, J = 17.6, 10.7, 4.13 Hz, 1H; CH=CH );
) δ 31.8, 66.4, 76.9, 93.6, 115.6, 137.7; HRMS
3
CN)
3
]PF
6
(12.5 mL of 10.0 mM CH
2
Cl
2
solution, 125
1H; OCHHN), 5.82 (ddd, J = 17.6, 10.7, 4.13 Hz, 1H; CH=CH );
2
1
3
2
Cl
2
3
C NMR (CDCl , 60 °C) δ 28.4, 28.6, 50.7, 63.5, 72.7, 80.3,
116.5, 136.2, 154.1; HRMS (ESI) calcd for C11H19NNaO
3
+
21
H
2
[M+Na] 236.1263, found 236.1263; [α]D =–44.2 (c=0.434 in
CHCl ); R:S = 2:98 (GC conditions: CP-CHIRASIL-DEX CB
3
2
2
4
column (0.25 mm x 0.25 mm x 25 m); 40 °C, 10 °C/min to 150
2
2
°C; tR = 23.0 min (R) and 23.9 min (S)). Figure S12 and S13
1
13
2
showed the H- and C-NMR spectra and GC charts, respective-
1
H NMR
ly.
3
2
Abs confign was determined by comparison of the optical rota-
1
2
tion
of
N-(5-hydroxypent-1-en-3-yl)-4-
methylbenzenesulfonamide (18), which was obtained by deprotec-
tion of the 1,3-O,N module followed by N-Ts protection.
2
2
2
2
5
1
2
S
1
3
C NMR (CDCl
(ESI) calcd for C
3
+
OH NHTs
6
H
10NaO
2
[M+Na] 137.0578, found 137.0574;
=–11.4 (c=0.759 in CHCl ); R:S = 4:96 (GC conditions:
CHIRALDEX G-BP column (0.25 mm x 0.125 mm x 30 m); 40
C, 40 °C/min to 100 °C; t = 5.1 min (R) and 5.3 min (S)). Fig-
2
3
18
[α]
D
3
Process (i): Reaction: N-Boc-4-ethenyl-1,3-oxazinane (1,3-
°
R
1
13
ure S9 and S10 showed the H- and C-NMR spectra and GC
charts, respectively.
O,N module) (146 mg, 685 µmol), 74:1 CH
HONH ·HCl (476 mg, 6.85 mmol), 80 °C, 10 h. After the reac-
tion mixture was cooled to rt, sat aq K CO (5 mL) was added.
3 2
OH–H O (7.0 mL),
2
Abs confign was determined by comparison of the optical rota-
tion of pent-4-ene-1,3-diol (17), which was obtained by hydroly-
sis of the 1,3-O,O module.
2
3
Filtration/evaporation afforded a nearly pure 3-aminopent-4-en-1-
ol (47.6 mg, 69% yield) as an oil, which was used for the next
reaction without further purification.
Process (ii): The amine compound (10.0 mg, 98.9 µmol) dis-
2 2
solved in CH Cl (1 mL) was transferred to a 5-mL Young-type
Schlenk tube. The solution was cooled to 0 °C, and to this was
added TsCl (18.8 mg, 98.9 µmol) and pyridine (8.8 µL, 109
µmol). After 24-h stirring at rt, the whole mixture was concen-
S
OH OH
17
trated in vacuo. The residue was partitioned between CH
mL) and H O (2 mL), and the aq layer was extracted with CH
2 mL x 2). Combined organic layers were washed with 1 M aq
HCl (2 mL), sat aq NaHCO (2 mL), and dried over Na SO (ca. 1
g). Filtration/evaporation afforded a pale yellow oil (ca. 49 mg),
which was purified by SiO -chromatography (SiO , 10 g; hexane–
2
Cl
2
(2
4-Ethenyl-1,3-dioxane (1,3-O,O module) (30.8 mg, 0.270
2
2
Cl
2
mmol) was dissolved in 74:1 CH
solution was transferred to a 20-mL Young-type Schlenk tube. To
this was added HONH ·HCl (188 mg, 2.70 mmol). After being
stirred at 80 °C for 18 h, the whole mixture was concentrated to
give the crude compound. This was purified by SiO
chromatography (SiO , 5 g; hexane–EtOAc 1:1 eluent) to give
pent-4-en-1,3-diol (20.3 mg, 73%): H NMR (CDCl
1.87 (m, 2H; CH CH CH), 2.19 (br, 1H; OH), 2.30 (br, 1H; OH),
3.82–3.92 (m, 2H; OCH CH ), 4.39–4.43 (br, 1H; CH CHCH),
.15 (d, J = 11.0 Hz, 1H; CH=CHH), 5.29 (d, J = 17.2 Hz, 1H;
CH=CHH), 5.91 (ddd, J = 17.0, 11.0, 6.20 Hz, 1H; CH=CH ).
Figure S11 showed the H-NMR spectrum. The spectrum was
3 2
OH–H O (1.5 mL), and the
(
3
2
4
2
2
2
2
-
EtOAc 2:1 to 1:1 eluent) to give N-(5-hydroxypent-1-en-3-yl)-4-
2
1
methylbenzenesulfonamide (18) (2.78 mg, 11% yield) as a pale
3
) δ 1.74–
1
yellow oil: H NMR (CDCl
3
) δ 1.53–1.58 (m, 1H; CHHCH
OH), 2.10 (br, 1H; OH), 2.43 (s, 3H;
), 3.68 (br, 1H; CHHOH), 3.88 (t, J = 10.33 Hz, 1H;
2
OH),
2
2
1
.79–1.85 (m, 1H; CHHCH
2
2
2
2
CH
3
5
CHHOH), 3.99–4.02 (m, 1H; NHCHCH), 4.90 (br, 1H; NH), 4.97
(d, J = 8.95 Hz, 1H; CH=CHH), 4.98 (d, J = 17.21 Hz, 1H;
CH=CHH), 5.57 (ddd, J = 16.87, 10.33, 5.51 Hz, 1H; CH=CH )),
2
2
1
3
0
consistent with the reported one. Comparison of the [α]
D
value
2
7
7.29 (d, J = 8.26 Hz, 2H; ArH), 7.75 (d, J = 8.26 Hz, 2H; ArH).
determined the abs confign to be S ([α]
D
=–11.0 (c=1.0 in
1
Figure S14 showed the H-NMR spectrum. The spectrum was
3
0
CH
3
OH); [α]
,3-O,N module. Reaction (10 mol% (R)-1): (E)-pent-2-ene-
,5-diol (6) (204 mg, 2.00 mmol), N-Boc-aminomethanol (4) (589
mg, 4.00 mmol), DMA (20.0 mL), [CpRu(CH CN) ]PF (20.0 mL
of 10.0 mM CH Cl solution, 200 µmol), (R)-Cl-Naph-PyCOOAll
(20.0 mL of 10.0 mM CH Cl solution, 200 µmol), 100 °C, 3 h.
Work up: partition between H O (50 mL) and pentane (20 mL);
D
=–11 (c=1 in CH
3
OH) for S ).
31
consistent with the reported one. Comparison of the [α]
D
value
=+20.9 (c=0.014 in
1
18
determined the abs confign to be S ([α]
D
1
3
D
1.2
31
CHCl
3
); [α]
3
=+22.94 (c=0.017 in CDCl ) for S ).
3
3
6
Reaction (1 mol% (R)-1). (E)-Pent-2-ene-1,5-diol (6) (235
mg, 2.28 mmol), N-Boc-aminomethanol (4) (673 mg, 4.56 mmol),
DMA (22.8 mL), [CpRu(CH CN) ]PF (2.28 mL of 10.0 mM
3 3 6
2
2
2
2
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
3
2
CH
of 10.0 mM CH
partition between H
2
Cl
2
solution, 22.8 µmol), (R)-Cl-Naph-PyCOOAll (2.28 mL
one. Comparison of the [α]
D
value determined the abs confign
2
1
23.1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
Cl
2
solution, 22.8 µmol), 100 °C, 3 h. Work up:
to be R ([α]
CDCl ) for R ).
3
D
=+66.8 (c=0.68 in CDCl
3
); [α]
D
=+71 (c=1 in
3
2
2
O (100 mL) and pentane (30 mL); extraction
of aq layer with pentane (30 mL x 3); washing of the combined
organic layers with H O (30 mL); dryness over Na SO (ca. 5 g);
filtration/evaporation. Purification: SiO -chromatography (SiO
0 g; pentane–Et O 8:2 eluent). Product: N-Boc-4-ethenyl-1,3-
oxadinane (1,3-O,N module) (224 mg, 46%); R:S = 25:75.
,2-N,O module. (E)-N-Boc-4-aminobut-2-en-1-ol (7) (214
mg, 1.14 mmol), 37% formalin (856 µL, 11.4 mmol), DMA (11.4
mL), [CpRu(CH CN) ]PF (1.14 mL of 10.0 mM CH Cl solu-
tion, 11.4 µmol), (R)-Cl-Naph-PyCOOAll (1.14 mL of 10.0 mM
CH Cl solution, 11.4 µmol), 100 °C, 3 h. Work up: partition
between H O (50 mL) and pentane (30 mL); extraction of aq layer
with pentane (20 mL x 4); washing of the combined organic lay-
ers with H O (50 mL); dryness over Na SO (ca. 5 g); filtra-
tion/evaporation. Purification: SiO -chromatography (SiO , 5 g;
pentane–Et O 9:1 eluent). Product: N-Boc-5-ethenyloxazolidine
1,2-N,N module. (E)-N-Boc-4-aminobut-2-en-1-ol (7) (214
mg, 1.14 mmol), N-Boc-aminomethanol (4) (336 mg, 2.28
2
2
4
2
2
,
mmol), DMA (11.4 mL), [CpRu(CH
3 3 6
CN) ]PF (1.14 mL of 10.0
1
2
mM CH Cl solution, 11.4 µmol), (R)-Cl-Naph-PyCOOAll (1.14
2
2
mL of 10.0 mM CH Cl solution, 11.4 µmol), 100 °C, 3 h. Work
2
2
1
up: partition between H O (50 mL) and pentane (30 mL); extrac-
2
tion of the aq layer with pentane (20 mL x 4); washing of the
3
3
6
2
2
combined organic layers with H O (50 mL); dryness over Na SO
2
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(ca.
5
g); filtration/evaporation.
Purification: SiO2-
chromatography (SiO
2
, 10 g; pentane–Et
2
O 9:1 eluent). Product:
2
2
N,N’-diBoc-3-ethenylimidazolidine (1,2-N,N module) (313 mg,
2
1
92%). Physical property: H NMR (CDCl
C(CH ), 3.51 (d, J = 9.64 Hz, 1H; NCHHCH), 3.60 (dd, J =
10.7, 6.89 Hz, 1H; NCHHCH), 4.47 (br, 1H; CHCH=CH ), 4.66
3
, 60 °C) δ 1.46 (s, 9H;
2
2
4
3 3
)
2
2
2
2
(d, J = 6.89 Hz, 1H; NCHHN), 4.73 (d, J = 6.89 Hz, 1H;
NCHHN), 5.14 (d, J = 11.0 Hz, 1H; CH=CHH), 5.17 (d, J = 19.3
1
(
(
1,2-N,O module) (207 mg, 91%). Physical property: H NMR
CDCl , 60 °C) δ 1.47 (s, 9H; C(CH ), 3.16 (dd, J = 8.95, 8.61
)
3
Hz, 1H; CH=CHH), 5.78 (ddd, J = 17.0, 10.7, 6.20 Hz, 1H;
3
3
13
Hz, 1H; NCHHCH), 3.62 (dd, J = 9.64, 6.20 Hz, 1H; NCHHCH),
.49 (ddd, J = 6.89, 6.54, 6.20 Hz, 1H; CHCH=CH ), 4.78 (d, J =
2 3
CH=CH ); C NMR (CDCl , 60 °C) δ 28.4, 49.7, 57.5, 60.2,
4
2
80.48, 80.51, 115.7, 136.2, 152.9, 153.4; HRMS (ESI) calcd for
+
21
3.44 Hz, 1H; NCHHO), 4.96 (br, 1H; NCHHO), 5.25 (d, J = 9.64
Hz, 1H; CH=CHH), 5.36 (d, J = 17.2 Hz, 1H; CH=CHH), 5.87
15 26 2 4 D
C H N NaO [M+Na] 321.1790, found 321.1788; [α] =+14.0
(c=0.288 in CHCl ); R:S = 99:1 (HPLC conditions: CHIRALCEL
3
1
3
(
ddd, J = 17.0, 10.3, 6.20 Hz, 1H; CH=CH
2
); C NMR (CDCl
3
,
OD-H column (0.46 cm φ x 250 mm); hexane–iPrOH 99.9:0.1
6
0 °C) δ 28.5, 48.9, 78.5, 78.9, 80.3, 118.0, 135.0, 153.0; HRMS
eluent; 1.00 mL/min flow rate; 210-nm light detection; t = 16.2
R
+
1
(
ESI) calcd for
C
10
H
17NNaO
3
[M+Na] 222.1106, found
); R:S = 96:4 (HPLC
min (R), 17.1 min (S)). Figure S18 and S19 showed the H- and
2
1
13
2
22.1105; [α]
D
=–55.87 (c=0.38 in CHCl
3
C-NMR spectra and HPLC charts, respectively.
conditions: CHIRALCEL IA-3 column (0.46 cm φ x 250 mm);
hexane–iPrOH 99.9:0.1 eluent; 1.00 mL/min flow rate; 210-nm
Abs confign was determined by comparison of the optical rota-
tion of N,N’-diBoc-but-3-ene-1,2-diamine (20), which was ob-
tained by deprotection of the 1,2-N,N module followed by Boc
protection.
R
light detection; t = 11.5 min (R), 12.5 min (S)). Figure S15 and
1
13
S16 showed the H- and C-NMR spectra and HPLC charts, re-
spectively.
Abs confign was determined by comparison of the optical rota-
tion of 5-ethenyloxazolidine-2-thione (19), which was obtained by
deprotection of the 1,2-N,O module followed by thiocarbonyla-
tion.
R
BocHN
NHBoc
20
Process (i): Reaction: N,N’-diBoc-4-ethenylimidazolidine
R
HN
(1,2-N,N module) (30 mg, 100 µmol), 74:1 CH
µL), HONH ·HCl (69.5 mg, 1.00 mmol), 80 °C, 48 h. After be-
ing cooled to rt, sat aq NaHCO (2 mL) was added. The mixture
was, concentrated, and the remained solid was washed with EtOH
5 mL x 2). The washings were filtered and concentrated to give
3 2
OH–H O (600
O
2
S
3
1
9
(
Process (i): Reaction: N-Boc-5-ethenyl-1,3-oxazolidine (1,2-
N,O module) (50.1 mg, 251 µmol), 74:1 CH OH–H O (2.5 mL),
HONH ·HCl (175 mg, 2.52 mmol), 80 °C, 12 h. After being
cooled to rt, sat aq K CO (3 mL) was added. Filtra-
tion/evaporation afforded a white solid (ca. 200 mg), which was
partitioned between CH Cl (2 mL) and H O (2 mL). The aq
layer was extracted with CH Cl (2 mL x 10), and the combined
organic layers were dried over Na SO (ca. 1 g). Filtra-
a crude but-3-ene-1,2-diamine (ca. 32 mg) as a brown solid. This
was used for the next reaction without purification.
Process (ii): The crude product (ca. 32 mg) dissolved in EtOH
3
2
2
2
3
(
2 5 3 2
1 mL), N(C H ) (31 µL, 220 µmol), and Boc O (48 µL, 210
µmol) were charged into a 5-mL Young-type Schlenk tube. The
mixture was stirred at rt for 24 h, and concentrated. The residue
2
2
2
2
2
was partitioned between CH
aq layer was extracted with CH
organic layers were washed with 1 M aq HCl (2 mL) and dried
over Na SO (ca. 1 g). Filtration/evaporation afforded the crude
diBoc product (ca. 26 mg), which was purified by SiO
chromatograpy (SiO , 1.5 g; hexane–EtOAc 10:1 then 3:1 eluent)
to give N,N’-diBoc-but-3-ene-1,2-diamine (20) (8.6 mg, 30%
2
Cl
2
(2 mL) and H
2
O (2 mL), and the
2
4
2
2
Cl (2 mL x 2). The combined
tion/evaporation afforded a pale yellow solid (ca. 17 mg). This
was used for the next reaction without further purification.
Process (ii): The crude amine compound (ca. 17 mg), TCDI
(34.0 mg, 191 µmol), and THF (1.9 mL) were placed in a 5-mL
Young-type Schlenk tube. After 15-h stirring at rt, the mixture
2
4
2
-
2
was concentrated in vacuo. The residue was purified by SiO
chromatography (SiO , 2 g; hexane–EtOAc 2:1 eluent) to give 5-
ethenyloxazolidine-2-thione (19) (13.7 mg, 42% yield) as a white
2
-
1
yield) as a white solid: H NMR (DMSO-d
9H; C(CH ), 1.392 (s, 9H; C(CH ), 3.02 (t, J = 6.20 Hz, 2H;
NHCH ), 4.04 (q, J = 6.20 Hz, 1H; NHCHCH), 5.05 (dt, J =
0.33, 1.38 Hz, 1H; CH=CHH), 5.11 (dt, J = 17.90, 2.07 Hz, 1H;
CH=CHH), 5.74 (ddd, J = 17.04, 10.67, 6.20 Hz, 1H; CH=CH ),
.42 (br, 2H; NH). Figure S20 showed the H-NMR spectrum.
6
, 80 °C) δ 1.389 (s,
2
3
)
3
3 3
)
1
2
solid: H NMR (CDCl
3
) δ 3.53 (t, J = 8.26 Hz, 1H; CHHCHCH),
1
3
.93 (t, J = 8.95 Hz, 1H; CHHCHCH), 5.34 (q, J = 8.26 Hz, 1H;
2
OCHCH), 5.41 (d, J = 10.33 Hz, 1H; CH=CHH), 5.47 (d, J =
1
6
17.21 Hz, 1H; CH=CHH), 5.96 (ddd, J =17.21, 10.33, 6.89 Hz,
33
1
The spectrum was consistent with the reported one. Comparison
of the [α] value determined the abs confign to be
1H; CH=CH
2
), 7.39 (br, 1H; NH). Figure S17 showed the H-
D
R
NMR spectrum. The spectrum was consistent with the reported
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
1
9
24.9
(
[α]
D
=+26.0 (c=0.43 in CHCl
3
); [α]
D
=+26.2 (c=1.09 in
H
2
O (30 mL) and pentane (20 mL); extraction of the aq layer with
pentane (20 mL x 4); washing with H O (30 mL); dryness over
Na SO (ca. 2 g); filtration/evaporation. Purification: SiO
chromatography (SiO , 5 g; pentane–Et O 9:1 eluent). Product:
N,N’-diBoc-4-ethenylhexahydropyrimidine (1,3-N,N module)
3
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CDCl
) for R ).
3
2
1,3-N,O module. N-Boc-5-aminopent-2-en-1-ol (8) (230 mg,
1.14 mmol), 37% formalin (856 µL, 11.4 mmol), DMA (11.4
2
4
2
-
2
2
mL), [CpRu(CH
tion, 11.4 µmol), (R)-Cl-Naph-PyCOOAll (1.14 mL of 10.0 mM
CH Cl solution, 11.4 µmol), 100 °C, 3 h. Work up: partition
between H O (50 mL) and pentane (30 mL); extraction of the aq
layer with pentane (20 mL x 4); washing of the combined organic
layers with H O (50 mL); dryness over Na SO (ca. 5 g); filtra-
tion/evaporation. Purification: SiO -chromatography (SiO , 5 g;
pentane–Et O 9:1 eluent). Product: 6-ethenyl-1,3-oxadinane
(1,3-N,O module) (219 mg, 90%). Physical property: H NMR
(CDCl , 60 °C) δ 1.47 (s, 9H; C(CH ), 1.57–1.67 (m, 2H;
NCH CH ), 3.02 (br, 1H; NCHHCH ), 4.00 (br, 1H;
CHCH=CH ), 4.18 (br, 1H; NCHHCH ), 4.36 (d, J = 10.3 Hz,
H; NCHHO), 5.14 (d, J = 11.0 Hz, 1H; CH=CHH), 5.26 (d, J =
7.2 Hz, 1H; CH=CHH), 5.54 (br, 1H; NCHHO), 5.84 (ddd, J =
3 3 6 2 2
CN) ]PF (1.14 mL of 10.0 mM CH Cl solu-
1
(275 mg, 88%). Physical property: H NMR (CDCl
.47 (s, 9H; C(CH ), 1.69 (ddd, J = 13.9, 7.57, 4.13 Hz, 1H;
CHHCH), 1.97 (ddd, 18.6, 12.4, 6.20 Hz, 1H;
CHHCH), 3.12 (dd, J = 12.4, 11.7 Hz, 1H; NCHHCH ), 3.78
), 4.10 (d, J = 13.1 Hz, 1H; NCHHN), 4.76
3
, 60 °C) δ
1
CH
CH
3 3
)
2
2
2
2
J =
2
2
(
br, 1H; NCHHCH
2
2
2
4
(br, 1H; CH
2
2
CHCH=CH ), 5.12 (d, J = 17.2 Hz, 1H; CH=CHH),
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5.22 (d, J = 11.7 Hz, 1H; CH=CHH), 5.72 (d, J = 13.1 Hz, 1H;
2
1
3
1
NCHHN), 5.78 (ddd, J = 17.4, 10.7, 4.13 Hz, 1H; CH=CH
NMR (CDCl , 60 °C) δ 27.8, 28.41, 28.44, 39.4, 51.8, 53.0, 80.1,
0.3, 116.1, 136.3, 154.2; HRMS (ESI) calcd for C16
2
); C
3 3
)
3
3
8
29 2 4
H N O
=–15.5 (c=0.288 in
2
2
2
+
21
[
M+H] 313.2127, found 313.2120; [α]
D
2
2
1
1
1
2
(
2
CHCl
3
); R:S = 1:99 (HPLC conditions: CHIRALCEL ID-3 col-
umn (0.46 cm φ x 250 mm); hexane–iPrOH 99.9:0.1 eluent; 1.00
mL/min flow rate; 210-nm light detection; t = 15.0 min (S), 17.0
min (R)). Figure S24 and S25 showed the H- and C-NMR
spectra and HPLC charts, respectively.
The 1,3-N,N module was converted to N,N’-diBoc-pent-4-ene-
1,3-diamine (22). The authentic sample was synthesized from
13
7.0, 11.0, 6.20 Hz, 1H; CH=CH
8.4, 31.0, 42.4, 76.2, 77.8, 80.3, 115.5, 138.0, 154.0; HRMS
ESI) calcd for C11
36.1264; [α]
ditions: CP-CHIRASIL-DEX CB column (0.25 mm x 0.25 mm x
25 m); 40 °C, 10 °C/min to 150 °C; t = 24.1 min (R), 24.2 min
S)). Figure S21 and S22 showed the H- and C-NMR spectra
2
); C NMR (CDCl
3
, 60 °C) δ
R
1
13
+
H
19NNaO
3
[M+Na]
236.1263, found
2
1
D
=–31.3 (c=0.56 in CHCl
3
); R:S = 6:94 (GC con-
(
S)-3-aminopent-4-en-1-ol obtained in determination of the abs
R
1
13
confign of 1,3-O,N module. Comparison of the optical rotation
determined the abs confgn to be S. The procedures were de-
scribed below.
(
and GC charts, respectively.
Abs confign was determined by comparison of the optical rota-
tion of N-Boc-1-aminopent-4-en-3-ol (21), which was obtained by
acidic hydrolysis of the 1,3-N,O module followed by N-Boc pro-
tection.
S
BocNH NHBoc
2
2
S
Process
ethenylhexahydropyrimidine (1,3-N,N module) (30.0 mg, 96.0
µmol), 74:1 CH OH–H O (600 µL), HONH ·HCl (66.7 mg, 960
µmol ), 80 °C, 48 h. After being cooled to rt, sat aq NaHCO (2
(i):
Reaction:
N,N’-diBoc-4-
BocNH OH
2
1
3
2
2
3
Process (i): A 5-mL Young-type Schlenk tube was charged
with N-Boc-6-ethenyl-1,3-oxazinane (1,3-N,O module) (32.4 mg,
152 µmol) dissolved in CH OH (4.40 mL) and 12 M aq HCl (220
3
µL). After being stirred at rt for 12 h, the reaction mixture was
concentrated to give a crude 1-aminopent-4-en-3-ol hydrochloride
20.9 mg) as an oil. This was used for the next reaction without
mL) was added. The mixture was filtered and concentrated. The
remained solid was washed with EtOH (5 mL x 2), and the wash-
ing was filtered and concentrated. The crude product (ca. 30 mg)
was used for the next reaction without further purification.
Process (ii): Reaction: the crude amine compound (ca. 30 mg),
Boc O (43.7 mg, 202 µmol), N(C H ) (29 µL, 211 µmol), EtOH
(
2
2
5 3
further purification.
2 2
(1 mL), rt, 24 h. Work up: partition between CH Cl (2 mL) and
H O (2 mL); extraction of aq layer with CH Cl (2 mL x 2); wash-
2 2 2
Process (ii): Reaction: 5-aminopent-1-en-3-ol hydrochloride
(
20.9 mg, 152 µmol), Boc
N(C (53.0 µL, 38.5 mg, 378 µmol) and EtOH (900 µL).
Work up: concentration. Purification: SiO -chromatography
(SiO , 5 g; hexane–EtOAc 8:2 eluent). Product: (3-hydroxypent-
4-en-1-yl)carbamate (21) (26 mg, 86%): H NMR (CDCl
(s, 9H; C(CH ), 1.59–1.64 (m, 1H; CH CHHCH), 1.67–1.74 (m,
H; CH CHHCH), 2.91 (br, 1H; OH), 3.12–3.19 (m, 1H;
NCHHCH ), 3.41–3.49 (m, 1H; NCHHCH ), 4.19 (br, 1H;
HOCH), 4.84 (br, 1H; NH), 5.12 (d, J = 10.3 Hz, 1H; CH=CHH),
2
O (42.0 µL, 39.9 mg, 183 µmol),
ing with 1 M aq HCl (2 mL) and brine (2 mL); dryness over
Na SO (ca. 1 g); filtration/evaporation. Purification: SiO
chromatography (SiO , 2.5 g; hexane–EtOAc 10:1 to 3:1 eluent).
Product: N,N’-diBoc-pent-4-ene-1,3-diamine (22) (10.4 mg, 36%
yield) as a white solid: H NMR (CDCl
C(CH ), 1.46 (s, 1H; C(CH ), 1.51–1.60 (m, 1H;
CH CHHCH), 1.80 (dq, J = 13.08, 6.89 Hz, 1H; CH CHHCH),
3.05 (dq, J = 14.12, 7.57 Hz, 1H; NHCHHCH ), 3.27–3.36 (br,
1H; NHCHHCH ), 4.19 (br, 1H; NHCHCH), 4.45 (br, 1H;
NHCHCH), 4.87 (br, 1H; NHCH CH ), 5.11 (d, J = 11.02 Hz,
2
H
5
)
3
2
4
2
-
2
2
2
1
1
3
) δ 1.45
3
, 60 °C) δ 1.45 (s, 1H;
3
)
3
2
3
)
3
3 3
)
1
2
2
2
2
2
2
2
5
6
.27 (d, J = 17.2 Hz, 1H; CH=CHH), 5.90 (ddd, J = 17.2, 10.3,
2
2
1
.2 Hz, 1H; CH=CH
2
). Figure S23 showed the H-NMR spec-
trum. The spectrum was consistent with the reported one.
Comparison of the [α] value determined the abs confign to be S
1H; CH=CHH), 5.19 (d, J = 17.21 Hz, 1H; CH=CHH), 5.79 (ddd,
J = 17.04, 11.02, 5.51 Hz, 1H; CH=CH )); C NMR (CDCl ) δ
28.4, 28.5, 35.7, 37.4, 50.6, 79.2, 79.6, 114.8, 138.6, 155.7, 156.0;
34
13
2
3
D
2
D
3
23
D
+
([α]
CHCl
=+8.64 (c=1.00 in CHCl
3
); [α]
=+8.62 (c=1.01 in
HRMS (ESI) calcd for C15
H
28
N
2
O
4
Na [M+Na] 323.1947, found
=–33.2 (c=0.15 in CHCl ). Figure S26 showed
the H- and C-NMR spectra.
3
4
19
3
) for S ).
323.1953; [α]
D
3
1
13
1,3-N,N module. Reaction (10 mol% (R)-1): (E)-N-Boc-5-
aminopent-2-en-1-ol (8) (201 mg, 1.00 mmol), N-Boc-
aminomethanol (4) (294 mg, 2.00 mmol), DMA (10.0 mL),
Synthesis of authentic (S)-N,N'-diBoc-pent-4-ene-1,3-
diamine ((S)-22) from (S)-3-aminopent-4-en-1-ol. Reaction:
the abs confign-determined (S)-3-aminopent-4-en-1-ol (20.0 mg,
198 µmol) obtained from 1,3-O,N module, Boc
µmol), N(C (33.1 µL, 237 µmol), EtOH (1 mL), rt, 18 h.
[
CpRu(CH
µmol), (R)-Cl-Naph-PyCOOAll (10.0 mL of 10.0 mM CH
solution, 100 µmol), 100 °C, 3 h. Work up: partition between
3
CN)
3
]PF
6
(10.0 mL of 10.0 mM CH
2
Cl
2
solution, 100
2
Cl
2
2
O (51.8 mg, 237
2
5 3
H )
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 13
Work up: partition between CH
extraction of aq layer with CH Cl
aq HCl (2 mL); dryness over Na
tion/evaporation. Purification: SiO -chromatography (SiO
hexane–EtOAc 1:3 eluent). Product: N-Boc-3-aminopent-4-en-1-
ol (23) (34.6 mg, 87% yield) as a yellow oil.
2
Cl
(2 mL x 2); washing with 1 M
SO (ca. 1 g); filtra-
, 10 g;
2
(2 mL) and H
2
O (2 mL);
3
NMR analysis (CDCl ), determining that the conversion was 79%
and the E/Z ratio of the product was 95:5. The whole reaction
mixture was concentrated and passed through a pad of silica gel
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
2
4
2
2
(SiO
2
, 15 g; hexane–EtOAc 2:1 eluent) to give a reddish crude
Cl (10 mL), and
product (ca. 300 mg). This was dissolved in CH
Quadrasil AP (1.0 g) was added to the pale red solution. After
being stood at rt for 8 h, the mixture was filtered and concentrat-
2
2
TM
ed. SiO
4:1 eluent) afforded the allylic alcohol 10 (233 mg, 65%):
NMR (CDCl , 60 °C) δ 1.45 (s, 9H; C(CH ), 2.12 (br, 1H; OH),
3.74 (dd, J = 8.95, 4.82 Hz, 1H; OCHHCH), 4.09 (dd, J = 8.26,
6.89 Hz, 1H; OCHHCH), 4.13 (br, 2H; CH=CHCH OH), 4.34
br, 1H; CHCH=CH), 4.75 (d, J = 4.13 Hz, 1H; OCHHN), 4.95
(d, J = 2.75 Hz, 1H; OCHHN), 5.65 (dd, J = 15.8, 6.89 Hz, 1H;
2 2
-chromatograpy of the residue (SiO , 25 g; hexane–THF
1
S
H
3
3 3
)
OH NHBoc
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
(
Compound 23 (20.1 mg, 99.4 µmol) charged into a 5-mL
Young-type Schlenk tube was dissolved in THF (500 µL). To this
1
3
CH=CH), 5.83 (dt, J = 15.8, 4.82 Hz, 1H; CH=CH); C NMR
was added PPh
nodicarboxylate (20.9 mg, 119 µmol). To this was added DIAD
62.6 µL, 119 µmol; 1.9 M toluene). After 16-h stirring at 50 °C,
the reaction mixture was concentrated in vacuo. The residue was
purified by SiO -chromatography (SiO , 10 g; hexane–EtOAc 8:1
3
(31.3 mg, 119 µmol) and tert-butyl methyl imi-
(CDCl , ca. 100 mM, 60 °C) δ 28.4, 56.8, 62.5, 72.5, 79.1, 80.3,
3
128.8, 131.9, 152.9; HRMS (ESI) calcd for C H NNaO
4
1
1
19
+
20
(
[M+Na] 252.1212, found 252.1213; [α]
D
=–32.5 (c=1.02 in
CHCl ). The er was determined to be 96.5:3.5 by HPLC analysis
3
2
2
(conditions: CHIRALPAK IA-3 column (0.46 cm φ x 250 mm);
hexane–iPrOH 95:5 eluent; 1.00 mL/min flow rate; 210-nm light
eluent) to give tert-butyl (3-((tert-butoxycarbonyl)amino)pent-4-
en-1-yl)(methoxycarbonyl)carbamate (24) (24.7 mg, 66% yield)
as colorless oil.
detection; t = 16.0 min (S), 18.3 min (R)). Figure S27 and S28
R
1
13
showed the H- and C-NMR spectra and HPLC charts, respec-
tively.
Methylene-relayed allylation. Two 10-mM CH
of [CpRu(CH CN) ]PF (0.660 mL, 6.60 µmol (2.865 mg)) and
R)-Cl-Naph-PyCOOAll (0.660 mL, 6.60 µmol (2.23 mg))) were
2 2
Cl solutions
S
3
3
6
(
BocNH NHBoc
charged in a 20-mL Young-type Schlenk tube, and concentrated.
To this was added a DMA solution (2.00 mL) of the allylic alco-
hol 10 (46.7 mg, 0.204 mmol) and H O (225 µL, 12.5 mmol).
2
The mixture was heated to 100 °C under Ar, and then the whole
system was sealed. After being stirred at 100 °C for 15 h, the
yellow-colored mixture was cooled to rt. A portion of the mixture
O
OCH3
24
Compound 24 (12.0 mg, 33.5 µmol), 1 M aq NaOH (200 µL),
EtOH (200 µL), and 1,4-dioxane (200 µL) were placed in a 5-mL
Young-type Schlenk tube. After 4-h stirring at rt, the reaction
mixture was concentrated in vacuo and the residue was partitioned
(ca. 0.2 mL) was taken and diluted with CDCl
3
(ca. 1 mL). The
H-NMR analysis determined the conversion to be 78%. The
whole reaction solution was partitioned with Et O (2 mL) and
O (5 mL), and the aq layer was extracted by Et O (2 mL x 3).
The combined organic layers were dried over Na SO , filtered,
and concentrated to give the crude product (ca. 100 mg). This
was purified by SiO -chromatography (SiO , 15 g; hexane–EtOAc
1
between EtOAc (2 mL) and H
tracted with EtOAc (2 mL x 2), and the combined organic layers
were washed with brine (2 mL), and dried over Na SO (ca. 1 g).
Filtration/evaporation afforded a pale yellow oil (ca. 16 mg),
which was purified by SiO -chromatography (SiO , 2.5 g; hex-
ane–EtOAc 3:1 eluent) to give N,N’-diBoc-pent-4-ene-1,3-
2
O (2 mL). The aq layer was ex-
2
H
2
2
2
4
2
4
2
2
2
2
4:1 eluent) to give a 80:20 mixture of 11 with a 97.8:2.2 RS/SR er
and epi-11 with a 97.6:2.4 RR/SS er (34.6 mg, 74% yield), and
(E)-10 with a 93.0:7.0 er was recovered (15% yield). The ways of
determination of the 11/epi-11 diastereomer ratio (dr), the ers of
11 and epi-11, and the er of the recovered (E)-10 were shown in
Figures S29, S30, and S31. For the calculation of catalyst control
(CC) and substrate control (SC) in the reaction, a three-digit accu-
racy was adopted in this particular case (see the next “Quantita-
tive analysis of catalyst control and substrate control”).
2
1
diamine (22) (6.0 mg, 60% yield) as a white solid: [α]
(c=0.16 in CHCl ). The sign of the optical rotation was identical
with that of N,N’-diBoc-pent-4-ene-1,3-diamine (22) derived from
R)-1-catalyzed allylation product, determining the abs confign of
D
=–31.7
3
(
the 1,3-N,N module to be S.
Reaction (1 mol% (R)-1). N-Boc-5-aminopent-2-en-1-ol (8)
(
230 mg, 1.14 mmol), N-Boc-aminomethanol (4) (336 mg, 1.14
mmol), DMA (11.4 mL), [CpRu(CH CN) ]PF (1.14 mL of 10.0
mM CH Cl solution, 11.4 µmol), (R)-Cl-Naph-PyCOOAll (1.14
mL of 10.0 mM CH Cl solution, 11.4 µmol), 100 °C, 3 h. Work
up: partition between H O (50 mL) and pentane (30 mL); extrac-
tion of the aq layer with pentane (30 mL x 3); washing of the
3
3
6
Pure 11 and epi-11 were obtained by a preparative HPLC of the
methylene-relayed product that was obtained in a different batch
under the same conditions described above (conditions: Develosil
2
2
2
2
2
3
9
0-3 (2.0 cm φ x 250 mm) column; hexane–iPrOH 99:1 eluent;
.0 mL/min flow rate; 210-nm light detection; t = 128.0 min
combined organic layers with H
ca. g); filtration/evaporation.
chromatography (SiO , 10 g; pentane–Et
N,N’-diBoc-4-ethenylhexahydropyrimidine (1,3-N,N module)
160 mg, 45%); R:S = 7:93.
7) Synthesis of sphingosine.
Olefin metathesis. A 80-mL Schlenk tube was charged with
2
O (30 mL); dryness over Na
2
SO
4
R
(
5
Purification: SiO
2
-
(epi-11), 134.7 min (11); 2.5 mg in 20 µL for each injection x 100
1
O 9:1 eluent). Product:
times). 11: H NMR (CDCl
3.93 (br, 1H; HOCHH) 4.00–4.10 (br, 2H; HOCHH and
CH CHCH), 4.31 (br, 1H; CHCHCH), 4.69 (d, J = 4.13 Hz, 1H;
3 3 3
, 60 °C) δ 1.48 (s, 9H; C(CH ) ),
2
2
(
2
(
NCHHO), 4.94 (br, 1H; NCHHO), 5.22 (d, J = 11.0 Hz, 1H;
CH=CHH), 5.36 (d, J = 17.2 Hz, 1H; CH=CHH), 5.85 (ddd, J =
1
3
1,2-O,N module (5) (309 mg, 1.55 mmol) dissolved in acetone
(15.5 mL) and (Z)-but-2-ene-1,4-diol (1.28 mL, 15.6 mmol). The
solution was degassed by three freeze-thaw cycles, and HG II
16.9, 11.4, 5.51 Hz, 1H; CH=CH2); C NMR (CDCl , 60 °C) δ
3
28.4, 60.2, 68.6, 73.2, 80.0, 81.3, 116.7, 136.5, 153.9; HRMS
+
(ESI) calcd for C H NNaO [M+Na] 252.1212, found
11 19
4
2
1
1
(
29.2 mg, 46.6 µmol) was added. After being stirred at rt for 4 h,
252.1215; [α]D =–43.4 (c=0.385 in CHCl3). epi-11: H NMR
(CDCl , 60 °C) δ 1.49 (s, 9H; C(CH ) ), 3.83 (dd, J = 8.61, 4.82
a portion of the reaction mixture (ca. 100 µL) was taken and
evaporated to give a pale yellow oil. This was subjected to the H
3
3 3
1
Hz, 1H; HOCHH), 3.92 (ddd, J = 8.95, 6.89, 4.82 Hz, 1H;
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CH
2
CHCH), 3.98 (dd, J = 8.95, 6.89 Hz, 1H; HOCHH), 4.19 (dd,
mmol) dissolved in 74:1 CH
(191 mg, 2.75 mmol). After 19-h stirring at 83 °C, the reaction
mixture was partitioned between CH Cl (10 mL) and 1 M aq
NaOH (50 mL). The aq layer was extracted by CH Cl (10 mL x
9), and the combined organic layers were dried over Na SO
filtered, and concentrated to give a 80:20 mixture of sphingosine
(9) and its epimer (81.7 mg, 98%). This was purified by SiO
chromatography (SiO , 5 g; CHCl –CH OH–aq NH 100:10:1
eluent) to give sphingosine (9) (30.4 mg, 37%):
3 2 2
OH–H O (1.8 mL) and HONH ·HCl
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
J = 6.54, 5.51 Hz, 1H; CHCHCH), 4.68 (d, J = 4.13 Hz, 1H;
NCHHO), 4.97 (d, J = 4.82 Hz, 1H; NCHHO), 5.22 (d, J = 10.3
Hz, 1H; CH=CHH), 5.35 (d, J = 16.5 Hz, 1H; CH=CHH), 5.80
2
2
2
2
1
3
(
6
ddd, J = 17.2, 10.3, 6.89 Hz, 1H; CH=CH
2
); C NMR (CDCl
0 °C) δ 28.4, 60.3, 69.0, 75.0, 79.7, 81.6, 117.6, 136.8, 154.6;
3
,
2
4
,
+
HRMS (ESI) calcd for C11
H
19NNaO
4
[M+Na] 252.1212, found
). The ers of 11 and
2
-
20
D
2
52.1213; [α]
=–59.3 (c=0.395 in CHCl
3
2
3
3
3
1
epi-11 were determined to be 97.8:2.2 and 97.6:2.4, respectively,
by HPLC analysis (conditions: CHIRALPAK IA-3 column (0.46
cm φ x 250 mm); hexane–iPrOH 97:3 eluent; 1.00 mL/min flow
H NMR
), 1.25–1.45 (m, 22H;
11), 2.09 (dt, J = 6.89, 6.89 Hz, 2H; CH=CHCH CH ), 2.76
NCH), 3.49 (dd, J = 11.0,
(CD
(CH
3
OD) δ 0.90 (t, J = 6.89 Hz, 3H; CH
3
)
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
rate; 210-nm light detection; t
= 13.5 (2R,3R), 17.0 min (2R,3S),
(ddd, J = 6.54, 6.54, 4.82 Hz, 1H; H
2
R
21.1 min (2S,3R), 32.0 (2S,3S)). Figure S32 and S33 showed the
H- and C-NMR spectra of the pure 11 and epi-11, respectively.
Quantitative analysis of catalyst control and substrate
6.89 Hz, 1H; HOCHH), 3.68 (dd, J = 11.0, 4.82 Hz, 1H;
HOCHH), 3.97 (dd, J = 6.89, 6.54 Hz, 1H; HOCH), 5.50 (dd, J =
15.5, 6.89 Hz, 1H; CHCH=CH), 5.74 (dt, J = 18.6, 6.89 Hz, 1H;
1
13
1
3
control. The ratio of the four stereoisomers was calculated to be
S,R):(S,S):(R,R):(R,S) = 78.2:19.5:0.5:1.8, determining the cata-
lyst control (CC) and the substrate control (SC) to be 1.05 and
CH=CHCH
2 3
); C NMR (CD OD) δ 15.8, 25.1, 31.7, 31.7, 31.8,
(
32.0, 32.1, 32.1, 32.1, 34.4, 34.8, 59.4, 65.6, 76.4, 132.1, 136.6;
22
1
[α]
D 3
=–3.99 (c=0.465 in CHCl ). Figure S35 showed the H-
1/2
3
[
.78, respectively (CC = [(78.2 x 0.5)/(19.5 x 1.8)] = 1.05, SC =
NMR spectrum together with that of the commercially obtained
sphingosine (9).
1
/2
13
(78.2 x 1.8)/(19.5 x 0.5)] = 3.78). The 78 part of the sub-
strate (E)-10 with a 96.5:3.5 R/S er is distributed to the four stere-
oisomers in 61.0 ((S,R)-11), 15.2 ((S,S)-11 (epi-11)), 0.4 ((R,R)-11
(
+
epi-11)), and 1.4 ((R,S)-11). Therefore, 76.2 part of (R)-10 (61.0
15.2) and 1.8 part of (S)-10 (0.4 + 1.4) are transformed to the
ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website.
NMR spectra, HPLC charts, and full screening
data for the reaction conditions (PDF)
product 11 and epi-11. Taking into consideration that the er of 10
is 96.5:3.5, the 20.3 part (96.5–76.2) of (R)-10 and the 1.7 part
(
3.5–1.8) of (S)-10 are calculated to be remained intact in the
reaction system, indicating that the er of the unreacted 10 is 92:8.
The er value is well agreed to the experimental result (93:7). The
results suggest that the reaction using the enantiomeric catalyst
(S)-1 should be slower than that with (R)-1, being consistent with
the next result.
AUTHOR INFORMATION
Corresponding Author
Reaction by use of the catalyst (S)-1. Allylic alcohol 10
kitamura@os.rcms.nagoya-u.ac.jp
(
[
50.3 mg), DMA (2.00 mL), H
2
O (220 µL), 10.0-mM solution of
Cl (660
CpRu(CH CN) ]PF and (S)-Cl-Naph-PyCOOAll in CH
3
3
6
2
2
ACKNOWLEDGMENT
µL). 30% convn, 29% isolated yield; 78:22 dr.
Olefin metathesis of 11. A 20-mL Young-type Schlenk tube
was charged with a 80:20 11/epi-11 mixture (49.7 mg, 0.217
This work was aided by JSPS KAKENHI Grant Number
JP16H02274, JP24106713, JP25410112, JP16F16339, the
Platform Project for Supporting Drug Discovery and Life
Science Research funded by Japan Agency for Medical
Research and Development (AMED), JST ACT-C Grant
Number JPMJCR12YC, Japan. ST acknowledes The Naito
Foundation.
2 2
mmol) dissolved in CH Cl (2.20 mL) and 1-pentadecene (0.590
mL, 2.17 mmol). The clear solution was degassed by three
freeze-thaw cycles, and then HG II (4.10 mg, 6.54 µmol) was
added. The resulting pale reddish solution was stirred at rt for 4 h.
A portion of the reaction mixture (ca. 100 µL) was taken. Con-
1
centration followed by the H-NMR analysis in CDCl
3
determined
the conversion to be 88%. The whole reaction mixture was con-
centrated, and the crude mixture was dissolved in CH Cl (2.5
REFERENCES
2
2
TM
mL). To this was added Quadrasil AP (0.5 g). After being
stood for 8 h, the mixture was filtered and concentrated. The
(1) (a) Natural Products Chemistry; Nakanishi, K., Goto, T., Ito,
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13 (69.9 mg, 78%). The pure 13 was obtained in 72% yield (33.6
(
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(
2
2
CDCl
3
, 60 °C) δ 0.88 (t, J = 6.89 Hz, 1H; CH
2H; (CH 11), 1.48 (s, 9H; C(CH ), 2.04 (dt, J = 6.89, 6.89 Hz,
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3
), 1.22–1.42 (m,
2
)
3 3
)
2
HOCHH and NCH), 4.24 (br, 1H; HOCH), 4.65 (d, J = 4.13 Hz,
H; NCHHO), 4.95 (br, 1H; NCHHO), 5.42 (dd, J = 15.5, 6.89
Hz, 1H; CHCH=CH), 5.74 (dt, J = 15.5, 6.89 Hz, 1H;
1
1
3
CH=CHCH
29.3, 29.5, 29.6, 29.7, 31.9, 32.4, 60.4, 68.7, 73.0, 80.0, 81.1,
128.1, 134.2, 154.1; HRMS (ESI) calcd for C24 45NNaO
=–14.4 (c=0.360 in
). Figure S34 showed H- and C-NMR spectra of major
2
); C NMR (CDCl
3
, 60 °C) δ 14.0, 22.7, 28.4, 29.2,
H
4
+
21
[
M+Na] 434.3246, found 434.3257; [α]
D
1
13
2
561–2574.
5) Intramolecular O- and N-allylation of an in-situ generated pro-
CHCl
3
(
diastereomer 13.
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1
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9
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3
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9
0
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015, 137, 9539–9542.
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(
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The Journal of Organic Chemistry
OH
n
O
1
2
3
4
5
6
7
8
9
*
HO
OH
H2O
cat*
–H2O
O
HO
12
NH2 sphingosine
–
n
BocN
cat* (A = O)
·
*
*
O
via methylen relay
β
3
steps
OH
HGII
·
*
HA
n
HGII
n = 1
deprotection
γ
α
n
O
·
A = O or NBoc
n = 1 or 2
NBoc
O
OH
NBoc
n
HO
NHBoc BocN
*
PF6
O
cat*
NBoc
– H+
All 8 possible
chiral modules
R
N
O
Ru
>
94:6 ers and >86% yields
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
3
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